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Novel cyclopentanoid annulation sequences : an approach to the synthesis of c19-oxygenated cyathanes Cook, Katherine Louise 1999

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N O V E L CYCLOPENTANOID A N N U L A T I O N SEQUENCES; A N A P P R O A C H TO T H E SYNTHESIS OF C19-OXYGENATED C Y A T H A N E S by K A T H E R I N E LOUISE C O O K B.Sc. (Hons.), The University of Toronto, 1991  A THESIS SUBMITTED IN P A R T I A L F U L F I L L M E N T OF T H E REQUIREMENTS FOR THE D E G R E E OF DOCTOR OF PHILOSOPHY in THE F A C U L T Y OF G R A D U A T E STUDIES (Department of Chemistry)  We accept this thesis as conforming to the required standard  T H E UNIVERSITY OF BRITISH C O L U M B I A March 1999 © Katherine Louise Cook, 1999  In presenting this thesis degree  at the  in partial fulfilment  University of British Columbia,  of the  requirements  I agree that the  for an advanced  Library shall make it  freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes department  or  by  his  or  her  representatives.  may be granted by the head of my It  is  understood  that  copying  or  publication of this thesis for financial gain shall not be allowed without my written permission.  Department of The University of British Columbia Vancouver, Canada  DE-6 (2/88)  n ABSTRACT  Two cyclopentanoid annulation sequences were developed. In the first sequence, (Z)-lbromo-3-iodo-2-butene (9) was employed in the preparation of the series of angular allylic alcohols 28-30. Upon treatment with an oxochromium(VI) amine reagent, the allylic alcohols 29 and 30 underwent oxidative rearrangement to provide the bicyclic enones 32 and 33, respectively. Similar treatment of the allylic alcohol 28 resulted in the formation of a mixture of the epoxides 70 and 71. In the second sequence, (Z)- and (£)-5-iodo-3-trimethylstannyl-2-pentene (10 and 11, respectively) were employed in the preparation of the series of angular allylic alcohols 138-143. [2,3]-Wittig rearrangement of either of the allylic alcohols 138 or 141 according to the Still-Mitra protocol provided the homoallylic alcohol 152. Similarly, rearrangement of either of the allylic alcohols 139 or 140 provided the homoallylic alcohol 155. Rearrangement of 142 and 143 provided 162 and 165, respectively. The success of the second sequence, in particular of the conversion of 143 into 165, was extended to the preparation of an advanced intermediate (236) in an approach to the total synthesis of (±)-sarcodonin G (40). (F)-5-iodo-3-trimethylgermyl-2-pentene (247) was employed in the formation of the five-membered ring of the angular allylic alcohol 237.  [2,3]-Wittig  rearrangement of 237 according to the Still-Mitra protocol then provided the homoallylic alcohol 236. Compound 236 possesses the complete A B ring system of sarcodonin G (40), with the correct relative configuration at all four stereocenters.  70  71  R  R  R  138 R=H, R'=Me 139 R=H, R'=Me 140 R=Me, R'=H 141 R=Me, R'=H  152  155  162  142 R=H, R'=Me 143 R=Me, R'=H  165  TABLE OF CONTENTS  Abstract  ii  List of Tables  ix  List  of Figures  x  List of Abbreviations  xi  Acknowledgements  xiv  Chapter 1 — Introduction  1  1.1  The Use of Bifunctional Conjunctive Reagents in Synthesis  1.2  A Cyclopentenone Annulation Sequence Employing (Z)-l-Bromo-3-iodo-2-butene  (9) 1.3  1  Still-Mitra [2,3]-Wittig Rearrangement of Angular Allylic Alcohols; A n Approach to the Synthesis of C19-Oxygenated Cyathanes  Chapter 2 — Discussion 2.1  6 10  A Cyclopentenone Annulation Sequence Employing (Z)-l-Bromo-3-iodo-2-butene  (9)  2.2  4  10  2.1.1  Introductory Remarks and Proposal  10  2.1.2  Preparation of (Z)-l-Bromo-3-iodo-2-butene (9)  12  2.1.3  Preparation of Angular Allylic Alcohols 28-30  13  2.1.4  Oxidation of Angular Allylic Alcohol 28  20  2.1.5  Oxidation of Angular Allylic Alcohols 29 and 30  27  2.1.5  Conclusions  29  Still-Mitra [2,3]-Wittig Rearrangement of Angular Allylic Alcohols  30  2.2.1  The [2,3]-Wittig Rearrangement  30  2.2.2  The Still-Mitra [2,3]-Wittig Rearrangement  39  2.2.3  Proposal  47  2.2.4  Preparation of Angular Allylic Alcohols 138-143  48  vi 2.2.5  Still-Mitra [2,3]-Wittig Rearrangement of Angular Allylic Alcohols 138-  143 2.2.6  2.2.7 2.3  Determination of the Relative Stereochemistry of 138-143,152,155,  162 and 165  71  Conclusions  76  A n Approach to the Total Synthesis of Sarcodonin G  77  2.3.1  The Cyathane Family of Natural Products  77  2.3.1.1 Isolation and Biological Activity  77  2.3.1.2 Proposed Biogenetic Pathway  84  2.3.2  Previous Approaches to the Total Synthesis of the Cyathanes  85  2.3.3  Retrosynthetic Analysis of Sarcodonin G  95  2.3.4  Synthesis of 236  99  2.3.5  Conclusions and Future Work  Chapter 3 — Experimental 3.1  3.2  62  General  Experimental  108 110 110  3.1.1  Data acquisition and presentation; experimental techniques  110  3.1.2  Solvents and reagents  112  A Cyclopentenone Annulation Sequence Employing (Z)-l-Bromo-3-iodo-2-butene  (9) 3.2.1  3.2.2  115 Alkylation of p-Keto Esters: General Procedure 1  115  Preparation of f3-Keto Ester 25  116  Preparation of fj-Keto Ester 26  117  Preparation of (3-Keto Ester 27  118  Butyllithium-mediated Cyclization of Keto Alkenyl Iodides: General  Procedure 2  119  Preparation of Angular Allylic Alcohol 28  120  Preparation of Angular Allylic Alcohol 29  121  Preparation of Angular Allylic Alcohol 30  123  Vll  3.2.3  Oxidation of Angular Allylic Alcohol 28 with P C C :  Formation of  Epoxides 70 and 71 3.2.4  126  Cr(VI)-Mediated Oxidative Rearrangement of Angular Allylic Alcohols::  General Procedure 3  128  Preparation of Bicyclic Enone 32  128  Preparation of Bicyclic Enone 33  129  Still-Mitra [2,3]-Wittig Rearrangement of Angular Allylic Alcohols  131  3.3.1  Preparation of (Z)-5-Iodo-3-trimethylstannyl-2-pentene (10)  131  3.3.2  Preparation of (£)-5-Iodo-3-trimethylstannyl-2-pentene (11)  132  3.3.3  Preparation of Dimethylhydrazone 126  .133  3.3.4  Preparation of Dimethylhydrazone 127  134  3.3.5  Preparation of Keto Alkenylstannane 128  136  3.3.6  Preparation of Keto Alkenylstannane 129  137  3.3.7  Preparation of Ketone 130  138  3.3.8  Preparation of Ketone 131  140  3.3.9  Iododestannylation: General Procedure 4  142  Preparation of Keto Alkenyl Iodide 132  143  Preparation of Keto Alkenyl Iodide 133  144  Preparation of Keto Alkenyl Iodide 134  145  Preparation of Keto Alkenyl Iodide 135  146  3.3.10  3.3.11  Butyllithium-Mediated Cyclization of Keto Alkenyl Iodides: General  Procedure 5  147  Preparation of Angular Allylic Alcohols 138 and 139  148  Preparation of Angular Allylic Alcohols 140 and 141  150  Preparation of Angular Allylic Alcohol 142  152  Preparation of Angular Allylic Alcohol 143  153  Still-Mitra [2,3]-Wittig Rearrangement of Angular Allylic Alcohols:  General Procedure 6  155  viii  3.4  Preparation of Homoallylic Alcohol 152, from 138  156  Preparation of Homoallylic Alcohol 155, from 139  158  Preparation of Homoallylic Alcohol 155, from 140  161  Preparation of Homoallylic Alcohol 152, from 141  162  Preparation of Homoallylic Alcohol 162  163  Preparation of Homoallylic Alcohol 165  165  Toward the Total Synthesis of Sarcodonin G  168  3.4.1  Preparation of (F)-3-Trimethylgermyl-3-penten-l-ol (246)  168  3.4.2  Preparation of (£)-5-Iodo-3-trimethylgermyl-2-pentene (247)  169  3.4.3  Preparation of Dimethylhydrazone 240  170  3.4.4  Preparation of Alkylated Dimethylhydrazone 248  172  3.4.5  Preparation of Ketone 249  174  3.4.6  Preparation of Ketone 250  175  3.4.7  Preparation of Keto Alkenylgermane 251  176  3.4.8  Preparation of Keto Alkenyl Iodide 238  178  3.4.9  Preparation of Angular Allylic Alcohol 237  179  3.4.10  Preparation of Homoallylic Alcohol 236  180  References and Endnotes  182  Appendix - X-Ray Crystallographic Data for Compounds 142 and 152  188  ix  LIST OF TABLES  Table 1.  Alkylation of (3-Keto Esters with (Z)-l-Bromo-3-iodo-2-butene (9)  15  Table 2.  Butylhthium-mediated Cyclization of Keto Alkenyl Iodides 25-27  16  Table 3.  Pyridine-Induced Shifts in the H N M R Spectra of 29 and 30  20  Table 4.  Cr(VI)-Mediated Oxidative Rearrangement of Angular Allylic Alcohols 29 and 30.  J  :  27  Table 5.  EIZ Selectivity in the Still-Mitra [2,3]-Wittig Rearrangement  43  Table 6.  Butyllithium-Mediated Cyclization of Keto Alkenyl Iodides 132-135  57  Table 7.  Still-Mitra [2,3]-Wittig Rearrangement of Angular Allylic Alcohols 138-143.... 67  Table 8.  Selected C O S Y Data for Angular Allylic Alcohol 28  Table 9.  Selected C O S Y Data for Angular Allylic Alcohol 29 in CDC1  Table 10.  Selected C O S Y Data for Angular Allylic Alcohol 29 in Pyridine-d .  123  Table 11.  Selected COSY Data for Angular Allylic Alcohol 30 in CDC1  124  Table 12.  Selected C O S Y Data for Angular Allylic Alcohol 30 in Pyridine-d  121 122  3  5  3  5  125  x  LIST OF FIGURES  Figure 1.  Proposed Transition State for the [2,3]-Wittig Rearrangement  Figure 2.  O R T E P Drawing of Angular A l l y l i c Alcohol 142, Crystallographic  Figure 3.  Data  O R T E P Drawing of Angular A l l y l i c Alcohol 152, Crystallographic  Data  32  Derived from X-Ray 74 Derived from X-Ray 75  xi  LIST OF ABBREVIATIONS  A  -  angstrom  a  -  below the plane of a ring OR 1,2-relative position  Ac  -  acetyl  anal.  -  analysis  APT  -  attached proton test  p  -  above the plane of a ring OR 1,3-relative position  9-BBN  -  bp  -  boiUng point  br  -  broad  Bu  -  butyl  18-C-6  -  18-crown-6  calcd  -  calculated  CD  -  circular dichroism  COSY  -  ('H/FTj-homonuclear correlation spectroscopy  CSA  -  (15)-(+)-10-camphorsulfonic acid  d  -  doublet  8  -  chemical shift in parts per million from tetramethylsilane OR partial  9-borabicyclo[3.3.1]nonane  charge DBU  -  l,8-diazabicylco[5.4.0]undec-7-ene  DEAD  -  diethyl azodicarboxylate  Dibal-H  -  diisobutylaluminum hydride  DMAP  -  dimethylaminopyridine  DME  -  1,2-dimethoxyethane  DMF  -  N,iV-dimethylformarnide  DMPU  -  l,3-dimethyl-3,4,5,6-tetrahydro-2(l//)-pyrimidinone (also N,N-  Xll  dimethylpropyleneurea) DMS  dimethyl sulfide  DMSO  dimethyl sulfoxide  ed.  edition  Ed.  editor  eq  equivalents  eq.  equation  Et  ethyl  FT  Fourier transform  GLC  gas-liquid chromatography  h  hour(s)  HMPA  hexamethylphosphoramide  HMQC  heteronuclear multiple bond quantum coherence  HPLC  high-pressure liquid chromatography  i  iso  IR  infrared  J  coupling constant in Hz  "•^Sn-H  n-bond coupling constant for tin and proton nuclei, in Hz  KDA  potassium diisopropylamide  KHMDS  potassium hexamethyldisilazide  LDA  hthium diisopropylamide  LiHMDS  htfiium hexamethyldisilazide  rn  multiplet  MCPBA  meta-chloroperoxybenzoic acid  Me  methyl  min.  minute(s)  mp  melting point  NIS  AModosuccinimide  NMR  —  nuclear magnetic resonance  nOe  -  nuclear Overhauser enhancement  P  -  para  PCC  -  pyridinium chlorochromate  PDC  -  pyridinium dichromate  pH  -  -logi [H+]  Ph  -  phenyl  ppm  -  parts per million  PPTS  -  pyridinium p-toluenesulfonate  Pr  -  propyl  0  q  -  quartet  Rf  -  retention factor  r.t.  -  room temperature  s  -  singlet  t  triplet  t  -  tertiary  TBAF  -  tetra-n-butylammonium fluoride  TBDMS  -  ^-butyldimethylsilyl  Tf  -  trifiuoromethanesulfonyl (OTf = triflate)  THF  -  tetrahydrofuran  TLC  -  thin-layer chromatography  TMEDA  -  tetramethylethylenediamine  TMS  -  Ts -ve  -  trimethylsilyl p-toluenesulfonyl (tosyl; OTs = tosylate) negative  xiv  ACKNOWLEDGEMENTS  I thank my supervisor, Dr. Edward Piers, for the opportunity to work in his group. His standards of scientific excellence will continue to be an inspiration to me. I am especially indebted to Dr. Piers for his patience and encouragement during the writing of the thesis. I also thank the other members of the Piers group, past and present, for the stimulating work environment which they provided, and for their generally pleasant company. The staff of the Main Office, and of the mass spectral, elemental analysis and N M R facilities, were very helpful. I would like to make special mention of the late Dr. Steven J. Rettig of the X-ray crystallography facility, whose kindness was much appreciated. Dr. Christine Rogers and M s . Eva Boehringer made excellent suggestions for the improvement of Chapter 2 of the thesis. I am very grateful to Mr. Rafael Sala for his assistance in arranging thesis-related matters on my behalf following my departure from Vancouver. I thank Dr. Larry Weiler for the final reading of the thesis prior to submission.  Mom and Dad and Peter  1  Chapter 1 Introduction  1.1 The Use of Bifunctional Conjunctive Reagents in Synthesis  Carbocycles are remarkably common structural features of natural products. As a result, the synthetic organic chemist has a great interest in the development of new methods for ring 1  formation.  2  One general annulation strategy involves the use of bifunctional conjunctive reagents,  reagents possessing two reactive (or potentially reactive) sites which may differ in their nature [donor (d) or acceptor (a)]; variation is also possible in the order of deployment of the reactive sites. An example of the use of a bifunctional conjunctive reagent in a ring-forming sequence is illustrated in Scheme 1. In a total synthesis of the diterpenoid (±)-ambliol B (1), Piers and Marais employed the bifunctional conjunctive reagent 4-iodo-2-trimethylgermyl-l-butene (2) as a synthetic equivalent to the d ,d -l-butene synthon (3) to fuse a methylehecyclohexane unit onto an existing 2  4  six-membered ring. Reaction of the enone 4 with the lower-order heterocuprate 5 (prepared from 4  2 by lithium-iodine exchange with 'BuLi at low temperature followed by addition of CuCN) gave the keto alkenylgermane 6. Butyllithium-mediated cyclization of the keto alkenyl iodide 7 (readily obtained from 6 by iododegermylation) provided a single, trans-fused product, the angular allylic alcohol 8, which was ultimately transformed into the target compound 1.  | OH  1 Conditions a) 5, TMSC1, THF, -78 °C; NH C1, H 0 ; b) I , C H C 1 , r.t. (42% yield from 4); c) 4  2  2  2  2  BuLi, THF, -78 °C (88% yield).  Scheme 1  The order of operations a-c followed in the synthesis of (±)-ambliol B is characteristic of many annulation sequences employing bifunctional conjunctive reagents: coupling of the bifunctional conjunctive reagent with a bifunctional substrate; if necessary, unmasking of the second (initially latent) reactive site of the conjunctive reagent; and finally, cyclization. The work described in this thesis resulted from proposals to employ the three bifunctional conjunctive reagents 9-11 in two different cyclopentanoid annulation sequences.  In both  sequences, the cyclization step would be followed by a sigmatropic rearrangement, to obtain variously functionalized products from the initially formed angular allylic alcohols. In the first sequence, it was envisaged that reagent 9 might be employed to generate angular allylic alcohols 5  of general structure 12, which should then undergo Cr(VI)-mediated oxidative rearrangement to 6  give the bicyclic enones 13. This sequence is further described in Section 1.2. The second sequence, further described in Section 1.3, conceived the use of reagents 10 and 11 to generate angular allylic alcohols of general structure 14 (E or Z configuration of the double bond; R=H or Me). These alcohols would be expected, when subjected to the conditions of the Still-Mitra variation of the [2,3]-Wittig rearrangement, to provide the homoallylic alcohols 15. The second sequence was proposed as a possible basis for an approach to the synthesis of C19-oxygenated cyathanes.  8  I  /  Br  SnMe,  SnMec  10  11  oxo-Cr(VI) reagent  sequence 1  C0 Me  C O o M e  2  13  CH,OH 1) KH; ICH SnBu 2) BuLi 2  3  sequence 2  14  15  1.2 A Cyclopentenone Annulation Sequence Employing (ZM-Bromo-3-iodo-2-butene 19)  In 1993 Piers and Renaud reported a total synthesis of the racemic tetraquinane crinipellin B (16). Known annulation methods had failed in the construction of the final five-membered A 9  ring (see 16), and so a novel sequence was developed (Scheme 2). The lithium enolate of ketone 17 was alkylated with (Z)-3-bromo-l-iodopropene (18); subsequent treatment of the alkylated ketone 19 with butyllithium resulted in hthium-iodine exchange and attack of the alkenyl anion on the carbonyl group to produce, after workup, the angular allylic alcohol 20. Cr(VI)-mediated oxidative rearrangement of the allylic alcohol 20 gave the enone 21 as the major product. In addition to the desired transformation of the A ring, the silyl ether function of the C ring underwent concurrent oxidative cleavage. Enone 21 was then further elaborated to the target 16.  OTBDMS  19  OTBDMS  20  Conditions a) L D A , THF, -78 °C; 18 (76% yield); b) BuLi, THF, -78 °C (93% yield); c) PCC, Celite, CH2CI2 (51% yield).  Scheme 2  The annulation method involved in the conversion of 17 into 21 (Scheme 2) was studied further in order to determine its scope.  10  Among the variations considered was the possibility of  introducing functionality at the a position of the enone product by beginning the sequence with a more highly substituted bifunctional conjunctive reagent, such as (Z)-l-bromo-3-iodo-2-butene (9). The proposed sequence is outlined in Scheme 3. The five-, six- and seven-membered cyclic 5  P-keto esters 22-24 were chosen as substrates. Alkylation of the P-keto esters 22-24 with the reagent 9 would be expected to give the keto alkenyl iodides 25-27. Butyllithium-mediated cyclization of each of these compounds should provide the series of angular allylic alcohols 2830. Finally, Cr(VI)-mediated oxidative rearrangement of the alcohols 28-30 would be expected 6  to result in the formation of the bicyclic enones 31-33. In this sequence, the bifunctional conjunctive reagent (Z)-l-bromo-3-iodo-2-butene (9) is functioning as a synthetic equivalent to the 1 3  (Z)-a ,d -2-butene synthon (34), with the acceptor site being deployed in the alkylation step and the donor site being deployed in the cyclization step.  22 n=l 23 n=2 24 n=3  25 n=l 26 n=2 27 n=3  28 n=l 29 n=2 30 n=3  Scheme 3  31 n=l 32 n=2 33 n=3  6 1.3 Still-Mitra [2.31-Wittig Rearrangement of Angular Allylic Alcohols: A n Approach to the Synthesis of C19-Oxygenated Cyathanes  In the 1970s, Ayer's group reported the isolation of some novel diterpenoid metabolites from the bird's nest fungus Cyathus helenae B r o d i e .  11,12  The metabolites were named the  cyathins, and their common carbon skeleton was named cyathane (35). The cyathane skeleton possesses the tricyclo[7.5.0.0 ' ]tetradecane ring system. Since the initial reports, Ayer's group has gone on to isolate cyathane-type compounds from other species of bird's nest fungus of the 13  genus Cyathus,  and other groups have reported the isolation of cyathanes from a variety of both  terrestrial and marine organisms.  14  While most of the cyathanes are highly oxygenated, relatively  few have an oxygen function incorporated into the isopropyl side chain. Cyathins A 4 (36) and C  5  (37), shown as their hydroxy ketone and internal hemiketal tautomers respectively, were isolated from Cyathus helenae,  Z&  onychiol B (38) was isolated from the fern Onychium japonicum  h  sarcodonins A (39) and G (40) were isolated from the fungus Sarcodon scabrosus.  &c  and The  absolute configuration of the cyathins was determined through X-ray crystallographic analysis of cyathin A , 3  1 3 a  while only the relative configuration of onychiol B is known. The absolute  configuration of the sarcodonins was established with an X-ray crystal structure of the pbromobenzoate of sarcodonin G . ' 8c  15  35  HO  CH OH  CHO  2  ^.OH H [,..* OH  36 HOCH  37  2  38 OH HOCH  HOCH  2  2  CHO  CHO 40  39  Very little synthetic work has been published on the cyathanes. In the work which has appeared in the literature, the target was either cyathin A 16  1 6 a c 3  or allocyathin B ,  1 6 d f  2  have an isopropyl group at C3, or (3R, 4R, 5R, 65, 9/?)-cyatha-12,18-diene,  16g  both of which which has an  isopropenyl group at C3. It is precisely the A ring complexity of the C19-oxygenated cyathanes, however, that suggested a connection to the methodology outlined above in sequence 2. This connection is further explained below, with specific reference to a proposed total synthesis of sarcodonin G (40) (Scheme 4). Butyllithium-mediated cyclization of a keto alkenyl iodide such as 41 would be expected, based upon previous results from our group, to give exclusively the ds-fused angular allylic 17  alcohol 42. Alkylation of the hydroxyl group with iodomethyl(tributyl)stannane should provide the requisite ether 43 for the Still-Mitra variation of the [2,3]-Wittig rearrangement.  7  Upon  treatment with butyllithium, the tributylstannylmethyl ether would be expected to undergo tinlithium exchange, and the resultant anion should undergo sigmatropic rearrangement to provide, upon workup, the homoallylic alcohol 44. This prediction of the stereochemical outcome of the  8 rearrangement is based upon the well-established suprafaciality of the process.  18  Alcohol 44 has  the correct relative configuration at the angular position and at the exocyclic stereocenter for sarcodonin G (40).  Scheme 4  Given the potential of the conversion of 41 into 44 with respect to an approach to the sarcodonins, it seemed that a more general study of the reaction sequence involved would prove useful. Thus it was proposed to prepare a series of keto alkenyl iodides of general structure 45 (Scheme 5; E or Z configuration of the double bond, R=H or Me) and then subject them to cyclization-rearrangement processes similar to those outlined in Scheme 4. The keto alkenyl iodides 45 would be expected to be readily accessible, via tin-iodine exchange reactions, from the corresponding keto alkenylstannanes 46. It was envisaged that these keto alkenylstannanes could be prepared in several steps, one of which would involve alkylation employing the bifunctional conjunctive reagents (Z)-5-iodo-3-trimethylstannyl-2-pentene  (10) or (E)-5-iodo-3-  trimethylstannyl-2-pentene (11), which would thus operate in the overall sequence as synthetic equivalents to the (Z)-a ,d -2-pentene (47) and (£)-a ,d -2-pentene (48) synthons respectively. 5  3  5  3  The preparation of these reagents in turn was expected to be straightforward. Piers and Gavai have reported the preparation of the alkenylstannanes 49 and 50.  19  Conversion of these primary  alcohols to the corresponding iodides 10 and 11 was expected to be possible using any number of reagents.  Scheme 5  10  Chapter 2 Discussion  2.1: A Cyclopentenone Annulation Sequence Employing (Z)-l-Bromo-3-iodo-2-butene (9)  2.1.1 Introductory Remarks and Proposal  As a result of the presence of five-membered rings in many natural products, methods for cyclopentanoid annulations are of great value to the synthetic organic chemist.  Several  approaches to cyclopentenones of general structure 51 have been devised, " including those 22  employing intramolecular Wittig-type reactions, intramolecular Pauson-Khand reactions.  23  intramolecular aldol condensations  and  24  51 n=l,2 R H , alkyl 1 =  R =H, alkyl, ester 2  The proposed cyclopentenone annulation sequence employing the bifunctional conjunctive reagent (Z)-l-bromo-3-iodo-2-butene (9) is summarized in Scheme 6. The sequence envisaged the alkylation of the cyclic P-keto esters 22-24 with 9 to give the keto alkenyl iodides 25-27. Butyllithium-mediated cyclization of these substances would be expected to provide the series of angular allylic alcohols 28-30. Finally, oxidative rearrangement of the allylic alcohols employing  an oxochromium(VI) reagent should generate the bicyclic enones 31-33. '  The reaction pathway  involved in the conversion of 28-30 into 31-33 will be discussed later. O  ^A^CQ Me 2  22 n=1 23 n=2 24 n=3  25 n=1 26 n=2 27 n=3  t  Scheme 6  The final step of the proposed sequence, the Cr(VI)-mediated oxidative rearrangement of the alcohols 28-30 to the enones 31-33, would result in a 1,3-transposition of the oxygen function. Many examples of the oxidative rearrangement of tertiary allylic alcohols to enones may 6 26-29  be found in the literature. '  In the majority of these cases, however, the tertiary allylic alcohol  (of general structure 52) is the result of an initial 1,2-addition of an organometallic reagent to an a,P-unsaturated five- or six-membered cyclic ketone (53), so that 1,3-transposition of the oxygen  function results in a product cyclopentenone or cyclohexenone (54) which is ^-substituted  27 29 (Scheme 7, n=l,2).  While a variety of oxochromium(VI) reagents have been employed to  effect the oxidative rearrangement of tertiary allylic alcohols, the most common are oxochromium(VI) amine reagents such as pyridinium chlorochromate ( C s H s N F ^ C r 0 C l , 3  PCC)  30  and pyridinium dichromate ( C H N H C r 0 ~ P D C ) . +  5  1) R-M (M=metaQ  5  2  31  7  R OH JX^ w  oxo-Cr(VI) reagent  2) workup  53  52  54  Scheme 7. Alkylative Carbonyl Transposition.  2.1.2 Preparation of (Z)-l-Bromo-3-iodo-2-butene (9)  While the concept of a cyclopentenone annulation sequence employing (Z)-l-bromo-3iodo-2-butene (9) was a promising one, the development of the sequence depended in part on a short and efficient route for the preparation of 9. Such a route had in fact been devised by our group, one which allows considerable flexibility in the substitution on the alkenyl moiety. '  5 32  Thus  (Z)-l-bromo-3-iodo-2-butene (9) could be obtained from ethyl 2-butynoate (55) in three steps in about 80% overall yield (Scheme 8). Stereoselective addition of HI across the alkyne gave the  32 iodo ester 56.  Hydride reduction of the ester resulted in the iodo alcohol 57, which was readily  converted into the corresponding iodo bromide 9 using triphenylphosphine dibromide.  5  13  a Me  =  C0 Et 2  >  C0 Et 2  56  55  b c Br  OH  9 Conditions:  57  (a) N a l , H O A c , 115 °C (98%); (b) Dibal-H, E t 0 , -78 °C to 0 °C (90%); (c) 2  Ph P«Br , C H C 1 , r.t. (93%). 3  2  2  2  Scheme 8  2.1.3 Preparation of Angular Allylic Alcohols 28-30  The selection of the readily available f5-keto esters 22-24 (Scheme 1) as substrates for alkylation with (Z)-l-bromo-3-iodo-2-butene (9) was intended to ensure a straightforward alkylation, with rapid and regioselective enolate formation as a result of the highly acidic proton a to both the ketone and ester carbonyls. The presence of the ester function, however, introduced a question of chemoselectivity in the cyclization step (25-27 -> 28-30). This potential complication is illustrated in Scheme 9. Would cyclization of the alkenyl anion 58-60 onto the ester carbonyl to give 61-63 compete with the desired cyclization onto the ketone carbonyl group to give 64-66?  14  64-66 workup 28-30, n=1-3  Scheme 9  The cyclic p-keto esters 22-24 were alkylated easily and in high yield (Table 1). For example, treatment of methyl 2-oxocyclopentanecarboxylate (22) with sodium hydride in D M E at room temperature, followed by addition of (Z)-l-bromo-3-iodo-2-butene (9), gave the alkylated Pketo ester 25 in 89% yield (entry 1). Methyl 2-oxocyclohexanecarboxylate (23) and methyl 2oxocycloheptanecarboxylate (24) were similarly converted into the alkylated P-keto esters 26 and 27, respectively (entries 2 and 3).  15  1) NaH (1.1 eq)  DME 0°Ctor.t.  C0 Me 2  2) 9(1.1 eq)  r.t.  Table 1. Alkylation of fl-Keto Esters with (Z)-l-Bromo-3-iodo-2-butene (9). entry  n  P-keto ester  product  yield  1  1  22  25  89%  2  2  23  26  83%  3  3  24  27  93%  The alkylated products exhibit spectral data consistent with the proposed structures 25-27. For example, the IR spectrum of 25 contains absorptions at 1754, 1729 and 1650 cm "\ which may be attributed to the ketone carbonyl, ester carbonyl and alkene stretching modes, respectively. In the H N M R spectrum of 25 in CDC1 , a signal at 5 5.37 (ddq, 1H, J = 6.7, 6.7, 1.2 Hz) !  3  corresponds to the vinyl proton, with the fine splitting arising from allylic coupling to the protons of the vinyl methyl group. A singlet at 8 3.71 (3H) is due to the protons of the methoxy group. Finally, the protons of the vinyl methyl group appear as a broad doublet centered at 8 2.49 (3H, J = 1.2 Hz). The  1 3  C N M R spectrum of 25 in CDCI3 contains resonances at  8 214.2 and 171.3,  which represent the ketone and ester carbonyl carbons, respectively, and resonances at 8 130.3 and 104.8, which represent the CH=C(Me)I and CH=C(Me)I carbons, respectively. With the requisite keto alkenyl iodides 25-27 in hand, the cyclization reaction could be performed. The results were encouraging, with chemoselective attack of the alkenyl anion on the ketone carbonyl. The desired angular allylic alcohols 28-30 were produced in fair yields (Table 2). For example, treatment of a chilled (-78 °C) solution of the keto alkenyl iodide 25 in T H F with a solution of butyllithium in hexanes gave, upon workup, the angular allylic alcohol 28 in 54% yield (entry 1). In general, a slight excess of butyllithium was employed; in some cases (entry 3) a greater excess was employed with no noticeable increase in side reactions.  16  1) BuLi THF -78 °C  C0 Me  2) work-up  2  Table 2. Butyllithium-mediated Cyclization of Keto Alkeny I Iodides 25-27. entry  n  keto  BuLi  alkenyl  (eq)  product  yield  iodide  1  1  25  1.3  28  54%  2  2  26  1.2  29  66%  3  3  27  1.9  30  68%  28  The cyclized products exhibit spectral data consistent with the proposed structures 28-30. For example, the IR spectrum of 28 contains absorptions at 3459, 1729 and 1646 cm" , which 1  were attributed to the hydroxyl, ester carbonyl and alkene stretching modes, respectively. In the U N M R spectrum of 28 in CDC1 , a broad signal at 8 5.40 (1H) corresponds to the vinyl proton.  l  3  A singlet at 8 3.71 (3H) is due to the protons of the methoxy group. A pair of signals at 8 2.08 (ddq, 1H, J = 17.1, 2.2, 2.2 Hz) and 3.01 (ddq, 1H, J = 17.1, 2.2, 2.2 Hz) was assigned to the geminal protons H > and H , respectively (vide infra). A singlet at 8 2.54 (1H) disappeared with a  a  the addition of D 0 and was attributed to the exchangeable hydroxyl proton. Finally, the protons 2  of the vinyl methyl group appear as a multiplet centered at 8 1.66 (3H). The C N M R spectrum of 1 3  28 in CDC1 contains a resonance at 8 176.4, which represents the ester carbonyl carbon, and 3  resonances at 8 140.9 and 126.1, which represent the C H = C M e and C H = C M e carbons, respectively. A signal at 8 97.2 is due to the carbinol carbon.  28  29  The assignment of the signal corresponding to H in the H N M R spectra of 28 and 29 J  a  (CDC1 ) was made by comparison of the data for these compounds with that previously published 3  for the corresponding compounds missing the ester substituent at the ring fusion, such as 67 and 33  68.  1  While the H N M R spectrum of 67 contains no signals further downfield than 8 2.87 except  for that arising from the vinyl proton, the H N M R spectrum of 28 is remarkable for the presence l  of a doublet with additional fine splitting at 8 3.01, downfield from the usual range for signals arising from aliphatic protons, even those which are allylic. The deshielding of this proton may be attributed to its proximity to the deshielding cone of the ester carbonyl group. The signal at 8 3.01 was therefore assigned to H . The doublet corresponding to H < was subsequently located at 8 a  a  2.08 as a result of its correlation to H in the C O S Y spectrum of 28 (see the experimental section a  for details). Similarly, the H N M R spectrum of 68 contains no signals further downfield than 8 !  2.56 except that arising from the vinyl proton, while the spectrum of 29 contains a signal at 8 2.87, which was therefore assigned to H . The signal corresponding to H < was again located as a a  a  result of its C O S Y correlation to H , and was found to occur at 8 2.02 (see the experimental a  section for details). The fine splitting of the H and H > signals is consistent with vicinal coupling a  a  to the vinyl proton and long-range coupling to the protons of the vinyl methyl group.  28  U N M R data (CDC1 ) for 28:  l  3  67  1.25-1.40 (m, 1H), 1.63-1.77 [overlapping multiplets, 6H,  contains C=CMe at 1.66 (m, 3H)], 1.93-2.00 (m, 1H), 1.85-1.94 (m, 1H), 2.08 (ddq, 1H, J =  18 17.1, 2.2, 2.2 H z , H 0 , 2.36-2.47 (m, 1H), 2.54 (s, 1H, exchanges with D 0 , OH), 3.01 a  2  (ddq, 1H, J = 17.1, 2.2, 2.2 Hz, H ), 3.71 (s, 3H, OMe), 5.40 (br signal, C=CH). a  H N M R data (CDC1 ) for 67:  :  1.72 (m, 3H, C=CMe), 1.94 (s, 1H, OH), 1.05-2.87 (m, 9H),  3  5.37 (m, 1H, C=CH).  29  68  *H N M R data (CDC1 ) for 29: 0.99-1.10 (m, 1H), 1.32-1.48 (overlapping raultiplets, 4H), 1.653  1.69 (m, 3 H , C=CMe), 1.72-1.85 (m, 1H), 1.85-1.94 (m, 1H), 1.95-2.04 [overlapping multiplets, 2 H , contains H > at 2.02 (dd, 3H, J = 16.0, 2.7 Hz)], 2.61 (s, 1H, exchanges with a  D 0 , OH), 2.87 (dd, 1H, J = 16.0, 1.9 Hz, H ), 3.71 (s, 3H, OMe), 5.52 (br dd, 1H, J a  2  =  2.7, 1.9 Hz, C=CH).  !  H N M R data (CDC1 ) for 68: 3  1.71 (m, 3H, C=CCH ), 0.96-2.56 (m, 12H), 5.49 (m, 1H, 3  C=CH).  30 Based upon the assignment of the signals corresponding to H and H > in the H N M R 1  a  a  spectra of 28 and 29, H and H - were assigned as follows in the H N M R spectrum of 30: H 8 !  a  3.05 (ddq, 1H,  J =  a  a  17.2, 2.3, 2.3 Hz), H - 8 2.14. a  19 In each cyclization reaction, only one isomer, presumably the ds-fused angular allylic alcohol, was isolated. This was expected for the case in which n=l, because of the strain which would be associated with the formation of a trans 5,5-ring fusion (entry 1, Table 2). The stereochemical outcome of the cyclization was less predictable for the cases in which n=2 or 3 (entries 2 and 3). A n experiment intended to confirm the ring fusion stereochemistry of the bicyclic products 29 and 30 was performed. The measurement of aromatic solvent-induced shifts (ASIS) in N M R spectra is a wellestablished method for determining stereochemical relationships in relatively rigid molecules.  34  For example, it is known, in cyclic systems, that the 'H N M R chemical shift of a proton that is vicinal and syn to a hydroxyl group is shifted downfield in pyridine-ds relative to the chemical shift 35  of that same proton in CDC1 . 3  The same effect is observed for protons which have a 1,3-diaxial 36  relationship to a hydroxyl group.  The deshielding is a through-space effect, resulting from  coordination of the highly anisotropic pyridine molecule with the polar hydroxyl group. In general, it is best to compare solvent-induced shift data to that derived from closelyrelated systems of known stereochemistry in order to make conclusions about the configuration of a given proton relative to the hydroxyl group.  (In the absence of experimental data for  comparison, it is possible to generate a theoretical model to predict the geometry of the solventsubstrate complex and thus the effect of the anisotropy of the solvent molecule on the chemical shifts of the protons in the substrate.)  29  34  30  In the case of the angular allylic alcohols 29 and 30, the proton H is neither vicinal to the A  hydroxyl group, nor in a 1,3-relationship with the hydroxyl group on a six-membered ring. As a result, the system in question is not strictly comparable to the available data. Nonetheless, the observation of a substantial downfield shift in the signal due to H in the pyridine-ds spectrum A  20 compared to the CDCI3 spectrum would be strongly suggestive of the spatial proximity of H to A  the hydroxyl group. significant.  In general, downfield shifts of greater than 0.3 ppm are considered  35  Thus, it was hoped that by comparing the H N M R spectra of compounds 29 and 30 !  acquired in pyridine-ds with those acquired in CDC1 , it could be established that a significant 3  downfield shift occurred in the signals corresponding to H , i.e. the allylic proton vicinal and syn A  to the ester function. The downfield shift would imply that H is on the same face of the molecule A  as the hydroxyl group, and thus that the ester and the hydroxyl group are also syn and that the ring fusion is in fact cis. The results are summarized in Table 3. The downfield shift of the signal assigned to H in pyridine-ds compared to CDC1 was approximately 0.5 ppm for both the 5,6A  3  ring system (29, entry 1) and the 5,7-ring system (30, entry 2). In fact, these were the only significant signal shifts which could be discerned by comparison of the spectra in CDC1 and 3  pyridine-ds. For example, A8 H - for both compounds 29 and 30 was found to be -0.02 ppm. A  Ha'  4/) C0 Me n  2  Table 3. Pyridine-induced Shifts in the 'H N M R Spectra of 29 and 30. entry  n  compound  5H  a  6H  A8 H  a  CDCb  py-d  a  5  1  2  29  2.87  3.39  +0.52  2  3  30  3.05  3.50  +0.45  2.1.4 Oxidation of Angular Allylic Alcohol 28  Having secured the series of angular allylic alcohols 28-30, oxidative rearrangement to the desired enone products could be attempted.  Unfortunately, no conditions could be found to  21 generate the enone 31 from the allylic alcohol 28; in every case a mixture of the epoxides 70 and 71 was formed, with starting material being recovered in many instances as well.  28  31  70  71  A variety of conditions was attempted, including P C C with Celite,  31 PDC,  P C C on alumina,  38 Ratcliffe's modification of Collins' reagent (Cr0 »py in CH C1 ) 3  2  2  2  and Corey's reagent  39 (Cr0 »3,5-dimethylpyrazole). 3  When the reaction was performed using P C C buffered with  30 NaOAc,  no starting material was recovered; a 1:1 mixture of 70 and 71 was obtained in 68%  yield. O  The structural assignment of the keto epoxide 70 was made on the basis of IR and mass spectral data. A n M peak possessing an exact mass of 210.0887 provided the molecular formula +  C n H i 0 4 . The molecular formula was confirmed by elemental analysis. The IR spectrum of 70 4  contains a strong, broad absorption at 1741 cm" . In addition to representing the ester carbonyl 1  stretch, this band is at a frequency appropriate for the C = 0 stretch of a five-membered ring ketone.  40  Were the ketone carbonyl in conjugation with a double bond, a lower stretching  frequency would be expected. The absence of an alkene stretch around 1650 cm" further 1  suggested that no double bond is present in 70. Finally, absorptions at 1248 and 821 cm" , in the 1  regions characteristic of the C-O-C asymmetric stretch of an epoxide, suggested that the structure  contains an epoxide in place of the desired double bond."  u  The assignment of the relative  stereochemistry of the three stereogenic centers in 70 is discussed later. The 'H and C N M R data corroborate the M S and IR evidence for the proposed structure 1 3  of compound 70. A singlet of 3H at 8 1.33 in the *H N M R spectrum of 70 in CDC1 certainly 3  corresponds to the protons of the methyl group, and the chemical shift is somewhat lower than that which would have been expected for the protons of a vinyl methyl group, as in the enone 31. There are only four signals in the  1 3  C N M R spectrum above 8 60. At 8 208.6 and 173.6 are the  signals due to the ketone and ester carbonyl carbons, respectively. The other two signals, at 8 80.6 and 65.6, are far upfield of the expected region for signals corresponding to the alkenyl carbons of a cyclopentenone, again confirming the absence of the double bond and supporting 40  the presence of an epoxide in its place. In addition to the *H N M R spectral data of 70 which aided in structure confirmation, the spectrum contains a doublet at 8 2.91, J = 19.3 Hz, which was assigned to H . A doublet at 8 a  2.32 with a matching coupling constant of 19.3 H z was assigned to H >; the C O S Y spectrum a  confirmed this assignment (see the experimental section for details). The protons of the methoxy group appear as a three-proton singlet at 8 3.77. Similarly, the structural determination of compound 71 was made on the basis of mass 13  spectral data, with additional information from the  C N M R spectrum. The high resolution mass  spectrum provided a value of 212.1046 for the molecular ion, corresponding to a molecular formula of C n H 0 . The molecular formula was confirmed by elemental analysis. Based on the 1 6  4  molecular formula, two structures could reasonably be proposed, the isomeric epoxy alcohols 71 13  and 72. The  C N M R spectrum in CDC1 , in addition to a signal at 8 177.7 corresponding to the 3  ester carbonyl carbon, and signals at 8 67.0 and 60.1 corresponding to the epoxide carbons, contains a signal at 8 92.6, corresponding to the carbinol carbon. The APT spectrum indicates that this carbon is quaternary, and therefore that the epoxy alcohol has indeed the structure 71 and not 72. The assignment of the relative stereochemistry of the four stereogenic centers in 71 is discussed later.  The other spectral data confirmed the structure. The IR spectrum of 71 contains a broad band at 3442 cm" , characteristic of the O-H stretching vibration. The IR spectrum also contains 1  bands at 1727 cm" (the C=0 stretch of the ester) and 847 cm" (characteristic of the asymmetric C1  1  O-C stretch of the epoxide). The H N M R spectrum of 71 in CDC1 contains a singlet integrating ]  3  to 3H at 8 1.42, corresponding to the methyl group on the epoxide. A broad signal at 8 3.26 arises from the proton on the epoxide. Finally, a singlet at 8 5.04 which exchanged with D 0 is due to 2  the hydroxyl proton. In addition to the H N M R spectral data which aided in structure confirmation, the *H l  N M R spectrum of 71 contains a three-proton singlet at 8 3.70 arising from the protons of the methoxy group. The spectrum also exhibits a doublet at 8 2.80 (7 = 14.8 Hz) which was assigned to H . The C O S Y spectrum indicated a correlation between this doublet and a doublet of doublets a  at 8 1.63 (7 = 14.8 Hz, 1.0 Hz) which was then assigned to H > (see the experimental section for a  details). H < apparently has a small coupling to the vicinal epoxide proton, resulting in a a  broadening of that proton's signal as well as the fine splitting of its own signal. No corresponding coupling is observed between H and the epoxide proton. This is not unexpected, since molecular a  models indicate that 71 may adopt a conformation in which the dihedral angle between the two protons is close to 90°. The mechanism of the Cr(VI)-mediated oxidation of tertiary allylic alcohols likely depends on the exact nature of the reagent, but it has generally been described as shown in Scheme 10.  6  The initial step is the formation of the chromate ester (73) of the alcohol (74). This is followed by [3,3]-sigmatropic rearrangement of the ester to give the isomeric ester (75). In the final step, the allylic alcohol, now secondary, undergoes oxidation to the corresponding carbonyl group, to give the enone (76).  24  »AAA/»  74  *AAA/»  «AA/V/»  .AAA/*  .AAA/  73  1  i A / W  IAA/V  75  .AAA/*  76  Scheme 10  The formation of epoxide mixtures in the attempted oxidative rearrangement of tertiary allylic alcohols is not unprecedented. " 41  43  In particular, sterically hindered alcohols seem prone to  undergo such side reactions. A pathway to account for the formation of epoxides 70 and 71 in the oxidation of the angular allylic alcohol 28 is shown in Scheme l l .  4 2  Again the initial step is the  formation of the chromate ester 77; here L represents the ligands on chromium, which depend on n  the reagent and the solvent. The chromate ester decomposes into the chromate dianion and the allyl cation 78. Recombination of the chromate dianion with the allyl cation at the less-substituted terminus (Path A ) with concomitant epoxidation generates the epoxide 79; this then undergoes further oxidation to the keto epoxide 70 (most likely with a second equivalent of the reagent, rather than with the Cr(IV) species shown). Recombination of the chromate dianion with the allyl cation at the other terminus (Path B) with epoxidation, however, generates the epoxide 80, which cannot undergo further oxidation, resulting in the epoxy alcohol 71. It has been observed that the epoxidation of secondary and tertiary allylic alcohols with 43  42  oxochromium(VI) reagents is stereospecific, always occurring on the same face of the molecule as the hydroxyl group. This applies whether or not a prior allylic rearrangement has taken place. If 43  the reaction pathway depicted in Scheme 11 is operational, then the chromium dianion must remain closely associated with the allyl cation system (78) on the same face as the initial complexation occurred (77). Based upon the established stereochemical characteristics of the epoxidation reaction, the keto epoxide 70 and the epoxy alcohol 71 have been assumed to have the relative  25 stereochemistry shown in Scheme 11, with the epoxide on the same face of the molecule as the hydroxyl group in the starting material 28 in both cases.  C0 Me 2  28  °  C0 Me 2  77  o  B  \ _ p ( C0 2 M(  78  Scheme 11  The oxidative rearrangement of tertiary allylic alcohols in which the hydroxyl group is located at the ring fusion of 5,5-systems has been previously reported (Scheme 12). '  9 10  For  example, both 81 and 20 underwent oxidation with PCC to give mostly the enone products 82  10  26 and 21, respectively. In the case of the oxidation of 20, oxidative conversion of the silyl ether 9  function to the corresponding carbonyl group was observed in the major product 21. The expected enone 83, in which the silyl ether remained intact, and the diketo epoxide 84 were also formed.  OTBDMS  O  83 (11%)  84 (6%)  Scheme 12  There are at least two critical differences, however, between 81 and 20, which underwent successful oxidative rearrangement, and 28, which formed a mixture of epoxides. The presence of the vinyl methyl group in 28 would tend to make the double bond more nucleophilic, and more prone to oxidation as a result. Secondly, the presence of the angular carbomethoxy group in 28  27 increases the steric hindrance around the angular hydroxyl group. It is possible that once the chroraate ester 77 has formed, subsequent [3,3]-sigmatropic rearrangement is retarded, allowing other processes to compete. Dissociation into the chromate dianion and allylic cation 78 would offer relief from unfavourable steric interactions. A combination of electronic and steric effects may thus be responsible for the tendency to epoxide formation in the attempted oxidative rearrangement of 28. It is interesting to note that while, in some cases, it is possible to decrease or eliminate epoxide formation by changing the nature of the reagent (in particular its acidity or the bulk of the ligands associated with the chromium atom),  42,43  none of the enone 31 was produced in the  oxidation of 28 regardless of the reagent used.  2.1.5 Oxidation of Angular Ally he Alcohols 29 and 30  In contrast to 28, both 29 and 30 underwent successful Cr(VI)-mediated oxidative rearrangement (Table 4). For example, addition of PCC adsorbed on alumina to a stirred solution of the angular allylic alcohol 29 in dry CH Ci2 produced the enone 32 in excellent yield (88%, 2  entry 1). The presence of alumina facilitated the work-up considerably. ' The yield of the enone 37 44  33 from the allylic alcohol 30 was somewhat more modest (68%, entry 2).  \ _ . HOW \ \  PCC/alumina CH CI 2  J\CQ Me 2  2  r.t.  Table 4. Cr(VI)-]Vlediated Oxidative Rearrangement o1f Angular Allylic Alcohols 29 and 30. entry  n  angular  product  yield  allylic alcohol  1  2  29  32  88%  2  3  30  33  68%  28  32  The cyclopentenone products exhibit spectral data consistent with the proposed structures 32 and 33. For example, the IR spectrum of 32 contains absorptions at 1736 cm" corresponding 1  to the C=0 stretch of the ester carbonyl group, at 1709 cm" corresponding to the O O stretch of 1  the ketone carbonyl group, and at 1655 cm" corresponding to the C=C stretch. The H N M R 1  !  spectrum in CDC1 shows two singlets integrating to 3H each, one at 8 1.71 corresponding to the 3  protons of the vinyl methyl group and one at 8 3.68 corresponding to the protons of the methoxy group. Two doublets, one at 8 2.22 (7 = 18.5 Hz) corresponding to H - and one at 2.59 (7 = 18.5 a  Hz) corresponding to H , are also present. The a  1 3  C N M R spectrum of 32 in CDC1 includes 3  signals at 8 134.8 and at 8 206.4, which were assigned to the alkenyl carbon a to the ketone carbonyl carbon, and to the ketone carbonyl carbon, respectively. Two signals at 8 172.6 and at 8 174.3 were not individually assigned, but correspond to the ester carbonyl carbon and to the other alkenyl carbon. The tendency to epoxide formation in the attempted oxidative rearrangement of 28 (the 5,5ring system) was attributed to a combination of steric and electronic effects. The successful oxidative rearrangement of both 29 and 30 (the 5,6- and 5,7-ring systems, respectively) would seem to imply that the flexibility of the ring system is a factor affecting the relative rates of the various oxidative processes in the oxidation of angular allylic alcohols. It is possible that the larger ring systems can more readily accomodate the steric demands of both chromate ester formation at the angular position and subsequent [3,3]-sigmatropic rearrangement (as depicted in Scheme 10), so that these processes become more rapid than competing ones, such as allylic cation formation and subsequent epoxidation (as depicted in Scheme 11).  29 2.1.5 Conclusions  22 n=l 23 n=2 24 n=3  25 n=l 26 n=2 27 n=3  28 n=l 29 n=2 30 n=3  32 n=2 33 n=3  Conditions: (a) NaH, D M E , 0 °C to r.t.; 9, r.t.; (b) B u L i , T H F , -78 °C; (c) PCC/alumina, CH C1 2  2)  r.t. Scheme 13  The bifunctional conjunctive reagent (Z)-l-bromo-3-iodo-2-butene (9) was used to prepare the angular allylic alcohols 28-30 in two steps from the P-keto esters 22-24. The second step, the BuLi-mediated cyclization of keto alkenyl iodides 25-27, was both chemoselective (with exclusive attack of the intermediate alkenyllithium onto the ketone carbonyl group), and stereoselective (with exclusive formation of the as-fused angular allylic alcohols). Cr(VI)mediated oxidative rearrangement of 29 and 30 provided the bicyclic enones 32 and 33, respectively. Attempted oxidative rearrangement of compound 28 resulted in the formation of a mixture of epoxides. While the cyclopentenone annulation sequence employing (Z)-l-bromo-3-iodo-2-butene (9) clearly has limitations in the case where n=l, the success of the sequence in the cases where n=2 and 3 indicates its potential. The sequence represents a useful addition to the existing repertoire of cyclopentenone annulation methods.  30 2.2 Still-Mitra r231-Wittig Rearrangement of Angular Allylic Alcohols'  2.2.1 The [2,3]-Wittig Rearrangement  A general equation for a [2,3]-sigmatropic rearrangement is shown in eq. 1. A sigmatropic rearrangement of order [i,j] is defined as the migration of a a bond, flanked by one or more n electron systems, to a new position whose termini are i-1 and j-1 atoms removed from the original bonded loci, in an uncatalyzed intramolecular process.  46  Considerable variation is possible in both  the atom pair X , Y and the type of electron pair on Y (nonbonding, for example, or anionic). Rearrangements involving an oxycarbanion as the migrating terminus are referred to as [2,3]Wittig rearrangements. The name is derived from that of another classic sigmatropic rearrangement of oxycarbanions, the Wittig rearrangement, which is a [l,2]-alkyl shift (eq. 2).  47  eq. 1  eq. 2 G  At least three types of stereoselection are involved in the [2,3]-Wittig rearrangement (Scheme 14).  47  First, the geometry of the double bond in the allylic ether substrate determines the  relative stereochemistry of the newly created vicinal stereocenters in the homoallylic alcohol product. This diastereoselection follows the general rule that (£)-alkenes favour anti (or threo) products, while (Z)-alkenes favour syn (or erythro) products. Second, geometrical stereoselection occurs in terms of the double bond being formed, with (E) -alkenes being formed preferentially to (Z )-alkenes in most cases (vide infra). Finally, there is the possibility of stereoselection at the  31 carbanionic center itself; experimental evidence for inversion when M=Li has been found, but ab initio calculations predict inversion or retention in the [2,3]-Wittig rearrangement of allyl 48  lithiomethyl ether (85) depending on the precise transition state conformation employed.  1) Diastereoselection O  "1-  O  x  "G  O  G  G E or Z  antt  syn  2) Geometrical Stereoselection  o  3) Stereoselection at the Carbanionic Center  MO  G  G  retention  Scheme 14  O ^ L i 85  M O * ' ~G inversion  Most of these observations may be rationalized in terms of a highly ordered five-membered cyclic transition state with a "folded envelope" conformation, such as that shown in Figure l .  4 9  This model, in which the hybridization at C5 is close to sp and the hybridization at C3 is close to 2  sp , reflects the assumption of an early transition state, as anticipated by the Hammond postulate for an exothermic process.  7  Figure 1. Proposed Transition State for the [2,3]-Wittig Rearrangement. 3  4  In a typical example, treatment of 86 with butyllithium in T H F at -78 °C followed by workup resulted in rearrangement to a 86:14 mixture of syn- and anti-81, while reaction of 88 under the same conditions gave a 26:74 mixture of syn- and anti-S7 (Scheme 15).  50  Since the  substrates 86 and 88 are (bis)allylic ethers, there is a question of regioselectivity in the deprotonation reaction; as is generally observed, deprotonation occurred selectively at the less substituted carbon. A reasonable transition state conformation for the [2,3]-Wittig rearrangement of 86 places the isopropyl group exo (on the opposite face to the "flap" of the envelope), and the oxycarbanion substituent pseudoequatorial (to avoid a 1,3-diaxial type interaction with H*). This transition state conformation predicts the preferential formation of syn-87. Similarly, a reasonable transition state conformation for the rearrangement of 88, placing the isopropyl group exo and the oxycarbanion substituent pseudoequatorial, predicts the preferential formation of anti-87, again in accord with the experimental result. While the 1,2-asymmetric induction resulting from the initial double bond geometries of 86 and 88 was modest, the geometrical stereoselection was complete,  33 with (£)-alkenes being formed exclusively, suggesting that the preference of the isopropyl group for an exo orientation is more pronounced than the preference of the oxycarbanion substituent for a pseudoequatorial orientation.  88 Scheme 15  34  Any number of substituents (G in eq. 2) may be used to facilitate the formation of an oxycarbanion at low temperature; thus, not only (bis)allyl ethers but also allyl benzyl ethers, allyl propargyl ethers and oc-allyloxy carbonyl compounds may be employed as substrates for the [2,3]Wittig rearrangement.  47  The oxycarbanion may also be generated by transmetallation methods  (vide infra) or by reductive lithiation of 0,5-acetals.  51  The scope of the rearrangement has also  been expanded to include substrates in which the allyl group involved in the bond migration is  52 replaced by a propargyl group, leading to allenic alcohol products. It is possible to achieve not only relative stereocontrol in the [2,3]-Wittig rearrangement, but also absolute stereocontrol. Strategies for absolute stereocontrol may be grouped into four types: asymmetric transition, in which an enantiomerically enriched allylic alcohol yields an enantiomerically enriched homoallylic alcohol via chirality transfer along the pericyclic array; asymmetric induction, in which a chiral group present anywhere along the pericyclic array introduces a question of diastereofacial selection (relative asymmetric induction) between the preexisting stereocenter and the new ones; use of a chiral nonracemic base; generation of a configurationally (either diastereo- or enantiomerically) defined carbanion.  47  A n example of the  second type of absolute stereocontrol, asymmetric induction, may be found in Marshall's approach to (+)-a-2,7,ll-cembratriene-4,5-diol (a-CBT) (89, Scheme 16). The remote silyl ether function in 90 is influential enough to bias the product mixture 9:1 in favour of the stereoisomer having a syn relationship between the silyl ether function and the isopropenyl group at the newly formed  53 stereocenter in 91.  Such [2,3]-Wittig ring contraction strategies have been employed in the  stereocontrolled synthesis of many medium and large ring carbocyclic natural products.  35  Many examples in the literature illustrate the potential of the [2,3]-Wittig rearrangement for acyclic stereocontrol.  54  One ingenious strategy takes advantage of both the relative ease of  establishing stereochemical relationships within the framework of a cyclic system, and the subsequent stereocontrol offered by the [2,3]-Wittig rearrangement, for the stereodirected construction of side chains bearing oxygen functionality. Several classes of cyclic [2,3]-Wittig rearrangement substrate may be employed in such a strategy. The two most common are the {3,4} and {3,5} classes, with the numbers referring to the carbons in the substrate to which the tether bridging the pericyclic array is attached (Scheme 17).  55  The stereochemistry at C3 in the allylic ether substrate is tranferred to C l and C5 of the  homoallylic alcohol rearrangement product.  36 4  G  {3,5}  Scheme 17  While the synthetic utility of the [2,3]-Wittig rearrangement of the {3,5} class of cyclic substrates is limited by competing [l,2]-rearrangement,  47  there are several impressive examples of  [2,3]-rearrangements of the {3,4} class. Nakai's approach to the stereocontrolled synthesis of steroid side chains involves the transfer of chirality from C16 of the steroidal nucleus to new stereocenters at C20 and C22 of the sidechain via [2,3]-Wittig rearrangement (Scheme 18).  56  From a single precursor, both the (205, 225)- and (205, 22i?)-22-hydroxy-23-acetylenic sidechains (94 and 95 respectively) are accessible, depending upon the substituent X on the acetylene. When X is H (92 to 94, path a), the rearrangement shows E to and selectivity, where E refers to the double bond geometry in the starting material and anti refers to the stereochemical  relationship between the newly formed vicinal chiral centers in the product. When X is TMS (93 to 95, path b), the diastereoselection is reversed and the rearrangement shows E to syn selectivity instead. The isomer 95 is also produced in the rearrangement of 96, which has the opposite stereochemistry at C16 (S instead of R) and the opposite double bond geometry (Z instead of E) compared to 93. Another example of the [2,3]-Wittig rearrangement of a member of the {3,4} class of cyclic substrates was studied by Marshall in an approach to the stereocontrolled synthesis of acyclic 57  alcohols from tertiary (bis)allylic ethers (equation 3).  While the ring in 97 no doubt constrains  the transition state conformation somewhat, it is still large enough to permit the formation of both (£)- and (Z)-alkenes, and initial experiments using standard conditions (1.4 eq butyllithium in THF at -85 °C) produced a low yield of a mixture of isomers. After a modification to the procedure (3 eq butyllithium and 5.7 eq H M P A in THF at -85 °C), 97 could be selectively converted to the (£)isomer 98 in 51% yield. The enantioselectivity of the reaction was estimated at 65%.  Scheme 18  39  H  (CH )io  BuLi (3 eq) ( - Q) THF, -85 °C M  P  A  5  7 e  eq. 3  2  51%  98  97  2.2.2 The Still-Mitra [2,3]-Wittig Rearrangement  Still and Mitra first reported their variation of the [2,3]-Wittig rearrangement in 1978. The reaction involves an oxycarbanion generated by transmetallation  of the corresponding  (trialkylstannyl)methyl ether. For example, alkylation of the potassium alkoxide of allylic alcohol 99  with iodomethyl(tributyl)stannane  in T H F at room temperature afforded  the  (tributylstannyl)methyl ether 100 (Scheme 19). While the ether could be isolated, it; was more conveniently treated in situ with butyllithium at -78 °C to effect tin-lithium exchange. The lithiomethyl ether underwent sigmatropic rearrangement to provide the homoallylic alcohol 101 in high yield (>95%).  40  1) KH, THF, r.t. 2) ICH SnBu 2  3  OH  OCH SnBu 2  99  3  100  excess BuLi -78 °C  101  Scheme 19  In certain cases, such as the one shown in Scheme 19, the Still-Mitra [2,3]-Wittig rearrangement produces exclusively the (Z)-alkene, in contrast to the usually high selectivity for (£)-alkenes exhibited by other [2,3]-Wittig rearrangements. This dichotomous stereoselection is attributed to steric interactions in the transition state which cause the usual exo orientation of the C3 substituent to be unfavourable, and promote the adoption of a conformation in which the C3 substituent is endo instead (Scheme 20). Presumably the steric interaction between the butyl group at C3 and the vinyl methyl group at C4 is greater than that between the butyl group and the methylene group at C5, making the transition state leading to the (£)-isomer 102 less favourable than that leading to the (Z)-isomer 101.  Bu  H  \  H  Scheme 20  In general, however, the preference of the Still-Mitra rearrangement for (Z)-alkene formation varies considerably, depending on the pattern of substitution of the double bond in the substrate (Table 5). In particular, disubstituted (Z)-alkene substrates almost invariably lead to (£)alkene products, because the steric interaction between the substituent at C3 and the proton at C4 in the transition state leading to the (E)-alkene product is much smaller than that between the  substituent at C3 and the alkenyl substituent at C5 in the transition state leading to the (Z)-alkene product (see, for example, entry 3).  Other noteworthy stereochemical features of the  rearrangement are illustrated by entries 4-7. Reversing either the C3 configuration of the allylic ether (entry 4 vs entry 5) or the double bond geometry (entry 6 vs entry 7) reverses the configuration of the newly-formed stereocenter in the rearrangement product.  43  Table 5. EIZ selectivity in the Still-Mitra [2,3]-Wittig Rearrangement. CH OH  entry  2  C H-  ^  7  C Hi5^^\^CH20H  _j_  7  ref. 7  OH  )  C  40:  <:60 E:Z 95%  H OH 2  2  C Hi5 7  C Hi5^^/CH OH ref. 7  OH  C H 7  C H 7  C  15-  35:65 E.Z 96%  2  7  V  1 £  ^  7H15\i^\/CH20H  91%  ref. 7  OH  TBDMS pCH SnMe 2  4  R^\  ==/  P( 3)20TBDMS  QCH SnMe 2  5  b  3  CH  R-"\  r e f  82-84%  CH OH  1 8 b  2  ^JTBDMS 3  82-84%  ^(CH ) OTBDMS 3  2  ref. 18b pCH SnBu 2  R  /  ^ ^ C H  2  O H  3  72%  CH OH 2  ref. 58 CH OH 2  OCH SnBu 2  b  3  ^CH OH  53:47 E:Z  +  2  ref. 58  OH BocMeN.  BocMeN ref. 59  CH OH 2  40%  Conditions a) K H , T H F , r.t; I C H S n B u ; B u L i , -78 °C b) B u L i , T H F , -78 °C to r.t. c) K H , 2  3  THF, r.t; 18-crown-6, ICH SnBu , -30 °C to -20 °C; BuLi, -78 °C. 2  3  44 In their initial report, Still and Mitra included an example of the rearrangement of a cyclic secondary  allylic  alcohol.  Treatment of the potassium alkoxide of 103  with  iodomethyl(tributyl)stannane, followed by the addition of butyllithium, gave the rearrangement product 104 in high yield (equation 4). It was remarked that the rearrangement proceeded only sluggishly and in low yield in cases in which the P-carbon is more hindered, such as the octalol 105.  The stereochemistry at the carbinol carbon did not seem to influence the success of the  rearrangement, with both the a- and (3-OH isomers of 105 giving similarly disappointing results.  1) KH,THF, r.t.;  eq.  4  105  Paquette and Sugimura, however, accomplished the Still-Mitra rearrangement sequence employing a cyclic secondary allylic alcohol in which the environment of the p-carbon is even more sterically congested than in 105, in their 1987 synthesis of the sesquiterpene antibiotics (-)punctatin A and (+)-punctatin D (Scheme 21).  60  The allylic alcohol 106,  obtained by  stereoselective hydride reduction of the oc,P-unsaturated ketone 107, was subjected to the StillMitra rearrangement sequence to provide the angularly hydroxymethylated cis-perhydroindane 108 in 34% overall yield.  45  1) KH; I C H S n B u .OH 2) BuLi, hexane -78 °C to 0 °C 2  SEMO  3 4 % over two steps  SEMO  107  3  SEMO  106  108  Scheme 21  The Still-Mitra rearrangement of a hindered cyclic secondary allylic alcohol was also a key step in the 1987 synthesis of (±)-laurenene by Crimmins and Gould (equation 5).  61  Treatment of  the (tributylstannyl)methyl ether of either 109 or 110 with butyllithium resulted in rearrangement to 111 or 112 respectively. Tosylation of the primary alcohol function in 112 and reduction with lithium triethylborohydride gave 15-epilaurenene in 70% yield. Similarly reduction of 111 via the tosylate gave (±)-laurenene in 72% yield. In 1988, Balestra and Kallmerten presented several examples of the Still-Mitra 62  rearrangement of tertiary allylic acyclic alcohols (Scheme 22).  Treatment of the  (tributylstannyl)methyl ethers 113 and 114 with butyllithium in T H F at -78 °C gave the diastereomeric homoallylic alcohols 115 and 116 respectively, in fair yield.  In order to account  for the observed selectivity, a six-membered ring chair-like transition state conformation was proposed, involving chelation of the lithium counterion with the benzyloxymethyl substituent at C5.  Rearrangement of the (tributylstannyl)methyl ethers epimeric with 113 and 114 at C4  produced mixtures of 116 and (Z)-115, and of 115 and (Z)-116, respectively, indicating that the relative configurations of C 4 and C5 are critical to the stereochemical outcome of the rearrangement, consistent with the chelation model.  1) KH, ICH SnBu , THF 2) BuLi, hexane, 0 °C 2  3  eq. 5  111 R =CH OH R =H; 57% 112 R H , R =CH OH; 60%  109 R O H , R =H 110 R H , R =OH 1=  1=  1=  2  Bu SnCH 0„ c3  1  2  2  OBOM  2  I  2  2  2  BuLi THF, -78° C 64%  HOCH OBOM 116  114  Scheme 22  47 2.2.3 Proposal  To the best of our knowledge, the Still-Mitra rearrangement of an angular allylic alcohol, or indeed of any cyclic tertiary allylic alcohol, was unprecedented prior to the work described in this thesis. Having formulated an approach to the series of angular allylic alcohols 117 (vide infra), we proposed to study the Still-Mitra [2,3]-Wittig rearrangement of these substances to the homoallylic alcohols 118 (eq. 6). The series of alcohols 118 belongs to the {3,4} class of cyclic substrates, in which the stereochemistry established on the cyclic framework is transferred to an acyclic unit.  eq. 6 W W *  ^ W V *  W W *  117  W \ A / *  118  EorZ R=H. Me  Of particular interest would be the stereochemical relationships between the angular allylic alcohols 117 and the rearrangement products 118 (Scheme 23). Subjection of either (Z)-trans alcohol 119 or (E)-cis alcohol 120 to the Still-Mitra sequence would be expected to provide the same rearrangement product 121.  Similarly, both alcohols 122 and 123, (Z)-cis and (E)-trans  respectively, would be expected to undergo rearrangement to give 124, which is a diastereomer of 121. These predictions of the stereochemical outcome of the rearrangement are based upon the evidence that it is a suprafacial process, with the migrating group remaining at all times associated  18 with the same face of the n system.  W W *  J V W *  122  «/N/W*  «/\/\/\/*  124  123  Scheme 23  2.2.4 Preparation of Angular Allylic Alcohols 138-143  The sequence proposed for the preparation of the angular allylic alcohol substrates is shown in Scheme 24. Alkylation of the iV,/V-dimethylhydrazone 125 with either (Z)- or (E)-5iodo-3-trimethylstannyl-2-pentene (10 or 11, respectively) would provide the alkenylstannanes 126 and 127. Hydrolysis of the hydrazone function would give the keto alkenylstannanes 128 and 129, respectively. Generation of the more stable enolate of these substances under equilibrating conditions followed by addition of methyl iodide would provide the gem-disubstituted ketones 130 and 131, respectively. Iododestannylation of each of the keto alkenylstannanes 128-131 would give the keto alkenyl iodides 132-135, respectively. Treatment of the alkenyl iodides with butyllithium would be expected to result in hthium-iodine exchange and cyclization of the alkenyllithium onto the ketone carbonyl group, generating upon workup the series of allylic  alcohols 136 and 137, which would form the basis for our study of the Still-Mitra [2,3]-Wittig rearrangement of angular allylic alcohols. The commercially-available 1,4-cyclohexanedione mono-2,2-dimethyltrimethylene ketal was chosen for the model studies since the A^/V-dimethylhydrazone of this keto ketal (125) had been prepared previously in our group, and such hydrazones had proven ideal for monoalkylation with primary iodides containing an alkenyltrimethylstannane group, with subsequent oxidative cleavage of the hydrazone function occurring under relatively mild, neutral conditions without  17 accompanying protiodestannylation.  50 I  126 R=H, R'=Me 127 R=Me, R'=H R  137  132 R=H, R'=Me 133 R=Me, R'=H  128 R=H, R'=Me 129 R=Me, R'=H  134 R=H, R'=Me 135 R=Me, R'=H  130 R=H, R'=Me 131 R=Me, R'=H  Scheme 24  51 The requisite electrophiles (Z)- and (F)-5-iodo-3-trimethylstannyl-2-pentene (10 and 11, respectively) were prepared from the known alcohols 49 and 50  19  in high yield using the  63  triphenylphosphine-iodine complex in CH2Q2 (eq. 7). !  The isomers were distinguishable by the  H N M R coupling constant between the vinyl proton and the tin atom, with the (Z)-isomer 10  having Js -n = 135.2 Hz and the (£)-isomer 11 having 3  D  3  7S„-H  = 75.2 H z .  64  The chemical shift of  the vinyl proton is also characteristic of its geometrical relationship to the tin atom, with vinyl protons trans to tin resonating downfield of vinyl protons cis to tin by about 0.35 ppm (6.11 ppm in compound 10 vs 5.80 ppm in compound 11). The IR spectrum of 10 displays a C=C stretch 64  at 1620 cm" , as well as bands at 770 and 526 cm" corresponding to the C-Sn and C-I stretching 1  1  modes, respectively. The IR spectrum of 11 is similar, except that the C=C stretch occurs at lower frequency (1609 cm" ). 1  OH R  R'  j ~ S  SnMe  P  h  E  3 t  #  3  I  2 R  N  CH CI r.t. 2  3  l  2  R'  / — \  e c  SnMe  l-  7  3  49 R=H, R'=Me  10 R=H, R'=Me 81%  50 R=Me, R'=H  11 R=Me, R'=H 80%  Metallation of the hydrazone 125 was accomplished readily using butyllithium (Scheme 25).  65  Subsequent addition of either of the electrophiles 10 or 11 in the presence of D M P U  resulted in the formation of the alkylated hydrazones 126 or 127, respectively. The presence of either H M P A or D M P U was found to increase the yields of the reactions; D M P U was used in preference to the more toxic H M P A . In general the H N M R spectrum of the crude reaction J  product indicated that the conversion was an extremely efficient one, and the alkylated hydrazones 126 and 127 were not purified before being subjected to the conditions for the oxidative cleavage of the hydrazone function. The alkylated hydrazones display spectra consistent with the proposed structures. For example, the IR spectrum of compound 126 contains bands at 1625 cm" , corresponding to the 1  C=N stretch and the C=C stretch, and at 1122 cm" , corresponding to the C-O-C asymmetric 1  stretch of the ketal moiety. The C N M R spectrum of 126 contains a resonance at 169.6 ppm, 1 3  corresponding to the carbon double-bonded to nitrogen. Finally, the H N M R spectrum of 126 !  exhibits three-proton singlets at 0.93 and 1.00 ppm and overlapping multiplets at 3.40-3.59 ppm, corresponding to the ketal methyl groups and the ketal methylene groups respectively, and a sixproton singlet at 2.39 ppm, corresponding to the hydrazone methyl groups. Another characteristic signal present in the alkylation products 126 and 127 is a one-proton multiplet downfield of the other aliphatic signals (2.71-2.80 ppm for 126), which may be assigned to the a' equatorial proton (where alkylation has occurred at the a position), since this proton experiences a deshielding effect from the adjacent hydrazone. '  168 66  A simple and mild procedure employing sodium periodate in a buffered solution was 65  successful for the hydrolysis of the hydrazones 126 and 127 to the keto alkenylstannanes 128 and 129, respectively, with very little protiodestannylated product being observed in the crude reaction mixtures. The spectral data of 128 and 129 confirmed the cleavage of the hydrazone function. For example, the IR spectrum of 128 contains a band arising from the O O stretching 1  vibration at 1718 cm , and the carbonyl carbon at 211.8 ppm.  13  C N M R spectrum contains a resonance corresponding to the  128 R=H, R'=Me 78% (over two steps) 129 R=Me, R'=H 76% (over two steps) buffer=KH P04-NaOH-H 0 pH 7.2 A=—OCH C(CH ) CH 0— 2  2  2  3  2  2  Scheme 25  Treatment of the potassium enolate of 128, prepared under equilibrating conditions (KO'Bu, THF-HMPA), with a large excess of methyl iodide provided the ketone 130 in 66% yield (Scheme 26). Methylation of 129 under similar conditions gave 131 in 57% yield. The ' H N M R spectra of 130 and 131 provided evidence for the introduction of the methyl group. For example, the spectrum of 130 contains a new three-proton singlet at 1.08 ppm (in addition to the threeproton singlets at 0.96 and 0.98 ppm arising from the ketal methyl groups). Iododestannylation of the keto alkenylstannanes 128-131 by titration with a solution of  67 iodine in C H C 1 2  2  was straightforward and provided the keto alkenyl iodides 132-135 in high  yields. Replacement of the tin atom with iodine produced characteristic changes in the N M R spectra. For example, while the resonance corresponding to the alkenyl carbon bonded to tin in 128 appears at 144.4 ppm in the  1 3  C N M R spectrum (downfield of the other alkenyl carbon at  134.8 ppm), the resonance corresponding to the alkenyl carbon bonded to iodine in 132 appears at 110.4 ppm (upfield of the other alkenyl carbon at 130.0 ppm).  68  The *H N M R signal  corresponding to the vinyl proton was also shifted upfield by the tin-iodine exchange, with the vinyl proton appearing at 6.04 ppm (with a tin-proton coupling constant J s -n =146.2 Hz) in the D  spectrum of 128 and at 5.57 ppm in the spectrum of 132. The keto alkenyl iodides 132-135 were treated with 3-4 eq of butyllithium in THF at -78 °C to effect the cyclization reactions (eq. 8 and Table 2). Without an excess of butyllithium, the reaction was incomplete. It has been suggested that the 2,2-dimethyltrimethylene ketal moiety (A) may form a complex with B u L i , thus effectively removing one or two equivalents of the alkyllithium from solution.  69  The coupling of B u L i with Bui, formed during the lithium-iodine  exchange process, also occurs, again reducing the amount of alkyllithium available for the desired transformation. No products arising from competitive addition of the alkyllithium to the ketone function were isolated, indicating that the lithium-iodine exchange process and the subsequent cyclization occur rapidly.  55  132 R=H, R'=Me 93% 133 R=Me, R'=H 90%  134 R=H, R'=Me 92% 135 R=Me, R'=H 90%  Scheme 26  In the cyclization of the keto alkenyl iodide 132, a mixture of isomers was produced, with the major isomer being the trans-fused allylic alcohol 138 (eq.8 and Table 6, entry 1). The H J  N M R spectrum of the crude material in CeD indicated that the initial ratio of the alcohols was 6  approximately 20:1. Purification of the mixture of alcohols resulted in an 84% yield. The isomers were not equally stable on silica gel, and repeated chromatography altered the ratio significantly. A second separation gave the trans-fused alcohol 138 in 47% yield, the cw-fused alcohol 139 in 1% yield, and a 23% yield of a mixture of the two. Similar results were obtained in the cyclization of the keto alkenyl iodide 133 (eq. 8 and Table 6, entry 2). In this case, the cyclization was somewhat less stereoselective, with the H !  N M R spectrum of the crude material in CDC1 indicating that the initial ratio of the alcohols was 3  56 approximately 4:1, with the trans-fused allylic alcohol again predominating. Purification of the mixture of alcohols resulted in a 78% yield. A second separation gave the trans-fused alcohol 140 in 66% yield and the cis-fused alcohol 141 in 8% yield.  R  132 R=H, R'=Me  R  138 R=H, R'=Me  139 R=H, R'=Me  20:1 (84%) 133 R=Me, R'=H  140 R=Me, R'=H  141 R=Me, R'=H  4:1 (78%)  Equation 8  By contrast, cyclization of the keto alkenyl iodides 134 and 135 gave exclusively the defused isomers 142 and 143, in 58% and 72% yield respectively (eq. 9 and Table 6, entries 3 and 4). Indeed, these were the expected results, based upon cyclization studies performed previously in our group on similar systems. In these studies, the presence of a methyl substituent at the same position as the side chain bearing the alkenyllithium function resulted in the exclusive formation of  17 ds-fused alcohols.  The stereochemical assignments of compounds 138-143 were confirmed by  X-ray crystallographic analyses (vide infra).  1) BuLi THF -78 °C  2) workup  134 R=H, R'=Me  142 R=H, R'=Me 58%  135 R=Me, R'=H  143 R=Me, R'=H 72%  Equation 9  1) BuLi, THF, -78 °C 2) workup  E or Z Table 6. Butyllithium-Mediated Cyc ization of Keto Alkeny I Iodides 132-135. entry  keto  R  alkenyl  alkene  angular allylic  geometry  alcohol(s)  Z  138 (trans),  ring fusion  yield  iodide 1  132  H  20:1 trans'.cis  84%  4:1 trans'.cis  78%  139 (cis) 2  133  H  E  140 (trans),  141 (cis) 3  134  Me  Z  142  cis  58%  4  135  Me  E  143  cis  72%  The stereochemical outcomes of the cyclization reactions may be rationalized in terms of both angle strain in the transition state leading to the formation of the five-membered ring and steric demands encountered by the alkenyllithium function in its approach to the carbonyl group. For example, treatment of the keto alkenyl iodide 132 with butyllithium results in the formation of the alkenyllithium species 144 (Scheme 27). Of the two conformational populations 144a and 144b, the former would be expected to be greater because of the stability conferred by the equatorial orientation of the side chain. From 144a, the alkenyllithium function may attack the carbonyl group either axially (path i) or equatorially (path ii). Axial attack is hindered because of 1,3-diaxial interactions with the protons shown in 144c, so that path i , leading to the ds-fused system 145, is disfavoured. From the conformer 144b, in which the sidechain is oriented axially, attack of the alkenyllithium function on the carbonyl group (path iii) is also somewhat hindered, in this case by an interaction with H * . Even though equatorial attack from 144a results in considerable angle strain in the transition state leading to the formation of the five-membered ring, this effect is presumably less significant than the steric interactions involved in paths i and iii so that path ii, leading to the trans-fused system 146, is favoured. Consequently, the trans-fused allylic alcohol 138 was obtained in a 20:1 ratio to the cw-fused alcohol 139. The cyclization of 133 to 140 and 141 was somewhat less selective than that of 132 to 138 and 139. The trans-fused allylic alcohol 140 was obtained in a 4:1 ratio to the cis-fused alcohol 141.  Clearly the steric interactions involved in paths i and iii, leading to the ds-fused  system, are decreased when the vinyl methyl group is trans to the alkenyllithium function instead of cis, allowing these paths to compete more effectively with path ii. In the cyclizations of 134 and 135, the ds-fused allylic alcohols 142 and 143, respectively, were obtained exclusively. These results, using the cyclization of 134 as an example, may be rationalized in terms of a scheme similar to that used to account for the predominant formation of the trans-fused allylic alcohol in the cyclization of 132 (Scheme 28). Because of the presence of the methyl substituent adjacent to the carbonyl group, the populations of the conformers 147a and 147b would be expected to be similar. Path i i , consisting of equatorial attack from conformer 147a, now suffers not only from angle strain in the transition  state leading to the formation of the five-membered ring but also from a gauche interaction between the incoming alkenyllithium function and the axial methyl group. Formation of the trans-fused system 148 is therefore disfavoured. While a similar gauche interaction develops during path iii, (equatorial) attack from conformer 147b, molecular models suggest that this interaction is quite small. Furthermore, path iii does not suffer as grave a disadvantage as path i (axial attack from conformer 147a), namely the 1,3-diaxial interactions between the incoming alkenyllithium function and the protons of the six-membered ring. Thus, it is proposed that path iii becomes the operative pathway, leading to the as-fused system 149.  138  The spectral data of the allylic alcohols 138-143 provided evidence for the proposed structures. For example, the IR spectrum of 138 as a K B r pellet contains a sharp band at 3494 cm" , corresponding to the O H stretch. The C=C stretch is either very weak or entirely absent in 1  the IR spectra of these compounds, as is often the case for tri- or tetrasubstituted alkenes. The 40  13  C N M R spectrum of 138 contains a resonance at 77.1 ppm, corresponding to the carbinol carbon, and resonances at 118.9 and 145.2 ppm, corresponding to the alkenyl carbons. The H !  N M R spectrum of 138 displays a signal at 1.11 ppm which exchanged with D 0 and was 2  assigned to the hydroxyl proton. The protons of the vinyl methyl group appear as a ddd at 1.74 ppm (7=7.3, 1.9, 1.9 Hz) and the vinyl proton appears as a qdd at 5.34 ppm (7=7.3, 2.0, 2.0 Hz).  145a  145b  Scheme 27  61  149a  149b  Scheme 28  While the angular allylic alcohols 138-143 were generally stable, it was occasionally observed that exposure to mildly acidic media (such as during silica gel chromatography) resulted in some decomposition. In the case of the (£)-allylic alcohol 141, the contaminant was identified as 150, in which the double bond has isomerized into the ring. The *H N M R spectrum of 150 does not contain a vinyl methyl signal, but instead a t (7=7.4 Hz) at 1.12 ppm corresponding to the methyl protons of the vinyl ethyl group.  62  HOJ H  150  141  2.2.5 Still-Mitra [2,3]-Wittig Rearrangement of Angular Allylic Alcohols 138-143  The remarkable contribution made by the work of Still and Mitra to the synthetic utility of the [2,3]-Wittig rearrangement has been dependent in part upon the simple route which has become available for the preparation of the (trialkylstannyl)methyl ethers of allylic alcohols. Early syntheses  of  the  requisite  electrophiles,  iodomethyl(trimethyl)stannane  or  iodomethyl(tributyl)stannane, were lengthy and involved the manipulation of air-sensitive organometallic intermediates.  For example, in 1971 Seyferth and Andrews described the  formation of iodomethyl(trimethyl)stannane by the reaction of trimethylchlorostannane with iodomethylzinc iodide, which in turn had been prepared from diiodomethane and a zinc-copper 70a  couple.  A great improvement in this method was realized with the development by the same  authors of an alternative preparation of iodomethylzinc iodide, from ethylzinc iodide and 70b  diiodomethane.  In 1978 Still employed this method to form iodomethyl(tributyl)stannane by the  reaction of tributylchlorostannane with iodomethylzinc iodide.  700  In 1983, Seitz and co-workers  suggested the conversion of chloromethyl(tributyl)stannane to iodomethyl(tributyl)stannane using sodium iodide. The chloro compound was prepared by sequential treatment of tributyltin hydride with lithium diisopropylamide, paraformaldehyde and methanesulfonyl chloride.  70d  1994, a truly simple preparation of iodomethyl(tributyl)stannane was announced by Somfai (Scheme 29).  70e  Finally, in A h m a n and  Treatment of tributyltin hydride with lithium diisopropylamide followed  by the addition of paraformaldehyde gives tributylstannylmethanol in yields exceeding 80%.  63 Conversion to the corresponding iodide is readily accomplished using N-iodosuccinimide, again in high yield.  Bu SnH 3  1) LDA, THF, 0 °C 2) (CH 0) , 0 °C to r.t. 2  n  NIS, Ph P THF, r.t. 3  Bu SnCH OH 3  2  Bu SnCH l 3  >80%  2  >90%  Scheme 29  The conditions employed for the [2,3]-Wittig rearrangement of the angular allylic alcohols 138-143 were similar to those reported by Still and Mitra.  Thus, treatment of the alcohol 138  with potassium hydride in T H F at room temperature,  followed by the addition of  iodomethyl(tributyl)stannane, resulted in the formation of the (tributylstannyl)methyl ether 151. This intermediate was not isolated, but was instead treated with butylhthium at low temperature to give, after the reaction mixture had been allowed to warm to room temperature and water had been added, the rearrangement product 152 in 63% yield (Scheme 30 and Table 7, entry 1). Also produced was a 33% yield of the methyl ether of the starting material (compound 153; vide infra). The homoallylic alcohol 152 was also obtained from Still-Mitra rearrangement of the angular allylic alcohol 141 in 56% yield, with accompanying formation of the methyl ether (compound 160) in 26% yield (Scheme 30 and Table 7, entry 4). Rearrangement of either of the angular allylic alcohols 139 or 140 gave the homoallylic alcohol 155, which is a diastereomer of 152. Rearrangement of 139 gave 155 in 50% yield (as well as a 22% yield of the methyl ether of 139, compound 156) (Scheme 30 and Table 7, entry 2); rearrangement of 140 gave 155 in 53% yield (as well as a 25% yield of the methyl ether of 140, compound 158) (Scheme 30 and Table 7, entry 3). In some cases, especially those in which the angular allylic alcohol was quite hindered, the addition of 18-crown-6 prior to that of iodomethyl(tributyl)stannane was found to increase the yield of the reaction products (Table 7, entries 2, 4, 5 and 6).  7  Still-Mitra rearrangement of the angular allylic alcohols 142 and 143 having a methyl group at the angular position gave the diastereomeric rearrangement products 162 and 165 in 52% and 46% yield respectively (Scheme 31 and Table 7, entries 5 and 6). In both cases the methyl ether of the starting material was isolated as well. In the rearrangement of 142 to 162 the methyl ether of 142, compound 163, was obtained in 28% yield; in the rearrangement of 143 to 165 the methyl ether of 143, compound 166, was obtained in 22% yield.  Scheme 30  Scheme 31  E or Z  E or Z  Table 7. Still-Mitra [2,3]-Wittig Rearrangement of Angular Allylic Alcohols 138-143. entry allylic R nng methyl alkene conditions product relative ether alcohol geometry fusion (yield) stereo(yield) chemistry 1 H Z trans a 138 152 9R*,\\S* 153 (63%) (33%) 2 H Z cis b 9/?*, 11/?* 139 155 156 (50%) (22%) 3 H E trans a 9R*, 11R* 140 155 158 (53%) (25%) 4 H E cis b 9R*,US* 141 152 160 (56%) (26%) 5 Me Z cis b 9R*,llR* 142 162 163 (52%) (28%) 6 Me Z cis b 9R*,llS* 143 165 166 (46%) (22%) 74  conditions a) K H , THF, r.t.; ICH SnBu 2  3>  r.t.; BuLi, -78 °C to r.t.; workup b) K H , THF, r.t.;  18-crown-6; ICH SnBu , r.t.; BuLi, -78 °C to r.t.; workup 2  3  The homoallylic alcohols 152,155,162 and 165 exhibit spectral data consistent with the proposed structures. For example, the IR spectrum of alcohol 152 contains a band at 3435 cm" , 1  corresponding to the O H stretch. Again, the C=C stretch is either very weak or entirely absent in the IR spectra of these compounds.  40  The C N M R spectrum of 152 displays resonances at 1 3  134.0 and 138.7 ppm, corresponding to the alkenyl carbons, at 66.2 ppm, corresponding to the carbon of the hydroxymethyl group, and at 15.4 ppm, corresponding to the secondary methyl group. In the *H N M R spectrum of 152, there is a doublet at 0.95 ppm (7=6.9 Hz) arising from the protons of the secondary methyl group, and a signal at 1.36 ppm which disappeared upon addition of D 0 and which may be attributed to the hydroxyl proton. The signals corresponding to 2  the other protons of the hydroxyraethyl group appear with the signals corresponding to the ketal methylene protons, 3.33-3.56 ppm. The methyl ethers of the angular allylic alcohols, produced in the reaction along with the desired rearrangement product, exhibit signals characteristic of the methoxy group in their N M R 13  spectra. For example, the  C N M R spectrum of 153 includes a resonance at about 47 ppm, and  the H N M R spectrum of 153 possesses a three-proton singlet at 3.10 ppm. J  The formation of such large amounts of the methyl ethers corresponding to the starting materials was a significant concern. No reference to side reactions generating such compounds could be found in the literature. One possible pathway by which the methyl ethers could arise is through quenching of the oxycarbanion before rearrangement has occurred. In order to confirm that premature quenching of the oxycarbanion was not responsible for the methyl ether formation, angular allylic alcohol 139  was treated with potassium hydride; 18-crown-6 and  iodomethyl(tributyl)stannane were then added (Scheme 32). On this occasion, the intermediate (tributylstannyl)methyl ether 154 was isolated; also present in the reaction product at this point was the methyl ether 156.  Subsequent treatment of 154 with butyllithium produced, after  workup, only the rearrangement product 155, with none of the methyl ether 156 being produced in this second step of the Still-Mitra sequence. Thus, the formation of the methyl ether 156 cannot be attributed to premature quenching of the oxycarbanion, as it was present in the reaction mixture prior to generation of the oxycarbanion. The origin of the methyl ethers remains unclear.  69  A  A  A  139  154  156  1) BuLi, THF, -78 °C t o r.t. 2) w o r k u p  155  Scheme 32  13  The  C N M R spectrum of the (tributylstannyl)methyl ether 154 contains resonances  corresponding to the carbons of the butyl groups at 8.9 ppm (Cl), 27.4 ppm (C2), 29.2 ppm (C3) and 13.7 ppm (C4). The protons of the - S n C H 0 - fragment appear in the H N M R spectrum !  2  72  along with the signals arising from the ketal methylene protons at 3.35-3.55 ppm. In a T L C analysis of the crude rearrangement product, trace amounts of a compound having an R value similar to that of the [2,3]-Wittig product could sometimes be detected. On one f  occasion involving the conversion of 139 into 155, this second alcohol was isolated and identified as the [1,2]-Wittig product 167, based on its spectral characteristics. The high-resolution mass spectrum provided a molecular formula of C 1 7 H 2 8 O 3 for 167, the same molecular formula as the  [2,3]-Wittig rearrangement product 155 (and of the methyl ether corresponding to the starting material, 156).  The IR spectrum of 167 contains an O H stretching band at 3441 cm" . The *H 1  N M R spectrum of 167 includes a signal at 1.41 ppm, corresponding to the hydroxyl proton, a ddd at 1.69 ppm (7=7.3, 2.0, 2.0 Hz), corresponding to the protons of the vinyl methyl group, and a qdd at 5.51 ppm (7=7.3, 2.0, 2.0 Hz), corresponding to the vinyl proton. Integration of the region of the spectrum containing the signals arising from the ketal methylene protons, 3.39-3.61 ppm, gave a value of six protons, evidence that within this set of overlapping multiplets are signals arising from the aliphatic protons of the angular hydroxymethyl group in 167.  y  y  139  155  w 167  71 2.2.6 Determination of the Relative Stereochemistry of 138-143,152,155,162 and 165  As a result of the predictable stereochemical relationships between the angular allylic 18  alcohols 138-143 and their rearrangement products 152, 155, 162 and 165,  it: was only  necessary to obtain confirmation of the relative stereochemistry of two compounds, one from the series in which there is an H at the angular position and one from the series with an angular methyl group. X-ray crystal structures were determined for the angular allylic alcohol 142 (Figure 2) and for the rearrangement product 152 (Figure 3).  73  Consider, for example, the series in which there is an H at the angular position (Scheme 33). While the double bond geometry of both of the angular allylic alcohols 138 and 141 was known, the stereochemistry at the ring fusion initially was not. Subjection of either (Z)-alcohol 138 or (E)-alcohol 141 to the Still-Mitra sequence provided the same rearrangement product 152. X-Ray crystallographic analysis of 152 established the relative stereochemistry of that compound (Figure 3). Based upon the well-documented suprafaciality of the rearrangement process (meaning that the migrating group, the oxycarbanion, remains at all times associated with the same face of 18  the TZ system),  and knowing the double bond geometries of 138 and 141, it was possible to use  the relative stereochemistry of 152 to deduce that of the ring fusions in 138 and 141. Similarly, both alcohols 139 and 140, possessing Z and E double bond geometries respectively, underwent rearrangement to give 155, the N M R spectral data of which established as a diastereomer of 152. Again, it was possible to use the relative stereochemistry of 155 to deduce that of the ring fusions in 139 and 140.  Scheme 33  Similar reasoning was applied to the series in which there is a methyl group at the angular position (Scheme 34). While the double bond geometry of both of the angular allylic alcohols 142 and 143 was known, the stereochemistry at the ring fusion initially was not.  X-Ray  crystallographic analysis of 142 established the relative stereochemistry of that compound (Figure 2). Subjection of (Z)-alcohol 142 to the Still-Mitra sequence provided the rearrangement product 162. Based upon the well-documented suprafaciality of the rearrangement process (meaning that the migrating group, the oxycarbanion, remains at all times associated with the same face of the n 18  system),  and knowing the relative stereochemistry of 142, it was possible to deduce that of the  rearrangement product 162. Subjection of (£)-alcohol 143 to the Still-Mitra sequence provided the rearrangement product 165, the N M R spectral data of which established as a diastereomer of 162. It was then possible to use the relative stereochemistry of 165 to deduce that of the ring fusion in 143.  Scheme 34  Figure 2. ORTEP Drawing of Angular Allylic Alcohol 142 Derived from X-Ray Crystallographic Data.  C16  C17 C15  C13 01  C12  75  Figure 3. ORTEP Drawing of Homoallylic Alcohol 152 Derived from X-Ray Crystallographic Data.  ii  76 2.2.7 Conclusions  The novel bifunctional conjunctive reagents 10 and 11 were employed in annulation sequences yielding the angular allylic alcohols 138-143. These alcohols were then carried through the Still-Mitra [2,3]-Wittig rearrangement sequence, to provide the homoallylic alcohols 152,155,162 and 165. These rearrangements offer the first examples of the application of the Still-Mitra sequence to cyclic tertiary allylic alcohols. For example, Still-Mitra rearrangement of the angular allylic alcohol 143 provided the homoallylic alcohol 165 in 46% yield (equation 10).  R R'  SnMe  3  10 R=H, R'=Me 11 R=Me, R'=H CHoOH  HCL  1) KH, THF, r.t. 2) 18-crown-6 3) ICH SnBu , r.t. 2  3  4) BuLi, -78 °C to r.t. 5) workup 46%  eq. 10  77 2.3 A n Approach to the Total Synthesis of Sarcodonin G  2.3.1 The Cyathane Family of Natural Products  2.3.1.1 Isolation and Biological Activity  In 1971, the isolation of C20 compounds from the fungus Cyathus helenae Brodie was reported by Ayer.  74  This "cyathin complex" was observed to have antibiotic activity. Structure  elucidation of some of the compounds revealed that they possess a novel diterpenoid skeleton, which was named cyathane (35). ' '  8a n 12  17  15  35  Cyathin A (168) 3  and allocyathin B (169) were the first of the cyathanes for which 3  complete structures were reported. ' n  In solution, both were found to exist in tautomeric  12b  equilibrium, as illustrated in equation 11 for cyathin A (168). The absolute configuration of 3  cyathin A (168) was determined by X-ray crystallographic analysis 3  the exciton chirality method.  13a  and was later confirmed by  Interestingly, cyathin A (168) was found to exist in the hemiketal 3  form in the solid state, while allocyathin B (169) crystallizes in the hydroxy ketone form. 3  12b  HO  CH OH  CH OH  2  168a  HO  2  CH OH 2  169  168b  hydroxy ketone  hemiketal eq. 11  Cyathins B (170) and C (171) were found to be responsible for most of the antibiotic 3  3  activity of the cyathin complex.  Neoallocyathin A 4 (172) contains an epoxide in place of the  123  C3-C4 double bond. Cyathins A 4 (36) and C 5 (37) are among the few cyathanes possessing oxygenation at C19.  8a  Cyathane-type diterpenoids have also been isolated from the fungus africanus. *' 13  75  Cyathus  Cyafrin A (173), like cyathin A (168) and allocyathin B (169), exists in 4  3  3  tautomeric equilibrium in solution, with the crystalline structure being that of the hemiketal tautomer. The A rings of cyafrin B (174) and of allocyafrin B (175) contain an a,P-unsaturated 4  4  79 ketone. While the stereochemistry at C4 of allocyafrin B (175) was not determined, a trans A B 4  ring fusion was suspected. Cyafrin A (176), which contains an epoxide in place of the C12-C13 5  double bond, exists in the hemiketal form in both solution and the solid state.  175  176  13b  Cyathus earlei Lloyd also yielded cyathane-type diterpenoids.  Cyathatriol (177), along  with various acetylated derivatives, allocyathin B (178) and cyathin B (179) were all found to 2  2  have moderate antibiotic activity against Staphylococcus aureus.  177  178  179  80 A fourth fungus of the genus Cyathus, Cyathus striatus, was found to contain three compounds comprising a cyathane skeleton linked to a pentose unit, striatins A - C (180-182).  14a  The relative configuration of the striatins was determined by X-ray crystallographic analysis of striatin A (180). The striatins exhibit antibacterial and antifungal properties.  180  181  182  Cyathane-type compounds have also been isolated from organisms, both terrestrial and marine, other than Cyathus spp. Onychiol B (38) was isolated from the fern Onychium japonicum (Thunb.) Kunze.  8b  The relative configuration of onychiol B (38) was determined by X-ray  crystallographic analysis.  HOCH  The sponge Higginsia sp. yielded the cyathane-type compounds 183-185. relative configuration of these compounds was determined.  14b  Only the  183  184  185  Sarcodonin G (40) and sarcodonin A (39) were isolated from the fungus scabrosus.  Sc  Sarcodon  Along with cyathins A 4 (36) and C 5 (37) and onychiol B (38), sarcodonins G 8a  8b  (40) and A (39) are oxygenated at C19. The absolute configuration of sarcodonin G (40) was determined by X-ray crystallographic analysis of its p-bromobenzoate derivative. The only biological activity cited for the sarcodonins was "intense bitterness" in organoleptic tests, at threshold values of 3.1 x 10~ M and 3.1 x 10" M for sarcodonins G (40) and A (39), 6  5  respectively.  HOCH CHO 40  CHO 39  Cyathanes 186-188 were isolated from the deep water chemotype of the sponge Myrmekioderma styx.  l4c  While the relative stereochemistry at C5 was not determined, a trans B C  ring fusion was suspected. Unlike most of the cyathanes, in these compounds the A B ring fusion is cis, and the C6 and C9 methyl groups are syn. Both 186 and 188 exhibit moderate cytotoxicity against the P388 murine leukemia cell line and the A549 human lung tumour cell line. Compound 186 produced I C  5 0  values of 11.2 u.g/mL and 4 u.g/mL for the P388 and A549 cell lines  respectively, and compound 188 produced IC50 values of 5.6 iig/mL and 7 u.g/mL for the P388 and A549 cell lines respectively.  82  186  187  188  Cyanthiwigins A - D (189-192) were isolated from the sponge Epipolasis reiswi,gi.  l4d  The  absolute configuration of cyanthiwigin A (189) was determined by X-ray crystallographic analysis. As in cyathanes 186-188, in these compounds the A B ring fusion is cis, and the C6 and C9 methyl groups are syn. The cyanthiwigins display moderate cytotoxicity against the P388 cell line with I C  189  50  values of 10, 5, 10 and 2.5 u.g/mL for cyanthiwigins A - D (189-192) respectively.  190  191  192  The hydrocarbon 193, which has been named (3R, 4R, 5R, 6S, 9fl)-cyatha-12,18diene,  16g  was isolated from the sponge Higginsia sp., eight years after the isolation of 183-185.  76  Only the relative configuration of 193 is known. Synthetic 193 exhibits cytotoxicity at IC50 20.7 Ug/mL against the P388 cell line.  16g  193  Erinacines A - C (194-196) were isolated from the fungus Hericium erinacium.  Since  the aglycon of erinacine A (194) is allocyathin B (178), the absolute configuration of erinacine A 2  (194) was assigned according to that of the cyathins. The absolute configuration of erinacine B (195) was determined by comparison of its C D spectrum with that of erinacine A (194), while the absolute configuration of erinacine C (196) was determined by chemical correlation to erinacine B (195). The erinacines were found to be potent stimulators of nerve growth factor synthesis.  CHO  OH  194  CHO 195  CH OH 2  196  2.3.1.2 Proposed Biogenetic Pathway  A biogenetic pathway leading to the cyathanes has been proposed.  77  Bond reorganization  of geranylgeraniol pyrophosphate (197) as shown in Scheme 35 could lead to an intermediate such as 198, with initial formation of the seven-membered C ring of the cyathanes. Further bond reorganization could lead to 199, in which the entire cyathane ring system is present. Quenching of the carbocation in 199 by loss of an a-proton would lead to the cyathane-type structure 200. 1  The results of biosynthetic studies employing pathway.  3  C-labelled acetate support the proposed  77a  200 Scheme 35  85 2.3.2 Previous Approaches to the Total Synthesis of the Cyathanes  Ayer's group has attempted the total synthesis of one of the cyathins (Scheme 3 6 ) .  16ab  In  their most recent report, they obtained a tricyclic intermediate in an approach to (±)-cyathin A  3  16a  (168) starting from 2,5-dimethyl-/?-benzoquinone (201).  The strategy began with two  cycloadditions: a Diels-Alder reaction to introduce what would become the seven-membered C ring, and a [2+2] addition to set up a sequence for the construction of the five-membered A ring. The sequential electrocyclic additions established from the early stages of the synthesis the anti relationship between the angular methyl groups at C6 and at C9 (cyathane numbering). After several further steps, they had in hand the key precursor 202. Reduction of the a,P-unsaturated carbonyl group in 202 was followed by treatment of the resulting dione epoxide with thiophenol and potassium hydroxide in ethanol.  The latter step accomplished a series of reactions:  nucleophilic attack of the benzenethiolate anion on the epoxide, retro-aldol reaction (opening up the cyclobutane ring) and finally aldol condensation to form the cyclopentenone 203. Unfortunately, they were unable to isomerize the B C ring fusion to the desired trans stereochemistry without prior removal of the thioether, which later led to difficulty in attaching the isopropyl group. Ward, who had worked on this route while in Ayer's group, was subsequently able to carry the tricyclic intermediate 203 ahead, via keto aldehyde 204, to the 5,6,7-ring system of the cyathanes, with the correct relative stereochemistry at the ring fusions and at C l 1 (205).  16b  CH OH 2  168  86  O 201  OH  202  203  g-q  205  204  Conditions a: 2,4-(fe)trimethylsilyloxy-l,3-pentadiene (1:1 mixture of stereoisomers), xylene, reflux (91%). b: allene, h\), THF, -40 - (-50) °C. c: MeOH, Rexyn 101 acidic ion exchange resin, T H F , r.t. d: M C P B A , C H C 1 , r.t. (-45% from 201). 2  2  e: 9-BBN, THF, r.t. f: PhSH,  2N K O H , EtOH, 8 h at 0 °C, 1.5 h at reflux, g: P h C 0 H , Ph P, D E A D , T H F , 15 °C. h: 2  3  N a B H , M e O H , C H C 1 , -78 °C. i : HOAc, -78 °C to r.t. j : NaOH, M e O H , H 0 , 50 °C. k: 4  2  2  2  Raney N i , M e O H , r.t. 1: NaOH, MeOH, reflux (65% from 203).  m: PhCOCl, E t N , D M A P , 3  C H C 1 , 3 °C (94%). n: M s C l , pyridine, 50 °C. o: D B U , toluene, reflux (76% over the two 2  2  steps n,o). p: H , (Ph P) RhCl, C H (92%). q: 0 , Sudan III, C H C 1 , -78 °C, D M S , pyridine 2  3  3  6  6  3  2  2  (quantitative), r: /?-TsOH, C H , r.t. 6  6  Scheme 36  Paquette's group has also published the results of synthetic studies on the cyathane skeleton (Scheme 37).  16c  Their route began with the product (206) of an inverse electron-demand  Diels-Alder reaction between tropane and 2-methylene-l,3-dithiolane (cat. Et N, 120 °C, 56%). A 3  1,4-reduction of the enone system, protection of the ketone carbonyl and oxidative removal of the dithiolane moiety gave the intermediate 207.  At this point the racemate was resolved by  derivatization of the ketones as chiral sulfoxamine adducts and subsequent separation of these adducts by H P L C , with the enantiomer shown being carried through the remaining steps. Reaction of the ketone carbonyl group with a chiral vinyllithium reagent derived from (£)-(+)carvone, (£)-(-)-l-lithio-3-isopropylcyclopentene, gave 208; subsequent anionic oxy-Cope rearrangement allowed rapid construction of the 5,6,7-ring system of the cyathanes (209). While 209 could be readily methylated at C9 (cyathane numbering) with the correct (3 stereochemistry, attempts to otherwise elaborate this intermediate were largely unsuccessful.  206  207  208  209  Conditions: a: Dibal-H, C H C N , H M P A , THF, -50 °C to r.t. (>90%). b: H O C H C H O H , p3  2  2  TsOH, C H , reflux (98%). c: chloramine-T, acetone, aqueous MeOH, 0 °C (56%). d: f-BuLi, 6  6  THF, -78 °C; (5)-(-)-l-lithio-3-isopropylcyclopentene, -78 °C to 0 °C (51%). e: K H , 18-C-6, THF, 90 °C (sealed tube); NH C1, H 0 (83%). 4  2  Scheme 37  The first successful synthesis of a cyathane natural product was reported by Snider in 1996 (Scheme 38). ' Conversion of the racemic bicyclic enone 210 to the conjugated dienyl triflate 16d  e  211, followed by Pd-catalyzed carbonylation to the dienoate and reduction-oxidation, gave the dienal 212.  TMSCl-accelerated cuprate addition to 212 followed by methylation gave 213.  Attack of the cuprate proceeded axially despite the presence of the angular methyl group; methylation then occurred axially from the least hindered face. A n intramolecular ene reaction of 213 gave 214, which has the 5,6,7-ring system of the cyathanes but the wrong B C ring fusion stereochemistry (cis instead of trans). While the initial target of the synthesis had been (±)-cyathin A  3  (168), the route was modified at this point to aim at (±)-allocyathin B (178) instead. 2  Protection of the hydroxyl group of 214 as a silyl ether was followed by ozonolysis of the exocyclic double bond. The a,P-unsaturated ketone 215 was then generated via a selenoxide elimination sequence. Desilylation and Dess-Martin oxidation of the resulting P-hydroxy ketone to the 1,3-dione was followed by formation of the enol triflate and Pd-catalyzed carbonylation to give the ester 216. Base-catalyzed isomerization of the C ring double bonds and reduction of the keto ester to the P-diol followed by M n 0 oxidation of the allylic alcohol gave (±)-allocyathin B (178), 2  which was then further elaborated to its xyloside erinacine A (194).  2  89  (Scheme 38 continued on next page)  Conditions:  a: l,8-(^)dimethylamino)naphthalene,  T f 0 , C H C 1 , -78 °C (88%). b: 2  2  2  Pd(OAc) , Ph P, C O , *'-Pr EtN, MeOH, r.t. (85%). c: Dibal-H, THF, 0 °C (97%). d: M n 0 , 2  3  2  2  C H C 1 , r.t. (95%). e: H C = C ( C H ) C H C H M g B r , CuBr«Me S, TMSC1, H M P A , THF, -78 °C 2  2  2  3  2  2  2  (91%). f: f-BuOK, M e l , 0 °C then r.t. (75%). g: M e A l C l , C H C 1 , -45 °C (87%). h: i2  2  2  PrMe SiCl, imidazole, D M F , r.t. (95%). i : O s 0 , K I 0 , f-BuOH, H 0 , N a H C 0 , r.t. (77%). j : 2  4  4  2  3  L i H M D S , PhSeCl, T H F , -78 °C to r.t.; H 0 , 40 °C (72%). k: H O A c , H 0 , THF, 45 °C. 1: 2  2  2  Dess-Martin reagent, C H C 1 , r.t. (72% from 215). m: K H M D S , PhNTf , THF, -78 °C to r.t. 2  2  2  (75%). n: Pd(OAc) , Ph P, C O , /-Pr EtN, MeOH, r.t. (75%). o: E t N , M e O H , 100 °C (sealed 2  3  2  3  tube) (94%). p: L i A l H , E t 0 , -78 °C to r.t. (89%). q: M n 0 , C H C 1 , r.t. (94%). r: 2,3,4-tri4  2  2  2  2  O-acetyl-a-D-xylopyranosyl bromide, Hg(CN) , H g C l , C H C N , r.t. (34%, 1:1 mixture of 2  2  3  diastereomers). s: K C 0 , MeOH, r.t. (>90%). 2  3  Scheme 38  In 1998, Tori also reported a total synthesis of (±)-allocyathin B (178) (Scheme 39).  16f  2  Copper-catalyzed 1,4-addition of the Grignard reagent of 4-bromo-l-butene to 3-methyl-2cyclohexenone (217), followed by protection of the carbonyl group as a ketal, gave 218. Ozonolysis of the double bond and alkylation of the resultant aldehyde with isopropylmagnesium bromide gave alcohol 219. Jones oxidation, with concomitant removal of the ketal protecting group, generated the dione 220. Upon treatment with base, intramolecular aldol condensation provided 221. Acylation of the lithium enolate of 221 employing the acid chloride 222, followed by methylation, gave 223. Surprisingly, acylation and alkylation occurred from the concave face of 221. The acylation step in the conversion of 221 into 223 was low-yielding as a result of the recovery of significant amounts of (9-acylated material and starting material.  Regio- and  stereoselective zinc borohydride reduction of 223 was followed by acetylation of the resultant alcohol; base-catalyzed aldol cyclization and subsequent S0C1 dehydration gave lactone 224. 2  Treatment of 224 with LiAlfL, provided the deprotected triol. Protection of the primary and allylic hydroxyl groups as silyl ethers and acetylation of the remaining secondary hydroxyl group was followed by desilylation and Swern oxidation to the dial 225. Intramolecular aldol condensation of 225 and deprotection of the acetate provided (±)-allocyathin B (178). As a result of Snider's 2  work, this synthesis also constitutes a formal total synthesis of erinacine A (194).  A total synthesis of (±)-cyathane 193 was completed in 1997 by Piers and Boulet,  16g  taking advantage of the preparation of a key intermediate in the total synthesis of several no  verrucosane natural products (Scheme 40).  Stereoselective TMSCl-facilitated conjugate addition  of the higher order cuprate 226 to the bicyclic enone 227 and equilibration of the resulting mixture of stereoisomers gave compound 228 as the major product. Alkylation of the potassium enolate of 228 with iodide 229 followed by methylation gave 230, with both alkylations occurring with high axial stereoselectivity. Conversion of 230 to the dione, ring closure via an intramolecular aldol condensation and dissolving metal reduction of the resultant a,p%unsaturated ketone gave 231, the key intermediate in the verrucosane route. Treatment of 231 with ethyl diazoacetate in the presence of boron trifluoride etherate gave a mixture of ring-expanded P-keto esters. Decarboxylation gave a mixture of ketones, the major one of which was 232. Regioselective enol triflate formation gave predominantly 233, which was then treated with lithium dimethylcuprate to provide (±)-cyathane 193.  93 Conditions: a: H C = C H C H C H M g B r , 2  TsOH,  2  2  CuBr»Me S, T H F , -30 °C. b: H O C H C H O H , p2  C H , reflux (99% from 217). 6  2  3  2  M e O H , reflux (73% from 219).  2  c: 0 , C H C 1 , -78 ° C ; Zn, H O A c , r.t.  6  ( C H ) C H M g B r , E t 0 , r.t. (83% from 218). 3  2  2  2  d:  e: Jones reagent, acetone, 0 °C. f: 5% K O H ,  g: L D A , T H F , -78 °C; 222 (33%). h: j-BuOK, THF, 0 °C  then r.t.; M e l (91%). i : Zn(BH ) , E t 0 , -78 °C (50%). j : A c 0 , D M A P , pyridine, r.t. (92%). 4  2  2  2  k: L i H M D S , T H F , - 7 8 °C (80%). 1: S O C l , pyridine, C H C 1 , 0 °C (50%). m: L i A l H , THF, 2  reflux,  n: TBDMSC1, E t N , C H C 1 (37% from 224). 3  2  2  2  2  4  o: A c 0 , D M A P , pyridine, r.t. 2  p:  PPTS, M e O H r.t. (52% over o,p). q: oxalyl chloride, D M S O , E t N , C H C 1 , -50 °C. r: 5% 3  K O H , MeOH, r.t. (74% over q,r).  Scheme 39  2  2  227  228  230 J e-h  OTf  O  233  232  231  193 Conditions:  a: 226, TMSC1, T H F , -78 °C (86%). b: NaOMe, M e O H , 40 °C (65%). c:  K H M D S , THF, -78 °C; 229, H M P A , -78 °C to -48 °C to r.t. (80%). d: L D A , THF, -78 °C to 0 °C; M e l , -78 °C to r.t. (96%). e: T B A F , THF, r.t. f: P C C , Celite, C H C 1 , r.t. g: NaOEt, 2  2  EtOH, reflux (81% from 230). h: L i , N H , MSuOH, T H F , -78 °C; solid NH C1 (98%). i : 3  4  BF «OEt , N C H C 0 E t , E t 0 , 0 °C to r.t.; DMSO, NaCl, H 0 , reflux (56%). j : K H M D S , THF, 3  2  2  2  2  2  -78 °C to 0 °C; H M P A , PhNTf , 0 °C to r.t. (70%). k: M e C u L i , E t 0 , -10 °C (98%). 2  2  Scheme 40  2  95 2.3.3 Retrosynthetic Analysis of Sarcodonin G (40)  In the previously reported synthetic approaches to cyathane natural products described above, the target was either cyathin A (168)  16a-c  3  or allocyathin B (178), " both of which have 16d  f  2  an isopropyl group at C3, or cyathane 193, which has an isopropenyl group at C3. 16g  The presence of the hydroxymethyl group as well as the A ring double bond in C19oxygenated cyathanes such as sarcodonin G (40), however, suggested that the C19-oxygenated cyathanes could be readily accessed via a [2,3]-Wittig rearrangement strategy. The results of the model studies designed to gauge the viability of this strategy are described in Section 2.2 of this thesis. In particular, the model studies demonstrated that butyllithium-mediated cyclization of a keto alkenyl iodide such as 135 provides exclusively the ds-fused allylic alcohol 143, which, when subjected to the conditions of the Still-Mitra [2,3]-Wittig rearrangement sequence,  7  rearranges to the homoallylic alcohol 165 (Scheme 41). The five-membered ring of 165 has the same substitution pattern as the A ring of sarcodonin G (40), as well as the same relative configuration at C9 and at C18 (using cyathane numbering for 165).  135  143  165  Conditions: a: BuLi, THF, -78 °C (72%). b: K H , THF, r.t.; 18-C-6; I C H S n B u ; BuLi, -78 °C 2  3  to r.t. (46%).  Scheme 41 19  165  40  The retrosynthetic analysis of (±)-sarcodonin G (40) is outlined in Scheme 42. The target compound (40) could presumably be obtained from y-keto ester 234 by introducing a double bond oc,(3 to both the ester and ketone functions and then performing a partial deconjugation, leaving the double bond only in conjugation with the ester function; other steps would involve the reduction of the ester to the aldehyde and the deprotection of the primary alcohol. y-Keto ester 234 is the likely product of a free-radical ring expansion  of the ketone 235, which in turn could be obtained from  the diene alcohol 236 by protection of the primary alcohol, oxidative cleavage of the less hindered double bond, and carboalkoxylation and bromomethylation a to the resultant carbonyl group.  Alcohol 236 is the product of the application of the Still-Mitra [2,3]-Wittig rearrangement sequence to the angular allylic alcohol 237, which in turn would be the expected product of the 80  butyllithium-mediated cyclization of the keto alkenyl iodide 238.  Keto alkenyl iodide 238 could  presumably be obtained from the bicyclic ketone trans-239, which had been previously prepared 81  in our group. In devising the retrosynthetic analysis of sarcodonin G (40), an early deployment of the key [2,3]-Wittig rearrangement methodology was desirable in the event that the total synthesis were not completed due to time constraints. Indeed, some complications arose (vide infra), and the work presented herein describes the preparation of an advanced intermediate in the proposed route to sarcodonin G (40), 236, in which the A B ring system has been constructed and all four stereocenters present in the target molecule have been established with the correct relative configuration.  CHO  234  40  HOCH  trans-239  Scheme 42  C02R  99 2.3.4 Synthesis of 236  The bicyclic ketone 239 had been previously prepared in our group, as a 78:22 mixture of the trans- and ds-fused isomers (Scheme 43).  The isomers could be distinguished by the  81  chemical shift of the angular methyl group in the H N M R spectrum: in the trans isomer, the !  protons of the methyl group resonate at 0.94 ppm, while in the cis isomer, the protons of the 81  methyl group resonate at 1.17 ppm.  The mixture of bicyclic ketones was treated with N,N-  dimethylhydrazine in the presence of a catalytic amount of C S A in refluxing benzene.  65  A mixture  of dimethylhydrazones was produced, with the trans isomer 240 predominating. The cis isomer 241 was actually a mixture of two isomers, presumably arising from the two possible orientations 82  of the dimethylamino group.  The isolated yields of the trans and cis isomers were 60% and  28%, respectively. The stereochemical assignments were again made on the basis of the chemical shift of the angular methyl group, with the cis mixture displaying methyl resonances at 1.06 and 1.08 ppm and the trans isomer displaying a methyl resonance at 0.88 ppm. The mixture of dimethylhydrazones 240 and 241 was metallated using butyllithium in THF at 0° C ; the lithiated hydrazones were then alkylated with the iodide 11 in the presence of 6 5  D M P U at 30° C. Curiously, a single stereoisomer 242 was isolated, in 60% yield; according to the chemical shift of the angular methyl group (0.88 ppm), it was trans-fused. While it seemed 83  probable that alkylation had occurred to orient the side chain axially,  this was not established until  later equilibration of the keto alkenyl iodide 244 (vide infra). At this early stage in the synthesis, an unforeseen disparity arose between the behaviour of the model systems studied earlier (see Section 2.2) and that of the bicyclic substrate 242.  It  proved impossible to hydrolyze the dimethylhydrazone function of 242 without concomitant protiodestannylation. With the hope that an alkenyl iodide function would better support the conditions of the hydrolysis than had the alkenylstannane,  168  a solution of dimethylhydrazone 242  67  was titrated with a solution of iodine in CH2CI2  to generate the iodide 243.  Indeed, the  dimethylhydrazone function of this compound could be hydrolyzed readily under neutral, oxidizing conditions to give the keto alkenyl iodide 244 in 52% yield (from 242). 65  Subjection of 244 to  equilibrating conditions gave a new trans-fused keto alkenyl iodide 245, with the side chain presumably equatorially-oriented. Small amounts of 244 and of the cis-fused isomers were also isolated. Unfortunately, attempts to introduce the methyl group at C9 (cyathane numbering) gave only starting material or mixtures of alkyne and allene products.  It was clear that the  trimethylstannyl group in 242 had to be replaced by one which would withstand the conditions for the hydrolysis of the hydrazone as well as those for the eventual C9 methylation. The obvious choice was the trimethylgermyl group, which offers greater stability than the corresponding trimethylstannyl group while undergoing many similar reactions. Of particular relevance is the 84  potential for the conversion of alkenylgermanes, like alkenylstannanes, to the corresponding iodides.  85  NalCU THF-water-buffer 4:1:1 40 °C  60%  Scheme 43  102  Preparation of the requisite trimethylgermyl analogue 247 of the electrophile 11 was straightforward (Scheme 44).  The alkenylstannane 50  19  underwent transmetallation with  methyllithium at low temperature; addition of trimethylgermanium bromide gave the 63  alkenylgermane 246 in 79% yield. Treatment of 246 with triphenylphosphine diiodide gave the iodide 247 in 95% yield.  OH  SnMe  OH  GeMe  3  50  I  GeMe  3  246  Conditions a:  3  247  1) M e L i , T H F , -78 °C, 30 min, -20 °C, 2.5 h; 2) Me GeBr, r.t. (79%). b: 3  Ph P«I , E t N , C H C 1 , r.t. (95%). 3  2  3  2  2  Scheme 44  The spectral data of the alkenylgermane 246 provided evidence for the conversion of 50 into 246. The protons of the trimethylgermyl group appear in the H N M R spectrum of 246 at 8 !  0.17 ppm (s, 9H). The tin-proton coupling observed in the spectrum of 50 is, of course, absent from that of 246. That the tin-germanium exchange had proceeded with retention of the double bond configuration was confirmed by a nOe experiment: irradiation at 8 1.72, the protons of the vinyl methyl group, resulted in enhancement of the signal at 8 2.51, the allylic methylene protons. The reciprocal enhancement was also observed (please see the Experimental section for details). Similarly, the spectral data of the iodide 247 provided evidence for the conversion of 246 into 247. The O H stretching vibration present in the IR spectrum of 246 at 3331 cm" is absent from 1  the spectrum of 247. In addition, the H N M R spectrum of 247 differs from that of 246 in the !  absence of a signal corresponding to the hydroxyl proton and in the upfield shift of signal corresponding to the homoallylic methylene protons (from 8 3.58 in 246 to 8 3.02 in 247). The trans-fused hydrazone 240 was treated with potassium diisopropylamide in THF at 86  -78° C; addition of the iodide 247 in the presence of H M P A gave the desired alkenylgermane 248  (eq. 12). The stereochemistry at the ring fusion was inferred from the chemical shift of the protons of the angular methyl group in the H N M R spectrum (0.88 ppm). Axial orientation of the side l  chain was expected but not established until later equilibration of the keto alkenylgermane 249 83  (vide infra).  eq.  240  12  248  The spectral data of compound 248 support the proposed structure. In the H N M R J  spectrum of 248, for example, the protons of the angular methyl group appear at 8 0.88, in the 81  range expected for a trans ring fusion.  The protons associated with the hydrazone function  appear at 8 2.37 (s, 6H). A signal at 8 3.53-3.59 (m, 1H) may be assigned to the equatorial proton a to the hydrazone function. '  168 66  The vinyl protons of the exocyclic methylene group  appear at 8 4.64 and 4.66 (broad signals, 2H total) and the vinyl proton of the sidechain appears at 8 5.64 (q, 1H, J = 6.6 Hz). The signal corresponding to the protons of the vinyl methyl group is located at 8 1.63 (d, 3H, J = 6.6 Hz). In general, the crude reaction mixture was not purified but was subjected immediately to the conditions for hydrazone hydrolysis.  65  The keto alkenylgermane 249 was produced in 46% yield  (from 240, eq. 13).  248  249  Evidence for the successful cleavage of the hydrazone function was provided by the presence, in the IR spectrum of 249, of a strong band at 1709 cm" , arising from the ketone 1  carbonyl stretching vibration. The stability of the carbon-germanium bond under the oxidizing conditions was also confirmed by the spectral data of 249: the H N M R spectrum of 249 contains l  a signal corresponding to the protons of the trimethylgermyl group at 8 0.13 (s, 9H). That the stereochemistry at the ring fusion had been unaffected was suggested by the chemical shift of the 81  angular methyl protons, at 8 0.91. 87  When the keto alkenylgermane 249 was subjected to equilibrating conditions, a mixture of isomers was produced, with the major component being a new trans-fused isomer, presumably having the side chain equatorial (250, eq. 14). The yield of the major isomer 250 was 69%; starting material (249) and the two possible cw-fused isomers were recovered in a total of 19% yield.  249  250  There was some doubt as to whether the keto alkenylgermane 250 would undergo methylation exclusively at the desired position under conditions favouring the formation of the kinetic enolate. A single methylated compound 251 was isolated in admirable yield (91%, eq. 15).  91% 250  251  The introduction of the methyl group at the desired position as shown in 251 was confirmed in the following manner: a H M Q C experiment showed a correlation between a signal at 8 2.44 in the *H N M R spectrum of 251 and a signal at 8 53.7 in the  1 3  C N M R spectrum. The  signal at 8 53.7 had been assigned to the unique methine carbon in the product as a result of both its chemical shift and its negative phase in an A P T spectrum. There would be only one methine carbon in the product regardless of which regioisomer was formed. The signal at 8 2.44, therefore, was assigned to the unique methine proton in the product. The signal at 8 2.44 appears as a sharp doublet of doublets (1H, J = 11.9 Hz, 3.5 Hz). This pattern is consistent only with the regioisomer in which the methine proton is the (axial) angular proton. Had methylation occurred at the angular position, none of the protons in the product would be expected to have such an appearance in the *H N M R spectrum (that is, a doublet of doublets with one large (axial-axial) coupling constant and one small (axial-equatorial) one). Indeed, the signal corresponding to the methine proton in that regioisomer would be expected to be a complicated one. A nOe experiment further established the fJ-stereochemistry of the new methyl group: irradiation at 8 1.17, the protons of the methyl group, resulted in enhancement of the signal at 8 2.44, the angular proton. The reciprocal enhancement was also observed (please see the Experimental section for details). The trans-fusion of the bicyclic system in 251 was suggested by the chemical shift of the angular methyl protons, at 8 0.86. Iododegermylation was readily accomplished employing N-iodosuccinimide in CH C1 at 0 2  2  88  °C.  Keto alkenylgermane 251 was converted to the corresponding keto alkenyl iodide 238 in 13  69% yield (eq. 16). The transformation produced characteristic changes in the  C NMR  spectrum. For example, while the resonance corresponding to the alkenyl carbon bonded to germanium in 251 appears at 8 143.5, the resonance corresponding to the alkenyl carbon bonded to iodine in 238 appears at 8 103.0.  68  106  With the keto alkenyl iodide 238 in hand, the formation of the five-membered ring could be attempted. Thus, treatment of 238 with butyllithium in THF at -78 °C followed by an aqueous workup gave a single angular allylic alcohol 237 in 87% yield (eq. 17). While the stereochemistry of the new ring fusion was not unambiguously determined to be cis, the assignment could be made with some confidence as a result of the model studies, in which the presence of the C9 methyl group (cyathane numbering) resulted in the exclusive formation of ds-fused angular allylic alcohols (see Section 2.2).  eq. 17  238  237  The IR spectrum of 237 contains a strong absorption at 3748 cm" , arising from the O H 1  stretching vibration. In the H N M R spectrum, the hydroxyl proton appears as a singlet at 8 1.17 l  1  which exchanges with D 0 . The 2  3  C N M R spectrum contains a resonance at 8 81.5,  corresponding to the carbinol carbon. The key step in the preparation of the advanced intermediate 236 in the proposed route to sarcodonin G (40) involved the [2,3]-Wittig rearrangement of the angular allylic alcohol 237 according to the Still-Mitra protocol. It was feared that the considerable steric congestion at the hydroxyl group in 237 might make formation of the intermediate tributylstannylmethyl ether difficult. In fact the ether was readily generated by treatment of the alcohol with potassium hydride  107 in  THF  at  room  temperature,  followed  by  addition  of  18-crown-6  and  iodomethyl(tributyl)stannane. The tributylstannylmethyl ether was not isolated but was treated in situ with butyllithium, upon which [2,3]-sigmatropic rearrangment of the intermediate oxycarbanion occurred.  Following workup, the homoallylic alcohol 236 was isolated in 88%  yield (eq. 18). No formation of the methyl ether of 237, nor of the [1,2]-Wittig rearrangement product, was observed. These side products had resulted in significantly decreased yields of the desired products in the model studies (see Section 2.2). The relative configuration of the newly-formed stereocenter was assigned based upon the well-established stereochemical features of the [2,3]-Wittig rearrangement. The rearrangement process is a suprafacial one, with the migrating group (the oxycarbanion) remaining at all times associated with the same face of the n system.  18  CH OH 2  1) KH, THF, r.t. 2) 18-crown-6; ICH SnBu 3) BuLi, -78°C 10 min, 0°C 10 min, r.t. 10 min 2  3  eq. 18  88% 237  236  Evidence for the formation of 236 was furnished by the spectral data of that compound. The IR spectrum displays an absorption at 3338 cm" , arising from the O H stretching vibration. In 1  the H N M R spectrum of 236, the hydroxyl proton appears as an exchangeable signal at 5 1.17 J  (dd, J = 7.6, 4.3 Hz). The region of the spectrum associated with vinyl protons contains only the overlapping multiplets due to the exocyclic methylene protons (8 4.64-4.68). The protons of the secondary methyl group appear as a doublet at 8 0.96 (3H, J = 6.8 Hz). As an advanced intermediate in the synthesis of sarcodonin G (40), compound 236 contains all four of the stereocenters of the natural product with the correct relative configurations, as well as the complete A B ring system.  108 2.3.5 Conclusions and Future Work  A route to the C19-oxygenated cyathane sarcodonin G (40) was proposed. The route is based upon a key sequence involving butyllithium-mediated cyclization of the keto alkenyl iodide 238 followed by Still-Mitra [2,3]-Wittig rearrangement of the resulting angular allylic alcohol 237 (Scheme 45). The key sequence was successfully executed, providing the homoallylic alcohol 236 in which the A B ring system has been constructed and all four stereocenters present in the target molecule have been established with the correct relative configurations.  238  237  236  Conditions: a: B u L i , THF, -78 °C (87%). b: K H , THF, r.t.; 18-crown-6; I C H S n B u ; BuLi, 2  3  -78 °C 10 min, 0 °C 10 min, r.t. 10 min (88%). Scheme 45  The completion of the total synthesis of sarcodonin G (40) is presently underway in our laboratories. Adaptation of the cyclization-[2,3]-Wittig strategy to encompass the total synthesis of other C19-oxygenated cyathane natural products is also possible.  The preparation of 236 from the trans-fused hydrazone 240 is summarized in Scheme 46.  238  237  236  Conditions a: 1) K D A , THF, -78 °C; 2) H M P A ; 247. b: NaI0 , THF-water-buffer, 40 °C (46% 4  from 240).  c: K O B u , B u O H , 30 °C (69%). d: 1) E t N L i , THF, -78 °C 10 min, 0 °C l h ; 2) l  l  2  M e l , 0 °C to r.t. (91%). e: NIS, C H C 1 , 0 °C (69%). f: B u L i , T H F , -78 °C (87%). g: 1) 2  2  K H , T H F , r.t.; 2) 18-crown-6; I C H S n B u ; 3) BuLi, -78 °C 10 min, 0 °C 10 min, r.t. 10 min 2  3  (88%).  Scheme 46  110  Chapter 3 Experimental  3.1 General Experimental  3.1.1 Data acquisition and presentation; experimental techniques  Proton ( H) nuclear magnetic resonance (NMR) spectra were recorded on a Bruker model 1  WH-400 (400 MHz) or AMX-500 (500.2 MHz) spectrometer using deuteriochloroform (CDC1 ) 3  or pyridine-ds as the solvent. CDCI3 was passed through a short column of dry activated basic aluminum oxide, which had been oven-dried (-120 °C) and cooled in a desiccator prior to use. Pyridine-d was purchased in 2 mL ampules from the Aldrich Chemical Co. Chemical shifts (8 5  values) are given in parts per million (ppm) from tetramethylsilane and were measured relative to the signal of CHCI3 (8 7.24 ppm) or to the furthest downfield signal of pyridine-ds (8 8.71 ppm). Coupling constants (7 values) are given in Hertz (Hz). The tin-proton coupling constants (7s -n) n  are given as the average of the  1 1 7  S n and  n 9  S n values. The multiplicity, number of protons,  coupling constants and assignments (where known) are given in parentheses following the chemical shift. Abbreviations used are: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.  Carbon ( C) N M R spectra were recorded on a Varian model XL-300 spectrometer (75.2 13  MHz), a Bruker model AM-400 spectrometer (100.6 M H z ) or a Bruker model A M X - 5 0 0 spectrometer (125.8 MHz) using CDCI3 as the solvent. Chemical shifts (8 values) are given in ppm from tetramethylsilane and were measured relative to the signal of CDC1 (8 77.0 ppm). 3  Attached proton tests (APT) were recorded along with the broadband-decoupled spectra; signals  Ill  with a negative phase (corresponding to carbons bearing an odd number of protons) are so indicated following the chemical shift.  Infrared (IR) spectra were recorded on a Perkin Elmer 1710 Fourier transform spectrophotometer with internal calibration, either as neat films between NaCl plates (liquid samples) or as K B r pellets (solid samples). Only selected absorption data are given for each compound.  Low and high resolution mass spectra were recorded on a Kratos M S 50 mass spectrometer with electron impact source, or on either a Kratos M S 80 or a Nermag RIO-10 C Quadrupole mass spectrometer equipped for desorption chemical ionization using C H or N H . The molecular ion 4  3  (M+) mass is given unless otherwise noted.  Elemental analyses were performed on a Carlo Erba C H N model 1106 or a Fisons E A model 1108 elemental analyzer.  Melting points (mp) were measured on a Fisher-Johns melting point apparatus and are uncorrected. Distillation temperatures refer to the temperature of the air bath during bulb-to-bulb (Kugelrohr) distillations.  Unless otherwise stated, all reactions were carried out under an atmosphere of dry argon using glassware that had been oven-dried (-120 °C) and/or flame-dried. Glass syringes, stainless steel needles and Teflon  cannulae used to handle anhydrous solvents and reagents were oven-  dried (-120 °C), cooled in a desiccator and flushed with argon prior to use. Plastic syringes were flushed with argon prior to use. Gas-tight microliter syringes (Hamilton series 1700) were stored in a desiccator and flushed with argon prior to use.  Thin layer chromatography (TLC) was performed using aluminum-backed silica gel 60 F254 plates (E. Merck, type 5554, thickness 0.2 mm). Visualization of the chromatograms was accomplished using ultraviolet light (254 nm) followed by heating the plate after staining with either an aqueous solution of ammonium molybdate (5% ammonium molybdate w/v and 10% H2SO4  v/v in water) or an ethanolic solution of anisaldehyde (5% anisaldehyde v/v and 5% H S 0 2  4  89  v/v in EtOH). Flash column chromatography  was performed using 230-400 mesh silica gel (E.  Merck, silica gel 60). Radial chromatography was carried out on a Chromatotron® model 7924 90  using plates coated with silica gel (E. Merck, silica gel 60 PF254, with gypsum as a binder) to an approximate thickness of 1, 2 or 4 mm. Short columns used for filtration were packed with Florisil® (F101-500, 100-200 mesh). Gas-liquid chromatography (GLC) was performed on a Hewlett-Packard model 5880A or 5890 gas chromatograph. Both chromatographs were equipped with flame-ionization detectors and fused silica columns (Hewlett-Packard HP-5), -25 m x 0.20 mm, coated with 5% phenylmethylsilicone.  Cold temperatures were maintained with the following baths: 0 °C, ice-water; -20 °C, aqueous C a C l / C 0 (27 g C a C l per 100 mL water); -78 °C, dry ice-acteone. 2  2  2  3.1.2 Solvents and reagents  The solvents and reagents mentioned below were prepared, purified and/or dried using standard procedures.  91  A l l other solvents and reagents were commercially available and were used  without further purification. Petroleum ether refers to a hydrocarbon mixture with bp 35-60 °C.  C H and C H C 1 were distilled from C a H under an atmosphere of dry argon. THF and 6  6  2  2  2  D M E were distilled from sodium benzophenone ketyl, also under an atmosphere of dry argon.  1 Triethylamine, diisopropylamine, diethylamine, H M P A and D M P U were distilled from CaH . 'Butanol was also distilled from CaH . These were stored under an atmosphere of argon in 2  2  Sure/Seal bottles (Aldrich Chemical Co.).  Solutions of methyllithium (as a complex with LiBr) in E t 0 and of butyllithium in hexanes 2  were obtained from the Aldrich Chemical Co. and were standardized by the procedure of Kofron and Baclawski.  92  Trimethylgermanium bromide was obtained from Organometallics Inc. and was distilled under argon, bulb-to-bulb, from C a H and used immediately. 2  Methyl iodide was dried and traces of acid were removed from it by passing it through a short column of oven-dried (-120 °C) activated basic aluminum oxide immediately before use.  Potassium hydride was obtained as a 35% suspension in mineral oil from the Aldrich Chemical Co. It was rinsed free of oil with dry T H F and the T H F was then removed under a stream of dry argon.  Iodine was sublimed, and was stored no longer than three months.  37  PCC on alumina was prepared according to the method of Cheng.  Calculations were  based on an activity of 1.2 mmol of oxidant per g of reagent. 18-Crown-6 was purified as its complex with C H C N .  9 1  3  The phosphate buffer (pH 7.2) was prepared from ACS reagent-grade K H P 0 and NaOH 2  in A S T M reagent grade 1 water and was obtained from the Aldrich Chemical Co.  4  114 Aqueous ammonium chloride-ammonium hydroxide ( N H 4 C I - N H 4 O H ) (pH ~8) was prepared by the addition of 50 mL of concentrated aqueous ammonium hydroxide to 950 mL of a saturated aqueous ammonium chloride solution.  Argon was dried by bubbling it through concentrated drying tube packed with K O H and Drierite®.  H2SO4  and then passing it through a  1 3.2 A Cyclopentenone Annulation Sequence Employing (Z)-l-Bromo-3-iodo-2-butene (9)  3.2.1 Alkylation of P-Keto Esters: General Procedure 1.  9  25 n=l 26 n=2 27 n=3  To a stirred solution-suspension of NaH (1.1 eq) in dry D M E (volume calculated to give a 93  reaction mixture -0.15 M in the P-keto ester) at 0 °C was added the freshly distilled P-keto ester, rinsing with small portions of dry D M E . After the mixture had been stirred for an hour at room temperature, freshly distilled (Z)-l-bromo-3-iodo-2-butene (9) (1.1 eq) was added, again rinsing 5  with small portions of dry D M E . The reaction mixture was stirred overnight at room temperature and then quenched with wet Et20 (volume equal to the volume of the reaction mixture). Saturated aqueous NH C1 (volume twice the volume of the reaction mixture) was added; in some cases water 4  was added in small amounts to dissolve any salts. The aqueous phase was extracted three times with E t 0 (each time with a volume twice the volume of the reaction mixture) and then the 2  combined organic extracts were dried over anhydrous N a S 0 . The crude material was purified by 2  4  flash column or radial chromatography using an appropriate solvent system, followed by bulb-tobulb distillation, to give the alkylated P-keto ester.  Preparation of P-Keto Ester 25.  O C0 Me 2  22  25  Following general procedure 1, methyl 2-oxocyclopentanecarboxylate (22) was alkylated with the following quantities of reagents and solvents: NaH, 48.7 mg (2.03 mmol); D M E , 9 mL; methyl 2-oxocyclopentanecarboxylate (22), 262 mg (1.84 mmol); D M E , 2 mL; (Z)-l-bromo-3iodo-2-butene (9), 529 mg (2.03 mmol); D M E , 1 mL. The crude material was purified by radial chromatography (2 mm silica gel plate, 5:1 hexane-EtOAc) and distillation (140 °C / 0.53 Torr) to give 529 mg (89%) of the alkylated P-keto ester 25 as a colourless oil.  IR (neat): 1754, 1729, 1650, 1434, 1290, 1229, 1164, 1125, 1014, 846, 815, 554  !  era" . 1  H N M R (400 M H z , CDC1 ) 8: 1.94-2.09 (overlapping multiplets, 3H), 2.25-2.54 (overlapping 3  multiplets, 7H, including br d at 2.49, 3H, J = 1.2 Hz, C=CMe), 2.69 (br dd, 1H, 7 = 14.7, 6.7 Hz, one of C = C H C H ) , 3.71 (s, 3H, OMe), 5.37 (ddq, 1H, J = 6.7, 6.7, 1.2 Hz, C=CHCH ). 2  1 3  2  C N M R (75.2 M H z , CDC1 ) 5: 19.6, 32.4, 33.8 (-ve), 37.9, 40.1, 52.6 (-ve), 59.7, 104.8, 3  130.3 (-ve), 171.3, 214.2.  Exact mass calcd f o r d i H 0 I : 323.0145. Found: 323.0137. 1 5  3  Anal, calcd for C H 0 I : C 41.01, H 4.69,1 39.39. Found: C 41.14, H 4.73,1 39.17. n  1 5  3  1 Preparation of P-Keto Ester 26.  I  Following general procedure 1, methyl 2-oxocyclohexanecarboxylate (23) was alkylated with the following quantities of reagents and solvents: NaH, 36.8 mg (1.53 mmol); D M E , 6 mL; methyl 2-oxocyclohexanecarboxylate (23), 218 mg (1.39 mmol); D M E , 2 mL; (Z)-l-bromo-3iodo-2-butene (9), 400 mg (1.53 mmol); D M E , 1 mL. The crude material was purified by radial chromatography (2 mm silica gel plate, 6:1 hexane-EtOAc) and distillation (110 °C / 0.8 Torr) to give 389 mg (83%) of the alkylated P-keto ester 26 as a colourless oil.  IR (neat): 1714, 1651, 1451, 1205, 1138, 847, 816 cm" . 1  !  H N M R (400 M H z , CDC1 ) 5: 1.45-1.80 (overlapping multiplets, 4H), 1.93-2.05 (m, 1H), 3  2.41-2.51 (overlapping multiplets, 7H, including br d at 2.47, 3H, J= 1.2 Hz, C=CMe), 2.62 (ddq, 1H, J= 15.2, 6.5, 1.4 Hz, one of C = C H C H ) , 3.72 (s, 3H, OMe), 5.35 (ddq, 1H, J = 2  6.5, 6.5, 1.2 Hz, C = C H C H ) . 2  1 3  C N M R (75.2 M H z , CDC1 ) 5: 22.4, 27.4, 33.9 (-ve), 35.6, 40.9, 41.6, 52.5 (-ve), 60.8, 3  104.0, 130.3 (-ve), 171.9, 207.4.  Exact mass calcd for C H 0 I : 336.0222. Found: 336.0216. 1 2  1 7  3  Anal, calcd for C H 0 I : C 42.87, H 5.10,1 37.75. Found: C 42.97, H 5.07,137.58. 1 2  1 7  3  118 Preparation of (3-Keto Ester 27.  I  24  27  Following general procedure 1, methyl 2-oxocycloheptanecarboxylate (24) was alkylated with the following quantities of reagents and solvents: NaH, 561 mg (23.4 mmol); D M E , 100 mL; methyl 2-oxocycloheptanecarboxylate (24), 3.61 g (21.2 mmol); D M E , 20 mL; (Z)-l-bromo-3iodo-2-butene (9), 5.96 g (22.8 mmol); D M E , 18 mL. The crude material was purified by flash column chromatography (240 g of silica gel, 10:1 pentane-EtOAc) and distillation (110 °C / 0.3 Torr) to give 6.94 g (93%) of the alkylated P-keto ester 27 as a low-melting colourless crystalline solid (mp 43-44 °C from pentane).  IR (KBr): 1734, 1703, 1657, 1435, 1202, 1146, 903, 531 cm" . 1  B N M R (400 M H z , CDC1 ) 6:  l  3  1.30-1.41 (m, 1H), 1.49-1.76 (overlapping multiplets, 6H),  1.98-2.08 (m, 1H), 2.35-2.45 (overlapping multiplets, 5H, including br d at 2.41, 3H, 7 = 1.4 Hz, C=CMe), 2.53-2.60 (m, 1H), 2.68 (ddq, 1H, 7 = 14.9, 5.4, 1.5 Hz, one of 0 = C H C H ) , 2  3.64 (s, 3H, OMe), 5.27 (ddq, 1H, 7 = 5.4, 5.4, 1.4 Hz, C = C H C H ) . 2  1 3  C N M R (75.2 M H z , CDC1 ) 5: 24.8, 25.8, 29.9, 32.2, 33.9 (-ve), 41.8, 41.9, 52.4 (-ve), 3  62.6, 104.2, 130.6 (-ve), 172.4, 208.8.  Exact mass calcd for C H 0 I : 351.0457. Found: 351.0464. 1 3  1 9  3  Anal, calcd for C i H 0 I : C 44.59, H 5.47,1 36.24. Found: C 44.73, H 5.49,136.40. 3  1 9  3  1 3.2.2 Butyllithium-mediated Cyclization of Keto Alkenyl Iodides: General Procedure 2.  25 26 27  n=l n=2  28 29  n=3  30  To a stirred solution of the keto alkenyl iodide in dry THF (-0.05 M ) at -78 °C was added a solution of butyllithium in hexanes (1.2-1.9 eq). The reaction mixture was stirred one hour at -78 °C and then quenched with a 5% aqueous solution of NaHC0 (volume equal to the volume of 3  the reaction mixture) and warmed to room temperature. The aqueous phase was extracted three times with Et20 (each time with a volume equal to the volume of the reaction mixture). The combined organic extracts were washed with brine (volume four times the volume of the reaction mixture) and dried over anhydrous Na2SC>4. The crude material was purified by flash column or radial chromatography using an appropriate solvent system to give the angular allylic alcohol.  120 Preparation of Angular Allylic Alcohol 28.  Following general procedure 2, the angular allylic alcohol 28 was prepared using the following quantities of reagents and solvents: keto alkenyl iodide 25, 108 mg (0.335 mmol); THF, 7 mL; butyllithium (1.42 M , 1.3 eq), 258 uL. The crude material was purified by flash column chromatography (4 g of silica gel, 2:1 hexanes-EtOAc) to give a 35.6 mg (54%) of the alcohol 28 as a colourless oil.  IR (neat): 3459, 1729, 1646, 1452, 1278, 1202, 1122, 1025, 805 cm" . 1  !  H N M R (400 M H z , CDC1 ) 8: 3  1.25-1.40 (m, 1H), 1.63-1.77 (overlapping multiplets, 6H,  including m at 1.66, 3H, C=CMe), 1.93-2.00 (m, 1H), 2.08 (ddq, 1H, J= 17.1, 2.2, 2.2 Hz, H -), 2.36-2.47 (m, 1H), 2.54 (s, 1H, exchanges with D 0 , OH), 3.01 (ddq, 1H, J= 17.1, 2.2, a  2  2.2 Hz, H ) , 3.71 (s, 3H, OMe), 5.40 (br signal, 1H, C=CH). a  The assignment of the signal at 8 2.08 to H > was confirmed with the help of a C O S Y a  experiment. Selected data are shown in Table 8. The C O S Y experiment also helped to confirm the presence of the vinyl methyl group at 8 1.66, within a set of overlapping multiplets.  121 Table 8. Selected COSY Data for Angular Allylic Alcohol 28. Chemical  Correlations  Assignment  Shift (ppm) 2.08  H -  H  3.01  H  H ' (2.08), C=CH (5.40), C=CMe (1.66)  5.40  1 3  a  a  (3.01), C=CH (5.40), C=CMe (1.66)  a  a  H  C=CH  C N M R (75.2 M H z , CDC1 ) 5: 3  a  (3.01), H . (2.08), C=CMe (1.66) a  11.9 (-ve), 23.2, 37.4, 38.0, 43.0, 52.0 (-ve), 60.2, 97.2,  126.1 (-ve), 140.9, 176.4.  Exact mass calcd for C „ H 0 : 196.1100. Found: 196.1096. 1 6  3  Preparation of Angular Allylic Alcohol 29.  Following general procedure 2, the angular allylic alcohol 29 was prepared using the following quantities of reagents and solvents: keto alkenyl iodide 26, 25 mg (0.073 mmol); THF, 1.5 mL; butyllithium (1.3 M , 1.2 eq), 68 U.L. The crude material was purified by flash column chromatography (3 g of silica gel, 3:1 pentane-Et 0) to give 8.3 mg (66%) of the alcohol 29 as a 2  colourless oil.  IR (neat): 3464, 1721, 1659, 1441, 1245, 1149, 1019 cm" . 1  H N M R (400 M H z , CDC1 ) 5: 0.99-1.10 (m, 1H), 1.32-1.48 (overlapping multiplets, 4H),  l  3  1.65-1.69 (m, 3H, C=CMe), 1.72-1.85 (m, 1H), 1.85-1.94 (m, 1H), 1.95-2.04 (overlapping multiplets, 2H, including dd at 2.02, 1H, J = 16.0, 2.7 Hz, H >), 2.61 (s, 1H, exchanges with a  D 0 , OH), 2.87 (dd, 1H, J= 16.0, 1.9 Hz, H ) , 3.71 (s, 3H, OMe), 5.52 (br dd, 111, J = 2.7, 2  a  1.9 Hz, C=CH).  The assignment of the signal at 8 2.02 to H < was confirmed with the help of a C O S Y a  experiment. Selected data are shown in Table 9.  Table 9. Selected C O S Y Data for Angular Allyhc Alcohol 29 in CDC1 . 3  Chemical  Assignment  Correlations  Shift (ppm) 1.65-1.69  C=CMe  H  a  (2.87), H - (2.02), C=CH (5.52)  2.02  H '  H  a  (2.87), C=CH (5.52), C=CMe (1.65-1.69)  2.87  H  H . (2.02), C=CH (5.52), C=CMe (1.65-1.69)  5.52  !  a  a  C=CH  a  a  H  a  (2.87), H ' (2.02), C=CMe (1.65-1.69) a  H N M R (400 M H z , py-d ) 8: 1.02-1.06 (m, 1H), 1.29-1.31 (m, 1H), 1.37-1.44 (m, 1H), 1.645  1.74 (m, 1H), 1.73-1.77 (m, 3H, C=CMe), 1.77-1.93 (m, 1H), 1.95-2.10 (overlapping multiplets, 3H), 2.20-2.23 (m, 1H), 3.37-3.40 (m, 1H, H ) , 3.68 (s, 3H, OMe), 5.51 (br signal, a  1H, C=CH), 5.78 (br s, 1H, OH).  The location of the signal corresponding to H > was established through a C O S Y a  experiment. Selected data are shown in Table 10.  123 Table 10. Selected C O S Y Data for Angular Allylic Alcohol 29 in Pyridine-d . 5  Chemical  Correlations  Assignment  Shift (ppm) 1.73-1.77  C=CMe  H  a  (3.37-3.40), H . (2.00), C=CH (5.51)  a'  H  a  (3.37-3.40), C=CH (5.51), C=CMe (1.73-  2.00  H  a  1.77) H - (2.00), C=CH (5.51), C=CMe (1.73-1.77)  3.37-3.40 5.51  a  C=CH  H  a  (3.37-3.40), H - (2.00), C=CMe (1.73a  1.77)  1 3  C N M R (75.2 M H z , CDC1 ) 5: 3  12.3 (-ve), 22.2, 23.0, 32.1, 35.7, 39.8, 51.7 (-ve), 55.8,  83.4, 126.9 (-ve), 142.5, 176.7.  Exact mass calcd for C H i 0 : 210.1256. Found: 210.1250. 1 2  Anal, calcd for  C12H18O3:  8  3  C 68.54, H 8.63. Found: C 68.55, H 8.68.  Preparation of Angular AllyUc Alcohol 30.  30  Following general procedure 2, the angular allylic alcohol 30 was prepared using the following quantities of reagents and solvents: keto alkenyl iodide 27, 4.00 g (11.4 mmol); THF,  230 mL; butyllithium (1.5 M , 1.9 eq), 18 mL. The crude material was purified by flash column chromatography (240 g of silica gel, 5:1:2 pentane-EtOAc-CH Ci2). The material obtained was 2  recrystallized from pentane at low temperature to give 1.74 g (68%) of the alcohol 30 as irregular colourless crystals with a melting point of 52-53 °C.  IR (KBr): 3494, 1718, 1675, 1448, 1266, 1200, 1165, 1006, 812, 459 cm" . 1  !  H N M R (400 M H z , CDC1 ) 8: 0.83-0.94 (m, 1H), 1.15-1.50 (overlapping multiplets, 3H), 3  1.62-1.64 (m, 3H, C=CMe), 1.50-1.83 (overlapping multiplets, 4H), 1.95-2.02 (m, 1H), 2.052.17 (overlapping multiplets, 2H), 2.79 (s, 1H, exchanges with D 0 , OH), 3.05 (ddq, 1H, J = 2  17.2, 2.3, 2.3 Hz, H ) , 3.69 (s, 3H, OMe), 5.44-5.48 (m, 1H, C=CH). a  The location of the signal corresponding to H > was established through a C O S Y a  experiment. Selected data are shown in Table 11.  Table 11. Selected COSY Data for Angular Allylic Alcohol 30 in CDC1 . 3  Chemical  Assignment  Correlations  Shift (ppm) 1.62-1.64 2.14  C=CMe  H  a  (3.05), H ' (2.14), C=CH (5.44-5.48)  a'  H  a  (3.05), C=CH (5.44-5.48), C=CMe (1.62-  H  a  1.64) 3.05  H  a  H ' (2.14), C=CH (5.44-5.48), C=CMe (1.62a  1.64) 5.44-5.48  C=CH  H  a  (3.05), H - (2.14), C=CMe (1.62-1.64) a  *H N M R (400 M H z , py-d ) 8: 1.08-1.48 (overlapping multiplets, 4H), 1.53-1.82 (overlapping 5  multiplets, 6H, including m at 1.74, 3H, C=CMe), 2.01-2.18 (overlapping multiplets, 2H), 2.24-  125 2.30 (m, 1H), 2.38-2.42 (m, 1H), 3.49-3.51 (m, 1H, H ) , 3.54 (s, 3H, OMe), 5.51 (br signal, a  1H, C=CH). No signal arising from the hydroxyl proton was observed.  The location of the signal corresponding to H < was established through a C O S Y a  experiment. Selected data are shown in Table 12. The C O S Y experiment also helped to confirm the presence of the vinyl methyl group at 8 1.74, within a set of overlapping multiplets.  Table 12. Selected C O S Y Data for Angular Allylic Alcohol 30 in Pyridine-d . 5  Chemical  Assignment  Correlations  Shift (ppm) 1.74  C=CMe  H  a  (3.49-3.51), H - (2.12), C=CH (5.51)  2.12  H -  H  a  (3.49-3.51), C=CH (5.51), C=CMe (1.74)  3.49-3.51  H  H - (2.12), C=CH (5.51), C=CMe (1.74)  5.51  1 3  a  a  a  a  C=CH  H  C N M R (75.2 M H z , CDC1 ) 8: 3  a  (3.49-3.51), H - (2.12), C=CMe (1.74) a  12.1 (-ve), 23.6, 24.0, 30.6, 35.3, 36.0, 40.7, 51.9 (-ve),  60.0, 89.3, 126.5 (-ve), 142.3, 177.0.  Exact mass calcd for  C13H20O3:  224.1412. Found: 224.1414.  Anal, calcd for CnHaoOs: C 69.61, H 8.99. Found: C 69.75, H 8.88.  126 3.2.3 Oxidation of Angular Allylic Alcohol 28 with PCC: Formation of Epoxides 70 and 71.  28  70  71  The angular allylic alcohol 28 (30.4 mg, 0.155 mmol) was added as a solution in dry CH2CI2 (0.9 mL) to a stirred solution-suspension of PCC (134 mg, 0.620 mmol) and NaOAc (50.8 mg, 0.620 mmol) in dry C H C 1 (1 mL) at room temperature. After 18 h, E t 0 (2 mL) was 2  2  2  added and the mixture was filtered through Florisil® (3 g), eluting with E t 0 and then EtOAc. The 2  E t 0 fractions contained predominantly the epoxy ketone 70 and the EtOAc fractions contained 2  predominantly the epoxy alcohol 71.  A complete separation of the two compounds was  accomplished by radial chromatography (1 mm silica gel plate, 5:1 hexane-EtOAc) to give, after removal of the solvents under reduced pressure (water aspirator then vacuum pump, 0.3 Torr) and further purification, 10.6 mg of the epoxy ketone 70 as a colourless oil (bulb-to-bulb distillation, 64-70 °C / 80 u.) and 10.1 mg of the epoxy alcohol 71 as a white solid (recrystallization from pentane, mp 28-29 °C).  The spectral data derived from the epoxy ketone 70 are as follows:  IR (neat): 1741, 1448, 1380, 1248, 1200, 1166, 1077, 821, 456 cm" . 1  J  H N M R (400 M H z , CDC1 ) 8: 1.33 (s, 3H, Me on epoxide), 1.41-1.51 (m, 1H), 1.71-1.79 (m, 3  1H), 1.82-1.92 (m, 1H), 2.05-2.18 (m, 1H), 2.32 (d, 1H, J= 19.3 Hz, H - ) , a  2.28-2.38  (overlapping multiplets, 2H), 2.91 (d, 1H, J = 19.3 Hz, H ) , 3.77 (s, 3H, OMe). a  1 3  C N M R (100.6 M H z , CDC1 ) 8: 9.2 (-ve), 20.8, 21.1, 33.9, 42.6, 51.5, 52.5 (-ve), 65.6, 3  80.6, 173.6, 208.6.  127 Exact mass calcd for C i i H 0 : 210.0892. Found: 210.0887. 1 4  Anal, calcd for  4  C 62.85, H 6.71. Found: C 62.58, H 6.95.  C11H14O4:  The spectral data derived from the epoxy alcohol 71 are as follows:  IR (KBr): 3442, 1727, 1438, 1280, 1208, 1119, 1067, 847 cm" . 1  :  H N M R (400 M H z , CDC1 ) 5: 1.42 (s, 3H, Me on epoxide), 1.63 (dd, 1H, J= 14.8, 1.0 Hz, 3  H -)> 1.71-1.86 (overlapping multiplets, 4H), 1.95-2.10 (overlapping multiplets, 2H), 2.80 (d, a  1H, J= 14.8 Hz, H ) , 3.26 (br signal, 1H, H on epoxide), 3.70 (s, 3H, OMe), 5.04 (s, 1H, a  exchanges with D 0 , OH). 2  1 3  C N M R (100.6 M H z , CDC1 ) 5: 12.4 (-ve), 23.5, 35.4, 36.4, 36.7, 52.2 (-ve), 54.7, 60.1 (3  ve), 67.0, 92.6, 177.7.  Exact mass calcd for C H 0 : 212.1048. Found: 212.1046. n  1 6  4  Anal, calcd for C H 0 : C 62.25, H 7.60. Found: C 61.95, H 7.67. u  1 6  4  128 3.2.4 Cr(VI) Oxidative Rearrangement of Angular Allylic Alcohols: General Procedure 3.  O  29 30  32 33  n=2 n=3  To a stirred solution of the angular allylic alcohol in dry CH2CI2 (~0.1 M) at room temperature was added PCC on alumina (2.2-3 eq). The reaction mixture was stirred overnight, during which time the suspension turned from bright orange to dark brown. The reaction mixture was then stirred with Et20 and filtered. Flash column chromatography followed by bulb-to-bulb distillation provided the bicyclic enone.  Preparation of Bicyclic Enone 32.  32  Following general procedure 3, the oxidative rearrangement of the angular allylic alcohol 29 was accomplished with the following quantities of reagents and solvents: angular allylic alcohol 29, 15.3 mg (0.073 mmol); C H C 1 , 1.2 mL; P C C on alumina, 133 mg (0.160 mmol). 2  2  The reaction mixture was stirred with Et20 (-10 mL) and then the mixture was filtered through a Pasteur pipette filled with Florisil®, eluting with E t 0 and then EtOAc. The crude material was 2  129 purified by flash column chromatography (2 g of silica gel, 7:2 pentane-EtiO) and distillation (86 °C / 0.6 Torr) to give 13.3 mg (88%) of the enone 32 as a colourless oil.  IR (neat): 1736, 1709, 1655, 1439, 1383, 1302, 1232, 1173, 1060, 1018 cm" . 1  H N M R (400 M H z , CDC1 ) 8:  l  3  1.17-1.35 (overlapping multiplets, 2H), 1.47-1.56 (m, 1H),  1.67-1.76 (overlapping multiplets, 4H, including s at 1.71, 3H, C=CMe), 1.93-2.00 (m, 1H), 2.16-2.25 (overlapping multiplets, 2H, including d at 2.22, 1H, 7 = 18.5 Hz, H «), 2.55-2.66 a  (overlapping multiplets, 2H, including d at 2.59, 1H, 7= 18.5 Hz, H ) , 2.78-2.82 (m, 1H), 3.68 a  (s, 3H, OMe).  1 3  C N M R (100.6 M H z , CDC1 ) 8: 7.9 (-ve), 23.3, 26.5, 27.3, 37.6, 46.8, 52.40 (-ve), 52.45, 3  134.8, 172.6, 174.3, 206.4.  Exact mass calcd for C H 0 : 208.1100. Found: 208.1097. 1 2  1 6  3  Anal, calcd for C H i 0 : C 69.21, H 7.74. Found: C 68.88, H 7.79. 1 2  6  3  Preparation of Bicyclic Enone 33.  O  33 Following general procedure 3, the oxidative rearrangement of the angular allylic alcohol 30 was accomplished with the following quantities of reagents and solvents: angular allylic  alcohol 30, 52.5 mg (0.234 mmol); C H C 1 , 3 mL; P C C on alumina, 600 mg (0.72 mmol). The 2  2  reaction mixture was stirred with E t 0 (-25 mL) and then the mixture was filtered through a short 2  column of Florisil (20 g), eluting with E t 0 and then EtOAc. The crude material was purified by 2  flash column chromatography (10 g of silica gel, 3:1 pentane-Et 0) and distillation (70 °C / 0.3 2  Torr) to give 35.3 mg (68%) of the enone 33 as a colourless oil.  IR (neat): 1736, 1707, 1647, 1451, 1318, 1241, 1168, 1083 cm" . 1  ]  H N M R (400 M H z , CDC1 ) 8: 1.20-1.30 (m, 1H), 1.36-1.47 (m, 1H), 1.48-1.65 (overlapping 3  multiplets, 3H), 1.70 (s, 3H, C=CMe), 1.72-1.82 (overlapping multiplets, 2H), 2.20 (d, 1H, 7 = 18.1 Hz, H . ) , 2.24-2.31 (m, 1H), 2.36-2.44 (m, 1H), 2.68-2.76 (m, 1H), 2.81 (d, 1H, 7 = a  18.1 Hz, H ) , 3.67 (s, 3H, OMe). a  1 3  C N M R (75.2 M H z , CDC1 ) 8: 8.1 (-ve), 24.5, 27.2, 29.2, 30.1, 36.2, 47.5, 52.4 (-ve), 55.6, 3  137.8, 174.0, 174.7, 206.8.  Exact mass calcd for C i H 0 : 222.1256. Found: 222.1251. 3  1 8  3  Anal, calcd for C H 0 : C 70.24, H 8.16. Found: C 70.13, H 8.24. 1 3  1 8  3  3.3 r2.31-Wittig Rearrangement of Angular Allylic Alcohols  3.3.1 Preparation of (Z)-5-Iodo-3-trimethylstannyl-2-pentene (10).  Solid I (6.16 g, 24.3 mmol) was added to a stirred solution of Ph P (6.36 g, 24.2 mmol) 2  3  in dry C H C 1 (200 mL) at room temperature. 2  The faintly yellow mixture was stirred for 10  2  minutes. A solution of freshly distilled (Z)-3-trimethylstannyl-3-penten-l-ol (49) (5.49 g, 22.0 19  mmol) in dry C H C 1 (22 mL) and dry triethylamine (3.4 mL, 24 mmol) was added. The orange 2  2  mixture was stirred for 4 h and then poured into petroleum ether [volume equal to the volume of the reaction mixture; on large scale, approximately 75% of the C H C 1 was removed first (water 2  2  aspirator)]. The slurry was filtered through a column of Florisil (-20 g per g of 49), eluting with petroleum ether. The solvent was removed under reduced pressure (water aspirator) and the residual material was subjected to bulb-to-bulb distillation (60-65 °C / 0.35 Torr) to give 6.42 g (81%) of (Z)-5-iodo-3-trimethylstannyl-2-pentene (10) as a colourless oil.  IR (neat): 1620, 1446, 1426, 1239, 1165, 770, 526 cm" . 1  J  H N M R (400 M H z , CDC1 ) 8: 0.18 (s, 9H, 7 . = 52.8 Hz, SnMe ), 1.69 (d, 3H, / = 6.5 Hz, 2  3  Sn  H  3  C = C H M e ) , 2.69 (t, 2H, J = 7.8 Hz, 7 . . = 25.6 Hz, C H C H I ) , 3.05 (t, 2H, J = 7.8 Hz, 3  Sn  CH CH2l), 6.11 (q, 1H, J = 6.5 Hz,  3  2  1 3  / „-H S  H  2  2  = 135.2 Hz, C=CHMe).  C N M R (75.2 M H z , CDC1 ) 8: -8.5 (-ve), 6.5, 19.6 (-ve), 44.2, 137.7 (-ve), 143.4. 3  Exact mass calcd for C H i I 7  4  120  S n (M -Me): 344.9164. Found: 344.9150. +  Anal, calcd for C H I S n : C 26.78, H 4.78,1 35.37. Found: C 26.95, H 4.79,1 35.22. 8  17  3.3.2 Preparation of (£)-5-Iodo-3-triraethylstannyl-2-pentene (11).  OH SnMe  SnMe  3  50  3  11  (£)-3-trimethylstannyl-3-penten-l-ol (50) was converted into the corresponding iodide iy  11 in a manner similar to that described above for the conversion of 49 into 10, with the following quantities of reagents and solvents: Ph P, 26.5 g (101 mmol); C H C 1 , 842 mL; I , 3  2  2  2  25.6 g (101 mmol); (£>3-trimethylstannyl-3-penten-l-ol (50), 21.0 g (84.3 mmol); CH C1 , 80 19  2  2  mL; triethylamine, 14.1 mL (101 mmol). The crude material was purified by distillation (106-110 °C / 0.7 Torr) to give 24.2 g (80%) of (E)-5-iodo-3-trimethylstannyl-2-pentene  (11) as a  colourless oil.  IR (neat): 1609, 1426, 1243, 1166, 768, 526 cm' . 1  !  H N M R (400 M H z , CDC1 ) 5: 0.12 (s, 9H, 7 . = 52.4 Hz, SnMe ), 1.68 (d, 3H, J = 6.5 Hz, 2  3  Sn  C = C H M e ) , 2.85 (br t, 2H, J = 7.9 Hz, 7 . 3  Sn  H  H  3  = 28.9 Hz, C H C H I ) , 3.05 (t, 2H, J = 7.9 Hz, 2  2  C H C H I ) , 5.80 (qt, 1H, J = 6.5, 1.1 Hz, 7 -H = 75.2 Hz, C=CHMe). 3  2  1 3  2  Sd  C N M R (75.2 M H z , CDC1 ) 8: -9.3 (-ve), 4.7, 14.5 (-ve), 36.8, 137.3 (-ve), 143.3. 3  Exact mass calcd for C H I 7  14  120  S n (M -Me): 344.9162. Found: 344.9162. +  Anal, calcd for C H I S n : C 26.78, H 4.78,1 35.37. Found: C 26.89, H 4.67,1 35.22. g  17  133 3.3.3 Preparation of Dimethylhydrazone 126.  125  126  To a stirred solution of the dimethylhydrazone 125  (4.60 g, 19.1 mmol) in dry THF  (100 mL) at -78 °C was added a solution of butyllithium in hexanes (1.6 M , 14 mL). The mixture was warmed to 0 °C and then stirred for 1 h. Dry D M P U (10.4 mL) was added, followed by a solution of freshly distilled (Z)-5-iodo-3-trimethylstannyl-2-pentene (10) (10.4 g, 29.1 mmol) in dry T H F (10 mL). The mixture was then heated to 35 °C for 1.5 h. Aqueous N H C 1 - N H 0 H 4  4  (pH ~8, volume equal to the volume of the reaction mixture) was added and the THF was removed (water aspirator). The remaining material was diluted with E t 0 (volume twice the volume of the 2  reaction mixture) and the layers were separated. The aqueous layer was extracted three times with E t 0 (each time with a volume twice the volume of the reaction mixture) and the combined ethereal 2  layers were washed with water (each time with a volume twice the volume of the reaction mixture) and dried over anhydrous M g S 0 . The solvent was removed under reduced pressure (water 4  aspirator) and the crude material was used without further purification in the subsequent hydrolysis of the hydrazone function. A small amount of the alkylated dimethylhydrazone 126 was purified for characterization (radial chromatography, 2:1 pentane-Et 0). 2  IR (neat): 1625, 1469, 1122, 769, 525 cm" . 1  !  H N M R (400 M H z , CDC1 ) 6: 0.15 (s, 9H, 3  2  / „-H S  = 52.4 Hz, SnMe ), 0.93 (s, 3H, ketal Me), 3  1.00 (s, 3H, ketal Me), 1.20-1.32 (m, 1H), 1.60-1.69 (overlapping multiplets, 4H, including d at  134 1.68, 3H, J = 6.5 Hz, C=CHMe), 1.71-1.79 (m, 1H), 1.81-1.94 (m, 1H), 1.96-2.04 (m, 1H), 2.14-2.22 (overlapping multiplets, 2H), 2.28-2.39 (overlapping multiplets, 3H), 2.39 (s, 6H, N N M e ) , 2.71-2.80 (m, 1H), 3.40-3.59 (overlapping multiplets, 4H, ketal C H ' s ) , 6.04 (q, 1H, 2  2  J = 6.5 Hz,  1 3  3  7 .H S n  = 141.0 Hz, C=CHMe).  C N M R (75.2 M H z , CDC1 ) 5: -8.4 (-ve), 19.5 (-ve), 22.6 (-ve), 22.76 (-ve), 22.84, 30.2, 3  32.1, 33.0, 36.8, 38.4, 40.3 (-ve), 47.7 (-ve), 70.26, 70.34, 97.1, 134.4 (-ve), 144.9, 169.6.  Exact mass calcd for C H N O 2 1  4 0  2  1 2 0 2  S n : 472.2112. Found: 472.2106.  3.3.4 Preparation of Dimethylhydrazone 127.  127  The alkylated dimethylhydrazone 127 was prepared in a manner similar to that described above for the preparation of 126, using the following quantities of reagents and solvents: dimethylhydrazone 125, 4.60 g (19.1 mmol); THF, 100 mL; butyllithium (1.6 M in hexanes), 17  14 mL; D M P U , 10.4 mL; (£)-5-iodo-3-trimethylstannyl-2-pentene (11), 10.3 g (28.6 mmol); THF, 10 mL.  IR (neat): 1636, 1469, 1123, 913, 768, 735, 525 cm" . 1  !  H N M R (400 M H z , CDC1 ) 5: 0.07 (s, 9H, / . 2  3  S n  H  = 51.9 Hz, SnMe ), 0.95 (s, 3H, ketal Me), 3  0.97 (s, 3H, ketal Me), 1.21-1.36 (m, 1H), 1.54-1.78 (overlapping multiplets, 5H, including d at 1.68, 3H, J = 6.4 Hz, C=CHMe), 1.80-1.90 (m, 1H), 2.03-2.11 (m, 1H), 2.11-2.18 (m, 1H), 2.26-2.39 (overlapping multiplets, 4H), 2.41 (s, 6H, N N M e ) , 2.75-2.82 (m, 1H), 3.45-3.54 2  (overlapping multiplets, 4H, ketal C H ' s ) , 5.63 (q, 1H, J= 6.5 Hz, V S n . H = 80.4 Hz, C=CHMe). 2  1 3  C N M R (75.2 M H z , CDC1 ) 8: -9.3 (-ve), 14.2 (-ve), 22.67 (-ve), 22.71 (-ve), 22.8, 30.2, 3  31.6, 32.1, 38.0, 40.5 (-ve), 47.7 (-ve), 70.3, 70.4, 97.2, 134.2 (-ve), 145.0, 169.4. "missing" quaternary signal belongs to the dimethylsubstituted carbon of the ketal moiety.  Exact mass calcd for C i H N O 2  4 0  2  1 2 0 2  S n : 472.2112. Found: 472.2116.  The  136 3.3.5 Preparation of Keto Alkenylstannane 128.  128  The alkylated dimethylhydrazone 126 (~9 g, 19 mmol) was dissolved in a stirred mixture of 4:1:1 THF-water-phosphate buffer [THF, 67 mL; water, 17 mL, phosphate buffer (pH 7.2), 17 mL]. Solid NalCu (16.4 g, 76.7 mmol) was added in one portion. The mixture was warmed to 40 °C for 5 h. Saturated aqueous NH C1 (volume equal to the volume of the reaction mixture) was 4  added and the layers were separated. The aqueous layer was extracted three times with Et 0 (each 2  time with a volume equal to the volume of the reaction mixture). The combined ethereal layers were dried over anhydrous MgSCv The crude material remaining after removal of the solvent under reduced pressure (water aspirator) was purified by flash column chromatography (1 kg of silica gel, 4:1 pentane-Et 0) to give the ketone 128 as a colourless oil (6.38 g, 78% from the 2  dimethylhydrazone 125).  It was possible to remove trace amounts of solvent by bulb-to-bulb  distillation (160-162 °C / 0.35 Torr) but in general distillation was accompanied by a considerable amount of decomposition.  IR (neat): 1718, 1623, 1121, 770, 525 cm" . 1  *H N M R (400 M H z , CDC1 ) 8: 0.16 (s, 9H, 7 . = 52.8 Hz, SnMe ), 0.98 (overlapping s, 3H, 2  3  Sn  H  3  3H, ketal Me's), 1.08-1.19 (m, 1H), 1.68 (d, 3H, J = 6.5 Hz, C = C H M e j ,  1.71-1.88  (overlapping multiplets, 2H), 2.06-2.21 (overlapping multiplets, 2H), 2.21-2.32 (overlapping  137 multiplets, 2H), 2.38-2.62 (overlapping multiplets, 4H), 3.53 (br signal, 4H, ketal C H ' s ) , 6.04 2  (q, 1H, J = 6.5 Hz, V „-H = 146.2 Hz, C=CHMe). S  1 3  C N M R (75.2 M H z , CDC1 ) 8: -8.5 (-ve), 19.5 (-ve), 22.6 (-ve), 29.3, 30.2, 32.1, 37.1, 37.4, 3  37.6, 44.2 (-ve), 70.3, 70.7, 96.5, 134.8 (-ve), 144.4, 211.8.  Exact mass calcd for C H 5 O 3 S n (M +H): 431.1608. Found: 431.1621. 120  19  +  3  Anal, calcd for C H 0 S n : C 53.18, H 7.98. Found: C 53.31, H 8.06. 1 9  3 4  3  3.3.6 Preparation of Keto Alkenylstannane 129.  129  The ketone 129 was prepared in a manner similar to that described above for the preparation of 128,  using the following quantities of reagents and solvents:  alkylated  dimethylhydrazone 127, ~9 g (19 mmol); THF, 67 mL; water, 17 mL; phosphate buffer (pH 7.2), 17 mL; N a I 0 , 16.4 g (76.7 mmol). 4  The crude material was purified by flash column  chromatography (1 kg of silica gel, 4:1 pentane-Et 0) to give the ketone 129 as a colourless oil 2  (6.26 g, 76% from the dimethylhydrazone 125).  IR (neat): 1714, 1613, 1120, 918, 767, 735, 526 cm" . 1  138 *H N M R (400 M H z , CDC1 ) 8: 0.08 (s, 9H, 7 . = 52.0 Hz, SnMe ), 0.95 (s, 3H, ketal Me), 2  Sn  3  H  3  1.02 (s, 3H, ketal Me), 1.12-1.24 (m, 1H), 1.67 (d, 3H, J = 6.4 Hz, C=CHMe), 1.68-1.85 (overlapping multiplets, 2H), 2.23-2.32 (overlapping multiplets, 4H), 2.44-2.58 (overlapping multiplets, 4H), 3.47-3.60 (overlapping multiplets, 4H, ketal C H ' s ) , 5.66 (q, 1H, J = 6.4 Hz, 2  VS„-H  1 3  =  7  9  2  H z  ' C=CHMe).  C N M R (75.2 M H z , CDC1 ) 8: -9.3 (-ve), 14.2 (-ve), 22.5 (-ve), 22.7 (-ve), 28.9, 29.4, 30.3, 3  31.2, 37.1, 38.7, 44.5 (-ve), 70.4, 70.7, 96.5, 134.8 (-ve), 144.5, 211.7.  Exact mass calcd for Ci9H35O  Anal, calcd for  C19H34O3S11:  120 3  Sn(M +H): 431.1608. Found: 431.1610. +  C 53.18, H 7.98. Found: C 53.60, H 7.96.  3.3.7 Preparation of Ketone 130.  O  130  A solution of the ketone 128 (586 mg, 1.36 mmol) in dry T H F (3 mL) was added to a stirred solution-suspension of K O ' B u (167 mg, 1.49 mmol) in dry T H F (10 mL). Dry H M P A (0.9 mL, 5 mmol) was added and the mixture was heated to 60 °C for 4 h and then cooled to room temperature. Methyl iodide (1.3 mL, 21 mmol) was added as a solution in dry T H F (1 mL); a thick white precipitate formed immediately. The reaction mixture was stirred overnight at room  temperature. The mixture was then poured into water (volume equal to the volume of the reaction mixture). The aqueous phase was extracted three times with E t 0 (each time with a volume equal 2  to the volume of the reaction mixture). Each organic phase was washed twice with water (each time with a volume equal to the volume of the reaction mixture). The combined organic phases were dried over anhydrous MgSCv The crude material obtained after removal of the solvent under reduced pressure (water aspirator) was purified by flash column chromatography (400 g of silica gel, 15:1 pentane-EtOAc ) to give 400 mg (66%) of the ketone 130 as a colourless oil.  IR (neat): 1711, 1623, 1108, 768, 525 cm" . 1  H N M R (400 M H z , CDC1 ) 8: 0.15 (s, 9H, 7 . = 52.4 Hz, SnMe ), 0.96 (s, 3H, ketal Me),  l  2  3  S n  H  3  0.98 (s, 3H, ketal Me), 1.08 (s, 3H, Me a to carbonyl), 1.37-1.46 (m, 1H), 1.65 (d, 3H, J = 6.5 Hz, C=CHMe), 1.67-1.77 (m, 1H), 1.84 (d, 1H, 7 = 14.6 Hz, H ) , 1.87-2.13 (overlapping a  multiplets, 3H), 2.13-2.22 (overlapping multiplets, 2H, including d at 2.19, 1H, J = 14.6 Hz, H - ) , 2.34-2.42 (m, 1H), 2.47-2.58 (m, 1H), 3.43-3.58 (overlapping multiplets, 4H, ketal a  C H ' s ) , 6.01 (q, 1H, J = 6.5 Hz, 2  1 3  3  /  S n  -H  = 145.6 Hz, C=CHMe).  C N M R (75.2 M H z , CDC1 ) 8: -8.4 (-ve), 19.5 (-ve), 22.6 (-ve), 22.7 (-ve), 24.0 (-ve), 30.1, 3  32.4, 34.8, 34.9, 39.9, 42.2, 47.0, 70.3, 70.5, 96.8, 134.9 (-ve), 144.2, 214.7.  Exact mass calcd for C i H O 9  3 3  1 2 0 3  S n (M -Me): 429.1452. Found: 429.1444. +  Anal, calcd for C H O S n : C 54.20, H 8.19. Found: C 54.58, H 8.32. 20  36  3  3.3.8 Preparation of Ketone 131.  131  The ketone 131 was prepared in a manner similar to that described above for the preparation of 130, using the following quantities of reagents and solvents: KO Bu, 227 mg (2.02 l  mmol); THF, 10 mL; ketone 129, 581 mg (1.35 mmol); THF, 3 mL; H M P A , 0.9 mL (5 mmol); Mel, 1.3 mL (21 mmol); THF, 1 mL. The reaction mixture was stirred at 40 °C for 20 min. The crude material was purified by flash column chromatography (400 g of silica gel, 4:1 hexanesEt 0) and then radial chromatography (4 mm silica gel plate, 5:1 hexanes-Et 0) to give 342 mg 2  2  (57%) of the ketone 131 as a colourless oil.  IR (neat): 1712, 1614, 1108, 766, 525 cm" . 1  !  H N M R (400 M H z , CDC1 ) 5: 0.07 (s, 9H, 7 -H = 52.2 Hz, SnMe ), 0.96 (s, 3H, ketal Me), 2  3  3  Sn  0.99 (s, 3H, ketal Me), 1.11 (s, 3H, M e a to carbonyl), 1.39-1.49 (m, 1H), 1.63-1.74 (overlapping multiplets, 4H, including d at 1.65, 3H, J = 6.4 Hz, C=CHMe), 1.86 (d, 1H, J = 14.3 Hz, H ) , 1.92-2.23 (overlapping multiplets, 2H, including d at 2.22, 1H, J= 14.3 Hz, H -), a  a  2.18-2.24 (m, 1H), 2.24-2.32 (overlapping multiplets, 2H), 2.35-2.44 (m, 1H), 2.48-2.58 (m, 1H), 3.51-3.55 (overlapping multiplets, 4H, ketal C H ' s ) , 5.62 (q, 1H, J = 6.4 Hz, 7 -H = 79.6 3  2  Hz, C=CHMe).  Sn  141 1 3  C N M R (75.2 M H z , CDC1 ) 5: -9.4 (-ve), 13.9 (-ve), 22.6 (-ve) (two signals superimposed), 3  23.8 (-ve), 26.8, 30.1, 31.7, 34.8, 38.5, 42.8, 47.2, 70.3, 70.5, 96.8, 134.6 (-ve), 144.1, 214.7.  Exact mass calcd for C H 3 3 O 19  120 3  S n (M -Me): 429.1452. Found: 429.1460. +  Anal, calcd for C oH3 0 Sn: C 54.20, H 8.19. Found: C 54.47, H 8.17. 2  6  3  142 3.3.9 Iododestannylation: General Procedure 4.  R=H, Me R'=H, R"=Me; R'=Me, R"=H  To a stirred solution of the keto alkenylstannane in dry C H C 1 (-0.02 M ) at room 2  2  temperature was added, dropwise, a 0.04 M solution of I in dry C H C 1 (slightly more than 1 eq) 2  2  2  until the pink colour of the I persisted in the reaction mixture. The reaction flask was covered 2  with foil. The mixture was stirred a further 10 min and then 0.1 M aqueous Na S C) (volume 2  2  3  equal to the volume of the reaction mixture) was added. The layers were separated. The aqueous layer was extracted with C H C 1 (volume equal to the volume of the reaction mixture). The 2  2  combined organic layers were washed with brine (volume twice the volume of the reaction mixture) and dried over anhydrous M g S 0 . The crude material obtained after removal of the 4  solvent under reduced pressure (water aspirator) was purified by flash column or radial chromatography to give the keto alkenyl iodide.  143 Preparation of Keto Alkenyl Iodide 132.  132  Following general procedure 4, the keto alkenylstannane 128 was converted into the corresponding keto alkenyl iodide 132 with the following quantities of reagents and solvents: alkenylstannane 128, 534 mg (1.24 mmol); CH C1 , 62 mL; 0.04 M I in C H C 1 , 31.1 mL. The 2  2  2  2  2  crude material was purified by radial chromatography (4 mm silica gel plate, 4:1 pentane-Et 0) to 2  give 472.2 mg (97%) of the alkenyl iodide 132 as a colourless oil.  IR (neat): 1714, 1647, 1440, 1279, 1121, 1019, 918 cm" . 1  H N M R (400 M H z , CDC1 ) 8: 0.98 (s, 3H, ketal Me), 0.99 (s, 3H, ketal Me), 1.35-1.47 (m,  l  3  1H), 1.51-1.54 (m, 1H), 1.70 (d, 3H, 7 = 6.3 Hz, C=CHMe), 1.73-1.80 (m, 1H), 1.93-2.04 (m, 1H), 2.23-2.31 (m, 1H), 2.41-2.57 (overlapping multiplets, 6H), 3.50-3.54 (overlapping multiplets, 4H, ketal CH 's), 5.57 (q, 1H, 7 = 6.3 Hz, C=CHMe). 2  1 3  C N M R (75.2 M H z , CDC1 ) 8: 22.1 (-ve), 22.6 (-ve) (two ketal Me's), 28.8, 30.2, 32.1, 37.1, 3  38.0, 42.5, 43.5 (-ve), 70.4, 70.8, 96.4, 110.4, 130.0 (-ve), 211.5.  Exact mass calcd for C H I 0 (M +H): 393.0927. Found: 393.0913. +  1 6  2 6  3  Anal, calcd for C H I 0 : C 48.99, H 6.42,1 32.35. Found: C 48.85, H 6.45,1 32.15. 1 6  2 5  3  Preparation of Keto Alkenyl Iodide 133.  133  Following general procedure 4, the keto alkenylstannane 129 was converted into the corresponding keto alkenyl iodide 133 with the following quantities of reagents and solvents: alkenylstannane 129, 1.60 g (3.73 mmol); C H C 1 2  2>  186 mL; 0.04 M I in C H C 1 , 93 mL. The 2  2  2  crude material was purified by flash column chromatography (100 g of silica gel, 3:1 pentaneEt 0) to give 1.40 g (90%) of the alkenyl iodide 133 as a colourless oil. 2  IR (neat): 1714, 1634, 1440, 1363, 1122, 1040, 1020, 991, 919 cm" . 1  *H N M R (400 M H z , CDC1 ) 8: 0.95 (s, 3H, ketal Me), 0.99 (s, 3H, ketal Me), 1.32-1.43 (m, 3  1H), 1.47-1.57 (m, 1H), 1.61 (d, 3H, J= 7.1 Hz, C=CHMe), 1.66-1.78 (m, 1H), 1.85-1.95 (m, 1H), 2.21-2.32 (m, 1H), 2.32-2.57 (overlapping multiplets, 6H), 3.49-3.56 (overlapping multiplets, 4H, ketal CH 's), 6.21 (q, 1H, J = 7.1 Hz, C=CHMe). 2  1 3  C N M R (75.2 M H z , CDC1 ) 8: 3  16.2 (-ve), 22.5 (-ve), 22.6 (-ve), 28.3, 30.2, 31.6, 35.6,  37.1, 38.7, 43.4 (-ve), 70.4, 70.7, 96.3, 102.6, 136.1 (-ve), 211.6.  Exact mass calcd for C H I 0 : 392.0850. Found: 392.0839. 1 6  2 5  3  Anal, calcd for C i H I 0 : C 48.99, H 6.42,1 32.35. Found: C 49.06, H 6.47,132.30. 6  2 5  3  145 Preparation of Keto Alkenyl Iodide 134.  134  Following general procedure 4, the keto alkenylstannane 130 was converted into the corresponding keto alkenyl iodide 134 with the following quantities of reagents and solvents: alkenylstannane 130, 303 mg (0.681 mmol); CH C1 , 34 mL; 0.04 M I in C H C 1 , 17 mL. The 2  2  2  2  2  crude material was purified by radial chromatography (2 mm silica gel plate, 3:1 pentane-Et 0) to 2  give 275 mg (99%) of the alkenyl iodide 134 as a colourless oil.  IR (neat): 1709, 1648, 1107, 460 cm" . 1  !  H N M R (400 M H z , CDC1 ) 5: 0.96 (s, 3H, ketal Me), 0.98 (s, 3H, ketal Me), 1.10 (s, 3H, Me 3  a to carbonyl), 1.63-1.73 (overlapping multiplets, 4H, including d at 1.68, 3H, / = 6.3 Hz, C=CHMe), 1.86-2.09 (overlapping multiplets, 3H, including br d at 1.90, 1H, J= 14.4 Hz, H ) , a  2.11-2.28 (overlapping multiplets, 3H, including br d at 2.34, 1H, J= 14.4 Hz, H <), 2.39-2.58 a  (overlapping multiplets, 3H), 3.45-3.61 (overlapping multiplets, 4H, ketal CH 's), 5.52 (q, 1H, J 2  = 6.3 Hz, C=CHMe). 1 3  C N M R (75.2 M H z , CDC1 ) 8: 22.1 (-ve), 22.56 (-ve), 22.64 (-ve), 24.0 (-ve), 30.2, 32.5, 3  34.8, 38.6, 40.1, 42.1, 46.6, 70.4, 70.5, 96.6, 110.3, 129.7 (-ve), 214.5.  Exact mass calcd for C H I 0 : 406.1005. Found: 406.0996. 1 7  Anal, calcd for  2 7  C17H27IO3:  3  C 50.25, H 6.70,1 31.23. Found: C 50.34, H 6.76,1 31.11.  Preparation of Keto Alkenyl Iodide 135.  135 Following general procedure 4, the keto alkenylstannane 131 was converted into the corresponding keto alkenyl iodide 135 with the following quantities of reagents and solvents: alkenylstannane 131, 256 mg (0.577 mmol); C H C 1 , 29 mL; 0.04 M I in CH C1 , 14.4 mL. 2  2  2  2  2;  The crude material was purified by radial chromatography (4 mm silica gel plate, 3:1 pentane-Et 0) 2  to give 211 mg (90%) of the alkenyl iodide 135 as a colourless oil.  IR (neat): 1709, 1632, 1107, 522 cm" . 1  J  H N M R (400 M H z , CDC1 ) 5: 0.96 (s, 3H, ketal Me), 0.98 (s, 3H, ketal Me), 1.11 (s, 3H, Me 3  a to carbonyl), 1.57-1.71 (overlapping multiplets, 4H, including d at 1.60, 3H, J - 7.0 Hz, C=CHMe), 1.79-1.94 (overlapping multiplets, 2H, including dd at 1.90, 1H, J= 14.3, 1.7 Hz, H ) , 1.99-2.08 (m, 1H), 2.10-2.26 (overlapping multiplets, 3H, including dd at 2.13, 1H, 7 = a  14.3, 2.3 Hz, H - ) , 2.38-2.57 (overlapping multiplets, 3H), 3.47-3.61 (overlapping multiplets, a  4H, ketal CH *s), 6.16 (q, 1H, J = 7.0 Hz, C=CHMe). 2  1 3  C N M R (75.2 M H z , CDC1 ) 8: 16.0 (-ve), 22.6 (-ve) (two ketal Me's), 23.9 (-ve), 30.1, 31.9, 3  33.5, 34.7, 37.4, 42.3, 46.6, 70.37, 70.45, 96.6, 102.1, 135.6 (-ve), 214.4.  Exact mass calcd for C H I 0 (M +H): 407.1083. Found: 407.1096. +  1 7  2 8  3  Anal, calcd for C H I 0 : C 50.25, H 6.70,1 31.23. Found: C 50.44, H 6.77,1 31.00. 1 7  2 7  3  147 3.3.10 ButyUithium-mediated Cyclization of Keto Alkenyl Iodides: General Procedure 5.  R=H, Me R'=H, R"=Me; R'=Me, R"=H  To a stirred solution of the keto alkenyl iodide in dry THF (~ 0.01 M) at -78 °C was added a solution of butyllithium in hexanes (4 eq). The reaction mixture was stirred for 1.5 h at -78 °C and then poured into water at 0 °C (volume twice the volume of the reaction mixture). The THF was removed (water aspirator) and the residue was diluted with Et20 (volume twice the volume of the reaction mixture). The layers were separated. The aqueous layer was extracted twice with E t 0 (each time with a volume twice the volume of the reaction mixture). The combined ethereal 2  layers were dried over anhydrous N a S 0 or M g S 0 . The crude material obtained after removal of 2  4  4  the solvent under reduced pressure (water aspirator) was purified by flash column or radial chromatography to give the angular allyhc alcohol.  148 Preparation of Angular Allylic Alcohols 138 and 139.  O  O  138  139  Following general procedure 5, the keto alkenyl iodide 132 underwent cyclization to give the diastereoisomeric allylic alcohols 138 and 139 with the following quantities of reagents and solvents: alkenyl iodide 132, 497 mg (1.27 mmol); THF, 125 mL; butyllithium (1.6 M), 3.2 mL. The crude mixture contained the isomeric allylic alcohols 138 and 139 in a ratio of 20:1 (*H N M R in C D ) . A n initial purification (4 mm, 1:1 pentane-Et 0 with 0.05% Et N) gave 138 and 139 as 6  6  2  3  a mixture in 84% yield (285 mg). A second purification (30 g T L C silica, 1:1 pentane-Et 0) gave 2  the major trans-fused alcohol 138 (159 mg, 47%), the minor ds-fused alcohol 139 (3.3 mg, 1%) and a mixture of the two alcohols (78.0 mg, 23%). The trans-fused alcohol 138 was eluted before the ds-fused alcohol 139.  The major trans-fused alcohol 138 could be recrystallized from heptane to give colourless translucent crystals with a melting point of 90 °C. The spectral data derived from 138 are as follows:  IR (KBr): 3494, 1363, 1184, 1140, 1085, 1030, 962, 920 cm" . 1  !  H N M R (400 M H z , CDC1 ) 8: 0.93 (s, 3H, ketal Me), 0.96 (s, 3H, ketal Me), 111 (s, 1H, 3  exchanges with D 0 , OH), 1.39-1.60 (overlapping multiplets, 3H), 1.64 (d, 1H, J =•• 13.0 Hz), 2  1.70-1.81 (overlapping multiplets, 4 H , including ddd at 1.74, 3H, J = 7.3, 1.9, 1.9 Hz,  C = C H M e ) , 1.81-1.91 (ra, 1H), 2.13-2.30 (overlapping multiplets, 4H), 2.34-2.45 (m, 1H), 3.41-3.60 (overlapping multiplets, 4 H , ketal C H ' s ) , 5.34 (qdd, 1H, 7 = 7.3, 2.0, 2.0 Hz, 2  C=CHMe).  1 3  C N M R (75.2 M H z , CDC1 ) 8: 13.5 (-ve), 22.7 (-ve), 22.8 (-ve), 26.2, 28.6, 30.2, 31.2, 3  31.7, 32.1, 46.1 (-ve), 70.1, 70.2, 77.1, 98.4, 118.9 (-ve), 145.2.  Exact mass calcd for C H 6 0 : 266.1882. Found: 266.1884. 16  2  3  Anal, calcd for C i H 0 : C 72.14, H 9.84. Found: C 72.44, H 9.98. 6  2 6  3  The minor c/s-fused alcohol 139 could be recrystallized from heptane to give colourless translucent crystals with a melting point of 130 °C. The spectral data derived from 139 are as follows:  IR (KBr): 3472, 1463, 1369, 1177, 1105, 1043, 1018, 999, 968 cm" . 1  !  H N M R (400 M H z , CDC1 ) 8: 0.92 (s, 3H, ketal Me), 0.97 (s, 3H, ketal Me), 1.58 (s, 1H, 3  exchanges with D 0 , OH), 1.62-1.70 (overlapping multiplets, 2H), 1.79 (ddd, 3H, J = 7.3, 2.1, 2  2.1 Hz, C=CHMe), 1.81-2.04 (overlapping multiplets, 7H), 2.22-2.44 (overlapping multiplets, 2H), 3.40-3.59 (overlapping multiplets, 4H, ketal C H ' s ) , 5.38 (qdd, 1H, J= 7.3, 2.1, 2.1 Hz, 2  C=CHMe).  1 3  C N M R (75.2 M H z , CDC1 ) 8: 13.2 (-ve), 22.7 (-ve), 22.8 (-ve), 26.9, 28.9, 29.3, 30.1, 3  30.3, 30.9, 48.0 (-ve), 69.96, 70.03, 79.1, 97.7, 119.2 (-ve), 145.6.  Exact mass calcd for C H 0 : 266.1882. Found: 266.1875. 1 6  2 6  3  150 Anal, calcd for C H 60 : C 72.14, H 9.84. Found: C 72.37, H 9.88. 16  2  3  Preparation of Angular Allylic Alcohols 140 and 141.  H  140  141  Following general procedure 5, the keto alkenyl iodide 133 underwent cyclization to give the diastereoisomeric allylic alcohols 140 and 141 with the following quantities of reagents and solvents: alkenyl iodide 133, 1.12 g (2.85 mmol); THF, 286 mL; butyllithium (1.50 M), 7.62 mL. The alcohols 140 and 141 were produced in a ratio of 4:1 in the crude mixture ( H N M R , l  CDC1 ). A n initial purification (4 mm, 1:1 pentane-Et20) gave 140 and 141 as a mixture in 78% 3  yield (594 mg). A second purification (150 g, 2:1 pentane-Et20) gave the major trans-fused alcohol 140 (504 mg, 66%) and the minor ds-fused alcohol 141 (61.7 mg, 8%). The trans-fused alcohol 140 was eluted before the ds-fused alcohol 141.  The major traws-fused alcohol 140 could be recrystallized from heptane to produce colourless translucent crystals with a melting point of 111-112 °C. The spectral data derived from 140 are as follows:  IR (KBr): 3483, 1685, 1271, 1136, 1088, 1034, 962, 915 cm" . 1  !  H N M R (400 M H z , CDC1 ) 8: 0.84 (s, 1H, exchanges with D 0 , OH), 0.93 (s, 3H, ketal Me), 3  2  0.95 (s, 3H, ketal Me), 1.42-1.68 (overlapping multiplets, 8H, including br d at 1.56, 3H, 7= 6.6 Hz, C=CHMe), 1.78-1.87 (overlapping multiplets, 2H), 2.13-2.28 (overlapping multiplets, 3H), 2.34-2.44 (m, 1H), 3.41-3.60 (overlapping multiplets, 4H, ketal C H ' s ) , 5.42 (qdd, 1H, J= 6.6, 2  2.5, 2.5 Hz, C=CHMe).  1 3  C N M R (75.2 M H z , CDC1 ) 8: 14.0 (-ve), 22.7 (-ve), 22.8 (-ve), 25.8, 26.6, 28.2, 30.0, 3  30.2, 31.3, 44.4 (-ve), 70.0, 70.2, 76.6, 99.0, 115.5 (-ve), 147.2.  Exact mass calcd for C H 0 : 266.1882. Found: 266.1887. 1 6  2 6  3  Anal, calcd for C H 0 : C 72.14, H 9.84. Found: C 72.47, H 9.64. 1 6  2 6  3  The minor ds-fused alcohol 141 resisted recrystallization; the spectral data were acquired on the viscous oil.  IR (NaCl): 3436, 1681, 1446, 1363, 1100, 1064, 1019, 956 cm" . 1  !  H N M R (400 M H z , CDC1 ) 8: 0.906 (s, 3H, ketal Me), 0.914 (s, 3H, ketal Me), 1.12-1.22 3  (overlapping multiplets, 3H, including s at 1.16, 1H, exchanges with D 0 , OH), 1.28-1.46 2  (overlapping multiplets, 2H), 1.59 (br d, 3H, J = 6.6 Hz, C=CHMe), 1.76 (td, 1H, J= 12.7, 3.8 Hz), 1.86-2.07 (overlapping multiplets, 4H), 2.21-2.40 (overlapping multiplets, 2H), 3.38-3.52 (overlapping multiplets, 4H, ketal CH 's), 5.50 (br q, 1H, / = 6.6 Hz, C=CHMe). 2  1 3  C N M R (75.2 M H z , CDC1 ) 8: 14.4 (-ve), 22.6 (-ve), 22.7 (-ve), 25.3, 26.2, 29.4, 29.7, 3  30.0, 33.4, 44.6 (-ve), 69.8, 70.1, 79.5, 97.5, 117.2 (-ve), 144.8. Exact mass calcd for C H 0 : 266.1882. Found: 266.1884. 1 6  2 6  3  Preparation of Angular Allylic Alcohol 142.  142  Following general procedure 5, the keto alkenyl iodide 134 underwent cyclization to give the allylic alcohol 142 with the following quantities of reagents and solvents: alkenyl iodide 134, 227 mg (0.560 mmol); THF, 50 mL; butyllithium (1.56 M), 1.44 mL. Purification of the crude reaction mixture (2 mm, 3:1 pentane-Et 0) gave the single cw-fused allylic alcohol 142 (colourless 2  translucent crystals from heptane, mp 88-89 °C) in 56% yield (88.2 mg).  IR (KBr): 3484, 1363, 1103, 1082, 1046, 982 cm" . 1  !  H N M R (400 M H z , CDC1 ) 5: 0.89 (s, 3H), 0.91 (s, 3H), 0.99 (s, 3H), 1.23 (m, 1H), 1.46 (d, 3  1H, J= 14.7 Hz), 1.48 (s, 1H, exchanges with D 0 , OH), 1.70-1.93 (overlapping multiplets, 2  7H, including ddd at 1.80, 3H, J= 7.3, 2.1, 2.1 Hz, C=CHMe), 1.97-2.10 (overlapping multiplets, 2H), 2.16-2.27 (m, 1H), 2.27-2.40 (m, 1H), 3.36-3.60 (overlapping multiplets, 4H, ketal C H ' s ) , 5.36 (qdd, 1H, J = 7.3, 2.2, 2.2 Hz, C=CHMe). 2  1 3  C N M R (75.2 M H z , CDC1 ) 8: 12.8 (-ve), 22.6 (-ve), 22.9 (-ve), 23.1 (-ve), 27.8, 29.2, 29.9, 3  30.1, 32.0, 36.7, 45.6, 69.9, 70.0, 81.0, 97.8, 119.6 (-ve), 145.5.  Exact mass calcd for C H 0 : 280.2039. Found: 280.2044. 1 7  2 8  3  153 Anal, calcd for C H 0 : C 72.82, H 10.06. Found: C 72.95, H 10.26. 1 7  2 8  3  Preparation of Angular Allylic Alcohol 143.  143  Following general procedure 5, the keto alkenyl iodide 135 underwent cyclization to give the allylic alcohol 143 with the following quantities of reagents and solvents: alkenyl iodide 135, 102 mg (0.251 mmol); THF, 25 mL; butyllithium (1.56 M), 0.64 mL. Purification of the crude reaction mixture (175 g, 2:1 pentane-Et 0) gave the single ds-fused allylic alcohol 143 (colourless 2  translucent crystals from heptane, mp 80-81 °C) in 72% yield (50.6 mg).  IR (KBr): 3482, 1683, 1463, 1363, 1106, 1056, 989, 734 cm" . 1  :  H N M R (400 M H z , CDC1 ) 5: 0.88 (s, 3H), 0.96 (s, 3H), 0.99 (s, 3H), 1.17 (s, 1H, exchanges 3  with D 0 , OH), 1.43-1.54 (m, 1H), 1.54-1.85 (overlapping multiplets, 10H, including ddd at 2  1.58, 3H, J= 6.7, 1.5, 1.5 Hz, C=CHMe), 2.13-2.26 (m, 1H), 2.26-2.40 (m, 1H), 3.33-3.60 (overlapping multiplets, 4H, ketal CH 's), 5.50 (qdd, 1H, J= 6.7, 2.7, 2.7 Hz, C=CHMe). 2  1 3  C N M R (75.2 M H z , CDC1 ) 8: 14.1 (-ve), 21.5 (-ve), 22.6 (-ve), 22.9 (-ve), 23.9, 30.0, 30.1, 3  30.9, 33.7, 36.9, 44.9, 70.0, 70.1, 80.3, 97.9, 116.7 (-ve), 147.2.  Exact mass calcd for C17H28O3: 280.2039. Found: 280.2033.  Anal, calcd for C  1 7  H280 : 3  C  72.82,  H  10.06. Found:  C  72.83,  H  10.17.  155 3.3.11 [2,3]-Wittig Rearrangement of Angular Allylic Alcohols: General Procedure 6.  CH OH 2  HOj  R  E or Z R=H, Me  To a stirred solution-suspension of K H in dry T H F at room temperature was added a solution of the allylic alcohol in dry THF. After 1-1.5 h (for specific times, see the individual procedures), a solution of 18-crown-6 in dry T H F was added in some cases (alcohols 139,141, 142 and 143); freshly distilled I C H S n B u 2  70e 3  was added as a solution in dry THF. A thick, very  pale yellow precipitate formed after this addition. After 1-3 h (for specific times, see the individual procedures), the reaction mixture was cooled to -78 °C and a solution of butyllithium in hexanes was added. The reaction mixture was allowed to warm slowly from -78 °C to room temperature over the course of 1 h; in some cases the mixture was stirred for a further hour at room temperature (alcohols 142 and 143).  Water was added (volume equal to the volume of the reaction mixture).  The layers were separated and the aqueous layer was extracted three times with E t 0 (each time 2  with a volume approximately three times the volume of the reaction mixture). The combined ethereal layers were dried over anhydrous M g S 0 . The crude material obtained after removal of 4  the solvent under reduced pressure (water aspirator) was purified by radial chromatography; any residual solvent was then removed by vacuum pump (0.3 Torr). In each case, a substantial amount of the methyl ether of the allylic alcohol was produced during the reaction; this sideproduct was eluted ahead of the desired rearrangement product.  156 Preparation of Homoallylic Alcohol 152, from 138.  138  152  153  Following general procedure 6, the allylic alcohol 138 was converted to the homoallylic alcohol 152 with the following quantities of reagents and solvents and the following reaction times: K H (1.2 eq), 25 mg; T H F , 6 mL; allylic alcohol 138, 140 mg; T H F , 2 mL; r.t. 1.5 h; ICH SnBu (3 eq), 680 mg; THF, 2 mL; r.t. 1 h; butyllithium (1.58 M , 4 eq), 1.3 mL. The crude 2  3  material was purified by radial chromatography (2 mm silica gel plate, 4:1 pentane-Et 0) to give 93 2  mg (63%) of the homoallylic alcohol 152 as colourless crystals (mp 84-85 °C, from rc-heptane), and 48 mg (33%) of the methyl ether of the allylic alcohol 138,153, as a colourless oil..  The spectral data derived from the homoallylic alcohol 152 are as follows:  IR (KBr): 3435, 1449, 1363, 1242, 1114, 1087, 1059, 1042, 993, 957 cm" . 1  *H N M R (400 M H z , CDC1 ) 8: 0.93 (s, 3H, ketal Me), 0.95 (s, 3H, ketal Me), 0.95 (d, 3H, J = 3  6.9 Hz, CH(CH3)CH OH), 1.02-1.05 (m, 1H), 1.16-1.33 (overlapping multiplets, 2H), 1.36 (br 2  signal, 1H, exchanges with D 0 , OH), 1.93-2.09 (overlapping multiplets, 2H), 2.11-2.22 (m, 2  1H), 2.24-2.35 (overlapping multiplets, 2H), 2.44 (ddd, 1H, J = 14.2, 4.6, 2.1 Hz), 2.51 (ddd, 1H, J = 12.8, 5.4, 2.9 Hz), 2.64-2.79 (overlapping multiplets, 2H), 3.33-3.56 (overlapping multiplets, 6H, signal changes upon addition of D 0 , ketal C H ' s and CH^OH). 2  2  157 1 3  C N M R (75.2 M H z , CDC1 ) 8: 15.4 (-ve), 21.6, 22.7 (-ve), 22.8 (-ve), 28.8, 29.9, 30.1, 3  32.6, 35.1 (-ve), 40.3, 43.0 (-ve), 66.2, 69.9, 70.1, 98.4, 134.0, 138.7.  Exact mass calcd for C H280 : 280.2039. Found: 280.2038. 17  3  Anal, calcd for C i H 0 : C 72.82, H 10.06. Found: C 72.63, H 10.13. 7  2 8  3  The spectral data derived from the methyl ether 153 are as follows:  IR (neat): 1465, 1361, 1245, 1139, 1086, 1042, 963, 901 cm" . 1  J  H N M R (400 M H z , CDC1 ) 8: 0.90 (s, 3H, ketal Me), 0.97 (s, 3H, ketal Me), 1.45-1.72 3  (overlapping multiplets, 8H, including d at 1.68, 3H, J = 7.2 Hz, C=CHMe), 1.77-1.86 (m, 1H), 2.02-2.08 (m, 1H), 2.10-2.22 (overlapping multiplets, 2H), 2.31-2.46 (overlapping multiplets, 2H), 3.10 (s, 3H, OMe), 3.41-3.57 (overlapping multiplets, 4H, ketal C H ' s ) , 5.41 (br q, 1H, J 2  = 7.2 Hz, C=CHMe).  1 3  C N M R (75.2 M H z , CDC1 ) 8: 13.7 (-ve), 22.6 (-ve), 22.8 (-ve), 25.3, 25.8, 28.7, 30.2, 3  30.9, 31.1, 46.1 (-ve), 49.6 (-ve), 70.0, 70.1, 81.6, 98.5, 119.4 (-ve), 141.1.  Exact mass calcd for C H 0 : 280.2039. Found: 280.2035. 1 7  2 8  3  Anal, calcd for C H 0 : C 72.82, H 10.06. Found: C 72.74, H 9.89. 1 7  2 8  3  158 Preparation of Homoallylic Alcohol 155, from 139.  139  155  156  154  Following general procedure 6, the allylic alcohol 139 was converted to the homoallylic alcohol 155 with the following quantities of reagents and solvents and the following reaction times: K H (1.4 eq), 16 mg; THF, 4 mL; allylic alcohol 139, 76 mg; T H F , 1 mL; r.t. 1 h; 18crown-6 (2 eq), 137 mg; T H F , 1 mL; I C H S n B u 2  3  (2 eq), 246 mg; T H F , 1 mL; r.t. 1.5 h;  butyllithium (1.60 M , 4 eq), 0.71 mL. The crude material was purified by radial chromatography (2 mm silica gel plate, 4:1 pentane-Et 0) to give 40 mg (50%) of the homoallylic alcohol 155 as a 2  colourless crystalline solid (mp 79-81 °C, from n-heptane), and 18 mg (22%) of the methyl ether of the allylic alcohol  139,154, as a colourless oil.  The spectral data derived from the homoallylic alcohol 155 are as follows:  IR (KBr): 3411, 1645 (weak), 1470, 1363, 1242, 1112, 1082, 1060, 1040 cm" . 1  !  H N M R (400 M H z , CDC1 ) 8: 0.91 (d, 3H, J = 6.9 Hz, CH(CH3)CH OH), 0.94 (s, 3H, ketal 3  2  Me), 0.95 (s, 3H, ketal Me), 0.96-0.99 (m, 1H), 1.16-1.29 (overlapping multiplets, 3H, integration decreases upon addition of D 0 , includes OH), 1.92-2.11 (overlapping multiplets, 2  2H), 2.19-2.26 (overlapping multiplets, 2H), 2.30-2.37 (m, 1H), 2.44 (ddd, 1H, J= 14.3, 4.6,  159 2.3 Hz), 2.53 (ddd, 1H, J = 12.8, 5.5, 2.9 Hz), 2.63-2.80 (overlapping multiplets, 2H), 3.353.56 (overlapping multiplets, 6H, signal changes upon addition of D 0 , ketal C H ' s and CH?OH). 2  1 3  C N M R (75.2 M H z , CDC1 ) 8: 3  2  15.0 (-ve), 21.4, 22.7 (-ve), 22.8 (-ve), 29.2, 30.0, 30.2,  32.7, 35.0 (-ve), 40.7, 43.1 (-ve), 65.6, 70.0, 70.1, 98.4, 133.7, 139.6.  Exact mass calcd for C i H 0 : 280.2039. Found: 280.2044. 7  2 8  3  Anal, calcd for C H 0 : C 72.82, H 10.06. Found: C 72.72, H 10.02. 1 7  2 8  3  The spectral data derived from the methyl ether 156 are as follows:  IR (neat): 1471, 1113, 1089, 1059, 978 cm" . 1  :  H N M R (400 M H z , CDC1 ) 8: 0.92 (s, 3H, ketal Me), 0.96 (s, 3H, ketal Me), 1.59-1.73 3  (overlapping multiplets, 6H, including ddd at 1.71, 3H, J = 7.2, 2.0, 2.0 Hz, C=CHMe), 1.781.91 (overlapping multiplets, 4H), 2.02 (dd, 1H, J = 14.2, 4.0 Hz), 2.20-2.28 (overlapping multiplets, 2H), 2.28-2.36 (m, 1H), 3.14 (s, 3H, OMe), 3.38-3.57 (overlapping multiplets, 4H, ketal C H ' s ) , 5.45 (qdd, 1H, J = 7.2, 2.1, 2.1 Hz, C=CHMe). 2  1 3  C N M R (75.2 M H z , CDC1 ) 8: 3  12.7 (-ve), 22.7 (-ve), 22.8 (-ve), 26.3, 28.5, 28.8, 29.7,  30.1, 31.6, 39.4 (-ve), 49.7 (-ve), 69.9, 70.0, 84.2, 97.6, 119.6 (-ve), 140.8.  Exact mass calcd for C H 0 : 280.2039. Found: 280.2042. 1 7  2 8  3  The intermediate tributylstannylmethyl ether in the Still variation of the [2,3]-Wittig rearrangement could also be isolated. The spectral data derived from the tributylstannylmethyl ether 154 are as follows:  160  IR (neat): 1465, 1376, 1113, 1045, 978 cm" . 1  J  H N M R (400 M H z , CDC1 ) 5: 0.83-0.89 (overlapping multiplets, 15H), 0.91 (s, 3H, ketal Me), 3  0.95 (s, 3 H , ketal Me), 1.22-1.33 (overlapping multiplets, 6H), 1.43-1.65 (overlapping multiplets, 10H), 1.69 (ddd, 3H, J = 7.2, 2.0, 2.0 Hz, C=CHMe), 1.74-1.87 (overlapping multiplets, 3H), 1.95-2.03 (m, 1H), 2.16-2.25 (overlapping multiplets, 2H), 2.37-2.45 (m, 1H), 3.35-3.55 (overlapping multiplets, 6H, ketal C H ' s and SnCH 0), 5.43 (qdd, 1H, J = 7.2, 2.1, 2  2  2.1 Hz, C=CHMe).  1 3  C N M R (75.2 M H z , CDC1 ) 5: 8.9, 13.0 (-ve), 13.7 (-ve), 22.8 (-ve), 22.9 (-ve), 26.5, 27.4, 3  28.6, 29.0, 29.2, 30.0, 30.1, 32.0, 38.5 (-ve), 50.4, 69.88, 69.93, 85.5, 97.8, 119.2 (-ve), 141.0.  Exact mass calcd for C 5 H O 2  4 5  1 2 0 3  S n (M -Bu): 513.2391. Found: 513.2384. +  161 Preparation of Homoallylic Alcohol 155, from 140.  CH OH 2  HO,,./ H  140  155  158  Following general procedure 6, the allylic alcohol 140 was converted to the homoallylic alcohol 155 with the following quantities of reagents and solvents and the following reaction times: K H (1.1 eq), 3 mg; THF, 0.75 mL; allylic alcohol 140, 18 mg; T H F , 0.5 mL; r.t. 1 h; I C H S n B u (3 eq), 81 mg; T H F , 0.25 mL; r.t. 1 h; butyllithium (1.58 M , 5 eq), 206 uL. The 2  3  crude material was purified by radial chromatography (2 mm silica gel plate, 2:1 pentane-Et 0) to 2  give 10 mg (53%) of the homoallylic alcohol 155, and 4.7 mg (25%) of the methyl ether of the allylic alcohol 140,158, as a colourless oil.  The spectral data derived from the methyl ether 158 are as follows:  IR (neat): 1683, 1465, 1362, 1247, 1219, 1138, 1079, 961, 900 cm" . 1  *H N M R (400 M H z , CDC1 ) 6: 0.92 (s, 3H, ketal Me), 0.96 (s, 3H, ketal Me), 1.18-1.31 (m, 3  1H), 1.50-1.74 (overlapping multiplets, 8H, including d at 1.59, 3H, J = 6.6 Hz, C=CHMe_), 2.00-2.12 (overlapping multiplets, 2H), 2.12-2.28 (overlapping multiplets, 3H), 2.94 (s, 3H, OMe), 3.40-3.60 (overlapping multiplets, 4H, ketal C H ' s ) , 5.25 (br q, 1H, J = 6.6 Hz, 2  C=CHMe).  162 1 3  C N M R (75.2 M H z , CDC1 ) 8:  13.8 (-ve), 22.7 (-ve), 22.9 (-ve), 23.3, 25.6, 26.4, 28.2,  3  30.2, 30.7, 45.2 (-ve), 48.3 (-ve), 70.0, 70.2, 80.5, 99.0, 117.4 (-ve), 142.2.  Exact mass calcd for C H280 : 280.2039. Found: 280.2038. 17  3  Preparation of Homoallylic Alcohol 152, from 141.  141  152  160  Following general procedure 6, the allylic alcohol 141 was converted to the homoallylic alcohol 152 with the following quantities of reagents and solvents and the following reaction times: K H (1.4 eq), 2 mg; THF, 1 mL; allylic alcohol 141, 11 mg; THF, 0.5 mL; r.t. 1 h; 18crown-6 (2 eq), 19 mg; T H F , 0.5 mL; I C H S n B u (2 eq), 34 mg; T H F , 0.5 mL; r.t. 1.5 h; 2  3  butyllithium (1.60 M , 4 eq), 99 (lL. The crude material was purified by radial chromatography (2 mm silica gel plate, 2:1 pentane-Et 0) to give 7.0 mg (56%) of the homoallylic alcohol 152, and 2  3.0 mg (26%) of the methyl ether of the allylic alcohol 141,160, as a colourless oil.  163 The spectral data derived from the methyl ether 160 are as follows:  IR (neat): 1678, 1446, 1363, 1103, 1041, 959 cm" . 1  !  H N M R (400 M H z , CDC1 ) 5: 0.92 (s, 3H, ketal Me), 0.95 (s, 3H, ketal Me), 1.04-1.12 (m, 3  1H), 1.23-1.34 (overlapping multiplets, 2H), 1.62-1.73 (overlapping multiplets, 4H, including ddd at 1.64, 3H, J = 6.7, 1.5, 1.5 Hz, C=CHMe), 1.94-2.10 (overlapping multiplets, 4H), 2.122.18 (m, 1H), 2.18-2.35 (overlapping multiplets, 2H), 3.01 (s, 3 H , OMe), 3.42-3.51 (overlapping multiplets, 4H, ketal C H ' s ) , 5.42 (qdd, 1H, J= 6.7, 2.6, 2.6 Hz, C=CHMe). 2  1 3  C N M R (75.2 M H z , CDC1 ) 8: 3  14.3 (-ve), 22.7 (-ve), 22.8 (-ve), 24.4, 25.4, 26.2, 29.4,  30.1, 33.8, 42.4 (-ve), 49.0 (-ve), 69.8, 70.2, 84.3, 97.5, 119.5 (-ve), 139.2.  Exact mass calcd for  C17H28O3:  280.2039. Found: 280.2036.  Anal, calcd for C H 0 : C 72.82, H 10.06. Found: C 72.81, H 10.06. 1 7  2 8  3  Preparation of Homoallylic Alcohol 162.  CH OH 2  1 ^-  142  162  163  Following general procedure 6, the allylic alcohol 142 was converted to the homoallylic alcohol 162 with the following quantities of reagents and solvents and the following reaction times: K H (1.5 eq), 2 mg; THF, 0.5 mL; allylic alcohol 142, 11 mg; THF, 0.5 mL; r.t. 1 h; 18crown-6 (2 eq), 20 mg; T H F , 0.5 mL; I C H S n B u 2  3  (4 eq), 66 mg; T H F , 0.5 mL; r.t. 3 h;  butyllithium (1.60 M , 6 eq), 155 | i L . The crude material was purified by radial chromatography (2 mm silica gel plate, 2:1 pentane-Et 0) to give 6.0 mg (52%) of the homoallylic alcohol 162 as a 2  viscous pale yellow oil, and 3.2 mg (28%) of the methyl ether of the allylic alcohol 142,163, as a colourless oil.  The spectral data derived from the homoallylic alcohol 162 are as follows:  IR (neat): 3413, 1650 (weak), 1466, 1364, 1113, 1090, 1039, 1000, 789 c m . 1  U N M R (400 M H z , CDC1 ) 8: 0.85 (s, 3H), 0.91 (d, 3H, J = 6.9 Hz, CH(CH3)CH 0H), 1.04  l  3  2  (s, 3H), 1.06 (s, 3H), 1.17 (d, 1H, J = 13.3 Hz), 1.23-1.34 (overlapping multiplets, 2H, integration decreases upon addition of D 0 , includes OH), 1.41-1.51 (m, 1H), 1.74 (ddd, 1H, J = 2  12.1, 7.6, 1.1 Hz), 2.04-2.21 (overlapping multiplets, 3H), 2.22-2.34 (m, 1H), 2.37 (ddd, 1H, J = 14.1, 4.6, 2.7 Hz), 2.60 (dd, 1H, J = 13.6, 2.7 Hz), 2.68-2.78 (m, 1H), 3.35-3.49 (overlapping multiplets, 4H, signal changes upon addition of D 0 , ketal C H and CH2OH), 3.542  2  3.63 (overlapping multiplets, 2H, ketal CH ). 2  1 3  C N M R (75.2 M H z , CDC1 ) 8: 14.9 (-ve), 19.4, 22.5 (-ve), 23.0 (-ve), 23.3 (-ve), 28.1, 30.1, 3  34.9 (-ve), 36.0, 40.9, 43.6, 47.3, 65.6, 70.08, 70.11, 98.5, 132.2, 143.8.  Exact mass calcd for C H O : 294.2195. Found: 294.2189. 1 8  3 0  3  165 The spectral data derived from the methyl ether 163 are as follows:  IR (neat): 1665 (weak), 1466, 1362, 1107, 1046, 1019, 977, 954, 931, 735 cm" . 1  H N M R (400 M H z , CDC1 ) 8: 0.83 (s, 3H), 1.04 (s, 3H), 1.06 (s, 3H), 1.18-1.26 (overlapping  l  3  multiplets, 2H), 1.39-1.50 (m, 1H), 1.58-1.74 (overlapping multiplets, 2H), 1.75 (ddd, 3H, J = 7.4, 2.0, 2.0 Hz, C=CHMe), 1.99-2.11 (overlapping multiplets, 2H), 2.22-2.40 (overlapping multiplets, 3H), 3.15 (s, 3H, OMe), 3.33-3.42 (overlapping multiplets, 2H, ketal C H ' s ) , 3.532  3.58 (overlapping multiplets, 2H, ketal C H ' s ) , 5.64 (qdd, 1H, J = 7.4, 2.1, 2.1 Hz, C=CHMe). 2  1 3  C N M R [100.6 M H z (75.2 M H z for APT), CDC1 ] 8: 13.5 (-ve), 19.4 (-ve), 22.5 (-ve), 23.0 (3  ve), 23.1, 29.8, 30.1, 32.5, 36.2, 38.3, 48.0, 50.3 (-ve), 70.0, 70.5, 86.3, 97.8, 122.4 (-ve), 139.2.  Exact mass calcd for C i H O : 294.2195. Found: 294.2193. 8  3 0  3  Preparation of Homoallylic Alcohol 165. CH OH 2  o o  143  o  o  165  o'  o  166  Following general procedure 6, the allylic alcohol 143 was converted to the homoallylic alcohol 165 with the following quantities of reagents and solvents and the following reaction times: K H (1.8 eq), 2 mg; THF, 1 mL; allylic alcohol 143, 7.8 mg; THF, 0.5 mL; r.t. 1.5 h; 18crown-6 (2 eq), 15 mg; T H F , 0.5 mL; I C H S n B u (2 eq), 24 mg; T H F , 0.5 mL; r.t. 2.5 h; 2  3  butyllithium (1.58 M , 4 eq), 70 uL. The crude material was purified by radial chromatography (2 mm silica gel plate, 1:1 pentane-Et 0) to give 3.8 mg (46%) of the homoallylic alcohol 165 as a 2  colourless crystalline solid (mp 58-59 °C, from n-heptane), and 1.8 mg (22%) of the methyl ether of the allylic alcohol 143,166, as a colourless oil.  The spectral data derived from the homoallylic alcohol 165 are as follows:  IR (KBr): 3424, 1463, 1364, 1112, 1085, 1038, 1021, 790 cm' . 1  !  H N M R (400 M H z , CDC1 ) 6: 0.85 (s, 3H), 0.97 (d, 3H, J = 6.9 Hz, CH(CH3)CH OH), 1.05 3  2  (s, 3H), 1.08 (s, 3H), 1.10 (br signal, 1H, exchanges with D 0 , OH), 1.17 (d, 1H, J = 13.8 Hz), 2  1.20-1.34 (m, 1H), 1.45-1.56 (m, 1H), 1.73 (ddd, 1H, J = 12.2, 5.7, 3.8 Hz), 2.05-2.26 (overlapping multiplets, 4H), 2.32-2.39 (m, 1H), 2.60 (dd, 1H, J = 13.6, 2.7 Hz), 2.66-2.76 (m, 1H), 3.32-3.48 (overlapping multiplets, 4H, signal changes upon addition of D 0 , ketal C H ' s 2  2  and CEbOH), 3.54-3.63 (overlapping multiplets, 2H, ketal CH 's). 2  1 3  C N M R (75.2 M H z , CDC1 ) 8: 15.4 (-ve), 19.6, 22.5 (-ve), 23.0 (-ve), 24.3 (-ve), 27.9, 30.1, 3  35.0 (-ve), 35.9, 40.6, 43.2, 47.5, 66.2, 70.06, 70.13, 98.5, 132.5, 143.4.  Exact mass calcd for C H O : 294.2195. Found: 294.2196. 1 8  3 0  3  167 The spectral data derived from the methyl ether 166 are as follows:  IR (neat): 1462, 1373, 1108, 1018, 977, 956, 932 cm" . 1  :  H N M R (400 M H z , CDC1 ) 5: 0.82 (s, 3H), 1.03 (s, 3H), 1.11 (s, 3H), 1.26-1.41 (overlapping 3  multiplets, 3H), 1.55-1.74 (overlapping multiplets, 5H, including ddd at 1.65, 3H, 7 = 6.6, 1.6, 1.6 Hz, C=CHMe). 1.89-2.02 (overlapping multiplets, 2H), 2.07 (dd, 1H, 7 = 14.2, 3.2 Hz), 2.11-2.29 (overlapping multiplets, 2H), 2.97 (s, 3H, OMe), 3.31-3.40 (overlapping multiplets, 2H, ketal C H ' s ) , 3.51-3.58 (overlapping multiplets, 2H, ketal C H ' s ) , 5.37 (qdd, 1H, 7 = 6.6, 2  2  2.6, 2.6 Hz, C=CHMe).  1 3  C N M R (75.2 M H z , CDC1 ) 8: 14.1 (-ve), 19.4 (-ve), 22.4 (-ve), 23.0 (-ve), 24.8, 29.7, 30.0, 3  32.7, 36.5, 37.5, 46.5, 48.8 (-ve), 69.9, 70.4, 85.0, 97.8, 120.4 (-ve), 139.4.  Exact mass calcd for C H O : 294.2195. Found: 294.2197. l g  3 0  3  Anal, calcd for C H O : C 73.43, H 10.27. Found: C 75.53, H 10.35. 1 8  3 0  3  168 3.4 Toward the Total Synthesis of Sarcodonin G  3.4.1 Preparation of (£T)-3-Trimethylgermyl-3-penten-l-ol (246).  OH  SnMe  OH  GeMe  3  50  3  246  To a stirred solution of freshly distilled (£)-3-trimethylstannyl-3-penten-l-ol (50)  (9.87  19  g, 39.7 mmol) in dry T H F (200 mL) at -78 °C was added methyllithium (complex with LiBr, 1.5 M in E t 0 , 110 mL). After 30 min, the -78 °C bath was replaced by one at -20 °C. The mixture 2  was stirred for a further 2.5 h. Trimethylgermanium bromide (47.0 g, 238 mmol) was added. The bath was allowed to warm gradually to room temperature. Saturated aqueous N a H C 0 (200 3  mL) was added and the layers were separated. The aqueous layer was extracted with E t 0 (2 x 2  200 mL). The combined ethereal layers were dried over anhydrous M g S 0 . The crude material 4  obtained after removal of the solvent under reduced pressure (water aspirator) was purified by flash chromatography (800 g silica gel, 8:1 pentane-Et 0) to give 5.36 g (79% based on 16% 2  recovered starting material, which was eluted first) of (F)-3-trimethylgermyl-3-penten-l-ol (246) as a colourless oil.  IR (neat): 3331, 1622, 1235, 1043, 824, 754, 597, 570 cm" . 1  J  H N M R (400 M H z , CDC1 ) 8: 0.17 (s, 9H, GeMe ), 1.28 (t, 1H, J = 6.0 Hz, exchanges with 3  3  D 0 , OH), 1.72 (d, 3H, J = 6.6 Hz, C=CHMe). 2.51 (t, 2H, J = 7.0 Hz, C l f c C ^ O H ) , 3.58 (td, 2  2H, J = 7.0, 6.0 Hz; addition of D 0 transforms this signal into a t, J = 7.0 Hz; C H C H O H ) , 2  2  2  5.88 (q, 1H, J = 6.6 Hz, C=CHMe). In nOe difference experiments, irradiation at 8 1.72 resulted  169 in enhancement of the signals at 2.51 and 5.88; irradiation at 8 2.51 resulted in enhancement of the signals at 1.72 and 3.58.  1 3  C N M R (75.2 M H z , CDC1 ) 8: -1.7 (-ve), 14.4 (-ve), 33.4, 61.7, 135.1 (-ve), 138.9. 3  Exact mass calcd for C H 7  7 4 1 5  G e O (M -Me): 189.0335. Found: 189.0336. +  Anal, calcd for C H G e O : C 47.38, H 8.95. Found: C 47.57, H 9.12. 8  18  3.4.2 Preparation of (£)-5-Iodo-3-trimethylgermyl-2-pentene (247).  G e M e  3  247  Triphenylphosphine (6.41 g, 24.4 mmol) was dissolved in dry C H C 1 (200 mL) at room 2  2  temperature. Iodine (6.20 g, 24.4 mmol) was added as a solid. The mixture was stirred for 20 min. (£)-3-Trimethylgermyl-3-penten-l-ol (246) (4.13 g, 20.4 mmol) was added as a solution in dry C H C 1 (20 mL) and dry triethylamine (3.4 mL, 24 mmol). The mixture was stirred 2  2  overnight. Most of the solvent was removed and the residual material was diluted with pentane (100 mL). The mixture was filtered (water aspirator) through a sintered glass funnel (8 cm diameter) containing Florisil  (10 cm depth) on top of a thin layer of Celite . The column was  flushed with a further 600 mL of pentane. The crude material obtained after removal of the solvent under reduced pressure (water aspirator) was purified by distillation (48-54 °C / 0.3 Torr) to give (£)-5-iodo-3-trimethylgermyl-2-pentene (247), a colourless oil (6.02 g, 95%).  170 IR (neat): 1619, 1236, 1168, 823, 756, 597, 567 cm" . 1  ]  H N M R (400 M H z , CDC1 ) 8: 0.18 (s, 9H, GeMe ), 1.67 (d, 3H, J = 6.7 Hz, C=CHMe). 2.78 3  (br  t, 2H,  J = 8.5  Hz,  3  C H 2 C H 2 I ) , 3.02  (t,  2H,  J = 8.5  Hz,  C H 2 C H 2 I ) , 5.82  (qt,  1H,  J = 6.7  Hz,  0.9 Hz, C=CHMe).  1 3  C N M R (75.2 M H z , CDC1 ) 8: -1.8 (-ve), 3.9, 14.4 (-ve), 35.2, 134.5 (-ve), 142.2. 3  Exact mass calcd for C H 7  74 14  G e I (M -Me): 298.9352. Found: 298.9359. +  Anal, calcd for C H G e I : C 30.73, H 5.48. Found: C 30.86, H 5.74. g  17  3.4.3 Preparation of Dimethylhydrazone 240.  0 O  239  240  241  1,1-Dimethylhydrazine (110 mL, 1.45 mol) was added to a stirred solution of the bicyclic 81  ketone 239 (a 78:22 mixture of the trans- and c/s-fused isomers)  (8.59 g, 48.2 mmol) in dry  CeH6 (240 mL). A catalytic amount of (15)-(+)-10-camphorsulfonic acid (1.1 g, 4.7 mmol) was added. The mixture was refluxed for 43 h employing a Dean-Stark trap. A further portion of 1,1dimethylhydrazine (40 mL, 530 mmol) was added and the mixture was refluxed for a further 21 h. The excess 1,1-dimethylhydrazine and much of the solvent were removed by distillation (90 °C, under argon). The crude material obtained after the residual solvent had been removed under  reduced pressure (vacuum pump, 0.3 Torr) was purified by flash chromatography (800 g silica gel, 4:1 pentane-Et20), with the trans-fused hydrazone 240 (5.73 g, 60% based on 11% recovered starting material) being eluted first, followed by a mixture of the two ds-fused hydrazones 241 in a ratio of -2:1 (2.66 g, 28% based on 11% recovered starting material). A l l the hydrazones were isolated as faintly yellow oils.  The spectral data derived from the frans-fused hydrazone 240 are:  IR (neat): 1638, 1446, 1373, 1022, 965, 894 cm" . 1  J  H N M R (400 M H z , CDC1 ) 8: 3  0.88 (s, 3H, angular Me), 1.22-1.26 (m, 1H), 1.54-1.79  (overlapping multiplets, 6H), 1.79-1.89 (overlapping multiplets, 2H), 1.95 (dd, 1H, 7 = 11.7 Hz, 3.7 Hz), 2.09-2.16 (m, 1H), 2.25-2.35 (m, 1H), 2.40 (s, 6H, N N M e ) , 3.26-3.32 (m, 1H), 2  4.63-4.68 (overlapping multiplets, 2H, C=CH ). 2  1 3  C N M R (75.2 M H z , CDC1 ) 8: 3  18.1 (-ve), 22.1, 23.1, 27.4, 28.5, 32.6, 36.5, 43.1, 47.8  (-ve), 52.5 (-ve), 105.3, 157.1, 169.5.  Exact mass calcd for  Anal, calcd for  C14H24N2:  Q4H24N2:  220.1940. Found: 220.1940.  C 76.31, H 10.98, N 12.71. Found: C 76.16, H 10.86, N 12.72.  The spectral data derived from the mixture of ds-fused hydrazones 241 are:  IR (neat): 1635, 1446, 1374, 1021, 967, 892 cm" . 1  !  H N M R (400 M H z , CDC1 ) 8: 1.06 (minor) and 1.08 (major) (s, s, 3H total, angular Me), 1.23  2.5 (overlapping multiplets, 12 H), 2.36 (minor) and 2.41 (major) (s, s, 6H total, NNMe ), 3.072  172 3.17 (major) and 3.19-3.26 (minor) (m, m, 1H total), 4.66-4.73 (overlapping multiplets, 2H, C=CH ). 2  1 3  C N M R (75.2 M H z , CDC1 ) 8: 3  21.6 (major), 22.7 (minor), 23.4 (-ve, major), 23.7 (-ve,  minor), 27.2 (minor), 27.3 (major), 27.4 (minor), 28.7 (major), 31.1 (minor), 31.5 (major), 31.7 (minor), 32.8 (major), 40.7 (minor), 41.0 (major), 47.4 (-ve, major), 47.7 (-ve, minor), 45.5 (ve, minor), 52.8 (-ve, major), 107.2, 155.1 (minor), 155.4 (major), 172.0 (major), 174.4 (minor). The C H signals "missing" from the above list are presumably one minor signal 2  underneath the major signal at 32.8, and one major signal superimposed on the major C H signal at 3  23.4.  Exact mass calcd for C i H N : 220.1940. Found: 220.1935. 4  2 4  2  3.4.4 Preparation of Alkyated Dimethylhydrazone 248.  GeMe  3  248 To a stirred solution of K O ' B u (2.56 g, 22.8 mmol) in dry T H F (60 mL) was added dry diisopropylamine (3.0 mL, 23 mmol). The mixture was cooled to -78 °C. Butyllithium (1.6 M in hexanes, 12 mL) was added and the mixture was stirred for 30 min. The trans-fused hydrazone 240 (2.53 g, 11.5 mmol) was added as a solution in dry T H F (4 mL). After a further period of 1 h, dry H M P A (3.9 mL, 22 mmol) was added, followed by a solution of freshly distilled (E)-5iodo-3-trimethylgermyl-2-pentene (247) (6.02 g, 19.2 mmol) in dry T H F (4 mL). A very thick  cream-coloured precipitate formed immediately. After 1.5 h, aqueous NH4CI-NH4OH (pH ~8, 80 mL) was added. The mixture was allowed to warm to room temperature. Et20 (80 mL) was added and the layers were separated. The aqueous layer was extracted with Et20 (3 x 80 mL). The combined ethereal layers were washed with water (2 x 400 mL) and dried over anhydrous MgSCv The crude material (-4.6 g) obtained after removal of the solvent under reduced pressure (water aspirator then vacuum pump, 0.3 Torr) was used directly in the next step involving hydrolysis of the hydrazone function. A small amount of material was purified for characterization (flash chromatography, silica gel, 30:1 pentane-Et 0). 2  IR (neat): 1636, 1446, 1373, 1235, 1021, 964, 895, 823, 753, 597, 569 cm" . 1  !  H N M R (400 M H z , CDC1 ) 5: 0.13 (s, 9H, GeMe ), 0.88 (s, 3H, angular Me), 1.19-1.31 3  3  (overlapping multiplets, 2H), 1.35-1.44 (overlapping multiplets, 2H), 1.49-1.57 (m, 1H), 1.581.99 (overlapping multiplets, 8H, including d at 1.63, 3H, J = 6.6 Hz, C=CHMe), 2.08-2.36 (overlapping multiplets, 5H), 2.37 (s, 6H, N N M e ) , 3.53-3.59 (m, 1H), 4.64 and 4.66 (br 2  signals, 2H total, C=CH ), 5.64 (q, 1H, J = 6.6 Hz, C=CHMe). 2  1 3  C N M R (75.2 M H z C D C l ) 5: -1.8 (-ve), 13.8 (-ve), 17.8 (-ve), 23.3, 26.0, 27.4, 28.2, 31.6 3  (two signals superimposed), 32.7, 35.6 (-ve), 43.4, 47.4 (-ve), 47.8 (-ve), 105.2, 131.5 (-ve), 143.2, 157.2, 173.8.  Exact mass calcd for C 2H4o GeN : 406.2403. Found: 406.2405. 74  2  2  174 3.4.5 Preparation of Ketone 249.  GeMe  3  249  The crude alkylated dimethylhydrazone 248 (-4.6 g) was dissolved in T H F (60 mL). Water (15 mL) and phosphate buffer (pH 7.2, 15 mL) were added, followed by solid N a I 0 (9.7 4  g, 45 mmol). The stirred mixture was heated to 40 °C. After 72 h, the mixture was allowed to cool to room temperature. Water (100 mL) and E t 0 (100 mL) were added and the layers were 2  separated. The aqueous layer was extracted twice with E t 0 (2 x 100 mL). The combined ethereal 2  layers were dried over anhydrous M g S 0 . After removal of the solvent under reduced pressure 4  (water aspirator), the crude material was purified by flash chromatography (640 g silica gel, 30:1 pentane-Et 0) to give the ketone 249 as a colourless oil (1.88 g, 46% from the dimethylhydrazone 2  240).  IR (neat): 1709, 1639, 1628, 1448, 1376, 1234, 952, 896, 823, 754, 597, 569 cm" . 1  J  H N M R (400 M H z , CDC1 ) 5: 0.13 (s, 9H, GeMe ), 0.91 (s, 3H, angular Me), 1.18-1.30 (m, 3  3  1H), 1.43-1.56 (m, 1H), 1.56-1.69 (overlapping multiplets, 7H, including d at 1.62, 3H, J = 6.6 Hz, C = C H M e ) , 1.82-1.89 (overlapping multiplets, 2H), 1.91-2.00 (m, 1H), 2.01-2.08 (overlapping multiplets, 2H), 2.10-2.40 (overlapping multiplets, 5H), 4.65-4.72 (overlapping multiplets, 2H, C=CH ), 5.67 (q, 1H, J = 6.6 Hz, C=CHMe). 2  175 1 3  C N M R (75.2 M H z , CDC1 ) 5: -1.7 (-ve), 13.9 (-ve), 18.8 (-ve), 20.9, 26.6 (two signals 3  superimposed), 28.2, 31.4, 32.0, 32.2, 44.9, 50.0 (-ve), 54.1 (-ve), 105.8, 132.2 (-ve), 142.4, 155.7, 215.3.  Exact mass calcd for C oH 4 GeO: 364.1822. Found: 364.1818. 74  2  3  Anal, calcd for C2oH GeO: C 66.16, H 9.44. Found: C 66.35, H 9.55. 34  3.4.6 Preparation of Ketone 250.  250  To a stirred solution of K O B u (663 mg, 5.91 mmol) in dry B u O H (20 mL) at 30 °C was l  l  added a solution of the ketone 249 (1.88 g, 5.18 mmol) in dry B u O H (6 mL). The mixture was l  stirred overnight and then cooled to -10 °C. Dilute aqueous HCI (0.2 M , 30 mL) was added, followed by E t 0 (60 mL). The layers were separated. The aqueous layer was extracted with E t 0 2  2  (3 x 30 mL). The combined organic layers were dried over anhydrous M g S 0 . After removal of 4  the solvent under reduced pressure (water aspirator), the crude oil was subjected to flash chromatography (600 g silica gel, 40:1 pentane-Et 0). The desired isomer 250 (trans-fused, with 2  the side chain equatorial) was isolated in 69% yield (1.30 g). A total of 349.3 mg (19%) of starting material (249) and the two ds-fused isomers was also recovered; while these isomers were separable, they were generally recombined and resubmitted to equilibrating conditions.  176 IR (neat): 1713, 1638, 1623, 1447, 1376, 1234, 1098, 940, 895, 823, 754, 597, 568 cm' . 1  H N M R (400 M H z , CDC1 ) 5: 0.15 (s, 9H, GeMe ), 0.86 (s, 3H, angular Me), 1.05-1.17 (m,  l  3  3  1H), 1.17-1.31 (overlapping multiplets, 2H), 1.53-1.69 (overlapping multiplets, 5H, including d at 1.66, 3H, J = 6.6 Hz, C=CHMe), 1.74-1.89 (overlapping multiplets, 3H), 1.90-2.00 (m, 1H), 2.10-2.32 (overlapping multiplets, 7H), 4.69 (br signal, 2H, C=CH ), 5.68 (q, 1H, J = 6.6 Hz, 2  C=CHMe).  1 3  C N M R (75.2 M H z , CDC1 ) 5: -1.7 (-ve), 14.0 (-ve), 18.9 (-ve), 21.0, 26.6, 27.7, 29.0, 30.0, 3  32.2, 36.0, 45.4, 49.7 (-ve), 58.3 (-ve), 105.6, 131.9 (-ve), 143.3, 155.8, 212.7.  Exact mass calcd for C H 1 9  7 4 3 1  G e O (M -Me): 349.1587. Found: 349.1590. +  Anal, calcd for C H G e O : C 66.16, H 9.44. Found: C 66.25, H 9.38. 20  34  3.4.7 Preparation of Keto Alkenylgermane 251.  H  O  251  Butyllithium (1.58 M in hexanes, 1.00 mL) was added to a stirred solution of dry diethylamine (178 U.L, 1.72 mmol) in dry T H F (10 mL) at -78 °C. The mixture was warmed to 0 °C for 10 min and then cooled back to -78 °C. The ketone 250 (480 mg, 1.32 mmol) was added as a solution in dry T H F (3 mL). The mixture was warmed to 0 °C. After 1 h, M e l (1.2 mL, 19  mmol) was added and the mixture was allowed to warm gradually to room temperature over a 1 h period. During this time a heavy white precipitate formed. A total of 1.5 h after the addition of M e l , aqueous N H 4 C I - N H 4 O H (pH ~8, 15 mL) was added and the layers were separated. The aqueous layer was extracted with E t 0 (3 x 20 mL). The combined ethereal layers were dried over 2  anhydrous MgSC>4. After removal of the solvent under reduced pressure (water aspirator), the crude material was purified by radial chromatography (4 mm silica gel plate, 40:1 pentane-Et 0) to 2  give 388 mg (91%, based on 14% recovered starting material, which was eluted second) of the keto alkenylgermane 251 as a colourless oil.  IR (neat): 1704, 1637, 1623, 1457, 1379, 1234, 1118, 896, 824, 754, 597, 569 cm" . 1  H N M R (400 M H z , CDC1 ) 8: 0.17 (s, 9H, GeMe ), 0.86 (s, 3H, angular Me), 1.17 (s, 3H, Me  l  3  3  a to carbonyl), 1.18-1.31 (m, 1H), 1.31-1.48 (overlapping multiplets, 2H), 1.48-1.61 (m, 1H), 1.63-1.79 (overlapping multiplets, 6H, including d at 1.70, 3H, J = 6.6 Hz, C=CHMe), 1.83I . 96 (overlapping multiplets, 2H), 2.04-2.33 (overlapping multiplets, 5H), 2.44 (dd, 1H, J = I I . 9 Hz, 3.5 Hz), 4.68-4.74 (overlapping multiplets, 2H, C=CH ), 5.67 (q, 1H, J = 6.6 Hz, 2  C=CHMe). In nOe difference experiments, irradiation at 8 1.17 resulted in enhancement of the signal at 2.44; irradiation at 8 2.44 resulted in enhancement of the signal at 1.17.  1 3  C N M R (75.2 M H z , CDC1 ) 8: -1.7 (-ve), 14.0 (-ve), 18.7 (-ve), 21.2, 24.1 (a C H and a C H 3  2  3  signal superimposed), 26.7, 32.1, 32.2, 33.4, 38.0, 44.6, 46.8, 53.7 (-ve), 105.7, 131.6 (-ve), 143.5, 155.9, 215.6. In a H M Q C experiment (500.2 M H z H , 125.8 M H z C ) , the signal at 8 1  13  2.44 in the H N M R spectrum was shown to correlate to the signal at 8 53.7 in the l  spectrum.  Exact mass calcd for C H 21  74 36  G e O : 378.1978. Found: 378.1986.  Anal, calcd for C H G e O : C 66.89, H 9.62. Found: C 66.63, H 9.69. 21  36  1 3  C NMR  178 3.4.8 Preparation of Keto Alkenyl Iodide 238.  238  To a stirred solution of the keto alkenylgermane 251 (310 mg, 0.823 mmol) in dry CH C1 2  2  (16 mL) at 0 °C was added solid N-iodosuccinimide (222 mg, 0.988 mmol) in one portion. After 15 min, the mixture was poured into 1:1 Na S 03 (aqueous, 1 M) - N a H C 0 (aqueous, saturated) 2  2  3  (chilled to 0 °C, 16 mL). E t 0 (20 mL) was added and the layers were separated. The aqueous 2  layer was extracted with E t 0 (3 x 20 mL) and the combined organic layers were dried over 2  anhydrous MgSO,*. The crude material remaining after removal of the solvent under reduced pressure (water aspirator) was purified by radial chromatography (4 mm silica gel plate, 40:1 pentane-Et 0) to give the keto alkenyl iodide 238 (219 mg, 69%) as a colourless oil. 2  IR (neat): 1703, 1637, 1448, 1380, 895 cm" . 1  U N M R (400 M H z , CDC1 ) 8: 0.85 (s, 3H, angular Me), 1.17 (s, 3H, M e a to carbonyl), 1.17-  l  3  1.30 (m, 1H), 1.48-1.76 (overlapping multiplets, 9H, including d at 1.67, 3H, J = 7.0 Hz, C=CHMe), 1.81-1.91 (overlapping multiplets, 2H), 2.04-2.17 (overlapping multiplets, 2H), 2.21-2.32 (m, 1H), 2.35-2.51 (overlapping multiplets, 3H), 4.67-4.73 (overlapping multiplets, 2H, C=CH ), 6.18 (q, 1H, J = 7.0 Hz, C=CHMe). 2  1 3  C N M R (75.2 M H z , CDC1 ) 8: 16.2 (-ve), 18.7 (-ve), 21.2, 24.11 (-ve), 26.6, 32.0, 32.1, 3  33.6, 33.8, 37.6, 44.8, 46.4, 53.7 (-ve), 103.0, 105.8, 135.5 (-ve), 155.7, 215.5.  179 Exact mass calcd for C H I O : 386.1107. Found: 386.1101. 18  27  Anal, calcd for C H I O : C 55.96, H 7.04. Found: C 56.09, H 7.01. 18  27  3.4.9 Preparation of Angular Allylic Alcohol 237.  237  Butyllithium (1.56 M in hexanes, 480 u,L) was added to a stirred solution of the keto alkenyl iodide 238 (194 mg, 0.503 mmol) in dry T H F (10 mL) at -78 °C. After 0.5 h, water (10 mL) and E t 0 (10 mL) were added and the layers were separated. The aqueous layer was extracted 2  with E t 0 (3 x 10 mL). The combined ethereal layers were dried over anhydrous M g S 0 . The 2  4  crude material obtained after removal of the solvent under reduced pressure (water aspirator) was purified by radial chromatography (2 mm silica gel plate, 16:1 pentane-Et 0) to give the angular 2  allylic alcohol 237 as a colourless viscous oil (114 mg, 87%).  IR (neat): 3478, 1660, 1635, 1448, 1375, 1034, 1000, 986, 949, 909, 891, 864, 819 cm" . 1  !  H N M R (400 M H z , CDC1 ) 8: 0.92 (s, 3H), 1.01 (s, 3H), 1.17 (s, 1H, exchanges with D 0 , 3  2  OH), 1.15-1.31 (overlapping multiplets, 2H), 1.31-1.42 (overlapping multiplets, 2H), 1.52-1.78 (overlapping multiplets, 7 H , including d at 1.59, 3H, J = 6.7 Hz, C=CHMe.), 1.81-1.95 (overlapping multiplets, 2H), 2.07-2.18 (overlapping multiplets, 2H), 2.27-2.40 (overlapping  180 multiplets, 3H), 4.56 and 4.58 (br signals, 2H total, C=CH ), 5.88 (q, 1H, J = 6.7 Hz, 2  C=CHMe).  1 3  C N M R (75.2 M H z , CDC1 ) 8:  15.2 (-ve), 19.3 (-ve), 19.8 (-ve), 22.6, 26.0, 29.3, 30.7,  3  32.4, 33.4, 36.4, 41.1, 47.0, 50.4 (-ve), 81.5, 104.3, 121.5 (-ve), 149.7, 158.9.  Exact mass calcd for C H 0 : 260.2140. Found: 260.2144. l g  2 8  3.4.10 Preparation of Homoallylic Alcohol 236.  236  A solution-suspension of K H (15.1 mg, 0.376 mmol) in dry T H F (0.2 mmol) was cannulated into a stirred solution of the angular allylic alcohol 237 (49.0 mg, 0.188 mmol) in dry THF (1.5 mL) at room temperature. After 1 h, 18-crown-6 (99.5 mg, 0.376 mmol) was added as a solution in dry T H F (0.2 mL). After a further 30 min, freshly distilled I C H S n B u 2  70e 3  (202 mg,  0.469 mmol) was added as a solution in dry THF (0.5 mL). A n extremely thick cream-coloured precipitate formed. After 40 min, the mixture was cooled to -78 °C and butyllithium (1.5 M in hexanes, 0.56 mL) was added. After 10 min, the mixture was warmed to 0 °C; after a further 10 min, the mixture was allowed to warm to room temperature. A total of 30 min after the addition of butyllithium, water (2 mL) was added followed by E t 0 (2 mL). The layers were separated. The 2  aqueous layer was extracted with E t 0 ( 3 x 2 mL). The combined ethereal layers were dried over 2  anhydrous MgSCv After removal of the solvent under reduced pressure (water aspirator), the crude material was purified by radial chromatography (2 mm silica gel plate, 7:1 pentane -Et 0) to 2  give the rearrangement product 236 as a colourless oil (45.4 mg, 88%).  IR (neat): 3338 (br), 1633, 1455, 1373, 1032, 894, 788 cm" . 1  J  H N M R (400 M H z , CDC1 ) 5: 0.92 (s, 3H), 0.96 (d, 3H, J = 6.8 Hz, CH(CH3)CH OH), 1.03 3  2  (s, 3H), 1.16-1.31 (overlapping multiplets, 2H, includes dd at 1.17, 1H, J = 7.6, 4.3 Hz, exchanges with D 0 , OH), 1.48-1.59 (overlapping multiplets, 4H), 1.59-1.68 (m, 1H), 1.752  1.91 (overlapping multiplets, 3H), 1.91-1.99 (m, 1H), 2.10-2.36 (overlapping multiplets, 5H), 3.18-3.29 (m, 1H), 3.38-3.45 (overlapping multiplets, 2H, simplify upon addition of D 0 , 2  CFbOH), 4.64-4.68 (overlapping multiplets, 2H, C=CH ). 2  1 3  C N M R (75.2 M H z , CDC1 ) 5: 3  16.1 (-ve), 18.4 (-ve), 24.7 (-ve), 27.8, 28.5, 28.6, 33.1,  34.0, 34.8 (-ve), 37.1, 38.8, 42.1, 46.6 (-ve), 49.3, 66.0, 105.6, 134.5, 144.0, 157.6.  Exact mass calcd for C i H O : 274.2297. Found: 274.2289. 9  3 0  182  REFERENCES AND ENDNOTES  1) Corey, E.J.; Cheng, X . - M . The Logic of Chemical Synthesis New York: John Wiley and Sons, 1989. 2) a) Trost, B . M . Acc. Chem. Res. 1978,11, 453 b) Piers, E.; Karunaratne, V. J. Org. Chem. 1983, 48, 1774 c) Seebach, D.; Knochel, P. Helv. Chim. Acta 1984, 67, 261. 3) Seebach, D . Angew. Chem. Int. Ed. Engl. 1979,18, 239. 4) Piers, E.; Marais, P.C. J. Chem. Soc. Chem. Commun. 1989, 1222. 5) Wong, T. Ph.D. Thesis, The University of British Columbia, 1993. 6) Dauben, W.G.; Michno, D. M . J. Org. Chem. 1977, 42, 682. 7) Still, W . C ; Mitra, A . J. Am. Chem. Soc. 1978,100, 1927. 8) a) Ayer, W . A . ; Browne, L . M . ; Mercer, J.R.; Taylor, D.R.; Ward, D.E. Can. I. Chem. 1978, 56, 717 b) Hseu, T.H.; Wang, J.L.; Tang, C P . Acta Cryst. 1980, b36, 2802 c) Shibata, H . ; Tokunaga, T.; Karasawa, D.; Hirota, A . ; Nakayama, M . ; Nozaki, H . ; Tada, T. Agric. Biol. Chem. 1989, 53, 3373. 9) a) Piers, E.; Renaud, J. J. Org. Chem. 1993, 58, 11 b) Piers, E.; Renaud, J.; Rettig, S J . Synthesis 1998, 590. 10) Piers E ; Cook, K . L . ; Rogers, C. Tetrahedron Lett. 1994, 35, 8573. 11) Ayer, W . A ; Taube, H . Tetrahedron Lett. 1972, 1917. 12) a) Ayer, W.A.; Carstens, L . L . Can. J. Chem. 1973, 51, 3157 b) Ayer, W.A.; Taube, H . Can. J. Chem. 1973,57, 3842. 13) a) Ayer, W.A.; Yoshida, T.; van Schie, D.M.J. Can. J. Chem. 1978, 56, 2113 b) Ayer, W.A.; Lee, S.-P. Can. J. Chem. 1979, 57, 3332. 14) a) Hecht, H.-J.; Hofle, G.; Steglich, W.; Anke, T. Oberwinkler, F. J.C.S. Chem. Comm. 1978, 665 b) Cassidy, M.P.; Ghisalberti, E.L.; Jefferies, P. R.; Skelton, B . W . ; White, A . H . Aust. J. Chem. 1985, 38, 1187 c) Sennett, S.H.; Pomponi, S.A.; Wright, A . E . J. Nat. Prod. 1992,55, 1421 d) Green, D.; Goldberg, I.; Stein, Z.; Han, M . ; Kashman, Y . Nat. Prod. Lett.  183 1992,1, 193 e) Kawagishi, H.; Shimada, A . Shirai, R.; Okamoto, K.; Ojim, F.; Sakamoto, H . ; Ishiguro, Y . ; Furukawa, S. Tetrahedron Lett. 1994, 35, 1569. 15) While the authors indicate the relative configuration at C9 of sarcodonin G (40) to be R, it is clear from the X-ray crystal structure published in the same paper (see reference 8c) that the configuration is in fact S. 16) a) Ayer, W.A.; Ward, D.E.; Browne, L . M . ; Delbaere, L.T.J.; Hoyano, Y . Can. J. Chem. 1981, 59, 2665 b) Ward, D.E. Can. J. Chem. 1987, 65, 2380 c) Dahnke, K.R.; Paquette, L . A . J. Org. Chem. 1994, 59, 885 d) Snider, B.B.; V o , N . H . ; O'Neil, S.V.; Foxman, B . M . J. Am. Chem. Soc. 1996,118, 7644 e) Snider, B.B.; V o , N . H . ; O'Neil, S.V. J. Org. Chem. 1998, 63, 4372 f) Tori, M . ; Toyoda, N ; Sono, M . J. Org. Chem. 1998, 63, 306 g) Boulet, S. Ph.D. Thesis, The University of British Columbia, 1998. 17) Piers, E.; Marais, P.C. Tetrahedron Lett. 1988, 29, 4053. 18) a) Baldwin, J.E.; Patrick, J.E. J. Am. Chem. Soc. 1971, 93, 3556 b) Midland, M . M . ; Kwon, Y . C . 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Organomet. Chem. 1979,166, 17). 85) Oda, H.; Morizawa, Y . ; Oshima, K.; Nozaki, H . Tetrahedron Lett. 1984, 25, 3221. 86) Gawley, R . E ; Termine, E.J.; Aube, J. Tetrahedron Lett. 1980,27,3115. 87) It has been proposed that axial protons are more readily abstracted than equatorial ones; equilibration of 249 to 250 would presumably make the subsequent methylation step more facile: Corey, E.J. J. Am. Chem. Soc. 1954, 76, 175. 88) a) Piers, E.; Kaller, A . M . Tetrahedron Lett. 1996, 37, 5857 b) Kaller, A . M . Ph.D. Thesis, The University of British Columbia, 1997. 89) Still, W . C ; Kahn, M . ; Mitra, A. J. Org. Chem. 1978, 43, 2923. 90) Harrison, I.T. Instruction Manual Harrison Research, Palo Alto, 1985. 91) Perrin, D.D.; Armarego, W.L.; Perrin, D.R. Purification of Laboratory Chemicals, 3 ed. rd  Oxford: Pergamon, 1988. 92) Kofron, W.G.; Baclawski, L . H . J. Org. Chem. 1976,47, 1879. 93) The P-keto esters 22 and 24 were obtained from the Aldrich Chemical Co. The P-keto ester 23 was readily prepared according to the procedure reported in Ruest, L . ; Blouin, G . ; Deslongchamps, P. Synth. Commun. 1976, 6, 169.  188  APPENDIX  X-Ray Crystallographic Data for Compounds 142 and 152.  compound  142  152  formula  C17H28O3  C17H28O3  formula weight  280.41  280.41  crystal system  monoclinic  orthorhombic  space group  P2i/n (#14)  / 2 2 2 (#19)  a (A)  15.857(2)  15.126(1)  b (A)  11.651(3)  15.809(1)  c (A)  17.704(2)  6.747(2)  P (°)  96.706(7)  V(A )  3248.4(8)  1613.3(4)  8  4  D^ (g/cm )  1.147  1.154  number of reflections used in refinement  3522  1123  R  0.047  0.031  R  0.045  0.028  J  1  1  1  lattice parameters  3  Z 3  c  w  A l l measurements were made on a Rigaku A F C 6 S diffractometer with graphite monochromated C u - K a radiation, at a temperature of 21 ± 1 °C.  

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