Ascorbic Acid: Chemistry, Metabolism, and Uses - American Chemical

3 Recent Advances in the Derivatization of L-Ascorbic A c i d

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GLENN C. ANDREWS and THOMAS CRAWFORD Central Research, Chemical Process Research, Pfizer Inc. Groton, CT 06340

A survey of work since 1975 on the derivatization of ascorbic acid is reviewed from the perspective of the organic chem istry of ascorbic acid. Recent advances in the control of regioselectivity of alkyhtive derivatization of ascorbic acid have been made possible by the utilization of di- and tri -anions of ascorbic acid. Their use has allowed the facile synthesis of inorganic esters of ascorbic acid. New synthesis of acetal and ketal, side-chain oxidized, and deoxy deriva tives are reviewed. The total synthesis of a new side-chain oxidized ascorbic acid denvative, 5-ketoascorbic acid, is reported.

There has been a great deal of recent work on the chemistry of Lascorbic acid and ascorbic acid derivatives since the subject was last reviewed by Tolbert et al. in 1975 (1). Much of this work has been generated in three major areas of interest: the biosynthesis and catabolism of ascorbic acid; the commercial need for safe, food grade antioxidants; and investigations into the biological role of ascorbic acid in vivo. The recent literature has generated a wealth of new data on the chemistry of ascorbic acid and has given us a better understanding of how this functionally complex molecule can be modified and manipulated. Since the purpose of this chapter is to review the recent literature from the perspective of the organic chemistry of ascorbic acid, it is convenient to correlate the literature with respect to the reactivity of ascorbic acid to alkylation and acylation under basic and acidic conditions, its acetal and ketal derivatives, and finally with respect to the chemistry of its oxidation and reduction. 0065-2393/82/0200-0059$06.25/0

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

60

ASCORBIC

ACID

The Alkylation and Acylation of L-Ascorbic Acid Under Basic Conditions T h e r e a c t i v i t y of ascorbic

acid toward

electrophiles

under

basic

c o n d i t i o n s is a f u n c t i o n of the a c i d i t y a n d steric e n v i r o n m e n t s of t h e f o u r h y d r o x y l g r o u p s at the C 2 , C 3 , C 5 , a n d C 6 positions ( F i g u r e 1 ) .

The

first i o n i z a t i o n of the m o l e c u l e takes p l a c e at the C 3 h y d r o x y l ( p K 4.25)

a

=

( 2 ) . W h i l e r e a d i l y i o n i z e d , the extensive d e l o c a l i z a t i o n of e l e c t r o n

d e n s i t y i n t o the e n o n o l a c t o n e r i n g results i n l o w r e a c t i v i t y to a l l b u t Downloaded by OHIO STATE UNIV LIBRARIES on May 5, 2012 | http://pubs.acs.org Publication Date: June 1, 1982 | doi: 10.1021/ba-1982-0200.ch003

r e a c t i v e a l k y l a t i n g a n d a c y l a t i n g agents s u c h as d i a z o m e t h a n e b e n z y l c h l o r i d e (4),

(1,3),

trimethylchlorosilane ( 5 ) , a n d a c i d chlorides

(I).

F u r t h e r m o r e , the u n s t a b l e n a t u r e of t h e r e s u l t i n g v i n y l ether or

ester

d e r i v a t i v e s has r e s u l t e d i n f e w reports of selective 0 3 d e r i v a t i z a t i o n ( I ) . U n d e r m o r e basic c o n d i t i o n s , the i o n i z a t i o n of t h e C 2 h y d r o x y l occurs (pK

0

=

11.79) ( 2 ) w i t h t h e f o r m a t i o n of t h e d i - a n i o n , 3. N M R i n v e s t i

gations of the m o n o - a n d d i - a n i o n s of ascorbic a c i d suggest r e t e n t i o n of t h e lactone r i n g a n d the f o r m u l a t i o n of these species as 2 a n d 3, r e s p e c t i v e l y (6,7,8).

T h e d i - a n i o n of ascorbic a c i d reacts w i t h

p r e f e r e n t i a l l y at t h e less stable 0 2 p o s i t i o n

(1,9,10),

electrophiles

and allows

the

selective f u n c t i o n a l i z a t i o n of this p o s i t i o n i n the p r e s e n c e of free h y d r o x y l s at C 3 , C 5 , a n d C 6 . Selective 0 2 a l k y l a t i o n has also b e e n o b s e r v e d w i t h b i o l o g i c a l m e t h y l a t i n g agents i n v i v o . C a t a b o l i s m of ascorbic a c i d i n the g u i n e a p i g forms 0 2 m e t h y l a s c o r b i c a c i d as a m i n o r p r o d u c t

(II).

U n d e r h i g h l y b a s i c c o n d i t i o n s , ascorbic a c i d m a y e x h i b i t c h e m i s t r y d e r i v e d f r o m i o n i z a t i o n of t h e C 4 h y d r o g e n , p r e s u m a b l y w i t h t h e f o r m a t i o n o f a t r i - a n i o n , 4. B r e n n e r et a l . (12) r a c e m i z a t i o n of ascorbic

r e p o r t e d the e p i m e r i z a t i o n a n d

a c i d at h i g h p H a n d elevated

6-sulfate, acyl, silyl, boryl and methyl derivatives

temperature.

5,6-O-Ketal and acetal derivatives

acyl, methyl, boryl and silyl derivatives proton exchange C-2, C-3 reduction and oxidation 3-phosphate, silyl, methyl, boryl and acyl derivatives

2-sulfate, phosphate, silyl, b o r y l , Derivatives

OH

methyl and acyl derivatives

Figure 1.

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

3.

ANDREWS AND CRAWFORD

Derivatization of L-Ascorbic Acid

61

B e l l et a l . ( 1 3 ) , u s i n g s i m i l a r c o n d i t i o n s , p r e p a r e d L - ( 4 - H ) a s c o r b i c a c i d 3

via t r i t i u m oxide exchange. If a l e a v i n g g r o u p resides at t h e C 5 p o s i t i o n of a s c o r b i c a c i d , e l i m i n a t i o n c a n o c c u r v i a i o n i z a t i o n of the C 4 h y d r o g e n w i t h t h e f o r m a t i o n of a 4 , 5 - d e h y d r o d e r i v a t i v e . T h i s has b e e n o b s e r v e d i n t h e case of a s c o r b i c a c i d d e r i v a t i v e 5, w h i c h o n t r e a t m e n t w i t h 1 , 5 - d i a z a b i c y c l o [4.3.0] n o n 5-ene

(DBN)

o r p o t a s s i u m h y d r i d e affords

the

d e r i v a t i v e 6 as a m i x t u r e of o l e f i n i c isomers (14). dehydroascorbic

a c i d 2 - O - s u l f a t e , 8, v i a t h e r e a c t i o n of 6 - O - v a l e r o y l

L - a s c o r b i c a c i d , 7, w i t h p y r i d i n e - S 0


5-deoxy-4,5-dehydroT h e f o r m a t i o n of 4 , 5 -

3

w a s r e p o r t e d to a f f o r d a s i n g l e

i s o m e r ( 1 5 ) . I n t e r s t i n g l y , t h e C 5 h y d r o x y e p i m e r of c o m p o u n d 7, ( 6 - 0 v a l e r o y l - D - e r y t h o r b i c a c i d ) w a s also r e p o r t e d to afford a s i n g l e 5 , 6 - d e hydro derivative isomeric w i t h compound

8, s u g g e s t i n g

stereoselective

e l i m i n a t i o n h a d o c c u r r e d . U n f o r t u n a t e l y , t h e c o n f i g u r a t i o n of t h e r e s u l t i n g olefins is u n k n o w n . If b o t h t h e C 2 a n d C 3 h y d r o x y groups a r e p r o t e c t e d , a l k y l a t i o n o r a c y l a t i o n occurs at t h e s t e r i c a l l y m o s t accessible C 6 h y d r o x y l ( I ) .

Alkyla

t i o n at the C 5 p o s i t i o n occurs o n l y after d e r i v a t i z a t i o n of t h e other t h r e e r-OH

r-OH

r—OH

> - N : H

R

3

-°

CH

r—OH

DBU

3

or K H ^

^

CHfi

DCHj


62

ASCORBIC ACID

functions.

N o 0 5 monosubstituted

d e r i v a t i v e s of a s c o r b i c

acid

have

been reported. T h e s e g e n e r a l i z a t i o n s a r e i l l u s t r a t e d b y t h e recent synthesis of L ascorbic

a c i d glucosides

11 a n d 12 (16).

T h e monosodium

salt o f

a s c o r b i c a c i d i n N , N - d i m e t h y l f o r m a m i d e ( D M F ) affords e x c l u s i v e l y t h e 03

monoalkylated derivative 9 on alkylation w i t h

glucopyranosyl bromide.

2,3,4,6-tetra-O-a-D-

T o o b t a i n t h e 0 2 g l u c o s y l a t e d d e r i v a t i v e 10,

u n d e r t h e same c o n d i t i o n s , r e q u i r e d t h e p r o t e c t i o n of t h e C 3 h y d r o x y l as a m e t h y l ether.


ascorbic

S e v e r a l w o r k e r s h a v e r e p o r t e d t h e biosynthesis of

a c i d glucosides

i n b a c t e r i a (17);

however, t h e structure a n d

p o s i t i o n of g l u c o s y l a t i o n i n these c o m p o u n d s has n o t b e e n u n a m b i g u o u s l y determined.

Carbon vs. Oxygen Alkylation of Ascorbic Acid T h e mono-anion

of a s c o r b i c

a c i d is a n a m b i d e n t a n i o n t h a t c a n

d i s p l a y n u c l e o p h i l i c i t y at t h e C 2 as w e l l as 0 3 positions. T h i s a m b i d e n t c h a r a c t e r w a s first o b s e r v e d b y J a c k s o n a n d Jones (4) i n t h e synthesis of 3-O-benzylascorbic

a c i d b y a l k y l a t i o n o f s o d i u m ascorbate w i t h b e n z y l

c h l o r i d e . I n s t r o n g l y c a t i o n s o l v a t i n g solvents, s u c h as d i m e t h y l s u l f o x i d e ( D M S O ) , e x c l u s i v e 0 3 a l k y l a t i o n w a s o b s e r v e d . I n w a t e r , a m i x t u r e of t h e e x p e c t e d 0 3 a l k y l a t e d 13 a n d C 2 b e n z y l a t e d p r o d u c t 14 w a s p r o d u c e d . M o r e r e c e n t l y , B r i m a c o m b e et a l . (18) h a v e also s h o w n C 2 a l k y l a t i o n o f a n a s c o r b i c a c i d d e r i v a t i v e i n t h e i r a t t e m p t e d use of a s c o r b i c a c i d as a s y n t h o n f o r t h e synthesis of s p i r o d i l a c t o n e s .

D e a l k y l a t i o n of

2-0-(E)-cinnamoyl-5,6-0-isopropylidene-3-0-methylascorbic

a c i d , 15, w i t h

l i t h i u m i o d i d e i n D M S O afforded t h e C 2 a l k y l a t e d i s o m e r , 16. I t w o u l d a p p e a r t h a t u n d e r c o n d i t i o n s of r e v e r s i b l e d e a l k y l a t i o n at o x y g e n , C 2 a l k y l a t i o n acts as a sink f o r t h e e q u i l i b r a t i n g m i x t u r e .

Inorganic Esters of Ascorbic Acid T h e o b s e r v a t i o n of L - a s c o r b i c a c i d 2 - O - s u l f a t e , 18, i n a n u m b e r of a n i m a l species, i n c l u d i n g h u m a n s , has p r o v o k e d extensive r e s e a r c h i n t o the c h e m i s t r y a n d b i o c h e m i s t r y of this i n o r g a n i c ester o f ascorbic a c i d (1, 19,20).

A s c o r b i c a c i d 2 - O - s u l f a t e has b e e n i m p l i c a t e d as a b i o l o g i c a l

s u l f a t i n g agent a n d p r o p o s e d as a n a n t i c h o l e s t e r e m i c agent

(21-24).

W h i l e e a r l y w o r k e r s suggested t h e 0 3 sulfate s t r u c t u r e f o r 18 b a s e d o n c h e m i c a l r e a c t i v i t y ( I ) , x - r a y analysis (26) a n d N M R d a t a (6) h a v e s h o w n t h e stable m o n o s u l f a t e t o b e t h e 0 2 s t r u c t u r e . S e v e r a l syntheses of a s c o r b i c a c i d 2 - O - s u l f a t e h a v e a p p e a r e d

that

r e q u i r e t h e p r o t e c t i o n of t h e C 5 a n d C 6 h y d r o x y l g r o u p s a n d t h e O s u l f a t i o n of t h i s p r o t e c t e d (20,26-29).

derivative w i t h S 0

D e b l o c k i n g the 5,6-O-protected

3

under basic

2-sulfate,

conditions

17, w i t h

acid

a n d p u r i f i c a t i o n u s i n g i o n e x c h a n g e c h r o m a t o g r a p h y affords t h e d e s i r e d





3.


63

64

ASCORBIC ACID

r—OH —OH

u < " > 6 O H


r—OH —OH

W PhCH 6

OH

2

13 /

-OH

H 0 2

HO

6H 14

sulfate d e r i v a t i v e 18 i n m o d e r a t e y i e l d s . T h i s r o u t e h a s b e e n u s e d t o prepare sulfur-labeled ascorbic a c i d 2-O-sulfate-( S) ( 2 7 ) . 85

O n e p r o b l e m w i t h t h e use of the ketal or acetal protecting group for 0 5 , 6 p r o t e c t i o n is t h e r e m o v a l of t h e k e t a l o r a c e t a l w i t h o u t c o n c o m i t a n t h y d r o l y s i s o f t h e 2-sulfate.

S u l f a t i o n o f free a s c o r b i c a c i d h a s b e e n

r e p o r t e d t o afford m i x t u r e s o r s u l f a t e d p r o d u c t s (23,26,30).

S e i b et a l .

(26) offered a r a t i o n a l s o l u t i o n t o t h e p r o b l e m of r e g i o s e l e c t i v e s u l f a t i o n of a s c o r b i c a c i d w i t h h i s o b s e r v a t i o n t h a t t h e d i - a n i o n o f a s c o r b i c a c i d reacts e x c l u s i v e l y at t h e 0 2 p o s i t i o n a f f o r d i n g 18 i n h i g h y i e l d . T h e formation

of 0 3 s u l f a t e d d e r i v a t i v e s of a s c o r b i c

a c i d has not been

o b s e r v e d , p o s s i b l y d u e t o t h e l a b i l i t y of t h e 3 - 0 - s u l f a t e s t o i n t e r m o l e c u l a r h y d r o l y s i s o r r e a r r a n g e m e n t t o t h e m o r e stable 18 ( 2 ) . T h e p h o s p h o r y l a t i o n of a s c o r b i c a c i d u n d e r b a s i c c o n d i t i o n s h a s b e e n s t u d i e d extensively. T h e synthesis of a s c o r b i c a c i d 2-phosphate, 22, h a s b e e n r e p o r t e d b y S e i b et a l . ( 9 ) v i a t r e a t m e n t of 5 , 6 - O - i s o p r o p y l i d e n e ascorbic acid, w i t h phosphorus oxychloride under h i g h l y basic conditions ( p H 1 2 ) . H y d r o l y s i s o f t h e k e t a l p r o t e c t i n g g r o u p of t h e 2 - p h o s p h a t e i n t e r m e d i a t e 20 affords t h e 2 - O - p h o s p h a t e 22, w h o s e s t r u c t u r e h a s b e e n


3.

ANDREWS A N D CRAWFORD


c o n f i r m e d b y N M R s p e c t r o s c o p y (7,9)

65

a n d b y spectroscopic a n d c h e m i

c a l means ( 2 ) . I n t e r e s t i n g l y , t h e site of p h o s p h o r y l a t i o n is d e p e n d e n t o n the c o n d i t i o n s of t h e p h o s p h o r y l a t i o n . J e r n o w et a l . ( 2 ) r e p o r t e d t h e 0 3 p h o s p h o r y l a t i o n of 5 , 6 - O - i s o p r o p y l i d e n e a s c o r b i c a c i d u s i n g e i t h e r t h a l l i u m h y d r o x i d e or p y r i d i n e as base.

T h e resulting 5,6-O-isopropylidene

3 - O - p h o s p h a t e d e r i v a t i v e , 21, w a s f o u n d to r e a r r a n g e t o t h e m o r e stable 2-O-phosphate

22 o n h y d r o l y s i s of the p r o t e c t i n g k e t a l .

also s t u d i e d t h e p h o s p h o r y l a t i o n of ascorbic conditions.

S e i b et a l . ( 9 )

acid under mildly

basic

A l k y l a t i o n w i t h phosphorus oxychloride i n pyridine/acetone


w a s s h o w n to afford, after h y d r o l y s i s of t h e p r o t e c t i n g g r o u p , a m i x t u r e of f o u r p r o d u c t s i n c l u d i n g 22 a n d t h e b i s - 2 - O - p h o s p h o r y l a t e d d i m e r , 19.



ASCORBIC ACID


3.

Acid Catalyzed Derivatization Acetal and Ketal

67



of Ascorbic

Acid:

Derivatives

O n e of the most s t u d i e d classes o f a s c o r b i c a c i d d e r i v a t i v e s is t h a t o f 5,6-O-ketals, 2 3 , a n d acetals, 2 4 (1).

T h e s e c o m p o u n d s a r e significant

not o n l y f r o m t h e i r u s e i n synthesis as p r o t e c t i n g g r o u p s f o r t h e 5,6h y d r o x y l f u n c t i o n s , b u t also f r o m t h e i r c o m m e r c i a l i m p o r t a n c e as l i p o p h i l i c i t y modifiers f o r ascorbic a c i d . F o d o r a n d c o w o r k e r s (31,32) presented

evidence

t h a t 2,3-O-acetals

of ascorbic

a c i d , 2 5 , a r e also

f o r m e d w i t h r e a c t i v e a l d e h y d e s u n d e r k i n e t i c c o n d i t i o n s (32).


have

Glyoxal

is r e p o r t e d to afford t h e n o v e l e n e - d i o l b i s acetal 26 ( 3 3 ) . The

observation

of 2,3-O-acetals

of ascorbic

a c i d opens u p t h e

p o s s i b i l i t y of d i r e c t o x i d a t i v e m o d i f i c a t i o n of t h e a s c o r b i c a c i d s i d e - c h a i n . In

recent w o r k , K a m o g a w a et a l . (34) r e p o r t e d

t h e synthesis of

5,6-acetals of ascorbic a c i d w i t h v i n y l s u b s t i t u t e d b e n z a l d e h y d e d e r i v a tives that, after p o l y m e r i z a t i o n , afford p o l y m e r i c a n t i o x i d a n t s c a p a b l e of r e l e a s i n g ascorbic a c i d u n d e r m i l d l y a c i d i c c o n d i t i o n s . Acid Catalyzed Esterification

of Ascorbic Acid

T h e a c i d c a t a l y z e d esterification of a s c o r b i c a c i d is a t h e r m o d y n a m i c process u s u a l l y r e s u l t i n g i n t h e f o r m a t i o n of m i x t u r e s of p r o d u c t s

with

a p r e p o n d e r a n c e of 0 6 s u b s t i t u t i o n . T h e r e is extensive p a t e n t l i t e r a t u r e o n the f o r m a t i o n of 6-ester d e r i v a t i v e s of ascorbic a c i d b o t h i n a p r o t i c ( a c e t o n e , D M F , D M S O ) (1,34,35,36) gen

fluoride)

(37,38)

solvents.

and protic (sulfuric acid, hydro

T h e fatty

acid

ester

d e r i v a t i v e s of

a s c o r b i c a c i d h a v e c o m m e r c i a l i m p o r t a n c e d u e t o t h e e n h a n c e m e n t of l i p o p h i l i c i t y t h a t d e r i v a t i z a t i o n confers

o n ascorbic acid.

These

ester

d e r i v a t i v e s a r e u s e d as a n t i o x i d a n t s i n e d i b l e oils, e m u l s i f y i n g agents, a n t i s c a l i n g agents, i n h i b i t o r s of n i t r o s a m i n e f o r m a t i o n , a n d i n b r e a d m a k i n g as d o u g h modifiers ( 3 9 ) . U n d e r m o r e stringent c o n d i t i o n s , 5,6diester d e r i v a t i v e s a r e f o r m e d

(36).

C o u s i n s et a l . (38) h a v e r e p o r t e d t h e f o r m a t i o n o f a s c o r b i c

acid

6 - O - s u l f a t e , 2 7 , f r o m t h e esterification of a s c o r b i c a c i d w i t h s u l f u r t r i o x i d e i n s u l f u r i c a c i d . T h e 6-sulfate d e r i v a t i v e s h a v e b e e n p r o p o s e d f o r use as a n t i - c h o l e s t e r e m i c s a n d as i n h i b i t o r s o f n i t r o s a m i n e f o r m a t i o n . A r e l a t i v e l y u n s t u d i e d area of a c i d c a t a l y z e d d e r i v a t i z a t i o n is i n t h e f o r m a t i o n of b o r y l a n d boronate esters of ascorbic a c i d . T h e r e a c t i o n of a s c o r b i c a c i d w i t h t r i e t h y l b o r a n e u s i n g o r g a n i c a c i d catalysis affords t h e 2,3,5,6-tetra-O-diethylborylated

derivative

(40).

T h e boryl

group

is

r e a d i l y r e m o v e d w i t h m e t h a n o l o r acetylacetone i n h i g h y i e l d s . A b o r a t e d e r i v a t i v e of a s c o r b i c characterized

a c i d a n d boric a c i d has been

claimed but not

(41).



ASCORBIC ACID

|—OH

r—OBEt

r—OH

r—OBEt,

2


3.

69

Derivatization of la-Ascorbic Acid


Oxidized Derivatives of Ascorbic Acid: Dehydroascorbic Acid O x i d a t i o n o f t h e r e d u c t o n e f u n c t i o n a l i t y o f a s c o r b i c a c i d is c e r t a i n l y its single m o s t i m p o r t a n t r e a c t i o n a n d results i n t h e f o r m a t i o n of its m o s t b i o l o g i c a l l y i m p o r t a n t d e r i v a t i v e , d e h y d r o a s c o r b i c a c i d , 28. A s c h e m i s t r y a n d b i o c h e m i s t r y of d e h y d r o a s c o r b i c

a c i d w i l l b e c o v e r e d i n a separate

section of this v o l u m e , o n l y a f e w of its reactions w i l l b e c o v e r e d here. A n i m p r o v e d synthesis o f d e h y d r o a s c o r b i c (42).

a c i d has b e e n

T h e o x i d a t i o n of a s c o r b i c a c i d i n a b s o l u t e m e t h a n o l w i t h

reported oxygen


o v e r a c t i v a t e d c h a r c o a l catalyst is r e p o r t e d t o afford 28 i n 9 5 % y i e l d . D e h y d r o a s c o r b i c a c i d has b e e n c h a r a c t e r i z e d i n s o l u t i o n as t h e m o n o m e r , 28 (43), a n d as t h e d i m e r (44,45) a n d its t e t r a a c e t y l d e r i v a t i v e 29 (46). S e v e r a l studies of m o n o - a n d d i - h y d r a z o n e

(48-53)

derivatives of dehydroascorbic

been reported.

d e r i v a t i v e s of d e h y d r o a s c o r b i c

a n d osazone

(54)

Hydrazone

acid have been used i n the reductive

synthesis of 2,3-diaza-2,3-dideoxytives 30, 31, a n d 32 (55,56).

acid have

a n d 2-aza-2-deoxyascorbic a c i d deriva

R e c e n t l y t h e r e a c t i o n p r o d u c t of d e h y d r o -

L - a s c o r b i c a c i d a n d L - p h e n y l a l a n i n e i n a q u e o u s s o l u t i o n has b e e n i s o l a t e d and

i d e n t i f i e d as t r i s ( 2 - d e o x y - 2 - L - a s c o r b y l ) a m i n e ,

33, b a s e d o n s p e c t r a l

a n d c h e m i c a l d a t a a n d its s y m m e t r y p r o p e r t i e s ( 5 7 ) .

H 28

29

R

H

R

Ac

Ar 31


70

ASCORBIC ACID

Side-Chain

Oxidized

Derivatives

of Ascorbic

Acid

D e r i v a t i v e s of a s c o r b i c a c i d i n w h i c h either o r b o t h of t h e C 5 a n d C 6 positions are i n a h i g h e r o x i d a t i o n state h a v e a c h i e v e d some i m p o r t ance as possible b i o c h e m i c a l precursors o r catabolites of a s c o r b i c

acid

in vivo. S a c c h a r o a s c o r b i c a c i d , 35, has b e e n p r o p o s e d as a m i n o r m e t a b o l i t e of a s c o r b i c

acid i n animals ( 5 7 - 6 0 ) .

T h e i s o l a t i o n of a s c o r b i c

acid

2 - O - s u l f a t e , 18, i n a v a r i e t y of a n i m a l species a n d t h e r e m a r k a b l e o x i d a t i v e Downloaded by OHIO STATE UNIV LIBRARIES on May 5, 2012 | http://pubs.acs.org Publication Date: June 1, 1982 | doi: 10.1021/ba-1982-0200.ch003

stability

of

the

2-O-sulfate

p r o m p t e d suggestions

(60)

substituted

enonolactone

moiety

have

t h a t saccharoascorbic a c i d 2 - O - s u l f a t e , 34, is

a c a t a b o l i t e of 18 i n v i v o . S t u b e r a n d T o l b e r t (61) u t i l i z e d the o x i d a t i v e s t a b i l i t y of the 2 - O sulfate i n a short synthesis of b o t h saccharoascorbic

a c i d a n d saccharo

ascorbic a c i d 2-O-sulfate. O x i d a t i o n of ascorbic a c i d 2 - O - s u l f a t e , 18, w i t h p l a t i n u m a n d o x y g e n afforded g o o d y i e l d s of a c i d 34 u n d e r c o n d i t i o n s i n w h i c h ascorbic a c i d itself is o x i d i z e d to d e h y d r o a s c o r b i c a c i d . H y d r o l y s i s of t h e sulfate i n a c i d afforded saccharoascorbic a c i d , 35, i n g o o d y i e l d . S i d e - c h a i n o x i d i z e d d e r i v a t i v e s of a s c o r b i c a c i d are also i m p l i c a t e d i n t h e c a t a b o l i s m of a s c o r b i c a c i d i n p l a n t s . L o e w u s et a l . (62)

h a v e estab

l i s h e d the i n t e r m e d i a c y of ascorbic a c i d i n the biosynthesis of t a r t a r i c a c i d i n the grape. L a b e l i n g studies h a v e established a m e t a b o l i c p a t h w a y t h a t m u s t i n v o l v e C 5 a n d C 6 o x i d a t i o n of a s c o r b i c a c i d . HO


3.

Derivatization of j.-Ascorbic Acid


71

Evidence from labeling studies (63, 64) has accumulated suggesting a dual pathway for ascorbic acid biosynthesis in plants involving not only the inversion of the glucose chain via glucuronic acid (65), but also via the inversion of stereochemistry at the C5 hydroxyl of glucose.

Such

an epimerization at the C5 position of glucose could occur through the stereoselective reduction of several possible biosynthetic intermediates including

5-ketogluconic,

2,5-diketogluconic,

and 5-ketoascorbic

acids

(as well as by epimerization through 6-formyl a n d / o r 4-keto derivatives). Of

the possible side-chain oxidized derivatives of ascorbic acid, all


but 5-keto-ascorbic reported.

acid and 5-keto-6-formylascorbic

Bakke and Theander (66)

acid have

been

formed 6-aldehydoascorbic

acid,

37, as an unisolated intermediate in the reductive hydrolysis of 38 to ascorbic acid.

Heyns and Linkies (67)

synthesized

5-keto-saccharo-

ascorbic acid, 40, via the oxidation and subsequent hydrolysis of mannarodilactone, 39.

5-Ketosaccharoascorbic acid appears to exist in solu

tion as its enol tautomer. As with previous 5,6-dehydro derivatives of ascorbic acid, configura tion about the 5,6-olefin has not been established. During the course of work directed toward the synthesis of ascorbic acid (68)

via the stereo- and regioselective reduction of D-threo-2,5-hexo-

dinlosonic acid, 41, we sought to synthesize 5-ketoascorbic acid directly by the lactonization of 41.

A c i d catalyzed lactonization of 41 and base

catalyzed lactonization of the methyl ester of 41 both failed to produce the desired 5-ketoascorbic

acid derivative.

dimethyl ketal methyl ester, 42 (69),

Lactonization of the

5,5-

with sodium bicarbonate in reflux-

ing methanol afforded the 5,5-dimethyl ketal of 5-keto-ascorbic acid, 43. Hydrolysis of the ketal protecting group with trifluoroacetic acid/water afforded 5-ketoascorbic acid, isolated as the hydrate 44. was shown by

1 3

Compound 44

C N M R spectroscopy to exist primarily (95%)

as its

hydrated keto tautomer in aqueous solution. The enol tautomer was not observed by

1 3

C N M R or U V spectroscopy; however, silylation of

with f-butyldimethylchlorosilane in D M F afforded the methylsilyl derivative 45 as a single isomer, shown by

1 3

44

tetra-£-butyldi-

C N M R and U V

analysis to be the 4,5-dehydro structure. The facile loss of the C4 proton of 44 in deuterium oxide and at p H 7; its rapid racemization in water at ambient temperature (ty = 2

2h)

argues strongly against the intermediacy

of 5-ketoascorbic acid in the biosynthesis of ascorbic acid intermediates.

Deoxy Derivatives of Ascorbic Acid The

instability of ascorbic acid has limited its utility in a variety of

applications

and

has

been

chemistry of ascorbic acid.

a major

impetus

for research into

Goshima, Maezono, and Tokuyama


the (70)

72

ASCORBIC ACID

H 0

—OH —OH

OS0 OH 2

^

- O H

0

HO

18 Downloaded by OHIO STATE UNIV LIBRARIES on May 5, 2012 | http://pubs.acs.org Publication Date: June 1, 1982 | doi: 10.1021/ba-1982-0200.ch003

HO

- O H

PT/AIR,

HO

y^

Y°

H+

j

T

HO

OS0 OH 2

^

^

0

OH 35

34

—OH - O H

/ ° V °

H

HO

OH

Q ^ O H

H O ^ y ^ O 0

H"

1

40

39

i l l u s t r a t e d one p o s s i b l e d e c o m p o s i t i o n p a t h w a y f o r a s c o r b i c a c i d u n d e r a c i d i c , a n a e r o b i c c o n d i t i o n s t h a t i n v o l v e d the i n i t i a l M i c h a e l a d d i t i o n of the 6 - h y d r o x y l f u n c t i o n i n t o t h e enonolactone. and

47,

T h e e p i m e r i c lactones, 46

i s o l a t e d i n l o w y i e l d f r o m the r e a c t i o n of

ascorbic

acid i n

m e t h a n o l w i t h b o r o n t r i f l u o r i d e catalysis, h a v e b e e n p r o p o s e d as i n t e r m e d i a t e s i n t h e f u r t h e r a c i d c a t a l y z e d d e g r a d a t i o n of a s c o r b i c a c i d t o f u r f u r a l a n d p o l y m e r i c m a t e r i a l s . T h i s h y p o t h e s i s has p r o m p t e d interest i n a s c o r b i c a c i d d e r i v a t i v e s i n w h i c h t h e C 6 h y d r o x y l g r o u p is absent or b l o c k e d so as to p r e v e n t t h e i n i t i a l M i c h a e l a d d i t i o n . R e c e n t l y t h e h a l o g e n a t i o n of a s c o r b i c a c i d i n a c i d i c m e d i a has b e e n reported b y Kiss and B e r g (71) coworkers ( 7 2 , 7 3 ) .

and independently by Pedersen and

T h e t r e a t m e n t of a s c o r b i c a c i d w i t h h a l o g e n a c i d s

i n acetic or f o r m i c acids as solvent affords 5-halo-5-acyloxy d e r i v a t i v e s


3.

Derivatization of L-Ascorbic


CHO

C0 H 2

1=0

l—OH HOH

HO-

Acetobacter cerinus 85%

—OH


Acid

—OH

—OH

= 0

—OH

—OH

41 OH O,

C H O H , HCI 3

(CH 0) CH 3

CH3O-

3

60-70%

OH H OCH,

42 1—OH

CH,

CH,

1) N a H C 0 , C H O H 3

3

2) Dowex 5 0 97% HO

OH

43 1—OH

TFA/H 0 2

95/5

10min0° 67%



74

ASCORBIC ACID

of ascorbic a c i d , 4 8 , w h i c h are r e a d i l y h y d r o l y z e d to

6-halo-6-deoxy-

a s c o r b i c a c i d d e r i v a t i v e s 4 9 c a n d 4 9 d . T h e 6-fluoro-, 6 - b r o m o - , 6-chloro-, a n d 6-iodo-derivatives, alternate approach hexlosonate,

4 9 a - d , have recently been synthesized b y

(74)

52, w h i c h is a v a i l a b l e f r o m t h e selective

esterification of

hydrolysis and

50, an early intermediate i n the Reichstein-Grussner

synthesis of a s c o r b i c a c i d ( 7 5 ) .

S e l e c t i v e f o r m a t i o n of t h e

allows displacement w i t h iodide or and

an

v i a m e t h y l 2,3-O-isopropylidine-D-xi/fo-furano-

6-iodo-derivatives

6-deox-6-halo-ascorbic

fluoride

6-tosylate

i o n p r o d u c i n g the

54a

and

54b,

w h i c h form

acids

on

acid

catalyzed

the

6-fluoro-

corresponding

lactonization.

These

6 - h a l o g e n a t e d d e r i v a t i v e s of a s c o r b i c a c i d , 4 9 a - d , a r e c l a i m e d to e x h i b i t


3.

Derivatization of i,-Ascorbic Acid


75

—OH O -OH

o II J>0

>

HX

R

C

0

H

OH

HO Downloaded by OHIO STATE UNIV LIBRARIES on May 5, 2012 | http://pubs.acs.org Publication Date: June 1, 1982 | doi: 10.1021/ba-1982-0200.ch003

-O-u-R

HO

OH

48

X = CI,Br R = CH , H 3

r—X —OH H 0 o

HO HO

OH

50

49 CH -CH 3

enhanced thermal stability (71). high antiscurvy activity

OH

2

T h e 6 - c h l o r o - d e r i v a t i v e has also s h o w n

(74).

P e d e r s e n f u r t h e r s t u d i e d t h e r e a c t i v i t y of the i n t e r m e d i a t e s 48 u n d e r dissolving metal conditions a n d synthesized the

5,6-dehydro-5,6-dideoxy

d e r i v a t i v e 55 w h i c h w a s c a t a l y t i c a l l y r e d u c e d to t h e 5,6-dideoxy p o u n d 56.


com

76

ASCORBIC

i—OH

i—X O II HX,RCOH


OH

h-o-c—R

HO

—OH

OH

HO

R = CH ,H

48

4

OH

49a x = F 4 9 b x = ci 49c x = I 49d x = Br

3

^

H

50 51

R = H R = CH

n

3

52

R = C H , R = H R = C H , R' = Tosyl 3

3

54a

X = F

54 b 54 C 54d

x = ci

CH -CH 3

48

ACID

X = Br

x=l

2

O

Zn/HOAc

HO

OH

5£


3. Andrews and Crawford Derivatization of 1,-Ascorbic Acid 77


Literature Cited 1. Tolbert, B. M.; Downing, M.; Carlson, R. W.; Knight, M. K.; Baker, E . M. Ann. N.Y. Acad. Sci. 1975, 258, 48-69. 2. Jernow, J.; Blount, J.; Oliveto, E.; Perrotta, A.; Rosen, P.; Toome, V. Tetrahedron 1979, 35, 1483-1486. 3. Shrihatti, V. R.; Nair, P. M. Indian J. Chem., Sect. B 1977, 15(9), 861863. 4. Jackson, K. G.; Jones, J. K. N. Can. J. Chem. 1965, 43, 450-457. 5. Veechi, M.; Kaiser, K. J. Chromatogr. 1967, 26, 22-29. 6. Radford, T.; Sweeny, J. G.; Iacobucci, G. A.; Goldsmith, D. J. J. Org. Chem. 1979, 44, 658-659. 7. Mutusch, R. Z. Naturforsch., Teil B 1977, 32(5), 562-568. 8. Berger, S. Tetrahedron 1977, 33, 1587-1589. 9. Seib, P.; Lee, C. H.; Liang, Y. T.; Hoseney, R. C.; Deyoe, C. W. Carbohydr. Res. 1978, 67, 127-138. 10. Seib, P. A.; Deyoe, C. W.; Hoseney, R. C. German Patent 2 719 303, 1977. 11. Gazave, J. M.; Truchard, M.; Parrot, J. L.; Achard, M.; Roger, C. Ann. Pharm. Fr. 1975, 33, 155-161. 12. Brenner, G. S.; Hinkley, D. F.; Perkins, L. M.; Weber, S. J. Org. Chem. 1964, 29, 2389—2392. 13. Bell, E. M.; Baker, E. M.; Tolbert, B. M. J. Labelled Compd. 1966, 2, 148-154. 14. Eitelman, S. J.; Hall, R. H.; Jordaan, A. J. Chem. Soc., Chem. Commun. 1976, 923-924. 15. Liang, Y. T.; Lillard, D.; Seib, P. A.; Paukstelis, J. V.; Mueller, D. D., presented at the 178th Nat. Meet. Am. Chem. Soc., Washington, D. C., Sept., 1979. 16. Szarek, W. A.; Kim, K. S. Carbohydr. Res. 1978, 67, C13-C16. 17. Suzuki, Y.; Miyake, T.; Uchida, K.; Mino, A. Vitamins 1973, 47(6), 259267. 18. Brimacombe, J. S.; Murray, A. W.; Haque, Z. Carbohydr. Res. 1975, 45, 45-53. 19. Tsujimura, M.; Kitamura, S. Vitamins 1979, 53, 247-252. 20. Lillard, D. W.; Seib, P. A. ACS Symp. Ser. 1978, 11, 1-18. 21. Chu, T. T. M.; Slaunwhite, W. R. Steroids 1968, 12, 309-312. 22. Tsujimura, M.; Yoshikawa, H.; Hasegawa, T.; Suzuki, T. Joshi Eiyo Daigaku Kiyo, 1975, 6, 35-44. 23. Hayashi, E.; Fujimoto, Y.; Nezu, M. Kokai Tokkyo Koho 1977, 83, 946. 24. Nezu, Y.; Hayashi, E.; Sato, H.; Ishihara, E . Kokai Tokkyo Koho 1977, 83, 946. 25. McClelland, B. W. Acta Crystallogr. 1974, 30, 178-186. 26. Seib, P. A.; Liang, Y.-T.; Lee, C.-H.; Hoseney, R. C.; Deyoe, C. W. J. Chem. Soc., Perkin Trans. 1 1974, 1220-1224. 27. Muccino, R. R.; Markezich, R.; Vernice, G. G.; Perry, C. W.; Liebman, A. A. Carbohydr. Res. 1976, 47, 172-175. 28. Nezu, Y.; Harakawa, M.; Shimizu, K.; Sato, H.; Takita, K. Kokai Tokkyo Koho 1976, 6, 956. 29. Ibid., 91, 251. 30. Okuyama, T.; Sakurai, K.; Yamaguchi, T.; Kamohara, S. Kokai Tokkyo Koho 1975, 64, 267. 31. Fodor, G.; Butterick, J.; Springsteen, A.; Mathelier, H., presented at the ACS-CSJ Chem. Congr., Honolulu, Apr., 1979. 32. Fodor, G.; Butterick, J.; Mathelier, H.; Arnold, R., presented at the 2nd Chem. Congr. North American Continent, Las Vegas, Aug., 1980. 33. Blaszczak, J. W. U.S. Patent 3 888 989, 1976.



78

ascorbic acid

34. Kamogawa, H.; Harmoto, Y.; Nanasawa, M. Bull. Chem. Soc. Jpn. 1979, 52, 846-848. 35. Seib, P. A.; Cousins, R. C.; Hoseney, R. C. German Patent 2 743 526, 1978. 36. Kobayashi, Y. Kokai Tokkyo Koho 1973, 67, 268. 37. Gruetzmacher, G.; Stephens, C. R. German Patent 2 584 353, 1979. 38. Cousins, R. C.; Seib, P. A.; Hoseney, R. C.; Deyoe, C. W.; Liang, Y. T.; Lillard, D. W. J. Am. Oil Chem. Soc. 1977, 54, 308-312. 39. Hoseney, R. C.; Seib, P. A.; Deyoe, C. W. Cereal Chem. 1977, 54, 10621069. 40. Koester, R.; Amen, K. R.; Dahlhoff, W. V. Justus Liebigs Ann. Chem. 1975, 752—788. 41. Ruskin, S. L. U.S. Patent 2 635 102, 1953. 42. Ohmori, M.; Takagi, M. Agric. Biol. Chem. 1978, 42, 173-174. 43. Pfeilsticker, K.; Marx, F.; Bockisch, M. Carbohydr. Res. 1975, 45, 269274. 44. Hvoslef, J.; Pedersen, B. Acta Chem. Scand., Ser. B 1980, 34, 285-288. 45. Ibid., 1979, 33, 503-510. 46. Yagishita, K.; Takahashi, N.; Yamamoto, H.; Jennouchi, H.; Kiyoshi, S.; Miyakawa, T. J. Nutr. Sci. Vitaminol. 1976, 22, 419-427. 47. Roberts, G. A. F. J. Chem. Soc., Perkins Trans. 1 1979, 603-605. 48. Soliman, R.; Elashry, E. S. H.; Elkholy, I. E.; Elkilany, Y. Carbohydr. Res. 1978, 67, 179-188. 49. Elashry, E. S. H.; Abdelrahman, M. M. A.; Nassr, M. A.; Amer, A. Carbohydr. Res. 1978, 67, 403-432. 50. Elashry, E. S. H. Carbohydr. Res. 1976, 52, 69-77. 51. Elashry, E. S. H.; Labib, G. H.; Elkilany, Y. Carbohydr. Res. 1976, 52, 251-254. 52. Mokhtar, H. M. Pharmazie 1978, 38, 709-711. 53. Sekily, M. A. E. Pharmazie 1979, 34, 531-534. 54. Pollet, P.; Gelin, S. Tetrahedron 1980, 36, 2955-2959. 55. Gross, B.; Sekily, M. A. E.; Mancy, S.; El Khadem, H. S. Carbohydr. Res. 1974, 37, 384-389. 56. Manousak, O. Z. Chem. 1971, 11, 18-19. 57. Hayashi, T.; Manou, F.; Namiki, M.; Tsuji, K. Agroc. Biol. Chem. 1981, 45, 711-716. 58. Tolbert, B. M.; Harkrader, R. J. Biochem. Biophys. Res. Commun. 1976, 71, 1004-1009. 59. Tolbert, B. M.; Harkrader, R. J.; Plunkett, L. M.; Stuber, H. A. Fed. Proc., Fed. Am. Soc. Exp. Biol. 1976, 35, 661. 60. Hornig, D. In "Vitamin C"; Birch, G.; Parker, K., Eds.; John Wiley & Sons: New York, 1974; pp. 91-103. 61. Stuber, H. A.; Tolbert, B. M. Carbohydr. Res. 1978, 60, 251-258. 62. Loewus, F. A.; Williams, M.; Saito, K. Phytochemistry 1979, 18, 953-956. 63. Loewus, F. A. Ann. N.Y. Acad. Sci. 1961, 92, 57-77. 64. Loewus, F. A. Ann. Rev. Plant Physiol. 1971, 22, 337-357. 65. Isherwood, F. A.; Mapson, L. W. Ann. Rev. Plant Physiol. 1961, 92, 6-20. 66. Bakke, J.; Theander, O. J. Chem. Soc. D 1971, 175-176. 67. Heynes, K.; Linkies, A. Chem. Ber. 1975, 108, 3633-3644. 68. Andrews, G. C.; Bacon, B. E.; Crawford, T.; Breitenbach, R. Chem. Commun. 1979, 740-749. 69. Andrews, G. C.; Bacon, B. E.; Bordner, J.; Hennessee, G. L. A. Carbohydr. Res. 1979, 79, 25-36. 70. Goshima, K.; Maezono, N.; Tokuyama, K. Bull. Chem. Soc. Jpn. 1973, 46, 902-904. 71. Kiss, J.; Berg, K. P. U.S. Patent 3 043 937, 1977.


3. Andrews and Crawford Derivatization of la-Ascorbic Acid 79 72. Pedersen, C.; Bock, K.; Ludt, I. Pure Appl. Chem. 1978, 50, 1385-1400. 73. Bock, K. M.; Lundt, I.; Pedersen, C. Carbohydr. Res. 1979, 68, 313-319. 74. Kiss, J.; Berg, K. P.; Dirscherl, A.; Oberhansli, W. E.; Arnold, W. Helv. Chim. Acta 1980, 63, 1728-1739. 75. Rumpf, P.; Marlier, S. Bull. Soc. Chem. Fr. 1959, 187-190.


Received for review February 9, 1981.ACCEPTEDJune 23, 1981.


Ascorbic Acid: Chemistry, Metabolism, and Uses - American Chemical

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