Ascorbic Acid - American Chemical Society

1 Synthesis of L-Ascorbic A c i d T H O M A S C.

CRAWFORD

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

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


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.


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.


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


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.


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


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 .


4

Scheme 3.



CRAWFORD



1.


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


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


(D

1.

CRAWFORD

9


OH

OH

HCOH

I

HCOH

I

CH OH


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


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).


labeled

1.


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


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 .


26

ASCORBIC

C0 H

C0 Me

2

2

OH

I

HO

RO


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.


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


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.



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Ascorbic Acid - American Chemical Society

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