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A synthetic approach to the C/D ring system of steroids Pendleton, Nevil 1987

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A SYNTHETIC APPROACH TO THE C / D RING SYSTEM OF STEROIDS  by Nevil B.Sc,  Pendleton  Brunei U n i v e r s i t y ,  London,  1984  A T H E S I S SUBMITTED I N P A R T I A L FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE  in  THE FACULTY OF GRADUATE STUDIES DEPARTMENT OF CHEMISTRY  We a c c e p t to  this  thesis  the r e q u i r e d  The U n i v e r s i t y  of  Nevil  conforming  standard  British  September,  c  as  1987  Pendleton  Columbia  In presenting degree  at  this  the  thesis  in  partial fulfilment  of  University of  British Columbia,  I agree  freely available for reference copying  of  this  department publication  or of  and study.  this  his  or  her  representatives.  Department of  ^HfcHt  ST^Y  The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date  DE-6(3/81)  f  f  e  QcJc, Hc??~  that the  may be It  thesis for financial gain shall not  permission.  requirements  I further agree  thesis for scholarly purposes by  the  for  an  advanced  Library shall make it  that permission  for extensive  granted  head  is  by the  understood be  that  allowed without  of  my  copying  or  my written  ABSTRACT  This thesis C/D r i n g  is  c o n c e r n e d w i t h an approach to  system and s i d e c h a i n of  (+)-9,10-Dibromocamphor bromocamphor diester  enediolate  intermediate  [prepared  a modified 154.  168 a n d 1 7 6 .  the d i e s t e r  mixture  Oxidative  to provide  the  cleavage of  isomeric  the  the  tricyclic  methoxy-  these methoxyketones  i n t o the c o r r e s p o n d i n g i s o m e r i c e s t e r s the C/D r i n g  ii  168  176  i s o m e r i c a l d e h y d e s 178 a n d 180 w h i c h w e r e  a synthesis of  The  acyloin  168  a n d 176 p r o v i d e d  represents  of  (+)-endo-3-  144 i n s i x s t e p s .  the  the  functionality.  steps from  acyloin reaction  154  transformed  i n three  A novel methanolysis of  154 g a v e a 1:1  s y n t h e s i s of  s t e r o i d s w i t h 11-oxygen  was c o n v e r t e d t o  144 u n d e r w e n t  silylated  ketones  (4)]  (18)  the  system of  181 a n d 1 8 2 .  steroids  with  then This  11-oxygen f u n c t i o n a l i t y stereochemistry  at  C(13)  and e s t a b l i s h m e n t and C ( 1 7 ) .  181  • • •  111  of  the  correct  absolu  TABLE OF CONTENTS Page  Abstract Table of  ii Contents  iv  List  of  Figures  v  List  of  Abbreviations  and N u m b e r i n g  System  vi  Acknowledgements  viii  1.  Introduction  1.1  The U s e o f  1.2  11-Oxysteroids  1.3  Approaches to  1  Camphor i n N a t u r a l  Product  Synthesis  1 10  the  C/D R i n g System o f  with Functionalised  Steroids  Side Chains  17  2.  Discussion  27  3.  Experimental  45  Bibliography Appendix  1 :  65 1  H 400 MHz NMR o f  S e l e c t e d Compounds  A p p e n d i x 2 : S t e r e o v i e w and C r y s t a l D a t a o f Alcohol  167  69  Tricyclic 73  iv  L I S T OF FIGURES  Figure  Title  Page  1  * H 400 MHz NMR o f  the E s t e r  181  41  2  * H 4 0 0 MHz NMR o f  the E s t e r  182  42  v  L I S T OF ABBREVIATIONS AND NUMBERING SYSTEM  (a)  List  of  Abbreviations  Ac  Acetyl  amu  A t o m i c Mass  br  Broad  Bu  Butyl  DMAP  4-Dimethylaminopyridine  DMF  N,N-Dimethylformamide  DMPU  N,N-Dimethylpropyleneurea  DMSO  Dimethylsulphoxide  Et  Ethyl  glc  G a s - l i q u i d Chromatography  h  Hour(s)  2,6-H  2,6-Hydride  HMPA  Hexamethylphosphoramide  ir  Infrared  Me  Methyl  2,3-Me  2,3-Methyl  m/e  Mass t o Charge R a t i o  Unit(s)  (ir)  Shift  Shift  min  Minute(s)  mp  Melting  Ms  Me t h a n e s u l p h o n y l  nmr  N u c l e a r M a g n e t i c Resonance  Ph  Phenyl  Point  vi  TBDMS  tertiary-Butyldimethylsilyl  THF  Tetrahydrofuran  THP  2-Tetrahydropyranyl  tic  Thin Layer  Chromatography  TMS  Trimethylsilyl  WM  Wagner-Meervein  Abbreviations for  Shift  *H NMR D a t a  d  Doublet  dd  Doublet of  ddd  Doublet  &  Chemical S h i f t  J  Coupling Constant  m  of Doublets of  Doublets  i n ppm f r o m t h e (in  TMS  Signal  Hz)  Multiplet  ppm  P a r t s per  s  Singlet  t  Triplet  (b)  Doublets  Million  Numbering System Camphor  (1)  and i t s  derivatives  a r e n u m b e r e d a s shown b e l o w .  T h e s t a n d a r d s t e r o i d n u m b e r i n g s y s t e m a s shown throughout t h i s only the  thesis.  C/D r i n g  T h i s numbering system i s  sub-unit  is  referred  vii  to.  is  used  a l s o u s e d when  ACKNOWLEDGEMENT  I  would l i k e  crystallographic  to thank D r .  S t e v e R e t t i g who p e r f o r m e d t h e X - r a y  a n a l y s i s a n d M r . B o r d a who c a r r i e d o u t  S p e c i a l t h a n k s go t o my t y p i s t w i f e s t r u c t u r e of Finally, Money, f o r  the m i c r o a n a l y s e s .  S h a m s h a d , who now knows  the  (+)-9,10-dibromocamphor! I would l i k e  to  t h a n k my r e s e a r c h s u p e r v i s o r , D r . Thomas  a l l h i s s u p p o r t and g u i d a n c e .  viii  To Shamshad  Ix  1.  1.1  The U s e o f  Camphor i n N a t u r a l P r o d u c t  (+)-Camphor (+)-Camphor  (1)  (-)-camphor  is  (-)-  forms  of  INTRODUCTION  (1),  (-)-camphor  and (±)-camphor  a constituent  of  the o i l  camphor a r e c o m m e r c i a l l y  commercially available  from a-pinene  (3)  its  together  of  with its  use as a v e r s a t i l e  synthesis of n a t u r a l  review of  whereas Both  a v a i l a b l e although  (2).*  but  sagebrush.  the  (+)-  by o x i d a t i o n  Camphor i s  the product  is  also  of  prepared  racemic.  2  ability  functionalised  t o be s e l e c t i v e l y  and C(10) starting  products.  In  functionalisation  of  enantiomeric at  carbon c e n t r e s , has r e s u l t e d material  addition,  C(l)-C(2),  and  (-)-camphor  pure  chiral  cleavage at  naturally.  camphor i n b o t h o p t i c a l l y  C ( 5 ) , C ( 6 ) , C ( 8 ) , C(9)  undergo r i n g  occur  2  The a v a i l a b i l i t y  C(3),  of  laboratory  (-)-borneol  I  forms,  all  c a n be i s o l a t e d f r o m t h e camphor l a u r e l  c a n be more c h e a p l y p r e p a r e d i n t h e  industrially  Synthesis  i n the  enantiospecific  camphor d e r i v a t i v e s  C(2)-C(3)  and C ( l ) - C ( 7 ) .  camphor and i t s  use i n  can  A  natural  2 product  s y n t h e s i s has been p u b l i s h e d r e c e n t l y ,  outline  of  provided  the  important  bromination  and r i n g  below.  1  in  and so o n l y a  brief  cleavage reactions  is  1.1a  C(3) and C(9)  Bromination  Br  J.  Br 4  Bromination of  Br 5  6  camphor w i t h b r o m i n e i n a c e t i c a c i d t o  (+)-endo-3-bromocamphor  (4)  yield  was c a r r i e d o u t b y K i p p i n g a n d P o p e  in  3 1873.  F u r t h e r b r o m i n a t i o n c a n be c a r r i e d o u t by t r e a t m e n t  (•f)-endo-3-bromocamphor provide  (4)  w i t h b r o m i n e and c h l o r o s u l p h o n i c a c i d  (+)-endo-3,9-dibromocamphor  (+)-endo-3,9,9-tribromocamphor initially camphor  of  (5),  7 8 (6). *  4 5 6 ' ' a n d a s m a l l amount The m e c h a n i s m  i n v o l v e s Wagner-Meerwein rearrangement of  (4_) (Scheme 1 ) . A N a m e t k i n s h i f t  of  Scheme 1 2  7  to of  postulated  (4)-endo-3-bromo-  the e x o - m e t h y l group f o l l o w e d  by  bromination processes  produces intermediate  (Pathway A) p r o v i d e s  (+)-endo-3,9,9-Tribromocamphor bromination  of  rearrangement 1.lb  intermediate  7_.  A r e v e r s a l of  the  rearrangement  (+)-endo-3,9-dibromocamphor (6)  is postulated  7_ ( P a t h w a y B ) b e f o r e  t o be f o r m e d b y r e v e r s a l of  Br  9  4 1952, N i s h i k a w a  found  (5)  i n c o l d fuming  dibromocamphor  (8)  w i t h the  laboratory  similarly  chlorosulphonic  acid at  interconversion  of  55°C. of  the  (-f)-endo-3,9-  a c i d produced  configuration.  Later  (+)-endo-3-bromocamphor  (-) - e n d o - 6-bromocamphor  has been c o n f i r m e d by d e u t e r i u m is  treatment  sulphuric  opposite  h a v e shown t h a t  rearranged to  12  that  dibromocamphor  involves  the  Derivatives  Br  i n our  further  processes.  5,6-Dehydrocamphor  In  (5).  (-)-endo-6,9studies^ (4)  c a n be  (9_) b y t r e a t m e n t  with  The p o s t u l a t e d m e c h a n i s m (Scheme 2 ) C(8)  and C ( 1 0 ) m e t h y l  labelling  formed by Wagner-Meerwein r e a r r a n g e m e n t  3  studies.^ followed  g r o u p s and Intermediate  by a N a m e t k i n  this 10  shift  of  the  exo-methyl  group.  f o l l o w e d by a 2 , 6 - h y d r i d e rearrangement framework  to  1  provides  shift  A second Wagner-Meerwein and a f u r t h e r  intermediate  Wagner-Meerwein  11_ w h i c h r e v e r t s  form (-)-endo-6-bromocamphor  rearrangement  to  the  camphor  (9).  (exo)  Scheme 2  Dehydrohalogenation of 5,6-dehydrocamphor  (12),  (-)-endo-6-bromocamphor  previously  s y n t h e s i s e d by  (9)  provides  multistep  12 13 procedures.  *  dibromocamphor  Similar dehydrohalogenation (8)  provides  of  (-)-endo-6,9-  9-bromo-5,6-dehydrocamphor  4  (13).  1.1c  C(8)-Bromination  Br 1  Br 15  (+)-8-Bromocamphor i n three  steps.^  (14)  Treatment  and H B r g a s [ w h i c h p r o v i d e s further  bromination  camphor  (16).  provides  16  14  c a n be c o n v e n i e n t l y p r e p a r e d f r o m camphor of  c a m p h o r (1)  with bromine,  (+)-3,3-dibromocamphor  in chlorosulphonic acid gives  (15)]  acetic  acid  followed  by  (+)-3,3,8-tribromo-  S e l e c t i v e d e b r o m i n a t i o n o f _16_ w i t h z i n c a n d a c e t i c  (+)-8-bromocamphor  (14).  The C ( 8 ) - b r o m i n a t i o n p r o c e s s  c o n s i d e r e d t o o c c u r b y a m e c h a n i s m (Scheme 3 ) i n the C ( 9 ) - b r o m i n a t i o n  of  similar  (->-)-endo-3-bromocamphor  5  to  (4).  that  7 13 '  acid  is  involved  The c r u c i a l d i f f e r e n c e  is  the p o s t u l a t e d o c c u r r e n c e of  shifts  i n t h e C ( 8 ) - b r o m i n a t i o n r e a c t i o n as opposed t o  shifts  i n the C ( 9 ) - b r o m i n a t i o n r e a c t i o n .  studies^"* provide support for 1.Id  2,3-endo-methyl the  2,3-exo-methyl  Again deuterium  labelling  t h i s mechanism.  8 , 1 0 - and 9,10-Dibromocamphor D e r i v a t i v e s  Br  In it  an e x t e n s i o n of  t h e w o r k c a r r i e d o u t b y N i s h i k a w a a n d Eagiwara,  was f o u n d t h a t p r o l o n g e d t r e a t m e n t  w i t h b r o m i n e and c h l o r o s u l p h o n i c a c i d (+)-endo-3,9,10-tribromocamphor (•f ) - e n d o - 3 , 8 - d i b r o m o c a m p h o r bromocamphor  (14)  (19)  w i t h bromine]  S e l e c t i v e debromination of (+)-9,10-dibromocamphor  of  (+)-endo-3,9-dibromocamphor  (5 d a y s ) g a v e  (5)  predominantly  ( 1 7 ) A n a l o g o u s treatment [ p r e p a r e d by t r e a t m e n t  of  of (+)-8-  gave ( + ) - e n d o - 3 , 8 , 1 0 - t r i b r o m o c a m p h o r  (20).  17_ a n d 20_ w i t h z i n c a n d a c e t i c a c i d p r o v i d e d  (18)  and (+)-8,10-dibromocamphor  6  (21)  respectively.  The mechanism and o f  of  the b r o m i n a t i o n of  (+)-endo-3,8-dibromocamphor  Wagner-Meerwein rearrangement (Scheme 4 ) . back to  Reaction of  (19)  to provide  (+)-endo-3,9-dibromocamphor  has been proposed to  t h e camphor framework  involve  t h e camphene i n t e r m e d i a t e  22 w i t h b r o m i n e a n d s u b s e q u e n t p r o v i d e s the  tribrominated  (5)  22  rearrangement c a m p h o r s 17_  and 2 0 .  X = Br  Y = H 20  22a Scheme 4  The d i b r o m o f e n c h o n e s 23 a n d 24_ (Scheme 5 ) during  the C ( 1 0 ) - b r o m i n a t i o n  of  a r e p r o d u c e d as  (+)-endo-3,9-dibromocamphor  by-products  (5)  and  2 (4)-endo-3,8-dibromocamphor derivatives  (19)•  The f o r m a t i o n  of  these  fenchone  i s p o s t u l a t e d to occur v i a a double Wagner-Meerwein 2  rearrangement  a s shown i n Scheme 5 .  (+)-9,10-dibromocamphor  (18)  C h e m i c a l Company f r o m whom i t  The s y n t h e t i c p o t e n t i a l  has been r e c e n t l y  r e c o g n i s e d by the  i s now c o m m e r c i a l l y a v a i l a b l e .  7  of Aldrich  Br  Br  Scheme 5  l.le  Cleavage of Cleavage of  t h e Camphor C ( l ) - C ( 2 ) the  camphor d e r i v a t i v e s 5-membered r i n g .  C(l)-C(2) results  b o n d i n camphor  i n the  Camphor ( 1 )  Bond  formation of  itself  (1) a  and i n  various  functionalised  undergoes c l e a v a g e upon  18-22 photoirradiation (18)  to  give the  c a n be c l e a v e d t o p r o v i d e  the  aldehyde 25.  (+)-9,10-dibromocamphor  c y c l o p e n t a n o i d r i n g s y s t e m s 2_6, 27_ a n d  23 28.  8  S t e v e n s and c o - w o r k e r s reaction i n routes with control centres.  of  utilised  f r o m camphor  (1)  stereochemistry at  (+)-9-Bromocamphor  which underwent  ring  w i t h the c o r r e c t  (29)  cleavage of  the C ( l ) - C ( 2 )  to the C/D r i n g  ring  cleavage  system of  t h e C ( 1 3 ) , C(17) and C(20)  the C ( l ) - C ( 2 )  a b s o l u t e stereochemistry at  intermediate  (31)  carbon  was c o n v e r t e d t o o x i m e e s t e r 30_ bond t o g i v e c y a n o e s t e r  C ( 1 3 ) and C ( 1 7 )  33 Scheme 6 The c y a n o e s t e r  steroids  (Scheme 6 ) .  32  was t h e n c o n v e r t e d i n s e v e r a l s t e p s t o  3_2_ w h i c h was c y c l i s e d t o p r o v i d e  the  the hydrindene  sulphone  derivative  33. The r e q u i r e d C ( 2 0 )  s t e r e o c h e m i s t r y was f o r m e d  stereoselective methylation  of  (+)-9-bromocamphor  (Scheme 7) (29)  to  by  give  25 (+)-endo-3-methyl-9-bromocamphor 34 t o  the h y d r o x y - t o s y l a t e s  cleavage of  the C ( l ) - C ( 2 )  resulted in formation  of  (34).  Subsequent c o n v e r s i o n  35a and 3 5 b , f o l l o w e d by  oxidative  b o n d w i t h e e r i e ammonium n i t r a t e the key monocyclic intermediate  9  (CAN)  36.  3^  of  I n c o r p o r a t i o n of  the  stereoselective methylation  step  i n the  former  Scheme 7 route  (Scheme 6) w o u l d be e x p e c t e d t o p r o v i d e  w i t h the 1.2  correct  absolute  stereochemistry  at  the  sulphone d e r i v a t i v e  33  C(20).  11-Oxysteroids  OH  39 One i m p o r t a n t g r o u p which include  cortisone  of  the  (37),  11-oxysteroids  aldosterone  10  (38),  are the  corticosteroids  and c o r t i c o s t e r o n e  (39)  as r e p r e s e n t a t i v e  examples.  Common s t r u c t u r a l  compounds a r e t h e p r e s e n c e o f enone f u n c t i o n a l i t y corticosteroids  features  a hydroxy or k e t o group at  i n r i n g A and a -COCI^OH group a t  metabolism,  inflammation  of  and  these  C(ll),an  C(17).  a r e among t h e m o s t i m p o r t a n t r e g u l a t o r y  c o n t r o l l i n g w a t e r and m i n e r a l b a l a n c e , p r o t e i n  of  The  hormones,  carbohydrate  tissues associated with injuries,  allergic  26 r e a c t i o n s and auto-immune p r o c e s s e s .  After  their  therapeutic  27 importance vas discovered i n  1949,  a c o n s i d e r a b l e e f f o r t was made  to  28 develop synthetic  routes  d i f f i c u l t y was t h e although  this  in high  t h e s e compounds.  introduction  of  a hydroxyl  One  synthetic  or k e t o group at  C(ll)  p r o b l e m was o v e r c o m e b y m i c r o b i o l o g i c a l o x i d a t i o n 29  desoxy p r e c u r s o r s , C(ll)  to  which enabled i n t r o d u c t i o n  of  of  a hydroxy group  at  yield.  T h e r e a r e a l s o many 1 1 - o x y s t e r o i d s o t h e r as c o r t i c o s t e r o i d s ; a r e two w e l l - k n o w n  adrenosterone examples.  (40)  than those  classified  and 1 1 - k e t o p r o g e s t e r o n e  (41)  R e c e n t l y there has been a resurgence  of  ,0  40 interest  i n the t o t a l  41 s y n t h e s i s of  f o c u s s e d on the f o r m a t i o n approach,  of  the  11-oxysteroids.  Efforts  have been  1 1 - o x y s t e r o i d s b y a n A + C / D — > ABCD  incorporating aldol condensations, intramolecular  r e a c t i o n s and t h e u s e o f  organosilicon chemistry.  c o n t r a s t s w i t h the e a r l y  s y n t h e t i c approaches to  This  Diels-Alder  approach 28  11  11-oxysteroids  which  were b a s e d on the outline steroids  of  initial  the recent  is provided  construction  approaches to  of t h e B / C r i n g  the C/D r i n g  system.  system of  An  11-oxygenated  below. 30  In  one a p p r o a c h  (Scheme 8 ) ,  racemic adrenosterone of  the d i a n i o n of  followed  (AO) f r o m e t h y l  ethyl  trans:cis  the  r~\  0  0  bromide addition  c o r r e s p o n d i n g a l d e h y d e 43_. formed the D r i n g by an  A l d o l c o n d e n s a t i o n gave the  ratio),  Alkylation  p h o s p h o n a t e g a v e t h e e n o n e e s t e r 42_.  with zirconium tetra-n-propoxide  (25:1  with a l l y l  o z o n o l y s i s and W i t t i g - H o r n e r  g r o u p was t h e n c o n v e r t e d t o  Michael addition.  synthesised  2-iDethylacetoacetate.  2-methylacetoacetate  by k e t a l i s a t i o n ,  3-methoxy-2-(oxopropyl)  S t o r k and c o - w o r k e r s  r~\  0 o  The  ester  Cyclisation  intramolecular  trans-hydrindenone  w i t h 11-oxygen f u n c t i o n a l i t y . rt  of  44  Conjugate  r~\  0  0  0  Me  42  43  t  45  addition  to  2-(trimethylsilyl)-l-penten-3-one  and a c i d h y d r o l y s i s p r o v i d e d e n e d i o n e 4 5 . c t - f a c e was a c c o m p l i s h e d b y t r e a t m e n t o f  12  followed  Alkylation  by of  the d i e n e d i o l a t e  cyclisation 45_ f r o m of  the  45 w i t h  l-bromo-3-chloro-2-butene.  F i n a l l y , m i l d a c i d h y d r o l y s i s gave  a l k e n y l c h l o r i d e A6_ w h i c h was h y d r o l y s e d a n d t h e n c y c l i s e d t o adrenosterone  the provide  (AO). 31  In a l a t e r synthetic route of  investigation, to  the p y r r o l i d i n e  S t o r k and c o - w o r k e r s  11-ketoprogesterone enamine o f  (Al)  (Scheme 9 ) .  substituent  was a c h i e v e d by t r e a t i n g  a c e t i c a n h y d r i d e and BF^ e t h e r a t e of  a d d i t i o n of  I n t r o d u c t i o n of  i n t o the  Reduction  t h e e n o l a c e t a t e gave enone 5 2 . 13/S-position by  conjugate steps.  the c o r r e s p o n d i n g d i o x o l a n e gave the  propionic  acid intermediate  5_3_ w h i c h was c o n v e r t e d v i a a n i n t r a m o l e c u l a r  Alder reaction to  11-ketoprogesterone  A8  (Al).  49  50  Al  53 Scheme 9  13  the  t h e d i e n o l a c e t a t e 50_ w i t h  a cyano group f o l l o w e d by s u c c e s s i v e r e d u c t i o n  Subsequent o x i d a t i o n of  unsaturated  to give enol acetate 5 1 .  the k e t o n e f o l l o w e d by c l e a v a g e o f  A m e t h y l g r o u p was i n t r o d u c e d  Annulation  c y c l o p e n t a n o n e (A7) w i t h t h e  k e t o e s t e r A8_ g a v e t h e b i c y c l i c k e t o e s t e r A9_. C(17)  developed a  Diels-  In  a recent  enantioselective  investigation, route  S t o r k and c o - w o r k e r s  (Scheme 10)  to adrenosterone  developed an (40).  I  Me 0,C^  ^5  1  R 0  Me0 C  P.  2  54  57  0  Me0 C 2  < ^  60  Cyclopentanoneacetic ester  54^ was u s e d a s t h e  was p r e p a r e d i n t h e p r o p e r  relative  the  stereoselective  chiral  ester  intramolecular  to produce the  correct  and a b s o l u t e  chirality.  57_ w h i c h u n d e r w e n t  with a l l y l  give 58.  to  material  and  stereochemistry  Michael r e a c t i o n of  ketone gave d i o x o l a n e bromide  starting  by  5_5 u s i n g a  P r o t e c t i o n of  the  stereoselective  alkylation  The C r i n g was f o r m e d b y  conversion  14  \  v£><  c  MeO,C  2  55  CN  0  R0,C  0  to  t h e d i m e s y l a t e 59_ w h i c h was t h e n c y c l i s e d b y r e a c t i o n w i t h  c y a n o a c e t a t e t o g i v e c y a n o a c e t a t e 60_. f o l l o w e d by o x i d a t i o n of the a n i o n o f introduced  the C ( l l )  p r o v i d e d the  trans-hydrindane  intramolecular In  carbonyl.  methyl  D e c a r b o m e t h o x y l a t i o n o f 60_  the  resulting n i t r i l e  with  H y d r o b o r a t i o n a n d PDC o x i d a t i o n derivative  then  61^ w h i c h was c o n v e r t e d v i a  D i e l s - A l d e r r e a c t i o n to adrenosterone  t h e a p p r o a c h (Scheme 11) t o  oxygen  11-oxysteroids  (40) ( c f .  an  Scheme 9 ) .  d e v e l o p e d by S n i d e r  33 and K i r k ,  c y c l i s a t i o n o f k e t o n e j62_ p r o v i d e d r a c e m i c h y d r i n d a n o n e  Conversion of a d d i t i o n of 66.  63 t o  e n o n e 65, v i a t h e e p o x i d e 64, f o l l o w e d b y  3-butenylmagnesium bromide p r o v i d e d the p e n t y n y l  I n t e r m e d i a t e 66 was o x i d i s e d t o  67  the  trione  68 Scheme 11  15  63.  conjugate derivative  67 a n d s u b s e q u e n t l y  c y c l i s e d to  the  tricyclic  enedione 68.  The c o r r e s p o n d i n g e n e d i o n e 45  30 was u s e d b y S t o r k a n d c o - w o r k e r s  i n one o f  their  routes  to  1 1 - o x y s t e r o i d s a s shown p r e v i o u s l y i n Scheme 8 . Denmark a n d G e r m a n a s utilised a vinyl silane acylation synthesis of  the  trans-hydrindanedione  40  72 (Scheme 1 2 ) .  74  in  the  Conjugate  73  72  Scheme 12 addition  of  2-trimethylsilyl  f o l l o w e d by q u e n c h i n g of the enol t r i m e t h y l s i l y l methylbromoacetate chloride  cuprate  ether  69.  The e t h e r  ester  70.  trans-hydrindanedione  capable of  gave  69_ was t h e n a l k y l a t e d 7_0_ t o  with  acid  Lewis-acid catalysed 72.  I n t e r m e d i a t e 72 i s  then  undergoing D i e l s - A l d e r r e a c t i o n w i t h a diene  T h i s would p r o v i d e  converted to  2-methylcyclopentenone  Conversion of  7_1 f o l l o w e d b y a n i n t r a m o l e c u l a r ,  potentially  to  the e n o l a t e w i t h t r i m e t h y l s i l y l c h l o r i d e  to provide  c y c l i s a t i o n gave the  as 7 3 .  vinyl  the D i e l s - A l d e r product  11-ketosteroids  such as adrenosterone  16  74_ w h i c h c o u l d be 40.  such  Fukuzaki, acylation  Nakamura and Kuwajima  i n a synthesis of  The i n t e r m e d i a t e 1-one  (76)  vinyl  the  similarly  used a v i n y l  trans-hydrindanedione  s i l a n e 75 was p r e p a r e d f r o m  in several conventional  78  steps.  78 (Scheme  C y c l i s a t i o n of  78 was f o r m e d b y i s o m e r i s a t i o n o f  The t r a n s - s t e r e o c h e m i s t r y  introduction 1.3  —  c i s - e n o n e 77 w i t h 1 1 - o x y g e n f u n c t i o n a l i t y .  acid.  of  a side chain at  Approaches to  the  is  75_ p r o v i d e d  C/^O  77  trans-enone  13).  3-methyl-2-cyclohexen-  Scheme 13 the  silane  required  C(20)  (cf.  C/D R i n g System of  The  corresponding  77 w i t h _ p _ - t o l u e n e s u l p h o n i c for  stereoselective  Schemes 14 a n d Steroids with  15).  Functionalised  Side Chains R e p r e s e n t a t i v e examples of chains include cholesterol the p l a n t  steroid  The b i o l o g i c a l prompted  (79),  stigmasterol  activity  of  steroids  possessing functionalised  cholecalciferol  (81)  and the b i l e  ( v i t a m i n D^)  considerable research into  their  17  (80),  acid cholic acid  steroids with functionalised synthesis.  In  side  (82)•  side chains has particular,  there has been i n t e r e s t  hormones r e g u l a t e plasma.  (80)  and i t s  metabolites.  c a l c i u m and p h o s p h a t e i o n c o n c e n t r a t i o n  The m a j o r i t y o f  c o n c e n t r a t e d on the structural  i n v i t a m i n D.  initial  sub-units of  trans-hydrindanone  recent  investigations  c o n s t r u c t i o n of  synthetic  derivatives  interest  in this  system.  The  c a n be r e p r e s e n t e d by S y n t h e t i c approaches  0 84  18  blood  a r e a have  the C/D r i n g  s u c h a s 83 a n d 8 4 .  83  in  These  to the  these s t r u c t u r a l  sub-units of  stereochemistry at  outline  of  s t e r o i d s r e q u i r e methods f o r  controlling  t h e C ( 1 3 ) , C ( 1 4 ) , C ( 1 7 ) and C ( 2 0 ) p o s i t i o n s .  r e c e n t l y p u b l i s h e d approaches i s provided  below. 36  Several research groups, notably  An  those of Lythgoe,  37 Trost  and  38 Johnson h a v e u s e d t h e ' I n h o f f e n d i o l ' 8_5 a s a k e y i n t e r m e d i a t e i n the s y n t h e s i s of systems i n c o r p o r a t i n g a f u n c t i o n a l i s e d s i d e c h a i n . 36 Johnson and c o - w o r k e r s  s y n t h e s i s e d the  Inhoffen d i o l  i n 48% o v e r a l l y i e l d f r o m t h e b r o m i d e 8 6 .  (85)  (Scheme 14)  The k e y s t e p i n t h e  synthesis  Scheme 14 was t h e L e w i s - a c i d c a t a l y s e d c y c l i s a t i o n o f the  trans-hydrindane  Removal o f  derivative  the c h i r a l a u x i l i a r y  a c e t a t e 89_ w h i c h u n d e r w e n t Inhoffen diol  (85)  t h e a c e t a l 8_7 t o  88_ i n h i g h c h e m i c a l a n d o p t i c a l and a c e t y l a t i o n gave t h e  hydrogenation to  g i v e the c i s - o l e f i n 90.  39 (cf.  Scheme 1 5 ) .  19  yield.  bicyclic  was t h e n f o r m e d f r o m 90_ u s i n g m e t h o d o l o g y  by U s k o k o v i c and c o - w o r k e r s  provide  The  developed  U s k o k o v i c and c o - w o r k e r s intermediate  and t r a n s f o r m e d  u s e d k e t o a c i d 91^ a s a it  chiral  i n t o t h e b i c y c l i c k e t o n e 92  previously  41 r e p o r t e d b y W i n d a u s a n d Grundmann  (Scheme 1 5 ) .  Stereoselective  h y d r o g e n a t i o n o f k e t o a c i d 91 g a v e a t r a n s - h y d r i n d a n e  92  derivative  96  which  95  Scheme 15  was c o n v e r t e d v i a t h e m e t h y l k e t o n e 9 3 , t o crucial  r e a c t i o n to  introduce  the c o r r e c t  the c i s - o l e f i n 94.  absolute stereochemistry  C ( 2 0 ) was a c c o m p l i s h e d b y a n e n e r e a c t i o n w i t h e t h y l g i v e d i e n e e s t e r 95_. correct  e s t e r g r o u p p r o v i d e d a l d e h y d e 96_. a s e r i e s of  conventional  Coupling of  ketone  s y n t h e s i s of  propiolate  S t e r e o s e l e c t i v e hydrogenation of  absolute stereochemistry at  steps to  The at  to  95_ e s t a b l i s h e d  the  C(17) and subsequent r e d u c t i o n o f  the  I n t e r m e d i a t e 96_ was c o n v e r t e d  in  t h e W i n d a u s a n d Grundmann k e t o n e  92_ w i t h a n A r i n g c o m p o n e n t  l e d to  (+)-lct,25-dihydroxycholecalciferol  (97).  20  the f i r s t  92.  total  U s k o k o v i c and  co-workers  later  devised routes  to  calcitriol  la,25(S)26-trihydroxycholecalciferol  (99) .  A  lactone  (98)  and  3  44 W i l s o n and Haque construct  u s e d an i n t r a m o l e c u l a r  the C/D r i n g system of  steroids  Diels-Alder  (Scheme 1 6 ) .  reaction  Allylic  TMS  -TMS HO 100  e-H  P-E  105a 105b  101  104  Scheme 16  21  103  alcohol of  100 was c o n v e r t e d i n t o e s t e r  Homo-Claisen rearrangement  101 p r o v i d e d a c i d 1 0 2 , w h i c h was c o n v e r t e d i n t h r e e  aldehyde 103. of  101.  R e a c t i o n of  3-vinyl-4-penten-l-ol  Alder  c y c l i s a t i o n of  steps to  103 w i t h t h e d i a n i o n d e r i v e d f r o m  gave t e t r a e n e  104.  the  lithiation  The i n t r a m o l e c u l a r  104 t h e n p r o v i d e d d i e n e s 105a a n d 105b (  Diels-  4:1).  45 Extension of  this  e l a b o r a t i o n of  work  i n c l u d i n g a r e s o l u t i o n of  T s u j i and c o - w o r k e r s route  (Scheme 1 7 ) .  106  100,  d i e n e 105a and s u b s e q u e n t c o u p l i n g t o an A r i n g  r e s u l t e d i n a n a s y m m e t r i c s y n t h e s i s o f v i t a m i n D^ 46  synthetic  alcohol  from  The f i r s t  (80).  s y n t h e s i s e d the hydrindenone  108 w h i c h f e a t u r e d  two C l a i s e n  C l a i s e n rearrangement  107 Scheme 17  22  of  component  106 b y a  rearrangements  the ether  formed by  110  r e a c t i o n of  108 w i t h t r i e t h y l o r t h o h e x e n a t e  e s t a b l i s h e d the c o r r e c t converted  109 t o  C(17)  the v i n y l  stereochemistry.  allyl  ether  109 a n d  A s e r i e s of  110, which underwent  C l a i s e n rearrangement  to provide  d o u b l e bond o f  the methyl k e t o n e ,  107 t o  provided ester  aldehyde  107.  steps a second  O x i d a t i o n of  decarbonylation of  group and an a l d o l c o n d e n s a t i o n p r o v i d e d t h e h y d r i n d e n o n e  the the  terminal aldehyde  106.  47 Desmaele and c o - w o r k e r s sulphone d e r i v a t i v e  devised a route to  111 (Scheme 1 8 ) .  111  the  trans-hydrindane  R e a c t i o n of ynamine  112 w i t h  116  115  Scheme 18  2-methylcyclopentenone hydrolysed to followed  the  (113)  substituted  by a s e r i e s of  gave t h e c y c l o b u t e n y l a m i n e cyclopentanone  conventional  23  115.  (114)  w h i c h was  R e s o l u t i o n of  steps provided hydrindenone  115 116.  S e v e r a l more s t e p s l e d t o  the  sulphone d e r i v a t i v e  111 u s i n g a p r o c e d u r e  48 d e v e l o p e d by L y t h g o e and W a t e r h o u s e la-hydroxyprecalciferol  Ziegler  (Scheme 1 9 ) .  synthesis  of  used an a n i o n i c oxy-Cope rearrangement  s y n t h e s i s of  1,2-Addition  123  their  (117).  and M e n c e l  the key step i n the  in  of  racemic trans-hydrindanone  dithiane  119, d e r i v e d from  122  125 Scheme 19 24  118  crotonaldehyde,  121  if  124  as  118  to 2-methylcyclopentenone  (113)  rearrangement y i e l d e d enolate 'in  f o l l o w e d by an a n i o n i c o x y - C o p e  120.  I n t e r m e d i a t e 120 was  s i t u ' w i t h a l l y l bromide to give ketene d i t h i o a c e t a l  elegant one-pot procedure c o n t r o l l e d and 0(20)  positions.  methyl ester  122.  the  alkylated 121.  stereochemistry at  The k e t e n e d i t h i o a c e t a l  the  C(17)  121 was c o n v e r t e d t o  Several conventional reactions then provided  k e t o a c i d 123 w i t h a s i x - c a r b o n s i d e c h a i n u n i t a t t a c h e d t o The C r i n g was f o r m e d v i a e n o l l a c t o n e  This  124 t o p r o v i d e t h e  the  the  C(20).  hydrindenone  125 w h i c h was c o n v e r t e d b y s t e r e o s e l e c t i v e r e d u c t i o n and e s t e r i f i c a t i o n the trans-hydrindanone  118.  Fukumoto, K a m e t a n i , and c o - w o r k e r s ' ^ d e v i s e d a r o u t e to  the  trans-hydrindane  sulphone d e r i v a t i v e  Scheme 20  25  126.  The  (Scheme 20)  chiral  to'  hydrindenedione intermediate  127 was c o n v e r t e d i n s e v e r a l s t e p s t o t h e  128.  Ozonolysis of  bicyclic  128 f o l l o w e d b y h y d r o l y s i s  a c e t a l i s a t i o n p r o v i d e d a c i d a c e t a l 129.  and  The c a r b o x y l i c a c i d  group  was c o n v e r t e d t o a m e t h y l g r o u p a n d a o n e - c a r b o n h o m o l o g a t i o n monocyclic alkene 130. a l k y l a t i o n of derivative  The C r i n g was t h e n c o n s t r u c t e d b y  t h e m e s y l a t e 131 t o g i v e t h e t r a n s - h y d r i n d a n e  126.  26  provided  intramolecular sulphone  2.  The o b j e c t i v e synthetic  route  from  and s i d e c h a i n o f target correct  of  strategy (18)  at  (18)  to  the C/D r i n g  132 w h i c h h a s  system  The the  C ( 1 3 ) , C(17) and C ( 2 0 ) .  involved  v i a the d i n i t r i l e this  Scheme 21 27  enantiospecific  11-oxygen f u n c t i o n a l i t y .  (Scheme 2 1 )  A c y l o i n c y c l i s a t i o n of  132  was t o d e v e l o p a n  r e p r e s e n t e d by the h y d r i n d e n o n e  (+)-9,10-dibromocamphor 134.  containing  stereochemistry  The s y n t h e t i c  diester  investigation  (+)-9,10-dibromocamphor  steroids  molecule i s absolute  this  DISCUSSION  the  133 t o  conversion the  d i e s t e r would  of  corresponding  then y i e l d  the  tricyclic  compound 135 w h i c h w o u l d be e x p e c t e d t o u n d e r g o  cleavage to p r o v i d e the  the hydrindene  corresponding ester  would enable a v a r i e t y the  desired  of  (4)  target  molecule  s i d e c h a i n s t o be i n t r o d u c e d  following  c o n v e r s i o n of  (18)  was s y n t h e s i s e d  previously  f£  procedures.5»l?»23c  (138)  the  at  132  C(20)  of and  with  'R'-configuration.  bromocamphor  dinitrile  Stereoselective alkylation  137 w o u l d p r o v i d e  (+)-9,10-Dibromocamphor  dinitrile.  136.  oxidative  r g t  g  t  e  £  p  (+)-9,10-dibromocamphor  Previous attempts 139 b y r e a c t i o n  of  n  t  h  e  s y n t  (18)  i n our the  developed  to  from (+)-3-endo-  bromination  hetic the  laboratory  to  ethylene ketal  of  p l a n was  corresponding synthesise  of  the C ( l ) - C ( 2 )  b o n d . ^ ' ^ c  t h e m o n o c y c l i c compound 140 i n a d d i t i o n To o v e r c o m e t h i s  fragmentation,  it  to  dibromocamphor 18 w i t h l i t h i u m  (18)  and p r o t e c t  the  aluminium hydride  the d e s i r e d d i n i t r i l e  28  139.  H O ^ ^ o ^  X = B r o r CN 140  proceeded smoothly  *H 400 MHz nmr showed t h e p r e s e n c e o f  provided  (+)-9,10-  corresponding a l c o h o l .  d i b r o m o i s o b o r n e o l J_41 i n 92% y i e l d .  complicated  This fragmentation  was d e c i d e d t o r e d u c e  139  the  (+)-9,10-dibromocamphor  w i t h s o d i u m c y a n i d e i n DMSO ( o r DMF, HMPA, DMPU) w e r e  by f r a g m e n t a t i o n  the  Capillary glc  Reduction  to provide  (OV-101,  a s i n g l e epimer.  of  9,10-  190°C)  By a n a l o g y  and with  the corresponding r e d u c t i o n of the e x o - a l c o h o l 141. exo a t t a c k ,  camphor (1)  Endo a t t a c k o f  52  t h i s was assumed t o  the h y d r i d e  ion is  be  favoured over  a s t h e e x o p a t h w a y i s b l o c k e d by t h e C ( 7 ) m e t h y l  group.  N^Br  VS*  HO,  H  141  The s e c o n d a r y a l c o h o l g r o u p was p r o t e c t e d a s t h e silyl  ether.  Treatment of  141 w i t h TBDMS t r i f l a t e  and  tert-butyldimethyl2,6-lutidene  53 i n dichloromethane in high y i e l d  (90%).  p r o v i d e d 9 , 1 0 - d i b r o m o i s o b o r n y l TBDMS e t h e r The e t h e r  142 was t h e n r e a c t e d w i t h  sodium  c y a n i d e i n DMF t o p r o v i d e 9 , 1 0 - d i c y a n o i s o b o r n y l TBDMS e t h e r 96% y i e l d .  The S^2 r e a c t i o n o f  a catalytic  amount o f p o t a s s i u m i o d i d e .  141  142 was f a c i l i t a t e d  142  The n e x t  However, the  143 t o  144.  the n i t r i l e  143 w i t h 40% p o t a s s i u m h y d r o x i d e i n  g l y c o l d i d not p r o v i d e the expected d i a c i d 145. of  the crude product  showed b a n d s a t  29  of  144  the d i n i t r i l e first  in  by t h e a d d i t i o n  corresponding diester groups of  (143)  143  s t e p was t h e c o n v e r s i o n o f  (142)  the  attempted h y d r o l y s i s  of  ethylene  The i n f r a r e d  spectrum  3 6 0 0 - 2 4 5 0 cm * a n d 1710 cm * w h i c h  are t y p i c a l carbonyl  of  carboxylic acid functionality.  stretch  hydrolysis  at  1755 cm * was e v i d e n t .  (89.5°C).  solid  (55% y i e l d ) ,  The i n f r a r e d  of  additional  peak a t It  the  white  w h i c h was c h a r a c t e r i s t i c  that after  of  the s i l y l protecting  a  group  (as e x p e c t e d i n s t r o n g b a s e ) , the h y d r o x y the a c i d lactone  conditions.  Subsequent treatment  provided  ester  the  lactone  of  146 i n  the a c i d i c  146 w i t h e t h e r e a l  protecting  145  work-up  diazomethane  147.  C0 Me 2  147  146  lactone  >1  d i a c i d product  °nb —. ° To p r e v e n t  had  146  145  143  at  5-membered  0.  had c y c l i s e d to p r o v i d e  point  e s t e r group and an  CN CN  -J-SiO  nitrile  a sharp melting  the expected methyl  1775 cm \  was e v i d e n t  which exhibited  additional  s p e c t r u m showed two c a r b o n y l p e a k s ; one  1735 cm * c o r r e s p o n d i n g t o  cleaved  Treatment  product w i t h e t h e r e a l diazomethane provided a  crystalline  lactone.  However, an  formation  group which would not  it  was d e c i d e d t o u s e a n  c l e a v e under  30  the n i t r i l e  alternative hydrolysis  conditions. its  The m e t h o x y e t h o x y m e t h y l  stability  protecting  i n strong base.  the a l c o h o l group  9,10-Dibromoisobornyl  It  (MEM) g r o u p was c h o s e n due  to  would a l s o have the advantage  of  i n a subsequent a c y l o i n  MEM e t h e r  45% y i e l d u s i n g t h e p r o c e d u r e  (148)  was p r e p a r e d  (MEM t r i e t h y l a m m o n i u m  condensation.  (Scheme 2 2 ) chloride  in in  54 acetonitrile)  r e p o r t e d by Corey and c o - w o r k e r s .  the p r o t e c t i o n  s t e p was a t t r i b u t e d t o  w h i c h was a y e l l o w o i l MEM e t h e r  instead of  148 was c o n v e r t e d t o  i s o b o r n y l MEM e t h e r gave d i a c i d  (149)  the  the use of  a white  i n 61% y i e l d .  150 w i t h e x p e c t e d r e t e n t i o n  from the d i n i t r i l e  derivative  dinitrile  to  hydrolysis  9,10-dicyanohydrolysis  dimethyl  ester  group.  151 i n 54%  149.  the corresponding p r o t e c t e d  decided to revert  The  t h e MEM p r o t e c t i n g  H o w e v e r , as h i g h e r y i e l d s were o b t a i n e d f r o m 141 t o  solid.  Subsequent n i t r i l e of  for  i m p u r e MEM r e a g e n t  crystalline  dinitrile  E s t e r i f i c a t i o n w i t h diazomethane provided yield  The l o w y i e l d  the use of (143-145)  dinitrile  this  protecting  lactone  formation  Scheme 22  31  with  9,10-dibromoisoborneol t h e TBDMS g r o u p ,  group.  In  the  was e l i m i n a t e d  it  was  problematic by  -  modifying  the work-up  carefully  a c i d i f i e d w i t h 0.1 N h y d r o c h l o r i c  extracted with ethyl hydroxy d i a c i d  procedure.  The b a s i c  acetate to prevent  a c i d and  75% o v e r a l l y i e l d  t h e TBDMS e t h e r  provided  formation.  dimethyl  152  from the d i n i t r i l e  143.  C0 Me  2  C0 Me 2  •  2  -j-SiO  C0 Me  I  2  144  152  a c y l o i n c o n d e n s a t i o n was e m p l o y e d t o p r e p a r e enediolate  C0 Me 2  C0 Me  R e p r o t e c t i o n as  144 i n 91% y i e l d .  C0 Me HO  silylated  the  145  152 i n  The  lactone  diazomethane p r o v i d e d the  143  was  immediately  prolonged exposure of  145 t o a c i d i c c o n d i t i o n s w h i c h f a v o u r  Esterification with ethereal  ester  reaction mixture  154 f r o m d i e s t e r  144.  The f i r s t  the  tricyclic  attempted  -f-SiO  2  144  153  32  154  a c y l o i n c o n d e n s a t i o n was c a r r i e d o u t b y r e f l u x i n g sodium and t r i m e t h y l s i l y l In  these modified  conditions^) and i n h i b i t  chloride  (TMSC1) f o r  acyloin conditions  TMSC1 was a d d e d t o  the occurrence of  trap  the  was u n r e a c t e d s t a r t i n g  144.  still  extra  material  care to  no e v i d e n c e o f  the  toluene.  t o as Ruhlmann  intermediate  enediolate  153  a competing Dieckmann c o n d e n s a t i o n . 'product'  taking  144 w i t h  16 h i n d r y  (often referred  However, the o n l y c h a r a c t e r i s e d  times,  diester  work-up  The r e a c t i o n was r e p e a t e d  exclude a i r  silylated  recovered after  and m o i s t u r e  enediolate  154.  but  there  Although  s u c c e s s f u l a c y l o i n c y c l i s a t i o n s using these conditions  several was  many  have been  56 reported,  the o n l y reasonable y i e l d  formation provides  is the  reported  the a c y l o i n c o n d e n s a t i o n of silylated  enediolate  for  dimethyl  (154)  which  156  Since these r e a c t i o n it  adipate  ring  156.^6>57,58  155  product  6-membered  conditions  did not  provide  the  was d e c i d e d t o u s e a s o d i u m - p o t a s s i u m a l l o y  desired  in  anhydrous  59 ether, to  i n s t e a d of  form the  tricyclic  i n o v e r 80% y i e l d Analogously,  sodium i n t o l u e n e .  it  Bloomfield  6-membered s i l y l a t e d  enediolates  from the corresponding d i e s t e r s  was h o p e d t h a t  the  silylated  33  used these  conditions  158 a n d 160  157 a n d 1 5 9 .  enediolate  154 w o u l d  form  w i t h the use of ether  a more p o w e r f u l  r e d u c i n g agent and t h a t use  as a s o l v e n t would m i n i m i s e any s i d e - r e a c t i o n s .  159  with sodium-potassium a l l o y ,  enediolate  154 was i n d e e d i s o l a t e d , a l t h o u g h  the d e s i r e d  some s t a r t i n g d i e s t e r  The p r o b l e m o f u n r e a c t e d s t a r t i n g d i e s t e r  sodium-potassium a l l o y  spectrum of  of  i n a n 86% y i e l d o f  silylated  154 showed a c h a r a c t e r i s t i c  presence of  (CH > Si] 3  the  3  and the  are r e a d i l y  1  cleaved to  enediolate  vinyl  ether  (CDC1  3 >  154.  band a t  peak and an i n t e n s e  H nmr  trimethylsilyloxy  Silylated enediolates but  excess  of ratio.  The  infrared  1690 cm  fragment  at  m/e  270 MHz) s p e c t r u m showed  protons.  are s t a b l e under n o n - h y d r o l y t i c the  144  144 was  and by i n c r e a s i n g t h e p o t a s s i u m : s o d i u m  t h e mass s p e c t r a showed t h e p a r e n t 73 [ l o s s  initial  silylated  overcome i n subsequent e x p e r i m e n t s by u s i n g a l a r g e r  This resulted  the  160  experiment  was a l s o e v i d e n t .  In  of  conditions  c o r r e s p o n d i n g a c y l o i n by a l c o h o l y s i s  34  or  the  acid-catalysed hydrolysis.  It  was d e c i d e d t o  treat  154 w i t h  m e t h a n o l s i n c e a c i d i c c o n d i t i o n s w o u l d p r o b a b l y c l e a v e t h e TBDMS g r o u p a n d p r o v i d e a p r o d u c t w i t h two s e c o n d a r y a l c o h o l g r o u p s . crude s i l y l a t e d e n e d i o l a t e p r o v i d e d a 1:1  mixture  y i e l d from the d i e s t e r  of  154 was r e f l u x e d i n d r y m e t h a n o l the  The  and  i s o m e r i c a c y l o i n s 161 a n d 162 i n 48%  144 ( b a s e d o n r e c o v e r e d 1 4 4 ) .  The i s o m e r s w e r e  s e p a r a t e d b y c o l u m n c h r o m a t o g r a p h y a n d a c y l o i n 161 was c o n v e r t e d the corresponding ketoacetate  144  163 i n 76% y i e l d .  154  161  162  T h e s t r a t e g y was t h e n t o c l e a v e t h e TBDMS g r o u p t o g i v e ketoacetate  164 f o l l o w e d b y CAN o x i d a t i v e  the hydrindenone  165.  cleavage of  a g a i n w i t h c r u d e 154 n o f r e e a c y l o i n s w e r e i s o l a t e d .  infrared  spectrum of  164 t o  deprotected provide  However, on r e p e a t i n g the m e t h a n o l y s i s  isomeric methoxyketones  to  166 a n d 167 ( 1 : 1 ,  74% y i e l d )  Instead,  step,  the  were i s o l a t e d .  166 a n d 167 showed n o - O H s t r e t c h a n d t h e mass  35  The  154  166  s p e c t r a l d a t a showed a p a r e n t acyloins  161 a n d 1 6 2 .  presence of  ether  deprotected with fluoride  structure analysis  of  than the  prosition  The i s o l a t i o n o f  the  3  group.  The m e t h o x y k e t o n e  i o n i n THF t o p r o v i d e  166 was  the a l c o h o l  168.  i n the  tricyclic  although  it  this  166 and 167 was a n u n e x p e c t e d  r e a c t i o n was f o u n d i n  s h o u l d be n o t e d t h a t  the  literature,  these a l c o h o l y s i s r e a c t i o n s  silylated enediolates.  In our c a s e ,  is  that  some TMSC1 was s t i l l  3  >  36  One  present which would r e a c t  the methanol to provide h y d r o c h l o r i c a c i d .  M e S i C l + MeOH  were  the  m e t h a n o l y s i s was p e r f o r m e d o n t h e c r u d e s i l y l a t e d e n e d i o l a t e . hypothesis  the  system.  the methoxyketones  No p r e c e d e n t f o r  The  crystallographic  The m e t h y l e t h e r was shown t o o c c u p y  result.  p e r f o r m e d on p u r i f i e d  corresponding  (CDC1 » 400 MHz) c o n f i r m e d  168 was u n a m b i g u o u s l y c o n f i r m e d b y X - r a y  (Appendix 2 ) .  equatorial  p e a k 14 amu h i g h e r  P r o t o n nmr  the methyl  167  A s o l u t i o n of  Me SiOCH 3  3  + HCl  the  with  crude s i l y l a t e d e n e d i o l a t e t o be a c i d i c t o l i t m u s .  In  154 i n m e t h a n o l was s u b s e q u e n t l y the a c i d h y d r o l y s i s  H  T  enediolates.  OH 3  a r e t h e a c y l o i n 170 a n d t h e  A mechanism c o n s i s t e n t w i t h t h i s r e s u l t  Scheme 23  37  3  171  170  r e p r e s e n t e d by 169, the p r o d u c t s 171.^"*  silylated  Me SiOSiMe  169  ether  of  found  disilyl  i s shown  in  Scheme 2 3 .  Protcraation of  nucleophilic attack intermediate ether  171.  the s i l y l a t e d  of water  provides  Loss of  methanolysis of  a proton  169 f o l l o w e d 172.  the  disilyl  from the oxonium i o n i n t e r m e d i a t e provides  166 a n d 1 6 7 .  the a c y l o i n 170.  154 f o l l o w e d b y n u c l e o p h i l i c  intermediate  174.  Desilylation followed  intermediate  175, which tautomerises  to  attack  In  173  our  (Scheme 24)  Protonation of  the  a proton  the methoxyketones  case,  will  silylated  of methanol w i l l  by l o s s o f  by  This  to provide  154 i n a n h y d r o u s a c i d i c c o n d i t i o n s  the methoxyketones  enediolate  intermediate  172 c a n t h e n u n d e r g o d e s i l y l a t i o n  and subsequent t a u t o m e r i s a t i o n  provide  enediolate  provide  provides  166 a n d 1 6 7 .  154b  154a  154  -H  4  174a  171  174  175  Scheme 24  38  166  I n subsequent m e t h a n o l y s i s  reactions of the s i l y l a t e d  154, a l a r g e excess o f TMSC1 was added w i t h the methanol.  enediolate I t was  hoped t h a t t h i s would ensure methoxyketone f o r m a t i o n and have t h e a d d i t i o n a l advantage o f c l e a v i n g t h e TBDMS group under the a c i d i c conditions.  T h i s e x p e c t a t i o n was r e a l i s e d and a c i d i c m e t h a n o l y s i s o f  154 p r o v i d e d a 1:1 m i x t u r e  of the deprotected  methoxyketones 168 and  176 i n 64% o v e r a l l y i e l d from t h e d i e s t e r 144.  OSiMej -T-SfO  I  OSi'Mej 154  168  O x i d a t i v e cleavage  176  o f the C ( l ) - C ( 2 ) bond o f the camphor s k e l e t o n  (Scheme 25) was r e a d i l y a c c o m p l i s h e d w i t h C A N ^ ' ^ f o l l o w i n g  experimental  procedure used by Stevens and co-workers ( c f . Scheme 7) on s i m i l a r  borneol  2 A 62  and i s o b o r n e o l systems.  '  T h i s p r o v i d e d t h e i s o m e r i c aldehydes 178 and  180, and e s t a b l i s h e d t h e c o r r e c t a b s o l u t e s t e r e o c h e m i s t r y and C ( 1 7 ) .  a t C(13)  The r e a c t i o n o f CAN w i t h methoxyketones 168 and 176 • OMe  MeO-T*-—L 168  0  H  177  39  178  r e s u l t e d i n the appearance of to  the  formation  of  a 1:1  a d e e p r e d c o l o u r w h i c h was  CAN:alcohol complex.  to a p a l e y e l l o w as the o x i d a t i o n  took p l a c e .  i s presumably a o n e - e l e c t r o n p r o c e s s ^ radical  intermediates  Due t o partial  purification  nature  showed a d o u b l e t was a s s i g n e d t o  of  infrared  5-membered r i n g  spectrum of is  free  in  However,  in  180.  doublets  consistent  the A band  crude 178, assigned to  the  corresponding keto  ( J = 12 H z , 7 H z ) a t  6 3.83  t h e d o u b l e b o n d i n t h e 5-membered  the  which with  ring.  The a l d e h y d e s 178 a n d 180 w e r e c o n v e r t e d by J o n e s (diazomethane)  to  the  0  182  180 40  oxidation  corresponding  181  178  at  the  aldehyde  t h e C(9) m e t h i n e p r o t o n and i s c o n s i s t e n t  f o l l o w e d by e s t e r i f i c a t i o n  only  c o n s i s t e n t w i t h the d o u b l e bond i n  The *H nmr o f of  cleavage  t h e a l d e h y d e s 178 a n d 1 8 0 ,  i n w h i c h the d o u b l e bond i s  178 and i n t h e  conjugated ketone group, 6-membered r i n g .  and p r o c e e d s v i a t h e  faded  t h e c r u d e k e t o a l d e h y d e s 178 and 180 was  w i t h the proposed s t r u c t u r e s  1675 cm * i n t h e  The o x i d a t i v e  was a c h i e v e d b y c o l u m n c h r o m a t o g r a p h y .  the s p e c t r a l data of  in  The r e d c o l o u r  177 a n d 1 7 9 .  the unstable  6-membered r i n g  attributed  180  esters  181 a n d 1 8 2 .  The o v e r a l l y i e l d  176 t o  181 a n d 182 was 53%.  from methoxyketones  The i s o m e r i c e s t e r s  s e p a r a t e d by column chromatography,  exhibited  181 a n d 1 8 2 ,  s p e c t r a l data  w i t h the proposed s t r u c t u r e s .  In  (Figure  (H ) a p p e a r e d a s a d o u b l e t  1),  the methine  ( J = 14 H z , 5 H z ) a t the  proton  The v i n y l  of  6 3 . 9 5 due t o c o u p l i n g w i t h p r o t o n s  proton  ( J = 2 H z ) due t o a l l y l i c confirmation  of  the  (H^)appeared as a t r i p l e t  coupling with protons  structure  5  400 MHz  consistent 181  doublets  H^ and H g ,  at  axial 6 5.78  H^, a n d H^,.  was o b t a i n e d f r o m t h e  s p e c t r u m , w h i c h showed a s t r o n g a b s o r p t i o n a t a conjugated  readily  t h e 400 MHz * H nmr s p e c t r u m o f  l a r g e and s m a l l c o u p l i n g c o n s t a n t s c o n s i s t e n t w i t h i t s  position.  of  168 a n d  infrared  1675 cm  Further (ir)  characteristic  ketone.  4  t  2  H nmr Figure  41  1  1  PP° °  In proton  t h e 4 0 0 MHz  H nor  spectrum of  (H„)appeared as a doublet  of  182 ( F i g u r e  doublets  the c o r r e s p o n d i n g v i n y l the d o u b l e bond i s not  at  proton  65.52. (H^)  methine  The v i n y l  the  at  proton  This signal is upfield  signal in  conjugated to  the  ( J = 14 H z , 7 H z )  6 3 . 0 2 due t o c o u p l i n g w i t h p r o t o n s H ^ and H ^ . (Hj) appeared as a m u l t i p l e t  2),  181, as i n t h i s  of isomer  ketone.  C0 Me 2  182  X  _r*L/  I  4  2  3  PP  1  l.  4 0 0 MHz * H nmr Figure 2 The f i n a l Scheme 2 5 .  P r o t e c t i o n of  I n t r o d u c t i o n of 183 a t  C(20)  s t e p s i n the  s y n t h e s i s a r e shown f o r  ester  the ketone would p r o v i d e k e t a l  a s i d e c h a i n u n i t by a l k y l a t i o n  i s expected to  g i v e the d e s i r e d  ^C0 Me  *R  of f  the  configuration  2  MeCK 181  183 Scheme 25 42  ester  in 183.  ester  C0 Me  2  181  at  tt  c  at C(20).  The e x p e c t a t i o n  of p r e v i o u s  o f s t e r o e s e l e c t i v i t y i s based on the r e s u l t s  alkylation studies. 63  Wicha and B a l  found t h a t a l k y l a t i o n o f the s t e r o i d a l systems  185 and 186 w i t h v a r i o u s s i d e c h a i n u n i t s gave e x c l u s i v e formation of 64 the C(20) 'R' a l k y l a t e d product (187-189). P a r t r i d g e and co-workers  C0 M  C0 Me  2  2  185 166  20 ^ R  e  2  187 R *THP, R = Me  R= THP R= H  2  188 Rj* H, 2 R  iii  R = H, a  = > C  ^^T^  R= 2  found t h a t a l k y l a t i o n o f the s t e r o i d a l systems 190 and 191 gave 192 and  193 ( l i t t l e o r none of the c o r r e s p o n d i n g  'S' a l k y l a t e d product was  ;o Et 2  X  f  T  1  I'  THPO  THPO' 190 191  detected).  X = H X = OTHP  192 193  I n our l a b o r a t o r y ,  c h i r a l e s t e r 194 w i t h v a r i o u s s t e r e o s e l e c t i v i t y to provide  X = H X • OTHP  i t was found t h a t a l k y l a t i o n o f the s i d e chains  proceeded w i t h 95-100%  'R' a l k y l a t e d products 195-198 i n  43  greater  t h a n 80% y i e l d .  by p o s t u l a t i n g preferred  65  The s t e r e o s e l e c t i v e a l k y l a t i o n was  electrophilic  conformation  (199)  attack of  on the  l e s s - h i n d e r e d face of  the enolate of  194.  194 199  used a s i m i l a r (40)  stereoselective alkylation  a s shown p r e v i o u s l y Thus,  followed  expected to p r o v i d e  184.  i n the  Stork  the  recently  195  R -  196  R = Me  197  R = CH CMe»CH  198  R =  s y n t h e s i s of  CH CH=CH 2  2  2  3  adrenosterone  a stereoselective alkylation  the e s t e r  to a methyl  of  C(17) and C ( 2 0 ) .  44  183  g r o u p and d e k e t a l i s a t i o n  T h i s would complete the s y n t h e t i c  shown i n Scheme 2 1 , w i t h c o n t r o l  of  is  p l a n as  the a b s o l u t e s t e r e o c h e m i s t r y  at  2  2  (CH ) CHMe  i n Scheme 1 0 .  from the above r e s u l t s ,  by c o n v e r s i o n o f  explained  C(13),  2  3.  EXPERIMENTAL  General M e l t i n g p o i n t s were d e t e r m i n e d on a K o f l e r m i c r o h e a t i n g are uncorrected.  Infrared  (ir)  M o d e l 710B s p e c t r o p h o t o m e t e r of polystyrene.  and a r e c a l i b r a t e d w i t h t h e  nuclear magnetic resonance s p e c t r a  a r e g i v e n i n cm  (*H nmr)  1601 cm The  were t a k e n i n  270 MHz on a h o m e - b u i l t  unit  and B r u k e r T T - 2 3 c o n s o l e .  on a V a r i a n X L - 3 0 0 , Signal positions  and a t  deuterochloro-  c o n s i s t i n g of  u s i n g the 6 s c a l e .  c o n s t a n t s , and i n t e g r a t e d  per m i l l i o n  32 K  recorded  instrument.  downfield  from  Signal multiplicity,  areas are i n d i c a t e d  an  coupling  in parentheses.  Low  mass s p e c t r a w e r e d e t e r m i n e d o n a V a r i a n MAT C H - 4 B mass  spectrometer. of  300 MHz w e r e  400 MHz o n a B r u k e r WH-400  are given i n p a r t s  tetramethylsilane  resolution  Spectra at  band  proton  O x f o r d I n s t r u m e n t 6 3 . 4 KG s u p e r c o n d u c t i n g magnet a n d a N i c o l e t computer  and  s p e c t r a were r e c o r d e d on a P e r k i n - E l m e r  Absorption positions  f o r m and r e c o r d e d a t  stage  The m a j o r  ion fragmentations  are reported  t h e b a s e p e a k , a n d a r e q u o t e d a s m/e_ v a l u e s .  as percentages  E x a c t mass m e a s u r e m e n t s  w e r e d e t e r m i n e d b y h i g h r e s o l u t i o n mass s p e c t r o s c o p y o n a K r a t o s MS50 mass s p e c t r o m e t e r .  G a s - l i q u i d c h r o m a t o g r a p h y was p e r f o r m e d  on a  H e w l e t t - P a c k a r d m o d e l 5830A g a s c h r o m a t o g r a p h ,  c o n n e c t e d t o a 18835B  capillary  The c o l u m n  inlet  s y s t e m a n d a 18850A t e r m i n a l .  (11.09 m  x 0 . 2 2 mm) was p a c k e d w i t h O V - 1 0 1 a n d h e l i u m was u s e d a s t h e  carrier  gas.  S.  X-ray crystallographic  a n a l y s i s was c a r r i e d o u t  by D r .  M i c r o a n a l y s e s were performed by M r . P . B o r d a , M i c r o a n a l y t i c a l  45  Rettig.  Laboratory,  U n i v e r s i t y of  B r i t i s h Columbia, Vancouver.  F l a s h c o l u m n c h r o m a t o g r a p h y was p e r f o r m e d u s i n g M e r c k s i l i c a 60,  230-400 mesh.  Merck s i l i c a  Thin l a y e r chromatography  g e l 60 F  2  ^  c o a t e c  e f f e c t e d w i t h a spray of acid  ^  (tic)  plastic sheets.  gel  was c a r r i e d o u t  on  V i s u a l i s a t i o n was  ammonium m o l y b d a t e i n a 9 : 1  ethanol/sulphuric  solution. All  reactions involving air  p e r f o r m e d under an atmosphere of flame-dried glassware.  or moisture  dry argon u s i n g e i t h e r  oven o r  The p e t r o l e u m e t h e r was o f b o i l i n g  3 5 ° C - 6 0 ° C a n d was d i s t i l l e d p r i o r as f o l l o w s :  s e n s i t i v e r e a g e n t s were  acetonitrile  to use.  range  Dry s o l v e n t s were p r e p a r e d  and d i c h l o r o m e t h a n e b y d i s t i l l a t i o n  from  o  calcium hydride; sieves;  diethyl  d i m e t h y l f o r m a m i d e by d i s t i l l a t i o n ether  and t e t r a h y d r o f u r a n by r e f l u x i n g  a l u m i n i u m h y d r i d e f o l l o w e d by d i s t i l l a t i o n ;  t o l u e n e by  f r o m c a l c i u m h y d r i d e f o l l o w e d by d i s t i l l a t i o n benzophenone.  (+)-3-endo-Bromocamphor  C h e m i c a l Company,  f r o m 4A m o l e c u l a r  (4)  over  lithium  distillation  f r o m s o d i u m and  was o b t a i n e d f r o m t h e  Aldrich  Inc.  (+)-9,10-Dibromocamphor  (18)  was p r e p a r e d f r o m  (+)-3-endo-bromo-  Br  Br  Br 4  i  Br  11  5  Br /C1S0 H/1 h 2  3  ii  Br /ClS0 H/5 d 2  3  46  18  iii  Br /H0Ac/0°C 2  camphor  (4)  i n 3 s t e p s a s shown f o l l o w i n g  used by H u t c h i n s o n et a l . 3-bromocamphor (25% o v e r a l l  Typically,  the  experimental  100 g - 1 5 0 g o f  (A) p r o v i d e d 30 g - 5 0 g o f  To a c o l d  (+)-9,10-dibromocamphor  (0 C) s o l u t i o n o f  3 h the r e a c t i o n mixture  (+)-9,10-dibromocamphor  was p o u r e d o n t o  dried  P u r i f i c a t i o n by f l a s h chromatography 5:1)  (1.85 g ,  A00 M H z ) : 1 . 2 0 (AH, m), J  *  -  2.21  (film):  (IH,  m),  3A00 ( b r ) ,  1.29  10 H z ) , 3 . A 7  (IH,  mmol).  The c o m b i n e d  ethereal  (1A1)  ether/  as a c o l o u r l e s s 1  3  3  1.A6  (IH,  e x c h a n g e a b l e w i t h D^), (IH,  d, J -  m),  1.63-1.88  3.2A  (IH,  10 H z ) ,  t h e p r o c e d u r e u s e d by Dadson e t al^.  A7  oil  1 2 A 0 , 1 0 7 5 , 10A0 c m ' ; « ( C D C 1 ,  d , J = 10 H z ) , 3 . 5 1  T h i s i s a m o d i f i c a t i o n of  g , 3.20  ( s i l i c a g e l ; petroleum  ( 3 H , s; CH_ ),  ( 2 H , m, 1 p r o t o n  in  (MgSO^,) a n d c o n c e n t r a t e d .  provided 9,10-dibromoisoborneol  92%); i r  (0.12  (18)  an i c e / 1 N h y d r o c h l o r i c  and e x t r a c t e d 3 t i m e s w i t h e t h e r .  l a y e r s were washed w i t h w a t e r ,  ether  (18)  1A1  THF ( 2 5 m L ) , was a d d e d l i t h i u m a l u m i n i u m h y d r i d e  acid mixture  (+)-endo-  yield).  9,10-Dibromoisoborneol  After  procedure  d,  3.77  (IH,  d , J <= 10 H z ) , 4 . 0 1  7 H z , 4 H z ; CHOH); m/e 215 ( 1 4 ) ,  213 ( 1 6 ) ,  E x a c t mass c a l c d . 231.0397; A n a l , found:  (IH,  (relative  188 ( 7 1 ) ,  for  C  calcd.  1 ( )  H  for  m, c o l l a p s e s t o dd i n D 0 , J « 2  intensity):  186 ( 7 3 ) ,  151 ( 4 1 ) ,  (M -Br,  3/6),  +  109 ( 5 5 ) ,  107  1 6  0 B r - B r : 233.0364/231.0384; found:  C  1 ( )  H  1 6  OBr :  (100); 233.0363/  2  C 38.49, H 5.17, Br 5 1 . 2 1 ;  2  C 38.44, H 5.20, Br 51.05.  9 , 1 0 - D i b r o m o i s o b o r n y l TBDMS E t h e r  (142)  1*1  To a c o l d 4 . 1 7 mmol)  (0°C)  142  s o l u t i o n of  i n dichloromethane  ( 0 . 9 m L , 10 mmol) of  233/231  stirring  9,10-dibromoisoborneol  ( 2 0 mL) was a d d e d  a n d TBDMS t r i f l a t e  a t 0°C t h e  s o l u t i o n was p o u r e d o n t o w a t e r  s o l u t i o n and w a t e r .  The o r g a n i c  (1.30  After  saturated  l a y e r was t h e n  dried  gel;  5:1)  (142)  as a c o l o u r l e s s o i l  2860,  1 2 5 5 , 1 1 2 5 , 1085 c m " ; 1  0.88  [9H, s ; S i C ( C H _ ) ] ,  1.75  (4H, m),  3  10 H z ) , 3 . 5 4  2.22 (IH,  3  1.16  provided 9,10-dibromoisobornyl (1.60 g , 90%); i r  (film):  6 ( C D C 1 , 400 M H z ) : 0 , 0 7  (IH, m), 3.25  m),  (IH,  1.27  48  TBDMS  2965, 2900, 0.11  (3H,  ( 3 H , s ; C H ) , 1.39  (IH,  m),  3  d , J = 10 H z ) , 3 . 3 7  d d , J = 10 H z , 1 H z ) , 3 . 7 0  (silica  (3H, s ) ,  3  (IH,  h  ammonium  P u r i f i c a t i o n by f l a s h chromatography  ether  2.5  and washed  (MgSO^) a n d c o n c e n t r a t e d . petroleum ether/ether  g,  2,6-lutidene  ( 1 . 2 mL, 5 . 2 m m o l ) .  s u c c e s s i v e l y w i t h 0.1 N h y d r o c h l o r i c a c i d , w a t e r , chloride  (141)  (IH,  (IH,  d, J =  d , J = 10 H z ) ,  3.91  (IH,  d d , J = 7 H z , 4 H z ; C H O S i ) ; m/e  371/369/367 133 ( 8 2 ) ,  tf-Cfa,  5/9/4),  107 ( 9 0 ) ,  105 ( 5 2 ) ,  347  (28),  93 ( 4 7 ) ,  (relative  345  (29),  91 ( 5 9 ) ,  intensity):  215 ( 4 7 ) ,  79 ( 6 2 ) ,  213  75  (49),  (99),  81  73 ( 1 0 0 ) ;  E x a c t mass c a l c d .  370.9675; Anal, found:  calcd.  for  for C  1 6  H  C^H^O 3 Q  OBr Si: 2  B r ^ i - C ^ :  C 45.08, H 7.09,  To a so l u t i o n o f 2 . 3 4 mmol)  143  9,10-dibromoisobornyl  amount o f  potassium iodide  reaction mixture  was h e a t e d a t  brine,  three  extracted  solid  (10 m g , 0 . 0 6 m m o l ) .  dried  (MgSO^) a n d c o n c e n t r a t e d .  (0.72 g,  9 6 % ) , mp 7 1 - 7 3 ° C ;  [9H, s ; SiC(CH_ ) ],  (IH,  (2H, m),  1.73  (IH,  3  3  ir  ether/  (143)  as a  (CHC1 ): 3  400 M H z ) :  1.28  (IH,  m),  2960,  0.07 1.32  (3H,  1.82 ( 2 H , m ) , 2 . 1 3 ( I H , m ) , 2 . 2 6  d , J = 17 H z ) , 2 . 3 8  49  onto  ( s i l i c a g e l ; petroleum  (3H, s ) , 0.89  d , J = 17 H z ) , 2 . 3 1  The  times w i t h e t h e r ,  3  m),  mmol)  c o o l e d , poured  1  a ; C H ) , 1.44  g,  48 h ,  2 9 0 0 , 2 8 6 0 , 2 2 5 0 , 1 2 5 5 , 1 1 1 0 , 1080 c m " ; & ( C D C 1 , s ) , 0.11  (1.00  (0.47 g , 9.60  p r o v i d e d 9 , 1 0 - d i c y a n o i s o b o r n y l TBDMS e t h e r  white c r y s t a l l i n e  (143)  110°C f o r  P u r i f i c a t i o n by column chromatography 1:1)  TBDMS e t h e r  i n DMF (50 m L ) , v a s a d d e d s o d i u m c y a n i d e  and a c a t a l y t i c  3  Br 3 7 . 4 9 ;  (143)  142  (3H,  found:  C 45.36, H 7.20, Br 37.20.  9 , 1 0 - D i c y a n o i s o b o r n y l TBDMS E t h e r  ether  370.9688;  (IH,  (IH,  d d , J = 17 H z , 1 H z ) ,  2.57  (IH,  d, J -  intensity):  261 ( M - C H , 4  18 30 H  O N  2  S i  " 4 9  C  18 30  O N  2  S i :  C  H  C  H y d r o l y s i s of  6  7  (IH,  100),  +  C  H  17 H z ) , 3 . 8 2 g  t,  ,  8  7  »  H  9  *  4 9  >  N  8  '  7  9  »  f  o  u  n  d  :  c  ir  in ethylene glycol  3  the  solvent  purification  16.5 h,  ir  ( 3 H , s ; CH_ ), 3  2.24  (3H, m),  2.37  3.69  (3H, s ; C0 CH_ ), 4.27 2  (IH, 3  cooled, times and  dried  3  1.32  solid  d , J = 14 H z ) , 2 . 4 9  1  (IH,  m),  then  ether/ether  1 7 7 5 , 1 7 3 5 , 1070 c m " ; 6 1.86  mg);  146  C o n c e n t r a t i o n and  ( s i l i c a g e l ; petroleum  (2H, m),  1.95  (2H, d , J = 1.5  d d , J = 8 H z , 4 H z ; CHOCO);  50  (275  ethereal  147 a s a w h i t e c r y s t a l l i n e  (CHCl ):  (IH,  with  The c r u d e a c i d - l a c t o n e  stand overnight.  lactone-ester  (130 m g , 7 6 % ) , mp 8 9 . 5 ° C ; 400 K H z ) : 1 . 0 8  three  ( 5 mL) t r e a t e d w i t h a n e x c e s s o f  by column chromatography  provided the  ( 1 8 0 mg,  g a v e c r u d e 146 a s a y e l l o w o i l 1  diazomethane and a l l o w e d t o  (143)  l a y e r s were washed w i t h w a t e r  3 6 0 0 - 2 4 5 0 , 1 7 5 5 , 1710 c m " .  was d i s s o l v e d i n e t h e r  3:1)  for  ( 1 0 mL) was a d d e d 40% p o t a s s i u m h y d r o x i d e  The s o l u t i o n was r e f l u x e d f o r  Removal of  for  147  9 , 1 0 - d i c y a n o i s o b o r n y l TBDMS e t h e r  The c o m b i n e d e t h e r e a l  (CHC1 ):  calcd.  146  (10 m L ) .  (MgSO^).  E x a c t mass c a l c d .  (143)  a c i d i f i e d w i t h 1 N h y d r o c h l o r i c a c i d and e x t r a c t e d ether.  (relative  67.91, H 9.43, N 8.78.  9 , 1 0 - D i c y a n o i s o b o r n y l TBDMS E t h e r  To a s o l u t i o n o f  solution  75 ( 8 1 ) :  261.1426; A n a l ,  143  0 . 5 6 6 mmol)  5 . 5 H z ; C H O S i ) ; m/e  120 ( 1 4 ) ,  261.1423; found:  :  J -  (CDC1 (2H,  Hz),  3 >  m),  m/e  (relative  intensity):  E x a c t mass c a l c d . for  C  1 3  H  l g  0 : 4  for  238 ( M , 8 ) , +  C^H^O^:  220 ( 2 9 ) ,  207 ( 2 9 ) ,  102  238.1205; found: 238.1208.  Anal,  (148)  141  To a s o l u t i o n o f i n dry a c e t o n i t r i l e  148  9 , 1 0 - d i b r o m o i s o b o r n e o l (141)  (2.00 g , 6.41  ( 2 5 mL) was a d d e d MEM t r i e t h y l a m m o n i u m  T h e r e a c t i o n m i x t u r e was r e f l u x e d f o r and e x t r a c t e d t h r e e  times w i t h ether.  22 h ,  triethylamine.  c o o l e d , poured onto  The c o m b i n e d e t h e r e a l  were washed w i t h w a t e r ,  dried  by f l a s h c h r o m a t o g r a p h y  ( s i l i c a g e l ; petroleum ether/ether  y i e l d e d t h e MEM e t h e r  (MgSO^) a n d c o n c e n t r a t e d .  148 a s a c o l o u r l e s s o i l  2 9 5 0 , 2 8 8 0 , 1035 c m " ; 6 ( C D C 1 , 3  3.38  1.46  (IH, m),  (IH, m), 3.39  m; CHOMEM), 4 . 7 5 (M -Br, +  1.70-1.90  (4H, m), 2.20  ( 3 H , s; 0CH_ ), 3 . 5 5 3  ( 2 H , m; - O C f l ^ - ) ; m/e  0.4/0.4),  E x a c t mass c a l c d .  (IH, m),  (3H, m), (relative  297/295/293 (M -0MEM, 2 / 4 / 2 ) , +  for  C^H^O^r^-Br:  321.0901/319.0927.  51  (IH,  3.74  m), 3.25  Purification 5:1)  1.24  intensity): 59  (film):  (3H,  (IH,  (3H, m),  89 ( 1 0 0 ) ,  water,  layers  (1.14 g , 45%); i r  400 M H z ) : 1.22  1  mmol)  chloride  ( 4 . 5 g , 2 0 . 0 mmol) f r e s h l y p r e p a r e d f r o m MEM c h l o r i d e a n d  3  calcd.  C 65.53, H 7.61; found: C 65.44, H 7.58.  9 , 1 0 - D i b r o m o i s o b o r n y l MEM E t h e r  CH_ ),  (100);  s;  m), 3.85  321/319 (65);  321.0888/319.0908; found:  (IR,  9 , 1 0 - D i c y a n o i s o b o r n y l MEM E t h e r  (149)  Br >Br  MEMO  CN  MEMO  148  To a s o l u t i o n o f 3 . 8 1 mmol)  149  9 , 1 0 - d i b r o m o i s o b o r n y l MEM e t h e r  (148)  (1.52  i n DMF ( 5 0 mL) was a d d e d s o d i u m c y a n i d e ( 0 . 7 2 g ,  and the r e a c t i o n m i x t u r e h e a t e d a t  90°C f o r  48 h .  1 4 . 6 mmol)  T h e s o l u t i o n was  c o o l e d , poured onto b r i n e ,  extracted three  (MgSO^) a n d c o n c e n t r a t e d .  P u r i f i c a t i o n by f l a s h chromatography  gel;  1:1)  petroleum ether/ether  ether  (149)  2250,  1040 c m " " ;  1.51  (IH, m),  J = 17 H z ) , 2 . 3 5  (0.68 g,  <$ ( C D C 1 , 4 0 0 M H z ) : 1 . 3 0  61%); i r  m),  (2H, m),  2.15  (IH,  m),  2.27  (IH,  d,  d , J = 17 H z ) , 2 . 3 9  (IH,  d , J = 17 H z ) ,  1.88  d , J = 17 H z ) , 3 . 3 5  3.91  (IH,  d d , J = 7 H z , 4 H z ; CHOMEM), 4 . 7 0  ( 3 H , s ; 0CH_ ), 3 . 5 7  2  59 ( 8 1 ) ;  187.1235; found: H 8.27, N 9.58;  Anal,  (d)  (relative  E x a c t mass c a l c d .  187.1237.  (2H, m), 3.72  3  J = 7 H z ; - 0 C H _ 0 - ) ; m/e  89 ( 1 0 0 ) ,  2960, 2900, (IH,  (IH,  21),  (film):  1.31  2.66  AB q u a r t e t ,  (silica  3  (2H, m),  (IH,  dried  ( 3 H , s ; CH_ ),  3  1.75  times with ether,  p r o v i d e d 9 , 1 0 - d i c y a n o i s o b o r n y l MEM  as a c o l o u r l e s s o i l 1  g,  calcd.  C  H 1 6  1  187  (2H, (M -0MEM,  4 3 2~ 4 9°3 0  2  N  C  C ,H 0,N : 16 24 3 2  found C 6 5 . 4 5 , H 8 . 3 0 , N 9 . 7 0 .  52  (d)  intensity):  for for  and 4 . 7 7  o /  o  H  (2H, m),  +  :  C 65.73,  To a s o l u t i o n o f  9 , 1 0 - d i c y a n o i s o b o r n y l MEM e t h e r  182 mmol)  in ethylene glycol  (20 m L ) .  The s o l u t i o n was r e f l u x e d f o r  ether, ether.  carefully  g);  ir  ( 3 H , s ; CH_ ),  3  (3H, m),  J = 14 H z ; C H C 0 H ) , 2  16 H z ; C H C 0 H ) , 2  3.68  2  (2H, m),  2.16  2  2.26  3.75  (IH,  m/e  intensity):  E x a c t mass c a l c d .  (d) m),  (d)  and 2 . 3 5  and 2 . 7 3 3.40  and 4.71  for  (d)  (d)  3.92  ( 2 H , AB  (silica  g e l ; ether)  m), quartet,  ( 2 H , AB q u a r t e t ,  J =  (2H, m),  dd, J = 7 Hz, 4 Hz;  ( 2 H , AB q u a r t e t ,  J = 7 H z ; -0CH_ 0-);  +  2  315 ( M - C H , +  3  1),  330.1678; found 330.1685. (5 mL ) ,  w h i c h was p u r i f i e d  to provide d i e s t e r  53  59  (100);  The  t r e a t e d w i t h an e x c e s s  e t h e r e a l diazomethane and a l l o w e d t o s t a n d o v e r n i g h t .  s o l v e n t p r o v i d e d an o i l  (br),  (IH,  c r u d e d i a c i d 150 was d i s s o l v e d i n e t h e r of  with dried  (IH,  3  330 ( M , 0 . 2 ) ,  C^n^O^:  (d)  1.19  ( 3 H , s ; 0CH_ ), 3 . 5 6  2  (d)  (relative  2.09  3  (2H, s ; 2 x C 0 H ) ,  CHOMEM), 4 . 6 5  times  ( C H C l - j ) : 3 6 0 0 - 2 5 0 0 , 2 9 6 0 , 2 9 0 0 , 1710  1  1.80  three  c r u d e d i a c i d 150 a s a p a l e  1040 c m " ; a ( C D C 1 , 400 M H z ) : 1 . 1 7 (2H, m),  g,  c o o l e d , washed w i t h  l a y e r s were washed w i t h w a t e r ,  (MgSO^) a n d c o n c e n t r a t e d t o p r o v i d e  1.59  18 h ,  a c i d i f i e d t o pH 3 a n d e x t r a c t e d  (0.41  (0.53  (20 mL) was a d d e d 40% p o t a s s i u m h y d r o x i d e  The combined e t h e r e a l  yellow solid  (149)  by column  Removal of  chromatography  151 a s a c o l o u r l e s s  oil  the  (354 m g , 5 4 % ) ; i r 400 M H z ) : 1.10 2.06  (d)  (film):  (d)  1  3  ( 3 H , s; CH_ ), (d)  ( 2 H , AB q u a r t e t ,  ( 3 H , s; CH_ ), 3 . 5 2  3.66  (3H, s ; C0 CH_ ), 3.84 (d)  intensity):  3  C  for  Diacid  145 and D i e s t e r  3 C )  0 :  C  calcd.  l g  H  for 7  l g  H  3 0  extracted  (IH,  3  253 ( M - O M E M , 6 ) , +  O -OCH : 7  3  m),  (2H,  m),  89 ( 1 0 0 ) ,  59  (95);  327.1807; found 327.1810. found:  three  dinitrile  Anal,  C 60.50, H 8.60.  152  143 ( 1 8 0 m g , 0 . 5 6 6 mmol)  (130°C)  in ether  solution  for  48 h ,  and d r i e d  in  ethylene  ( 3 . 0 g i n 3 . 0 mL c o o l e d , washed  a c i d i f i e d w i t h 0.1 N h y d r o c h l o r i c  times with e t h y l  2 8 9 0 , 1710 ( b r ) ,  (d)  152  The s o l u t i o n was r e f l u x e d carefully  (d)  (relative  2  a c i d and  acetate.  The combined o r g a n i c  (MgSO^).  Removal of  t h e c r u d e d i a c i d 145_ a s a y e l l o w o i l  dissolved  2.19  145  were washed w i t h b r i n e  2970,  2  2  ( 1 5 mL) was a d d e d p o t a s s i u m h y d r o x i d e  with ether,  (3H, m),  2  (3H, s; C0 CH_ ), 3 . 6 5  C 60.32, H 8.44;  To a s o l u t i o n o f  water).  1.79  d d , J = 7 H z , 4 . 5 H z ; CHOMEM), 4 . 6 4  143  glycol  2  J = 7 H z ; - O C H _ 0 - ) ; m/e  0.1),  +  (2H, m),  J = 14 H z ; C H _ C 0 M e ) , 2 . 1 0 2  ( 2 H , AB q u a r t e t , 327 ( M - O C H ,  1.52  J = 16 H z ; C H C 0 M e ) ,  (IH,  3  E x a c t mass c a l c d .  m),  (2H, m), 3.63  3  2  (IH,  ( 2 H , AB q u a r t e t ,  3.38  and 4 . 7 0  1.15  3  and 2 . 2 9  and 2 . 6 8  2 9 5 0 , 1 7 3 5 , 1 2 0 0 , 1040 c m " ; 6 ( C D C 1 ,  (220 m g ) ;  1 0 8 0 , 1040 c m " . 1  ir  (film):  provided  3700-2400,  The c r u d e d i a c i d 145 was  (5 m L ) , t r e a t e d w i t h a n e x c e s s o f  54  solvent  layers  ethereal  diazomethane and a l l o w e d to purification ether ir  by column chromatography  152 a s a c o l o u r l e s s o i l  (film):  3 7 0 0 - 3 2 5 0 , 1735 c m "  (br);  2.27  (d)  C H ) , 1.51  ( 2 H , AB q u a r t e t , J -  1  m),  4 (CDC1 ,  1.61-1.85  13 H z ; C H C 0 M e ) , 2  2.21  2  2  3  s i g n a l at  (IH,  6 3.84  to  Decoupling at  a s i n g l e t ; m/e  197 ( 3 9 ) , found:  m; C H O H ) .  Anal,  of  intensity):  calcd.  (IH, 3  for  C  1 A  at  239 ( M - O C H » +  3  for H  9 9  C  0,.:  1 4  H  2 2  238  0 "CH 0: 5  (d)  d, (3H,  (J = 7.5 H z ,  6 2.66 to 1), 3  collapse (1),  239.1283;  C 62.20, H 8.20;  found:  C 62.42, H 8.25. Diester  144  C0 Me  .  2  +  To a c o l d 2 . 1 8 mmol) (1.0 m l ,  (0°C)  s o l u t i o n of  i n dichloromethane  1 1 . 2 mmol)  I \^C02Me f ^ C 0 M e 2  144  152  the hydroxy d i e s t e r  ( 2 0 mL) was a d d e d  a n d TBDMS t r i f l a t e  55  (d  63.08 causes  doublets  62.13 causes the doublet  m),  and 2 . 2 7  and 2.66  m), 3.08 2  75%);  (IH,  (3H, s ; C0 CH_ ), 3.69  to a doublet  153 ( 1 0 0 ) ; E x a c t mass c a l c d .  239.1266.  (IH,  (d)  (d)  D e c o u p l i n g the p r o t o n at  simplify  (relative  (115 mg,  2.04  2.13  2  2  C0 CH_ ), 3.84  (4H, m),  J = 13 H z ; C H C 0 M e ) , 2  ether/  400 M H z ) : 1.10  3  3 Hz, exchangeable w i t h D 0 ; OH), 3.66  4.5 Hz). to  (IH,  3  ( 2 H , AB q u a r t e t ,  the  ( s i l i c a g e l ; petroleum  provided the d i e s t e r  ( 3 H , s;  s;  C o n c e n t r a t i o n and  1:1)  1.16  J -  stand overnight.  152 ( 0 . 5 8 8  g,  2,6-lutidene  ( 1 . 3 mL, 5 . 6 6 m m o l ) .  After  2.5 h of  stirring  at 0 C, the  s o l u t i o n wa6 poured onto w a t e r  washed s u c c e s s i v e l y w i t h 0.1 N h y d r o c h l o r i c a c i d , w a t e r , ammonium c h l o r i d e dried  s o l u t i o n and w a t e r .  (MgSO^) a n d c o n c e n t r a t e d .  colourless o i l cm" ;  3  1.15  3  (3H, m),  2.09  CH_ C0 Me), 2.20 4.00  (M -CH , +  3  t,  20 36°5  S i  C  20 36°5  S i :  H  H  1.18  m),  3.66  (d)  353 ( M - 0 C H , 3  " 4 9 C  H  C  6 2  :  -  3  A 6  2  »  7  '  1  H  6  9  2  8  ;  *  A 3  f  5  144  327 ( 1 0 0 ) ;  u  n  d  :  f  o  u  n  d  144  d i s p e r s i o n of  an argon atmosphere by m e l t i n g  of  diester  TMSC1 ( 2 . 0 m L , 16 mmol)  s;  J « 7.5 H z ) ,  J = 14 H z ; (3H, s ;  intensity):  Anal,  (br)  C0 CH_ ), 2  calcd.  3  369 for  for  62.58, H 9.55.  : Isolation  o f A c y l o i n s 161 a n d 162  161  162  sodium-potassium a l l o y  [formed under  s o d i u m ( 0 . 2 0 g , 8 . 6 mmol)  ( 0 . 2 5 g , 6 . 4 mmol) w i t h a h e a t - g u n ] added a m i x t u r e  c  [9H,  E x a c t mass c a l c d .  327.1629. :  0.88  (2H, t ,  3  (relative  154  To a s t i r r e d  ( 3 H , s),  ( 2 H , AB q u a r t e t , 2  o  A c y l o i n R e a c t i o n of D i e s t e r  0.11  (3H, s ; C0 CH_ ), 3.69  1),  +  144 a s a  2 9 6 5 , 2 9 0 0 , 2 8 6 0 , 1735  ( 3 H , s; C H ^ ) , 1 . 5 6  and 2 . 3 1  then  chromatography  provided diester  (film):  J = 5 . 5 H z ; C H O S i ) ; m/e  1),  C  m),  (d)  (IH,  2  (IH,  (IH,  5:1)  ( 3 H , s),  3  SiC(CH_ ) ],  2  91%); i r  a ( C D C 1 , 400 M H z ) : 0 . 0 7  1  1.77  (0.76 g,  saturated  The o r g a n i c l a y e r was  P u r i f i c a t i o n by f l a s h  ( s i l i c a g e l ; petroleum ether/ether  and  i n anhydrous ether  144 ( 1 . 0 2 g ,  2 . 6 6 mmol)  i n anhydrous ether  56  and p o t a s s i u m  (25 mL) was  and f r e s h l y  (200 m L ) .  The  distilled  reaction  mixture  was s t i r r e d  through  a sintered  the  at  room t e m p e r a t u r e  glass funnel  crude s i l y l a t e d  for  and the  enediolate  20 h , v a c u u m  solvent  16 h .  Removal of  the  compounds b y t i c .  solvent  elution  3:1)  provided  1715,  gave s t a r t i n g  1080 c m " ;  (CDC1 ,  1  0  3  0.88  [9H,  (IH,  m),  1.40  (3H, s ; C H ) , 1.60-1.73  (d)  s ; SiC(CH_ ) ], 3  (d)  91),  1.00  ( 2 H , AB q u a r t e t ,  exchangeable w i t h D 0 ;  129 ( 8 4 ) ,  (relative  75 ( 1 0 0 ) ;  267.1416; found:  (IH,  m),  found:  309 C  (br),  provided  2960, 2900, 2860,  (M -CH , +  3  18 32°3 H  S i  1),  ~ 4 9 C  E  (150 mg,  (br),  (IH,  309  m),  1.37  d d , J = 12 H z ,  m),  1.99  calcd.  +  3  for  for  (IH,  (M -CH , C  l g  H  3 2  2960,  0.02  (IH,  2  m) ,  ( 2 H , m,  d d , J =12 H z ,  1),  267  ( M ^ C ^ ,  0 Si-C K : 3  C.-H-.O-Si: ID J / j  the  isomeric acyloin  ( 1 6 0 m g , 25% b a s e d o n r e c o v e r e d s t a r t i n g  3500  (IH,  gel;  36%).  (3H, s ) , (IH,  1.80  major  A  9  C 66.62,  C 66.48, H 9.90.  Further elution oil  g,  J = 14 H z ; CH_ C=0), 3 . 5 6  E x a c t mass c a l c d . Anal,  3500  1.10  1.91  ——— H 9.94;  for  (silica  (0.37  (film):  (2H, m),  intensity):  267.1415.  ir  CHOSi and O H ) , 4 . 3 1  2  7 . 5 H z ; C H O H ) ; m/e  144  400 K H z ) : 0 . 0 0  d d , J = 12 H z , 7 . 5 H z ) ,  and 2 . 8 0  1 proton  3  3  (IH,  material  material);  s),  2.28  ( 2 0 0 mL) a n d r e f l u x e d  t h e a c y l o i n 161 a s a c o l o u r l e s s o i l  (3H,  7.5 H z ) , 2.04  g).  p r o v i d e d an o i l w h i c h showed t h r e e  23% b a s e d on r e c o v e r e d s t a r t i n g 2900, 2860,  yield  (1.3  P u r i f i c a t i o n by column c h r o m a t o g r a p h y  petroleum ether/ether Further  removed t o  154 a s a p a l e y e l l o w o i l  T h e c r u d e 154 was d i s s o l v e d i n d r y m e t h a n o l  filtered  :  267 2  6  7  ,  1715,  (M -C H , A  1  A  1  6  i  f  g  o  u  n  d  :  material);  1080 c m " ; m/e 1  72),  +  75 ( 1 0 0 ) ;  267.1414.  57  162 a s a c o l o u r l e s s ir  (relative  (film): intensity):  E x a c t mass c a l c d .  for  Ketoacetate  163  — —• —-  161  163  T h e a c y l o i n 161 ( 7 5 m g , 0 . 2 3 mmol) was d i s s o l v e d i n d r y (10 mL) a n d t r e a t e d w i t h a c e t i c a n h y d r i d e (50 m g , 0 . 4 1 mmol) a t  room t e m p e r a t u r e f o r  ( 0 . 1 mL, 1.1 mmol) 16 h .  Water  times  e t h e r , washed w i t h s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n ,  (silica  & (CDC1 , 3  1.03 m), 2.23  (IH, m),  1.13  3:1)  (64 m g , 7 6 % ) ; i r  400 M H z ) , 0 . 0 0  (2H, m),  1.93  (d)  and 2 . 8 1  (d)  1.44  (2H, m),  (IH, m),  5.42  m/e  351 ( M - C H ,  117 ( 5 7 ) , 309.1525.  (IH,  calcd.  for  J -  2.15  [9H, s ; (IH,  m),  (3H, s ;  SiC(CH_ ) ], 3  1.72  3  (IH,  CH 0C0), 3  14 H z ; CH_ C=0), 3 . 5 6 2  (IH,  dd,  d d , J = 12.5 H z , 7 H z ; CHOAc); 1),  +  3  75 ( 1 0 0 ) ; E x a c t mass c a l c d . Anal,  (3H, s ) , 0.88  ( 2 H , AB q u a r t e t ,  intensity):  1  3  2.00  163  1 7 5 0 , 1 7 2 5 , 1 2 3 5 , 1080 c m " ;  ( 3 H , s ; C H ) , 1.46  J = 7.5 H z , 3 H z ; CHOSi), (relative  dried  provided the k e t o a c e t a t e  (film):  (3H, s ) , 0.02  (IH, m),  1.82  with  P u r i f i c a t i o n by column chromatography  g e l ; petroleum ether/ether  as a c o l o u r l e s s o i l  a n d DMAP  ( 1 0 mL) was  a d d e d , a n d t h e n t h e r e a c t i o n m i x t u r e was e x t r a c t e d t h r e e  (MgSO^) a n d c o n c e n t r a t e d .  pyridine  for  C^H^O^Si:  H 9.41.  58  309 ( M - C H , +  4  C ^ H ^ O ^ i :  9  70),  249  (34),  309.1522; found:  C 65.53, H 9.35; found: C 65.80,  A c y l o i n R e a c t i o n of D i e s t e r  144  : Isolation  of  Silylated Enediolate  154  a n d M e t h o x y k e t o n e s 166 a n d 167  144  154  To a s t i r r e d  166  d i s p e r s i o n of  sodium-potassium a l l o y  an argon atmosphere by m e l t i n g (1.0  sodium (0.6  g , 26 mmol) w i t h a h e a t g u n ]  a mixture  of  diester  144 ( 2 . 8  TMSC1 ( 1 0 . 0 mL, 7 9 . 0 mmol) mixture,  g,  i n anhydrous e t h e r 7 . 2 9 mmol)  (25 ml)  the r e a c t i o n f l a s k and f i l t e r Removal of  the  of which  (silica  g e l ; petroleum ether/ether  enediolate  g) was p u r i f i e d  154 a s a c o l o u r l e s s o i l  2 9 0 0 , 2 8 6 0 , 1690 c m " ; 6 ( C D C 1 , 1  3  0.16  [9H, s ; S i ( C H ) ] , 0.18  1.00  (IH,  m),  1.10  ( 3 H , s ; CH_ ),  2.49  (IH, m),  3.57  (IH,  25),  321 ( 6 5 ) ,  3  468.2911;  3  found:  40 h  3:1)  (3.68  by column to provide  270 M H z ) : 0 . 0 1 3  1.50-1.80  the  [6H,  3  (8H, m),  (relative  59  and  ether.  g),  a small  silylated  (film):  2960,  s; OSi(CH_ ) ], 3  [9H, 2.29  s;  for  3  (IH,  C  2 Z (  2  SiC(CH_ ) ],  intensity):  73 ( 1 0 0 ) ; E x a c t mass c a l c d .  468.2912.  The  chromatography  (0.10 g , 86%); i r  m; C H O S i ) ; m/e  at  a sintered glass funnel  [9H, s ; S i ( C H ) ] , 0.88 3  75 ( 6 6 ) ,  for  reaction  (OV-101, 225°C).  solvent provided a pale yellow o i l (0.126  The  f u n n e l washed w i t h anhydrous  portion  was a d d e d  distilled  (175 m L ) .  and m o n i t o r e d by c a p i l l a r y g l c through  and p o t a s s i u m  and f r e s h l y  i n anhydrous e t h e r  was t h e n v a c u u m f i l t e r e d  [formed under  g , 26 mmol)  w h i c h d e v e l o p e d a p u r p l e c o l o u r , was s t i r r e d  room t e m p e r a t u r e mixture  167  m), 468  H  4 8  (M , +  0 Si : 3  3  3  The r e m a i n i n g c r u d e s i l y l a t e d e n e d i o l a t e 154 ( 3 . 5 5 g ) was d i s s o l v e d i n dry methanol  ( 2 0 0 mL) a n d r e f l u x e d f o r  16 h .  Removal of  t h e s o l v e n t p r o v i d e d a n o i l w h i c h i n d i c a t e d one compound b y glc  (OV-101,  190°C) b u t  s h o w e d two s p o t s o n t i c .  ( s i l i c a g e l ; petroleum ether/ether as a c o l o u r l e s s o i l 1),  323 ( M - C H , +  3  Column chromatography  p r o v i d e d the methoxyketone  ( 8 9 0 m g , 4 4 % ) ; ro/e ( r e l a t i v e  2),  281  intensity):  (CHC1 ):  1 7 2 0 , 1 1 1 5 , 1075 c m " ; 6 ( C D C L j , 4 0 0 M H z ) : - 0 . 0 4  -0.03  (3H, s ) , 0.80  1  0CH_ ), 3.61  (IH,  3  [9H, s ; S i C ( C H _ ) ] , 3  (4H, m),  dd, J •  9 H z ; CHOMe); m/e  +  2.50  3  1.02  (3H,  s),  (3H, s ; C H ) , 1.20  ( I H , d , J = 13 H z ) , 3 . 4 4  intensity):  (IH,  338 ( M , 1 ) , +  (3H,  s;  d d , J = 11 H z ,  323 ( M - C H , +  3  1),  281 ( 1 0 0 ) ; E x a c t mass c a l c d .  for  Anal,  C 67.41, H 10.12; found: C 67.40, H 10.00.  calcd.  for  C  i g  H  3 A  0 Si: 3  C^H^OgSi:  (2H, m),  3  7 H z ; 2 H z ; CHOSi), 3.96  (relative  2960, 2875,  3  2860,  2.05  (M ,  i s o m e r i c m e t h o x y k e t o n e 167 a s a w h i t e  s o l i d ( 6 1 0 mg, 3 0 % ) , mp 5 8 - 5 9 ° C ; i r  1.68-1.91 (4H, m),  338  166  (100).  F u r t h e r e l u t i o n p r o v i d e d the crystalline  3:1)  capillary  338.2277; found: 338.2283.  T r i c y c l i c A l c o h o l 168  166  To m e t h o x y k e t o n e fluoride for  168  166 ( 8 8 0 m g , 2 . 6 mmol) was a d d e d  tetrabutylammonium  (20 m L , 20 m m o l : 1 M s o l u t i o n i n THF) a n d t h e s o l u t i o n  1 h at  room t e m p e r a t u r e .  The r e a c t i o n m i x t u r e was e x t r a c t e d  60  stirred three  times w i t h e t h y l water,  dried  a c e t a t e and t h e combined o r g a n i c l a y e r s washed w i t h  (MgSO^) a n d c o n c e n t r a t e d .  chromatography  ( s i l i c a g e l ; ether)  as a w h i t e c r y s t a l l i n e  solid  P u r i f i c a t i o n by  column  provided the t r i c y c l i c  (330 mg, 57%).  alcohol  168  R e c r y s t a l l i s a t i o n from  e t h e r / p e n t a n e p r o v i d e d c o l o u r l e s s n e e d l e s mp 1 3 0 - 1 3 1 C ; i r  (CHC1 ):  3 6 2 0 , 3475 ( b r ) ,  (IH,  1.11  (IH,  m),  1 7 2 0 , 1120 c m " ;  6 (CDC1  1  1.43  ( 3 H , s ; CH_ ),  1.48  3  proton exchangeable w i t h DjO), 2.03 ( 2 H , AB q u a r t e t ,  (relative  calcd. C  for  13 20°3 H  :  H 1  C  3  2  6 9 , 6 1  (IH,  0°3 >  H  :  2  8  '  2  9  * ' 9  (IH,  224 ( M , 3 0 ) , +  1  5  3.94  4  1  2  '  f  o  u  n  d  2 2  400 M H z ) : 1.01 m),  1.65-1.99  m), 2.28  2  intensity):  C  (IH,  J = 1 3 . 5 H z ; CH_ C0), 3 . 4 8  d d , J = 7.5 H z , 3 H z ; CH0H), m/e  3 >  3  (d)  m),  ( 6 H , m, one  and 2 . 8 7  ( 3 H , s ; OCE^),  3.68  (d) (IH,  d d , J = 12 H z , 7 H z ; CHOMe); 206 ( 1 1 ) ,  4.1406.  79 ( 1 0 0 ) ;  Anal,  found C 6 9 . 5 0 , H 9.00.  calcd.  E x a c t mass for  The s t r u c t u r e  was  c o n f i r m e d by X - r a y c r y s t a l l o g r a p h i c a n a l y s i s . A c y l o i n R e a c t i o n of D i e s t e r  144  : Isolation  o f T r i c y c l i c A l c o h o l s 168  a n d 176  144  154  To s o d i u m - p o t a s s i u m a l l o y  168  (0.4  g,  potassium)  d i s p e r s e d i n anhydrous ether  of  144  diester  7 9 . 0 mmol)  (2.42 g,  6 . 3 mmol)  i n anhydrous e t h e r  17 mmol s o d i u m ; 1.2 (25 mL) was a d d e d a  and f r e s h l y  (175 m L ) .  61  176  distilled  The r e a c t i o n  g , 31 mmol mixture  TMSC1 (10 m L ,  mixture  was s t i r r e d provide  for  40 h a t  room t e m p e r a t u r e  the crude s i l y l a t e d e n e d i o l a t e  i n dry methanol  a n d w o r k e d up a s b e f o r e  154.  dried  acetate  g e l ; ether)  alcohols  p r o v i d e d a 1:1 m i x t u r e  ( 3 H , s ; CH_ ), 2 . 2 8 3  J = 13.5 H z ; CH C=0), 3.48 2  J = 13.5 H z ) , 3.49 (IH,  of  (d)  ( 3 H , s ; OCELj), 3 . 6 8  (IH,  (d)  (IH,  t,  J •  litmus,  tricyclic 6 (CDC1 ( 2 H , AB  quartet,  (IH,  d,  5 H z ; CHOMe),  I s o m e r i c E s t e r s 181 a n d 182  180  62  3 >  m; C E O H ) , 3 . 9 4  ( 3 H , s ; CH_ ), 2 . 5 7 3  to  d d , J = 11 H z , 7 H z ; CHOMe).  176  16 h ,  chromatography  64%);  and 2 . 8 7  3  1.06  isomeric  (0.90 g,  ( 3 H , s ; 0CH_ ), 3 . 6 8  d d , J = 12 H z , 7 H z ; CHOMe); 1 7 6 :  for  The r e s i d u e was d i s s o l v e d  P u r i f i c a t i o n by f l a s h  168 a n d 176 a s a p a l e y e l l o w o i l  300 M H z ) : 1 6 8 : 1 . 4 3  4.05  trimethylsilylchloride  (100 m L ) , washed w i t h b r i n e u n t i l n e u t r a l  (MgSO^) a n d c o n c e n t r a t e d .  (silica  of  T h e r e a c t i o n m i x t u r e was r e f l u x e d  c o o l e d and the methanol removed i n v a c u o . in ethyl  The c r u d e 154 was d i s s o l v e d  ( 2 0 0 mL) a n d a f u r t h e r q u a n t i t y  (5 m L , 40 mmol) was a d d e d .  to  182  (IH,  To a c o l d (0 C ) s o l u t i o n o f and 176 ( 0 . 9 g , 4 . 0 mmol) was a d d e d a c o l d 1 0 . 4 mmol)  (0°C)  i n water  isomeric t r i c y c l i c  in acetonitrile  s o l u t i o n of  (5 m L ) .  (5 mL) a n d w a t e r  e e r i e ammonium n i t r a t e  The r e a c t i o n m i x t u r e ,  d e v e l o p e d a d e e p r e d c o l o u r , was s t i r r e d warmed t o room t e m p e r a t u r e this  time  was e x t r a c t e d dried  and s t i r r e d  the r e a c t i o n mixture three  (MgSO^).  the  purification  a t 0°C f o r  for  due t o  a further  g).  1:1)  to provide  a pale yellow oil;fi(CDCl , 3  20 m i n . The  instability.  and  the  (silica  partial gel;  c r u d e k e t o a l d e h y d e 180 a s  270 M H z ) : 0 . 8 5  ( 3 H , s;  CH_ ); 3  d d , J = 14 H z , 7 H z ; one C ( 8 ) p r o t o n ] ,  3.45  3.83  (IH,  d d , J = 12 H z , 7 H z ; CHOMe), 5 . 4 9  m; v i n y l  9.79  (IH,  t,  (IH,  ( 3 H , s ; OCE^), proton),  J = 2 H z ; CHO).  Further elution (film):  1730,  provided crude keto aldehyde  oil;  ir  3.58  ( 3 H , s ; 0CH_ ), 3 . 9 5  1675 c m " ; <j ( C D C 1 1  (IH,  3  J = 2 H z ; C(E) v i n y l To a s o l u t i o n , o f  (1.2  (1.0 mL).  g,  dd, J -  proton],  9.82  3 >  178 a s a p a l e  400 M H z ) ; 1 . 1 2  13 H z , 5 H z ; CHOMe), 5 . 8 0 (IH,  t,  chromic a c i d ,  12 mmol)  i n water  63  CH_ ), 3  [IH,  J = 2 H z ; CHO).  p r e p a r e d by d i s s o l v i n g  ( 2 0 mL) a n d c o n c e n t r a t e d  The r e a c t i o n m i x t u r e  yellow  (3H, s ;  t h e c r u d e a l d e h y d e s 178 a n d 180 i n a c e t o n e  was a d d e d a s o l u t i o n o f  acid  During solution  However,  [IH,  trioxide  then  crude aldehydes  3.01  t,  g,  immediately  P u r i f i c a t i o n of  was a c h i e v e d b y c o l u m n c h r o m a t o g r a p h y  petroleum ether/ether  (5.7  a c e t a t e , washed w i t h b r i n e  (0.86  their  (3 mL)  15 m i n . a n d  s o l v e n t p r o v i d e d the  178 a n d 180 a s a p a l e y e l l o w o i l a l d e h y d e s was d i f f i c u l t  which  faded to a pale y e l l o w .  times w i t h e t h y l  Removal of  a l c o h o l s 168  was s t i r r e d  for  2 h at  (10 mL)  chromium sulphuric room  temperature. extracted  The a c e t o n e was t h e n r e m o v e d i n v a c u o a n d t h e  three  times with e t h y l  were washed w i t h b r i n e  and d r i e d  provided a pale yellow o i l treated  w i t h an e x c e s s of  Removal of by g l c  the e t h e r  ir  (film):  3050,  1725 ( b r )  2.07  (IH,  2.25-2.62  3.45  ( 3 H , s ; 0CH_ ), 3.68  220 ( 5 9 ) ,  208  mass c a l c d . f o r for  C  1 A  H  2 0  0 :  oil  1 A  H  2 Q  A  ir  ( 3 E , s ; C E ) , 1.62  2.28  (2H, m),  (3E,  s; C0 CH ),  J -  3  3  2 H z ; CE= ) ;  194 ( 2 1 ) , 252.1366. E  2.47  121  m/e  (100);  Anal,  (IH,  (2H, m),  3.95  3.84  3  (relative  (IH,  (73),  (IH,  (300 m g ,  105 ( 7 9 ) ,  30%);  (3H, s ;  CH_ ), 3  d d , J = 12 E z , 7 H z ;  intensity):  252  (M ,  58),  +  91 ( 1 0 0 ) ;  252.1355.  isomeric ester  1735,  Exact  Anal,  calcd.  181 a s a c o l o u r l e s s  1675 c m " ; 6 ( C D C 1 1  m),  1.76  (IH,  2.62  (IH,  m),  3 >  400 M H z ) :  t,  J = 13 H z ) , 2 . 1 0  3.57  (3H, s ; 0CE_ ),  intensity):  E x a c t mass c a l c d . f o r C^B^O^:  252 C  (M , 0.4), +  H 1  8  2  0  ° 4  :  7.98.  64  (IH,  222  252.1361;  C 66.65, E 7.99;  found:  (2H,  m),  3.69  3  d d , J = 14 H z , 5 H z ; CHOMe), 5 . 7 8  (relative  calcd. for  petroleum  found C 66.52, B 8.00. the  (film):  (silica gel;  d d , J = 14 H z , 7 H z ) ,  252.1361; found:  provided  components  3.02  (IH,  mL),  overnight.  400 M H z ) : 0 . 8 5  3  2  119  (20  6 (CDC1 ,  (3H, s ; C0 CH_ ),  0 :  1.12  2  1  149 ( 6 5 ) ,  elution  ( 2 3 0 mg, 2 3 % ) ;  solvent  stand  182 a s a c o l o u r l e s s o i l  cm" ;  C 66.65, H 7.99;  A  Further  C  the  layers  g) w h i c h was d i s s o l v e d i n e t h e r  ester  m, C H = ) ; m/e  (58),  Removal of  A  (7H, m),  3  (IH,  (MgS0 ).  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Commun., 1 9 8 6 , 288.  68  APPENDIX 1  S  4  3  2  400 MHz H nmr X  69  i  ppo 0  70  71  72  APPENDIX 2  Bono  lengths  standard  Bond 0( 1 ) - C ( 3 ) 0(2)-CU) 0(2)-C(13) 0(3)-C(9) C(1)-C(2) C<1)-C(6) C( 1 ) - C ( 9 ) C(l)-COO) C(2)-C<3)  deviations  Length(A)  Bond  C(4) -0(2) -C(13) C(2) - C ( l ) -C(6) C(2> - C O ) - C ( 9 ) C ( 2 ) - C ( 1 )- C O O ) C(6) - C O ) -C(9) C(6) - C O ) - C O O ) C(9) - C O ) - C O O ) C ( 1 )- C ( 2 ) - C ( 3 ) 0 ( 1 )- C ( 3 ) - C ( 2 ) 0 ( 1 )- C ( 3 ) - 0 ( 4 ) C(2) -C(3) -C(4) 0(2) -C(4) -C(3) 0(2) -C(4) -C(5) C(3) -C(4) -C(5> C(4) -C(5) -C(6)  estimated  i n parentheses  Bond  1.212(2) 1.416(2) 1.408(3) 1.421(3) 1.519(3) 1.555(2) 1.536(3) 1.541(3) 1.511(3)  Length(A)  C(3)-CU) C(4)-C(5) C(5)-C(6) C(6)-C(7) C(6)-C(12) C(7)-C(B) C(7)-C(11) C(B)-C(9) C(10)-C(11 )  angles  standard  Bonds  (A) w i t h  (deg)with  1.522(3) 1.545(3) 1.528(3) 1.550(2) 1.534(3) 1.543(3) 1.534(3) 1.547(3) 1.543(3)  estimated  deviations i n parentheses  Angle(deg) 1 1 3 ,. B ( 2 ) 113. . B 8 ( 1 5 ) 116. . 9 ( 2 ) U 3 .B(2> 103 . 8 9 ( 1 5 ) 101,. 8 1 ( 1 5 ) 104 . 9 ( 2 ) 108. . 6 ( 2 ) 122.. 3 ( 2 ) 122, . 3 ( 2 ) 115, . 4 ( 2 ) 1 1 1 ,. 4 ( 2 ) 108 . 8 ( 2 ) 111 . 8 1 ( 1 5 ) 111.. 2 ( 2 )  Bonds  Angle(deg)  C O ) -C(6)-C(5) CO )-C(6)-C(7) C O )-CI6I-CI12) C(5) - C ( 6 ) - C ( 7 ) C(5) - C I 6 I - C I I 2 ) C(7) -C(6)-C(12) C(6) - C ( 7 ) - C ( 6 ) C(6) - C ( 7 ) - C ( 1 1 ) C(8) - C ( 7 ) - C ( 1 1 ) C(7) - C ( 6 ) - C ( 9 ) 0(3) - C ( 9 ) - C O ) 0(3) -C(9)-C(8) C O ) -C(9)-C(8) CO )-CO0)-C(1 1 ) C(7) - C O D - C O O )  73  109. 6 1 ( 1 4 ) 92. 62(13) 116. , 3 ( 2 ) 116. . 8 ( 2 ) ioe..4(2) 112. . 7 ( 2 ) 101 ., 9 6 ( 1 5 ) 103. . 4 ( 2 ) 106. , 9 ( 2 ) 1 04 ,.0 ( 2 ) 1 1 5 ., 0 ( 2 ) 109. .5(2 ) 102, . 2 ( 2 ) 1 04 . ,6 ( 2 ) 101 .. 8 ( 2 )  

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