Selective Substitution of Hydroxyl Groups in Sucrose

2 Selective Substitution of Hydroxyl Groups in Sucrose LESLIE HOUGH

Downloaded by TUFTS UNIV on October 14, 2014 | http://pubs.acs.org Publication Date: June 1, 1977 | doi: 10.1021/bk-1977-0041.ch002

Chemistry Department, Queen Elizabeth College, Camp Hill Rd., London W8 7AH, England

The c h e m i s t r y o f s u c r o s e ( A ) , o f t e n t e r m e d ' S u c r o chemistry , has played a s p e c i a l r o l e i nour studies o f carbohydrates i n view o f i t s u b i q u i t y and g r e a t import a n c e i n commerce. Our i n t e r e s t has been c o n c e n t r a t e d upon s t e r e o s e l e c t i v e c h e m i c a l r e a c t i o n s , i n t h e main by r e p l a c e m e n t o f s p e c i f i c h y d r o x y l g r o u p s b y o t h e r f u n c t i o n a l groups. T h e c o n s i d e r a b l e p r o g r e s s made i n this f i e l d , despite thecomplexities associated with the c h e m i s t r y o f t h i s unique m o l e c u l e , have been due t o t h e a p p l i c a t i o n o f mass s p e c t r o m e t r y , ^-H n.m.r. a n d C n.m.r. t o t h e s t r u c t u r e d e t e r m i n a t i o n o f t h e p r o ducts obtained by simple b u t e f f e c t i v e chromatographic c o n t r o l and, i n t h e case o f complex m i x t u r e s o f p r o ducts, through p u r i f i c a t i o n by column chromatography. A p r o f i l e o f c h e m i c a l r e a c t i v i t y h a s emerged such t h a t wider a p p l i c a t i o n s i n sugar and a s s o c i a t e d t e c h n o l o g i e s c a n now b e e x p e c t e d a s t h e f o s s i l i z e d m a t e r i a l s become increasingly expensive. Sucrose and i t s d e r i v a t i v e s show s t e r e o s e l e c t i v i t y i n many o f t h e i r r e a c t i o n s , w h i c h i s f o r t u n a t e , s i n c e a l a r g e number o f p a r t i a l l y substituted derivatives aretheoretically possible. (See T a b l e I ) . 1

1 3

(• = OH)

* 9

In Sucrochemistry; Hickson, J.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.

SUCROCHEMISTRY

10 Table I No. o f I s o m e r s o f S u c r o s e

Derivatives PENTA HEXA HEPTA OCTA

MONO 8 DI 28 TRI 56 TETRA 70

56 28 8 1

Thus w h i l s t o n l y one o c t a d e r i v a t i v e o f sucrose c a n e x i s t , s u c h a s t h e o c t a m e s y l a t e ( B ) , t h e r e a r e 70 p o s s i b l e t e t r a d e r i v a t i v e s a n d 56 a l t e r n a t i v e s i n t h e c a s e o f b o t h t r i - a n d pentä-derivatives. Our s t u d i e s (1,2) h a v e r e v e a l e d t h a t t h e e i g h t h y d r o x y l s o f s u c r o s e (A) react s e l e c t i v e l y and four, i n c l u d i n g the three primary g r o u p s , c a n b e r e p l a c e d t o g i v e p u r e 6 , 6 ' - d i - , 4,6,6'triand 1',4,6,6'-tetrasubstituted products, depend e n t upon t h e r e a c t a n t s and t h e r e a c t i o n c o n d i t i o n s . F o r e x a m p l e , w h e n s u c r o s e o c t a m e s y l a t e (B) w a s t r e a t e d w i t h n u c l e o p h i l e s , such as i o d i d e , bromide, c h l o r i d e , a z i d e , e t c , i n an a p r o t i c solvent,such as N,N-dimethylf o r m a m i d e (D.M.F.) o r h e x a m e t h y l p h o s p h o r i c t r i a m i d e


f

C

B

E

D

( • = 0-S0 CH ) 2

3

(x = Nucleophile)


2.

HOUGH

Substitution of Hydroxyl Groups

11

(H.M.P.T.), s p e c i f i c m e s y l o x y s u b s t i t u e n t s u n d e r w e n t nucleophilic substitution t o give 6,6'-disubstituted ( C ) , 4 , 6 , 6 ' - t r i s u b s t i t u t e d (D) a n d 1 , 4 , 6 , 6 - t e t r a s u b s t i t u t e d (E) p r o d u c t s t h a t c o u l d r e a d i l y b e i s o l a t e d by c a r e f u l c o n t r o l o f t h e r e a c t i o n c o n d i t i o n s a n d subsequent p u r i f i c a t i o n by column chromatography. I t was e s t a b l i s h e d t h a t t h e order o f replacement i s 6^6'> 4 >1'» a l l other p o s i t i o n s . The o b s e r v e d s t e r e o s e l e c t i v i t y ( 1 , 2 ) i s i n a c c o r d w i t h t h e b i m o l e c u l a r t r a n s i t i o n s t a t e t h e o r y (3). The s u b s t i t u e n t s a t t h e l e a s t h i n d e r e d , p r i m a r y 6- a n d 6 ' - p o s i t i o n s r e a c t i n g p r e f e r e n t i a l l y and t h e other p r i mary s u b s t i t u e n t , o f t h e more c r o w d e d n e o - p e n t y l t y p e a t t h e 1 ' - p r i m a r y p o s i t i o n , r e a c t i n g more s l o w l y t h a n t h e more f a v o r a b l e , b u t s e c o n d a r y , 4 - p o s i t i o n . In accord w i t h t h i s mechanism, i n v e r s i o n o f c h i r a l i t y i s a l w a y s o b s e r v e d when n u c l e o p h i l i c s u b s t i t u t i o n o c c u r s a t a c h i r a l c e n t r e , i n t h i s c a s e a t C-4. By t h i s p r o cess, 4-sulphonate e s t e r s o f sucrose a r e converted by s u b s t i t u t i o n a n d i n v e r s i o n o f c o n f i g u r a t i o n a t C-4 i n t o 3-D-fructofuranosyl a - D - g a l a c t o p y r a n o s i d e (F) ( ' g a l a c t o ' - s u c r o s e ) a n d i t s d e r i v a t i v e s (D a n d E) (4,5). I t i s o f i n t e r e s t t o note that galacto-sucrose (F) i s n o t s w e e t , d u e t o t h e p r e s e n c e o f a n a x i a l 4h y d r o x y l g r o u p (6) ( s e e l a t e r , h o w e v e r ) .


1

1

HO

F By s e l e c t i v e e s t e r i f i c a t i o n w i t h s u l p h o n y l h a l i d e s p a r t i a l l y substituted sulphonate esters o f sucrose can be p r e p a r e d . F o r example, u s i n g l i m i t e d q u a n t i t i e s o f toluene-p-sulphonyl ('tosyl') c h l o r i d e i n p y r i d i n e and subsequent p u r i f i c a t i o n by column chromatography, t h e 6 , 6 ' - d i t o s y l a t e ( G ) , 1 ' 6 , 6 ' - t r i t o s y l a t e ( H ) , a n d 1', 2 , 6 , 6 ' - t e t r a t o s y l a t e (iE) w e r e o b t a i n e d . Advantage was s u b s e q u e n t l y t a k e n o f t h e i n c r e a s e d s e l e c t i v i t y o f b u l k i e r sulphonyl h a l i d e s (!), such as t r i i s o p r o p y l b e n zene s u l p h o n y l c h l o r i d e ( ' t r i p s y l c h l o r i d e ' ) and m e s i t y lene sulphonyl c h l o r i d e t o prepare t h e corresponding 1',6,6'-trisulphonate e s t e r s d i r e c t l y and i n good y i e l d (8,9) , w i t h o u t t h e u s e o f c o l u m n c h r o m a t o g r a p h y .


12

SUCROCHEMISTRY

»Ts

G

A

OTs


'OTs

H

I

(• =OH) (*TsCl = Tosyl Chloride PY Pyridine) =

Nucleophilic substitution of the sulphonyloxy substituents i n these p a r t i a l l y s u b s t i t u t e d sulphonate e s t e r s of s u c r o s e r e a d i l y a f f o r d s 6 , 6 ' - d i - and l 6 6 - t r i s u b s t i t u t e d sucrose d e r i v a t i v e s , such as t h e c o r r e s ponding c h l o r i d e s and a z i d e s , from which t h e deoxy- and a m i n o - d e r i v a t i v e s , r e s p e c t i v e l y , c a n be p r e p a r e d . As an a l t e r n a t i v e , t h e s e l e c t i v e d e - e s t e r i f i c a t i o n o f s u c r o s e o c t a a c e t a t e ( J ) was e x a m i n e d . When a c h l o r o f o r m s o l u t i o n o f t h e l a t t e r (10) w a s p a s s e d through a column o f a l u m i n a , t h r e e h e p t a a c e t a t e s were o b t a i n e d w i t h f r e e h y d r o x y l s a t C - 6 , C - 4 a n d C-4 r e s p e c t i v e l y ( K , L a n d M) (1£) . Since a c e t y l groups r e a d i l y m i g r a t e , v i a an 4 , 6 - o r t h o e s t e r i n t e r m e d i a t e , f r o m t h e 4- t o t h e 6 - p o s i t i o n o f t h e D - g l u c o p y r a n o s y l r i n g , a n d p r e s u m a b l y l e s s r e a d i l y f r o m 4 - a n d 6'- we (10) s u g g e s t e d , w i t h s u p p o r t i n g e v i d e n c e , t h a t t h e i n i t i a l p r o d u c t s were t h e two h e p t a a c e t a t e s , w i t h t h e 6-hydroxyl and t h e 6'-hydroxyl r e s p e c t i v e l y f r e e . The f i n a l p r o d u c t s p r o b a b l y r e s u l t e d f r o m a c e t y l m i g r a tion. S e l e c t e d h y d r o x y l s i n s u c r o s e c a n be r e p l a c e d by c h l o r i d e by e x p l o i t i n g r e a c t i o n s w i t h e i t h e r s u l p h u r y l c h l o r i d e i n p y r i d i n e ( L I ) o r m e s y l c h l o r i d e i n D.M.F. (12,13). The r e a c t i o n w i t h s u l p h u r y l c h l o r i d e i n v o l v e s t h e i n i t i a l f o r m a t i o n o f a c h l o r o s u l p h a t e e s t e r (N) which then undergoes an i n t r a m o l e c u l a r n u c l e o p h i l i c substitution reaction with the insertion of chloride. ,

l

f

1

f

1

1

}


HOUGH



2.


13

14

SUCROCHEMISTRY

Under c o n t r o l l e d c o n d i t i o n s , s u c r o s e r e a c t s w i t h sulphuryl chloride i n pyridine i n a highly selective manner t o g i v e e i t h e r 6,6'-dichloro-6,6'dideoxysucrose (0) o r 4 , 6 , 6 ' - t r i c h l o r o - 4 , 6 , 6 ' - t r i d e o x y - g a l a c t o - s u c r o s e (P) which can be o b t a i n e d d i r e c t l y , a f t e r d e - c h l o r o s u l p h a t i o n , w i t h o u t r e s o r t i n g t o p r e p a r a t i v e chromatography. (16) I n t h e s e s u b s t i t u t i o n r e a c t i o n s , t h e l e a s t crowcTed, p r i m a r y 6- and 6 ' - p o s i t i o n s r e a c t p r e f e r e n t i a l l y and t h e f a v o r a b l e secondary 4 - p o s i t i o n r e a c t s f a s t e r than t h e more h i n d e r e d b u t p r i m a r y l -position. I n a r e l a t e d study P a r o l i s (14) has a l s o i s o l a t e d t h e 4 , 6 , 6 ' - t r i c h l o r o s u c r o s e (P) d i r e c t l y but as t h e c r y s t a l l i n e 1',2,3,3',4'-pentachloro-sulphate. More e x t e n s i v e r e a c t i o n o f s u c r o s e o c c u r s w i t h s u l p h u r y l c h l o r i d e a t h i g h e r temperatures t o g i v e t h r e e 4,6-dichloro-4,6-dideoxy-a-D-glucopyranosyl 2,3-sulphate d e r i v a t i v e s (Q,R and S ) , d i f f e r i n g i n t h e m o d i f i c a t i o n s t o t h e f r u c t o f u r a n o s y l moiety ( 1 5 ) . The c h l o r o s u c r o s e s (0) and (P) a r e r e a d i l y c o n v e r t e d i n t o anh y d r i d e s (167 and d e o x y d e r i v a t i v e s ( 1 7 ) . Thus t h e 6 , 6 ' - d i c h l o r i d e (0) was r e a d i l y t r a n s f o r m e d i n t o t h e 3 , 6 ; 3 ' , 6 ' - d i a n h y d r o d e r i v a t i v e (T) when t r e a t e d w i t h m e t h a n o l i c sodium methoxide, whereas, under s i m i l a r c o n d i t i o n s , t h e 4 , 6 , 6 ' - t r i c h l o r i d e (P) gave i n i t i a l l y the 3 , 6 - a n h y d r o - 4 , 6 ' - d i c h l o r i d e (U), due t o r a t e - e n hancement by t h e a x i a l 4 - c h l o r o group which moves t o the more f a v o r a b l e e q u a t o r i a l p o s i t i o n ( Ci-+ C ) f o l l o w e d by t h e f o r m a t i o n o f t h e f i n a l p r o d u c t , t h e 4-chloro-4-deoxy-3,6;3',6'-dianhydro d e r i v a t i v e (16) (V) .


1

h

l

k

(• = OH)


HOUGH



2.


15

16

SUCROCHEMISTRY

The 4 , 6 , 6 ' - t r i c h l o r i d e (P) w a s c o n v e r t e d i n t o 4 , 6 , 6 ' - t r i d e o x y s u c r o s e (W) b y c a t a l y t i c , r e d u c t i v e dehalogenation i n t h e presence o f potassium hydroxide (17). On t h e o t h e r h a n d , i n t h e p r e s e n c e o f t r i e t h y lamine, d e c h l o r i n a t i o noccurred e x c l u s i v e l y a t the secondary 4 - p o s i t i o n t o g i v e t h e 4-deoxy-6,6'-dichloride (X) a s e x p e c t e d f r o m t h e r e s u l t s o f L a w t o n , Wood, Szarek and Jones (18). N u c l e o p h i l i c replacement o f t h e 6 , 6 ' - c h l o r o - s u b s t i t u e n t s o f t h e l a t t e r (X) b y b e n z o a t e t h e n g a v e 4 - d e o x y - s u c r o s e (11) ( Y ) • T h e i s o m e r i c 1', 6 , 6 ' - t r i c h l o r o - l , 6 , 6 ' - t r i d e o x y s u c r o s e (AA) w a s c o n v e n i e n t l y prepared from 1 ' , 6 , 6 ' - t r i m e s i t y l e n e sulphon y l s u c r o s e (Z), a n d t h e n c o n v e r t e d a s a b o v e i n t o 1', 4';3,6;3',6'-trianhydrosucrose (BB)and 1 ' , 6 , 6 ' - t r i deoxysucrose (CC) (19) • Further chlorination of the


f

cc ((§) = Sucrose) (.

= OH)

(M

= Mesitylenesulfonyloxy)



2.

HOUGH


17

1 ' , 6 , 6 ' - t r i c h l o r i d e (AA) b y r e a c t i o n w i t h s u l p h u r y l c h l o r i d e i n p y r i d i n e o c c u r r e d a t C-4 a s p r e d i c t e d , t o give 1',4,6,6'-tetrachloro-1',4,6,6'-tetradeoxy-galact o - s u c r o s e (DP)• An o b j e c t i v e i n o u r c h e m i c a l s t u d i e s on s u c r o s e h a s b e e n t o e n h a n c e i t s n a t u r a l s w e e t n e s s , and we h a v e b e e n c o n s i d e r a b l y e n c o u r a g e d i n t h i s d i r e c t i o n by t h e s u r p r i s i n g d i s c o v e r y t h a t t h i s t e t r a c h l o r i d e (DP) i s i n t e n s e l y s w e e t , c o m p a r a b l e t o s a c c h a r i n b u t w i t h a p l e a s a n t a f t e r - t a s t e (20). The a p p a r e n t l y c o n t r a r y l o s s o f s w e e t n e s s i n g a l a c t o - s u c r o s e (F) has been a t t r i b u t e d t o h y d r o g e n b o n d i n g f r o m t h e a x i a l 4-hydroxyl group t o t h e r i n g oxygen which cannot, o f c o u r s e , o c c u r a t C-4 i n t h e s w e e t 1 ' , 4 , 6 , 6 ' - t e t r a c h l o r i d e d e r i v a t i v e (PP). The c o n s i d e r a b l e enhancement o f the sweetness o f sucrose by s e l e c t i v e s u b s t i t u t i o n by c h l o r i d e , n o t observed h i t h e r t o i n t h i s d i s a c c h a r i d e nor i n any o t h e r carbohydrate, i s c l e a r l y o f importance not o n l y i n n u t r i t i o n i n t h edevelopment o f a l t e r n a t i v e sweeteners t o sucrose, b u t i n r e l a t i o n t o t h e o r i e s o f sweetness.


18

SUCROCHEMISTRY 1 3

A p p l i c a t i o n o f C n.m.r. t o t h e c h a r a c t e r i s a t i o n o f d e r i v a t i v e s o f s u c r o s e h a s r e v e a l e d (21) t h a t i n addition to n.m.r. a n d m a s s s p e c t r o m e t r y , i t i s a powerful a i d since t h e p o s i t i o n o f replacement o f h y d r o x y l s by o t h e r s u b s t i t u e n t s and t h e i r stereochemist r y i s e a s i l y r e c o g n i s e d b y t h e s h i f t s . The r e s o n a n c e s o f C - l , C-6 a n d C - 6 ' , t h e p r i m a r y c a r b o n s i n s u c r o s e , h a v e b e e n a s s i g n e d ( 2 1 ) ( F i g u r e 1) a n d a r e d i s t i n c t i v e i n that they occur a t high f i e l d . The s i g n a l s f o r C-2, -3 a n d -5 o f s u c r o s e (A) h a v e n o t s o f a r b e e n a s s i g n e d u n e q u i v o c a l l y , b u t t h e y were u n a f f e c t e d by t h e i n t r o d u c t i o n o f c h l o r i n e a t C-6 w h e r e a s e p i m e r i s a t i o n a t C-4 t o g i v e g a l a c t o - s u c r o s e ( F ) r e s u l t s i n u p f i e l d s h i f t s o f C - 2 , -3 a n d -5 ( F i g u r e 2 ) . I n an attempt t o a s s i g n t h e s i g n a l f o r C - 3 , s u c r o s e (A) h a s b e e n o x i d i s e d t o 3-keto-sucrose (DP) b y A g r o b a c t e r i u m t u m e f a c i e n s ( 2 2 ) a n d t h e p r o d u c t (EE) r e d u c e d w i t h s o d i u m b o r o d e u t e r i d e , w h i c h showed t h e e x p e c t e d s t e r e o s p e c i f i c i t y t o g i v e {(3- H) - a - P - a l l o p y r a n o s y l ß - P - f r u c tofuranoside (FF); 'alio'-sucrose}( 2 3 ) .


1

2

Acknowledgements We a r e g r a t e f u l t o t h e I n t e r n a t i o n a l S u g a r R e search Foundation I n c . and Tate & L y l e L t d . f o r t h e i r continued support and i n t e r e s t i n these s t u d i e s .

Abstract In studying the fundamental chemistry of sucrose over the past two decades, we have discovered a profile of chemical reactivity that is unique to sucrose and devised procedures for the isolation and characterisation of the products. Thus precise control of the reactions of sucrose with sulphuryl chloride in pyridine can effect replacement of two, three or four hydroxyl groups in sucrose. By variation of the reaction conditions we can isolate 6,6'-dichloro-6,6'-dideoxysucrose, or 4,6,6'-trichloro-4,6,6'-trideoxy-galactosucrose in good yield, each crystalline or as a crystalline derivative, directly from the reaction without using chromatographic columns for isolation. Likewise, sulphonate esters of sucrose can be made d i rectly, such as 1',6,6'-tri-O-mesitylenesulphonyl-sucrose. We have studied the conversion of chlorosucroses into potentially useful products. Thus the d i - and trichloro compounds are readily converted into 3,6:3', 6'-dianhydrosucrose and its 4-chloro derivative respectively. Furthermore, reductive dehalogenation of



2.


HOUGH

>'

OH

1

4'

OH

OH

^ £ / o K ^ c . OH

CH

3 Q

OH

OH

^OH

6 1'6

3 5 ' 2 .35 4

' ^ ^ o ^ ^ c . OH

19

I

\

I 1

>

1

i

"~

_

/

Q

OH

3

110

100

90

80

70

60

50

40

Figure 2


30

20

20

SUCROCHEMISTRY

the chlorosucroses with hydrogen-Raney nickel in the presence of base, afforded d i - , tri- and tetradeoxysucroses in high yield. Studies on the application of C n.m.r.to sucrose and its derivatives have shown that i t is a valuable tool for characterisation.


13

Literature Cited 1. Bolton, C.H., Hough, L. and Khan, R., Carbohyd. Res., (1972) 21, 133 2. Hough, L. and Mufti, K.S. Carbohyd. Res., (1972) 25, 497; (1973) 27, 47 3. Richardson, A.C., Carbohyd. Res., (1969), 10, 395 4. Khan, R., Carbohyd. Res., (1972), 25, 232 5. Fairclough, P.H., Hough, L. and Richardson, A.C., Carbohyd. Res. (1975), 40, 285 6. Lindley, M.G.,Birch, G.G. and Khan, R.,J. Sci. Fd Agric., (1976), 27, 140 7. Creasey, S.E. and Guthrie, R.D., J. Chem. Soc. Perkin, (1974) 1, 1373 8. Almquist, R.G. and Reist, E.J.,J.Carbohyd. Nucleosides, (1974) 1, 461 9. Hough, L.,Phadnis, S.P. and Tarelli, E.,Carbohyd. Res. (1975) 44, C12 10. Ballard, J.M. Hough, L. and Richardson, A.C., Carbohyd. Res., (1974) 34, 184 11. Szarek, W.A.,Adv. In Carbohyd. Chem. and Biochem. (1973) 28, 225 12. Edwards, R.G, Hough, L.,Richardson, A.C. and Tarelli, E.,Tetrahedron Lett, (1973) 2369 13. Khan, R.,Jenner, M.R.,and Mufti, K.S. Carbohyd. Res., (1975) 39, 253 14. Parolis, H.,Carbohyd. Res., (1976) 48, 132 15. Ballard, J.M.,Hough, L.,Richardson, A.C. and Fairclough, P.H.,J. Chem. Soc., Perkin (1973) 1, 1524 16. Hough, L.,Phadnis, S.P. and Tarelli, E.,Carbohyd. Res., (1975) 44, 37 17. Phadnis, S.P. and Hough, L.,unpublished results 18. Lawton, B.T.,Wood, D.J.,Szarek, W.A. and Jones, J. K.N.,Canad. J. Chem., (1969) 47, 2899 19. Hough, L.,Phadnis, S.P. and Tarelli, E.,Carbohyd. Res., (1975) 44, C12 20. Hough, L.,Khan, R. and Phadnis, S.P.,British Patent Applications No. 616/76 and 19570/76; Hough,L., and Phadnis, S.P., Nature, (1976) 263,800. 21. Hough, L.,Phadnis, S.P. Tarelli, E. and Price, R., Carbohyd. Res. (1976) 47, 151 22. Fukui, S. and Hayano, K.,Agr. Biol. Chem. (1976) 33, 1013 23. Hough, L. and O'Brien, E. unpublished results.


2. HOUGH


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Biographic Notes Professor Leslie Hough, D.S., F.R.I.C., Prof. Chem. Educated at Manchester Univ. and at Bristol Univ. On staff at Bristol, leaving as Reader in 1967 to become Head of the Dept. of Chem. at Queen Elizabeth Coll. of the Univ. of London. Some 200 papers in carbohydrate chemistry. Dept. of Chem., Queen Elizabeth C o l l . , University of London, Atkins Building, Campden Hill, London W.8. England.


Selective Substitution of Hydroxyl Groups in Sucrose

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