Fluorinated Carbohydrates - ACS Publications - American Chemical

Chapter 2

Preparation and Reactions of Glycosyl Fluorides 1

Downloaded by UNIV OF MELBOURNE on March 28, 2016 | http://pubs.acs.org Publication Date: August 2, 1988 | doi: 10.1021/bk-1988-0374.ch002

Jared L. Randall and K. C. Nicolaou Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104 In recent years, fluorinated carbohydrates have been studied i n t e n s i v e l y , both as biochemical probes and as glycosylating agents. In t h i s paper, the preparation and reactions of glycosyl fluorides will be reviewed with emphasis on the use of glycosyl fluorides prepared from thioglycosides. Applications of t h i s technology to the synthesis of carbohydrate - containing natural products will be presented. A d d i t i o n a l l y , the novel 1,2-migration reaction induced by diethylaminosulfur t r i f l u o r i d e (DAST) will be discussed.

Although f l u o r i n a t e d carbohydrates have been a s u b j e c t o f i n t e r e s t f o r decades (1), t h e recent r e a l i z a t i o n »that g l y c o s y l f l u o r i d e s can be s y n t h e t i c a l l y u s e f u l has sparked renewed i n v e s t i g a t i o n i n t h i s a r e a . The modern advances i n the p r e p a r a t i o n and r e a c t i o n s o f g l y c o s y l f l u o r i d e s have been surveyed r e c e n t l y i n an e x t e n s i v e review (2.); t h e r e f o r e , t h i s l e c t u r e w i l l focus on the use o f g l y c o s y l f l u o r i d e s i n n a t u r a l product s y n t h e s i s and t h e s t u d i e s c a r r i e d out i n o u r laboratories. Preparation

of Glycosyl

Fluorides

The review by Card (2.) c o n c i s e l y p r e s e n t s t h e v a r i e t y o f r e p o r t e d methods f o r the p r e p a r a t i o n o f g l y c o s y l f l u o r i d e s from a number o f p r e c u r s o r s . Although they have been prepared from g l y c o s y l c h l o r i d e s , a c e t a t e s , and p i v a l o a t e s and g l y c o s e s , we have found t h i o g l y c o s i d e s t o be more v e r s a t i l e p r e c u r s o r s t o g l y c o s y l f l u o r i d e s . The employment of t h i o g l y c o s i d e s a l l o w s t h e s e l e c t i v e a c t i v a t i o n o f t h e anomeric c e n t e r e a r l y i n the s y n t h e t i c scheme, o b v i a t i n g the s e l e c t i v e deprot e c t i o n o r a c t i v a t i o n o f the anomeric c e n t e r d i r e c t l y b e f o r e f l u o r i nation. The N i c o l a o u group's i n t e r e s t i n t h e development o f m i l d methods f o r the formation o f 0 - g l y c o s i d i c l i n k a g e s t o complex n a t u r a l Current address: The Procter and Gamble Company, Miami Valley Laboratories, P.O. 398707, Cinncinnati, O H 45239-8707

•

0097-6156/88/0374-0013$06.00A) 1988 American Chemical Society

TAYLOR; Fluorinated Carbohydrates ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

Box


14

FLUORINATED CARBOHYDRATES: C H E M I C A L AND

BIOCHEMICAL ASPECTS

products l e d t o i n v e s t i g a t i o n s of g l y c o s y l f l u o r i d e s as g l y c o s y l donors. The key d i s c o v e r y t h a t l e d t o these a p p l i c a t i o n s was the r e a l i z a t i o n t h a t phenyl t h i o g l y c o s i d e s can be e f f i c i e n t l y converted t o g l y c o s y l f l u o r i d e s (Figure 1) Q) . Treatment of phenyl t h i o g l y c o sides (1) w i t h d i e t h y l a m i n o s u l f u r trifluoride (DAST) or hydrogen f l u o r i d e - p y r i d i n e complex (HF-pyr), and N-bromosuccinimide (NBS) in dichloromethane at -15-0°C p r o v i d e s g l y c o s y l f l u o r i d e s (3) i n good t o e x c e l l e n t y i e l d s . A d d i t i o n a l l y , i t was found t h a t many p r o t e c t i n g groups, which cannot w i t h s t a n d the more d r a s t i c c o n d i t i o n s commonly used f o r g l y c o s y l donor formation, t o l e r a t e these c o n d i t i o n s ; indeed, even s i l y l e t h e r s are s t a b l e t o the r e a c t i o n c o n d i t i o n s when DAST i s u t i l i z e d as the f l u o r i n a t i n g agent. I t i s reasonable t o assume t h a t t h i s f l u o r i n a t i o n r e a c t i o n proceeds v i a an i n t e r m e d i a t e bromosulfonium i o n (2, F i g u r e 1) which i s a t t a c k e d by a f l u o r i d e i o n . The f l u o r i d e i o n donor a b i l i t y of HFp y r i d i n e complex i s w e l l known; however, i n t h i s case the mechanism by which DAST i s able t o donate the f l u o r i d e i o n i s not as s t r a i g h t forward. We propose two p o s s i b l e mechanisms by which t h i s r e a c t i o n may proceed (Figure 2) . Mechanism A i n v o l v e s the s u c c i n i m i d e ion which i s formed as a byproduct i n the b r o m i n a t i o n r e a c t i o n . The s u c c i n i m i d e i o n may a t t a c k the s u l f u r atom i n the DAST reagent and d i s p l a c e a f l u o r i d e i o n which, i n t u r n , opens the bromo-sulphonium i o n (4). An a l t e r n a t i v e mechanism (B) i n v o l v e s the lone p a i r of e l e c t r o n s i n the DAST reagent which d i s p l a c e s the f l u o r i d e i o n which then a t t a c k s the bromosulphonium s p e c i e s (5) . The second mechanism seems more p l a u s i b l e i n view of the f a c t t h a t t h i s r e a c t i o n , i n most cases, proceeds t o completion v e r y q u i c k l y . R e a c t i o n s of G l y c o s y l

Fluorides

The use of g l y c o s y l f l u o r i d e s as g l y c o s y l donors i s advantageous f o r the s y n t h e t i c chemist because, they are r e a d i l y prepared, s t a b l e t o column chromatography, and t o l e r a n t of storage f o r extended p e r i o d s of time. U n t i l r e c e n t l y , g l y c o s y l f l u o r i d e s were c o n s i d e r e d t o be too s t a b l e f o r use as g l y c o s y l donors (1) . However, the advent of the Mukaiyama c o n d i t i o n s f o r the formation of the O - g l y c o s i d i c linkage generated i n t e n s i v e study of the r e a c t i o n s of g l y c o s y l f l u o r i d e s ilrl) • A f t e r s u r v e y i n g many a c t i v a t i n g agents, Mukaiyama and cowork e r s found t h a t u t i l i z i n g a combination of s i l v e r p e r c h l o r a t e and stannous c h l o r i d e as promoters c o n v e r t e d p - g l y c o s y l f l u o r i d e s t o 0g l y c o s i d e s i n h i g h y i e l d s and w i t h good a - g l y c o s i d e selectivities. We have found the Mukaiyama r e a c t i o n t o be e x t r e m e l y u s e f u l and have extended the a p p l i c a t i o n of t h i s method t o the s e l e c t i v e synthe s i s of p - g l y c o s i d e s as w e l l as a - g l y c o s i d e s . By t a k i n g advantage of s o l v e n t e f f e c t s and p r o t e c t i n g groups at the 2 - p o s i t i o n , remarkable s t e r e o s e l e c t i v i t y i n the formation of O - g l y c o s i d i c l i n k a g e s has been obtained (£) . Once the optimum c o n d i t i o n s were a s c e r t a i n e d , the anomeric c o n f i g u r a t i o n of the g l y c o s y l f l u o r i d e was not found t o have any s i g n i f i c a n t e f f e c t on the s t e r e o s e l e c t i v i t y of the g l y c o s i d a t i o n r e a c t i o n Q ) . This phenomenon has a l s o been r e p o r t e d by Ogawa e£ a l . (£,1) . We concur w i t h these i n v e s t i g a t o r s ' p r o p o s i t i o n t h a t the high s t e r e o s e l e c t i v i t y of these r e a c t i o n s i s due t o the formation of i n t i m a t e i o n p a i r s , as p r e v i o u s l y proposed by Lemieux (£) and Paulsen (2) f o r o t h e r g l y c o s y l donors.


2.

R A N D A L L & NICOLAOU

Preparation and Reactions of Glycosyl Fluorides 15


When used i n c o n j u n c t i o n w i t h t h e m i l d p r e p a r a t i o n o f g l y c o s y l f l u o r i d e s from t h i o g l y c o s i d e s , t h e Mukaiyama c o n d i t i o n s p r o v i d e t h e key t o a m i l d , s e l e c t i v e method f o r t h e s y n t h e s i s o f t h e O - g l y c o s i d i c l i n k a g e . We have found t h i s method t o be p r a c t i c a b l e f o r t h e forma t i o n o f g l y c o s i d e bonds t o s e n s i t i v e , complex a g l y c o n e s and f o r t h e r e p e t i t i v e , b l o c k - t y p e s y n t h e s e s o f o l i g o s a c c h a r i d e s . The u s e o f t h i o g l y c o s i d e s as p r e c u r s o r s t o g l y c o s y l f l u o r i d e s i s k e e n l y s u i t e d f o r t h e s e a p p l i c a t i o n s because t h e t h i o g l y c o s i d e f u n c t i o n a l i t y c a n : 1) be used t o mask t h e anomeric c e n t e r e a r l y i n t h e s y n t h e t i c scheme; 2) e x i s t i n t h e g l y c o s y l a c c e p t o r w i t h o u t i n t e r f e r i n g w i t h t h e g l y c o s i d a t i o n r e a c t i o n ; and 3) when d e s i r e d , be c o n v e r t e d t o t h e g l y c o s y l f l u o r i d e under m i l d c o n d i t i o n s . Formation o f O - G l y c o s i d i c Linkages t o S e n s i t i v e Aalvcones. The f i r s t a p p l i c a t i o n o f t h i s t e c h n o l o g y t o n a t u r a l p r o d u c t s s y n t h e s i s was t h e p a r t i a l s y n t h e s i s o f a v e r m e c t i n B Q ) .The o l e a n d r o s e d e r i v a t i v e (6, F i g u r e 3) was p r e p a r e d from L-rhamnose and c o n v e r t e d t o g l y c o s y l f l u o r i d e (7) i n 80% y i e l d b y r e a c t i o n w i t h NBS and DAST. Removal o f t h e s i l y l e t h e r p r o t e c t i n g group o f t h e t h i o g l y c o s i d e (6) a f f o r d e d t h e h y d r o x y l component (8) . C o u p l i n g o f these two components, u t i l i z i n g t h e Mukaiyama c o n d i t i o n s , s e l e c t i v e l y p r o v i d e d t h e al i n k e d d i s a c c h a r i d e (9) . The d i s a c c h a r i d e was t h e n c o n v e r t e d t o g l y c o s y l f l u o r i d e (10) (a:P r a t i o = 5:1) i n 85% y i e l d by t r e a t m e n t w i t h NBS and DAST. C o u p l i n g o f t h e d i s a c c h a r i d e g l y c o s y l donor t o t h e a v e r m e c t i n a g l y c o n e d e r i v a t i v e proceeded w i t h complete a-anomeric s e l e c t i v i t y i n 62% y i e l d . D e s i l y l a t i o n o f t h e r e s u l t a n t p r o d u c t p r o v i d e d avermectin B . T h i s s y n t h e s i s demonstrates t h e s y n t h e t i c u t i l i t y o f t h e method f o r t h e f o r m a t i o n o f O - g l y c o s i d i c l i n k a g e s t o complex, s e n s i t i v e a g l y c o n e s . Our method was a l s o employed i n t h e t o t a l s y n t h e s i s o f e f r o t o m y c i n (jJl) . The d e s i r e d c a r b o h y d r a t e u n i t s (11 and 12, F i g u r e 4) were e f f i c i e n t l y p r e p a r e d from D - a l l o s e and L-rhamnose, r e s p e c t i v e l y . Con v e r s i o n o f t h e rhamnose-derived t h i o g l y c o s i d e (12) t o t h e c o r r e s p o n d i n g g l y c o s y l f l u o r i d e (13) was a c c o m p l i s h e d i n 88% y i e l d w i t h t h e NBS/DAST c o n d i t i o n s . By e m p l o y i n g t h e Mukaiyama c o n d i t i o n s , t h i s g l y c o s y l f l u o r i d e was e f f i c i e n t l y c o u p l e d w i t h g l y c o s y l a c c e p t o r (11) i n 75% y i e l d t o p r o v i d e d i s a c c h a r i d e (14) w i t h t o t a l a-anomeric s e l e c t i v i t y . B u t , when t h e t h i o g l y c o s i d e o b t a i n e d (14) was c o n v e r t e d to t h e g l y c o s y l f l u o r i d e (15) w i t h t h e NBS/DAST c o n d i t i o n s and c o u p l e d w i t h g o l d i n o l a c t o n e ( 1 8 ) , t h e u n d e s i r e d a-anomeric p r o d u c t was o b t a i n e d . N e v e r t h e l e s s , p r o t e c t i n g group i n t e r c h a n g e o f t h e s i l y l p r o t e c t i n g groups t o n e i g h b o r i n g - g r o u p - a c t i v e a c e t y l groups p r o v i d e d d i s a c c h a r i d e (16). A f t e r conversion o f t h i s d i s a c c h a r i d e t o g l y c o s y l f l u o r i d e (17), c o u p l i n g t o goldinolactone allowed t h e p r e p a r a t i o n o f t h e d e s i r e d p - g l y c o s i d e ( 1 9 ) , e x c l u s i v e l y , i n 86% y i e l d . T h i s i n t e r m e d i a t e was t h e n f u r t h e r e l a b o r a t e d t o p r o v i d e t h e f i r s t total synthesis of efrotomycin. la

la

Synthesis o f Oligosaccharides. To demonstrate t h e e f f e c t i v e n e s s o f t h i s t e c h n o l o g y f o r t h e r e p e t i t i v e and b l o c k - t y p e s y n t h e s i s o f o l i g o s a c c h a r i d e s , we t a r g e t e d t h e l i n e a r h e x a s a c c h a r i d e (28, F i g u r e 5) c o n s i s t i n g o f s i x g l u c o s e u n i t s l i n k e d i n an a(l-*6) f a s h i o n Q ) . From t h e r e a d i l y p r e p a r e d phenyl t h i o g l y c o s i d e (20), both t h e g l y c o s y l f l u o r i d e (22, NBS/DAST, 90%, a:p r a t i o = 1 : 1 ) and t h e g l y c o -


16

FLUORINATED CARBOHYDRATES: C H E M I C A L AND BIOCHEMICAL ASPECTS

NBS

-SPh

HF-pyr. L_

1.


Figure

2

Formation o f G l y c o s y l F l u o r i d e s from T h i o g l y c o s i d e s .

F -S—NEt 2

F i g u r e 2.

3

2

The Mechanism

o f t h e DAST R e a c t i o n .

MeO

RO Me

a(85/o) | _ Y

a(80/o)|__

7

p _ si BuMe , Y = F 2

2

1) Aglycone-Bis(silyl ether), c (62%) 2) b (89%)

b(100%)

t

t

p _ Si BuMe , Y = F

1 0

8 R = H, Y = SPh Avermectin B

1 a

n

a) NBS, DAST, CH CI , -15°C; b) Bu NF, THF, 0°C; c) AgCI0 , SnCI , 4A MS, Et 0, -15-*20°C. 2

4

Figure

3.

P a r t i a l Synthesis

2

2

4

2

o f A v e r m e c t i n B . ( A d a p t e d from R e f . 3.) la


Preparation and Reactions of Glycosyl Fluorides


R A N D A L L & NICOLAOU

a) NBS, DAST, CH CI , -15°C; b) AgCI0 , SnCI , 4A MS, Et 0, -15— 0°C; c) i) Bu NF, THF, 0-25°C, ii) Ac 0, DMAP, CH CI , 25°C. 2

2

4

2

2

n

4

F i g u r e 4.

2

2

2

Attachment o f t h e C a r b o h y d r a t e P o r t i o n o f E f r o t o m y c i n . ( A d a p t e d f r o m R e f . 10.)


F L U O R I N A T E D CARBOHYDRATES: C H E M I C A L AND B I O C H E M I C A L ASPECTS

'BuPh SiO 2

AcO SPh

PhCH 0


2

20

a (90%)/

OCH Ph

(98%)

2

>v

HO

AcO SPh

PhCH 0 2

21 OCH Ph 2

_in n = 0, R=OSi«BuPh , X=F . 25 I

a ( 8 8 % )

n = 2, R=OSi'BuPh , X=F . 27 J22,c(66%)

a ( 8 9 % )

2

,

R=Si BuPh X=SPh(|5) 23

PhCHzOOs^-^-A^x OCH Ph 2

b ( 9 7 / o )

• R=H, X=SPh (P)

2>

2 4

1 | c (70%)

2

R=Si

Fluorinated Carbohydrates - ACS Publications - American Chemical

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