UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

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

You don't seem to have a PDF reader installed, try download the pdf

Item Metadata

Download

Media
UBC_1980_A6_7 C56.pdf [ 10.15MB ]
Metadata
JSON: 1.0060808.json
JSON-LD: 1.0060808+ld.json
RDF/XML (Pretty): 1.0060808.xml
RDF/JSON: 1.0060808+rdf.json
Turtle: 1.0060808+rdf-turtle.txt
N-Triples: 1.0060808+rdf-ntriples.txt
Citation
1.0060808.ris

Full Text

C-NUCLEOSIDES, C-NUCLEOSIDE PRECURSORS AND A NOVEL EXOCYCLIC GLYCAL by © JACK KENNY CHOW Sc., The Univ e r s i t y of B r i t i s h Columbia, 1976 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF THE FACULTY OF GRADUATE STUDIES In the Department of' Chemistry We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA February 1980 (cT) Jack Kenny Chow, 1980 MASTER OF SCIENCE i n I n p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f t h e r e q u i r e m e n t s f o r a n a d v a n c e d d e g r e e a t t h e 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 , I a g r e e t h a t t h e L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e a n d s t u d y . I f u r t h e r a g r e e t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r 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 by t h e Head o f my D e p a r t m e n t o r by h i s r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . D e p a r t m e n t o f 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 , C a n a d a V6T 1W5 D a t e FEBRUARY 13, 1980 ABSTRACT The synthesis of 3-(R and S0-3,4-dihydroshowdomycin (171) and (170) and the novel 3-(S)-(2,3-0-isopropylidene-a-D-ribofuranosyl)succinimide [3-(S)-a-dihydroshowdomycin acetonide 176] are reported. Several functionalized C-glycosides along with the addition products of a novel exocyclic e n o l i c sugar, methyl (E,Z^-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-0-isopropylidene- p-ribo-oct-3-enonate (172), are also described. A p p l i c a t i o n of the photoamidation reaction 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 sj5)-(5-0-benzoyl-2,3-0-isopropylidene-8-D-ribofuranosyl)-4-hydroxy-4- 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 (and a l t r o ) octonate (140) and (141). C y c l i z a t i o n of the 6-carbamoyl esters 140 and 141 with concomitant debenzoylation with sodium methoxide gave 170 and 171 a f t e r removal of the isopropylidene groups. Isomerization of the carbon-carbon double bond of 1_8 with sodium azide i n a N,N-dimethylformamide s o l u t i o n gave 172 which when photoamidated and treated with sodium methoxide gave compound 176. Treatment of 18 with sodium azide gave methyl (E)-4,7-anhydro-8-0_- benzoyl-2,3,5-trideoxy-g-erythro-oct-2,4-dienonate (178) along with 172. When excess hydrazoic acid was added to the above reaction mixture methyl 4,7-anhydro-3-azido - 8-()-benzoyl-2,3-dideoxy-5,6-0-isopropylidene-D-glycero- D- a l l o , altro-octonate (189) and small amounts of 172 were i s o l a t e d . Reducing the amount of hydrazoic acid i n the l a t t e r reaction gave compound 172 as the predominant product with small amounts of 189 along with methyl 3-amino-4,7- anhydro-8-£-benzoyl-2-diazo-2,3-dideoxy-5,6-0-isopropylidene-g-glycero-D-allo (and altro)-octonate (192) and (193), r e s p e c t i v e l y . Hydrogenation of 189 i n i i i the presence of 5% palladium on carbon gave the corresponding amino compounds, methyl 3-amino-A,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-^-isopropylidene-D- glycero-D-allo, altro-octonates (190) and (191), r e s p e c t i v e l y . Hydrogenation of 192 and 193 as above i n separate reactions gave the corresponding hydro- genolysis products 190 and 191, along with the hydrazones of methyl 3-amino- 4,7-anhydro-8-0-benzoyl-3-deoxy-5,6-0-isopropylidene- Tj-glycero-D-allo (and altro)-2-octulosonate (195) and (196), r e s p e c t i v e l y . The slow evaporation of the solvent from a d i e t h y l ether-hexane s o l u t i o n of 172 or prolonged storage of 172 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 (202), and methyl 8-J3-benzoyl- 2-deoxy-5,6-0-isopropylidene-a,B-D-allo (and altro)-4-octulofuranosonate (203) and (204), r e s p e c t i v e l y . Treatment of 204 with para-toluenesulfonic acid i n an azeotroping benzene s o l u t i o n yielded the furan d e r i v a t i v e , 2-benzoyloxymethyl-5- (carbomethoxyacetyl)furan (212). i v TABLE OF CONTENTS Page ABSTRACT i i LIST OF TABLES v i i LIST OF FIGURES v i i i ACKNOWLEDGEMENTS ix I. OBJECTIVE 1 II . INTRODUCTION 3 1. Unsaturated Sugars 3 1.1. Synthesis of Unsaturated Sugars 6 2. Photochemical Reactions 12 2.1. Photoamidation of Unsaturated Sugars 12 2.2. Photochemical c i s - t r a n s Isomerization 22 3. Carbon-Carbon Double Bonds 25 3.1. Nucleophilic Addition to a,3-Unsaturated Esters 26 3.2. Reactions of Enol Ethers 29 3.2.1. Addition of Oxygen and Hydrogen 30 3.2.2. Addition of Bromine and Bromomethoxylation 32 3.2.3. Methoxymercuration 33 3.2.A. Reaction with meta-Chloroperbenzoic Acid 35 3.2.5. Oxidation with Osmium Tetroxide 37 3.2.6. Oxidation with Molecular Oxygen 38 3.2.7. Periodate Oxidation 42 3.2.8. Azido-Nitration A3 3.2.9. Reaction with N-Bromosuccinimide 4 4 V TABLE OF CONTENTS - continued Page 4. C-Nucleosides 46 4.1. Showdomycin 48 4.2. C-Nucleoside Precursors 54 5. Ketose N-Nucleosides 56 I I I . RESULTS AND DISCUSSION 58 1. Synthesis of a- and 8-Dihydroshowdomycin: Photoamidation of Methyl (E,_Z)-4,7-anhydro-8^0-benzoyl-2,3-dideoxy- 5,6-0-isopropylidene-D-allo-oct-2 (and 3)-enonate (18) and (172), r e s p e c t i v e l y . 58 1.1. Synthesis of Dihydroshowdomycin v i a Photoamidation of the Methyl oct-2-enonate (18). 60 1.2. Synthesis of a-Dihydroshowdomycin Acetonide v i a Photoamidation of Methyl (E,Z)-4,7-anhydro-8- 0^-benzoyl-2,3-dideoxy-5, 6-0-isopropylidene-D- ribo-oct-3-enonate (172). 88 2. Synthesis of Functionalized Precursors to C-Nucleosides 95 2.1. Synthesis of Unsaturated and Amino Sugars 95 2.1.1. Attempted add i t i o n of Sodium Azide to the Methyl oct-2-enonate 1_8 to Y i e l d the Methyl oct-3-enonate 172 and Methyl (E)-4,7-anhydro-8-0-benzoyl-2,3,5- trideoxy-g-erythro-oct-2,4-dienonate (178). 95 2.1.2. Addition of Hydrazoic Acid to 18 to Y i e l d 172 and Methyl 4,7-anhydro-3-azido-8-0-benzoyl- 2,3-dideoxy-5,6-0-isopropylidene-D-glycero-D- a l l o , altro-octonate (189). 1 1 1 v i TABLE OF CONTENTS - continued Page 2.1.3. Addition of Sodium Azide to 1_8 to Give 172, 189, and Methyl 3-amino-A,7-anhydro-8-0- benzoyl-2-diazo-2,3-dideoxy-5,6-0-isopropy- lidene-rj-glycero-D-allo (and altro)-actonate (192) and (193), re s p e c t i v e l y . 113 2.2. Attempted Synthesis of a V i c i n a l Diazido Sugar 118 2.2.1. Treatment of 1_8 with Sodium Azide and Ceric Ammonium N i t r a t e (CAN) 118 3. Oxidation and Hydration Products of Methyl (E,_Z)-4,7- anhydro-8 - / J-benzoyl-2,3-dideoxy-5, 6-0-isopropylidene-D- ribo-oct-3-enonate (172). 119 4. Attempted Synthesis of Analogues of Psicofuranine 136 IV. EXPERIMENTAL 139 1. General Methods 139 2. Chromatography 139 2.1. Column Chromatography 140 2.2. Thin Layer Chromatography 140 3. Abbreviations 140 4. (R) and (jS)-Dihydroshowdomycin 140 5. 3- (S)-cc-Dihydroshowdomycin Acetonide 157 6. Unsaturated, Azido, Diazo, and Amino Sugars 162 7. Hemiketals, y-Lactones and A l k y l and Acyl Ketals 178 8. Attempted Synthesis of a Ketose N-nucleoside 195 V. BIBLIOGRAPHY 200 VI. ADDENDUM • , i r i v i i LIST OF TABLES Table Page I. Calculated Dihedral Angles between H-3 and H-l'. 86 II . Coupling Constants and Optical Rotations of the ' a - ' and '3-' D-Ribosylsuccinimide Derivatives and t h e i r H - l ' Chemical S h i f t s . 93 III:. C-13 N.M.R. Chemical S h i f t s of the 5,6-O-Iso- propylidene Quaternary Carbon and H i g h - f i e l d Methyl of Various Ketofuranosides. 211 v i i i LIST OF FIGURES Figure Page 1 Naturally Occurring C-Nucleosides 47 2A P a r t i a l 100 MHz Proton N.M.R. Spectrum of 3-(S^-(2,3-0-isopropylidene-B-D-ribofuranosyl) succinimide [(S)-dihydroshowdomycin acetonide, 153] i n CDC13 72 2B P a r t i a l 100 MHz Proton N.M.R. Spectrum of (S)-Dihydroshowdomycin Acetonide (153) i n DMSO-d, 73 o 3. 60 MHz Proton N.M.R. Spectrum of the Hydrogenation Product of Showdomycin Acetonide (157) i n CDCl^ 74 4 P a r t i a l 100 MHz Proton N.M.R. Spectrum of 3-(R)- (2,3-0-isopropylidene-B-D-ribofuranosyl)succinimide [(R)-dihydroshowdomycin] (154) i n DMS0-d6 78 5A P a r t i a l 100 MHz Proton N.M.R. Spectrum of Methyl (E,Z_)- 4,7-anhydro-8-_0-benzoyl-2,3-dideoxy-5,6-0-isopropylidene- D-ribo-oct-3-enonate (172). A 5:95 r a t i o of the E-to Z-isomers i n CDC13 99 5B P a r t i a l 100 MHz Proton N.M.R. Spectrum of Methyl (E,Z)- 4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-^-isopropylidene- D-ribo-oct-3-enonate (172). A 55:45 r a t i o of the E- to Z-isomers i n CDC1, 100 ACKNOWLEDGEMENTS I wish to thank Dr. Alex Rosenthal for h i s guidance, suggestions and patience during the course of t h i s research. The cooperation and invaluable p r a c t i c a l assistance provided by Drs. B. L. C l i f f and R. H. Dodd during my period at U.B.C. are g r a t e f u l l y acknowledged. To Pam and my mother, for t h e i r patient understanding during the preparation of t h i s t h e s i s , I wish to express my deepest appreciation. F i n a l l y , the f i n a n c i a l support of the University of B r i t i s h Columbia (1976-1979) and the National Research Council of Canada (through Dr. Rosenthal (1979-1980))is acknowledged. 1 I. OBJECTIVE The 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 of b i o l o g i c a l compounds s t r u c t u r a l l y related to the purine and pyrimidine nucleosides and/or nucleotides. The u t i l i t y of these compounds have been equally diverse i n that they have been used as models for con- formational and spectroscopic studies. used as probes i n the b i o l o g i c a l systems to elucidate the complex steps involved i n converting the genetic message to new biopolymers and i n the determination of the stages of other metabolic and anabolic pathways. The possible and e x i s t i n g chemotherapeutic value of these n a t u r a l l y occurring nucleosides and th e i r analogues and/or homologues however, re- present an unlimited use for these compounds. The s t r u c t u r a l analogues of the common nucleosides, obtained either from natural sources or by synthetic means, have often 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 , antifungal, or antitumor i n th e i r action. Four classes of modified nucleosides can be distinguished: (1) nucleosides i n which the r i b o s y l portion i s altered by the incorporation and/or elimination of various groups, (2) base-modified nucleosides, i n which the common purine or pyrimidine d e r i v a t i v e has been a l t e r e d , (3) C-nucleosides, i n which the hete r o c y c l i c base i s linked to the sugar moiety by a carbon-carbon rather than a carbon-nitrogen bond, and (4) the more recent homo-C-nucleosides, i n which a methylene unit resides between the nitrogenous heterocyclic base and sugar moiety. The fact that pyrazofurin (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 ) (possible a n t i v i r a l agent) anomers and both exhibit some degree of a n t i b i o t i c a c t i v i t y i s of p a r t i c u l a r relevance i n th i s present work. The objective of the work described i n t h i s thesis i s to synthesize various C-nucleosides and various ketose nucleosides. In the f i r s t part of t h i s work, the synthesis of the normal- and a-dihydro d e r i v a t i v e of showdomycin by way of photoamidation of unsaturated octonates was studied. The second part of t h i s thesis i s concerned with the synthesis of fun c t i o n a l i z e d precursors to C-nucleosides. The precursors envisioned were the C-glycosyl diamino acid d e r i v a t i v e s , the amino and carboxylic groups of the amino a c i d being p o t e n t i a l l y amenable to further d e r i v a t i - zation and the p o s s i b i l i t y of c y c l i z a t i o n of the v i c i n a l amino groups to give analogues of pyrazofurin. The two routes employed for the synthesis of such precursors were the condensation of sodium azide with an a, 8- unsaturated octonate 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 part of t h i s t h e s i s , the de r i v a t i v e s of a novel exocyclic g l y c a l i s investigated. Various compounds which are produced from the a i r oxidation of the g l y c a l are resynthesized using known procedures. The ketohexose nucleoside psicofuranine which i s both a n t i b a c t e r i a l and antitumor i n i t s a c t i v i t y was found to be absorbed externally by animals but not absorbed i n man unless i t was converted to the tetraacetate. It seemed p l a u s i b l e the elongation of the hydroxymethyl group at C-2' with a hydrophobic moiety such as carbomethoxymethyl might r e s u l t i n i n t e r e s t i n g b i o l o g i c a l consequences. Therefore, the f o r t h and f i n a l part of t h i s thesis deals with the attempted synthesis of analogues of psicofuranine u t i l i z i n g both the novel exocyclic g l y c a l and i t s acetylated hemiketal d e r i v a t i v e . The fusion method and the one-step synthesis of a N-nucleoside using t i n te t r a c h l o r i d e and methanesulfonic acid c a t a l y s t s were employed with the l a t t e r compound. 3 I I . INTRODUCTION 1. Unsaturated Sugars The f i r s t laboratory synthesis of an unsaturated sugar d e r i v a t i v e dates back to 1913 when Emil Fisher and K. Zach produced t r i a c e t y l - D-glucal (.1).* Since t h i s f i r s t synthesis of an enol ether f u n c t i o n a l i t y i n a carbohydrate, the range of d i s c r e t e carbohydrate d e r i v a t i v e s which possess a carbon-carbon double bond i n the sugar chain has increased to cover a large v a r i e t y of unsaturated sugars which have one or more carbon- carbon double bonds which may be i n conjugation with themselves or other f u n c t i o n a l groups. The increased a c t i v i t y i n the l a s t quarter century i n t h i s important group of d i v e r s i f i e d compounds has prompted several reviews. 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 dealt with in two e a r l i e r 2 3 papers by H e l f e r i c h and B l a i r , r e s p e c t i v e l y . A broader scope of t h i s 4 5 6 f i e l d i s r e f l e c t e d i n two reviews by F e r r i e r . * Recently, Kiss has given an in depth review of 8-eliminative degradation of carbohydrates containing a c t i v a t i n g groups while Feather and H a r r i s ' reviewed the area of dehydration reactions of carbohydrates. Formation of unsaturated sugars by enlarging g the carbon skeleton v i a the W i t t i g reaction has been reviewed by Zhdanov. The present and p o t e n t i a l value of the unsaturated sugars i n both t h e i r d i r e c t u t i l i t y as well as t h e i r use as synthetic intermediates i s exemplified by the presence of unsaturated carbohydrates in the naturally occurring nucleoside a n t i b i o t i c s Decoyinine 9 [Angustmycin A, 9-6-D-(5,6- AcO 1 4 psicofuranoseenyl)-6-amino purine, 2] and B l a s t i c i d i n S 1 0 [ l - ( l ' - c y t o s i n y l ) - 4-[L-3'-amino-5(1''-N-methylguanidino)-valerylamino]-1,2,3,4-tetradeoxy-2, 3-dehydro -B-p-erythro-hex-2-ene uronic a c i d , 3]. The unsaturated carbo- H 0NCHQ-UCN 2 I H CH- I ' HoNCNCH^j 2 g 3 NH hydrates themselves can have a n t i b i o t i c behavior 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-D- glycero-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 6-S-benzyl- 12 2 >3-bis-0-(para-nitrobenzoyl)-6-thio-L-xylo-hex-l-enulofuranose (5).The unsaturated C H 2 N H 2 4. R̂ disaccharide B z l S - 1 !5 R=pjara-nitroben2oyl sugars can be used as synthetic intermediates as shown by these examples: (1) Ethyl 4,6-di-j)-acetyl-2,3-dideoxy-a-D-erythro-hex-2-enopyranoside (6) 5 i s transformed into the a n t i b i o t i c sugar, AmicetoseJ""'' (2,3,6-trideoxy- g-erythro-hexopyranose, 7), (2) 6-chloro-9-(3,4-di-0-acetyl-2-deoxy-a (and 0) Q-erythro-pentopyranosyl) purines''""' (8) are produced from 3,4- di-O-acetyl-D-arabinal (9) and 6-chloropurine (10), and (3) from 2-methyl- furan (11) was produced the female sex hormone progesterone"*"^ (12) . The discussion on t h i s broad topic however, w i l l be necessarily s e l e c t i v e and b r i e f . Reactions of the unsaturated sugars w i l l follow i n Sections 2, 3 and 4. * Amicetose i s also a constituent of the a n t i b i o t i c nucleosides'^ Amicetin, P l i c a c e t i n and Bamicetin. 6 1.1. Synthesis of Unsaturated Sugars. As one of the few synthetic methods which can elongate the carbon skeleton of an organic molecule along with concomitant introduction of a 17 18 new carbon-carbon double bond, the W i t t i g reaction and i t s modifications , has quickly become one of the fundamental synthetic methods of modern organic chemistry, mild reaction conditions, together with high y i e l d s and the absence of migration of the bond formed are the main features of t h i s method. The simultaneous i n s e r t i o n of an alkene bond and a carboxyl f u n c t i o n a l i t y into a carbohydrate i s very a t t r a c t i v e i n view of possible useful d e r i v a t i z a t i o n of both functional groups. The f i r s t synthesis of 19 t h i s kind was reported by Kuhn and Brossmer . Thus, 1,2-0-isopropylidene- D-glyceraldehyde (13) and carboethoxymethylenetriphenylphosphorane (14) were condensed to give the higher-carbon unsaturated ester, e t h y l 2,3- dideoxy-4,5-0-isopropylidene-Tj-glycero-pent-2-enonate (15). Moffatt et 20 a l , i n an analogous reaction with 2,5-anhydro-6-benzoyl-3,4-0-isopropylidene- 13 14 15 D-allose (16) and carbomethoxymethylenetriphenylphosphorane (17) synthesized methyl (E_,Z)-4,7-anhydro-8-0_-benzoyl-2,3-dideoxy-5,6-0-isopropylidene-D-allo- oct-2-enonate (18) . BzO n / C U 1 A ^ 0 0 ^ + MeO2CCH=P03 > 12 18 Unsaturated sugars can also be synthesized by reactions involving 4 5 13 a l l y l i c rearrangements ' ' of i n i t i a l l y unsaturated carbohydrates. 8 21 Thus, when Jones and coworkers ' attempted to synthesize a nucleotide analogue by condensing 2',3'-0-isopropylideneuridine-5'-aldehyde (19) with phosphorane 14_ generated in s i t u , four unsaturated carbohydrate de r i v a t i v e s were obtained. Two of the unsaturated d e r i v a t i v e s , l-(5,6- dideoxy-2,3-0-isopropylidene-g-D-erythro-hept-4-enofuranosyl uronic acid u r a c i l (20) and i t s ethyl ester 21_, arose as a r e s u l t of a base-catalyz a l l y l i c rearrangement of the expected hept-5-enofuranosyl ester Z2 v i a the resonance s t a b i l i z e d intermediate anion 23. 8 + 1* EtOpCCHNCH o ]§ B= 1 N H 21 V=CH—CH=/ EtCT \ 0L«O EtC^CCH -ch=-4 / / B O " R02CCH2CH Et0 2 CCH=CH 2Q R=H 21 R=B R02CCH=CH Scheme I The formation of the other two o l e f i n i c carbohydrate d e r i v a t i v e s , 1- (3,5,6-trideoxy-g-D-glycero-hept-3,5-dienofuranosyl uronic acid) u r a c i l (24) and i t s e t h y l ester 25_ arose from a B-elimination of the, normally a l k a l i stable, fr-isopropylidene group. Although elimination reactions B to a c t i v a t i n g functions^ are common i n carbohydrate chemistry, the leaving groups usually only have one covalent bond (except epoxides) l i n k i n g i t to the sugar molecule (eg 22 23 24 -OMe , -OAc and -OSC^Me ). The B-elimination of the O-isopropylidene group (acetone) which has two points of linkage to the carbohydrate molecule, 9 although rare, does occur. The normally a l k a l i - s t a b l e 0_-isopropylidene group i f situated 6 to an a c t i v a t i o n group such as the carbonyl of an 25 ester or i n a vinylog system such as 22_ w i l l , i n the presence of an appropriate base, eliminate acetone to give the intermediate activated 26 a l l y l i c 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 are also capable of enhancing such eliminations. Unsaturated sugars are also formed from the acid dehydration of carbohydrates and t h e i r d e r i v a t i v e s . The t e r t i a r y a l c o h o l i c groups and t h e i r d e r i v a t i v e s (eg ethers and esters) are p a r t i c u l a r l y susceptible to 27a dehydration ; therefore, i t can be expected that c y c l i c ketose derivatives 28 w i l l dehydrate more r e a d i l y than the aldoses. The reaction of carbohydrates i n a l k a l i n e or a c i d i c solutions usually r e s u l t i n a myriad of products^ but one product which i s usually formed i n s i g n i f i c a n t quantities i s 5-hydroxy- methylfurfural (26) . The key step i n the formation of 26_ from sugars i s 26 29 30 the formation of 1,2- and 2,3-enediols. ' Two mechanisms have been proposed for the formation of compound 26: (1) based on the fa c t 26̂  i s formed from D-fructose (27) i n higher y i e l d and at a much greater rate than i s formed from D-glucose (28) ( t h i s 31 differ e n c e was p a r t i c u l a r l y evident when lb_ was prepared from sucrose (29) , only the D-fructose (27) portion of the molecule reacted, and D-glucose (28) 32 was recovered i n almost quantitative y i e l d ) , the mechanism states that D-fructose (27) i s present i n the furanose form, and that the ri n g remains 10 i n t a c t . The i n i t i a l reaction i s the elimination of water to form the 1,2-enolic form of 2,5-anhydro-D-mannose (30), and that further dehydration r e s u l t s i n compound 2J3. The necessity for 28_ to isomerize to 27 before dehydration accounts f o r the much lower reaction rate of 28. 2* R = H H O . 29 R = Scheme II 29 33 (2) The second mechanism ' proposed suggest that the dehydration proceeds v i a an a c y c l i c 1,2-enediol _31_ which eliminates a molecule of water through ^-elimination of a hydroxy group to give 3_2. Compound 3_2 undergoes rapid elimination of a second hydroxyl group to give 3_3. The loss of a t h i r d molecule of water occurs a f t e r , or simultaneously with the c y c l i z a t i o n of 33 and r e s u l t s i n the formation of 26. H-C-OH H-C=0 H-C=0 27 or 2 8 ^ ( t o n i f f o ^ io H O j i H Q C H L H C - O H H C T O H H C - O H I l b I R j R R 2L R=HC-OH 32 32a CH 20H 0 I H-C=>0 CHO 4H 2 0 H 33a HC-OH CH 33 Scheme III Other approaches to the synthesis of unsaturated sugars involve the dehydrohalogenation of g l y c o s y l bromides i n the presence of nitrogenous bases. Thus, 2,3,4,6-tetra-O-acetyl-l-deoxy-g-arabino-hex-l-enopyranose (34) was obtained i n ̂ 80% from i t s corresponding glycosyl bromide i n the presence diethylamine. l,5-diazabicyclo-[5.4.0]-undec-5-ene (DBU, 35) has 35 been u t i l i z e d in e f f e c t i n g dehydrohalogenation of glycosyl halides. 15 2. Photochemical Reactions Along with the increased a c t i v i t y i n the synthesis of unsaturated sugars and other f u n c t i o n a l i z e d carbohydrates i n the l a s t two decades, the use of photochemistry with these functionalized carbohydrates has also increased notably. The following discussion w i l l , however, be l i m i t e d to the a p p l i c a t i o n of photoamidation to carbohydrates possessing a si n g l e carbon-carbon double bond and the related side reactions of t h i s process. Reactions such as photoelimination and rearrangements i s beyond 36a the scope of t h i s thesis and further discussion i s unnecessary. P h i l l i p s has dealt with the area of photo-degradation of simple sugars i n a review 3 6b a r t i c l e . Bohm and A b e l l have reviewed the stereochemistry of free- r a d i c a l additions and t h i s topic w i l l be dealt with b r i e f l y . 2.1. Photoamidation of Unsaturated Sugars The addition of carboxamide free 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 that substituted formamides add to o l e f i n s i n the presence of peroxides to give products r e s u l t i n g from the addition of both •CON(CH3)2 and HCON(CH3)CH2 38 r a d i c a l s to o l e f i n s . In an independent study formamide was reported to have added to o l e f i n s i n the presence of peroxides at elevated temperatures. The light-induced addition of formamide to terminal o l e f i n s was shortly 39 reported by Elad. This i n i t i a l communication by Elad was soon followed 13 40a)-d) by four paper by Elad and Rokach describing the photoaddition of c ., . , , ... 40a , 40b . , , c . 40c formamide to terminal o l e f i n s , norbornene , nonterminal o l e f i n s and a,3-unsaturated esters. These photoreactions gave high y i e l d s of 1:1 adducts and served as a method of obtaining higher homologous amides and t h e i r d e r i v a t i v e s from unsaturated compounds. The addition of formamide to the unsaturated compound may occur when induced d i r e c t l y by sunlight (wavelengths of 220-250 nm) but the y i e l d s are f a i r l y low (^20% of the 1:1 adducts). Light f i l t e r e d through Pyrex (wavelength >300 nm) gave very poor y i e l d s of the derived 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 reaction proceeded at a greater rate 40a and gave high y i e l d s of the desired amide. With terminal o l e f i n s the 1:1 addition products were predominantly formed v i a an anti-Markovnikov addition. Formamide addition to unsubstituted nonterminal or c y c l i c o l e f i n s was nonregio- and nonstereospecific and products r e s u l t i n g from addition to eit h e r carbon of the double bond were formed. However, i f s t e r i c i n t e r a c t i o n s are 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 addition of formamide can occur. Thus, the photochemical addition of formamide to norbornene (36) proceeded i n a ste r e o s e l e c t i v e manner to give the norbornane-2-exo-carboxamide (37) enantiomorphs, e x c l u s i v e l y 14 Therefore, one might expect the p o s s i b i l i t y of stereochemical induction i n s u i t a b l y s t e r i c a l l y hindered o l e f i n i c compound i n the photoamidation reactio n . When the photoamidation reaction was applied to simple a,g-unsaturated esters, the expected g-addition of the carbamoyl r a d i c a l to the unsaturated ester occurred to give derivatives of alkalyted succinic acids, e.g. 8 a RCH=CHCO„R. + -C0NHo -»- RCHCHCO-R.. Z L z | Z 1 CONH2 38 R^,R=alkyl groups — As i n the case of the photoamidation of the o l e f i n s , the o r i e n t a t i o n of addition of the carbamoyl r a d i c a l to the carbon-carbon double bond depends upon the r e l a t i v e s t a b i l i t i e s of the r a d i c a l s formed and the stereochemical o r i e n t a t i o n i s dependant on s t e r i c f a c t o r s . In the case of terminal o l e f i n s the i n i t i a l attack i s on the primary carbon to produce a secondary r a d i c a l 41 which i s more stable than the primary r a d i c a l produced upon i n i t i a l attack at the nonterminal 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 a d d i t i o n . With unsubstituted nonterminal o l e f i n s , the addition of the carbamoyl r a d i c a l to either carbon produces secondary r a d i c a l s , thereby r e s u l t i n g i n s k e l e t a l isomers. With the simple a,6-unsaturated esters, which i s i n essence an nonterminal o l e f i n , i n i t i a l attack of the carbomyl r a d i c a l to the 8 carbon r e s u l t s i n the formation of a free r a d i c a l (38) which obtains i t s s t a b i l i z a t i o n through resonance with the ester group Therefore, with the simple a l k y l a,g-unsaturated esters, only products with respect to the acid portion of the ester. 15 r e s u l t i n g from B-addition of the carbamoyl r a d i c a l were i s o l a t e d . Interesting r e s u l t s occurred when a s t a b i l i z i n g group was introduced at the B p o s i t i o n of the unsaturated ester. With ethyl cinnamate (39) the r e l a t i v e s t a b i l i t i e s of the two r a d i c a l intermediates 40a and 40b would determine the o r i e n t a t i o n of the addition of the carbamoyl r a d i c a l . (JENH2 ^0NH2 CgHgO ĈHCĈ Et C 6 H 5 C H C H C ^ C H C r i 39 40a C ° 2 E t 40b * 2 E t S t e r i c factors should not be ignored but i n t h i s p a r t i c u l a r instance 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 over-riding f a c t o r s . A 42 comparison of the s t a b i l i t y of free r a d i c a l s which are s t a b i l i z e d by conjugation with these two fun c t i o n a l groups lead to the expectation that a benzyl malonic acid d e r i v a t i v e would r e s u l t from the a-addition of the carbamoyl r a d i c a l (structure 40a). However, experimental evidence showed that the major product formed from the photoamidation of ethyl cinnamate (39) i n the presence of benzophenone (41) as s e n s i t i z e r , was 2-carbamoyl-3,4,4-triphenyl-y-butyrolactone (42). As can be seen i n the following scheme, the stable intermediate benzylic r a d i c a l **3_ i n which the unpaired electron i s de l o c a l i z e d over the phenyl group, f a i l s to perform the hydrogen abstraction from formamide. Instead, the intermediate r a d i c a l 43_ forms a 1:1 adduct with a semipinacol r a d i c a l t̂4_ (or a molecule of benzophenone (41)) thus leading to the amido ester alcohol 45 which,under the conditions of the reaction, lactonizes to the amido lactone 42. 39 + HCONH' « > ( c ^ c o 41 C6H5CHCHC0NH2" iooEt 43 ;—> ( C 6 H 5 , 2 C 0 H 44 CgHgCH—CHC0NH2 ^ C^HcCH—CHC0NH2 (Cgr^COH C 0 2 E t 45 42 Scheme IV A side reaction that was detected i n the photoamidation reactions s e n s i t i z e d with benzophenone was the addition of the s e n s i t i z e r to the a,B-unsaturated ester with subsequent l a c t o n i z a t i o n of the y-hydroxy esters to give the substituted y-butyrolactones as shown i n the following scheme: RCH=CHC0 2 Et + R ^ H - C H 2 C02Et QCOH 0. \ 0 COH R = a l k y l , C 0 2 E t Scheme V + H" The free r a d i c a l chain mechanism was proposed for the photoamidation reaction. As mentioned previously, the light-induced amidation reaction can occur without an i n i t i a t o r but i t s presence increases the rate of the reaction and y i e l d s are s i g n f i c i a n t l y higher. The course of the reaction may be i l l u s t r a t e d i n the following scheme: H-CONH0 h y . s . (H-CONHJ* -CONH0 (1) 2 deactivation 2 -H 2 hv * H C 0 N H 2 ( C & H 5 ) 2 C=0 - i i — > ((C 6H 5) 2C=0) =-) -CONH2 + (CgH^COH (2) -HC=CH- + -C0NHo > -HC-CHC0N1I„ (3) 2 | 2 -HC-CHCONH2 + HCONH2 -H2C-CHCONH2 + •CONH2 ( 4 ) I -HC-CKCONH2 +-HC = CH- -> -HC-CHCONH2 (5) -HC-CH- -HC-CHCONH2 + -CONH2 -HC-CHCONH2 ( 6 ) ioNH 2 Scheme VI 18 In systems without added s e n s i t i z e r s (ketones) the generation of the carbamoyl r a d i c a l (step 1) r e s u l t from either the collapse of the phbtoactivated (*) formamide molecule or through hydrogen abstraction from formamide by other r a d i c a l s formed. In the presence of 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 abstracts a hydrogen from the formamide molecule to form the carbamoyl and k e t y l r a d i c a l s (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) with the a v a i l a b l e r a d i c a l s which leads to the is o l a t e d amide and a l c o h o l i c products. The desired amide products can be synthesized i n high y i e l d s by adjusting the concentrations of the appropriate reagents. Reactions (1) and (2) are the i n i t i a t i o n steps whereas reactions (3) - (5) are chain propagation steps with (3) and (4) giving 1:1 adduct and reaction * (5) leads to 2:1 telomer or further telomerization can occur to give higher telomer. Chain termination 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). Alkylated succinamides 40a have been i s o l a t e d from the photoamidation of terminal o l e f i n s and oxamide i s o l a t e d when o l e f i n i s absent. The r o l e of the s e n s i t i z e r , usually acetone or benzophenone, was i n i t i a l l y i n dispute as to whether i t s primary r o l e was one of a photo- i n i t i a t o r i n which the photoactivated ketone abstracted hydrogen from formamide (step 1) or that of a photosensitizer whereby the photoactivated t r i p l e t energy of the ketone was transferred to formamide which would 40a then collapse to form the carbamoyl r a d i c a l . This c o n f l i c t was 44 resolved when the t r i p l e t energy of formamide (4.2 eV) was found to be a n : l telomer i s defined as a molecule formed from n molecules of o l e f i n and one molecule of formamide. 19 greater than that of e i t h e r excited t r i p l e t acetone (3.5 eV) or benzo- 46 phenone (3.03 eV) . Therefore, the photosensitization of formamide by these ketones i s impossible, and, as a consequence, the only possible mechanism i s one i n which the formyl hydrogen i s abstracted by the n-̂ rr t r i p l e t of the ketone. Chemical proof i s also present i n the form of products i s o l a t e d from the reaction of the intermediate k e t y l r a d i c a l s , such as 2-methyl alkane-2-ols 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 considerable amounts of benzpinacol 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 of photochemical addition of formamide to unsaturated sugars has been undertaken by Rosenthal and coworkers i n an e f f o r t to determine the stereochemical outcome of t h i s reaction on various un- saturated sugars, as well as, u t i l i z i n g t h i s reaction to synthesize branch chain amido and amino sugars which may be used to synthesize 47 nucleoside analogues. Rosenthal and R a t c l i f f e photoamidated (Z) and (Z,E)-3-deoxy-3-C-(methoxycarbonyl)-methylene-l,2:5,6-di-0-isopropylidene- a-D-ribo-hexofuranose (46) to afford 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 anti-Markovnikov addition of formamide to the carbon- carbon double bond. The exclusive addition 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 ester 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 of E l a d ' s ^ ^ work with simple a,8-unsaturated ester to af f o r d the corres- ponding 6-carbamoyl esters. However, i n view of the work of Rosenthal and co-workers (vide infra) with substituted (enolic) unsaturated sugars which r e s u l t i n an anti-Markovnikov photoaddition of formamide and the previously discussed a-addition of the carbamoyl r a d i c a l to ethyl cinnamate (38) , the p o s s i b i l i t y of a-carbamoylation to give the 48 intermediate 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 unexpected. Upon photoamidation of various unsubstituted, mono- and disu b s t i t u t e d , endocyclic, enolic and enediolic unsaturated sugars, Rosenthal and coworkers 47 40a) b) concluded that, i n accord with Elad's ' findings with terminal and nonterminal o l e f i n s : the photoaddition of formamide proceeds i n an a n t i - Markovnikov fashion and substrates i n which both carbons of the unsaturated group bears hydrogen or in which the unsaturated group i s f u l l y substituted (with saturated groups), the photoamidation i s non-regiospecific. The stereochemistry of the carbamoyl r a d i c a l addition and the subsequent hydrogen abstraction step 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 the reactive centre of the unsaturated substrate. The c i s - 1 , 2 - s t e r i c i n t e r a c t i o n s provide the predominate d i r e c t i n g influence with the attacking species approaching from the least hindered side. 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 r a t i o s 47 49 found by Rosenthal and coworkers. ' Thus, photoamidation of t r i a c e t y l - D-glucal (1_) . Yielded three major carbamoyl sugars 50_, _51 and _52 in an approximate r a t i o of 2:2:3, re s p e c t i v e l y " ^ , with product 5_2_ ex h i b i t i n g a trans-orientation of the carbamoyl group to C-3 a c e t y l . 21 H H C O N H 2 5Q. R = C 0 N H 2 R*=H 52 51 R=H F f = C 0 N H 2 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 formamide adducts _54 and 5_5 were formed i n about equal amounts. This r e g i o - and s t e r e o s p e c i f i c addition was an e x c l u s i v e l y trans-hydrocarbomoylation since there was only a s i n g l e 1,2-c_is_-interact ion i n the abstraction step. The addition of the carbamoyl r a d i c a l s c i s to 53 54 55 0-2 of 53_ ( i . e . , the endo face of the fused r i n g system) i s not t o t a l l y s u r p r i s i n g i n l i g h t of the f a c i l e displacement reactions of s t r u c t u r a l l y s i m i l a r substrates when the attacking species i s n e u t r a l , small and 52a capable of hydrogen bonding to the oxygen on C-2 (e.g., hydrazine and , 52b, ammonia ). Photoamidation of the f u l l y substituted 3-0-acetyl-l,2:5,6-di-0- isopropylidene-ot-D-erythro hex-3-enofuranose (56) afforded carboxamide 53 sugars 51_ and _58_ i n 65 and 26% y i e l d s , r e s p e c t i v e l y . Expectedly, the major components added the carbamoyl r a d i c a l to the exo-face of the substrate with hydrogen abstraction i n 57_ on the same side due to two l,2-c_is-interactions on the s t e r i c a l l y crowded endo-face. The hydrogen abstraction i n the synthesis of compound j>8_ occurs on the endo-face but 22 on the least hindered p o s i t i o n of the fused r i n g system. Also, the o v e r - a l l addition i s trans since a 1 , 2 - c i s - s t e r i c repulsion from a carbon (e.g., the carbamoyl group) i s expected to be greater than an oxygen (e.g., 0-3) which might also provide hydrogen bonding to the hydrogen donor. CONH x0°q 2.2. Photochemical .c_is_-trans Isomerization The phenomenon of c i s - t r a n s isomerization i s well established, not only for thermal ground state reactions"'"', but also for excited state reactions. x h e ease with which the carbon-carbon double bond under- goes geometric isomerization upon i r r a d i a t i o n has been known for a con- siderable time, but the d e t a i l s of the reaction remain the subject of 58 many in v e s t i g a t i o n s . The dependence of the photochemical equilibrium of o l e f i n i c , aromatic and a,6-unsaturated ester systems on concentration temperature and t r i p l e t energy have been investigated."^ However, a detailed discussion on these topics and the mechanism of the photochemical isomeri- zation i s beyond the scope of t h i s thesis and only the mechanism and e f f e c t s of t r i p l e t energy w i l l b r i e f l y discussed. In a ground state isomerization the thermal reaction proceeds by way of a non-planar t r a n s i t i o n common to both cjis- and trans-isomers. The t r a n s i t i o n state w i l l collapse to give a greater proportion of the thermodynamically more stable isomer, usually the trans-isomer. However, the product composition i n the photochemically induced isomerization d i f f e r s from that i n the thermal process and the thermodynamically less stable isomer usually predominates. I r r a d i a t i o n of a trans-isomer w i l l produce an excited species which i s usually lower i n energy than the corresponding cis-isomer and the geometric isomerization i s brought about by a d i s t o r t i o n of the excited states i n i t i a l l y produced, to an excited state common to both c i s - and _trans-isomers. The common excited state i s termed a phantom state and involves a small a c t i v a t i o n energy.^ Collapse of the phantom state to the ground state w i l l a f f o r d both c i s - and trans-isomers. The cis-isomer i s less l i a b l e to undergo e x c i t a t i o n than the trans-isomer but nevertheless, an excited state population w i l l be obtained from t h i s isomer, and isomerization from c i s - to trans- w i l l occur v i a the phantom state. In t h i s manner, an equilibrium termed a photostationary state i s established i n which the cis-isomer usually predominates. Therefore, the photostationary state i s a function of the ext i n c t i o n c o e f f i c i e n t of the two geometric isomers with the isomer with the lower value predominating when the isomerization i s brought about by di r e c t i r r a d i a t i o n . However, when the geometric isomerization i s brought about by t r i p l e t s e n s i t i z a t i o n (e.g. from excited t r i p l e t acetone or benzophenone), the composition of the photostationary state d i f f e r s from that of d i r e c t i r r a d i a t i o n . If the energy of the donor i s greater than that of both isomers, then t r i p l e t energy transfer to both the c i s - and trans-isomer w i l l occur. 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 excited species undergo d i s t o r t i o n to the common phantom t r i p l e t which, on co l l a p s i n g to the ground state, affords a mixture of isomers. Because the s e n s i t i z e r can excite both isomers, the proportion of cis-isomer i n the photostationary state from a sen s i t i z e d reaction i s lower than that obtained from d i r e c t i r r a d i a t i o n . S e n s i t i z e r s of high energy (acetone) give photostationary states with approximately the same composition of isomers (^55% c i s ) , while reducing the energy of the s e n s i t i z e r gives anomolous r e s u l t s . ^ When the t r i p l e t energy of the s e n s i t i z e r i s low but s t i l l capable of t r a n s f e r r i n g energy to both isomers, the s e n s i t i z e r then functions as a true "photocatalyst' ! and the photostationary mixture approaches that at thermal equilibrium."^ Photochemical c i s - t r a n s isomerization has led to the synthesis of trans-double bonds in both cis-cyclohept-2-enone (59) and c i s - c y c l o - o c t - 2-enone (60) to afford the corresponding trans-isomers 61 and 6_2_ when i r r a d i a t e d with l i g h t greater than 300 nm, the isomerization being effected * 59 by the n->-TT e x c i t a t i o n . In the case of a, 6-unsaturated esters the energy- transfer from the excited carbonyl compound to the ester has been reported to be e f f i c i e n t and led to ci s - t r a n s isomerization or cycloaddition. "^ Thus, with respect to the photoamidation reaction, the quenching of the excited 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 of the a,6-unsaturated ester must be considered. Elad and Rokach^^^ found that when the acetone-initiated 25 reaction of formamide with ethyl maleate (cis-isomer) or ethyl fumarate (trans-isomer) was c a r r i e d out under conditions s i m i l a r to the ones used for i s o l a t e d double bonds ( i . e . , l i m i t e d amount of acetone employed), no addition products of formamide and the unsaturated ester could be detected. However, the recovered s t a r t i n g a,3-unsaturated ester consisted of a mixture of geometric isomers, p a r t i c u l a r l y i n the case of ethyl fumarate which was recovered mainly as e t h y l maleate (e.g., trans to c i s isomerization). Increased amounts of acetone produced some addition of formamide to the above esters but y i e l d s were s t i l l low. On the other hand, using benzophenone as the p h o t o i n i t i a t o r the addition of formamide to ethyl fumarate and maleate were achieved i n almost quantitative y i e l d . However, the undesir- able isomerization s t i l l occurred and t h i s energy-transfer step was found to be more e f f i c i e n t and more rapid than the hydrogen abstraction step from formamide. 3. Carbon-Carbon Double Bonds Hydrocarbons possessing a carbon-carbon double bond have the most basic f u n c t i o n a l group i n organic chemistry. By various simple trans- formation t h i s f u n c t i o n a l group may be transformed into a saturated hydrocarbon, an hydrocarbon possessing a higher degree of unsaturation or various other f u n c t i o n a l i z e d molecules containing hetero-atoms. This section w i l l deal mainly with addition reactions to compounds possessing a carbon-carbon double bond. There are b a s i c a l l y four ways in which addition to a double or t r i p l e bond can take place. Three of these are two step processes, with an i n i t i a l attack by a nucleophile, an e l e c t r o p h i l e , or a free r a d i c a l . The second step consists of combination of the r e s u l t i n g intermediate with a p o s i t i v e species, a negative species, or a neutral e n t i t y , r e s p e c t i v e l y . In the fourth type of mechanism, attack at the two carbon atoms of the double or t r i p l e bond i s simultaneous. The mechanism which i s operating in any given case i s determined by the nature of the substrate, the reagent, and the reaction conditions. P e r i c y c l i c ^ reactions are beyond the scope of t h i s thesis and no further discussion on t h i s process i s necessary. Photochemical free r a d i c a l additions have been dealt with i n d e t a i l i n the previous section and two non-photochemical methods w i l l be b r i e f l y dealt with here. Nucleophilic and p a r t i c u l a r l y e l e c t r o p h i l i c s u b s t i t u t i o n w i l l be the main focus of t h i s section. 3.1. Nucleophilic Addition to a,B-Unsaturated Esters The numerous examples of Michael-type addition to conjugated o l e f i n s are too varied in substrate and addition products to be discussed at any length. The focus of t h i s section w i l l be the addition of hydrazoic acid and sodium azide to a,B-unsaturated esters. Based on O l i v e r i - M a n d a l a ' s ^ addition of hydrazoic acid to benzo- 68 quinone i n 1915, Boyer in 1951, established that o l e f i n s conjugated with electron withdrawing groups (e.g., C=0, -C=N, -NC^ and J^jj) ) undergo Michael-type addition reactions with hydrazoic acid to give the corresponding 8-azido compound. The a,B-unsaturated carbonyl compounds exhibited intermediate r e a c t i v i t y and the azide products were found to thermally unstable with elimination of hydrazoic acid and nitrogen. The thermal s t a b i l i t y of the azides apparently increased with the number and the molecular weight of the substituents on the carbon bearing the azido g r o u p ^ or i f the azido compound was stored in a high molecular weight solvent (e.g., chloroform). Since hydrazoic acid i s a very weak aci d , the mechanism of t h i s reaction i s considered to 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 enolate ion predominantly at the oxygen leading to an enol which tautomerizes. The mechanism i s i l l u s t r a t e d i n Scheme VIII. No - C = C - ^ C = 0 l i N 3 fjJ3 -C—C=C—§«-» - C — ? — c = o I I I •c—c=c—OH; N 3 H - i — i — C = 0 Scheme VIII The Michael-type addition of hydrazoic acid to various conjugated unsaturated sugars has been studied. when Rosenthal and R a t c l i f f e ^ treated (Z)-3-deoxy-l ,2:5,6-di-0-isopropylidene-3-C- (methoxycarbonyl) methylene-q-g-ribo-hexofuranose (46) with excess sodium azide and hydrazoic a c i d , the azido-product a r i s i n g from the ster e o s e l e c t i v e addition of hydrazoic acid to the double bond to give the gluco-diastereomer (64) was is o l a t e d i n 80% y i e l d . I n t e r e s t i n g l y , along with expect addition product a second component i s o l a t e d i n a low y i e l d (7%) was found to be 3-amino-3-deoxy-3-C_-[3'-diazo (methoxycarbonyl) methyl]-1,2:5,6-di-0- isopropylidene-ct-D-glucofuranose (65) . 28 Upon t r e a t i n g the unsaturated sugar 46_ with sodium azide i n the absence of hydrazoic acid and a non-protic solvent, they i s o l a t e d the diazo-amino sugar 6_5 as the major addition product (46%) and the azido sugar 6_4_ i n trace amounts (2%) . The mechanistic pathway to the novel diazo-amino sugar 65_ i s thought to a r i s e from the base-catalyzed tautomerization 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 intramolecular c y c l i z a t i o n 73 of the azido enolate anion. This mechanism i s i l l u s t r a t e d i n the following scheme. 3.2. Reactions of Enol Ethers Just as o l e f i n i c compounds activated with electron-withdrawing groups undergo numerous n u c l e o p h i l i c addition reactions with the electron- 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 reaction, o l e f i n s , which are n a t u r a l l y more susceptable 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 or e l e c t r o p h i l e s when electron-donating groups are present. As with the electron-withdrawing groups a b i l i t y to influence the d i r e c t i o n of attack i n n u c l e o p h i l i c addition reactions, the electron- donating groups also play an 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 various a d d i t i o n reactions. This section w i l l deal with various e l e c t r o p h i l i c , free r a d i c a l and c y c l i c additions to the e n o l i c double bond, along with a d i s - cussion on the general s u s c e p t a b i l i t y of ethers and o l e f i n s to a i r oxidation. 74 P e r i c y c l i c and Diels-Alder cyclo-addition reactions are however, beyond the scope of t h i s thesis and w i l l not be discussed. The mode of addition of i o n i c reagents to the carbon-carbon double bond of enol ethers ( i . e . , v i n y l ethers) i s governed by the mesomeric release of electrons from the oxygen of the ether, which give r i s e to the contributing canonical structure 6_6_ and d i r e c t s the e l e c t r o p h i l e to \=AHR' R- C—CHR' R and R'= alkyl 66 the g-carbon. In those reactions which involve a 1,2-cyclic onium ion either the negative inductive 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 exert a d i r e c t i n g influence during the approach of the nucleophile i n the second step. However, the stereochemistry of the addition which depends upon the c h a r a c t e r i s t i c s of each reaction and governs the r a t i o of the i n i t i a l products may not be obvious i n the i s o l a t e d products due to the epimerization (or anomerization) about the a-carbon due to the a c t i v a t i o n e f f e c t of the enolic oxygen. 3.2.1. Addition of Oxygen and Hydrogen Enol ethers r e a d i l y add water or primary alcohols i n the presence of a c i d . Protonation (by the e l e c t r o p h i l e , H"*") takes place at the g-carbon to give intermediate carbonium ion 6_7 s t a b i l i z e d by the mesomeric release of electrons to the a-carbon to give contributing structure 68_. The intermediate cation then adds a molecule of the hydroxy reagent (ROH) to give the protonated species 69_ which looses a proton to give the hemi-ketal or k e t a l from the addition of water or alcohol, r e s p e c t i v e l y . This mechanism i s i l l u s t r a t e d i n Scheme X. This mechanism i s termed an A-SE.2 mechanism^ because the substrate (enol ether) i s protonated i n the rate determining step. As can be seen from the above scheme, the addition of the n u c l e o p h i l i c reagent i s an r e v e r s i b l e step catalyzed by the presence of the acid; therefore, - C = C — O R slow H Scheme X 31 the -OR1 groups attached to the a-carbon w i l l approach a thermodynamic equilibrium i r r e g a r d l e s s of the s t e r i c f a c t ors a f f e c t i n g the i n i t i a l a ddition of the nucleophile. The acid-catalyzed addition of water to the enolic system of 1,2- deoxy-l-eno sugars (glycals) has been applied with success i n the synthesis of numerous 2-deoxy derivatives of pentoses, hexoses, 6-deoxyhexoses, 2 4 disaccharides, and methylated aldoses. ' The y i e l d s of the 2-deoxy products vary considerably 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 products a r i s i n g from acid-catalyzed elimination reactions. For example, from D-glucal (1,2-dideoxy-D-arabino-hex-l^eno- pyranose, _70, R=H) and D-galactal (1,2-dideoxy-D-lyxo-hex^l-enopyranose, 71, R=H), acid-catalyzed addition of water gave, i n addition to the 2- deoxyhexoses (72 and 7_3 i n 42% and 78%, resp.), 3-hydroxy-2-(hydroxmethyl)- 2H-pyran (74) i n 16% and 1% y i e l d , r e s p e c t i v e l y . ' ^ Ik 32 In the acid-catalyzed addition of alcohols to the enolic system of the 1,2-unsaturated sugars, 2-deoxy a l k y l glycosides r e s u l t s . In some c a s e s ^ t h i s method of synthesis of the 2-deoxy glycoside i s preferred over the glycosidation of the free sugar. As i n the hydration of g l y c o l s , the competing elimination reaction i n t e r f e r e s and various a c y c l i c and unsaturated c y c l i c products may r e s u l t , along with the hydrolysis of a c i d - l a b i l e groups. 3.2.2. Addition of Bromine and Bromomethoxylation In the e l e c t r o p h i l i c attack of the bromonium ion (Br +, or a c a r r i e r of i t ) on a simple o l e f i n , the bromonium ion 7_5 i s often an intermediate © Br * o 9 I R — C — C - R — C — C - T i75 i i 76 that leads to an attack of the nucleophile from the opposite face (of the 78 double bond) to give s t e r e o s p e c i f i c a n t i addition. However, a number 79 of examples have been found where addition of bromine i s not stereospeci- f i c a l l y a n t i . The r e s u l t s indicate that there i s a spectrum of mechanisms between complete brominium-ion 75_ formation and complete open-cation 80 formation, with p a r t i a l l y bridged bromonium ions in between. The lo 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 to s t a b i l i z e the open-cation _76- Therefore, where R i s an alkoxyl group which gives a r e l a t i v e l y stable oxonium cation such as 6J5, the i n t e r - mediate cation w i l l possess much open-cation character, thereby lowering the s t e r e o s e l e c t i v i t y of the addition reaction. 81 In a report on the halomethoxylation (addition of X=halogen and -0CH3) of tri - O - a c e t y l - D - g l u c a l (70, R=Ac) and tri-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 proportions of a-cis addition products a r i s i n g from the open-cation. 3.2.1, Methoxymercurat ion Another route to the 2-deoxy glycosides i s by the use of the oxy- 82a mercuration reaction. The enol ethers (or o l e f i n s ) can be alkylated (or hydrated) quickly, under mild conditions, i n high y i e l d s without re- arrangement or elimination products. The oxymercuration reaction involve the e l e c t r o p h i l i c addition, to the carbon-carbon double bond, of the mercuric ion to form a c y c l i c mercurinium ion 77_. This ion i s then attacked by the n u c l e o p h i l i c solvent (water or 1° or 2° alcohol) to y i e l d the addition product. The net reaction i s a n t i addition and the ori e n t a t i o n corresponds to Markovnikov addition of alcohol (or water). 8 2b The mechanism i s i l l u s t r a t e d i n Scheme XI. HgOAc HgtOAc^, ROH ^ R = 1 o r 2 ° a l k y l o r H -C-I OR - H Ac 0 Ha -fV J R O H HgOAc -C C- ®0H ' Scheme XI The attack of the hydroxy reagent i s of the S N2 type, even though the o r i e n t a t i o n of the addition shows that the nucleophile attacks the more highly substituted carbon-carbon. The seeming contradiction i s due to the f a c t that the t r a n s i t i o n state i n c a t i o n i c three-membered rings possess much S^l character and, therefore the e l e c t r o n i c factor play a greater r o l e . Thus, the attack of the nucleophile (ROH) occurs at carbon that can best accommodate the p o s i t i v e charge ( i . e . , usually the more substituted centre). The oxymercuration re a c t i o n i s usually followed by a i n s i t u reductive demercuration with sodium borohydride (see Scheme XI) to give the net Markovinikov addition of water or alcohol to the unsaturated bond. The intermediate oxymercurial i f i s o l a t e d i s usually p r e c i p i t a t e d as the c h l o r i d e . Thus, the oxymercuration of tri-O-acetyl-D-glucal (70, R=Ac), a f t e r replacement of the i o n i c acetate by chl o r i d e , gave methyl 3,4,6-tri-O-acetyl- 2-(chloromercuri)-2-deoxy-3-D-glucopyranoside ( 7 8 ) ^ a ^. Reductive cleavage of the carbon mercury bond and simultaneous deacetylation were brought about 28 R=Ac 79 R=R=H R=HgCl with potassium borohydride i n a l k a l i n e s o l u t i o n and gave methyl 2-deoxy-g- D-arabino-hexopyranoside (79). 35 3 . 2 . 4 . Reaction with meta-Chloroperbenzoic Acid Another f a c i l e method for the synthesis of a l k y l or a c y l glycosides involves the use of meta-chloroperbenzoic acid (MCPBA, 80) on the g l y c a l s . The reaction of o l e f i n s with peracid 80 usually 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, with enol ethers the intermediate epoxy acetals appear to react with the carboxylic acid i n the reaction 85b mixture too r a p i d l y to permit i s o l a t i o n . Therefore, the usual product of t r e a t i n g a g l y c a l with peracid 80 i s the a-hydroxy glycosyl esters. Two mechanisms have been proposed for epoxidation of carbon-carbon 8 6 double bonds with peracids. The f i r s t proposed by B a r t l e t t i n 1957 involves the following one-step mechanism. Another, more recent, mechanism which i s also in accord with the re a c t i o n k i n e t i c s , solvent e f f e c t s and stereochemistry of the reaction r ,, 87 involves a two step process as follows. — c — c — R R R R H H O H 0© oe The key step of th i s mechanism involves the 1,3-dipolar addition of a tautomer of the peracid. The five-member adduct then rearranges to give the products. In the hydroxylation of D-galactal (71,R=H) with peroxybenzoic acid a regio- and s t e r e o s p e c i f i c addition of the reagents occurred to give 88 a-D-talopyranosyl benzoate (81) . The mechanistic aspects of the opening 81 82 of the epoxide are i d e n t i c a l to those proposed for the oxymercuration reaction (previous section) except the three-membered c a t i o n i c species i s structure 82. An i n t e r e s t i n g modification to the hydroxylation reaction with the peracid involves the slow a d d i t i o n of the enoli c substrate to an excess of peracid which r e s u l t s i n a cleavage of 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) with excess MCPBA 80_, they i s o l a t e d 6-ketononanolide (86) i n 92% y i e l d . xs 1 RC03H RC03H 65 °V&CR + S0H « fi ' a 0 86 Scheme XII The mechanism proposed for t h i s cleavage i s depicted i n Scheme XII and involves the usual formation of the epoxy-acetal 84 from the epoxi- dation of the e n o l i c double bond, the epoxide 84_ reacts with the excess peracid to give the ct-hydroxy k e t a l perester 85_ which then decomposes to give 86_ and meta-chlorobenzoic a c i d . 3.2.5. Oxidation with Osmium Tetroxide 89 Osmium tetroxide adds to carbon-carbon double bonds from the least 90 hindered side for the s e l e c t i v e conversion 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 ester 87_ i s an intermediate and can be i s o l a t e d , but i s 0 Q -I a? U n - usually decomposed i n s o l u t i o n , with sodium s u l f i t e i n ethanol or other 90,91a-b reagents. Bases (e.g. pyridine) catalyze the reaction by coordinating 90 with the e s t e r . " " Electron-withdrawing substituents retard the rate of 92 the inorganic ester formation and strained, unhindered o l e f i n s 'usually 93 react with osmium tetroxide more r a p i d l y than unstrained or s t e r i c a l l y hindered o l e f i n s . 38 Hydroxylation of 4,4'-dimethoxystilbene (88) with osmium tetroxide 92 has been achieved to give the corresponding d i o l (89). R — C = C R 0 s 0 4 7 R OH (j)H C C R H H H OMe g9 3.2.6- Oxidation with Molecular Oxygen Oxidation with molecular oxygen provides another route to the hydro- x y l a t i o n and oxidative cleavage of enolic double bonds. The slow atmospheric oxidation of a C-H bond to a C-O-OH group or any slow oxidation with atmos- pheric oxygen i s termed autoxidation. The i n i t i a l autoxidation products often react further to give a more complicated mixture and the purpose of th i s section i s to explore some of the possible routes to the hydroxy- l a t i o n and oxidative cleavage of the enolic double bond with these auto- xid a t i o n intermediates. The formation of hydroperoxides from ground state molecular oxygen 94 (a t r i p l e t ) i s a free r a d i c a l process , however, oxygen i t s e l f (a d i r a d i c a l ) i s too unreactive to abstract the hydrogen. The chain must be i n i t i a t e d by the production of some free r a d i c a l s (ag„ R'*) produced by some i n i t i a t i o n process, the r a d i c a l combines with molecular oxygen to give R'-0-0-, a species which can abstract hydrogen. The chain i s propagated by the following two steps: R'OO- + RH R'OOH + R- (1) * R-0-0- (2) The C-H bonds which most rea 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 the a-position of ethers. Hydroperoxides can also be formed by the d i r e c t action of photo- s e n s i t i z e d molecular oxygen on o l e f i n s . The active reagent here i s the 95 excited s i n g l e t state oxygen molecule. This reaction always takes place with 100% a l l y l i c rearrangement which i s incompatable with a free r a d i c a l mechanism; therefore, two mechanisms have been proposed for production of hydroperoxides from s i n g l e t oxygen. The f i r s t mechanism proposed^ involves a one-step p e r i c y c l i c mechanism, s i m i l a r to that of 97 the ene synthesis. The second mechanism proposed involves the i n i t i a l addition of s i n g l e t oxygen to the double bond to form either a dioxetane intermediate 90 or three-membered dipolar peroxirane 90a. Decomposition of these intermediates by i n t e r n a l proton transfer and bond rearrangements affords the a l l y l hydroperoxide 90b. Oxidative-cleavage of the carbon-carbon double bond may occur by an a l t e r n a t i v e decomposition of the dioxetane to give the carbonyl products. These steps are i l l u s t r a t e d i n Scheme XIII. H I * - c = c C - + 0 = 0 o e — ^ 0 — Q - H I H - c — c , — c - + - c — c — c- ' » ' \ " 1 i '90a' ^ Ox V ^ — c + c — c - - c — c 90b Scheme XIII The formation of epoxides from the reaction between the hydroperoxides 9 9 and o l e f i n may take place by at le a s t three routes. 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 , involves the base catalyzed addition of the hydro- peroxide to a,8-unsaturated carbonyl compounds (reaction 3). The i n t e r - mediate anion attacks the 0-0 bond to close the epoxide. The epoxides may ROf 4 - -Z— C C = 0 > 1 ^ I I I R 0 — 0 < ^ I e /K - C C C = 0 > - C — C C = 0 + R 0 e (3) i l l T i l * be formed by the addition of the peroxy r a d i c a l to the carbon-carbon double bond follow by r i n g closure and expulsion of an alkoxy r a d i c a l (reaction 4). RO; + - c = c - RO- (4) The t h i r d route involves a nonradical n u c l e o p h i l i c displacement by C=C on the oxygen-oxygen bond to give an epoxide i n manner sim i l a r to that of epoxidation with peracid (reaction 5 and also see Section 3.2.4.). H ^ y O - R - C = C - > - C C - -f- ROH (5) I I I I As was seen i n the oxidation of the o l e f i n with s i n g l e t oxygen, the reaction could lead to an oxidative cleavage of the o l e f i n i c bond. Another route to the cleavage of the o r i g i n a l double bond with the formation of two carbonyl compound involves the rearrangement of the a l l y l i c hydro- peroxide."'"^^ The mechanism i s seen i n the following scheme. — C = n C C - —) - C m C - ^ - C - - I I I I I I + + 0 H 2 + H 7 0 I u - H ' v - C = C 0 C - — C = C 0 C - > I I | I I I - C = C — OH -I- 0 = C — i r i i Hv I - c — c = o Scheme XIV 42 When D-glucal (70,R=H) was i r r a d i a t e d " ^ 1 i n the presence of oxygen, D-arabinose(91), formed by an oxidative cleavage of the double bond, was 102 i s o l a t e d as the main product. Goodman and co-workers reported that p u r i f i e d samples of methyl 5,6-dideoxy-2,3-j0-isopropylidene -8-D-allofuranoside- 4-ene (92) slowly polymerized on standing and indicated an increased oxygen content, suggestive of an oxidative polymerization. 2Q R = H 02 91 3.2.7. Periodate Oxidation As was seen i n the previous three sections the enol ethers can be hydroxylated or o x i d a t i v e l y cleaved ina one-step synthesis; however, the hydroxylated products ( i . e . , a-hydroxy ketone/aldehydes or t h e i r corresponding hemi-acetals) can be i s o l a t e d and then o x i d a t i v e l y cleaved i n a subsequent step. 1,2-Glycals, a-hydroxy aldehydes and ketones are 103 easily, cleaved by aqueous solutions of sodium periodate r e s u l t i n g in the formation of carbonyl f u n c t i o n a l i t i e s . The mechanism of the oxidative 104 cleavage involves the rapid and r e v e r s i b l e formation of a c y c l i c periodate ester 9_3, decomposition of the ester r e s u l t s i n the oxidative cleavage of the carbon-carbon bond of the 1,2-diol. This mechanism i s shown i n Scheme XV. I 92 OH i I - c = o Scheme XV - f - c = o I The reaction, therefore, i s l i m i t e d to substrates that can form the c y c l i c ester 93. 3.2.8. Azido-Nitration The a z i d o - n i t r a t i o n reaction i s a recently developed'*'^ reaction for the r e g i o s p e c i f i c addition of azide (-N̂ ) and n i t r a t e (-ONC^) across the enolic double bond. The reaction involves the addition of the enol ether i n a s u i t a b l e solvent to a mixture of eerie ammonium n i t r a t e (CAN) and sodium azide to give the 1:1:1 adduct. The mechanism proposed'*'^ for t h i s a d d i t i o n involves both f r e e - r a d i c a l and i o n i c intermediates. CAN oxidizes the azide anion to the azido r a d i c a l which adds to the 8-carbon of the e n o l i c substrate. The intermediate r a d i c a l 9_4 s t a b i l i z e d by the oxygen i s oxidized by another molecule of CAN to give the s t a b i l i z e d oxo-carbonium ion 94a which accepts a n i t r a t e nucelo- p h i l e associated with leaving CAN complex to give the f i n a l a d d i t i o n product. This mechanism i s i l l u s t r a t e d i n the following scheme. OH OH N® + CAN •N3 * > No i 1 - C C - — O R (N03)xCe V 0 - c — c 134 1 No I 3 — C - CAN OR * I C- OR 0N02 Scheme XVI When 3,4,6-tri-O-acetyl-D-galactal (71, R=Ac) was treated with CAN and sodium azide three 2-azido galactopyranosylnitrates (95a, b and c i n 37, 55 and 8% y i e l d resp.). AcO V-0 QN02 0N02 K 9 N 0 2 95c 3.2.9. Reaction with N-Bromosuccinimide Olefins can be halogenated at the a l l y l i c p o s i t i o n with N-bromo- succinimide (NBS) and when th i s reagent i s used, the reaction i s known as the "Wohl-Ziegler bromination". With t h i s reagent an i n i t i a t o r i s required and i s usually a peroxide or, l e s s often, u.v. l i g h t . The reaction i s usually quite s p e c i f i c at the a l l y l i c 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 free r a d i c a l type and i s i n i t i a t e d by small amounts of Br. Once the bromine r a d i c a l i s formed the main propagation steps are: Br - + RH R- + HBr (1) 45 R- + Br, -> RBr + Br- ( 2 ) The source of the B r 2 i s a fast i o n i c reaction between NBS and the HBr li b e r a t e d i n step 1: N—Br HBr N — H + B r 2 (3) Therefore, the function of NBS i s provided a source for molecular bromine, i n a low, steady-state concentration and to use up the hydrogen bromide l i b e r a t e d i n step 1. The fact the concentration of molecular bromine i s low provides the proper conditions for a l l y l i c s u b s t i t u t i o n rather than add i t i o n to the double bond. The atomic bromine adds to the double bond i n a equilibrium process and when the concentration of bromine i s low, there w i l l not be high p r o b a b i l i t y that the proper species w i l l be i n the v i c i n i t y once the intermediate r a d i c a l 9_6 forms and the equilibrium w i l l l i e to the l e f t . This slows the rate of addition so that a l l y l i c bromination can compete s u c c e s s f u l l y . This r a t i o n a l e i s i l l u s t r a t e d below: H Br- + — C C—C- _ I I I 1' stepd) HBr + step (3) — C = C - JBr 2 ,step (2) f . f — c — c — c - 1 'as 1 (Br2Kow H f f — c — c — c - •C C = C - + Br- i T I Scheme X V I I A. C-Nucleosides The nucleosides and t h e i r analogues are a broad range of compounds i n which an unsaturated hetereocycle i s attached to a polyhydric alcohol, aldehyde or ketone. The common or normal, naturally-occurring N-nucleosides consist of a pyrimidine or purine base joined by an N-glycosyl linkage to D-ribose. In 1959, Cohn 1 1^ i s o l a t e d a nucleoside that was d i f f e r e n t from the previously known N-nucleosides. This compound, which was is o l a t e d from an a l k a l i n e hydrolysate of c a l f l i v e r , was f o u n d 1 1 1 3 ^ to be 5-(6-D-ribo- furanosyl) u r a c i l (pseudouridine, 97), a nucleoside possessing a C-glycosyl linkage. Since then, a number of other C-nucleosides have been i s o l a t e d (se 112 Figure 1) mainly from fermentation sources. A l l , except pseudouridine 112 113 97 and Indochrome BII (10*5), possess a n t i b i o t i c properties. ' The b i o l o g i c a l a c t i v i t y of the C-nucleosides stems from t h e i r s t r u c t u r a l s i m i l a r i t i e s to the N-nucleoside, which allows the b i o l o g i c a l system to accept them as metabolites plus the 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 for d i f f e r e n t 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 system. One of the larger and more important differences i s the presence of the gl y c o s i d i c carbon-carbon bond which has an enhanced hydrolytic s t a b i l i t y compared to the more l a b i l e carbon-nitrogen bond of the common N-nucleosides 47 Pyrazofurin B Indochrome BII Figure 1: Naturally-Occurring C-Nucleosides 48 The b i o l o g i c a l properties"'"''"^ q ^ n a t u r a 2 i y _ o c c u r r i n g c_ nucleosides along with the s y n t h e s i s " ' " ' ' " ^ D f both na t u r a l l y - o c c u r r i n g C-nucleoside and t h e i r analogues have been extensively reviewed. This section, then, w i l l focus i t s attention on the synthetic approaches to showdomycin (99) and follow with a b r i e f discussion of the general approaches to the synthesis of C-nucleoside precursors. 4.1. Showdomycin Showdomycin (99) was discovered by Nishimura and coworkers'*""''' i n 1964 and i s elaborated by Streptomyces showdoensis. The structure of showdomycin has been established''""'"^3 C as 2 - ( B-D-ribofuranosyl) maleimide (99) by chemical and s p e c t r a l analysis and i t s structure i s c l o s e l y related to pseudouridine (97). Showdomycin exhibits both a n t i b a c t e r i a l and antitumor a c t i v i t y . Showdomycin i s s t r u c t u r a l l y unique among the C-nucleosides of n a t u r a l o r i g i n , i n that i t has the five-membered maleimide h e t e r o c y c l i c aglycon. Synthetic approaches to showdomycin must take into account i t s l a b i l i t y i n base, a t t r i b u t a b l e to a rapid Michael type of intramolecular addition of the 5'-hydroxy1 group to the double bond.^"'"^3 Two methods"*""*̂ have been u t i l i z e d i n the synthesis of C-nucleosides, one involves the d i r e c t condensation of the preformed hete r o c y c l i c base on the sugar and the other u t i l i z e s anomerically 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 with the hetereocyclic base elaborated from the functionalized 'aglycon'. The successful synthesis of showdomycin have u t i l i z e d the l a t t e r approach. The f i r s t three syntheses of showdomycin were very s i m i l a r in that each used a s t a b i l i z e d W i t t i g reagent on the keto 'aglycon' of the sugar to complete the maleic acid portion of the molecule. The f i r s t synthesis was reported i n 1970 when Kalvoda, FarkaS and Sorm u t i l i z e d methyl 4,5,7-tri-0-acetyl-3,6-anhydro-g-allo-heptulosonate (106,R=Ac), which was ingeniously prepared v i a the ozonolysis of l-(2',3',5'-tri-0-acetyl-8-D- ribofuranosyl)-2,4,6-trimethoxy benzene (107) a as t h e i r key intermediate. The keto ester 106 was then condensed with the Wi t t i g reagent (ethoxy- 0R OR OAc OAc 106 107 carbonylmethylene)triphenylphosphorane. The r e s u l t i n g mixture of esters ( c i s and trans) was hydrolyzed, and the c i s - a c i d (108) was c y c l i z e d with a c e t i c anhydride to afford the maleic anhydride d e r i v a t i v e (109). Treatment with 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 acid i n the presence of ethyl polyphosphate (EPP) gave showdomycin t r i a c e t a t e (110) which, when treated with methanolic hydrogen-chloride, gave c r y s t a l l i n e showdomycin (99) (see Scheme XVIII). Although y i e l d s for the ozonolysis and Wi t t i g reaction were not given showdomycin was i s o l a t e d i n about 16% o v e r a l l from 108. Three years l a t e r , TrummTitz and Moffat 120 described a two-step synthesis s t a r t i n g from the benzyl analogue (R-Bzl) of the keto ester 106. This key compound was synthesized from the dimethylsulfoxide- dicyclohexylcarbodiimide (DMSO-DCC) oxidation of the epimeric hydroxyl precursor (111). The construction of the ri n g was achieved in a key, one- step W i t t i g reaction, u t i l i z i n g (carbamoylmethylene)triphenylphosphorane Presumably, 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 acid ester (112) intermediate occurred to give the maleimide r i n g . To avoid hydrogenation of the maleimide r i n g , the debenzylation was accomplished i n good y i e l d s by treatment of 111 with boron t r i c h l o r i d e to give an o v e r a l l y i e l d of 29.6% from the epimeric hydroxy ester 111. 106 OR OR 111 R=CH 2 0 Scheme XIX Kalvoda searched for other routes J"^" L c l u to showdomycin and i n 1976 122 reported the synthesis of showdomycin v i a the condensation 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 cyanide. The key step i n t h i s synthesis involves the i n s i t u generation of the acyl cyanide followed by reaction with the Wit t i g reagent to give the methyl 3-cyano-2-alkenoate. Thus 3,4,6-tri-0-acetyl-2,5-anhydro-D-allonyl chloride (113) was treated with hydrogen cyanide i n the presence of excess (methoxycarbonylmethylene)tri- phenylphosphorane (114) to give an intermediary a c y l cyanide 115 which i s converted to a mixture of c i s and trans isomers of the W i t t i g adduct 116. The c i s (or E) isomer i s c y c l i z e d i n a mixture of acetic a c i d , acetic OR OR OR OR 117 R=H 116 1J8 R=Ac Scheme XX 52 anhydride, and s u l f u r i c acid to give a mixture of the free (117) and N- acetylated (118) maleimides which were de-acetylated i n methanolic hydrochloric acid to give showdomycin (99) i n an o v e r a l l y i e l d of 16.7% from the n i t r i l e precursor 119. At f i r s t glance Kalvoda's more recent OBz OBz U9 synthesis has an lower o v e r a l l y i e l d but on closer inspection Trummlitz and Moffatt's procedure also have the n i t r i l e 119 as an intermediate i n the t o t a l synthesis of showdomycin from ribose. Therefore, Trummlitz and Moffatt's y i e l d of showdomycin i s c a l c u l a t e from the common intermediate 119, the o v e r a l l y i e l d drops from 29.6% to 8.5%, making Kalvoda's synthesis much more appealing. 123 In a very recent paper Buchanan, Edgar and coworkers reported the synthesis of showdomycin (99) using the terminal acetylenic sugar, 2,3,5- tri-0-benzyl-8-D-ribofuranosylethyne (120) as t h e i r key intermediate. The key re a c t i o n involved the dicarboxylation of the terminal acetylene to the maleic ester d e r i v a t i v e 121, i n 80% y i e l d , s i m i l a r to the intermediate 119 in Kalvoda's f i r s t synthesis (see Scheme XVIII, structure 108). In a series of transformations s i m i l a r to Kalvoda's, the intermediate 121 was converted to the maleamic acid d e r i v a t i v e 122 and c y c l i z e d to the maleimide 53 R 0 - , OR OR 1 2 0 R=CH 2Ph R O - i CO, Me OH P d C l 2 , H g C l 2 C02R' V ^ R 1 121 R=Ff=Me 122R = N H 2 R*=Me 119 with a c e t y l c h l o r i d e (cf EPP of Kalvoda ). After debenzylation with boron t r i c h l o r i d e , showdomycin was i s o l a t e d 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-ribose. The o v e r a l l y i e l d of showdomycin from D-ribose (calculated from 122 known procedures) using Kalvoda's l a t e s t procedure i s 10%; therefore, t h i s recent procedure compares favourably. In a recent preliminary communication, Noyori, Sato, and Hayakawa"*^3 ^ reported the synthesis of showdomycin s t a r t i n g from noncarbohydrate materials. One of the key steps i n t h i s i n t e r e s t i n g synthesis involves the synthesis of 8-oxabicyclo[3.2.1]oct-6-en-3-one (123) from acetone and furan. Following hydroxylation with osmium tetroxide and isopropylidenation, subsequent Baeyer- V i l l i g e r oxidation of the ketone gave a racemic mixture of lactone 124. After r e s o l v i n g the mixture, the C-B-D-glycono-lactone 124 was converted to show- domycin (99) i n a seven step sequence involving the formation of a ot-keto ester 125 followed by c y c l i z a t i o n with the amide s t a b i l i z e d W i t t i g reagent 120 (cf. Trummlitz and Moffatt ). 1 2 3 HC—i 1124 I 54 The y i e l d of showdomycin based on the lactone acetonide 124 was l e s s than 22% and le s s than 7% based on 123 (cf. 10% based on D-ribose 122 for Kalvoda's procedure). The advantage of t h i s synthesis i s the fact the s t a r t i n g materials are r e a d i l y a v a i l a b l e and inexpensive, and 125 the a-keto ester intermediate i s amenable to the synthesis of other i -A 1 2 8 A C-nucleosides. Other synthetic procedures involving the condensation of a hetero- c y c l i c base containing the necessary elements for the maleimide ri 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 reported , however, the f i n a l transformation to showdomycin (99) has not been accomplished. 4.2, C-Nucleoside Precursors A great number of analogues^^' of the n a t u r a l l y - o c c u r r i n g C- nucleosides have been synthesized over the l a s t decade i n an e f f o r t to obtain chemotheropeutic compounds with 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 . This endeavour 125 has been highlighted by the synthesis of pseudo-isocytidine [5-(8-D- ri 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 synthetic C-nucleoside to 126 d i s p l a y antitumour properties. Four synthetic strategies have been employed i n the synthesis of novel C-nucleosides. Three of these approaches have been mentioned i n the 122 previous section and involve the elaboration of a het e r o c y c l i c base from sugar d e r i v a t i v e functionalized at C-l and the second involves the d i r e c t coupling of a preformed h e t e r o c y c l i c with an appropriately blocked sugar d e r i v a t i v e . ' T h e t h i r d procedure mentioned, prepares the 128a C-nucleoside from noncarbohydrate sources and the l a s t method involves the modification of n a t u r a l l y - o c c u r r i n g C-nucleosides. By f a r the most p r a c t i c a l and v e r s a t i l e synthetic route to modified C-nucleosides consists 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 followed by a stepwise elaboration of a h e t e r o c y c l i c base from t h i s f u n c t i o n a l group. Two general methods for obtaining 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 involves the intramolecular c y c l i z a t i o n of 112 129 a c y c l i c carbohydrate d e r i v a t i v e s which lead to precursor 120 for 123 Buchanan's synthesis of showdomycin (99). The second method involves the formation of a carbon-carbon bond at the anomeric centre formed usually from a g l y c o s y l halide and an appropriate carbanion. 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-ribosyl cyanide d e r i v a t i v e which w i l l be discussed i n more d e t a i l . 130 131 Based on the previous work by Coxon , Bobek and Farkas prepared tri-0-benzoyl-3-D-ribofuranosyl cyanide (127 R=CN) i n high y i e l d by reacting the bromide 126 with mercuric cyanide. Only the 6-isomer was i s o l a t e d , 112 presumably owing to neighbouring group p a r t i c i p a t i o n . The o r i e n t a t i o n 1 3 3 1 3 of the C - l substituents i s important since,but for a few exceptions, ' only the ^ - d e r i v a t i v e s exhibit therapeutic a c t i v i t i e s . The value of the r i b o s y l cyanide 127 i s that the various d e r i v a t i v e s of the n i t r i l e group have used to elaborate a v a r i e t y of naturally-occurring C-nucleosides 120 122 13A (e.g., showdomycin , _ (99), formycin B (101) and oxoformycin (102)) BzO-i Hg(CN)2 B z 0 - i 7 )Bz Ubz 127 R=CN 127a R=CH0 and C-nucleoside analogues 112 141a To t h i s end, Moffatt and coworkers have prepared 2,5-anhydro-D-allose 56 protected with various blocking groups. The key step and key i n t e r - mediate i n formation of these derivatives was the reductive-hydrolysis of the n i t r i l e 127 with Raney n i c k e l and sodium hypophosphite i n the presence of 1,2-dianilinoethane to trap the aldehyde as the N.N'-diphenylimidazo- l i d i n e d e r i v a t i v e 128. The aldehyde 127a (R=CHO) could be regenerated from 128 by mild acid hydrolysis. The aldehyde 127a (R=CHO) or i t s various protected analogues are key intermediates i n the synthesis of a v a r i e t y of C-nucleosides previously discussed. 5. Ketose N-Nucleosides The ketose N-nucleosides are a rare group of nucleoside a n t i b i o t i c s 113 of which only two are known. Psicofuranine [angustmycin C, 6-amino-9- (B-D-psicofuranosyl) purine, 129] and decoyinine (2) are a n t i b a c t e r i a l and antitumor nucleoside a n t i b i o t i c s elaborated by the Streptomyces. As can be seen i n structure 129 (and 2) these nucleosides have the common N-glycosyl 57 linkage between the sugar and base but the uncommon feature i s the hydroxymethyl group at ' C - l ' which requires a keto-sugar precursor and which makes the h e t e r o c y c l i c base both acid and base l a b i l e . Therefore synthetic approaches to the ketose N-nucleoside must take these properties into consideration. The synthesis of psicofuranine (129) has been reported by two groups and the synthesis of decoyinine (2) from psicofuranine was reported by Robins and h i s coworkers. 138 Farkas and Sorm synthesized the l'-deoxy analogue (130) of psico- furanine and found t h i s compound to be i n a c t i v e against Escherichia c o l i . A s t r u c t u r a l isomer 131 of psicofuranine (129) was synthesized by Rosenthal 53 and R a t c l i f f e v i a the photoamidation of the enolic sugar 5_6, however, t h i s analogue no longer possesses the N-ketal s t r u c t u r a l feature of ketose HO-i HO—1 HO OH 131 Ad=Adeny1 nucleosides. 58 I I I . RESULTS AND DISCUSSION The work to be described has been divided into four basic u n i t s . These are: (1) the synthesis of a- and B-dihydroshowdomycin, (2) the synthesis of functionalized precursors to C-nucleosides, (3) the oxidation products of Methyl(E,Zj-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-0- isopropylidene-D-allo-oct-3-enonate (172) , a novel exocyclic enolic sugar, and (4) the attempted synthesis of a ketose N-nucleoside. Each unit has been organized according to the o u t l i n e l i s t e d i n the table of contents. The mechanistic and stereochemical aspects of the basic chemical reactions have been dealt with i n the introduction and a det a i l e d discussion i n these areas w i l l only be made where stereochemical assignments appear possible. D e t a i l s of the experimental procedure and work-up conditions along with spectroscopic data w i l l appear i n the experimental section. 1. Synthesis of a- and B-Dihydroshowdomycin: Photoamidation of Methyl (E, Zj-4 ,7-anhydro-8-0-benzoyl-2,3-dideoxy-5 ,6-.0-isopropylidene-D- allo - o c t - 2 (and 3)-enonate (,18) and (172), respectively . The work to be presently discussed was undertaken i n an attempt to 113 provide a new synthetic path to the a n t i b a c t e r i a l and antitumor C- nucleoside showdomycin (99). P r i o r to the s t a r t of t h i s work only two 120 122 p r a c t i c a l synthetic routes to showdomycin had been reported. ' Both, 120 however, possessed undesirable synthetic steps such as DMSO-DCC oxidation 120 122 or reactions involving cyanide reagents. ' In view of the a n t i b i o t i c properties of showdomycin and the undesirable features of the previous syntheses, 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 synthetic route to t h i s C-nucleoside seemed j u s t i f i e d . Based on the photoamidation of unsaturated sugars by Rosenthal and 47 51 40 coworkers ' and on the o r i g i n a l photoamidation work by Rokach and Elad 59 (see Introduction Section 2.1.)» i t seemed reasonable that photoamidation of the a,8-unsaturated ester sugar de r i v a t i v e 12>_ should lead to predominant carbamoylation at the 8-carbon to give the substituted succinic acid d e r i v a t i v e 132 (Scheme XXI), providing the necessary elements for the formation of the maleimide aglycon. C y c l i z a t i o n of 132 followed by dehydro- genation would give the protected showdomycin (99) which could be recovered by mild aqueous acid hydrolysis of the protecting groups. During the course of t h i s work a novel 3-ene analogue of 1S_ (described i n d e t a i l in Section 2.1.) became a v a i l a b l e and i t seemed plausible that t h i s new compound might provide a route to the hitherto unknown a-showdomyci; (133). The photoamidation work with t h i s novel compound i s described in Sections 1.2. and 1.3. 60 1.1. Synthesis of normal- ( 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 t i t l e compound was prepared i n a five-step process s t a r t i n g from 139a 140a-b the commercially a v a i l a b l e l-0-acetyl-2,3,5-tri-0-benzoyl-8-D-ribose (134) . Compound 134 was converted to the glycosyl bromide 126 with hydrogen bromide. The bromide 126 was then treated with excess mercuric cyanide i n nitromethane for 20 hours. The crude 2,3,5-tri-0-benzoyl-3-D-ribofuranosyl 131 cyanide (127) was worked up in chloroform solution rather than ethyl acetate to achieve a more e f f i c i e n t removal of the mercuric s a l t s . Following the procedure of Moffatt et a l . " ^ l a , the cyanide 127 was p a r t i a l l y debenzoylated i n a chloroform solution of methanolic ammonia to give 5-0-benzoyl -B-D-ribofuranosyl cyanide (135) . This v i c i n a l d i o l 135 was isopropylidenated i n a solution of acetone and 2,2-dimethoxypropane with p e r c h l o r i c acid catalyst to afford the 5-0-benzoyl-2,3-0-isopropylidene- B-D-ribofuranosyl cyanide (136). The cyanide 136 was reductively hydrolyzed with Raney n i c k e l in presence of 1,2-dianilinoethane to trap the intermediate aldehyde 137 and give 1,3-diphenyl-2-(5-0_-isopropylidene -B-D-ribof uranosyl) imidazolidine (138). F i n a l l y , the synthesis of the unsaturated ester 1_8 was achieved by acid-catalyzed hydrolysis of the N-acetal protecting group i n acetone-methylene chloride and t r e a t i n g the regenerated aldehyde 137 with(carbomethoxymethylene)triphenylphosphorane i n methylene chloride for one hour at room temperature to afford the t i t l e compound 18_. Column chromato- graphy, with s i l i c a g e l , of the r e s u l t i n g syrup using 2:1 ether-hexanes as developer afforded a 8:1 mixture of the trans and c i s isomers of the t i t l e compound. This mixture was used i n subsequent reactions without  62 further separation (see Scheme XXII). 1.1.2. Photoamidation of 18 to give 3-(R,S)-(5-0-Benzoyl-2,3-0- isopropylidene-g-p.-ribofuranosyl)-4-hydroxy-4--methylpentanoic 1,4- lactone (139), Methyl 4,7-anhydro-8-0-benzoyl-3-C-carbamoyl-2,3- dideoxy-5,6-0-isopropylidene - D-glycero - r j-allo (and altro)-octonate (140 and 141) and Methyl 4,7-anhydro-8-0-benzoyl-2-C-carbamoyl- 2,3-dideoxy-5,6-0-isopropylidene - D-glycero - D-allo (and a l t r o ) - octonate (142 and 143). When a s o l u t i o n of the a,g-unsaturated ester sugar d e r i v a t i v e 1_8 i n formamide containing acetone and tert-butanol was i r r a d i a t e d through pyrex 40 f i l t e r according to Elad's procedure , two major product bands could be discerned by t . l . c . of the reaction mixture. The t . l . c . also indicated (by char) s i g n i f i c a n t carbohydrate material of intermediate R^ and lower R^ than the two major bands. Column chromatography on s i l i c a gel of the worked-up r e a c t i o n mixture afforded the two major bands i n y i e l d s of 10 and 25% y i e l d s of the higher and lower R^ bands, r e s p e c t i v e l y . The faster-moving component was found to be a R,S-mixture of lactone 139 and the slower-moving component was a mixture of the possible formamide addition products 140, 141, 142 and 143. The lactone mixture 139 was not resolvable by chromatography nor by c r y s t a l l i z a t i o n from various solvents. The lactones were therefore characterized as a mixture. The n.m.r. spectrum of 139 i n benzene-d, showed o si x h i g h - f i e l d signals a t t r i b u t e d to the methyl resonances. Two of these signals were very strong i n d i c a t i n g the overlap of two methyl resonances and the other four were moderate strong for the remaining methyls i n d i c a t i n g the presence of eight methyl groups. The loss of the l o w - f i e l d v i n y l i c signals of 18_ and the presence of new signals at ca. 62.2 (three hydrogen 63 18 I hv), H C 0 N H 2 m u l t i p l e t ) suggested a d d i t i o n to the double bond had taken place, also, the methoxy s i g n a l of 18_ had disappeared possibly due to the hydrolysis of the ester 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 carboxylic acid proton was present. Moreover, the i . r . spectrum of 139 was free of absorbances above 3000 cm ^ and possessed two strong carbonyl signals at 1780 and 1728 cm due to the y-lactone and benzoate, r e s p e c t i v e l y . Also, the absorbance at 1672 cm (C=C) of 18_ was no longer present. The mass spectrum of 139 possessed a weak signal of 390 for the molecular ion (m+) and a very strong fragment at 375 (m^-CH^) i n d i c a t i v e the formation of an acetoxonium ion from the 0-isopropylidene group of 139. These r e s u l t s i n d i c a t e that a k e t y l r a d i c a l [(CH^COH] had added to C-2 of 18_ forming a resonance s t a b i l i z e d r a d i c a l ( s i m i l a r to 38) which abstracts a hydrogen and intramolecularly c y c l i z e s to give the y-lactones 139 (see Introduction, Section 2.1, Scheme V). Addition of the k e t y l r a d i c a l 64 to the a-carbon may have occurred (although not isolated) but the 142 r e s u l t i n g 8-hydroxy ester would require s p e c i a l conditions to form the necessary 8-lactone which would also have an i . r . absorbance of 143a 40d a larger frequency than that observed. Rokach and Elad also reported the i s o l a t i o n of y-lactones from benzophenone-initiated photoamidation of a,B-unsaturated esters. The structure of amides 140 through 143 could not be elucidated by sp e c t r a l means alone because these isomers could not be separated by chromatography nor by c r y s t a l l i z a t i o n . The structures were ultimately established by chemical transformation of the mixture (described below, Sections 1.1.3. and 1.1.4.). Therefore, spectral analysis of the mixture was used to determine the presence of the carbamoyl group and show that formamide did add to the carbon-carbon double bond. The n.m.r. spectrum of 140-143 in deuterchloroform showed, as with lactone 139, the disappearance of the low - f i e l d v i n y l i c protons, with the generation of a broad three-proton multiplet i n the 62.24-3.25 region (H-2 and H-3). The spectrum also showed one broad signal at 66.40 (one- proton) and two broad signals at 65.88 and 6.00 (one-proton) which were D20-exchangeable, i n d i c a t i n g two major amide products. S u r p r i s i n g l y , a l l three methyl groups were present as s i n g l e t s . Based on the n.m.r. spectrum and on mechanistic grounds the substituted malonic acid d erivatives 142 and 143 were not expected in any appreciable amounts because the a-hydrogen of 47 the malonates resonate at 63.50-63.65 and no appreciable signals were present (except for OCH^) in that region and since both o l e f i n i c carbons of the o l e f i n i c carbon chain possessed hydrogens, B-addition of the carbamoyl r a d i c a l was expected to occur (Section 2.1.). 65 The i . r . spectrum of the above amide mixture showed amide peaks at 3180, 3365, 3480 and 1690 cm , i n d i c a t i v e of a primary amide. Again the o l e f i n i c absorption of 1_8_ was absent. Though a molecular ion (m+) peak was not observed i n the mass spectrum of the mixture 140-143, the charac- t e r i s t i c (m+-CH3) was predominant along with a strong signal at m/e 376 (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 to form the protonated maleimide fragment. Elemental analysis of 140-143 also established the empirical formula of the mixture to be at 1:1 telomer of _18 and formamide. Although Rokach and Elad^** only i s o l a t e d alkylated succinic acid d e r i v a t i v e s from the photoamidation of a,B-unsaturated esters, th e un- saturated acid parent compounds were simple straight chain compounds. 47 Rosenthal and R a t c l i f f e ' s substrate 46_ (see Introduction, Section 2.1.) was f u l l y substituted at the B-position and gave, exc l u s i v e l y , the malonic acid d e r i v a t i v e upon photoamidation and they at t r i b u t e d t h i s reversal to a greater s t a b i l i z a t i o n of the C-3 r a d i c a l over the alternate r a d i c a l formed by carbamoyl attack at C-3. However, the high degree of r e g i o s p e c i f i c i t y was no doubt aided by the s t e r i c bulk of the protected sugar r i n g attached to C-3 of compound _46_. This s t e r i c i n t e r a c t i o n presumably accounts for the presence of the substituted malonic acid 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 of the c h i r a l sugar i n 46̂  did not contribute to the o p t i c a l induction of the amide products (47 and 4j3) which were formed in equal amounts. This lack of s t e r e o s e l e c t i v i t y i s presumably due to the photochemical c i s - t r a n s isomerization of the i n i t i a l l y geometrically pure s t a r t i n g material ( i . e . , (Z)-46), brought about by t r i p l e t s e n s i t i z a t i o n of the substrate by excited t r i p l e t acetone (Section • 2.2.). Amides 140 and 141 were found (Subsection 1.1.3.3.) to be synthesized i n equal amounts from a predominantly (89%) trans-18 and t h i s lack of o p t i c a l induction i s also attributed to the geometric isomerization of the s t a r t i n g material to give a photostationary state with approximately the same composition of geometric isomers. The n.m.r. spectra of other components i s o l a t e d from the chromato- graphy column indicated more than s i x protons in the h i g h - f i e l d region of the isopropylidene methyls; these compounds were assumed to be other k e t y l or a c e t o n y l ^ 3 r a d i c a l addition or d i r a d i c a l (not telomers) addition products. Since none of these compounds were is o l a t e d pure, these components were not further studied. The y i e l d of the formamide addition products was rather low (25% 47 40d c f . , Rosenthal and R a t c l i f f e , 45%, and Rokach and Elad , 77-81%). This low y i e l d may be the r e s u l t of a competition for the excited t r i p l e t energy of acetone^^^, the reaction with 1_8 which leads to a geometric isomerism and the reaction with formamide which leads to hydrogen atom abstraction. When the former process i s more e f f i c i e n t than the l a t e r , poor y i e l d s of formamide-ester adduct r e s u l t along with an increase i n acetone addition products. Rokach and E l a d ^ C ' found that benzophenone provided e f f i c i e n t hydrogen atom abstraction with the isomerization as an unavoidable side reaction and t h i s i n i t i a t o r gave high y i e l d s of the desired amide products. 1.1.3. C y c l i z a t i o n of 140 and 141 to give the Glycosylated Succinimide Derivatives The reaction between amides and esters can either be thermally induced 144 or base-catalyzed. However, disproportionation of primary amides occurs at elevated temperatures and may compete with the ester reaction. Base- catalyzed intramolecular ac y l a t i o n of amides by neighbouring ester groups 145a have been reported. Treating ethyl malonamate (144) with sodium ethoxid 67 de Mouilpied and Rule"'"^^ found no r i n g compound but rather, acid 146 r e s u l t i n g from the dimerization of malonamic acid (145); however, when ONH- 2 C H , 2)HX0 C 0 2 E t 144 ^ C 0 N H 2 2 C H 2 C 0 2 H 145 i M ^ N C C H 2 C 0 N H 2 H N C 0 C H 2 C 0 2 H 146 methyl succinamate (147) was the substrate, succinimide (148) was i s o l a t e d , 145c a l b e i t i n rather small y i e l d . Sondheimer and Holley found that R- -C0 2 Me Base R- — C O N H 2 147 R=H 149 R=NHCO 2 CH 2 0 NH 148 R=H 150 R=NHCO 2CH 20 treatment of carbobenzoxy-L-asparagine methyl ester (149) with sodium hydroxide gave good y i e l d s (77%) of the c y c l i c aminosuccinimide 150. Keeping i n mind the thermal i n s t a b i l i t y of sugar derivatives and the base l a b i l e groups present, various methods were attempted to form the succinimide aglycon from the amido-esters 140 and 141. The retention of the benzoate group was desirable i n the event the subsequent dehydro- genation r e a c t i o n required protected hydroxyl groups. 1.1.3.1. Attempted C y c l i z a t i o n of 140 and 141 i n Refluxing Solvents Taking into consideration the base s e n s i t i v e benzoate and methyl ester, as well as, 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 mixture 140-143 i n a mildly basic (weakly n u c l e o p h i l i c ) , high-boiling point solvent appeared to a sensible route to the formation of succinimide r i n g from 140 and 141. When the amide mixture 140-143 was refluxed in 68 ei t h e r pyridine or xylene for f i v e hours no change i n the s t a r t i n g mixture was observed. 1.1.3.2. C y c l i z a t i o n of 140 and 141 by Thermal Ring Closure i n Absence of a Solvent to Give 3-(R) and (S)-(5-0-Benzoyl-2,3-0- isopropylidene-B-£-ribofuranosyl) succinimide (151) and (152). When a solvent free sample of amides 140-143 was heated at approxi- mately 200° under reduced pressure (^100 torr) two higher R̂  products could be detected by t . l . c . a f t e r a few minutes. Prolonged heating produced la r g e r amounts of the f a s t e r moving materials but simultaneously a greater amount of decomposition (charring) of the reaction sample occurred. I n i t i a l p u r i f i c a t i o n of the reaction mixture on a weakly a c i d i c r e s i n column followed by chromatography on a s i l i c a gel plate gave two protected epimeric ribofuranosylsuccinimides 151 and 152 i n y i e l d s of 6 and 7%, r e s p e c t i v e l y . A small portion (25%) of the s t a r t i n g mixture was also The n.m.r. spectrum of the higher R̂  (18:4:1 benzene-ethyl acetate- ethanol as developer) succinimide 151 i n deuterochloroform indicated the presence of predominantly one compound (^95% p u r i t y , impurity mainly lower R^ succinimide). The spectrum showed two sharp s i n g l e t s at 61.38 and 1.57 for the methyl protons of the isopropylidene group, as well as, a loss of the methoxy s i g n a l of the methyl ester. The broad signal at 67.90 was a t t r i b u t e d to the imide proton (Nil) and an ABM pattern centered at 63.0 was 69 assigned to the protons of the succinimide r i n g ( J g e m 18.0 Hz). The sugar protons were well separated and-assignable (see Experimental). Then.m.r. spectrum of the lower R^ succinimide 152 i n deuterochloro- form indicated a second diasteromeric succinimide of lower purity (^90%, mainly contaminated with 151). The imide (NH) proton was at lower f i e l d , 58.20, the succinimide protons exhibited an A£M s p i t t i n g centered at 63.0 (ABM pattern i n deuterobenzene) and although the sugar protons signals were within a 50 Hz packet, they were assignable with the aid of i r r a d i a t i o n s , coupling constants and comparison with a spectrum of 152 i n deuterobenzene. Both succinimide products 151 and 152 were found to possess l a b i l e 0-isopropylidene protecting groups and storage of the syrups under ambient (room temperature) conditions caused p a r t i a l hydrolysis of the blocking group. Therefore, the succinimide products containing 0-isopropylidene groups should be kept r e f r i g e r a t e d and dry. The syrups also had a tendency to c r y s t a l l i z e but i n s u f f i c i e n t quantities prevented r e c r y s t a l l i z a t i o n of these samples. No other products (e.g., disproportionation products) from the thermal c y c l i z a t i o n of the amide mixture were detected; however, due to the low y i e l d s of the succinimide products and large amount of decomposition of the reaction mixture no firm conclusion could be made about the composition of the s t a r t i n g amide mixture. Therefore, 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 decomposing any of the components. Due to the low s o l u b i l i t y of the amides 140-143 in aqueous solvent systems and the possible s a p o n i f i c a t i o n of the methyl ester or the amide with sodium hydroxide, i t was decided that methanolic sodium methoxide would be the most sui t a b l e of the base-catalyzed ring-closure procedures. 1.1.3.3. Treatment of Amides 140, 141, 142 and 143 with Methanolic Sodium Methoxide to give 151, 152, 3-(s) and (R)-(2,3-0-isopro- pylidene - B-n-ribofuranosyl) succinimide [ ( s ) and (R)-dihydroshow- domycin acetonide] (153) and (154), and Methyl 4,7-anhydro-2-C- carbamoyl-2,3-dideoxy-5,6-0-isopropylidene-D-glycero-D-allo (and g-altro)-octonate (155) and (156) When the amide mixture 140-143 was treated with 0.5 equivalents of methanolic sodium methoxide s i x compounds, 151, 152, 153, 154, 155 and 156, were produced. These products were separated chromatographically on a column of s i l i c a gel to give three major charring components. The faster-running component was found, by n.m.r. spectroscopy, to be a 50/50 mixture of the protected ribosylsuccinimides 151 and 152 (55% combined y i e l d ) previously i s o l a t e d (Section 1.1.1.2). The fr a c t i o n s of these two stereoisomers were p a r t i a l l y resolved but no further attempts were made to separate them because the possible conversion of these succinimide derivatives to the analogous maleimide compound would destroy the c h i r a l i t y of the aglycon to give i d e n t i c a l products and the showdomycin ( 9 9 ) five-membered base r i n g . 71 140-143 4" NaOMe MeOH 153 R= + 151 + 152 H O - ! 155 R = / \ / C 0 2 M e doNH-, 156 R r ^ y C C ^ M e C 0 N H 2 The f r a c t i o n s of the second component, eluted from the chromato- graphy column, upon close t . l . c . analysis were also found to consist of two c l o s e l y overlapping compounds (153 and 154). Fortunately, the 3-S- succinimido 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 gel adsorbant and also charred an i n i t i a l pink upon spraying with acid and heating (the lower R^ compound 154 charred black). The structure of compound 153 was e a s i l y deduced from i t s n.m.r. spectrum (in CDCl^, see Figure 2a). The spectrum c l e a r l y showed two D 2 O - exchangeable protons at 62.31 and 8.83 for the 5'-primary hyroxyl proton and the succinimide proton, r e s p e c t i v e l y . The methoxy methyl along with the aromatic signals were no longer present while the other protons signals were e a s i l y assignable from i r r a d i a t i o n s and coupling values. Upon changing the spectroscopic solvent to dimethylsulfoxide-d^,the primary hydroxyl Figure 2A. P a r t i a l 100 MHz Proton N.M.R. Spectrum of 3-(S)-(2,3-0-isopropylidene-B-D- ribofuranosyl)succinimide [(S)-dihydroshowdomycin acetonide, 153] i n CDCl tS3 Figure 2B. P a r t i a l 100 MHz Proton N.M.R. Spectrum of (S)-Dihydroshowdomycin Acetonide (153) i n DMS0-d6. I • . . . I • . . . I • . . . I . . . . I • . . . I . . . . I . . . . I . . . . I • . . . I • . . . I 7.0 6.0 5.0 PPM (6) 4.0 3.0 2 0 Figure 3. 60 MHz Proton N.M.R. Spectrum of the Hydrogenation Product of Showdomycin Acetonide (157) i n CDC1-. proton s h i f t e d downfield to 64.87 and exhibited a t r i p l e t with a coupling value of 5.0 Hz with the v i c i n a l protons on C-5' (also D^O-exchangeable); 146a thereby, e s t a b l i s h i n g the presence of the primary hydroxyl group. Unequivocal proof of structure of compound 153 came from a comparison of the n.m.r. spectrum of 153 i n deuterochloroform with that of the hydro- genation p r o d u c t 1 ^ ^ of 2',3"-O-isopropylidene-showdomycin (157) (see Figure 3). The two spectra, except for the p o s i t i o n of the D^O-exchange- able s i g n a l s , were i d e n t i c a l . 153 118a In the o r i g i n a l paper by Nakagawa et a l . , the hydrogenation product 153 was the only succinimide d e r i v a t i v e reported. This stereo- s p e c i f i c reduction i s also supported by the t i t l e of n.m.r. spectrum i n Figure 3 and i n a personal communication with the author. Townsend and 118c coworkers also reported a highly st e r e o s e l e c t i v e hydrogenation of showdomycin (99) to give the de-isopropylidenated d e r i v a t i v e of 153 (see Section 1.1.7.). The s e l e c t i v i t y i n the hydrogenation of showdomycin (99) or i t s acetonide 157 may be due to a conformational preference of the maleimide r i n g . In order to minimize s t e r i c i n t e r a c t i o n s with the furanoid r i n g of 9_9 or 157, a plane which i s perpendicular to the maleimide r i n g and intercepts the C-3/C-1' bond would bisect the angle 0-4'/C-l'/C-2'. This p a r t i c u l a r conformation has two possible rotamers 158 and 159 and structure 158 possesses the least amount of s t e r i c interaction with H-2'. Structure 158 also i s capable of intramolecular hydrogen-bonding between 76 the C-5' hydroxyl and the C-2 oxo group. The conformational preference 147 and t h e o r e t i c a l c a l c u l a t i o n s . of showdomycin to structure 158 has been v e r i f i e d by X-ray analysis" 148 Q H ^\ n HO' 159 HO OH The X-ray analysis also shows that the C-5' hydroxyl i s staggered between 0-4' and C-3'. If t h i s conformation preference i s only s l i g h t l y affected by the presence of the 2',3'-O-isopropylidene (either enhancing or lessening the preference) hydrogenation should proceed p r e f e r e n t i a l l y from the 'exo-face' (back-side on structure 158) of 158 to give predominantly the 3-S stereoisomer. Therefore i t i s suggested that the higher dihydro- showdomycin acetonide 153 i s the 3-J5 diastereomer. This conformational 118b preference under reaction conditions i s also supported by the synthesis of N-methylbisdeoxycycloshowdomycin acetonide hydrobromide (160) which from X-ray structure analysis proved to be the 3-S diastereomer. H-HBr 77 Compound 160 i s synthesized from the base-catalyzed intramolecular Michael-type addition of the 5'-hydroxyl group to the double bond. Addition v i a structure 158 would lead to the 3-S isomer which was i s o l a t e d and addition v i a structure 159 would give the 3-R isomer which was not obtained. Therefore, chemical, s t r u c t u r a l , and t h e o r e t i c a l considerations support the above assignment of compound 153 as the 3-S- succinimide d e r i v a t i v e . (See Section 1.1.9. for n.m.r. spe c t r a l c o r r e l a t i o n support.) I n t e r e s t i n g l y , compound 153 was found to c r y s t a l l i z e quite r e a d i l y i n chloroform to form a 1:1 complex with the solvent. Solutions as low as 0.5% would form c r y s t a l s at room temperature. The complex was v e r i f i e d by micro-analysis which gave the expected carbon, hydrogen and chlorine content. The lower R^, 3-R-succinimide d e r i v a t i v e 154 could not be p u r i f i e d as e a s i l y as i t s epimer 153. The n.m.r. spectrum of the lower R^ component i s o l a t e d by chromatography indicated the presence of at least two minor contaminants. The presence of aromatic signals along with a strong signal i n the methoxy region (63.5-3.8) suggested t r a n s - e s t e r i f i c a t i o n products either i n t e r - or intramolecularly formed. Pure 154 was obtained by s e l e c t i v e c r y s t a l l i z a t i o n and i t s n.m.r. spectrum in dimethylsulfoxide-d^ (Figure 4) showed no aromatic nor methoxy resonances and possessed a D^O-exchange- able s i g n a l at 611.15 for the imide proton. The other proton signals were again well separated and e a s i l y assignable by coupling values and i r r a d i a t i o n s . The mass spectra of 153 and 154 were nearly i d e n t i c a l possessing a very weak peak of 272 (m+ + H) and a very strong expected signal at 256 (m+ - CH^) from the formation of the acetoxonium ion. Figure 4. P a r t i a l 100 MHz Proton N.M.R. Spectrum of 3-(R)-(2,3-0-isopropylidene-3-D- ribofuranosyl)succinimide [(R)-dihydroshowdomycinJ (154) i n DMSO-d^. ^-4 0 0 79 The t h i r d and f i n a l component eluted from the s i l i c a gel column consisted of a mixture of the a-carbamoylation adducts 155 and 156. These components could not be chromatographically separated nor could they be c r y s t a l l i z e d . The i . r . spectrum of this mixture showed amide peaks at 3500, 3360 (N-H), 1680 (C=0) and 1580 cm"1 (Amide I I ) 1 4 3 b (1725 cm - 1 (CO^e)). Expectedly, no o l e f i n i c absorbances were present. The exact composition of t h i s mixture i s unknown since the n.m.r. spectrum in deuterochloroform showed only s i n g l e t s for the methyl s i g n a l s . The basis for assignment of t h i s component-as a mixture of the a-carbamoyl esters i s based on chemical s h i f t s i n the n.m.r. spectrum of the above mixture. The H-3 resonance occurs at f a i r l y high f i e l d (62.20) which indicates the presence of a methylene group which does not have electron withdrawing groups d i r e c t l y bonded. The methylene group i s broad and does not possess any fin e structure i n d i c a t i n g the presence of a mixture. A l o w - f i e l d multiplet at 64.68 assigned to either H-5 or H-6 possess f i v e signals also i n d i c a t i n g a mixture of compounds. The f i n a l evidence for the malonamic esters structure comes from the p o s i t i o n of a-hydrogen (63.51) which i s i n close 47 agreement to previous a-hydrogen of t h i s structure (Rosenthal and R a t c l i f f e , 63.53) and which resonate at l o w e r - f i e l d than the a-hydrogens of the 8 - carbamoylation products. Two broad D20-exchangeable signals were also present at 66.40 and 6.80 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 else a non-equivalence of the amide protons. The mass spectrum spectrum exhibited a strong acetoxonium peak at 288 (m+ - CH^). 1.1.4. Debenzoylation of Compounds 151 and 152 to give 153 and 154 Treatment of an equal mixture of the protected ribosylsuccinimides 151 and 152 with sodium methoxide gave two c l o s e l y overlapping bands on the t . l . c . p l a t e . Chromatography of these components on a column of s i l i c a gel gave 80 two compounds which had n.m.r. spectra i d e n t i c a l to the (R) and (S)- dihydroshowmycin (153) and (154) is o l a t e d i n the preceding section. Unfortunately, neither 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 in order to d i r e c t l y r e l a t e the benzoylated and corresponding debenzoylated dihydroshowdomycin d e r i v a t i v e s . However, based on the fact that the lower R^ benzoylated compound 152 chars pink as does the higher R^ debenzoylated compound 153, along with the fact that the n.m.r. spectra of these two compounds have H-3' at lower f i e l d than H-2' and that the succinimide protons exhibit an A^M s p l i t t i n g pattern, the lower R̂  benzoylated compound 152 i s t e n t a t i v e l y assigned the 3-S configuration. Analogously, the other two dihydroshowdomycin derivatives (151 and 154) both char black and the n.m.r. spectra have H-2' at lower f i e l d than H-3' and the succinimide protons exhibit an ABM s p l i t t i n g pattern. Therefore, the higher R^ benzoylated compound 151 i s t e n t a t i v e l y assigned the opposite, 3-R, configuration. (See Section 1.1.9. for a discussion on the s i g n i f i c a n c e of these chemical s h i f t s ) . 1.1.5. Attempted Dehydrogenation of Succinimide and i t s Alkylated Derivatives. Dehydrogenation of six-membered a l i c y c l i c or heterocyclic f i v e - and 149a six-membered rings may be achieved i n a number of ways. However, the dehydrogenation of an a l i p h a t i c compound to give a double bond i n a s p e c i f i c l o c a t i o n i s much more d i f f i c u l t unless the new double bond can be in con- jugation with a double bond or an unshared pair of electrons already present. The dehydrogenation process i s also enhanced by the presence 149b ^ . of unsaturation i n the substrate. There are three types of reagents most frequently used to ef f e c t dehydrogenation or aromatization. They 149c are 7 L : 81 1) Hydrogenation ca t a l y s t such as platinum, palladium and n i c k e l . In t h i s case the reaction i s the reverse of double bond hydrogenation. 2) The elements s u l f u r and selenium (and selenium dioxide). 3) Quinones, which are reduced to the corresponding hydroquinone. The more reactive and most widely used i s 2,3-dichloro-5,6-dicyano-l,4- benzoquinone (DDQ). For example, treatment of the unsaturated fused-ring succinimide compound 161 with n i c k e l peroxide 1"^ gave the corresponding aromatic compound, N-methylphthalimide (162), i n 62% y i e l d while no attempts were made to dehydrogenate the corresponding saturated compound 163. 1.1.5.1 Palladium and Succinimide When a mixture of succinimide, biphenyl (B.P. 254-255°) and 10% palladium on charcoal was refluxed for 25 hours while carbon dioxide was passed through the s o l u t i o n , succinimide was qu a n t i t a t i v e l y recovered. No attempts were made to modify t h i s reaction. 1.1.5.2. Treatment of Compound 151, 152, 153 and 154 with Nickel Peroxide Treatment of the protected ribosylsuccinimides 151 and 152 i n re f l u x i n g i ... . , , 149c,150,151 , n , , , _ , xylene with n i c k e l peroxide for 60 hours produced only broad u.v. active slow charring bands and base-line materials. The isolated crude syrup was five-times the s t a r t i n g materials weight; therefore, 82 polymerized solvent along with decomposed carbohydrate materials were presumably the main components and were not further analyzed. Treatment of the debenzoylated succinimide derivatives 153 and 154 with n i c k e l peroxide i n r e f l u x i n g benzene for 26 hours gave negative r e s u l t s . The s t a r t i n g material was present but no u.v. active component was produced. Treatment of 153 and 154 with n i c k e l peroxide i n water for 7 days also gave negative r e s u l t s . D i f f i c u l t i e s were anticipated with use of the n i c k e l peroxide oxidative dehydrogenation process because the presence of a methoxy- methyl substituent on the c y c l i c substrate was reported"'""^ to decrease the e f f i c i e n c y of the dehydrogenation process. Also, a l l the substrates u t i l i z e d possessed endocyclic unsaturations which lead to aromatic products upon dehydrogenation. 1.1.5.3. Attempted Dehydrogenation of Compounds 153 and 154 with DDQ. 149a-c 152a b Treatment of the ribosylsuccinimides 153 and 154 with DDQ ' ' i n r e f l u x i n g dioxan for 3 days gave the anticipated p r e c i p i t a t i o n of the dihydroquinone; however, chromatography of the reaction mixture gave no u.v. a c t i v e charring bands. This r e s u l t was not t o t a l l y unexpected since Evan et a l . " * ^ , reported that DDQ gave poorer r e s u l t s with oxazolines compare to dehydrogenation with n i c k e l peroxide. As for the other methods mentioned i n the introduction to t h i s 149c section (1.1.5), the use of s u l f u r require dehydrogenation i n a melt (^250°) i n which the s t a r t i n g carbohydrate i s not expected to be very 149c sta b l e . The same problem e x i s t s with the use of elemental selenium 149c The use of the selenium dioxide reagent, however, may give 153 the desired r e s u l t since Barnes and Barton reported the dehvdro- genation of c i s hydrogens from t r i t e r p e n o i d 1,4-diketones to enediones. 154 However, H i l l showed that phenylsuccinic acid (164) can be dehydro- genated with selenium dioxide to give phenylmaleic anhydride (165) but the phenyl group appears e s s e n t i a l to the reaction since succinic acid and e t h y l s u c c i n i c acid do not react. 0 . r — C 0 2 H -C0 2H 4 0 1 6 4 1 6 5 The high degree of d i f f i c u l t y in dehydrogenating the succinimide ri n g to the corresponding maleimide in one step i s exemplified by the Russian1"'"' process in which succinimide was heated to 300-400° in the presence of a Vanadium oxide ca t a l y s t to give maleimide. 1.1.6. Attempted Synthesis of (R,S)-3-Bromo-3-(5-0-benzoyl-2,3- O-isopropylidene-B-p-ribofuranosyl)succinimide (169). Due to the d i f f i c u l t y involved with a one step dehydrogenation of an alkylated succinimide i t was thought that s u b s t i t u t i o n of an eliminatable group at the t e r t i a r y a-position of the alkylated succinimides 151 and 152 might lead to the desired maleimide product. The d i f f i c u l t y i n t h i s approach was due to the fact that the carbohydrate moiety also possesses t e r t i a r y hydrogen on the furanoid r i n g . It was hoped that treatment of the protected sugars 151 and 152 with NBS would lead to s e l e c t i v e bromination at C-3 to give t e r t i a r y bromide (169) or perhaps d i r e c t l y to unsaturated maleimide p r o d u c t . » 1 5 7 a , b 84 151 and 152 N B $ X > ~ ~ — (BzO) 2 BzO-i 1.1.6.1. Treatment of 151 and 152 with NBS. When 151 and 152 were treated with NBS and benzoyl peroxide in r e f l u x i n g carbontetrachloride for 32 minutes, a five-component mixture resulted. The n.m.r. spectrum of the major higher (cf. s t a r t i n g material) band in deuterochloroform indicated the presence of the t e r t i a r y hydrogen of the alkylsuccinimide along with an absence of any v i n y l i c 118c protons (ca. 66.8 ) due to an alkylmaleimide group. 1.1.7. 3-(S)-(B-D-ribofuranosyl)succinimide (170) Treatment of the (S^)-dihydroshowdomycin acetonide (153) with a s o l u t i o n of 3:1 t r i f l u o r o a c e t i c acid-methanol gave the de-isopropylidenated compound 170 i n almost quantitative y i e l d . The clear syrup was p u r i f i e d by chromatography on Bio-Rex 70 cation exchange re s i n (H + form). HN- 153 H" HO-i HO OH The n.m.r. spectrum of (S)-dihydroshowdomycin (170) in dimethyl- sulfoxide-d^ was consistent with the assigned structure, having three D20-exchangeable proton at 64.63 and one at 611.0. From the coupling values and chemical s h i f t s of the remaining s i g n a l s , the doublet of doublets at 64.06 was assigned to H-l'. This assignment was confirmed 85 when i r r a d i a t i o n of H-3 collapsed t h i s s i g n a l to a doublet. The coupling constant between H - l ' and H-3 (J ^) was 2.0 Hz which increased to 2.5 Hz upon changing the spectroscopic solvent to D 20 containing a few drops acetic acid-d^. This l a t t e r value i s i d e n t i c a l to the value reported by Townsend 118c and coworkers for the major product of the hydrogenation of showdomycin (99). 1.1.8. 3-(R)-(g-D-ribofuranosyl)succinimide (171) I d e n t i c a l treatment of the (R)-acetonide 154 as above gave 3-(R)- dihydroshowdomycin (171). The n.m.r. spectrum of 171 in dimethylsulfoxide- d^ again possessed three mi d - f i e l d and one lo w - f i e l d D^O-exchangeable protons. As with i t s acetonide and benzoylated acetonide precursors (154 154 H O O H and 151, resp.), the H-2' signal of 171 resonated at lower f i e l d than i t s H-3' signal (64.30 and 4.00, resp.). (This pattern was also retained for the 3-_S-isomers 152, 153 and 170 with H-3' resonating at l o w e r - f i e l d ) . The coupling constant J for 171 was 6.0 Hz; therefore, t h i s isomer, -> > i expectedly i s not the same as Townsend's major hydrogenation product. 1.1.9. General Considerations As mentioned i n Section 1.1.4. the positions of the n.m.r. resonances of H-2' and H-3' of compounds 151, 152, 153 and 154 (along with other information) were used to assign the configuration of C-3 of compounds 151 and 152. The question arises as to why the r e l a t i v e positions of these two resonances change i n going from the 3-R-to the 3-S-isomer. From molecular models of compounds 153 and 154, i f , based on s t e r i c grounds, the preferred conformation of the aglycon i s one i n which hydrogens H-3 and H - l ' are in a trans or a n t i r e l a t i o n s h i p then the furanoid and maleimide rings would also be i n a trans r e l a t i o n s h i p . From a f i r s t - order analysis of the observed coupling constants between H-3 and H - l ' of the various ribosylsuccinimide d e r i v a t i v e s and t h e i r calculated 158 dihedral angles , i t i s suggested that a possible explanation to the r e v e r s a l of the H-3' and H-2' resonances i s due to the anisotropic 159 s h i e l d i n g of H-2' by the C-2 carbonyl of the maleimide ri n g of the 3-^-isomers. Molecular models of these compounds show that r o t a t i o n about t h e ' g l y c o s i d i c ' bond (C-3/C-1') i s r e s t r i c t e d due to s t e r i c i n t e r - ference with H-2 which would cause deshielding of H-2' (therefore, lower 159 f i e l d resonance) due to intramolecular van der Waals forces ; however, as the figures in Table I indicate,the preferred conformation i s one i n which the dihedral angle between H-3 and H - l ' i s between 119 and 134.6°. This preferred conformation would only allow one of the diastereomers to p o s i t i o n a carbonyl group (C-2 carbonyl of the S-isomer) of the maleimide rin g over H-2' to cause and anisotropic e f f e c t . Therefore, the 3-S- ribofuranosylsuccinimides (152, 153 and 170) might be expected to possess higher H-2' resonances which i s indeed observed. Table I. Calculated Dihedral Angles between H-3 and H - l ' R 0 - , 0 87 Compound and C h i r a l i t y (C-3) 151-R , £ J52-S R = B z R ~ R = I P 153-S Y5^_R R=H R'-R'=Ipa 170- S 171- R R=R'=H Solvent CDCI3 CDCI3 DMS0-d6 DMS0-d6 DMSO-d6 D 20 Chem. H-2' 5.25 4.54 4.46 4.90 3.60 4.30 Shift(6) •H-3' 4.75 4.72 4.61 4.51 3.83 4.00 J 3 , l ' (Hz) 2.5 3.8 3.5 4.0 2.0* 4.4 Dihedral Angle 123 131 129 132 119.3 134.6 a) Ip = Isopropylidene b) 2.5 Hz i n D 20 (123°) From the above table and the above discussion, i t can be seen that the reversal of the two resonances H-2' and H-3' i s due to large s h i f t s i n H-2' rather than complementary s h i f t s i n H-2' and H-3'. It might also be suggested that the large chemical s h i f t of H-2' in the ̂ -isomers may be due to an enhanced s t e r i c deshielding due to e l e c t r i c dipole repulsions of the furanoid oxygen and the carbonyl group of C-2. This e l e c t r o n i c repulsion tends to bring the C-4 methylene group and the C-2' hydrogen into closer proximity and thereby increase the van der Waals repulsion causing a downfield s h i f t i n H-2' and H-4. This downfield s h i f t i n H-4, although not as predominant as H-2', i s observed for the ̂ -isomers (see Experimental). 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 and might even provide a t t r a c t i v e forces which may explain the s t a b i l i t y of the nearly eclipsed conformation, with respect to the substituents on C-3 and C - l ' of the S-isomer. This evidence, therefore, supports the stereochemical assignments made previously (Section 1.1.3.3.) for the 8- D-ribofuranosylsuccinimide d e r i v a t i v e s . It should be noted that the acetonides of these succinimide derivatives are very l a b i l e and unless they are c r y s t a l l i n e , the stored syrups w i l l slowly de-isopropylidenate. Therefore, the syrups should be stored in a 88 cool and dry container. 1.2. Synthesis of g-Dihydroshowdomycin Acetonide v i a Photoamidation of Methyl (E,Z)-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-0- isopropylidene-J3-ribo-oct-3-enonate (172) . 1.2.1. Photoamidation of 172 to give 140, 141, Methyl 4,7-anhydro- 8-0-benzoyl-3-C-carbamoyl-2,3-dideoxy-5,6-0-isopropylidene-£-glycero- p-gluco (and manno)-octonate (173) and (174), re s p e c t i v e l y . I r r a d i a t i o n of 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 of i t s synthesis to be discussed i n Section 2.), by the same procedure used for the i r r a d i a t i o n of the methyl oct-2-enonate 18 produced a mixture that possessed a band on t . l . c . which was i d e n t i c a l i n to that of amides 140-143 produced from the l a t t e r unsaturated compound. Spectral analysis of t h i s band indicated a mixture of amide products also,but only a f t e r chemical transformation (see following section) was t h i s band found to consist of the previously i s o l a t e d (Section 1.1.2.) amides 140 and 141 and the new carbamoyl products 173 and 174. Column chromatography of the i r r a d i a t i o n mixture f a i l e d to separate any of the four components and c r y s t a l l i z a t i o n of t h i s mixture did not a f f e c t i t s composition. As with the n.m.r. spectrum of amides 140-143, th i s new mixture exhibited three broad peaks at ca. 66.2 and a broad three-proton multiplet i n the 62.4 to 3.4 region. The i . r . spectrum possessed a strong primary amide band"'"*'^ at 1685 cm 89 1.2.2. Treatment of Amides 140, 141, 173 and 174 with Methanolic Sodium Methoxide to give 151, 152, 153, 154, 3-(R) and (S)-(2,3- O-Isopropylidene-ot-D-ribofuranosyl)succinimide [ (R) and (S)-ot- dihydroshowdomycin Acetonide] (175) and (176) and Methyl 4,7- anhydro-3-C-carbamoyl-2,3-dideoxy-5,6-0-isopropylidene-D-glycero- D-gluco-octonate (177), re s p e c t i v e l y . When the amide mixture 140, 141, 173 and 174 was treated with 0.12 equivalents of sodium methoxide a multicomponent mixture was seen on the t . l . c . of the rea c t i o n mixture. Column chromatography of the worked-up reaction mixture gave compounds 151, 152, 153, 154, 175, 176 and 177. The n.m.r. spectrum of the faster moving band indicated p a r t i a l l y resolved f r a c t i o n s of the previously i s o l a t e d (see Sections 1.1.1.2 and 1.1.3.3.) 6-ribosylsuccinimides 151 and 152, present i n an o v e r a l l r a t i o 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 also showed minor components which are presumably the 'a'- analogues of 151 and 152. This presumption i s based on the i s o l a t i o n (vide i n f r a ) of the debenzoylated a-ribosylsuccinimides 175 and 176 and 90 the presence of a prominant doublet of doublets at ca. 64.94 i n the n.m.r. spectra which i s also present i n the spectra of the debenzoylated a-compounds but i n none of the 8-ribosylsuccinimide compounds. U 0 , 1_41.173 + 174 NaOMe 151+152 153+154 175 R= >X~\o 176 R= T^>=0 177 R= V ^ c C ^ M e 6 0 N H 2 The f i r s t of the slower-moving components eluted from the column was compound 153, the n.m.r. spectrum of which was i d e n t i c a l to the 3-(S)-dihydroshowdomycin (153) previously i s o l a t e d (Section 1.1.3.3.). This compound was followed by a mixture of two ribosylsuccinimide acetonides whose n.m.r. spectrum i d e n t i f i e d the minor component as the previously i s o l a t e d 3-(R)-dihydroshowdomycin (154) (30% of th i s mixture). The n.m.r. spectrum also showed the loss of the benzoate and methyl ester of the s t a r t i n g compounds and possessed two D20-exchangeable protons at 62.07 and 9.00 for the primary hydroxyl and imide groups. 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 doublet of doublets at 64.75 which i s also present for a pure a-ribosylsuccinimide described below. Therefore, the major component of th i s mixture i s te n t a t i v e l y assigned as 3-(R)-(2,3-C)-isopropylidene-a- D-ribofuranosyl)succinimide [(R)-cx- dihydroshowdomycin acetonide] (175). (Assignment of the new c h i r a l center to be discussed below). Continued el u t i o n of the column gave the 3-(S)-a-ribosylsuccinimide acetonide 176 i n 12% y i e l d as a pure isomer. The n.m.r. spectrum of 176 91 also showed the loss of the benzoate and methyl ester groups. Two broad D^O-exchangeable signals at 62.16 and 8.28 for the primary hydroxyl and imide protons, r e s p e c t i v e l y , were also present. The mass spectrum of 176 was very s i m i l a r to that of i t s B-analogues i n possessing a pro- tonated molecular ion at 272 (m+1) and a very strong acetoxonium fragment at 256 (m-CH3). The c o n f i g u r a t i o n a l assignment of the new c h i r a l center at C-3 of the succinimide r i n g i s based on model studies of the two diastereomers 175 and 176 and on the coupling constants between H-3 and H - l ' ( i . e . J ). •J»i With J of 175 equal to 2.0 Hz and 8.0 Hz for 176, the respective 158 di h e d r a l angles calculated from the Karplus r e l a t i o n s h i p are 59(119) and 159°(9°), r e s p e c t i v e l y . From models or diagrams of these two compounds i t can be seen that the c i s - r e l a t i o n s h i p between the C)-isopropylidene group and the succinimide r i n g greatly hinders r o t a t i o n about C-3 and C - l ' bond. From calculated dihedral angles and models of the two isomers i t can be seen that the 3-R isomer would prefer the smaller dihedral angle of 59° while the 3-S_ isomer prefers the larger dihedral angle of 159°. [The values i n parenthesis represent unstable conformers.] These preferences are based mainly on s t e r i c considerations but i t appears as though the e l e c t r o s t a t i c repulsions are also minimized. Therefore, the lower R^, a- product 176 i s t e n t a t i v e l y assigned the 3-jS configuration and the higher R^, a-product 176 the 3-R configuration. The f i n a l component i s o l a t e d , compound 177, was found to be an un- c y c l i z e d , debenzoylated amide. This pure stereoisomer was found to possess a strong carbonyl absorption at 1732 and 1678 cm 1 in the i n f r a r e d for the methyl ester and primary amide , r e s p e c t i v e l y . The i . r . spectrum also showed a broad peak at about 3450 with two sharp absorbances overlapping i t at 3500 and 3410 cm~l, i n d i c a t i n g the presence of a hydroxyl group and 92 the primary amide N-H stretching bands. For these two l a t t e r groups the n.m.r. spectrum of 177 i n dimethylsulfoxide-d^ possessed a s i n g l e - proton, D2U-exchangeable t r i p l e t at 64.80 for the C-8 primary hydroxyl and two broad D20-exchangeable signals at 66.77 and 7.24 of the carbamoyl group. Moreover, the n.m.r. spectrum possessed three sharp, three-proton s i n g l e t s of 63.57, 1.42 and 1.28 for the methoxy methyl and the isopropylidene methyls, r e s p e c t i v e l y . The mass spectrum possessed a protonated molecular ion peak 304 (m+1) and micro-analysis confirmed the empirical formula. Assignment of the configuration of C-3 and C-4 of t h i s amide i s again based on n.m.r. evidence. As can be seen i n Table I I , the coupling constants between the furanoid hydrogens of the a-series of compounds are very s i m i l a r , e s p e c i a l l y the J , ., values r e l a t i v e to the 8-series. This difference and J , 4 > magnitude of the J , values have been observed for a series of 2',3'-0- isopropylidenated C-a and B-g-ribofuranosides. The assignment of the c h i r a l i t y of C-3 i s based on the coupling values ^, of the a-series. If the conformational preference about C-3 and C - l ' does not change s i g n i f i c a n t l y from the c y c l i c and a c y c l i c compounds then amide 177 can be assigned the 3-S- configuration. This assumption should be v a l i d since the conformations assigned to succinimides 175 and 176 (vide supra) are roughly i n staggered conformations with s t e r i c and repulsive e l e c t r o n i c i n t e r a c t i o n s minimized. The 3-j5-a-ribosylsuccinimide 176 i s expected to r e t a i n i t s trans-orientat ion of H-3 and H - l ' i n the open-chain form ( i . e . , amide 177) since the above i n t e r a c t i o n s are s t i l l minimized. This conformation should give maximum coupling 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 i n the observed J value of 10 Hz. The 3-R-a-ribosylsuccinimide 175 i s also expected to r e t a i n i t s conformation i n the open-chain form and, therefore, lower ^ . value, since the rotamer i n which H-3 and H - l ' are trans-orientated would 93 bring about an unfavourable s t e r i c and electron i c i n t e r a c t i o n between the C-3-carbamoyl group and 0-2'. Therefore, i t i s suggested that 177 has the a-3-^-configuration. Table I I . Coupling Constants and Optical Rotations of the 'a- 1 and '8-' D-Ribosylsuccinimide Derivatives and th e i r H - l ' Chemical S h i f t s . Compd. , 6H-1 153 8-3-S^ -9.27 C D C 1 - 3.3 6 0 6 . 0 3 5 4.34 DMSO 3.3 5 0 6.5 4 0 4.14 154 8-3-R -35.3 DMSO 4 . 0 4 5 6.5 4 5 4.04(4 14) 175 a-3-R +8.04* C D C 1 3 2 . 0 3 5 6 . 0 0 0 4.56 176 a-3-S - 1 . 0 C D C I 3 8 . 0 3. 8 6 .0 1 0 4.47 177 a-3-S +16.1 H 2 0 1 0 . 0 3. 5 6 . 0 0 0 4.18(4 23) * contaminated with approx. 30% compd. 154. ** o p t i c a l rotations measured i n methanol s o l u t i o n . ( ) values i n parenthesis are i n C D C 1 ~ . Generally speaking, the sp 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 compounds l i s t e d i n Table II are consistent with the spe c t r a l properties of 2' ,3'-0-isopropylidenated C_-a and 8-D-ribofuranosides. The 'anomeric' proton (H-l') i s generally downfield i n the ct-anomer and the o p t i c a l 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 consistent with Hudson's 53,167,168 ru l e s . The s u r p r i s i n g l y low degree of s t e r e o s e l e c t i v i t y i n both steps of t h i s photoamidation reaction i s not obviously clear but the fact that 94 i s o l a t e d double bonds have been photochemically isomerized using benzo- phenone"^ indicated that an alkene possessing an auxochrome such as an alkoxyl group (as i n the methyl oct-3-enonate 172) should be more 159e 43b e f f i c i e n t l y s e n s i t i z e d v i a the n-^ir* t r a n s i t i o n with a higher energy s e n s i t i z e r such as excited t r i p l e t acetone (see Introduction, Sections 2.1. and 2.2.). The lack of a v i c i n a l c h i r a l group may also contribute to the low s t e r e o s e l e c t i v i t y of carbamoylation step. The hydrogen abstraction step however was expected to proceed with a higher 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 i n i t i a l a ddition step (see Introduction, Section 2.1.). In view of the ste s p e c i f i c i t y of the hydrogen abstraction step i n the photoamidation of unsaturated sugars ^»6, _53 and _56̂  the lack s p e c i f i c i t y here can perhaps be a t t r i b u t e d to the 8-0-benzoyl group of 172 which might provide either 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 to counteract the s t e r i c repulsion i n the endo-face of the fused-ring system. The r e g i o s p e c i f i c i t y i n the i n i t i a l reaction i s expected due to the anti-Markovnikov orientation of the photoamidation reaction. A f i n a l question which might be asked about t h i s l a t t e r chemical transformation of the mixture of amides i s why was there a r e a c t i v i t y d i f f e r e n c e between the a- and 8-anomers towards debenzoylation. Two possible answers are immediately obvious; f i r s t , i f c y c l i z a t i o n occurs before debenzoylation the perhaps the conjugate base of the 'B'-imide provides both s t e r i c and predominantly e l e c t r o s t a t i c repulsion to the methoxide anion, both forces which are minimized in the a-anomer; secondly, i f debenzoylation occurs before c y c l i z a t i o n perhaps the conjugate base of the 6-amide again provides both s t e r i c and e l e c t r o s t a t i c repulsion which 95 i s again minimized i n the a-isomer. Therefore, either mechanism provides for a predominance of the debenzoylated a-anomers i f a c a t a l y t i c amount of base i s used. 2. Synthesis of Functionalized Precursors to C-Nucleosides The importance of the natural and synthetic C-Nucleosides as a n t i - tumor and a n t i b i o t i c agents was emphasized i n the Introduction (Section 4.). The synthesis of analogues of these b i o l o g i c a l l y important compounds has thus been pursued i n a desire to produce more active and more s e l e c t i v e d e rivatives with le s s toxic and other undesirable c h a r a c t e r i s t i c s . 1 1 ^ ' 1 1 * ^ Several synthetic pathways to possible intermediates of new analogues are described i n t h i s section. Each synthesis involves the use of azide reagents as either an a c i d , base, nucleophile, f r e e - r a d i c a l or organic intermediate. The f i r s t part of the work to be described i s based on the synthesis 72 of branched-chain gl y c o s y l amino-acids by Rosenthal and R a t c l i f f e who added hydrazoic acid and sodium azide to an unsaturated sugar. The second part of t h i s section i s based on the a z i d o - n i t r a t i o n of unsaturated sugars V T • « _ .. . „ 105 by Lemieux and R a t c l x f f e . 2.1 Synthesis of Unsaturated and Amino Sugars 2.1.1. Attempted Addition of Sodium Azide to the Methyl oct-2-enonate 18 to y i e l d Methyl(E,Z)-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-0-isopro- pylidene-D-ribo—oct-3-enonate (172) and Methyl (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 Section 1.1.1.) in N,N-dimethylformamide was heated at 50-55° i n the presence of excess sodium azide, two new unsaturated compounds, 172 and 178, were is o l a t e d i n 21.5 and 51.5% y i e l d , r e s p e c t i v e l y , from the chromatographed reaction mixture a f t e r work-up. T . l . c . of the reaction mixture with various solvent systems indicated that the reaction had only gone to p a r t i a l completion a f t e r 21 hours, with no s i g n i f i c a n t changes i n i t s composition a f t e r an a d d i t i o n a l 24 hours at 50-55°. After an a d d i t i o n a l 48 hours at approxi- mately 6 3 ° , the unchanged mixture was worked-up. Upon side-by-side develop ment of the s t a r t i n g compound 1J5 with the reaction mixture on a t . l . c . p l a t e , i t was observed that the faster-moving component of the reaction mixture had the same as 1_8_ but the i n i t i a l charring c o l o r a t i o n d i f f e r e d , with 18_ producing an orange colour and the reaction mixture producing a d u l l grey and bright purple colouration for i t s f a s t e r - moving and slower-moving components, res p e c t i v e l y , i n d i c a t i n g the con- sumption of the s t a r t i n g material. The slower-moving component, 178, was e a s i l y i d e n t i f i e d as the acetone elimination product from an inspection of i t s n.m.r. spectrum which indicated the loss of the _0-isopropylidene group along with the presence of only one D20-exchangeable doublet at 62.57 for the secondary hydroxyl at C-5 and with the loss of one furanoid hydrogen (H-4) and the s h i f t of another (H-5) to the enolic region'*""'^*' at 65.52. Moreover, the stereochemical p u r i t y of t h i s compound i s also i n evidence from the n.m.r. spectrum, i n which the v i n y l i c protons of C-2 and C-3 are present as sharp doublets at 66.29 and 7.13 with a coupling constant of 16.0 Hz i n d i c a t i v e of the trans-(or E-) isomer. 1*' 0 The i . r . spectrum of t h i s c r y s t a l l i n e material i s also consistent with the assigned structure 178: 1) the hydroxyl absorbed at 3500 cm 1 to give a broad band, 2) the methyl ester 20 -1 exhibited a moderate s h i f t ( s t a r t i n g material , 18, at 1730 c m ) to -21 -1 159c lower frequency (1712 cm ) due to extended conjugation , 3) the Z-'i C-3 double bond exhibited a s i m i l a r s h i f t 1 " ' ^ ( i . e . , from 1672 to 1660 cm 1 ) and 4) a moderate band at 1607 cm 1 can be assigned to the new carbon-carbon double bond between C-4 and C-5 with the low frequency a t t r i b u t a b l e to a combination of r i n g s t r a i n , conjugation and the presence of an electronegative substituent. jhe m a s s spectrum of the dienonate 178 also provides a great deal of supportive evidence for the assigned structure. The f i r s t four major signals at 304, 286, 272 and 254 ( r e l a t i v e i n t e n s i t y , 1.4:1.4:1:2, resp.) represent the molecular ion (m+) and the los s of water, methanol and the combined loss of both, res p e c t i v e l y . The r e l a t i v e strength of the molecular ion and i t s loss of groups possessing even numbers of electrons indicate the high degree of s t a b i l i t y of enolic 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 exhibited by other enolic sugars which also possess strong molecular ion signals r e l a t i v e to corresponding non-enolic or saturated compounds 1^ 1 (also, see compd. 172 below and compd. 220 i n Section 4.). The dienonate 178 i n i t s c r y s t a l l i n e form i s quite unreactive and can be stored at room temperature; however, as a syrup, the unprotected compound reacts further to form both lower and higher materials. I s o l a t i o n of the s i n g l e higher by-product gave 2-benzoyloxymethyl-5-((E)- carbomethoxyethylene)furan (179) which has been i s o l a t e d by Moffatt et a l . , and r e s u l t s from a dehydration of 178. Compound 178 can be synthesized as the sole product i n 64% by an increase in the i n i t i a l reaction temperature i n the absence hydrazoic a c i d . 98 1 7 9 The structure of the minor component, 172, i s also consistent with the various s p e c t r a l data. A d d i t i o n a l proof of i t s structure comes from various chemical transformations. This section w i l l deal with the 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 provide evidence for the stereochemistry of the enolic double-bond. Following subsections (2.1.1.1., 2.1.1.2., 2.1.1.3. and 2.1.1.4.) w i l l deal with several addition products of the oct-3-enonate 172 and i n Section 3, a i r oxidation products of 172 w i l l be explored. The methyl oct-3-enonate 172 has been synthesised following the method outlined above and i n higher y i e l d s under modified conditions (see Section 2.1.3.). In each case, one and the same geometric isomer of 172 predominated (usually ^95% as determined by the n.m.r. spectrum of the mixture) and can be p a r t i a l l y resolved by column chromatography on s i l i c a g e l . For convenience, the n.m.r. spectrum of the major (Z)-isomer (vide i n f r a ) w i l l be discussed; however, the important and resolvable resonances of the minor (E)-isomer w i l l be dealt with when the geometric assignment i s discussed. With the anticipated addition of sodium azide to the double bond (see Introduction: Section 3.1.) and the known r e a c t i v i t y of organic azide compounds (e.g., formation of nitrenes or 1,3-dipolar 162 cycloadditions to unsaturated compounds;, the assignment of the n.m.r. spectrum (see Figure 5) of faster-moving chromatographic component to the unsaturated compound 172 was not immediately clear since the v i n y l i c protons I I i I i I i i i ; I i I ; I I I i l l I I J I . • • • I . • • i i i I i i — _ i u _ J i i I i i I_J—I—t—i—i—i—I—•—i—•—i—I—i—•—i—i—I i i ure 5A. P a r t i a l 100 MHz Proton N.M.R. Spectrum of Methyl (E,Z)-4,7-anhydro-8-0- benzoyl-2,3-dideoxy-5 t6-0-isopropylidene-g-ribo-oct-3-enonate (172). A 5:95 r a t i o of the E- to Z-isomers i n CDC1.,. X 172 Figure 5B. P a r t i a l 100 MHz Proton N.M.R. Spectrum of Methyl (E,Z)-4,7-anhydro-8-0- benzoyl-2,3-dideoxy-5,6-0-isopropylidene-D-ribo-oct-3-enonate (172) . A 55:45 r a t i o of the E- to Z-isomers i n CDC1~. o o 101 of the s t a r t i n g material (see Figure 5) was no longer present nor did the i . r . spectrum indicate the presence of an carbon double-bond (vide i n f r a ) . Moreover, 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 methylene ABX pattern at ca. 63.12; however, the spectrum did not indicate any sort of dimerization since the methyl groups were sharp s i n g l e t s and H-8 appeared as a doublet. The spectrum also integrated for the same number of protons as the s t a r t i n g material. 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 material enabled the assign- ment of the broadened doublet 65.03 to H-5 with the broadening due to a l l y l i c coupling with H-3 which was present as a pseudo-triplet at 64.82. It might also be suggested that presence of the hydrogens of C-8 as a doublet indicates an averaging of environments of these diastereomeric 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 a l s o ) . The i . r . spectrum of 172 exhibited a s p l i t t i n g of the carbonyl absorbances with the higher frequency band at 1743 cm ^ i n d i c a t i n g the 159c deconjugation of the methyl ester. The carbon-carbon double bond absorbance of the 2-enonate 1_8 was no longer resolvable but the presence of a shoulder at ca. 1710 cm ^ might be a t t r i b u t a b l e to an up-frequency s h i f t of the double-bond due to deconjugation in the presence of v • 1 5 9 d „ . . , 1 0 2 an electronegative substituent. Goodman and coworkers reported an absorption at c_a. 1700 cm ^ for the exocyclic e n o l i c acetal 9_2; therefore, the above assignment appears v a l i d . The mass spectrum of the two unsaturated sugars 1_8 and 172 also warrant d i r e c t comparison. The peak r a t i o s of the f i r s t four ions are 1.0:0.4:1.0: 2.0 for the 3-ene 172 and 1.0:21.5:12.2:11.2 for the 2-ene 18 representing (m ), (m -CH^), (m -OCH^), and (m -acetone), r e s p e c t i v e l y . C l e a r l y , the 102 s t a b i l i t y of the molecular ion of 172 indicates the s t a b i l i z i n g e f f e c t of the enoli c system i n forming an a l l y l i c c a t i o n i c r a d i c a l . The assignment of the geometric configuration of the 3-ene 172 i s prim a r i l y based on chemical s h i f t of the enolic hydrogen H-3 and, to a le s s e r extent, on the a l l y l i c hydrogen H-5. H-3 of the major isomer resonates at 64.82, the assignment of which i s confirmed by i r r a d i a t i o n of the pair of doublets of doublets at £a. 63.12 (H-2a and H-2b) which collapses the pseudo-triplet of H-3 to a s i n g l e t . H-3 of the minor isomer 163 resonates at l o w e r - f i e l d (ca. 65.08). Since the net shiel d i n g e f f e c t from the alkoxyl (0.7) and alkoxymethyl ( i . e . , C-5) groups of the enolic system on H-3 i n the Z-isomer ( i . e . , furanoid oxygen and C-2 are c i s ) i s expected to be greater than that of the E-isomer, we can t e n t a t i v e l y assign the isomer with the h i g h e r - f i e l d H—3 resonance to the Z-isomer ( i . e . , the isomer predominantly formed). Secondary support for t h i s assignment comes from the chemical s h i f t 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 assigned the E-configuration i n which C-5 and C-2 are i n a c i s - r e l a t i o n s h i p H-5 resonates at l o w e r - f i e l d . This down-field s h i f t might be a t t r i b u t e d to a s t e r i c deshielding of H-5 by the substituents on C-2. Although the s t e r i c deshielding of the C-2 hydrogen are not c l e a r l y evident, the downfield s h i f t of the methyl ester i s c l e a r l y seen, i n d i c a t i n g a mutual deshielding of the cis-groups. Confirmatory evidence for the geometric assignment of the isomers was sought i n the carbon-13 n.m.r. spectrum of the two isomers. It has been observed that a-carbons i n c i s - o l e f i n s are appreciably shielded r e l a t i v e 164 to those i n the corresponding trans-isomers. The C-13 n.m.r. spectrum showed a down-field s h i f t for C-2 and an u p - f i e l d s h i f t for C-5 i n going from the major (previously assigned ^-isomer) to minor E-isomer; therefore, 103 t h i s r e s u l t cannot be considered d i r e c t confirmatory evidence for the geometric assignment. However, i t should be pointed out that although l i t e r a t u r e information on substituted enol ethers i s lacking, the i n - fluence of cis-methyl groups i s known and, therefore, 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 of the c i s - and trans-alkoxyl 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 respect to i t s i n t e r a c t i o n with H-3 i n the _E- and _Z-isomers of 3-enonate 172, res p e c t i v e l y . Therefore, the anomolous r e s u l t s of the C-13 n.m.r. spectrum p a r t i a l l y support the Z-assignment of the major isomer. The s t e r e o s e l e c t i v i t y of t h i s base-catalyzed isomerization presumably r e s u l t s from a requirement i n which the i r - o r b i t a l s of a,8-unsaturated ester 18_ must be p a r a l l e l with the C-4/H-4 bond i n order to ef f e c t deprotonation of C-4. This requirement allows for two possible conformations of 118, one leading to the E-extended enolate 180 and the other to the Z- 6a extended enolate 181. Models studies of 18_ suggest that the conformational precursor to the EJ-enolate 180 experiences greater s t e r i c i n t e r a c t i o n with C-5 (therefore, higher energy t r a n s i t i o n state) than the corresponding precursor to 181 which leads to a predominance of Z-enolate 181 and the Z-isomer of 172 (i.e.,.the predominant isomer i s o l a t e d ) . 104 18 178 < 4 E - 3 - e n e , 172 Me > 1" 3 ~ene» Ul Scheme XXIV As can be seen from the above scheme, the o r i g i n a l carbon double- bond i s now part of a conjugated enolate system and r o t a t i o n about C-2/C-3 bond i s made easier. The trans- or _E s t a r t i n g material JL8 leads d i r e c t l y to a transoid or s-trans conformation (180 and 181) while the inherent s t e r i c i n s t a b i l i t y of the c i s o i d or s - c i s conformation probably leads to a r o t a t i o n about C-2/C-3 i n the t r a n s i t i o n state i n the deprotonation of Z-18. The high degree of thermodynamic i n s t a b i l i t y of 182 (and i t s E- analogue) then give a probable explanation for the ster e o s e l e c t i v e synthesis of the _Z-isomer of 178. Although the isomerization and elimination reaction involved here i s 21 rather unusual, there i s precedent for such a st e r e o s e l e c t i v e dual r e a c t i o n taking place with analogous compound such as 22 (see Introduction, Section 1.1.). The lack of any azide addition products here might be due to the ease i n which the 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 with the activated hydrogen leading to ready deprotonation whereas compound 4JS (Introduction, Section 2.1.) requires a strained r i n g conformation to achieve the same alignment. Also, 8-azido carbonyl compounds 105 have been r e p o r t e d 1 ^ to be f a i r l y unstable and undergo B-elimination to regenerate the a,B-unsaturated carbonyl precursor. Therefore, an equilibrium between the s t a r t i n g material 1_8 and an azido adduct might have occurred with the isomerization and elimination reaction i r r e v e r s a b l y consuming s t a r t i n g material. The isomerization reaction i s presumed to be i r r e v e r s a b l e since treatment of 172 under the same conditions as JL8 does not give any 18 nor 178. Several d e r i v a t i v e s of 172 w i l l now be described before modifications to t h i s reaction are reported. 2.1.1.1. Hydrogenation of 18 and 172 to give Methyl 4,7-anhydro-8-0- benzoyl-2,3-dideoxy-5,6-0-isopropylidene-ot-D-allo (and altro)-octonate (183) and (184), respectively. C a t a l y t i c hydrogenation of the methyl oct-2-enonate 1J3 and oct-3- enonate 172 i n separate reductions gave two epimeric saturated compounds 183 and 184, r e s p e c t i v e l y . The c h a r a c t e r i s t i c changes i n each s t a r t i n g compound w i l l be described f i r s t before a d i r e c t comparison i s made between the two products. | ^ / S ^ C 0 2 M e H 2 - f t i /C^ 18 B z O - , The v i n y l i c hydrogens of 1J3 were no longer present i n the n.m.r. spectrum of the hydrogenation product, 183, and two h i g h - f i e l d methylene mu l t i p l e t s were present at c_a. 61.96 and 2.44. The stereochemical purity of t h i s compound was exemplified by three sharp methyl resonances. The 159c i . r . spectrum showed a small s h i f t i n the saturated methyl ester to 1738 cm 1 (cf. 1730 of 18) and a disappearance of the carbon-carbon double bond absorption at 1672 cnT^. 106 C0 2 Me B z 0 H 2 / P d - ^ CC^Me The hydrogenation product 184, the 'a'-analogue of 183,produced a n.m.r. spectrum i n deuterochloroform which indicated and u p - f i e l d s h i f t i n the C-2 methylene to _ca_. 62.58 and a new methylene mul t i p l e t at ca_. 62.08. The methyl groups of 184 were also present as sharp s i n g l e t s . The i . r . spectrum of 184 retained the close doublet for the carbonyls (1738 for the methyl ester and 1727 cm ^ for the benzoate, c f . above) but the moderate shoulder at 1710 cm (C=C) was no longer present. Both saturated compounds 183 and 184 exhibit weak molecular ions at 364 i n the mass spectrum and very strong acetoxonium and acylium fragments. As seen above,the carbonyl absorbances are nearly i d e n t i c a l i n the i . r . spectrum of these compounds. The o t p i c a l r o t a t i o n of these anomers are -11.4 and -9.0° for 183 and 184, r e s p e c t i v e l y . This r e s u l t i n d i c a t e s a very low c o n t r i b u t i o n of c h i r a l centre at C-4 to the o v e r a l l r o t a t i o n of the a n o m e r s . T h e above information shows the s i m i l a r i t y and p u r i t y of the two compounds, therefore, there i s a need to show the i r d i f f e r e n c e s and probable stereochemistry. 85 Based on mechanistic grounds and on the fact that d i f f e r e n t products are formed i n the two hydrogenations, the '8-anomer' 18_ should r e t a i n i t s stereochemistry ( i . e . C-4) a f t e r hydrogenation. The hydrogenation of the 102 185 3-enonate 172 should proceed from the least hindered side ' ( i . e . , away from the C^-isopropylidene) to give the 'a-anomer'. The differences i n the n.mr. spectra of these two 'anomeric' isomers support the above assignment. H-4 resonates of 63.93 and 4.07 for compounds 183 and 184, r e s p e c t i v e l y . As was seen with the a and 8-dihydroshowdomycin acetonides 107 (Section 1.2.2.) the 'anomeric' proton (H-4) of the 'a-anomers' are con s i s t e n t l y downfield of the ' 8 - a n o m e r s ' . T h e r e f o r e , the hydro- genation product of the 3-enonate 172 ( i . e . , compd. 183) can be t e n t a t i v e l y assigned the 'a'-configuration (eg. D-altro) and compound 184 the '8'- configuration. Additional supportive evidence i s also found i n the chemical s h i f t differences of the gem-dimethyl groups of the 0-isopropy- lidene group of 183 and 184. In the '8-anomer' 183 the resonances of the gem-dimethyls are separated by 20 Hz while the resonances of the gem-dimethyls of the 'a-anomer' 184 are separated by 17 Hz. This difference i s consistent with the larger chemical s h i f t differences of the gem-dimethyl groups of isopropylidenated 8-C-glycosides. Although not as s i g n i f i c a n t a l o n e 1 ^ , the 'a-anomer' 184 shows a more p o s i t i v e r o t a t i o n expected for 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 (185) When a sol u t i o n of the methyl oct-3-enonate 172 i n absolute methanol was treated with mercuric acetate followed by sodium chl o r i d e , the chromato- graphed reaction mixture r e a d i l y gave c r y s t a l l i n e 185 from a methanol so l u t i o n . 1) Hg (0Ac)o_ ^ ° \ V A s ^ C 0 2 M e 2) NaCl The carbonyl region in the i . r . spectrum of 185 indicated the loss of the shoulder at 1710 cm 1 due to the carbon-carbon double bond and the mass spectrum exhibited a complex pattern at the anticipated regions due to the isotopes of chlorine and mercury. The chemical analysis was 108 consistent with the empirical formula of 185 and the n.m.r. spectrum exhibited four sharp methyl resonances. The predominance of the g-D-altro isomer i s expected on mechanistic grounds. As i n the hydrogenation of 172 (predominantly Z-isomer), the 5,6-0-isopropylidene group i s expected to hinder the approach of the mercuric reagent from the a-face to give the intermediate 'i3'-3,4- mercurium ion which leads to the methyl a-D-altro-glycoside 185 from an 4 o v e r a l l trans-addition to the double bond of the ̂ -isomer of 172 ( i . e . , the a-D-allo-glycoside would form from the E-isomer of 172). The attempted reductive-demercuration of 185 i s described i n the next subsection. 2.1.1.2.1. Reduction of 185 with Sodium Borohydride to Y i e l d 172 Treatment of an ethanolic solution of the organomercury compound 185 with sodium borohydride resulted 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 to be the corresponding methyl glycoside but a product a r i s i n g from a reductive-elimination to regenerate the enolic precursor 172 of 185. The n.m.r. spectrum of the d i f f e r e n t f r a c t i o n s i s o l a t e d from column chromatography indicated an enhancement of the weak signals present in compound 172 previously i s o l a t e d . These enhanced signals were attributed to the E-isomer of 172 and were predominant i n the faster-moving portion of the eluent. Expectedly, the o p t i c a l r o t a t i o n of an 55:45 molar r a t i o 109 of the E-to Z-isomers exhibited the same strong negative ro t a t i o n of a predominantly (^95%) Z-mixture of 172(-167 and -156, resp.). The o v e r a l l r a t i o of the E_- to Z-isomer of 172 was found to be 42:58. The de-alkoxymercuration reaction i s usually accomplished under 82b a c i d i c conditions and with a high degree of s t e r e o s e l e c t i v i t y ; therefore, the elimination seen here must proceed by a d i f f e r e n t mechanism. 2.1.1.3. Methyl (methyl 8-0-benzoyl-3-bromo-2,3-dideoxy-5,6-0- isopropylidene-a-D.-altro-4-octulofuranosid)onate (186) 4 5 169 Bromomethoxylation ' ' of a 95 to 5 mixture of the Z to E-isomers of the methyl oct-3-enonate 172 i n a methanol solution in the presence of s i l v e r carbonate produced a mixture of adducts which a f t e r column chromato- graphy on s i l i c a gel gave a major component (41% y i e l d ) which i s t e n t a t i v e l y assigned the a-D-altro-glycoside 186. Several slower-moving minor components were also 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 , the clear syrups turned into black tars before any spectral analysis could be i n i t i a t e d . The n.m.r. spectrum of 186 exhibited a c l e a r l y defined ABX system for H-2 and H-3 and showed four sharp methyl resonances. The i . r . spectrum again showed a loss of the shoulder at 1710 cm ^ in the carbonyl band but more s i g n i f i c a n t l y , the mass spectrum of 186 indicated a trace molecular ion and strong acetoxium ion doublets ( i . e . due to Br 79 and 81) and a very strong s i n g l e t at 307 (m+-CHBrCH2C02Me) due to the C-4 s t a b i l i z e d carbonium ion from a C-3/C-4 cleavage. The stereochemical assignment of 186 implies an o v e r a l l trans-addition of the reagents which have been observed for other enolic sugars."' 110 85d 2.1.1.3.1. Attempted Hydrogenolysis of 186. When the bromoglycoside 186 was hydrogenated i n methanolic potassium hydroxide i n the presence of 5% palladium on carbon"^ 0, t . l . c . of the reaction mixture showed lower plus base-line materials but none of these could be c l e a r l y resolved and further attempts to i s o l a t e the products were not i n i t i a t e d . Also, none of the components had the R^ of the expected debrominated methyl glycoside. 2.1.1.4. Methyl(methyl 8-0-benzoyl-2,3-dideoxy-5,6-0-isopropylidene- B-D-ribo-4-octulofuranosid)onate (187) When a so l u t i o n of the methyl oct-3-enonate 172 (95:5 mixture of the _E to Z-isomers) i n pyridine, acetic a c i d , methanol, and water was allowed to stand for several months, a high R̂  band ( r e l a t i v e to 172) was isol a t e d from the myriad of products to give the methyl glycoside 187. The i . r . and MeOH 1 2 2 n.m.r. spectra were completely consistent with the proposed structure. The mass spectrum possessed the acetoxonium fragment plus the C-4 s t a b i l i z e d carbonium fragment at 307 (m^-Ci^C^CX^Me). Since the methyl glycoside was formed under equilibrium conditions, the assignment of the anomeric centre (C-4) i s based on the work of Moffatt and c o w o r k e r w h o found that fused five-member rings with epimerizable substituents ( i . e . C-glycosides of 2,3-0-isopropylidene-D-ribofuranose) under equilibrium conditions prefer a c i s - o r i e n t a t i o n of the isopropylidene and the 'non-polar' group. The study also indicated that these glycosides I l l with polar substituents (e.g., OH,OR,CIjNl^) prefer to adopt a 1,2-trans- r e l a t i o n s h i p . These r e s u l t s are also consistent with the various d e r i - vatives of D - p s i c o s e . F o r example, the main component i n a equilibrium mixture of D-psicose in acetone i s 1,2 :3,4-di-_0-isopropylidene-B-D- psicofuranose (188). Therefore, the methyl glycoside i s o l a t e d i s t e n t a t i v e l y assigned the 8- configuration. The chemical s h i f t s of H-5 and H-6 (64.49 and 4.79, resp.) also support t h i s assignment (see Section 3.1.2. for discussion of this t o p i c ) . 2.1.2. Addition of Hydrazoic Acid to the Methyl oct-2-enonate 18 to Y i e l d 172 and Methyl 4,7-anhydro-3-azido-8-0-benzoyl-2,3-dideoxy- 5,6-0-isopropylidene-D-glycero-D-allo, altro-octonate (189). Due to the lack of addition products in section 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 (see Introduction, Section 3.1.) to obtain azido-compounds from an unsaturated isopropylidenated sugar was used. Therefore, treatment of the 2-enonate 1_8_ i n N,N-dimethylformamide with hydrazoic acid i n the presence of "sodium azide produced the expected epimeric mixture of the 3-azido compounds 189. Chromatography of the worked-up reaction mixture gave one major band, the n.m.r. spectrum of which indicated a mixture of s i m i l a r compounds (e.g., s i n g l e t s for the isopropylidene methyls and a close doublet (̂ 2 Hz) for the methoxyl methyl of the epimers of 189) plus a small amount (<10%) of the methyl oct-3-enonate 172 as evidenced by the presence of i t s H-2 and methoxyl methyl signal at ca. 63.05 and 3.50, r e s p e c t i v e l y . The i . r . spectrum of t h i s band possessed a strong doublet at 2110 and 2140 cm 1 i n d i c a t i n g the presence of two 143c azido components. The epimeric azides were is o l a t e d pure as t h e i r corresponding amino derivatives (following subsection). Two other minor impure components were also i s o l a t e d and were l a t e r (Section 2.1.3.) shown to be the desired a-diazo-esters 192 and 193. 2.1.2.1. Methyl 3-amino-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6- O-isopropylidene-D-glycero-D-allo (and altro)-octonate (190) and (191) . Hydrogenation of the contaminated (with 172) epimeric azido mixture 72 189 i n the presence of 5% palladium on charcoal as c a t a l y s t gave the corresponding amino compounds 190 and 191 as a chromatographically homo- geneous mixture. The n.m.r. spectrum of this mixture i n deuterochloroform was e n t i r e l y consistent with a composite spectrum made up from the i n d i v i d u a l amines 190 and 191 (see Section 2.1.3.1.). The composite spectrum also i n - dicated a predominance (^67%) of the D-glycero-D-allo epimer (e.g., 3-S- isomer; see Section 2.1.3.) 190 which might explain the stronger band at 2140 cm 1 of the azido doublet i n the i . r . spectrum of 189. This r e s u l t indicates a small degree of s t e r e s e l e c t i v i t y i n t h i s n u c l e o p h i l i c addition reaction which was lacking i n the photoamidation reaction (Sections 1.1.3.1. and 1.2.2.). 113 190,191 2.1.3. Addition of Sodium Azide to 18 to give 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 altro)-octonate (192) and (193), r e s p e c t i v e l y . With the production of small quantities of lower compounds (Section 2.1.2.) which showed absorption bands at ca_. 2100 cm the r e s u l t s which 72 p a r a l l e l those of Rosenthal and R a t c l i f f e , the addition reaction was modified to increase the y i e l d of these minor components but keeping i n mind the s u s c e p t a b i l i t y of the substrate to elimination of acetone. The optimum conditions for the synthesis of the a-diazo-esters, 192 and 193, using hydrazoic a c i d , excess sodium azide, and N,N-dimethylformamide as solvent was determined (see Experimental) but the y i e l d of 192 and 193 were s t i l l very low, 9 and 6%, r e s p e c t i v e l y . The main product was the methyl oct-3-enonate 172 (^70%), of which the chromatographically f a s t e r - running portion was contaminated with small portions of the azido mixture 189. Higher concentration of the acid produced larger portions of 189 and decreased 192 and 193. Lower concentrations of a c i d , replacement of 172 the hydrazoic acid by excess ammonium chloride or the usage of hexa- methylphosphoramide as c a t a l y s t resulted i n the elimination of acetone to give 178 which has the same r e l a t i v e R^ (ether-hexane as developer) as 193 and also resulted i n lower y i e l d s of 192 and 193. 114 B z O - i 1 f t NaN- (HN 3) l j lH 2 * * * 192 R= A^COJMG 133 R= ^ s n ^ C 0 2 M e - ^ X 0 2 M e l N 2 N 2 J The two diastereomers 192 and 193 were e a s i l y separable by column chromatography on s i l i c a g e l . Both compounds showed c h a r a c t e r i s t i c absorbances i n t h e i r i . r . spectra at 3400, 3340, 2100 and 1698 cm 1 f o r the primary amine, conjugated diazo, and a-diazo-carbonyl ester, „. , 72,143d,173 , . . , res p e c t i v e l y . The benzoate carbonyl remained unchanged at 1730 cm ̂ . The n.m.r. spectrum of both possessed a broad two-proton D 20-exchangeable s i n g l e t at c_a. 61.64 which confirms the presence of the primary amine.' The mass sepctrum of both diazo compounds showed characte- r i s t i c fragments at 377 (M +-N 2) and 362 (M +-N 2"Me). 4 8 b' 1 7 4 A tentative assignment of the configuration at C--3 i s based on Brewster's Rules 1 7"' and Hudson's Rules of Isorotation. "*"̂  The molecular r o t a t i o n of the high and low R^ (using 2:1 ether-hexanes as developer) 8-amino-a-diazo-esters (on s i l i c a gel) are -194 and +84°, re s p e c t i v e l y . A p p l i c a t i o n of Hudson's Rules predicts a value of -55° for the molecular r o t a t i o n of a non-functionalized C-3 analogue of the above epimers depicted i n structure 194. An analogous compound to 194 i s compound 183 (see Section 2.1.1.1.) which has a molecular r o t a t i o n of -41.5°. This close agreement suggest an a p p l i c a t i o n of Brewster's Rule to the c h i r a l center at C-3 and i f the p o l a r i z a b i l i t i e s of substituents decrease i n the order C2>C^>NH2>H, then Brewster's Rule predicts a higher p o s i t i v e r o t a t i o n for the 3-S or 115 D-glycero-D-allo diastereomer. The lower-R^ diazo compound 192 has the greater p o s i t i v e r o t a t i o n and i t i s therefore suggested to possess the 3-j>-configuration and the higher R^ diazo component 193, the corresponding 3-R-configuration ( i . e . , D-glycero-D-altro). 2.1.3.1. Hydrogenation of 192 and 193 to give 190, 191 and Methyl 3-amino-A, 7-anhydro-8-0-benzoyl-3-deoxy-5,6-0-isopropylidene-p_- glycero-D-allo (and altro)-2-octulosonate Hydrazone (195) and (196), r e s p e c t i v e l y . Hydrogenation of the diazo compounds 192 and 193 (in separate reactions) i n the presence of palladium catalyst gave the corresponding B-amino compounds 190 and 191 (30 and 40%, resp.) and B-amino hydrazones 1_95 and 196 (26 and 16%, resp.), r e s p e c t i v e l y . 1 7 ^ The structures were r e a d i l y deduced from t h e i r i . r . and n.m.r. spectra. Both 8-amino compounds, 190 and 191, possessed the c h a r a c t e r i s t i c absorption bands at 3405, 3340, 1740 and 1730 cm 1 for the primary amine 1 4"^ 159c and esters groups i n t h e i r i . r . spectra. Both amines possessed s u r p r i s i n g l y sharp two-proton s i n g l e t s at ca. 61.58 in t h e i r n.m.r. spectra which exchanged with D^O and, moreover, resolvable ABX systems were present for the new methylene groups, the presence of which caused an u p - f i e l d s h i f t i n H-3. The mass spectrum of 190 contained a s i g n i f i c a n t molecular ion (m+) signal plus a strong acetoxonium fragment (m^-CH^) at 3 6 4 . 1 4 1 b Chemical analysis for both amines confirmed the empirical formulas. The structure of 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. spectra and decomposition products. Both hydrazones have s i g n i f i c a n t l y lower R^'s than 190 and 191 a fact which i s exemplified by the presence of two broad, two-proton D20-exchangeable s i n g l e t s i n the n.m.r. spectra at ca. 61.78 and 8.40. Compared to the i r 116 diazo precursors, the n.m.r. spectrum of both hydrazones presented H-3 as a broad resolvable doublet. Hydrazone 195 o r i g i n a t i n g from the lower diazo compound 192 was c r y s t a l l i z a b l e and gave the expected chemical analysis but syrups of both compounds 195 and 196 stored at room temperature or reduced temperature (^5°) would slowly show increasing amounts of a higher R^ material with 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 compounds 190 and 191, respectively. Chromatographic separation of t h i s higher R^ component gave n.m.r. spectra which were i d e n t i c a l to the corresponding 8-amino compounds. F? NH2 / N 2 \NH2 190 R= ^Oc02Me|35 R= AT^CC^Me N H 2 * H 2 % H 2 ^ X ^ ° 1_91 R= >^C02Me1_95 R _ A^C0 2 M e The transformation of the hydrazones 195 and 196 to the corresponding 8-amino compounds 190 and 191, 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 that of the Wolf f-Kishner"*^ ̂  reduction. The base i n t h i s reduction being the primary amine at C-3 and the mild conditions of the transformation 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 of the ester carbonyl on the intermediate anions. Whether the reduction i s intramole- c u l a r l y or intermolecularly catalyzed cannot be distinguished at t h i s time (although both pathways might be operating simultaneously). For s i m p l i c i t y the following scheme depicts the intramolecular-route. 117 2.1.3.2. Attempted Ring Closure of 195 with N,N'-Carbonyldiimadazole (197) to give 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 desire to synthesize an analogue of the C-nucleoside pyrazo- 112 178 * f u r i n ' (see Introduction, Section 4.), i t was hoped that the i n t r o - duction of a carbonyl group i n the preparation of a six-membered he t e r o c y c l i c system s t a r t i n g from the aminohydrazones 195 and 196 would lead to products amenable to aromatization and r e s u l t i n the synthesis of an analogue of pyrazofurin. Thus, treatment of the c r y s t a l l i n e aminohydrazone 195 with 197 i n r e f l u x i n g tetrahydrafuran gave a major higher R^ product which has been t e n t a t i v e l y assigned structure 198."^^'^ 118 195 0 2 Me 198 The i . r . spectrum of 198 showed absorbances at 3410, 3300 and 3270 cm 1 for the N-H stretching and possessed a new carbonyl absorbance at -1 159g 1665 cm i n d i c a t i v e of a urea type compound. The n.m.r. spectrum in DMSO-d^ contained several l o w - f i e l d non-aromatic si g n a l s , the lowest of which (99.32) disappeared quickly upon addition of D 2 O . The methyl re- sonances were also present as sharp peaks. The mass spectrum of 198 s i g n i f i c a n t l y showed strong fragments at 418, 277 and 156 representing the acetoxium ion (m +-CH 3), the sugar fragment ( i . e . , C-l'/C-5 cleavage) and the aglycon, r e s p e c t i v e l y . 2.2. Attempted Synthesis of a V i c i n a l Diazido Sugar 2.2.1. Treatment of 18 with Sodium Azide and Ceric Ammonium Nitra t e (CAN). 178 The C-nucleoside pyrazofurin (103) possesses strong a n t i v i r a l a c t i v i t y and i t was thought that a re-arrangement of the bond sequence in the aglycon might provide i n t e r e s t i n g b i o l o g i c a l consequences. Based on the proposed mechanism of the a z i d o - n i t r a t i o n reaction (see Introduction, Section 3.2.8.) and on the work done by other researcher on the addition of azide r a d i c a l s to unsaturated esters (e.g., compd. 1_8 which undergoes a f r e e - r a d i c a l addition i n the photoamidation reaction, see Introduction, Section 2.1.), i t was hoped that the treatment of the methyl oct-2-enonate 180 18 with CAN and sodium azide might give a v i c i n a l diazido adduct which 112 178 might lead to a s t r u c t u r a l isomer of pyrazofurin (103). ' Thus, 119 following the method described by R a t c l i f f e ^ " * , compound 1_8_ was treated with CAN and sodium azide at -33 to -22° i n a c e t o n i t r i l e for f i f t e e n hours. T . l . c . of the reaction mixture indicated 10 to 15% consumption' of s t a r t i n g material with two new higher components. Chromatography of the reaction mixture on s i l i c a gel gave unreacted s t a r t i n g material (^73%) and two minor components i n 8 and 2% y i e l d s (based on s t a r t i n g material and azido a l l y l i c s u b s t i t u t i o n , vide i n f r a ) with the f a s t e r - moving component predominating. The n.m.r. spectra of both components showed them to be impure with the presence of lo w - f i e l d v i n y l i c doublets (16 Hz) ( i . e . , an i s o l a t e d AB system). The i . r . spectrum of both components -1 143c possessed sharp bands and ca. 2120 cm (-N̂ ) and the major component possessed a strong mass spectral peaks at 388 (nf^-CH^), 375(m+-N2), and 361(m+-N2) suggesting a l l y l i c s u b s t i t u t i o n rather than addition took place. The low y i e l d s of these impure products and the lack of any i s o l a t e d 181 add i t i o n products precluded further work on t h i s reaction. 3. Oxidation and Hydration Products of Methyl (E,Z)-4,7-anhydro-8-0- benzoyl-2,3-dideoxy-5,6-0-isopropylidene-D-ribo-oct-3-enonate (172). The 3-enonate 172, obtained by a base-catalyzed isomerization of the 20 methyl oct-2-enonate 1_8_ (see Section 2.1.1., 2.1.2., and 2.1.3.), when allowed to stand i n a etheral solvent system or as a syrup exposed to ambient conditions (e.g., a i r , l i g h t , moisture, room temperature) for prolonged periods w i l l slowly react with atmospheric moisture, oxygen, 27b or ether autoxidation products to give a myriad of carbohydrate products. This section w i l l present ( i ) those carbohydrate products which have been i s o l a t e d pure, ( i i ) possible mechanism of formation, ( i i i ) assign- ment of sterochemistry, (iv) methods and r e s u l t s of reactions to s e l e c t i v e l y obtain some of these products, and (v) derivatives of the k e t a l products. 120 The oxidation and hydration products w i l l be presented i n order of chromatographic mobi l i t y , s t a r t i n g with the faster-moving components and w i l l be followed by t h e i r chemical synthesis and d e r i v a t i z a t i o n . The rate of the autoxidation process i s dependent to the carbon- 182 hydrogen bond strengths of the substrates and the a-position of ethers and, i n p a r t i c u l a r , the C-2 p o s i t i o n of the 3-enonate i s susceptable to autoxidation since the secondary hydrogens are 'a' to an carbonyl and a l l y l i c to a substituted enol ether group. The s u s c e p t a b i l i t y of 172 to 183 autoxidation i s exemplified by reports of f a c i l e peroxide formation 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-octulofuranosono- 1,4-lactone (200), Methyl(E)-8-0-benzoy1-2,3-dideoxy-5,6-0-isopropy- lidene-g-D-ribo-oct-2-en-4-ulofuranosonate (201), Methyl 8-0-benzoyl- 2,3-dideoxy-5,6-0-isopropylidene-B-D-ribo-4-octulofuranosonate (202), Methyl 8-0-benzoyl-2-deoxy-5,6-0-isopropylidene-ct,B-D-allo (and a l t r o ) - 4-octulofuranosonate (203) and (204), r e s p e c t i v e l y . When the methyl oct-3-enonate 172, contained i n open test-tubes, was l e f t i n the chromatographic solvent (2:1 ether-hexanes) used for i t s p u r i - f i c a t i o n and the solvents allowed to slowly evaporate while exposed to l i g h t and atmosphere of the room or when stored as a syrup i n a stoppered glass f l a s k , t . l . c . of the remaining syrup using 2:1 ether-hexanes as developer showed two major lower products. Lesser amounts of i n t e r - mediate and lower R̂  charring materials were also observed ( a l l slower moving than 172). Preliminary separation of the mixture was achieved by gradient e l u t i o n of the syrupy mixture on a column of s i l i c a gel using 121 ether-hexanes. The various bands were i s o l a t i o n and rechromatographed with s u i t a b l e solvent systems (see Experimental) to achieve separation of some of the many components. Thus, compounds 199, 200, 201, 202, 203 and 204 were i s o l a t e d i n 3.5, 8.2, 0.3, 2.7, 4.5 and 17.6% y i e l d s , r e s p e c t i v e l y with compounds 203 and 204 as the major lower R^ products mentioned above since compounds 172 and 199-202 possessed s i m i l a r R^'s using 2:1 ether-hexanes as developer. 200 | > ~ 0 H , Y ^ 0 2 M « | > ~ 0 H , Y ^ C 0 2 M < 204 COoMe 1 OH 202 203 Bz with The i . r . spectrum of the ribono-1,4-lactone 199 gave a strong absorption of 1802 cm 1 i n d i c a t i n g the presence of the five-membered 143a lactone r i n g . The n.m.r. spectrum of 199 c l e a r l y showed the absence of the methyl peak of the methyl ester and showed the e a s i l y resolvable m u l t i p l e t of the ribo-sugar protons between 64.44 and 4.94. The mass spectrum of 199 possessed a weak s i g n a l at 293 which was a t t r i b u t e d to the protonated parent molecule and an extremely intense acetoxonium fragement at 277 (m+-CH.j). The structure of 199 was also proven by chemical 122 synthesis. Treatment of the methyl oct-3-enonate 172 with excess meta- chloroperbenzoic acid (see Introduction, Section 3.2.4.) or oxidative cleavage of the v i c i n a l hydroxy hemiketals 203 or 204 with periodate gave lactone 199. The _sp_iro-lac tone 200 exhibited the c h a r a c t e r i s t i c i . r . carbonyl peak at 1800 cm 1 while the n.m.r. spectrum showed four high- f i e l d methylene signals at ca. 2.60 along with the absence of the methoxy methyl group. The mass spectrum again showed a trace molecular ion s i g n a l (348) and a very intense acetoxium fragment at 333 (m +-CH 3). The unsaturated k e t a l 201 was i s o l a t e d as a syrup and gave broad absorption bands at 3440 and 1720 cm 1 for the hydroxyl group and degenerate carbonyl groups, r e s p e c t i v e l y . The n.m.r. spectrum of 201 i n DMSO-d^ con- tained three sharp methyl resonances and a pair of doublets at 64.56 and 4.96 for H-5 and H-6, respectively. The assignment of the doublets i s based on a s l i g h t broadening of the low- f i e l d doublet a t t r i b u t a b l e to a small i n t e r a c t i o n with H-7 and on the fact these doublets are in s i m i l a r positions i n the n.m.r. spectrum of the saturated ketal 202 in which the low - f i e l d doublet i s further s p l i t by ca. 1.0 Hz. Moreover, two sharp doublets (J 16.0 Hz) at 66.14 and 6.87 (H-2 and H-3, resp.) i n the spectrum of 201 confirms the presence of an a,8-unsaturated ester grouping i n the trans-orientation"*"^ and a sharp, D20-exchangeable, one proton s i n g l e t 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 moelcular ion (378) and the anticipated acetoxium fragment at 363 (m+-CH.j). The saturated ket a l 202 produced a broad absorption band at 3430 cm 1 in i t s i . r . spectrum i n d i c a t i n g the presence of a hydroxyl group. The n.m.r. spectrum of 202 i n DMSO-d, confirmed t h i s assignment by the presence of a o sharp, one-proton s i n g l e t at 66.16 which disappeared upon addition of I^O; 123 moreover, two h i g h - f i e l d methylene groups along with a doublet ( J c , 6.0 Hz) 5,6 for H-5 at 64.44 and doublet of doublets ( J , n 1.0 Hz) for H-6 at 64.86 o, / were also present. The mass spectrum contained the acetoxonium fragment (m^-CH^) at 365 and weaker fragment at 363 (m+-0H) due to the loss of the C-4 hydroxyl and r e s u l t i n g i n an C-4 oxo-carbonium fragment. The next component i s o l a t e d was the higher v i c i n a l hydroxy B-ketal of 203 which was r e a d i l y c r y s t a l l i z e d from dichloromethane-hexanes. The i . r . spectrum of 203 contained a broader and more intense absorption band at 3480 cm ^ than the previous two ketals which suggest the presence of more than one hydroxyl group. The n.m.r. spectrum of 203 i n DMSO-d, 6 possessed a sharp, one-proton s i n g l e t and doublet at 65.25 and 6.08, re s p e c t i v e l y , both of which disappeared upon addition of D 2 O . H-6 and H-5 were present as doublets at 64.95 and ca_. 4.52, res p e c t i v e l y . This assignment was confirmed by a comparison with the n.m.r. spectrum of 203 i n deuterochloroform which showed H-6 to be l o w e r - f i e l d , broadened doublet (J^ g 6.0 Hz i n both solvents). The n.m.r. spectrum of 203 i n DMSO-d^ produced a s p l i t t i n g inthemethyl resonances upon addition of D 2 O . These new signals were at t r i b u t e d to the presence of the a-anomer of 203, the presence of which was caused by the D20/HDO-catalyzed anomerization of the 13b B-anomer of 203. The mass spectrum and chemical analysis corroborated the assigned empirical formula of 203. The syrupy, lower R^, v i c i n a l hydroxy-ketal 204 was iso l a t e d as the major component (17.6%). The major differences between the two hydroxy- ketals 203 and 204 are the i r chromatographic mobility, t h e i r a b i l i t y to form c r y s t a l s , t h e i r o p t i c a l r o t a t i o n (-29.1 and +9.27° for 203 and 204, resp.) and t h e i r n.m.r. spectra. In regards to the l a t t e r , the n.m.r. spectrum of 204 i n DMSO-d, indicated a 2:1 r a t i o of anomers which increased o 124 (to approx. 4:1) upon addition of D^O. The addition of D^O also resulted i n the loss of two s i n g l e t s and a doublet at 65.95, 5.60 and 5.29, r e s p e c t i v e l y . The loss of a second doublet at ca. 64.89 may have occurred but was obscured by an overlapping s i g n a l and a change i n anomeric r a t i o s . 3.1.1. Possible Mechanistic Pathways to Compounds 199 to 204. Although the mechanistic pathways to the above carbohydrates (199 to 204, i n c l u s i v e ) have not been investigated, the known reactions of o l e f i n s with oxygen and hydroperoxides and t h e i r r a d i c a l precursors w i l l be applied here to r a t i o n a l i z e the formation of the above products from the methyl oct-3-enonate 172. References to structures of intermediates, reactions, and reaction schemes w i l l b e found i n section 3.2.6. of the Introduction. Although several routes might lead to the desired product, the shortest and most probable route(s) w i l l be presented. The pathway to the ribono-l,4-lactone 199 can be envisioned as pro- u u C • • A- 95,184a,b ceedmg through the formation of a dioxetane intermediate such as 9_0_, formed by the addition s i n g l e t oxygen to the 3-enonate 172, and subsequent decomposition of intermediate to give the carbonyl compound 199 (see Scheme XIII). A second route which involves t r i p l e t ground state oxygen requires the autoxidation of the 3-enonate 172 to the unsaturated peroxy keta l 205 which undergoes rearrangement (Scheme XIV) to give lactone 199. Other routes involving the hemiketals 201-204 or t h e i r precursors (vide i n f r a ) might provide a route to 199 v i a the Baeyer- V i l l i g e r rearrangement or a reaction s i m i l a r to one depicted in Scheme XII (see Introduction, Section 3.2.4.). The spiro-lactone 200, obviously a r i s e s from an intramolecular c y c l i z a t i o n of the saturated hemiketal 202 or i t s precursor. The unsaturated hemiketal 201 can come about by two routes; the f i r s t , 125 involves the dehydration of either of the 6-hydroxy esters 203 or 204 to give 201 d i r e c t l y . The second route involves the peroxy-radical precursor (206a)to the peroxy hemiketal 205. This r a d i c a l adds to a molecule of the 3-enonate 172 which then rearranges to form an epoxide of 172 (compd. 206b) and the alkoxy r a d i c a l of 201 (compd. 206c, see Scheme XXVI below) which abstracts a hydrogen atom to give 201 (which also r e s u l t s i n the propagation of the autoxidation process). Z-172 + Scheme X X V I The saturated hemiketal 202 obviously r e s u l t s from a hydration of the enol ether 172 (see Introduction, Section 3.2.1.). Intramolecular c y c l i z a t i o n of 202 gives the spiro-lactone 200. The hydroxy hemiketals 203 and 204 can a r i s e from epoxide procursors as depicted i n Scheme XXVI (vide i n f r a ) which hydrate to give the desired products. If other r e a d i l y oxidizable substrates such as ethyl ether are present, the peroxide r a d i c a l formed (si m i l a r to 206a) w i l l also 126 compete for substrate 172. Another route to 203 and 204 and t h e i r oxirane precursors involve the hydroperoxide 205 and the hydroperoxides of ethyl ether. These hydroperoxides might react with 172 i n a manner analogous to peracid reactions (see Introduction, Section 3.2.4.) with carbon-carbon double bonds (see Reaction (5)). The peroxy hemiketal structure of these hydroperoxides should enhance t h i s l a t t e r mechanism and r e s u l t i n another pathway to 201. Hydration of 201 would also give to 203 and 204, although t h i s hydration i s not expected to contribute s i g n i f i c a n t l y . 3.1.2. Stereochemistry of 200-204. The sterochemistry of the ketals of the methyl oct-3-enonate 172 has been b r i e f l y discussed i n section 2.1.1.4 when the methyl glycoside 187 of the saturated hemiketal 202 was i s o l a t e d . The conclusion reached i n that discussion was that under equilibrium conditions ketals with an 0-isopropylidene group at the 3,4-position of the furanoid r i n g ( i e . , the 2,3-position of aldofuranoses) prefer the B-configuration. A further c o r r e l a t i o n a r i s i n g from the proton n.m.r. of the psicose d e r i v a t i v e s concerns the chemical s h i f t s of H-2 and H-3 (aldofuranose r i n g or H-5 and H-6 i n the octulosonates under d i s c u s s i o n ) . 1 7 1 The H-3 chemical s h i f t s i n the B-D-psicofuranosides were consistently downfield from the H-2 chemical s h i f t s by 0.14 part per m i l l i o n (ppm) or more and i n the a-anomers H-3 was u p - f i e l d from H-2 (see Section 3.3.2. for an example of t h i s s h i f t i n H-3). Another c o r r e l a t i o n which has been found for these isopropylidenated d e r i - vatives i s that the chemical s h i f t differences i n the gem-dimethyl groups of the C - g l y c o s i d e s 1 ^ 7 have greater differences when the isopropylidene group and the anomeric substituent are i n a t r a n s - r e l a t i o n s h i p . Both studies also showed that both the a-0 and ^-glycosides shows a greater 127 p o s i t i v e o p t i c a l r o t a t i o n . In a l l four of the 2,3-dideoxy-4-octulofuranose derivatives 187, 201, 202 and 203, the B-configuration was given to the anomeric centre. These tentative assignments are basedon the above thermodynamic con- siderations and on the r e l a t i v e positions the H-5 and H-6 resonances. Only one anomer was i s o l a t e d i n each case (therefore, assigned the more stable B-configuration) and H-6 was consistently l o w e r - f i e l d than H-5 (consistent with the B-configuration). For the hydroxy hemiketals 203 and 204, two new c h i r a l centres are present and both compounds exhibit an equilibrium in a DMS0-d,/D„0 solvent o z system. The assignment of the stereochemistry at C-3 i s based on the stereochemistry of the methyl oct-3-enonate 172 which has been determined (Section 2.1.) to be predominantly the Z-isomer and on the s t e r e o s e l e c t i v i t y of a d d i t i o n reactions to 172 and other exocyclic double bonds with s i m i l a r 102 185 s t e r i c environments. With substrates such 172, 46, and 9_2, hydrogenation, ' , « , . . , . . , 186 , , , . 102 hydroxylation with osmium tetroxide or permanganate , or hydroboration , a l l proceed from the side opposite of the isopropylidene group ( i . e . , the least hindered s i d e ) . The hydroxylation of 172 with osmium tetroxide and meta-chloroperbenzoic acid gave predominantly the lower hydroxy hemiketal 204, r e s u l t s which are analogous to the a i r oxidation of 172. Therefore, whatever the mechanism and stereochemical s e l e c t i v i t y of the l a t t e r process, the former r e s u l t s i n d i c a t e that topside (8-face) attack by the hydroxylation reagents on the major Z-isomer of 172 w i l l give the 3-R-isomer ( i . e . , D-altro- isomer) 204 and topside attack on the E-isomer of 172 w i l l give the 3-^-isomer ( i . e . , D-allo-isomer) 203 (for a d d i t i o n a l support see Section 3.3.2.). The fact that the r a t i o of the two components present in the proton 128 n.m.r. spectrum of both hydroxy hemiketals 203 and 204 can be varied by the addition of D 20 i s s u f f i c i e n t evidence to prove that the components i n both compounds are anomeric or tautomeric components of the same parent carbohydrate. The synthesis of ribono-l,4-lactone 199 from 203 or 204 by periodate cleavage corroborates the v i c i n a l o r i e n t a t i o n of the carbonyl at C-4 and hydroxyl at C-3. Additional proof of t h i s structure for 203 and 204 i s obtained by the i s o l a t i o n of 203 and 204 from the hydroxylation of the oct-3-enonate 172 with osmium tetroxide and meta-chloroperbenzoic acid. Although the proton n.m.r. spectra of 203 and 204 could not unequi- v o c a l l y e s t a b l i s h whether or not a mixture of c y c l i c or a c y c l i c and c y c l i c modifications of the parent carbohydrate were present i n s o l u t i o n , the fact that a one-proton s i n g l e t and one-proton doublet (combined in t e g r a t i o n i n the mixtures) which disappeared upon addition of D 20 did strongly suggest the presence of two c y c l i c modifications. This conclusion was supported by the fact that D-psicose and i t s 6-0-methyl d e r i v a t i v e 54 existed only i n c y c l i c modications either i n D„0 or DMSO-d, sol u t i o n . Z t> Confirmatory evidence for t h i s conclusion was found i n the carbon-13 n.m.r. spectra of 203 and 204 which contained only two carbonyl resonances ( i . e . , the benzoate and methyl ester)and a pair of k e t a l doublets ( i . e . , C-4 and the quaternary carbon of the isopropylidene group of the anomers) for both compounds; thus, providing unequivical support for the presence of the two anomers rather than a mixture of c y c l i c and a c y c l i c tautomers. Based on the discussion presented e a r l i e r i n t h i s subsection, the 6- anomers of 203 and 204 would be expected to predominate. Support for t h i s anticipated-predominance comes from a v a r i e t y of spectroscopic c o r r e l a t i o n s . In the D-psicose seri e s the anomeric hydroxyl proton proton was found to 54 resonate at lower f i e l d i n i t s B-furanose configuration - ketose 203 and 204 had stronger l o w - f i e l d s i n g l e t s . The B-anomer of g-psicose and i t s 129 d e r i v a t i v e s produces i t s anomeric C-13 s i g n a l downfield from that of the a-anomer^ 4' 1 8 7 - the l o w - f i e l d s i g n a l of the C-4 doublet of 203 and 204 predominated. The c i s - o r i e n t a t i o n of C-3 and 0-5 produces a smaller chemical s h i f t difference i n the gem-dimethyl group of the a c e t o n i d e s 1 ^ 7 - the major anomeric component of 203 and 204 chemical s h i f t d i f f e r e n c e of ca_. 15 Hz while the minor component has a difference of ca. 21 Hz; there- fore, the major component possesses a c i s - o r i e n t a t i o n of the isopropylidene and C-4 side chain ( i . e . , the 6-anomer). F i n a l l y , the H-5 resonances of major anomers are found to be a sharp doublet at s i g n i f i c a n t l y higher f i e l d than H-6 thereby providing a d d i t i o n a l support for the predominance ^ t - n 171 of the p-anomer. 3.2. Treatment of 172 with meta-Chloroperbenzoic Acid (MCPBA) to i e l d Methyl (ethyl 8-0-benzoyl-2-deoxy-5,6-0-isopropylidene-B-D-altro- 4-octulofuranosid)onate (207) and Compound 204. Treatment of a dichloromethane so l u t i o n of the methyl oct-3-enonate (172) with MCPBA gave a major product which was higher i n than the desire v i c i n a l hydroxy hemiketals, 203 and 204. The hemiketal 204 was i s o l a t e d i n 10% y i e l d a f t e r column chromatography of the re a c t i o n mixture but the ethyl glycoside 207 was i s o l a t e d i n 39%. 122 2 ) H 2 0 The i . r . spectrum of 207 possessed a broad band at 3560 cm 1 i n d i c a t i n g the presence of a hydroxyl group and a broad carbonyl band 1727 cm 1 . The 130 n.m.r. spectrum of 207 i n DMSO-d^ exhibited three methyl groups and A^I^ quartet and t r i p l e t f o r the e t h y l group at 63.61 and 1.07, r e s p e c t i v e l y . Moreover, H-6 was present as a broadened doublet at 64.87 compared to 4.67 for H-5 which suggest the presence of the 8-anomer. Since only one isomer of 207 was i s o l a t e d , thermodynamic considerations s i m i l a r to those for compounds 201-204 suggest that the 8-anomer predominates (see previous sect i o n ) . Compound 207 probably a r i s e s from the acid-catalyzed opening of the intermediate epoxide (e.g., compd. 206b) i n the presence of trace alcohol used to s t a b i l i z e d halogenated solvents. 3.3. Derivatives of Ketals 202-204 The purpose of the synthesis of d e r i v a t i v e s of ketals 202-204 was two-fold. F i r s t , the d e r i v a t i v e s might give c r y s t a l l i n e compounds ( i . e . , k e t a l 204 i s a syrup) which are anomerically stable and thus, amenable to unambiguous char a c t e r i z a t i o n and possibly corroborate the configuration of C-3 of ketals 203 and 204. Secondly, i t was hoped that some of these de r i v a t i v e s might lead to precursors of analogues of ketose N-nucleosides (see Section 4. and Introduction, Section 5.). 3.3.1. 5,6-Di-0-acetyl-8-0-benzoyl-2,3-dideoxy-a(and8)-D-ribo-4- octulofuranosono-1,4-lactone (208a) and (208b), respectively Treatment of the saturated hemiketal 202 with 80% aqueous t r i f l u o r o - a c e t i c a c i d followed by a c e t i c anhydride give the spiro-lactones 208a and 208b i n 24 and 34% y i e l d , r e s p e c t i v e l y . The n.m.r. spectra of 208a and 208b showed the loss of the methyl ester methyl group along with the s h i f t of two of the furanoid hydrogens to l o w e r - f i e l d . This acetylated lactone structure was confirmed by the presence of three carbonyl bands at ca. 1730, 131 1760 and 1805 cm for the five-membered lactone , acetates and benzoates, re s p e c t i v e l y . 208a 208b The assignment of the anomeric configuration i s again based on the pos i t i o n s of the H-6 resonance i n the n.m.r. spectrum."*^ The chromato- gra p h i c a l l y more mobile component (compd. 208a) possessed a h i g h e r - f i e l d (0.17 ppm) H-6 si g n a l and i s therefore assigned the a-configuration and thus the 6-configuration for 208b. This assignment i s also 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 for 208a (eg., +57.5° ^ f . -11.1° for 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), respectively. Treatment of the v i c i n a l hydroxy hemiketal 203 with t r i f l u o r o a c e t i c acid, 2,2-dimethoxypropane, and acetone gave an anomeric pair of diacetonides 209a and 209b in 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 diacetonides showed f i v e , sharp three-proton s i n g l e t s for the methyl groups and an overlapping multiplet for H-3, H-5 and H-6. The multiplet for K-3 was e a s i l y resolved due to the coupling with H-2a and H-2b which enabled a f a c i l e assignment of H-5 and H-6 since H-6 was present as a broadened doublet. 132 The configuration of the two anomers was again assigned on the basis of the r e l a t i v e chemical s h i f t s of H-5 and H-6. The p o s i t i o n of H-5 and H-6 i n the a-anomer was 64.76 and 4.66 and 64.65 and 4.85 i n the 8-anomer, resp e c t i v e l y ; therefore, these r e l a t i v e chemical s h i f t s support the assigned configurations with secondary support provided by o p t i c a l r o t a t i o n measurements ( i . e . , a-anomer possessing a more p o s i t i v e r o t a t i o n ) . A d d i tional spectroscopic c o r r e l a t i o n which supports the anomeric assignment along with the c o n f i g u r a t i o n a l assignment of 0 3 was found i n the chemical s h i f t of H-2a and H-2b of the B-anomer 209b. H-2b resonates at s i g n i f i c a n t l y lower f i e l d r e l a t i v e to H-2a (0.52 ppm) - t h i s difference has been observed in other di-O-isopropylidenated spiro-ketals and has been at t r i b u t e d to the 188 deshielding e f f e c t of the oxygen at C-5. Therefore, i t can be seen from models of the various diastereomers that only the diacetonide of the B - anomer of the D-allo-octulose 203 ( i . e . , compd. 209b) can a t t a i n an o r i e n t a t i o n wherein the hydrogens of H-2 are i n close proximity to 0-5 in a conformationally confined system where one hydrogen on C-2 projects into the space occupied by one of the lone pairs on 0-5; thus, supplying supportive evidence for the c o n f i g u r a t i o n a l assignment of C-3 i n compounds 203 and 204. 3.3.3. Methyl 8-0-benzoyl-2-deoxy-3,4:5,6-di-0-isopropylidene - B-D- altro-4-octulofuranosonate (210) and 8-0-benzoyl-2-deoxy-5,6-0-iso- propylidene - B - P_-altro-4-octulofuranono-l ,4-lactone (211). Treatment of epimeric hemiketal 204 as above gave only one diacetonide 210 i n 33% y i e l d and a lactone 211 i n 10% y i e l d . The chemical and spectro- scopic analyses of 210 were completely consistent with the proposed structure. The anomeric configuration of 211 i s t e n t a t i v e l y assigned the B-configuration and i s based on the chemical s h i f t of H-5 and H-6 ( i . e . , H-6 lower f i e l d 133 than H-5 cf_. compels. 209a and 209b) with the o p t i c a l r o t a t i o n again providing secondary support. 210 211 The structure of compound 211 was evident from the loss of the methoxy methyl group of 204 i n the n.m.r. spectrum of 211; moreover, the presence of a broad, single-proton t r i p l e t which disappeared upon ad d i t i o n of D^O and resulted i n the collapse of a h i g h - f i e l d multiplet to a doublet of doublets ( i . e . , H-2b) and a m i d - f i e l d doublet of doublets to a doublet ( i . e . , H-3) suggested a rather r i g i d spiro-lactone structure. I . r . absorbances at 3580 and 1812 cm 1 supported the presence of the hydroxyl and five-membered lactone g r o u p s . 1 4 3 3 Comparison of lactone 211 with a chromatographically le s s mobile spiro-lactone (compd. 213; see Section 3.2.4.) i s o l a t e d from a l a t e r synthesis s t a r t i n g with 204 suggested the 6-configuration for 211 (e.g., from a comparison of chemical s h i f t s of H-6 and o p t i c a l r o t a t i o n s ) . Models of the spiro-lactone 211 indicate a s t e r i c a l l y hindered spiro-system wherein 0-3 and 0-5 are i n close proximity (cf. compd. 209b) ; however, t h i s s t e r i c i n t e r a c t i o n might be s t a b i l i z e d by possible hydrogen-bonding between the C-3 hydroxyl and 0-5. These two in t e r a c t i o n s produce a conformationally r i g i d spiro-system which r e s u l t s i n a favourable o r i e n t a t i o n for a four- bond coupling between the hydroxyl proton and H-2b (2.0 Hz). Proton- proton spin-coupled i n t e r a c t i o n s through four bonds has been observed for conformationally favourable r i g i d 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 i n t e r a c t i o n . The conformational immobility of 211 i s also exemplified be the lack of an observable coupling i n t e r a c t i o n between H-2a and H-3. 3.3.4. Compounds 210, 211, 2-Benzoyloxymethyl-5-(carbomethoxyacetyl) furan (212) and 8-0—Benzoyl-2-deoxy-5,6-0-isopropylidene-a-p.-altro- 4-octulofuranosono-l,4-lactone (213) from 204. When the hemiketal 204 was continuouslyazeotroped i n a benzene sol u t i o n i n the presence of para-toluenesulfonic acid, four components, compounds 210, 211, 212 and 213, were i s o l a t e d from the reaction mixture i n 1.3, 39, 11 and 2% y i e l d s , r e s p e c t i v e l y . The n.m.r. spectrum of the substituted furan d e r i v a t i v e 212 showed three s i n g l e t s and two doublets along with the benzoate signals and the i . r . spectrum of 212 exhibited three carbonyl bands at 1750, 1730 and 1670 cm for the methyl ester, benzoate and conjugated ketone, r e s p e c t i v e l y . The U.V. spectrum of 212 exhibited a strong absorption 190 band at 276 nm which i s consistent with the assigned structure. The acid-degradation of 204 to 212 probably arose from a series of eliminations s i m i l a r to those outlined i n schemes II and III (see Intro- duction, Section 1.1.). The 0-isopropylidene group of 204 might have hydrolyzed before the degradation process to give acetone which reacts with 204 to give the diacetonide 210 or the v i c i n a l hydroxy hemiketal 204 might have reacted with an intermediate i n the degradation reaction which r e s u l t s i n an exchange reaction to give intermediates which lead to 210 194 and 212, r e s p e c t i v e l y . The l a t t e r route i s expected to predominate. 135 Similar to i t s 8-anomer 211, spiro-lactone 213 indicated the loss of methoxy methyl group of 204 i n i t s n.m.r. spectrum. Also, H-3 showed s i g n i f i c a n t broadening due to coupling with the hydroxyl proton. This i n t e r a c t i o n disappeared upon addition of D^O and H-3 collapsed to a sharp t r i p l e t which when i r r a d i a t e d collapsed H-2a and H-2b to a p a i r of doublets. The i . r . spectrum confirmed the presence of the above functional groups with absorbances at 3500 and 1805 cm 1 for the hydroxyl and f i v e - membered l a c t o n e 1 4 ^ 3 , r e s p e c t i v e l y . 3.3.5. Methyl 3,4,5,6-tetra-0-acetyl-8-0-benzoyl-2-dexoy-ct(andg)-D- altro-4-octulofuranosonate (214) and (215), r e s p e c t i v e l y. Treatment of the hemiketal 204 with 80% t r i f l u o r o a c e t i c acid and a c e t y l a t i o n of the r e s u l t i n g mixture with acetic anhydride gave two t e t r a - acetates 214 and 215 i n 7 and 25% y i e l d s , r e s p e c t i v e l y . Separation of the two anomers on a column of s i l i c a gel gave the faster-moving 8-anomer 215 followed by the a-anomer 214. The n.m.r. spectrum of both anomers in deuterochloroform showed f i v e sharp methyl resonances and three s i n g l e - proton m u l t i p l e t s at l o w e r - f i e l d due to the acetylated secondary hydroxyls of H-3, H-5 and H-6. H-6 of the faster-moving component was at lower - f i e l d than the slower-moving tetraacetate (65.80 and 5.44, resp.) and was assigned the B - c o n f i g u r a t i o n . 1 7 1 The faster-moving tetraacetate also possessed a smaller p o s i t i v e r o t a t i o n . The i . r . of both compounds possessed a strong band a ca_. 1757 cm 1 and at strong shoulder at c_a_. 1731 cm 1 for the acetates 136 204 and benzoate groups, r e s p e c t i v e l y . Attempted hydrogenation of the a-anomer 214 in the presence of platinum ca t a l y s t f a i l e d . The recovery of 214 supports the assigned c y c l i c structure of the tetraacetate. 4. Attempted Synthesis of Analogues of Psicofuranine (129). 113 The ketose N-nucleosides , of which psicofuranine (129) i s one of i t s two known natural members, are a rare group of nucleoside 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 novel epimeric homologues of D-psicose, namely methyl 8-0-benzoyl-2-deoxy-5,6-0-isopropylidene-g-allo (and a l t r o ) - 4 - octulofuranosonate (203) and (204), re s p e c t i v e l y (Section 3.1.), prompted an i n v e s t i g a t i o n into the f e a s a b i l i t y of synthesis of a homologue of the a n t i - b a c t e r i a l and antitumor nucleoside psicofuranine (129). 136b FarkaS and §orm reported the synthesis of psicofuranine (129) i n 4.6% y i e l d s t a r t i n g from the benzoylated methyl psicofuranosides v i a the condensation of the mercuric chloride s a l t of N-benzoyl-adenine on the corresponding sugar bromide. Several attempts were made to condense a purine or pyrimidine base onto d e r i v a t i v e s of ketose 204; however, none of the attempts gave any s i g n i f i c a n t amount of nucleoside material. The synthetic s t r a t e g i e s w i l l , therefore, be only b r i e f l y discussed. Synthetic . . 112,116,191a , . . 192 . . , methods and mechanisms of the condensation reactions have been thoroughly reviewed and w i l l not be dealt with here. 193 a) Following the method of Vorbruggen and Bennua , the acylated D- ribofuranoside 134 was condensed with u r a c i l (216) to give 2',3',5'-tri-0- benzoyl-uridine (217) i n 69% y i e l d . Substitution of 134 with the acylated 137 134 + HN BzQ - i methyl 4-octulofuranosonate 214 gave a multicomponent mixture, none of which could be reconciled with the desired adduct. b) U t i l i z a t i o n of the fusion procedure 1^ 1' 5 with 214 and 2,6-dichlo purine (218) also gave negative r e s u l t s . ro- V> 218 c) An attempt to u t i l i z e the methyl oct-3-enonate 172 d i r e c t l y 4 i n the synthesis of a ketose N-nucleoside was also unsuccessful. Thus, the addition of bromine to 172 followed 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 (219) gave a predominantly faster-moving product upon s i l i c a gel chromatography. This unstable product has been t e n t a t i v e l y assigned 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). 172 1) B r 2 2) Bz0-> M e 3 S i < r ^ 2 1 ? 02Me 138 The n.m.r. spectrum of 220 showed a broadening of the isopropylidene methyl signals and doublets for H-2 and the methoxy methyl. The mass spectrum of 220 showed a very intense molecular ion doublet of 440/442 due to the bromine isotopes and the strength of the s i g n a l supports the enolic structure for 220. The f a c i l e loss of hydrogen bromide from bromine 102 adducts of e n o l i c compounds has been reported and the possible c a t a l y t i c a c t i v i t y of amino compounds i n the elimination to give enolic compounds has also been used s y n t h e t i c a l l y (see Introduction, Section 1.1.). 139 IV EXPERIMENTAL 1. General Methods P.m.r. spectra were determined i n chloroform-d or dimethyl sulfoxide-d, o with tetramethylsilane as the i n t e r n a l standard (set at 6=0) or i n deuterium oxide with sodium 2,2-dimethyl-2-silapentane-5-sulfonate as the external standard (set at 6=0) by using a Varian HA-100, Varian XL-100, Bruker 270 or Bruker 400 spectrometer. Values given for coupling constants are f i r s t order. Carbon-13 n.m.r. spectra were determined i n chloroform-d or dimethylsulfoxide-d^ with tetramethylsilane as the i n t e r n a l standard by using a Varian CFT-20 spectrometer. Optical rotations were measured at ambient temperature with a Perkin-Elmer Model 141 automatic polarimeter. Infrared spectra were recorded on a Perkin-Elmer 710B or 727B spectrometer. A l l melting points were done on a L e i t z microscope heating stage, Model 350, and are corrected v i a a c a l i b r a t i o n curve. Mass spectra were determined on a Varian/MAT CH4B or Kratos MS902 low r e s o l u t i o n or a Kratos MS50 h i - r e s o l u t i o n spectrometer. U l t r a v i o l e t spectra were recorded on a Cary 15 spectrometer. Reaction temperatures were measured v i a an external o i l bath unless other- wise stated. Elemental analyses were performed by Mr. P. Borda of the Micro- a n a l y t i c a l Laboratory of the Un i v e r s i t y of B r i t i s h Columbia. 2. Chromatography 2.1. Column Chromatography S i l i c a gel column chromatography was performed using s i l i c a gel H for t h i n layer chromatography (Merck). The r a t i o of substrate to absorbent was approximately 1:100 (w/w) and the r a t i o of column length to diameter was approximately 10:1. Columns were pressurized above the solvent res e r v o i r at 8-12 p . s . i . providing flow rates of 30-500 ml h 140 2.2. Thin Layer Chromatography A l l thin layer chromatography was performed using s i l i c a gel (Camag) containing 5% calcium s u l f a t e . Compounds were detected by u l t r a v i o l e t absorption and/or by spraying with 50% s u l f u r i c acid followed by heating on a hot p l a t e . 3. Abbreviations The abbreviations used i n the following descriptions are as follows: n.m.r.(nuclear magnetic resonance), p.m.r.(proton magnetic resonance), u . v . ( u l t r a v i o l e t ) , i . r . ( i n f r a r e d ) , m.p.(melting point ) , t . l . c . ( t h i n layer chromatography), DMF(N,N,-dimethylformamide), DMSO(dimethyl s u l f o x i d e ) , THF(tetrahydrofuran), MeOH(methanol), s ( s i n g l e t ) , d(doublet) dd(doublet of doublets), t ( t r i p l e t ) , q(quartet), and m(multiplet). 4. (R) and (S)-Dihydroshowdomycin (171) and (170), r e s p e c t i v e l y . 4.1. Synthesis of Methyl (E,Z)-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-0- isopropylidene-p-allo-oct-2-enonate (18) from l-0-Acetyl-2,3,5-tri-0-benzoyl- 8-D-ribofuranose (134). 2,3,5-Tri-0-benzoyl - B-D-ribofuranosyl Cyanide (127) Dry gaseous hydrogen bromide (passed through granular ?2^5^ w a s bubbled through a s t i r r e d s o l u t i o n of l-0-acetyl-2,3,5-tri-0-benzoyl-8-D-ribofuranose 134 (126 g, 0.25 mol) i n anhydrous benzene (500 ml). The mixture was cooled i n an ice bath while the gas flow was c a r e f u l l y maintained to r e t a i n a p o s i t i v e gas pressure. The s o l u t i o n was saturated and gas flow continued for 60 min a f t e r which the gas i n l e t and ice bath were removed and the reaction mixture was allowed to stand at room temperature for an a d d i t i o n a l 45 minutes. Dry nitrogen gas was passed through the solution to displace the hydrogen bromide and the s o l u t i o n was evaporated under reduced pressure (bath temperature 40°C) and the residue coevaporated with 400 ml anhydrous benzene. The r e s u l t i n g amber syrup was dissolved in nitromethane (300 ml) 141 (dried by d i s t i l l a t i o n over P20,.), powdered mercuric cyanide (125 g, 0.485 mol)(predried at 140°, 0.10 mm Hg for 24 hours) added and a drying tube was then attached to the reaction f l a s k (performed i n a dry-box). The mixture was s t i r r e d for 20 hours at room temperature a f t e r which the insoluble portion was f i l t e r e d o ff and washed with benzene to y i e l d a greenish f i l t r a t e . The combined f i l t r a t e s were evaporated under reduced pressure and the r e s u l t i n g syrup was dissolved i n chloroform (2.0£) and washed with 5% aqueous potassium iodide (2 x 200 ml) and water (2 x 100 ml), dried over sodium s u l f a t e , evaporated under reduced pressure, and the crude syrup dissolved i n ethanol (200 ml). Approximately half the ethanol was evaporated under reduced pressure, the concentrate seeded and allowed to c r y s t a l l i z e at room temperature over-night. The c r y s t a l l i n e mass was t r i t u r a t e d with a mixture of ethanol-ether (85:15, 100 ml), the c r y s t a l s c o l l e c t e d and washed with ethanol. The f i l t r a t e s were combined, evaporated and the residue c r y s t a l l i z e d from ethanol over several weeks with periodic evaporation (under reduced pressure) of small portions of ethanol 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 cyanide 127 was c o l l e c t e d and washed with ethanol ( o v e r a l l y i e l d : 96.5 g, 8 1 . 6 % ) ( l i t . ~ 8 8 % ) ; 1 31 m.p. 78-80.5°, ( l i t . m.p.78.5-80°); n.m.r. (60 MHz, CDC1 3): 64.91(d,lH, J x 2 4.0 H z , H - l ) ( l i t . 1 3 1 64.425,d,H-l) ; [cx]^ 4 + 23.9 (cO. 5,CHC13) , ( l i t * 3 1 + 23.8 (cO.5jCHCl^)). F i n a l v e r i f i c a t i o n of structure was evident i n the following d e r i v a t i z a t i o n s . 5-0-Benzoyl-8-p-ribofuranosyl Cyanide (135) A s o l u t i o n of the blocked r i b o s y l cyanide 127 (90 g) i n anhydrous chloro- form (900 ml) was added to a s t i r r e d , ice-cooled s o l u t i o n of saturated meth- ano l i c ammonia (1350 ml) and kept i n an ice bath for 4.5 h. The solvent was then evaporated under reduced pressure (in 500 ml portions), and the r e s u l t i n g 142 clear syrup was dissolved i n ethyl acetate (300 ml), washed with saturated aqueous sodium bicarbonate (30 ml), water (30 ml), dried over anhydrous sodium s u l f a t e and evaporated under reduced pressure 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 overnight i n the r e f r i g e r a t o r to give the c r y s t a l l i n e p a r t i a l l y unblocked cyanide 135 (37.2 g , 7 2 . 5 % ) ( l i t . 83%); m.p. 117-118.5, ( l i t . 117- 117.5(118)). Smaller scale reactions were found to give y i e l d s comparable to the l i t e r a t u r e y i e l d . 5-0-Benzoyl-2,3-0-isopropylidene - B-D-ribofuranosyl Cyanide (136) To a s o l u t i o n of 70% p e r c h l o r i c acid (3.6 ml), 2,2-dimethoxypropane (30 ml), and acetone (180 ml) was added the p a r t i a l l y unblocked r i b o s y l cyanide 135 (25.0 g). The r e s u l t i n g dark red s o l u t i o n was s t i r r e d at room temperature for 2 h. The reaction mixture was then neutralized (as indicated by litmus paper) with ammonium hydroxide and evaporated, leaving a residue which was dissolved i n chloroform (250 ml) and washed with water (2 x 25 ml). The organic layer was dried over anhydrous sodium s u l f a t e , evaporated and the crude yellow syrup c r y s t a l l i z e d from ether-hexane to 141a yield the isopropylidenated cyanide 136 (26.4 g, 91.6%) ( l i t . 95%); 141a m.p. 62° ( l i t . 60-61). 1,3-Diphenyl-2-(5-0-benzoy1-2,3-0-isopropylidene - B-g-ribofuranosyl) imidazolidine (138) 195 * To a suspension of Raney n i c k e l (100 g) ' , 1,1-dianilinoethane (27 g), and sodium hypophosphite (55 g) i n 212 ml of a mixture of pyridine, acetic acid and water (2:1:1) was added to the blocked r i b o s y l cyanide 136 (26.35 g) which r e s u l t e d i n a vigorous exothermic reaction with an evolution of vapors. The mixture was s t i r r e d vigorously for 1 h. The mixture was then f i l t e r e d * 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 caution must be exercised during the f i l t r a t i o n and washing. 143 and the residue washed thoroughly with chloroform. The combined f i l t r a t e s were d i l u t e d to a volume of 4.5 I with chloroform. This mixture was divided into 3 portions and each portion was washed with water (2 x 300 ml). The organic phase was dried over anhydrous sodium s u l f a t e , f i l t e r e d and evaporated 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 syrup that completely s o l i - d i f i e d under vacuo, over-night, at room temperature. The s o l i d mass was t r i t u r a t e d with methanol to y i e l d a yellow paste that was f i l t e r e d , washed with methanol and dried to y i e l d the blocked r i b o s y l imidazolidine 138 (32.5 g, 74.5%) ( l i t . 1 4 1 a 78%); m.p. 144.5-148 ( l i t . 1 4 l a 144-145). 196 Carbomethoxymethylenetriphenylphosphorane (17) To a s t i r r e d s o l u t i o n of triphenylphosphine (135 g, 0.51 mol) i n benzene (600 ml) was added dropwise methyl bromoacetate (76 g, 0.50 mol) over 30 min r e s u l t i n g i n a mildly exothermic reaction which p r e c i p i t a t e d the phosphonium bromide. The mixture was cooled i n the r e f r i g e r a t o r for 3h, f i l t e r e d and washed with a small portion of benzene. The f i l t r a t e was concentrated u n t i l c r y s t a l s appeared and allowed to cool overnight i n the r e f r i g e r a t o r . The second batch of the bromide was c o l l e c t e d and dried (combined y i e l d ; 182 g,85%). To a s t i r r e d s o l u t i o n of carbomethoxymethyltriphenylphorphonium bromide (182 g) i n water (4 I) was added slowly a IN aqueous sodium hydroxide s o l u t i o n u n t i l the reaction mixture was a l k a l i n e to phenolphthalein. The pink, milky s l u r r y was f i l t e r e d and washed with water to n e u t r a l i t y . The f i l t e r cake was then transferred i n small portions to a f l a s k containing s t i r r i n g methylene chloride (250 ml) and s u f f i c i e n t methylene chloride was added to permit complete d i s s o l u t i o n of the crude, wet phosphorane. The aqueous phase was withdrawn and the organic phase washed with water, dr i e d , evaporated and r e c r y s t a l l i z e d from ethyl acetate-petroleum ether (30-60) to y i e l d the 144 triphenylphosphorane 17 (128g,77%); m.p. 170.5-172 ( l i t . 1 9 6 a ' b 162-163°, 170-172° r e s p e c t i v e l y ) ; n.m.r. (60 MHz, CDC1 3); 62.74(s,lH,H-2), 3.43(s,3H,-0CH3) and 7.17-7.74(m,15H,AT). Methyl(E,^)-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-0-isopropylidene-D- allo-oct-2-enonate (18). To a s t i r r e d s o l u t i o n of the blocked r i b o s y l imidazolidine 138 (12.5 g, 25 mmol) and methylene ch l o r i d e (250 ml) i n an ice-water bath was added a sol u t i o n of p-toluenesulfonic acid monohydrate (13.0 g, 68.5 mmol) i n acetone over 10 min. The r e s u l t i n g mixture was s t i r r e d an a d d i t i o n a l 20 min. The mixture was then f i l t e r e d through c e l i t e d i r e c t l y onto s o l i d sodium hydrogen carbonate (5.0 g) and the residue washed with methylene c h l o r i d e . 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 clear syrup which produced a wide band on the t . l . c . plate (2:1 ether-hexanes as developer) with the absence of any s t a r t i n g compound. This syrup of the anhydroaldehyde 137 was immediately dissolved i n a s o l u t i o n of the phosphorane 17 (16.6 g) i n m e t h y l e n e c h l o r i d e (125 ml) and s t i r r e d for 1 h at room temperature. The mixture was evaporated and triphenylphosphine oxide s o l i d i f i e d i n the r e s u l t i n g syrup. The mixture was t r i t u r a t e d with a minimum of methylene chloride, f i l t e r e d , washed with methylene chloride and the f i l t r a t e s evaporated to y i e l d a golden syrup which was chromatographed on s i l i c a gel (500 g) using 2:1 ether-hexanes as developer. The major chromatographically pure band was c o l l e c t e d to 20 y i e l d the unsaturated ester 18 (7.45 g , 8 2 % ) ( l i t . 88%) as a c o l o r l e s s syrup that was shown to be mixture of geometric isomers by n.m.r. (^8:1) with the E-isomer predominating: v C C 1 4 1730(C=0), 1670 c m " 1 ( - C = C - ) ( l i t . 2 0 — max v f i l m 1 7 3 ( ) c m - l ) ; n # n u r e ( 1 0 0 MH2,CDC1_) 61.29 and 1.52(s,3H,C(CH,),), 3.62 max J - j J 145 (s,3H,-0Me), 6.11(dd,lH,J 2 3 16 Hz,J 2 4 1.5 Hz,H-2), 6.99(dd,1H,J 3 4.0 Hz, 20 H - 3 ) ( l i t . n.m.r. 61.38 and 1.60, C(CH 3) 2; 3.73, -OMe; 6.21, H-2; 7.10, J 3 ^ 3.5 Hz,H-3; r e s p e c t i v e l y ) . 4.2 Photoamidation of Unsaturated Sugars Photoamidation reactions were ca r r i e d out using a procedure previously described"^. The l i g h t source i n these reactions was a Hanova 450 W type L lamp. The photochemical reactions were ca r r i e d out by placing the lamp and a pyrex f i l t e r i n s i d e a water cooled quartz immersion well apparatus which was placed in s i d e a 3-necked pyrex v e s s e l containing the reaction solvents (capacity with lamp ^300 ml). The photolysis mixture was agitated v i a a magnetic s t i r r i n g bar and the whole apparatus wrapped i n aluminum f o i l . D i s t i l l e d tert-butanol, spectrograde acetone and reagent grade formamide were used. A l l photochemical reaction mixtures were deoxygenated with nitrogen overnight and during the course of the i r r a d i a t i o n s . Photoamidation of Methyl(E,Z)-4,7-anhydro-8-0-benzoyl-2,3-dideoxy- 5,6-0-isopropylidene-D-allo-oct-2-enonate (18) to Y i e l d 3-(R,S)-(5-0- Benzoyl-2,3-0-isopropylidene-B-p-ribofuranosyl)-4-hydroxy-4-methyl- pentanoic 1,4-lactone (139), Methyl 4,7-anhydro-8-0-benzoyl-3-C-carbamoyl- 2,3-dideoxy-5,6-0-isopropylidene-D-glycero-D-allo (and altro)-octonate (140), (141) and Methyl 4,7-anhydro-8-0-benzoyl-2-C-carbamoyl-2,3-dideoxy- 5,6-0-isopropylidene- n-glycero-D-allo (and altro)-octonate (142), (143), r e s p e c t i v e l y . A s o l u t i o n of the a, B-unsaturated ester 18_ (3.7 g), acetone (15 ml), tert-butanol (15 ml) and formamide (30 ml) was added slowly to a mixture of tert-butanol (10 ml) and formamide (200 ml) contained i n the photolysis c e l l over 3.5 h. The mixture was i r r a d i a t e d during the addition 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 material had been consumed, as evidenced by t . l . c . of the reaction mixture using 8:4:1 benzene-ethylacetate- ethanol as developer). The reaction mixture was then concentrated by removal of the tert-butanol and acetone under reduced pressure at ^50°. The r e s u l t i n g s o l u t i o n i n formamide was d i l u t e d with saturated aqueous sodium chloride (200 ml), extracted with dichloromethane (4 x 200 ml), the combined extracts concentrated to approximately 100 ml and the concentrated extracts were then washed with saturated aqueous sodium chloride (50 ml). The organic phase was c o l l e c t e d , d r i e d over anhydrous sodium s u l f a t e , f i l t e r e d and evaporated to y i e l d a crude syrup (3.9 g). Chromatography of t h i s syrup on s i l i c a gel (470 g) using 8:4:1 benzene-ethyl acetate-ethanol as developer gave crude lactone (139) as a clear syrup (1.46 g) which was contaminated with lower impurities. This mixture was l a t e r rechromatographed using a weaker solvent system. Continued e l u t i o n of the chromatography column gave, as a s i n g l e amide band, compounds 140, 141, 142 and 143 (combined y i e l d : 1.3 g, 31%). The amide band was shown to be a mixture of the four isomers by n.m.r. and by d e r i v a t i z a t i o n with sodium methoxide. The d e r i v a t i z a t i o n mixture indicated that photoamidation of compound 1_8̂  favors B-addition to ct-addition by an approximate r a t i o of 10:1 and that compounds 140 and 141 were formed i n equal amounts. Since the amides could not be separated by chromatography 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 , they were charactered as a mixture of four amides. An a n a l y t i c a l sample was obtained by c r y s t a l l i z a t i o n from chloro- form-hexane: m.p. 141-145° (fine neeldes); [ a ] 2 5 -29.5 ( c l . 0 , CHC1 3); vCCl4 3 1 3 3 3 A g 0 ( b r o a d m ) 1 6 9 0 (amide, C=0), 1727, 1738 cm"1 max > 2 ' ' shoulder (esters, C=0); n.m.r. (100 MHz, CDC13) 61.33 and 61.53(s,3H,C(CH 3) 2), 61.98-3.25(m,2.5H,H-2,H-3), 3.64 with 3.71 side band (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 s,2H t o t a l , N H 2 > exchange- able with D 20, 7.52(m,3H,Ar), 8.06(m,2H,Ar); mass spectrum: m/e 392 (m+- CH 3), 376(m +-OCH 3). Anal. Calc.for C„ nH 0 cN0 o:C,58.96;H,6.14;N,3.44. Found:C,58.76;H,6.14; N.3.50. Rechromatography of the high R̂  (with respect to the amides) components on s i l i c a gel using 40:8:1 to 5:4:1 benzene-ethyl acetate-ethanol gradient, yielded only one chromatographically homogeneous band, c o n s i s t i n g of the diastereomeric mixture of lactone 139 (0.45 g, 11%, ^50/50 mixture). The lactones were inseparable on t . l . c . and could not be c r y s t a l l i z e d from various solvents: [a] 2 3-23.4 ( c l . 4 , CHC1.) '; v C C 1 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 o o and 1.43(s,3H,4xCH_), 2.24(d(overlapping H-2b,lH,J 9 „ 9 Hz,H-2a), 2.25 (d(overlapping H-2a),lH,J 2 b 3 11 Hz,H-2b), 3.66(pseudo-t,1H,J 3 ^, and 2,6 Hz,H-l'), (isomer no.2), 61.14(s,6H,2xCH3),118 and 2.40(s,3H,2xCH 3), 2.38(d(overlapping H-2b),lH,J„ „ 8 Hz,H-2a), 2.39(d(overlapping H-2a),lH, Z3.9 j J „ v . 9 Hz,H-2b), 3.225(pseudo-t,lH,J 0 and J,„ 4.5 Hz,H-l'), (combined 2b,J j , l 1 i ^ isomers), 61.84-2.12(m,1H.H-3), 3.91-4.42(m,5H.H-2',H-3',H-4',H-5 ), 7.12 (broad s(overlapping C^D^), 5.3H,Ar), 8.10(m,2H,Ar). I r r a d i a t i o n of the m u l t i p l e t at 61.94 p a r t i a l l y collapsed the p a i r of pseudo-triplet at 63.64 to a broad t r i p l e t . I r r a d i a t i o n of the pair of pseudo-triplets at 63.64 collapsed the m u l t i p l e t a 61.94 to a broad quartet(J„ _ 8 to 12 Hz); mass spectrum m/e 390(m +), 375(m +-CH 3), 332(m +-Acetone). Anal. Calc. for C 2 1 H 2 o 0 7 : 0,64.60; H,6.72. Found: C.63.88; H.6.77. Attempted C y c l i z a t i o n of Compounds 140 and 141 by Refluxing i n Basic Solvent A mixture of the amides 140, 141, 142 and 143 (125 mg) was dissolved i n pyridine (6 ml) and refluxed (bath temperature: 135-145°) for 5h. T . l . c . 148 of the s o l u t i o n showed only one charring band i d e n t i c a l to that of the s t a r t i n g materials. Attempted C y c l i z a t i o n of Compounds 140 and 141 by Refluxing i n High B o i l i n g Point Solvent A mixture of the amides 140, 141, 142, and 143 (22 mg) was dissolved i n xylene (1 ml) and refluxed for 5h. T . l . c . of the s o l u t i o n showed only one charring band which was i d e n t i c a l to the s t a r t i n g amides. C y c l i z a t i o n of Compounds 140 and 141 by Thermal Ring Closure i n the Absence of a Solvent to give 3-(R) and (S)-(5-0-Benzoyl-2,3-0-isopropylidene- B-D-ribofuranosyl)succinimide (151) and (152), r e s p e c t i v e l y . A round bottom f l a s k containing a mixture of amides 140, 141, 142 and 143 (130 mg) equipped with two traps i n series joined together by standard- taper ground glass j o i n t s was placed i n a Kugelruhr vacuum d i s t i l l a t i o n apparatus. The reaction f l a s k along with the f i r s t trap was placed i n the heated compartment, the i n t e r n a l pressure was reduced (^100 t o r r ) , and the reaction f l a s k heated to 200-217° (surrounding a i r temperature) for 45 min while the f l a s k was gently rocked. After t h i s time the material i n the f l a s k had begun to char. The apparatus was allowed to cool and then the reaction f l a s k and c e n t r a l trap was rinsed out with methanol to give a brown suspension which was f i l t e r e d and evaporated to y i e l d a brown syrup (72 mg). The syrup was dissolved i n a small amount of methanol and applied to a column of Bio-Rex 70(H +) r e s i n (^90 ml) and eluted with methanol. The major higher R^ (0.42 using 15:4:1 benzene-ethyl acetate- ethanol as developer) material was i s o l a t e d (26 mg) and rechromatographed on a s i l i c a gel plate (15x20 cm, 1.0 mm, x2 with 18:4:1 mixture of the above solvents) to y i e l d two p a r t i a l l y overlapping bands. Careful removal and e l u t i o n of the faster-moving component gave compound 151 as a 149 clear syrup (7.0 mg,6%,>95% p u r i t y ) ; n.mr. (100 MHz,CDCl3) 61.38 and 1.57(s,3H,C(CH 0)„), 2.71(dd(overlapped by H-4b),lH,J 18.0 Hz,J, . 8.0 Hz, — j l gem Jj^ta H-4a), 2.93(dd(overlapped by H-4a),IH,J g e m 18.0 Hz,J 3 4 b 8.0 Hz,H-4b), 3.26 (m,lH,J . 2.5 Hz,H-3), 4.14-4.33(m,2H.H-1',H-4'), 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,^. ^ 4.0 Hz, H-2'), 7.55(m,3H,Ar), 7.90(broad s,lH,NH), 8.09(m,2H,Ar). I r r a d i a t i o n of the doublet of doublets at 65.25 or the mul t i p l e t at 63.26 p a r t i a l l y collapsed the high f i e l d portion of the mul t i p l e t at 64.14-4.33. The 100 MHz spectrum with benzene-d, solvent confirmed the assignment order as: H-l',H-4',H-5', o H-3' and H-2' from high- to l o w - f i e l d . Removal and extraction of the slower-moving component from the plate afforded the epimeric 3-J3 compound 152 (8.5 mg,7%,>90% with compound 151 as the main impurity), n.m.r. (100 MHz, CDC13) 61.37 and 1. 58 (s ,3H,C (CH_3) ̂ ) , 2.73(d,2H,J 7.0 Hz,H-4), 3.19(m,1H.H-3), 4.32(pseudo-q(partially over- lapped by H-1'),1H,J . 4.0 Hz, J . 4.0 Hz,H-4'), 4.38(dd(partially overlapped by H-4'),1H,J . 3.8 Hz,J . . 5.3 Hz,H-l'), 4.51(d,2H,H-5'), 4.54 (dd ( p a r t i a l l y overlapped by H-5'),1H,J ; L. ^ 5.3Hz,J 2. ^ 6.5 Hz,H-2'), 4.72(dd,lH,H-3'), 7.56(m,3H,Ar), 8.05(m,2H,Ar), 8.20(broad s ( p a r t i a l l y buried under the l o w - f i e l d aromatic resonances),1H,NH). I r r a d i a t i o n of the m u l t i p l e t at 63.19 p a r t i a l l y collapsed the doublet of doublet at 64.38 to a doublet (J-, - 9 ^ 5.3Hz) overlapping two of the l o w - f i e l d signals of the H-4' pseudo-quartet. The higher R̂  minor component eluted by the r e s i n column was, therefore, not analyzed and a small portion (33 mg,25%) of s t a r t i n g material was recovered. 150 Treatment of a Mixture of the Amides 140, 141, 142, and 143 with Methanolic Sodium Methoxide to Y i e l d (151), (152), 3(s) and (R)-(2 >3-0-isopropylidene- 6-D-ribofuranosyl)succinimide[(S) and (R)-dihydroshowdomycin acetonide], (153), (154), and Methyl 4,7-anhydro-2-C-carbamoyl-2,3-dideoxy-5,6-0- isopropylidene-D-glycero-D-allo (and D-altro)-octonate (155) and (156), resp. To a s t i r r e d s o l u t i o n of the amides 140, 141, 142, and 143 (330 mg, ^45:45:5:5 mixture, resp.) i n anhydrous methanol (33 ml) was added methanolic sodium methoxide (2.0 ml,0.2N) i n 0.2 ml portions over 2.5 h at room tempera- ture under dry nitrogen atmosphere. The reaction mixture was then neutralized with s u f f i c i e n t Bio Rex 70(H +) r e s i n (in methanol) as indicated by pH paper. The mixture was f i l t e r e d and the methanol evaporated under reduced pressure to y i e l d a crude syrup (400 mg) which released the sweet odor of an ester (e.g. methyl benzoate). Preliminary p u r i f i c a t i o n of the syrup on s i l i c a gel (35 g) using a 15:4:1 to 5:4:1 benzene-ethyl acetate-ethanol gradient as developer yielded the blocked r i b o s y l succinimides 151 and 152 (168 mg, 55%) as p a r t i a l l y resolved (by t . l . c . using 15:4:1 developer) f r a c t i o n s which by n.m.r. were shown to be i d e n t i c a l to the succinimides produced by the thermal r i n g closure of the s t a r t i n g amides (see page 148). Continued e l u t i o n of the chromatography column gave a mixture of imides 153 and 154 (86 mg,28%)(which were l a t e r rechromatographed) and a f i n a l band of the debenzoylated, ct-addition amides 155 and 156 (21.5 mg,9%). Very c a r e f u l chromatography of the mixture of acetonides 153 and 154 i n small portions (^30 mg) on s i l i c a gel (6.0 g) using 8:4:1 benzene-ethyl acetate-ethanol as developer afforded a s l i g h t l y higher R^ (0.329) pink charring band which could be induced to c r y s t a l l i z e r a p i d l y i n a chloroform s o l u t i o n to y i e l d a 1:1 complex with the solvent (chloroform): m.p. 77.5- 80.5*(neeldes). 151 Anal. Calc. for 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 higher band from hexane-benzene- ethanol yielded c r y s t a l s of 153 which were free of solvent; m.p.123-125° ( l i t . 1 1 8 a 173-174°); [ a ] " -9.27°(cl.O.CHCl,); v C H C 1 3 3475,3410(NH), ' D — 3 max 3225(broad,OH),1725,1780 cm"1 weak shoulder (amide carbonyl); n.m.r. (100 MHz,DMS0-d,) 61.29 and 1.47(s,3H,C(CH,) n), 2.63(d,2H,J. . 7.0 Hz,H-4), o —J l J , k 3.16(t of d.lH.J, . 7.0 Hz,J. 3.5 Hz,H-3), 3.49(dd,2H,J. „ 4.0Hz,J 3,4 3,1 k , D Un, J 5.0Hz, collapses to a doublet of 4.0Hz upon addition of D 20,H-5'), 3.87 (pseudo-q.lH.J^ 5 > 4.0 H z . J ^ ^, 4.0Hz,H-3'), 4.14(dd,IH,J 3 ^ 3.5Hz, J 1> 2 , 5.0Hz,H-l'), 4.46(dd,lH,J 1. ^ 5.0Hz,J 2^ ^ 6.5Hz,H-2'), 4.61(dd, 1H,J.. 6.5Hz,J_. ., 4.0Hz,H-3'), 4.87(t,IH,J „ 5.0Hz,OH,exchangeable z , J 3 ,A On,J — with D 20) , 11.13(broad s,1H,NH,exchangeable with D^O). I r r a d i a t i o n of the pseudo-quartet at 63.87 p a r t i a l l y coallpsed the doublet of doublets of 64.61 to a broad doublet and collapsed the doublet of doublets at 63.49 to a doublet. I r r a d i a t i o n of the t r i p l e t of doublets at 63.16 collapsed the' doublet of doublets at 64.14 to a doublet and collapsed the doublet at 62.63 to a broad s i n g l e t m/e 272(m++H), 256(m +-CH 3), 240(m +-0CH 3). Anal. Calc. for C, _H,,N0,:C,53.13;H,6.32;N,5.16. Found:C,53.00; H,6.38;N,5.10. Continued e l u t i o n of the acetonide mixture yielded the 3-R-diastereomer (154) as a clear syrup which was c r y s t a l l i z e d i n methanol: m.p. 159.5-161° (granular); [a]£ 5 -35.3° (c0.5,CH3OH), v ^ L 3 3500(broad), 3420 (sharp ,NH) , 3250(broad, OH), 1725, 1785 cm"1 weak shoulder (imide carbonyls); n.m.r. (100 MHz,DMS0-d6) 61.30 and 1.46(s,3H,C(CH.j)2>, 2.45(dd(partially obscured by DMSO),IH,J g e m 18.0Hz,J o . 5.0Hz,H-4a), 2.82(dd,lH,J 18.0Hz,J, 9.0Hz,H-4b), 3.24 3,4a gem 3,4b (m,lH,J 3 4 b 9.0Hz,J 3 4 a 5.0Hz,J 3 ^ 4.0Hz,H-3), 3.42 (d,2H,J 4, 5.5.0Hz,H-5'), 152 3.83(pseudo-q,lH,J 4. ^ 5.0Hz,J 3. ^ 4.5Hz,H-4'), A.05(pseudo-t,1H, 2 * A.5Hz,J 3 ^ 4.0Hz,H-l'), 4.51(dd,lH,J 2* y 6.5Hz,J 3. ^ A.5Hz,H-3'), A.90(dd,lH,J 2, 3 , b.bViZ,!^ ^ 4.5Hz,H-2'), 11.15(broad s,1H,NH,exchangeable with D 20). I r r a d i a t i o n of the pseudo-quartet at 63.83 collapsed the doublet of doublets at 6A.51 to a d o u b l e t ( J 2 ^ 3 ^ 6.5Hz) while the doublet at 63.A2 collapsed to a broad s i n g l e t . I r r a d i a t i o n of the doublet of doublets at 6A.90 collapsed the pseudo-triplet at 64.05 to a broad doublet while the collapse of the doublet of doublets at 64.51 to a s i n g l e t appear anomolous due to i t s proximity to the i r r a d i a t i o n frequency. I r r a d i a t i o n of the pseudo-triplet at 64.05 collapsed the doublet of doublets at 64.90 to a doublet (J 9> ~, 7.0Hz) while the m u l t i p l e t at 63.24 collapsed to a doublet of doublets (J- . 5.0Hz and J„ ,, 9.0Hz); mass spectrum; m/e 272 (m++H), 256(m +-CH 3), 2A0(m+-OCH3). Anal. Calc. for 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 and 156 f a i l e d to separate the two diastereomers nor could they be c r y s t a l l e d from various solvents:n.m.r. (mixture, 100MHz,CDC13) 61.34 and 1.52(s,3H,C(CH 3) 2), 2.20(broad band without 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 3), 4.02(m,2H.H-A.H-7), 4.40(dd,1H.H-5 or H-6) A.68(m,lH,H-5 or H-6), 6.40 and 6.80(broad s,lH,NH 2); [a]^ 3-16 (£1.3, CHC1 3); v m C 1 3 3500, 3360 (N-H) , 1725 (-CO.Me) , 1680 (-CONH.) , 1580 cm"1 (N-H) ; max 2 2 mass spectrum; m/e 304 (m++H), 288 (m+-Me), 272 (m +-0CH 3). Debenzoylation of Compounds 151 and 152 to give compounds 154 and 153.resp. To a s t i r r e d s o l u t i o n of a mixture (^50/50) of the blocked succinimides 151 and 152 (100 mg) i n anhydrous methanol (10 ml) was added methanolic sodium methoxide (1.0 ml,0.2N) i n 0.2 ml portions over 1.5h at room temperature under dry nitrogen atmosphere. T . l . c . of the reaction mixture using 8:4:1 153 benzene-ethyl acetate-ethanol as developer showed complete consumption of s t a r t i n g materials and two overlapping lower (0.33 and 0.31) bands i d e n t i c a l to that of compounds 153 and 154. After n e u t r a l i z a t i o n of the r e a c t i o n mixture with Bio-Rex 70(H +) r e s i n , f i l t r a t i o n , and evaporation of the methanol, the crude syrup (109 mg) was chromatographed i n small portions (^30 mg) on s i l i c a gel (6.0 g) using 8:4:1 benzene-ethyl acetate- ethanol as developer to achieve r e s u l t s described previously. Thus, compounds 153 and 154 obtained from 151 and 152 were i d e n t i c a l (by n.m.r.) to those of 153 and 154 obtained from t r e a t i n g the amide mixture, from the photoamidation of 18_, with sodium methoxide. Attempted Dehydrogenation of Succinimide with Palladium. A mixture of succinimide (28 mg), biphenyl (11 g) and 10% palladium on charcoal (102 mg) was heated u n t i l r e f l u x (^270° external temperature). A slow stream of dry carbon dioxide gas was passed through the r e f l u x i n g mixture which was heated for 25 h. The reaction mixture was then allowed to cool (^100°C) and was extracted with hot water (2x12 mis). The combined extracts were f i l t e r e d and evaporated to y i e l d a c r y s t a l l i n e residue (28 mg) the n.m.r. of t h i s product was i d e n t i c a l to that of the s t a r t i n g succinimide. Preparation of Nickel Peroxide Following the procedure of Nakagawa, Konaka and Nakata 1^ 1, a s o l u t i o n of sodium hydroxide (42 g) i n 5.3% aqueous sodium hypochlorite (300 ml) was added dropwise to a mechanically s t i r r e d s o l u t i o n of n i c k e l sulfate-hexahydrate (130 g) i n water (300 ml). The addition was completed i n 10 min and the mixture was s t i r r e d f o r an a d d i t i o n a l 30 min at room temperature. Attempts to f i l t e r and wash the fin e n i c k e l peroxide suspension f a i l e d due to clogging of the f i l t r a t i o n apparatus ( i . e . , Whatman no.l f i l t e r paper and sintered g l a s s ) . A portion of the suspension was removed, transfered to centrifuge 154 bottles (200 ml c a p a c i t y / b o t t l e ) , centrifuged, the supernatant removed, fresh d i s t i l l e d water added (^150 ml suspension), and recentrifuged. This process was continued u n t i l part of the suspension f a i l e d to separate i n d i c a t i n g the removal of the excess base. The supernatant was discarded and the residue was f i l t e r e d , dried under vacuo, and crushed to a powder. The a c t i v i t y of the n i c k e l peroxide was determined iodometrically _3 to be: 1.7 x 10 g-atom oxygen/g n i c k e l peroxide. Attempted Dehydrogenation of the Ribosyl Succinimides using Nickel Peroxide. A s o l u t i o n of the blocked r i b o s y l succinimides 151 and 152 (42 mg, 0.11 mmol) i n xylene (2 ml) was added to n i c k e l peroxide (200 mg, ^3 equiv., _3 a c t i v i t y : 1.7 x 10 equiv/g Ni02). The mixture was refluxed for 60 h a f t e r which the reaction mixture was allowed to s e t t l e , the supernatent s o l u t i o n removed and f i l t e r e d through c e l i t e . Evaporation of the solvent under reduced pressure resulted i n a pale green syrup (220 mg) which produced four wide bands and baseline material on t . l . c . with various developers. Attempts to i s o l a t e the carbohydrate product from t h i s mixture were not considered. Similar treatment of compounds 153 and 154 i n r e f l u x i n g benzene for 26 h did not give any products of d i f f e r e n t R̂  nor did the charring bands absorb U.V. l i g h t . Treatment of compounds 153 and 154 at room temperature with n i c k e l peroxide (50 equiv.) for 7 days using water as the solvent f a i l e d to produce any U.V. a c t i v e charring bands. Attempted Dehydrogenation of Compounds 153 and 154 with Dicyanodichloro- quinone (DDQ). A s o l u t i o n of a 60:40 mixture of the r i b o s y l succinimides 153 and 154 (20 mg) and dicyanodichloroquinone i n dioxan (1.5 ml) was refluxed for 155 3 days. The mixtures was cooled, f i l t e r e d and the off-white s o l i d s (25 mg) washed with dioxan (2.0 ml). The combined f i l t r a t e s were then evaporated to give a crude syrup (43 mg) which on t . l . c . showed two broad U.V. a c t i v e bands (9:1 ethyl acetate-ethanol developer). The higher (0.23-0.36) U.V. a c t i v e band also overlapped a charring band (R^ 0.27). Chromatography of the syrup on s i l i c a gel (5.0 g) using 9:1 ethylacetate- ethanol as developer yielded the charring band as a clear syrup (12.5 g) which did not absorb U.V. l i g h t . Further analysis of t h i s band, therefore, was not attempted. Attempted Synthesis of (R,S)-3-Bromo-3-(5'-0-benzoyl-2',3'-0-isopropylidene- g-D-ribofuranosyl)succinimide (169). A mixture of the blocked r i b o s y l succinimides 151 and 152 (85 mg, 0.23 mmol), N-bromosuccinimide (50 mg, 0.29 mmol), and benzoyl peroxide (5 mg) i n 5 ml anhydrous carbon t e t r a c h l o r i d e was refluxed under anhydrous conditions. After r e f l u x for a few minutes, most of the s o l i d material had gone into s o l u t i o n . After 17 min of reflux,an o i l began to separate from the reaction mixture. The mixture was refluxed an a d d i t i o n a l 15 min a f t e r which i t was cooled, d i l u t e d with chloroform (6 ml), washed with 5% aqueous sodium hydrogen carbonate, and dried over anhydrous sodium s u l f a t e . Evaporation of the solvents under reduced pressure and chromatography of the r e s i d u a l syrup on a t . l . c . plate using 20:4:1 benzene-ethylacetate-ethanol as developer (developed twice) gave a five-component mixture. I s o l a t i o n of the major band (R^ 0.43) gave a c l e a r syrup (11 mg) which by n.m.r. showed a mixture of compounds which s t i l l retained H-3 of the succinimide r i n g . Further analyses of t h i s band and the other minor components were not pursued. 156 3- (S)-(3-D-ribofuranosyl)succinimide (170), from Compound 153. A s o l u t i o n of acetonide 153 (124 mg) i n 3:1 t r i f l u o r o a c e t i c a c i d - methanol (4.0 ml) was s t i r r e d for 45 min at room temperature. After evaporation of the solvents under reduced pressure, the r e s i d u a l syrup was chromatographed on a column of Bio-Rex 70(H +) r e s i n which was developed with water to y i e l d (S_)-dihydroshowdomycin 170 as a clear syrup (96 mg, 91%). An a n a l y t i c sample was obtained by c r y s t a l l i z a t i o n from benzene- acetone; m.p. 136-140° ( l e a f l e t s ) ; [ a ] 2 3 -10.2° (c3.4,H 20); n.m.r. (100 MHz, DMS0-d6) 62.48(dd ( p a r t i a l l y obscured by DMSO), l H > J g e m 17.5Hz,J 3 ^ 9.0Hz, H-4a), 2.72(dd,lH,J 17.5Hz,J_ 5.0Hz,H-4b), 3.06(m,1H,H-3),3.43(d,2H, gem 3, 4b 5 . 4.0Hz,H-5'), 3.60(dd ( p a r t i a l l y obscured by H-4') . l H . J ^ ^ 8.0Hz, J 2 . 3 . 5.5Hz,H-2'), 3.70(m,lH,H-4'), 3 . 8 3 ( d d , 1 H , y 5.5Hz,J 3^ ^ 3.0Hz, H-3'); 4.06(dd,lH,J 2.0Hz,J , _ 8.0Hz,H-l'), 4.54(broad s,3H,3xOH, j , J. J. , z exchangeable with D 20), 11.0(broad s,lH,NH, exchangeable with D 20). I r r a d i a t i o n of the doublet of doublets at 64.06 collapsed the doublet of doublet at 63.60 to a doublet ~* 5.5Hz) while the m u l t i p l e t at z , j 63.06 collapsed to a doublet of doublets (J„ . 9.0Hz and J n ., 5.0Hz). 3,4a 3,4b I r r a d i a t i o n of the mu l t i p l e t at 63.06 collapsed the doublet of doublets at 64.06 to a doublet (J^ ^ 8.0Hz): n.m.r. (100MHz,D20-D3CCO2D) 64.13 (dd,lH,J 3 ^ 2.5Hz,J 1 > 2,7.0Hz,H-l'), ( l i t . n.m.r. (60MHz,D20-D3CCO2D, i n t e r n a l D.S.S. standard) 64.50(J. 2.5Hz)); mass spectrum:m/e 232(m++H), » - t 213(m +-H 20), 200(m+-CH2OH). Anal. Calc. for CgH13N06:C,46.75;H,5.67;N,6.06. Found: C,47.21; H,5.76;N,6.06. 3-(R)-(g-D-ribofuranosyl)succinimide (171) from Compound 154. A s o l u t i o n of acetonide 154 (98 mg) i n 3:1 t r i f l u o r o a c t i c acid-methanol (4.0 ml) was s t i r r e d for 45 min. at room temperature. Af t e r evaporation of 157 the solvents under reduced pressure, 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 eluted with water to y i e l d (R)- dihydroshowdomycin (171) as a clear syrup (72.5 mg, 87%). The syrup f a i l e d 25 to c r y s t a l l i z e from a v a r i e t y of solvents: [a]^ -16.6° (c3.4,1^0), n.m.r. (270 and 400MHz,Do0) 62.72(dd,lH,J 19.0Hz,J o . 4.3Hz,H-4a), 3.00(dd, 2 gem 3,4a ' 1H,J 19.0Hz,J o ., 9.4Hz,H-4b), 3.33(m,lH,H-3), 3.54(dd,lH,J 12.3Hz, gem 3,4b ' gem ' J . . c , 5.6Hz,H-5'a),3.69(dd,IH,J 12.3Hz,J., 3.6Hz,H-5'b), 3.87 4 , 5 a gem 4 , 5 b (m,lH,H-4'),4.00(pseudo-t,lH,J 2. ^ 6.0Hz,J 3^ ^ 4.8Hz,H-3'), 4.05(q,lH, J 3 ^ 4.4Hz,J 1 > 2 . 6 . 2 H z , H - l ' ) , 4 . 3 0 ( p s e u d o - t , l H , ^ 3.0Hz,J 2. ^ 3.0Hz, H-2'). I r r a d i a t i o n of the multiplet at 63.33 collapsed the doublet of doublets at 64.05 to a doublet(J , 6.4Hz) while the doublet of doublets 1 » J at 62.72 and 63.00 collapsed to two doublets with J . 19Hz. 4a, 4b 5. 3-(S)-a-Dihydroshowdomycin Acetonide Photoamidation of Methyl(E,Z)-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6- 0-isopropylidene-D-ribo-oct-3-enonate (172) to y i e l d Diastereomers 140, 141, Methyl 4,7-anhydro-8-0-benzoyl-3-C-carbamoyl-2,3-dideoxy-5,6-0-isopropylidene- D-glycero-D-gluco (and manno)-octonate (173), (174), r e s p e c t i v e l y . A s o l u t i o n of the enol ether 172 (6.0 g), acetone (15 ml), tert-butanol (15 ml) and formamide (30 ml) was added over 3h to a mixture of tert-butanol (10 ml) and formamide (200 ml) contained i n a photolysis c e l l . The mixture was i r r a d i a t e d during the addition and continued for 4 days (or u n t i l a l l of the s t a r t i n g material had been consumed, as evidenced by t . l . c . of the reaction mixture using 8:4:1 benzene-ethylacetate-ethanol as developer). The reaction mixture was then concentrated by removal of the tert-butanol and acetone under 158 reduced pressure at ^55°. The r e s u l t i n g s o l u t i o n i n formamide was d i l u t e d with saturated aqueous sodium chloride (200 ml), extracted with d i c h l o r o - methane (4x200 ml), the combined extracts concentrated to approximately 100 ml and the concentrated so l u t i o n then washed with saturated aqueous sodium c h l o r i d e (50 ml). The organic phase was c o l l e c t e d , dried over anhydrous sodium s u l f a t e , f i l t e r e d and evaporated to y i e l d a crude syrup which was chromatographed on s i l i c a gel (465 g) using 9:1 benzene-ethanol as developer. I s o l a t i o n of the band corresponding to the amides previously synthesized (see photoamidation of compd. 18) gave a clear syrup (1.5 g, 22%). The amide band was shown to be a mixture of the diastereomeric amides 140, 141, 173 and 173 by n.m.r. and by conversion of the amides to c y c l i c imides. An analysis of the n.m.r. spectra of the above imides indicated an approximately 2:1 r a t i o of the a to 8-anomers of the amides. An a n a l y t i c a l sample of a mixture of the amides was obtained by c r y s t a l l i z a t i o n from 23 chloroform-hexane; m.p. 180-185° (amorphous s o l i d ) ; [ a ] Q + 3.6° (cl.O, CHC1„); v C H C 1 3 3410, 3515(N-H), 1722(ester carbonyls), 1685(amide carbonyl), j in 3.x 1596 cm _ 1(amide I I band); n.m.r.(100MHz,CDC13) 51.34 and 1.54(s,3H,C(CH 3) 2), 2.41-3.44(m,3H,H-2,H-3), 3.65(s,3H,-OCH3), 4.05-4.85(m,6H.H-4 to H-8), 5.97, 6.19,6.49(broad overlapping s i n g l e t s , approx.2H,NH 2), 7.54(m,3H,Ar), 8.05(m, 2H,Ar); mass spectrum: m/e 392(m +-CH 3), 376(m+-OCH3). Anal. Calc. f o r C2QH25NOg:C,58.96;H,6.19;N,3.44. Found:C,58.60; H,6.05;N,3.39. used i n the extended sense 159 Treatment of a Mixture of the Amides 140, 141, 173, and 174 with Methanolic Sodium Methoxide to y i e l d 151, 152, 153, 154, 3-(R) and (S)-(2,3-0-Isopropy- lidene-a-D-ribofuranosyl)succinimide (175),(176), Methyl 4,7-anhydro-3-C- carbamoyl-2,3-dideoxy-5,6-0-isopropylidene-D-glycero-D-gluco-octonate (177), re s p e c t i v e l y . To a s t i r r e d s o l u t i o n of amides 140, 141, 173, and 174 (400 mg) i n anhydrous methanol (15 ml) was added methanolic sodium methoxide (0.4 ml, 0.2N). The mixture was allowed to s t i r at room temperature under dry nitrogen atmosphere for 8h a f t e r which time t . l . c . of the reaction mixture (9:5:1 benzene-ethylacetate-ethanol as developer) indicated the presence of the s t a r t i n g compounds (R^ 0.28) and higher and lower R^ materials. An a d d i t i o n a l 0.1 ml of the methanolic sodium methoxide s o l u t i o n was added and the mixture was allowed to s t i r overnight (14h). T . l . c . analysis of the reaction mixture showed l i t t l e change so that the reaction was terminated by n e u t r a l i z a t i o n of the s o l u t i o n with Bio-Rex 70(H +) r e s i n (as indicated by pH paper). The mixture was f i l t e r e d , evaporated and the r e s i d u a l syrup p a r t i t i o n e d between chloroform-water (25:25, V/V) to separate the water soluble components (195 mg, crude syrup) from the organic solvent soluble components (240 mg, crude syrup). The syrup from the chloroform soluble layer was dissolved i n a small quantity of methanol, applied to a column (23 x 2.6 cm) of Bio-Rex 70(H +) r e s i n and eluted with methanol. The slower-moving c o l o r l e s s component was i s o l a t e d and the solvent 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 syrup (185 mg). T . l . c . of t h i s syrupy mixture using 1:1 benzene-ethylacetate as developer indicated two bands, a major broad band (R^ 0.32-0.43) and a lower R^ (0.13) minor narrow band corresponding to the s t a r t i n g amides. Column chromatography on s i l i c a gel (15 g) of the syrup using a 2:1 to 1:1 160 benzene-ethyl acetate gradient afforded mainly the blocked r i b o s y l succimides 151 and 152 (^60% of i s o l a t e d material) plus other minor components (^40%)(total: 124 g, 34% based on 151 and 152) as p a r t i a l l y resolved f r a c t i o n s as indicated by t h e i r n.m.r. spectra. The head and t a i l of t h i s broad band corresponded mainly to the '8' r i b o s y l succinimides 151 and 152, re s p e c t i v e l y , previously i s o l a t e d while the ce n t r a l portion of the band corresponded to a mixture of the above and other u n i d e n t i f i e d materials. Further p u r i f i c a t i o n or ch a r a c t e r i z a t i o n of these mixtures was not attempted. The syrup from the water soluble portion of the reaction mixture was dissolved i n a small quantity of water, applied to a column (33.0 x 3.5 cm) of Bio-Rex 70(H +) r e s i n and eluted with water to y i e l d 3 major bands. T . l . c . of the faster-moving band on s i l i c a gel using 5:4:1 benzene-ethyl acetate- ethanol as developer indicated two major bands, a broad higher R^ (0.33) band charring pink on the faster-moving portion of the band and a narrower low R^ (0.24) band which charred more uniformly. The f i r s t band (85 mg) eluted from the r e s i n column was therefore rechromatographed on s i l i c a g el (5 g) i n two portions using 5:4:1 benzene- eth y l acetate-ethanol as developer. A portion of the faster-moving, pink- charring band was i s o l a t e d pure (5.0 mg, 2%) and was found to be i d e n t i c a l , by n.m.r. spectroscopy and by the melting point of the 1:1 c r y s t a l l i n e complex with chloroform, to the 3-S-(8-ribosyl)succinimide 153 previously synthesized. Continued e l u t i o n of the column gave a portion (21 mg, 7.5%) of the higher R^ band which was free of the pink charring material. The n.m.r. spectrum of t h i s f r a c t i o n indicated the presence of two compounds the major component (^2:1) being the a-3-(R)-ribosylsuccinimide acetonide 175 and the minor com- ponent being the previously synthesized lower R̂ . 6-3-R-isomer 154. The 161 pure a-anomer could not be obtained by chromatography nor by c r y s t a l l i - zation', therefore, the o p t i c a l r o t a t i o n of the 2:1 mixture of the a/8 25 i s reported along with a tentative n.m.r. assignment: + 8.04° (c2.0,MeOH); n.m.r. (100MHz,CDC13> 61.30 and 1.47(s,3H,C(CH 3) 2), 2.70 (dd,lH,J 19.0Hz,J_ . 10.0Hz,H-4a), 2.86(dd,lH,J 19.0Hz,J, ., gem '3,4a gem '3,4b 5.0Hz,H-4b), 3.17(m,lH,H-3), 3 . 6 0 ( d , 2 H , ^ 4.5Hz,H-5'), 2.07(broad s, approx. 1H,0H), 4.14(t,lH,J , 4.5Hz,H-4'), 4.56(dd,lH,J , 2.0Hz, 2 , 3.5Hz,H-l'), 4.70(d,lH,J 2, 6.0Hz), 4.75(dd ,1H, ^ 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- succinimide acetonide 176 (32 mg,12%) as pure diastereomer e a s i l y separable from the other three and c r y s t a l l i z e d i n chloroform: m.p. 141.5-144.5*", [ a ] J 5 -1.0° (c0.5,MeOH); n.m.r. (100MHz,CDC13) 61.22 and 1.41(s,3H,C(CH 3) 2), 2.16(broad s,lH,0H, exchangeable with D o0), 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 (broad d,2H,J 4^ ^ 4.0Hz,H-5'), 4.22(broad t , l H , J 4 ^ ^ 4.0Hz,H-4'), 4.40(dd, 1H,J 3 1 ^ S.OHz.H.^ 2 . 3.8Hz,H-l'), 4. 65 (dd, IH, J ̂  y 6.0Hz,J 3^ ^ 1.0Hz, H-3'), 4.76(dd,lH,J , , 6.0Hz,J 3.8Hz,H-2'), 8.28(broad s,lH,NH, D 20-exchangeable); mass spectrum; m/e 272(m++H), 256(m +-CH 3), 240(m+-HOCH2). Anal. Calc. f o r C, 0H, -.NO,:C,53 .13;H,6.32;N,5.16. Found:C,53. 35; i z 1/ b H,6.38;N,5.17. The f i n a l slower moving bands of the water soluble components was found to be minor component. Rechromatography of t h i s component (33 mg) on s i l i c a gel (.5.0 g) using 5:4:1 benzene-ethyl acetate-ethanol yielded only one chromatographically and stereochemically pure band of the debenzoylated, a-3-(S)-amide 177 (17 mg, 6%); m.p. 161-163°; [ a ] ^ 5 + 16.1° (cl.5,CHC1 3); 162 v C H C l 3 3 5 0 0 3 4 1 0 (broad,NH,OH), 1732 (ester carbonyl) 1678 (amide max carbonyl), 1593 cm"1 (amide II band); n.m.r. (100 MHz,D20) 61.38 and 1.53(s,3H,C(CH 3) 2), 2.69(d,2H,J 2 3 7.5Hz,H-2), 3.14(m,1H.H-3) 3.60(d, 2H,J ? g 6.0Hz,H-8), 3. 70 (s, 3H,-OCH_3), 4.13 (dd (overlapped by H-7),1H,J 3 4 lO.OHz.J, c 3.5Hz,H-4), 4.16(t(overlapped by H-4),1H,J, „ 6.0Hz,H-7), 4,3 / ,o 4.82(d,lH,J c , 6.0Hz,H-6), 4.95(dd,lH,J, c 3.5Hz,J c , 6.0Hz,H-5); mass 5,0 4 , J 3,b spectrum: m/e 304(m++H), 288(m +-CH 3), 272(m+-OCH3/HOCH2). Anal. Calc. for C 1 3H 2 1NO ?: C.51.48; H,6.98;N,4.62. Found: C.51.01; H,7.00;N,4.58. 6. Unsaturated, Azido, Diazo and Amino Sugars Treatment of Compound 18 with Sodium Azide 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 (172) and Methyl (E)-4,7-anhydro-8-0-benzoyl-2,3,5-trideoxy-D-erythro-oct-2,4- dienonate (178). A mixture of the methyl oct-2-enonate 1_8̂  (88 mg) and sodium azide (89 mg) i n anhydrous DMF (4.5 ml) was sealed (rubber septum) i n a f l a s k under dry nitrogen atmosphere and s t i r r e d for 45h at 50-55°. Af t e r increasing the temperature to 60-65°, the reaction mixture was s t i r r e d for an a d d i t i o n a l 48h. The mixture was then evaporated under vacuo to remove the v o l a t i l e components. The residue was dissolved i n a mixture of 1:1 dichloromethane and saturated aqueous sodium chl o r i d e (10 ml). The organic layer was separated and the aqueous suspension extracted twice with d i c h l o r o - methane (2x5 ml). The combined organic extracts were dried over anhydrous sodium s u l f a t e , f i l t e r e d and evaporated, leaving a crude syrup which was chromatographed on s i l i c a gel (10 g) using 2:1 ether-hexanes as developer. The faster-moving component, compound 172, was i s o l a t e d as a clear syrup (18 mg, 20.5%) and was found to be a 9:1 mixture of the Z. and E_ 25 C'1• isomers, r e s p e c t i v e l y , from n.m.r.; [ct] D - 156.3 (c 0.95,CHCl3); v max 163 1743, 1733 (methyl ester and benzoate carbonyls, resp.) and 1710 cm shoulder (C=C) ; n.m.r. (100MHz,CDC13) 61.33 and 1. 46(s ,3H,C(CH_3) 2 ) , 3.02(dd,lH,J 18.0Hz,J o . 7.0Hz,H-2a), 3.22(dd,1H,J 7.0Hz,H-2b), gem 2a,3 zb,3 3.53(s,3H,-OCH_), 4.37(d,2H,J 7 B 4Hz,H-8), 4.59-4.71(m,2H,H-7,H-6), 4.82 J 1,0 (pseudo-t,lH,J„ . and J o u . 7.0Hz,H-3), 5.03 (broad-d,lH,J. , 5.5Hz,H-5), za, 3 zb,3 3,o 7.46(m,3H,Ar), 7.95(m,2H,Ar). I r r a d i a t i o n of the two doublet of doublets at 63.02 and 3.22 collapsed the pseudo-triplet at 64.82 to a s i n g l e t . (A 270 MHz n.m.r. spectrum of 172 confirmed these assignments) C-13 n.m.r. (20 MHz, CDC13, proton decoupled) 625.73 and 26.92 (C(CH 3) 2>, 30.73(C-2),51.60 (-0CH3), 64.79(C-8), 79.85, 8.53(C-6 and C-7), 83.79(C-5), 94.71(C-3), 113.23 (C(CH 3) 2), 128.53,129.67,130.94,133.31(Ar), 156.55(C-4), 166.00(A.C=0), 172.10(C0 2CH 3); mass spectrum: m/e 362(m +), 347(M +-15), 330(m+-CH3OH), 304(m +-Acetone). Although neither geometric isomers could be i s o l a t e d free from the other ( e s p e c i a l l y the minor E_-isomer), varying concentrations of each would allow some s p e c i f i c s p e c t r a l data for the E-isomer of 172. A 55:45 mixture (see Reduction of compound 185) of the E to Z geometric isomers gave the following data: n.m.r. (100MHz,CDC13) 61.33 and 1.44(s,3H,C(CH 3)), 3.58(s, 3H,-OCH3), 5.08(H-3), 5.22(broad d,H-5); C-13 n.m.r. (20MHz,CDC13) 625.93 and 26.92 (C ( C H 3 ) 2 ) , 31.62(C-2), 79.28, 80.92 (C-6 and C-7), 82.90(C-5), 94.29(C-3), 157.73(C-4), 172.66(CC^Me), a l l other bands were degenerate with the ^-isomer; [ a ] 2 3 -167(c 1.0,CHC13). Anal. Calc. for C 1 9 H 2 2 0 7 : C,62.97;H,6.12. Found: C,63.30;H,6.06. Continued e l u t i o n of the column gave the dienonate 178 as a clear syrup (38 mg, 51.5%). The c h a r a c t e r i z a t i o n of 178 appears i n the subsection d i r e c t l y below. 164 Methyl(E)-4,7-anhydro-8-0-benzoyl-2,3,5-trideoxy-D-erythro-oct-2,4- dlenonate (178) A mixture of the E_(and _Z)-2,3-unsaturated ester 18_ (0.57, 1.6 mmol) , and sodium azide (0.5 g, 77 mmol) i n anhydrous DMF (50 ml) under nitrogen atmosphere i n a sealed (rubber septum) f l a s k was s t i r r e d for 24 h at 85-90°. The solvent was then evaporated _in vacuo with the water bath temperature kept below 50°. The r e s u l t i n g syrup was dissolved i n a 1:1 mixture of dichloromethane and saturated aqueous sodium chloride (30 ml). The organic layer was separated and the aqueous suspension extracted twice with d i c h l o r o - methane (2x15 ml). The combined organic extracts were dried over anhydrous sodium s u l f a t e , f i l t e r e d and evaporated, leaving a crude syrup which was chromatographed on s i l i c a gel (42 g) using 1:1 benzene-ethyl acetate as developer. The major band was c o l l e c t e d and evaporated to y i e l d a clear syrup which on storage under vacuum produced a c r y s t a l l i n e mass of compound 178 (0.306 g, 64%). Compound 178 was r e c r y s t a l l i z e d from benzene-hexane to y i e l d f i n e neeldes: m.p. 99.5-102°; [ a ] ^ 8 + 98.68 (cl.26,CHC1_); v C H C l 3 3500 D — 3 max (broad,OH), 1712 and 1725 (-CO-Me and PhCO.- carbonyls, r e s p e c t i v e l y ) , 1660 and 1607 cm"1 (-C=C-); n.m.r. (100 MHz.CDCl-): 62.57(d,1H,J, n „ 7.5Hz, OH, J b,Oh — exchangeable with D o0), 3. 74(s,3H,-0CH-), 4.42(d,2H,J, 0 5.0Hz,H-8), 4.74 £. J I , O (t of d,lH,J, Q 5.0Hz,J^ _, 3.0 Hz,H-7), 4.95(d of t , l H , J , n „ 7.5Hz, J, _, /,o b, / b,UH b, / 3.0Hz, collapses to a doublet of 3.0Hz upon D-0 exchange,H-6), 5.52(d,lH, J c , 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 7.30-8.06(m,5H,Ar); mass spectrum: m/e 304(m +), 286(m +-H 20), 272(m+-CH30H). Anal. Calc. for C-,H.,0-: C,63.15;H,5.30. Found: C,63.01;H,5.46. lo lb b 2-Benzoyloxymethyl-5-((E)-carbomethoxyethylene)furan (179) . Prolonged (several months) storage of the methyl oct-2,4-dienonate 178 produced a dark amber syrup which by t . l . c . showed both baseline and 165 higher charring materials (9:1 benzene-ethyl acetate developer) and an absence of s t a r t i n g compound 178. The r e s i d u a l syrup (200 mg) was chromato- graphed on s i l i c a gel (10 g) using 15:1 benzene-ethyl acetate as developer. C o l l e c t i o n of the high R. (0.32) band yielded the substituted furan 179 (14 mg, 7%); n.m.r. (100 MHz, CDC1-) 63.73(s,3H,-0CH-), 5.28(S,2H.H-8), 6.31 (d , l H , J 2 3 16Hz,H-2), 6.49 and 6.54(d,lH,J 5 fi 3.5Hz,H-5,H-6), 7.37(d,lH,J- - 16Hz,H-3), 7.43(m,3H,Ar) 8.01(m,2H,Ar). This n.m.r. data was i d e n t i c a l to 20 those obtained by Moffat et a l for compound 179. C a t a l y t i c Hydrogenation of 18 to y i e l d Methyl 4,7-anhydro-8-0-benzoyl-2,3- dideoxy-5,6-0-isopropylidene-D-allo-octonate (183) A s o l u t i o n of the methyl oct-2-enonate 1_8_ (147 mg) i n methanol (10 ml) was hydrogenated at 60 p . s . i . for 48 h at room temperature i n the presence of 5% palladium on charcoal (60 mg) 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 clear syrup (134 mg) which was shown by t . l . c . to be homogeneous with a R^ s l i g h t l y lower than the s t a r t i n g unsaturated compound (R. 0.36 with 4:1 benzene-ethyl acetate developer). Chromatography of the syrup on s i l i c a gel (12 g) using 4:1 benzene-ethylacetate developer gave the saturated methyl octonate 183 (127 mg, 82%): [ a ] ^ 5 -11.4(jcl.0,CHCl 3) ; v c c l 4 1 7 2 7 1 7 3 8 cm"1 shoulder (C=0); n.m.r. (100 MHz,CDCl,) 61.30 and 1.50 max 3 (s,3H,C(CH 3) 2), 1.78-2.04(m,2H,H-3), 2.35-2.51(m,2H.H-2), 3.58(s,3H,-OCH3), 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 of the multiplet at 61.94 p a r t i a l l y collapsed the mul t i p l e t structure at 63.92 but no discernable information on the coupling at H-4 with H-3 nor H-5 could be ascertained. Mass spectrum: m/e 364(m +), 349 (m +-CH 3), 333(m +-OCH 3). Anal. Calc. for C.QH ,0,: C,62.63; H,664. Found: C,62.71;H,6.66. 166 C a t a l y t i c Hydrogenation of 172 to y i e l d Methyl 4,7-anhydro-8-0-benzoyl-2,3- dideoxy-5,6-0-isopropylidene-D-altro-octonate (184). A s o l u t i o n of the methyl oct-3-enonate 172 (192 mg) i n methanol (10 ml ) was hydrogenated at atmospheric pressure for lOh at room temperature i n the presence of 5% palladium on charcoal (85 mg) as c a t a l y s t . The mixture was then f i l t e r e d and evaporated under reduce pressure to give a crude syrup which by t . l . c . was shown to contain charring materials having higher and lower than the s t a r t i n g unsaturated sugar. Chromatography of the crude mixture on s i l i c a gel (17 g) using 4:1 benzene-ethylacetate as developer afforded the saturated compound 184 (97 mg, 50%) as a c o l o r l e s s syrup which s o l i d i f i e d on standing but could not be c r y s t a l l i z e d from various solvents. 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 pressure (0.02 mm, 100°) to give s o l i d 184; m.p. 43.5-45.5°C; [ a ] 2 5 -9.0(cl.0,CHCl ); v C C l 4 1 7 2 7 f 1 7 3 8 c m - 1 shoulder (C=0); n.m.r. (100 MHz,CDCl„) 61.36 and 1.52 (s,3H,C(CH ) 2 ) , 1.94-2.16(m,2H,H-3), 2.42-2.58(m,2H,H-2), 3.66(s,3H,-OMe), 4.07(t of d , l H , J 3 4 6.0Hz,J 4 5 3.0Hz,H-4), 4.22-4.55(m,3H,H-7,H-8), 4.68- 4.83(m,2H,H-5,H-6), 7.54(m,3H,Ar), 8.06(m,2H,Ar). I r r a d i a t i o n of the mul t i p l e t at 62.06 collapsed the t r i p l e t of doublets at 64.07 to a doublet (J, 3.0Hz); mass spectrum: m/e 364(m +), 349(m +-CH 3), 333(m +-0CH 3). Anal. Calc. for C 1 9H 2 40 ?:C,62.63;H,6.64. Found: C,62.81;H,6.71. Methyl(methyl 8-0-benzoyl-3-(chloromercuri)-2,3-dideoxy-5,6-0-isopropylidene- ct-D-altro-4-octulofuranosid)onate (185) . To a s t i r r e d s o l u t i o n of the methyl oct-3-enonate 172 (0.8 g) i n methanol (40 ml) was added mercuric acetate (0.8 g). The r e s u l t i n g t h i c k suspension was s t i r r e d for l h a f t e r which the mixture was refluxed for 15 min to give a c l e a r s o l u t i o n . A f t e r the so l u t i o n was allowed to cool, sodium chloride (0.3 g) and ac e t i c acid (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 . of the reaction mixture indicated complete consumption of the s t a r t i n g compound and indicated a new lower (0.39) compound using 2:1 ether-hexanes as developer. The reaction mixture was f i l t e r e d and evaporated and the re s i d u a l syrup (1.23 g) chromatographed on s i l i c a gel (60 g) using the above developer to 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 r e c r y s t a l l i z e d from methanol: m.p. 118.5-120.5°; [cx]^ 5 -32.1(c2.0,CHCl 3); v C D C l 3 1 7 1 g ^ 1 7 - 2 c m - l ( c a r b o n y l s ) . n > m . r . (lOOMHz.CDCl ) 61.34 and 1.53 (s,3H,C(CH 3) 2), 2. 79-3. 21(m,approx.3H,H-2,H-3), 3.37 (s,3H,-OCH_3) , 3.75(s,3H, -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,lH,J. , 6.0Hz,J, , <1.0Hz,H-6), 7.55(m,3H,Ar), 8.12(m,2H,Ar). The mass spectrum was a complex pattern due to 5 abundant mercury isotopes and 2 chlorine isotopes. The complex patterns were present at: 630(m +), 615 (m +-CH 3), 599(m+-OCH3). Anal. Calc. for C^H^ClHgOg : C,38.16;H,4. 00;Hg,31. 87. Found: C,38.02; H,4.00;Hg,31.55. Reduction of Compound 185 to Give Compound 172. A mixture of the mercuric compound 185 (350 mg, 0.56 mmol) i n ethanol (12 ml) was gently heated over a steam bath u n t i l the sugar completely dissolved. The s o l u t i o n was allowed to cool with s t i r r i n g and then sodium borohydride (27 mg, 0.7 mmol) was added to the so l u t i o n i n si x portion. The s o l u t i o n turned a darker opaque grey a f t e r each addition of the reducing agent. A f t e r 3 min, the mixture was concentrated (̂ 1 ml) under reduced pressure and the concentrate dissolved i n a mixture of ether (10 ml) and water (4 ml). The r e s u l t i n g mixture was s t i r r e d for several minutes and then the aqueous layer along with the l i b e r a t e d elemental murcury was with- drawn and the organic layer washed with IN HC1 (2x5 ml), water (5 ml) and 168 dried over anhydrous sodium s u l f a t e . T . l . c . of the organic phase indicated only one band s l i g h t l y lower i n than the s t a r t i n g material (using 4:1 benzene-ethylacetate as developer, R^ 0.48 and 0.55,resp.). The s o l u t i o n was then f i l t e r e d and evaporated and the r e s i d u a l syrup (255 mg) chromato- graphed on a column of s i l i c a gel (16.5 g) using 4:1 benzene-ethyl acetate as developer giving back the unsaturated compound 172 (185 mg, 92%) as a clear syrup. This reaction, however, gave a mixture of the methyl ( E , Z ) oct-3-enonate 172 that 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 (approx. 8:10 of the E to Z isomers,resp.). One f r a c t i o n c o l l e c t e d had 55% of the E_ isomer and was used to determine some of the c h a r a c t e r i s t i c s of this minor isomer (see page 163). Methyl(methyl 8-0-benzoyl-3-bromo-2,3-dideoxy-5,6-0-isopropylidene-ct-D- altro-4-octulofuransid)onate (186). To a mixture of the methyl oct-3-enonate 172 (0.8 g, 2.2 mmol), powdered D r i e r i t e (0.8 g), s i l v e r carbonate (0.8 g) i n anhydrous methanol (13 ml) was slowly added bromine (2.75 ml of an 0.8 Molar methanolic solution) while the mixture was s t i r r e d . The reaction quickly consumed the added bromine evidenced by the loss of color a f t e r the addition of the bromine solu t i o n . The mixture was s t i r r e d 1.8 h, then f i l t e r e d through c e l i t e and the s o l i d materials washed with chloroform (3x5 ml). The combined f i l t r a t e s were evaporated under reduced pressure and the residue redissolved i n chloroform (75 ml) and washed with water (15 ml), 5% aqueous sodium hydrogen carbonate (15 ml) and water (2 x 15 ml). The organic phase was then dried over anhydrous sodium s u l f a t e overnight. T . l . c . of the organic phase using 9:1 benzene-ethyl acetate as developer indicated two prominent charring components, the major component (R^ 0.456) moving fas 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 rate (R. 0.280). The organic layer was evaporated at reduced pressure and the r e s i d u a l syrup (0.83 g) chromato- graphed on s i l i c a gel (67 g) using 9:1 benzene ethyl acetate as developer. I s o l a t i o n of the faster-moving component gave the methyl bromoglycoside 186 (0.424 g, 41%) as a clear syrup which turned black upon heating or 25 CC1 prolonged storage at room temperature: [a]^ -13.9° (cl.34,CHC1-) : v 4 D — J max 1728, 1740 cm - 1 shoulder (carbonyls); n.m.r. (100 MHz.CDCl-) 61.34 and 1.54(s,3H,C(CH„)-), 2.94(dd,lH,J 16.5Hz,J 0- 0 10.0Hz,H-2a), 3.31(s,3H, —3 2 gem 2a, 3 -0CH-), 3.41(dd(partially buried under -0CH_),1H,J VL6. 5Hz, J„, „ 3.5Hz, —3 r J —3 gem 2b,3 H-2b), 3.68(s,3H,-C0-CH_3) , 4.32(d(overlapped by H-8b),lH,J ? g a 8.5Hz,H-8a), 3.34(d(overlapped by H-8a),lH,J_, Q, 5.5Hz,H-8b), 4.41-4.53(m,lH,H-7), 4.60 / , ob (d,lH,J. , 6.0Hz,H-5), 4.75(dd(partially obscured by H-3),1H,J C , 6.0Hz, D,o i,o J , ., 2.0Hz,H-6), 4.84(dd,lH,J 0 _ 10.0Hz,J o, _ 3.5Hz,H-3), 7.45(m,3H,Ar), 8.02(m,2H,Ar). I r r a d i a t i o n of the doublet of doublets at 63.41 collapsed the doublet of doublets at 64.84 to a doublet with J„ - 10.0Hz, mass 2a, 3 spectrum: m/e 459/457(m +-CH 3), 443/441(m +-0CH 3), 307(m+-CHBrCH2CO-Me). Anal. Calc. for C^H.-BrOg: C, 50.75 ;H, 5. 32 ;Br, 16.88. Found: C,49.59; H,5.10;Br,16.47. Several minor lower R^ charring components were also i s o l a t e d but these decomposed before they were characterized. Attempted Hydrogenolysis of 186 To a prehydrogenated mixture of potassium hydroxide (18 mg) and 5% palladium on carbon (25 mg), i n methanol (5 ml) was added a s o l u t i o n of the bromo methyl glycoside 186 (130 mg) i n methanol (5 ml). The r e s u l t i n g mixture was vigorously s t i r r e d overnight under hydrogen atmosphere (^760 t o r r ) . A f t e r n e u t r a l i z i n g the reaction mixture with Bio-Rex 70 (H +) r e s i n , the mixture was f i l t e r e d and evaporated. T . l . c . of the syrup with 2:1 ether- 170 hexanes as developer gave only lower (0.143) and baseline material (R^ for compound 172 and 186, 0.43 and 0.50, resp.). Methyl(methyl 8-0-benzoyl-2,3-dideoxy-5,6-0-isopropylidene-a(or B)-D- ribo-4-octulofuranosid)onate (187). In an attempt to obtain the azido compound 189 free from the methyl oct-3-enonate 172, a sample of a mixture of compounds 189 and 172 was dissolved i n a mixture of pyridine, a c e t i c a c i d , and methanol and then water added u n t i l the so l u t i o n turned cloudy. The solution was then stored for several months. T . l . c . of the so l u t i o n using 2:1 ether-hexanes as developer indicated a myriad of products ranging from the baseline to the s t a r t i n g compounds. Evaporation of the solvents gave a dark whisky colored syrup (4.6 g) which was chromatographed on s i l i c a gel (230 g) using 2:1 ether-hexane as developer. I s o l a t i o n of a portion (0.53 g) of the eluent which had the same R^ as the s t a r t i n g compounds, indicated the presence of the azido compound 189 by i . r . spectroscopy and the n.m.r. spectrum indicated the presence of a new methyl resonance (^2H) at 63.15. This sample was hydro- genated i n methanol (35 ml) at atmospheric pressure for 18 hours i n the presence of 5% palladium on carbon. After f i l t r a t i o n and evaporation of the methanol s o l u t i o n , the r e s i d u a l syrup (490 mg) was chromatographed on s i l i c a gel (45 g) using 4:1 benzene-ethyl acetate to give 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 from benzene-hexane: m.p. 73-74.5°; [ a ] 2 4 -35.1(c2.0,CHC1,); v C C 1 4 1724 (benzoate), U — j max 1740 cm"1 (-C0 2CH 3); n.m.r. (100 MHz,CDCl3) 61.34 and 1. 51 (s , 3H, C(CH_3) £ ) , 2.08-2.57(m,4H,H-2,H-3), 3 . 22(s, 3H,-OCH_3) ,3. 71(s ,3H,-C02CH3) , 4.31-4.48(m, 3H,H-7,H-8), 4.49(d(overlapped by H-7 and H-8 mu l t i p l e t ) , 1 H , J 5 6 6.0Hz,H-5), 4.79(broad d , l H , J 5 g 6.0Hz,H-6), 7.54(m,3H,Ar), 8.10(m,2H,Ar); mass spectrum; m/e 379(m +-CH 3), 363(m +-0CH 3), 307(m +-CH 2CH 2C0 2CH 3). 171 Anal. Calc. for C n nH„,0 o;C,60.90;H,6.65. Found:C,61.25;H,6.61. Z U Z D O Addition of Hydrazoic acid to Compound 18 i n the Presence of Sodium Azide to Give 172 and Methyl 4,7-anhydro-3-azido-8-0-benzoyl-2,3-dideoxy-5,6- Q-isopropylidene-D-glycero-D-(allo,altro)-octonate (189). To an a z e o t r o p i c a l l y dried mixture of the methyl oct-2-enonate 18_ (1.0 g) was added sodium azide (0.44 g), anhydrous DMF (35 ml), and hydrazoic aeid (7.0 ml of a 1.39N s o l u t i o n of HN^ i n CHCl^). The mixture was sealed (rubber septum) and s t i r r e d for 4 days at 52-55°. The r e s u l t i n g opaque, pale orange mixture was evaporated In vacuo and the residue dissolved i n a 1:1 mixture of dichloromethane and saturated aqueous sodium chloride (50 ml). The aqueous phase was extracted with dichloromethane (25 ml) and the combined organic extracts dried over anhydrous sodium s u l f a t e . Following f i l t r a t i o n and evaporation of the organic extracts, t . l . c . of the r e s i d u a l syrup i n - dicated a sin g l e major band i d e n t i c a l i n to the s t a r t i n g compound. The in f r a r e d spectrum of t h i s syrup, however, indicated a new absorption at 2110 cm 1 i n d i c a t i v e of the azido f u n c t i o n a l group. Chromatography of t h i s syrup on s i l i c a gel (100 g) using 1:1 hexanes-ether as developer yielded f r a c t i o n s containing mainly the azido mixture 189 (^60:40) and increasing amounts of the methyl oct-3-enonate 172 ranging from less than 5% i n the f a s t e r moving portion of the band to approximately 25% i n the t a i l and of the azido band (^72% y i e l d of 189). No attempts were made to i s o l a t e compound 189 i n a pure state: v ^ 1 ^ 1732, 1745 shoulder (benzoate and max -C0 oMe,resp.), 2140, 2110 cm"1 shoulder (azide); n.m.r. (100 MHz,DMSo-d,) Z b 61.32 and 1. 48(s ,3H,C (CH_3) 2 ) , 2.30-2.84 (m, 2H,H-2) ,3. 60,3. 61 (two overlapping singlets,3H,-OCH 3),3.90-4.14(m,2H,H-3,H-4), 4.28-4.53(m,3H,H-7,H-8), 4.68- 4.84(m,2H,H-5,H-6), 7.56(m,3H,Ar), 8.01(m,2H,Ar); mass spectrum: m/e 405(m +), 390(m +-CH 3), 377(m +-N 2). 172 Continued e l u t i o n of the chromatography column with an increasing percentage of ether (2:1,3:1, and 4:1,ether-hexane) produced two minor components which proved to be impure from t h e i r n.m.r. spectra but possessed absorption bands at ca. 2100 cm 1 i n t h e i r i . r . spectra. These components were l a t e r i s o l a t e d i n higher y i e l d and purity (see compounds 192 and 193 below). Hydrogenation of Compound 189 to give a Mixture 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) azido mixture 189 (^725 mg) in methanol (100 ml) was hydrogenated at atmospheric pressure for 13 h at room temperature i n the presence of 5% palladium on charcoal (260 mg, prehydrogenated) as c a t a l y s t . After f i l t r a t i o n and evaporation of the reaction mixture, t . l . c . of the r e s i d u a l syrup indicated a new lower R. spot i d e n t i c a l to the amino compounds 190 and 191 i s o l a t e d below. Chromatography of the syrup on s i l i c a gel (60 g) using 9:1 benzene-ethanol as developer yielded a chromatographically pure syrup (625 mg, ^92%) that was an approximately 2:1 mixture of compound 190 to 191 by n.m.r. Treatment of Compound 18 with Sodium Azide i n the Presence of Hydrazoic acid to give Compounds 172, 189, and Methyl 3-amino-4,7-anhydro-8-0-benzoyl-2- diazo-2,3-dideoxy-5,6-0-isopropylidene-D-glycero-D-allo (and altro)-octonate (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 dried mixture of the (E,Z) oct-2-enonate 18_ (2.4 g, 50 mmol) was added sodium azide (1.2 g) , anhydrous DMF (72 ml), and hydrazoic acid (0.83 ml of a 2.17 N solution of NH- i n CHC1-). The mixture was sealed (rubber septum), wrapped i n aluminum f o i l and s t i r r e d for 4d at 52-55°. The r e s u l t i n g opaque, pale orange mixture was evaporated in vacuo and the residue 173 dissolved i n a 1:1 mixture of dichloromethane and saturated aqueous sodium chloride (100 ml). The aqueous phase was extracted with dichloromethane (50 ml) and the combined organic extracts dried over anhydrous sodium sul f a t e and evaporated to y i e l d a bright yellow syrup (2.7 g). Chromato- graphy of t h i s syrup on s i l i c a gel (200 g) with a gradient of 1:1 hexane ether to 100% ether as developer yielded a faster-moving component having the same R. as the s t a r t i n g compound 1_8_. This component (1.7 g, ^70%) was a mixture of methyl oct-3-enonate 172 and hydrazoic addition product 189. The head of this band was r i c h e r i n compound 189 as evidenced by a decreasing i n t e n s i t y of the band at 2120 cm 1 (N-_) i n subsequent f r a c t i o n s of this band. From the n.m.r. spectrum (in CDCl^) of t h i s faster-moving component, the azide 189 was found to be less than 5% of t h i s band. Continued e l u t i o n of the chromatography column resulted i n an observable, d e f i n i t i v e separation of two slower-moving yellow components on the column. C o l l e c t i o n of the f i r s t band gave a bright yellow syrup of the altro-B-amino- ct-diazo octonate 193 (180 mg, 6%); [ a j ^ 8 -47.8° (c0.56,CHCl_); v C C 1 4 3400, D — J max 3340 (weak, -NH-,), 2105(-N-), 1734(benzoate), 1697 cm"1 (-C0-CH3); n.m.r. (100MHz,CDCl3) 61.31 and 1.50(s ,3H,c (CH.^), 1.63(broad s ( p a r t i a l l y overlapped by C(CK 3) 2),2H,NH., exchangeable with D 20), 3.72(s,3H,-OCH3), 3.91(broad m, 1H.H-3), 4.08(pseudo-t,lH,J_ . and J. . 4.0Hz,H-4), 4.26(pseudo-q,1H,J, , 3.5 5 ,k H, _> 0,1 Hz.J-, - 4.5Hz,H-7), 4.45 (d, 2H, J-. 0 4.5Hz,H-8), 4. 63 (dd ,1H, J . , 7.0Hz,J. . 4.0Hz,H-5(6)), 4.77(dd,lH,J. , 7.0Hz,J, _ 3.5Hz,H-6(5)), 7.49(m,3H,Ar), 8.04 (m,2H,Ar); mass spectrum: m/e 377(m +-N 2), 362(m +-(N 2+CH 3)), 345(m +-(N 2+HOCH 3)), 330(345-CH 3). Metastable peak at approximately 316 which could be a t t r i b u t e d to 377 fragmenting to 345 or 345 fragmenting to 330. The former i s favored due to t h e i r comparable i n t e n s i t i e s . Further e l u t i o n of the column yielded the slower-moving diazo compound 174 192 (264 mg, 9%); [a]t° + 20.7° (cl.O.CHCl,); v C U 1 4 3400, 3340(-NH„), 2102 (diazo), 1730(benzoate), 1698 cm"1 (-C0 2CH 3); n.m.r.(100MHz,CDC13) 61.30 and 1.50(s,3H,C(CH_3)2) , 1.66(broad s ( p a r t i a l l y overlapped by CH 3 at 61.50), 2H,NH2, exchangeable with D 20), 3.70(s,3H,-OCH3), 3.96(broad m,lH,H-3), 4.05(dd,lH,approx. 4.0 and 5.5Hz,H-4), 4.18-4.30(m,1H.H-7), 4.41(d,lH, J38a 2 - 0 H z » H - 8 a ) > 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 to compound 193. Anal. Calc. for C ^ H ^ N ^ :C, 56. 29; 5. 72;N, 10.36. Found: C,60.78; H,6.54; 3.10. Compound 192 was dried at 78° for 18 h in vacuo p r i o r to micro-analysis. I f elimination of nitrogen did occur to give the a z i r i d i n e d e r i v a t i v e , analysis should give: C19H23N07:C,60.5;H,6.2;N,3.7. C a t a l y t i c Hydrogenolysis and Hydrogenation of Compound 193 to give Methyl 3-amino-4,7-anhydro-8-0-benzoy1-2,3-dideoxy-5,6-0-isopropylidene-D-glycero- D-altro -octonate (191) and Methyl 3-amino-4,7-anhydro-8-0-benzoyl-3-deoxy- 5,6-0-isopropylidene-D-glycero-D-altro -2-octulosonate Hydrazone (196). A s o l u t i o n of the diazo compound 193 (1.16 g) i n methanol (75 ml) was hydrogenated at atmospheric pressure for 3 h at room temperature i n the presence of 5% palladium on charcoal (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 pale yellow syrup which on t . l . c . using 9:1 benzene-ethanol as developer gave two new lower (0.35 and 0.16) bands. The higher R̂  band, however, also overlapped a fa s t e r moving, minor, broad band. Chromatography of the crude syrup on s i l i c a gel (124 g) using 9:1 benzene-ethanol as developer gave a portion of the high R^ (0.35) 25 B-amino compound 1 9 l (0.32 g, 30%) free of higher R f impurities: [ a ] D -12.8° 175 (cl.O.CHCl-j)J vmax 4 3 4 0 5 ' 3 3 4 0 ( w e a k » N _ H ) » 1 7 3 0 > 1 7 4 0 cm"1 shoulder(benzoate and -C0 2CH 3, resp.); n.m.r. (100MHz,CDC13) 61.33 and 1.53(s,3H,C(CH 3) 2), 1.56(s(buried under CH_3 at 51.53) ,2H,NH_2, exchangeable with D 20) , 2.34 (dd.lH.J 16.0Hz,J o . 9.0Hz,H-2a), 2.58(dd,lH,J 16.0Hz,J„, _ 4.0Hz, gem ' 2a,3 ' gem 2b,3 ' H-2b), 3.18-3.36(broad m,lH,H-3), 3.62(s,3H,-OCH3), 3.81-3.90(m,1H.H-4), 4.14-4.30(m,lH,H-7), 4.44(d,lH,J_ . 4.0Hz,H-8a), 4.45(d,lH,J, 4.0Hz, /,oa /,ob H-8b),4.59-4.69(m,2H,H-5,H-6), 8.46(m,3H,Ar), 8.02(m,2H,Ar). I r r a d i a t i o n of the mul t i p l e t centered at 64.62 collapsed the multiplet at 63.81-3.90 to a doublet with J_ , 5.0Hz. I r r a d i a t i o n of the broad multiplet at 63.24 3,4 collapsed the doublet of doublets at 6 2.34 and 2.58 to doublets (J 16.0Hz) gem while the mul t i p l e t at 63.85 p a r t i a l l y collapsed. Anal. Calc. for C ^ H ^ N C y C, 60.15 ;H,6. 64 ;N,3. 69. Found: C, 59.92 ;H, 6. 58; N,3.71. Further e l u t i o n of the column gave the hydrazone 196 (0.31 g, 26%) as a clear syrup which could not be c r y s t a l l i z e d from various solvents: n.m.r. (100MHz,CDCl3) 61.32 and 1. 52 (s, 3H, C(CH_3) 2 ) , 1.78(broad s,2H,NH_2, exchange- able with D 20), 3.69(s,3H,-OCH3), 3.86(broad d , l H , J 3 4 ^4.0Hz,H-3), 4.16-4.28 (pseudo-q(overlapping bands),2H,approx. 4.0Hz between the four resonance signals,H-4,H-7) , 4.42(d,lH, J-, Q 4.0Hz,H-8a), 4.44(d,lH,J, 4.0Hz,H-8b), /,oa /,ob 4.58(dd,lH,J. , 4.0Hz,J, , 7.0Hz,H-5), 4.68(dd,lH,J c , 6.0Hz,J, n 3.0Hz,H-6), 7.46(m,3H,Ar), 8.03(m,2H,Ar), 8.47(broad s,2H, -NNH_2, exchangeable with D 20); v C C 1 4 3400, 3350, 3300 (weak,-N-H„), 3310, 3270(weak,-NNH9), 1725(benzoate), 1700 (-C0 2CH 3), 1570 cm"1(broad,-C=N-). C a t a l y t i c Hydrogenolysis and Hydrogenation of Compound 19 2 to give Methyl 3-amino-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-0-isopropylidene-D-glycero- D-allo-octonate (190) and Methyl 3-amino-4,7-anhydro-8-0-benzoyl-3-deoxy- 5,6-0-isopropylidene-D-glycero-D- a l i o 2-octulosonate Hydrazone (195). 176 A s o l u t i o n of the diazo compound 192 (670 mg) i n methanol (55 ml) was hydrogenated at atmospheric pressure for 3 h at room temperature i n the presence of 5% palladium on charcoal (200 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 l i g h t yellow syrup (613 mg) which on t . l . c . using 9:1 benzene-ethanol as developer gave two new lower R. (0.30 and 0.22) component and indicated the complete consumption the s t a r t i n g compound (R^ 0.40). Chromatography of the crude syrup on s i l i c a gel (45 g) using the above 9:1 solvent pair as developer gave the 8-amino 25 compound 190 (249 mg, 40%) as a c l e a r syrup: [<x]D -11.0 (c2.4,CHC13) ; V C C 1 4 3405, 3340 (weak,N-H), 1730, 1740 cm"1 shoulder (benzoate and -CO-CH. max z j resp.); n.m.r. (100MHz, CDC13) 61.32 and 1. 52 (s ,3H, C (CH 3)-), 1. 61(s,2H,NH_2, exchangeable with D o0), 2.28(dd,lH,J 16.0Hz,J„ . 9.0Hz,H-2a), 2.60(dd, z gem za,j 1H.J 16.0Hz,J o, _ 4.0Hz,H-2b), 3.24-3.41(m,lH,H-3), 3.60(s,3H,-0CHo), gem 2b, 3 —3 3.76(dd,lH,J_ . 6.0Hz,J. c 4.0Hz,H-4), 4.19 (pseudo-q, IH, J_ Q and J., o v 4.0Hz,jL _ 4.0Hz,H-7), 4.34(dd(partially overlapped by H-7 and H-8b),lH, b, / Jgem 1 ] L - 5 H z » J 7 8 a 4 - 0 H z » H - 8 a ) » 5.48 ( d d ( p a r t i a l l y overlapped by H-8a and H-5(6)), J 11.5Hz,J_, Q, 4.0Hz,H-8b), 4.57 (dd, IH, J. c 4.0Hz,J. , 6.5Hz,H-5), gem 7,8b 4,5 5,6 ' ' 4.71(dd,lH,J. _ 4.0Hz,H-6) 7.44(m,3H,Ar), 8.00(m,2H,Ar); mass spectrum: m/e b, / 379(m +), 364(m +-CH 3), 348(m +-0CH 3). Anal. Calc. for C19H-5NO-, :C,60.15;H,6. 64;N,3. 69. Found.: C.60.06; H,6.49;3.61. Further e l u t i o n of the column gave hydrazone 195 (110 mg, 16%) as a viscous syrup which was c r y s t a l l i z e d from hexane-ethylacetate: m.p. 109.5- lll°; n.m.r. (100MHz,CDC13) 61.34 and 1.52(s,3H,C(CH 3)-), 1.78(broad s,2H, -NH2, exchangeable with D 20), 3.68(s,3H,-OCH_3) 3.94(broad d , l H , J 3 4 6.5Hz, 1-3), 4.10-4.28(m,2H,H-4,H-7), 4.42(m,2H,J, _ ^3.0Hz,H-8), 4.62(dd,lH, H 177 J. _ 3.7Hz,J c , 6.0Hz,H-5), 4.74(dd,lH,J c , 6.0Hz,J, n 3.5Hz,H-6), 7.48(m, 4,5 J,D D,O o, / 3H,Ar), 8.02(m;2H,Ar), 8.36(broad s,approx.2H, -NNH2, exchangeable with D 20); mass spectrum: m/e 407(m +), 398(m +-CH 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 of Compound 195 with N,N'-Carbonyldiimidazole (197) to give 5-(S)-(5-0-Benzoyl-2,3-0-isopropylidene-g-D-ribofuranosyl)-6- carbomethoxy-4,5-dihydro-2H-as-triazin-3-one (198) A s o l u t i o n of the hydrazone 198 (63 mg) and N,N'-carbonyldiimidazole (^30 mg) i n anhydrous THF (2.4 ml) was mildly refluxed for 1.5 h. The mixture was then cooled and the THF evaporated. The res i d u a l syrup was dissolved i n a small amount of dichloromethane, applied to three t . l . c . plates (15x20 cm, 1.0mm) and developed with 15:8:2 benzene-ethylacetate- ethanol to give 4 major bands. The slowest moving band at 0.11 was i d e n t i c a l by n.m.r. spectroscopy to imidazole. The intermediate bands of R̂  0.22 and 0.385 were mixtures by n.m.r. and no further attempts to puri f y them were made. The faster-moving band at R̂  0.56 (44 mg, 65%) was the most prominent of the charring bands and possessed single peaks for i t s methyl resonances i n the n.m.r. spectrum: n.m.r. (100MHz, DMSO-d^, assignments are tentative and are based on compound 198) 61.24 and 1. 43 (s ,3H,C(CH_3) 2 ) , 3.57 (s,3H,-OCH3), 4.00-4.36(m,4H,H-l',H-4',H-5'), 4.74-4.92(m,3H,H-5,H-2',H-3'), 6.38(d,2/3H,^8.0Hz,no assignment), 7.10(broad s,2/3H, no assignment), 7.60 (m,3H,Ar), 8.12(m,2H,Ar), 9.32(broad s,lH,N(2)-H, exchangeable with D 20); mass spectrum: m/e 431(m+-2H), 418(m +-CH„); v C C l 4 3410, 3300, 3270(NH), 3 max ' 1725 (PhCO), 1700(-C0 2Me), 1665(HN-CO-NH), ̂ 1550 cm - 1(C=N). Treatment of Methyl(E,Z)-4,7-anhydro-8-0-benzoyl-2,3-dideoxy-5,6-0-isopro- pylidene-D-allo-oct-2-enonate (18) with Ceric Ammonium Nitr a t e (CAN) and 178 Sodium Azide. 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 cooled to -25° under nitrogen atmosphere. This cooled solution was transfered v i a a syringe to a mixture of s o l i d CAN (1.29 g) and sodium azide (0.06 g). The r e s u l t i n g mixture was vigorously s t i r r e d for 15 h at -33 to -22°. Cold ethyl ether (5 ml) was added and the r e s u l t i n g mixture f i l t e r e d and the s o l i d residue washed with ether (2x2 ml). The combined f i l t r a t e s were washed with ice cold water (4x5 ml), dried over anhydrous sodium s u l f a t e , f i l t e r e d and evaporated to give a yellow syrup (398 mg). Column chromatography of the syrup on s i l i c a gel (50 g) with 20:1 benzene-ether as developer gave two faster-moving components (31 mg and 8 mg, 8.5 and 2%, resp., based on the molecular weight of 18) which proved to be impure upon inspection of t h e i r n.m.r. spectra. The major slower-moving band (260 mg, 73%) had the same R- and i . r . spectrum as 18. 7. Hemiketals, y-Lactones, and A l k y l and Acyl Ketals A i r Oxidation and Hydration of Methyl (E,Z )-4,7-anhydro-8-0-benzoyl-2,3- dideoxy-5,6-0-isopropylidene-D-ribo-oct-3-enonate (172) to y i e l d 5-0-Benzoyl- 2,3-0-isopropylidene-D0ribono-l,4-lactone (199), 8-0-Benzoyl-2,3-dideoxy-5,6- 0-isopropylidene-3-D-ribono-4-octulofuranosono-1,4-lactone (200), Methyl(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 (202), Methyl 8-0-benzoyl-2-deoxy-5,6-0-isopropylidene- q , B - D - a l l o (and altro)-4-octulofuranosonate (203) and (204), respectively . The methyl oct-3-enonate 172 (approx. 13.5 g) which was synthesized i n various attempts to improve the y i e l d of the B-amino-a-diazo compounds 192 and 193 was allowed to stand for prolonged periods (1.5-9 months) as a syrup 179 or i n the chromatography developer (2:1 ether-hexanes). In the cases where compound 172 was l e f t i n the developer both solvents had completely evaporated leaving a pale yellow syrup. T . l . c . analysis of these syrups indicated that the unsaturated compound had reacted further to form products ranging i n (using 2:1 ether-hexanes as developer) from the base-line to the s t a r t i n g compound. The various f r a c t i o n s and syrups were c o l l e c t e d to give a deep whisky colored syrup (^15 g) which was chromatographed on s i l i c a gel (400 g) using a gradient of 1:1 (600 ml), 2:1 (600 ml), 4:1 (315 ml) ether-hexanes and 100% ether to achieve a crude separation of the components. The eluent which contained charring compounds was i s o l a t e d as seven bands (A to G) according to descending R̂  using ether-hexanes as developer. Frac t i o n A (^2.0 g): This f r a c t i o n had the same R. as the s t a r t i n g methyl oct-3-enonate 172. The n.m.r. spectrum indicated a preponderance (^70%) of 172 (resonance at ^63.14,H-2) and the s p l i t t i n g of the methyl peaks at 61.6 and 3.6 indicated a second component. The i . r . spectrum of t h i s mixture had an absorption of ^2120 cm 1 i n d i c a t i v e of the azido compound 189. Fraction B (2.14 g): The i . r . spectrum of t h i s component possessed a broad, weak absorption band at 3350 cm 1 and a stronger, sharper peak at 1804 cm T . l . c . of this f r a c t i o n using 1:1 ether-hexane as developer indicated the p o s s i b i l i t y of 3 overlapping bands which were slower-moving than the s t a r t i n g compound 172. A change of the developer to 4:1 benzene- ethyl acetate, however, gave better separation to show 3 d i s t i n c t components plus a minor charring band just above the base-line (R^ 0.41, 0.35, 0.28 and 0.03 with 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 gel (250 g) using 4:1 benzene-ethyl acetate as developer afforded the r i b o n i c , 1,4-lactone 199 180 (375 mg, 3.5%*) as the faster-moving component which c r y s t a l l i z e d under vacuo. R e c r y s t a l l i z a t i o n of this component from benzene-hexane gave an o CC1 ~1 a n a l y t i c a l sample: m.p. 101.5-102.5°; v m a x 4 1802 (lactone), 1733 cm (benzoate); [ a ] 2 5 -50.4°(cl.5,CHCl 3) ; n.m.r. (100MHz ,CDC13) 61.40 and 1. 51 (s, 3H, C(CH_3) 2 ) , 4.52(dd,lH,J 12.3Hz,J, c 3.0Hz,H-5a), 4.69(dd,lH,J 12.3Hz,J. 2.5Hz, gem '4,5a gem 4,5b ' H-5b), 4.79 and 4.87(d,lH,J 5 g 6.0Hz,H-5,H-6), 4.92(pseudo-t,1H.H-4), 7.56(m, 3H,Ar), 7.96(m,2H,Ar); mass spectrum: m/e 293(m++H), 277(m +-CH 3). Anal. Calc. for C,CH,£0,:C,61.64;5.52. Found: C,61.49;5.50. I i lb o Continued e l u t i o n of the chromatography column gave the keto 1,4- lactone 200 (1.03g, 8.2%) 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 re- e 25 c r y s t a l l i z e d from benzene-hexane; m. p. 101-102. 5°; [ c ] ^ -49.9(cl.5,CHC1 3); v C C l 4 1 8 0 0 (lactone), 1725 cm"1 (benzoate); n.m.r. (100MHz.CDC1-) 61.37 and max J 1.51(s,3H,C(CH_ 3) 2), 2.24-2.89(m,4H,H-2,H-3), 4.42 (d (overlapping H-8b),lH,J 7 g a 7.5Hz,H-8a), 4.43(d(overlapping-H-8a) , 1H,J., „, 5.0Hz), 4.60(broad dd,lH,H-7), 4.77(d,lH,J. , 6.0Hz,H-5), 4.92(dd,lH,J, , 6.0Hz,J, _ vL.0Hz,H-6), 7.54 5,6 J,b b, / (m,3H,Ar), 8.08(m,2H,Ar); mass spectra: m/e 348(m +), 333(m +-CH 3), 213(m+- PhC0 2CH 2). Anal. Calc. for C, oHon0_,:C, 62. 06;H, 5. 79. Found: C.61.94; H,5.66. Further e l u t i o n of the column gave f r a c t i o n s which by t . l . c . with the 4:1 solvent pair were mixtures of a least two compounds overlapped by a broader, more dif f u s e d band. Continued e l u t i o n of the column eventually gave the lower spot (0.28) as a chromatographically pure compound. The mixture ( f r a c t i o n B-A) was l a t e r rechromatographed and the slower-moving component was c o l l e c t e d to give the saturated ket a l 202 (370 mg, 2.7%) 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 from chloroform-hexane; m.p. 109-112.5°; [ a ] 2 5 -2.7°(cl.0.CHC1-); v C C 1 4 3430(broad,OH), 1727 cm"1 U — -J max (e s t e r s ) ; n.m.r. (100MHz ,DMS0-d6) 61.28 and 1. 41 (s ,3H,C(CH_3)2), 1.92-1.16 y i e l d s here w i l l be based on 13 g of compd. 172 consumed. 181 (m,2H,H-3), 1.30-1.46(impartially obscured by DMS0-d6),2H.H-2), 3.60 (s,3H,-OCH3), 4.24(broad dd,lH,H-7) 4.37(d(overlapped by H-8b),lH,J ? g a 4.0Hz,H-8a), 4.40(d(overlapped by H-8a),J y g b 10.5Hz,H-8b), 4.44(d,lH, J. , 6.0Hz,H-5), 4.86(dd,lH,J c , 6.0Hz,J, ., 1.3Hz,H-6), 6.16(sharp s.lH, OH, exchangeable with D-0), 7.62(m,3H,Ar), 8.02(m,2H,Ar); mass spectrum: m/e 365(m +-CH 3), 349(m +-0CH 3), 333(m +-(H0CH 3 + CH3>). Anal. Calc. for C 1 9H 2 A0 g:C,59.99;H,6.36. Found: C,59.87;H,6.36. Rechromatography of the above mixture (320 mg)(fraction B-A) on s i l i c a gel (17 g) using 29:1 benzene-ethanol as developer removed the broad, d i f f u s e band from the overlapping pa i r s of compounds. A portion of the lower R- material was i s o l a t e d pure and was i d e n t i c a l to k e t a l 202 (190 mg). The remaining mixture (108 mg) was again rechromatographed on s i l i c a (17 g) using 4:1 benzene-ethyl acetate to a f f o r d the unsaturated k e t a l 201 (28 mg, C C I A -1 0.3%) as a c l e a r syrup: v 4 3440,(broad,OH), 1720 cm (broad, benzoate max and unsaturated es t e r ) ; n.m.r. (100MHz, DMS0-d6) 61.27 and 1.41(s,3H,C(CH 3) 2), 1.72(s,3H,-OCH3), 4.22(broad s,3H,H-7,H-8), 4.56(d,lH,J 5 fi 5.5Hz,H-5), 4.96 (d.lH.J. 6 6.0Hz,H-6), 6.14(d,lH,J 2 3 16.0Hz,H-2), 6.87(d,lH,J- 3 16.0Hz,H-3), 6.89(sharp s,lH,0H, exchangeable with D 20), 7.62(m,3H,Ar), 8.04(m,2H,Ar); mass spectra: m/e 378(m +), 363(m+-CH.), 347(m+-0CH3); [a]^ 3 , 5-25.4 (cl.24,CHC1 3)* Anal. Calc. for C i gH 2 2O g:C,60.31;H,5.86. Found: (Syrup) C,60.62;H,5.99; ( S o l i d ) * * C,60.61;H,6.00. Further e l u t i o n of the column gave a mixture of ketals 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 y i e l d ) . *The n.m.r. spectrum of compd. 201 in CDC13 indicated a 4:1 mixture of anomers. * * S o l i d : M.P. 78-88°. 182 Fraction C(0.55 g): The i . r . spectrum of t h i s component possessed two broad bands at approximately 3400 and 3500 cm 1 and a strong broad carbonyl at 1722 cm \ T . l . c . of t h i s f r a c t i o n with various solvent systems gave a broad charring band i n which no major component could be detected nor could any appreciable separation of components be seen. Chromatography of the syrup on s i l i c a gel (60 g) using 4:1 benzene- ethyl acetate yielded one chromatographically pure band which from i t s n.m.r. spectrum indicated a mixture of compounds. Due to the r e l a t i v e small amount of sample and the number of compounds observed for t h i s chromatographic region, no further attempts were made to separate the various components. Fraction D (1.5 g): The i . r . spectrum of t h i s f r a c t i o n had a broad band at 3500 cm \ a weak band at 1810 cm 1 and a strong carbonyl absorption at 1727 cm 1 . T . l . c . of the syrup using 4:1 ether-hexanes as the developer showed two charring bands (R^ 0.32 and 0.37) with the higher R^ band pre- dominating. However, i f 2:1 benzene-ethyl acetate was used as the mobile phase, two bands could s t i l l be observed but the faster-moving material was much more d i f f u s e (R^ 0.27 to 0.47) and the slower-moving, major component at R̂  0.22 was a much narrower band. Therefore, the crude syrup (1.2 g) was rechromatographed on s i l i c a g e l (95 g) using 4:1 ether-hexane as developer to give the faster-moving component (0.96 g) as clear syrup. The slower-moving component was found to be chromatographically i d e n t i c a l to the major band in f r a c t i o n E and were combined. T . l . c . of the higher R^ band using the benzene-ethyl acetate developer s t i l l gave the previously described d i f f u s e bands; therefore, t h i s syrup was again rechromatographed but using 4:1 benzene-ethyl acetate as developer to y i e l d the hydroxy keta l 203 (0.64 g, 4.5%) as a white c r y s t a l l i n e mass which was r e c r y s t a l l i z e d from dichloromethane-hexanes to 183 give f i n e needles: m.p. 126-128° (smaller c r y s t a l s ) , 130-132° (larger c r y s t a l s ) ; [ a ] 2 3 -29.1° (c2.0,CHC1 Q); v C C 1 4 3480(broad,OH), 1725 cm"1 D — 3 max (esters); n.m.r.(100MHz,DMSO-dJ 61.30 and 1.45(s,3H,C(CH_).), 2.28-2.70 b — J Z (m(obscured by the DMSO resonance), 4H(incl. DMSO),H-2), 3.64(s,3H, -OCH_3), 4.14-4.56(m,5H,H-3,H-5,H-7,H-8), 4.95(d,lH,J c , 6.0Hz,H-6), 5.25(d,lH, 5,6 J_ _„ 5.5Hz,CHOH, exchangeable with D o0) , 6.08(sharp s,lH,C0H, exchangeable J , UH — Z — with D 20, 7.70(m,3H,Ar), 8.08(m,2H,Ar). Addition of D 20 to the n.m.r. sample induced a s p l i t t i n g i n the methyl resonances to give approximately 20% i n t e n s i t y to the new resonances. These occurred at 61.36, 1.50 and 3.59. The n.m.r. spectrum using deuterochloroform as solvent c l e a r l y indicated the C-2 methylene hydrogens and also showed the keto sugar as a 4:1 r a t i o of the a and 3 anomers, re 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 26.38(C(CH 3) 2), 37.69(C-2), 51.13(0CH 3), 66.03(C-8), 69.16(C-3), 82.75 (degenerate), 84.72(C-5,C-6,C-7) , 107.39(C-4), 111.89(C(CH ) 2 ) , 165.47(PhC=0), 171.56(C02Me); minor isomer-625.39 and 26.38(C(CH 3) 2), 37.09 (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), 114.42(C(CH 3) 2), 165.47(PhC=0), 171.74(C0 2Me). The aromatic signals centered at 6120 were not assigned. High res. mass spectrum (deviation): m/e 396.1440(1.9,m+), 381.1193(0.7,m+-CH3), 349.0927(0.4,m+- (CH 3+CH 3OH)), 293.1028(0.3,m+-CHOHCH2C02CH3). Anal. Calc. for C^H^Og :C, 57 . 57 ;H, 6.10. Found: C, 58. 06 ;H, 6.46. Fraction E (4.7 g): This f r a c t i o n was mainly contaminated with slower- moving pale yellow impurities. The i . r . spectrum possessed a broad, weak band at 3530 cm 1 and a strong band at 1725 cm 1 . The amber syrup was rechromato- graphed on s i l i c a gel (230 g) using 19:1 benzene-ethanol as developer to give the epimeric hydroxy ketal 204 (2.5 g,17.6%) as a clear syrup which f a i l e d CC1 to c r y s t a l l i z e from various solvents, [al + 9.27(cl.1,CHC1_); v 4 3510 J D — 3 max 184 (broad,OH), 1720 cm """(esters); n.m.r. (100MHz,DMSO-d^, minor isomer i n parenthesis) 61.33(1.36) and 1.48(1.57)(s,3H,C(CH-) 2), 2.34-2.80(m(obscured by DMSO), 3H(incl.DMSO),H-2), 3.65(3.63)(S,3H.-OCH ), 3.84-4.92(m,6H,H-3,H-5, H-6,H-7,H-8), 5.29(d,approx. 1/2H,J0 _„ 6.5Hz,CHOH, exchangeable with D„0), J , OH Z 5.95 (5.60)(sharp s (broad s ) , approx. 2/3H (1/3H), COH, exchangeable with D^O), 8.65(m,3H,Ar), 8.05(m,2H,Ar). a to 6 r a t i o was approximately 2:1 using DMSO-d, as solvent. Addition of D o0 to the solu t i o n increased the r a t i o to 6 L approximately 4:1 (a to 8, resp.). The n.m.r. spectrum i n C^D^ gave two broad doublets at 63.56 and 3.62 with J 7.0Hz for the 2°-hydroxyls and J , O H a sharp s i n g l e t at 64.59 for the 3"-hydroxyl, a l l of which were exchangeable with D 20. A s i m i l a r pattern also occurred i n deuterochloroform for the 2°- hydroxyls; mass spectrum; m/e 396(m +), 381(m +-CH 3), 365(m +-0CH 3), 293(m+- CHOHCH2C02CH3); C-13 n.m.r. (20MHz,DMS0-d6, proton-decoupled) major isomer- 625.21 and 26.66(C(CH 3) 2), 36.63 (C-2), 66.19(C-8), 67.72(C-3), 82.44, 83.54, 84.94(C-5,C-6,C-7), 107.34(C-4), 112.03(C(CH 3) 2), 165.62(PhC=0), 172.19 (C0 2Me); minor isomer-625.50 and 26.66(C(CH 3) 2), 36.33(C-2), 51.19(OCH 3), 65.05 (C-8), 70.57(C-3), 79.94, 80.68, 81.23(C-5,C-6,C-7), 105.07(C-4), 113.94(C ( C H 3 ) 2 ) , 165.62(Ph£=0), 172.19(C0 2Me). The aromatic signals were not assigned. Anal. Calc. f o r C^H^Og: C, 57 . 57 ;H, 6.10. Found: C, 57 .24 ;H, 6.18. Fr a c t i o n F (^3.0 g); This pale yellow syrup did not give any d e f i n i t i v e bands upon t . l . c . a n a l y s i s ; therefore, no attempts were made to determine i t s composition. Synthesis of 199 from 172 Using Excess meta-Chloroperbenzoic a c i d . 89a Using a modification of the procedure of Borowitz et a l , a so l u t i o n of the methyl oct-3-enonate 172 (362 mg, 1.0 mmol) i n anhydrous 1,2-dichloro- ethane (3.0 ml) was added to an ice-cooled, s t i r r e d , p a r t i a l suspension of 185 meta-chloroperbenzoic acid (530 mg, 3.1 mmol) i n 1,2-dichloroethane (4.0 ml) over 15 min. The ice-bath was then removed and the mixture s t i r r e d f o r 4 days at room temperature. The reaction mixture remained cloudy during the course of the reaction and a small amount of p r e c i p i t a t e was present at the end of the 4 days. The mixture was then f i l t e r e d , d i l u t e d to 15 mis with d i c h - loromethane, the r e s u l t i n g s o l u t i o n washed with 7% aqueous sodium hydrogen carbonate (5 ml), water (5 ml) and the organic phase was dried over anhydrous sodium s u l f a t e . After f i l t r a t i o n and evaporation of the organic phase, the r e s i d u a l syrup (142 mg) was chromatographed on s i l i c a gel (17 g) using 9:1 benzene-ethylacetate as developer to afford the lactone 199 (49 mg, 17%), the n.m.r. spectrum of which was i d e n t i c a l to the lactone 199 i s o l a t e d from the a i r oxidation of 172. Treatment of Compound 172 with meta-Chloroperbenzoic Acid i n the Presence of Ethanol to give Compound 204 and Methyl (ethyl 8^0-benzoyl-2-deoxy-5,6-0- isopropylidene- 8 -D-altro-4-octulofuranosid)onate (207). To a s t i r r e d s o l u t i o n of the methyl oct-3-enonate 172 (180 mg, 0.5 mmol) i n reagent grade dichloromethane (4.0 ml) at 0° was added dropwise a s o l u t i o n of meta-chloroperbenzoic acid (114 mg, 0.65 mmol) i n dichloromethane (2 mis). The reaction was s t i r r e d at 0° for 1 h a f t e r which the mixture was allowed to reach room temperature and s t i r r i n g was continued for an a d d i t i o n a l 2 h. The excess peracid was destroyed with 10% aqueous sodium s u l f i t e (3.5 ml). The aqueous layer was extracted with dichloromethane, the organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate (5 ml), water (5 ml) and then dried over anhydrous sodium s u l f a t e . Removal of the drying agent by f i l t r a t i o n and evaporation of the solvent gave a cl e a r syrup (195 mg) which by t . l . c . using 4:1 benzene-ethyl acetate showed two major components at R- 0.275 and 0.13. The syrup was applied to a column 186 of s i l i c a gel (30 g) and eluted with a gradient of benzene-ethyl acetate (4:1,60 ml; 3:1,20 ml; 2:1,36 ml; 1.5:1,53 ml). The faster-moving com- ponent was c o l l e c t e d to give the ethyl glycoside 207 (85 mg,39%) as a cle a r syrup: [ a ] 2 5 -13 (c_0. 6 .CHCLj); v ^ 4 3560 (broad,OH) , 1727 c m - 1 ( e s t e r s ) ; n.m.r.(100MHz,DMS0-d,) 61.07(t,3H, J _ „ _„ 7.0Hz, -0CH oCH Q), 1.32 and 1.48 (s,3H,C(CH_ 3) 2), 2.49(dd(partially buried under DMSO),lH , J g e m VL5.0Hz , J 2 a 3 9.5Hz,H-2a), 2.76(dd,lH , J 15.0Hz , J 3.5Hz, H-2b), 3.61(q(partially buried under -0CHJ ,1H,J _ , 7.0Hz, -0CH„CH„), 3.62(s,3H, -OCH,), 4.24-4.47(m, J C n 3 , L H 2 Z j j 4H,H-3,H-7,H-8), 4.67(d,1H,J c , 6.0Hz,H-5), 4.79(broad s (buried under H-5 5,6 and H-6),1H,0H, exchangeable with D 20), 4.87(broad d , l H , J 5 & 6.0Hz,H-6), 7.66(m,3H,Ar), 8.05(m,2H,Ar). I r r a d i a t i o n of the t r i p l e t at 61.07 collapsed the quartet at 63.61 to a s i n g l e t ; mass spectrum: m/e 424(m +), 409(m +-CH 3), 321(m+-CHOHCH2C02CH3). Anal. Calc. for C 2 ]H 2g0 9:C,59.43;H,6.65. Found: C,59.70;H,6.87. Continued e l u t i o n of the column gave the 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) using 2:1 benzene- ethylacetate and 1:4 hexane-ether as the ketal previously i s o l a t e d . The n.m.r. spectra of these two ketals were also i d e n t i c a l . Treatment of Compound 172 with Osmium Tetroxide to give Ketals 203 and 204 To a s t i r r e d s o l u t i o n of the methyl oct-3-enonate 172 (195 mg, 0.54 mmol) i n anhydrous pyridine (2.0 ml) was added s o l i d osmium tetroxide (138 mg, 0.58 mmol). The r e s u l t i n g brown so l u t i o n grew darker as the reaction progressed. Af 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 mixture rigorously s t i r r e d f o r 10 min. The mixture was then extracted with chloroform (10 ml and 2x5 ml), and the combined organic extracts washed with water (10 ml) and dried over anhydrous sodium s u l f a t e . A f t e r removal 187 of the drying agent by f i l t r a t i o n and evaporation of the s o l u t i o n , xylene (3x4 ml) was added and evaporated at reduced pressure to remove the r e s i d u a l pyridine. The remaining brown syrup was chromatographed on s i l i c a gel (16 g) using 14:7:4 benzene-ethylacetate-ether as developer to give keta l 203 (6 mg, 3%) as the faster-moving minor component and keta l 204 (80 mg, 37.5%) as the slower-moving major component. The n.m.r. spectra of both ketals were i d e n t i c a l to those obtained from the a i r oxidation of compound 172 and a c r y s t a l l i n e sample of keta l 203 melted at 123-128° in agreement with previous r e s u l t s . Treatment of Ketal 203 with Sodium Periodate to give Lactone 199 To a s t i r r e d s o l u t i o n of the hydroxy hemi-ketal 203 (23 mg) i n ethanol (0.5 ml) shielded with f o i l was added a s o l u t i o n (0.5 ml) of sodium periodate (570 mg) and sodium hydrogen carbonate (36 mg), i n water (10 ml). T . l . c . of the mixture a f t e r 4 h indicated a higher spot and a slower-moving material approximately the same R^ as s t a r t i n g material. The reaction was allowed to run for 30 days a f t e r which the reaction mixture was coevaporated with xylene (3 ml) and the residue dissolved i n ethylacetate, f i l t e r e d and r e s u l t i n g s o l u t i o n evaporated to give a crude syrup (29 mg). Chromatography of t h i s syrup on a preparative s i l i c a gel plate (15x20 cm,250 pm) using 3:2 ether- hexanes as developer gave a minimum of f i v e components (detected v i a a U.V. lamp). I s o l a t i o n of the components gave only one band which was greater than 2 mg. This major band (7.5 mg, 44%) had the same R- (0.45 on the above plate) as lactone 199 and the n.m.r. spectra were i d e n t i c a l . Treatment of Compound 204 with Sodium Periodate to give Compound 199 and 211 To a s t i r r e d solution of the hydroxy hemi-ketal 204 (60 mg) i n methanol (1.3 ml) protected with f o i l was added a s o l u t i o n of sodium periodate (60 mg) i n water (1.3 ml). The solution was s t i r r e d for 30 days a f t e r which the mixture was f i l t e r e d and coevaporated with toluene (2x3 ml), redissolved i n 188 ethyl 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 preparative t . l . c . p l ate (20x20 cm, 1.5 mm) using 1.5:1 ether-hexanes as developer to give 3 U.V. active components. The faster-moving band at 0.48 was c o l l e c t e d to give the c r y s t a l l i n e lactone 199 (22 mg,50%) which had an n.m.r. spectrum i d e n t i c a l to the one obtained for compound 199 i s o l a t e d from the a i r oxidation of the methyl oct- 3-enonate 172. The intermediate band (R- 0.29) was extracted to y i e l d an impure sample of spiro-lactone 211 (3 mg). The n.m.r. spectrum of this syrup showed that i t was predominantly the spiro-lactone 211 synthesized i n a l a t e r r e a c t i o n . The slower-moving band (R^ 0.22) yielded a syrup (5.5 mg) which by n.m.r. spectroscopy showed a mixture of 3 compounds. Due to the small amount of material no further attempts were made to pu r i f y the l a s t two bands. 5,6-Di-0-acetyl-8-0-benzoyl-2,3-dideoxy-a(and 8)-D-ribo-4-octulofuranosono-1, 4-lactone (208a) and (208b), r e s p e c t i v e l y . A s o l u t i o n of the ketal 202 (245 mg) i n 80% aqueous t r i f l u o r o a c e t i c acid was s t i r r e d f o r 0.5 h at room temperature a f t e r which toluene (6 ml) was added and the mixture evaporated under reduced pressure. The treatment with toluene was repeated twice and the re s i d u a l syrup was dissolved i n a so l u t i o n of a c e t i c anhydride (3 ml), a c e t i c acid (1.5 ml) and para-toluenesulfonic acid monohydrate (600 mg) and s t i r r e d overnight at room temperature. To the r e s u l t i n g brown so l u t i o n was added sodium acetate (0.56 g) and the re- action mixture s t i r r e d for 15 min. Xylene (6 ml) was added and the mixture was evaporated under reduced pressure. The treatment with xylene was repeated 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 with benzene (25 ml) and the mixture 189 f i l t e r e d . The s o l i d residue was washed with benzene (2x15 mis) and the combined f i l t r a t e s evaporated under reduced pressure to give crude syrup which was chromatographed on s i l i c a gel (40 g) using 4:1 benzene-ethyl acetate as developer to a f f o r d two major bands. The fa s t e r moving band gave lactone p p CC\ 208a (60 mg,24%) as a clear syrup: [a]"" +57.7° (cl.O.CHCl ); v 4 1805 (lactone ), 1752 (acetates), 1730 cm 1 (b enzoate); n.m.r. (100MHz,CDC13) 62,14 and 2.16(s,3H,2xCH 3), 2.27-2.45(m,2H.H-3), 2.57-2.81(m,2H.H-2), 4.46 (dd,lH,J 11.0Hz,J_ - 3.5Hz,H-8a),4.59(pseudo-q(partially overlapped by gem 7,oa H-8a),lH,H-7),4.62(dd,lH,J 11.0Hz,J_ Q, 2.0Hz,H-8b), 5.21(d,lH,J. , 7.0Hz, gem /,ob 5,b H-5), 5.43(dd,lH,J c , 7.0Hz,J, , 2.5Hz,H-6), 7.57(m,2H,Ar), 8.08(m,1H,Ar); D , b o, I mass spectra: m/e 392(m +), 347(m +-C0 2H), 336(iZ-CH-CH-CO) 270(m+-PhCO-H), 257(m +-PhC0 2CH 2). Anal. Calc. for C-^H-.O- :C,58.16;H,5.14. Found:C,58. 31;H,5.29. The slower moving prominant band gave the anomeric lactone 208b (86 mg, 34%) also as a clear syrup: [a]J2 -11.1 (c2.0,CHCl.); v C C 1 4 1805 (lactone), D — 3 max 1765, 1758 (acetates), 1730 cm"1 (benzoate); n.m.r. (100MHz,CDC13) 62.03 and 2.18(s,3H,2xCH 3), 2.28-2.45(m,2H,H-3), 2.57-2.82(m,2H,H-3), 4.41-4.65(m,3H, H-7.H-8), 5.52(d,lH,J. , 4.5Hz,H-5) 5.60(dd,IH,J, _ 2.5Hz,H-6), 7.56(m,3H, J,b b,i Ar); 8.14(m,2H,Ar); mass spectrum: i d e n t i c a l to 208a. Anal. Calc. for C^H^O.: C.58.16; H.5.14. Found: C, 58.44; H,5.13. Methyl 8-0-benzoyl-2-deoxy-3,4:5,6-di-O-isopropylidene-a(and B)-D-allo-4- octulofuranosonate (209a) and (209b), r e s p e c t i v e l y . A dark orange so l u t i o n of 2:2:1 (V/V) 2,2 dimethoxypropane-acetone- t r i f l u o r o a c e t i c acid (5 ml) was added to the hydroxy k e t a l 203 (335 mg) and the r e s u l t i n g s o l u t i o n was s t i r r e d at room temperature for 2.5 d. Toluene 190 (2x4 ml) and benzene (4 ml) were evaporated from the reaction mixture to give a crude dark brown syrup which on t . l . c . using 9:1 benzene-ethyl acetate as developer gave 2 charring bands (R^ 0.28 and 0.35) with the slower-moving band predominating. Chromatography of the. syrup on s i l i c a gel (38 g) using the above solvent p a i r gave the 8-ketal methyl ester 209b (43 mg, 12%) as a clear syrup: [ a ] 2 3 -59.1° (cl.l.CHCl ); v C C l 4 1747 JJ j ITlcLX (-C0 2CH 3), 1732 cm" 1(benzoate); n.m.r. (100MHz,CDC13) 61.33,1.43,1.46 and 1.48(s,3H,2xC(CH_) 0), 2.54(dd,lH,J 16.0Hz,J„ , 9.7Hz,H-2a), 3.16(dd, —1 Z gem za, J 1H,J 16.0Hz,J_, _ 4.0Hz,H-2b), 3.74(s,3H,-0CH„), 4.45(s,3H,H-7,H-8), gem 2b, 3 — J 4.65(d,lH,J 6.0Hz,H-5), 4.82(dd(partially overlapped by H-6),1H,J , 9.7Hz,J„, ^ 4Hz,H-3), 4.85(broad d,lH,J c , 6.0Hz,H-6), 7.52(m,3H,Ar), 8.08 ZD,3 3,0 (m,2H,Ar); mass spectrum: m/e 436(m +), 421(m +-CH 3), 405(m +-0CH 3). Continued e l u t i o n of the chromatography column gave the a-ketal methyl ester 209b (277 mg, 75%) as a clear syrup which could not be c r y s t a l l i z e d 24 CCI — 1 from various solvent: [ct]^ -13.6(cl.1,CHC1 0); v 4 1 7 3 3 c m (esters); D — 3 max n.m.r. (100MHz ,CDC13) 61.38, 1.42, 1.52 and 1. 62(s,3H,2xC(CH_3) 2 ) , 2.59(dd ( p a r t i a l l y overlapped by H-2b),lH,J 17.0Hz,J o _ 6.0Hz,H-2a), 2.76(dd gem 2a,3 ( p a r t i a l l y overlapped by H-2a),lH,J ^17.0Hz,J.1_ „ 6.0Hz,H-2b), 4.58(s,3H, gem zb, J -0CH_), 4.47(broad s, 3H,H-7 ,H-8) , 4. 58 (pseudo-t, 1H, J _ and J o t_ . 6.5Hz, J 2a,3 ZD , 3 H-3), 4.66(broad d , l H , J 5 fi 7.0Hz,H-6), 4.76(d,lH,J 5 g 7.0Hz,H-5), 7.53(m,3H, Ar), 8.04(m,2H,Ar) ; mass spectrum: m/e 436(m +), 421(m +-CH 3), 405(m +-0CH 3). Anal. Calc. for C^H^Og :C, 60. 54 ;H, 6.47 . Found: C, 60. 72 ;H, 6.45. Methyl 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 (211). A s o l u t i o n of acetone (8 ml), 2,2-dimethoxypropane (2 ml) and t r i - f l u o r o a c e t i c acid (2 ml) was added to the hydroxy hemiketal 204 (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 for 2 days. Coevaporation with xylene (2x4 ml) gave a dark syrup which was chromatographed on a column of s i l i c a gel (40 g) using a gradient of 9:1 to 1:1 benzene-ethyl acetate as developer. C o l l e c t i o n of the faster-moving U.V. a c t i v e , charring band gave the di-isopropylidenated d e r i v a t i v e 210 (136 mg, 33%) as a c l e a r syrup: [ct]^ 4 -36.0°(cl.0,CHCl 3) ; v ^ 1 * 1748 (-CO-Me), 1730 cm"1 (benzoate); n.m.r. (100MHz,CDCl3) 61.32, 1.37, 1.43 and 1.48(s,3H,2xC(CH 3)-), 2.80(d(overlapped by H-2b),lH,J__ 3 7.0Hz,H-2a), 2.81(d(overlapped by H-2a),lH,J- b 3 5.0Hz,H-2b), 3.74(s,3H,-0CH 3), 4.42-4.49(m,3H,H-7,H-8), 4.73 and 4.84(d(overlapped by H-3), 2H,J. 6 6.0Hz,H-5,H-6), 4.75(dd(partially overlapped by H-5 and H-6), J - a 3 7.0Hz,7o, „ 5.0Hz,H-3), 7.52(m,3H,Ar) 8.10(m,2H,Ar); mass spectrum: m/e 436 (m +), 421(m +-CH 3), 405(m +-OCH 3). Anal. Calc. for C-^H-gO-;C,60.54;H,6.47. Found:C,60.30; H.6.57. Continued e l u t i o n of the column gave the spiro 8-1,4-lactone 211 (34 mg,10%) as a clear syrup: [a]*2 -43.4(c0.7,CHC1-); v C C 1 4 3580 (OH), 1812 u -5 m__x (lactone), 1730 cm" 1(benzoate); n.m.r. (100MHz,CDCl3) 61.40 and 1.57(s,3H, C ( C H 0 ) 0 ) , 2.54(d,lH,J 17.5Hz,H-2a), 2.91(d,lH,J 17.5Hz,J„, . 4.7Hz,H-2b), —3 - gem gem _b,3 4.42(d(overlapped by H-8b),lH,J R 7.5Hz,H-8a), 4.43(d(overlapped by H-8a), 1H,J_ g b 6.0Hz,H,8b), 4.52(d,IH,J 2 a 3 4.5Hz,H-3), 4.67(dd,IH,J_ g a 7.5Hz, J_ g b 6.0Hz,H-7), 4.95 and 5.03(d,lH,J. g 6.0Hz,H-5,H-6), 7.54(m,3H,Ar), 8.10(m,2H,Ar), 3.32(broad s,lH,0H, exchangeable with D 20); mass spectrum: m/e 364(m +), 399(m +-CH 3), 277(m+-(CH3+CH0HCH2C0). Anal. Calc. for C-^H^Og:C,59 .33;H,5.53. Found: C,59 . 29 ;H,5.69. 192 Treatment of Ketal 204 with para-Toluenesulfonic Acid Monohydrate to give Compound 210, 211, 2-Benzoyloxymethyl-5-(carbomethoxyacetyl)furan (212), and 8-0-Benzoyl-2-deoxy-5,6-0-isopropylidene-g-D-altro-4-octulofuranosono-l,4- lactone (213) To a gently azeotroping s o l u t i o n of ketal 204 (220 mg) i n benzene (25 ml) was added a suspension of para-toluenesulfonic acid monohydrate (23 mg) i n benzene (10 ml) over 15 min while the reaction reaction mixture was main- tained at a volume of 20 to 25 ml. The s o l i d residue from the suspension was washed into the reaction f l a s k with methanol (0.5 ml) and s u f f i c i e n t fresh benzene was added to the azeotroping mixture to maintain the above volume. Af t e r a further 45 min, the mixture was allowed to cool and was then washed with saturated aqueous sodium hydrogen carbonate (6 ml), water (6 ml) and dried 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 evaporation of the benzene under reduced pressure gave a bright yellow syrup which was chromatographed on a column of s i l i c a gel (10 g) using a gradient of 4:1 to 1:1 benzene-ethylacetate as developer. A fast-moving component was quickly eluted to give the diisopropylidenated d e r i v a t i v e 210 (3 mg, 1.3%) which produced a n.m.r. spectrum i d e n t i c a l to the one obtained previously. Continued e l u t i o n of the column gave the di s u b s t i t u t e d furan d e r i v a t i v e MeOH 212 (19 mg, 11%) as a clear syrup: A 228 nm (e26,400), 276 nm (e27,800); Til 3.X v C H C l 3 1 7 5 Q (_ c o M e ) 1730(benzoate), 1670 cm"1 (ketone); n.m.r. (100MHz, max 2 CDC1.) 63.74(s,3H,OCH_), 3.88(s,2H.H-2), 5.39(s,2H,H-8), 6.67(d,1H,JC , 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 of the doublet at 66.67 collapsed to doublet at 67.28 to a s i n g l e t ; mass spectrum: m/e 302(m ), 229(m -CH 2C0 2CH 3). Anal. Calc. f o r C^H^Og :C, 63. 57 ;H,4.75. Found :C, 63.39 ;H, 4. 75. Further e l u t i o n of the column gave the spiro ct-1,4-lactone 211 (79 mg, 39%) as a cl e a r syrup: n.m.r. (100MHz,CDC13) 61.39 and 1.56(s,3H,C(CH 3) 2), 2.52 193 (d,lH,J 17.0Hz,H-2a), 2.91(m,lH,J 17.5Hz,J., _ 5.0Hz,Jo, n „ 2.0Hz, gem ' ' gem 2b, 3 2b, OH ' H-2b, add i t i o n of D o0 collapses m to a doublet of doublets with J 0 Z ZD , 3 5.0Hz and J 17.5Hz), 3.36(broad-pseudo-t,1H,J„, n „ 2.0Hz,J_ .„ 1.7Hz,0H, gem ' r 2b, OH 3, OH ' —' exchangeable with D 20), 4.42(d(overlapped by H-8b),lH,J 7 g a 7.5Hz,H-8a), 4.43 (d (overlapped by H-8a),lH, J , 6.0Hz,H-8b), 4.53(dd,lH,J„, _ 4.7Hz,J 0 „ T T /,ob z b , 3 j,OH 1.7Hz,H-3, the doublet of doublets collapsed to a doublet of 4.5Hz upon addit i o n of D 20) . The remainder of the spectrum was i d e n t i c a l to the spectrum of compound 211 previously produced. I r r a d i a t i o n of the doublet of doublet at 64.53 collapsed the m u l t i p l e t at 62.91 to a doublet of doublets (J gem 17.0Hz and J„ 2.0Hz). The addition of D„0 produced a spectrum which was Zb,On Z i d e n t i c a l to the one previously obtained from compound 211 i n deuterochloroform and D20. Continued e l u t i o n of the column with 1:1 benzene-ethyl acetate gave the 22 spiro S - l , 4 - l a c t o n e 213 (3.5 mg, 2%) as a clear syrup: [ « ] n -14.3 (c0.35, CHC1_); v C C 1 4 3500 (weak,broad,OH), 1805(lactone), 1727 cm" 1(benzoate); 3 max n.m.r. (100MHz,CDC13) 61.38 and 1. 65(s ,3H,C(CH_3)2) , 1.72(broad s(overlapped by CH-),1H,0H, exchangeable with D o0) , 62.57(dd,lH,J 17.5Hz,J„ _ 6.5Hz, J — z gem Za, j H-2a), 2.83(dd,lH,J 17.5Hz,J01_ _ 6.5Hz,H-2b), 4.38(broad pseudo-t,lH, gem zb,J J 2 3^6.5Hz,H-3,addition of D 20 produces a sharp t r i p l e t with 3 6.5Hz), 4.62(d(overlapped by H-8b),lH,J 4.0Hz,H-8a), 4.63(d(overlapped by H-8a), 1H,J-, 2.0Hz,H-8b), 4.75(d,lH,J c , 6.0Hz,H-5), 4.86(dd,lH,J c , 6.0Hz, / , o b , J , b -5,b J 6 ? 2.0Hz,H-6) approx. 4.82(m(buried under H-5 and H-6),1K.H-7), 8.58(m,3H, Ar ) , 8.09(m,2H,Ar). I r r a d i a t i o n of the broad pseudo-triplet at 64.38 collapsed the doublet of doublet at 62.57 and 2.83 to doublets (J ^17.5Hz): gem mass spectrum: m/e 349(m +-CH 3), 293(m++H-CH0HCH2C0), 235(293-acetone). 194 Treatment of Compound 204 with T r i f l u o r o a c e t i c Acid and Acetic Anhydride to give 3 >4 )5 >6-tetra-0-acetyl-8-0-benzoyl-2-deoxy-a(and 8)-D-altro- 4-octulofuranosonate (214) and (215), r e s p e c t i v e l y . A s o l u t i o n of the hydroxy hemiketal 204 (240 mg) i n 80% aqueous t r i f l u o r o a c e t i c acid was s t i r r e d for 20 min a f t e r which toluene (6 ml) was added and the r e s u l t i n g mixture was evaporated under reduced pressure to one ha l f the volume. Another aliquot of toluene (2 ml) was added and the mixture evaporated to dryness. The r e s i d u a l syrup was dissolved i n a mixture of acetic anhydride (2 ml), acetic acid (1 ml) and para-toluenesulfonic acid monohydrate (200 mg) and s t i r r e d a 0° for 3 h. Sodium acetate hydrate (250 mg) was then added to the mixture and s t i r r e d for an a d d i t i o n a l 15 min. The mixture was coevaporated with toluene (2x5 ml) to give a crude syrup which was then dissolved i n a 1:1 mixture of chloroform-water (20 ml). The aqueous phase was extracted with chloroform (2x10 ml) and the combined extracts washed with water (5 ml) and dried over anhydrous sodium s u l f a t e overnight. The drying agent was removed by f i l t r a t i o n and the r e s u l t i n g solution evaporated to give a crude brown syrup which was chromatographed on a column of s i l i c a gel (40 g) using 4:1 benzene-ethyl acetate as developer to give 22 the 8-tetraacetate 215 (23 mg, 7%) as a clear syrup: [a] + 10.7° ( c l . 4 , CHC1-); v C C l 4 1752(acetates), 1730 cm"1 (benzoate), n.m.r. (100 MHz,CDCl_) J max J 61.96, 2.03,2.04 and 2.14 (s,3H,4xCH.), 2.66(dd,lH,J 15.7Hz,J„ _ 8.3Hz, —3 gem 2a,3 H-2a), 3.06(dd,lH,J 15.7Hz,J-, - 4.5Hz,H-2b), 3.68(s,3H,-0CH,), 4.36- gem zb, 3 — J 4.71(m,3H,H-7,H-8), 5.82 (pseudo-q(overlapped by H-6),J 2 a . 8.3Hz,J_ b _ 4.5Hz, H-3), 5.80(pseudo-t(overlapped by H-3),J. , 6.0Hz,J £ _ 6.0Hz,H-6), 6.04(d, 1H,J. 6 6.0Hz,H-5), 7.55(m,3H,Ar), 8.10(m,2H,Ar). Continued e l u t i o n with 4:1 benzene-ethyl acetate gave the anomeric ct-tetraacetate 214 (80 mg, 25%) as a clear syrup: [ a ] 2 2 +21.7 (£0.9,CHC1 3); 195 CC1 v max 4 1762 (very strong, broad band of the acetates), 1733 cm 1 (benzoate); n.m.r. (100 MHz,CDCl3) 61.83 and 2. 02 (s, 3H, 2xCH_3) , 2.08 (s, 6H, 2xCH_3), 2.57 (dd.lH.J 16.0Hz,J o _ 8.0Hz,H-2a), 2.85(dd,lH,J 16.0Hz,J O L . 5.0Hz, gem za, 3 gem 2b, 3 H-2b), 3.58(s,3H,-OCH„), 4.45(dd,lH,J 12.0Hz,J_ 0 2.7Hz,H-8a), 4.54-4.67 — J gem /,oa (m,lH,H-7), 4.77(dd,lH,J 12.0Hz,J^ 2.0Hz,H-8b), 5.33(dd,1H,J c , 5.5Hz, gem /,ob D,b J , _ 7.3Hz,H-6), 5.49(d,lH,J c , 5.5Hz,H-5), 6.02(dd,1H,J. _ 8.0Hz,J„, _ b, / j,b za, J Zb,J 5.0Hz,H-3), 7.68(m,3H,Ar) 8.09(m,2H,Ar). I r r a d i a t i o n of the doublet of doublets at 66.02 collapsed the two doublet of doublets at 62.57 and 2.85 to doublets with J 16.0Hz. I r r a d i a t i o n of the multiplet at 64.61 gem collapsed the doublet of doublets at 65.33 to a doublet with J c , 5.5Hz; 5,6 mass spectra: m/e 524(m +), 493(m +-0CH 3), 465(m +-0 2CCH 3), 379(m +-CH(OAc)CH 2C0 2CH 3) 8. Attempted Synthesis of a Ketose N-nucleoside 2',3",5'-Tri-O-benzoyl-uridine (217) 193 Following the method of Vorbruggen and Bennua , a mixture of 1-0- acetyl-2,3,5-tri-0-benzoyl - B-D-ribofuranose (134) (526 mg, 1.04 mmol) and u r a c i l (216)(119 mg, 1.08 mmol) was a z e o t r o p i c a l l y dried with toluene and then a s o l u t i o n of trimethylchlorosilane (0.10 ml), hexamethyldisilazane (0.17 ml), stannic chloride (0.14 ml) i n anhydrous a c e t o n i t r i l e (15 ml) was added and 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 at room temperature for 2 h. The reaction mixture was then poured into a s t i r r e d mixture of ice-cooled dichloromethane (75 ml) and saturated aqueous sodium hydrogen carbonate (30 ml) and s t i r r e d for 10 min. The organic phase was separated and the emulsified residue was extracted with dichloromethane (20 ml). The organic extracts were combined and dried over anhydrous sodium s u l f a t e p r i o r to evaporation to give a clear syrup (557 mg). Column chromatography of the product on s i l i c a gel (40 g) using 2:1 benzene-ethylacetate as developer yielded the benzoylated uridine 196 193 d e r i v a t i v e 217 (398 mg, 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 which was r e c r y s t a l l i z e d from chloroform-hexanes; m.p. 146.5-149T ( l i t 146-148°). Two smaller scale reaction with 40 mg of compound 134 gave comparable y i e l d s . Attempted Synthesis of Methyl[1-(3,5,6-tri-0-acetyl-8-Q-benzoyl-2-deoxy- q(and/or 8)-D-altro-4-octulofuranosyl)uraciljonate 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 mixture of the acetylated ketose 214 (40 mg) and u r a c i l (9 mg) was added 1.1 ml of the same s i l a t i n g mixtured used i n the synthesis of compound 217 (see previous page). The mixture was s t i r r e d at room temperature for 3 days a f t e r which time the mixture was poured into an ice-cooled mixture of dichloromethane (4 ml) and saturated aqueous sodium hydrogen carbonate (2 ml). The mixture was vigorously s t i r r e d f o r 10 min and the organic phase withdrawn and dried over sodium s u l f a t e . Removal of the drying agent by f i l t r a t i o n and evaporation of the solvents under reduced pressure gave a crude syrup (20 mg) which was chromatographed on a pre- parative t . l . c . plate (15x20 cm, 1.0 mm) to give s i x components none of which from t h e i r n.m.r. spectra i n DMSO-d^ exhibited any l o w - f i e l d hydrogens (eg NH) nor a doublet at ^65.5-6.0 for H-5 of the u r a c i l moiety. (b) A mixture of the acetylated ketose 214 (60.5 mg) and u r a c i l (13.8 mg) was azeotroped with benzene (2 ml). To the residue was added a s o l u t i o n of t r i f l u o r o s u l f o n i c acid (12 u£), trimethylchlorosilane (18 u£), hexamethyldisila- zane (27 y2,) and a c e t o n i t r i l e (1.6 ml). This mixture was protected with a phosphorus pentoxide drying tube and refluxed for 22 h a f t e r which time the cool s o l u t i o n was poured into a vigorously s t i r r e d ice-cooled mixture of dichloromethane (3 ml) and saturated aqueous sodium hydrogen carbonate (2 ml). The aqueous phase was extracted with dichloromethane and the combined organic extracts 197 dried over anhydrous sodium s u l f a t e . T . l . c . of the extract indicated the presence of at least s i x components, none of which predominated nor exhibited strong U.V. a c t i v i t y ; therefore, the mixture was not analyzed further. A p p l i c a t i o n of the Fusion Reaction to Compound 214 (a) A mixture of compound (214) (100 mg, 0.2 mmol) and2,6-dichloro- purine (218) (62 mg, 0.3 mmol) was a z e o t r o p i c a l l y dried with toluene (5 ml) and the r e s i d u a l mixture fused at 150-155° (bath temperature) to a clear melt which was s t i r r e d for 30 min at 15 t o r r . The darkened melt was then allowed to cool and t . l . c . analysis of the mixture indicated only one charring band that absorbed u.v. l i g h t and had the same R. as the s t a r t i n g compound. (b) Para-toluenesulfonic acid monohydrate (12 mg) was added to the above mixture and t h i s new mixture was a z e o t r o p i c a l l y dried with toluene (3 ml). The residue was fused at 150-155° to a c l e a r , l i g h t brown melt which was s t i r r e d for 30 minutes at 15 t o r r . T . l . c . of the cooled melt gave the same r e s u l t s of part (a). B i s ( t r i m e t h y l s i l y l ) t h y m i n e (219) A suspension of powdered thymine (5.16 g, predried at 100°/0.10 torr for 1 h) i n d i s t i l l e d hexamethyldisilazane (32 ml) and trimethylchlorosilane (10 drops) was refluxed for 12 h a f t e r which time very l i t t l e change was observed i n the suspension. The suspension was then allowed to cool and s o l i d ammonium s u l f a t e (140 mg) was added to the mixture which was again refluxed. After 10 h a l l of the thymine had gone into s o l u t i o n and the excess hexamethyldisilazane was then removed under vacuo. The r e s i d u a l amber syrup was dissolved i n anhydrous 1,2-dichloroethane (67 ml, ^0.5M solution) and 198 used In subsequent reactions without further p u r i f i c a t i o n . Synthesis of Methyl(E,Z)-4,7-anhydro-8-0-benzoyl-3-bromo-2,3-dideoxy- 5,6-0-isopropylidene-D-ribo-oct-3-enonate (220) from 172 To a s o l u t i o n of the methyl oct-3-enonate 172 (174 mg, 0.5 mmol) i n anhydrous 1,2-dichloroethane (2 ml) was added bromine (^0.5 ml of a 1.0M solu t i o n of bromine i n 1,2-dichloroethane). The s o l u t i o n was s t i r r e d for 10 min at room temperature a f t e r which time b i s ( t r i m e t h y l s i l y l ) t h y m i n e (219)(1.0 ml of a ^0.5M s o l u t i o n of 219 i n 1,2-dichloroethane) was added followed by t i n t e t r a c h l o r i d e (0.06 ml, 1.0 equiv i n 1.0 ml 1,2-dichloroethane). The mixture was s t i r r e d at room temperature for 16 h a f t e r which time t . l . c . a n a l y s i s of the rea c t i o n mixture indicated complete consumption of the s t a r t i n g compound and the presence of one faster-moving component (R^ 0.443, s t a r t i n g compound 0.385 using 4:1 benzene-ethylacetate as developer) 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 mixture was d i l u t e d with chloroform (5 ml) and washed with saturated aqueous sodium hydrogen carbonate (2x3 ml) and water (3 ml) and dried over anhydrous sodium s u l f a t e . F i l t r a t i o n and evaporation of the organic phase gave a crude dark syrup which was chromatographed on a column of s i l i c a gel (10 g) using 4:1 benzene- ethylacetate as developer to give 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, 34%) as a clear syrup which from i t s n.m.r. spectrum was a 2:1 r a t i o of the geometric isomers: 1750(-CO2<IH3), 1732(benzoate), 1692 cm _ 1(C=C); n.m.r. (100MHz, DMS0-d6, major(M) and minor(m) isomers) 61.34 and 1.40(s,3H,C(CH 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), 4.89 — J / , o (t,lH,J_, _ 3.4Hz,H-7), 5.03(d,lH,J c , 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). Addition of D 20 does not a f f e c t the above resonances; mass spectrum; m/e 440/442(m+), 425/427(m +-CH 3), 408/410 199 (m+-CH3OH), 261/263(m++H-BzOH-Acetone). Storage of compound 220 at room temperature as a syrup or i n so l u t i o n (chloroform) resulted i n a slow au t o - c a t a l y t i c decomposition giving a black charred s o l i d or s o l u t i o n . Heating compound 220 under vacuo at 65° for several hours also produced a black char. 200 V BIBLIOGRAPHY 1) E. Fisher and K. Zach, Sitzber, Kgl. preuss. Akad. Wiss., 16, 311 (1913); Chem. Zentr., 1668 (1913,1). 2) B. H e l f e r i c h , Adv. Carbohydr. Chem., 7_, 209 (1952). 3) M.G. B l a i r , Adv. Carbohydr. Chem., 9_, 97 (1954). 4) R.J. F e r r i e r , Adv. Carbohydr. Chem., 20, 67 (1965). 5) R.J. F e r r i e r , Adv. Carbohydr. Chem., 24, 199 (1969). 6) J . K i s s , Adv. Carbohydr. Chem., 29, 229 (1974); a) p.277-80. 7) M.S. Feather and J.F. Ha r r i s , Adv. Carbohydr. Chem., ̂ 8, 161 (1973). 8) Y.A. Zhdanov, Y.E. Alexeev, and V.G. Alexeeva, Adv. Carbohydr. Chem., 27_, 227 (1972). 9) H. Hoeksema, G. Slomp, and E.E. van Tamelen, Tetrahedron L e t t . , 1787 (1964). 10) N. Stake, S. Takeuchi, T. EndO, and H. Yonehara, Tetrahedron L e t t . , 1405 (1965); i b i d . , 1411 (1965); Agr. B i o l . Chem. (Tokyo), 30, 132 (1966); J . J . Fox and K.A. Watanabe, Tetrahedron L e t t . , 897 (1966); H. Yonehara and N. 5take, i b i d . , 3785 (1966). 11) D.J. Cooper, R.S. Joret and H. Reimann, Chem. Commun., 285 (1971). 12) K. Tokuyama, Japan Pat. 18,622 (1967); Chem. Abstr. 68, 59845 (1968). 13) R.J. F e r r i e r and P.M. C o l l i n s , "Monosaccharide Chemistry", Penguin Books Ltd., England, 1972; a) p.181; b) p.45. 14) R.J. Suhadolnik, "Nucleoside A n t i b i o t i c s " , Wiley-Interscience, New York, 1970, p.170. 15) W.A. Bowles and R.K. Robins, J. Am. Chem. S o c , 86, 1252 (1964). 16) W.S. Johnson, M.B. Gravestock, R.J. Parry, R.F. Myers, T.A. Bryson, and D.H. Miles, J . Am. Chem. S o c , 9_3, 4330 (1971). 17) G. W i t t i g and G. G e i s s l e r , Ann., 580, 44 (1953). 18) L. Horner, H. Hoffman, and H.G. Wippel, Chem. Ber., 91, 61 (1958); W.S. Wadsworth, O.E. Schupp, I I I , E.J. Seus, and J.A.~Ford, J r . , J.' Org. Chem., 30, 680 (1965). 19) R. Kuhn and R. Brossmer, Angew. Chem., 74_, 252 (1962). 201 20) H.P. Albrecht, D.B. Repke, and J.G. Moffat, J . Org. Chem., 39, 2176 (1974). 21) P. Howgate, A.S. Jones, and J.R. Tettensor, Carbohydr. Res., 12, 403-408 (1970). 22) Y.A. Zhdanov and V.A. Polenov, Carbohydr. Res., 1_6, 466 (1971). 23) C P . Moss, C.B. Reese, K. S c h o l f i e l d , R. Shapiro, and Lord A. Todd, J. Chem. S o c , 1149 (1963). 24) J. Zemlicka, R. Gasser, and J.P. Horwitz, J . Am. Chem. S o c , 4744 (1970). 25) K.L. Nogpal and J.P. Horwitz, J . Org. Chem., 3_6, 3743 (1971). 26) D. Horton and J.D. Wander, Carbohydr. Res., 13, 33-47 (1970). 27) J . March, "Advanced Organic Chemistry", 2nd Ed., McGraw-Hill Book Company, New York, 1977; a) p.923; b) p.644; c) p.1011. 28) F.H. Newth, Adv. Carbohydr. Chem., 6, 83 (1951). 29) H.S. I s b e l l , J . Res. Nat. Bur. Stand., _32, 45 (1944). 30) R.E. M i l l e r and S.M. Cantor, J. Am. Chem. S o c , 74, 5236 (1952). 31) W.N. Haworth and W.G.M. Jones, J. Chem. S o c , 667 (1944). 32) M.L. Mednick, J . Org. Chem., 27, 398 (1962); C.J. Moye and Z.S. Krzeminski, Aust. J. Chem., 1_6, 258 (1963); C.J. Moye, Aust. J . Chem., 19_, 2317 (1966); T.G. Bonner, E.J. Bourne, and M. Ruskiewicz, J. Chem. Soc. 787 (1960). 33) M.L. Wolfrom, E.G. Wallace, and E.A. Metcalf, J. Am. Chem. S o c , 21» 3518 (1949). 34) R.J. F e r r i e r , i n "Methods i n Carbohydrate Chemistry", R.L. Whistler and J.N. BeMiller, ed., Academic Press, New York, Vol. VI, 1972, p.307. 35) D.R. Rao and L.M. Lerner, Carbohydr. Res., 1_9, 133 (1971). 36) a) G.O. P h i l l i p s , Adv. Carbohydr. Chem., 18, 9(1963). b) B.A. Bohm and P.I. A b e l l , Chem. Rev., 62, 599-609 (1962). 37) L. Friedman and H. Schechter, Tetrahedron Lett. , No. 7, 238 (1961). 38) A. Rieche, E. Schmitz, and E. Grundemann, Angew. Chem., 73., 621, (1961). 39) D. Elad, Chem.Ind. (London), 362 (1962). 40) a) D. Elad and J . Rokach, J . Org. Chem., 29, 1855 (1964); b) J. Chem. S o c , 800, (1965); c) J . Org. Chem. 30, 3361 (1965); d) i b i d . , 4210 (1966). 202 41) Reference (27), p.688. 42) R.L. Huang, J. Chem. S o c , 1342 (1957). 43) J.M. Coxon and B. Halton, "Organic Photochemistry", Cambridge U n i v e r s i t y Press, London, 1974; a) p.167; b) p.24. 44) J . O i l i v i e r and C. L e i b o u i c i , Tetrahedron, 27_, 5515 (1971). 45) H.E. O'Neal and C.W. Larson, J. Phys. Chem. 73, 1011 (1969). 46) V.L. Ermolaev, Uspekhi F i z . Nauk, 80, 3 (1963). English Translation; Soviet Physics, Uspekhi, Nov.-Dec, 1963, p.333. 47) A. Rosenthal and M. R a t c l i f f e , Can. J. Chem., _54, 91-96 (1976). 48) M. R a t c l i f f e , Ph.D. Thesis, University of B r i t i s h Columbia, 1975, a) p.108-109; b) p.116. 49) A. Rosenthal and M. R a t c l i f f e , Carbohydr. Res., 39, 79-86 (1975). 50) A. Rosenthal and Zanlungo, Can. J . Chem., 50, 1192 (1972). 51) A. Rosenthal and K. Shudo, J. Org. Chem., 37_, 1608 (1972). 52) a) F. Shafizadeh i n "Methods of Carbohydrate Chemistry", R.L. Whistler and M.L. Wolfrom, ed., Academic Press, New York, 1962, Vol. 1, p.208. b) K. Freudenberg, 0. Burkhard, and E. Braun, Ber., 59_, 714 (1926). 53) A. Rosenthal and M. R a t c l i f f e , Carbohydr. Res., 54, 61-73 (1977). 54) A.S. P e r l i n and P. Herve duPenhoat, Carbohydr. Res., 36, 111-120 (1974) . 55) CM. Wyman, Chem. Rev., 55, 625-657 (1955). 56) A.C. Testa, J . Org. Chem., 29.» 2 4 & 1 (1964), and references c i t e d t h e r e i n . 57) G.S. Hammond, J . S a l t i e l , A.A. Lamola, N.J. Turro, J.S. Bradshaw, D.O. Cowan, R.C. Counsell, V. Vogt, and C. Dalton, J. Am. Chem. S o c , 86, 3197 (1964). 58) J . S a l t i e l , J. Am. Chem. S o c , 90_, 6394 (1968); J. S a l t i e l and E.D. Megarity, i b i d . , 91, 1265 (1969); J . S a l t i e l , K.R. Neuberger, and M. Wrighton, i b i d . , 91, 3658 (1969). 59) See reference (43), p.24. 60) A. Cox and T.J. Kemp, "Introductory Photochemistry", McGraw-Hill, London, 1971, p.138. 61) See reference 27, p.626-627. 62) S.C. Dickerman and G.B. Vermont, J. Am. Chem. S o c , 84, 4150 (1962); R.T. Morrison, J . Cazes, W. Samkoff, and CA. Howe, J . Am. Chem. S o c , 84, 4152 (1962). 203 63) R.F. Heck, J. Am. Chem. S o c , 9_0, 5518, 5526, 5535 (1968). 64) C.S. Rondestvedt, J r . , Org. React., 11, 189-260 (1960). 65) W. Wolf and N. Karasch, J. Org. Chem. 30.. 2493 (1965). 66) J.B. Hendrickson, Angew. Chem. Int. Ed. Engl., 13_, 47-76 (1974). 67) E. Oliveri-Mandala and E. Calderao, Gazz. chim. i t a l . , _t5_, I, 307 (1915); E. Oliveri-Mandala, i b i d . , 45, II , 120 (1915). 68) J.H. Boyer, J . Am. Chem. S o c , 73, 5248 (1951). 69) M.E.C. B i f f i n , J. M i l l e r , and D.B. Paul i n "The Chemistry of the Azido Group", S. Pa t a i , ed., Interscience Publishers, London, 1971, p. 61. 70) N. Gregersen and C. Pedersen, Acta. Chem. Scand., 26_, 2695 (1972). 71) T. Sakakibara, R. Sudoh, and T. Nakagawa, J. Org. Chem., 38_, 2179 (1973). 72) A. Rosenthal and M. R a t c l i f f e , Carbohydr. Res., j$0, 39-49 (1978). 73) See reference (48), p.120. 74) J.B. Hendrickson, Angew. Chem. Int. Ed. Engl., 1_3, 47-76 (1974). 75) See reference (27), p.345-346. 76) A.S. Matthews, W.G. Overend, F. Shafizadeh, and M. Stacey, J. Chem. Soc., 2511 (1955). 77) R.J. F e r r i e r , J. Chem. S o c , 5443 (1964). 78) A. McKenzie, J. Chem. S o c , 1196 (1912). 79) R.C. Fahey and H. Schneider, J. Am. Chem. S o c , 90, 4429 (1968). 80) J.A. Pincock and K. Yates, Can. J . Chem., 48, 2944 (1970). 81) R.U. Lemieux and B. Frazer-Reid Can. J. Chem., 43, 1460 (1965). 82) a) W. Kitching, Organomet. React., 3>» 319-398 (1972), Organomet. Chem. Rev., 3, 61-134 (1968). b) N.S. Zefir o v , Russ. Chem. Rev., 34, 527-36 (1965). 83) H.C. Brown and P. Geophegan, J r . , J. Am. Chem. S o c , 89, 1522, (1967). 84) a) G.R. I n g l i s , J.C.P. Schwarz, and L. McLaren, J . Chem. S o c , 1014 (1962); b) P.T. Manolopoulos, M. Mednick, and N.N. L i c h t i n , J . Am. Chem. S o c , 84, 2203 (1962). 204 85) H.O. House, "Modern Synthetic Reactions", 2nd Ed., W.A. Benjamin, Inc., C a l i f . , 1972, a) p.298; b) p.314; c) pp.19-22; d) pp.12-13. 86) P.O. B a r t l e t t , Rec. Chem. Prog. 11, 47 (1950). 87) a) H. Kwart and D.M. Hoffman, J . Org. Chem., 31, 419 (1966). b) For another mechanism, see R.P. Hanzlik and G.O. Shearer, J . Am. Chem. S o c , 97, 5231 (1975). 88) H.B. Wood, J r . , and H.C Fletcher, J r . , J . Am. Chem. S o c , _79_, 3234 (1957). 89) a) I.J. Borowitz, G. Gonis, R. Kelsey, R. Rapp, and G.J. Williams, J. Org. Chem., 31, 3032 (1966). b) F i r s t used for hydroxylation by R. Criegee, Jutus Liebigs Ann. Chem., 522, 75 (1936). 90) F.D. Gunstone, Adv. Org. Chem., JL, 103 (1960). 91) a) D.H.R. Barton and D. Elad, J. Chem. S o c , 2085 (1956); b) J . C a s t e l l s , CD. Meakins, and R. Swindells, i b i d . , 2917 (1962). 92) H.B. Henbest, W.R. Jackson, and B.C.G. Robb, J . Chem. S o c , B, 803 (1966). 93) R.E. Erickson and R.L. Clark, Tetrahedron L e t t . , No. 45, 3997 (1969). 94) J. Betts, Q. Rev., Chem. S o c , 25, 265-288 (1971). 95) D.R. Kearns, Chem. Rev., 71, 395-427 (1971). 96) A. Nickon and W.L. Mendelson, J . Am. Chem. S o c , 87, 3921 (1965). 97) H.M.R. Hoffmann, Angew. Chem. Int. Ed. Engl., 8, 556-577 (1969). 98) W. F e n i c a l , D.R. Kearns, and P. Radlick, J . Am. Chem. S o c , 3396, 7771 (1969); D.R. Kearns, Chem. Rev., 71, 395-427 (1971). 99) R. Hiatt i n "Oxidation", R.L. Augustine and D.J. Trecker, ed., Marcel Dekker, Inc., New York, 1971, p.113. 100) See reference (27), p.1012. 101) A.J. Bailey, S.A. Barker, and M. Stacey, J. Chem. S o c , 1663 (1963). 102) H. Arzoumanian, E.M. Acton, and L. Goodman, J . Am. Chem. S o c , 86, 74 (1964). 103) R.D. Guthrie i n "Methods i n Carbohydrate Chemistry". R.L. Whistler and M.L. Wolfrom, ed. Academic Press, Vol. I, 1962, p.432. 104) G.J. Buist, C A. Bunton, and J.H. Miles, J . Chem. S o c , 743 (1959). 205 105) Personal communication with Dr. Robert Murray R a t c l i f f e , Edmonton, Alberta. 106) Personal discussions with Professor S i r Derek H.R. Barton. 107) C. Dj e r a s s i , Chem. Rev. 43, 271-317 (1948). 108) H.P. Dauben, J r . and L.L. McCoy, J. Am. Chem. S o c , 81, 4863 (1959); J. Adam, R.A. Gosselain, and P. Goldfinger, Nature, 171, 704 (1953). 109) B.P. McGrath and J.M. Tedder, Proc. Chem. S o c , 80 (1961). 110) W.E. Cohn, Biochim. Biophys. Acta, 32, 569-571 (1959). 111) a) W.E. Cohn, J. B i o l . Chem., 235, 1488-1498 (1960). b) A.M. Michelson and W.E. Cohn, Biochemistry, 1, 490 (1962). 112) S. Hanessian and A.G. Pernet, Advan. Carbohydr. Chem. Biochem., 33, 111 (1976). 113) R.J. Suhadolnik, "Nucleoside A n t i b i o t i c s " , Wiley-Interscience, New York, 1970. 114) L. Sasse, M. Rabinowitz and I. Golberg, Biochim. Biophys. Acta, 7_2, 353 (1963). 115) F.F. Snyder and J.F. Henderson, J . B i o l . Chem., 248, 5899 (1963). 116) G. Doyle Daves, J r . and C.C. Cheng, Prog. Med. Chem., 13, 303 (1976). 117) H. Nishimura, M. Mayama, Y. Komatsu, H. Kato, N. Shimaoka, and Y. Tanaka, J. A n t i b i o t i c s (Tokyo), 17A, 148 (1964). 118) a) Y. Nakagawa, H. Kano, Y. Tsukuda, and H. Koyama, Tetrahedron L e t t . , No. 42, 4105-4109 (1967). b) Y. Tsukuda, Y. Nakagawa, H. Kano, T. Sato, M. Shiro, and H. Koyama, Chem. Commun., 975 (1967). c) K.R. D a r n e l l , L.B. Townsend, and R.K. Robins, Proc. N a t l . Acad. S c i . (U.S.), 57_> 548 (1967). 119) L. Kalvoda, J . Farkas, and F. Sorm, Tetrahedron L e t t . , 2297 (1970). 120) G. Trummlitz and J.G. Moffatt, J. Org. Chem.,38, 1841 (1973). 121) a) L. Kalvoda, C o l l . Czech. Chem. Commun., 37_, 4046 (1972); b) i b i d . , 41, 2034 (1976). 122) L. Kalvoda, J. Carbohydr. Nucleos, Nucleot., 3, 47 (1976). 123) J.G. Buchanan, A.R. Edgar, M.J. Power, and C.T. Shanks, J . Chem. S o c , Perkin Trans. I, 225 (1979). 206 124. a) R.E. Harmon, G. Wellman, and S.K. Gupta, Carbohydr. Res., 11_, 574 (1969); b) i b i d . , 14, 123 (1970). 125. C.K. Chu, K.A. Watanabe, A. Kyoichi, and J. J . Fox, J. Heterocycl. Chem., 12, 817 (1975). 126. J.H. Burchenal, K. Ciovacco, K. Kalaher, T. O'Toole, R. Kiefner, M.D. Dowling, C.K. Chu, K.A. Watanabe, I. Wempen, and J. J . Fox, Cancer Res., 3_6, 1520 (1976). 127. M. Bobek, J. Farkas, and F. Sorm, C o l l e c t . Czech. Chem. Commun., 34_, 1690 (1969). 128. a) R. Noyori, T. Sato, Y. Hayakawa, J. Am. Chem. S o c , 100, 2561-3 (1978); b) Tetrahedron L e t t . , 1829-1832 (1978). 129. J.G. Buchanan, A.R. Edgar, and M.J. Power, J. Chem. S o c , Perkin Trans. I, 1943-1949 (1974); Chem. Commun., 346-347 (1972); 501-502 (1975). 130. B. Coxon, Tetrahedron, Z2, 2281 (1966). 131. M. Bobek and J . Farkas, C o l l . Czech. Commun., 34, 247-252 (1969). 132. H.-J. Knackmuss, Angew. Chem. Int. Ed. Engl., 12, 139 (1973). 133. G.E. Gutowsky, M. Chaney, H.D. Jones, R.L. Hamill, F.A. Davis, and R.D. M i l l e r , Biochem. Biophys. Res. Commun., 51_, 312 (1973). 134. E.M. Acton, K.J. Ryan, D.W. Henry, and L. Goodman, J. Chem. S o c , Chem. Commun., 986 (1971). 135. M. Bobek, J. Farkas, and F. Sorm, Tetrahedron L e t t . , 4611 (1970). 136. a) W. Schroeder, and H. Hoeksema, J . Am. Chem. S o c , 81, 1767 (1959). b) J. Farkas and F. Sorm, C o l l . Czech, Commun., 28_, 882 (1963). 137. J.R. McCarthy, J r . , R.K. Robins, and M.J. Robins, J . Am. Chem. Soc., 90, 4993 (1968). 138. J. Farkas and F. Sorm, C o l l . Czech. Commun., 3_2, 2663 (1967). 139. Terochem Laboratories Ltd. (Edmonton, Alberta, Canada). 140. a) H.M. Kissman, C. Pidacks, and B.R. Baker, J. Am. Chem. S o c , 77, 18 (1955). b) E.F. Recondo and H. Rinderkneecht, Helv. Chim. Acta., 42, 1171-3 (1959). 141. a) H.P. Albrecht, D.B. Repke, and J.G. Moffatt; J . Org. Chem., 3_8, 1836 (1973) . b) D.C. DeJongh and K. Biemann, J. Am. Chem. S o c , 86̂ , 67 (1964). 207 142. a) W. Adam, J. Baeza, and J-C. L i u , J . Am. Chem. S o c , 94_, 2000 (1970); b) F. Merger, Chem. Ber., 101, 2413 (1968); c) R.G. Blume, Tetrahedron L e t t . , 1047 (1969). 143. a) R.T. Conley, "Infrared Spectroscopy", A l l y n and Bacon, Inc., Boston, 1966, p.141; b) p.164; c) p.113 and 116; d) 135. 144. B.C. C h a l l i s and J.A. C h a l l i s , i n "The Chemistry of Amides" J . Zabicky, ed. Interscience Publishers (John Wiley and Sons), London, 1970, p.767. 145. a) M. Brenner, Ger. Pat., 1,068,721 (1959). b) A.T. de Mouilpied and A. Rule, J. Chem. S o c , 91, 176 (1907). c) E. Sondheimer and R.W. Holley, J. Am. Chem. S o c , 7_6, 2467 (1954). 146. a) O.L. Chapman and R.W. King, J. Am. Chem. S o c , 86, 1259 (1964). b) We are indebted to Dr. Y. Nakagawa of the Shionogi Research Laboratory for the n.m.r. spectrum of dihydroshowdomycin and rep r i n t s of showdomycin papers. 147. M. Sundaralingham, Ann. N.Y. Acad. S c i . , 255, 3 (1975). 148. A. Saran, C.K. Mitra, and B. Pullman, Int. J. Quantum Chem., Quantum B i o l . Symp. , 4(Proc. Int. Symp. Quantum B i o l . Quantum Pharmacol., 4th), 43-54 (1977); Chem. Abstr., 88, 74512 g. 149. a) see reference (27), pp. 1077-1081. b) see reference (85), pp. 34-44. c) L.F. Fieser and M. Fiese r , "Reagents for Organic Synthesis", John Wiley and Sons, Inc., New York, 1967. 150. D.L. Evans, D.K. Minster, U. J o r d i s , S.M. Hecht, A.L. Mazzu, J r . , and A.I. Meyers, J. Org. Chem., 44, 497 (1979). 151. K. Nakagawa, R. Konaka, and T. Nakata, J . Org. Chem., 27_, 1597 (1962). 152. a) P.W.O. M i t c h e l l , Can. J . Chem., 41, 550 (1963). b) D. Walker and T.D. Waugh, J . Org. Chem., 30, 3240 (1965). 153. C.S. Barnes and D.H.R. Barton, J. Chem. S o c , 1419 (1953). 154. R.K. H i l l , J. Org. Chem., 26, 4745 (1961). 155. M.A. Kovbuz, I.I. Artym, K.R. Gorbachevskaya, S.S. Ivanchev, Chem. Abs., 88, 22158b (1978). 156. E.D. Hughes and H.B. Watson, J. Chem. S o c , 1733-40 (1930). 157. a) R.A. Barnes, J . Am. Chem. S o c , 7_0, 145-7 (1948). b) R.A. Barnes and G.R. Buckwalter, J . Am. Chem. S o c , 7_3, 3858-61 (1951). 208 158. M. Karplus, J . Chem. Phys., 30, 11 (1959). 159. a) V.M. Parikh, "Absorption Spectroscopy of Organic Molecules", Addison- Wesley Publishing Company, Canada, 1974, pp.106-9; b) pp. 262-7; c) p.257; d) pp.59-62; e) p.19; f) p.99; g) p.250. 160. L.M. Jackman and S. S t e r n h e l l , "Applications of Nuclear Magnetic Resonance Spectroscopy i n Organic Chemistry", 2nd Ed., Pergamon Press, New York, 1969, p.278. 161. A. Rosenthal, Carbohydr. Res., 8_, 61-71 (1968). 162. G. L'abbe, Chem. Rev., 69_, 345 (1969). 163. S.W. Tobey, J. Org. Chem., 34, 1281 (1969). 164. J.B. Stothers, "Carbon-13 NMR Spectroscopy", Academic Press, New York, 1972, pp. 405-408. 165. T. Sakakibara, T. Kawahara, and R. Sudoh, Carbohydr. Res., 58, 39- 46 (1977). 166. L. Hough and A.C. Richardson i n , "Rodd's Chemistry of Carbon Compounds", 2nd Ed., S. Coffey, ed., E l s e v i e r Publishing Company, Amsterdam, 1967, Vol. 1, Part F, pp.168-169. 167. H. Ohrui, G.H. Jones, J.G. Moffat, M.L. Maddox, A.T. Christensen, and S.K. Byram, J . Am. Chem. S o c , 9_7, 4602 (1975). 168. C.S. Hudson, J . Chem. Educ., 18, 353 (1941). 169. C i r c u l a r #400 of the U.S.A. National Bureau of Standards, 1942, p.516. 170. C.K. Alden and D.I. Davies, J. Chem. S o c , C, 700 (1968). 171. P.CM. Herve du Penhoat and A.S. P e r l i n , Carbohydr. Res., 71_, 149-167 (1979). 172. C L . Stevens, R.P. G l i n s k i , K.G. Taylor, P. Blumbergs, and S.K. Gupta, J. Am. Chem. S o c , 92, 3160 (1970). 173. R. Huisgen G. Szeimes, and L. Mobius, Chem. Ber., 89, 475 (1966). 174. G. Szeimes and R. Huisgen Chem. Ber., 89_, 491 (1966). 175. J.H. Brewster, J . Am. Chem. S o c , 81_, 5475. This a p p l i c a t i o n i s based on the conformational s i m i l a r i t i e s of the compounds i n question and ignores possible intramolecular factors such as hydrogen- bonding. 176. A. Rosenthal and M. R a t c l i f f e , J . Carbohydr. Nucleos. Nucleot., 4_, 199-214 (1977). 209 177. D. Todd, Org. Reactions, 4̂  378 (1948). 178. G.E. Gutowski, M.J. Sweeney, D.C. Delong, R.L. Hamill, K. Gerzon, and R.W. Dyke, Ann. N.Y. Acad. S c i . , 255, 544 (1975). 179. a) M. Fieser and L.F. Fie s e r , "Reagents for Organic Synthesis", Vol. 1, Wiley-Interscience, New York, 1969, p.61, b) W.B. Wright, J r . , J. Heterocyclic Chem., 2_, 41 (1965). 180. a) F. M i n i s c i and R. G a l l i , Chem. Abstr., 62, 8239f (1964). b) H. Schafer, Angew. Chem. Int. Ed. Engl., 9_, 158 (1970). 181. F. M i n i s c i and R. G a l l i , Tetrahedron L e t t . , 533-8 (1962); Chem. Abstr., 57, 14913f (1962). 182. S. Korcek, J.H.B. Chenier, J.A. Howard, and K.U. Ingold, Can. J . Chem., 50_, 2285 (1972). 183. H.J. Dauben, J r . , and L.L. McCoy, J. Org. Chem., 24, 1577 (1959). 184. a) S. Mazur and C.S. Foote, J . Am. Chem. S o c , 92, 3223, 3225 (1970). b) A.P. Schaap and P.D. B a r t l e t t , i b i d . , 92, 6055 (1970). 185. A. Rosenthal and L. (Benzing) Nguyen, Tetrahedron L e t t . , 2393 (1967). 186. A. Rosenthal and K. Shudo, J. Org. Chem., 37, 4391 (1972). 187. A.S. P e r l i n , N. Cyr, H.J. Koch, and B. Korsch, Ann. N.Y. Acad. S c i . 222, 935 (1974). 188. P.M. C o l l i n s and P. Gupta, Chem. Commun., 1288 (1969). 189. R.A.Y. Jones i n , "ANNUAL REVIEW OF NMR SPECTROSCOPY" E.F. Mooney, ed., Academic Press, London, 1968, Vol. 1, pp.27-9. 190. U.V. spectrum of 5-hydroxymethyl-2-furaldehyde from the Sadtler catalogue of U.V. spectra, no. 836, Sadtler Research Laboratories, P h i l a d e l p h i a , Pa. 191. a) W.W. Zorbach and R.S. Tipson, e d i t o r s , Synthetic Procedures i n Nucleic Acid Chemistry", Interscience, New York, 1968, Vol. 1; b) pp.264-8. 192) K.A. Watanabe, D.H. Hollenberg, and J . J . Fox, J . Carbohydr. Nucleos. Nucleot., 1_, 1 (1974). 193) H. Vorbruggen and B. Bennua, Tetrahedron L e t t . , 1339-1342 (1978). 194. A. Rosenthal and J.K. Chow, unpublished data. 195. A.A. P a v l i c and H. Adkins, J . Am. Chem. S o c , 68, 1471 (1946). 196. a) 0. I s l e r , H. Gutmann, M. Montavon, R. Ruegg, G. Ryser and P. Z e l l e r , Helv. Chim. Acta, 40, 1242 (1957). b) "Fisher Chemical Index 77C", Fisher S c i e n t i f i c Co., Limited, 1977, p.59. 210 ADDENDUM 1) Re: Stereochemical Assignment of Compounds 192 and 193. B z O - i N H 2 BzO-, N H 2 192 193 A d d i t i o n a l supportive evidence for the stereochemical assignment made for C-3 of the diazo-amino compounds above (see page 114), comes from an a p p l i c a t i o n of Cram's Rule to the n u c l e o p h i l i c addition of the azide anion to the unsaturated ester 18 (see page 7 and 113). The preponderant epimer predicted i s the 3-S_-epimer. The major diazo-amino compound i s o l a t e d was compound 192 which was p r e v i o s l y assigned the 3-S_- or g-glycero-g-allo- configuration. S i g n i f i c a n t l y , the major amino epimer determined for the amino mixture, i s o l a t e d from the hydrogenation of azide 189 (see pages 111-12), was the amino compound 190 (i.e.,the hydrogenolysis product of 192). Therefore, the predominant epimers (the 3-S_-epimer of 189 and compd. 192) predicted by Cram's Rule were shown to be stereochemically i d e n t i c a l and were also the same stereochemistry as previously assigned. 2) Re: Sterochemical Assignment of the Anomer Centre of the Ketofuranoses. The stereochemical assignments of the anomeric centres of the isopro- pylidenated ketofuranoses (see Results and Discussion, section 3.) were p a r t i a l l y made on the basis of the work of Moffatt and c o w o r k e r s 1 ^ on *8ee reference 8, page 263 and reference (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. anomer Chemical Shift assignment Quaternary Carbon High-field Methyl 112.00 114.42 25.39 111.89 24.86 113.94 25.50 112.03 25.21 114.62 112.20 113.23 - ) **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 its 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. 187 6 203 0 B 204 " B 209a a 209b g (172

Cite

Citation Scheme:

    

Usage Statistics

Country Views Downloads
China 4 41
United States 4 0
France 3 0
Russia 2 0
Iraq 2 0
Switzerland 1 0
City Views Downloads
Unknown 7 6
Beijing 4 0
Ashburn 3 0
Zurich 1 0
Macomb 1 0

{[{ mDataHeader[type] }]} {[{ month[type] }]} {[{ tData[type] }]}

Share

Share to:

Comment

Related Items