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Diastereoselective Synthesis of Substituted Tetrahydropyrans and 1,3-Dioxanes via Gold (I) Catalysis

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Title:
Diastereoselective Synthesis of Substituted Tetrahydropyrans and 1,3-Dioxanes via Gold (I) Catalysis
Creator:
Goodwin, Justin A
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[Gainesville, Fla.]
Florida
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University of Florida
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Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Chemistry
Committee Chair:
APONICK,AARON
Committee Co-Chair:
BRUNER,STEVEN DOUGLAS
Committee Members:
GRENNING,ALEXANDER JAMES
SUMERLIN,BRENT S
SLOAN,KENNETH B
Graduation Date:
12/18/2015

Subjects

Subjects / Keywords:
Alcohols ( jstor )
Aldehydes ( jstor )
Alkynes ( jstor )
Chromatography ( jstor )
Dienes ( jstor )
Epoxy compounds ( jstor )
Ethers ( jstor )
Hexanes ( jstor )
Nucleophiles ( jstor )
Room temperature ( jstor )
Chemistry -- Dissertations, Academic -- UF
catalysis -- gold -- methodology -- synthetic
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bibliography ( marcgt )
theses ( marcgt )
government publication (state, provincial, terriorial, dependent) ( marcgt )
born-digital ( sobekcm )
Electronic Thesis or Dissertation
Chemistry thesis, Ph.D.

Notes

Abstract:
Over the past two decades, gold-catalyzed reactions have proven to be powerful synthetic tools, due to the ability of gold (I) complexes to act as carbophilic pi-acids for the activation of allenes, alkenes, and alkynes. These complexes typically activate pi-systems towards nucleophilic addition to form C-C, C-O, or C-N bonds, which is then followed by protodeauration to give olefin addition products. This dissertation details research efforts aimed at developing the activation of alkynes and alkenes by cationic gold complexes towards addition/elimination pathways involving heteroatom nucleophiles, whereby protodeauration is circumvented to give products with the pi-bond relocated. Building on this concept, a novel tandem gold-catalyzed cyclization-epoxidation-reduction sequence has been developed. This sequence relies on an initial gold (I)-catalyzed dehydrative cyclization of propargylic ethers to form a unique diene intermediate. Treatment of this diene intermediate with dimethyldioxirane furnishes an epoxide. Finally, Lewis acid-catalyzed epoxide opening and reduction of the resultant oxocarbenium generates 3-hydroxy substituted tetrahydropyrans. This novel process demonstrates promise towards applications in the total synthesis of natural products, in particular, ladder shaped polyether compounds, an important class of marine natural products. Work presented in this dissertation also aims at expanding the pi-activation of allylic alcohols. Studies on the diastereoselective synthesis of protected 1,3-diols by catalytic diol relocation are described here. A complementary diastereoselective gold (I)- or bismuth (III)-catalyzed tandem hemiacetalization/dehydrative cyclization of allylic diols was developed providing access to substituted dioxolanes and dioxanes. This methodology provides efficient access to protected syn 1,3-diols. Deprotection and further elaboration of these protected synthons allowed access to 2,5-trans-tetrahydrofuran motifs that are found in a wide range of natural products and biologically relevant compounds. ( en )
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In the series University of Florida Digital Collections.
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Includes vita.
Bibliography:
Includes bibliographical references.
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Description based on online resource; title from PDF title page.
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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, 2015.
Local:
Adviser: APONICK,AARON.
Local:
Co-adviser: BRUNER,STEVEN DOUGLAS.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2016-12-31
Statement of Responsibility:
by Justin A Goodwin.

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Applicable rights reserved.
Embargo Date:
12/31/2016
Classification:
LD1780 2015 ( lcc )

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DIASTEREOSELECTIVE SYNTHESIS OF SUBST ITUTED TETRAHYDROPYRANS AND 1,3 DIOXANES VIA GOLD (I) CATALYSIS By JUSTIN ANDREW GOODWIN A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2015

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© 2015 Justin Andrew Goodwin

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To all those who have supported me along the way

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4 ACKNOWLEDGMENTS I would like to thank my beautiful wife Laura for being such an amazing source of strength and support throughout the years. Since we met during our undergraduate studies she has been beside me through every endeavor I have undertaken and I certainly would not have made it through this process without her constant support and inspiration. I would like to thank my parents, Richar d and Tammy, as well as my sister Mariann. My family has always provided encouragement to pursue my aspirations in life and motivation to achieve them. They were always there to give advice and were an invaluable support system along the way. I would lik e to thank Professor Brian Goess for instilling me with a passion for organic chemistry and allowing me to work under his direction as an undergraduate researcher. His mentorship provided me with a strong foundation that has aided me greatly. I would lik e to thank Professor Aaron Aponick who has been an exceptional mentor to me during my time here at the University of Florida. Witnessing his unwavering determination to build an exemplary research program has been truly remarkable and provided an example t o follow. His passion for organic chemistry has kept me motivated throughout my doctoral studies. Through his guidance, I am able to leave the University of Florida confident that I have been well prepared for the future. I would like to thank my committe e membe rs Professors Steven D. Bruner, Alexander J. Grenning, Kenneth B. Sloan, and Brent S. Sumerlin for all the time they have spent helping me during my doctoral studies. I appreciate all the suggestions and guidance they have provided during this proce ss.

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5 I would like to thank Dr. Tammy Davidson and Dr. Jason Portmess for their advice about life and chemistry throughout the years. I would especially like to thank Dr. Davidson for all of the hard work she puts into the organic teaching laboratories, the compassion she shows for her teaching assistants, and motivating me to be an excellent teacher. To the Aponick group members, I have thoroughly enjoyed all the times we have shared together. The lab environment created by such an outstanding group of indiv iduals has been truly remarkable. Through s pending so much time together I feel as though I have acquired a second family. I appreciate all of the advice, support and laughter that each of you has brought to my graduate school experience. I would especiall y like to thank Dr. John Ketcham and Paulo Paioti for their support.

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6 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF SCHEMES ................................ ................................ ................................ ........ 8 LIST OF ABBREVIATIONS ................................ ................................ ........................... 13 ABSTRACT ................................ ................................ ................................ ................... 17 CHAPTER 1 REGIOSELECTIVITY IN THE GOLD CATALYZED HYDRATION AND HYDROALKOXYLATION OF ALKYNES ................................ ................................ 19 1.1 Introduction ................................ ................................ ................................ ....... 19 1.2 Hydration of Alkynes ................................ ................................ ......................... 21 1.2.1 General Introduction and Current State Of The Art ................................ . 21 1.2.2 Hydration of Internal Alkynes ................................ ................................ ... 22 1.2.3 Substrate Directing Group Strategies ................................ ...................... 25 1.2.4 Catalyst Design Strategies ................................ ................................ ...... 27 1.3 Hydroalkoxylation of Alkynes ................................ ................................ ............ 28 1.3.1 Introduction ................................ ................................ .............................. 28 1.3.2 Intramolecular Hydroalkoxylation of Terminal Alkynes ............................ 29 1.3.3 Intramo lecular Hydroalkoxylation of Internal Alkynes .............................. 31 1.3.4 Intermolecular Hydroalkoxylation of Terminal Alkynes ............................ 37 1.3.5 Intermolecular Hydroalkoxylation of Internal Alkynes .............................. 40 1.4 Conclusions ................................ ................................ ................................ ...... 47 2 TANDEM GOLD (I) CATALYZED CYCLIZATION EPOXIDATION REDUCTION SEQUENCE TOWARDS MARINE POLYETHER NATURAL PRODUCTS ............ 49 2.1 Introduction ................................ ................................ ................................ ....... 49 2.1.1 Metal catalyzed Generation of 2 oxodienes ................................ ............ 49 2.1. 2 Synthetic Strategies Targeting Epoxide Opening Cascades Towards Marine Polyethers ................................ ................................ ......................... 53 2.2 Results and Discussion ................................ ................................ ..................... 63 2.2.1 Preliminary Studies ................................ ................................ .................. 63 2.2.2 Tandem gold catalyzed cyclization epoxidation reduction ...................... 66 2.3 Conclusions and Outlook ................................ ................................ .................. 77 3 DIASTEREOSELECTIVE S YNTHE SIS OF PROTECTED 1,3 DIOLS BY CATALYTIC DIOL RELOC ATION ................................ ................................ .......... 79 3.1 Introduction ................................ ................................ ................................ ....... 79 3.1.1 Transition Metal Catalyzed Allylic Substitution ................................ ........ 79

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7 3.1.2 Pseudo intermolecular Tandem Hemiacetalizaion/Allylic Substitution .... 83 3.2 Results and Discussion ................................ ................................ ..................... 85 3.2.1 Preliminary Studies ................................ ................................ .................. 85 3.2.2 Expansion of the Substrate Scope For the Pseudo Intermolecular Tandem Hemiacetalization/Allylic Substitution of Monoallylic Alcohols ......... 91 3.2.3 Deprotection to Unmask Syn 1,3 Diols and Elaboration to More Complex Motifs ................................ ................................ ............................. 96 3.3 Conclusions ................................ ................................ ................................ .... 100 4 EXPERIMENTAL SECTION ................................ ................................ ................. 101 4.1 General Experimental Procedures ................................ ................................ .. 101 4.2 Tandem Gold (I) Catalyzed Cyclization Epoxidation Reduction Sequence Towards Marine Polyether Natural Products ................................ ..................... 102 4.2.1.General tandem cyclization oxidation reduction procedure. .................. 114 4.3 Diastereoselective Synthesis of Protected 1,3 Diols by Catalytic Diol Relocation ................................ ................................ ................................ .......... 125 4.3.1 Synthesis of Diols 3 45g, and 3 45h ................................ ...................... 129 4.3.2 Synthesis of diol 3 51b ................................ ................................ .......... 137 LIST OF REFERENCES ................................ ................................ ............................. 145 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 154

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8 LIST OF SCHEMES Scheme page 1 1 General metal catalyzed addition to C C triple bonds ................................ ........ 19 1 2 Gold catalyzed hydroalkoxylation in the formal synthesis of ( ) polycavernoside A ................................ ................................ .............................. 20 1 3 Gold Catalyzed hydration of alkynes ................................ ................................ .. 21 1 4 Current state of the art conditions for gold catalyzed alkyne hydration .............. 22 1 5 Early Au (III) catalyzed alkyne hydration ................................ ............................ 23 1 6 Phosphine ligand effects in gold (I) catalyzed alkyne hydration ......................... 24 1 7 Employment of a NHC gold catalys t system to furnish regioselective alkyne hydration ................................ ................................ ................................ ............. 24 1 8 Directing group strategy for alkyne hydration ................................ ..................... 25 1 9 Regioselective alkyne hydration directed by pendant nucleophile ...................... 25 1 10 Use of a neighboring ester to direct alkyne hydration ................................ ......... 26 1 11 Use of an aldehyde directing group for alkyne hydration ................................ .... 27 1 12 Effect of bulky NHC liga nds on alkyne hydration ................................ ................ 28 1 13 Gold catalyzed hydroalkoxylation of alkynes ................................ ...................... 29 1 14 Tandem Au(I) catalyzed hydroalkoxylation Prins type cyclization ..................... 30 1 15 Double intramolecular hydroalkoxylation of terminal alkynes ............................. 30 1 16 Intramolecular hydroalkoxylation of 2 (prop 2 yn 1 ylamino)phenols ................. 31 1 17 Tandem cycloisomerization/hydroalkoxylation of homopr opargylic alcohols ...... 32 1 18 Hydroalkoxylation of 4 bromo 3 yn 1 ols ................................ ............................ 32 1 19 Hydroalkoxylation of conjugated ynoates ................................ ........................... 33 1 20 Spiroketalization of alkynediols ................................ ................................ ........... 33 1 21 Substituent effect on alkynediol spiroketalization ................................ ............... 34

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9 1 22 Regiochemical control of alkyne hydroalkoxylation using an acetonide; JohnPhos= [P( t Bu) 2 (o biphenyl)] ................................ ................................ ....... 35 1 23 Spiroketalization studies on the rubromycin core ................................ ............ 36 1 24 Sterically imposing ligand effects in alkynediol spiroketalization ........................ 36 1 25 Gold (III) catalyzed hydroalkoxylation ................................ ................................ . 37 1 26. Gold (I) catalyzed hydroalkoxylation ................................ ................................ ... 38 1 27 Gold catalyzed addition of diols to alkynes ................................ ......................... 38 1 28 Gold catalyzed hydroacylation of terminal alkynes ................................ ............. 39 1 29 Effect of the nature of phosphine ligands on regioselectivity of mono hydroalkoxylation; DavePhos=2 Dicyclohexylphosphino (N,N dimethylamino)biphenyl ................................ ................................ ...................... 40 1 30 Steric effect on regioselective hydroalkoxylation ................................ ................ 41 1 31 Regioselective alkyne hydroalkoxylation with diols ................................ ............. 41 1 32 Gold catalyzed hydroacylation of internal alkynes ................................ .............. 42 1 33 Au(III) catalyzed intermolecular hydroalkoxylation of alkynes ............................ 43 1 34 Au(I) catalyzed intermolecular hydroalkoxylation ................................ ............... 45 1 35 Tandem hydroalkoxylatio n Claisen rearrangement ................................ ............ 46 1 36 Overview of selectivity ................................ ................................ ........................ 47 2 1 Gold catalyzed addition of a nucleophile across an alkyne ................................ 49 2 2 Gold catalyzed spiroketalization of monopropargylic triols. ................................ 50 2 3 Control experiment leading to the formation of diene 2 7 ................................ ... 50 2 4 Various strategies for the preparation of 2 oxodienes ................................ ........ 51 2 5 catalyzed diene formation ................................ .......... 52 2 6 Tandem gold catalyzed dehydrative cyclization / Diels Alder process ............... 52 2 7 Application of a tandem gold catalyzed dehydrative cyclization / Diels Alder process to the synthesis of Boc protected Arcyriaflavin A ................................ .. 53 2 8 Proposed conversion of intermediates 2 10 to tetrahydropyrans 2 13 ............... 54

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10 2 9 Common structural elements of ladder polyethers. ................................ ............ 55 2 10 Biosynthetic hypothesis for brevetoxin B proposed by Nakanishi and Shimizu .. 56 2 11 Two possible cyclization pathways for epoxide 2 29 ................................ .......... 57 2 12 opening reactions ................................ ................................ ............................... 58 2 13 Rationale for the directing effects of alkenyl epoxides ................................ ........ 58 2 14 Examples of other strategies employed to control regioselectivity in intramolecular epoxide openings. ................................ ................................ ....... 60 2 15 openings. ................................ ................................ ................................ ............ 61 2 16 opening cascades ................................ ................................ ............................... 61 2 17 Epoxide opening cascade of template polyepoxides in H 2 O .............................. 62 2 18 Proposed iterative sequen ce to form complex polyether from simple starting materials ................................ ................................ ................................ ............. 63 2 19 Synthesis of monoropagylic diols 2 69 and 2 70 ................................ ................ 64 2 20 Initial attempts of a tandem gold catalyzed cyclization hydroboration oxidation sequence ................................ ................................ ............................. 64 2 21 Synthesis of propargyl ethers 2 75 and 2 76 ................................ ...................... 65 2 22 Studies on protected nucleophiles 2 73 74 propargyl ethers 2 75 76 ................ 66 2 23 DMDO / triethylsilane oxidation reduction sequence to generate 2 82a and 2 82b ................................ ................................ ................................ ..................... 66 2 24 Proposed one pot tandem gold catalyzed di ene formation epoxidation reduction process. ................................ ................................ .............................. 67 2 25 Successful tandem gold catalyzed cyclization oxidation reduction sequence .... 67 2 26 Proposed conversion of THP 2 85 to alkyne 2 66 ................................ .............. 68 2 27 Synthesis of propargyl alcohol 2 87 and propargyl ether 2 88 . .......................... 68 2 28 Optimization studies for the formation of THP 2 85 ................................ ............ 69 2 29 Synthesis of propargyl ether 2 91 ................................ ................................ ....... 70

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11 2 30 Conversion of propargyl ether 2 91 to THP 2 91 ................................ ................ 70 2 31 Synthesis of propargyl ether 2 94 ................................ ................................ ....... 70 2 32 Additional examples of viable substrates ................................ ............................ 71 2 33 Proposed stereochemical rational for the reduction of oxocarbenium 2 97 ........ 72 2 34 Synthesis of alternate heteroatom nucleophiles ................................ ................. 72 2 35 Synthesis of phenol 2 105 ................................ ................................ .................. 73 2 36 Exploring the reactivity of alternative nucleophiles. ................................ ............ 74 2 37 Synthesis of propargyl ether 2 114 ................................ ................................ ..... 75 2 38 Attempts to synthesize THF 2 116 from propargyl ether 2 114 .......................... 75 2 39 Synthesis of propargyl ether 2 120 . ................................ ................................ .... 76 2 40 Studies on the formation of oxepane 2 122 ................................ ........................ 76 2 41 Synthesis of THP 2 129 ................................ ................................ ...................... 77 3 1 General transition metal catalyzed ................................ ................................ ..... 79 3 2 Diastereoselective formation of THPs 3 5 from monoallylic diols ....................... 80 3 3 Chirality transfer in the gold (I) cat alyzed dehydrative cyclization of monoallylic diols ................................ ................................ ................................ . 80 3 4 Possible mechanistic pathways for the gold (I) catalyzed dehydrative cyclization of monoallylic diols. ................................ ................................ ........... 81 3 5 Intermolecular gold catalyzed substitution of allyilic alcohols ............................. 82 3 6 Chirality transfer in the intermolecular dehydrative substitution of allylic alcohols ................................ ................................ ................................ .............. 83 3 7 Prop osed pseudo intermolecular gold catalyzed dehydrative substitution ......... 83 3 8 Rhenium catalyze allylic diol transposition. ................................ ........................ 84 3 9 Pd(0) catalyzed tandem hemiacetalization /Tsuji Trost process ......................... 85 3 10 Conversion of trichloroacetim idates 3 39 to 5,6 dihydro 1,3 oxazines 3 40 ....... 85 3 11 Catalyst optimization for the formation of 3 43 ................................ ................... 86

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12 3 12 Determination of an optimal aldehyde ................................ ................................ 88 3 13 Optimization of reaction conditions for the formation of 1,3 dioxane 3 46a ........ 89 3 14 Scope of 1,5 monoallylic diols ................................ ................................ ............ 91 3 15 Synthesis of diols E 3 45g , Z 3 45g , and Z 3 45h ................................ .............. 92 3 16 Tests employing branched aliphatic and nitrogen containing substrates ............ 93 3 17 Proposed relocation of the allylic moiety to afford 1 3 dioxanes 3 52 ................. 93 3 18 Synthesis o f diols E 3 51a and Z 3 51a ................................ .............................. 94 3 19 Use of chloral hydrate as the aldehyde equivalent ................................ ............. 95 3 20 Scope of transposed 1,5 monoallylic diols ................................ ......................... 96 3 21 Unsuccessful attempted deprotection of 1,3 dioxolane 3 57d ............................ 97 3 22 Deprotection of 1,3 dioxolane 3 57d using n BuLi ................................ .............. 98 3 23 Examples of 2,5 trans THFs in natural products ................................ ................. 98 3 24 Iodoetherification of diol 3 58 ................................ ................................ .............. 99 3 25 Conversion of diol 3 51g to THF 3 67 . ................................ ............................. 100

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13 LIST OF ABBREVIATIONS Ac Acetyl Anhyd Anhydrous aq Aqueous Ar Aromatic Atm Atmosphere BBN (9 BBN) 9 Borabicyclo[3.3.1]nonane (9 BBN) Bn Benzyl Boc t Butyloxycarbonyl BOM Benzyloxymethyl bp Boiling Point BQ Benzoquinone Bz Benzoyl Bu (nBu) n Butyl ca Circa (approximately) CAN Cerium (IV) Ammonium Nitrate Calcd Calculated cat. Catalytic Cbz Benzyloxycarbonyl conc. Concentrated Cond Conditions CSA Camphorsulfonic Acid Cy Cyclohexyl Heat d Days (length of reaction time)

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14 DBU 1,8 diazabicclo[5.4.0]undec 7 ene DCE 1,2 Dichloro ethane DDQ 2,3 Dichloro 5,6 Dicyano 1,4 Benzoquinone DHP 3,4 Dihydro 2H Pyran DIAD Diisopropyl Azodicarboxylate DIBAL H Diisobutylaluminium Hydride DMAP N,N 4 Dimethylamineopyridine DMF N,N Dimethylformamide DM S Dimethylsulfide DMSO Dimethylsulfoxide DMDO Dimethyldioxirane dr Diastereomeric Ratio E + Electrophile ee Enantiomeric Excess Et Ethyl e q. Equivalent EWG Electron Withdrawing Group g Gas GC Gas Chromatography h Hours (length of reaction time) Het Heterocycle HMDS 1,1,1,3,3,3 Hexamethyldisilazane HPLC High Pressure Liquid Chromatography HWE Horner Wadworth Emmons i Iso

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15 IPA Isopropyl Alcohol Ipc Isopinocamphenyl IR infrared spectroscopy L ligand LA Lewis Acid LAH Lithium Aluminim Hydride liq. Liquid m Meta m CPBA 3 Chloroperbenzoic Acid Me Methyl MOM Methyoxymethyl mp Melting Point MS Molecular Sieve n Normal (e.g. unbranched alkyl chain) NHPI N Hydroxy phthalimide NMR Nuclear Magnetic Reson ance NR No Reaction Nuc Nucleophile o Ortho Oxone Potassium Peroxymonosulfate p Para PCC Pyridinium Chlorochromate Ph Pheynyl Piv Pivaloyl PMB 4 Methoxybenzyl

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16 PPTS Pyridinium p Toluenesulfonate psi Pounds Per Square Inch P.T. Proton Transfer PTSA (or TsOH) p Toluenesulfonic Acid Py Pyridine rt Room Temperature rac Racemic Red Al Sodium Bis(2 methoxyethoxy) Aluminium Hydride R f Retention Factor s Solid Sec Secondary TBAF Tetra n Butylammonium Fl u oride TBS t Butyldimethlsilyl TBDPS t Butyldiphenylsilyl TEA Triethylamine TES Triethylsilyl TFA Trifluoroacetic Acid

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17 Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy DIASTEREOSELECTIVE SYNTHESIS OF SUBSTITUTED TETRAHYDROPYRANS AND 1,3 DIOXANES VIA GOLD (I) CATALYSIS By Justin Andrew Goodwin December 2015 Chair: Aaron Aponick Major: Chemistry Over the past two decades, gold catalyzed reacti ons have proven to be powerful synthetic tools, due to the ability of gold (I) complexes to act as carbophilic acids for the activation o systems towards nucleophilic addition to form C C, C O, or C N bonds , which is then followed by protodeauration to give olefin addition products . This dissertation details research efforts aim ed at developing the activation of alkynes and alkenes by cationic gold complexes to wards addition/elimination pathways involving heteroatom nucleophiles bond relocated . Building on this concept, a novel tandem gold catalyzed cyclization epoxidation reduction sequence has been developed. This seq uence relies on an initial gold (I) catalyzed dehydrative cyclization of p roparg ylic ethers to form a unique diene intermediate . Treatment of this diene intermediate with dimethyldioxirane furnishes an epoxide. Finally, Lewis acid catalyzed epoxide opening and reduction of the resultant oxocarbenium generate s 3 hydroxy substituted tetrahydropyrans. T his novel process

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18 demonstrates promise towards application s in the total synthesis of natural products, in particular, ladder shaped polyether compounds, an important class of marine natural products. activation of allylic alcohols. Studies on the d iastereoselective synthesis of p rotected 1,3 d iols by catalytic diol r elocation are described here. A complementary diastereoselective gold (I) or bismuth (III) catalyzed tandem hemiacetalization/dehydrative cyclization of allylic diols was developed providing access to substituted dioxolanes and dioxanes. This methodology provides efficient access to protected syn 1,3 diols. Deprotection and further elaboration of these protected synthons allowed access to 2,5 trans tetrahydrofuran motifs that are found in a wide range of natural products and biologically relevant compounds.

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19 CHAPTER 1 REGIOSELECTIVITY IN THE GOLD CATALYZED HYDRATION AND HYDROALKOXYLATION OF ALKYNES 1 1.1 Introduction The addition of oxygen nucleophiles to carbon carbon triple bonds is a classic research area that has generated many highly useful transformations for organic synthesis. These reactions can be catalyzed by a variety of metal complexes including mercury, 1 palladium, 2 ruthenium, 3 rhodium, 4 platinum, 5 and other metals with varying levels of success via a generalized mechanism ( Scheme 1 1) . 6 In addition to catalysts based on these metals, the gold catalyzed hydration and hydroalkoxylation of alkynes is a well developed general class of reactions that has been brought to the forefront of organic synthesis over the past 15 years. 7 A variet y of Au I and Au III catalyst systems have been shown to effect these transformations with such high efficiency that they might now be considered the standard for alkyne hydration and hydroalkoxylation. 8 Scheme 1 1 General metal catalyzed addition to C C t riple bonds The utility of this class of reactions has been demonstrated by a multitude of examples in natural product total syntheses. 9 The high atom economy coupled with the ability for rapid generation of structural complexity and high functional group tolerance has established Au catalyzed alkyne addition as an invaluable synthetic tool. For electivity in the Au catalyzed h ydration and hydroalkoxylation of Chem. Commun., 2015 , 51 , 8730 8741 Reproduced by permission of The Royal Society of Chemistry

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20 example, a recent report from F ü rstner and coworkers demonstrated the power of these transformations in their formal synthesis of ( ) polycavernoside A. 10 The Au I catalyzed hydroalkoxylation of alkyne 1 5 afforded the advanced intermediate 1 6 that could be further elaborated to the des ired natural product (Scheme 1 2 ) . 11 Scheme 1 2 Gold catalyzed hydroalkoxylation in the formal synthesis of ( ) polycavernoside A Although this research platform has been greatly advanced in recent times, there is significant room for improvement, particularly in the area of the regioselective hydration and hydroalkoxylation of internal alkynes. Our interest in this chemistry stem s from our own attempts to develop a tandem hydroalkoxylation / Claisen rearrangement sequence that proved to be extremely challenging ( vide infra) . This article is not intended to be a comprehensive review of gold catalyzed alkyne hydration and hydroalko xylation, but aims to use select recent examples to outline the inherent challenge of this issue and to highlight some of the unique strategies employed to address this problem.

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21 1.2 Hydration of Alkynes 1. 2.1 General Introduction and Current State Of The A rt Although t he g old catalyzed hydration of alkynes was first reported over 100 years ago, 12 further exploration of this significant finding was not undertaken until 1976 when Thomas and coworkers reported the conversion of phenylacetylene to acetophenone using tetrachloroauric acid. 13 Over the past decade and a half, much pro gress has been made in the gold catalyzed hydration of alkyn es. 6,14 This methodology provides rapid access to a variety of ketone products. It is well known that hydration of terminal alkynes 1 7 proceeds with a high level of regio selectivit y to furnish predominately the Markovnikov products 1 8 (Scheme 1 3); however, hydration of internal alkynes often results in multiple regioisomeric products and the problem is illustrated by the hy dration of 1 9 to form 1 10 and 1 11 . Scheme 1 3 Gold Catalyzed hydration of alkynes Currently, a recent report by Nolan and coworkers could be considered the benchmark in the hydration of alkynes with respect to reaction conditions (Scheme 1 4 , eq 1). Through the use of N heterocyclic carbene (NHC) ligands, they were able to develop a highly efficient catalyst system requiring only part per million loadings for addition to internal alkyl and aryl alkynes. 15 This mild catalytic system provides a signif icant advantage as it obviates the need for high temperatures or acid additives. In

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22 a subsequent report, they later demonstrated that the process could also be conducted without a silver salt (Scheme 1 4 , eq 2). This was achieved by activating a mononucle ar gold hydroxide complex with HBF 4 to generate a dinuclear gold hydroxide species that efficiently catalyzed the hydration of alkynes. 16 Scheme 1 4 Current state of the art conditions for gold catalyzed alkyne hydration While great strides have been m ade in terms of improving the catalytic efficiency of the title transformation, there is room for further development in this class of reactions. Specifically, internal alkyne hydration leaves much to be desired with respect to regioselectivity. 1. 2 .2 Hyd ration of Internal Alkynes As mentioned above, the hydration of terminal alkynes has been well established and proceeds with high levels of selectivity; however, in contrast, the hydration of internal alkynes often leads to the formation of regioisomeric p roducts. Several factors appear to influence which position of the alkyne is attacked including both the steric and electronic nature of the substituents. As a general observation, the selectivity for the intramolecular hydration of internal alkynes is lo w and is highly substrate dependent. This observation was made early on and, in their initial report, Utimoto and coworkers reported the hydration of internal alkynes 1 9 to generate a mixture of the desired ketone products 1 10 and 1 11 (Scheme 1 5 ). 17 1 Phenyl 1 butyne was treated with NaAuCl 4 in water and methanol to afford a mixture of ketones 1 1 0a and 1 1 1a in low

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23 yield with a slight preference for attack at the phenyl substituted alkyne carbon. It should be noted that this level of selectivity requi res only a very small difference in energy between the two product forming pathways. Interestingly, hydration of 2 nonyne gave a mixture of 1 10b and 1 11b in high yield with a similar level of selectivity, modestly favoring the formation of the methyl ket one. Scheme1 5 Early Au (III) catalyzed alkyne hydration further illustrate the persistence of regiochemical issues with internal alkyne hydration. Exploring different ligands and counterions, Leyva and Corma observed that both yie ld and selectivity could be increased to varying extents in the hydration of internal alkyne 12 (Scheme 1 6 ). 18 A series of cationic gold complexes bearing phosphine ligands were screened. In all examples, a mixture of ketone products 1 13 and 1 14 was ob served. Employing the catalytic Ph 3 PAuNTf 2 complex gave a 50:50 mixture of products in low yield. Switching to more highly donating phosphines such as SPhos, greatly improved the reaction yield but provided the products in a 60:40 ratio favoring the aryl ketone 1 13 . This small enhancement in selectivity may arise from either the increased steric bulk or enhanced electron donating ability of the phosphine ligand.

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24 Scheme 1 6 Phosphine ligand effects in gold (I) catalyzed alkyne hydration Interestingly, using a gold NHC catalyst system, Nolan and coworkers reported higher, albeit modest, selectivities for the hydration of internal alkynes 1 9 (Scheme 1 7 ). 15,19 Hydration of 1 phenyl 1 butyne gave a mixture of ketones 1 10a and 1 11a in a 19:81 ratio. It is noteworthy that this selectivity is opposite of that reported by Utimoto and coworkers. Hydration of 2 octyne afforded a mixture of 1 10c and 1 11c , favoring formation of the methyl ketone, while hydration of non 4 yn 1 ol exclusively gave product 1 1 0d in high yield. The exquisite selectivity observed with this substrate is presumably due to a directing effect of the alkyne substituent. Scheme 1 7 Employment of a NHC gold catalyst system to furnish regioselective alkyne hydration

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25 1.2.3 Substrate Directing Group S trategies Although a general solution to the regioselective hydration of internal alkynes remains an unsolved problem, several strategies employing either substrate or catalyst design have been implemented to address this challenge. One p articular strategy that has proven to be successful is the manipulation of the alkyne substituents to direct attack of the incoming nucleophile. By including a directing group as a substituent on the alkyne, selective hydration can be achieved generating a single regioisomer ( Scheme 1 8 ). Scheme 1 8 Directing group strategy for alkyne hydration As briefly described above, one particularly effective method used to induce selectivity is the inclusion of a tethered nucleophile as a substituent on the alkyne (Scheme 1 9 ). Initial selective intramolecular attack by the pendant nucleophile onto the alkyne 1 15 would lead to intermediate 1 17 and the selectivity of this initial attack 20 This intermediate could then be attac ked by water to liberate the directing group. Upon proto deauration, ketone 1 16 would be generated regioselectively. This strategy has been effectively used with a variety of nucleophilic directing groups and several examples are described below. Sch eme 1 9 Regioselective alkyne hydration directed by pendant nucleophile

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26 Hammond and coworkers demonstrated that esters 1 18 could be employed to furnish alkyne hydration products 1 19 with complete selectivity (Scheme 1 10 ). 21 The authors proposed that an initial attack of the ester group would generate intermediate 1 20 via a 5 endo dig cyclization, which is favored over the alternative 4 exo dig process. Hydrolysis of the resulting oxonium ion and proto deauration would the n form the desired keto esters 1 19 . Scheme 1 10 Use of a neighboring ester to direct alkyne hydration In a similar fashion, Oh and coworkers showed that aldehydes were suitable directing groups for the regioselective hydration of internal alkynes (Scheme 1 11 ). 22 Treatment of ortho alkynyl arylaldehydes 1 21 under cationic gold conditions in the presence o f water generated hydration products 1 22 selectively. An initial 6 endo dig cyclization by the aldehyde was proposed to direct the attack of water. When the aldehyde substituent on the aromatic ring was changed to a ketone, a complete reversal of select ivity was observed, suggesting that the reaction proceeded through an unexpected 5 exo dig pathway to produce the opposite regioisomer. Interestingly, when a substrate lacking a directing group was treated under the reaction conditions, the authors report that no reaction occurred.

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27 Scheme 1 11 Use of an aldehyde directing group for alkyne hydration 1.2.4 Catalyst Design S trategies While including directing groups in the substrate can provide highly regioselective examples, by definition the selectivity o bserved using this approach will always be directly related to the functional groups incorporated into each substrate. A more general approach may be achieved if a catalyst could be designed to provide regioselectivity based either on steric or electronic considerations. Many examples of different catalyst systems have been reported, but to the best of our knowledge, this has not yet been achieved. Differences in selectivity based on catalyst, albeit small, have been observed suggesting that this may be po ssible with further development. During their studies on bulkier NHC ligands, Cavell and coworkers screened a variety of sterically imposing six and seven membered ring ligands. 23 The steric demand imparted by these ligands was shown to be beneficial in th e hydration of substrates such as 4 octyne, which was previously shown to be ineffective under similar conditions employing 5 membered ring NHC ligands bearing mesityl substituents. 15 Hydration of 2 hexyne was accomplished in high yields but only moderate levels of selectivity were observed (Scheme 1 12 ). Interestingly, the bulkier DIPP ligand 1 27 gave slightly higher selectivity than the less bulky Mes ligand 1 26 , suggesting that this could

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28 eventually be an effective strategy for addressing regioselectivity issues. The development of selective new ligands could lead to vast improvements in this field. Scheme 1 12 Effect of bulky NHC ligands on alkyne hydration 1.3 Hydroalkoxylation of Alkynes 1.3.1 Introduction A similar class of reaction s, the metal catalyzed addition of alcohol nucleophiles to alkynes (hydroalkoxylation) has been extensively explored with a variety of metal catalysts, 24 and a gold catalyzed version of this reaction was first reported by Utimoto in 1991. 17 Over the past t wo decades, this gold catalyzed variant has been well explored. 25 Recently, several experimental studies have been performed to gain insight into the mechanism of this transformation 26 as well as to determine the effect of a silver salt 27 and its counterio n 28 when employed in gold catalyzed additions to alkynes. In general, addition to terminal alkynes occurs at the internal carbon to give the corresponding ketal 1 29 or enol ether 1 30 products ( Scheme 1 13) . In contrast, internal alkynes can potentially furnish the two possible enol ether products. Depending on which position of the alkyne is attacked by the nucleophile, 1 31a and 1 31b , in addition to the corresponding ketals 1 32a and 1 32b , could all be formed. There are several considerations for determining the selectivity of these reactions including sterics,

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29 electronics, and the identity of the nucleophile, but the effects of these factors can often be difficult to predict. Scheme 1 13 Gold catalyzed hyd roalkoxylation of alkynes 1.3 .2 Intramolecular Hydroalkoxyla t i on of Terminal Alkynes The intramolecular hydroal koxylation of terminal alkynes generally proceeds through the initial attack of a tethered alcohol nucleophile and a wide variety of gold catalyz ed intramolecular cyclizations have been developed in recent times. 29 These reactions have been shown to proceed with selectivity for attack at the internal position to generate a vinyl gold intermediate that is often used in an additional tandem process. Barluenga and coworkers demonstrated the selective attack in their tandem hydroalkoxylation/Prins type cyclization (Scheme 1 14 ). 30 Initial gold catalyzed exo addition of the hydroxyl group in alkynols 1 33 selectively furnished enol ether 1 35 via proto deauration of the organogold intermediate. A subsequent Prins type cyclization 31 involving the allyl group then afforded the desired products 1 34 in high yield.

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30 Scheme 1 14 Tandem Au(I) catalyzed hydroalkoxylation Prins type cyclization In similar fashion, Hashmi and co workers also demonstrated nucleophilic attack exclusively at the internal position. 32 Treatment of diyne diols 1 36 with the acyclic carbene complex I initiated a hydroalkoxylation sequence to form bis enol ethers via 5 exo dig cycl ization. These intermediates were trapped with an external nucleophile such as water to afford the bis ketal products 1 37 (Scheme 1 15 ). Scheme 1 15 Double intramolecular hydroalkoxylation of terminal alkynes Manzo and coworkers further demonstrated this selectivity pattern in their intramolecular hydroalkoxylation of 2 alkynyl substituted phenols 1 38 (Scheme 1 16 ). 33 Treatment with AuCl and potassium carbonate induced a 6 exo dig cyclization of the

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31 phenol onto the tethered alkyne to exclusively affo rd the corresponding enol ether products 1 39 . Scheme 1 16 Intramolecular hydroalkoxylation of 2 (prop 2 yn 1 ylamino)phenols 1.3.3 Intramolecular Hydroalkoxyla t i on of Internal Alkynes In contrast to their terminal alkyne counterparts, internal alkynes pose a more significant regiochemical problem for intramolecular hydroalkoxylations because attack at both positions of the alkyne is frequently observed unless the substrates are engineer ed such that the ring size formed or electronics of the alkyne favor the formation of one regiosisomer. When there is little electronic bias, the initial cyclization pres ence of an external nucleophile, hydroalkoxylation of homopropargyl alcohols 1 40 proceeds to give the five membered acetals 1 41 selectively (Scheme 1 17 ). 34 An initial 5 endo cyclization furnished a dihydrofuran intermediate, which could be further conve rted to the desired products by the Brønsted acid catalyst and external nucleophile.

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32 Scheme 1 17 Tandem cycloisomerization/hydroalkoxylation of homopropargylic alcohols Further highlighting the preference for formation of the favored ring size, Reddy and coworkers showed that 4 bromo 3 yn ols 1 42 were smoothly converted to the corresponding butyrolactone products 1 43 upon treatment with AuCl 3 (Scheme 1 18 ). 35 Selective attack at the bromine bearing terminal position of the alkyne exclusively afforded the five membered lactones. Scheme 1 18 Hydroalkoxylation of 4 bromo 3 yn 1 ols Tuning the electronic nature of the alkyne substituents can greatly influence the regioselectivity of the intramolecular attack of a pendant nucleophile onto an internal alky ne. Vazquez and colleagues demonstrated the gold catalyzed synthesis of five , six , and seven membered cyclic acetals 1 45 via an oxo Michael typ e reaction sequence (Scheme 1 19 ). 36 Treatment of the corresponding hydroxyalkyneoates 1 44 with AuCl 3 initiated the selective alkyne hydroalkoxylation and conversion to the corresponding acetal product in the presence of the external alcohol nucleophile. 7 -

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33 hydroxyheptynoates proceeded through a 6 exo cyclization whereas 6 hydroxyhexynoates followed a 5 e xo pathway. The electronic nature of the ester substituent favored the conjugate addition to the ester carbon, dictating the selectivity of the cyclization. Scheme1 19 Hydroalkoxylation of conjugated ynoates With less biased systems, controlling the re gioselectivity is much more problematic. The double hydroalkoxylation of internal alkynes, which is an example of this, is a useful transformation to rapidly generate complex structures from alkynes. A variety of metal catalyzed strategies to convert alky nes into spiroketals have been developed. 37 In terms of regioselectivity, the gold catalyzed addition of the two nucleophiles has been reported to produce mixtures of spiroketal products, as observed by several groups (Scheme 1 20 ). 38 Scheme1 20 Spiroketalization of alkynediols In their spiroketa l ization studies, De B ra bander and coworkers showed that the identity of the catalyst and having the alcohols protected plays a significant role in the product distribution. 39 The [6.6] spiroketal motif 1 47 is more commonly found in natural products and is often the desired product of this reaction; however, treatment of the diol 1 46a favors formation of the [7.5] spiroketal 1 48 (Scheme 1 21 ). Monoprotected diols

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34 were explored and it was found that wh en R 1 =TBS and R 2 =H ( 1 46b ) , the [7.5] spiroketal 1 48 is still the major product. In contrast, when the protecting group is placed on the other alcohol, R 2 =THP ( 1 46c e) , the [6,6] spiroketal 1 47 was then favored over spiroketal 1 48. Scheme 1 21 Subs tituent effect on alkynediol spiroketalization Aponick and coworkers recently reported a strategy for controlling the regiochemistry of spirok etalization of alkyne triols emp loying an acetonide protecting group. 40 Previously, the group reported that the gold catalyzed cyclization of triol 1 59 gave a mixture of the three regioisomeric spiroketal products 1 60 1 62 in a combined 80% yield (Scheme 1 22 ). 41 By masking one of the alcohol nucleophiles as an acetonide ( 1 63 ), the regioselectivity of the reacti on could be completely controlled and spiroketal 1 60 was formed exclusively in comparable yield. As illustrated, this approach offers an alternative strategy for spiroketalization when regiochemistry problems arise. In other systems, such as arene contai ning spiroketals, additional problems may arise. During their studies on the synthesis of the spiroketal core of the rubromycin class of natural products, Li and coworkers screened a variety of substrates in a gold catalyzed double intramolecular hydroalkoxylation o f substituted alkynes (Scheme 1 23 ). 42

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35 Scheme 1 22 Regiochemical control of alkyne hydroalkoxylation using an acetonide; JohnPhos= [P( t Bu) 2 (o biphenyl)] When bisphenol 1 49 was treated under cationic gold conditions only spiroketal 1 50 was observed along with the aromatized product, benzofuran 1 51 . The authors also screened a series of benzyl alcohol nucleophiles. Diols 1 52 and 1 57 cyclized smoothly to give the corresponding spiroketal products 1 53 and 1 58 as single regioisom ers. Conversely, diol 1 54 cyclized with poor selectivity and afforded a mixture of regioisomeric spiroketals 1 55 and 1 56 in a 60:40 ratio. Recently, Hashmi and coworkers reported the use of gold (I) catalysts bearing phosphite ligands with sterically imposing substituents for the intramolecular hydroalkoxylation of alkynediols. 43 Spiroketalization of diol 1 54 afford ed a mixture of spiroketals 1 55 and 1 56 with the formation of 1 55 being favored in a 67:33 ratio (Scheme 1 24 ). This preference is consistent with the previous findings of Li and coworkers, but the level of selectivity is somewhat improved.

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36 Scheme 1 23 Spiroketalization studies on the rubromycin core Scheme 1 24 Sterically imposing ligand effects in alkyn ediol spiroketalization Although the problem of controlling the regiochemistry of intramolecular alkyne hydroalkoxylation has yet to be completely resolved, a significant amount of progress has been made in the development of strategies to address this iss ue. Further progress

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37 in this area could lead to more widespread use of this transformation in a variety of settings. 1.3 .4 Intermolecular Hydroalkoxyla t i on of Terminal Alkynes T he gold catalyzed intermolecular hydroalkoxylation of alkynes is extremely challenging from a regioselectivity standpoint; however, as expected, terminal alkynes have been shown to exhibit very high selectivities. In their seminal report, Utimoto and coworkers demonstrated that terminal alkynes 7 r eacted in the presence of NaAuCl 4 in refluxing methanol to afford the corresponding dimethyl acetals 64, (Scheme 1 25 ). 17 Predictably, only a single regioisomer resulting from addition at the internal carbon was observed. Scheme 1 25 Gold (III) catalyzed hydroalko xylation In a subsequent report, Teles and coworkers further demonstrated the high selectivity of the hydroalkoxylation of terminal alkynes. 44 Treatment of terminal alkynes 1 7 with a gold (I) catalyst in the presence of an acid co catalyst and an alcohol nucleophile provided the corresponding dimethyl acetals 1 65 with exclusive selectivity for addition at the more substituted position (Scheme 1 26 ). Acetal formation was observed in nearly all cases. Interestingly, reaction of phenylacetylene with bulkier alcohol nucleophiles such as isopropanol resulted in a mixture of the acetal product 1 65 and enol ether product 1 66 .

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38 Scheme 1 26 . Gold (I) catalyzed hydroalkoxylation Corma and co workers demonstrated that diol nucleophiles also selectively added to t he internal carbon of terminal alkynes. 45 Treatment of the alkynes 1 7 under cationic gold (I) conditions in the presence of a diol produced the desired cyclic ketals 1 67 (Scheme 1 27 ). Nucleophilic attack of unsubstituted diols occurred exclusively at t he more substituted position of the alkyne and the corresponding 5 , 6 , 7 , and 8 membered ketals 1 67a d could be generated. When diols bearing an additional substituent were employed with phenylac e tylene, the desired ketals 1 67g h were isolated as the major product but a small amount of the cyclic acetal ( 1 68h h ) was also observed. Scheme 1 27 Gold catalyzed addition of diols to alkynes Carboxylic acids can also be used as nucleophiles and this was recently demonstrated by th e Kim lab. 46 Treatment of terminal alkynes 1 7 with a gold (I) salt and silver activator catalyzed the selective addition of carboxylic acids 1 69 to give the corresponding enol esters 1 70 (Scheme 1 28 ). For alkyl substituted terminal alkynes only the Ma rkovnikov addition products 1 70a/b were observed. Reactions employing

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39 phenylacetylene gave a mixture of products with a significant amount of the anti Markovnikov product 1 71 seen. Scheme 1 28 Gold catalyzed hydroacylation of terminal alkynes While th e examples mentioned above involved studies on different types of nucleophiles, the catalyst may also affect product distribution and aspects such as the ratio of acetal to enol could also be influenced. 47 To this end, a series of gold catalysts were scree ned for the addition of n BuOH to phenyl acetylene 1 72 (Scheme1 29 ). In these examples, the predicted product of addition to the internal carbon was observed; however, the results demonstrate that the electronic nature of the phosphine ligand greatly affe cts the product distribution. Although both electronic and steric factors may affect the selectivity, when catalysts containing phosphine ligands with all aryl substituents were employed, the enol ether product 1 73 was heavily favored (entries 1,2). Conve rsely, complexes containing an electron donating alkyl phosphines favored the formation of the ketal product 1 74 (entries 3 5).

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40 Scheme 1 29 Effect of the nature of phosphine ligands on regioselectivity of mono hydroalkoxylation; DavePhos=2 Dicyclohexylphosphino (N,N dimethylamino)biphenyl Although addition to terminal alkynes has been shown to be highly regioselective for nucleophilic attack at the internal alkyne position, a gold catalyzed variant f avoring addition to the terminal carbon has yet to be reported. Further development in this area would provide a valuable addition to this class of reactions. 1.3 .5 Intermolecular Hydroalkoxyla t i on of Internal Alkynes In contrast to the selectivity observ ed for terminal alkynes, internal alkynes can generally be attack ed by the nucleophile at both positions . The substituents on the alkyne as well as the identity of the nucleophile play a large role in the regio selectivity . In the earliest example of regio selective addition to an internal alkyne, Teles and coworkers reported the selective addition of methanol to alkyne 1 75 (Scheme 1 30 ). 44 Limited details are described, but the authors state that the nucleophile added exclusively to the methyl substituted position to give dimethyl ketal 1 76 as the major product with only a small amount of enol ether 1 77 detected. The authors suggest that this selectivity is derived from the steric nature of the substituents with attack being favored at the least sterica lly hindered position.

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41 Scheme 1 30 Steric effect on regioselective hydroalkoxylation Corma and coworkers also demonstrated that bisaddition to internal alkynes to form a cyclic ketal was possible, but led to a mixture of products (Scheme 1 31 ). 45,47 Addition of diols to alkynes 1 9 afforded the corresponding cyclic ketal products 1 78 and 1 79 . When R 1 = alkyl, R 2 = aryl, addition was selective for the alkyl substituted carbon of the alkyne in all reported examples. The identity of the diol substituent had a moderate effect on the regioselectivity of the reaction. Employing ethylene glycol afforded the correspondin g cyclic ketals 1 78a and 1 78c with a slight enhancement in regioselectivity when compared to substituted glycols. Scheme 1 31 Regioselective alkyne hydroalkoxylation with diols During their studies on the addition of carboxylic acids to internal alkyne s, Kim and coworkers reported excellent regioselectivities with aryl alkynes. 46 Addition of carboxylic acids 1 80 to internal alkynes 1 9 resulted in vinyl acetate products 1 81 in high yields a s single regioisomers (Scheme 1 32 ). Addition to the carbon of an ynoate

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42 occurred selectively to afford 1 81a . Interestingly, addition to 1 phenylpropyne also afforded the vinyl acetate 1 81b as a single product. Scheme 1 32 Gold catalyzed hydroacylation of internal alkynes Sahoo and coworkers reported the gold (III) catalyzed intermolecular addition of substituted phenol nucleo philes 1 82 to unsymmetrical internal alkynes 1 9 to generate vinyl ethers 1 83 and 1 84 (Schem e 1 33 ). The autho rs varied the electronic nature of both the alkyne substituents as well as the substituents on the incoming phenol nucleophile and the effect of these factors on the regioselectivity of the transformation can be observed. When an electron rich unsymmetrical alkyne was employed using 4 n itrophenol as the nucleophile a slight preference for attack at the phenyl substituted position to give enol ether 1 84a was observed. Phenyl alkyl acetylenes reacted with similar regioselectivity to give enol ethers 1 84b and 1 84c as the major products. When a meta substituted phenol was employed with an unsymmetrical electron rich alkyne, the selectivity was reversed to give enol ether 1 83d in tenfold excess. Addition of para phenylphenol to an electron deficient alkyne showed modest selectivity for formation of enol ether 1 84e , albeit in low yield.

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43 Scheme 1 33 Au(III) catalyzed intermolecular hydroalkoxylation of alkynes Catalyst modification also imparts changes to the level of regioselectivity in this reaction. In a recent report , Nolan and coworkers demonstrated the use of cooperative gold catalysis for the hydropheno xylation of alkynes (Scheme 1 34 ). 49 Reaction of

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44 unsymmetrical internal alkynes 1 9 with a dinuclear gold hydroxide species and phenol nucleophiles 1 82 afforded the correspondi ng vinyl ethers 1 83 and 1 84 . The assorted substituents on both the alkyne as well as the phenol nucleophile were screened to assess the regioselectivity of the transformation. Alkynes bearing a p methoxyaryl substituent demonstrated moderate regiosele ctivities with attack at the electron rich aromatic substituted position to give vinyl ethers 1 83f and 1 83h as the major products. Treatment of 1 phenylpropyne gave the opposite regioselectivity observed by Sahoo and coworkers to generate enol ethers 1 83i and 1 83b , when phenol and 4 nitrophenol were employed as nucleophiles. The dependence of regioselectivity on the nucleophile employed (85:15 versus 74:26) indicates that the electronic nature of both the alkyne and the nucleophile plays a role in d etermining the regioselectivity of the transformation. The authors also demonstrated that the regioselectivity could be controlled by the inclusion of directing group substituents to give single regioisomeric products 1 83j and 1 83k , albeit in reduced yi elds. Enol ethers are valuable synthetic intermediates and they are easily produced in these reactions. Aponick and coworkers reported a tandem hydroalkoxylation/Claisen rearrangement in which the first step of the transformation was the Au(I) catalyzed hy droalkoxylation of internal alkynes. 51 Treatment of alkynes 1 9 under cationic Au(I) conditions in the presence of an allylic alcohol generated the desired ketone products 1 86 (Scheme 1 35 ).

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45 Scheme 1 34 Au(I) catalyzed intermolecular hydroalkoxylation A variety of unsymmetrical internal alkynes with varying alkyne substituents were screened. Interestingly, an electron rich alkyl aryl alkyne afforded the aryl ketone as

PAGE 46

46 the major product but, when electron deficient alkynes were employed, the selectivit y was reversed to give the aryl ketone (e.g. 1 86a vs. 1 86b ) . When an ether or acetate substituent was incorporated on electron rich alkynes, the selectivity was improved to give ketones 1 86d and 1 86e as the major products in a 90:10 and 89:11 ratio respectively. When ester or phthalimide substituents were included, the regioselectivity was vastly improved and the corresponding ketones 1 86f and 1 86g were produced as single regioisomers. This dramatic improvement in regioselectivity could be attrib uted to an inductive effect and or neighboring group participation. When the authors subjected 1 phenyl 1 propyne to their conditions, the opposite regioselectivity from Sahoo and coworkers 48 (Scheme 1 32) was observed with attack at the alkyl substituted position to generate ketone 1 86h favored in an 80:20 ratio. Nolan and coworkers later reported a solvent and silver free variant of this transformation. 51 The authors observed similar levels of regioselectivity for addition to unsymmetrical alkynes. Scheme 1 35 Tandem hydroalkoxylation Claisen rearrangement

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47 1.4 Conclusions Over the past decade and a half, gold catalyzed hydration and hydroalkoxylation reactions of alkynes have been extensively explored and vast improvements in these research platforms have been made. Overall, these transformations have been demonstrated to be reliable synthetic tools for the rapid and atom economical generation of valuable synthetic building blocks or complex natural products. Various highly efficient cataly tic systems have been developed to effect these transformations, but in general these classes of reactions are still plagued by selectivity issues. The regioselectivity has been shown to vary depending on the catalyst system, nature of the substituents on the alkyne, and identity of the inc oming nucleophile (Scheme 1 36 ). Scheme 1 36 Overview of selectivity Much progress has been made in developing measures to control the regioselectivity of these reactions and inventive solutions have been devised for many substrate classes. Terminal alkynes have been widely shown to give almost exclusively the Markovnikov products. Regioselectivity issues still plague the hydration of alkyl alkyl substituted alkynes in the absence of directing groups. The hydroalkoxyla tion of alkyl alkyl substituted alkynes can offer moderate levels of selectivity. Regioselectivity in

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48 intramolecular reactions can governed, although not always entirely, by the size of the ring being formed or the electronic nature of the substituents. In termolecular variants employing alkyl alkyl substituted alkynes have not been widely reported, but limited examples suggest that differentiation based on the steric nature of the substituents could be possible. When the substituents are relatively dissimil ar, such as the case of alkyl aryl substituted alkynes, product distribution for alkyne hydrat ion can be difficult to control, but moderate levels of selectivity can be observed under carefully developed conditions . Hydroalkoxylation reactions offer simila r challenges with rega rds to regioselective addition. The product distribution for these reactions seems to be very substrate dependent. Intermolecular hydroalkoxylation of aryl aryl substituted alkynes offers modest control of regioselectivity. The electr onic nature of the substituents plays a key role in product distribution with attack at the more electron deficient alkyne position usually favored. Directing group strategies have been developed for to control hydration of both alkyl and aryl substituted alkynes, but there is still room for development of directing groups for hydroalkoxylation reactions. While it may be difficult to engineer a catalytic system that can offer high levels of selectivity when the alkyne substituents are very similar, there is still ample room for improvement and ideally a general catalytic system to control regioselectivity for alkynes with differing substituents could be realized. Advances in this area are likely to be made in the future as innovative new ligand systems are developed.

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49 CHAPTER 2 TANDEM GOLD (I) CATALYZED CYCLIZATION EPOXIDATION REDUCTION SEQUENCE TOWARDS MARINE POLYETHER NATURAL PRODUCTS 2.1 Introduction 2.1.1 Metal c atalyzed G eneration of 2 oxodienes During the previous decade, research efforts in the a rea of homogenous gold catalysis have dramatically increased. 7 Gold catalyzed reactions offer several advantages when compared to other transition metal catalyzed transformations . In general, gold catalyzed reactions offer relatively mild reaction conditions, high functional group tolerance, utilize air and moisture stable catalysts, and exhibit high atom acidity, the ability of both Au (I) and Au (III) compl exes to bonds toward nucleophilic attack has been widely reported. 8,52,53 One interesting mode of reactivity is the formation of C C, C N, and C O bonds by the addition of X H (X= O, N, C) bonds across a carbon bond of an alkyne (Scheme 2 1). After complexatio n of the gold catalyst with the alkyne 2 1 , the nucleophile attack occurs via anti addition of the gold catalyst and incoming nucleophile to generate intermediate 2 2 . Upon protodeauaration, the addition product 2 3 is formed . Scheme 2 1 Gold catalyzed a ddition of a nucleophile across an alkyne More recently, propargyl alcohols and their derivatives have been shown to be viable substrates for a multitude of gold catalyzed transformations. 29 In 2009, Aponick and coworkers reported the gold catalyzed spirok etalization of monopropargylic triols. 41

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50 Treatment of monopropargylic triols 2 4 with a gold (I) catalyst and a halide scavenger, triggered a dehydrative cyclization to afford monounsaturated spiroketals 2 5 . Scheme 2 2 Gold catalyzed spiroketalization of monopropargylic triols. The methodology was demonstrated to be efficient, high yielding, and tolerant of many functional groups. When probing possible mechanistic pathways, a control experiment was performed where each of the primary alcohols were selec tively protected (Scheme 2 3). Interestingly, exposure of monoprotected triol 2 6 to the standard reaction conditions yielded diene 2 7 , as well as the, Meyer Schuster rearrangement product 2 8 , which is likely derived from 2 7 Scheme 2 3 Control experim ent leading to the formation of diene 2 7 The unique structure 2 7 proved to be appealing, due to the potential for novel synthetic transformations taking advantage of the electron rich diene. 1,3 d ienes have been shown to undergo a variety of organic reac tions . 54,55 Conversely, electron rich dienes similar to 2 7 have been less widely reported in the literature . 56 Several synthetic strategies have been developed to generate dienes 2 10 . For example, t hese include

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51 both Wittig type olefinations 57 as well as cross coupling reactions 58 (Scheme 2 4) . Although these strategies have been well explored they require preparation of preformed activated substrates. Scheme 2 4 Various strat egies for the preparation of 2 oxodienes Following the initial report by the Aponick g roup, De Brabander and coworkers reported a platinum catalyzed synthesis of 2 oxodienes 59 (Scheme 2 5). Utilizing a 2 12 were converted into the corresponding dienes 2 13 in good yiel ds and with high levels of E / Z selectivity. Although they demonstrate d the formation of 2 oxo dienes under meta catalyzed conditions, no further elaboration of the diene intermediates was performed.

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52 Sch eme 2 catalyzed diene formation In 2015 , the Aponick research group further established the utility of these type s of transformations when they reported a tandem gold catalyzed dehydrative cyclization / Diels Alder reaction sequence taking advantage of the in situ generated dienes 60 (Schem e 2 6 ). Starting with monopropargylic alcohols 2 1 4 , dienes 2 10 coul d be generated via a gold cataly zed dehydrative cyclization and upon heating w ith alkenes 2 1 5 the corresponding Diels Alder adducts 2 1 6 were furnished in high yields and levels of diaster e oselectivity. Scheme 2 6 Tandem gold catalyzed dehydrative cyclization / Diels Alder process The group further demonstrated the synthetic utility of this transformation through the application of th e process to the synthesis of Boc pr otected A rc y ri aflavin A 2 20 (Scheme 2 6). Diene 2 18 was efficiently generated from propargyl alcohol 2 1 7 . This intermediate was then reacted with maleimide to generate oxidized Diels Alder adduct 2 19 , which was further elaborated to afford Boc protected Arcyriaflavin A 2 19 .

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53 Scheme 2 7 Application of a t andem gold catalyzed dehydrative cyclization / Diels Alder process to the synthesis of Boc protected Arcyriaflavin A 2.1. 2 Synthetic Strategies Targeting Epoxide Opening Cascades T owards Marine P olyethers Wanting to take advantage of the functionality of diene intermediate 2 10 , we envisioned that a myriad of other possible reaction pathways might be possible. Looking at the structure of 2 10 , we proposed that it would be possible to exploit the difference in the electronic nature of the two alkene moieties present. Dienes 2 10 possess an electron rich enol moiety that should allow for selective functionalization (Scheme 2 8). Employing one of two possible pathways would provide tetrahydropyrans 2 21 starting from monopropargylic diols 2 14 . (Scheme 2 8) The first possible pathway would involve a hydroboration oxidation sequence that would result in a trans relationship between the C 2 alkene and C 3 hydroxyl group . Alternatively, a sequence entailing an initial oxidation followed by selective reduction could also be employed to arrive at same product.

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54 Scheme 2 8 Proposed conversio n of i ntermediate s 2 10 to tetrahydropyrans 2 13 Looking at the trans relationship of the substituents at the C 2 and C 3 positions and the resulting hydroxyl group at the C 3 position of the predicted tetrahydropyran products 2 21 , it became apparent to u s that these compounds contained the structural elements of an important class of marine natural products , the ladder shaped polyethers . Marine ladder polyethers are a large, diverse family of compounds with a wide range of bioactivities ranging from potential therapeutic properties to extreme toxicity. 61 They are arguably best known for their involvement in the phenomenon several members of this family are produced by marine dinoflagel lates which cause this harmful algal bloom. 62 Compounds in this family display several key stru ctural characteristics (Scheme 2 9 ). In general they are composed of fused 5 to 9 membered cyclic ethers in which a common repeating C C O moti f, as shown in hem ibrevetoxin B 2 22 , is present. The ring junctures occur in a trans syn trans geometry, exemplified in yesso toxin 2 23 .

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55 Scheme 2 9 Common structural elements of ladder polyethers. Marine ladder polyethers demonstrate deadly toxicity to a wide range of ma rine life and can eve n cause poisoning in humans who consume animals that have ingested the toxins . 63 Many members of this family have been show to have a binding affinity for cellular membrane proteins that serve as ion channels . 64 Although highly toxic, these compounds are of great interest to t he synthetic community because several members also exhibit a variety of advantageous anti fungal and anti tumor activities . 61 As a result, several strategies have been developed to facilitate the synthesis of the se compounds. Following the early discovery and structural elucidation of mem ber of this family, brevetoxin B 65 2 24 , both Nakanishi and coworkers 66 and Shimizu and coworkers 67 separately proposed a biosynthetic pathway to explain the origins of this compound . This hypothesis proposed that brevetoxin B could be formed through an epoxide opening casc ade sequence of a polyepoxide s u c h as 2 2 5 (Scheme 2 10) that would explain the characteristic repeating C C O motif arising from the two carbons and one ox ygen atom of an epoxide . This theory also accounted for the trans syn trans

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56 geometr y of the rin g junctures as long as each epo x i de opening occurred with inversion and the all of the alkenes in precursor polyene 2 2 6 possessed E geometry. Scheme 2 10 Bios ynthetic hypothesis for brevetoxin B proposed by Nakanishi and Shimizu Due to the elegant nature of the proposed biosynthetic pathway, many research efforts have att e mpted to mimic this strategy in the lab. An epoxide opening cascade sequence would allow f or the rapid generation of the structurally complex ladder poly e thers from relatively simple organic substrates. Taking a look at the epoxide opening cascade sequence ( Scheme 2 10 ) , two possible cyclization pathways are apparent and each epoxide opening event would need to occur via a n intramolecular 6 -

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57 endo tet cyclization of the pendant nucleophile onto the epoxide as o pposed to the alternative 5 exo tet pathway . The results of intramolecular cyclizations can often be predicted by examining the empirical guidelines reported by Jack Baldwin in 1976. 20 This set of principals, s r , can be used to predict the relative rates of ring closure pro cesses in organic chemistry. Al t h ough this set of rules was not designed for epoxide openings, this particular class of reaction s adheres closely to the guidelines. In general, for simple intramolecular epoxide openings, these processes favor the formation of the smaller ring over the larger ring . Looking at the two possible cyclization pathways for simple epoxide 2 29 , the exo product 2 27 arising from transition state 2 28 is favored over the endo product 2 31 arising from transition state 2 30 (Scheme 2 11) This selectivity is opposite that required for the formation of the desired ladder polyethe r architectures. Scheme 2 11 Two possible cyclization pathways for epoxide 2 29 Modern synthetic chemists have not let this deter their pursuit of an epoxide opening cascade and many creative strategies have been developed to circumvent this undesired regioselectivity . 68 Initially research efforts were focused on developing a strategy that would incorporate a directing group into the substrate. During their early stud ies on the synthesis of brevetoxin B, the Nicolaou research group reported the inclusion of an alkene substituent on the epoxide to control the regioselectivity of the incoming nucleophilic attack in the acid catalyzed opening of epoxide 2 32 to afford 2 3 3 (S chem e 2 12) . 69

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58 Scheme 2 roups in intramolecular epoxide opening reactions Inclusion of this directing substituent in epoxide 2 33 provided electronic stabilization develo ping positive charge in transition state 2 34 leading to the desired endo product 2 33 (Scheme 2 13). In transition state 2 35 leading to undesired exo product 2 36 , this added stabilization of the transition state is not available and therefore this pathw ay was disfavored. The group used this strategy to iteratively synthesize the F and G rings of brevetoxin. 70 Scheme 2 13 Rationale for the directing effects of alkenyl epoxides In the years since the pioneering report from Nicolaou and coworkers, several other directing group strategies have been developed. Groups such as methoxy methyl substituted epoxides 2 37 , 71 epoxy halides 2 45 , 72 and trialkysusbtituted epoxides 2 -

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59 52 , 73 have been employed to control the regioselectivity of intramolecular epox ide opening reactions in an attempt to enact the desir ed cascade sequence (Scheme 2 14 ). Murai and cowork er s demonstrated that the inclusion of a methoxy methyl substituent in epoxides 2 37 favored the formation of THP 2 38 when treated with La(OTf) 3 (Sche me 2 14 eq . 1) . The authors suggest two possible explanations for the observed regioselectivity. The methoxy methyl substituent could have a small destabilizing effect for the developing positive charge in the 5 exo pathway. It is also possible that a chel ating effect is present where the lanthanum chelates both the epoxide oxygen as well as the methoxy group to favor the 6 endo pathway. The group attempted an epoxide opening cascade on poly epoxide 2 40 under their standard conditions and observed the desir ed 2 41 in moderate yield but also observed s everal undesired side products. Another drawback to this strategy is that the directing group is not native to the ladder polyether framework. The group later developed a strategy employing epoxy halides 2 45 that would undergo cyclization when activate d by a silver salt to form THF 2 46 as the major product (Scheme 2 14 eqn. 2) . In 2003 , McDonald and coworkers employed dimethyl substituted epoxides 2 52 in Lewis acid catalyzed cascade reaction to form bicycle 2 53 (Scheme 2 14 eqn. 3). The group studied the effect of varying the substituent on the nucleophile and found that amides gave the best selectivities for the desired product. The methyl substituent provide d stabilization of the developing positive charg e in the transition but this motif is not found in the natural polyether framework.

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60 Scheme 2 14 Examples of other strategies employed to control regioselectivity in intramolecular ep oxide openings. In a similar fashion, Jamison and coworkers developed a n eleg ant directing group strategy to lead to the 6 endo opening of epoxides . The group s early work took advantage of the transition state stabilization provided by a trimethylsilyl substituent

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61 during the Lewis acid catalyzed epoxide opening in epoxide 2 56 to form the desired THP 2 57 (Scheme 2 15) . 74 Scheme 2 openings. Although the trimethylsilyl substituent is not natural to the ladder polyethers, the group later demonst rated that the directing group could be easily removed to reveal the required carbon framework for this family of compounds. Treatment of epoxysilane 2 58 w ith base and a fluoride source e ffected the desired epoxide opening sequence with subsequent removal of the silyl directing group (Scheme 2 16). 75 The authors suggest ed that the trialkylsilyl group effects the desired initial cyclization and then is transferred to the resulting hydroxyl substituent before being removed by hydroxyl assisted protiodesilyla tion. Using this strategy , th e authors were able to synthesize THP tetrad 2 61 from poly epoxide 2 60 in a single cascade sequence Scheme 2 epoxide opening cascades In a subsequent repo rt, Jamison and coworkers reported the discovery of a directing group free strategy for epoxide opening cascades. Using templated

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62 polyepoxides 2 62 and 2 64 in which one THP moiety is already formed , the authors demonstrated that , in an aqueous environment, the desired cascade sequence could be achieved in good yields to form triad 2 63 and tetrad 2 65 respectively (Scheme 2 17). 76 These results provided evidence to support the proposed biosynthetic pa thway for the ladder polyether via an epoxide opening cascade occurring in a natural aqueous environment. Scheme 2 17 Epoxide opening cascade of template polyepoxides in H 2 O While many well designed strategies for intramolecular epoxide opening to form the THP motifs found in ladder p olyethers have been developed , the necessity for directing groups not present in the natural products as well as a lack of developed methods for the con s truction of the larger rings inherent in this class of molecules motivated us to envision an alternativ e strategy. Although the elegant approach by Jamison and coworkers obviates the need for directing groups, the method requires lengthy substrate syntheses as well as long reaction of up to 28 days at ambient temperatures. These lengthy reaction times could be shortened with an increase in temperature but still required several days. Based upon the characteristic repe ating structural features of the ladder polyethers , we proposed that the synthesis of these THP motifs could be achieved in an iterative fashio n employing a tandem gold -

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63 catalyzed reaction of monopropargylic diols 2 14 (Scheme 2 18 .) The THP products 2 21 from the first cyclization sequence could be elaborated, in a few steps, to install another propargylic moiety to afford alkynes 2 66 . These alk ynes would then be set up for another gold catalyzed cyclization sequence under the same conditions to yield structurally complex polycyclic THP diad 2 67 in relatively few steps. This process could then be repeated furt her append additional THP moietie s until the desired polyether is achieved. Scheme 2 18 Proposed it erative sequence to form complex polyether from simple starting materials 2.2 Results and Discussion 2.2.1 Preliminary S tudies Initial attempts to rapidly generate tetrahydropyrans 2 21 in a single reaction sequence focused on the proposed gold catalyzed cyclization hydroboration oxidation approach. Simple Test substrates were synthesized in three steps from commercially available alkynol 2 67 (Sc heme 2 20 ). After protection of the prima ry alcohol 2 6 7 as the silyl ether, protected alkyne 2 68 was converted to propargyl alcohol 2 69 and 2 70 via base catalyzed addition to an aldehyde and subsequent deprotection of the silyl ether .

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64 Scheme 2 19 Synthesis of monoropagylic diols 2 69 and 2 70 From previous studies in our laboratory 60 , the cationic gold complex generated by mixing pre catalyst 2 71 with silver triflate in THF containing 4Ã… molecular sieves was shown to be optimal for the generation of the desired diene intermediate. T reatm ent of 2 69 under these optimized conditions a fforded the diene intermediate as seen by TLC analysis. Unfortunately , addition of a hydroboration reagent such as 9 BBN or followed by the addition of an oxidant did not yield the desired THP produc t 2 72 and only decomposition was observed (Scheme 2 20 ). Scheme 2 20 Initial attempts of a tandem gold catalyzed cyclization hydroboration oxidation sequence At the same time we wanted to explore the viability of using a protected nucleophile to perfor m the cyclization as well as assess the feasibility of using alternate

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65 leaving groups for diene formation. O ur group showed that a variety of alternate leaving groups, such as methyl ethers, were amenable to gold catalyzed cyclizations. 77 We rationalized t hat the use of a methyl ether would not produce water as a byproduct of the cyclization, therefore reducing the amount of Meyer Schuster product seen. With these considerations in mind, we synthesized a series of compounds to test our h y pothesis . (Scheme 2 21 ). Protected alcohol 2 6 7 was converted to propargyl alcohols 2 73 and 2 7 4 via addition of the lithium acetylide to an aldehyde. Alkylation with methyl iodide followed by deprotection of the silyl ether afforded propargyl ethers 2 7 5 and 2 7 6 , which contained a pendant primary alcohol . Scheme 2 21 Synthesis of propargyl ethers 2 75 and 2 76 With these substrates in hand , a series of experiments were performed to tes t the ability to employ a protected nucleophile under the standard conditions as wel l as test the leaving group ability of the methyl ether (Scheme 2 22 ). When propargyl alcohols 2 73 and 2 74 were treated under cationic gold conditions the cyclization occurred to afford the diene in a 2:1 ratio with the open chain form as observed by NMR . However, treatment of the diene under subsequent hydroboration oxidation conditions failed to provide the desired THP product s 2 77 and 2 78 . Propargyl ethers 2 75 and 2 76 were also shown to cyclize to give the diene intermediates 2 79 and 2 80 .

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66 Scheme 2 22 Studies on protected nucleophiles 2 73 74 propargyl ethers 2 75 76 2.2. 2 Tandem gold cata l yzed cyclizatio n epox i dation reduction Given the previous unsuccessful attempts, we shifted our focus to the second possible synthetic pathway towards the desired THP products . Examination of the lite rature provided precedent for a possible epoxidation reduction sequence that would arrive at the desired THP products. In a report from the Clark group 78 on their synthesis of a fragment of Ciguatox in CTX3C, the authors demonstrated that treatment of diene 2 81 with dimethyl dioxirane (DMDO) afforded an epoxide that was then reduced with BF 3 2 and triethylsilane to afford a diasteromeric mixture of alcohols 2 82 a and 2 82 b with 2 82a bearing the desired trans relationship as the major product (Scheme 2 23) . Scheme 2 23 DMDO / triethylsilane oxidation reduction sequence to generate 2 82a and 2 82b

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67 Coupling this ep oxidation reduction sequence with the gold catalyzed formation of a di ene in a one pot tandem process would allow for the rapid generation of THPs 2 13 in a single step (Scheme 2 24 ). After the initial cyclization, diene 2 10 could be converted to epoxide 2 8 3 employing DMDO as an oxidant. Selective r eduction with triethylsilane in the presence of a Lewis acid such as BF 3 2 would yield the desired tetrahydropyran products 2 13 with the desired trans geometry and hydroxyl substituent at the 3 position . Scheme 2 24 Proposed one pot tandem gold catalyzed diene fo rmation epoxidation reduction process. To investigate this reaction sequence propargyl alcohol 2 73 was subject e d to cationic gold conditions and rapid cyclization to the diene occurred. Treatment of this diene with DMDO at low temperatures, followed by re duction with triethylsilane in the presence of BF 3 2 afforded the desired trans substituted tetrahydropyran 2 77 in good yield as a single diaster e omer (Scheme 2 25 ). Alternatively, when superhydride was used as the reducing agent, the cis substituted t etrahydropyran 2 84 was formed. Scheme 2 25 Successful tandem gold catalyzed cyclization oxidation reduction sequence

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68 In order to perform the proposed iterative sequenc e, a substrate that would furnish a product bearing a functional handle that could easily be elaborated to provide the required alkyne needed for the ensuing gold catalyzed cyclization was needed. Ideally, this manipulation would be performed in as few synthetic steps as possible. Mic alizio and coworkers ha ve reported the conversion of terminal olefins into disubstituted alkynes via a formal hydroalkynylation . 79 Application of this reaction sequence to the desired iterative pathway would afford alkyne 2 66 from THP 2 85 in a single step v ia intermediate 2 86 (Scheme 2 26) . Hydroboration of terminal olefin 2 85 would yield a trialky lborane. Site selective oxidation of this organoborane and subsequent addition of a lithium acetylide would furnish intermediate 2 86 that could then undergo a 1,2 alkyl migration init i ated by iodine. Finally, base catalyzed elimination would give the desired alkyne 2 66 . Scheme 2 26 Proposed conversion of THP 2 85 to alkyne 2 66 Formation of THP 2 85 would require alkyne 2 87 to be s ubjected to the developed reaction conditions. Addition of protected alcohol 2 67 to paraformaldehyde gave propargyl alcohol 2 87 in high yield. 2 87 was further converted to propargyl ether 2 88 in two steps via a lkylation of the propargyl alcohol followe d by deprotection of the silyl ether (Scheme 2 27 ). Scheme 2 27 Synthesis of propargyl alcohol 2 87 and propargyl ether 2 88 .

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69 This se t of compounds with two primary alcohols was then subjected to a series of reactions to explore optimal conditions. First , the combinations of substitution patterns possible on both the nucleophilic alcohol as well as propargyl alcohol of 2 87 were tested ( Scheme 2 28 ). When the nucle ophilic alcohol was protected as the silyl ether the in itial gold catalyzed cyclization did not occur, independent of the identity of the leaving group ( Scheme 2 28 , entries 1 2) . Alternatively, when the nucleophilic alcohol was left unprotected, the cyclization occurred rapidly, employing the methyl ether as a leaving group. The tetrahydropyran product 2 85 was isolated, albeit in poor yield ( Scheme 2 28 , entry 3) . The relatively low yield of this transformation was thought to be due to the difficulty of isolation due to volatility of THP 2 85 , but a ttempts to improve the yield by acylation of the resultant secondary alcohol were unsuccessful ( Scheme 2 28 , entry 4) . Scheme 2 28 Optimization studies for the formation of THP 2 85 Due to the difficulties experience during the isolation of THP 2 85 , a substrate, which would result in a less volatile product, was synthesized in an attempt to increase the y ield. To add molecular weight geminal diphenyl substitution was added to the carbon chain . Propargyl methyl ether 2 91 was synthesized in four steps from known

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70 alkynol 2 89 (Scheme 2 29 ). Protection of the primary alcohol as the silyl ether followed by addition to paraformaldehyde gave propargyl alcohol 2 90 . Alkylation followed by deprotection of the silyl ether gave the desired propargyl methyl ether 2 91 . Scheme 2 29 Synthesis of propargyl ether 2 91 Propargyl methyl ether 2 91 was then subjected to th e standard conditions (Scheme 2 30 ). Pleasingly, The gold catalyzed c yc lization oxidation reduction sequence proceeded smoothly and the desired THP p roduct 2 92 was isolated in moderate yield as a single diaster e omer . Scheme 2 30 Conversion of propargyl ether 2 91 to THP 2 91 Having optimized the standard conditions, the generality of the reaction sequence needed to be established . Following a similar synthetic scheme as before, protected alkynol 2 6 7 was converted to propargyl alcohol 2 93 (Scheme 2 31 ). Alkylation of the propargyl alcohol and subsequent deprotection afforded pr o pargyl ether 2 94 . Scheme 2 3 1 Synthesis of proparg yl ether 2 94

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71 Propargyl methyl ethers 2 75, 2 76 , and 2 9 4 were then subjected to th e optimized reaction conditions (Scheme 2 32 ). Propargyl ether 2 75 afforded THP 2 77 in high yield as a single diaster e omer. Both alk yl and aryl substituents were tolerate d as propargyl ethers 2 76 and 2 94 were converted to the respective THP products 2 95 and 2 96 . Scheme 2 32 Additional examples of viable substrates In all cases , the resulting product possessed the desired trans relationship desired for the substituents at the two and three positions. This high level of s e lectiv it y arises from the selective reduction step. This reaction presumably proceeds through an oxocarbenium ion 2 97 formed during the Lewis acid catalyzed epoxide openin g (Scheme 2 33). 80 The incoming n ucleophile can then add to one of two diastereotopic faces of this oxocarbenium ion to furnish THP 2 98 or 2 99 . The high level of selectivity most likely arises from the preference for axial attack (Scheme 2 33, pathway A) which would direc tly lead to 2 98 . 81 Pathway B would be disfavored, as this attack would have to go through a higher energy twist boat intermediate to furnish 2 99 .

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72 Scheme 2 33 Proposed stere o chemical rational for the reduction of oxocarbenium 2 97 Having demonstrated that primary alcohol nucleophiles performed well in the transformation , a set of compounds designed to explore the scope of possible viable nucleophiles were synthesized . T o test a variety of alternate oxygen and other heteroatom nucleophiles, secondary alcohol 2 98 , carboxylic acid 2 99 , and sulfonamide 2 100 were all furnished employing 2 88 as a common synthetic intermediate (Scheme 2 34 ). Oxidation of the primary alcohol of 2 88 to the corresponding aldehyde followed by Grignard addition aff orded secondary alcohol 2 9 9 . Direct oxidation of 2 88 with PDC in wet DMF yielded carboxylic acid 2 99 . Displacement of the primary alcohol activate d with DIAD and triphenyl phosphine with a protected sulfonamide under Mitsunobu conditions followed by bas e catalyzed carbonate deprotection gave sulfonamide 2 100 . Scheme 2 34 Synthesis of alternate heteroatom nucleophiles

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73 Phenol 2 105 was synthesized from known protected phenol 2 101 in 6 steps (scheme 2 35 ). Hydroboration oxidation of 2 101 afforded prima ry alcohol 2 102 which was then converted to aldehyde 2 103 via Swern oxidation in. Using standard Corey Fuchs conditions, alkyne 2 104 was afforded in 62% yield over two steps. Finally alkylation with chloromethyl methyl ether and subsequent deprotection gave the desired phenol 2 105. Scheme 2 35 Synthesis of phenol 2 105 This series of compounds was then subjected to the optimized reaction conditions (Scheme 2 36) . Secondary alcohol 2 98 afforded THP 2 106 , albeit in low yield. Carboxylic acid 2 99 and phenol 2 105 failed to give the desired product. Sulfonamide 2 100 cyclized rapidly to the diene intermediate but subsequent epoxidation and reduction proved to be problematic.

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74 Scheme 2 36 Exploring the reactivity of alternative nucleophiles. Studies on the potential formation of larger and smaller ring sizes were also explored. Propargyl ether 2 114 which would afford a tetrahydrofuran product was synthesized i n six steps from commercially available methyl diphenylacetate 2 110 (Scheme 2 37). Deprotonation and a lkylation with propargyl bromide gave alkyne 2 111 which was reduced with LAH to give alkynol 2 112. Protection of the primary alcohol as the silyl ether followed by alkylation with MOMCl afforded propargyl ether 2 113 . S ubsequent deprotection of the silyl ether gave propargyl ether 2 114.

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75 Scheme 2 37 Synthesis of propargyl ether 2 114 Initially propargyl ether 2 114 was subjected to the standard reacti on conditions for the gold catalyzed cyclization and the reaction mixture was filtered through celite in an attempt to identify diene 2 115 (Scheme 2 38). The compound was then subjected to the full reaction sequence but unfortunately THF product 2 116 was not observed and only decomposition products were found. Scheme 2 38 Attempts to synthesize THF 2 116 from propa r gyl ether 2 114 To probe the formation of larger ring sizes, propa r gyl ether 2 120 was synthesized from commercially available carboxylic ac id 2 117 (Scheme 2 39). Reduction of 2 117 to the primary alcohol followed by protection afforded protected alkynol 2 118 . Addition into hydrocinnamaldehyde gave propargyl alcohol 2 119 . Finally, methylation and deprotection afforded propargyl ether 2 120 .

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76 Scheme 2 39 Synthesis of propargyl ether 2 120 . When propargyl ether 2 120 was subjected to the standard gold catalyzed cyclization conditions no reaction was seen at room temperature (Scheme 2 40). However at an elevated temperature the reaction proceeded to furnish diene 2 121 . Unfortunately when the compound was subjected to the full tandem process, the desired oxepane 2 122 was not observed and only side product 2 123 was isolated. Scheme 2 40 Studies on the formation of oxepane 2 122 In order to synthesize ladder polyether like subunits, a THP product bearing a secondary alcohol and pendent propargyl ether would have subjected to the tandem reaction sequence. THP 2 129 was designed as a test substrate to explore this reactivity and syn thesized s tarting from 3,4 dihydro 2H pyran (Scheme 2 41) . Epoxidation with m CPBA followed by ring opening by the carboxylate byproduct gave

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77 THP 2 124 . Lewis acid catalyzed allylation led to an inseparable 1:1 mixture of THPs 2 125a and 2 125b . Upon conve rsion to the acetate, the mixture was separated by flash column chromatography and deprotection of the acetate followed by reprotection afforded silyl ether 2 126 with the requisite t rans substitution pattern. Hydroboration oxidation of the terminal olefin followed by Swern oxidation afforded aldehyde 2 217 which was further elaborated to alkyne 2 12 8 using Corey Fuchs conditions. Alkyne 2 12 8 was converted to THP 2 129 via alkylation and dep rotection, albeit in very low yields. Scheme 2 41 Synthesis of THP 2 129 2.3 Conclusions and Outlook A novel one pot tandem gold (I) catalyzed diene formation epoxidation reduction sequence has been developed. Thus far, several different types propargyl ethers have been tested and the reaction conditions have been sho wn to be general for the formation of THP products. Alternate oxygen and nitrogen nucleophiles are also being explored. At this juncture, conditions need to be developed that can access 5, 7, and 8 membered ring products as these motifs are commonly found in ladder polyether

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78 natural products. In order to fully harness the potential of this novel transformation an iterative reaction sequence also need to be explored.

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79 CHAPTER 3 DIASTEREOSELECTIVE S YNTHESIS OF PROTECTE D 1,3 DIOLS BY CATALYTIC DIOL RELOCATION 3.1 Introduction 3.1.1 Transition Metal Ca talyzed Allylic Substitution The transition metal catalyzed nucleophilic allylic substitution reaction is a powerful synthetic tool for bond formation in organic synthesis (Scheme 3 1) . 8 2 A wide array of transition metal catalysts have been shown to be effective in this transformation. 8 3 In general , for this class of reactions , a variety of heteroatom nucleophiles have been employed. For example, oxygen nucleophiles such as phenolates, al koxides, and carboxylates , have been explored. Typically these transformations require a good leaving group in order give efficient conversion for the reaction . Scheme 3 1 General transition metal catalyzed In comparison , examples involving simple allyl ic alcohols as leaving groups are far less common in the literature. T here have been several reports of intramolecular variants employing oxygen nucleophiles in the direct substitution of unactivated allylic alcohols . 84 Catalyt i c systems employing Pd (II) 8 5 and Ru (II) 8 6 have been reported. Recently, synthetic efforts in the use Au(I) complexes for this transformation have increased . In 2008 , our group reported the intramolecular dehydrative cyclization of monoallylic diols 3 4 to form substituted THPs 3 5 (Scheme 3 2) . 8 7 The transformation proved to be high yielding and tolerant of a variety of functional groups and showed

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80 preference for the formation of the cis diaster e omer of the 2 6 disubstituted THP products. Scheme 3 2 Diastereoselective formation of THPs 3 5 from monoallylic diols In a subsequent report, the group also demonstrated that the reaction pr oceeded with excellent levels of chirality transfer from e nantio enriched monoallylic d i ols 3 6 to the desired THP or morpholine products 3 7 and 3 8 (Scheme 3 3) . 8 8 Interestingly, the transformation allowed for formation of either enantiomer of the product by switching the olefin geometry of the starting material. When the E isomer of diol s 3 6 was subjected to the reaction conditions products THP and morpholine products 3 7 were obtained . Conversely the Z isomer of diols 3 6 afforded THP and morpholine products 3 8 . In all cases the products possessed E olefin geometry. Scheme 3 3 Chirality transfer in the gold (I) catalyzed deh y drative cyclization of monoallylic diols Based on these results , two possible mechanisms for this transformation seemed most plausible, due to the observed stereochemistry. First the reaction could occur via a syn addition/ syn elimination pathway (Scheme 3 4). After complexa tion with the cationic gold complex, syn addition would furnish intermediate 3 10 , which wou ld undergo proton transfer and syn elimination of the gold complex and water to furnish product 3 7 with the observed ster e ochemistry. Alternatively, anti addition to form intermediate 3 12

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81 followed by proton transfer and anti elimination of the gold complex and water would also furnish 3 7 . Scheme 3 4 Possi ble mechanistic pathways for the gold (I) catalyzed dehydrative cyclization of monoallylic diols. After exte n sive mechanistic studie s performed by our laboratory in collaboration with the Ess group , 8 9 it was determined through both experimentation and DFT calculations that the reaction proceeds through an anti addition / anti elimination pathway and that hydrogen bonding played a critical role in the transition state . This

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82 mechanism allowed for an intramolecular proton transfer as well as templating the molecule to arrive at the observed ster e ochemistry. Although there have now been many reports of intramolecular gold catalyzed substitution of allylic alcohols, intermolecular variants of this reaction with simple alkoxy nucleophiles are scarce. In 2013, the intermolecular substitution of allylic alcohols with alcohol nucleophile was reported by the Lee group. 90 Tr eatment of allylic alcohols 3 14 with Ph 3 P AuNTf2 in the presence of an excess of alcohol nucleophile 3 15 afforded the desired allylic alcohols 3 16 (Scheme 3 5). Scheme 3 5 Intermolecular gold catalyzed substitution of allyilic alcohols Similarly, Widenhoefer and coworkers also reported that dehydrative alkoxylation of allylic alcohols proceeded with transfer of chirality when employing an NHC gold complex. 91 Enantioenriched a llylic alcohol 3 17 was shown to undergo allylic substitution when treated with four equivalents of n butan ol to afford allylic alcohols 3 18 3 21 (Scheme 3 6). The major product 3 18 was afforded with almost complete transfer of chirality and minor product 3 19 was observed with high level of chirality transfer as well. Products 3 20 and 3 21 which have substitution at the gamma position presumably arise from a second substitution reaction involving allylic ethers 3 18 and 3 19 . The authors proposed that the reacti on also proceeds through a similar anti addition/ anti eli mination pathway, which leads to the high levels of chirality transfer.

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8 3 Scheme 3 6 Chirality transfer in the intermolecular dehydrative substitution of allylic alcohols 3.1.2 Pseudo intermo lecular Tandem Hemiacetalizaion/ Allylic Substitution These two ex amples illustrate the substantial challenges associated with the intermolecular variant of this class of reactions. As an extension of the method ologies developed in our laboratory we envisioned a process where generation of a transiently tethered nucleophile would allow for a pseudo intermolecular dehydrative substi t ut ion of allylic alcohols (Scheme 3 7). I nitial ly, monoallylic diols 3 22 would undergo a hemiacetalization reaction with an aldehyde to form a h emiacetal nucleophile. Subsequen t gold catalyzed cyclization of the pendent alcohol of the hemiacetal onto the allylic alchol and elimination of water would yield protec ted 1,2 or 1,3 diols 3 23. By generating a tethered nucleophile , the formation of unwa nted side products should be avoided. Scheme 3 7 Proposed pseudo intermolecular gold catalyzed dehydrative substit ut ion The synthesis of syn 1,3 diols has garnered significant interest from the synthetic community due to the abundance of this motif in na tural products 92 as well as their discernible presence in pharmaceutically relevant compounds. 93 Additionally , these synthons are valuable intermediates that can easily be elaborated into more complex

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84 architectures which are found in a variety of natural products and bioactive molecules. 94 Due to their broad applicability, m any synthetic strategies have been developed to prepare 1,3 diols . 9 5 Similar tandem strategies employing other transition metal complexes to generate protected 1,2 and 1,3 diols and ami no alcohols from transiently tethered nucleophiles have been reported with varying levels of success . In 2010 , Zakarian an d coworkers reported a rhenium catalyzed transposition of allylic alcohols . 9 6 Treatment of monoallylic diols 3 34 with Re 2 O 7 in the pr esence of acetal 3 35 afforded protected 1,3 diols 3 36 in good yields with high levels of diastereoselectivity (Scheme 3 8). A lthough effective, the reaction conditions cleaved acid sensitive protecting groups such as PMB and silyl ethers and also removed acetal and ketal protecting groups already in place. Scheme 3 8 R henium catalyze allylic diol transposition. A later report from the Menche group , demonstrate d that allylic carbonates could be employed in tandem hemiacetal formation/ Tsuji Trost reaction s (Scheme 3 9) . 9 7 Treatment of allylic carbonates 3 37 with a Pd (0) catalyst, triphenyl pho sphine, base, employing an acetaldehyde in toluene solvent system afforded protected syn 1,3 dols 3 38 . The reaction proved to be high yielding in most cases and sho wed tolerance for aromatic and aliphatic substituents but the diastereoselectivity of the reaction was moderate. The re action conditions also require d the use of KHMDS, a strong base , which could be problematic for sensitive substrates .

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85 Scheme 3 9 Pd (0) catal yzed tandem hemiacetalization / Tsuji Trost process Although not a tandem process, Gu and coworkers reported that the synthesis of protec ted 1,3 amino alcohols via a Pd (0) catalyzed allylic subst itu tion of carbonates (Scheme 3 10). 9 8 The authors showe d that preformed trichloroacetimidates 3 39 could undergo cycl ization to form 5,6 dihydro 1,3 oxazines 3 40 . The reacti on conditions were suit a b le for a variety of functional groups but the diastereoselectivity of the reaction varied drastically based upon the identity of the substituents. These compounds served as protected 1,3 amino alcohols as the products could be hydrolyzed under mild conditions. Scheme 3 10 Conversion of trichloroacetimidates 3 39 to 5,6 dihydro 1,3 oxazines 3 40 3.2 Results and Discussion 3.2.1 Preliminary Studies diols to the synthesis of protected 1,2 and 1,3 (Scheme 3 7). Preliminary studies to test the viability of this hypothesis were performed by Dr. Carl Ballesteros. Initially, a series

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86 of catalytic systems were screened to test the conversion of commercially available cis 1,4 butene diol 3 41 to the corres ponding 1,3 dioxolane 3 43 via hemiacetalization with cyclohexanal 3 42 and subsequent cyclizat i on (Schem e 3 11). These studies s howed that Au(I) ( Scheme 3 11, entries 1 6) salts perform ed better than Au(III) salts ( Scheme 3 11, entry 8) for the desired reaction and that the I a nd AgOTf catalyst system gave the best results in terms of reaction yield , but offered only moderate diaster e oselectivity. Scheme 3 11 Catalyst optimization for the formation of 3 43 Next a series of aldehydes were screened e mploying I , and AgOTf catalytic system to determine which aldehyde provided optimal results (Scheme 3 12). Initially it was thought that aromatic aldehydes would be best suited for the

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87 transformat ion. Gratifyingly, when benzaldehyde 3 42 a was used ( Scheme 3 12, entry 1) , a moderate yield of the desired protected 1,2 diol 3 44 a was observed, albeit with low diastereo selectivity. A lter ing the electronics of the al dehyde to increase the yield , functionalized benzaldehydes were tested but did not provide improved results ( Scheme 3 12 , entries 2 and 3) . Given the poor performance of benzaldehydes a series of aliphatic aldehydes ( Scheme 3 12 , entries 4 8) were then tested. These aldehydes greatly increased the yield , with substitut ed aldehydes providing increased levels of selectivity . C hloral hydrate 3 4 2i provided almost quantitative yield of the product, albeit with poor selectivity. With i sobutyraldehyde 3 4 2 f , a good balance of yield and s electivity was attained. These results , coupled with the fact that purification and isolation of the desired products was easier with a volatile , led to selection of 3 4 2f as the aldehyde of choice at this stage. Having established that the desired reacti vity could be achieved under Au catalysis conditions, the generality of the reaction was explored. Initial studies attempting to use the previously optimized reaction conditions on the more complex diol E 3 45a were performed. This catalytic system was mil dly effective but only gave t he corresponding 1,3 dioxane 3 46a in moderate yield with good levels of selectivity (Scheme 3 13). Several experiments were performed to attempt to increase the yield of the desired transformation. The use of a B rønsted acid additive such as PTSA or increased reaction temperatures ( Scheme 3 13, entries 2 and 3) did not improve the reaction yield or selectivit y. Increasing the concentration of the reaction had a positive effect on the reactivity , especially when coupled with i ncreased temperature (entry 6) , afford ing the desired product in 85% yield in only 4 hours .

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88 Scheme 3 12 Determination of an optimal aldehyde This suggested that the initial hemiacetal formation may be sluggish with these mildly oxophilic catalysts . It wa s proposed that using a more electron deficient gold complex could increase the overall reacti on rate by slightly increasing the Lewis acidity of the cata lyst, thereby facilitat ing the initial hemiacet a lization while retaining the necessary ac idity requi red to perform the dehydrative cyclization . 9 9 Using the phosphite gold complex IV , 3 46a was isolated in 91% yield after only 4.5 hours at room temperature

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89 with excellent selectivity ( 22:1 dr, entry 7) . Unfortunately, under the same conditions E 3 45a did not produce the same results as a longer reaction time and lower selectivity was observed (entry 8) . After extensive screening, it was found that E alkenes were viable substrates for the desired transformation when Bi(OTf) 3 100 was used as the catalys t (entry 9) . Interestingly, when Z 3 45a was subjected to the Bi(OTf) 3 conditions, only direct acetal formation between the starting material and aldehyde were observed, 101 demonstrating substrate based catalyst complementarity. Scheme 3 13 Optimiza t i on of reaction conditions for the formation of 1,3 dioxane 3 46a Having established a set of comple menta ry reaction conditions , substituted monoallylic diols 3 45a f were investigated to determine the reaction scope ( Scheme 3 14 ) . In general, a variety of functional groups were tolerated for the transformation to give the desired 1,3 dioxolanes or 1,3 dioxanes 3 46a f in high yields and good selectivities from the corresponding monoallylic diols 3 45a f .The electronic nature of

PAGE 90

90 the aromatic substituent prov ed to be significant f o r the transformation. When an electron donating substituent was added to the phenyl ring the reaction pathway was shut down, as diol 3 4 5 b afforded no desired product. Introduction of an electron withdrawing group on the phenyl ring improved the reaction yield as diol 3 45 c furnished 3 46 c in almost quantitative yield. Diol 3 45d bearing an a liphatic subst ituent gave excellent yield and selectivity . Diols 3 45e and 3 45f also gave high yields of the desired 1,3 dioxolanes 3 46e and 3 46f with moderate to good diastereoselectivity. Unfortunately, when the corresponding E diols 3 45e and 3 45f , were allowed to react under the bismuth catalyzed conditions , the desir ed 1,3 dioxolanes 3 46e and 3 46f were not formed. This was due to the p reference for direct formation of the larger 7 membered hemiacetals . The cis relationship of 1,3 dioxane products was confirmed through NMR analysis as an nOe enhancement of the methane protons was observed upon irradiation of the acteal proton for 3 46a .

PAGE 91

91 Scheme 3 14 Scope of 1,5 monoallylic diols 3.2.2 Expansion of the Substrate Sc ope For the Pseudo I ntermolecular Tandem Hemiacetaliza tion/ Allylic Substitution of Monoallylic Alcohols Looking to expand upon the substrate scope demonstrated by the initial studies , additional diol substrates were synthesized (Scheme 3 15). Deprotonation and addition of protected alcohol 3 47 to cyclohexanal followed by deprotection of the silyl ether gave propargyl alcohol 3 48. Propargyl alcohol 3 48 was then c onverted to the corresponding monoallylic diols E 3 45g and Z 3 45g vi a reduction with LAH or Lindlar hydrogen respectively. Propargyl alcohol 3 50 was prepared via addition of the dianion formed by double deprotonation of alkynol 3 49 with ethylmagnesium bromide.

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92 Su bsequent reduction with Lindlar Z 3 45 h . However attempts to convert 3 50 to E 3 45h by reduction with LAH were unsuccessful. Scheme 3 15 Synthesis of diols E 3 45g , Z 3 45g , and Z 3 45h These diols were then subjected to the reaction conditions to test their viability (S cheme 3 16). Diols E 3 45g and Z 3 45g bearing branching in the aliphatic chain gave excellent yields for the corresponding 1 3 dioxane 3 46g . The diaster e oselectvity for the bismuth catalyzed process was excellent, however the gold catalyzed pathway gave a lower diastereoselectivi ty. Protected amines were also shown to be tolerated under the reaction conditions as the protected n itrogen containing diol 3 45 h gave 3 46g in high yiel d a s a single diastereomer.

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93 Scheme 3 16 Tests employing branched aliphatic and nitrogen containing substrates Wanting to add to the utility of the products from the reaction, we envisioned that transposing the allylic moiety of diols 3 45 to give diols with 3 51 with a primary allylic leaving group . This would install a terminal olefin in the product thus allowing for future manipulation s of the corresponding 1,3 dioxane s 3 52 (Scheme 3 17). Scheme 3 17 Proposed relocation of the allylic moiety to afford 1 3 dioxanes 3 52 Unfortunately, all p revious efforts by Dr. Ballesteros to employ this type of diol in the desired transformation using the established reaction conditions were unsuccessful a s only trace amounts of the desired product were observed. To address this issue we proposed that changin g the aldehyde component of the reaction to one that would more readily form the hemiacetal might alleviate these problems. Looking back at the initial aldehyde optimization, chloral hydrate 3 42i gave the highest yield for the simple

PAGE 94

94 transform ation so it seemed logical that it migh t improve the yield of the reaction of 1,5 monoallylic diols 3 51 also . To test this theory diol s E 3 51 a and or Z 3 51a wer e synthesized starting from simple alkene 3 53 (Scheme 3 18) . Epoxidation with mCPBA proceeded smoothly to give epoxide 3 54 in high yield which was converted to diol 3 56 via epoxide opening with protected propargyl alcohol 3 55 and subsequent acid catalyzed deprotection. Selective reduction using Lindlar conditions or with LAH gave diol 3 51 a with the requisite E or Z olefin geometry . Scheme 3 18 Synthesis of diol s E 3 51 a and Z 3 51a To test our theory, d iol s Z 3 51a and E 3 51a were then treated under either the gold or bismuth catalyzed reaction conditions substituting chloral hydrate as the init ial electrophile (Scheme 3 19). W hen five equivalents of chloral hydrate 3 42i were used the desire d 1,3 dioxolane 3 57a was isolated, albeit in low yield , with high levels of diastereoselectivity. Gratifyingly, lowering the number of equivalents of 3 42 i greatly

PAGE 95

95 increased the reaction yield without affecting the selectivity and 3 57a was isolated in 87% yield as a single di aster e omer. 1 H NMR analysis studies confirmed the all cis configuration for the product as a n nOe enhanceme nt of the methine proton signals was observed upon irradiation of the acetal proton . Unfortunately attempts to employ E 3 51a under the bismuth cata lyzed conditions only led to decomposition of the starting material and no desired product was seen. Scheme 3 19 Use of chloral hydrate as the aldehyde equivalent Having demonstrated the effectiveness of chloral hydrate for the transformation , we wanted to explore the substrate scope fo r the reaction. A series of 1,5 monoallylic diols 3 51b f were synthesized using the same strategy as reported above. These diols were then subjected to th e optimal reaction conditions ( Scheme 3 20) . Aliphatic subs t ituents were generally well tolerated, although presence of an additional alkene moiety in diol 3 51f led to reduced yields. Diol 3 51e bearing an aromatic substituent also proved to be viable. In all cases only a single diastereomer was observed .

PAGE 96

96 Scheme 3 20 Scope of transposed 1,5 monoallylic diols 3.2.3 Deprotection to Unmask Syn 1,3 D iols and Elaboration to More Complex Motifs As our interest in thi s project stemmed from the abund ance of 1,3 diol in natural product and pharmaceutically relevant compounds, it was necessary to unmask the protected 1,3 diols to allow for further manipulations W e set out to investigate reaction conditions under which this group co uld be cleaved without affecting the remainder of the molecule. S everal sets of conditions for the depro tection of trichloromethylacetals have been reported . 102 A series of known reaction conditions were screened to affect the desired transformation on 1,3 dioxolane 3 57d and provide free 1,3 diol 3 58 (Scheme 3 21). Attempts to use acid catalyzed conditions to deprotect 3 57d were unsuccessful as only starting material was recovered. E ither reductive reaction conditions to afford diol 3 58 or reagents known to perform a site selective oxidation 10 3 to give ester 3 59 also resulted in no desired conversion. We then attempted to convert the trichloromethyl acetal into a more readily cleaved group that might be removed

PAGE 97

97 under acidic conditions. Unfortunately, employing known method s to convert 3 57d to the corresponding methyl acetal 3 60 via radical dehalogenation were also unsuccessful. Sch eme 3 21 Unsuccessful attempted deprotection of 1,3 dioxolane 3 57d Given the failures of these known reaction conditions , we set out to inve stigate alternate methods for the selective cleavage of the tr ichloromethyl acetal group. We envisioned that removal of this protecting group would possible via an initial lithiation of the trichloromethyl group followed by an aqueous quench. Employing suc h a process would provide an alternative strategy to traditional methods for deprotection of this moiety that could be advantageous. The strategy was explored using 3 57d as a test substrate with n BuLi selected as the lithiating reagent (Scheme 3 22). Upo n exposure to 1.1 equivalents at low temperature followed by warming the mixture to room temperature , partial deprotection was observed following an aqueous quench.

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98 Gratifyingly, increasing the number of equivalent of the lithium reagent afforded he desire d diol 3 58 in high yield as a single diaster e omer. Scheme 3 22 Deprotection of 1,3 dioxolane 3 57d using n BuLi After demonstrating that the trichloromethyl acetal could be cleaved to unmask free syn 1,3 diols, we set out to convert these compounds more complex architectures. The terminal olefin moiety of diol 3 58 positioned atoms away from a free hydroxyl group led us to investigate the formation of tetrahydrofurans. 2,5 trans substituted tetrahydrofura ns (THFs) bearing a hydroxyl substituent at the 3 position are found in a variety of natural products 94 (Scheme 3 23) . Scheme 3 23 Examples of 2,5 trans THFs in natural products

PAGE 99

99 Looking to target this common motif we envisioned that an intramolecular cy clization of the pendent alcohol onto the alkene functional group would provide a THF product. An iodoetherification reaction would provide access to the desired stereoisomer as they are known to give the 2,5 trans THF product s from the corresponding syn 1 ,3 diols. 10 4 Treatment of diol 3 58 under standard iodoetherification conditions (Scheme 3 24) afforded the desired 2,5 trans THF product 3 66 . Scheme 3 24 Iodoetherification of diol 3 58 While this result was encouraging, the t butyl substituent failed to provide opportunity for further transformations. To address this drawback diol 3 51g was synthesized starting from glycidol using the same strategy as reported above. With this compound in hand we envisioned a three step sequence to provide THF 3 67 (Sc heme 3 25). This compound intrigued us because a multitude of further manipulations to the free alcohol, the benzyl protected alcohol, or the alkyl iodide substituents could be used for further functionalization if this sequence could be realized. Diol 3 5 1g proved to require slight alteration to the optimal gold catalyzed reaction conditions as increased catalyst loading and slow addition of the diol proved to be required to achieve high yields of acetal 3 57g . Attempts to use n BuLi for the c leavage of t he trichloromethyl acetal group were unsuccessful but procee ded smoothly when t BuLi was employed as the lithiating reagent. Finally, iodoetherfication of the resulting diol gave THF 3 67 as a single diaster e omer in a 46% overall yield.

PAGE 100

100 Scheme 3 25 Con version of diol 3 51g to THF 3 67 . 3.3 Conclusions In summary, building upon the foundational studies performed by Dr. Carl Ballestero s, a novel hemiacetalization/dehydrative cyclization sequence employing monoallylic diols has been developed . This transformation allows for the highly efficient formation of 1,3 dioxolanes and dioxanes with excellent levels of diasteroselectivity . Although gold catalyzed conditions do not work for E monoallylic diols, a set of complementary bismuth catalyzed condition s has been demonstrated. Employing monoallylic diols 3 51 allows for the formation of protected 1,3 diols bearing a terminal alkene, which allows a multitude of further transformations. Furthermore, dep rotection of the acetal through lithiation followed b y an aqueous quench provides facile access to the corresponding syn 1,3 diols under mild conditions en route to 2,5 trans tetrahydrofurans. This synthetic strategy for the formation of syn 1,3 diols compliments other similar strategies nicely as it does no t require derivatization of the allylic alcohol moiety or the use of electron withdrawing groups seen in Michael addition strategies.

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101 CHAPTER 4 EXPERIMENTAL SECTION 4.1 General Experimental Procedures All reactions were carried out under an atmosph ere 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, ether, dichloromethane (DCM), pentane Gel. The eluents employed are reported as volume:volume percentages. Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded at 500 MHz and 300 MHz as indicated. tetra methylsilane (TMS, 0.0 ppm), or CDCl 3 (7.26 ppm), Coupling constants ( J ) are reported in Hz. Multiplicities are reported using the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; Carbon 13 nuclear magnetic resonance ( 13 C NMR) spectra were recorded at 75 MHz and 125 MHz. Chemical shift is reported in ppm relative to the carbon resonance of CDCl 3 (77.00 ppm). High resolution mass spectra (HRMS) were obtained by Mass Spectrometry Core Laboratory at the Universi ty of Florida, and are reported as m/z (relative ratio) with the technique indicated. Accurate masses are reported for the molecular ion (M+) or a suitable fragment ion.

PAGE 102

102 4.2 Tandem Gold (I) Catalyzed Cyclization Epoxidation Reduction Sequence Towards Mari ne Polyether Natural Products Tert butyldimet hylsilyl hex 5 yn 1 yl ether (2 67 ). A stirred solution of hex 5 yn 1 ol (1.42g, 15 mmol) and imidazole (1.33 g, 19.5 mmol) in 45 mL of DCM was cooled to 0 °C. A solution of tert butyldimethylsilyl chloride (2.25mg, 15.0 mmol) in 15 mL DCM was then added, and the mixture allowed to warm to room temperature while stirring overnight. The reaction was diluted with hexanes (50 mL) then filtered over a silica plug. The combined organic layers were washed with brine (10 mL), dried over MgSO4, and concentrated. Purification by flash chromatography (5%EtOAc/hexane) yielded the product as a colorless oil (3.18 g, quantitative) with spectral data matching those previously reported 105 8 me thylnon 5 yne 1,7 diol (2 69 ) A stirred solution of 2 67 (750 mg, 3.53 mmol) in 15 mL of dry THF was cooled to 78 °C and was treated with n BuLi (1.7 mL, 2.5 M in hexane) over 5 minutes, and stirred for 0.5 h. At the same temperature, isobutyraldehyde (3. 2 mL, 35.3 mmol) was added neat over 5 minutes. The mixture was stirred for an additional 0.5 h at 78 °C, then allowed to warm to room temperature. The reaction was quenched with H 2 O (10 mL) and diluted with EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3x10 mL), and the combined extracts were dried over MgSO4, filtered and evaporated in vacuo. The crude mixture was taken up in 20 mL dry

PAGE 103

103 THF, treated with a solution of TBAF (7.06 mL, 1.0 M in THF) and stirred at room temperature overnight. The reaction was diluted with 20 mL H 2 O, and extracted with EtOAc (3x30 mL). The organics were washed with brine (20 mL) then dried over MgSO 4 . The residue was subjected to flash chromatography (50% EtOAc/hexane) to furnish the product as a colorless oil (268 mg, 46% over 2 steps) 1 H NMR (300 MHz, CDCl 3 4.11 3.96 (m, 1H) , 3.53 (t, J = 6.2 Hz, 2H), 2.15 (t , J = 6.8, 2H), 1.83 1.62 (m, 1H), 1.63 1.39 (m, 4H), 0.86 (d , J = 6.6 Hz, 6H); 13 C NMR (75 MHz, CDCl3 80.4, 67.9 , 62.0 , 34.7, 31.7, 25.1, 18.5, 18.5, 18.3, 17.6 . 1 cyclohexylhept 2 yne 1,7 diol ( 2 70 ) A stirred solution of 2 6 7 (750 mg, 3.53 mmol) in 15 mL of dry THF was cooled to 78 °C and was treated with n BuLi (1.7 mL, 2.5 M in hexane) over 5 minutes, and stirred for 0.5 h. At the same temperature, cyclohexanecarboxaldehyde (0.64 mL, 5.3 mmol) was added neat over 5 minutes. The mixture was stirred for an additional 0.5 h at 78 °C, then allowed to warm to room temperature. The reaction was quenched with H 2 O (10 mL) and diluted with EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3x10 mL), and the combined extracts were dried over MgSO 4 , filtered and evaporated in vacuo. The crude mixture was taken up in 20 mL dry THF, treated with a solution of TBAF (7.06 mL, 1.0 M in THF) and stirred at room temperature overnight. The reaction was diluted with 20 mL H 2 O, and extracted with EtOAc (3x30 mL). The organics were washed with brine (20 mL) then dried over MgSO 4 . The residue was subjected to flash chromatography (50% EtOAc/hexane) to f urnish the product as a colorless oil (233 mg, 30% over 2 steps) 1 H

PAGE 104

104 1.42 (m, 12H), 1.33 0.95 (m, 5H). 13 C NMR (75 MHz, CDCl 3 28.8, 28.2, 26.6, 26.0, 25.1, 18.6 9 (( tert butyldimethylsilyl)oxy) 1 p henylnon 4 yn 3 ol (2 73 ) A stirred solution of 2 6 7 (1.08g, 5.08 mmol) in 25 mL of dry THF was cooled to 78 °C and was treated with n BuLi (2.1 mL, 2.5 M in hexane) over 5 minutes, and stirred for 0.5 h warmed to °C for 5 minutes and cooled back to 78°C. At the same temperature, hydrocinnamaldehyde (0.79 mL, 5.2 mmol) was added neat over 5 minutes. The mixture was stirred for an additi onal 0.5 h at 78 °C, then allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with sat. NH 4 Cl (aq) (10 mL) and diluted with EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3x10 mL), and the combined extracts we re dried over MgSO 4 , filtered and evaporated in vacuo. The residue was subjected to flash chromatography (15% EtOAc/hexane) to furnish the product as a pale yellow oil (1.44 g, 82% ). 1H NMR (300 MHz, CDCl 3 7.11 (m, 5H), 4.41 4 .30 (m, 1H), 3.64 (t, J = 6.1, 2H), 2.7 9 (t, J = 7.9 Hz, 2H), 2.24 (td, J = 6.7, 1.9, Hz, 2H), 2.10 1.90 (m, 2H), 1.71 1.52 (m, 4H), 0.97 0.87 (m, 9H), 0.13 0.02 (m, 6H). 13 C NMR (75 MHz, CDCl 3 31.6 , 25.9, 25.7, 25.2, 18.5, 18.3, 5.3 .

PAGE 105

105 1 (( tert butyldimeth ylsilyl)oxy)hexadec 5 yn 7 ol (2 74 ) A stirred solution of 2 6 7 (500 mg, 2.35 mmol) in 15 mL of dry THF was cooled to 78 °C and was treated with n BuLi (1.05 mL, 2.5 M in hexane) over 5 minutes, and stirred for 0.5 h warmed to °C for 5 minutes and cooled back to 78°C. At the same temperature decanal (0.47 mL, 2.5 mmol) was added neat over 5 minutes. The mixture was stirred for an additional 0.5 h at 78 °C, then allowed to warm to room temperatur e and stirred for 3 hours. The reaction was quenched with sat. NH 4 Cl (aq) (5 mL) and diluted with EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3x10 mL), and the combined extracts were dried over MgSO 4 , filtered and evaporated in vacuo. The res idue was subjected to flash chromatography (15% EtOAc/hexane) to furnish the product as an oil (837 mg, 95%). 1 H NMR (500 MHz, CDCl 3 J = 6.5, 2.0 Hz, 1H), 3.63 (td, J = 6.2, 0.6 Hz, 2H), 2.26 2.21 (m, 2H), 2.17 (bs, 1 H), 1.72 1.51 (m, 9H), 1.47 1.38 (m, 1H ), 1.27 1.26 (m, 16H), 0.89 (s, 9H), 0.87 (dd, J = 7.1, 0.7 Hz, 3H), 0.05 (s, 6H). tert butyl((7 methoxy 9 phenylnon 5 yn 1 yl)oxy)dimethylsilane (4 1) A solution of 2 73 (270 mg, 0 .78 mmol) in 1 mL of dry THF was added to a suspension of sodium hydride (93 mg, 2.34 mmol) in 2 mL at 0°C. At the same temperature methyl iodide (0.29 mL, 4.68 mmol) was added. The mixture was then allowed to warm to room temperature and stirred for overnight. The reaction was quench ed with sat. NH 4 Cl (aq) (1 mL) and diluted with EtOAc (2 mL). The aqueous layer was extracted with EtOAc (3x5 mL), and the combined extracts were dried over MgSO 4 , filtered and evaporated in vacuo. The residue was subjected to flash chromatography (20% EtOA c/hexane) to

PAGE 106

106 furnish the product as a clear oil (257 mg, 91%) 1 H NMR (300 MHz, CDCl 3 6.80 (m, 5H), 3.93 (tt, J = 6.6, 1.9 Hz, 1H), 3.78 3.60 (m, 2H) , 3.41 (s, 3H), 2.80 (t, J = 8.1, 2H), 2.30 (td, J = 6.8, 2.0 Hz, 2H), 2.14 1.85 (m, 2H), 1.77 1.50 (m, 4H), 0.92 (s, 9H), 0.08 (s, 6H). tert butyl((7 methoxyhexadec 5 yn 1 yl)oxy)dimethylsilane (4 2) A solution of 2 74 (823 mg, 2.23 mmol) in 5 mL of dry THF was added to a suspension of sodium hydride (267 mg, 6.69 mmol) in 5 mL at 0°C. At the same temperature methyl iodide (0.832 mL, 13.38 mmol) was added. The mixture was then allowed to warm to room temperature and stirred for overnight. The reaction was quenched with sat. NH 4 Cl (aq) (5 mL) and diluted with EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3x5 mL), and the combined extracts were dried over MgSO 4 , filtered and evaporated in vacuo . The residue was subjected to flash chromatography (20% EtOAc/hexane) to furnish the product as a clear oil (555 mg, 65%) 1 H NMR (300 MHz, CDCl 3 Hz, 1H), 3.67 3.48 (m, 2H), 3.33 (s, 3H), 2.21 (td, J = 6.7, 1.9 Hz, 2H), 1.73 1.46 (m, 6H), 1.49 1.36 (m, 2H 1.23) (s, 14H), 0.85 (s, 9H), 0.01 (s, 6H). 13 C NMR (75 MHz, CDCl 3 2, 36.1, 32.2, 29.9, 29.7, 29.7 , 29.6, 29.5, 26.1, 25.5 , 25.42, 22. 9, 18.7, 18.4, 14.2, 5.2 . 7 methoxy 9 phenylnon 5 yn 1 ol (2 75 ) To a solution of 4 1 (257 mg, 0.7126 mmol) dissolved in THF (5 mL) at 0°C, was added TBAF (1.0 M in THF, 1.42 mL, 1.42 mmol).

PAGE 107

107 The soluti on was stirred overnight and diluted with water (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3x 10 ml), dried over MgSO 4 , and the combined extracts were dried over MgSO 4 , filtered and evaporated in vacuo. The residue w as subjected to flash chromatography (20% EtOAc/hexane) to furnish the product as clear oil (154 mg, 88%) 1 H NMR (300 MHz, CDCl 3 7.04 (m, 5H), 3.90 (tt, J = 6.5, 1.9 Hz, 1H), 3.68 (t, J = 6.1 Hz, 2H), 3.39 (s, 3H), 2.77 (dd, J = 8.6, 6.8 Hz, 2H), 2.30 (td, J = 6.8, 1.9 Hz, 2H), 2.16 1.81 (m, 2H), 1.81 1.50 (m, 4H), 1.34 (s, 1H). 13 C NMR (75 MHz, CDCl 3 62.6, 56.5, 37.7, 32.1, 31.7, 25.2, 18.7 . 7 methoxyhexadec 5 yn 1 ol (2 76 ) To a solution of 4 2 (1.37 g, 3.608 mmol) dissolved in THF (20mL) at 0°C, was added TBAF (1.0 M in THF, 7.2 mL, 7.2 mmol). The solution was stirred overnight and diluted with water (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3x 10 ml ), dried over MgSO 4 , and concentrated in vacuo. The residue was subjected to flash chromatography (20% EtOAc/hexane) to furnish the product as clear oil (968 mg, 65%) 1 H NMR (300 MHz, CDCl 3 .64 (t, J = 6.1 Hz, 2H), 3.35 (s, z 3H), 2.34 (s, 1H), 2.25 (td, J = 6.8, 2. 0 Hz, 2H), 1.72 1.52 (m, 6H), 1.48 1.33 (m, 2H) , 1.32 1.18 (m, 12H), 1.01 0.78 (m, 3H). 13 C NMR (75 MHz, CDCl 3 56.3, 36.1, 32.1, 31.9, 29.7, 29.7, 29.5, 29.5, 25.5, 25.2, 22.8, 18.7, 14.3 .

PAGE 108

108 (±) cis 2 (( E ) 4 phenylbut 1 en 1 yl)tetrahydro 2 H pyran 3 ol (2 84 ) In a round bottom flask at room temperature Au[P( t Bu)2( o biphenyl)]Cl (2.0 mg, 0.004 mmol), AgOTf (1.0 mg, 0.004 mmol), and THF (1mL) were combined , The solution was stirred for 10 minutes, after which time a solution of 2 73 (50 mg, 0.2 mmol) in THF (0.5 ml) was added. After 1 hour, TLC analysis indicated that the Au catalyzed cyclization was complete and the solution was cooled to 78°C and DMDO (2.7 ml, 0.075 M in a cetone) was added. The solvent was removed in vacuo and then THF (1.5 mL) was added. The solution was cooled to 0° C and superhydride (1.2 ml, 1.2 M in THF) was added dropwise. The solution was stirred for 1 hour and q uenched with water (2 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3x 5 ml). The combined organic extract was dried over MgSO 4 , filtered and evaporated in vacuo . The residue was subjected to flash chromatography (25% EtOAc/hexane) to furnish the product as clear oil (15mg, 40%) 1 H NMR (300 MHz, CDCl 3 7.08 (m, 5H), 5.77 (dt, J = 15.5, 6.7 Hz, 1H), 5.47 (dd, J = 15.5, 7.7 Hz, 1H), 4.35 4.25 (m, 1H), 4.2 3 (d, J = 4.0 Hz, 1H), 4.00 3.77 (m, 3H), 3.68 (d, J = 5.7 Hz, 1H), 2.82 2.57 (m, 3H), 2.39 2.25 (m, 2H), 0.88 0.66 (m, 4H) 7 (( tert butyldim ethylsilyl)oxy)hept 2 yn 1 ol (2 87 1) A stirred solution of 2 6 7 (2.494g, 11.75 mmol) in 25 mL of dry THF was cooled to 78 °C and was treated with n BuLi (4.9 mL, 2.5 M in hexane) over 5 minutes, and stirred for 0.5 h warmed to °C for 5 minutes and cooled back to 78°C. At the same temperature, paraformaldehyde (1.059 g, 35.2 mmol) was added neat over 5 minu tes. The mixture was stirred for an additional

PAGE 109

109 0.5 h at 78 °C, then allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with sat. NH 4 Cl (aq) (10 mL) and diluted with EtOAc (10 mL). The aqueous layer was extracted with EtO Ac (3x10 mL), and the combined extracts were dried over MgSO 4 , filtered and evaporated in vacuo. The residue was subjected to flash chromatography (15% EtOAc/hexane) to furnish the product as a pale yellow oil (2.5 g, 88% ). The spectroscopic data matched previously reported data 10 6 tert butyl((7 methoxyhept 5 yn 1 yl)oxy)dimethylsilane (4 3) A solution of 2 87 (1.0 g, 4.126 mmol) in 5 mL of dry THF and was added to a suspension of sodium hydride (297 mg, 12.38 mmol) in 5 mL at 0°C. At the same temperatur e , methyl iodide (0.770 mL, 12.38 mmol) was added. The mixture was then allowed to warm to room temperature and stirred for overnight. The reaction was quenched with sat. NH 4 Cl (aq) (5 mL) and diluted with EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3x5 mL), and the combined extracts were dried over MgSO 4 , filtered and evaporated in vacuo . The residue was subjected to flash chromatography (20% EtOAc/hexane) to furnish t he product as a clear oil (1.06 g, quant) . 1 H NMR (300 MHz, CDCl 3 (t, J = 2.2 Hz, 2H), 3.68 (s, 2H), 3.37 (s, 3H), 2.29 (tt, J = 6.7, 2.2 Hz, 2H), 1.74 1.57 (m, 4H), 1.31 (s, 1H). 7 methoxyhept 5 yn 1 ol ( 2 88 ) To a solution of 4 3 (1.058 g, 3.608 mmol) dissolved in THF (20mL) at 0°C, was added TBAF (1.0 M in THF, 8 .2 mL, 8.2 mmol). The solution

PAGE 110

110 was stirred overnight and diluted with water (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3x 10 ml), dried over MgSO4, and concentrated in vacuo. The residue was subjected to flash chroma tography (20% EtOAc/hexane) to furnish the product as clear oil (419 mg, 70%) The spectroscopic data matched previously reported data. 107 tert butyl((2,2 diphenylhex 5 yn 1 yl)oxy )dimethylsilane (4 4) A stirred solution of 2 89 41 (608 mg, 2.43 mmol) and imidazole (924 mg, 4.3 mmol) in 10 mL of DCM was cooled to 0 °C. A solution of tert butyldimethylsilyl chloride (346 mg, 2.3 mmol) in 5 mL DCM was then added and the mixture allowed to warm to room temperature while stirring overni ght. The reaction was diluted with hexanes (10 mL) then filtered over a silica plug. The combined organic layers were washed with brine (10 mL), dried over MgSO4, and concentrated. Purification by flash chromatography (5%EtOAc/hexane) yielded the product a s a colorless oil ( 853 mg, 92%). The spectroscopic data matched previously reported data. 41 7 (( tert butyldimethylsilyl)ox y) 6,6 diphenylhept 2 yn 1 ol (2 90 ) A stirred solution of 4 4 (243 mg, 0.666 mmol) in 5 mL of dry THF was cooled to 78 °C and was treated with n BuLi (0.27 mL, 2.5 M in hexane) over 5 minutes, and stirred for 0.5 h warmed to °C for 5 minutes and cooled back to 78°C. At the same temperature, paraformaldehyde (60 mg, 1.99 mmol) was added neat over 5 minutes. The mixture was stirred for an

PAGE 111

111 additional 0.5 h at 78 °C, then allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with sat. NH 4 Cl (aq) (5 mL) and diluted with EtOAc (5 mL). The aqueous layer was extracted with EtOAc (3x5 mL), and the combined extracts were dried over MgSO 4 , filtered and evaporated in vacuo . The residue was subjected to flash chromatography (15% EtOAc/hexane) to furnish the product as a pale yellow oil (1.15 g, 54 % ). 1 H NMR (300 MHz, CDCl 3 6.64 (m, 10H), 4.20 (s, 2H), 4.09 (s, 2H), 2.54 2.39 (m, 2H), 2.07 1.94 (m, 2H), 0.79 (s, 9H), 0.17 (s, 6H). 13 C NMR (75 MHz, CDCl 3 25.9, 1 8.3 , 14. 7, 5.7 . tert butyl((7 methoxy 2,2 diphenylhept 5 yn 1 yl)oxy)dimethylsilane (4 5) A solution of 2 90 (112 mg, 0.284 mmol) in 2 mL of dry THF and was added to a suspension of sodium hydride (20 mg, 0.851 mmol) in 1 mL at 0°C. At the same temperat ure methyl iodide (0.106 mL, 1.704 mmol) was added. The mixture was then allowed to warm to room temperature and stirred for overnight. The reaction was quenched with sat. NH 4 Cl (aq) (2 mL) and diluted with EtOAc (5 mL). The aqueous layer was extracted with EtOAc (3x5 mL), and the combined extracts were dried over MgSO4, filtered and evaporated in vacuo . The residue was subjected to flash chromatography (20% EtOAc/hexane) to furnish the product as a pale yellow oil (116 mg, quant) 1 H NMR (300 MHz, CDCl 3 .41 7.00 (m, 10H), 4.09 (s, 2H), 4.07 4.03 (m, 2H), 3.36 (s, 3H), 2.78 2.35 (m, 2H), 2.14 1.84 (m, 2H), 0.80 (s, 9H), 0.16 (s, 6H). 13 C NMR (75 MHz, CDCl 3 57.6, 51.6, 35.9, 29.9 , 25 .9, 18.3, 5.7 .

PAGE 112

112 7 metho xy 2,2 diphenylhept 5 yn 1 ol (2 91 ) To a solution of 4 5 (881 mg, 2.157 mmol) dissolved in THF (20mL) at 0°C, was added TBAF (1.0 M in THF, 4.7 mL, 4.7 mmol). The solution was stirred overnight and diluted with water (20 mL). The layers wer e separated and the aqueous layer was extracted with EtOAc (3x 20 ml), dried over MgSO 4 , and concentrated in vacuo. The residue was subjected to flash chromatography (20% EtOAc/hexane) to furnish the product as clear oil (563 mg, 88%) 1H NMR (300 MHz, CDCl 3 6.99 (m, 10H), 4.14 (s, 2H), 4.03 (t, J = 2.1 Hz, 2H), 3.34 (s, 3H), 2.61 2.33 (m, 2H ), 2.11 1.88 (m, 2H) , 1.33 (s, 1H). 13 C NMR (75 MHz, CDCl 3 144.9, 128.5, 128.3, 126.7, 87.1, 76.1, 67.9, 60.4 , 57.7, 51.9, 35.7, 14.6 . 7 (( tert butyld imethylsily l)oxy) 1 phenylhept 2 yn 1 ol (2 93 ) A stirred solution of 2 6 7 (1.0g, 4.71 mmol) in 25 mL of dry THF was cooled to 78 °C and was treated with n BuLi (2.8 mL, 2.5 M in hexane) over 5 minutes, and stirred for 0.5 h warmed to °C for 5 minutes and cooled back to 78°C. At the same temperature, benzaldehyde (0.950 mL, 7.42 mmol) was added neat over 5 minutes. The mixture was stirred for an additional 0.5 h at 78 °C, then allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with sat. NH 4 Cl (aq) (10 mL) and diluted with EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3x20 mL), and the combined extracts were dr ied over MgSO 4 , filtered and evaporated in vacuo. The residue was subjected to flash chromatography (15% EtOAc/hexane) to furnish the product as a pale yellow oil (1.49 g,

PAGE 113

113 99% ). 1 H NMR (300 MHz, CDCl 3 7.29 (m, 5H), 5.42 5.22 (m, 1H), 3.70 3.55 ( m, 2H), 2.39 2.24 (m, 2H), 1.73 1.56 (m, 4H), 0.89 (s, 9H), 0.03 (s, 6H). tert butyl((7 methoxy 7 phenylhept 5 yn 1 yl)oxy)dimethylsilane (4 6) A solution of 2 93 (1.49 g, 4.677 mmol) in 20 mL of dry THF and was added to a suspension of sodium hydrid e (2336mg, 14.01 mmol) in 1 mL at 0°C. At the same temperature methyl iodide (1.45 mL, 23.3 mmol) was added. The mixture was then allowed to warm to room temperature and stirred for overnight. The reaction was quenched with sat. NH 4 Cl (aq) (10 mL) and dilut ed with EtOAc (20 mL). The aqueous layer was extracted with EtOAc (3x20 mL), and the combined extracts were dried over MgSO 4 , filtered and evaporated in vacuo . The residue was subjected to flash chromatography (20% EtOAc/hexane) to furnish the pro duct as a pale yellow oil (1.44 g, 92%) 1 H NMR (300 MHz, CDCl 3 7.27 (m, 5H), 5.22 4.92 (m, 1H), 3.71 3.54 (m, 2H), 3.20 (s, 3H), 2.41 2.21 (m, 2H), 1.71 1.51 (m, 4H), 0.88 (s, 9H), 0.02 (s, 6H). 7 m ethoxy 7 phenylhept 5 yn 1 ol (2 9 4 ) To a solu tion of 4 6 (1.43 g, 4.319 mmol) dissolved in THF (40mL) at 0°C, was added TBAF (1.0 M in THF, 8.6 mL, 8.6 mmol). The solution was stirred overnight and diluted with water (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 25 ml), dried over MgSO 4 , and concentrated in vacuo. The residue was subjected to flash chromatography

PAGE 114

114 (20% EtOAc/hexane) to furnish the product as clear oil (500 mg, 53%) 1 H NMR (300 MHz, CDCl 3 7.44 (m, 2H), 7.40 6.96 (m, 3H), 5.04 (t, J = 2.0 Hz, 1H), 3.79 3.45 (m, 2H), 3.36 (s, 3H), 2.55 2.19 (m, 2H), 1.80 1.43 (m, 4H). 13 C NMR (75 MHz, CDCl 3 , 12 7.3, 88.2, 77.7, 73.1, 61.6, 55.4, 31.6, 24.8, 18.5 . 4. 2. 1. General tandem cyclization oxidation reduction procedure. (±) tran 2 (( E ) 4 phenylbut 1 en 1 yl)tetrahydro 2 H pyran 3 ol (2 77 ) In a round bottom flask at room temperature were combined Au[P( t Bu)2( o biphenyl)]Cl (5.3 mg, 0.01 mmol), AgOTf (2.6 m g, 0.01 mmol), and THF (1mL), The solution was stirred for 10 minutes, after which time a solution of 2 75 (50 mg, 0.2 mmol) in THF (0.5 ml) After 1 hour, TLC analysis indicated that the Au catalyzed cyclization was complete and the solution was cooled to 78°C and DMDO (2.7 ml, 0.075 M in acetone) was added. The solvent was removed in vacuo and then azeotoped with benzene (2 x 1mL). The mixture was re disolved in 2 mL acetonitrile and the solution was cooled to 40° C and boron trifluoride diethyl ethera te (28 mg, 0.2 mmol) was added dropwise followed by addition of triethylsilane (67 mg, 0.6 mmol). The solution was stirred for 45 min warmed to room temperature and quenched with saturated K 2 CO 3 (2 mL). The layers were separated and the aqueous layer was e xtracted with EtOAc (3x 5 ml). The combined extracts were dried over MgSO 4 , filtered and evaporated in vacuo . The residue was subjected to flash chromatography (25% EtOAc/hexane) to furnish the product as clear oil (34 mg, 74%) 1 H NMR (500 MHz, CDCl 3 7.25 (m, 2H), 7.24 7.13 (m, 3H),

PAGE 115

115 5.85 (dt, J = 15.5, 7.0 Hz, 1H), 5.40 (dd, J = 15.5, 8.0 Hz, 1H), 3.92 (dd, J = 12.5, 2.0 Hz, 1H), 3.50 3.29 (m, 2H), 3.26 3.06 (m, 1H) , 2.93 2.77 (m, 1H) , 2.77 2.64 (m, 1H ), 2.57 2.46 (m, 1H), 2.45 2.32 (m , 1H), 2.17 2.09 (m, 1H), 1.72 1.65 (m, 2H), 1. 49 1.34 (m, 2H). 13 C NMR (125 MHz, CDCl 3 128.6, 126.2 , 84 .1, 69.7, 67.7, 35.3, 34.3, 31.3, 25.6 . (±) trans 2 vinyltetrahydro 2 H pyran 3 ol (2 85 ) The typi cal procedure was followed with 2 88 (98 mg, 0.689 mmol) to give the title compound (10 mg, 11 %) as clear oil. 1 H 1H NMR (300 MHz, CDCl 3 5.12 (m, 2H), 3.92 (dd, J = 12.0, 3.0 Hz, 1H), 3.56 3.09 (m, 3H), 1.83 1.59 (m, 2H), 1.52 1.38 (m, 2H). 13 C NMR (75 MHz, CDCl 3 . (±) trans 5,5 diphenyl 2 vinyltetrahydro 2 H pyran 3 ol (2 92 ) The typical procedure was followed with 2 91 (58 mg, 0.2 mmol) to give the title compound (31 mg, 56 %) as clear oil. 1 H NMR (299 MHz, CDCl 3 7.39 (m, 2H), 7.38 7.25 (m, 5H ) 7.25 7.08 (m, 5H) , 5.86 (ddd, J = 17.5, 10.5, 7.0 Hz, 1H), 5. 45 (d , 17.5 Hz, 1 H), 5. 45 (d , 10.5 Hz, 1 H), 4.70 (dd, J = 12.2 , 2.7 Hz, 1H), 3.66 (td, J = 8.7 Hz, 1H), 3.56 (d, J = 12.0 Hz, 1H), 3.38 3.13 (m, 1H) , 2.83 (dt , J = 12.2, 4.0, Hz, 1H), 2.37 (t, J = 11.4 Hz, 1H), 1.90 (s, 1H). 13C NMR (75 MHz, CDCl 3 128.4, 126.9, 126.8, 126.1, 119.6, 84.3, 74.2, 67.2, 48.3, 42.7 .

PAGE 116

116 (±) trans (2 (( E ) undec 1 en 1 yl)tetrahydro 2 H pyran 3 ol (2 95) The typical procedure was followed with 2 76 (53 mg, 0.2 mmol) to give the title compound (33 mg, 66 %) as clear oil. 1 H NMR (500 MHz, CDCl 3 (ddt, J = 15.5, 8.0 , 1.5 Hz, 1H), 3.99 3.89 (m, 1H) , 3.49 3.34 (m, 2H ), 3.36 3.27 (m, 1H) , 2.21 2.13 (m, 1H), 2.13 2.02 (m, 2H) , 1.82 1.61 (m , 2H), 1.49 1.37 (m, 2H), 1.34 1.22 (m, 11H), 0.98 (t, J = 8.0 Hz, 2H), 0.89 (t, J = 6.9 Hz, 3H), 0.61 (q, J = 8.0 Hz, 1H). 13 C NMR (75 MHz, CDCl 3 69.89, 67.70, 32.69, 32.09, 31.50, 29.73, 29.68, 29.52, 29.45, 29.22, 25.64, 6.79, 6.01. (±) trans ( (2 S ,3 R ) 2 (( E ) styryl)tetrahydro 2 H pyran 3 ol (2 96 ) The typical procedure was followed with 2 94 (50 mg, 0.23 mmol) to give the title compound (35 mg, 76 %) as clear oil. 1 H NMR (300 MHz, CDCl 3 7.38 (m, 2H), 7.38 7.20 (m, 3H), 6.74 (d, J = 16.0 Hz, 1H), 6.25 (dd, J = 16.0, 7.2 Hz, 1H), 4.00 (ddt, J = 11.6, 4.0, 2.1 Hz, 1H), 3.76 3.61 (m, 1H), 3.44 (dddd, J = 13.7, 10.5, 6.3, 4.4 Hz, 2H), 2. 20 (ddd, J = 11.4, 5.6, 2.4 Hz, 1H), 1.91 1.69 (m, 2H), 1.64 (s, 1H), 1.61 1.40 (m, 1H). 13 C NMR (75 MHz, CDCl 3 31.8, 25.6 .

PAGE 117

117 7 methoxyhept 5 ynal (4 7) Following the same procedure 1 07 To a solution of oxalyl chloride (2.7mL, 5.4mmols, 1.5eq) in dichloromethane (15mL) cooled at 78°C was added a solution of dimethylsulfoxyde (0.75mL, 10.56mmols, 3eq) in dichloromethane (10mL). The resulting solution was stirred for 30 minutes. To the solut ion was added dropwise a solution of 2 88 (0.4995g, 3.51mmols, 1eq) in dichloromethane (10mL). The mixture was stirred 50 minutes and triethylamine (2.38mL, 17.62mmols, 5 eq) was added. The mixture was stirred 2 hours, quenched with water, extracted with e thyl acetate. The organic layer was purified by flash column chromatography (15% ethyl acetate) to give (430 mg, 87%) of product. 1 H NMR (300 MHz, CDCl 3 4.07 (s, 2H), 3.37 (s, 3H), 2.60 (td, J = 7.3, 1.3 Hz, 2H), 2.36 2.25 (m, 2H), 1.86 (m, J = 6.9 Hz, 2H). 1 methoxytridec 2 yn 7 ol ( 2 98 ) To a solution of 4 7 (0 .420 g, 3.00 mmol ) in diethyl ether (8mL) was added, at room temperature, a solution of hexylmagneisum bromid e (2.0 mL at 2M in THF, 4 mmols ), and the solution was stirred for 3 hours. The reaction mixture was poured on hydrochloric acid in ice (5mL of 0.1M HCl in 10mL of ice), extracted with ethyl acetate and purified using a flash chromatography column (25% ethyl ac etate / hexane) to yield ( 630 mg, 48 %). 1 H NMR (300 MHz, CDCl 3 ) J = 2.1 Hz, 2H), 3.59 (t, J = 6.6 Hz, 2H), 3.33 (s, 3H), 2.31 2.16 (m, 2H), 1.66 1.35 (m, 2H), 1.79 1.15 (m, 12H), 0.85 (t, J = 2.9 Hz, 3H). 13 C NMR (75 MHz, CDCl 3 86.9, 75.9, 71.4 , 62.85, 57.30, 37.51, 36.42, 32.69, 31.60, 29 .31, 25.5 5, 24.71, 18.71, 14.01.

PAGE 118

118 7 methoxyhept 5 ynoic acid (2 99 ) To a solution of 2 88 (300 mg , 2.11 mmol) dissolved in a DMF:H 2 O mixture (5:1, 6 mL) PDC (2.6 g, 7 mmol) was added. The solution was stirred overnight and filtered over a celite pad and the solv ent was removed in vacuo . The residue was subjected to flash chromatography (33% EtOAc/hexane) to afford the title compound (300 mg, 90%) as an oil. 1 H NMR (300 MHz, CDCl 3 3.92 (m, 2H), 3.23 (s, 3H), 2.36 (t, J = 7.4 Hz, 2H), 2.26 2.13 (m, 2H), 1.79 1.65 (m, 2H). 13 C NMR (75 MHz, CDCl 3 32.7, 23.5, 18.1 . tert butyl (7 methoxyhept 5 yn 1 yl)(tosyl)carbamate (4 8) In a roundbottom flask at room temperature, triphenylphosphine (1.405 g, 5.8 mmol) and tert butyl tosylcarbamate 108 (1.58 g, 5.8 mmol were combined. The flask was evacuated and backfilled with N 2 3 times. The mixture was dissolved in THF (20 mL), cooled to 0°C and 2 88 (825 mg, 5.8 mmol) then DIAD (1.14 ml, 5.8 mmol) were added dropwise. The solution w as stirred overnight and the solvent was removed in vacuo . The residue was subjected to flash chromatography (20% EtOAc/hexane) to afford the title compound (1.93 g, 84%) as a clear colorless oil. 1 H NMR (300 MHz, CDCl 3 2H), 7.51 7.06 (m, 2H), 4.09 (t, J = 2.1 Hz, 2H), 3.99 3.73 (m, 2H), 3.56 3.23 (m, 3H), 2.45 (s, 3 H), 2.31 (ddt, J = 7.0, 4.4, 2.1 Hz, 2H), 2.00 1.78 (m, 2H), 1.74 1.53

PAGE 119

119 (m , 2H), 1.34 (s, 9H). 13 C NMR (75 MHz, CDCl 3 86.6, 84.3, 76.4, 60.4, 57.6, 46.8, 29.6, 28.1, 25.9, 21.8, 18.7 . N (7 methoxyhept 5 yn 1 yl) 4 methy lbenzenesulfonamide (2 100 ) To a solution of 4 8 (1.927 g, 4.867 mmol) in MeOH (30 mL), potassium carbonate (3.36 g, 24.38 mmol) was added. The solution was refluxed overnight and diluted with H 2 O (50 ml). The solution was extracted with DCM (3x30 ml), dried over MgSO 4 , filtered and the solvent was removed in vacuo . The residue was subjected to flash chromatography (20% EtOAc/hexane) to afford the title compou nd (1.11 g, 77%) as a pale yellow oil. 1 H NMR (300 MHz, CDCl 3 7.66 (m, 2H), 7.46 7.09 (m, 2H), 4.76 (t, J = 6.2 Hz, 1H), 4.02 (t, J = 2.1, 2H), 3.33 (s, 3H), 3.20 2.82 (m, 2H), 2.42 (s, 3H), 2.36 2.01 (m, 2H) , 1.65 1.36 (m, 4H). 13 C NMR (75 MHz, CDCl 3 76.60, 60.4, 57.7, 42.9, 28.8, 25.6, 21.7, 18.4 . 3 (2 ((tert butyldime thylsilyl)oxy)phenyl)propanal (2 103 ) At 78°C, to a solution of oxalyl chloride (7.1mL, 14.1mmols, 1.5eq) in dichloromethane (50mL) was added a solution of dimethylsulfoxide (2.53mL, 33mmols, 3.5eq) in dichloromethane (6.5mL). A solution of 2 102 ( 2.51 g, 9.42mmols, 1eq) in dichloromethane (26mL) was added dropwise to the first solution and the mixture was stirred for 15 minutes. Then , at 0°C, triethylamine (5.4mL, 40mmols, 4.2eq) was added dropwise and the mixture was stirred for 15 minutes. The reaction mixture was quenched by 30mL of water and 200mL of

PAGE 120

120 ethyl acetate. The reaction mixture was extracted using ethyl acetate, and the or ganic layer was dried over magnesium sulfate and concentrated to give 1.495 g (60%) of aldehyde. The spectroscopic data matched previously reported data. 109 tert butyl(2 (4,4 dibromobut 3 en 1 yl)phenoxy)dimethylsilane (S9) : At 0°C, to a solution of 48 (0.503 g, 1.90 mmol ) in dichloromethane (21mL) were add ed triphenylphosphine (2.01g, 7.68mmol ) and triethylamine (1.0mL, 7.41mmols, 3.9eq). Then, a solut ion of tetrabromomethane (1.31 g, 3.94 mmol) in dichloromethane (21mL) was added slowly and the mixtur e was stirred for 2 hours. The reaction mixture was quenched using 21mL of sodium carbonate. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate and purified by flash column chrom atography (5% ethyl acetate/hexane) to give 0.6862g (86%) of product. The spectroscopic data matched previously reported data. 110 (2 (but 3 yn 1 yl)pheno xy)(tert butyl)dimethylsilane (2 104 ) At 78°C, a solution of n butyllithium (1.9mL at 2.5M, 4.55 mmol) was added dropwise to a solution of 4 9 (0.686 g, 1.63 mmol , 1eq) in THF (16mL). The mixture was stirred for 2 hours. The solution was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried ov er magnesium sulfate and purified by flash column

PAGE 121

121 chromatography (3% ethyl a cetate/hexane) to give (344 mg, 72%). The spectroscopic data matched previously reported data. 109 tert butyl(2 (5 methoxypent 3 y n 1 yl)phenoxy)dimethylsilane (4 10) At 78°C, 0 .44mL of a solution at 2.5M of n butyllithium (1.1mmols ) was added drop wise to a solution of 4 9 (0.240 g, 0.92 mmol ) in THF (6mL). The mixture was stirred for 45 minutes, then warmed up at room temperature for 5 minutes and cooled again at 78°C. Then ch loromethyl methyl ether (1 . 05 mL, 1.38 mmol ) was added slowly to the mixture. The solution was stirred for 30 minutes. The reaction mixture was quenched with ammonium chloride, extracted with ethyl acetate and brine and purified by flash column chromatogra phy to give (213 mg, 76%) of product. 1 H NMR (300 MHz, CDCl 3 7.17 (dd, J = 7.7 , 1.9 Hz, 1H), 7.09 (td, J = 7.7, 1.9 Hz, 1H), 6.87 (td, J = 7.4 , 1.3 Hz, 1H), 6.78 (dd, J = 8.0, 1.2 Hz, 1H), 4.06 (t, J = 2.1 Hz, 2H), 3.34 (s, 2H), 2.82 (t, J = 7.6 Hz, 2H), 2.57 2.41 (m, 2H), 1.02 (s, 9H), 0.24 (s, 6 H). 2 (5 methoxypent 3 yn 1 yl)phenol (2 105 ) At 0°C, to a solution of 4 10 ( 0.136 g, 0.45 mmol ) in THF (3mL) was added a solution of tetra n butylammonium fluoride (0.90mL at 1M, 0.90 mmol ). The reaction mixture was stirred during 12 hours, and then quenched with 2mL of water and 3mL of ethyl acetate. The organic layer was extracted with ethyl

PAGE 122

122 acetate, washed with brine and purified by flash c olumn chromatography to give (51 mg, 61%) of produc t. 1 H NMR ( 300 MHz, CDCl 3 J = 7.5, 1.8 Hz, 1H), 7.07 (dd, J = 7.7, 1.8 Hz, 1H), 6.85 (td, J = 7.4, 1.1 Hz, 1H), 6.75 (dd, J = 8.0, 1.2 Hz, 1H), 4.08 (t, J = 2.1 Hz, 2H), 3.35 (s, 3H), 2.85 (t, J = 7.4 Hz, 2H), 2.59 2.49 (m, 2H). 13 C NMR (75 MHz, CDCl 3 19.6 (±) trans 6 hexyl 2 vinyltetrahydro 2H pyran 3 ol (2 106) The typical procedure was followed with 2 98 (45 mg, 0.2 0 mmol) to give the title compo und (16 mg, 38 z %) as clear oil. 1 H NMR (500 MHz, CDCl 3 (ddd, J = 17.5, 10.5, 7.0 Hz, 1H), 5.41 ( d, J = 17.5, 1H), 5.33 (d, J = 10.5 Hz, 1H) , 3.53 (t, J = 8.0 Hz, 1H), 3.37 3.18 (m, 2H), 2.19 2.12 (m, 2 H) , 1.82 1.11 (m, 12H), 0.89 (t , 7.0 Hz 3 H). ; 13 C NMR (75 MHz, CDCl 3 ) 136.4, 118.7, 83.8, 77.3, 69.6, 35.8, 31.8, 31.7 , 30 .8, 29.4, 25.7, 22.6, 14.1. tert butyl((6 methoxy 2,2 diphenylhex 4 yn 1 yl)oxy)dimethylsilane (2 11 3) A stirred solution of tert butyl((2,2 diphenylpent 4 yn 1 yl)oxy)dimethylsi lane 41 (2.00 g, 5.70 mmol) in 5 mL of dry THF was cooled to 78 °C and was treated with n BuLi (2.8 mL, 2.5 M in hexane) over 5 minutes, and stirred for 0.5 h warmed to °C for 5 minutes and cooled back to 78°C. At the same temperature, chloromethyl methyl ether (688 mg, 8.55 mmol) was added neat over 5 minutes. The mixture was stirred for an

PAGE 123

123 additional 0.5 h at 78 °C, then allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with sat. NH 4 Cl (aq) (5 mL) and diluted with EtO Ac (5 mL). The aqueous layer was extracted with EtOAc (3x5 mL), and the combined extracts were dried over MgSO 4 , filtered and evaporated in vacuo . The residue was subjected to flash chromatography (15% EtOAc/hexane) to furnish the pr oduct as a pale yellow oil (1.52 g, 68 % ) ; 1 H NMR (300 MHz, CDCl 3 7.12 (m, 10H), 4.20 (s, 2H), 3.98 (t , J = 2.1 Hz , 2H), 3.17 (s, 3H), 3.11 (t , 2.1 Hz, 2H), 0.82 (s , 9H), 0.08 (s, 6 H). 13 C NMR (75 MHz, CDCl 3 ) 145.7, 128.4, 127.9, 126.4, 85.0, 78.5 , 68.5 , 57.3, 51.8, 27.6, 25.9, 18.4, 5.6 . 6 methoxy 2,2 diphenylhex 4 yn 1 ol (2 114 ) : To a solution of 2 113 (1.50 g, 3.80 mmol) dissolved in THF (20mL) at 0°C, was added TBAF (1.0 M in THF, 7.6 mL, 7.6 mmol). The solution was stirred overnight and diluted with water (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3x 20 ml), dried over MgSO 4 , and concentrated in vacuo. The residue was subjected to flash chromatography ( 20% EtOAc/hexane) to furni sh the product as clear oil (980 mg, 92 %) ; 1 H NMR (300 MHz, CDCl 3 7.08 (m, 10zH), 4.30 (app d, J = 6.9, 2H), 3.97 (t, J = 2.1 Hz, 2H), 3.17 (s, Hz, 3H), 3.13 (t, J = 2.1 Hz, 2H); 13 C NMR (75 MHz, CDCl 3 ) 144.6 , 128.4 , 1 28.2, 126.9, 84.1, 79.3, 68.6, 60.2, 57.3, 51.9, 27.9.

PAGE 124

124 tert butyl(2 (5 methoxypent 3 y n 1 yl)phenoxy)dimethylsilane (2 1 2 0) At 78°C, a solution of n butyllithium (2.1mL at 2.5M, 5.25mmols) was added dropwise to a solution of tert butyl(hept 6 yn 1 yloxy)dimethylsilane 111 (1.00g, 4.41mmols) in THF (20mL). The mixture was stirred for 30 minutes and hydrocinnamaldehyde (591 mg, 4.41 mmol) was added. The solution was stirred for two hours, quenched with ammonium chloride and extracted with ethyl acetate. The combined organic extract was washed with brine, dried over magnesium sulfate and concentrade in vacuo . The crude compound was dissolved in THF and slowly added to a suspension of NaH (205 mg, 8.5 mmol) at 0°C. Methyl iodide (2.05 g , 14.3 mmol) was then added dropwise and the solution was allowed to warm to room temperature overnight. The reaction wasquenched with ammonium chloride and extracted with ethyl acetate. The combined organic extract was washed with brine, dried over magnes ium sulfate and concentrade in vacuo. The crude compound was dissolved in THF and TBAF (1.0 M in THF, 5.7 mL, 5.7 mmol) was added. The solution was stirred overnight and diluted with water (20 mL). The layers were separated and the aqueous layer was extrac ted with EtOAc (3x 20 ml), dried over MgSO 4 , and concentrated in vacuo. The residue was subjected to flash chromatography (20% EtOAc/hexane) to furnish the product as clear oil (742 mg, 58%); 1 H NMR (300 MHz, CDCl 3 7.44 6.97 (m, 5H), 3.97 3.76 (m, 1 H), 3.61 (t, J = 6.3 Hz, 2H), 3.36 (s, 3H), 2.74 (t, J = 7.8 Hz, 1H), 2.23 (dt, J = 6.9, 3.3 Hz, 2H), 1.99 1.83 (m, 2H), 1.69 1.36 (m, 6H).

PAGE 125

125 ( E ) 6,10 dihydroxy 1 phenyldec 3 en 5 one (2 123 ) The typical procedure was followed with 2 120 (52 mg, 0.20 mmol) to gi ve the title compound (10 mg, 19 %) as clear oil . 1 H NMR (5 00 MHz, CDCl 3 6.92 6.85 (m, 2H), 6.82 6.72 (m, 3H), 6.48 6.35 (m, 1H), 5.73 5.63 (m, 1H), 4.68 (t, 6.0 Hz, 1H), 3.52 3.37 (m, 2H), 3.29 3.13 (m, 1H), 3.02 2.82 (m, 1H), 2.42 2.26 (m, 2H), 2.18 1.96 (m, 2H), 1.63 1.32 (m, 2H), 1.24 1.08 (m, 4 H). 4.3 Diastereoselective Synthesis of Protec ted 1,3 Diols by Catalytic Diol Relocation General Procedure A (Aldehyde Optimization): Catalyst I (5 mol %) and AgOTf (5 mol %) w ere combined with molecular sieves (4Ã…) in a test tube under an argon atmosphere in a glove box). The reaction vessel was wrapped with aluminum foil before being removed from the glove box, and the mixture was dissolved in CH 2 Cl 2 (0.2 M). The mixture was a llowed to stir at room temperature for 5 minutes before addition of the aldehyde (3 eq). Z But 2 en 1,4 diol 11 (1 eq) was then added. Progress was monitored by TLC and upon completion the reaction was quenched by filtration of the crude mixture over a silica gel plug. The solution was then concentrated under reduced pressure and, at this stage, the diastereomeric ratio was determined by integration of the acetal pro ton or other suitably resolved peaks. The residue was then purified by flash column chromatography. If the aldehyde was not volatile, the excess aldehyde was reduced to the corresponding alcohol with NaBH 4 and then purified by flash column chromatography .

PAGE 126

126 2 phenyl 4 vinyl 1,3 dioxolane (3 43a) . Following general procedure A, reaction of 3 41 (0.025 g, 0.28 mmol) and benzaldehyde ( 3 42a ) afforded the title compound as an oil (0.027 g, 55%, yield, 2:1 dr). R f = 0.40 (20% CH 2 Cl 2 /hexanes); Proton and car bon NMR spectra were found to match reported data. 113 2 p henylethyl 4 vinyl 1,3 dioxolane (3 43d). Following general procedure A, reaction of 3 41 (0.018 g, 0.20 mmol) and hydrocinnamaldehyde ( 3 42d ) afforded the title compound as a clear and colorless oil (0.028 g, 68% yield, 5:1 dr). R f = 0.30 (10% CH 2 Cl 2 /pentane); 1 H NMR (500 MHz, CDCl 3 7.26 (m, 2H), 7.26 7.09 (m, 3H), 5.86 (ddd, J = 17.5, 10.5, 7.0 Hz, 1H), 5.38 (d, J = 17.5, 1H), 5.26 (d, 10.5, 1H), 5.10 (t, J = 4.7 Hz, 1H), 4.57 4.50 ( m, 1H), 4.23 (dd, J = 8.5, 5.5 Hz, 1H), 3.57 (t, J = 8.0 Hz, 1H), 2.81 2.76 (m, 2H), 2.04 1.99 (m, 2H); 13 C NMR (125 MHz, CDCl 3 135.6, 128.4 (2 signals), 125.9, 117.9, 103.9, 77.1, 70.3, 35.8, 30.1; HRMS (ESI) calcd for C 13 H 16 O 2 Na [M+Na] + 227 .1043, found 207.1048

PAGE 127

127 2 Heptyl 4 vinyl 1,3 dioxolane (3 43e). Following general procedure A, reaction of 3 41 (0.018 g, 0.20 mmol) and octanal ( 3 42e ) afforded the title compound as a colorless oil (0.032 g, 81% yield, 3:1 dr). R f = 0.40 (20% CH 2 Cl 2 /hexanes); 1 H NMR (300 MHz, CDCl 3 J = 17.4, 10.5, 6.9 Hz, major 1H), 5.91 5.78 (m, minor 1H), 5.38 5.28 (m, major 1H, minor 1H), 5.25 5.18 (m, major 1H, minor 1H), 5.02 (t, J = 4.8 Hz, major 1H), 4.94 (t, J = 4.8 Hz, minor 1H) 4.53 4 .39 (m, major 1H, minor 1H), 4.17 (dd, J = 8.4, 6.3 Hz, major 1H), 3.98 (dd, J = 8.1, 7.2 Hz, minor 1H) 3.61 (dd, J = 8.1, 6.6 Hz, minor 1H), 3.52 (dd, J = 8.4, 7.5 Hz, major 1H), 1.75 1.58 (m, major 2H, minor 2H), 1.49 1.12 (m, major 10H, minor 10H), 0.95 0.78 (m, major 3H, minor 3H); 13 C NMR (75 MHz, CDCl 3 22.9, 14.3; HRMS (ESI) calcd for C 12 H 22 O 2 K [M+K] + 237.1251, found 237.1254 2 Isopropyl 4 vinyl 1,3 dioxolane (3 43f). Followi ng general procedure A, reaction of 3 41 (0.062 g, 0.70 mmol) and isobutyraldehyde ( 3 42f ) afforded the title compound as a colorless oil (0.079 g, 80% yield, 8:1 dr). R f = 0.40 (20% CH 2 Cl 2 /hexanes); Proton and carbon NMR spectra were found to match repor ted data. 114 2 Cyclohexyl 4 vinyl 1,3 dioxolane (3 43g). Following general procedure A, reaction of 3 41 (0.018 g, 0.20 mmol) and cyclohexylcarboxaldehyde ( 3 42g ) afforded the title

PAGE 128

128 compound as a colorless oil (0.034 g, 93%yield, 8:1 d.r) R f = 0.23 (20% CH 2 Cl 2 /pentanes); Proton and carbon NMR spectra were found to match reported data. 115 2 Tert butyl 4 vinyl 1,3 dioxolane (3 43h). Following general procedure A, reaction of 3 41 (0.028 g, 0.32 mmol) and pivaldehyde ( 3 42h ) afforded the tit le compound as a colorless oil (0.035 g, 70% yield, 18:1 dr). R f = 0.5 (5% EtOAc/hexane) 0.50. 1 H NMR (500 MHz, CDCl 3 J = 17.5, 10.5, 7.0 Hz, major 1H, minor 1H), 5.34 (d, 17.5, major 1H, minor 1H), 5.22 (d, J = 10.5, maj or 1H, minor 1H), 4.68 (s, major 1H), 4.61 (s, minor 1H) 4.46 4.39 (m, major 1H, minor 1H), 4.15 (dd, J = 8.0, 6.0 Hz, major 1H), 4.00 (dd, J = 8.0, 7.0 Hz, minor 1H) 3.53 (app t, major 1H, minor 1H), 0.93 (s, major 9H, minor 9H); 13 C NMR (125 MHz, CDCl 3 ) 77.8, 70.7, 34.9, 24.5; HRMS (ESI) calcd for C 9 H 16 O 2 Na [M+Na] + 179.1043, found 179.1034 2 Trichloromethyl 4 vinyl 1,3 dioxolane (3 43i). Following general procedure A, reaction of 3 41 (0.018 g, 0.20 mmol) and chloral hydrate ( 3 42i ) afforded the title compound as a clear colorless oil (0.035 g, 98% yield, 2:3 dr). R f = 0.6 (15% EtOAc/hexanes): 1 H NMR (500 MHz, CDCl 3 J = 17.5, 10.5, 8.0 Hz, minor

PAGE 129

129 1H) 5.83 (ddd, J = 17.0, 10.0, 7.0 Hz, major 1H), 5.53 5.38 (m, maj or 3H, minor 3H), 5.0 (app q, J = 6.5 Hz, major 1H), 4.75 (app q , J = 7.0 Hz, minor 1H), 4.50 (dd, J = 8.0, 7.5 Hz, major 1H), 4.28 (dd, J = 7.0, 6.5 Hz, minor 1H), 3.96 (dd, J = 8.5, 8.0 Hz, minor 1H) 3.84 (app t, J = 7.5 major 1H); 13 C NMR (125 MHz, CDCl 3 minor 120.7 major, 119.7 minor 107.8 major, 107.7 minor, 99.9 (major or minor), 99.6 (major or minor), 80.7 minor, 79.7 major, 71.7 major, 70.9 minor; HRMS (ESI) calcd for C 6 H 7 Cl 3 O 2 Na [M+Na] + 238.9404, found 238.9413 4.3.1 Synth esis of Diols 3 45g, and 3 45h ( Z ) 1 cyclohexylpent 2 ene 1,5 diol ( Z 3 45e). A solution of 1 cyclohexylpent 2 yne 1,5 diol 116 (54.0 mg) in EtOAc (9.00 mL) was allowed to stir under a hydrogen atmosphere (1 atm) for 15 hours. The reaction mixture was then filtered over celite and the filtrate was concentrated to give a crude yellow oil, which was purified via flash column chromatography to yield a clear colorless oil (0.230 g, 7 5%). R f = 0.24 (50% EtOAc/hexanes). 1 H NMR (500 MHz, CDCl 3 5.43 (m, 2H), 4.10 (t, J = 7.5 Hz, 1H), 3.783 (dt, J =10.0, 5.0 Hz, 1H), 3.58 (td, J = 9.5, 4.0 Hz, 1H), 2.98 (br s, 2H), 2.56 2.45 (m, 1H), 2.26 2.17 (m, 1H), 1.99 1.91 (m, 1H), 1. 81 1.63 (m, 5H), 1.45 1.34 (m, 1H), 1.30 1.12 (m, 2H), 1.06 0.87 (m, 2H); 13 C NMR (125 MHz, CDCl 3 129.1, 71.1, 61.2, 43.5, 30.9, 28.9, 28.6, 26.6, 26.1, 25.9; HRMS (ESI) calcd for C 11 H 20 O 2 Na [M+Na]+ 207.1356, found 207.1359

PAGE 130

130 ( E ) 1 cyclo hexylpent 2 ene 1,5 diol ( E 3 45e). A solution of 1 cyclohexylpent 2 yne 1,5 diol 116 (1.48 mmol, 271 mg) in THF (3 mL) was added slowly to a suspension of room temperature and stirred for 18 hours. After this time, the reaction was quenched by the sequent ial addition of 0.120 mL H 2 O, 0.120 mL 15% aqueous NaOH solution, and 0.360 mL H 2 O. Solids were removed by filtering over a bed of celite and the filtrate was concentrated to give a crude oil that was purified by flash column chromatography to yield a clea r colorless oil (0.120 g ,44%). R f = 0.24 (50% EtOAc/Hexanes). 1 H NMR (500 MHz, CDCl 3 5.59 (m, 2H), 3.85 (t, J = 5.5 Hz, 1H), 3.70 (t, J = 6.5 Hz, 2H), 2.38 2.33 (m, 2H), 2.22(br s, 1H) 1.90 1.85 (m, 1H), 1.82 1.72 (m, 2H), 1.72 1.65 (m, 2H) , 1.60 1.35 (m, 4H) 1.31 1.10 (m, 2H), 1.05 0.95 (m, 2H); 13 C NMR (125 MHz, CDCl 3 (ESI) calcd for C 11 H 20 O 2 Na [M+Na] + 207.1356, found 207.1365 tert butyl 4 (1,5 dihydroxypen t 2 yn 1 yl)piperidine 1 carboxylate ( 3 50 ). Ethylmagnesium bromide (3.0 M solution in Et 2 O, 11 mmol, 3.67 mL) was slowly added butyn 1 ol (5 mmol, 0.38 mL) in THF (20 mL). The mixture was allowed to warm to room temperature and then heated to reflux for 1 hour, before

PAGE 131

131 tert butyl 4 formylpiperidine 1 carboxylate 117 (5 mmol, 1.06 g) in THF (10 mL). This mixture was allowed to stir for 16 hours and was quenched with a saturated ammoni um chloride solution. The aqueous layer was extracted with EtOAc and the combined organic extract was dried over magnesium sulfate. The solvent was evaporated and the crude mixture was purified flash column chromatography to yield a clear colorless oil (0. 560 g, 41%) R f = 0.2 (50% EtOAc/Hexanes). 1 H NMR (300 MHz, CDCl 3 4.05 (m, 3H), 3.69 (t, J = 6.0 Hz, 2H), 2.73 2.58 (m, 2H), 2.45 (td, J = 6.0, 1.9 Hz, 2H), 1.83 1.56 (m, 3H), 1.43 (s, 9H), 1.38 1.15 (m, 2H); 13 C NMR (125 MHz, CDCl 3 83.5, 81.3, 79.5, 66.2, 60.9, 42.6, 28.4, 27.8, 27.3, 22.9; HRMS (ESI) calcd for C 15 H 25 NO 4 Na [M+Na] + 306.1676, found 306.1676 ( Z ) tert butyl 4 (1,5 dihydroxypent 2 en 1 yl)piperidine 1 carboxylate ( Z 14h). A solution of 3 50 (0.39 mmol, 106.0 mg), quino catalyst (21.0 mg) in EtOAc (2.00 mL) was allowed to stir under a hydrogen atmosphere (1 atm) for 15 hours. The reaction mixture was then filtered over celite and the filtrate was concentrated to give a crude yellow oil, which was purified via flash column chromatography to yield a clear colorless oil (0.070 g, 66%). R f = 0.24 (50% EtOAc/hexanes). 1 H NMR (300 MHz, CDCl 3 5.51 (m, 2H), 4.19 4.01 (m, 3H), 3.71 (dt, J = 10.2, 5.1 Hz, 1H), 3.55 (td, J = 10.2, 4.2 Hz, 1H), 3.02 ( brs, 2H), 2.74 2.57 (m, 2H), 2.55 2.40 (m, 1H), 2.24 2.11 (m, 1H), 1.93 1.82 (m,1H), 1.65 1.47 (m,

PAGE 132

132 2H), 1.43 (s, 9H), 1.28 1.01 (m, 2H); 13 C NMR (125 MHz, CDCl 3 129.8, 79.4, 70.2, 61.1, 41.9, 30.8, 28.4, 28.2, 2 7.7; C 15 H 27 NO 4 Na [M+Na] + 308.1832, found 308.1839 General Procedure B: Catalyst I V (5 mol%) and AgSbF 6 (5 mol %) were combined with molecular sieves (4 Ã…) in a test tube under argon in a glove box. The reaction vessel was wrapped in aluminum foil before be ing taken out of the glove box. CH 2 Cl 2 (0.8 M) was then added to the mixture and the solution was dissolved and allowed to stir for five minutes at room temperature. Isobutyraldehyde 3 4 2f (5 eq.) and the corresponding Z 1,5 monoallylic diol (1 eq) were then added. Progress was monitored by TLC for the disappearance of diol and the reaction was quenched by filtering the crude mixture over a plug of silica. The solution was then concentrated under reduced pressure and, at th is stage, the diastereomeric ratio was determined by integration of the acetal proton or other suitably resolved peaks. The residue was then purified by flash column chromatography. General Procedure C: Bismuth (III) triflate (5 mol %) and molecular siev es (4 Ã…) were combined in a test tube under argon in a glove box. The reaction vessel was taken out of the glove box, and CH 2 Cl 2 (0.2 M) was added at room temperature. Isobutyraldehyde (5 eq.) and the corresponding E 1,5 monoallylic diol (1 eq) were then a dded. Progress was monitored by TLC for the disappearance of diol and the reaction was quenched by filtering the crude mixture over a plug of silica. The solution was then concentrated under reduced pressure and, at this stage, the diastereomeric ratio was determined by integration of the acetal proton or other suitably resolved peaks. The residue was then purified by flash column chromatography.

PAGE 133

133 2 Isopropy l 4 ((E) styryl) 1,3 dioxane (3 46 a). Following general procedure B, the reaction of Z 3 45 a 118 (0. 036 g, 0.20 mmol) afforded 3 46 a as a colorless oil (0.042 g, 91% yield, 22:1 dr). Following general procedure C, the reaction of E 3 45 a 119 (0.036 g, 0.20 mmol) afforded 3 46 a as a colorless oil (0.046 g, 98% yield, >25:1 dr) R f = 0.20 (40% CH 2 Cl 2 /hexane ): 1 H NMR (300 MHz, CDCl 3 7.19 (m, 5H), 6.62 (d, J = 16.2 Hz, 1H), 6.23 (dd, J = 16.2, 5.7, 1H) 4.35 (d, 5.1 Hz, 1H), 4.33 4.25 (m, 1H), 4.18 (dd, J = 11.1, 4.8 Hz, 1H), 3.80 (td, J = 11.1, 2.4 Hz, 1H), 1.97 1.77 (m, 2H), 1.62 1.52 (m, 1H), 0.98 (d, J = 6.8 Hz, 6H). 13 C NMR (75 MHz, CDCl 3 ) 136.9, 130.4, 129.8, 128.7, 127.8, 126.7, 105.8, 77.1, 66.7, 33.1, 32.0, 17.5, 17.3. HRMS (ESI) calcd for C 15 H 20 O 2 K [M+K] + 271.1095, found 271.1 091 nOe data for 3 46 a: 2 Isopropyl 4 ((E) 4 fluorostyryl) 1,3 dioxane (3 46 c). Following general procedure B, the reaction of Z 3 45 c (0.039 g, 0.20 mmol) afforded 3 46 c as a colorless oil (0.049 g, 98% yield, > 25:1 dr). Following general procedure C, the reaction of E 3 45 c (0.039

PAGE 134

134 g, 0.20 mmol) afforded 3 46 c as a colorless oil (0.040 g, 80% yield, >25:1 dr) R f = 0.20 (40% CH 2 Cl 2 /hexane). 1 H NMR (500 MHz, CDCl 3 7.35 (m, 2H), 7.02 (app t, J = 8.5 Hz, 2H), 6.58 (d, J = 16.0, 1H), 6.14 (dd, J = 16.0, 6.0 Hz, 1H), 4.37 (d, J = 5.0 Hz, 1H), 4.36 4.26 (m, 1H), 4.19 (dd, J = 11.5, 5.0 Hz,1H), 3.82 (td, J = 11.5, 2.5 Hz, 1H), 1.93 1.76 (m, 1H), 1.60 1.49 (m, 1H), 0.98 (d, 7.5 Hz, 6H); 13 C NMR (125 MHz, CDCl 3 J = 246.9 Hz) 132.9 (d, J = 3.4 Hz), 129.3, 129.2, 128.0 (d, J = 8.1 Hz) 115.4 (d, J = 21.6 Hz), 104.9, 77.5, 66.6, 33.1, 31.9, 16.9; HRMS (ESI) calcd for C 15 H 19 FO 2 Na [M+Na] + 273.1261, found 271.1271 2 Isopropyl 4 ((E) ph eny lbut 1 en yl) 1,3 dioxane (3 46 d). Following general procedure B, the reaction of Z 3 4 5 d 120 (0.039 g, 0.19 mmol) afforded 3 46 d as a clear colorless oil (0.041 g, 83% yield, >25:1 dr). Following general procedure C, the reaction of E 3 4 5 d 120 (0.078 g, 0.38 mmol) afforded 3 46 d as a clear colorless oil (0.094 g, 95% yield, >25:1 dr). R f = 0.20 (40% CH 2 Cl 2 /hexane). 1 H NMR (300 MHz, CDCl 3 7.11 (m, 5H), 5.83 5.65 (m, 1H), 5.53 (dd, J = 15.5, 6.0 Hz, 1H), 4.28 (d, J = 5.0 Hz, 1H), 4.13 (dd, J = 11.5, 5.0 Hz, 1H), 4.11 4.06 (m, 1H) 3.81 3.65 (m, 1H), 2.73 (t, J = 8 Hz, 2H), 2.48 2.20 (m, 2H), 1.91 1.69 (m, 3H), 0.97 (d, 6.8 Hz, 6H); 13 C NMR (125 MHz, CDCl 3 33 .0, 31.9, 17.5, 17.2; HRMS (ESI) calcd for C 17 H 24 O 2 Na [M+Na] + 283.1669, found 283.1678

PAGE 135

135 2 Iso propyl 4 vinyl 1,3 dioxolane (3 46e ). Following general procedure B, the reaction of Z 2 butene 1,4 diol (0.018 g, 0.20 mmol) ( 3 4 1 ) afforded 3 46e as a colorless oil (0.023 g, 80% yield, 5:1 dr). Proton and carbon NMR spectra were found to match reported data. 114 (2 Isopropyl 4 ((E) styryl) 1 ,3 dioxolane (3 46f ). Following general procedure B, the reaction of Z 3 45f 121 (0.033 g, 0.20 mmol) afforded 3 46f as a colorless oil (0.038 g, 87% yield, 15:1 dr). R f = 0.20 (40% CH 2 Cl 2 /hexane). 1 H NMR (500 MHz, CDCl 3 ) 7.42 7.36 (m, 2H), 7.35 7.30 (m, 2H), 7.28 7.23 (m, 1H) 6.65 (d, 15.5 Hz, 1H), 6.17 (dd, J = 15.5, 7.5 Hz, 1H), 4.87 (d, J = 5.0 Hz, 1H), 4.67 4.57 (m, 1H), 4.23 (dd, J = 8.5, 6.0 Hz, 1H), 3.62 (t, J =8.0 Hz, 1H), 1.92 1.82 (m,1H), 0.99 (d, 6.5 Hz, 6H); 13 C NMR (125 MHz, CDCl 3 16.9; HRMS (ESI) calcd for C 14 H 18 O 2 Na [M+Na] + 241. 1989, found 241.1188 ( E ) 4 (2 cyclohexylvi nyl) 2 isopropyl 1,3 dioxane (3 46g ) . Following general procedure B, the reaction of Z 3 4 5g (0.037 g, 0.20 mmol) afforded 3 46g as a colorless oil (0.039 g, 81% yield, 11:1 dr). Following general procedure C, the reaction of E 3 4 5g

PAGE 136

136 (0.037 g, 0.20 mmol) afforded 3 46g as a colorless oil (0.041 g, 86% yield, >25:1 dr) R f = 0.20 (40% CH 2 Cl 2 /hexane): 1 H NMR (500 MHz, CDCl 3 d, 15.5, 6.5 Hz, 1H), 5.46 (dd, J = 15.5, 6.0 Hz, 1H), 4.29 (d, J = 5.0 Hz, 1H), 4.14 (dd, J = 11.5, 5.0 Hz, 1H), 4.10 4.04 (m, 1H), 3.75 (td, J = 11.5, 3.0 Hz, 1H), 2.04 1.92 (m, 1H), 1.89 1.79 (m, 1H), 1.79 1.71 (m, 5H), 1.70 1.63 (m, 1H), 1.49 1.42 (m, 1H), 1.36 1.04 (m, 5H), 0.96 (d, J = 6.5, Hz, 6H); 13 C NMR (125 MHz, CDCl 3 ) 137.8, 127.6, 105.6, 77.2, 66.5, 40.3, 32.9, 32.7, 31.9, 26.2, 26.1, 17.5, 17.0; HRMS (ESI) calcd for C 15 H 26 O 2 K [M+K] + 277.1564, found 277.1566 Tert butyl (E) 4 (2 (2 isopropyl 1,3 dioxan 4 yl)vinyl)piperidine 1 carboxylate (3 46h ). Following general procedure B, the reaction of Z 3 45h (0.034 g, 0.12 mmol) afforded 3 46h as a colorless oil (0.033 g, 80% yield, 3:1 dr). R f = 0.20 (40% CH 2 Cl 2 /hexane): 1 H NMR (500 MHz, CDCl 3 J = 15.5, 6.5 Hz, 1H), 5.50 (dd, J = 15.5, 6.0 Hz, 1H), 4.28 (d, J = 5.0 Hz, 1H), 4.18 4.00 (m, 3H), 3.75 (td, J = 11.5, 2.5 Hz, 1H), 2.80 2.67 (m, 2H), 2.20 2.04 (m, 1H), 1.90 1.63 (m, 4H), 1.47 (s, 9H), 1.36 1.2 3 (m, 2H), 0.95 (d, J = 6.5 Hz, 6H); 13 C NMR (125 MHz, CDCl 3 135.4, 128.9, 105.6, 79.3, 76.8, 66.4, 38.5, 32.9, 31.8, 31.6, 28.5, 17.4, 17.0; HRMS (ESI) calcd for C 17 H 27 NO 4 Na [M+Na] + 362.2302, found 362.2313

PAGE 137

137 4.3.2 Synthesis of diol 3 51 b 5 cyclohexylpent 2 yne 1,5 diol ( 4 12 ). n BuLi 2.5 M solution in hexanes (14.4 mmol, 7.2 mL ) was added to a solution of 2 (prop 2 yn 1 yloxy)tetrahydro 2 H pyran 1 22 (12 mmol, 2.04 g ) in THF (100 mL) at 78 °C. The solution was allowed to stir for 30 minutes before BF 3 2 (10 mmol, 1.41 g) and 2 cyclohexyloxirane 1 23 (10 mmol, 1.26 g) were added. The solution was allowed to warm to room temperature and stir overnigh t, at which point the reaction was quenched with a saturated ammonium chloride solution. The aqueous layer was extracted with EtOAc and the combined organic extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the crude mixture was dissolved in MeOH (15 ml) and PPTS (0.27 mmol, 68 mg) was added. The solution was stirred overnight and the solvent was evaporated. The crude mixture was purified via flash column chromatography to yield S3 as a clear colorless oil (0.691 g, 38%) R f = 0.30 (40% EtOAc/Hexanes): 1 H NMR (500 MHz, CDCl 3 J = 1.5 Hz, 2H), 3.53 3.48 (m, 1H), 2.55 2.48 (m, 1H), 2.44 2.37 (m, 1H), 1.96 1.87 (m, 1H), 1.82 1.74 (m, 2H), 1.74 1.52 (m, 8H), 1.53 1.42 (m, 1H), 1.34 1.12 (m, 3H), 1 .11 0.97 (m, 2H); 13 C NMR (125 MHz, CDCl 3 74.2, 51.4, 42.6, 29.0, 28.2, 26.4, 26.1, 26.0, 24.9; HRMS (ESI) calcd for C 11 H 18 O 2 Na [M+Na] + 205.1199, found 209.1194

PAGE 138

138 ( Z ) 5 cyclohexylpent 2 ene 1,5 diol ( 3 51 b ). A solution of 4 12 (2.06 mmol , 376.0 mL) was allowed to stir under a hydrogen atmosphere (1 atm) for 15 hours. The reaction mixture was then filtered over celite and the filtrate was concentrated to g ive a crude yellow oil, which was purified via flash column chromatography to yield a clear colorless oil (0.251 g, 66%). R f = 0.25 (50% EtOAc/hexanes). 1 H NMR (500 MHz, CDCl 3 5.83 (m, 1H), 5.77 5.59 (m, 1H), 4.23 (dd, J = 11.5, 7.0 Hz, 1H), 4. 11 (dd, J = 12.0, 7.0 Hz, 1H), 3.51 3.19 (m, 1H), 2.42 2.22 (m, 2H), 2.13 (bs, 2H), 1.94 1.98 (m, 1H), 1.84 1.75 (m, 2H), 1.75 1.65 (m, 2H), 1.46 1.34 (m, 1H), 1.33 0.95 (m, 6H). 13 C NMR (125 MHz, CDCl 3 28.3, 26.5, 26.2, 26.1. HRMS (ESI) calcd for C 11 H 20 O 2 Na [M+Na] + 207.1356, found 207.1361 General Procedure D: Catalyst II (5 mol %) and AgSbF 6 (5 mol%) were combined with molecular sieves (4 Ã…) in a test tube under argon in a glove box. The reaction vessel was wrapped in aluminum foil before being taken out of the glove box. CH 2 Cl 2 (0.8 M) was then added to the mixture and the solution was allow ed to stir five minutes at room temperature. Chloral Hydrate 3 4 2i (1 eq) and the corresponding Z 1,5 monoallylic diol (1 eq) were then added. Progress was monitored by TLC for the disappearance of diol and the reaction was quenched by filtering the crude mixture over a plug of silica. The solvent was removed in vacuo and the crude mixture was purified by flash column chromatography.

PAGE 139

139 4 phenethyl 2 (trichloromethyl) 6 vinyl 1,3 dioxane ( 3 52 a ). Following general procedure D, the reaction of 3 51 a 12 4 (0.0 21 g, 0.10 mmol) afforded 3 52 a as a colorless oil (0.029 g, 87% yield, > 25:1 dr). R f = 0.20 (40% CH 2 Cl 2 /hexane): 1 H NMR (300 MHz,CDCl 3 7.10 (m, 5H), 5.90 (ddd, J = 17.1, 10.8, 5.4 Hz, 1H), 5.34 (dd, J = 17.1, 2.5 Hz, 1H), 5.20 (dd, J = 10.8, 2 .5 Hz, 1H), 4.87 (s,1H), 4.35 4.21 (m,1H), 3.82 3.68 (m, 1H), 2.90 2.74 (m, 2H), 2.13 1.94 (m, 1H), 1.91 1.72 (m, 1H), 1.65 1.57 (m, 2H); 13 C NMR (125 MHz, CDCl 3 102.7, 77.3, 75.5, 36.8, 36.1, 30.7; HRMS (ESI) calcd for C 15 H 17 Cl 3 O 2 Na [M+Na] + 357.0186, found 357.0197 nOe data for 3 52 a: 4 cyclohexyl 2 (trichloromethyl) 6 vinyl 1,3 dioxane ( 3 52 b ). Following general procedure D, the reaction of 3 51 b (0.037 g, 0.20 mmol) afforded 3 52 b as a colorless oil (0.055 g, 89% yield, > 25:1 dr). R f = 0.20 (40% CH 2 Cl 2 /hexane). 1 H NMR (500 MHz, CDCl 3 J = 17.0, 11.0, 5.5 Hz, 1H), 5.38 (dd, J = 17.0, 1.5 Hz, 1H), 5.22

PAGE 140

140 (dd, J = 11.0, 1.5 Hz, 1H), 4.88 (s, 1H) 4.37 4.23 (m, 1H), 3.63 3.5 0 (m, 1H), 2.06 1.95 (m,1H), 1.86 1.63 (m, 5H), 1.61 1.49 (m, 2H), 1.33 1.15 (m, 4H), 1.13 0.91 (m, 2H); 13 C NMR (75 MHz, CDCl 3 28.1, 26.5, 25.9, 25.8; HRMS (ESI) calcd for C 13 H 19 Cl 3 O 2 Na [M +Na]+ 335.0343, found 335.0343 4 octyl 2 (trichloromethyl) 6 vinyl 1,3 dioxane ( 3 52 c ). Following general procedure D, the reaction of 3 51 c 12 4 (0.023 g, 0.11 mmol) afforded 3 52 c as a colorless oil (0.031 g, 82% yield, > 25:1 dr). R f =0.20 (40% CH 2 Cl 2 /hexane): 1 H NMR (500 MHz, CDCl 3 5.91 (ddd, J = 17.0, 11.0, 5.5 Hz, 1H), 5.36 (d, J = 17.0, 1.5 Hz, 1H), 5.21 (dd, J = 11.0 Hz, 1.5 Hz, 1H), 4.88 (s, 1H), 4.42 4.06 (m, 1H), 3.92 3.62 (m, 1H), 1.77 1.63 (m, 2H), 1.61 1.12 (m, 14H), 0.88 (t, J = 7 .0 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 116.2, 102.7, 97.0, 77.5, 77.3, 36.2, 35.4, 31.9, 29.5, 29.4, 29.2, 24.9, 22.7, 14.1. HRMS (ESI) calcd for C 15 H 25 Cl 3 O 2 Na [M+Na] + 365.0812, found 365.0822 4 ( tert butyl) 2 (trichloromethyl) 6 vinyl 1,3 dioxane ( 3 52 d ). Following general procedure D, the reaction of 3 51 d 1 25 (0.032 g, 0.20 mmol) afforded 3 52 d as a colorless oil (0.048 g, 83% yield, > 25:1 dr). R f = 0.20 (40% CH 2 Cl 2 /hexane): 1 H NMR (500 MHz, CDCl 3 J = 16.5, 10.5, 5.0 Hz, 1H), 5.39 (dd, J = 16.5, 1.5 Hz,

PAGE 141

141 1H), 5.23 (dd, J = 10.5, 1.5 Hz, 1H), 4.90 (s,1H), 4.32 4.27 (m, 1H), 3.47 (dd, J = 11.0, 3.0 Hz, 1H), 1.69 1.46 (m, 2H), 0.98 (s, 9H); 13 C NMR (125 MHz, CDCl 3 116.1, 102.6, 97.3, 84.3, 7 7.5, 34.17, 30.7, 25.4; HRMS (ESI) calcd for C 11 H 17 Cl 3 O 2 Na [M+Na]+ 309.0186, found 309.0198 4 phenyl 2 (trichloromethyl) 6 vinyl 1,3 dioxane ( 3 52 e ). Following genera l procedure D, the reaction of 3 51 e 126 (0.027 g, 0.15 mmol) afforded 3 52 e as a colorl ess oil (0.025 g, 55% yield, > 25:1 dr). R f = 0.20 (40% CH 2 Cl 2 /hexane). 1 H NMR (500 MHz, CDCl 3 7.34 (m, 5H), 5.96 (ddd, J = 16.5, 10.5, 5.0 Hz, 1H), 5.42 (d, J = 16.5 Hz, 1H), 5.25 (d, J = 10.5 Hz, 1H), 5.12 (s, 1H), 4.98 4.91 (m,1H), 4.56 4.48 ( m, 1H), 2.0 1.93 (m, 1H), 1.90 1.71 (m, 1H); 13 C NMR (125 MHz, CDCl 3 136.1, 128.5, 128.1, 125.6, 116.6, 109.9, 102.7, 78.4, 76.7, 38.3; HRMS (ESI) calcd for C 13 H 13 Cl 3 O 2 Na [M+Na] + 328.9873 found 328.9863 4 (but 3 en 1 yl) 2 (trichloromethyl) 6 vinyl 1,3 dioxane phenyl 2 (trichloromethyl) 6 vinyl 1,3 dioxane ( 3 52 f ). Following genera l procedure D, the reaction of 3 51 f 126 (0.031 g, 0.20 mmol) afforded 3 52 f as a colorless oil (0.020 g, 40% yield, > 25:1 dr) . R f =0.20 (40% CH 2 Cl 2 /hexane): 1 H NMR (500 MHz, CDCl 3 J = 16.5, 10.5, 5.0 Hz, 1H), 5.88 5.77 (m, 1H), 5.38 (dd, J = 16.5, 1.5 Hz, 1H), 5.23 (dd, J = 10.5, 1.5 Hz, 1H), 5.08 (dd, J = 17.0, 1.5 Hz, 1H), 5.02 (dd, J = 10.0, 1.5,1H),

PAGE 142

142 4.90 (s,1H ), 4.37 4.30 (m,1H), 3.92 3.79 (m, 1H), 2.40 2.15 (m, 2H), 1.89 1.77 (m,1H), 1.72 1.61 (m, 2H), 1.60 1.49 (m, 2H); 13 C NMR (125 MHz, CDCl 3 136.6, 116.3, 115.3, 102.7, 96.9, 77.4, 76.2, 36.1, 34.4, 28.9; HRMS (ESI) calcd for C 11 H 15 Cl 3 O 2 Na [ M+Na] + 307.0030, found 307.0031 4 (9benzyloxy)methyl) 2 (trichloromethyl) 6 vinyl 1,3 dioxane ( 3 52 g ). Catalyst II (0.01 mmol, 8.3 mg) and AgSbF 6 (0.01 mmol, 3.4 mg) were combined with molecular sieves (4 Ã…) in a test tube under argon in a glove box. The reaction vessel was wrapped in aluminum foil before being taken out of the glove box. CH 2 Cl 2 (0.25 mL) was then added to the mixture and the solut ion was dissolved allowed to stir five minutes at room temperature. Chloral Hydrate 3 42 i (0.1 mmol, 17 mg) and the ( Z ) 6 (benzyloxy)hex 2 ene 1,5 diol (0.10 mmol 22mg) 3 51 g 127 were then added. Progress was monitored by TLC for the disappearance of diol and the reaction was quenched by filtering the crude mixture over a plug of silica. The solvent was removed in vacuo and the crude mixture was purified by flash column chromatography to afford 3 52 g as a clear oil (28.5 mg, 81% yield). R f = 0.15 (40% CH 2 Cl 2 /hexane): 1 H NMR (500 MHz, CDCl 3 7.29 (m, 5H), 5.94 (ddd, J = 16.5, 10.5, 5.0 Hz, 1H), 5.39 (d, J = 16.5 Hz, 1H), 5.25 (d, J = 10.5 Hz, 1H), 4.96 (s, 1H), 4.77 4.60 (m, 2H), 4.42 4.31 (m, 1H), 4.20 4.07 (m, 1H), 3.71 (dd, J = 11.0, 5.5 Hz, 1 H), 3.60 (dd, J = 11.0, 4.5 Hz, 1H), 1.80 1.70 (m,1H), 1.71 1.59 (m, 1H); 13 C NMR (125 MHz, CDCl 3 102.5, 96.8, 77.2, 76.5, 73.5, 71.9, 32.8; HRMS (ESI) calcd for C 15 H 17 Cl 3 O 2 Na [M+Na] + 373.0135, found 373.0148

PAGE 143

143 Syn 6, 6 dimethylhept 1 ene 3,5 diol (3 5 8) . n BuLi 1.86 M solution in hexanes (0.168 mmol, 0.091 mL) was to a solution of 3 52 d (0.076 mmol, 22 mg) in THF (1 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 1 hr. The reac tion was quenched with a saturated ammonium chloride solution. The aqueous layer was extracted with EtOAc and the combined organic extract was washed with brine and dried over MgSO 4 . The solvent was evaporated and the crude mixture was purified via flash c olumn chromatography to afford 3 5 8 as a colorless oil (8.6 mg 71% yield). R f =0.25 (20% EtOAC/hexane). 1 H NMR (300 MHz, CDCl 3 J = 17.0, 10.5, 6.0 Hz, 1H), 5.27 (d, 17.0, 1H), 5.11 (d, J = 10.5, 1H), 4.46 4.27 (m, 1H), 3.52 (dd, J = 10.5, 1.8 Hz, 1H), 1.87 1.42 (m, 2H), 0.90 (s, 9H); 13 C NMR (75 MHz, CDCl 3 9 H 18 O 2 Na [M+Na] + 181.1199, found 181.1207 Syn 1 (benzyloxy)hex 5 ene 2,4 diol (4 13 ) . t BuLi 1.7 M solution in hexanes (0.25 mmol, 0.147 mL) was added to a solution of 3 52 g (0.104 mmol, 36 mg) in THF (1.25 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 1 hr. The reaction was quenched with a saturated ammonium chloride solution. T he aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine and dried over MgSO 4 . The solvent was evaporated and the crude mixture was purified via flash column chromatography to afford 4 13 as a clear colorless oil (15 mg,

PAGE 144

144 65% yield). R f = 0.2 (20% EtOAC/hexane) Proton and carbon NMR spectra were found to match reported data. 1 28 Anti 5 ((benzyloxy)methyl) 2 (iodomethyl)tetrahydrofuran 3 ol (3 67 ) . I 2 (0.043 mmol, 11mg) was added to a solution of 4 13 (0.036 mmol, 8 mg) in 2:1 Et 2 O:H 2 O (1.4 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 20 hr. The reaction was quenched with a saturated Na 2 SO 3 solution and the aqueous layer was extracted with EtOAc and the combined organic extract was washed with brine and dried over Na 2 SO 4 . The solvent was evaporated and the crude mixture was purified via flash column chromatography to afford 3 67 (11 mg ,88%) as a colorless oil R f = 0.7 (20% EtOAC/hexane) 1 H NMR (500 MHz, CDCl 3 7.30 (m, 5H) , 4.60 (s, 2H), 4.57 4.39 (m,1H), 4.24 (td, J = 7.5, 3.0 Hz, 1H), 3.56 (dd, J = 10.5, 3.0 Hz,1H), 3.48 (dd, J = 10.5, 5.5 Hz, 1H), 3.36 3.26 (m, 2H), 2.18 1.96 (m, 2H). 13 C NMR (125 MHz, CDCl 3 13 C NMR 138.1, 128.4, 127.7, 127.6, 82.8, 78.3, 73.4, 72 .7, 72.4, 37.5, 1.77. HRMS (ESI) calcd for C 13 H 17 IO 3 Na [M+Na]+ 371.0115, found 371.0212

PAGE 145

145 LIST OF REFERENCES (1) For representative examples see: (a) Suzuki, M. ; Yanagisawa, A. ; Noyori R. Tetrahedron Lett . , 1983 , 24 , 1187 ; (b) Riediker , M.; Schwartz, J. J. Am. Chem. Soc ., 1982, 104 , 5842 . (2) For representative examples see: (a) Zeni, G.; Larock, R. C. Chem. Rev ., 2004 , 104 , 2285 ; (b) Cacchi, S. J. Organomet. Chem. , 1999 , 576 , 42; (c) Compain, P.; Gore , J. ; J. M. Tetrahedron , 1996 , 52 , 10405; (d) Utimoto, K. Pure Appl. Chem . , 1983 , 55 , 1845 . (3) For representative examples see: (a) Trost , B. M.; Rhee, Y. H. ; J. Am. Chem. Soc., 2002 , 124 , 2528; (b) Tokunaga, M. ; Suzuki, M. ; Kog a, Fukushima, N. T.; Horiuchi, A.; and Wakatsuki, Y.; J. Am. Chem. Soc ., 2001 , 123 , 11917; (c) Tokunaga, M.; Wakatsuki , Y. Angew. Chem. Int. Ed. , 1998 , 37 , 2867 ; (d ) Khan, T. M. M.; Halligudi, S. B.; Shukla , S. J. J . Mol . Catal . , 1990 , 58 , 299 ; (e) Halpern, J.; James, B. R.; Kemp, A. L. W. J. Am. Chem. Soc . , 1961 , 83 , 4097 ; (f ) Halpern, J.; James, B. R.; Kemp, A. L. W. J. Am. Chem. Soc., 1966 , 88 , 5142. (4) For representative examples see: (a) Ho, J. H. H. ; Choy, S. W. S. ; Macgregor, S. A.; Messerle, B. A. Organometallics , 2011 , 30 , 5978 ; (b) Kondo, M. ; Kochi, T.; Kakiuchi, F. J. Am. Chem. Soc ., 2011 , 133 , 32; (c) Ho, J. H. H. ; Hodgson, R. ; Wagler, J. ; Messerle, B. A. Dalton Trans ., 2010 , 39 , 4062; (d) Blum, J.; Huminer, H.; Alper, H. J. Mol. Catal., 1992 , 75 , 153 . (5) For representative examples see: (a) Hartman, J. W.; Sperry, L. Tetrahedron , 2004 , 45 , 3787 ; (b) B aidossi, W.; Lahav, M.; Blum , J. J. Org. Chem., 1997 , 62 , 669 ; (c) Hartman, J. W.; Hiscox, W. C.; Jennings, P. W. J. Org. Chem . , 1993 , 58 , 7613 (6) For a comprehensive review of alkyne hydration see : Hintermann, L. ; Labonne, A. Synthesis, 2007 , 8 , 1121 and references therein. (7) For selected reviews on gold catalysis see: ( a) Rudolph, M.; Hashmi, A. S. K. Chem. Soc. Rev., 2012 , 41 , 2448; (b) Corma, A.; Leyva Peréz, A.; Sabater, M. J. Chem. Rev., 2011 , 111 , 1657; (c) B andini, M. Chem. Soc. Rev., 2011 , 40 , 1358; (d) Boorman, T. C.; Larrosa, I. Chem. Soc. Rev., 2011 , 40 Aldrichimica Acta, 2010 , 43 , 27; (f) Shapiro, N. D.; Toste, F. D.; Synlett, 2010 , 675; (g) Sengupta, S.; Shi, X. ; ChemCatChem, 2010 , 2 , 609; (h) Bongers, N.; Krause, N. Angew. Chem. Int. Ed ., 2008 , 47 , 2178; (i) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev., 2008 , 108 , 3351; (j) Jiménez Núñez, E.; Echavarren, A. M. Chem. Rev ., 2008 , 108 , 3326; (k) Li, Z.; Bro uwer, C.; He, C. Chem. Rev., 2008 , 108 , 3239; (l) Arcadi, A. Chem. Rev., 2008 , 108 , 3266; (m) Muzart, J. Tetrahedron, 2008 , 64 , 5815; (n) Shen, H. C.; Tetrahedron, 2008 , 64 , 7847; (o) Widenhoefer, R. A. Chem. Eur. J., 2008 , 14 , 5382; (p) Gorin, D. J.; Toste, F. D. Nature, 2007 , 446 , 395; (q) Hashmi, A. S. K . Chem. Rev., 2007 , 107 , 3180. (r) F ü rstner, A.; P. W. Davies, Angew. Chem. Int. Ed ., 2007 , 46 , 3410.

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154 BIOGRAPHICAL SKETCH Justin Andrew Goodwin was born in Reno, Nevada to the proud parents of Richard P. and Tammy L. Goodwin . He relocated to Bristol, Tennessee with his family in 1991 and spent his formative years there. Justin attended Bristol Tennessee High School, and graduated in the s pring of 2005 . Thereafter, he attended the Furman Univer s ity where he conducted undergraduate research in synthetic organic chemistry under the direction of Professor Brian C. Goess. Justin gradu ated with a Bachelor of Science degree in the s pring of 2009 having majored in b io chemistry. He went on to attend the graduate program at the University of Florida, D epartmen t of C hemistry in 2010. During his doctoral studies under the guidance of Professor Aaron Aponick, his research focused on the developmen t of novel gold catalyzed transformations to form substituted heterocycles and he received his Doctor of Philosophy degree in the fall of 2015 .