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Gold-Catalyzed Cyclizations of Mono-Allylic Diols and Ethers

Permanent Link: http://ufdc.ufl.edu/UFE0043659/00001

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Title: Gold-Catalyzed Cyclizations of Mono-Allylic Diols and Ethers
Physical Description: 1 online resource (189 p.)
Language: english
Creator: Biannic, Berenger
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2011

Subjects

Subjects / Keywords: alcohols -- allylic -- catalysis -- chromene -- gold -- heterocycles -- tetrahydropyran
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Over the past decade, gold catalysis has emerged as an important methodology for the construction of complex organic structures. Its capability to form C C and C X bonds by activation of p systems under mild conditions makes it a valuable asset for the synthetic community. The work presented in this thesis is aimed at expanding the p activation to allylic alcohols in order to synthesize oxygen heterocycles from readily accessible mono allylic diols. Saturated oxygen heterocycles are found in numerous biologically active natural products, and my thesis work has focused on developing a mild and general method for the preparation of substituted chiral 2-vinyltetrahydropyrans. The method was expanded to the cyclization of allylic ethers and the relative rate of reaction was studied for different protecting groups on the allylic moiety. This thesis also documents the synthesis of substituted 2H-chromenes via gold catalyzed cyclization of o-(1-hydroxyallyl)-phenols obtained from inexpensive and readily available salicylaldehydes. The products are obtained in good to excellent yields and the substrate scope of this reaction is quite broad. As such, a diverse range of products with varied substitution patterns and differing electronics in the aromatic ring is readily available. This method gives direct access to substituted 2H-chromenes which should be useful for further modification toward the preparation of biologically active molecules.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Berenger Biannic.
Thesis: Thesis (Ph.D.)--University of Florida, 2011.
Local: Adviser: Aponick, Aaron Steven.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2011
System ID: UFE0043659:00001

Permanent Link: http://ufdc.ufl.edu/UFE0043659/00001

Material Information

Title: Gold-Catalyzed Cyclizations of Mono-Allylic Diols and Ethers
Physical Description: 1 online resource (189 p.)
Language: english
Creator: Biannic, Berenger
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2011

Subjects

Subjects / Keywords: alcohols -- allylic -- catalysis -- chromene -- gold -- heterocycles -- tetrahydropyran
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Over the past decade, gold catalysis has emerged as an important methodology for the construction of complex organic structures. Its capability to form C C and C X bonds by activation of p systems under mild conditions makes it a valuable asset for the synthetic community. The work presented in this thesis is aimed at expanding the p activation to allylic alcohols in order to synthesize oxygen heterocycles from readily accessible mono allylic diols. Saturated oxygen heterocycles are found in numerous biologically active natural products, and my thesis work has focused on developing a mild and general method for the preparation of substituted chiral 2-vinyltetrahydropyrans. The method was expanded to the cyclization of allylic ethers and the relative rate of reaction was studied for different protecting groups on the allylic moiety. This thesis also documents the synthesis of substituted 2H-chromenes via gold catalyzed cyclization of o-(1-hydroxyallyl)-phenols obtained from inexpensive and readily available salicylaldehydes. The products are obtained in good to excellent yields and the substrate scope of this reaction is quite broad. As such, a diverse range of products with varied substitution patterns and differing electronics in the aromatic ring is readily available. This method gives direct access to substituted 2H-chromenes which should be useful for further modification toward the preparation of biologically active molecules.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Berenger Biannic.
Thesis: Thesis (Ph.D.)--University of Florida, 2011.
Local: Adviser: Aponick, Aaron Steven.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2011
System ID: UFE0043659:00001


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1 GOLD CATALYZED CYCLIZATIONS OF MONO ALLYLIC DIOLS AND ETHERS By BERENGER BIANNIC 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 2011

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2 2011 Berenger Biannic

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3 To my family

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4 ACKNOWLEDGMENTS I would like to thank my advisor Aaron Aponick for his support and guidance throughout my five years spent at the Univers ity of Florida. He has always been available every time I needed advice in my research, to talk about chemistry in general and to brainstorm to generate new ideas. Dr. Aponick trusted me on exciting projects to investigate and believed in my abilities, I w ill always be thankful to him for that. I would like to thank all my friends I made along those years in Gainesville for their full support and fun time spent outside of the lab. Also, I would like to thank Matthieu Dumont and Romain Stalder with whom I s hared amazing moments around Florida; especially fishing for catfish and grilling random food surrounded by a hostile wildlife in lovely Florida States Parks. Our mutual support and sharing during the course of this program has been very important to me a nd will be missed I would like to thank all the people from the Aponick group for all the fun we had working together and for the good times spend in the lab : Carl, Flavio, Frida, Jean, Jeremy, John, Justin, Lucas, Nick, Pau lo and Romain. I am very grate ful to Mic heal Jong, Barry B. Buttler, Dr. Chuan Ying Li and Thomas Ghebreghiorgis with whom I closely work ed with during the past five years on several projects Working with them has been a productive and enriching experience. I am very thankful to the Hong group members for their help with the HPLC instrument and discussion s we had about chemistry. Sharing Friday group meeting s with them has been very enriching. I would like to thank Yousoon for the support she g ave me during this year and all the enjoy able time we have spen t together.

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5 Lastly, my family has been extremely supportive of my decisions since I decided to follow an academic path. I am very thankful to my parents and my grandparents for their love and patience during th e se past five years.

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6 T ABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 9 LIST OF FIGURES ................................ ................................ ................................ ........ 10 LIST OF ABBREVIATIONS ................................ ................................ ........................... 15 ABSTRACT ................................ ................................ ................................ ................... 19 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .... 21 1.1 General Considerations in Homogeneous Gold Catalysis ............................ 21 1.2 Gold Systems ................................ ........................ 24 1.3 Metal Catalyzed Activation of Unsaturated Alcohols ................................ ..... 28 1.4 Gold Catalyzed [3,3] Sigmatropic Rearrangement ................................ ........ 33 2 GOLD CATALYZED SYNTHESIS OF SUBSTITUTED HEX 5 EN ONES BY CLAISEN REARRANGEMENT ................................ ................................ ............... 36 2.1 Gold Catalyzed Claisen Rearrangements ................................ ..................... 36 2.1.1 Generalities ................................ ................................ ......................... 36 2.1.2 Gold Catalyzed Propargylic and Allenic Claisen Rearrangement ....... 37 2.1.3 Gold Catalyzed Heterocy cle Synthesis through Claisen Rearrangement ................................ ................................ .................. 39 2.1.4 Gold Catalyzed Aromatic Claisen Rearrangement ............................. 40 2.2 Gold Catalyzed Synthes is of Substituted Hex 5 en 2 ones, an Initial Study ................................ ................................ ................................ ............. 41 2.2.1 Initial Considerations ................................ ................................ ........... 41 2.2.2 Results ................................ ................................ ................................ 42 2.3 Outcome ................................ ................................ ................................ ........ 45 3 GOLD CATALYZED CYCLIZATION OF MONO ALLYLIC DIOLS TO FORM 2 VINYL TETRAHYDROPYRANS ................................ ................................ .......... 47 3.1 Background and Significance ................................ ................................ ........ 47 3.1.1 Tetrahydropyrans in Nature ................................ ................................ 47 3.1.2 Transition Metal Catalyzed Synthesis of Tetrahydropyrans ................ 48 3.1.3 Gold Catalyzed Activation of Allylic Alcohols ................................ ...... 52 3.2 Au Catalyzed Synthesis of 2 Vinyltetrahydropyr ans ................................ ..... 53 3.2.1 Initial Study, Optimization and Control Experiments ........................... 53 3.2.2 Substrate Scope ................................ ................................ .................. 56

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7 3.2.3 Diastereoselective Synthesis of 2,6 Disubstituted THPs. ................... 59 3.2.4 Scalable Preparation of 2 Vinyltetrahydropyrans ................................ 60 3.3 Stereoselective Au Catalyzed Synthesis of 2 VinylTHPs .............................. 61 3.3.1 Olefin Dependant Transfer of Chirality ................................ ................ 61 3.3.2 Additional Stereocenters Influence ................................ ...................... 70 3.3.3 Failed Attempts ................................ ................................ ................... 72 3.3.4 Predictive Stereochemical Mnemonic ................................ ................. 74 3.3.5 Proposed Catalytic Cycle ................................ ................................ .... 75 3.4 Au Catalyzed Cyclization of Mono Allylic Ethers to Form 2 Vinyltetrahydropyrans, a Comparative Study ................................ ............. 76 3.4.1 Initial Approach ................................ ................................ ................... 76 3.4.2 Synthetic Aspect ................................ ................................ ................. 78 3.4.3 Val idation of Au Catalyst Quenching Method Using QuadraPure TM .... 79 3.4.4 Comparison of Different Leaving/Protecting Groups ........................... 81 3.4.5 I nfluence of Olefin Geometry and Substituent on the Allyl Moiety ....... 83 3.5 Outcome and Current Work ................................ ................................ .......... 85 4 AU CATALYZED CYCLIZATION OF O (1 HYDROXYALLYL) PHENOLS TO FORM 2 H CHROMENES ................................ ................................ ....................... 88 4.1 Background and Significance ................................ ................................ ........ 88 4.1.1 2 H Chromenes in Biological Active P harmaceuticals .......................... 88 4.1.2 Classical Methods of 2 H Chromenes Synthesis, Scope and Limitations ................................ ................................ .......................... 89 4.1.3 Modern Metal Catalyzed Synth esis of 2 H Chromenes ....................... 92 4.2 Rationale ................................ ................................ ................................ ....... 94 4.3 Optimization of Reaction Conditions ................................ ............................. 95 4.4 Substrate Scope ................................ ................................ ............................ 96 4.5 Substituent Effects on the Allyl Moiety ................................ .......................... 98 4.6 A Convenient Synthesis of Neoflave nes ................................ ..................... 101 4.6.1 Neoflavenes ................................ ................................ ...................... 101 4.6.2 Au Catalyzed Synthesis of Neoflavene ................................ ............. 103 4.7 Mechanistic Considerations and Control Experiments ................................ 104 4.8 Outcome ................................ ................................ ................................ ...... 107 5 CONCLUSION AND OUTLOOK ................................ ................................ ........... 108 6 EXPERIMENTAL SECTION ................................ ................................ ................. 110 6.1 General Remarks ................................ ................................ ........................ 110 6.2 Chemical Procedures ................................ ................................ .................. 111 6.2.1 Synthesis of Substituted 2 Vinyltetrahydropyrans ............................. 111 6.2.2 Gram Scale Preparation of 3 89 ................................ ....................... 119 6.2.3 Representative Procedures for the Preparations of 3 71 3 75 ........ 121 6.2.4 Synthesis of 3 111 and 3 112 ................................ ........................... 130 6.2.5 Synthesis of 3 120 and 3 121 ................................ ........................... 136 6.2.6 Synthesis of 3 129 and 3 131 ................................ ........................... 143

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8 6.2.7 Synthesis of 3 144 an d 3 146 ................................ ........................... 149 6.2.8 Synthesis of 3 154 and 3 156 ................................ ........................... 153 6.2.9 Synthesis of 3 163 and 3 165 ................................ ........................... 159 6.2.10 Synthesis of 3 199 and 3 200 ................................ ........................... 167 6.2.11 Synthesis of 3 206 and 3 208 ................................ ........................... 16 9 6.2.12 Synthesis of 3 207 ................................ ................................ ............ 170 6.2.13 Synthesis of 3 211 and 3 212 ................................ ........................... 171 6.2.14 Determination of Conversion of 3 41. ................................ ................ 173 6.2.15 Determination of Conversion of 3 52. ................................ ................ 174 6.2.16 General Procedures for the Preparation of 2 H Chromenes .............. 175 6.2.17 Caracterization of New 2 H Chromenes. ................................ ............ 176 LIST OF REFERENCES ................................ ................................ ............................. 179 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 189

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9 LIST OF TABLES Table page 1 1 Precious metals price/gram as of August 2011. ................................ ................. 22 2 1 Attempts of cascade Au catalyzed addition of allylic alcohols on alkynes/Claisen rearrangements. ................................ ................................ ....... 43 3 1 Optimization and control experiment. ................................ ................................ 56 3 2 Au catalyzed transfer of chirality. ................................ ................................ ........ 65 4 1 Optimization and control experiment. ................................ ................................ 96 4 2 Reaction scope. ................................ ................................ ................................ .. 98

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10 LIST OF FIGURES Figure page 1 1 Gold(I) salts commonly used in homogeneous catalysis. ................................ ... 22 1 2 Gold and relativistic eff ect. ................................ ................................ ................. 23 1 3 system activation by gold(I). ................................ ................................ ........... 24 1 4 Selected examples of gold catalyzed activation of alkynes. ............................... 25 1 5 Au catalyzed alkoxylation of alkyne applied to the total synthesis of Bryostatin 16. ................................ ................................ ................................ ...... 25 1 6 Selected examples of gold catalyzed activation of allenes. ................................ 26 1 7 Selec ted examples of enantioselective addition on allenes. ............................... 27 1 8 Selected examples of gold catalyzed activation of alkenes. ............................... 28 1 9 Selecte d examples of Pd, Ru and Pt catalyzed activation of allylic alcohols. ..... 29 1 10 Selected recent examples of metal catalyzed activation of propargyl alcohols. 31 1 11 Mechanism of metal catalyzed nucleophilic substitutions on benzylic alcohols. ................................ ................................ ................................ ............. 31 1 12 Selected examples of metal catalyzed activation of benzylic alcohols. .............. 32 1 13 Selected examples of metal catalyzed arylation of benzyl alcohols. .................. 32 1 14 [3,3] sigmatropic rearrangement. ................................ ................................ ........ 33 1 15 Types of [3,3] sigmatropic rearrangement. ................................ ......................... 34 1 16 Selected examples of Au catalyzed [3,3] sigmatropic rearrangements. ............. 35 2 1 Different types of Claisen rearrangement. ................................ .......................... 36 2 2 Gold catalyzed propargylic and allenic Claisen rearrangement. ......................... 38 2 3 Detailed mechanism of Au catalyzed propargyl Claisen rearrangement. ........... 38 2 4 Au catalyzed Claisen rearrangement applied to the total synthesis of Azadirachtin. ................................ ................................ ................................ ....... 38 2 5 Au catalyzed cascade synthesis of 5 membered heterocycles. ......................... 39

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11 2 6 Au catalyzed aromatic Claisen rearrangement. ................................ .................. 40 2 7 Au catalyzed cascade activation of alkyne/Claisen rearrangement. ................... 41 2 8 Detailed proposed mechanism. ................................ ................................ .......... 42 2 9 Gold catalyzed reactions with crotyl alcohol and phenylacetylene. .................... 43 2 1 0 Gold catalyzed cascade addition on alkynes/Claisen rearrangement using diphenylacetylene. ................................ ................................ .............................. 45 2 11 Au catalyzed activation of allylic alcohols. ................................ .......................... 46 2 12 Au catalyzed alkoxylation of allylic alcohols. ................................ ...................... 46 3 1 S elected examples of natural molecules containing tetrahydrofuran motifs. ...... 47 3 2 Metal catalyzed cyclization of alkenol. ................................ ................................ 49 3 3 Metal catalyzed hydroalkoxylation/cyclization of unactivated alkenes. ............... 49 3 4 Metal catalyzed activation of allylic alcohols. ................................ ...................... 50 3 5 Selected examples of metal catalyzed cyclization of mono allylic diols. ............. 51 3 6 Enantioselective gold catalyzed hydroalkoxylation of allenes. ........................... 52 3 7 Gold(III) catalyzed activation of allylic alcohols. ................................ ................. 52 3 8 Selected examples of Au(III) catalyzed activation of activated allylic alcohols. .. 53 3 9 Synthesis of 3 41 ................................ ................................ ............................... 54 3 1 0 Synthesis of 3 45 ................................ ................................ ............................... 54 3 11 Synthesis of 2 vinylTHPs 3 50 and 3 52 ................................ ........................... 55 3 12 A u catalyzed cyclization of 3 51 ................................ ................................ ........ 56 3 13 Synthesis of 3 52 from cis monoallylic diol 3 57 ................................ ................ 57 3 14 S ynthesis of 3 61 ................................ ................................ ............................... 57 3 15 Synthesis of 3 67 ................................ ................................ ............................... 58 3 16 Functional group scope. ................................ ................................ ..................... 59 3 17 Diastereoselective synthesis of 2,6 disubstituted THPs and THF. ..................... 60 3 18 Scalable preparation of 3 89 ................................ ................................ ............. 61

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12 3 19 Evidence for a non cationic mechanism. ................................ ............................ 61 3 20 Synthesis of 3 100 and 3 102 ................................ ................................ ............ 63 3 21 Synthesis of 3 109 and 3 110 ................................ ................................ ............ 64 3 22 Absolute configuration of 3 111 and 3 112 ................................ ........................ 65 3 23 Synthesis of morpholines 3 120 and 3 121 ................................ ....................... 66 3 24 Absolute configuration of 3 120 ................................ ................................ ......... 66 3 25 Synthesis of 3 129 and 3 131 ................................ ................................ ............ 67 3 26 Absolute configura tion of 3 129 and 3 133 ................................ ....................... 68 3 27 Synthesis of propargyl alcohol 3 142 ................................ ................................ 69 3 28 Synthesis of 3 144 and 3 146 ................................ ................................ ............ 69 3 28 Synthesis of 3 154 and 3 156 ................................ ................................ ............ 71 3 29 Synthesis of 3 163 and 3 165 ................................ ................................ ............ 72 3 30 Failed attempt s. ................................ ................................ ................................ .. 73 3 31 Synthesis of 3 173 ................................ ................................ ............................. 74 3 32 Cyclization of 3 177 and 3 179 ................................ ................................ .......... 74 3 33 Stereochemical mnemonic. ................................ ................................ ................ 75 3 34 Proposed mechanism. ................................ ................................ ........................ 75 3 35 Partial retrosynthetic analysis of Spirastrellolide A. ................................ ............ 77 3 36 Attempts to synthesize 3 193 ................................ ................................ ............ 77 3 37 Efficient synthesis of 3 200 ................................ ................................ ................ 78 3 38 A llylic alcohol purpose. ................................ ................................ ....................... 79 3 39 QuadraPure TM MPA 3 201 ................................ ................................ ................. 80 3 40 Quenching experiment using 3 201 ................................ ................................ ... 80 3 41 Illustrated protocol for monitoring the conversion of 3 40 ................................ .. 81 3 42 Synthesis of 3 204 3 208 ................................ ................................ .................. 81

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13 3 43 Screening of commonly used protecting groups. ................................ ................ 82 3 44 Reaction progress in cis and trans diols. ................................ ........................... 83 3 45 Reaction progress in cis an d trans methyl ethers. ................................ ............. 84 3 46 Comparison of 1 and 2 allylic ethers. ................................ ............................... 85 3 47 Evidence for a Au catalyzed anti addition. ................................ ......................... 87 4 1 2 H and 4 H chromenes. ................................ ................................ ..................... 88 4 2 Selected examples of 2 H chromenes in pharmaceuticals. ................................ 89 4 3 Summary of 2 H chromenes synthesis classical methods. ................................ .. 89 4 4 Synthesis of 2 H chromenes by addition to the benzaldehyde. ........................... 90 4 5 Synthesis of 2 H chromenes through aromatic nucleophilic substitutions. .......... 91 4 6 Oxidative pyranocyclization. ................................ ................................ ............... 92 4 7 Metal catalyzed electrophilic aromatic substitutions. ................................ .......... 92 4 8 Selected examples of metal catalyzed hydroarylation. ................................ ....... 93 4 9 Other selected modern example s of 2 H chromenes synthesis. .......................... 94 4 10 Endo cyclization of mono allylic diols. ................................ ................................ 95 4 11 Au catalyzed cyclization of 3 52 ................................ ................................ ........ 96 4 12 Preparation of substrates. ................................ ................................ .................. 97 4 13 Synthesis of substrates 4 68 ................................ ................................ ............. 99 4 14 Substit uent effect on the allyl moiety. ................................ ................................ 99 4 15 Synthesis of 4 80 ................................ ................................ ............................. 101 4 16 Neoflavonoid and Neoflavene. ................................ ................................ .......... 101 4 17 Selected examples of natural products from the neoflavonoid family. .............. 102 4 18 Metal catalyzed synthesis of Neoflavenes. ................................ ....................... 102 4 19 Preparation of 4 94 ................................ ................................ .......................... 103 4 20 Au catalyzed synthesis of Neoflavene. ................................ ............................. 104

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14 4 21 Control experiments. ................................ ................................ ........................ 105 4 22 Control experiments using triflic acid. ................................ ............................... 105 4 23 activation of the olefin. ................................ ................................ .................. 106 4 24 Model Study Daedalin A. ................................ ................................ .................. 106 5 1 D ehydrative gold cyclization of allylic alcohols and ethers. .............................. 109 6 1 Chemical structures of known compounds. ................................ ...................... 169 6 2 Synthesis of 3 211 and 3 212 ................................ ................................ .......... 171 6 3 Calibration plot of 3 41 vs n decane. ................................ ................................ 173 6 4 Calibration plot of 3 52 vs n decane. ................................ ................................ 174

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15 LIST OF ABBREVIATION S Ac Acetyl Anhyd Anhydrous Ar A roma tic Atm Atmosphere BBN Borabicyclo[3.3.1]nonane Bn B enzyl BQ Benzoquinone Bz B enzoyl Calcd Calculated Cat C atalyst Cbz Benzyloxycarbonyl Cod 1,5 cyclooctadiene Cond Conditions Cp C yclopentadienyl Cp* P entamethylcyclopentadienyl CSA Camphorsulfonic acid Cy Cyclohexyl DCE Dichloroethane DMA N N dimethylacetamide DMAP 4 dimethylaminopyridine DMF Dimethylformamide d r D iastereomeric ratio DPEphos B is(2 diphenylp hosphinophenyl)ether E Electrophile

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16 ee Enantiomeric excess ESI Electrospray ionization Et Ethyl FID Flame ionization detector G2 Grubbs second generation catalyst GC Gas chromatography h Hour/Hours n Hex Normal/unbranched hexyl HPLC High performance liquid chromatography HRMS High resolution mass spectroscopy i Pr iso propyl IR Infrared LA Lewis acid lit Literature M Metal Me M ethyl min Minutes Mol % Percent molar equivalents MS 4 Four angstrom m olecular sieves LDA Lithium diisopropylami d e Ln Lant h anide Ms Methanesulfonyl NME N methylephedrine NMO N m ethylmorpholine N oxide NMR Nuclear magnetic resonance

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17 NOE DIFF Nuclear overhauser effect difference NR N o reaction n Pent N ormal/unbranched pentyl Nu Nucleophile [O] Oxidation OPnB para Nitrobenzoate PCC Pyridinium chlorochromate Piv Pivaloyl Ph P henyl PMB para methoxybenzyl PPTS Pyridinium p ara toluenesulfonate Pyr Pyridine R G roup Red Al Sodium bis(2 methoxyethoxy)aluminumhydride Ref Reference R f Retention factor Sat Saturated S N 2 Bimolecular nucleophilic substitution Std Standar d TBAB Tetrabutylammonium bromide TBAC Tetrabutylammonium chloride TBAF Tetrabutylammonium fluoride TBDMS tert butyldimethylsilyl t Bu tert butyl temp Temperature

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18 TES T riethylsilyl Tf Trifluoromethane sulfonyl THF T etrahydrofuran THP T etrahydropyran TLC Thi n layer chromatography t R Retention time Tr Trityl Ts T osyl TsDPEN N (4 toluenesulfonyl) 1,2 diphenylethylenediamine v s Versus X Halogens Xylyl Dimethylphenyl

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19 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 GOLD CATALYZED CYCLIZATIONS OF MONO ALLYLIC DIOLS AND ETHERS By Berenger Biannic December 2011 Chair: Aaron Aponick Major: Chemistry Over the past decade, gold ca talysis has emerged as a n important methodology for the construction of complex organic structures. Its capability to form C C and C X systems under mild conditions makes it a valuable asset for the synthetic community. The work pr esented in this thesis is aimed at expanding the activation to allylic alcohols in order to synthesize oxygen heterocycles from readily accessible mono allylic diols. Saturated oxygen heterocycles are found in numerous biologically active natural product s, and my thesis work has focused on developing a mild and general method for the prep aration of substituted chiral 2 vinyltetrahydropyrans The method was expanded to the cyclization of allylic ethers and the relative rate of reaction was studied for dif f erent protecting group s on the allylic moiety. This thesis also documents the synthesis of substituted 2 H chromenes via gold c atalyzed cyclization of o (1 hydroxyallyl) phenols obtained from inexpensive and readily available salicylaldehyde s The products are obtained in good to excellent yields and the substrate scope of this reaction is quite broad. As such, a diverse range of products with varied substitution patterns and differing electronic s in the aromatic ring is

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20 readily available This method gives direct access to substituted 2 H chromenes which should be useful for further modification toward the preparation of biologically active molecules.

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21 CHAPTER 1 INTRODUCTION 1.1 General Considerations in Homogeneous Gold C atalysis Throughout history, gold h as served many roles. First used in art due to its color and its outstanding durability, gold grew to be the bas is of the universal currency in civilizations until the last hundred years 1 For thousands of years, gold has kept its s tatus as a precious rar e metal, indicator of wealth for antique civilizations and striking material used to decorate ancient items and palaces. Although European chemists during the Renaissance tried to investigate the transmutation of common metals (lead, gold, the scientific community did not show a strong interest in studying the features of this element The neglect of gold in modern science was mostly due to the common belief that material s made out of gold would be extremely expensive. T he development of homogeneous organome ta l lic catalysis applied to synthesis opened a n innovative area of investigation in organic chemistry giving access to more complex structures in shorter reaction times. One the most famous example was reported by Richard F. Heck 2 a and Tsunomu Mizoroki 2 b with the discovery of palladium catalyzed coupling reactions Although catalysts based on expensive metals such as palladium, ruthenium, rhodium or platinum have been intensively investigated for synthe t i c purpose s the study of gold catalysis begun relatively late on the organometallic time scale Even if few applications of gold catal ysis were described in the 1990 s, 3 evelopment of new phosphine or carbene ligated gold salts as catalysts. 4 In comparison with other precious metal catalysts used in organic

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22 chemistry, gold salts are relatively affordable even though gold metal is one of the most expensive (Table 1 1) 5 6 many factors influence the price of the catalysts including the nature of the ligand sensitivity and demand 7 Table 1 1. Precious metals price/gram as of August 2011 Metal Price/gram in US $ Catalyst Price/gram in US $ Gold 64.22 AuCl/ AuCl 3 171.50/ 143. 00 Iridium 37.10 IrCl 3 174.20 Osmium 14.13 OsCl 3 537.00 Palladium 26.80 PdCl 2 46.50 Platinum 65.12 PtCl 2 /PtCl 4 137.00/117.00 Rhenium 10.58 ReCl 3 291.00 Rhodium 65.37 RhCl 3 295.00 Ruthenium 5.83 RuCl 3 44.00 Silver 1.43 AgCl 5.40 The three most prev alent oxidation states of gold are Au(0), Au(I) and Au (III). Without stabilizing ligands, Au(I) salts disproportionate into Au(0) and Au(III) in aqueous media. 1 New robust water and air stable gold complexes ( Figure 1 1) have been designed by synthetic chemists to counter those limitations in the course of a chemical reaction. 4 Figure 1 1. Gold(I) salts commonly used in homogeneous catalysis The u nusual and surprising chemical and physical properties of gold complexes have been proposed to be closely related to relativis tic effect s (Figure 1 2) A mong the elements gold is the element that exhibits the largest relativistic effect. 8 G old metal is more resistant to oxidation than silver or mercury but gold element also accounts for

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23 reaching a higher oxidation state (Au 3+ vs Ag + or Hg 2+ ) This relativistic effect is described as gold having a contracted s orbital and expanded 5d orbita l. As a result, the size of the atom of gold is comparable to that of silver. The tighter binding of the s electrons coupled to a greater energy cohesion of gold metal make s this metal harder to oxidize and gold cationic species excellent Lewis acid s Both gold(I) and gold(III) species are considered soft carbophilic Lewis acids that can easily activate soft electrophiles such as double and triple C C bonds (Figure 1 2) The high Lewis acidity of gold is explained by a relatively low lying lowest unoccupied molecular orbital Also, since it is a soft Lewis acid, coordination to soft L ewis base s such as phosphine ligands or thioether s are highly favored (Figure 1 1) Finally, the trapping of an electrophile by a gold cation is facilitated by the strong back bonding character of this atom The relativistic expansion of the 5d orbitals increases the back bonding effect and therefore facilitates the electron delocalization (Figure 1 2) Figure 1 2. Gold and relativis tic effect. The robustness of gold catalysts combined with their exceptional chemoselectivity 9 to bind systems makes Au catalysis a major area of investigation for synthetic chemists and has become a significant tool in total synthesis. 10 In fact, the requirement

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24 for low catalyst loadings, minimal use of additives, mild reaction conditions and tolerance o f oxygen functional groups are the key argument s for the use of gold catalysis and t hose properties can be appl ied to a diverse set of reactions. 1.2 Gold C atalyze S ystems Gold catalyzed activation of alkynes has been one the first an d most investigated reaction since the development of robust ligated gold complexes 4 Gold cationic species behave as acid s by taking electron density from multiple bonds to induce electrophilic character (Fi gure 1 3 ) This complex can be further attacked by a nucleophile. Figure 1 3 system activation by gold(I) Alkyne s can be activated very easily by cationic gold complexes under mild conditions. Arcadi and co workers r eported in 2004 an efficient synthesis of indole 1 7 starting from 2 ethynylaniline 1 6 in high yield at room temperature (F igure 1 4) 11 Addition on the alkyne can also be performed intermolecularly H ydration of 1 8 using only 0.01 mol% of catalyst was in vestigated by Nolan and co workers (F igure 1 4) 12 The reaction proceed ed in high yield using water as a co solvent. In 2000, Hashmi developed the synthesis of substituted phenols catalyzed by gold(III) chloride starting from furan 1 10 (F igure 1 4) 13 They are notorious ly unreactive

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25 diene s in Diels Alder reactions even in intramolecular transformations 14 However, in the presence of AuCl 3 1 10 under went a Diels Alder reaction to form 1 11 through activation of the alkyne moiety and a fter break ing the oxyge n bridge mediated by the catalyst, 1 12 was obtained in 97% yield. Figure 1 4 Selected examples of gold catalyzed activation of alkynes. Figure 1 5 Au catalyzed alkoxylation of alkyne a p plied to the total synthesis of Bryostatin 16. Trost and co workers applied the gold catalyzed alkoxylation of alkynes to the total synthesis of a complex natural molecule: Bryostain 16 (Figure 1 5). 15 They reported the

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26 intramolecular alkoxylation of 1 13 catalyzed by 20 mol % of gold(I) species in 73% yield. It is worth noting that the reaction proceeds smoothly in the presence of an acetal, conjugated systems and an unprotected free alcohol. Nucleophilic a ddition to allenes is also carried out under mild conditions. I n 2006 Widenhoefer and co workers reported the gold catalyzed cyclization of 1 1 5 to form 1 1 6 in high yield and moderate dr (F igure 1 6 ) 16 In 2008, t he same group also published the int ermolecular hydroamination of 1 1 7 with 1 1 8 at room te mperature. 17 C C bond form ing reactions have also been reported by Ohno and co workers in 2007 to synthesize dihydroquinoline 1 21 from allenic aniline 1 20 18 This hydro arylation of allenes proceeds at room temperature and g a ve high yields. Figure 1 6 Selected examples of g old catalyzed activation of allenes. Formation of a chiral center is one of the advantages of using allenes as electrophiles. The development of chiral bisphosphines ligands 19 or phosphate counter anion s 20 for stereoselective activation of allenes or alkenes by cationic gold complexes

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27 has been successfully investigated by several synthetic groups and has prove n to be highly efficient. 21 For example, Toste and co workers reported the enantioselective intram olecular hydroamination of allenes using a chiral phosphine ligand based gold catalyst 1 24 (F igure 1 7). 22 Pyrolidine 1 23 was synthesized in excellent yield and 99% ee from allene 1 22 under mild conditions. In 2007, the same group reported the hydroalkox ylation of allene promoted by a Au(I) using a chiral counter anion silver salt 1 27 23 Excellent enantioselectivity is obtained for 1 26 as well. In gold catalysis, low enantioselectivity is often found, mostly due to the distance between the chiral ligand and the substrate. 20 This problem could be overcome by using chiral counter anions which are much closer to the metal and consequently to the substrate. These two different approaches should give access to a l arger library of chiral species to screen in a process optimization. Figure 1 7. Selected examples of enantioselective addition on allenes. Despite the success of gold catalyzed activation of alkynes or allenes, addi tion of nucleophiles to olefins remains limited. Several examples have been reported in the

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28 literature; however higher temperatures are needed in order to fully activate the ol e fin For example, He and co workers published the gold catalyzed addition of a phenol derivative 1 2 9 to the alkene 1 2 8 in 84% yield in toluene at 85 C (F igure 1 8 ) 24 For the intramolecular reaction, Windenhoefer and co workers reported the cyclization of the carbamate protected amine 1 31 to form the substituted py r rolidine 1 32 in 91% yield at the same temperature 25 Figure 1 8 Selected examples of gold catalyzed activation of alkenes. 1.3 Metal Catalyzed Activation of Unsaturated A lcohols Unsaturated alcohols are readily available intermediate s in organic chemistry. T ransformations of unsaturated alcohols under protic or Lewis acidic conditions have been extensively studied and reviewed. 26 31 A selection of revelant, modern metal catalyzed reactions of allylic, propargylic and benzylic alcohols will be presented in this dissertation Allylic alcohols can be easily prepared from inexpensive compounds (usually by reduction of a propargylic alcohol s or reduct ion of unsaturated carbonyl compounds ). Their rea ctivity in the presence of Lewis acids (Pd, 26 Ru, 27 Rh, 28 Fe 29 Pt 30 and Bi 31 ) is

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29 well documented but still needs further advancements since the catalyst loadings necessary remain relatively high (usually more th an 5 mol %) Select examples of this activation are shown Figure 1 9 Although the method developed by Uenishi 26 g is efficient and highly diastereoselective, a relatively high loading of palladium catalyst is required for full conversion (F igure 1 9 ) Intermolecular Friedel Craft s reactio ns can also be performed using ruthenium based catalysts 27 a 1 35 was readily converted into 1 3 7 at room temperature using campho rsulfonic acid as a co catalyst P latinum(II) salts have been used b y Ma shi ma and co work ers to activate allylic alcohol 1 36 32 Only 1 mol % of catalyst is necessary but the reaction required heating to reflux for 6 hours to afford 1 39 Figure 1 9 Selected examples of Pd Ru and Pt catalyzed activation of allylic alcohols. Activation of allylic alcohol s by gold catalysts has been extensively investigated by our group; 33 these developments will be discussed in detail in the chapter s 2 and 3 of this dissertation.

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30 Propargyl alcohols are extremely versatile intermediates in complex synthesis. They can be transformed in to a myriad of different functional groups depending on the reaction conditions. 34 Activated by a transition m etal salt, they are commonly used in the synthesis of 5 membered heterocycles. 35 Our group reported in 2009 the synthe sis of furans, pyrroles and thi o p henes by gold catalyzed activation of propargyl alcohols. 36 The selected example (F igure 1 10 ) shows that the starting material 1 40 can easily be converted into 1 41 with a 92% yield using only 0.05 mol % of catalyst. In 2010, Castanet and co workers developed a method to synthesize furans from a propargylic alcohol 1 42 a boronic acid 1 43 and carbon monox ide with a low loading of r hodium catalyst (F igure 1 10) 37 The y ield is moderate but the reaction proceeds from commercially available starting material s Ru catalyzed propargyl nucleophilic substitutions have also been reported. Uemura and co workers show ed in 2005 that 1 4 5 can be easily transformed into 1 4 6 using 5 mol % of catalyst with the nucleophile as the solvent (F igure 1 10) 38 The reaction procee ded at 6 0 C in only 15 minutes Ionization under mild acidic conditions of benzylic alcohols has been also througly investigated by the synthetic community. Any type of C X bond can be formed in the benzylic position through an S N 1 mechanism (Figure 1 11). Cation 1 48 is formed after treatment of 1 47 under Lewis acidic conditions and 1 49 is obtained afte r addition of the nucleophile and loss of water. Campagne et al. reported in 2006 the direct activation of benzyl alcohols in presence of 5 mol % of Lewis acid and tosylamine (F igure 1 12). 39 Among the different Lewis acids tested, Au 3+ species proved to b e the best catalyst for this transformation.

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31 Use of organic acids or TiCl 4 gave poor yields and side products. ketoesters can also be used as nucleophiles for this type of transformation (F igure 1 12). 40 Despite the fact that this reaction needs a high catalyst loading, a broad range of metals can be used. Better yields are given by treating 1 52 with 10 mol % of inexpensive FeCl 3 6H 2 O. Figure 1 10 Selected recent examples of metal catalyzed activation of propargyl alcohols. Figure 1 1 1 Mechanism of metal catalyzed nucleophilic substitutions on b enzylic alcohols

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32 Figure 1 1 2 Selected examples of metal catalyzed activation of benzylic alcohols. Friedel Craft s reactions can also be achieve d through the same methodology using electron rich aromatic nucleophile s (Fig ure 1 1 3 ) Bismuth triflate was successfully used by Rueping and co workers to do an intramolecular arylation (F igure 1 1 3 ) 41 The reaction conditions are very mild and give an easy access to fluorene de rivatives. Using 10 mol % of HAu Cl 3 (F igure 1 1 3 ) Bel ler et al. developed a method to arylate benzylic alcohol 1 5 6 with o xylene. 42 This method can also be extended to the ionization of benzylic acetates and carboxylates. Figure 1 1 3 Selected examples of metal catalyzed arylation of benzyl alcohols.

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33 Ove r the past decade, metal catalyzed activation of unsaturated alcohols has been extensively studied. The susbtrates are e asily accessible through synthesis and relatively stable but they are also very reactive under the correct conditions and give access to complex structures. However, allylic alcohols are much more difficult to activate under mild conditions. Therefore, innovative new methodologies warrant investigation to expand this area. 1.4 Go ld Catalyzed [3,3] Sigmatropic R earrangement Unsaturated alc ohols and ethers are important intermediate s used in sigmatropic rearrangement. Transition metal catalysts can easily activate unsaturations and therefore favor the formation of carbon carbon or carbon heteroatom sigma bonds via addition to the bond Gol d catalysts were described as excellent acids 1 consequently they became an efficient tool to catalyze sigmatropic rearrangements. A [3,3] sigmatropic rearrangement is a pericylic reaction where three pairs of electrons are shifted in a suprafacial manner and where a bond migrates to another position on the same molecule [3,3] s igmatropic rearrangement s typically proceed at high temperature but can be catalyzed by Lewis acid s in order to use milder reactio n conditions (Figure 1 1 4 ) 43 The best known [3,3] sigmatropic rearrangements are the Cope rearrangement ( Figure 1 1 5 ) 44 Claisen r earrangement 45 Carroll rearrangement 46 and the Fischer indole synthesis 47 Figure 1 1 4 [3,3] sigmatropic rearrangement

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34 Figure 1 1 5 Types of [3,3] sigmatropic rearrangement. In recent years, gold cataly sts have been successfully applied to a series of [3,3] sigmatropic rearrangements, such as the Claisen rearrangement (Chapter 2 ) rearrangement of allylic/ propargyl esters 48 50 and the Overmann rearrangement 49 as well In 2007, Nolan and co workers reported the Au catalyzed rearrangement of allylic acetates 1 5 8 using a N heterocyclic ligand into a linear allylic aceta te 1 60 (F igure 1 1 6 ) 48 The scope of the reaction proved to be broad and high yielding. More recently, Y ang and co workers developed a highly efficient gold(I) catalyzed Overman rearrangement of allylic trichloroacetimidates 1 61 to allylic t richloroacetam ides 1 62 in water (F igure 1 1 6 ) 49 This reaction is very cl ean, d id not need further purification and can be conducted on a multi gram scale. The r eactivity of more reactive propargylic acetates in the presence of gold catalysts has also been investigate d. In 2007, Toste and co workers gave evidence for

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35 a cationic intermediate during the gold catalyzed sigmatropic rearrangement of 1 63 to form 1 6 5 (F igure 1 1 6 ) 50 The ring expansion of 1 64 to form 1 65 catalyzed by gold showed the strong cationic natur e of the allene formed in the first step. Figure 1 1 6 Selected examples of Au catalyzed [3,3] sigmatropic rearrangements. Among [3,3] sigmatropic rearrangements, Claisen type reactions have been the most popular transfor mations catalyzed by gold cation ic species. However, most reports showed the activation of propargylic or allenic derivatives. We aimed at exploring further this type of rearrangement catalyzed by gold using allyl vinyl ethers to synthesize hex 5 en ones in a one pot process.

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36 C HAPTER 2 GOLD CATALYZED SYNTHESIS OF SUBSTITUTED HEX 5 EN ONES BY CLAISEN REARRANGEMENT 2.1 Gold C atalyzed Claisen R earrangements 2.1.1 Generalities The [3,3] sigmatropic rearrangement of allyl vinyl ethers is one of the oldest a nd most versatile way s to make carbon carbon bonds in organic synthesis 51 Discovered by Rainer Ludwig Claisen in 1912, the Claisen rearrangement usually requires high temperature s (F igure 2 1) but more convenient methods have been developed by the synthet ic community over the past 50 years to catalyze th is reaction 51 Two different class es of catalysts ca n be defined; hard Lewis acids such as protic acids (F igure 2 1) catalyze the reaction by coordination to th e oxygen atom and soft Lewis acids such as Pd 2+ or Hg 2+ catalyze the reaction by coordination to the bonds. 51 Figure 2 1 Different types of Claisen rearrangement. Gold complexes have proven to be efficient soft Lewis acids that activate unsaturated C C bonds. Therefore they could be employed to catalyze Claisen rearrangement s Gold catalysts are usually more chemoselective than other metals used to catalyze Claisen rearrangement such as Pd(II) or Ir(III) 52 species They are also described as mild Lewis acids that are mo isture and oxygen stable 1 52 The mild Lewis

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37 acidity is usually not suitable to activate olefins but performs extremely well with alkyne s or allenes. Consequently, gold catalyzed r earrangements of allyl vinyl ethers have not been explored. This Chapter will describe the different types of gold catalyzed Claisen rearrangement s of propargylic and allenic ethers and our attempts to expand this reactivity to the rearrangement of allyl v inyl ethers. 2.1.2 Gold Catalyzed Propargylic and Allenic Claisen R earrangement In the Claisen rearrangement reactions catalyzed by soft Lewis acids, the electrophilic metals bind to the enol ether and thus cannot activate the olefin This limitation is also true for gold complexes. Using a more electron rich olefin c ould counter this limitation. Gold complexes are carbophilic and easily form complexes with alkynes or allenes With this me t hod of activation, p ropargylic or allenic Claisen rearrange ment s catalyzed by gold salts have become possible In 2004, Toste and co workers reported the first gold catalyzed acetylenic Claisen rearrangement (Figure 2 2 ). 53 This method provided easy access to homo allenic alcohols under mild conditions and low cat alyst loadings. The reaction was also highly stereoselective; enantio enriched propargyl vinyl ether 2 1 was converted t o 2 2 in 91% yield with high transfer of chirality. The reaction work ed through a 6 exo dig addition of the enol ether to the gold alkyn e complex 2 6 followed by rearrangement of 2 7 to form allene 2 8 (Figure 2 3 ). More recently, Krafft and co workers reported the Au(I) catalyzed Claisen rearrangement of allenyl vinyl ether 2 3 to form substituted 1,3 dienes 2 4 54 The reaction proceed ed u nder mild conditions with low catalyst loading s as well (F igure 2 2 ).

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38 Figure 2 2 Gold catalyzed propargylic and allenic Cla is en rearrangement. Figure 2 3 Detailed mechanism of Au ca talyzed propargyl Claisen rearrangement. Figure 2 4. Au catalyzed Claisen rearrangement applied to the total synthesis of Azadirachtin.

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39 This methodology has been applied to the total synthesis of Azadirchtin in 2007 by Ley and co workers (Figure 2 4). 55 The key Claisen rearrangement step cata lyzed by a gold(I) complex gave access to allene 2 11 from vinyl propargyl ether 2 10 in 80% yield. The reaction proceeded with 5 mol % of catalyst (15 mol % of gold(I) species) which is a relatively high catalyst loading in gold catalysis. 2.1.3 Gold Catalyzed Heterocycle Synthesis through Claisen R earrangement Cationic gold complexes are excellent catalysts for cascade reactions; they have proven to be very stable under various set s of conditions and can promote unusual processes. 1 As described above, they are very efficient at catalyz ing propargylic and allenic Claisen rearrangement which led to either the allene or the diene that can be fu rther activated using the same catalyst. Figure 2 5 Au catalyzed cascade synthesis of 5 membered heterocycles. In 2005, Kirsch and co workers investigated the Au catalyzed cascade propargyl Claisen rearrangement/hete rocyclization of propargyl vinyl ether 2 12 to form substituted p yran 2 14 (F igure 2 5) 56 This method is very high yielding and can give access to tri or tetra substituted furans. The same methodology was applied to the

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40 synthesis of pyrrole by Saito and co workers in 2010 using vinyl propargyl tosylamide 2 15 57 2.1.4 Gold Catalyzed Aromatic Claisen R earrangement The aromatic Cla is en rearrangement catalyzed by gold salts w as reported in 2006 by He and co workers. 58 Rearrangement of aryl allyl ether 2 18 ca talyzed by generated in situ Ph 3 PAuOTf g ave o allyl phenol 2 19 which was further transformed into the dihydrobenzofuran by addition of the phenol to the olefin (F igure 2 6). To show that the first step was a Claisen rearrangement, the authors synthesized the 2,6 disubstituted aryl allyl ether 2 21 (F igure 2 6) This compound was treated under the same conditions as 2 18 and 2 22 was afforded The first step was presumably a Claisen rearrangement to give 2 23 Since this compound c ould not be re aromatized the allyl group must undergo a Cope rearrangement 59 to give phenol 2 22 Figure 2 6. Au catalyzed aromatic Claisen rearrangement.

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41 T hese reports demonstrate that gold complexes can catalyze the Claisen rearrangement but s urprisingly, gold catalyzed rearrangement of allyl vinyl ethers has not been explored 2.2 Gold Catalyzed Synthesis of S ubstituted H ex 5 en 2 one s, a n I nitial S tudy 2.2.1 Initial Considerations At the beginning of my PhD study, we were interested in developing new methodologies using cationic gold catalysts to form complex structures by cascade reactions. The a bsence of reports describing activation of allyl vinyl ethers by gold led us to investigate this area. We a lso proposed that the carbophilicity of Au(I) species could be used to form allyl vinyl ethers through addition of an allyl alcohol to an alkyne. This process would afford hex 5 ene 2 ones derivatives 2 28 (Figure 2 7) by cascade reactions both catalyzed by the same gold(I) specie s from inex pensive commercially available allylic alcohols and alkynes. Many different reliable methods have been developed over the past 100 years to synthe size vinyl allyl ethers. 60 However, a simple methodology using environmentally benign activators remains unex plored. Also, allyl vinyl ethers are not easy to process and purify by flash chromatography they are sensitive to moisture and unstable under protic conditions. Figure 2 7. Au catalyzed cascade activation of alkyne/C laisen rearrangement.

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42 The alkyne 2 26 could be activated with a gold(I) salt which would catalyze addition of the allylic alcohol 2 25 to obtain intermediate 2 27 The latter could then perform a thermal or Au catalyzed Claisen rearrangement to form 2 28 ( Figure 2 7). The proposed mechanism of this sequential transformation can be detailed as follow ed (Figure 2 8) A Au(I) complex activates alkyne 2 30 and the allylic alcohol attacks it to form the allyl vinyl ether 2 31 The latter would then rearrange to form 2 32 and, after protodeauration, give the expected product 2 33 An alternative pathway could be envisioned. P rotodeauration c ould occur earlier in the sequence and allyl vinyl ether 2 34 c ould be obtained from 2 31 R earrange ment would then form 2 35 which, after d ecomplexation of the gold specie s would afford 2 33 Figure 2 8. Detailed proposed mechanism. 2.2.2 Results To test this hypothesis, we initiated a study of the gold catalyzed cascade addition of allylic alcohol to alkyne s followed by Claisen rearrangement to form h ex 5 en 2 one s 2 33 (Figure 2 8) This reaction was tried using many different conditions and different types of substrates. However, t he expected reaction did not occur and other transformatio ns took place instead (F igure 2 9 ). Instead of the desired transformation

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43 the activation of the allylic alcohol by the gold complex was observed an d the product 2 3 6 of the condensation between two allylic alcohols 2 34 was isolated Interestingly, the f o rmation of acetophenone 2 37 was also observed. It is likely that t he molecule of water released during the formation of 2 36 hydrate s the alkyne in presence of a gold complex. 12 This problem was overcome by sc reening different types of drying agents (Entries 3 and 4, Table 2 1). It was found that 4 molecular sieves were the most efficient water scavenger since no acetophenone 2 37 was detected by 1 H NMR of the crude material (Entries 4 7, Table 2 1) Product 2 36 was obtained when CH 2 Cl 2 and benzene were used as solvent (Entries 1 and 6, Table 2 1). Figure 2 9. Gold catalyzed reactions with crotyl alcohol and phenylacetylene. Table 2 1. Attempts of c ascade Au catalyzed addit ion of allylic alcohols on alkynes/Claisen rearrangements Entry Solvent Catalyst (mol %) Conditions Products 1 CH 2 Cl 2 PPh 3 AuCl/AgOTf (5) rt 2 36 + 2 37 2 Toluene PPh 3 AuCl/AgOTf (5) rt and reflux 2 38 + 2 39 + 2 37 3 Toluene PPh 3 AuCl/AgOTf (5) CaCl 2 rt 2 38 + 2 39 + 2 37 4 Toluene PPh 3 AuCl/AgOTf (5) MS 4 rt 2 38 + 2 39 (3:1) 5 a Toluene PPh 3 AuCl/AgOTf (5) MS 4 rt 2 38 + 2 39 (3:1) 6 Benzene PPh 3 AuCl/AgOTf (5) MS 4 rt 2 36 7 PhNMe 2 AuCl 3 /AgOTf (2) MS 4 rt N.R. a No phenylacetylene used. Surprisingly, when toluene was used as solvent for this transformation (F igure 2 9), the allylic alcohol 2 34 was activated by the gold complex to act as an electrophile.

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44 The reaction proceeded as a Friedel Crafts reaction where toluene was alkylated in both the ortho and p ara positions. Both products 2 38 and 2 39 (ratio 3:1) were obtained but were too volatile to be isolated. No Friedel Crafts product was formed when benzene was used as solvent (Entry 6, Table 2 1) but the reaction gave ether 2 36 as a single product. The reaction using dimethylphenylamine as an electron rich solvent was also tried, but no conversion was observed (Entry 7, Table 2 1). These observations form the basis for studying the Au catalyzed dehydrative transformations that form the majority of this thesis. Several years later, after working on the Au catalyzed activation of allylic alcohols, we decided to drastically change the reaction conditions and substrates of this cascade reaction. A more activated alkyne and a more hindered allylic alcohol w ere chosen as substrates. Steric hindrance on the olefin moiety of 2 40 should disfavor the condensation of two molecule s of allylic alcohol (Figure 2 10) and therefore should favor the addition to alkyne 2 41 Also, diphenyl acetylene 2 41 is an electro n rich alkyne and thus a better soft Lewis base for complexation with gold(I) (Figure 2 10). In this event, 2 42 was observed in 30% yield using 3 methyl 2 buten 1 ol 2 40 and di phenylacetylene 2 42 in a 1:1 ratio A m ore coordinating solvent (THF ) and a mo re stable catalyst 1 3 seem ed to favor the formation of the hex 5 en 2 one 2 42 (F igure 2 10) When three equivalents of alkyne 2 41 were used the yield was increased from 30 % to 65 % When l ess steric ally hindered allylic alcohol 2 43 was used 2 44 was o btained in 89% yield in a 10:1 d iastereomeric mixture

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45 Figure 2 10. Gold catalyzed cascade addition on alkynes/Claisen rearrangement using diphenylacetylene. Despite these encouraging results further experiments carried out in our laboratory showed that this method is limited to a narrow substrate scope However, we believe that this methodology is still of interest and can become an efficient tool for the formation of chiral h ex 5 en 2 one s 2 28 Further optimization rea ctions are being conducted in our laboratory. 2.3 O utcome The set of experiment s described in the previous section show ed that the Au catalyzed intermolecular addition of allylic alcohol s to alkynes followed by Claisen rearrangement work ed only for a spec ific type of substrate and can hardly be extended to a broader scope of reactants (F igure 2 11 ) However, it was also demonstrated that, in the presence of cationic gold specie s allylic alcohols can be activated and act as

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46 electrophile s (F igure 2 11 ) A s shown above alkylation of toluene (solvent) in the ortho and para positions took place (F igure 2 9) in lieu of the hydro alkoxylation of the alkyne (F igure 2 11) Figure 2 11 Au catalyzed activation of allylic alcohols This conclusion led us to investigate a different set of n ucleophiles and allylic alcohol electrophiles for activation by a cationic gold species (Figure 2 1 2 ) The major work presented in this thesis is the formation of saturated oxygen containing heter ocycles by intramolecular alkoxylation of allylic alcohols catalyzed by gold complexes. Figure 2 1 2 Au catalyzed alkoxylation of allylic alcohols. This work, described herein, represents a new and exciting mode of reactiv ity in Au catalysis.

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47 C HAPTER 3 GOLD CATALYZED CYCLIZATIO N OF MONO ALLYLIC DIOLS TO FORM 2 VINYL TETRAHYDROPYRANS 3.1 Background and Significance 3.1.1 Tetrahydropyrans in N ature Saturated oxygen heterocycles are commonly found in biologically active na tural molecules and consequently, they have been extensively studied by the scientific community. Among these, tetrahydropyrans are found very frequently in synthetic targets due to their potent biological activities (Figure 3 1) 61 Figure 3 1. Selected examples of natural molecules containing tetrahydrofuran motifs. For example, Spirastrellollide A 3 1 extracted from the marine sponge Spirastrella coccine 62 shows a potent inhibition of the protein phosphatase 2. This mole cule has three different saturated oxygen heterocycles types: a tetrahydrofuran, a spiroketal and a bis sp iroketal. (+) SCH 351448 3 2 isolated from a microbial metabolite by Hedge

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48 and co workers at the Schering Plough Research Institute selectively acti vates low density lipoprotein receptors (LDL R). 63 This molecule is a macrolactone containing two different tetrahydropyran motifs. Brevetoxin 1 3 3 is a cyclic polyether produced by k arenia brevis a marine dinoflagellate found in the Gulf of Mexico, known to be the organism responsible for the Florida red tide. 64 For human beings 3 3 is a neurotoxin that binds to voltage gated sodium channels in nerve cells This complex structure is very challenging to synthesize due to the ten fused oxygen heterocycles, and thus, is still an important synthetic target for chemists. Classical methods of tetrahydropyran synthesis are efficient but still remain limited when applied to the preparation of complex chiral structures. 65 Organometallic chemistry proved to be a unique tool to create diversity in high yield and high stereoselectivity. 3.1.2 Transition Metal Catalyzed Synthesis of T etrahydropyrans Due to the exceptional abundance of tetrahydropyrans in nature, the synthetic community continues to expand the scope of new methodologies to synthesize THPs Even though a variety of cla ssical methods to synthesize the se structures have proven to be very efficient, this section will only focus on modern metal catalyzed cyclization reactions forming the THP ring system 61 65 Most recent methods using cationic metals as catalysts involve the intramolecular hydroalkoxylation of unactivated alkenes (Figure 3 2 ). 66 68 In this general reaction, the metal coordinate s to the double bond in 3 4 to form complex 3 5 activating it towards nucleophilic addition. Proton transfer then gives 3 7 Even though this method usually requires high temperature s and long reaction times, the substrates are extremely easy to synthesize.

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49 Figure 3 2. Metal catalyzed cyclization of alkenol. Figure 3 3. Metal catalyzed hydroalkoxylation/cyclization of unactivated alkenes. Widenhoefer and co workers reported the platinum catalyzed cyclization of alkeno l 3 8 to form 3 9 in moderate yield and very high diastereoselectivity (F igure 3 3). 66 This transformation tolerated a large number of functional groups including pivaloate and acetate esters, amides, silyl and benzyl ethers. The same reaction has been inve stigated by He and co workers using silver triflate as catalyst. 67 3 11 was obtained in high yield from 3 10 using 5 mol % of catalyst and triphenylphosphine. This reaction stands as one of the simplest modern methods to construct cyclic ethers. Lanthanides have also been studied for the activation of non activated olefins. Marks and co workers developed the hydroalkylation of 3 12 by ytterbium (III) triflate to form 3 13 in ionic liquid. 68 Ln(OTf) 3 catalyzed processes usually require toxic, highly polar, mode rately

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50 coordinating solvents 69 therefore the authors used a non volatile, environmentally benign imidazolium based ionic liquid. Even though activation of non activated olefins by a cationic metal is very practical, reaction conditions remain vigorous, wit h long reaction times, and high temperatures. Therefore, substitution on allylic alcohols appears to be a good alternative for the preparation of unsaturated oxygen heterocycles. Inter and intr a molecular s ubstitution reactions of allylic alcohols have bee n reported using various metal based catalyst systems. Different mechanistic scenarios were suggested: a syn S N 2 process with Pd (II) 70 (F igure 3 4), a allyl metal complex formation with Pd (0) 71 Pt (0) 72 Rh (I) 73 or Ru (II) 74 and a stabilized allyl cation wit h Fe (III) 75 or Bi (III) 76 Figure 3 4. Metal catalyzed activation of allylic alcohols. Selected examples of preparation of tetrahydropyrans from mono allylic diols are presented in Figure 3 5. Cossy and co workers investigate d the cyclization of 3 14 to form 3 15 catalyzed by 5 mol % of iron trichloride (F igure 3 5). 75 The reaction proceed ed through formation of an allyl cation intermediate and g ave access to 2,6 disubstituted tetr ahydropyrans in high dr. Uenishi and co workers used palladium(II) as catalyst to perform the same transformation. 70 Although the catalyst loading was

PAGE 51

51 relatively high, the reaction proceed ed under mild conditio ns and g ave 3 17 in high yield as a single diastereomer. The enantioselective formation of 3 20 through cyclization of 3 18 has been devel oped by Kitamura and co workers. 74 c They designed a new ligand 3 19 whic h they combined with a Trost type r uthenium(II) catalyst [CpRu(CH 3 CN) 3 ]PF 6 to perform the extremely efficient formation of 3 20 in high yield and high ee. Figure 3 5. Selected examples of metal catalyzed cyclization of mo no allylic diols. Among all the metal catalyzed strategies reported to synthesize unsaturated oxygen heterocycles, gold catalyzed hydroalkylation of allenes has proven to be highly efficient. E xo h ydrofunctionalization of a llenes with o xygen nucleophiles h a d been reported by Widenhoefer and co workers in 2006 (F igure 3 6). 77 Allenes were activated under mild conditions and 3 22 was obtained in high yield with a moderate cis : trans ratio. Inspired by Echavarren and co workers recent report, 78 the same group dev eloped the enantioselective cyclization of 3 23 to form 3 25 in 96% yield and 88% ee (F igure 3 6). 79 3 24 was identified to be the most efficient ligan d for this hydroalkoxylation.

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52 Figure 3 6. Enantioselective gold catalyz ed hydroalkoxylation of allenes. Even though allenes are very reactive unsaturated C C bonds, they are not as practical to synthesize as unsaturated alcohols Therefore, allylic alcohols could be used as potential surrogates giving similar outcomes. 3. 1.3 Gold Catalyzed Activation of Allylic A lcohols Surprisingly, gold catalyzed activation of allylic alcohol was poorly investigated before 2006. 1 80 Only few reports have been published and they usually involve d the formation of an allyl cation intermediate generated by gold(III) species (Figure 3 7). Subsequent nucleophilic attack form ed the regioisomeric substitution products 3 27 and 3 28 Figure 3 7. Gold(III) catalyzed act ivation of allylic alcohols.

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53 Chan and co workers reported the Au( III) catalyzed nucle ophilic substitution of allylic alcohols with carbon nucleophiles. 81 Under mildly Lewis acidic conditions, 1,3 diketones 3 29 c ould be added to phenyl substituted allylic a lcohols such as cinnamyl alcohol 3 30 (F igure 3 8). The same group also reported the allylic alkylation of arenes and heteroaromatics with allylic alcohols under similar conditions 82 For formation of C N bonds, Liu and co workers reported the Au ( III ) catal yzed direct aminations of all ylic alcohol 3 35 with tosylamine 83 It is noteworthy that this report contain ed several examples of non aromatic allylic alcohol substrates. Figure 3 8. Selected examples of Au(III) catalyzed activation of activated allylic alcohols. More development of gold catalyzed activation of allylic alcohols reported by our group will be discussed in detail below and in chapters 4 and 5 of this dissertation. 3.2 Au Catalyzed S ynthesis of 2 V inyltetrahyd ropyrans 3.2.1 Initial Study, O ptimiza tion and Control E xperiment s To prove the hypothesis that allylic alcohols c ould be activated under mild conditions with a gold(I) specie s to form 2 vinyltetrahydropyran from mono allylic diols,

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54 the synthesis of 3 40 was designed (Figure 3 9) Diol 3 40 84 was synthesized in three synthetic steps from the commercially available v alerolactone 3 37 The cyclization of 3 40 to synthesize 3 41 85 proceeded in 10 minutes at room temperature using 5 mol % of the catalyst syste m Ph 3 PAuCl/AgOTf. Unfortunately, the product is volatile and was not fully isolate d The reaction was very fast and a full conversion was observed Following this encour agin g result, the synthesis of diols with a higher molecular weight was carried out T he preparation of 3 45 had been attempted but oxidation of 3 43 failed under various conditions (Figure 3 10). Figure 3 9. Synthesis of 3 41 Figure 3 10. Synthesis of 3 45 An alternate method for substrate synthesis was attempted and t wo different diols 3 49 and 3 51 were synthesized from 3 48 (Figure 3 11) The latter was the product of the cross metathesis of 3 47 86 and crotonaldehyde catalyzed by Grubbs 2 nd generation catalyst 87 3 49 a nd 3 51 were synthesized using one equivalent of Grignar d reagent f ol lowed by deprotection of the terminal alcohol with potassium carbonate in methanol

PAGE 55

55 The hydrolysis of the ester and the addition to the aldehyde 3 48 using an excess of Grignard reagent in a one pot process was attempted but did not give satisfactory yields Cyclization of 3 51 proceeded smoothly in 15 minutes using 5 mol % of catalyst and 3 52 was obtained in 91% yield. The transformation proceeded for 3 49 as well but, 3 50 was too vola tile to easily be isolated and the yield quantified Nevertheless, 3 50 has been clearly identified by 1 H NMR. Figure 3 11. Synthesis of 2 vinylTHPs 3 50 and 3 52 A large r amount of diol 3 51 was synthesized for catalyst screening using different conditions (Figure 3 12, Table 3 1). High yields were obtained using only 1 mol % of PPh 3 AuCl/AgOTf or 2 mol % AuCl 3 (Entry 1 and 4, T ab le 3 1) The table also show s that the cationic gold(I) complex was the active species because n o conversion was observed using PPh 3 AuC l or AgOTf separately. W hen 3 51 was treated in presence of a protic acid (Entry 9, Ta b le 3 1), only 9% yield of 3 52 was isolated. 88

PAGE 56

56 Figure 3 12. Au catalyzed cyclization of 3 5 1 Table 3 1. Optimization and control experiment. Entry Catalyst Loading (mol %) Time Yield of 3 5 2 (%) 1 AuCl 3 2 30 min 96 2 AuCl 3 1 100 min 87 3 PPh 3 AuCl, AgOTf 5 20 min 91 4 PPh 3 AuCl, AgOTf 1 40 min 96 5 a AuCl 1 16 h 41 6 PPh 3 AuCl 5 16 h 0 7 AgOTf 5 16 h 0 8 AgCl 5 48 h 0 9 b TfOH 1 40 min 9 a 49% diol 3 51 recovered b 46 % diol 3 5 1 recovered 3.2.2 Substrate S cope The scope of this transformation has been investigated using the optimized conditions showed above (Entry 4, Table 3 1). Prior to ex ploring the functional group and substituent tole rance, 3 57 was synthesized in order to test the reaction with a different olefin geometry (Figure 3 13) 3 55 was synthesized by addition of 3 54 89 to cyclohex ane carboxaldehyde using n BuLi followed by hydr ogenation of the propargylic alcohol and d eprotection of the terminal sil yl ether with hydrogen fluoride. When diol 3 57 was subjected to the standard conditions, tran s product 3 52 was isolated in similar yield and similar reaction time as 3 51

PAGE 57

57 F igure 3 13. Synthesis of 3 52 from cis monoallylic diol 3 57 Further s ubstitution on the olefin moiety ha s also been investigated Trans d iol 3 60 was prepared in two steps by addition of vinyl magnesium chloride to 3 59 90 follo wed by cross metathesis with hex 5 en 1 ol (Figure 3 14) 87 When 3 60 was treated under the standard conditions, 3 61 was obtained in 91% yield after 2.5 hours. The same substrate was used to test the lower lim it of catalyst loading. Gratifyingly, 3 61 was obtained in 82% yield by treating 3 60 with only 0. 1 mol % of catalyst system for 48 hours. Figure 3 14. Synthesis of 3 61 T he influence of substituents on the 2 and 6 positions of the THP ring was then investigated Oxidation of geraniol 3 62 to form geranial 3 63 91 using standard Swern conditions gave 92% yield without isomerization of the double bond (oxidation with PCC gave 3 62 as a mixture E : Z 70:30). A ddition of cy clohexylmagnesium chloride to 3 63

PAGE 58

58 followed by quenching of the reaction with acetyl chloride then provided 3 64 The non allylic double bond was selectively epoxidized with m CPBA and diol 3 66 was afforded after reduction and epoxide ring opening using an excess of LiAlH 4 at reflux in ether. Au catalyzed cyclization of 3 66 under standard conditions provided 3 67 in 89% yield. Figure 3 15. Synthesis of 3 67 To further test the functional group compatibility of this transf ormation, the synthesis of a set of molecules with various groups suited for further synthetic transformations was designed Substrates were prepared by addition of an excess of Grignard or organolithium reagents to 3 68 at 78 C (synthesis of 3 68 will be described in detail section 3.2.4.) Cyclization reactions of 3 69 were conducted using the optimized conditions and t he functional group tolerance proved to be broad with the transformations proceed ing smoothly at room temperature. To our delight, 3 73 w as successfully synthesized but required 5 mol % of catalyst at reflux. Interestingly, cyclization reactions to form 3 76 and 3 77 both failed The starting materials were recovered after treating them under standard conditions or with 5 mol % of catalyst at reflux This is probabl y due to the

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59 deactivation of the hydroxyl group by hydrogen bonding to form 3 76 On the other hand, strong affinity of sulfur for gold cationic species inhibits the cyclization to obtain 3 77 Figure 3 16. Functional group scope 3.2.3 Diastereoselec tive Synthesis of 2,6 D isubstituted THP s Dr. Chuan Ying Li investigated the diastereoselective synthesis of 2,6 disubstituted THPs and 2,5 disubstituted THF (Figure 3 17) 33 a Compounds 3 80 to 3 84 were succes sfully synthesized in high yield with moderate to high diastereomeric ratio by reducing the reaction temperature to 50 C or 78 C.

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60 Figure 3 17 Diastereoselective synthesis of 2,6 disubstituted THPs and THF 3.2.4 Scalabl e P r eparation of 2 V inyltetrahydropyrans In the course of this study, a scalable preparation of 2 vinyl tetrahydropyrans 3 89 through Au catalyzed cyclization of 3 88 (Figure 3 18) was required 3 68 was prepared by cross metathesis of 3 85 and 3 86 using o nly 1 mol % of Grubbs 2 nd generation catalyst 87 T he reaction was first attempted using 3 mol % of catalyst and a TBDMS protected hex 5 en 1 ol 3 87 Unfortunately, the product proved to be difficult to purify by flash chromatography due to the formation of various byproducts. This issue was overcome by reducing the catalyst loading to 1 mol % and by using free alcohol 3 85 92 Since Grignard reagent s are not particularly expensive, the unsaturated aldehyde 3 68 w as treated with an excess of n h exyl magnesium bromide at 0 C to form 3 88 in high yield. The Au catalyzed cyclization of 3 88 smoothly provided 3 89 in 91% yield on a 10 mmol scale with a 0.5 mol % catalyst loading. Only 25 mg of gold catalyst was used to cyclize 2.14 grams of diol 3 88 We have never encountered any difficulty when performing this reaction; and predict that this transformation can tolerate larger scale and much lower catalyst loading.

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61 Figure 3 18. Scala ble preparation of 3 89 3.3 Stereoselective Au Catalyzed Synthesis of 2 V inylTHPs 3.3.1 Olefin Dependant Transfer of C hirality C is and trans allylic diols ga ve access to the trans vinyl THP in similar reaction times and similar yields (Figures 3 12 and 3 13). F ormation of a cationic intermediate has also been ruled out (Figure 3 19) by treating 3 40 and 3 90 under the same conditions. 3 9 0 3 91 and 3 92 failed to cyclize even using higher temperatures, higher catalyst loading or even using more Lewis aci dic gold catalysts such as AuCl 3 Figure 3 19. Evidence for a non cationic mechanism.

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62 In the previous section, we used racemic substrates and therefore, we obtained same trans racemic products. Since the mechanism prove d to be non cationic, we hypothesized that using enantioenriched allylic alcohols would provide non racemic tetrahydropyrans under optimized conditions. The synthesis of chiral substrates with different olefin geometries was designed in order to understand the mechanism of this transformation and also to demonstrate that this methodology can give access to enantiorich 2 vi nyltetrahydropyrans. Aldehyde 3 97 was synthesized using the osmium catalyzed dihydroxylation of terminal olefin 3 95 followed by cleavag e of the diol using lead (IV ) acetate. Enantioenriched propargyl alcohol 3 98 was prepared by enantioselective addition of the TBDMS protected hex 5 yn 1 ol to 3 97 using the method developed by Carreira and co workers (Figure 3 20) 93 Reduction of the alkyn e by either hydrogen in presence of Lindlar catalyst or hydrosilylation catalyzed by ruthenium(II) catalyst 94 both followed by fluoride anion mediated deprotection gave 3 99 and 3 101 in good yield and high ee. Enantiomers 3 100 and 3 102 were synthesize d from cis 3 99 and trans 3 101 in high yield and excellent transfer of chirality with both 90% ee T h ese structures were designed in order to determine the absolute configuration of 3 100 and 3 102 by X ray crystallography (with a heavy atom on the phenyl ring). Unfortunately, growing crystals from products 3 100 and 3 102 was not successful However, HPLC analysis and optical rotation measurements showed that 3 100 and 3 102 were enantiomer s

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63 Figure 3 20. Synthesis of 3 1 00 and 3 102 A scalable and more practical synthesis of substrates 3 109 and 3 110 was developed ( Figure 3 21) Ynone 3 107 was first synthesized by addition of 3 54 to 3 10 5 followed by Swern oxidation of the propargyl alcohol. Even though this method wa s very efficient, this process provided a small amount of impurities with 3 107 not separable by flash chromatography and did not give acceptable yields when treated with the Noyori catalyst. Addition of the acetylide of 3 54 to Weinreb amide 3 104 95 gave ynone 3 107 in slightly lower yield but excellent purity suitable for the next step. Using a m odified protocol of the asymmetric transfer hydrogenation 96 with 1 mol % of Noyori catalyst ( R R TsDPEN Ru ) 3 108 was obtained in good yield and high ee. Conventi onal

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64 reductions of the triple bond to form cis and trans diols followed by deprotection of the terminal alcohols gave 3 109 and 3 110 in excellent yields and 96% ee. Figure 3 21. Synthesis of 3 109 and 3 110 Substrates 3 109 and 3 110 were subjected to the standard conditions (Table 3 2). They both transferred the chirality to 3 111 and 3 112 in presence of gold(I) species (Entries 1 and 2, Table 3 2) also giving enantiomers. Interestingly, reducing or increasing the temp erature of the reaction led to significant ly lower yields and a small loss of chirality (Entries 3 and 4, Table 3 2) A control experi ment was conducted showing that the product d id not epimerize in presence of a cationic gold complex (Entry 5, Table 3 2)

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65 Table 3 2. Au catalyzed transfer of chirality. Entry Substrate ee (%) Cond a Product ee(%) Yield (%) 1 3 109 96 40 min r t 3 111 93 9 4 2 3 110 96 35 min rt 3 112 93 91 3 3 109 96 100 min 0 C 3 111 87 78 4 3 109 96 10 min reflux 3 111 87 60 5 a 3 111 93 60 min rt 3 111 93 a 1 mol % Ph 3 PAuC/AgOTf, CH 2 Cl 2 MS 4 The absolute configuration of 3 111 and 3 112 were determined by comparing optical rotations of known derivatives (Figu re 3 22). 3 111 and 3 112 both were treated with ozone and the reaction was quenched with NaBH 4 to reduce the ozonides to form alcohols 3 113 and 3 114 97 Figure 3 22. Absolute configuration of 3 111 and 3 112 T he scope o f the reaction was expanded to more complex chiral structures sharing similar skeletons with naturally occurring molecules. Following the same synthetic

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66 strategies described above in this section ( 3 115 was synthesized in three synthetic step from aminoeth anol) 98 enantioen rich ed morpholines 3 120 and 3 121 were synthesized in high yield from 3 118 and 3 119 (Figure 3 23) The Au catalyzed cyclization proceeded smoothly even in presence of a tosyl protected nitrogen in the allylic position. Figure 3 23. Synthesis of morpholines 3 120 and 3 121 The absolute configuration of 3 120 was determined by comparing optical rotation of the known derivative 3 122 obtained after reductive ozonolysis, mesylation and reduction with Li AlH 4 to the literature value (Figure 3 24). 99 Figure 3 24. Absolute configuration of 3 120 Phenols have also been investigated as nucleophiles (Figure 3 25). Alkyne 3 126 100 was synthesized by protection of 3 123 followed by hydroboration of the olefin,

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67 oxidation of the alcohol followed by Corey Fuchs alkynation of the aldehyde 3 125 Following the same strategy as described above 3 128 and 3 130 we re obtained in high yields and 9 7 % ee When these substrates were exposed to the reaction conditions chirality transfer was observed but with a substantial loss of ee The absolute configuration of the products was also consistent with the previously shown examples (Figure 3 26) 101 Figure 3 25. Synthesis of 3 129 and 3 131

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68 Figure 3 26. Absolute configuration of 3 129 and 3 133 Enantioen rich ed methylene tetrahydropyrans have been successfully synthesized (Figure 3 27). Starting from in expensive starting materia ls, propargylic alcohol 3 142 was synthesized by a copper catalyzed coupling 102 reaction between 3 136 103 and 3 141 104 in 96% yield. 3 136 is the product of the allylic chlorination of TBDMS protected alcohol 3 134 Propargyl alcohol 3 141 has been prepared by e limination of 3 140 using an excess of LDA. 3 143 and 3 145 were obtained following standard procedures described above in this section in high yield and high ee (Figure 3 28). The Au catalyzed cyclization of these two substrates proceeded smoothly and gav e 3 144 and 3 146 in high yields and excellent ee via chirality transfer.

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69 Figure 3 27. Synthesis of propargyl alcohol 3 142 Figure 3 28. Synthesis of 3 144 and 3 146

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70 3.3.2 Additional St ereocenters I nfluence The influence of additional stereocenters on positions 4 and 6 of the tetrahydropyran ring has also been studied. In theory, our method should give access to two different diastereomers depending on the olefin geometry but having ano ther stereocenter on the substrate might also alter the transfer of chirality To study this influence, t he synthesis of 3 154 and 3 156 was first investigated (Figure 3 28) Ring opening of the chiral epoxide 3 149 followed by removal of the TMS group and benzylation of the homopropargylic alcohol gave 3 150 in 40% yield. 105 The ynone formed by addition of 3 150 to Weinreb amide 3 151 106 was subjected to the modifie d protocol of Noyori transfer hydrogenation 96 to g ive 3 152 in 71% yield. Reduction of the alkyne s and deprotection of the terminal alcohols gave 3 153 and 3 155 (dr was determined by Mosher ester analysis) 107 which were treated under the optimized conditions to afford the two diastereomers 3 154 and 3 156 in high yields and diastereoselectivity with excellent chirality transfer T he dr of the products 3 154 and 3 156 was determined by 1 H NMR. 2,6 Disubstituted morpholines with a stereocenter in 6 position (Figure 3 29) were also synthesized. 3 159 108 was prepared by ring opening of epoxide 3 158 protection of the resulting alcohol and propargylation of the N tosylamide. 3 160 was obtained in only 20% yield, due to the presence of the sulfonamide in the propargylic position. The asymmetric Noyori transfer hydrogenation of an ynone containing a N sulfonamide in propargylic position has never been reported to date. 3 162 and 3 164 (dr was determined by Mosher ester analysis) 107 were then synthesized following sta ndard procedures in 93:7 dr and both cyclized to form 3 163 and 3 165 with high transfer of

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71 chirality and good yields. The dr of the products 3 163 and 3 165 was determined by 1 H NMR. Figure 3 28. Synthesis of 3 154 and 3 156

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72 Figure 3 29. Synthesis of 3 163 and 3 165 Gratifyingly, in presence of additional stereocenters, this method prove d to be highly efficient and gave access to two diastereomers starting from a common propargylic a lcohol. 3.3.3 Failed A ttempts Several substrates did not give satisfactory results under the optimized conditions (Figure 3 30). Those substrates have been synthesize d following similar procedures developed in this chapter. 3 166 fully reacted after 2 h but did not give the expected product. Unfortunately, no material was recovered after work up Dioxolane 3 168 and benzodioxolane 3 170 failed to react even using a higher catalyst loading and longer reaction tim e. This can be explained by hydrogen bonding be tween the two hydroxyl

PAGE 73

73 groups. It appears likely that the terminal alcohol hydrogen bonds with the central ether e al oxygen and not with the allylic alcohol. Figure 3 30. Failed attempts. In the course of the initial study of chirality tra nsfer the synthesis of 3 173 was undertaken (Figure 3 31) Surprisingly, while 3 172 easily converted to 3 173 in high yield and 95% ee, 3 174 failed to cyclize and a trityl shift to the primary alcohol was observed. It seems that a subst rate containing a tertiary carbon next to the trans allylic alcohol will fail to cyclize under the optimized conditions. Experiments shown Figure 3 31 also suggested that cis allylic alcohols are more reactive substrates than trans allylic alcohols in pres ence of gold(I) species. T o support the s e statement s 3 177 and 3 179 were synthesized and also both failed to provide the desired product s (Figure 3 32)

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74 Figure 3 31. Synthesis of 3 173 Figure 3 32. Cyclization of 3 177 and 3 179 3.3.4 Predictive Stereochemical M nemonic Analysis of the stereochemi cal outcome of the reaction should help to gain an understanding of how the allylic alcohol influences the facial discrimination. From these data it was show n that the nucleophile add ed to the olefin in a syn manner to the h ydroxyl group. Th is mnemonic shown in Figure 3 30 has proven to be a reliable stereochemical predictor for this transformation that prov ide d both enantiomeric and diastereomeric products.

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75 Figure 3 3 3 Stereochemical mnemonic. 3.3.5 P roposed Catalytic C ycle With these studies, it has demonstrated that gold catalyzed cyclization reactions of mono allylic dio ls exhibit a large functional group tolerance and a high degree of facial selectivity The desired tetrahydropyran enantiomer and diastereomer can be easily synthesized from chiral allylic alcohol s based on olefin geometry. Figure 3 34. Proposed mechanism. A mechanistic study has also b een undertaken to understand the high reactivity and selectivity observed with allylic alcohol substrates. This dehydrative transformation

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76 g ave products resulting from a formal syn S N 2' mechanism ( Figure 3 32). It is proposed that t he Au complex first acti vate s the bond of 3 185 to form complex 3 186 followed by anti addition of the pend ant nucleophilic alcohol. This attack c ould be facilitated by hydrogen bonding with the alcohol ( 3 187 ) Loss of water by anti elimination then form s 3 189 and regenerate s the a ctive catalyst. Our group is currently exploring the mechanism of this reaction with more details. We are studying especially the position of the gold towards the bond as well as the importance of the hydrogen bonding between the two alcohols. 3.4 Au Ca talyzed Cyclization of Mono Allylic Ethers to Form 2 Vinyltetrahydropyran s a Comparative Study 3.4.1 Initial Approach We strongly believed that the method shown above would be highly suitable for the preparation of chiral natural molecules containing tetr ahydropyran motifs. In the course of the application of th is method ology to the synthesis of the Spirastrellolide A, 109 the synthesis of 2,6 disubstituted THP 3 191 was designed Unfortunately difficulties were encountered due to the protecting group scheme Partial retrosynthesis of 3 190 ( Figure 3 35 ) shows that a scalable and enantioselective synthesis of 3 191 was required to further attach this THP to the other fragments of the molecule. The first approach was to prepare 3 191 from an aldol reaction 110 me diated by titanium chloride with 3 19 5 111 3 194 as the source of chirality followed by removal of the TBDMS group (figure 3 36) However, cleavage of the silyl ether 3 196 using TBAF or acidic conditions lead to the elimination of the hydroxy acetyloxazolidin one 3 197 Various temperature s and reaction conditions were examined but did not give satisfactory results.

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77 F igure 3 35. Partial retrosynthet i c analysis of Spirastrellolide A. Figure 3 36. Attempts to synthesize 3 193 One potential solution to this problem is to use a different leaving group. T he same transformation was attempted but a methyl ether instead of the free allylic hydroxyl group Aldol reaction gave the enantiopure alcohol 3 199 in moderate yield which was treated with 5 mol % catalyst at 0 C To our delight, the expected product 3 200 was obtained as a single diastereomer in 89% yield. It appear s that other groups can eliminate during this tra nsformation and also that the reaction was perfectly

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78 diastereoselective. In comparison, Dr. Chuan Yang Li showed that low temperat ure s ( 50 or 78 C) were required in order to obtain a dr up to 12:1 starting from mono allylic diols. 33 a Figure 3 37. Efficient synthesis of 3 200 3.4.2 Synthetic Aspect Although the features of Au catalyzed cyclization of mono allylic diol are attractive from a synthetic point of view, the disadva ntage is that both the nucleophile and the electrophile are alcohols (Figure 3 38) Having two unprotected non equivalent alcohols on the same molecule might involve a complex protection/deprotection scheme The problem would be partially solved if the ele ctrophilic alcohol was protected with a group that would tolerate a large panel of reaction conditions and that would not need to be remove d before the Au catalyzed cyclization. This lead us to expand the method to the elimination of other leaving groups which can be used as protecting group if needed. Since alcohols are considered very poor leaving groups, but perform extremely well in this system, it seemed likely that a fairly robust group could perform satisfactorily here. As part of a shared project w ith Thomas Ghebreghiorgis, the relative speed of reaction using different types of leaving groups on the allylic moiety was studied. First, we faced several challenging practical aspects. Since the reaction proved to be very

PAGE 79

79 fast, a continuous analytical m ethod was necessary. The monitoring of the reaction by GC analysis using n decane as an internal standard was explored. Also, it was observed that reproducible results could not be obtained when using the catalyst system Ph 3 PAuCl/AgOTf. Therefore, the use (MeCN) Au[P(t Bu) 2 (o biphenyl)]SbF 6 1 5 emerge d as a better alternative. This catalyst has the advantages of higher molecular weight and the catalyst is already activated. Figure 3 38. Allylic alcohol purpose. The reaction proved to be very fast and our initial studies showed that the reaction proceed ed even after high dilution of the reaction mixture for GC analysis. In a typical experiment, the reaction is generally filtered through a short p lug of silica, but for small To address this problem, the use of a metal scaveng ing reagent was explored to stop the reaction To the best of our knowledge, the use of resin bound scavenging agents in homogeneous gold catalysis has nev er been repo rted in the literature and needed to be validated. 3.4.3 Validation of Au Catalyst Quenching M ethod U sing QuadraP ure TM To determine if this method would be reliable, a validation experiment was performed 3 40 was treated with 5 mol % of 1 5 a nd the reaction quenched with QuadraPure TM MPA beads 3 201 after 1, 3 and 5 minutes (Figure 3 39 and 3 40) As a control experiment, a 25 L sample taken after 3 minutes was diluted in 400 L of

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80 CH 2 Cl 2 but w as not expose d to the resin. After 16 hours, this aliquot showed a 95% conversion showing that 3 201 is necessary to stop the reaction. Figure 3 39. Quad raPure TM MPA 3 201 Figure 3 40. Quenching experiment using 3 201 The reproducibility of the analysis needs to be mentioned At several point s in the experiment showed above (Figure 3 40), the analysis ha s been done fi ve times with the same sample. For each set of data an error of 2% in average was obtained with a standard deviation of 0.92%. This experiment validated the method to study the relative speed of reaction between different substrates and show ed that the analytic method is reliable (Figure 3 41)

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81 Figure 3 41. Illustrated protocol for monitoring the conversion of 3 40 3.4.4 Comparison of Different Leaving/Protecting Groups Several common ly used protecting groups have bee n screened under the optimized conditions. The synthesis of compounds 3 204 3 208 was performed by reduction of propargyl alcohol 3 202 to form trans allylic alcohol 3 203 112 (Figure 3 42). The latter was protected on the allylic moiety followed by the dep rotection of the terminal non allylic alcohol with PPTS in methanol or TBAF. Figure 3 42. Synthesis of 3 204 3 208 Cyclizations of protected allylic alcohols have been achieved using 5 mol % catalyst at rt. The reactions were monitored by GC analysis and the conversions of each substrates are reported Figure 3 43 From the graph, it was shown that Me, Bn, TBDPS

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82 and THP groups could be suitable for this transformation (Figure 3 43) However, the allyl ester 3 208 cyclized very slowly. This method could provide a good alternative synthetic strategy to the Pd(0) activation of allyl esters to form allylpalladium complexes 113 since this transformation is chemoselective for acetals ( 3 207 ) and ethers 3 208 failed to cyclize du e to the hydrogen bonding involved between the hydroxyl group and the ester moiety. The proposed mechanism (Figure 3 34) shows that the bond is facilitated by the hydrogen bonding. When 3 208 is used as substrate, the oxygen from the este r doing the hydrogen bonding is less rich in electrons than an ethereal oxygen. Therefore, Au catalyzed addition of the alcohol to the olefin is slower (Figure 3 43) Figure 3 4 3 Screening of commonly used protecting g roups.

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83 After studying the different leaving groups, it was also important to investigate the tunability of the olefin. Depending on the synthetic st rategy, two different types of o l e fin s could be obtained ; it was then important to compare the ir behavior u nder the same reaction conditions. 3.4.5 Influence of Olefin Geometry and Substituent on the Allyl Moiety The rate of the reaction with different olefin geometries of substrates 3 40 and 3 209 were compared Both molecules cyclize d very rapidly in similar times and percent conversions (Figure 3 44) 3 209 proceed ed slightly faster but 3 40 ga ve a higher conversion. Conditions: 5 mol % Au[P( t Bu) 2 ( o biphenyl)]SbF 6 CH 2 Cl 2 MS 4 Figure 3 44. Reaction progress in cis and trans diols. T he conversions of cis and trans methyl ethers 3 204 and 3 210 to form 3 41 under standard conditions has also been explored This experiment show ed that the

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84 cyclization proceed ed extremely well with methyl ethers with almost no noticeabl e difference between both substrates 3 204 (89% conversion) and 3 210 (93% conversion) Methyl ethers prove d to be suitable for this transformation and c ould be used in a complex synthetic scheme. T hey have the advantage of being resist ant to a large varie ty of reaction conditions. Conditions: 5 mol % 1 5 CH 2 Cl 2 MS 4. Figure 3 45. Reaction progress in cis and trans methyl ethers. Finally, the effect of a substituent on the allylic alcohol has been explored Primar y ethers 3 204 and 3 210 and secondary ethers 3 211 and 3 212 were compared under the standard conditions (Figure 3 46) This set of experiments show ed that secondary allyl ethers 3 211 and 3 212 slowly convert ed to 3 52 However, acceptable yields were

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85 o btained if the reaction is run for 48 hours. Also, it appeared that cis ethers 3 210 and 3 212 react ed slightly faster than the trans ethers 3 204 and 3 211 Conditions: 5 mol % 1 5 CH 2 Cl 2 MS 4 Figure 3 46. Co mparison of 1 and 2 allylic ethers. 3.5 Outcome and Current Work Gold catalyzed dehydrative transformation s is a growing field of investigation with many new avenues to be explored. The initial studies demonstrated that the gold catalyzed exo cyclization of monoallylic diols to form 2 vinyltetrahydropyrans occurs in high yield; has a large functional group tolerance ; and exhibits a high degree facial selectivity. The reaction scope has been extended to a large variety of leaving groups on the allylic moiety. We believe that having the choice of different

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86 protecting groups on the allylic alcohols for the Au cyclization is a very useful tool that warrants further exploration in a synthetic project. Even though the chirality transfer study provided sev eral evidence about the mechanism of the reaction; further investigation need s to be conducted to rule out any other type of potential mechanism such as a syn addition/ syn elimination To explore the reaction mechanism, Thomas Ghebreghiorgis and I are stud ying the relative position of the gold specie s on the olefin. Compounds 3 213 3 214 and 3 215 were designed to show that the activation of the olefin proceeds in an anti manner and rule out a potential syn addition of the hydroxyl group to the metal (Figu re 3 47) Thomas Ghebreghiorgis first showed that the reaction d id not proceed when both allylic and non allylic alcohols were on opposite side and that no hydrogen bonding was possible between them (F igure 3 47). It show s that the reaction was an anti add ition, indeed the concave structure of 3 214 d oes not give much room to the gold specie s to complex on the opposite side of the pend ant non allylic alcohol and therefore drastically slowed the reaction down On the other hand, if the reaction was proceedin g as a syn addition, the transformation should be favored and proceed ed more rapidly. 3 216 was isolated in 83% yield after 24 hours using 5 mol % of catalyst. The last experiment performed was to treat 3 215 under the standard conditions (F igure 3 47) Wi th this substrate, t he nucleophilic attack comes from inside the concavity of 3 215 allowing for H bonding In theory, complexation of gold should favor the reaction and syn addition would be unfavored due to the difficult access to the internal position. The reaction proceeded extremely fast with only 1 mol % of catalyst and 3 217 was isolated in 96% yield. This set of experiments shown Figure

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87 3 47 is consistent with an anti addition of the pendant non allylic alcohol to the gold olefin complex. Moreover Thomas Ghe breghiorgis demonstrated that hydrogen bonding is necessary for the reaction to proceed. Figure 3 47. Evidence for a Au catalyzed anti addition. Further studies are on going in our la boratory in collaboration with P rofessor Daniel H. Ess a computational chemist at Brigham Young University.

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88 CHAPTER 4 AU CATALYZED CYCLIZATIO N OF O (1 HYDROXYALLYL) PHENOLS TO FORM 2 H CHROMENES 4.1 Background and Significance 4.1.1 2 H C hromenes in Biological Active Pharmaceuti cals The 2 H chromene structural motif is an important core structure found in many different biologically active molecules (Figure 4 1) 114 Examples include numerous types of pharmaceutical fungicidal and insecticidal agents Figure 4 1. 2 H and 4 H chromenes. Selected examples of biologically active 2 H chromenes are shown Figure 4 2. They include anti HIV agent 4 3 115 anti tumor drug Acronycine 4 4 116 anti oxidant vitamin K 1 4 5 117 and antibiotic Iclaprim 4 6 118 The latter is currently on phase II of clinical trials for treatment of nosocomial infection s. Anti fungal and insecticidal activity was also reported for 2 H chromenes. Selected examples are shown Figure 4 2 for 4 7 119 and 4 8 120 Although 2 H chromenes are important in a variety of fields, their preparation remain s a challenge and synthetic methods are often limited to specific substrates. For these reasons, more general methods need to be developed to have fast and efficient access to a wide variety of these highly usef ul compounds.

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8 9 Figure 4 2. Selected examples of 2 H chromenes in pharmaceuticals. 4.1.2 Classical Methods of 2 H Chromenes Synthesis, Scope and Limitations Efficient classical methods have been reported for the synthes is of 2 H chromenes. They have prove n to be highly reliable for the preparation of simple molecules (Figure 4 3 ) A brief description of each of these types of reactions follows. Figure 4 3 Summary of 2 H chromenes synthesis cl assical methods.

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90 2 H chromenes can be easily synthesized by addition of unsaturated carbonyl 4 14 to salicylaldehyde 4 13 Kay and co workers reported the synthesis of 3 ketochromenes 4 16 by an intermolecular Baylis Hillman reaction followed by Michael addition and subsequent elimination (F igure 4 4 ) 121 122 This method is extremely practical and easy to scale up however, reaction times are long and this transformation is limited to a narrow substra te scope A Petasis condensation has been reported by Finn and co workers to synthesize substituted 2 H chromenes (F igure 4 4 ) 123 This reaction gave 4 20 in high yield through coordination of the phenolate to the boronic acid 4 17 and addition to the iminium ion followed by S N cyclization This reaction appears t o be limited to benzaldehydes as no examples has been reported with ketone substrates. Figure 4 4 Synthesis of 2 H chromenes by addition to the benzaldehyde. Electrophilic aromatic substitution is a very efficient way to synthesize chromenes. Larock and co workers reported the alkyne activation by iodide to synthesize 4 aryl chromenes (F igure 4 5 ) 124 Compound 4 23 was obtained in 77% yield from 4 21 using 2 equivalents of iodine at room temperature. This method is also ver y reliable but all the

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91 reported examples contain an aryl group on the alkyne moiety and g a ve low yields with electron withdrawing groups on the phenol ring. A more conventional protocol has been reported by Nichols and co workers (F igure 4 5 ) 125 They synthe sized 4 27 from 4 24 in three synthetic steps. Triflate 4 25 was obtained by treating carboxylic acid 4 24 with thionyl chloride under Friedel Crafts conditions followed by formation of the enolate with NaHMDS and trapping with (TfO) 2 NPh Pd (0) catalyzed c oupling of 4 26 and 4 25 gave 4 27 in 77% yield. This method require d three synthetic steps but c ould give access to a large variety of 2 H chromenes. Figure 4 5 Synthesis of 2 H chromenes through aromatic nucleophil ic substitutions. One of the most common way s to synthesize 2,2 dimethylchromenes is by oxidative pyranocyclization. Use of this method has been well documented 126 and an example is shown Figure 4 6. As can be seen, 4 30 was readily prepared from 4 28 in 81% yield using one equivalent of DDQ in benzene at reflux. 127 This method is limited to the synthesis of 2,2 disubstituted chromenes

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92 Figure 4 6 Oxidative pyranocyclization. 4.1.3 Modern Metal Catalyzed Synthesis of 2 H Chro menes More recent developments have been reported over the past 10 years using transition metal catalysts. These transforma tions usually occur under mild conditions and exhibit a larger substrate scope with a high chemoselectivity. Transition metal catalyz ed hydroarylation reactions ha ve been extensively employed to synthesize 2 H chromenes (Figure 4 7 ) Figure 4 7 Metal catalyzed electrophilic aromatic substitutions. Youn and co workers reported the Pd(II) catalyzed oxida tive cyclization of ether 4 33 to form 2 H chromene 4 34 (F igure 4 8 ) 128 The reaction proceeded in good yield at room temperature in dioxane using one equivalent of oxidizing agent (benzoquinone). Ohno and co workers successfully activated allenes with a gol d(I) species to form benzopyrans (F igure 4 8 ). 129 Compound 4 35 was obtained from 4 36 using 1 mol % of catalyst in dioxane at 60 C for 1 hour In 2003, Echavarren and co workers investigated the reaction of alkyne s with electron rich arene s catalyzed by Pt( II) (F igure 4 8 ). 130 Product 4 38 can be easily prepared from 4 37 using only 1 mol % of catalyst.

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93 The reactions presented above all require d electron rich arene s in order to facilitate the electrophilic aromatic substitution. Low or moderate yields were ob tained with neutral or electron poor aromatic rings. However, reaction conditions were mild and allowed for low catalyst loading s Figure 4 8 Selected examples of metal catalyzed hydroarylation. Other modern methods ha ve been investigated. Among the se, the Ru catalyzed ring closing metathesis of dienes to form 2 H chromenes is a practical and versatile transformation (F igure 4 9 ) 131 Compound 4 39 was treated with 2 mol % of Grubbs 2 nd generation catalyst at room temperature and gave 4 40 in 97% yield. This method tolerates a large variety of functional groups on the phenyl moiety but an additional substitution on the diene requires much higher catalyst loading s and temperatures. Additionally, styrenes are not always the most stable substituents. Jana and co workers recently reported the FeCl 3 catalyzed intramolecular alkyne/carbonyl metathesis of 4 41 to form 4 43 (F igure 4 9 ) 132 The reaction proceeded using 15 mol % of catalyst in good yield. The su bstrates are easily synthesi zed from salic yl aldehyde derivatives and the

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94 catalyst used is in expensive. However, this transformation doe s not tolerate any substitution at the 2 and 4 positions of the 2 H chromene. Figure 4 9 Other selected modern ex amples of 2 H chromenes synthesis. 4.2 Rationale A large panel of interesting methodologies ha s been reported for the synthesis of 2 H chromenes but a more general and relia ble methodology ha s remain ed elusive In a n ideal synthesis, t he new method should to lerate a large variety of functional groups and substi tution while also allowing for substrates originating from easily accessible and in expensive starting materials. In the course of the study of Au catalyzed conve r s i on of mono allylic diols to form tetra hydropyrans 33 the endo cylization was investigated (Figure 4 1 0 ) Unsu c c e ss ful results were obtained with aliphatic alcohols 4 44 a and 4 44b but we were interested in the behavior of a benzylic allylic al c ohol under the same optimized conditions Additionally, w e hypothesized that the conformational constraint of 4 46 may favor the cyclization to form 4 1

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95 Figure 4 1 0 Endo cyclization of mono allylic diols. 4. 3 Optimization o f Reaction Conditions To test this hypothesis, 4 47 was prepared from the corresponding benzaldehydes and treated with Au complexes. A variety of conditions were screened for the dehydrative cylization of 2 (1 hydroxyallyl)phenol 4 47 to form 2H chromene 4 48 ( Figure 4 1 1 and Table 4 1). For r eactions using dichloromethane as solvent, only decompos ition products were observed (Entries 1 4 Table 4 1 ). More coordinating solvents such as THF, Dioxane or MeCN proved to be better alternatives for this reaction. Gratifyingly, t he highest yield was obtained using 5 mol % of catalyst 1 3 and AgOTf in THF at reflux (Entry 9 Table 4 1 ). Surprisingly, t he reaction required heat ing and no conversion was observed at room temperature. A control experiment was conducted with 5 mol % of AgOTf but no conversion was observed, demonstrating that both the Au and Ag complex are required for the reaction (Entry 15 Table 4 1 ).

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96 Figure 4 1 1 Au catalyzed cyclization of 3 52 Table 4 1. Optimi zation and control experiment. Entry a R Cat (mol %) Solvent Time Temp Yield (%) b 1 H Ph 3 PAuCl/AgOTf (5) CH 2 Cl 2 30 min rt Decomp 2 H AuCl 3 (2) CH 2 Cl 2 10 min rt Decomp 3 H AuCl/AgOTf (2) CH 2 Cl 2 30 min rt Decomp 4 H 1 3 /AgOTf CH 2 Cl 2 20 min rt Decomp 5 H Ph 3 PAuCl/AgOTf THF 16 h rt NR 6 Cl Ph 3 PAuCl/AgOTf THF 16 h 66 C 21 7 H 1 3 /AgOTf (5) THF 16 h rt NR 8 H 1 3 /AgOTf (5) MeCN 16 h 82 C 42 9 H 1 3 /AgOTf (5) THF 5 h 66 C 82 10 H 1 3 /AgOTf (5) Dioxane 1 h 101 C 55 11 H 4 49 (5) THF 4 h 66 C Decomp 12 Cl 1 3 /AgOTf (5) Toluene 1 h 0 C NR 13 Cl 1 3 /AgOTf (5) Toluene 20 min rt Decomp 14 Cl 1 3 /AgOTf (5) Toluene 20 min 111 C Decomp 1 5 Cl AgOTf (5) THF 16 h 66 C NR a The reactions were carried out on a 0.5 mmol scale at 0.2 M in substrate with the indicat ed solvent temperature, and time. b Isolated yields. Several additional Lewis acids such as BF 3 OEt 2 Zn(OTf) 2 InBr 3 Yb(OTf) 3 FeCl 3 and Pd(OAc) 2 were also screened, but in all cases only trace amount of product were observed accompanied by extensive decomposition 4.4 Substrate Scope Using the optimized conditions, the substr a te scope of this transformation w as explored with emphasis on the electronic nature of the benzene ring. A ll substrates contain a phenolic hydroxyl group ortho to the allylic alcohol. Su b s t r a tes 4 51 were synthesized by addition of an excess of Grignard reagent to salicylaldehyde derivatives 4 50 (Figure 4 1 2 ) The se substrates proved to be fairly reactive and the best results

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97 were obtained when they are quickly purified by flash chromatography and immediately subjected to the Au catalyzed cyclization condition s Figure 4 1 2 Preparation of substrates. T he electronics of the group para to the nucleophilic hydrox yl group was first varied The reaction proceeded in a similar fashion when the p hydrogen was replaced with a methoxy group ( E ntry 1 Table 4 2 ). Addition of an activating group on the phenyl moiety might fac ilitate the formation of a carbocation and does not alter the yields or reaction times. Inclusion of the dioxolane moiety however failed to c yclize and gave a fast decomposition of 4 62 after one hour (Entry 7, Table 4 2). These results imply that the formation of a stabilized carbocation is not suitable for this transformation. T he yield was higher and the reaction time shortened with a p nitr o substituent ( E ntry 2 Table 4 2 ). This reaction was observed to be smoother and can be conducted at room temperature giving 79% yield after 48 hours (Entry 3 Table 4 2 ). In this case, having a deactivating group on the benzene ring makes the substrate m ore stable under Lewis acidic conditions and the cyclization proceeds more easily. When 4 56 was treated under the optimized conditions, the reaction time was shortened and gave 75% yield. Deactivating substituents on the benzene ring increase the acidity of the phenol and therefore facilitate the addition to the olefin. The same trend was observed with other benzenoid substrates and substituted napht h ol also reacted cleanly (Entries 4 6 and 8 Table 4 2)

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98 T able 4 2 Reaction scope. Entry Substrate Produc t Time (h) Yield (%) a 1 4 52 4 53 20 74 2 3 4 54 4 55 5 48 b 91 79 4 4 56 4 57 0.3 75 5 4 58 4 59 20 72 6 4 60 4 61 2 80 7 4 62 4 63 1 Decomp 8 4 64 4 65 2 53 a Isolated yields. b Reaction performed at room temperature. 4.5 Substituent Effect s on the Allyl Moiety As can be se en in Table 4 2, the functional group tolerance on the aryl moiety seem ed to be quite broad in this transformation The next step of the investigation was

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99 to study the substitution on the allyl moiety. To this end, su b s trates 4 68 were prepared by addition of an excess of the corresponding Grignard reagent to 5 chloro salicylaldehyde 4 66 or 5 chloro 2 hydroxyacetophone 4 67 (Figure 4 13) Figure 4 1 3 Synthesis of substrates 4 68 Figure 4 1 4 Substituent effect on the allyl moiety. Using this method, a methyl group was systematically included on each position in the substrates and the effect on the Au catalyzed cyclization was studied. Methyl substitution in position 2 of the 2 H chromene d oes not affect the yield or reaction time (Figure 4 14). An increased in the reaction rate was observed when tertiary allylic alcohol 4 73 was treated under the standard conditions and gave similar yield (F igure

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100 4 14). This rate accelartion can be due to t he Thorpe Ingold effect having germinal substituents in allylic position. Also, the elimination step could proceed faster because a teriary alcohol should be easier to eliminate than a secondary or primary alcohol. Surprisingly, 4 76 was obtained only in t race amounts, even after 48 h ours with the majority of the starting diol 4 75 recovered. It is likely that s ubstitution at this position is difficult because alkoxymeta lation would form a 3 alkyl gold intermediate (F igure 4 14) Geminal dimethyl groups in position of 2 of 2 H chromenes are commonly found in natural products. 114 T he formation of 4 80 through cyclization of 4 78 using the optimized conditions (Figure 4 1 5 ) was explored Unfortunately, purification by flash chromatography of 4 78 produced the allylic alcohol 4 79 which failed to cyclize under the standard conditions. 133 To solve this isomerization problem, it was decided to use the crude material of 4 78 for the Au catalyzed endo cyclization. G ratifyingly 4 80 was obtained in 73% yield over two steps. The nature of the different substituents on the allylic region appeared to have a large impact on the reactivity o f this transformation. The type of substituent on the benzylic alcohol is also important because it may control the elimination step. Therefore, a broader substituent scope on the allylic moiety was investigated.

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101 Figu re 4 1 5 Synthesis of 4 80 4.6 A Convenient Synthesis of Neoflavenes 4.6.1 Neoflavenes Neoflavenes, also called 4 phenyl 2 H chromenes were originally isolated from a natural source. It is one of the five main structural types found in the neoflavonoid d erivatives (Figure 4 1 6 ). 134 Attention to their biological action appeared relatively late and their acti vity remains limited. However, n eoflavenes are extremely important intermediates for the synthesis of more complex structures (Figure 4 1 7 ) such as Haema toxylin 4 83 135 ( stain used in microbiology ) or Procyanidin B 2 4 84 136 (promotes hair growth) 137 Figure 4 1 6 Neoflavonoid and Neoflavene.

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102 Figure 4 1 7 Selected e xamples of n atural p roducts fro m the n eoflavonoid f amily. Several synthetic methods have been developed to prepare n eoflavenes. Suzuki cross c oupling (F igure 4 1 8 ) 138 and ring closing metathesis (F igure 4 1 8 ) 139 gave good yields but the scope of the reaction is limited to electron rich aren es. In addition the synthesis of 4 87 required five synthetic steps. An alternative method relie s on electrophilic aromatic substitution by metal activation of an alkyne (F igure 4 1 8 ) 140 141 h owever, selectivity between 4 90 and 4 91 is moderate Figure 4 1 8 Metal catalyzed synthesis of Neoflavenes.

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103 4.6.2 Au Catalyzed Synthesis of Neoflavene Using the same methodology described in Chapter 4 of this dissertation; a convenient synthesis of neoflavenes starting from in expensiv e starting materials was developed Substrates were synthesized in two steps from salicylaldehyde 4 13 by palladium cata lyzed coupling with iodobenzene derivatives 142 followed by addition of vinyl magnesium bromide to ketone 4 93 at low temperature (Figure 4 19 ) Figure 4 19 Preparation of 4 94 Substrates 4 94 were treated under the previously optimized conditions (Figure 4 20 ) and 4 95 was obtained in excellent yield a fter a brief reaction time. Elimination step is faci litated by having an electron donating group on the top phenyl moiety. Compounds 4 96 and 4 97 proceeded smoothly in 3 and 24 hours respectively, in good yields. Inclusion of a nitro group in para position reduced the reactivity significantly and only 33% of 4 98 was obtained after 24 hours at reflux. The elimination of water after addition to the bond can be drastically slowed down with the presence of a nitro group in para position of the top phenyl ring. It appears very clearly from these results that electro n donating groups in para position to the allylic alcohol accelerate the reaction and electron withdrawing groups slow down the elimination step To further probe this hypothesis 4 99 was treated under the same standard conditions and gave 4 100 i n

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104 good yield after 4 hours. As expected, adding an electron donating group in para position of the other benzene ring gave shorter reaction time. Figure 4 2 0 Au catalyzed synthesis of Neoflavene. 4.7 Mechanistic Conside rations and Control Experiments Mechanistically, formation of a cationic intermediate was first suggested where g old would behave as a typical Lewis Acid and ionize the benzylic position. 143 However, a set of experiments conducted using transposed allylic al cohols showed that gold(I) was not Lewis acidic enough to form a carbocation and therefore 4 101 and 4 102 failed to cyclize. Nevertheless we cannot rule out the formation of a cationic intermediate for substrates such as 4 94 which may be more ionizable (Figure 4 21) Alternatively, the mechanism may proceed via a fully formed cation, but instead may have partial positive charge on this cation and thus be accelerated by electron donating groups. It is also possible that more than one mechanism exists. The se results are congruent with the data discussed Table 4 2. Formation of a cationic intermediate is highly unlikely since

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105 activating groups on the benzene moiety did not give satisfactory yields and since having withdrawing groups give smoother conversion. Figure 4 2 1 Control experiments. In further control experiments, c ycliz ation of s ubstrates 4 103 and 4 104 using triflic acid (Figure 4 2 2 ) did not proceed and gave extensive decomposition. This set of experiment s also demonstrates that formation of a cation ic intermediate was not suitable for this transformation. Figure 4 2 2 Control experiments using triflic acid The other mechanistic explanation is that gold(I) acts as a acid and activates the olefin, which is the generally accepted role in Au catalyzed processes 1 Allyl alcohol 4 105 would be activated by the gold(I) specie s followed by nucleophilic addition to form 4 106 wh ich after protodeauration and elimination would give 4 107 ( Figure 4 2 3 )

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106 Figure 4 2 3 activation of the olefin. In the course of a related project, the synthesis of Daedalin A 4 108 144 ( prevent s hyperpigmentation and ex hibits anti inflammatory activity ) 145 has been investigated. Daedalin A was an in teresting target as known synthese s of this molecule are relatively long (over 10 steps) 146 and the utility of this method for the transfer of chirality from the allylic alcohol t o the 2 position of the 2 H chromene could be proven (F igure 4 24) However, the model substrate 4 111 failed to give the expected result (F igure 4 24) Surprisingly, 4 112 was obtained as major product resulting from the exo cyclization. Only traces of end o product 4 113 were detected by 1 H NMR and a longer investigation was not pursued This experiment confirmed the complex formation between the olefin and the gold catalyst and again giving further evidence to rul e out the cationic nature of this transfo rmation with the s e type s of substrates. Figure 4 2 4 Model Study Daedalin A.

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107 4.8 Outcome In conclusion, a convenient and a highly adabtable catalyst/substrate system for the gold( I ) catalyzed endo cyclization of o (1 h ydroxyallyl) phenols to form 2H c hromenes has been reported. The susbstrate scope proved to be broad including electron rich and electron deficient groups on the benzene moiety. This method was extended to the synthesis of neoflavenes. C ontrol experiment s show n in this section suggest that the mechanism may be substrate dependant. However, for a majority of substrates, it appear s that the olefin is activated by the cationic gold(I) specie s followed by dehydrative elimination. For more electron rich substr ate s formation of a cationic intermediate could not be ruled out

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108 C HAPTER 5 CONCLUSION AND OUTLO OK Over the past five years, the activation of unsaturated alcohols by gold complexes has been intensively investigated and these studies have led to the discovery of efficient methodologies that utilize readily available substrates to increase molecular complexity. These transformations are typically simple to perform, the reactions conditions are mild and the yields are high The work described in this t hesis work focused on the development of new m ethodologies for the construction of oxygen heterocycles using gold salts as catalysts. Gold catalyzed dehydrative cyclization is a growing field of investigation with m any new avenues to be explored. Our initi al studies demonstrated that the gold catalyzed exo cyclization of monoallylic diols to form 2 vinyltetrahydropyrans occurs in high yields (F igure 5 1) ; it has a large functional group tolerance and exhibit s a high degree of facial selectivity with trace less transfer of chirality Further investigations showed that allylic ethers can be used as electrophiles and perform in high yield and high diastereoselectivity. From a synthetic prospective the tuning of the allylic moiety could become an efficient too l in the synthesis of complex natural molecule s and could save multiple protection/deprotection steps. The methodology was also exten ded to e ndo cyclization reactions which appear to be a much more challenging transformation (F igure 5 1) but the synthes is of substituted 2H chromenes was readily accomplished This methodology has a broad scope and the substrates are extremely easy to synthesize from inexpensive starting materials.

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109 Despite the progress made in this field, challenging aspects such as enant ioselective intermolecular reactions remain unsolved. However, intermolecular additions of allylic alcohols to alkynes are being investigated by our group and will provide a more thorough mechanistic understanding of the reactivity of unsaturated alcohols in the presence of cationic gold species. Application of these methodologies to the total synthesis of complex natural products has started to emerge and reports are expected to multiply as new reactions are developed. Fi gure 5 1. Dehydrative gold cyclization of allylic alcohols and ethers.

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110 CHAPTER 6 EXPERIMENTAL SECTION 6 .1 General R emarks All reactions were carried out under an atmosphere of nitrogen unless otherwise specified. Anhydrous solvents were transfer red via syringe to flame dried glassware, which had been cooled under a stream of dry nitrogen. Anhydrous tetrahydrofuran (THF), acetonitrile, ether, dichloromethane, and pentane were dried using a m Braun solvent purification system. Analytical thin layer chromat ography (TLC) was performed pre coated plates (EMD Chemicals Inc.). Flash column chromatography was performed using 230 400 Mesh 60 Silica Gel (Whatman Inc.). The eluents empl oyed are reported as volume/ volume percentages. Melting points were recorded on a MEL TEMP capillary melting point apparatus and are uncorrected. High performance liquid chromatography (HPLC) was performed on Shimadzu. Gas Chromatography analyses were obtained using a Hewlet t Packard HP 5890 Series II FID Detector. Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded using Varian Unity Inova 500 MHz and Varian Mercury 300 MHz spectrometers. Chemical shift ( ) is reported in parts per million (ppm) downfield rel ative 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 nucl ear magnetic resonance ( 13 C NMR) spectra were recorded using a Varian Unity Inova 500 MHz and Varian Unity Mercury 300 spectrometer at 75 MHz. Chemical shift is reported in ppm relative to the carbon resonance of CDCl 3 (77.00 ppm). Specific Optical rotati ons were obtained on a JASCD P 2000 Series Polarimeter (wavelength = 589 nm). Infrared

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111 spectra were obtained on a Perkin Elmer Spectrum RX 1 at 0.5 cm 1 resolution and are reported in wave numbers. High resolution mass spectra (HRMS) were obtained by The M ass 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. 6 .2 Chemical P rocedures 6 .2.1 Synthesis of Substituted 2 Vinyl tetrahyd ropyrans 2 vinyltetrahydro 2H pyran ( 3 41 ). Dry CH 2 Cl 2 ( 1.0 mL) was added to an aluminum foil covered test tube containing PPh 3 AuCl (12.0 mg, 0.025 mmol), AgOTf (6.1 mg, 0.025 mmol) and activated MS 4 (25 mg) After stirr ing for 10 minutes, a solution of ( E ) hex 1 ene 1,6 diol 3 40 (75.2 mg, 0.50 mmol) in dry CH 2 Cl 2 (1.0 mL) was added After TLC analysis showed the reaction to be complete ( 15 min ), it was diluted with CH 2 Cl 2 and filtered through a short plug of silica. The solution of crude product was concentrated, and then purified by flash chromatography (5% EtOAc/ hexanes ) to give the product as a colorless oil that satisfactorily matched all reported data above. ( E ) 7 oxohept 5 enyl ace tate ( 3 48 ). A solution of hex 5 enyl acetate 3 47 (170.1 mg, 1 mmol) and crotonaldehyde (350.1 mg, 5 mmol) in dry CH 2 Cl 2 (2 mL) was added to a solution of Grubbs 2 nd generation catalyst (25.5 mg, 0.03 mmol, 3 mol %) in dry CH 2 Cl 2 (3 mL). The mixture

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112 was stirred at reflux for 2 hours and then cooled to rt. Silica gel (200 mg) was added and the reaction mixture was stirred open to air for 30 min. The solvent was removed and the crude product was purified by f lash chromatography (50% EtOAc/hexanes ) to give t he product as a yellow oil (116.8 mg, 92%) that satisfactorily matched all previously reported data. ( E ) 1 cyclohexylhept 2 ene 1,7 diol ( 3 51 ). A solution of cyclohexylmagnesium bromide (2 M in Et 2 O, 1.120 mL, 3.3 eq.) w as added dropwise to a solution of 3 48 (100 mg, 0.78 mmol) in dry THF (6 mL) at 78C. The mixture was stirred 2 h ours and then quenched with NH 4 Cl (6 mL of a saturated aqueous solution), diluted with water (30 mL) and extracted with CH 2 Cl 2 (3x20 mL). The combined organic layers were dried over MgSO 4 concentrated, and purified by f lash chromatography (30% EtOAc/hexanes ) to give the product as a colorless oil (146.9 mg, 71%). R f = 0.12 (20% EtOAc/ hexanes ); IR (neat) 3356, 2924, 2852, 1449, 1003, 433 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): 5.59 (dt, J = 6.3, 15.3 Hz, 1H), 5.45 (dd, J = 6.9, 15.3 Hz, 1H), 3.75 (t, J = 7.2 Hz, 1H), 3.63 (t, J = 6 Hz, 2H), 2.06 (q, J = 6.9 Hz, 2H), 1.86 0.88 (m, 18H); 13 C NMR (75 MHz, CDCl 3 ): 132.7, 132.1, 77.84, 62.93, 43.88, 32.40 32.18, 29.0, 28.9, 26.7, 26.3, 26.2, 25.6; HRMS (ESI) Calcd for C 13 H 23 O 2 (M H) + 211.1693, found 211.1704. ( E ) 2 (2 cyclohexylvinyl) tetrahydropyran ( 3 52 )

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113 Dry CH 2 Cl 2 ( 0.7 mL) was added to an aluminum foil covered test tube containing PPh 3 AuCl ( 1. 3 mg, 0.00 3 mmol), AgOTf (0.7 mg, 0.00 3 mmol) and activated MS 4 ( 25 mg) After stirring for 10 minutes, a solution of diol 3 51 (56.1 mg, 0. 2 6 mmol) in dry CH 2 Cl 2 (0.7 mL) was added After TLC analysis showed the reaction to be complete ( 40 min ), it was diluted with CH 2 Cl 2 and filtered through a short plug of silica. The solution of crude product was concentrated, and then pur ified by flash chromatography (5 % EtOA c/ hexanes ) to give the product as a colorless oil (48.6 mg, 96%) R f = 0.81 (5% EtOAc/ hexanes ); IR (neat) 2925, 2851, 1448, 1085, 968, 412 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): 5.59 (dd, J = 6.3, 15.3 Hz, 1H), 5.39 (dd, 6.3, 15.3 Hz, 1H), 3.98 (dt, J = 2.7, 10.8 Hz, 1H), 3.70 (dd, J = 6.0, 10.5 Hz, 1H), 3.45 (dt, J = 2.4, 11.7 Hz, 1H), 1.95 0.97 (m, 17H); 13 C NMR (75 MHz, CDCl 3 ): 137.8, 128.9, 78.7, 68.6, 40.5, 32.9, 33.0, 32 .5, 26.4, 26.3, 26.1, 23.7; HRMS (ESI) Calcd for C 13 H 23 O (M+H) + 195.1754, found 195.1749. 7 ( tert butyldimethylsilyloxy) 1 cyclohexylhept 2 yn 1 ol ( 3 55 ). A solution of n BuLi in hexane 2.5M (1.04 mL, 2.6 mmol) was added dropwise over 10 minutes at 78C to a solution of tert butyl(hex 5 ynyloxy)dimethylsilane 3 54 (500.8 mg, 2.36 mmol) in dry THF (35 mL). The reaction was then stirred at the same temperature for 45 minutes and a solution of cyclohexane carb oxa ldehyde (34 4.2 mg, 3.07 mmol) in dry THF (3 mL) was added. The mixture was allowed to warm to 30C and stirred for 30 minutes, quenched with NH 4 Cl (20 mL of a saturated aqueous solution), diluted with water (20 mL) and extracted with CH 2 Cl 2 (2x30 mL). The organic

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114 la yers were dried over MgSO 4 and then purified by flash chromatography (20% EtOAc/ Hexanes ) to give the product as a colorless oil (697.2 mg, 91%). R f = 0.42 (10% EtOAc/ hexanes ); IR (neat) 3333, 3011, 2852, 1446 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): 4.01 (d, J = 7.2 Hz, 1H), 3.61 (t, J = 7.2 Hz, 2H), 2.21 (q, J = 7.1 Hz, 2H), 1.99 0.95 (m, 15H), 0.86 (s, 9H), 2.20 0.91 (m, 19H), 0.86 (s, 9H), 0.08 (s, 6H); 13 C NMR (75 MHz, CDCl 3 86.2, 80.5, 67.6, 62.9, 44.5, 32.1, 28.8, 28.3, 26.6, 26.1, 25.4, 1 9.7, 18.7, 18.5, 5.1; HRMS (ESI) Calcd for C 19 H 35 O 2 Si (M H) + 323.2401, found 323.2398 ( Z ) 1 cyclohexylhept 2 ene 1,7 diol ( 3 56 ). Lindlar catalyst (5% palladium on calcium carbonate, poisoned with lead, 30 mg) was added t o a solution of 3 55 (150.2 mg, 0.46 mmol) in a mixture of EtOAc/pyridine/1 H 2 (1 atm). After filtration over celite and removal of the solvent, crude product was recovered as colorless oil which was used for the next step without further purification. A solution silane obtained above (116.1 mg, 0.35 mmol) in dry THF (4 mL) The reaction was stirred for 2 hours at the same temperature and NaHCO 3 saturated (30 mL of a saturated aqueous solution) was added dropwise. After dilution in water (20 mL), the crude product was extracted with CH 2 Cl 2 (2x30 mL), t he combined organic layers were dried over MgSO 4 and the solvent removed by vacuum. Flash chromatography (3 0% EtOAc/ Hexanes ) afforded the product a s a colorless oil ( 58.4 mg, 78 %). R f = 0.12 (20% EtOAc/ hexanes ); IR (neat) 3330, 2924, 2852, 1449 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ):

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115 5.42 (dt, J = 7.2, 11.1 Hz, 1H), 5.36 (dd, J = 9, 10.5 Hz, 1H), 4.09 (t, J = 7.2 Hz, 1H), 3.61 (t, J = 6.3 Hz, 2H), 2.06 (q, J = 6.9 Hz, 2H), 2.20 0.81 (m, 19H); 13 C NMR (75 MHz, CDCl 3 ): 132.7, 131.6, 72.1, 62.9, 44.2, 32.4, 29.0, 28.8, 27.7, 26.7, 26. 3, 26.2, 26.1; HRMS (ESI) Calcd for C 13 H 23 O 2 (M H) + 211.1693, found 211.1704. ( E ) 2 (2 cycloh exylvinyl)tetrahydro 2H pyran ( 3 52 ). Dr y CH 2 Cl 2 ( 0.3 mL) was added to an aluminum foil covered test tube containing PPh 3 AuCl ( 0. 7 mg, 0.00 1 mmol), AgOTf (0.4 mg, 0.00 1 mmol) and activated MS 4 ( 25 mg) After stirring for 10 minutes, a solution of diol 3 57 (21.1 mg, 0.10 mmol) in dry CH 2 Cl 2 (0.3 mL) was added After TLC analysis showed the reaction to be complete ( 40 min ), it was diluted with CH 2 Cl 2 and filtered through a short plug of silica. The solution of crude product was concentrated, and then pur ified by flash chromatography (5 % EtOA c/ hexanes ) to give the product as a colorless oil (17.9 mg, 92%) that satisfactorily matched all reported data above. ( E ) 1 (6 hydroxyhex 1 enyl) cyclohexanol ( 3 60 ) A solution of hex 5 en 1 ol (100.2 mg, 1 mmol) and 1 vinylcyclohexanol 3 59 (252.4 mg, 2 mmol) in dry CH 2 Cl 2 (2 mL) was added to a solution of Grubb nd generation catalyst (42.5 mg, 0.05 mmol, 5 mol %) in dry CH 2 Cl 2 (3 mL). The mixture was stirred at reflux for 1 hour and then cooled to rt. Silica gel (200 mg) was added and the reaction mixture was stirred open to air for 1 hour. The solvent was re moved and

PAGE 116

116 the crude product was purified by flash chromatography (20% EtOAc/ h exanes ) to give the product as a yellow oil (116.8 mg, 93%). R f = 0.18 (20% EtOAc/ hexanes ); IR (neat) 3417, 2976, 2932, 2860, 1382, 1120, 423 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): 5.63 (m, 2H), 3.63 (t, J = 6.6 Hz, 2H), 2.06 (q, J = 6.9 Hz, 1H), 1.74 1.26 (m, 16H); 13 C NMR (75 MHz, CDCl 3 ): 138.2, 127.8, 89.1, 81.9, 71.5, 62.9, 38.3, 32.3, 32.2, 25.7, 25.6, 22.4, 22.3; HRMS (ESI) Calcd for C 12 H 19 O (M H) + 179.1427, found 179.1436. 2 (cycl ohexylidenemethyl)tetrahydro pyran ( 3 61 ) Dry CH 2 Cl 2 ( 0.7 mL) was added to an aluminum foil covered test tube containing PPh 3 AuCl ( 1.3 mg, 0.00 3 mmol), AgOTf (0.7 mg, 0.00 3 mmol) and activated MS 4 ( 25 mg) After stirring for 10 minutes, a solution of diol 3 60 (51.5 mg, 0.26 mmol) in dry CH 2 Cl 2 (0.7 mL) was added After TLC analysis showed the reaction to be complete ( 2.5 h ours ), it was diluted with CH 2 Cl 2 and filtered through a short plug of silica. The solution of crude product was concentrated, and then pur ified by flash chromatography (5 % EtOA c/ hexanes ) to give the product as a colorless oil (42.1 mg, 91%) R f = 0.85 (5% EtOAc/ hexanes ); IR (neat) 2929, 2852, 1086, 1033 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): 5 .08 (dd J = 8.1, 0.9 Hz, 1H), 4.04 3.92 (m, 2H), 3.44 (dt, J = 11.7, 2.7 Hz, 1H), 2.14 2.03 (m, 4H), 1.82 1.22 (m, 12H); 1 3 C NMR (75 MHz, CDCl 3 ): 142.9, 123.4, 74.4, 68.4, 37.1, 32.8, 29.7 28.6, 28.0, 26.9, 26.0, 23.7; HRMS (ESI) Calcd for C 12 H 19 O (M H) + 179. 1427, found 179.1436.

PAGE 117

117 ( E ) 1 cyclohexyl 3,7 di methylocta 2,6 dienyl acetate ( 3 64 ). A solution of cyclohexylmagnesium bromide (2 M in Et 2 O, 1.083 mL, 1.1 eq.) was added dropwise at 0C to a solution of geranial 3 63 (300 mg 1.97 mmol) in dry THF mmol) was added dropwise. The reaction mixture was warmed to rt and stirred for 2h, then quenched with water (20 mL) and extracted with Et 2 O (3x20 mL ). The organic layers were dried over MgSO 4 concentrated, and the crude product was purified by flash chromatography (10% EtOAc/ Hexanes ) to give the product as a colorless oil (477.2 mg, 87%). R f = 0.57 (20% EtOAc/ hexanes ); IR (neat) 2928, 2854, 1727, 126 4, 1247, 740 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): 5.24 (dd, J = 7.5, 9.6 Hz, 1H), 5.00 (m, 2H), 2.07 1.98 (m, 7H), 1.75 0.85 (m, 20H); 1 3 C NMR (75 MHz, CDCl 3 ): 170.7, 140.8, 131.8, 124.2, 122.6, 75.5, 42.4, 39.9, 29.0, 28.5, 26.6, 26.4, 26.2, 26.0, 25.9, 21.5, 17.9, 17.0; HRMS (ESI) Calcd for C 18 H 2 9 O 2 (M H) + 277.2185, found 277.2168. ( E ) 1 cyclohexyl 3 ,7 dimethyloct 2 ene 1,7 diol ( 3 66 ). A solution of meta chloroperoxybenzoic acid (77% max., 244.7 mg, 1.09 mmol) in CH 2 Cl 2 (2 mL) was added dropwise at 0C to a solutio n of 3 64 (276.4 mg, 0.99 mmol) in CH 2 Cl 2 (8 mL). After for 3 hours, the reaction mixture was quenched with NaOH (10 mL of a 1M aqueous solution), diluted with water (20 mL) and extracted with CH 2 Cl 2 (2x40 mL). The combined organic layers were dried over M gSO 4 and the solvent removed to give the product as a crude colorless oil which was used for the next step without further purification.

PAGE 118

118 A solution of the epoxide 3 65 obtained above (292 .0 mg, 0.99 mmol) in Et 2 O (5 mL) was added dropwise over 10 min at 0 C to a vigorously stirred suspension of lithium aluminum hydride 95% (119 mg, 2.98 mmol) in dry Et 2 O (10 mL). The reaction mixture was allowed to warm to rt and was then stirred at reflux for 45 minutes. The reaction was cooled to 0C and was added success dried over MgSO 4 and purified by flash chromatography (15% to 30% EtOAc/ h exanes ) to give the product as a colorless oil (110.2 mg, 40% over 2 steps). IR (neat) 3373, 2923, 2851, 1001, 423 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): 5.15 (d, J = 9.0 Hz, 1H), 4.04 (t, J = 8.7 Hz, 1H), 1.99 (t, J = 6.6 Hz, 2H) 1.91 0.86 (m, 24H); 1 3 C NMR (1 00 MHz, CDCl 3 ): 139.05, 126.84, 73.08, 71.11, 44.52, 44.39, 43.67, 40.27, 29.49, 29.17, 28.79, 26.79, 26.35, 26.23, 22.63, 16.89. HRMS (ESI) Calcd for C 16 H 29 O 2 (M H) + 253.2162, found 253.2175. ( E ) 2 (2 cyclohexylvinyl) 2 ,6,6 trimethyltetrahydropyran ( 3 67 ) Dry CH 2 Cl 2 ( 0.5 mL) was added to an aluminum foil covered test tube containing PPh 3 AuCl ( 0.9 mg, 0.00 2 mmol), AgOTf (0.5 mg, 0.00 2 mmol) and activated MS 4 ( 25 mg) After stirring for 10 minutes, a solution of diol 3 66 (45.0 mg, 0.18 mmol) in dry CH 2 Cl 2 (0.4 mL) was added Aft er TLC analysis showed the reaction to be complete ( 6 h ours ), it was diluted with CH 2 Cl 2 and filtered through a short plug of silica. The solution of crude product was concentrated, and then pur ified by flash chromatography (5 % EtOA c/ hexanes ) to give the p roduct as a colorless oil (37.2 mg, 89%) R f = 0.81 (5%

PAGE 119

119 EtOAc/ hexanes ); IR (neat) 2970, 2925, 2852, 1093, 430, 409 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): 5.45 (d, J = 16.2 Hz, 1H), 5.27 (dd, J = 15.9, 6.3 Hz, 1H), 1.92 0.81 (m, 26H). 1 3 C NMR (1 00 MHz, CDCl 3 ): 136.1, 132.0, 73.3, 72.3, 40.7, 37.0, 33.9, 33.1, 32.9, 32.8, 32.5, 27.7, 26.5, 26.3, 17.2.; HRMS (ESI) Calcd for C 16 H 27 O (M H) + 235.2049, found 2 35.2062 6 .2.2 Gram Scale P reparation of 3 89 ( E ) 7 Hydroxyhept 2 enal ( 3 68 ) A solution of Grubbs 2 nd generation catalyst (169.6 mg, 0.2 mmol, 1 mol %) in anhyd CH 2 Cl 2 (50 mL, degassed by bubbling with argon for 30 min ) was prepared in a flame dried 250 mL flask equipped with a reflux condenser. To the reaction vessel, a solution of 5 hexen 1 ol 3 85 (2.0032 g, 20 mmol) and crotonaldehyde 3 86 (7.0050 g, 100 mmol) in anhyd CH 2 Cl 2 (50 mL, degassed by bubbling with argon for 30 min) was added and the mixture was immediately heated to reflux for 2 h by immersing into an oil bat h that had been preheated to 50 reaction. The crude mixture was then cooled to rt, silica gel (8 g) was added to the flask, and the resulting slurry was vigorously stirred open to air for 30 min. The mixture was then adsorbed onto the silica gel under reduced pressure and purified by flash chromatography (50% EtOAc hexanes ) to give 2.4601 g (96%) of t he title compound as a brown oil; R f = 0.25 (50% EtOAc hexanes ) ; IR (neat): 3418, 2937, 2863, 2741, 1683, 1635, 1134, 1060, 977 cm ; H NMR (300 MHz, CDCl 3 ): = 9.49 (d, J = 7.8 Hz, 1 H), 6.87 (dt, J = 15.6, 6.6 Hz, 1 H), 6.13 (ddt, J = 15.6, 7.8, 1.8 Hz, 1 H), 3.68 (t, J = 6.2 Hz,

PAGE 120

120 2 H), 2.43 2.35 (m, 2 H), 2.0 1 (br, 1 H), 1.67 1.59 (m, 4 H); C NMR (75 MHz, CDCl3): = 194.4, 159.1 133.0, 62.1, 32.4, 32.0, 24.1; HRMS (ESI) Calcd for C 7 H 16 NO 2 (M +NH 4 ) + 146.1176, found 146.1165. ( E ) Tridec 5 ene 1,7 diol ( 3 88 ) A solution of n hexylmagnesium bromide (0.97 M in Et 2 O, 34.02 mL, 2.2 equiv) was added in a dropwise fashion to a solu tion of 3 68 (1.9225 g, 15.0 mmol) in THF (75 with aq sat. NH 4 Cl (50 mL), diluted with H 2 O (100 m L), and extracted with EtOAc (3 80 mL). The combined organic layers were dried (MgSO 4 ), concentrated, and the residue was purified by flash chromatography (40% EtOAc hexanes ) to give 2.8244 g (88%) of the title compound as a yellow oil: R f = 0.33 (50% EtOAc hexanes ); IR (neat): 3346, 2929, 2857, 1457, 1058, 968 cm ; H NMR (300 MHz, CDCl 3 ): = 5.62 (dt, J = 15.6, 6.3 Hz, 1 H), 5.45 (dd, J = 15.6, 6.9 Hz, 1 H), 4.02 (q, J = 6.3 Hz, 1 H), 3.63 (t, J = 6.0 Hz, 2 H), 2.06 (q, J = 6.9 Hz, 2 H), 1.94 (br, 1 H), 1.60 1.23 (m, 14 H), 0.88 (t, J = 7.2 Hz, 3 H); C NMR (75 MHz, CDCl 3 ): = 133.7, 131 .6, 73.3, 62.8, 37.5, 32.3, 32.0, 32.0, 29.4, 25.6, 25.5, 22.8, 14.2; HRMS (ESI) C alcd for C 13 H 23 (M+H 2H 2 O) + 179.1794 found 179.1790. ( E ) 2 (Oct 1 enyl)tetrahydro 2 H pyran ( 3 89 )

PAGE 121

121 Anhyd CH 2 Cl 2 (25 mL, degassed by bubbling with argon for 30 min) was added to an aluminum foil covered, flame dried, 100 mL flask containing Ph 3 PAuCl (24.8 mg, 0.05 mmol, 0.5 mol %), AgOTf (12.8 mg, 0.05 mmol, 0.5 mol %), and activated 4 MS (950 mg). The heterogeneous mixture was vigorously st irred for 10 min and a solution of the diol 3 88 (2.1432 g, 10.0 mmol) in anhyd CH 2 Cl 2 (25 mL, degassed by bubbling with argon for 30 min) was then added. After 5 h ours TLC analysis indicated a complete reaction and the mixture filtered through a short pl ug of silica with CH 2 Cl 2 (30 mL). The solution of crude product was concentrated in vacuo, and purified by flash chromatography (5% EtOAc / hexanes ) to give 1.7944 g (91%) of the title compound as a colorless oil; R f = 0.95 (5% EtOAc / hexanes ); IR (neat): 292 7, 2854, 2728, 1463, 1086, 967 cm ; H NMR (300 MHz, CDCl 3 ): = 5.65 (ddt, J = 15.6, 6.6, 0.9 Hz, 1 H), 5.44 (ddt, J = 15.6, 6.3, 1.5 Hz, 1 H), 4.01 3.95 (m, 1 H), 3.75 3.70 (m, 1 H), 3.46 (dt, J = 11.4, 1.5 Hz, 1 H), 2.00 (q, J = 6.3 Hz, 2 H), 1.85 1.22 (m, 14 H), 0.86 (t, J = 6.3 Hz, 3 H); C NMR (75 MHz, CDCl 3 ): = 132.1, 131.3, 78.5, 68.5, 32.5, 32.4, 31.9, 29. 3, 29.1, 26.1, 23.6, 22.8, 14.2; HRMS (ESI ) calcd for C 13 H 25 O (M + H) + 197.1891 found 1 97.1900. 6 .2.3 Representative P rocedures for the P repar ations of 3 71 3 75 ( E ) Trimethyl[3 (tetrahydro 2 H pyran 2 yl)allyl]silane ( 3 74 ) Anhyd CH 2 Cl 2 (1.6 mL) was added to an aluminum foil covered, flame dried, test tube containing Ph 3 PAuCl (2.3 mg, 0.0046 mmol, 1.0 mol %), AgOTf (1.2 mg, 0.0046 mmol, 1.0 mol %), and activated 4 MS (30 mg). The heterogeneous mixture was vigorously stirred for 10 min and a solution of the corresponding diol (100.2 mg, 0.46

PAGE 122

122 mmol) in anhyd CH 2 Cl 2 (1.6 mL) was then added. After 40 min, TLC anal ysis indicated a complete reaction and the mixture filtered through a short plug of silica with CH 2 Cl 2 (4 mL). The solution of crude product was concentrated in vacuo and purified by flash chromatography (5% EtOAc / hexanes ) to give 83.8 mg (92%) of the tit le compound 3 74 as a colorless oil; R f = 0.95 (50% EtOAc / hexanes ); IR (neat): 3418, 2937, 2863, 2741, 1683, 1635, 1134, 1060, 977 cm ; H NMR (300 MHz, CDCl 3 ): = 5.61 (dt, J = 15.3, 7.8 Hz, 1 H), 5.30 (dd, J = 15.3, 6.3 Hz, 1 H), 4.95 (d, J = 11.4 Hz, 1 H), 3.69 (t, J = 8.4 Hz, 1 H), 3.43 (t, J = 11.1 Hz, 1 H), 1.81 1.34 (m, 8 H), 0.03 (s, 9 H) ; C NMR (75 MHz, CDCl 3 ): = 130.2, 128.5, 78.9, 69.4 6, 32.8, 26. 1, 23.7, 22.9, 1.8; HRMS (ESI) calcd for C 11 H 23 OSi (M+ H) + 199.1513 found 199.1525. ( E ) 2 [4 (1,3 Dioxolan 2 yl)but 1 enyl]tetrahydro 2 H pyran ( 3 71 ) Colorless oil; R f = 0.92 (50% EtOAc / hexanes ); IR (neat): 2935, 2850, 18 08, 1083, 1048 cm ; H NMR (300 MHz, CDCl 3 ): = 5.61 (ddt, J = 15.3, 7.4, 1.5, Hz, 1 H), 5.43 (ddt, J = 15.3, 6.0, 0.9 Hz, 1 H), 4.80 (t, J = 4.8 Hz, 1 H), 3.95 3.64 (m, 5 H), 3.40 (dt, J = 11.7, 3.3 Hz, 2 H), 2.10 (q, J = 7.4 Hz, 2 H), 1.79 1.18 (m, 8 H); C NMR (75 MHz, CDCl 3 ): = 132.0, 130.8, 104.3, 78.3, 68.5, 65. 1, 33.5, 32.4, 27.0, 26.1, 23.6; HRMS (ESI) calcd for C 12 H 21 O 3 (M+ H) + 213.1485 found 213.1482. ( E ) 2 [2 (Furan 2 yl)vinyl]tetrahydro 2 H pyran ( 3 72 )

PAGE 123

123 Yellow oil; R f = 0.95 (50% EtOAc / hexanes ) ; IR (nea t): 2937, 2848, 1726, 1083, 1013 cm ; H NMR (300 MHz, CDCl 3 ): = 7.32 (d, J = 1.8 Hz, 1 H), 6.41 (dd, J = 16.2, 1.5 Hz, 1 H), 6.34 (dd, J = 3.9, 1.8 Hz, 1 H), 6.21 (d, J = 3.3 Hz, 1 H), 6.15 (dd, J = 16.2, 5.4 Hz, 1 H), 3.46 (dt, J = 11.7, 2.7 Hz, 1 H), 4.08 4.03 (m, 1 H), 3.94 (ddt, J = 10.8, 5.4, 1.8 Hz, 1 H), 3.5 2 (dt, J = 11.4, 3 .0 Hz, 1 H), 1.90 1.41 (m, 6 H); C NMR (75 MHz, CDCl 3 ): = 152.9, 141.9, 129.7, 118.1, 111.4, 107. 9, 77.6, 68.6, 32.4, 26.1, 23.7; HRMS (ESI ) calcd for C 11 H 14 O 2 (M) + 178.0984 found 178.0994. ( E ) 2 [2 (Cyanomethyl)vinyl]tetrahydro 2H pyran ( 3 73 ) Pale yellow oil; R f = 0.78 (5% EtOAc / hexanes ); IR (neat): 2920, 2849, 2732, 2251, 1723, 1119, 1083 cm ; H NMR (300 MHz, CDCl 3 ): = 5.88 (ddt, J = 15.6, 5.1, 1.5 Hz, 1 H), 5.61 (ddt, J = 15.6, 5.4, 1.5 Hz, 1 H), 4.04 3.99 (m, 1 H), 3.85 3.79 (m, 1 H), 3.48 (dt, J = 5.4, 2.7 Hz, 1 H), 3.11 (dt, J = 11.4, 1. 5 Hz, 2 H), 1.89 1.25 (m, 6 H); C NMR (75 MHz, CDCl 3 ): = 136.7, 117.9, 117.5, 76. 9, 68.6, 32.0, 25.9, 23.5, 20.5; HRMS (ESI) calcd for C 9 H 14 NO (M+ H) + 152 .1075 found 152.1072. ( E ) 2 (3 Phenylprop 1 enyl)tetrahydro 2H pyran ( 3 75 ) Colorless oil; R f = 0.95 (50% EtOAc / hexanes ); IR (neat): 3026, 2934, 2843, 1495, 1452, 1085, 698 cm ; H NMR (300 MHz, CDCl 3 ): = 7.30 7.16 (m, 5 H), 5.82 (dt, J = 15.3, 6.9 Hz, 1 H), 5.53 (dd, J = 15.3 6.3 Hz, 1 H), 3.99 (dt, J = 11.4, 2.1 Hz, 1 H), 3.81 3.75 (m, 1 H), 3.46 (dt, J = 11.4, 2.7 Hz, 1 H), 3.36 (d, J = 6.9 Hz, 2 H), 1.66 1.26 (m, 6 H); C NMR (75 MHz, CDCl 3 ): = 140.3, 132.9, 130. 3, 128.8, 128.6, 128.6, 78. 2,

PAGE 124

124 68.5, 38.9, 32.3, 26.0, 23.6; HRMS (ESI) calcd for C 14 H 17 O (M H) + 209.1302, found 201.1279. 1 bromo 4 (pent 4 enyloxy)benzene ( 3 95 ). To a solution of 4 bromophenol 3 93 (346.2 mg, 2 mmol) in dry DMF (10 mL), was added successively 5 bromopentene 3 94 (327.8 mg, 2.2 mmol) and K 2 CO 3 (552.0 mg, 4 mmol). The reaction mixture was stirred at 70C overnight and then quenched with water (20 mL) and extracted with Et 2 O (3x20 mL). The organic layers wer e dried over MgSO 4 concentrated, and the crude product was purified by flash chromatography (100% hexanes ) to give the product as a colorless oil. (444.3 mg, 92%). R f = 0.77 (100% hexanes ); 1 H NMR (300 MHz, CDCl 3 ): = 7.37 (d, J = 9 Hz, 2H), 6.80 (d, J = 9 Hz, 2H), 5.95 5.82 (m, 1 H), 5.14 5.03 (m, 2 H), 3.94 (t J = 6.6 Hz, 2H), 3.94 (t J = 6.6Hz, 2 H), 2.26 (q J = 6.6 Hz, 2 H); 13 C NMR (75 MHz, CDCl 3 ): = 158.3, 137.8, 132.3, 116.4, 115.5, 112.8, 67.5, 30.2, 28.5. 5 (4 bromophenoxy)pentane1,2 diol ( 3 96 ). A solution of osmium tetroxyde 4% in water (83 t to a mixture of 3 95 (300.0 mg, 1.24 mmol) in acetone/water 5/1 (15 mL) and NMO 5% as stirred at rt overnight and

PAGE 125

125 quenched with Na 2 SO 4 (75 mL). D iluted with water (20 mL) and extracted with ethyl acetate (3x20 mL). The organic layers were dried over MgSO 4 concentrated and the crude product was purified by re crystallization in hexanes to give the product as a white solid (293.4 mg, 86%); 1 H NMR (300 MHz, CDCl 3 ): = 7.38 (d J = 9 Hz, 2H ), 6.81 (d J = 9 Hz, 2H ) 5.96 5.83 (m 1 H), 3. 98 ( t J = 6.6 Hz, 2H), 3.74 3.46(m 2 H), 2.81 ( s 1 H) 2.52 ( s 1 H) 1.95 (m, 2H), 1.68 (m, 2H); 13 C NMR (75 MHz, CDCl 3 ): = 158.2, 132.5, 116.5, 113.1, 72.1, 68.3, 67.0, 29.9, 25 .6; HRMS (ESI) calcd for C 11 H 15 Br O 3 Na (M +Na ) + 297.0097 found 297.0083 4 (4 bromophenoxy)butanal ( 3 97 ). Pb(OAc) 4 (266.9 mg, 0.59 mmol) was added portionwise over 20 minutes at 0 C to a solution of 3 96 (150.0 mg, 0.54 mm ol) in dry benzene (2 mL). The reaction mixture was stirred at rt 3 hours and then filtered t h r ough a short plug of celite. The solvent was removed and the crude was then diluted in CH 2 Cl 2 (5 mL) to be applied to a short plug of silica to give the product as a white solid (96.5 mg, 74%). R f = 0.82 (100% CH 2 Cl 2 ); 1 H NMR (300 MHz, CDCl 3 ): = 9.84 (t J = 1.5 Hz, 1H), 7.35 (d J= 9 Hz, 2H ), 6.75 (d J = 9 Hz, 2H ) 5.96 5.83 (m 1 H), 3. 98 ( t J = 6.6 Hz, 2H), 3.96 (t J = 6.6 Hz, 2 H), 2.66 ( t J = 6.9 Hz, 2 H) 2.12 ( q J = 6.6 Hz, 2 H) ; 13 C NMR (75 MHz, CDCl 3 ): = 201.8, 157.9, 132.5, 116.4, 113.2, 67.1, 40.7, 22.1; HRMS (ESI) C alcd for C 10 H 11 Br O 2 Br (M ) + 241.9918 found 241.9942

PAGE 126

126 ( R ) 1 (4 bromophenoxy) 10 ( tert butyldimethylsi lyloxy)dec 5 yn 4 ol ( 3 98 ). A 10 mL flask was charged with Zn(OTf) 2 (1.4540 g, 4.0 mmol) and (+) N methylephedrine (717.0 mg, 4.0 mmol) was added. To the flask was added sti rred for 2 h at r.t. before tert butyl(hex 5 ynyloxy)dimethylsilane 3 54 (807.1 mg, 3.8 mmol) was added in one portion. After stirring for 0.25 h at rt aldehyde 3 97 (243.1 mg, 1 mmol) was added in one portion. The reaction mixture was stirred at r.t. for 5 hours. The reaction was quenched by addition of NH 4 Cl (sat.) (3 mL). The reaction mixture was poured into a separatory funnel containing diethyl ether (10 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (3 x 10 mL). The combined ethereal portion was washed with NaCl (sat.) (10 mL), dried over anhydrous MgSO 4 filtered and concentrated invacuo The crude material was purified by flash chromatography (30% Hexanes /CH 2 Cl 2 ) to give the product as a colorless oil (364.4 mg, 80%) and 90% e e as determined by HPLC analysis (Chiralcel OD H 10% i PrOH in hexanes 1.0 mL/min, 254 nm), t r 4.8 (minor), 5.5 (major ); R f = 0.11 (30% h exanes /CH 2 Cl 2 ); 1 H NMR (300 MHz, CDCl 3 ): = 7.3 6 (d, J = 9 Hz, 2H), 6.77 (d, J = 9 Hz, 2H), 4.44 ( q J = 6Hz 1 H), 3.98 (t J = 6.6 Hz, 2H), 3. 63 ( t J = 6.9 Hz, 2H), 2. 2 6 (t J = 6.6 Hz, 2H), 1.98 1.52 (m, 10H), 0.90 (s, 9H), 0.05 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ): = 158.2, 132.4, 116.5, 113.0, 85.9, 81.3, 68.0, 62.8, 62.5, 34.8, 32.1, 26.2, 25.3, 25.2,

PAGE 127

127 18.7, 18.5, 5.1; HRMS (ESI) C alcd for C 22 H 34 Br O 2 Si (M+ Na ) + 477.1486 found 477.1431 ( R ) ( Z ) 10 (4 bromorphenoxy)dec 5 ene 1,7 diol ( 3 99 ). Lindlar catalyst (5% palladium on calcium carbonate, poisoned with lead, 30 mg) was added to a solution of 3 98 (228.5 mg, 0.50 mmol) in a mixture of EtOAc/pyridine/1 h 2 days under H 2 (1 atm). After filtration over celite and removal of the solvent, crude product was recovered as a colorless oil which was used for the next step without further purification. A solut ion of TBAF ( 1.0M in THF, 2.0 mL ) was added dropwise at 0C to a solution of the silane obtained above in dry THF (5 mL). The reaction was stirred 16h at the same temperature and NaHCO 3 saturated (30 mL of a saturated aqueous solution) was added dropwise. After dilution in water (20 mL), the crude product was extracted with EtOAc (2x 30 mL), the combined organic layers were dried over MgSO 4 and the solvent removed by vacuum. Flash chromatography ( 4 0% EtOAc/ Hexanes ) afforded the product as a colorless oil (15 6.4 mg, 91 %) and 90% e e as determined by HPLC analysis (Chiralcel OD H 10% i PrOH in hexanes 1.0 mL/min, 254 nm), t r 3.3 (minor), 11.7 (major ); R f = 0.16 (5 0% EtOAc/ hexanes ); 1 H NMR (300 MHz, CDCl 3 ): = 7.3 6 (d, J = 9 Hz, 2H), 6.77 (d, J = 9 Hz, 2H), 5.5 9 5.39 (m, 2H), 4.48 ( q J = 6 Hz, 2H), 3. 95 ( t J = 6.6 Hz, 2H), 3 64 (t J = 6.9 Hz, 2H), 2.24 1.39 (m, 12H); 13 C NMR (75 MHz, CDCl 3 ): =

PAGE 128

128 158.2, 132.8, 132.4, 132.4, 116.5, 113.0, 68.3, 67.5, 62.8, 34.1, 32.2, 27.5, 26.0, 25.4; HRMS (ESI) C alcd for C 16 H 2 3 Br O 3 Na (M+ Na ) + 365.0723 found 365.0715 ( R ) ( E ) 10 (4 bromorphenoxy)dec 5 ene 1,7 diol ( 3 101 ). [Cp*Ru(MeCN) 3 ]PF 6 catalyst ( 3 mol %, 7.6 mg 0.015 mmol ) was added to a solution of 3 98 (228.5 mg, 0.50 mmol) and ethoxydim ethylsilane (78 0.75 mmol) in CH 2 Cl 2 (3 mL) at 0 C The ice bath was removed and the reaction mixt ure stirred for 15 minutes at rt After filtration over a short plug of florisil and removal of the solvent, crude product was recovered as a yellow oil which was used fo r the next step without further purification. A solution of TBAF ( 1.0M in THF, 2.0 mL ) was added dropwise at 0C to a solution of the silane obtained above and CuI (19.0 mg, 0.1 mmol) in dry THF (5 mL). The reaction was stirred 16h at the same temperature and NH 4 Cl (sat ) (5 mL) was added dropwise. After dilution in water (20 mL), the crude product was extracted with EtOAc (2x 30 mL), the combined organic layers were dried over MgSO 4 and the solvent removed by vacuum. Flash chromatography ( 4 0% EtOAc/ hexanes ) afforded the product as a colorless oil (123.5 mg, 72 %) and 90% e e as determined by HPLC analysis (Chiralcel OD H 10% i PrOH in hexanes 1.0 mL/min, 254 nm), t r 12.3 (major), 13.6 (major ); R f = 0.18 (5 0% EtOAc/ hexanes ); 1 H NMR (300 MHz, CDCl 3 ): 7.35 (d J = 9Hz, 2H), 6.77 (d J = 9 Hz, 2H), 5.67 (dt J = 15.0, 6.6 Hz, 1H), 5.51 (dd J = 15.0, 6.6 Hz, 1H), 4.12 (q J = 6.3 Hz, 1H), 3.95 (t J = 5.7 Hz, 2H), 3.64 (t J = 6.3 Hz, 2H), 2.07 (q J = 7.2 Hz, 2H), 1.90 1.26 (m, 8H); 13 C NMR (75 MHz, CDCl 3 ): = 158.2, 133.3, 132.4,

PAGE 129

129 132.1, 116.5, 112.9, 72.8, 68.3, 62.9, 33.9, 32.3, 32.0, 25.5, 25.5; HRMS (ESI) C alcd for C 16 H 23 Br O 3 Na (M+Na ) + 365.0728 found 365.0707 (+) ( E ) 2 (5 (4 bromophenoxy)pent 1 enyl)tetrahydro 2H pyra n (3 100) Anhyd CH 2 Cl 2 (1.0 mL) was added to an aluminum foil covered, flame dried, test tube containing Ph 3 PAuCl (1.6 mg, 0.00 29 mmol, 1.0 mol %), AgOTf (0.8 mg, 0.00 29 mmol, 1.0 mol %), and activated 4 MS (30 mg). The heterogeneous mixture was vigorou sly stirred for 10 min and a solution of the corresponding diol R 4 2 (100.0 mg, 0. 29 mmol) in anhyd CH 2 Cl 2 (0.5 mL) was then added. After 40 min, TLC analysis indicated a complete reaction and the mixture filtered through a short plug of silica with CH 2 Cl 2 (4 mL). The solution of crude product was concentrated in vacuo, and purified by flash chromatography (5% Et OAc/ hexanes ) to give 74.5 mg (79 %) of the title compound ( ) 3 100 as a colorless oil; R f = 0.9 0 ( 5 % EtOAc/ hexanes ) and 90% ee as determined by HPL C analysis (Chiralcel OD H 1% i PrOH in hexanes 1.0 mL/min, 254 nm), t r 5.5 (major), 6.0 (minor ) that satisfactorily mat ched previously reported data. ( ) ( E ) 2 (5 (4 bromophenoxy)pent 1 enyl)tetrahydro 2H pyran (3 102) Anhyd CH 2 Cl 2 (1.0 mL) was added to an aluminum foil covered, flame dried, test tube containing Ph 3 PAuCl (1.6 mg, 0.00 29 mmol, 1.0 mol%), AgOTf (0.8 mg, 0.00 29 mmol, 1.0 mol%), and activated 4 MS (30 mg). The heterogeneous mixture was vigorously stirred for 10 min utes and a solution of the corresponding diol 3 101 (100.0

PAGE 130

130 mg, 0. 29 mmol) in anhyd CH 2 Cl 2 (0.5 mL) was then added. After 40 min, TLC analysis indicated a complete reaction and the mixture filtered through a short plug of silica with CH 2 Cl 2 (4 mL) The solution of crude product was concentrated in vacuo, and purified by flash chromatography (5% Et OAc/ hexanes ) to give 80.1 mg (85 %) of the title compound ( ) 3 102 as a colorless oil; R f = 0.9 0 ( 5 % EtOAc/ hexanes ); and 90% ee as determined by HPLC anal ysis (Chiralcel OD H 1% i PrOH in hexanes 1.0 mL/min, 254 nm), t r 5.5 (minor), 6.0 (major ); D = 5.8 ( c 1.0, CHCl 3 ); IR (neat): 3058 2 945 2 866 1734 1 690 1 242 737 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): = 7.3 6 (d, J = 9 Hz, 2H), 6.77 (d, J = 9 Hz, 2H), 5.65 5.48 (m, 2H), 4.00 ( d J = 13.5 Hz, 1 H), 3. 94 ( t J = 6.6 Hz, 2H), 3 75 (t J = 10.8 Hz, 1 H), 3.47 (t J = 11.1Hz, 1H), 2.24 (q J = 7.5 Hz, 2H), 1.91 1.31 (m, 10H); 13 C NMR (75 MHz, CDCl 3 ): = 158.2, 132.8, 132.4, 132.4, 119.1, 103.6, 68.6, 67.7, 62.8, 34.2, 32.5, 27.3, 26.0, 25.3; HRMS (ESI) C alcd for C 16 H 20 Br O 2 (M H ) + 323.0667 found 323.0 647 6 2.4 Synthesis of 3 111 and 3 112 Compounds 3 54 and 3 104 95 have been described in the literature and when prepared here satisfactorily matched all previously reported data. 9 (tert butyldimethylsilyloxy) 1 phenylnon 4 yn 3 one ( 3 107 ). A solution of n BuLi in hexane 1.6M (2.41 mL, 3.85 mmol) was added dropwise over 10 minutes at 78C to a solution of 3 54 (742.0 mg, 3.5 mmol) in dry THF (12 mL). The reaction was then sti rred at the same temperature for 45 minutes and a solution of 3 104 (773.2 mg, 4 mmol) in dry THF (5 mL) was added. The mixture was allowed to

PAGE 131

131 warm to room temperature and stirred for 2 hours, quenched with NH 4 Cl (10 mL of a saturated aqueous solution), di luted with water (20 mL) and extracted with CH 2 Cl 2 (2x30 mL). The organic layers were dried over MgSO 4 and then purified by flash chromatography (gradient; 1 5% EtOAc/ hexanes ) to give the product as a colorless oil (759.8.2 mg, 63%). R f = 0.75 (10% EtOAc/ h exanes ); IR (neat) 3028, 2942, 2871, 17.29, 1673, 1603, 1496, 1454 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): 7.30 7.17 (m,5H), 3.62 (t, J = 5.1 Hz, 2H), 2.97 (t, J = 6.9 Hz, 2H), 2.86 (t, J = 7.8 Hz, 2H), 2.39 (t, J = 6.5 Hz, 2H),1.66 1.61 (m, 4H), 0.89 (s, 9H), 0. 04 (s, 6H); 13 C NMR (75 MHz, CDCl 3 140.5, 128.7, 128.5, 126.4, 94.8, 81.1, 62.5, 47.1, 32.0, 30.1, 26.1, 24.5, 18.9, 18.5, 5.2; HRMS (ESI) Calcd for C 21 H 33 O 2 Si (M+H) + 344.2213, found 344.2217 ( R ) 9 (tert butyl dimethylsilylo xy) 1 phenylnon 4 yn 3 ol ( 3 108 ) Noyori catalyst [( R R ) TsDPEN Ru ( p cymene)Cl] (13.8 mg, 0.022 mmol, 0.01 eq ) was added to a mixture of ynone 3 107 (747.3 mg, 2.17 mmol), sodium formate (1.4758 g, 21.7 mmol, 10 eq), TBAC (180.9 mg, 0.65 mmol 0.3 eq) in CH 2 Cl 2 (5 mL) and deionized H 2 O (5 mL). The biphasic mixture was strongly stirred for 20 hours at room temperature, diluted with water (10 mL) and extracted with CH 2 Cl 2 (2 x 10 mL). The organic layers were dried over MgSO 4 and then purified b y flash chromatography (gradient; 2 10% EtOAc/ Hexanes ) to give the product as a colorless oil (550.8 mg, 73%) and matched all the previously reported data. R f = 0.25 (10% EtOAc/ hexanes D = 7.7 (c 1.00, CH 2 Cl 2 ); IR (neat) 3372, 2930, 2858 1712, 1673, 1496, 1454 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): 7.46 7.31 (m, 5H), 4.50 (q, J = 5.7 Hz, 1H), 3.78 (t, J = 6.3

PAGE 132

132 Hz, 2H), 2.93 (t, J = 7.5 Hz, 2H), 2.40 (t, J = 5.1 Hz, 2H), 2.14 (m, 2H), 1.94 (bs, 1H), 1.80 1.71 (m, 4H), 1.04 (s, 9H), 0.20 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ): 141.7, 128.7, 128.6, 126.1, 86.0, 81.4, 62.8, 62.2, 39.9, 32.1, 31.7, 26.2, 25.3, 18.7, 18.5, 5.1. The enantiomeric excess (96%) was determined by HPLC analysis (Chiralcel OD H, 3% i PrOH in hexanes 0.5 mL/min, 254 nm), t r 15.9 (minor), 20 .3 (major). ( R Z ) 9 phenylnon 5 ene 1,7 diol ( 3 109 ). Lindlar catalyst (5% palladium on calcium carbonate, poisoned with lead, 100 mg) was added to a solution of 3 108 (508.1 mg, 1.44 mmol) in a mixture of Pentane/EtOAc (1 0:1, 14.5 mL, 0.1M). The reaction mixture was stirred 1 h ours under H 2 (1 atm). After filtration over celite and removal of the solvent, crude product was recovered as a colorless oil which was used for the next step without further purification. A soluti on of TBAF 1M in THF (5.76 mL, 5.76 mmol, 4 eq) was added dropwise at 0C to a solution of the silane obtained above (511.3 mg, 1.44 mmol) in dry THF (14 mL, 0.1M). The reaction was stirred for 3 hours at the same temperature and water (10 mL) was added dr opwise. After dilution in brine (4 mL), the crude product was extracted with EtOAc (3 x 30 mL), the combined organic layers were dried over MgSO 4 and the solvent removed by vacuum. Flash chromatography (gradient; 30 40% EtOAc/ hexanes ) afforded the product as a colorless oil (275.8 mg, 82% over two steps). R f = 0.29 (50% EtOAc/ hexanes D = +33.9 (c 1.00, CH 2 Cl 2 ); IR (neat) 3328, 2931, 1452, 1153, 1044, 913, 699 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): 7.30 7.15 (m,5H), 5.50 5.41 (m, 2H), 4.43 (q, J = 7.0 Hz, 1H) 3.62 (t, J = 6.3 Hz, 2H), 2.71 2.65 (m, 2H), 2.16 1.37 (m, 10H); 13 C NMR (75 MHz, CDCl 3 ): 142.1, 132.9, 132.4, 128.6, 128.6, 126.0, 67.2.5, 62.8, 39.2,

PAGE 133

133 32.2, 31.9, 27.6, 26.0; HRMS (ESI) Calcd for C 15 H 26 NO 2 (M+NH 4 ) + 252.1958 found 252.1958. The enanti omeric excess (96%) was determined by HPLC analysis (Chiralcel OD H, 5% i PrOH in hexanes 0.8 mL/min, 254 nm), t r 22.8 (minor), 27.5 (major). ( R E ) 9 phenylnon 5 ene 1,7 diol ( 3 1 10) Red Al (65%wt in Toluene, 3.3 mL, 6.5 mmol, 10 eq) was added dropwise at 0C to a solution of 3 108 (224.8 mg, 0.65 mmol) in dry THF (7 mL, 0.1M). The reaction mixture was stirred 20h under N 2 quenched with sodium potassium tartrate (7 mL of a saturated aqueous solution), diluted with brine ( 3 mL) and extracted with EtOAc (3x30 mL). The organic layers were dried over MgSO 4 and the crude product was recovered as a colorless oil which was used for the next step without further purification. A solution of TBAF 1M in THF (1.95 mL, 1.95 mmol, 3 eq ) was added dropwise at 0C to a solution of the silane obtained above (226.2 mg, 0.65 mmol) in dry THF (7 mL, 0.1M). The reaction was stirred for 3 hours at the same temperature and water (5 mL) was added dropwise. After dilution in brine (2 mL), the crud e product was extracted with EtOAc (3x15 mL), the combined organic layers were dried over MgSO4 and the solvent removed by vacuum. Flash chromatography (gradient; 30 40% EtOAc/ hexanes ) afforded the product as a colorless oil (141.1 mg, 93% over two steps); R f = 0.16 (40% EtOAc/ hexanes D = 8.7 (c 1.00, CH 2 Cl 2 ); IR (neat) 3340, 2932, 2860, 1054, 970, 699 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): 7.30 7.15 (m, 5H), 5.70 5.60 (dt, J = 6.3, 15.3 Hz, 1H), 5.54 5.46 (ddt, J = 1.5, 6.6, 15.3 Hz, 1H), 4.07 (q, J = 6.5 Hz, 1H), 3.63 (t, J =

PAGE 134

134 6.5 Hz, 2H), 2.72 2.65 (m, 2H), 2.07 (q, J = Hz, 2H), 1.91 1.42 (m, 8H); 13 C NMR (75 MHz, CDCl 3 ): 142.2, 133.4, 132.1, 128.6, 128.6, 126.0, 72.5, 62.9, 39.0, 32.3, 32.1, 32.0, 25.5; HRMS (ESI) Calcd for C 15 H 26 NO 2 (M+NH 4 ) + 252.1958, found 252.1960. The enantio meric excess (96%) was determined by HPLC analysis (Chiralcel OD H, 5% i PrOH in hexanes 0.8 mL/min, 254 nm), t r 29.7 (minor), 32.3 (major). ( R E ) 2 (4 phenylbut 1 enyl)tetrahydro 2H pyran (3 111) Dry CH 2 Cl 2 (1.1 mL) was a dded to an aluminum foil covered test tube containing PPh 3 AuCl (2.1 mg, 0.0042 mmol, 1 mol %), AgOTf (1.1 mg, 0.0042 mmol, 1 mol %) and activated MS 4 (80 mg). After stirring for 10 minutes, a solution of diol 3 109 (100.3 mg, 0.42 mmol) in dry CH 2 Cl 2 (1. 1 mL) was added. After TLC analysis showed the reaction to be complete (40 min), it was diluted with CH 2 Cl 2 and filtered through a short plug of silica. The solution of crude product was concentrated, and then purified by flash chromatography (5% EtOAc/ hex anes ) to give the product as a colorless oil (86.5 mg, D = 14.1 (c 1.00, CH 2 Cl 2 ). The enantiomeric excess (93%) was determined by HPLC analysi s (Regis Pirkle Covalent 1% i PrOH in hexanes 0.5 mL/min, 254 nm), t r 13.3 (minor), 19.8 (major); The abso lute configurations of 3 111 and 3 112 have been determined by comparison of optical rotations with known derivatives ( R ) 3 11 3 and ( S ) 3 11 4 97 ( S E ) 2 (4 phenylbut 1 eny l)tet rahydro 2 H pyran (3 112 ).

PAGE 135

135 Dry CH 2 Cl 2 (1.4 mL) was added to an aluminum foil covered test tube containing PPh 3 AuCl (2.8 mg, 0.0056 mmol, 1 mol %) AgOTf (1.4 mg, 0.0056 mmol, 1 mol %) and activated MS 4 (80 mg). After stirring for 10 minutes, a solution of diol 3 110 (131.2 mg, 0.56 mmol) in dry CH 2 Cl 2 (1.4 mL) was added. After TLC analysis showed the reaction to be complete (35 min), it was diluted with CH 2 Cl 2 and filtered through a short plug of silica. The solution of crude product was concentrated, and then purified by flash chromatography (5% EtOAc/ hexanes ) to give the product as a colorless oil (109.8 mg, 91%) and matched all the previously reported data; 18 R f = 0.80 (5% EtOAc/ hexanes ); D = +13.6 (c 1.00, CH 2 Cl 2 ); IR (neat) 2931,1158, 1083, 1035 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): 7.30 7.15 (m, 5H), 5.72 (dt, J = 15.6, 6.6 Hz,1H), 5.51 (dd, J = 15.6 ,6.3 Hz, 1H), 3.99 (m, 1H), 3.74 (m, 1H), 2.46 (dt, J = 2.7, 11.4 Hz, 1H), 2.70 (t, J = 7.2, 2H), 2.34 (q, J = 7.5 Hz, 2H), 1.85 1.26 (m, 6H); 13C NMR (75 MHz, CDCl3): 142.2, 132.1, 131.0, 128.6, 128.5, 126.0, 78.4, 68.5, 35.8, 34.4, 32.3, 26.1 23.6; HRMS (ESI) Calcd for C 15 H 21 O (M+H) + 217.1587, found 217.1593. The enantiomeric excess (93 %) was determined by HPLC analysis (Regis Pirkle Covalent 1% i PrOH in hexanes 0.5 mL/min, 254 nm) t r 13.3 (major), 19.8 (minor). ( R ) (tetrahydro 2H pyran 2 yl)methanol (3 113 ). 3 111 (74.6 mg, 0.35 mmol) was dissolved in dry CH 2 Cl 2 /MeOH (1/1, 8 mL), and the solution was cooled to 78C. Ozone was passed into the solution using a gas dispersion tube. At the end of the reaction, after approximately 30 min, the solution becomes blue, was purged 5 min with O 2 warmed up to 0C, NaBH 4 (131.5 mg, 3.46 mmol, 10 eq) was added portionwise at the same temperature and stirred 2 hours at

PAGE 136

136 room temperature. H 2 O (5 mL) was added and the crude was extracted with CH 2 Cl 2 (3x10mL) and dried over MgSO 4 The solution of crude product was con centrated, and then purified by flash chromatography (gradient; 5, 10, 20% EtOAc/ hexanes ) to give the 16.3 (c 1.00, CHCl 3 ) that satisfactorily matched all previously reported data.17 ( S ) (tetrahydro 2H pyran 2 yl)methanol (3 114) 3 112 (60.8 mg, 0.28 mmol) was dissolved in dry CH 2 Cl 2 /MeOH (1/1, 6mL), and the solution was cooled to 78C. Ozone was passed into the solution using a gas dispersion tube. At the end of the reaction, after approximately 30 min, the solution becomes blue, was purged 5 min with O 2 warmed up to 0C, NaBH 4 (106.7 mg, 2.82 mmol, 10 eq) was added portionwise at the same temperature and stirred 2 hours at room temperature. H 2 O (5 mL) was added and the crude was extracted with CH 2 Cl 2 (3x10mL) and dried over MgSO 4 The solution of crude pr oduct was concentrated, and then purified by flash chromatography (gradient; 5, 10, 20% EtOAc/ hexanes ) to give the D = +15.7 (c 1.00, CHCl 3 ) that satisfactorily matched all previously reported data. 6 2. 5 Synt hesis of 3 120 and 3 121 Compound 3 115 has been described in the literature and when prepared here satisfactorily matched all previously reported data.

PAGE 137

137 ( R ) N (2 (tert butyldimethylsilyloxy)ethyl) N (4 hydroxy 5 methylhex 2 ynyl) 4 me thylbenzenesulfonamide ( 3 117 ). A 100 mL flask was charged with Zn(OTf) 2 (3.9996 g, 11.0 mmol) and (+) N methylephedrine (1.9723 g, 10.0 mmol) was added. To the flask was added toluene (29 mL) and triethylamine (1.1110 g, 11 mmol,). The result ing m ixture was stirred for 2 h at rt before 3 115 (3.6758 g, 10.0 mmol) in toluene (1 mL) was added in one portion. After stirring for 0.25 h at rt isobutylaldehyde 3 116 (721.1 mg, 10 mmol) was added in one portion. The reaction mixture was stirred at r. t. for 24 hours. The reaction was quenched by addition of NH 4 Cl (sat.) (10 mL). The reaction mixture was poured into a separatory funnel containing CH 2 Cl 2 (10 mL). The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (2 x20 mL). The com bined organic portion was washed with NaCl (sat.) (10 mL), dried over anhydrous MgSO 4 filtered and concentrated in vacuo. The crude material was purified by fla sh chromatography (gradient; 10 20% EtOAc/ hexanes ) to give the product as a colorless oil (4.0 432 g, 92%) which decomposed rapidly and was used for the next steps the same day; R f = 0.78 (50% EtOAc/ hexanes ); 1 H NMR (300 MHz, CDCl 3 ) : = 7.74 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 4.30 (s, 2H), 3.91 (br, 1 H), 3.82 (t, J = 6.0 Hz, 2H), 3.32 (dt, J = 1.5, 5.5 Hz, 2H), 2.42 (s,1H), 1.64 (m, J = 6.5 Hz, 1H), 1.29 (d, J = 5.5 Hz, 1H), 0.88 (s, 9H), 0.81 (dd, J = 6.5, 1.5 Hz, 6H), 0.06 (s, 6H); HRMS (ESI) Calcd for C 22 H 34 NNaO 4 SSi (M+Na) + : 462.2105, found 462.2093.

PAGE 138

138 ( R,Z ) N (4 hydroxy 5 methylhex 2 enyl) N (2 hydroxyethyl) 4 methylbenzene sulfonamide ( 3 118 ) Lindlar catalyst (5% palladium on calcium c arbonate, poisoned with lead, 141.6 mg) and quinoline (141.6 mg) were added to a solution of 3 117 (708.4 mg, 0.68 mmol) in dry MeOH (8.1 mL). The reaction mixture was stirred 2 days under H 2 (1 atm). After filtration over celite and removal of the solvent crude product was recovered as a colorless oil which was used for the next step without further purification. A solution of TBAF (1.0M in THF, 4.83 mL) was added dropwise at 0C to a solution of the silyl ether obtained above in dry THF (5 mL). The reac tion was stirred 16h at the same temperature and NaHCO 3 saturated (30 mL of a saturated aqueous solution) was added dropwise. After dilution in water (3 mL), the crude product was extracted with CH 2 Cl 2 (2x 20 mL), the combined organic layers were dried over MgSO 4 and the solvent removed by vacuum. Flash chromatography (Gradient 20%, 50%, 70% EtOAc/ hexanes ) afforded the product as a colorless oil (489.0 mg, 93%); R f = 0.15 (60% EtOAc/ hexanes ); D = +23.3 ( c 1.00, CH 2 Cl 2 ); IR (neat) 3333, 2959, 2873, 1593, 1 503, 1456, 1384, 1368 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): = 7.65 (d, J = 8.5 Hz, 2H), 7.27 (d, 8.5 Hz, 2H), 5.53 (t, J = 10.0 Hz, 1H), 5.37 5.32 (m, 1H), 4.02 3.85 (m, 3H), 3.69 (t, J = 11.0 Hz, 2H), 3.26 3.16 (m, 2H), 3.08 (br, 1H), 2.87 (br, 1H), 2.43 (s, 3 H), 1.65 1.58 (m, 1H), 0.87 (d, J = 6.5 Hz, 3H), 0.77 (d, J = 6.5 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ): = 143.8, 136.6, 135.5, 130.0, 127.3, 127.0, 72.0, 61.8, 49.9, 46.4, 34.1, 21.7, 18.4, 18.1; HRMS (ESI) Calcd for C 16 H 25 NNaO 4 S (M+Na) + : 350.1397; found 350 .1387. Enantiomeric excess (97%) was determined by HPLC analysis (Chiralpack IA, 10% i PrOH in hexanes 1.0 mL/min, 254 nm), t r 14.1 (minor), 15.3 (major).

PAGE 139

139 ( R,E ) N (4 hydroxy 5 methylhex 2 enyl) N (2 hydroxyethyl) 4 methylb enzene sulfonamide ( 3 119 ). A solution of 3 117 (794.0 mg, 1.80 mmol) in THF (2 mL) was added dropwise at 0 C to a suspension of LiAlH 4 (205.2 mg, 5.40 mmol) in THF (2.5 mL). The reaction was stirred at the same temperature for 3h and quenched by addition o f H 2 crude mixture was treated with a NaOH solution (15% in H 2 2 and stirred at r.t. for 1h. After filtration,the crude mixture was dried over MgSO 4 recovered as a colorless oil which was used for the next step withou t further purification. A solution of TBAF (1.0M in THF, 5.4 mL) was added dropwise at 0C to a solution of the silyl ether obtained above in dry THF (9 mL). The reaction was stirred 16h at the same temperature and NaHCO 3 saturated (30 mL of a saturated aq ueous solution) was added dropwise. After dilution in water (20 mL), the crude product was extracted with CH 2 Cl 2 (3 x20 mL), the combined organic layers were dried over MgSO 4 and the solvent removed by vacuum. Flash chromatography (Gradient 30, 40, 50, 60 70% EtOAc/ hexanes ) afforded the product as a colorless oil (394.7 mg, 67%); R f = 0.18 (60% EtOAc/ hexanes ); D = +14.7 ( c 0.60, CH 2 Cl 2 ); IR (neat) 3408, 2959, 2929, 2874, 1598, 1469, 1446, 1335 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): = 7.70 (d J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz), 5.63 (dd, J = 15.5, 6.5 Hz, 1H), 5.54 (dt, J = 15.5, 6.0 Hz, 1H), 3.88 (dd, J = 15.0, 5.5 Hz, 1H), 3.80 3.72 (m, 4H), 3.28 3.17 (m, 2H), 3.04 (br, 1H), 2.52 (br, 1H), 2.43 (s, 3H), 1.70 1.64 (m, 1H), 0.86 (dd, J = 21.0, 6.5 Hz, 6H); 13 C NMR (75 MHz,

PAGE 140

140 CDCl 3 ): = 143.8, 136.5, 136.3, 130.0, 127.5, 126.6, 77.2, 61.2, 51.4, 50.0, 33.8, 21.7, 18.3, 18.1; HRMS (ESI) Calcd for C 16 H 25 NNaO 4 S (M+Na) + 350.1397 found 350.1389. Enantiomeric excess (94%) was determined by HPLC analysis (Chiralpack IA, 20% i PrOH in hexane s 1.0 mL/min, 254 nm), t r 9.4 (major), 15.8 (minor). ( S E ) 2 (3 methylbut 1 enyl) 4 tosylmorpholine (3 120 ). Anhyd CH 2 Cl 2 (1.3 mL) was added to an aluminum foil covered, flame dried, test tube containing Ph 3 PAuCl (5.0 m g, 0.010 mmol, 2.0 mol%), AgOTf (2.5 mg, 0.010 mmol, 2.0 mol%), and activated 4 MS (100 mg). The heterogeneous mixture was vigorously stirred for 10 min and a solution of the corresponding diol 3 118 (163.0 mg, 0.50 mmol) in anhyd CH 2 Cl 2 (1.3 mL) was the n added. After 3 h, TLC analysis indicated a complete reaction and the mixture filtered through a short plug of silica with CH 2 Cl 2 (10 mL). The solution of crude product was concentrated in vacuo, and purified by flash chromatography (Gradient 50%, 90% CH 2 Cl 2 / hexanes ) to give 143.2 mg (93%) of the CH 2 Cl 2 ). Enantiomeric excess (96%) was determined by HPLC analysis (Regis Pirckel Covalent, 10% i PrOH in hexanes 1.5 mL/min, 254 nm), t r 22.0. (minor), 31.5 (major). ( R,E ) 2 (3 methylbut 1 enyl) 4 tosylmorpholine (3 121)

PAGE 141

141 Anhyd CH 2 Cl 2 (0.7 mL) was added to an aluminum foil covered, flame dried, test tube containing Ph 3 PAuCl (3.2 mg, 0.006 mmol, 2.0 mol%), AgOTf (1.6 mg, 0.006 mmol, 2.0 mol%), and activated 4 MS (50 mg). The heterogeneous mixture was vigorously stirred for 10 min and a solution of the corresponding diol 3 119 (105.6 mg, 0.32 mmol) in anhyd CH 2 Cl 2 (0.8 mL) was then added. After 3 h, TLC analysis indicated a complete reac tion and the mixture filtered through a short plug of silica with CH 2 Cl 2 (10 mL). The solution of crude product was concentrated in vacuo and purified by flash chromatography (Gradient 50%, 90% CH 2 Cl 2 / hexanes ) to give 90.1 mg (91%) of the title compound a s a white solid; mp 93 95 C; R f = 0.16 (50% CH 2 Cl 2 / hexanes D = 121.0 ( c 1.00, CH 2 Cl 2 ); IR (neat) 2960, 2867, 1725, 1597, 1449, 1349 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): = 7.64 (d J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 5.76 (ddd, J = 15.5, 6.5, 1.0 Hz, 1H), 5.26 (ddd, J = 15.5, 6.5, 1.0 Hz, 1H), 3.99 (dt, J = 7.0, 2.5 Hz, 1H), 3.92 (dd, J = 12.0, 2.0 Hz, 1H), 3.70 (dt, J = 12.0, 2.5 Hz, 1H), 3.55 (ddd, J = 23.5, 11.0, 2.0 Hz, 2H), 2.44 (s, 3H), 2.39 (dt, J = 11.0, 3.0 Hz, 1H), 2.28 2.50 (m, 1H), 2.11 (t, J = 10.8 Hz, 1H), 0.97 (d, J = 6.6 Hz, 6H); 13 C NMR (7 5 MHz, CDCl 3 ): = 144.1, 142.4, 130.0, 129.8, 128.0, 123.6, 76.1, 65.9, 50.5, 45.5, 31.0, 22.1, 21.7; HRMS (ESI) Calcd for C 16 H 24 NO 3 S (M+H) + 310.1471 found 310.1476. Enantiomeric excess (93%) was determined by HPLC analysis (Regis Pirckel Covalent, 10% i PrOH in hexane s 1.5 mL/min, 254 nm), t r 22.0. (major), 31.5 (minor). The absolute configurations of 3 120 and 3 121 have been determined by comparison of optical rotation with known derivative 3 122

PAGE 142

142 ( S ) 2 methyl 4 tosylmorpholine ( 3 122 ). 3 120 (80.3 mg, 0.25 mmol) was dissolved in dry CH 2 Cl 2 /MeOH (1/1, 10mL), and the solution was cooled to 78C. Ozone was passed into the solution using a gas dispersion tube. At the end of the reaction, after approximately 10 min, the solution become s blue, was purged 5 min with O 2 warmed up to 0C, NaBH 4 (47.3.3 mg, 1.25 mmol, 3 eq) was added portionwise at the same temperature and stirred 2 hours at room temperature. H 2 O (2 mL) was added and the crude was extracted with CH 2 Cl 2 (3x10mL) and dried ov er MgSO 4 The crude product was concentrated and recovered as a colorless oil which was used for the next step without further purification. Et 3 N (37.8 mg, 0.38 mmol) and MsCl (43.0 mg, 0.38 mmol) were added to a solution of the alcohol obtained above in d ry CH 2 Cl 2 (2 mL) at 0C. The reaction mixture was stirred at r.t. for 18h and applied to a short plug of silica. The crude was concentrated and recovered as a yellow oil which was used for the next step without further purification. A solution of the mesyl ate obtained above in dry THF (1 mL) was added dropwise at 0C to a suspension of LiAlH 4 (47.7 mg, 1.17 mmol) in dry THF (1 mL). After 40 min at reflux, TLC analysis indicated a complete reaction and the mixture was quenched by addition of H 2 H 2 2 dried over MgSO 4 and purified by flash chromatography (100% CH 2 Cl 2 ) to give 33.3 mg (64%) o f the title compound as a colorless oil that satisfactorily matched all previously D = +29.8 (c = 0.8, CH 2 Cl 2 D = +31.7 (c = 0.8, CH 2 Cl 2 ). 99

PAGE 143

143 6 .2. 6 Synthesis of 3 129 and 3 131 Compou nd 3 126 has been described in the literature and when prepared here satisfactorily matched all previously reported data. ( R ) 7 (2 (tert butyldimethylsilyloxy)phenyl) 2 methylhept 4 yn 3 ol ( 3 127 ). A 50 mL flask was char ged with Zn(OTf) 2 (1.6750 g, 4.61 mmol) and (+) N methylephedrine (827.5 mg, 4.61 mmol) was added. To the flask was added toluene (9 mL) and ixture was stirred for 2 h at r t before 3 126 (1.00 g, 3.85 mmol) in toluene (1 mL) was added in one portion. Afte r stirring for 0.25 h at r t iso butylaldehyde (415.8 mg, 5.77 mmol) was added in one portio n. The re action mixture was stirred at r t for 20 hours. The reaction was quenched by addition of NH 4 Cl (sat.) (3 mL). The reaction mixture was poured into a separatory funnel containing diethyl ether (10 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (3 x 10 mL). The combined ethereal portion was washed with NaCl (sat.) (10 mL), dried over anhydrous MgSO 4 filtered and concentrated invacuo. The crude material was purified by flash chromatography (gradient; 5,10% EtOAc/ hexanes ) to give the product as a colorless oil (1.0987 g, 87%); R f = 0.15 (10% EtOAc/ hexanes D = +4.5 (c 1.00, CH 2 Cl 2 ); IR (neat) 3399, 2958, 2931, 2859, 1491, 1254, 925, 838, 780 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): = 7.17 7.06 (m, 2H), 6.87 (t, J = 7. 4 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 4.13 (t, J = 5.4Hz, 1 H), 2.81 (t, J = 7.8 Hz, 2H), 2.50 (dt, J = 7.5, 1.5 Hz, 2H), 1.87 1.76 (m,1H), 1.64 (d, J = 5.7 Hz, 1H), 1.02 (s, 9H), 0.95 (dd, J = 6.9, 4.5 Hz, 6H) 0.24 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ):

PAGE 144

144 = 153 .8, 131.4, 130.6, 127.6, 121.2, 118.6, 86.1, 80.5, 68.4, 34.8, 30.6, 26.0, 19.5, 18.4, 18.3, 17.6, 3.9; HRMS (ESI) Calcd for C 20 H 33 O 2 Si (M+H) + : 333.2244, found 333.2257. Enantiomeric excess (98%) was determined by HPLC analysis (Regis Pirckel Covalent, 2% i PrOH in hexanes 0.3 mL/min, 254 nm), t r 19.1 (minor), 20.3 (major); (R,E) 2 (5 hydroxy 6 methylhept 3 eny l)phenol ( 3 128 ). [Cp*Ru(MeCN) 3 ]PF 6 catalyst (3 mol%, 23.0 mg, 0.045 mmol) was added to a solution of 3 127 (500.0 mg, 1.51 mmol) and ethoxydimethylsilane (236.0 mg, 2.26 mmol) in CH 2 Cl 2 (5 mL) at 0C. The ice bath was removed and the reaction mixture stirred for 15 minutes at rt. After filtration over a short plug of florisil and removal of the solvent, crude product was recovered as a yellow oil which was used for the next step without further purification. A solution of TBAF (1.0M in THF, 6.04 mL) was added dropwise at 0C to a solution of the silane obtained above and CuI (28.7 mg, 0.15 mmol) in dry THF (7.5 mL). T he reaction was stirred 16h at the same temperature and NH 4 Cl (sat.) (5 mL) was added dropwise. After dilution in water (20 mL), the crude product was extracted with EtOAc (2x30 mL), the combined organic layers were dried over MgSO 4 and the solvent removed by vacuum. Flash chromatography (20% EtOAc/ Hexanes ) afforded the product as a colorless oil (265.4 mg, 80%); R f = 0.18 (50% EtOAc/ hexanes D = 8.0 (c 1.00, CH 2 Cl 2 ); IR (neat) 3347, 2960, 2930, 2874, 1457, 1368, 1240, 1000, 973, 752 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): = 7.12 (m, 2H), 6.85 (t, J = 7.4 Hz, 2H), 6.57 (d, J = 7.8 Hz, 1H), 5.70 (dt, J = 15.3, 6.6 Hz, 1H), 5.49

PAGE 145

145 (ddt, J = 15.3, 7 .5, 1.2 Hz, 1H), 5.29 (bs, 1H), 3.77 (t, J = 6.9 Hz, 1H), 2.71 (t, J = 6.9 Hz, 2H), 2.38 (q, J = 7.5 Hz, 2H), 1.66 (m, 2H), 0.87 (dd, J = 18.3, 6.3 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ): = 153.8, 132.6, 131.9, 130.5, 128.0, 127.4, 120.9, 115.6, 78.6, 33.9, 32 .7, 30.1, 18.4, 18.3; HRMS (ESI) Calcd for C 14 H 24 NO 2 (M+NH 4 ) + : 238.1802, found 238.1803. Enantiomeric excess (98%) was determined by HPLC analysis (Chiralcel OD H, 10% i PrOH in hexanes 1.0 mL/min, 254 nm), t r 12.3 (major), 13.6 (major). ( S,E ) 2 (3 methylbut 1 enyl)chroman (3 129 ). Anhyd CH 2 Cl 2 (1.4 mL) was added to an aluminum foil covered, flame dried, test tube containing Ph 3 PAuCl (16.9 mg, 0.034 mmol, 5.0 mol %), AgOTf (8.7 mg, 0.034 mmol, 5.0 mol%), and activated 4 M S (90 mg). The heterogeneous mixture was vigorously stirred for 10 min and a solution of the corresponding diol 3 128 (150.0 mg, 0.68 mmol) in anhyd CH 2 Cl 2 (1 mL) was then added. After 2.5 h ours TLC analysis indicated a complete reaction and the mixture f iltered through a short plug of silica with CH 2 Cl 2 (10 mL). The solution of crude product was concentrated in vacuo, and purified by f lash chromatography (Gradient 0 5% Et 2 O / hexanes ) to give 122.1 mg (89%) of the title compound 3 129 as a colorless oil; R f = 1.0 (5% EtOAc/ hexanes D = +69.4 ( c 1.04, CH 2 Cl 2 ); IR (neat) 2958, 2928, 2869, 2583, 1488, 1230, 971, 752 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): = 7.11 7.02 (m, 2H), 6.85 6.80 (m, 2H), 5.79 (ddt, J = 15.6, 6.3, 1.2 Hz, 1H), 5.56 (ddt J = 15.6, 6.6, 0.9 Hz, 1H), 4.50 4.43 (m, 1H), 2.92 2.71 (m, 2H), 2.40 2.28 (m,1H), 2.05 1.99 (m, 1H), 1.88 1.77 (m, 1H), 1.02 (dd, J = 6.6, 0.9 Hz, 6H);

PAGE 146

146 13 C NMR (75 MHz, CDCl 3 ): = 154.9, 140.6, 129.7, 127.4, 126.7, 122.0, 120.2, 117.0, 76.8, 30.9, 28.3, 24.7, 22.4, 22.3; HRMS (ESI) Calcd for C 14 H 19 O (M+H) + : 203.1430 found 203.1433. ( R,Z ) 2 (5 hydroxy 6 methylhept 3 enyl)phenol ( 3 130 ). Lindlar catalyst (5% palladium on calcium carbonate, poisoned with lead, 30 mg) was added to a solution of 3 127 (335.6 mg, 1.01 mmol) in dry MeOH (5 mL). The reaction mixture was stirred 1.5 h our under H 2 (1 atm). After filtration over celite and removal of the solvent, crude product was recovered as a colorless oil which was used for the next step without further purification. A solution of TBAF (1.0M in THF, 4.0 mL) was added dropwise at 0C to a solution of the silane obtained above in dry THF (5 mL). The reaction was stirred 16h at the same temperature and NaHCO 3 saturated (30 mL of a saturated aqueous solution) was added dropwise. After dilution in water (20 mL), the crude product was extracted with EtOAc (2 x 30 mL), the combined organic layers were dried over MgSO 4 and the solvent removed by vacuum. Flash chromato graphy (Gradient 15, 20% EtOAc/ hexane s ) afforded the product as a colorless oil (192.7 mg, 87%); R f = 0.35 (30% EtOAc/ hexanes D = +1.2 (c 1.00, CH 2 Cl 2 ); IR (neat) 3337, 2959, 2930, 1491, 1457, 1259, 1015, 924, 838, 753 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): = 7.12 (m, 2H), 6.85 (t, J = 7.4 Hz, 2H), 6.57 (d, J = 7.8 Hz, 1H), 6.47 (br, 1H), 5.70 5.60 (m, 1H), 5.41 (t, J = 9.0 Hz, 1H), 4.08 (t, J = 8.0 Hz, 1H), 2.82 2.25 (m, 4H), 1.71 1.60 (m, 2H), 1.80 (br, 1H); 0.87 (dd, J = 27.0, 6.9 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ): = 154.2, 132.9, 131.3,

PAGE 147

147 13 0.8, 128.0, 127.6, 120.5, 115.7, 72.9, 33.8, 30.6, 28.2, 18.5, 18.1; HRMS (ESI) Calcd for C 14 H 24 NO 2 (M+NH 4 ) + : 238.1802, found 238.1800. Enantiomeric excess (97%) was determined by HPLC analysis (Chiralcel OD H, 3% i PrOH in hexanes 1.0 mL/min, 254 nm), t r 12.8 (minor), 13.4 (major) ( R,E ) 2 (3 methylbut 1 enyl)chroman (3 131 ). Anhyd CH 2 Cl 2 (1.2 mL) was added to an aluminum foil covered, flame dried, test tube containing Ph 3 PAuCl (10.8 mg, 0.022 mmol, 5.0 mol%), AgOTf (5.6 m g, 0.022 mmol, 5.0 mol%), and activated 4 MS (80 mg). The heterogeneous mixture was vigorously stirred for 10 min and a solution of the corresponding diol 3 130 (96.4 mg, 0.43 mmol) in anhyd CH 2 Cl 2 (1 mL) was then added. After 2 h, TLC analysis indicated a complete reaction and the mixture filtered through a short plug of silica with CH 2 Cl 2 (10 mL). The solution of crude product was concentrated in vacuo, and purified by flash chromatography (Gradient 0, 5% Et 2 O / hexanes ) to give 80.8 mg (92%) of the title compound ( R ) 42 as a colorless oil; R f = 1.0 (5% EtOAc/ hexanes D = 67.4 ( c 1.00, CH 2 Cl 2 ). The absolute configurations and ee of 3 130 and 3 131 have been determined by HPLC analysis and comparison of optical rotations with known derivatives 3 132 an d 3 133 ( S ) chroman 2 ylmethanol (3 132 ).

PAGE 148

148 3 129 (64.3 mg, 0.32 mmol) was dissolved in dry CH 2 Cl 2 /MeOH (1/1, 10mL), and the solution was cooled to 78C. Ozone was passed into the solution using a gas dispersion tube. At t he end of the reaction, after approximately 10 min, the solution becomes blue, was purged 5 min with O 2 warmed up to 0C, NaBH 4 (35.3 mg, 0.95 mmol, 3 eq) was added portionwise at the same temperature and stirred 2 hours at room temperature. H 2 O (5 mL) wa s added and the crude was extracted with CH 2 Cl 2 (3x10mL) and dried over MgSO 4 The solution of crude product was concentrated, and then purified by flash chromatography (20% EtOAc/ hexanes ) to give the product as a D = +87.6 (c = 1.01, MeOH) that satisfactorily matched all previously reported data. 101 Enantiomeric excess (70%) was determined by HPLC analysis (Chiralcel AD, 3% i PrOH in hexanes 0.6 mL/min, 254 nm), t r 25.4 (major), 30.7 (minor). ( R ) chroman 2 ylmethanol (3 133 ). 3 131 (31.4 mg, 0.15 mmol) was dissolved in dry CH 2 Cl 2 /MeOH (1/1, 8mL), and the solution was cooled to 78C. Ozone was passed into the solution using a gas dispersion tube. At the end of the reaction, after approximately 10 min, the solution becomes blue, was purged 5 min with O 2 warmed up to 0C, NaBH 4 (28.6 mg, 0.77 mmol, 5 eq) was added portionwise at the same temperature and stirred 1 hours at room temperature. H 2 O (5 m L) was added and the crude was extracted with CH 2 Cl 2 (3x10 mL) and dried over MgSO 4 The solution of crude product was concentrated, and then purified by flash chromatography (20% EtOAc/ hexanes ) to give the product as a colorless oil (19.6 mg, 77%) that sa tisfactorily matched all previously reported data.

PAGE 149

149 Enantiomeric excess (70%) was determined by HPLC analysis (Chiralcel AD, 3% i PrOH in hexanes 0.6 mL/min, 254 nm), t r 25.4 (minor), 30.7 (major) 6 .2. 7 Synthesis of 3 144 and 3 146 Compounds 3 136 103 and 3 141 (>98% ee) 104 have been described in the literature and when prepared here satisfactorily matched all previously reported data. ( R ) 1 (benzyloxy) 8 (tert butyldimethylsilyloxy) 6 methyleneoct 3 yn 2 ol ( 3 142 ). To a solution of 3 141 (573.5 mg, 3.25 mmol) and in dry DM F (3.25 mL) was added at rt, potassium carbonate (583.8 mg, 4.22 mmol), tetrabutylammonium bromide (157.0 mg, 0. 49 mmol 10 mol %) and copper iodide (61.9 mg, 0.33 mmol, 10 mol%). The mixture was stirred at the same temperature for 10 minutes and 3 136 (1.5210 g, 6.5 mmol, 2 eq) was added in one portion. After 48 h ours TLC analysis showed disappearance of the alco hol, water (3 mL) was added, the crude extracted with CH 2 Cl 2 (3x10 mL), dried over MgSO 4 purified by flash chromatography (Gradient 5, 10% EtOAc/ hexanes ) to give the product as a colorless oil (669.6 mg, 55%); R f = 0.26 (10% EtOAc/ hexanes D = 0.8 (c 1.00, CH 2 Cl 2 ); IR (neat) 3421, 2954, 2929, 2858, 1255, 1102, 835, 776 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): = 7.36 7.25 (m, 5H), 5.09 (q, J = 1.5Hz, 1H), 4.87 (q, J = 1.5 Hz, 1H), 4.60 (d, J =2.1 Hz, 2H), 3.73 3.52 (m, 5H), 2.98 (d, J = 1.5 Hz, 2H) 2.40 2.28 (m,1H), 2.05 1.99 (m, 1H), 1.88 1.77 (m, 1H), 1.02 (dd, J = 0.9, 6.6 Hz, 6H), 2.48 (d, J = 4.5 Hz, 1H), 2.29 (t, J = 6.8 Hz, 2H), 0.88 (s, 9H), 0.04 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ): = 141.5, 137.9, 128.7, 128.1, 128.0, 112.8, 83.6,

PAGE 150

150 80.4, 74.1, 73.6, 62. 4, 62.1, 39.1, 26.7, 26.1, 18.5, 5.1; HRMS (ESI) Calcd for C 22 H 35 O 3 Si (M+H) + : 375.2350 found 375.2346. ( R E ) 8 (benzyloxy) 3 methyleneoct 5 ene 1 ,7 diol ( 3 143 ). [Cp*Ru(MeCN) 3 ]PF 6 catalyst (15.4 mg, 0.03 mmol, 3 mol%) w as added to a solution of 3 142 (372.1 mg, 0.99 mmol) and ethoxydimethylsilane (207.0 mg, 1.98 mmol) in CH 2 Cl 2 (3 mL) at 0C. The ice bath was removed and the reaction mixt ure stirred for 15 minutes at r t. After filtration over a short plug of florisil and removal of the solvent, crude product was recovered as a yellow oil which was used for the next step without further purification. A solution of TBAF (1.0M in THF, 2.97 mL) was added dropwise at 0C to a solution of the silane obtained above and CuI (38.0 mg, 0.20 mmol, 20 mol %) in dry THF (5 mL). The reaction was stirred 16 h at the same temperature and NH 4 Cl (sat.) (5 mL) was added dropwise. After dilution in water (20 mL), the crude product was extracted with EtOAc (2 x 30 mL), the combined organic lay ers were dried over MgSO 4 and the solvent removed by vacuum. Flash chromatography (40% EtOAc/ Hexanes ) afforded the product as a colorless oil (183.4 mg, 70%); R f = 0.23 (50% EtOAc/ hexanes D = +5.8 (c 1.00, CH 2 Cl 2 ); IR (neat) 3416, 2954, 2929, 2858, 14 71, 1454, 1389, 1361 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): = 7.38 7.26 (m, 5H), 5.77 (dt, J = 15.9, 6.6 Hz, 1H), 5.50 (ddd, J = 15.6, 6.6, 1.5 Hz, 1H), 4.87 (d, J = 8.1 Hz, 2H), 4.56 (s, 2H), 4.33 (m,1H), 3.68 (t, J = 6.3 Hz, 2H), 3.51 (dd, J = 9.6, 3.3 Hz, 1H) 3.37 (dd, J = 9.6, 8.4 Hz, 1H), 2.77 (d, J = 6.6 Hz, 1H), 2.62 (br, 1H), 2.28 (t, J = 6.3 Hz, 1H), 1.71 (br, 1H); 13 C NMR (75 MHz, CDCl 3 ): = 144.5, 138.0,

PAGE 151

151 130.8, 130.6, 128.7, 128.0, 128.0, 113.1, 74.4, 73.5, 71.3, 60.5, 39.2, 39.1; HRMS (ESI) Calcd fo r C 16 H 26 NO 3 (M+NH 4 ) + : 280.1907; found 280.1916. ( R E ) 2 (3 (benzyloxy)prop 1 enyl) 4 methylenetetrahydro 2H pyran (3 144) Anhyd CH 2 Cl 2 (0.6 mL) was added to an aluminum foil covered, flame dried, test tube containing Ph 3 P AuCl (3.4 mg, 0.007 mmol, 3.0 mol%), AgOTf (1.7 mg, 0.007 mmol, 3.0 mol%), and activated 4 MS (50 mg). The heterogeneous mixture was vigorously stirred for 10 min utes and a solution of the corresponding diol 3 143 (61.4 mg, 0.22 mmol) in anhyd CH 2 Cl 2 (0. 6 mL) was then added. After 3 h ours TLC analysis indicated a complete reaction and the mixture filtered through a short plug of silica with CH 2 Cl 2 (10 mL). The solution of crude product was concentrated in vacuo, and purified by flash chromatography (Grad ient 0%, 10% Et 2 O / hexanes ) to give 46.2 mg (85%) of the title compound as a colorless oil; R f = 0.25 (10% Et 2 O/ hexanes D = 13.3 (c 1.00, CH 2 Cl 2 ); IR (neat) 2945, 1721, 1658, 1452, 1366 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): = 7.34 7.24 (m, 5H), 5.88 5.75 (m, 2H), 4.75 (d, J = 1.8 Hz, 2H), 4.52 (s, 2H), 4.11 (ddd, J = 10.8, 5.4, 1.8 Hz, 1H), 4.03 (d, J = 3.9 Hz, 2H), 3.84 3.78 (m, 1H), 3.43 (dt, J = 11.7, 2.7 Hz, 1H), 2.36 2.07 (m, 4H); 13 C NMR (75 MHz, CDCl 3 ): = 144.2, 138.5, 133.41, 128.6, 128.0, 127.9, 127.8, 109.1, 78.6, 72.4, 70.3, 68.8, 41.3, 35.2; HR MS (ESI) Calcd for C 16 H 21 O 2 (M+H) + : 245.1536, found 245.1529. Th e enantiomeric excess (98%) was determined by HPLC analysis (Regis Pirckel Covalent, 1% i PrOH in hexanes 0.8 mL/min, 254 nm), t r 14.9 (minor), 19.6 (major).

PAGE 152

152 ( R Z ) 8 (benzyloxy) 3 methyleneoct 5 ene 1,7 diol (3 145) Lindla r catalyst (5% palladium on calcium carbonate, poisoned with lead, 25 mg) and quinoline (25 mg) were added to a solution of 3 142 (254.3 mg, 0.68 mmol) in dry MeOH (5 mL). The reaction mixture was stirred 3 days under H 2 (1 atm). After filtration over celi te and removal of the solvent, crude product was recovered as a colorless oil which was used for the next step without further purification. A solution of TBAF (1.0M in THF, 2.04 mL) was added dropwise at 0C to a solution of the silane obtained above in dry THF (5 mL). The reaction was stirred 16h at the same temperature and NaHCO 3 saturated (30 mL of a saturated aqueous solution) was added dropwise. After dilution in water (20 mL), the crude produc t was extracted with EtOAc (2x 30 mL), the combined organi c layers were dried over MgSO 4 and the solvent removed by vacuum. Flash chromatography (Gradient 20, 40% EtOAc/ hexanes ) afforded the product as a colorless oil (192.7 mg, 87%); R f = 0.30 (50% EtOAc/ hexanes D = +4.0 (c 1.00, CH 2 Cl 2 ); IR (neat) 3398, 29 24, 1722, 1453, 1381, 1275 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): = 7.38 7.26 (m, 5H), 5.65 5.45 (m, 2H), 4.85 (d, J = 10.2 Hz, 2H), 4.64 (dt, J = 7.8, 3.6 Hz, 1H), 4.56 (s, 2H), 3.68 (t, J = 7.8 Hz, 2H), 3.48 3.36 (m, 2H), 2.97 2.71 (m, 3H), 2.27 (t, J = 6.0H z, 2H), 1.91 (br, 1H); 13 C NMR (75 MHz, CDCl 3 ): = 144.7, 138.0, 131.2, 129.8, 128.7, 128.1, 128.0, 112.8, 74.1, 73.6, 66.9, 60.8, 38.3, 34.7; HRMS (ESI) Calcd for C 16 H 23 O 3 (M+H) + : 263.1642 found 263.1651.

PAGE 153

153 ( S E ) 2 (3 (b enzyloxy)prop 1 enyl) 4 methylenetetrahydro 2H pyran (3 146 ). Anhyd CH 2 Cl 2 (0.8 mL) was added to an aluminum foil covered, flame dried, test tube containing Ph 3 PAuCl (4.4 mg, 0.009 mmol, 3.0 mol%), AgOTf (2.2 mg, 0.009 mmol, 3.0 mol%), and activated 4 MS (60 mg). The heterogeneous mixture was vigorously stirred for 10 min and a solution of the corresponding diol 3 145 (80.1 mg, 0.29 mmol) in anhyd CH 2 Cl 2 (0.8 mL) was then added. After 2.5 h ours TLC analysis indicated a complete reaction and the mixture f iltered through a short plug of silica with CH 2 Cl 2 (10 mL). The solution of crude product was concentrated in vacuo, and purified by flash chromatography (Gradient 0, 10% Et 2 O/ hexanes ) to give 65.2 mg (92%) of the D = +12.9 (c 1.00, CH 2 Cl 2 ). The enantiomeric excess (97%) was determined by HPLC analysis (Regis Pirckel Covalent, 1% i PrOH in hexanes 0.8 mL/min, 254 nm), t r 14.9 (major), 19.3 (minor). 6 2.8 Synthesis of 3 154 and 3 156 Compound 3 150 has been synthesized b y benzylation of the known ( S ) 1 (tert butyldimethylsilyloxy)hex 5 yn 3 ol (99% ee). 105 Compound 3 151 has been described in the literature and when prepared here satisfactorily matched all previously reported data. 106 ( S ) (3 (benzyloxy)hex 5 ynyloxy)(tert butyl)dimethylsilane ( 3 150 ).

PAGE 154

154 ( S ) 1 (tert butyldimethylsilyloxy)hex 5 yn 3 ol (191.4 mg, 0.83 mmol) in THF (1mL) was added dropwi se at 0 C to a suspension of sodium hydride (39.8 mg, 1.67 mmol) in THF (2 mL). The mixture was stirred at rt for 1 h our mmol) was added in one portion. The reaction was stirred 16h at the same temperature and H 2 O (5 mL) was added dropwise. The crude product was extracted with CH 2 Cl 2 (2x20 mL), the combined organic layers were dried over M gSO 4 and the solvent removed by vacuum. Flash chromatography (Gradient 0, 5% EtOAc/ Hexanes ) afforded the product as a colorless oil (223.8 mg, 85%); R f = 0.71 (10% EtOAc/ hexanes D = 18.6 (c = 1.00, CH 2 Cl 2 ); IR (neat) 2956, 2859, 1472, 1259, 1113, 838 774, 666 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): 7.37 7.25 (m,5H), 4.58 (ABq, J Hz, 2H), 3.80 3.69 (m, 3H), 2.48 (dd, J = 5.7, 2.7 Hz, 2H), 2.00 (t, J = 2.7 Hz, 1H), 1.90 1.82 (m, 2H), 0.89 (s, 9H), 0.04 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ): = 138.8, 128.6, 128.0, 127.8, 81.4, 74.4, 71.9, 70.3, 59.6, 37.5, 26.2, 24.3, 18.5, 5.1; HRMS (ESI) Calcd for C 19 H 31 O 2 Si (M+H) + : 319.2088 found 319.2078. ( S ) 3 (benzyloxy) 1 (tert butyldimethylsilyloxy)tridec 5 yn 7 o ne ( 3 151a ). A solution of n BuLi in hexane 1.6M (2.41 mL, 3.85 mmol) was added dropwise over 10 minutes at 78C to a solution of 3 150 (451.3 mg, 1.42 mmol) in dry THF (6 mL). The reaction was then stirred at the same temperature for 45 minutes and a solu tion of 3 151 (367.4 mg, 2.12 mmol) in dry THF (1 mL) was added. The mixture was allowed to warm to room temperature and stirred for 2 hours, quenched with NH 4 Cl (10 mL of a saturated aqueous solution), diluted with water (20 mL) and extracted with

PAGE 155

155 CH 2 Cl 2 (2x30 mL). The organic layers were dried over MgSO 4 and then purified by fl ash chromatography (gradient; 0 5% EtOAc/ Hexanes ) to give the product as a colorless oil (476.6 mg, 78%). R f = 0.43 (5% EtOAc/ hexanes D = +22.4 (c 1.00, CH 2 Cl 2 ); IR (neat) 295 6, 2930, 2860, 1720, 1672, 1273, 1168, 1099, 1071, 699 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): 7.35 7.28 (m,5H), 4.62 (ABq, J 3.87 3.80 (m, J = 6.0 Hz, 1H), 3.76 (m, 2H), 2.68 (dd, J = 5.5, 2.5 Hz, 2H), 2.54 (t, J = 7.5 Hz, 2H), 1 .87 (q, J = 6.0Hz,, 2H), 1.67 (m, J = 7.3 Hz, 2H), 1.35 1.30 (m, 6H), 0.92 0.88 (m, 12H), 0.07 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ): 188.5 138.4, 128.6, 128.0, 127.9, 90.9, 82.4, 74.2, 72.1, 59.4, 45.8, 37.7, 31.7, 28.9, 26.2, 26.0, 25.0, 24.3, 22.7, 18.5, 1 4. 3, 5.1, 5.1; HRMS (ESI) Calcd for C 26 H 43 O 3 Si (M+H) + : 431.3122; found 431.31125. (3S,7R) 3 (benzyloxy) 1 (tert butyldimethylsilyloxy)tridec 5 yn 7 ol ( 3 152). Noyori catalyst [( R R) TsDPEN Ru (p cymene)Cl] (11.6 mg, 0.0 18 mmol, 0.02 eq) was added to a mixture of ynone 3 151a (396.3 mg, 0.92 mmol), sodium formate (635.6 mg, 9.20 mmol, 10 eq), TBAC (85.4 mg, 0.28 mmol, 0.3 eq) in CH 2 Cl 2 (4 mL) and deionized H 2 O (4 mL). The biphasic mixture was strongly stirred for 20 hours at room temperature, diluted with water (10 mL) and extracted with CH 2 Cl 2 (2x10 mL). The organic layers were dried over MgSO 4 and then purified by flash chromatography (gradient; 5 10% EtOAc/ hexanes ) to give the product as a colorless oil (274.1 mg, 71% ); R f = 0.23 (10% EtOAc/ hexanes D = +11.9 (c 1.00, CH 2 Cl 2 ); IR (neat) 3428, 2924, 2857, 1470, 1256, 1097, 836, 776, 734, 607 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ):

PAGE 156

156 7.45 7.28 (m, 5H), 4.62 (ABq, J J = 6.0 Hz, 1H), 3.80 3.71 (m, 3H), 2.57 2.48 (m, 2 H), 1.92 1.41 (m, 13H), 1.36 1.26 (m, 12H), 0.08 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ): 138.7, 128.6, 127.9, 127.8, 83.4, 82.1, 74.7, 71.8, 62.9, 59.6, 38.3, 37.6, 32.0, 29.2, 26.1, 25.4, 24.5, 22.8, 18.5, 14.3, 5.1, 5.1; HRMS (ESI) Calcd for C 26 H 45 O 3 Si (M+ H) + : 433.3133, found 433.3146. (3S,7R,Z) 3 (benzyloxy)tridec 5 ene 1,7 diol ( 3 153 ). Lindlar catalyst (5% palladium on calcium carbonate, poisoned with lead, 14.0 mg) and quinoline (14.0 mg) were added to a solution of 3 152 (69.3 mg, 0.16 mmol) in dry MeOH (1 mL). The reaction mixture was stirred 1.5 h under H 2 (1 atm). After filtration over celite and removal of the solvent, crude product was recovered as a colorless oil which was used for the next step without further purification. of the silyl ether obtained above in dry THF (1 mL). The reaction was stirred 16h and the m ixture applied directly to flash chromatography (Gradient 30, 40 50% EtOAc/ hexanes ) to afford the product as a colorless oil (41.3 mg, 81%); R f = 0.24 (50% EtOAc/ hexanes ); D = +20.3 ( c 1.00, CH 2 Cl 2 ); IR (neat) 3368, 2928, 2857, 1454, 1063, 736, 697 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): = 7.36 7.26 (m, 5H), 5.54 (m, 2H), 4.56 (AB q J = AB = 43.5 Hz, 2H), 4.36 (q J = 6.8 Hz, 1H), 3.78 3.66 (m 3H), 2.58 2.54 (m, 2H), 2.32 2.27 (m, 2H), 2.12 (bs, 1H), 1.85 1.71 (m, 2H), 1.2 1.27 (m, 9H), 0.88 (t, J = 6.8 Hz, 3H); 13 C NMR (75 MHz, CDCl 3

PAGE 157

157 128.1, 127.7, 77.6, 71.7, 67.5, 60.5, 37.5, 36.5, 32.5, 32.0, 29.5, 25.6, 22.8, 14.3; HRMS (ESI) Calcd for C 20 H 33 O 3 (M+H) + : 321.2424 found 321.2434. (2 R ,4 R ) 4 (benzyloxy) 2 (( E ) oct 1 enyl)tetrahydro 2H pyran ( 3 154 ). Anhyd CH 2 Cl 2 tube containing Ph 3 PAuCl (0.4 mg, 0.001 mmol, 1.0 mol %), AgOTf (0.2 mg, 0.001 mmol, 1.0 mol%), and activated 4 MS (20 mg). The heterogeneous mixture was vigorously stirred for 10 min and a solution of the corresponding diol 3 153 (24.1 mg, 0.08 mmol) in anhyd CH 2 Cl 2 indicated a complete reaction and the mixtur e filtered through a short plug of silica with CH 2 Cl 2 (5 mL). The solution of crude product was concentrated in vacuo, and purified by flash chromatography (Gradient 50, 70% CH 2 Cl 2 / hexanes ) to give 19.0 mg (84%) of the pure diastereomer 3 154 as a colorles s oil; R f = 0.65 (80% CH 2 Cl 2 / hexanes D = 9.2 (c 0.50, CH 2 Cl 2 ); IR (neat) 2925, 2857, 1459, 1252, 1069, 735, 707 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): = 7.38 7.26 (m, 5H), 5.68 (ddt, J = 15.5, 6.5, 1.0 Hz, 1H), 5.44 (ddt, J = 15.5, 7.5, 1.0 Hz, 1H), 4.55 (d, J = 2.0 Hz, 2H), 4.23 4.20 (m, 1H ), 3.95 3.78 (m, 3H), 2.01 (q, J = 7.5 Hz, 2H), 1.90 1.21 (m, 14H), 0.88 (t, J = 6.5 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ): 139.1, 132.7, 130.9, 128.6, 127.7, 127.6, 72.9, 71.0, 70.2, 63.0, 36.5, 32.6, 31.9, 30.1, 29.3, 29.1, 22.8, 14.3; HRMS (ESI) Calcd for C 20 H 31 O 2 (M+H) + : 303.2319, found 303.2321. Diastereomeric ratio (4:96) was determined by 1 H NMR of the crude material.

PAGE 158

158 (3 S ,7 R E ) 3 (benzyloxy)tridec 5 ene 1,7 diol ( 3 155 ). A solution of 3 152 (184.0 mg, 0.43 mmol) in THF (1 mL) was added dropwise at 0C to a suspension of LiAlH 4 (49.0 mg, 1.29 mmol) in THF (1 mL). The reaction was stirred at the same temperature for 48h, diluted with Et 2 O (3 mL) and quenched by addition of H 2 H 2 2 dried over MgSO 4 recovered as a colorless oil which was used for the next step without furth er purification. A solution of TBAF (1.0M in THF, 1 mL) was added dropwise at 0C to a solution of the silyl ether obtained above in dry THF (3 mL). The reaction was stirred 16h and the mixture applied directly to flash chromatography (Gradient 30%, 40%, 5 0% EtOAc/ Hexanes ) to afford the product as a colorless oil (120.6 mg, 88%); R f = 0.22 (50% EtOAc/ hexanes D = +14.1 (c 1.00, CH 2 Cl 2 ); IR (neat) 3364, 2928, 2851, 1061, 1071, 739, 690 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): = 7.63 7.26 (m, 5H), 5.63 (dt, J = 15.0, 7.5 Hz, 1H), 5.56 (dd, J = 15.0, 6.3 Hz, 1H); 4.56 (ABq, J 72.1 Hz, 2H), 4.03 (q, J = 6.5 Hz, 1H), 3.76 3.67 (m, 3H), 2.43 2.30 (m, 3H), 1.79 1.75 (m, 3H), 1.52 1.27 (m, 10H), 0.87 (t, J = 7.0 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ): 138.4, 136.5, 128.7, 128.1, 128.0, 127.0, 78.0, 73.1, 71.3, 60.8, 37.5, 36.5, 36.3, 32.0, 29.4, 25.6, 22. 8, 14.3; HRMS (ESI) Calcd for C 20 H 33 O 3 (M+H) + : 321.2424, found 321.2431.

PAGE 159

159 ((2 S ,4 R ) 4 (benzyloxy) 2 (( E ) oct 1 enyl)tetrahydro 2H pyran ( 3 156 ). Anhyd CH 2 Cl 2 tube containing Ph 3 PAuCl (0.6 mg, 0.001 mmol, 1.0 mol%), AgOTf (0.3 mg, 0.001 mmol, 1.0 mol%), and activated 4 MS (20 mg). The heterogeneous mixture was vigorously stirred for 10 min and a solution of the corresponding diol 3 155 (37.3 mg, 0.12 mmol) in anhyd CH 2 Cl 2 indicated a complete reaction and the mixture filtered through a short plug of silica with CH 2 Cl 2 (5 mL). The solution of crude product was concentrated in vacuo, and purified by flash chromatography (Gr adient 50, 70% CH 2 Cl 2 / hexanes ) to give 30.5 mg (87%) of the pure diastereomer 3 156 as a colorless oil; R f = 0.60 (80% CH 2 Cl 2 / hexanes D = +2.3 (c 0.50, CH 2 Cl 2 ); IR (neat) 2925, 1466, 1150, 1080 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): = 7.37 7.24 (m, 5H), 5.7 1 (ddt, J = 15.5, 6.5, 1.0 Hz, 1H), 5.51 (ddt, J = 15.5, 6.0, 1.5 Hz, 1H), 4.60 (s, 2H), 4.08 (ddd, J = 11.5, 5.0, 2.0 Hz, 1H), 3.75 (dd, J = 11.0, 6.5 Hz, 1H), 3.62 3.56 (m, 1H), 3.44 (dt, J = 13.0, 2.5 Hz, 1H), 2.13 1.97 (m, 4H), 1.64 1.25 (m, 10H), 0.90 (t, J = 7.5 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ): 138.9, 132.0, 130.3, 128.6, 127.8, 127.8, 74.8, 69.7, 66.2, 38.9, 32.8, 32.5, 31.9, 29.3, 29.1, 22.8, 14.3; HRMS (ESI) Calcd for C 20 H 31 O 2 (M+H) + : 303.2319 found 303.2322. 6 .2. 9 Synthesis of 3 163 and 3 165 Compound 3 159 has been synthesized in two step s from the known ( S ) N (3 (benzyloxy) 2 hydroxypropyl) 4 methylbenzenesulfonamide 3 159a (99%

PAGE 160

160 ee). 108 Compound 3 151 has been described in the literature and when prepared here satisfactorily matched all previo usly reported data. 106 ( S ) N (3 (benzyloxy) 2 (tert butyldimethylsilyloxy)propyl) 4 methyl N (prop 2 ynyl)benzenesulfonamide ( 3 159 ). To a solution of ( S ) N (3 (benzyloxy) 2 hy droxypropyl) 4 methylbenzenesulfonamide 3 159a (2.1503 g, 6.42 mmol) and imidazole (1.3110 g, 19.3 mmol) in DMF (32.1 mL) was added portionwise at r.t. TBDMSCl (1.9352 g, 12.8 mmol). The reaction mixture was stirred at 80 C for 2 h ours cooled to rt and qu enched with H 2 O (50 mL). The crude product was extracted with Et 2 O (2 x100 mL), the combined organic layers were dried over MgSO 4 and the solvent removed by vacuum. The recovered colorless oil was used for the next step without further purification. To a so lution of the silyl ether obtained above and CsCO 3 (8.3200 g, 25.7 mmol) in dry acetone (40 mL) was added propargyl bromide (80% wt in toluene, 3.8199 g, 25.7 mmol) in one portion. The reaction mixture was stirred at rt for 2h, cooled to rt and quenched wi th H 2 O (40 mL). The crude product was extracted with CH 2 Cl 2 (2x50 mL), the combined organic layers were dried over MgSO 4 and the solvent removed by vacuum. Purification by flash column chromatography (10% EtOAc/ hexanes ) gave 1.6431 g (53%) of 3 159 as a pa le yellow oil; R f = 0.44 (10% EtOAc/ hexanes D = 2.5 (c 1.00, CH 2 Cl 2 ); IR (neat) 2955, 2928, 2857, 1453, 1349, 1256, 1161, 837cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): = 7.73 (d, J = 8.0 Hz, 2H), 7.35 7.27 (m, 7H), 4.55 (ABq, J =

PAGE 161

161 (dABq, J 4.11 (m, 1H), 3.57 3.50 (m, 2H), 3.33 (dd, J = 14.5, 5.0 Hz, 1H), 3.23 (dd, J = 14.5, 5.0 Hz, 1H), 2.42 (s, 3H), 1.97 (t, J = 2.0 Hz, 1H), 0.89 (s, 9H), 0.09 (d, J = 10.5 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ): 143.7, 138.5, 136.1, 129.6, 128.5, 128.2, 127.9, 127.8, 73.3, 74.0, 73.6, 72.6, 71.5, 49.6, 39.2, 26.0, 21.7, 18.2, 4.5, 4.6; HRMS (ESI) Calcd for C 26 H 38 NO 4 SSi (M+H) + : 488.2285, found 488.2292. N ((S) 3 (benzyloxy) 2 ( tert butyldimethylsilyloxy)propyl) N ((R) 4 hydroxyde c 2 ynyl) 4 methylbenzenesulfonamide ( 3 160 ). A solution of n BuLi in hexane 1.6M (1.20 mL, 3.0 mmol) was added dropwise over 10 minutes at 78C to a solution of 3 159 (976.1 mg, 2.0 mmol) in dry THF (9 mL). The reaction was then stirred at the same temperature for 45 minutes and a solution of 3 151 (519.9 mg, 3.0 mmol) in dry THF (1 mL) was added. The mixture was allowed to warm to room temperature and stirred for 2 hours, quenched with NH 4 Cl (10 mL of a saturated aqueous solution), diluted with water (20 mL) and extracted with CH 2 Cl 2 (3x20 mL). The organic layers were dried over MgSO 4 and then purified by flash chromatography (gradient; 5 10% EtOAc/ hexanes ) to give an inseparable mixture of product and unreacted 3 159 which was used for the next step; R f = 0.44 (10% EtOAc/ hexanes D = 0.8 (c 1.00, CH 2 Cl 2 ); IR (neat) 2955, 2929, 2858, 1678, 1352, 1163, 1092, 837, 778, 663 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): 7.73 (d, J = 8.0 Hz, 2H), 7.36 7.29 (m, 7H), 7.35 7.28 (m, 5H), 4.55 (ABq, J 4.45 (ABq, J = 4.10 (m, 1H), 3.57 3.50 (m, 2H),

PAGE 162

162 3.35 `3.27 (m, 2H), 2.42 (s, 3H), 2.23 (t, J = 7.0 Hz, 2H), 1.49 1.43 (m, 2H), 1.30 1.22 (m, 5H), 0.91 0.86 (m, 12H), 0.09 (d, J = 10 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ): 186.9, 144.1, 138. 3, 135.8, 129.8, 128.6, 128.1, 128.0, 127.9, 85.3, 84.6, 73.7, 72.3, 71.8, 50.1, 45.4, 39.4, 31.7, 28.8, 26.0, 23.9, 22.7, 21.7, 18.2, 14.2, 4.5, 4.6. Noyori catalyst [( R R) TsDPEN Ru (p cymene)Cl] (19.3 mg, 0.030 mmol, 0.02 eq) was added to a mixture of above product and 3 159 (891.3 mg, 1.48 mmol), sodium formate (1.006 mg, 14.8 mmol, 10eq), TBAC (123.4 mg, 0.44 mmol, 0.3 eq) in CH 2 Cl 2 (8 mL) and deionized H 2 O (8 mL). The biphasic mixture was strongly stirred for 20 hours at rt diluted with water (10 m L) and extracted with CH 2 Cl 2 (2x 10 mL). The organic layers were dried over MgSO 4 and then purified by flash chromatography (Gradient; 5, 10, 20% EtOAc/ hexanes ) to give the product as a colorless oil (177.9 mg, 20%); R f = 0.15 (10% EtOAc/ hexanes D = + 6.9 (c 1.00, CH 2 Cl 2 ); IR (neat) 3513, 2954, 2928, 2857, 1349, 1162, 1092, 837, 778, 660 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): 7.76 (d, J = 8.5 Hz, 2H), 7 37 (dABq, J 2H), 4.17 4.13 (m, 1H), 4.04 (br, 1H), 3.60 3.52 (m, 2H), 3.35 (dt, J = 15.0, 5.0 Hz, 1H), 3.23 (dt, J = 14.5, 6.0 Hz, 1H), 2.43 (s, 3H), 1.45 1.24 (m, 11H), 0.92 0.88 (m, 12H), 0.11 (d, J = 11.0 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ): 143.6, 138.4, 136.4, 1 29.6, 128.5, 128.3, 127.9, 127.8, 87.0, 78.2, 73.6, 72.6, 71.5, 71.5, 62.3, 49.8, 39.4, 37.6, 37.6, 31.9, 29.1, 26.0, 25.1, 22.8, 21.7, 18.2, 14.3, 4.5, 4.6; HRMS (ESI) Calcd for C 33 H 52 NO 5 SSi (M+H) + : 602.3330, found 600.3354. Diastereomeric ratio (93:7)

PAGE 163

163 N (( S ) 3 (benzyloxy) 2 hydroxypropyl) N (( R Z ) 4 hydroxydec 2 enyl) 4 methy lbenzenesulfonamide ( 3 162) Lindlar catalyst (5% palladium on calcium carbonate, poisoned with lead, 30 .0 mg) and quinoline (30.0 mg) were added to a solution of 3 160 (60.3 mg, 0.16 mmol) in dry MeOH (1 mL). The reaction mixture was stirred 2 h ours under H 2 (1 atm). After filtration over cotton and removal of the solvent, crude product was recovered as a c olorless oil which was used for the next step without further purification. of the silyl ether obtained above in dry THF (1 mL). The reaction was stirred 16h and the mixture applied directly to flash chromatography (Gradient 40, 50 % EtOAc/ hexanes ) to afford the product as a colorless oil (34.8 mg, 71%); R f = 0.17 (50% EtOAc/ hexanes ); D = +14.7 (c 1.00, CH 2 Cl 2 ); IR (neat) 3410, 2918, 2851, 1451, 1333, 1158, 1018, 814, 658 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): = 7.67 (d, J = 8.0 Hz, 2H), 7.35 7.27 (m, 7H), 5.51 (dd, J = 11.0, 9.0 Hz, 1H), 5.22 5.17 (m, 1H), 4.52 (s, 2H), 4.30 (q, J = 8.5 Hz, 1H), 4.05 3.95 (m, 3H), 3.53 (d, J = 5.5 Hz, 2H), 3.29 (dd, J = 15.0, 3.5 Hz, 1H), 3.20 (dd, J = 15.0, 6.5 Hz, 1H), 2.91 (br, 1H), 2.55 (br, 1H), 2.41 (s, 3H), 1.54 1.2 3 (m, 11H), 0.85 (t, J = 6.5 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ): 143.8, 138.0, 137.8, 136.9, 130.0, 128.7, 128.2, 128.1, 127.4, 125.4, 73.8, 71.8, 69.8, 66.7, 50.3, 46.4, 37.1, 32.0, 29.4, 25.5, 22.8, 21.7, 14.3; HRMS (ESI) Calcd for C 27 H 39 NNaO 5 S (M+Na) + : 512.2441 found 512.2435.

PAGE 164

164 (2 S ,6 S ) 2 (benzyloxymethyl) 6 (( E ) oct 1 enyl) 4 tosylmorpholine ( 3 163 ). Anhyd CH 2 Cl 2 tube containing Ph 3 PAuCl (1.0 mg, 0.001 mmol, 3.0 mol%), AgOTf (0.5 mg, 0.001 mmol, 3.0 mol%), and activat ed 4 MS (20 mg). The heterogeneous mixture was vigorously stirred for 10 min and a solution of the corresponding diol 3 162 (31.3 mg, 0.06 mmol) in anhyd CH 2 Cl 2 h ours TLC analysis indicated a complete reaction and the mixture filtered through a short plug of silica with CH 2 Cl 2 (5 mL). The solution of crude product was concentrated in vacuo and purified by f lash chromatography (Gradient 0 5% EtOAc/ hexanes ) to give 23.8 mg (79%) of the pure diastereomer 3 163 as a color less oil; R f = 0.44 (10% EtOAc/ hexanes D = +2.6 ( c 1.00, CH 2 Cl 2 ); IR (neat) 2918, 2850, 1347, 1168, 981, 815, 663 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): = 7.60 (d, J = 8.0 Hz, 2H), 7.34 7.26 (m, 7H), 5.77 (ddt, J = 15.0, 6.5, 1.0 Hz, 1H), 5.30 (ddt. J = 15.0, 6.5, 1.0 Hz, 1H), 4.50 (s, 2H), 4. 05 4.02 (m, 1H), 3.83 3.78 (m, 1H), 3.64 (dt, J = 11.5, 2.0 Hz, 1H), 3.55 (dd, J = 11.5, 2.0 Hz, 1H), 3.50 (dd, J = 10.5, 5.0 Hz, 1H), 3.40 (dd, J = 10.5, 5.5 Hz, 1H), 2.42 (s, 3H), 2.11 (t, J = 11.5 Hz, 1H), 2.02 (t, J = 11.5 Hz, 1H), 1.99 (q, J = 7.0 Hz, 2H), 1.33 1.20 (m, 8H), 0.86 (t, J = 7.0 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ): 144.1, 138.0, 135.8, 132.5, 130.0, 128.7, 128.1, 128.0, 128.0, 126.4, 76.4, 74.4, 73.7, 70.7, 50.2, 47.6, 32.6, 31.9, 29.1, 29.0, 22.8, 21.8, 14.3; HRMS (ESI) Calcd for C 27 H 38 NO 4 S (M+H) + : 472.2516; found 472.2534.

PAGE 165

165 Diastereomeric ratio (93:7) was determin ed by 1 H NMR of the crude material. The relative configuration of the major diastereomer was determined by NOE DIFF experiments as follows: N ((S) 3 (benzyloxy) 2 hydroxypropyl) N ((R,E) 4 hydroxydec 2 enyl) 4 methy lbenzenesulfonamide ( 3 164 ). A solution of 3 161 0C to a suspension of LiAlH 4 (13.3 mg, 0.35 mmol) in THF (0.5 mL). The reaction was stirred at the same temperature for 1h, diluted with Et 2 O (1 m L) and quenched by addition of H 2 crude mixture was treated with a NaOH solution (15% in 2 t for 1h. After filtration, the crude mixture was dried over MgSO 4 recovered as a colorless oil which was used for the next step without further purification. of the silyl ether obtained above in dry THF (1 mL). The reaction was stirred 16 h and the mixture applied directly to flash chromatography (Gradient 40, 50% EtOAc/ h exanes ) to afford the product as a colorless oil (120.6 mg, 88%); R f = 0.21 (50% EtOAc/ hexanes D = +5.5 (c 1.00, CH 2 Cl 2 ); IR (neat) 3429, 2926, 2858, 1335, 1159,

PAGE 166

166 1091, 1020, 922, 815, 751, 657 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): = 7.65 (d, J = 8.0 Hz, 2H), 7.31 7. 23 (m, 7H), 5.54 (dd, J = 15.5, 6.5 Hz, 1H), 5.43 (dt, J = 15.5, 6.5 Hz, 1H), 4.50 (s, 2H), 3.95 (br, 2H), 3.80 (dABq, J 3.19 (dd, J = 14.5, 4.0 Hz, 1H), 3.14 (dd, J = 15.0, 7.0 Hz, 1H), 2.86 (d, J = 3.5 Hz, 1H), 2.39 ( s, 3H), 1.42 1.22 (13H), 0.84 (t, J = 6.5 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ): 143.8, 138.7, 137.9, 136.5, 130.0, 128.7, 128.1, 128.0, 127.6, 125.1, 73.7, 72.2, 71.8, 69.6, 51.6, 50.7, 37.1, 32.0, 29.4, 25.5, 22.8, 21.7, 14.3; HRMS (ESI) Calcd for C 27 H 43 N 2 O 5 S (M+NH 4 ) + : 507.2887, found 507 2908. (2 S ,6 R ) 2 (benzyloxymethyl) 6 (( E ) oct 1 enyl) 4 tosylmorpholine ( 3 165 ). Anhyd CH 2 Cl 2 tube containing Ph 3 PAuCl (0.9 mg, 0.001 mmol, 3.0 mol %), AgOTf (0.5 mg, 0.001 mmol, 3.0 mol%), and activated 4 MS (20 mg). The heterogeneous mixture was vigorously stirred for 10 min and a solution of the corresponding diol 3 164 (29.3 mg, 0.06 mmol) in anhyd CH 2 Cl 2 n added. After 2 h ours TLC analysis indicated a complete reaction and the mixture filtered through a short plug of silica with CH 2 Cl 2 (5 mL). The solution of crude product was concentrated in vacuo, and purified by flash chromatography (Gradient 0, 5% EtO Ac/ hexanes ) to give 23.5 mg (83%) of the pure diastereomer 3 165 as a colorless oil; R f = 0.55 (10% EtOAc/ hexanes D = 18.3 (c 1.00, CH 2 Cl 2 ); IR (neat) 2922, 1347, 1168, 815, 668, 649 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): = 7.59 (d, J = 8.0 Hz, 2H), 7.32 7.26 (m, 7H), 5.77 (ddt, J = 15 .5, 7.0, 1.5 Hz, 1H), 5.48 (ddt, J = 15.5, 6.0, 1.5 Hz, 1H), 4.51 (ABq, J = 12.0 Hz

PAGE 167

167 4.22 (q, J = 5.0 Hz, 1H), 4.06 4.02 (m, 1H), 3.60 3.55 (m, 2H), 3.00 (dd, J = 11.5 Hz, 2H), 2.90 (dd, J = 11.0, 5.5 Hz, 1H), 2.81 (dd, J = 11.5, 6.0 Hz, 1H), 2.42 (s, 3H), 2.00 (q, J = 7.0 Hz, 2H), 1.35 1.17 (m, 8H), 0.85 (t, J = 7.0 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 69.3, 69.1, 49.2, 46.9, 32.6, 31.8, 29.0, 22.8, 21.7, 14.3; HRMS (ESI) Calcd for C 27 H 37 NNaO 4 S (M+Na) + : 494.2336, found 494.2332. Diastereomeric ratio (8:92) was determined by 1 H NMR of the crude material 6 .2.10 Synthesis of 3 199 and 3 200 ( S ) 3 (( R Z ) 3 hydroxy 9 methoxynon 7 eno yl) 4 isopropyloxazolidin 2 one (3 199). A solution of TiCl 4 in toluene 1. 0M (5 0 mL 5 .0 mmol) was added dropwise over 5 minutes at 78C to a solution of Evans auxiliary 3 194 ( 428.0 mg, 2.5 mmol) in dry CH 2 Cl 2 ( 5 mL). The reaction was then stirred at the same temperature for 10 minutes and a solution of i Pr 2 NEt ( 869.3 L 5 .0 mmol) in dry CH 2 Cl 2 (1 mL) was added. The dark red mixture was stirred at the same temperature for 1 hour. Aldehyde 3 198 (711.0 mg, 5 mmol) in CH 2 Cl 2 (1 mL) was added dropwise over 5 minutes and stirred at the same temperature for 2 hours. The rea ction mixture was quenched with NH 4 Cl ( 3 mL of a saturated aqueous solution), diluted with water (20 mL) and extracted with CH 2 Cl 2 (3x20 mL). The organic layers were dried over MgSO 4 and then purified by flash chromatography (G radient; 30 35, 40% EtOAc/ h e xanes ) to give 297.7 mg (38%) of product as a yellow oil ; R f = 0.22 (5 0% EtOAc/ hexanes ); IR (neat) 3444, 2921, 1771,

PAGE 168

168 1698, 1386, 1203, 1091, 1020 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): = 5.59 5.49 (m, 2H), 4.44 4.41 (m, 1H), 4.35 3.92 (m, 6H), 3.31 (s, 3H), 3.07 3.04 (m, 2H), 2.39 2.35 (m, 1H), 2.10 (q, J = 4.5 Hz, 1H), 1.58 1.43 (m, 4H), 0.91 (d, J = 7 Hz, 3H), 0.87 (d, J = 7 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ): 172.9, 154.3, 133.4, 12 6.5, 68.2, 68.0, 63.7, 58.6, 58.1, 42.7, 36.3, 28.6, 27.5, 25.5, 18.1, 14.8. ( S ) 4 isopropyl 3 (2 ((2R,6S) 6 vinyltetrahydro 2H pyran 2 yl)acetyl)oxazolidi n 2 one (3 200) Anhyd CH 2 Cl 2 ( 0.4 mL ) was added to an aluminum foi l covered, flame dried, test tube containing Ph 3 PAuCl ( 4.2 mg, 0.00 7 mmol, 5 .0 mol %), AgOTf ( 2.1 mg, 0.00 7 mmol, 5 .0 mol %), and activated 4 MS ( 30 mg). The heterogeneous mixture was vigorously stirred for 10 min and a solution of the corresponding alco hol 3 1 99 ( 43.4 mg, 0. 14 mmol) in anhyd CH 2 Cl 2 ( 0.4 mL ) was then added at 5 C After 2 h ours at 0 C TLC analysis indicated a complete reaction and the mixture filtered through a short plug of silica with CH 2 Cl 2 (5 mL). The solution of crude product was c oncentrated in vacuo and purified by flash chromatography ( 100% CH 2 Cl 2 ) to give 34.6 mg (8 9 %) of the pure diastereomer 3 200 as a colorless oil; R f = 0.30 (10 % EtOAc/ hexanes D = +35.5 ( c 1.00, CH 2 Cl 2 ); IR (neat) 2937, 2862, 1782, 1702, 1388, 1304, 1205, 1121, 1074, 1021, 920 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): = 5.84 5.78 (m, 1H), 5.17 (dt, J = 1.5, 17.5 Hz, 1H), 5.03 (dt, J = 1.5, 10.5 Hz, 1H), 4.44 (dt, J = 8.5, 3.5 Hz, 1H), 4.25 (t, J = 9 Hz, 1H), 4.18 (dd, J = 9, 3.5 Hz, 1H), 3.95 3.83 (m, 2H), 3.41 (dd, J = 16, 7.5 Hz, 1H), 2.91 (dd, J = 16 5 Hz, 1H), 2.40 2.33 (m, 1H), 1.89 1.84 (m, 1H), 1.67 1.54 (m, 3H), 1.35 1.25 (m,

PAGE 169

169 2H), 0.91 (d, J = 7 Hz, 3H), 0.86 (d, J = 7 Hz 3H); 13 C NMR (75 MHz, CDCl 3 ): 171.2, 154, 139.5, 114.3, 78.3, 74.3, 63.5, 58.6, 42.2, 31.3, 31.2, 28.5, 23.5, 18.1, 14.9; HRMS (ESI) Calcd for C 15 H 24 NO 4 (M+H) + : 282.1700, found 282.1701. 6 .2.11 Synthesis of 3 206 and 3 208 Compounds 3 40 147 3 41 147 3 52 Error! Bookmark not defined. a 3 204 148 3 205 149 3 207 150 3 209 148 and 3 210 148 have been described in the literature and when prepared here satisfactorily matched all previously reported data (Figure 6 1) Figure 6 1. Chemical structures of known compounds 3 206 and 3 208 were prepared in two steps from ( E ) 7 (tetrahydro 2H pyran 2 yloxy)hept 2 en 1 ol 3 20 7 ; protection of the allyl alcohol with 3 equivalen ts of TBDPSCl or BzCl in presence of 3 equivalen ts of Et 3 N in CH 2 Cl 2 at room temperature followed by deprotection of the terminal non allylic alcohol using 10 mol % of PPTS in MeOH at room temperature. ( E ) 7 (tert butyldiphenylsilyloxy)hept 5 en 1 ol ( 3 206 ).

PAGE 170

170 Colorless oil; R f = 0.30 (30% EtOAc/ hexanes ); IR (neat) 3343, 2932, 2857, 1471, 1462, 1427, 1112, 1055, 969 cm 1 ; 1 H NMR (500 MHz, CDC l 3 ): 7.69 7.66 (m 4H), 7.42 7.36 (m, 6H), 5.65 (dt J = 15.0, 6.5 Hz, 1H), 5.55 (dt J = 15.0, 5.5 Hz, 1H) 4.16 ( d J = 5.5 Hz, 1H), 3.64 (t, J = 6.5 Hz, 2H), 2.05 (q, J = 7.0 Hz, 2H), 1.59 1.41 (m, 4H), 1.29 (bs, 1H), 1.05 (s, 9H); 13 C NMR (75 MHz, CDC l 3 ): 135.8, 134.2, 131.1, 129.8, 129.4, 127.8, 64.9, 63.1, 32.5, 32.2, 27.1, 25.6, 19 ; HRMS (ESI) Calcd for C 23 H 32 Na O 2 Si (M+Na) + : 391.2064, found 391.2082 ( E ) 7 hydroxyhept 2 enyl benzoate ( 3 208 ). Colorless oil; R f = 0 .18 (30% EtOAc/ hexanes ); IR (neat) 3390, 2936, 2862, 1418, 1452, 1273, 113, 1070, 1026, 973, 712 cm 1 ; 1 H NMR (3 00 MHz, CDCl 3 ): 8.01 (d, J = 6.3 Hz, 2H), 7.53 7.36 (m, 3H), 5.82 (dt, J = 15.6, 6.3 Hz, 1H), 5.65 (dt, J = 15.3, 6.9 Hz, 1H), 4.72 (d, J = 6. 0 Hz, 2H), 3.60 (t, J = 6.3 Hz, 2H), 2.08 (q, J = 6.9 Hz, 2H), 1.71 (bs, 1H), 1.60 1.41 (m, 4H) ; 13 C NMR (75 MHz, CDCl 3 ): 166.6, 136.2, 133.1, 130.5, 129.8, 128.5, 124.4, 65.8, 62.8, 32.3, 32.1, 25.2 ; HRMS (ESI) Calcd for C 14 H 18 NaO 3 (M+Na) + : 257.1148 fo und 257.1152 6 .2.12 Synthesis of 3 207 3 207 was prepared in two steps from ( E ) 7 (tert butyldimethylsilyloxy)hept 2 en 1 ol ; 151 protection of the allyl alcohol using 3 equivalen ts of 3,4 dihydro 2 H pyran and 10 mol % of PPTS in CH 2 Cl 2 at room

PAGE 171

171 temperature f ollowed by deprotection of the terminal non allylic alcohol using 2 equivalen t s of TBAF in THF at room temperature. ( E ) 7 (tetrahydro 2H pyran 2 yloxy)hept 5 en 1 ol ( 3 207 ). Colorless oil; R f = 0.35 (30% EtOAc/ hexanes ); IR (neat) 3410, 2938, 2864, 1117, 1075, 1023, 970 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): 5.73 (dt J = 15.5, 7.0 Hz, 1H), 5.59 (dt J = 15.5, 7.0 Hz, 1H), 4.63 ( dd J = 4.0, 3.0 Hz, 1H), 4.19 (ddq, J = 12.0, 5.5, 1.0 Hz, 1H), 3.92 (dd, J = 12.0, 7.0 Hz, 1H), 3.8 7 (dd J = 8.5, 5.0 Hz, 1H), 3.64 (t, J = 6.5 Hz, 2H), 3.52 3.48 (m, 1H), 2.09 (q, J = 7.0 Hz, 2H) 1.86 1.36 (m, 11H); 13 C NMR (75 MHz, CDCl 3 ): 134.3, 126.7, 98.0, 68.0, 63.0, 62.4, 32.4, 32.2, 30.9, 25.7, 25.4, 19.8 ; HRMS (ESI) Calcd for C 11 H 22 NaO 3 (M+N a) + : 237.1467; found 237.1463. 6 .2.13 Synthesis of 3 211 and 3 212 3 211 and 3 212 were prepared in three steps from 2 (hex 5 ynyloxy)tetrahydro 2H pyran 5 1 (Figure 5.2) 152 Figure 6 2. Synthesis of 3 211 and 3 212

PAGE 172

172 ( E ) 7 cyclohexyl 7 methoxyhept 5 en 1 ol ( 3 211 ). Colorless oil; R f = 0.28 (30% EtOAc/ hexanes ); IR (neat) 3402, 2928, 2853, 1450, 1095, 972 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): 5.55 (dt J = 15.3, 7.0 Hz, 1H), 5.25 (dd J = 15.3, 8.1 Hz, 1H), 3.64 ( t J = 6.0 Hz, 2H), 3.22 (s, 3H), 3.17 (t, J = 7.7 Hz, 1H), 2.10 (q J = 7.0 Hz, 2H), 1.94 1.83 (m, 2H), 1.73 0.89 (m, 14H); 13 C NMR (75 MHz, CDCl 3 ): 134.7, 129.4, 87.6, 62.8, 56.2 42.6, 32.4, 32.2, 29.5, 29.0, 26.8, 26.3, 26.3, 25.7 ; HRMS (ESI) Calcd for C 14 H 26 NaO 2 (M+Na) + : 249.1825 ; found 249.1832 ( Z ) 7 cyclohexyl 7 methoxyhept 5 en 1 ol ( 3 212 ). Colorless oil; R f = 0.30 (30% EtOAc/ hexanes ); IR (neat) 3375, 2924, 2852, 1450, 1085, 970 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): 5.64 (dt J = 11.1, 7.5 Hz, 1H), 5.20 (dd J = 11.1, 9.6 Hz, 1H), 3.68 3.59 ( m 3H), 3.21 (s, 3H), 2.17 2.02 (m 2H), 1.91 0.88 (m, 16H); 13 C NMR (75 MHz, CDCl 3 ): 134.0, 129.7, 81.1, 63.0, 56.2, 43.0, 32.6, 29.5, 28.8, 27.8, 26.9, 26.4, 26.1 ; HRMS (ESI ) Calcd for C 14 H 26 NaO 2 (M+Na) + : 249.1825 ; found 249.1835 General procedure for the Au catalyzed cyclization A solution of n decane (0.15 mmol) and the substrate (0.3 mmol) in dry CH 2 Cl 2 (1 mL) was added in one portion at room temperature to an aluminum fo iled covered 5 mL vial containing a solution of (Acetonitrile)[(2 biphenyl)di tert butylphosphine]gold(I)

PAGE 173

173 hexafluoroantimonate (11.6 mg, 0.015 mmole, 5 mol%) in dry CH 2 Cl 2 (0.5 mL) and activated MS 4 (70 mg) under N 2 The reaction was monitored by taking dry CH 2 Cl 2 containing 15 20 mg of beads Quadrapure TM analysis. 6 .2.14 Determination of C onversion of 3 41. The conversion was determin ed by Gas Chromatography analysis of 2 vinyltetrahydro 2H pyran 3 41 and n decane. A calibration plot had been made using known quantities of 3 41 and n decane (Figure 5 3 ). Column: RESTEK Rtx 5 (Crossbond 5% diphenyl 95% dimethyl polysiloxane), 30 meters f C, 275 C for 2 min. Time: t R ( 3 41 ): 5.1 min; t R ( n decane): 7.4 min. Figure 6 3 Calibration plot of 3 41 vs n decane. y = 2.0225x + 0.0135 R = 0.9989 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 mmoles ( 3 41 )/mmoles ( n decane) Peak area( 3 41 ) / Peak area ( n decane)

PAGE 174

174 6 .2.15 Determination of C onversi on of 3 52. The conversion was determined by Gas Chromatography analysis of ( E ) 2 (2 cyclohexylvinyl)tetrahydro 2 H pyran 3 52 and n decane. A calibration plot had been made using known quantities of 3 52 and n decane (Figure 5 4 ). Column: RESTEK Rtx 5 (Cro ssbond 5% diphenyl 95% dimethyl polysiloxane), C, 275 C for 8 min. Time: t R ( n decane): 7.4 min; t R ( 3 52 ): 13.4 min. Figure 6 4 Calibration plot of 3 52 vs n decan e. y = 1.0782x + 0.013 R = 0.9976 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 mmoles (3 52) / mmoles ( n decane) Peak area ( 3 52 ) / Peak area ( n decane)

PAGE 175

175 6 .2.16 General Procedures for the Preparation of 2 H Chromenes Compounds 4 1 153 4 53 154 4 55 155 4 61 155 4 80 156 4 48 157 4 76 158 4 74 159 4 95 160 4 96 161 and 4 100 162 have been described in the literature and when prepar ed here satisfactorily matched all previously reported data. Representative procedure for the preparation of substrates : To a solution of salicylaldehyde derivative (1 mmol) in anhydrous THF (5 mL) was added dropwise vinyl magnesium bromide (1.0 M solution in THF, 2.5 mL, 2.5 eq ) at 78C. After TLC analysis indicated a complete conversion, the reaction was quenched with a saturated aqueous solution of NH 4 Cl (5 mL) and warmed to room temperature. The crude mixture was extracted with CH 2 Cl 2 (2 x 10 mL). The combined organic extract was dried over MgSO 4 purified by flash chromatography and immediately taken on to the next step. Representative procedure for the Au catalyzed preparation of 2 H chromenes : Anhydrous THF (2.5 mL) was added to an aluminum foil cover ed, flame dried, flask containing 12 (26.5 mg, 0.05 mmol, 5.0 mol %), 10 (12.3 mg, 0.05 mL, 5.0 mol%), and activated 4 MS (80 mg). The heterogeneous mixture was vigorously stirred for 10 min and a solution of the corresponding o (1 hydroxyallyl)phenol (1 mmol) in THF (2.5 mL) was added. The mixture was then immediately heated to reflux by immersing into an oil bath that has been preheated to 70C. After TLC analysis indicated a complete reaction, the mixture was filtered through a short plug of silica wit h CH 2 Cl 2 (4 mL). The solution of the crude product was concentrated in vacuo, and purified by flash chromatography (5% EtOAc/ hexanes or 100% hexanes ).

PAGE 176

176 6 .2.17 Caracterization of New 2 H Chromenes. 8 bromo 6 nitro 2 H chromene ( 4 57 ) Pale yellow solid; mp 130 133 C; R f = 0.75 (20% EtOAc/ hexanes ); IR (neat) 3090, 2919, 1507, 1471, 1347, 1265, 1097, 902, 741, 694 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): 8.25 (d, J = 2.5 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 6.42 (dt, J = 10.0, 2.0 Hz, 1H), 5.91 (dt, J = 10.0, 3.3 Hz, 1H), 5.14 (dd, J = 3.3, 2.0 Hz, 2H); 13 C NMR (75 MHz, CDCl 3 ): 156.3, 141.9, 128.8, 124.3, 122.9, 122.6, 121.1, 109.9, 67.9; HRMS (ESI) Calc d for C 9 H 7 BrNO 3 (M+H) + : 255.9609 found 255.9599. 6 bromo 8 methoxy 2 H chromene ( 4 59 ) Colorless oil; R f = 0.64 (10% EtOAc/ hexanes ); IR (neat) 2917, 2849, 1567, 1480, 1271, 1215, 1033, 845 cm 1; 1 H NMR (500 MHz, CDCl 3 ): 6.87 (d, J = 2.0 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.33 (dt, J = 10.0, 2.0 Hz, 1H), 5.82 (dt, J = 10.0, 3.5 Hz, 1H), 4.88 (dd, J = 3.5, 2.0 Hz, 2H), 3.85 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ): 148.7, 142.1, 124.4, 123.8, 123.3, 121.7, 115.4, 113.0, 66.0, 5 6.5; HRMS (ESI) Calcd for C 10 H 8 BrO 2 (M H) + : 238.9708; found 238.9713.

PAGE 177

177 2 (2 bromophenyl) 2 H chromene ( 4 65 ) Colorless oil; R f = 0.15 ( hexanes ); IR (neat) 1684, 1653, 1560, 1507, 1457, 1227, 1203, 1112, 1020, 748 cm 1 ; 1 H N MR (500 MHz, CDCl 3 ): 7.61 (dd, J = 8.0, 1.5 Hz, 1H), 7.57 (dd, J = 8.0, 1.0 Hz, 1H), 7.30 (ddt, J = 7.8, 1.5, 0.5 Hz, 1H), 7.15 (m, 2H), 7.00 (dd, J = 7.5, 1.5 Hz, 1H), 6.87 (dt, J = 7.5, 1.0 Hz, 1H), 6.82 (dd, J = 8.0, 0.5 Hz, 1H), 6.51 (ddd, J = 10.0, 2.0, 0.5 Hz, 1H), 6.3 3 (dd, J = 3.5, 2.5, 1H), 5.79 (dd, J = 10.0, 3.5, 1H) ; 13 C NMR (75 MHz, CDCl 3 ): 153.5, 140.2, 133.1, 129.8, 129.8, 128.9, 128.1, 126.9, 124.3, 124.0, 121.7, 121.6, 121.2, 116.0, 76.4; HRMS (ESI) Calcd for C 15 H 12 BrO (M+H) + : 2 87.0072, found 287.0078. 4 (4 bromophenyl) 2 H chromene ( 4 9 7 ) Colorless oil; R f = 0.55 (5% EtOAc/ hexanes ); IR (neat) 3047, 2964, 2832, 1481, 1447, 1222, 1114, 1066, 1011, 805, 757 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): 7.52 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 7.16 (dt, J = 7.8, 2.0 Hz, 1H), 6.89 (m, 3H), 5.78 (t, J = 4.0 Hz, 1H), 4.83 (d, J = 4.0 Hz, 2H); 13 C NMR (75 MHz, CDCl 3 ): 154.9, 137.4, 136.4, 131.8, 130.5, 129.7, 125.8, 123.5, 122.0, 121.5, 120.5, 116.5, 65.3; HRMS (ESI) Calcd for C 15 H 11 BrO (M) + : 285.9993 found 285.9999.

PAGE 178

1 78 4 (4 nitrophenyl) 2 H chromene ( 4 98 ) Yellow solid; mp 88 92 C; R f = 0.35 (10% EtOAc/ hexanes ); IR (neat) 2849, 1597, 1516, 1484, 1346, 1224, 853, 761, 697 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): 8.27 (d, J = 7.0 Hz, 2H), 7.52 (d, J = 7.0 Hz, 2H), 7.20 (dt, J = 7.0, 2.0 Hz, 1H), 6.90 (m, 3H), 5.91 (t, J = 4.0 Hz, 1H), 4.88 (d, J = 4.0 Hz, 2H); 13 C NMR (75 MHz, CDCl 3 ): 154.9, 145.2, 135.9, 130.2, 129.7, 125.6, 124.0, 122.8, 122.2, 121.7, 116.8, 100.0, 65.2; HRMS (ESI) Calcd for C 15 H 12 NO 3 (M+H) + : 254.0817; found 254.0814.

PAGE 179

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189 BIOGRAPHICAL SKETCH Berenger Biannic was born in 1982 in Toulouse (France) where he was raised and graduated from Lyc e Marcellin Berthelot in 2000. He atten ded the University of Paul Sabatier in the same city and moved to the where he receveived his b m aster in synthesis of bioactive m olecules under the supervision of Pr o f Jean Yves Mero ur and D r Sylvain Routier. His research focused on the synthesis of a new class of potent indolic topisomerase inhibitors. In 2006 he started his doctoral research at the University of F lorida under the guidance of D r. Aaron Aponick where he works on the development of gold catalyzed transfomations of allylic alcohols and its applications towards the synthesis of natural molecules.