Stereoselective Synthesis and Properties of 1-0-Acyl

9 Stereoselective Synthesis and Properties of 1-0-Acyl-

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D-Glucopyranoses PHILIP E. PFEFFER, GORDON G. MOORE, PETER D. HOAGLAND, and EDWARD S. ROTHMAN Eastern Regional Research Center, Agricultural Research Service, U.S. Department of Agriculture, Philadelphia, Pa. 19118 In general, 1-0-acylaldoses, and in particular the derivatives with a cis hydroxyl group at C-2, are difficultly accessible substances. A few 1-0-acyl-D-glucoses have been found in nature, e.g., 1-0-benzoyl-β-D-glucopyranose (peri -planetin) in insects (1), stevioside in Stevia Rebaudiana Bertoni (2), asiaticoside from Cantella asiatica (3) and 1-0galloyl-β-D-glucopyranose in Chinese rhubarb (4). Over the years there have been numerous attempts at preparing anomerically pure H

H

I c=o I R

Ια

\β

1-α and β-D-glucopyranose esters 1α and 1β using various reactions aimed at controlling the anomerism of the C-1 acylation site. Schmidt (5) prepared the sterically hindered 1-0-galloyl-α-D— glucopyranose 2a in 5% yield through a lengthy five-step synthesis.

2a

OH

155

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

156

SYNTHETIC METHODS

F O R CARBOHYDRATES

The key steps in this scheme involved a BF isomerization for five days of the more accessible 2,3,4,6-tetra-0-acety1-1-0(triacetyl-galloy1)-ß-D-glucopyranose followed by preferential deacylation of the more labile acetyl protecting groups. This work represented the first reported preparation of a 1-0-acyl-αD-glucopyranose 1α. In later studies Fletcher (6) questioned the positional assignment of the ester grouping of Schmidt's compound 2a and took another approach to solve the problem. In his attempt using a silver benzoate displacement reaction on D-glucose diethyl dithioacetal, Fletcher prepared in very low conversions 2-0-benzoyl-ß-D-glucose, which was isolated as its tetraacetate. A similar treatment of ethyl-1-thio-ß-D-glucopyranoside gave after acetylation both 1,3,4,6-tetra-0-acetyl-2-0-benzoyl-α-Dglucopyranose and 2,3,4,6-tetra-0-acetyl-1-0-benzoyl-α-Dglucopyranose (6). Although, the 1-α-D-glucosyl ester was apparently an initially formed product, ester migration to the 2-position evidently took place upon isolation. Successful preparation of a stable 1-0-α-D-glucosyl ester, which did not undergo migration, was finally realized in the synthesis of the hindered mesitoate derivative 2b in 17% yield (6).


3

Although 2b was stable to neutral conditions, i t could be induced to undergo C- to C« ester migration under basic conditions (7). I t was concluded (6) that 2b would be "the only example of a cis-l-O-acylaldose that could be prepared and isolated" without rapid rearrangement. Preparation of the 1-0-acyl-p-D-glucopyranoses 1β i s less complex because of the i n a b i l i t y of the trans


9.

oriented

157

1-O-Acyl-O-glucopyranoses

PFEFFER E T A L .

1-0-acylaldose

to undergo

Acylation of p a r t i a l l y protected glucopyranose 3 yielded l b a f t e r

analogous

ester

shifting.

4,6-O-benzylidine-l-O-sodio-Dd e b l o c k i n g (8). Nevertheless,

o v e r a l l conversions of the anomerically pure product ester l b based on g l u c o s e were o n l y 30-40% due t o t h e l o w and v a r i a b l e results

obtained

for

the i s o l a t i o n and p u r i f i c a t i o n of

benzylidine-D-glucopyranose In to

report

we w i l l

the preparation of

their


this

acyl

spectral

which

We w i l l

are important

achieved

describe

glucosyl

properties

migration.

4 and i t s corresponding

Stereoselective

esters

3. approaches

l a and l b , and examine

discuss

reactivity including the mechanistic

i n explaining the stereochemical

i n the key acylation

glycopyranose

some new s y n t h e t i c

and chemical also

4,6-0-

salt

implications control

reaction.

Acylation of 2,3,4,6-tetra-O-benzyl-l-O-lithio-D(TBG L i

+

)

(9)

One o f t h e m o s t e l e g a n t m e t h o d s f o r a c h i e v i n g stereoselective g l y c o s i d a t i o n has r e c e n t l y been demonstrated by Schuerch (10), e q u a t i o n 1, and Lemieux ( 1 1 ) , e q u a t i o n 2. Utilizing 2,3,4,6tetra-O-benzyl-l-bromo-a-D-glucopyranose (TBGB), these workers c a r r i e d out double i n v e r s i o n displacement reactions i n which the f i n a l glycoside linkage had the desired configuration. Equation 1

.

C ]

«»0

v

u

«*0v

N(Et)s

- o

Ihl3u

wc'f"

*CH CI 2

w

2

0

V

^ C

M

+,_..

ROH

^0

B r

^VH

H

**C

0

(ID R

d e p i c t s s t e r e o c h e m i c a l c o n t r o l through t h e agency of the " r e v e r s e anomeric" effect exhibited by the e q u a t o r i a l preference of ammonium s a l t i n t e r m e d i a t e ( 1 0 ) , w h i l e e q u a t i o n 2 d e m o n s t r a t e s the approach through e q u i l i b r a t i o n effected by s o l u b i l i z e d bromide i o n . I n each case a h i g h s e l e c t i v i t y f o r α - g l y c o s i d e l i n k a g e f o r m a t i o n was shown. l a t t e r r e a c t i o n ( e q u a t i o n 2)

However, i n the e a r l y stages a p r e f e r e n c e f o r t h e β-anomer

of the could

be r e a l i z e d , b u t o v e r a l l c o n v e r s i o n t o t h i s s p e c i e s was l o w . F o r t h e s t u d y o f t h e a c y l a t i o n o f t h e a n o m e r i c OH o f g l u c o s e , w e e x a m i n e d t h e r e a c t i o n s f 2 , 3 , 4 , 6 - t e t r a - O - b e n z y l - l - O - l i t h i o - D g l u c o p y r a n o s e 5 (TBG L i ) b e c a u s e o f at the position. Furthermore, i f could be c a r r i e d out d i r e c t l y on 5, i prepare the unstable bromide d e r i v a t i displacement reaction. (10

i t s n o n p a r t i c i p a t i n g group stereoselective acylation t would o b v i a t e t h e need t o v e TBGB ( 1 1 ) f o r a n i n d i r e c t

Metalation of 2,3,4,6-tetra-O-benzyl-D-glucopyranose (TBG) 6 mmol) i n 1 2 5 m l o f t e t r a h y d r o f u r a n (THF) a t - 3 0 t o - 4 0 ° w i t h


158

SYNTHETIC METHODS FOR CARBOHYDRATES

1.1 equivalents of η-butyl lithium (1.6 M i n hexane) followed by acylation with 1.1 equivalents of acyl halides, (20 minutes) produced a mixture of 2,3,4,6-tetra-O-benzyl-l-O-acyl-D-glucopyranose esters (TBG esters) 7a and 0 i n 90-95% yield with a Η

B 0^CH^

π Bu Li THF or Benzene

N


1

ρ V^0B^^0Li n

"

5

7

decided preference for the α-configuration 7α. Often the isolated products were o i l s which could not be crystallized; however, the anomeric composition was easily determined by evaluation of the proton nmr spectrum of the characteristic anomeric hydrogens. Table I l i s t s the physical properties of esters prepared by this procedure. For each member i n this series, the anomeric composi tion of the isolated product esters was always at least 90% α and 10% 3 by nmr analysis. However, selectivity for the a-anomer diminished (70% a, 30% 0) with acylation temperature elevation to 60°. Metalation of 6 i n benzene at 0-5°C followed by acylation at this temperature produced a mixture of esters 7a and 70, con taining equal amounts of both a- and 0-anomeric forms. At higher temperatures, ^60°, we observed unexpectedly high selectivity for the production of the 0-anomeric ester 70. In a l l cases studied at ^60° we obtained products with a 0/a ratio of 9/1, a complete reversal of the selectivity shown i n THF at -30°. Table II contains physical properties of ester products obtained from acylation of 5 i n benzene at 60°. This stereoselectivity i s much greater than previously reported. For example, the direct acylation of 6 i n methylene chloride-pyridine over a wide range of temperatures gives only slight selectivity for formation of the a-anomer (60-70% a, 30-40% 0) (12) as does the dehydrationacylation reaction with the N-acylamino acid f a c i l i t a t e d by dicyclohexylcarbodiimide (13). To establish the mechanism responsible for the stereoselective control of this reaction we studied the products as a function of solvents and temperature using a single acylating agent. Table III shows the results obtained through acylation of 5 with hexadecanoyl chloride i n benzene and i n THF at temperatures from -40° to +62°C. As previously noted i n the THF, the α-glycosyl ester 7a i s the predominant product over the temperature range of -40° to +60°. However, selectivity for the α-anomer decreased (70% a, 30% 0) when the reaction temperature was raised to 25°, and



H

H

C

b

17

33

b

6.70(d,3.3)

e

1740

6.60 (d,3.3) 6.66(d,2.7)

e

e

1737

1740

5.90 (m)

f

+73.7

+72.0

f

5.90(m)

+73.5

+42.8

f

5.90(m)

5.85(d,6.8)

+45.9

5.85(d,6.8)

6.65(d,2.6) 6.65(d,2.6)

C

2

2

(CH C1 , l c ) +39.2

5

5.85(d,6.8)

M p

6.65 (d,2.6)

1

Stereoselective Synthesis and Properties of 1-0-Acyl

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