Cucn and Cubpme2s

PART I : CHEMICAL AND SPECTROSCOPIC INVESTIGATIONS OF TRIALKYLSILYL AND TRIALKYLSTANNYL METALLOIDS. PART I1 : THE SYNTHESIS OF POTENTIAL INHIBITORS OF SQUALENE SYNTHETASE by Sunaina Sharma A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in the Department of Chemistry at Simon Fraser University Burnaby, BC. O Sunaina Sharma, July 1989 Simon Fraser University All rights reserved. This thesis may not be reproduced in whole or part, by photocopy or other means, without permission of the author. APPROVAL Name: Sunaina Sharma Dew: DOC& of Philosophy Title of Thesis: PART I: CHEMICAL AND SPECTROSCOPIC INVESTIGATIONS OF TRIALKYLSILYL AND TRIALKYLSTANNYL METALLOIDS. Part 11: THE SYNTHESIS OF POTENTIAL INHIBITORS OF SQUALENE SYNTHETASE. Examining Comrnmittee: Chairman: Prof. P.W. Percival Prof. A.C. Oehlschlager, Senior Supervisor -- - - Pr0f.S. Ki@tlqann, Supervisory Committee m - -" - Pmf. V.A. Snieckus, External Examiner Department of Chemistry, Guelph-Waterloo Centre for Graduate Work in Chemistry, University of Waterloo, Waterloo. Date Approved: December 14, 1989 PARTIAL COPYRIGHT LICENSE I hereby grant to Simon Fraser Unlverslty the rlght to lend my thesis, proJect or extended essay (the title of which is shown below) to users of the Simon Fraser University Library, and to make partial or single copies only for such users or In response to a request from the library of any other unlverslty, or other educatlonal Institution, on its own behalf or for one of its users. I further agree that permission for multiple copying of this work for scholarly purposes may be granted by me or the Dean of Graduate Studies. It is understood that copying or publication of this work for flnanclal gain shall not be allowed without my written permission. Title of Thes i s/Project/Extended Essay Part of TrInvestigationsoflkylsilvl and Trialkylstannyl Metalloids. Part 11: The synthesis of Potential Inhibitors and Squalene Synthetase. Author: - (signature) Sunaina Sharma ( name December 14. 1989 (date) ABSTRACT Low-temperature, heteronuclear (IH, 7~i,13~ 2% and 119~n)NMR spectroscopy was used to study the constitution of triakylsilyl [(R3Si)nCuLin-1*LiX] and trialkylstannyl [(R3Sn)nCuLin-l*LiX;R = alkyl, n=l, 2 or 3 and X = CN or Br] cuprates derived fhm CuCN and CuBpMe2S. These studies revealed that in composition, the metallocuprates are similar to alkylcyanocuprates (RnCuLin-l*LiCN) in that the sequential addition of R3SiLi, R3SnLi or RLi to CuCN yields RCu(CN)Li and R2Cu(CN)Li2. Further addition of R3MLi (M = Si or Sn, R = alkyl) leads to the formation of hitherto unknown (R3M)3CuLi2. In the case of alkylcyanocuprates addition of RLi beyond a RLi:CuCN ratio of 2: 1 yields no new species but gives solutions with hydrogen abstracting ability attributable to RLi. The foxmation of mixed cuprates R3M(Me)nCuLin*LiCN(M = Si or Sn, n = 1 or 2) was also studied by low-temperature. NMR spectroscopy. These studies revealed that like mixed akylcyanocuprates, ligands on copper readily exchanged in these metallocuprates. The ability of methyl as a ligand to tenaciously bind to copper resulted in the exclusive transfer of R3Si and R3Sn ligands in additions to cc,~unsaturatedenones and 1-alkynes. Low-temperature heteronuclear (2~,l~, 2% and 119~n)NMR spectroscopy was also employed to study the cuprous salt catalyzed addition of bimetallic [(M~~S~AIEQ,M~~S~AIEQ, (Me3Sn-9-BBN*OMe)'Li+ and (Me3Si-9-BBN*OMe)- Li+; BBN = 9-borabicyclo[2.2.1]nonane)] reagents to 1-alkynes. This wtiysuggesd that metallometallations involve initial silyl- or stannylcupration followed by transmetallation of a vinyl-copper bond by the electrophilic metal partner generated in sim. Hence, metallometallations could be conducted either by addition of "R3SiCuWor "R3SnCuWto 1-alkynes followed by addition of E t2AlC1 or Br-9-BBN, or by preformation of (R3Sn-9-BBN*OMe)-Li+or (R3Si-g-BBN*OMe)'Li+ and R3SnAlEt2 or R3SiAlEt2 followed by addition of 1-alkynes and catalytic amounts of cuprous salts. The 12-dimetallic adducts produced by metallometallation of 1-alkynes contain well differentiated 1,2-dianion equivalents capable of forming new carbon-carbon bonds. This chemistry yielded mild and efficient methods for the synthesis of stereo- and redo-defined trisubstituted olefms. Also described in this thesis are the total syntheses of some sulfonium ion analogues of carbocationic intermediates presumed to be involved in the dimerization of farnesyl pyrophosphate to squalene by squalene synthetase. These sulfonium ions are presumptive inhibitors of this enzyme. llie lijt of tliose to whom I am ituik6ted is Ibng. Among thcm, the one of premier importance is not an individd 6ut a uenedlk and in many respects a unique institution. At Simon Fraser University I found encouragement to st4and to rib mearch unrikr the gudmce of and in associati-on mi&chemists of outstanding a6iCity such as I)t. fin Cam Oefiljdlager. whitkxaldli aduice was dwyavaiGa6lk to me in or out ofthe rikpartment. I am unriergreat o6liation to I)t. %K Pmroy whewfioh-W cooperation and pilibnce eased nry task immensely. I am also dkepGjpatefd to Dr. Bnrce N Lipsfiutz of tfie University of Calif&. Santa Bar6amI who hud dway.5 6een a some of inspiration and more &en than one wants to admitI of information. I wiM 6e faicing in my duty if I umclirrii! tfiis ac~pudk&ementwitbut refening to the courteous 6eliaviour and woperation of the committee at tfie University of ~rithh Columbia, rrp.ciuUij IX. S.O. Chan and Mrs. M. lust& for dngthc 131; 7~i~Jcand - 119~nmspectna . TABLE OF CONTENTS TITLE PAGE i APPROVAL ii ABSTRACT iii DEDICATION v ACKNOWLEDGEMENTS vi TABLE OF CONTENTS vii ... LIST OF TABLES xlll LIST OF FIGURES xiv LIST OF ABBREVIATIONS xix PART I: CHEMICAL AND SPECTROSCOPIC INVESTIGATIONS OF TRIALKYLSILYL AND TRIALKYLSTANNYL METALLOIDS. I. CHEMICAL AND SPECTROSCOPIC INVESTIGATIONS OF ORGANOCUPRATES. I. 1 Introduction 1.2 Alkylcuprates derived from cuprous halides I. 3 Alkylcuprates derived from cuprous cyanide 1.4 Solid statelX-ray analyses 11. CHEMICAL AND SPECTROSCOPIC INVESTIGATIONS OF TRIALKYLSILYL AND TRIALKYLSTANNYLCUPRATES. Introduction Research proposal 11.1 Trialkylsilylcuprates derived from cuprous cyanide 11.1.1 Silicon-29 NMR studies 11.1.2 Carbon- 13 NMR studies 11.1.3 Hydrogen- 1 NMR studies 11.1.4 Lithium-7 NMR studies 11.1.5 Chemical tests 11.1.6 Gilman tests 11.1.7 Conclusion 11.2 Trialkylsilylcuprates derived from cuprous halides 11.2.1 Silicon-29, Carbon-13 and Lithium-7 NMR studies 11.2.2 Chemical tests II. 2.3 Conclusion 11.3 Mixed trialkylsilyl and homo- and mixed trialkylstannylcuprates derived from cuprous cyanide 11.3.1 Silicon-29 and Carbon- 13 NMR studies on mixed Trialkylsilylcuprates 11.3.1 .a Results and discussion 11.3.2 Tin- 119, Carbon- 13 and Hydrogen- 1 NMR studies on Homotriallcylstannylcuprates 11.3.3 Tin- 119, Carbon- 13 and Hydrogen- 1 NMR studies on mixed Trialkylstannylcuprates 11.3.4 Reactions of Silyl- and Stannylcuprates with a$-unsaturated Ketones. 11.3.5 Conclusion 11.3.6 Find Comments m. IN SITU GENERATION OF ACTIVATED METALLO- CUPRATES 111.1 Copper(1) mediated metallometallation of 1-alkynes 110 Proposed work 115 Effect of method of preparation of eialkylstannyllithium 116 On the efficiency of stannylalumination and stannylboronation Effect of catalyst on stannylalumination 118 Effect of mode of addition of reagents on stannylalurnination 120 and stannylboronation Effect of solvent on stannylalumination and stannylboronation 121 Compatibility of polar functional groups with stannylalumination 122 and stannylboration Reactions of 1,2-cis-dimetallo-1 -akenes with electrophiles 123 Synthesis of trisubstituted alkenes 124 111.1.10 Synthesis of pheromone of the square-necked grain 126 beetle 111.2 Mechanistic studies IIL2.1 Results and discussion III.L.2 Spectroscupi~scuciies III.2.3 Conclusion IV. EXPERIMENTAL IV.l Preparation of trialkylsilylcuprates, 2% NMR sample preparation IV.1.1 Generation of silylcuprates deived from CuCN IV. 1.2 Generation of silylcuprates derived from CuBraMe2S IV. 1.3 Generation of mixed silylcuprates IV.2 13C and 1~ NMR sample preparation IV.2.1 Generation of silylcuprates derived from CuCN IV.2.2 Generation of LiCl-free silylcuprates derived from CuCN IV.2.3 Generation of silylcuprates derived from CUBPM~~S IV.2.4 Generation of silylcuprates derived from CuBr in DMS IV .2.5. Generation of mixed silylcuprates IV.3 Preparation of 34rialkylsilyl cyclohexanone IV.4 Typical procedure for silylcupration with "PhMe2SiCu1' IV.5 Preparation of trialkylstannylcuprates, 119Sn NMR sample preparation nrc i A ..&. Gzixiz5an of stannylcuprates derived from CuCN IV.5.2 Generation of stannylcuprates derived from CuBrMe2S IV.5.3 Generation of mixed stannylcuprates IV.6 1~ and 1342 NMR sample preparation IV.6.1 Generation of stannylcuprates derived from CuCN IV.6.2 Generation of stannylcuprates derived from CuBr*Me2S IV.6.3 Generation of mixed stannylcuprates IV.7 Preparation of 3-trialkylstannyl cyclohexanone IV.8 METALLOMETALLATION OF 1-ALKYNES IV. 8.1 Preparation of trialkylstannyllithium and quenching with Me1 IV.8.2 Reaction of 1-decyne with BU~S~A~EQ IV. 8.3 Reaction of 1-nonyne with (Bu3Sn-9-BBN*OMe)-Li+ IV.8.4 General procedure for the preparation of disubstituted vinyl stannanes IV.8.5 Metallometallation of functionalized allcynes IV. 8.6 Preparation of trisubstituted alkenes IV .8.7 Synthesis of pheromone of the square-necked grain beetle 200 V. REFERENCES AND NOTES 204 PART 11: THE SYNTHESIS OF POTENTIAL INHIBITORS OF SQUALENE SYNTHETASE VI. INTRODUCTION VI. 1.O Proposed work VI. 1.1 Synthesis of Sulfonium ion mimic 32 VI. 1.1a Future directions VI. 1.2 Synthesis of Sulfonium ion mimic 33 VI. 1.2a Future directions VI. 1.3 Synthesis of Sulfonium ion mimic 34 VI. 1.3a Future directions VII. EXPERIMENTAL VIII. REFERENCES LIST OF TABLES Table Page I.

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