Utilizing Allylic Alcohols as Both Electrophiles and Nucleophiles in Gold-Catalyzed Reactions

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Title:
Utilizing Allylic Alcohols as Both Electrophiles and Nucleophiles in Gold-Catalyzed Reactions
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english
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Ketcham, John Michael
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Degree:
Doctorate ( Ph.D.)
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University of Florida
Degree Disciplines:
Chemistry
Committee Chair:
Aponick, Aaron
Committee Members:
Miller, Stephen Albert
Stewart, Jon Dale
Dolbier, William R, Jr
Luesch, Hendrik

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Subjects / Keywords:
claisen -- gold-catalysis -- heterocycles
Chemistry -- Dissertations, Academic -- UF
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Chemistry thesis, Ph.D.
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Abstract:
Gold-catalysis has emerged as a powerful tool for the synthetic community, allowing for new transformations that are not easily accessed through other methods.  Detailed in this dissertation, are the studies leading to a gold-catalyzed dehydrative cyclization to form azacycles via an intramolecular SN2’ type allylic alkylation reaction.  Formation of the desired heterocycles occurs through the nucleophilic attack of a tethered nitrogen nucleophile on an allylic alcohol that is rendered electrophilic by a gold-catalyst.  During these cyclization studies, an efficient transfer of chirality was observed. Interestingly, with cation stabilizing substituents in the allylic position a competing ionization pathway was observed.    Allylic alcohols are commonly used as electrophiles in dehydrative cyclization reactions, however, their use as nucleophiles is described here in the context of an efficient gold-catalyzed tandem hydroalkoxylation/Claisen rearrangement. This reversal in reactivity posed a significant challenge which required tuning the reaction conditions to circumvent the SN2’ side reactions and allow for selective hydroalkoxylation of the alkyne reaction partner.  Fortunately, optimized conditions were found that gave facile formation of the desired gamma, delta-unsaturated ketones.  Successful implementation of this synthetic methodology provides a new protocol for rapidly building complex acyclic ketone products from an allylic alcohol and an alkyne.  Additionally, the observed diastereoselectivities for the tandem process have given invaluable insight into the possible mechanistic pathways. During our studies of a gold-catalyzed Claisen rearrangement, an efficient sequential gold-catalyzed enol formation/ruthenium-catalyzed 1,3-O to –C migration was also developed.  The process allows for rapid access to highly functionalized cyclic ketone products in a highly diastereoselective fashion.
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Statement of Responsibility:
by John Michael Ketcham.
Thesis:
Thesis (Ph.D.)--University of Florida, 2013.
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Adviser: Aponick, Aaron.
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RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2014-02-28

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1 UTILIZING ALLYLIC ALCOHOLS AS BOTH ELECTROPHILES AND NUCLEOP HILES IN GOLD CATALYZED REACTIONS By JOHN MICHAEL KETCHAM 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 2013

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2 2013 John Michael Ketcham

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3 To my family and friends

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4 ACKNOWLEDGMENTS I am a firm believer that every experience happens for a reason. I believe that the conversations and interac tions I have had with others have le d me to this place, and for that I am forever grateful to all of the people that have affected my life with their presence. I would like to thank my beautiful wife Judy for all of her support and love throughout the years. After she tutored me in high school chemistry, I decided to try chemistry as a career path. Since that point she has been overly supportive of every career and life choice I have m ade and I am certain I would not have made it through this program without her love and support. I would like to thank my parents Lee and Vicki, and my brothers Jason and Matthew My family has been a constant source of support throughout my life and for that I am very grateful. They have never pressured me or swayed my decisions and their constant love is a source of inspiration. I would like to thank Professors Seth Elsheimer and Clovis A. Linkous for allowing me to work under their direction as an undergradu ate researcher at the University of Central Florida. I would especially like to thank Seth, for inspiring me to become a chemist through his mentoring and friendship throughout the years. Professor Aaron Aponick has been an exemplary mentor during my tim e at the University of Florida. I have watched him put his heart into build ing his group from the beginning and it has been a tr uly remarkable experience. Since the first day his genuine excitement and knowledge of organic chemistry has kept me motivat ed throughout my doctora l studies. With his help, I am able to leave this place with

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5 confidence that I have been well trained in synthetic organic chemistry. For all of these reasons, I would like to thank my advisor Prof. Aaron Aponick. I would like to thank my committee members Professors William R. Dolbier, Jon D. Stewart Stephen A. Miller, and Hendri k Luesch for all the time they have spent helping me during my doctoral studies. I appreciate all the suggesti ons and guidance they have provided during this process. I would especially like to thank Professor Dolbier for his guidance during the beginning of my doctoral studies. Even though he was not officially a part of my committee I would like to thank Professor Sukwon Hong for all of his suggesti ons a nd input through the years. I would also like to thank the past Hong group members for helping me through the struggle of synthetic organic chemistry. I would especially like to th ank David Snead and Mike Rodig for their advice and friendship. I w ould like to thank Dr. Davidson and Dr. Portmess for their discussion s about life and chemistry throughout the years. I would especially like to commend Dr. Davidson for all of the ha rd work she puts in to planning and scheduling the organic teaching labor atories. To the Aponick group members, I would like to thank you all for being a second family to me, which inevitably happens when you spend so much time with each other I appreciate all of the advice, laughter, food, and time that we have shared togeth er. I would especially like to thank Berenger Biannic, Carl Ballesteros, Flavio Cardoso, and Justin Goodwin for their support. I would also like to thank the research exchange undergraduate (REU) students that have helped advance my research projects: Fl avio Cardoso, Henri P iras, and Sydney Villa ume.

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6 Without my close friendships I would have never made it through the struggles of a doctoral program. In this respect I would like to thank th e following people: Brian Julian, Ben, Kyle, Gary, Andy, Nath an, Matt Baker, Matt Burnstein, Kevin, Luke, Tim, John, Arthur, Isaac, and Mark.

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7 TABLE OF CONTENTS Page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 9 LIST OF FIGURES ................................ ................................ ................................ ........ 10 LIST OF ABBREVIATIONS ................................ ................................ ........................... 14 ABSTRACT ................................ ................................ ................................ ................... 16 CHAPTER 1 SYNTHESIS OF SATURATED HETEROCYCLES VIA METAL CATALYZED ALLYLIC ALKYLATION REACTIONS ................................ ................................ ..... 18 Introduction ................................ ................................ ................................ ............. 18 Formation of Saturated Heterocycles via allyl Metal Complexes ......................... 20 Heterocycle Synthesis via allyl Palladium Intermediates ............................... 20 Heterocycle Synthesis via allyl Iridiu m Intermediates ................................ .... 24 Heterocycle Synthesis via allyl Nickel Intermediates ................................ ..... 26 Heterocycle Synthesis via allyl Ruthenium Interme diates ............................. 27 Formation of Saturated Heterocycles via Formal S N ........................... 29 Formal S N s ............................ 30 Formal S N ................................ .... 34 Formal S N ............................... 38 Formal S N ............................... 39 Formation of Saturated Heterocycles via Cationic Intermediates ........................... 40 Ionization using Magnesium Complexes ................................ .......................... 41 Ionization using Gold Complexes ................................ ................................ ..... 42 Ionizatio n using Iron Complexes ................................ ................................ ...... 43 Ionization using Palladium Complexes ................................ ............................. 44 Miscellaneous Cases ................................ ................................ .............................. 45 Formation of Heterocycles via a Sequential Ruthenium enyne/Palladium Allylation Process ................................ ................................ .......................... 45 Formation of Heterocycles via a Tandem Iridium catalyzed Vinylation/Allylic Amination Reaction ................................ ................................ ....................... 47 Formation of Heterocycles via C H Activation of Allylic Systems ..................... 48 Conclusion ................................ ................................ ................................ .............. 49 2 FORMATION OF AZACYCLES VIA GOLD CATALYZED DEHYDRATIVE CYCLIZATIONS ................................ ................................ ................................ ...... 50 Introduction ................................ ................................ ................................ ............. 50

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8 G old Catalyzed Dehydrative Cyclizations of Carbamates ................................ ....... 53 Initial Studies ................................ ................................ ................................ .... 53 Substrate Scope and Limitations ................................ ................................ ...... 55 Studies in the Transfer of Chirality for Carbamate Nucleophiles ...................... 59 Synthesis of Mefloquine and Analogs ................................ ................................ ..... 65 Historical and Biological Significance ................................ ............................... 65 Synthesis of Mefloquine and Its Derivatives ................................ ..................... 67 Initial Experim entation ................................ ................................ ...................... 70 3 STUDIES IN THE TANDEM GOLD CATALYZED HYDROALKOXYLATION/CLAISEN REARRANGEMENT ................................ ...... 74 Introduction ................................ ................................ ................................ ............. 74 Gold catalyzed Claisen Rearrangements ................................ ............................... 76 Gold catalyzed Tandem Hydroalkoxylation/Claisen Rearrangement ...................... 79 Results and Discussion ................................ ................................ .................... 82 Sequential Gold catalyzed Enol Formation/Ru catalyzed Allylation ........................ 96 Introducti on ................................ ................................ ................................ ....... 96 Results and Discussion ................................ ................................ .................... 97 4 EXPERIMENTAL SECTION ................................ ................................ ................. 111 Gener al Experimental Procedures ................................ ................................ ........ 111 Formation of Azacycles via Gold Catalyzed Dehydrative Cyclizations ................. 112 Synthesis of Mefloquine an d Analogs ................................ ................................ ... 124 Gold catalyzed Tandem Hydroalkoxylation/Claisen Rearrangement .................... 127 Sequential Gold catalyzed Enol Formation/Ru cata lyzed Allylation to form Functionalized Cyclohexanones and Tetrahydropyrans ................................ .... 153 REFERENCES ................................ ................................ ................................ ............ 170 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 179

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9 LIST OF TABLES Table Page 2 1 Optimization for the formation of piperidines ................................ ...................... 53 2 2 Optimizati on for the formation of pyrrolidines ................................ ..................... 54 2 3 Substrate scope for the dehydrative cyclization of sulfonamides and carbamates ................................ ................................ ................................ ......... 56 2 4 Limitations of the method ................................ ................................ ................... 57 2 5 pKa of analogous compounds in relation to the reactivity ................................ ... 58 2 6 Screening for the metal halogen exchange of 2 48 ................................ ............ 71 2 7 Literature examples detailing the addition of 2 48 to aldehydes ......................... 72 3 1 Preliminary Studies ................................ ................................ ............................. 84 3 2 Optimization Studies ................................ ................................ ........................... 85 3 3 Selected Substrate Scope ................................ ................................ .................. 87 3 4 Regioselectivity Studies ................................ ................................ ...................... 90 3 5 Selected Substrate Scope II ................................ ................................ ............... 91 3 6 Effects of Gold catalyst and heat on enol rearrangement ................................ ... 93 3 7 Effects of Ligand of the Tandem Hydroalkoxylation/Claisen Rearrangement ..... 94 3 8 Solvent effects on enol ether formations ................................ ............................ 98 3 9 Comparison of Pd and Ru catalyzed alkylation reactions ............................... 102 3 10 Optimization of ruthenium catalyzed allylation ................................ ................. 104 3 11 Selected substrate scope for the sequential enol formation/allylic alkylation reaction ................................ ................................ ................................ ............. 105 3 12 Limitations of ortho substituted aromatic substrates ................................ ......... 107

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10 LIST OF FIGURES Figure Page 1 1 Activation modes for allyl, formal S N ......................... 19 1 2 Pd catalyzed synthesis of chromans from phenyl allyl carbonates ..................... 21 1 3 Synthesis of piperazinone 8 ................................ ................................ ................ 22 1 4 Pd catalyzed synthesis of vinyl tetrahydropyran and tetrahydrofuran phosphonates ................................ ................................ ................................ ..... 23 1 5 Total synthesis of Frog Alkaloid ( ) 205B ................................ ............................ 23 1 6 Iridi um catalyzed sequential allylic amination to form azacycles ........................ 24 1 7 First enantioselective iridium catalyzed intramolecular allylic amination ............ 25 1 8 Iridium catalyzed allylic alkylations used as a configurational switch ................. 26 1 9 Iridium catalyzed formation of isoquinolines ................................ ....................... 26 1 10 Nickel catalyzed formation of oxazolidinones ................................ ..................... 27 1 11 Ruthenium catalyzed formation of cyclic ethers ................................ ................. 28 1 12 Ruthenium catalyzed formation of azacycles ................................ ..................... 29 1 13 Pd(II) catalyzed transfer of chirality ................................ ................................ .... 30 1 14 Studies in the total synthesis ( ) laulimalide ................................ ....................... 31 1 15 Pd(II) catalyzed formation of piperidines ................................ ............................ 32 1 16 Pd(II) catalyzed formation contiguous furan rings ................................ .............. 33 1 17 Pd(II) catalyzed spiroketalization in the synthesis of acortatarin A ..................... 33 1 18 Gold catalyzed dehydrative cyclization to form cyclic ethers .............................. 34 1 19 Gold catalyzed chirality transfer process ................................ ............................ 35 1 20 Gold catalyzed formation of azacycles ................................ ............................... 36 1 21 Enantioselective formation of azacycles by a bis(phosphine)gold complex ....... 37 1 22 Pivotal role of hydrogen bonding, and evidence for anti addition ....................... 37

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11 1 23 Mercury catalyzed dehydrative cyclization to form azacycles ............................ 38 1 24 Mercury catalyzed enantioselective formation of indolines ................................ 39 1 25 Bismuth catalyzed chiral transfer to form tetrahydroisoquinolines ...................... 40 1 26 Tetrahydroisoquinoline natural products ................................ ............................. 40 1 27 Magnesium promoted formatio n o f a z e p a n e 1 79 ................................ .............. 41 1 28 Formation of azacycles by magnesium catalyzed dehydrative cyclization ......... 42 1 29 Gold catalyzed formation of 1,2 dihydroquinolines ................................ ............. 42 1 3 0 Iron catalyzed formation of saturated heterocycles ................................ ............ 43 1 31 Rationale for high diastereoselectivity ................................ ................................ 44 1 32 Iron catalyzed formation of dihydroquinolines ................................ .................... 44 1 33 Stereoselective formation of 1,3 cis dihydropyrans ................................ ............ 45 1 34 Sequential Ru/Pd catalysis to form N and O heterocycles ................................ 46 1 35 Enantioselective tandem iridium catalyzed allylic vinylation/amination reaction to form azepines ................................ ................................ ................... 47 1 36 Allyl carbonate intermediate ................................ ................................ ............... 47 1 37 Macrolactonization via palladium catalyzed C H activatio n ................................ 49 2 1 Gold catalyzed dehydrative cycli zations to form tetrahydropyran s .................... 50 2 2 Go ld catalyzed dehydrativ e cyclizations to form azacycle s ................................ 51 2 3 Caulophyllumine B ................................ ................................ .............................. 59 2 4 Retrosynthetic considerations for the synthesis of 2 26 ................................ ..... 60 2 5 Synthesis of substrate 2 27 ................................ ................................ ................ 60 2 6 Synthesis of 2 33 ................................ ................................ ................................ 61 2 7 Mechanistic Pathways analogous to previous studies ................................ ........ 62 2 8 Possible ionization pathway s ................................ ................................ ............. 63 2 9 Transfer of chirality from 2 41 to 2 42 ................................ ................................ 65 2 10 Mefloquine and its biolo gical activity ................................ ................................ ... 67

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12 2 11 Hoffman ................................ ........................... 68 2 12 Proposed Retrosynthesis of Mefloquine Der ivatives ................................ .......... 68 2 1 3 Diamine Quinoline Methanols ................................ ................................ ............. 69 2 14 Highly potent mefloquine analog 2 54 ................................ ................................ 69 2 15 Potential Analogs of WR621308 ( 2 54 ) ................................ .............................. 70 2 16 Synthesis of 2 48c ................................ ................................ .............................. 70 2 17 Treatment of ozonide with 2 51a ................................ ................................ ........ 73 3 1 General Claisen Rearrangement ................................ ................................ ........ 74 3 2 First Repor ted Claisen Rearrangement ................................ .............................. 75 3 3 Classical Variants of the Claisen Rearrangement ................................ .............. 75 3 4 Possible Transition St at es of the Claisen Rearrangement ................................ 76 3 5 Stereochemical Considerations ................................ ................................ .......... 76 3 6 Gold catalyzed propargyl Claisen rearrangement ................................ .............. 77 3 7 Gold catalyzed tandem Claisen rearrangement/hydroalkoxylation reaction ....... 78 3 8 Spirocycles via gold catalyzed Claisen type rearrangement .............................. 78 3 9 Proposed mechanism for the gold catalyzed rearrangement o f enynols ............ 79 3 10 Classical Claisen Methodologies ................................ ................................ ........ 80 3 11 Cu catalyzed C O coupling/Claisen Rearrangement ................................ .......... 81 3 12 Iridium catalyzed isomerization Claisen rearrangement (ICR) ............................ 81 3 13 Proposed Hydroalkoxylation/Claisen rea rrangement process ............................ 82 3 14 Inherent difficulties ................................ ................................ .............................. 83 3 15 Tuning the regioselectivity ................................ ................................ .................. 89 3 16 Epimerization experiments ................................ ................................ ................. 91 3 17 Possible transition states ................................ ................................ .................... 92 3 18 Gold catalyzed intramolecular hydroalkoxylation/Claisen rearrangement .......... 96

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13 3 19 Selected gold catalyzed intramolecular Claisen re arrangements. ...................... 97 3 20 Proposed mechanism for the gold catalyzed formation of 3 93 .......................... 99 3 21 Proposed mechanism for the gold catalyzed formation of 3 94 .......................... 99 3 22 Formation of [1,3] rearrangement product 3 99 ................................ ................ 100 3 23 Palladium catalyzed [1,3] O to C migrations ................................ ................... 100 3 24 Comparable process by Harrity et al. ................................ ............................... 101 3 25 Diastereoselective access to trans 3 99 ................................ ........................... 106 3 26 Proposed coordi nation of the ruthenium complex to allyl alcohols ................. 108 3 27 Proposed mechanism for the ruthenium catalyzed [1,3] rearrangement .......... 109 4 1 Confirmation of S tereochemistry ................................ ................................ ...... 132 4 2 Confirmation of Enol geometry via NOE experiment ................................ ........ 151

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14 LIST OF ABBREVIATIONS Ac Acetyl ( R ) BINAPHANE ( R R ) 1,2 bis[( R ) 4,5 dihydro 3H binaptho(1,2 c e)phosphineobenzene MeO BIPHEP Bis(diphenylphosphino) dimethoxy biphenyl Boc tert butylcarbonyl Bn benzyl Bz benzoyl Cbz benzyloxycarbonyl cod 1,5 cyclooctadiene DACH Ph 1,2 Diaminocyclohexane bis(2 diphenylphosphinobenzoyl) DABCO 1,4 diazabicyclo[2.2.2]octane dba d ibenzylideneacetone DBU 1,8 diazabicyclo[5.4.0]undec 7 ene DMPS dimethylphenylsilyl DPPBA diphenylphosphinobenzoic acid dppe 1,2 bis(diphenylphosphino)ethane Fmoc 9 fluorenylmethoxycarbonyl Ns 2 nitrobenzenesulfonyl Ph phenyl PMB p methoxybenzyl PMP p met hoxyphenyl TBD 1,5,7 triazabicyclo [4.4.0]undec 5 ene Tf trifluoromethanesulfonyl TMS trimethylsilyl

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15 Troc 2,2,2 trichloroethoxycarbonyl Ts p toluenesulfonyl

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16 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 UTILIZING ALLYLIC ALCOHOLS AS BOTH ELECTROPHILES AND NUCLEOP HILES IN GOLD CATALYZED REACTIONS By John Michael Ketcham August 2013 Chair: Aaron Aponick Major: Chemis try Gold catalysis has emerged as a powerful tool for the synthetic community allowing for new transformations that are not easily accessed through other methods. Detailed in this dissertation, are the studies leading to a gold catalyzed dehydrative cyc lization to form azacycles via an intramolecular S N allylic alkylation reaction. Formation of the desired heterocycles occurs through the nucleophilic attack of a tethered nitrogen nucleophile on an allylic alcohol that is rendered electrophilic by a gold catalyst During these cyclization studies, an efficient transfer of chirality was observed. Interestingly, with cation stabilizing substituents in the allylic position a competing ionization pathway was observed. A llylic alcohols are commonly us ed as electrophiles in dehydrative cyclization reaction s however their use as nucleo philes is described here in the context of an efficient gold catalyzed tandem hydroalkoxylation/Claisen rearrangement This rever s al in reactivity posed a significant cha llenge which required t uning the reaction conditions to circumvent the S N alkyne reaction partner. Fortunately optimized conditions were found that gave facile

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17 formation of the desired gam ma, delta unsaturated ketones. Successful implementation of this synthetic methodology provides a new protocol for rapidly build ing complex acyclic ketone products from an allylic alcohol and an alkyne. Additionally, the observed diastereoselectivit i es f or the tandem process have given invaluable insight into the possible mechanistic pathways. During our studies of a gold catalyzed Claisen rearra n g ement an efficient sequential gold catalyzed enol formation/ruthenium catalyzed [1,3] O to C migration was also developed The process allows for rapid access to highly functionalized cyclic ketone products in a highly diastereoselective fashion.

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18 CHAPTER 1 SYNTHESIS OF SATURATED HETEROCYCLES VIA METAL CATALYZED ALLYLIC ALKYLATION REACTIONS Introduction The ub iquity of heterocycles in biologically active natural products has led to an ever growing abundance of methodologies aimed at the production of these cyclic structures. Among these strategies, metal catalyzed intramolecular allylic alkylations have been p articularly fruitful. These facile processes accommodate a broad rang e of substrates for cyclization under relatively mild conditions with low catalyst loadings. The following chapter is a review of the synthesis of saturated heterocycles via metal catal yzed allylic alkylation reactions over the past ten years. Mechanistically, m etal catalyzed allylic alkylation reactions can be placed into three distinct mechanistic categories: allyl, formal S N Figure 1 1 ). Although these systems can give identical products, their mechanistic pathways vary greatly depending on many fa ctors including: solvent, metal complex, leaving group, and additi ves. allyl systems ( 1 1 ) in general contain nucleophilic/electron rich metal complexes, and highly reactive leaving groups such as carbonates, halides, etc. Throughout the catalytic cycle, the metal will go through a redox reaction wherein two electrons are lost and regained during the reaction course. More recently, these reactions have focused on the use of new metal complexes that do not incorporate palladium. Formal S N 1 3 ) typically involve electrophilic acid metal complex that prefers the formation of a complex without alternating oxidation states during the

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19 transformation These metal catalyzed intramolecular formal S N relatively new class of reaction pathway when compared t o the well known allyl systems. New methodologies and mechanistic insights are still being reported, which has presented the scientific community with an overwhelming wealth of reports in the past ten years. Cationic systems ( 1 4 ) normally incorporate h ighly electrophilic transition metals that can easily ionize the allyl system by abstracting the leaving group thereby producing an allyl cation. The metal complex is usually comprised of a hard metal that coordinates directly to the leaving group. The cationic nature of these systems adds a significant challenge when enantioenriched products are desired. Figure 1 1 Activation modes for allyl formal S N cationic systems Over the past decade, various groups have reported these intramolecular cyclizations with numerous substrates and catalyst systems for use in the synthesis of natural products and other biologically relevant compo unds The following chapter is organized chronologically, by which mechanistic pathway was first reported. Each

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20 mechanistic system is then organized by which metal complex was first employed to promote the desired transformation and further of those com plexes which studies were first reported. This chapter reviews selected examples of saturated heterocycles construct ed by c arbon heteroatom bond formation via metal catalyzed allylic alkylation reaction s For brevity, heterocycles formed through carbon ca rbon formation via allylic alkylation reactions will not be discussed in this chapter. Formation of Saturated Heterocycles via allyl Metal Complexes The following section covers select examples of allyl metal intermediates in the formation of heterocyc les. These redox processes generally go through the following sequential mechanistic steps: coordination, oxidative addition, and reductive elimination. Heterocycle Synthesis via allyl Palladium Intermediates Since the initial discoveries of Tsuji et al 1 and Trost and coworkers 2 the Tsuji Trost reaction has stood as one of the most versatile synthetic transformations 3 for the formation of carbon carbon and carbon heteroatom bonds. During their syntheses of () desethylibogamine and (+) ibogamine in th e late 1970s, Trost et al. reported some of t he earliest examples utilizing their methodology to form a carbon heteroatom bond in an intramolecular fashion 4 Over the past forty years, intramolecular Tsuji Trost type cyclizations have become commonplace i n the synthesis of heterocycles, and have been utilized in a myriad of natural product syntheses 5 Driven by their initial studies toward the construction of the core ring structure of vitamin E 6 Trost and coworkers extensively studied a palladium cataly zed intramolecular asymmetric allylic alkylation (AAA) of phenyl allyl carbonates ( 1 5 ) to form chromans ( 1 6 ) ( Figure 1 2) 7 These highly useful synthons could be formed in

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21 high yield and good enantioselectivities with the use of Pd 2 dba 3 and L1 under mil d conditions. In general the E allylic carbonates give the ( R ) chroman products while Z allylic carbonates (which usually give higher enantioselectivities) give the ( S ) chroman products. 7 a Figure 1 2 Pd catalyzed synthesi s of chromans from phenyl allyl carbonates Their work culminates in the utilization of these Pd catalyzed cyclizations in the total syntheses of (+) clusifoliol 7b and ( ) siccanin 7c Lastly, their mechanistic studies suggest that the enantiodiscriminating step involves the cyclization of the more reactive diastereomeric allyl intermediate. 7b In 2006, the same group found that similar conditions could be used to achieve a one pot cascade reaction 8 forming piperazinone 1 9 from a palladium catalyzed asymm etric allylic alkylation (AAA) reaction between dicarbonate 1 7 and pyrrole 1 8 This reaction was further used in the formal total synthesis of ( ) agelastatin A ( Figure 1 3). Additional studies revealed that a sequential palladium catalyzed process gav e access to a regioisomer of 1 9 which was used in the synthesis of the opposite enantiomer, (+) agelastatin A.

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22 In addition to the use of chiral palladium complexes, enantioenriched starting materials can also furnish products with high enantioselectivi ty without the use of a chiral catalyst. Spilling and coworkers utilized this strategy by creating a method to form enantioenriched ketophosphonates. These versatile synthons are commonly employed in the Horner Wadsworth Emmons (HWE) olefination, a rea ction that is consistently used in natural product syntheses. 9 Figure 1 3 Synthesis of piperazinone 8 via Pd catalyzed intramolecular Tsuji Trost allylation As an extension of their previously reported pr ocess for vinyl N heterocyclic phosphonates, Spilling and coworkers reported an attractive method to synthesize vinyl tetrahydropyran and tetrahydrofuran phosphonates. 10 Although 7 and 8 membered rings could not be formed under the reaction conditions, the products obtain ed for the 5 and 6 membered rings formed with complete transfer of chirality from carbonates 1 10 to the products 1 11 (Figure 1 4). 10 b These vinyl phosphonates are easily transformed into their ketophosphonates analogs via a regioselective Wacker oxida tion. Their methodology was exemplified in the formal synthesis of (+) centrolobine, 10 b the synthesis of an Amphidinolide F fragment, 10c and more recently the synthesis of both diastereomeric nematocidal oxylipids isolated from the Australian sea sponge N otheia anomala 10d

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23 Figure 1 4. Pd catalyzed synthesis of vinyl tetrahydropyran and tetrahydrofuran phosphonates As a final example of the synthetic versatility of these pall adium catalyzed intramolecular Tsuji T rost type reactions, work done by Comins and coworkers demonstrates the ease with which natural products can be constructed using this methodology. 11 Isolated in 1987 by Daly et al. 12 f rog alkaloid ( ) 205B is structurally unique when compared t o other indolizidine alkaloids. Furthermore, its enantiomer has shown selective inhibition for a receptor that is linked to various neurological diseases. 11 Comins synthesis provides a concise and efficient pathway to the alkaloid 1 14 in eleven steps 11 An intramolecular Tsuji Trost reaction using a v inyl amine nucleophile 1 12 gives the product 1 13 in high diastereoselectivity with the bulky P( t Bu) 3 ligand (Figure 1 5 ). It was also found that the use Cs 2 CO 3 was critical to the efficiency of the reaction, the use of other bases led to significant de composition of the substrate. After this key step the total synthesis of the natural product was easily completed from 1 13 in seven steps. Figure 1 5. Total synthesis of Frog Alkaloid ( ) 205B

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24 Heterocycle Synthesis via allyl Iridium Intermediates Approximately forty years after the discovery of the Tsuji Trost reaction Takeuchi et al 13 and Helmchen and coworkers 14 reported that iridium complexes were effective catalysts for allyl type allylic alkylation reactions. Their pioneering work demonstrated that iridium allylic alkylations preferentially form the branched alkylation products, which is in contrast to the linear alkylation products formed by palladium catalysis. Since these initial reports numerous advances h ave demonstrated the advantages of iridium complexes in allylic alkylation reactions. 15 Given the latent development of these iridium catalyzed allylic alkylations it is not surprising that these complexes were not utilized in the formation heterocycles until the early 2000s. In 2003, Takemoto et al. reported the iridium catalyzed diallylic amination of bis(allylic carbonates) 1 15 to form various azacycles 1 17 (Figure 1 6) 16 The yields and regioselectivities were high for the reaction, albeit with l ow diastereoselectivities More significantly, their report demonstrated the first synthesis of heterocycles via an iridium catalyzed intramolecular allylic amination strategy. Figure 1 6. Iridium catalyzed sequential allylic amination to form azacycl es Soon after this report, Helmchen and coworkers demonstrated the first enantioselective iridium catalyzed intramolecular allylic amination 17 After testi ng various solvent, ligands, additives, etc. it was f ound that iridium complexes with

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25 phosphoramidi te ligands of the general structure L2 18 have a dramatic impact on both the reactivity and selectivity of the process (Figure 1 7). 17 a Under these conditions allylic carbonates 1 18 undergo smooth cyclization to their corresponding azacycles 1 19 in up t o 99% yield and 97% ee Using similar reaction conditions, they were able to design systems for the enantioselective formations of chromans and an enantioselective sequential inter /intramolecular allylic amination reaction. 17 b Figure 1 7. First enantio selective iridium catalyzed intramolecular allylic amination As an extension of their methodology the Helmchen group found that these systems could be used as configurational switches to form selectively the 2,6 cis or 2,6 trans piperidines. 17 c,d For exa mple, the isomeric mixture 1 20 can be treated under the same reaction conditions to form either the cis 1 21 or trans 1 22 diastereomeric products depending on which enantiomer of the ligand L 3 is used (Figure 1 8) Although only primary amines were used in these cyclizations, the yields and selectivities were excellent and their methodology has been utilized in the total syntheses of prosopis, dendrobate, and spruce alkaloids 17 d More recently, Feringa et al. demonstrated a similar process for the const ruction of tetrahydroisoquinolines 19 Under their conditions, t rifluoroacetylamides 1 23 were readily cyclized into the corresponding tetrahydroisoquinolines 1 24 with high yields and enantiosele ctivities (Figure 1 9). Their method was also used to synth esize saturated pyrrolid ines and piperidines, however, competing hydride elimination made the

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26 formation of azepane derivatives quite challenging. The resulting products could then be easily deprotected using K 2 CO 3 in MeOH/H 2 O, without any appreciable epimerization of the product. Figure 1 8. Iridium catalyzed ally lic alkylations used as a configurational switch Figure 1 9. Iridium catalyzed formation of isoquinolines Heterocycle Synthesis via allyl Nickel Intermediates Examples of nickel catalyzed intramolecular allylic alkylations to form heterocycles are sp arse, however, Berkowitz and coworkers undertook a commendable

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27 study in 2004. 20 Their interests in combinatorial catalysis lead to an in situ enzymatic screening (ISES ) process that indicated nickel complexes could be used to form oxazolidinones via an asy mmetric allylic amination reaction. During their studies they screened more than twenty five different bis(phosphine) 20 a and P,N ligands. 20 b Their findings suggest that best catalyst systems was produced with Ni(cod) 2 and ( R ) MeO BIPHEP. This complex g ave a facile cyclization of 1 25 to 1 26 in an 88% yield with a 75% ee (97% ee after one recrystallization ) (Figure 1 10). After a five step synthesis the TFA salt of L glycine 1 27 was obtained in 21% overall yield. Figure 1 10. Nickel catalyzed forma tion of oxazolid in ones Heterocycle Synthesis via allyl Ruthenium Intermediates Pioneering studies by the Tsuji, 21 Watanabe, 22 and Trost 23 research groups demonstrated the practicality of ruthenium complexes for allylic alkylation reactions, however, their applications in intramolecular heterocyclic for mation was not reported until recently. As an extension of their previous ly reported methodology for the intermolecular catalytic dehydrative allylation of alcohols, 24 in 2009, Kitamura et al. published a very efficient ruthenium catalyzed dehydrative cycl ization to form cyclic ethers. 25 Reactions were performed in various solvents with very low catalyst loadings (as low as 0.0001

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28 mol%) with high yields and enantioselectivities (Figure 1 11). Tetrahydropyrans and furans 1 29 as well as, chromans could be formed from their corresponding diols 1 28 however, the formation of seven membered rings was pre vented by the formation of oligo meric side products The authors suggest that the chlorine atom in ligand L3 plays two pivotal role s in the reactivity of the complex Firstly, the inductively with drawing nature of the chlorine may decrease the energy level of the LUMO, and allow for a more facile redox process. Additionally, a Cp H Cl R hydrogen bond between the two ligands on the ruthenium could also stabilize the transition state. Figure 1 11. Ruthenium catalyzed formation of cyclic ethers complex could be used in an intramolecular dehydrative cyclization to form azacycles. 26 Various nitrogen heterocycles 1 31 were synthesized from the corresponding allylic alcohols 1 30 with catalyst loadings as low as 0.05 mol% (Figure 1 12). A variety of protecting gr oups on the nitrogen could be used, and the yields and enantiomeric ratios were excellent. Interestingly, arene fused azepane 1 33 could be easily produced from subsequent cyclization of allylic alcohol 1 32 Conversely, when sulfonamide 1 34 was treate d under the optimized conditions a competing hydride elimination dominated resulting in the production of diene 1 35 as the major product In

PAGE 29

29 the case of the arene fused azepanes, the authors suggest that the sp 2 carbons of the aniline may permit a bet ter HOMO/LUMO interaction allowing for a higher propensity toward cyclization. The geometric constraints imparted by the aromatic substituent could also give 1 32 a greater predisposition toward cyclization because of it is more geometrically constrained than the alkyl analog 1 35 Figure 1 12. Ruthenium catalyzed formation of azacycles Formatio n of Saturated Heterocycles via Formal S N Reactions Metal catalyzed formal S N sequences encompass a relatively new reaction class in the formation of heteroc ycles. In contrast to the mechanistic pathways of the other systems discussed in this chapter these reactions can produce heterocycles without the formation of a carbocation or a metal bound cation.

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30 Formal S N Reactions Catalyzed by Palladium Complexes Given the vast history of palladium activation in allylic systems it is not surprising that the earliest examples of metal catalyzed formal S N heterocycle s were performed with palladium complexes. 27 Hirai and coworkers were the firs t to exhibit the effectiveness of a palladium(II) catalyzed formal S N heterocyclization in an enantioselective fashion. 27 The successful chirality transfer from the starting allylic alcohol 1 36 gave the piperidine 1 37 which was shown to have complete transfer of chirality after conversion to the natural product alkaloid 1 38 (+) coniine (Figure 1 13). 27 a Throughout the late nineties their group applied these methods to the total synthesis of numerous natural products including: (+) prosopinine, 27b (+) palustrine, 27 b SS20846A, 27 c and 1 d eoxymannojirimycin 27 d Figure 1 13. Pd(II) catalyzed transfer of chirality More recently, Uenishi and coworkers have advanced this strategy to apply to their own methodology in the formation of tetrahydro and dihyd ropyrans. 28 These methods were applied directly to the total synthesis of the marine natural product ( ) laulimalide. 28 b During the synthesis a comparis on between the Pd(0) and Pd(II) catalyzed cyclizations in the formation of tetrahydropyran 1 40 and 3 ,6 dihydropyran 1 42 indicated that Pd(II) was superior (Figure 1 14). For both cyclizations complete chirality transfer was observed, however, in the case of 1 39 the process was much higher yielding with the Pd(II) source due to the competing triene for mation found with

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31 the Pd(0) complex. Additionally cyclization of 1 41 to form pyran 1 42 did not occur under standard Pd(0) conditions. Mechanistically, the cyclization is assumed to go through a syn addition/ syn eliminatio n with respect to the palladiu m complex. 28b,c Lastly fragments 1 40 and 1 42 were successfully used to finish the asymmetric total synthesis of ( ) laulimalide. Uenishi and coworkers have since applied these oxypalladation cyclizations to the construction of several intricate comp ounds including tetrasubstituted chiral carbon centers, 28c and more recently in the total synthesis of ( ) apicularen A and its analogues. 28d Figure 1 14. Studies in the total synthesis ( ) laulimalide Shortly after their preliminary reports their g roup applied these S N to the formation of nitrogen heterocycles. 29 Various nitrogen protecting groups (Cbz, Boc, Ts, Fmoc, etc.) are tolerated but cyclization with the Cbz protected amines gave

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32 the best results. Efficient transfer of chi rality was also observed for these systems When the enantioenriched allylic alcohols ( R ) and ( S ) 1 43 were treated with 10 mol% of (CH 3 CN) 2 PdCl 2 the 2 vinylpiperidines were produced in 93% and 92% enantiomeric excess, respectively (Figure 1 15). The pr oducts ( R ) 1 44 and ( S ) 1 44 were further used to synthesize the hydrochloride salts of ( S ) (+) and ( R ) ( ) coniine respectively. These conditions were also found to be hi ghly diastereoselective, which was demonstrated in the cyclization of both epimers of 1 45 to give the product 1 46 with a high diastereoselectivity for both substrates. Figure 1 15. Pd(II) catalyzed formation of piperidines In 2011, the Uenishi group demonstrated a cascade epoxide ring opening to form bis and tris contiguous tet rahydropyran rings. 30 Both epimers of epoxide 43 undergo cyclization in under an hour to form the corresponding bis(tetrahydropyran) 44 with good diastereoselectivity (Figure 1 16). This method can also accommodate both epimers of diepoxide 45 to give the desired tris(tetrahydropyran) compound 46 with

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33 good selectivities. Preliminary mechanistic studies suggest that the sequence is most likely a domino process rather than a stepwise addition. Figure 1 16. Pd(II) cataly zed formation contiguous furan ri ngs Figure 1 17. Pd(II) catalyzed spiroketalization in the synthesis of acortatarin A Recent studies by Aponick and coworkers have revealed a facile spiroketalization methodology utilizing a palladium(II) catalyzed S N 1 17). 31 Th ese spiroketalizations occur at room temperature, transforming ketodiol 1 51 to the cyclization product 1 52 in a 53% yield. Most notably they were able to apply this method to the key step in their total synthesis of acortatarin A. 31 b Treatment of allyli c

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34 ether 1 53 with 10 mol% of (CH 3 CN) 2 PdCl 2 produced the desired spiroketal 1 54 in an 87% yield as a 1:1 mixture of epimers which were further elaborated to obtain the desired natural product. Formal S N Gold Complexes Gold cataly sis is an ever expanding field that has recently brought about many changes in the scientific community. 32 With low catalyst loadings and high functional group tolerance gold complexes have become a competitive alternative to traditionally used transition metals. In 2008, Aponick and coworkers were the first to demonstrate a gold catalyzed dehydrative formal S N cis tetrahydro pyrans and furans. 33 The process is selective for the cis cyclic ethers 1 56 from monoallylic diols 1 55 with high diastereoselectivities and yields using very low catalyst loadings (Figure 1 18). With ease of the substrate syntheses and catalyst loadings as low as 0.1 mol%, the production of gram scale quantiti es of these tetrahydro pyrans and furans was readily achieved. Further experimentation demonstrated that the cyclizations did not proceed through a cationic mechanism but rather through formal S N pathway Figure 1 18. Gold catalyzed dehydrative cyclization to form cyclic ethers With respect to heteroc yclic formation our group 34 as well as others 35 have made significant extensions to these methods including the synthesis of substituted

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35 chromenes, 34 c a stereoselective 2 vinyl morpholine methodology, 35 a and applications to the total synthesis of (+) isoal tholactone, 35 b to name a few. I n 2011, the Aponick group reported an efficient transfer of chirality for the cyclization of monoallylic diols 1 57 to form tetrahydropyrans and morpholines 1 58 and 1 59 (Figure 1 19 ). 34 d Selective access to either enantiome r can be achieved from substrates that differ only by the olefin geometry allowing for selective access to either stereoisomer. This synthetically practical process provides the desired products in high yields with excellent diastereo and enantioselecti vities. Later that year, a comparative study showed that in lieu of allylic alcohols, allylic ethers could also be used to furnish these 2 vinyltetrahydropyran products. 34 e Figure 1 19. Gold catalyze d chirali ty transfer process In 2011, Widenhoefer and coworkers demonstrated an efficient transfer of chirality in the gold catalyzed intramolecular amination to form azacycles. 35 c The yields and diastereoselectivities are high in selected cases however, substrates are limited to alkyl amine nucleophiles 1 60 that require higher temperatures (60 100 C) for cyclization to the desired azacycles 1 61 (Figure 1 20). Additionally, t reating amine 1 62 under their optimized conditions produced the desired piperidine 1 63 with a complete

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36 transfer of chirality. The enantiopurity and absolute configuration of 1 63 was then confirmed by the synthesis of the hydrochloric acid salt of ( S ) (+) coniine. Figure 1 20. Gold catalyzed formation of azacycles Soon after, Widenhoefer and coworkers reported a highly effecti ve enantioselective intramolecular amination catalyzed by a chiral bis(gold)phosphine complex 35b The new method accommodates a wide range of carbamates 1 64 to give the desired piperidines and piperazines 1 65 in high yields and enantioselectivities with the use of a bis(gold)phosphine complex prepared from bispho s phine L4 ( Figure 1 21). Further experiments demonstrated a net syn displacement of the allylic a lcohol by the incoming carbamate nucleophile. Mechanistic studies by the Aponick and Ess groups ha s given an unequivocal insight into the mechanism of these gold ca talyzed dehydrative cyclization 34f The ir experimental and computational studies illustrate the importance of hydrogen bonding with respect to both reactivity and stereoselectivity in the c yclization of 1 66 to 1 67

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37 Between the three transition states TS anti TS syn and TS concerted the lowest calculated energy state is TS anti ( Figure 1 22 ) Their results suggest the cyclizations must go through a non concerted anti alkoxyauration/ anti elimination mechanism, which is accelerated by and stereochemically defined through the intramolecular hydrogen bonding between the allylic alcohol and the incoming hydroxyl nucleophile. Figure 1 21. Enantioselective formation of azacycles by a bis(phos phine)gold complex Figure 1 22. Pivotal role of hydrogen bonding and evidence for anti addition in gold catalyzed dehydrative cyclizations of monoallylic diols

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38 Experimentally this concept was demonstrated in the gold catalyzed cyclizations of bicyclic diols 1 68 1 70 The requisite distance fo r these intramolecular hydrogen bonding interactions cannot be achieved with substrate 1 68 and consequently no desired cyclization was observed under the optimized conditions. In contrast, as this interaction a nd the ability of the catalyst to affect an anti addition become more accessible, the desired cyclization become s much more facile ( compare cyclizations of 1 69 and 1 70 Figure 1 22 ). Formal S N Mercury Complexes Nishizawa and cowo rkers have recently reported efficient mercury catalyzed dehydrative cyclizations to form various saturated azacycles and indolines. 36 In 2008, they were able to demonstrate that sulfonamides 1 71 underwent facile ring closure to form the desired 2 vinylaz acycles 1 72 in high yields with very lo w catalyst loadings (Figure 1 23 ). 36 a Allylic alcohols and ethers also underwent the desired cyclization, however, allylic esters were unable to cyclize under the optimized conditions. Figure 1 23. Mercury catal yzed dehydrative cyclization to form aza cycles The same group then established an enantioselective version of these cyclizations using the chiral ( R ) BINAPHANE ligand with Hg(OTf) 2 (Figure 1 24 ) 36 b After screening various ligands and nitrogen protecting groups it was determined that the highest enantioselectivities were achieved with tert butyl substituted sulfonamides.

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39 Treating sulfonamides 1 73 with the chiral mercury complex at low temperatures gave the desired indolines 1 74 in high yields with moder ate to good enantioselectivities. Sulfonamide products 1 74 could be easily deprotected with anisole in a solution of TFA/CH 2 Cl 2 without appreciable epimerization of the product Figure 1 24. Mercury catalyzed enantioselective formation of indolines F ormal S N Bismuth Complexes During their investigations of a chirality transfer in metal catalyzed intramolecular allylic aminations Kawai/Uenishi et al screened over ten different metals to find that bismuth (III) triflate gave th e best results. 37 Under their optimized bismuth catalyzed conditions enantiopure allylic alcohols 1 75 could be treated under relatively mild conditions to form the desired tetrahydroisoquinolines 1 76 (Figure 1 25 ). 37 a Boc protected amines achieved the highest selectivities, while substituted olefins (where R 1 = Me) were found to significantly lower the enantiomeric ratio. Interestingly, under their previously reported palladium conditions ( analogous to those found in Figure 1 14) good

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40 enantioselectivit y was given only at 20 C, however, the reactivity degraded forming only 20% of the desired product. From these findings a chelation intermediate 1 77 was proposed to rationalize the higher selectivities obtained with carbamate starting materials F igur e 1 25. Bismuth catalyzed chiral transfer to form tetrahydroisoquinolines In 2011, an extension of the bismuth methodology was reported to include substituted tetrahydroisoquinolines and gi ve further insight into the mechanism of the reaction. 37 b Lat er that year a variety of tetrahydroisoquinoline natural product alkaloids were prepared that showcase their methodology, these include: ( S ) ( ) trolline, ( R ) (+) crispine A, and ( R ) (+) oleracein (Figure 1 26 ). 37 c Figure 1 26. Tetrahydroisoquinoline n atural products Formatio n of Saturated Heterocycles via Cationic Intermediates The use of c ationi c intermediates in the synthesis of heterocycles has become more prominent over the past ten years. Much like the intermediates found in allyl systems an allyl cation is produced, however, the metal is not covalently associated with the cation making enantioinduction rather difficult

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41 Ionization using Magnesium Complexes During a total synthesis of ( ) cis clavicipitic acid Jia and cowor kers made a serendipitous discovery. 38 Deprotection of bis(carbamate) 1 78 using Mg(ClO 4 ) 2 was followed by an unexpected magnesium promoted cyclization to give the desired azepane 1 79 with reasonable selectivity for the cis isom er (Figure 1 27 ). 38a Thi s process provided simple access to the desired natural product after several steps. The magnesium promoted process was later used in a one pot tandem palladium catalyzed H eck reaction /magnesium promoted dehydrative cyclization in the total syntheses of aurantioclavine and clavicipitic acid. 38b Figure 1 27. Magnesium promoted formation of azepane 1 79 in the total synthesis of ( ) cis Clavicipitic acid I n 2012, the conditions were optimized to allow for a process that is catalytic in magnesium. 39 T reating sulfonamides or carbamates 1 80 with 10 mol% of Mg(ClO 4 ) 2 at 80 C in acetonitrile gave the desired tetrahydroisoquinolines 1 81 in reasonable yields

PAGE 42

42 for secondary and tertiary allylic alcohols, as well as, primary all ylic acetates (Figure 1 28 ). Piperidines and pyrrolidines could also be prepared, however substrates containing primary alcohols were s hown to be sluggish even with a full equivalent of magnesium. After further optimization this methodology was then applied to the total synthesis of a known fungal inhibitor demethoxyfumitremorgin C. Figure 1 28. Formation of azacycles by magnesium catalyzed dehydrative cyclization Ionization using Gold Complexes In 2009, Chan et al. described an efficient gold catalyzed dehydrative cyclization to form 1,2 dihydroquinolines. 40 Under very mild conditions arylsulfonamides 1 82 were transformed into the desired dihydroquinolines 1 83 in rel atively good yields (Figure 1 29 ). Figure 1 29. Gold catalyzed formation of 1,2 dihydroquinolines The authors speculate that the process proceeds via a cationic mechanism. Interestingly this is in contrast to the gold catalyzed synthesis of chromenes reported

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43 by our group, 34c which does not form a cationic intermediate in many cases. Furthermore, they were ab le to use this methodology for the racemic total synthesis of the tetrahydroquinoline alkaloid ( + ) angustureine. Ionization using Iron Complexes Cossy and coworkers recently reported an attractive method for the diastereoselective formation of cis piperid ines and tetrahydropyrans. 41 This iron catalyzed process provides the desired products 1 85 from allylic alcohols 1 84 in high yields and very high diastereoselective for the cis products under mild conditions (Figure 1 30 ). Given the cationic nature of the reaction transposed allylic alcohols were also readily cyclized under the reaction conditions. Figure 1 30. Iron catalyzed formation of saturated heterocycles Interestingly, this catalyst system can also be applied to the cyclization of ketoalcoh ol 1 86 to form the desired spiroketal 1 87 in a diastereomeric ratio of >99:1. The high stereoselectivity is believed to be a product of the epimerization/equilibration of the trans 1 88 to the more stable cis 1 88 throug h an allyl cation intermediate 1 89

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44 (Figure 1 31 ). Although the method demonstrates broad functional group tolerance and high diastereoselectivities it does not provide access to enantiopure products. Figure 1 31. Rationale for high diastereoselectivity Sun et al later used this c atalyst system for the formation of substituted dihydroquinolines and quin olines. 42 The process offers cyclizations of anilines 1 90 to form dihydroquinolines 1 91 with low catalysts loadings and good y ields in most cases (Figure 1 32 ). When enantiopure allylic alcohols were used they exhibited no transfer of chirality, instead producing a racemic mixture of dihydroquinoline products. Treating the products 1 91 with sodium hydroxide in ethanol at reflux furnished the corresponding quinoline products all owing selective access to either azacycle. Figure 1 32. Iron catalyzed formation of dihydroquinolines Ionization using Palladium Complexes During their studies of the total synthesis of jerangolid A, Hanessian and coworkers discovered a highly diastere oselective cyclization of monoallylic diols 1 92 to form 1,3 cis dihydropyrans 1 93 with very high d iastereoselectivity (Figure 1 33 ). 43 The

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45 cyclizations are facile using either the cationic palladium complex (CH 3 CN) 4 Pd(BF 4 ) 2 or BF 3 OEt 2 with 10 mol% catalyst loadings. Their systems gave selectively the cis products, r egardless of the stereochemical configuration of the alk ene and/or the allylic alcohol. These results suggest that the cyclization s likely go through a cationic mechanism. Furthermore the cycloetherification protocol was used to complete the first total synthesis of jerangolid A which was completed in sixteen linear steps from an enantiopure glycidol. 43 a Figure 1 33. Stereoselective formation of 1,3 cis dihydropyrans Miscellan eous Cases The following section encompasses selected examples that would not necessarily fit in the previous sections, however, they demonstrate interesting cases for metal catalyzed formation of saturated heterocycles from allylic systems. Formation of Heterocycles via a Sequential Ruthenium enyne/Palladium Allylation Process In 2006, Trost and coworkers demonstrated a sequential one pot ruthenium enyne coupling followed by a palladium catalyzed allylation to form nitrogen and oxygen heterocycles. 44 All ylic p nitrophenyl ethers 1 97 generated after the ruthenium enyne coupling of 1 94 and 1 95 give the desired heterocycles 1 96 with moderate to good e nantioselectivities (Figure 1 34 ). The process can also be used to form oxygen

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46 heterocycles 1 99 from se quential coupling and cyclization with substrates 1 94 and 1 98 Diastereoselective syntheses of piperidines, furans, and tetrahydropyrans were also possible through this methodology, generally providing excellent stereoselectivity with the use of chiral ligands. Interestingly, diastereomers that are generally thermodynamically disfavored can be obtained through this protocol. Figure 1 34. Sequential Ru/Pd catalysis to form N and O heterocycles Additionally, the stereochemistry seems to be determin ed by the hard/soft nature of the incoming nucleophiles. For sulfonamides (soft) the initial allyl system formed is kinetically trapped, whereas, alcohols (hard) go through a slow trapping mechanism allowing for the equilibration/interconversion of the allyl diastereomers. Lastly, their

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47 methods were applied to the synthesis of the B ring of the chemotherapeutic natural product bryostatin. Formation of Heterocycles via a Tandem Iridium catalyzed Vinylation/Allylic Amination Reaction A short time later You and coworkers reported an efficient enantioselective iridium catalyzed tandem allylic vinylation/amination method to form 2,3 dihydro 1H benzo[ b ]azepines. 45 The reaction sequence starts with an allylic vinylation of 1 100 with 1 101 thereby creating a monoallylic carbonate intermediate that further undergoes intramolecular allylic amination to give the desired azepines 1 102 (Figure 1 35 ). In most cases yields were high, and enantioselectivities were consistently good. Figure 1 35. Enantioselectiv e tandem iridium catalyzed allylic vinylation/amination reaction to form azepines Figure 1 36. Allyl carbonate intermediate

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48 Evidence for the proposed pathway was found through experiments that verified the monoallylic carbonate intermediates 1 103 could both be formed and cyclized under the o ptimized conditions (Figure 1 36 ). Moreover, it is interesting to note that this method is one of the few processes in this chapter that gives dependable enantioselective access to 7 membered nitrogen heterocycles. F ormation of Heterocycles via C H Activation of Allylic Systems Metal catalyzed C H functionalization has recently become a prominent strategy in the formation of complex structures. 46 The White group has developed various methodologies for the formation of saturated heterocycles via C H activation of allylic systems, and has applied this approach to the syntheses of biologically relevant compounds. 47 While most of the heterocycles formed in their reports are intermediates toward 1,2 and 1,3 aminoalcohols or diols, this strategy can also be used to synthesize intricate heterocycles. For instance, during the total synthesis of 6 d eoxyerythronolide B, and during studies determining the influence of a configurational bias during macrolactonization of erythrom ycin cores, an efficient macrolactonization was achieved using a palladium cata lyzed C H oxidation (Figure 1 37 ). 47 c,f Treating compounds 1 104 and 1 106 gave the 14 membered macrolides 1 105 and 1 107 respectively. Even though Y amaguchi macrolactonizati ons were also performed, the C H oxidation macrolactonization provides a complementary route without the need for oxidation at the C13 center (which can also be made through C H activation). In most cases, diastereoselectivities were also higher for the C H oxidation method when compared to the Yamaguchi protocol, albeit with lower yields. 47f More importantly, this report demonstrates that there is no need for conformational elements that shape or

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49 preorganize the desired macrolactonization, a philosophy tha t has been well accepted for over twenty years. 47f Figure 1 37. Macrolactonization via palladium catalyzed C H activation Conclusion The formation of heterocycles through metal catalyzed allylic alkylation reactions is an important s ynthetic technique t hat is ever growing From the reports discussed in this chapter it is easy to appreciate the role these reactions play in the syntheses of various natural products and biologically active compounds. In the past ten years numerous research groups have dem onstrated the abundance of catalysts and reaction pathways that can be used to produce structurally unique heterocycles of all varieties. Given the fresh nature of this field there is a clear path for new discoveries.

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50 CHAP TER 2 FORMATION OF AZACYCLES VI A GOLD CATALYZED DEHYDRATIVE CYCLIZATIONS Introduction Recently, there has been an influx of publications focused on the metal catalyzed formation of nitrogen and oxygen heterocycles via allylic alkylation reactions, 48 due to their prevalence in natural pr oducts and biologically relevant compounds. In 2008, Aponick and coworkers reported the first intramolecular gold catalyzed dehydrative cyclization of monoallylic diols 2 1 in the formation of tetrahydropyrans and furans 2 2 (Figure 2 1, A). 33 Since this report, many extensions have been reported by our group 34 as well as many others, 35 including an efficient process for the transfer of chirality for these diols (Figure 2 1, B). 34 d With low catalyst loadings, facile substrate syntheses, and water as the on ly by product, these methods have become powerful tools for the synthesis of complex heterocycles. Figure 2 1. Gold catalyzed dehydrative cyclizations to form tetrahydropyrans reported by Aponick et al.

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51 Figure 2 2. Gold catalyzed dehydrative cy clizations to form azacycles reported by the Widenhoefer group As a logical extension of the previously reported cyclization of monoallylic diols, we were interested in utilizing these dehydrative cyclization reactions for the formation of nitrogen heteroc ycles. During these studies, Widenhoefer and coworkers published two reports concerning the gold catalyzed dehydrative cyclization of alkyl amines 35 c and carbamates 35 d (Figure 2 2 A and B ) however, our efforts were focused on general

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52 conditions that wou ld not require excessive heating or the use of a chiral bis(gold) complex. In their first report, Widenhoefer and coworkers demonstrated the first gold catalyzed cyclization of alkyl amines 2 6 to form piperidines and pyrrolidines 2 7 (Figure 2 2, A). 35 c The scope was limited to basic alkyl amines, most of which required heating to 100 C. Furthermore, many of the substrates shown incorporate geminal substituents that cause a Thorpe Ingold ( gem dimethyl) effect ; because of this effect the substrates have a higher propensity to undergo the desired cyclization. Their studies demonstrated that the benzyl amine 2 8 could undergo an efficient transfer of chirality to the product 2 9 at 100 C in dioxane. Later, in 2012, the same group reported a similar dehy drative cyclization using carbamates nucleophiles. 35 d The enantioselective cyclization of carbamates 2 10 to form azacycles 2 11 is relatively facile taking place at room temperature over 2 days; however, the method has some major drawbacks (Figure 2 2, B). Nearly all of the substrates include gem dialkyl substituents to facilitate cyclization. Additionally, substitution at the allylic position gives rise to matched and mismatched cases with respect to the chiral gold complex. As a result of these matche d/mismatched interactions, a mixture of E and Z olefins products 2 11 can be obtained when an allylic substituent is present, unless an enantioenriched allylic alcohol is used. Given the drawbacks of the aforementioned systems we were still interested in finding gold catalyzed conditions that would facilitate the cyclization for a broad range of substrates without the use of gem dialkyl substituents, higher temperatur es, and a chiral gold complex.

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53 Gold Catalyzed Dehydrative Cyclizations of Carbamates Init ial Studies Initial experiments demonstrated an inherent preference for sulfonamides to undergo cyclization more readily than carbamates 2 12 Furthermore, it was previously demonstrated that Z allylic alcohols cyclize more easily than the corresponding E allylic alcohols. 34 e Given this difficulty efforts were focused on finding optimized conditions that would enable the formation of piperidines 2 13 from carbamates 2 12 (Table 2 1) Table 2 1. Optimization for the formation of piperidines Entry G old salt Silver salt Solvent Yield [a] 1 Ph 3 PAuCl AgOTf CH 2 Cl 2 <5 [b] 2 AuCl AgOTf CH 2 Cl 2 9 3 [( o biphenyl) di t butyl P]AuCl ( 2 14 ) AgOTf CH 2 Cl 2 <5 [b] 4 (Ph 3 PAu) 3 O + BF 4 CH 2 Cl 2 N.R. 5 (IPr)AuCl ( 2 15 ) AgBF 4 CH 2 Cl 2 93 6 (IPr)AuCl ( 2 15 ) AgBF 4 CH 2 Cl 2 8 7 [c] 7 (IPr)AuCl ( 2 15 ) AgBF 4 THF <5 [b] 8 AgBF 4 CH 2 Cl 2 N.R. [a] Purified yields [b] C onversion by 1 H NMR (300 MHz) [c] 4 MS omitted.

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54 To begin these studies, the complex generated in situ from Ph 3 PAuCl and AgOTf was used, because this complex effici ently catalyzed the formation of tetrahydropyrans via dehydrative cyclizations of monoallylic diols. 33 Surprisingly treatment of 2 1 2 under the optimized conditions for the formation of tetrahydropyrans resulted in little conversion to the desir ed produc t (Table 2 1, entry 1). Furthermore, little product formation was observed with the more Lewis acidic (Table 2 1, entry 2), and other gold complexes that have been utilized in the activation of analogous allylic/propargylic systems (Table 2 1, entries 3 4 ). Gratifyingly, s witching to a more electron donating carbene ligand (IPr 2 15 ) gave the product 2 13 in a 93% yield after 20 hours at room temperature in CH 2 Cl 2 (Table 2 1, entry 5 ). R emoving molecular sieves from the reaction had little effect on th e cyclization givin g the desired product in 87% (Table 2 1, entry 6 ). When 2 12 was treated with AgBF 4 no reaction occurred with only the silver salt, demonstrating that the cationic gold complex is required for the desired reaction to occur (Table 2 1, e ntry 7 ) Table 2 2 Optimization for the formation of pyrrolidines entry gold salt silver salt yield [a] 1 Ph 3 PAuCl Ag OTf 62 2 (IPr)AuCl AgBF 4 71 3 [( o biphenyl) di t butyl P]AuCl AgOTf <5 b [a] Purified yields [b] Conversion by 1 H NMR (300 MHz)

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55 In terestingly, formation of pyrrolidine 2 17 from 2 16 can be done either with the previously reported conditions (Ph 3 PAuCl/AgOTf) or using ( IPr ) AuCl as the gold salt (Table 2, entries 1 2). The combined results from the cyclization of piperidines and pyrrol idines, showed that the cyclizations were consistently more facile using the cationic gold complex formed from (IPr)AuCl/AgBF 4 For this reason, these conditions were adopted as the optimized catalyst system for the formation of these aza cycles. Substrate Scope and Limitations With the optimum conditions established the substrate scope was then explored. Sulfonamides 2 18 a and 2 18 b were readily cyclized with cata lyst loadings as low as 1 mol% at room temperature (Table 2 3, entries 1 3). This result dem onstrated that the cyclizations of sulfonamides were much more facile than their carbamate analog ue s. When treated under the standard conditions E allylic alcohol 2 18 c gave little conversion to the desired piperazine 2 19 c. Conversely, Z allylic alcohol 2 18 d underwent smooth cyclization to give 89% of the product 2 19 c after 16 hours at room temperature (Table 2 3, entries 4 5). The method also allows easy access to morpholines such as 2 19 d although the cyclization was again more facile when the Z all ylic alcohol isomer was used (Table 2 3, entries 6 8). Lastly, it was found that even though carbamates and sulfonamides readily undergo cyclization, amides such as 2 20 were unable to produce any of the desired lactams 2 21 u nder v arious conditions (Tabl e 2 4). Despite attempts to electronically tune the substrates to facilitate cyclization by varying the substituents on the nitrogen, and at the allylic position, the desired products were not observed with substrates 2 20(a d) even while refluxing the r eaction mixture (Table 2 4, entries 3 and 5). Interestingly, although terminal carbamates like that of 2 18 readily undergo the desired

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56 cyclization, internal carbamate 2 20d did not cyclize under the optimized conditions (Compare Table 2 3 to Table 2 4 en try 5). Table 2 3 Substrate scope for the dehydrative cyclization of sulfonamides and carbamates entry substrate mol (%) time (h) product yield (%) [a] 1 1 20 71 2 3 2.5 5 6 1 88 92 4 5 16 <20 [b] 5 5 16 89 6 5 24 30 7 8 5 5 7 24 51 81 [a] Purified yields [b] Conversion by 1 H NMR (300 MHz)

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57 Table 2 4 Limitations of the method entry substrate time (h) product yield (%) 1 24 2 24 3 4 [a] 24 24 5 [a] 24 [a] Reaction run at reflux. Various f actors could cause the low reactivity observed by the amide substrates 2 20(a c) One factor could be a general decrease in nucleophilicity for these amides with respect to other substrates that successfully undergo formal S N type cyclizations (which is unprecedented for amides). The second could be that these relatively unhindered amides may coordinate to the cationic gold complex thereby shutting down the catalytic cycle, a type of coordination that could be minimized in the tert

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58 butylcarbamate substr ates because of the increase in steric hindrance from the tertiary butyl group. Although the lower reactivity observed for these amides is not well understood, it should be noted that there seems to be a correlation between the pK a of the substrates, and their ability to undergo the dehydrative cyclization. To estimate the pK a substrates, a comparis on was made to analogous amides with known pK a values (Table 2 5) Table 2 5 pKa of analog ou s compounds in relation to the reactivity substrate reaction conditions and yield analogous compounds pK a of N H for analogs (in DMSO) 1 mol%, r.t. 20 hrs. 71% 16. 3 49 a 5 mol%, r.t. 24 hrs. 71% 20.8 49 b 5 mol%, r.t. 24 hrs. No reaction 21.5 49 c 5 mol%, reflux 24 hrs. No reaction 26. 5 49 d As demonstrated in Table 2 5 the reactivity of the substrate increases with increasing acidity of the N H bond. Furthermore, as the pK a of the N H bond approaches that of an alcohol, the reactivity of the amine substrate become s more like that of a monoallylic diol for these cyclizations 33,34 This relationship between acidity and

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59 reactivity, may be due to the requisite hydrogen bonding interactions between the incoming nucleophile and the allylic alcohol that are needed to facilitate these dehydra tive cyclizations (see Fig 1 22). 34 f The more acidic N H bonds should have a higher tendency for hydrogen bonding, and thus a higher propensity to undergo dehydrative cyclizations. Studies in the Tran sfer of Chirality for Carbamate Nucleophiles A great deal of information was obtained through the studies of the optimization and scope of these cyclizations. G iven the broad range of functionality t hat can be tolerated under the conditions, we set out to apply this method to the synthesis of a relatively s imple natural product, Caulophyllumine B ( 2 26 Figure 2 3 ) 50 The simplicity of the structure and the requisite stereocenter made it a great candidate for observing the transfer of chirality for the dehydrative cyclization of enantioenriched carbamates. Figure 2 3 Caulophyllumine B Retrosynthetically 2 26 could easily come from the product of the gold catalyzed cyclization of 2 27 ( Figure 2 4 ) Additionally 2 27 could be easily made in a few simple steps starting from commercially available 5 hexyn 1 ol ( 2 29 ), allowing for short, direct stereoselective synthesis of 2 26 The synthesis first commenced with the production of the bis car bamate 2 28 ( Figure 2 5 ). Treating 2 28 under the standard Carreira asymmetric alkynylation conditions 51 with the p ivaloyl protected 4 hydroxybenzaldehyde, gave the desired propargyl alcohol 2 30 in a reasonable yield with a good enantiomeric excess (92% ee).

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60 Surprisingly, after reduction under Lindlar conditions and select ive deprotection of one of the t butoxycarbon yl ( Boc) groups with LiBr, a significant decrease in enantiomeric excess of the desired allylic alcohol 2 27 was observed Figure 2 4. Retrosynthetic considerations for the synthesis of 2 26 The racemization most likely occurred during the hydrogenation process, wherein the allylic alcohol could coordinate to the palladium and the electron donating oxygen in the para position could help facilitate the inversion of the chiral center. Since the enantiomeric excess of 2 27 was already relatively low, our efforts were focused on finding a new substrate that would furnish higher ee before and, hopefully after the cyclization. Figure 2 5. Synthesis of substrate 2 27

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61 To a ccomplish this goal a more deactivating (inductively withdrawing) 4 bromophenyl substit uent was used, in hopes to circumvent the undesired racemization of the allylic alcohol and allow for a group that could be easily converted to the desired phenol. Again treating alkyne 2 28 under the standard Carreira alkynylation conditions with 4 brom obenzaldehyde gave the desired propargyl alcohol 2 31 in a good yield with a 97% ee (Figure 2 6) Reduction of the alkyne, followed by partial deprotection of the bis carbamate occurred with only minor racemization of the desired substrate 2 32 allowing f or an ideal demonstration of the previously reported transfer of chirality via a gold catalyzed dehydrative cyclization. 34 d,f However, upon treatment of substrate 2 32 with the optimized conditions the product 2 33 wa s formed in only one hour in an unant icipated 30% ee. This result was somewhat puzzling and contrary to the high chirality transfer observed in the formation of tetrahydropyrans. 34 d,f Fig ure 2 6. Synthesis of 2 33

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62 If these amine substrates followed a similar reaction pathway to their di ol analogs, it would stand to reason that the substrate would undergo a similar mechanistic pathway and allow for a high transfer of chirality (Figure 2 7). The intermediate 2 34 can form a complex with the gold catalyst, this intermediate can then undergo anti addition of the carbamate to the complex to generate 2 35 (Figure 2 7). Loss of water and the cationic gold species (deauration) should give the enantioenriched product whose ster eospecificity can be partially attributed to the hydrogen bonding interaction between the carbamate and the allylic alcohol, which acts as a stereochemical template throughout the mechanistic pathway. Figure 2 7. Mechanistic Pathways analogous to prev ious studies A plausible explanat ion for the low enantiomeric excess found for 2 37 could be that the aromatic substituent brings about a competing pathway that causes the allylic system to undergo complete ionization thereby giving a lower enantiomeric e xcess than would be expected Additionally, when compared to their alcohol analogs, the carbamate nucleophiles may have a higher tendency for coordinating to the gold

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63 complex which could also account for the longer reaction times observed for these azacy clizations. With these inte ractions in mind, we envisioned two possible mechanistic pathway s for the racemization of the enantioenriched allylic alcohol 2 32 ( Figure 2 8 ) In pathway A, coordination of the alcohol to the gold complex 52 2 37 followed by ion ization 2 38 creates an intermediate cation that is highly stabilized through resonance because it is both benzylic and allylic. Figure 2 8. Possible ionization pathways. A : pathway A, B : pathway B. In pathway B, coordination of the carbonyl oxygen in the carbamate to the gold complex could sequester the catalyst creating a highly acidic proton on the nitrogen

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64 Protonation of the allylic alcohol in 2 39 would then create a hydronium ion that can easily be extruded as water creating a highly stabilize d cationic system in 2 40 After cyclization/rearomatization the product 2 33 would be form ed as a racemic mixture. While coordination of the carbamate followed by deprotonation could be an equilibrium process occurring throughout any of the aforemention ed azacy clizations, having an aromatic group in the allylic position should give a higher potential for cation formation, thereby creating the conjugated ionic system in 2 40 Although these possible competitive pathways have not been conclusively identi fied, they could account for the observed epimerization. Furthermore, if these pathways are in fact the main cyclization pathway for substrate 2 32 then there must be some memory of chirality 53 within the cyclization event since the product 2 33 is formed as a 65:35 mixture of enantiomers. Given the aforementioned rationale for the observed epimerization, we were interested in learning more about the effect of having an aryl group in the allylic position and wanted to understand if it does in fact create a higher propensity for ionizatio n of the allylic alcohol under these conditions. T o test this theory, a similar cyclization precursor 2 41 with an alkyl substituent in the allylic position was prepared This alkyl tether would create an allylic system tha t would be less susceptible toward ionization ho pefully resulting in a higher enatioselectivity after subsequent cyclization. Gratifyingly, after treating carbamate 2 41 under gold catalyzed conditions transfer of chirality was achieved with only small loss of enantiomeric excess to the product 2 42 (from 96% to 92% ee ) albeit with somewhat mor e demanding conditions (Figure 2 9 ). Significantly, this result demonstrates the first gold catalyzed transfer of

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65 chirality using carbamates without the use of a chiral gold complex, 54 and correlates well with the previously reported chiral transfer methodology for monoallylic diols. 34 d Figure 2 9. Transfer of chirality from 2 41 to 2 42 The studies on the gold catalyzed dehydrati ve cyclization of carbamates have given invaluable insight into the potential mechanistic pathways that can occur for these reactions The f ormation of azacycles under these conditions present s a mild and efficient route for the transfer of chirality without the n eed for a chiral met al complex, and gives access to products with a broad range of functionality. These finding have since been accepted for publication, 55 and the methods are currently being applied to the synthesis and biological testing of various mefloquine analogs. Synt hesis of Mefloquine and Analogs Historical and Biological Significance Malaria is an infectious disease most commonly found within tropical or subtropical regions of the globe that have high mosquito populations. 56 There are currently five known species of parasites that can be attributed to the cause of malaria in humans; however, the most deadly form is caused by the parasite P. falciparum 56 These parasites are normally transferred to humans by an infected female mosquito, allowing for various avenues fo r preventative intervention measures in the spread of t his devastating disease. 56 All humans that travel or inhabit areas that are highly populated by these infected mosquitoes are at risk for contracting this treatable disease, especially in the sub

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66 Saha ran African regions. 57 It is estimated that in 2012 alone, the United States spent nearly $1.84 billion to finance and implement malaria control measures across the globe In 2010 there were an estimated 219 million cases of malaria worldwide, as well as 660,000 reported deaths. 56 During the Vietnam War the Walter Reed Army Institute of Research (WRAIR) began researching an antimalarial drug for the treatment and possible prevention of malaria. 58 Throughout their experiments, over 250,000 compounds wer e screened as potential candidates From these screenings, mefloquine 2 43 (trade name Lariam) was discovered as a potent drug for the treatment of malaria and was subsequently patented by the Hoffman La Roche company. Lariam was then approved by the Fo od and Drug Administration (FDA ) in 1989 and has since been marketed globally as an antimalarial drug. 58 chloroquine resistant Plasmodium falciparum (CRPF) strain of malaria a strain that can be fatal in up to 4% o f travelers who contract the disease 57 It is defined as a suppressive chemoprophylactic because it s mode of action involves targeting the parasites that have invaded the erythrocytes within the blood stream. 57 Alt hough the drug suffers potential drawbacks it is still one of the most prescribed antimalar ial drugs worldwide because of its low cost, the women, children, etc.), and its once weekly dosage regimen In fa ct, for pregnant women, no alternative antimalarial drug exists 57 The drug is sold as the erythro isomer in its racemic form 2 43 and has gained much attention in recent years because of the long term neurological side effects that

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67 can develop before and after its use (Fi gure 2 10 ). 59 It is also s peculated that (+) mefloquine 2 44 is the active antimalarial dr ug whereas the ( ) mefloquine 2 45 enantiomer may cause the neurological problems associated with taking the commercial product. 60 For this reason, many researchers have focused on a stereoselective synthesis of (+) 2 44 61 Figure 2 10. Mefloquine and its biological activity Synthesis of Mefloquine and Its Derivatives Given the recurrent use of this drug, its potential side effects, and a recent re port that has unequivocally established the absolute configuration of (+) 2 44 62 the need for a divergent asymmetric synthesis that could provide quick access to various analogs of this drug is critical. In the same respect, these analogs may increase th e antimalarial properties while hopefully eradicating the potential psychotic side effects that can develop with its use With this in mind, we set out to create a novel divergent asymmetric synthesis of (+) mefloquine ( 2 44 ) and various enantioenriched an alogs for the eventual biological testing against various malaria strains and psychotic effects Hoffman La R oche gains rapid access to 2 43 by reduction of 2 46 which can be easily made by attachment of pyridine 2 47 to quinoline 2 48 (Figure 2 11 ). 63 Wh ile divergent and effective, this method generally only allows access to the racemic

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68 mixture. T he use of pyridine 2 47 is also somewhat limiting as it gives little potential for certain analogs because of the lack of f unctional groups that can be incorpora ted into the pyridine ring. Figure 2 11. Hoffman La Our proposed retrosynthesis allows for a variety of mefloquine analogs 2 49 that have not be en previously reported (Figure 2 12). Synthesis of unique analogs is of increasi ng importance due to the multitude of recent reports that have demonstrated the potential effectiveness of mefloquine and its derivatives against various diseases including: multiresistant tuberculosis, 64 multifocal leukoencephalopathy, 65 and vibrio chole ra 66 to name a few. In addition to the potential health benefits, these analogs could also give further insight into the mechanism by which mefloquine functions in a biological setting. Figure 2 12. Proposed Retrosynthesis of Mefloquine Derivatives

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69 Mo re recently, researchers at the Walter Reed Army Institute of Research screened various analogs that encompass diamine tethers like that in 2 52 (Figure 2 13) 67 These derivatives can be easily constructed through the epoxide opening of 2 53 using various diamines. During their studies, Milner and coworkers found a highly potent analog 2 54 (Figure 2 14 aka WR621308 ) that has a reduced accumulation in the central nervous system (CNS) in comparison to mefloquine. Figure 2 13. Diamine Quinoline Metha nols In reference to 2 54 t curative after single dose administration and has a longer half life, lower pa rti ti oning in t o the CNS, and an improved cardiac safe ty index relative to mefloquine 67 In addi tion to the aforementioned analogs of the parent mefloquine (Figure 2 12), it would be advantageous to construct analogs based on the structure of 2 52 Figure 2 14. Highly potent mefloquine analog 2 54 With this in mind we h ave also devised a plan to construct analogs with the general structure s 2 55 and 2 56 E nantioenriched azacycles can be easily synthesized

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70 via the gold catalyzed dehydrative cyclizations These azacycles could then be easily tethered onto the epoxy quinoline 2 53 via an epoxi de ring opening, allowing rapid access to these analogs. Figure 2 15. Potential Analogs of WR621308 ( 2 54 ) Initial Experimentation The initial studies for this project have focused on the design of an efficient asymmetric synthesis of mefloquine. Exper imentation has thus far been concentrated on optimizing the addition of the metallated quinoline 2 51 to to an aldehyde Isobutry aldehyde was chosen because its volatility would allow for easy purification, while its substitution pattern makes it a good m odel for the piperidine aldehyde 2 50 Figure 2 16. Synthesis of 2 48c In order to generate the metallated 2 51 both the chloro and iodo analogs were synthesized to determine which halide would undergo a more facile metal halogen exchange. Synthesis of the known 4 chloro 2,8 bis(trifluoromethyl)quinoline 2 48b was easily achieved through literature procedures. 68 Additionally, the iodo quinoline 2 48c was easily accessed by treating 2 48b with hydroiodic acid (Figure 2 16).

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71 With both halides in hand, studies of the lithium 69 and magensium 70 halogen exchange reactions, followed by subsequent addition of these metallated quinolines to isobutyr aldehyde were underway (Table 2 6) Unfortunately, under various conditions the metal halogen exchange for the chloroquinoline 2 48b was unsuccessful. Switching to the more inductively withdrawing iodoquinoline 2 48c gave the desired product 2 58 in a 45% yield after lithiation with n butyllithium (Table 2 6 entry 4) Furthermore, treatment of 2 48c under Knochel conditions, 7 0 gave the desired product 2 58 in a 58% yield (Table 2 6 entries 5 6). Table 2 6. Screening for the metal halogen exchange of 2 48 entry halide c onditions y ield (%) [a ] 1 2 48b Mg 0 I 2 2 2 48b n BuLi <10 [b ] 3 2 48b i PrMgCl LiCl 4 2 48 c n BuLi 45 5 2 48 c i PrMgCl LiCl 50 [b ] 6 2 48 c i PrMgCl 58 [a] Purified yields. [b] Conversion by 1 H NMR (300 MHz) Although the yields for the additions of the metallated quinoline were rather low, when searching through the literature similar re sults have been shown for analogous reactions 71 For instance, l ithiation of the bromoquionoline 2 48a gave poor results for

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72 the addition to ben z aldehyde and the pyrrolidine aldehyde 2 60 (Table 2 7, entries 1 2). Additionally, sulfoxide 2 48d gave a 5 5% yield of the desired product after the sulfoxide magnesium exchange with phenylmagnesium bromide and subsequent addition to the aldehyde 2 61 (Table 2 7, entry 3). These examples demonstrate some of the only reported reactions for addition of 2 48 to a n aldehyde. The combined data (Table 2 6 and 2 7) demonstrate that lithiation of the halide gives dismal results, while exchange of the iodide or sulfoxide with magnesium can give moderate yields. Table 2 7. Literature examples detailing the addition of 2 48 to aldehydes entry 2 48 conditions aldehyde yield (%) [a] reference 1 a n BuLi benzaldehyde 36 71a 2 a n BuLi 21 71a 3 d PhMgBr 55 71b [a] Purified yields As an alternateive to the direct addition of these metallated quinolines to an aldehyd e, recent efforts have been focused on the addition of 2 48c to the ozonide of 2 42 This addition would be advantageous because it has been reported that the enantioenriched formyl piperi dine 2 62 ca n undergo epimerization. 72 Although the addition of g rignard reagent to ozonides has been well known for quite some time 73 its

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73 use in synthetic chemistry is less common when compared to grignard addition to an aldehyde. Surprisingly, treatment of the in situ generated ozonide produced from the ozonlysis of 2 42 produced the undesired product 2 62 in a 60% yield along with some residual formyl piperidine 2 63 and possibly a small amount of desired product (Figure 2 17) Figure 2 17. Treatment of ozonide with 2 51a Further experimentation for this projec t will focus on the optimization of the aforementioned processes in hopes to find a facile synthesis that efficiently stitches the quinoline and piperidine pieces together. These studies are currently underway and will be reported in due course.

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74 CHAPTE R 3 STUDIES IN THE TANDEM GOLD CATALYZED HYDROALKOXYLATION/ CLAISEN REARRANGEMENT Introduction The Claisen Rearrangement is a versatile synthetic transformation that enables the formation of two stereogenic centers and an unsaturated ketone 3 2 in one c oncerted step from an allyl vinyl ether 3 1 (Figure 3 1). This [3,3] sigmatropic rearrangement was first discovered by Rainer Ludwig Claisen in 1912 and has since become one of the most well known synthetic methods for the construction of carbon carbon bo nds. 74 Figure 3 1. General Claisen Rearrangement In 1912, Claisen released a report that described the transformation of allyl phenyl ethers 3 3 to ortho allylphenols 3 4 at high temperatures (Figure 3 2). 75 Since this initial account, many research g roups have focused on the development of new variants of this sigmatropic process, especially in the field of catalysis. Some of the more well known modifications are now considered classical methods, including: the Johnson(orthoester) Claisen, 76 Eschenmo ser Claisen, 77 and the Ireland Claisen 78 rearrangements (Figure 3 3). The carbonyl products formed in these reactions are highly functionalized and diverse synthons with various handles for further synthetic elaboration. As a

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75 consequence of this utility many groups have applied these methods in the construction of numerous natural products and biologically rele vant building blocks. 79 Figure 3 2. First Reported Claisen Rearrangement Figure 3 3. Classical Variants of the Claisen Rearrangement Mecha nistically, it is well established that this [3,3] rearrangement goes through a 6 membered chair transition state, like that of 3 7 (Figure 3 4). Although many transition state extremes ( 3 8 3 11 ) have been proposed, there is still no consensus for the precise transition state because it is highly dependent on the types of substituents. The stereochemical outcome of the reaction is also dictated by the substituents in the allyl vinyl ether. In general, the chirality of the starting allyl vinyl ether is transferred to the ketone product after rearrangement (Figure 3 5). 74 In the case of the allyl vinyl ether 3 12 there are two major possible transition states 3 13 and 3 15 ; however, 3 15 is disfavored because of the 1,3 diaxial interactions between subs tituents R 1 and X, thus the product 3 14 is formed rather than 3 16 In substrates where no

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76 satisfactory chair transition state exists the rearrangement can also take place through a boat like transition state to alleviate many of the steric interactions. Figure 3 4. Possible Transition States of the Claisen Rearrangement; A : Chair like transition state; B : Possible transition state extremes Figure 3 5. Stereochemical Considerations Gold catalyzed Claisen Rearrangements Gold catalysis has sparked a new wave of synthetic transformations, allowing for access to complex structures. 32 In 2004, Toste and coworkers reported the first gold catalyzed formal Claisen rearrangement, which details a stepwise [3,3] rearrangement of propargyl vinyl ethers 3 17 to form allenols 3 18 with low catalyst loadings and high yields (Figure 3 6). 80 They were also able to demonstrate that the highest transfer of chirality from the starting material to the product was achieved using the cationic

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77 oxonium gold complex [(PP h 3 Au) 3 O]BF 4 In their best example, substrate 3 19 formed product 3 20 with high transfer of chirality and an extremely high diastereoselectivity. Figure 3 6. Gold catalyzed propargyl Claisen rearrangement Since this report many groups have published a variety of Claisen rearrangements catalyzed by gold complexes 81 In 2006, He et al. published a tandem gold catalyzed Claisen rearrangement/hydroalkoxylation reaction for the synthesis of dihydrobenzofurans 3 23 from aryl allyl ethers 3 21 (Figure 3 7) 81 c The process is believed to go through a gold catalyzed Claisen rearrangement to give intermediate 3 22 followed by a gold catalyzed hydroalkoxylation of the alkene. The authors state that the Claisen rearrangement is m uch faster when treated with a cationic gold(III) complex, whereas the hydroalkoxylation step is much faster with a cationic gold(I) complex. This is demonstrated in the formation of 3 26 from 3 24 however, the experimental data does not detail these studies and the gold complexes ar e not explicitly stated. For these reasons, it is hard to extrapolate any useful conclusions from their statements.

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78 Figure 3 7. Gold catalyzed tandem Claisen rearrangement/hydroalkoxylation reaction A few years later, in 2010, Yeh and coworkers descr ibed the synthesis of spirocycles 3 29 from enynols 3 27 through a gold catalyzed Claisen process followed by reduction of the subsequent alkene of 3 28 (Figure 3 8). 81 f The Claisen type rearrangement from 3 27 to 3 28 was nutes at room temperature with 5 mol% of a cationic gold complex generated in situ from Ph 3 P AuCl and AgOTf. Figure 3 8. Spirocycles via gold catalyzed Claisen type rearrangement

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79 The authors propose a mechanism that involves the activation of the alkyne in 3 30 with the cationic gold complex to give intermediate 3 31 (Figure 3 9). After anti addition of the alcohol to the alkyne to give the 9 membered oxonium ring 3 32 a Claisen type rearrangement occurs to give the bicyclic intermediate 3 33 followed b y deauration and proton exchange to give the desired product 3 34 This highly efficient cycloisomerization allows access to complex bicyclic carbocycles, however, the synthesis of the requisite enynols 3 27 may impede the synthetic usefulness of this pro cess. Furthermore, the alkyne substituents reported are always aromatic which severely limits the scope of this methodology. Figure 3 9. Proposed mechanism for the gold catalyzed rearrangement of enynols Gold catalyzed Tandem Hydroalkoxylation/Claisen Rearrangement In general, synthetic methodologies developed for the Claisen rearrangement involve preformed or highly activated substrates that have a high propensity to undergo the [3,3] sigmatropic rearrangement (Figure 3 10). While surveying the litera ture we

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80 noticed that, while these methodologies are well explored, processes for the formation of highly stereodefined acyclic allyl vinyl ethers are much less common, especially when Z enol ethers that are not activated with additional functional groups a re desired ( where R 1 = H and R 2 = alkyl, aryl; 3 35 ). 74 82 Figure 3 10. Classical Claisen Methodologies Additionally, the synthesis and purification of the desired enol ether substrates has posed quite a challenge to the synthetic community. As a res ult of these challenges, many research groups have started focusing on tandem processes, which involve the formation of these enol ethers in situ followed by the sigmatropic rearrangement, in order to circumvent the problems associated with the stability o f these compounds. 82 e g 83 In 2004, Buchwald and coworkers reported a tandem copper catalyzed C O coupling/Claisen rearrangement. 82 f During the reaction course an allylic alcohol 3 37 goes through a Cu(I) catalyzed C O coupling with a vinyl iodide 3 38 to form an allyl vinyl ether, which undergoes the rearrangement over 2 days at 120 C to give the desired product 3 39 (Figure 3 11) The process occurs with reasonable yields and diastereoselectivity, however the formation of the requisite vinyl iodides ca n limit the

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81 utility of the products. Moreover, the catalyst loadings, temperature and reaction times are quite high which may take away from the value of the reaction. Figure 3 11. Cu catalyzed C O coupling/Claisen Rearrangement In the same respect, N elson and coworkers reported an attractive asymmetric iridium catalyzed isomerization Claisen rearrangement (ICR) as an extension of their previously reported iridium methodologies. 83 e, g This elegant transformation converts diallyl ethers 3 41 into the de sired Claisen products 3 42 with good yields and high stereoselectivity with low catalyst loadings (Figure 3 12). The isomerization of the terminal olefin is a good strategy to obtain the allyl vinyl ether, however, it limits the functionality of the prod carbon can be produced. In the same respect, the steric differentiation required for the selective iridium catalyzed isomerization to occur results in the production of only aldehyde products only. Figur e 3 12. Iridium catalyzed isomerization Claisen rearrangement (ICR)

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82 Although the aforementioned tandem enol ether formation/Claisen rearrangement reactions are elegant, they have many drawbacks. In order to broaden the scope of these sequences we envisi oned a tandem hydroalkoxylation/Claisen rearrangement process to give ketone products (Figure 3 13). This seemed like an attractive atom economic approach to help broaden the ac cess to these diverse products. Additionally, a metal catalyzed hydroalkoxyl ation would generate the enol ether in a stereodefined manner in situ based on the mechanism of alcohol addition. 84 Interestingly, while metal catalyzed hydroalkoxylations of alkynes is well known, 85 the tandem process we envisioned had never been reporte d. Figure 3 13. Proposed Hydroalkoxylation/Claisen rearrangement process Results and Discussion Preliminary studies utilized gold complex 3 50 to test this tandem process, because this complex worked well during our studies of the intramolecular deh ydrative alkoxylation of alkynes to form spiroketals. 34 a However, the inherent difficulties of the se quence became abundantly clear at the beginning of our studies When alkyne 3 48 was treated with alcohol 3 49 i n the presence of gold complex 3 50 /AgOTf a complex mixture of hydration ( 3 52 3 53 ) and self condensation ( 3 54) products was formed, however, the desired product 3 51 was not observed ( Figure 3 14 ). This result further

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83 exemplified the challe nges we would need to overcome in order to allow the se allylic al cohols to serve as nucleophiles, since all of our previous methodologies have focused on the ability of propargyl and allylic alcohols to act as electrophiles under gold catalyzed conditions. 34 Figure 3 14. Inherent difficulties Initially we began our studies by testing various metal complexes to see which, if any, could catalyze the tandem process. Crotyl alcohol was first employed ( 3 49 ) as the nucleophile, because it is a commercially available and inexpensive starting material. The v olatility of the alcohol would also make purification much easier during these preliminary tests. In the same respect, alkyne 3 48 was readily available, had a high molecular weight, and could give preliminary insight into the regioselectivity of the reac tion. Unfortunately, w hen alcohol 3 49 was treated with various catalyst systems none of the desired product was obtained (Table 3 1 entries 1 4). Given the susceptibility of the allylic alcohol 3 49 to undergo intermolecular dehydrative S N the nucleophile was replaced with a more hindered alcohol 3 55 in hopes to avoid these possible side reactions. Surprisingly, switching to the more hindered alcohol also did not produce any of the desired product, even under more harsh conditions (Table 3 1,

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84 entries 5 6). Diphenylacetylene 3 56 was then used as the alkyne partner, in hopes to have a higher reactivity and alleviate any regioselectivity issues. The catalyst system and solvent were also switched to analogous conditions of a recent report th at demonstrated an extremely high efficiency for the hydration of alkynes with water. 86 Table 3 1 Preliminary Studies entry alcohol alkyne catalyst system solvent temp (C) yield (%) [a] 1 3 49 3 48 I THF 65 0 [b] 2 3 49 3 56 AuCl THF 65 0 [b] 3 3 49 3 56 PtCl 2 THF 65 0 [b] 4 3 49 3 56 AuCl 3 /AgOTf [c] THF 65 0 [b] 5 [d] 3 55 3 48 I THF 90 0 [b] 6 3 55 3 48 I THF 65 0 [b] 7 3 55 3 56 II 1,4 dioxane 100 25 ( 3 58 ) 8 [d] 3 55 3 56 II 1,4 dioxane 120 34 ( 3 58 ) 9 3 55 3 56 II THF 65 50 ( 3 58 ) [a] Isolated yi elds. [b ] A complex mixture of hydration and self condensation products was observed. [c ] AuCl 3 (5 mol%)/AgOTf (15 mol%). [d ] Reaction run in sealed tube. I =( o biphenyl di tert butylphosphine)gold(I) chloride/ AgOTf; II = (IPr)AuCl/AgBF 4. Gratifyingly, all of these changes were steps in the right direction, giving the desired product 3 58 in a 25% yield when 3 55 and 3 56 were treated with catalyst system II in 1,4 dioxane at 100 C (Table 3 1, entry 7). Further increasing the

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85 temperature of the reaction t o 120 C gave a slightly higher 34% yield of the product (Table 3 1, entry 8). Counterintuitively, the best yield was given when the reaction was run in refluxing tetrahydrofuran (65 C), which is a much lower temperature than is normally required for t hese [3,3] rearrangements. 74 Under these conditions the desired product 3 58 was produced in a 50% yield (Table 3 1, entry 9). Table 3 2 Optimization Studies g alcohol additional conditions yield (%) [a] 3 61:3 62 [b] 1 3 59 73 5:1 2 3 59 (IMes)AuCl /AgBF 4 0 3 3 59 PPh 3 AuNTf 2 0 4 3 59 AgBF 4 only 0 5 3 59 HBF 4 OEt 2 only 0 6 3 60 0 7 3 60 Slow addition of 3 60 33 [c] 1:7 8 3 60 Slow addition of 3 60 then 120C for 6 hrs. 75 1:11 [a] Isolated yields. [b] Determined by 1 H NMR (500 MHz). [c] Enol ether adduct of 3 56 + 3 60 was also isolated in 37%, see supporting information. The preliminary studies demonstrated that cationic gold complexes could catalyze the tandem process, however, we were still interested in optimizing the condition s to include the use of relatively unhindered allylic alcohols that have a higher propensity for S N side reactions Additionally, to quickly evaluate the progress of the reactions a less volatile alcohol was desired in order to monitor its conversion to the

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86 product by crude 1 H NMR. To satisfy all of these requirements, alcohols 3 59 and 3 60 were used for the optimization studies (Table 3 2). We were delighted to find that treating the E allylic alcohol 3 59 with the same conditions used in our prelimin ary studies (Table 3 1, entry 9) gave the product 3 61 in a 73% yield with a 5:1 diastereoselectivity (Table 3 2, entry 1). Several gold complexes were then tested under the reaction conditions, and it was found that the process was selective for the orig inal conditions (Table 3 2, entries 2 5). Treating the substrates with the cationic silver source or the protic acid that could be produced by the counter ion proved that the reaction was indeed catalyzed by the cationic gold complex (Table 3 1, entries 4 5). Unfortunately, treating the Z allylic alcohol 3 60 under the aforementioned conditions did not give any of the desired product 3 62 (Table 3 2, entry 6). Since the Z allylic alcohol 3 60 may have a higher predisposition toward self condensation by a n S N reaction, the solution of the alcohol was then added slowly (over 12 hrs.) to the reaction mixture. Fortunately, slow addition of the alcohol provided the syn product 3 62 in a 33% yield with a 7:1 dr (Table 3 2, entry 7), however, the mixture cont ained residual enol ether formed from the hydroalkoxylation of 3 56 with 3 60 In hopes to fully convert the enol ether to the desired product, the slow addition was then followed by heating the solution at 120 C in a sealed tube for six hours. Under th ese conditions the product 3 62 was formed in 75% yield with a 11:1 dr, which is higher than that of the E allylic alcohol (compare Table 3 2 entries 1 and 8). Although higher temperatures are required, the conditions are still milder than most reported C laisen protocols, and these parameters were adopted as the optimized conditions.

PAGE 87

87 Table 3 3 Selected Substrate Scope [ a ] Isolated yields. [b] diastereoselectivity determined by 1 H NMR (500 MHz). [c] Slow addition of alcohol not required. [d] Yield ob tained using co nditions from Table 3 1, entry 9. [e] Substrates: 15 3 hexyne. [f] Ratio (arylketone:alkylketone) determined by 1 H NMR (500 MHz). [g] Only a single diastereomer of each regioisomer was observed. With the optimum conditions established, t he substrate scope of the rea ction was then examined (Table 3 3 ). Hindered allylic alcohols with a lower susceptibility toward etherification cleanly produced the product in reasonable yields (Table 3 2, 3 65a 3 65c ). Furthermore, as demonstrated during t he optimization process, Z allylic alcohols give consistently higher diastereoselectivity in all cases when compared to the E allylic alcohols (Table 3 2 entries 1,7 and Table 3 3 compare 3 65b and 3 65 c ) Under the optimized conditions the disubsti tu t ed olefin cinnamyl alcohol was efficiently converted to 3 65d in a 96% yield with 5:1 dr, however when the more sterically hindered

PAGE 88

88 OTBDPS substituent was used the diastereoselectivity increased dramatically ( 3 65 e >25:1 dr). Much to our delight, commerci ally available, unhindered allyl alcohol was also smoothly transformed to the product 3 65f in a 95% yield under the optimized conditions. It was also found that the aliphatic alkyne 3 hexyne could easily undergo the desired tandem process to give the prod uct 3 65g with a high yield, albeit with a lower dr (1:1) than was found for the diphenylacetylene. Lastly, when 1 p henyl 1 propyne was used as the alkyne reaction partner with alcohol 3 59 the desired product 3 65h was obtained in a 78% yield as a 1:4 mix ture of regioisomers, where each regioisomer was obtained as a pure diastereomer. The above studies demonstrated that various allylic alcohols, and aliphatic or aromatic acetylenes could form the desired product with a cationic gold complex. Nevertheless, examining the factors that dictate the regioselectivity for the hydroalkoxylation could give further insight into the utilization of this methodology. Furthermore, if the reaction could preferentially form aryl ketones it would broaden the synthetic utili ty of the process, because electron rich aromatic ketones can be easily oxidized to the ester. 8 7 This would allow for a synthetic handle that could be easily removed if necessary. From the outset of this project it was demonstrated that the regioselecti vity would pos e a significant problem when un symmetrical alkynes were used (Figure 3 14). Allyl alcohol was used to further examine the regioselectivity in order to decrease the mixture of possible products caused by stereo and regioselectivity issues. The commercial

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89 availability and low boiling point also made it a great candidate for easy scalability and purification of the reactions. Initial studies focused on tuning the sterics and electronics of the aromatic portion of the alkyne while leaving the a liphatic portion untouched (Figure 3 15). Additionally by careful tuning of the electronics and sterics of the aromatic ring, (Figure 3 15) the gold complex would hopefully reside more toward the alkyl portion of the alkyne, thereby directing nucleophilic attack at the benzylic position. Figure 3 15. Tuning the regioselectivity. A: Electronic Tuning B: Steric Tuning With this rationale in mind, studies of the regioselectivity were undertaken (Table 3 4). It was somewhat disappointing to find that p lacing a methyl group in the ortho position of the ring gave the product 3 68a with a 2:1 regioselectivity, while having an electron donating methoxy group in the para position of the ring gave the exact same selectivity in the formation of 3 68b It was then assumed that these steric and electronic effects could be additive to give an even higher regioselectivity, however when a 2 methyl 4 methoxylphenyl substituent was used on the alkyne the product 3 68c was formed with an even lower regioselectivity an d yield than the previous alkynes.

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90 Since tuning the electronics on the aromatic group did not produce as big of an effect as was expected, the aliphatic portion of the alkyne was then modified to determine what effect this would have on the system (Table 3 4). Surprisingly, by placing an inductively withdrawing methoxyether on the aliphatic chain provided the desired product 3 68d with a 3:1 distribution of regioisomers. Furthermore, combining this inductive effect with an electron rich aryl substituent e nabled the production of the desired aryl ketone 3 68e with a 9:1 regioselectivity. Lastly, placing an electron arylation product 3 68f with a high yield and regioselectivity. Table 3 4 Regioselectivity St udies [ a ] Isolated yields. [b] Ratio (arylketone:alkylketone) determined by 1 H NMR (500 MHz). [g] Only a single diastereomer of each regioisomer was observed. Ar = p OMe phenyl.

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91 Table 3 5 Selected Substrate Scope II [ a ] Isolated yields. [b] Ratio (arylketone:alkylketone) determined by 1 H NMR (500 MHz). [c] diastereoselectivity determined by 1 H NMR (500 MHz). Delighted with the resulting selectivities and functional group tolerance, a rationale for the observed difference in diastereoselectivitie s for E and Z allylic alcohols was investigated. The ketone products contain an alpha hydrogen that could be epimerizing during the reaction course, or after filtration with potentially acidic silica gel. Control experiments were run to test this theory and it was shown that pure diastereomers of 3 61 and 3 62 do not epimerize under the optimized conditions (Figure 3 16). Figure 3 16. Epimerization experiments

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92 Upon further inspection of the literature, it was found that only a few reports give select ive access to the trisubstituted Z enol ethers that are formed under our conditions. To deduce the possible mechanistic pathways the observed diastereoselectivities were used to shed light on the probable transitions states. Since the chair transition states for most thermal Claisen rearrangements are generally lower in energy than the boat conformation, the Z allylic alcohols will lead to syn products 3 72 and the E allylic alcohols lead to anti products 3 73 (Figure 3 17). Interestingly, when comparin g the possible transition states chair 1 / boat 1 vs. chair 2 / boat 2 one can see that the G should be much higher for the C1/B1 than the C2/B2 transition states (Figure 3 17). This energy difference is due to the eclipsing interactions between the psued oaxial R 2 and R 3 substituents of boat 1 which should be significantly higher in energy than the 1,3 diaxial interactions found in chair 1 Since this eclipsing interaction between the R 2 and R 3 substituents is absent in boat 2 the energy barrier between C2/B2 transition states is lower, thereby making the boat conformer a more accessible intermediate. This rationale correlates well with our empirical results, and may be the cause of the lower diastereoselectivity for products formed from E allylic alcoho ls. Figure 3 17. Possible transition states

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93 Table 3 6 Effects of Gold catalyst and heat on enol rearrangement entry enol conditions [a] product conversion(%) [b] dr [b] 1 2 A (heat) B (Au) 30 40 >25:1 >25:1 3 4 5 A (heat) B (Au) C (Au) 65 6 9 60 14:1 18:1 15:1 6 7 A (heat) B (Au) 65 60 9:1 10:1 [ a ] Conditions A: THF 65C, 18 hrs; Conditions B: (IPr)AuCl/AgBF 4 (5 mol%), THF 65C, 18 hrs; Conditions C: Me 3 PAuCl/AgBF 4 (5 mol%), THF 65C, 18 hrs. [ b ] Determined by 1 H NMR ( 500 MHz ) The aforeme ntioned transition states are based on thermal rearrangement processes, however we cannot ignore the possibility that the process can be partially or completely gold catalyzed. To investigate this, various enol ethers ( 3 74 3 76 ) were treated under therma l and gold catalyzed conditions to observe their effects (Table 3 6). The results show that allyl vinyl ethers 3 75 and 3 76 are more readily converted to the product than 3 74 most likely due to the higher steric encumbrance of the trisubstituted olefin s. As previously found, the Z allylic alcohols give a higher dr than the E allylic alcohols, when treated with a gold complex or thermal conditions (Table 3 6, compare entries 3 5 to 6 7). Interestingly, changing the ligand on the gold from IPr ( 1,3 Bis( 2,6 diisopropylphenyl imidazol 2 ylidene ) to PMe 3 decreased the diastereoselectivity significantly (Table 3 6, entries 4 5). This decrease in diastereoselectivity with respect

PAGE 94

94 to the ligand prompted a study on the effects the ligand on the gold complex m ay have on the tandem process. Table 3 7. Effects of Ligand of the Tandem Hydroalkoxylation/Claisen Rearrangement entry ligand (L) diastereoselectivity [a] yield (%) [b] 1 8:1 71 2 10:1 56 3 4 [ a ] Det ermined by 1 H NMR ( 500 MHz ) [b] Isolated yields. To monitor the change in diastereoselectivity the commercially available geraniol 3 77 was used because it gave a moderate dr for the reaction, which would make it a good candidate to observe any changes in the selectivity. From th e ligands screened in

PAGE 95

95 this process only the gold complexes made from the NHC (IPr) ligand 3 78 and the phosphine ligand 3 79 were able to catalyze the tandem process under the optimized conditions (Table 3 7, entries 1 2). The phosphine ligand 3 79 gave a higher dr than the NHC ligand 3 78 and this could be attributed to the rate of protodeauration. Recently, Xu et al. discovered that the phosphine ligand 3 73 helps the gold complex protodeaurate faster than the NHC ligand 3 72 88 A faster protodeaurati on would cause the complex to undergo faster decomplexation with the intermediate enol ether, and it is possible that this could create a transition state that leads to a higher selectivity. Lastly, it is interesting to note that the trimethylphosphine ( 3 81 ) gold complex could not catalyze the tandem process, however the enol ether 3 75 underwent facile rearrangeme nt with this complex at 65 C (compare Table 3 6 entry 5 to Table 3 7 entry 4). The combined data from the aforementioned tables does not conc lusively demonstrate the role of the gold complex in the reaction, because the thermal promoted and gold catalyzed conditions give comparable results (Table 3 6). Additional experimentation at lower temperatures could give further insight into whether the complex is catalyzing both steps, or only the initial hydroalkoxylation step. Although the following experiments have not given a decisive mechanistic pathway, valuable insight was gained into the possible pathways and the factors governing them. Collabo rative computational studies are still ongoing, however initial studies have proven to be quite challenging since there are a very high number of possible transition states with the gold complex involved. Our gold catalyzed tandem hydroalkoxylation/Claise n rearrangement methods give a complimentary method to the

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96 other valuable Claisen methodologies. The method allows access to highly functionally diverse synthons from very simple, and/or commercially available starting materials and many of these advances have since been described in our recent publication. 89 Sequential Gold catalyzed Enol F ormat ion/Ru catalyzed Allylation Introduction During the studies of the gold catalyzed tandem hydroalkoxylation/Claisen rearrangement, we became interested in an intra molecular variant of the process. Conceivably, an enyne such as 3 82 could easily undergo a gold catalyzed formation of the Z enol ether 3 83 and subsequently form the [3,3] rearrangement product 3 84 under thermal or Lewis acid catalyzed conditions. Fig ure 3 18. Gold catalyzed intramolecular hydroalkoxylation/Claisen rearrangement Although similar processes were recently reported by Rhee et al. 81 d as well as in collaborative studies between the Rhee and Kirsch research groups, 81 e the substrate scope is limited to terminal alkynes (Figure 3 19). Furthermore, their rearrangements are charge accelerated by an oxonium ion intermediate, so the use of allylic alkyl or silyl ethers are required for the process to work. Consequently, the removal of these ether s is then required to obtain the desired ketone products. Conditions that would not require the use of these allylic ethers could reduce the synthetic steps to the desired products. Furthermore, a process that would accommodate substituted alkynes would increase the scope of these reactions

PAGE 97

97 immensely. For these reasons we began our studies of an intramolecular sequence that would be analogous to our intermolecular reactions. Figure 3 19. Selected gold catalyzed intramolecular Claisen rearrangement s. A : Work by Rhee et al. ; B : Collaborative studies from the Rhee and Kirsch research groups. Results and Discussion The studies began by finding the optimal conditions for the formation of the requisite allyl vinyl ether 3 93 (Table 3 8). During this analysis it was intriguing to find that the formation of 3 93 from 3 92 is highly dependent on the solvent in the reaction. For instance, when a non coordinating solvent such as CH 2 Cl 2 is used, the undesired internal vinyl ether 3 94 is formed selectively regardless of the substrate or gold complex used (Table 3 8, entries 1 3). Conversely, when a more coordinating solvent such as THF or 1,4 dioxane is used, selective formation of the desired exocyclic vinyl enol ether 3 93 is achieved (Table 3 8, entrie s 4 7). The formation of product 3 94 was somewhat interesting because it was not the anticipated exocyclic enol ether product (Figure 3 20). During the catalytic cycle, the

PAGE 98

98 gold complex 3 95 coordinates to the alkyne in 3 92 to form 3 96 After coordina tion, the alkyne undergoes selective anti alkoxylation to form the oxonium 3 97 which subsequently forms product 3 93 after protodeauration. Table 3 8 Solvent effects on enol ether formations [a] entry substrate gold salt silver salt solvent time (h) 3 93:3 94 [b] 1 3 92a PPh 3 AuCl AgOTf CH 2 Cl 2 1.5 1:2 ( a ) 2 3 92b PPh 3 AuCl AgOTf CH 2 Cl 2 1 1:>25 ( b ) 3 3 92b (IPr)AuCl AgBF 4 CH 2 Cl 2 1 1:5 ( b ) 4 3 92a ( o biphenyl di t butylphosphine)AuCl AgOTf THF 0.5 >25:1 ( a ) 5 3 92a (I P r)AuCl AgBF 4 THF 0.5 >25:1 ( a ) 6 3 92b (I P r)AuCl AgBF 4 THF 1.0 >25:1 ( b ) 7 3 92b (I P r)AuCl AgBF 4 1,4 dioxane 1.5 >25:1 ( b ) [a] Conditions: Substrate (0.2 mmol), [Au] (5 mol%), [Ag] (5 mol%) [ b ] Determined by 1 H NMR ( 300 MHz ). A probable explanation for the formation of 3 94 is that th e gold complex recoordinates to the product 3 93 after decomplexation to form an intermediate like that of 3 98 (Figure 3 21). The oxonium ion can causes proton H b to become more acidic, allowing for a facile proton exchange to give the undesired internal enol ether 3 94 Of course, if this process occurs a possible equilibrium between the formation of 3 93 and 3 94 cannot be ruled ou t, since the reverse process could easily regenerate the exocyclic 3 93 The formation of the oxonium 3 98 is most likely impeded by solvents that can provide further stabilization of the cationic gold complex; this increase in

PAGE 99

99 stabilization could decrease the acidity of the complex and inhibit the formation of the enol ether 3 94 Figure 3 20. Proposed mechanism for the g old catalyzed formation of 3 93 Figure 3 21. Proposed mechanism for the gold catalyzed formation of 3 94 After finding conditions that gave selective access to the desired enol ether 3 93 a test reaction was run to determine if these allyl vinyl ethers could perform the [3,3] rearrangement. Surprisingly, when 3 93a was heated in refluxing toluene overnight the expected product 3 100 was formed in a dismal 23% yield, however, the [1,3] rearrangement product 3 99 was formed as one diastereomer in a 51% yield (Figure 3 22). These results changed the direction of the project to finding conditions that would

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100 give selectively the [1,3] rearrangement products, because of the high utility of these 3 vinylcyclohexanones. Figure 3 22. Formation of [1,3] rear rangement product 3 99 Metal catalyzed formation of cyclic 3 vinylketones 3 102 via [1,3] O to C migrations have been well known for quite some time, yet they are generally limited to allyl vinyl ethers like that of 3 101 that produce highly stabilized en olate intermediates. 90 Although, Trost and coworkers were the first to report this type of palladium catalyzed isomerization, 90 a Tsuji published similar results shortly after. 90 b After their initial publication, Trost expanded the studies to give further insight into the mechanism of the reaction and the factors dictating the stereo and regioselectivity of the rearrangement. 90 c e Figure 3 23. Palladium catalyzed [1,3] O to C migrations via highly stabilized enolate intermediates More recently, in 2010 Harrity and coworkers published the first and only case of these [1 3] rearrangements with nonstabilized enolate intermediates (Figure 3 24). 91 Their method gave the trans cyclohexanone products with good yields and high

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101 selectivity. Nevertheless, high catalyst loadings and increased temperatures are required which poses a major drawback for this method. Additionally, requisite enol ethers 3 93 require a long synthetic route that produces a mixture of E and Z vinyl ether products. Since the geometry of the vinyl ether has a great influence on the stereochemistry of the product, a process that could give selective access to either E or Z vinyl ether would be advantageous. Establishing a sequential gold catalyzed enol formation/[1,3] rearrangement pro cess, and/or a tandem one pot reaction sequence could provide a better synthetic route to these highly functionalized carbocycles. Figure 3 24. Comparable process by Harrity et al. Inspired by the ruthenium catalyzed allylic alkylation reactions report ed by Kitamura and coworkers (Figure 1 12), 24 26 it was surmised that their cationic ruthenium complex could help catalyze the [1,3] rearrangement for substrates with a lower propensity for ionization. This could further expand the scope of these reaction s and possibly lead to different selectivities, depending on the mechanistic pathway. To test this theory, a catalyst screening was carried out to determine how the ruthenium complex would compare to palladium for these isomerizations (Table 3 9). Gratif yingly, treatment of enol 3 93b with the ruthenium complex created in situ from [CpRu(CH 3 CN) 3 ]PF 6 and quinaldic a cid gave the desired product 3 99b in an 80% yield with a 2:1 dr in favor of the cis substituted cyclohexanone. While treatment under palladi um catalyzed conditions also gave the desired product, heating was required and a lower selectivity and yield were observed (Table 3 9, entries 1 2). The electron rich

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102 para methoxyphenyl enol ether 3 93c was also readily cyclized under the ruthenium condi tions to give product 3 99c however with the palladium complex the desired product was not formed in an appreciable amount (Table 3 9, entries 3 4). 92 This could be due to the fact that the electron rich system is more difficult to ionize, and requires a stronger Lewis acidic catalyst system. Table 3 9 Comparison of Pd and Ru catalyzed alkylation reactions entry substrate conditions [a] time (h) product yield [b] dr (cis:trans) [c] 1 2 A B [d] 18 1.5 80% 61% 2:1 1:1 3 4 A B 6 18 77% <10% [c] 2:1 5 6 A B 14 20 86% 70% 10:1 [e] 1:10 [ a ] Conditions A : [CpRu(CH 3 CN) 3 ]PF 6 /Quinaldic Acid (5 mol%), THF, r.t.; Conditions B : Pd(dppe) 2 (5 mol%), CH 2 Cl 2 r.t.; [b] Isolated yield from overall sequence (Au, then Pd or Ru) [c] Determined by 1 H NMR ( 5 00 MHz ). [d] Reaction run at 40 C [e] The product epimerized to the trans isomer during purification. When the dioxane derivative 3 93d was treated with the ruthenium complex facile formation of the desired pyran product 3 99d was observed with a 10:1 dr and

PAGE 103

103 86% yield, again forming selectively the cis product. Furthermore, treating 3 93d with 5 mol% of Pd(dppe) 2 gave trans 3 99c with the same level of selectivity, albeit with a lower yield and longer reaction time (Table 3 9, entries 3 4). These ini tial results demonstrated that the selectivity and yields were higher when the ruthenium complex was used. Interestingly, these conditions produced the cis products, which is contrary to the trans products formed under palladium catalyzed conditions. Thi s suggests that the mechanistic pathway for the ruthenium catalyzed rearrangements is somewhat different than that of the well known palladium process. It is also noteworthy to realize that the conditions A and B gave access to the desired products with l ower catalyst loadings and temperature than the previous report from Harrity and coworkers. 91 Furthermore, these conditions allow for simple access to highly functionalized pyrans, which are frequently found in natural products. 93 Encouraged by the resul ts of the initial screenings, further experimentation was run to find the optimized conditions for the [1,3] rearrangement. Various modifications to the initial conditions (Table 3 9, entry 1, same as Table 3 10, entry 1) were made in order to determine i f the diastereoselectivity or yield could be increased. Adding molecular sieves had little effect on the reaction outcome (Table 3 10, entry 2). Furthermore, changing the catalyst system or attempting one pot process, resulted in poor yields (Table 3 10, entries 3 6). These results demonstrated that the best catalyst system for the rearrangements was the complex created in situ from [CpRu(MeCN) 3 ]PF 6 and quinaldic acid

PAGE 104

104 Table 3 10 Optimization of ruthenium catalyzed allylation entry modifications of conditions (ii) yield [a] dr [b] 1 80% 2:1 2 4 MS added 75% 2:1 3 [Cp*Ru(MeCN) 3 ]PF 6 [c] 4 catalyst system was quinaldic acid (10 mol%), 4 MS [c] 5 picolinic acid instead of quinaldic 30% 1:1 6 (i) transferred directly to (ii) without filtr ation 37% 2:1 7 solvent mixture THF:CH 3 CN (1:1) [c] 8 solvent mixture THF: acetone (1:1) 91% 2:1 [a] Isolated yields [b] Determined by 1 H NMR ( 500 MHz ). [c] No desired product. During these studies, an appreciable amount of solid precipitate would form during the ruthenium catalyzed alkylation. Concerned that this was a result of a solubility issue with the active complex, a few solvent mixtures were screened in hopes to increase the yield of the reaction. When a mixture of acetonitrile and THF w as used the reaction was completely shut down. Conversely, when a mixture of THF and acetone was used the product 3 99b was formed in a 91% with a 2:1 diastereoselectivity (Table 3 10, entries 7 8). The highest yield and selectivity for

PAGE 105

105 product 3 99b was o btained under these conditions, which were consequently deemed the optimized reaction conditions. Table 3 11 Selected substrate scope for the sequential enol formation/allylic alkylation reaction entry substrate time (h, Ru) product yield [a] dr [b] ( cis:trans) 1 R = H, 3 92b 18 R = H, 3 99b 91 2:1 2 R = p NO 2 3 92a 4.5 R = p NO 2 3 99a 98 2:1 3 R = p OMe, 3 92c 18 R = p OMe, 3 99c 90 2:1 4 3.5 92 1:1 5 4 [c] [a] Isolated yields [b] Determined by crude 1 H NMR on 500 MHz [c] No desired product, enol left untouched. With the optimized conditions in hand, the focus was set on determining the scope and limitations of the sequential process. As previously demonstrated, the

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106 phenyl substituted 3 92b gave the desired product in a h igh yield and a 2:1 dr (Table 3 11, entry 1). Electron withdrawing and donating substituents on the aromatic ring also give the desired product in high yields (Table 3 11, entries 2 3). Interestingly, the nitro substituted enol ether undergoes the alkyla tion reaction in only 4.5 hours, which is much faster than any other substrate. It is likely that this electron withdrawing group gives the enol ether a higher susceptibility for ionization, thereby allowing for a faster rearrangement to occur. Gratifying ly, other aromatic substituents can also be tolerated under these conditions. The thiophene substituted 3 92e underwent smooth gold catalyzed cyclization, followed by the ruthenium catalyzed rearrangement to gave the desired product 3 99e in a 92% yield a s a 1:1 mixture of diastereomers (Table 3 11, entry 4). Furthermore, treating product 3 99e with sodium methoxide in methanol at room temperature overnight, provided selectively the trans 3 99e in a 90% yield (Figure 3 25). Lastly, removing one methylene spacer from the chain ( 3 92f ) resulted in an enol ether that was unable to rearrange with the optimized ruthenium conditions (Table 3 11, entry 5). Figure 3 25. Diastereoselective access to trans 3 99 During these trials, a common trend was observed wi th ortho substituted phenyl substrates in that they were unable to produce the desired product under our conditions. For instance, when an ortho methyl group was placed in the phenyl ring 3 92g the enol

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107 ether from the gold reaction was left untouched dur ing the allylic alkylation reaction (Table 3 12, entry 1). Additionally, placing heteroatoms that are relatively non nucleophilic in the ortho position resulted in various heterocyclic byproducts during the gold reaction (Table 3 12, entries 2 4). Table 3 12 Limitations of ortho substituted aromatic substrates entry substrate time (h, Ru) product yield [a] 1 18 [b] 2 92% [c] 3 50% [c] 4 35% [c,d] [a] Isolated yields. [b] No desired product, enol left untouched. [c] Formed du ring gold cyclization [d] Unidentifiable product.

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108 While gold catalyzed formation of indoles 94 and isoxazoles 95 is well known with alkynyl anilines and nitrophenyls respectively, it was somewhat surprising that these cyclizations were much faster than the desired hydroalkoxylation of the alkyne. Of course, this is most likely due to the proximity of these ortho substitutions to the alkyne. Mechanistically, we envision that the bifunctional ruthenium complex coordinates to the allyl vinyl ethers in a simil ar fashion to the proposed mechanism for allyl alcohols (Figure 3 26). 24 The authors suggest a type of synergy between the ruthenium complex and the quinaldic acid ligand, wherein the nitrogen in the quinoline ring donates electron density to the rutheniu m metal, making it more Lewis basic, while the carboxylic acid helps to ionize the allylic system via hydrogen bonding to the allylic alcohol. Figure 3 26. Proposed coordination of the ruthenium complex to allyl alcohols Analogous to their proposed mechanism, the current [1,3] O to C rearrangement could start with the coordination of the ruthenium complex to ether 3 92 to form the intermediate 3 108 (Figure 3 27). Hydrogen bonding between the carboxylic acid ligand, and the enol ether helps to faci litate the oxidative addition of the complex to form 3 10 9 The enolate formed in 3 10 9 allyl system, followed by subsequent reductive elimination and decomplexation of the ruthenium complex to form the desired carbocycle 3 99 and the active catalyst 3 10 7

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109 The preferential formation of cis substituted products for th e ruthenium rearrangement suggests that the mechanism of these [1,3] rearrangements is different than the palladium catalyzed sequence. Furthermore, the higher diastereoselectivity found in the formation of the ketopyran 3 99d suggests that the dimethylen e ether may play a role in the mechanism of the reaction. Mechanistic studies are currently ongoing in our laboratory and will be reported in due course. Figure 3 27. Proposed mechanism for the ruthenium catalyzed [1,3] rearrangement The reported sequ ential enol formation/allylation process has a few minor drawbacks, however it allows simple access to highly functionalized cyclohexanones

PAGE 110

110 and pyrans. The process is higher yielding than the previously reported palladium catalyzed process, and provides a short synthetic route for these cis cyclic ketones.

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111 CHAPTER 4 EXPERIMENTAL SECTION General Experimental Procedures All reactions were carried out under an atmosphere of dry nitrogen unless otherwise specified. Anhydrous solvents were transferred via syr inge to flame dried glassware, which had been cooled under a stream of dry nitrogen. Anhydrous tetrahy drofuran (THF), dichloromethane (CH 2 Cl 2 ) diethyl ether, benzene, and acetonitrile were dried using a n mBraun solvent purification system. 5 hexyn 1 ol, 6 chloro 1 hexyne, and N (5 hexynyl)phthalimide were graciously donate d to us by Petra Research, Inc. Gold and silver catalysts were weighed in a glovebox under a dry argon atmo sphere unless otherwise stated. All other reagents were ordered from Sigma Ald rich and used without any further purification. Analytical thin layer chr omatography 60 pre coated plates (Whatman Inc.). Flash column chromatography was performed using 230 400 Mesh 60 Silica Gel (Whatman Inc. ). The eluents employed are reported as volume:volume percentages. Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded using Varian Unity I nova 500 MHz and Varian Mercury 300 MHz spectrometers. Chemical shift ( ) is reported in parts per mill ion (ppm) downfield relative to tetramethylsilane (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 using Varian Unity Mercury 300 and 500 spectrometers at 75 MHz, and 125 MHz respectively. Chemical shift is reported in ppm relative to the carbon resonance of CDCl 3 (77.23 ppm). Infrared spectra were obtained on a PerkinElmer Spectrum RX1

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112 FTIR spectrometer at 1.0 cm 1 resolution and are reported in wavenumbers. Melting points were recorded on a MEL TEMP capillary melting point apparatus and are uncorrected. High performance liqu id chromatography (HPLC) was performed on Shimadzu. Gas Chromatography analyses were obtained using a Hewlett Packard HP 5890 Series II FID Detector. Specific Optical rotations were obtained on a JASCD P 2000 Series Polarimeter (wavelength = 589 nm). H igh resolution mass spectra (HRMS) were obtained by Mass Spectrometry Core Laboratory of University of Florida, and are reported as m/e (relative ratio). Accurate masses are reported for the molecular ion (M+) or a suitable fragment ion. All diastereosele ctivi ti es and regioselectivit ies for the reactions were observed in the spectrum of the crude reaction mixture on a Varian Unity Inova 500 MHz spectrometer or a Varian Mercury 300 MHz spectrometer Formation of Azacycles via Gold Catalyzed Dehydrative C ycl izations General Procedure: Although the catalyst systems varied in these experiments, the reactions conditions involve the same setup. An example procedure is as follows (Table 2 1, entry 5): A test tube with a septum on top, containing 1,3 bis(2,6 diis opropylphenyl imidazol 2 ylidene)gold(I) chloride (6.2 mg, 0.01 mmol, 5 mol%), silver tetrafluoroborate (1.9 mg, 0.01 mmol, 5 mol%) 4 MS (4 5 pellets, previously activated by flame drying under vacuum) and a stir bar, was taken from the glove box wrapped in aluminum foil and placed directly under dry nitrogen. A small portion of CH 2 Cl 2 (0.2 mL) was added to the solid catalysts and the mixture was left to stir at room temperature for ten minutes, after which time a solution of the substrate in CH 2 Cl 2 (0.8 mL) was added to the mixture all at once. The vessel was left to stir at room temperature. After TLC analysis had shown complete conversion the reaction mixture

PAGE 113

113 was filtered through a short plug of silica with EtOAc placed under vacuum to remove the sol vents and purified by flash column chromatography E ) tert butyl (7 hydroxy 8 methylnon 5 en 1 yl)carbamate ( 2 13 ): The following compound was made under the optimized gold catalyzed dehydrative cyclization conditions (Table 2 1, entry 5) with 2 12 (39. 4 mg, 0.14 mmol), 1,3 bis(2,6 diisopropylphenyl imidazol 2 ylidene)gold(I) chloride (4.7 mg, 0.008 mmol, 5 mol%), silver tetrafluoroborate (1.4 mg, 0.007 mmol, 5 mol%), 4 MS (4 pellets), and 1.0 mL of CH 2 Cl 2 Purified by flash column chromatography usin g a solvent gradient (0 5% EtOAc/hexanes) to yield the product as a clear oil (34.2 mg, 93%). R f = 0.47 (10% EtOAc/hexanes). IR (neat) 2934, 2862, 1690, 1403, 1363, 1161 cm 1 1 H NMR (300 MHz, CDCl 3 ): 5.48 5.28 (m, 2H), 4.72 4.71 (m, 1H), 3.96 3.84 (m, 1H), 2.81 (td, J = 12.8, 3.0 Hz, 1H), 2.28 (dq, J = 13.1, 6.6 Hz, 1H), 1.73 1.29 (m, 13H), 0.98 (d, J = 6.8, 6H). 13 C NMR (75 MHz, CDCl 3 ): 155.7, 139.1, 125.1, 79.3, 52.2, 39.8, 31.2, 29.7, 28.7, 25.9, 22.8, 22.7, 19.7. ( E ) tert butyl (6 hydroxy 7 me thyloct 4 en 1 yl)carbamate ( 2 17 ): The following compound was made under the optimized gold catalyzed dehydrative cyclization conditions (Table 2 2 entry 2) with 2 16 (76.8 mg, 0.3 mmol), 1,3 bis(2,6

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114 diisopropylphenyl imidazol 2 ylidene)gold(I) chloride (9.3 mg, 0.015 mmol, 5 mol%), silver tetrafluoroborate (2.9 mg, 0.015 mmol, 5 mol%), 4 MS (5 pellets), and 1.5 mL of CH 2 Cl 2 Purified by flash column chromatography using a solvent gradient (0 5% EtOAc/hexanes) to yield the product as a clear oil (50.6 m g, 71%). R f = 0.70 (20% EtOAc/hexanes). IR (neat) 2958, 2870, 1693, 1390, 1363, 1164, 1115 cm 1 1 H NMR (300 MHz, CDCl 3 ): 5.46 5.36 (m, 1H), 5.29 5.20 (m, 1H), 4.16 (br s, 1H), 3.44 3.27 (m, 2H), 2.29 2.20 (m, 1H), 1.96 (br s, 1H), 1.87 1.73 (m, 2H), 1 .67 160 (m, 1H), 1.42 (s, 10H), 0.96 (d, J = 6.7 Hz, 6H). 13 C NMR (125 MHz, CDCl 3 ): 154.8, 137.5, 127.7, 79.0, 58.8, 46.3, 32.7, 30.9, 29.9, 28.7, 28.6, 22.8. ( E ) 2 (3 methylbut 1 en 1 yl) 1 tosylpyrrolidine ( 2 19 a ) : 9 6 The following compound was made under the optimized gold catalyzed dehydrative cyclization conditions (Table 2 3, entry 1) with 2 18a (159.6 mg, 0.5 mmol), 1,3 bis(2,6 diisopropylphenyl imidazol 2 ylidene)gold(I) chloride (3.1 mg, 0.005 mmol, 1 mol%), silver tetrafluoroborate (1.0 mg, 0. 005 mmol, 1 mol%), 4 MS (10 pellets), and 2.5 mL of CH 2 Cl 2 Purified by flash column chromatography using a solvent gradient (20 50% EtOAc/hexanes) to yield the product as a pale yellow oil (106.8 mg, 71%). All data matched that of the previously report ed data. 9 6

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115 ( E ) 2 (2 cyclohexylvinyl) 1 tosylpyrrolidine ( 2 19b ): The following compound was made under the optimized gold catalyzed dehydrative cyclization conditions (Table 2 3, entry 2) with 2 18b (72.8 mg, 0.21 mmol), 1,3 bis(2,6 diisopropylphenyl i midazol 2 ylidene)gold(I) chloride (6.4 mg, 0.01 mmol, 5 mol%), silver tetrafluoroborate (2.0 mg, 0.01 mmol, 5 mol%), 4 MS (5 pellets), and 1.5 mL of CH 2 Cl 2 Purified by flash column chromatography with a 20% EtOAc/hexanes solution to yield the product a s a clear oil (64.0 mg, 92%). R f = 0.60 (20% EtOAc/hexanes). IR (neat) 3046, 2923, 2850, 1447, 1342, 1156 cm 1 1 H NMR (500 MHz, CDCl 3 ): 7.70 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 5.56 (ddd, J = 15.4, 6.4, 1.1 Hz, 1H), 5.27 (ddd, J = 15.4, 6. 8, 1.4 Hz, 1H), 4.10 (td, J = 7.1, 3.9 Hz, 1H), 3.41 (ddd, J = 9.7, 7.3, 4.6 Hz, 1H), 3.29 (dt, J = 9.9, 7.1 Hz, 1H), 2.42 (s, 3H), 1.97 1.87 (m, 1H), 1.85 1.57 (m, 5H), 1.30 1.19 (m, 2H), 1.14 (qt, J = 12.6, 3.1 Hz, 1H), 1.08 0.96 (m, 2H). 13 C NMR (125 M Hz, CDCl 3 ): 143.2, 137.7, 136.0, 129.6, 127.8, 127.7, 61.9, 48.7, 40.2, 33.0, 32.8, 26.4, 26.2, 26.1, 24.0, 21.7. tert butyl 4 tosyl 2 vinylpiperazine 1 carboxylate ( 2 19 c): The following compound was made under the optimized gold catalyzed dehydrative cyclization conditions (Table 2 3, entry 5) with 2 18d (150.3 mg, 0.39 mmol), 1,3 bis(2,6 diisopropylphenyl imidazol 2 ylidene)gold(I) chloride (12.1 mg, 0.02 mmol, 5 mol%), silver tetrafluoroborate (3.8 mg, 0.02 mmol, 5 mol%), 4 MS (10 pellets), and 2.0 mL of CH 2 Cl 2 Purified by flash column chromatography using a solvent gradient (10 30% EtOAc/hexanes) with a 20% EtOAc/hexanes solution to yield the product as a white solid (127.2 mg, 89%). R f = 0.80 (60% EtOAc/hexanes). IR (neat) 2976, 2930, 1702,

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116 1 455, 1415, 1342, 1159 cm 1 1 H NMR (500 MHz, CDCl 3 ): 7.69 (d, J = 8.2 Hz, 2H), 7.34 7.26 (m, 2H), 5.70 5.55 (m, 1H), 5.23 5.10 (m, 2H), 4.79 4.68 (m, 2H), 3.81 (s, 2H), 3.47 (s, 2H), 3.32 3.19 (m, 2H), 2.42 (s, 3H), 1.47 (s, 9H). 13 C NMR (125 MHz, CDCl 3 ): 155.4, 154.9, 143.6, 136.8, 133.2, 130.0, 127.5, 119.6, 80.9, 51.9, 46.4, 45.8, 28.6, 21.8. ( E ) tert butyl 3 styrylmorpholine 4 carboxylate ( 2 19 d): The following compound was made under the optimized gold catalyzed dehydrative cyclization conditions (Table 2 3, entry 8) with 2 18f (100.0 mg, 0.32 mmol), 1,3 bis(2,6 diisopropylphenyl imidazol 2 ylidene)gold(I) chloride (10.0 mg, 0.016 mmol, 5 mol%), silver tetrafluoroborate (3.1 mg, 0.016 mmol, 5 mol%), 4 MS (6 pellets), and 1.6 mL of CH 2 Cl 2 Purifie d by flash column chromatography using a solvent gradient (10 30% EtOAc/hexanes) with a 20% EtOAc/hexanes solution to yield the product as an off white solid (75.0 mg, 81%). R f = 0.85 (60% EtOAc/hexanes). IR (neat) 2975, 2922, 2857, 1699, 1683, 1394, 11 68 cm 1 1 H NMR (500 MHz, CDCl 3 ): 7.43 7.26 (m, 5H), 5.96 5.90 (m, 1H), 5.87 5.81 (m, 1H), 5.23 (d, J = 6.1 Hz, 1H), 4.90 (s, 1H), 4.00 (dt, J = 5.0, 0.9 Hz, 2H), 3.48 (t, J = 5.2 Hz, 2H), 3.35 3.19 (m, 2H), 2.25 (s, 1H), 1.44 (s, 10H). 13 C NMR (125 MHz CDCl 3 ): 156.2, 142.9, 135.4, 128.8, 128.0, 127.6, 126.5, 79.6, 74.7, 71.1, 69.6, 40.7, 28.7.

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117 N N di tert butyloxycarbonyl 6 amino 1 hexyne ( 2 28 ): To a flask containing di (tert butyl) imidodicarbonate (3.1 g, 14.3 mmol, 1.2 eq.), a stir bar and DMF (25 mL) was added NaH (60% in mineral oil, 0.399g, 14.26 mmol, 1.4 eq.) portion wise at room temperature. The solution was placed at 60 C for 1 hr., then allowed to cool back to room temperature. The reaction mixture was then added to a solution of he x 5 yn 1 yl 4 methylbenzenesulfonate 97 (3.0 g, 11.9 mmol, 1.0 eq.) in DMF (10 mL) at room temperature. After stirring overnight the reaction was placed at 0 C and quenched with deionized water (100 mL) and extracted with CH 2 Cl 2 (3x50mL). The organic phas e was then dried over MgSO 4 filtered, and the solvents were evaporated in vacuum. Purified by flash column chromatography using a solvent gradient (5 10% EtOAc/hexanes) to yield the product as an off white solid (1.41 g, 40%). R f = 0.70 (20% EtOAc/hexanes ). IR (neat) 2980, 2935, 1744, 1696, 1368, 1139, 1114 cm 1 1 H NMR (300 MHz, CDCl 3 ): 3.58 (t, J =6.9 Hz, 2H), 2.22 (dt, J = 7.6, 2.7 Hz, 2H), 1.94 (t, J = 2.6 Hz, 1H), 1.75 1.64 (m, 2H), 1.62 1.45 (m, 20H). 13 C NMR (75 MHz, CDCl 3 ) 152.8, 84.3, 82.3, 68.7, 46.0, 28.4, 28.3, 25.9, 18.4. HRMS (APCI) Calcd for C 16 H 28 NO 4 (M+H) + : 298.2013; found 298.2000. ( S ) 4 7 ( N N di tert butyloxycarbonyl) 1 hydroxyhept 2 yn 1 yl)phenyl pivalate( 2 30 ): The following compound was made using conditions similar to the standard Carreira asymmetric alkynylation conditions 51 To a solution of Zn(OTf) 2 (1.2 g, 3.3 mmol, 1.1 eq.) and ( ) N methylephedrine (0.54 g, 3.0 mmol, 1.0 eq.) in toluene (10

PAGE 118

118 mL) was added Et 3 N (0.46 mL, 3.3 mmol, 1.1 eq.) and the solution as left to s tir at room temperature for 2 hrs, at which point 2 28 (892.2 mg, 3.0 mmol, 1.0 eq.) in toluene (1 mL) as added to the mixture. The solution was left to stir for 20 mins. and a solution of 4 (pivaloyloxy)benzaldehyde 98 (618.7 mg, 3.0 mmol, 1.0 eq.) in tol uene (1.0 mL) was added. The reaction mixture was left to stir at room temperature overnight, then quenched with NH 4 Cl (30 mL) and extracted with CH 2 Cl 2 (3x30mL). The organic phase was then dried over MgSO 4 filtered, and the solvents were evaporated in v acuum. Purified by flash column chromatography using a solvent gradient (10 25% EtOAc/hexanes) to yield the product as a clear pale yellow oil (876.1 mg, 58%). R f = 0.64 (30% EtOAc/hexanes). IR (neat) 2980, 2935, 1744, 1696, 1368, 1139, 1114 cm 1 1 H NMR ( 300 MHz, CDCl 3 ): 3.58 (t, J =6.9 Hz, 2H), 2.22 (dt, J = 7.6, 2.7 Hz, 2H), 1.94 (t, J = 2.6 Hz, 1H), 1.75 1.64 (m, 2H), 1.62 1.45 (m, 20H). 13 C NMR (75 MHz, CDCl 3 ) 152.8, 84.3, 82.3, 68.7, 46.0, 28.4, 28.3, 25.9, 18.4. HRMS (APCI) Calcd for C 16 H 28 NO 4 (M +H) + : 298.2013; found 298.2000. IR (neat) 3478, 2978, 2935, 1749, 1694, 1368, 1138, 1116 cm 1 1 H NMR (300 MHz, CDCl 3 ): 7.47 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 5.37 (s, 1H), 3.54 (t, 2H), 2.25 (dt, J = 7.0, 2.0 Hz, 2H), 1.72 1.57 (m, 2H), 1 .57 1.37 (m, 20H), 1.31 (s, 9H). 13 C NMR (75 MHz, CDCl 3 ) 177.1, 152.9, 151.0, 138.9, 127.8, 121.6, 87.0, 82.4, 80.7, 77.43, 64.2, 46.0, 39.2, 28.2, 27.3, 25.7, 18.6. HRMS (ESI) Calcd for C 28 H 41 NNaO 7 (M+Na) + : 526.2775; found 526.2792. The enantiomeric excess (92%) was determined by HPLC analysis (Chiralpak IB, 5% i PrOH in hexanes, 1.0 mL/min, 254 nm), tr 7.7 (minor), 9.2 (major).

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119 (R Z ) 4 (7 (( tert butoxycarbonyl)amino) 1 hydroxyhept 2 en 1 yl)phenyl pivalate ( 2 27 ) : A two necked flask containing 2 30 (503.6 mg, 1.0 mmol, 1.0 eq.), pentane:EtOAc (4.2 mL: 0.42 mL) and a stir bar was evacuated and backfilled with H 2 (g) The solution was stirred vigorously at room temperature un der the H 2 (g) atmosphere. The reaction was monitored by obtaining 1 H NMRs from small aliquots of the reaction mixture. When the reaction was complete the mixture was filtered through a plug of cotton with EtOAc to remove the palladium, and the volatile s were removed under vacuum. The crude material was sufficient to use in the next step. To a flask containing the crude alkene (from reduction of 11) acetonitrile (5 mL) and a stir bar, was added LiBr (260.5 mg, 3.0 mmol, 3.0 eq.) at room temperature. The react ion mixture was then placed at 65 C and left to stir at this temperature overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc (30 mL) and washed with 0.01M HCl (3x20mL). The organic phase was then dried over MgSO 4 filtered, and the solvents were evaporated in vacuum. Purified by flash column chromatography using a solvent gradient (5 40% EtOAc/hexanes) to yield the product as a clear pale yellow oil (315.9 mg, 78% over 2 steps). R f = 0.15 (30% D = 16.2 ( c 1.00, CH 2 Cl 2 ); IR (neat) 3355, 2931, 1709, 1691, 1681, 1514, 1278, 1172 cm 1 1 H NMR (300 MHz, CDCl 3 ): 7.38 (d, J = 0.5 Hz, 2H), 7.02 (d, J = 8.6 Hz, 2H), 5.71 5.45 (m, 3H), 4.66 4.49 (m, 1H), 3.25 2.98 (m, 1H), 2.57 2.45 ( m,

PAGE 120

120 1H), 2.40 2.25 (m, 1H), 2.22 2.06 (m, 1H), 1.56 1.37 (m, 14H), 1.35 (s, 9H). 13 C NMR (75 MHz, CDCl 3 ) 177.3, 156.3, 150.4, 141.3, 132.8, 131.6, 127.2, 121.6, 79.4, 69.1, 40.4, 39.2, 29.6, 28.6, 27.3, 27.1, 26.4. HRMS (ESI) Calcd for C 23 H 35 NNaO 5 (M+N a) + : 428.2407; found 428.2449. The enantiomeric excess (42%) was determined by HPLC analysis (Chiralpak IB, 10% i PrOH in hexanes, 1.0 mL/min, 254 nm), tr 7.8 (minor), 8.5 (major). ( S ) 7 (N N di tert butyloxycarbonyl) 1 (4 bromophenyl)hept 2 yn 1 ol ( 2 31 ): The following compound was made using conditions similar to the standard Carreira asymmetric alkynylation conditions. 51 To a solution of Zn(OTf) 2 (400.0 mg, 1.1 mmol, 1.1 eq.) and ( ) N methylephedrine (180.0 mg, 1.0 mmol, 1.0 eq.) in toluene (4 mL) was added Et 3 N (0.16 mL, 1.1 mmol, 1.1 eq.) and the solution as left to stir at room temperature for 2 hrs, at which point 2 28 (297.4 mg, 1.0 mmol, 1.0 eq.) in toluene (1 mL) as added to the mixture. The solution was left to stir for 20 mins. and a solut ion of 4 bromobenzaldehyde (182.0 mg, 1.0 mmol, 1.0 eq.) in toluene (1.0 mL) was added. The reaction mixture was left to stir at room temperature overnight, then quenched with NH 4 Cl (10 mL) and extracted with CH 2 Cl 2 (3x10mL). The organic phase was then dr ied over MgSO 4 filtered, and the solvents were evaporated in vacuum. Purified by flash column chromatography using a solvent gradient (10 25% EtOAc/hexanes) to yield the product as a colorless oil (366.6 mg, 76%). R f = 0.32 (20% EtOAc/hexanes). IR (neat) 3464, 2979, 2931, 1729, 1691, 1366, 1134, 1112 cm 1 1 H NMR (300 MHz, CDCl 3 ):

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121 7.47 7.43 (m, 2H), 7.39 7.35 (m, 2H), 5.38 5.31 (m, 1H), 3.59 3.52 (m, 2H), 2.74 2.70 (m, 1H), 2.29 2.22 (m, 2H), 1.73 1.61 (m, 2H), 1.57 1.41 (m, 20H). 13 C NMR (75 MHz, CDCl 3 ) 153.0, 140.5, 131.7, 128.5, 122.2, 87.3, 82.5, 80.5, 64.2, 46.0, 28.3, 28.1, 25.6, 18.6. HRMS (APCI) Calcd for C 23 H 32 BrNNaO 5 (M+Na) + : 504.1379; found 504.1356. The enantiomeric excess (97%) was determined by HPLC analysis (Chiralpak IB, 5% i PrOH in hexanes, 0.8 mL/min, 254 nm), tr 16.4 (major), 17.5 (minor). ( R Z ) tert butyl (7 (4 bromophenyl) 7 hydroxyhept 5 en 1 yl)carbamate ( 2 32 ): A two necked flask containing 12 (73.3 mg, 20% by wt.), quinoli ne (73.3 mg, 20% by wt.), MeOH (4 mL) and a stir bar was evacuated and backfilled with H 2 (g) The solution was stirred vigorously at room temperature under the H 2 (g) atmosphere. The reaction was monitored by obtaining 1 H NMRs from small aliquots of the reaction mixture. When the reaction was complete the mixture was filtered through a plug of cotton with EtOAc to remove the palladium, and the volatiles were removed under vacuum. The crude material was sufficient to use in the next step. To a flask c ontaining the crude alkene (from reduction of 11) MeOH (5 mL) and a stir bar, was added K 2 CO 3 (525.2 mg, 3.8 mmol, 5.0 eq.) at room temperature. The reaction mixture was then placed at reflux and left to stir overnight. The reaction mixture was cooled t o room temperature, and the excess K 2 CO 3 was filtered off and the

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122 solution was placed under vacuum to remove the MeOH. The crude product was then diluted with EtOAc (30 mL) and washed with brine (2x10mL). The organic phase was then dried over MgSO 4 filt ered, and the solvents were evaporated in vacuum. Purified by flash column chromatography using a solvent gradient (0 30% EtOAc/hexanes) to yi D = 100.3 ( c 1.00, CH 2 Cl 2 ); R f = 0.22 (20% EtOAc/hexanes). IR (neat) 3339, 2930, 1687, 1516, 1486, 1169 cm 1 1 H NMR (300 MHz, CDCl 3 ): 7.47 7.41 (m, 2H), 7.28 7.22 (m, 2H), 5.6 1 5.44 (m, 3H), 4.65 4.45 (m, 1H), 3.24 3.10 (m, 1H), 3.10 2.97 (m, 1H), 2.76 (s, 1H), 2.42 2.23 (m, 1H), 2.20 2.04 (m, 1H), 1.58 1.31 (m, 12H). 13 C NMR (75 MHz, CDCl 3 ) 156.3, 142.9, 132.7, 131.8, 131.7, 127.9, 126.1, 121.3, 79.6, 68.9, 40.3, 29.5, 28.7, 27.0, 26.3. The enantiomeric excess (91%) was determined by HPLC analysis (Chiralpak IB, 5% i PrOH in hexanes, 0.8 mL/min, 254 nm), tr 15.9 (major), 20.3 (minor). ( S E ) tert butyl 2 (4 bromostyryl)piperidine 1 carboxylate ( 2 33 ): The following compoun d was made under the optimized gold catalyzed dehydrative cyclization conditions with 2 32 (20.0 mg, 0.05 mmol), 1,3 bis(2,6 diisopropylphenyl imidazol 2 ylidene)gold(I) chloride (1.6 mg, 0.0026 mmol, 5 mol%), silver tetrafluoroborate (0.5 mg, 0.0026 mmol, 5 mol%), 4 MS (2 pellets), and 1.0 mL of CH 2 Cl 2 Purified by flash column chromatography using a solvent gradient (0 5% EtOA c/hexanes) to yield the product as a clear, colorless oil (16.8 mg, 92%). R f = 0.56

PAGE 123

123 (20% EtOAc/hexanes). R f = 0.56 (20% EtOAc/he xanes). D = 8.5 ( c 1.00, CH 2 Cl 2 ); IR (neat) 2935, 2857, 1684, 1486, 1399, 1159 cm 1 1 H NMR (500 MHz, CDCl 3 ): 7.45 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 6.34 (dd, J = 16.2, 1.9 Hz, 1H), 6.20 (dd, J = 16.1, 4.8 Hz, 1H), 4.97 (s, 1H), 4.02 (d, J = 13.9 Hz, 2H), 2.91 (td, J = 13.0, 2.8 Hz, 1H), 1.88 1.74 (m, 2H), 1.72 1.61 (m, 2H), 1.61 1.37 (m, 9H). 13 C NMR (125 MHz, CDCl 3 ) 155.6, 136.2, 131.8, 129.9, 129.8, 128.0, 121.3, 79.8, 52.4, 40.2, 29.7, 28.7, 25.7, 19.9. The enantiomeric excess (30%) was determined by HPLC analysis (Chiralpak IB, 0.5% i PrOH in hexanes, 0.8 mL/min, 254 nm), tr 18.1 (minor), 20.3 (major). ( R E ) tert butyl 2 (4 phenylbut 1 en 1 yl)piperidine 1 carboxylate ( 2 42 ) : The following compound was made under the optimize d gold catalyzed dehydrative cyclization conditions with 2 41 (13.0 mg, 0.04 mmol), 1,3 bis(2,6 diisopropylphenyl imidazol 2 ylidene)gold(I) chloride (2.4 mg, 0.004 mmol, 10 mol%), silver tetrafluoroborate (0.8 mg, 0.004 mmol, 10 mol%), 4 MS (3 pellets), and 1.0 mL of CH 2 Cl 2 at 40 C. Purified by flash column chromatography using a solvent gradient (0 5% EtOAc/hexanes) to yield the product as a white solid (10.4 mg, 87%). R f = 0.62 D = 30.1 ( c = 0.70, CH 2 Cl 2 ); IR (neat) 2931, 2857, 1687, 1407, 1363, 1159 cm 1 1 H NMR (300 MHz, CDCl 3 ): 7.29 7.25 (m, 2H), 7.20 7.15 (m, 3H), 5.48 (dtd, J = 15.1, 6.6, 1.7 Hz, 1H), 5.41 5.35 (m, 1H), 4.72 (s, 1H), 3.88 (d, J = 13.5 Hz, 1H), 2.78 2.66 (m, 3H), 2.39 2.33 (m, 2H), 1.66 1.61 (m, 2H), 1.58 1.50 (m, 3H),

PAGE 124

124 1.45 (s, 9H), 1.42 1.33 (m, 1H). 13 C NMR (125 MHz, CDCl 3 ) 155.6, 142.0, 130.9, 129.4, 128.7, 128.5, 126.0, 79.4, 52.0, 39.8, 36.0, 34.5, 29.6, 28.7, 25.8, 19 .6. The enantiomeric excess (92%) was determined by HPLC analysis (Chiralcel OJ H, 1.0% i PrOH in hexanes, 1.0 mL/min, 215 nm) tr 8.8 (major), 13.2 (minor). Synthesis of Mefloquine and Analogs 4 iodo 2,8 bis(trifluoromethyl)quinoline (2 48c) : To a flask containing 4 chloro 2,8 bis(trifluoromethyl)quinoline 68 (1.0 g, 3.3 mmol) and a stir bar was added hydroiodic acid (57% in water, 3 mL). The solution was placed in a 130 C bath, and was left to stir at this temperature overnight. The solution was then taken out of the bath and cooled to room temperature and further in an ice bath. The mixture was diluted with water and chloroform, and the pH of the solution was raised to 14 using NaOH (3.0 M solution in water). The aqueous phase was extracted with CHC l 3 (3x30mL). The combined organic phases were then washed with water (2x30mL), sodium thiosulfate (sat. in water, 2x30mL), and brine respectively. The crude product was then purified by flash column chromatography using a solvent gradi ent (0 10% CH 2 Cl 2 /h exanes) to yield th e product as a white solid (734.9 mg, 61 %). R f = 0.72 (40 % CH 2 Cl 2 /hexanes). IR (neat) 2922 2849, 1573, 1419, 1302, 1141, 1103 cm 1. 1 H NMR (500 MHz, CDCl 3 ): 8.39 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 7.4 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H). 13 C NMR (12 5 MHz, CDCl 3 ) 148.0 (q, J = 35.8 Hz), 143.2, 136.2, 131.6 130.3 (q, J = 5.4 Hz), 129.5 (q, J = 2.2 Hz) 129.0, 128.6 128.5, 123.3 (q, J =

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125 2 72.5 Hz) 120.3 (q, J = 2 75.0 Hz) 118.5 113.4 19 F NMR (282 MHz, CDCl 3 ): 59.9 67.5 1 (2,8 bis(trifluoromethyl)quinolin 4 yl) 2 methylpropan 1 ol (2 57 ) : The following compound wa s made through various routes, and example procedure is given here. To a solution of 4 iodo 2,8 bis(trifluoromethyl)quinoline (90.6 mg, 0.23 mmol, 1. 0 eq.) and THF (1.0 mL) was added i PrMgCl (2.0 M, 0.12 mL, 0.25 mmol, 1.1 eq.) at 40 C. The solution was left to stir for 15 minutes until all of the iodide had disappeared by 1.0 eq.) was added (neat) to the mixture at 40 C The reaction was left to stir at the same temperature for 1.5 hrs., at which point phosphate buffer (2.0 mL) was added to the mixture. The solution was then diluted with water, extracted with EtOAc, d ried over Na 2 SO 4 filtered and evaporated to give the crude product. The crude product was then purified by flash column chromatography using a solvent gradi ent (0 20% EtOAc /hexanes) to yield th e product 2 58 as a white solid (45.0 mg, 58 %). R f = 0.31 (2 5 % EtOAc /hexanes). IR (neat) 3443, 3086, 2971, 2936, 2880, 1713, 1604, 1586, 1519, 1470, 1433, 1371, 1311, 1153 cm 1. 1 H NMR (500 MHz, CDCl 3 ): 8.28 (d, J = 8.7 Hz, 1H), 8.15 (d, J = 6.9 Hz, 1H), 7.99 (s, 1H) 7.71 (t J = 7.5 Hz, 1H), 5.30 (dd, J = 4 .8 Hz, 1H), 2.12 2.20 (m, 1H), 1.05 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H). 13 C

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126 NMR (12 5 MHz, CDCl 3 ) 152.7, 148.2, 144.0, 128.9, 128.8, 127.8, 125.6, 121.9, 119.7, 115.4, 75.2, 35.0, 20.3, 16.4. 19 F NMR (282 MHz, CDCl 3 ): 60.3, 68.0 1 (2,8 b is(trifluoromethyl)quinolin 4 yl) 3 phenylpropan 1 ol (2 61 ) : A solution of 2 42 (31.5 mg, 0.1 mmol, 1.0 eq.) and Sudan III (1.0 mg used as an indicator) in CH 2 Cl 2 (1.0 mL) was treated with ozone at 78 C for 10 minutes. During this time a solution of 4 iodo 2,8 bis(trifluoromethyl)quinoline 2 48c ( 142 mg, 0. 36 mmol, 3.6 eq.) and THF (1.0 mL) was added i PrMgCl (2.0 M, 0.18 mL, 0.36 mmol, 3.6 eq.) at 78 C. The solution was left to stir for 15 minutes until all of the iodide had disappeared by TLC. The solution of ozonide produced from o zo n lysis of 2 42 was then flushed with Ar(g) for 10 mins., after this time the grignard was then added to the ozonide at 78 C. The mixture was left ot stir at this temperature for 2 hrs. and the reaction was then quenc hed with deionized water (3 mL) The solution was then diluted with water, extracted with EtOAc, and dried over Na 2 SO 4 filtered and evaporated to give the crude product, which was primarily composed of 2 6 1 2 6 2 and 4 1 The crude product was then puri fied by flash column chromatography using a solvent gradi ent (0 20% EtOAc /hexanes) to yield th e product as a clear oil (45.0 mg, 58 %). R f = 0.31 (25% EtOAc/hexanes). IR (neat) 3439, 3078, 3030, 2929, 2362, 1603, 1586, 1430, 1372, 1310, 1189, 1144, 1109, 7 70 cm 1. 1 H NMR (500 MHz, CDCl 3 ) 8.16 (d, J = 7.2 Hz, 1H), 8.08 (s, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.39 7.34 (m, 2H),

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127 7.31 7.26 (m, 3H), 5.47 5.42 (m 1H), 2.95 (t, J = 7.3 Hz, 2 H), 2.20 2.02 (m, 3 H). 13 C NMR (125 MHz, CDCl 3 ) 153.5, 140.8, 128.9, 128.8, 127.2, 126.7, 114.4, 69.3, 40.3, 32.3 19 F NMR (282 MHz, CDCl 3 ): 60.4, 68.0. 2,8 bis(trifluoromethyl)quinoline (4 1) : The following compound was a common byproduct obtained from the halogen exchange experiments. The fol lowing data was obtained: R f = 0.40 (25% EtOAc/hexanes). IR (neat) 2919, 2847, 1585, 1326, 1290, 1190, 1145, 1098 cm 1 1 H NMR (3 00 MHz, CDCl 3 ): 8.43 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 7.2 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.84 (d J = 8.4 Hz, 1H) 7.7 3 (t J = 8.1 Hz, 1H) 19 F NMR (282 MHz, CDCl 3 ): 60.4, 67.9. Gold catalyzed Tandem Hydroalkoxylation/Claisen Rearrangement Optimized Conditions: A pressure tube (screw cap) containing a stir bar was taken from the oven and placed directly into a glove box. To this vessel was added 1,3 bis(2,6 diisopropylphenyl imidazol 2 ylidene)gold(I) chloride (6.2 mg, 0.01 mmol, 5 mol%), and silver tetrafluoroborate (1.9 mg, 0.01 mmol, 5 mol%). The vessel was capped with a septum and then taken out of the glovebox where it was immediately placed under dry nitrogen atmosphere. 0.5 mL of THF was added to the tube and the mixture was left to stir ~10 mins to activate the complex. After this time a solution of alkyne (0.6 mmol in 0.5 mL of THF) was transferred to the tube, and the vessel was then placed in a 65 C oil bath. 1.0 mL of a 0.2 M soln. of an allylic alcohol (in THF) was then added slowly over 12 hrs. via syringe pump (~0.8 mL/hr). After the addition was

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128 complete the solution was allowed to stir at this tem perature for an additional 3 hrs. The tube is then sealed with a screwcap and placed in a 120 C oil bath for 6 hrs. (Note: No problems occurred during this process, however, when sealed the reactions were placed behind a blast shield for added safety.) After cooling to room temperature the screwcap was removed and the solution was filtered over a plug of silica with EtOAc. The solution was then evaporated, the crude was characterized, and purified. 3,3 dimethyl 1,2 diphenylpent 4 en 1 one (3 58 ) : Th e following compound was made through various conditions, a representative reaction is shown here. The optimized conditions were employed with prenyl alcohol ( 3 55 ) (1.0 mL of 0.2M soln., 0.2 mmol) diphenylacetylene (107 mg, 0.6 mmol, 3.0 eq.). Purified b y flash column chromatography using a solvent gradient (0 20% CH 2 Cl 2 /hexanes) to yield the product as a clear colorless oil (43.5 mg, 83%). R f = 0.66 (20% EtOAc/hexanes). IR (neat) 3086, 3055, 2966, 2924, 1684, 1540, 1507, 1457, 1447 cm 1 1 H NMR (500 MH z, CDCl 3 ): 7.87 (d, J = 7.5 Hz, 2H), 7.49 7.46 (m, 1H) 7.40 7.37 (m, 4H), 7.32 7.29 (m, 2H), 7.26 7.23 (m, 1H), 6.11 (dd, J = 17.5, 11.0, 1H), 4.95 (dd, J = 11.0, 1.0 Hz, 1H), 4.88 (dd, J = 17.5, 1.0 Hz, 1H), 4.59 (s, 1H), 1.17 (s, 3H), 1.14 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ): 200.2, 146.3, 138.7, 135.8, 132.7, 130.7, 128.7, 128.5, 128.3, 127.3, 112.2, 62.3, 50.0, 26.4, 24.9; HRMS (DART) Calcd for C 19 H 21 O (M+H) + 265.1587, found 265.1593

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129 anti 1,2 diphenyl 3 vinylun decan 1 one (3 61 ) : The following com pound was made with the optimized conditions with ( E ) undec 2 en 1 ol 99 ( 3 59 ) (1.0 mL of 0.2M soln., 0.2 mmol) and diphenylacetylene (110.0 mg, 0.62 mmol, 3.0 eq.). Purified by flash column chromatography using a solvent gradient (0 20% CH 2 Cl 2 /hexanes) t o yield the product as a white solid (50.2 mg, 72%; major diastereomer, 5:1 dr ): mp = 66 68C R f = 0.36 (2% Et 2 O/pentanes). IR (neat) 3064, 3022, 2926, 2854, 2361, 2334, 1683, 1267, 913 cm 1 1 H NMR (500 MHz, CDCl 3 ): 7.98 (d, J = 8.5 Hz, 2H), 7.51 7.46 ( m, 1H), 7.42 7.38 (m, 2H), 7.29 7.22 (m, 4H), 7.17 7.13 (m, 1H), 5.38 (dt, J = 17.1, 10.3, Hz, 1H), 4.82 (dd, J = 10.3, 1.9 Hz, 1H), 4.76 (dd, J = 17.1, 1.9 Hz, 1H), 4.49 (d, J = 10.2 Hz, 1H), 3.06 2.98 (m, 1H), 1.43 1.51 (m, 1H), 1.22 1.28 (m, 15H), 0.85 (t, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ): 200.1, 139.8, 139.1, 137.8. 133.1, 129.3, 128.8, 128.7, 128.7, 127.1, 116.7, 58.6, 47.8, 33.9, 32.1, 29.7, 29.7, 29.5, 27.6, 22.9, 14.3; HRMS (DART) Calcd for C 25 H 33 O (M+H) + 349.2526, found 349.2547 syn 1 ,2 d iphenyl 3 vinylundecan 1 one (3 62 ) : The following compound was made through various methods. A representative method is shown. Following the optimized conditions with ( Z ) undec 2 en 1 ol 100 ( 3 60 ) (1.0 mL of 0.2M soln., 0.2 mmol) and diphenylacetylen e (107.0 mg, 0.6 mmol, 3.0 eq.). Purified by flash column chromatography using a solvent gradient (0 20% CH 2 Cl 2 /hexanes) to yield the product

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130 as a white solid (52.3 mg, 75%; major diastereomer, 11:1 dr ): mp = 74 76C; R f = 0.36 (40% CH 2 Cl 2 /hexanes). IR (n eat) 3078, 3045, 2920, 2852, 1673, 1644, 1557, 1538, 1445 cm 1 1 H NMR (500 MHz, CDCl 3 ): 7.96 7.92 (m, 2H), 7.50 7.45 (m, 1H), 7.42 7.35 (m, 3H), 7.32 7.27 (m, 3H), 7.23 7.18 (m, 1H), 5.62 (dddd, J = 17.2, 10.1, 8.7, 0.9 Hz, 1H), 5.07 (ddd, J = 17.2, 1 .6, 0.9, 1H), 4.99 (dd, J = 10.3, 1.6 Hz, 1H), 4.54 (d, J = 10.2 Hz, 1H), 3.07 2.98 (m, 1H),1.34 1.05 (m, 14H), 0.90 0.83 (m, 3H). 13 C NMR (125 MHz, CDCl 3 ): 199.9, 140.6, 137.9, 137.7, 132.9, 129.3, 128.9, 128.7, 128.6, 127.3, 116.9, 58.3, 46.9, 32.0, 3 1.8, 29.7, 29.6, 29.4, 26.9, 22.8, 14.3; HRMS (DART) Calcd for C 25 H 33 O (M+H) + 349.2526, found 349.2530. 1,2 diphenylpent 4 en 1 one (3 65b ) : 101 The following compound was made with the optimized conditions with allyl alcohol (1.0 mL of 0.2M soln., 0.2 m mol) and diphenylacetylene (107.0 mg, 0.6 mmol, 3.0 eq.). Purified by flash column chromatography using a solvent gradient (0 20% CH 2 Cl 2 /hexanes) to yield the product as a clear colorless oil (45.0 mg, 95%), that satisfactorily matched all previously rep orted data. 101 anti 1, 2,3 triphenylpent 4 en 1 one (3 65c ) : The following compound was provided via Procedure A, with cinnamyl alcohol (40.0 mg, 0.3 mmol, 1.0 eq.), diphenylacetylene (160.0 mg, 0.9 mmol, 3.0 eq.), 1,3 bis(2,6 diisopropylphenyl

PAGE 131

131 imidazol 2 ylidene)gold(I) chloride (9.3 mg, 0.015 mmol, 5 mol%), and silver tetrafluoroborate (3.0 mg, 0.015 mmol, 5 mol%) in 1.0 mL of THF. Purified by flash column chromatography using a solvent gradient (0 20% CH 2 Cl 2 /hexanes) to yield the product as a white so lid (60 mg, 96%; major diastereomer; 5:1 dr ). mp = 161 163 C; R f = 0.15 (15% EtOAc/hexanes). IR (neat) 3065, 3027, 1673, 1595, 1447, 1267, 910 cm 1 1 H NMR (500 MHz, CDCl 3 ): 7.98 7.95 (m, 2H), 7.51 7.46 (m, 1H), 7.42 7.37 (m, 2H), 7.31 7.29 (m, 4 H), 7. 23 7.20 (m, 1H), 5.82 (ddd, J = 17.0, 10.2, 8.0 Hz, 1H), 5.10 (d, J = 11.5 Hz, 1H), 4.87 (ddd, J = 10.3, 1.6, 1.0 Hz, 1H) 4.75 (dt, J = 17.0, 1.6 Hz, 1H), 4.36 (dd, J = 11.5, 8.0 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): 198.8, 142.6, 139.6, 137.5, 137.3, 132.9 129.4, 129.0, 128.7, 128.6, 128.5, 128.2, 127.6, 126.6, 116.6, 58.6, 53.2; HRMS (DART) Calcd for C 23 H 21 O (M+H) + 313.1587, found 313.1578 anti 1,2,3 triphenylpentan 1 on e (4 2 ) : The following compound was synthesized by the chemoselective reduction of anti 1,2,3 triphenylpent 4 en 1 one ( 3 65c ) following a known procedure. 10 2 A flask containing a stir bar, anti 1,2,3 triphenylpent 4 en 1 one ( 3 65c 60.0 mg, 0.19 mmol), Pd/C (6 mg, 10% by wt.), Ph 2 S (1.0 mg, 3 mol%) and 2 mL of MeOH was evacuated and ba ckfilled 3 times with H 2 gas via a three way valve attached to a hydrogen balloon. The solution was allowed to mix at room temperature for 24 hrs. The solution wa s filtered through a plug of ce lite with CH 2 Cl 2 and the solvent was evaporated. Purified by flash column chromatography using a solvent gradient (0 20% CH 2 Cl 2 /hexanes) to yield the product as a white solid (60 mg, quantitative, one observable diastereomer) which matched the well known

PAGE 132

132 melting point of the anti (erythro) product. 103 mp = 169 170C ; R f = 0.32 (40% CH 2 Cl 2 /hexanes). IR (neat) 3055, 3029, 2952, 2917, 2857, 1673, 1446, 1271 cm 1 1 H NMR (500 MHz, CDCl 3 ): 7.78 7.71 (m, 2H), 7.49 7.44 (m, 1H), 7.41 7.36 (m, 1H), 7.35 7.30 (m, 2H), 7.30 7.26 (m, 4H), 7.24 7.19 (m, 2H), 7.11 7.08 (m, 1H), 4.91 (d, J = 10.9 Hz, 1H), 3.46 (td, J = 10.7, 4.3 Hz, 1H), 1.48 1.36 (m, 2H), 0.60 (t, J = 7.3 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ): 199.6, 143.5, 138.1, 137.7, 132.7, 129.3, 129.2, 129.0, 128.5, 128.5, 128.5, 128.4, 128.4, 127.5, 126.34, 60.0, 50.5, 26.6 11.9. ; HRMS (DART) Calcd for C 23 H 22 O (M+H) + 315.1743, found 315.1735. Figure 4 1 Confirmation of Stereochemistry via synthesis of anti 1,2,3 triphenylpentan 1 one (erythro) syn 3 ((( tert butyldiphenylsilyl)oxy)methyl) 1,2 diphenylpent 4 en 1 one ( 3 65d ) : The following compound was with the optimized conditions optimized conditions with ( Z ) 4 (tert butyldiphenylsilanyloxy) but 2 ene 1 ol (1.0 mL of 0.2M soln., 0.2 mmol) and diphenylacetylene (107.0 mg, 0.6 mmol, 3.0 eq.). Purified by flash column c hromatography using a solvent gradient (0 1% Et 2 O/hexanes) to yield the product as a clear, colorless oil (70.0 mg, 70%; >25:1 dr ): R f = 0.62 (20% Et 2 O/hexanes). IR (neat)

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133 3071, 2958, 2857, 2822, 1683, 1447, 1109 cm 1 1 H NMR (300 MHz, CDCl 3 ): 8.05 7.94 (m, 2H), 7.61 7.55 (m, 2H), 7.53 7.17 (m, 14H), 6.03 (ddd, J = 17.2, 10.4, 8.2 Hz, 1H), 5.18 5.00 (m, 3H), 3.57 (dd, J = 10.0, 3.2 Hz, 1H), 3.48 (dd, J = 10.0, 4.1 Hz, 1H), 3.34 3.05 (m, 1H), 1.06 (s, 9H). 13 C NMR (125 MHz, CDCl 3 ): 199.6, 164.6, 138.4, 137.2, 135.9, 135.7, 133.0, 129.8, 129.7, 129.5, 128.9, 128.8, 127.8, 127.7, 127.4, 117.5, 106.8 64.8, 53.5, 49.2, 27.1, 19.6. anti 3,7 dimethyl 1,2 di phenyl 3 vinyloct 6 en 1 one (3 65e ) : The following compound was made using the optimized conditions w ith geraniol (1.0 mL of 0.2M soln., 0.2 mmol) and diphenylacetylene (108.0 mg, 0.6 mmol, 3.0 eq.). Purified by flash column chromatography using a solvent gradient (0 20% CH 2 Cl 2 /hexanes) to yield the product as a clear colorless oil (42.5 mg, 64%; major d iastereomer; 5:1 dr ). R f = 0.55 (40% CH 2 Cl 2 /hexanes). IR (neat) 3085, 3062, 3027, 2968, 2925, 1682, 1597, 1581, 1447, 1212, 1002, 915 cm 1 1 H NMR (500 MHz, CDCl 3 ): 7.90 7.87 (m, 2H), 7.47 7.43 (m, 1H), 7.38 7.34 (m, 4H), 7.28 7.25 (m, 2H), 7.23 7.21 (m, 1H), 5.97 (ddd, J = 17.5, 10.8, 0.9 Hz, 1H), 5.06 (dd, J = 10.8, 1.2 Hz, 1H), 5.04 4.99 (m, 1H), 4.81 (dd, J = 17.5, 1.2 Hz, 1H), 4.64 (s, 1H), 1.97 1.80 (m, 2H), 1.70 1.42 (12H), 1.20 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ): 200.1, 144.4, 138.8, 135.4, 132.7 131.4, 130.9, 128.7, 128.5, 128.2, 127.3, 124.9, 113.8, 61.8, 44.3, 38.4, 25.8, 23.2, 20.3, 17.7; HRMS (DART) Calcd for C 24 H 29 O (M+H) + 333.2213, found 333.2229.

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134 syn 3,7 dimethyl 1,2 di phenyl 3 vinyloct 6 en 1 one (3 65f ) : The following compound was ma de with the optimized conditions with nerol (1.0 mL of 0.2M soln., 0.2 mmol) and diphenylacetylene (108.0 mg, 0.6 mmol, 3.0 eq.). Purified by flash column chromatography using a solvent gradient (0 20% CH 2 Cl 2 /hexanes) to yield the product as a clear color less oil (47.2 mg, 71%; major diastereomer; 8:1 dr ). R f = 0.56 (40% CH 2 Cl 2 /hexanes). IR (neat) 3063, 3020, 2969, 2924, 1684, 1447, 1215 cm 1 1 H NMR (300 MHz, CDCl 3 ): 7.91 7.85 (m, 2H), 7.49 7.41 (m, 1H), 7.40 7.33 (m, 4H), 7.31 7.17 (m, 3H), 6.17 (d d, J = 17.6, 10.9 Hz, 1H), 5.06 (dd, J = 10.9, 1.4 Hz, 1H), 5.03 4.96 (m, 1H), 4.82 (dd, J = 17.6, 1.4 Hz, 1H), 4.66 (s, 1H), 1.93 1.78 (m, 1H), 1.62 (s, 3H), 1.61 1.38 (m, 6H), 1.14 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ): 200.2, 144.3, 138.8, 135.5, 132.7, 1 31.5, 131.0, 128.6, 128.5, 128.2, 127.4, 124.8, 114.2, 62.12, 44.5, 39.7, 25.9, 23.1, 20.3, 17.8. HRMS (DART) Calcd for C 24 H 29 O (M+H) + 333.2213, found 333.2207. 4 ethyl 5 vinyltridecan 3 one (3 65g ) : The following compound was made with the optimized con ditions with ( E ) undec 2 en 1 ol 9 9 ( 3 59 ) (1.0 mL of 0.2M soln., 0.2 mmol) and 3 hexyne (70 L, 0.6 mmol, 3.0 eq.). Purified by flash column chromatography using a solvent gradient (0 2% Et 2 O/pentanes) to yield the product as a clear colorless oil (45.5 mg, 90%; 1:1 mixture of diastereomers). R f = 0.95 (10%

PAGE 135

135 Et 2 O/pentanes). IR (neat) 2985, 2935, 1742, 1373, 1241, 1047 cm 1 1 H NMR mixture of diastereomers (500 MHz, C 6 D 6 ): 5.44 5.35 (m, 1H), 5.02 (dd, J = 10.5, 2.0 Hz, 2H), 4.98 4.93 (m, 1H), 2.45 2.37 ( m, 3H), 2.30 3.26 (m, 1H), 1.57 (q, J = 7.0 Hz), 1.26 1.16 (m, 16 H), 1.02 (t, J = 7.5 Hz, 1H), 0.95 (d, J = 7.0 Hz, 2 H), 0.89 0.84 (m, 5H), 0.76 (t, J = 7.5 Hz). 13 C NMR (125 MHz, CDCl 3 ): 214.6, 140.3, 139.6, 116.7, 116.6, 58.2, 50.5, 46.8, 46.7, 44.2, 37.1, 33.1, 33.9, 32.0, 29.7, 29.7, 29.7, 29.5, 29.5, 27.5, 27.5, 23.2, 22.8, 17.2, 14.3, 14.2, 14.0, 12.1, 7.7, 1.2. HRMS (DART) Calcd for C 17 H 33 O (M+H) + 253.2526, found 253.2527. 2 allyl 1 ( o tolyl)octan 1 one (3 68 a) and 4 ( o tolyl)undec 1 en 5 one (3 68 b) : The following products were obtained using the optimized conditions with allyl alcohol (1.0 mL of 0.2M soln., 0.2 mmol) and 1 methyl 2 (oct 1 yn 1 yl)benzene 102 (120.2 mg, 0.6 mmol, 3.0 eq.) Purified by flash column chromatography using a solvent gradient (0 20% CH 2 Cl 2 /hexanes) to yield the product as a clear colorless oil (33.0 mg, 64%; 2:1 mixture of regioisomers aryl:alkyl ketone). Analytical fractions of each were obtained; their characterization is as follows: Aryl Ketone ( 3 68a ) : R f = 0.45 ( 40% CH 2 Cl 2 /hexanes). IR (neat) 3066, 2954, 2928, 2856, 1686, 1458, 1210 cm 1 1 H NMR (300 MHz, CDCl 3 ): 7.56 (d, J = 7.3 Hz, 1H), 7.38 7.32 (m, 1H), 7.29 7.21 (m, 2H), 5.75 (ddt, J = 17.2, 10.1, 7.1 Hz, 1H), 5.08 4.95 (m, 2H), 3.31 (tt, J = 7.6, 5.8 Hz, 1H), 2.54 2.39 (m, 4H), 2.32 2.18 (m, 1H), 1.82 1.67 (m, 1H), 1.47 (dt, J = 14.8, 6.1 Hz, 1H), 1.36

PAGE 136

136 1.14 (m, 6H), 0.87 0.81 (m, 3H). 13 C NMR (125 MHz, CDCl 3 ): 208.1, 139.3, 138.2, 136.2, 132.0, 131.1, 128.2, 125.7, 116.9, 49.4, 36.3, 31.9, 31.8, 29.6, 27.5 22.8, 21.1, 14.3. HRMS (DART) Calcd for C 17 H 32 O (M+H) + 259.2056, found 259.2068. The following data was accrued from a fraction obtained as a mixture of products that is primarily the alkyl ketone. Alkyl Ketone ( iso 3 68 b) : R f = 0.40 (40% CH 2 Cl 2 /hexane s). IR (neat) 3066, 2956, 2927, 2857, 1715, 1490, 1458, cm 1 1 H NMR (500 MHz, CDCl 3 ): 7.27 7.22 (m, 1H), 7.21 7.13 (m, 2H), 7.07 7.03 (m, 1H), 5.67 (ddd, J = 17.1, 10.2, 6.9 Hz, 1H), 5.03 4.98 (m, 1H), 4.93 (ddd, J = 10.1, 2.1, 1.1 Hz, 1H), 3.96 3.91 ( m, 1H), 2.87 (t, 1H), 2.82 2.74 (m, 1H), 2.40 (s, 4H), 2.35 (dtq, J = 14.2, 7.1, 1.2 Hz, 2H), 2.28 2.23 (m, 2H), 1.70 (h, J = 7.4 Hz, 1H), 1.53 1.41 (m, 2H), 1.37 1.08 (m, 11H), 0.83 (t, 2H). 13 C NMR (125 MHz, CDCl 3 ): 210.2, 137.3, 136.3, 131.0, 127.4, 12 7.2, 125.8, 126.8, 116.6, 54.5, 42.0, 36.5, 31.7, 28.9, 23.9, 22.6, 20.3, 14.2. HRMS (DART) Calcd for C 18 H 27 O (M+H) + 259.2056, found 259.2065. 4 methoxy 2 meth yl 1 (oct 1 yn 1 yl)benzene (4 3 ) : To a mixture of Et 3 N (3.0 mL), PPh 3 PdCl 2 (46.0 mg, 0.07 mm ol, 5 mol%), CuI (25.0 mg, 0.13 mmol, 10 mol%), and 1 octyne (0.24 mL, 1.6 mmol, 1.2 eq.) at room temperature was added 2 methyl 4 methoxyiodobenzene (320.0 mg, 1.3 mmol, 1.0 eq.). The mixture was left to stir at room temperature overnight, then diluted w ith EtOAc and washed with sat. NH 4 Cl (x2). The organic phase was washed with brine, dried over NaSO 4 and filtered. Purified by flash column chromatography using a solvent gradient (0 20% CH 2 Cl 2 /hexanes) to yield the product as a clear colorless oil (196 .5 mg, 66%). R f = 0.8 (30% EtOAc/hexanes). IR

PAGE 137

137 (neat) 2999, 2955, 2930, 2858, 1606, 1497, 1567, 1464, 1234 cm 1 1 H NMR (500 MHz, CDCl 3 ): 7.31 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H), 6.66 (dd, J = 8.4, 2.7 Hz, 1H), 3.79 (s, 3H), 2.46 (t, J = 6.9 H z, 2H), 2.42 (s, 3H), 1.69 1.57 (m, 2H), 1.55 1.43 (m, 2H), 1.41 1.27 (m, 4H), 0.93 (t, J = 7.0 Hz 3H). 13 C NMR (75 MHz, CDCl 3 ): 159.0, 141.7, 133.1, 116.4, 115.1, 111.2, 92.8, 79.3, 55.3, 31.6, 29.2, 28.8, 22.8, 21.2, 19.7, 14.3. HRMS (DART) Calcd for C 16 H 23 O (M+H) + 231.1743 found 231.1745. 2 allyl 1 (4 methoxy 2 methylphenyl)oct an 1 one (3 68c ) and 4 (4 methoxy 2 me thylphenyl)undec 1 en 5 one ( iso 3 68c ) : The following products were obtained using the optimized conditions with allyl alcohol (1.0 mL of 0.2M soln., 0.2 mmol) and 4 methoxy 2 methyl 1 (oct 1 yn 1 yl)benzene ( 4 3 ) (138.2 mg, 0.6 mmol, 3.0 eq.). Purified by flash column chromatography using a solvent gradient (0 20% EtOAc/hexanes) to yield the product as a clear orangeish oil, mixture of p roducts (26.5 mg, 46%; 2:1 mixture of regioisomers aryl:alkyl ketone). An analytical fraction of the aryl ketone was obtained; the characterization is as follows: Aryl Ketone ( 3 68c ) : R f = 0.24 (40% CH 2 Cl 2 /hexanes). IR (neat) 3066, 2954, 2927, 2855, 1674, 1603, 1567, 1247, 1126 cm 1 1 H NMR (500 MHz, CDCl 3 ): 7.66 7.62 (m, 1H), 6.78 6.73 (m, 2H), 5.74 (ddt, J = 17.1, 10.2, 7.1 Hz, 1H), 5.02 (dd, J = 17.1, 1.1, 1H), 4.96 (dd, J = 10.2, 1.1 Hz, 1H), 3.84 (s, 3H), 3.33 (tt, J = 7.7, 5.8 Hz, 1H), 2.49 (s, 3H) 2.48 2.42 (m, 1H), 2.25 2.18 (m, 1H), 1.77 1.66 (m, 1H), 1.52 1.42 (m, 1H), 1.32 1.15 (m, 6H), 0.84 (t, J = 6.7, 3H). 13 C

PAGE 138

138 NMR (125 MHz, CDCl 3 ): 206.2, 161.7, 141.9, 136.4, 131.6, 131.1, 117.6, 116.6, 110.7, 55.5, 48.5, 36.8, 32.3, 31.9, 29.7, 27.6, 22 .8, 22.1, 14.3. HRMS (DART) Calcd for C 19 H 29 O 2 (M+H) + 289.2162, found 289.2166. 2 allyl 1 (4 methoxyphenyl)octan 1 one (3 65h ) and 4 (4 methoxyphenyl)undec 1 en 5 one ( iso 3 65h ) : The following mixture was made using the optimized conditions with allyl alcohol (1.0 mL of 0.2M soln., 0.2 mmol) and 1 (4 methoxyphenyl) 1 octyne 103 ( 129.8 mg, 0.6 mmol, 3.0 eq.) Purified by flash column chromatography using a solvent gradient (0 20% EtOAc/hexanes) to yield the inseparable mixture of products as a clear pale y ellow oil (38.4 mg, 70%; 2:1 mixture of regioisomers aryl:alkyl ketone) R f = 0.24 (40% CH 2 Cl 2 /hexanes). IR (neat) 3077, 2997, 2956, 2930, 1712, 1672, 1601, 1510, 1254, 1171, 1034 cm 1 1 H NMR (500 MHz, CDCl 3 ): 7.94 (d, J = 8.9 Hz, 2H, major), 7.12 (d, J = 8.7 Hz, 2H, minor), 6.94 (d, J = 8.9 Hz, 2H, major), 6.85 (d, J = 8.7 Hz, 2H, minor), (ddd, J = 17.5, 10.5, 7.0 Hz 1H, major), 5.65 (ddd, J = 17.1, 10.2, 6.9 Hz, 1H, minor), 5.01 (dddd, J = 17.5, 3.5, 2.0, 1.5 Hz 1H, major), 4.99 (dddd, J = 17.5, 3.5, 2.0, 1.5 Hz 1H, minor), 4.97 4.91 (m, 4H, major and minor), 3.87 (s, 3H, major), 3.79 (s, 3H, minor), 3.64 (t, J = 7.5 Hz, 1H, minor), 3.44 (tt, J = 7.6, 5.8 Hz, 1H, major), 2.79 2.72 (m, 1H, minor), 2.53 2.45 (m, 1H, major), 2.43 2.36 (m, 1H, minor), 2.3 6 2.31 (m, 2H, minor), 2.28 2.21 (m, 1H, major), 1.80 1.70 (m, 1H, major), 1.56 1.41 (m, 2H, major and minor), 1.29 1.09 (m, 18 H,

PAGE 139

139 major and minor), 0.88 0.79 (m, 6H, major and minor). 13 C NMR (125 MHz, CDCl 3 ): 210.4, 202.5, 163.6, 136.3, 136.3, 130.8, 130 .7, 129.5, 116.7, 116.6, 114.4, 114.0, 58.0, 55.7, 55.5, 45.7, 42.0, 36.8, 36.7, 32.4, 31.86, 31.71, 29.7, 28.9, 27.6, 23.9, 22.8, 22.7, 14.3, 14.2. HRMS (DART) Calcd for C 18 H 27 O2 (M+H) + 275.2006, found 275.1996. 4 (4 nitrophenyl)undec 1 en 5 one (3 65i ) and 2 allyl 1 (4 nitrophenyl)octan 1 one ( iso 3 65i ) : The following products were obtained using the optimized conditions with allyl alcohol (1.0 mL of 0.2M soln., 0.2 mmol) and 1 (4 nitrophenyl) 1 octyne 106 (138.2 mg, 0.6 mmol, 3.0 eq.) Purified by flash column chromatography using a solvent gradient (0 20% CH 2 Cl 2 /hexanes) to yield the product as a clear pale yellow oil (57.9 mg 99%; 8:1 mixture of regioisomers alkyl:aryl ketone). Analytical fractions of each were obtained; their characterization is as f ollows: Alkyl Ketone (3 65i) : R f = 0.27 (40% CH 2 Cl 2 /hexanes). IR (neat) 3079, 2956, 2930, 2858, 1716, 1606, 1521, 1346 cm 1 1 H NMR (300 MHz, CDCl 3 ): 8.18 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 5.61 (ddt, J = 17.1, 10.1, 6.9 Hz, 1H), 5.07 4.9 1 (m, 2H), 3.85 (t, J = 7.5 Hz, 1H), 2.81 (dtt, J = 14.2, 7.0, 1.3 Hz, 1H), 2.50 2.42 (m, 1H), 2.38 (dt, J = 7.1, 2.2 Hz, 2H), 1.57 1.41 (m, 2H), 1.28 1.09 (m, 8H), 0.82 (t, J = 6.9 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ): 208.7, 147.4, 146.0, 134.8, 129.4, 12 4.2, 117.8, 58.4, 42.9, 36.9, 31.7, 28.8, 23.7, 22.6, 14.2. HRMS (DART) Calcd for C 17 H 24 NO 3 (M+H) + 290.1751, found 290.1745 Aryl Ketone (iso 3 65i ) : R f = 0.29 (40% CH 2 Cl 2 /hexanes). IR (neat) 3075, 2929, 2857, 1689, 1526, 1346

PAGE 140

140 cm 1 1 H NMR (300 MHz, CDCl 3 ): 8.32 (d, J = 8.9 Hz, 2H), 8.07 (d, J = 8.8 Hz, 2H), 5.72 (ddd, J = 17.1, 10.1, 7.1 Hz, 1H), 5.09 4.93 (m, 2H), 3.49 (tt, J = 7.5, 5.7 Hz, 1H), 2.58 2.45 (m, 1H), 2.34 2.22 (m, 1H), 1.85 1.67 (m, 2H), 1.33 1.11 (m, 8H), 0.91 0.78 (m, 3H). 13 C NMR (1 25 MHz, CDCl 3 ): 202.6, 142.2, 135.4, 129.4, 124.2, 124.1, 117.4, 47.0, 36.4, 32.1, 31.8, 29.6, 27.5, 22.7, 14.2. HRMS (DART) Calcd for C 17 H 24 O (M+NH 4 ) + 307.2016, found 307.2005. 2 (2 methoxyet hyl) 1 phenylpent 4 en 1 one (3 65j ) and 1 methoxy 4 phenylh ept 6 en 3 one ( iso 3 65j ) : The following products were obtained using the optimized conditions with allyl alcohol (1.0 mL of 0.2M soln., 0.2 mmol) and 4 methoxy 1 phenyl 1 butyne 10 7 Purified by flash column chromatography using a solvent gradient (0 20% EtOAc/hexanes) to yield the product as a clear colorless oil (34.5 mg, 79%; 3:1 mixture of regioisomers aryl:alkyl ketone). An analytical fraction of the aryl ketone was obtained; the characterization is as follows: Aryl Ketone (3 65j) : R f = 0.65 (30% Et OAc/hexanes). IR (neat) 2928, 1671, 1601, 1508, 1396, 1247, 1171 cm 1 1 H NMR (500 MHz, CDCl 3 ): 8.00 7.95 (m, 2H), 7.59 7.53 (m, 1H), 7.49 7.45 (m, 2H), 5.73 (ddt, J = 17.1, 10.1, 7.0 Hz, 1H), 5.03 (dd, J = 17.0, 1.7 Hz, 1H), 4.97 (dd, J = 10.1, 1.7 Hz, 1H), 3.76 3.70 (m, 1H), 3.43 3.38 (m, 1H), 3.28 (ddd, J = 9.6, 7.6, 5.1 Hz, 1H), 3.22 (s, 3H), 2.55 2.47 (m, 1H), 2.31 2.23 (m, 1H), 2.07 (dddd, J = 13.9, 8.7, 6.2, 5.2 Hz, 1H), 1.81 (ddt, J = 14.0, 7.6, 5.3 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): 203.9, 137 .7, 135.6,

PAGE 141

141 133.1, 128.8, 128.5, 117.2, 70.5, 58.7, 42.7, 37.0, 32.1. HRMS (DART) Calcd for C 14 H 19 O 2 (M+H) + 219.1380, found 219.1372. From a mixture of products the following NMR peaks were deduced as the alkyl ketone. Alkyl Ketone ( iso 3 65j ) : R f = 0.65 (30% EtOAc/hexanes). 1 H NMR (500 MHz, CDCl 3 ): 7.34 7.30 (m, 2H), 7.22 7.18 (m, 2H), 5.68 5.61 (ddd, J = 17.3, 10.1, 7.0 Hz, 1H), 5.05 4.92 (m, 2H), 3.59 (dt, J = 9.6, 6.6 Hz, 1H), 3.51 (dt, J = 9.6, 6.3 Hz, 1H), 3.25 (s, 3H), 2.81 (dtt, J = 14.3, 7.2, 1 .3 Hz, 1H), 2.68 2.56 (m, 2H), 2.47 2.39 (m, 1H). 13 C NMR (125 MHz, CDCl 3 ): 208.1, 138.3, 135.9, 129.1, 128.6, 127.6, 116.8, 67.7, 59.3, 58.9, 42.0, 36.3. 1 methoxy 4 (4 methoxybut 1 yn 1 yl)benzene (4 4 ) : The following compound was made through a rela ted procedure for facile methylation of alcohols. 10 7 To a flask containing a stir bar and a mixture of MeI (0.31 mL, 5.0 mmol, 2.0 eq.), NaH (60% in mineral oil, 200 mg, 5.0 mmol, 2.0 eq.) and 3.0 mL of THF at room temperature was slowly and carefully adde d 4 (4 methoxyphenyl) but 3 yn 1 ol 101 (neat, 440.0 mg, 2.5 mmol, 1.0 eq.) Minor bubbling occurred and the solution was placed in a 40 C oil bath for 1 hr. After this point the solution was cooled to r.t. and slowly quenched with 10 mL of deionized water The solution was taken up in ether and washed with NaHCO 3 and brine, dried over NaSO 4 and filtered. Purified by flash column chromatography using a solvent gradient (0 20% EtOAc/hexanes) to yield the product as a clear colorless oil (237.8 mg, 50%). R f = 0.5 (20% EtOAc/hexanes). IR (neat) 3040, 2931, 2837, 1608, 1506, 1464, 1289, 1246, 1174, 1117 cm 1 1 H NMR (300 MHz, CDCl 3 ): 7.34 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H), 3.58 (t, J = 7.0 Hz, 2H), 3.41 (s, 3H),

PAGE 142

142 2.67 (t, J = 7.0 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ): 159.3, 133.1, 115.9, 113.9, 85.2, 81.3, 71.1, 58.8, 55.3, 20.8. HRMS (DART) Calcd for C 12 H 15 O 2 (M+H) + 191.1067, found 191.1073. 2 (2 methoxyethyl) 1 (4 m ethoxyphenyl)pent 4 en 1 one (3 65k ) and 1 methoxy 4 (4 methoxy phenyl)hept 6 en 3 one ( iso 3 65k ) : The following products were obtained using the optimized conditions with allyl alcohol (1.0 mL of 0.2M soln., 0.2 mmol) and 1 methoxy 4 (4 methoxybut 1 yn 1 yl)benzene. Purified by flash column chromatography using a so lvent gradient (0 20% EtOAc/hexanes) to yield the product as a white crystalline solid (43.2 mg, 87%; 9:1 mixture of regioisomers aryl:alkyl ketone). An analytical fraction of the aryl ketone 3 65k was obtained; the characterization is as follows: R f = 0. 53 (50% Et 2 O/hexanes). IR (neat) 3064, 2925, 2874, 2822, 1682, 1447, 1117 cm 1 1 H NMR (500 MHz, C 6 D 6 ): 8.06 (d, J = 8.9 Hz, 2H), 6.68 6.63 (d, J = 8.8 Hz 2H), 5.76 (ddd, J = 17.0, 10.2, 7.0 Hz, 1H), 5.02 (ddt, J = 17.0, 2.0, 1.5 Hz, 1H), 4.92 (ddt, J = 10.2, 2.0, 1.5 Hz, 1H), 3.74 (dddd, J = 8.6, 7.5, 6.1, 5.1 Hz, 1H), 3.24 3.12 (m, 5H), 2.99 (s, 3H), 2.63 2.55 (m, 1H), 2.27 2.19 (m, 1H), 2.20 2.12 (m, 1H), 1.78 (ddt, J = 14.0, 7.8, 5.2 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): 202.3, 163.7, 135.8, 130.8, 1 30.7, 117.0, 113.9, 70.5, 58.7, 55.7, 42.2, 37.1, 32.3. HRMS (DART) Calcd for C 15 H 21 O 3 (M+H) + 249.1485, found 249.1489.

PAGE 143

143 4 (4 methoxyp henyl)but 3 yn 1 yl acetate (4 5 ) : The following compound was made via acetylation of the known alcohol 4 (4 methoxyphen yl) but 3 yn 1 ol 10 8 The procedure is as follows: To a solution of 4 (4 methoxyphenyl) but 3 yn 1 ol 108 (358 .0 mg, 2 mmol, 1.0 eq.), DMAP (12.0 mg, 0.1 mmol, 5 mol%) and pyridine (10 mL) submerged in an ice bath, was added acetic anhydride (0.4 mL, 4.2 mmol, 2.0 eq.). The solution was stirred for 2 hours then quenched with NaHCO 3 (10 mL), and diluted with EtOAc (30 mL). The organic phase was then washed with CuSO 4 (3x10mL). The organic phase was then dried over NaSO 4 and filtered. Purified by flash column chromatography using a solvent gradient (0 20% EtOAc/hexanes) to yield the product as a clear colorless oil (100.0 mg, 23%). R f = 0.44 (20% EtOAc/hexanes). IR (neat) 2960, 2838, 1737, 1606, 1509, 1442, 1234 cm 1. 1 H NMR (300 MHz, CDCl 3 ): 7.33 ( d, J = 8.9 Hz, 2H), 6.81 (d, J = 8.9 Hz, 2H), 4.24 (t, J = 7.0 Hz, 2H), 3.79 (s, 3H), 2.73 (t, J = 7.0 Hz, 2H), 2.09 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ) 171.0, 159.4, 133.1, 115.6, 114.0, 84.0, 81.9, 62.7, 55.4, 21.1, 20.1. 3 (4 methoxybenzoyl)hex 5 en 1 yl acet ate (3 65l ) : The following product was obtained using the optimized conditions with allyl alcohol (1.0 mL of 0.15 M soln., 0.15 mmol) and 4 (4 methoxyphenyl)but 3 yn 1 yl acetate 4 5 (100 mg, 0.45 mmol, 3.0 eq.). Purified by flash column chromatogr aphy on florisil using a solvent gradient (0 20%

PAGE 144

144 EtOAc/hexanes) to yield the product as a clear oil (36.0 mg, 65% as an 8:1 mixture of regioisomers aryl:alkyl ketone). Data for the major isomer reported: R f = 0.45 (20% EtOAc/hexanes) IR (neat) 3077, 293 6, 2842, 1735, 1670, 1598, 1510, 1365, 1234, 1169, 1029 cm 1. 1 H NMR (500 MHz, CDCl 3 ): 7.94 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 5.72 (ddt, J = 17.0, 10.1, 7.1 Hz, 1H), 5.07 5.02 (m, 1H), 5.01 4.98 (m, 1H), 4.09 (dt, J = 11.3, 6.4 Hz, 1H), 4 .01 (dt, J = 11.2, 6.5 Hz, 1H), 3.87 (s, 3H), 3.58 (dtd, J = 8.7, 6.7, 5.0 Hz, 1H), 2.53 2.45 (m, 1H), 2.30 2.22 (m, 1H), 2.21 2.11 (m, 1H), 1.93 (s, 3H), 1.86 (dtd, J = 11.4, 6.4, 4.8 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): 201.2, 171.1, 163.8, 135.3, 130.8 130.1, 129.6, 117.4, 114.6, 114.1, 62.89, 55.70, 42.45, 37.19, 30.70, 21.04. 4 (4 methoxyphenyl)but 3 yn 1 yl 2,2,2 trifluoroacetate (4 6 ): To a solution of 4 (4 methoxyphenyl) but 3 yn 1 ol 108 ( 358.0 mg, 2 mmol, 1.0 eq.), DMAP (12.0 mg, 0.1 mmol, 5 m ol%) and pyridine (10 mL) submerged in an ice bath, was added acetic anhydride (0.4 mL, 4.2 mmol, 2.0 eq.). The solution was stirred for 2 hours then quenched with NaHCO 3 (10 mL), and diluted with EtOAc (30 mL). The organic phase was then washed with CuS O 4 (3x10mL). The organic phase was then dried over NaSO 4 and filtered. Purified by flash column chromatography using a solvent gradient (0 20% EtOAc/hexanes) to yield the product as a clear colorless oil (100.0 mg, 23%). R f = 0.61 (20% EtOAc/hexanes). IR (neat) 2970, 2841, 1785, 1607, 1509, 1447, 1142 cm 1. 1 H NMR (500 MHz, CDCl 3 ): 7.33 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.9 Hz, 1H), 4.52 (t, J = 6.9 Hz, 2H), 3.80 (s, 3H), 2.86 (t, J = 6.9 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 )

PAGE 145

145 159.7, 133.2, 116.6, 115.2 114.1, 82.9, 82.1, 65.8, 55.4, 19.8. 19 F NMR (282 MHz, CDCl 3 ): 75.39. 3 (4 methoxybenzoyl)hex 5 en 1 yl 2,2,2 trifluoroacetate (3 65m ) : The following product was obtained using the optimized conditions with allyl alcohol (1.0 mL of 0.16 M soln., 0.16 mmol) and 4 (4 methoxyphenyl)but 3 yn 1 yl 2,2,2 trifluoroacetate 4 6 (130 mg, 0.48 mmol, 3.0 eq.). Purified by flash column chromatography on florisil using a solvent gradient (0 50% EtOAc/hexanes) to yield the product as a clear oil (26.0 mg, 50%; >25:1 mixture of regioisomers aryl:alkyl ketone). R f = 0.35 (20% EtOAc/hexanes) IR (neat) 2984, 1736, 1673, 1601, 1237, 1044 cm 1 1 H NMR (500 MHz, CDCl 3 ): 8.04 7.93 (m, 2H), 6.97 6.92 (m, 2H), 5.74 (ddt, J = 17.1, 10.1, 7.1 Hz, 1H), 5.07 4.96 (m, 2H), 3.8 7 (s, 3H), 3.82 3.57 (m, 3H), 2.52 (dt, J = 14.0, 6.9 Hz, 1H), 2.27 (dt, J = 14.1, 7.1 Hz, 1H), 2.10 2.00 (m, 1H), 1.85 1.74 (m, 1H). 13 C NMR (125 MHz, CDCl 3 ): 202.5, 163.8, 135.7, 130.9, 130.3, 124.5, 117.1, 114.6, 60.92, 55.70, 42.35, 37.04, 34.56, 29 .05. 19 F NMR (282 MHz, CDCl 3 ): 84.08. 2 (3 (4 methoxyphenyl)prop 2 yn 1 yl)isoindoline 1,3 dione (4 7 ) : The following compound was made via sonogashira coupling between N propargylphthalimide 109 and 4 iodoanisole, the reaction is as follows: To a fla sk

PAGE 146

146 containing N propargylphth alimide (500 mg, 2.7 mmol, 1.0 eq.), 4 iodoanisole (631 mg, 2.7 mmol, 1.0 eq.), PPh 3 PdCl 2 (37.0 mg, 0.05 mmol, 2 mol%), CuI (20.0 mg, 4 mol%) and CH 3 CN (12 mL) under a N 2 atmosphere, was added Et 3 N (1.3 mL) at room temperature. The solution was stirred for 2 hours at room temperature then the volatiles were evaporated and the solid residue was triturated with EtOAc to give an light brown solid that was used without further purification (668.0 mg, 85%). R f = 0.71 (CH 2 Cl 2 ). IR ( neat) 2971, 2943, 1768, 1715, 1604, 1508, 1390, 1252 cm 1. 1 H NMR (500 MHz, CDCl 3 ): 7.89 (dd, J = 5.5, 3.1 Hz, 2H), 7.73 (dd, J = 5.5, 3.1 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 4.66 (s, 2H), 3.78 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ): 167.40, 165.61, 165.55, 159.95, 134.43, 134.33, 133.62, 132.35, 123.73, 114.62, 114.03, 110.22, 83.09, 81.45, 55.47, 28.16. 2 (2 (4 methoxybenzoyl)pent 4 en 1 yl)isoindoline 1,3 dione (3 65n ) The following product was obtained using the optimized cond itions with allyl alcohol (1.0 mL of 0.12M soln., 0.12 mmol) and 2 (3 (4 methoxyphenyl)prop 2 yn 1 yl)isoindoline 1,3 dione 4 7 (107 mg, 0.6 mmol, 3.0 eq.). Purified by flash column chromatography using a solvent gradient (20 100% CH 2 Cl 2 /hexanes) to yield the product as a clear oil (31.3 mg, 72%; >25:1 mixture of regioisomers aryl:alkyl ketone). R f = 0.41 (40% EtOAc/hexanes). IR (neat) 3076, 2935, 2842, 1711, 1671, 1598, 1511, 1172 cm 1.1 H NMR (500 MHz, CDCl 3 ): 8.03 7.98 (m, 2H), 7.85 7.81 (m, 2H), 7.74 7 .69 (m, 2H), 6.94 6.89 (m, 2H), 5.75 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.05 (d, J = 17.3 Hz, 1H), 4.96 (d, J = 10.1 Hz,

PAGE 147

147 1H), 4.15 (p, J = 6.8 Hz, 1H), 4.03 (dd, J = 13.5, 6.5 Hz, 1H), 3.94 3.87 (m, 1H), 3.85 (s, 3H), 2.64 (dt, J = 14.3, 7.0 Hz, 1H), 2.34 (dt, J = 14.0, 6.6 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): 199.2, 168.5, 163.9, 134.8, 134.2, 132.1, 131.0, 129.9, 123.5, 117.4, 114.1, 55.67, 44.09, 39.93, 34.68. anti 3 phenyl 4 vinyldodecan 2 one (3 65o ) and anti 2 methyl 1 phenyl 3 vinylundecan 1 one ( is o 3 65o ) The following compounds were made with the optimized conditions with ( E ) undec 2 en 1 ol 99 (1.0 mL of 0.2M soln., 0.2 mmol) and 1 phenyl 1 propyne (70 mg, 0.6 mmol, 3.0 eq.). Purified by flash column chromatography using a solvent gradient (0 20 % CH 2 Cl 2 /hexanes) to yield the mixture of products as a clear colorless oil (45.0 mg, 78%; 4:1 mixture of regioisomers alkyl:aryl ketone; only one observable diastereomer for each regioisomer). Analytical fractions of each were obtained; their characteriza tion is as follows: Alkyl Ketone (3 65o ) : R f = 0.40 (40% CH 2 Cl 2 /hexanes). 2926, 2856, 1715, 1455, 1354, 1151 cm 1 1 H NMR (300 MHz, CDCl 3 ): 7.32 7.22 (m, 2H), 7.22 7.14 (m, 3H), 5.26 (ddd, J = 16.9, 10.4, 9.3 Hz, 1H), 4.82 4.72 (m, 2H), 3.59 (d, J = 1 0.2 Hz, 1H), 2.92 2.79 (m, 1H), 2.10 (s, 3H), 1.49 1.14 (m, 12H), 0.84 (t, J = 6.2 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ): 208.3, 139.5, 137.5, 129.4, 128.7, 127.4, 116.7, 64.8, 46.1, 33.6, 32.1, 30.5, 29.8, 29.8, 29.5, 27.4, 22.9, 14.3. HRMS (DART) Calcd f or C 17 H 32 O (M+H) + 287.2369, found 287.2362. Aryl Ketone ( iso 3 65o ) : R f = 0.42 (40% CH 2 Cl 2 /hexanes). IR (neat) 3067, 2927, 2855, 1684, 1458, 1355, 1214 cm 1 1 H NMR (300 MHz, CDCl 3 ): 7.97 7.92 (m, 2H), 7.60

PAGE 148

148 7.53 (m, 1H), 7.51 7.44 (m, 2H), 5.51 (ddd, 17. 0, 10.3, 9.6 1H), 5.07 (dd, J = 10.3, 2.0 Hz, 1H), 4.95 (ddd, J = 17.0, 2.0, 0.7 Hz, 1H), 3.42 (q, J = 7.0 Hz, 1H), 2.52 2.39 (m, 1H), 1.33 1.15 (m, 14H), 1.11 (d, J = 6.9 Hz, 3H), 0.86 (t, J = 6.5 Hz 3H). 13 C NMR (125 MHz, CDCl 3 ): 204.6, 139.6, 137.6, 1 33.0, 128.8, 128.4, 116.9, 47.3, 44.7, 33.4, 32.1, 29.7, 29.5, 27.7, 22.9, 15.2, 14.3. HRMS (DART) Calcd for C 20 H 31 O (M+H) + 287.2369, found 287.2359. syn 2 (4 methoxybenzoyl) 3 vinylu ndecyl)isoindoline 1,3 dione (3 65p ) The following products were obtai ned using the optimized conditions with ( Z ) undec 2 en 1 ol 100 (3 60) (1.0 mL of 0.2M soln., 0.2 mmol) and 4 7 (180 mg, 0.6 mmol, 3.0 eq.). Purified by flash column chromatography using a solvent gradient (20 100% CH 2 Cl 2 /hexanes) to yield the product as a clear oil (56.0 mg, 59%, >25:1 dr; >25:1 mixture of regioisomers aryl:alkyl ketone). R f = 0.2 (80% CH 2 Cl 2 /hexanes). IR (neat) 3075, 2925, 2854, 1773, 1712, 1671, 1598, 1393, 1170 cm 1 1 H NMR (500 MHz, CDCl 3 ): 7.90 7.82 (m, 2H), 7.75 (dd, J = 5.4, 3.1 Hz, 2H), 7.64 (dd, J = 5.5, 3.0 Hz, 2H), 6.83 (d, J = 8.9 Hz, 2H), 5.71 (ddd, J = 17.1, 10.2, 9.0 Hz, 1H), 5.17 4.74 (m, 2H), 4.28 4.05 (m, 2H), 3.87 3.75 (m, 4H), 2.50 2.36 (m, 1H), 1.55 1.44 (m, 1H), 1.36 1.02 (m, 10H), 0.86 (t, J = 7.1 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ): 199.8, 168.4, 163.6, 138.9, 134.0, 132.1, 131.2, 130.8, 123.4, 117.0, 113.9, 55.6, 47.6, 45.8, 38.6, 32.0, 31.3, 29.7, 29.6, 29.5, 27.5, 22.9, 14.3.

PAGE 149

149 Epimerization experiments (Figure 3 16): Single diastereomers of ketones 3 61 and 3 62 wer e obtained by careful separation via column chromatography. An example of these experiments is as follows: A pressure tube (screw cap) containing a stir bar was taken from the oven and placed directly into a glovebox. To this vessel was added 1,3 bis(2, 6 diisopropylphenyl imidazol 2 ylidene)gold(I) chloride (6.2 mg, 0.01 mmol, 5 mol%), and silver tetrafluoroborate (1.9 mg, 0.01 mmol, 5 mol%). The vessel was capped with a septum and then taken out of the glovebox where it was immediately placed under a d ry nitrogen atmosphere. 0.5 mL of THF was added to the tube and the mixture was left to stir ~10 mins to activate the complex. After this time a solution of ketone 3 61 or 3 62 (0.2 mmol in 0.5 mL of THF) was transferred to the tube, and the vessel was t hen placed in a 65 C oil bat h and left to stir for 15 hrs. The tube was then sealed with a screwcap and placed in a 120 C oil bath for 6 hrs (behind a safety shield). After cooling to room temperature the screwcap was removed and the solution was filte red over a plug of silica with EtOAc. The solution was then evaporated, and the crude was ch aracterized by 1H NMR (500 MHz) which showed exclusively the unaltered isomers 3 61 and 3 62 respectively. (( Z ) 1 (( Z ) undec 2 en 1 yloxy)ethene 1,2 diyl)diben zene enol ( 3 74; adduct of 3 56 + 3 60 ) : The following enol was obtained using the conditions discussed in Table 2, Entry 4. A pressure tube (screw cap) containing a stir bar was taken from the oven and placed directly into a glovebox. To this vessel wa s added 1,3 bis(2,6 diisopropylphenyl imidazol 2 ylidene)gold(I) chloride (6.2 mg, 0.01 mmol, 5 mol%), and

PAGE 150

150 silver tetrafluoroborate (1.9 mg, 0.01 mmol, 5 mol%). The vessel was capped with a septum and then taken out of the glovebox where it was immediatel y placed under dry nitrogen atmosphere. 0.5 mL of THF was added to the tube and the mixture was left to stir ~10 mins to activate the complex. After this time a solution of alkyne (107.0 mg, 0.6 mmol, 3.0 eq. in 0.5 mL of THF) was transferred to the tube and the vessel was then placed in a 65 C oil bath. ( Z ) undec 2 en 1 ol 100 ( 3 60 ) (1.0 mL of 0.2M soln., 0.2 mmol)) was then added slowly over 12 hrs. via syringe pump (~0.8 mL/hr). After the addition was complete the solution was allowed to stir at this temperature for an additional 6 hrs. After cooling the to room temperature the solution was filtered over a plug of silica with CH 2 Cl 2 The solution was t hen evaporated, and the mixture was purified by flash column chromatography using a solvent gr adient (0 20% CH 2 Cl 2 /hexanes) to give the desired product 3 6 2 (23.0 mg, 33%), and 3 74 (25.8 mg, 37%) as a clear, colorless oil. Characterization of the enol 3 74 is as follows: R f = 0.70 (40% CH 2 Cl 2 /hexanes). IR (neat) 3057, 3022, 2925, 2855, 1634, 160 0, 1492, 1448, 1199, 1058, 1026, 914 cm 1 1 H NMR (500 MHz, CDCl 3 ): 7.77 (d, J = 7.5 Hz, 2H), 7.60 (d, J = 7.0 Hz, 2H), 7.42 (t, J = 7.0 Hz, 2H), 7.34 7.37 (m, 3H), 7.22 (t, J = 7.5 Hz, 1H) 6.14 (s, 1H), 5.69 5.74 (m, 1H), 5.57 5.63 (m, 1H), 4.38 (d, J = 6.5 Hz, 2H), 1.95 1.88 (m, 1H), 1.31 1.18 (m, 14H), 0.86 (t, J = 7.0, 3H). 13 C NMR (125 MHz, CDCl 3 ): 155.3, 137.0, 136.3, 134.7, 128.9, 128.6, 128.5, 128.4, 126.8, 126.7, 125.0, 113.7, 66.2, 32.0, 29.7, 29.6, 29.5, 29.4, 27.7, 22.8, 14.3; HRMS (DART) Calcd for C 25 H 33 O (M+H) + 349.2526, found 349.2523.

PAGE 151

151 Figure 4 2 Confirmation of Enol geometry via NOE experiment The Z enol configuration of 3 74 is established based on NOE DIFF experiments. The NOEs between vinyl H (s = 6.14 ppm) and ortho hydrogens ( H a ), 7.60 ( H b ) ppm) of the phenyl groups of 3 74 is clearly seen allowing for the elucidation of the Z enol configuration. (( Z ) 1 ((( Z ) 3,7 dimethylocta 2,6 dien 1 yl)oxy)ethene 1,2 diyl)dibenzene (3 75) : A test tube containing a stir bar was taken from the oven and placed directly into a glovebox. To this vessel was added 1,3 bis(2,6 diisopropylphenyl imidazol 2 ylidene)gold(I) chloride (12.4 mg, 0.02 mmol, 5 mol%), a nd silver tetrafluoroborate (4.0 mg, 0.02 mmol, 5 mol%). The vessel was cap ped with a septum and then taken out of the glovebox where it was immediately placed und er dry nitrogen atmosphere. 1.0 mL of THF was added to the tube and the mixture was left to stir ~10 mins to activate the complex. After this time a solution of diphe nylacetylene (107.0 mg, 0.6 mmol, 3.0 eq. in 1.0 mL of THF) was transferred to the tube, and the vessel was then placed in a 65 C oil bath. A solution of nerol (1.0 mL of 0.4M soln., 0.4 mmol ) was then added slowly over 12 hrs. via syringe pump (~0.8 mL/hr). After the addition was complete the solution was allowed to stir at this temperature for an additional 3 hrs. After cooling the

PAGE 152

152 to room temperature the solution was filtered over a plug of silica with CH 2 Cl 2 The solution was t hen evaporated, an d the mixture was purified by flash column chromatography using a solvent gradient (0 4 % CH 2 Cl 2 /hexanes) to give the desired enol 3 75 as a clear, colorless oil (45.0 mg, 34 %) R f = 0.25 (20% CH 2 Cl 2 /hexanes) 1 H NMR (5 00 MHz, CDCl 3 ): 7.81 7.76 (m, 2H), 7.62 7.58 (m, 2H), 7.44 7.40 (m, 2H), 7.39 7.34 (m, 3H), 7.25 7.21 (m, 1H), 6.14 (s, 1H), 5.55 (td, J = 7.2, 1.7 Hz, 1H), 5.02 (ddq, J = 6.9, 5.3, 1.6 Hz, 1H), 4.32 (dd, J = 6.8, 1.3 Hz, 2H), 2.06 1.96 (m, 4H), 1.78 (s, 3H), 1.65 (s, 3H), 1.55 (s, 3H). 1 3 C NMR (125 MHz, CDCl 3 ): 155.5, 141.3, 137.2, 136.4, 128.9, 128.6, 128.5, 128.4, 126.8, 126.7, 123.9, 121.2 11 3.6, 67.0 3 2.4, 26.8, 25.8, 23.7, 17.8 (( Z ) 1 ((( E ) 3,7 dimethylocta 2,6 dien 1 yl)oxy)ethene 1,2 diyl)dibenzene (3 76) : A test tube contai ning a stir bar was taken from the oven and placed directly into a glovebox. To this vessel was added 1,3 bis(2,6 diisopropylphenyl imidazol 2 ylidene)gold(I) chloride (12.4 mg, 0.02 mmol, 5 mol%), a nd silver tetrafluoroborate (4.0 mg, 0.02 mmol, 5 mol%). The vessel was capped with a septum and then taken out of the glovebox where it was immediately placed und er dry nitrogen atmosphere. 1.0 mL of THF was added to the tube and the mixture was left to stir ~10 mins to activate the complex. After this time a solution of diphenylacetylene (107.0 mg, 0.6 mmol, 3.0 eq. in 1.0 mL of THF) was transferred to the tube, and the vessel was then placed in a 65 C oil bath. A solution of geraniol (1.0 mL of 0.4M soln., 0.4 mmol ) was then added slowly over 12 hrs. via syringe pump (~0.8 mL/hr). After the addition was complete the

PAGE 153

153 solution was allowed to stir at this temperature for an additional 3 hrs. After cooling the to room temperature the solution was filtered over a plug of silica with CH 2 Cl 2 The solution was t hen evaporated, and the mixture was purified by flash column chromatography using a solvent gradient (0 4% CH 2 Cl 2 /hexanes) to give the desired enol 3 75 as a clear, colorless oil (33.0 mg, 25 %) R f = 0.22 (20% CH 2 Cl 2 /hexanes) 1 H NMR (3 00 MHz, CDCl 3 ): 7.78 7.73 (m, 2H), 7.60 7.55 (m, 2H), 7. 43 7.29 (m, 5H), 7.22 7.1 6 (m, 1H), 6.10 (s, 1H), 5.54 5.45 (m, 1H), 5.12 5.04 (m, 1H), 4.35 4.28 (m, 2H), 2.12 1.98 ( m, 4H), 1.67 (s, 3H), 1.59 (s, 3H), 1.52 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ): 155.4, 141.4, 13 7.2, 136.4, 131.9, 128.9, 128.6, 128.5, 128.4, 126.9, 126.6, 124.1, 120.2 11 3.7, 67.2, 39.8, 26.6, 25.9, 17.9, 16.6 Sequential Gold catalyzed Enol F ormation/Ru catalyzed Allylation to form Functionalized Cyclohexanones and Tetrahydropyrans Optimized cond itions: A flask containing a stir bar was taken from the oven and placed directly into a glovebox. To this vessel was added 1,3 bis(2,6 diisopropylphenyl imidazol 2 ylidene)gold(I) chloride (6.2 mg, 0.01 mmol, 5 mol%), and silver tetrafluoroborate (1.9 m g, 0.01 mmol, 5 mol%). The vessel was capped with a septum and then taken out of the glovebox where it was immediately placed under dry nitrogen atmosphere. 0.5 mL of THF was added to the tube and the mixture was left to stir ~10 mins to activate the com plex. After this time a solution of alkyne (0.2 mmol in 0.5 mL of THF) was transferred to the active gold complex at r.t. During this time 0.3 mL of acetone (previ ously distilled and degassed via freeze pump thaw) was added to a mixture of [CpRu(MeCN) 3 ]P F 6 (4.4 mg, 0.01 mmol, 5 mol%) and quinaldic acid (1.7 mg, 0.01 mmol, 5 mol%). The ruthenium solution was left to stir at r.t. for 30 mins. to form the active complex. After the gold reaction shows full conversion by TLC the solution

PAGE 154

154 was filtered over a p lug of florisil with EtOAc. The crude reaction was then evaporated, and the crude enol was then transferred to a solution of the active ruthenium complex wit h 0.3 mL of acet one (previously distilled and deoxygenated via freeze pump thaw) and 0.6 mL of THF (distilled over Na, benzophenone). The ruthenium solution is left to stir at r.t. until TLC shows full conversion of enol ether to the product. The crude mixture is then filtered over a plug of florisil with EtOAc, evaporated and purified via flash colum n chromatography. 8 (4 nitrophenyl)oct 1 en 7 yn 3 ol (3 92 a): A flask containing bis(triphenylphosphine) palladium(II) dichloride (37.1 mg, 0.05 mmol, 1.5 mol%) and copper (I) iodide (17.6 mg, 3 mol%), and 1 iodo 4 nitrobenzene (279.1 mg, 1.1 mmol, 1.1 eq.) was evacuated and backfilled three times with dry nitrogen. The solids were dissolved in 5.0 mL of CH 3 CN and oct 1 en 7 yn 3 ol 110 (134 .0 mg, 1.07, 1.0 eq) was added neat to the flask. Et 3 N (0.5 mL, 3.6 mmol, 3.6 eq.) was added portionwise to the so lution at room temperature. The solution was left to stir at room temperature for 1 hour after which time the solvents were removed under vacuum. Purified by flash chromatography using a solvent gradient (15 35% EtOAc/hexanes) to yield the product as a cl ear, slightly yellow oil (221.4 mg, 84%). R f = 0.40 (30% EtOAc/hexanes). IR (neat) 3404, 3079, 2935, 2226, 1593, 1514, 1339 852, 734 cm 1 1 H NMR (300 MHz, CDCl 3 ): 8.16 (m, 2H), 7.51 (m, 2H), 5.90 (ddd, J = 6.0, 10.2, 16.8 Hz, 1H), 5.13 5.29

PAGE 155

155 (m, 2H), 4.18 (m, 1H), 2.50 (m, 2H) 1.66 1.79 (m, 4H). 13 C NMR (75 MHz, CDCl 3 ): 159.0, 143.8, 137.7, 128.2, 123.8, 116.3, 79.1, 30.0, 30.0, 21.0. 8 phenyloct 1 en 7 yn 3 ol (3 92 b): The following compound was made under standard sonogashira coupling condition s with oct 1 en 7 yn 3 ol 110 (250.0 mg, 2.0 mmol, 1.0 eq.) and iodobenzene (0.33 mL, 2.9 mmol, 1.4 eq.) PPh 3 PdCl 2 (14.0 mg, 0.05 mmol, 1 mol%), CuI (7.6 mg, 0.04 mmol, 2 mol%) and CH 3 CN (5 mL) under a N 2 atmosphere, was added Et 3 N (0.5 mL) at room tempera ture. The solution was stirred overnight at room temperature then the volatiles were evaporated and the solid residue was purified by flash chromatography using a solvent gradient (0 20% EtOAc/hexanes) to yield the product as a clear, colorless oil (501.0 mg, 83%). R f = 0.40 (20% EtOAc/hexanes). IR (neat) 3369, 3080, 2933, 2869, 1598, 1490, 1442, 1429, 1330 cm 1 1 7.40 (m, 2H), 7.25 7.30 (m, 3H), 5.90 (m, 1H), 5.25 (dt, J = 1.5, 17.1 Hz, 1H), 5.13 (dd, J = 1.2, 10.5 Hz, 1H), 4.17 (m, 1H), 2.46 (m, 2H), 1.66 1.75 (m, 4H). 13 115 .1, 90.0, 81.2, 73.0, 36.3, 24.8, 19.5; HRMS (ESI) Calcd for C 20 H 31 O (M+H) + 201.1274, found 210.1277.

PAGE 156

156 8 (4 methoxyphenyl)oct 1 en 7 yn 3 ol (3 92c ): The following compound was made under standard sonogashira coupling conditions with oct 1 en 7 yn 3 ol 1 1 0 (250.0 mg, 2.0 mmol, 1.0 eq.) and iodobenzene (0.33 mL, 2.9 mmol, 1.4 eq.) PPh 3 PdCl 2 (14.0 mg, 0.05 mmol, 1 mol%), CuI (7.6 mg, 0.04 mmol, 2 mol%) and CH 3 CN (5 mL) under a N 2 atmosphere, was added Et 3 N (0.5 mL) at room temperature. The solution was stirr ed overnight at room temperature then the volatiles were evaporated and the solid residue was purified by flash chromatography using a solvent gradient (0 20% EtOAc/hexanes) to yield the product as a clear, colorless oil (228.0 mg, 90%). R f = 0.40 (20% Et OAc/hexanes). IR (neat): 3377, 2935, 2886, 2838, 1607, 1509, 1246, 1033 cm 1 1 H NMR (500 MHz, CDCl 3 ): 7.32 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 5.89 (ddd, J = 17.3, 10.4, 6.2 Hz, 1H), 5.24 (dt, J = 17.2, 1.4 Hz, 1H), 5.12 (dt, J = 10.4, 1.3 Hz, 1H), 4.17 (qt, J = 6.0, 1.3 Hz, 1H), 3.79 (s, 3H), 2.46 2.40 (m, 2H), 1.76 1.61 (m, 4H). 13 C NMR (125 MHz, CDCl 3 ): 159.2, 141.2, 133.1, 116.3, 115.0, 114.0, 88.4, 80.9, 73.0, 55.4, 36.3, 24.9, 19.5.

PAGE 157

157 1 ((3 phenylprop 2 yn 1 yl)oxy)but 3 en 2 ol (3 9 2d ) : The following compound was made under standard sonogashira coupling conditions with 1 (prop 2 yn 1 yloxy)but 3 en 2 ol 110 (252 .0 mg, 2.0 mmol, 1.0 eq.) and iodobenzene (0.33 mL, 2.9 mmol, 1.4 eq.) PPh 3 PdCl 2 (14.0 mg, 0.05 mmol, 1 mol%), CuI (7.6 mg, 0.04 mmol, 2 mol%) and CH 3 CN (5 mL) under a N 2 atmosphere, was added Et 3 N (0.5 mL) at room temperature. The solution was stirred overnight at room temperature then the volatiles were evaporated and the solid residue was purified by flash chromatography us ing a solvent gradient (0 20% EtOAc/hexanes) to yield the product as a clear, colorless oil (501.0 mg, 83%). R f = 0.61 (30% EtOAc/hexanes). IR (neat) 3405 3062, 2911, 2224, 1599, 1490, 1070 cm 1 1 H NMR (300 MHz, CDCl 3 ): 7.49 7.41 (m, 2H), 7.35 7.28 ( m, 3H), 5.87 (dddd, J = 17.3, 10.6, 5.6, 0.6 Hz, 1H), 5.39 (dtd, J = 17.3, 1.5, 0.6 Hz, 1H), 5.22 (dtd, J = 10.6, 1.5, 0.6 Hz, 1H), 4.44 (dd, J = 2.4, 0.6 Hz, 2H), 4.42 4.36 (m, 1H), 3.70 (ddd, J = 9.6, 3.3, 0.6 Hz, 1H), 3.50 (ddd, J = 9.6, 7.8, 0.6 Hz, 1H ), 2.47 (br s, 1H). 13 C NMR (75 MHz, CDCl 3 ): 136.6, 132.0, 128.7, 128.5, 122.6, 116.8, 86.9, 84.8, 74.0, 71.6, 59.5. 8 (thio phen 2 yl)oct 1 en 7 yn 3 ol (3 92e ): The following compound was made under standard sonogashira coupling conditions with oct 1 en 7 yn 3 ol 1 10 (206.4 mg, 1.6 mmol, 1.0 eq.) and 2 iodothiophene (0.19 mL, 1.8 mmol, 1.1 eq.) PPh 3 PdCl 2 (17.7 mg, 0.02 mmol, 1.5 mol%), CuI (10.0 mg, 0.05 mmol, 3 mol%) and CH 3 CN (5 mL) under a N 2 atmosphere, was added Et 3 N (0.5 mL) at room temperature. The solution

PAGE 158

158 was stirred overnight at room temperature then the volatiles were evaporated and the solid residue was purified by flash chromatography using a solvent gradient (0 15% EtOAc/hexanes) to yield the product as a clear, colorless oil (297.0 mg, 87 %). R f = 0.40 (20% EtOAc/hexanes). IR (neat) 3334, 3076, 2931, 2865, 2226, 1643, 1518, 1427, 1190, 989, 922 cm 1 1 H N MR (300 MHz, CDCl 3 ): 7.16 (dd, J = 5.2, 1.1 Hz, 1H), 7.11 (dd, J = 3.6, 1.1 Hz, 1H), 6.93 (dd, J = 5.2, 3.6 Hz, 1H), 5.88 (ddd, J = 16. 9, 10.4, 6.2 Hz, 1H), 5.24 (dt, J = 17.2, 1.4 Hz, 1H), 5.13 (dt, J = 10.4, 1.3 Hz, 1H), 4.15 (d, J = 5.9 Hz, 1H), 2.46 (td, J = 6.6, 3.3 Hz, 2H), 1.80 1.61 (m, 4H). 13 C NMR (125 MHz, CDCl 3 ) : 141.2, 131.2, 126.9, 126.1, 124.2, 115.1, 94.1, 74.3, 73.0, 36. 2, 24.6, 19.8. tert butyl (2 (6 hydroxyoct 7 en 1 yn 1 yl)phenyl)carbamate ( 3 92h ): The following compound was made under standard sonogashira coupling conditions with oct 1 en 7 yn 3 ol 1 10 ( 100.0 mg, 0.81 mmol, 1.0 eq.) and N Boc 2 iodoaniline (299 mg, 0.93 mmol, 1.1 eq.) PPh 3 PdCl 2 (7.0 mg, 0.01 mmol, 1 mol%), CuI(3.0 mg, 0.02 mmol, 2 mol%) and CH 3 CN (5 mL) under a N 2 atmosphere, was added Et 3 N (0.5 mL) at room temperature The solution was stirred overnight at room temperature then the volatiles were e vaporated and the solid residue was purified by flash column chromatography using a solvent gradient (0 40% EtOAc/hexanes) to yield the product as a viscous oil (135 mg, 50%). R f = 0.71 (CH 2 Cl 2 ). IR (neat) 2971, 2943,1768, 1715, 1604, 1508, 1390, 1252 cm 1 1 H NMR (300 MHz, CDCl 3 ): 8.09 (d, J = 8.4 Hz, 1H), 7.36 7.18 (m, 2H), 6.92 (td, J = 7.6, 1.2 Hz, 1H), 5.90 (ddd, J = 17.3, 10.4, 6.1 Hz, 1H), 5.26 (dt, J = 17.2,

PAGE 159

159 1.4 Hz, 1H), 5.13 (dt, J = 10.4, 1.4 Hz, 1H), 4.19 (d, J = 5.8 Hz, 1H), 2.59 2.50 (m, 2H) 1.82 1.65 (m, 4H), 1.54 (s, 9H). 13 C NMR (75 MHz, CDCl 3 ): 152.7, 141.2, 139.6, 131.8, 129.0, 122.2, 117.6, 115.1, 112.0, 97.1, 81.0, 76.6, 72.9, 36.2, 28.5, 24.7, 19.7. 8 (2 nitrophenyl)oct 1 en 7 yn 3 ol (3 92i): The following compound was made under standard sonogashira coupling conditions with oct 1 en 7 yn 3 ol 1 10 (10 0.0 mg, 0.81 mmol, 1.0 eq.), 1 bromo 2 nitrobenzene (202.0 mg, 1.0 mmol, 1.0 eq.) PPh 3 PdCl 2 (40.0 mg, 0.05 mmol, 5 mol%), CuI (18.0 mg, 0.09 mmol, 9 mol%) and Et 3 N (2.0 mL) under a N 2 atmosphere at room temperature. The solution was stirred overnight at room temperature then the volatiles were evaporated and the solid residue was purified by flash column chromatograph y using a solvent gradient (30 % EtOAc/hexanes) to yield the product a s a viscous oil (96.4 mg, 40 %). R f = 0.31 (30% EtOAc /hexanes). IR 3379, 3078, 2937, 2865, 2228, 1608, 1567, 1520, 1341, 743. 1 H NMR (300 MHz, CDCl 3 ): 7.96 (dd, J = 8.2, 1.3 Hz, 1H), 7.59 7.47 (m, 2H), 7.39 (ddd, J = 8.7, 7.2, 1.8 Hz, 1H), 5.90 (ddd, J = 17.1, 10.4, 6.1 Hz, 1H), 5.25 (dt, J = 17.2, 1.4 Hz, 1H), 5.12 (dt, J = 10.4, 1.4 Hz, 1H), 4.30 4.11 (m, 1H), 2.63 2.47 (m, 2H), 1.91 1.64 (m, 4 H). 13 C NMR (75 MHz, CDCl 3 ) : 141.2, 134.9, 132.7, 128.1, 124.6, 119.4, 115.0, 99.0, 82.1, 76.5, 72.9, 36.1, 24 .3, 19.9

PAGE 160

160 ( Z ) 2 (4 nitrobenzylidene) 6 vinyltetrahydro 2 H pyran (3 93 a) : A test tube with septum containing a stir bar, 1,3 bis(2,6 diisopropylphenyl imidazol 2 ylidene)gold(I) chloride (6.4 mg, 0.01 mmol, 5 mol%), and silver tetrafluoroborate (2.0 mg, 0 .01 mmol, 5 mol%) was taken from the glove box and placed directly under dry nitrogen. A small portion of THF (0.3 mL) was added and the mixture was left to stir at room temperature for 5 minutes after which time a solution of the allylic alcohol 3 92 a (4 9.0 mg, 0.2 mmol) in THF (0.7 mL) was added to the catalyst mixture all at once at room temperature. The reaction was left to stir at this temperature for 1.5 h and filtered through a short plug of silica with CH 2 Cl 2 then placed under vacuum to remove the solvents. The crude product was verified by NMR data. 1 H NMR (300 MHz, CDCl 3 ): 8.12 (m, 2H), 7.71(m, 2H), 5.98 (ddd, J = 5.4, 10.8, 17.4, 1H), 5.43 (s, 1H), 5.38 (dt, J = 1.2, 17.4 Hz, 1H), 5.25 (dt, J = 1.2, 10.8 Hz, 1H), 4.45 (m, 1H), 2.41 (m, 2H), 1 .62 1.97 (m, 4H). 13 C NMR (75 MHz, CDCl 3 ): 159.0, 143.8, 137.7, 128.2, 123.8, 116.3, 79.1, 30.0, 30.0, 21.0. ( Z ) 2 benzylidene 6 vinyltetrahydro 2 H pyran (3 93b). 84 A test tube with septum containing a stir bar, 1,3 bis(2,6 diisopropylphenyl imidazol 2 ylidene)gold(I)

PAGE 161

161 chloride (6.4 mg, 0.01 mmol, 5 mol%), and silver tetrafluoroborate (2.0 mg, 0.01 mmol, 5 mol%) was taken from the glove box and placed directly under dry nitrogen. A small portion of THF (0.3 mL) was added and the mixture was left to stir at room temperature for 5 minutes after which time a solution of the allylic alcohol 3 92 b (40.0 mg, 0.2 mmol) in THF (0.7 mL) was added to the catalyst mixture all at once at room temperature. The reaction was left to stir at this temperature for 30 min utes and filtered through a short plug of silica with CH 2 Cl 2 then placed under vacuum to remove the solvents. The crude product was verified by NMR data. 1 H NMR (300 MHz, CDCl 3 ): 7.59 (m, 2H), 7.23 7.28 (m, 2H), 7.11 (m, 1H), 5.98 (ddd, J = 5.4, 11.1, 17.4 Hz, 1H), 5.39 (s, 1H enol proton), 5.38 (dt, J = 1.2, 17.4 Hz, 1H), 5.21 (dt, J = 1.2, 11.1 Hz, 1H), 4.31 (m, 1H), 2.34 (m, 2H), 1.84 1.92 (m, 2H), 1.61 Z vinyl ether geometry can be confirmed by comparison to the known E Z vinyl ether mixture. 84 Note that the E enol is much farther upfield at 6.05 ppm, and no trace of this stereoisome r was found. ( Z ) 2 ben zylidene 6 vinyl 1,4 dioxane (3 93d ) : A test tube with septum containing a stir bar, triphenylphosphine gold(I) c hloride (5.1 mg, 0.01 mmol, 5 mol%), and silver trifluoromethanesulfonate (2.5 mg, 0.01 mmol, 5 mol%) was taken from the glove box and placed directly under dry nitrogen. A small portion of THF (0.3 mL) was added and the mixture was left to stir at room t emperature for 5 minutes after which time a solution of the allylic alcohol 3 92d (40.4 mg, 0.2 mmol) in THF (0.7 mL) was added to the catalyst all at once at room temperature. The reaction was left to stir at this

PAGE 162

162 temperature for 1.5 h and filtered throug h a short plug of silica with CH 2 Cl 2 then placed under vacuum to remove the solvents. The crude product was verified by NMR data as 11 : 1 H NMR (500 MHz, CDCl 3 ): 7.66 7.62 (m, 1H), 7.34 7.30 (m, 2H), 7.22 7.18 (m, 1H), 5.96 5.89 (m, 1H), 5.55 5.50 (m, 1 H), 5.50 (s, 1H), 5.36 (ddt, J = 10.7, 2.4, 1.3 Hz, 1H), 4.60 4.55 (m, 1H), 4.23 (s, 2H), 3.95 (ddd, J = 11.8, 3.2, 1.6 Hz, 1H), 3.65 3.60 (m, 1H). 6 (4 nitrobenzyl) 2 vinyl 3,4 dihydro 2 H pyran (3 94 a) : A test tube with septum containing a stir bar, tr iphenylphosphine gold(I) chloride (5.1 mg, 0.01 mmol, 5 mol%), and silver trifluoromethanesulfonate (2.5 mg, 0.01 mmol, 5 mol%) was taken from the glove box and placed directly under dry nitrogen. A small portion of CH 2 Cl 2 (0.3 mL) was added and the mixtu re was left to stir at room temperature for 5 minutes after which time a solution of the allylic alcohol 3 92 a (49.0 mg, 0.2 mmol) in CH 2 Cl 2 (0.7 mL) was added to the catalyst all at once at room temperature. The reaction was left to stir at this temperatu re for 1.5 h and filtered through a short plug of silica with CH 2 Cl 2 then placed under vacuum to remove the solvents. The crude product was verified by NMR data predominately 3 94 a: 1 H NMR (300 MHz, CDCl 3 ): 8.12 (m, 2H), 7.43 (m, 2H), 5.85 (ddd, J = 5. 4, 10.8, 17.1 Hz, 1H), 5.38 (dt, J = 1.2, 17.1 Hz, 1H), 5.25 (dt, J = 1.2, 10.8 Hz, 1H), 4.58 (t, J = 3.6 Hz, 1H), 4.31 (m, 1H), 3.42 (s, 2H) 1.97 2.14 (m, 2H), 1.83 1.92 (m, 1H), 1.52 1.67 (m, 1H).

PAGE 163

163 6 benzyl 2 vinyl 3,4 dihydro 2 H pyran ( 3 94 b): A test t ube with septum containing a stir bar, triphenylphosphine gold(I) chloride (5.1 mg, 0.01 mmol, 5 mol%), and silver trifluoromethanesulfonate (2.5 mg, 0.01 mmol, 5 mol%) was taken from the glove box and placed directly under dry nitrogen. A small portion o f CH 2 Cl 2 (0.3 mL) was added and the mixture was left to stir at room temperature for 5 minutes after which time a solution of the allylic alcohol 3 92b (40.0 mg, 0.2 mmol) in CH 2 Cl 2 (0.7 mL) was added to the catalyst all at once at room temperature. The re action was left to stir at this temperature for 1 h and filtered through a short plug of silica with CH 2 Cl 2 then placed under vacuum to remove the solvents. The crude product was verified by NMR data predominately 3 94 b: 1 H NMR (300 MHz, CDCl 3 ): 7.05 7. 39 (m, 7H), 5.90 (ddd, J = 5.4, 10.8, 17.1 1H), 5.21 (dt, J = 1.2, 17.1 Hz, 1H), 5.12 (dt, J = 1.2, 10.8 Hz, 1H), 4.46 (t, J = 3.9 Hz, 1H), 4.33 (m, 1H), 3.32 (s, 2H), 1.53 2.08 (m, 4H). trans 2 (4 nitrophenyl) 3 vinylcyclohexan 1 one (3 99a ): A test tub e containing a stir bar was placed under dry nitrogen with a septum on top. To this vessel was added crude 3 9 3 a ( 49.0 mg, 0.2 mmol) in 1.0 mL of toluene. The solution was heated a reflux overnight and the resulting mixture was purified by flash

PAGE 164

164 chromato graphy with a gradient (2 5% EtOAc/hexanes) affording products 3 99a (25.0 mg, 51% as a white solid) and 3 100 (10.2 mg, R f = 0.37 (30% EtOAc/hexanes). IR (neat) 3080, 2939, 2867, 1712, 1518, 1346 cm 1 1 H NMR (300 MHz, CDCl 3 ): 8.18 (d, J = 8.8 Hz, 1H) 7.22 (d, J = 8.7 Hz, 1H), 5.48 (ddd, J = 16.8, 10.6, 7.9 Hz, 1H), 4.85 4.77 (m, 2H), 3.55 (dd, J = 12.1, 1.0 Hz, 1H), 2.72 (tdd, J = 11.5, 7.9, 3.6 Hz, 1H), 2.62 2.56 (m, 1H), 2.55 2.47 (m, 1H), 2.23 (ddd, J = 12.5, 5.9, 2.9 Hz, 1H), 2.12 2.06 (m, 1H), 1 .94 1.76 (m, 2H). 13 C NMR (75 MHz, CDCl 3 ): 208.0, 145.0, 139.4, 130.7, 123.6, 116.2, 62.7, 50.3, 41.9, 32.2, 25.9. Assignment of relative stereochemistry was accomplished by 2D COSY ( 500 MHz, CDCl 3 ). 2 phenyl 3 vinylcyclohexanone (3 99b ): 91 The foll owing compound was formed during the gold catalyzed cyclization using the optimized conditions using 3 92b (46.0 mg, 0.22 mmol). Purified by flash chromatography (2% EtOAc/hexanes) to give the product as a clear, colorless oil (43.2 mg, 94% as a mixture o f diastereomers (2:1 c is:trans before purification)). IR (neat) 2929, 1710, 1681, 1597, 1448, 1218, 920 cm 1 cis diastereomer : 1 H NMR (300 MHz, CDCl 3 ): 7.38 7.22 (m, 5H), 5.82 (ddd, J = 1.8, 10.8, 16.8 Hz, 1H),5.03 (dt, J = 1.8, 10.8 Hz, 1H), 4.93 (dt J = 1.8, 16.8 Hz, 1H), 3.88 (d, J = 4.8 Hz, 1H cis H H), 3.02 (m,1H), 2.54 (m, 2H) 2.14 1.95 (m, 1H). trans diastereomer : 1 H NMR (300 MHz,CDCl 3 ): 7.29 7.21 (m, 3H), 7.05 (m, 2H), 5.53 (ddd, J = 7.5, 10.5, 17.4 Hz, 1H) 4.87 4.80 (m, 2H), 3.39 (d, J = 11 .7 Hz, 1H trans H H), 2.74

PAGE 165

165 (m, 1H), 2.41 2.59 (m, 2H), 1.71 2.22 (m, 4H). The data for the trans diastereomer satisfactorily matched that of the known compound. 91 trans 2 (4 methoxyphenyl) 3 vinylcyclohexan 1 one (3 99c) : 8 (4 methoxyphenyl)oct 1 en 7 yn 3 ol 3 92c (58.2 mg, 0.25 mmol) was treated with the optimized conditions to give the diastereomeric mixture of 2 (4 methoxyphenyl) 3 vinylcyclohexan 1 one (52.0 mg, 90% as a 2:1 mixture of diastereomers (cis:trans)). An analytical fraction of the cis 2 (4 methoxyphenyl) 3 vinylcyclohexan 1 one was obtained to give the following data: 1 H NMR (500 MHz, CDCl 3 ): 7.19 7.15 (m, 2H), 6.84 6.82 (m, 2H), 5.90 5.74 (m, 1H), 5.04 (ddt, J = 10.4, 1.7, 0.8 Hz, 1H), 4.98 4.89 (m, 1H), 3.86 3.83 (m, 1H), 3.78 (s, 3H), 3.04 2.94 (m, 1H), 2.59 2.53 (m, 1H), 2.51 2.44 (m, 2H), 2.16 2.06 (m, 2H), 2.03 1.93 (m, 2H). For char acterization the diastereomeric mixture of 2 (4 methoxyphenyl) 3 vinylcyclohexan 1 one was then treated with NaOMe R f = 0.48 (20% EtOAc/hexanes). Extracted with EtOAc, dried over sodium sulfate, filtered, and evapora ted to give the crude product. Purified by flash column chromatography using a solvent gradient (0 5% EtOAc/hexanes) to yield the trans product as a clear colorless oil (15.0 mg, 40%). R f = 0.48 (20% EtOAc/hexanes). IR (neat) 3076, 2934, 2864, 1713, 1514 1248 cm 1 1 H NMR (500 MHz, CDCl 3 ): 6.97 (d, J = 8.7 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 5.58 5.50 (m, 1H), 4.89 4.80 (m, 2H), 3.79 (s, 3H), 3.36 (d, 1H), 2.74 2.64 (m, 1H), 2.56 (ddd, J = 4.4, 3.0, 1.7 Hz, 1H), 2.54 (td, J = 3.0, 1.5 Hz, 1H), 2.46 (tdd J = 13.6, 6.0, 1.1 Hz, 1H),

PAGE 166

166 2.21 2.15 (m, 1H), 2.09 2.03 (m, 1H), 1.91 1.73 (m, 2H). 13 C NMR (125 MHz, CDCl 3 ): 209.8, 158.6, 140.6, 130.6, 129.3, 115.1, 113.9, 62.2, 55.4, 49.7, 42.1, 32.2, 26.0. trans 4 phenyl 5 vinyldihydro 2 H pyran 3(4 H ) one (3 9 9d ) : 1 ((3 phenylprop 2 yn 1 yl)oxy)but 3 en 2 ol 3 92d (40.4 mg, 0.20 mmol) was treated with the optimized conditions to give the diastereomeric mixture of predominately the cis 4 phenyl 5 vinyldihydro 2 H pyran 3(4 H ) one (10:1 dr; cis:trans). During pur ification using flash column chromatography with silica gel the mixture epimerized to give predominately the trans isomer of 3 99d Assignment of relative stereochemistry was accomplished by 2D COSY ( 500 MHz, CDCl 3 ). R f = 0.48 (25% EtOAc/hexanes). IR (nea t) 3062, 2927, 1719, 1679, 1597, 1449, 1123, 1016, 753 cm 1 1 H NMR (500 MHz, CDCl 3 ): 7.36 7.32 (m, 2H), 7.30 7.27 (m, 1H), 7.11 7.08 (m, 2H), 5.54 (ddd, J = 17.2, 10.5, 7.8 Hz, 1H), 4.99 (dt, J = 10.5, 1.0 Hz, 1H), 4.94 (dt, J = 17.2, 1.1 Hz, 1H), 4.23 (dd, J = 15.7, 1.0 Hz, 1H), 4.16 4.12 (m, 1H), 4.10 (dd, J = 15.8, 0.7 Hz, 1H), 3.76 (dd, J = 11.8, 10.1 Hz, 1H), 3.53 (d, J = 11.4 Hz, 1H), 3.17 3.09 (m, 1H). 13 C NMR (125 MHz, CDCl 3 ): 205.9, 135.9, 135.3, 129.6, 128.7, 127.6, 118.2, 74.9, 71.2, 60.2, 48.0. trans 2 (thiophen 2 yl) 3 vinylcyclohexan 1 one (3 99e ) : 8 (thiophen 2 yl)oct 1 en 7 yn 3 ol 3 92e (40.0 mg, 0.2 mmol) was treated with the optimized conditions to

PAGE 167

167 give the diastereomeric mixture of 2 (thiophen 2 yl) 3 vinylcyclohexan 1 one (37.4 m g, 92% as a 2:1 mixture of diastereomers (cis:trans)). 1 H NMR (300 MHz, CDCl 3 ): 7.24 (ddd, J = 5.1, 1.2, 0.6 Hz, 1H), 7.22 (s, 1H), 6.98 6.93 (m, 4H), 6.77 (ddt, J = 3.5, 1.2, 0.6 Hz, 1H), 5.78 5.56 (m, 2H), 5.07 4.88 (m, 5H), 4.17 (dd, J = 5.1, 0.9 Hz, 1H), 3.77 (d, J = 11.0 Hz, 1H), 3.09 2.98 (m, 2H), 2.73 2.59 (m, 3H), 2.58 2.54 (m, 1H), 2.51 2.38 (m, 3H), 2.22 2.01 (m, 7H), 1.97 1.85 (m, 2H), 1.85 1.67 (m, 2H). For characterization the diastereomeric mixture of 2 (thiophen 2 yl) 3 vinylcyclohexan 1 one (37.0 mg, 0.18 stir overnight then quenched with 5.0 mL of NH 4 Cl (sat. in water) at 0 C. Extracted with EtOAc, dried over sodium sulfate, filtered, and evaporated to g ive the crude product. Purified by flash column chromatography using a solvent gradient (0 5% EtOAc/hexanes) to yield the product as a clear colorless oil (33.3 mg, 90%). R f = 0.36 (15% EtOAc/hexanes). IR (neat): 3076, 2934, 2864, 1713, 1613, 1514, 1248 cm 1 1 H NMR (500 MHz, CDCl 3 ): 7.24 (ddd, J = 5.1, 1.2, 0.5 Hz, 1H), 6.96 (dd, J = 5.1, 3.5 Hz, 1H), 6.77 (ddd, J = 3.5, 1.2, 0.6 Hz, 1H), 5.63 (ddd, J = 17.1, 10.4, 7.5 Hz, 1H), 4.97 4.89 (m, 2H), 3.77 (d, J = 11.1 Hz, 1H), 2.73 2.64 (m, 1H), 2.58 (ddd d, J = 13.7, 4.4, 3.7, 1.7 Hz, 1H), 2.45 (dddd, J = 13.7, 12.7, 5.9, 1.1 Hz, 1H), 2.16 (dddd, J = 12.7, 6.9, 5.8, 3.7 Hz, 1H), 2.11 2.03 (m, 1H), 1.90 1.71 (m, 2H). 13 C NMR (126 MHz, CDCl 3 ) 208.2, 140.1, 139.6, 126.6, 126.5, 124.9, 115.6, 57.5, 50.9, 41. 6, 31.9, 25.7.

PAGE 168

168 ( Z ) 2 (4 nitrophenyl)cyclooct 4 en 1 one (3 100 ): A test tube containing a stir bar was placed under dry nitrogen with a septum on top. To this vessel was added crude 3 93a (49.0 mg, 0.2 mmol) in 1.0 mL of toluene. The solution was heat ed a reflux overnight and the resulting mixture was purified by flash chromatography with a gradient (2 5% EtOAc/hexanes) affording products 3 99a (25.0 mg, 51% as a white solid) and 3 100 (10.2 mg, 23% as a clear colorless oil) respectively. The followin g was data obtained for compound 3 100 : IR (neat) 3079, 2939, 2867, 1712, 1600, 1518, 1346, 1170 cm 1 1 H NMR (300 MHz, CDCl 3 ): 8.21 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 9.0 Hz, 2H), 5.92 5.76 (m, 2H), 3.92 (dd, J = 11.3, 4.1 Hz, 1H), 3.01 (ddd, J = 13.0, 11.2, 8.1 Hz, 1H), 2.65 2.46 (m, 2H), 2.38 2.18 (m, 3H), 1.86 1.76 (m, 1H), 1.70 1.58 (m, 1H). 13 C NMR (75 MHz, CDCl 3 ): 189.2, 157.8, 145.1, 132.7, 129.0, 128.3, 124.0, 62.1, 39.4, 27.7, 26.8, 25.3. tert butyl 2 (3 hydroxypent 4 en 1 yl) 1 H indole 1 ca rboxylate ( 3 104 ): The following compound was formed during the gold catalyzed cyclization using the optimized conditions using 3 92h (68.0 mg, 0.2 mmol). Purified by flash column chromatography using a solvent gradient (0 20% EtOAc/hexanes) to yield the product as a off white solid (60.0 mg, 92%). R f = 0.66 (20% EtOAc/hexanes). IR (neat) 3386, 3071, 3056, 2978, 2933, 2872, 1731, 1455, 1370, 1329, 1158 cm 1 1 H NMR (500 MHz, CDCl 3 ): 8.11 8.04 (m, 1H), 7.46 7.41 (m, 1H), 7.24 7.15 (m, 2H), 6.36 (apq, J = 0.9 Hz, 1H), 5.88 (ddd, J = 17.2, 10.4, 6.1 Hz, 1H), 5.24 (dt, J = 17.2, 1.4 Hz, 1H), 5.11 (dt,

PAGE 169

169 J = 10.4, 1.3 Hz, 1H), 4.22 4.14 (m, 1H), 3.11 2.95 (m, 2H), 1.87 1.74 (m, 3H), 1.62 1.72 (m, 12H). 13 C NMR (125 MHz, CDCl 3 ): 150.8, 142.2, 141.3, 136.8, 1 29.5, 123.4, 122.8,119.9, 115.8, 114.9, 107.5, 84.0, 73.0, 36.8, 30.0, 28.5, 25.0. 1 (benzo[ c ]isoxazol 3 yl) 5 hydroxyhept 6 en 1 one (3 105 ): The following compound was formed during the gold catalyzed cyclization using the optimized conditions using 3 92i (68.0 mg, 0.2 mmol). Purified by flash column chromatography using a solvent gradient (0 20% EtOAc/hexanes) to yield the product as a off white solid (60.0 mg, 92%). IR (neat) 3426, 3072, 2925, 2365, 2337, 1683, 1558 cm 1 1 H NMR (500 MHz, CDCl 3 ): 8.09 8.01 (m, 1H), 7.77 7.70 (m, 1H), 7.46 7.37 (m, 1H), 7.32 7.22 (m, 1H), 5.97 5.82 (m, 1H), 5.26 (dt, J = 17.2, 1.3 Hz, 1H), 5.14 (dt, J = 10.4, 1.3 Hz, 1H), 4.26 4.15 (m, 1H), 3.24 (t, J = 7.2 Hz, 2H), 2.03 1.81 (m, J = 6.4 Hz, 2H), 1.74 1.52 (m, 2 H). 13 C NMR (125 MHz, CDCl 3 ) 190.2, 159.8, 157.7, 141.0, 131.5, 128.7, 121.4, 119.4, 116.1 11 5.2, 73.0, 40.0, 36.4, 19.5.

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179 BIOGRAPHICAL SKETCH John Michael Ketcham was born in Ocala, Florida on July 23 rd 1984 to the proud parents of Huey L. Ketcham and Vicki J. Ketcham. The youngest of three sons, he has spent most of his life in the central Florida area enjoying the outdoors. After graduating from Forest High School in 2002, he attended the Univ ersity of Central Florida (UCF) w here he studied Organic Chemistry under the direction of Professor Seth Elsheimer. During his time at UCF, a collaboration between Professor Clovis A. Linkous at the Florida Solar Energy Cente r (FSEC) and Prof. Elsheimer le d him to study the synthesis of a superacid substituted PEEK (polyether ether ketone) monomer for eventual use in proton exchange membranes (PEMs). In 2007, John received his bachelor of science in Chemistry from UCF and moved to the University of Florida to pursue a doctoral degree in Organic Chemistry. Since moving to UF, he has been working under the supervision of Professor Aaron Aponick in the field of gold catalysis. During his doctoral pursuit his projects were focused on the utilization of allylic alcohols as both ele ctroph ile s and nucleophiles in gold catalyzed reactions After obtaining his d octoral degree in the summer of 2013 he started a postdoctoral position at the University of Texas at Austin working under the direction of Professor Michael J. Krische.