Trends in Synthetic Carbohydrate Chemistry - American Chemical

Chapter 8

Approaches to Deoxy Oligosaccharides of Antibiotics and Cytostatics by Stereoselective Glycosylations

Downloaded by MIT on May 21, 2013 | http://pubs.acs.org Publication Date: December 30, 1989 | doi: 10.1021/bk-1989-0386.ch008

Joachim Thiem Organisch-Chemisches Institut, Westfälische Wilhelms-Universität, Orléans-Ring 23, D-4400 Münster, Federal Republic of Germany Problems associated with stereoselective glycosy lations in the 2-deoxy sugar series are outlined and exemplified. General solutions are provided for the 2-deoxy-α-glycosides employing the N -iodosuccinimide glycosylation. The 2-deoxy-βglycosides are available via certain 2-bromo -2-deoxyglycosyl bromides accessible from simple isopropylidene derivatives by dibromomethyl methyl ether reactions. Syntheses of four different E-D-C trisaccharides of the various aureolic acids are reported that make extensive use of these procedures. A novel approach for the preparation of the G-B-A trisaccharide gly coside of class II anthracyclines is described. Here the combined azide --N-iodosuccinimide procedure is applied to construct a precursor of the aminodeoxy sugar unit. After subsequent N-iodosuccinimide glycosylations, the precursor trisaccharide is converted straightforwardly into the target molecule. The b a s i c c o n c e p t s o f g l y c o s y l a t i o n have b e e n known f o r more t h a n e i g h t y y e a r s . N e v e r t h e l e s s , t h e s e l e c t i v e f o r m a t i o n o f a f u l l a c e t a l c o n s t i t u t e s a n d r e m a i n s one o f the major c h a l l e n g e s i n c a r b o h y d r a t e c h e m i s t r y . W i t h i n t h e c u r r e n t d e c a d e , a number o f a t t r a c t i v e a p p r o a c h e s f o r t h e g l y c o s y l a t i o n o f s i m p l e a l c o h o l s and a l s o more-com p l e x a g l y c o n s ( i n c l u d i n g s u g a r d e r i v a t i v e s ) have b e e n d e v e l o p e d (e.g. 1,2). I n a l l cases a h i g h s t e r e o s e l e c -

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0097-6156/89/0386-0131$06.00/0 1989 American Chemical Society

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.


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t i v i t y i s d e s i r e d , and as has b e e n a b u n d a n t l y shown, t h e s i m p l e t r a n s f e r o f a p r o c e d u r e worked o u t f o r a c e r t a i n sugar s e r i e s does not n e c e s s a r i l y a p p l y t o a n o t h e r , i s o m e r i c s e r i e s . A l l o f t h e p r e s e n t l y u s e d and e f f e c t i v e g l y c o s y l a t i o n procedures i n the normal sugar s e r i e s i n g e n e r a l make use o f a n e i g h b o r i n g g r o u p a t t h e p o s i t i o n n e x t t o t h e a n o m e r i c c e n t e r , be i t by a r e a l a n c h i m e r i c a s s i s t a n c e o r by t h e o p e r a t i o n o f s t e r i c i n f l u e n c e . The p r e s e n t c o n t r i b u t i o n c e n t e r s on s t e r e o s e l e c t i v e s y n t h e s e s o f mono- and i n p a r t i c u l a r o l i g o - s a c c h a r i d e s o f t h e 2-deoxy- and t h e 2 , 6 - d i d e o x y s e r i e s as w e l l as some branched-chain s p e c i e s . These are the p r i n c i p a l sugar p o r t i o n s i n a l a r g e number o f i m p o r t a n t n a t u r a l g l y c o s i d e s , s u c h as t h e c a r d i a c g l y c o s i d e s ( 3 ) , t h e o r t h o s o m y c i n s ( £ ) , t h e t e t r o n i c a c i d s ( 5 ) , t h e a u r e o l i c a c i d s (6, s e e b e l o w ) , and t h e a n t h r a c y c l i n e s (7, s e e b e l o w ) , t o name j u s t a few. N a t u r e ' s a p p r o a c h t o t h e 6-deoxy s u g a r s i s known t o i n v o l v e o x i d a t i o n of a n u c l e o t i d e - s u g a r g l y c o s i d e with o x i d o r e d u c t a s e and s u b s e q u e n t r e d u c t i o n w i t h NADPH (8.) · The i n t r o d u c t i o n o f m e t h y l b r a n c h e s was shown (9) t o p r o ceed a t the stage of the keto sugar i n t e r m e d i a t e s under the a c t i o n of " a c t i v e methionine" [S-(5 -adenosyl)methio n i n e ] . T h e r e i s l i t t l e known a b o u t t h e f o r m a t i o n o f t h e 2 - d e o x y f u n c t i o n . The t r a n s f e r o f c y t i d i n e d i p h o s p h a t e i n t o 2 ' - d e o x y c y t i d i n e 5 - d i p h o s p h a t e i s c a t a l y z e d by CDP r e d u c t a s e i n E s c h e r i c h i a c o l i (10). A l s o d e s c r i b e d i s the formation of 2-deoxy-D-ervthro-pentofuranose 5'-phosphate c a t a l y z e d by an a l d o l a s e i n L a c t o b a c i l l u s p l a n t a r u m (10). The d e t a i l e d mechanism i s unknown, and u n t i l now t h e r e have b e e n no s t u d i e s i n t h e 2 - d e o x y h e x o s e s e r i e s (H.G. F l o s s , p e r s o n a l communication 1986). E v i d e n t l y the p a r t i c u l a r problems i n the c h e m i c a l s y n t h e s i s o f 2-deoxy s u g a r g l y c o s i d e s a r e t h e m i s s i n g n e i g h b o r i n g g r o u p , and a r e a l s o a s s o c i a t e d w i t h t h e e n hanced l a b i l i t y of t h e i r g l y c o s y l h a l i d e s . For i n s t a n c e , t r e a t m e n t o f t h e a - o r t h e β-glycosyl h a l i d e ( t h e f o r m e r b e e i n g s l i g h t l y more s t a b l e b e c a u s e o f t h e a n o m e r i c e f f e c t ) i n the 2,6-dideoxv-D-arabino s e r i e s ^ or 2 w i t h an a l c o h o l i n t h e p r e s e n c e of a s i l v e r p r o m o t e r i s s u p p o s e d t o p r o c e e d v i a t h e o x o c a r b e n i u m i n t e r m e d i a t e 4,. A f t e r n u c l e o p h i l i c a t t a c k of the a l c o h o l , both of the p r o t o n a t e d p r e c u r s o r s are formed, which a f t e r r e l e a s e of t h e p r o t o n g i v e t h e a - and t h e β-glycosides 5 and &. M o s t l y t h e f o r m e r p r e v a i l s , p r o b a b l y a g a i n by t h e o p e r a t i o n o f an a n o m e r i c e f f e c t . A n o t h e r f r e q u e n t s t a b i l i z a t i o n o f 4 i n t h i s s e r i e s o c c u r s by d i r e c t d e p r o t o n a t i o n t o g i v e t h e c y c l i c e n o l e t h e r ( g l y c a l ) 7. T h e s e g l y c a l s b e a r i n g a l e a v i n g group a t the a l l y l i c p o s i t i o n (carbon 3) c a n e a s i l y u n d e r g o a c i d - c a t a l y z e d g l y c o s y l a t i o n w i t h 1

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a l l y l i c r e a r r a n g e m e n t ( F e r r i e r r e a c t i o n , 11,12.) and g i v e t h e a l k y l a- and 6 - D - e r v t h r o - h e x - 2 - e n o p y r a n o s i d e s 3, and 6. I t i s n o t a t t r a c t i v e t o r e f u n c t i o n a l i z e s u c h a l k e n i c s u g a r s as 3, o r 6 i n t o t h e r e q u i r e d t a r g e t g l y c o s i d e s s u c h as 5, o r 8. ~ T h i s g e n e r a l o v e r v i e w may be i l l u s t r a t e d by an ex ample: t r e a t m e n t o f 3 , 4 - d i - 0 - a c e t y l - 2 , 6 - d i d e o x y - a - D - a r a b i n o - h e x o p v r a n o s v l b r o m i d e (9) w i t h m e t h y l 4 - 0 - a c e t y l 2 , 6 - d i d e o x y - a - D - l y x o - h e x o p y r a n o s i d e (10) u n d e r s y s t e m a t i c a l l y developed and a d j u s t e d c o n d i t i o n s g a v e i n 56% o p t i m i z e d y i e l d both the a - ( l - > 3 ) - and the β-(l->3)-linked d i s a c c h a r i d e s 11 and 12 i n the r a t i o o f a p p r o x i m a t e l y 2:1 (13.rU.) . ApartHÉrom tfîis d e l i c a t e chemistry, a t l e a s t one separation step i s r e q u i r e d . Consequently, s t e r e o s e l e c t i v e or even b e t t e r s t e r e o s p e c i f i c s o l u t i o n s f o r the p r e p a r a t i o n o f t h e s e o l i g o s a c c h a r i d e s w o u l d be c e r t a i n l y appreciated. We have d e v e l o p e d s u c h methods, and t h e s e a r e b r i e f l y o u t l i n e d i n g e n e r a l . Treatment of a g l y c a l d e r i v a t i v e 13 w i t h N - h a l o s u c c i n i m i d € î (X = B r , : 15.; X = I , 16.) s u p p o s e d l y g i v e s 1,2-halonium i o n s (perhaps i n resonance w i t h a 2 - h a l o - o x o c a r b e n i u m i o n ) . T h e s e a r e a t t a c k e d by t h e n u c l e o p h i l e R'OH t o g i v e m a i n l y t h e 1 , 2 - t r a n s - 2 - h a l o g l y c o s i d e s 14. F u r t h e r r e d u c t i v e c l e a v a g e o f t h e 2 - h a l o s u b s t i t u e n t c o n c l u d e s an e a s y , a t t r a c t i v e and h i g h l y s t e r e o s e l e c t i v e a p p r o a c h t o 2 , 6 - d i d e o x y α - g l y c o s i d e s 1§ i n t h e D - a r a b i n o , - l y x o , and - r i b o s e r i e s . As d e m o n s t r a t e d c o n c l u s i v e l y i n many examples ( e g . 17) t h e use o f NIS (16) i s c o n s i d e r a b l y s u p e r i o r t o NBS (1£) w i t h r e s p e c t t o t h e y i e l d s o f t h e g l y c o s y l a t i o n (13->14) as w e l l as t h e h a l i d e - c l e a v a g e s t e p (14->15). T h e " N l S ^ p r o c e d u r e has a l s o been t r i e d f o r t h e s y n t h e s i s o f 2-deoxy^-glycosides. A l t h o u g h t h i s c o u l d be r e a l i z e d , t h e method p r o v e d a t t r a c t i v e o n l y i n p a r t i c u l a r s i t u a t i o n s (18-20). The most a t t r a c t i v e a p p r o a c h f o r t h e 2 - d e o x y ^ g l y c o s i d e s s t a r t s with 2-bromo-2,6-dideoxyhexopyranosyl b r o m i d e s (22.) s u c h as 16,. T h e s e a r e a v a i l a b l e r e g i o - and s t e r e o - s p e c i f i c a l l y f r o m r e a d i l y a c c e s s i b l e and simple p r e c u r s o r s by r e a c t i o n w i t h d i b r o m o m e t h y l m e t h y l e t h e r (DBE) (22,£3). In p r i n c i p l e , the f o r m a t i o n of r e l a t e d compounds may be a n t i c i p a t e d by t h e a d d i t i o n o f b r o m i n e t o g l y c a l p r e c u r s o r s . P r e v i o u s s t u d i e s ( 2 4 - 2 7 ) , however, proved these processes to y i e l d s e v e r a l isomers which renders t h i s approach of l i t t l e p r e p a r a t i v e v a l u e . T r e a t m e n t o f t h e h a l i d e s 16 w i t h an a l c o h o l p r o m o t e d by s i l v e r s a l t s does y i e l d m a i n l y t h e β-glycosides 17 (28., 29) . O b v i o u s l y t h e bromo s u b s t i t u e n t d i r e c t s t h e " i n c o m i n g n u c l e o p h i l e by s t e r i c r e a s o n s o r p o s s i b l y v i a a 1,2-bromoniumbromo-oxocarbenium i n t e r m e d i a t e . F o l l o w i n g a r e d u c t i o n s t e p , t h e s y n t h e s e s o f β-glycosides 18


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i n t h e D - a r a b i n o (28,29) and - l v x o s e r i e s (30) were r e a l i z e d . A n o t h e r a p p r o a c h f o r t h e D - r i b o s e r i e s was d e m o n s t r a t e d by W i e s n e r ' s g r o u p (3lT. S t a r t i n g f r o m t h e t h i o g l y c o s i d e 1?, m e r c u r y - a s s i s t e d s o l v o l y s i s i s c o n s i d e r e d t o g e n e r a t e a 1 , 3 - a c y l o x o n i u m i n t e r m e d i a t e 2p w h i c h i s a t t a c k e d by t h e a l c o h o l p r i n c i p a l l y f r o m t h e β-face t o g i v e 21. Even t h o u g h t h e r e r e m a i n some i n c o n s i s t e n c i e s w i t h r e s p e c t t o the anomeric r a t i o s o b t a i n e d i n the s y n t h e s i s o f mono- o r o l i g o - s a c c h a r i d e g l y c o s i d e s , t h i s method p r o v e d u s e f u l i n t h e s e l e c t i v e p r e p a r a t i o n o f cardiac glycosides. B o t h p r o c e d u r e s f o r s e l e c t i v e s y n t h e s e s o f 2,6d i d e o x y - α - and β-glycosides w i l l be o u t l i n e d i n t h e a u r e o l i c a c i d and a l s o t h e a n t h r a c y c l i n e o l i g o s a c c h a r i d e series. Aureolic Acid

Oligosaccharides

These t e t r a h y d r o a n t h r a c e n o n e o l i g o s a c c h a r i d e a n t i b i o t i c s r e c e i v e d t h e i r name f r o m t h e i r c h a r a c t e r i s t i c g o l d e n a p p e a r a n c e . The most p r o m i n e n t members, chromom y c i n A3 ( 2 2 ) , o l i v o m y c i n A ( 2 3 ) , and m i t h r a m y c i n (24) c o n s t i t u t e p o t e n t c y t o s t a t i c agents which, even though they are extremely t o x i c , enjoy s e l e c t e d c l i n i c a l a p p l i c a t i o n i n t h e t r e a t m e n t o f c e r t a i n tumors ( 6 ) . The c y t o s t a t i c a c t i v i t y i s s u p p o s e d t o r e s u l t f r o m a s t r o n g and s e l e c t i v e i n h i b i t i o n o f t h e DNA-dependent RNA s y n t h e s i s (32., 33.) . I n t h e p r e s e n c e o f Mg2+, a c o m p l e x a t i o n o f g u a n o s i n e - r i c h DNA f r a g m e n t s was o b s e r v e d , and further i n f o r m a t i o n as t o t h i s mechanism has been r e c e n t l y d i s c u s s e d (34.) . E a r l i e r s t u d i e s proved the s t r u c t u r e of the almost s i m i l a r t e t r a h y d r o c e n o n e a g l y c o n s i n 22-24 h a v i n g t h e c h i r a l , f i v e - c a r b o n s i d e c h a i n a t C - 3 ^ s ^ w e l l as t h o s e o f t h e i n d i v i d u a l m o n o s a c c h a r i d e s ( 3 5 , 3 6 ) . A t t e m p t s were made t o a p p l y K l y n e ' s r u l e and d e d u c e t h e s t r u c t u r e o f t h e o l i g o s a c c h a r i d e s and t h e i r a t t e c h m e n t t o t h e a g l y c o n b u t t h i s was n o t u n i f o r m l y c o n v i n c i n g (37.) · complete s u g a r s e q u e n c e and t h e d i r e c t i o n and t y p e o f t h e i r i n t e r g l y c o s i d i c l i n k a g e s were a s s i g n e d by e x t e n d e d n.m.r. s p e c t r o c o p y and s u p p o r t e d by s y n t h e s e s (13,14,38., 39) . T h e r e a r e o n l y m i n o r d e v i a t i o n s between 22 and 23, a l t h o u g h t h e y a r e p r o d u c e d by d i f f e r e n t s t r e p t o m y c e s s t r a i n s . I n b o t h o f t h e s e compounds a d i f f e r e n t l y s u b s t i t u t e d a - ( l - > 3 ) - l i n k e d b i s - 2 , 6 - d i d e o x y - D - l y x o - u n i t B-A i s a t t a c h e d t o t h e p h e n o l i c s i t e a t C-6. T h e i r E-D-C t r i s a c c h a r i d e shows a t e r m i n a l 3 - C - m e t h y l - b r a n c h e d s u g a r , L - o l i v o m y c o s e E, a t t a c h e d by an a - ( l - > 3 ) - l i n k a g e t o t h e F ~ ( l - > 3 ) - b o u n d d i m e r i c o l i v o s y l - o l i v o s e D-C. I n m i t h r a m y c i n (24), the B-sugar i s a 2.6-dideoxv-D-arabino u n i t a t t a c f i e d t o A v i a a β - ( l - > 3 ) - l i n k a g e . I n t h e E-D-C tri s a c c h a r i d e p a r t , o n l y β - ( l - > 3 ) - l i n k a g e s o c c u r . The D-C u n i t i s l i k e w i s e s i m i l a r , and t h e t e r m i n a l s u g a r a g a i n i s o f t h e 3 - C - m e t h y l - b r a n c h e d t y p e , b u t t h i s t i m e i t i s Dmycarose. T

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We have p r e v i o u s l y r e p o r t e d t h e p r e p a r a t i o n o f t h e v a r i o u s B-A u n i t s (13., 40) and have a l s o d e v e l o p e d s y n t h e s e s f o r t h e E-D (41) as w e l l as t h e u n i f o r m D-C u n i t (42). T h i s p r e s e n t a t i o n f o c u s e s on a s e q u e n t i a l assemb l i n g o f t h e s e complex o l i g o s a c c h a r i d e u n i t s , and d i s c u s s e s n o v e l a p p r o a c h e s t o a number o f E-D-C t r i s a c c h a r i d e s . S t a r t i n g w i t h methyl α-D-mannopyranoside t h e r e i s ready a c c e s s t o the 2 , 3 - O - i s o p r o p y l i d e n e rhamnoside 25. T r e a t m e n t o f 25 i n d i c h l o r o m e t h a n e w i t h DBE and z i n c b r o m i d e f o r 5.5 h o u r s a t room t e m p e r a t u r e g i v e s t h e 2,3O - i s o p r o p y l i d e n e r h a m n o s y l b r o m i d e 26 as a v e r y r e a c t i v e i n t e r m e d i a t e w h i c h may p r o v e u s e f u l i n f u r t h e r r e a c t i o n s t o g i v e m a n n o s i d e s (29). A f t e r a n o t h e r 6.5 hours (12 hours a l t o g e t h e r ) the 3-O-formylated 2-bromo-2,6-dideoxyα - g - g l u c o p y r a n o s y l b r o m i d e 27 i s o b t a i n e d i n h i g h y i e l d . The mechanism o f f o r m a t i o n may be s u p p o s e d t o p r o c e e d v i a 2 , 3 - f o r m o x o n i u m i n t e r m e d i a t e s (21). Benzylglycosylation o f 27 l e a d s v i r t u a l l y e x c l u s i v e l y t o t h e c r y s t a l l i n e g l y c o s i d e 28. T r e a t m e n t w i t h h o t m e t h a n o l c o n t a i n i n g one drop of concentrated h y d r o c h l o r i c a c i d achieves s e l e c t i v e c l e a v a g e o f t h e f o r m y l g r o u p and f u r n i s h e s t h e c r y s t a l l i n e monohydroxy compound 29,. The g l y c o s y l b r o m i d e 27 and t h e s u g a r a g l y c o n i c component were c o n d e n s e d u n d e r d i l i g e n t l y o p t i m i z e d c o n d i t i o n s with r e s p e c t to the s o l v e n t m i x t u r e (4:1 toluene—nitromethane), the temperature r a n g e and r a t e o f i n c r e a s e (-78° o v e r 2 d a y s t o room t e m p e r a t u r e ) , and t h e p r o m o t e r ( s i l v e r t r i f l a t e , 43.) . T h i s r e s u l t e d i n a v e r y g o o d y i e l d (92%) and a f a v o u r a b l e α:β r a t i o o f 30:31 - 1:6.5. F o r t u n a t e l y the d e s i r e d β - ( l - > 3 ) - l i n k e d d i s a c c h a r i d e 31 c o u l d be f r a c t i o n a l l y c r y s t a l l i z e d from the mixture^ A f t e r h a v i n g a s s e m b l e d t h e D-C p r e c u r s o r t h e a - ( l - > 3 ) - a t t a c h m e n t o f t h e Ε u n i t was t o be p e r f o r m e d by t h e NIS method. T h e r e f o r e a f a v o r a b l e a c c e s s t o t h e Lo l i v o m y c a l 3J was n e e d e d . We had p r e v i o u s l y p r e p a r e d t h i s compound by a f i v e s t e p r o u t e f r o m |±-arabinose (4£) . R e c e n t l y an a d v a n t a g e o u s p r e p a r a t i o n o f 3J and i t s e p i m e r t-mycaral (36) by t r e a t m e n t o f m e t h y l 2 , 3 - O - b e n z y l i d e n e a - L - r h a m n o p y r a n o s i d e (35) w i t h m e t h y l l i t h i u m , was worked out ( 4 5 ) · ~ F o l l o w i n g the s e l e c t i v e removal of the 3'-formyloxy f u n c t i o n , t h e d i s a c c h a r i d e 32 was o b t a i n e d and t h i s d i d n o t u n d e r g o any r e a c t i o n w i t h t h e g l y c a l 37 i n t h e p r e s e n c e o f NIS. The a s s u m p t i o n was a t hand t h a t t h e 2'bromo s u b s t i t u e n t m i g h t impede t h e a c c e s s i b i l i t y o f t h e 3 ' - h y d r o x y g r o u p . However, t r i b u t y l s t a n n a n e r e d u c t i o n o f 32 gave compound 3^, and a g a i n , t h i s p r o d u c t showed no r e a c t i o n i n t h e NIS g l y c o s y l a t i o n w i t h 37. Amazingly, i t was o b s e r v e d t h a t a d i s a c c h a r i d e g l y c a l made up f r o m two m o l e c u l e s o f 37 c o u l d be o b t a i n e d i n modest y i e l d (46). T h i s r e s u l t r e f l e c t s a h i g h e r n u c l e o p h i l i c i t y of the t e r t i a r y h y d r o x y g r o u p i n 37 t h a n t h a t o f t h e s e c o n d a r y one i n 33.


138


F i n a l l y , t h e 4 ' - b e n z o a t e f u n c t i o n was a l s o s a p o n i f i e d . The u n b l o c k e d S ' ^ ' - d i o l component 3£ d i d i n d e e d u n d e r g o a smooth NIS g l y c o s y l a t i o n w i t h tfie L - o l i v o m y c a l 37. T h i s o c c u r e d r e g i o s p e c i f i c a l l y i n o v e r a l l 64% y i e l d w i t h f o r m a t i o n of o n l y the i n t e r g l y c o s i d i c ( l " - > 3 ' ) l i n k a g e and a l s o p r o c e e d e d s t e r e o s p e c i f i c a l l y t o w a r d s t h e α - g l y c o s i d e w i t h r e s p e c t t o t h e t e r m i n a l s a c c h a r i d e . The E-D-C derivative * s f u r t h e r hydrogenated t o the t r i s a c c h a r i d e u n i t 39 o f chromomycin A 3 (22) and o l i v o m y c i n A (23). ~ ~ M i t h r a m y c i n (24) b e a r s t h e t e r m i n a l s u g a r u n i t £ - m y c a r o s e . By a s i m i l a r p r e p a r a t i o n as f o r t h e m e t h y l b r a n c h e d g l y c a l s J§ 37* t h e D ^ e n a n t i o m e r o f 36, namely t h e l a b i l e D - m y c a r a l 40 was o b t a i n e d ( 4 5 ) ? " ' l t s NIS c o n d e n s a t i o n w i t h t h e 3 , 4 - < ï ï o l d i s a c c h a r i d e £4 p r o c e e d s s m o o t h l y , b u t t h e r e a c t i o n t u r n e d o u t t o be r a t h e r s l o w w i t h r e s p e c t to the s t a b i l i t y of the D-mycaral. T h i s r e s u l t s i n o n l y a modest y i e l d (12%) o f t h e t r i s a c c h a r i d e 41 w h i c h was h y d r o g e n o l y z e d t o compound 42. T h i s i n t u r n c o n s t i t u t e s an i s o m e r o f t h e t r i s a c c h a r i d e s e q u e n c e i n 24. A n o v e l approach f o r the mithramycin t r i s a c c h a r i d e r e q u i r e d a c o n c e p t i o n a l change. Thus, the u n i f o r m l y β - ( l - > 3 ) - l i n k e d t h r e e s u g a r u n i t s were t o be a s s e m b l e d f i r s t , and o n l y t h e n t h e b r a n c h i n t h e t e r m i n a l u n i t was t o be g e n e r a t e d . I n d e e d , g l y c o s y l a t i o n o f t h e 3'-monohyd r o x y d i s a c c h a r i d e 32 w i t h t h e g l y c o s y l b r o m i d e 2J, fol lowing the p r e v i o u s l y e s t a b l i s h e d procedure proceeded w i t h a l m o s t 70% y i e l d . The r a t i o α:β = 1:10 was again a d v a n t a g e o u s i n f a v o r o f t h e d e s i r e d d e r i v a t i v e 43, w h i c h c o u l d be c r y s t a l l i z e d f r o m t h e m i x t u r e . F u r t h e r s u b s e quent s t e p s (methanol—HC1) r e l e a s e d s e l e c t i v e l y the 3 - f o r m y l o x y g r o u p , r e d u c e d t h e t h r e e bromo f u n c t i o n s (BueSnH), and o x i d i z e d a t C-3" w h i c h gave t h e t r i s a c c h a r i d e 3 " - u l o s i d e 44, i n h i g h o v e r a l l y i e l d . F i n a l l y , t r e a t ment o f 44 w i t h m e t h y l l i t h i u m gave s t e r e o s p e c i f i c a l l y t h e t r i s a c c h a r i d e s 45 and 46 ( p e c u l i a r l y w i t h an a d d i t i o n a l b e n z o a t e g r o u p a t C-3)'T which b o r e e x c l u s i v e l y a t e r m i n a l g - o l i v o m y c o s e u n i t E. Previous branching r e a c t i o n s of a l k y l a-hexopyranos3 - u l o s i d e s gave m a i n l y o r e x c l u s i v e l y t h e r i b o d e r i v a t i v e s (45», 47-49) . T h i s i s i n a c c o r d a n c e w i t h e x p e c t a t i o n s , because of p a r t i a l b l o c k i n g of the n u c l e o p h i l e from the lower f a c e of the molecule. Q u i t e r e c e n t e x p e r i ments w i t h t h e c o r r e s p o n d i n g a l k y l β - 1 ι β χ ο ρ ν Γ 3 η ο 3 - 3 - ^ ο s i d e s s u c h as 47 r e s u l t e d i n a r a b i n o : r i b o r a t i o s o f a p p r o x i m a t e l y 2:1 ( J . Thiem, M. G e r k e n , B. S c h ô t t m e r , J.Weigand, C a r b o h y d r . Res., i n p r e s s ) . Owing t o t h e l a c k of an a x i a l a n o m e r i c s u b s t i t u e n t i n t h i s c a s e , n u c l e o p h i l i c a t t a c k from below p r e v a i l s . A comparable r a t i o w i t h t h e t r i s a c c h a r i d e u l o s i d e 44 w o u l d have b e e n e x p e c t e d . The e x c l u s i v e n u c l e o p h i l i c ^ t t a c k f r o m b e l o w may be assumed t o be g o v e r n e d by s e c o n d a r y b i n d i n g s o f t h e reagent i n the course of i t s approach t o the c a r b o n y l site. w

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A n o t h e r r o u t e t o a m e t h y l - b r a n c h e d d e r i v a t i v e makes use of r e d u c t i v e c l e a v a g e of s p i r o e p o x i d e s ( 5 0 ) . The r e a l i z a t i o n o f t h i s p r o c e s s was t e s t e d i n t h e m o n o s a c c h a r i d e s e r i e s . W i t t i g o l e f i n a t i o n o f 4 J , was u s e d t o f o r m t h e e x o c y c l i c m e t h y l e n e compound 4 8 . T h i s s u g a r c o n t a i n s an i n h e r e n t a l l y l a l c o h o l f r a g m e n t the c h i r a l C-4 alcoh o l f u n c t i o n o f w h i c h s h o u l d be i d e a l y s u i t e d t o d e t e r mine t h e c h i r a l i t y o f t h e e p o x i d e t o be f o r m e d by t h e S h a r p l e s s method. W i t h t e r t - b u t v l h y d r o p e r o x i d e , t i t a n i u m t e t r a i s o p r o p o x i d e and ( - ) - t a r t r a t e ( f o r a " l i k e mode" p r o c e s s ) no r e a c t i o n o c c u r e d . A f t e r a number o f a t t e m p t s , t h e S h a r p l e s s method was abandoned and e x t e n d e d b a c k t o the w e l l - e s t a b l i s h e d m-chloroperoxybenzoic a c i d epoxidat i o n . The ( 3 R ) - e p o x i d e 4 £ was o b t a i n e d s t e r e o s p e c i f i c a l l y i n e x c e l l e n t y i e l d ( 8 3 % f ; and t h i s c o u l d be r e a d i l y r e d u c e d t o g i v e t h e D - r i b o compound 50. The e x c l u s i v e f o r m a t i o n o f 4 9 i s u n e x p e c t e d and may be a s s o c i a t e d w i t h a s t r o n g s t e r e o c h e m i c a l i n d u c t i o n by t h e c h i r a l c e n t e r s at C - l , C-4, and C-5. Subsequent to t h i s s u c c e s s , e x t e n s i o n to the t r i s a c c h a r i d e s e r i e s was a t t e m p t e d . I n t h i s c a s e , P e t e r s o n o l e f i n a t i o n o f t h e 3 " - u l o s i d e 4 4 gave t h e 3"-exo-methyl e n e d e r i v a t i v e 51. T r e a t m e n t o f 5 1 w i t h m.-chloroperoxyb e n z o i c a c i d u n d e r c o n d i t i o n s s i m i l a r t o t h o s e as e l u c i dated f o r the monosaccharides gave s t e r e o s p e c i f i c a l l y t h e ( 3 " R ) - s p i r o e p o x i d e compound 5 £ . S u b s e q u e n t r e d u c t i o n f u r n i s h e d t h e c o r r e c t E-D-C t r i s a c c h a r i d e s e q u e n c e 53 o f mithramicin. Anthracycline Oligosaccharides D a u n o r u b i c i n (54) and t h e l e s s - t o x i c a d r i a m y c i n (55) belong to the c l a s s I a n t h r a c y c l i n e a n t i b i o t i c s · Owing t o t h e i r p r o n o u n c e d c y t o s t a t i c a c t i v i t y t h e y a r e v a l u a b l e c h e m o t h e r a p e u t i c a g e n t s ( 5 3 - 5 5 ) . Ant h r a c y c l i n e s h a v i n g o l i g o s a c c h a r i d e c h a i n s , s u c h as a c l a c i n o m y c i n (56) ( 5 6 ) o r m a r c e l l o m y c i n (57.) , named c l a s s I I anthracycline a n t i b i o t i c s , e x h i b i t a more-favorable ther a p e u t i c b r e a d t h . Among o t h e r a d v a n t a g e s , t h e c l a s s I I compounds a r e o f s i m i l a r c y t o s t a t i c a c t i v i t y as t h e c l a s s I compounds b u t show c o n s i d e r a b l e l e s s c u m u l a t i v e c a r d i o toxicity (£8). A few s t r u c t u r e — a c t i v i t y c o r r e l a t i o n s have b e e n o u t l i n e d , e.g. t h e i m p o r t a n c e o f a 3 - a m i n o 2 , 3 , 6 - t r i d e o x y - L - l y x o d e r i v a t i v e a t t a c h e d as t h e s u g a r A unit (58). ~~ Thus, i t i s of i n t e r e s t t o g e n e r a t e o l i g o s a c c h a r i d e s o f t h e t y p e C-B-A i n 56, a l l o f w h i c h a r e l i n k e d i n t e r g l y c o s i d i c a l l y by a - ( 1 ^ > 4 ) - b o n d s . We have p r e v i o u s l y s y n t h e s i z e d v a r i o u s d e r i v a t i v e s o f t h e t e r m i n a l C-B d i s a c c h a r i d e s employing the F e r r i e r g l y c o s y l a t i o n approach (59, 6 0 ) . A t t h a t same t i m e we c o u l d combine t h e a z i d e f u n c t i o n a l i z a t i o n of g l y c a l s (61) w i t h the N - i o d o s u c c i n i m i d e method ( 1 6 ) and d e v e l o p a g e n e r a l a p p r o a c h t o 3 -




8. THIEM


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a m i n o - 2 , 3 , 6 - t r i d e o x y - a - g l y c o s i d e s (62). I n essence t h i s p r o c e s s was f u r t h e r a p p l i e d t o g e n e r a t e o t h e r precursors i n t h i s f i e l d (63). R a t h e r e a r l y i t became e v i d e n t t h a t t h e NIS g l y c o s y l a t i o n o f an a x i a l 4-OH g r o u p , e v e n i n a b l o c k e d 3-amino s u g a r l i k e d a u n o s a m i n e o r r h o d o s a m i n e , c o u l d n o t be e f f e c t e d e f f i c i e n t l y (64). Consequently, a t r i s a c c h a r i d e s y n t h e s i s was r e q u i r e d t h a t a l l o w e d f a c i l e i n v e r s i o n o f a p r e c u r s o r s t r u c t u r e subsequent t o the advantageous use o f NIS g l y c o s y l a t i o n s t e p s . The a z i d e — f i - i o d o s u c c i n i m i d e g l y c o s y l a t i o n (62) e m p l o y e d w i t h t r i - O - a c e t y l - D ^ g l u c a l (57) and b e n z y l a l c o h o l g a v e i n 92% y i e l d a 2:1 m i x t u r e o'P'the 3 - a z i d o - 2 , 3 dideoxy-2-iodo-D-altro and D-manno e p i m e r s (62 and 6 4 ) . The r e a c t i o n p r o c e s s i s u n d e r s t o o d t o i n v o l v e p r i m a r y n u c l e o p h i l i c a t t a c k o f t h e a z i d e under a l l y l i c rearrangement t o f u r n i s h t h e a - a n d t h e B - D - e r v t h r o - h e x - 2 - e n o p y r a n o s y l a z i d e s 5 § and 59. T h e s e a r e ^ i n e q u i l i b r i u m v i a a [3.3]-sigmatropic rearrangement with the 3-azido-3-deoxyI ) - r i b o (60,) o r D - a r a b i n o g l y c a l s (61) . The m o r e - r e a c t i v e e n o l e t h e r s a r e p a r t i c u l a r l y proneHEo a t t a c k by an e l e c t r o p h i l e l i k e I"K and t h e r e s u l t i n g i o d o n i u m ( o r 2 - i o d o o x o c a r b e n i u m ) i n t e r m e d i a t e s a r e s u b s e q u e n t l y a t t a c k e d by the n u c l e o p h i l e t o g i v e p r e d o m i n a n t l y t h e p r o d u c t s o f t r a n s - d i a x i a l g e o m e t r y . F o l l o w i n g d e a c e t y l a t i o n , t h e Da l t r o d e r i v a t i v e 63 c o u l d by c r y s t a l l i z e d f r o m t h e mixture . ^ R e d u c t i v e d e i o d i n a t i o n w i t h BusSnH s m o o t h l y gave t h e 3 - a z i d o - D - r i b o d e r i v a t i v e 66. I n v e r s i o n a t C-5 and r e d u c t i o n a t C-6 and o f t h e a z i d o f u n c t i o n s h o u l d g i v e t h e L - l y x o t a r g e t m o l e c u l e . The most c o n v e n i e n t p a t h f o r t h e C-5 i n v e r s i o n employs s t e r e o s p e c i f i c h y d r o g é n a t i o n o f an e x o c y c l i c g l y c a l (60, 6 5 ) . A p p l i c a t i o n o f t h e NIS/PI13P r e a g e n t (66, 61) and s u b s e q u e n t a c e t y l a t i o n g a v e t h e 6i o d o component 67 i n g o o d y i e l d . E l i m i n a t i o n o f h y d r o g e n i o d i d e i s g e n e r a l l y performed with s i l v e r f l u o r i d e i n a n h y d r o u s p y r i d i n e (68.) , b u t was e f f e c t e d h e r e p r e f e r e n t i a l l y by u s e of DBU ( 6 9 ) . T h i s gave t h e h e x - 5 - e n o p y r a n o s i d e £g, i n v i r t u a l l y q u a n t i t a t i v e y i e l d . As t h e f i n a l s t e p , t h e l a b i l e e n o l e t h e r 68, was h y d r o g e n a t e d i n methanol with platinum/charcoal a t 30 b a r p r e s s u r e o f h y d r o gen. A c e t y l a t i o n t h e n g a v e s t e r e o s p e c i f i c a l l y b e n z y l Na c e t y l - p - L - d a u n o s a m i n i d e (70), o b t a i n e d c r y s t a l l i n e i n good y i e l d . T h i s r e a c t i o n s e q u e n c e was n o t meant a t t h e o u t s e t t o add a n o t h e r d a u n o s a m i n i d e s y n t h e s i s t o t h e number r e p o r t e d i n t h e l i t e r a t u r e (70.). However, w i t h o n l y s i x s t r a i g h t f o r w a r d s t e p s f r o m D - g l u c o s e and an o v e r a l l y i e l d o f a p p r o x . 20% i t may indeecT c o n s t i t u t e a r a t h e r f a v o r a b l e a l t e r n a t i v e . The main p u r p o s e f o r t h e d e v e l o p ment o f t h i s s e q u e n c e r e s i d e s i n t h e a d v a n t a g e o u s i n c o r poration of the precursor f o r the u n i t A i n t o the t r i s a c charide synthesis. By t r e a t m e n t o f t h e D - r i b o compound 66 w i t h t e r t -



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z

0

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1.H -Pt 2

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0

AcO 69


144


b u t y l c h l o r o d i m e t h y l s i l a n e s e l e c t i v e b l o c k i n g of the p r i mary h y d r o x y g r o u p was a c h i e v e d t o g i v e 71. T h i s d e r i v a t i v e was t o s e r v e as t h e A u n i t p r e c u r s o r o n t o w h i c h t h e o t h e r s u g a r s a r e a t t a c h e d , and w h i c h f i n a l l y was t o be c o n v e r t e d i n t o a product having the L - l v x o c o n f i g u r a t i o n . As t h e p r e c u r s o r f o r t h e Β u n i t , t h e s e l e c t i v e l y b e n z y l a t e d ^ - f u c a l d e r i v a t i v e TO, c o u l d be o b t a i n e d c r y s t a l l i n e f r o m L - f u c a l by a p p l y i n g a p h a s e - t r a n s f e r - c a t a l y z e d p r o c e s s T64). By a F e r r i e r r e a c t i o n o f d i - O - a c e t y l L - r h a m n a l and a s u b s e q u e n t r e t r o e n o l e t h e r f o r m a t i o n t h r o u g h h y d r i d e a t t a c k a t C-3 (71.) t h e t - a m i c e t a l o b t a i n e d (64.) ; t h i s r e a c t i o n was c o n c u r r e n t l y a l s o ^ c i e s c r i b e d by o t h e r s ( 7 2 ) . G l y c o s y l a t i o n o f t h e g l y c a l 70 w i t h t h e s u g a r a g l y c o n 71 i n t h e p r e s e n c e o f N - i o d o s u c c i n i m i d e p r o c e e d e d s m o o t h l y and i n good y i e l d t o g i v e t h e d i s a c c h a r i d e d e r i v a t i v e 73. C l e a v a g e o f t h e 4 ' - a c e t o x y g r o u p y i e l d e d t h e new d i s a c c h a r i d e a g l y c o n 74. T h i s a g a i n c o u l d be g l y c o s y l a t e d by t h e NIS p r o c e d u r e t o L - a m i c e t a l 72 i n h i g h y i e l d , and t h i s gave t h e t r i s a c c h a r T d e 75. I n t e r e s t i n g l y , there i s no p r o b l e m i n g l y c o s y l a t i o n o i i t h e a x i a l h y d r o x y l g r o u p at the 4 ' - p o s i t i o n of the t e r m i n a l I r - a a l a c t o r e s i d u e i n 7£, i n c o n t r a s t t o t h o s e d e r i v a t i v e s h a v i n g a 3-amino s u b s t i t u e n t and o t h e r w i s e s i m i l a r s t r u c t u r e . A f t e r h a v i n g assembled the t h r e e sugar u n i t s they had t o be t r a n s f o r m e d i n t o t h e d e o x y - and a m i n o d e o x y - L l v x o s t r u c t u r e s . The i o d o f u n c t i o n s a r e r e a d i l y removed by t h e r a d i c a l l y - i n d u c e d r e d u c t i o n w i t h BU3 SnH t o g i v e JS. T r e a t m e n t o f 76 w i t h f l u o r i d e i n a n h y d r o u s t e t r a h y d r o f u r a n y i e l d e d q u a n t i t a t i v e l y t h e d e r i v a t i v e 77, w h i c h i n t u r n was s e l e c t i v e l y i o d i n a t e d a t p o s i t i o n 6 t o g i v e J§. The d e h y d r o h a l o g e n a t i o n w i t h DBU p r o c e e d e d even b e t t e r t h a n i n t h e m o n o s a c c h a r i d e s e r i e s and gave t h e e x o c y c l i c t r i s a c c h a r i d e e n o l e t h e r , compound 79. H y d r o g é n a t i o n under p r e s s u r e w i t h p l a t i n u m / c h a r c o a l i n methanol and s u b s e q u e n t a c e t y l a t i o n a c c o m p l i s h e d t h e s y n t h e s i s o f t h e C-B-A t r i s a c c h a r i d e g l y c o s i d e 80, i n s a t i s f a c t o r y y i e l d . T h i s compound c o n s t i t u t e s tiie c a r b o h y d r a t e s e q u e n c e o f d i h y d r o a c l a c i n o m y c i n . I t may c e r t a i n l y be f u r t h e r processed i n t o the t r i s a c c h a r i d e p a r t of a c l a c i n o m y c i n ( 5 § ) . The main a d v a n t a g e o f t h i s n o v e l a p p r o a c h r e s i d e s i n i t s v e r s a t i l i t y f o r the c o n s t r u c t i o n of s e l e c t i v e l y v a r i e d o l i g o m e r s s i m i l a r t o t h a t i n 56. F i n a l l y , c r e d i t s h o u l d be g i v e n t o M o n h e r e t ' s g r o u p who were t h e f i r s t (73.) t o a s s e m b l e C-B-A trisaccharide p r e c u r s o r s o f c l a s s I I a n t h r a c y c l i n e s . The f u c o s y l b r o mide 82 was o b t a i n e d f r o m t h e m e t h y l g l y c o s i d e 81 f o l l o w i n g o u r b r o m o t r i m e t h y l s i l a n e p r o c e d u r e (74.) . TÎîe b e n z y l oc-daunosaminide 84 o b t a i n e d f r o m t h e d i f f i c u l t l y a c c e s s i b l e compound 83 s e r v e d as t h e a g l y c o n s u g a r u n i t . C o n d e n s a t i o n o f ^ É h e s e components made use o f t h e H e l f e r i c h c o n d i t i o n s and gave t h e a - ( l - > 4 ) - l i n k e d d i s a c c h a r i d e 85 i n o n l y 40% y i e l d . The t e r m i n a l s t e p was a g a i n a NIS g l y c o s y l a t i o n (16.) o f t h e L - a m i c e t a l 72, w h i c h gave t h e


7


2

w

a

s



8. T H I E M

79

80


145



146

t r i s a c c h a r i d e component 86. A n o t h e r c o r r e s p o n d i n g p r e p a r a t i o n o f t h e m a r c e l l o m y c m t r i s a c c h a r i d e u n i t s was r e c e n t l y p u b l i s h e d by t h e same g r o u p ( 7 5 ) . A few f i n a l words f o c u s on t h e g l y c o s y l a t i o n o f a n t h r a c y c l i n o n e s . A number o f e a r l i e r r e p o r t s . u s e d t h e g l y c o s y l h a l i d e s prepared i n s i t u from 1-acyloxy d e r i v a t i v e s o f 3 - a m i n o - 2 , 3 , 6 - t r i d e o x y - s u g a r d e r i v a t i v e s and f o l l o w e d the Koenigs-Knorr c o n d i t i o n s w i t h amazing s t e r e o s e l e c t i v i t i e s ( c f . 52). R e c e n t l y the d i r e c t condensa t i o n o f t h e 1 - a c y l o x y compounds t o a n t h r a c y c l i n o n e s was reported to operate with t r i m e t h y l s i l y l trifluoromethane s u l f o n a t e (TMSOTf) i n e x t r e m l y h i g h y i e l d ( 7 6 ) . A n o t h e r approach s u c c e s s f u l y used the F e r r i e r g l y c o s y l a t i o n p r o c e d u r e ( 6 4 ) . O b v i o u s l y d e p e n d e n t on t h e t y p e o f a n t h r a c y c l i n o n e , t h e NIS p r o c e d u r e may a l s o be a p p l i e d . As a p a r t i c u l a r n i c e a p p l i c a t i o n , t h e NIS g l y c o s y l a t i o n o f d i a c e t y l - ^ - r h a m n a l 87 w i t h t h e r a c e m i c a n t h r a c y c l i n o n e 88 s h o u l d be m e n t i o n e d Γ ' T h i s gave good y i e l d s o f t h e d i a s t e ^ r e o m e r i c (7S,9S) and (7£,9R) g l y c o s i d e s 89 and 9Q w h i c h c o u l d be s e p a r a t e d r e a d i l y (77, c f . a l s o ^ 7 8 ) , t h u s c o n s t i t u t i n g a convenient r e s o l u t i o n s t e p i n the t o t a l syn t h e s i s of a n t h r a c y c l i n e g l y c o s i d e s .

HO NHC0CF

3

0

rac. 14 -Q -TBOMS-4 - demethoxyadriamycinone

87

OTBDMS ΌΗ

89 (9S) 29% 90 19 R 1 27%


8. THIEM


147

Acknowledgments S t u d i e s o f t h i s g r o u p have e n j o y e d c o n t i n u o u s s u p p o r t f r o m t h e D e u t s c h e F o r s c h u n g s g e m e i n s c h a f t and t h e Fonds der Chemischen I n d u s t r i e , which i s g r a t e f u l l y acknowled ged.


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148


27. Horton, D.; Priebe, W.; Varela, O. J . Org. Chem. 1986, 51, 3479. 28. Thiem, J.; Gerken, M.; Bock, K. Liebigs Ann. Chem. 1983, 462. 29. Thiem, J.; Gerken, M. J. Carbohydr. Chem. 1982/83, 1, 229. 30. Schöttmer, Β. Diplomarbeit, University of Munster 1985. 31. Wiesner, K.; Tsai, T.Y.R.; Jin, H. Helv. Chim. Acta 1985, 68, 300. 32. Ward, D.C.; Reich, E . ; Goldberg, I.H. Science 1965, 149, 1259. 33. Behr, W.; Honikel, K.; Hartmann, G. Europ. J . Biochem. 1969, 9, 82. 34. van Dyke, M.; Dervan, P.B. Biochem. 1983, 22, 2373. 35. Miyamoto, M.; Morita, K.; Kawamatsu, Y.; Naguchi, S.; Marumoto, R.; Sasai, M.; Nohara, Α.; Nakadaira, Y.; Lin, Y.Y.; Nakanishi, K. Tetrahedron 1966, 22, 2761. 36. Berlin, Yu.A.; Kolosov, M.N.; Schemyakin, M.M. Tetrahedron Lett. 1966, 1431. 37. Miyamoto, M.; Kawamatsu, Y.; Kawashima, K.; Shino hara, M.; Tanaka, K.; Tatsuoka, S.; Nakanishi, K. Tetrahedron 1967, 23, 421. 38. Thiem, J.; Meyer, B. J . Chem. Soc., Perkin Trans. 2, 1979, 1331. 39. Thiem, J.; Meyer, B. Tetrahedron 1981, 37, 551. 40. Thiem, J.; Meyer, B. Chem. Ber. 1980, 113, 3058. 41. Thiem, J.; Elvers, J . Chem. Ber. 1980, 113, 3049. 42. Thiem, J.; Karl, H. Chem. Ber. 1980, 113, 3039. 43. Hanessian, S.; Banoub J . Carbohydr. Res. 1977, 53, C 13. 44. Thiem, J.; Elvers, J . Chem. Ber. 1979, 112, 818. 45. Jung, G.; Klemer, A. Chem.Ber. 1981, 114, 740. 46. Thiem, J.; Gerken, M. J . Org. Chem. 1985, 50, 954. 47. Thiem, J.; Elvers, J . Chem. Ber. 1981, 114, 1442. 48. Dyong, I.; Merten, H.; Thiem J . Liebigs Ann. Chem. 1986, 600. 49. Thiem, J.; Elvers, J . Chem. Ber. 1978, 111, 3514. 50. Yoshimura, J . Advan. Carbohydr. Chem. Biochem. 1984, 42, 69. 51. Crooke, S.T.; Reich, S.D. (Eds.) Anthracyclines Current Status and Development, Academic Press, New York 1980. 52. El Khadem, H.S. (Ed.) Anthracycline Antibiotics, Academic Press, New York 1982. 53. Füllenbach, D.; Nagel, G.A.; Seeber, S. (Eds.) Adriamycin-Symposium: Ergebnisse und Aspekte, Karger, Basel 1981. 54. Arcamone, F. Doxorubicin - Anticancer Antibiotics, Academic Press, New York 1981. 55. Jones, S.E. (Ed.) Current Concepts in the Use of Doxorubicin Chemotherapy, Farmitalia Carlo Erba, Milano 1982. 56. Oki, T. Aclacinomycin A, Chap. 19, p. 323 in lit. 50.



8. THIEM Deoxy Oligosaccharides of Antibiotics

149

57. Reich, S.D.; Bradner, W.T.; Rose, W.C.; Schurig, J . Ε . ; Madissoo, Η.; Johnson, D.F.; DuVernay, V.H.; Crooke, S.T. Marcellomycin, Chap. 20, p. 343 in lit. 50. 58. Doyle, T.W. Anthracycline Oligosaccharides, Chap. 4, p. 27 in L i t . 50. 59. Thiem, J.; Hoist, M.; Schwentner, J . Chem. Ber. 1980, 113, 3488. 60. Thiem, J.; Kluge, W.; Schwentner, J . Chem. Ber. 1980, 113, 3497. 61. Heyns, K.; Hohlweg, R. Chem. Ber. 1978, 111, 1632. 62. Heyns, K.; Feldmann, J.; Hadamczyk, D.; Schwentner, J.; Thiem, J . Chem. Ber. 1981, 114 232. 63. Thiem, J.; Springer, D. Carbohydr. Res. 1985, 325. 64. Springer, D. Dissertation, University of Hamburg 1985. 65. Horton, D.; Weckerle, W. Carbohydr. Res. 1975, 44, 227. 66. Appel, R. Angew. Chem. 1975, 87, 863. 67. Hanessian, S.; Lavallee, P. Meth. Carbohydr. Chem. 1976, 7, 49. 68. Helferich, B.; Himmen, E. Ber. Dtsch. Chem. Ges. 1928, 61, 1825. 69. Oediger, H.; Möller, F. Angew. Chem. 1967, 79, 53. 70. Hauser, F.M.; Ellenberger, S.R. Chem. Rev. 1986, 86, 35. 71. Fraser-Reid, B.; Radatus, B.; Tarn, S.Y.-K. Meth. Carbohyr. Chem. 1980, 8, 219. 72. Martin, Α.; Pais, M.; Monneret, C. Carbohydr. Res. 1983, 113, 21. 73. Martin, Α.; Pais, M.; Monneret, C. J. Chem. Soc., Chem. Commun. 1983, 305. 74. Thiem, J.; Meyer, B. Chem. Ber. 1980, 113, 3075. 75. Monneret, C.; Martin, Α.; Pais, M. Tetrahedron Lett. 1986, 22, 575. 76. Kimura, Y.; Suzuki, M.; Matsumoto, T . ; Abe, R.; Terashima, S. Chem. Lett. 1984, 501. 77. Horton, D.; Priebe, W.; Varela, O. Carbohydr. Res. 1984, 130, C 1. 78. Horton, D.; Priebe, W. Carbohydr. Res. 1985, 136, 391. RECEIVED May 31, 1988


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