Citation
Group 11 Transition Metal Catalyzed Reactions of Alkynes

Material Information

Title:
Group 11 Transition Metal Catalyzed Reactions of Alkynes From Spiroketals to Chiral Amines
Creator:
Paioti, Paulo H
Place of Publication:
[Gainesville, Fla.]
Florida
Publisher:
University of Florida
Publication Date:
Language:
english
Physical Description:
1 online resource (329 p.)

Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Chemistry
Committee Chair:
APONICK,AARON
Committee Co-Chair:
MURRAY,LESLIE JUSTIN
Committee Members:
MILLER,STEPHEN ALBERT
DOLBIER,WILLIAM R,JR
JAMES,MARGARET O
Graduation Date:
12/17/2016

Subjects

Subjects / Keywords:
Alcohols ( jstor )
Aldehydes ( jstor )
Alkynes ( jstor )
Amines ( jstor )
Catalysts ( jstor )
Diynes ( jstor )
Hexanes ( jstor )
Ligands ( jstor )
Room temperature ( jstor )
Triols ( jstor )
Chemistry -- Dissertations, Academic -- UF
asymmetric-catalysis -- chiral-amines -- chiral-ligands -- gold-catalysis -- spiroketals
Genre:
bibliography ( marcgt )
theses ( marcgt )
government publication (state, provincial, terriorial, dependent) ( marcgt )
born-digital ( sobekcm )
Electronic Thesis or Dissertation
Chemistry thesis, Ph.D.

Notes

Abstract:
The use of gold-complexes to activate pi-bonds became a well-known and reliable mode of reactivity in organic synthesis. In Chapter 1, a literature review covers the use of gold-catalysts to effect substitution in allylic and propargylic alcohols with concomitant loss of water. This review is focused on reactions where the pi-acidity of the gold-catalysts appears to overcome their inherent Lewis acidity (or sigma-acidity). Examples from the literature which demonstrate advances made since 2011 are presented. In the context of activation of propargyl alcohols we report, in Chapter 2, a gold-catalyzed synthesis of spiroketals which addresses regioselectivity issues reported in metal-catalyzed spiroketal synthesis from alkynols. The reaction is regulated by an acetonide which undergoes extrusion of acetone, delivering spiroketals in good yields and diastereoselectivities. The reaction is carried out under mild conditions employing AuCl as the catalyst and should be widely applicable to the synthesis of spiroketals. Our group utilized this new method for the construction of the spiroketal of spirastrellolide A. We recently have been interested in copper-catalyzed enantioselective alkynylation reactions using StackPhos, a P,N-ligand developed in our group. Using this ligand we report, in Chapter 3, a copper-catalyzed synthesis of nonracemic 3-amino-1,4-diynes via a carbon-carbon bond formation. Despite challenging issues of reactivity and stereoselectivity inherent to these molecules, the reaction tolerates a broad scope. The alkynes are shown to be useful synthetic handles, rendering amino skipped diynes convenient building blocks for asymmetric synthesis. The method adresses the challenge of synthesizing nonracemic chiral amines with two similar aliphatic groups. The design of StackPhos demonstrates it is possible to stabilize the axial configuration in 5-membered heterocyclic P,N-Ligands. In Chapter 4, we demonstrate that axial chirality in phosphinomidazolines can be controlled, creating P,N-ligands called StackPhim. One StackPhim was superior in a copper-catalyzed alkynylation which was required for the preparation of C2-methylamine heterocycles with biological relevance. These compounds were prepared via an alkynylation/cyclization sequence which is convergent, highly modular, and allows for a complementary scope to equivalent enantioselective heteroarylations. The StackPhim ligands contain chiral centers and a chiral axis, and these two elements of chirality proved essential for achieving high enantioselectivities. ( en )
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Thesis:
Thesis (Ph.D.)--University of Florida, 2016.
Local:
Adviser: APONICK,AARON.
Local:
Co-adviser: MURRAY,LESLIE JUSTIN.
Statement of Responsibility:
by Paulo H Paioti.

Record Information

Source Institution:
UFRGP
Rights Management:
Copyright Paioti, Paulo H. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
Classification:
LD1780 2016 ( lcc )

Downloads

This item has the following downloads:


Full Text

PAGE 1

G ROUP 11 TRANSITION METAL CATALYZED REACTIONS OF ALKYNES: FROM SPIROKETALS TO CHIRAL AMINES By PAULO HENRIQUE DE SOUZA PAIOTI A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFIL LMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2016

PAGE 2

2016 Paulo Henrique de Souza Paioti

PAGE 3

To my parents brothers and teachers

PAGE 4

4 ACKNOWLEDGMENTS Ackno w ledging is recognizing our own limitations I believe s uccess can only be achieved with the help of others. I would not move forward without truly a c knowledging the people who helped to shape the person and the professional I am today Words cannot express my grati tude to my advisor, Professor Aaron Aponick. I am eternally grateful for everything he has taught me. I have learned from a very great scientist and this will give me the confidence I will need in the future I thank him for his original ideas for his amb ition and for his hard work which kept me motivated throughout my entire PhD studies In many circumstances, he believed in me more than I did and, for that, I am truly thankful. Essentially, I thank him for his endless efforts to mak e me a better scientis t and for showing me the true meaning of excellence I am a very proud member of the Aponick group. I have learned so much from so many talented individuals. I would like to thank my old friend Flavi o Cardoso for the time we spent in So Jos, Campinas an d Gainesville. I thank the friends hip the kindness and enthusiasm of Lindsey DeRatt, Romain Miotto, Barry Butler, Justin Goodwin, John Ketcham, Ji Liu, Sourabh Mishra, Mukesh Pappoppula, Owen Garrett, Eddie Laguna, Berenger Biannic and Nick Borrero as we ll as all of the other members of the group I also thank the m for our weekly Journal Club, which was always very enjoyable I thank Lindsey DeRatt and Eddie Laguna for doing an exceptional job in proof reading this d ocument Before coming to UF I interact ed with many great scientists at the University of Campinas (UNICAMP) in Brazil. I am grateful to Professor Fernando A. S. Coelho for being a great first mentor and for creating a n excellent environment for learning organic chemistry I thank Professors Lu iz C. Dias and Carlos R. D. Correia for being excellent teachers and for all their support throughout the years. I also thank my high school teacher Mario Fukushima for helping me discover that I wanted to do chemistry for life.

PAGE 5

5 I would like to thank my committee members: Professors William R. Dolbier Jr., Stephen A. Miller, Leslie J. Murray, and Marg aret O. James for all of their assistance throughout my academic studies. I am also indebted to Professor Adam S. Veige who genuinely shared so much of his own personal experience with me I am eternally thankful to my parents Maria Bernadete and Antonio Carlos Paioti for putting m y and my brother s own course in life. the amount of work, time and money they invested in my education which allowed me to be here today. I thank them for their love and for being my role models of honesty and integrity I am equally thank ful to my brothers, Pedro Ivo and Joo Marcelo, for everything th ey have done to me. I cheer for them more than I do for my self and I know the feeling is mutual Early on in life I strived to be like them and this still I thank also their wives, Isa bela and Tati ana for always being so lovely and, i n t he future, I w ould like Joo Henrique and Lorenzo to know that it was extremely hard for their uncle to be so far away when they had their first steps I thank St ella Gonsales for her love, her patience her beautiful smile and for the great moments we ha d in the past nine years I am so blessed to have such a n amazing person to share my life with me. I admire so much the scientist she ha s become and I hope I am able to help more exceptional women like her succeed in science, a field which is unfortunately dominated by men. I would also like to thank her for taking the time to proofread this dissertation. Friendship is the fuel of life and I could not live without my friends. I would like to thank all of my Brazilian friends from Gainesville and all of my friends from So Jos dos Campos and Campinas. I hope to see them all at my wedding in two months. In closing I thank God for my life, for my health for placing incredible people around me and for having the privilege of doing something I love as my lif e long career.

PAGE 6

6 TABLE OF CONTENTS page ACKNOWLED GMENTS ................................ ................................ ................................ .. 4 LIST OF FIGURES ................................ ................................ ................................ .......... 9 LIST OF ABBREVIATIONS ................................ ................................ ........................... 18 ABSTRACT ................................ ................................ ................................ ................... 22 CHAPTER 1 GOLD CATALYZED SUBSTITUTION REACTIONS OF ALLYLIC AND PROPARGYLIC ALCOHOLS ................................ ................................ ................. 24 Introduction ................................ ................................ ................................ ............. 24 Reaction discovery ................................ ................................ ................................ 25 Mechanism ................................ ................................ ................................ ............. 27 Mechanism of the Addition of Oxygen Nucleophiles to Allylic Alcohols ............ 28 Mechanism of the Addition of Carbon Nucleophiles to Allylic Alcohols ............ 31 Reactions of Allylic Alcohols ................................ ................................ ................... 33 Intramolecular Reactions of Allylic Alcohols ................................ ..................... 34 Intermolecular Reactions of Allylic Alcohols ................................ ..................... 45 Reactions of Propargylic Alcohols ................................ ................................ .......... 51 Intramolecular Reactions of Propargylic Alcohols ................................ ............ 51 Intermole cular Reactions of Propargylic Alcohols ................................ ............ 61 Conclusions and Outlook ................................ ................................ ........................ 63 2 CONTROLLING REGIOCHEMISTRY IN METAL CATALYZED SPIROKE TAL SYNTHESIS FROM ALKYNOLS ................................ ................................ ............ 65 Spiroketals: Importance and Synthesis ................................ ................................ ... 65 Relevance of Unsaturated Spiroketals ................................ ............................. 67 Acid Catalyzed Synthesis of Spiroketals Using Ketodiols ................................ 69 Metal Catalyzed Synthesis of Spiroketals Using Alkynols ................................ 72 Gold Catalyzed Synthesis of Spiroketals Using Monopropargylic Triols .......... 75 Gold Catalyzed Synthesis of Spiroketals Using Acetonides ................................ ... 80 General Idea for Controlling the Regioselectivity Using Acetonides ................. 81 Reaction Optimization ................................ ................................ ...................... 84 Reaction Scope ................................ ................................ ................................ 86 Reaction Mechanism ................................ ................................ ........................ 93 Conclusions and Outlook ................................ ................................ ...................... 104 3 COPPER CATALYZED ENANTIOSELECTIVE SYNTHESIS OF AMINO SKIPPED DIYNES ................................ ................................ ................................ 105

PAGE 7

7 The Relevance of Branched Chiral Amines ................................ ....................... 105 Branched Aliphatic Chiral Amines: Mono and Polyamine Natural Products ................................ ................................ ................................ ...... 107 Enantioselective Synth esis of Branched Aliphatic Chiral Amines ............... 109 Copper Catalyzed A3 Reaction Toward Amino Skipped Diynes: Access to Branched Aliphatic Chiral Amines? ................................ ................................ ... 116 Challenges for the Enantioselective Synthesis of Amino Skipped Diynes ...... 119 Reaction Optimization and Scope ................................ ................................ .. 122 Synthesis of a Branched Aliphatic Chiral Amine Natural Product and Beyond ................................ ................................ ................................ ........ 126 A3 Coupling: Proposed Reaction Pathway ................................ ..................... 130 Conclusions and Outl ook ................................ ................................ ...................... 13 5 4 DEVELOPMENT OF STACKPHIM LIGANDS FOR ENANTIOSELECTIVE CATALYSIS ................................ ................................ ................................ .......... 136 Axially Chiral P,N Ligands and the Development of StackPhos ........................... 136 Preparation of Optically Pure Axially Chiral P,N Ligands ................................ ...... 141 Phosphinooxazoline (PHOX) and Phosphinoimidazoline (PHIM) Ligands ............ 146 Preparation of Optically Pure PHOX and PHIM Ligands ................................ ....... 148 Incorporation of Axial Chirality into Phosphinoimida zolines: Development of StackPhim Ligands ................................ ................................ ............................ 151 Preparation of the First Generation of StackPhim Ligands ............................. 155 Palladium Catalyzed A symmetric Allylic Alkylation ................................ ........ 159 Copper Catalyzed Enantioselective A3 Reaction ................................ ........... 161 Preparation of the Second Generation of Stack Phim Ligands ........................ 165 Barrier to Rotation of StackPhim Ligands: Thermal Epimerization Studies .... 169 Preparation of the F 5 Phim Ligand a s a Non Axially Chiral Control ................ 172 Copper catalyzed A3 Reaction and the Synthesis of Amino Skipped Diynes 173 Copper catalyzed A 3 Reaction: Synthesis of 2 Methylamine Heterocycles ... 178 Palladium Catalyzed Enantioselective Baeyer Villiger Oxidation and Silver Catalyzed [3 + 2] cycloaddition of Azomethine Ylides ................................ 187 Proposed Model for the Enantioselectivity in the Copper Catalyzed A3 Reaction ................................ ................................ ................................ ...... 189 Conclusions and Outlook ................................ ................................ ...................... 193 5 EXPERIMENTAL SECTION ................................ ................................ .................. 194 General Considerations ................................ ................................ ........................ 194 General Scheme for the Synthes is of Triols and Acetonides Utilized in the Gold Catalyzed Spiroketal Synthesis ................................ .......................... 195 Preparation of Alkynes and Aldehydes: Synthetic Intermediates for the Triols and Acetonides ................................ ................................ .................. 195 Preparation of Triols Employed in the Gold Catalyzed Spiroketal Synthesis .. 202 Preparation of Acetonides Employed in the Gold Catalyzed Spiro ketal Synthesis ................................ ................................ ................................ ..... 210

PAGE 8

8 Preparation of Monounsaturated Spiroketals: Gold Catalyzed Cyclization of Acetonides and Triols ................................ ................................ .................. 216 Preparat ion of Cyclobutane via Gold Catalyzed Dimerization of Allenoether 220 Determination of the Relative Stereochemistry of Acetonides and Triols ....... 223 Determination of the Relative Stereochemistry of Spiroketals ........................ 225 Preparation of Aldehydes, Alkynes and Amines Employed as Starting Materials in the Synthesis of Amino Skipped Diynes ................................ .. 226 Preparation of Enantioenriched Amino Skipped Diynes via A3 reaction ........ 235 Preparation of the Alkynyl Aminoindole, of th e Pauson Khand Product and of Orthogonally Functionalized Amino Skipped Diynes ............................... 257 Preparation of Aliphatic Branched Chiral Amines ................................ ....... 262 X Ray Crystallographic Data of Brominated Amino Skipped Diyne ................ 265 Preparation of StackPhim Ligands 4 76 and 4 77 ................................ .......... 269 Pr eparation of F 5 Phim Ligand 4 84 ................................ ............................... 275 Thermal Epimerization Studies of StackPhim 4 76 and 4 77 ......................... 279 Preparation of 2 Methylamine H eterocyclic Compounds ................................ 282 Preparation of Alkynediols for the Alkynylation/ Cyclization Sequence .......... 302 X Ray Crystallographic Data of StackPhim 4 77 ................................ ............ 307 X Ray Crystallographic Data of StackPhim 4 60 ................................ ............ 311 LIST OF REFERENCES ................................ ................................ ............................. 315 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 329

PAGE 9

9 LIST OF FIGURES Figure page 1 1 Gold catalyzed nucleophilic addition of oxygen nucleoph iles to bonds ............ 25 1 2 Protodeauration studies of alkyl gold organometallic species ............................. 26 1 3 First report of a gold catalyzed form al S N ............... 27 1 4 Transfer of chirality in the gold catayzed cyclization of monoalyllic diols ............ 29 1 5 Possible pathways for the gold catalyzed addition to allylic alcohols .................. 30 1 6 Calculated reaction coordinate for the gold catalyzed cyclization of monoallylic diols and the importanc e of hydrogen bonding ................................ 31 1 7 Enantioselective gold catalyzed cyclization of indole nucleophiles ..................... 32 1 8 Proposed pathway for the gold catalyzed cyclization of indole nucleophiles ...... 33 1 9 Enantioselective gold catalyzed cascade toward oxazino indoles ...................... 34 1 10 Proposed pathway for the gold catalyzed synthesis of oxazino indoles .............. 35 1 11 Gold catalyzed spiroketalization of monoallylic ketodiols ................................ .... 36 1 12 Proposed pathway for the cascade spiroketal synthesis ................................ ..... 36 1 13 Gold catalyzed cyclization in the total synthesis of (+) isoaltholactone ............... 37 1 14 Gold catalyzed enantioselective synthesis of azacycles ................................ ..... 38 1 15 Proposed pathway for the enantioselective synthesis of azacycles .................... 39 1 16 Cyclization of enantiomerically enriched allylic alcohols ................................ ..... 40 1 17 Chirality transfer in the gold catalyzed cyclization toward azacycles .................. 41 1 18 Proposed pathway for the amination of allylic alcohols ................................ ....... 42 1 19 Enamine catalysis meets gold catalysis in t he enantioselective allylic alkylation of aldehydes ................................ ................................ ....................... 43 1 2 0 Proposed pathway for the enantioselective alkylation of aldehydes .................... 44 1 21 ld catalyzed dehydrative intermolecular allylic alkylation ....................... 45 1 22 catalyzed dehydrative intermolecular allylic alkylation ......... 46

PAGE 10

10 1 23 Stereospecificity in the gold catalyzed intermolecular allylic alkylation with E allylic alcohol ................................ ................................ ................................ ...... 47 1 24 Stereospecificity in the gold catalyzed intermolecular ally lic alkylation with Z allylic alcohol ................................ ................................ ................................ ...... 48 1 25 Gold catalyzed intermolecular dehydrative synthesis of chromans ..................... 49 1 26 Mechan ism of the gold catalyzed intermolecular synthesis of chromans ............ 50 1 27 Mesoionic carbene ligand in the gold catalyzed allylic alkylations ...................... 50 1 28 Gold catalyzed polycyclic fused indole synthesis ................................ ................ 52 1 29 Proposed pathway for the gold catalyzed polycyclic fused indole synthesis ....... 53 1 30 Gold catalyzed dehydrative cyclizations in water ................................ ................ 54 1 31 Proposed pathway for the gold catalyzed dehydrative synthesis of furans ......... 55 1 32 Gold catalyzed dehydrative furan synthesis in a PEG matrix .............................. 56 1 33 Total synthesis of () cafestol via a gold catalyzed furan synthesis .................... 57 1 34 Gold catalyzed dehydrative 1,3 sulfonyl migration toward polysubstituted 3 sulfonyl pyrroles ................................ ................................ ................................ 58 1 35 Proposed pathway fo r the gold catalyzed dehydrative 1,3 sulfonyl migration toward polysubstituted 3 sulfonyl pyrroles ................................ .......................... 59 1 36 Gold catalyzed benzannulation towards o phenolic esters ................................ 60 1 37 Proposed pathway for the gold catalyzed benzannulation toward o phenolic esters ................................ ................................ ................................ .................. 61 1 38 Gold catalyzed intermolecular dehydration of propargyl alcohols ....................... 62 1 39 Proposed catalytic cycle for the intermolecular gold catalyzed reaction of propargylic alcohols with arenes ................................ ................................ ......... 63 2 1 Olean, the simplest spiroketal isolated, and its biological activity ........................ 65 2 2 The rubromycins and their corresponding activity as human telomerase inhibitors ................................ ................................ ................................ ............. 66 2 3 Okadaic acid, a potent protein phosphatase inhibitor ................................ .......... 67 2 4 Representative unsaturated spiroketals in natural products ................................ 67

PAGE 11

11 2 5 The structure of avermectin B 1a ................................ ................................ .......... 69 2 6 Proposed biosynthesis of pheromones of olive fruit flies ................................ ..... 70 2 7 ............ 71 2 8 The two most common strategies for spiroketal synthesis ................................ .. 72 2 9 Lack of regioselectivity in metal catalyzed spiroketalization of alkynediols ......... 74 2 10 Gold catalyzed synthesis of tetrahydrop yrans and the synthesis of monounsaturated spiroketals ................................ ................................ .............. 75 2 11 Gold catalyzed synthesis of spiroketals from monopropargylic triols .................. 76 2 12 Retrosynthesis analysis comparing the traditional and gold catalyzed synthesis of monounsaturated spiroketals ................................ .......................... 77 2 13 Poor selectivity in the gold catalyzed spiroketal synthes is from monopropargylic triols observed by Aponick ................................ ...................... 78 2 14 Poor selectivity in the gold catalyzed spiroketal synthesis from monopropargylic triols observed by Forsyth ................................ ....................... 79 2 15 of the synthesis of the spiroketal ................................ ................................ ........ 80 2 16 The regioselective deacylative cyclization of acetonides toward spiroketals ....... 81 2 17 Selectivity issues on metal catalyzed spiroketal synthesis from alkynols ............ 82 2 18 Gold catalyzed synthesis of monounsaturated spiroketals from acetonides ....... 83 2 19 Unsuccessful gold catalyzed cyclization of monopropargylic triol 2 80 ............... 84 2 20 Optimization of the gold catalyzed spiroketalization using an acetonide ............. 85 2 21 Use of diastereomeric acetonides 2 83 and 2 84 in the spiroketalization ........... 87 2 22 Expanding the scope of the reaction with acetonides 2 87 and 2 89 .................. 88 2 23 Model studies for the sp iroketal of the spirastrellolides ................................ ....... 89 2 24 Attempted transfer of chirality in the gold catalyzed spiroketalization ................. 90 2 25 Si milar yields for a triol and for the corresponding acetonide in the gold catalyzed spiroketalization reaction ................................ ................................ .... 90 2 26 The most difficult substrates in the gold catalyzed spiroketal synthesis .............. 91

PAGE 12

12 2 27 ................................ ... 92 2 28 The allenoether pathway in the gold catalyzed s ynthesis of spiroketals ............. 94 2 29 The diene pathway in the gold catalyzed synthesis of spiroketals ...................... 95 2 30 Possible intermedia tes in the diene pathway ................................ ...................... 96 2 31 The incorporation of gem dimethyl groups at the propargylic position ................ 97 2 32 The gold catal yzed dimerization of the allenoether intermediate 2 122 .............. 98 2 33 Proposed mechanism for the dimerization of the allenoether 2 122 ................... 99 2 34 Elimination as the rate determining step for the cyclization of acetonides ........ 100 2 35 The proposed transition state for the gold catalyzed spiroketalization .............. 101 2 36 The influence of gold catalysts in the transition state of the reaction ................ 102 2 37 The influence of substituents in the transition state of the gold catalyzed spiroketal synthesis from acetonides ................................ ................................ 102 2 38 The influence of substituents in the transition state of the gold catalyzed spiroketal synthesis of more hindered acetonides ................................ ............ 103 3 1 Representative applications of branched chiral amines ................................ 106 3 2 The taveuniamides are non racemic natural products ................................ ...... 107 3 3 The zeamines and the fabclav ines natural products ................................ ......... 108 3 4 Problems arising from enantioselective hydrogenation toward branched aliphatic chiral amines ................................ ................................ ...................... 110 3 5 Enantiodiscrimination is a problem in enantioseletive reduction of iminium ions toward branched aliphatic chiral amines ................................ ................ 111 3 6 Main problems in enantioseletive C H aminatio n reactions toward branched aliphatic chiral amines ................................ ................................ ...................... 112 3 7 branched aliphatic chiral amines ................................ ................................ ................................ .... 113 3 8 ...... 114 3 9 Problems in the enantioselective 1,2 addition into imines and iminium io ns toward branched aliphatic chiral amines ................................ ....................... 115

PAGE 13

13 3 10 Enantioselective synthesis of diarylmethylamines via 1,2 addition ................... 116 3 11 Coppe r StackPhos catalyzed A3 reaction ................................ ......................... 117 3 12 Enantioselective A3 reaction toward amino skipped diynes .............................. 118 3 13 Amino skipped d iynes can be precursors of branched aliphatic amines ........ 119 3 14 Undesired addition to the position of the alkynyl iminium ion ......................... 120 3 15 Deprotonation at the position of the alkynyl iminium ion ................................ 121 3 16 Configurational stability of amino skipped diynes ................................ .............. 121 3 17 Optimizatio n of the reaction with racemic ligand ................................ ............... 122 3 18 The first enantioselective preparation of an amino skipped diyne ..................... 123 3 19 Sco pe of the enantioselective synthesis of amino skipped diynes .................... 124 3 20 Optimization of the reaction with non racemic ligand ................................ ........ 126 3 21 Synthesis of the branched aliphatic chiral amine natural product 3 12 .......... 127 3 22 Intramolecular hydroamination of alkynes toward C2 methylamine indole ........ 128 3 23 Chemoselective Pauson Khand reaction ................................ .......................... 128 3 24 Orthogonal functionalization of amino skipped diynes ................................ ...... 129 3 25 General pathway for the copper catalyzed A3 coupling ................................ .... 130 3 26 Induction period and positive non linear effect in the Cu StackPhos catalyzed A3 reaction. ................................ ................................ ................................ ...... 131 3 27 Structure of CuBr bound to StackPhos and QUINAP from X Ray analysis ....... 132 3 28 Proposed catalytic cycle for the Cu StackPhos c atalyzed A3 reaction .............. 134 4 1 Axially Chiral Ligands: from BINAP to QUINAP and PINAP .............................. 137 4 2 Racemization of an indole con taining P,N Ligand ................................ .............. 138 4 3 Six versus five membered rings and the configurational stability of biaryls ...... 139 4 4 Destabiliz ation of the transition state through steric interactions increases the barrier to rotation about biaryl bonds ................................ ................................ 139

PAGE 14

14 4 5 Stabilization of the ground state through stacking interactions increases the barrier to rotation around biaryl bonds ................................ ........................ 140 4 6 ................................ ........................ 142 4 7 Resolution of optically pure QUINAP using a chiral palladacycle ...................... 143 4 8 Preparation of optically pure PINAP ligands ................................ ..................... 144 4 9 Deracemization of StackPhos using a chiral palladacycle ................................ 145 4 10 ................................ ......................... 146 4 11 From Semicorrins and bisoxazolines to PHOX ligands ................................ ..... 147 4 12 The development of highly modular PHIM ligands ................................ ............ 148 4 1 3 Retrosynthetic Analysis to PHOX and PHIM ligands ................................ ......... 149 4 14 Representative synthesis of PHOX ligands ................................ ....................... 150 4 15 Representati ve synthesis of PHIM ligands ................................ ........................ 150 4 16 Incorporation of axial chirality into PHIM ligands ................................ ............... 152 4 17 stacking interactions stabilizing axially chiral conformations ....................... 153 4 18 StackPhim ligands: initial motivation ................................ ................................ 154 4 19 Preparation of 2 iodo 1 nap hthoic acid ................................ ............................. 155 4 20 Preparation of StackPhim 4 60 and 4 61 ................................ .......................... 156 4 21 Optically pure StackPhim 4 60 obtained via crystallizat ion induced dynamic resolution ................................ ................................ ................................ .......... 157 4 22 Single crystal X Ray diffraction analysis of StackPhim 4 60 shows the expected stacking ................................ ................................ ....................... 158 4 23 Palladium catalyzed asymmetric allylic alkylation with P,N ligands .................. 160 4 24 Preliminary results in the copper catalyzed enantioselective A3 reaction with StackPhim 4 60 ................................ ................................ ................................ 162 4 25 The enantiomeric excess increases with the amount of StackPhim 4 61 in the copper catalyzed A3 reaction ................................ ................................ ........... 163 4 26 Spatia l orientation of groups in StackPhim 4 60 and 4 61 ................................ 164

PAGE 15

15 4 27 ...................... 165 4 28 Design of StackPhim 4 76 and 4 77 ................................ ................................ .. 166 4 29 Preparation of StackPhim 4 76 and 4 77 ................................ .......................... 167 4 30 Single crystal X Ray diffraction analysis of StackPhim 4 77 shows the expected stacking ................................ ................................ ....................... 168 4 31 Barrier to rotation of atropisomeric P,N ligands ................................ ................ 170 4 32 Preparation of ligand F 5 Phim 4 84 ................................ ................................ ... 172 4 33 Fluorinated P,N ligands containing chiral centers and chiral axis ..................... 173 4 34 Copper catalyzed enantioselective A3 reaction with StackPhim Ligands ......... 174 4 35 The expected lateral view of all synthesized StackPhim ligands ....................... 175 4 36 A3 reaction toward amino skipped diynes using StackPhim ligands ................. 176 4 37 Scope of the enantioselective A3 reaction using StackPhim 4 76 ..................... 177 4 38 Representative examples of 2 methylamine heterocyclic compounds .............. 178 4 39 Traditional approach for preparation of 2 methylamine hetero cycles ................ 179 4 40 Rhodium catalyzed reaction of arylboronic esters with aromatic imines ........... 179 4 41 New approach for preparation of 2 methylamine heterocycles ......................... 180 4 42 Preliminary results in the alkynylation/cyclization sequence ............................. 181 4 43 Alkynylation/ c ylization with StackPhos, StackPhim and F 5 Phim ..................... 182 4 44 Scope of the alkynylation/ cyclization toward chiral furylamines ....................... 184 4 45 Enantioselective synthesis of indolyl and benzofurylamines ............................ 185 4 46 Enantioselective synthesis of indolylamines using PINAP ligand ...................... 185 4 47 Enantioselective synthesis of syn and anti 1,4 aminoalcohols .......................... 186 4 48 Palladium catalyzed enantioselective Baeyer Villiger oxidation ........................ 188 4 49 Silver catalyzed enantioselective [3+2] cycloaddition ................................ ....... 1 88 4 50 Proposed transition state for the alkynylation of iminium ions ........................... 189 4 51 Proposed stereochemical model for the alkynylation of iminium ions ............... 190

PAGE 16

16 4 52 Proposed stereochemical model for the Cu ( S ) StackPhos cataly zed A3 reaction ................................ ................................ ................................ ............. 190 4 53 Proposed stereochemical model for the Cu ( S ) StackPhos catalyzed quinoline alkynylation ................................ ................................ ....................... 191 4 54 Th e proposed differences between StackPhos and StackPhim ligands in the stereochemical model ................................ ................................ ....................... 192 5 1 Synthetic route for the synthesis of triols and acetonides employed in the gold catalyzed spiroketal synthesis ................................ ................................ .. 195 5 2 Synthetic route for the synthesis of aldehydes: synthetic intermediates for triols and acetonides ................................ ................................ ......................... 198 5 3 Synthetic route for the synthesis of triols via an alkynylation reaction ............... 202 5 4 Preparation of acetonides from the corresponding triols ................................ ... 210 5 5 Preparation of unsaturated spiroketals from acetonides and triols .................... 216 5 6 Synthetic route for the cyclobutane via dimerization of allenoether ................... 220 5 7 Determination of the relative stereochemistry of 1,3 acetonides ....................... 224 5 8 Determination of the relative stereochemistry of 1,2 acetonides ....................... 224 5 9 Determination of the relative stereochemistry of spiroketals through the synthesis of an anomeric spiroketal ................................ ................................ .. 225 5 10 Determination of the relative stereochemistry of major and minor spiroketals synthesized through the gold catalyzed spiroketalization ................................ 226 5 11 Preparation of alkynyl aldehydes via alkynylation of DMF ................................ 226 5 12 Preparation of alkynyl aldehydes via Sonogashira followed by oxidation .......... 228 5 13 P reparation of alkynyl aldehydes containing a sulfonamide group .................... 231 5 14 Preparation of aromatic alkyne containing a sulfonamide group ....................... 233 5 15 Preparation of amino skipped diynes via copper catalyzed A3 reaction with StackPhos ................................ ................................ ................................ ........ 235 5 17 Synthetic route for the preparation of aliphatic branched chiral amines ......... 262 5 18 X Ray structure of brominated amino skipped diyne ................................ ......... 265 5 19 Synthetic route for the prepara tion of StackPhim ligands 4 76 and 4 77 .......... 269

PAGE 17

17 5 20 Synthetic route for the preparation of F 5 Phim ligand 4 84 ............................... 275 5 21 Epimeri zation: data collected by 1 H NMR ................................ .......................... 280 5 22 Finding the rate constant from the rate law ................................ ....................... 281 5 23 Graph of ln ([4 77] t [4 77] eq / [4 77] 0 [4 77] eq ) versus time ............................. 281 5 24 Barrier to rotation of StackPhim 4 76 and 4 77 ................................ ................. 282 5 25 Preparation of proparg ylamines via A3 reaction toward methylamine heterocycles ................................ ................................ ................................ ..... 282 5 26 Preparation of furylamines via gold catalyzed cyclization ................................ 283 5 27 Preparation of benzofuryl and indolylamines ................................ ................... 284 5 28 X Ray structure of StackPhim 4 77 ................................ ................................ ... 307 5 29 X Ray structure of StackPhim 4 60 ................................ ................................ ... 311

PAGE 18

18 LIST OF ABBREVIATIONS Angstrom(s) Ac Acetyl acac acetylacetonate aq Aqueous Ar Aryl Bn Benzyl Boc Tert butyloxycarbonyl BSA Bis(trimethylsilyl)acetamide Bz Benzoyl C Celsius or centigrade Cat Catalyst cm Centimeter CSA Camphorsulfonic acid Cy Cyclohexyl d Doublet DABCO 1,4 diazabicyclo[2.2.2]octane DART Direct analysis in real time DCM Dichloromethane DIPEA N,N diisopropylethylamine DMAP 4 D imethylamino pyridine DMF Dimethylformamide DMSO Dimethyl sulfoxide DPEN Diphenylethylenediamine dr Diastereomeric ratio

PAGE 19

19 E Electrophile eq uiv Equivalent e e Enantiomer ic excess Et Ethyl ESI Electrospray g Gram GABA aminobutyric acid h H our HIV Human immunodeficiency virus HPLC High performance liquid chromatography HRMS High resolution mass spectr a Hz Hertz IC 50 Half maximum inhibitory concentration IPr 1,3 bis(2,6 diisopropylphenyl)imidazol 2 ylidene IR In frared LAH Lithium aluminum hydride LDA Lithium diisopropylamide L TMP Lithium tetramethylpiperidide m Multiplet M Metal m/z Mass to charge ratio Me Methyl Mes Mesityl mg Miligram MHz Megahertz

PAGE 20

20 min Minute mL Milliliter mM Millimolar mmol Milim ol MP Melting point MS Molecular sieves MW Microwave n Bu Normal (primary) butyl NHC Nitrogen heterocyclic carbene NMR Nuclear magnetic resonance Nuc Nucleophile p Pentet Ph Phenyl PMB p Methoxybenzyl ppm Part(s) per million PPTS P yridinium par a toluenesulfonate q Quartet R Alkyl or aryl rac Racemic R f Retention factor s S econd or singlet S N 1 Mono mlecular nucleophilic substitution S N 2 Bimolecular nucleophilic substitution S N Conjugate bimolecular nucleophilic substitution t Triplet

PAGE 21

21 TBAF Tetrabutylammonium fluoride TBDPS Tert butyldiphenylsilyl TBS Tert butyldimethylsilyl t Bu T ert butyl TES Trie thylsilyl Tf Trifluoromethanesulfonyl TFA Trifluoroacetic acid THF Tetrahydrofuran THP Tetrahydropyran TIPS Triisopropylsilyl TLC T hin layer chromatography TMS Trimethylsilyl TOF Time of flight mass analyzer t r Retention time Ts Para toluenesulfonyl (tosyl) UV Ultraviolet O bserved optical rotation in degrees G Gibbs free energy change H Enthalpy change S Entropy change Chemical shift in parts per million downfield from tetramethylsilane L Microliter

PAGE 22

22 Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree o f Doctor of Philosophy GROUP 11 TRANSITION METAL CATALYZED REACTIONS OF ALKYNES: FROM SPIROKETALS TO CHIRAL AMINES By Paulo Henrique de Souza Paioti December 2016 Chair: Aaron Aponick Major: Chemistry The use of gold complexes to activate bonds bec a me a well known and reliable mode of reactivity in organic synthesis. In C hapter 1, a literature review cover s the use of gold catalysts to effect substitution in allylic and propargylic alcohols with concomitant loss of water This review is f ocused on re actions where the acidity of the gold catalysts appear s to overcome the ir inherent Lewis acidity (or acidity). E xamples from the literature which demonstrate advances made since 2011 are presented. In the context of activation of propargyl alcohols we report, i n C hapte r 2, a gold cat alyzed synthesis of spiroketals which addresses regioselectivity issues reported in metal catalyzed spiroketal synthesis from alkyn ols The reaction is regulated by an acetonide which undergoes extrusion of acetone delivering spiroketals in good yields and diastereoselectivities. The reaction is carried out under mild conditions employing AuCl as the catalyst and should be widely applicable to the synthesis of spiroketals. O ur group utilized this new method for the construction of the spirok etal of spirastrellolide A. W e recently have been interested in copper catalyzed enantioselective alkynylation reactions using StackPhos, a P,N ligand developed in our group. Using this ligand we report, in Chapter 3, a copper catalyzed synthesis of nonra cemic 3 amino

PAGE 23

23 1, 4 diynes via a bond formati on. D espite challenging issues of reactivity and stereoselectivity inherent to these molecules the reaction tolerates a broad scope The alkyne s are shown to be useful synthetic handles, rendering amino skipped diynes convenient building b locks for asymmetric synthesis. The method adresses the challenge of synthesizing nonr acemic chiral amines with two similar aliphatic groups The de sign of StackPhos demonstrates it is possible to stabilize the axial configuration in 5 membered heterocyc lic P,N Ligands In C hapter 4, we demonstrate that axial chirality in phosphinomidazolines can be controlled, creating P,N ligands called StackPhim. One StackPhim was superior i n a copper catalyzed alkynylation which was required for the preparation of C2 methylamine heterocycles with biological relevance These compounds were prepared via a n alkynylation/cyclization sequence which is convergent, highly modular, and allows for a complementary scope to equivalent enantioselective heteroarylation s The StackP him ligands contain chiral centers and a chiral axis, and these two elements of chirality proved essential for achieving high enantioselectivities.

PAGE 24

24 CHAPTER 1 GOLD CATALYZED SUBSTITUTION REACTIONS OF ALLYL IC AND PROPARGYL IC ALCOHOLS Introduction R eactions of alkynes, alkenes and allenes have dominated the landscape of the chemical literature on homogeneous gold catalysis due to the extreme ease of bond formation in a wide variety of settings in combination with a bro ad functional group tolerance. N umerous reviews documented the progress of this field since approximately 1998 1 when some of the most influential seminal contributions began to appear 2 In h omogeneous gold catalysis, catalyst development and s ubstrate design have had a tremendous impact and to date one of the most important reactions continues to be the gold catalyzed addition of heteroatom nucleophiles to bonds 3 In addition to nucleophilic addition s, substitution reactions can also be effected with judicious substrate choice While substitution reactions can be performed by utilizing gold catalyst s as acid s ( Lewis acid s ) for cation formation the traditional acidity of gold catalysts can also be harnessed in alternative mechanistic scenarios For the past ten years, our group ha s been interested in using gold catalysts as acids to accomplish substitution reactions in allylic and propargylic alcohols In 2011 we reviewed this area 4 while separate reviews also covered this now broad topic. 5 This chapter describe s more recent adv ances in the field that have appeared since 2011 and focus es mostly on transformations where the catalyst effects substitution reactions by activating the bond of unsaturated alcohols which generally results in two step processes.

PAGE 25

25 Reaction discovery G old catalyzed reactions of heteroatom nucleophiles with alkynes, alkenes and allenes are well known and effective conditions for these transformations have long been established 6 While r eactions of alkynes and allenes typically proceed under very mild con ditions, the gold catalyzed nucleophilic addition to olefins requires much more forcing conditions (Figure 1 1 ). 7 Figure 1 1. Gold catalyzed nucleophilic addition of oxygen nucleophiles to bonds It is now well accepted that protodeauration of Au complexes containing a Au C sp3 bond is extremely difficult (Figure 1 2) 8 A protodemetallation step can generally be seen as a formal protonation of an organometallic bond ; and it is remarkable that alkyl gold organometallic species cannot be easily protonated, even in the presence of Br nsted acids. For instance, Toste and coworkers have demonstrated that the alkyl gold substrate 1 8 does not react with TsOH to deliver the protodeauration produc t 1 9 Instead, the reaction delivers 60% of the elimination product 1 10 and 40 % of unreacted starting material 1 8 is recovered 9 The elimination step that is responsible for the

PAGE 26

26 formation of 1 10 is the microscop ic reverse of the nucleophilic addition an alternative pathway when protodeaur ation is difficult Figure 1 2 Protodeauration studies of alkyl gold organometallic species In 2006 our group began to explore various conditions in an attempt to develop a o ne pot hydroalkoxylation/Claisen rearrangement whereby the addition of an allylic alcohol to an alkyne to form an allyl vinyl ether would be immediately followed by the Claisen rearrangement. T his reaction proved to be very difficult due to competing sid e reactions of the substrates. Although we and others were eventually successful at developing a protocol for this reaction, 10 a very interesting competing reaction was responsible for this difficulty. During these attempted reactions, two molecules of the a llylic alcohol underwent condensation to form diallyl ether, albeit in a very inefficient process. O ur group published in 2008 what was to the best of our knowledge, the first gold catalyzed formal S N 1 1 1 ( Figure 1 3 ). 11 In contrast to previous reports on the gold catalyzed nucleophilic addition of heteroatoms to alkenes, the reactions proceeded under very mild conditions most often observed for addition to alkynes and allenes. Although there are many other catalysts based u pon different metals, 12 the gold catalyzed variant developed in our group has two distinct advantages: 1) the catalyst loading is usually very low and the conditions are very mild; and 2) it appears that gold catalyzed reactions proceed by a non cationic me chanism, enabling

PAGE 27

27 the development of highly stereoselective processes. The report from the Aponick group was preceded by a single report of a gold catalyzed amination of aryl substituted allyl ic alcohols; however in this case the g old catalyst acts as a Lewis acid for the formation of stabilized allylic carbocation s 13 Figure 1 3 First report of a gold catalyzed formal S N allylic alc ohols Mechanism As described above, Aponick and coworkers reported the a ddition of alcohol nucleophiles to allylic alcohols Widenhoefer later reported the addition of amines 14 and Bandini reported the use of indoles as nucleophiles. 15 Aponick and Bandini have performed d etailed mechanistic studies on systems using both the alc ohol and indole nucleophiles respectively The mechanisms proposed by the original authors are presented and many of the principles found will be applicable throughout the remainder of the C hapter 1

PAGE 28

28 Mechanism of the Addition of Oxygen Nucleophiles to A llylic Alcohols A variety of mechan isms is possible for the metal catalyzed addition of nucleophiles to allylic systems. In the case of the gold catalyzed cyclization of monoallylic diols in a formal S N ervations were intriguing. Firstly, t he reactions proceed ed under conditions typically employed for alkynes and allenes instead of the more forcing conditions typical of gold catalyzed olefin addition reactions. The reactions were usually complete in minutes to one hour at room temperature ( Figure 1 4 ) ; 4 however w ith olefins, the reactions typically require d elevated temperatures for up to 48 h ours 7 Secondly, the reaction proved to be highly stereo selective with the enantiomeric excess being transferred from the starting material to the product. This chirality transfer was interesting not only because the synthesis of enantioenriched compounds could be envisioned, but it also suggested a non cationi c mechanism. Apart from the chirality transfer, it is important to mention that trans alkene products have always been produced in our group; however there have now been reports of cis olefin products 16 We view these cases where cis olefins are synthesized as being more of an exception than the rule. These observations were suggestive of two possible mechanisms ( Figure 1 5 ). I nformation about the mechanism can be extracted b ecause there are two pieces of stereochemical information embedded in the starting materials and products namely a bsolute ster eochemi stry and olefin geometry. The reaction outcome shows that it must proceed by a syn addition/ syn elimination or by an anti addi tion/ anti elimination mechanism. Other mechanistic hypothesis would not explain the outcome of the reactions. For instance, i f a syn / anti or an anti / syn mechanism is followed either the absolute configuration of the product or the olefin geometry w ould be incorrect.

PAGE 29

29 Figure 1 4 Tran s fer of chirality in the gold catayzed cyclization of monoaly l lic diols A pure ly cationic mechanism was ruled out mainly because of three dif ferent features of the reaction: f irst, a thermodynamic mixture of products would be expected if carbocations were intermediates, but clearly the transfer of chirality is a kinetic process Second, f ormation of an allyl cation would only be favorable in the presence of stabilizing substituents such as aryl groups but the reactions proceed smoothly even in the absence of such groups. Th ird formation of a carbocation is usually favored by good leaving groups, bu t the reaction proce eds smoothly to elim a poor leaving group.

PAGE 30

30 Figure 1 5 Possible pathways for the gold catalyzed addition to allylic alcohols While it is well accepted that gold catalyzed addit ion reactions occur via an anti addition mechanis m, 17 both the anti and syn mechanisms were explored experimentally and computationally by a collaborative work between the Aponick and the Ess groups. 18 It was found that the reaction does indeed follow an anti addition/ anti elimination pathway The calculat ed relative enthalpy and free energies of the transition states and intermediates have been reported in kcal/mol related to the starting material 1 38 (Figure 1 6 ). In summary, h ydrogen bonding plays a vital role throughout the entire reaction coordinate b y stabilizing inte rmediates and transition states. Intramolecular hydrogen bonding obviates the need for intermolecular hydrogen bonding interactions, thus templating the reaction stereochemistry. The reaction s proceed under mild

PAGE 31

31 conditions because an alte rnative pathway to protodeauration is essentially provided by the anti elimination of water. In gold catalyzed nucleophilic additions, as shown by Toste and coworkers (Figure 1 2) the alternative pathway for the protodeauration is the retro addition which essentially results in reversibility toward the starting material. On the other hand, i n the reaction developed by Aponick, the elimination of water results in a thermodynamic sink which makes reversibility unlikely Fi gure 1 6 Calculated r eaction coordinate for the gold catalyzed cyclization of monoallylic diols and the importance of hydrogen bonding In earlier work, Widenhoefer had also suggested the importance of intramolecular hydrogen bonding in analogous aminatio n reactions 19 As it turns out, th e mechanism prop o sed by Aponick and Ess can also explain most of the reactions in which nitrogen nucleophiles are utilized. Mechanism of the Addition of Carbon Nucleophiles to Allylic Alcohols In the case of carbon nucleo philes, the hydrogen bonding described above a s being crucial is not possible; however Bandini and coworkers have successfully proposed a mechanism even in the absence of this hydrogen bonding. The reaction

PAGE 32

32 reported by Bandini proceeds under very mild con ditions and work s quite well (Figure 1 7). 15 Indoles 1 44 act intramolecularly as nucleophile s delivering the cycl i zed products 1 45 in high enantiomeric excess es Th e enantio s elective process is achieved due to the use of a c hiral dinuclear bis(gold)pho s phine complex. Figure 1 7 Enantioselective g old catalyzed cyclization of indole nucleophiles To explain the reactivity and the selectivity the authors propose based on calculations, that the counterion is involved in proton shuttling ( Figure 1 8 ). 20 Bandini and coworkers propose d initial anti carboauration with the triflate counterion templating the reaction by interacti ng with both th e indole NH and the alcohol OH in a process the Rearomatizatio n by proton transfer give s intermediate 1 5 3 and anti elimination of [Au] OH provides the product. Interestingly, the reaction provides the product with a variety of counterions including BF 4 S bF 6 and NTf 2

PAGE 33

33 Figure 1 8 Proposed pathway for the g old catalyzed cyclization of indole nucleophiles Reactions of Allylic Alcohols This section covers intra and intermolecular gold catalyzed dehydrative transformat ions of allylic alcohols which have appeared in the literature since 2011. As previously mentioned t here are generally two main pathways in which these reactions take place; the formal S N complex acts as a acidic late transition metal and is often involved in the aforementioned addition/ elimination seque nce; and the cationic pathway, in which a gold complex acts as a Lewis acid or acid generating a stabilized allylic carbocation. The mechanisms proposed b y the authors will be presented as well as a selected substrate scope for each reaction.

PAGE 34

34 Intramolecular Reactions of Allylic Alcohols The development of intramolecular gold catalyzed dehydrative cyclization reactions of monoallylic diols has allowed for the rapid construction of functionalized saturated tetrahydropyran and tetrahydrofuran rings. 4 12 Among reactions of allylic and propargylic systems presented in th is chapter, this class of reactions was the first to be developed. These intramolecular catalytic processes encompass successful diastereoselective reactions 4 as well as transformations in which the chirality e mbedded in the substrate is fully transferred to the product. 21 More recently, Bandini and coworkers have employed chiral bis(gold)phosphine complex es which enabled an enantioselective preparation of oxazino indoles 1 55 ( Figure 1 9) 22 Figure 1 9 Enantioselective gold catalyzed cascade toward oxazino indoles

PAGE 35

35 The reactions occurred under relatively mild conditions and among the chiral bisphosphine ligands studied, the ( R ) DTBM segphos gave the best results. The reaction tolerates a variety of substrates, delivering oxazino indoles in good to excellent yields and enantioselectivities. The cascade reaction initiates with the formation of the indole through intramolecular gold catalyzed hydroaminati on reaction. The first c yclization places the distal alcohol nucleophile in close proximity to the double bond ( Figure 1 10 ). The second cyclization, which is inherently the enantiodetermining step, is facilitated by the activation of the double bond by the chiral dinuclear go ld complex. The gold catalyst and the pendant alcohol are believed to have an anti relationship in both the alkoxyauration and the elimination step s. Figure 1 10. Proposed pathway for the gold catalyzed synthesis of ox azino indoles

PAGE 36

36 A gold catalyzed cascade cyclization of allylic alcohols has also been successfully utilized by Aponick and coworkers in the synthesis of [6,6] spiroketal s. ( Figure 1 11 ) 23 Because of the biological relevance of spiroketal containing molecule s, sev eral reports on metal catalyzed synthesis of spiroketals have recently appeared 24 and these methods aim at complementing the well known Br nsted acid catalyzed spiroketalization of ketodiols 25 In this report, the Aponick group has employed the allyl ic ketodiol 1 68 as precursor for the synthesis of the vinyl spiroketal 1 69 Figure 1 11. Gold catalyzed spiroketalization of monoallylic ketodiols Mechanistically, Aponick and coworkers proposed a cascade process, in w hich the in situ formed ketal 1 70 undergoes the alko xyauration/elimination sequence ( Figure 1 12 ) Overall, the reaction cascade generates two new stereocenters, in very high diastereoselectivity favoring the most thermodynamic stable spiroketal This se quential spiroketal synthesis could also be realize d with palladium (II) complexes which, in terms of yields, outperform the gold (I) complexes. This reaction was later on utilized by the Aponick group in the synthesis of acortatarin A 26 Figure 1 1 2 Proposed pathway for the cascade spiroketal synthesis

PAGE 37

37 Robertson and coworkers have also utilized a dehydrative cyclization in their total synthesis of (+) isoaltholactone 1 77 ( Figure 1 13 ) 16 The tetrahydropyran moiety of the isoaltholactone was generated from the corresponding diastereomeric mixture of the monoallylic diols 1 73 The gold catalyzed cylization occurred smoothly, furnishing a diastereomeric mixture of the tetrahy dropyran containing molecules 1 74 1 75 and 1 76 which were further elaborated to the desired natural product. The stereospecificity of the go ld catalyzed transformation was studied with single diastereomers separately suggesting that reactions of anti d iastereomers are more selective than the corresponding syn diols Figure 1 1 3 Gold catalyzed cyclization in the total s ynthesis of (+) isoaltholactone The importance of nitrogen containing heterocycles such as pyrrol idine and piperidine derivatives in natural product synthesis has led the synthetic community to design stereoselective methods for their preparation 27 In th e context of developing new

PAGE 38

38 ways to make C N bonds Widenhoefer and coworkers showed that such azac yclic struct ures could be synthesized by gold catalyzed dehydration o f allylic alcohols which contain a pendant amine functionality. 19 More recently, two new complementary reports by the Widenhoefer 16 and the Aponick 28 groups have appeared on this topic, broadening the scope of preparation of substituted pyrrolidines and piperidines. Widenhoefer et al. have elegantly demonstrated that axially chiral dinuclear bis(go ld)phosphine complexes could be employed for the enantioselective preparation of several azacycles 1 79 ( Figure 1 14 ). 16 The reactions were performed under mild conditions with various carbamates 1 78 furnish ing the products 1 79 in high yields and with moderate to excellent levels of enantioselectivity Figure 1 14. Gold catalyzed enantioselective synthesis of azacy cles Similar to the Aponick and Ess for the gold catalyzed preparation of tetrahydropyrans and tetrahydrofurans, 18 Widenhoefer and coworkers proposed an anti aminoauration, followed by an anti elimination step. The carbamate

PAGE 39

39 acts as a nucleophile at the nitrogen, and the chiral environment created by the bisphosphine ligand dictates the face selectivity in the aminoauration step ( Figure 1 15 ). Figure 1 15. Proposed pathway for the enantioselective synthesis of azacycles The mechanis tic hypothesis was supported by experiments with the chiral enantiopure allylic alcohol 1 91 which was separately submitted to the standard reaction conditions with two different enantiomers of the bisphosphine ligand ( Figure 1 16 ). 16 The reaction employing the ( R ) enantiomer of the ligand afforded exclusively the compound 1 92 (40:1 ratio of 1 92 : 1 93 ) containing a ( S ) stereocenter and a ( E ) olefin. In contrast the reaction with the ( S ) enantiomer of the ligand almost exclusively afforded 1 94 (25:1 ratio of 1 9 4 : 1 9 5 ) containing a ( R ) stereocenter and a ( Z ) olefin. This set of experiments show s that the chirality of the ligand is responsible for the face selectivity regarding to the o lefin add i tion (catalyst control) and that the olefin geometry in the final product is a consequence of a stereospecific and most likely anti e limination

PAGE 40

40 pathway. In these transformations, formation of less thermodynamic stable cis olefin s are a ssociated with 1,2 allylic strain, thus for the formation of 1 94 the catalyst controlled face selectivity overcomes this strain. Figure 1 16. Cyclization of enantiomerically enriched allylic alcohols In order to expand the scope of the gold catalyzed synthesis of azacycles, Aponick and coworkers have shown that carbamates and sulfonamides could be succes s fully employ ed in the cyclizations, delivering several azacycles 1 97 in high yields, under very mild conditions ( Figure 1 17 ) 28 More interestingly, this report demonstrated that the chirality present in the substrate can be fully transferred to the product in the cases where alkyl substituted allylic alcohol s such as 1 103 is utili zed; however, transfer of chirality is only partially successful if the compound 1 105 containing a n aryl substituent is employed.

PAGE 41

41 Figure 1 17. Chirality transfer in the gold catalyzed cyclization toward azacycles The t ransfer of chirality in the alkyl substituted allylic alcohol 1 107 is likely a result of the aforementioned anti aminoauration/ anti eli mination sequence (Figure 1 18) In the cyclization of 1 1 1 2 Aponick et al. attributed the loss of enantiomeric excess to a competing cationic mechanism which causes the formation of racemic product. T he transfer of chirality in aryl substituted allylic alcohols is indeed quite challenging and further development in this area will be necessary for this transformation to b e successfully accomplished. Nonetheless, i t is remarkable that there is some degree of

PAGE 42

42 chirality transfer in the cyclization of 1 112 as this demonstrates that the catalyst can act as a acid even when formation of a carbocation is highly favored Figure 1 18. Proposed pathway for the amination of allylic alcohols Following the work on the synthesis of heterocycles by means of C O and C N bond formatio n, the Bandini group reported the use of carbon nucleophiles i n gold catalyzed intramolecular dehydrative cy clization of allylic alcohols. To accomplish this task, the authors initially employed indole derivatives, which have been shown to be suitable nucl eophiles in this type of cyclization ( as seen in the mechanistic section below ) 15 Moreover, Bandini et al. have demonstrated that enamine catalysis 29 and gold catalysis could be combined for the enantioselectiv e construction of a C C bond

PAGE 43

43 resulting in two new stereocenters via allylic alkylation of aldehydes ( Figure 1 19 ) 30 Chiral secondary amines were shown to be compatib le with the reaction conditions and were condensed with aldehydes in situ for the genera tion of the enamines The formation of a chiral nucleophile in combination with an achiral gold complex allowed for the enantioselective construction of the allylic stereocenter. In general, the reactions proceeded smoothly, and the products 1 11 6 were sy nthesized from the aldehydes 1 11 5 in excellent yields enantioselectivities and diastereoselectivities. Figure 1 19. Enamine catalysis meets gold catalysis in the enantioselective allylic alkylation of aldehydes The proposed pathway is comp rised of two main catalytic cycles ; the well known enanime activation of carbonyl groups for asymmetric catalysis and the catalytic cycle for gold cataly zed dehydrative intramolecular cyclizati on of allylic alcohols ( Figure 1 20 ). The authors proposed that the condensation of the secondary amine 1 117 with the aldehyde 1 123 generates the enamine 1 124 which undergoes anti carboauration upon activation of the double bond by the cationic gold c omplex, forming the trans ring

PAGE 44

44 system of 1 125 Elimination then generates the ( E ) olefin in the product, recycling the cationic gold complex. Figure 1 20. Proposed pathway for the enantioselective alkylation of aldehydes The intramolecular gold catalyzed cyclization of allylic alcohols i s a powerful method for the synthesis of very useful oxygen and n itrogen containing heterocycles as well as carbocycles. Facile preparation of the substrates and mild reaction conditions a re f eatures that should render these cyclizations attractive for the preparation of complex natural products and biologically active molecules. Currently, there are many reports of highly diastereoselective and enantioselective reactions and their high fun ctional group tolerance allows for application in a variety of settings.

PAGE 45

45 Intermolecular Reactions of Allylic Alcohols Intermolecular palladium catalyzed allylic alkylations such as the Tsuji Trost reactions are well documented processes ; 31 but, with minima l exceptions, the presence of relatively strong nucleophiles and good leaving groups is required In addition to this, catalysis with other metals such as rhodium 32 ruthenium 33 and the seminal work of Hartwig 34 and Carreira 35 on iridium cataly sis bro adened the scope of th e allylic alkylation. One particular relevant advance of these methods is the ability to include poor leaving groups such as hydroxyl to generate water as a byproduct At approximately the same time the first examples of the intramolecular gold catalyzed dehydrative appeared and these reports motivated the groups of Lee 36 and Widenhoefer 37 to disclose the first intermolecular etherification of allylic alcohols. Lee and coworkers have show ed that primary, secondary and tertiary alcohols are su itable nucleophiles in the gold cata lyzed intermolecular etherification of allylic alcohols 1 128 ( Figure 1 21 ). 36 Figure 1 21. catalyzed dehydrative in termolecul ar allylic alkylation

PAGE 46

46 The overall formal S N reported by Lee and coworkers takes place with superstoichiometric amounts of the nucleophile and isolated yields rang e from good to excellent, depending on the nature of the electrophile nucleophile p air. Widenhoefer et al. have not only expanded the scope of the gold catalyzed intermolecular allylic alkylation, but have also given more insights into the reaction mechanism 37 The reactions reported by Widen hoefer were carried out at room temperature (Figure 1 22) with yields comparable to those reported by Lee 36 Figure 1 2 2 Widenhoefer catalyzed dehydrative in termolecu lar allylic alkylation Based on our work on the chirality transfer in intramolecular gold catalyzed dehydrations, 21 the Widenhoefer group also envisioned the possibility of transferr ing the chirality from the a llylic alcohol to the allylic ether product. To test the feasibility of this process the authors employed enantioenriched allylic alcohol s in the cyclization 37 When employing the enantioenriched, chiral ( E ) allylic alcohol 1 148 under the standard reaction conditions ( Figure 1 23) the authors observed that compound 1 149

PAGE 47

47 was formed as the major product with the optical purity maintained. The authors realized that th e hydrogen bonding model proposed by Aponi ck and Ess account s for the st ereospecificity of the reaction 18 T he second major component of the reaction mixture, the compound 1 151 was most likely formed from the product 1 149 as ethers may also be leavi ng group in th is reaction 38 Interestingly, t he enantiomeric excess was also maintained in this case which supports the stereospecific allylic alkylation. Figure 1 23. Stereospecificity in the gold catalyzed in termolecula r allylic alkylation with E allylic alcohol One more evidence of the anti alkoxyauration/ anti elimination sequence would c o me from the reaction with ( Z ) allylic alcohol 1 153 If this mechanism was operative, the reaction ( Z ) allylic alcohol 1 153 under t he same conditions would generate the compound 1 154 enantiomer of 1 149 In fact, com pound 1 154 was synthesized as th e major product in the reaction and the second major product 1 156 was believed to come from 1 154 ( Figure 1 24 ) The reason why minor c ompounds containing a ( Z ) olefin were also generated in the reactions is not clearly understood at this point; however no

PAGE 48

48 more than 10% of these compounds were present in the reaction mixture. The fact that the mechanism proposed by Aponick and Ess can be expanded to the intermolecular version of the reaction is of interest because it shows the potential for using gold catalysts in stereoselective intermolecular allylic alkylations. Figure 1 2 4 Stereospecificity in the g old catalyzed in termolecular allylic alkylation with Z allylic alcohol Having disclosed the gold catalyzed etherification of allylic alcohols, Lee and coworkers have also reported that carbon nucleophiles could be successfully utilized in intermolecular go ld catalyzed dehydration reactions. More precisely, the authors employed a variety of phenol derivatives 1 158 as nucleophiles, targeting the synthesis of polysubstituted chromans 1 160 ( Figure 1 25 ) 39 The reactions were carried out under similar conditi ons to those reported in the previous work 36 and several chromans were synthesized in good yields.

PAGE 49

49 Figure 1 25. Gold catalyzed intermolecular dehydrative synthesis of chromans Mechanistically, Le e et al. proposed that the gold complex simply acts as a Lewis acid, creating a stabilized allyl carbocation which is then attacked by the arene nucleophile via a Friedel Crafts type reaction. The reaction takes place at the most activ ated and less hindered position of the arene, generating the intermediate 1 174 along with a molecule of water ( Figure 1 26 ) Following the formation of the C C bond, the cationic gold complex or a source of proton reactivates the olefin, generating a st abilized tertiary carbocation. The carbocation is trapped by the oxygen nucleophile, forming the C O bond and delivering the chroman 1 176

PAGE 50

50 Figure 1 26. Mechanism of the gold catalyzed intermolecular synthesis of chroman s In order to improve catalytic efficiency and reactivity in the gold catalyzed intermolecular dehydrative allylic etherification, combined studies from the Lee and Crowley groups revealed that a 1,2,3 triazolylidine mesoionic carbene ligand resulted in m ilder reaction condit ions, improved regioselectivity, and dispensed the use of excess nucleophile ( Figure 1 27 ) 40 Figure 1 2 7 Mesoionic carbene ligand in the gold catalyzed allylic alkylations

PAGE 51

51 The intermolecular gold c atalyzed allylic alkylations are relatively new transforma tions, especially if compared to its intramolecular version As a consequence, improve as well as expansion of substrate scope regarding both electrophiles and nucleophiles are desired. The development of such processes would certainly complement the current synthetic methods for the preparation of intere sting allylic building blocks, impacting the state of the art of the synthesis of natural products and other relevant molecules. Reactions of Propargylic Alcohols Over the past five years, there has been an influx of publications on intra and intermolecu lar gold (I) and gold (III) catalyzed dehydrative transfo rmations of propargyl ic alcohols. In analogy to the reactions of allylic alcohols, either formal S N cationic pathway are often implied to explain reaction outcomes. Although reactions of propar gyl ic and allyl ic alcohols are mechanistically similar, these two types of reactions differ considerably on th eir synthetic target. As a consequence, gold catalyzed dehydrations of propargy lic alcohols deserve particular attention. Intramolecular Reaction s of Propargylic Alcohols Gold catalyzed intramolecular dehydrative reactions of propargylic alcohols appeared in the literature shortly after the first examples of the intramolecular reactions of allylic alcohols. The work of Aponick 41 and Arai 42 groups on the go ld catalyzed synthesis of furan s, pyrroles and thiophenes in addition to the Aponick synthesis of monounsaturated spiroketals 43 gave rise to a series of reactions in which molecular complexity is increased in one step from readi ly prepared starting m aterials. The reports from the Aponick and Arai groups were reviewed elsewhere 4 and will not be discussed in detail herein

PAGE 52

52 Since the reports from Aponick and Arai Bandini and coworkers have shown that poly cyclic fused indoles 1 183 could be prepared via gold catalyzed dehydrative cascade reactions ( Figure 1 2 8 ) 44 The cascade reaction encompasses an indole synthesis followed by C O bond formation between the pendant alcohol and the propargylic carbon. The reaction furnished various interesting in dole derivatives in good yields and, in some cases at ambient temperatures. Figure 1 2 8 Gold catalyzed polycyclic fused indole synthesis The catalytic cycle begins with the for mation of the indole upon activation of the triple bond by the gold complex placing the pendant alcohol in proximity to the propargylic carbon ( Figure 1 2 9 ). For the construction of the second ring, the authors proposed the form ation of a benzylic carboc ation followed by nucleophilic attack of the terminal alcohol via S N 1 reaction. Th is cascade is a good example of a reaction in which the gold catalyst is utilized as a and acid in the same transformation.

PAGE 53

53 Figure 1 2 9 Proposed pathway for the g old catalyzed polycyclic fused indole synthesis Recently, Lipshutz and coworkers have shown that the intramolecular gold catalyzed synth esis of furans and pyrroles 41 as well as the synthesis of unsaturated spiroketals 43 first reported by the Aponick group could be carried out in water in the pre sence of a surfactant ( Figure 1 30 ) 45 T he authors emp loyed the TPGS 750 M surfactant which is responsible for creating lipophilic nanomicelles in the reaction medium. In this work, syntheses of spiroketals 1 201 as well as furans and pyrroles derivatives 1 203 were accomplished in water with excellent yields and short reaction times It should be noted that dehydrative reactions are often carried out in the presence of dehydrating agent s such as molecular sieves In the micellar approach, water is generate d inside the lipophilic core of the micelles and, for entropic reasons, is expelled to the outside of the micellar nanoparticle. The fact that dehydrative reactions can ta ke

PAGE 54

54 place in water is remarkable. T his micellar approach was also demonstrated in othe r important organic transformations 46 including those in which water sensitive organometallic reagents are employed 47 Figure 1 30 Gold catalyzed dehydrative cyclizations in water The mechanism for the gold catalyzed s ynthesis of unsaturated spiroket als will be discussed in detail in C hapter 2 and for this reason it will not be discussed here. Nonetheless, the initial steps for the gold catalyzed spiroketalization are similar to those proposed for the furan synthesis. For the synthesis of furans, Aponick proposed that intermediate 1 215 is formed upon nucleophilic attack of the pendant alcohol to the

PAGE 55

55 activated triple bond via 5 endo dig cyclization ( Figure 1 3 1 ) 41 In a pro cess which is favored by aromatization, p rotodeauration and elimination of water furnishes the 5 membered hetero cycle 1 217 This reaction is usually takes place in less than 30 minutes and could be performed by the Aponick group with catalyst loadings as low as 0.05 mol %. Figure 1 3 1 Proposed pathway for the g old catalyzed dehydrative synthesis of furans Lamaty and coworkers have since then demonstrated that the aforementioned gold catalyzed dehydrative furan synthesi s could also be accomplished in poly(ethyleneglycol) matrix (PEG) ( Figure 1 3 2 ) 48 Unfortunately, transmission electronic microscopy showed that undesired gold (0) containing nanop articles were initially formed o n the surface of the PEG matrix. To solve th is prob lem, the authors used catalytic amounts of an oxidant, namely benzoquinone, to bring elemental gold (0) back to the gold (I) active species. By using benzoquinone, the PEG matrix containing the

PAGE 56

56 gold catalyst could be reutilized and even after five subsequent runs, the yield for the preparation of 1 219 did not decrease Figure 1 3 2 Gold catalyzed dehydrative furan synthesis in a PEG matrix The gold catalyzed dehydrative furan synthesis was then elegantly expl ored by Hon g and coworkers in the total synthesis of () cafestol 1 225 ( Figure 1 3 3 ) 49 Inspired by the biosynthesis of cafestol 50 the authors synthesized t as it is propose d in its biosynthetic pathway. The gold cataly zed reaction pr oceeded smoothly to generate the desired advanced synthetic intermediate 1 224 in excellent yield. I nterestingly, the authors mentioned that the presence of silver salts in the reaction triggered double bond isomerization, forming the more stable tertiary endo olefin. The authors did not understand why the isomerization occurred; however, t o overcome this problem, the silver salt had to be filter ed off prior to the gold catalyzed reaction. After the furan synthesis, a dihydroxylation of the terminal olefin using osmium tetroxide as the oxygen transfer reagent delivered the desired natural product 1 225 in a total of twenty steps from simple start ing materials This report highlights the utility of the Aponick and Arai reaction in natural product synthesis In short, it shows how propargylic diols can be used as furan surrogates which is a concept that is explored in Chapter 4

PAGE 57

57 Figure 1 3 3 Total synthesis of () cafestol via a gold catalyzed furan synthesis Chan and coworkers reported a gold catalyzed dehydrativ e 1,3 sulfonyl migration toward sulfonyl substituted pyrroles. In this report, the authors have sho wn that propargyl ic alcohols bearing a sulfonamide group at the homopropargylic position undergo a 1,3 sulfonyl migration during the cyclization event, furnishing a variety of 3 sulfonyl pyrroles 1 227 in moderate to good yields ( Figure 1 34 ) 51 The reactio n conditions were not particularly mild; however, the reaction tolerates an excellent substrate scope. It should be noted, nonetheless, that the pyrroles synthesized are in most cases, substituted at all carbons and at the nitrogen of the pyrrole ring (Fi gure 1 34) While the aforementioned total synthesis of cafestol (Figure 1 33) shows that alkynediols can be transformed into oxygen heterocycles such as furans, the reaction reported by Chan is clear demonstration of a similar process toward more abundan t nitrogen heterocycles. In their original report, Aponick has also shown that even thiophenes can be

PAGE 58

58 synthesized in the same reaction, which is extraordinary as sulfides are extremely good ligands for gold and can easily deactivate gold catalysts. 41 Figure 1 34. Gold catalyzed dehydrativ e 1,3 sulfonyl migration toward polysubstituted 3 sulfonyl pyrroles The mechanism reported by Chan initiates with an aminocyclization to for m the intermediate 1 245 ( Figure 1 35 ) In the absence of a proton source, th is intermediate undergoes a nitrogen to carbon 1,3 sulfonyl migration, generating the intermediate 1 246 w hich is prone to aromatization. Th is sulfonyl migration is thermodynamic ally favorable because the C S bond is stronger than the N S bond most likely making this process irreversible. The rates of the 1,3 sulfonyl migration and the aromatizatio n have not been studied by the authors With this said, it is also possible that a romatization takes place prior to the sulfonyl migration. This is an interesting mechanistic feature as the vinyl gold

PAGE 59

59 intermediate 1 245 undergoes a migration reaction, which differs from protodeauration or elimination shown throughout Chapter 1 Figure 1 35. Proposed pathway for the gold catalyzed dehydrative 1,3 sulfonyl migration toward polysubstituted 3 sulfonyl pyrroles Very recently, Chan and coworkers have also demonstrated that carbonyl carbons are suitable n ucleophiles for intramolecular gold catalyzed dehydrative cyclizations of propargyl ic alcohols. Chan et al. reported a gold catalyzed dehydrative benzannulation of hydroxy oxoalkynoates 1 248 toward o phenolic esters 1 249 ( Figure 1 36 ) 52 The reactions wer e carried out in the presence of the gold complex 1 250 wit h one equivalent of acetic acid with yields ranging from moderate to good. In this case, alkynes are used as six membered non heterocyclic arene surrogates, showing that dehydrative cyclizations of propargyl alcohols can also impact the synthesis of substituted benzenes.

PAGE 60

60 Figure 1 36. Gold catalyzed benzannulati on towards o phenolic esters In regards to the mechanism of the reaction, the authors proposed that the enol form of the 1,3 dicarbonyl compound acts as a nucleophile, and the activated triple bond as the electrophile ( Figure 1 37 ) The vinyl gold intermediate 1 259 then undergoes protodeauration, furnishing 1 260 Elimination of water and tautomerization of intermediate 1 260 results in the formation of the final product 1 262 The gold catalyzed intramolecular dehydrative cylization of propargyl ic alcohols is very effective in creating interesting heterocyclic compounds via structurally simple substra tes. Several methods for synthesizing propargyl ic alcohols are available 53 which can definitely contribute for the development of new reactions in this area. To date, dehydrative reactions of propargyl ic alcohols are mostly applied to the preparation of ve ry useful aromatic compounds and new methods could certainly be developed for the construction of other interesting molecules.

PAGE 61

61 Figure 1 37. Proposed pathway for the g old catalyzed benzannulati on toward o phenolic esters Intermolecular Reactions of Propargylic Alcohols The intermolecular gold catalyzed dehydrative cyclization of propargyl ic alcohols is the most underdeveloped transformation covered in Chapter 1 A report by Li and coworkers exemplifies how this type of reaction can be utilized for the preparation of useful polysubstituted allenes 1 265 Li et al. have shown that arenes 1 26 4 undergo a gold (III) catalyzed formal S N on with propargyl ic alcohols 1 263 to deliver a variety of allenes in good to exc ellent yields ( Figure 1 38 ) 54 This intermocular allene synthesis is very useful because synthesis of allenes is difficult; however, it is believed that in this case the acidity of the gold (III) catalyst overcomes its acidity The first evidence for this comes from the fact that the reaction was only successful with propargyl alcohols which can form stabilized carbocations. Second gold (III) catalysts

PAGE 62

62 are generally m ore effective in ionizing unsaturated alcohols when compare to analogous gold (I) catalysts. Figure 1 38. Gold catalyzed intermolecular dehydration of propargyl alcohols Mechanistically, the authors then proposed that t he gold (III) complex acts as a Lewis acid, forming the propargyl carbocation 1 259 which undergoes Friedel Crafts type alkylation to form the new C C bond. Rearomatization delivers the final product 1 262 along with water, regenerating the active gold spe cies ( Figure 1 3 9 ) Regarding the construction of the second ring, the authors proposed formation of a benzylic carbocation, followed by nucleophilic attack of the terminal alcohol via S N 1 reaction. Allenes are very often difficult to be synthesiz ed; thu s, opinion the development of this reaction can positively impact the state of the art in

PAGE 63

63 terms of the synthesis of substituted allenes, mainly because the propargyl ic alcohol substrates are very easily prepared. Figure 1 39 Proposed catalytic cycle for the intermolecular gold catalyzed reaction of propargyl ic alcohols with arenes As previously mentioned, intermolecular dehydrative reactions of propargyl ic alcohols have potential utility and, a s a consequence, new reactivity as well as the design of asymmetric variants may be the object of future research in this area. These reactions can be applied to the preparation of a llenes which are well known synthetic building blocks that undergo many interesting transformations. Conclusions and Outlook The use of unsaturated alcohols in gold catalyzed substitution reactions is a burgeoning research area. The foundation for significant advancements has been established and the impetus to do so is clear ; the substrates are simple, the conditions

PAGE 64

64 are generally mild, the only byproduct is water, and the reactions can build complexity in a stereochemically defined manner. In the coming years, catalyst s for intermolecular reactions will become more sophisti cated and the reactions will likely be employed in increasingly more complicated settings for natural product and fine chemical synthesis.

PAGE 65

65 CHAPTER 2 CONTROLLING REGIOCHEMISTRY IN METAL CATALYZED SPIROKETAL SYNTHESIS FROM ALKYNOLS Spiroke tals: Importance and Synthesis Spiroketals or spiroacetals, are bicyclic ketals which contain one oxygen on each ring and are joined by a single carbon often called the spirocarbon. 55 Spiroketal containing molecules are found in nature and hundreds of thes e molecules have been isolated from insects, plants, bacterial and marine sources. 56 Their importance rel ies mostly on their interaction in living systems and, to date, a very broad range of biological activities ha s been associated with molecules that cont ain one or more spiroketal ring system s 56 57 There are two main ways by which spiroketals interact with enzymes triggering a biological response : first, spiroketa ls can be responsible for the biological activity itsel f or in other words, can be part of the pharmacophore of the molecule ; and second, their bicyclic structure can influence a particular molecular conformation needed for the ir high affinity with the ac tive site of the enzyme. 57 One of the most fascinating examples of how the structure of spiroketals can impact their biological activity come s from olean, a sex pheromone of olive fruit flies and the simplest spiroketal ever isolated (Figure 2 1) 58 Olean is a [6,6] spiroketal as it contains two six membered rings I nterestingly, the ( S ) enantiomer is active on the fe males of the olive fruit flies whereas the ( R ) enantiomer is active on the males Figure 2 1. Olean, the si mplest spiroketal isolated, and its biological activity

PAGE 66

66 Low molecular weight spiroketals isolated from nature such as olean are normally pheromones and can be utilized in the control of insect overpopulation in crops 59 On the other hand the most relevan t spiroketal containing natural products usually have a relatively large molecular weight (more than 4 00 g/mol) and display various biological activities such as anti mitotic antibacterial antiviral antiparasitic and antifung al 55 58 For instance, the rubromycins are human telorase inhibitors and, as a consequence, are lead compounds for cancer treatment (Figure 2 2) 60 The spiroketal moiety is essential for th is activity as the rubromycin 2 3 containing the spiroketal, is much more active than its open chain form rubromycin 2 4 Figure 2 2 The rubromycins and their corresponding activity as human telomerase inhibitors Along with the ru bromycins, large molecules containing spiroketals are innumerous and, herein we will foc us mostly on spiroketals that are not aromatics and that contain at least one unsaturation in the bicy clic system Okadaic acid 2 5 fits into this category by having a n unsaturated spiroketal as well as two others one saturated and one fused with a tetrahydropyran (Figure 2 3) 61 Okadaic acid is a polyketide which was first isolated from marine sponges and is a very selective and potent protein phosphatase type 1 (PP1) and type 2A (PP2A) inhibitor 62

PAGE 67

67 Figure 2 3. Okadaic aci d, a potent protein phosphatase inhibitor Relevance of Unsaturated Spiroketals M onounsaturated spiroketals are present in the structure of many natural products such as okadaic acid and are essen t ial for the biological activity encountered in salinomycin, 63 spirastrellolides, 64 phorbaketals, 65 alo ta ketals 66 and many other molecules (Figure 2 4) 67 Figure 2 4. Representative unsaturated spiroketals in natural products

PAGE 68

68 The presen ce of unsaturation in one of the rings can drastically impact biological activity and other properties of spiroketals most likely by modifying the conformation of the six member ring which due to strain, becomes more boat like In addition, the double bo nd moiety allows for further functionalization or simple reduction to generate saturated derivatives. 68 We would like to anticipate that the novel gold catalyzed synthesis of unsaturated spiroketals presented herein can solve problems regarding the preparat ion of both unsaturated as well as saturated spiroketals. R ecen tly, our group has been interested in using gold catalyzed cyclizations such as the ones presented in C hapter 1 for the preparation of the natural product spirastrellolide A a member of the s pirastrellolide family of molecules 69 The s pirastrellolide s are macrolides isolated from sponges such as Spirastrella coccinea which present very potent and selective PP2A inhibitor activity S everal biological studies have suggested that spiras trellolide A is a promising lead compound for cancer treatment 70 Our group has already utilized the cyclization of monoallylic diols for the synthesis of the tetrahydropyran ring of spirastrellolide A Chapter 2 focuses on the development of a cyclization toward its unsaturated spiroketal. In 2015, the popularity of unsaturated spiroketals increased because half of the Nobel Prize in Physiology or Medicine was awarded to Willia m C. Campbell and Satoshi Omura for their discoveries concerning a novel therapy for infect io us diseases caused by roundworm parasites (nematodes) 71 Th e novel therapy is essentially related to the discovery of avermectin, 72 a very potent antiparasitic which contains a mono unsaturated spiroketal (Figure 2 5). Following the discovery isolation an d ch aracterization of the avermectin s the researchers found that the spiroketal ring was essential for the activity

PAGE 69

69 H owever the double bond could be reduced to form antiparasitic and the molecule which is in fact administered as a drug. 73 Ivermectin is used in the treatment of many parasitic diseases such as river blindness, lymphatic filiarisis, head lice, scabies and strongyloidialisis among others. 74 The avermectins are structurally related to the milbemycins, a group of spiro ketal containing macrolides used as veterinary antiparasitic agents. 75 Figure 2 5 The structure of a vermectin B 1a The avermectins have currently been produced in large scale by microorganisms and, as a consequence, the commercialization of these molecules does not depend on chemical synthesis. 76 This is very fortunate as laborious synthesis would be required for the preparation of these structurally c omplex molecules. O ther highly complex natural products such as spirast rellolide A nonetheless, cannot be isolated in large quantities from the sponge thus making biological a ssays dependent on organic synthesis 70 Currently s piroketal synthese s are very popular among synthetic chemists as a tool for studying the chemistry and biochemistry of spiroketal containing molecules. Acid Catalyzed Synthesis of Spiroketals Using Ketodiols The biosynthesis of volatile spiroketals is well known for some species of flies where fatty acid s ynthases usually play an important role 77 The biosynthetic pathways

PAGE 70

70 may vary slightly according to the different species, but in most cases ultimately a ketodiol substrate is proposed as an intermediate. For instance, the major sex pheromones of pestiferou s fruit flies have been demonstrated to come from fatty acids by using labelling experiments. 78 A decarboxylation of the ketoacid intermediate 2 11 in combination with a remote C H oxidation in 2 13 generates the putative ketodiol which cyclizes to form a mixture of the spiroketal s 2 14 and 2 15 (Figure 2 6) Figure 2 6 Proposed biosynthesis of pheromones of olive fruit flies different spiroke rees that ketodiol s are key intermediate s The synthesis of spiroketals from ketodiols was easily recognized by organic chemists as the best and the simplest way for making these important class es of molecules. 55 As a consequence, t he pioneering synthesis of spiroketals employ ketodiols as substrates, and currently, almost fifty years after these initial studies, the Br nsted acid catalyzed spiroketal synthesis is stil l the most reliable and robust method for making these molecules 56 Evans and coworkers have nicely demonstrated that both

PAGE 71

71 spiroketals 2 18 and 2 20 of spongistatin 2 2 16 could be made using this strategy (Fig ure 2 7) 79 The s ynthesis of 2 20 is particularly extraordinary as the magnesium salt seems to favor the equilibrium toward the non anomeric spiroketal through preferential complexation. Figure 2 7 Evans synthesis of t he spiroketals of the natural product spongistatin 2 There are innumerous examples of ketodiols as synthetic intermediates in the synthesis of highly complex spiroketal containing molecules I mportant contributions to this field have been made by many dif ferent groups in the world and this cyclization is employed in a wide variety of settings 55 57 Various acidic catalysts can be used under

PAGE 72

72 many different conditions to achieve success and this will at least in the near future continue being the most employed method for making spiroketals Metal Catalyzed Synthesis of Spiroketals Using Alkynols The development of metal catalyzed spiroketal synthesis from alkynedio ls can ultimately be related to two very important pieces of information regarding alkynes: first, alkynes are well known carbonyl surrogates, 80 or more specifically, internal alkynes are ketone surro gates; and second, as shown in C hapter 1, alkynes can eas ily be activated by acidic late transition metals toward nucleophilic attack. 81 Thus, it is not very surprising that metal catalyzed cyclois omerization s of alkynediols 2 23 are currently an alternative to the Br nsted acid catalyzed cycl ocondensation of corresponding ketodio ls 2 21 toward spiroketals 2 22 (Figure 2 8 ) 82 Figure 2 8 The t wo most common strategies for spiroketal synthesis The cycloisomerization of alkynediols was first reported in 198 3 by Utimoto using palladium catalysts 83 a nd since this report many others based on iridium, 84 rhodium, 84

PAGE 73

73 platinum, 85 gold, 86 silver 87 and mercury catalysts have appeared 88 While the development of the transition metal catalyzed cycloisomerization is not unexpected, one simple question arises: why are chemists interested in using more precious catalysts to accomplish what could potentially be done in high robustness and reliability using very simple and cheap Br nsted acid catalysts? There are definitely r easons why alkynediols can, in some circumstances, be advantageous in the synthesis of complex spiroketals such as : 89 1) alkyne reactivity is orthogonal to ketone reactivity thus enhanced kinetic stability toward, for instance, reduction s with metal hydrid es can be observed throughout a difficult total synthesis; 2) a lkynes offer complementarity in terms of substrate preparation; 3) even though reactions using Br nsted acids are robust, problems may arise when acid sensitive substrates are employed and, in this context, the reactions using acids are generally carried out under much milder conditions; 4) t he cyclizations of ketodiols usually give rise to thermodynamic distribution of spiroketals, while metal catalyzed reactions can generate non therm odynamic spiroketals because it proceeds through a different mechanism; 5) cycl ization of alkynediols are highly exothermic ( H is approximately 46 .42 kcal/mol) whereas cycl ization of ketodiols are m ostly entropically driven ( H is only 1.17 kcal/ mol). W hile all of the aforementioned features can be advantageous, there is a clear financial disadvantage of using more expensive catalysts Nonetheless, this financial aspect is not really a major concern as spiroketal syntheses are usually performed in highly valuable materials 90 The major drawbac k of using al kyn es is according to this related to the intrinsic l ack of regioselectivity in the cycloisomerization as both carbons of the alkyne can be attacked by the nucleophile giving rise to a n

PAGE 74

74 undesired mixture of spiroketals (Fig ure 2 9 ) 82 For instance, if the simple alkynediol 2 24 is used as the substrate, a 6 [exo] cyclization would generate the [6,6] spiroketal 2 27 whereas a 5 [exo] cyclization would furnish a [5,7] spiroketal 2 30 T he distribution of the spiroketal products w ould in this case, depend solely on the rates of the competing cycliz a tion s Furthermore, crude reaction mixtures can be much more complex as mixture s of diastereomers are synthesized when substrates are ch iral which is often the case In practical terms, using alkynediols as substrates in the synthesis of spiroketals can be problematic because synthetic chemists do not want to take the risk of having to deal with complex mixture of compounds at a late stag e of a total synthesis 91 In other words, synthetic chemists would avoid relying on rates of cyclization because high selectivity is a very important factor in the synthesis of complex molecules. 92 Figure 2 9 Lack of reg ioselectivity in metal catalyzed spiroketalization of alkynediols Chapter 2 will address th e regioselectivity issue that ar ises from metal catalyzed spiroketal synthesis from alkynols. In the next sections, a reaction that was discovered

PAGE 75

75 in our laboratory in 2008 which led us to a possible solution to this gen eral problem in metal catalyzed spiroketal synthesis is presented Gold Catalyzed Synthesis of Spiroketals Using Monopropargylic Triols In 2008, our group developed the gold catalyzed dehydrative for mal S N cyclization of monoallylic diols 2 31 toward tetrahydropyrans 2 32 (Figure 2 10 ) 11 In this context allenoether such as 2 34 could potentially be formed from 2 33 if a similar mechanism was operative 43 The incorporation of a pendant oxygen nucleophile to the substrate ultimately gave rise to unsaturated spi roketals 2 35 after the allenoether 2 34 undergoes a second cyclization. Figure 2 10 Gold catalyzed synthesis of tetrahydropyrans and the synthesis of monounsaturated spiroketals The gold catalyzed cyclization of mono propargylic triols 2 36 toward monounsaturated spiroketals 2 3 7 is carried out under mild conditions and very short reaction times, delivering various spiroketals in very good yields (Figure 2 1 1 ) 43 The optima l catalytic system for this reaction was achieved by the use of (JohnPhos)AuCl in the presence of AgOTf as a chloride scavenger.

PAGE 76

76 Figure 2 1 1 Gold catalyzed synthesis of spiroketals from monopropargylic triols The mai n advantage of the gold catalyzed synthesis of monounsaturated spiroketals is related to the easy preparation of the monopropargylic triol substrates. The retrosynthetic analysis of the traditional acid catalyzed spiroketal synthesis and our gold catalyzed synthesis toward 2 45 shows that if not advantageous, our synthesis is complementary to the traditional spiroketal synthesis (Figure 2 1 2 ). One of the main problems in the traditional synthesis is the preparation of the unsaturated ketodiol 2 46 with the required cis double bond. 93 Compounds such as 2 46 are usually prepared from propargyl alcohols 2 47 after tedious oxidation and reduction reactions in which stoichiometric metal based reagents are employed. Other appr oaches are also dependent on tedious steps such as, for example, highly cis s elective olefination s. In the spiroketal synthesis reported by our group, these redox steps are unnecessary as

PAGE 77

77 propargyl alcohol s such as 2 50 are employed as substrate s in the cy clization. Another interesting aspect is the complem entarity of these two different approaches While in the traditional synthesis the alkyne 2 48 becomes part of the ring A in the spiroketal 2 45 in the gold catalyzed spiroketalization the alkyne 2 53 be comes part of its ring B. Similarly, the aldehydes become part of different rings in the spiroketal, as the aldehyde 2 49 is eventually part of the ring B in the traditional synthesis and the aldehyde 2 52 is part of the ring A in the gold catalyzed cycliz ation. Figure 2 1 2 Retrosynthesis analysis comparing the traditional and gold catalyzed synthesis of monounsaturated spiroketals Another feature of the gold catalyzed synthesis of monopropargylic triols i s related to it s selectivity. Initially, the reaction s were highly selective toward the dehydrated spiroketal s even when the parental compound 2 38 was synthesized (Figure 2 1 1 ). 43 This is a remarkable feature since spiroket als derived from gol d

PAGE 78

78 catalyzed cycloisomerization of alkynediols could have been easily synthesized under the same conditions. The high selectivity observed in the reactions was a strong indication that the rate of the dehydrative spiroketalization w as gr eater than the rates of the competing cycloisomerizations. Unfortunately, this was not true for all the substrates. Our group first observed that the diastereomeric pair 2 54 and 2 56 had completely different cyclization patterns (Figure 2 1 3 ) While the 1 ,3 anti diol 2 54 reacted under the standard conditions to give the desired spiroketal 2 55 in excellent yield, the 1,3 syn diol 2 56 gave a complex mixture of the spiroketals 2 55 2 57 and 2 58 The undesired diastereomeric pair 2 57 and 2 58 originated from competing gold catalyzed cycloisomerization reactions. Figure 2 1 3 Poor selectivity in the gold catalyzed spiroketal synthesis from monopropargylic triols observed by Aponick Later on, Forsyth and coworkers observe d the same proble m when applying our method to their synthesis of one of the spiroketal s present in okadaic acid (Figure 2 1 4 ) 94 The cyclization with the 1,3 anti diol 2 5 9 gave 65% yield of the desired spiroketal 2 60 whereas using the 1,3 syn diol 2 61 g ave only 16% yield of 2 60 In the cyclization

PAGE 79

79 of 2 61 the major compound in the crude reaction mixture was the undesired spiroketal 2 62 which was formed in 75% yield. Figure 2 1 4 Poor selectivity in the gold catalyz ed spiroketal synthesis from monopropargylic triols observed by Forsyth The aforementioned problems of selectivity are exacerbated by the following reason: this spiroketalization was designed so that both diastereomers could undergo the cyclization to give the same spiroketal product. This is possible because the propargyl alcohol stereocenter is lost during the cyclization event. Thus, the ideal synthetic sequence is realized through a n unselective alkynylation of an aldehyde, followed by the spirocyclizat ion This was exactly what the Forsyth group attempted to realize ; however, because the diastereomer 2 61 failed, they were forced to transform 2 6 4 into the diastereomer 2 65 to move on in their total synthesis with the maximum amount of material (Figure 2 1 5 ). 94

PAGE 80

80 Figure 2 1 5 and the completion of the synthesis of the spiroketal With the proper amount of the 1,3 anti diol 2 59 the Forsyth group completed the synthesis of the saturated spiroketal 2 67 which is a fragment of okadaic acid. 94 This synthe tic route highlights that the spiroketal synthesis developed in our group can be also utilized for the synthesis of saturated spiroketals as a very simple and high yielding double bond reduction can follow the cyclization In fact, the double bond reduction and the benzyl group deprotection occurred in the same pot, thus the red uction of the double bond synthesis. Gold Catalyzed Synthesis of Spiroketals Using Acetonides Our goal when designing the reaction presented herein was to solve the selectivity issues encountered in our own gold catalyzed spiroketalization of monopropargyl ic triols During the development of this project we realized that, in fact, the problem of selectivity in spiroketal synthesis from alkynols is much more general since the cyclizatio n of alkynediols also has a major limitation regarding its

PAGE 81

81 regioselectivity. As a general rule when two nucleophiles are available, competing cyclizations may occur at both alkyne carbons, regardless which metal catalyst and reaction conditions are employ ed. To solve this problem, De Brabander report ed a platinum catalyzed cyclization of monoprotected alkynediols; however, controlling the separate cyclization and the in situ deprotection events is extremely challenging. 85 To overcome these issues and allow for a more robust method, we postulated that competing reactions could be precluded by a method where the rates of cyclization would no longer dictate the product distribution. To this end, we decided to expl ore the feasibility of a gold catalyzed deacylative cyclization of acetonides 2 68 for the selective formation of [6,6] monounsaturated spiroketals 2 69 (Figure 2 1 6 ) 95 Figure 2 1 6 The regioselective deacylative cycli zation of acetonides toward spiroketals The synthesis of acetonides such as 2 68 can be easily accomplished from the corresponding monopropargylic triols using a redox neutral condensation between a diol with an acetone equivalent, which is carried out und er mild conditions and does not generate stoichiometric waste. 96 Furthermore, acetonides are widely used protecting groups and, in the case of a successfull spiroketalization, the only byproduct formed would be acetone, which is easily remov ed from the reac tion mixture. General Idea for Controlling the Regioselectivity Using Acetonides As previously discussed, the metal catalyzed synthesis of spiroketals from alkynediols and the gold catalyzed synthesis of monounsaturated spiroketals have a

PAGE 82

82 major drawback r egarding regioselectivity. In the case of the cycloisomerization of alkynediols 2 70 the cyclization occur s to give [5,7] and [6,6] spiroketals such as 2 71 and 2 72 respectively (Figure 2 17) In our reaction, the outcome can be even more complex, as t here is a competition between the dehydration, which forms the spiroketal 2 74 and the cycloisomerization, which forms the spiroketals 2 75 and 2 76 The outcome of these reactions is completely dependent on the rates of the corresponding cyclizations Figure 2 17. Selectivity issues on metal catalyzed spiroketal synthesis from alkynols In order to solve this problem, we assumed that the development of a method where the rates do not determine product distribution would be extremely useful. Taking inspiration from our own cyclization of monopro pa rgylic triols we hypothesized that we by making an acetonide in the 1, 3 diol portion of the molecule (Figure 2 18). 95 By u tilizing an acetonide, only one nucleophile would be available in the beginning of the reaction and the first gold catalyzed hydroalkoxylation would, in principle, occur without major problems. The second step is

PAGE 83

83 cruci al since we did not know, at the outset, whether or not acetone could be a leaving group in this reaction. A successful elimination of acetone would turn the catalyst over, forming the allenoether 2 79 a key intermediate The elimination of acetone reveal s the second nucleophile in situ, and this is the reason why this r eaction can be highly selective. T he second nucleophile is available only when the first cyclization is already complete The synthesis of the desired spiroketal 2 74 from the intermediate 2 79 had previously been demonstrated and it should be a very fast process even under mildly acidic conditions. 43 Figure 2 1 8 Gold catalyzed synthesis of monounsaturated sp iroketals from acetonides It is worth mentioning why gold catalysts were chosen for the initial optimization of this reaction, as there are many other acidic late transition metals that could also be considered. First, the initial hydroalkoxylation can probably be accomplished using many different metal based catalysts; however gold complexes are comparatively the most acidic of all. 1 Second and probably the most important, a much less common elimination step has been previously demonstrated by our group using gold catalysts Thus, it was a combination between these two factors which led us to believe that gold catalysts could be the most suitable for this transformation. Nonetheless, other catalysts based on other acidic metals can in principle function well in these reactions.

PAGE 84

84 Reaction Optimization The optimization of the reaction started with a large scale preparation of the monopropargylic triol 2 80 which was chosen for two main reasons: first, the triol 2 8 0 was easily sy nthesized in a gram scale (see C hapter 5 for substrate preparation); and second, because the only chiral center in this molecule is at the propargyl alcohol position so this molecule does not present diastereomers. We then tested the reactiv ity of the triol 2 80 in the gold catalyzed spiroketalization It is important to mention that throughout this discussion there will be always a comparison between triols and acetonides on the same reaction so the reader can have a sense of whether or not making an acetonide is necessary. 95 As it turns out, the triol 2 80 gave only very low yields of the spiroketal 2 81 under the two standard gold catalyzed conditions previously published by our group (Figure 2 19). The analysis of the crude reaction mixture by 1 H and 13 C NMR showed a very complex mixture. The starting material was fully consumed but other spiroketals were also present. Presumably, the other spiroketals are formed via cycloisomerization reaction and are analogous to 2 75 and 2 76 (Figure 2 17). Unfortunately these compounds could not be separated from the complex mixture and cha racterized, but these side products are believed to be saturated spiroketals. Figure 2 19. Unsuccessful gold catalyzed cyclization of monop ro pa r gylic triol 2 80

PAGE 85

85 The unsuccessful cyclization of 2 80 encouraged us to prepare the acetonide 2 82 in order to test our hypothesis. With 2 82 in hand, several gold (I) complexes were screened, usi ng THF as the solvent ( Figure 2 20 ). 95 The reactions were all carried out for one hour and, i n con trast to our previously reported method for the cyclization of triols, 43 molecular sieves were not necessary because water would no longer be generated in this new process. Gold (I) complexes containing phosphine, phosphite, NHC carbene and sulfide as ligands were screened and were fairly unsuccessful. H owever, using AuC l as the catalyst gave the best yield, furnishing the desired product 2 81 in 48% isolated yield with 5 mol % of catalyst loading Increasing the catalyst loading to 10 mol % of AuCl improved the yield to 67% and these conditions were deemed optimal. This substrate appears to be fairly challenging likely due to the steric hindrance added by the two n butyl substituents (see mechanism section for details ). Figure 2 20 Optimization of the gold catalyzed spiroketalization using a n acetonide

PAGE 86

86 Importantly, the cyclization of the acetonide 2 82 was much higher yielding in the direct comparison with the corresponding triol 2 80 67% versus 25% yield (Figures 2 19 and 2 20) Moreover, a much cleaner reaction was also obtained w ith the acetonide which simplified the purification process. Th is was a promising result and set the stage for the development of the gold catalyzed spiroketalization presented. Reaction Scope Having established the optim al conditions, the scope of the r eaction was studied. 95 For reference, it was important to compare results of the acetonides with the corresponding triols. The acetonides 2 83 and 2 84 were very important ones, because their corresponding trio ls 2 54 and 2 56 were previously tested in our laboratory and the results were somewhat int riguing A s mentioned before the 1,3 anti diol 2 54 works really well in the reaction, giving a 94% yield of the spiroketal 2 55 ; however, the cyclization of the 1, 3 syn diol 2 56 gives a complex mixtures of spiroketals and only 31% yield of the desired spiroketal could be isolated (Figure 2 13) The cyclizations of the acetonides 2 83 and 2 84 worked well for both diastereomers instead, providing the spiroketal 2 55 as a single diastereomer in 72 and 74% isolated yield respectively with no trace of saturated spiroketal side products (Figure 2 21) This was a very encouraging result because it is a clear demonstration that one can succeed when using both diastereome rs in the spiroketalization. The use of both diastereomers as substrates in the spiroketalization is at the heart of this project because this essentially means that an unselective alkynylation step can be used for the preparation of a propargyl alcohol h ighlighting the easy disconnection of our spiroketal synthesis.

PAGE 87

87 Figure 2 21. Use of diastereomer ic acetonides 2 83 and 2 84 in the spiroketal ization As substrate stereochemistry can aff ect the spiroketalization, add itional subst itution patterns were explored and 1,2 substitution in the 1,3 diol moiety was evaluated. 95 The t riols 2 85 and 2 88 as well as the corresponding acetonides 2 87 and 2 89 were prepared and expose d to the reaction conditions ( Figure 2 22 ) With these substrates, the difference between the triols and the acetonides was even more pronounced. The cyclization of the triols 2 85 and 2 88 furnished the desired spiroketal 2 86 in only 15% yield in both ca ses whereas the cyclization of the 1,2 cis acetonide 2 87 and the 1,2 trans acetonide 2 89 gave the desired spiroketal 2 86 in 77% and 67% yields, respectively. The reactions were carried out in Et 2 O instead of THF because the desire d spiroketal 2 86 is v olatile. This set of substrates presented the greatest differences between the cyclization of acetonides and triols Interestingly, both diastereomers of the triol failed, which essentially shows that using acetonides is the only solution for the synthesis of the unsaturated spiroketal 2 86 using our chemistry.

PAGE 88

88 Figure 2 22. Expanding the scope of the reaction with acetonides 2 87 and 2 89 The substrates 2 90 and 2 92 w ere particularly important because the ir stereochemi stries are found in the monounsaturated spiroketal of the spirastrellolides. 69 Cyclization of the triol 2 90 proved to be extremely difficult, and the spiroketal 2 9 1 could be isolated in only 10% yield from a very complex crude reaction mixture. In contrast, the cyclization of the acetonide 2 92 delivered 2 9 1 in 52 % yield (Figure 2 23) This was an important result in our laboratory as our group was, at the same time, interested in the synthesis of the monouns aturated spiroketal of the spirastrellolide A. The diastereoselectivity in the synthesis of the unsaturated spiroketal 2 9 1 was very high, with a ratio of 16:1 when starting with both substrates 2 90 and 2 92 In all previous cases, the diastereoselectivi ty did not depend on whether an acetonide or a triol was used. This is a strong indication that the reactions are under thermodynamic control or, in other words, the diastere o selectivity directly correlates to the energy difference between the major and th e minor spiroketals.

PAGE 89

89 Figure 2 2 3 Model studies for the spiroketal of the spirastrellolides Further evidence that the reactions are under thermodynamic control comes from a series of experiments that were run early i n my PhD program months before we designed the spiroketal synthesis from acetonides. We prepared the chiral enantioenriched substrate 2 94 enantioselective transfer hydrogenation to set the propargyl alcohol stereoc enter The triol 2 94 was then submitted to more than ten different reaction conditions in order to evaluate if the chirality could be transferred to the product via formation of the chiral allenoether 2 95 (Figure 2 24). Different gold catalys ts and condi tions were tested; h owever, the enantiomeric excess measured for the product 2 39 w as invariably 0% in all the reactions. While the loss of enantiomeric excess can be caused by many different factors, the thermodynamic equilibration of the product would ea sily explain why the enantiomeric excess w as always 0%. It is more likely that at least low enantiomeric excesses would have been observed if other factors played a major role in the erosion of selectivity during the spiroketalization.

PAGE 90

90 Figure 2 24. Attempted transfer of chirality in the gold catalyzed spiroketalization In order t o evaluate if the spirocyclization of acetonides could be more general than the cyclization of triols the substrate 2 97 was synthesized. H owev er, it should be noted that, in this case the corresponding triol 2 96 works really well for the synthesis of the spiroketal 2 39 (Figure 2 25) 95 As it turns out, the acetonide 2 97 does not adversely affect the cyclization, delivering the unsaturated spiroketal 2 39 in 74% yield under the standard conditions, compared to 81% yield for the triol. It is possible that the gem diphenyl group in 2 96 increases the rate of the 6 [exo] dig hydroalkoxylation ( Thorpe Ingold effect ) to the point where controlling the order of cyclization events by employing the acetonide is unnecessary. 97 Figure 2 2 5 Similar yields for a triol and for the corresponding acetonide in the gold catalyzed spiroketalization reaction The most challenging substrates employed in this project were the triols 2 98 and 2 101 as well as their corresponding acetonides 2 100 and 2 10 2 (Figure 2 26) The sterics w ere significantly increased with the introduction of a very bulky isopropyl group adjacent to the methyl group in the diol moiety More bulky substituents such as t butyl

PAGE 91

91 groups could probably be incorporated which would be fundamentally interesting; however this would not have practical meaning in natural product synthesis, as isolated spiroketals do not usually encompass extremely bulky substituents. 56 The triols 2 98 and 2 101 were submitted to the standard gold catalyzed conditions and essentially failed comp letely. For the triol 2 98 no traces of the desired spiroketal was observed in the crude reaction mixture. On the other hand, the corresponding acetonide 2 100 gave a 50% yield of the unsaturated spiroketal 2 99 as a 12:1 mixture of diastereomers. In the cyclization of triol 2 101 the spiroketal 2 99 was isolated in only 10% yield, with the same 12:1 dr. Interestingly, the cyclization of the corre sponding acetonide 2 102 also gave a poor yield of 37% but for the first time the observed dr was changed wit h 2 99 being isolated as a 2:1 mixture of diastereomers. The reason for this difference in diastereoselectivity in the cyclization of 2 100 and 2 102 is not well underst ood at this point but it seems that the cyclization of 2 102 is so difficult that the reaction mechanism changes. As mentioned before this w as a very problematic set of substrates in which the only reasonable yield was obtained with the acetonide 2 100 Figure 2 2 6 The most difficult substrates in the gold catalyzed spiroketal synthesis

PAGE 92

92 Since the early stages of this project, our main goal was to develop a robust methodology for the synthesis of monounsaturated spiroketals in order to utilize the reaction in the synthesis of spirastrellolide A. The sp irastrellolide project was initiated in our laboratory prior to my arrival to the group, and the synthesis of the spiroketal was concluded by my labmate Dr. Barry Butler in 2015 69 To summarize the results our group found that the use of an acetonide was essential because its cyclization was much superior to the cyclizati on of the corresponding triol. After several attempts, the reaction was optimized to the point where the cyclization of the mixture of diaster eomers 2 10 3 occurred smoothly in one minute, in dichloromethane as the solvent delivering the spiroketal 2 10 4 in 99% isolated yield. T his reaction did not work with AuCl as decomposition was mostly observed in the crude reaction mixture upon use of this catalyst ; however, it was enabled by the use of Me 3 P as the ligand for gold. In the mechanism section the hypothesis for why possibly very small and electron rich phosphines such as Me 3 P are used successfully in this reaction will be presented Figure 2 2 7 At the same time we published our synthesis of the spiroketal 2 10 4 the group of Amos Smith III reported a very elegant use of our reaction toward the uns aturated spiroketal of the spirastrellolide E 98 There are many similarities between the two

PAGE 93

93 reports; however, our findings related to the use of acetonides in combination with the Me 3 P AuCl catalyst were unique and seemed to solve all the problems in this c yclization. Reaction Mechanism There are at least two main reaction mechanisms which can explain the outcome of the gold catalyzed spiroketaliza tion of acetonides The first proposed catalytic cycle will herein be called the allenoether pathway. In this cy cle, it is postulated that the gold (I) activates the triple bond in 2 105 for the nucleophilic attack of the pendant hydroxyl group across the alkyne, to generate the vinyl gold intermediate 2 10 7 via a 6 [ exo ] dig cyclization ( Figure 2 28 ). The free hydr oxyl present in 2 105 will exclusively act as the nucleophile, while the other nucleophile is masked in the form of the acetonide, and is revealed through out the course of the reaction. In the key step, the vinyl gold intermediate 2 10 7 undergoes eliminati on of gold and extrusion of acetone, forming the intermediate allen o ether 2 10 8 and unmasking the second hydroxyl group. U pon reactivation by gold (I), the vinyl gold oxocarbenium 2 109 is formed, followed by the second cyclization, furnishing the monounsa turated spiroketal core of 2 110 Lastly, protodeauration of 2 110 is responsible for the catalyst turnover and for the formation of the desired spiroketal 2 111 Alternatively, 2 108 can undergo Br nsted acid catalyzed cyclization to furnish 2 11 1 in a pr ocess similar to other well known spirocyclizations 99 In the proposed catalytic cycle, the first hydroalkoxylation is likely a fast process in the presence of gold (I) catalysts and innumerous examples of this process are found in the literature. 1 3 2 108 toward spiroketal 2 111 is also fast under slightly acidic conditions, as observed in various spiroketal synthes e s. 99 Because of these r formation of 2 108 from the vinyl gold intermediate 2 107 is proposed to be the rate

PAGE 94

94 determining step of this catalytic cycle and it is possible that hydrogen bonding plays a major role in this step. 18 In other words, t he hydrogen bonding previously proposed in the addition/ elimination sequence can be extended to this spiroketalization 18 Figu re 2 28. The allenoether pathway in the gold catalyzed synthesis of spiroketals The second p roposed catalytic cycle will be called the diene pathway (Figure 2 29) In this cycle, the formation of 2 107 happens in the same way it does in the allenoether pa thway. F ormation of the enol 2 11 3 from the common intermediate 2 107 is subsequently proposed via enol ether equilibrium. E limination of acetone and regeneration of the gold (I) species from the intermediate 2 113 generates the intermediate 2 114 The d iene intermediate 2 114 can cyclize under gold catalyzed

PAGE 95

95 conditions or simply under slightly acidic conditions, delivering the monounsaturated spiroketal 2 111 Figure 2 29. The diene pathway in the gold catalyzed synth esis of spiroketals The two me chanisms have some similarities. F or example, the first and the second cyclizations (hydroalkoxylations) are very similar and should take place without major problems. The elimination of acetone also has some similarities; ho wever, the double bond position differs between the two mechanisms I n the allenoether pathway the double bond is exocyclic before the elimination step whereas in the diene pathway the double bond is endocyclic. However, t he main difference between the two catalytic cycle s is related to the enol equilibrium which occurs from the intermediate 2 107 to the

PAGE 96

96 intermediate 2 113 This equilibrium has to occur in the diene pathway for the reaction to proceed and the question that arises is whether or not this is a possibility. The formation of 2 112 from 2 107 is a very facile process in gold catalysis as this is likely the first step of a protodeauration in vinyl gold species (Figure 2 30). While this is fast the formation of 2 113 from 2 112 is competing with the corresponding protodeauration to generate the intermediate 2 11 6 It is possible that if the diene mechanism was operative, substantial formation of unproductive side products such as the enol ether 2 11 6 would be observed in the reactions but this wa s n ot the case. Nonetheless, it is important to mention that the diene pathway cannot be ruled out on this argument because formation of 2 116 from 2 112 is reversible. Figure 2 30. Possible intermediates in the diene p athway During the development of our gold catalyzed spiroketalization, we hypothesized that the allenoether mechanism could be operative To test this mechanistic hypothesis, we designed an experiment with the triol 2 117 and with the acetonide 2 119 The se compounds were prepared and subjected to the standa r d conditions (Figure 2 31). T he formation of a n intermediate such as 2 113 would be precluded in these reactions because 2 117 and 2 119 contain a gem dimethyl group at the propargylic position. The

PAGE 97

97 tw o reactions took place smoothly, delivering the spiroketal 2 118 as the major product under the optimized gold catalyzed conditions The yields were somewhat low due to the volatility of the spiroketal product This result suggests that an allenoether such as 2 108 is most likely formed during th ese cyclization s and is good evidence that the allenoether pathway is operative, at least for these substrates However, the diene pathway cannot be ruled out for other substrates where proton shuttling at the propa rgylic position is a possibility Figure 2 31. The incorporation of gem dimethyl groups at the propargylic position Further strong support for the allenoether mechanism comes from the cyclization of the substrate 2 1 2 0 Ideally, we were interested in the characterization of the intermediate 2 108 ; however, because this intermediate readily cyclizes and cannot be isolated, we sought for the possibility of characterizing a similar intermediate, the allenoether 2 1 22 (Fig ure 2 32) To accomplish this task, we prepared substrate 2 1 20 containing a propargylic gem dimethyl groups in order to avoid tautomerization of the allen o ether to a diene via proton transfer. This tautomerization was in fact utilized in our group for the preparation of indolocarba z ole alkaloids via a gold catalyzed cyclization/Diels Alder sequence. 100 Furthermore 2 1 20 contains a silylether at the propargylic position. This functionality was employed so that the leaving group would not be as nucleophilic as water, since gold catalyzed Meyer Schuster rearrangement or

PAGE 98

98 hydration reactions can easily take place if water is the leaving group. 101 The compound 2 1 20 was then reacted with 102 in THF, forming the compound 2 1 21 in less than 20 min. While we did not observe the formation of allenoether 2 1 22 compound 2 1 21 was most likely formed from a gold catalyzed formal [2+2] cycloaddition of two molecules of 2 1 22 103 A similar process was very recently reported by Shi and coworkers, suppor t i ng the putative formation of 2 1 22 104 To the best of our knowledge, this is the first evidence for the formation of an allenoether such as 2 1 22 in the context of gold catalyzed cyclization of propargylic alcohols and ethers. Figure 2 32. The gold catalyzed dimerization of the allenoether intermediate 2 122 The proposed mechanism for the formation of 2 121 begins with a 5 [exo] dig cyclization and elimination of t butyldimethylsilyl alcohol for the formation of two molec ules of the allenoether 2 122 The allenoether 2 122 is activated by gold (I)

PAGE 99

99 species to form the Michael acceptor vinyl gold oxocarbenium 2 125 (Figure 2 33) A Michae l addition reaction takes place between the intermediates 2 122 and 2 125 generating a vinyl gold oxocarbenium 2 126 Intramolecular cyclization forms the spirocycl e 2 127 containing a 4 membered ring. Finally, elimination of the gold (I) catalyst generates the compound 2 121 which is essentially a [2+2] dimer of 2 122 Figure 2 33. Proposed mechanism for the dimerization of the allenoether 2 122 In summary, all the mechanistic studies combined show that the allenoether pathway is likely to be operative in the gold catalyzed spiroketalization of aceto ni des. However, at this point, the diene pathway cannot be completely ruled out as an alternative mechanism. In addition to the aforementioned studies, it would be relevant to understand why distinct gold catalysts gave such different results during the rea ction optimization or in other words, the reason why only AuCl was a suitable catalyst during the reaction optimization (Figure 2 20). Moreover, we were interested in understanding why different substrates gave a broad range of y ields whic h varied from 3 7 to 77 %, under the standard conditions In an attempt to understand these variations, the transition state in

PAGE 100

100 the proposed rate determining st ep was analyzed in a qualitative way. The substrate 2 80 was chosen as a model because different gold catalysts w ere reacted with 2 80 under the same condition s during the optimization (Figure 2 20). The rate determining step for the gold catalyzed spiroketal synthesis is proposed herein to be the elimination step because both the hydroalkoxylation events are known t o be facile processes (Figure 2 34). As it turns out, it is proposed that the energy of the transition state for the formation of the allenoether 2 129 from the vinyl gold intermediate 2 128 plays a major role in the reaction. Figure 2 34. Elimination as the rate determining step for the cyclization of acetonides Th e transition s t ate in the elimination step should resemble the structure of the intermediate 2 128 because 2 129 is likely much more stable than 2 128 mainly due to strain release As a consequence, an early transition state is proposed according to the 105 In addition to this, a partial positive charge should be formed

PAGE 101

101 o n the gold atom in the cleavage of the Au C bond whereas a par tial negat ive charge is formed o n the oxygen atom in the C O bond cleavage. Taking all this information into consideration, the transition st ate 2 130 is proposed (Figure 2 35). Figure 2 35. The proposed transition state for the gold catalyzed spiroketalization The transition state 2 130 shows very destabilizing syn pentane interactions between one of the R group s and the gold atom, 106 thus small ligands should lower the energy of th is transition state by reducing its sterics (Figur e 2 36) Additionally, the creation of partial positive charge on the gold center can be stabilized if the gold center is electron rich. Interestingly, AuCl satisfies the two conditions F irst the chloride ligands should be smaller than the bulky phosphine s the phosphite and the NHC carbene tested during optimization Second AuCl is neutral and as a consequence is much more electron rich than the highly electrophilic cationic gold species formed upon react ion of the gold catalysts with silver salt s such a s AgOTf and AgBF 4 (Figure 2 20). Another piece of evidence of how a small and less electrophilic gold center can play a major role in this reaction was found by Dr. Barry Butler in the synthesis of the spiroketal of spirastrellolide A. During the synthesis of the spiroketal of spirastrellolide, i t was found that Me 3 PAuCl in combination with silver salts is the optimal catalytic system for the spiroketalization. 69 Me 3 P as a ligand also satisfies both requirements considering that Me 3 P is the smallest tertiary phosphine and that trialkyl phosphines are

PAGE 102

102 in general more nucleophilic than aryl substituted ones, making the gold relatively more electron rich. Figure 2 3 6 The influe nce of gold catalysts in the transition state of the reaction Another interesting feature of this transition state is that a correlation can be made between the yields of the reactions and their expected transition state energy, based on non bonding intera ctions (Figure 2 37 and 2 38). Figure 2 37. The influence of substituents in the transition state of the gold catalyzed spiroketal synthesis from acetonides

PAGE 103

103 As a general rule, t he reaction yield is usually inversely pr oportional to the number and extent of the non bonding steric interactions in the transition state (Figure 2 37 and 2 38). There are two main destabilizing interactions which are either the presence of substituents in the axial position of the transition s tate or the syn pentane interactions. In this model, e nantiomers were sometimes drawn for a matter of comparison of the drawings and this does not affect the energy of the transition state Figure 2 3 8 The influence of substituents in the transition state of the gold catalyzed spiroketal synthesis of more hindered acetonides The proposed model correlating yield and steric interactions in the transition state is qualitative and should be seen essentially as a hypothesis of why the yield of

PAGE 104

104 the reactions can vary so much depending on the substrate utilized. It is important to mention that the rates of reactions were not measured; however, increasing the energy of the transition state of the desired reaction could in prac tice, favor undesired reactions such as protodeauration of the vinyl gold intermediate, which can contribute to decrease in reaction yield. Conclusions and Outlook In summary, the chemistry outlined in Chapter 2 shows that it is possible to overcome the r egioselectivity issues in the metal catalyzed spiroketalization of alkynols. The new developed method utilizes an acetonide to function as a regioselectivity regulator in the production of monounsaturated spiroketals It is fortuitous that this common prot ecting group serves this purpose and that either saturated or functionalized spiroketals can easily be prepared from these compounds Our group has utilized this method for the preparation of the unsaturated spiroketal of 1 spirastrellolide A, where the us e of an acetonide proved to be essential for achieving efficient cyclization. This synthesis complex settings. The reaction conditions ar e very mild and the reaction seems to be very robust. The synthesis of okadaic acid by Forsyth, and the synthesis of the monounsaturated spiroketal of the spirastrellolides by Aponick and Amos Smith III are highlights of the chemistry presented herein. Acc because the disconnections for making the substrates are relatively simple, this method has the potential to become a very important and elegant alternative to the Br nsted acid catalyzed spiroketal synthesis.

PAGE 105

105 CHAPTER 3 C OPPER CATALYZED ENANTIOSELECTIVE SYNTHESIS OF AMINO SKIPPED DIYNES The Relevance of Branched Chiral Amines The most important branched chiral amines are undoubtedly the well known amino acids which, along with carbohydrates and nucleic acids form es sential building blocks for life and its replication. 107 Amino acids are the monomers of peptide s and because proteins are made of peptide bonds, amino acids are thus the main constituent of proteins. 108 Branched chiral amines are also exceedingly important i n biochemistry and chemical biology as biological processes are largely affected by these molecules For instance branched chiral amines have extensively been used as bioconjugates 109 However, it is i n the field of medicinal chemistry that branched chiral amines probably f ind most of their application. A mines or amine derived functional groups are highly prevalent in pharmaceutical s and agrochemicals and, currently hundreds of these molecules have been commercialized as drugs used for the treatment of various diseases. 110 In addition to their biological importance branched chiral amines are also essential in asymmetric catalysis. These chiral amines are embedded in the structure of many chiral ligands for metal based catalysis as well as in organocatalysts. 111 Many of the greatest processes in asymmetric catalysis are enabled by branched chiral amines or amine derived catalysts Seminal contributions to this area to name a few, were reported by the groups of Corey, 112 Trost, 113 Evans, 114 Pfalt z, 115 Brown, 116 Carreira, 117 Katsuki 118 Jacobsen, 119 List, 120 Hayashi 121 J rgensen, 122 Macmillan 123 and Maruoka 124 Lastly, chiral amines are utilized i n polymer chemistry and material science in order to create chiral environments or to induce chirality 125

PAGE 106

106 Arguably bran ched chiral amines, along with branched chiral alcohols, are the two most utilized class es of chiral molecules finding a myriad of applications in essentially every area of research where chirality plays a role (Figure 3 1) Figure 3 1. Representative application s of branched chiral amines Chiral amines also appear e x tensively in the structure of bioactive natural products. There are innumerous examples of alkaloids as well as polypeptides which have been isolated f rom natural sources and that have potential utility in medicinal chemistry. In the next section, the structure and the biological relevance of a relatively new class of nitrogenated natural products will be discussed

PAGE 107

107 Branched Aliphatic Chiral Amines: Mono and Polyamine Natural Products Recently, our group became aware of structurally and biologically interesting mono and polyamine natural products M onomeric primary amines are structurally related to the taveuniamide s, a class of chlorinated bioacti ve toxins isolated from marine sources in 2004. 126 Examples of these molecules are the taveuniamide F ( 3 11 ) and the acetamide 3 12 which were independently iso lated from marine cyanobacteria (Figure 3 2) 127 Interestingly, these compounds present either p os itive or negative values of optical rotation which essentially means the se natural ly occurring molecules have been isolated as non racemic mixtures. Figure 3 2. The taveuniamides are non racemic natural products The ta veuniamide s and the acetamide 3 12 s hare a common structural motif. Th is common core is comprised of an amine functionality, or amide, with two very similar aliphatic carbon chains. The carbon chains have different degrees of unsaturation and chlorination and these functionalities usually appear three or more carbons away from the amine containing carbon These compounds are referred to as chiral remote amines (or branched aliphatic chiral amines) and as a general rule, the synthesis of these molecules po ses a challenge as there is no functional group around the amine stereocenter to assist with its installation. Chapter 3 addresses the challenge of synthesizing enantioenriched remotely chiral amines and that the synthesis of 3 12 in 82% ee will be acknowl edged as a proof of concept.

PAGE 108

108 The monoamine natural products encompass interesting structural features and these marine toxins were studied as potential anti HIV agents; however, the biological assays did not show any promise for their therapeutic use. On the other hand, p olyamine natural products such as the zeamines 3 13 128 and the fabclavines 3 14 129 which have been isolated in 2010 and 2014, respectively, have shown great potential as antibiotics. U nlike the monoa min es, these molecules display very promis ing biological activity against many different types of microorganisms, mainly bacteri a. 130 Thus, various research groups have been interested in the biosynthesis, bioactivity and other biological properties of these natural products Recently, t here has bee n an urge for the discovery of new molecules with antibacterial activity as multi resistance shown by some types of bacteria to current therapeutics is a global concern. 131 Figure 3 3. The zeamines and the fabclavines natural products The biosynthesis of the zeamines and fabclavines are realized by a combination of polyketide synthases ( PKS ), fatty acid synthases ( FAS ) and non ribosomal peptide synthetases ( NRPS ). 128 130 PKS and FAS modules are responsible for the biosynthesis of the polyamine motif whereas the NRPS synthesizes the ir peptide chain While the microroganisms utilize PKS and FAS assembly lines to iteratively build up the carbon chain and stereoselectively introduce the primary amine moieties with concurrent removal of the ancillary functional groups, chemists have many problems on doing so in

PAGE 109

109 the laboratory. C hemists would like to, ideally, design simple ways to ena ntioselectively introduce the stereocenter in the absence of directing groups because introduction and removal of these groups requires tedious steps. As such the synthesis of optically pure chiral remote stereocenters is significantly challenging for syn thetic chemists Enantioselective Synthesis of Branched Aliphatic Chiral Amines As previously discussed, chiral amines are of great importance, thus innumerous methodologies have been developed toward the ir non racemic preparation. It is clear that a diastereoselective synthesis by means of chiral a uxiliary chemistry plays a pivotal role in this topic. 132 For example, Ellman chiral auxiliary is extremely useful and ha s been utilized for the synthesis of many chiral amines, including in industrial settings. 133 However, installation and remov al of the chiral auxiliary and the generation of stoichiometric waste render this chemistry in principle less attractive than enantioselective catalysis. The use of enantioselective catalysis for making chiral am ines became popular in the 1970 s with the necessity for making enantiomerically pure L DOPA. 134 Th e large body of work related to the preparation of L DOPA and derivatives resulted in the 2001 Nobel Prize in Chemistry Half of the prize was awarded to Ry ji Noyori and Richard S. Knowles for their se minal contributions to the rhodium catalyzed enantioselective hydrogenation of enamides 135 Currently, there are many useful reactions for preparing chiral amines using enantioselective catalysis such as: 136 1) hydrogenation of enamines and enamides ; 2) reduct ion of imines and iminium ions; 3) C H insertion of amines; 4) hydroamination of olefins; and 5) 1,2 addition of C centered nucleophiles to imines and iminium ions. By using these methods, synthetic chemists have been able to synthesize a multitude of str ucturally different chiral amines;

PAGE 110

110 however, synthes e s of enantioenriched branched chiral amines having t w o aliphatic groups are rare. 137 A careful analysis of the aforementioned methods toward this type of remotely chiral amine reveals problems that can b e difficult to overcome. For example, the synthesis of branched chiral amines could, in principle, be accomplished via enantioselective hydrogenation of substrates such as 3 15 (Figure 3 4). 138 However two main problems arise. First, it would be difficult to control the E / Z ratio when preparing the required enamine (or enamide) substrate ( 3 17 and 3 18 ) Second, the regioselectivity of the enamine formation is also an issue as there two protons which can be deprotonated ( 3 1 9 and 3 20 ) Nugent stated tha t enantioselective hydrogenations can be performed only in substrates where the substituents on the enamine position are t butyl, adamantyl or aryl groups. 136 These three substituents do not allow for the for mation of two regioisomeric enamines as there is no removable proton and they also force the enamine to adopt the Z geometry by steric repulsion With all of these requirements, achieving asymmetric control is less problematic. Figure 3 4 Problems arising from enantioselective hydrogenation toward branched aliphatic chiral amines

PAGE 111

111 Imines, as well as iminium ions, are very good chiral amine precursors for enantioselective reduction reactions. 139 These transformations ar e very useful and are inspired by the mechanism in which transaminases act to form amino acids from ketoacids in living systems 140 Conceptually a chiral enantiopure source of hydride can preferentially attack one of the enantiotopic face s of a prochiral im ine The imine can be preformed or formed in situ from a ketone in a process known as reductive amination; however, r egardless of whether or not the electrophile is formed in situ, these reductions are generally employed o n electronically or sterically bia sed substrates. O btaining h igh e nantio selectivity is challenging if the imines contain two non branched alkyl groups such as 3 21 (Figure 3 5) 136 The difficulty relies on the similarity of the imine Re and Si prochiral faces of the imine which makes the enantiodiscrimination necessary for high enantioselectivities very unlikely. In fact, highly enantioselective reduction s of completely aliphatic imines are achieved only if one of the substituents is very small as for example, methyl or ethyl groups. Figure 3 5. E nantiodiscrimination i s a problem in enantioseletive reduction of iminium ions toward branched aliphatic chiral amines Recently, there has been an influx of publ ications regarding aliphatic C H insertion reactions. 141 The main reason for this is simple : introducing functional ity into aliphatic C H bond is a direct way to increase molecular complexity. Enantioselective i nsertion of oxygen and carbon into aliphatic C H bonds are comparatively much more

PAGE 112

112 frequently reported than nitrogen based insertions 142 C H aminations require elaborate reagents and tolerate only a very limited scope mainly its e nantioselective version. 143 Enantioselective C H amination in substrates su ch as 3 24 is elusive and two main problems can be anticipated on this reaction apart from reactivity (Figure 3 6). First, a chemo selectivity issue as to which C H bond in the carbon chain will be cleaved and, second, enantiodiscrimination issues as the tw o enantiotopic C H bonds have very similar chemical environments. Figure 3 6 Main problems in enantioseletive C H amination reactions toward branched aliphatic chiral amines Another straightforward way to prepare chiral amines is through enantioselective hydroamination of alkenes. 144 While these reactions are mostly performed in tramolecularly there are seminal reports from the groups of Buchwa ld, Miura and Hartwig on the intermolecular version of this reaction These intermolecular reactions w ere first independently reported by Buchwald 145 and Miura 146 for styrene like substrates and the Buchwald group also utilized aliphatic substrates such as 3 2 7 and 3 29 (Figure 3 7) 147 The reactions are catalytic o electrophilic aminating reagent 148 in the presence of hydrosilanes as the hydride source. Buchwald has shown that the enantiodetermining step of this reaction is a hydrocu pration into the alkene to form an enantioenriched alkyl copper species such as 3 32 Th is alkyl copper intermediate i s then trapped by the electrophilic aminating reagent in an enantiospecific fashion. This is a very interesting mechanistic scenario as

PAGE 113

113 ot her electrophiles c an be employed w i thout changing the enantiodetermining step In fact, the Buchwald group has already employed aryl and allylic electrophiles as well as ketones and imines in this process 149 Even though these are very successful reactions there are intrinsic problems of regioselectivity which are somewhat similar to the problems of hydroalkoxylations of alkynes presented in C hapter 2. For example, the reaction works really well for symmetrical alkenes such as 3 27 because only 3 28 can be formed (Figure 3 7) 147 On the other hand, for unsymmetrical alkenes mixtures of products can be found depending on the regioselectivity of the hydrocupration As it turns out, even highly sterically biased sub strates such as 3 29 containing a very bulky t butyl group present s problems, as the regioselectivity of the reaction was only 6:1. T he reactions are highly enantioselective for both 3 30 and 3 31 which clearly shows that face selectivity is well controlle d ; however, the regioselectivity was moderate. Figure 3 7 enantioseletive hydroamination toward branched aliphatic chiral amines

PAGE 114

114 In order to control the regioselectivity, Hartwig 150 employed substrates containing ester directing groups such as 3 34 (Figure 3 8). The regioselectivities observed w ere mostly very high favoring the proximal isomer but ob viously the requirement for directing groups can be un desirable in some circumstances. However, for challenging substrate s such as 3 34 the regioselectivity was usually moderate. Figure 3 8 droamination using esters as directing groups Another common way for preparing branched chiral amines is to perform a 1,2 addition of carbon nucleophiles to imines and iminiums ions. Many examples of 1,2 additions can be found in the literature clearly demonstrating that these are very robust reactions in some circumstances 151 Non etheless, the success of the 1,2 addition reactions for aliphatic imines or iminium ions such as 3 36 is rather limited The first problem i s related to the stability of the electrophile (Figure 3 9) I mines and iminium ions which contain protons can eas ily undergo deprotonation to form thermodynamic more stable and unreactive enamines such as 3 38 The second issue is related to the instability of the nucleo phile. P erforming catalytic reactions can be quite challenging in this situation since mild forma tion of alkyl organometallic species 3 39 is difficult. 152 Unfortunately, h ighly reactive alkyl organometallic species can undergo many side

PAGE 115

115 reactions such as hydride elimination and milder organometallic species can often be formed but are unreactive In fact, most of the 1,2 additions are performed usin g stoichiometric organometallic reagents This is an undesirable scenario in asymmetric catalysis as chiral reagents should be ideally used substoichiometrically Figure 3 9 Problems in the e nantioselective 1,2 addition into imines and iminium ions toward branched aliphatic chiral amines Interestingly, there is a large b ody of literature in the enantioselective arylation of aryl substituted imines and iminium ions Two independent seminal reports, from Hayashi 153 and from Bolm and Brse 154 have demonstrated that diarylmethylamines ( 3 42 and 3 45 ) could be synthesized in high enantiomeric excess (Figure 3 10) Hayashi utilized arylstannanes in combination with sulfonyl imines 3 40 in the presence of a rhodium catalyst and a phosphine ligand. Bolm and Brse employed acyl imine precursors 3 44 in the presence of a zinc catalyst and a N,O ligand. I n both case s the imine cannot be isomerized to an enamine as there are no available protons and the aryl organometallic species employed are much more stable than the corresponding alkyl ones Many other very interesting similar react ions have been developed following these two reports; however, alkyl imines and alkyl org anometallic species have not been employed. It is possible that in the future the challenge of using alkyl substrates will be overcome because the main problems rely o n reactivity but not on more complicated matter s such as regioselectivity or enantiodiscrimination.

PAGE 116

116 Figure 3 10 Enantioselective synthesis of diarylmethylamines via 1,2 addition Taking all this into consideration i t is clear that there is a significant challenge involving the enantioselective prep a ration of branched chiral amines bearing two non branched alkyl groups, or dialkylmethylamines. Herein an enantioselective preparation of branched chiral amines beari ng two different alkynyl groups is reported and these compounds are ultimately precursors of dialkylmethylamines. Copper Catalyzed A3 Reaction Toward Amino Skipped Diynes: Access to Branched Aliphatic Chiral Amines? In 2013, our group reported the devel opment of StackPhos, an imidazole based P,N ligand which ha s been successfully employed in asymmetric catalysis 155 A much more in depth discussion about StackPhos will be found in C hapter 4. At this point, it is important to mention that StackPhos excelled in enantioselective alkynylations of iminium ions. More specifically, StackPhos was a supreme ligand in the copper catalyzed enantioselective A3 r eaction. 155 The A3 reaction which is also sometimes called A3 c oupling, is a very useful transformation in which an aldehyde, an alkyne and an amine react in the presence of a transition metal to afford propargylamines such as

PAGE 117

117 3 47 upon elimination of water. 156 In the presence of a chiral ligand, the preparation of enan tioenriched propargylamines is possible and this has been previously reported by many different groups. Our group became interested in the enantioselective Cu QUINAP catalyzed A3 reaction developed by Knochel and coworkers. 157 The same reaction was also perf ormed by the Carreira group with PINAP ligands. 158 As it turns out, our group demonstrated that StackPhos 3 48 is even superior to QUINAP and PINAP ligands in the A3 reaction. According to the reports of Knochel and Carreira, aromatic aldehydes were much les s reactive than alkyl substituted ones. However, with StackPhos, the substrate scope is broader and aromatic as well as aliphatic aldehydes can be employed in high yields and high enantiomeric excesses (Figure 3 11). Figu re 3 11. C opper StackPhos catalyzed A3 reaction With these results in hand, we wondered whether or not alkynyl aldehydes 3 49 could have also been employed in the A3 reaction (Figure 3 12) A search in the literature showed that e nantioselective A3 coup ling s using alkynyl aldehydes ha ve not been previously reported 159 At the outset, we believed that the 3 amino 1,4 diyne products such as 3 54 or amino skipped diynes, were not only structurally interesting molecules, but also possibly synthetically useful Moreover, we also wondered whether or not amino skipped diynes could even be isolated in high enantiomeric excess and if these molecules would be configurationally stable. Structurally, amino skipped diynes

PAGE 118

118 are trifunctional chiral building blocks contai ning two alkynes and one amine functionality. Alkynes and amines are really useful functional groups in organic synthesis so we thought that possibly many interesting compounds could be synthesized from the se highly functionalized compounds Amino skipped diynes ha ve five consecutive highly oxidized carbons so we envisioned increasing molecular complexity in simple steps. More over the chirality at the C3 position could potentially be utilized for the generation of other stereocenters in a diastereoselectiv e fashion. Figure 3 1 2 Enantioselective A3 reaction toward amino skipped diynes In addition to increasing molecular complexity by using the alkyne oxidation state, it was obvious that the diynes could potentially b e reduced to form saturated chiral amines especially after being aware of all of the challenges associated with the preparation of branched dialkylmethylamines The preparation of aliphatic chiral remote amines is generally biased either sterically or e lectronically, as demonstrated in the previous section. As such, we envisioned preparing enantioenriched branched

PAGE 119

119 aliphatic chiral amines 3 56 from amino skipped diynes 3 55 (Figure 3 13) Th e proposed synthetic route would be useful because a highly con vergent two step sequence is required : a n enantioselective A3 reaction followed by diyne reduction Figure 3 13. Amino skipped diynes can be precursors of branched aliphatic amines To summarize, our interest in the e nantioselective synthesis of amino skipped diynes stems from structural aspects related to these molecules that could render them synthetically useful. Additionally from a more academic point of view, we anticipate d some synthetic challenges which are dis cussed in the next section. Challenges for the Enantioselective Synthesis of Amino Skipped Diynes In the A3 reaction, an iminium ion is formed in situ from the condensation of an aldehyde with a secondary amine. One of the possible problems that could ar ise from this process is that alkynyl iminium 3 57 ions are also Michael acceptors The reaction contains various nucleoph iles such as the copper acetylide, the secondary amine and the tertiary amine product. Nucleophilic addition to the highly electrophil ic position of 3 57 could, subsequently, make the position activated for nucleophilic attack Activation of the position c ould lead to decomposition pathways (Figure 3 14)

PAGE 120

120 Figure 3 14. Undesired a ddition to the po sition of the alkynyl iminium ion Another issue is related to the ability of iminium ions to undergo deprotonation to form enamines. Iminium ions 3 59 and enamines 3 60 probably exist in equilibrium (Figure 3 15) Formation of enamine is not really a prob lem in the A3 reaction with aliphatic aldehydes, because enamines can be re protonated, regenerating the iminium ion. In fact, before the development of the A3 reaction, the Knochel group showed that preformed enamines can undergo alkynylation under Cu QUIN AP catalysis 160 However, if alkynyl aldehydes bearing aliphatic substituents are employed, deprotonation would form the intermediate 3 62 This can become a serious problem as the reprotonation can occur at the and carbons (Figure 3 15). 161 If reproto nation is reversible, in other words, it takes place at the carbon, an alkynyl iminium 3 61 ion would be formed and this is not problematic In contrast, protonation at the position would give rise to undesired allenyl iminium ions 3 63 In addition t o the potential problems regarding reactivity, there were reasons to believe that the amino skipped diynes could be configurationally unstable. In the summer of 2015, I had the opportunity to present a poster about this work in the Graduate Research Sympos ium organized by the Division of Organic Chemistry of the American Chemical Society and, many participants on th at conference asked me the following question: Are these amino skipped diynes configurationally stable?

PAGE 121

121 Figur e 3 1 5 Deprotonation at the position of the alkynyl iminium ion Th e question of whether or not amino skipped diynes would be configurationally stable was a valid one as 3 64 could undergo racemization by forming the very stable bispropargylic carbocat ion 3 65 (Figure 3 16) 162 Moreover diynes can coexist in equilibrium with allenynes via a process first described in 1955. 163 The diyne allenyne equilib ri um of 3 66 and 3 67 can be stereospecific ; however, this likely encompasses a non stereospecific proton transfer which would result in loss of optical purity Figure 3 16. Configurational stability of amino skipped diynes All of the se challenges and the potential utility of amino skipped diynes made this project an inter esting one to pursue. Furthermore, we had StackPhos in our hand and enantioenriched amino skipped diynes had not been previously synthesized.

PAGE 122

122 Reaction Optimization and Scope Initially, 3 phenylp ropynal 3 68 dibenzylamine 3 69 and TMS acetylene 3 70 we re reacted in toluene at 0 C for 24 h in the presence of 5 mol % of CuBr and 5.5 mol % rac StackPhos (Figure 3 17). Under these conditions, the amino skipped diyne 3 71 was isolated in only 20% yield The remainder of the material was unreacted aldehyde w hich shows that the aldehyde was stable under the reaction conditions or, in other words, the Michael addition did not occur or it was reversible (Figure 3 1 7 ). Toluene was the optimal solvent for Knochel and for our group in the enantioselective A3 react ions; however it did not work very well for alkynyl aldehydes. Carreira reported the A3 reaction in dichloromethane as a solvent and this proved beneficial for making amino skipped diynes, improv ing the yield to 94%. Importantly the reaction g ave only 5% yield in the absence of StackPhos ligand which clearly demonstrate d that the synthesis of the amino skipped diyne 3 71 is essentially enabled by the ligand. Figure 3 1 7 Optimization of the reaction with racemic ligand The fact that the ligand accelerates the reaction is not required, but it is desired in asymmetric catalysis as it decreases the impact of the background reaction. When 99% ee ( S ) StackPhos was used the desired amine 3 72 was isolated in 73% yield and 95 % ee ( Figure 3 18). A t ambient temperature t he yield improved to 85% an d the enantiomeric excess decrease d almost insignificantly to 94% ee, effectively showing

PAGE 123

123 that 3 72 could be obtained in high chemical and optical yield. This compound was stable over long periods of time. The chemical structure and the optical purity of 3 72 we re maintained even after months, as shown by NMR spectroscopy and HPLC analysis, respectively. The preparation of 3 72 constituted the first synthesis of a enantioenriched 3 amin o 1,4 diyne. Figure 3 1 8 The first enantioselective preparation of a n amino skipped diyne With optimal conditions established, the scope of the reaction was studied and it was found that this enantioselective transform ation is quite versatile and robust, tolerating several different aldehydes, alkynes, and amines (Figure 3 19) The aromatic group in the aldehyde could be substituted ( 3 73 and 3 74 ) or be heteroaromatic ( 3 75 ), leading to products in 96% ee, 94% ee, and 96% ee, respectively. Reversing the position of the silyl and aryl groups led to the preparation of compound 3 76 in 95% ee. A fter desilylation 3 72 and 3 76 are enantiomers and, 164 w hile this is not unexpected due the reaction pattern, making two enantiom ers using the same enantiomer of the ligand is a considerable advantage. Two silyl groups or two aromatics could be incorporated ( 3 77 and 3 78 ) and aliphatic groups were also well tolerated on both reaction components ( 3 79 3 80 and 3 81 ) P ropiolates pr oved to be most reactive, generating the unsaturated GABA analogue 3 82 in 1 h, all forming products in high yields and e nantiomeric excesses

PAGE 124

124 Figure 3 19. Scope of the enantioselective synthesis of amino skipped diyne s Remarkably, only small changes in enantioselectivity were observed by chang ing the alkyne substituents It is possible that having two similar groups may present general practical difficulties for forming stereocenters; but since the structural

PAGE 125

125 permutati ons are remote, the scope can be expanded due to spatially diminished steric and electronic perturbations. The aforementioned examples all employed dibenzylamine, but it would be synthetically useful to incorporate other secondary amines, especially compo unds with two different amine substituents. In order to evaluate the reaction scope to this end, morpholine, piperidone and amines with different substituents were evaluated. Using the symmetric amines, 3 83 and 3 84 were isolated in 95% and 90% ee, respe ctively ( Figure 3 19 ). More challenging, unsymmetrical secondary amines could also be employed in high yields and high enantioselectiv ities ( compounds 3 85 3 86 and 3 87 ) which is quite uncommon feature. In general the reactions took place under the sta ndard conditions and the lowest e nantiomeric e xcess obtained was 84 %. As described above, the substrate scope is broad and tolerates different reaction partners by essentially exchan ging the groups on the alkyne. This offers flexibility in the same way as cross coupling reactions where the halide and the organometallic can be interchanged to produce a new pair of reactants. 165 During studies on the reaction scope it was observed that the synthesis of 3 90 completely fails when the aldehyde is o substituted w ith a sulfonamide moiety ( Figure 3 20 ). Reaction of th e aldehyde 3 88 with dibenzylamine and phenylacetylene under the standard conditions resulted in an intractable mixture as the aldehyde appears to be un stable under the reaction conditions. 166 It is like ly that the sulfonamide group reacts intramolecularly with the electrophilic position of the Michael acceptor, leading to undesired pathways related to what was p roposed previously (Figure 3 14). In contrast if the aldehyde is exchanged the reaction pr oceeds smoothly to deliver 3 91 in 92% yield and 90% ee.

PAGE 126

126 The compounds 3 90 and 3 91 are enantiomers and a lthough th ese reaction s lead to the enantiomeric product s this is not limiting as both enantiomers of the ligand are available. The method allows fo r two different sets of substrates to be used toward the same molecule which is advantage ous for optimizing reactivity and enantioselectivity. Figure 3 20. Optimization of the reaction with non racemic ligand The optimi zation of this reaction was very straightforward, as relatively simple changes were made compared to our own work and the work of Knochel and Carreira. On the other hand, in terms of scope, the differences are striking. T he scope of the A3 reaction w as con siderably broadened because alkynyl aldehydes were used as well as various amines and alkynes some for the first time The reaction tolerates alkynes with various functionalities such as nitro groups, sulfonamides, propiolates and alkyl groups. In terms o f amines, the use of unsymmetrical amines in high e nantiomeric excess should be highlighted as these are u seful for increasing molecular complexity. Synthesis of a Branched Aliphatic Chiral Amine Natural Product and Beyond To demonstrate that the amino s kipped diynes can be precursor s of branched aliphatic chiral amine s we prepared the simple natural product 3 12 in a straightforward

PAGE 127

127 manner (Figure 3 21 ) The branched aliphatic chiral amine 3 92 was synthesized from the amino skipped diyne 3 81 in on in the presence of hydrogen gas The free amine 3 9 2 was then ac etylated to complete the synthesis of the natural product 3 12 127 The enantiomeric excess was indirectly determ ined by the 3 94 from the common synthetic intermediate 3 9 3 C ompound 3 94 was isolated in 91: 9 dr thus 3 12 was likel y prepared in 82% ee. Figure 3 2 1 Synthesis of the branched aliphatic chiral amine natural product 3 12 In addition to simply reducing the triple bond toward saturated chiral remote amines, t he newly synthesized amino skipped diynes offer many positions for further functionalization and sho uld be highly useful synthons. The 2 substituted indole 3 95 was prepared via hydroamination of 3 9 1 using K 2 CO 3 without loss of e nantiomeric

PAGE 128

128 purity ( Figure 3 22 ). Non racemic C2 meth yl amine indole s are found in many alkaloid natural product s as well as in lead compoun ds broadly utilized in medicinal chemis try 167 but these compounds are difficult to prepare without C3 substituents. 168 A more in depth discussion about these types of heterocyclic amines is found in C hapter 4. Figure 3 2 2 Intramolecular hydroamination of alkynes toward C2 methylamine indole The substituents on the amine moiety can also be utilized, especially when two different groups are present. Chemoselective Pauson Khand reaction of 3 86 generates the heterocycle 3 96 as a single diastereomer, in 95% ee ( Figure 3 23 ). 169 The N allyl group reacts preferentially with the alkyl substituted alkyne and no reaction involving the silyl substituted alkyne is observed. Figure 3 23. Chemoselec tive Pauson Khand reaction The silyl substituted amines can be removed and different substituents appended ( Figure 3 24 ) although the broad substrate scope may preclude the need for this type of strategy The amine 3 77 was desilylated to form the TMS de protected compound 3

PAGE 129

129 97 a candidate for diversity oriented synthesis, 170 and 3 99 is obtained after a Sonogashira reaction and TIPS deprotection Figure 3 24. Orthogonal functionalization of amino skipped diynes Amino ski pped diynes are highly functional molecules a s the two triple bonds and the amine can be useful in many different ways, especially since these three groups are in close proximity. In this section we showed preliminary applications to demonstrate what could be accomplished with these trifunctional building blocks. W e demonstrated among other things, that the triple bond can be reduced for the synthesis of enantioenriched chiral remote amines. It is clear that non branched alkyl aldehydes could be employed fo r the synthesis of chiral remote amines instead of alkynyl aldehydes; however, preliminary results from our laboratory show ed that the combination of alkyl aldehydes with alkyl substituted alkynes led to poor enantioselectivities and low reactivity. Furthe rmore it seem ed that the A3 reactions of alkynyl aldehydes are comparatively much faster and more high yielding than the reactions with alkyl aldehydes.

PAGE 130

130 A3 Coupling: Proposed Reaction Pathway It is generally accepted that the C C bond formation in the co pper catalyzed A3 coupling involves the reaction of an iminium ion with a copper acetylide such as 3 10 5 and 3 10 6 respectively (Figure 3 25) 156 The iminium ion is formed via condensation of an aldehyde with a secondary amine and t he copper acetylide is formed after deprotonation of a terminal alkyne which is realized by relatively mild bases upon copper activation The presence of a chiral ligand for copper creates a chiral nucleophile (copper acetylide) whic h can effect enantioselective addition to the iminium ion. Figure 3 25. General pathway for the copper catalyzed A3 coupling While there are some well accepted mechanistic generalities, there are details which should be analyzed on a case by case basis. We show herein preliminary data which could help us to understand the mechanism of the Cu (I) StackPhos catalyzed A3 reaction in the context of the amino skipped diynes preparation. Most of the A 3 coupling reactions are c arried out in our laboratory with 1 equivalent of the three main components: the aldehyde, the alkyne and the amine The few exceptions are related to some volatile substrates in which 1.5 equivalents were used. In order to have a better understanding of r eaction rates, we follow ed the formation of racemic 3 76 by 1 H NMR using CH 2 Br 2 as an internal standard. Experimentally, reactions were run according to the general procedure and filtered over a plug of silica at different times. Solvent was evaporated and the internal standard was added to the CDCl 3 The data shows that the synthesis of 3 76 reached full conversion in 90 min, with an induction period of

PAGE 131

131 approximately 50 minutes ( Figure 3 26 ). Different factors could explain induction periods, including: 171 1 ) relatively slow forma tion of reactive intermediates; 2) existence of a pre catalyst which is activated in solution and ; 3) autocatalytic reaction which means that formation of product contributes to reaction rate enhancement In addition to this inductio n period a very slightly positive non liner effect 172 was observed for the formation of 3 72 A p os i tive non linear effect was also reported by Knochel in the A 3 coupling catalyzed by a Cu(I) QUINAP complex 173 Figure 3 2 6 Induction period and positive non linear effect in the Cu StackPhos catalyzed A3 reaction. A few years ago in our research group Dr. Flavio Cardoso grew X Ray quality crystals of ( S ) StackPhos in the presence of CuBr in a toluene/dichloromethane solut ion. 174 The structure of the heterochiral Cu Br StackPhos complex is dimeric, containing a bridged bromine ligand. The first StackPhos is a monodentate ligand which binds to the copper by the phosphorus. The second StackPhos is bidentate and bridged between two copper atoms The bidentate StackPhos binds to one copper by the phosphorus and to the other one by the nitrogen of the imidazole (Figure 3 2 7 ) The X

PAGE 132

132 Ray structure found for the CuBr QUINAP complex is also dimeric; however the two bromines are bridg ed and each ligand is connected to one copper. QUINAP binds through the phosphorus atom, and a weak ligation is proposed between the copper and the nitrogen based on the N Cu bond length 169 Figure 3 27. Structure of CuBr bound to StackPhos and QUINAP from X Ray analysis The positive non linear effect observed for the synthesis of 3 72 (Figure 3 26) could be related to the dimeric structure 3 10 8 N on linear effects manifest i n the reactions where high order catalytic species play a role in the rate of the reaction. T here are generally t wo main reasons why positive non linear effects (asymmetric ampli fi cation) are observed in asymmetric catalysis: 172 1) because homochiral metal complexes (e.g. [CuBr{( S ) StackPhos}] 2 ) are more reactive than the corresponding meso heterochiral complexes (e.g. [CuBr{( S )/( R ) StackPhos}] 2 ) or; 2) because of the reservoir effect which means that a reser voir of high order inactive catalytic species outside the catalytic cycle (off cycle) c ould, indirectly, impact the enantiopurity of active catalytic species inside the cycle. Because of these reasons, the catalytic cycle proposed herein will involve dimer ic species and suggest that homochiral copper complexes are more reactive than the corresponding meso and heterochiral complex. Nonetheless, we simply cannot rule out the fact that the reservoir effect is also playing a

PAGE 133

133 role in the ampli fi cation of enantio meric excess It is in general very difficult to correctly a t tribute whether the asymmetric amplification is a result of more reactive high order catalytic species or a result of the reservoir effect. In addition to the non linear effects, the induction period observed for the synthesis of racemic 3 76 may suggest that 3 10 8 is a pre catalyst (Figure 3 2 8 ). This is possible because the bridged bromide may be labile upon the addition of all of the reagents to the reaction. Most likely the dimer 3 10 8 is f ormed upon the addition of the ligand to CuBr in solution ; however, it is unlikely that 3 10 8 can be regenerated in the catalytic cycle, especially because there are highly nucleophilic species in solution (amines and acetylide) that could easily break lab ile bromine bridges. Other possibilities were also considered. For example, the equilibrium between aldehydes and amines to form active iminium species could also explain the induction period; however, a shorter induction period would likely be observed if this played a major role in the reaction rate. E ven after 30 minutes t here is essentially no reaction which suggests that this equilibrium is not the primary effect accounting for the induction period. Lastly, the product formation can also increase the r eaction rate; however by experience we know that tertiary amines such as DIPEA do not increase reaction rates. Taking all this information into account the proposed mechanism for the A3 reaction catalyzed by a Cu StackPhos complex could possibly involv e a precatalyst such as 3 110 which activates the alkyne to form the copper alkyne complex 3 11 1 (Figure 3 28) Concomitantly, t he aldehyde reacts with the amine to form the aminal 3 103 and t hese two processes are proposed to take place off cycle. It is p roposed that the aminal 3 103 could then displace the bridged bromine to generate the intermediate

PAGE 134

134 3 112 This bromine bridge is labile and should not be formed again in the catalytic cycle. Deprotonation of the alkyne and formation of the iminium ion 3 10 5 takes place upon elimination of water generating the copper acetylide 3 113 Th e deprotonation step is still not very well understood but certainly either the ligand or any other base in solution c ould deprotonate the terminal alkyne. C C bond formation between 3 113 and 3 105 generates the intermediate 3 114 which is a copper dimer bound with the product. The aminal 3 103 displaces the desired product 3 107 from the copper center and the terminal alkyne 3 104 undergoes coordination, turn ing the catalyst over. Figure 3 2 8 Pro posed catalytic cycle for the Cu StackPhos catalyzed A3 reaction

PAGE 135

135 At this moment i t is very premature to propose the transition state for the enantiodetermining step. According to Hartwig, 175 the enantiodetermining step in a given catalytic cycle is the first irreversible step with a diastereomeric transition state. Thus, in our catalytic cycle, two possible enantiodetermining steps arise. The first possibility is v ery intuitive and involves the C C bond formation or, in other words, the addition of the copper acetylide to the iminium ion to generate 3 114 The second one is somewhat counterintuitive and would involve the coordination of the iminium ion to the copper which can occur from either face of the iminium ion, forming diastereomeric complexes in a process similar to what is proposed for the rhodium catalyzed asymmetric hydrogenation. 176 Probably, the C C bond formation is enantiodetermining because the iminium ion should not make a strong coordination with copper. It would also be early to have more detailed mechanistic hypothes e s and, in the future, r eaction kinetics can give us more insights into the mechanism of the reaction Conclusions and Outlook In conc lusion we have disclosed the first preparation of enantioenriched amino skipped diynes, a class of chiral molecules with minimal differences in two of the subs tituents rendering them chiral. Despite this challenging issue and potential reactivity issues, a n enantioselective Cu(I) StackPhos catalyzed C C bond formation proved to be rapid and high yielding under very mild conditions while tolerating an exceptionally broad substrate scope Due to the unique structural features of chiral 3 amino skipped diynes we believe these building blocks will find application in a variety of areas and we have demonstrated several preliminary applications. Th e method presented should enable the synthesis of more complex primary amine and polyamine natu ral products which w ill be the object of future research in our lab.

PAGE 136

136 CHAPTER 4 DEVELOPMENT OF STACKPHIM LIGANDS FOR ENANTIOSELECTIVE CATALYSIS Axially Chiral P,N Ligands and the Development of StackPhos The presence of ancillary ligands is often essential in metal based ho mogeneous catalysis as ligands can drastically impact the reactivity and s electivity of a given transformation. 177 Ligands can positively impact reaction rates or even enable processes w hich cannot be pe rformed with naked metal sources. On the other hand, th e presence of ligands could stabilize the metal center, decreasing the likelihood of undesired pathways. A good balance between reactivity and stability is often required in metal catalyzed transformations and could eventually lead to lower catalyst loadin gs and more mild reaction conditions In addition to changes in reactivity, the presence of ligands is also esse ntial for controlling one pathway over another or, in other words, the reaction selectivity. In fact, t he main advantage of homogeneous catalysi s is that it allowed for the development of highly chemo regio diastereo and enantioselective transformations 178 In terms of enantios elective catalysis, the development of chiral ligands is crucial. There are rare examples of enantioselective transform ations which proceed with chiral at metal complexes containing achiral ligands, 179 thus most of these processes are performed with chiral ligands bound to the metal. As mentioned in C hapter 3, t he first well studied asymme tric reaction was the rhodium cataly zed enantioselective hydrogenation of enamides. 135 In the 1970 s, th ese reaction s w ere successfully performed with C 2 symmetric bisphosphine ligands derived from tartaric 180 or with liga nds which were chiral at phosphorus (Knowles DIPAMP ligand). 181 In 1980, Noyori introduced an axially chiral C 2 symmetric bisphosphine ligand derived from BINOL, namely BINAP, 182 which is arguably the most

PAGE 137

137 successful chiral ligand ever made. BINAP excelled in many hydrogenation reactions as metals, especially late transition metals, renders it the ligand of choice for the initial optimization of many reactions. BINAP is also e xtremely cheap if compared to other chiral ligands. For a long time, the scientific community attributed the success of DIOP, DIPAMP and BINAP to the reduced number of possib le transition states given by C 2 symmetric ligands, 183 in comparison with C 1 symmetr ic ones. Currently, it is accepted that this was an erroneous belief as many other C 1 symmetric ligands have succeeded in many asymmetric transformations. For instance, in 1994, Brown and coworkers developed a C 1 symmetric atropisomeric P,N ligand called Q UINAP 184 and, in 2004, Carreira and coworkers developed a new class of ligands called PINAP (Figure 4 1). 185 Figure 4 1 Axially Chiral Ligands: from BINAP to QUINAP and PINAP QUINAP has been shown to be an excellent ligand for a diverse array of enantioselective transformation s 186 such as: 1) palladium catalyzed allylic alkylation; 187 2) rhodium catalyzed hydrogenation and hydroboration; 188 3) copper catalyzed alkynylation of iminium ions additions (A3 reaction and quinolinium/i soquinolinium ion addition); 157 4) silver catalyzed [3+2] cycloaddition of azomethine ylides and electron

PAGE 138

138 deficient alkenes; 189 5) iridium catalyzed hydrogenation of alkenes ; 190 among others. PINAP has been develop additi derived Michael acceptors 191 and has been shown to succeed in other alkynylation reactions. 158 QUINAP and PINAP share a common structural feature as both ligands contain a naphthalene ring and a six membered nitrogenated heterocycle on their backbone. Interestingly, Brown has attempted to incorporate a five member heterocycle to make a QUINAP analog, hypothesizing that this could influence reactivity as well as selectivity. In 1997, Brown has synthesized the indole containing P,N ligand 4 4 ; however, This molecule has a relatively low barrier to rotation around its axis and is configurationally labile, leading to fa st racemization. Thus, this ligand is ineffective for use in asymmetric catalysis (Figure 4 2) 192 Figure 4 2. Racemization of an indole containing P,N Ligand QUINAP 4 1 and ligand 4 4 are relatively similar but only QUINA P is configurationally sta ble. This is attributed to small angle difference s imposed by six and five membered aromatics. Five membered cyclic compounds have, in general, smaller internal angles and larger external angles when compared to six membered cycl ic molecules (Figure 4 3). As it turns out, the indole ring pushes the substituents away from the axis in 4 4 which descreases the sterics around the biaryl bond, resulting in a decreased barrier to rotation when compared to QUINAP. In other words, the ang les 6

PAGE 139

139 and 4 1 ) are smaller than 5 and 4 4 ), making the five membered biaryl 4 4 more prone to racemization due to reduced sterics. Figure 4 3. Six versus five membered rings and the configurational stability of biaryls The barrier to rotation of atropisomeric, axially chiral biaryl compounds, is highly dependent on the substituents appended around the axis (Figure 4 4) For example, binaphthalene has a barrier to rotation of 24 kcal/ mol 193 while BINOL has a barrier to rotation of 38 kcal/ mol 194 Binaphthalene thus racemizes in less than one hour at 50 C whereas BINOL is configurationally stable for 24 hours at 100 C. Figure 4 4. Destabilization of the transition state through steric interactions increases the barrier to rotation a bout biaryl bonds

PAGE 140

140 Increasing non bonding steric interactions around the axis in atropisomers increase their barrier to rotation by destabilizing their planar transition state which is related r acemization. Destabilization of the planar transition state is well explored in the literature for the development of atropisomeric chiral ligands. In 2013, our group reported a new strategy for increasing the barrier to rotation of biaryls which was cruci al for the development of StackPhos, 155 a atropisomeric imidazole based P,N ligand which excelled in many enantioselective alkynylation reactions such as the one shown in C hapter 3. 159 The barrier to rotation of StackPhos is increased by stabilization of the ground state using non covalent interactions, in this case stacking (Figure 4 5) The design of StackPhos takes advantage of a stacking interaction between the pentafluorobenzyl substituent appended to the imidazole with the naph thalene ring. The energy difference between t he s tacking of StackPhos 3 48 and i ts non flu or inated analog 4 10 is 2.2 kcal/mol, which is in the range of stacking interactions 195 Figure 4 5. Stabilization of the ground state through stacking interactions increases the barrier to rotation aroun d biaryl bonds

PAGE 141

141 At first, t he 2.2 kcal/ mol ground state stabilization may seem very small; however, it was essential f or the isolation of the ligand i n its optically pure form. StackPhos has been isolated in 99% ee as opposed to only 56% ee for compound 4 10 using the same synthetic sequence. The overall barrier to rotat ion for StackPhos is 28.4 kcal/ mol and 26.2 kcal/mol for 4 10 both measured experimentally through thermal racemization studies 155 The barri er to rotation of StackPhos is comparable to the barrier to rotation of PINAP, 196 which is quite remarkable. The expected stacking was also observed in the solid state via single crystal X Ray analysis of racemic 3 48 155 Preparation of Optically Pure Axially Chiral P,N Ligands The development of chiral ligands and catalysts is essential for the discovery of new enantioselective transformations and for the improvement upon existing ones. It is possible that e very week a chiral ligand, or catalyst, appear s in the literature, demonstrating the relevance of this topic in organic chemistry However, d espite the amount of structures that have been successful ly utilized in asymmetric catalysis, only a few are consid ered privilege d Th e concept of privileged chiral catalysts was introduced by Yoon and Jacobsen, and it refers to the generality by which certain small molecules act as chiral ligands and catalysts. 197 Knowles, in his Nobel lecture, stated that it is very s urprising that man made catalysts can, in contrast to enzymes, function well in many different enantioselective reactions. 135 BINAP is an example of such a privileged chiral ligand since it performs well in man y transformations. It is obvious that the primary factor to be considered when designing a new catalyst is its performance ; h owever, only analyzing the catalyst perform ance in a given reaction leaves out one very important feature its synthesis and isol ation.

PAGE 142

142 Chiral catalysts are utilized as single enantiomers but obtaining synthetic molecules with 99% enantiomeric excess is often a hard task. Thus, a chiral catalyst should be analyzed in a broader context, especially if industrial application is envis ioned. 198 BINAP is a great ligand not only because of its exceptional performance, but also because it is synthesized from readily available and cheap starting materials, in kilogram scale BINAP is synthesized from BINOL, a readily available and optically p ure biaryl, in two steps which involve activation of the hydroxyl groups for a metal catalyzed C P coupling. 199 200 utilize s a sulfonylation of the phenol moiety followed by a nickel catalyzed phosphination reaction (Figure 4 6). Figure 4 6. BINAP is derived from a enantiomerically pure molecule, BINOL, but very often chiral ligands are synthesized i n its racemic form and are resolved using chiral auxiliaries Enantiomerically pure BINOL itself is obtained from racemic BINOL using resolving agents. 201 QUINAP can also be obtained by resolution as rac QUINAP reacts with the chiral palladacycle 4 14 (Figure 4 7) delivering two diastereomeric complexes 4 15 and 4 16 which can be fully separat ed by their difference in solubility (one diastereomer precipitates preferentially in solution ) 202 Optically pure QUINAP is obtained after decomplexation of the P,N ligand from the palladium coordination sphere using dppe, 188 a bidentate bisphosphine ligand with a better binding constant than

PAGE 143

143 QUINAP. While this resolution process is conceptually interesting, there is a severe practical drawback which is related to the use of stoichi ometric amount s of a chiral amine and palladium In addition to this, very often these processes lead to irreproducible results. Figure 4 7. Resolution of optically pure QUINAP using a chiral palladacycle Since QUINAP is an excellent ligand, it is very unfortunate that its resolution is difficult, limiting both its application as well as analog synthesis. Aware of the utility of QUINAP, Carreira and coworkers synthesized the PINAP ligands, which is a set of more readily a vailable atropisomeric P,N ligands. The synthesis of PINAP utilized the concept of introducing more than one stereocenter to a chiral molecule in order to create diastereomers which can often be separated using simple chromatographic methods. The preparati on of PINAP ligands begins with a Friedel Crafts reaction between 2 naphthol and 1,4 dichlorophthalazine followed by triflation to form compound 4 20 (Figure 4 8) 185 Two subsequent couplings insert the chiral amine 4 24 and the diphenyl phosphine group delivering the diastereomeric structures 4 22 and 4 23 in a 1 : 1 diastereomeric ratio. The diastereomeric PINAP ligands 4 22 and 4 23 are easily separated by column chromatography in silica gel and essentially h ave the same chiral

PAGE 144

144 center but opposite sense of axial chirality. Various analogs of PINAP ligands have been prepared and while there are certainly advantages with this strategy, the separation of diastereomers is often tedious and there is an intrinsic lo ss if utility is found for only one of the diastereomers. Figure 4 8. Preparation of optically pure PINAP ligands In our laboratory, we developed a deracemization strategy to obtain optically pure StackPhos. The strategy developed by Dr. Flavio Cardoso utilizes the same chiral palladacycle 4 14 which was used for the resolution of QUINAP. It was found that rac StackPhos reacts with 4 14 in acetone, at 60 C for 12 ho urs to deliver only one diastereomeric palladium comple x 4 25 (Figure 4 9) 155 The decomplexation of ( S ) StackPhos from palladium is achieved at low temperature with the bidentate ligand

PAGE 145

145 dppe. If compared to the resolution of QUINAP, the deracemization of StackPhos is advantageous because 100% of the racemic ligand is converted to a single enantiomer. Importantly, both ( S ) and ( R ) StackPhos can be obtained as either enantiomer of the chiral amine is available. Nonetheless, the major drawback regarding the use of st oichiometric chiral palladacycle applies to StackPhos as well. Figure 4 9. Deracemization of StackPhos using a chiral palladacycle The Stoltz group recently reported a very elegant and useful asymmetric synthesis of QUI NAP 203 Because t he energy for the barrier to rotation a bout biaryl bonds of P,N ligands such as QUINAP is relatively low, the Stoltz group hypothesized that intermediates in the C P coupling reaction from 4 26 to QUINAP 4 2 could rapidly interconvert, allo wing for a n enantiodetermining and irreversible reductive elimination (C P bond formation) As it turns out, the palladium Josiphos metal complex catalyze s a dynamic kinetic resolution that transforms the triflate 4 26 into 90% ee QUINAP. Conceptually, thi s is likely the best way to obtain enantiomerically pure QUINAP; however, 99% ligand is achieved only after recrystallization and the Josiphos ligand itself is rather expensive. The strategy of designing asymmetric synthes e s of atropisomeric P,N ligands is not precluded by first principles, however many practical problems can arise. One of the main issues is related to the fact that it is often hard to

PAGE 146

146 co mbine asymmetric steps with the high temperatures required for the C P couplings. Furthermore elevated temperatures can contribute to ligand racemization. It is possible that the development of mild phosphination reaction s will, in the future, open up avenues in terms of the enantioselective synthesis of these ligands. Fi gure 4 Clearly, the efficiency of a chiral ligand in a given reaction cannot solely be responsible for determining the ligand usefulness. Having easy access to optically pure catalysts is also of great import ance. Currently, the discovery of new molecules with utility in asymmetric catalysis is very challenging, and very complex structures should a priori be avoided. Great ligands can simply become underexplored if chemical synthesis is not practical Phosphi nooxazoline (PHOX) and Phosphinoimidazoline (PHIM) Ligands The emergence of C 2 symmetric bisphosphine ligands for asymmetric catalysis paved the way for the development of C 2 symmetric N,N ligands such as the semicorrins 204 and bisoxazolines (BOX) 205 Interest ingly, a lmost at the same time, various groups began exploring the performance of C 1 symmetric ligands. In this context, Brown developed QUINAP, 116 Togni developed C 1 symmetric ferrocenyl bidentate ligands such as Josiphos 206 207 Helmchen 208

PAGE 147

147 and W illiam s 209 independently developed the well known phosphinooxazoline (PHOX) ligands (Figure 4 11) PHOX ligands are C 1 symmetric P,N ligands containing a single stereocenter which is usual ly amino acid derived 210 Figure 4 11. From Semicorrins and bisoxazolines to PHOX ligands The success of PHOX ligands is remarkable and at least two seminal contributions in this field should be highlighted: the work of P faltz on the iridium PHOX catalyzed hydrogenation of olefin s 211 and the work of Stoltz on the palladium PHOX catalyzed decarboxylative asymmetric allylic alkylation. 212 To date, many other asymmetric transformations using PHOX are known such as allylic alkylat ion s allylic amination s H eck reactions, cycloadditions transfer hydrogenations and others. 213 Early on, PHOX ligands were deemed very promising mainly because of their modularity and, in 2000, a research team at Bo e h ri nger Ingelheim patented a new class o f ligands called phosphinoimidazoline (PHIM) ligands for hydrogenation reactions (Figure 4 12) 214 Soon after the Pfaltz group released their first contribution using iridium PHIM catalyst s to perform asymmetric hydrogenations of alkenes. 215 The reasoning beh ind the development of PHIM ligands is related to the electronic tunability conferred by the

PAGE 148

148 imidazoline ring, as the trivalent nitrogen accommodates one more substituent which cannot be incorportated in to PHOX ligands To date, P HIM ligands have been succ e ss fully employed in asymmetric transformations such as iridium catalyzed hydrogenation of alkenes 216 and imines, 217 rhodium catalyzed hydrogenation of enamides 218 and palladium catalyzed intramolecular Heck reactions. 219 Figur e 4 1 2 The development of highly modular PHIM ligands Phosphinooxazolines and phosphinoimidazolines are interesting scaffolds which have been shown to be superior ligands for asymmetric catalysis. The development of asymmetric reactions is an ever growin g area of research and, as a consequence, it is likely that in the future more reports on the use of PHOX and PHIM ligands will appear Preparation of Optically Pure PHOX and PHIM Ligands As previously mentioned PHOX and PHIM are excellent ligands for ena ntioselective catalysis and, over the past 20 years, have found a much more widespread use than other P,N ligands such as QUINAP and PINAP. While these ligands are complementary and the use of PHOX/ PHIM over QUINAP/PINAP could, most of the time, be attrib uted to performance, syntheses of PHOX/PHIM ligands are comparatively more easi ly accomplished, usually requiring a few simple steps Moreover, PHOX and PHIM ligands can be sterically and electronically tuned because

PAGE 149

149 their synthesis is straightforward. 220 Th us, hundreds of PHOX and PHIM ligands have been prepared 221 unlike QUINAP and PINAP which have only a few analogues. In general, PHOX ligands 4 33 are simply synthesized from oxazolines 4 34 through C P bond formation reaction (Figure 4 13) Compounds such as 4 34 can be synthesized by condensation between benzoic acids 4 35 (or other molecule s with carboxylic acid oxidation state) containing a halogen at the ortho position with aminoalcohols 4 36 which are usually derived from amino acids 4 37 PHIM ligands are generally very similarly synthesized except diamines 4 38 rather than aminoalcohols, are employed Figure 4 13. Retrosynthetic Analysis to PHOX and PHIM ligands There are innumero us ways to synthesize PHOX ligands. For example, Guiry and coworkers synthesized the well known CF 3 PHOX ligand 4 41 i n two steps from the aromatic nitrile 4 39 (Figure 4 14) 222 This is a very simple synthesis that can be performed on a large scale. Notably several phosphinoimidazoline ligands are commercially available and many others can be prepared in a simple manner

PAGE 150

150 Figure 4 14. Representative synthesis of PHOX ligands Many PHIM ligands have been previously synthes ized, mainly by Bo e hringer Ingelheim and by the Pfaltz group. 221 In fact, more than one hundred ligands of this type have been made where essentially everything on the phosphinoimidazoline backbone ha s been ch anged. For example, Pfaltz has shown that the imidate 4 42 reacts with a optically pure chiral diamine to deliver the imidazoline 4 43 N ucleophilic aromatic substitution on 4 43 using potassium diphenylphosphide followed by simple benzylation forms the ph osphino imidazoline 4 45 in only three steps from the imidate (Figure 4 15) 221 Figure 4 15. Representative synthesis of PHIM ligands The synthesis of PHOX and PHIM ligands is, in general, very simple because it utilizes readily available molecules from the chiral pool, namely chiral aminoalcohols and diamines. In principle, t he same approach can be used to induce axial chirality and this is one of the topics which is address ed in Chapter 4

PAGE 151

151 In corporati on of Axial Chirality into Phosphinoimidazoline s: Development of StackPhim Ligands As mentioned previously there are hundreds of PHOX and PHIM ligands. Nonetheless, none of these molecules is axially chiral. 221 This is really surprising as these ligands could at least in principle, be atropisomeric if the rotation about the restricted. It is important to point out that PHOX and PHIM are not truly biaryls ; however, we are assuming that the non aromatic imidazoline could act just as the imidazole does in StackPhos. Thus, throughout Chapter 4, the bond which connects the naphthalene with the imidazoline ring will be referred to as the biaryl bond Herein we prese nt a strategy for controlling the axial chirality in PHIM type ligands t o create a new class of ligands named StackPhim. However, why do we want to control the axial chirality in these ligands? Because we hypothesized that controlling chirality (axial chirality) in PHIM ligands can be beneficial to asymmetric catalysis. This hypothesis was formulated based on the fact that m any congeners of PHIM ligands have been developed in order to improve reactivity and stereoselectivity and, it is well accepted that in many cases very subtle changes have been crucial for efficient catalysis From another point of view we would be also studying the effects of the i ncorporation of central chirality into StackPhos Essentially combining the axial ch irality of StackPhos with the central chirality of PHIM ligands to create new P,N ligands could be useful to enantioselective catalysis (Figure 4 16) Herein, we discuss o ur strategy that involves the formation of diastereomeric phosphines and the various implications this has.

PAGE 152

152 Figure 4 1 6 Incorporation of axial chirality in to PHIM ligands The development of axially chiral PHIM ligand is challenging because the five substituents away from the axis, decreasing its barrier to rotation. 192 In order to create atropisomeric PHIM ligands, we envisioned that the same stacking interaction which has been utilized fo r the axial stabilization of StackPhos could also be used for increasing the barrier to rotation in PHIM ligands (Figure 4 17) 155 In the case of StackPhos, the two stereoisomers are enantiomers however for the StackPhim the stereoisomers would have a diastereomeric relationship Enantiomeric atropisomers have, by first principles, the same free energy and their barrier to rotation is the energy barrier for the racemization (or enantiomerization). In contrast, d iastereomeric atropisomers could have different free energies and in this situation two different energy barrier s arise, one related to the epimerization from the most thermodynamic stable diastereomer to the

PAGE 153

153 least and one i n the opposite direction, from t he least to the most stable. 223 The unpredictability related to the energy of the diastereomeric pair of potential StackPhim ligands was another feature which made this project interesting from its beginning. Figure 4 17. stacking intera c tions stabilizing axially chiral conformations Nonetheless, most of our interest stemmed from the fact that t he incorporation of axial chirality into a ligand c ould drastically impact the reactivity and the stereoselectivity o n a given reaction A xially chiral ligands have very particular dihedral and bite angles when bound to a metal. For example, a very useful meta analysis performed by Brown and Guiry showed that i Pr PHOX ligands bind to different metal s with dihedral angles which ran ge from 0 to 35 224 In contrast, the dihedral angle of QUINAP bound to different metals is always ranging from 55 to 70 In many circumstances dihedral and bite angles given by atropisomeric ligands are critical for obtaining high reactivity and

PAGE 154

154 enantiose lectivity. The dihedral angle of StackPhim ligands is expected to be similar to the ones of StackPhos because the presence of axial chirality would likely preclude dihedral angles in the range of PHIM ligands (0 35 ). This is interesting because we could potentially harness the reactivity of PHIM ligands with the dihedral angle typical of axially chiral molecules such as StackPhos and QUINAP (Figure 4 18) Further motivation for making the StackPhim ligands was related to their synthes e s. As previously sho wn, the synthesis of optically pure axially chiral P,N ligands such as StackPhos, QUINAP and PINAP is still difficult, limiting their application. However, the synthesis of StackPhim could be straightforward because it would follow well known synthes e s of common PHIM ligands. Moreover, obtaining optically pure ligands could be facilitated because StackPhim ligands would be diastereomeric, allowing for separation by basic methods such as column chromatography Figure 4 1 8. StackPhim ligands: initial motivation In Chapter 4 the synthesis, isolation, characterization and implementation of StackPhim ligands in various asymmetric transformations are presented It was i n the context of C hapter 4 that we discovered the prepara tion of amino skipped diynes shown in C hapter 3 Later, we developed a highly enantioselective asymmetric alkynylation/ cyclization sequence which clearly demonstrates the success of the newly designed StackPhim ligands.

PAGE 155

155 Preparation of the First Generati on of StackPhim Ligands Overman and coworkers reported a very straightforward synthesis of a diverse array of imidazoline naphthalene containing chiral palladacycles which were called PIN complexes. 225 Following this report, we performed a n ortho iodination of the nitrile 4 52 mediated by lithium 2,2, 6,6 tetramethylpiperidide to install the iodide at the 2 p osition of the naph thalene (Figure 4 19) Compound 4 53 was hydrolyzed under strong acidic conditions to deliver the primary amide 4 54 which underwent d iazotization followed by hydrolysis, delivering 2 iodo 1 naphthoic acid 4 55 This synthesis was accomplished reproducibly in a 5 10 g scale with yields ranging from 60 to 75% for the three steps. Figure 4 19. Preparatio n of 2 iodo 1 naphthoic acid With the carboxylic a cid 4 55 in hand, we turned our attention to the preparation of the imidazoline moiety. According to the same report by Overman and coworkers, 225 the carboxyli c acid was transformed into an acyl chloride and reacted with ( S ) valinol to generate 4 57 (Figure 4 20 ) The amidoalcohol 4 57 was then reacted with excess thionyl chloride at 85 C to form an imidoyl chloride containing a pendant primary chloride which w as directly reacted with pentafluorobenzylamine to form the 5 member ring and complete the synthesis of the desired imidazoline 4 59 This three step sequence deliver s 4 59 from 4 55 in 54 % overall yield. T he preparation of the phosphine was accomplished v ia a copper catalyzed Ullman type C P coupling which

PAGE 156

156 was reported by Buchwald and coworkers. 226 This phosphine synthesis is very attractive because it takes place using a relatively cheap combination of reagents such as copper iodide and N N dimethylethylen ediamine. Moreover, only one equivalent of diphenylphosphine is required and the crude reaction mixture shows predominantly the diastereomeric pair of StackPhim ligands 4 60 and 4 61 Figure 4 20. Preparation of StackPhi m 4 60 and 4 61 The diastereomeric ratio of 4 60 and 4 61 in the crude reaction mixture was found to be 2 : 1, favoring the StackPhim 4 60 Using NMR spectroscopy, two diastereomers were observed confirming the restricted rotation around the biaryl bond a t room temperature, in the NMR time scale The observed diastereomeric ratio reflects the thermodynamic distribution of these two compounds in toluene since t he C P coupling was carried out at 110 C for 12 h U nder these conditions, the thermodynamic equi librium between these relatively labile atropisomeric phosphinoimidazoline s should

PAGE 157

157 be established. TLC analysis of the mixture of the StackPhim 4 60 and 4 61 using different solvent systems showed no separation and these two compounds were deemed inseparab le by column chromatography in silica gel. In an attempt to recrystallize the phosphine s in order to perform single crystal X Ray diffraction analysis, we observed that only the major diastereomer, the StackPhim 4 60 precipitated in a solution of dichloro methane and hexanes (Figure 4 21) With this procedure, we obtained the StackPhim 4 60 as a single diastereomer as seen by NMR spectroscopy. This result allowed us to, first, obtain an optically pure sample of one of the diastereomers and second, to measu re experimentally the energy barrier for the interconversion of one diastereomer to the other and vice versa In the mother liquor, we found a 55 : 45 dr favoring the major StackPhim 4 60 Remarkably the combined amount of StackPhim 4 60 in the precipitat e and in the mother liquor was larger than the initial amount of 4 60 which is evidence of a crystallization induced dynamic resolution 227 This is a result of the Le Chatelier principle 228 as precipitation of StackPhim 4 60 disturbs the equilibrium in solut ion which tends to be reestablished, causing epimerization from the least thermodynamic ally stable StackPhim 4 61 to the most stable 4 60 through rotation about the atropisomeric bond. Figure 4 21. Optically pure Sta ckPhim 4 60 obtained via crystallization induced dynamic resolution

PAGE 158

158 Nonetheless, the epimerization was also evidence of a relatively low barrier to rotation because the recrystallization was carried out at room temperature. StackPhos, for example, does not undergo observable racemization in solution at room temperature. The thermal epimerization studies (vide infra) showed a ba rrier to rotation of 25.4 kcal/ mol from 4 60 to 4 61 and of 24.9 kcal/ mol from 4 61 to 4 60 which a re 3.0 and 3.5 kcal/ mol lower tha n the one found for StackPhos respectively These relatively low energy barriers unfortunately precluded the isolation of optically pure samples of StackPhim 4 61 The characterization of the StackPhim 4 60 was performed via single crystal X Ray diffracti on which shows the expected stacking between the pentafluoroarene and the naphthalene (Figure 4 22). The parallel, offset stacking is very similar to the one observed for StackPhos in the solid state. Figure 4 2 2 Single crystal X Ray diff raction analysis of StackPhim 4 60 shows the expected stacking The X Ray analysis also shows that the axial absolute configuration of the StackPhim 4 60 is R thus, by exclusion, the axial absolute configuration of StackPhim 4 61 is S However, much mo re important than assigning the descriptors R and S to the atropisomers would be to analyze the relat ive spatial dispositions of atoms and groups within the molecules. One interesting feature, for example, can be seen by comparing

PAGE 159

159 how close the phosphorus atom is from the i propyl group. Considering the imidazoline i propyl group in 4 60 but pointed 4 61 This spatial relationship is expected to impact reactivity and selectivity as the chiral center is relatively close to the reactive groups, and this will also be the object of study in Chapter 4. Following the synthesis, t he obvious next step was to analyze the potential of the se new axially chiral phosphinoimidazoline l igands in asymmetric t ransformation s Palladium Catalyzed Asymmetric Allylic Alkylation The palladium catalyzed asymmetric allylic alkylation is a very useful transformation because it creates a carbon carbon or a carbon heteroatom bond in an enantioselective fashion. Over th e past thirty years, many researchers have contributed to the development of this reaction. We decided to test our new ligand the StackPhim 4 60 in the palladium catalyzed asymmetric allylic alkylation employing diethylmalonate as the nucleophile and the allylic acetate 4 64 as the electrophile. The reaction is carried out with stoichiometric bis(trimethylsilyl)acetamide (BSA) and substoichiometric potassium acetate as a base. As it turns out, the StackPhim 4 60 is a very good ligand for this reaction and generates the ( S ) enantiomer of the product, the compound 4 65 (Figure 4 23). As a reference, relevant literature results of other P,N ligands such as QUINAP 187 and PHOX 207 under the same reaction conditions, have been listed not only for ee comparison, but also to show how the sense of chirality of the chiral ce nter and the chiral axis affect the product absolute configuration. For instance, in the reaction with ( R ) QUINAP the ( S ) product is isolated in 7 6 % ee, whereas with ( S ) StackPhos the ( R ) product is isolated in 94% ee. 174 Ligands ( S ) Ph PHOX as well as ( S ) i Pr PHOX generate the ( S ) enantiomer of the product, in 99 and 96% ee,

PAGE 160

160 respectively. StackPhim 4 60 which combines a chiral axis of R configuration with a chiral center of S configuration gives, in the same reaction, the ( S ) enantiomer of the product in 97% ee This is not a surprising result in terms of pr oduct absolute configuration because both of the two element s of chirality in the ligand, namely the chiral center R and the chiral axis S should converge the previous results with QUINAP, StackPhos and PHOX ligands. In ter ms of selectivity it should be noted that the introduction of the chiral center was slightly beneficial because StackPhos g ives a 94 % ee in th is transformation The yields for the reactions with all of the ligands were considerably high (> 80%) and the re actions proceeded quickly under mild conditions, thus the discussion is limited to the reaction selectivity. Figure 4 23. Palladium catalyzed asymmetric allylic alkylation with P,N ligands To determine whether the ligand chiral center or chiral axis play s a major role in controlling the selectivity, a valuable experiment could, in principle, be performed with a ligand such as StackPhim 4 61 This ligand has a R chiral center and a R chiral axis

PAGE 161

161 thus these two elements of configuration. However, as previously mentioned, this ligand could not be isolated i n its optically pure form and this experiment could not be performed. According to Knowles 135 man made catalysts, as opposed to enzymes, are surprisingly very often suitable for more than one reaction. As a consequence, the 97% ee obtained in the palladium catalyzed asymmetric allylic alkylation with StackPhim 4 60 as a li gand was an encouraging result. However, this result should be analyzed with caution as a multitude of other ligands, containing different structural features, also succeeded in th e same transformation. 229 Copper Catalyzed Enantioselective A3 Reaction Unli ke the palladium catalyzed asymmetric allylic alkylation, only a few ligands succeeded in the copper catalyzed enantioselective A3 reaction using secondary amines as the amine source. Until recently, only QUINAP and PINAP enabled highly enantioselective re actions and, 186 in 2013, StackPhos was shown to be a superior ligand for the A3 reaction in terms of enantioselectivity, reactivity and scope. 155 A very interesting recent report from Seidel and coworkers also demonstrated that a thiourea carboxylic acid ligand can also promote the same transformation in high enantiomeric excess es using aromatic aldehydes. 156 Carreira a nd coworkers reported highly enantioselective A3 reactions using 4 piperidone hydrate hydrochloride salt 4 68 as the secondary amine source using PINAP ligands. 158 This amine sou rce is employed because it can b e deprotected after the alkynylation step to generate unprotected propargyl amines via retro Michael reaction In order to test the potential of our new ligand in the A3 reaction, we initially reacted the amine 4 68 isobutyraldehyde and phenylacetylene fo r 24 h at 0 C in the presence of

PAGE 162

162 triethylamine, CuBr and StackPhim 4 60 (Figure 4 24). Under these conditions, the synthesis of the ( S ) enantiomer of the propargyl amine ( 4 70 ) was accomplished in 62% yield and in 36% ee. This was a very discouraging res ult as ( S ) StackPhos allows the same reaction to be performed in 80% yield and in 92% ee and PINAP in 82% yield and 85% ee. However, something really interesting occurred when we employed a mixture of StackPhim 4 60 and 4 61 in a 78 : 22 ratio ( 4 60 : 4 61 ) in the reaction The major product formed reversed as the mixture of ligands gave the ( R ) enantiomer of the propargyl amine ( 4 7 1 ) in 38% ee. This result was somewhat intriguing because the mixture contains only 22 % of the StackPhim 4 61 This set of dat a shows that the reaction is axially controlled and that the ligand 4 61 could likely be more reactive and selective than 4 60 Figure 4 24. Preliminary results in the copper catalyzed enantioselective A3 reaction with StackPhim 4 60

PAGE 163

163 With this intriguing result in hand, we tested the same reaction in the presence of a mixture of StackPhim 4 60 and 4 61 in different ratios, ranging from 99 : 1 to 45 : 55 ( 4 60 : 4 61 ) As it turns out increasing the amount of the ligand 4 61 in the ligand mixture increase d the ee (Figure 4 25) Figure 4 25. The enantiomeric excess increases with the amount of StackPhim 4 6 1 in the copper catalyzed A3 reaction It would be really interesting to have acces s to a mixtu re of ligands more enriched in StackPhim 4 61 in order to know in which ratio the ee is maximized Even though the graph suggests that increasing the amount of 4 61 increases the ee, there could be two possible hypothetical scenarios: 1) the ee reaches its maximum when the ratio 4 60 : 4 61 becomes 0 : 100 or; 2) the graph has an inflexion point and the maximum ee is reached with a mixture of ligands. The two scenarios are possible because non line a r effects can play a role in the reaction. 172 Experimentally, it was not possible to determine whether the first or the second scenario is correct because 4 61 has a very low barrier to rotation and the ligand mixture has never been accessed in a ratio grea ter than 45 : 55 ( 4 60 : 4 61 ) favoring 4 61 Because of this practical

PAGE 164

164 experimental problem, the graph could not be expanded and the maximum hypothetical ee is unknown. Nonetheless, these results generally suggest that the ligand with the sense of chirali ty of StackPhim 4 61 is a better ligand for the copper catalyzed A3 reaction in comparison to its diastereomer, StackPhim 4 60 In other words, in this reaction i propyl group i s more reactive and selective than the ligand in which the phosphine is i propyl group (Figure 4 26). Figure 4 26. Spatial orientation of groups in StackPhim 4 60 and 4 61 At this point it is unclear why 4 61 seems to be a better ligand than 4 60 because many factors should be considered to understand reactivity. As shown in Chapter 3, the A3 coupling often presents a non linear effect which makes formulation of a hypothesis very difficult. It is clear that analyzing the free ligand itself does not give us information of reactivity because in the reaction the ligand binds to a copper atom However, it was clear for us that we needed to increase the axial barrier to rotation of StackPhim ligands since optically pure 4 61 was inaccessible due to its low barrier to rotation.

PAGE 165

165 Preparation of the Second Generation of StackPhim Ligands The previously made StackPhim ligands, 4 60 and 4 61 had relatively low barrier to rotation which ultimately led to their epimerization even at room temperature. To make this matter worse the results in the A3 reaction suggested that the inaccessible, less stable diastereomer which ha d the lowest barrier to epimerization ( StackPhim 4 61 ) was the one which had the potential for making the reaction highly enantioselective (Figure 4 25). Naturally w e began wondering how we could increase the barrier to rotation on StackPhim type ligands since this could be fundamental for isolating the desired diastereomeric axially stable pho sphinoimidazolines. Aware of the relative stability of StackPhos, we hypothesized that the barrier to rotation about the biaryl bond would be enhanced by the addition of a substituent to the 5 position of the imidazoline (Figure 4 27) Increasing the barri er to rotation in biaryls by enhancing relatively remote steric interactions is well known and it has first been described for benzene containing biaryls 230 In benzene biaryls such as 4 73 and 4 74 the torsional barr ier is considera bly increased by the hydrogen iodin e exchange at the meta position (23.4 versus 30.1 kcal/ mol). 231 Figure 4

PAGE 166

166 The availability of optically pure chiral amine s such as 4 7 5 ( R R DPEN) was essential to the design of potential StackPhim ligands with relatively higher barrier to rotation. A variety of those enantiopure amines are commercially available or can be readily synthesized, thus it is not surprisin g that these str uctures appear in many chiral ligands employed in asymmetric catalysis. 111 S ynthes e s of 4 7 6 and 4 7 7 w ere initially targeted for two main reasons beyond increasing the barrier to rotation: firs t, both enantiomers of the chiral amine 4 7 5 are commercially available and are relatively cheap ( ~ 5 $ trans version of StackPhos which would eventually allow for very direct comparison. Figure 4 28. Design of StackPhim 4 7 6 and 4 7 7 The preparation of StackPhim 4 7 6 and 4 7 7 was inspired by the preparation of the PIN complexes of Overman 225 and, as a consequence, has some similarities with the synthesis of StackPhim 4 60 and 4 61 (Figure 4 20) The synthesis begins with an amide formation by treating the acyl chloride formed from 4 55 with the chiral amine 4 7 5 (Figure 4 29). The primary amine formed is monopenta fluorobenzylated under basic conditions to afford 4 79 in 62% yield over two steps. Excess POCl 3 in toluene, under reflux, promotes the dehydration of 4 79 toward the StackPhim precursor, the

PAGE 167

167 imidazoline 4 80 The purification of 4 80 is performed by colu mn chromatography and this is the only one required up to this point as a ll the previous intermediates are purified by recrystallization. The phosphine synthesis follows the same previously reported Buchwald procedure, 226 affording StackPhim 4 76 and 4 77 in 54% yield, in a 2.5 : 1 dr ( 4 77 : 4 76 ). This synthetic route h as been successively performed o n gram scale and, in this case, gram scale reactions facilitate d the purification at all synthetic steps Impor tantly, the synthetic sequence is performed with very cheap and readily available reagents and expensive transition metals are avoided This contrasts with the original synthesis of QUINAP 116 and the preparatio n of StackPhos 155 which require a stoichiometric amount of a chiral palladacycle. Figure 4 29. Preparation of StackPhim 4 7 6 and 4 7 7

PAGE 168

168 Remarkably, t he two diastereomeric Stack Phim ligands 4 76 and 4 77 were fully separated by simple column chromatography and both molecules were axially stable in solution at room temperature for long periods of time as seen by NMR spectroscopy. The addition of the phenyl group to the position 5 of the imidazoline indeed increased the barrier to rotation of the newly synthesized ligands and all of these experimental energy values have been measured (vide infra). This is, to the best of our knowledge, the first time in which axially stabilized dia stereomeric phosphinomidazoline ligands have been synthesized, separated and characterized. Their absolute stereochemistry was confir med by X Ray crystallography of StackPhim 4 77 which again shows a parallel stacking between the naphthalene and the pe rfluorinated ring (Figure 4 30) The absolute configuration of the StackPhim 4 76 was assigned by analogy. Figure 4 30 Single crystal X Ray diffraction analysis of StackPhim 4 77 shows the expected stacking Before showing the results given by the second generation of StackPhim ligands in enantioselective transformations, a brief section on the experimentally measured barrier to rotation of all of the ligands shown in Chapter 4 is presented.

PAGE 169

169 Barrier to Rotation of S tackPhim Ligands: Thermal Epimerization Studies The barrier to rotation of atropisomers is the activation energy of the rotation about the chiral axis and in atropisomeric biaryl s the two aryl groups are coplanar in the transition state 232 If atropisomer s have enantiomeric relationship, racemization can occur and, because the two enantiomers have the same energy level, one barrier to rotation is determined. On the other hand, atropdiastereomers do not necessarily have the same energy level and two epimeri zation barriers can arise. It is relatively easy to determine, experimentally, the barrier to rotation about single bonds. It is required, though, to find a method where the racemization (or epimerization) can be instantly followed at a given temperature The two main ways to measure barrier to rotation is by using NMR spectroscopy or liquid chromatography (HPLC). NMR spectroscopy is a very simple and a very useful technique to measure real time epimerization; however it does not work for atropenantiomers. HPLC gives very accurate results, and it can distinguish enantiomers if chiral columns are employed. More details about how the barriers to rotation of the StackPhim ligands were experimentally measured will be found in Chapter 5. Here in, we would like to compare them to the atropisomerization of similar P,N ligands found in the literature. StackPhos had a ba rrier to rotation of 28.4 kcal/ mol as measured by HPLC in dichloroethane at 75 C (Figure 4 3 1 ) 155 Th is is a relatively high energy barrier as the activation energy for the epimerization of 6 membered PINAP is 27.6 kcal/ mol as measured in toluene at different temperatures (> 100 C) by HPLC 196 In theory, PIN AP could have two rotation barriers because PINAP ligands are diastereomeric; however, PINAP diastereomeric ratio is approximately 1 : 1 allowing them to be treated as

PAGE 170

170 enantiomers. The non fluorinated StackPhos ha s a ba rrier to rotation of 26.2 kcal/mol which is 2.2 kcal/ mol lower than the one of StackPhos due to lack of stacking. T he two axially stable StackPhim 4 76 and 4 77 have barrier to rotation s within t he range of StackPhos and PINAP, unlike the StackPhim 4 60 and 4 61 which presented much lower energy barriers. For StackPhim, two energy barriers arise because the atropdiastereomers are not in the same energy level. For example, the barrier to rotation of 4 76 is 26.8 kcal/ mol and of 4 77 is 27.2 kcal/ ol, as measured by NMR in CDCl 3 at 50 C. StackPhim 4 60 and 4 61 have barriers of 25.6 and 24.9 kcal/ mol, resp ectively, as measured by NMR in CDCl 3 at room temperature Figure 4 31. Barrier to rotation of atropisomeric P,N ligands

PAGE 171

171 It is not very surprising that the StackPhim 4 60 and 4 61 are labile as rotational energy barrier are similar to the one of binaphthalene (24 kcal/ mol) which is known to racemize in minutes at 50 C. 193 These results also show that these ligands have a barrier to rotation which is in the borderline of iso merization at room temperature because the energy difference of the axially stable StackPhim 4 76 and the labile StackPhim 4 60 is only 1.2 kcal/ mol (26.8 versus 25.6 kcal/ mol). Moreover, StackPhos, PINAP and StackPhim 4 77 which have the rotation barrie r around 28 kcal/ mol are relatively much more stable. PINAP, for instance, does not epimerize at 80 C in toluene even after 20 hours. Barrier to rotation measurements are important in order to understand the behavior of the free ligands and, because th e energy barrier of some of these P,N ligands are borderline for the isomerization, knowing them can be crucial when analyzing whether or not the isolation of an optically pure sample is possible. However, it should be pointed out that in a given reaction, the ligand will be bound to the metal center and the barrier to rotation can change drastically. The changes can increase or decrease the energy barrier. Taking all this into account, it is possible to imagine that some of the reactions catalyzed by P,N l igands give low enantiomeric excesses because of ligand racemization, especially when the ligand is bidentate which can cause planarization and lower activation energy. Interestingly, failures in asymmetric catalysis of atropisomeric P,N ligands are not us ually attributed to ligand racemization, even when reactions are carried out at high temperatures.

PAGE 172

172 Preparation of the F 5 Phim Ligand as a Non Axially Chiral Control After succeeding in the preparation, isolation and characterization of the StackPhim 4 76 and 4 77 which contain ed the imidazoline chiral centers and a stable chiral axis, we prepared a related PHIM ligand which display s only the chiral centers. The ligand is herein called F 5 Phim and it was prepared to act as a non axially chiral control This ligand is axially labile because it contains a benzene ring, instead of naphthalene, thus the biaryl barrier to rotation decreases drastically. The preparation F 5 Phim 4 84 ligand was carried out using the same synthetic route utilized for the synth esis of 4 76 and 4 77 starting with 2 iodo benzoic acid (Figure 4 32) Figure 4 3 2 Preparation of ligand F 5 Phim 4 84 The ligands StackPhos 3 48 StackPhim 4 76 StackPhim 4 77 and F 5 Phim 4 84 have similar connectivi ties and possibly electronics, but differ drastically on the spatial arrangement of atoms as the se possess different elements of chirality (Figure 4 33).

PAGE 173

173 Figure 4 33. Fluorinated P,N ligands containing chiral centers and chiral axis This set of ligands was designed in order to determine which element of chirality, namely chiral centers and chiral axis, is important in a given asymmetric transformation. For example, if a new asymmetric transformation catalyzed by P,N liga nds is discovered, these ligands could be initially screened to determine which element of chirality gives optimal yield and selectivity. From the results, further optimization can be performed because the four structures allow for relatively simple modifi cations. Copper catalyzed A3 Reaction and the Synthesis of Amino Skipped Diynes The second generation of StackPhim ligands ( 4 76 and 4 77 ) was tested in the A3 reaction toward the propargyl amine 4 70 (or 4 71 ) which was previously performed employing t he first generation of StackPhim ligands ( 4 60 and 4 61 ). As it turns out, the StackPhim 4 76 excelled in the reaction, generating the ( S ) enantiomer of the product ( 4 70 ) in 90% yield and 84 % ee (Figure 4 34). The reaction was carried out for 72 h in ord er to maximize the yield. On the other hand, the StackPhim 4 77 gave the ( R ) enantiomer of the product ( 4 7 1 ) in 38% yield and in very poor 61% ee

PAGE 174

174 Figure 4 34. C opper catalyzed enantioselective A3 reaction with StackPhi m Ligands The analysis of the A3 coupling for the preparation of the propargyl amine 4 70 and 4 71 shows clearly that the reaction is axially controlled. In other words, the axial configuration determines the absolute confirmation of the product since the reactions performed with ( R ax ) ligand gives ( S ) product and vice versa, in all cases. This was somewhat expected by knowing the potential of atropisomeric P,N ligand in the copper catalyzed A3 reaction. 186 None theless, a much more interesting conclusion can be drawn from these reactions. The sense of chirality of StackPhim 4 77 has similarities with the sense of chirality of 4 60 and both of these ligands gave poor enantioselecivities in the reaction (Figure 4 3 5) On the other hand, StackPhim 4 76 has similarities with the inaccessible StackPhim 4 61 and, as expected, 4 76 gave a very good enantioselectivity. For the same reaction, PINAP gives 85% ee 158 which shows t he potential of StackPhim 4 76 in this transformation. It should be noted that the discussion

PAGE 175

175 is based on sense of chirality and not on axial absolute configuration. Similar sense of chirality in this case means for example, that the phosphine is closer i n space to the group at the 4 position of the imidazole in 4 60 and 4 77 However, the best ligands are the ones with the opposite sense of chirality or, in other words, those where the phosphine is more distant from the group at the 4 position ( 4 61 and 4 76 ) This is a very interesting finding that was only discovered once access to axially stabilized PHIM ligands was obtained Figure 4 35. The expected lateral view of all synthesized StackPhim ligands As previously men tioned, the enantioselective synthesis of the amino skipped diynes shown in Chapter 3 was, in fact, discovered in the context of the development of StackPhim ligands. Thus, the preparation of aminodiynes such as 3 72 and its enantiomer 4 85 w as studied wi th all the ligands: StackPhos 3 48 StackPhim 4 76 StackPhim 4 77 and F 5 Phim 4 84 (Figure 4 36) StackPhos 3 48 and StackPhim 4 76

PAGE 176

176 excelled in the reaction, giving 95 and 97% ee, respectively. StackPhim 4 77 and F 5 Phim 4 84 gave very poor yields and 70 and 84% ee, respectively. While the enantioselectivities with these two ligands were reasonably good, the isolated yields were very disappointing. Considering that the ligands are electronically very similar, it is somewhat unexpected that the reactivity varied drastically. The differences in reactivity are reflected in the broad range of isolated yields (15 to 73%). The r eaction is also controlled by the ligand chiral axis as 4 76 and 4 77 gave opposite enantiomers. Nonetheless, the chiral centers have a considerable impact as ligand 4 76 gave 97% ee and 4 77 only 70% ee. More evidence of the impact of the chiral centers in the reaction come s from the result with the non axially chiral ligand 4 84 which remarkably generate d 4 85 in 84% ee. It is possible t hat 4 84 adopts a reactive, axially chiral conformation similar to 4 76 demonstrating how chirality, namely chiral axis, in PHIM and PHOX ligands can be beneficial Figure 4 36. A3 rea ction toward amino skipped diynes using StackPhim ligands

PAGE 177

177 The scope of the copper catalyzed enantioselective A3 reaction using the StackPhim 4 76 is very good, mainly in terms of enantioselectivity (Figure 4 37). Different aldehydes, amines and a lkynes wer e tolerated and the enantioselectivities are similar to the ones achieved with StackPhos (Figure 3 19), the state of the art ligand for this reaction. 155 The scope of the amino skipped diynes was expanded with StackPhos because clearly the reactions were much faster with this ligand. W ith StackPhos, the yields were higher and the scope was broader. 159 Figure 4 37. Scope of the enan tioselective A3 reaction using StackPhim 4 76 The StackPhim ligands showed preliminary potential in asymmetric catalysis and, as a consequence, were explored further.

PAGE 178

178 Copper catalyzed A3 Reaction: Synthesis of 2 Methylamine Heterocycles Five membered he terocycles functionalized at the C2 position appear in many bioactive natural products as well as in lead compounds and clinical agents. 233 Among the diverse set of C2 substituents found in these heterocycles, chiral methylamino groups are highly prevalent and appear in pharmaceutical agents that display a broad range of bioactivities. 234 Select examples of furan, 235 benzofuran 236 and indole 237 heterocycles from natural and non natural sources are shown in Figure 4 38 Figure 4 38. Representative examples of 2 methylamine heterocyclic compounds Traditionally, the synthesis of this highly important non racemic amine motif is accomplished using chiral auxiliary chemistry 238 employing preformed imines and stoichiometric organometallics ( Figure 4 39 ). 239 The heteroaromatic compound can be either in the imine reaction partner or in the organometallic reagent. The preparation of chiral amines using this chemistry is very well developed and there are various combinations of reagents which are robust and reliable for such transformations.

PAGE 179

179 Figure 4 39. Traditional approach for preparation of 2 methylamine heterocycles In the context of asymmetric catalysis, one of the few examples for the preparation of these c hiral amines utilizes a rhodium catalyzed reaction of arylboronic esters with aromatic imines concomitantly reported by Yamamoto 240 Hayashi 241 and, more recently, by Feng and coworkers. 242 The reactions are high yielding and highly enantioselective ; h owever, t he scope is limited and alkyl groups have not been employed (Figure 4 40) Yamamoto reported that heteroaromatic imines and arylboronic acids can be used toward amines such as 4 105 and, interestingly, in the same report showed t hat arylimines and heteroar ylboron ates could be employed toward 4 108 240 Figure 4 40 R hodium catalyzed reaction of arylboronic esters with aromatic imines

PAGE 180

180 Because of the lack of methodologies for prep aring these compounds, a different and modular approach utilizing an alkynylation/cyclization sequence could greatly expand the reaction scope as the heterocycle would no longer be preformed but would instead come from an alkyne ( Figure 4 4 1 ). We hypothesi zed that propargylamines such as 4 110 could be synthesized via asymmetric A3 reaction. The compound 4 110 could then undergo cyclization toward the heteroarylamines 4 109 The alkynes are chiral racemic such as 4 113 and, as a consequence, this strategy c an only be successful if the copper catalyzed A3 is highly ligand controlled. Interestingly, using alkynes as heterocycle surrogates is a well explored concept in chemistry, 81 but examples are scarce in the con text of asymmetric alkynylation reactions. 243 We envisioned that the proposed asymmetric alkynylation/cyclization sequence could be a surrogate for asymmetric heteroarylation reactions. Figure 4 4 1 New approach for prepara tion of 2 methylamine heterocycles Having the preparation of furans in mind, we began using alkynediols as alkynylating agents The copper catalyzed A3 reaction using StackPhos was initially attempted with 3 butyne 1,2 diol, isobutyraldehyde and dibenzylam ine. T he reaction using ( S ) StackP hos as ligand proceeded in only 4h at 0 C, and gave 86% yield of the propargylamine 4 115 as a 1:1 mixture of diastereomers (Figure 4 4 2 ) The reaction tolerates a rarely seen unprotected racemic alkynediol as the alkyne partner, which is quite remarkable as these would likely be problematic in combination with harsh and

PAGE 181

181 highly basic organometallic reagents A gold catalyzed furan synthesis from alkynediols was concomitantly reported by our group 41 and by Akai group, 42 months after our report on the spiroketalization of monopropargylic triols shown in Chapter 2. 43 The furan synthesis is very robust and tolerates various functional groups with extremely high turnover number; however the cyclization of 4 115 was sluggish and generat ed the chiral furylamine 4 116 in only 15% yield after 12 hours The enantiomeric excess of 4 116 was measure d to be only 6 6 % ee. Later on, we were able to show that the gold catalyzed cyclization takes place without racemization so this step was not the source of the low ee. Thus, the copper catalyzed A3 reaction with StackPhos was clearly not very selective. Figure 4 4 2 Preliminary results in the alkynylation/cyclization sequence The reason why StackPhos failed, in terms of enantioselectivity, w hen propargyl alcohols are used as the alkyne source is unknown up to this point. Based on this preliminary result we needed to improve two things to make the new strategy successful. First, the stereo selectivity would need to be improved by a ligand which could deliver high levels of ligand controlled selectivity and second, the yield in the cyclization would also need to be improved. The first problem was solved by the use of the StackPhim 4 76 which delivered the compound 4 118 after the alkynylation/ cyclization sequence in 94% ee (Figure 4

PAGE 182

182 43) It is remarkable that this ligand re ached such a level of stereocontrol in the alkynylation with the racemic alkyne 4 114 The yield of the alkynylation with 4 76 was 76% after only 4h, at 0 C. The problem in the gold catalyzed cyclization was nicely solved by the addition of 1.0 equivalent of TFA to the reaction medium. The basic amine was probably quenching the reaction by sequestrating the proton needed for protodeauration. TFA likely protonate s the basic amine, reestablishing the proton transfer processes needed for the catalytic cycle t urnover. The yield in the gold catalyzed reaction was then improved to 81%. Figure 4 43. Alkynylation/ cylization with StackPhos, StackPhim and F 5 Phim

PAGE 183

183 StackPhim 4 77 which was not a very good ligand in the regular A3 reaction, gave better results than StackPhos as the amine 4 116 was isolated in 82% ee (Figure 4 43) The fact that StackPhim 4 76 and 4 77 ultimately generated opposite enantiomers indicates that t he alkynylation is axially controlled. Finally, the non ax ially chiral ligand F 5 Phim 4 84 gave 4 118 in 81% ee. This set of results confirms our hypothesis that a combination of axial and central chirality in 5 membered P,N ligands can be beneficial to asymmetric catalysis, as both of the StackPhim ligands furni shed higher stereoselectivities than StackPhos and F 5 Phim. Moreover, StackPhim 4 76 was the only ligand which gave an excellent result in terms of stereoselectivity, 94% ee The substrate scope for the alkynylation/ gold cyclization sequence is broad and tolerates aliphatic branched, aliphatic non branched, and aromatic aldehydes, as well as symmetrical and less common non symmetrical secondary amines, all in very goods copper and the gold catalyzed reactions ( Figure 4 44 ). The reaction not only tolerates synthesis of simple furans but also substitution at the C2 and C3 positions Racemic and even a diastereomeric mixture of the alkynes can be employed, which demonstrates how powerful the copper Stac kPhim 4 76 complex is in selecting which face of the iminium the alkyne is added to. Moreover, in this sequence, substitution on the furan is achieved through the use of different alkynes, whereas in other common strategies substitution comes mostly from e lectrophilic aromatic reactions and couplings. 244 This complementary reaction pattern is interesting, as very often late stage functionalization of heteroaromatics is difficult, especially when substitution is preferentially needed at the less nucleophilic C 3 position. 245

PAGE 184

184 Figure 4 44. Scope of the alkynylation/ cyclization toward chiral furylamines To demonstrate that the alkynylation/cyclization sequence can be performed toward other important heterocycles, we have also suc cessfully synthesized the benzofurylamine 4 135 and the indolylamine 4 138 in good enantioselectivities, 84 and 91% ee, respectively (Figure 4 45). The sulfonamide and the phenol were not problematic in the A3 reactions, and the gold cyclization was not ne eded in this case, as the cyclization occurred smoothly under simple basic conditions for both substrates. A similar reaction was also shown in Chapter 3 (Figure 3 22) 168

PAGE 185

185 Fig ure 4 45. Enantioselective synthesis of indolyl and ben zo furylamines Fujii and Ohno demonstrated one example of an enantioselective preparation of an indole containing chiral amine via A3 reaction using QUINAP and PINAP as ligands. 168 The amine 4 140 was prepared via a n one pot alkynylation/ cyclization sequence in excellent yields but low enantioselectivities, 43 and 63% ee with QUINAP and PINAP, respectively (Figure 4 46) In this report, the cyclization occu rred under the A3 coupling conditions, in contrast to the reaction with the StackPhim 4 76 where 4 137 was isolated It is likely that the solvent or the reaction time is responsible for the different outcome; however, the fact that different catalytic spe cies could be formed when PINAP (or QUINAP) and StackPhim are employed cannot be ruled out. Figure 4 46. Enantioselective synthesis of indolylamines using PINAP ligand

PAGE 186

186 One more piece of evidence that StackPhim 4 76 give s superior results when compared to StackPhos when propargyl alcohols are employed as the alkyne source comes from the preparation of the aminoalcohols 4 142 and 4 143 To prepare these compounds, racemic 1 phenyl 2 propyn 1 ol was utilized under the stand ard conditions. The reactions proceeded smoothly giving almost quantitative yields of a 1 : 1 mixture of diastereomers, with both StackPhim 4 76 and StackPhos ligand. The differences in ee, nonetheless, were striking. StackPhos gave 72 and 69% ee while St ackPhim 4 76 gave 93 and 93% ee for the diastereomeric pair. The differences in ee for the diastereomeric pair were, in both cases, minimal, which suggest that the ligand does not discriminate which enant iomer of the alkyne is employed and that the new ste reocenter is completely formed under ligand control. 246 This is desirable since important syn and anti aminoalcohols 247 would be accessible starting with readily available enantioenriched propargyl alcohols. 248 Figure 4 47. Ena ntioselective synthesis of syn and anti 1,4 aminoalcohols With the success of StackPhos and StackPhim ligands in the copper catalyzed A3 reaction, we turned our attention to other enantioselective transformations that are successfully catalyzed by P,N liga nds.

PAGE 187

187 Palladium Catalyzed Enantioselective Baeyer Villiger Oxidation and Silver Catalyzed [3 + 2] cycloaddition of Azometh ine Ylides Stoltz and coworkers have reported an interesting palladium catalyzed Baeyer Villiger oxidation of prochiral cyclobutanone s toward enantioenriched lactones (Figure 4 48) 249 Highly enantioselective oxidation of cyclobutanones has previously been demonstrated enzymatic ally using Baeyer Villiger mono oxi genases ; however, the chemical enantioselective synthesis is very challenging. 250 The reaction reported by Stoltz proceeds via cationic palladium (II) species bound to P,N ligands such as PHOX ligands. Various PHOX congeners were tested during their optimization studies but the maximum enantioselectivity found was 8 0 % using t Bu PHOX The reaction was teste d, under the same conditions, with all the ligands synthesized in Chapter 4 and the conversion was analyzed by 1 H NMR in all cases StackPhim 4 76 and 4 77 gave the best enantioselectivities among our ligands (54 and 50% ee) and generated the opposite enan tiomers 4 146 and 4 145 respectively. This piece of information suggest s that the reaction is somewhat axially controlled and that the combination of the chiral axis and the chiral center s is slightly beneficial to catalysis, at least among our ligands. However, PHOX gave the best enantioselectivies among all the ligands, clearly demonstrating that, for this reaction, the presence of a chiral axis is likely unnecessary. Interestingly, the presence of a chiral axis slows down the reaction as PHOX and F 5 Ph im 4 84 were the only ligands which gave full conversion. One problem with this transformation is that in general, the reactions are very sluggish when carried out at the very low temperatures required for maximizing the enantioselectivity.

PAGE 188

188 Figure 4 48. Palladium catalyzed enantioselective Baeyer Villiger oxidation In the silver catalyzed enantioselective [3+2] cycloaddition of the azomethine ylide precursor 4 147 with t butylacrylate 4 148 251 the StackPhim ligands as well as the StackPhos performed poorly in terms of reactivity as the yields were very low (Figure 4 49). The reaction is again controlled by the axis, which is not very surprising considering that QUINAP is an outstanding ligand for this reaction. 252 The maximum ee obtained in the cycloaddition was 64% with StackPhim 4 77 albeit in a very low yield of 19%. Figure 4 4 9 Silver catalyzed enantioselective [3+2] cycloaddition The palladium catalyzed Baeyer Villiger oxidation an d the silver catalyzed cycloaddition are synthetically useful enantioselective transformations that can, in the future, be optimized to function well with ligands synthesized in our laboratory.

PAGE 189

189 Proposed Model for the Enantioselectivity in the Copper Catal yzed A3 Reaction According to the general catalytic cycle proposed in Chapter 3, the C C bond formation occurs from the intermediate 3 113 to 3 114 (Figure 3 28). The re could be, in between these two intermediates, a transition state in which the P,N liga nd is bidentate, making the copper acetylide more nucleophilic. The d 10 copper (I) center is proposed to be tetrahedral in this transition state since it contains four liga nds: 253 the phosphorus, the nitrogen, the terminal alkyne and the posi tively charged i minium ion Because StackPhos is C 1 symmetric, two main possibilities for the transition state arise, 4 151 and 4 152 Considering that alkynes are relatively small, a transition state such as 4 151 would be favored over 4 152 since there would be a strong steric interaction 4 152 (Figure 4 50 ). Figure 4 50 Proposed trans ition state for the alkynylation of iminium ions The transition state 4 151 could simply be rep resented by the mnemonic 4 155 (Figure 4 5 1 ) Th e mnemonic containing the four quadrants such as 4 155 was first created in order to understand the rhodium BINAP catalyzed hydrogenation of enamides and it has been extended to many other asymmetric transfor mations where the metal center is octahedral, tetrahedral or square planar. 254 In this stereochemical model, a bidentate and C 1 symmetric ligand generates four sterically different

PAGE 190

190 quadrants. With the help of a molecular model, the quadrant 1 was assigned as the most sterically hindered, then quadrant 2 as the second one and so on. Notably, the quadrant 1 is not merely more sterically hindered, but also seems to be closer to the copper atom in comparison with, for example, the quadrant 2. Figure 4 5 1 Proposed stereochemical model for the alkynylation of iminium ions To include the iminium ion in the proposed stereochemical model, the Brgi Dunitz trajectory 255 was considered which render s 4 156 preferred over 4 158 (Figure 4 5 2 ) The transition state corresponding to 4 158 should be higher in energy because of a repulsive interaction between the R 3 substituent on the iminium io n and the quadrant 1 which is non existent in 4 156 Figure 4 5 2 Proposed stereochemical model for the Cu ( S ) StackPhos catalyzed A3 reaction Similarly, the same model can be extended to our alkynylation of quinolinium ion; however, in this case, the most sterically bulky substituent is assigned to the

PAGE 191

191 naphthalene, w hich should be placed in quadrant 4 i nstead of in quadrant 2 (Figure 4 5 3 ) Quadrant four is the least sterically encumbered of all. The model previously proposed by our group for the quinolinium alkynylation using a copper StackPhos complex is slightly d ifferent and it does not seem to be extendable to the A3 reaction. Herein, a unified model is proposed. Figure 4 5 3 Proposed stereochemical model for the Cu ( S ) StackPhos catalyzed quinoline alkynylation The model has a lso been extended to the StackPhim ligands 4 77 and for 4 76 (Figure 4 5 4 ). In fact, the enantiomer of 4 76 has been drawn just for a matter of comparison as in all the drawings the axial configuration is S As mentioned before in the free ligand, the phe nyl group at the 4 position of the imidazoline is closer to the phosphorus atom in the StackPhim 4 77 Nonetheless, when the ligand is bound to copper, the same phenyl group is in closer proximity with the copper atom in StackPhim 4 76 in the direct compa rison with the StackPhim 4 77 This information was taken from analyzing a molecular model and t his is represented with the transition states 4 164 and 4 165 one with the most destabilizing interaction, it is expected that the enantioselectivity is higher when StackPhim 4 76 is utilized. Quadrant 1 is much mor e in accessible in the transition state 4 165 (corresponding to StackPhim 4 76 ). The

PAGE 192

192 transition state proposed for StackPhos, 4 153 assumes an intermediate position between 4 164 and 4 165 This explain s why in some cases the order of stereoselectivity follow s the sequence StackPhim 4 76 StackPhos and StackPhim 4 77 but it does not explain why StackPhos is more selective in some cases. Figure 4 5 4 The proposed differences between StackPhos and StackPhim ligands in the stereo chemical model Th e stereochemical model proposed should be analyzed with caution because there were many proposed requirements, for example, that the ligand is bidentate and tetrahedral. It was also shown in Chapter 3 that the A3 reaction occurs with slig htly positive non linear effects thus, it is very likely that another copper ligand complex is weakly associated with the proposed transition state via either a bridged atom or via ionic interactions. Moreover, it is still unknown the reason why StackPhi m 4 76 is a superior ligand when propargyl alcohols are employed because clearly, in some other cases, StackPhos is a much better ligand in terms of selectivity. In the model proposed

PAGE 193

193 herein we did not address how the substituent on the alkyne can affect t he enantioselectivity. Conclusions and Outlook In conclusion, w e disclosed the preparation, characterization and implementation of new axially chiral phosphino imidazoline ligands called StackPhim. In these ligands the chiral axis was stabilized through stacking interactions which allow ed for the development of the first axially chiral phosphino imidazolines The ( R ax R R ) StackPhim containing two phenyl groups enabled highly enantioselective A3 reactions using alkynols and remarkably both the chiral centers and chiral axis on this ligand have been demonstrated essential for th is reaction. In conclusion, we report the asymmetric preparation of extremely valuable 2 methylamine heterocyclic building blocks that find a myriad of applications in medicinal chemistry. The asymmetric alkynylation of in situ generated iminium ions/cyclization sequence can be seen as a formal heteroarylation of imines, and we believe this alkynylation/cyclization strategy can be extended to other enantioselective heteroarylation s. Finally, we believe that the ligands tested in StackPhos, StackPhim and the no n axially chiral F 5 Phim could, in the future, be tested in any given P,N ligand enantioselective reaction in order to understand which element of chiral ity is essential for enantioselectivity and reactivity. Further optimization and synthesis of analogues can be eventually designed by analyzing the preliminary obtained results.

PAGE 194

194 CHAPTER 5 EXPERIMENTAL SECTION General Considerations All reactions were carried out under an atmosphere of nitrogen unless otherwise specified. Anhydrous solvents were transferred via syringe to flame dried glassware, which had been cooled under a stream of dry nitrogen. Anhydrous tetrahydrofuran (THF), acetonitrile, diethyl e ther, dichloromethane, and pentane were dried using an mBraun solvent purification system. Analytical thin layer chromatography (TLC) was performed using 250 m Silica Gel 60 F254 pre coated plates (EMD Chemicals Inc.). Flash column chromatography was perf ormed using 230 400 Mesh 60A Silica Gel (Whatman Inc.). Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded using Varian Unity Inova 500 MHz and Varian Mercury 300 MHz spectrometers. Chemical shifts ( ) are reported in parts per million (ppm) downfield relative to tetramethylsilane (TMS, 0.0 ppm) or CDCl 3 (7.27 ppm). Coupling constants ( J ) are reported in Hz. Multiplicities are reported using the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; p, pentet; m, multiplet; b broad; Carbon 13 nuclear magnetic resonance ( 13 C NMR) spectra were recorded using a Varian Unity Mercury 300 spectrometer at 75 MHz and a Varian Unity Inova 500 MHz at 125 MHz. Chemical shifts are reported in ppm relative to the carbon resonance of CDCl 3 (77.23 ppm). Phosphorus 31 ( 31 P NMR) and Fluorine 19 ( 19 F NMR) nuclear magnetic resonance spectra were recorded using Varian Unity Mercury 300 spectrometer at 121 MHz, and 281 MHz, respectively. The 31 P NMR chemical shifts were calibrated using an externa l reference sample of 85% H 3 PO 4 in D 2 O. The 19 F NMR chemical shifts were calibrated using an external reference sample of CCl 3 F in CDCl 3 ( 0.0 ppm). Specific Optical

PAGE 195

195 rotations were obtained on a JASCD P 2000 Series Polarimeter (wavelength = 589 nm). High resolution mass spectra (HRMS) were obtained by Mass Spectrometry Core Laboratory of University of Florida, and are reported as m/z (rel ative ratio). A n Agilent 6200 instrument was used for ESI TOF analysis A IonSense DART ET 100 ionization source was coupled to the instrument for DART TOF analysis. Accurate m/z are reported for the molecular ion [M+H] + [M+NH 4 ] + or [M+Na] + Enantiomeric ratios were determined by chiral HPLC analysis (Shimadzu) using Chiralpak IA, Chiralcel OD H and OJ H columns. General Scheme for the Synthesis of Triols and Acetonides Utilized in the Gold Catalyzed Spiroketal Synthesis Figure 5 1. Synthetic route for the synthesis of triols and acetonides employed in the gold catalyzed spiroketal synthesis Preparation of Alkynes and Aldehydes: Synthetic Intermediates for the Triols and Acetonides tert butyl(hex 5 yn 1 yloxy)dimethylsilane ( 5 1 ) Synthesis of alkyne 5 1 was accomplished according to previous reported literature procedure, and the

PAGE 196

196 spectroscopic data matched the reported data for this compound. Obtained as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ): 3.63 (t, 2H, J = 6.0 Hz), 2.24 2.18 (m, 2H), 1.94 (t, 1H, J = 2.7 Hz), 1.56 1.65 (m, 4H), 0.89 (s, 9H), 0.04 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): 84.5, 68.2, 62.6, 31.8, 26.0, 24.9, 18.3, 18.2, 5.3. tert butyl ((2,2 diphenylhex 5 yn 1 yl)oxy)dimethylsilane ( 5 2 ) Synthesis of alkyne 5 2 was accomplished according to previous reported literature procedure, and the spectroscopic data matched the reported data for this compound. Obtained as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ): 7.27 7.11 (m, 10H), 4.10 (s, 2H), 2.51 2.44 (m, 2H), 1.98 1.88 (m, 3H), 0.81 (s, 9H), 0.15 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): 145.8, 128.2, 127.8, 126.0, 85.0, 68.4, 68.0, 51.4, 35.6, 25.8, 18.1, 14.3, 5.9. 3,3 dime thylpent 4 yn 1 ol ( 5 3 ) : Synthesis of the alkynol 5 3 was accomplished according to previously reported experimental procedures, and the spectroscopic data matched the reported data for this compound. Obtained as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ): 3.87 (t, J = 6.6 Hz, 2H), 2.17 (s, 1H ), 1.78 (bs, 1H), 1.73 (t, J = 6.8 Hz, 2H), 1.26 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): 91.4, 68.8, 60.3, 45.2, 29.5, 29.3. tert butyl((3,3 dimethylpent 4 yn 1 yl)oxy)dimethylsilane ( 5 4 ) TBSCl (0.580 g, 3.85 mmol, 1. 1 equiv) was added in one portion to a solution of 5 3 (0.393 g, 3.50 mmol, 1.0 equiv) and imidazole (0.524 g, 7.70 mmol, 2.2 equiv) in dry CH 2 Cl 2 (15 mL) at

PAGE 197

197 room temperature. The reaction was stirred for 12 h and quenched by the addition of water (10 mL). The mixture was diluted with CH 2 Cl 2 (10 mL), and the organic layer was washed with brine (10 mL). The aqueous layer was washed with CH 2 Cl 2 (10mL). The organic layers were combined, dried over MgSO 4 concentrated, and purified by flash chromatography (5% E tOAc/Hexanes) to give 5 4 as a colorless oil (0.547 g, 69%). R f = 0.73 (10% EtOAc/hexanes, KMnO 4 stain). 1 H NMR (300 MHz, CDCl 3 ): 3.83 (dd, J = 7.7 Hz, J = 7.0 Hz, 2H), 2.09 (s, 1H), 1.69 (t, J = 7.4 Hz, 2H), 1.24 (s, 6H), 0.91 (s, 9H), 0.07 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): 91.4, 68.3, 60.9, 45.5, 29.9, 26.2, 26.2, 18.5, 5.0, 5.1. 1 (((3,3 dimethylpent 4 yn 1 yl)oxy)methyl) 4 methoxybenzene ( 5 5 ). To a flask containing t riphenylcarbenium tetrafluoroborate (0.15 1 g, 0.5 mmol, 0.1 equiv) was added, at room temperature, a solution of 5 3 (0.561 g, 5.0 mmol, 1.0 equiv) and 4 methoxybenzyl 2,2,2 trichloroacetimidate (1.413 g, 5.0 mmol, 1.0 equiv) in dry THF (10.0 mL). The mixture was stirred at room temperature for 3 h. Then EtOAc was added (20 mL) and the mixture was washed with 3M NaOH solution (2 x 10 mL). The organic layer was separated, dried over MgSO 4 and evaporated under reduced pressure. The residue was subjected to flash chromatography (0 5% EtOAc/ Hexanes) to furnish the product 5 5 as a colorless oil (0.651 g, 56%). R f = 0.71 (20% EtOAc/hexanes, KMnO 4 stain) 1 H NMR (300 MHz, CDCl 3 ): 7.33 7.25 (m, 2H), 6.93 6.87 (m, 2H), 4.48 (s, 2H), 3.82 (s, 3H), 3.71 (t, J = 7.0 Hz, 2H), 2.13 (d, 1H), 1.80 (t, J = 7.2, 2H), 1.28 (s,

PAGE 198

198 6H). 13 C NMR (75 MHz, CDCl 3 ): 159.3, 130.8, 129.4, 129.3, 113.9, 91.3, 72.8, 68.3, 55.4, 42.3, 29.9, 29.7. Figure 5 2. Synthetic route for the synthesis of alde hydes: synthetic intermediates for triols and acetonides TBSCl (1.506 g, 10 mmol, 1.0 equiv) was added in one portion to a solution of the corresponding commercially available 1,3 propanediol derivative (10 mmol, 1.0 equiv), Et 3 N (2.79 mL, 20.0 mmol, 2.0 e quiv) in dry CH 2 Cl 2 (50 mL) at room temperature. The reaction was stirred for 14 h and quenched by the addition of water (20 mL). The mixture was diluted with CH 2 Cl 2 (20 mL), and the organic layer was washed with brine (30 mL). The aqueous layer was extrac ted with CH 2 Cl 2 (30 mL). The organic layers were combined, dried over MgSO 4 concentrated, and purified by flash chromatography (5 10% EtOAc/Hexanes) to give the alcohol in 80 95% yield. A solution of oxalyl chloride (3.75 mL, 2M in CH 2 Cl 2 7.5 mmol, 1.5 e quiv) was added in a dropwise fashion to a 78C solution of anhydrous DMSO (0.71 mL, 10 mmol, 2.0 equiv) in CH 2 Cl 2 (20 mL). The mixture was stirred for 30 min and the monoprotected alcohol 5 6 5 7 or 5 8 (5 mmol, 1.0 equiv) was added in a dropwise fashio n. The mixture was stirred for 30 min before the addition of Et 3 N (2.09 mL, 15.0 mmol, 3.0 equiv). The reaction was then slowly warmed up to room temperature and stirred for 2 h. If stirring became difficult, CH 2 Cl 2 (20 mL) was added to the reaction mixtu re. After 2 h, the reaction was quenched with the addition of water (20 mL). The

PAGE 199

199 organic layer was successively washed with 5 portions of 10 mL of water and the combined extract was dried over MgSO 4 and concentrated to furnish an oil. The crude residue wa s then dissolved in Et 2 O (10 mL) and a white precipitate was formed, which was then filtered and the residual ether was evaporated under reduced pressure to yield the title aldehydes 5 9 5 10 or 5 11 which were used in the next step without further purif ication. 2 butyl 2 ((( tert butyldimethylsilyl)oxy)methyl)hexanal ( 5 9 ) The following compound was obtained according to the aforementioned general procedure in 78% yield as a slightly yellowish oil. R f = 0.68 (10% EtOAc/h exanes, KMnO 4 stain). 1 H NMR (300 MHz, CDCl 3 ): 9.52 (s, 1H), 3.65 (s, 2H), 1.50 (q, J = 7.5 Hz, 4H), 1.30 (p, J = 7.2 Hz, 4H), 1.20 1.11 (m, 4H), 0.90 (t, J = 7.5 Hz, 6H), 0.87 (s, 9H), 0.03 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): 207.2, 63.9, 54.4, 29.4 25.9, 25.6, 23.6, 14.2, 5.9. 3 (( tert butyldimethylsilyl)oxy) 2 methylpropanal ( 5 10 ) The spectroscopic data of 5 10 matched the reported data for this compound. The aldehyde 5 10 was synthesized in its racemic form in 76% yield as a slightly yellowish oil. R f = 0.71 (20% EtOAc/hexanes, KMnO 4 stain). 1 H NMR (300 MHz, CDCl 3 ): 9.72 (d, J = 1.6 Hz, 1H), 3.83 (dd, J = 10.2 Hz, J = 5.2 Hz, 1H), 3.79 (dd, J = 10.2 Hz, 6.3 Hz, 1H), 2.54 2.49 (m, 1H), 1.07 (d, J = 7.1 Hz, 3H), 0.86 (s, 9H), 0.04 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): 204.7, 63.4, 48.8, 25.8, 18.2, 10.2, 5.6, 5.6.

PAGE 200

200 3 (( tert butyldimethylsilyl)oxy)propanal ( 5 11 ) The spectroscopic data of 5 11 matched the reported data for this compound. Obtained in 83% yield, as a slightly yellowish oil. R f = 0.43 (10% EtOAc/hexanes, KMnO 4 stain). 1 H NMR (300 MHz, CDCl 3 ): 9.77 (t, J =2.1 Hz, 1H, H), 3.96 (t, J =6.0 Hz, 2H), 2.57 (td, J =6.0, 2.1 Hz, 2H), 0.85 (s, 9H), 0.04 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): ( S ) 3 (( tert butyldimethylsilyl)oxy) 4 (( ter t butyldiphenylsilyl)oxy)butanal ( 5 12 ) Synthesis of non racemic 5 12 was accomplished according to a previously reported experimental procedure and the spectroscopic data matched the reported data for this compound. Obtained as a slightly yellowish oil. R f = 0.54 (10% EtOAc/hexanes, KMnO 4 stain). 1 H NMR (300 MHz, CDCl 3 ): 9.86 (t, J = 2.7 Hz, 1H), 7.70 7.65 (m, 4H), 7.48 7.36 (m, 6H), 4.28 4.19 (m, 1H), 3.67 (dd, J = 10.2 Hz, J = 4.5 Hz, 1H), 3.53 (dd, J = 10.2 Hz, J = 7.5 Hz, 1H), 2.78 (ddd, J = 16.2 Hz, J = 4.5 Hz, J = 2.1 Hz, 1H), 2.61 (ddd, J = 16.2 Hz, J = 6.6 H z, J = 3.0 Hz, 1H). 1.06 (s, 9H), 0.01 (s, 3H), 0.06 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ): 201.8, 135.6, 135.5, 133.1, 133.0, 129.8, 129.7, 127.8, 127.7, 68.7, 67.4, 48.8, 26.8, 25.7, 19.1, 17.9, 5.5. ethyl (2S,3S) 5 (b enzyloxy) 3 ((tert butyldimethylsilyl)oxy) 2 methylpentanoate (5 13) Synthesis of the ester 5 13 was accomplished according to

PAGE 201

201 previously reported experimental procedures, and the spectroscopic data matched with the reported data for this compound. The es ter 5 13 was synthesized in its racemic form and obtained as a colorless oil. 1 H NMR (500 MHz, CDCl 3 7.27 (m, 5H), 4.48 (s, 2H), 4.18 4.07 (m, 3H), 3.54 (t, J = 6.8 Hz, 2H), 2.64 (ddd, J= 13.3 Hz, J =7.0 Hz, J =7.0 Hz, 1H), 1.83 1.77 (m, 2H), 1.24 (t, J =7.2 Hz, 3H), 0.86 (s, 9H), 0.04 (s, 6H). 13 C NMR (125 MHz, CDCl 3 ): 174.5, 138.6, 128.3, 127.5, 127.4, 72.8, 70.7, 66.5, 60.2, 45.7, 33.1, 25.8, 18.0, 14.2, 11.6, 24.7, 24.9. (2 S ,3 S ) 5 (benzyloxy) 3 ((tert butyldimethylsilyl)oxy) 2 methylpentanal ( 5 14 ) A solution of diisobutylaluminum hydride in hexanes (9.81 mmol, 1.0 M in hexanes, 3.0 eq uiv) was added to a solution of the ester 5 13 (1.244 g, 3.27 mmol, 1.0 equiv) in CH 2 Cl 2 (15 mL) at 25 C, and the reaction was stirred for 45 min. The reaction was 4 Cl (saturated solution, 20 mL) and Et 2 O (150 mL) was added to the mixture. After 30 min, the aqueous layer was extracted, and the combined extracts dried over MgSO 4 and concentrated to furnish an oil. The residue was subjected to flash chromatography (10% EtOAc/ Hexanes) to provide the primary alcohol as a colorless oil (0.907 g, 82%), which was directly taken to the oxidation step. Dess Martin periodinane (1.14 g, 2.69 mmol, 1.2 equiv) was added to a solution of the alcohol obtained above (0.760 g, 2.25 mmol, 1 equiv) in CH 2 Cl 2 (15 mL) at 0C After 1h, CH 2 Cl 2 (30 mL) was added, followed by NaHCO 3 (saturated solution, 20 mL). The aqueous layer was extracted and the combined extracts dried over MgSO 4 and concentrated to furnish an oil. The residue was subjected to flash chromatography (10% EtO Ac/ Hexanes) to furnish the aldehyde 5 14 as a colorless oil (0.673 g, 89%). R f

PAGE 202

202 = 0.65 (20% EtOAc/hexanes, KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ): 9.73 (d, J = 2.1 Hz, 1H), 7.39 7.25 (m, 5H), 5.31 (s, 2H), 4.53 4.49 (m, 2H), 4.17 (dt, J = 6.7 Hz J = 4.9 Hz, 1H), 2.54 (qdd, J = 7.0 Hz, J = 4.7 Hz, J = 2.1 Hz, 1H), 1.92 1.72 (m, 2H), 1.12 (d, J = 7.1 Hz, 3H), 0.88 (s, 9H), 0.07 (s, 6H). 13 C N MR (125 MHz, CDCl 3 ): 204.9, 138.50, 128.6, 127.8, 73.2, 70.7, 66.5, 53.6, 51.9, 34.9, 26.0, 18.2, 10.3, 4.3, 4.5. Preparation of Triols Employed in the Gold Catalyzed Spiroketal Synthesis Figure 5 3. Synthetic route for the synthesis of triols via an alkynylation reaction To a solution of the protected alkyne 5 1 5 2 5 4 or 5 5 (5 30 mmol, 1.0 equiv) in dry THF (15 100.0 mL) was added n BuLi (2.1 mL per 5 mmol of substrate, 2.5 M in hexanes, 1.05 equiv) dropwise at 78 C. The mixture was kept at this temperature for 30 min, and then stirred at room temperature for 15 min (this was performed by taking the flask out of the acetone/dry ice bath). The reaction mixture was then cooled to 78 C and a solution of the alde hyde 5 9 5 10 5 11 5 12 or 5 14 (5.5 33 mmol, 1.1 equiv) in dry THF (5 20 mL) was added. The mixture was stirred for 1 h at 78 C, then warmed to room temperature and stirred for an additional 1 h. The reaction was diluted with EtOAc (30 150.0 mL) and quenched with saturated NH 4 Cl (10 50.0 mL). The aqueous layer was extracted with EtOAc (2x5 30 mL) and the combined organic extracts were dried over MgSO 4 and evaporated under reduced pressure. The residue was subjected to flash chromatography (0 5% EtOAc/ Hexanes) to furnish the desired

PAGE 203

203 silyl protected monopropargylic triols The diastereomeric protected triols were separated a t this stage by column chromatography without major problems. To a solution of silyl protected monopropargylic triols (0.5 2.0 mmol 1.0 equiv) in a mixture of THF: H 2 O (10 : 1, 10.0 mL per mmol of substrate) at room temperature was added TsOH (0.188 g per mmol of substrate, 0.5 2.0 mmol, 1.0 equiv). The mixture was stirred for 15 h, and quenched with Et 3 N (0.191 mL per mmol of substr ate, 0.5 2.0 mmol, 1.0 equiv). The solvent was removed under reduced pressure, and the residue was subjected to flash chromatography (40 90% EtOAc/ Hexanes) to furnish the desired unprotected monopropargylic triols 2 80 and its analogues. 6,6 dibutyl 2,2,3,3,15,15,16,16 octamethyl 4,14 dioxa 3,15 disilaheptadec 8 yn 7 ol ( 5 15 ) The following compound was obtained according to the aforementioned general procedure. Obtained in 59% yield as a colorless oil. R f = 0.61 (10% EtO Ac/hexanes, KMnO 4 stain). 1 H NMR (300 MHz, CDCl 3 ): 4. 21 ( d, J = 10.0 Hz, 1H), 4. 10 ( d, J = 8.8 Hz, 1H), 3.88 ( d, J = 9.7 Hz, 1H), 3 61 ( t, J = 6.0 Hz, 2H), 3.45 ( d, J = 9.7 Hz, 1H), 2.25 (td, J = 6.8 Hz, J = 1.9 Hz, 2H), 1.67 1.07 (m, 16H), 0.93 0.85 (m, 6H), 0.89 (s, 9H), 0.88 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H), 0.03 (s, 6H). 13 C NMR (75MHz, CDCl 3 ): 86.0, 80.2, 70.2, 68.8, 62.7, 43.3, 32.2, 31.2, 29.6, 26.3, 26.1, 26.0, 25.5, 25.2, 23.8, 18.8, 18.5, 18.3, 14.3, 14.2, 5.2, 5.6. 2,2 dibutylnon 4 yne 1,3,9 triol ( 2 80) The following compound was obtained according to the aforementioned general procedure. Obtained in 85% yield as a colorless oil. R f = 0.14 (40% EtOAc/hexanes, KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ):

PAGE 204

204 4.34 (s, 1H), 3.87 (d, J = 10. 8 Hz, 1H), 3.70 (t, J = 6.2 Hz, 2H), 3.56 (d, J = 11.1 Hz, 1H), 2.97 (bs, 1H), 2.42 (bs, 1H), 2.31 (t, J = 7.6Hz, 2H), 1.77 1.42 (m, 8H), 1.41 1.14 (m, 8H), 0.98 0.87 (q, J = 8.8 Hz, 6H). 13 C NMR (75 MHz, CDCl 3 ): 86.9, 80.1, 70.0, 67.9, 62.4, 43. 6, 31.9, 31.1, 29.9, 25.5, 25.2, 25.1, 23.8, 18.8, 14.3, 14.2. HRMS (DART TOF) m/z: [M+NH 4 ] + Calcd for C 17 H 36 NO 3 + 302.2690; Found 302.2698. ( 6 S ,8 R ) 6 ((tert butyldimethylsilyl)oxy) 2,2,16,16,17,17 hexamethyl 3,3 diphenyl 4,15 dioxa 3,16 disilaoctadec 9 yn 8 ol ( 5 16 ) Synthesis of compound 5 16 was accomplished according to previously reported experimental procedures, and the spectroscopic data matched the reported data for this compound. Obtained as a colorless oil. 1 H N MR (300 MHz, CDCl 3 ): 7.71 7.65 (m, 4H), 7.48 7.35 (m, 6H), 4.69 4.58 (m,1H), 4.12 4.01 (m, 1H), 3.64 (t, J = 5.4 Hz, 1H), 3.62 (dd, J = 10.2, 5.4 Hz, 1H), 3.55 (dd, J = 10.2,7.2 Hz, 1H), 3.04 (d, J = 5.1 Hz, 1H), 2.26 (dt, J = 6.9, 2.1 Hz, 2H), 2.08 (ddd J = 15.2, 8.4, 3.6 Hz,1H), 1.96 (ddd, J = 15.2, 6.9, 3.6 Hz, 1H), 1.67 1.55 (m, 4H), 1.06 (s, 9H), 0.90 (s, 9H), 0.84 (s, 9H), 0.06 (s, 6H), 0.04 (s, 3H), 0.08 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ): 135.6, 135.5, 133.3, 133.2,129.8, 129.7, 127.7, 84.8, 81. 4, 70.9, 66.9, 62.6, 59.9, 41.6, 32.0, 26.8, 26.0, 25.8, 25.1, 19.2, 18.6,18.3, 17.9, 5.2, 5.5. (7 R ,9 S ) 10 (( tert butyldiphenylsilyl)oxy)dec 5 yne 1,7,9 triol ( 2 54 ) Synthesis of compound 2 54 was accomplished according to previously reported experiment al procedures, and the spectroscopic data matched the reported data for this compound. Obtained as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ): 7.68 7.64 (m, 4H), 7.44 7.35

PAGE 205

205 (m, 6H), 4.68 4.57 (m, 1H), 4.28 4.19 (m, 1H), 3.68 3.62 (m, 3H), 3.57 (dd, J = 10.2 Hz, J = 3.6 Hz, 1H), 2.77 (bs, 3H), 2.25 (dt, J = 6.6 Hz, J = 1.8 Hz, 2H), 1.91 1.80 (m, 1H), 1.70 1.53 (m, 5H), 1.07 (s, 9H). 13 C NMR (75 M Hz, CDCl 3 ): 135.5, 135.5, 133.0, 133.0, 129.8, 127.8, 85.3, 81.2, 69.7, 67.7, 62.2, 60.6, 39.4, 31.7, 26.8, 24.8, 19.2, 18.4. (6 S ,8 S ) 6 ((tert butyldimethylsilyl)oxy) 2,2,16,16,17,17 hexamethyl 3,3 diphenyl 4,15 dioxa 3,16 disilaoctadec 9 yn 8 ol ( 5 17 ) Synthesis of compound 5 17 was accomplished according to previously reported experimental procedures, and the spectroscopic data matched the reported data for this compound. Obtained as a colorless oil. 1 H NMR (300 MHz CDCl3): 7.71 7.66 (m, 4H), 7.47 7.35 (m, 6H), 4.62 4.54 (m,1H), 4.02 3.93 (m, 1H), 3.63 (t, J = 5.7 Hz, 1H), 3.62 (dd, J = 9.9, 4.8 Hz, 1H), 3.53 (dd, J = 9.9, 7.2Hz, 1H), 2.83 (d, J = 5.1 Hz, 1H), 2.26 (dt, J = 6.9, 1.8 Hz, 2H), 2.10 (ddd, J = 13.8, 6.6, 4.5 Hz 1H), 2.00 1.90 (m, 1H), 1.66 1.56 (m, 4H), 1.07 (s, 9H), 0.90 (s, 9H), 0.82 (s, 9H), 0.05 (s, 6H), 0.01 (s,3H), 0.12 (s, 3H). 13 C NMR (75 MHz, CDCl3): 135.6, 135.5, 133.2, 133.1, 129.8, 129.7,127.7, 127.7, 85.5, 81.2, 71.0, 68.0, 62.6, 60.8, 43.4, 32. 0, 26.8, 25.9, 25.8, 25.2, 19.2, 18.6, 18.3,17.9, 5.2, 5.6. (7 S ,9 S ) 10 (( tert butyldiphenylsilyl)oxy)dec 5 yne 1,7,9 triol ( 2 56 ) Synthesis of compound 2 56 was accomplished according to previously reported experimental procedures, and the spectroscopic data matched with the reported data for this compound. Obtained as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ): 7.68 7.64 (m, 4H), 7.44 7.35 (m, 6H), 4.64 4.59 (m, 1H), 4.02 3.93 (m, 1H), 3.67 3.61 (m, 3H), 3.57 (dd, J = 10.2 Hz, J = 6.9Hz, 1H), 3.35 (bs, 1H), 3.03 (bs, 2H), 2.23 (dt, J = 6.3 Hz, J =

PAGE 206

206 1.8 Hz, 2H), 1.92 1.81 (m, 2H), 1.74 1.51 (m, 4H), 1.07 (s, 9H) 13 C NMR (75 MHz, CDCl 3 ): 135.5, 133.0, 132.9, 129.8, 127.8, 85.1, 81.1, 71.2, 67.7, 62.2, 61.6, 40.8, 31.6, 26.8, 24.7, 19.2, 18.4. (6 S* ,7 R* ) 2,2,3,3,6,15,15,16,16 nonamethyl 4,14 dioxa 3,15 disilaheptadec 8 yn 7 o l ( 5 18 ) The following compound was obtained according to the aforementioned general procedure in 22% yield as a colorless oil. R f = 0.54 (10% EtOAc/hexanes, KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ): 4.43 (ddd, J = 7.8 Hz, J = 3.4 Hz, J = 1.9 Hz, 1H), 3 .85 (dd, J = 9.8 Hz, J = 9.1 Hz, 1H), 3.77 (d, J = 7.9 Hz, 1H), 3.66 (ddd, J = 9.8 Hz, J = 4.4 Hz, J = 0.7 Hz, 1H), 3.63 (t, J = 6.0 Hz, 2H), 2.27 (td, J = 6.9, 2.1 Hz, 2H), 2.12 (m, 1H), 1.67 1.55 (m, 4H), 0.91 (s, 9H), 0.90 (s, 9H), 0.92 0.86 (m, 3H ), 0.10 (s, 3H), 0.09 (s, 3H), 0.05 (s, 6H). 13 C NMR (125 MHz, CDCl 3 ): 86.1, 79.6, 67.4, 66.9, 62.8, 40.2, 32.2, 26.1, 26.0, 25.4, 18.8, 18.5, 18.3, 12.7, 5.1, 5.4, 5.5. (2 S* ,3 R* ) 2 methylnon 4 yne 1,3,9 triol ( 2 85 ) The following compound was obtained according to the aforementioned general procedure in 47% yield as a colorless oil. R f = 0.40 (pure EtOAc, KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ): 4.48 (dt, J = 4.0 Hz, J = 2.0 Hz, 1H), 3.85 (dd, J = 10.7 Hz, J = 8.6 Hz, 1H), 3.70 3.65 (m, 3H), 2.83 (bs, 3H), 2.29 (td, J = 6.8 Hz, J = 2.0 Hz, 2H), 2.13 2.04 (m, 1H), 1.74 1.57 (m, 4H), 0.93 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ): 86.8, 79.7, 67.1, 66.0, 62.5, 40.5, 31.9, 25.1, 18.7, 12.7. HRMS (DART TOF) m/z: [M+NH 4 ] + Calcd for C 10 H 22 NO 3 + 204.1594; Found 204.1602.

PAGE 207

207 (6 S* ,7 S* ) 2,2,3,3,6,15,15,16,16 nonamethyl 4,14 dioxa 3,15 disilaheptadec 8 yn 7 ol ( 5 19 ) The following compound was obtained according to the aforementioned general procedure in 20% yield as a colorless oil. R f = 0.42 (10% EtOAc/hexanes, KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ): 4.38 (ddt, J = 6.8 Hz, J = 4.9 Hz, J = 2.0 Hz, 1H), 3.89 (dd, J = 10.0 Hz, J = 4.1 Hz, 1H), 3.63 (t, J = 6.0 Hz, 2H), 3.57 (dd, J = 10.0 Hz, J = 6.9 Hz, 1H), 3.37 (d, J = 5.0 Hz, 1H), 2.26 (td, J = 6.9 Hz, J = 2.0 Hz, 2H), 1.90 (qd, J = 6.7 Hz, J = 4.1 Hz, 1H), 1.66 1.54 (m, 4H), 1.00 (d, J = 6.9 Hz, 3H), 0.90 (s, 9H), 0.90 (s, 9H), 0.08 (s, 3H), 0.08 (s, 3H), 0.05 (s, 6H). 13 C NMR (125 MHz, CDCl 3 ): 85.9, 80.4, 67.2, 67.1, 62.8, 41.2, 32.2, 26.2, 26.0, 25.4, 18.8, 18.5, 18.4, 13.2, 5.1, 5.4, 5.4 (2 S* ,3 S* ) 2 methylnon 4 yne 1,3,9 triol ( 2 89 ) The following compound was obtained according to the aforementioned general procedure in 52% yield as a colorless oil. R f = 0.40 (pure EtOAc, KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ): 4.37 (dt, J = 7.0 Hz J = 2.2 Hz, 1H), 3.80 (dd, J = 11.0 Hz, J = 3.9 Hz, 1H), 3.68 (t, J = 6.3 Hz, 2H), 3.64 (dd, J = 11.0 Hz, J = 7.2 Hz, 1H), 2.64 (bs, 3H), 2.28 (td, J = 6.8 Hz, J = 2.0 Hz, 2H), 1.95 (ddt, J = 10.9 Hz, J = 7.0 Hz, J = 3.9 Hz, 1H), 1.74 1.54 (m, 4H), 1.0 0 (dd, J = 7.0 Hz, J = 0.7 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ): 86.4, 80.7, 67.3, 66.7, 62.5, 41.6, 31.9, 25.1, 18.7, 13.3. HRMS (DART TOF) m/z: [M+NH 4 ] + Calcd for C 10 H 22 NO 3 + 204.1594; Found 204.1597.

PAGE 208

208 (5 S *,6 R *) 5 (2 (benzyloxy)ethyl) 2,2,3,3,6,15,15,16,16 nonamethyl 4,14 dioxa 3,15 disilaheptadec 8 yn 7 ol ( 5 2 0 ) The following compound was obtained according to the aforementioned general procedure in 68% yield as a colorless oil. R f = 0.63 and 0.57 for each of the two diastereomers (20% EtOAc/ Hexanes, KMnO 4 stain). 1 H NMR (500 MHz CDCl 3 ): (mixture of diastereomers) 7.38 7.25 (m, 10H), 4.61 (dd, J = 2.3 Hz, J =1.3 Hz, 1H), 4.50 (s, 2H), 4.49 (s, 2H), 4.43 4.37 (m, 1H), 4.04 (q, J = 5.5 Hz, 1H), 3.92 (td, J = 6.1 Hz, J = 4.2 Hz, 1H), 3.68 3.49 (m, 5H), 3.37 (d, J = 4.3 Hz, 1H), 2.45 ( d, J = 4.7 Hz, 1H), 2.25 (tdd, J = 6.8 Hz, J = 3.7 Hz, J = 2.0 Hz, 4H), 1.97 1.77 (m, 8H), 1.69 1.52 (m, 5H), 1.08 (d, J = 7.0 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H), 0.93 0.86 (m, 36H), 0.13 0.04 (m, 24H). 13 C NMR (125 MHz, CDCl 3 ): (mixture of diast ereomers) 138.6, 138.6, 128.6, 127.9, 127.8, 127.8, 127.7, 86.6, 85.7, 80.4, 80.2, 74.0, 73.3, 73.2, 72.0, 66.8, 66.5, 65.4, 64.5, 62.8, 62.8, 44.7, 42.4, 34.6, 33.7, 32.2, 26.2, 26.1, 26.1, 25.4, 18.8, 18.6, 18.2, 18.2, 12.4, 11.8, 4.2, 4.5, 5.1. (8 S ,9 S *) 11 (benzyloxy) 8 methylundec 5 yne 1,7,9 triol ( 2 90 ) The following compound was obtained according to the aforementioned general procedure in 52% yield as a colorless oil. R f = 0.62 and 0.54 for each of the 2 diastereomers (pure EtOAc, KMnO 4 stain) 1 H NMR (500 MHz, CDCl 3 ): (mixture of diastereomers) 7.38 7.24 (m, 10H), 4.54 4.48. (m, 6H), 4.14 (bs, 1H), 4.01 (td, J = 8.9 Hz, J =2.4 Hz, 2H), 3.80 3.57 (m, 6H), 3.61 (t, J = 6.5 Hz, 4H), 2.50 (bs, 2H), 2.30 2.21 (m, 4H), 1.97 1.69 (m, 6 H), 1.71 1.53 (m, 8H), 0.93 (dd, J = 10.6, 6.9 Hz, 6H). 13 C NMR (125 MHz, CDCl

PAGE 209

209 3 ): (mixture of diastereomers) 137.9, 137.8, 128.6, 128.6, 128.0, 127.9, 127.9, 86.0, 80.4, 80.0, 75.2, 74.5, 73.5, 69.1, 66.8, 66.5, 62.2, 44.8, 43.4, 34.3, 34.0, 31.8, 25. 1, 25.0, 18.7, 13.4, 12.8. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 19 H 29 O 4 + 321.2060; Found 321.2051. 2,2,3,3,15,15,16,16 octamethyl 12,12 diphenyl 4,14 dioxa 3,15 disilaheptadec 8 yn 7 ol ( 5 21 ) Synthesis of compound 5 21 was accomplished according to previously reported experimental procedures, and the spectroscopic data matched with the reported data for this compound. Obtained as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ): 7.28 7.13 (m, 10H), 4.60 4.52 (m, 1H), 4.07 (s, 2H), 4.04 3.96 (m, 1H), 3.84 3.76 (m, 1H), 3.24 (d, J = 5.7 Hz, 1H), 2.50 2.43 (m,2H), 2.05 1.76 (m, 4H), 0.90 (s, 9H), 0.78 (s, 9H), 0.08 (d, J = 2.1 Hz, 6H), 0.18 (s, 6H). 13 C NMR (75MHz, CDCl 3 ): 145.9 128.3, 127.8, 126.0, 85.6, 80.5, 68.4, 62.0, 61.2, 51.4, 39.0, 35.8, 25.8, 25.7,18.2, 18.1, 14.5, 5.5, 5.5, 5.9. 8,8 diphenylnon 4 yne 1,3,9 triol ( 2 96 ) Synthesis of compound 2 96 was accomplished according to previously reported experimental proced ures, and the spectroscopic data matched with the reported data for this compound. Obtained as a colorless oil. R f = 0.05 (20% EtOAc/hexanes, KMnO 4 stain). 1 H NMR (300 MHz, CDCl 3 ): 7.30 7.11(m, 10H), 4.55 4.51 (m, 1H), 4.16 (s, 2H), 3.92 3.84 (m, 1H), 3.79 3.71 (m, 1H), 2.43 (t, J = 7.5 Hz, 2H), 2.04 1.79 (m, 4H). 13 C NMR (75 MHz, CDCl 3 ): 145.0, 128.3, 128.0, 126.4, 85.8, 80.8, 67.4, 61.4, 60.2, 51.6, 39.1, 34.8, 14.2.

PAGE 210

210 2,2,3,3,10,10,14,14,15,15 decamethyl 4,13 dioxa 3,14 disilahexadec 8 yn 7 ol ( 5 22 ) The following compound was obtained according to the aforementioned general procedure in 51% as a colorless oil. R f = 0.36 (10% EtOAc/ Hexanes KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ): 4.60 (t, J = 5.5 Hz, 1H), 4.07 3.96 (m, 1H), 3.81 (t, J = 7.5 Hz, 2H), 3.84 3.78 (m, 1H), 2.02 1.90 (m, 1H), 1.89 1.79 (m, 1H), 1.67 (t, J = 7.5 Hz, 2H), 1.22 (s, 6H), 0.91 (s, 9H), 0.90 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H), 0.07 (s, 6H). 13 C NMR (125 MHz, CDCl 3 ): 92.0, 80.9, 62.2, 61.4, 61.1, 45.7, 39.4, 30.0, 29.9, 26.2, 26.1, 18.5, 18.4, 5.0, 5.3. 6,6 dimethyloct 4 yne 1,3,8 triol ( 2 117 ) : The following compound was obtained according to the aforementioned general procedure in 78% yield a colorless oil. R f = 0.31 (pure EtOAc, KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ): 4.60 (dd, J = 6.7 Hz, J = 5.0 Hz, 1H), 3.93 (ddd, J = 11.3 Hz, J = 7.3 Hz, J = 4.3 Hz, 1H), 3.83 (t, J = 6.7 Hz, 2H), 3.84 3.78 (m, 1H), 3.30 (bs, 3H), 1.99 1.85 (m, 2H) 1.71 (t, J = 6.7 Hz, 2H), 1.23 (s, 6H). 13 C NMR (125 MHz, CDCl 3 ): 92.6, 81.5, 61.5, 60.4, 60.3, 45.4, 39.5, 29.9, 29.8, 29.7. HRMS (DART TOF) m/z: [M+NH 4 ] + Calcd for C 10 H 22 NO 3 + 204.1594; Found 204.1603. Preparation of Acetonides Employed in the Gold Catalyzed Spiroketal Synthesis Figure 5 4. Preparation of acetonides from the corresponding triols

PAGE 211

211 To a solution of the unprotected monopropargylic triols (0.2 1.0 mmol, 1.0 equiv) and 2,2 dimethoxypropane (1.23 mL per m mol of substrate, 2.0 10.0 mmol, 10 equiv) in CH 2 Cl 2 (1.0 5.0 mL) was added PPTS (25.1 mg per mmol of substrate, 0.02 mmol 0.1 mmol, 0.1 equiv). The mixture was stirred for 10 min, and then diluted with NaHCO 3 saturated solution (1 5 mL) and EtOAc (5 20 mL ).The organic layer was washed with water (1 3 mL) and brine (1 3 mL), dried over MgSO 4 and concentrated under reduced pressure. The residue was then dissolved in wet CH 2 Cl 2 (2 10mL), and silica gel (1.0 g per mmol of substrate) was added, the mixture was then stirred for 2h and subjected to flash chromatography (5 10% EtOAc/Hexanes) to furnish the desired acetonides 2 82 and its analogues which were taken to the gold catalyzed cyclization. 6 (5,5 dibutyl 2,2 dimethyl 1,3 dioxan 4 yl)hex 5 yn 1 ol ( 2 82 ) The following compound was obtained according to the aforementioned general procedure in 52% as a colorless oil. R f = 0.29 (20% EtOAc/hexanes, KMnO 4 stain). 1 H NMR (300MHz, CDCl 3 ): 4.52 (s, 1H), 3.63 (t, J = 6.2 Hz, 2H ), 3.56 (s, 2H), 2.26 (t, J = 5.7 Hz, 2H), 1.87 1.77 (m, 1H), 1.71 1.53 (m, 3H), 1.41 (s, 6H), 1.37 1.16 (m, 12H), 0.90 (q, J = 6.4 Hz, 6H). 13 C NMR (75 MHz, CDCl 3 ): 99.1, 87.1, 69.2, 65.9, 62.42, 38.5, 33.8, 32.0, 30.2, 28.8, 25.8, 25.6, 24.9, 2 3.9, 23.9, 20.2, 18.9, 14.3, 14.1. HRMS (ESI TOF) m/z: [M+Na] + Calcd for C 20 H 36 NaO 3 + 347.2557; Found 342.2472.

PAGE 212

212 6 ((4 S ,6 S ) 6 ((( tert butyldiphenylsilyl)oxy)methyl) 2,2 dimethyl 1,3 dioxan 4 yl)hex 5 yn 1 ol ( 2 83 ) Synthes is of compounds 2 83 was accomplished according to aforementioned general procedure, and the spectroscopic data matched the reported data for this compound. Obtained in 47% yield as a colorless oil. 1 H NMR (500 MHz, CDCl 3 ): 7.71 7.67 (m, 4H), 7.45 7.33 (m, 6H), 4.69 (tt, J = 5.7 Hz, J = 2.1 Hz, 1H), 4.12 (ddd, J = 10.2 Hz, J = 6.0 Hz, J = 5.1 Hz,1H), 3.72 (dd, J = 10.5 Hz, J = 6.0 Hz, 1H), 3.67 (t, J = 6.3 Hz, 2H), 3.61 (dd, J = 10.5 Hz, J = 5.1 Hz, 1H), 2.28 (dt, J = 6.6 H z, J = 2.1 Hz, 2H), 1.89 1.79 (m, 2H), 1.71 1.58 (m, 4H), 1.54 (s, 3H), 1.36 (s, 3H), 1.06 (s, 9H). 13 C NMR (125 MHz, CDCl 3 ): 135.7, 135.6, 133.6, 133.6, 129.6, 129.6, 127.6, 127.6, 100.2, 85.9, 80.5, 66.8, 66.7, 62.4, 59.3, 34.2, 31.9, 28.0, 26.8, 24. 8, 23.8, 19.3, 18.6. 6 ((4 R ,6 S ) 6 ((( tert butyldiphenylsilyl)oxy)methyl) 2,2 dimethyl 1,3 dioxan 4 yl)hex 5 yn 1 ol ( 2 84 ) The following compound was obtained according to the aforementioned general procedure. Obtained in 45% yield as a colorless oil. R f = 0.41 (40% EtOAc/hexanes, KMnO 4 stain). 1 H NMR (300 MHz, CDCl 3 ): 7.71 7.67 (m, 4H), 7.45 7.33 (m, 6H), 4.66 (dq, J = 10.5 Hz, J = 3.2 Hz, 1H), 4.02 3.90 (m, 1H), 3.70 (dd, J = 10.5 Hz, J = 6.0 Hz, 1H), 3.67 (t, J = 6.3 Hz, 2H), 3.55 (dd, J = 10.5 Hz, J = 5.1 Hz, 1H), 2.29 (td, J = 9.5 Hz, J = 1.5 Hz, 2H), 2.29 (dt, J = 18.0 Hz, J = 2.5 Hz, 1H), 1.69

PAGE 213

213 1.52 (m, 5H), 1.44 (s, 3H), 1.42 (s, 3H), 1.06, (s, 9H). 13 C NMR (75 MHz, CDCl 3 ): 135.8, 133.7, 129.8, 127.9, 127.8, 127.8, 99.2, 85.2, 79.5, 69.6, 67.3, 62.5, 60.7, 35.0, 32.0, 30.1, 27.0, 24.9, 19.6, 19.5, 18.8. HRMS (DART TOF) m/z: [M+NH 4 ] + Calcd for C 29 H 44 NO 4 Si + 498.3034; Found 498.3029. 6 ((4 R* ,5 S* ) 2,2,5 trimethyl 1,3 dioxan 4 yl)hex 5 yn 1 ol ( 2 87 ) The following compound was obtained according to the aforementioned general procedure. Obtained in 52% yield as a colorless oil. R f = 0.29 (20% EtOAc/hexanes, KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ): 4.81 (dt, J = 3.8 Hz, J = 2.0 Hz, 1H), 4.02 (dd, J = 11.7 Hz, J = 3.2 Hz, 1H), 3.67 (t, J = 6.4 Hz, 2H), 3.63 (dd, J = 11.7 Hz, J = 3.1 Hz, 1H), 2.29 (td, J = 6.9 Hz, J = 2.0 Hz, 2H), 2.17 (s, 1H), 1.76 1.57 (m, 4H), 1.47 (s, 3H), 1.45 (s, 3H), 1.22 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ): 99.3, 86.7, 78.5, 65.2, 64.7, 62.6, 33.2, 32.1, 28.9, 25.0, 20.6, 18.9, 12.3. HRMS (DART TOF) m/z: [M+NH 4 ] + Calcd for C 13 H 26 NO 3 + 244.1907; Found 244.1903. 6 ((4 S* ,5 S* ) 2,2 ,5 trimethyl 1,3 dioxan 4 yl)hex 5 yn 1 ol ( 2 89 ) The following compound was obtained according to the aforementioned general procedure. Obtained in 53% yield as a colorless oil. R f = 0.30 (40% EtOAc/hexanes, KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ): 4.2 4 (dt, J = 10.6 Hz, J = 2.0 Hz, 1H), 3.75 (dd, J = 11.9 Hz, J = 5.0 Hz, 1H), 3.67 (t, J = 6.2 Hz, 2H), 3.52 (t, J = 11.6 Hz, 1H), 2.29 (td, J = 6.7 Hz, J =

PAGE 214

214 1.9 Hz, 2H), 1.93 (m, 1H), 1.73 1.56 (m, 4H), 1.45 (s, 3H), 1.44 (s, 3H), 0.88 (d, J = 6.8 Hz, 3H) 13 C NMR (125 MHz, CDCl 3 ): 99.0, 85.9, 78.4, 67.4, 66.0, 62.6, 35.8, 32.1, 29.9, 25.0, 19.0, 18.9, 13.2. HRMS (DART TOF) m/z: [M+NH 4 ] + Calcd for C 13 H 26 NO 3 + 244.1907; Found 244.1911. 6 ((5S*,6S*) 6 (2 (benzyloxy)ethyl) 2,2,5 trimethyl 1,3 dioxan 4 yl)hex 5 yn 1 ol ( 2 92 ) The following compound was obtained according to the aforementioned general procedure. Obtained in 65% yield as a colorless oil. R f = 0.34 and 0.26 for each of the 2 diastereomers (40% EtOAc/ Hexanes, KMnO 4 stain). 1 H NMR (500 MHz CDCl 3 ): (mixture of diastereomers) 7.38 7.24 (m, 10H), 4.65 (dt, J = 5.7 Hz, J = 2.1 Hz, 1H), 4.57 4.44 (m, 4H), 4.24 (dt, J = 10.5Hz, J = 1.9 Hz, 1H), 3.76 (td, J = 9.5 Hz, J = 2.7 Hz, 1H), 3.70 3.52 (m, 9H), 2.28 (tt, J = 6.8 Hz, J = 2.2 Hz, 4H), 2.05 1.90 (m, 2H), 1.81 (ddt, J = 12.0 Hz, J = 7.9, J = 6.0 Hz, 1H), 1.72 1.53 (m, 11H), 1.52 (s, 3H), 1.43 (s, 3H), 1.41 (s, 3H), 1.35 (s, 3H), 0.95 (t, J = 7.1 Hz, 6H). 13 C NMR (125 MHz, CDCl 3 ): (mixture of diastereomers) 138.7, 128.5, 128.5, 127.8, 127. 8, 100.5, 98.9, 88.1, 85.6, 78.7, 78.1, 73.2, 71.5, 69.6, 67.1, 66.7, 66.4, 64.7, 62.4, 40.4, 38.9, 33.8, 33.6, 32.1, 32.0, 30.2, 28.3, 25.0 23.7, 19.5, 18.9, 18.8, 13.4, 13.0. HRMS (DART TOF) m/z: [M+NH 4 ] + Calcd for C 22 H 36 NO 4 + 378.2639; Found 378.2637.

PAGE 215

2 15 6 (2,2 dimethyl 1,3 dioxan 4 yl) 2,2 diphenylhex 5 yn 1 ol ( 2 97 ) The following compound was obtained according to the aforementioned general procedure. Obtained in 50% yield as a colorless oil. R f = 0.19 (20% EtOAc/hexanes KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ): 7.34 7.09 (m, 10H), 4.64 (dq, J = 11.4 Hz, J = 3.5 Hz, 1H), 4.14 (s, 2H), 3.93 (dt, J = 11.6 Hz, J = 2.4 Hz, 1H), 3.81 (ddd, J = 11.6 Hz, J = 4.9 Hz, J = 2.1 Hz, 1H), 2.49 2.39 (m, 2H), 2.05 1.87 (m, 2H), 4 .64 (dq, J = 16.2 Hz, J = 2.8 Hz, 2H), 1.44 (s, 3H), 1.42 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ): 144.9, 128.5, 128.3, 126.8, 99.1, 85.6, 79.3, 68.0, 60.7, 59.6, 52.0, 35.5, 32.4, 29.9, 19.5, 14.6. HRMS (DART TOF) m/z: [M+NH 4 ] + Calcd for C 24 H 32 NO 3 + 382.2377; Found 382.2395. 5 (2,2 dimethyl 1,3 dioxan 4 yl) 3,3 dimethylpent 4 yn 1 ol ( 2 119 ) The following compound was obtained according to the aforementioned general procedure. Obtained in 60% yield as a colorless oil. R f = 0. 32 (40% EtOAc/ Hexanes, KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ): 4.67 (dd, J = 11.2 Hz, J = 2.9 Hz, 1H), 3.94 (td, J = 11.8 Hz, J = 2.9 Hz, 1H), 3.84 (t, J = 6.4 Hz, 1H), 3.86 3.82 (m, 1H), 1.95 (qd, J = 11.9, 4.8 Hz, 1H), 1.72 (t, J = 6.6 Hz, 1H), 1.67 (dq, J = 13.2 Hz, J = 2.7 Hz, 1H), 1.46 (s, 3H), 1.44 (s, 3H), 1.24 (s, 6H). 13 C NMR (125 MHz, CDCl 3 ): 99.1, 92.0, 80.1 60.6, 60.5, 59.5, 45.7, 32.5, 29.8, 29.7, 19.8. HRMS (DART TOF) m/z: [M+NH 4 ] + Calcd for C 13 H 26 NO 3 + 244.1907; Found 244.1911.

PAGE 216

216 Preparation of Monounsaturated Spiroketals: Gold Catalyzed Cyclizatio n of Acetonides and Triols Figure 5 5. Preparation of unsaturated spiroketals from acetonides and triols To a test tube (previously dried in the oven at 120 C overnight), under nitrogen atmosphere, was added AuCl (5 or 10 mol %). Then, a mixture containing the solvent of the reaction (THF or Et 2 O) and the substrate (1.0 mL solvent/ mmol of substrate) was added into the test tube, and the mixture was stirred for 1h. After the reaction to be complete, it was filtered thr ough a short plug of silica, which was flushed with CH 2 Cl 2 and concentrated under reduced pressure to afford the crude mixture that was subjected to flash chromatography (0 2% EtOAc/ Hexanes) to deliver the desired spiroketals. For the more volatile spirok etals 2 86 and 2 118 the plug of silica was flushed with Et 2 O instead of CH 2 Cl 2 and the concentration was performed at ambient pressure passing nitrogen through the sample, and flash chromatography was performed with 0 5% Et 2 O/ pentanes. In the case triol s were employed as substrates, the catalyst. 3,3 dibutyl 1,7 dioxaspiro[5.5]undec 4 ene ( 2 81 ) The following compound was obtained accor ding to the aforementioned general procedure. Obtained in 67% (from acetonide) and 20% (from triol ) yield as a colorless oil. R f = 0.86 (20% EtOAc/

PAGE 217

217 Hexanes, KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ): 5.70 (d, J = 10.1 Hz, 1H), 5.54 (d, J = 10.1 Hz, 1H), 3 .83 (td, J = 11.6 Hz, J = 2.7 Hz, 1H), 3.73 (d, J = 11.1 Hz, 1H), 3.66 3.60 (m, 1H), 3.43 (d, J = 11.5 Hz, 1H), 1.87 (dt, J = 14.2, 4.1 Hz, 1H), 1.71 1.06 (m, 17H), 0.90 (q, J = 6.7 Hz, 6H). 13 C NMR (75 MHz, CDCl 3 ): 137.0, 128.9, 93.2, 67.0, 61.2, 37.1, 36.8, 35.6, 35.6, 35.1, 26.5, 25.8, 25.3, 23.8, 18.9, 14.4. HRMS (DART TOF) m/z: [M+H] + Calcd for C 17 H 31 O 2 + 267.2319; Found 267.2320. ((2 S ,6 S ) 1,7 dioxaspiro[5.5]undec 4 en 2 ylmethoxy)(tert butyl)diphenylsilane ( 2 55 ) The following compound was obtained according to the aforementioned general procedure, and the spectroscopic data matched with the reported data for this compound. Obtained in 72% (from trans acetonide ), 74% (from cis acetonide ), 95% (from anti triol ) and 30% (from syn triol ) yield as a colorless oil. R f = 0.89 (40% EtOAc/ Hexanes, KMnO 4 stain). 1 H NMR (300 MHz, CDCl 3 ): 7.78 7.71 (m, 4H), 7.46 7.35 (m, 6H), 5.99 (dt, J = 10.0 Hz, J = 5.0 Hz, 1H), 5.67 (d, J = 10.0 Hz, 1H), 4.05 4.17 4.08 (m, 1H), 3.97 (dt, J = 12.0, 2.7 Hz, 1H), 3.79 (dd, J = 10.2, 6.6 Hz, 1H), 3.68 (dd, J = 10.2, 4.5 Hz, 1H), 3.63 3.57 (m, 1H), 2.35 (dddt, J = 18.0 Hz, J = 9.0 Hz, J = 5.5 Hz, J = 2.5 Hz, 1H), 2.01 1.93 (m, 3H), 1.73 1.45 (m, 5H), 1.06 (s, 9H). 13 C NMR (75 MHz, CD Cl 3 ): 135.8, 135.7, 133.9, 130.9, 129.5, 127.6, 93.4, 70.6, 67.7, 57.6, 34.7, 27.1, 26.8, 24.8, 19.3, 18.6.

PAGE 218

218 (3 R* ,6 R* ) 3 methyl 1,7 dioxaspiro[5.5]undec 4 ene ( 2 86 ) The following compound was obtained according to the aforem entioned general procedure. Obtained in 77% ( from cis acetonide ), 67% ( from trans acetonide ), 15% ( from syn triol ) and 15% (from anti triol ) yield as a colorless oil. R f = 0.59 (20% EtOAc/ Hexanes, KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ): (major diastereo mer 2 86 ) 5.76 (d, J = 10.1 Hz, 1H), 5.62 5.55 (m, 1H), 3.89 3.82 (m, 1H), 3.70 (dd, J = 11.1 Hz, J = 6.0 Hz, 1H), 3.66 3.61 (m, 2H), 3.49 (t, J = 10.8 Hz, 1H), 2.47 2.35 (m, 1H), 1.86 (m, 1H), 1.73 1.45 (m, 6H), 0.96 0.87 (m, 3H). (minor diast ereomer 5 23 ) 5.90 (dd, J = 10.2 Hz, J = 5.4 Hz, 1H), 5.62 5.54 (m, 1H), 4.07 (dd, J = 11.1 Hz, J = 3.8 Hz, 1H), 3.89 3.81 (m, 1H), 3.66 3.61 (m, 1H), 3.49 (d, J = 11.1 Hz, J = 1.1 Hz, 1H), 2.08 2.01 (m, 1H), 1.86 (m, 1H), 1.74 1.46 (m, 6H), 1.10 (d, J = 7.1 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ): misture of diastereomers) 134.6, 133.5, 129.8, 129.6, 93.1, 64.8, 63.9, 61.2, 61.2, 35.0, 29.5, 29.3, 25.2, 18.9, 18.8, 18.3, 16.1. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 10 H 17 O 2 + 169.1223; Found 169.1227. ( 2 R *,3 S *,6 S *) 2 (2 (benzyloxy)ethyl) 3 methyl 1,7 dioxaspiro[5.5]undec 4 ene ( 2 91 ) The following compound was obtained according to the aforementioned general procedure. Obtained in 52% (from acetonide ), and 10% (from triol ) yield as a colorless oil. R f = 0.65 (20% EtOAc/ Hexanes, KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 7.25 (m, 5H), 5.67 (dd, J = 10.0 Hz, J =1.8 Hz, 1H), 5.58 (dd, J = 10.0 Hz, J =2.5 Hz, 1H), 4.55 (s, 2H), 3.81 3.68 (m, 3H), 3.68 3.55 (m, 2H), 2.16 2.01 (m, 2H), 1.90 1.79 (m, 1H), 1.79 1.69 (m, 1H), 1.68 1.53 (m, 4H), 1.51 1.44 (m, 1H),

PAGE 219

219 0.97 (d, J = 7.2 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ): 127.9, 127.7, 93.5, 73.3, 70.5, 67.6, 61.3, 35.2, 34.9, 33.6, 25.3, 18.8, 17.0. HRMS (DART TOF) m/z: [M+H] + Calcd for C 19 H 27 O 3 + 303.1955; Found 303.1955. 9,9 diphenyl 1,7 dioxaspiro[5.5]undec 4 ene ( 2 39 ) The following compound was obtained according to the aforementioned general procedure, and the spectroscopic data matched with the reported data for this compound. Obtained in 74% (from acetonide ), and 81% (from triol) yield as a colorless oil. R f = 0.70 (20% EtOAc/ Hexanes, KMnO 4 stain). 1 H NMR (300 MHz, CDCl 3 ): 7.48 7.31(m, 2H), 7.30 7.15 (m, 8H), 5.99 5.93 (m, 1H), 5.53 (ddd, J = 10.2 Hz J =2.7 Hz J = 1.5 Hz, 1H), 4.32 (dd, J =11.7 Hz, J = 3.0 Hz, 1H), 4.00 3.90 (m, 2H), 3.80 3.74 (dd, J =11.1 Hz, J = 6.3 Hz, 1H), 2.88 (dt, J = 13.2 Hz, J = 3.9 Hz, 1H), 2. 38 2.20 (m, 2H), 1.89 (dt, J = 18.0 Hz, J = 4.5 Hz, 1H), 1.66 (dt, J = 13.5 Hz, J = 3.6 Hz, 1H), 1.48 (dt, J =13.5, J = 3.6 Hz, 1H). 13 C NMR (75 MHz, CDCl 3 ): 146.6, 145.3, 130.1, 128.5, 128.3, 128.2, 128.0, 127.0, 126.3, 125.8, 92.5, 67.5, 57.8, 45.4, 31.2, 29.3, 24.7. 1,1 dimethyl 6 oxaspiro[4.5]dec 9 ene ( 2 118 ) The following compound was obtained according to the aforementioned general procedure. Obtained in 47% (from acetonide ), and 45% (from triol ) yield as a colo rless oil. R f = 0.55 (20% EtOAc/ Hexanes, KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ): 6.14 (dd, J = 11.1 Hz, J = 7.4Hz, 1H), 5.68 (d, J = 10.2 Hz, 1H), 3.90 (m, dd, J = 19.9 Hz, J = 9.8 Hz, 2H), 3.93 3.86 (m,

PAGE 220

220 1H), 3.75 (dd, J = 12.1 Hz, J = 5.6 Hz, 1H), 2.24 (t, J = 15.1 Hz, 1H), 2.16 (q, J = 10.4 Hz, 1H), 1.84 (d, J = 18.0 Hz, 1H), 1. 70 1.61 (m, 1H), 1.03 (s, 3H), 1.02 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ): 131.8, 124.8, 104.7, 65.1, 58.8, 45.4, 38.9, 25.2, 25.1, 22.2. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 10 H 17 O 2 + 169.1223; Found 169.1228. Preparation of Cyclobutane via Gold Catalyz ed Dimerization of Allenoether Figure 5 6. Synthetic route for the cyclobutane via dimerization of allenoether 6 (( tert butyldimethylsilyl)oxy) 3,3 dimethylhex 4 yn 1 ol ( 2 120 ) To a solution of 5 5 (0.232 g, 1.0 mmol, 1.0 equiv) in dry THF (5.0 mL) was added n BuLi (0.48 mL, 2.5 M in hexanes, 1.2 mmol, 1.2 equiv) dropwise at 78C. The mixture was kept at this temperature for 30 min, and then stirred at room temperature for 15 min (t his was performed by taking the flask out of the acetone/dry ice bath). After the reaction mixture was cooled to 78 C, the flask was quickly opened and paraformaldehyde (0.600 g, 20.0 mmol, 20.0 equiv) was added. The mixture was stirred for 30 min at 78 C, then warmed to room temperature and stirred for an additional 1 h. The reaction was diluted with EtOAc (15.0 mL) and quenched with saturated NH 4 Cl (10.0 mL). The

PAGE 221

221 aqueous layer was extracted with EtOAc (2x10 mL) and the combined organic extracts were d ried over MgSO 4 and evaporated under reduced pressure. The residue was subjected to flash chromatography (5% EtOAc/ Hexanes) to furnish the product 5 24 (0.126 g, 48%) as a colorless oil. R f = 0.15 (20% EtOAc/ Hexanes, KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ): 7.26 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.45 (s, 2H), 4.23 (s, 2H), 3.81 (s, 3H), 3.65 (t, J = 7.2 Hz, 2H), 1.76 (t, J = 7.2 Hz, 2H), 1.23 (s, 6H). 13 C NMR (125 MHz, CDCl 3 ): 159.3, 130.8, 129.5, 114.0, 93.1, 78.6, 72.8, 67.9, 55.5, 51.6, 42.4, 30.1, 29.8. TBSCl (0.068 g, 0.45 mmol, 1.5 equiv) was added in one portion to a solution of 5 24 (0.079 g, 0.3 mmol, 1.0 equiv) and imidazole (0.061 g, 0.9 mmol, 3.0 equiv) in dry CH 2 Cl 2 (5 mL) at room temperature. The reaction was stirred for 13 h and quenched by the addition of water (2 mL). The mixture was diluted with CH 2 Cl 2 (10 mL), and the organic layer was washed with brine (4 mL). The aqueous layer was washed with CH 2 Cl 2 (2 mL). The organic layers were combined, dried over MgSO 4 concentrated and the compound 5 25 (0.107 g, 95%) as a colorless oil was taken to the next step without further purification. R f = 0.67 (20% EtOAc/ Hexanes, KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ): 7.27 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 4.44 (s, 2H), 4 .30 (s, 2H), 3.81 (s, 3H), 3.66 (t, J = 7.7 Hz, 2H), 1.76 (t, J = 7.4 Hz, 2H), 1.22 (s, 6H), 0.92 (s, 9H), 0.12 (s, 6H). 13 C NMR (125 MHz, CDCl 3 ): 159.3, 130.9, 129.4, 127.7, 114.0, 91.8, 79.1, 72.9, 68.1, 64.9, 55.5, 52.2, 42.5, 30.1, 29.8, 26.2, 26.1 18.5, 4.8. DDQ (0.055 g, 0.24 mmol, 1.2 equiv) was added in one portion to a solution of 5 25 (0.079 g, 0.2 mmol, 1.0 equiv) in dry CH 2 Cl 2 : H 2 O (9 : 1, 10 mL) at room temperature. The reaction was stirred for 2 h and the precipitated formed was filtere d off

PAGE 222

222 over a plug of celite. Celite was washed with with CH 2 Cl 2 (20 mL). The crude mixture was then washed with NaHCO 3 saturated solution (5 mL) The organic layer was washed with water (2x5 mL), combined, dried over MgSO 4 and concentrated. Flash chromato graphy (1 10% EtOAc/ Hexanes) gave the title compound 2 120 (0.024 g, 45%) as a colorless oil. R f = 0.33 (20% EtOAc/ Hexanes, KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ): 4.29 (s, 2H), 3.84 (t, J = 6.6 Hz, 2H), 1.71 (t, J = 6.6 Hz, 2H), 1.24 (s, 6H), 0.91 (s 9H), 0.12 (s, 6H). 13 C NMR (125 MHz, CDCl 3 ): 92.0, 79.8, 60.7, 52.1, 45.6, 29.8, 29.7, 26.0, 26.0, 18.5, 4.8. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 14 H 29 O 2 Si + 257.1931; Found 257.1942. 1 (3,3 dimethyldihydrofuran 2( 3H) ylidene) 8,8 dimethyl 3 methylene 5 oxaspiro[3.4]octane (2 121 ). To a test tube (previously dried in the oven at 120C overnight), under nitrogen atmosphere, was added [( t Bu) 2 ( o 6 ] f substrate). Then, a mixture containing THF (2.1 mL) and the compound 2 120 (0.0532 g, 0.21 mmol, 1.0 equiv) was added into the test tube, and the mixture was stirred for 20 min. After TLC showed that the reaction was complete, the mixture was filtered through a short plug of silica, which was flushed with CH 2 Cl 2 : Et 3 N (99 : 1) and concentrated under reduced pressure to afford the crude mixture that was subjected to flash chromatography (1% Et 3 N/ 20 50% CH 2 Cl 2 / Hexanes) to deliver the title compound 2 12 1 (0.010 g, 39%) as a colorless oil. R f = 0.69 (20% EtOAc/ Hexanes, KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ): 4.99 (dt, J = 2.3 Hz, J = 1.1 Hz, 1H), 4.83 (dt, J = 2.2 Hz, J = 1.1 Hz, 1H), 4.18 4.06 (m, 2H),

PAGE 223

223 4.04 3.99 (m, 2H), 2.92 (dt, J = 17.7 Hz, J = 2.4 Hz, 1H), 2.65 (dt, J = 17.7 Hz, J = 1.0 Hz, 1H), 2.11 (dt, J = 12.1 Hz, J = 9.1 Hz, 1H), 1.79 (ddd, J = 12.1 Hz, J = 5.4 Hz, J = 4.1 Hz, 1H), 1.72 (ddd, J = 15.0 Hz, J = 11.2 Hz, J = 4.3 Hz, 1H), 1.51 (ddd, J = 13.6 Hz, J = 3.9 Hz, J = 2.6 Hz, 1H), 1 .26 (s, 3H), 1.19 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ): 152.5, 151.8, 117.3, 105.3, 99.4, 66.2, 64.0, 43.6, 41.3, 40.4, 36.7, 30.7, 30.5, 29.4, 28.4, 25.2. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 16 H 25 O 2 + 249.1849; Found 249.1851. Determination of the Relative Stereochemistry of Acetonides and Triols Regard ing the relative stereochemistries of the diastereomeric pair of acetonides 2 83 / 2 84 and 2 87 / 2 89 it is important to mention that these were directly determined, while stereochemistry of the precursors were indirectly determined, based on the assignment of the acetonides. Thus, relative stereochemistries of the acetonides were extrapolated to the triols. According to Rychnovsky and coworkers, 1,3 cis acetonides and 1,3 trans acetonides present different 13 C NMR chemical shifts for the 2 diastereotopic g em dimethyl groups of the acetonide. 1,3 cis acetonides are most likely in the most stable chair conformation, the chemical shifts of the axial and equatorial methyl groups are different, with values around 20 and 30 ppm, respectively. Differently, 1,3 tra ns acetonides can be distorted to a twisted boat conformation so that the methyl groups become pseudo axial and pseudo equatorial, and both methyl groups should have chemical shifts closer to 25 ppm. The diastereomers 2 83 and 2 84 were first analyzed, and in the case of 2 83 the signals corresponding to the methyl groups appear at 28.0

PAGE 224

224 and 23.8 ppm, meaning that 2 83 has a 1,3 trans relative stereochemistry. The signals for 2 84 appear at 30.1 and 19.6 ppm, thus 2 84 has a 1,3 cis relative stereochemistry. Figure 5 7. Determination of the relative stereochemistry of 1,3 acetonides After determining the relative stereochemistry of 2 83 and 2 84 the relative stereochemistry of the compounds 2 87 and 2 89 were assigned by analyzing the 1 H NMR chemical shift of the propargylic proton. Considering the chair conformation as the most stable one, it is expected that axial protons should appear in more shielded regions. For 2 87 the propargylic proton appears at 4.8 ppm, and in 2 89 at 4.2 ppm. Figure 5 8. Determination of the relative stereochemistry of 1,2 acetonides

PAGE 225

225 Determination of the Relative Stereochemistry of Spiroketals For the assignment of the relative stereochemistries of the spirok etals, it is important to note that all major diastereomers formed in the gold catalyzed reactions are thermodynamic spiroketals. In other words, the major diastereomers synthesized in this project are pseudoanomeric spiroketals containing the maximum numb er of substituents in the pseudoequatorial position. Previously, it was demonstrated that compound 2 55 could be hydrogenated to form the anomeric saturated spiroketal 5 26 which was synthesized under thermodynamic conditions. As a consequence, the stereo chemistry at the spirocarbon could easily be extrapolated, since 2 56 has a doubly anomeric spirocarbon, and the substituent in the equatorial position. Figure 5 9. Determination of the relative stereochemistry of spiroke tals through the synthesis of an anomeric spiroketal The stereochemistry of the other spiroketals were assigned by comparison with the spiroketal 2 55 and with the unsaturated spiroketals 5 28 and 5 29 synthesized by Brimble and coworkers. In this report, the chemical shifts of the olefinic protons (in the position with relation to the spirocarbon) for the diastereomers 5 28 and 5 29 were 5.9 and 6.1 ppm, respectively. A direct comparison with other spiroketals synthesized in the project showed that the major spiroketals show, in all cases, the presence of a more shielded signal for the same type of proton, in comparison with the minor diastereomer. Note that the major diastereomer 2 86 shows, in the 1 H NMR spectrum, a signal at 5.7

PAGE 226

226 ppm, while the minor 5 23 presents a more deshielded signal at 5.9 ppm. The same occurs with the pair of diastereomers 2 91 and 5 27 Figure 5 10. Determination of the relative stereochemistry of major and minor spiroketals synthesized through the gold catalyzed spiroketalization Preparation of Aldehydes, Alkynes and Amines Employed as Starting Materials in the Synthesis of Amino Skipped Diynes Figure 5 11 Preparation of alkynyl aldehydes via alkynylation of DMF According to a similar literature procedure, a n BuLi solution (2.0 M) in hexanes (3.64 mL, 9.105 mmol, 1.0 equiv) was added, at 78 C, to a stirr ed solution of phenylacetylene (0.930 g, 9.105 mmol, 1.0 equiv) in THF (25 mL). The mixture was stirred f or 30 minutes, and the flask containing the reaction mixture was taken out of the

PAGE 227

227 dry ice/acetone bath and stirred for 10 minutes and place again in the 78 C bath. Then, DMF (1.40 mL, 18.210, 2.0 equiv) was added and the reaction was stirred at 78 C fo r 10 minutes, warmed up to room temperature and stirred for 45 minutes. The reaction mixture was poured into a stirred solution prepared from a 10% aqueous solution of KH 2 PO 4 (100 mL) and Et 2 O (100 mL) cooled to 0C and stirred for 5 min. The organic layer was washed with water (50 mL), separated, dried over MgSO4, filtered and concentrated under reduced pressure to give a residue which was purified through flash column chromatography on silica gel (0 5% EtOAc in hexanes) to afford the desired alkynyl alde hyde 3 68 in 75% yield (0.889 g, 8.092 mmol) as a yellowish oil. 3 phenylpropiolaldehyde ( 3 68 ) The synthesis of 3 68 was accomplished according to the aforementioned representative procedure and 3 68 was stable over the period of months upon storage at 5C. The spectroscopic data matched the reported data for this compound. The compound 3 68 was obtained as a yellowish oil in 75% yield (0.889 g, 8.092 mmol). R f = 0.47 (10% EtOAc in hexanes). 1 H NMR (50 0 MHz, CDCl 3 ) d 9. 44 (s, 1H), 7.66 7.57 (m, 2H), 7.53 7.48 (m, 1H), 7.45 7.39 (m, 2H). 3 (triisopropylsilyl)propiolaldehyde ( 5 30 ) The synthesis of 5 30 was accomplished according to the aforementioned representative procedure and 5 30 was stable over the periods of months upon storage at 5C. The spectroscopic data matched the reported data for this compound. The compound 5 30 was obtained as a

PAGE 228

228 colorless oil in 78% yield (1.475 g, 7.023 mmol). R f = 0.70 (10% EtOAc in hexanes). 1 H N MR (500 MHz, CDCl 3 ) 9.21 (s, 1H), 1.12 (s, 18H), 1.12 1.10 (m, 3H). oct 2 ynal ( 5 31 ) The synthesis of 5 31 was accomplished according to the aforementioned representative procedure and 5 31 was stable over the periods of weeks upon sto rage at 5C. The spectroscopic data matched the reported data for this compound. The compound 5 31 was obtained as a colorless oil in 86% yield (1.627 g, 13.102 mmol). R f = 0.60 (10% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 ) 9.19 (s, 1H), 2.42 (s, 2H), 1.72 1.50 (m, 2H), 1.52 1.24 (m, 4H), 0.92 (td, J = 7.2, 1.4 Hz, 3H). Figure 5 12. Preparation of alkynyl aldehydes via Sonogashira followed by oxidation According to a similar literature procedure, CuI (47.6 mg, 0. 25 mmol, 5 mol %), PdCl 2 (PPh 3 ) 2 (175.5 mg, 0.25 mmol, 5 mol %) and propagyl alcohol (0.37 mL, 6.25 mmol, 1.25 equiv) were added to a stirred solution of 1 bromo 4 iodobenzene (1.415 g, 5.000 mmol, 1.0 equiv) in Et 3 N (13.9 mL, 100 mmol, 20 equiv), at room t emperature. The mixture was stirred for 12 h, concentrated under reduced pressure and submitted to

PAGE 229

229 flash colum chromatography on silica gel (40% EtOAc in hexanes) to afford the 3 (4 bromophenyl)prop 2 yn 1 ol (0.988 g, 4.70 mmol) in 94 % yield as a yellow solid. According to a similar literature procedure, PCC (0.689 g, 3.198 mmol, 1.5 equiv) and celite (0. 689 g) were added to a stirred solution of 3 (4 bromophenyl)prop 2 yn 1 ol (0.450 g, 2.132 mmol, 1.0 equiv) in dichloromethane (20 mL), at room temperat ure. The mixture was stirred for 12 h and directly submitted to flash column chromatography on silica gel (10% EtOAc in hexanes) to afford the 3 (4 bromophenyl)propiolaldehyde 5 35 (0.272 g, 1.30 mmol) in 61% yield as a yellow solid. 3 (4 bromophenyl)propiolaldehyde ( 5 35 ) The synthesis of 5 35 was accomplished according to aforementioned representative procedure and 5 35 was stable over the periods of months upon storage at 5C. The spectroscopic data matched the reporte d data for this compound. The compound 5 35 was obtained as a yellow solid in 61% yield (0.272 g, 1.30 mmol) R f = 0.56 (20% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 ) 9.37 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.42(d, J =8.4Hz, 2H). 3 (4 bromophenyl)prop 2 yn 1 ol ( 5 32 ) The synthesis of 5 32 was accomplished according to aforementioned representative procedure. The spectroscopic data matched the reported data for this compound. The compound 5 32 was obtained as a yellow solid in 94% yield (0.988 g, 4.70 m mol) R f = 0.09 (20% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 ) 7.43 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 4.48 (s, 2H), 2.12 (bs, 1H).

PAGE 230

230 3 (4 methoxyphenyl)propiolaldehyde ( 5 36 ) The synthesis of 5 36 was accomplished according to the aforementioned representative procedur e and 5 36 was stable over the period of months upon storage at 5C. The spectroscopic data matched the reported data for this compound. The compound 5 36 was obtained as a yellow solid in 41% yield ( 0.194g, 1.21 mmol) R f = 0.56 (20% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 ) 9.37 (s, 1H), 7.53 (dd, J = 7.0, 2.0 Hz, 2H), 6.89 (dd, J = 7.0, 2.0 Hz, 2H), 3.82 (s, 3H). 3 (4 methoxyphenyl)prop 2 yn 1 ol ( 5 33 ) The synthesis of 5 33 was accomplished according to the aforementioned representative procedure. The spectroscopic data matched the reported data for this compound. The compound 5 33 was obtained as a yellow solid in 85% yield ( 1.051 g, 6.48 mmol) R f = 0.20 (20% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 ) 7.38 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 4.49 (d, J = 4 .4 Hz, 2H), 3.82 (s, 3H), 1.77 (bs, 1H). 3 (thiophen 2 yl)propiolaldehyde ( 5 37 ) The synthesis of 5 37 was accomplished according to the aforementioned representative procedure and 5 37 was stored at 5C and freshly use d. The spectroscopic data matched the reported data for this compound. The compound 5 37 was obtained as a yellow solid in 37% yield (0.219,

PAGE 231

231 1.61 mmol). R f = 0.50 (20% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 ) 9.41 (d, J = 0.7 Hz, 1H), 7.68 7.44 (m, 2H), 7.11 (ddd, J = 5.0, 3.7, 0.7 Hz, 1H). 3 (thiophen 2 yl)prop 2 yn 1 ol ( 5 34 ) The synthesis of 5 34 was accomplished according to the aforementioned representative procedure. The compound 5 34 was obtained as an orange solid in 82% yield (1.108 g, 8.02 mmol). R f = 0.20 (20% EtOAc in hexanes) 1 H NMR (500 MHz, CDCl 3 ) 7.28 (dd, J = 5.2, 1.2 Hz, 1H), 7.24 (dd, J = 3.6, 1.2 Hz, 1H), 6.99 (dd, J = 5.2, 3.6 Hz, 1H), 4.53 (s, 2H), 2.25 (bd, J = 23.2 Hz, 1H). Figure 5 13. Preparation of alkynyl aldehydes containing a sulfonamide group 3 (2 aminophenyl)prop 2 yn 1 ol ( 5 38 ) According to a similar literature procedure, CuI (43.5 mg, 0.23 mmol, 5 mol %), PdCl 2 (PPh 3 ) 2 (160.2 mg, 0.2 3 mmol, 5 mol %) and propagyl alcohol (0.34 mL, 5.70 mmol, 1.25 equiv) were added to a stirred solution 2 iodoaniline (1.00 g, 4.566 mmol, 1.0 equiv) in Et 3 N (12.7 mL, 91.32 mmol, 20 equiv), at room temperature. The mixture was stirred for 18 h, concentra ted under reduced pressure and submitted to flash colum chromatography on silica gel (40% EtOAc in hexanes) to afford the compound 5 38 (0.416 g, 2.83 mmol) in 61% yield as a orange solid. R f = 0.23 (40% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 ) 7.29 ( dd, J = 8.3, 1.5 Hz, 1H), 7.16 (td, J = 7.8, 1.5 Hz, 1H), 6.72 (d, J = 7.8 Hz, 2H), 4.55 (s, 2H), 4.30 (s, 1H), 4.28 (bs, 2H).

PAGE 232

232 4 methyl N (2 (3 oxoprop 1 yn 1 yl)phenyl)benzenesulfonamide ( 3 88 ) According to a similar li terature procedure, pyridine (0.27 mL, 3.28 mmol, 3.0 equiv), catalytic DMAP (1 crystal) and TsCl (0.209 g, 1.094 mmol, 1.0 equiv) were added to a solution of 5 38 (0.161 g, 1.094 mmol) in dichloromethane (4.0 mL), at room temperature, and the mixture was stirred for 16 h. The reaction was diluted with dichloromethane (4.0 mL) and quenched with NH 4 Cl saturated solution (4.0 mL). The organic layer was separated, dried over MgSO 4 concentrated and subjected to flash column chromatography on silica gel (20 40 % EtOAc in hexanes) to furnish compound N (2 (3 hydroxyprop 1 yn 1 yl)phenyl) 4 methylbenzenesulfonamide in 55% yield (0.181g, 0.602 mmol) as a white solid. PCC (0.0778 g, 0.361 mmol, 1.5 equiv) and celite (0. 0778 g) were added to a stirred solution of N (2 (3 hydroxyprop 1 yn 1 yl)phenyl) 4 methylbenzenesulfonamide (0.0725 g, 0.240 mmol, 1.0 equiv) in dichloromethane (2.5 mL), at room temperature. The mixture was stirred for 13 h and directly subjected to flash column chromatography on silica gel (20 40% EtOAc in hexanes) to afford compound 3 88 (0.0321 g, 0.107 mmol) in 45% yield as a slightly red solid. The compound 3 88 was stored at 5C and used freshly. R f = 0.69 (40% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 ) 9.36 (s, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.45 (ddt, J = 7.5, 4.8, 2.4 Hz, 2H), 7.32 (s, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.12 (t, J = 7.5 Hz, 1H), 2.37 (s, 3H).

PAGE 233

233 N benzyl 2 bromoprop 2 en 1 amine ( 5 39 ) According to a similar literature procedure K 2 CO 3 (0.422 g, 3.055 mmol, 1.0 equiv) was added, at 0 C to a stirred solution of benzylamine ( 1.0 mL, 9.164 mmol, 3 .0 equiv) and 2,3 bromopropene (0.373 mL, 80% sln, 1.0 equiv) in DMF ( 45 mL ). The re action was warmed up to room temperature, stirred for 16h and Et 2 O (100 mL) and H 2 O (30 mL) were added. The organic layer was separated, dried over MgSO 4 concentrated and subjected to flash column c hromatography on silica gel (20 % EtOAc in hexanes) to fur nish compound 5 39 in 62 % yield ( 0.431 g, 1.906 mmol) as a yellowish oil. T he spectroscopic data matched the reported data for this compound. R f = 0.46 (40% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 ) 7.44 7.18 (m, 5H), 5.82 (s, 1H), 5.61 (s, 1H), 3.7 7 (s, 2H), 3.49 (d, J = 1.3 Hz, 2H), 1.78 (bs, 1H). Figure 5 14. Preparation of aromatic alkyne containing a sulfonamide group 2 ethynylaniline ( 5 40 ) According to a similar literature procedure CuI (43.5 mg, 0.23 mmol, 5 mol %), PdCl 2 (PPh 3 ) 2 (160.2 mg, 0.23 mmol, 5 mol %) and TMS acetylene (0. 97 mL, 6.85 mmol, 1. 5 equiv) were added to a stirred solution of 2 iodoaniline (1.00 g, 4.566 mmol, 1.0 equiv) in Et 3 N (12.7 mL, 91.32 mmol, 20 equiv), at room temperature. The mi xture was stirred for 18 h, concentrated under reduced pressure and submitted to flash colum chromatography on silica gel ( 2 0% EtOAc in

PAGE 234

234 hexanes) to afford 4 methyl N (2 ((trimethylsilyl)ethynyl)phenyl)benzenesulfonamide (0.416 g, 2.83 mmol) in 85 % yield a s a yellowish oil R f = 0.60 (20% EtOAc in hexanes). A solution (1.0 M) of TBAF (1.90 mL, 1.90 mmol, 1.5 equiv) was added t o a stirred solution of 4 methyl N (2 ((trimethylsilyl)ethynyl)phenyl)benzenesulfonamide in THF (8.0 mL), at room temperature. The re action was stirred for 1h and EtOAc (15 mL) and H 2 O (5 mL) were added. The organic layer was separated, dried over MgSO 4 concentrated and subjected to flash column chromatography on silica gel (20 3 0% EtOAc in hexanes) to furnish compound 5 40 in 64 % yiel d (0.0952 g, 0.813 mmol) as a yellowish oil The spectroscopic data matched the reported data for this compound. 6 R f = 0.60 (20% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 ) 7.33 (d, J = 7.0 Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 6.76 6.57 (m, 2H), 4.25 (bs, 2H), 3.40 (s, 1H). N (2 ethynylphenyl) 4 methylbenzenesulfonamide ( 3 89 ) P yridine (0. 16 mL, 1.94 mmol, 5 .0 equiv), catalytic DMAP (1 cry stal) and TsCl (0. 0813 g, 0.426 mmol, 1. 1 equiv) was added t o a stirred solution of 5 40 in dichloromethane ( 1.6 mL), at room temperature .T he mixture was stirred for 24 h diluted with dichloromethane (4.0 mL) and quenched with NH 4 Cl saturated solution (4. 0 mL). The organic layer was separated, dried over MgSO 4 concentrated and subjected to flash column chromatography on silica gel (2 1 0% EtOAc in hexanes) to furnish compound 3 89 in 5 8 % yield (0.062 g, 0.229 mmol) as a white solid. T he spectroscopic data matched the reported data for this compound. R f = 0.43 (20% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 ) d 7.70 (d, J

PAGE 235

235 = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.36 7.31 (d, J = 8.4 Hz, 1H), 7.31 7.24 (m, 2H), 7.22 (d, J = 7.8 Hz, 2H), 7.01 (td, J = 7.8, 1.2 Hz, 1H), 3.38 (s, 1H), 2.36 (s, 3H). Preparation of Enantioenriched Amino Skipped Diynes via A3 reaction Figure 5 15. Preparation of amino skipped diynes via copper catalyzed A3 reaction with StackPhos CuBr (0.5 2. 0 mg, 0.0035 0.0139 mmol, 5 mol %) and previously activated 4 molecular sieves (50 mg/ mg of CuBr) was added to an oven dried test tube which was then capped with a rubber septum. ( S ) StackPhos (2.7 10.9 mg, 0.0038 0.0153 mmol, 5.5 mol %) was added to the test tube, followed by anhydrous dichloromethane (1.0 mL/ mg of CuBr). The mixture was stirred for 20 min at room temperature and formation of a yellowish solution was observed. To the stirring solution were added the alkyne (0.0697 0.2788 mmol, 1.0 equiv ) and the aldehyde (0.0697 0.2788 mmol, 1.0 equiv). The mixture was then placed at 0C and stirred for 5 min. To the reaction flask was then added the amine (0.0697 0.2788 mmol, 1.0 equiv), followed by anhydrous dichloromethane (0.4 mL/ mg of CuBr). The te st tube was then capped with a plastic cap and the final concentration of substrate in dichloromethane was maintained (0.1 M). The reaction was followed by TLC (20% EtOAc in hexanes), and directly subjected to flash column chromatography on silica gel (0 5 % EtOAc in hexanes) to deliver the desired 3 amino 1,4 diynes. For the preparation of racemic products, the same procedure was followed with rac StackPhos. In the cases where TMS acetylene and

PAGE 236

236 pentyne were employed, 1.5 equiv of the alkyne were added in th e reactions due to their volatility. Any modification of this procedure, full characterization of compounds, as well as the determination of enantiomeric excesses can be found in the section 3.2. N N dibenzyl 1 phenyl 5 (t rimethylsilyl)penta 1,4 diyn 3 amine ( 3 71 ). The following compound 3 71 was prepared via the aforementioned procedure with rac StackPhos in 95% yield (54.0 mg, 0.132 mmol) as a yellowish oil. The reaction was carried out for 24h. R f = 0.81 (20% EtOAc in h exanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 7.55 (ddd, J = 4.8, 3.4, 1.7 Hz, 2H), 7.52 7.47 (m, 4H), 7.42 7.36 (m, 7H), 7.35 7.29 (m, 2H), 4.64 (s, 1H), 3.87 (d, J = 5.5 Hz, 2H), 3.82 (d, J = 5.5 Hz, 2H), 0.30 (s, 9H). 13 C NMR (125 MHz, CDCl 3 ) 139.2, 132.1, 129.3, 128.5, 127.3, 123.0, 100. 5, 89.2, 84.6, 84.3, 55.0, 45.5, 0.3. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 28 H 30 NSi + 408.2142; Found 408.2151. ( R ) N N dibenzyl 1 phenyl 5 (trimethylsilyl)penta 1,4 diyn 3 amine ( 3 72 ). The following compound 3 72 was p repared via the aforementioned procedure with ( S ) StackPhos in 73% yield (95.2 mg, 0.233 mmol) as a white solid. The reaction was carried out for 24h. [ ] 24 D = 69.65 ( c 1.0, CHCl 3 ). MP = 76 C. Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 0.2 mL/min, 254 nm); minor t r = 30.2 min; major t r = 32.7 min; 96% ee Chromatograms of 3 71 and 3 72 :

PAGE 237

237 N N dibenzyl 1 (4 bromophenyl) 5 (trimethylsilyl)penta 1,4 diyn 3 amine ( 5 41 ). The following compound 5 41 was prepared via the aforementioned procedure with rac StackPhos in 83% yield (30.8 mg, 0.063 mmol) as a white solid. T he reaction was carried out for 24h. R f = 0.79 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 7.35 7.28 (m, 6H), 7.24 7.19 (m, 6H), 7.17 7.12 (m, 2H), 4.45 (s, 1H), 3.67 (d, J = 13.5 Hz, 2H), 3.63 (d, J = 13.5 Hz, 2H), 0.12 (s, 9H). 13 C NMR (125 MHz, CDCl 3 ) 139.1, 133.6, 131.7, 129.2, 128.5, 127.4 122.8, 121.9, 100.0, 89.5, 86.0, 83.2, 55 .1, 45.5, 0.3. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 28 H 29 NSiBr + 486,1247; Found 486,1254. ( R ) N N dibenzyl 1 (4 bromophenyl) 5 (trimethylsilyl)penta 1,4 diyn 3 amine ( 3 73 ). The following compound 3 73 was prepared via the aforementioned procedure with ( S ) StackPhos in 79% yield (59.2 mg, 0.122 mmol) as a white solid. The reaction was carried out for 24h. [ ] 24 D = 84.58 ( c 1.0, CHCl 3 ). MP = 109 C. Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100:0 n

PAGE 238

238 hexane:isopropanol, 0.2 mL/min, 254 nm); minor t r = 47.2 min; major t r = 41.6 min; 96% ee ( S ) N N dibenzyl 1 (4 bromophenyl) 5 (trimethylsilyl)penta 1,4 diyn 3 amine ( 5 42 ). The following compound 5 42 was prepared via the aforementioned procedure 3.1 with ( R ) StackPhos in 74% yield (41.4 mg, 0.085 mmol) as a white solid. The reaction was carried o ut for 24h. [ ] 24 D = +64.25 ( c 0.5, CHCl 3 ). Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 0.2 mL/min, 254 nm); minor t r = 40.6 min; major t r = 45.1 min; 96% ee The absolute configuration was determined by single c rystal X Ray crystallography analysis with Flack parameter = 0.013 (see below) Chromatograms of 5 41 and 3 73 : Chromatograms of 5 41 and 5 42 :

PAGE 239

239 N N dibenzyl 1 (4 methoxyphenyl) 5 (trimethylsilyl)penta 1,4 diyn 3 ami ne ( 5 43 ). The following compound 5 43 was prepared via the aforementioned procedure with rac StackPhos in 84% yield (23.1 mg, 0.053 mmol) as a white solid. The reaction was carried out for 24h. R f = 0.62 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (50 0 MHz, CDCl 3 ) 7.48 7.43 (m, 6H), 7.39 7.34 (m, 4H), 7.29 (tt, J = 6.5, 1.4 Hz, 2H), 6.90 6.85 (m, 2H), 4.59 (s, 1H), 3.85 (s, 3H), 3.84 (d, J = 13.4 Hz, 2H), 3.78 (d, J = 13.4 Hz, 2H), 0.27 (s, 9H). 13 C NMR (125 MHz, CDCl 3 ) 159.8, 139.3, 133. 6, 129.3, 128.5, 127.3, 115.1, 114.1, 100.7, 89.0, 84.2, 83.2, 55.5, 55.0, 45.6, 0.3. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 29 H 32 NOSi + 438.2248; Found 438.2256. ( R ) N N dibenzyl 1 (4 methoxyphenyl) 5 (trimethylsilyl)penta 1 ,4 diyn 3 amine ( 3 74 ). The following compound 3 74 was prepared via the aforementioned procedure with ( S ) StackPhos in 77% yield (32.7 mg, 0.075 mmol) as a white solid. The reaction was carried out for 24h. [ ] 24 D = 72.98 ( c 1.0, CHCl 3 ). MP = 85 C. Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 0.5 mL/min, 254 nm); minor t r = 38.6 min; major t r = 42.6 min; 94% ee

PAGE 240

240 Chromatograms of 5 43 and 3 74 : N N dibenzyl 1 (thiophen 2 yl) 5 (trimethylsilyl)penta 1,4 diyn 3 amine ( 5 44 ). The following compound 5 44 was prepared via the aforementioned procedure with rac StackPhos in 44% yield (20.1 mg, 0.049 mmol) as a colorless oil The reaction was carried out for 24h. R f = 0.73 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 7.49 7.44 (m, 4H), 7.38 (t, J = 7.5 Hz, 4H), 7.34 7.26 (m, 4H), 7.02 (dd, J = 5.1, 3.6 Hz, 1H), 4.64 (s, 1H), 3.81 (s, 4H), 0.28 (s, 9H). 13 C NMR (125 MHz, CDCl 3 ) 139.1, 132.6, 129.3, 128.5, 127.4, 127.3, 127.1, 122.9, 100.2, 89.5, 88.6, 77.6, 55.1 45.8, 0.3. HRMS (DART TOF) m/z: [M+H] + Calcd for C 26 H 28 NSSi + 414.1706; Found 414,1714. ( R ) N N dibenzyl 1 (thiophen 2 yl) 5 (trimethylsilyl)penta 1,4 diyn 3 amine ( 3 75 ). The following compound 3 75 was prepared via t he aforementioned procedure with ( S ) StackPhos in 72% yield (33.2 mg, 0.080 mmol) as a colorless oil. The reaction

PAGE 241

241 was carried out for 24h. [ ] 24 D = 59.80 ( c 1.0, CHCl 3 ). Enantiomeric excess was determined to be 96% ee after desilylation (see synthesis of 5 45 ). ( S ) N N dibenzyl 1 (thiophen 2 yl)penta 1,4 diyn 3 amine ( 5 45 ). KF (9.5 mg, 0.25 mmol, 10.0 equi v) was added to a stirred solution of 3 75 (10.3 mg, 0.025 mmol, 1.0 equiv) in MeCN (1.0 mL) and H 2 O (0.25 mL), at room temperature. The reaction was stirred for 16 h at room temperature. The mixture was concentrated under reduced pressure and EtOAc (2.0 m L) was added. The organic layer was washed with water (1.0 mL), separated, dried over MgSO 4 concentrated, and subjected to flash column chromatography (0 5% EtOAc in hexanes) to deliver compound 5 45 in 75% yield (6.2 mg, 0.018 mmol) as a colorless oil. R f = 0.58 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 7.48 7.44 (m, 4H), 7.39 7.34 (m, 4H), 7.32 7.26 (m, 4H), 7.01 (dd, J = 5.1, 3.7 Hz, 1H), 4.64 (d, J = 2.4 Hz, 1H), 3.82 (s, 4H), 2.48 (d, J = 2.4 Hz, 1H). 13 C NMR (125 MHz, C DCl 3 ) 138.9, 132.7, 129.2, 128.6, 127.5, 127.1, 122.7, 88.1, 78.7, 77.8, 72.6, 55.0, 44.9. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 23 H 19 NS + 342.1311; Found 342.1319. [ ] 24 D = 124.31 ( c 0.5, CHCl 3 ). Enantiomeric excess was determined by HPLC with a Chiralc el OD H column (99.9:0.1 n hexane:isopropanol, 0.5 mL/min, 215 nm); minor t r = 26.7 min; major t r = 31.7 min; 96% ee

PAGE 242

242 Chromatograms of racemic 5 45 and enantioenriched 5 45 : N N dibenzyl 1 phenyl 5 (triisopropylsil yl)penta 1,4 diyn 3 amine ( 5 46 ). The following compound 5 46 was prepared via the aforementioned procedure with rac StackPhos in 47% yield (51.3 mg, 0.104 mmol) as a yellowish oil. The reaction was carried out for 24h. R f = 0.57 (10% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 7.51 7.45 (m, 7H), 7.39 7.33 (m, 6H), 7.32 7.27 (m, 2H), 4.63 (s, 1H), 3.92 (d, J = 13.4 Hz, 2H), 3.78 (d, J = 13.4 Hz, 2H), 1.18 (s, 9H). 13 C NMR (125 MHz, CDCl 3 ) 139.3, 132.1, 129.3, 128.5, 128.4, 127.3, 1 23.2, 102.2, 85.5, 85.3, 83.9, 55.1, 45.6, 18.9, 11.5. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 34 H 42 NSi + 492.3081; Found 492.3087. ( S ) N N dibenzyl 1 phenyl 5 (triisopropylsilyl)penta 1,4 diyn 3 amine ( 3 76 ). The followi ng compound 3 76 was prepared via the aforementioned procedure with ( S ) StackPhos in 73% yield (30.1 mg, 0.061 mmol) as a yellowish oil. The reaction was carried out for 24h. [ ] 24 D = +29.69 ( c 1.0, CHCl 3 ). Enantiomeric excess was determined

PAGE 243

243 by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 0.25 mL/min, 254 nm); minor t r = 23.1 min; major t r = 22.1 min; 96% ee Chromatograms of 5 46 and 3 76 : N,N dibenzyl 1 (triisopropylsilyl) 5 (trimethylsilyl)penta 1,4 diyn 3 amine ( 5 47 ). The following compound 5 47 was prepared via the aforementioned procedure with rac StackPhos in 82% yield (140.1 mg, 0.287 mmol) as a yellowish oil. The re action was carried out for 6h. R f = 0.83 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 7.42 (d, J = 7.5 Hz, 4H), 7.34 (t, J = 7.5 Hz, 4H), 7.31 7.23 (m, 2H), 4.38 (s, 1H), 3.82 (d, J = 13.4 Hz, 2H), 3.69 (d, J = 13.4 Hz, 2H), 1.15 (s, 21H), 0.22 (s, 9H). 13 C NMR (125 MHz, acetone d 6 ) 139.9, 130.0, 129.5, 128.4, 103.5, 101.8, 89.7, 86. 1, 55.6, 46.4, 19.3, 12.3, 0.3. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 31 H 46 NSi 2 + 488.3163; Found 488.3174. ( S ) N,N dibenzyl 1 (triisopropylsilyl) 5 (trimethylsilyl)penta 1,4 diyn 3 amine ( 3 77 ). The following compound 3 7 7 was prepared via the aforementioned procedure with ( S ) StackPhos in 72% yield (34.2 mg, 0.070 mmol) as a yellowish oil.

PAGE 244

244 The reaction was carried out for 6h. Enantiomeric excess was determined to be 96% ee after TMS deprotection (see below) N N dibenzyl 1 (2 nitrophenyl) 5 phenylpenta 1,4 diyn 3 amine ( 5 48 ). The following compound 5 48 was prepared via the aforementioned procedure with rac StackPhos in 77% yield (34.6 mg, 0.101 mmol) as a yellowish oil. The reaction was carried out for 3h. R f = 0.43 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 8.11 (dd, J = 8.3, 1.3 Hz, 1H), 7.73 (dd, J = 7.8, 1.5 Hz, 1H), 7.62 (td, J = 7.6, 1.3 Hz, 1H), 7.57 7.48 (m, 7H), 7.41 7.34 (m, 7H), 7.33 7.29 (m, 2H), 4.92 (s, 1H), 3.99 (d, J = 13.5 Hz, 2H), 3.92 (d, J = 13.5 Hz, 2H). 13 C NMR (125 MHz, CDCl 3 ) 150.1, 139.1, 135.4, 133.0, 132.2, 129.3, 129.0, 128.7, 128.6, 128.5, 127.4, 124.8, 122.8, 118.4, 93.0, 84.7, 84.2, 79.8, 55.2, 45.7. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 31 H 25 N 2 O 2 + 457.1911; Found 457.1922. ( R ) N N d ibenzyl 1 (2 nitrophenyl) 5 phenylpenta 1,4 diyn 3 amine ( 3 78 ). The following compound 3 78 was prepared via t he aforementioned procedure with ( S ) StackPhos in 86% yield (38.5 mg, 0.084 mmol) as a yellowish oil. The reaction was carried out for 3h. [ ] 24 D = 4.00 ( c 1.0, CHCl 3 ). Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (99.9:0.1 n hexane:isopropanol, 0.5 mL/min, 215 nm); minor t r = 75.1 min; major t r = 80.9 min; 95% ee

PAGE 245

245 Chromatograms of 5 48 and 3 78 : N N dibenzyl 1 (2 nitrophenyl)deca 1,4 diyn 3 amine ( 5 49 ). The following compound 5 49 was prepared via the aforementioned procedure with rac StackPhos in 71% yield (81.7 mg, 0.148 mmol) as a colorless oil. The reaction was carried out for 3h. R f = 0.59 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 8.07 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.61 7.55 (m, 1H), 7.48 (d, J = 7.6 Hz, 5H), 7.35 (t, J = 7.5 Hz, 4H), 7.27 (t, J = 7.3 Hz, 2H), 4.65 (s, 1H), 3.90 (d, J = 13.5 Hz, 2H), 3.81 (d, J = 13.5 Hz, 2H), 2.29 (td, J = 7.2, 2.2 Hz, 2H), 1.5 9 (p, J = 7.2 Hz, 2H), 1.49 1.29 (m, 4H), 0.93 (t, J = 7.2 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) 150.1, 139.3, 135.4, 132.9, 129.3, 128.9, 128.5, 127.3, 124.8, 118.5, 93.9, 85.5, 79.3, 74.8, 54.9, 45.2, 31.3, 28.6, 22.4, 19.0, 14.2. HRMS (ESI TOF) m/z: [M+ H] + Calcd for C 30 H 31 N 2 O 2 + 451.2380; Found 451.2388. ( R ) N N dibenzyl 1 (2 nitrophenyl)deca 1,4 diyn 3 amine ( 3 79 ). The following compound 3 79 was prepared via the aforementioned procedure with ( S ) StackPhos in

PAGE 246

246 64% yiel d (29.3 mg, 0.053 mmol) as a colorless oil. The reaction was carried out for 6h. [ ] 24 D = +57.80 ( c 1.0, CHCl 3 ). Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (99.1:0.1 n hexane:isopropanol, 0.2 mL/min, 254 nm); minor t r = 96.7 min; major t r = 99.0 min; 96% ee Chromatograms of 5 49 and 3 79 : N N dibenzyl 1 phenylocta 1,4 diyn 3 amine ( 5 50 ). The following compound 5 50 was prepared via the aforementioned procedure with rac StackPhos in 72% yield (36.2 mg, 0.096 mmol) as a colorless oil. The reaction was carried out for 24h. R f = 0.73 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 7.55 7.52 (m, 2H), 7.51 7.47 (m, 4H), 7.41 7.33 (m, 7H), 7.33 7.28 (m, 2H), 4.62 (t, J = 2.2 Hz, 1H), 3.86 (d, J = 13.5 Hz, 2H), 3.83 (d, J = 13.5 Hz, 2H), 2.31 (td, J = 7.0, 2.2 Hz, 2H), 1.65 (h, J = 7.3 Hz, 2H), 1.09 (t, J = 7.4 Hz, 3H). 13 C NM R (125 MHz, CDCl 3 ) 139.4, 132.1, 129.2, 128.5, 128.4, 127.3, 123.1, 85.5, 84.9, 83.9, 75.4, 55.0, 44.9, 22.5, 21.0, 13.8. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 28 H 28 N + 378.2216; Found 378.2225.

PAGE 247

247 ( S ) N N dibenzyl 1 phe nylocta 1,4 diyn 3 amine ( 3 80 ). The following compound 3 80 was prepared via the aforementioned procedure with ( S ) StackPhos in 84% yield (27.8 mg, 0.074 mmol) as a colorless oil. The reaction was carried out for 24h and 3 80 was isolated in 86% ee. [ ] 24 D = 69.37 ( c 1.0, CHCl 3 86% ee sample). The preparation of compound 3 80 was also carried out for 24 h, at 25C, generating 3 80 in 65% yield (21.3 mg, 0.057 mmol) and 88% ee Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100: 0 n hexane:isopropanol, 1.0 mL/min, 254 nm); minor t r = 11.0 min; major t r = 15.4 min. Chromatograms of 5 50 and 3 80 : N N dibenzyltrideca 4,7 diyn 6 amine ( 5 51 ). The following compound 5 51 was prepared via the afor ementioned procedure with rac StackPhos in 93% yield (97.4 mg, 0.277 mmol) as a colorless oil. The reaction was carried out for 24h. R f = 0.82 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 7.42 (d, J = 6.6 Hz, 4H), 7.32 (t, J = 7.1 Hz, 4H), 7.30 7.15 (m, 2H), 4.34 (s, 1H), 3.72 (s, 4H), 2.32 2.16 (m, 4H), 1.69 1.50 (m, 4H), 1.49 1.30 (m, 4H), 1.04 (td, J = 7.4, 1.5 Hz, 3H), 0.92

PAGE 248

248 (td, J = 7.3, 1.4 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) 139.6, 129.2, 128.4, 127.2, 84.4, 84.3, 76.1, 7 6.0, 54.8, 44.4, 31.3, 28.7, 22.5, 21.0, 19.0, 14.2, 13.8. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 27 H 34 N + 372.2686; Found 372.2695. ( S ) N N dibenzyltrideca 4,7 diyn 6 amine ( 3 81 ). The following compound 3 81 was prepared via the aforementioned procedure with ( S ) StackPhos in 86% yield (17.9 mg, 0.051 mmol) as a colorless oil. The reaction was carried out for 24h. [ ] 24 D = 8.70 ( c 1.0, CHCl 3 ). Enantiomeric excess was determined to be 82% by HPLC af ter (91 : 9 dr, see synthesis and chromatograms below) methyl 4 (dibenzylamino) 6 phenylhexa 2,5 diynoate ( 5 52 ). The following compound 5 52 was prepared via the aforementioned procedure with rac StackPhos in 90% yield (94.0 mg, 0.238 mmol) as a dark yellowish oil. The reaction was carried out for 3h. R f = 0.50 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 7.53 7.50 (m, 2H), 7.47 (d, J = 7.0 Hz, 4H), 7.40 7.36 (m, 7H), 7.33 7.28 (m, 2H), 4.76 (s, 1H), 3.90 (d, J = 13.5 Hz, 2H), 3.85 (s, 3H), 3.79 (d, J = 13.5 Hz, 2H). 13 C NMR (125 MHz, CDCl 3 ) 153.9, 138.5, 132.2, 129.2, 128.9, 128.7, 128.5, 127.6, 122.3, 85.6, 82.9, 82.3,75.8, 55.2, 53.1, 44.9. HRMS (DART TOF) m/z: [M+H] + Calcd for C 27 H 24 NO 2 + 394.1802; Found 394.1819.

PAGE 249

249 methyl ( R ) 4 (dibenzylamino) 6 phenylhexa 2,5 diynoate ( 3 82 ). The following compound 3 82 was pr epared via the aforementioned procedure with ( S ) StackPhos in 96% yield (50.5 mg, 0.128 mmol) as a dark yellowish oil. The reaction was carried out for 1h and 3 82 was isolated in 82% ee. The compound 3 82 was found to be unstable over silica gel, then the reaction was quenched with H 2 O, and the organic layer was separated, dried over MgSO 4 concentrated to deliver the product without the presence of impurities (see 1 H and 13 C NMR spectra of the crude reaction mixture in section 8). [ ] 24 D = 14.83 ( c 1.0 CHCl 3 82% ee sample). The preparation of compound 3 82 was also carried out for 1 h at 25C, generating 3 82 in 93% yield (24.7 mg, 0.062 mmol) and 86% ee Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (99:1 n hexane:isopropan ol, 0.5 mL/min, 254 nm); minor t r = 11.9 min; major t r = 12.6 min. Chromatograms of 5 52 and 3 82 : 4 (1 phenyl 5 (trimethylsilyl)penta 1,4 diyn 3 yl)morpholine ( 5 53 ). The following compound 5 53 was prepared via the af orementioned procedure with rac StackPhos in 73% yield (30.2 mg, 0.101 mmol) as a colorless oil. The reaction was carried out for 24h. R f = 0.53 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500

PAGE 250

250 MHz, CDCl 3 ) 7.56 7.43 (m, 2H), 7.41 7.28 (m, 3H), 4. 58 (s, 1H), 3.83 (t, J = 4.7 Hz, 2H), 2.78 (t, J = 4.7 Hz, 2H), 0.24 (s, 9H). 13 C NMR (125 MHz, CDCl 3 ) 132.1, 128.7, 128.4, 122.6, 98.9, 90.2, 85.1, 83.3, 67.1, 50.2, 49.6, 0.1. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 18 H 24 NOSi + 298.1622; Found 298.1632. ( R ) 4 (1 phenyl 5 (trimethylsilyl)penta 1,4 diyn 3 yl)morpholine ( 3 83 ). The following compound 3 83 was prepared via the aforementioned procedure with ( S ) StackPhos in 69% yield (28.6 mg, 0.096 mmol) as a colorless oil. The reaction was carried out for 24h. [ ] 24 D = 72.98 ( c 1.0, CHCl 3 ). Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (99:1 n hexane:isopropanol, 0.5 mL/min, 215 nm); minor t r = 10.5 min; major t r = 18.3 min; 96% ee Chromatograms of 5 53 and 3 83 : 1 (1 phenyl 5 (trimethylsilyl)penta 1,4 diyn 3 yl)piperidin 4 one ( 5 54 ). The following compound 5 54 was prepared via the aforementioned procedure with rac

PAGE 251

251 StackPhos, however, Et 3 N (38.9 L, 0.278 mmol, 2 equiv) was added after the addition of the amine, to deliver the product in 51% yield (26.4 mg, 0.085 mmol) as a yellowish oil. The reaction was carried out for 24h at room temperature. R f = 0.38 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 7.50 7.44 (m, 2H), 7.36 7.28 (m, 3H), 4.74 (s, 1H), 3.03 (t, J = 6.1 Hz, 4H), 2.57 (t, J = 6.2 Hz, 4H), 0.21 (s, 9H). 13 C NMR (125 MHz, CDCl 3 ) 208.6, 132.1, 128.9, 128.5, 122.4, 98.7, 90.2, 85.0, 83.2, 49.6, 49.4, 41.4, 0.1. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 19 H 24 NOSi + 310. 1622; Found 310.1623. ( R ) 1 (1 phenyl 5 (trimethylsilyl)penta 1,4 diyn 3 yl)piperidin 4 one ( 3 84 ). The following compound 3 84 was prepared via the aforementioned procedure with ( S ) StackPhos, however, Et 3 N (38.9 L, 0. 278 mmol, 2 equiv) was added after the addition of the 4 piperidone hydrate hydrochloride to deliver the product in 62% yield (31.2 mg, 0.101 mmol) as a yellowish oil. The reaction was carried out for 24h at room temperature. [ ] 24 D = +1.97 ( c 1.0, CHCl 3 ) Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (99:1 n hexane:isopropanol, 0.5 mL/min, 215 nm); minor t r = 19.4 min; major t r = 28.1 min; 91% ee

PAGE 252

252 Chromatograms of 5 54 and 3 84 : N (2 (3 (a llyl(methyl)amino) 5 (triisopropylsilyl)penta 1,4 diyn 1 yl)phenyl) 4 methylbenzenesulfonamide ( 5 55 ). The following compound 5 55 was prepared via the aforementioned procedure with rac StackPhos in 93% yield (41.2 mg, 0.091 mmol) as a slightly red oil. Th e reaction was carried out for 3h. R f = 0.18 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 7.69 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.3 Hz, 1H), 7.35 7.15 (m, 4H), 7.01 (td, J = 7.6, 1.2 Hz, 1H), 5.90 (ddt, J = 16.8, 10.2, 6.7 Hz, 1H), 5.30 (dd, J = 17.3, 2.0 Hz, 1H), 5.23 (d, J = 9.8 Hz, 1H), 4.70 (s, 1H), 3.20 3.16 (m, 1H), 2.40 (s, 3H), 2.36 (s, 3H), 1.13 (s, 21H). 13 C NMR (125 MHz, CDCl 3 ) 144.2, 138.2, 136.4, 135.3, 132.6, 129.9, 127.6, 124.3, 119.5, 118.9, 113.5, 110.2, 100.2, 92.1, 86.9, 78.8, 57.7, 48.3, 38.4, 21.7, 18.9, 11.4. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 31 H 43 N 2 O 2 + 535.2809; Found 535.2813. ( S ) N (2 (3 (allyl(methyl)amino) 5 (triisopropylsilyl)penta 1,4 diyn 1 yl)phenyl) 4 methylb enzenesulfonamide ( 3 85 ). The following compound 3 85 was

PAGE 253

253 prepared via the aforementioned procedure with ( S ) StackPhos in 63% yield (23.2 mg, 0.043 mmol) as a slightly red oil. The reaction was carried out for 3h. [ ] 24 D = 14.38 ( c 1.0, CHCl 3 ). Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (99.9:0.1 n hexane:isopropanol, 0.9 mL/min, 254 nm); minor t r = 57.7 min; major t r = 52.6 min; 92% ee Chromatograms of 5 55 and 3 85 : N allyl N methyl 1 (trimethylsilyl)deca 1,4 diyn 3 amine ( 5 56 ). The following compound 5 56 was prepared via the aforementioned procedure with rac StackPhos in 89% yield (85.6 mg, 0.311 mmol) as a yellowish oil. The reaction was carried out for 3h. R f = 0.55 (10% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 5.95 5.79 (m, 1H), 5.24 (d, J = 17.2 Hz, 1H), 5.17 (d, J = 10.5 Hz, 1H), 4.44 (d, J = 2.1 Hz, 1H), 3.12 (s, 2H), 2.34 (s, 3H), 2.27 2.20 (m, 2H), 1.54 (qt, J = 7.0, 3.5 Hz, 2H), 1.46 1.25 (m, 4H), 0.98 0.84 (m, 2H), 0.20 (s, 9H). 13 C NMR (125 MHz, CDCl 3 ) 135.6, 118.5, 100.3, 88.8, 85.4, 74.4, 57.5, 47.7, 38.0, 31.3, 28.5, 22.4, 18.9, 14.2, 0.2. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 17 H 30 NSi + 276.2142; Found 276.2150.

PAGE 254

254 ( R ) N allyl N methyl 1 (trimethylsilyl)deca 1,4 diyn 3 amine ( 3 86 ). The following compound 3 86 was prepared via the aforementioned procedure with ( S ) StackPhos in 71% yield (22.6 mg, 0.082 mmol) as a slightly red oil. The reaction was carried out for 3h. [ ] 24 D = 4.19 ( c 1.0, CHCl 3 ). Enantiomeric excess was determined to be 95% ee after Pauson Khand reaction (see synthesis and chromatogram of 3 96 below ) N (2 (3 (benzyl(2 bromoallyl)amino) 5 phenylpenta 1,4 diyn 1 yl)phenyl) 4 methylbenzenesulfonamide ( 5 57 ). Th e following compound 5 57 was prepared via the aforementioned procedure with rac StackPhos in 77% yield (41.2 mg, 0.091 mmol) as a yellowish solid. The reaction was carried out for 3h. R f = 0.39 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDC l 3 ) 7.67 (d, J = 8.0 Hz, 3H), 7.59 (dd, J = 6.7, 3.0 Hz, 2H), 7.53 (d, J = 7.5 Hz, 2H), 7.45 7.27 (m, 8H), 7.23 7.17 (m, 1H), 7.13 7.03 (m, 3H), 6.10 (d, J = 2.2 Hz, 1H), 5.73 (s, 1H), 4.87 (s, 1H), 3.87 (s, 1H), 3.59 (s, 1H), 2.31 (s, 1H). 13 C NMR (125 MHz, CDCl 3 ) 144.1, 138.3, 137.9, 136.2, 132.5, 132.2, 131.4, 130.1, 129.7, 129.3, 129.0, 128.8, 128.6, 127.9, 127.5, 124.6, 122.3, 120.4, 119.7, 113.8, 91.6, 85.4, 83.0, 79.2, 59.4, 55.0, 45.3, 21.7. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 34 H 30 N 2 O 2 S Br + 609.1206; Found 609.1186.

PAGE 255

255 ( R ) N (2 (3 (benzyl(2 bromoallyl)amino) 5 phenylpenta 1,4 diyn 1 yl)phenyl) 4 methylbenzenesulfonamide ( 3 87 ). The following compound 3 87 was prepared via the aforementioned procedure with ( S ) StackPhos in 63% yield (36.6 mg, 0.060 mmol) as a white solid. The reaction was carried out for 6h. [ ] 24 D = 24.25 ( c 1.0, CHCl 3 ). Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (98:2 n hexane:isopropanol, 1.0 mL/min, 254 nm); minor t r = 15.5 min; major t r = 20.6 min; 83% ee Chromatograms of 5 57 and 3 87 : N (2 (3 (dibenzylamino) 5 phenylpenta 1,4 diyn 1 yl)phenyl) 4 methylbenzenesulfonamide ( 5 58 ). The following compound 5 58 was prepared via the aforementioned procedure with rac StackPhos in 78% yield (31.4 mg, 0.054 mmol) as a yellowish oi l. The reaction was carried out for 3h. R f = 0.35 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 7.67 (dd, J = 8.3, 1.1 Hz, 1H), 7.64 (d, J = 8.3 Hz, 2H), 7.61 7.56 (m, 2H), 7.51 7.47 (m, 4H), 7.43 7.36 (m, 7H),

PAGE 256

256 7.37 7.26 (m, 4H), 7.21 (s, 1H), 7.08 7.00 (m, 2H), 4.82 (s, 1H), 3.88 (d, J = 13.5 Hz, 2H), 3.80 (d, J = 13.5 Hz, 2H), 2.26 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) 144.1, 138.7, 138.3, 136.2, 132.4, 132.2, 130.0, 129.7, 129.2, 128.9, 128.7, 128.6, 127.6, 127.5, 124.6, 122.5, 120.2, 113.9, 92.1, 85.3, 83.7, 79.2, 55.3, 45.5, 21.7. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 38 H 33 N 2 O 2 S + 581.22 57; Found 581.2253. ( R ) N (2 (3 (dibenzylamino) 5 phenylpenta 1,4 diyn 1 yl)phenyl) 4 methylbenzenesulfonamide ( 3 91 ). The following compound 3 91 was prepared via the aforementioned procedure with ( S ) StackPhos in 92% y ield (44.8 mg, 0.077 mmol) as a yellowish oil. The reaction was carried out for 3h. [ ] 24 D = 26.23 ( c 1.0, CHCl 3 ). Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (99:1 n hexane:isopropanol, 0.5 mL/min, 215 nm); minor t r = 38.7 min; major t r = 41.5 min; 90% ee Chromatograms of 5 58 and 3 91 :

PAGE 257

257 Preparation of the Alkynyl Aminoindole, of the Pauson Khand Product and of Orthogonally Functionalized Amino Skipped Diynes ( R ) N,N dibenzyl 3 phenyl 1 (1 tosyl 1H indol 2 yl)prop 2 yn 1 amine ( 3 95 ). To a stirred solution of 3 91 (16.2 m g, 0.028 mmol, 1.0 equiv) in MeCN (1.0 mL) was added K 2 CO 3 (19.2 mg, 0.140 mmol, 5.0 equiv) and the mixture was stirred for 7h at 7 0 C The solids were then filtered off and MeCN was evaporated under reduced pressure. The crude was subjected to flash colum n chromatography on silica gel (0 5% EtOAc in hexanes) to deliver 3 95 ( 10.7 mg, 0.019 mmol ) in 67 % yield as a white oil R f = 0.50 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 8.03 (d, J = 8.4 Hz, 1H), 7.55 (dd, J = 6.6, 3.0 Hz, 2H) 7.49 (d, J = 8.3 Hz, 2H), 7.42 7.32 (m, 7H), 7.29 7.20 (m, 5H), 7.16 (td, J = 7.4, 3.3 Hz, 3H), 7.08 (d, J = 8.1 Hz, 2H), 7.01 (s, 1H), 5.92 (s, 1H), 3.96 (d, J = 13.7 Hz, 2H), 3.75 (d, J = 13.7 Hz, 2H), 2.31 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) 144.6 139.5, 139.0, 138.2, 135.9, 132.1, 129.7, 129.6, 129.2, 128.6, 128.2, 127.0, 126.8, 124.9, 123.8, 123.5, 123.2, 121.1, 115.7, 114.3, 87.4, 85.3, 55.8, 52.9, 21.8. [ ] 24 D = 32.08 ( c 1.0, CHCl 3 ). HRMS (ESI TOF) m/z: [M+H] + Calcd for C 38 H 33 N 2 O 2 S + 581.2257; Found 581.2253. Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (99:1 n hexane:isopropanol, 0.5 mL/min, 254 nm); minor t r = 47.1 min; major t r = 31.1 min; 90% ee Chromatograms of racemic 3 95 and enantioenriched 3 95 :

PAGE 258

258 (1 R ,3 S ) 2 methyl 6 pentyl 1 ((trimethylsilyl)ethynyl) 2,3,3a,4 tetrahydro cyclopenta [c]pyrrol 5(1H) one ( 3 96 ). Co 2 (CO) 8 (26.0 mg, 0.076 mmol, 2.0 equiv) and cyclohexylamine (25.0 L, 0.190 mmol, 5.0 equiv) were added to a stirred solution of 3 86 (10.5 mg, 0.038 mmol, 1.0 equiv) in PhMe (0.6 mL). The mixture was stirred for 2h at 70C and the reaction mixture was then directly subjected to flash column chromatography on silica gel (0 5% EtOAc in hexanes) to deliver 3 96 (5.3 mg, 0.017 mmol) in 46 % yield as a brownish oil. R f = 0.34 (10% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 4.44 (s, 1H), 3.50 (t, J = 7.5 Hz, 1H), 3.32 (q, J = 8.0 Hz, 1H), 2.64 (ddd, J = 18. 4, 6.5, 1.9 Hz, 1H), 2.60 (s, 3H), 2.44 2.33 (m, 1H), 2.24 2.10 (m, 2H), 2.01 (dd, J = 10.7, 8.5 Hz, 1H), 1.62 1.37 (m, 4H), 1.38 1.23 (m, 4H), 0.90 (td, J = 7.2, 1.9 Hz, 3H), 0.33 (s, 9H). 13 C NMR (125 MHz, CDCl 3 ) 209.2, 176.4, 137.4, 112.5, 79. 24 D = +4.67 ( c 0.5, CHCl 3 ). HRMS (ESI TOF) m/z: [M+H] + Calcd for C 18 H 30 NOSi + 304.2091; Found 304.2099. Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (99:1 n he xane:isopropanol, 1.0 mL/min, 254 nm); minor t r = 3.9 min; major t r = 4.7 min; 95% ee The diastereoselectivity was determined by 1 H NMR, where only one

PAGE 259

259 diastereomer was observable. The relative stereochemistry was determined in analogy to a similar compou nd prepared by Knochel and coworkers. Chromatograms of racemic 3 96 and enantioenriched 3 96 : Figure 5 16. Orthogonal f unctionalization of amino skipped diynes ( S ) N N dibenzyl 1 (triisopropylsilyl)penta 1,4 diyn 3 ami ne ( 3 97 ). K 2 CO 3 (33.9 mg, 0.246 mmol, 5.0 equiv) was added to a stirred solution of 3 77 (24.0 mg, 0.049 mmol, 1.0 equiv) in THF : MeOH (2: 1 mixture, 1.5 mL total) and the mixture was stirred for 1h at room temperature. The reaction was quenched with 1M HCl (0.5 mL), then CH 2 Cl 2 (5.0 mL) and H 2 O (2.0 mL) were added. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to give a residue which was purified through flash column chromatography on silica gel (0 5% EtOAc in hexanes) to afford 3 97 (18.9 mg, 0.045 mmol) in 92% yield as a colorless oil. R f = 0.73 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 7.43 (d, J =

PAGE 260

260 7.5 Hz, 4H), 7.37 7.31 (m, 4H), 7.30 7.23 (m, 2H), 4.41 (d, J = 2.4 Hz, 1H), 3.83 (d, J = 13.5 Hz, 2H), 3.72 (d, J = 13.4 Hz, 2H), 2.39 (d, J = 2.4 Hz, 1H), 1.15 (s, 21H). 13 C NMR (125 MHz, CDCl 3 ) 139.8, 129.9, 129.5, 128.4, 103.1, 85.9, 79.7, 74.2, 55.5, 24 D = 64.34 ( c 1.0, CHCl 3 ). HRMS (ESI TOF) m/z: [M+H] + Calcd for C 28 H 38 NSi + 416.2768; Found 416.2771. Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 0.2 mL/min, 215 nm); minor t r = 22.5 min; major t r = 23.5 min; 96% ee ( S ) N N dibenzyl 1 (4 fluoro phenyl) 5 (triisopropylsilyl)penta 1,4 diyn 3 amine ( 3 98 ). CuI (0.6 mg, 0.0031 mmol, 10 mol %), PdCl 2 (PPh 3 ) 2 (2.2 mg, 0.0031 mmol, 10 mol %) were added to a stirred solution of 4 fluoro 1 iodobenzene (3.6 L, 0.031 mmol, 1.0 equiv) and 3 97 (13.0 mg, 0.031 mmol, 1.0 equiv) in Et 3 N (0.15 mL, 1.25 mmol, 40.0 equiv), at room temperature. The mixture was stirred for 1 h, concentrated under reduced pressure and submitted to flash colum chromatography on silica g el (2% EtOAc in hexanes) to afford 3 98 (14.3 mg, 0.028 mmol) in 90% yield as a yellowish oil. R f = 0.79 (10% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 7.44 (dd, J = 8.1, 5.8 Hz, 6H), 7.35 (t, J = 7.5 Hz, 4H), 7.31 7.23 (m, 2H), 7.02 (t, J = 8.7 Hz, 2H), 4.60 (s, 1H), 3.89 (d, J = 13.4 Hz, 2H), 3.75 (d, J = 13.4 Hz, 2H), 1.16 (s, 21H). 13 C NMR (125 MHz, CDCl 3 ) 163.7, 161.72, 139.2, 134.0, 129.2, 128.5, 127.4, 119.2, 115.8, 115.6, 102.0, 85.7, 85.1, 82.8, 55.1, 45.6, 18.9, 11.5. 2 4 D = 9.96 ( c 1.0, CHCl 3 ). HRMS (ESI TOF) m/z: [M+H] + Calcd for C 34 H 41 NSiF + 510.2987; Found 510.2986. Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 1.0 mL/min, 254 nm); minor t r = 5.8 min; major t r = 6 .3 min; 96% ee

PAGE 261

261 ( R ) N N dibenzyl 1 (4 fluorophenyl)penta 1,4 diyn 3 amine ( 3 99 ). H 2 O (1.6 L, 0.0882 mmol, 15.0 equiv) and TBAF (11.8 L, 1M in THF, 0.0118 mmol, 2.0 equiv) were added to a stirred solution of 3 98 (3.0 mg, 0.0059 mmol, 1.0 equiv) in THF (0.3 mL) and the mixture was stirred for 14h at room temperature. The reaction was quenched with H 2 O (0.5 mL) and EtOAc (5.0 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to give a residue which was purified through flash column chromatography on silica gel (0 5% EtOAc in hexanes) to aff ord 3 99 (1.4 mg, 0.0040 mmol) in 67% yield as a colorless oil. R f = 0.58 (10% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 7.50 7.42 (m, 6H), 7.35 (t, J = 7.4 Hz, 4H), 7.29 (t, J = 8.7 Hz, 2H), 7.02 (t, J = 8.7 Hz, 2H), 4.62 (s, 1H), 3.84 (q, J = 14.6 Hz, 4H)2.49 (s, 1H). [ ] 24 D = 14.78 ( c 0.2, CHCl 3 ). HRMS (ESI TOF) m/z: [M+H] + Calcd for C 25 H 21 NF + 354.1653; Found 354.16 60. Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 1.0 mL/min, 254 nm); minor t r = 33.4 min; major t r = 18.8 min; 96% ee Chromatograms of racemic 3 97 and enantioenriched 3 97 : Chromatograms of race mic 3 98 and enantioenriched 3 98 :

PAGE 262

262 Chromatograms of racemic 3 99 and enantioenriched 3 99 : Preparation of Aliphatic Branched Chiral Amines Figure 5 1 7 Synthetic route for the preparation of aliphatic branched chiral amines ( S ) N,N dibenzyltridecan 6 amine ( 3 92 ). Rh(Ph 3 P) 3 Cl (0.0050 g, 0.0054 mmol, 0.1 equiv) and a magnetic stirr er were added to a flask which was capped with a rubber septum. A mixture of THF : MeOH (1 : 1, 0.4 mL total) was added to the flask containing the catalyst. A balloon containing hydrogen was coupled to a needle and inserted into

PAGE 263

263 the flask. Another needle was inserted and hydrogen was bubbled in the solution for 5 min. A solution of 3 81 (0.0202 g, 0.054 mmol, 1.0 equiv) in THF : MeOH (1 : 1, 0.4 mL total) was then added to the solution containing the catalyst and hydrogen, and the reaction mixture was sti rred for 24 h. Reaction was quenched with silica gel, and the solvent was removed under reduced pressure. Purification through a plug of flash silica gel (3% EtOAc in hexanes) afforded 3 92 (0.0165 mg, 0.0435 mmol) in 80% yield as a colorless oil. R f = 0 .90 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 7.37 7.32 (m, 4H), 7.30 7.24 (m, 2H), 7.22 7.16 (m, 2H), 3.54 (s, 1H), 2.42 2.35 (m, 1H), 1.63 1.43 (m, 2H), 1.43 1.04 (m, 18H), 0.88 (t, J = 7.1 Hz, 3H), 0.85 (t, J = 7.1 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) 141.2, 129.1, 128.2, 126.8, 57.3, 53.6, 32.3, 32.2, 30.0, 29.9, 29.9, 29.6, 27.4, 27.1, 22.9, 14.4, 14.3. 24 D = 13.76 ( c 1.0, CHCl 3 ). HRMS (ESI TOF) m/z: [M+H] + Calcd for C 27 H 42 N + 380.3312; Found 380.3343. ( S ) tridecan 6 amine ( 3 93 ). Pd(OH) 2 /C (0.0021 g, 10 % palladium content, 20 % weight in relation to substrate) and a magnetic stirrer were added to a flask which was capped with a rubber septum. A solution of 3 92 (0.0105 g, 0.028 mmol, 1.0 equiv) in MeOH (0.8 mL) was then added to the solution containing the catalyst, and the reaction mi xture was stirred for 7 h under 1 atm atmosphere of hydrogen (a hydrogen baloon was coupled to a needle and inserted into the reaction flask). Reaction was filtered through a plug of celite which was washed with EtOAc (3.0 mL). The solvent was removed unde r reduced pressure to afford 3 93 (0.0049 g, 0.025 mmol) in 88% yield as a colorless oil. R f = 0.0 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 2.69 (bs, 1H), 1.44 1.17 (m, 22H), 0.90 (t, J = 7.0 Hz, 3H), 0.88 (t, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) 51.4, 38.3, 32.2, 32.0, 30.0, 29.5,

PAGE 264

264 26.4, 26.0, 22.8, 14.2. [ ] 24 D = 23.69 ( c 0.5, CHCl 3 ). HRMS (ESI TOF) m/z: [M+H] + Calcd for C 13 H 30 N + 200.2373; Found 200.2385. ( S ) 3,3,3 trifluoro 2 methoxy 2 phenyl N (( S ) tridecan 6 yl)pro panamide ( 3 94 ). Et 3 N (10.5 L, 0.0377 mmol, 2.5 equiv) and ( S ) L, 0.0158 mmol, 1.05 equiv) were added to a stirred solution of 3 93 (0.0030 mg, 0.015 mmol, 1 equiv) in CH 2 Cl 2 (0.5 mL), at room temperature. The reaction was que nched with silica gel, and the solvent was removed under reduced pressure. Purification via flash column chromatography of silica gel (5% EtOAc in hexanes) afforded 3 94 (0.0056 g, 0.0135 mmol) in 90% yield as a colorless oil. R f = 0.65 (20% EtOAc in hexan es, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 7.58 7.52 (m, 2H), 7.41 7.38 (m, 3H), 6.43 (d, J = 9.3 Hz, 1H), 4.03 3.87 (m, 1H), 3.44 (s, 3H), 1.61 1.46 (m, 2H), 1.45 1.16 (m, 18H), 0.94 0.81 (m, 6H). 19 F NMR (282 MHz, CDCl 3 ) 68.79. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 23 H 37 NF 3 O 2 + 416.2771; Found 416.2794. All the peaks for the two diastereomers of 3 94 overlap in the 1 H and 19 F NMR, thus diastereomeric ratio was determined by HPLC with a Chiralcel OD H column (99.75 : 0.25 n hexane:isopropanol, 0.2 mL/min, 254 nm); minor t r = 31.9 min; major t r = 32.8 min; 91 : 9 dr. ( S ) N (tridecan 6 yl)acetamide ( 3 12 ). Et 3 N (10.5 L, 0.0377 mmol, 2.5 equiv), and acetyl chloride (1.1 L, 0.0158 mmol, 1.05 equiv) were added to a stirred solution of 3 93 (0.0030 mg, 0.015 mmol, 1 equiv) in CH 2 Cl 2 (0.5 mL), at room temperature. The reaction was quenched with silica gel, and the solvent was removed under reduced pressure. Purification via flash column chromatography of silica gel (5% EtOAc in hexanes) afforded 3 12 (0.0032 g, 0.0132 mmol) in 88% yield as white solid. NMR data

PAGE 265

265 for this compound matches with the reported for the isolated n atural sample. The optical rotation of the natural sample was not reported, thus it is not possible to determine whether the natural product is racemic or non racemic. However, it should be noted that similar isolated natural products (chlorinated derivati ves and taveuniamides) are non racemic. R f = 0.15 (20% EtOAc in hexanes, UV/ KMnO 4 stain). 1 H NMR (500 MHz, CDCl 3 ) 5.13 (d, J = 9.3 Hz, 1H), 3.88 (bs, 1H), 1.96 (s, 3H), 1.51 1.40 (m, 2H), 1.29 1.20 (m, 18H), 0.86 (t, J = 6.6 Hz, 6H). 13 C NMR (125 MH z, CDCl 3 ) 169.7, 77.5, 77.2, 77.0, 49.6, 35.5, 35.4, 32.0, 29.8, 29.5, 26.0, 25.7, 23.8, 22.9, 22.8, 14.3, 14.2. 24 D = +11.17 ( c 0.1, CHCl 3 ). MP = 64 C. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 15 H 32 NO + 242.2478; Found 242.2485. Chromatograms of Moshe 3 94 (50 : 50 and 91 : 9 mixture of diastereomers): X Ray Crystallographic Data of Brominated Amino Skipped Diyne Figure 5 18. X Ray structure of brominated amino skipped diyne

PAGE 266

266 X Ray experimental: The X Ray quality single crystals were gro wn from a 50 : 50 mixture of hexanes and dichloromethane. The amine 5 4 2 (enantiomer of 3 73 ) (25 mg, 96% ee determined by Chiral HPLC, had a ( S ) configuration and it was synthesized from ( R ) StackPhos according to the general procedure. For the recrystal lization, the amine was placed in a vial (15 mg) and dissolved in dichloromethane (3 drops). Then hexanes (1.0 mL) were added to the vial. The vial was capped, and placed in the freezer at 20 C. Single crystals were observed after one week. X Ray Intensi ty data were collected at 100 K on a Bruker DUO diffractometer using MoK radiation ( = 0.71073 ) and an APEXII CCD area detector. Raw data frames were read by program SAINT and integrated using 3D profiling algorithms. The resulting data were reduced to produce hkl reflections and their intensities and estimated standard deviations. The data were corrected for Lorentz and polarization effects and numerical absorption corrections were applied based on indexed and measured faces. The structure was solved and refined in SHELXTL2013, using full matrix least squares refineme nt. The non H atoms were refined with anisotropic thermal parameters and all of the H atoms were calculated in idealized positions and refined riding on their parent atoms. The correct enantiomer is refined and reported here as can be evidenced by the va lue of the Flack x parameter of 0.0131(12). In the final cycle of refinement, 5836 reflections (of which 5707 are observed with I > 2 (I)) were used to refine 283 parameters and the resulting R 1 wR 2 and S (goodness of fit) were 1.82 %, 5.13 % and 1.121 r espectively. The refinement was carried out by minimizing the wR 2 function using F 2 rather than F values. R 1 is

PAGE 267

267 calculated to provide a reference to the conventional R value but its function is not minimized. SHELXTL2013 (2013). Bruker AXS, Madison, Wi sconsin, USA. Datablock: paulo4 Bond precision: C C = 0.0030 A Wavelength=0.71073 Cell: a=5.8781(3) b=10.3144(6) c=21.1393(12) alpha=90 beta=94.3996(11) gamma=90 Temperature: 100 K Calculated Reported Volume 1277.88(12) 1277.88(12) Space group P 21 P 21 Hall group P 2yb P 2yb Moiety formula C28 H28 Br N Si ? Sum formula C28 H28 Br N Si C28 H28 Br N Si Mr 486.50 486.51 Dx,g cm 3 1.264 1.264 Z 2 2 Mu (mm 1) 1.670 1.670 F000 504.0 504.0 h,k,lmax 7,13, 27 7,13,27 Nref 5893[ 3111] 5836 Tmin,Tmax 0.720,0.827 0.735,0.883

PAGE 268

268 Correction method= ANALYTICAL Data completeness= 1.88/0.99 Theta(max)= 27.496 R(reflections)= 0.0182( 57 07) wR2(reflections)= 0.0575( 5836) S = 1.121 Npar= 283 Table 1. Crystal data and structure refinement for paulo4. Identification code paulo4 Empirical formula C28 H28 Br N Si Formula weight 486.51 Temperature 100(2) K Wavelength 0.71073 Crystal sy stem Monoclinic Space group P 2 1 Unit cell dimensions a = 5.8781(3) = 90. b = 10.3144(6) = 94.3996(11). c = 21.1393(12) = 90. Volume 1277.88(12) 3 Z 2 Density (calculated) 1.264 Mg/m3 Absorption coefficient 1.670 mm 1 F(000) 504 Crystal s ize 0.346 x 0.169 x 0.114 mm3 Theta range for data collection 0.966 to 27.496.

PAGE 269

269 Index ranges Reflections collected 17946 Independent reflections 5836 [R(int) = 0.0156] Completeness to theta = 25.242 99.9 % Absorption correction Analytical Max. and min. transmission 0.8830 and 0.7353 Refinement method Full matrix least squares on F2 Data / restraints / parameters 5836 / 1 / 283 Goodness of fit on F2 1.121 Final R indices [I>2sigma(I)] R1 = 0.0182, wR2 = 0.0513 [5707] R indices (a ll data) R1 = 0.0193, wR2 = 0.0575 Absolute structure parameter 0.0131(12) Largest diff. peak and hole 0.399 and 0.201 e. 3 Preparation of StackPhim Ligands 4 76 and 4 77 Figure 5 19. Synt hetic route for the preparati on of StackPhim ligands 4 76 and 4 77

PAGE 270

270 A solution (2.0 M) of oxalyl chloride in dichloromethane (7.96 mL, 15.918 mmol, 2.0 equiv) was added dropwise (gas evolved), at room temperature, to a stirred solution containing the c arboxylic acid 4 55 (2.372 g, 7.959 mmol, 1.0 equiv) and catalytic amount of DMF (16 L) in dichloromethane (20 mL). After the reaction mixture becomes homogeneous (30 min to 1 hour), the reaction is concentrated under reduced pressure to yield the acyl chloride as a yellow residue. The residue is redissolved in dichloromethane (25 mL), an d the solution containing the acyl chloride is added dropwise over 1h using syringe pump to another flask containing a solution of Et 3 N (3.33 mL, 23.877 mmol, 3.0 equiv) and (1 R ,2 R ) DPEN (1.774 g, 8.357 mmol, 1.05 equiv) in dichloromethane (25 mL) maintain ed at 0C. The reaction was slowly warmed up to room temperature, and quenched after 3h with a saturated aqueous solution of NaHCO 3 (150 mL). The organic layer was washed 2x with a 20% aqueous solution of NH 4 Cl (15 mL) and 1x with brine (15 mL). The crude material was then dissolved in a minimum amount of dichloromethane (5 mL) and upon vigorous stirring hexanes (250 mL) was slowly added until precipitation. The recrystallized material was then filtered using a sintered funnel, dried under reduced pressure to deliver compound 5 59 in 83% yield (3.252 g, 6.605 mmol) as a slightly yellowish solid. R f = 0.53 (10% MeOH/ 45% dichloromethane/ 45% hexanes, UV/ KMnO 4 stain). MP = 172 C. 1 H NMR (500 MHz, CDCl 3 ) 7.76 (dd, J = 8.3, 5.0 Hz, 2H), 7.63 7.15 (m, 15H), 5.55 (d, J = 8.5 Hz, 1H), 4.50 (s, 1H), 1.55 (bs, 2H). HRMS (ESI TOF) m/z: [M+H] + Calcd for C 25 H 22 N 2 IO +

PAGE 271

271 493.0771; Found 493.0768. To a vigorous stirred solution of compound 5 59 (3.253 g, 6.607 mmol, 1.0 equiv) in MeCN (250 mL) was added, at room temperature, K 2 CO 3 (0.913 g, 6.607 mmol, 1.0 equiv), followed by pentafluorobenzylbromide (1.0 mL, 6.607 mmol, 1.0 equiv). After 24 h, the solids were filtered, and MeCN was evaporated under reduced pressure. The resultant residue was then dissolved in a minimum amount of dichloromethane (5 mL) and upon vigorous stirring hexanes (250 mL) was slowly added until precipitation. The recrystallized material was then filtered using a sintered funnel, dried under red uced pressure to deliver compound 4 79 in 75% yield (3.312 g, 4.926 mmol) as a slightly yellowish solid. R f = 0.73 (10% MeOH/ 45% dichloromethane/ 45% hexanes, UV/ KMnO 4 stain) and R f = 0.71 (40% EtOAc in hexanes, UV/ KMnO 4 stain) and R f = 0.50 (dichlorome thane, UV/ KMnO 4 ). MP = 135 C. 1 H NMR (500 MHz, CDCl 3 ) 7.76 (dd, J = 8.3, 5.8 Hz, 2H), 7.52 (d, J = 8.7 Hz, 1H), 7.47 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 7.42 7.23 (m, 12H), 6.75 (d, J = 7.8 Hz, 1H), 5.50 (t, J = 6.7 Hz, 1H), 4.00 (d, J = 5.3 Hz, 1H), 3.74 (dt, J = 13.7, 1.7 Hz, 1H), 3.59 (d, J = 13.6 Hz, 1H) 2.09 1.97 (bs, 1H). 13 C NMR (125 MHz, CDCl 3 ) 169.4, 145.2 (d, J = 245.0 Hz), 140.8, 140.5 (d, J = 242.5 Hz), 139.2, 139.0, 137.4 (d, J = 257.5 Hz), 135.3, 132.4, 131.2, 130.4, 129.0, 128.7, 128.0, 128.0, 127.9, 127.8, 127.2, 126.9, 125.4, 113.0 (t, J = 18.9 Hz), 91.0, 66.7, 59.9, 38.9. 19 F NMR (281 MHz, CDCl 3 ) 144.3 (d, J = 23.1 Hz), 155.9 (t, J = 20.8 Hz), 162.6 (td, J = 20.9, 6.9 Hz). HRMS (ESI TOF) m/z: [M+H] + Calcd for C 32 H 23 N 2 F 5 IO + 673.0770; Found 673.0739. To a stirred solution of compound 4 79 (3.180 g, 4.729 mmol, 1.0 equiv) in toluene (100 mL) placed at 105 C, was added phosphorus oxychloride (17.7 mL, 189.17 mmol, 40.0 equiv). The mixture was stirred for 24 h and concentrated under reduced pressure. The residue was dissolved in EtOAc

PAGE 272

272 ( 40 mL) and washed 2x with 1M NaOH aqueous solution (20 mL). The organic layer was separated, dried and concentrated to give a residue which was purified by flash column chromatography on silica gel (5 15% EtOAc in hexanes) to afford compound 4 80 as a 10:1 mixture of diastereomers (observed by NMR) in 63% yield (1.950 g, 2.980 mmol) as a slightly grayish solid. R f = 0.10 (dichloromethane, UV/ KMnO 4 ). MP = 147 C. 1 H NMR (500 MHz, CDCl 3 ) (major diastereomer) 8.14 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 8.3, 6.8 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.42 (d, J = 7.2 Hz, 2H), 7.38 7.22 (m, 8H), 5.30 (d, J = 11.8 Hz, 1H), 4.58 (d, J = 11.9 Hz, 1H), 4.28 (d, J = 14.4 Hz, 1H), 4.19 (d, J = 1 4.3 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ) (major diastereomer) 165.2, 144.7 (d, J = 247.8 Hz), 142.4, 140.2 (d, J = 252.5 Hz), 140.0, 136.6 (d, J = 247.1 Hz), 135.0, 134.5, 132.6, 132.4, 130.9, 128.5, 128.5, 128.2, 128.0, 127.8, 127.4, 127.4, 127.2, 125.7, 110.3 (t, J = 18.9 Hz), 96.9, 79.4, 78. 5, 38.9. 19 F NMR (281 MHz, CDCl 3 ) (major diastereomer) 141.3 (dd, J = 22.7, 8.2 Hz), 156.0 (t, J = 20.8 Hz), 163.6 (td, J = 21.9, 6.7 Hz). HRMS (ESI TOF) m/z: [M+H] + Calcd for C 32 H 21 N 2 F 5 I + 655.0664; Found 655.0699. A pear shaped flame dried Schlenk flask (100 mL) was evacuated and refilled with argon for three times. To the flask was added, CuI (14.6 mg, 0.0764 mmol, 5 mol %) followed by anhydrous toluene (3 mL), diphenylphosphine (0.29 mL, 1.681 mmol, 1.1 equiv) an d N,N' dimethylethylenediamine (57.6 L, 0.535 mmol, 35 mol %). The

PAGE 273

273 mixture (colorless or slightly yellowish) was stirred for 10 min. Then, iodine 4 80 (1.00 g, 1.528 mmol, 1.0 equiv) and Cs 2 CO 3 (1.867 g, 5.730 mmol, 3.75 equiv) were added at once, followed by anhydrous toluene (3 mL). The re action mixture quickly turned bright yellow/orangeish and the reaction was stirred for 12h at 105 C, with the Schlenk flask sealed with a Teflon valve on the side arm and a glass stopper on the top. Reaction mixture was cooled down to room temperature, di luted with water (4 mL) and extracted 2x with EtOAc (5 mL). The organic layers were combined, dried over MgSO4, concentrated, and the residue was purified by flash column chromatography on silica gel. The separation of diastereomers was achieved by using a column of silica gel of size 26.0 x 4.5 (height in cm x width in cm), eluted with a gradient of 3 8% Et 2 O in dichloromethane. The diastereomers were fully separated (see the TLC below). The major diastereomer (as shown in the NMR of the crude reaction mi xture) StackPhim 4 77 was isolated in 38% yield (0.413 g, 0.580 mmol) as a white solid and the minor diastereomer StackPhim 4 76 was isolated in 16% yield (0.174 g, 0.245 mmol) as a white solid. The relative and, as a consequence, the absolute configuratio n of the diastereomer StackPhim 4 77 was determined by single crystal X Ray crystallography analysis and the absolute and relative stereochemistry of StackPhim 4 76 were then determined by analogy with StackPhim 4 77 TLC after the column chromatography (eluting with 10% Et 2 O in dichloromethane):

PAGE 274

274 (4 R ,5 R R ax ) 2 (2 (diphenylphosphanyl)naphthalen 1 yl) 1((perfluorophenyl)methyl) 4,5 diphenyl 4,5 dihydro 1H imidazole (StackPhim 4 76 ) : R f (mi nor) = 0.19 (10% Et 2 O in dichloromethane, UV/ KMnO 4 stain). MP = 87 C. 1 H NMR (500 MHz, CDCl 3 ) 7.85 (ddd, J = 12.8, 8.6, 5.5 Hz, 3H), 7.68 (d, J = 7.5 Hz, 2H), 7.58 7.48 (m, 3H), 7.48 7.25 (m, 18H), 5.25 (d, J = 10.6 Hz, 1H), 4.86 (d, J = 10.4 Hz, 1 H), 4.20 (d, J = 15.3 Hz, 1H), 3.87 (d, J = 15.3 Hz, 1H). 19 F NMR (281 MHz, CDCl 3 ) 141.1 (d, J = 23.2 Hz), 155.4 (t, J = 20.8 Hz), 162.6 (td, J = 22.2, 7.3 Hz). 31 P NMR (121 MHz, CDCl 3 ) 12.3 (t, J = 5.2 Hz). HRMS (ESI TOF) m/z: [M+H] + Calcd for C 44 H 31 N 2 F 5 P + 713.2140; Found 713.2141. (4 R ,5 R S ax ) 2 (2 (diphenylphosphanyl)naphthalen 1 yl) 1((perfluorophenyl)methyl) 4,5 diphenyl 4,5 dihydro 1H imidazole (StackPhim 4 77 ) : R f (major) = 0.37 (10% Et 2 O in dichloromethane, UV/ KMnO 4 stain). MP = 111 C. 1 H NMR (500 MHz, CDCl 3 ) 8.27 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.71 (t, J = 7.0 Hz, 1H), 7.61 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.47 7.21 (m, 16H), 7.18 7.12 (m, 1H), 7.07 (t, J = 7.5 Hz, 2H), 6.85 (d, J = 7.5 Hz, 2H), 5.22 (dd, J = 12.0, 2.9 Hz, 1H), 4.60 (d, J = 11.9 Hz, 1H), 4.52 (d, J = 14.0 Hz, 1H), 4.35 (d, J = 14.0 Hz, 1H). 13 C NMR

PAGE 275

275 (125 MHz, CDCl 3 ) 164.6, 142.2, 145.8 (d, J = 247.3 Hz), 140.4, 140.3 (d, J = 254.5 Hz), 137.3, 137.2, 137.0, 136.7, 136.6 (d, J = 254.1 Hz), 136.1, 136.0, 134.6, 134.4, 134.3, 134.2, 133.6, 133.5, 133.4, 131.7, 131.6, 110.8 (t, J = 12.6 Hz), 79.9, 78.7, 39.7, 39.6, 29.9. 19 F NMR (281 MHz, CDCl 3 ) 140.7 (dd, J = 22.9, 8.1 Hz), 155.9 (t, J = 20.8 Hz), 163.4 (td, J = 22.0, 8.2 Hz). 31 P NMR (121 MHz, CDCl 3 ) 11.6 (bt, J = 2. 1 Hz). HRMS (ESI TOF) m/z: [M+H] + Calcd for C 44 H 31 N 2 F 5 P + 713.2140; Found 713.2137. Preparation of F 5 Phim Ligand 4 84 Figure 5 20 Synthetic route for the preparation of F 5 Phim ligand 4 84 To a stirred solution of benzoic acid 4 81 (1.9740 g, 7.959 mmol, 1.0 equiv) in dichloromethane (20 mL) was added, at room temperature, catalytic amount of DMF (16 L), followed by dropwise addition (gas evolved) of a solution (2.0 M) of oxalyl chloride

PAGE 276

276 in dichloromethane (7.96 mL, 15.918 mmol, 2.0 equiv). After the reaction mixture becomes homogeneous (30 min to 1 hour), the reaction is concentrated under reduced pr essure to yield the acyl chloride as a yellow residue. The residue is redissolved in dichloromethane (25 mL), and the solution containing the acyl chloride is added dropwise over 1h using syringe pump to another flask containing a solution of Et 3 N (3.33 mL 23.877 mmol, 3.0 equiv) and (1 R ,2 R ) DPEN (1.774 g, 8.357 mmol, 1.05 equiv) in dichloromethane (25 mL) maintained at 0C. The reaction was slowly warmed up to room temperature, and quenched after 3h with a saturated aqueous solution of NaHCO 3 (150 mL). Th e organic layer was washed 2x with a 20% aqueous solution of NH 4 Cl (15 mL) and 1x with brine (15 mL). The crude material was then dissolved in a minimum amount of dichloromethane (5 mL) and upon vigorous stirring hexanes (250 mL) was slowly added until pre cipitation. The solid formed upon recrystallization were in fact impurities and the mother liquor contained pure compound 5 60 The mother liquor was then concentrated, to furnish compound 5 60 in 43% yield (1.5203 g, 3.437 mmol) as a slightly yellowish so lid. MP = 124 C. 1 H NMR (500 MHz, CDCl 3 ) 7.79 (dd, J = 7.9, 1.1 Hz, 1H), 7.41 (td, J = 8.4, 1.3 Hz, 3H), 7.38 7.20 (m, 7H), 7.10 7.00 (m, 2H), 5.30 (dd, J = 8.0, 3.3 Hz, 1H), 4.49 (d, J = 3.3 Hz, 1H), 1.50 (bs, 2H). To a vigorous stirred solution of compound 5 60 (1.4250 g, 3.222 mmol, 1.0 equiv) in MeCN (120 mL) was added, at room temperature, K 2 CO 3 (0.432 g, 3.222 mmol, 1.0 equiv), followed by pentafluorobenzylbromide (0.48 mL, 3.222 mmol, 1.0 equiv). After 36 h, the solids were filtered, and MeCN was evaporated under reduced pressure. The resultant residue was then dissolved in a minimum amount of dichloromethane (2 mL) and upon vigorous stirring hexanes (150 mL) was slowly added until precipitation. The recrystallized

PAGE 277

277 material was then filtered us ing a sintered funnel, dried under reduced pressure to deliver compound 4 82 in 92% yield (1.8448 g, 2.964 mmol) as a slightly yellowish solid. R f = 0.67 (40% EtOAc in hexanes, UV/ KMnO 4 stain). MP = 163 C. 1 H NMR (500 MHz, CDCl 3 ) 7.79 (dd, J = 8.0, 1.1 Hz, 1H), 7.33 7.19 (m, 10H), 7.14 7.00 (m, 3H), 6.69 (d, J = 7.7 Hz, 1H), 5.27 (dd, J = 7.8, 5.1 Hz, 1H), 4.00 (d, J = 5.1 Hz, 1H), 3.71 (d, J = 13.6 Hz, 1H), 3.58 (d, J = 13.6 Hz, 1H), 1.89 (s, 1H). 19 F NMR (281 MHz, CDCl 3 ) 143.3 (dd, J = 22.9, 8. 6 Hz), 155.3 (t, J = 20.8 Hz), 162.2 (td, J = 22.3, 8.7 Hz). To a stirred solution of compound 4 82 (1.845 g, 2.965 mmol, 1.0 equiv) in toluene (50 mL) placed at 105 C, was added phosphorus oxychloride (11.1 mL, 118.60 mmol, 40.0 equiv). The mixture was stirred for 24 h and concentrated under reduced pressure. The residue was dissolved in EtOAc (40 mL) and washed 2x with 1M NaOH aqueous solution (20 mL). The organic layer was separated, dried and concentrated to give a residue which was purified by flash column chromatography on silica gel (5 15% EtOAc in hexanes) to afford compound 4 83 as a 2:1 mixture of diastereomers in 46% yield (0.8243 g, 1.364 mmol) as a white solid. R f = 0.52 (40% EtOAc in hexanes, UV/ KMnO 4 ). MP = 55 C. 1 H NMR (500 MHz, CDCl 3 ) (major diastereomer) 7.91 (dd, J = 8.1, 1.1 Hz, 1H), 7.64 7.08 (m, 14H), 5.03 (d, J = 10.8 Hz, 1H), 4.39 (d, J = 10.7 Hz, 1H), 4.21 (bs, 2H). 1 H NMR (500 MHz, CDCl 3 ) (minor diastereomer) 7.91 (dd, J = 8.1, 1.1 Hz, 1H), 7.64 7.08 (m, 14H), 5.10 (bs, 1H), 4.39 (bs, 3H), 4.21 (bs, 2H). 13 C NMR (125 MHz, CDCl 3 ) (mixture of diastereomers) 166.1, 145.1 (d, J = 235.5 Hz), 142.9, 140.8, 140.6 (d, J = 248.1 Hz), 139.3, 137.1(d, J = 255.5 Hz), 136.9, 131.3, 130.2, 128.9, 128.6, 128.5, 128.1, 128.3, 127.5, 12 7.4, 127.3, 126.7, 110.7 (t, J = 14.9 Hz), 97.2, 95.9, 79.8, 78.9, 74.6, 39.5, 37.9. 19 F NMR (281 MHz, CDCl 3 ) (major

PAGE 278

278 diastereomer) 142.10 (d, J = 23.0 Hz), 155.3 (t, J = 21.1 Hz), 163.9 (bt, J = 22.2 Hz). 19 F NMR (281 MHz, CDCl 3 ) (minor diastereomer ) 141.2 (d, J = 20.5 Hz), 154.0 (t, J = 19.4 Hz), 161.9 (bt, J = 21.6 Hz). HRMS (ESI TOF) m/z: [M+H] + Calcd for C 28 H 19 N 2 F 5 I + 605.0508; Found 605.0514. A pear shaped flame dried Schlenk flask (50 mL) was evacuated and refilled with argon for three times. To the flask was added, CuI (6.3 mg, 0.0331 mmol, 5 mol %) followed by anhydrous toluene (1.5 mL), diphenylphosphine (0.13 mL, 0.728 mmol, 1.1 equiv) and N,N' dimethylethylenediamine (25.0 L, 0.232 mmol, 35 mol %). The mixture (colorless or slightly yellowish) was stirred for 10 min. Then, iodine 4 83 (0.400 g, 0.662 mmol, 1.0 equiv) and Cs 2 CO 3 (0.809 g, 2.482 mmol, 3.75 equiv) were added at once, followed by anhydrous toluene (1.5 mL). The reaction mixture quickly turned bright yellow/orangeish and the reaction was stirred for 20h at 105 C, with the Schlenk flask sealed with a Teflon valve on the side arm and a glass stopper on the top. Reaction mixture was cooled down to room temperature, diluted with water (4 mL) and extracted 2x with EtOAc (5 mL). The organic layer was separated, dried over MgSO 4 concentrated, and subjected to flash column chromatography (5 10% Et 2 O in dichloromethane) to deliver the ligand F 5 Phim 4 84 in 52% yield (0. 2281 g, 0.344 mmol) as a white solid.

PAGE 279

279 (4 R ,5 R ) 2 (2 (diphenylphosphanyl)phenyl) 1 ((perfluorophenyl)methyl) 4,5 diphenyl 4,5 dihydro 1H imidazole (F 5 Phim 4 84 ) : R f (major) = 0.35 (40% EtOAc in hexanes, UV/ KMnO 4 stain). M P = 79 C. 1 H NMR (500 MHz, CDCl 3 ) 7.78 7.73 (m, 1H), 7.53 (td, J = 7.5, 1.3 Hz, 1H), 7.43 (td, J = 7.6, 1.4 Hz, 1H), 7.40 7.31 (m, 10H), 7.25 7.14 (m, 9H), 7.01 (dd, J = 7.1, 2.3 Hz, 2H), 4.96 (d, J = 10.6 Hz, 1H), 4.29 (d, J = 10.8 Hz, 2H), 4.15 (d, J = 14.5 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ) 165.3, 145.1 (d, J = 234.6 Hz), 143.1, 141.2, 140.6 (d, J = 277.8 Hz), 137.7, 137.5, 137.3, 137.2, 137.2, 137.0 (d, J = 235.5 Hz), 136.2, 136.1, 134.5, 134.4, 134.2, 134.0, 133.8, 130.0, 129.7, 129.4, 129.1, 128.9, 128.8, 128.8, 128.8, 128.7, 128.4, 128.4, 127.9, 127.5, 127.1, 127.0, 110.8 (t, J = 18.2 Hz), 110.2, 79.9, 76.6, 39.7, 29.9. 19 F NMR (281 MHz, CDCl 3 ) 141.7 (d, J = 20.8 Hz), 155.3, 163.1. 31 P NMR (121 MHz, CDCl 3 ) 12.5. HRMS (ESI TOF) m/z: [M+H] + Calcd for C 40 H 29 N 2 F 5 P + 663.19 83; Found 663.2007. Thermal Epimerization Studies of StackPhim 4 76 and 4 77 Initially, it was observed that both StackPhim ligands 4 76 and 4 77 were configurationally stable over long periods of time in CDCl 3 solution at room temperature. However, at 50 C, it was observed that StackPhim 4 77 would slowly eprimerize to StackPhim 4 76 In order to measure experimentally the barrier to rotation related to this process, the epimerization of StackPhim 4 77 to StackPhim 4 76 was followed by 1 H NMR, over the p eriod of 5 days, at 50 C. A 0.021 M solution of StackPhim 4 77 in CDCl 3 (15 mg of StackPhim 4 77 / mL of CDCl 3 ) was placed in oil bath at 50 C. Various

PAGE 280

280 1 H NMR spectra were acquired at different times until the equilibrium was established, according to th e data collected shown below. The NMR spectra were acquired at room temperature, and during the time the NMR tube was outside the 50 C bath the clock was stopped. This time is negligible since no observable epimerization occurs at room temperature, for bo th diastereomers. Th e data collected, a general explanation of how the barrier to rotation can be experimenta lly measured using the rate law, the Eyring equation, and the measured barrier to rotation can be seen below: Fi gure 5 21. Epimerization: data collected by 1 H NMR

PAGE 281

281 Figure 5 22. Finding the rate constant from the rate law Figure 5 23. Graph of ln ([4 7 7 ] t [4 7 7 ] eq / [4 7 7 ] 0 [4 7 7 ] eq ) versus time

PAGE 282

282 Figure 5 24. Barrier to rotation of StackPhim 4 76 and 4 77 The barrier to rotation of ligands 4 60 and 4 61 were measured in the same way, with the only difference being that the epimerization was followed at room temperature Preparation of 2 Methylamine Heterocyclic Compounds Figure 5 25 Preparation of propargylamine s via A3 reaction toward methylamine heterocycles CuBr (0.5 2.0 mg, 0.0035 0.0139 mmol, 5 mol %) and previously activated 4 molecular sieves (50 mg/ mg of CuBr) was added to an oven dried test tube which was then capped with a rubber septum. StackPhim 4 76 (2.7 10.9 mg, 0.0038 0.0153 mmol, 5.5 mol %) was added to the test tube, followed by anhydrous dichloromethane (1.0 mL/ mg of CuBr). The mi xture was stirred for 20 min at room temperature and formation of a yellowish solution was observed. To the stirring solution were added the alkyne (0.0697 0.2788 mmol, 1.0 equiv) and the aldehyde (0.0697 0.2788 mmol, 1.0 equiv). The mixture was then place d at 0C and stirred for 5 min. To the reaction flask was then added the amine (0.0697 0.2788 mmol, 1.0 equiv), followed by anhydrous dichloromethane (0.4 mL/ mg of CuBr). (Note: the test tube was opened for the addition

PAGE 283

283 of the reagents, which suggests tha t the reaction is not very sensitive to water and oxygen).The test tube was then capped with a plastic cap and the final concentration of substrate in dichloromethane was maintained (0.1 M). The reaction was followed by TLC, and directly subjected to flash column chromatography on silica gel to deliver the desired propargyl amines. For the preparation of racemic products, the same procedure was followed with rac StackPhos. 1.5 equivalents of isobutyraldehyde, n butanal were added, since these are relatively volatile compounds. Figure 5 26. Preparation of furylamines via gold catalyzed cyclization AgOTf (0.7 1.4 mg, 0.0027 0.0054 mmol, 10 mol %), (JohnPhos)AuCl (1.4 2.8 mg, 0.0027 0.0054 mmol, 10 mol %) and previously activ ated 4 molecular sieves (50 mg/ mg of AgOTf) was added to an oven dried test tube which was then capped with a rubber septum. Anhydrous THF (0.4 mL/ mg of AgOTf) was then added to the test tube and the mixture was stirred for 5 min. A solution of the alky nediol (0.0269 0.0537 mmol, 1.0 equiv) and TFA (2.1 4.2 L, 0.0269 0.0537, 1.0 equiv) in THF (0.4 mL/ mg of AgOTf) was prepared in a small conical flask. The flask containing the solution of alkynediol and TFA was added via syringe to the flask contain in g the solution of the catalyst. The reaction was followed by TLC, and quenched by the addition of EtOAc (2 4 mL) and 1M NaOH solution (2 4 mL). The mixture was added to a separatory funnel and upon phase separation the organic layer was recovered, washed with NaCl saturated solution, dried with MgSO 4 and concent rated under reduced pressure The

PAGE 284

284 crude mixture was subjected to column chromatography on silica gel (EtOAc in hexanes) providing the desired fur ylamines Figure 5 27. Preparation of benzofuryl and indolylamines K 2 CO 3 (42 mg, 0.305 mmol, 5.0 equiv) was added to a mixture containing the phenol (22.5 mg, 0.0609, 1.0 equiv) or the sulfonamide in MeCN (1.2 mL), and the mixture was stirred at 7 0 C until full conversion was observed by TLC. The solids were then filtered off a nd MeCN was evaporated under reduced pressure. The crude was subjected to flash column chromatography on silica gel (0 5% EtOAc in hexanes), de livering the benzofurylamine or the indolylamine respectively. (5 S ) 5 (dib enzylamino) 6 methylhept 3 yne 1,2 diol (4 117 ) The following compound 4 117 was prepared via aforementioned procedure with StackPhim 4 76 in 74% yield (22.2 mg, 0.0657 mmol) as a colorless oil. The reaction was carried out for 4h. The configuration at th e amine stereocenter was determined according to previous A3 reactions reported by our group. R f = 0.33 (40% EtOAc in hexanes, UV/ KMnO4 stain). 1 H NMR (500 MHz, CDCl 3 mixture of diastereomers) 7.41 (d, J = 7.6 Hz, 4H), 7.33 (t, J = 7.5 Hz, 4H), 7.27 (q, J = 7.2, 2H), 4.67 4.55 (m, 1H), 3.84 (d, J = 13.6 Hz, 2H), 3.76 (dd, J = 11.6, 6.7 Hz, 1H), 3.36 (d, J = 13.8 Hz, 2H), 2.98 (d, J = 10.4 Hz, 1H),

PAGE 285

285 2.32 (bs, 2H), 1.93 (dt, J = 10.9, 6.4 Hz, 1 H), 1.03 (d, J = 6.5 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 mixture of diastereomers) 139.6, 129.0, 128.6, 127.1, 84.1, 83.6, 67.3, 63.7, 59.3, 55.2, 30.8, 21.1, 20.1. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 22 H 28 NO 2 + 338.2115; Found 3 38.2101. ( S ) N N dibenzyl 1 (furan 2 yl) 2 methylpropan 1 amine ( 4 118 ) The following compound 4 118 was prepared via aforementioned procedure in 81% yield (8.6 mg, 0.0270 mmol) as a colorless oil. The reaction was car ried out for 9h. R f = 0.90 (20% EtOAc in hexanes, UV/ KMnO4 stain). [ ] 24 D = 103.25 ( c 0.1, CHCl 3 ). Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 0.2 mL/min, 254 nm); minor t r = 43.7.X min; major t r = 45.4 min; 94% ee 1 H NMR (500 MHz, CDCl 3 ) 7.40 7.32 (m, 4H), 7.2 7 7.21 (m, 5H), 7.19 7.13 (m, 2H), 6.31 (s, 2H), 6.01 (s, 2H), 3.85 (d, J = 14.1 Hz, 2H), 3.10 (d, J = 11.0 Hz, 1H), 2.97 (d, J = 14.1 Hz, 2H), 2.36 2.22 (m, 1H), 1.08 (d, J = 6.4 Hz, 3H), 0.55 (d, J = 6.4 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) 153.7, 1 41.7, 140.5, 129.0, 128.4, 126.9, 110.1, 109.7, 109.2, 63.0, 54.7, 28.6, 20.9, 20.8. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 22 H 26 NO+ 320.2009; Found 338.2015. Chromatograms of racemic 4 118 and 4 118 (from StackPhim 4 76 ):

PAGE 286

286 Chromatograms of racemic 4 118 a nd 4 118 (from F 5 Phim 4 84 ): Chromatograms of racemic 4 116 and 4 116 (from ( S ) StackPhos 3 48 ): Chromatograms of racemic 4 116 and 4 116 (from StackPhim 4 77 ): The synthesis of 4 118 was also achieved from diol 4 117 via a silver catalyzed cyclizat ion, according to the following reaction scheme: Under the silver catalyzed cyclization, the product 4 118 was isolated in low yield (33%), with essentially the same enantiomeric excess (93% ee) which was observed for

PAGE 287

287 the formation of 4 118 under the gold catalyzed cyclization. This result suggests that there is no racemization under the gold catalyzed cyclization. (5 S ) 5 (dibenzylamino) 5 phenylpent 3 yne 1,2 diol ( 4 119 ) The following compound 4 119 was prepared via aforementioned procedure with StackPhim 4 76 in 78% yield (16.2 mg, 0.0436 mmol) as a colorless oil. The reaction was carried out for 18h at room temperature. R f = 0.30 (40% EtOAc in hexanes, UV/ KMnO4 stain). 1 H NMR (500 MH z, CDCl 3 mixture of diastereomers) 7.61 (d, J = 7.6 Hz, 2H), 7.37 (d, J = 7.1 Hz, 4H), 7.33 7.27 (m, 6H), 7.23 (dt, J = 13.0, 7.5 Hz, 3H), 4.75 (s, 1H), 4.71 (bs, 1H), 3.91 (dd, J = 11.5, 3.4 Hz, 1H), 3.84 (dd, J = 11.3, 7.0 Hz, 1H), 3.71 (d, J = 13.5 Hz, 2H), 3.40 (d, J = 13.5 Hz, 2H), 2.65 (bs, 2H). 13 C NMR (125 MHz, CDCl 3 mixture of diastereomers) 139.4, 138.7, 129.0, 128.5, 128.4, 128.3, 127.8, 127.3, 86.3, 81.7, 67.26, 63.8, 55.7, 54.7. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 25 H 26 NO 2 + 372.1958; Found 372.1942. ( S ) N N dibenzyl 1 (furan 2 yl) 1 phenylmethanamine ( 4 120 ) The following compound 4 120 was prepared via aforementioned procedure 5.2 in 50% yield (3.9 mg, 0.0110 mmol) as a colorless oil. The reaction was carried out for 48h. R f = 0.90 (20% EtOAc in hexanes, UV/ KMnO4 stain). [ ] 24 D = +2.01 ( c 0.5, CHCl 3 ). Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 1.0 mL/min, 215 nm); minor t r = 19.2 min; major t r = 25.8 min; 91%

PAGE 288

288 ee 1 H NMR (500 MHz, CDCl 3 ) 7.46 7.43 (m, 1H), 7.37 (d J = 7.5 Hz, 4H), 7.34 (d, J = 7.7 Hz, 2H), 7.28 7.22 (m, 6H), 7.20 7.13 (m, 3H), 6.36 (dd, J = 3.2, 1.8 Hz, 1H), 6.21 (d, J = 3.2 Hz, 1H), 4.97 (s, 1H), 3.73 (d, J = 14.0 Hz, 2H), 3.36 (d, J = 14.0 Hz, 2H). 13 C NMR (125 MHz, CDCl 3 ) 153.5, 142.6, 14 0.2, 139.9, 128.8, 128.7, 128.5, 128.3, 127.4, 127.1, 110.5, 110.1, 60.4, 54.6, 29.9. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 25 H 24 NO+ 354.1852; Found 354.1829. Chromatograms of racemic 4 120 and enantioenriched 4 120 : (5 S ) 5 (dibenzylamino)oct 3 yne 1,2 diol ( 4 121 ) The following compound 4 121 was prepared via aforementioned procedure with StackPhim 4 76 in 95% yield (22.2 mg, 0.0657 mmol) as a colorless oil. The reaction was carried out for 4h. R f = 0.33 (40% EtOAc i n hexanes, UV/ KMnO4 stain). 1 H NMR (500 MHz, CDCl 3 mixture of diastereomers) 7.39 (d, J = 7.1 Hz, 4H), 7.32 (t, J = 7.6 Hz, 4H), 7.28 7.21 (m, 2H), 4.58 (s, 1H), 3.83 (d, J = 13.7 Hz, 2H), 3.73 (dd, J = 11.2, 7.0 Hz, 1H), 3.46 (td, J = 7.7, 1.6 Hz, 1 H), 3.38 (d, J = 13.8 Hz, 2H), 2.47 (bs, 2H), 1.81 1.65 (m, 1H), 1.63 1.54 (m, 1H), 1.51 1.30 (m, 2H), 0.81 (t, J = 7.4 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 mixture of diastereomers) 139.8, 129.0, 128.4, 127.1, 85.0, 82.7, 67.2, 63.6, 55.0,

PAGE 289

289 51.6, 36.0 19.7, 13.9. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 22 H 28 NO 2 + 338.2115; Found 338.2136. ( S ) N N dibenzyl 1 (furan 2 yl)butan 1 amine ( 4 122 ) The following compound 4 122 was prepared via the aforementioned procedure 5.2 in 75% yield (10.0 mg, 0.0313 mmol) as a colorless oil. The reaction was carried out for 12h. R f = 0.90 (20% EtOAc in hexanes, UV/ KMnO4 stain). [ ] 24 D = 88.24 ( c 1.0, CHCl 3 ). Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 1.0 mL/min, 215 nm); minor t r = 10.8 min; major t r = 17.6 min; 88% ee 1 H NMR (500 MHz, CDCl 3 ) 7.47 (s, 1H), 7.44 (d, J = 7.6 Hz, 4H), 7.34 (t, J = 7.5 Hz, 4H), 7.26 (q, J = 7.4 Hz, 2H), 6.40 (s, 1H), 6.15 (s, 1H), 3.90 (d, J = 13.9 Hz, 2H), 3.74 (t, J = 7.6 Hz, 1H), 3.23 (d, J = 13.9 Hz, 2H), 1.95 (t, J = 13.9, 8.3, 4.4 Hz, 1H), 1.76 (ddt, J = 16.2, 13.6, 6.8 Hz, 1H), 1.54 1.43 (m, 1H), 1.28 (td, J = 13.4, 6.9 Hz, 1H), 0.83 (t, J = 7.4 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) 155.5, 141.7, 140.6, 129.0, 128.4, 126.9, 109.8, 107.9, 55.4, 54.6, 33.4, 20.0, 14.1. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 22 H 26 NO+ 320.2009; Found 320.2000. Chromatograms of racemic 4 12 2 and enantioenriched 4 122 :

PAGE 290

290 (5 S ) 6 methyl 5 morpholinohept 3 yne 1,2 diol ( 4 123 ) The following compound 4 123 was prepared via aforementioned procedure with StackPhim 4 76 in 91% yield (25.9 mg, 0.1139 mmol) as a yellowish oil. The reaction was carried out for 6h. R f = 0.25 (70% EtOAc in hexanes, UV/ KMnO4 stain). 1 H NMR (500 MHz, CDCl 3 mixture of diastereomers) 4.50 (bs, 1H), 3.77 3.60 (m, 4H), 2.83 (d, J = 9.6 Hz, 1H), 2.83 (bs, 2H), 2.60 2.54 (m, 2H), 2.47 2.34 (m, 2H), 1.80 (dp, J = 9.8, 6.6 Hz, 1H), 1.02 (d, J = 6.5 Hz, 3H), 0.97 (d, J = 6.5 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 mixture of diastereomers) 84.5, 83.1, 67.3, 67.1, 64.8, 63.5, 50.1, 29.8, 20.3, 19.9. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 12 H 22 NO 3 + 228.1594; Found 228.1585. ( S ) 4 (1 (furan 2 yl) 2 methylpropyl)morpholine ( 4 124 ) The following compound 4 12 4 was prepared via aforementioned procedure in 67% yield (5.3 mg, 0.0253 mmol) as a colorless oil. The reaction was carried out for 12h. R f = 0.90 (70% EtOAc in hexanes, UV/ KMnO4 stain). [ ] 24 D = 17.64 ( c 0.5, CHCl 3 ). Enantiomeric excess was determined b y HPLC with a Chiralcel OD H column (99.5:0.5 n hexane:isopropanol, 0.5 mL/min, 215 nm); minor t r = 14.3 min; major t r = 13.3 min; 93% ee 1 H NMR (500 MHz, CDCl 3 ) 7.40 7.33 (m, 1H), 6.32 (dd, J = 3.2, 1.8 Hz, 1H), 6.08 (d, J = 3.1 Hz, 1H), 3.68 (qdd, J = 10.9, 6.3, 3.0 Hz, 4H), 3.06 (d, J = 9.9 Hz, 1H),

PAGE 291

291 2.47 (ddd, J = 10.4, 6.6, 3.3 Hz, 2H), 2.31 (ddd, J = 10.8, 6.3, 3.0 Hz, 2H), 2.21 (dp, J = 9.8, 6.6 Hz, 1H), 1.03 (d, J = 6.6 Hz, 3H), 0.78 (d, J = 6.6 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) 153.5, 141.6, 109.8, 108.6, 69.7, 67.6, 50.3, 27.9, 20.5, 20.0. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 12 H 20 NO 2 + 210.1489; Found 210.1475. Chromatograms of racemic 4 12 4 and enantioenriched 4 124 : 1 ((3 S ) 6,7 dihydroxy 2 methylhept 4 yn 3 yl)piperidin 4 one ( 4 125 ) The following compound 4 125 was prepared via aforementioned procedure with StackPhim 4 76 in 61% yield (14.2 mg, 0.0593 mmol) as a yellowish oil. Because 4 piperidone monohydrate hydrochloride salt was used as amine sourc e, Et 3 N (13.6 L, 0.0976 mmol, 1.0 equiv) was added to the reaction flask after addition of the aldehyde to neutralize the acid. The reaction was carried out for 24h. R f = 0.42 (eluting twice in 70% EtOAc in hexanes, UV/ KMnO4 stain). 1 H NMR (500 MHz, CDC l 3 mixture of diastereomers) 4.54 4.45 (m, 1H), 3.76 3.69 (m, 1H), 3.69 3.60 (m, 1H), 3.01 (d, J = 10.0 Hz, 1H), 2.90 2.83 (m, 2H), 2.66 (dt, J = 12.4, 6.3 Hz, 2H), 2.58 (bs, 2H), 2.55 2.37 (m, 4H), 1.82 (ddd, J = 12.7, 6.3, 3.1 Hz, 1H), 1.06 (d, J = 5.6 Hz, 3H), 1.02 (d, J = 6.8Hz, 3H). 13 C NMR (125 MHz, CDCl 3 mixture of diastereomers) 209.6, 84.3, 82.8,

PAGE 292

292 67.1, 64.0, 63.5, 49.7, 41.7, 31.1, 20.7, 20.0. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 13 H 22 NO 3 + 240.1594; Found 240.1579. ( S ) 1 (1 (furan 2 yl) 2 methylpropyl)piperidin 4 one ( 4 126 ). The following compound 4 126 was prepared via aforementioned procedure in 53% yield (6.2 mg, 0.0280 mmol) as a colorless oil. The reaction was carried out for 9h. R f = 0.48 ( 20% EtOAc in hexanes, UV/ KMnO4 stain). [ ] 24 D = 25.04 ( c 1.0, CHCl 3 ). Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (99:1 n hexane:isopropanol, 1.0 mL/min, 215 nm); minor t r = 43.4 min; major t r = 32.5 min; 92% ee 1 H NMR (500 MHz, CDCl 3 ) 7.35 (d, J = 1.2 Hz, 1H), 6. 31 (d, J = 1.3 Hz, 1H), 6.08 (d, J = 3.1 Hz, 2H), 3.24 (d, J = 10.6 Hz, 1H), 2.86 2.71 (m, 2H), 2.57 2.49 (m, 2H), 2.51 2.31 (m, 4H), 2.24 (dp, J = 10.6, 6.6 Hz, 1H), 1.11 (d, J = 6.6 Hz, 3H), 0.80 (d, J = 6.5 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) 209. 9, 153.4, 141.6, 109.8, 108.3, 68.9, 49.6, 42.2, 28.8, 20.6. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 13 H 20 NO 2 + 222.1489; Found 222.1470. Chromatograms of racemic 4 12 6 and enantioenriched 4 12 6 :

PAGE 293

293 (5 S ) 5 (benzyl(methyl)am ino) 5 cyclohexylpent 3 yne 1,2 diol ( 4 127 ) The following compound 4 127 was prepared via aforementioned procedure with StackPhim 4 76 in 82% yield (20.6 mg, 0.0683 mmol) as a colorless oil. The reaction was carried out for 4h. R f = 0.25 (40% EtOAc in he xanes, UV/ KMnO4 stain). 1 H NMR (500 MHz, CDCl 3 mixture of diastereomers) 7.40 7.17 (m, 5H), 4.62 4.53 (m, 1H), 3.82 (d, J = 11.3 Hz, 1H), 3.73 (dd, J = 11.3, 6.9 Hz, 1H), 3.65 (d, J = 13.4 Hz, 1H), 3.44 (d, J = 13.4 Hz, 1H), 3.07 (dd, J = 10.5, 1.7 Hz, 1H), 2.17 (s, 3H), 2.17 (bs, 2H), 2.04 1.93 (m, 1H), 1.80 1.70 (m, 2H), 1.71 1.62 (m, 1H), 1.54 (qt, J = 11.0, 3.5 Hz, 1H), 1.35 1.06 (m, 4H), 1.02 0.74 (m, 2H). 13 C NMR (125 MHz, CDCl 3 mixture of diastereomers) 139.6, 129.0, 128.4, 127.1 84.0, 83.6, 67.3, 63.7, 61.6, 59.6, 40.0, 37.8, 31.4, 30.4, 26.8, 26.3, 26.1. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 19 H 28 NO 2 + 302.2115; Found 302.2126. ( S ) N benzyl 1 cyclohexyl 1 (furan 2 yl) N methylmethanamine ( 4 12 8 ) The following compound 4 128 was prepared via aforementioned procedure in 81% yield (9.2 mg, 0.0325 mmol) as a colorless oil. The reaction was carried out for 12h. R f = 0.85 (20% EtOAc in hexanes, UV/ KMnO4 stain). [ ] 24 D = 41.94 ( c 1.0, CHCl 3 ). Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 1.0 mL/min, 215 nm); minor t r = 11.2 min; major t r = 11.8 min; 92%

PAGE 294

294 ee 1 H NMR (500 MHz, CDCl 3 ) 7.43 (d, J = 1.3 Hz, 1H), 7 .39 7.20 (m, 5H), 6.38 (dd, J = 3.1, 1.8 Hz, 1H), 6.10 (d, J = 3.1 Hz, 1H), 3.63 (d, J = 13.6 Hz, 1H), 3.33 (d, J = 10.8 Hz, 1H), 3.29 (d, J = 13.6 Hz, 1H), 2.33 (d, J = 13.4 Hz, 1H), 2.12 (s, 3H), 2.04 1.92 (m, 1H), 1.84 1.78 (m, 1H), 1.72 1.61 (m 2H), 1.44 (d, J = 15.6 Hz, 1H), 1.40 0.73 (m, 6H). 13 C NMR (125 MHz, CDCl 3 ) 153.8, 141.5, 140.5, 128.9, 128.3, 126.9, 109.7, 108.6, 66.1, 58.9, 38.1, 31.2, 30.9, 29.9, 27.0, 26.4. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 19 H 26 NO+ 284.2009; Found 284.2019. Chromatograms of racemic 4 12 8 and enantioenriched 4 128 : (5 S ) 1 cyclohexyl 5 (dibenzylamino) 6 methylhept 3 yne 1,2 diol ( 4 129 ) The following compound 4 129 was prepared via aforementioned procedure with StackPhim 4 76 in 84% yield (24.5 mg, 0.0584 mmol) as a colorless oil. The reaction was carried out for 7h. R f = 0.68 and 0.62 (two diastereomers, 40% EtOAc in hexanes, UV/ KMnO4 stain). 1 H NMR (500 MHz, CDCl 3 mixture of diastereomers) 7.42 (d, J = 7.5 Hz, 4H), 7.38 7.31 (m, 4H), 7.30 7.24 (m, 2H), 4.64 4.60 (m, 1H, major), 4.50 (dd, J = 6.3, 1.7 Hz, 1H, minor), 3.91 3.82 (m, 3H), 3.51 3.43 (m, 1H), 3.43 3.33 (m, 2H), 3.00 (dd, J = 10.4, 1.8 Hz, 1H), 2.18 (bs, 2H), 1.95 (dt d, J = 13.2, 6.6, 3.3 Hz, 1H), 1.90 1.62 (m, 6H), 1.40 1.08 (m, 4H), 1.05 (d, J = 6.5 Hz, 3H), 1.01 (d, J = 6.4

PAGE 295

295 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 mixture of diastereomers) 139.7, 129.0, 128.7, 128.5, 127.3, 127.1, 84.5, 84.3, 83.0, 79.7, 78.57, 65.0, 64.6, 59.3, 55.3, 55.3, 53.2, 41.7, 41.6, 39.7, 31.0, 30.9, 30.9, 30.2, 29.5, 29.0, 27.2, 26.7, 26.6, 26.5, 26.4, 26.3, 26.1, 21.2, 21.1, 20.1. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 28 H 38 NO 2 + 420.2897; Found 420.2896. ( S ) N N dibenzyl 1 (5 cyclohexylfuran 2 yl) 2 methylpropan 1 amine ( 4 130 ) The following compound 4 130 was prepared via aforementioned procedure in 76% yield (10.0 mg, 0.0313 mmol) as a colorless oil. The reaction was carried out for 12h. R f = 0.90 (20% E tOAc in hexanes, UV/ KMnO4 stain). [ ] 24 D = 117.22 ( c 1.0, CHCl 3 ). Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 0.5 mL/min, 254 nm); minor t r = 11.2 min; major t r = 9.7min; 90% ee 1 H NMR (500 MHz, C DCl 3 ) 7.45 (d, J = 7.2 Hz, 4H), 7.34 (t, J = 7.6 Hz, 4H), 7.30 7.21 (m, 2H), 5.99 (d, J = 3.0 Hz, 1H), 5.95 (dd, J = 3.0, 1.0 Hz, 1H), 3.95 (d, J = 13.9 Hz, 2H), 3.11 (d, J = 10.8 Hz, 1H), 3.06 (d, J = 13.9 Hz, 2H), 2.71 2.64 (m, 1H), 2.37 (dq, J = 1 1.1, 6.4 Hz, 1H), 2.09 (dd, J = 9.7, 4.5 Hz, 2H), 1.88 1.79 (m, 2H), 1.75 (d, J = 12.8 Hz, 1H), 1.50 1.37 (m, 4H), 1.17 (d, J = 6.5 Hz, 3H), 0.66 (d, J = 6.5 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) 160.0, 151.2, 140.7, 129.1, 128.4, 126.9, 109.4, 102.5, 63 .1, 54.8, 37.4, 31.7, 29.9, 28.5, 26.4, 26.1, 20.8. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 28 H 36 NO+ 402.2791; Found 402.2766. Chromatograms of racemic 4 1 30 and enantioenriched 4 130 :

PAGE 296

296 (5 S ) 5 (dibenzylamino) 2,6 dimethyl hept 3 yne 1,2 diol ( 4 131 ) The following compound 4 131 was prepared via aforementioned procedure with StackPhim 4 76 in 72% yield (21.2 mg, 0.0603 mmol) as a colorless oil. The reaction was carried out for 6h. R f = 0.40 (40% EtOAc in hexanes, UV/ KMnO4 stain). 1 H NMR (500 MHz, CDCl 3 mixture of diastereomers) 7.38 (d, J = 7.2 Hz, 2H), 7.35 7.20 (m, 8H), 3.84 (s, 1H), 3.81 (d, J = 13.8 Hz, 2H), 3.70 (dd, J = 11.0, 1.7 Hz, 1H), 3.55 (d, J = 11.0 Hz, 1H), 3.32 (dd, J = 13.8, 1.7 Hz, 1H), 3.16 (bs, 2H), 2.94 (dd, J = 10.5, 1.2 Hz, 1H), 1.89 (ddt, J = 13.5, 6.7, 3.5 Hz, 1H), 1.17 (d, J = 7.0 Hz, 3H), 1.00 (d, J = 6.5 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 mixture of diastereomers) 139.6, 129.03 128.7, 128.4, 127.5, 127.1, 87.7, 82.1, 71.3, 69.0, 59.3, 55.3, 52.6, 30.9, 26.2, 21.2, 20.1, 19.4. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 23 H 30 NO 2 + 352.2271; Found 352.2269. ( S ) N N dibenzyl 2 methyl 1 (4 methylfuran 2 yl)propan 1 amine ( 4 132 ) The following compound 4 132 was prepared via aforementioned procedure in 61% yield (7.5 mg, 0.0225 mmol) as a colorless oil. The reaction was carried out for 12h. R f = 0.85 (20% EtOAc in hexanes, UV/ KMnO4 stain). [ ] 24 D = 130.10 ( c 1.0, CHCl 3 ).

PAGE 297

297 Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 0.1 mL/min, 215 nm); minor t r = 71.5 min; major t r = 75.8 min; 91% ee 1 H NMR (500 MHz, CDCl 3 ) 7.44 7.40 (m, 4H), 7.31 (dd, J = 8.4, 6.9 Hz, 4H), 7.24 7.18 (m, 3H), 5.94 (s, 1H), 3.91 (d, J = 13.9 Hz, 2H), 3.14 2.97 (m, 3H), 2.39 2.24 (m, 1H), 2.07 (d, J = 1.2 Hz, 3H), 1.14 (d, J = 6.5 Hz, 3H), 0.62 (d, J = 6.5 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ,) 153.6, 140.6, 138.3 129.0, 128.4, 126.9, 120.0, 112.0, 63.0, 54.7, 28.5, 20.8, 10.1. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 23 H 28 NO+ 334.2165; Found 334.2183. Chromatograms of racemic 4 1 32 and enantioenriched 4 132 : ( S ) 2 (3 (dibenzylam ino) 4 methylpent 1 yn 1 yl)phenol ( 4 134 ) The following compound 4 134 was prepared via aforementioned procedure with StackPhim 4 76 in 79% yield (28.5 mg, 0.0771 mmol) as a colorless oil. The reaction was carried out for 3h. R f = 0.60 (20% EtOAc in hexa nes, UV/ KMnO4 stain). Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (98:2 n hexane:isopropanol, 1.0 mL/min, 254 nm); minor t r = 8.2 min; major t r = 5.7 min; 84% ee 1 H NMR (500 MHz, CDCl 3 ) 7.39 (dd, J = 7.4, 1.8 Hz, 4H), 7.29 ( t, J = 7.6 Hz, 5H), 7.26 7.17 (m, 3H), 6.96 (dd, J = 8.3, 1.1 Hz, 1H), 6.88 (td, J = 7.6, 1.2 Hz, 1H), 3.88 (d, J = 13.7 Hz, 3H),

PAGE 298

298 3.38 (d, J = 13.7 Hz, 2H), 3.17 (d, J = 10.4 Hz, 1H), 2.00 (qd, J = 6.6, 3.8 Hz, 1H), 1.04 (d, J = 6.6 Hz, 3H), 1.01 (d, J = 6.6 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) 156.7, 139.5, 132.0, 130.3, 129.0, 128.5, 127.3, 120.5, 114.7, 110.0, 95.0, 80.2, 60.1, 55.4, 31.1, 21.3, 20.1. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 26 H 28 NO+ 370.2165; Found 370.2140. ( S ) 1 (benzofuran 2 yl) N,N diben zyl 2 methylpropan 1 amine ( 4 135 ) The following compound 4 135 was prepared via aforementioned procedure in 81% yield (18.6 mg, 0.0503 mmol) as a colorless oil. The reaction was carried out for 3h. R f = 0.70 (20% EtOAc in hexanes, UV/ KMnO4 stain). [ ] 24 D = 183.02 ( c 1.0, CHCl 3 ). The enantiomeric excess was extrapolated based on the ee of compound 4 134 1 H NMR (500 MHz, CDCl 3 ) 7.62 (d, J = 7.4 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 7.6 Hz, 4H), 7.36 (t, J = 7.5 Hz, 4H), 7.32 7.23 (m, 4H), 6 .49 (s, 1H), 4.05 (d, J = 14.0 Hz, 2H), 3.33 (d, J = 10.9 Hz, 1H), 3.16 (d, J = 13.9 Hz, 2H), 2.61 2.44 (m, 1H), 1.24 (d, J = 6.5 Hz, 3H), 0.72 (d, J = 6.5 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) 156.4, 154.9, 140.3, 129.0, 128.5, 127.0, 123.7, 122.8, 120.8, 111.5, 106.2, 63.5, 54.7, 28.2, 21.0, 20.7. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 26 H 28 NO+ 370.2165; Found 370.2142. Chromatograms of racemic 4 1 34 and enantioenriched 4 134 :

PAGE 299

299 ( S ) N (2 (3 (dibenzylamino) 4 methylpent 1 yn 1 yl)phenyl) 4 methylbenzenesulfonamide ( 4 137 ) The following compound 4 137 was prepared via aforementioned procedure with StackPhim 4 76 in 92% yield (40.1 mg, 0.0767 mmol) as a yellowish oil. The reaction was carried out for 5h. R f = 0.66 (eluting twice in 20% EtOAc in hexanes, UV/ KMnO4 stain). 1 H NMR (500 MHz, CDCl 3 ) 7.71 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 7.6 Hz, 4H), 7.41 7.23 (m, 8H), 7.20 (d, J = 8.0 Hz, 2H), 7.06 (t, J = 7.6 Hz, 1H), 3.91 (d, J = 13.7 Hz, 2H), 3.3 5 (d, J = 13.7 Hz, 2H), 3.17 (d, J = 10.4 Hz, 1H), 2.36 (s, 3H), 2.01 (dt, J = 10.6, 6.4 Hz, 1H), 1.09 (d, J = 6.4 Hz, 3H), 1.02 (d, J = 6.6 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) 144.3, 139.3, 138.0, 136.5, 132.5, 129.9, 129.0, 128.6, 127.4, 124.2, 118.8, 11 4.1, 95.2, 81.0, 60.0, 55.5, 31.1, 21.8, 21.3, 20.2. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 33 H 35 N 2 O 2 S+ 523.2414; Found 523.2409. ( S ) N,N dibenzyl 2 methyl 1 (1 tosyl 1H indol 2 yl)propan 1 amine ( 4 138 ) The following co mpound 4 138 was prepared via aforementioned procedure in 78% yield (10.6 mg, 0.0203 mmol) as a yellowish oil. The reaction was carried out for 15h. R f = 0.70 (eluting twice in 20% EtOAc in hexanes, UV/ KMnO4 stain). [ ] 24 D = 109.58 ( c 1.0, CHCl 3 ). Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (97.5:2.5 n hexane:isopropanol, 0.5 mL/min, 254 nm); minor t r = 17.9 min; major

PAGE 300

30 0 t r = 13.1 min; 91% ee 1 H NMR (500 MHz, CDCl 3 ) 8.24 8.16 (m, 1H), 7. 57 7.52 (m, 1H), 7.52 7.46 (m, 2H), 7.40 (d, J = 7.6 Hz, 4H), 7.36 7.24 (m, 6H), 7.24 7.18 (m, 2H), 7.10 7.05 (m, 2H), 6.64 (s, 1H), 4.71 (d, J = 10.6 Hz, 1H), 3.75 (d, J = 14.3 Hz, 2H), 3.39 (d, J = 14.3 Hz, 2H), 2.35 (dq, J = 12.9, 6.5 Hz, 1H), 2.30 (s, 3H), 1.36 (dd, J = 6.4, 1.0 Hz, 3H), 0.92 (d, J = 6.6 Hz, 2H). 13 C NMR (125 MHz, CDCl 3 ) 144.7, 140.5, 130.1, 129.4, 129.2, 128.1, 127.1, 126.7, 124.4, 124.1, 120.9, 116.4, 111.9, 63.7, 54.7, 30.7, 21.6. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 33 H 35 N 2 O 2 S+ 523.2414; Found 523.2406. Chromatograms of racemic 4 1 38 and enantioenriched 4 138 : (4 R ) 4 (dibenzylamino) 5 methyl 1 phenylhex 2 yn 1 ol ( 4 142 ) The following compound 4 142 was prepared via aforementioned procedure with ( S ) StackPhos 3 48 in 92% yield (41.2 mg, 0.107 mmol) as a colorless oil. The reacti on was carried out for 2h. R f = 0.35 (20% EtOAc in hexanes, UV/ KMnO4 stain). The enantiomeric excess as well as the diastereoselective ratio were determined by HPLC with a Chiralcel OD H column (95:5 n hexane:isopropanol, 0.5 mL/min, 215 nm); minor (1) t r = 20.2 min; major (1) t r = 15.5 min; minor (2) t r = 13.9 min; major (2) t r = 21.5 min; dr 51 : 49, 71% and 67% ee for each pair of diastereomers, respectively

PAGE 301

301 (4 S ) 4 (dibenzylamino) 5 methyl 1 phenylhex 2 yn 1 ol ( 4 1 43 ) The following compound 4 143 was prepared via aforementioned procedure with StackPhim 4 76 in 94% yield (42.2 mg, 0.110 mmol) as a colorless oil. The reaction was carried out for 5h. R f = 0.35 (20% EtOAc in hexanes, UV/ KMnO4 stain). The enantiomeric excess as well as the diastereoselective ratio were determined by HPLC with a Chiralcel OD H column (95:5 n hexane:isopropanol, 0.5 mL/min, 215 nm); minor (1) t r = 15.4 min; major (1) t r = 20.4 min; minor (2) t r = 21.8 min; major (2) t r = 14.0 min; dr 50 : 50, 93% and 93% ee for each pair of diastereomers, respectively 1 H NMR (500 MHz, CDCl 3 mixture of diastereomers) 7.71 7.66 (m, 2H), 7.50 7.39 (m, 9H), 7.35 (t, J = 7.5 Hz, 4H), 7.27 (t, J = 7.3 Hz, 2H), 5.65 (s, 1H), 3.88 (d, J = 13.8 Hz, 2H), 3.43 (d, J = 13.8 Hz, 2H), 3.10 3.01 (m, 1H), 2.27 (bs, 1H), 2.00 (dq, J = 10.3, 6.6 Hz, 1H), 1.07 (d, J = 6.5 Hz, 3H ), 1.03 (d, J = 6.6 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 mixture of diastereomers) 141.5, 139.8, 129.0, 128.8, 128.6, 128.4, 127.1, 126.9, 85.9, 84.9, 65.1, 59.4, 55.3, 30.9, 21.2, 20.1. HRMS (ESI TOF) m/z: [M+H]+ Calcd for C 27 H 30 ON+ 384.2322; Found 384.232 1. Chromatograms of racemic 4 142 (dr 60 : 40) and enantioenriched 4 142 (dr 51 : 49):

PAGE 302

302 Chromatograms of racemic 4 143 (dr 60 : 40) and enantioenriched 4 143 (dr 50 : 50): Preparation of Alkynediols for the Alkynylation/ Cyclization Sequence n BuLi solution (1.7 M) in hexanes (11.1 mL, 18.9 mmol, 1.1 equiv) was added dropwise to a stirred solution of TMS acetylene (3.2 mL, 22.3 mmol, 1.3 equiv) in THF (35 mL) at 78 C. The mixture was stirred for 30 minutes, and the flask containing the reaction mixture was taken out of the dry ice/acetone bath and stirred for 10 minutes. After 10 minutes, the reaction mixture was again placed at 78 C, and the aldehyde 5 61 (1.40 mL, 18.2 mmol, 2.0 equiv) was added to the reaction flask. The reaction mixture was stirred at 78 C for 10 minutes, warmed to room temperature and stirred for 45 minutes. The reaction was quenched with ammonium chloride saturated solution (35 mL) and extracted with Et 2 O (2 x 50 mL).The organic layers were separated, combined, dried over MgSO 4 filtered and concentrated under reduced pressure to give a residue which was purified through flash column chromatography on silica gel (0 5% EtOAc in hexanes) to afford the desired propargyl al cohol 5 62 (3.7 g, 13. 6 mmol) in 79% yield as a yellowish oil. R f = 0.60 (20% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 ) 4.39 (s, 1H), 3.77 (dd, J = 10.0, 3.8 Hz, 1H), 3.65 (dd, J = 10.0, 6.7 Hz, 1H), 2.61 (bs, 1H), 2.18 (s, 1H), 0.19 (s, 9H), 0.17 (m, 9H), 0.11 (d, J = 3.2 Hz, 6H). 13 C NMR

PAGE 303

303 (125 MHz, CDCl 3 ) 103.7, 90.4, 67.1, 63.8, 32.1, 26.1, 18.6, 0.0, 0.1, 5.1. K 2 CO 3 (5.6 g, 40.7 mmol, 3.0 equiv) was added at room temperature to a stirred solution of 5 62 (3.7g, 13.6 mmol, 1.0 equiv) in MeOH (27 mL). The reaction mixture was stirred for 4h, filtered with filter paper and concentrated to give the compound 1 (( tert but yldimethylsilyl)oxy)but 3 yn 2 ol as a yellowish oil which was taken to the next step without further purification. R f = 0.75 (40% EtOAc in hexanes). TsOH (2.6 g, 13.6 mmol, 1.0 equiv) was added to a solution containing the crude mixture from the previous step. The reaction mixture was stirred for 16 h at room temperature and quenched with Et 3 N (1.9 mL, 13.6 mmol, 1.0 equiv). The solvent was then evaporated under reduced pressure and the crude mixture was purified through flash column chromatography on sil ica gel (10 50% EtOAc in hexanes) to afford the alkynediol 4 114 (0.53 g, 6.16 mmol) as a yellowish oil in 46% yield over two steps. but 3 yne 1,2 diol ( 4 114 ) R f = 0.15 (40% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 ) 4.47 (ddd, J = 6.2, 3.6, 2.1 Hz, 1H), 3.78 (dd, J = 11.4, 3.7 Hz, 1H), 3.71 (dd, J = 11.5, 6.5 Hz, 1H), 2.95 (bs, 1H), 2.51 (d, J = 2.2 Hz, 1H). 13 C NMR (125MHz, CDCl 3 ) 81.8, 74.6, 66.5, 63.2. MeMgBr solution (2.46 m L, 3.0 M, 7.39 mmol, 2.0 equiv) in diethylether was added dropwise to a stirred solution of the ketone 5 6 3 (1.00 g, 3.70 mmol, 1.3 equiv) in

PAGE 304

304 diethylether (15 mL) at 78 C. The mixture was stirred for 30 minutes, quenched with ammonium chloride saturated solution (15 mL) and extracted with Et 2 O (15 mL). The organic layers were separated, combined, dried over MgSO 4 filtered and concentrated under reduced pressure to give 1 (( tert butyldimethylsilyl)oxy) 2 methyl 4 (trimethylsilyl)but 3 yn 2 ol which was ta ken to the next step without further purification. R f = 0.55 (20% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 ) 3.66 (d, J = 9.5 Hz, 1H), 3.49 (d, J = 9.5 Hz, 1H), 2.93 (s, 1H), 1.41 (s, 3H), 0.93 (s, 9H), 0.16 (s, 9H), 0.11 (d, J = 4.9 Hz, 6H). Concentrate d HCl (1.0 mL) was added to a solution containing the crude mixture from the previous step in MeOH (10 mL) at room temperature. The reaction mixture was stirred for 1h at room temperature and quenched with sodium carbonate saturated solution (10 mL). The s olvent was removed under reduced pressure and the crude mixture was extracted with EtOAc (3 x 15 mL). The organic layers were combined, dried over MgSO 4 filtered and concentrated under reduced pressure to give 2 methyl 4 (trimethylsilyl)but 3 yne 1,2 diol which was taken to the next step without further purification. R f = 0.45 (40% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 ) 3.65 (dd, J = 11.0, 4.7 Hz, 1H), 3.47 (dd, J = 11.1, 9.0 Hz, 1H), 2.55 (s, 1H), 2.01 (dd, J = 9.1, 4.9 Hz, 1H), 1.46 (s, 3H), 0.18 ( s, 9H). K 2 CO 3 (1.92 g, 14.0 mmol, 5.0 equiv) was added to a solution containing the crude mixture from the previous step in MeOH (10 mL) at room temperature. The reaction mixture was stirred for 1h, filtered with filter paper concentrated under reduced pre ssure, and purified through flash column chromatography on silica gel (10 50% EtOAc in hexanes) to afford the alkynediol 5 6 4 (0.134 g, 1.34 mmol) as a yellowish oil in 38% yield over three steps.

PAGE 305

305 2 methylbut 3 yne 1, 2 diol ( 5 6 4 ) R f = 0.25 (40% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 ) 3.68 (d, J = 11.1 Hz, 1H), 3.51 (d, J = 11.1 Hz, 1H), 2.75 (bs, 1H), 2.49 (s, 1H), 2.18 (bs, 1H), 1.48 (s, 3H). 13 C NMR (125MHz, CDCl 3 ) 85.7, 72.7, 70.8, 68.4, 25.3. n BuLi solution (1.7 M) in hexanes (2.78 mL, 4.73 mmol, 1.1 equiv) was added dropwise to a stirred solution of TMS acetylene (0.67 mL mL, 4.73 mmol, 1.1 equiv) in THF (15 mL) at 78 C. The mixture was stirred for 30 minutes, and the flask containing the reaction mixture was taken out of the dry ice/acetone bath and stirred for 10 minutes. After 10 minutes, the reaction mixture was again placed at 78 C, and the aldehyde 5 6 5 (1.10 g, 4.30 mmol, 1.0 equiv) was added to the reaction fl ask. The reaction mixture was stirred at 78 C for 10 minutes, warmed to room temperature and stirred for 2h. The reaction was quenched with ammonium chloride saturated solution (15 mL) and extracted with Et 2 O (2 x 15 mL).The organic layers were separated combined, dried over MgSO 4 filtered and concentrated under reduced pressure to give 1 (( tert butyldimethylsilyl)oxy) 1 cyclohexyl 4 (trimethylsilyl)but 3 yn 2 ol as a mixture of diastereomers. The crude mixture was taken to the next step without further purification. R f = 0.70 (20% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 mixture of

PAGE 306

306 diastereomers) 4.36 (d, J = 4.9 Hz, 1H), 3.80 3.69 (m, 1H), 3.51 (dd, J = 5.4, 3.9 Hz, 1H), 1.97 1.48 (m, 4H), 1.30 1.05 (m, 6H), 0.94 (s, 9H), 0.18 (s, 9H), 0.11 ( d, J = 6.4 Hz, 6H). Concentrated HCl (1.0 mL) was added to a solution containing the crude mixture from the previous step in MeOH (10 mL) at room temperature. The reaction mixture was stirred for 1h at room temperature and quenched with sodium carbonate sa turated solution (10 mL). The solvent was removed under reduced pressure and the crude mixture was extracted with EtOAc (3 x 15 mL). The organic layers were combined, dried over MgSO 4 filtered and concentrated under reduced pressure to give 1 cyclohexyl 4 (trimethylsilyl)but 3 yne 1,2 diol as a mixture of diastereomers. The crude mixture was taken to the next step without further purification. R f = 0.25 (20% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 mixture of diastereomers) 4.44 (d, J = 3.9 Hz, 1H, maj or), 4.36 (d, J = 4.8 Hz, 1H, minor), 3.43 3.30 (m, 1H), 1.86 1.54 (m, 4H), 1.25 0.95 (m, 6H), 0.19 (s, 9H). K 2 CO 3 (2.97 g, 21.5 mmol, 5.0 equiv) was added to a solution containing the crude mixture from the previous step in MeOH (10 mL) at room temp erature. The reaction mixture was stirred for 1h, filtered with filter paper concentrated under reduced pressure, and purified through flash column chromatography on silica gel (10 50% EtOAc in hexanes) to afford the alkynediol 5 6 6 (0.182 g, 1.08 mmol) as a 4 : 1 ( anti : syn ) mixture of diastereomer in 25% yield over three steps. 1 cyclohexylbut 3 yne 1,2 diol ( 5 6 6 ) R f = 0.40 (40% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 mixture of diastereomers) 4.46 (dd, J = 3 .4, 2.0 Hz, 1H,

PAGE 307

307 major), 4.38 (dd, J = 5.3, 2.2 Hz, 1H, minor), 3.41 (dq, J = 8.7, 4.5, 3.5 Hz, 1H), 2.82 (bs, 1H), 2.50 (d, J = 2.1 Hz, 1H), 2.12 2.01 (m, 1H), 1.85 1.48 (m, 4H), 1.37 0.92 (m, 6H). 13 C NMR (125 MHz, CDCl 3 mixture of diastereomers) 8 1.5, 78.9, 78.4, 75.1, 74.5, 64.5, 63.7, 40.8, 39.3, 29.9, 29.3, 28.9, 27.7, 26.5, 26.2, 26.0, 25.8. X Ray Crystallographic Data of StackPhim 4 77 Figure 5 28. X Ray structure of StackPhim 4 77 X Ray experimental: The X Ray quality single crystals were grown from a mixture of hexanes and dichloromethane. StackPhim 4 77 (15 mg, major diastereomer confirmed by NMR) was placed in a vial and dissolved in dichloromethane (2 drops). Then hexanes (0.5 mL) were added to the vial. The vial was capped, and placed in the freezer at 20 C. Single crystals were observed after three days. X Ray Intensity data were collected at 100 K on a Bruker DUO diffractometer using MoK radiation ( = 0.71073 ) and an APEXII CCD area detector. Raw data frames were read by program SAINT and integrated using 3D profiling algorithms. The resulting data were reduced to produce hkl reflections and their intensities and estimated standard deviations. The data were corrected for Lorentz and

PAGE 308

308 polarization effects and numerical absorption corrections were applied based on indexed and measured faces. The structure was solved and refined in SHELXTL2013, using full matrix least squares refine ment. The non H atoms were refined with anisotropic thermal parameters and all of the H atoms were calculated in idealized positions and refined riding on their parent atoms. The asymmetric unit consists of four chemically equivalent but crystallographic ally independent molecules. In the final cycle of refinement, 32537 reflections (of which 26176 are observed with I > 2 (I)) were used to refine 1873 parameters and the resulting R 1 wR 2 and S (goodness of fit) were 4.03 %, 8.35 % and 0.959 respectively. The refinement was carried out by minimizing the wR 2 function using F 2 rather than F values. R 1 is calculated to provide a reference to the conventional R value but its function is not minimized. SHELXTL2013 (2013). Bruker AXS, Madison, Wisconsin, USA. Datablock: paulo3 Bond precision: C C = 0.0047 A Wavelength=0.71073 Cell: a=12.3700(4) b=45.6483(14) c=12.6634(4) alpha=90 beta=97.6938(9) gamma=90 Temperature: 100 K Calculated Report ed Volume 7086.3(4) 7086.3(4) Space group P 21 P 21 Hall group P 2yb P 2yb Moiety formula C44 H30 F5 N2 P ?

PAGE 309

309 Sum formula C44 H30 F5 N2 P C44 H30 F5 N2 P Mr 712.67 712.67 Dx,g cm 3 1.336 1.336 Z 8 8 Mu (mm 1) 0.139 0.139 F000 2944.0 2944.0 h,k,lmax 16,59,16 16,59,16 Nref 32592[ 16502] 32537 Tmin,Tmax 0.965,0.990 0.969,0.993 Correction method= EMPIRICAL Data completeness= 1.97/1.00 Theta(max)= 27.499 R(reflections)= 0.0403( 26176) wR2(reflections)= 0.0873( 32537) S = 0.959 Npar= Npar =1873 Table 1. Crystal data and st ructure refinement for paulo3. Identification code paulo3 Empirical formula C44 H30 F5 N2 P Formula weight 712.67 Temperature 100(2) K Wavelength 0.71073 Crystal system Monoclinic Space group P 2 1

PAGE 310

310 Unit cell dimensions a = 12.3700(4) = 90. b = 45.6483(14) = 97.6938(9). c = 12.6634(4) = 90. Volume 7086.3(4) 3 Z 8 Density (calculated) 1.336 Mg/m3 Absorption coefficient 0.139 mm 1 F(000) 2944 Crystal size 0.304 x 0.213 x 0.074 mm3 Theta range for data collection 0.892 to 27.499. Index ranges Reflections collected 125872 Independent reflections 32537 [R(int) = 0.0473] Completeness to theta = 25.242 100.0 % Absorption correction Empirical Max. and min. transmission 0.9926 and 0.9687 Refinement method Full ma trix least squares on F2 Data / restraints / parameters 32537 / 1 / 1873 Goodness of fit on F2 0.959 Final R indices [I>2sigma(I)] R1 = 0.0403, wR2 = 0.0835 [26176] R indices (all data) R1 = 0.0551, wR2 = 0.0873 Absolute structure parameter 0.01(2) Larges t diff. peak and hole 0.725 and 0.380 e. 3

PAGE 311

311 X Ray Crystallographic Data of StackPhim 4 60 Figure 5 29. X Ray structure of StackPhim 4 60 X Ray experimental: The X Ray quality single crystals were grown from a mixture of hexanes and dichloromethane. St ackPhim 4 60 (15 mg, major diastereomer confirmed by NMR) was placed in a vial and dissolved in dichloromethane (2 drops). Then hexanes (0.5 mL) were added to the vial. The vial was capped and s ingle crystals were observed after 12 h at room temperature. X Ray Intensity data were collected at 100 K on a Bruker DUO diffractometer using CuK radiation ( = 1.54178 ), from an ImuS power source, and an APEXII CCD area detector. Raw data frames were read by program SAINT and integrated using 3D profiling algorithms. The resulting data were reduced to produce hkl reflections and their intensit ies and estimated standard deviations. The data were corrected for Lorentz and polarization effects and numerical absorption corrections were applied based on indexed and measured faces. The structure was solved and refined in SHELXT2013, using full matr ix least squares refinement. The non H atoms were refined with anisotropic thermal parameters and all of the H atoms were calculated in idealized positions and refined riding on their parent atoms. In the final cycle of refinement, 4928

PAGE 312

312 reflections (of w hich 4839 are observed with I > 2 (I)) were used to refine 390 parameters and the resulting R 1 wR 2 and S (goodness of fit) were 2.90 %, 7.73 % and 1.027 respectively. The refinement was carried out by minimizing the wR 2 function using F 2 rather than F val ues. R 1 is calculated to provide a reference to the conventional R value but its function is not minimized. Datablock: paulo1 Bond precision: C C = 0.0036 A Wavelength=1.54178 Cell: a=6.7813(1) b=15.3774(3) c=14.0325(3) alpha=90 beta=102.8236(8) gamma=90 Temperature: 100 K Calculated Reported Volume 1426.79(5) 1426.79(5) Space group P 21 P 21 Hall group P 2yb P 2yb Moiety formula C35 H28 F5 N2 P ? Sum formula C35 H28 F5 N2 P C35 H28 F5 N2 P Mr 602.56 602.56 Dx,g cm 3 1.403 1.403 Z 2 2 Mu (mm 1) 1.385 1.385 F000 624.0 624.0 h,k,lmax 8,18,16 7,18,16

PAGE 313

313 Nref 5188[ 2699] 4928 Tmin,Tmax 0.892,0.951 0.833,0.957 Correction method= ANALYTICAL Data completeness= 1.83/0.95 Theta(max)= 67.997 R(reflections)= 0.0290( 4839) wR2(reflections)= 0.0777 ( 4928) S = 1.027 Npar= Npar = 390 Identification code paulo1 Empirical formula C35 H28 F5 N2 P Formula weight 602.56 Temperature 100(2) K Wavelength 1.54178 Crystal system Monoclinic Space group P 21 Unit cell dimensions a = 6.7813(1) = 90. b = 15.3774(3) = 102.8236(8). c = 14.0325(3) = 90. Volume 1426.79(5) 3 Z 2 Density (calculated) 1.403 Mg/m3 Absorption coefficient 1.385 mm 1 F(000) 624 Crystal size 0.285 x 0.069 x 0.036 mm3

PAGE 314

314 Theta range for data collection 3.230 to 67. 997. Index ranges Reflections collected 18785 Independent reflections 4928 [R(int) = 0.0754] Completeness to theta = 67.679 96.4 % Absorption correction Analytical Max. and min. transmission 0.9570 and 0.8334 Refinement method Full matrix least squares on F2 Data / restraints / parameters 4928 / 1 / 390 Goodness of fit on F2 1.027 Final R indices [I>2sigma(I)] R1 = 0.0290, wR2 = 0.0773 [4839] R indices (all data) R1 = 0.0294, wR2 = 0.0777 Absolute structure parameter 0.019(12) Extinction coefficient n/a Largest diff. peak and hole 0.289 and 0.205 e. 3

PAGE 315

315 LIST OF REFERENCES ( 1 ) (a) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem. Int. Ed. 2006 45 7896. (b) Gorin, D. J.; Toste, F. D. Nature 2007 446 395. (c) Corma, A.; Leyva Prez, A.; Sabater, M. J. Chem. Rev. 2011 111 1657. (d) Shapiro, N. D.; Toste, F. D. Synlett 2010 5 675. (e) Hashmi, A. S. K. Acc. Chem. Res. 2014 47 864. (f) Zhang L. Acc. Chem. Res. 2014 47 877. (g) Obradors, C.; Echavarren, A. M. Acc. Chem. Res. 2014 47 902. (h) F rstner A. Acc. Chem. Res. 2014 47 925. (i) Wang Y M.; Lackner A. D.; Toste F. D. Acc. Chem. Res. 2014 47 889. (j) Fensterbank, L.; Malacria, M. Acc. Chem. Res. 2014 47 953. ( 2 ) (a) Teles, J. H.; Brode, S.; Chabanas, M. Angew. Chem. Int. Ed. 1998 37 1415. (b) Prati, L.; Rossi, M. J. Catal. 1998 17 6 552. ( 3 ) F rstner A. Che m. Soc. Rev. 2009 38 3208. ( 4 ) Biannic B.; Aponick A. Eur. J. Org. Chem. 2011 6605. ( 5 ) (a) Muzart, J. Tetrahedron 2008 64 5815. (b) Bandini, M. Chem. Soc. Rev. 2011 40 1358. ( 6 ) (a) Rudolph, M.; Hashmi, A. S. K. Chem. Soc. Rev. 2012 41 2448. (b) Winter C.; Krause N. Chem. Rev. 2011 111 1994. ( 7 ) Yang, C G.; He, C. J. Am. Chem. Soc. 2005 127 6966. ( 8 ) Liu, L P.; Hammond, G. B. Chem. Soc. Rev. 2012 41 3129. ( 9 ) Lalonde R. L.; Brenzovich Jr .; W. E. Benitez D.; Tkatchouk E.; Keley K. ; Goddard III W. A. Toste F. D. Chem. Sci. 2010 1 226. ( 10 ) (a) Ketcham, J. M.; Biannic, B.; Aponick, A. Chem. Commun. 2013 49 4157. (b) Gmez Surez, A.; Gasperini, D.; Vummaleti, S. V. C.; Poater, A.; Cavallo, L.; Nolan, S. P. ACS Catal. 2014 4 27 01. ( 11 ) Aponick, A.; Li, C Y.; Biannic, B. Org. Lett. 2008 10 669. ( 12 ) (a) Ketcham, J. M.; Aponick, A. Top. Heterocycl. Chem. 201 3 32 157. (b) Hirai Y.; Terada T.; Amemiya Y.; Momose T. Tetrahedron Lett. 1992 33 7893. ( 13 ) Guo, S.; Song, F.; Liu, Y. Synlett 2007 964. ( 14 ) Mukherjee P.; Widenhoefer R. A. Org. Lett. 2010 12 1184. ( 15 ) Bandini M.; Eichholzer A. Angew. Chem. Int. Ed. 2009 121 9697. ( 16 ) (a) Unsworth, W. P.; Stevens, K.; Lamont S. G.; Robertson, J. Chem. Commun. 2011 4 7 7659. (b) Mukherjee P.; Widenhoefer R. A. Angew. Chem. Int. Ed. 2012 51 1405.

PAGE 316

316 ( 17 ) F rstner, A.; Davies, P. W. Angew. Chem. Int. Ed. 2007 46 3410. ( 18 ) Ghebreghiorgis T.; Biannic B.; Kirk B. H.; Ess D. H.; Aponick A. J. Am. Chem. Soc. 2012 1 34 16307. ( 19 ) Mukherjee P.; Widenhoefer R. A. Org. Lett. 2011 13 1334. ( 20 ) Bandini M.; Bottoni A.; Chiarucci M.; Cera G.; Miscione G. P. J Am Chem Soc 2012 134 20690. ( 21 ) Aponick A.; Biannic B. Org. Lett. 2011 13 1330. ( 22 ) Chiarucci M.; Mocci R.; Syntrivanis L D.; Cera G.; Mazzanti A.; Bandini M. Angew. Chem. Int. Ed. 2013 52 10850. ( 23 ) Palmes, J. A.; Paioti, P. H. S.; de Souza, L. P.; Aponick, A. Chem. Eur. J. 2013 19 11613. ( 24 ) Palmes, J. A.; Aponick, A. Synthesis 2012 4 4 3699. ( 25 ) Brimble, M. A .; Stubbing L. A. Top. Heterocycl. Chem. 2014 35 189. ( 26 ) Borrero, N.; Aponick, A. J. Org. Chem. 2012 77 8410. ( 27 ) Thansandote, P.; Lautens, M. Chem. Eur. J. 2009 15 5874. ( 28 ) Ketcham, J. M.; Cardoso, F. S. P.; Biannic, B.; Piras, H.; Aponick, A. Isr. J. Chem. 2013 53 1. ( 29 ) Mukherjee S.; Yang J. W.; Hoffmann S.; List B. Chem. Rev. 2007 107 5471. ( 30 ) Chiarucci M.; di Lillo M.; Romaniello A.; Cozzi P. G.; C era G.; Bandini M. Chem Sci 2012 3, 2859. ( 31 ) Trost, B. M. J. Org. Chem. 2004 69 5813. ( 32 ) Evans, P. A.; Leahy, D. K.; Andrews, J. W.; Uraguchi, D. Angew. Chem. Int. Ed. 2004 43 4788. ( 33 ) Onitsuka, K.; Okuda, H.; Sasai, H. Angew. Chem. Int. Ed. 2008 47 1454. ( 34 ) Ueno, S.; Hartwig, J. F. Angew. Chem. In t. Ed. 2008 47 1928. ( 35 ) Roggen, M.; Carreira, E. M. Angew. Chem. Int. Ed. 2011 50 5568. ( 36 ) Young, P. C.; Schopf, N. A.; Lee, A L. Chem. Commun. 2013 49 4262. ( 37 ) Mukherjee P.; Widenhoefer R. A. Chem. Eur. J. 2013 19 3437. ( 38 ) Biannic B.; Ghe breghiorgis T.; Aponick A. Beilstein J. Org. Chem. 2011 7 802.

PAGE 317

317 ( 39 ) Coutant E.; Young P. C.; Barker G.; Lee A L Beilstein J. Org. Chem. 201 3 9 1797. ( 40 ) Wright J. R.; Young P. C.; Lucas N. T.; Lee A L.; Crowley J. D. Organometallics 2013 32 7065. ( 41 ) Aponick, A.; Li, C Y.; Malinge, J.; Marques, E. F. Org. Lett. 2009 11 4624. ( 42 ) Egi, M; Azechi, K.; Akai, S. Org. Lett. 2009 11 5002. ( 43 ) Aponick, A.; Li, C Y.; Palmes, J. A. Org. Lett. 2009 11 121. ( 44 ) Chiarucci, M.; Matteucci, E.; Cera, G. ; Fabrizi, G.; Bandini, M. Chem. Asian J. 2013 8 1776. ( 45 ) Minkler S. R. K.; Isley N. A.; Lippincott D, J.; Krause N.; Lipshutz B. H. Org. Lett. 2014 16 724. ( 46 ) Manabe K.; Iimura S.; Sun X M .; Kobayashi S. J. Am. Chem. Soc. 2002 124 11971 ( 47 ) Krasovskiy A.; Duplais C.; Lipshutz B. H. J. Am. Chem. Soc. 2009 131 15592. ( 48 ) Spina, R.; Colacino, E.; Martinez, G.; Lamaty, F. Chem. Eur. J. 2013 19 3817. ( 49 ) Zhu L.; Luo J.; Hong R. Org. Lett. 2014 16 2162. ( 50 ) Fischbach M. A.; Cla rdy J. Nat. Chem. Biol. 2007 3 353. ( 51 ) Teo W. T.; Rao W.; Koh M. J.; Chan P. W. H. J. Org. Chem. 2013 78 7508. ( 52 ) Teo, W. T.; Rao, W.; Ng, C. J. H.; Koh, M. J.; Chan, P. W. H. Org. Lett. 2014 16 1248. ( 53 ) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000 122 1806. ( 54 ) Xu, C F.; Xu, M.; Yang, L Q.; Li, C Y. J. Org. Chem. 2012 77 3010. ( 55 ) (a) Peron, F.; Albizati, K. F. Chem Rev. 1989 89 1617 (b) Raju, B. R.; Saikia, A. K. Molecules 2008 13 1942. ( 56 ) Brimble, M. A.; St ubbing, L. A. Synthesis of Saturated Oxygenated Heterocycles I, Topics in Heterocyclic Chemistry 35; Cossy, J.; Ed.; Springer Verlag; Berlin; 2014 189. ( 57 ) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Re v 2005 105 4406. ( 58 ) (a) Haniotakis, G.; Francke, W.; Mori, K.; Redlich, H.; Schurig, V. J. Chem. Ecol. 1986 1559 (b) Redlich, H.; Francke, W. Angew. Chem. Int. Ed. 1984 23 519 ( 59 ) (a) Mazomenos, B.E.; Haniotakis, G.E. J. Chem. Ecol. 1985 11 397. (b) De Shong, P.; Waltermire, R. E.; Ammon H. L. J Am. Chem Soc. 1988 110 1901.

PAGE 318

318 ( 60 ) Ueno, T.; Takahashi, H.; Oda, M.; Mizunuma, M.; Yokoyama, A. ; Goto, Y.; Mizushina, Y .; Sakaguchi, K.; Hayashi, H Biochemistry 2000 39 5995. ( 61 ) Tachibana, K.; Scheuer, P. J.; Tsukitani, Y.; Kikuchi, H.; Engen, D.V .; Clardy, J.; Gopichand, Y.; Schmitz, F. J. J. Am. Chem. Soc. 1981 103 2469 ( 62 ) Cohen, P.; Holmes, C. F. B.; Tsukitani, I. Trends. Biochem. Sci. 1990 15 98 ( 63 ) Kinashi, H.; Otake, N.; Yonehara, H.; Sato, S.; Saito, Y Tetrahedron Lett. 1973 14 4 955. ( 64 ) Williams, D. E.; Roberge, M.; Soest, R. V.; Andersen, R. J. J. Am. Chem. Soc. 2003 125 5296 ( 65 ) Rho, J. R.; Hwang, B. S.; Sim, C. J.; Joung, S.; Lee, H. Y.; Kim, H. J. Org. Lett. 2009 11 5590. ( 66 ) Forestieri, R.; Merchant, C. E.; de Voogd, N. J.; Matainaho, T.; Kieffer, T. J.; Andersen, R. J. Org. Lett. 2009 11 5166. ( 67 ) (a) Ma, L. Y.; Liu, W. Z.; Shen, L.; Huang, Y. L.; Rong, X. G.; Xu, Y. Y.; Gao, X. D. Tetrahedron 2012 68 2276. (b) Igarashi, Y.; Iida, T.; Yoshida, R.; Furumai, T. J. Antibiot. 2002 55 764. (c) Davies, H. G.; Green, R. H. Nat. Prod. Rep. 1986 3 87. ( 68 ) (a) Urbanek, R. A.; Sabes, S. F.; Forsyth, C. J. J. Am. Chem. Soc. 1998 120 2523. (b) Brimble, M. A.; Edmonds, M. K.; Williams, G. M. Tetrahedron 1992 48 6455. (c) Brimble, M. A.; Edmonds, M. K.;Williams, G. M. Tetrahedron Lett. 1990 51 7509. (d) Wu, Y. B.; Tang,Y.; Luo, G. Y.; Chen, Y.; Hsung, R. P. Org. Lett. 2014 16 4550. ( 69 ) Butler, B. B., Jr.; Manda, J. N .; Aponick, A. Org Lett. 2015, 17 1902. ( 70 ) Butl er, B. B., Jr. Gold Catalyzed Cyclizations: Problems and Solutions En Route to the Southern Hemisphere of Spirastrellolide A, PhD Dissertation, University of Florida, August 2016 13 49. ( 71 ) Campbell W. C. Angew. Chem. Int. Ed. 2016 55 ,10184 ( 72 ) (a) Eg erton, J. R.; Ostlind, D. A.; Blair, L. S.; Eary, C. H.; Suhayda, D.; Cifelli, S.; Riek R. F.; Campbell W. C. Antimicrob. Agent Chemother. 1979 15 372. ( 73 ) Ostlind, D. A.; Mickle, W. G.; Smith, S.; Ewanchiw, D. V.; C ifelli, S. J. Parasitol. 2013 99 1 68 ( 74 ) Fisher, M. H.; Mzorik, Annu. Rev. Pharmacol. Toxicol. 1992 32 537. ( 75 ) Hood, J. D.; Banks, R. M.; Brewer, M. D.; Fish, J. P.; Manger, B. R.; Poulton, M. E. J. Anti biot 1989 42 1593. ( 76 ) Qiu, J.; Zhuo, Y.; Zhu, D.; Zhou, X.; Zhang, L.; Bai. L.; Deng, Z. Appl. Microbiol. Biotechnol. 2011 92 337.

PAGE 319

319 ( 77 ) Booth, Y. K.; W. Kitching W.; De Voss, J. J. Nat. Prod. Rep. 2009 26 490. ( 78 ) Schwartz, B. D.; Booth, Y. K.; Fletcher, M. T.; Kitching, W.; De Voss, J. J. Chem. Commun. 2010 46 1526 ( 79 ) (a ) Evans, D. A.; Tro tter, B. W.; Coleman, P. J.; Ct , B.; Dias, L. C.; Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999 55 8671. (b) Evan s, D. A.; Trotter, B. W.; C t B.; Coleman, P. J.; Dias, L. C.; T yler, A. N. Angew. Chem. Int. Ed. 1997 36 2744. ( 80 ) Brenzovich, W. E. Angew. Chem. Int. Ed. 2012 51, 8933. ( 81 ) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004 104 ,3079. (b) Corma, A.; Leyva Perez, A.; Sabater, M. J. Chem. Rev. 2011 111 1657. ( 82 ) Palmes, J. A.; Aponick, A. Synthesis 2012 44 3699. ( 83 ) Utimoto, K. Pure Appl. Chem. 1983 55 1845. ( 84 ) (a) Elgafi, S.; Field, L. D.; Messerle, B. A. J. Organomet. Chem. 2000 607 97. (b) Messerle, B. A.; Vuong, K. Q. Pure Appl. Chem. 2006 78 385. (c) Messerle, B. A.; Vuong, K. Q. Organometallics 2007 26 3031. (d) Ho, J. H. H.; Hodgson, R.; Wagler, J.; Messerle, B. A. Dalton Trans. 2010 39 4062. ( 85 ) Liu, B.; De Brabander, J. K. Org. Lett. 2006 8 4907. ( 86 ) (a) Tlais, S. F.; Dudley, G. B. Org. Lett. 2010 12 4698. (b) Li, Y.; Zhou, F.; Forsyth C. J. Angew. Chem. Int. Ed. 2007 46 279. ( 87 ) Faans, F. J.; Mendoza, A.; Arto, T.; Temelli, B.; Rodrguez, F. Angew. Chem. Int. Ed. 20 12 51 4930 ( 88 ) Ravindar, K.; Reddy, M. S.; Lindqvist, L.; Pelletier, J.;Deslongchamps, P. Org. Lett. 2010 12 44 20. ( 89 ) Tlais, S. F.; Dudley, G. B. Beilstein J. Org. Chem. 2011 7 570 ( 90 ) Newman, D. J.; Cragg, G. M.; Snader, K. M. J. Nat. Prod. 2003 66 1022. ( 91 ) Chen, M. S.; White, M. C. Science 2007 318 783. ( 92 ) Trost, B. M. Science 1991 251 1471. ( 93 ) (a) P aterson, I.; Anderson, E. A.; Dalby, S. M.; Loiseleur, O. Org. Lett. 2005 7, 4125 (b) Dias, L. C.; Salles Jr., A. G. J. Org. Chem. 2009 74, 5584 ( 94 ) Fang, C.; Pang, Y.; Forsyth, C. J. Org. Lett. 2010 12 4528 ( 95 ) Paioti, P. H. S.; Ketcham, J. M.; Ap onick, A. Org. Lett. 201 4 1 6 5320. ( 96 ) Koci en ski, P. J. Protecting Groups Foundations of Organic Chemistry Series Thieme 1994, 103.

PAGE 320

320 ( 97 ) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc ., Trans 1915 105 1080. ( 98 ) Sokolsky, A.; Cattoen, M.; Smith, A. B., III Org. Lett. 2015 17 1898 ( 99 ) (a) Coric, I.; List, B. Nature 2012 483 315. (b) Sun, Z.; Winschel, G. A.; Borovika, A.; Nagorny, P. J. Am. Chem. Soc. 2012 134 1792. (c) Takaoka, L. R.; Buckmelter, A. J.; LaCruz, T. E.; Rychnovsky, S D. J. Am. Chem. Soc. 2005 127 528. (d) Potuzak, J. S.; Moilanen, S. B.; Tan, D. S. J. Am. Chem. Soc. 2005 127 13796. ( 100 ) Borrero, N. V.; DeRatt, L. G.; Barbosa, L. F.; Abboud, K. A.; Aponick, A. Org. Lett. 2015 17 1754 ( 101 G.; Nolan, S. P. Organometallics 2010 29, 3665. (b) Engel, D. A.; Dudley, G. B. Org. Lett. 2006 8 4027. ( 102 ) Nieto Oberhuber, C.; Munoz, M. P.; Bunuel, E.; Nevado, C.; Cardenas, D. J.;Echavarre n, A. M. Angew. Chem., Int. Ed. 2004 43 2402. ( 103 ) (a) Alonso, I.; Faustino, H.; Lpez, F.; Mascareas, J. L. Angew. Chem. Int. Ed. 2011 50 11496. (b) Gonzalez, A. Z.; Benitez, D. Tkatchouk, E.; Goddard III, W. A.; Toste, F. D. J. Am. Chem. Soc. 2011 133 5500. (c) Zhang, L. J. Am. Chem. Soc. 2005 127 16804. ( 104 ) Su, Y.; Zhang, Y.; Akhmedov, N. G.; Pettersen, J. L.; Shi, X. Org Lett. 2014 16 2478. ( 105 ) Hammond, G. S. J. Am. Chem. Soc. 1955 77 334. ( 106 ) Hoffmann, R. W. Angew. Chem. Int. Ed. 2000 3 9 2054 ( 107 ) Miller, S. L. Science 1958 117 823. ( 108 ) Nelson, D. L.; Cox, M. M. Lehninger Principleas of Biochemistry 6 th edition (W. H. Freeman and Company, 2013 ) ( 109 ) (a) Beal, D. M.; Jones, L. H. Angew. Chem. Int. Ed. 2012 51 6320. (b) Yin, H.; Hami lton, A. D. Angew. Chem. Int. Ed. 2005 44 4130. ( 110 ) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. J. Chem. Educ. 2010 87 1348. ( 111 ) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis (Springer, 1999 ). ( 112 ) Corey, E. J.; Bak shi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987 109 5551. ( 113 ) Trost, B. M.; Machacek, M. R.; Aponick, A. Acc. Chem. Res. 2006 39 747. ( 114 ) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000 33 325

PAGE 321

321 ( 115 ) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000 33 336 ( 116 ) Alcock, N. W.; Brown, J. M.; Hulme s, D. I., Tetrahedron Asymmetry 1993 4 743. ( 117 ) Kn pfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T .; Carreira, E. M. Angew. Chem. Int. Ed. 2004 43 5971. ( 118 ) R. Irie, K. Noda, Y. Ito, N. Matsumoto an d T Katsuki, Tetrahedron Lett. 1990 31 7345. ( 119 ) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1990 112, 2801 ( 120 ) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000 122 2395 ( 121 ) Hayashi, Y.; Gotoh, H.; Ha yashi, T.; Shoji, M. Angew. Chem. Int. Ed. 2005 44 4212. ( 122 ) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jrgensen, K. A. Angew. Chem. Int. Ed. 2005 44 794. ( 123 ) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000 122 4243. ( 124 ) O oi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 1999 121 6519. ( 125 ) (a) Yashima, E.; Maeda, K. Macromolecules 2008 41 3. (b) Eelkema, R.; Feringa, B. L. Org. Biomol. Chem. 2006 4 3729. (c) Zhang, J.; Albelda, M. T.; Liu, Y.; Canary, J. W. Chirality 2005 17 404. (d) Levine, M.; Kenesky, C. S.; Zheng, S.; Quinn, J.; Breslow, R. Tetrahedron Lett. 2008 49 5746. (e) McKnight, A. L.; Waymouth, R. M. Chem. Rev. 1998 98 2587. ( 126 ) Williamson, R. T.; Singh, I. P.; Gerwick, W. H. Tetrahedron 2004 60 70 25. ( 127 ) (a) Tan, L. T. Phytochemistry 2007 68 954. (b) Orsini, M. A.; Pannell, L. K.; Erickson, K. L. J. Nat. Prod. 2001 64 572. ( 128 ) Wu, J.; Zhang, H B.; Xu, J L.; Cox, R.J.; Simpson, T. J.; Zhang, L H. Chem. Commun. 2010 46 333. ( 129 ) Fuchs, S. W.; Gr undmann, F.; Kurz, M.; Kaiser, M.; Bode, H. B. ChemBioChem 2014 15 512. ( 130 ) (a) Masschelein, J.; Mattheus, W.; Gao, L. J.; Moons, P.; v an Houdt, R.; Uytterhoeven, B.; Lamberigts, C.; Lescrinier, E.; Rozenski, J.; Herdewijn, P.; Aertsen, A.; Michiels, C.; Lavigne, R. PLoS ONE 2013 8 e54143. (b) Masschelein, J.; Clauwers, C.; Awodi, U. R.; Stalmans, K.; Vermaelen, W.; Lescrinier, E.; Aertsen, A.; Michiels, C.; Challis, G. L.; Lavigne, R. Chem. Sci. 2015 6 923.

PAGE 322

322 ( 131 ) Woodford, N.; Turton, J. F.; Livermore D. M. FEMS Microbiol. Rev. 2011 35 736. ( 132 ) (a) Lin, G. Q.; Xu, M. H.; Zhong, Y. W.; Sun, X. W. Acc. Chem. Res. 2008 41 831. ( 133 ) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002 35 984. ( 134 ) Knowles, W. S. J. Chem. Educ. 1986 63 222. ( 135 ) (a) Noyori, R. Angew. Chem. Int. Ed. 2002 41 2008. (b) Knowles, W. S. Angew. Chem. Int. Ed. 2002 41 1998 ( 136 ) Nugent, T. C.; El Shazly, M. Adv. Synth. Catal. 2010 352 753. ( 137 ) Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and Appl ications (Wiley, 2010 ). ( 138 ) Tang, W.; Zhang, X. Chem. Rev. 2003 103 3029. ( 139 ) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997 30 97. ( 140 ) Oshima, T.; Tam i ya, N. Biochem J 1961 78 11 6. ( 141 ) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003 103 2861 ( 142 ) (a) Uyanik, M.; Okamoto, H.; Yasui, T.; Ishihara, K. Science 2010 328 1376 (b) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010 110 704. ( 143 ) Mu ller, P.; Fruit, C. Chem. Rev 2003 103 2905. ( 144 ) Pirnot, M. T.; Wang, M T.; Buchwald, S. L. Angew. Chem. Int. Ed. 2015 55 48. ( 145 ) Zhu, S.; Niljianskul, N.; Buchwald, S. L. J. Am. Chem. Soc. 2013 135 15746 ( 146 ) Miki, Y.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem. Int. Ed. 2013 10 830. ( 147 ) (a) Yang, Y.; Shi, S. L.; Niu, D.; Liu, P.; Buchwald, S. L. Science 2015 349 62. (b) Zhu, S.; Buchwald, S. L. J. Am. Chem. Soc. 20 14 1 3 6 15913. (c) Niu, D.; Buchwald, S. L. J. Am. Chem. Soc. 20 15 1 37 9716. (d) Zhu, S.; N iljianskul, N.; Buchwald, S. L. Nat. Chem. 2016 8 144. ( 148 ) Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004 126 5680 ( 149 ) (a) Yang, Y.; Perry I. B.; Lu, G.; Liu, P.; Buchwald, S. L. Science 2016 353 144 (b) Wang, Y M.; Buchwald, S. L. J. Am. C hem. Soc. 20 16 1 38 5024. ( 150 ) Xi, Y.; Butcher, T. W.; Zhang, J.; Hartwig, J. F. Angew. Chem. Int. Ed. 2015 55, 776 ( 151 ) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999 99 1069.

PAGE 323

323 ( 152 ) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011 111 1417. ( 153 ) Hay ashi, T.; Ishigedani, M. J. Am. Chem. Soc. 2000 122 976. ( 154 ) Hermanns, N.; Dahmen, S.; B olm, C.; Brse, S. Angew. Chem. Int. Ed. 2002 41 3692. ( 155 ) (a) Cardoso, F. S. P.; Abboud, K. A.; Aponick, A. J. Am. Chem. Soc. 2013 135 14548. (b) Pappoppula, M ., Cardoso, F. S. P.; Garrett, B. O.; Aponick, A. Angew. Chem. Int. Ed. 2015 54 15202. (c) Pappoppula, M., Aponick, A. Angew. Chem. Int. Ed. 2015 54 15827. ( 156 ) (a) Peshkov, V. A.; Pereshivko, O. P.; Van der Eycken, E. V. Chem. Soc. Rev. 2012 41 3790. (b) Zhao, C.; Seidel, D. J. Am. Chem. Soc. 2015 137 4650. ( 157 ) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem. Int. Ed. 2003 42 5763. ( 158 ) Aschwanden, P.; Stephenson, C. R. J.; Carreira, E. M. Org. Lett. 2006 8 2437. ( 159 ) Paioti, P. H. S.; Abboud, K. A.; Aponick, A. J. Am. Chem. Soc. 2016 138 2150. ( 160 ) Koradin, C.; Polbor n, K.; Knochel, P. Angew. Chem. Int. Ed. 2002 41 2535. ( 161 ) Bergonzini, G.; Vera, S.; Melchiorre, P. Angew. Chem. Int. Ed. 2010 49 9685. ( 162 ) Naredla, R. R.; Kl umpp, D. A. Chem. Rev. 2013 113 6905. ( 163 ) (a) Mathai, I. M.; Taniguchi, H.; Miller, S. I. J. Am. Chem. Soc. 1967 89 115. (b) Gensler, W. J.; Casella, J., Jr. J. Am. Chem. Soc. 1958 80 1376. ( 164 ) (a) Braga, A. L.; Ldtke, D. S.; Vargas, F.; Paixo, M. W. A. Chem. Commun. 2005 19 2512. (b) Hayashi, T.; Ishigedani, M. J. Am. Chem. Soc. 2000 122 976. (c) Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997 62 444. ( 165 ) Prieto, M.; Zurita, E., Rosa, E.; Munoz, L.; Lloyd Williams, P.; Giralt, E. J. Org. Chem. 2004 69 6812. ( 166 ) (a) Palomo, C.; Oiarbide, M.; Halder, R.; Kelso, M.; Gomez Bengoa, E.; Garcia, J. M. J. Am. Chem. Soc. 2004 126 9188. (b) Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004 69 1126. ( 167 ) (a) Yoshihiro, B.; Ryoma, H.; Ryosuke, T. WO2009110520 (A1), September 11, 2009 (b) Gurmit, G.; Vibbha, O. WO2008059238 (A1), May 22, 2008 ( 168 ) (a) Pan, S.; Ryu, N.; Shibata, T. J. Am. Chem. Soc. 2012 134 17474. (b) Ohta, Y.; Chiba, H.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2 009 74 7052. (c) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006 128 1086. (d) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004 126 10558.

PAGE 324

324 ( 169 ) Koradin, C.; Gommermann, N.; Polborn, K.; Knochel, P. Chem. Eur. J. 2003 9 2797. ( 170 ) Burk e, M. D.; Schreiber, S. L. Angew. Chem. Int. Ed. 2004 43 46. ( 171 ) Schilstra, M. J.; Veldink, G. A.; Vliegenhart, J. F. G. Biochemistry 1993 32 7686 7691. ( 172 ) (a) Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. 1998 37 2922. (b) Blackmond, D. G. J. Am. Chem. Soc. 1997 119 12934. ( 173 ) Gommermann, N.; Knochel, P. Chem. Eur. J. 2006 12 4380. ( 174 ) Cardoso, F. S. P. A New Approach to Atropisomerism PhD Dissertation, University of Florida, August 201 4 100 107 ( 175 ) Hartwig, J. F. Organotransition Metal Ch emistry: From Bonding to Catalysis (University Science Books, 2010 ). ( 176 ) Gridnev, I. D.; Imamoto, T. Acc. Chem. Res. 2004 37 633. ( 177 ) Crabtree, R. H. The Organometallic Chemistry of Transition Metals (John Wiley & Sons, 5 th ed., 2009 ). ( 178 ) Trost, B. M. A ngew. Chem. Int. Ed. 1995 34, 259. ( 179 ) Huo, H.; She se, P.; Chen, L. A.; Harms, K.; Marsch, M.; Hilt, G.; Meggers, E. Nature 2014 515, 100. ( 180 ) Kagan, H. B.; Dang, T. P. J. Am. Chem. Soc. 1972 94 6429 ( 181 ) Knowles, W. S. Acc. Chem. Res. 1983 16 106 ( 182 ) Miyashita, A.; Ya suda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T.; Noyori, R. J. Am. Chem. Soc. 1980 102 7932. ( 183 ) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000 33 336 ( 184 ) Alcock, N. W.; Brown, J. M.; Hulmes, D. I. Tetrahedron: Asymmetry 1993 4 743. ( 185 pf el, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew. Chem. Int. Ed. 2004 43 5971. ( 186 ) Fernandez, E.; Guiry, P. J.; Connole, K. P. T.; Brown, J. M. J. Org. Chem. 2014 79, 5391 ( 187 ) Brown, J. M.; Hulmes, D. I.; Guiry, P. J. Tetra hedron 1994 50 4493 ( 188 ) Brown, J. M.; Hulmes, D. I.; Layzell, T. P. J. Chem. Soc., Chem. Commun. 1993 1673.

PAGE 325

325 ( 189 ) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003 125 10174. ( 190 ) Li, X.; Kong, L.; Gao, Y.; Wang, X. Tetrahedron Lett. 2007 48 3 915. ( 191 ) Kn pfel, T. F.; Zarotti, P.; Ichikawa, T.; Carreira, E. M. J. Am. Chem. Soc. 2005 127 9682. ( 192 ) Claridge, T. D. W.; Long, J. M.; Brown, J. M.; Hibbs, D.; Hursthouse, M. B. Tetrahedron 1997 53 4035. ( 193 ) Cooke, A. S.; Harris, M. M. J. Chem. Soc. 1963 2365. ( 194 ) Meca, L.; Reha, D.; Havlas, Z. J. Org. Chem. 2003 68 5677. ( 195 ) Meyer, E. A.; Castellano, R. K.; Diederich, F. Angew. Chem., Int. Ed. 2003 42 1210. ( 196 ) pfel, T. F.; Zarotti, P.; Ichikawa, T.; Boyall, D.; Carreira, E. M. Bull. Chem. Soc. Jpn. 2007 80 1635. ( 197 ) (a) Yoon, T. P.; Jacobsen, E. N. Science 2003 299 1691. (b) Zhou, Q. L., Ed. Privileged Chiral Ligands and Catalysts (WileyVCH : Weinheim, 2011 ). ( 198 ) Nugent, W. A.; RajanBabu, T. V.; Burk, M. J. Science 1993 259 479. ( 199 ) Berthod, M; Mignani, G.; Woodward, G.; Lemaire, M. Chem. Rev. 2005 105 1801. ( 200 ) Cai, D.; Payack, J. F.; Bender, D. R.; Hughes, D. L.; Verhoeven, T. R.; Reide r, P. J. J. Org. Chem. 1994 59 7180. ( 201 ) Cai, D.; Payack, J. F.; Bender, D. R.; Hughes, D. L.; Verhoeven, T. R.; Reider, P. Org. Synth. 2014 91 1. ( 202 ) Otsuka, S.; Nakamura, A,; Kano, T.; Tani, K. J. Am. Chem. Soc. 1971 93 430 1 ( 203 ) Bhat, V.; Wang, S. ; Stoltz, B. M.; Virgil, S. C. J. Am. Chem. Soc. 2013 135 16829 ( 204 ) Leutenegger, U.; Madin, A.; Pfaltz, A. Angew. Chem., Int. Ed. 1989 101 60. ( 205 ) Desimoni, G.; Faita, G.; Jrgensen, K. A. Chem. Rev. 2006 106 3561. ( 206 ) Togni, A.; Breutel, C.; Schnyd er, A.; Spindler, F.; Landert, H.; Tijani, A. J. Am. Chem. Soc. 1994 116 4062. ( 207 ) Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993 32 566. ( 208 ) Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1993 34 1769.

PAGE 326

326 ( 209 ) Dawson, G. J.; Frost, C. G.; Williams, J. M. J.; Coote, S. J. Tetrahedron Lett. 1993 34 3149. ( 210 ) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000 33 336. ( 211 ) Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res. 2007 40 1402. ( 212 ) (a) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004 126 15044. (b) Koch, G.; Pfaltz, A. Tetrahedron: Asymmetry 1996 7 2213. ( 213 ) Pfaltz, A.; Drury, W. J., III. Proc. Natl. Acad. Sci. 2004 101 5723. ( 214 ) Bus ac c a, C. US6316620, November 2001 ( 215 ) Menges, F.; Neuburger, M.; Pfaltz, A. Org. Lett. 2002 4 4713. ( 216 ) Gan ic, A.; Pfaltz, A. Chem. Eur. J. 2012 18 6724. ( 217 ) (b) Guiu, E.; Claver, C.; Benet Buchholz, J.; Castillon, S. Tetrahedron: Asymmetry 2004 15 3365. ( 218 ) Busacca, C. A.; Lorenz, J. C.; Grinberg, N.; Haddad, N.; Lee, H.; Li, Z.; Liang, M.; Reeves, D.; Sah a, A.; Varsolona, R.; Senanayake, C. H. Org. Lett. 2008 10 341. ( 219 Org. Lett. 2003 5 595. ( 220 Reeves, D.; Haddad, N.; Eriksson, M.; Wu, J. P.; Grinberg, N.; Lee, H.; Li, Z.; Lu, B.; Chen, D .; Hong, Y.; Ma, S.; Senanayake C. H. Adv. Synth. Catal. 2013 355 1455. ( 221 ) (a ) Franzke, A.; Pfaltz, A. Chem. Eur. J. 2011 17 4131. (b) Busacca, C. A.; Lorenz, J. C.; Saha, A. K.; Cheekoori, S.; Haddad, N.; Reeves, D.; Lee, H.; Li, Z.; Rodriguez, S.; Senanayake, C. H. Cat. Sci. Technol. 2012 2 2083. ( 222 B unz, H.; Guiry, P. J. Chem. Commun. 2012 48 11142 ( 223 ) Barrett, K. T.; Metrano, A. J.; Rablen, P. R.; Miller, S. J. Nature 2014 509 71. ( 224 ) Carroll, M. P.; Guiry, P. J.; Brown, J. M. Org. Biomol. Chem. 2013 11 4591. ( 225 ) Cannon, J. S.; Frederich, J. H .; Overman, L. E. J. Org. Chem. 2012 77 1939. ( 226 ) Gelman, D.; Jiang, L.; Buchwald, S. L. Org. Lett. 2003 5 2315. ( 227 ) Brands, K. M.; Davies, A. J. Chem. Rev. 2006 106 2711. ( 228 ) Le Chatelier, H.; Boudouard, O. Bull. Soc. Chim. Fr. 1898 19 483. ( 229 ) Ca rroll, M. P.; Guiry, P. J. Chem. Soc. Rev. 2014 43 819.

PAGE 327

327 ( 230 ) Patton, A.; Dirks, J. W.; Gust, D. J. Org. Chem. 1979, 44 4749. ( 231 ) M. Rieger, M.; Westheimer, F. H. J. Am. Chem. Soc. 1950 72 19. ( 232 ) Leroux, F. ChemBioChem 2004 5 644 ( 233 ) (a) Sperry, J. B.; Wright, D. L. Curr. Opin. Drug Discovery Dev. 2005 8 723. (b) Li, J. J. Heterocycles in Life and Society ; John Wiley & Sons: Weinheim, 2013 (c) Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Heterocycles in Life and Society ; John Wiley & Sons: Weinheim, 1997 ( 234 ) Laine, A. E.; Lood, C.; Koskinen, A. M. P. Molecules 2014 19 1544. ( 235 ) (a) Carlsson, J.; Coleman, R. G.; Setola, V.; Irwin, J. J.; Fan, H.; Schlessinger, A.; Sali, A.; Roth, B. L.; Shoichet, B. K. Nature Chem. Biol 2011 7 769. (b) Scapecchi, S.; Nesi, M.; Matucci, R.; Bellucci, C.; Buccioni, M.; Dei, S.; Guandalini, L.; Manetti, D.; Martini, E.; Marucci, G.; Romanelli, M. N.; Teodori, E.; Cirilli, R. J. Med. Chem. 2008 51 3905. ( 236 ) Yoshihiro, B.; Ryoma, H.; R yosuke, T. EP2251326, November 2010 ( 237 ) (a) Zenk, M. H. J. Nat. Prod. 1980 43 438. (b) Gurmit, G.; Vibbha, O. WO2008059238, May 2005 ( 238 ) (a) Harwood, L. M.; Currie, G. S.; Drew, M. G. B.; Luke, R. W. A. Chem. Commun. 1996 1953. ( 239 ) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011 111 2626. ( 240 ) Yamamoto, Y.; Takahashi, Y.; Kurihara, K.; Miyaura, N. Aust. J. Chem. 2011 64 1447. ( 241 ) Shintani, R.; Narui, R.; Tsutsumi, Y.; Hayashi, S.; Hayashi, T. Chem. Commun. 2011 47 ,6123. ( 242 ) Chen, Y. J.; Cui, Z.; Feng, C. G.; Lin, G. Q. Adv. Synth. Catal. 2015 357 2815. ( 243 ) Nakamura, I.; Yamamoto, Y. Chem. Rev 2004 104 2127. ( 244 ) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007 36 1173. ( 245 ) Lipshutz, B. H. Chem. Rev. 1986 86 795. ( 246 ) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Science 2013 340 1065. ( 247 ) (a) Kochi, T.; Tang, T. P.; Ellman J. A. J. Am. Chem. Soc. 2003 125 11276. (b) Lutz, C.; Lutz, V.; Knochel, P. Tetrahedron 1998 54 6385. ( 248 ) Cozzi, P. G.; Hil graf, R.; Zimmermann, N. Eur. J. Org. Chem. 2004 4095.

PAGE 328

328 ( 249 ) Petersen, K. S.; Stoltz, B. M. Tetrahedron 2011 67 4352 ( 250 ) Reetz, M. T.; Wu, S. J. Am. Chem. Soc. 2009 131 15424. ( 251 ) Pandey, G.; Banerjee P. Gadre S. R. Chem. Rev. 2006 106 4484. ( 252 ) Lim, A. D.; Codelli, J. A.; Reisman, S. E. Chem. Sci. 2013 4, 650. ( 253 ) Kaupp, M.; von Schnering, H. G. Angew. Chem., Int. Ed. 1995 34 986. ( 254 ) Mori, S.; Vreven, T.; Morokuma, K. Chem. Asian J. 2006 1 391. ( 255 ) B rgi, H. B.; Dunitz, J. D.; Lehn, J. M. ; Wipff, G. Tetrahedron 1974 30 1563.

PAGE 329

329 BIOGRAPHICAL SKETCH Paulo Henrique de Souza Paioti was born in Jacare in 1987 and grew up in S o Jos dos Campos, in the state of So Paulo Brazil He spent most of his life with his parents Antonio Carlos Paioti and Maria Bernadete de Souza Paioti, and with his two older brothers, Pedro Ivo and Joo Marcelo in So Jos dos Campos He attended primary, middle and high school at Olavo Bilac Ayres de Moura. In 2005 he moved to Campinas to study chemistry at the University of Campinas (UNICAMP), also in the state of So Paulo, where he graduated with a Ba chelor of Science in c hemistry in 20 09 He begun undergraduate research with Dr. Fernando Coelho in 2007 and joined the Master of Science program at the same university In 2011, he d the preparation of the natural products leiocarpin A an d goniodiol along with other applicati ons of the Baylis Hillman reaction In August 2011, h e then got into an airplane for the first time and moved to Florida, where he started his doctoral degree at the University of Florida in the fall of 2011 under the guidanc e of Dr. Aaron Aponick. In the Aponick group, he developed the gold and copper catalyzed reactions shown in this dissertation as well as the StackPhim ligands which appeared in C hapter 4 He obtained his doctorate in chemistry in December 2016, and moved to Boston MA to work with Dr. X. Peter Zhang at Boston College as a postdoctoral scholar on cobalt based metalloradical catalysis.