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UBC Theses and Dissertations

C-nucleosides, C-nucleoside precursors and a novel exocyclic glycal Chow, Jack Kenny 1980

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C-NUCLEOSIDES, C-NUCLEOSIDE PRECURSORS AND A NOVEL EXOCYCLIC GLYCAL  ©  by  JACK KENNY CHOW  Sc., The U n i v e r s i t y of B r i t i s h Columbia,  A THESIS SUBMITTED  1976  IN PARTIAL FULFILMENT OF  THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE  in THE FACULTY OF GRADUATE STUDIES In t h e Department o f ' Chemistry  We accept t h i s  t h e s i s as conforming  to the r e q u i r e d  standard  THE UNIVERSITY OF BRITISH COLUMBIA February 1980  (cT)  J a c k Kenny Chow, 1980  In p r e s e n t i n g t h i s  thesis in partial  an advanced d e g r e e a t t h e U n i v e r s i t y the L i b r a r y I further for  shall  make i t f r e e l y  agree that  this  written  i s understood  permission.  CHEMISTRY  The U n i v e r s i t y o f B r i t i s h C o l u m b i a 2075 W e s b r o o k P l a c e V a n c o u v e r , Canada V6T 1W5  Date  FEBRUARY 13, 1980  that  copying of t h i s  thesis  by t h e Head o f my D e p a r t m e n t o r  thesis for f i n a n c i a l gain shall  Department o f  I agree  for  a v a i l a b l e f o r r e f e r e n c e and s t u d y .  s c h o l a r l y p u r p o s e s may be g r a n t e d It  of the requirements  of B r i t i s h Columbia,  permission for extensive  by h i s r e p r e s e n t a t i v e s . of  fulfilment  that  copying or p u b l i c a t i o n  n o t be a l l o w e d w i t h o u t my  ABSTRACT  The and  s y n t h e s i s o f 3-(R  and  S0-3,4-dihydroshowdomycin (171) and  (170)  the n o v e l 3 - ( S ) - ( 2 , 3 - 0 - i s o p r o p y l i d e n e - a - D - r i b o f u r a n o s y l ) s u c c i n i m i d e  [3-(S)-a-dihydroshowdomycin a c e t o n i d e 176]  are r e p o r t e d .  Several functionalized  C - g l y c o s i d e s a l o n g w i t h the a d d i t i o n products of a n o v e l e x o c y c l i c sugar, m e t h y l  enolic  (E,Z^-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-0-isopropylidene-  p-ribo-oct-3-enonate  (172), are a l s o d e s c r i b e d .  A p p l i c a t i o n of the photoamidation  r e a c t i o n to methyl  (E,Z)-4,7-anhydro-  8-0-benzoyl-2,3-dideoxy-5,6-0-isopropylidene-D-allo-oct-2-enonate  (18)  yielded  3-(R j5)-(5-0-benzoyl-2,3-0-isopropylidene-8-D-ribofuranosyl)-4-hydroxy-4s  methylpentanoic  1,4-lactone  (139) and methyl 4,7-anhydro-8-0-benzoyl-3-C-  carbamoyl-2,3-dideoxy-5,6-0-isopropylidene-D-glycero-D-allo octonate  (140)  and  (141).  141 w i t h concomitant  (and  altro)  C y c l i z a t i o n of the 6-carbamoyl e s t e r s 140  d e b e n z o y l a t i o n w i t h sodium methoxide gave 170  and  and  171  a f t e r removal o f the i s o p r o p y l i d e n e groups. I s o m e r i z a t i o n of the carbon-carbon  double bond of 1_8 w i t h sodium a z i d e  i n a N,N-dimethylformamide s o l u t i o n gave 172 which when photoamidated t r e a t e d w i t h sodium methoxide gave compound  176.  Treatment of 18 w i t h sodium a z i d e gave methyl benzoyl-2,3,5-trideoxy-g-erythro-oct-2,4-dienonate When excess h y d r a z o i c a c i d was 4,7-anhydro-3-azido -  and  (E)-4,7-anhydro-8-0_(178) a l o n g w i t h  added to the above r e a c t i o n mixture  172. methyl  8-()-benzoyl-2,3-dideoxy-5,6-0-isopropylidene-D-glycero-  D - a l l o , a l t r o - o c t o n a t e (189) and the amount of h y d r a z o i c a c i d  s m a l l amounts of 172 were i s o l a t e d .  i n the l a t t e r r e a c t i o n gave compound 172  predominant product w i t h s m a l l amounts of 189  Reducing as  the  a l o n g w i t h methyl 3-amino-4,7-  anhydro-8-£-benzoyl-2-diazo-2,3-dideoxy-5,6-0-isopropylidene-g-glycero-D-allo (and a l t r o ) - o c t o n a t e (192) and  (193), r e s p e c t i v e l y .  Hydrogenation  of 189 i n  iii  the presence methyl  of 5% p a l l a d i u m on carbon gave the c o r r e s p o n d i n g amino compounds,  3-amino-A,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-^-isopropylidene-D-  g l y c e r o - D - a l l o , a l t r o - o c t o n a t e s (190) and o f 192  and  (191), r e s p e c t i v e l y .  Hydrogenation  193 as above i n s e p a r a t e r e a c t i o n s gave the c o r r e s p o n d i n g  g e n o l y s i s p r o d u c t s 190 and  191,  a l o n g w i t h the hydrazones  of methyl  hydro3-amino-  4,7-anhydro-8-0-benzoyl-3-deoxy-5,6-0-isopropylidene- j-glycero-D-allo T  altro)-2-octulosonate The  (195) and  (196), r e s p e c t i v e l y .  slow e v a p o r a t i o n o f the s o l v e n t from a d i e t h y l  s o l u t i o n of 172  or prolonged  (and  s t o r a g e o f 172  ether-hexane  exposed to room atmosphere gave  5-0-benzoyl-2,3-0-isopropylidene-D-ribono-l,4-lactone  (199),  8-0-benzoyl-  2,3-dideoxy-5,6-0-isopropylidene-B-D-ribo-4-octulofuranosono-1,4-lactone (200), methyl  (E)-8-0-benzoyl-2,3-dideoxy-5,6-0-isopropylidene-B-D-ribo-  oct-2-en-4-ulofuranosonate  (201), methyl  8-0-benzoyl-2,3-dideoxy-5,6-0-  isopropylidene-B-D-ribo-4-octulofuranosonate 2-deoxy-5,6-0-isopropylidene-a,B-D-allo (203) and  (202), and methyl  8-J3-benzoyl-  (and a l t r o ) - 4 - o c t u l o f u r a n o s o n a t e  (204), r e s p e c t i v e l y .  Treatment  o f 204 w i t h p a r a - t o l u e n e s u l f o n i c a c i d  benzene s o l u t i o n y i e l d e d  the f u r a n d e r i v a t i v e ,  ( c a r b o m e t h o x y a c e t y l ) f u r a n (212).  i n an a z e o t r o p i n g  2-benzoyloxymethyl-5-  iv  TABLE OF CONTENTS Page ABSTRACT  i i  LIST OF TABLES  v i i  LIST OF FIGURES  viii  ACKNOWLEDGEMENTS  ix  I.  OBJECTIVE  1  II.  INTRODUCTION  3  1.  Unsaturated  Sugars  3  1.1. S y n t h e s i s of Unsaturated 2.  Photochemical  6  Reactions  2.1. Photoamidation 2.2. Photochemical 3.  Sugars  of Unsaturated  12 Sugars  12  cis-trans Isomerization  22  Carbon-Carbon Double Bonds 3.1. N u c l e o p h i l i c A d d i t i o n t o a,3-Unsaturated  25 Esters  3.2. R e a c t i o n s of E n o l E t h e r s  26 29  3.2.1.  A d d i t i o n o f Oxygen and Hydrogen  30  3.2.2.  A d d i t i o n of Bromine and Bromomethoxylation  32  3.2.3.  Methoxymercuration  33  3.2.A.  R e a c t i o n w i t h meta-Chloroperbenzoic  3.2.5.  O x i d a t i o n w i t h Osmium T e t r o x i d e  37  3.2.6.  O x i d a t i o n w i t h M o l e c u l a r Oxygen  38  3.2.7.  Periodate Oxidation  42  3.2.8.  Azido-Nitration  A3  3.2.9.  R e a c t i o n w i t h N-Bromosuccinimide  44  Acid  35  V  TABLE OF CONTENTS - c o n t i n u e d Page 4.  5.  C-Nucleosides  46  4.1.  Showdomycin  48  4.2.  C-Nucleoside P r e c u r s o r s  54  Ketose N-Nucleosides  I I I . RESULTS AND 1.  56  DISCUSSION  58  S y n t h e s i s o f a- and 8-Dihydroshowdomycin: P h o t o a m i d a t i o n of M e t h y l  (E,_Z)-4,7-anhydro-8^0-benzoyl-2,3-dideoxy-  5 , 6 - 0 - i s o p r o p y l i d e n e - D - a l l o - o c t - 2 (and 3)-enonate and 1.1.  (172), r e s p e c t i v e l y .  58  S y n t h e s i s of Dihydroshowdomycin v i a P h o t o a m i d a t i o n o f the M e t h y l oct-2-enonate  1.2.  (18)  (18).  60  S y n t h e s i s of a-Dihydroshowdomycin A c e t o n i d e v i a Photoamidation of Methyl  (E,Z)-4,7-anhydro-8-  0^-benzoyl-2,3-dideoxy-5, 6 - 0 - i s o p r o p y l i d e n e - D r i b o - o c t - 3 - e n o n a t e (172). 2.  88  S y n t h e s i s of F u n c t i o n a l i z e d P r e c u r s o r s to C-Nucleosides  95  2.1.  95  S y n t h e s i s of U n s a t u r a t e d and Amino Sugars 2.1.1.  Attempted  a d d i t i o n of Sodium A z i d e to the  Methyl oct-2-enonate  1_8 to Y i e l d  Methyl oct-3-enonate  172 and  the  Methyl  (E)-4,7-anhydro-8-0-benzoyl-2,3,5trideoxy-g-erythro-oct-2,4-dienonate 2.1.2.  (178).  A d d i t i o n of H y d r a z o i c A c i d t o 18 t o Y i e l d and Methyl  95  172  4,7-anhydro-3-azido-8-0-benzoyl-  2,3-dideoxy-5,6-0-isopropylidene-D-glycero-Da l l o , altro-octonate  (189).  1  1  1  vi TABLE OF CONTENTS - c o n t i n u e d Page 2.1.3.  A d d i t i o n o f Sodium A z i d e to 1_8 t o Give 172, 189, and M e t h y l 3-amino-A,7-anhydro-8-0benzoyl-2-diazo-2,3-dideoxy-5,6-0-isopropylidene-rj-glycero-D-allo  (and a l t r o ) - a c t o n a t e  (192) and (193), r e s p e c t i v e l y . 2.2.  Attempted 2.2.1.  S y n t h e s i s of a V i c i n a l D i a z i d o Sugar  Treatment  anhydro-8-/J-benzoyl-2,3-dideoxy-5,  4. IV.  (CAN)  O x i d a t i o n and H y d r a t i o n P r o d u c t s of Methyl  ribo-oct-3-enonate Attempted  118  o f 1_8 w i t h Sodium A z i d e and  C e r i c Ammonium N i t r a t e 3.  113  118 (E,_Z)-4,7-  6-0-isopropylidene-D-  (172).  119  S y n t h e s i s of Analogues  of Psicofuranine  136  EXPERIMENTAL  139  1.  General Methods  139  2.  Chromatography  139  2.1.  Column Chromatography  140  2.2.  T h i n Layer Chromatography  140  3.  Abbreviations  140  4.  (R) and (jS)-Dihydroshowdomycin  140  5.  3- (S)-cc-Dihydroshowdomycin  157  6.  U n s a t u r a t e d , A z i d o , D i a z o , and Amino Sugars  162  7.  H e m i k e t a l s , y-Lactones and A l k y l and A c y l K e t a l s  178  8.  Attempted  195  Acetonide  S y n t h e s i s o f a Ketose N - n u c l e o s i d e  V.  BIBLIOGRAPHY  200  VI.  ADDENDUM  •  ,iri  vii  LIST OF TABLES  Table  I.  Page  C a l c u l a t e d D i h e d r a l Angles between H-3 and H - l ' .  I I . C o u p l i n g Constants 'a-' and  86  and O p t i c a l R o t a t i o n s of the  and ' 3 - ' D - R i b o s y l s u c c i n i m i d e t h e i r H - l ' Chemical  III:. C-13 N.M.R. Chemical  Derivatives  Shifts.  93  S h i f t s o f t h e 5,6-O-Iso-  p r o p y l i d e n e Quaternary  Carbon and H i g h - f i e l d Methyl  of V a r i o u s K e t o f u r a n o s i d e s .  211  viii  LIST OF FIGURES Figure  Page  1  N a t u r a l l y O c c u r r i n g C-Nucleosides  47  2A  P a r t i a l 100 MHz P r o t o n N.M.R. Spectrum o f 3-(S^-(2,3-0-isopropylidene-B-D-ribofuranosyl)  2B  succinimide  [(S)-dihydroshowdomycin  153] i n CDC1  3  acetonide, 72  P a r t i a l 100 MHz P r o t o n N.M.R. Spectrum o f (S)-Dihydroshowdomycin  A c e t o n i d e (153) i n  DMSO-d, o 3.  73  60 MHz P r o t o n N.M.R. Spectrum  o f the Hydrogenation  Product o f Showdomycin A c e t o n i d e (157) i n CDCl^ 4  P a r t i a l 100 MHz P r o t o n N.M.R. Spectrum  74  o f 3-(R)-  (2,3-0-isopropylidene-B-D-ribofuranosyl)succinimide [(R)-dihydroshowdomycin] 5A  (154) i n DMS0-d  P a r t i a l 100 MHz P r o t o n N.M.R. Spectrum  78  6  o f Methyl  (E,Z_)-  4,7-anhydro-8-_0-benzoyl-2,3-dideoxy-5,6-0-isopropylideneD-ribo-oct-3-enonate Z-isomers 5B  Partial  i n CDC1  (172).  A 5:95 r a t i o o f the E - t o 99  3  100 MHz P r o t o n N.M.R. Spectrum  o f Methyl  (E,Z)-  4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-^-isopropylideneD-ribo-oct-3-enonate Z-isomers  i n CDC1,  (172).  A 55:45 r a t i o  o f the E- t o 100  ACKNOWLEDGEMENTS  I wish t o thank Dr. A l e x Rosenthal f o r h i s guidance,  suggestions  and p a t i e n c e d u r i n g t h e course of t h i s r e s e a r c h . The c o o p e r a t i o n and i n v a l u a b l e p r a c t i c a l D r s . B. L. C l i f f gratefully  a s s i s t a n c e p r o v i d e d by  and R. H. Dodd d u r i n g my p e r i o d a t U.B.C. a r e  acknowledged.  To Pam and my mother, f o r t h e i r p a t i e n t u n d e r s t a n d i n g d u r i n g the preparation of this thesis,  I wish t o express my deepest  appreciation.  F i n a l l y , the f i n a n c i a l support of the U n i v e r s i t y o f B r i t i s h Columbia  (1976-1979) and the N a t i o n a l Research  (through Dr. Rosenthal  (1979-1980))is  C o u n c i l of Canada  acknowledged.  1  I. The  OBJECTIVE  n a t u r a l l y occurring nucleoside  a n t i b i o t i c s represent  a diverse  group o f b i o l o g i c a l compounds s t r u c t u r a l l y r e l a t e d to the p u r i n e and pyrimidine  nucleosides  and/or n u c l e o t i d e s .  have been e q u a l l y d i v e r s e formational  The u t i l i t y  i n that they have been used as models f o r con-  and s p e c t r o s c o p i c  s t u d i e s . used as probes i n the b i o l o g i c a l  systems t o e l u c i d a t e the complex s t e p s  involved  i n converting  message to new biopolymers and i n t h e d e t e r m i n a t i o n m e t a b o l i c and a n a b o l i c The  present  pathways. o f these n a t u r a l l y  and t h e i r analogues and/or homologues however, r e -  an u n l i m i t e d use f o r these compounds.  the common  the genetic  of the stages of other  p o s s i b l e and e x i s t i n g chemotherapeutic v a l u e  occurring nucleosides  o f these compounds  nucleosides,  obtained  The s t r u c t u r a l analogues of  e i t h e r from n a t u r a l sources or by s y n t h e t i c  means, have o f t e n been found to be a n t i v i r a l ,  a n t i b a c t e r i a l , a n t i f u n g a l , or  antitumor i n t h e i r a c t i o n . Four c l a s s e s o f m o d i f i e d  nucleosides  can be d i s t i n g u i s h e d : (1) n u c l e o s i d e s  i n which the r i b o s y l p o r t i o n i s a l t e r e d by the i n c o r p o r a t i o n and/or e l i m i n a t i o n of v a r i o u s  groups,  or p y r i m i d i n e  (2) b a s e - m o d i f i e d n u c l e o s i d e s ,  i n which the common  d e r i v a t i v e has been a l t e r e d , (3) C - n u c l e o s i d e s ,  i n which the  h e t e r o c y c l i c base i s l i n k e d to the sugar moiety by a carbon-carbon than a c a r b o n - n i t r o g e n  bond, and (4) the more recent  purine  rather  homo-C-nucleosides,  i n which a methylene u n i t r e s i d e s between the n i t r o g e n o u s h e t e r o c y c l i c base and sugar moiety. The f a c t  that p y r a z o f u r i n  (PF) ( a n t i v i r a l and  antitumor) e x i s t s both as an a (PF) and 3 (PF ) ( p o s s i b l e a n t i v i r a l anomers and both e x h i b i t some degree o f a n t i b i o t i c a c t i v i t y relevance  i n t h i s present  work.  agent)  i s of p a r t i c u l a r  The  o b j e c t i v e of the work d e s c r i b e d  various C-nucleosides  and v a r i o u s ketose  i n t h i s t h e s i s i s to s y n t h e s i z e nucleosides.  In the f i r s t  o f t h i s work, the s y n t h e s i s o f the normal- and a-dihydro showdomycin by way of photoamidation of unsaturated The  functionalized precursors  to C - n u c l e o s i d e s .  d e r i v a t i v e of  octonates  second p a r t of t h i s t h e s i s i s concerned w i t h  part  was  studied.  the s y n t h e s i s of  The p r e c u r s o r s  envisioned  were the C - g l y c o s y l diamino a c i d d e r i v a t i v e s , the amino and c a r b o x y l i c groups o f the amino a c i d b e i n g p o t e n t i a l l y amenable t o f u r t h e r d e r i v a t i z a t i o n and the p o s s i b i l i t y o f c y c l i z a t i o n of the v i c i n a l amino groups to g i v e analogues of p y r a z o f u r i n .  The two r o u t e s employed f o r the s y n t h e s i s  of such p r e c u r s o r s were the condensation unsaturated  octonate  of sodium a z i d e w i t h an a, 8-  and the a z i d o - n i t r a t i o n of the same  unsaturated  compound. In the t h i r d p a r t of t h i s t h e s i s , the d e r i v a t i v e s of a n o v e l e x o c y c l i c glycal i s investigated.  Various  compounds which are produced from the a i r  o x i d a t i o n of the g l y c a l a r e r e s y n t h e s i z e d u s i n g known The and  procedures.  ketohexose n u c l e o s i d e p s i c o f u r a n i n e which i s both a n t i b a c t e r i a l  antitumor  i n i t s a c t i v i t y was found to be absorbed e x t e r n a l l y by  animals but not absorbed i n man u n l e s s  i t was converted  to the t e t r a a c e t a t e .  I t seemed p l a u s i b l e the e l o n g a t i o n of the hydroxymethyl group a t C-2' w i t h a hydrophobic moiety such as carbomethoxymethyl might r e s u l t b i o l o g i c a l consequences. deals with  Therefore,  in interesting  the f o r t h and f i n a l p a r t of t h i s t h e s i s  the attempted s y n t h e s i s of analogues of p s i c o f u r a n i n e  utilizing  both the n o v e l e x o c y c l i c g l y c a l and i t s a c e t y l a t e d h e m i k e t a l d e r i v a t i v e . The  f u s i o n method and the one-step s y n t h e s i s of a N - n u c l e o s i d e  t e t r a c h l o r i d e and m e t h a n e s u l f o n i c latter  compound.  using t i n  a c i d c a t a l y s t s were employed w i t h the  3 INTRODUCTION  II.  1.  Unsaturated The  first  Sugars  l a b o r a t o r y s y n t h e s i s of an u n s a t u r a t e d sugar  d a t e s back t o 1913 D-glucal  when E m i l F i s h e r and K. Zach produced  (.1).* S i n c e t h i s f i r s t  i n a c a r b o h y d r a t e , the range possess a carbon-carbon  derivative  triacetyl-  s y n t h e s i s of an e n o l e t h e r  functionality  of d i s c r e t e carbohydrate d e r i v a t i v e s which  double bond i n the sugar c h a i n has  i n c r e a s e d to  cover a l a r g e v a r i e t y of u n s a t u r a t e d sugars which have one or more carboncarbon double bonds which may f u n c t i o n a l groups. t h i s important  The  be i n c o n j u g a t i o n w i t h themselves  increased a c t i v i t y  group of d i v e r s i f i e d  i n the l a s t  or other  quarter century i n  compounds has prompted s e v e r a l  reviews.  AcO  1 The  g l y c a l s and  t h e i r 2-hydroxy d e r i v a t i v e s , were d e a l t w i t h i n two  papers by H e l f e r i c h field  2  is reflected  an i n depth  and  i n two  Blair  3  , respectively.  reviews by F e r r i e r .  A broader  4 5 *  scope  Recently, Kiss  of 6  earlier this  has  given  review of 8 - e l i m i n a t i v e d e g r a d a t i o n of c a r b o h y d r a t e s c o n t a i n i n g  a c t i v a t i n g groups w h i l e F e a t h e r and H a r r i s ' reviewed r e a c t i o n s of carbohydrates.  the area of d e h y d r a t i o n  Formation o f u n s a t u r a t e d sugars by e n l a r g i n g g  the carbon s k e l e t o n v i a the W i t t i g r e a c t i o n has been reviewed  by Zhdanov.  The p r e s e n t and p o t e n t i a l v a l u e of the u n s a t u r a t e d sugars i n both their direct u t i l i t y  as w e l l as t h e i r use as s y n t h e t i c  e x e m p l i f i e d by the presence  intermediates i s  of u n s a t u r a t e d c a r b o h y d r a t e s  occurring nucleoside a n t i b i o t i c s Decoyinine  9  [Angustmycin  i n the n a t u r a l l y A, 9-6-D-(5,6-  4  p s i c o f u r a n o s e e n y l ) - 6 - a m i n o p u r i n e , 2] and B l a s t i c i d i n  S  1 0  [l-(l'-cytosinyl)-  4-[L-3'-amino-5(1''-N-methylguanidino)-valerylamino]-1,2,3,4-tetradeoxy-2, 3-dehydro-B-p-erythro-hex-2-ene u r o n i c a c i d , 3 ] .  The u n s a t u r a t e d  carbo-  H NCHQ-UCN 2 I H CHI ' 0  HoNCNCH^j 2 g 3 NH h y d r a t e s themselves can have a n t i b i o t i c b e h a v i o r as shown by Sisomicin'*'^ which has the s t r u c t u r a l component 2,6-diamino-2,3,4,6-tetradeoxy-a-Dglycero-hex-4-enoside  (4) and by the a n t i b i o t i c sugar d e r i v a t i v e  2 3-bis-0-(para-nitrobenzoyl)-6-thio-L-xylo-hex-l-enulofuranose >  CH NH 2  6-S-benzyl-  12  (5).The u n s a t u r a t e d  2  BzlS-  4. R^disaccharide sugars can be used as s y n t h e t i c  !5  1  R=pjara-nitroben2oyl  i n t e r m e d i a t e s as shown by these  examples:  (1) E t h y l 4,6-di-j)-acetyl-2,3-dideoxy-a-D-erythro-hex-2-enopyranoside  (6)  5  i s transformed i n t o the a n t i b i o t i c g-erythro-hexopyranose,  7),  sugar, Amicetose ""'' J  (2,3,6-trideoxy-  (2) 6 - c h l o r o - 9 - ( 3 , 4 - d i - 0 - a c e t y l - 2 - d e o x y - a  (and 0) Q - e r y t h r o - p e n t o p y r a n o s y l ) purines''""' (8) are produced di-O-acetyl-D-arabinal furan  (11)  was  (9) and  produced  6 - c h l o r o p u r i n e (10), and  and b r i e f .  S e c t i o n s 2, 3 and *  (3) from  3,42-methyl-  the female sex hormone progesterone"*"^ (12) .  The d i s c u s s i o n on t h i s broad selective  from  t o p i c however, w i l l  be  necessarily  R e a c t i o n s of the u n s a t u r a t e d sugars w i l l  follow i n  4.  Amicetose i s a l s o a c o n s t i t u e n t o f the a n t i b i o t i c n u c l e o s i d e s ' ^ A m i c e t i n , P l i c a c e t i n and B a m i c e t i n .  6  1.1.  S y n t h e s i s of U n s a t u r a t e d Sugars. As one of the few s y n t h e t i c methods which can e l o n g a t e the carbon  s k e l e t o n of an o r g a n i c molecule a l o n g w i t h concomitant new  carbon-carbon double bond, the W i t t i g  has q u i c k l y become one of the fundamental  17  i n t r o d u c t i o n of a  r e a c t i o n and i t s m o d i f i c a t i o n s  18  ,  s y n t h e t i c methods of modern  organic chemistry, mild r e a c t i o n c o n d i t i o n s , together with high y i e l d s and the absence  of m i g r a t i o n of the bond formed  of t h i s method. functionality  a r e the main f e a t u r e s  The simultaneous i n s e r t i o n of an alkene bond and a c a r b o x y l  i n t o a c a r b o h y d r a t e i s v e r y a t t r a c t i v e i n view of p o s s i b l e  u s e f u l d e r i v a t i z a t i o n of both f u n c t i o n a l groups.  The  first  s y n t h e s i s of  19 t h i s k i n d was  r e p o r t e d by Kuhn and Brossmer  D-glyceraldehyde were condensed  .  Thus, 1 , 2 - 0 - i s o p r o p y l i d e n e -  (13) and carboethoxymethylenetriphenylphosphorane  to g i v e the h i g h e r - c a r b o n u n s a t u r a t e d e s t e r , e t h y l  dideoxy-4,5-0-isopropylidene-Tj-glycero-pent-2-enonate  (15).  (14) 2,3-  M o f f a t t et  20 al  , i n an analogous  13 D-allose methyl  (16) and  reaction with  14  2,5-anhydro-6-benzoyl-3,4-0-isopropylidene-  15  carbomethoxymethylenetriphenylphosphorane  (17) s y n t h e s i z e d  (E_,Z)-4,7-anhydro-8-0_-benzoyl-2,3-dideoxy-5,6-0-isopropylidene-D-allo-  oct-2-enonate  (18) .  BzO  n  /CU  1 + MeO CCH=P0 2  A ^  allylic  18  4 5 13 rearrangements ' ' of i n i t i a l l y  Thus, when Jones and  unsaturated  carbohydrates.  21  coworkers '  analogue by condensing  attempted  to s y n t h e s i z e a n u c l e o t i d e  2',3'-0-isopropylideneuridine-5'-aldehyde  w i t h phosphorane 14_ generated d e r i v a t i v e s were o b t a i n e d .  in s i t u ,  Two  four unsaturated  of the u n s a t u r a t e d d e r i v a t i v e s ,  allylic  i t s e t h y l e s t e r 21_, a r o s e  rearrangement of the expected  the resonance  stabilized  l-(5,6-  uronic acid  as a r e s u l t of a b a s e - c a t a l y z  hept-5-enofuranosyl  i n t e r m e d i a t e anion  (19)  carbohydrate  dideoxy-2,3-0-isopropylidene-g-D-erythro-hept-4-enofuranosyl (20) and  ^  sugars can a l s o be s y n t h e s i z e d by r e a c t i o n s i n v o l v i n g  8  uracil  0  >  3  12  Unsaturated  0  23.  e s t e r Z2 v i a  8  EtOpCCHNCH  o  + 1*  ]§  B=  1  N  21  H  V=CH—CH=/  EtCT  \  0L«O EtC^CCH  -=-4 / ch  Et0 CCH=CH 2  /BO"  R02CCH2CH R02CCH=CH 2Q R=H 21  R=B  Scheme I The  f o r m a t i o n o f the other two o l e f i n i c carbohydrate  (3,5,6-trideoxy-g-D-glycero-hept-3,5-dienofuranosyl  d e r i v a t i v e s , 1uronic acid) u r a c i l  (24) and i t s e t h y l e s t e r 25_ arose from a B - e l i m i n a t i o n o f t h e , normally a l k a l i stable,  fr-isopropylidene  group.  Although e l i m i n a t i o n r e a c t i o n s B t o a c t i v a t i n g f u n c t i o n s ^ a r e common i n carbohydrate  c h e m i s t r y , the l e a v i n g groups u s u a l l y o n l y have one  c o v a l e n t bond (except epoxides) -OMe  22  23 24 , -OAc and -OSC^Me ) .  l i n k i n g i t t o the sugar molecule (eg The B - e l i m i n a t i o n o f the O - i s o p r o p y l i d e n e  group (acetone) which has two p o i n t s of l i n k a g e to the carbohydrate  molecule,  9  a l t h o u g h r a r e , does o c c u r . group i f s i t u a t e d  The n o r m a l l y a l k a l i - s t a b l e 0_-isopropylidene  6 to an a c t i v a t i o n group such as the c a r b o n y l o f an  25 ester  or i n a v i n y l o g system such as 22_ w i l l ,  i n the presence of an  a p p r o p r i a t e base, e l i m i n a t e acetone to g i v e the i n t e r m e d i a t e a c t i v a t e d allylic  alkoxide.  Other a c t i v a t i o n groups such as d i t h i o a c e t a l s  a l s o c a p a b l e o f enhancing such  are  eliminations.  U n s a t u r a t e d sugars a r e a l s o formed c a r b o h y d r a t e s and t h e i r d e r i v a t i v e s . their derivatives  26  from the a c i d d e h y d r a t i o n of The t e r t i a r y a l c o h o l i c groups and  (eg e t h e r s and e s t e r s ) are p a r t i c u l a r l y s u s c e p t i b l e to  27a dehydration  ; t h e r e f o r e , i t can be expected that c y c l i c ketose d e r i v a t i v e s 28  w i l l dehydrate more r e a d i l y than the a l d o s e s . i n a l k a l i n e or a c i d i c one product which methylfurfural  solutions usually result  i s u s u a l l y formed  (26) .  The r e a c t i o n of c a r b o h y d r a t e s i n a myriad of p r o d u c t s ^ but  in significant  q u a n t i t i e s i s 5-hydroxy-  The key step i n the f o r m a t i o n of 26_ from sugars i s  26 29 the  f o r m a t i o n of 1,2Two  and 2 , 3 - e n e d i o l s .  30 '  mechanisms have been proposed f o r the f o r m a t i o n of compound  (1) based on the f a c t 26^ i s formed  26:  from D - f r u c t o s e (27) i n h i g h e r y i e l d  and a t a much g r e a t e r r a t e than i s formed  from D-glucose  (28)  (this  31 d i f f e r e n c e was p a r t i c u l a r l y e v i d e n t when lb_ was prepared from s u c r o s e o n l y the D - f r u c t o s e (27) p o r t i o n of the molecule r e a c t e d , and D-glucose  (29) , (28)  32 was  r e c o v e r e d i n almost q u a n t i t a t i v e y i e l d ) ,  D-fructose  the mechanism  states  (27) i s p r e s e n t i n the f u r a n o s e form, and that the r i n g  that remains  10  intact.  The i n i t i a l  r e a c t i o n i s the e l i m i n a t i o n of water t o form the  1 , 2 - e n o l i c form of 2,5-anhydro-D-mannose r e s u l t s i n compound d e h y d r a t i o n accounts  2J3.  (30), and t h a t f u r t h e r d e h y d r a t i o n  The n e c e s s i t y f o r 28_ to i s o m e r i z e to 27 b e f o r e  f o r the much lower  2*  R  29  Scheme  =  r e a c t i o n r a t e of 28.  H O .  H  R =  II  29 33 (2) The second mechanism  '  proposed suggest  that the d e h y d r a t i o n  v i a an a c y c l i c 1 , 2 - e n e d i o l _31_ which e l i m i n a t e s a molecule ^ - e l i m i n a t i o n of a hydroxy group to g i v e 3_2.  through  Compound 3_2 undergoes r a p i d  e l i m i n a t i o n of a second h y d r o x y l group to g i v e 3_3. molecule  of water  proceeds  The l o s s of a t h i r d  of water o c c u r s a f t e r , or s i m u l t a n e o u s l y w i t h the c y c l i z a t i o n of  33 and r e s u l t s i n t h e f o r m a t i o n of 26.  H-C-OH 27 or 2 8 ^  H-C=0  ( t o n  iffo  HOjiH  R  ^  io  QCH  HC-OH  I  H-C=0  L  HCTOH  l  j  b  R  2L R=HC-OH  32  HC-OH I R 32a  CH 0H 2  H-C=>0 0  I  CHO 4H 33a  HC-OH CH 0 H 2  33 Scheme III Other approaches t o the s y n t h e s i s o f u n s a t u r a t e d sugars i n v o l v e t h e d e h y d r o h a l o g e n a t i o n o f g l y c o s y l bromides i n t h e presence o f n i t r o g e n o u s bases.  Thus,  2,3,4,6-tetra-O-acetyl-l-deoxy-g-arabino-hex-l-enopyranose  (34) was o b t a i n e d i n ^80% from i t s c o r r e s p o n d i n g g l y c o s y l bromide i n the presence d i e t h y l a m i n e . l , 5 - d i a z a b i c y c l o - [ 5 . 4 . 0 ] - u n d e c - 5 - e n e (DBU, 35) has been u t i l i z e d  i n e f f e c t i n g dehydrohalogenation of g l y c o s y l  halides.  35  15 2.  Photochemical  Reactions  Along w i t h the i n c r e a s e d a c t i v i t y  i n the s y n t h e s i s of u n s a t u r a t e d  sugars and o t h e r f u n c t i o n a l i z e d c a r b o h y d r a t e s i n the l a s t  two  decades,  the use o f photochemistry w i t h these f u n c t i o n a l i z e d c a r b o h y d r a t e s has also increased notably.  The  f o l l o w i n g d i s c u s s i o n w i l l , however, be  l i m i t e d t o the a p p l i c a t i o n o f photoamidation t o c a r b o h y d r a t e s p o s s e s s i n g a s i n g l e carbon-carbon process.  double bond and the r e l a t e d  s i d e r e a c t i o n s of t h i s  R e a c t i o n s such as p h o t o e l i m i n a t i o n and rearrangements  the scope of t h i s t h e s i s and  i s beyond  f u r t h e r d i s c u s s i o n i s unnecessary.  Phillips  36a  has d e a l t w i t h the a r e a of p h o t o - d e g r a d a t i o n of simple sugars i n a review 3 6b article.  Bohm and A b e l l  have reviewed  the s t e r e o c h e m i s t r y of f r e e -  r a d i c a l a d d i t i o n s and t h i s t o p i c w i l l be d e a l t w i t h b r i e f l y . 2.1. Photoamidation  of Unsaturated  Sugars  The a d d i t i o n o f carboxamide f r e e r a d i c a l s to o l e f i n s was  f i r s t reported  37 by Friedman  and  Shechter  l e s s than two decades ago.  They found  substituted  formamides add t o o l e f i n s i n the presence o f p e r o x i d e s to  g i v e p r o d u c t s r e s u l t i n g from the a d d i t i o n of both •CON(CH )  that  and HCON(CH )CH 38 r a d i c a l s to o l e f i n s . In an independent study formamide was r e p o r t e d to have added t o o l e f i n s i n the presence o f p e r o x i d e s a t e l e v a t e d temperatures. 3  2  3  The l i g h t - i n d u c e d a d d i t i o n of formamide to t e r m i n a l o l e f i n s was  shortly  39 r e p o r t e d by E l a d .  This i n i t i a l  communication by E l a d was  soon f o l l o w e d  2  13  by  f o u r paper by E l a d and Rokach  40a)-d)  describing  the p h o t o a d d i t i o n of  ., . , , ... 40a , 40b . , , . 40c formamide t o t e r m i n a l o l e f i n s , norbornene , nonterminal o l e f i n s c  c  and  a,3-unsaturated e s t e r s .  These p h o t o r e a c t i o n s gave h i g h y i e l d s  of 1:1 adducts and served as a method of o b t a i n i n g  h i g h e r homologous  amides and t h e i r d e r i v a t i v e s from u n s a t u r a t e d compounds.  The a d d i t i o n  of formamide t o t h e u n s a t u r a t e d compound may occur when induced by  sunlight  (^20%  directly  (wavelengths o f 220-250 nm) but the y i e l d s a r e f a i r l y low  o f t h e 1:1 a d d u c t s ) .  Light  filtered  through Pyrex  >300 nm) gave v e r y poor y i e l d s of the d e r i v e d  (wavelength  amides but i n the presence  of acetone as a p h o t o i n i t i a t o r the r e a c t i o n proceeded a t a g r e a t e r  rate  40a and  gave h i g h y i e l d s of the d e s i r e d  amide.  With t e r m i n a l  o l e f i n s the  1:1 a d d i t i o n p r o d u c t s were predominantly formed v i a an anti-Markovnikov addition.  Formamide a d d i t i o n t o u n s u b s t i t u t e d  o l e f i n s was n o n r e g i o - and n o n s t e r e o s p e c i f i c from a d d i t i o n if  steric  n o n t e r m i n a l or c y c l i c  and products r e s u l t i n g  t o e i t h e r carbon o f the double bond were formed.  However,  i n t e r a c t i o n s a r e s i g n i f i c a n t l y d i f f e r e n t about the o l e f i n i c  bond, a s t e r e o s e l e c t i v e a d d i t i o n of formamide can o c c u r . photochemical a d d i t i o n  Thus, the  o f formamide to norbornene (36) proceeded i n a  s t e r e o s e l e c t i v e manner t o g i v e enantiomorphs, e x c l u s i v e l y  the norbornane-2-exo-carboxamide (37)  14  T h e r e f o r e , one might expect t h e p o s s i b i l i t y o f s t e r e o c h e m i c a l i n d u c t i o n in  s u i t a b l y s t e r i c a l l y h i n d e r e d o l e f i n i c compound i n t h e photoamidation  reaction. When the photoamidation r e a c t i o n was a p p l i e d esters,  t o simple  a,g-unsaturated  t h e expected g - a d d i t i o n of the carbamoyl r a d i c a l t o the u n s a t u r a t e d  e s t e r o c c u r r e d t o g i v e d e r i v a t i v e s of a l k a l y t e d s u c c i n i c a c i d s , e.g.  8 a RCH=CHCO„R.  Z L  +  -C0NH -»- RCHCHCO-R.. z | Z 1 o  CONH  2  38 R^,R=alkyl  groups  —  As i n the case of the photoamidation o f the o l e f i n s , t h e o r i e n t a t i o n of a d d i t i o n o f the carbamoyl r a d i c a l t o the carbon-carbon double bond depends upon t h e r e l a t i v e s t a b i l i t i e s of t h e r a d i c a l s formed and the s t e r e o c h e m i c a l o r i e n t a t i o n i s dependant on s t e r i c the  factors.  In t h e case o f t e r m i n a l o l e f i n s  i n i t i a l a t t a c k i s on t h e primary carbon t o produce a secondary r a d i c a l 41  which i s more s t a b l e  than t h e primary r a d i c a l produced upon  initial  a t t a c k a t t h e n o n t e r m i n a l carbon, thereby r e s u l t i n g i n a r e g i o s p e c i f i c addition.  With u n s u b s t i t u t e d n o n t e r m i n a l o l e f i n s , the a d d i t i o n o f t h e  carbamoyl r a d i c a l t o e i t h e r carbon produces secondary r a d i c a l s , thereby resulting  i n s k e l e t a l isomers.  With t h e simple a,6-unsaturated  which i s i n essence an n o n t e r m i n a l o l e f i n ,  initial  esters,  a t t a c k o f the carbomyl  r a d i c a l t o t h e 8 carbon r e s u l t s i n the f o r m a t i o n o f a f r e e r a d i c a l (38) which o b t a i n s i t s s t a b i l i z a t i o n through resonance w i t h t h e e s t e r group T h e r e f o r e , w i t h t h e simple a l k y l  a,g-unsaturated e s t e r s , o n l y products  w i t h r e s p e c t t o t h e a c i d p o r t i o n of the e s t e r .  15  r e s u l t i n g from B - a d d i t i o n  of the carbamoyl r a d i c a l were i s o l a t e d .  I n t e r e s t i n g r e s u l t s o c c u r r e d when a s t a b i l i z i n g group was at t h e B p o s i t i o n o f the u n s a t u r a t e d e s t e r .  introduced  With e t h y l cinnamate (39)  the r e l a t i v e s t a b i l i t i e s o f the two r a d i c a l i n t e r m e d i a t e s 40a and 40b would determine the o r i e n t a t i o n of the a d d i t i o n of the carbamoyl r a d i c a l .  (JENH2 CgHgO^CHCC^Et  ^0NH  2  C6H5CHCH  40a ° 2  39  C  C^CHCri  40b * 2  Et  S t e r i c f a c t o r s should not be i g n o r e d but i n t h i s p a r t i c u l a r the  e l e c t r o n i c s t a b i l i t i e s are obviously  the o v e r - r i d i n g  E t  instance  factors.  A  42 comparison o f t h e s t a b i l i t y o f f r e e r a d i c a l s by  which a r e s t a b i l i z e d  c o n j u g a t i o n w i t h these two f u n c t i o n a l groups l e a d t o the e x p e c t a t i o n  t h a t a b e n z y l m a l o n i c a c i d d e r i v a t i v e would r e s u l t from t h e a - a d d i t i o n of the carbamoyl r a d i c a l ( s t r u c t u r e 40a). showed t h a t  However, e x p e r i m e n t a l evidence  t h e major product formed from the photoamidation of e t h y l  cinnamate (39) i n the presence o f benzophenone (41) as s e n s i t i z e r , was 2-carbamoyl-3,4,4-triphenyl-y-butyrolactone following  (42).  scheme, t h e s t a b l e i n t e r m e d i a t e b e n z y l i c  As can be seen i n the r a d i c a l **3_ i n which  the u n p a i r e d e l e c t r o n i s d e l o c a l i z e d over the phenyl group, f a i l s to perform the hydrogen a b s t r a c t i o n  from formamide. I n s t e a d , t h e i n t e r m e d i a t e  r a d i c a l 43_ forms a 1:1 adduct w i t h a s e m i p i n a c o l r a d i c a l ^t4_ (or a molecule of benzophenone (41))  thus l e a d i n g  t o the amido e s t e r a l c o h o l  45 which,under  the c o n d i t i o n s  of the r e a c t i o n , l a c t o n i z e s t o the amido l a c t o n e 42.  39 + HCONH'  «  >  C 6 H5CHCHC0NH 2 "  ( c ^ c o  iooEt  CgHgCH—CHC0NH2  ;—> 6 5 2C0H H  ,  44  43  41  (Cgr^COH  ( C  ^ C^HcCH—CHC0NH2  C02Et  45  42 Scheme IV  A s i d e r e a c t i o n that was d e t e c t e d  i n the photoamidation  reactions  s e n s i t i z e d w i t h benzophenone was the a d d i t i o n of the s e n s i t i z e r  to the  a,B-unsaturated e s t e r w i t h subsequent l a c t o n i z a t i o n of the y-hydroxy e s t e r s t o g i v e t h e s u b s t i t u t e d y - b u t y r o l a c t o n e s as shown i n the f o l l o w i n g scheme:  RCH=CHC0 2 Et  +  0.\  0 R^H-CH C02Et 2  QCOH R=alkyl,C02Et  Scheme V  COH + H"  The f r e e r a d i c a l reaction.  c h a i n mechanism was proposed  As mentioned  previously,  f o r the photoamidation  the l i g h t - i n d u c e d  amidation r e a c t i o n  can occur w i t h o u t an i n i t i a t o r but i t s presence i n c r e a s e s the r a t e of the r e a c t i o n and y i e l d s a r e s i g n f i c i a n t l y may be i l l u s t r a t e d  y . s. deactivation h  H-CONH 2 0  (C H ) &  5  2  i n the f o l l o w i n g  -HC=CH- +  o  -HC-CHCONH + HCONH 2  2  -CONH 2  2  (1)  0  -H  H C 0 N H  2  2 =-) -CONH + ( C g H ^ C O H  (2)  2  > -HC-CHC0N1I„ | 2  -C0NH 2  -HC-CKCONH  5  The course o f the r e a c t i o n  scheme:  (H-CONHJ* 2  hv * C=0 - i i — > ( ( C H ) C = 0 ) 6  higher.  -H C-CHCONH 2  2  (3)  + •CONH  2  I +-HC = CH- -> -HC-CHCONH  2  ( 4 )  (5)  -HC-CH-  -HC-CHCONH + -CONH 2  2  -HC-CHCONH  2  ioNH  2  S c h e m e VI  (  6  )  18  In systems without added s e n s i t i z e r s carbamoyl r a d i c a l phbtoactivated  (step 1) r e s u l t  (ketones) the g e n e r a t i o n of the  from e i t h e r the c o l l a p s e o f the  (*) formamide m o l e c u l e or through hydrogen  from formamide by o t h e r r a d i c a l s formed.  abstraction  In the presence o f a s e n s i t i z e r ,  the p h o t o — a c t i v a t e d s e n s i t i z e r a b s t r a c t s a hydrogen molecule to form the carbamoyl and k e t y l r a d i c a l s  from the formamide  (step 2 ) . The o l e f i n  43 which  serves a r a d i c a l scavenger  then forms 1:1 adduct  (step 3) w i t h  the a v a i l a b l e r a d i c a l s which l e a d s to the i s o l a t e d amide and a l c o h o l i c products.  The d e s i r e d amide p r o d u c t s can be s y n t h e s i z e d i n h i g h y i e l d s  by a d j u s t i n g the c o n c e n t r a t i o n s of the a p p r o p r i a t e r e a g e n t s . (1) and (2) a r e the i n i t i a t i o n s t e p s whereas r e a c t i o n s c h a i n p r o p a g a t i o n steps w i t h  Reactions  (3) - (5) a r e  (3) and (4) g i v i n g 1:1 adduct and r e a c t i o n  * (5) l e a d s to 2:1 telomer  or f u r t h e r t e l o m e r i z a t i o n can occur to g i v e  h i g h e r telomer. Chain t e r m i n a t i o n can occur when two r a d i c a l s combine to form a new sigma-bond as shown i n step ( 6 ) .  have been i s o l a t e d  Alkylated  succinamides 40a  from the photoamidation o f t e r m i n a l o l e f i n s  oxamide i s o l a t e d when o l e f i n  and  i s absent.  The r o l e o f the s e n s i t i z e r , u s u a l l y acetone or benzophenone, was initially  i n d i s p u t e as t o whether i t s primary r o l e was one of a photo-  initiator  i n which  the p h o t o a c t i v a t e d ketone a b s t r a c t e d hydrogen  from  formamide (step 1) or t h a t o f a p h o t o s e n s i t i z e r whereby the p h o t o a c t i v a t e d triplet  energy o f the ketone was t r a n s f e r r e d  then c o l l a p s e to form the carbamoyl  radical.  to formamide which would 40a T h i s c o n f l i c t was  44 i hsed et fr ii np el de t as a m o l eocfu lformamide e formed from m o was l e c u lfound e s ofto o lbe efin rea s o lnv:e l d telomer when t energy (4.2 n eV) and one m o l e c u l e o f formamide.  19  g r e a t e r than t h a t o f e i t h e r e x c i t e d t r i p l e t  acetone  (3.5 eV)  or benzo-  46 phenone (3.03 eV)  .  T h e r e f o r e , the p h o t o s e n s i t i z a t i o n o f formamide by  these ketones i s i m p o s s i b l e , and, as a consequence, mechanism i s one triplet  i n which the f o r m y l hydrogen  the o n l y p o s s i b l e  i s a b s t r a c t e d by the n-^rr  o f the ketone. C h e m i c a l proof i s a l s o present i n the form of  p r o d u c t s i s o l a t e d from the r e a c t i o n o f the i n t e r m e d i a t e k e t y l  radicals,  such as 2-methyl a l k a n e - 2 - o l s from a c e t o n e - i n i t i a t e d photoamidation of o l e f i n s and c o n s i d e r a b l e amounts of b e n z p i n a c o l when benzophenone  was  used as the p h o t o i n i t i a t o r . The a p p l i c a t i o n o f photochemical a d d i t i o n of formamide to u n s a t u r a t e d sugars has been undertaken by R o s e n t h a l and coworkers determine  i n an e f f o r t  to  the s t e r e o c h e m i c a l outcome of t h i s r e a c t i o n on v a r i o u s un-  s a t u r a t e d s u g a r s , as w e l l as, u t i l i z i n g  t h i s r e a c t i o n to s y n t h e s i z e  branch c h a i n amido and amino sugars which may  n u c l e o s i d e analogues.  be used 47  R o s e n t h a l and R a t c l i f f e  to s y n t h e s i z e  photoamidated  (Z) and  (Z,E)-3-deoxy-3-C-(methoxycarbonyl)-methylene-l,2:5,6-di-0-isopropylidenea-D-ribo-hexofuranose  (46) to a f f o r d  3-C-[R and  S-carbamoyl(methoxy  carbonyl)methyl]-3-deoxy-l,2:5,6-di-0-isopropylidene-a-D-allofuranose (47) and  (48) by an a n t i - M a r k o v n i k o v a d d i t i o n of formamide t o the carbon-  carbon double bond.  The  e x c l u s i v e a d d i t i o n of the carbamoyl  r a d i c a l to  C02Me 46_  47 R=C0NH2 R=H  R=H  R=C0NH  2  20  the a-carbon  of e s t e r 4_6 was a r e s u l t which was s u r p r i s i n g i n view o f  E l a d ' s ^ ^ work w i t h simple a,8-unsaturated e s t e r to a f f o r d the c o r r e s ponding 6-carbamoyl e s t e r s . However, i n view o f the work of R o s e n t h a l and co-workers  (vide infra) with substituted  sugars which r e s u l t  (enolic) unsaturated  i n an a n t i - M a r k o v n i k o v p h o t o a d d i t i o n of formamide  and the p r e v i o u s l y d i s c u s s e d a - a d d i t i o n of the carbamoyl e t h y l cinnamate  r a d i c a l to  (38) , the p o s s i b i l i t y of a - c a r b a m o y l a t i o n to g i v e the 48  i n t e r m e d i a t e t e r t i a r y r a d i c a l at C-3 was not t o t a l l y Upon photoamidation  unexpected.  of v a r i o u s u n s u b s t i t u t e d , mono- and d i s u b s t i t u t e d ,  e n d o c y c l i c , e n o l i c and e n e d i o l i c u n s a t u r a t e d sugars, Rosenthal and coworkers 47 40a) b) concluded t h a t , i n accord w i t h E l a d ' s ' f i n d i n g s w i t h t e r m i n a l and n o n t e r m i n a l o l e f i n s : the p h o t o a d d i t i o n of formamide proceeds Markovnikov  f a s h i o n and s u b s t r a t e s i n which both carbons of the u n s a t u r a t e d  group bears hydrogen  or i n which the u n s a t u r a t e d group  (with s a t u r a t e d g r o u p s ) , the photoamidation The hydrogen  i n an a n t i -  s t e r e o c h e m i s t r y of the carbamoyl  is fully  substituted  i s non-regiospecific.  r a d i c a l a d d i t i o n and the subsequent  a b s t r a c t i o n s t e p can be r a t i o n a l i z e d predominantly from the s t e r i c  environment  about  cis-1,2-steric  the r e a c t i v e c e n t r e of the u n s a t u r a t e d s u b s t r a t e . The  i n t e r a c t i o n s p r o v i d e the predominate  directing  influence  w i t h the a t t a c k i n g s p e c i e s approaching from the l e a s t h i n d e r e d s i d e . The r e s u l t s of these s t e r i c  i n t e r a c t i o n s are evidenced by the product 47 49  found by Rosenthal and coworkers. D - g l u c a l (1_) . approximate  '  Thus, photoamidation  Y i e l d e d t h r e e major carbamoyl  ratios  of t r i a c e t y l -  sugars 50_, _51 and _52 i n an  r a t i o of 2:2:3, r e s p e c t i v e l y " ^ , w i t h product 5_2_ e x h i b i t i n g a  t r a n s - o r i e n t a t i o n of the carbamoyl  group  to C-3 a c e t y l .  21  H  H  5Q. R = C 0 N H 2 51  R=H  R*=H  CONH2 52  Ff=C0NH2  When 3-deoxy-l,2:5,6-di-0-isopropylidene-ct-g- erythro- hex-3-enofuranose (53) was  i r r a d i a t e d , two  equal amounts.  formamide adducts _54 and  T h i s r e g i o - and  s t e r e o s p e c i f i c a d d i t i o n was  t r a n s - h y d r o c a r b o m o y l a t i o n s i n c e there was i n the a b s t r a c t i o n s t e p . The  surprising  s i m i l a r substrates  55  endo f a c e of the  i n l i g h t of the  fused  r i n g system) i s not  f a c i l e displacement r e a c t i o n s  when the a t t a c k i n g  species  isopropylidene-ot-D-erythro  fully  substituted  (e.g.,  totally  of s t r u c t u r a l l y  i s neutral, small  c a p a b l e of hydrogen bonding to the oxygen on C-2 , 52b, ammonia ). Photoamidation of the  exclusively  o n l y a s i n g l e 1,2-c_is_-interact i o n  54  of 53_ ( i . e . , the  an  a d d i t i o n of the carbamoyl r a d i c a l s c i s to  53 0-2  5_5 were formed i n about  and  hydrazine  52a  and  3-0-acetyl-l,2:5,6-di-0-  hex-3-enofuranose (56)  afforded  carboxamide  53 sugars 51_ and _58_ i n 65 and  26%  yields, respectively.  major components added the carbamoyl r a d i c a l to the substrate  w i t h hydrogen a b s t r a c t i o n  i n 57_ on  the  Expectedly, exo-face of  same s i d e due  l , 2 - c _ i s - i n t e r a c t i o n s on the s t e r i c a l l y crowded endo-face. abstraction  i n the s y n t h e s i s  of compound j>8_ o c c u r s on the  The  the  the to  two  hydrogen  endo-face but  22  on the l e a s t h i n d e r e d p o s i t i o n of the fused o v e r - a l l a d d i t i o n i s trans carbon  (e.g.,  oxygen (e.g., hydrogen  group) i s expected t o be g r e a t e r  which might  a l s o p r o v i d e hydrogen  to the  donor.  Photochemical .c_is_-trans  x°q  f o r thermal ground  reactions.  0  Isomerization  The phenomenon of c i s - t r a n s i s o m e r i z a t i o n only  the  than an  bonding  CONH  2.2.  Also,  s i n c e a 1 , 2 - c i s - s t e r i c r e p u l s i o n from a  the carbamoyl 0-3)  r i n g system.  i s well  established,  s t a t e reactions"'"', but a l s o f o r e x c i t e d  x h e ease w i t h which  not  state  the carbon-carbon double bond  under-  goes geometric i s o m e r i z a t i o n upon i r r a d i a t i o n has been known f o r a cons i d e r a b l e time, but the d e t a i l s of the r e a c t i o n remain  the s u b j e c t  of  58 many i n v e s t i g a t i o n s .  The dependence of the photochemical  of o l e f i n i c , aromatic and a,6-unsaturated e s t e r systems on temperature and  triplet  energy have been i n v e s t i g a t e d . " ^  d i s c u s s i o n on these t o p i c s and  In a ground  concentration However, a d e t a i l e d  the mechanism of the photochemical  z a t i o n i s beyond the scope of t h i s t h e s i s and o n l y e f f e c t s of t r i p l e t  equilibrium  energy w i l l b r i e f l y  state isomerization  isomeri-  the mechanism and  discussed.  the thermal r e a c t i o n proceeds by  of a non-planar t r a n s i t i o n common to both cjis- and t r a n s - i s o m e r s . The t r a n s i t i o n s t a t e w i l l c o l l a p s e to g i v e a g r e a t e r p r o p o r t i o n of the  way  thermodynamically more s t a b l e isomer, u s u a l l y the t r a n s - i s o m e r . However, the  product c o m p o s i t i o n i n the p h o t o c h e m i c a l l y induced i s o m e r i z a t i o n  differs  from t h a t  i n the thermal p r o c e s s and t h e thermodynamically  s t a b l e isomer u s u a l l y predominates. produce an e x c i t e d s p e c i e s which  less  I r r a d i a t i o n of a t r a n s - i s o m e r w i l l  i s u s u a l l y lower i n energy than the  c o r r e s p o n d i n g c i s - i s o m e r and t h e geometric i s o m e r i z a t i o n i s brought about by a d i s t o r t i o n o f the e x c i t e d s t a t e s i n i t i a l l y  produced, t o an  e x c i t e d s t a t e common t o both c i s - and _trans-isomers.  The common e x c i t e d  s t a t e i s termed  a phantom s t a t e and i n v o l v e s a s m a l l a c t i v a t i o n  C o l l a p s e of t h e phantom s t a t e t o t h e ground and t r a n s - i s o m e r s .  energy.^  s t a t e w i l l a f f o r d both c i s -  The c i s - i s o m e r i s l e s s l i a b l e to undergo  than t h e t r a n s - i s o m e r but n e v e r t h e l e s s , an e x c i t e d  excitation  state population  will  be o b t a i n e d from t h i s isomer, and i s o m e r i z a t i o n from c i s - to t r a n s -  will  occur v i a t h e phantom s t a t e . In t h i s manner, an e q u i l i b r i u m termed a photostationary state i s established predominates.  usually  T h e r e f o r e , the p h o t o s t a t i o n a r y s t a t e i s a f u n c t i o n of the  extinction coefficient the  i n which the c i s - i s o m e r  o f the two geometric isomers w i t h the isomer w i t h  lower v a l u e p r e d o m i n a t i n g when t h e i s o m e r i z a t i o n i s brought about by  direct  irradiation.  about by t r i p l e t  However, when the geometric i s o m e r i z a t i o n i s brought  sensitization  (e.g. from e x c i t e d  benzophenone), t h e c o m p o s i t i o n of the from t h a t o f d i r e c t  irradiation.  excited  occur.  acetone or  photostationary state  I f the energy of the donor  than t h a t o f both isomers, then t r i p l e t and t r a n s - i s o m e r w i l l  triplet  differs i s greater  energy t r a n s f e r t o b o t h the c i s -  The i n i t i a l l y  formed  c i s - and t r a n s - t r i p l e t  s p e c i e s undergo d i s t o r t i o n to the common phantom t r i p l e t which, on  c o l l a p s i n g t o the ground  s t a t e , a f f o r d s a mixture of isomers.  Because the  s e n s i t i z e r can e x c i t e both isomers, the p r o p o r t i o n of c i s - i s o m e r i n the  p h o t o s t a t i o n a r y s t a t e from a s e n s i t i z e d o b t a i n e d from d i r e c t  irradiation.  r e a c t i o n i s lower than that  S e n s i t i z e r s of h i g h energy  (acetone)  g i v e p h o t o s t a t i o n a r y s t a t e s w i t h approximately the same c o m p o s i t i o n of isomers  (^55% c i s ) , w h i l e r e d u c i n g the energy of the s e n s i t i z e r g i v e s  anomolous r e s u l t s . ^ but s t i l l  When the t r i p l e t  energy  capable o f t r a n s f e r r i n g energy  of the s e n s i t i z e r i s low  to both isomers, the s e n s i t i z e r  then f u n c t i o n s as a t r u e " p h o t o c a t a l y s t ' and the p h o t o s t a t i o n a r y mixture !  approaches that a t thermal Photochemical  equilibrium."^  cis-trans  i s o m e r i z a t i o n has l e d to the s y n t h e s i s of  t r a n s - d o u b l e bonds i n both c i s - c y c l o h e p t - 2 - e n o n e (59) and c i s - c y c l o - o c t 2-enone (60) t o a f f o r d i r r a d i a t e d with l i g h t  the c o r r e s p o n d i n g t r a n s - i s o m e r s 61 and 6_2_ when g r e a t e r than 300 nm, the i s o m e r i z a t i o n b e i n g e f f e c t e d  * 59 by the n->-TT e x c i t a t i o n .  In the case of a, 6-unsaturated  e s t e r s the energy-  t r a n s f e r from the e x c i t e d c a r b o n y l compound to the e s t e r has been r e p o r t e d to be e f f i c i e n t  and l e d to c i s - t r a n s  i s o m e r i z a t i o n or c y c l o a d d i t i o n . "^  Thus, w i t h r e s p e c t t o the photoamidation  r e a c t i o n , the quenching  of the  e x c i t e d p h o t o i n i t i a t o r v i a the s e n s i t i z a t i o n o f the a,6-unsaturated must be c o n s i d e r e d .  E l a d and Rokach^^^ found  ester  that when the a c e t o n e - i n i t i a t e d  25  r e a c t i o n of formamide w i t h e t h y l maleate ( c i s - i s o m e r ) or e t h y l fumarate ( t r a n s - i s o m e r ) was for  c a r r i e d out under c o n d i t i o n s s i m i l a r to the ones used  i s o l a t e d double bonds ( i . e . , l i m i t e d amount of acetone employed),  a d d i t i o n products  of formamide and  However, the r e c o v e r e d mixture  of geometric  the u n s a t u r a t e d  s t a r t i n g a,3-unsaturated  isomers,  particularly  e s t e r c o u l d be  no  detected.  e s t e r c o n s i s t e d of a  i n the case of e t h y l fumarate  which was  r e c o v e r e d mainly  as e t h y l maleate (e.g., t r a n s to c i s i s o m e r i z a t i o n ) .  Increased  amounts of acetone produced some a d d i t i o n of formamide to the above  e s t e r s but y i e l d s were s t i l l  low.  On  the other hand, u s i n g benzophenone  as the p h o t o i n i t i a t o r the a d d i t i o n of formamide to e t h y l fumarate maleate were achieved  i n almost q u a n t i t a t i v e y i e l d .  able isomerization s t i l l to  be more e f f i c i e n t  occurred  and  and  However, the u n d e s i r -  t h i s e n e r g y - t r a n s f e r step was  and more r a p i d than  found  the hydrogen a b s t r a c t i o n step from  formamide.  3.  Carbon-Carbon Double Bonds Hydrocarbons p o s s e s s i n g a carbon-carbon double bond have the most  b a s i c f u n c t i o n a l group i n o r g a n i c c h e m i s t r y . formation  t h i s f u n c t i o n a l group may  be  By v a r i o u s simple  transformed  trans-  into a saturated  hydrocarbon, an hydrocarbon p o s s e s s i n g a h i g h e r degree of u n s a t u r a t i o n v a r i o u s o t h e r f u n c t i o n a l i z e d molecules s e c t i o n w i l l d e a l mainly  c o n t a i n i n g hetero-atoms.  or  This  w i t h a d d i t i o n r e a c t i o n s to compounds p o s s e s s i n g  a carbon-carbon double bond. There are b a s i c a l l y bond can take p l a c e .  f o u r ways i n which a d d i t i o n to a double or  Three of these are two  step p r o c e s s e s , w i t h an  a t t a c k by a n u c l e o p h i l e , an e l e c t r o p h i l e , or a f r e e r a d i c a l . s t e p c o n s i s t s of combination  of the r e s u l t i n g  The  triple initial  second  intermediate with a p o s i t i v e  species, a negative  s p e c i e s , or a n e u t r a l e n t i t y , r e s p e c t i v e l y .  f o u r t h type of mechanism, a t t a c k at the two t r i p l e bond i s simultaneous. g i v e n case and  i s determined by  the r e a c t i o n c o n d i t i o n s .  scope of t h i s t h e s i s and necessary. in d e t a i l  no  carbon atoms of the double or  the nature  of the  s u b s t r a t e , the  reagent,  P e r i c y c l i c ^ r e a c t i o n s are beyond f u r t h e r d i s c u s s i o n on t h i s process  the is  P h o t o c h e m i c a l f r e e r a d i c a l a d d i t i o n s have been d e a l t w i t h i n the p r e v i o u s  electrophilic  s e c t i o n and  two  non-photochemical methods  N u c l e o p h i l i c and  s u b s t i t u t i o n w i l l be  numerous examples of M i c h a e l - t y p e  a r e too v a r i e d i n s u b s t r a t e and  particularly  the main focus of t h i s s e c t i o n .  N u c l e o p h i l i c A d d i t i o n to a,B-Unsaturated The  the  The mechanism which i s o p e r a t i n g i n any  w i l l be b r i e f l y d e a l t w i t h here.  3.1.  In  Esters  a d d i t i o n to conjugated  a d d i t i o n products  length.  The  f o c u s of t h i s s e c t i o n w i l l be  a c i d and  sodium a z i d e to a , B - u n s a t u r a t e d  olefins  to be d i s c u s s e d at  the a d d i t i o n of  any  hydrazoic  esters.  Based on O l i v e r i - M a n d a l a ' s ^ a d d i t i o n of h y d r a z o i c  acid  to benzo-  68 quinone i n 1915, with  Boyer  i n 1951,  e s t a b l i s h e d that o l e f i n s  e l e c t r o n withdrawing groups (e.g.,  undergo M i c h a e l - t y p e corresponding exhibited  8-azido compound.  intermediate  stability  the m o l e c u l a r  The  r e a c t i v i t y and  (e.g.,  -NC^  and  J^jj) to g i v e  the a z i d e products  of the a z i d e s a p p a r e n t l y  increased with  were found nitrogen.  the  to The  the number and  weight of the s u b s t i t u e n t s on the carbon b e a r i n g the  chloroform).  )  a,B-unsaturated c a r b o n y l compounds  e l i m i n a t i o n of h y d r a z o i c a c i d and  g r o u p ^ or i f the a z i d o compound was solvent  -C=N,  a d d i t i o n reactions with hydrazoic acid  thermally unstable with thermal  C=0,  conjugated  s t o r e d i n a high m o l e c u l a r  azido  weight  Since hydrazoic acid  i s a v e r y weak a c i d , the mechanism o f t h i s  r e a c t i o n i s c o n s i d e r e d t o be a 1,4  n u c l e o p h i l i c addition, with protonation  of the r e s u l t i n g e n o l a t e i o n predominantly e n o l which t a u t o m e r i z e s .  The mechanism i s i l l u s t r a t e d  N -C = C-^C=0  No  l  a t the oxygen l e a d i n g to an  fjJ  3  3  -C—C=C—§«-» - C — ? — c = o I I I  i  N  •c—c=c—OH; Scheme  treated  sugars has been s t u d i e d .  to v a r i o u s  (64) was i s o l a t e d product a second  conjugated  when Rosenthal and R a t c l i f f e ^  (46) w i t h excess  h y d r a z o i c a c i d , the a z i d o - p r o d u c t a r i s i n g from a d d i t i o n of h y d r a z o i c a c i d  H  VIII  (Z)-3-deoxy-l ,2:5,6-di-0-isopropylidene-3-C-  methylene-q-g-ribo-hexofuranose  3  - i — i — C=0  The M i c h a e l - t y p e a d d i t i o n of h y d r a z o i c a c i d unsaturated  i n Scheme V I I I .  (methoxycarbonyl)  sodium a z i d e and  the s t e r e o s e l e c t i v e  to the double bond to g i v e the g l u c o - d i a s t e r e o m e r  i n 80% y i e l d .  I n t e r e s t i n g l y , a l o n g w i t h expect  component i s o l a t e d  3-amino-3-deoxy-3-C_-[3'-diazo  i n a low y i e l d  (methoxycarbonyl)  isopropylidene-ct-D-glucofuranose  (65) .  (7%) was found  addition to be  methyl]-1,2:5,6-di-0-  28  Upon t r e a t i n g the u n s a t u r a t e d absence of h y d r a z o i c a c i d and  sugar 46_ w i t h sodium a z i d e i n the  a n o n - p r o t i c s o l v e n t , they  diazo-amino sugar 6_5 as the major a d d i t i o n product  (46%)  isolated and  the  the azido  sugar 6_4_ i n t r a c e amounts (2%) . The m e c h a n i s t i c  pathway to the n o v e l diazo-amino sugar 65_ i s thought  to a r i s e from the b a s e - c a t a l y z e d  t a u t o m e r i z a t i o n and bond rearrangement  of the charged t r i a z o l i n e which r e s u l t s from the i n t r a m o l e c u l a r c y c l i z a t i o n 73 of the a z i d o e n o l a t e a n i o n . scheme.  T h i s mechanism i s i l l u s t r a t e d  i n the f o l l o w i n g  3.2.  R e a c t i o n s of E n o l E t h e r s J u s t as o l e f i n i c compounds a c t i v a t e d w i t h e l e c t r o n - w i t h d r a w i n g  groups undergo numerous n u c l e o p h i l i c a d d i t i o n r e a c t i o n s w i t h the withdrawing group d i r e c t i n g the  r e g i o s p e c i f i c i t y of the r e a c t i o n , o l e f i n s ,  which are n a t u r a l l y more s u s c e p t a b l e to e l e c t r o p h i l e s than  nucleophiles,  have enhanced a f f i n i t y f o r e l e c t r o p h i l e s when e l e c t r o n - d o n a t i n g are p r e s e n t .  As w i t h the  the d i r e c t i o n of a t t a c k  e l e c t r o n - w i t h d r a w i n g groups a b i l i t y  in nucleophilic addition reactions,  d o n a t i n g groups a l s o p l a y an addition reactions. r a d i c a l and cussion  on  the  groups to  the  influence electron-  important r o l e i n the r e g i o s p e c i f i c i t y of  This section w i l l deal with various  c y c l i c additions  electron-  to the  various  e l e c t r o p h i l i c , free  e n o l i c double bond, a l o n g w i t h a d i s -  g e n e r a l s u s c e p t a b i l i t y of e t h e r s and  o l e f i n s to a i r  oxidation.  74  Pericyclic the  and  cyclo-addition  scope of t h i s t h e s i s and The  release  w i l l not  reactions  be  ethers  of e l e c t r o n s  contributing  are however, beyond  discussed.  mode of a d d i t i o n of i o n i c reagents to the  bond of e n o l  the  Diels-Alder  carbon-carbon double  ( i . e . , v i n y l e t h e r s ) i s governed by from the oxygen of the  canonical  structure  6_6_ and  R-  \=AHR'  ether,  the mesomeric  which g i v e r i s e  d i r e c t s the  e l e c t r o p h i l e to  C—CHR' R and R'=  66  the  g-carbon.  In those r e a c t i o n s  e i t h e r the n e g a t i v e i n d u c t i v e  to  which i n v o l v e  a 1,2-cyclic  alkyl  onium i o n  or p o s i t i v e mesomeric e f f e c t of the  enolic  30  o x  y g e n w i l l e x e r t a d i r e c t i n g i n f l u e n c e d u r i n g the approach of  n u c l e o p h i l e i n t h e second s t e p . However, the s t e r e o c h e m i s t r y  the  of  the  a d d i t i o n which depends upon the c h a r a c t e r i s t i c s of each r e a c t i o n and governs the r a t i o of the i n i t i a l products i s o l a t e d products the a-carbon due  due  may  to the e p i m e r i z a t i o n  to the a c t i v a t i o n e f f e c t  3.2.1. A d d i t i o n of Oxygen and  not be obvious i n the  (or a n o m e r i z a t i o n ) about of the e n o l i c oxygen.  Hydrogen  E n o l e t h e r s r e a d i l y add water or primary a l c o h o l s i n the presence of a c i d .  Protonation  to g i v e i n t e r m e d i a t e  (by the e l e c t r o p h i l e , H"*")  takes p l a c e at the  carbonium i o n 6_7 s t a b i l i z e d by the mesomeric r e l e a s e  of e l e c t r o n s to the a-carbon to g i v e c o n t r i b u t i n g s t r u c t u r e 68_. intermediate  c a t i o n then adds a m o l e c u l e of the hydroxy reagent  g i v e the protonated  s p e c i e s 69_ which l o o s e s a proton  illustrated  i n Scheme X.  -C=C—OR  As can be reagent  to  hemi-ketal  T h i s mechanism  T h i s mechanism i s termed an A-SE.2 m e c h a n i s m ^  H  slow  Scheme because the s u b s t r a t e  The (ROH)  to g i v e the  or k e t a l from the a d d i t i o n of water or a l c o h o l , r e s p e c t i v e l y . is  g-carbon  (enol e t h e r )  X  i s protonated  i n the r a t e d e t e r m i n i n g  step.  seen from the above scheme, the a d d i t i o n of the n u c l e o p h i l i c  i s an r e v e r s i b l e step c a t a l y z e d by the presence of the a c i d ; t h e r e f o r e ,  31  the -OR  groups a t t a c h e d to the a-carbon w i l l approach a thermodynamic  1  equilibrium addition  i r r e g a r d l e s s of the s t e r i c f a c t o r s a f f e c t i n g the  of the  initial  nucleophile.  The a c i d - c a t a l y z e d  a d d i t i o n of water to the e n o l i c system of  deoxy-l-eno sugars ( g l y c a l s ) has been a p p l i e d w i t h success i n the of numerous 2-deoxy d e r i v a t i v e s  of pentoses, hexoses,  1,2-  synthesis  6-deoxyhexoses,  2 4 disaccharides,  and methylated a l d o s e s .  vary considerably  '  The y i e l d s of the 2-deoxy p r o d u c t s  and the main by-products are those a r i s i n g from the hydro-  l y s i s of a c i d - l a b i l e groups and p r o d u c t s a r i s i n g from a c i d - c a t a l y z e d e l i m i n a t i o n reactions.  For example, from D - g l u c a l  pyranose, _70, R=H) 71, R=H),  and D - g a l a c t a l  acid-catalyzed  deoxyhexoses  (1,2-dideoxy-D-arabino-hex-l^eno-  (1,2-dideoxy-D-lyxo-hex^l-enopyranose,  a d d i t i o n o f water gave, i n a d d i t i o n t o the 2-  (72 and 7_3 i n 42% and 78%, r e s p . ) ,  2H-pyran (74) i n 16% and 1% y i e l d ,  3-hydroxy-2-(hydroxmethyl)-  respectively.'^  Ik  32  In the a c i d - c a t a l y z e d the  a d d i t i o n of alcohols  t o the e n o l i c system of  1,2-unsaturated s u g a r s , 2-deoxy a l k y l g l y c o s i d e s  cases^ the  t h i s method o f s y n t h e s i s  r e s u l t s . I n some  of the 2-deoxy g l y c o s i d e  g l y c o s i d a t i o n o f the f r e e sugar.  i s preferred  As i n the h y d r a t i o n  over  of g l y c o l s , the  competing e l i m i n a t i o n r e a c t i o n i n t e r f e r e s and v a r i o u s  a c y c l i c and u n s a t u r a t e d  c y c l i c p r o d u c t s may r e s u l t , a l o n g w i t h the h y d r o l y s i s  of a c i d - l a b i l e groups.  3.2.2. A d d i t i o n o f Bromine and Bromomethoxylation In the e l e c t r o p h i l i c a t t a c k of i t ) on a simple o l e f i n ,  of the bromonium i o n ( B r ,  the bromonium i o n 7_5 i s o f t e n an  ©  that  leads  o 9 I R—C—C-  i75  t o an a t t a c k  intermediate  Br  * R—C—CT  or a c a r r i e r  +  i 76  i  of the n u c l e o p h i l e  from the o p p o s i t e  double bond) t o g i v e s t e r e o s p e c i f i c a n t i a d d i t i o n .  78  face  (of the  However, a number 79  of examples have been found where a d d i t i o n of bromine i s not fically  anti.  The r e s u l t s i n d i c a t e that  there  stereospeci-  i s a spectrum of mechanisms  between complete brominium-ion 75_ f o r m a t i o n and complete o p e n - c a t i o n 80 formation, with p a r t i a l l y bridged  bromonium ions  i n between.  The  l o c a t i o n i n t h i s spectrum i s determined by the r e l a t i v e a b i l i t i e s of the R-groups t o s t a b i l i z e group which g i v e s  the o p e n - c a t i o n _76-  Therefore,  where R i s an a l k o x y l  a r e l a t i v e l y s t a b l e oxonium c a t i o n such as 6J5, the i n t e r -  mediate c a t i o n w i l l possess much o p e n - c a t i o n c h a r a c t e r , the  s t e r e o s e l e c t i v i t y o f the a d d i t i o n  thereby  lowering  reaction.  81 In a r e p o r t  on the h a l o m e t h o x y l a t i o n  -0CH ) o f t r i - O - a c e t y l - D - g l u c a l 3  ( a d d i t i o n of X=halogen and  (70, R=Ac) and t r i - O - a c e t y l - D - g a l a c t a l  (71,  R=Ac), the adducts i s o l a t e d showed s i g n i f i c a n t p r o p o r t i o n s  of a - c i s  a d d i t i o n products a r i s i n g from the o p e n - c a t i o n .  3.2.1, Methoxymercurat i o n Another r o u t e  t o the 2-deoxy g l y c o s i d e s  i s by the use of the oxy-  82a mercuration r e a c t i o n .  The enol  (or h y d r a t e d ) q u i c k l y , under m i l d  ethers  conditions,  arrangement or e l i m i n a t i o n p r o d u c t s . the  electrophilic addition,  (or o l e f i n s ) can be a l k y l a t e d i n h i g h y i e l d s without r e -  The oxymercuration r e a c t i o n  to t h e carbon-carbon double bond, of t h e  m e r c u r i c i o n t o form a c y c l i c mercurinium i o n 77_. T h i s a t t a c k e d by t h e n u c l e o p h i l i c s o l v e n t yield  the a d d i t i o n product.  i o n i s then  (water or 1° o r 2° a l c o h o l ) t o  The net r e a c t i o n  i s anti  a d d i t i o n and t h e  o r i e n t a t i o n corresponds to Markovnikov a d d i t i o n of a l c o h o l  (or w a t e r ) .  8 2b The  mechanism  i s illustrated  i n Scheme X I .  Ac  0  Ha  -fV  HgtOAc^, ROH ^ R=1or2°alkylorH  JROH HgOAc  HgOAc  -C-  I  involve  -H  -C  C-  ®0H  '  OR  Scheme XI  The a t t a c k of the hydroxy  reagent i s of the S 2  t y p e , even  N  though  the o r i e n t a t i o n of the a d d i t i o n shows t h a t the n u c l e o p h i l e a t t a c k s the more h i g h l y s u b s t i t u t e d carbon-carbon. to  The  seeming c o n t r a d i c t i o n i s due  the f a c t that the t r a n s i t i o n s t a t e i n c a t i o n i c three-membered  possess much S ^ l c h a r a c t e r and, greater r o l e .  t h e r e f o r e the e l e c t r o n i c f a c t o r p l a y a  Thus, the a t t a c k of the n u c l e o p h i l e (ROH)  t h a t can b e s t accommodate the p o s i t i v e charge substituted  rings  o c c u r s at carbon  ( i . e . , u s u a l l y the more  centre).  The oxymercuration r e a c t i o n i s u s u a l l y f o l l o w e d by a i n s i t u r e d u c t i v e d e m e r c u r a t i o n w i t h sodium b o r o h y d r i d e (see Scheme XI) to g i v e the net M a r k o v i n i k o v a d d i t i o n of water or a l c o h o l to the u n s a t u r a t e d bond. The intermediate oxymercurial i f i s o l a t e d  i s u s u a l l y p r e c i p i t a t e d as the  chloride. Thus, the oxymercuration replacement  of t r i - O - a c e t y l - D - g l u c a l  o f the i o n i c a c e t a t e by c h l o r i d e , gave methyl 3 , 4 , 6 - t r i - O - a c e t y l -  2-(chloromercuri)-2-deoxy-3-D-glucopyranoside of  (70, R=Ac), a f t e r  the carbon mercury bond and  28  (78)^  a  ^.  R e d u c t i v e cleavage  simultaneous d e a c e t y l a t i o n were brought  R=Ac 79 R=HgCl  R=R=H  w i t h potassium b o r o h y d r i d e i n a l k a l i n e s o l u t i o n and gave methyl D-arabino-hexopyranoside  (79).  about  2-deoxy-g-  35  3 . 2 . 4 . R e a c t i o n w i t h meta-Chloroperbenzoic Another  Acid  f a c i l e method f o r the s y n t h e s i s of a l k y l or a c y l g l y c o s i d e s  i n v o l v e s the use of m e t a - c h l o r o p e r b e n z o i c  acid  (MCPBA, 80) on the g l y c a l s .  The r e a c t i o n of o l e f i n s w i t h p e r a c i d 80 u s u a l l y permits the i s o l a t i o n of the i n i t i a l l y  formed e x p o x i d e ^ , 3  however, w i t h e n o l e t h e r s the i n t e r m e d i a t e  epoxy a c e t a l s appear to r e a c t w i t h the c a r b o x y l i c a c i d  i n the r e a c t i o n  85b m i x t u r e too r a p i d l y to permit of  isolation.  T h e r e f o r e , the u s u a l product  t r e a t i n g a g l y c a l w i t h p e r a c i d 80 i s the a-hydroxy g l y c o s y l Two  mechanisms have been proposed  double bonds w i t h p e r a c i d s .  The  first  f o r e p o x i d a t i o n of  proposed  carbon-carbon 86  by B a r t l e t t  i n v o l v e s the f o l l o w i n g one-step mechanism.  esters.  in  1957  R  — c — c —  Another, more r e c e n t , mechanism which i s a l s o i n a c c o r d w i t h the r e a c t i o n k i n e t i c s , s o l v e n t e f f e c t s and i n v o l v e s a two  s t e p p r o c e s s as  ,, 87 follows.  r  R  H  s t e r e o c h e m i s t r y of the r e a c t i o n  R  R  O  H  0©  H  oe  The key s t e p o f t h i s mechanism i n v o l v e s t h e 1 , 3 - d i p o l a r a d d i t i o n o f a tautomer  of t h e p e r a c i d .  The five-member adduct then r e a r r a n g e s t o g i v e  the p r o d u c t s . I n the h y d r o x y l a t i o n o f D - g a l a c t a l  (71,R=H) w i t h peroxybenzoic a c i d  a r e g i o - and s t e r e o s p e c i f i c a d d i t i o n o f the r e a g e n t s o c c u r r e d t o g i v e a - D - t a l o p y r a n o s y l benzoate  88 (81) . The m e c h a n i s t i c a s p e c t s o f the opening  81  82  of the epoxide a r e i d e n t i c a l t o those proposed reaction  f o r the oxymercuration  ( p r e v i o u s s e c t i o n ) except the three-membered c a t i o n i c s p e c i e s i s  s t r u c t u r e 82. An i n t e r e s t i n g m o d i f i c a t i o n t o the h y d r o x y l a t i o n r e a c t i o n w i t h the p e r a c i d i n v o l v e s t h e slow a d d i t i o n o f t h e e n o l i c s u b s t r a t e t o an excess of p e r a c i d which r e s u l t s i n a c l e a v a g e o f o r i g i n a l carbon-carbon  double  89 bond.  Thus, when Borowitz  , Gonis and coworkers  treated 5,6,7,8-tetra-  hydrochroman (83) w i t h excess MCPBA 80_, they i s o l a t e d (86) i n 92% y i e l d .  6-ketononanolide  RC03H  xs 1  RC03H 65  « fi '  + S  °V&CR  0H 0  a  86  Scheme  XII  The mechanism proposed f o r t h i s cleavage and  i s d e p i c t e d i n Scheme X I I  i n v o l v e s the u s u a l f o r m a t i o n o f the e p o x y - a c e t a l  84 from the e p o x i -  d a t i o n of the e n o l i c double bond, the epoxide 84_ r e a c t s w i t h the excess p e r a c i d t o g i v e t h e ct-hydroxy  k e t a l p e r e s t e r 85_ which then decomposes to  g i v e 86_ and meta-chlorobenzoic  3.2.5.  acid.  O x i d a t i o n w i t h Osmium T e t r o x i d e  Osmium t e t r o x i d e  89  adds to carbon-carbon double bonds from the l e a s t 90  hindered  s i d e f o r the s e l e c t i v e c o n v e r s i o n of o l e f i n s to c i s - 1 , 2 - d i o l s .  The c y c l i c osmate e s t e r 87_ i s an i n t e r m e d i a t e  0  -I a? u s u a l l y decomposed reagents. with  90,91a-b  90 the e s t e r . " "  and can be i s o l a t e d , but i s  Q Un-  i n s o l u t i o n , w i t h sodium s u l f i t e i n e t h a n o l or other Bases  (e.g. p y r i d i n e ) c a t a l y z e the r e a c t i o n by c o o r d i n a t i n g  Electron-withdrawing  the i n o r g a n i c e s t e r f o r m a t i o n  92  s u b s t i t u e n t s r e t a r d the r a t e of  and s t r a i n e d , unhindered  o l e f i n s 'usually 93  r e a c t w i t h osmium t e t r o x i d e more r a p i d l y than u n s t r a i n e d hindered  olefins.  or s t e r i c a l l y  38  Hydroxylation of 4,4'-dimethoxystilbene  (88) w i t h osmium t e t r o x i d e  92 has been a c h i e v e d  to give the corresponding d i o l  (89).  OH  R — C = C  0s0  R  4  7  H OMe  R  (j)H  C  C  H  H  g9  R  3.2.6- O x i d a t i o n w i t h M o l e c u l a r Oxygen O x i d a t i o n w i t h m o l e c u l a r oxygen p r o v i d e s another r o u t e to t h e hydrox y l a t i o n and o x i d a t i v e c l e a v a g e of e n o l i c double bonds.  The slow  atmospheric  o x i d a t i o n o f a C-H bond t o a C-O-OH group o r any slow o x i d a t i o n w i t h atmosp h e r i c oxygen i s termed a u t o x i d a t i o n .  The i n i t i a l a u t o x i d a t i o n products  o f t e n r e a c t f u r t h e r t o g i v e a more c o m p l i c a t e d mixture and the purpose of t h i s s e c t i o n i s t o e x p l o r e some o f the p o s s i b l e r o u t e s t o the hydroxyl a t i o n and o x i d a t i v e c l e a v a g e o f the e n o l i c double bond w i t h these autoxidation intermediates. The  formation of hydroperoxides  from ground s t a t e m o l e c u l a r oxygen  94 (a t r i p l e t )  i s a f r e e r a d i c a l process  , however, oxygen i t s e l f  too u n r e a c t i v e t o a b s t r a c t the hydrogen. the p r o d u c t i o n o f some f r e e r a d i c a l s  (a d i r a d i c a l ) i s  The c h a i n must be i n i t i a t e d by  (ag„ R'*) produced  by some i n i t i a t i o n  p r o c e s s , the r a d i c a l combines w i t h m o l e c u l a r oxygen t o g i v e R'-0-0-, a s p e c i e s which can a b s t r a c t hydrogen.  The c h a i n i s propagated  f o l l o w i n g two s t e p s : R'OO- + RH  R'OOH + R* R-0-0-  (1) (2)  by the  The C-H  bonds which most r e a c t i v e are t e r t i a r y , a l l y l i c ,  and  benzylic  p o s i t i o n s and t h e a - p o s i t i o n of e t h e r s . Hydroperoxides can a l s o be formed  by the d i r e c t a c t i o n of photo-  s e n s i t i z e d m o l e c u l a r oxygen on o l e f i n s .  The a c t i v e reagent here i s the  95 excited  singlet  state  p l a c e w i t h 100% a l l y l i c  oxygen m o l e c u l e . rearrangement  T h i s r e a c t i o n always  which  takes  i s incompatable w i t h a f r e e  r a d i c a l mechanism; t h e r e f o r e , two mechanisms have been proposed f o r p r o d u c t i o n of h y d r o p e r o x i d e s from s i n g l e t  oxygen.  The f i r s t  mechanism  proposed^ the  ene  i n v o l v e s a one-step p e r i c y c l i c mechanism, s i m i l a r t o t h a t of 97 synthesis.  The second mechanism proposed  i n v o l v e s the i n i t i a l a d d i t i o n of  s i n g l e t oxygen t o the double bond t o form e i t h e r a d i o x e t a n e i n t e r m e d i a t e 90 or three-membered d i p o l a r p e r o x i r a n e 90a.  Decomposition  of these  i n t e r m e d i a t e s by i n t e r n a l p r o t o n t r a n s f e r and bond rearrangements the  a l l y l h y d r o p e r o x i d e 90b.  bond may the  affords  O x i d a t i v e - c l e a v a g e of the carbon-carbon  double  occur by an a l t e r n a t i v e d e c o m p o s i t i o n of the d i o x e t a n e t o g i v e  carbonyl products.  These s t e p s are i l l u s t r a t e d  i n Scheme X I I I .  H I C-  -c=c  +  0 = 0  0—Q  *  o e — ^ I H  - H  - c — c , — c -  '» ^ —  c  '  V  Ox  +  +  - c —  \ "  1  c —  c-  i '90a'  ^  c — c -  - c — c  90b Scheme XIII  The f o r m a t i o n o f epoxides from the r e a c t i o n between the h y d r o p e r o x i d e s 99  and o l e f i n may take p l a c e by a t l e a s t t h r e e r o u t e s .  The f i r s t ,  and most  s y n t h e t i c a l l y u s e f u l , i n v o l v e s the base c a t a l y z e d a d d i t i o n o f the hydrop e r o x i d e t o a , 8 - u n s a t u r a t e d c a r b o n y l compounds ( r e a c t i o n 3 ) . mediate  a n i o n a t t a c k s the 0-0 bond t o c l o s e the epoxide.  ROf 1  4-  I  R 0 — 0 < ^ -C  I  i  be formed  C  -Z—  ^  e  C l  C=0  I  The epoxides may  >  I  C=0 l  The i n t e r -  /K  > - C — C T  C=0+R0 i  l  e  (3)  *  by the a d d i t i o n o f the peroxy r a d i c a l t o the carbon-carbon  bond f o l l o w by r i n g c l o s u r e and e x p u l s i o n o f an a l k o x y r a d i c a l  double  (reaction 4).  RO; +  The  -c=c-  RO-  t h i r d r o u t e i n v o l v e s a n o n r a d i c a l n u c l e o p h i l i c displacement  on the oxygen-oxygen bond to g i v e an epoxide e p o x i d a t i o n w i t h p e r a c i d ( r e a c t i o n 5 and  (4)  by  C=C  i n manner s i m i l a r to t h a t of  a l s o see S e c t i o n 3.2.4.).  H^yO-R - C = C I I As was  >  - C  C I I  -f-  ROH  (5)  seen i n the o x i d a t i o n of the o l e f i n w i t h s i n g l e t oxygen, the  r e a c t i o n c o u l d l e a d to an o x i d a t i v e cleavage  of the o l e f i n i c bond. Another  r o u t e t o the cleavage  bond w i t h the f o r m a t i o n  two  of the o r i g i n a l double  c a r b o n y l compound i n v o l v e s the rearrangement of the a l l y l i c  peroxide."'"^^  - C = C  C -  0  I I  —) + C -  - C m C - ^ - C I I I H 0 7  OH  —C=C I I  -I-  0 = C —  i  i  Hv I - c — c = o  Scheme  +  0H I C -  u  |  - C = C— r  hydro-  The mechanism i s seen i n the f o l l o w i n g scheme.  —C=nC I I I  i  of  XIV  0  I  2  +  -H'  v  >  42  When D - g l u c a l D-arabinose(91),  (70,R=H) was  irradiated"^  i n the presence of oxygen,  1  formed by an o x i d a t i v e cleavage  of the double bond,  was  102 i s o l a t e d as the main p r o d u c t . Goodman and purified  samples of methyl  4-ene (92) content,  2Q  co-workers  reported  that  5,6-dideoxy-2,3-j0-isopropylidene-8-D-allofuranoside-  s l o w l y polymerized  on s t a n d i n g and  i n d i c a t e d an  i n c r e a s e d oxygen  s u g g e s t i v e of an o x i d a t i v e p o l y m e r i z a t i o n .  R=H 02  91  3.2.7. P e r i o d a t e As was  Oxidation  seen i n the p r e v i o u s  hydroxylated  t h r e e s e c t i o n s the enol e t h e r s can  or o x i d a t i v e l y c l e a v e d  the h y d r o x y l a t e d corresponding  products  hemi-acetals)  i n a subsequent s t e p .  i n a one-step s y n t h e s i s ; however,  ( i . e . , a-hydroxy ketone/aldehydes or can be  isolated  1,2-Glycals,  and  a-hydroxy aldehydes and  of c a r b o n y l f u n c t i o n a l i t i e s .  their  then o x i d a t i v e l y c l e a v e d  e a s i l y , c l e a v e d by aqueous s o l u t i o n s of sodium p e r i o d a t e the f o r m a t i o n  be  103  ketones are resulting in  The mechanism of the o x i d a t i v e  104 cleavage  i n v o l v e s the r a p i d and  p e r i o d a t e e s t e r 9_3, decomposition cleavage  reversible  formation  cyclic  of the e s t e r r e s u l t s i n the o x i d a t i v e  of the carbon-carbon bond of the 1 , 2 - d i o l .  i n Scheme XV.  of a  T h i s mechanism i s shown  I  92  OH  i  I  OH  - c = o  Scheme  -f  XV - c = o  I  The  reaction, therefore,  c y c l i c ester  3.2.8.  i s l i m i t e d to s u b s t r a t e s  form  the  93.  a z i d o - n i t r a t i o n r e a c t i o n i s a r e c e n t l y developed'*'^ r e a c t i o n  f o r the r e g i o s p e c i f i c a d d i t i o n of a z i d e e n o l i c double bond.  The  ether  i n a s u i t a b l e solvent  (CAN)  and The  and  that can  Azido-Nitration  The  the  OH  sodium a z i d e  (-N^)  reaction involves  and  n i t r a t e (-ONC^) a c r o s s  the a d d i t i o n of the  enol  to a m i x t u r e of e e r i e ammonium n i t r a t e  to g i v e the 1:1:1  adduct.  mechanism proposed'*'^ f o r t h i s a d d i t i o n i n v o l v e s both f r e e - r a d i c a l  i o n i c intermediates.  CAN  oxidizes  the a z i d e a n i o n to the a z i d o r a d i c a l  which adds t o the 8-carbon of the e n o l i c s u b s t r a t e . r a d i c a l 9_4 s t a b i l i z e d by to g i v e the s t a b i l i z e d phile associated  The  intermediate  the oxygen i s o x i d i z e d by another molecule of  CAN  oxo-carbonium i o n 94a which a c c e p t s a n i t r a t e n u c e l o -  w i t h l e a v i n g CAN  T h i s mechanism i s i l l u s t r a t e d  complex to g i v e the  i n the  following  scheme.  f i n a l a d d i t i o n product.  •N3  N® + CAN  * >  - c — c  134  No  No  - Ci  I3 — C-  1  C-—OR  V  (N0 3 ) x Ce  When 3 , 4 , 6 - t r i - O - a c e t y l - D - g a l a c t a l  *  I C-  OR 2  XVI  (71, R=Ac) was t r e a t e d w i t h CAN  sodium a z i d e t h r e e 2-azido g a l a c t o p y r a n o s y l n i t r a t e s  37, 55 and 8% y i e l d  CAN  1  0N0  0  Scheme  and  OR  (95a, b and c i n  resp.).  AcO  V-0 QN0  K9N0  2  2  0N0  2  95c 3.2.9. R e a c t i o n w i t h N-Bromosuccinimide O l e f i n s can be halogenated succinimide  a t the a l l y l i c  (NBS) and when t h i s reagent  as t h e " W o h l - Z i e g l e r b r o m i n a t i o n " .  p o s i t i o n w i t h N-bromo-  i s used,  the r e a c t i o n i s known  With t h i s reagent an i n i t i a t o r i s  r e q u i r e d and i s u s u a l l y a p e r o x i d e o r , l e s s o f t e n , u.v. l i g h t . r e a c t i o n i s u s u a l l y q u i t e s p e c i f i c at the a l l y l i c  The  p o s i t i o n and good 108  y i e l d s are obtained.  The mechanism i s of the f r e e r a d i c a l type  i n i t i a t e d by s m a l l amounts of B r .  Once the bromine r a d i c a l i s formed the  main p r o p a g a t i o n s t e p s a r e :  Br  -  + RH  R- + HBr  and i s  (1)  45  R- + Br, The  source  liberated  ->  RBr + Br-  o f the B r  2  i s a fast  i o n i c r e a c t i o n between NBS and the HBr  i n s t e p 1:  N—Br  Therefore,  (2)  HBr  N— H  t h e f u n c t i o n of NBS i s p r o v i d e d  a source  +  Br  f o r molecular  (3)  2  bromine,  i n a low, s t e a d y - s t a t e c o n c e n t r a t i o n and t o use up the hydrogen bromide liberated  i n s t e p 1.  The f a c t the c o n c e n t r a t i o n of m o l e c u l a r  low p r o v i d e s the proper  conditions for a l l y l i c  a d d i t i o n t o t h e d o u b l e bond. i n a e q u i l i b r i u m process  bromine i s  substitution rather  than  The atomic bromine adds t o t h e double bond  and when the c o n c e n t r a t i o n of bromine i s low,  t h e r e w i l l not be h i g h p r o b a b i l i t y t h a t the proper  s p e c i e s w i l l be i n  the v i c i n i t y once t h e i n t e r m e d i a t e r a d i c a l 9_6 forms and the e q u i l i b r i u m will  l i e to the l e f t .  bromination  T h i s slows the r a t e of a d d i t i o n so that  c a n compete s u c c e s s f u l l y .  This rationale i s i l l u s t r a t e d  below:  H Br-  +  —C C—CI I I  allylic  _  f .f  — c — c 1  —  'as  c -  1  stepd)  1'  (Br Kow 2  H HBr  +  —C=C-  f  f  — c — c — c -  JBr ,step (2) 2  step (3) •C i  C = C - + BrI  T  Scheme  XVII  A.  C-Nucleosides The n u c l e o s i d e s and t h e i r analogues  a r e a broad  range o f compounds  i n which an u n s a t u r a t e d h e t e r e o c y c l e i s a t t a c h e d to a p o l y h y d r i c a l c o h o l , aldehyde  or ketone.  The common or normal, n a t u r a l l y - o c c u r r i n g  N-nucleosides  c o n s i s t o f a p y r i m i d i n e or p u r i n e base j o i n e d by an N - g l y c o s y l l i n k a g e to D-ribose.  I n 1959, C o h n ^ i s o l a t e d a n u c l e o s i d e t h a t was d i f f e r e n t  from  1 1  the p r e v i o u s l y known N - n u c l e o s i d e s . T h i s compound, which was i s o l a t e d an a l k a l i n e h y d r o l y s a t e of c a l f l i v e r , was f o u n d furanosyl) u r a c i l linkage.  1 1 1 3  from  ^ t o be 5-(6-D-ribo-  ( p s e u d o u r i d i n e , 97), a n u c l e o s i d e p o s s e s s i n g a C - g l y c o s y l  S i n c e then, a number o f o t h e r C - n u c l e o s i d e s have been i s o l a t e d (se  F i g u r e 1)  mainly  from  fermentation sources.  112  A l l , except  pseudouridine  112 113 97 and Indochrome B I I (10*5), possess a n t i b i o t i c p r o p e r t i e s . b i o l o g i c a l a c t i v i t y o f t h e C - n u c l e o s i d e s stems from t h e i r similarities accept  The  structural  t o the N - n u c l e o s i d e , which a l l o w s the b i o l o g i c a l system to  them as m e t a b o l i t e s p l u s t h e s t r u c t u r a l d i s s i m i l a r i t i e s which 114  allow f o r d i f f e r e n t One  '  chemical  i n t e r a c t i o n s i n the b i o l o g i c a l  o f the l a r g e r and more important  glycosidic  carbon-carbon  system.  d i f f e r e n c e s i s the presence  bond which has an enhanced h y d r o l y t i c  compared t o t h e more l a b i l e c a r b o n - n i t r o g e n bond o f the common  of the  stability N-nucleosides  47  Pyrazofurin B  Figure 1: Naturally-Occurring C-Nucleosides  Indochrome  BII  48  The  b i o l o g i c a l properties"'"''"^  nucleosides  a  t  u  r  a  2 i y _  focus i t s a t t e n t i o n on  and  approaches to the  the  o  c  c  u  of C - n u c l e o s i d e  r  i g  c_  n  reviewed.  This  s y n t h e t i c approaches to  f o l l o w w i t h a b r i e f d i s c u s s i o n of the  synthesis  r  both n a t u r a l l y - o c c u r r i n g  t h e i r analogues have been e x t e n s i v e l y  showdomycin (99)  general  precursors.  Showdomycin Showdomycin (99) was and  i s elaborated  showdomycin has (99)  n  D  s e c t i o n , then, w i l l  1964  ^  a l o n g w i t h the s y n t h e s i s " ' " ' ' " ^ f  C - n u c l e o s i d e and  4.1.  q  by  antitumor  by Nishimura and  Streptomyces showdoensis.  been established''""'"^  c h e m i c a l and  to p s e u d o u r i d i n e  by  discovered  3  C  The  structure  2-(B-D-ribofuranosyl)  as  s p e c t r a l a n a l y s i s and  (97).  coworkers'*""''' i n  i t s structure  maleimide  is closely related  Showdomycin e x h i b i t s b o t h a n t i b a c t e r i a l and  activity.  Showdomycin i s s t r u c t u r a l l y unique among the C - n u c l e o s i d e s n a t u r a l o r i g i n , i n that aglycon. lability  Synthetic  approaches to showdomycin must take i n t o account i t s  i n the  synthesis  other u t i l i z e s anomerically  of C - n u c l e o s i d e s , one  latter  Two  successful  methods"*""*^  involves the  the  sugar  and  f u n c t i o n a l i z e d C-B-D-pentofuranosyl  d e r i v a t i v e s w i t h the h e t e r e o c y c l i c base e l a b o r a t e d The  intramolecular  3  c o n d e n s a t i o n of the preformed h e t e r o c y c l i c base on  'aglycon'.  of  the five-membered maleimide h e t e r o c y c l i c  5'-hydroxy1 group to the double bond.^"'"^  have been u t i l i z e d  the  i t has  i n base, a t t r i b u t a b l e to a r a p i d M i c h a e l type of  a d d i t i o n of the  direct  of  synthesis  from the  functionalized  of showdomycin have u t i l i z e d  the  approach. The  first  three  syntheses of showdomycin were v e r y s i m i l a r i n that  each used a s t a b i l i z e d W i t t i g reagent on  the  keto ' a g l y c o n ' of the  to complete the m a l e i c a c i d p o r t i o n of the m o l e c u l e .  The  first  sugar  synthesis  was  r e p o r t e d i n 1970  when Kalvoda, FarkaS  and Sorm  4,5,7-tri-0-acetyl-3,6-anhydro-g-allo-heptulosonate  utilized  methyl  (106,R=Ac), which  was  i n g e n i o u s l y prepared v i a the o z o n o l y s i s of l - ( 2 ' , 3 ' , 5 ' - t r i - 0 - a c e t y l - 8 - D r i b o f u r a n o s y l ) - 2 , 4 , 6 - t r i m e t h o x y benzene (107) as t h e i r key i n t e r m e d i a t e . a  The keto e s t e r 106 was  then condensed w i t h the W i t t i g reagent  OAc  OR  0R 106  t r a n s ) was  h y d r o l y z e d , and  a c e t i c a n h y d r i d e to a f f o r d  OAc  107  carbonylmethylene)triphenylphosphorane. ( c i s and  The r e s u l t i n g mixture of e s t e r s  the c i s - a c i d  (108) was  the m a l e i c anhydride d e r i v a t i v e  cyclized  of e t h y l polyphosphate  with  (109).  w i t h ammonia, and c y c l i z a t i o n of the r e s u l t i n g maleamic a c i d presence  (ethoxy-  Treatment  i n the  (EPP) gave showdomycin t r i a c e t a t e  (110)  which, when t r e a t e d w i t h m e t h a n o l i c h y d r o g e n - c h l o r i d e , gave c r y s t a l l i n e showdomycin (99)  (see Scheme X V I I I ) .  Although y i e l d s f o r the o z o n o l y s i s and W i t t i g r e a c t i o n were not g i v e n showdomycin was  isolated  i n about 16% o v e r a l l from  Three y e a r s l a t e r , TrummTitz and M o f f a t synthesis starting 106.  d e s c r i b e d a two-step  from the b e n z y l analogue (R-Bzl) of the keto e s t e r  T h i s key compound was  dicyclohexylcarbodiimide precursor  120  108.  synthesized  from the d i m e t h y l s u l f o x i d e -  (DMSO-DCC) o x i d a t i o n of the e p i m e r i c h y d r o x y l  (111). The c o n s t r u c t i o n of the r i n g was  a c h i e v e d i n a key,  one-  step W i t t i g r e a c t i o n , u t i l i z i n g (carbamoylmethylene)triphenylphosphorane Presumably, ester  a spontaneous c y c l i z a t i o n of the c i s - o r i e n t maleamic  (112) i n t e r m e d i a t e o c c u r r e d to g i v e the maleimide r i n g .  h y d r o g e n a t i o n of the maleimide r i n g , the d e b e n z y l a t i o n was  acid  To avoid  accomplished  i n good y i e l d s by treatment o f 111 w i t h boron t r i c h l o r i d e t o g i v e an overall yield  of 29.6%  from the e p i m e r i c hydroxy e s t e r  106 OR  OR 111 R = C H 0 2  Scheme  XIX  111.  Kalvoda  searched  f o r o t h e r routes "^" J  Lcl u  to showdomycin and i n 1976  122 reported  t h e s y n t h e s i s of showdomycin v i a the c o n d e n s a t i o n of a s t a b i -  l i z e d W i t t i g reagent  on an a c y l c y a n i d e .  The key step i n t h i s s y n t h e s i s  i n v o l v e s the i n s i t u g e n e r a t i o n of the a c y l cyanide f o l l o w e d by r e a c t i o n w i t h the W i t t i g reagent  to g i v e the methyl 3-cyano-2-alkenoate.  3,4,6-tri-0-acetyl-2,5-anhydro-D-allonyl chloride hydrogen c y a n i d e i n the presence of excess  Thus  (113) was t r e a t e d w i t h  (methoxycarbonylmethylene)tri-  phenylphosphorane (114) to g i v e an i n t e r m e d i a r y a c y l cyanide 115 which i s c o n v e r t e d t o a m i x t u r e of c i s and t r a n s isomers o f the W i t t i g adduct The c i s (or E) isomer  i s c y c l i z e d i n a mixture of a c e t i c a c i d ,  OR OR 117 R=H 1J8 R=Ac  OR  116 Scheme XX  acetic  OR  116.  52  anhydride,  and s u l f u r i c  acetylated  (118) maleimides which were d e - a c e t y l a t e d  hydrochloric acid from the n i t r i l e  acid  to g i v e a m i x t u r e  to g i v e showdomycin p r e c u r s o r 119.  of the f r e e (117) and Ni n methanolic  (99) i n an o v e r a l l y i e l d  At f i r s t  OBz  of 16.7%  g l a n c e Kalvoda's more recent  OBz  U9 s y n t h e s i s has an lower o v e r a l l y i e l d but on c l o s e r i n s p e c t i o n Trummlitz and M o f f a t t ' s procedure a l s o have the n i t r i l e  119 as an i n t e r m e d i a t e i n  the t o t a l s y n t h e s i s of showdomycin from r i b o s e .  Therefore,  Trummlitz and  M o f f a t t ' s y i e l d of showdomycin i s c a l c u l a t e from the common 119, the o v e r a l l y i e l d  intermediate  drops from 29.6% to 8.5%, making Kalvoda's s y n t h e s i s  much more a p p e a l i n g . 123 In a v e r y r e c e n t paper Buchanan, Edgar and coworkers s y n t h e s i s of showdomycin  r e p o r t e d the  (99) u s i n g the t e r m i n a l a c e t y l e n i c sugar,  tri-0-benzyl-8-D-ribofuranosylethyne  (120) as t h e i r key i n t e r m e d i a t e .  The key r e a c t i o n i n v o l v e d the d i c a r b o x y l a t i o n of the t e r m i n a l to  the m a l e i c  2,3,5-  e s t e r d e r i v a t i v e 121, i n 80% y i e l d ,  acetylene  s i m i l a r to the i n t e r m e d i a t e  119 i n Kalvoda's  first  s y n t h e s i s (see Scheme XVIII,  s e r i e s of t r a n s f o r m a t i o n s converted  s i m i l a r to Kalvoda's,  s t r u c t u r e 108).  the i n t e r m e d i a t e  to the maleamic a c i d d e r i v a t i v e 122 and c y c l i z e d  In a  121 was  to the maleimide  53  C02R'  R0-,  V^R  RO-i  1  CO, Me OH PdCl ,HgCl 2  2  OR OR 1 2 0 R=CH Ph  121 R=Ff=Me  2  122R=NH  with acetyl chloride boron t r i c h l o r i d e ,  ( c f EPP of Kalvoda  119  ).  showdomycin was i s o l a t e d  2  R*=Me  After debenzylation with i n an o v e r a l l y i e l d of 23% from  the ethyne 120 and 8% o v e r a l l from D - r i b o s e . The o v e r a l l y i e l d  of showdomycin from D - r i b o s e ( c a l c u l a t e d  from  122 known p r o c e d u r e s ) u s i n g Kalvoda's  l a t e s t procedure i s 10%; t h e r e f o r e ,  t h i s r e c e n t procedure compares f a v o u r a b l y . In a r e c e n t p r e l i m i n a r y communication,  N o y o r i , Sato, and Hayakawa"*^  3  ^  r e p o r t e d the s y n t h e s i s o f showdomycin s t a r t i n g from noncarbohydrate m a t e r i a l s . One of the key s t e p s i n t h i s i n t e r e s t i n g s y n t h e s i s i n v o l v e s the s y n t h e s i s of 8 - o x a b i c y c l o [ 3 . 2 . 1 ] o c t - 6 - e n - 3 - o n e (123) from acetone and f u r a n . F o l l o w i n g h y d r o x y l a t i o n w i t h osmium t e t r o x i d e and i s o p r o p y l i d e n a t i o n , subsequent  Baeyer-  V i l l i g e r o x i d a t i o n of the ketone gave a racemic m i x t u r e of l a c t o n e 124. A f t e r resolving domycin  the m i x t u r e , the C-B-D-glycono-lactone 124 was c o n v e r t e d to show-  (99) i n a seven step sequence i n v o l v i n g the f o r m a t i o n of a ot-keto  e s t e r 125 f o l l o w e d by c y c l i z a t i o n w i t h the amide s t a b i l i z e d W i t t i g reagent 120 ( c f . Trummlitz and M o f f a t t ).  HC—i  123  1124 I  54  The y i e l d  of showdomycin based on the l a c t o n e a c e t o n i d e 124  l e s s than 22% and  l e s s than 7% based on 123  ( c f . 10% based on  was  D-ribose  122 f o r Kalvoda's  procedure).  The advantage of t h i s s y n t h e s i s i s the  f a c t the s t a r t i n g m a t e r i a l s a r e r e a d i l y a v a i l a b l e and the a-keto e s t e r i n t e r m e d i a t e C - n u c li e o s i-Ad e s .  1  2  8  125  inexpensive,  and  i s amenable to the s y n t h e s i s of other  A  Other s y n t h e t i c procedures  i n v o l v i n g the condensation  c y c l i c base c o n t a i n i n g the n e c e s s a r y  of a h e t e r o -  elements f o r the maleimide r i n g 126  d i r e c t l y onto a sugar d e r i v a t i v e have been r e p o r t e d t r a n s f o r m a t i o n to showdomycin (99) has not been 4.2,  C-Nucleoside  , however, the  accomplished.  Precursors  A g r e a t number of a n a l o g u e s ^ ^ '  of the n a t u r a l l y - o c c u r r i n g C-  n u c l e o s i d e s have been s y n t h e s i z e d over the l a s t decade i n an e f f o r t chemotheropeutic  final  to o b t a i n  compounds w i t h s p e c i f i c b i o l o g i c a l a c t i v i t y . T h i s endeavour  has been h i g h l i g h t e d by the s y n t h e s i s  125  of p s e u d o - i s o c y t i d i n e [5-(8-D-  r i b o f u r a n o s y l ) i s o c y t o s i n e (125a)], the f i r s t d i s p l a y antitumour p r o p e r t i e s .  s y n t h e t i c C-nucleoside  to  126  Four s y n t h e t i c s t r a t e g i e s have been employed i n the s y n t h e s i s of novel C-nucleosides.  Three of these approaches have been mentioned i n the 122  p r e v i o u s s e c t i o n and from sugar  i n v o l v e the e l a b o r a t i o n  of a h e t e r o c y c l i c base  d e r i v a t i v e f u n c t i o n a l i z e d a t C - l and  the second i n v o l v e s the  d i r e c t c o u p l i n g of a preformed h e t e r o c y c l i c w i t h an a p p r o p r i a t e l y blocked sugar  d e r i v a t i v e . ' T h e  C-nucleoside  t h i r d procedure 128a  from noncarbohydrate sources  mentioned, prepares  and  the  the l a s t method i n v o l v e s  the m o d i f i c a t i o n of n a t u r a l l y - o c c u r r i n g C - n u c l e o s i d e s . By  f a r the most p r a c t i c a l and  C-nucleosides  v e r s a t i l e s y n t h e t i c r o u t e to m o d i f i e d  c o n s i s t s of f u n c t i o n a l i z a t i o n of the sugar  d e r i v a t i v e at  55  C - l f o l l o w e d by a stepwise f u n c t i o n a l group.  Two  e l a b o r a t i o n of a h e t e r o c y c l i c base from t h i s  g e n e r a l methods f o r o b t a i n i n g these f u n c t i o n a l i z e d  precursors are a v a i l a b l e .  One  i n v o l v e s the i n t r a m o l e c u l a r c y c l i z a t i o n of 112  a c y c l i c carbohydrate  derivatives  129 which l e a d  t o p r e c u r s o r 120  for  123 Buchanan's  s y n t h e s i s of showdomycin (99).  the f o r m a t i o n  of a carbon-carbon bond at the anomeric c e n t r e formed  u s u a l l y from a g l y c o s y l h a l i d e and  The  second method i n v o l v e s  an a p p r o p r i a t e c a r b a n i o n .  The most  v e r s a t i l e d e r i v a t i v e formed from t h i s l a t t e r procedure i s the D - r i b o s y l cyanide  d e r i v a t i v e which w i l l be d i s c u s s e d i n more d e t a i l . 130 131 Based on the p r e v i o u s work by Coxon , Bobek and Farkas prepared t r i - 0 - b e n z o y l - 3 - D - r i b o f u r a n o s y l cyanide (127 R=CN) i n h i g h y i e l d by r e a c t i n g the bromide 126 w i t h m e r c u r i c  cyanide.  presumably owing to n e i g h b o u r i n g  Only the 6-isomer was  group p a r t i c i p a t i o n .  112  isolated,  The o r i e n t a t i o n 133  of the C - l s u b s t i t u e n t s i s important  s i n c e , b u t f o r a few  exceptions,  o n l y the ^ - d e r i v a t i v e s e x h i b i t t h e r a p e u t i c a c t i v i t i e s . The v a l u e of r i b o s y l cyanide  127  i s t h a t the v a r i o u s d e r i v a t i v e s of the n i t r i l e  13  ' the  group  have used to e l a b o r a t e a v a r i e t y of n a t u r a l l y - o c c u r r i n g C - n u c l e o s i d e s 120 122 13A (e.g., showdomycin (99), f o r m y c i n B (101) and oxoformycin (102)) , _  Bz0-i  BzO-i  Hg(CN)2 7  )Bz  and  C-nucleoside  analogues  Ubz  127  R=CN  127a  R=CH0  112  To t h i s end, M o f f a t t and  coworkers  141a  have prepared  2,5-anhydro-D-allose  56  p r o t e c t e d w i t h v a r i o u s b l o c k i n g groups.  The key s t e p and key i n t e r -  mediate i n f o r m a t i o n o f these d e r i v a t i v e s was t h e r e d u c t i v e - h y d r o l y s i s of t h e n i t r i l e 127 w i t h Raney n i c k e l and sodium hypophosphite i n t h e presence of 1 , 2 - d i a n i l i n o e t h a n e l i d i n e d e r i v a t i v e 128.  t o t r a p the aldehyde as the N.N'-diphenylimidazoThe aldehyde 127a (R=CHO) c o u l d be regenerated  from 128 by m i l d a c i d h y d r o l y s i s . The aldehyde 127a (R=CHO) or i t s v a r i o u s p r o t e c t e d analogues a r e key i n t e r m e d i a t e s of C - n u c l e o s i d e s  5.  i n t h e s y n t h e s i s of a v a r i e t y  previously discussed.  Ketose N-Nucleosides The  ketose N - n u c l e o s i d e s  a r e a r a r e group o f n u c l e o s i d e  antibiotics  113 of which o n l y two a r e known. (B-D-psicofuranosyl)  antitumor  Psicofuranine  [angustmycin C, 6-amino-9-  p u r i n e , 129] and d e c o y i n i n e  (2) a r e a n t i b a c t e r i a l and  n u c l e o s i d e a n t i b i o t i c s e l a b o r a t e d by t h e Streptomyces.  As can  be seen i n s t r u c t u r e 129 (and 2) these n u c l e o s i d e s have the common N - g l y c o s y l  57  l i n k a g e between the sugar and hydroxymethyl group at  base but  the uncommon f e a t u r e i s the  ' C - l ' which r e q u i r e s a keto-sugar p r e c u r s o r  which makes the h e t e r o c y c l i c base b o t h a c i d and base l a b i l e . s y n t h e t i c approaches t o the ketose N - n u c l e o s i d e  and  Therefore  must take these  properties  into consideration. The  s y n t h e s i s of p s i c o f u r a n i n e  and  the s y n t h e s i s o f d e c o y i n i n e  and  h i s coworkers.  (129)  has  been r e p o r t e d by  (2) from p s i c o f u r a n i n e was  two  groups  r e p o r t e d by  Robins  138 Farkas and f u r a n i n e and  Sorm  synthesized  the l'-deoxy analogue  found t h i s compound to be  A s t r u c t u r a l isomer 131  (130)  of p s i c o -  i n a c t i v e against Escherichia c o l i .  of p s i c o f u r a n i n e (129) was  s y n t h e s i z e d by  Rosenthal  53 and  Ratcliffe  analogue no  v i a the photoamidation of the e n o l i c sugar 5_6, however, t h i s  l o n g e r possesses the N - k e t a l  HO-i  HO—  1  HO  OH  131 Ad=Adeny1 nucleosides.  s t r u c t u r a l f e a t u r e of  ketose  58  III.  RESULTS AND  DISCUSSION  The work to be d e s c r i b e d has been d i v i d e d These a r e : (1) the s y n t h e s i s of a- and  into four basic u n i t s .  B-dihydroshowdomycin, (2) the  s y n t h e s i s of f u n c t i o n a l i z e d p r e c u r s o r s to C - n u c l e o s i d e s , p r o d u c t s of  Methyl(E,Zj-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-0-  isopropylidene-D-allo-oct-3-enonate and  (3) the o x i d a t i o n  (4) the attempted  (172) , a n o v e l e x o c y c l i c e n o l i c  s y n t h e s i s of a ketose N - n u c l e o s i d e .  been o r g a n i z e d a c c o r d i n g to the o u t l i n e l i s t e d The m e c h a n i s t i c and  sugar,  Each u n i t  has  i n the t a b l e of c o n t e n t s .  s t e r e o c h e m i c a l a s p e c t s of the b a s i c chemical r e a c t i o n s  have been d e a l t w i t h i n the i n t r o d u c t i o n and  a detailed discussion in  these areas w i l l o n l y be made where s t e r e o c h e m i c a l assignments appear possible.  D e t a i l s of the e x p e r i m e n t a l procedure  along with s p e c t r o s c o p i c data w i l l 1.  S y n t h e s i s of a- and  and work-up c o n d i t i o n s  appear i n the experimental  B-Dihydroshowdomycin: Photoamidation  section. of  Methyl  (E, Zj-4 ,7-anhydro-8-0-benzoyl-2,3-dideoxy-5 ,6-.0-isopropylidene-Dallo-oct-2  (and 3)-enonate (,18)  and  (172),  The work to be p r e s e n t l y d i s c u s s e d was p r o v i d e a new  undertaken  s y n t h e t i c path to the a n t i b a c t e r i a l and  n u c l e o s i d e showdomycin  (99).  however, possessed  i n an attempt antitumor  113  P r i o r to the s t a r t of t h i s work o n l y  p r a c t i c a l s y n t h e t i c r o u t e s to showdomycin had  or  respectively.  been r e p o r t e d .  120  '  122  to Ctwo Both,  u n d e s i r a b l e s y n t h e t i c steps such as DMSO-DCC o x i d a t i o n 120 122  r e a c t i o n s i n v o l v i n g cyanide reagents.  p r o p e r t i e s of showdomycin and  '  In view of the  120  antibiotic  the u n d e s i r a b l e f e a t u r e s of the p r e v i o u s  s y n t h e s e s , the development of a h i g h - y i e l d i n g , p r a c t i c a l s y n t h e t i c r o u t e to  t h i s C - n u c l e o s i d e seemed  justified.  Based on the photoamidation of u n s a t u r a t e d sugars by Rosenthal and 47 51 40 coworkers ' and on the o r i g i n a l photoamidation work by Rokach and E l a d  59  (see I n t r o d u c t i o n S e c t i o n 2.1.)» i t seemed reasonable of the a,8-unsaturated  that photoamidation  e s t e r sugar d e r i v a t i v e 12>_ should  l e a d to predominant  carbamoylation  at the 8-carbon to g i v e the s u b s t i t u t e d s u c c i n i c a c i d  d e r i v a t i v e 132  (Scheme XXI),  formation  p r o v i d i n g the n e c e s s a r y  of the maleimide a g l y c o n .  elements f o r the  C y c l i z a t i o n of 132  f o l l o w e d by  g e n a t i o n would g i v e the p r o t e c t e d showdomycin (99) which could be  dehydro-  recovered  by m i l d aqueous a c i d h y d r o l y s i s of the p r o t e c t i n g groups. During in detail t h i s new  (133).  the course  of t h i s work a n o v e l  i n S e c t i o n 2.1.)  became a v a i l a b l e and  compound might p r o v i d e  The  and  1.3.  i t seemed p l a u s i b l e that  a r o u t e to the h i t h e r t o unknown a-showdomyci;  photoamidation work w i t h  S e c t i o n s 1.2.  3-ene analogue of 1S_ ( d e s c r i b e d  t h i s novel  compound i s d e s c r i b e d i n  60  1.1.  S y n t h e s i s of n o r m a l - ( B - )  Dihydroshowdomycin v i a Photoamidation of  the Methyl oct-2-enonate  18.  1.1.1.  Methyl  (E, Z)-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-0-  isopropylidene-p-allo-oct-2-enonate (18). The  title  the commercially (134) .  compound was prepared 139a  i n a f i v e - s t e p process s t a r t i n g  from  available l-0-acetyl-2,3,5-tri-0-benzoyl-8-D-ribose  140a-b  Compound 134 was c o n v e r t e d t o t h e g l y c o s y l bromide 126 w i t h hydrogen  bromide. The bromide 126 was then t r e a t e d w i t h excess m e r c u r i c cyanide i n nitromethane  f o r 20 hours. The crude 2 , 3 , 5 - t r i - 0 - b e n z o y l - 3 - D - r i b o f u r a n o s y l  131 cyanide  (127) was worked up i n c h l o r o f o r m s o l u t i o n r a t h e r than  a c e t a t e t o a c h i e v e a more e f f i c i e n t F o l l o w i n g the procedure partially  debenzoylated  removal  of the m e r c u r i c  o f M o f f a t t et a l . " ^  l a  ,  salts.  the cyanide 127 was  i n a c h l o r o f o r m s o l u t i o n of methanolic  g i v e 5 - 0 - b e n z o y l - B - D - r i b o f u r a n o s y l cyanide  (135) .  ethyl  This v i c i n a l  ammonia to d i o l 135  was i s o p r o p y l i d e n a t e d i n a s o l u t i o n of acetone and 2,2-dimethoxypropane with p e r c h l o r i c acid  catalyst  B - D - r i b o f u r a n o s y l cyanide w i t h Raney n i c k e l aldehyde  to a f f o r d  (136).  i n presence  the 5 - 0 - b e n z o y l - 2 , 3 - 0 - i s o p r o p y l i d e n e -  The cyanide 136 was r e d u c t i v e l y h y d r o l y z e d  of 1 , 2 - d i a n i l i n o e t h a n e to t r a p the i n t e r m e d i a t e  137 and g i v e 1 , 3 - d i p h e n y l - 2 - ( 5 - 0 _ - i s o p r o p y l i d e n e - B - D - r i b o f u r a n o s y l )  imidazolidine  (138).  Finally,  the s y n t h e s i s of the u n s a t u r a t e d e s t e r 1_8  was a c h i e v e d by a c i d - c a t a l y z e d h y d r o l y s i s of t h e N - a c e t a l p r o t e c t i n g group in  acetone-methylene  c h l o r i d e and t r e a t i n g the regenerated aldehyde  with(carbomethoxymethylene)triphenylphosphorane hour a t room temperature graphy, w i t h s i l i c a  to a f f o r d  the t i t l e  137  i n methylene c h l o r i d e f o r one compound 18_.  g e l , of the r e s u l t i n g syrup u s i n g 2:1  Column chromatoether-hexanes  as d e v e l o p e r a f f o r d e d a 8:1 m i x t u r e of the t r a n s and c i s isomers of the title  compound.  T h i s mixture was used  i n subsequent  r e a c t i o n s without  62  further separation  1.1.2.  (see Scheme X X I I ) .  P h o t o a m i d a t i o n of 18 t o g i v e  3-(R,S)-(5-0-Benzoyl-2,3-0-  isopropylidene-g-p.-ribofuranosyl)-4-hydroxy-4--methylpentanoic lactone  (139), M e t h y l  4,7-anhydro-8-0-benzoyl-3-C-carbamoyl-2,3-  dideoxy-5,6-0-isopropylidene-D-glycero-rj-allo (140 and 141)  and M e t h y l  (and a l t r o ) - o c t o n a t e  4,7-anhydro-8-0-benzoyl-2-C-carbamoyl-  2,3-dideoxy-5,6-0-isopropylidene-D-glycero-D-allo octonate  (142 and  1,4-  (and  altro)-  143).  When a s o l u t i o n of the a,g-unsaturated e s t e r sugar d e r i v a t i v e 1_8 i n formamide c o n t a i n i n g acetone and t e r t - b u t a n o l was  irradiated  through pyrex  40 filter  a c c o r d i n g t o E l a d ' s procedure  d i s c e r n e d by t . l . c . (by R^  , two major p r o d u c t bands c o u l d  of the r e a c t i o n m i x t u r e .  char) s i g n i f i c a n t  The t . l . c .  also  indicated  c a r b o h y d r a t e m a t e r i a l of i n t e r m e d i a t e R^ and  than the two major bands.  Column chromatography  be  lower  on s i l i c a g e l of the  worked-up r e a c t i o n m i x t u r e a f f o r d e d the two major bands i n y i e l d s of 10 and 25% y i e l d s o f the h i g h e r and lower R^ bands, The f a s t e r - m o v i n g component was 139 and the slower-moving a d d i t i o n p r o d u c t s 140,  found to be a R,S-mixture  component was  141,  142 and  The l a c t o n e m i x t u r e 139 was  six  high-field  of l a c t o n e  a m i x t u r e of the p o s s i b l e formamide  143.  not r e s o l v a b l e by chromatography  by c r y s t a l l i z a t i o n from v a r i o u s s o l v e n t s . c h a r a c t e r i z e d as a m i x t u r e .  respectively.  The l a c t o n e s were t h e r e f o r e  The n.m.r. spectrum of 139  i n benzene-d, showed o  s i g n a l s a t t r i b u t e d t o the methyl r e s o n a n c e s .  s i g n a l s were v e r y s t r o n g i n d i c a t i n g the o v e r l a p of two methyl  Two  of these  resonances  and the o t h e r f o u r were moderate s t r o n g f o r the remaining methyls the  presence of e i g h t methyl groups.  s i g n a l s o f 18_ and the presence o f new  nor  The l o s s of the l o w - f i e l d s i g n a l s a t c a . 62.2  (three  indicating  vinylic hydrogen  63  18 I  multiplet)  hv), H C 0 N H  2  suggested a d d i t i o n t o the double bond had taken p l a c e ,  also,  the methoxy s i g n a l o f 18_ had d i s a p p e a r e d p o s s i b l y due t o t h e h y d r o l y s i s of the e s t e r but no l o w - f i e l d s i g n a l a t t r i b u t a b l e to a c a r b o x y l i c  acid  p r o t o n was p r e s e n t . Moreover, the i . r . spectrum o f 139 was f r e e o f absorbances above 3000 cm ^ and possessed two s t r o n g due  to the y-lactone  1672 cm  c a r b o n y l s i g n a l s a t 1780 and 1728 cm  and benzoate, r e s p e c t i v e l y .  (C=C) o f 18_ was no l o n g e r p r e s e n t .  Also,  the absorbance a t  The mass spectrum of 139  possessed a weak s i g n a l of 390 f o r the m o l e c u l a r i o n (m ) and a v e r y +  strong  fragment a t 375 (m^-CH^) i n d i c a t i v e t h e f o r m a t i o n o f an acetoxonium i o n from the 0 - i s o p r o p y l i d e n e group o f 139. These r e s u l t s i n d i c a t e t h a t a k e t y l r a d i c a l [ ( C H ^ C O H ] had added to C-2 o f 18_ forming a resonance s t a b i l i z e d abstracts  a hydrogen and i n t r a m o l e c u l a r l y  139 (see I n t r o d u c t i o n ,  Section  r a d i c a l ( s i m i l a r t o 38) which  c y c l i z e s to give  2.1, Scheme V ) .  Addition  the y - l a c t o n e s  o f the k e t y l r a d i c a l  64  to the a-carbon may  have o c c u r r e d (although not i s o l a t e d ) but the  r e s u l t i n g 8-hydroxy e s t e r would r e q u i r e s p e c i a l c o n d i t i o n s the n e c e s s a r y 8 - l a c t o n e which would a l s o have an i . r . a l a r g e r frequency than t h a t observed. reported  143a  t o form  absorbance  Rokach and E l a d  40d  of  also  the i s o l a t i o n of y - l a c t o n e s from b e n z o p h e n o n e - i n i t i a t e d  photoamidation of a,B-unsaturated The  s t r u c t u r e of amides 140  s p e c t r a l means a l o n e because chromatography  esters. through 143 could not be e l u c i d a t e d  nor by c r y s t a l l i z a t i o n .  S e c t i o n s 1.1.3. and 1.1.4.).  The s t r u c t u r e s were u l t i m a t e l y (described  below,  T h e r e f o r e , s p e c t r a l a n a l y s i s of the mixture  used to determine the presence of the carbamoyl  formamide d i d add  by  these isomers could not be s e p a r a t e d by  e s t a b l i s h e d by c h e m i c a l t r a n s f o r m a t i o n of the mixture  was  142  group and  show that  to the carbon-carbon double bond.  The n.m.r. spectrum of 140-143 i n d e u t e r c h l o r o f o r m showed, as w i t h l a c t o n e 139,  the d i s a p p e a r a n c e of the l o w - f i e l d v i n y l i c  g e n e r a t i o n of a broad t h r e e - p r o t o n m u l t i p l e t (H-2 and H-3). proton) and  The  p r o t o n s , w i t h the  i n the 62.24-3.25 r e g i o n  spectrum a l s o showed one broad s i g n a l at 66.40 (one-  two broad s i g n a l s a t 65.88 and  D20-exchangeable, i n d i c a t i n g  6.00  two major amide p r o d u c t s .  t h r e e methyl groups were present as s i n g l e t s . and on m e c h a n i s t i c grounds 143 were not expected  (one-proton) which were  Based  Surprisingly, a l l  on the n.m.r. spectrum  the s u b s t i t u t e d malonic a c i d d e r i v a t i v e s 142  i n any a p p r e c i a b l e amounts because  the a-hydrogen  and of  47 the malonates present  resonate  (except f o r OCH^)  at 63.50-63.65 and no a p p r e c i a b l e s i g n a l s were i n that r e g i o n and  s i n c e both o l e f i n i c  of the o l e f i n i c carbon c h a i n possessed hydrogens, r a d i c a l was  expected to occur  (Section  2.1.).  carbons  B - a d d i t i o n of the  carbamoyl  65  The i . r . 3180,  spectrum of the above amide m i x t u r e showed amide peaks a t  3365, 3480 and 1690  cm  , i n d i c a t i v e of a primary amide.  the o l e f i n i c a b s o r p t i o n of 1_8_ was was  absent.  Again  Though a m o l e c u l a r i o n (m )  peak  +  not observed i n the mass spectrum of the mixture 140-143, the c h a r a c -  teristic  (m -CH ) was  predominant  +  3  a l o n g w i t h a s t r o n g s i g n a l at m/e  (m -0CH.j) i n d i c a t i n g the c y c l i z a t i o n of 140 and 141 +  maleimide  fragment.  to form the protonated  E l e m e n t a l a n a l y s i s of 140-143 a l s o e s t a b l i s h e d  e m p i r i c a l formula of the m i x t u r e to be at 1:1  376  telomer of _18 and  formamide.  A l t h o u g h Rokach and E l a d ^ * * o n l y i s o l a t e d a l k y l a t e d s u c c i n i c d e r i v a t i v e s from the photoamidation of a,B-unsaturated  the  acid  e s t e r s , th e un-  s a t u r a t e d a c i d parent compounds were simple s t r a i g h t c h a i n compounds. 47 R o s e n t h a l and R a t c l i f f e ' s was  fully  s u b s t r a t e 46_ (see I n t r o d u c t i o n , S e c t i o n  2.1.)  s u b s t i t u t e d a t the B - p o s i t i o n and gave, e x c l u s i v e l y , the malonic  a c i d d e r i v a t i v e upon photoamidation and g r e a t e r s t a b i l i z a t i o n of the C-3  they a t t r i b u t e d  t h i s r e v e r s a l to a  r a d i c a l over the a l t e r n a t e r a d i c a l  formed  by carbamoyl  a t t a c k at C-3.  was  a i d e d by the s t e r i c b u l k of the p r o t e c t e d sugar r i n g a t t a c h e d  no doubt  to C-3  of compound _46_.  However, the h i g h degree of r e g i o s p e c i f i c i t y  This s t e r i c  i n t e r a c t i o n presumably  accounts f o r  the presence of the s u b s t i t u t e d m a l o n i c a c i d d e r i v a t i v e s 142 and  143.  S u r p r i s i n g l y , the presence o f the c h i r a l sugar i n 46^ d i d not c o n t r i b u t e to the o p t i c a l formed  i n d u c t i o n o f the amide p r o d u c t s (47 and 4j3) which were  i n equal amounts.  T h i s l a c k of s t e r e o s e l e c t i v i t y  to the photochemical c i s - t r a n s pure s t a r t i n g m a t e r i a l  (i.e.,  of the s u b s t r a t e by e x c i t e d 141 were found  i s o m e r i z a t i o n of the i n i t i a l l y  geometrically  ( Z ) - 4 6 ) , brought about by t r i p l e t  triplet  acetone  ( S e c t i o n • 2.2.).  due  sensitization  Amides 140  and  ( S u b s e c t i o n 1.1.3.3.) to be s y n t h e s i z e d i n equal amounts  from a predominantly also attributed  i s presumably  (89%) trans-18 and t h i s l a c k of o p t i c a l  induction i s  to the geometric i s o m e r i z a t i o n of the s t a r t i n g m a t e r i a l to  g i v e a p h o t o s t a t i o n a r y s t a t e w i t h approximately geometric  the same c o m p o s i t i o n of  isomers.  The n.m.r. s p e c t r a of other components i s o l a t e d graphy  from the chromato-  column i n d i c a t e d more than s i x protons i n the h i g h - f i e l d  of the i s o p r o p y l i d e n e methyls; k e t y l or a c e t o n y l ^ addition products.  these compounds were assumed to be other  r a d i c a l a d d i t i o n or d i r a d i c a l  3  region  (not  telomers)  Since none of these compounds were i s o l a t e d  pure,  these components were not f u r t h e r s t u d i e d . The y i e l d of the formamide a d d i t i o n p r o d u c t s was c f . , Rosenthal and R a t c l i f f e T h i s low y i e l d may energy  and  abstraction.  and Rokach and E l a d  40d  the r e a c t i o n with 1_8 which l e a d s to a  (25%  , 77-81%). triplet  geometric  the r e a c t i o n w i t h formamide which l e a d s to hydrogen atom When the former p r o c e s s i s more e f f i c i e n t  poor y i e l d s of formamide-ester acetone a d d i t i o n p r o d u c t s . provided  , 45%,  be the r e s u l t of a c o m p e t i t i o n f o r the e x c i t e d  of acetone^^^,  isomerism  47  r a t h e r low  efficient  adduct  than the  later,  r e s u l t a l o n g w i t h an i n c r e a s e i n  Rokach and  E l a d ^ ' found C  that benzophenone  hydrogen atom a b s t r a c t i o n with the i s o m e r i z a t i o n as an  u n a v o i d a b l e s i d e r e a c t i o n and  t h i s i n i t i a t o r gave high y i e l d s of the  d e s i r e d amide p r o d u c t s . 1.1.3.  C y c l i z a t i o n o f 140 and  141  to g i v e the G l y c o s y l a t e d  Succinimide D e r i v a t i v e s The r e a c t i o n between amides and  e s t e r s can e i t h e r be t h e r m a l l y induced  144 or b a s e - c a t a l y z e d .  However, d i s p r o p o r t i o n a t i o n of primary amides occurs  at e l e v a t e d temperatures catalyzed  and may  compete w i t h the e s t e r r e a c t i o n .  Base-  i n t r a m o l e c u l a r a c y l a t i o n of amides by n e i g h b o u r i n g e s t e r groups 145a have been r e p o r t e d . T r e a t i n g e t h y l malonamate (144) w i t h sodium ethoxid  67  de M o u i l p i e d and Rule"'"^^ found no r i n g compound but r a t h e r , a c i d 146 resulting  from the d i m e r i z a t i o n o f malonamic a c i d  ONH-  2CH,  ^C0NH  2  2)H 0  CH  2  (145); however, when  ^ CCH C0NH N  i M  X  C02Et  2  146  (147) was the s u b s t r a t e , s u c c i n i m i d e (148) was i s o l a t e d ,  i n rather small y i e l d .  R-  2  2  145  methyl succinamate  2  HNC0CH C0 H  C0 H  144  albeit  2  2  Sondheimer and H o l l e y  -C0 2 Me —CONH  Base  145c  R-  found  that  NH  2  148 R=H  147 R=H 149 R = N H C O C H 0 2  2  150 R=NHCO CH 0 2  treatment o f carbobenzoxy-L-asparagine methyl e s t e r h y d r o x i d e gave good y i e l d s  (77%) of the c y c l i c  2  (149) w i t h  sodium  aminosuccinimide 150.  Keeping i n mind the thermal i n s t a b i l i t y o f sugar d e r i v a t i v e s and the base l a b i l e groups p r e s e n t , v a r i o u s methods were attempted s u c c i n i m i d e a g l y c o n from the amido-esters 140 and 141. of  to form the  The r e t e n t i o n  the benzoate group was d e s i r a b l e i n the event the subsequent  dehydro-  g e n a t i o n r e a c t i o n r e q u i r e d p r o t e c t e d h y d r o x y l groups. 1.1.3.1.  Attempted  C y c l i z a t i o n of 140 and 141 i n R e f l u x i n g S o l v e n t s  T a k i n g i n t o c o n s i d e r a t i o n the base s e n s i t i v e benzoate and methyl  ester,  as w e l l a s , the thermal i n s t a b i l i t y of the benzoate, r e f l u x i n g the amide m i x t u r e 140-143 i n a m i l d l y b a s i c p o i n t s o l v e n t appeared r i n g from 140 and 141.  (weakly n u c l e o p h i l i c ) ,  high-boiling  t o a s e n s i b l e r o u t e to the f o r m a t i o n of s u c c i n i m i d e When the amide m i x t u r e 140-143 was r e f l u x e d i n  68  e i t h e r p y r i d i n e or x y l e n e m i x t u r e was  f o r f i v e hours no change i n the  starting  observed.  1.1.3.2.  C y c l i z a t i o n of 140  Absence of a Solvent  to Give  and  141  3-(R)  by Thermal Ring  and  (S)-(5-0-Benzoyl-2,3-0-  isopropylidene-B-£-ribofuranosyl) s u c c i n i m i d e  (151)  When a s o l v e n t f r e e sample of amides 140-143 was mately 200° under reduced p r e s s u r e be d e t e c t e d by t . l . c .  (^100  t o r r ) two  l a r g e r amounts of the f a s t e r moving m a t e r i a l s but  and  (152).  heated at  h i g h e r R^  a f t e r a few minutes. Prolonged  amount of d e c o m p o s i t i o n  Closure i n  heating  approxi-  products  could  produced  simultaneously  a greater  ( c h a r r i n g ) of the r e a c t i o n sample o c c u r r e d .  Initial  p u r i f i c a t i o n of the r e a c t i o n m i x t u r e on a weakly a c i d i c r e s i n column f o l l o w e d by chromatography on a s i l i c a g e l p l a t e gave two epimeric  r i b o f u r a n o s y l s u c c i n i m i d e s 151  respectively.  A s m a l l p o r t i o n (25%)  and  presence of predominantly one R^ for  succinimide).  The  the methyl protons  151  R^  compound  (^95%  spectrum showed two  7%, also  (18:4:1 b e n z e n e - e t h y l a c e t a t e -  i n deuterochloroform  i n d i c a t e d the  p u r i t y , i m p u r i t y mainly  sharp s i n g l e t s at 61.38  lower  and  1.57  of the i s o p r o p y l i d e n e group, as w e l l as, a l o s s of  the methoxy s i g n a l of the methyl e s t e r . attributed  i n y i e l d s of 6 and  of the s t a r t i n g m i x t u r e was  The n.m.r. spectrum of the h i g h e r e t h a n o l as d e v e l o p e r ) s u c c i n i m i d e  152  protected  to the imide p r o t o n  (Nil) and  The  broad s i g n a l at 67.90  an ABM  pattern centered  was  at 63.0  was  69  a s s i g n e d t o the protons of the s u c c i n i m i d e r i n g sugar protons were w e l l s e p a r a t e d a n d - a s s i g n a b l e Then.m.r. spectrum form i n d i c a t e d a second m a i n l y contaminated  of the lower R^  (  J g e m  18.0  Hz).  The  (see E x p e r i m e n t a l ) .  s u c c i n i m i d e 152  i n deuterochloro-  d i a s t e r o m e r i c s u c c i n i m i d e of lower p u r i t y  w i t h 151).  The  imide  (NH) p r o t o n was  (^90%,  a t lower  field,  58.20, the s u c c i n i m i d e protons e x h i b i t e d an A£M s p i t t i n g c e n t e r e d at (ABM  p a t t e r n i n deuterobenzene) and a l t h o u g h the sugar protons  were w i t h i n a 50 Hz packet,  w i t h a spectrum  Both s u c c i n i m i d e products 151  and  0 - i s o p r o p y l i d e n e p r o t e c t i n g groups and (room temperature) group.  c o n d i t i o n s caused  of 152  152 were found  in  irradiations,  deuterobenzene.  to possess  labile  s t o r a g e of the syrups under ambient  p a r t i a l h y d r o l y s i s of the b l o c k i n g  T h e r e f o r e , the s u c c i n i m i d e products c o n t a i n i n g 0 - i s o p r o p y l i d e n e  groups should be kept r e f r i g e r a t e d and dry. t o c r y s t a l l i z e but i n s u f f i c i e n t these  signals  they were a s s i g n a b l e w i t h the a i d of  c o u p l i n g c o n s t a n t s and comparison  63.0  The  syrups a l s o had a  tendency  q u a n t i t i e s prevented r e c r y s t a l l i z a t i o n of  samples. No o t h e r p r o d u c t s  (e.g., d i s p r o p o r t i o n a t i o n p r o d u c t s ) from the  c y c l i z a t i o n o f the amide mixture were d e t e c t e d ; however, due y i e l d s o f the s u c c i n i m i d e p r o d u c t s and  the  Due  aqueous s o l v e n t systems and  of  composition  T h e r e f o r e , i t was necessary to f i n d a method  to s e l e c t i v e l y d e r i v a t i z e the components of amide mixture without any o f the components.  low  l a r g e amount of decomposition  the r e a c t i o n mixture no f i r m c o n c l u s i o n c o u l d be made about of the s t a r t i n g amide m i x t u r e .  to the  thermal  decomposing  to the low s o l u b i l i t y of the amides 140-143 i n the p o s s i b l e s a p o n i f i c a t i o n of the methyl  or the amide w i t h sodium h y d r o x i d e , i t was  decided that methanolic  ester  sodium  methoxide would be the most s u i t a b l e of the b a s e - c a t a l y z e d r i n g - c l o s u r e procedures.  1.1.3.3.  Treatment  of Amides 140, 141, 142 and 143 w i t h M e t h a n o l i c  Sodium Methoxide to g i v e 151, 152, 3-(s) and  (R)-(2,3-0-isopro-  p y l i d e n e - B - n - r i b o f u r a n o s y l ) s u c c i n i m i d e [ ( s ) and domycin a c e t o n i d e ] (153) and (154), and Methyl  (R)-dihydroshow-  4,7-anhydro-2-C-  carbamoyl-2,3-dideoxy-5,6-0-isopropylidene-D-glycero-D-allo g-altro)-octonate  (and  (155) and (156)  When the amide mixture 140-143 was t r e a t e d w i t h 0.5 e q u i v a l e n t s of methanolic  sodium methoxide s i x compounds, 151, 152, 153, 154, 155 and 156,  were produced. column of s i l i c a The  These p r o d u c t s were s e p a r a t e d c h r o m a t o g r a p h i c a l l y on a g e l to g i v e t h r e e major c h a r r i n g  components.  f a s t e r - r u n n i n g component was found, by n.m.r. s p e c t r o s c o p y , to  be a 50/50 m i x t u r e  of t h e p r o t e c t e d r i b o s y l s u c c i n i m i d e s 151 and 152 (55%  combined y i e l d ) p r e v i o u s l y i s o l a t e d  ( S e c t i o n 1.1.1.2).  The f r a c t i o n s of  these two s t e r e o i s o m e r s were p a r t i a l l y r e s o l v e d but no f u r t h e r  attempts  were made t o s e p a r a t e them because t h e p o s s i b l e c o n v e r s i o n of these s u c c i n i m i d e d e r i v a t i v e s t o t h e analogous  maleimide  compound would d e s t r o y  the c h i r a l i t y o f the a g l y c o n t o g i v e i d e n t i c a l p r o d u c t s and the showdomycin (99)  five-membered base r i n g .  71  140-143 NaOMe  4"  + 153  MeOH  151 + 152  R= HO-!  155  156  R=/\/C02Me  Rr^yCC^Me C0NH  doNH-,  The  2  f r a c t i o n s of the second component, e l u t e d from the chromato-  graphy column, upon c l o s e t . l . c .  a n a l y s i s were a l s o found  two c l o s e l y o v e r l a p p i n g compounds  (153 and 154).  to c o n s i s t of  F o r t u n a t e l y , the 3-S-  s u c c i n i m i d o d e r i v a t i v e 153 was s l i g h t l y more mobile on the s i l i c a g e l adsorbant heating  and a l s o c h a r r e d an i n i t i a l pink upon s p r a y i n g w i t h a c i d and ( t h e lower R^ compound 154 c h a r r e d b l a c k ) .  The spectrum  s t r u c t u r e o f compound  ( i n CDCl^, see F i g u r e 2a).  exchangeable protons and  153 was e a s i l y deduced from i t s n.m.r. The spectrum c l e a r l y showed two D 2 O -  a t 62.31 and 8.83 f o r the 5'-primary h y r o x y l  the s u c c i n i m i d e p r o t o n , r e s p e c t i v e l y .  the aromatic  proton  The methoxy methyl along  s i g n a l s were no l o n g e r present w h i l e  with  the other protons s i g n a l s  were e a s i l y a s s i g n a b l e from i r r a d i a t i o n s and c o u p l i n g v a l u e s . the s p e c t r o s c o p i c s o l v e n t t o d i m e t h y l s u l f o x i d e - d ^ , t h e primary  Upon changing hydroxyl  F i g u r e 2A. P a r t i a l 100 MHz Proton N.M.R. Spectrum o f 3 - ( S ) - ( 2 , 3 - 0 - i s o p r o p y l i d e n e - B - D r i b o f u r a n o s y l ) s u c c i n i m i d e [(S)-dihydroshowdomycin a c e t o n i d e , 153] i n CDCl  tS3  F i g u r e 2B. P a r t i a l 100 MHz Proton N.M.R. Spectrum o f (S)-Dihydroshowdomycin A c e t o n i d e (153) i n DMS0-d . 6  I  7.0  F i g u r e 3.  •  .  .  .  I  •  . . .  I  6.0  •  .  .  .  I  . . . .  I  5.0  •  .  .  .  I  .  P P M (6)  .  .  .  I  4.0  60 MHz Proton N.M.R. Spectrum of the Hydrogenation A c e t o n i d e (157) i n CDC1-.  .  .  .  .  I  .... I •  .  .  .  I  •  3.0  Product of Showdomycin  . . .  I  20  proton s h i f t e d d o w n f i e l d to 64.87 and v a l u e of 5.0  exhibited a t r i p l e t with a coupling  Hz w i t h the v i c i n a l protons on C-5'  ( a l s o D^O-exchangeable); 146a  thereby, e s t a b l i s h i n g the presence Unequivocal  proof of s t r u c t u r e of compound 153  of the n.m.r. spectrum genation p r o d u c t ^ ^ 1  Figure 3).  of the primary h y d r o x y l group.  The  two  a b l e s i g n a l s , were  of 153  came from a comparison  i n d e u t e r o c h l o r o f o r m w i t h t h a t of the  of 2',3"-O-isopropylidene-showdomycin s p e c t r a , except  (157)  hydro-  (see  f o r the p o s i t i o n of the D^O-exchange-  identical.  153  118a In the o r i g i n a l paper by Nakagawa et a l . product  153 was  , the  hydrogenation  the only s u c c i n i m i d e d e r i v a t i v e r e p o r t e d .  This stereo-  s p e c i f i c r e d u c t i o n i s a l s o supported by the t i t l e of n.m.r. spectrum Figure 3  and  i n a p e r s o n a l communication w i t h the author.  in  Townsend  and  118c coworkers  a l s o r e p o r t e d a h i g h l y s t e r e o s e l e c t i v e hydrogenation  showdomycin (99) to g i v e the d e - i s o p r o p y l i d e n a t e d d e r i v a t i v e of 153 S e c t i o n 1.1.7.).  The  selectivity  (99) or i t s a c e t o n i d e 157 may the maleimide r i n g .  be due  steric  of showdomycin  i n t e r a c t i o n s with  the  a plane which i s p e r p e n d i c u l a r to the maleimide  i n t e r c e p t s the C-3/C-1' bond would b i s e c t  This p a r t i c u l a r conformation  (see  to a c o n f o r m a t i o n a l p r e f e r e n c e of  In order to minimize  f u r a n o i d r i n g of 9_9 or 157, r i n g and  i n the hydrogenation  of  has  two  the angle 0-4'/C-l'/C-2'.  p o s s i b l e rotamers  158  and  159  the l e a s t amount of s t e r i c i n t e r a c t i o n w i t h  and  s t r u c t u r e 158  possesses  H-2'.  S t r u c t u r e 158  a l s o i s capable of i n t r a m o l e c u l a r hydrogen-bonding between  76  the C-5'  h y d r o x y l and  the C-2  oxo group.  The c o n f o r m a t i o n a l p r e f e r e n c e  of showdomycin to s t r u c t u r e 158 has been v e r i f i e d by X-ray and  theoretical  calculations.  147 analysis"  148  Q  H  ^\  n  HO'  HO The X-ray  a n a l y s i s a l s o shows t h a t the C-5'  0-4'  C-3'.  and  I f t h i s conformation presence  the p r e f e r e n c e ) h y d r o g e n a t i o n  3-S  the  or l e s s e n i n g  p r e f e r e n t i a l l y from  of 158  T h e r e f o r e i t i s suggested  showdomycin a c e t o n i d e 153  h y d r o x y l i s staggered between  ( e i t h e r enhancing  should proceed  ( b a c k - s i d e on s t r u c t u r e 158)  stereoisomer.  OH  p r e f e r e n c e i s o n l y s l i g h t l y a f f e c t e d by  of the 2 ' , 3 ' - O - i s o p r o p y l i d e n e  'exo-face'  159  the  to g i v e predominantly  t h a t the h i g h e r  i s the 3-J5 d i a s t e r e o m e r .  the  dihydro-  This conformational 118b  p r e f e r e n c e under r e a c t i o n c o n d i t i o n s i s a l s o supported by the s y n t h e s i s of N-methylbisdeoxycycloshowdomycin a c e t o n i d e hydrobromide (160) which from X-ray  s t r u c t u r e a n a l y s i s proved  to be the 3-S  H-HBr  diastereomer.  77  Compound 160  i s s y n t h e s i z e d from the b a s e - c a t a l y z e d i n t r a m o l e c u l a r  M i c h a e l - t y p e a d d i t i o n of the 5'-hydroxyl group  to the double bond.  A d d i t i o n v i a s t r u c t u r e 158 would l e a d t o the 3-S  isomer which  i s o l a t e d and a d d i t i o n v i a s t r u c t u r e 159 would g i v e the 3-R which was  not o b t a i n e d .  isomer  T h e r e f o r e , c h e m i c a l , s t r u c t u r a l , and  c o n s i d e r a t i o n s support the above assignment succinimide d e r i v a t i v e .  was  theoretical  of compound 153 as the  (See S e c t i o n 1.1.9. f o r n.m.r. s p e c t r a l  3-S-  correlation  support.) I n t e r e s t i n g l y , compound 153 was c h l o r o f o r m t o form a 1:1 0.5%  found to c r y s t a l l i z e q u i t e r e a d i l y i n  complex w i t h the s o l v e n t .  would form c r y s t a l s at room temperature.  S o l u t i o n s as low  The complex was  by m i c r o - a n a l y s i s which gave the expected carbon, hydrogen  as  verified  and  chlorine  c o u l d not be  purified  content. The  lower R^,  3-R-succinimide d e r i v a t i v e 154  as e a s i l y as i t s epimer  153.  The n.m.r. spectrum of the lower R^  i s o l a t e d by chromatography i n d i c a t e d contaminants.  the presence of at l e a s t  two minor  The presence of aromatic s i g n a l s a l o n g w i t h a s t r o n g s i g n a l  i n the methoxy r e g i o n (63.5-3.8) suggested e i t h e r i n t e r - or i n t r a m o l e c u l a r l y formed. c r y s t a l l i z a t i o n and 4)  component  i t s n.m.r. spectrum  trans-esterification Pure 154 was  products  o b t a i n e d by  selective  i n dimethylsulfoxide-d^ (Figure  showed no aromatic nor methoxy resonances  and possessed a D^O-exchange-  a b l e s i g n a l at 611.15 f o r the imide p r o t o n . The o t h e r proton s i g n a l s were a g a i n w e l l s e p a r a t e d and  e a s i l y a s s i g n a b l e by c o u p l i n g v a l u e s and  irradiations.  The mass s p e c t r a of 153 and 154 were n e a r l y i d e n t i c a l p o s s e s s i n g a very weak peak of 272  (m  +  + H) and a v e r y s t r o n g expected  from the f o r m a t i o n of the acetoxonium  ion.  s i g n a l at 256  (m  +  -  CH^)  F i g u r e 4.  P a r t i a l 100 MHz P r o t o n N.M.R. Spectrum of 3 - ( R ) - ( 2 , 3 - 0 - i s o p r o p y l i d e n e - 3 - D r i b o f u r a n o s y l ) s u c c i n i m i d e [(R)-dihydroshowdomycinJ (154) i n DMSO-d^.  ^-4 00  79  The  third  and  final  component e l u t e d from the s i l i c a g e l column  c o n s i s t e d of a mixture of the a-carbamoylation  adducts 155 and 156.  These  components c o u l d not be c h r o m a t o g r a p h i c a l l y s e p a r a t e d nor c o u l d they be crystallized.  The  i . r . spectrum  3500, 3360 (N-H), 1680  (C=0)  of t h i s mixture showed amide peaks at  and  1580  cm"  1  (Amide I I )  E x p e c t e d l y , no o l e f i n i c absorbances were p r e s e n t . of  4  3  b  (1725  o c c u r s at f a i r l y  high f i e l d  The b a s i s f o r assignment  of the above m i x t u r e .  The H-3  The methylene group  64.68 a s s i g n e d to e i t h e r H-5  a m i x t u r e of compounds.  on chemical  resonance  The  groups  i s broad and does not possess any  s t r u c t u r e i n d i c a t i n g the presence of a m i x t u r e . at  of  (62.20) which i n d i c a t e s the presence of a  methylene group which does not have e l e c t r o n withdrawing bonded.  (CO^e)).  -1  i n deuterochloroform  t h i s component-as a mixture of the a-carbamoyl e s t e r s i s based s h i f t s i n the n.m.r. spectrum  cm  The exact composition  t h i s m i x t u r e i s unknown s i n c e the n.m.r. spectrum  showed o n l y s i n g l e t s f o r the methyl s i g n a l s .  1  or H-6  final  A low-field  directly fine  multiplet  possess f i v e s i g n a l s a l s o  indicating  evidence f o r the malonamic e s t e r s  s t r u c t u r e comes from the p o s i t i o n of a-hydrogen (63.51) which i s i n c l o s e 47 agreement to p r e v i o u s a-hydrogen of t h i s s t r u c t u r e  (Rosenthal and R a t c l i f f e  ,  63.53) and which r e s o n a t e a t l o w e r - f i e l d than the a-hydrogens of the 8 carbamoylation products.  Two  p r e s e n t a t 66.40 and  i n d i c a t i n g the p o s s i b i l i t y of a 50:50 mixture  or  6.80  e l s e a non-equivalence of the amide p r o t o n s .  e x h i b i t e d a s t r o n g acetoxonium 1.1.4.  peak a t 288  +  -  spectrum  CH^). 152  to g i v e 153 and  154  of an equal mixture of the p r o t e c t e d r i b o s y l s u c c i n i m i d e s  152 w i t h sodium methoxide gave two  plate.  (m  The mass spectrum  D e b e n z o y l a t i o n of Compounds 151 and  Treatment and  broad D20-exchangeable s i g n a l s were a l s o  c l o s e l y o v e r l a p p i n g bands on the  Chromatography of these components on a column of s i l i c a  151 t.l.c.  g e l gave  80  two compounds which had n.m.r. s p e c t r a i d e n t i c a l dihydroshowmycin  (153) and (154) i s o l a t e d  to the (R) and ( S ) -  i n the p r e c e d i n g s e c t i o n .  U n f o r t u n a t e l y , n e i t h e r s t a r t i n g compounds 151 nor 152 was  debenzoylated  as a pure compound nor as a predominant component i n a mixture of the two i n order t o d i r e c t l y  r e l a t e the b e n z o y l a t e d and c o r r e s p o n d i n g  dihydroshowdomycin d e r i v a t i v e s .  However, based  on the f a c t  R^ b e n z o y l a t e d compound 152 c h a r s p i n k as does the h i g h e r R^ compound 153, a l o n g with the f a c t compounds have H-3' at lower  field  debenzoylated  that the lower debenzoylated  that the n.m.r. s p e c t r a of these two than H-2' and that the s u c c i n i m i d e  protons e x h i b i t an A^M s p l i t t i n g p a t t e r n , the lower R^ b e n z o y l a t e d compound 152 i s t e n t a t i v e l y a s s i g n e d the 3-S c o n f i g u r a t i o n . Analogously,  the other two dihydroshowdomycin d e r i v a t i v e s  154) both char b l a c k and the n.m.r. s p e c t r a have H-2' at lower H-3'  (151 and field  than  and the s u c c i n i m i d e protons e x h i b i t an ABM s p l i t t i n g p a t t e r n .  T h e r e f o r e , the h i g h e r R^ b e n z o y l a t e d compound 151 i s t e n t a t i v e l y a s s i g n e d the o p p o s i t e , 3-R, c o n f i g u r a t i o n . the s i g n i f i c a n c e o f these chemical 1.1.5.  Attempted  (See S e c t i o n 1.1.9. f o r a d i s c u s s i o n on shifts).  Dehydrogenation  o f S u c c i n i m i d e and i t s A l k y l a t e d  Derivatives. Dehydrogenation  o f six-membered a l i c y c l i c  or h e t e r o c y c l i c  f i v e - and  149a six-membered r i n g s may be achieved i n a number of ways. dehydrogenation location  of an a l i p h a t i c compound t o g i v e a double bond i n  i s much more d i f f i c u l t  p a i r of e l e c t r o n s a l r e a d y  process i s a l s o enhanced by the presence 149b ^ . of u n s a t u r a t i o n i n t h e s u b s t r a t e . There a r e t h r e e types of reagents most f r e q u e n t l y used t o e f f e c t dehydrogenation or a r o m a t i z a t i o n . They a r e 149c: 7 L  The dehydrogenation  a specific  u n l e s s the new double bond can be i n con-  j u g a t i o n w i t h a double bond or an unshared present.  However, the  81  1) Hydrogenation  catalyst  such as p l a t i n u m , p a l l a d i u m and n i c k e l .  In t h i s case the r e a c t i o n i s the r e v e r s e of double bond 2) The elements  s u l f u r and selenium  3) Quinones, which  are  reduced  The more r e a c t i v e and most w i d e l y used benzoquinone  (and selenium  hydrogenation. dioxide).  to the c o r r e s p o n d i n g  i s 2,3-dichloro-5,6-dicyano-l,4-  (DDQ).  For example, treatment  o f the u n s a t u r a t e d f u s e d - r i n g s u c c i n i m i d e  compound 161 w i t h n i c k e l p e r o x i d e " ^ gave the c o r r e s p o n d i n g 1  compound,  N-methylphthalimide  aromatic  (162), i n 62% y i e l d w h i l e no attempts  were made t o dehydrogenate the c o r r e s p o n d i n g  1.1.5.1  hydroquinone.  s a t u r a t e d compound 163.  P a l l a d i u m and S u c c i n i m i d e  When a m i x t u r e o f s u c c i n i m i d e , b i p h e n y l (B.P. 254-255°) and 10% p a l l a d i u m on c h a r c o a l was r e f l u x e d was  passed  through  the s o l u t i o n , s u c c i n i m i d e was q u a n t i t a t i v e l y  No attempts were made t o modify 1.1.5.2.  f o r 25 hours w h i l e carbon d i o x i d e  Treatment  this  recovered.  reaction.  of Compound 151, 152, 153 and 154 w i t h N i c k e l  Peroxide Treatment  o f the p r o t e c t e d r i b o s y l s u c c i n i m i d e s 151 and 152 i n r e f l u x i n g  i ... . , , 149c,150,151 , , , , _ , xylene with n i c k e l peroxide f o r 60 hours produced only broad n  u.v.  a c t i v e slow c h a r r i n g bands and b a s e - l i n e m a t e r i a l s .  The i s o l a t e d  crude syrup was f i v e - t i m e s the s t a r t i n g m a t e r i a l s weight; t h e r e f o r e ,  82  p o l y m e r i z e d s o l v e n t a l o n g w i t h decomposed c a r b o h y d r a t e m a t e r i a l s were presumably the main components and were not f u r t h e r a n a l y z e d . Treatment  of the debenzoylated  s u c c i n i m i d e d e r i v a t i v e s 153  and  154 w i t h n i c k e l p e r o x i d e i n r e f l u x i n g benzene f o r 26 hours gave n e g a t i v e results. was  The s t a r t i n g m a t e r i a l was  present but no u.v.  a c t i v e component  produced. Treatment  o f 153 and  a l s o gave n e g a t i v e  154 w i t h n i c k e l p e r o x i d e i n water f o r 7 days  results.  D i f f i c u l t i e s were a n t i c i p a t e d w i t h use of the n i c k e l o x i d a t i v e dehydrogenation methyl  p r o c e s s because the presence of a methoxy-  s u b s t i t u e n t on the c y c l i c  s u b s t r a t e was  the e f f i c i e n c y of the dehydrogenation utilized upon  possessed  peroxide  process.  reported"'""^ to decrease A l s o , a l l the s u b s t r a t e s  e n d o c y c l i c u n s a t u r a t i o n s which l e a d to aromatic  products  dehydrogenation. 1.1.5.3.  Attempted  Dehydrogenation  of Compounds 153  and  154 w i t h  DDQ.  149a-c 152a Treatment  of the r i b o s y l s u c c i n i m i d e s 153 and  154 w i t h DDQ  '  b '  i n r e f l u x i n g d i o x a n f o r 3 days gave the a n t i c i p a t e d p r e c i p i t a t i o n of the d i h y d r o q u i n o n e ; however, chromatography of the r e a c t i o n m i x t u r e gave no u.v.  a c t i v e c h a r r i n g bands. T h i s r e s u l t was  t h a t DDQ  not t o t a l l y unexpected  s i n c e Evan et a l . " * ^ , r e p o r t e d  gave poorer r e s u l t s w i t h o x a z o l i n e s compare to  dehydrogenation  with n i c k e l peroxide. As f o r the o t h e r methods mentioned i n the i n t r o d u c t i o n to t h i s section  (1.1.5), the use o f s u l f u r r e q u i r e dehydrogenation  i n a melt  149c  (^250°) i n which the s t a r t i n g c a r b o h y d r a t e i s not expected  to be very  stable.  selenium  The  same problem  e x i s t s w i t h the use of e l e m e n t a l  149c  The use of the selenium d i o x i d e the d e s i r e d r e s u l t  149c  reagent, however, may  s i n c e Barnes and Barton  153  g e n a t i o n of c i s hydrogens from t r i t e r p e n o i d  give  r e p o r t e d the dehvdro-  1,4-diketones  to  enediones.  154 However, H i l l  showed that p h e n y l s u c c i n i c a c i d  (164) can be  genated w i t h selenium d i o x i d e to g i v e phenylmaleic anhydride phenyl group appears  essential  e t h y l s u c c i n i c a c i d do not  dehydro(165) but  to the r e a c t i o n s i n c e s u c c i n i c a c i d  the  and  react.  r—C0 H 2  4 0.  -C0 H 2  0  1 6 4  The h i g h degree  165  of d i f f i c u l t y  r i n g to the c o r r e s p o n d i n g maleimide  i n dehydrogenating i n one  step i s e x e m p l i f i e d by  Russian "'"' p r o c e s s i n which s u c c i n i m i d e was 1  presence  of a Vanadium oxide c a t a l y s t  1.1.6.  Attempted  S y n t h e s i s of  heated  to g i v e  to the d i f f i c u l t y  an a l k y l a t e d  maleimide.  (R,S)-3-Bromo-3-(5-0-benzoyl-2,3-  i n v o l v e d w i t h a one  s u c c i n i m i d e i t was  thought  approach was  due  (169).  step dehydrogenation  of  t h a t s u b s t i t u t i o n of an e l i m i n a t a b l e  group at the t e r t i a r y a - p o s i t i o n of the a l k y l a t e d might l e a d t o the d e s i r e d maleimide  the  to 300-400° i n the  O-isopropylidene-B-p-ribofuranosyl)succinimide Due  the s u c c i n i m i d e  product.  s u c c i n i m i d e s 151  The d i f f i c u l t y  to the f a c t t h a t the carbohydrate moiety  and  152  in this  also  possesses  t e r t i a r y hydrogen on the f u r a n o i d r i n g . I t was NBS  hoped that treatment  would lead  (169) or perhaps  of the p r o t e c t e d sugars 151 and  to s e l e c t i v e bromination at C-3  directly  to u n s a t u r a t e d maleimide  152  to g i v e t e r t i a r y  with bromide  product.»157a,b  84  BzO-i  151 and 152 ~~ —  X> (BzO) N  and  $  2  1.1.6.1. Treatment of 151 When 151  B  and  152 w i t h  152 were t r e a t e d w i t h NBS  NBS. and b e n z o y l p e r o x i d e i n  r e f l u x i n g c a r b o n t e t r a c h l o r i d e f o r 32 minutes, a five-component resulted.  The n.m.r. spectrum  of the major h i g h e r  m a t e r i a l ) band i n d e u t e r o c h l o r o f o r m  indicated  mixture  (cf. starting  the presence  of the  hydrogen of the a l k y l s u c c i n i m i d e a l o n g w i t h an absence of any  tertiary  vinylic  118c protons  (ca. 66.8  ) due  to an a l k y l m a l e i m i d e group.  1.1.7. 3 - ( S ) - ( B - D - r i b o f u r a n o s y l ) s u c c i n i m i d e Treatment of the s o l u t i o n of 3:1 compound 170  (S^)-dihydroshowdomycin a c e t o n i d e  t r i f l u o r o a c e t i c acid-methanol  i n almost  (170)  quantitative yield.  (153) w i t h a  gave the d e - i s o p r o p y l i d e n a t e d  The  clear  by chromatography on Bio-Rex 70 c a t i o n exchange r e s i n  syrup was (H  +  purified  form).  HNHO-i  H"  153  HO The n.m.r. spectrum s u l f o x i d e - d ^ was  of  (S)-dihydroshowdomycin  (170)  i n dimethyl-  c o n s i s t e n t w i t h the a s s i g n e d s t r u c t u r e , having  D20-exchangeable p r o t o n at 64.63 and v a l u e s and  OH  one  at 611.0.  c h e m i c a l s h i f t s of the remaining  d o u b l e t s at 64.06 was  a s s i g n e d to H - l ' .  signals,  three  From the c o u p l i n g the d o u b l e t of  T h i s assignment was  confirmed  85  when i r r a d i a t i o n of H-3  c o l l a p s e d t h i s s i g n a l to a d o u b l e t .  constant between H - l ' and upon changing acid-d^.  H-3  (J  ^) was  2.0  coupling  Hz which i n c r e a s e d to 2.5  the s p e c t r o s c o p i c s o l v e n t to D 0  Hz  c o n t a i n i n g a few drops a c e t i c  2  This l a t t e r value i s i d e n t i c a l  The  to the v a l u e r e p o r t e d by Townsend  118c and  coworkers  f o r the major product  of the hydrogenation  of showdomycin  (99). 1.1.8.  3-(R)-(g-D-ribofuranosyl)succinimide  I d e n t i c a l treatment  of the  (R)-acetonide 154  dihydroshowdomycin  (171).  d^ a g a i n possessed  three m i d - f i e l d  protons.  i t s acetonide  As w i t h  (171) as above gave  The n.m.r. spectrum of 171 and  and  one  low-field  benzoylated  3-(R)-  in dimethylsulfoxideD^O-exchangeable  acetonide precursors  (154  154 H O and H-3'  151,  r e s p . ) , the H-2'  signal  (64.30 and  the 3-_S-isomers 152, The  s i g n a l of 171  4.00,  153  and  coupling constant J  resp.).  O H  resonated  at lower  ( T h i s p a t t e r n was  170 w i t h H-3' f o r 171 was  6.0  than i t s  also retained for  r e s o n a t i n g at Hz;  field  lower-field).  therefore, this  isomer,  -> > i  expectedly  i s not  1.1.9.  the same as Townsend's  General  major hydrogenation  Considerations  As mentioned i n S e c t i o n 1.1.4. the p o s i t i o n s of the n.m.r. of H-2'  and H-3'  of compounds 151,  152,  153  and  154  (along w i t h  i n f o r m a t i o n ) were used to a s s i g n the c o n f i g u r a t i o n of C-3 151  and  152.  two  resonances  The  product.  q u e s t i o n a r i s e s as to why  resonances other  of compounds  the r e l a t i v e p o s i t i o n s of  change i n going from the 3-R-to the 3-S-isomer.  these  From molecular  models of compounds 153 preferred and  and  154,  i f , based on  c o n f o r m a t i o n of the a g l y c o n i s one  H - l ' are  s t e r i c grounds,  i n which hydrogens  i n a t r a n s or a n t i r e l a t i o n s h i p then the  maleimide r i n g s would a l s o be  of the v a r i o u s  furanoid  i n a trans r e l a t i o n s h i p .  order a n a l y s i s of the observed c o u p l i n g ribosylsuccinimide  the  d e r i v a t i v e s and  their  and  From a  c o n s t a n t s between H-3  H-3  firstand  H-l'  calculated  158 d i h e d r a l angles  , i t i s suggested that a p o s s i b l e e x p l a n a t i o n  r e v e r s a l of the H-3'  and  H-2'  resonances i s due  to the  to  the  anisotropic  159 shielding  of H-2'  3-^-isomers.  by  the C-2  field as the  of the maleimide r i n g of  w i t h H-2  (C-3/C-1') i s r e s t r i c t e d due  which would cause d e s h i e l d i n g  resonance) due  to i n t r a m o l e c u l a r  van  of H-2'  which the d i h e d r a l angle between H-3  conformation would only  p o s i t i o n a carbonyl r i n g over H-2'  and  group  (C-2  to cause and  ribofuranosylsuccinimides  carbonyl  153  and  one  of the  170)  lower  ; however,  and  in  134.6°.  of the d i a s t e r e o m e r s to  S-isomer) of the maleimide Therefore,  might be  0  the  3-S-  expected to possess  h i g h e r H-2' resonances which i s indeed observed. Table I. C a l c u l a t e d D i h e d r a l Angles between H-3  R0-,  (therefore, 159  H - l ' i s between 119  allow  inter-  conformation i s one  anisotropic effect.  (152,  to s t e r i c  der Waals f o r c e s  f i g u r e s i n Table I i n d i c a t e , t h e p r e f e r r e d  This preferred  the  M o l e c u l a r models of these compounds show t h a t r o t a t i o n  about t h e ' g l y c o s i d i c ' bond ference  carbonyl  and  H-l'  87  Compound and C h i r a l i t y (C-3)  151-R J52-S  R  =  B  z  , ~  R  R  153-S Y5^_  R=H  170- S 171- R  R=R'=H  R  £ = I  P  R'-R'=Ip  Solvent  Chem. H-2'  Shift(6) •H-3'  CDCI3 CDCI3  5.25 4.54  4.75 4.72  2.5 3.8  123 131  4.46 4.90  4.61 4.51  3.5 4.0  129 132  3.60 4.30  3.83 4.00  2.0* 4.4  119.3 134.6  DMS0-d DMS0-d  a  6  6  DMSO-d D 0  6  2  a) Ip = I s o p r o p y l i d e n e  b) 2.5 Hz i n D 0 2  J  3 , l ' Dihedral Angle (Hz)  (123°)  From the above t a b l e and the above d i s c u s s i o n , i t can be seen that the r e v e r s a l o f the two resonances H-2' and H-3' i s due to l a r g e i n H-2' r a t h e r be  than complementary s h i f t s  i n H-2' and H-3'.  shifts  I t might  also  suggested t h a t the l a r g e c h e m i c a l s h i f t o f H-2' i n the ^ - i s o m e r s may  be due t o an enhanced s t e r i c of t h e f u r a n o i d  d e s h i e l d i n g due t o e l e c t r i c d i p o l e  oxygen and the c a r b o n y l  group of C-2.  repulsions  This e l e c t r o n i c  r e p u l s i o n tends t o b r i n g t h e C-4 methylene group and the C-2' hydrogen into closer proximity causing  a downfield  and thereby i n c r e a s e the van der Waals r e p u l s i o n  shift  i n H-2' and H-4.  T h i s downfield  shift  i n H-4,  a l t h o u g h not as predominant as H-2', i s observed f o r the ^ - i s o m e r s (see Experimental). and  might even p r o v i d e  o f the n e a r l y C-3  For the _S-isomer, t h i s e l e c t r o n i c i n t e r a c t i o n i s minimized a t t r a c t i v e f o r c e s which may e x p l a i n the s t a b i l i t y  e c l i p s e d conformation, with respect  and C - l ' o f the S-isomer.  stereochemical  I t should are v e r y  This evidence, therefore,  assignments made p r e v i o u s l y  D-ribofuranosylsuccinimide  slowly de-isopropylidenate.  supports the  ( S e c t i o n 1.1.3.3.) f o r the 8-  derivatives.  be noted that the a c e t o n i d e s  l a b i l e and u n l e s s  to the s u b s t i t u e n t s on  of these s u c c i n i m i d e  they a r e c r y s t a l l i n e , Therefore,  the s t o r e d  the syrups should  derivatives  syrups w i l l  be s t o r e d  ina  88  c o o l and d r y c o n t a i n e r .  1.2.  S y n t h e s i s of g-Dihydroshowdomycin A c e t o n i d e v i a Photoamidation of M e t h y l  (E,Z)-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-0-  i s o p r o p y l i d e n e - J 3 - r i b o - o c t - 3 - e n o n a t e (172) . 1.2.1.  Photoamidation o f 172 t o g i v e 140, 141, Methyl 4,7-anhydro-  8-0-benzoyl-3-C-carbamoyl-2,3-dideoxy-5,6-0-isopropylidene-£-glycerop-gluco  (and manno)-octonate  Irradiation  (173) and (174), r e s p e c t i v e l y .  o f the methyl oct-3-enonate 172 (^95:5 r a t i o of Z-to E-  isomers, resp., d e t a i l s  o f i t s s y n t h e s i s t o be d i s c u s s e d i n S e c t i o n 2.),  by t h e same procedure used f o r the i r r a d i a t i o n of the methyl  oct-2-enonate  18 produced a m i x t u r e t h a t possessed a band on t . l . c . which was in  t o t h a t o f amides 140-143 produced  compound.  identical  from the l a t t e r u n s a t u r a t e d  S p e c t r a l a n a l y s i s of t h i s band i n d i c a t e d a mixture of amide  products also,but only a f t e r  c h e m i c a l t r a n s f o r m a t i o n (see f o l l o w i n g  s e c t i o n ) was t h i s band found to c o n s i s t o f the p r e v i o u s l y  isolated  ( S e c t i o n 1.1.2.) amides 140 and 141 and t h e new carbamoyl p r o d u c t s 173 and  174.  Column chromatography  o f the i r r a d i a t i o n m i x t u r e f a i l e d t o  s e p a r a t e any o f the f o u r components and c r y s t a l l i z a t i o n o f t h i s m i x t u r e did  not a f f e c t  i t s composition.  As w i t h the n.m.r. spectrum of amides 140-143, t h i s new m i x t u r e exhibited  t h r e e broad peaks a t c a . 66.2 and a broad t h r e e - p r o t o n m u l t i p l e t  i n t h e 62.4 t o 3.4 r e g i o n . The i . r . spectrum possessed a s t r o n g primary amide band"'"*'^ a t 1685 cm  89  1.2.2.  Treatment  Sodium Methoxide  o f Amides 140, 141, 173 and 174 w i t h M e t h a n o l i c t o g i v e 151, 152, 153, 154, 3-(R) and ( S ) - ( 2 , 3 -  O-Isopropylidene-ot-D-ribofuranosyl)succinimide dihydroshowdomycin  [ (R) and (S)-ot-  A c e t o n i d e ] (175) and (176) and Methyl 4,7-  anhydro-3-C-carbamoyl-2,3-dideoxy-5,6-0-isopropylidene-D-glyceroD-gluco-octonate  (177), r e s p e c t i v e l y .  When the amide m i x t u r e 140, 141, 173 and 174 was t r e a t e d w i t h 0.12 e q u i v a l e n t s of sodium methoxide a multicomponent t.l.c.  of the r e a c t i o n m i x t u r e .  m i x t u r e was seen on the  Column chromatography  o f the worked-up  r e a c t i o n m i x t u r e gave compounds 151, 152, 153, 154, 175, 176 and 177. The n.m.r. spectrum o f the f a s t e r moving band i n d i c a t e d resolved  f r a c t i o n s o f the p r e v i o u s l y  isolated  partially  (see S e c t i o n s 1.1.1.2 and  1.1.3.3.) 6 - r i b o s y l s u c c i n i m i d e s 151 and 152, present i n an o v e r a l l  ratio  of 4:6 (^20% combined y i e l d ) , r e s p e c t i v e l y . The n.m.r. spectrum of these f r a c t i o n s a l s o showed minor analogues  o f 151 and 152.  components which a r e presumably T h i s presumption  i s based  the 'a'-  on the i s o l a t i o n  ( v i d e i n f r a ) o f the debenzoylated a - r i b o s y l s u c c i n i m i d e s 175 and 176 and  90  the presence of a prominant doublet o f d o u b l e t s at ca. 64.94 i n the n.m.r. s p e c t r a which i s a l s o present i n the s p e c t r a of the debenzoylated a-compounds but i n none o f t h e 8 - r i b o s y l s u c c i n i m i d e compounds.  U 0 , 1_41.173 + 174 NaOMe  151+152 153+154  175 R=  X~\o  >  176 R= T^>=0 177 R=  V^cC^Me 60NH2  The f i r s t  of the slower-moving components e l u t e d from the column  was compound 153, the n.m.r. spectrum of which was i d e n t i c a l t o the 3-(S)-dihydroshowdomycin  (153) p r e v i o u s l y i s o l a t e d  (Section  1.1.3.3.).  T h i s compound was f o l l o w e d by a m i x t u r e of two r i b o s y l s u c c i n i m i d e a c e t o n i d e s whose n.m.r. spectrum i d e n t i f i e d previously isolated  t h e minor component as t h e  3-(R)-dihydroshowdomycin  (154) (30% of t h i s m i x t u r e ) .  The n.m.r. spectrum a l s o showed t h e l o s s of the benzoate and methyl e s t e r of t h e s t a r t i n g compounds and possessed two D20-exchangeable 62.07 and 9.00 f o r the primary h y d r o x y l and imide groups.  protons at  Of p a r t i c u l a r  s i g n i f i c a n c e i s the presence of a prominent d o u b l e t o f d o u b l e t s at which i s a l s o p r e s e n t f o r a pure a - r i b o s y l s u c c i n i m i d e d e s c r i b e d  64.75  below.  T h e r e f o r e , t h e major component of t h i s m i x t u r e i s t e n t a t i v e l y a s s i g n e d as 3-(R)-(2,3-C)-isopropylidene-a- D - r i b o f u r a n o s y l ) s u c c i n i m i d e dihydroshowdomycin  a c e t o n i d e ] (175).  [(R)-cx-  (Assignment of the new c h i r a l  center  to be d i s c u s s e d below). Continued e l u t i o n of the column a c e t o n i d e 176  i n 12% y i e l d  gave the 3 - ( S ) - a - r i b o s y l s u c c i n i m i d e  as a pure isomer.  The n.m.r. spectrum of 176  91  a l s o showed the l o s s of the benzoate and methyl e s t e r groups. broad and  D^O-exchangeable s i g n a l s a t 62.16  and  8.28  very s i m i l a r  tonated molecular at 256  hydroxyl  The mass spectrum  to t h a t of i t s B-analogues i n p o s s e s s i n g a pro-  i o n a t 272  (m+1)  and  a very s t r o n g acetoxonium fragment  (m-CH ). 3  The c o n f i g u r a t i o n a l assignment of the new the s u c c i n i m i d e r i n g 175  f o r the primary  imide p r o t o n s , r e s p e c t i v e l y , were a l s o p r e s e n t .  of 176 was  Two  and  176  and  c h i r a l c e n t e r a t C-3  i s based on model s t u d i e s of the two  on the c o u p l i n g c o n s t a n t s between H-3  of  diastereomers  and H - l ' ( i . e . J  ). •J»i  With J  of 175  equal to 2.0  Hz and  8.0  Hz  f o r 176,  the r e s p e c t i v e  158 d i h e d r a l a n g l e s c a l c u l a t e d from the K a r p l u s and it and  159°(9°),  respectively.  r e l a t i o n s h i p a r e 59(119)  From models or diagrams of these two  compounds  can be seen t h a t the c i s - r e l a t i o n s h i p between the C)-isopropylidene group the s u c c i n i m i d e r i n g g r e a t l y h i n d e r s r o t a t i o n about C-3  From c a l c u l a t e d d i h e d r a l a n g l e s and models of the two seen t h a t the 3-R  and  isomers  C - l ' bond.  i t can  isomer would p r e f e r the s m a l l e r d i h e d r a l angle of  w h i l e the 3-S_ isomer p r e f e r s the l a r g e r d i h e d r a l angle of 159°. v a l u e s i n p a r e n t h e s i s r e p r e s e n t u n s t a b l e conformers.] a r e based m a i n l y  on s t e r i c  c o n s i d e r a t i o n s but  e l e c t r o s t a t i c r e p u l s i o n s a r e a l s o minimized. product R^,  176  i s t e n t a t i v e l y assigned  a-product The  176  final  [The  These p r e f e r e n c e s  T h e r e f o r e , the lower R^,  the 3-jS c o n f i g u r a t i o n and  a-  the h i g h e r  the 3-R c o n f i g u r a t i o n .  c y c l i z e d , debenzoylated  amide.  primary amide  and  1678  cm  , respectively.  showed a broad  peak at about 3450 w i t h two  it  3410  cm~l,  was  found  T h i s pure s t e r e o i s o m e r was  a s t r o n g c a r b o n y l a b s o r p t i o n at 1732  at 3500 and  59°  i t appears as though the  component i s o l a t e d , compound 177,  m e t h y l e s t e r and  be  1  to be an found  to  i n the i n f r a r e d The  i.r.  unpossess  f o r the  spectrum a l s o  sharp absorbances o v e r l a p p i n g  i n d i c a t i n g the presence  of a h y d r o x y l group  and  92  the primary  amide N-H s t r e t c h i n g bands.  For these two l a t t e r  the n.m.r. spectrum o f 177 i n d i m e t h y l s u l f o x i d e - d ^ possessed p r o t o n , D2U-exchangeable t r i p l e t and  two broad  group.  a t 64.80 f o r the C-8 primary  groups a singlehydroxyl  D20-exchangeable s i g n a l s a t 66.77 and 7.24 o f the carbamoyl  Moreover, the n.m.r. spectrum possessed  t h r e e sharp,  three-proton  s i n g l e t s o f 63.57, 1.42 and 1.28 f o r the methoxy methyl and the i s o p r o p y l i d e n e methyls,  respectively.  The mass spectrum possessed  i o n peak 304 (m+1) and m i c r o - a n a l y s i s confirmed  a protonated  molecular  the e m p i r i c a l formula.  Assignment o f the c o n f i g u r a t i o n of C-3 and C-4 o f t h i s amide i s a g a i n based on n.m.r. evidence.  As can be seen i n Table I I , t h e c o u p l i n g c o n s t a n t s  between the f u r a n o i d hydrogens o f the  a - s e r i e s o f compounds a r e very  e s p e c i a l l y the J , ., v a l u e s r e l a t i v e to t h e 8 - s e r i e s . J ,4 > magnitude o f the J ,  v a l u e s have been observed  i s o p r o p y l i d e n a t e d C-a and B - g - r i b o f u r a n o s i d e s . chirality  T h i s d i f f e r e n c e and  f o r a s e r i e s of 2',3'-0The assignment of the  o f C-3 i s based on the c o u p l i n g v a l u e s  ^, of the a - s e r i e s . I f  the c o n f o r m a t i o n a l p r e f e r e n c e about C-3 and C - l ' does not change  significantly  from the c y c l i c and a c y c l i c compounds then amide 177 can be a s s i g n e d configuration. assigned  with s t e r i c  and r e p u l s i v e e l e c t r o n i c  3 - j 5 - a - r i b o s y l s u c c i n i m i d e 176 i s expected  of H-3 and H - l ' i n the open-chain i n t e r a c t i o n s a r e s t i l l minimized.  form  v a l u e o f 10 Hz.  retain  i n staggered  interactions  to r e t a i n  minimized.  i t s t r a n s - o r i e n t a t ion  ( i . e . , amide 177) s i n c e the above  T h i s conformation  should g i v e maximum  c o u p l i n g i n t e r a c t i o n between H-3 and H - l ' , thereby r e s u l t i n g J  the 3-S-  s i n c e the conformations  to s u c c i n i m i d e s 175 and 176 ( v i d e supra) a r e roughly  conformations The  T h i s assumption should be v a l i d  similar,  i n the observed  The 3 - R - a - r i b o s y l s u c c i n i m i d e 175 i s a l s o expected to  i t s conformation  i n the open-chain  form and, t h e r e f o r e , lower  ^ .  v a l u e , s i n c e the rotamer i n which H-3 and H - l ' a r e t r a n s - o r i e n t a t e d would  93  b r i n g about an u n f a v o u r a b l e  s t e r i c and e l e c t r o n i c  C-3-carbamoyl group and 0-2'.  i n t e r a c t i o n between the  T h e r e f o r e , i t i s suggested  t h a t 177 has  the a - 3 - ^ - c o n f i g u r a t i o n .  Table I I . and  C o u p l i n g Constants  '8-' D - R i b o s y l s u c c i n i m i d e  and O p t i c a l R o t a t i o n s o f the ' a -  D e r i v a t i v e s and t h e i r H - l ' Chemical  Shifts.  Compd.  153 154 175 176 177  1  , 6H-1  8-3-S^  -9.27  8-3-R a-3-R a-3-S a-3-S  3.3 3.3  CDC1-  DMSO DMSO  -35.3 +8.04*  CDC1  4.0 3  2.0  -1.0  CDCI3  8.0  +16.1  H 0  10.0  2  6 0 5 0 4 5 3 5 3. 8 3. 5  6.5 6.5  3 5 4 0 4 5  6.0  0  6.0  1  0  6.0  0  0  6.0  0  4.34 4.14 4.04(4 14) 4.56 4.47 4.18(4 23)  * contaminated w i t h approx. 30% compd. 154. ** o p t i c a l r o t a t i o n s measured i n methanol s o l u t i o n . ( ) v a l u e s i n p a r e n t h e s i s are i n C D C 1 ~ .  G e n e r a l l y speaking, compounds l i s t e d  the s p e c t r a l c h a r a c t e r i s t i c s of the a and 8  i n T a b l e I I are c o n s i s t e n t w i t h the s p e c t r a l p r o p e r t i e s  of 2' , 3 ' - 0 - i s o p r o p y l i d e n a t e d C_-a and 8 - D - r i b o f u r a n o s i d e s . proton  (H-l') i s g e n e r a l l y downfield  The 'anomeric'  i n the ct-anomer and the  optical  r o t a t i o n i s more p o s i t i v e i n the a-anomer which i s c o n s i s t e n t w i t h Hudson's 53,167,168 rules. The  surprisingly  t h i s photoamidation  low degree o f s t e r e o s e l e c t i v i t y  i n both s t e p s o f  r e a c t i o n i s not o b v i o u s l y c l e a r but the f a c t  that  94  i s o l a t e d double bonds have been p h o t o c h e m i c a l l y phenone"^ i n d i c a t e d  t h a t an alkene p o s s e s s i n g an auxochrome such as  a l k o x y l group (as i n the methyl oct-3-enonate efficiently energy  159e  s e n s i t i z e d v i a the n-^ir*  s e n s i t i z e r such as e x c i t e d  S e c t i o n s 2.1.  and  i s o m e r i z e d u s i n g benzo-  2.2.).  The  172)  should be more  transition  triplet  l a c k of a  acetone  43b  with a higher  (see I n t r o d u c t i o n ,  v i c i n a l c h i r a l group may  c o n t r i b u t e t o the low s t e r e o s e l e c t i v i t y of c a r b a m o y l a t i o n hydrogen a b s t r a c t i o n s t e p however was  expected  an  step.  also The  to proceed w i t h a h i g h e r  degree of s e l e c t i v i t y i r r e g a r d l e s s of the s t e r e o s e l e c t i v i t y of the initial  a d d i t i o n step  s p e c i f i c i t y of the unsaturated  (see I n t r o d u c t i o n , S e c t i o n 2.1.).  hydrogen a b s t r a c t i o n step i n the photoamidation  sugars ^»6, _53 and _56^  be a t t r i b u t e d  In view of the s t e  the l a c k s p e c i f i c i t y here can perhaps  to the 8-0-benzoyl group of 172 which might p r o v i d e  s t e r i c or e l e c t r o n i c i n t e r a c t i o n s on the exo-face r e p u l s i o n i n the endo-face in  the i n i t i a l  of  the photoamidation  due  steric  regiospecificity  to the anti-Markovnikov  orientation  reaction.  A f i n a l q u e s t i o n which might be asked mixture  d i f f e r e n c e between the a- and  about t h i s  of amides i s why  was  latter  chemical  there a r e a c t i v i t y  8-anomers towards d e b e n z o y l a t i o n .  p o s s i b l e answers are immediately  obvious;  first,  i f cyclization  b e f o r e d e b e n z o y l a t i o n the perhaps the conjugate base of the p r o v i d e s both s t e r i c and predominantly  Two occurs  'B'-imide  e l e c t r o s t a t i c r e p u l s i o n to the  methoxide a n i o n , both f o r c e s which a r e minimized if  either  to c o u n t e r a c t the  of the f u s e d - r i n g system. The  r e a c t i o n i s expected  t r a n s f o r m a t i o n of the  of  i n the a-anomer; secondly,  d e b e n z o y l a t i o n o c c u r s b e f o r e c y c l i z a t i o n perhaps the conjugate  the 6-amide a g a i n p r o v i d e s both s t e r i c and  base of  e l e c t r o s t a t i c r e p u l s i o n which  95  i s a g a i n minimized i n the a-isomer. f o r a predominance  T h e r e f o r e , e i t h e r mechanism p r o v i d e s  of the debenzoylated a-anomers i f a c a t a l y t i c amount  of base i s used. 2.  S y n t h e s i s of F u n c t i o n a l i z e d P r e c u r s o r s to C-Nucleosides The importance of the n a t u r a l and s y n t h e t i c C-Nucleosides as a n t i -  tumor and a n t i b i o t i c agents was 4.).  emphasized  i n the I n t r o d u c t i o n  The s y n t h e s i s of analogues of these b i o l o g i c a l l y  (Section  important compounds  has thus been pursued i n a d e s i r e t o produce more a c t i v e and more s e l e c t i v e d e r i v a t i v e s w i t h l e s s t o x i c and o t h e r u n d e s i r a b l e  characteristics. ^' *^ 1 1  S e v e r a l s y n t h e t i c pathways to p o s s i b l e i n t e r m e d i a t e s of new described i n this section.  1 1  analogues are  Each s y n t h e s i s i n v o l v e s the use of a z i d e  r e a g e n t s as e i t h e r an a c i d , base, n u c l e o p h i l e , f r e e - r a d i c a l or o r g a n i c intermediate. The f i r s t  part  of the work to be d e s c r i b e d  i s based on the s y n t h e s i s 72  of b r a n c h e d - c h a i n g l y c o s y l amino-acids by Rosenthal and R a t c l i f f e  who  added  second  h y d r a z o i c a c i d and  sodium a z i d e to an u n s a t u r a t e d sugar.  The  p a r t of t h i s s e c t i o n i s based on the a z i d o - n i t r a t i o n of u n s a t u r a t e d sugars • « _ .. . „ 105 by Lemieux and R a t c l x f f e . V  T  2.1  S y n t h e s i s of U n s a t u r a t e d and Amino Sugars 2.1.1. Attempted 18 to y i e l d  A d d i t i o n of Sodium A z i d e to the Methyl  oct-2-enonate  Methyl(E,Z)-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-0-isopro-  pylidene-D-ribo—oct-3-enonate  (172) and M e t h y l  (E)-4,7-anhydro-8-0-  benzoyl-2,3,5-trideoxy-D-erythro-oct-2,4-dienonate  (178).  When a s o l u t i o n of the methyl oct-2-enonate 18^ (see S e c t i o n 1.1.1.) i n N,N-dimethylformamide sodium a z i d e , two new 21.5  was  heated at 50-55°  i n the presence of excess  u n s a t u r a t e d compounds, 172 and 178, were i s o l a t e d i n  and 51.5% y i e l d , r e s p e c t i v e l y , from the chromatographed  r e a c t i o n mixture  a f t e r work-up.  T . l . c . of the r e a c t i o n mixture w i t h v a r i o u s s o l v e n t  systems i n d i c a t e d  that the r e a c t i o n had o n l y gone to p a r t i a l  a f t e r 21 hours, w i t h no s i g n i f i c a n t a d d i t i o n a l 24 hours at 50-55°. 63°,  mately  completion  changes i n i t s c o m p o s i t i o n a f t e r  A f t e r an a d d i t i o n a l 48 hours at a p p r o x i -  the unchanged mixture was  worked-up. Upon s i d e - b y - s i d e develop  ment o f the s t a r t i n g compound 1J5 w i t h the r e a c t i o n mixture on a p l a t e , i t was mixture had  observed  the same  as 1_8_ but the i n i t i a l  p r o d u c i n g a d u l l grey and b r i g h t p u r p l e  sumption  acetone  slower-moving  of the s t a r t i n g  The  slower-moving  charring  presence  the r e a c t i o n  mixture  colouration for i t s faster-  components, r e s p e c t i v e l y , i n d i c a t i n g the  of another  con-  material.  component, 178, was  easily identified  as  the  spectrum  the l o s s o f the _ 0 - i s o p r o p y l i d e n e group a l o n g w i t h the  o f o n l y one D20-exchangeable doublet at 62.57 f o r the  h y d r o x y l at C-5 shift  coloration  e l i m i n a t i o n product from an i n s p e c t i o n of i t s n.m.r.  which i n d i c a t e d  t.l.c.  t h a t the f a s t e r - m o v i n g component of the r e a c t i o n  d i f f e r e d , w i t h 18_ p r o d u c i n g an orange c o l o u r and  moving and  an  and w i t h the l o s s of one (H-5)  secondary  f u r a n o i d hydrogen (H-4)  to the e n o l i c region'*""'^*' a t 65.52.  and  the  Moreover, the  s t e r e o c h e m i c a l p u r i t y of t h i s compound i s a l s o i n evidence from the n.m.r. spectrum,  i n which the v i n y l i c protons of C-2  d o u b l e t s a t 66.29 and  7.13  and  C-3  are present as  w i t h a c o u p l i n g constant of 16.0  Hz  sharp  indicative  of  the t r a n s - ( o r E-)  isomer. *' 1  The i . r . spectrum  0  of t h i s  crystalline  m a t e r i a l i s a l s o c o n s i s t e n t w i t h the a s s i g n e d s t r u c t u r e 178: h y d r o x y l absorbed  at 3500 cm  e x h i b i t e d a moderate s h i f t lower frequency C-3 cm  (1712  cm  -1  t o g i v e a broad band, 2) the methyl  1  (starting material ) due  to extended 1  )  and 4) a moderate band  carbon-carbon  at 1607  double bond between C-4  a t t r i b u t a b l e to a combination  cm  1  20  , 18, at 1730  conjugation  double bond e x h i b i t e d a s i m i l a r s h i f t " ' ^ 1  1) the  159c  -1 cm)  to  can be a s s i g n e d to the  jhe  m a  ss  1660 new  frequency  of r i n g s t r a i n , c o n j u g a t i o n and  presence o f an e l e c t r o n e g a t i v e s u b s t i t u e n t .  to  , 3) the Z-'i -21  ( i . e . , from 1672  and C-5 w i t h the low  ester  the  spectrum of the  d i e n o n a t e 178 a l s o p r o v i d e s a g r e a t d e a l of s u p p o r t i v e evidence f o r the assigned s t r u c t u r e . 254 (m ) +  The  first  f o u r major s i g n a l s at 304,  286,  272  and  ( r e l a t i v e i n t e n s i t y , 1.4:1.4:1:2, r e s p . ) r e p r e s e n t the m o l e c u l a r i o n and  the l o s s of water, methanol and the combined l o s s of b o t h ,  respectively. groups  The r e l a t i v e s t r e n g t h of the m o l e c u l a r i o n and  i t s l o s s of  p o s s e s s i n g even numbers of e l e c t r o n s i n d i c a t e the h i g h degree of  stability  of e n o l i c r a d i c a l c a t i o n i c species.  This s t a b i l i t y  has  also  been e x h i b i t e d by o t h e r e n o l i c sugars which a l s o possess s t r o n g m o l e c u l a r ion  s i g n a l s r e l a t i v e t o c o r r e s p o n d i n g n o n - e n o l i c or s a t u r a t e d compounds ^ 1  ( a l s o , see compd. 172 below and compd. 220 The dienonate 178  i n S e c t i o n 4.).  i n i t s c r y s t a l l i n e form i s q u i t e u n r e a c t i v e and  can be s t o r e d a t room temperature;  however, as a syrup, the u n p r o t e c t e d  compound r e a c t s f u r t h e r to form both lower and h i g h e r I s o l a t i o n of the s i n g l e h i g h e r by-product carbomethoxyethylene)furan  gave  materials.  2-benzoyloxymethyl-5-((E)-  (179) which has been i s o l a t e d by M o f f a t t et a l . ,  and r e s u l t s from a d e h y d r a t i o n of 178.  Compound 178  the s o l e product i n 64% by an i n c r e a s e i n the i n i t i a l i n the absence  1  hydrazoic acid.  can be s y n t h e s i z e d as reaction  temperature  98  1 7 9  The  s t r u c t u r e of the minor component, 172,  the v a r i o u s s p e c t r a l data. from v a r i o u s c h e m i c a l  A d d i t i o n a l proof of i t s s t r u c t u r e comes  transformations.  s p e c t r a l c h a r a c t e r i z a t i o n and of  the e n o l i c double-bond.  2.1.1.3. and  and  This section w i l l  p r o v i d e evidence  f o r the  Following subsections  2.1.1.4.) w i l l  oct-3-enonate 172  i s also consistent with  deal with  the  stereochemistry  (2.1.1.1., 2.1.1.2.,  d e a l w i t h s e v e r a l a d d i t i o n products  i n S e c t i o n 3, a i r o x i d a t i o n products  of  the  of 172 w i l l  be  explored. The methyl oct-3-enonate 172 has been s y n t h e s i s e d f o l l o w i n g the method o u t l i n e d above and  i n h i g h e r y i e l d s under m o d i f i e d  (see S e c t i o n 2.1.3.). In each case, one of  172  of  the m i x t u r e ) and  silica  predominated  gel.  ( u s u a l l y ^95%  the same geometric  as determined by  can be p a r t i a l l y  For convenience,  and  conditions  the n.m.r. spectrum  r e s o l v e d by column chromatography  the n.m.r. spectrum of the major  ( v i d e i n f r a ) w i l l be d i s c u s s e d ; however, the important  on  (Z)-isomer  and r e s o l v a b l e  resonances of the minor (E)-isomer w i l l be d e a l t w i t h when the assignment i s d i s c u s s e d .  isomer  geometric  With the a n t i c i p a t e d a d d i t i o n of sodium a z i d e  to  the double bond  (see I n t r o d u c t i o n : S e c t i o n 3.1.)  and  the known r e a c t i v i t y  of  o r g a n i c a z i d e compounds (e.g., f o r m a t i o n of n i t r e n e s or  1,3-dipolar  162 c y c l o a d d i t i o n s to u n s a t u r a t e d spectrum  (see F i g u r e  unsaturated  5)  compounds;, the assignment of the n.m.r.  of f a s t e r - m o v i n g  compound 172 was  not  chromatographic component to the  immediately  clear  s i n c e the v i n y l i c  protons  I  J  I .  •  •  •  I  .  •  •  i  i  I  i  I i  i  I  i  I  i—_i u_J i  i i i  i  I  ;  I  II  I  ;  I  i  I i  i  I_J—I—t—i—i—i—I—•—i—•—i—I—i—•—i—i—I  i  l  l  I  i  i  ure 5A. P a r t i a l 100 MHz P r o t o n N.M.R. Spectrum o f Methyl (E,Z)-4,7-anhydro-8-0b e n z o y l - 2 , 3 - d i d e o x y - 5 6 - 0 - i s o p r o p y l i d e n e - g - r i b o - o c t - 3 - e n o n a t e (172). A 5:95 r a t i o o f t h e E- to Z-isomers i n CDC1.,. t  X  172  F i g u r e 5B. P a r t i a l 100 MHz Proton N.M.R. Spectrum of Methyl (E,Z)-4,7-anhydro-8-0b e n z o y l - 2 , 3 - d i d e o x y - 5 , 6 - 0 - i s o p r o p y l i d e n e - D - r i b o - o c t - 3 - e n o n a t e (172) . A 55:45 r a t i o o f the E- to Z-isomers i n CDC1~. o o  101  of  the s t a r t i n g m a t e r i a l  i.r.  no l o n g e r p r e s e n t nor d i d the  spectrum i n d i c a t e the presence of an carbon double-bond  Moreover, ABX  (see F i g u r e 5) was  the n.m.r. spectrum showed a r e l a t i v e l y l o w - f i e l d  (vide  infra).  methylene  p a t t e r n at c a . 63.12; however, the spectrum d i d not i n d i c a t e  any  s o r t of d i m e r i z a t i o n s i n c e the methyl groups were sharp s i n g l e t s  and  H-8  appeared as a d o u b l e t .  The spectrum a l s o i n t e g r a t e d f o r the same  number o f protons as the s t a r t i n g m a t e r i a l .  The i d e n t i f i c a t i o n of t h i s  component as the 3-ene isomer of the s t a r t i n g m a t e r i a l enabled the a s s i g n ment of the broadened allylic  d o u b l e t 65.03 to H-5  c o u p l i n g w i t h H-3  which was  w i t h the broadening due to  present as a p s e u d o - t r i p l e t at 64.82.  I t might a l s o be suggested t h a t presence of the hydrogens  of C-8  as a  d o u b l e t i n d i c a t e s an a v e r a g i n g of environments of these d i a s t e r e o m e r i c hydrogen  due to f r e e r r o t a t i o n about the C-7/C-8 bond  (observed i n 178  also). The i . r . spectrum of 172 e x h i b i t e d a s p l i t t i n g of the c a r b o n y l absorbances w i t h the h i g h e r frequency band at 1743  cm ^ i n d i c a t i n g  the  159c d e c o n j u g a t i o n o f the methyl e s t e r . absorbance of the 2-enonate 1_8 was of  a s h o u l d e r a t c a . 1710  shift  of the double-bond  The carbon-carbon double bond no l o n g e r r e s o l v a b l e but the presence  cm ^ might be a t t r i b u t a b l e to an up-frequency  to d e c o n j u g a t i o n i n the presence of 9d „ . . , 1 0 2 an e l e c t r o n e g a t i v e s u b s t i t u e n t . Goodman and coworkers reported v  a b s o r p t i o n a t c_a. 1700 the  above assignment  •  due  1 5  cm ^ f o r the e x o c y c l i c e n o l i c a c e t a l 9_2;  an  therefore,  appears v a l i d .  The mass spectrum o f the two u n s a t u r a t e d sugars 1_8 and 172 a l s o warrant direct 2.0  comparison.  The peak r a t i o s of the f i r s t  f o u r ions are 1.0:0.4:1.0:  f o r the 3-ene 172 and 1.0:21.5:12.2:11.2 f o r the 2-ene 18  (m ) , (m -CH^), (m -OCH^), and  (m - a c e t o n e ) , r e s p e c t i v e l y .  representing  Clearly,  the  102  s t a b i l i t y o f the m o l e c u l a r i o n of 172 i n d i c a t e s the s t a b i l i z i n g of  the e n o l i c system i n forming an a l l y l i c  cationic  effect  radical.  The assignment o f t h e geometric c o n f i g u r a t i o n o f t h e 3-ene 172 i s p r i m a r i l y based on c h e m i c a l s h i f t l e s s e r e x t e n t , on the a l l y l i c  of the e n o l i c hydrogen H-3 and, to a  hydrogen H-5.  H-3 of the major  isomer  r e s o n a t e s a t 64.82, the assignment o f which i s confirmed by i r r a d i a t i o n of  the p a i r o f d o u b l e t s o f d o u b l e t s a t £ a . 63.12 (H-2a and H-2b) which  c o l l a p s e s t h e p s e u d o - t r i p l e t o f H-3 t o a s i n g l e t . H-3 o f the minor  isomer 163  resonates at l o w e r - f i e l d from t h e a l k o x y l  (ca. 65.08).  S i n c e the net s h i e l d i n g  effect  (0.7) and a l k o x y m e t h y l ( i . e . , C-5) groups of the e n o l i c  system on H-3 i n the Z-isomer  ( i . e . , f u r a n o i d oxygen and C-2 a r e c i s ) i s  expected t o be g r e a t e r than t h a t of the E-isomer, we can t e n t a t i v e l y the  isomer w i t h t h e h i g h e r - f i e l d H—3 resonance to the Z-isomer  isomer p r e d o m i n a n t l y formed). from t h e c h e m i c a l s h i f t  assign  ( i . e . , the  Secondary support f o r t h i s assignment comes  of the H-5 s i g n a l , i n the minor isomer which has  been t e n t a t i v e l y a s s i g n e d the E - c o n f i g u r a t i o n i n which C-5 and C-2 a r e i n a c i s - r e l a t i o n s h i p H-5 r e s o n a t e s a t l o w e r - f i e l d . might be a t t r i b u t e d C-2.  This down-field s h i f t  t o a s t e r i c d e s h i e l d i n g of H-5 by the s u b s t i t u e n t s on  A l t h o u g h the s t e r i c d e s h i e l d i n g of the C-2 hydrogen a r e not c l e a r l y  e v i d e n t , the d o w n f i e l d s h i f t  o f t h e methyl e s t e r i s c l e a r l y seen,  indicating  a mutual d e s h i e l d i n g o f the c i s - g r o u p s . C o n f i r m a t o r y e v i d e n c e f o r the geometric assignment of the isomers was sought i n t h e carbon-13 n.m.r. spectrum of the two isomers.  I t has been  observed t h a t a-carbons i n c i s - o l e f i n s a r e a p p r e c i a b l y s h i e l d e d 164 to  those i n the corresponding trans-isomers.  showed a d o w n - f i e l d s h i f t from the major  f o r C-2 and an u p - f i e l d  relative  The C-13 n.m.r. spectrum shift  f o r C-5 i n going  ( p r e v i o u s l y a s s i g n e d ^ - i s o m e r ) to minor E-isomer;  therefore,  103  this result geometric  cannot be c o n s i d e r e d d i r e c t  assignment.  literature  c o n f i r m a t o r y evidence  However, i t should be p o i n t e d out t h a t  f o r the although  i n f o r m a t i o n on s u b s t i t u t e d e n o l e t h e r s i s l a c k i n g , the i n -  f l u e n c e o f c i s - m e t h y l groups i s known and, t h e r e f o r e , i r r e g a r d l e s s of the r e l a t i v e e f f e c t o f the c i s - and t r a n s - a l k o x y l group on C-2, C-5 should experience  the s t e r i c  s h i e l d i n g of C-2 with r e s p e c t t o i t s i n t e r a c t i o n  w i t h H-3 i n t h e _E- and _Z-isomers of 3-enonate 172, r e s p e c t i v e l y . the anomolous r e s u l t s of t h e C-13 n.m.r. spectrum p a r t i a l l y Z-assignment o f t h e major The results  from a requirement  i s o m e r i z a t i o n presumably  i n which the i r - o r b i t a l s of  a,8-unsaturated  e s t e r 18_ must be p a r a l l e l w i t h the C-4/H-4 bond i n order of C-4.  support the  isomer.  s t e r e o s e l e c t i v i t y of t h i s b a s e - c a t a l y z e d  deprotonation  Therefore,  T h i s requirement  of 118, one l e a d i n g t o the E-extended  to e f f e c t  a l l o w s f o r two p o s s i b l e  conformations  e n o l a t e 180 and the other to the Z-  6a extended e n o l a t e 181.  Models s t u d i e s of 18_ suggest  p r e c u r s o r t o t h e EJ-enolate 180 e x p e r i e n c e s  t h a t the c o n f o r m a t i o n a l  greater s t e r i c  i n t e r a c t i o n with  C-5 ( t h e r e f o r e , h i g h e r energy t r a n s i t i o n s t a t e ) than the c o r r e s p o n d i n g p r e c u r s o r to 181 which l e a d s t o a predominance of Z-enolate Z-isomer o f 172 ( i . e . , . t h e predominant  isomer  isolated).  181 and the  104  4 E - 3 - e n e , 172  18  Me  178  > 1" ~ » Ul 3  <  Scheme  XXIV  As can be seen from t h e above scheme, the o r i g i n a l carbon bond i s now p a r t o f a conjugated bond i s made e a s i e r .  e n o l a t e system  steric instability to a r o t a t i o n about  double-  and r o t a t i o n about  C-2/C-3  The t r a n s - o r _E s t a r t i n g m a t e r i a l JL8 l e a d s d i r e c t l y  t o a t r a n s o i d or s - t r a n s c o n f o r m a t i o n  of Z-18.  ene  (180 and 181) w h i l e the i n h e r e n t  o f the c i s o i d or s - c i s c o n f o r m a t i o n p r o b a b l y l e a d s C-2/C-3 i n the t r a n s i t i o n s t a t e i n the d e p r o t o n a t i o n  The h i g h degree  o f thermodynamic i n s t a b i l i t y o f 182 (and i t s E-  analogue) then g i v e a p r o b a b l e e x p l a n a t i o n f o r the s t e r e o s e l e c t i v e s y n t h e s i s of t h e _Z-isomer  o f 178.  A l t h o u g h the i s o m e r i z a t i o n and e l i m i n a t i o n r e a c t i o n i n v o l v e d here i s 21 r a t h e r u n u s u a l , t h e r e i s precedent  f o r such a s t e r e o s e l e c t i v e d u a l  r e a c t i o n t a k i n g p l a c e w i t h analogous  compound such as 22 (see I n t r o d u c t i o n ,  S e c t i o n 1.1.).  The l a c k o f any a z i d e a d d i t i o n p r o d u c t s here might be due  t o t h e ease i n which t h e a c y c l i c a c t i v a t i n g groups i n 1_8 and 22 a l i g n themselves w i t h the a c t i v a t e d hydrogen l e a d i n g t o ready  deprotonation  whereas compound 4JS ( I n t r o d u c t i o n , S e c t i o n 2.1.) r e q u i r e s a s t r a i n e d c o n f o r m a t i o n t o a c h i e v e the same alignment.  ring  A l s o , 8-azido c a r b o n y l compounds  105  have been r e p o r t e d ^ 1  to r e g e n e r a t e  to be  f a i r l y unstable  and  undergo B - e l i m i n a t i o n  the a,B-unsaturated c a r b o n y l p r e c u r s o r .  e q u i l i b r i u m between the s t a r t i n g m a t e r i a l 1_8 and have o c c u r r e d w i t h the i s o m e r i z a t i o n and consuming s t a r t i n g m a t e r i a l .  The  g i v e any  18 nor  178.  an a z i d o adduct might  elimination reaction irreversably  S e v e r a l d e r i v a t i v e s of 172 w i l l now  Hydrogenation of 18 and  172  and  183  and  184,  i n separate  to g i v e Methyl 4,7-anhydro-8-0(and a l t r o ) - o c t o n a t e  of the methyl oct-2-enonate 1J3 and  reductions  respectively.  compound w i l l be d e s c r i b e d the two  described  (184), r e s p e c t i v e l y .  C a t a l y t i c hydrogenation enonate 172  be  reported.  benzoyl-2,3-dideoxy-5,6-0-isopropylidene-ot-D-allo (183)  be  under the same c o n d i t i o n s as JL8 does  b e f o r e m o d i f i c a t i o n s to t h i s r e a c t i o n are 2.1.1.1.  an  i s o m e r i z a t i o n r e a c t i o n i s presumed to  i r r e v e r s a b l e s i n c e treatment of 172 not  Therefore,  The  gave two  epimeric  saturated  c h a r a c t e r i s t i c changes i n each  first  before  a direct  oct-3compounds starting  comparison i s made between  products.  BzO-, | ^ / S ^  C  0  2  M  e  H -fti/C^ 2  18  The  v i n y l i c hydrogens of 1J3 were no  spectrum of the hydrogenation m u l t i p l e t s were present of t h i s compound was  product,  at c_a. 61.96  l o n g e r present  183,  and  and  2.44.  two The  i n the n.m.r.  high-field  methylene  stereochemical  e x e m p l i f i e d by t h r e e sharp methyl resonances.  purity The  159c i.r.  spectrum showed a s m a l l s h i f t  1738  cm  1  ( c f . 1730  of 18)  bond a b s o r p t i o n at 1672  and  cnT^.  i n the s a t u r a t e d methyl e s t e r to  a d i s a p p e a r a n c e of the carbon-carbon double  106  C0 Me  B  z  0  2  H /Pd-^ 2  CC^Me  The  hydrogenation  product  184,  the  'a'-analogue of 183,produced a  n.m.r. spectrum i n d e u t e r o c h l o r o f o r m which i n d i c a t e d and the C-2  methylene  to _ca_. 62.58 and  a new  r e t a i n e d the c l o s e d o u b l e t  the methyl e s t e r and  1727  cm  moderate s h o u l d e r at 1710  cm  Both s a t u r a t e d compounds 183 at 364  singlets.  was  and  f o r the c a r b o n y l s  no  184  longer  (1738  As seen above,the c a r b o n y l absorbances are n e a r l y  i n the i . r .  spectrum of these compounds. f o r 183  and  184,  and  p u r i t y of the two  d i f f e r e n c e s and  identical  o t p i c a l r o t a t i o n of  these  respectively. This result  i n d i c a t e s a v e r y low c o n t r i b u t i o n of c h i r a l c e n t r e a t C-4 r o t a t i o n of the a n o m e r s . T h e  ions  acylium  fragments.  and -9.0°  the  e x h i b i t weak m o l e c u l a r  The  for  present.  i n the mass spectrum and v e r y s t r o n g acetoxonium and  anomers are -11.4  n  The i . r .  ^ f o r the benzoate, c f . above) but (C=C)  shift i  methylene m u l t i p l e t a t ca_. 62.08.  The methyl groups of 184 were a l s o present as sharp spectrum of 184  up-field  t o the  above i n f o r m a t i o n shows the  overall  similarity  compounds, t h e r e f o r e , t h e r e i s a need to show t h e i r  probable  stereochemistry. 85  Based on m e c h a n i s t i c a r e formed i n the two stereochemistry  3-enonate 172  grounds  and  hydrogenations,  ( i . e . C-4)  on the f a c t  the  away from the C^-isopropylidene) to g i v e the s p e c t r a of these two  assignment.  H-4  resonates  r e s p e c t i v e l y . As was  The  from the l e a s t h i n d e r e d  i n the n.mr.  seen w i t h the a and  4.07  hydrogenation 102 185 side  'a-anomer'.  'anomeric' isomers  of 63.93 and  products  '8-anomer' 18_ should r e t a i n i t s  a f t e r hydrogenation.  should proceed  that d i f f e r e n t  '  of  the  (i.e.,  The d i f f e r e n c e s  support  the above  f o r compounds 183  8-dihydroshowdomycin  and  184,  acetonides  107  ( S e c t i o n 1.2.2.) the  'anomeric' proton  c o n s i s t e n t l y d o w n f i e l d of the  of the  chemical s h i f t  the  ( i . e . , compd. 183)  ' a ' - c o n f i g u r a t i o n (eg. D - a l t r o ) and  configuration.  'a-anomers' are  '8-anomers'.Therefore,  g e n a t i o n product of the 3-enonate 172 a s s i g n e d the  (H-4)  A d d i t i o n a l s u p p o r t i v e evidence  can be  compound 184  i s a l s o found  184.  In the  '8-anomer' 183  'a-anomer' 184  are separated by 17 Hz.  w i t h the l a r g e r chemical s h i f t isopropylidenated the  i n the 0-isopropyof the  of the gem-dimethyls  This difference i s consistent  d i f f e r e n c e s of the gem-dimethyl groups of  8-C-glycosides.  'a-anomer' 184  '8'-  the resonances  gem-dimethyls a r e s e p a r a t e d by 20 Hz w h i l e the resonances the  tentatively  the  d i f f e r e n c e s of the gem-dimethyl groups of the  l i d e n e group of 183 and  of  hydro-  Although not as s i g n i f i c a n t  shows a more p o s i t i v e r o t a t i o n expected  alone ^, 1  f o r an  a,8-pair  , , , 53,167,168 of anomers . 2.1.1.2.  Methyl  (methyl  8-0-benzoyl-3-(chloromercuri)-2,3-dideoxy-  5,6-0-isopropylidene-a-D-altro-4-octulofuranosid)onate When a s o l u t i o n of the methyl was  oct-3-enonate  172  (185)  i n a b s o l u t e methanol  t r e a t e d w i t h m e r c u r i c a c e t a t e f o l l o w e d by sodium c h l o r i d e , the chromato-  graphed r e a c t i o n mixture  r e a d i l y gave c r y s t a l l i n e 185  from a methanol  solution.  1)  Hg (0Ac)o_  ^ ° \  V  A  s  ^ C 0  2  M e  2) NaCl  The  c a r b o n y l r e g i o n i n the i . r . spectrum  the s h o u l d e r at 1710 mass spectrum to  cm  1  due  of 185  indicated  to the carbon-carbon  the l o s s of  double bond and  e x h i b i t e d a complex p a t t e r n at the a n t i c i p a t e d  the i s o t o p e s of c h l o r i n e and mercury.  The  the  regions  chemical a n a l y s i s  was  due  108  c o n s i s t e n t w i t h the e m p i r i c a l formula of 185 and the n.m.r. e x h i b i t e d f o u r sharp methyl  spectrum  resonances.  The predominance o f the g - D - a l t r o isomer i s expected on m e c h a n i s t i c grounds.  As i n the h y d r o g e n a t i o n of 172 (predominantly Z-isomer), the  5 , 6 - 0 - i s o p r o p y l i d e n e group  i s expected  to h i n d e r the approach  of the  m e r c u r i c reagent from the a - f a c e t o g i v e the i n t e r m e d i a t e 'i3'-3,4mercurium i o n which l e a d s to the methyl a - D - a l t r o - g l y c o s i d e 185 from an 4 overall trans-addition  to the double bond of the ^-isomer  the a - D - a l l o - g l y c o s i d e would form from the E-isomer  o f 172  (i.e.,  of 172). The attempted  r e d u c t i v e - d e m e r c u r a t i o n of 185 i s d e s c r i b e d i n the next s u b s e c t i o n . 2.1.1.2.1. Treatment  Reduction of 185 w i t h Sodium Borohydride to Y i e l d 172 o f an e t h a n o l i c s o l u t i o n of the organomercury compound 185  w i t h sodium b o r o h y d r i d e r e s u l t e d  i n the expected p r e c i p i t a t i o n of elemental  mercury; however, the sugar d e r i v a t i v e i s o l a t e d a f t e r column chromatography 4 proved not t o be the c o r r e s p o n d i n g methyl g l y c o s i d e  but a product  arising  from a r e d u c t i v e - e l i m i n a t i o n to r e g e n e r a t e the e n o l i c p r e c u r s o r 172 of 185.  The n.m.r. spectrum  of the d i f f e r e n t  fractions isolated  from column  chromatography i n d i c a t e d an enhancement of the weak s i g n a l s present i n compound 172 p r e v i o u s l y  isolated.  These enhanced s i g n a l s were a t t r i b u t e d  to the E-isomer  o f 172 and were predominant  i n the f a s t e r - m o v i n g p o r t i o n  of the e l u e n t .  E x p e c t e d l y , the o p t i c a l r o t a t i o n of an 55:45 molar  ratio  109  of the E - t o Z-isomers e x h i b i t e d predominantly  the same s t r o n g n e g a t i v e r o t a t i o n of a  (^95%) Z-mixture of 172(-167 and -156, r e s p . ) .  The o v e r a l l  r a t i o of the E_- t o Z-isomer of 172 was found to be 42:58. The d e - a l k o x y m e r c u r a t i o n r e a c t i o n i s u s u a l l y accomplished under 82b a c i d i c c o n d i t i o n s and w i t h a h i g h degree o f s t e r e o s e l e c t i v i t y  ;  t h e r e f o r e , the e l i m i n a t i o n seen here must proceed by a d i f f e r e n t mechanism. 2.1.1.3.  M e t h y l (methyl  8-0-benzoyl-3-bromo-2,3-dideoxy-5,6-0-  i s o p r o p y l i d e n e - a - D . - a l t r o - 4 - o c t u l o f u r a n o s i d ) o n a t e (186) 4 5 169 Bromomethoxylation  o f a 95 t o 5 m i x t u r e o f the Z t o E-isomers  ' '  of the methyl oct-3-enonate 172 i n a methanol  s o l u t i o n i n the presence of  s i l v e r carbonate produced a m i x t u r e of adducts which a f t e r column graphy on s i l i c a  g e l gave a major component  a s s i g n e d the a - D - a l t r o - g l y c o s i d e 186.  (41% y i e l d ) which i s t e n t a t i v e l y  S e v e r a l slower-moving minor  were a l s o i s o l a t e d , but due to t h e i r thermal i n s t a b i l i t y , turned  chromato-  components  the c l e a r syrups  i n t o b l a c k t a r s b e f o r e any s p e c t r a l a n a l y s i s could be i n i t i a t e d .  The n.m.r. spectrum of 186 e x h i b i t e d a c l e a r l y d e f i n e d ABX system f o r H-2 and H-3 and showed f o u r sharp methyl resonances.  The i . r .  spectrum  a g a i n showed a l o s s of the s h o u l d e r at 1710 cm ^ i n the c a r b o n y l band but more s i g n i f i c a n t l y ,  the mass spectrum of 186 i n d i c a t e d a t r a c e m o l e c u l a r  i o n and s t r o n g acetoxium i o n d o u b l e t s ( i . e . due to Br 79 and 81) and a v e r y s t r o n g s i n g l e t a t 307 (m -CHBrCH C0 Me) due to the C-4 s t a b i l i z e d +  2  carbonium 186  i o n from a C-3/C-4 c l e a v a g e .  2  The s t e r e o c h e m i c a l assignment of  i m p l i e s an o v e r a l l t r a n s - a d d i t i o n o f the reagents which have been  observed  f o r o t h e r e n o l i c sugars."'  110  85d 2.1.1.3.1.  Attempted  Hydrogenolysis  o f 186.  When the bromoglycoside 186 was hydrogenated  i n m e t h a n o l i c potassium  h y d r o x i d e i n t h e presence of 5% p a l l a d i u m on c a r b o n " ^ , t . l . c . o f the 0  r e a c t i o n m i x t u r e showed lower  p l u s b a s e - l i n e m a t e r i a l s but none of these  c o u l d be c l e a r l y r e s o l v e d and f u r t h e r attempts t o i s o l a t e the p r o d u c t s were not i n i t i a t e d . debrominated  A l s o , none of the components had the R^ of the expected  methyl  glycoside.  2.1.1.4. M e t h y l ( m e t h y l 8 - 0 - b e n z o y l - 2 , 3 - d i d e o x y - 5 , 6 - 0 - i s o p r o p y l i d e n e B - D - r i b o - 4 - o c t u l o f u r a n o s i d ) o n a t e (187) When a s o l u t i o n o f the methyl oct-3-enonate _E t o Z-isomers)  i n p y r i d i n e , a c e t i c a c i d , methanol,  to stand f o r s e v e r a l months, a h i g h R^ band from the myriad  172 (95:5 mixture of the and water was allowed  ( r e l a t i v e t o 172) was i s o l a t e d  of p r o d u c t s to g i v e the methyl g l y c o s i d e 187.  The i . r . and  MeOH 1 2 2  n.m.r. s p e c t r a were c o m p l e t e l y c o n s i s t e n t w i t h the proposed mass spectrum possessed t h e acetoxonium carbonium  fragment  fragment  and  o f the anomeric  coworkerwho  substituents  p l u s the C-4 s t a b i l i z e d  a t 307 (m^-Ci^C^CX^Me).  Since the methyl g l y c o s i d e was formed the assignment  s t r u c t u r e . The  under e q u i l i b r i u m  conditions,  c e n t r e (C-4) i s based on t h e work of M o f f a t t  found that fused five-member r i n g s w i t h e p i m e r i z a b l e  ( i . e . C-glycosides of 2,3-0-isopropylidene-D-ribofuranose)  under e q u i l i b r i u m c o n d i t i o n s p r e f e r a c i s - o r i e n t a t i o n of the i s o p r o p y l i d e n e and  t h e 'non-polar' group.  The study a l s o i n d i c a t e d  that these g l y c o s i d e s  Ill  with polar substituents relationship.  (e.g., OH,OR,CIjNl^) p r e f e r to adopt a 1,2-trans-  These r e s u l t s are a l s o c o n s i s t e n t w i t h the v a r i o u s d e r i -  v a t i v e s of D - p s i c o s e . F o r  example, the main component i n a e q u i l i b r i u m  m i x t u r e of D - p s i c o s e i n acetone i s 1,2 :3,4-di-_0-isopropylidene-B-Dpsicofuranose  (188).  T h e r e f o r e , the methyl g l y c o s i d e i s o l a t e d configuration.  i s t e n t a t i v e l y a s s i g n e d the  The chemical s h i f t s of H-5  a l s o support t h i s assignment  and H-6  (64.49 and 4.79,  (see S e c t i o n 3.1.2. f o r d i s c u s s i o n of  8resp.)  this  topic).  2.1.2. to Y i e l d  A d d i t i o n of H y d r a z o i c A c i d to the Methyl oct-2-enonate 172 and M e t h y l  4,7-anhydro-3-azido-8-0-benzoyl-2,3-dideoxy-  5,6-0-isopropylidene-D-glycero-D-allo, altro-octonate Due  18  (189).  to the l a c k of a d d i t i o n p r o d u c t s i n s e c t i o n 2.1.1., the o r i g i n a l 72  procedure of Rosenthal and R a t c l i f f e obtain used.  (see I n t r o d u c t i o n , S e c t i o n 3.1.)  azido-compounds from an u n s a t u r a t e d i s o p r o p y l i d e n a t e d  sugar  to  was  T h e r e f o r e , treatment of the 2-enonate 1_8_ i n N,N-dimethylformamide  with hydrazoic acid  i n the presence of "sodium  e p i m e r i c m i x t u r e of the 3-azido compounds 189.  a z i d e produced  the expected  Chromatography of the  worked-up r e a c t i o n m i x t u r e gave one major band, the n.m.r. spectrum of which  i n d i c a t e d a mixture of s i m i l a r compounds (e.g., s i n g l e t s f o r the  i s o p r o p y l i d e n e methyls and a c l o s e doublet  (^2  of the epimers of 189)  (<10%) of the methyl  p l u s a s m a l l amount  Hz) f o r the methoxyl  methyl  oct-3-enonate  172  as evidenced  c a . 63.05 and  by the presence of i t s H-2  3.50,  a s t r o n g doublet  respectively.  at 2110  and  2140  The cm  1  i.r.  and methoxyl methyl s i g n a l at spectrum of t h i s band  possessed  i n d i c a t i n g the presence of  two  143c a z i d o components. corresponding Two  The  e p i m e r i c a z i d e s were i s o l a t e d pure as  their  amino d e r i v a t i v e s ( f o l l o w i n g s u b s e c t i o n ) .  other minor impure components were a l s o i s o l a t e d and were l a t e r  ( S e c t i o n 2.1.3.) shown to be  2.1.2.1.  the d e s i r e d a - d i a z o - e s t e r s 192  and  193.  M e t h y l 3-amino-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-  O-isopropylidene-D-glycero-D-allo  (and a l t r o ) - o c t o n a t e (190)  Hydrogenation of the contaminated  (with 172)  epimeric azido  and  (191) .  mixture  72 189  i n the presence of 5% p a l l a d i u m on c h a r c o a l as c a t a l y s t  corresponding  amino compounds 190  geneous m i x t u r e . was  The  and  191  as a c h r o m a t o g r a p h i c a l l y  n.m.r. spectrum of t h i s mixture  in  191  (see S e c t i o n 2.1.3.1.). The  homo-  deuterochloroform  e n t i r e l y c o n s i s t e n t w i t h a composite spectrum made up  amines 190 and  gave the  from the  individual  composite spectrum a l s o i n -  d i c a t e d a predominance (^67%) of the D - g l y c e r o - D - a l l o  epimer  (e.g.,  3-S-  isomer; see S e c t i o n 2.1.3.) 190 which might e x p l a i n the s t r o n g e r band a t 2140  cm  1  of the a z i d o doublet  i n the i . r .  spectrum of 189.  i n d i c a t e s a s m a l l degree of s t e r e s e l e c t i v i t y r e a c t i o n which was and  1.2.2.).  This  result  in this nucleophilic addition  l a c k i n g i n the photoamidation  r e a c t i o n ( S e c t i o n s 1.1.3.1.  113  190,191 2.1.3. A d d i t i o n of Sodium A z i d e  to 18 to g i v e 172,  189,  and  Methyl  3-amino-4,7-anhydro-8-0-benzoyl-2-diazo-2,3-dideoxy-5,6-0-isopro pylidene-B-glycero-D-allo  (and a l t r o ) - o c t o n a t e (192)  and  (193),  respectively. With the p r o d u c t i o n  of s m a l l q u a n t i t i e s of lower  2.1.2.) which showed a b s o r p t i o n bands at ca_. 2100  cm  compounds ( S e c t i o n the r e s u l t s which  72 p a r a l l e l those modified  of Rosenthal  and  to i n c r e a s e the y i e l d  Ratcliffe  , the a d d i t i o n r e a c t i o n  of these minor components but  was  keeping i n  mind the s u s c e p t a b i l i t y of the s u b s t r a t e to e l i m i n a t i o n of acetone. optimum c o n d i t i o n s f o r the s y n t h e s i s of the using hydrazoic s o l v e n t was were s t i l l  a c i d , excess sodium a z i d e , and  determined very  low,  (see E x p e r i m e n t a l ) but  9 and  methyl oct-3-enonate 172 running 189. and  a - d i a z o - e s t e r s , 192  p o r t i o n was  6%,  and  of  192  The main product  and was  (^70%), of which the c h r o m a t o g r a p h i c a l l y  contaminated w i t h  the h y d r a z o i c  192  and  a c i d by  193.  193 the  faster-  s m a l l p o r t i o n s of the a z i d o m i x t u r e  H i g h e r c o n c e n t r a t i o n of the a c i d produced l a r g e r p o r t i o n s of decreased  193,  N,N-dimethylformamide as the y i e l d  respectively.  The  189  Lower c o n c e n t r a t i o n s of a c i d , replacement 172  excess ammonium c h l o r i d e  of  or the usage of hexa-  methylphosphoramide as c a t a l y s t r e s u l t e d i n the e l i m i n a t i o n of acetone to g i v e 178 which has and  the same r e l a t i v e R^  a l s o r e s u l t e d i n lower y i e l d s of 192  (ether-hexane as d e v e l o p e r ) as and  193.  193  114  BzO-i  NaN1ft  (HN )  ljlH  3  * * *  2  192 R= A^COJMG ^s ^C0 Me  133 R=  n  J  -^X0 Mel 2  N  2  2  N  2  The two d i a s t e r e o m e r s 192 and 193 were e a s i l y s e p a r a b l e by column chromatography absorbances for  on s i l i c a  gel.  Both compounds showed c h a r a c t e r i s t i c  i n t h e i r i . r . s p e c t r a a t 3400, 3340, 2100 and 1698 cm  1  t h e primary amine, conjugated d i a z o , and a - d i a z o - c a r b o n y l e s t e r ,  „. , 72,143d,173 respectively. 1730  cm ^.  , . . , The benzoate c a r b o n y l remained unchanged a t  The n.m.r. spectrum o f b o t h possessed a broad  two-proton  D 0-exchangeable s i n g l e t a t c_a. 61.64 which c o n f i r m s the presence of the 2  primary amine.' ristic  The mass sepctrum of both d i a z o compounds showed c h a r a c t e -  fragments a t 377 (M -N ) and 362 ( M - N " M e ) . +  +  2  A t e n t a t i v e assignment  2  4 8 b  '  1 7 4  of the c o n f i g u r a t i o n a t C--3 i s based on  Brewster's R u l e s " ' and Hudson's Rules of I s o r o t a t i o n . "*"^ 1 7  The m o l e c u l a r  r o t a t i o n o f the h i g h and low R^ ( u s i n g 2:1 ether-hexanes as d e v e l o p e r ) 8-amino-a-diazo-esters  (on s i l i c a  g e l ) a r e -194 and + 8 4 ° ,  respectively.  A p p l i c a t i o n o f Hudson's Rules p r e d i c t s a v a l u e of -55° f o r the m o l e c u l a r r o t a t i o n o f a n o n - f u n c t i o n a l i z e d C-3 analogue o f the above epimers in  s t r u c t u r e 194.  depicted  An analogous compound to 194 i s compound 183 (see S e c t i o n  2.1.1.1.) which has a m o l e c u l a r r o t a t i o n of -41.5°.  T h i s c l o s e agreement  suggest an a p p l i c a t i o n o f Brewster's Rule t o the c h i r a l c e n t e r a t C-3 and if  t h e p o l a r i z a b i l i t i e s o f s u b s t i t u e n t s decrease i n the o r d e r C >C^>NH >H, 2  2  then Brewster's Rule p r e d i c t s a h i g h e r p o s i t i v e r o t a t i o n f o r the 3-S or  115  D-glycero-D-allo diastereomer.  The lower-R^ d i a z o compound 192 has the  g r e a t e r p o s i t i v e r o t a t i o n and i t i s t h e r e f o r e suggested to possess the 3-j>-configuration and t h e h i g h e r R^ d i a z o component 193, t h e c o r r e s p o n d i n g 3-R-configuration 2.1.3.1.  (i.e., D-glycero-D-altro).  Hydrogenation o f 192 and 193 to g i v e 190, 191 and Methyl  3-amino-A, 7-anhydro-8-0-benzoyl-3-deoxy-5,6-0-isopropylidene-p_glycero-D-allo  (and a l t r o ) - 2 - o c t u l o s o n a t e Hydrazone (195) and (196),  respectively. Hydrogenation  o f t h e d i a z o compounds 192 and 193 ( i n s e p a r a t e r e a c t i o n s )  i n the presence of p a l l a d i u m c a t a l y s t  gave the c o r r e s p o n d i n g B-amino compounds  190 and 191 (30 and 40%, r e s p . ) and B-amino hydrazones 16%,  resp.), r e s p e c t i v e l y . ^ 1 7  their  i.r. Both  1_95 and 196 (26 and  The s t r u c t u r e s were r e a d i l y deduced  from  and n.m.r. s p e c t r a . 8-amino compounds, 190 and 191, possessed the c h a r a c t e r i s t i c  a b s o r p t i o n bands a t 3405, 3340, 1740 and 1730 cm  1  f o r the primary  amine "^ 14  159c and  e s t e r s groups  sharp two-proton  i n their  i.r.  s p e c t r a . Both amines possessed  surprisingly  s i n g l e t s a t c a . 61.58 i n t h e i r n.m.r. s p e c t r a which  exchanged  w i t h D^O and, moreover, r e s o l v a b l e ABX systems were p r e s e n t f o r t h e new methylene  groups, t h e presence of which  The mass spectrum  caused an u p - f i e l d  shift  i n H-3.  of 190 c o n t a i n e d a s i g n i f i c a n t m o l e c u l a r i o n (m ) s i g n a l  p l u s a s t r o n g acetoxonium  +  fragment  (m^-CH^) a t 3 6 4 .  Chemical  1 4 1 b  analysis  f o r b o t h amines confirmed the e m p i r i c a l f o r m u l a s . The  s t r u c t u r e o f hydrazones  195 and 196 was deduced  primarily  from  t h e i r chromatographic m o b i l i t y , n.m.r. s p e c t r a and decomposition p r o d u c t s . Both hydrazones  have s i g n i f i c a n t l y  lower R^'s than 190 and 191 a f a c t  i s e x e m p l i f i e d by t h e presence of two broad, two-proton s i n g l e t s i n the n.m.r. s p e c t r a at c a . 61.78 and 8.40.  which  D20-exchangeable Compared to t h e i r  116  d i a z o p r e c u r s o r s , the n.m.r. spectrum of both hydrazones presented a broad r e s o l v a b l e d o u b l e t . d i a z o compound 192 a n a l y s i s but  was  syrups  c r y s t a l l i z a b l e and  of b o t h compounds 195  or reduced temperature (^5°) h i g h e r R^ m a t e r i a l w i t h compounds 190 h i g h e r R^  and  Hydrazone 195  191,  o r i g i n a t i n g from the gave the expected and  as  lower  chemical  s t o r e d at room temperature  would s l o w l y show i n c r e a s i n g amounts of a  i d e n t i c a l m o b i l i t i e s to that of the 8-amino respectively.  Chromatographic s e p a r a t i o n of  component gave n.m.r. s p e c t r a which were i d e n t i c a l  corresponding  to  this  the  8-amino compounds.  F? 190  R=  NH2 /  ^X^°  transformation  8-amino compounds 190  1_91  R=  191,  R= AT^CC^Me *H2%H  2  >^C0 Me _95 _ 2  of the hydrazones 195  and  \NH2  N2  ^Oc02Me|35 NH  The  196  H-3  and  1  A^C0 Me  R  196  2  to the  corresponding  r e s p e c t i v e l y , presumably occurs by a  mechanism s i m i l a r to t h a t of the Wolf f-Kishner"*^ ^ r e d u c t i o n .  The  i n t h i s reduction being  conditions  of the t r a n s f o r m a t i o n carbonyl  the primary amine at C-3  and  the m i l d  a t t r i b u t a b l e to the s t a b i l i z i n g e f f e c t  on the i n t e r m e d i a t e  anions.  base  of the e s t e r  Whether the r e d u c t i o n i s i n t r a m o l e -  c u l a r l y or i n t e r m o l e c u l a r l y c a t a l y z e d cannot be d i s t i n g u i s h e d a t t h i s (although  2  both pathways might be o p e r a t i n g s i m u l t a n e o u s l y ) .  the f o l l o w i n g scheme d e p i c t s the  intramolecular-route.  For  time  simplicity  117  2.1.3.2. (197)  Attempted Ring C l o s u r e of 195 w i t h N,N'-Carbonyldiimadazole  to g i v e  5-(S)-(5-0-Benzoyl-2,3-0-isopropylidene-B-ri-ribo-  furanosyl)-6-carbomethoxy-4,5-dihydro-2H-as-triazin-3-one (198). In a d e s i r e to s y n t h e s i z e an analogue of the C - n u c l e o s i d e  112 178 furin  '  pyrazo-  * (see I n t r o d u c t i o n , S e c t i o n 4.), i t was  hoped that the  d u c t i o n of a c a r b o n y l group i n the p r e p a r a t i o n of a six-membered system s t a r t i n g from the aminohydrazones 195 amenable to a r o m a t i z a t i o n and p y r a z o f u r i n . Thus, treatment 197  result  and  heterocyclic  196 would l e a d to  products  i n the s y n t h e s i s of an analogue of  of the c r y s t a l l i n e aminohydrazone 195  i n r e f l u x i n g t e t r a h y d r a f u r a n gave a major h i g h e r R^ product  has been t e n t a t i v e l y a s s i g n e d  intro-  s t r u c t u r e 198."^^'^  with  which  118  195 0 Me 2  198 The i . r . cm  1  1665  spectrum of 198 showed absorbances at 3410,  f o r the N-H cm  -1  s t r e t c h i n g and possessed a new  i n d i c a t i v e of a urea type compound.  3300 and 3270  c a r b o n y l absorbance a t  159g  The n.m.r. spectrum i n  DMSO-d^ c o n t a i n e d s e v e r a l l o w - f i e l d non-aromatic s i g n a l s , the lowest of which  (99.32) d i s a p p e a r e d q u i c k l y upon a d d i t i o n of D 2 O .  The methyl r e -  sonances were a l s o present as sharp peaks. The mass spectrum of significantly  showed s t r o n g fragments at 418,  the acetoxium i o n (m -CH ), the sugar fragment +  3  277 and 156  198  representing  ( i . e . , C-l'/C-5 c l e a v a g e )  and the a g l y c o n , r e s p e c t i v e l y . 2.2.  Attempted 2.2.1.  S y n t h e s i s of a  Treatment  Nitrate  V i c i n a l Diazido  Sugar  of 18 w i t h Sodium A z i d e and C e r i c Ammonium  (CAN). 178  The C - n u c l e o s i d e p y r a z o f u r i n a c t i v i t y and i t was the a g l y c o n might  (103)  possesses s t r o n g  thought t h a t a re-arrangement  antiviral  of the bond sequence i n  p r o v i d e i n t e r e s t i n g b i o l o g i c a l consequences.  the proposed mechanism of the a z i d o - n i t r a t i o n r e a c t i o n  Based  on  (see I n t r o d u c t i o n ,  S e c t i o n 3.2.8.) and on the work done by other r e s e a r c h e r on the a d d i t i o n of a z i d e r a d i c a l s t o u n s a t u r a t e d e s t e r s  (e.g., compd. 1_8 which  undergoes  a f r e e - r a d i c a l a d d i t i o n i n the photoamidation r e a c t i o n , see I n t r o d u c t i o n , S e c t i o n 2.1.), i t was  hoped that the treatment of the methyl oct-2-enonate 180 18 w i t h CAN and sodium a z i d e might g i v e a v i c i n a l d i a z i d o adduct which 112 178 might l e a d t o a s t r u c t u r a l isomer of p y r a z o f u r i n (103). ' Thus,  119  f o l l o w i n g the method d e s c r i b e d by R a t c l i f f e ^ " * , compound 1_8_ was w i t h CAN hours.  and  sodium a z i d e at -33  to -22°  T . l . c . of the r e a c t i o n mixture  treated  i n acetonitrile for fifteen  i n d i c a t e d 10 to 15%  of  s t a r t i n g m a t e r i a l w i t h two new  higher  of  the r e a c t i o n mixture on s i l i c a  g e l gave unreacted s t a r t i n g m a t e r i a l  (^73%) and  components.  consumption'  two minor components i n 8 and  m a t e r i a l and a z i d o a l l y l i c  2% y i e l d s  Chromatography  (based on  starting  s u b s t i t u t i o n , v i d e i n f r a ) w i t h the  moving component predominating.  The n.m.r. s p e c t r a of both  faster-  components  showed them t o be impure w i t h the presence of l o w - f i e l d v i n y l i c (16 Hz)  ( i . e . , an i s o l a t e d AB  system).  The  i . r . spectrum  -1 possessed  sharp bands and c a . 2120  cm  +  place.  The  of both  components  143c (-N^)  and  possessed a s t r o n g mass s p e c t r a l peaks at 388 361(m -N2) s u g g e s t i n g a l l y l i c  doublets  the major component  (nf^-CH^), 375(m -N2), and +  s u b s t i t u t i o n r a t h e r than a d d i t i o n  low y i e l d s of these impure p r o d u c t s and  took  the l a c k of any  isolated  181 a d d i t i o n products 3.  p r e c l u d e d f u r t h e r work on t h i s  O x i d a t i o n and H y d r a t i o n P r o d u c t s of Methyl  reaction.  (E,Z)-4,7-anhydro-8-0-  benzoyl-2,3-dideoxy-5,6-0-isopropylidene-D-ribo-oct-3-enonate The  3-enonate 172,  (172).  o b t a i n e d by a b a s e - c a t a l y z e d i s o m e r i z a t i o n of the 20  methyl  oct-2-enonate  1_8_  (see S e c t i o n 2.1.1., 2.1.2., and  allowed t o stand i n a e t h e r a l s o l v e n t system  2.1.3.), when  or as a syrup exposed to  ambient c o n d i t i o n s (e.g., a i r , l i g h t , m o i s t u r e , room temperature) prolonged p e r i o d s w i l l s l o w l y r e a c t w i t h atmospheric 27b or  ether a u t o x i d a t i o n  products.  p r o d u c t s to g i v e a myriad  T h i s s e c t i o n w i l l present  of  for  m o i s t u r e , oxygen,  carbohydrate  ( i ) those c a r b o h y d r a t e p r o d u c t s which  have been i s o l a t e d pure,  ( i i ) p o s s i b l e mechanism of f o r m a t i o n , ( i i i ) a s s i g n -  ment o f s t e r o c h e m i s t r y ,  ( i v ) methods and  o b t a i n some o f these p r o d u c t s , and  r e s u l t s of r e a c t i o n s to s e l e c t i v e l y  (v) d e r i v a t i v e s of the k e t a l p r o d u c t s .  120  The o x i d a t i o n and h y d r a t i o n p r o d u c t s w i l l be presented i n order of chromatographic  m o b i l i t y , s t a r t i n g w i t h the f a s t e r - m o v i n g components  w i l l be f o l l o w e d by t h e i r c h e m i c a l s y n t h e s i s and  and  derivatization.  The r a t e o f the a u t o x i d a t i o n p r o c e s s i s dependent to the  carbon-  182 hydrogen bond s t r e n g t h s e t h e r s and,  of the s u b s t r a t e s and  i n p a r t i c u l a r , the C-2  to a u t o x i d a t i o n s i n c e the secondary allylic  the a - p o s i t i o n of  p o s i t i o n of the 3-enonate i s s u s c e p t a b l e hydrogens are  'a' to an c a r b o n y l and  to a s u b s t i t u t e d e n o l ether group. The  s u s c e p t a b i l i t y of 172 to 183 a u t o x i d a t i o n i s e x e m p l i f i e d by r e p o r t s of f a c i l e p e r o x i d e f o r m a t i o n or 102 oxidative polymerization  (e.g. compound 92) of s i m i l a r l y  activated  compounds. 3.1.  5-0-Benzoyl-2,3-0-isopropylidene-D-ribono-l,4-lactone  (199),  8-0-  Benzoyl-2,3-dideoxy-5,6-0-isopropylidene-8-D-ribo-4-octulofuranosono1,4-lactone  (200),  Methyl(E)-8-0-benzoy1-2,3-dideoxy-5,6-0-isopropy-  l i d e n e - g - D - r i b o - o c t - 2 - e n - 4 - u l o f u r a n o s o n a t e (201), Methyl  8-0-benzoyl-  2,3-dideoxy-5,6-0-isopropylidene-B-D-ribo-4-octulofuranosonate M e t h y l 8-0-benzoyl-2-deoxy-5,6-0-isopropylidene-ct,B-D-allo 4-octulofuranosonate When the methyl left  oct-3-enonate  i n the chromatographic  f i c a t i o n and  (203) and  (202),  (and  altro)-  (204), r e s p e c t i v e l y . 172,  c o n t a i n e d i n open t e s t - t u b e s , was  s o l v e n t (2:1 ether-hexanes)  used  for i t s puri-  the s o l v e n t s allowed to s l o w l y evaporate w h i l e exposed to  l i g h t and atmosphere of the room or when s t o r e d as a syrup i n a stoppered glass flask,  t.l.c.  of the remaining syrup u s i n g 2:1  d e v e l o p e r showed two major lower mediate and  lower R^  moving than 172).  products.  ether-hexanes  L e s s e r amounts of  c h a r r i n g m a t e r i a l s were a l s o observed  as inter-  ( a l l slower  P r e l i m i n a r y s e p a r a t i o n of the mixture was  g r a d i e n t e l u t i o n of the syrupy m i x t u r e on a column of s i l i c a  achieved by gel using  121  ether-hexanes.  The v a r i o u s bands were i s o l a t i o n and  w i t h s u i t a b l e s o l v e n t systems  (see E x p e r i m e n t a l ) to a c h i e v e s e p a r a t i o n  of some o f the many components. and 204 were i s o l a t e d  i n 3.5,  Thus, compounds 199, 200, 201, 202,  8.2,  0.3,  2.7,  4.5 and 17.6%  r e s p e c t i v e l y w i t h compounds 203 and 204 as the major mentioned  rechromatographed  203  yields,  lower R^ p r o d u c t s  above s i n c e compounds 172 and 199-202 possessed s i m i l a r  R^'s  u s i n g 2:1 ether-hexanes as d e v e l o p e r .  200 |>~0H,  COoMe 1  202  203  Y ^ 0 2 M « OH  Bz Y^C0 M<  |>~0H,  2  with  204  The i . r .  spectrum of the r i b o n o - 1 , 4 - l a c t o n e 199 gave a s t r o n g  a b s o r p t i o n of 1802  cm  1  i n d i c a t i n g the presence of the  five-membered  143a lactone ring.  The n.m.r. spectrum of 199 c l e a r l y showed the absence  of the methyl peak of the methyl e s t e r and showed the e a s i l y  resolvable  multiplet  The mass  of the r i b o - s u g a r p r o t o n s between 64.44 and 4.94.  spectrum of 199 possessed a weak s i g n a l a t 293 which was the p r o t o n a t e d parent m o l e c u l e and an extremely i n t e n s e fragement a t 277  (m -CH.j). +  The s t r u c t u r e of 199 was  a t t r i b u t e d to acetoxonium  a l s o proven by c h e m i c a l  122  synthesis.  Treatment  chloroperbenzoic acid  o f the methyl oct-3-enonate 172 w i t h excess meta(see I n t r o d u c t i o n , S e c t i o n 3.2.4.) or o x i d a t i v e  c l e a v a g e of the v i c i n a l hydroxy h e m i k e t a l s 203 or 204 w i t h p e r i o d a t e gave l a c t o n e 199.  The _sp_iro-lac tone 200 e x h i b i t e d  c a r b o n y l peak a t 1800 cm f i e l d methylene methyl group.  1  the c h a r a c t e r i s t i c i . r .  w h i l e the n.m.r. spectrum showed f o u r h i g h -  s i g n a l s at c a . 2.60 along w i t h t h e absence of the methoxy The mass spectrum a g a i n showed a t r a c e m o l e c u l a r i o n s i g n a l  (348) and a v e r y i n t e n s e acetoxium fragment  a t 333 (m -CH ). +  3  The u n s a t u r a t e d k e t a l 201 was i s o l a t e d as a syrup and gave broad a b s o r p t i o n bands at 3440 and 1720 cm c a r b o n y l groups, r e s p e c t i v e l y . tained 4.96  1  f o r the h y d r o x y l group and degenerate  The n.m.r. spectrum of 201 i n DMSO-d^ con-  t h r e e sharp methyl resonances and a p a i r of d o u b l e t s a t 64.56 and  f o r H-5 and H-6, r e s p e c t i v e l y .  based on a s l i g h t  The assignment  of the d o u b l e t s i s  broadening o f t h e l o w - f i e l d d o u b l e t a t t r i b u t a b l e t o a  s m a l l i n t e r a c t i o n w i t h H-7 and on the f a c t these d o u b l e t s a r e i n s i m i l a r p o s i t i o n s i n t h e n.m.r. spectrum of the s a t u r a t e d k e t a l 202 i n which the l o w - f i e l d doublet i s f u r t h e r s p l i t doublets  (J  by ca. 1.0 Hz.  Moreover,  two sharp  16.0 Hz) a t 66.14 and 6.87 (H-2 and H-3, r e s p . ) i n the  spectrum of 201 c o n f i r m s t h e presence o f an a,8-unsaturated e s t e r grouping i n t h e t r a n s - o r i e n t a t i o n " * " ^ and a sharp, D20-exchangeable, singlet  one p r o t o n  at 66.89 suggests the presence of a t e r t i a r y h y d r o x y l .  1 4  ^  a  The  mass spectrum showed a weak m o e l c u l a r i o n (378) and the a n t i c i p a t e d acetoxium fragment  at 363  (m -CH.j). +  The s a t u r a t e d k e t a l 202 produced a broad a b s o r p t i o n band at 3430 cm in  1  i t s i . r . spectrum i n d i c a t i n g the presence of a h y d r o x y l group. The n.m.r.  spectrum o f 202 i n DMSO-d, confirmed t h i s assignment o sharp, one-proton s i n g l e t  by the presence of a  at 66.16 which d i s a p p e a r e d upon a d d i t i o n of I^O;  123  moreover, two h i g h - f i e l d methylene groups a l o n g w i t h a doublet f o r H-5 a t 64.44 and doublet o f d o u b l e t s were a l s o p r e s e n t .  The mass spectrum  ( J , 6.0 Hz) 5,6 c  ( J , 1.0 Hz) f o r H-6 a t 64.86 o, / n  c o n t a i n e d the acetoxonium fragment  (m^-CH^) a t 365 and weaker fragment a t 363 (m -0H) due t o the l o s s of the +  C-4 h y d r o x y l and r e s u l t i n g The next  i n an C-4 oxo-carbonium fragment.  component i s o l a t e d was the h i g h e r  of 203 which was r e a d i l y c r y s t a l l i z e d i.r.  spectrum  v i c i n a l hydroxy B - k e t a l  from dichloromethane-hexanes.  o f 203 c o n t a i n e d a broader  and more i n t e n s e a b s o r p t i o n band  at 3480 cm ^ than the p r e v i o u s two k e t a l s which suggest more than one h y d r o x y l group.  possessed  a sharp, one-proton  The n.m.r. spectrum  singlet  The  the presence of  o f 203 i n DMSO-d, 6  and doublet a t 65.25 and 6.08,  r e s p e c t i v e l y , both of which disappeared  upon a d d i t i o n of D 2 O . H-6 and  H-5 were p r e s e n t as d o u b l e t s at 64.95 and ca_. 4.52, r e s p e c t i v e l y . T h i s assignment was confirmed by a comparison w i t h the n.m.r. spectrum i n d e u t e r o c h l o r o f o r m which showed H-6 t o be l o w e r - f i e l d , broadened (J^ g  6.0 Hz i n both s o l v e n t s ) .  produced  a splitting  inthemethyl  new s i g n a l s were a t t r i b u t e d presence  of which was caused  The n.m.r. spectrum resonances  t o the presence  of 203 doublet  of 203 i n DMSO-d^  upon a d d i t i o n of D 2 O . These of the a-anomer of 203, the  by the D20/HDO-catalyzed a n o m e r i z a t i o n of the  13b B-anomer o f 203.  The mass spectrum  and chemical a n a l y s i s c o r r o b o r a t e d  the a s s i g n e d e m p i r i c a l formula o f 203. The  syrupy,  major component  lower R^, v i c i n a l h y d r o x y - k e t a l 204 was i s o l a t e d as the (17.6%).  The major d i f f e r e n c e s between the two hydroxy-  k e t a l s 203 and 204 a r e t h e i r chromatographic form c r y s t a l s ,  their optical rotation  m o b i l i t y , t h e i r a b i l i t y to  (-29.1 and +9.27° f o r 203 and 204,  r e s p . ) and t h e i r n.m.r. s p e c t r a . In r e g a r d s to the l a t t e r , the n.m.r. spectrum o f 204 i n DMSO-d, i n d i c a t e d a 2:1 r a t i o of anomers which i n c r e a s e d o  124  (to  approx. 4:1)  upon a d d i t i o n of D^O.  i n the l o s s of two r e s p e c t i v e l y . The but was  obscured  s i n g l e t s and  The  a d d i t i o n of D^O  a doublet a t 65.95, 5.60  l o s s of a second doublet  at ca.  by an o v e r l a p p i n g s i g n a l and  and  64.89 may  204,  the m e c h a n i s t i c  hydroperoxides  to  ratios.  204.  pathways to the above carbohydrates  and  (199  References  The  from the methyl  i n s e c t i o n 3.2.6. of the I n t r o d u c t i o n .  s e v e r a l r o u t e s might l e a d to the d e s i r e d product,  and most p r o b a b l e  r o u t e ( s ) w i l l be  the s h o r t e s t  presented.  pathway to the r i b o n o - l , 4 - l a c t o n e 199  u c e e d m g throughu the f o r m a t i• o n of a dioxetane C  can be e n v i s i o n e d as  • n t e r m e Ai d i a t e 95,184a,b  as 9_0_, formed by the a d d i t i o n s i n g l e t oxygen to the 3-enonate 172, subsequent decomposition 199  (see Scheme X I I I ) .  A second r o u t e which i n v o l v e s t r i p l e t  peroxy k e t a l 205 which undergoes rearrangement  precursors Villiger XII  prosuch and  of i n t e r m e d i a t e to g i v e the c a r b o n y l compound  oxygen r e q u i r e s the a u t o x i d a t i o n of the 3-enonate 172  l a c t o n e 199.  olefins  to s t r u c t u r e s of i n t e r m e d i a t e s , r e a c t i o n s ,  r e a c t i o n schemes w i l l b e found  Although  to  t h e i r r a d i c a l p r e c u r s o r s w i l l be a p p l i e d  to r a t i o n a l i z e the f o r m a t i o n of the above products  oct-3-enonate 172. and  have o c c u r r e d  i n c l u s i v e ) have not been i n v e s t i g a t e d , the known r e a c t i o n s of  w i t h oxygen and here  5.29,  a change i n anomeric  3.1.1. P o s s i b l e M e c h a n i s t i c Pathways to Compounds 199 Although  also resulted  to the  (Scheme XIV)  Other r o u t e s i n v o l v i n g the hemiketals  ground s t a t e unsaturated  to g i v e  201-204 or  their  ( v i d e i n f r a ) might p r o v i d e a route to 199 v i a the Baeyer-  rearrangement or a r e a c t i o n s i m i l a r to one d e p i c t e d i n Scheme  (see I n t r o d u c t i o n , S e c t i o n 3.2.4.). The  s p i r o - l a c t o n e 200,  o b v i o u s l y a r i s e s from an i n t r a m o l e c u l a r  c y c l i z a t i o n of the s a t u r a t e d h e m i k e t a l The  unsaturated  hemiketal  201  202  or i t s p r e c u r s o r .  can come about by two  r o u t e s ; the  first,  125  i n v o l v e s the d e h y d r a t i o n g i v e 201 (206a)to  directly.  The  of e i t h e r of the 6-hydroxy e s t e r s 203  second r o u t e i n v o l v e s the p e r o x y - r a d i c a l  the peroxy h e m i k e t a l  205.  the alkoxy  r a d i c a l of 201  to form an epoxide of 172  Z-172  +  The  products.  o b v i o u s l y r e s u l t s from a h y d r a t i o n of  g i v e s the s p i r o - l a c t o n e  hydroxy h e m i k e t a l s  as d e p i c t e d  202  XXVI  (see I n t r o d u c t i o n , S e c t i o n 3.2.1.).  c y c l i z a t i o n of 202  propagation  process).  saturated hemiketal  e n o l e t h e r 172  (compd. 206b)  (which a l s o r e s u l t s i n the  Scheme  The  203  and  204  200.  can a r i s e  from epoxide  procursors  to g i v e the d e s i r e d  I f other r e a d i l y o x i d i z a b l e s u b s t r a t e s such as e t h y l ether the p e r o x i d e  r a d i c a l formed  the  Intramolecular  i n Scheme XXVI ( v i d e i n f r a ) which hydrate  are present,  the  (compd. 206c, see Scheme XXVI below) which  a b s t r a c t s a hydrogen atom to g i v e 201 of the a u t o x i d a t i o n  to  precursor  T h i s r a d i c a l adds to a molecule of  3-enonate 172 which then r e a r r a n g e s and  or 204  ( s i m i l a r to 206a) w i l l  also  126  compete f o r s u b s t r a t e 172. oxirane precursors  Another r o u t e to 203  and  204  i n v o l v e the h y d r o p e r o x i d e 205  and  the h y d r o p e r o x i d e s  of e t h y l e t h e r . These h y d r o p e r o x i d e s might r e a c t w i t h  and  172  their  i n a manner  analogous to p e r a c i d r e a c t i o n s (see I n t r o d u c t i o n , S e c t i o n 3.2.4.) w i t h carbon-carbon double bonds (see R e a c t i o n  (5)).  s t r u c t u r e of these h y d r o p e r o x i d e s should  enhance t h i s l a t t e r mechanism  result 203  i n another pathway to 201.  and  204,  although  Hydration  t h i s h y d r a t i o n i s not  The  peroxy  hemiketal and  of 201 would a l s o g i v e to expected to c o n t r i b u t e  significantly. 3.1.2. S t e r e o c h e m i s t r y The  sterochemistry  of the k e t a l s of the methyl oct-3-enonate  has been b r i e f l y d i s c u s s e d 187  of 200-204.  i n s e c t i o n 2.1.1.4 when the methyl g l y c o s i d e  of the s a t u r a t e d h e m i k e t a l  i n t h a t d i s c u s s i o n was 0-isopropylidene  172  202 was  isolated.  The  c o n c l u s i o n reached  t h a t under e q u i l i b r i u m c o n d i t i o n s k e t a l s w i t h  group at the 3 , 4 - p o s i t i o n of the f u r a n o i d r i n g  2 , 3 - p o s i t i o n of a l d o f u r a n o s e s )  p r e f e r the B - c o n f i g u r a t i o n .  an  ( i e . , the  A further  c o r r e l a t i o n a r i s i n g from the p r o t o n n.m.r. of the p s i c o s e d e r i v a t i v e s concerns the c h e m i c a l and  H-6  s h i f t s of H-2  i n the o c t u l o s o n a t e s  i n the B - D - p s i c o f u r a n o s i d e s s h i f t s by 0.14 up-field  H-3  (aldofuranose  under d i s c u s s i o n ) .  1 7 1  (ppm)  or more and  r i n g or  H-3  H-5  chemical  from the H-2  v a t i v e s i s that the c h e m i c a l of the C - g l y c o s i d e s ^ 1  7  shifts chemical  i n the a-anomers H-3  (see S e c t i o n 3.3.2. f o r an example of t h i s s h i f t  Another c o r r e l a t i o n which has been found f o r these  group and  The  were c o n s i s t e n t l y downfield  p a r t per m i l l i o n  from H-2  and  was  in  isopropylidenated  H-3). deri-  s h i f t d i f f e r e n c e s i n the gem-dimethyl groups  have g r e a t e r d i f f e r e n c e s when the  isopropylidene  the anomeric s u b s t i t u e n t are i n a t r a n s - r e l a t i o n s h i p .  s t u d i e s a l s o showed t h a t both the a-0  Both  and ^ - g l y c o s i d e s shows a g r e a t e r  127  positive optical rotation. In a l l four o f the 2 , 3 - d i d e o x y - 4 - o c t u l o f u r a n o s e d e r i v a t i v e s 201,  202  and  203,  the B - c o n f i g u r a t i o n was  g i v e n to the anomeric  187, centre.  These t e n t a t i v e assignments are basedon the above thermodynamic cons i d e r a t i o n s and Only one  on the r e l a t i v e p o s i t i o n s the H-5  anomer was  isolated  i n each case  more s t a b l e B - c o n f i g u r a t i o n ) and H-5  (consistent with  and  was  H-6  resonances.  ( t h e r e f o r e , assigned  the  c o n s i s t e n t l y l o w e r - f i e l d than  the B - c o n f i g u r a t i o n ) .  For the hydroxy h e m i k e t a l s present  H-6  and  203  and  204,  two  new  c h i r a l centres  both compounds e x h i b i t an e q u i l i b r i u m i n a DMS0-d,/D„0 s o l v e n t o  system.  are  The  assignment of the s t e r e o c h e m i s t r y  stereochemistry ( S e c t i o n 2.1.)  at C-3  z  i s based on  the  of the methyl oct-3-enonate 172 which has been determined to be predominantly the Z-isomer and  of a d d i t i o n r e a c t i o n s to 172  and  other  on the  stereoselectivity  e x o c y c l i c double bonds w i t h  similar  102 185 s t e r i c environments. With s u b s t r a t e s such 172, 46, and 9_2, hydrogenation, ' , « , . . , . . , 186 , , , . 102 h y d r o x y l a t i o n w i t h osmium t e t r o x i d e or permanganate , or h y d r o b o r a t i o n , all  proceed from the s i d e o p p o s i t e  l e a s t hindered  side).  meta-chloroperbenzoic 204,  The  of the i s o p r o p y l i d e n e group ( i . e . ,  h y d r o x y l a t i o n of 172 w i t h  osmium t e t r o x i d e and  a c i d gave predominantly the lower  hydroxy  r e s u l t s which a r e analogous to the a i r o x i d a t i o n of 172.  whatever the mechanism and  stereochemical  the former r e s u l t s i n d i c a t e t h a t t o p s i d e reagents  on the major Z-isomer of 172  isomer) 204  fact  will  203  two  of the l a t t e r  process,  hydroxylation  g i v e the 3-R-isomer ( i . e . , D - a l t r o -  ( f o r a d d i t i o n a l support  that the r a t i o of the  hemiketal  Therefore,  (8-face) a t t a c k by the  and t o p s i d e a t t a c k on the E-isomer of 172  ( i . e . , D-allo-isomer) The  selectivity  the  see  w i l l g i v e the  3-^-isomer  S e c t i o n 3.3.2.).  components present  i n the  proton  128  n.m.r. spectrum  o f both hydroxy h e m i k e t a l s 203 and 204 can be v a r i e d  the a d d i t i o n o f D 0 2  i s sufficient  i n b o t h compounds a r e anomeric carbohydrate.  by  evidence to prove t h a t the components  or t a u t o m e r i c components of the same parent  The s y n t h e s i s of r i b o n o - l , 4 - l a c t o n e 199  from 203 or  204  by p e r i o d a t e c l e a v a g e c o r r o b o r a t e s the v i c i n a l o r i e n t a t i o n of the c a r b o n y l a t C-4 204  and h y d r o x y l a t C-3.  A d d i t i o n a l proof of t h i s s t r u c t u r e f o r 203  i s o b t a i n e d by the i s o l a t i o n of 203 and  oct-3-enonate  172  204  and  from the h y d r o x y l a t i o n of the  w i t h osmium t e t r o x i d e and m e t a - c h l o r o p e r b e n z o i c  Although the p r o t o n n.m.r. s p e c t r a of 203 and 204 c o u l d not v o c a l l y e s t a b l i s h whether or not a m i x t u r e of c y c l i c or a c y c l i c  acid.  unequiand  c y c l i c m o d i f i c a t i o n s of the parent c a r b o h y d r a t e were present i n s o l u t i o n , the f a c t  t h a t a one-proton  s i n g l e t and one-proton  doublet  (combined  i n t e g r a t i o n i n the m i x t u r e s ) which d i s a p p e a r e d upon a d d i t i o n of D 0 2  s t r o n g l y suggest the presence of two c y c l i c m o d i f i c a t i o n s . was  supported by the f a c t  that D - p s i c o s e and  did  This conclusion  i t s 6-0-methyl d e r i v a t i v e  e x i s t e d o n l y i n c y c l i c m o d i c a t i o n s e i t h e r i n D„0 or DMSO-d, s o l u t i o n .  Z  C o n f i r m a t o r y evidence f o r t h i s c o n c l u s i o n was s p e c t r a of 203 and the benzoate  found  54  t>  i n the carbon-13 n.m.r.  204 which c o n t a i n e d o n l y two c a r b o n y l resonances  (i.e.,  and methyl e s t e r ) a n d a p a i r of k e t a l d o u b l e t s ( i . e . , C-4  and  the quaternary carbon of the i s o p r o p y l i d e n e group of the anomers) f o r b o t h compounds; t h u s , p r o v i d i n g u n e q u i v i c a l support f o r the presence of the two anomers r a t h e r than a m i x t u r e o f c y c l i c and a c y c l i c Based on the d i s c u s s i o n presented e a r l i e r anomers of 203 and  tautomers.  i n t h i s s u b s e c t i o n , the  204 would be expected t o predominate.  Support  6-  for this  a n t i c i p a t e d - p r e d o m i n a n c e comes from a v a r i e t y of s p e c t r o s c o p i c c o r r e l a t i o n s . In the D - p s i c o s e s e r i e s the anomeric  h y d r o x y l p r o t o n p r o t o n was  found to  54 r e s o n a t e a t lower f i e l d and  i n i t s B-furanose c o n f i g u r a t i o n  204 had s t r o n g e r l o w - f i e l d s i n g l e t s .  - ketose  203  The B-anomer of g - p s i c o s e and i t s  129  d e r i v a t i v e s produces a-anomer^ ' 4  i t s anomeric  C-13  s i g n a l d o w n f i e l d from that of the  - the l o w - f i e l d s i g n a l of the C-4  1 8 7  and 0-5  d o u b l e t of 203 and produces a  204  predominated.  The c i s - o r i e n t a t i o n of C-3  smaller  chemical s h i f t  d i f f e r e n c e i n the gem-dimethyl group of the a c e t o n i d e s ^ 1  the major anomeric  component of 203 and  of ca_. 15 Hz w h i l e the minor  204  chemical s h i f t  7  -  difference  component has a d i f f e r e n c e of c a . 21 Hz; t h e r e -  f o r e , the major component p o s s e s s e s a c i s - o r i e n t a t i o n of the i s o p r o p y l i d e n e and C-4  side chain ( i . e . ,  the 6-anomer).  F i n a l l y , the H-5  resonances of  major anomers a r e found to be a sharp d o u b l e t a t s i g n i f i c a n t l y h i g h e r field  than H-6  t h e r e b y p r o v i d i n g a d d i t i o n a l support f o r the predominance  tn o f^ the p-anomer. 171  3.2.  Treatment Methyl  o f 172 w i t h meta-Chloroperbenzoic A c i d  Treatment  (207) and Compound  d e s i r e v i c i n a l hydroxy h e m i k e t a l s , 203 and  but the e t h y l g l y c o s i d e 207 was  The  204.  i n 10% y i e l d a f t e r column chromatography  122  i.r.  204.  of a dichloromethane s o l u t i o n of the methyl  w i t h MCPBA gave a major product which was  isolated  ield  (ethyl 8-0-benzoyl-2-deoxy-5,6-0-isopropylidene-B-D-altro-  4-octulofuranosid)onate  (172)  (MCPBA) to  2  isolated  higher i n  oct-3-enonate than the  The h e m i k e t a l 204  was  of the r e a c t i o n m i x t u r e  i n 39%.  ) H 0 2  spectrum of 207  possessed a broad band at 3560 cm  the presence of a h y d r o x y l group and a broad c a r b o n y l band 1727  1  indicating cm . 1  The  130  n.m.r. spectrum of 207 quartet  and  triplet  Moreover, H-6 4.67  f o r H-5  was  i n DMSO-d^ e x h i b i t e d three methyl groups and  f o r the e t h y l group at 63.61  present  as a broadened doublet  which suggest the presence of the  isomer o f 207  was  and  1.07,  i s o l a t e d , thermodynamic c o n s i d e r a t i o n s  f o r compounds 201-204 suggest t h a t the  respectively.  at 64.87 compared  8-anomer.  A^I^  to  Since only  one  s i m i l a r to those  8-anomer predominates  (see  previous  section). Compound 207 intermediate  p r o b a b l y a r i s e s from the a c i d - c a t a l y z e d  D e r i v a t i v e s of K e t a l s The  k e t a l 204  solvents.  202-204  purpose of the s y n t h e s i s  two-fold.  First,  of d e r i v a t i v e s of k e t a l s 202-204  i s a syrup) which are a n o m e r i c a l l y  of k e t a l s 203  and  204.  (see S e c t i o n 4. and  s t a b l e and  Introduction,  thus,  possibly corroborate  Secondly, i t was  d e r i v a t i v e s might l e a d to p r e c u r s o r s  3.3.1.  was  the d e r i v a t i v e s might g i v e c r y s t a l l i n e compounds  to unambiguous c h a r a c t e r i z a t i o n and of C-3  the  (i.e.,  amenable configuration  hoped that some of  these  of analogues of ketose N - n u c l e o s i d e s  Section  5.).  5,6-Di-0-acetyl-8-0-benzoyl-2,3-dideoxy-a(and8)-D-ribo-4octulofuranosono-1,4-lactone  Treatment of the s a t u r a t e d a c e t i c a c i d followed 208b i n 24 and  34%  by  (208a) and  (208b), r e s p e c t i v e l y  h e m i k e t a l 202 w i t h 80%  aqueous  trifluoro-  a c e t i c a n h y d r i d e g i v e the s p i r o - l a c t o n e s  y i e l d , r e s p e c t i v e l y . The  208a  n.m.r. s p e c t r a of 208a  of the f u r a n o i d hydrogens to l o w e r - f i e l d .  s t r u c t u r e was  confirmed by  the presence of t h r e e  This acetylated carbonyl  and  and  208b showed the l o s s of the methyl e s t e r methyl group along w i t h the of two  the  epoxide (e.g., compd. 206b) i n the presence of t r a c e a l c o h o l  used to s t a b i l i z e d halogenated  3.3.  opening of  shift  lactone  bands at ca.  1730,  131  1760  and 1805 cm  f o r the five-membered  lactone  , a c e t a t e s and benzoates,  respectively.  208a The assignment  208b  of the anomeric c o n f i g u r a t i o n i s again based on the  p o s i t i o n s of the H-6 resonance i n the n.m.r. spectrum."*^ g r a p h i c a l l y more mobile component  The chromato-  (compd. 208a) possessed a h i g h e r - f i e l d  (0.17 ppm) H-6 s i g n a l and i s t h e r e f o r e a s s i g n e d the a - c o n f i g u r a t i o n and thus the 6 - c o n f i g u r a t i o n f o r 208b.  T h i s assignment  i s a l s o supported by  the more p o s i t i v e o p t i c a l r o t a t i o n f o r 208a (eg., +57.5° ^ f . -11.1° f o r 208b).  3.3.2.  Methyl 8-0-benzoy1-2-deoxy-3,4:5,6-di-0-isopropylidene-a(and S ) -  D-allo-4-octulofuranosono-1,4-lactone  (209a) and (209b), r e s p e c t i v e l y .  Treatment o f the v i c i n a l hydroxy h e m i k e t a l 203 w i t h t r i f l u o r o a c e t i c a c i d , 2,2-dimethoxypropane,  and acetone gave an anomeric p a i r of d i a c e t o n i d e s  209a and 209b i n 75 and 12% y i e l d s , r e s p e c t i v e l y , the n.m.r. spectrum of both d i a c e t o n i d e s showed f i v e , sharp t h r e e - p r o t o n s i n g l e t s f o r the methyl groups and an o v e r l a p p i n g m u l t i p l e t was e a s i l y  f o r H-3, H-5 and H-6.  The m u l t i p l e t  f o r K-3  r e s o l v e d due to the c o u p l i n g w i t h H-2a and H-2b which enabled  a f a c i l e assignment o f H-5 and H-6 s i n c e H-6 was present as a broadened doublet.  132  The  c o n f i g u r a t i o n of the two  of the r e l a t i v e chemical H-6  i n the a-anomer was  s h i f t s of H-5 64.76 and  r e s p e c t i v e l y ; t h e r e f o r e , these assigned  anomers was  4.66  again assigned  and  H-6.  The  and  64.65 and  r e l a t i v e chemical  c o n f i g u r a t i o n s w i t h secondary support  the c o n f i g u r a t i o n a l assignment of 0 3  of H-2a  lower f i e l d i n other  and  H-2b  of the B-anomer 209b.  r e l a t i v e to H-2a  (0.52  di-O-isopropylidenated  ppm)  4.85  provided  and  i n the 8-anomer,  by  the  optical  a more p o s i t i v e r o t a t i o n ) .  A d d i t i o n a l s p e c t r o s c o p i c c o r r e l a t i o n which supports  shift  p o s i t i o n of H-5  s h i f t s support  r o t a t i o n measurements ( i . e . , a-anomer p o s s e s s i n g  along with  on the b a s i s  the anomeric assignment  was  H-2b  found i n the  resonates  at  chemical  significantly  - t h i s d i f f e r e n c e has been observed  s p i r o - k e t a l s and  has been a t t r i b u t e d to  the  188 deshielding effect  of the oxygen at C-5.  models of the v a r i o u s d i a s t e r e o m e r s anomer  ( i . e . , compd. 209b) can a t t a i n  o r i e n t a t i o n wherein the hydrogens of H-2 confined  the space occupied  by  evidence  one  are i n c l o s e p r o x i m i t y  system where one  hydrogen on C-2  of the lone p a i r s on 0-5;  f o r the c o n f i g u r a t i o n a l assignment of C-3  3.3.3.  i t can be  thus,  an  to 0-5  in  projects into  supplying  i n compounds 203  (210)  and  supportive and  204.  8-0-benzoyl-2-deoxy-5,6-0-iso-  p r o p y l i d e n e - B - P _ - a l t r o - 4 - o c t u l o f u r a n o n o - l ,4-lactone Treatment of e p i m e r i c i n 33%  B-  Methyl 8-0-benzoyl-2-deoxy-3,4:5,6-di-0-isopropylidene-B-D-  altro-4-octulofuranosonate  210  seen from  t h a t o n l y the d i a c e t o n i d e of the  of the D - a l l o - o c t u l o s e 203  a conformationally  Therefore,  yield  scopic analyses  and  hemiketal  a l a c t o n e 211  204  The  anomeric c o n f i g u r a t i o n of 211  and  i s based on  the chemical  shift  as above gave only one  i n 10% y i e l d .  of 210 were c o m p l e t e l y  (211).  The  consistent with  chemical  and  H-6  and  spectro-  the proposed s t r u c t u r e .  i s t e n t a t i v e l y assigned of H-5  diacetonide  the B - c o n f i g u r a t i o n  ( i . e . , H-6  lower  field  133  than H-5  cf_. compels. 209a and  p r o v i d i n g secondary  209b) w i t h the o p t i c a l r o t a t i o n a g a i n  support.  210 The  211  s t r u c t u r e of compound 211 was  methoxy methyl group of 204 the presence  of a broad,  a d d i t i o n of D^O  and  i n the n.m.r. spectrum  single-proton t r i p l e t  resulted  a d o u b l e t of d o u b l e t s  ( i . e . , H-2b)  to  a doublet  suggested  I.r.  absorbances  h y d r o x y l and  at 3580 and  the l o s s of the of 211;  moreover,  which disappeared  i n the c o l l a p s e of a h i g h - f i e l d  to  ( i . e . , H-3)  e v i d e n t from  1812  1  multiplet  a m i d - f i e l d d o u b l e t of d o u b l e t s  a rather r i g i d cm  five-membered l a c t o n e  and  supported  groups.  spiro-lactone structure. the presence  of the  1 4 3 3  Comparison of l a c t o n e 211 w i t h a c h r o m a t o g r a p h i c a l l y l e s s spiro-lactone  (compd. 213;  s y n t h e s i s s t a r t i n g w i t h 204  0-3  the s p i r o - l a c t o n e 211 and  0-5  mobile  see S e c t i o n 3.2.4.) i s o l a t e d from a l a t e r suggested  the 6 - c o n f i g u r a t i o n f o r 211  from a comparison of c h e m i c a l s h i f t s of H-6 of  upon  and  indicate a sterically  (e.g.,  optical rotations).  Models  hindered spiro-system  are i n c l o s e p r o x i m i t y ( c f . compd. 209b) ; however, t h i s  wherein steric  i n t e r a c t i o n might be s t a b i l i z e d by p o s s i b l e hydrogen-bonding between the C-3  h y d r o x y l and  rigid  0-5.  These two  i n t e r a c t i o n s produce a c o n f o r m a t i o n a l l y  s p i r o - s y s t e m which r e s u l t s i n a f a v o u r a b l e o r i e n t a t i o n f o r a f o u r -  bond c o u p l i n g between the h y d r o x y l p r o t o n and H-2b p r o t o n s p i n - c o u p l e d i n t e r a c t i o n s through for  conformationally favourable r i g i d  (2.0 Hz).  Proton-  f o u r bonds has been  observed  systems and  the presence  of a  134  heteroatom i n the path between these i n t e r a c t i n g protons  enhance t h i s  189 interaction.  The  conformational  be the l a c k of an o b s e r v a b l e 3.3.4. Compounds 210, furan  (212)  and  i m m o b i l i t y of 211  c o u p l i n g i n t e r a c t i o n between H-2a  211,  211,  11 and  212  204 was  (213)  from  of p a r a - t o l u e n e s u l f o n i c a c i d , f o u r components, compounds  and  213,  were i s o l a t e d  from the r e a c t i o n mixture  showed t h r e e s i n g l e t s and  benzoate s i g n a l s and  the i . r .  and  1670  ketone, r e s p e c t i v e l y .  cm  spectrum of 212  two  39,  d o u b l e t s along w i t h  the  e x h i b i t e d t h r e e c a r b o n y l bands  f o r the methyl e s t e r , benzoate and  The U.V.  i n 1.3,  The n.m.r. spectrum of the s u b s t i t u t e d  f u r a n d e r i v a t i v e 212  1730  204.  c o n t i n u o u s l y a z e o t r o p e d i n a benzene s o l u t i o n  2% y i e l d s , r e s p e c t i v e l y .  at 1750,  H-3.  8-0—Benzoyl-2-deoxy-5,6-0-isopropylidene-a-p.-altro-  When the h e m i k e t a l  210,  and  2-Benzoyloxymethyl-5-(carbomethoxyacetyl)  4-octulofuranosono-l,4-lactone  i n the presence  i s also exemplified  spectrum of 212  conjugated  exhibited a strong absorption 190  band at 276 nm which i s c o n s i s t e n t w i t h the a s s i g n e d s t r u c t u r e . The  a c i d - d e g r a d a t i o n of 204  to 212  probably a r o s e from a s e r i e s of  e l i m i n a t i o n s s i m i l a r to those o u t l i n e d i n schemes I I and d u c t i o n , S e c t i o n 1.1.).  The  0 - i s o p r o p y l i d e n e group of 204 might have  h y d r o l y z e d b e f o r e the d e g r a d a t i o n with  204  I I I (see I n t r o -  process  to g i v e the d i a c e t o n i d e 210  to g i v e acetone which r e a c t s  or the v i c i n a l hydroxy h e m i k e t a l  204  might have r e a c t e d w i t h an i n t e r m e d i a t e i n the d e g r a d a t i o n r e a c t i o n which r e s u l t s i n an exchange r e a c t i o n to g i v e i n t e r m e d i a t e s which l e a d to 194 210 and 212, r e s p e c t i v e l y . The l a t t e r r o u t e i s expected to predominate.  135  S i m i l a r to i t s 8-anomer 211, of methoxy methyl group of 204 s i g n i f i c a n t broadening  due  s p i r o - l a c t o n e 213  i n i t s n.m.r. spectrum.  t r i p l e t which when i r r a d i a t e d  doublets.  The  i.r.  spectrum  groups w i t h absorbances membered l a c t o n e  3.3.5.  1 4  confirmed  at 3500 and  and  H-3  c o l l a p s e d H-2a  A l s o , H-3  1805  cm  f o r the h y d r o x y l and  1  3,4,5,6-tetra-0-acetyl-8-0-benzoyl-2-dexoy-ct(andg)-D-  Treatment of the h e m i k e t a l  204 w i t h 80%  215  i n 7 and  and  (215),  respectively.  t r i f l u o r o a c e t i c acid  25% y i e l d s , r e s p e c t i v e l y .  anomers on a column of s i l i c a  f o l l o w e d by the a-anomer 214.  The n.m.r. spectrum  H-5  H-6  the B - c o n f i g u r a t i o n .  1 7 1  cm  1  and  The  faster-moving The  8-anomer  three  of the f a s t e r - m o v i n g component was  a smaller p o s i t i v e r o t a t i o n . band a ca_. 1757  S e p a r a t i o n of the  to the a c e t y l a t e d secondary  than the slower-moving t e t r a a c e t a t e (65.80 and  i.r.  tetra-  215  of both anomers i n  showed f i v e sharp methyl resonances  and H-6.  and  gave two  g e l gave the f a s t e r - m o v i n g  p r o t o n m u l t i p l e t s at l o w e r - f i e l d due of H-3,  five-  3  (214)  deuterochloroform  to a p a i r of  of the above f u n c t i o n a l  a c e t y l a t i o n of the r e s u l t i n g m i x t u r e w i t h a c e t i c anhydride  two  This  ^ , respectively.  Methyl  and  showed  c o l l a p s e d to a  and H-2b  the presence  altro-4-octulofuranosonate  a c e t a t e s 214  loss  to c o u p l i n g w i t h the h y d r o x y l p r o t o n .  i n t e r a c t i o n d i s a p p e a r e d upon a d d i t i o n of D^O sharp  i n d i c a t e d the  5.44,  at  singlehydroxyls lower-field  r e s p . ) and was  tetraacetate also  possessed  of both compounds possessed  and at s t r o n g shoulder at c_a_. 1731  cm  1  assigned  a strong  f o r the a c e t a t e s  136  204  and benzoate  groups,  Attempted  hydrogenation of the a-anomer 214  platinum c a t a l y s t cyclic  4.  respectively.  failed.  The r e c o v e r y of 214  i n the presence  of  supports the a s s i g n e d  s t r u c t u r e of the t e t r a a c e t a t e .  Attempted  S y n t h e s i s of Analogues of P s i c o f u r a n i n e (129). 113  The ketose N - n u c l e o s i d e s i t s two  , of which p s i c o f u r a n i n e (129)  i s one  of  known n a t u r a l members, are a r a r e group of n u c l e o s i d e a n t i b i o t i c s .  The a v a i l a b i l i t y of two n o v e l e p i m e r i c homologues of D - p s i c o s e , namely methyl  8-0-benzoyl-2-deoxy-5,6-0-isopropylidene-g-allo  octulofuranosonate  (203) and  (204), r e s p e c t i v e l y  (and  altro)-4-  ( S e c t i o n 3.1.), prompted an  i n v e s t i g a t i o n i n t o the f e a s a b i l i t y of s y n t h e s i s of a homologue of the a n t i b a c t e r i a l and  FarkaS 4.6%  yield  antitumor n u c l e o s i d e p s i c o f u r a n i n e (129). 136b  and  §orm  r e p o r t e d the s y n t h e s i s of p s i c o f u r a n i n e (129) i n  s t a r t i n g from the b e n z o y l a t e d methyl  c o n d e n s a t i o n o f the m e r c u r i c c h l o r i d e s a l t c o r r e s p o n d i n g sugar bromide.  p s i c o f u r a n o s i d e s v i a the  of N-benzoyl-adenine  gave any  the  S e v e r a l attempts were made to condense a  p u r i n e or p y r i m i d i n e base onto d e r i v a t i v e s of ketose 204; of the attempts  on  however, none  s i g n i f i c a n t amount o f n u c l e o s i d e m a t e r i a l .  The  s y n t h e t i c s t r a t e g i e s w i l l , t h e r e f o r e , be o n l y b r i e f l y d i s c u s s e d . S y n t h e t i c . . 112,116,191a , . . 192 . . , methods and mechanisms of the c o n d e n s a t i o n r e a c t i o n s have been t h o r o u g h l y reviewed and w i l l not be d e a l t with here. 193 a) F o l l o w i n g the method of Vorbruggen and r i b o f u r a n o s i d e 134 was benzoyl-uridine  (217)  condensed w i t h u r a c i l i n 69% y i e l d .  Bennua  (216)  , the a c y l a t e d D-  to g i v e 2 ' , 3 ' , 5 ' - t r i - 0 -  S u b s t i t u t i o n of 134 w i t h the a c y l a t e d  137  134 +  BzQ-i  HN  m e t h y l 4 - o c t u l o f u r a n o s o n a t e 214 gave a multicomponent which c o u l d be r e c o n c i l e d w i t h the d e s i r e d  adduct.  b) U t i l i z a t i o n o f the f u s i o n p r o c e d u r e ^ ' 1  purine  m i x t u r e , none of  1  5  w i t h 214 and 2 , 6 - d i c h l o r o -  (218) a l s o gave n e g a t i v e r e s u l t s .  > 218  V  c) An attempt t o u t i l i z e the m e t h y l oct-3-enonate 172 d i r e c t l y the s y n t h e s i s of a k e t o s e N - n u c l e o s i d e was a d d i t i o n o f bromine  t o 172  also unsuccessful.  Thus,  f o l l o w e d by b i s ( t r i m e t h y l s i l y l ) t h y m i n e  gave a predominantly f a s t e r - m o v i n g product upon s i l i c a g e l  4  in the  (219)  chromatography.  T h i s u n s t a b l e product has been t e n t a t i v e l y a s s i g n e d as methyl  (E,Z)-4,7-anhydro-  8-0-benzoyl-3-bromo-2,3-dideoxy-5,6-0-isopropylidene-D-ribo-oct-3-enonate (220).  Bz0-> 1)  172  Br2  2)  Me Si<r^21? 3  02Me  138  The  n.m.r. spectrum of 220  methyl s i g n a l s and of 220  doublets  showed a v e r y  f o r H-2  and  intense molecular  the bromine i s o t o p e s and s t r u c t u r e f o r 220.  showed a broadening of the  The  isopropylidene  the methoxy methyl. The mass spectrum i o n doublet  of 440/442 due  the s t r e n g t h of the s i g n a l supports  to  the e n o l i c  f a c i l e l o s s of hydrogen bromide from bromine 102  adducts of e n o l i c compounds has been r e p o r t e d  and  the p o s s i b l e c a t a l y t i c  a c t i v i t y of amino compounds i n the e l i m i n a t i o n t o g i v e e n o l i c compounds has  a l s o been used s y n t h e t i c a l l y  (see I n t r o d u c t i o n , S e c t i o n  1.1.).  139  IV 1.  EXPERIMENTAL  G e n e r a l Methods P.m.r. s p e c t r a were determined  i n chloroform-d or d i m e t h y l ( s e t a t 6=0)  w i t h t e t r a m e t h y l s i l a n e as the i n t e r n a l standard  sulfoxide-d, o  or i n deuterium  o x i d e w i t h sodium 2 , 2 - d i m e t h y l - 2 - s i l a p e n t a n e - 5 - s u l f o n a t e as the e x t e r n a l (set at 6=0)  standard or  Bruker 400  order.  by u s i n g a V a r i a n HA-100, V a r i a n XL-100, Bruker  spectrometer.  Values g i v e n f o r c o u p l i n g c o n s t a n t s are  Carbon-13 n.m.r. s p e c t r a were determined  270 first  i n c h l o r o f o r m - d or  d i m e t h y l s u l f o x i d e - d ^ w i t h t e t r a m e t h y l s i l a n e as the i n t e r n a l standard by u s i n g a V a r i a n CFT-20 spectrometer. ambient temperature  O p t i c a l r o t a t i o n s were measured a t  w i t h a P e r k i n - E l m e r Model 141 automatic p o l a r i m e t e r .  I n f r a r e d 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  710B  A l l m e l t i n g p o i n t s were done on a L e i t z microscope and are c o r r e c t e d v i a a c a l i b r a t i o n c u r v e .  or 727B  spectrometer.  h e a t i n g s t a g e , Model  Mass s p e c t r a were determined  350, on  a Varian/MAT CH4B or K r a t o s MS902 low r e s o l u t i o n or a K r a t o s MS50 h i - r e s o l u t i o n spectrometer.  Ultraviolet  R e a c t i o n temperatures  s p e c t r a were r e c o r d e d on a Cary 15  were measured v i a an e x t e r n a l o i l b a t h u n l e s s o t h e r -  w i s e s t a t e d . E l e m e n t a l a n a l y s e s were performed  by Mr.  a n a l y t i c a l L a b o r a t o r y of the U n i v e r s i t y o f B r i t i s h 2.  spectrometer.  P. Borda of the M i c r o -  Columbia.  Chromatography 2.1.  Column Chromatography  S i l i c a g e l column chromatography was t h i n l a y e r chromatography (Merck).  using s i l i c a  gel H for  The r a t i o of s u b s t r a t e to absorbent  a p p r o x i m a t e l y 1:100  (w/w)  approximately  Columns were p r e s s u r i z e d above the s o l v e n t r e s e r v o i r  at  8-12  10:1.  and  performed  the r a t i o of column l e n g t h to diameter  p . s . i . p r o v i d i n g flow r a t e s of 30-500 ml h  was  was  140  2.2.  T h i n Layer  All  Chromatography  t h i n l a y e r chromatography was  c o n t a i n i n g 5% c a l c i u m s u l f a t e .  performed u s i n g s i l i c a  Compounds were d e t e c t e d by  a b s o r p t i o n and/or by s p r a y i n g w i t h 50% on a hot  3.  sulfuric acid  g e l (Camag)  ultraviolet  f o l l o w e d by  heating  plate.  Abbreviations The  a b b r e v i a t i o n s used i n the f o l l o w i n g d e s c r i p t i o n s are as f o l l o w s :  n.m.r.(nuclear  magnetic r e s o n a n c e ) ,  u.v.(ultraviolet),  p.m.r.(proton magnetic  resonance),  i . r . ( i n f r a r e d ) , m.p.(melting p o i n t ) , t . l . c . ( t h i n  layer  chromatography), DMF(N,N,-dimethylformamide), DMSO(dimethyl s u l f o x i d e ) , T H F ( t e t r a h y d r o f u r a n ) , MeOH(methanol), s ( s i n g l e t ) , d ( d o u b l e t ) dd(doublet doublets), t ( t r i p l e t ) ,  of  q ( q u a r t e t ) , and m ( m u l t i p l e t ) .  4.  (R) and  (S)-Dihydroshowdomycin  4.1.  S y n t h e s i s of Methyl  (171)  and  (170),  respectively.  (E,Z)-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-0-  i s o p r o p y l i d e n e - p - a l l o - o c t - 2 - e n o n a t e (18) from l - 0 - A c e t y l - 2 , 3 , 5 - t r i - 0 - b e n z o y l 8-D-ribofuranose  (134).  2,3,5-Tri-0-benzoyl-B-D-ribofuranosyl Dry through 134  gaseous hydrogen bromide (passed a stirred  (126 g, 0.25  mol)  The  flow was  r e a c t i o n m i x t u r e was  allowed  w  a  bubbled  s  gas  flow  to stand at room temperature f o r an passed  through  continued the  additional  the s o l u t i o n to d i s p l a c e  evaporated  the r e s i d u e coevaporated  r e s u l t i n g amber syrup was  cooled  to r e t a i n a  i c e bath were removed and  the s o l u t i o n was  (bath temperature 40°C) and  The mixture was  s a t u r a t e d and  i n l e t and  Dry n i t r o g e n gas was  the hydrogen bromide and  The  g r a n u l a r ?2^5^  c a r e f u l l y maintained  s o l u t i o n was  a f t e r which the gas  45 minutes.  through  i n anhydrous benzene (500 m l ) .  p o s i t i v e gas p r e s s u r e . f o r 60 min  (127)  s o l u t i o n of l - 0 - a c e t y l - 2 , 3 , 5 - t r i - 0 - b e n z o y l - 8 - D - r i b o f u r a n o s e  i n an i c e bath w h i l e the gas  benzene.  Cyanide  under reduced w i t h 400 ml  d i s s o l v e d i n nitromethane  pressure  anhydrous (300  ml)  141  ( d r i e d by d i s t i l l a t i o n over P 0,.), powdered m e r c u r i c c y a n i d e (125 g, 0.485 2  m o l ) ( p r e d r i e d a t 140°, 0.10 was  mm  Hg f o r 24 hours) added and a d r y i n g  then a t t a c h e d t o the r e a c t i o n f l a s k  m i x t u r e was  stirred  i n a dry-box).  f o r 20 hours a t room temperature  i n s o l u b l e p o r t i o n was greenish f i l t r a t e .  (performed  filtered  The  a f t e r which the  o f f and washed w i t h benzene to y i e l d  a  The combined f i l t r a t e s were evaporated under reduced  p r e s s u r e and the r e s u l t i n g syrup was washed w i t h 5% aqueous potassium  dissolved  iodide  i n c h l o r o f o r m (2.0£) and  (2 x 200 ml) and water  (2 x 100 m l ) ,  d r i e d over sodium s u l f a t e , evaporated under reduced p r e s s u r e , and syrup d i s s o l v e d  tube  i n e t h a n o l (200 m l ) .  Approximately  h a l f the e t h a n o l was  evaporated under reduced p r e s s u r e , the c o n c e n t r a t e seeded c r y s t a l l i z e at room temperature  over-night.  the crude  and allowed to  The c r y s t a l l i n e mass  was  t r i t u r a t e d w i t h a m i x t u r e of e t h a n o l - e t h e r (85:15, 100 m l ) , the c r y s t a l s c o l l e c t e d and washed w i t h e t h a n o l . and  the r e s i d u e c r y s t a l l i z e d  evaporation  The  f i l t r a t e s were combined,  evaporated  from e t h a n o l over s e v e r a l weeks w i t h  periodic  (under reduced p r e s s u r e ) of s m a l l p o r t i o n s of e t h a n o l u n t i l a  brown o i l formed  a f t e r which the c r y s t a l l i n e r i b o s y l c y a n i d e 127  c o l l e c t e d and washed w i t h e t h a n o l ( o v e r a l l y i e l d :  96.5  g,  was  81.6%)(lit.~88%);  1 31  m.p. J  x  2  78-80.5°, 4.0  + 23.8  (lit.  Hz,H-l)(lit. (cO.5jCHCl^)).  following  m.p.78.5-80°); n.m.r. (60 MHz, 1 3 1  64.425,d,H-l) ; [cx]^  4  + 23.9  3  64.91(d,lH,  (cO. 5,CHC1 ) , 3  F i n a l v e r i f i c a t i o n of s t r u c t u r e was  (lit*  3 1  e v i d e n t i n the  derivatizations.  5-0-Benzoyl-8-p-ribofuranosyl Cyanide  (135)  A s o l u t i o n of the b l o c k e d r i b o s y l cyanide 127 form  CDC1 ):  (900 ml) was  (90 g) i n anhydrous c h l o r o -  added to a s t i r r e d , i c e - c o o l e d s o l u t i o n of s a t u r a t e d meth-  a n o l i c ammonia (1350 ml) and kept i n an i c e bath f o r 4.5  h.  The  then evaporated under reduced p r e s s u r e ( i n 500 ml p o r t i o n s ) , and  solvent  was  the r e s u l t i n g  142  clear syrup was d i s s o l v e d i n e t h y l a c e t a t e (300 m l ) , washed w i t h s a t u r a t e d aqueous sodium b i c a r b o n a t e (30 m l ) , water (30 m l ) , d r i e d over anhydrous sodium s u l f a t e and evaporated under reduced p r e s s u r e to y i e l d a c l e a r syrup.  The r e s i d u a l syrup was allowed to c r y s t a l l i z e from benzene-hexane  o v e r n i g h t i n the r e f r i g e r a t o r t o g i v e the c r y s t a l l i n e p a r t i a l l y c y a n i d e 135  (37.2 g , 7 2 . 5 % ) ( l i t .  117.5(118)).  83%); m.p.  117-118.5, ( l i t .  Smaller s c a l e r e a c t i o n s were found  comparable t o the l i t e r a t u r e  To a s o l u t i o n of 70% p e r c h l o r i c a c i d  c y a n i d e 135  (180 ml) was  (25.0 g ) .  to g i v e y i e l d s  (136)  (3.6 m l ) , 2,2-dimethoxypropane  added the p a r t i a l l y unblocked  The r e s u l t i n g dark red s o l u t i o n was  room temperature f o r 2 h.  117-  yield.  5 - 0 - B e n z o y l - 2 , 3 - 0 - i s o p r o p y l i d e n e - B - D - r i b o f u r a n o s y l Cyanide  (30 m l ) , and acetone  unblocked  The r e a c t i o n mixture was  ribosyl  stirred  at  then n e u t r a l i z e d  i n d i c a t e d by l i t m u s paper) w i t h ammonium h y d r o x i d e and evaporated, a r e s i d u e which was (2 x 25 m l ) . evaporated  The  and  dissolved  (as  leaving  i n c h l o r o f o r m (250 ml) and washed w i t h water  o r g a n i c l a y e r was  d r i e d over anhydrous sodium  the crude y e l l o w syrup c r y s t a l l i z e d  sulfate,  from ether-hexane  to  141a  yield the i s o p r o p y l i d e n a t e d c y a n i d e 136 (26.4 g, 91.6%) ( l i t .  95%);  141a m.p.  62°  (lit.  60-61).  1,3-Diphenyl-2-(5-0-benzoy1-2,3-0-isopropylidene-B-g-ribofuranosyl) imidazolidine  (138) 195  To a s u s p e n s i o n o f Raney n i c k e l  and sodium hypophosphite  (100 g)  * ' , 1 , 1 - d i a n i l i n o e t h a n e (27 g ) ,  (55 g) i n 212 ml of a m i x t u r e of p y r i d i n e ,  acetic  acid and water (2:1:1) was added t o the b l o c k e d r i b o s y l cyanide 136 (26.35 g) which r e s u l t e d i n a v i g o r o u s exothermic r e a c t i o n w i t h an e v o l u t i o n of v a p o r s . The  m i x t u r e was  s t i r r e d v i g o r o u s l y f o r 1 h.  The mixture was  then  filtered  * The Raney nickel was measured by a c t i v a t i n g 200 g of Raney n i c k e l a l l o y . **The Raney nickel was s t i l l very a c t i v e , so that c a u t i o n must be e x e r c i s e d during the f i l t r a t i o n and washing.  143  and  the r e s i d u e washed thoroughly w i t h c h l o r o f o r m .  The combined  filtrates  I with chloroform.  This mixture  was  were d i l u t e d divided  t o a volume of 4.5  i n t o 3 p o r t i o n s and  The o r g a n i c phase was evaporated  each p o r t i o n was  washed w i t h water  d r i e d over anhydrous sodium s u l f a t e , f i l t e r e d  t o y i e l d a p a r t i a l l y c r y s t a l l i n e syrup t h a t c o m p l e t e l y  d i f i e d under vacuo, o v e r - n i g h t , a t room temperature.  The  t r i t u r a t e d w i t h methanol to y i e l d a y e l l o w paste t h a t was w i t h methanol and d r i e d (32.5  (2 x 300  g, 74.5%) ( l i t .  1  to y i e l d 4  1  a  ml).  and  soli-  s o l i d mass  was  f i l t e r e d , washed  the b l o c k e d r i b o s y l i m i d a z o l i d i n e 138  78%); m.p.  144.5-148 ( l i t .  1  4  l  a  144-145).  196 Carbomethoxymethylenetriphenylphosphorane To a s t i r r e d (600 ml) was min  resulting  s o l u t i o n of t r i p h e n y l p h o s p h i n e (135 g, 0.51  added dropwise methyl bromoacetate (76 g, 0.50 i n a m i l d l y exothermic  phosphonium bromide.  The m i x t u r e was  and washed w i t h a s m a l l p o r t i o n of benzene.  was  c o n c e n t r a t e d u n t i l c r y s t a l s appeared  dried  (182 g) i n water  (4 I)  filtered  permit  The  filtrate  and allowed to c o o l o v e r n i g h t  b a t c h of the bromide was  collected  and  a l k a l i n e to p h e n o l p h t h a l e i n . The  solution  The p i n k , m i l k y filter  cake  i n s m a l l p o r t i o n s to a f l a s k c o n t a i n i n g s t i r r i n g  (250 ml)  and  s u f f i c i e n t methylene c h l o r i d e was  complete d i s s o l u t i o n of the crude, wet withdrawn and  recrystallized  bromide  added s l o w l y a IN aqueous sodium hydroxide  and washed w i t h water to n e u t r a l i t y .  then t r a n s f e r r e d  phase was and  was  30  the  s o l u t i o n of carbomethoxymethyltriphenylphorphonium  methylene c h l o r i d e to  over  g,85%).  the r e a c t i o n m i x t u r e was  s l u r r y was was  second  (combined y i e l d ; 182  To a s t i r r e d  until  The  mol)  i n benzene  c o o l e d i n the r e f r i g e r a t o r f o r  filtered  the r e f r i g e r a t o r .  mol)  r e a c t i o n which p r e c i p i t a t e d  3h,  in  (17)  phosphorane.  added  The  the o r g a n i c phase washed w i t h water, d r i e d ,  from e t h y l a c e t a t e - p e t r o l e u m  ether  aqueous evaporated  (30-60) to y i e l d  the  144  t r i p h e n y l p h o s p h o r a n e 17 (128g,77%); m.p. 170.5-172 ( l i t . 170-172° r e s p e c t i v e l y ) ; n.m.r. (60 MHz,  CDC1 );  1  9  6  a  '  162-163°,  b  62.74(s,lH,H-2),  3  3.43(s,3H,-0CH ) and 7.17-7.74(m,15H,AT). 3  Methyl(E,^)-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-0-isopropylidene-Da l l o - o c t - 2 - e n o n a t e (18). To a s t i r r e d s o l u t i o n of the b l o c k e d r i b o s y l i m i d a z o l i d i n e 25 mmol) and methylene  chloride  s o l u t i o n of p - t o l u e n e s u l f o n i c acetone over 10 min. 20 min. solid  sodium hydrogen  methylene  (250 ml) i n an i c e - w a t e r b a t h was  (12.5 g, added a  a c i d monohydrate (13.0 g, 68.5 mmol) i n  The r e s u l t i n g m i x t u r e was  The m i x t u r e was  138  then f i l t e r e d  s t i r r e d an  additional  through c e l i t e d i r e c t l y onto  carbonate (5.0 g) and the r e s i d u e washed w i t h  chloride.  The combined f i l t r a t e s were f i l t e r e d  through  CELITE  and evaporated to y i e l d a c l e a r syrup which produced a wide band on the t . l . c . plate compound. in  (2:1 ether-hexanes as d e v e l o p e r ) w i t h the absence of any s t a r t i n g  T h i s syrup of the anhydroaldehyde  a s o l u t i o n of  the phosphorane  17  (16.6  137 was g)  in methylene  (125 ml) and s t i r r e d f o r 1 h a t room temperature. and t r i p h e n y l p h o s p h i n e o x i d e s o l i d i f i e d was  immediately  dissolved chloride  The m i x t u r e was  evaporated  i n the r e s u l t i n g syrup. The mixture  t r i t u r a t e d w i t h a minimum of methylene  chloride,  f i l t e r e d , washed w i t h  methylene  c h l o r i d e and the f i l t r a t e s evaporated to y i e l d a golden syrup  which was  chromatographed  as d e v e l o p e r .  on s i l i c a g e l (500 g) u s i n g 2:1  The major c h r o m a t o g r a p h i c a l l y pure band was  y i e l d the u n s a t u r a t e d e s t e r syrup that was  18  (7.45 g , 8 2 % ) ( l i t .  C C 1  film max  1 7 3 ( )  c  m  - l  20  c o l l e c t e d to  88%) as a c o l o r l e s s  shown to be mixture o f geometric isomers by n.m.r. (^8:1)  w i t h the E-isomer predominating: v 4 — max v  ether-hexanes  )  ;  n  #  n  u  r  e  (  1 0 0  1730(C=0), 1670 c m " ( - C = C - ) ( l i t .  MH ,CDC1_) 61.29 J 2  1  and 1.52(s,3H,C(CH,),), - j J  2 0  3.62  145  (s,3H,-0Me), 6 . 1 1 ( d d , l H , J  2  16 H z , J  3  2  1.5  4  Hz,H-2), 6.99(dd,1H,J  4.0  3  Hz,  20 H-3)(lit. J  3  4.2  ^ 3.5  n.m.r. 61.38  and  3  2  -OMe;  6.21,  H-2;  7.10,  Photoamidation  of Unsaturated  Photoamidation  r e a c t i o n s were c a r r i e d out u s i n g a procedure p r e v i o u s l y  The  light  a pyrex  which was solvents  filter  Sugars  source i n these r e a c t i o n s was  L lamp. The photochemical  via  C ( C H ) ; 3.73,  Hz,H-3; r e s p e c t i v e l y ) .  described"^.  and  1.60,  a Hanova 450 W  r e a c t i o n s were c a r r i e d out by p l a c i n g the lamp  i n s i d e a water c o o l e d quartz immersion w e l l  p l a c e d i n s i d e a 3-necked pyrex v e s s e l c o n t a i n i n g the ( c a p a c i t y w i t h lamp ^300  a magnetic s t i r r i n g bar and  Distilled  ml).  A l l photochemical  n i t r o g e n o v e r n i g h t and  Photoamidation  reaction  the whole apparatus wrapped i n aluminum and  reagent  foil.  grade formamide  r e a c t i o n m i x t u r e s were deoxygenated w i t h  d u r i n g the course of the  of  apparatus  The p h o t o l y s i s mixture was a g i t a t e d  t e r t - b u t a n o l , s p e c t r o g r a d e acetone  were used.  type  irradiations.  Methyl(E,Z)-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-  5,6-0-isopropylidene-D-allo-oct-2-enonate  (18) t o Y i e l d  3-(R,S)-(5-0-  Benzoyl-2,3-0-isopropylidene-B-p-ribofuranosyl)-4-hydroxy-4-methylpentanoic  1,4-lactone  (139), M e t h y l  4,7-anhydro-8-0-benzoyl-3-C-carbamoyl-  2,3-dideoxy-5,6-0-isopropylidene-D-glycero-D-allo (140),  (141) and Methyl  (and a l t r o ) - o c t o n a t e  4,7-anhydro-8-0-benzoyl-2-C-carbamoyl-2,3-dideoxy-  5,6-0-isopropylidene- -glycero-D-allo n  (and a l t r o ) - o c t o n a t e (142),  (143),  e s t e r 18_ (3.7 g ) , acetone  (15 m l ) ,  respectively. A s o l u t i o n of the a, B-unsaturated tert-butanol  (15 ml) and  formamide (30 ml) was  tert-butanol  (10 ml)  formamide (200 ml)  over 3.5  The mixture was  h.  and  added s l o w l y to a m i x t u r e  of  c o n t a i n e d i n the p h o t o l y s i s c e l l  i r r a d i a t e d d u r i n g the a d d i t i o n and  continued  146  for  25 h (or u n t i l a l l of the s t a r t i n g m a t e r i a l had been consumed, as  evidenced by t . l . c .  of the r e a c t i o n m i x t u r e u s i n g 8:4:1  e t h a n o l as d e v e l o p e r ) . of  The r e a c t i o n mixture was  concentrated  c o l l e c t e d , d r i e d over anhydrous y i e l d a crude syrup  (3.9 g ) .  (470 g) u s i n g 8:4:1  crude l a c t o n e lower  removal resulting  chloride  (4 x 200 m l ) , the combined  extracts  to a p p r o x i m a t e l y 100 ml and the c o n c e n t r a t e d e x t r a c t s were then  washed w i t h s a t u r a t e d aqueous sodium  gel  The  d i l u t e d w i t h s a t u r a t e d aqueous sodium  (200 m l ) , e x t r a c t e d w i t h dichloromethane  to  then c o n c e n t r a t e d by  the t e r t - b u t a n o l and acetone under reduced p r e s s u r e at ^ 5 0 ° .  s o l u t i o n i n formamide was  was  benzene-ethylacetate-  sodium  The o r g a n i c phase  sulfate, filtered  and evaporated silica  b e n z e n e - e t h y l a c e t a t e - e t h a n o l as d e v e l o p e r gave (1.46 g) which was  T h i s mixture was  later  contaminated w i t h  rechromatographed  using a  system.  Continued e l u t i o n of the chromatography band, compounds 140, amide band was  (50 m l ) .  Chromatography of t h i s syrup on  (139) as a c l e a r syrup  impurities.  weaker s o l v e n t  chloride  141,  142  and 143  column gave, as a s i n g l e amide  (combined  y i e l d : 1.3  g,  31%).  The  shown to be a m i x t u r e o f the f o u r isomers by n.m.r. and  d e r i v a t i z a t i o n w i t h sodium methoxide.  The d e r i v a t i z a t i o n m i x t u r e  by  indicated  t h a t photoamidation of compound 1_8^ f a v o r s B - a d d i t i o n to c t - a d d i t i o n by an approximate  r a t i o of 10:1  equal amounts.  and t h a t compounds 140 and  Since the amides c o u l d not be s e p a r a t e d by  nor f r a c t i o n a l c r y s t a l l i z a t i o n , amides.  CCl4 max  3  1  shoulder  3  3  o b t a i n e d by c r y s t a l l i z a t i o n from  141-145° ( f i n e n e e l d e s ) ; [ a ] 3  A  g  0  (  ( e s t e r s , C=0);  b  r  o  a  d  m  ) >2'' 1  6  9  0  n.m.r. (100 MHz,  61.98-3.25(m,2.5H,H-2,H-3), 3.64  chromatography  they were c h a r a c t e r e d as a m i x t u r e of f o u r  An a n a l y t i c a l sample was  form-hexane: m.p. v  141 were formed i n  2 5  -29.5  (amide, C=0), CDC1 ) 61.33  w i t h 3.71  3  s i d e band  (cl.0,  1727, and  1738  chloro-  CHC1 ); 3  cm"  1  61.53(s,3H,C(CH ) ), 3  2  (s,3H.-0CH,), 3.94-4.80  147  (m,6H,H-4,H-5,H-6,H-Tfl-Q), 5.96,6.08,6.43 (broad a b l e w i t h D 0, 2  CH ),  s,2H  total,NH  exchange-  2 >  7.52(m,3H,Ar), 8.06(m,2H,Ar); mass spectrum: m/e  392  (m +  376(m -OCH ). +  3  3  A n a l . C a l c . f o r C„ H N0 :C,58.96;H,6.14;N,3.44. Found:C,58.76;H,6.14; n  0c  o  N.3.50. Rechromatography of the h i g h R^ on s i l i c a g e l u s i n g 40:8:1 to 5:4:1 y i e l d e d o n l y one  (with r e s p e c t to the amides) components benzene-ethyl  chromatographically  diastereomeric mixture  gradient,  homogeneous band, c o n s i s t i n g of  of l a c t o n e 139  l a c t o n e s were i n s e p a r a b l e on t . l . c .  acetate-ethanol  (0.45  and  g, 11%,  ^50/50 m i x t u r e ) .  c o u l d not be c r y s t a l l i z e d  the The  from  v a r i o u s s o l v e n t s : [ a ] - 2 3 . 4 ( c l . 4 , CHC1.) '; v 4 1728(benzoate,C=0), D — ' 3 max 1780(lactone,C=0); n.m.r.(100 MHz, C,D,),(isomer n o . l ) , 61.08, 1.18, 1.30 2 3  C C 1  o  and  1.43(s,3H,4xCH_),  2.24(d(overlapping  (d(overlapping H-2a),lH,J 2  ,6  Hz,H-l'),  o  2 b  3  H-2b,lH,J  11 Hz,H-2b), 3.66(pseudo-t,1H,J 3  H-2b),lH,J„  j  9  J„ . 9 Hz,H-2b), 3 . 2 2 5 ( p s e u d o - t , l H , J and 2b,J j , l v  0  J,„ 1  i ^  s ( o v e r l a p p i n g C^D^), 5.3H,Ar), 8.10(m,2H,Ar). at 61.94  a broad  collapsed  4.5  and  2.40(s,3H,2xCH ), 3  H-2a),lH,  Hz,H-l'),  (combined  I r r a d i a t i o n of  7.12 the  p a r t i a l l y c o l l a p s e d the p a i r of p s e u d o - t r i p l e t at 63.64  triplet.  I r r a d i a t i o n of the p a i r of p s e u d o - t r i p l e t s at 63.64  the m u l t i p l e t a 61.94  spectrum m/e  to a broad  quartet(J„ _ 8 to 12 Hz); mass  390(m ), 375(m -CH ), 332(m -Acetone). +  +  +  3  Anal. Calc. for C  2 1  H  2 o  0 : 0,64.60; H,6.72. Found: C.63.88; H.6.77. 7  Attempted C y c l i z a t i o n of Compounds 140 A mixture pyridine  ^,  2.25  61.84-2.12(m,1H.H-3), 3.91-4.42(m,5H.H-2',H-3',H-4',H-5 ),  multiplet to  3  „ 8 Hz,H-2a), 2 . 3 9 ( d ( o v e r l a p p i n g  Z3.  (broad  „ 9 Hz,H-2a),  (isomer no.2), 61.14(s,6H,2xCH ),118 and  2.38(d(overlapping  isomers),  9  (6 ml)  of the amides 140, and  141,  and  141  by R e f l u x i n g i n B a s i c  142  and  143  (125 mg)  was  Solvent  dissolved in  r e f l u x e d (bath temperature: 135-145°) f o r 5h.  T.l.c.  148  of  the s o l u t i o n showed o n l y one c h a r r i n g band i d e n t i c a l to t h a t of  the  starting materials.  Attempted C y c l i z a t i o n of Compounds 140  and  141 by R e f l u x i n g i n High  B o i l i n g Point Solvent A mixture in xylene one  of the amides 140,  (1 ml)  and  141,  r e f l u x e d f o r 5h.  c h a r r i n g band which was  142,  and  B-D-ribofuranosyl)succinimide  and  t a p e r ground g l a s s j o i n t s was apparatus. heated  (152),  respectively.  the f i r s t  g e n t l y rocked.  the f l a s k had begun to char.  The  f i l t e r e d and  syrup was  dissolved  The major h i g h e r R^  (0.42  e t h a n o l as d e v e l o p e r ) m a t e r i a l was gel plate  (15x20 cm,  above s o l v e n t s ) to y i e l d and  standard-  (^100  p l a c e d i n the torr),  and  evaporated  two  to y i e l d a brown  (^90  ml)  and e l u t e d w i t h  u s i n g 15:4:1 b e n z e n e - e t h y l  mm,  then  i n a s m a l l amount of methanol  isolated  1.0  allowed to c o o l and  r i n s e d out w i t h methanol to g i v e  +  on a s i l i c a  and  A f t e r t h i s time the m a t e r i a l i n  and a p p l i e d t o a column of Bio-Rex 70(H ) r e s i n methanol.  t r a p was  reduced  The apparatus was  c e n t r a l t r a p was  a brown s u s p e n s i o n which was (72 mg).  142  to 200-217° ( s u r r o u n d i n g a i r temperature) f o r  45 min w h i l e the f l a s k was  syrup  141,  p l a c e d i n a Kugelruhr vacuum d i s t i l l a t i o n  compartment, the i n t e r n a l p r e s s u r e was  the r e a c t i o n f l a s k and  of amides 140,  t r a p s i n s e r i e s j o i n e d t o g e t h e r by  The r e a c t i o n f l a s k a l o n g w i t h  the r e a c t i o n f l a s k heated  amides.  (S)-(5-0-Benzoyl-2,3-0-isopropylidene-  (151) and  w i t h two  dissolved  T . l . c . of the s o l u t i o n showed o n l y  A round bottom f l a s k c o n t a i n i n g a m i x t u r e equipped  was  141 by Thermal Ring C l o s u r e i n the  Absence of a S o l v e n t to g i v e 3-(R)  (130 mg)  (22 mg)  i d e n t i c a l to the s t a r t i n g  C y c l i z a t i o n of Compounds 140 and  143  143  (26 mg)  and  acetate-  rechromatographed  x2 w i t h 18:4:1 m i x t u r e  p a r t i a l l y o v e r l a p p i n g bands.  of the  C a r e f u l removal  e l u t i o n of the f a s t e r - m o v i n g component gave compound 151 as a  149  c l e a r syrup  (7.0 mg,6%,>95% p u r i t y ) ; n.mr.  (100 MHz,CDCl ) 61.38 and 3  1.57(s,3H,C(CH )„), 2.71(dd(overlapped by H-4b),lH,J 18.0 H z , J , . 8.0 Hz, —j l gem Jj^ta 0  H-4a), 2.93(dd(overlapped by H - 4 a ) , I H , J (m,lH,J  g e m  18.0 H z , J  . 2.5 Hz,H-3), 4.14-4.33(m,2H.H-1',H-4'),  3  4  8.0 Hz,H-4b), 3.26  b  4.39-4.62(m,2H.H-5'),  j , X  4.74(dd,lH,J ^ 2  3  . 7.0 Hz,J.^ ^, 4.8 Hz,H-3'), 5.25(dd,1H,^. ^  7.55(m,3H,Ar), 7.90(broad s,lH,NH), 8.09(m,2H,Ar).  4.0 Hz, H-2'),  I r r a d i a t i o n of the  d o u b l e t of d o u b l e t s a t 65.25 or the m u l t i p l e t a t 63.26 p a r t i a l l y  collapsed  the h i g h f i e l d p o r t i o n o f t h e m u l t i p l e t a t 64.14-4.33. The 100 MHz spectrum w i t h benzene-d, s o l v e n t confirmed the assignment o r d e r a s : H-l',H-4',H-5', o H-3' and H-2' from h i g h - to l o w - f i e l d . Removal and e x t r a c t i o n of the slower-moving component from the p l a t e a f f o r d e d the e p i m e r i c 3-J3 compound the  152 (8.5 mg,7%,>90% w i t h compound  main i m p u r i t y ) , n.m.r. (100 MHz,  2.73(d,2H,J  CDC1 ) 61.37 and 1. 58 (s ,3H,C (CH_ ) ^ ) , 3  3  7.0 Hz,H-4), 3.19(m,1H.H-3), 4 . 3 2 ( p s e u d o - q ( p a r t i a l l y  lapped by H-1'),1H,J .  4.0 Hz, J .  overlapped by H-4'),1H,J  . 3.8 Hz,J .  . 5.3 H z , H - l ' ) , 4.51(d,2H,H-5'), ;L  5.3Hz,J . ^ 2  4.72(dd,lH,H-3'), 7.56(m,3H,Ar), 8.05(m,2H,Ar), 8.20(broad b u r i e d under the l o w - f i e l d aromatic resonances),1H,NH).  6.5 Hz,H-2'), s(partially  I r r a d i a t i o n of  m u l t i p l e t a t 63.19 p a r t i a l l y c o l l a p s e d the d o u b l e t of d o u b l e t at  64.38 t o a d o u b l e t of  the H-4'  (J-, - ^ 5.3Hz) o v e r l a p p i n g two of the l o w - f i e l d 9  a n a l y z e d and a s m a l l p o r t i o n  recovered.  signals  pseudo-quartet.  The h i g h e r R^ minor component e l u t e d by the r e s i n column was, not  over-  4.0 Hz,H-4'), 4 . 3 8 ( d d ( p a r t i a l l y  4.54 (dd ( p a r t i a l l y overlapped by H-5'),1H,J . ^  the  151 as  therefore,  (33 mg,25%) of s t a r t i n g m a t e r i a l was  150  Treatment  o f a M i x t u r e of the Amides 140,  Sodium Methoxide t o Y i e l d  (151), (152),  6 - D - r i b o f u r a n o s y l ) s u c c i n i m i d e [ ( S ) and (153), (154), and Methyl  3(s)  142,  and 143 w i t h M e t h a n o l i c  and ( R ) - ( 2 3 - 0 - i s o p r o p y l i d e n e >  (R)-dihydroshowdomycin a c e t o n i d e ] ,  4,7-anhydro-2-C-carbamoyl-2,3-dideoxy-5,6-0-  isopropylidene-D-glycero-D-allo To a s t i r r e d  141,  (and D - a l t r o ) - o c t o n a t e (155) and  s o l u t i o n of the amides 140,  141,  142,  and  143  ^45:45:5:5 m i x t u r e , r e s p . ) i n anhydrous methanol (33 ml) was sodium methoxide (2.0 ml,0.2N) i n 0.2  ml p o r t i o n s over 2.5  (156), r e s p . (330  added  mg,  methanolic  h a t room tempera-  t u r e under dry n i t r o g e n atmosphere.  The r e a c t i o n m i x t u r e was  w i t h s u f f i c i e n t Bio Rex  ( i n methanol) as i n d i c a t e d by pH  The m i x t u r e was  70(H ) r e s i n +  f i l t e r e d and the methanol evaporated under reduced  to y i e l d a crude syrup  (400 mg)  (e.g. methyl b e n z o a t e ) . gel  P r e l i m i n a r y p u r i f i c a t i o n of the syrup on  paper.  pressure  which r e l e a s e d the sweet odor of an  (35 g) u s i n g a 15:4:1 to 5:4:1  as d e v e l o p e r y i e l d e d 55%)  then n e u t r a l i z e d  ester  silica  benzene-ethyl a c e t a t e - e t h a n o l g r a d i e n t  the b l o c k e d r i b o s y l s u c c i n i m i d e s 151 and 152  as p a r t i a l l y r e s o l v e d (by t . l . c . u s i n g 15:4:1 d e v e l o p e r )  (168  mg,  fractions  which by n.m.r. were shown to be i d e n t i c a l to the s u c c i n i m i d e s  produced  by the thermal r i n g c l o s u r e o f the s t a r t i n g amides (see page 148). Continued 153 and  154  e l u t i o n o f the chromatography column gave a mixture of imides  (86 mg,28%)(which were l a t e r rechromatographed) and a f i n a l band  of the d e b e n z o y l a t e d , ct-addition amides 155 and 156  (21.5 mg,9%).  Very c a r e f u l chromatography of the mixture of a c e t o n i d e s 153 and i n s m a l l p o r t i o n s (^30  mg)  on s i l i c a  g e l (6.0 g) u s i n g 8:4:1  a c e t a t e - e t h a n o l as d e v e l o p e r a f f o r d e d a s l i g h t l y h i g h e r R^ c h a r r i n g band which c o u l d be induced to c r y s t a l l i z e r a p i d l y s o l u t i o n to y i e l d a 1:1 80.5*(neeldes).  154  benzene-ethyl (0.329) p i n k i n a chloroform  complex w i t h the s o l v e n t ( c h l o r o f o r m ) : m.p.  77.5-  151  A n a l . C a l c . f o r C, _H. ,N0,. CHC1, :C, 39. 96 ;H, 4 . 65 ;C1, 27 . 23 ;N, 3. 56. 12 1/ o J Found:C,40.04;H,4.47;CI,27.11;N,3. 63. R e c r y s t a l l i z a t i o n of the same h i g h e r  band from hexane-benzene-  e t h a n o l y i e l d e d c r y s t a l s of 153 which were f r e e of s o l v e n t ; m.p.123-125° (lit.  173-174°); [ a ] " -9.27°(cl.O.CHCl,); v 3 3475,3410(NH), ' D — 3 max 3225(broad,OH),1725,1780 cm" weak shoulder (amide c a r b o n y l ) ; n.m.r. (100 1  1  8  a  C H C 1  1  MHz,DMS0-d,) 61.29 and 1.47(s,3H,C(CH,) ), 2.63(d,2H,J. . 7.0 Hz,H-4), o —J l J, k n  3.16(t of d . l H . J , . 7.0 H z , J . 3,4 3,1  3.5 Hz,H-3), 3.49(dd,2H,J. „ k ,  4.0Hz,J Un, J  D  5.0Hz, c o l l a p s e s to a doublet of 4.0Hz upon a d d i t i o n of D 0,H-5'),  3.87  2  (pseudo-q.lH.J^ J > 1  2  5  4.0 H z . J ^ ^, 4.0Hz,H-3'), 4.14(dd,IH,J ^  >  , 5.0Hz,H-l'), 4 . 4 6 ( d d , l H , J . ^  5.0Hz,J ^ ^  1  1H,J.. z ,J  3.5Hz,  3  6.5Hz,J_. ., 4.0Hz,H-3'), 3 ,A  2  6.5Hz,H-2'), 4.61(dd,  4.87(t,IH,J „ 5.0Hz,OH,exchangeable On,J —  w i t h D 0) , 11.13(broad s,1H,NH,exchangeable w i t h D^O).  I r r a d i a t i o n of the  2  pseudo-quartet at 63.87 p a r t i a l l y  coallpsed  the doublet of d o u b l e t s of  64.61 t o a broad d o u b l e t and c o l l a p s e d the d o u b l e t of d o u b l e t s a t 63.49 to a d o u b l e t .  I r r a d i a t i o n of the t r i p l e t  of d o u b l e t s at 63.16 c o l l a p s e d  the' d o u b l e t of d o u b l e t s a t 64.14 t o a d o u b l e t and c o l l a p s e d the doublet at 62.63 to a broad s i n g l e t m/e  272(m +H), 256(m -CH ), +  240(m -0CH ).  +  +  3  A n a l . C a l c . f o r C, _H,,N0,:C,53.13;H,6.32;N,5.16.  3  Found:C,53.00;  H,6.38;N,5.10.  Continued e l u t i o n of the a c e t o n i d e mixture y i e l d e d the 3-R-diastereomer (154) as a c l e a r syrup which was c r y s t a l l i z e d [a]£  5  -35.3° (c0.5,CH OH), v ^  L  3  OH), 1725, 1785 cm"  3  weak s h o u l d e r  1  i n methanol: m.p.  159.5-161° ( g r a n u l a r ) ;  3500(broad), 3420 (sharp ,NH) , 3250(broad, (imide c a r b o n y l s ) ; n.m.r. (100 MHz,DMS0-d ) 6  61.30 and 1.46(s,3H,C(CH.j) >, 2 . 4 5 ( d d ( p a r t i a l l y obscured by  DMSO),IH,J  2  18.0Hz,J . 5.0Hz,H-4a), 2.82(dd,lH,J 18.0Hz,J, 9.0Hz,H-4b), 3,4a gem 3,4b o  (m,lH,J  3  4  b  9.0Hz,J  3  4  a  5.0Hz,J  3  ^  gem  3.24  4.0Hz,H-3), 3.42 ( d , 2 H , J , .5.0Hz,H-5'), 4  5  152  3.83(pseudo-q,lH,J . ^ 4  2  *  A.5Hz,J  A.90(dd,lH,J , 2  with D 0).  ^  3  3  5.0Hz,J . ^  4.5Hz,H-4'), A.05(pseudo-t,1H,  3  4.0Hz,H-l'), 4 . 5 1 ( d d , l H , J * 2  ,  b.bViZ,!^ ^  d o u b l e t o f d o u b l e t s at 6A.51  A.5Hz,H-3'),  3  4.5Hz,H-2'), 11.15(broad s,1H,NH,exchangeable  I r r a d i a t i o n of the pseudo-quartet  2  6.5Hz,J . ^  y  at 63.83 c o l l a p s e d the  to a d o u b l e t ( J ^ ^ 2  at 63.A2 c o l l a p s e d t o a broad  singlet.  3  6.5Hz) w h i l e the d o u b l e t  I r r a d i a t i o n of the d o u b l e t  of  d o u b l e t s at 6A.90 c o l l a p s e d the p s e u d o - t r i p l e t at 64.05 to a broad w h i l e the c o l l a p s e of the d o u b l e t of d o u b l e t s a t 64.51 anomolous due  doublet  to a s i n g l e t  t o i t s p r o x i m i t y to the i r r a d i a t i o n frequency.  appear  Irradiation  of the p s e u d o - t r i p l e t a t 64.05 c o l l a p s e d the d o u b l e t of d o u b l e t s at 64.90 to a d o u b l e t  (J >  ~, 7.0Hz) w h i l e the m u l t i p l e t a t 63.24 c o l l a p s e d to a  9  d o u b l e t of d o u b l e t s  (J- .  5.0Hz and  J„  ,, 9.0Hz); mass spectrum; m/e  272  (m +H), 256(m -CH ), 2A0(m -OCH ). +  +  +  3  3  A n a l . C a l c . f o r C, -H, -.NO, :C,53.13;H,6 . 32;N,5.16. Found :C,53 .08; H.6.45; N.5.16. Rechromatography of amides 155 diastereomers  156  nor c o u l d they be c r y s t a l l e d  ( m i x t u r e , 100MHz,CDC1 ) 61.34 3  without  and  and  failed  to s e p a r a t e the  from v a r i o u s  solvents:n.m.r.  1 . 5 2 ( s , 3 H , C ( C H ) ) , 2.20(broad band 3  2  f i n e s t r u c t u r e , approx.2H,H-3),3.51(m,lH,H-2), 3. 69 (d, 2H, J., _  3.5Hz,H-8), 3.77(s,3H,-0CH ), 4.02(m,2H.H-A.H-7), 4.40(dd,1H.H-5 or 3  A.68(m,lH,H-5 or H-6), v 3 max m  C  mass spectrum; m/e Debenzoylation  and  and  152  304  6.80(broad s,lH,NH ); [ a ] ^ - 1 6  (-CO.Me) , 1680 2  +  and  (m -Me), 272 +  152  s o l u t i o n of a m i x t u r e  (100 mg)  (-CONH.) , 1580 2  under d r y n i t r o g e n atmosphere.  3  cm"  (N-H) ;  1  (m -0CH ). +  3  to g i v e compounds 154  and  (^50/50) of the b l o c k e d  i n anhydrous methanol (10 ml) was  sodium methoxide (1.0 ml,0.2N) i n 0.2  H-6)  (£1.3, CHC1 );  3  2  (m +H), 288  of Compounds 151  To a s t i r r e d 151  6.40  3500, 3360 (N-H) , 1725  1  two  added  ml p o r t i o n s over 1.5h  153.resp. succinimides  methanolic a t room  T . l . c . of the r e a c t i o n m i x t u r e  using  temperature 8:4:1  153  b e n z e n e - e t h y l a c e t a t e - e t h a n o l as d e v e l o p e r showed complete of  s t a r t i n g m a t e r i a l s and  two  o v e r l a p p i n g lower  i d e n t i c a l to t h a t of compounds 153 and 154.  (0.33 and  +  the methanol, the crude syrup  portions  (^30  mg)  on s i l i c a  (109 mg)  was  compounds 153 and to  154  those of 153 and  photoamidation  Attempted  evaporation  benzene-ethyl a c e t a t e -  152 were i d e n t i c a l  (by n.m.r.)  154 o b t a i n e d from t r e a t i n g the amide m i x t u r e , from  the  o f 18_, w i t h sodium methoxide.  Dehydrogenation  on c h a r c o a l (102 mg)  of Succinimide with Palladium.  was  b i p h e n y l (11 g) and  heated u n t i l r e f l u x  A slow stream of dry carbon d i o x i d e gas was m i x t u r e which was cool  and  d e s c r i b e d p r e v i o u s l y . Thus,  o b t a i n e d from 151 and  A m i x t u r e of s u c c i n i m i d e (28 mg),  to  bands  chromatographed i n s m a l l  g e l (6.0 g) u s i n g 8:4:1  e t h a n o l as d e v e l o p e r to a c h i e v e r e s u l t s  0.31)  A f t e r n e u t r a l i z a t i o n o f the  r e a c t i o n m i x t u r e w i t h Bio-Rex 7 0 ( H ) r e s i n , f i l t r a t i o n , of  consumption  heated  (^100°C) and was  e x t r a c t s were f i l t e r e d  f o r 25 h.  (^270° e x t e r n a l temperature). passed  through  the r e f l u x i n g  The r e a c t i o n mixture was  e x t r a c t e d w i t h hot water  and evaporated  the n.m.r. o f t h i s product was  10% p a l l a d i u m  then allowed  (2x12 m i s ) .  The  combined  to y i e l d a c r y s t a l l i n e r e s i d u e (28  mg)  i d e n t i c a l to t h a t of the s t a r t i n g s u c c i n i m i d e .  P r e p a r a t i o n of N i c k e l P e r o x i d e F o l l o w i n g the procedure o f Nakagawa, Konaka and N a k a t a ^ , a s o l u t i o n 1  sodium h y d r o x i d e added dropwise  (42 g) i n 5.3%  m i x t u r e was  stirred  filter  of  the f i l t r a t i o n apparatus  The a d d i t i o n was  completed  i n 10 min and  and wash the f i n e n i c k e l p e r o x i d e s u s p e n s i o n f a i l e d due ( i . e . , Whatman n o . l f i l t e r  A p o r t i o n of the s u s p e n s i o n was  of  was  s o l u t i o n of n i c k e l s u l f a t e - h e x a h y d r a t e  f o r an a d d i t i o n a l 30 min a t room temperature.  to  glass).  aqueous sodium h y p o c h l o r i t e (300 ml)  to a m e c h a n i c a l l y s t i r r e d  (130 g) i n water (300 m l ) .  1  paper and  the  Attempts to c l o g g i n g sintered  removed, t r a n s f e r e d to c e n t r i f u g e  154  bottles  (200 ml c a p a c i t y / b o t t l e ) , c e n t r i f u g e d , the supernatant  f r e s h d i s t i l l e d water added  (^150  process was  p a r t of the s u s p e n s i o n  indicating and  continued u n t i l  The  ml s u s p e n s i o n ) , and r e c e n t r i f u g e d .  the removal of the excess base.  the r e s i d u e was activity  removed,  The  failed  of the n i c k e l p e r o x i d e was  to s e p a r a t e  supernatant was  f i l t e r e d , d r i e d under vacuo, and  crushed  determined  This  discarded  to a powder.  iodometrically  _3 to be: 1.7  x 10  g-atom oxygen/g n i c k e l  Attempted Dehydrogenation  peroxide.  of the R i b o s y l S u c c i n i m i d e s u s i n g N i c k e l P e r o x i d e .  A s o l u t i o n of the b l o c k e d r i b o s y l s u c c i n i m i d e s 151 and 0.11  mmol) i n x y l e n e  (2 ml) was  added to n i c k e l p e r o x i d e  152  (200 mg,  (42 ^3  mg, equiv.,  _3 activity:  1.7  x 10  equiv/g N i 0 2 ) .  which the r e a c t i o n m i x t u r e was removed and reduced  filtered  through  The mixture was  allowed to s e t t l e ,  celite.  refluxed  f o r 60 h a f t e r  the supernatent  solution  E v a p o r a t i o n of the s o l v e n t under  p r e s s u r e r e s u l t e d i n a p a l e green syrup  (220 mg)  which  produced  f o u r wide bands and b a s e l i n e m a t e r i a l on t . l . c . w i t h v a r i o u s d e v e l o p e r s . Attempts to i s o l a t e the carbohydrate  product  from  t h i s mixture were not  considered. S i m i l a r treatment 26 h d i d not g i v e any absorb  U.V.  of compounds 153  and  products of d i f f e r e n t  154  i n r e f l u x i n g benzene f o r  R^ nor d i d the c h a r r i n g bands  light.  Treatment of compounds 153  and  154  at room temperature  with  peroxide  (50 e q u i v . ) f o r 7 days u s i n g water as the s o l v e n t f a i l e d  any U.V.  a c t i v e c h a r r i n g bands.  Attempted Dehydrogenation  of Compounds 153  and  nickel t o produce  154 w i t h D i c y a n o d i c h l o r o -  quinone (DDQ). A s o l u t i o n of a 60:40 mixture 154  (20 mg)  of the r i b o s y l s u c c i n i m i d e s 153  and d i c y a n o d i c h l o r o q u i n o n e i n dioxan  (1.5 ml) was  and  refluxed for  155  3 days. mg)  The m i x t u r e s was  washed w i t h d i o x a n  evaporated U.V.  cooled, f i l t e r e d  (2.0 m l ) .  t o g i v e a crude syrup  and  the o f f - w h i t e s o l i d s  The combined f i l t r a t e s were then (43 mg)  which on t . l . c .  a c t i v e bands (9:1 e t h y l a c e t a t e - e t h a n o l d e v e l o p e r ) .  (0.23-0.36) U.V.  (25  showed two The  a c t i v e band a l s o overlapped a c h a r r i n g band  broad  higher (R^ 0.27).  Chromatography of the syrup on s i l i c a g e l (5.0 g) u s i n g 9:1 e t h y l a c e t a t e e t h a n o l as developer y i e l d e d which d i d not absorb U.V. was  not  Attempted  the c h a r r i n g band as a c l e a r syrup  light.  g)  F u r t h e r a n a l y s i s of t h i s band, t h e r e f o r e ,  attempted.  S y n t h e s i s of  (R,S)-3-Bromo-3-(5'-0-benzoyl-2',3'-0-isopropylidene-  g-D-ribofuranosyl)succinimide  (169).  A m i x t u r e of the b l o c k e d r i b o s y l s u c c i n i m i d e s 151 and mmol), N-bromosuccinimide (50 mg,  0.29  152  A f t e r 17 min  (5  0.23 mg)  r e f l u x e d under anhydrous c o n d i t i o n s .  A f t e r r e f l u x f o r a few minutes, most of the s o l i d m a t e r i a l had solution.  (85 mg,  mmol), and b e n z o y l p e r o x i d e  i n 5 ml anhydrous carbon t e t r a c h l o r i d e was  mixture.  (12.5  gone i n t o  of r e f l u x , a n o i l began to s e p a r a t e from the r e a c t i o n  The mixture was  r e f l u x e d an a d d i t i o n a l 15 min a f t e r which i t was  c o o l e d , d i l u t e d w i t h c h l o r o f o r m (6 m l ) , washed w i t h 5% aqueous sodium hydrogen c a r b o n a t e , and d r i e d over anhydrous sodium s u l f a t e . s o l v e n t s under reduced on a t . l . c .  p r e s s u r e and chromatography of the r e s i d u a l  p l a t e u s i n g 20:4:1 b e n z e n e - e t h y l a c e t a t e - e t h a n o l as  (developed twice) gave a five-component band  E v a p o r a t i o n of the  (R^ 0.43)  gave a c l e a r syrup  o f compounds which s t i l l a n a l y s e s of t h i s band and  developer  m i x t u r e . I s o l a t i o n of the major  (11 mg)  r e t a i n e d H-3  syrup  which by n.m.r. showed a m i x t u r e  o f the s u c c i n i m i d e r i n g .  the o t h e r minor components were not  Further pursued.  156  3- ( S ) - ( 3 - D - r i b o f u r a n o s y l ) s u c c i n i m i d e (170), from Compound A s o l u t i o n of a c e t o n i d e 153 methanol  (4.0 ml) was  stirred  (124 mg)  i n 3:1  153.  trifluoroacetic  f o r 45 min at room temperature.  acid-  After  e v a p o r a t i o n of the s o l v e n t s under reduced p r e s s u r e , the r e s i d u a l syrup was  chromatographed  on a column o f Bio-Rex 70(H ) r e s i n which was +  w i t h water to y i e l d 91%).  (S_)-dihydroshowdomycin  An a n a l y t i c sample was  acetone; m.p.  136-140°  DMS0-d ) 62.48(dd 6  H-4a),  J . 2  3  [a]  2 3  -10.2°  17.5Hz,J_  benzene-  2  H  2.72(dd,lH,J  from  mg,  (c3.4,H 0); n.m.r. (100  ( p a r t i a l l y obscured by DMSO), l >  17.5Hz,J  J g  e  m  3  ^  MHz,  9.0Hz,  5.0Hz,H-4b), 3.06(m,1H,H-3),3.43(d,2H,  3, 4b  gem 5  170 as a c l e a r syrup (96  o b t a i n e d by c r y s t a l l i z a t i o n  (leaflets);  developed  . 4.0Hz,H-5'), 3.60(dd  ( p a r t i a l l y obscured by H-4') . l H . J ^  . 5.5Hz,H-2'), 3.70(m,lH,H-4'), 3 . 8 3 ( d d , 1 H ,  H-3'); 4.06(dd,lH,J  2.0Hz,J j , J.  J.  exchangeable w i t h D 0 ) ,  , _ ,z  y  ^  8.0Hz,  5.5Hz,J ^ ^  3.0Hz,  3  8.0Hz,H-l'), 4.54(broad  s,3H,3xOH,  11.0(broad s,lH,NH, exchangeable w i t h D 0 ) .  2  2  I r r a d i a t i o n o f the d o u b l e t of d o u b l e t s at  64.06 c o l l a p s e d  the d o u b l e t  of d o u b l e t a t 63.60 t o a d o u b l e t 63.06 c o l l a p s e d  ~* 5.5Hz) w h i l e the m u l t i p l e t a t z ,j to a d o u b l e t o f d o u b l e t s (J„ . 9.0Hz and J ., 5.0Hz). 3,4a 3,4b n  I r r a d i a t i o n o f the m u l t i p l e t at 63.06 c o l l a p s e d the d o u b l e t of d o u b l e t s at  64.06 to a d o u b l e t (J^  (dd,lH,J  3  ^  2.5Hz,J  1>  2  ^  8.0Hz): n.m.r. (100MHz,D 0-D CCO D) 2  ,7.0Hz,H-l'),  i n t e r n a l D.S.S. s t a n d a r d ) 64.50(J.  2  64.13  n.m.r. (60MHz,D 0-D CCO D, 2  3  2  2.5Hz)); mass spectrum:m/e 232(m +H), +  »-t  213(m -H 0), 200(m -CH OH). +  (lit.  3  +  2  2  A n a l . C a l c . f o r C H N0 :C,46.75;H,5.67;N,6.06. g  13  6  Found:  C,47.21;  H,5.76;N,6.06. 3-(R)-(g-D-ribofuranosyl)succinimide A s o l u t i o n of a c e t o n i d e 154 (4.0 ml) was  stirred  (171) from Compound  (98 mg)  i n 3:1  154.  trifluoroactic  f o r 45 min. a t room temperature.  acid-methanol  A f t e r e v a p o r a t i o n of  157  the  s o l v e n t s under reduced p r e s s u r e , the r e s u l t i n g syrup was  chromatographed  on a column of Bio-Rex 70(H ) r e s i n and e l u t e d w i t h water to y i e l d  (R)-  +  dihydroshowdomycin  (171) as a c l e a r syrup (72.5 mg,  to c r y s t a l l i z e from a v a r i e t y of s o l v e n t s : (270 and 400MHz,D 0) 62.72(dd,lH,J 2 gem o  1H,J  gem  J.. , 4,5a c  19.0Hz,J  ^  5.6Hz,H-5'a),3.69(dd,IH,J  4.4Hz,J  H-2').  1>  2  3.00(dd, ' 12.3Hz, '  gem  12.3Hz,J.,  6.0Hz,J ^ ^ 3  4,5b  3.6Hz,H-5'b),  3.87  4.8Hz,H-3'), 4.05(q,lH, 3.0Hz,J . ^ 2  3.0Hz,  I r r a d i a t i o n of the m u l t i p l e t a t 63.33 c o l l a p s e d the d o u b l e t of , 1  5.  . 4.3Hz,H-4a), 3,4a  o  . 6.2Hz,H-l'),4.30(pseudo-t,lH,^  d o u b l e t s a t 64.05 to a d o u b l e t ( J at  19.0Hz,J  (c3.4,1^0), n.m.r.  ., 9.4Hz,H-4b), 3.33(m,lH,H-3), 3.54(dd,lH,J 3,4b ' gem  2  3  25 [ a ] ^ -16.6°  The syrup f a i l e d  o  (m,lH,H-4'),4.00(pseudo-t,lH,J . ^ J  87%).  62.72 and 63.00 c o l l a p s e d  6.4Hz) w h i l e the d o u b l e t o f d o u b l e t s »  J  to two d o u b l e t s w i t h J . 4a, 4b  3-(S)-a-Dihydroshowdomycin  19Hz.  Acetonide  Photoamidation of Methyl(E,Z)-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,60-isopropylidene-D-ribo-oct-3-enonate  (172) to y i e l d Diastereomers 140,  141,  M e t h y l 4,7-anhydro-8-0-benzoyl-3-C-carbamoyl-2,3-dideoxy-5,6-0-isopropylideneD-glycero-D-gluco  (and manno)-octonate  A s o l u t i o n of the e n o l e t h e r 172 (15 ml) and formamide (30 ml) was  (173), (174), r e s p e c t i v e l y . (6.0 g ) , acetone (15 m l ) , t e r t - b u t a n o l  added over 3h to a m i x t u r e o f t e r t - b u t a n o l  (10 ml) and formamide (200 ml) c o n t a i n e d i n a p h o t o l y s i s c e l l . was  i r r a d i a t e d d u r i n g the a d d i t i o n and c o n t i n u e d f o r 4 days  the  s t a r t i n g m a t e r i a l had been consumed, as evidenced by t . l . c .  m i x t u r e u s i n g 8:4:1 m i x t u r e was  The m i x t u r e  (or u n t i l a l l of  b e n z e n e - e t h y l a c e t a t e - e t h a n o l as d e v e l o p e r ) .  of the r e a c t i o n The  reaction  then c o n c e n t r a t e d by removal of the t e r t - b u t a n o l and acetone under  158  reduced p r e s s u r e at ^ 5 5 ° .  The r e s u l t i n g s o l u t i o n i n formamide was  w i t h s a t u r a t e d aqueous sodium c h l o r i d e  diluted  (200 m l ) , e x t r a c t e d w i t h d i c h l o r o -  methane (4x200 m l ) , the combined e x t r a c t s c o n c e n t r a t e d to a p p r o x i m a t e l y 100 ml and the c o n c e n t r a t e d s o l u t i o n then washed w i t h s a t u r a t e d sodium c h l o r i d e  (50 m l ) .  The o r g a n i c phase was  anhydrous sodium s u l f a t e , f i l t e r e d  aqueous  c o l l e c t e d , d r i e d over  and evaporated to y i e l d a crude syrup  which was chromatographed on s i l i c a g e l (465 g) u s i n g 9:1 b e n z e n e - e t h a n o l as d e v e l o p e r . I s o l a t i o n of t h e band c o r r e s p o n d i n g t o the amides synthesized 22%).  previously  (see photoamidation of compd. 18) gave a c l e a r syrup  (1.5 g,  The amide band was shown to be a m i x t u r e of the d i a s t e r e o m e r i c amides  140, 141, 173 and 173 by n.m.r. and by c o n v e r s i o n of the amides to c y c l i c imides.  An a n a l y s i s o f the n.m.r. s p e c t r a of the above imides  a p p r o x i m a t e l y 2:1 r a t i o o f the a to 8-anomers  of the amides.  i n d i c a t e d an An  analytical  sample o f a m i x t u r e o f the amides was o b t a i n e d by c r y s t a l l i z a t i o n from chloroform-hexane; m.p. CHC1„); j vin 3.x 3 C H C 1  23 [ a ] Q + 3.6°  3410, 3515(N-H), 1722(ester c a r b o n y l s ) , 1685(amide  1596 c m ( a m i d e _1  180-185° (amorphous s o l i d ) ;  (cl.O, carbonyl),  I I band); n.m.r.(100MHz,CDC1 ) 51.34 and 1 . 5 4 ( s , 3 H , C ( C H ) ) , 3  2.41-3.44(m,3H,H-2,H-3), 3.65(s,3H,-OCH ), 3  3  4.05-4.85(m,6H.H-4 to H-8),  6.19,6.49(broad o v e r l a p p i n g s i n g l e t s , approx.2H,NH ), 2  2H,Ar); mass spectrum: m/e  +  +  3  25  H,6.05;N,3.39.  used i n the extended sense  g  5.97,  8.05(m,  392(m -CH ), 376(m -OCH ). 3  A n a l . C a l c . f o r C H NO :C,58.96;H,6.19;N,3.44. 2Q  7.54(m,3H,Ar),  2  Found:C,58.60;  159  Treatment  of a M i x t u r e o f the Amides 140,  Sodium Methoxide to y i e l d  151,  152,  153,  lidene-a-D-ribofuranosyl)succinimide  141, 154,  173,  and  3-(R)  and  (175),(176), Methyl  174 w i t h M e t h a n o l i c (S)-(2,3-0-Isopropy4,7-anhydro-3-C-  carbamoyl-2,3-dideoxy-5,6-0-isopropylidene-D-glycero-D-gluco-octonate  (177),  respectively. To a s t i r r e d  s o l u t i o n of amides 140,  anhydrous methanol (15 ml) was 0.2N).  The m i x t u r e was  141,  173,  and 174  allowed to s t i r a t room temperature  the s t a r t i n g compounds (R^ 0.28)  the  and h i g h e r and lower R^ m a t e r i a l s .  allowed to s t i r o v e r n i g h t (14h).  the r e a c t i o n m i x t u r e showed l i t t l e  f i l t e r e d , evaporated  p a r t i t i o n e d between chloroform-water s o l u b l e components (195 mg, components (240 mg, The  and  (25:25, V/V)  was  (185 mg).  crude syrup) from the o r g a n i c s o l v e n t  by  syrup  soluble  crude s y r u p ) .  e l u t e d w i t h methanol.  The slower-moving  dissolved  cm)  i n a small  of Bio-Rex 70(H ) +  c o l o r l e s s component  the s o l v e n t removed to y i e l d a p a r t i a l l y c r y s t a l l i n e  T . l . c . o f t h i s syrupy mixture u s i n g 1:1  developer i n d i c a t e d lower R^  (as i n d i c a t e d  the r e s i d u a l  syrup from the c h l o r o f o r m s o l u b l e l a y e r was  i s o l a t e d and  terminated  to s e p a r a t e the water  q u a n t i t y of methanol, a p p l i e d t o a column (23 x 2.6 r e s i n and  added  change so that the r e a c t i o n was +  The m i x t u r e was  An  T . l . c . a n a l y s i s of  by n e u t r a l i z a t i o n o f the s o l u t i o n w i t h Bio-Rex 70(H ) r e s i n pH paper).  mixture  presence  a d d i t i o n a l 0.1 ml of the m e t h a n o l i c sodium methoxide s o l u t i o n was the m i x t u r e was  ml,  under dry  of the r e a c t i o n  (9:5:1 b e n z e n e - e t h y l a c e t a t e - e t h a n o l as d e v e l o p e r ) i n d i c a t e d  and  in  added m e t h a n o l i c sodium methoxide (0.4  n i t r o g e n atmosphere f o r 8h a f t e r which time t . l . c .  of  (400 mg)  two bands, a major broad band  syrup  b e n z e n e - e t h y l a c e t a t e as (R^ 0.32-0.43) and  a  (0.13) minor narrow band c o r r e s p o n d i n g to the s t a r t i n g amides.  Column chromatography on s i l i c a g e l (15 g) of the syrup u s i n g a 2:1  to  1:1  160  benzene-ethyl succimides  a c e t a t e g r a d i e n t a f f o r d e d mainly  the b l o c k e d  151 and 152 (^60% o f i s o l a t e d m a t e r i a l ) p l u s o t h e r minor  components ( ^ 4 0 % ) ( t o t a l : 124 g, 34% based  on 151 and 152) as p a r t i a l l y  r e s o l v e d f r a c t i o n s as i n d i c a t e d by t h e i r n.m.r. s p e c t r a . of  t h i s broad band corresponded  and  ribosyl  mainly  The head and t a i l  t o the '8' r i b o s y l s u c c i n i m i d e s 151  152, r e s p e c t i v e l y , p r e v i o u s l y i s o l a t e d w h i l e the c e n t r a l p o r t i o n o f  the band corresponded materials. was  t o a mixture of the above and o t h e r  unidentified  F u r t h e r p u r i f i c a t i o n or c h a r a c t e r i z a t i o n of these  mixtures  not attempted. The  dissolved  syrup from the water s o l u b l e p o r t i o n o f the r e a c t i o n m i x t u r e was i n a s m a l l q u a n t i t y of water, a p p l i e d to a column (33.0 x 3.5 cm)  of  Bio-Rex 7 0 ( H ) r e s i n and e l u t e d w i t h water to y i e l d  of  the f a s t e r - m o v i n g band on s i l i c a  +  e t h a n o l as d e v e l o p e r  3 major bands. T . l . c .  g e l u s i n g 5:4:1 b e n z e n e - e t h y l  acetate-  i n d i c a t e d two major bands, a broad h i g h e r R^ (0.33) band  c h a r r i n g pink on the f a s t e r - m o v i n g p o r t i o n of the band and a narrower low R^ (0.24) band which c h a r r e d more u n i f o r m l y . The  f i r s t band  (85 mg) e l u t e d from  rechromatographed on s i l i c a  the r e s i n column was t h e r e f o r e  g e l (5 g) i n two p o r t i o n s u s i n g 5:4:1 benzene-  e t h y l a c e t a t e - e t h a n o l as d e v e l o p e r .  A p o r t i o n o f the f a s t e r - m o v i n g ,  pink-  c h a r r i n g band was i s o l a t e d pure (5.0 mg, 2%) and was found t o be i d e n t i c a l , by n.m.r. s p e c t r o s c o p y and by the m e l t i n g p o i n t of the 1:1 c r y s t a l l i n e  complex  w i t h c h l o r o f o r m , t o the 3 - S - ( 8 - r i b o s y l ) s u c c i n i m i d e 153 p r e v i o u s l y s y n t h e s i z e d . Continued  e l u t i o n o f the column gave a p o r t i o n (21 mg, 7.5%) of t h e h i g h e r  R^ band which was f r e e o f t h e p i n k c h a r r i n g m a t e r i a l . of  this fraction  indicated  the presence  The n.m.r.  spectrum  o f two compounds the major component  (^2:1) b e i n g the a - 3 - ( R ) - r i b o s y l s u c c i n i m i d e a c e t o n i d e 175 and the minor component b e i n g the p r e v i o u s l y s y n t h e s i z e d lower R^.  6-3-R-isomer 154.  The  161  pure  a-anomer c o u l d not be o b t a i n e d by chromatography nor by  crystalli-  zation', t h e r e f o r e , the o p t i c a l r o t a t i o n of the 2:1 m i x t u r e o f the a/8 25  i s r e p o r t e d a l o n g w i t h a t e n t a t i v e n.m.r. assignment:  + 8.04°  (c2.0,MeOH); n.m.r. (100MHz,CDC1 > 61.30 and 1 . 4 7 ( s , 3 H , C ( C H ) ) , 2.70 3  (dd,lH,J  gem  3  19.0Hz,J_ . 10.0Hz,H-4a), 2.86(dd,lH,J 19.0Hz,J, ., '3,4a gem '3,4b  5.0Hz,H-4b), 3.17(m,lH,H-3), 3 . 6 0 ( d , 2 H , ^ approx. 1H,0H), 4 . 1 4 ( t , l H , J 2  ,  2  ,  4.5Hz,H-5'), 2.07(broad s,  4.5Hz,H-4'), 4.56(dd,lH,J  3.5Hz,H-l'), 4 . 7 0 ( d , l H , J ,  , 2.0Hz,  6.0Hz), 4.75(dd ,1H,  2  ^  3.5Hz,J ,  ^  2  6.0Hz,H-2'), 9.00(broad s, approx.1H,NH). Continued e l u t i o n of the column gave the low  a-3-(S_)-ribosyl-  s u c c i n i m i d e a c e t o n i d e 176 (32 mg,12%) as pure d i a s t e r e o m e r e a s i l y from the o t h e r t h r e e and c r y s t a l l i z e d [a]J5  i n c h l o r o f o r m : m.p.  separable  141.5-144.5*",  -1.0° (c0.5,MeOH); n.m.r. (100MHz,CDC1 ) 61.22 and 1 . 4 1 ( s , 3 H , C ( C H ) ) , 3  3  2  2.16(broad s,lH,0H, exchangeable w i t h D 0 ) , 2.68(dd,lH,J 18.5Hz,J„ , / gem J,4a 9.5Hz,H-4a), 2.96(dd,lH,J 18.5Hz.J_ 5.0Hz,H-4b), 3.40(m,lH,H-3), S63 gem 3,4b o  (broad d,2H,J ^ ^  4.0Hz,H-5'), 4.22(broad t , l H , J ^ ^  4  1H,J  3  1  4.0Hz,H-4'), 4.40(dd,  4  ^ S.OHz.H.^ . 3.8Hz,H-l'), 4. 65 (dd, IH, J ^ 2  H-3'), 4.76(dd,lH,J ,  , 6.0Hz,J  3  1.0Hz,  3.8Hz,H-2'), 8.28(broad s,lH,NH,  D 0 - e x c h a n g e a b l e ) ; mass spectrum; m/e 2  6.0Hz,J ^ ^  y  272(m +H), 256(m -CH ), +  +  3  A n a l . C a l c . f o r C, H, -.NO,:C,53 .13;H,6.32;N,5.16. i z 1/ b 0  240(m -HOCH ). +  2  Found:C,53. 35;  H,6.38;N,5.17. The f i n a l  slower moving bands of the water s o l u b l e components was  found to be minor component. on  Rechromatography of t h i s component  (33 mg)  s i l i c a g e l (.5.0 g) u s i n g 5:4:1 b e n z e n e - e t h y l a c e t a t e - e t h a n o l y i e l d e d  only  one c h r o m a t o g r a p h i c a l l y and s t e r e o c h e m i c a l l y pure band o f the d e b e n z o y l a t e d , a-3-(S)-amide 177 (17 mg,  6%); m.p.  161-163°; [ a ] ^  5  + 16.1° ( c l . 5 , C H C 1 ) ; 3  162  v  CHCl max  3  3  5  0  0  3  4  1  (broad,NH,OH), 1732  0  c a r b o n y l ) , 1593  cm"  2H,J  ?  (amide  (amide I I band); n.m.r. (100 MHz,D 0) 61.38  1  2  1 . 5 3 ( s , 3 H , C ( C H ) ) , 2.69(d,2H,J 3  ( e s t e r c a r b o n y l ) 1678  2  2  and  7.5Hz,H-2), 3.14(m,1H.H-3) 3.60(d,  3  6.0Hz,H-8), 3. 70 (s, 3H,-OCH_ ), 4.13 (dd (overlapped by H-7),1H,J  g  3  lO.OHz.J,  3  4  3.5Hz,H-4), 4 . 1 6 ( t ( o v e r l a p p e d by H-4),1H,J, „ 6.0Hz,H-7), / ,o  c  4,3  4.82(d,lH,J  c  , 6.0Hz,H-6), 4.95(dd,lH,J,  spectrum: m/e  3.5Hz,J  c  4,J  5,0  c  , 6.0Hz,H-5); mass  3,b  304(m +H), 288(m -CH ), 272(m -OCH /HOCH ). +  +  +  3  Anal. Calc. for C  1 3  H  3  2  N O : C.51.48; H,6.98;N,4.62.  2 1  ?  Found: C.51.01;  H,7.00;N,4.58. 6.  U n s a t u r a t e d , A z i d o , Diazo and Amino  Treatment  Sugars  of Compound 18 w i t h Sodium A z i d e to Y i e l d  Methyl(E,Z)-4,7-anhydro-  8-0-benzoyl-2,3-dideoxy-5,6-0-isopropylidene-D-ribo-oct-3-enonate Methyl  (172)  and  (E)-4,7-anhydro-8-0-benzoyl-2,3,5-trideoxy-D-erythro-oct-2,4-  dienonate  (178).  A m i x t u r e of the methyl oct-2-enonate (89 mg)  i n anhydrous DMF  (4.5 ml) was  under d r y n i t r o g e n atmosphere and i n c r e a s i n g the temperature an a d d i t i o n a l 48h.  d i c h l o r o m e t h a n e and l a y e r was  s e a l e d (rubber septum) i n a f l a s k  stirred  f o r 45h at 50-55°.  After stirred for  then evaporated under vacuo to remove  The r e s i d u e was  dissolved  i n a m i x t u r e of  s a t u r a t e d aqueous sodium c h l o r i d e  (10 m l ) .  1:1  The o r g a n i c  s e p a r a t e d and the aqueous s u s p e n s i o n e x t r a c t e d t w i c e w i t h d i c h l o r o -  methane (2x5 m l ) .  The combined o r g a n i c e x t r a c t s were d r i e d over anhydrous  sodium s u l f a t e , f i l t e r e d chromatographed on s i l i c a The  and sodium a z i d e  to 60-65°, the r e a c t i o n m i x t u r e was  The m i x t u r e was  the v o l a t i l e components.  1_8^ (88 mg)  and e v a p o r a t e d , l e a v i n g a crude syrup which g e l (10 g) u s i n g 2:1  ether-hexanes  f a s t e r - m o v i n g component, compound 172, was  s y r u p (18 mg,  20.5%) and was  was  as d e v e l o p e r .  i s o l a t e d as a c l e a r  found to be a 9:1 m i x t u r e of the Z. and E_  25 isomers, r e s p e c t i v e l y , from n.m.r.; [ c t ] - 156.3 D  C' • 1  (c 0.95,CHCl3); v  max  163  1743,  1733  shoulder  (methyl e s t e r and benzoate c a r b o n y l s , r e s p . ) and 1710  (C=C) ; n.m.r. (100MHz,CDC1 ) 61.33 3  3.02(dd,lH,J  gem  18.0Hz,J  cm  and 1. 46(s ,3H,C(CH_ ) ) , 3  2  . 7.0Hz,H-2a), 3.22(dd,1H,J 7.0Hz,H-2b), 2a,3 zb,3  o  3.53(s,3H,-OCH_), 4.37(d,2H,J  4Hz,H-8), 4.59-4.71(m,2H,H-7,H-6), 4.82 1,0 (pseudo-t,lH,J„ . and J . 7.0Hz,H-3), 5.03 ( b r o a d - d , l H , J . , 5.5Hz,H-5), za, 3 zb,3 3,o 7  B  J  o  u  7.46(m,3H,Ar), 7.95(m,2H,Ar). at 63.02 and 3.22 (A 270 MHz (20 MHz,  collapsed  I r r a d i a t i o n of the two doublet of d o u b l e t s  the p s e u d o - t r i p l e t a t 64.82 to a s i n g l e t .  n.m.r. spectrum of 172 confirmed these assignments) C-13  CDC1 , p r o t o n decoupled) 625.73 and 26.92 ( C ( C H ) > , 3  3  2  n.m.r.  30.73(C-2),51.60  (-0CH ), 64.79(C-8), 79.85, 8.53(C-6 and C-7), 83.79(C-5), 94.71(C-3), 113.23 3  ( C ( C H ) ) , 128.53,129.67,130.94,133.31(Ar), 3  2  172.10(C0 CH ); mass spectrum: m/e 2  3  156.55(C-4),  166.00(A.C=0),  362(m ), 347(M -15), 330(m -CH OH), +  +  +  3  304(m -Acetone). +  Although n e i t h e r geometric isomers could be i s o l a t e d other  f r e e from the  ( e s p e c i a l l y the minor E_-isomer), v a r y i n g c o n c e n t r a t i o n s of each would  a l l o w some s p e c i f i c  s p e c t r a l d a t a f o r the E-isomer of 172.  A 55:45 m i x t u r e  (see R e d u c t i o n of compound 185) of the E to Z geometric isomers gave the f o l l o w i n g d a t a : n.m.r. (100MHz,CDC1 ) 61.33 3  3H,-OCH ), 5.08(H-3), 3  and 1.44(s,3H,C(CH )),  5.22(broad d,H-5); C-13  3  3.58(s,  n.m.r. (20MHz,CDC1 ) 625.93 3  and 26.92 ( C ( C H ) ) , 31.62(C-2), 79.28, 80.92 (C-6 and C-7), 82.90(C-5), 3  2  94.29(C-3), 157.73(C-4), 172.66(CC^Me), a l l other bands were degenerate w i t h the ^ - i s o m e r ; [ a ]  2 3  -167(c 1.0,CHC1 ). 3  Anal. Calc. for C  1 9  H  2 2  0 : C,62.97;H,6.12. 7  Found: C,63.30;H,6.06.  Continued e l u t i o n of the column gave the d i e n o n a t e 178 as a c l e a r syrup  (38 mg,  directly  51.5%).  below.  The c h a r a c t e r i z a t i o n of 178 appears i n the s u b s e c t i o n  164  Methyl(E)-4,7-anhydro-8-0-benzoyl-2,3,5-trideoxy-D-erythro-oct-2,4dlenonate  (178)  A m i x t u r e of the E_(and _Z)-2,3-unsaturated e s t e r 18_ (0.57, 1.6 mmol) , and sodium a z i d e (0.5 g, 77 mmol) i n anhydrous DMF atmosphere i n a s e a l e d (rubber septum) f l a s k was The  s o l v e n t was  kept below 50°.  The r e s u l t i n g  syrup was  dissolved  developer.  (30 m l ) .  The major band was  (0.306 g, 64%).  cm"  1712  and 1725  a c r y s t a l l i n e mass of compound  recrystallized  99.5-102°;  from benzene-hexane to  [ a ] ^ + 98.68 (cl.26,CHC1_); v D — 3 max (-CO-Me and PhCO.- c a r b o n y l s , r e s p e c t i v e l y ) , 8  C  (-C=C-); n.m.r. (100 MHz.CDCl-): 62.57(d,1H,J, „  1  n  with D 0), o  Q  /,o  J  5.0Hz,J^ _, 3.0 b, /  H  C  l  3500  3  1660  7.5Hz,  OH, —  b,Oh  3. 74(s,3H,-0CH-), 4.42(d,2H,J,  £. (t o f d , l H , J ,  was  to y i e l d a c l e a r  J  exchangeable  over anhydrous  b e n z e n e - e t h y l a c e t a t e as  c o l l e c t e d and evaporated  Compound 178 was  f i n e n e e l d e s : m.p.  (broad,OH),  I,  5.0Hz,H-8),  0  4.74  O  Hz,H-7), 4.95(d of t , l H , J , „ n  b,UH  3.0Hz, c o l l a p s e s to a d o u b l e t of 3.0Hz upon D-0 J  The o r g a n i c  and evaporated, l e a v i n g a crude syrup which  syrup which on s t o r a g e under vacuum produced  1607  temperature  The combined o r g a n i c e x t r a c t s were d r i e d  chromatographed on s i l i c a g e l (42 g) u s i n g 1:1  and  85-90°.  s e p a r a t e d and the aqueous suspension e x t r a c t e d twice w i t h d i c h l o r o -  sodium s u l f a t e , f i l t e r e d  yield  f o r 24 h at  i n a 1:1 m i x t u r e of  s a t u r a t e d aqueous sodium c h l o r i d e  methane (2x15 m l ) .  178  stirred  then evaporated _in vacuo w i t h the water bath  d i c h l o r o m e t h a n e and l a y e r was  (50 ml) under n i t r o g e n  7.5Hz, J , _,  exchange,H-6),  b, /  5.52(d,lH,  , 3.0Hz,H-5), 6.29(d,lH,J. , 16.0Hz,H-2), 7.13(d,lH,J. , 16.0Hz,H-3), 5,o 2,3 2,3  c  7.30-8.06(m,5H,Ar); mass spectrum: m/e  304(m ), 286(m -H 0), 272(m -CH 0H). +  A n a l . C a l c . f o r C-,H.,0-: C,63.15;H,5.30. lo lb b  +  178 produced  (179) .  ( s e v e r a l months) s t o r a g e of the methyl  a dark amber syrup which by t . l . c .  3  Found: C,63.01;H,5.46.  2-Benzoyloxymethyl-5-((E)-carbomethoxyethylene)furan Prolonged  +  2  oct-2,4-dienonate  showed both b a s e l i n e and  165  higher  c h a r r i n g m a t e r i a l s (9:1 b e n z e n e - e t h y l a c e t a t e d e v e l o p e r ) and an  absence  o f s t a r t i n g compound 178.  graphed  on s i l i c a  The r e s i d u a l syrup  g e l (10 g) u s i n g 15:1 b e n z e n e - e t h y l a c e t a t e as d e v e l o p e r .  C o l l e c t i o n o f the h i g h R. (0.32) band y i e l d e d (14 mg, 7%); n.m.r. (100 MHz, CDC1-) (d,lH,J  2  3  (200 mg) was chromato-  the s u b s t i t u t e d  f u r a n 179  63.73(s,3H,-0CH-), 5.28(S,2H.H-8), 6.31  16Hz,H-2), 6.49 and 6 . 5 4 ( d , l H , J  16Hz,H-3), 7.43(m,3H,Ar) 8.01(m,2H,Ar).  5  fi  3.5Hz,H-5,H-6), 7.37(d,lH,J- -  T h i s n.m.r. data was i d e n t i c a l to  20 those o b t a i n e d by M o f f a t e t a l f o r compound 179. C a t a l y t i c Hydrogenation  o f 18 to y i e l d Methyl 4,7-anhydro-8-0-benzoyl-2,3-  d i d e o x y - 5 , 6 - 0 - i s o p r o p y l i d e n e - D - a l l o - o c t o n a t e (183) A s o l u t i o n of the methyl oct-2-enonate was hydrogenated of  a t 60 p . s . i .  1_8_ (147 mg) i n methanol (10 ml)  f o r 48 h a t room temperature  5% p a l l a d i u m on c h a r c o a l (60 mg) as c a t a l y s t .  and  evaporated  to y i e l d a c l e a r syrup  be homogeneous w i t h a R^ s l i g h t l y  The m i x t u r e was  lower than the s t a r t i n g u n s a t u r a t e d compound  4 max  c c l  1 7 2  1 7 3 8 cm"  7  (s,3H,C(CH ) ), 3  2  Chromatography of the  g e l (12 g) u s i n g 4:1 b e n z e n e - e t h y l a c e t a t e d e v e l o p e r gave  the s a t u r a t e d methyl v  filtered  (134 mg) which was shown by t . l . c . to  (R. 0.36 w i t h 4:1 b e n z e n e - e t h y l a c e t a t e d e v e l o p e r ) . syrup on s i l i c a  i n the presence  octonate 183 (127 mg, 8 2 % ) : [ a ] ^  5  -11.4(jcl.0,CHCl ) ; 3  s h o u l d e r (C=0); n.m.r. (100 MHz,CDCl,) 61.30 and 1.50 3  1  1.78-2.04(m,2H,H-3), 2.35-2.51(m,2H.H-2), 3.58(s,3H,-OCH ), 3  3.84-4.02(m,lH,H-4),4.14-4.67(m,5H.H-5 to H-8), 7.48(m,3H,Ar), 8.03(m,2H,Ar). I r r a d i a t i o n o f the m u l t i p l e t a t 61.94 p a r t i a l l y c o l l a p s e d the m u l t i p l e t s t r u c t u r e a t 63.92 but no d i s c e r n a b l e i n f o r m a t i o n on the c o u p l i n g a t H-4 w i t h H-3 nor H-5 c o u l d be a s c e r t a i n e d . (m -CH ), +  3  Mass spectrum: m/e 364(m ), 349 +  333(m -OCH ). +  3  A n a l . C a l c . f o r C. H Q  ,0,: C,62.63; H,664. Found: C,62.71;H,6.66.  166  C a t a l y t i c Hydrogenation  o f 172 to y i e l d Methyl  4,7-anhydro-8-0-benzoyl-2,3-  dideoxy-5,6-0-isopropylidene-D-altro-octonate A s o l u t i o n o f the methyl was hydrogenated  oct-3-enonate  a t atmospheric  (184). 172 (192 mg) i n methanol (10 ml )  p r e s s u r e f o r l O h a t room temperature  presence o f 5% p a l l a d i u m on c h a r c o a l (85 mg) as c a t a l y s t . then f i l t e r e d  i n the  The mixture  and evaporated under reduce p r e s s u r e to g i v e a crude  was  syrup  which by t . l . c . was shown to c o n t a i n c h a r r i n g m a t e r i a l s having h i g h e r and lower  than t h e s t a r t i n g u n s a t u r a t e d sugar.  m i x t u r e on s i l i c a  Chromatography o f the crude  g e l (17 g) u s i n g 4:1 b e n z e n e - e t h y l a c e t a t e as d e v e l o p e r  a f f o r d e d the s a t u r a t e d compound 184 (97 mg, 50%) as a c o l o r l e s s syrup which solidified  on s t a n d i n g but c o u l d not be c r y s t a l l i z e d  from v a r i o u s s o l v e n t s .  An a n a l y t i c a l sample was prepared by d i s t i l l a t i o n under reduced (0.02 mm, v  CCl  100°) t o g i v e s o l i d -  4  1  7  2  7  f  1  7  3  8  c  m  1  shoulder  184; m.p.  43.5-45.5°C;  [ a ]  2  5  pressure  -9.0(cl.0,CHCl );  (C=0); n.m.r. (100 MHz,CDCl„) 61.36 and 1.52  (s,3H,C(CH ) ) , 1.94-2.16(m,2H,H-3), 2.42-2.58(m,2H,H-2), 3.66(s,3H,-OMe), 2  4.07(t  of d , l H , J  3  4  4.83(m,2H,H-5,H-6),  6.0Hz,J  4 5  3.0Hz,H-4), 4.22-4.55(m,3H,H-7,H-8),  7.54(m,3H,Ar), 8.06(m,2H,Ar).  at 62.06 c o l l a p s e d the t r i p l e t  4.68-  I r r a d i a t i o n o f the m u l t i p l e t  o f d o u b l e t s a t 64.07 to a d o u b l e t  (J,  3.0Hz);  mass spectrum: m/e 364(m ), 349(m -CH ), 333(m -0CH ). +  +  +  3  3  A n a l . C a l c . f o r C H 0 :C,62.63;H,6.64. 19  Methyl(methyl  24  ?  8-0-benzoyl-3-(chloromercuri)-2,3-dideoxy-5,6-0-isopropylidene-  ct-D-altro-4-octulofuranosid)onate To a s t i r r e d  (185) .  s o l u t i o n o f the methyl  oct-3-enonate  (40 ml) was added m e r c u r i c a c e t a t e (0.8 g ) . was s t i r r e d  Found: C,62.81;H,6.71.  The r e s u l t i n g t h i c k s u s p e n s i o n  f o r l h a f t e r which the mixture was r e f l u x e d  a clear solution.  172 (0.8 g) i n methanol  f o r 15 min to g i v e  A f t e r the s o l u t i o n was allowed to c o o l , sodium  (0.3 g) and a c e t i c a c i d  chloride  (0.05 ml) were then added and the mixture was  refluxed  167  for  an a d d i t i o n a l hour.  T . l . c . o f the r e a c t i o n mixture  indicated  consumption o f the s t a r t i n g compound and i n d i c a t e d a new lower compound u s i n g 2:1 ether-hexanes filtered silica  and evaporated  as d e v e l o p e r .  complete (0.39)  The r e a c t i o n mixture was  and the r e s i d u a l syrup  (1.23 g) chromatographed on  g e l (60 g) u s i n g the above d e v e l o p e r t o y i e l d  the organo-mercury  compound 185 (1.14 g, 82%) as a p a r t i a l l y c r y s t a l l i n e , hard syrup which was recrystallized v  CDCl  3  1  7  1  g  ^  1  from methanol: m.p. 118.5-120.5°; 7  -  (s,3H,C(CH ) ), 3  2  c  m  - l  (  c  a  r  b  o  n  y  l  s  ) .  n > m  . . r  [cx]^  5  -32.1(c2.0,CHCl ); 3  (lOOMHz.CDCl ) 61.34 and 1.53  2. 79-3. 21(m,approx.3H,H-2,H-3), 3.37 (s,3H,-OCH_ ) , 3.75(s,3H,  2  3  -C0-CH-), 4.27-4.46(m,3H,H-7,H-8), 4.53(sharp  d,lH,J  c  , 6.0Hz,H-5), 4.82(broad  d , l H , J . , 6.0Hz,J, , <1.0Hz,H-6), 7.55(m,3H,Ar), 8.12(m,2H,Ar).  The mass  spectrum was a complex p a t t e r n due to 5 abundant mercury i s o t o p e s and 2 chlorine isotopes.  The complex p a t t e r n s were p r e s e n t a t : 630(m ), 615 +  (m -CH ), 599(m -OCH ). +  +  3  3  A n a l . C a l c . f o r C ^ H ^ C l H g O g : C,38.16;H,4. 00;Hg,31. 87.  Found: C,38.02;  H,4.00;Hg,31.55.  R e d u c t i o n o f Compound 185 t o G i v e Compound 172. A m i x t u r e o f the m e r c u r i c compound 185 (350 mg, 0.56 mmol) i n e t h a n o l (12 ml) was g e n t l y heated over a steam b a t h u n t i l  the sugar  completely  dissolved.  The s o l u t i o n was allowed t o c o o l w i t h s t i r r i n g and then sodium  borohydride  (27 mg, 0.7 mmol) was added to the s o l u t i o n i n s i x p o r t i o n .  The s o l u t i o n t u r n e d a d a r k e r opaque grey a f t e r each a d d i t i o n o f the r e d u c i n g agent.  A f t e r 3 min, the m i x t u r e was c o n c e n t r a t e d (^1 ml) under  p r e s s u r e and the c o n c e n t r a t e d i s s o l v e d water  (4 m l ) .  reduced  i n a m i x t u r e o f e t h e r (10 ml) and  The r e s u l t i n g mixture was s t i r r e d  f o r s e v e r a l minutes and  then the aqueous l a y e r a l o n g w i t h the l i b e r a t e d e l e m e n t a l murcury was w i t h drawn and the o r g a n i c l a y e r washed w i t h IN HC1 (2x5 m l ) , water (5 ml) and  168  d r i e d over anhydrous sodium s u l f a t e . o n l y one band s l i g h t l y  lower i n  T . l . c . of the o r g a n i c phase  than the s t a r t i n g m a t e r i a l  b e n z e n e - e t h y l a c e t a t e as d e v e l o p e r , R^ 0.48 was  then f i l t e r e d  graphed  and  and 0.55,resp.).  evaporated and the r e s i d u a l syrup  on a column of s i l i c a g e l (16.5 g) u s i n g 4:1  as d e v e l o p e r g i v i n g back the u n s a t u r a t e d compound 172  indicated  (using The  (255 mg)  4:1  solution chromato-  benzene-ethyl acetate (185 mg,  92%)  as a  c l e a r syrup.  T h i s r e a c t i o n , however, gave a m i x t u r e of the m e t h y l ( E , Z )  oct-3-enonate  172  8:10  t h a t was  s i g n i f i c a n t l y r i c h e r i n the E isomer  of the E to Z i s o m e r s , r e s p . ) .  E_ isomer and was minor isomer  used  (see page  Methyl(methyl  to determine  One  f r a c t i o n c o l l e c t e d had  some of the c h a r a c t e r i s t i c s of t h i s  8-0-benzoyl-3-bromo-2,3-dideoxy-5,6-0-isopropylidene-ct-D(186).  To a m i x t u r e o f the methyl oct-3-enonate (0.8 g ) , s i l v e r carbonate  (0.8 g, 2.2 mmol), powdered was  Molar m e t h a n o l i c s o l u t i o n ) w h i l e the  s t i r r e d . The r e a c t i o n q u i c k l y consumed the added bromine evidenced  by the l o s s of c o l o r a f t e r the a d d i t i o n was  172  (0.8 g) i n anhydrous methanol (13 ml)  s l o w l y added bromine (2.75 ml of an 0.8 m i x t u r e was  55% of the  163).  altro-4-octulofuransid)onate  Drierite  (approx.  s t i r r e d 1.8  h, then f i l t e r e d  washed w i t h c h l o r o f o r m (3x5 m l ) .  of the bromine s o l u t i o n .  through c e l i t e and  The  mixture  the s o l i d m a t e r i a l s  The combined f i l t r a t e s were evaporated under  reduced p r e s s u r e and the r e s i d u e r e d i s s o l v e d i n c h l o r o f o r m (75 ml) and washed w i t h water (15 m l ) , 5% aqueous sodium hydrogen (2 x 15 m l ) . overnight.  The o r g a n i c phase was  carbonate  (15 ml) and water  then d r i e d over anhydrous sodium s u l f a t e  T . l . c . of the o r g a n i c phase u s i n g 9:1 b e n z e n e - e t h y l a c e t a t e as  d e v e l o p e r i n d i c a t e d two  prominent  c h a r r i n g components, the major component  (R^ 0.456) moving f a s t e r than the s t a r t i n g compound (R^ 0.294) and the minor  169  component moving at a s i m i l a r r a t e  (R. 0.280).  evaporated  the r e s i d u a l syrup  graphed  at reduced  on s i l i c a  p r e s s u r e and  g e l (67 g) u s i n g 9:1  The o r g a n i c l a y e r (0.83  (0.424 g, 41%)  prolonged 1728,  as a c l e a r  cm  shoulder  -1  25 [a]^  -13.9° (cl.34,CHC1-) : v  D  —  0  H-2b), 3.68(s,3H,-C0-CH_ ) , 4.32(d(overlapped 3  Q  and  0  J  by H-8a),lH,J_, ,  CC1 4 max  16.5Hz,J 10.0Hz,H-2a), 3.31(s,3H, 2a, 3  -0CH-), 3 . 4 1 ( d d ( p a r t i a l l y b u r i e d under -0CH_),1H,J —3 —3 gem  3.34(d(overlapped  J  ( c a r b o n y l s ) ; n.m.r. (100 MHz.CDCl-) 61.34  1.54(s,3H,C(CH„)-), 2.94(dd,lH,J —3 2 gem r  bromoglycoside  syrup which turned b l a c k upon h e a t i n g or  s t o r a g e a t room temperature:  1740  g) chromato-  benzene e t h y l a c e t a t e as d e v e l o p e r .  I s o l a t i o n o f the f a s t e r - m o v i n g component gave the methyl 186  was  VL6. 5Hz, J„, „ 3.5Hz, 2b,3  by H - 8 b ) , l H , J  ?  g  8.5Hz,H-8a),  a  5.5Hz,H-8b), 4.41-4.53(m,lH,H-7),  4.60  / , ob  ( d , l H , J . , 6.0Hz,H-5), 4 . 7 5 ( d d ( p a r t i a l l y obscured by H-3),1H,J , 6.0Hz, D,o i,o C  J , ., 2.0Hz,H-6), 4 . 8 4 ( d d , l H , J 8.02(m,2H,Ar).  0  _ 10.0Hz,J , o  _ 3.5Hz,H-3), 7.45(m,3H,Ar),  I r r a d i a t i o n of the d o u b l e t o f d o u b l e t s a t 63.41  collapsed  the doublet o f d o u b l e t s at 64.84 to a d o u b l e t w i t h J„ - 10.0Hz, mass 2a, 3 spectrum:  m/e  459/457(m -CH ), 443/441(m -0CH ), 307(m -CHBrCH CO-Me). +  +  3  +  3  2  A n a l . C a l c . f o r C^H.-BrOg: C, 50.75 ;H, 5. 32 ;Br, 16.88.  Found: C,49.59;  H,5.10;Br,16.47. S e v e r a l minor lower R^  c h a r r i n g components were a l s o i s o l a t e d  but  these decomposed b e f o r e they were c h a r a c t e r i z e d . Attempted  H y d r o g e n o l y s i s of  To a prehydrogenated p a l l a d i u m on carbon bromo methyl m i x t u r e was  mixture of potassium h y d r o x i d e  (25 mg),  g l y c o s i d e 186  i n methanol (5 ml) was  (130 mg)  vigorously stirred  After neutralizing m i x t u r e was  186  and  and  5%  added a s o l u t i o n of the  i n methanol (5 m l ) .  The  resulting  o v e r n i g h t under hydrogen atmosphere (^760  the r e a c t i o n mixture w i t h Bio-Rex 70  filtered  (18 mg)  evaporated.  (H ) +  resin,  T . l . c . o f the syrup w i t h 2:1  the ether-  torr).  170  hexanes as d e v e l o p e r gave o n l y lower for  (0.143) and b a s e l i n e m a t e r i a l (R^  compound 172 and 186, 0.43 and 0.50, r e s p . ) .  Methyl(methyl 8-0-benzoyl-2,3-dideoxy-5,6-0-isopropylidene-a(or ribo-4-octulofuranosid)onate In  an attempt  oct-3-enonate dissolved  (187).  t o o b t a i n the a z i d o compound 189 f r e e from the methyl  172, a sample o f a m i x t u r e o f compounds 189 and 172 was  i n a m i x t u r e o f p y r i d i n e , a c e t i c a c i d , and methanol and then  water added u n t i l for  the s o l u t i o n turned c l o u d y . The s o l u t i o n was then s t o r e d  s e v e r a l months.  T . l . c . of the s o l u t i o n u s i n g 2:1 ether-hexanes  d e v e l o p e r i n d i c a t e d a myriad s t a r t i n g compounds. syrup  B)-D-  of products r a n g i n g from the b a s e l i n e to the  E v a p o r a t i o n of the s o l v e n t s gave a dark whisky  (4.6 g) which was chromatographed on s i l i c a  ether-hexane  as d e v e l o p e r .  I s o l a t i o n of a p o r t i o n  (0.53 g) of the e l u e n t the presence of the  a z i d o compound 189 by i . r . s p e c t r o s c o p y and the n.m.r. spectrum presence o f a new methyl resonance  (^2H) a t 63.15.  i n methanol (35 ml) a t atmospheric  silica  i n d i c a t e d the  T h i s sample was  p r e s s u r e f o r 18 hours  presence o f 5% p a l l a d i u m on carbon. A f t e r f i l t r a t i o n the methanol s o l u t i o n , the r e s i d u a l syrup  colored  g e l (230 g) u s i n g 2:1  which had the same R^ as the s t a r t i n g compounds, i n d i c a t e d  genated  as  hydro-  i n the  and e v a p o r a t i o n of  (490 mg) was chromatographed on  g e l (45 g) u s i n g 4:1 b e n z e n e - e t h y l a c e t a t e to g i v e the methyl  glycoside  187 (182 mg) as a p a r t i a l l y c r y s t a l l i n e syrup which was r e c r y s t a l l i z e d benzene-hexane: m.p.  1740 cm"  73-74.5°;  2  -35.1(c2.0,CHC1,); v 4 — j max  4  C C 1  1724 ( b e n z o a t e ) ,  (-C0 CH ); n.m.r. (100 MHz,CDCl ) 61.34 and 1. 51 (s , 3H, C(CH_ ) ) ,  1  2  3  3  2.08-2.57(m,4H,H-2,H-3),  4.79(broad  d,lH,J  5  g  3  +  3  2  £  3  by H-7 and H-8 m u l t i p l e t ) , 1 H , J  56  6.0Hz,H-5),  6.0Hz,H-6), 7.54(m,3H,Ar), 8.10(m,2H,Ar); mass  379(m -CH ), 363(m -0CH ), +  3  3 . 22(s, 3H,-OCH_ ) ,3. 71(s ,3H,-C0 CH ) , 4.31-4.48(m,  3H,H-7,H-8), 4.49(d(overlapped  m/e  [a] U  from  3  307(m -CH CH C0 CH ). +  2  2  2  3  spectrum;  171  Anal. Calc. f o r C H„,0 ;C,60.90;H,6.65. nn  o  ZU  A d d i t i o n of H y d r a z o i c a c i d to  G i v e 172 and M e t h y l  O  ZD  Found:C,61.25;H,6.61.  to Compound 18 i n the Presence of Sodium A z i d e  4,7-anhydro-3-azido-8-0-benzoyl-2,3-dideoxy-5,6-  Q - i s o p r o p y l i d e n e - D - g l y c e r o - D - ( a l l o , a l t r o ) - o c t o n a t e (189). To an a z e o t r o p i c a l l y d r i e d m i x t u r e of the methyl oct-2-enonate 18_ (1.0 g) was aeid  added  sodium a z i d e  (7.0 ml of a 1.39N  s o l u t i o n of HN^  (rubber septum) and s t i r r e d p a l e orange m i x t u r e was  (0.44 g ) , anhydrous DMF i n CHCl^).  f o r 4 days at 52-55°.  (35 m l ) , and h y d r a z o i c  The m i x t u r e was The r e s u l t i n g  sealed  opaque,  evaporated In vacuo and the r e s i d u e d i s s o l v e d  in a  1:1 m i x t u r e of dichloromethane and s a t u r a t e d aqueous sodium c h l o r i d e  (50 m l ) .  The aqueous phase was  combined  e x t r a c t e d w i t h dichloromethane (25 ml) and  o r g a n i c e x t r a c t s d r i e d over anhydrous  sodium s u l f a t e .  and e v a p o r a t i o n of the o r g a n i c e x t r a c t s , t . l . c . d i c a t e d a s i n g l e major band  identical in  Following  filtration  of the r e s i d u a l syrup i n -  to the s t a r t i n g compound. The  infrared  spectrum of t h i s syrup, however, i n d i c a t e d a new  2110 cm  i n d i c a t i v e o f the a z i d o f u n c t i o n a l group.  1  the  a b s o r p t i o n at  Chromatography  of t h i s  syrup on s i l i c a g e l (100 g) u s i n g 1:1 hexanes-ether as d e v e l o p e r y i e l d e d f r a c t i o n s c o n t a i n i n g mainly the a z i d o mixture 189  (^60:40) and  increasing  amounts of the methyl oct-3-enonate 172 r a n g i n g from l e s s than 5% i n the f a s t e r moving p o r t i o n of the band the  a z i d o band  compound 189  61.32  yield  o f 189).  i n a pure s t a t e : v ^ ^ max 1  -C0 Me,resp.), Z o  (^72%  to a p p r o x i m a t e l y 25% i n the t a i l and of  2140,  2110  cm"  and 1. 48(s ,3H,C (CH_ ) ) , 3  2  1  No attempts were made to i s o l a t e 1732,  1745  s h o u l d e r (benzoate and  s h o u l d e r ( a z i d e ) ; n.m.r. (100 MHz,DMSo-d,) b 2.30-2.84 (m, 2H,H-2) ,3. 60,3. 61 (two o v e r l a p p i n g  singlets,3H,-OCH ),3.90-4.14(m,2H,H-3,H-4), 4.28-4.53(m,3H,H-7,H-8), 3  4.84(m,2H,H-5,H-6), 7.56(m,3H,Ar), 8.01(m,2H,Ar); mass spectrum: m/e 390(m -CH ), +  3  377(m -N ). +  2  4.68405(m ), +  172  Continued percentage  e l u t i o n o f the chromatography column w i t h an  of e t h e r (2:1,3:1, and 4:1,ether-hexane) produced  components which proved  two minor  to be impure from t h e i r n.m.r. s p e c t r a but  a b s o r p t i o n bands at c a . 2100 were l a t e r i s o l a t e d  increasing  cm  1  possessed  i n t h e i r i . r . s p e c t r a . These components  i n h i g h e r y i e l d and p u r i t y  (see compounds 192  and  193  below). Hydrogenation  of Compound 189  to g i v e a M i x t u r e of Methyl  3-amino-4,7-  anhydro-8-0-benzoyl-2,3-dideoxy-5,6-0-isopropylidene-D-glycero-D-(alio, altro)-octonate  (190) and  (191), r e s p e c t i v e l y .  A s o l u t i o n of the (R,S) was  hydrogenated  presence  a t atmospheric  i s o l a t e d below.  9:1  benzene-ethanol ^92%)  mg)  i n methanol (100  prehydrogenated)  as  e v a p o r a t i o n of the r e a c t i o n m i x t u r e , t . l . c .  syrup i n d i c a t e d a new 191  (^725  p r e s s u r e f o r 13 h a t room temperature  of 5% p a l l a d i u m on c h a r c o a l (260 mg,  A f t e r f i l t r a t i o n and  (625 mg,  a z i d o mixture 189  ml)  i n the  catalyst. of the  residual  lower R. spot i d e n t i c a l to the amino compounds 190  and  Chromatography of the syrup on s i l i c a g e l (60 g) u s i n g as d e v e l o p e r y i e l d e d a c h r o m a t o g r a p h i c a l l y pure  t h a t was  an a p p r o x i m a t e l y  syrup  2:1 mixture of compound 190  to  191  by n.m.r.  Treatment to  of Compound 18 w i t h Sodium A z i d e i n the Presence  g i v e Compounds 172,  189, and Methyl  of H y d r a z o i c  acid  3-amino-4,7-anhydro-8-0-benzoyl-2-  d i a z o - 2 , 3 - d i d e o x y - 5 , 6 - 0 - i s o p r o p y l i d e n e - D - g l y c e r o - D - a l l o (and a l t r o ) - o c t o n a t e (192) and  (193), r e s p e c t i v e l y .  To an a z e o t r o p i c a l l y d r i e d m i x t u r e of the (E,Z) oct-2-enonate 50 mmol) was acid  added sodium a z i d e (1.2 g) , anhydrous DMF  (0.83 ml of a 2.17  N s o l u t i o n of NH-  18_ (2.4  (72 m l ) , and h y d r a z o i c  i n CHC1-).  The mixture was  (rubber septum), wrapped i n aluminum f o i l  and  f o r 4d a t 52-55°.  r e s u l t i n g opaque, p a l e orange m i x t u r e was  evaporated  stirred  g,  in vacuo and  sealed The  the r e s i d u e  173  d i s s o l v e d i n a 1:1 chloride (50 ml)  mixture of dichloromethane  (100 m l ) .  The aqueous phase was  and s a t u r a t e d aqueous sodium  extracted with  dichloromethane  and the combined o r g a n i c e x t r a c t s d r i e d over anhydrous sodium  s u l f a t e and graphy  evaporated  to y i e l d a b r i g h t y e l l o w syrup  of t h i s syrup on s i l i c a  e t h e r to 100%  Chromato-  g e l (200 g) w i t h a g r a d i e n t of 1:1  hexane  e t h e r as d e v e l o p e r y i e l d e d a f a s t e r - m o v i n g component having  the same R. as the s t a r t i n g compound 1_8_. a mixture of methyl oct-3-enonate The head o f t h i s band was  From the n.m.r. spectrum found  Continued  T h i s component  (1.7 g, ^70%)  172 and h y d r a z o i c a d d i t i o n product  richer  i n t e n s i t y of the band a t 2120  a z i d e 189 was  (2.7 g ) .  was 189.  i n compound 189 as evidenced by a d e c r e a s i n g  cm  1  (N-_) i n subsequent  f r a c t i o n s of t h i s band.  ( i n CDCl^) of t h i s f a s t e r - m o v i n g component, the  to be l e s s than 5% of t h i s band.  e l u t i o n of the chromatography column r e s u l t e d  d e f i n i t i v e s e p a r a t i o n of two  slower-moving  i n an o b s e r v a b l e ,  y e l l o w components on the column.  C o l l e c t i o n of the f i r s t band gave a b r i g h t y e l l o w syrup of the altro-B-aminoct-diazo o c t o n a t e 193  (180 mg,  6%);  [aj^ D  8  -47.8° (c0.56,CHCl_); — J  3340 (weak, -NH-,), 2105(-N-), 1734(benzoate), (100MHz,CDCl ) 61.31 3  and 1.50(s ,3H,c ( C H . ^ ) ,  by C(CK ) ),2H,NH., exchangeable 3  with D 0),  2  1H.H-3), 4.08(pseudo-t,lH,J_  2  4.0Hz,H-5(6)), 4.77(dd,lH,J.  3  to due  377  3  1.63(broad s ( p a r t i a l l y  overlapped  3.72(s,3H,-OCH ), 3.91(broad  m,  3  m/e  0  3.5  0,1  4.5Hz,H-8), 4. 63 (dd ,1H, J .  , 7.0Hz,J. .  , 7.0Hz,J, _ 3.5Hz,H-6(5)), 7.49(m,3H,Ar),  8.04  377(m -N ), 362(m -(N +CH )), 345(m -(N +HOCH )), +  +  2  t o 345 or 345  fragmenting  t o t h e i r comparable i n t e n s i t i e s . F u r t h e r e l u t i o n of the column y i e l d e d  +  2  M e t a s t a b l e peak at a p p r o x i m a t e l y  fragmenting  (-C0-CH ); n.m.r.  1  H, _>  Hz.J-, - 4.5Hz,H-7), 4.45 (d, 2H, J-.  330(345-CH ).  cm"  4 3400, max  C C 1  . and J . . 4.0Hz,H-4), 4.26(pseudo-q,1H,J, , 5 ,k  (m,2H,Ar); mass spectrum:  1697  v  3  2  316 which c o u l d be  to 330.  The  former  the slower-moving  3  attributed  i s favored  d i a z o compound  174  192  (264 mg, 9%); [a]t° + 20.7°  (cl.O.CHCl,); v  ( d i a z o ) , 1730(benzoate), 1698 cm"  1  and 1.50(s,3H,C(CH_ ) ) , 1.66(broad 3  2  2H,NH , exchangeable w i t h D 0 ) , 2  J  38a 2  0 H z  » H  8 a  )>  4  3400, 3340(-NH„), 2102  (-C0 CH ); n.m.r.(100MHz,CDC1 ) 61.30 2  3  3  s ( p a r t i a l l y o v e r l a p p e d by CH  3  a t 61.50),  3.70(s,3H,-OCH ), 3.96(broad m,lH,H-3),  2  4.05(dd,lH,approx.  C U 1  3  4.0 and 5.5Hz,H-4), 4.18-4.30(m,1H.H-7), 4.41(d,lH, 4.45(d,lH,J  7  g  b  2.5Hz,H-8b), 4.62-4.67(m,2H,H-5,H-6), 7.48  (m,3H,Ar), 8.01(m,2H,Ar); mass spectrum: i d e n t i c a l t o compound 193. A n a l . C a l c . f o r C ^ H ^ N ^ :C, 56. 29; 5. 72;N, 10.36.  Found: C,60.78;  H,6.54; 3.10. Compound 192 was d r i e d a t 78° f o r 18 h in vacuo p r i o r to m i c r o - a n a l y s i s . If  e l i m i n a t i o n o f n i t r o g e n d i d occur to g i v e the a z i r i d i n e  derivative,  a n a l y s i s should give: C H N0 :C,60.5;H,6.2;N,3.7. 19  23  7  C a t a l y t i c H y d r o g e n o l y s i s and Hydrogenation o f Compound 193 t o g i v e M e t h y l 3-amino-4,7-anhydro-8-0-benzoy1-2,3-dideoxy-5,6-0-isopropylidene-D-glyceroD - a l t r o - o c t o n a t e (191) and M e t h y l  3-amino-4,7-anhydro-8-0-benzoyl-3-deoxy-  5 , 6 - 0 - i s o p r o p y l i d e n e - D - g l y c e r o - D - a l t r o - 2 - o c t u l o s o n a t e Hydrazone A s o l u t i o n o f the d i a z o compound 193 (1.16 g) i n methanol hydrogenated  (196). (75 ml) was  at atmospheric p r e s s u r e f o r 3 h a t room temperature i n t h e  presence o f 5% p a l l a d i u m on c h a r c o a l  (190 mg, prehydrogenated) as c a t a l y s t .  The mixture was f i l t e r e d and evaporated to y i e l d a p a l e y e l l o w syrup which on t . l . c .  u s i n g 9:1 benzene-ethanol as d e v e l o p e r gave two new lower  and 0.16) bands. minor, broad band. u s i n g 9:1  (0.35  The h i g h e r R^ band, however, a l s o overlapped a f a s t e r moving, Chromatography o f the crude syrup on s i l i c a  g e l (124 g)  benzene-ethanol as d e v e l o p e r gave a p o r t i o n of the h i g h R^ (0.35)  B-amino compound 1 9 l (0.32 g, 30%) f r e e o f h i g h e r R  f  impurities:  25 [a]  D  -12.8°  175  (cl.O.CHCl-j)J m a x v  4  3  4  0  5  '  3  3  4  0  (  w e a k  »  N _ H  )»  1 7 3 0  >  1  7  4  cm"  0  and - C 0 C H , r e s p . ) ; n.m.r. (100MHz,CDC1 ) 61.33 and 2  3  1  shoulder(benzoate  1.53(s,3H,C(CH ) ),  3  3  2  1 . 5 6 ( s ( b u r i e d under CH_ a t 51.53) ,2H,NH_ , exchangeable w i t h D 0) , 2.34 3  (dd.lH.J  2  2  16.0Hz,J . 9.0Hz,H-2a), 2.58(dd,lH,J 16.0Hz,J„, _ 4.0Hz, ' 2a,3 ' gem 2b,3 ' o  gem  H-2b), 3.18-3.36(broad  m,lH,H-3), 3.62(s,3H,-OCH ),  3.81-3.90(m,1H.H-4),  3  4.14-4.30(m,lH,H-7), 4.44(d,lH,J_ . 4.0Hz,H-8a), 4.45(d,lH,J, /,oa /,ob H-8b),4.59-4.69(m,2H,H-5,H-6), of  8.46(m,3H,Ar), 8.02(m,2H,Ar).  4.0Hz,  Irradiation  t h e m u l t i p l e t c e n t e r e d a t 64.62 c o l l a p s e d the m u l t i p l e t a t 63.81-3.90  to a d o u b l e t w i t h J_ , 5.0Hz. I r r a d i a t i o n of the broad m u l t i p l e t a t 63.24 3,4 c o l l a p s e d the d o u b l e t o f d o u b l e t s a t 6 2.34 and 2.58 to d o u b l e t s ( J 16.0Hz) gem w h i l e the m u l t i p l e t a t 63.85 p a r t i a l l y c o l l a p s e d . Anal. Calc. f o r C ^ H ^ N C y  C, 60.15 ;H,6. 64 ;N,3. 69.  Found: C, 59.92 ;H, 6. 58;  N,3.71. F u r t h e r e l u t i o n o f the column gave the hydrazone 196 (0.31 g, 26%) as a c l e a r syrup which c o u l d not be c r y s t a l l i z e d  from v a r i o u s s o l v e n t s : n.m.r.  (100MHz,CDCl ) 61.32 and 1. 52 (s, 3H, C(CH_ ) ) , 1.78(broad 3  3  2  a b l e w i t h D 0 ) , 3.69(s,3H,-OCH ), 3.86(broad 2  3  ( p s e u d o - q ( o v e r l a p p i n g bands),2H,approx.  d,lH,J  3 4  s,2H,NH_ , 2  exchange-  ^4.0Hz,H-3), 4.16-4.28  4.0Hz between the f o u r  resonance  signals,H-4,H-7) , 4.42(d,lH, J-, 4.0Hz,H-8a), 4.44(d,lH,J, 4.0Hz,H-8b), /,oa /,ob Q  4.58(dd,lH,J.  , 4.0Hz,J, , 7.0Hz,H-5), 4 . 6 8 ( d d , l H , J  7.46(m,3H,Ar), 8.03(m,2H,Ar), 8.47(broad v  C C 1  4  , 6.0Hz,J,  c  n  3.0Hz,H-6),  s,2H, -NNH_, exchangeable w i t h D 0 ) ; 2  2  3400, 3350, 3300 (weak,-N-H„), 3310, 3270(weak,-NNH ), 9  1725(benzoate),  1700 (-C0 CH ), 1570 cm" (broad,-C=N-). 1  2  3  C a t a l y t i c H y d r o g e n o l y s i s and Hydrogenation of Compound 19 2 to g i v e Methyl 3-amino-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-0-isopropylidene-D-glyceroD-allo-octonate  (190)  and Methyl  5,6-0-isopropylidene-D-glycero-D- a l i o  3-amino-4,7-anhydro-8-0-benzoyl-3-deoxy2 - o c t u l o s o n a t e Hydrazone  (195).  176  A s o l u t i o n of the d i a z o compound 192 (670 mg) i n methanol (55 ml) was hydrogenated a t atmospheric p r e s s u r e f o r 3 h a t room temperature i n the presence o f 5% p a l l a d i u m on c h a r c o a l The  (200 mg, prehydrogenated) as c a t a l y s t .  m i x t u r e was f i l t e r e d and evaporated t o y i e l d a l i g h t y e l l o w syrup (613 mg)  which on t . l . c .  u s i n g 9:1 benzene-ethanol as d e v e l o p e r gave two new lower  R. (0.30 and 0.22) component and i n d i c a t e d the complete consumption the s t a r t i n g compound gel  (R^ 0.40).  Chromatography o f the crude syrup on s i l i c a  (45 g) u s i n g the above 9:1 s o l v e n t p a i r as d e v e l o p e r gave the 8-amino  25 compound 190 (249 mg, 40%) as a c l e a r s y r u p : [<x] D  4 max  3405, 3340 (weak,N-H), 1730, 1740 cm"  C C 1  V  1  -11.0 (c2.4,CHC1 ) ; 3  shoulder  (benzoate and -CO-CH. z j  r e s p . ) ; n.m.r. (100MHz, CDC1 ) 61.32 and 1. 52 (s ,3H, C ( C H ) - ) , 1. 61(s,2H,NH_ , 3  3  2  exchangeable w i t h D 0 ) , 2.28(dd,lH,J 16.0Hz,J„ . 9.0Hz,H-2a), 2.60(dd, z gem za,j o  1H.J  gem  16.0Hz,J , _ 4.0Hz,H-2b), 3.24-3.41(m,lH,H-3), 3.60(s,3H,-0CH ), 2b, 3 —3 o  3.76(dd,lH,J_  o  . 6.0Hz,J.  4.0Hz,H-4), 4.19 (pseudo-q, IH, J_  c  Q  and J.,  o  v  4.0Hz,jL _ 4.0Hz,H-7), 4 . 3 4 ( d d ( p a r t i a l l y overlapped by H-7 and H-8b),lH, b, / J  gem  1 ] L  -  5 H z  H-5(6)), J  » 7 J  gem  4 8  a  -  0 H z  »  )»  H - 8 a  5.48 ( d d ( p a r t i a l l y overlapped by H-8a and  11.5Hz,J_, , 4.0Hz,H-8b), 4.57 (dd, IH, J . 4.0Hz,J. , 6.5Hz,H-5), 7,8b 4,5 5,6 ' ' Q  c  4.71(dd,lH,J. _ 4.0Hz,H-6) 7.44(m,3H,Ar), 8.00(m,2H,Ar); mass spectrum: b, / 379(m ), 364(m -CH ), +  +  3  m/e  348(m -0CH ). +  3  A n a l . C a l c . f o r C H- NO-, :C,60.15;H,6. 64;N,3. 69. 19  5  Found.: C.60.06;  H,6.49;3.61. F u r t h e r e l u t i o n o f t h e column gave hydrazone 195 (110 mg, 16%) as a v i s c o u s syrup which was c r y s t a l l i z e d  from h e x a n e - e t h y l a c e t a t e : m.p.  109.5-  lll°; n.m.r. (100MHz,CDC1 ) 61.34 and 1.52(s,3H,C(CH )-), 1.78(broad s,2H, 3  3  -NH ,  exchangeable w i t h D 0 ) , 3.68(s,3H,-OCH_ )  H1-3),  4.10-4.28(m,2H,H-4,H-7),  2  2  3  3.94(broad d , l H , J  3  4  6.5Hz,  4.42(m,2H,J, _ ^3.0Hz,H-8), 4.62(dd,lH,  177  J . _ 3.7Hz,J , 6.0Hz,H-5), 4 . 7 4 ( d d , l H , J , 6.0Hz,J, 3.5Hz,H-6), 7.48(m, 4,5 J,D D,O o, / c  c  3H,Ar), 8.02(m;2H,Ar), 8.36(broad  n  s,approx.2H, -NNH2, exchangeable  with  D 0 ) ; mass spectrum: m/e 407(m ), 398(m -CH ). +  +  2  3  Anal. Calc.  f o r C ^ H ^ N ^ :C,56.01 ;H,6.19;N, 10.31.  Found: C,56.00;  H,6.25;N,10.23.  Attempted  C y c l i z a t i o n o f Compound 195 w i t h N , N ' - C a r b o n y l d i i m i d a z o l e  (197)  to g i v e 5 - ( S ) - ( 5 - 0 - B e n z o y l - 2 , 3 - 0 - i s o p r o p y l i d e n e - g - D - r i b o f u r a n o s y l ) - 6 carbomethoxy-4,5-dihydro-2H-as-triazin-3-one A s o l u t i o n o f the hydrazone (^30  mg) i n anhydrous  (198)  198 (63 mg) and N , N ' - c a r b o n y l d i i m i d a z o l e  THF (2.4 ml) was m i l d l y r e f l u x e d  m i x t u r e was then c o o l e d and the THF evaporated. dissolved plates  f o r 1.5 h.  The  The r e s i d u a l syrup was  i n a s m a l l amount o f dichloromethane, a p p l i e d  to t h r e e t . l . c .  (15x20 cm, 1.0mm) and developed w i t h 15:8:2 b e n z e n e - e t h y l a c e t a t e -  e t h a n o l t o g i v e 4 major bands.  The slowest moving band a t  i d e n t i c a l by n.m.r. s p e c t r o s c o p y t o i m i d a z o l e .  0.11 was  The i n t e r m e d i a t e bands o f  R^ 0.22 and 0.385 were mixtures by n.m.r. and no f u r t h e r attempts them were made. prominent  The f a s t e r - m o v i n g band a t R^ 0.56 (44 mg, 65%) was the most  o f the c h a r r i n g  resonances  to p u r i f y  bands and possessed s i n g l e peaks f o r i t s methyl  i n the n.m.r. spectrum: n.m.r. (100MHz, DMSO-d^, assignments  t e n t a t i v e and are based on compound 198)  61.24  are  and 1. 43 (s ,3H,C(CH_ ) ) , 3.57 3  2  (s,3H,-OCH ), 4.00-4.36(m,4H,H-l',H-4',H-5'), 4.74-4.92(m,3H,H-5,H-2',H-3'), 3  6.38(d,2/3H,^8.0Hz,no assignment), 7.10(broad (m,3H,Ar), 8.12(m,2H,Ar), 9.32(broad  s,2/3H, no assignment), 7.60  s,lH,N(2)-H,  exchangeable w i t h  D 0); 2  mass spectrum: m/e 431(m -2H), 4 1 8 ( m - C H „ ) ; v 3410, 3300, 3270(NH), 3 max ' 1725 (PhCO), 1700(-C0 Me), 1665(HN-CO-NH), ^1550 cm (C=N). +  +  C C l 4  -1  2  Treatment  o f Methyl(E,Z)-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-0-isopro-  pylidene-D-allo-oct-2-enonate  (18) w i t h C e r i c Ammonium N i t r a t e  (CAN) and  178  Sodium A z i d e . A s o l u t i o n of the enonate 1_8 (362 mg)  i n anhydrous a c e t o n i t r i l e  (5.4 ml) was  c o o l e d to -25° under n i t r o g e n atmosphere.  s o l u t i o n was  t r a n s f e r e d v i a a s y r i n g e to a m i x t u r e  and sodium a z i d e (0.06 f o r 15 h at -33 mixture  g).  to -22°.  filtered  and  C o l d e t h y l e t h e r (5 ml) was  8 mg,  8.5  and  2%,  (1.29  and  evaporated  as d e v e l o p e r gave two r e s p . , based  g)  vigorously stirred added and  the  resulting The  (4x5 m l ) , d r i e d  over  to g i v e a y e l l o w syrup  Column chromatography of the syrup on s i l i c a  benzene-ether  CAN  the s o l i d r e s i d u e washed w i t h e t h e r (2x2 m l ) .  anhydrous sodium s u l f a t e , f i l t e r e d  20:1  of s o l i d  The r e s u l t i n g m i x t u r e was  combined f i l t r a t e s were washed w i t h i c e c o l d water  (398 mg).  This cooled  g e l (50 g) w i t h  f a s t e r - m o v i n g components  on the m o l e c u l a r weight  (31 mg  of 18) which  and  proved  to be impure upon i n s p e c t i o n of t h e i r n.m.r. s p e c t r a . The major slower-moving band spectrum  7.  as  (260 mg,  73%)  had  the same R- and i . r .  18.  H e m i k e t a l s , y - L a c t o n e s , and A l k y l and A c y l K e t a l s  A i r O x i d a t i o n and H y d r a t i o n of Methyl  (E,Z )-4,7-anhydro-8-0-benzoyl-2,3-  dideoxy-5,6-0-isopropylidene-D-ribo-oct-3-enonate 2,3-0-isopropylidene-D0ribono-l,4-lactone  (172)  to y i e l d  5-0-Benzoyl-  (199), 8-0-Benzoyl-2,3-dideoxy-5,6-  0-isopropylidene-3-D-ribono-4-octulofuranosono-1,4-lactone  (200), M e t h y l ( E ) - 8 -  benzoyl-2,3-dideoxy-5,6-0-isopropylidene-B-D-ribo-oct-2-en-4-ul,ofuranosonate (201),Methyl  8-0-benzoyl-2,3-dideoxy-5,6-0-isopropylidene-B-D-ribo-4-  octulofuranosonate q,B-D-allo  v a r i o u s attempts 193 was  8-0-benzoyl-2-deoxy-5,6-0-isopropylidene-  (and a l t r o ) - 4 - o c t u l o f u r a n o s o n a t e (203) and  The methyl  and  (202), M e t h y l  oct-3-enonate  172  (approx.  to improve the y i e l d  13.5  (204),  g) which was  o f the B-amino-a-diazo  respectively. synthesized i n compounds  192  a l l o w e d to stand f o r prolonged p e r i o d s (1.5-9 months) as a syrup  179  or  i n the chromatography developer  compound 172 was  left  (2:1 ether-hexanes).  In the cases where  i n the d e v e l o p e r both s o l v e n t s had c o m p l e t e l y evaporated  l e a v i n g a p a l e y e l l o w syrup.  T . l . c . a n a l y s i s of these syrups i n d i c a t e d  that  the u n s a t u r a t e d compound had r e a c t e d f u r t h e r to form p r o d u c t s r a n g i n g i n (using 2:1  ether-hexanes  as d e v e l o p e r ) from the b a s e - l i n e to the  starting  compound. The v a r i o u s f r a c t i o n s c o l o r e d syrup  (^15  a g r a d i e n t of 1:1 100%  and syrups were c o l l e c t e d  g) which was (600 m l ) , 2:1  chromatographed on s i l i c a g e l (400 g) u s i n g (600 m l ) , 4:1  (315 ml)  isolated  a c c o r d i n g t o descending R^ u s i n g ether-hexanes Fraction A  (^2.0  methyl oct-3-enonate of 172  172.  and  3.6  cm  1  indicative  i n d i c a t e d a preponderance  The  1  i . r . spectrum of t h i s  of the a z i d o compound  i . r . spectrum  broad, weak a b s o r p t i o n band a t 3350 cm  indicated  (^70%)  mixture  189.  of t h i s component possessed a  and a s t r o n g e r , sharper peak at  T . l . c . of t h i s f r a c t i o n u s i n g 1:1  ether-hexane  as developer  the p o s s i b i l i t y of 3 o v e r l a p p i n g bands which were  than the s t a r t i n g compound 172.  starting  the s p l i t t i n g of the methyl peaks at  i n d i c a t e d a second component.  F r a c t i o n B (2.14 g ) : The  cm  as seven bands (A to G) as d e v e l o p e r .  The n.m.r. spectrum  (resonance a t ^63.14,H-2) and  and  The e l u e n t  g ) : T h i s f r a c t i o n had the same R. as the  had an a b s o r p t i o n of ^2120  1804  ether-hexanes  e t h e r to a c h i e v e a crude s e p a r a t i o n of the components.  which c o n t a i n e d c h a r r i n g compounds was  61.6  to g i v e a deep whisky  slower-moving  A change of the d e v e l o p e r to 4:1  benzene-  e t h y l a c e t a t e , however, gave b e t t e r s e p a r a t i o n to show 3 d i s t i n c t components p l u s a minor c h a r r i n g band j u s t above the b a s e - l i n e 0.03  (R^ 0.41,  0.35,  0.28  w i t h compd. 202 at 0.38). Rechromatography of t h i s f r a c t i o n on s i l i c a  g e l (250 g) u s i n g  b e n z e n e - e t h y l a c e t a t e as d e v e l o p e r a f f o r d e d the r i b o n i c ,  1,4-lactone  4:1 199  and  180  (375 mg, vacuo.  3.5%*) as the f a s t e r - m o v i n g component which c r y s t a l l i z e d under R e c r y s t a l l i z a t i o n of t h i s component from benzene-hexane gave an o  a n a l y t i c a l sample: m.p. [a]  2 5  101.5-102.5°;  CC1  v  1802 ( l a c t o n e ) ,  4  m  a  x  -50.4°(cl.5,CHCl ) ; n.m.r. (100MHz ,CDC1 ) 61.40 3  4.52(dd,lH,J H-5b), 4.79  3  5  g  6.0Hz,H-5,H-6), 4.92(pseudo-t,1H.H-4),  3H,Ar), 7.96(m,2H,Ar); mass spectrum: m/e C  v 1800 max  +  1.51(s,3H,C(CH_ ) ), 2  +  Found: C,61.49;5.50. column gave the keto  1,4-  as a p a r t i a l l y c r y s t a l l i n e syrup which was r e -  from benzene-hexane;  (lactone),  7.56(m,  3  £  (1.03g, 8.2%)  3  2  293(m +H), 277(m -CH ).  A n a l . C a l c . f o r C, H, 0,:C,61.64;5.52. I i lb o Continued e l u t i o n of the chromatography  C C l 4  3  c  and 4 . 8 7 ( d , l H , J  crystallized  and 1. 51 ( s , 3H, C(CH_ ) ) ,  12.3Hz,J, 3.0Hz,H-5a), 4.69(dd,lH,J 12.3Hz,J. 2.5Hz, '4,5a gem 4,5b '  gem  l a c t o n e 200  ~1 (benzoate);  1733 cm  1725  cm"  1  e 25 m. p. 101-102. 5°; [ c ] ^  -49.9(cl.5,CHC1 ); 3  (benzoate); n.m.r. (100MHz.CDC1-) 61.37 J  and  2.24-2.89(m,4H,H-2,H-3), 4.42 (d ( o v e r l a p p i n g H - 8 b ) , l H , J  7.5Hz,H-8a), 4.43(d(overlapping-H-8a) , 1H,J., „,  5.0Hz), 4.60(broad  4 . 7 7 ( d , l H , J . , 6.0Hz,H-5), 4.92(dd,lH,J, , 6.0Hz,J, _ vL.0Hz,H-6), 5,6 J,b b, / (m,3H,Ar), 8.08(m,2H,Ar); mass s p e c t r a : m/e  7  7.54  +  +  3  PhC0 CH ). 2  2  A n a l . C a l c . f o r C, H 0_,:C, 62. 06;H, 5. 79. o  on  F u r t h e r e l u t i o n of the column 4:1  gave the lower  band.  gave f r a c t i o n s which by t . l . c . w i t h the  component was  Continued e l u t i o n of the column  eventually  spot (0.28) as a c h r o m a t o g r a p h i c a l l y pure compound. The  m i x t u r e ( f r a c t i o n B-A) was collected  l a t e r rechromatographed and the slower-moving  to g i v e the s a t u r a t e d k e t a l  p a r t i a l l y c r y s t a l l i n e syrup which was m.p.  Found: C.61.94; H,5.66.  s o l v e n t p a i r were m i x t u r e s o f a l e a s t two compounds o v e r l a p p e d by a  broader, more d i f f u s e d  109-112.5°;  202  (370 mg,  2.7%)  as a  r e c r y s t a l l i z e d from chloroform-hexane;  [a] -2.7°(cl.0.CHC1-); v 4 3430(broad,OH), 1727 cm" U — -J max ( e s t e r s ) ; n.m.r. (100MHz ,DMS0-d ) 61.28 and 1. 41 (s ,3H,C(CH_ ) ), 1.92-1.16 2 5  C C 1  6  3  y i e l d s here w i l l be based on 13 g of compd. 172 consumed.  2  a  dd,lH,H-7),  348(m ), 333(m -CH ), 213(m +  g  1  181  (m,2H,H-3), 1.30-1.46(impartially obscured by DMS0-d ),2H.H-2),  3.60  6  (s,3H,-OCH ), 4.24(broad dd,lH,H-7) 4.37(d(overlapped by H - 8 b ) , l H , J 3  4.0Hz,H-8a), 4.40(d(overlapped by H - 8 a ) , J J . , 6.0Hz,H-5), 4 . 8 6 ( d d , l H , J  c  y  g  +  +  +  3  3  3  2A  spectrum:  CH >). 3  A n a l . C a l c . f o r C H 0 :C,59.99;H,6.36. 19  a  , 6.0Hz,J, ., 1.3Hz,H-6), 6.16(sharp s . l H ,  365(m -CH ), 349(m -0CH ), 333(m -(H0CH +  g  10.5Hz,H-8b), 4.44(d,lH,  b  OH, exchangeable w i t h D-0), 7.62(m,3H,Ar), 8.02(m,2H,Ar); mass m/e  ?  Found: C,59.87;H,6.36.  g  Rechromatography of the above mixture (320 m g ) ( f r a c t i o n B-A) on s i l i c a gel  (17 g) u s i n g 29:1 benzene-ethanol as d e v e l o p e r removed the broad,  band from the o v e r l a p p i n g p a i r s of compounds.  diffuse  A p o r t i o n of the lower R-  m a t e r i a l was i s o l a t e d pure and was i d e n t i c a l t o k e t a l 202 (190 mg). The r e m a i n i n g m i x t u r e (108 mg) was a g a i n rechromatographed  on s i l i c a  (17 g)  u s i n g 4:1 b e n z e n e - e t h y l a c e t a t e to a f f o r d the u n s a t u r a t e d k e t a l 201 (28 mg, C C I4 A  0.3%) as a c l e a r s y r u p : v max  3440,(broad,OH), 1720 cm  -1  (broad, benzoate  and u n s a t u r a t e d e s t e r ) ; n.m.r. (100MHz, DMS0-d ) 61.27 and  1.41(s,3H,C(CH ) ),  6  1.72(s,3H,-OCH ), 4.22(broad 3  (d.lH.J.  6  6.89(sharp  s,3H,H-7,H-8),  6.0Hz,H-6), 6 . 1 4 ( d , l H , J s,lH,0H,  mass s p e c t r a : m/e  2  3  4.56(d,lH,J  5  fi  3  2  5.5Hz,H-5), 4.96  16.0Hz,H-2), 6.87(d,lH,J-  3  16.0Hz,H-3),  exchangeable w i t h D 0 ) , 7.62(m,3H,Ar), 8.04(m,2H,Ar); 2  378(m ), 363(m -CH.), 347(m -0CH ); [ a ] ^ +  +  +  3  3 , 5  -25.4  (cl.24,CHC1 )* 3  A n a l . C a l c . f o r C H O :C,60.31;H,5.86. ig  22  g  Found: (Syrup) C,60.62;H,5.99;  (Solid)**  C,60.61;H,6.00.  F u r t h e r e l u t i o n o f the column gave a m i x t u r e of k e t a l s 201 and 202 (40 mg; a 30:70 r a t i o , resp.) and a f i n a l sample of the pure k e t a l 202 (55 mg, 3.8% o v e r a l l  yield).  *The n.m.r. spectrum of compd. 201 i n CDC1 * * S o l i d : M.P.  78-88°.  3  i n d i c a t e d a 4:1 mixture of anomers.  182  F r a c t i o n C(0.55 g ) :  The  i . r . spectrum  broad bands at a p p r o x i m a t e l y 3400 and at  1722  cm \  of t h i s component possessed 3500 cm  1  two  and a s t r o n g broad c a r b o n y l  T . l . c . of t h i s f r a c t i o n w i t h v a r i o u s s o l v e n t systems gave  a broad c h a r r i n g band i n which no major component c o u l d be d e t e c t e d nor c o u l d any a p p r e c i a b l e s e p a r a t i o n of components be Chromatography of the syrup on s i l i c a  seen.  g e l (60 g) u s i n g 4:1  benzene-  e t h y l a c e t a t e y i e l d e d one c h r o m a t o g r a p h i c a l l y pure band which from i t s n.m.r. spectrum of  i n d i c a t e d a m i x t u r e of compounds.  sample and  Due  the number of compounds observed  to the r e l a t i v e s m a l l amount for this  chromatographic  r e g i o n , no f u r t h e r attempts were made to separate the v a r i o u s components. Fraction D band at 3500 cm at  1727  cm  1  .  (1.5 g ) : The \  a weak  i . r . spectrum  band at 1810  However, i f 2:1  phase, two bands c o u l d s t i l l much more d i f f u s e at  R^ 0.22  was  (R^ 0.27  component  to 0.47)  as the d e v e l o p e r  w i t h the h i g h e r R^ band p r e used as the mobile  and  the slower-moving,  was  major component  band. (1.2 g) was  ether-hexane  (0.96 g) as c l e a r  ether-hexanes  be observed but the f a s t e r - m o v i n g m a t e r i a l  a much narrower  (95 g) u s i n g 4:1  and 0.37)  and a s t r o n g c a r b o n y l a b s o r p t i o n  b e n z e n e - e t h y l a c e t a t e was  T h e r e f o r e , the crude syrup gel  1  T . l . c . of the syrup u s i n g 4:1  showed two c h a r r i n g bands (R^ 0.32 dominating.  cm  of t h i s f r a c t i o n had a broad  syrup.  rechromatographed  on  silica  as d e v e l o p e r to g i v e the f a s t e r - m o v i n g The slower-moving  component was  found  to be c h r o m a t o g r a p h i c a l l y i d e n t i c a l to the major band i n f r a c t i o n E and were combined.  T . l . c . of the h i g h e r R^ band u s i n g the b e n z e n e - e t h y l a c e t a t e  developer s t i l l t h i s syrup was  gave the p r e v i o u s l y d e s c r i b e d d i f f u s e a g a i n rechromatographed  as d e v e l o p e r to y i e l d the hydroxy c r y s t a l l i n e mass which was  ketal  but u s i n g 4:1 203  recrystallized  (0.64  bands; t h e r e f o r e , benzene-ethyl  g, 4.5%)  acetate  as a white  from dichloromethane-hexanes  to  183  g i v e f i n e n e e d l e s : m.p. crystals);  [a] D  126-128°  -29.1°  2 3  ( s m a l l e r c r y s t a l s ) , 130-132°  (c2.0,CHC1 ); — 3 Q  ( e s t e r s ) ; n.m.r.(100MHz,DMSO-dJ 61.30 b  v  4 3480(broad,OH), max  (larger 1725  C C 1  and 1.45(s,3H,C(CH_).), —J Z  cm"  1  2.28-2.70  (m(obscured by the DMSO r e s o n a n c e ) , 4 H ( i n c l . DMSO),H-2), 3.64(s,3H,  -OCH_ ), 3  4.14-4.56(m,5H,H-3,H-5,H-7,H-8), 4 . 9 5 ( d , l H , J , 6.0Hz,H-6), 5.25(d,lH, 5,6 c  J_  _„ 5.5Hz,CHOH, exchangeable w i t h D 0) , 6.08(sharp s,lH,C0H, o  J , UH  —  w i t h D 0,  Z  —  7.70(m,3H,Ar), 8.08(m,2H,Ar).  2  induced a s p l i t t i n g i n t e n s i t y t o the new  exchangeable  A d d i t i o n of D 0 2  to the n.m.r. sample  i n the methyl resonances to g i v e a p p r o x i m a t e l y 20% resonances.  These o c c u r r e d at 61.36, 1.50  The n.m.r. spectrum u s i n g d e u t e r o c h l o r o f o r m as s o l v e n t c l e a r l y  and  3.59.  i n d i c a t e d the  C-2 methylene hydrogens and a l s o showed the keto sugar as a 4:1 r a t i o of the a and 3 anomers, r e s p e c t i v e l y ; C-13 n.m.r. (20MHz, DMSO-d,, proton-decoupled) b major isomer-624.86  and 2 6 . 3 8 ( C ( C H ) ) , 37.69(C-2), 51.13(0CH ), 3  2  66.03(C-8),  3  69.16(C-3), 82.75 (degenerate), 84.72(C-5,C-6,C-7) , 107.39(C-4), 165.47(PhC=0), 171.56(C0 Me); minor 2  isomer-625.39  111.89(C(CH ) ) , 2  and 2 6 . 3 8 ( C ( C H ) ) , 37.09 3  2  (C--2), 51.13(0CH ), 64.74(C-8), 70.49(C-3), 78.97, 79.85, 81.00(C-5,C-6, C-7), 104.30(C-4), 1 1 4 . 4 2 ( C ( C H ) ) , 165.47(PhC=0), 171.74(C0 Me). 3  2  The  2  aromatic s i g n a l s c e n t e r e d at 6120 were not a s s i g n e d . High r e s . mass spectrum ( d e v i a t i o n ) : m/e  396.1440(1.9,m ), 381.1193(0.7,m -CH ), 349.0927(0.4,m +  +  +  3  (CH +CH OH)), 293.1028(0.3,m -CHOHCH C0 CH ). +  3  3  2  2  3  A n a l . C a l c . f o r C ^ H ^ O g :C, 57 . 57 ;H, 6.10.  Found: C, 58. 06 ;H, 6.46.  F r a c t i o n E (4.7 g ) : T h i s f r a c t i o n was m a i n l y contaminated w i t h s l o w e r moving  pale yellow i m p u r i t i e s .  at 3530 cm  1  spectrum possessed a broad, weak band  and a s t r o n g band at 1725 cm . 1  graphed on s i l i c a  to c r y s t a l l i z e  The amber syrup was  rechromato-  g e l (230 g) u s i n g 19:1 benzene-ethanol as d e v e l o p e r to g i v e  the e p i m e r i c hydroxy k e t a l J  The i . r .  204  (2.5 g,17.6%) as a c l e a r syrup which CC1 from v a r i o u s s o l v e n t s , [ a l + 9.27(cl.1,CHC1_); v D — 3 max 4  failed 3510  184  (broad,OH), 1720 cm """(esters); n.m.r. (100MHz,DMSO-d^, minor isomer i n p a r e n t h e s i s ) 61.33(1.36) and 1.48(1.57)(s,3H,C(CH-) ), 2  by DMSO), 3H(incl.DMSO),H-2), H-6,H-7,H-8), 5.29(d,approx.  2.34-2.80(m(obscured  3.65(3.63)(S,3H.-OCH ) , 3.84-4.92(m,6H,H-3,H-5, 1/2H,J  0  _„ 6.5Hz,CHOH, exchangeable w i t h D „ 0 ) ,  Z  J , OH  5.95  ( 5 . 6 0 ) ( s h a r p s (broad s ) , approx. 2/3H (1/3H), COH, exchangeable w i t h  D^O),  8.65(m,3H,Ar), 8.05(m,2H,Ar).  DMSO-d, as s o l v e n t . 6  a t o 6 r a t i o was a p p r o x i m a t e l y 2:1 u s i n g  A d d i t i o n of D 0 t o the s o l u t i o n i n c r e a s e d the r a t i o t o  L o  a p p r o x i m a t e l y 4:1 (a t o 8, r e s p . ) .  The n.m.r. spectrum i n C^D^ gave two  broad d o u b l e t s a t 63.56 and 3.62 w i t h J  7.0Hz f o r t h e 2°-hydroxyls and  J , OH  a sharp s i n g l e t a t 64.59 f o r the 3 " - h y d r o x y l , a l l of which were exchangeable with D 0.  A s i m i l a r p a t t e r n a l s o o c c u r r e d i n d e u t e r o c h l o r o f o r m f o r the 2 ° -  2  h y d r o x y l s ; mass spectrum; m/e 396(m ), 381(m -CH ), 365(m -0CH ), 293(m +  +  +  +  3  3  CHOHCH C0 CH ); C-13 n.m.r. (20MHz,DMS0-d , proton-decoupled) major isomer2  2  3  6  625.21 and 2 6 . 6 6 ( C ( C H ) ) , 36.63 (C-2), 66.19(C-8), 67.72(C-3), 82.44, 83.54, 3  84.94(C-5,C-6,C-7),  2  107.34(C-4), 1 1 2 . 0 3 ( C ( C H ) ) , 165.62(PhC=0), 172.19  (C0 Me); minor isomer-625.50 2  3  2  and 2 6 . 6 6 ( C ( C H ) ) , 36.33(C-2), 51.19(OCH ), 65.05 3  2  3  (C-8), 70.57(C-3), 79.94, 80.68, 81.23(C-5,C-6,C-7), ( C H ) ) , 165.62(Ph£=0), 172.19(C0 Me). 3  2  2  105.07(C-4),  113.94(C  The a r o m a t i c s i g n a l s were not a s s i g n e d .  A n a l . C a l c . f o r C ^ H ^ O g : C, 57 . 57 ;H, 6.10.  Found: C, 57 .24 ;H, 6.18.  F r a c t i o n F (^3.0 g ) ; T h i s p a l e y e l l o w syrup d i d not g i v e any d e f i n i t i v e bands upon t . l . c .  a n a l y s i s ; t h e r e f o r e , no attempts were made t o determine i t s  composition.  S y n t h e s i s o f 199 from 172 U s i n g Excess m e t a - C h l o r o p e r b e n z o i c a c i d . 89a U s i n g a m o d i f i c a t i o n o f t h e p r o c e d u r e o f Borowitz e t a l of the methyl oct-3-enonate 172 (362 mg, 1.0 mmol) i n anhydrous  , a solution 1,2-dichloro-  ethane (3.0 ml) was added t o an i c e - c o o l e d , s t i r r e d , p a r t i a l s u s p e n s i o n o f  185  meta-chloroperbenzoic a c i d over 15 min.  (530 mg,  The i c e - b a t h was  3.1 mmol) i n 1 , 2 - d i c h l o r o e t h a n e (4.0  then removed and the m i x t u r e s t i r r e d  f o r 4 days  at  room temperature.  of  the r e a c t i o n and a s m a l l amount of p r e c i p i t a t e was  p r e s e n t at the end  of  the 4 days. The m i x t u r e was  to 15 mis w i t h d i c h -  loromethane,  The r e a c t i o n m i x t u r e remained  ml)  then f i l t e r e d , d i l u t e d  the r e s u l t i n g s o l u t i o n washed w i t h 7% aqueous sodium  carbonate (5 m l ) , water sodium  sulfate.  (5 ml) and the o r g a n i c phase was  was  chromatographed  b e n z e n e - e t h y l a c e t a t e as d e v e l o p e r to a f f o r d n.m.r. spectrum of which was a i r o x i d a t i o n of  d r i e d over  the l a c t o n e 199  (49 mg,  the 9:1  17%), the  isolated  from the  172.  of Compound 172 w i t h meta-Chloroperbenzoic A c i d i n the Presence o f  isopropylidene-  s o l u t i o n of the methyl oct-3-enonate 172  i n reagent grade dichloromethane of m e t a - c h l o r o p e r b e n z o i c a c i d The r e a c t i o n was  ( e t h y l 8^0-benzoyl-2-deoxy-5,6-0-  8 - D - a l t r o - 4 - o c t u l o f u r a n o s i d ) o n a t e (207).  To a s t i r r e d  stirred  (4.0 ml) at 0° was  (114 mg,  The aqueous l a y e r was  (180 mg,  at 0° f o r 1 h a f t e r which  the m i x t u r e was  (2 m i s ) .  allowed  c o n t i n u e d f o r an a d d i t i o n a l 2 h.  d e s t r o y e d w i t h 10% aqueous sodium  sulfite  (3.5 m l ) .  e x t r a c t e d w i t h dichloromethane, the o r g a n i c l a y e r s  were combined and washed w i t h s a t u r a t e d aqueous sodium hydrogen (5 m l ) , water  0.5 mmol)  added dropwise a s o l u t i o n  0.65 mmol) i n dichloromethane  r e a c h room temperature and s t i r r i n g was  The excess p e r a c i d was  of  anhydrous  on s i l i c a g e l (17 g) u s i n g  i d e n t i c a l to the l a c t o n e 199  E t h a n o l to g i v e Compound 204 and Methyl  to  hydrogen  A f t e r f i l t r a t i o n and e v a p o r a t i o n of the o r g a n i c phase,  r e s i d u a l syrup (142 mg)  Treatment  cloudy d u r i n g the course  (5 ml) and then d r i e d over anhydrous  sodium  carbonate  sulfate.  Removal  the d r y i n g agent by f i l t r a t i o n and e v a p o r a t i o n of the s o l v e n t gave a  c l e a r syrup (195 mg)  which by t . l . c . u s i n g 4:1 b e n z e n e - e t h y l a c e t a t e showed  two major components a t R- 0.275 and 0.13.  The syrup was  a p p l i e d to a column  186  of s i l i c a  g e l (30 g) and e l u t e d w i t h a g r a d i e n t o f b e n z e n e - e t h y l a c e t a t e  (4:1,60 ml; 3:1,20 ml; 2:1,36 ml; 1.5:1,53 m l ) . ponent was c o l l e c t e d c l e a r syrup:  [a]  t o g i v e t h e e t h y l g l y c o s i d e 207 (85 mg,39%) as a  -13 (c_0. 6 .CHCLj); v ^  2 5  The f a s t e r - m o v i n g com-  n.m.r.(100MHz,DMS0-d,) 6 1 . 0 7 ( t , 3 H , J _ „  4  _„  3560 (broad,OH) , 1727 c m ( e s t e r s ) ; - 1  7.0Hz, - 0 C H C H ) , 1.32 and 1.48 o  Q  (s,3H,C(CH_ ) ), 2 . 4 9 ( d d ( p a r t i a l l y b u r i e d under D M S O ) , l H , J g e m V L 5 . 0 H z , J 2 a 3  3  2  9.5Hz,H-2a), 2 . 7 6 ( d d , l H , J under - 0 C H J , 1 H , J _ , J  Cn ,LH2  15.0Hz,J  3.5Hz, H-2b), 3 . 6 1 ( q ( p a r t i a l l y  7.0Hz, - 0 C H „ C H „ ) , 3.62(s,3H, Z  3  j  -OCH,), 4.24-4.47(m, j  4H,H-3,H-7,H-8), 4.67(d,1H,J c , 6.0Hz,H-5), 4.79(broad s ( b u r i e d under 5,6 and H-6),1H,0H, exchangeable w i t h D 0 ) , 4.87(broad d , l H , J 5 2  7.66(m,3H,Ar), 8.05(m,2H,Ar).  I r r a d i a t i o n o f the t r i p l e t  the q u a r t e t a t 63.61 t o a s i n g l e t ; mass spectrum: m/e  buried  H-5  6.0Hz,H-6),  &  a t 61.07 c o l l a p s e d  424(m ), 409(m -CH ), +  +  3  321(m -CHOHCH C0 CH ). +  2  2  3  A n a l . C a l c . f o r C H g0 :C,59.43;H,6.65. 2]  2  9  Found: C,59.70;H,6.87.  Continued e l u t i o n o f t h e column gave t h e k e t a l 204 (20 mg, 10%) as a c l e a r syrup which had the same  (0.254 and 0.232) u s i n g 2:1 benzene-  e t h y l a c e t a t e and 1:4 hexane-ether as the k e t a l p r e v i o u s l y n.m.r. s p e c t r a o f these two k e t a l s were a l s o  isolated.  The  identical.  Treatment o f Compound 172 w i t h Osmium T e t r o x i d e to g i v e K e t a l s 203 and 204 To a s t i r r e d  s o l u t i o n o f t h e m e t h y l oct-3-enonate 172 (195 mg, 0.54 mmol)  i n anhydrous p y r i d i n e mmol).  (2.0 ml) was added s o l i d osmium t e t r o x i d e  The r e s u l t i n g brown s o l u t i o n grew d a r k e r as the r e a c t i o n  (138 mg,  0.58  progressed.  A f t e r 22 h, a 5% s o l u t i o n of aqueous sodium hydrogen s u l f i t e was added and the m i x t u r e r i g o r o u s l y s t i r r e d with chloroform w i t h water  f o r 10 min. The m i x t u r e was then e x t r a c t e d  (10 ml and 2x5 m l ) , and the combined  o r g a n i c e x t r a c t s washed  (10 ml) and d r i e d over anhydrous sodium s u l f a t e .  A f t e r removal  187  of  the d r y i n g agent  (3x4 ml) was pyridine.  by f i l t r a t i o n and  added and  evaporated  e v a p o r a t i o n of the s o l u t i o n ,  a t reduced  The r e m a i n i n g brown syrup was  xylene  p r e s s u r e to remove the r e s i d u a l  chromatographed on s i l i c a  g e l (16  u s i n g 14:7:4 b e n z e n e - e t h y l a c e t a t e - e t h e r as developer to g i v e k e t a l 203 3%)  as the f a s t e r - m o v i n g minor component and k e t a l 204  slower-moving to  major component.  (80 mg,  g)  (6  mg,  37.5%) as the  The n.m.r. s p e c t r a of both k e t a l s were i d e n t i c a l  those o b t a i n e d from the a i r o x i d a t i o n of compound 172 and a c r y s t a l l i n e  sample of k e t a l 203 melted  Treatment  a t 123-128° i n agreement w i t h p r e v i o u s r e s u l t s .  o f K e t a l 203 w i t h Sodium P e r i o d a t e to g i v e Lactone  To a s t i r r e d  s o l u t i o n of the hydroxy  (0.5 ml)  s h i e l d e d w i t h f o i l was  (570 mg)  and  h e m i - k e t a l 203  added a s o l u t i o n  sodium hydrogen carbonate  (36 mg),  the m i x t u r e a f t e r 4 h i n d i c a t e d a h i g h e r approximately  the same R^  and  s o l u t i o n evaporated  i n water  The r e a c t i o n was coevaporated  gel plate  (29 mg).  2 mg.  and  as l a c t o n e 199 and  Treatment  (7.5 mg,  44%)  had  (15x20 cm,250 pm)  the same R-  the n.m.r. s p e c t r a were  allowed to with xylene  u s i n g 3:2  s o l u t i o n of the hydroxy  (1.3 ml)  p r o t e c t e d w i t h f o i l was  i n water  (1.3 m l ) .  mixture was  filtered  The  ether-  (detected v i a a  U.V.  g r e a t e r than  (0.45 on the above p l a t e )  identical.  of Compound 204 w i t h Sodium P e r i o d a t e to g i v e Compound 199  To a s t i r r e d  material  resulting  I s o l a t i o n o f the components gave o n l y one band which was T h i s major band  T . l . c . of  Chromatography o f t h i s  hexanes as d e v e l o p e r gave a minimum of f i v e components lamp).  (10 m l ) .  in ethylacetate, f i l t e r e d  to g i v e a crude syrup  syrup on a p r e p a r a t i v e s i l i c a  i n ethanol  spot and a slower-moving  as s t a r t i n g m a t e r i a l .  the r e s i d u e d i s s o l v e d  (23 mg)  (0.5 ml) of sodium p e r i o d a t e  run f o r 30 days a f t e r which the r e a c t i o n mixture was (3 ml)  199  h e m i - k e t a l 204  (60 mg)  and  i n methanol  added a s o l u t i o n o f sodium p e r i o d a t e (60  s o l u t i o n was  and coevaporated  stirred  211  mg)  f o r 30 days a f t e r which the  w i t h t o l u e n e (2x3 m l ) , r e d i s s o l v e d i n  188  e t h y l a c e t a t e , f i l t e r e d and evaporated  to y i e l d  a crude syrup  (68 mg). The  syrup was chromatographed on a p r e p a r a t i v e t . l . c . p l a t e (20x20 cm, 1.5 mm) u s i n g 1.5:1 ether-hexanes The  as d e v e l o p e r to g i v e 3 U.V. a c t i v e components.  f a s t e r - m o v i n g band at  0.48 was c o l l e c t e d  to g i v e the c r y s t a l l i n e  l a c t o n e 199 (22 mg,50%) which had an n.m.r. spectrum o b t a i n e d f o r compound 199 i s o l a t e d  i d e n t i c a l t o t h e one  from the a i r o x i d a t i o n of the methyl o c t -  3-enonate 172. The  i n t e r m e d i a t e band (R- 0.29) was e x t r a c t e d t o y i e l d an impure  sample of s p i r o - l a c t o n e 211 (3 mg). showed that i t was predominantly later  The n.m.r. spectrum  of this  syrup  the s p i r o - l a c t o n e 211 s y n t h e s i z e d i n a  reaction. The slower-moving  band  (R^ 0.22) y i e l d e d a syrup  n.m.r. s p e c t r o s c o p y showed a mixture of 3 compounds.  (5.5 mg) which by Due to the s m a l l  amount o f m a t e r i a l no f u r t h e r attempts were made to p u r i f y  the l a s t two  bands.  5,6-Di-0-acetyl-8-0-benzoyl-2,3-dideoxy-a(and 4-lactone  (208a) and (208b),  8)-D-ribo-4-octulofuranosono-1,  respectively.  A s o l u t i o n o f the k e t a l 202 (245 mg) i n 80% aqueous a c i d was s t i r r e d  f o r 0.5 h a t room temperature  trifluoroacetic  a f t e r which t o l u e n e (6 ml) was  added and the m i x t u r e evaporated under reduced p r e s s u r e .  The treatment  t o l u e n e was repeated twice and the r e s i d u a l syrup was d i s s o l v e d of a c e t i c anhydride  (3 m l ) , a c e t i c a c i d  with  i n a solution  (1.5 ml) and p a r a - t o l u e n e s u l f o n i c  a c i d monohydrate (600 mg) and s t i r r e d o v e r n i g h t a t room temperature.  To  the r e s u l t i n g brown s o l u t i o n was added sodium a c e t a t e (0.56 g) and the r e a c t i o n mixture s t i r r e d  f o r 15 min. Xylene  evaporated under reduced p r e s s u r e .  (6 ml) was added and the mixture was  The treatment w i t h x y l e n e was r e p e a t e d  twice and r e s u l t i n g s l u r r y was t r i t u r a t e d w i t h benzene (25 ml) and the mixture  189  filtered.  The s o l i d r e s i d u e was washed w i t h benzene (2x15 mis) and  the  combined f i l t r a t e s evaporated under reduced p r e s s u r e to g i v e crude syrup which was  chromatographed  on s i l i c a  g e l (40 g) u s i n g 4:1 benzene-ethyl a c e t a t e  as d e v e l o p e r to a f f o r d two major bands.  The f a s t e r moving band gave l a c t o n e  pp CC\ 208a (60 mg,24%) as a c l e a r s y r u p : [a]"" +57.7° (cl.O.CHCl ); v 4 ( l a c t o n e ), 1752 62,14  ( a c e t a t e s ) , 1730  cm  1805  (b e n z o a t e ) ; n.m.r. (100MHz,CDC1 )  1  3  and 2.16(s,3H,2xCH ), 2.27-2.45(m,2H.H-3), 2.57-2.81(m,2H.H-2), 3  (dd,lH,J  11.0Hz,J_ - 3 . 5 H z , H - 8 a ) , 4 . 5 9 ( p s e u d o - q ( p a r t i a l l y o v e r l a p p e d by 7,oa  gem  H-8a),lH,H-7),4.62(dd,lH,J H-5),  4.46  5.43(dd,lH,J  Q  2.0Hz,H-8b), 5.21(d,lH,J. , 7.0Hz,  /,ob  gem 5,b , 7.0Hz,J, , 2.5Hz,H-6), 7.57(m,2H,Ar), 8.08(m,1H,Ar);  c  D  mass s p e c t r a : m/e  11.0Hz,J_ ,  ,b  o, I  392(m ), 347(m -C0 H), 336(iZ-CH-CH-CO) 270(m -PhCO-H), +  +  +  2  257(m -PhC0 CH ). +  2  2  A n a l . C a l c . f o r C-^H-.O- :C,58.16;H,5.14. The slower moving prominant 34%) a l s o as a c l e a r syrup: [a]J D  2  1765,  1758  ( a c e t a t e s ) , 1730  cm"  1  Found:C,58. 31;H,5.29.  band gave the anomeric -11.1  l a c t o n e 208b (86  (c2.0,CHCl.); v 4 1805 — 3 max  mg,  (lactone),  C C 1  ( b e n z o a t e ) ; n.m.r. (100MHz,CDC1 ) 62.03 and 3  2.18(s,3H,2xCH ), 2.28-2.45(m,2H,H-3), 2.57-2.82(m,2H,H-3), 4.41-4.65(m,3H, 3  H-7.H-8), 5.52(d,lH,J. , 4.5Hz,H-5) 5.60(dd,IH,J,  J,b  _ 2.5Hz,H-6), 7.56(m,3H,  b,i  A r ) ; 8.14(m,2H,Ar); mass spectrum: i d e n t i c a l to 208a. A n a l . C a l c . f o r C ^ H ^ O . : C.58.16; H.5.14. Found: C, 58.44; H,5.13. M e t h y l 8-0-benzoyl-2-deoxy-3,4:5,6-di-O-isopropylidene-a(and o c t u l o f u r a n o s o n a t e (209a) and A dark orange t r i f l u o r o a c e t i c acid  (209b), r e s p e c t i v e l y .  s o l u t i o n of 2:2:1 (5 ml) was  the r e s u l t i n g s o l u t i o n was  B)-D-allo-4-  (V/V) 2,2  dimethoxypropane-acetone-  added t o the hydroxy k e t a l 203  s t i r r e d a t room temperature  (335 mg)  f o r 2.5 d.  and  Toluene  190  (2x4 ml) and benzene (4 ml)  were evaporated  from the r e a c t i o n mixture  g i v e a crude dark brown syrup which on t . l . c .  u s i n g 9:1  a c e t a t e as d e v e l o p e r gave 2 c h a r r i n g bands (R^ 0.28 slower-moving gel  and  0.35)  with  band predominating. Chromatography of the. syrup on  12%)  as a c l e a r syrup:  [a]  2 3  -59.1°  ( c l . l . C H C l ); v  JJ  (-C0 CH ), 1732 2  3  cm" (benzoate); 1  j  9.7Hz,J„,  l  e s t e r 209b 1747  4  ITlcLX  16.0Hz,J„ , 9.7Hz,H-2a), 3.16(dd, za, J  16.0Hz,J_, _ 4.0Hz,H-2b), 3.74(s,3H,-0CH„), 2b, 3 —J  4.65(d,lH,J  C  silica  3  0  gem  C  the  n.m.r. (100MHz,CDC1 ) 61.33,1.43,1.46 and  1.48(s,3H,2xC(CH_) ), 2.54(dd,lH,J —1 Z gem 1H,J  benzene-ethyl  (38 g) u s i n g the above s o l v e n t p a i r gave the 8 - k e t a l methyl  (43 mg,  to  4.45(s,3H,H-7,H-8),  6.0Hz,H-5), 4 . 8 2 ( d d ( p a r t i a l l y overlapped by H-6),1H,J  ^ 4Hz,H-3), 4.85(broad d , l H , J  c  ,  , 6.0Hz,H-6), 7.52(m,3H,Ar),  8.08  3,0  ZD,3  (m,2H,Ar); mass spectrum: Continued  m/e  436(m ), 421(m -CH ), 405(m -0CH ). +  +  +  3  3  e l u t i o n of the chromatography column gave the a - k e t a l methyl  e s t e r 209b (277 mg,  75%)  as a c l e a r syrup which c o u l d not be c r y s t a l l i z e d 24 CCI 1 from v a r i o u s s o l v e n t : [ct]^ - 1 3 . 6 ( c l . 1 , C H C 1 ) ; v 1733 (esters); D — 3 max n.m.r. (100MHz ,CDC1 ) 61.38, 1.42, 1.52 and 1. 62(s,3H,2xC(CH_ ) ) , 2.59(dd —  4  0  c  m  3  3  ( p a r t i a l l y o v e r l a p p e d by H-2b),lH,J ( p a r t i a l l y o v e r l a p p e d by H-2a),lH,J  gem  17.0Hz,J  _ 6.0Hz,H-2a), 2.76(dd 2a,3  o  ^17.0Hz,J. _ „ 6.0Hz,H-2b), 4.58(s,3H, zb, J 1  gem  -0CH_), 4.47(broad s, 3H,H-7 ,H-8) , 4. 58 (pseudo-t, 1H, J J  H-3), Ar),  4.66(broad d , l H , J  5  fi  7.0Hz,H-6), 4 . 7 6 ( d , l H , J  8.04(m,2H,Ar) ; mass spectrum:  m/e  5  g  _ and J _ . 6.5Hz, 2a,3 ZD , 3 ot  7.0Hz,H-5), 7.53(m,3H,  436(m ), 421(m -CH ), 405(m -0CH ). +  A n a l . C a l c . f o r C ^ H ^ O g :C, 60. 54 ;H, 6.47 . Methyl  2  +  +  3  3  Found: C, 60. 72 ;H, 6.45.  8-0-benzoyl-2-deoxy-3,4:5,6-di-0-isopropylidene-g-D-altro-4-octulo-  furanosonate  (210),  8-0-benzoyl-2-deoxy-5,6-0-isopropylidene-ct-D-altro-4-  octulofuranosono-1,4-lactone A s o l u t i o n of acetone fluoroacetic acid  (2 ml) was  (211). (8 m l ) , 2,2-dimethoxypropane (2 ml) added to the hydroxy  h e m i k e t a l 204  and t r i (370  mg)  191  and the r e s u l t i n g dark red s o l u t i o n s t i r r e d  f o r 2 days.  x y l e n e (2x4 ml) gave a dark syrup which was  chromatographed  silica  g e l (40 g) u s i n g a g r a d i e n t o f 9:1  developer.  [ct]^  -36.0°(cl.0,CHCl ) ; v ^ *  4  (100MHz,CDCl ) 61.32, 1.37, 3  by H-2b),lH,J__  3  (136 mg,  1.43  cm"  1  (benzoate); n.m.r.  3  7.0Hz,H-2a), 2.81(d(overlapped by H - 2 a ) , l H , J -  3  7.0Hz,7 ,  b  5.0Hz,H-2b),  3  and 4.84(d(overlapped by  6.0Hz,H-5,H-6), 4 . 7 5 ( d d ( p a r t i a l l y o v e r l a p p e d by H-5  6  and H-6), J -  „ 5.0Hz,H-3), 7.52(m,3H,Ar) 8.10(m,2H,Ar); mass spectrum: m/e  o  (m ),  33%) as a c l e a r s y r u p :  and 1.48(s,3H,2xC(CH )-), 2.80(d(overlapped  3.74(s,3H,-0CH ), 4.42-4.49(m,3H,H-7,H-8), 4.73 2H,J.  a c t i v e , c h a r r i n g band gave  1748 (-CO-Me), 1730  1  3  on a column o f  to 1:1 b e n z e n e - e t h y l a c e t a t e as  C o l l e c t i o n of the f a s t e r - m o v i n g U.V.  the d i - i s o p r o p y l i d e n a t e d d e r i v a t i v e 210  Coevaporation with  H-3), a  3  436  421(m -CH ), 405(m -OCH ).  +  +  +  3  3  A n a l . C a l c . f o r C-^H-gO-;C,60.54;H,6.47.  Found:C,60.30; H.6.57.  Continued e l u t i o n o f the column gave the s p i r o 8-1,4-lactone  211  (34 mg,10%) as a c l e a r s y r u p : [a]* -43.4(c0.7,CHC1-); v 4 3580 (OH), 1812 u -5 m__x ( l a c t o n e ) , 1730 c m " ( b e n z o a t e ) ; n.m.r. (100MHz,CDCl ) 61.40 and 1.57(s,3H, 2  C C 1  1  3  C(CH ) ), —3 0  2.54(d,lH,J  0  gem  17.5Hz,H-2a), 2.91(d,lH,J  4.42(d(overlapped by H-8b),lH,J 1H,J_  g  J_  6.0Hz,H-7), 4.95  g  b  b  4.5Hz,H-3), 4.67(dd,IH,J_  3  and 5 . 0 3 ( d , l H , J .  8.10(m,2H,Ar), 3.32(broad m/e  2a  s,lH,0H,  17.5Hz,J„, . 4.7Hz,H-2b), _b,3  7.5Hz,H-8a), 4.43(d(overlapped by H-8a),  R  6.0Hz,H,8b), 4 . 5 2 ( d , I H , J  gem  g  g  a  7.5Hz,  6.0Hz,H-5,H-6), 7.54(m,3H,Ar),  exchangeable w i t h D 0 ) ; mass 2  spectrum:  364(m ), 399(m -CH ), 277(m -(CH +CH0HCH C0). +  +  +  3  3  2  A n a l . C a l c . f o r C-^H^Og:C,59 .33;H,5.53.  Found: C,59 . 29 ;H,5.69.  192  Treatment  o f K e t a l 204 w i t h p a r a - T o l u e n e s u l f o n i c A c i d Monohydrate to g i v e  Compound 210, 211, 2-Benzoyloxymethyl-5-(carbomethoxyacetyl)furan and  (212),  8-0-Benzoyl-2-deoxy-5,6-0-isopropylidene-g-D-altro-4-octulofuranosono-l,4-  l a c t o n e (213) To a g e n t l y a z e o t r o p i n g s o l u t i o n o f k e t a l 204 (220 mg) i n benzene (25 ml) was added a s u s p e n s i o n of p a r a - t o l u e n e s u l f o n i c a c i d monohydrate (23 mg) i n benzene (10 ml) over 15 min w h i l e the r e a c t i o n r e a c t i o n mixture was maint a i n e d a t a volume o f 20 to 25 ml. The s o l i d r e s i d u e from the s u s p e n s i o n was washed i n t o t h e r e a c t i o n f l a s k w i t h methanol (0.5 ml) and s u f f i c i e n t  fresh  benzene was added t o t h e a z e o t r o p i n g m i x t u r e t o m a i n t a i n t h e above volume. A f t e r a f u r t h e r 45 min, the m i x t u r e was allowed t o c o o l and was then washed w i t h s a t u r a t e d aqueous sodium hydrogen carbonate  (6 ml), water (6 ml) and  d r i e d over anhydrous sodium s u l f a t e . Removal of the s o l i d s by f i l t r a t i o n and e v a p o r a t i o n o f t h e benzene under reduced p r e s s u r e gave a b r i g h t y e l l o w syrup which was chromatographed on a column o f s i l i c a g e l (10 g) u s i n g a g r a d i e n t of 4:1 t o 1:1 b e n z e n e - e t h y l a c e t a t e as d e v e l o p e r .  A fast-moving component  was q u i c k l y e l u t e d to g i v e the d i i s o p r o p y l i d e n a t e d d e r i v a t i v e 210 (3 mg, 1.3%) which produced  a n.m.r. spectrum  Continued  i d e n t i c a l t o t h e one o b t a i n e d p r e v i o u s l y .  e l u t i o n of t h e column gave t h e d i s u b s t i t u t e d f u r a n d e r i v a t i v e  MeOH (19 mg, 11%) as a c l e a r syrup: A 228 nm (e26,400), 276 nm (e27,800); Til3.X CHCl (_ ) 1730(benzoate), 1670 cm" ( k e t o n e ) ; n.m.r. (100MHz, max 2  212  1  v  3  1  7  5  Q  co  M e  CDC1.) 63.74(s,3H,OCH_), 3.88(s,2H.H-2), 5.39(s,2H,H-8), 6.67(d,1H,J  ,  C  3.5Hz,H-6), 7.28(d,lH,J. , 3.5Hz,H-5), 7.54(m,3H,Ar), 8.09(m,2H,Ar). I r r a d i ->, o a t i o n o f t h e d o u b l e t a t 66.67 c o l l a p s e d t o d o u b l e t a t 67.28 t o a s i n g l e t ; mass spectrum:  m/e 302(m ) , 229(m - C H C 0 C H ) . 2  2  3  A n a l . C a l c . f o r C ^ H ^ O g :C, 63. 57 ;H,4.75.  Found :C, 63.39 ;H, 4. 75.  F u r t h e r e l u t i o n o f the column gave the s p i r o ct-1,4-lactone 211 (79 mg, 39%)  as a c l e a r syrup: n.m.r. (100MHz,CDC1 ) 61.39 and 1 . 5 6 ( s , 3 H , C ( C H ) ) , 2.52 3  3  2  193  (d,lH,J H-2b,  gem  17.0Hz,H-2a), 2.91(m,lH,J ' ' gem  a d d i t i o n of D 0 Z o  5.0Hz and J  gem  17.5Hz,J., _ 5.0Hz,J , „ 2.0Hz, 2b, 3 2b, OH ' o  c o l l a p s e s m to a d o u b l e t o f d o u b l e t s w i t h J  0  ZD , 3  17.5Hz), 3.36(broad-pseudo-t,1H,J„, „ 2.0Hz,J_ .„ 1.7Hz,0H, ' 2b, OH 3, OH ' —' n  r  exchangeable w i t h D 0 ) ,  4.42(d(overlapped by H - 8 b ) , l H , J  2  (d (overlapped by H-8a),lH, J , /,ob  a d d i t i o n of D 0) .  of compound 211 p r e v i o u s l y produced. at 64.53 c o l l a p s e d  7.5Hz,H-8a),  a  _ 4.7Hz,J „ j,OH 0  TT  to a d o u b l e t o f 4.5Hz upon i d e n t i c a l to the spectrum  to a d o u b l e t o f d o u b l e t s ( J  gem The a d d i t i o n of D„0 produced a spectrum which Z  i d e n t i c a l to the one p r e v i o u s l y  4.43  I r r a d i a t i o n of the d o u b l e t of d o u b l e t  the m u l t i p l e t a t 62.91  17.0Hz and J„ 2.0Hz). Zb,On  g  zb,3  The remainder of the spectrum was  2  7  6.0Hz,H-8b), 4.53(dd,lH,J„,  1.7Hz,H-3, the d o u b l e t of d o u b l e t s c o l l a p s e d  and  n  was  o b t a i n e d from compound 211 i n d e u t e r o c h l o r o f o r m  D 0. 2  Continued e l u t i o n o f the column w i t h 1:1 b e n z e n e - e t h y l a c e t a t e gave the s p i r o S - l , 4 - l a c t o n e 213 CHC1_); v 4 3 max C C 1  (3.5 mg,  22 2%) as a c l e a r s y r u p : [ « ]  3500 (weak,broad,OH), 1 8 0 5 ( l a c t o n e ) , 1727  n.m.r. (100MHz,CDC1 ) 61.38  3  o  J  2  3  produces a sharp t r i p l e t w i t h  4.62(d(overlapped by H-8b),lH,J  J  6  ?  2.0Hz,H-8b), 4 . 7 5 ( d , l H , J  c  , 6.0Hz,H-5), 4 . 8 6 ( d d , l H , J  , 6.0Hz,  and H-6),1K.H-7), 8.58(m,3H,  I r r a d i a t i o n of the broad p s e u d o - t r i p l e t  the d o u b l e t o f d o u b l e t a t 62.57 and 2.83  mass spectrum: m/e  c  -5,b  J,b  A r ) , 8.09(m,2H,Ar).  6.5Hz),  3  4.0Hz,H-8a), 4.63(d(overlapped by H-8a),  2.0Hz,H-6) approx. 4.82(m(buried under H-5  collapsed  17.5Hz,J„ _ 6.5Hz, Za, j  17.5Hz,J _ _ 6.5Hz,H-2b), 4.38(broad p s e u d o - t , l H , zb,J 2  /,ob,  s(overlapped  01  gem  ^6.5Hz,H-3,addition of D 0  1H,J-,  1  2  by CH-),1H,0H, exchangeable w i t h D 0) , 62.57(dd,lH,J J — z gem  (c0.35,  cm" (benzoate);  and 1. 65(s ,3H,C(CH_ ) ) , 1.72(broad  3  H-2a), 2.83(dd,lH,J  -14.3  n  at 64.38  to d o u b l e t s ( J gem  ^17.5Hz):  349(m -CH ), 293(m +H-CH0HCH C0), 235(293-acetone). +  +  3  2  194  Treatment  of Compound 204 w i t h T r i f l u o r o a c e t i c A c i d and A c e t i c  to g i v e 3 4 5 6 - t e t r a - 0 - a c e t y l - 8 - 0 - b e n z o y l - 2 - d e o x y - a ( a n d >  )  (215), r e s p e c t i v e l y .  A s o l u t i o n o f the hydroxy h e m i k e t a l 204 t r i f l u o r o a c e t i c a c i d was added and  stirred  Another  mixture evaporated to d r y n e s s . m i x t u r e of a c e t i c anhydride a c i d monohydrate (200 mg) was  was  The r e s i d u a l syrup was  stirred  was  p r e s s u r e to added and  dissolved  the  in a  (1 ml) and p a r a - t o l u e n e s u l f o n i c  a 0° f o r 3 h. stirred  Sodium a c e t a t e h y d r a t e f o r an a d d i t i o n a l  coevaporated w i t h t o l u e n e (2x5 ml)  then d i s s o l v e d  phase was  a l i q u o t of t o l u e n e (2 ml) was  (2 m l ) , a c e t i c a c i d  and  i n 80% aqueous  evaporated under reduced  then added to the m i x t u r e and  The m i x t u r e was  (240 mg)  f o r 20 min a f t e r which t o l u e n e (6 ml)  the r e s u l t i n g m i x t u r e was  one h a l f the volume.  (250 mg)  8)-D-altro-  >  4 - o c t u l o f u r a n o s o n a t e (214) and  Anhydride  15  min.  to g i v e a crude syrup which  i n a 1:1 m i x t u r e of chloroform-water  (20 m l ) .  e x t r a c t e d w i t h c h l o r o f o r m (2x10 ml) and the combined  The aqueous  extracts  washed w i t h water (5 ml) and d r i e d over anhydrous sodium s u l f a t e o v e r n i g h t . The d r y i n g agent was  removed by f i l t r a t i o n and  evaporated to g i v e a crude brown syrup which was of s i l i c a  g e l (40 g) u s i n g 4:1  the 8 - t e t r a a c e t a t e 215 CHC1-); v J max C  C  l  4  (23 mg,  H-2a), 3.06(dd,lH,J  2.14  gem  chromatographed on a column  7%)  as a c l e a r syrup: [a] cm"  1  1H,J.  (s,3H,4xCH.), 2.66(dd,lH,J —3 gem  + 10.7°  (cl.4,  15.7Hz,J„ _ 8.3Hz, 2a,3  15.7Hz,J-, - 4.5Hz,H-2b), 3.68(s,3H,-0CH,), zb, 3 —J  5.80(pseudo-t(overlapped 6  22  ( b e n z o a t e ) , n.m.r. (100 MHz,CDCl_) J  4.71(m,3H,H-7,H-8), 5.82 (pseudo-q(overlapped by H - 6 ) , J H-3),  solution  b e n z e n e - e t h y l a c e t a t e as developer to g i v e  1 7 5 2 ( a c e t a t e s ) , 1730  61.96, 2.03,2.04 and  the r e s u l t i n g  by H-3),J.  , 6.0Hz,J  £  2 a  . 8.3Hz,J_  4.36-  b  _ 4.5Hz,  _ 6.0Hz,H-6), 6.04(d,  6.0Hz,H-5), 7.55(m,3H,Ar), 8.10(m,2H,Ar). Continued e l u t i o n w i t h 4:1 b e n z e n e - e t h y l a c e t a t e gave the  c t - t e t r a a c e t a t e 214  (80 mg,  25%)  as a c l e a r s y r u p : [ a ]  2 2  +21.7  anomeric  (£0.9,CHC1 ); 3  195  v  CC1 max  1762  4  ( v e r y s t r o n g , broad band o f the a c e t a t e s ) , 1733  n.m.r. (100 MHz,CDCl ) 61.83  and  3  (dd.lH.J  gem  cm  (benzoate);  1  2. 02 (s, 3H, 2xCH_ ) , 2.08 (s, 6H, 2xCH_ ), 3  2.57  3  16.0Hz,J _ 8.0Hz,H-2a), 2.85(dd,lH,J za, 3 gem  16.0Hz,J . 5.0Hz, 2b, 3  o  OL  H-2b), 3.58(s,3H,-OCH„), 4.45(dd,lH,J —J gem  12.0Hz,J_ 2.7Hz,H-8a), 4.54-4.67 /,oa  (m,lH,H-7), 4.77(dd,lH,J  2.0Hz,H-8b), 5.33(dd,1H,J  12.0Hz,J^ /,ob  gem  0  , 5.5Hz,  c  D,b  J , _ 7.3Hz,H-6), 5 . 4 9 ( d , l H , J , 5.5Hz,H-5), 6.02(dd,1H,J. _ 8.0Hz,J„, _ b, / j,b za, J Zb,J c  5.0Hz,H-3), 7.68(m,3H,Ar) 8.09(m,2H,Ar). d o u b l e t s a t 66.02 c o l l a p s e d the two to d o u b l e t s w i t h J collapsed  d o u b l e t of d o u b l e t s a t 62.57 and  I r r a d i a t i o n o f the m u l t i p l e t at  the d o u b l e t of d o u b l e t s at 65.33 to a d o u b l e t w i t h J  mass s p e c t r a : m/e  8.  16.0Hz.  gem  I r r a d i a t i o n o f the d o u b l e t o f 2.85  64.61 , 5.5Hz; 5,6 c  524(m ), 493(m -0CH ), 4 6 5 ( m - 0 C C H ) , 379(m -CH(OAc)CH C0 CH ) +  +  +  +  3  Attempted S y n t h e s i s of a Ketose  2',3",5'-Tri-O-benzoyl-uridine  2  3  2  2  N-nucleoside  (217) 193  F o l l o w i n g the method of Vorbruggen and acetyl-2,3,5-tri-0-benzoyl-B-D-ribofuranose uracil  (216)(119  mg,  1.08  mmol) was  a s o l u t i o n of t r i m e t h y l c h l o r o s i l a n e stannic chloride  (0.14  ml)  Bennua (134)  , a mixture  (526 mg,  (0.10 m l ) , h e x a m e t h y l d i s i l a z a n e  ml),  a t room temperature  s a t u r a t e d aqueous sodium hydrogen carbonate The  o r g a n i c phase was  e x t r a c t e d w i t h dichloromethane and  mixture  f o r 2 h.  (75 ml)  10 min.  into a stirred  (15 ml) was  then poured  for  mmol) and then  m i x t u r e was and  1-0-  a z e o t r o p i c a l l y d r i e d w i t h t o l u e n e and  i n anhydrous a c e t o n i t r i l e  the r e s u l t i n g s o l u t i o n s t i r r e d  1.04  of  of i c e - c o o l e d  s e p a r a t e d and  (20 m l ) .  The  The  (0.17  added  and  reaction  dichloromethane  (30 ml)  and  stirred  the e m u l s i f i e d r e s i d u e  was  o r g a n i c e x t r a c t s were combined  d r i e d over anhydrous sodium s u l f a t e p r i o r to e v a p o r a t i o n to g i v e a c l e a r  syrup  (557 mg).  u s i n g 2:1  Column chromatography of the product on s i l i c a g e l (40  benzene-ethylacetate  as d e v e l o p e r y i e l d e d  the b e n z o y l a t e d  g)  uridine  3  196  d e r i v a t i v e 217 which was  193 69%, l i t 83%) as a p a r t i a l l y c r y s t a l l i n e syrup  (398 mg,  recrystallized  from chloroform-hexanes; m.p.  146.5-149T ( l i t  146-148°). Two  s m a l l e r s c a l e r e a c t i o n w i t h 40 mg  of compound 134  gave  comparable  yields.  Attempted q(and/or  Synthesis of  Methyl[1-(3,5,6-tri-0-acetyl-8-Q-benzoyl-2-deoxy-  8 ) - D - a l t r o - 4 - o c t u l o f u r a n o s y l ) u r a c i l j o n a t e from Compound  214.  (a) To an a z e o t r o p i c a l l y d r i e d m i x t u r e o f the a c e t y l a t e d k e t o s e (40 mg) the at  and u r a c i l  (9 mg)  was  s y n t h e s i s of compound 217 room temperature  added 1.1 ml of the same s i l a t i n g m i x t u r e d used i n (see p r e v i o u s page).  f o r 3 days a f t e r which  an i c e - c o o l e d m i x t u r e of dichloromethane hydrogen the  c a r b o n a t e (2 m l ) .  The m i x t u r e was  time the m i x t u r e was  poured  p r e s s u r e gave a crude syrup (20 mg)  sulfate.  NH)  (15x20 cm,  which was  1.0 mm)  chromatographed  o f the u r a c i l  (b) A m i x t u r e o f the a c e t y l a t e d k e t o s e 214 was azeotroped w i t h benzene (2 m l ) .  zane  reduced  on a p r e -  phosphorus  To the r e s i d u e was  (1.6 m l ) .  s o l u t i o n was  poured  into a vigorously s t i r r e d  (3 ml) and s a t u r a t e d aqueous sodium hydrogen phase was  and u r a c i l  (13.8  mg)  added a s o l u t i o n of (18 u £ ) , h e x a m e t h y l d i s i l a -  T h i s m i x t u r e was  p e n t o x i d e d r y i n g tube and r e f l u x e d  hydrogens  moiety.  (60.5 mg)  (12 u £ ) , t r i m e t h y l c h l o r o s i l a n e  (27 y2,) and a c e t o n i t r i l e  and  to g i v e s i x components none o f  nor a d o u b l e t a t ^65.5-6.0 f o r H-5  t r i f l u o r o s u l f o n i c acid  sodium  Removal of the  which from t h e i r n.m.r. s p e c t r a i n DMSO-d^ e x h i b i t e d any l o w - f i e l d (eg  into  The m i x t u r e was v i g o r o u s l y s t i r r e d f o r 10 min  d r y i n g agent by f i l t r a t i o n and e v a p o r a t i o n o f the s o l v e n t s under  plate  stirred  (4 ml) and s a t u r a t e d aqueous  o r g a n i c phase withdrawn and d r i e d over sodium  parative t . l . c .  214  protected with a  f o r 22 h a f t e r which time the c o o l i c e - c o o l e d mixture of dichloromethane carbonate  (2 m l ) .  The aqueous  e x t r a c t e d w i t h dichloromethane and the combined o r g a n i c e x t r a c t s  197  d r i e d over anhydrous  sodium  s u l f a t e . T . l . c . of the e x t r a c t  indicated  presence of a t l e a s t s i x components, none of which predominated exhibited  s t r o n g U.V.  activity;  t h e r e f o r e , the m i x t u r e was  the  nor  not a n a l y z e d  further.  Application  o f the F u s i o n R e a c t i o n  (a) A m i x t u r e o f compound purine  (218)  (62 mg,  to Compound  (214)  0.3 mmol) was  (100 mg,  214  0.2 mmol) a n d 2 , 6 - d i c h l o r o -  a z e o t r o p i c a l l y d r i e d w i t h t o l u e n e (5 ml)  and the r e s i d u a l m i x t u r e f u s e d at 150-155° (bath temperature) m e l t which was  stirred  f o r 30 min a t 15 t o r r .  a l l o w e d to c o o l and t . l . c . charring  The darkened melt was  a n a l y s i s of the m i x t u r e i n d i c a t e d  band t h a t absorbed u.v.  to a c l e a r  l i g h t and had  then  o n l y one  the same R. as the s t a r t i n g  compound. (b) P a r a - t o l u e n e s u l f o n i c a c i d monohydrate (12 mg) above m i x t u r e and t h i s new m i x t u r e was (3 m l ) . which was  The r e s i d u e was stirred  was  added to the  a z e o t r o p i c a l l y d r i e d with toluene  f u s e d at 150-155° to a c l e a r , l i g h t  f o r 30 minutes  at 15 t o r r .  brown melt  T . l . c . of the c o o l e d melt  gave the same r e s u l t s o f p a r t ( a ) .  Bis(trimethylsilyl)thymine  (219)  A s u s p e n s i o n of powdered thymine for  1 h) i n d i s t i l l e d  (10 drops) was  h e x a m e t h y l d i s i l a z a n e (32 ml) and  refluxed  f o r 12 h a f t e r which  observed i n t h e s u s p e n s i o n .  change  was  then a l l o w e d t o c o o l  and  added t o the m i x t u r e which was  A f t e r 10 h a l l o f the thymine had gone i n t o s o l u t i o n and  h e x a m e t h y l d i s i l a z a n e was was  was  trimethylchlorosilane  time v e r y l i t t l e  The s u s p e n s i o n was  s o l i d ammonium s u l f a t e (140 mg) refluxed.  (5.16 g, p r e d r i e d at 100°/0.10 t o r r  dissolved  then removed under vacuo.  i n anhydrous  again the excess  The r e s i d u a l amber syrup  1 , 2 - d i c h l o r o e t h a n e (67 ml, ^0.5M  s o l u t i o n ) and  198  used In subsequent r e a c t i o n s  without further p u r i f i c a t i o n .  S y n t h e s i s of Methyl(E,Z)-4,7-anhydro-8-0-benzoyl-3-bromo-2,3-dideoxy5 , 6 - 0 - i s o p r o p y l i d e n e - D - r i b o - o c t - 3 - e n o n a t e (220) from 172 To a s o l u t i o n of the methyl oct-3-enonate 172 anhydrous 1 , 2 - d i c h l o r o e t h a n e (2 ml) was  added bromine  s o l u t i o n of bromine i n 1 , 2 - d i c h l o r o e t h a n e ) .  analysis  ml of a  1.0M  stirred for  bis(trimethylsilyl)thymine  s o l u t i o n of 219 i n 1 , 2 - d i c h l o r o e t h a n e ) was  f o l l o w e d by t i n t e t r a c h l o r i d e The m i x t u r e was  (^0.5  0.5 mmol) i n  The s o l u t i o n was  10 min at room temperature a f t e r which time (219)(1.0 ml of a ^0.5M  (174 mg,  (0.06 ml, 1.0 equiv i n 1.0 ml  added  1,2-dichloroethane).  s t i r r e d a t room temperature f o r 16 h a f t e r which time  o f the r e a c t i o n m i x t u r e i n d i c a t e d  t.l.c.  complete consumption of the  s t a r t i n g compound and t h e p r e s e n c e of one f a s t e r - m o v i n g component  (R^ 0.443,  s t a r t i n g compound 0.385 u s i n g 4:1 b e n z e n e - e t h y l a c e t a t e as d e v e l o p e r ) which had the same weak U.V.  a c t i v i t y as the s t a r t i n g compound. The m i x t u r e was  d i l u t e d with chloroform carbonate  (5 ml) and washed w i t h s a t u r a t e d aqueous sodium hydrogen  (2x3 ml) and water (3 ml) and d r i e d over anhydrous sodium s u l f a t e .  F i l t r a t i o n and e v a p o r a t i o n o f the o r g a n i c phase gave a crude dark syrup which was  chromatographed on a column of s i l i c a  ethylacetate  g e l (10 g) u s i n g 4:1  benzene-  as d e v e l o p e r t o g i v e Methyl(E,Z)-4,7-anhydro-8-0-benzoyl-3-bromo-  2,3-dideoxy-5,6-isopropylidene-D-r_ibo-oct-3-enonate (220) (72 mg, c l e a r syrup which from i t s n.m.r. spectrum was isomers:  34%) as a  a 2:1 r a t i o of the geometric  1750(-CO <IH ), 1732(benzoate), 1692 cm (C=C); n.m.r. (100MHz, _1  2  3  DMS0-d , major(M) and minor(m) isomers) 61.34 6  and 1 . 4 0 ( s , 3 H , C ( C H ) ) , 3  2  3.46-M,  3.50-m(s,2H,H-2) , 3.58-m, 3. 62-M(s,3H,OCH_) , 4 .46 (d, 2H, J., „ ^3.2Hz,H-8), (t,lH,J_, _ 3.4Hz,H-7), 5 . 0 3 ( d , l H , J  c  4.89  /,o  — J  , 6.0Hz,H-6), 5 .31-m, 5.47-M(d, 1H, J , ,  6.0Hz,H-5), 7.64(m,3H,Ar), 7.98(m,2H,Ar). the above r e s o n a n c e s ; mass spectrum; m/e  Addition  of D 0 2  does not a f f e c t  440/442(m ), 425/427(m -CH ), 408/410 +  +  3  199  (m -CH OH), +  3  261/263(m +H-BzOH-Acetone). +  Storage of compound (chloroform) r e s u l t e d charred s o l i d  220 a t room temperature as a syrup o r i n s o l u t i o n  i n a slow a u t o - c a t a l y t i c  or s o l u t i o n .  H e a t i n g compound  s e v e r a l hours a l s o produced a b l a c k c h a r .  decomposition g i v i n g a b l a c k  220 under vacuo a t 65° f o r  200  V  BIBLIOGRAPHY  1)  E. F i s h e r and K. Zach, S i t z b e r , K g l . p r e u s s . Akad. 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T i p s o n , e d i t o r s , S y n t h e t i c Procedures i n N u c l e i c A c i d Chemistry", I n t e r s c i e n c e , New York, 1968, V o l . 1; b) pp.264-8. 192)  K.A. Watanabe, D.H. H o l l e n b e r g , and J . J . Fox, J . Carbohydr. N u c l e o t . , 1_, 1 (1974).  Nucleos.  193)  H. Vorbruggen  194.  A. R o s e n t h a l and J.K. Chow, u n p u b l i s h e d d a t a .  195.  A.A. P a v l i c and H. A d k i n s , J . Am. Chem. S o c , 68, 1471 (1946).  and B. Bennua, T e t r a h e d r o n L e t t . , 1339-1342 (1978).  196. a) 0. I s l e r , H. Gutmann, M. Montavon, R. Ruegg, G. Ryser and P. Z e l l e r , H e l v . Chim. A c t a , 40, 1242 (1957). b) " F i s h e r Chemical Index 77C", F i s h e r S c i e n t i f i c Co., L i m i t e d , 1977, p.59.  210  ADDENDUM 1)  Re: S t e r e o c h e m i c a l Assignment o f Compounds 192 and  BzO-i  N 2 H  BzO-,  192  N H  193.  2  193  A d d i t i o n a l s u p p o r t i v e e v i d e n c e f o r t h e s t e r e o c h e m i c a l assignment made f o r C-3 o f t h e diazo-amino compounds above a p p l i c a t i o n of Cram's Rule  (see page 114), comes from an  to t h e n u c l e o p h i l i c a d d i t i o n of t h e a z i d e a n i o n  t o t h e u n s a t u r a t e d e s t e r 18 (see page 7 and 113). The preponderant epimer p r e d i c t e d i s t h e 3-S_-epimer. The major diazo-amino compound i s o l a t e d compound 192 which was  was  p r e v i o s l y a s s i g n e d t h e 3-S_- or g - g l y c e r o - g - a l l o -  c o n f i g u r a t i o n . S i g n i f i c a n t l y , t h e major amino epimer determined f o r t h e amino m i x t u r e , i s o l a t e d from the h y d r o g e n a t i o n o f a z i d e 189 was t h e amino compound  190  (see pages  111-12),  ( i . e . , t h e h y d r o g e n o l y s i s product of 192).  T h e r e f o r e , the predominant epimers ( t h e 3-S_-epimer  of 189 and compd.  192)  p r e d i c t e d by Cram's Rule were shown t o be s t e r e o c h e m i c a l l y i d e n t i c a l and were a l s o t h e same s t e r e o c h e m i s t r y as p r e v i o u s l y  2)  assigned.  Re: S t e r o c h e m i c a l Assignment o f t h e Anomer Centre o f t h e K e t o f u r a n o s e s . The s t e r e o c h e m i c a l assignments of t h e anomeric c e n t r e s of the i s o p r o -  p y l i d e n a t e d k e t o f u r a n o s e s (see R e s u l t s and D i s c u s s i o n , s e c t i o n 3.) were p a r t i a l l y made on t h e b a s i s o f t h e work o f M o f f a t t and c o w o r k e r s ^ on 1  *8ee r e f e r e n c e 8, page 263 and r e f e r e n c e  (64) c i t e d  therein.  211  isopropylidenated C-glycosides. An extention of the C-13 n.m.r. work by Cousineau and Secrist  has shown that a ci_s-orient at ion of the alkyl side-  chain (at C-4) and the 5,6-0- isopropylidene group (i.e., the 8-octulofuranoses) results in a higher-field resonance for the isopropylidene methyls and quaternary carbon. The chemical shift values given for the quaternary carbon are 114.5+0.6 ppm and 112.7+0.6 ppm for the trans- and cis-orientated compounds, respectively. These values are in close agreement with the values found for the C-13 n.m.r. values found for the compounds listed in Table III.  AA  Table III. C-13 N.M.R. Chemical Shifts  of the 5,6-O-Isopropylidene  Quaternary Carbon and High-field Methyl of Various Ketofuranosides. Compd. 187 203 204 209a 209b (172  anomer assignment 6 0  B " B a g  Chemical Shift Quaternary Carbon High-field Methyl 112.00 114.42 111.89 113.94 112.03 114.62 112.20 113.23  25.39 24.86 25.50 25.21  - )  **Parts Per Million (ppm) from TMS. As the table clearly shows, the quaternary carbons of the 6-anomers (thus, a cis-orientation of the C-4 alkyl side-chain and the isopropylidene group) resonate at ^112 ppm while the ct-anomers resonate at ^114 ppm. Interestingly, compound 172 in which the alkyl chain is neither 'a' nor 'B' has i t s quaternary carbon signal at 113.23 ppm, intermediate in chemical shift. *T.J.Cousineau and J.A.Secri6t III, J. Org. Chem., 44, 4351, 1979.  

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