Studies on the Synthesis of Serologically Active Glycolipids - ACS

15 Studies on the Synthesis of Serologically Active Glycolipids

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ROY GIGG Laboratory of Lipid and General Chemistry, National Institute for Medical Research, Mill Hill, London NW7 1AA.

Many of the g l y c o l i p i d s present in mammalian t i s s u e s and in microorganisms are " f o r e i g n " to the human and are thus capable of inducing the formation of antibodies i.e. they are a n t i g e n i c . The immunochemical a c t i v i t y of the g l y c o l i p i d s resides in the o l i g o s a c c h a r i d e p o r t i o n and most of t h i s a c t i v i t y (as in other a n t i g e n i c o l i g o s a c c h a r i d e s ) is e x h i b i t e d by the terminal two or three sugars of the molecule(1). As i s o l a t e d 'homogenous' molecules, these r e l a t i v e l y low molecular weight compounds e x h i b i t low a n t i g e n i c a c t i v i t y whereas they are h i g h l y a c t i v e as components of the t i s s u e s to which they belong. The g l y c o l i p i d s e x i s t in the n a t i v e s t a t e as components of the membranes (2) of c e l l s i . e . as part of a macromolecular aggregate, and t h i s macromolecular form is required f o r the ex h i b i t i o n of immunochemical a c t i v i t y in g l y c o l i p i d s ( 3 ) . The presence of an antigen in guinea p i g organs which would induce an antibody capable of l y s i n g sheep erythrocytes was dem onstrated by Forssman (4) in 1911 and subsequently i t was shown that s i m i l a r antigens ("Forssman antigens") were present in the lipid f r a c t i o n s of many other mammalian t i s s u e s although i t was not u n t i l 1971 ( 5 , 6) that the s t r u c t u r e of the Forssman antigen (1) was e s t a b l i s h e d and the a n t i g e n i c a c t i v i t y was a s s o c i a t e d with the terminal α-NAcgal (l->3)β-NAcgal (1->3)Gal - p o r t i o n of the molecule.

253

El Khadem; Synthetic Methods for Carbohydrates ACS Symposium Series; American Chemical Society: Washington, DC, 1977.

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T h e b l o o d g r o u p s u b s t a n c e s o f human e r y t h r o c y t e s a r e g l y c o l i p i d s w i t h perhaps a small c o n t r i b u t i o n from g l y c o p r o t e i n s (Z>8) . T h e c l a s s i c a l w o r k (9 J 0 ) on t h e s t r u c t u r e o f t h e immunoc h e m i c a l l y a c t i v e p o r t i o n s o f t h e b l o o d g r o u p s u b s t a n c e s was c a r r i e d o u t on g l y c o p r o t e i n b l o o d g r o u p a c t i v e s u b s t a n c e s w h i c h w e r e r e a d i l y i s o l a t e d and p u r i f i e d f r o m body f l u i d s . However t h e g l y c o l i p i d type blood group substances present in the e r y t h r o cytes (e.g. I I , I I I S- I V ) h a v e b e e n s h o w n ( 8 ) t o p o s s e s s i d e n t i c a l terminal o l i g o s a c c h a r i d e p o r t i o n s to those of the g l y c o p r o t e i n s a n d some o f t h e s e t e r m i n a l d i - a n d t r i s a c c h a r i d e s h a v e b e e n synthesised (JJ) . The s t r u c t u r e s of s e v e r a l g l y c o l i p i d s from microorganisms h a v e been e s t a b l i s h e d ( 1 2 - 1 4 ) and t h e s e r o l o g i c a l a c t i v i t i e s o f some o f t h e s e h a v e been d e m o n s t r a t e d . The r e a l i s a t i o n of the v a r i e t y of s t r u c t u r a l (and t h e r e f o r e a n t i g e n i c ) i n f o r m a t i o n t h a t can be i n c o r p o r a t e d i n t o a t r i s a c c h a r i d e u n i t and o f t h e t e n d e n c y o f g l y c o l i p i d s t o a s s o c i a t e w i t h o t h e r membranous s t r u c t u r e s l e d t h e a u t h o r (15) t o f o r m u l a t e a h y p o t h e s i s , r e l a t i n g t h e g l y c o l i p i d s of microorganisms w i t h p o s s i b l e îmmunopathologîcal p h e n o m e n a , w h i c h may b e s t a t e d b r i e f l y a s f o l l o w s . G l y c o l i p i d s o r i g i n a t i n g from microorganisms i n v a d i n g the h o s t may b e c o m e i n s e r t e d i n t o t h e c e l l u l a r m e m b r a n e s o f host tissues. A n t i b o d i e s , r a i s e d against these " f o r e i g n " g l y c o l i p i d s present in the macromolecular environment of the microorganism, may t h e n a t t a c k t h e h o s t t i s s u e c o n t a i n i n g t h e " f o r e i g n " g l y c o l i p i d l e a d i n g ( i n the p r e s e n c e of complement) t o "immune l y s i s " (16) o f t h e h o s t c e l l s i . e . t o a t y p e o f a u t o i m m u n e a t t a c k on t h e host t i s s u e s . One o f t h e m i c r o o r g a n i s m s f o r w h i c h t h e p r e s e n c e o f serol o g i c a l l y a c t i v e g l y c o l i p i d s has been e s t a b l i s h e d ( 1 7 - 2 0 ) is Mycoplasma pneumoniae, the c a u s a t i v e agent of primary a t y p i c a l pneumonia. The s t r u c t u r e s of t h e a c t i v e g l y c o l i p i d s have been t e n t a t i v e l y r e l a t e d (19) by s e r o l o g i c a l r e a c t i o n s t o t h e g a l a c t o s y l d i g l y c e r i d e s o f p l a n t l i p i d s t h e s t r u c t u r e s ( e . g . V) o f w h i c h have been e s t a b l i s h e d (21-25) . The s t r u c t u r e s ( e . g . V I ) of g l y c o l i p i d s i s o l a t e d f r o m S t r e p t o c o c c i have been fully d e t e r m i n e d (26-28) and the s e r o l o g i c a l a c t i v i t i e s of t h e s e have been e s t a b l i s h e d ( 2 9 , 3 0 ) . W i t h some o f t h e s e g l y c o l i p i d s t r u c t u r e s e s t a b l i s h e d we c o n s i d e r e d i t p e r t i n e n t t o a t t e m p t t h e i r s y n t h e s i s , f i r s t l y to prove that these s t r u c t u r e s were in f a c t t h e a c t i v e components and s e c o n d l y t o make t h e m a t e r i a l s more r e a d i l y a v a i l a b l e for t e s t i n g our h y p o t h e s i s . A t t h e o u t s e t i t was r e a l i s e d t h a t t h e s y n t h e t i c m e t h o d s to prepare the types of g l y c o s i d i c linkages present in these molec u l e s were not f u l l y e s t a b l i s h e d . In p a r t i c u l a r r o u t e s t o 1,2c i s - 1 i n k e d n e u t r a l and 2 - a m i n o s u g a r s were not a v a i l a b l e w i t h any degree of c e r t a i n t y ( a l t h o u g h the methods f o r the p r e p a r a t i o n of 1 . 2 - t r a n s - l i n k e d n e u t r a l and 2 - a m i n o - 2 - d e o x y s u g a r s were w e l l


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documented) and moreover t h e p r o b l e m o f t h e p r o t e c t i o n o f h y d r o x y l g r o u p s had a l s o t o be c o n s i d e r e d . We had p r e v i o u s l y i n t r o d u c e d (31-35) t h e a11 y1 e t h e r p r o t e c t i n g group i n t o c a r b o h y d r a t e c h e m i s t r y and had shown i t s p a r t i c u l a r v a l u e in the p r e p a r a t i o n o f benzyl ethers o f carbo h y d r a t e s . Awareness o f e a r l i e r work (36-38) on t h e p r e v a l e n c e o f 1 , 2 - c j _ s - g l y c o s i d e f o r m a t i o n when n o n - p a r t i c i p a t i n g g r o u p s w e r e p r e s e n t on t h e 2 - h y d r o x y l g r o u p , l e d u s t o c o n s i d e r (39) a general type of o l i g o s a c c h a r i d e s y n t h e s i s using benzyl ethers f o r ' p e r s i s t e n t ' p r o t e c t i o n and a 11 y1 e t h e r s f o r ' t e m p o r a r y ' p r o t e c t i o n f hydroxyl groups. It is therefore relevant at this s t a g e t o r e v i e w o u r d e v e l o p m e n t o f t h e a l l y l e t h e r s as p r o t e c t ing groups. Q

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E t h e r s a s P r o t e c t i n g Groups

In t h e c o u r s e o f s t u d i e s on t h e c h e m i c a l s y n t h e s i s (40-42) o f t h e p h o s p h o l i p i d s known a s t h e p l a s m a l o g e n s ( e . g . V I I ) i t was n e c e s s a r y t o i n v e s t i g a t e new methods f o r t h e s y n t h e s i s o f v i n y l ethers. P r i o r t o t h i s w o r k , two p a p e r s (42»Μ) appeared d e s c r i b i n g the rearrangement of a l l y l ethers ( V I I I ) t o c i s - p r o p 1-enyl e t h e r s ( I X ) u n d e r b a s i c c o n d i t i o n s and t h e r e a r r a n g e m e n t was shown (44) t o be p a r t i c u l a r l y r a p i d and q u a n t i t a t i v e w i t h p o t a s s i u m t , - b u t o x i d e i n d i m e t h y l s u l p h o x i d e . For o u r work on t h e p l a s m a l o g e n s we a t t e m p t e d a s i m i l a r r e a r r a n g e m e n t w i t h a y - s u b s t i t u t e d a l l y l e t h e r and a s a model compound we c h o s e t h e hept a d e c - 2 - e n y l e t h e r ( X ) . We f o u n d h o w e v e r , t h a t w i t h p o t a s s i u m ' t . - b u t o x i d e i n d i m e t h y l s u l p h o x i d e , t h i s compound was r a p i d l y de graded t o heptadecadiene (XI) and i t s isomers. A t t h i s t i m e we w e r e a l s o i n t e r e s t e d i n t h e s y n t h e s e s o f t h e p h o s p h o l i p i d known as p h o s p h a t i d y l i n o s i t o l (45) and o f t h e l o n g - c h a i n s p i n g o l i p i d b a s e s , p h y t o s p h i n g o s i n e (46.47) and sphingosine (48,4^) ^ carbo h y d r a t e p r e c u r s o r s and t h i s work r e q u i r e d t h e e x t e n s i v e u s e o f carbohydrate p r o t e c t i n g groups. I t o c c u r r e d t o us t h a t t h e ready e l i m i n a t i o n o f d i e n e s f r o m γ-substituted a l l y l e t h e r s c o u l d f o r m t h e b a s i s o f a new p r o t e c t i n g g r o u p and we f o u n d (33) f o r e x a m p l e , t h a t t h e r e a d i l y p r e p a r e d b u t - 2 - e n y l e t h e r o f 1,2:5, 6-di-0-isopropylîdene-D" g l u c o f u r a n o s e was r a p i d l y c o n v e r t e d i n t o 1,2:5,6-di-0-isopropylidene-D-glucofuranose by p o t a s s i u m _ t - b u t o x i d e i n d i m e t h y l s u l p h o x i d e a t room t e m p e r a t u r e . A t t h e same t i m e we r e a l i s e d t h a t t h e a l l y l e t h e r i t s e l f was p e r h a p s a p o t e n t i a l l y more u s e f u l p r o t e c t i n g g r o u p i n t h e c a r b o h y d r a t e s e r i e s than t h e b u t - 2 - e n y l g r o u p . The a l l y l g r o u p was s t a b l e t o aqueous a c i d and b a s e and was r a p i d l y i s o m e r i s e d t o t h e p r o p - l - e n y l g r o u p w i t h p o t a s s i u m t,-butoxide i n dimethyl s u l p h o x i d e w i t h o u t a f f e c t i n g o t h e r conv e n t i o n a l base-stable p r o t e c t i n g groups. The p r o p - l - e n y l g r o u p was s t a b l e t o b a s e but was v e r y a c i d l a b i l e and c o u l d a l s o be removed by o x i d a t i o n w i t h a l k a l i n e p e r m a n g a n a t e , by o z o n o l y s i s n

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f o l l o w e d by a l k a l i n e h y d r o l y s i s (31 .32) o r by t h e a c t i o n o f m e r c u r i c c h l o r i d e (33) . T h u s , b o t h t h e a l l y l and p r o p - 1 - e n y l groups c o u l d be u s e d u n d e r t h e a p p r o p r i a t e c o n d i t i o n s as p r o t e c t i n g groups. T h e i n s t a n t a n e o u s h y d r o l y s i s o f t h e p r o p - l - e n y l g r o u p by m e r c u r i c c h l o r i d e (33) was p a r t i c u l a r l y u s e f u l s i n c e by t h e a d d i t i o n of m e r c u r i c o x i d e t o t h e r e a c t i o n m i x t u r e the h y d r o l y s i s c o u l d be c a r r i e d o u t u n d e r n e u t r a l c o n d i t i o n s t h u s p r e s e r v i n g other a c i d - l a b i l e p r o t e c t i n g groups in the m o l e c u l e . Moreover m e r c u r i c c h l o r i d e was f o u n d t o r e a c t o n l y v e r y s l o w l y w i t h a l l y l e t h e r s and t h u s p r o p - l - e n y l g r o u p s c o u l d be removed i n t h e p r e s e n c e o f a l l y l g r o u p s by t h i s m e t h o d . Amido groups were a l s o s t a b l e (33)to t h e a c t i o n o f p o t a s s i u m _ t - b u t o x i d e i n d i m e t h y l s u l p h o x i d e and t h u s t h e a l l y l e t h e r s c o u l d be u s e d f o r t h e p r o t e c t i o n of 2-acylamino sugars. Mono p r o p - l - e n y l e t h e r s o f v i c i n a l g l y c o l s a r e a l s o c o n v e r t ed i n t o p r o p y l i d e n e a c e t a l s (33) by a c i d c a t a l y s t s a n d t h u s t h e a l l y l e t h e r s c o u l d be u s e d f o r t h e p r e p a r a t i o n o f t h i s t y p e o f protecting group. S u b s e q u e n t work by o t h e r g r o u p s has shown t h a t a l l y l e t h e r s can be removed by o x i d a t i o n w i t h s e l e n i u m d i o x i d e (50) and t h a t t h e a l l y l g r o u p c a n be i s o m e r i s e d t o t h e p r o p - l - e n y l g r o u p by t r i s t r i p h e n y l p h o s p h i n e r h o d i u m c h l o r i d e u n d e r c o n d i t i o n s suff i c e n t l y m i l d t o p r e s e r v e a l k a l î - 1 a b i 1 e g r o u p s s u c h as e s t e r s (51). A l s o in the presence of d i e t h y l d i a z o d i c a r b o x y l a t e the a l l y l e t h e r g i v e s an a d d i t i o n p r o d u c t w h i c h i s a v i n y l e t h e r and i s t h u s r e a d i l y h y d r o l y s e d (j>2, jj£) · We h a v e a l s o shown (54) t h a t t h e a c t i o n o f N - b r o m o s u c c i n î m i d e on a l l y l e t h e r s ( e . g . XII) g i v e s a m i x t u r e o f t h e bromo e t h e r (XI I l ) and t h e s u c c i n i m i d e d e r i v a t i v e (XIV) b o t h o f w h i c h can be h y d r o l y s e d by aqueous b a s e r e s u l t i n g i n t h e removal o f t h e a l l y l g r o u p . Thus v a r i o u s o t h e r methods f o r t h e removal o f t h e a l l y l g r o u p a r e a v a i l a b l e f o r u s e i n c i r c u m s t a n c e s where t h e v e r y b a s i c c o n d i t i o n s of p o t a s s i u m t _ - b u t o x i d e i n d i m e t h y l s u l p h o x i d e a r e not acceptable. Some o f t h e s e o t h e r methods f o r t h e removal o f t h e a l l y l g r o u p s u f f e r from d i s a d v a n t a g e s e . g . t h e r h o d i u m c a t a l y s t i s e x p e n s i v e , has t o be s e p a r a t e d f r o m t h e p r o d u c t and does n o t e f f e c t complete i s o m e r i s a t i o n of the a l l y l g r o u p . We h a v e f o u n d o n l y a few c a s e s w h e r e t h e s t r o n g l y b a s i c c o n d i t i o n s of potassium t - b u t o x i d e in dimethyl s u l p h o x i d e cause other rearrangements in the carbohydrate m o l e c u l e . The r e a c t i o n w i t h t h e p h e n y l o x a z o l î n e (XV) l e d r a p i d l y (33) to the f o r m a t i o n o f t h e o x a z o l e (XVI) a l t h o u g h t h e p h e n y l o x a z o l î n e g r o u p i n c o m pound (XVI I ) was c o n s i d e r a b l y more s t a b l e t o t h e s e c o n d i t i o n s and compound ( X V I l ) was r e a d i l y c o n v e r t e d (49) i n t o the p r o p - l e n y l g l y c o s i d e ( X V I l l ) u n d e r m i l d c o n d i t i o n s a l t h o u g h i t was d e g r a d e d t o o t h e r p r o d u c t s ( e . g . XIX) u n d e r more v i g o r o u s c o n d i t i o n s (55) . T h e o x a z o l i n e g r o u p i s however s t a b l e i n t h e


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p r e s e n c e o f t h e r h o d i u m c a t a l y s t (56) . The a l l y l d e r i v a t i v e (XX) o f 1 . 2 - 0 - i s o p r o p y l i d e n e - m y o i n o s i t o l was a l s o d e g r a d e d by t h e a c t i o n o f p o t a s s i u m _ t - b u t o x i d e in dimethyl s u l p h o x i d e t o g i v e t h e h y d r o x y h y d r o q u i n o n e d e r i v a t i v e (XXIII) . T h i s b e h a v i o u r was a l s o shown by t h e b e n z y l e t h e r (XXI). Compound ( X X I l ) was i s o l a t e d as an i n t e r m e d i a t e i n t h e c o n v e r s i o n o f t h e b e n z y l e t h e r (XXI) i n t o t h e a r o m a t i c e t h e r (XXIV) (57) . I s o p r o p y l i d e n e groups i n p y r a n o s i d e s and f u r a n o s i d e s a r e however, s t a b l e t o these c o n d i t i o n s . We have r e c e n t l y (58) observed that the v i c i n a l b i s p r o p - l e n y l e t h e r (XXV) i s f u r t h e r d e g r a d e d by t h e a c t i o n o f p o t a s s i u m t . - b u t o x î d e i n d i m e t h y l s u l p h o x i d e and t h e n a t u r e o f t h e p r o d u c t s is being i n v e s t i g a t e d . Having thus e s t a b l i s h e d t h e a l l y l and p r c p - l - e n y l groups as u s e f u l p r o t e c t i n g g r o u p s i n t h e c a r b o h y d r a t e s e r i e s , we t h e n i n v e s t i g a t e d (34) the potential of the but-2-enyl group. It i s removed much more r a p i d l y t h a n t h e a l l y l g r o u p i s i s o m e r i s e d and i t i s t h e r e f o r e p o s s i b l e t o remove a b u t - 2 - e n y l g r o u p w i t h o n l y p a r t i a l î s o m e r i s a t i o n o f an a l l y l g r o u p when b o t h a r e p r e s e n t i n t h e same m o l e c u l e (34). Thus t h e a l l y l e t h e r (XXVII) was o b t a i n e d (59) f r o m t h e b u t - 2 - e n y l e t h e r (XXVI) i n a b o u t 40% y i e l d by t h i s p r o c e d u r e . One o f t h e main u s e s t h a t we h a v e f o u n d f o r t h e b u t - 2 e n y l g r o u p i s as a t e m p o r a r y p r o t e c t i n g g r o u p d u r i n g t h e p r e paration of other a l l y l ethers. Thus t h e a l l y l glycoside (XXVIII) g a v e (£2) t h e p r o p - 1 - e n y 1 g l y c o s i d e (XXIX) on t r e a t m e n t with potassiurn Jt-butoxide in dimethyl s u l p h o x i d e . A l l y l a t i o n of compound (XXIX) t o g i v e (XXX) and s u b s e q u e n t h y d r o l y s i s o f t h e p r o p - 1 - e n y î group gave 2 - 0 - a l l y l - 3 , 4 , 6 - t r i - 0 - b e n z y l - D - g l u c o p y r a n o s e (XXXI ) . A f u r t h e r e x t e n s i o n o f t h e u s e o f a l l y l e t h e r s came when we i n v e s t i g a t e d t h e c o m p a r a t i v e r a t e s o f i s o m e r i s a t ion o f o t h e r methyl s u b s t i t u t e d a l l y l e t h e r s . Both 1-methyl-(34) a n d 2 m e t h y l a l l y l (33.35) e t h e r s were i s o m e r i s e d a t a c o n s i d e r a b l y lower r a t e t h a n t h e a l l y l e t h e r s by p o t a s s i u m _ t - b u t o x i d e i n d i m e t h y l s u l p h o x i d e and t h e 2 - m e t h y l a l 1 y l e t h e r s (35) w h i c h a r e r e a d i l y prepared a r e convenient p r o t e c t i n g groups i n the presence o f b u t - 2 - e n y l g r o u p s s i n c e t h e l a t t e r c a n be removed c o m p l e t e l y (35) w i t h o u t i s o m e r i s a t i o n o f 2-methy1 a l 1yl g r o u p . We a l s o showed t h a t t h e b u t - 2 - e n y l g r o u p i s i s o m e r i s e d much more s l o w l y t h a n t h e a l l y l g r o u p by t h e r h o d i u m c a t a l y s t and t h i s a l l o w e d (£6, 60) t h e removal o f t h e a l l y l g r o u p i n t h e presence of the but-2-enyl group. Thus t h e a l l y l g a l a c t o p y r a n o s i d e d e r i v a t i v e (XXXIl) gave p r e d o m i n a n t l y t h e p r o p - l - e n y l g l y c o s i d e (XXXIV) on t r e a t m e n t w i t h t h e r h o d i u m c a t a l y s t a n d compound (XXXIV) was t h e n h y d r o l y s e d t o t h e f r e e s u g a r (XXXV) (60). T h i s t r a n s f o r m a t i o n o f compound (XXXI I) i n t o t h e p r o p - l e n y l g l y c o s i d e (XXXIV) was however a c c o m p l i s h e d i n h i g h e r y i e l d and w i t h fewer b y p r o d u c t s by f i r s t t r e a t i n g compound (XXXI I) w i t h


SYNTHETIC

260

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METHODS

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Serologically Active

Glycolipids

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butoxide, to isomerîse the a l l y l group and remove the b u t - 2 - e n y l group, g i v i n g the p r o p - l - e n y l g l y c o s i d e (XXXI Il) which was then treated with ' c r o t y l bromide and sodium hydride to give the but2-enyl ether (XXXIV) (6l_) . In a l l of our e a r l y work on the use of potassium Jt-butoxide in dimethyl sulphoxide f o r the rearrangement of a l l y l ethers we used laboratory prepared potassium _t-butoxide. Recently t h i s material has become commercially a v a i l a b l e in the U.K. and the commercial material i s considerably more a c t i v e than our own p r e p a r a t i o n . A l l y l ethers are r a p i d l y isomerised at 20 by the commercial material whereas we r o u t i n e l y used higher temperatures in our e a r l y work. Many other groups (62-75) have found the a l l y l ethers useful as p r o t e c t i n g groups in the preparation of carbohydrate d e r i v a t i v e s and other compounds. 1

1 , 2 - C i s - G l y c o s i d e Synthesis The long standing problem of 1.2-ci s - q l y c o s i d e synthesis has been f u l l y reviewed (36-38) and at the outset of our work on the synthesis of the g l y c o l i p i d s t h i s was our major concern s i n c e many of these compounds contained t h i s g l y c o s i d i c l i n k a g e . When considering our projected general o l i g o s a c c h a r i d e synthesis using benzyl ethers f o r ' p e r s i s t e n t ' p r o t e c t i o n and a l l y l ethers f o r 'temporary' p r o t e c t i o n we were encouraged by e a r l i e r work which showed higher y i e l d s of 1 . 2 - c i s - q l y c o s i d e s when n o n - p a r t i c i p a t i n g groups were present on the 2 - p o s i t i o n (36-38) and by the work of Ishikawa and F l e t c h e r (76).on the r e l a t i v e rates of reaction of f u l l y benzylated a - and β - glycosyl h a l i d e s . We adopted these ideas in our i n i t i a l work and developed (39) simultaneously, a s i m i l a r route to 1.2-ci s-g1ycosi des as that used by Lemieux and his co-workers (11.77.78) and termed by him " h a l i d e c a t a l y s e d g l y c o s i d a t i o n r e a c t i o n s " . However, s i n c e we intended to use a l l y l ethers as p r o t e c t i n g groups in the glycosyl h a l i d e s , we decided to avoid using the g l y c o s y l bromides s i n c e t h e i r preparation could lead to problems with the unsaturated centres of the a l l y l groups and we therefore concentrated on the reactions of the g l y c o s y l chlorides. Our other concern at t h i s stage was the f e a s i b i l i t y of using perbenzylated intermediates; the degree of s t e r i c hindrance that might r e s u l t from t h e i r use and a l s o the physical p r o p e r t i e s of the p r o d u c t s . Our i n i t i a l experiments (39) were c a r r i e d out with f u l l y benzylated glucosyl c h l o r i d e s and some of the t r i - 0 benzyl ethers of benzyl α - D - g a l a c t o p y r a n o s i d e . Using d i c h l o r o methane as a s o l v e n t , tetraethylammonium c h l o r i d e as a c h l o r i d e source and t r i e t h y l ami ne as a base, to remove the hydrogen c h l o r i d e l i b e r a t e d , we showed that the f u l l y benzylated glucosyl c h l o r i d e (XXXVI) gave high y i e l d s of g l y c o s i d e s when condensed with benzyl 2 , 3 , 4 - t r i - 0 - b e n z y l - α - D - g a l a c t o p y r a n o s i d e (XXXVIl) and the product was moreover c r y s t a l l i n e . N.m.r. spectroscopy of the crude d i s a c c h a r i d e d e r i v a t i v e a l s o showed a high proportion of the


262

SYNTHETIC METHODS

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Studies on the Synthesis of Serologically Active Glycolipids - ACS

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