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
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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
In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.
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.
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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
In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.
ANDREWS AND CRAWFORD
Derivatization of L-Ascorbic Acid
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3.
In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.
63
64
ASCORBIC ACID
r—OH —OH
u < " > 6 O H
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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
In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.
3.
ANDREWS A N D CRAWFORD
Derivatization of L-Ascorbic Acid
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
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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.
In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.
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ASCORBIC ACID
In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.
3.
Acid Catalyzed Derivatization Acetal and Ketal
67
Derivatization of L-Ascorbic Acid
ANDREWS A N D CRAWFORD
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).
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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).
In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.
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ASCORBIC ACID
|—OH
r—OBEt
r—OH
r—OBEt,
2
In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.
3.
69
Derivatization of la-Ascorbic Acid
ANDREWS A N D CRAWFORD
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
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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
In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.
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
In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.
3.
Derivatization of j.-Ascorbic Acid
ANDREWS AND CRAWFORD
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
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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
In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.
the (70)
72
ASCORBIC ACID
H 0
—OH —OH
OS0 OH 2
^
- O H
0
HO
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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
In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.
3.
Derivatization of L-Ascorbic
ANDREWS AND CRAWFORD
CHO
C0 H 2
1=0
l—OH HOH
HO-
Acetobacter cerinus 85%
—OH
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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%
In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.
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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
In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.
3.
Derivatization of i,-Ascorbic Acid
ANDREWS A N D CRAWFORD
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.
In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.
com
76
ASCORBIC
i—OH
i—X O II HX,RCOH
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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£
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 1,-Ascorbic Acid 77
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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.
In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.
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78
ascorbic acid
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Received for review February 9, 1981.ACCEPTEDJune 23, 1981.
In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.