Ascorbic Acid - American Chemical Society

ASCORBIC. ACID. L-ASCORBIC ACID. 6. \\. C H 9 O H. HCOH. C H 9 0 H. I 2. HCOH. O H .... and esterification produced ethyl 3,4,5,6-tetra-0-acetyl-DL-o:...
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1 Synthesis of L-Ascorbic A c i d T H O M A S C.

CRAWFORD

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Central Research, C h e m i c a l Process Research, Pfizer Inc., Groton, CT 06340

The methods by which L-ascorbic acid has been synthesized are readily divided into three major categories. The first involves coupling a C fragment and a C fragment, and the second involves coupling a C fragment and a C fragment. The third involves the conversion of a C chain into the correct oxidation state and stereochemical configuration. All of these approaches will be reviewed with special regard given to those syntheses that are suitable for the prepara­ tion of analogues of L-ascorbic acid, the preparation of radiolabeled derivatives of L-ascorbic acid, and the current commercial synthesis of L-ascorbic acid. 1

5

2

4

6

Following the isolation of crystalline "hexuronic acid" from the adrenal cortex of the ox and from orange juice in 1928 (1) and the determina­ tion in 1933 (2) that the structure of this material was 1 (with other proton tautomers shown in Scheme 1), efforts were begun to synthesize this novel vitamin. In a very short time several syntheses were success­ fully accomplished that confirmed that the structure of L-ascorbic acid or vitamin C was indeed that proposed (2). Complete details of the crystal structure of 1 have since been obtained by both x-ray (3,4) and neutron diffraction (5) analysis and are approximated by structure 1a. Efforts directed toward the synthesis of L-ascorbic acid have been governed by the following factors: 1. The need to synthesize material to confirm the structure and provide larger quantities of material for further study. 2. The desire to synthesize analogues of L-ascorbic acid. 3. The desire to prepare radiolabeled material for use in the study of L-ascorbic acid metabolism in plants,fish,animals, and humans. 4. The need to develop a commercially viable, low cost syn­ thesis. This is illustrated by the fact that in 1934 1 kg of L-ascorbic acid sold for $7000 (6). 0065-2393/82/0200-0001$10.00/0 © 1982 American Chemical Society In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

ASCORBIC

L-ASCORBIC

ACID

ACID

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6

\\ CH 0H

CH OH

9

9

I

HCOH

2

HCOH

OH

Scheme 1.

In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

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1.

CRAWFORD

3

Synthesis of ia-Ascorbic Acid

T h e d e s i g n of syntheses of L - a s c o r b i c a c i d m u s t t a k e i n t o c o n s i d e r a ­ tion the following points: 1.

T h e synthesis m u s t b e c h i r a l since o n l y t h e L - e n a n t i o m e r is biologically active.

2.

T h e final step i n t h e synthesis m u s t b e c a r r i e d o u t u n d e r n o n o x i d a t i v e c o n d i t i o n s b e c a u s e of t h e v e r y f a c i l e o x i d a ­ t i o n of L - a s c o r b i c a c i d to d e h y d r o - L - a s c o r b i c a c i d f o l l o w e d b y further degradation.

3.

L - A s c o r b i c a c i d m u s t b e stable t o t h e c o n d i t i o n s u s e d to enerate i t (i.e., n o v i g o r o u s a c i d or b a s e t r e a t m e n t i n t h e n a l step b e c a u s e d e g r a d a t i o n of L - a s c o r b i c a c i d c a n result).

4.

F o r c o m m e r c i a l use, t h e synthesis m u s t b e

economical.

T h i s c h a p t e r p r o v i d e s a n o v e r v i e w of t h e v a r i o u s a v a i l a b l e syntheses of L - a s c o r b i c a c i d . T h e k e y s y n t h e t i c d i s c o v e r i e s t h a t h a v e r e s u l t e d i n t h e p r e p a r a t i o n of L - a s c o r b i c a c i d a n a l o g u e s , the p r e p a r a t i o n of r a d i o ­ l a b e l e d d e r i v a t i v e s of L - a s c o r b i c a c i d , a n d t h e p r o d u c t i o n of c o m m e r c i a l q u a n t i t i e s of L - a s c o r b i c a c i d are h i g h l i g h t e d . F o r a c o m p r e h e n s i v e r e v i e w of a l l these a p p r o a c h e s , see R e f e r e n c e

7.

In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

4

ASCORBIC

A l l syntheses of L - a s c o r b i c a c i d are a c t u a l l y p a r t i a l syntheses

ACID

be­

c a u s e t h e c h i r a l i t y at C5 a n d C4 is o b t a i n e d v i a n a t u r a l l y d e r i v e d sugars a n d n o t b y t o t a l synthesis. V a r i o u s m e t h o d s b y w h i c h the six c a r b o n s of a s c o r b i c a c i d h a v e b e e n a s s e m b l e d w i t h t h e a p p r o p r i a t e o x i d a t i o n state a n d s t e r e o c h e m i s t r y are s h o w n i n S c h e m e 2. O n e a p p r o a c h to t h e synthesis of L - a s c o r b i c a c i d is b y c o m b i n i n g a C

5

f r a g m e n t a n d a C i f r a g m e n t ( i n effect m a k i n g t h e

b o n d b e t w e e n C l a n d C2 i n l ) .

carbon-carbon

Intermediates derived from L-xylose

a n d L - a r a b i n o s e h a v e b e e n u s e d i n these syntheses. L - A s c o r b i c a c i d has been synthesized b y combining a C

2

fragment a n d a C

4

fragment ( i n

effect m a k i n g t h e c a r b o n - c a r b o n b o n d b e t w e e n C2 a n d C3 i n 1) s t a r t i n g

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w i t h L-threose.

N o syntheses of L - a s c o r b i c a c i d h a v e b e e n r e p o r t e d i n

w h i c h t h e c a r b o n - c a r b o n b o n d b e t w e e n C3 a n d C4 or b e t w e e n C4 a n d C5 (see 1) has b e e n f o r m e d ( i n effect a C or a C

4

fragment plus a C

2

3

fragment plus a C

3

fragment

f r a g m e n t r e p r e s e n t i n g C5 a n d C6,

respec­

t i v e l y ) . M o s t m e t h o d s f o r m a k i n g these c a r b o n - c a r b o n b o n d s w i l l r e s u l t i n t h e f o r m a t i o n of a m i x t u r e of e n a n t i o m e r s a n d / o r diastereomers. M o s t syntheses of L - a s c o r b i c a c i d start w i t h p r e f o r m e d C

6

sugars,

w h i c h b y m a n i p u l a t i o n of t h e o x i d a t i o n state at C l , C2, C5, a n d / o r

C6

C-j + C5 ( x y l o s e , a r a b i n o s e )

HCOH

C2 + C4 ( t h r e o s e )

HO

\>H

Scheme 2.

In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

1.

CRAWFORD

5

Synthesis of L-Ascorbic Acid

a n d b y m a n i p u l a t i o n of t h e stereochemistry a t C 2 o r C 5 h a v e b e e n c o n ­ v e r t e d i n t o L - a s c o r b i c a c i d b y a v a r i e t y of r e a c t i o n sequences. T h e m o s t common C

6

s u g a r s t a r t i n g m a t e r i a l is D - g l u c o s e , w h i c h has b e e n

con­

verted into intermediates formally derived f r o m L - g u l o s e , L-galactose, L-idose, or L-talose. A s u r v e y o f t h e r e p o r t e d syntheses o f L - a s c o r b i c a c i d reveals t h a t d e r i v a t i v e s r e l a t e d t o 2-keto a c i d

(Scheme 3 ) are the most fre­

(2)

quently used intermediate to L-ascorbic acid. lactone

(4)

( i n protected

are less f r e q u e n t l y u s e d .

form),

3-Keto

acid

(3), keto-

a n d 6-aldehydo-L-ascorbic acid

T h e use of e a c h of these i n t e r m e d i a t e s

w i l l b e i l l u s t r a t e d i n t h e f o l l o w i n g d i s c u s s i o n of t h e different

(5)

(2-5)

syntheses

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of L - a s c o r b i c a c i d .

Ascorbic

Acid via Ct and C

5

Fragments

T h e first synthesis of L - a s c o r b i c a c i d

( l ) was reported

i n 1933,

b e f o r e t h e correct s t r u c t u r e h a d b e e n d e t e r m i n e d . I n e a r l y 1933, M i c h e e l a n d K r a f t (8) s u g g e s t e d t h a t c a r b o x y l i c a c i d (6) w a s t h e s t r u c t u r e f o r L - a s c o r b i c a c i d . A short t i m e l a t e r t h e synthesis of D - a s c o r b i c a c i d s h o w n i n Scheme 4 starting w i t h D-xylosone was reported ( 9 - 1 2 ) . T h i s synthe­ sis g a v e m a t e r i a l i d e n t i c a l w i t h n a t u r a l L - a s c o r b i c a c i d , except f o r t h e specific r o t a t i o n , a n d w a s u s e d ( 9 - 1 2 ) as e v i d e n c e t o s u p p o r t s t r u c t u r e 6 as t h e s t r u c t u r e f o r L - a s c o r b i c a c i d . (9-12),

S h o r t l y after these i n i t i a l

t h e same s e q u e n c e of reactions w a s r e p o r t e d (13-15)

reports

and, hav­

i n g t h e a d v a n t a g e o f k n o w i n g t h e correct s t r u c t u r e of L - a s c o r b i c a c i d , t h e s e q u e n c e of reactions l e a d i n g f r o m L - x y l o s o n e t o L - a s c o r b i c a c i d w a s c o r r e c t l y d e p i c t e d as t h a t s h o w n i n S c h e m e 5; t h e synthesis p r o c e e d s v i a 3-keto a c i d d e r i v a t i v e 3 a. I t is i r o n i c t h a t o n e o f t h e m o r e d i f f i c u l t a n d important problems

of those t i m e s — t h e synthesis of L - a s c o r b i c a c i d —

w a s a c c o m p l i s h e d b e f o r e t h e correct s t r u c t u r e of 1 w a s k n o w n . T h i s C i h o m o l o g a t i o n of osones p r o v e d to b e v a l u a b l e i n the p r e p a r a ­ t i o n of L - a s c o r b i c a c i d analogues

(16) as w e l l as i n t h e p r e p a r a t i o n o f

r a d i o l a b e l e d L - a s c o r b i c a c i d (17-20).

T h i s synthesis w a s g r e a t l y i m ­

p r o v e d w h e n aldoses w e r e d i s c o v e r e d t o b e d i r e c t l y o x i d i z e d t o osones w i t h c u p r i c acetate ( E q u a t i o n 1) (21).

Subsequently, the conditions

w e r e m o d i f i e d so t h a t D - x y l o s e c o u l d b e o x i d i z e d t o D - x y l o s o n e i n 5 0 55%

y i e l d w i t h c u p r i c acetate i n m e t h a n o l .

T h e i n t e r m e d i a c y of t h e

i m i n o ether w a s p r o v e d b y the isolation of 7 w h e n D-glucosone w a s treated w i t h potassium cyanide (3a)

(16).

T h e initial cyanohydrin

adduct

e a s i l y u n d e r g o e s c y c l i z a t i o n to t h e i m i n o ether i n t e r m e d i a t e ( a q u e ­

ous s o l u t i o n f o r 10 m i n at r o o m t e m p e r a t u r e , S c h e m e 5 ) . T h i s f e a t u r e w i l l b e c o m p a r e d w i t h t h e c o n d i t i o n s r e q u i r e d f o r t h e l a c t o n i z a t i o n of other i n t e r m e d i a t e s .

In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

4

Scheme 3.

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In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

CRAWFORD

Synthesis of L-Ascorbic Acid

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1.

In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

ASCORBIC

CHO

CN

c=o

CHOH

I

I

I I

KCN

c=o

HCOH

I

I

HCOH

HOCH

I

I

HOCH

CH OH

I

2

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ACID

CH OH 2

3a

CH?OH HCOH

HCI

4 0 % overall Scheme 5.

CHO

CHO

I

I

c=o

HOCH

I

HCOH

I

Cu(OAc) 50-55%

HOCH

2

I I

HCOH

HOCH

I CH OH 2

I

CH OH 2

In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

(D

1.

CRAWFORD

9

Synthesis of L-Ascorbic Acid

OH

OH

HCOH

I

HCOH

I

CH OH

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2

7 A s e c o n d synthesis i n w h i c h a C i f r a g m e n t w a s c o u p l e d w i t h a C fragment was reported i n w h i c h acid chloride (8) a c y l n i t r i l e (9) and

b y use of s i l v e r c y a n i d e (23)

esterification p r o d u c e d

sonate.

5

w a s c o n v e r t e d to t h e

(Scheme 6).

Hydrolysis

e t h y l 3,4,5,6-tetra-0-acetyl-DL-o:t/Zo-2-hexulo-

T h e c o n d i t i o n s r e q u i r e d for the c o n v e r s i o n of t h i s m a t e r i a l t o

D L - a s c o r b i c a c i d w i l l b e d i s c u s s e d later. N o y i e l d s w e r e r e p o r t e d f o r this r e a c t i o n sequence. T h i s synthesis has n o t b e e n u s e d f o r the p r e p a r a t i o n of analogues or r a d i o l a b e l e d d e r i v a t i v e s of L - a s c o r b i c a c i d as has t h e osone-cyanide

synthesis first r e p o r t e d (9-12).

I n contrast t o t h e o s o n e -

c y a n i d e synthesis ( S c h e m e 5 ) i n w h i c h a 3 - k e t o g u l o n i c

acid derivative

is p r o d u c e d , the a c i d c h l o r i d e - s i l v e r c y a n i d e synthesis ( S c h e m e 6 ) sults i n t h e f o r m a t i o n of a 2 - k e t o g u l o n i c

a c i d d e r i v a t i v e (2a)

re­

as a n

i n t e r m e d i a t e i n the a s c o r b i c a c i d synthesis. A t h i r d synthesis u t i l i z i n g a C i a n d C

5

c o u p l i n g p r o c e d u r e to p r o ­

d u c e L - a s c o r b i c a c i d w a s r e c e n t l y r e p o r t e d (24) (10)

(Scheme 7). L-Arabinose

w a s r e d u c e d to L - a r a b i n i t o l a n d p r o t e c t e d w i t h f o r m a l d e h y d e

to

p r o v i d e l , 3 : 2 , 4 - d i - 0 - m e t h y l e n e - L - a r a b i n i t o l ( l l ) a l o n g w i t h a n u m b e r of other p r o d u c t s .

C o m p o u n d 11 w i t h the free h y d r o x y l g r o u p at C 5 a n d

a l l other h y d r o x y l g r o u p s p r o t e c t e d is s u i t a b l y p r o t e c t e d f o r

conversion

i n t o L - a s c o r b i c a c i d b y o x i d a t i o n to the a l d e h y d e , c a r b o n - c h a i n extension w i t h p o t a s s i u m c y a n i d e , t h e n c o n v e r s i o n to L - a s c o r b i c a c i d . T h i s s y n t h e ­ sis uses L - a r a b i n o s e as t h e source of c h i r a l i t y b y c a r b o n - c h a i n i n v e r s i o n . T h u s C 2 a n d C 3 i n a r a b i n o s e , w h i c h h a v e t h e same stereochemistry as C 4 a n d C 5 i n L-ascorbic acid, become C 4 a n d C 5 i n 1 b y reducing C l of a r a b i n o s e , s e l e c t i v e l y ( b u t inefficiently) p r o t e c t i n g C 1 - C 4 , o x i d i z i n g , a n d e x t e n d i n g the c h a i n at C 5 . Ascorbic Acid via C and C 2

k

Fragments

L - A s c o r b i c a c i d w a s p r e p a r e d b y u s i n g L-threose as t h e c h i r a l C

4

u n i t a n d e x t e n d i n g to t h e r e q u i r e d six c a r b o n s w i t h t h e c o r r e c t o x i d a t i o n

In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

10

ASCORBIC

C0 H

COCI

I

9

I

ACID

2

AcOCH

AcOCH

I

I

HCOAc

PCI
9 0 % ) fol­

l o w e d b y h y d r o l y s i s of t h e r e s u l t i n g p r o d u c t t o e t h y l 2 - k e t o - L - g u l o n a t e (L-xt/Zo-hexulosonate)

( 8 6 % ) a n d l a c t o n i z a t i o n b y e i t h e r a c i d o r base

( 9 0 % ) to L-ascorbic acid. E i t h e r this synthesis o r t h a t s h o w n i n S c h e m e 16 is s u i t a b l e f o r t h e p r e p a r a t i o n of C 6 d e u t e r a t e d reducing

or tritated derivatives of L-ascorbic a c i d

27 w i t h d e u t e r i u m o r t r i t i u m e n r i c h e d

sodium borohydride

gas o r w i t h

(51).

In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

labeled

1.

Synthesis of L-Ascorbic Acid

CRAWFORD

CHO

I

CH 0H

I

HCOH

9

2

Me C



2

HOCH

I

0

C

H

|

2

OCH

HOCH

I I HCOH I HCOH

0-CMe 80% Xanthomonas

HOCH

I

HOCH

I

translucens

HCOH

HCOH

I

I

HOCH

HOCH

I

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2

I

CH OH 2

CH OH 2

Scheme 18.

i n S c h e m e 19 (56-58).

T h i s m u l t i s t e p synthesis i n v o l v e s t h e c o n v e r s i o n

of D - g l u c u r o n i c a c i d i n t o 33 ( a d e r i v a t i v e of g u l o n i c a c i d ) f o l l o w e d b y o x i d a t i o n t o 3 4 a n d h y d r o l y s i s t o m e t h y l L-xt/Zo-2-hexulosonate

(36)

via 35. No

C A R B O N - C H A I N INVERSION.

T h i s section w i l l discuss the m e t h o d s

b y w h i c h D - g l u c o s e has b e e n c o n v e r t e d t o L - a s c o r b i c a c i d w i t h o u t c a r ­ b o n - c h a i n i n v e r s i o n . T h e s e syntheses of L - a s c o r b i c a c i d f r o m D - g l u c o s e w i t h o u t c a r b o n - c h a i n i n v e r s i o n i n v o l v e t h e o x i d a t i o n of D - g l u c o s e a t C l a n d C 2 , a n d t h e i n v e r s i o n of c h i r a l i t y a t C 5 . T h e first synthesis r e p o r t e d i n this class is s h o w n i n S c h e m e 20. D G l u c o s e c a n b e efficiently ( > 9 0 % ) o x i d i z e d f e r m e n t a t i v e l y to c a l c i u m D-xt/Zo-5-hexulosonate

( 3 7 ) u s i n g Acetobacter

suboxydans

(59).

The

r e d u c t i o n of 37 has b e e n s t u d i e d b y s e v e r a l researchers.

T h e best results

were obtained

a n d afforded

using palladium boride

a n d hydrogen

a

m i x t u r e of c a l c i u m i d o n a t e ( 3 8 ) a n d c a l c i u m g l u c o n a t e ( 3 9 ) i n t h e r a t i o of 7 3 : 2 7 (60).

Other catalytic hydrogenation

conditions resulted i n a

l o w e r y i e l d of 3 8 , b u t r e d u c t i o n w i t h s o d i u m b o r o h y d r i d e afforded a 1:1 m i x t u r e of 38 a n d 39 (61).

T h e m i x t u r e of 38 a n d 39 c a n b e efficiently

c o n v e r t e d t o p u r e L-xt/Zo-2-hexulosonic a c i d ( 2 3 ) b y f e r m e n t a t i v e o x i d a ­ t i o n of 38 to 23 a n d f e r m e n t a t i v e d e s t r u c t i o n of 39 u s i n g v a r i o u s o r g a ­ n i s m s , i n c l u d i n g Pseudomonas

fluorescens

(62,63).

T h e y i e l d of 23

b a s e d o n s t a r t i n g i d o n i c a c i d is greater t h a n 9 0 % . B a s e d o n D-xylo-5h e x u l o s o n i c a c i d , t h e y i e l d of 23 is 5 0 - 6 0 % . to L - a s c o r b i c a c i d as p r e v i o u s l y d e s c r i b e d . o x i d i z e d , t h e stereochemistry

A c i d 23 c a n b e c o n v e r t e d

T h u s i n this synthesis, C l is

at C 5 is i n v e r t e d v i a o x i d a t i o n t o t h e

ketone a n d r e d u c t i o n , a n d t h e n C 2 is o x i d i z e d .

T h i s synthesis is n o t

s u i t a b l e f o r the p r e p a r a t i o n of analogues, b u t c o u l d b e u s e d f o r p r e p a r i n g C 5 - l a b e l e d d e r i v a t i v e s of L - a s c o r b i c a c i d .

In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

26

ASCORBIC

C0 H

C0 Me

2

2

OH

I

HO

RO

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OH

OR 33

C0 Me 2

Br
co

-u—u—u—u—u X o X o X

X

o X

o O X X X CN x o x o o x u—u—u—u—u—u X

O X

X

X

u CN

o

X X x |i o x o o X -o—o—u—u—

8 w

1.

Synthesis of L-Ascorbic Acid

CRAWFORD

« CN

O

5 O

2E O

O II X ( J — U — U — U

5 ™

3 c o

X U — U

O x

o

X

"O

o

0>

X

*

X

o

z

O ^ O x o x X u—u—u—u—u—u O X o 1

CN

X

Z

Downloaded by DUKE UNIV on May 31, 2012 | http://pubs.acs.org Publication Date: June 1, 1982 | doi: 10.1021/ba-1982-0200.ch001

CN

X

©

ii x o x u—u- -u—u—yO

O

o

X

X

o CN

X

cn

X

CN

o>

X

-p.

o

X

CN

cn

2

z

x o X X u—u—u—u—u—u

O II

X

•u

CN

O

o

x

X

O

II

-u—u—uO X

M

X

X

o CN

X

•u

X

o

X

o

t

in 3

3

O

O

X

O

o 0>

JD

o v
H

HCOH

I

CH OH 2

Scheme 25. b i c a c i d w a s p r e p a r e d (83,84) is s h o w n . A s e c o n d m e t h o d f o r L - ( 4 - H ) 3

a s c o r b i c a c i d synthesis w a s r e c e n t l y r e p o r t e d ( 8 5 ) .

This material was

p r e p a r e d v i a t h e a s c o r b i c a c i d synthesis s h o w n i n S c h e m e 14 ( t h e B a k k e Theander synthesis), starting w i t h D - ( 3 - H ) g l u c o p y r a n o s e prepared b y 3

the catalytic reduction of l,2:5,6-di-0-isopropylidene-a-D-rifoo-hex-3-ulofuranose u s i n g t r i t i u m gas.

Literature Cited 1. Szent-Györgyi, A. Biochem. J. 1928, 22, 1387-1409. 2. Hirst, E. L.; Herbert, R. W.; Percival, E. G. V.; Reynolds, R. J. W.; Smith, F. Chem. Ind. (London) 1933, 221-222. 3. Hvoslef, J. Acta Chem. Scand. 1964, 18, 841-842. 4. Hvoslef, J. Acta Crystallogr., Sect. B 1968, 24, 23-35. 5. Ibid., 1431-1440. 6. Burns, J. J. "Kirk-Othmer Encyclopedia of Chemical Technology," 2nd ed.; Interscience: New York, 1963; Vol. 2, pp. 747-762. 7. Crawford, T. C.; Crawford, S. A. Adv. Carbohydr. Chem. Biochem. 1980, 37, 79-155. 8. Micheel, F.; Kraft, K. Hoppe-Seyler's Z. Physiol. Chem. 1933, 215, 215224. 9. Reichstein, T.; Grüssner, A.; Oppenauer, R. Helv. Chim. Acta 1933, 16, 561-565. 10. Reichstein, T.; Grüssner, A.; Oppenauer, R. Nature (London) 1933, 132, 280.

In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

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1. Crawford Synthesis of L-Ascorbic Acid

35

11. Reichstein, T.; Grüssner, A.; Oppenauer, R. Helv. Chim. Acta 1934, 17, 510-520. 12. Ibid., 1933, 16, 1019-1033. 13. Haworth, W. N. Chem. Ind. (London) 1933, 52, 482-485. 14. Haworth, W. N.; Hirst, E. L. Chem. Ind. (London) 1933, 52, 645-646. 15. Ault, R. G.; Baird, D. K.; Carrington, H. C.; Haworth, W. N.; Herbert, R. W.; Hirst, E. L.; Percival, E. G.; Smith, F.; Stacey, M. J. Chem. Soc. 1933, 1419—1423. 16. Haworth, W. N.; Hirst, E. L. Helv. Chim. Acta 1934, 17, 520-523. 17. Burns, J. J.; King, C. G. Science 1950, 111, 257-258. 18. Salomon, L. L.; Burns, J. J.; King, C. G. J. Am. Chem. Soc. 1952, 74, 5161-5162. 19. von Schuching, S. L.; Frye, G. H. Biochem. J. 1966, 98, 652-654. 20. Rudoff, S., Univ. Microfilms, 58-2712; Diss. Abstr. 1959, 19, 1551-1552. 21. Stone, I. U.S. Patent 2 206 374, 1940; Chem. Abstr. 1940, 34, 7545. 22. Hamilton, J. K.; Smith, F. J. Am. Chem. Soc. 1952, 74, 5162-5163. 23. Major, R. T.; Cook, E. W. U.S. Patent 2 368 557, 1945; Chem. Abstr. 1946, 40, 354. 24. Othman, A. A.; Al-Timari, U. S. Tetrahedron 1980, 36, 753-758. 25. Helferich, B.; Peters, O. Ber. Dtsch. Chem. Ges. 1937, 70, 465-468. 26. Stedehouder, P. L. Recl. Trav. Chim. Pays-Bos 1952, 71, 831-836. 27. Helferich, B. U.S. Patent 2 207 680, 1940; Chem. Abstr. 1940, 34, 8184. 28. Loewus, F. Annu. Rev. Plant Physiol. 1971, 22, 337-364. 29. Reichstein, T,; Grüssner, A. Helv. Chim. Acta 1934, 17, 311-328. 30. Kristallinskaya, R. G. Proc. Sci. Inst. Vitam. Res., Moscow 1941, 3, 78-84; Chem. Abstr. 1942, 36, 3007. 31. Slobodin, Y. M. J. Gen. Chem. USSR 1947, 17, 485-488. 32. Strukov, I. T.; Kopylova, N. A. Farmatsiya 1947, 10, 8-12; Chem. Abstr. 1950, 44, 8327b. 33. Reichstein, T. British Patent 466 548, 1937; Chem. Abstr. 1937, 31, 8124. 34. Bassford, H. H.; Harmon, W. S.; Mahoney, J. F. U.S. Patent 2 462 251, 1949; Chem. Abstr. 1970, 72, 133,146k. 35. Politechnika Slaska, British Patent 1 222 322, 1971; Bogaczek, R.; Bogaczek, Fr. Demandé Pat. 2 001 090, 1969; Chem. Abstr. 1970, 72, 133,146k. 36. Flueck, N.; Wuersch, J. J. Carbohydr. Nucleosides, Nucleotides 1976, 3, 273-279. 37. Bothner-By, A. A.; Gibbs, M.; Anderson, R. C. Science 1950, 112, 363. 38. Dayton, P. B. J. Org. Chem. 1956, 21, 1535-1536. 39. Shnaidman, L. O.; Siling, M. I.; Kushchinskaya, I. N.; Eremina, T. N.; Shevyreva, O. N.; Shishkov, U. R.; Kosolapova, N. A.; Kazakevich, L. C.; Timafeeva, T. P. Tr., Latv. Inst. Eksp. Klin. Med. Akad. Med. Nauk SSSR 1962, 27, 1-14; Chem. Abstr., 1963, 58, 4508a. 40. Karr, D. B.; Baker, E. M.; Tolbert, B. M. J. Labelled Compd. 1970, 6, 155-165. 41. Hinkley, D. F.; Hoinowski, A. M. U.S. Patent 3 721 663, 1973; Chem. Abstr. 1973, 78, 160,063m. 42. Heyns, K. Justus Liebings Ann. Chem. 1947, 558, 177-187. 43. Bakke, J.; Theander, O. J. Chem. Soc. D 1971, 175-176. 44. Mackie, W.; Perlin, A. S. Can. J. Chem. 1965, 43, 2921-2924. 45. Heyns, K.; Alpers, E.; Weyer, J. Chem. Ber. 1968, 101, 4209-4213. 46. Williams, M.; Loewus, F. A. Carbohydr. Res. 1978, 63, 149-155. 47. Kitahara, T.; Ogawa, T.; Naganuma, T.; Matsui, M. Agric. Biol. Chem. 1974, 38, 2189—2190 48. Dax, K.; Weidmann, H. Carbohydr. Res. 1972, 25, 363-370. 49. Crawford, T. C.; Breitenback, R. J. Chem. Soc., Chem. Commun. 1979, 388-389. 50. Crawford, T. C. U.S. Patent 4 111 958, 1978. 51. Taylor, R. L.; Conrad, H. E. Biochemistry 1972, 11, 1383-1388.

In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

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36

ASCORBIC ACID

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In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.