Rational approach to selective and direct 2-O-alkylation of 5,6-O-isopropylidine-L-ascorbic acid

Article abstract of DOI:10.1021/jo049319i

L-Ascorbic acid is a versatile radical scavenger widely distributed in aerobic organisms that plays a central role in the protection of cellular components against oxidative damage by free radicals and oxidants. It also functions as a physiological reduct

Full text of DOI:10.1021/jo049319i

Ra tion a l Ap p r oa ch to Selective a n d Dir ect 2-O-Alk yla tion of
5,6-O-Isop r op ylid in e-L-a scor bic Acid
Ayodele O. Olabisi and Kandatege Wimalasena*
Department of Chemistry, Wichita State University, Wichita, Kansas 67260-0051
kandatege.wimalasena@wichita.edu
Received April 22, 2004
L-Ascorbic acid is a versatile radical scavenger widely distributed in aerobic organisms that plays
a central role in the protection of cellular components against oxidative damage by free radicals
and oxidants. It also functions as a physiological reductant for key enzymatic transformations in
catecholamine neurotransmitters, amidated peptide hormones, and collagen biosynthetic pathways.
Simple derivatives of L-ascorbic acid have been shown to possess antioxidant, antitumor, and
immunostimulant activities. The antioxidant and redox properties of L-ascorbic acid are closely
associated with the electron-rich 2,3-enediol moiety of the molecule, and therefore, selective
functionalization of the 2- and 3-OH groups is essential for the detailed structure-activity studies.
Reactions of 5- and 6-OH-protected ascorbic acid with electrophilic reagents exclusively produce
the corresponding 3-O-alkylated products under mild basic conditions due to the high nucleophilicity
of the C-3-OH. Based on the density functional theory (B3LYP) electron density calculations, we
have devised a novel and general method for the direct alkylation of the 2-OH group of ascorbic
acid with complete regio- and chemoselectivity. We have also carried out a complete spectroscopic
analysis of two complementary series of 2-O-acetyl-3-O-alkyl- and 2-O-alkyl-3-O-acetylascorbic acid
derivatives to define their spectroscopic characteristics and to resolve common inconsistencies in
the literature.
In tr od u ction
synthetic pathways. In addition, simple derivatives of
L-ascorbic acid have been shown to possess important
pharmacological properties. For example, (a) 5,6-O-
modified ascorbic acid derivatives have been found to be
effective antitumor agents for various human cancers and
to induce apoptosis in tumor cells;10-17 (b) C-2-alkylated
derivatives have been shown to have immunostimulant
activity;18-23 (c) O-2- and O-3-alkylated derivatives are
Ascorbic acid is a versatile water-soluble radical scav-
enger widely distributed in aerobic organisms that plays
a central role in the protection of the cellular components
against oxidative damage by free radicals and oxidants
that are involved in the development and exacerbation
of a multitude of chronic diseases such as cancer, heart
disease, brain dysfunction, aging, rheumatism, inflam-
mation, stroke, emphysema, and AIDS.1-9 It also plays
a critical role as a physiological reductant for key
enzymatic transformations in catecholamine neurotrans-
mitters, amidated peptide hormones, and collagen bio-
(9) (a) Wimalasena, K.; Herman, H. H.; May, S. W. J . Biol. Chem.
1989, 264, 124. (b) Wimalasena, K.; Wimalasena, D. S. Biochem.
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* To whom correspondence should be addressed. Phone: 316-978-
7386. Fax: 316-978-3431.
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U.S.A. 1993, 90, 7915-22.
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10.1021/jo049319i CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/18/2004
7026
J . Org. Chem. 2004, 69, 7026-7032

2-O-Alkylation of 5,6-O-Isopropylidine-L-ascorbic Acid
TABLE 1. 3-O-Alk yla tion of 5,
6-O-Isop r op ylid en e-L-a scor bic Acid
known to protect against peroxidation of lipids of the
biomembrane.24,25 Recently, the chemistry of ascorbic acid
has also been exploited to develop strategies for central
nervous system drug delivery.26
The antioxidant as well as redox and pharmacological
properties of ascorbic acid are closely associated with the
electron-rich 2,3-enediol moiety of the five-membered
lactone ring.27 Therefore, the selective modification of the
2- and 3-OH groups is essential for the detailed structure-
activity studies of ascorbic acid. Reactions of 5- and 6-OH-
protected ascorbic acid with electrophilic reagents under
mild basic conditions exclusively takes place at the 3-OH
due to its high nucleophilicity.27 Preferential direct
alkylation of 3-OH of the 5- and 6-OH unprotected
ascorbic acid under the Mitsunobu conditions has been
recently reported.28-30 Therefore, the O-2-alkylated prod-
ucts could only be obtained after the protection of the
3-OH group with protecting groups such as acetyl, MOM,
etc.31-33 In the literature, the acetyl group has been
commonly used as an O-3 protecting group in the
alkylation of the 2-OH of ascorbic acid. However, the high
instability of the 3-O-acetyl derivatives and facile migra-
tion of acyl groups from 3-O to 2-O, even under mild
reaction conditions,34-37 have led us32 and others38,39 in
the misidentification and characterization of O-2- and
O-3-substituted ascorbic acid derivatives. Although the
products of these reactions were characterized as 3-O-
acetyl-2-O-alkyl derivatives, in most cases they were 2-O-
acetyl-3-O-alkyl derivatives which were predominantly
formed due to the fast acetyl migration under the reaction
conditions.32 A detailed characterization of 2-O- and 3-O-
acetyl esters of 1 has been previously reported.39
product
R
yielda (%)
2a
2b
2c
2d
CH3
91
86
72
80
CH2C6H5
CH2CHdCHCH3
CH2CHdCH2
a
The yields are given for the purified products.
ascorbic acid (1), which has not been reported in the
literature to our knowledge. We have used density
functional theory (B3LYP) calculations to determine the
electron density distributions and reactivities of the
neutral, monoanion, and dianion of ascorbic acid and
found that electrophilic reactions with the monoanion
and dianion of ascorbic acid should preferentially occur
at the O-3 and O-2 positions, respectively. Based on these
findings, we have devised a novel and general method
for the direct alkylation of 2-O of 1 in good yields with
complete regio- and chemoselectivity with both activated
and unactivated electrophiles. We have also carried out
a complete spectroscopic analysis of two complementary
series of 2-O-acetyl-3-O-alkyl- and 2-O-alkyl-3-O-acetyl-
ascorbic acid derivatives in order to clearly define the
spectroscopic characteristics of these derivatives for
future studies.
To resolve the discrepancies of the structure assign-
ments of O-2- and O-3-substituted ascorbate derivatives,
we sought to develop a specific and direct method to
alkylate the O-2 position of 5,6-O-isopropylidine-L-
Resu lts a n d Discu ssion
As mentioned above, the 3-OH group of L-ascorbic acid
is more reactive toward electrophiles under mild basic
conditions in comparison to 2-OH (Table 1). This is
primarily due to the preferential deprotonation of 3-OH
over 2-OH under mild basic conditions to produce pri-
marily the monoanion (experimentally determined pKa’s
of 3-OH and 2-OH are 4.2 and 11.6, respectively).27 The
electron density distribution diagram of the monoanion
of 1 clearly shows that the negative charge of the
monoanion is distributed between the 3-O and C-1
carbonyl of the lactone ring with little electron density
on 2-OH (Figure 1a). Therefore, the reactions of 5,6-OH-
protected ascorbic acid with electrophilic reagents under
mild basic conditions should predominantly occur at the
O-3 position as experimentally observed. In addition, the
electron density at the C-2 carbon of the monoanion is
significantly higher than that of the 2-OH (Figure 1a),
suggesting that the C-2 position of the monoanion may
also be susceptible to electrophilic reactions. In agree-
ment, C-2-alkylated products were also observed as minor
products in the alkylation of 1 under mild alkaline
conditions.32 These analyses show that the reactions of
1 with simple electrophiles under mild basic conditions
could be qualitatively predicted from the calculated
electron density distribution of the monoanion. However,
the kinetically controlled 3-O-acylated and 3-O-alkylated
products must be thermodynamically relatively unstable
due to the partial delocalization of the 3-O-alkyl or -acyl
bonding electrons with the C-1 carbonyl group of the
lactone ring, as mentioned above. Therefore, especially
(20) Woolverton, C. J .; Veltri, R. W.; Snyder, I. S. J . Biol. Response
Modifiers 1986, 5, 527-38.
(21) Maxim, P. E.; Veltri, R. W.; Baseler, M. W.; Cameransi, B. G.
Fed. Proc. 1986, 45, 628.
(22) Maxim, P. E.; Veltri, R. W. FASEB J . 1988, 2, A370.
(23) Maxim, P. E.; Veltri, R. W. Proc. Am. Ass. Cancer Res. 1988,
29, 374.
(24) Veltri, R. W.; Maxim, P. E.; Baseler, M. W.; Klinger, M. R. Fed.
Proc. 1986, 45, 269.
(25) Nihro, Y.; Miyataka, H.; Sudo, T.; Matsumoto, H.; Satoh, T. J .
Med. Chem. 1991, 34, 2152-7.
(26) Manfredini, S.; Pavan, B.; Vertuani, S.; Scaglianti, M.; Compag-
none, D.; Biondi, C.; Scatturin, A.; Tanganelli, S.; Ferraro, L.; Prasad,
P.; Dalpiaz, A. J . Med. Chem. 2002, 45, 559-562.
(27) Andrews, G. C.; Crawford, T. In Ascorbic Acid: Chemistry,
Metabolism, and Uses; Seib, P. A., Tolbert, B. M., Eds.; American
Chemical Society: Washington, D.C., 1982; pp 59-79.
(28) Tahir, H.; Hindsgaul, O. J . Org. Chem. 2000, 65, 911-913.
(29) Vilaca, G.; Rubio, C.; Susperregui, J .; Latxague, L.; Deleris, G.
Tetrahedron 2002, 58, 9249-9256.
(30) Rubio, C.; Susperregui, J .; Latxague, L.; Deleris, G. Synlett
2002, 1910-1912
(31) Kato, K.; Terao, S.; Shimamoto, N.; Hirata, M. J . Med. Chem.
1988, 31, 793-8.
(32) Wimalasena, K.; Mahindaratne, M. P. D. J . Org. Chem. 1994,
59, 3427-3432.
(33) Beifuss, U.; Kunz, O.; Aguado, G. P. Synlett 1999, 147-49.
(34) Szarek, W. A.; Kim, K. S. Carbohydr. Res. 1978, 67, C13.
(35) Cabral, J .; Haake, P.; Kessler, K. J . Carbohydr. Chem. 1988,
17, 1321.
(36) Mumora, R.; Verlangieri, A.; Weber, W. Carbohydr. Res. 1971,
19, 127.
(37) Redford, T.; Sweeny, J .; Iacobucci, G. J . Org. Chem. 1979, 44,
658.
(38) Vestling, C.; Rebstock, M. J . Biol. Chem. 1944, 152, 585.
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J . Org. Chem, Vol. 69, No. 21, 2004 7027

Olabisi and Wimalasena
F IGURE 1. Calculated electrostatic potential diagrams of the neutral, monoanionic, and dianionic forms of 5,6-O-isopropylidene-
L-ascorbic acid (1). Calculated electron density diagrams of (a) neutral, (b) monoanionic, and (c) dianionic forms of 1. Order of
electron density: blue < green < yellow < red.
TABLE 2. 2-O-Alk yla tion of
5,6-O-Isop r op ylid en e-L-a scor bic Acid
TABLE 3. 3-O-Acetyla tion of
5,6-O-Isop r op ylid en e-2-O-a lk yla ted -L-a scor bic Acid
product
R
yielda (%)
3a
3b
3c
3d
3e
3f
CH2CHdCH2
CH3
CH2CHdCHCH3
CH2C6H5
CH2CHdCHC6H5
CH2(CH2)5CH3
80
91
72
83
87
96
product
R
yielda (%)
4a
4b
4c
4d
4e
CH2CHdCH2
CH3
CH2CHdCHCH3
CH2C6H5
70
80
84
82
76
CH2CHdCHC6H5
a
The yields are given for the purified products.
a
The yields are given for the purified product.
the 3-O-acyl derivatives of ascorbic acid could undergo
facile intramolecular acyl migration to produce the
thermodynamically more stable 2-O-acyl derivatives,
which is also in agreement with the previous experimen-
tal observations.32
TABLE 4. 2-O-Acetyla tion of
5,6-O-Isop r op ylid en e-3-O-a lk yla ted -L-a scor bic Acid
Inspection of the electron density distribution of the
dianion of 1 (Figure 1c) shows that the negative charge
of the 3-O- is highly delocalized to the lactone carbonyl
similar to that of the monoanion. However, the electron
density of the 2-O- is highly localized in the dianion,
suggesting that electrophilic reagents should preferen-
tially react with the 2-O- rather than 3-O_ of the dianion
of 1. In excellent agreement, the dianion of 1, generated
by reacting 2 equiv of potassium tert-butoxide (t-BuOK)
in DMSO/THF (3:2) at -10 °C, reacts with 1 equiv of a
number of activated and unactivated electrophilic alky-
lating agents (Table 2) to exclusively produce the corre-
sponding O-2-alkylated products in good yields (80-90%).
Furthermore, regardless of the nature of the electrophile,
no detectable amounts of O-3- or C-2-substituted products
were produced, under these experimental conditions.
However, the addition of 2 equiv of the electrophile
cleanly produces the corresponding 2-O- and 3-O-disub-
stituted derivative. In addition, both 3-O- and 2-O-
alkylated ascorbic acid derivatives undergo clean 2-O-
and 3-O-acetylations under standard reaction conditions,
respectively (Tables 3 and 4).
product
R
yielda (%)
5a
5b
5c
5d
5e
CH3
90
90
78
70
76
CH2C6H5
CH2CHdCHCH3
CH2CHdCH2
CH2CHCHC6H5
a
The yields are given for the purified products
derivatives of ascorbic acid were unavailable, incorrect,
or misassigned.32 Therefore, we have synthesized a
complementary series of O-2- and O-3-substituted de-
rivatives of 1 according to the above procedures, and their
13C and 1H NMR data were completely assigned and
discussed for future reference. The data presented in
Table 5 demonstrate that O-2- and O-3-monosubstituted
derivatives of 1 display characteristic 13C NMR chemical
shifts for their C-2 and C-3 carbons and 1H NMR
chemical shifts for their C-4-H that could be used to
unequivocally identify the O-2- and O-3-monosubstituted
NMR An a lysis. As mentioned above, the literature on
1H and 13C NMR data of most O-2- and O-3-substituted
7028 J . Org. Chem., Vol. 69, No. 21, 2004

2-O-Alkylation of 5,6-O-Isopropylidine-L-ascorbic Acid
TABLE 5. 1H NMR (C-4-H) a n d 13C NMR (C-2 a n d C-3) Ch em ica l Sh ifts (δ) of 2-O-Alk yl-3-O-a lk yl, 2-O-Alk yl-3-O-a cetyl,
a n d 3-O-Alk yl-2-O-a cetyl Der iva tives of 5,6-O-Isop r op ylid en e-L-a scor bic Acid (1)
a
a
derivative
R2
R3
δ(C-2)
∆
δ(C-3)
∆
δ(C-4 1H)
(C-2)
(C-3)
1
H
H
H
H
H
H
CH3
120.5
119.5
119.1
119.5
119.2
121.4
123.1
120.8
121.1
130.1
131.2
132.2
130.1
134.8
114.5
114.8
114.4
114.6
114.7
-
158.4
149.9
148.6
148.6
148.2
156.4
155.8
157.9
157.5
143.8
142.3
143.8
144.6
144.6
160.7
159.8
159.7
159.5
159.7
-
4.91
4.53
4.55
4.57
4.58
4.72
4.71
4.69
4.60
5.18
5.15
5.18
5.15
5.17
4.67
4.71
4.66
4.69
4.70
2a
2c
2b
2d
3a
3b
3c
3d
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
-1.0
-1.4
-1.0
-1.3
+0.9
+2.6
+0.3
+0.6
+9.6
+10.7
+11.7
+9.6
+14.3
-6.0
-5.7
-6.1
-5.9
-5.8
-8.5
-9.8
-9.8
CH2CHdCHCH3
CH2C6H5
CH2CHdCH2
H
H
H
-10.2
-2.0
CH2CHdCH2
CH3
CH2CHdCHCH3
CH2C6H5
CH2CHdCH2
CH3
CH2CHdCHCH3
CH2C6H5
CH2-CHdCHC6H5
OdCCH3
OdCCH3
OdCCH3
-2.6
-0.5
H
-0.9
OdCCH3
OdCCH3
OdCCH3
OdCCH3
OdCCH3
CH3
CH2C6H5
CH2CHdCHCH3
CH2CHdCH2
CH2CHdCHC6H5
-14.6
-16.1
-14.6
-13.8
-13.8
+2.3
+1.4
+1.3
OdCCH3
OdCCH3
+1.1
+1.3
a
The difference in 13C chemical shifts of C-2 and C-3 (∆(C-2) and ∆(C-3)) were calculated by subtracting the chemical shifts of various
derivatives from the corresponding values of compound 1.
derivatives. The standard 13C chemical shifts of C-2 and
C-3 of ascorbic acid and 1 are 118.8, 120.5, 156.3, and
158.4 ppm, respectively.32,40 The 13C NMR signals of C-2
and C-3 are in the ranges of 119-120 ppm and 148-150
ppm for 3-O-alkylated derivatives and 121-123 ppm and
156-158 ppm for 2-O-alkylated derivatives, respectively
(Table 5), and are in good agreement with the previously
reported values.28-33 The O-3 alkylation causes an upfield
shift (8.5 to 10.2 ppm) of 13C signals of C-3 (2a -d ) with
respect to 1 depending on the nature of the alkyl
substituent. On the other hand, the effects of the O-2-
substitution (3a -d ) on the 13C signals of C-2 are con-
siderably smaller and in the range of 0.3-2.6 ppm
(upfield). The large chemical shift difference in the 13C
signals of C-3 in the 3-O-substituted derivatives (2a -d )
in comparison to the C-2 in the 2-O-substitituted deriva-
tives (3a -d ) must be due to the lack of efficient delocal-
ization of the 3-O electron density into the C-1-carbonyl
in 3-O-substituted derivatives (2a -d ) in comparison to
2-O-substituted derivatives (3a -d ). This effect is also
of these derivatives showed large downfield shifts (in the
range of 9-14 ppm) with respect to 1. As discussed above
for 3-O-alkylated derivatives (2a -2d ), these large 13C
shifts of C-3 of 3-O-acetylated derivatives (4a -4e) must
be due to the significant perturbation of the native
electronic structure of 1 by the electron withdrawing 3-O-
acetate group. The inhibition of the delocalization of 3-O
oxygen electron to the C-1 carbonyl by the 3-O-acetate
group leads to the increase of the electron density at C-3
causing 13C signal to shift upfield, and a decrease of
electron density at C-2 causing 13C signal to shift
significantly downfield. A significant downfield shift of
1
the H NMR signal of C-4-H of 4a -e, in comparison to
1, further confirms the significant perturbation of the
native electronic structure of 1 by the electron-withdraw-
ing nature of the 3-O-acetyl group. Interestingly, in 2-O-
acetyl-3-O-alkyl-substituted derivatives (5a -e), the ef-
fects were more localized to the C-2 as expected. The 13C
signals of the C-2 of these derivatives shifted upfield in
comparison to 1, which is in sharp contrast to the effects
of C-3-O-acetyl substitution, suggesting that the direct
electron-withdrawing effect of the C-2-O-acetate group
primarily determines the 13C chemical shift of the C-2 of
these derivatives. The C-4-H of 2-O-acetyl substituted
derivatives (5a -e) showed a small but significant upfield
shift, again demonstrating the electron withdrawing
inductive effect of the 2-O-acetyl group.
1
clearly visible in H NMR chemical shifts of C-4-H, where
3-O-substitution (2a -d ) caused an upfield shift of the
C-4-H in comparison to the O-2-substituted derivatives
(3a -d ).
In the O-2- and O-3-disubstituted series, the C-2 and
C-3 showed characteristic shifts of 13C signals with
respect to 1 that could be used to distinguish the 3-O-
acetyl-2-O-alkyl derivatives (4a -e) from the 2-O-acetyl-
3-O-alkyl derivatives (5a -e). The 13C signals of C-3 of
3-O-acetyl-2-O-alkyl-substituted derivatives (4a -e)
showed a large upfield shift in the range of 16-14 ppm
with respect to 1. On the other hand, 13C signals of C-2
Exp er im en ta l Section
General procedural information is reported on page 2 of the
Supporting Information.
5, 6-O-Isop r op ylid en e-L-a scor bic Acid (1). This was
synthesized in 82% yield according to the procedure of J ung
(40) Paukstelis, J . V.; Mueller, D. D.; Seib, P. A.; Lillard, D. W., J r.
In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P. A.,
Tolbert, B. M., Eds.; American Chemical Society: Washington, D.C.,
1982; pp 125-151.
mp
1
et al.:42 mp 204-206 °C (lit.25
201-203 °C); H NMR (400
MHz, D2O) δ 1.37 (6H, s), 4.17 (1H, dd, J ) 9.1, 5.0 Hz), 4.31
(1H, dd, J ) 9.1, 7.3 Hz), 4.59 (1H, ddd, J ) 7.3, 5.0, 2.4 Hz),
J . Org. Chem, Vol. 69, No. 21, 2004 7029

Olabisi and Wimalasena
4.91 (1H, d, J ) 2.4 Hz); 13C NMR (100 MHz, D2O) δ 26.70,
of 3 min with stirring continued for an additional 5 min at
-10 °C. The cooling bath was removed, and the reddish orange
reaction solution was stirred for 3 h at room temperature. The
reaction mixture was quenched with a cold solution of 0.25 M
HCl (20 mL) and extracted with ethyl acetate (3 × 100 mL).
The organic layer was dried over Na2SO4, and the solvents
were removed under reduced pressure. The product was
purified by conventional silica gel column chromatography
using 3:1 n-hexane/ethyl acetate to give 80% yield as a white
solid: 1H NMR (300 MHz, CDCl3) δ 1.38 (3H, s), 1.43 (3H, s),
4.02 (1H, dd, J ) 9.0, 6.8 Hz), 4.16 (1H, dd, J ) 9.0, 6.8 Hz),
4.43 (1H, dt, J ) 6.8, 3.6 Hz), 4.62 (2H, dt, J ) 6.3, 1.2 Hz),
4.72 (1H, d, J ) 3.6 Hz), 5.28 (1H, dq, J ) 10.2, 2.0 Hz), 5.36
(1H, dq, J ) 17.3, 2.0 Hz), 5.98 (1H, ddt, J ) 17.3, 10.2, 6.3
Hz); 13C NMR (75 MHz, CDCl3) δ 25.2, 25.7, 64.9, 72.1, 73.8,
73.9, 110.6, 119.6, 121.4, 133.0, 156.4, 168.8. Anal. Calcd for
C12H16O6: C, 56.24; H, 6.29; O, 37.47. Found: C, 56.31; H, 6.21;
O, 37.48.
5,6-O-Isop r op ylid en e-2-O-m eth yl-L-a scor bic Acid (3b).
This was synthesized from 1 and methyl iodide in 91% yield
as a semisolid using the standard procedure for 3a : 1H NMR
(300 MHz, CDCl3) δ 1.40 (3H, s), 1.45 (3H, s), 3.87 (3H, s),
4.07 (1H, dd, J ) 9.0, 6.8 Hz), 4.19 (1H, dd, J ) 9.0, 6.8 Hz),
4.46 (1H, dt, J ) 6.8, 3.3 Hz), 4.71 (1H, d, J ) 3.3 Hz); 13C
NMR (75 MHz, CDCl3) δ 25.4, 25.8, 59.6, 65.1, 73.96, 74.2,
111.0, 123.1, 155.8, 169.3. Anal. Calcd for C10H14O6: C, 52.17;
H, 6.13; O, 41.70. Found: C, 52.43; H, 6.34; O, 41.23.
5,6-O-Isop r op ylid en e-2-O-tr a n s-cr otyl-L-a scor bic Acid
(3c). This was synthesized from 1 and trans-crotyl bromide
in 72% yield as a light yellow oil using the standard procedure
for 3a : 1H NMR (300 MHz, CDCl3) δ 1.37 (3H, s), 1.41 (3H,
s), 1.71 (3H, dq, J ) 6.9, 1.7 Hz), 4.05 (1H, dd, J ) 8.5, 6.8
Hz), 4.17 (1H, dd, J ) 8.5, 6.8 Hz), 4.39 (1H, dt, J ) 6.8, 3.6
Hz), 4.49 (2H, dt, J ) 6.6, 1.0 Hz), 4.69 (1H, d, J ) 3.6 Hz),
5.64 (1H, dtq, J ) 15.7, 6.9, 1.6 Hz), 5.797 (1H, dtq, J ) 15.7,
6.9, 1.6 Hz); 13C NMR (75 MHz, CDCl3) δ 17.8, 25.3, 25.7,
64.99, 72.3, 73.9, 74.6, 110.4, 120.8, 125.8, 132.6, 157.9, 170.1;
HRMS (FAB +) m/z exact mass calcd for C13H19O6 (M + 1)
271.1180, found m/z 271.1182.
27.51, 67.75, 75.65, 78.54, 113.46, 120.54, 158.37, 176.08.
5, 6-O-Isop r op ylid en e-3-O-m eth yl-L-a scor bic Acid (2a ).
This compound was synthesized according to the procedure of
Wimalasena and Mahindaratne.32 A mixture of 1 (1 g, 4.63
mmol) and 1.2 equiv of K2CO3 (0.77 g, 5.56 mmol) in DMSO/
THF (9:8) was stirred for 20 min at room temperature. Then
1.2 equiv of methyl iodide (0.79 g, 5.56 mmol) in the same
solvent was added dropwise, and the mixture was vigorously
stirred for 4-6 h at room temperature. The reaction mixture
was diluted (4-fold) with water and extracted with ethyl
acetate. The organic layer was thoroughly washed with water
and dried over anhydrous Na2SO4, and the solvents were
removed under reduced pressure. The product was purified
by conventional silica gel column chromatography using 4:1
n-hexane/ethyl acetate to give 91% yield as a viscous oil: 1H
NMR (300 MHz, CDCl3) δ 1.37 (3H, s), 1.40 (3H, s), 4.02 (1H,
dd, J ) 8.5, 6.6 Hz), 4.13 (1H, dd, J ) 8.5, 6.7 Hz), 4.18 (3H,
s), 4.23 (1H, dt, J ) 6.7, 3.8 Hz), 4.53 (1H, d, J ) 3.8 Hz); 13
C
NMR (75 MHz, CDCl3) δ 25.2, 25.6, 59.4, 65.0, 73.9, 75.3,
110.0, 119.5, 149.9, 171.2.
5,6-O-Isop r op ylid en e-3-O-ben zyl-L-a scor bic Acid (2b).
This was synthesized from 1 and benzyl bromide in 86% yield
as a semisolid using the standard procedure for 2a : 1H NMR
(300 MHz, CDCl3) δ 1.36 (3H, s), 1.39 (3H, s), 4.02 (1H, dd, J
) 8.6, 6.7 Hz), 4.10 (1H, dd, J ) 8.6, 6.7 Hz), 4.26 (1H, dt, J
) 6.7, 3.8 Hz), 4.57 (1H, d, J ) 3.8 Hz), 5.52 (2H, two d), 7.35-
7.42 (5H, m); 13C NMR (75 MHz, CDCl3) 25.5, 25.9, 65.3, 73.5,
74.2, 75.7, 110.3, 119.5, 128.4, 128.6, 128.7, 135.7, 148.6, 171.1.
5,6-O-Isop r op ylid en e-3-O-tr a n s-cr otyl-L-a scor bic Acid
(2c). This was synthesized from 1 and trans-crotyl bromide
in 72% yield as a light yellow oil using the standard procedure
for 2a : 1H NMR (300 MHz, CDCl3) δ 1.37 (3H, s), 1.40 (3H,
s), 1.75 (3H, dq, J ) 6.5, 1.5 Hz), 4.02 (1H, dd, J ) 8.6, 6.7
Hz), 4.13 (1H, dd, J ) 8.6, 6.7 Hz), 4.26 (1H, dt, J ) 6.7, 3.9
Hz), 4.55 (1H, d, J ) 3.9 Hz), 4.89 (2H, m), 5.68 (1H, dtq, J )
15.3, 6.6, 1.5 Hz), 5.90 (1H, dtq, J ) 15.3, 6.5, 1.5 Hz); 13C
NMR (75 MHz, CDCl3) δ 17.8, 25.6, 25.9, 65.3, 72.4, 74.4, 75.7,
110.3, 119.1, 125.2, 132.6, 148.6, 171.8.
5,6-O-Isop r op ylid en e-2-O-ben zyl-L-a scor bic Acid (3d ).
This was synthesized from 1 and benzyl bromide in 83% yield
as a semisolid using the standard procedure for 3a : 1H NMR
(400 MHz, CDCl3) δ 1.34 (3H, s), 1.37 (3H, s), 3.86 (1H, dd, J
) 8.2, 6.7 Hz), 4.04 (1H, dd, J ) 8.2, 6.7 Hz), 4.31 (1H, dt, J
) 6.7, 3.6 Hz), 4.60 (1H, d, J ) 3.6 Hz), 5.11 (2H, two d), 7.31-
7.41 (5H, m); 13C NMR (100 MHz, CDCl3) δ 25.3, 25.8, 64.9,
73.3, 73.9, 74.2, 110.4, 121.1, 128.4, 128.5, 128.7, 136.4, 157.5,
169.3. Anal. Calcd for C16H18O6: C, 62.74; H, 5.92; O, 31.34.
Found: C, 62.95; H, 5.80; O, 31.25.
5,6-O-Isop r op ylid en e-3-O-a llyl-L-a scor b ic Acid (2d ).
This was synthesized from 1 and allyl bromide in 80% yield
as a light transparent oil using the standard procedure for
2a : 1H NMR (300 MHz, CDCl3) δ 1.37 (3H, s), 1.40 (3H, s),
4.04 (1H, dd, J ) 8.6, 6.7 Hz), 4.15 (1H, dd, J ) 8.6, 6.7 Hz),
4.28 (1H, dt, J ) 6.6, 3.8 Hz), 4.58 (1H, d, J ) 3.8 Hz), 4.97
(2H, d, J ) 5.7 Hz), 5.31 (1H, dq, J ) 10.4, 1.4 Hz), 5.41 (1H,
dq, J ) 17.2, 1.4 Hz), 6.01 (1H, ddt, J ) 17.2, 10.4, 5.7 Hz);
13C NMR (75 MHz, CDCl3) δ 25.5, 25.9, 65.3, 72.3, 74.3, 75.6,
110.3, 119.1, 119.2, 132.2, 148.2, 171.0.
5,6-O-Isopr opylidn e-2-O-tr a n s-cin n am yl-L-ascor bic Acid
(3e). This was synthesized from 1 and trans-cinnamyl bromide
in 87% yield as a semisolid using the standard procedure for
3a : 1H NMR (300 MHz, CDCl3) δ 1.30 (3H, s), 1.35 (3H, s),
3.99 (1H, dd, J ) 8.8, 6.7 Hz), 4.09 (1H, dd, J ) 8.8, 6.7 Hz),
4.36 (1H, dt, J ) 6.7, 3.6 Hz), 4.64 (1H, d, J ) 3.6 Hz), 4.74
(2H, d, J ) 6.6 Hz), 6.32 (1H, dt, J ) 13.8, 6.6 Hz), 6.36 (1H,
d, J ) 13.8 Hz), 7.213-7.375 (5H, m), 8.667 (1H, s); 13C NMR
(75 MHz, CDCl3) δ 25.13, 25.63, 64.85, 72.00, 73.73, 74.13,
110.59, 121.25, 123.77, 126.69, 128.15, 128.59, 135.09, 136.06,
157.11, 169.50. Anal. Calcd for C18H20O6: C, 65.05; H, 6.07;
O, 28.88. Found: C, 65.34; H, 5.75; O, 28.91.
5,6-O-Isop r op ylid en e-2-O-h ep tyl-L-a scor bic Acid (3f).
This was synthesized from 1 and 1-bromoheptane in 96% yield
as a semisolid using the standard procedure for 3a : 1H NMR
(400 MHz, CDCl3) δ 0.88 (3H, t), 1.28-1.35 (8H, m), 1.38 (3H,
s), 1.42 (3H, s), 1.66 (2H, quin, J ) 7.0 Hz), 4.03-4.10 (2H,
m), 4.18 (2H, dd, J ) 8.8, 7.0 Hz), 4.43 (1H, dt, J ) 6.6, 3.4
Hz), 4.71 (1H, d, J ) 3.4 Hz), 8.79 (1H, s); 13C NMR (100 MHz,
CDCl3) δ 13.7, 22.51, 25.18, 25.46, 25.72, 29.00, 29.57, 31.69,
64.99, 72.04, 73.82, 74.47, 110.50, 121.78, 156.58, 170.01;
HRMS (FAB+) m/z exact mass calcd for C16H27O6 (M + 1)
315.1810, found m/z 315.1808.
5,6-O-Isop r op ylid en e-2-O-a llyl-L-a scor bic Acid (3a ). A
solution of 2 equiv of potassium tert-butoxide (t-BuOK) (1.04
g, 9.26 mmol) in dry DMSO/THF (3:2) was added dropwise to
a solution of 1 (1 g, 4.63 mmol) in the same solvent at -10 °C
under nitrogen to produce a bright yellow solution with an
orange tint. The stirring of the mixture was continued for
about 2 min after which 1.1 equiv of allyl bromide (0.62 g, 5.09
mmol) in the same solvent was added dropwise over a period
(41) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B. G.; Chen,
W.; Wong, M. W.; Andres, J . L.; Head-Gordon, M.; Replogle, E. S.;
Pople, J . A. Gaussian 98, revision A.7; Gaussian, Inc.: Pittsburgh, PA,
1998.
(42) J ung, M. E.; Shaw, T. J . J . Am. Chem. Soc. 1980, 102, 6304-
6311.
7030 J . Org. Chem., Vol. 69, No. 21, 2004

2-O-Alkylation of 5,6-O-Isopropylidine-L-ascorbic Acid
5,6-O-Isop r op ylid en e-2-O-a llyl-3-O-a cet yl-L-a scor b ic
Acid (4a ). This was synthesized from 3a (1 g, 3.90 mmol) and
1.4 equiv of pyridine (0.43 g, 5.46 mmol) in CH2Cl2 and stirred
for 20 min at room temperature. Then, 1.2 equiv of acetyl
chloride (0.37 g, 4.68 mmol) was added dropwise under
nitrogen. The mixture was vigorously stirred until the solution
became homogeneous and was further stirred for 2 h at room
temperature. The reaction mixture was diluted with water
(4-fold) and extracted with ethyl acetate. The organic layer
was dried over Na2SO4, and the solvents were removed under
reduced pressure. The product was purified by conventional
silica gel column chromatography using 7:1 n-hexane/ethyl
acetate to give 70% yield as a light yellow oil: 1H NMR (300
MHz, CDCl3) δ 1.36 (3H, s), 1.38 (3H, s), 2.31 (3H, s), 4.02
(1H, dd, J ) 8.3, 6.6 Hz), 4.15 (1H, dd, J ) 8.3, 6.6 Hz), 4.29
(1H, dt, J ) 6.6, 2.5 Hz), 4.78 (2H, tt, J ) 5.1, 1.5 Hz), 5.18
(1H, d, J ) 2.5 Hz), 5.28 (1H, dq, J ) 10.5, 2.1 Hz), 5.37 (1H,
dq, J ) 17.3, 2.1 Hz), 5.97 (1H, ddt, J ) 17.3, 10.5, 5.1 Hz);
13C NMR (75 MHz, CDCl3) δ 20.6, 25.3, 25.6, 65.1, 71.3, 72.8,
74.5, 110.5, 118.9, 130.1, 132.4, 143.8, 166.3, 166.4; HRMS
(FAB+) m/z exact mass calcd for C14H19O7 (M + 1) 299.1130,
found m/z 299.1131.
CH2Cl2 was stirred for 20 min at room temperature, and 1.2
equiv of acetyl chloride (0.409 g, 5.21 mmol) was added
dropwise. The mixture was vigorously stirred until the solution
became homogeneous and was further stirred for 2 h at room
temperature. The reaction mixture was diluted (4-fold) with
water and extracted with ethyl acetate. The organic layer was
thoroughly washed with water and dried over anhydrous
Na2SO4, and the solvents were removed under reduced pres-
sure. The product was isolated and purified with conventional
silica gel column chromatography using 7:1 n-hexane/ethyl
acetate to give 90% yield as a transparent oil: 1H NMR (300
MHz, CDCl3) δ 1.36 (3H, s), 1.39 (3H, s), 2.31 (3H, s), 4.00
(3H, s), 4.02 (1H, dd, J ) 8.5, 6.6 Hz), 4.15 (1H, dd, J ) 8.5,
6.6 Hz), 4.29 (1H, dt, J ) 6.6, 2.4 Hz), 5.14 (1H, d, J ) 2.4
Hz); 13C NMR (75 MHz, CDCl3) δ 20.5, 25.3, 25.6, 58.4, 65.1,
72.9, 74.4, 110.6, 131.3, 142.4, 166.3, 166.4.
5,6-O-Isop r op ylid en e-3-O-b en zyl-2-O-a cet yl-L-a scor -
bic Acid (5b). This was synthesized from 2b and acetyl
chloride in 90% yield as a light yellow oil using the standard
procedure for 5a : 1H NMR (300 MHz, CDCl3) δ 1.36 (3H, s),
1.39 (3H, s), 2.22 (3H, s), 4.07 (1H, dd, J ) 8.6, 6.7 Hz), 4.14
(1H, dd, J ) 8.6, 6.7 Hz), 4.38 (1H, dt, J ) 6.7, 2.9 Hz), 4.71
(1H, d, J ) 2.9 Hz), 5.31 (1H, d, J ) 11.5 Hz), 5.37 (1H, d, J
) 11.5 Hz), 7.30-7.50 (5H, m); 13C NMR (75 MHz, CDCl3) δ
20.1, 25.5, 25.7, 65.1, 73.6, 73.9, 75.2, 110.5, 114.8, 127.5, 128.8,
129.0, 134.5, 159.8, 166.8, 167.5.
5,6-O-Isop r op ylid e n e -3-O-tr a n s-cr ot yl-2-O-a ce t yl-L-
a scor bic Acid (5c). This was synthesized from 2c and acetyl
chloride in 78% as a light yellow semisolid using the standard
procedure for 5a : 1H NMR (300 MHz, CDCl3) δ 1.36 (3H, s),
1.40 (3H, s), 1.76 (3H, dq, J ) 6.5, 1.6 Hz), 2.27 (3H, s), 4.07
(1H, dd, J ) 8.6, 6.6 Hz), 4.15 (1H, dd, J ) 8.6, 6.6 Hz), 4.36
(1H, dt, J ) 6.6, 3.1 Hz), 4.66 (1H, d, J ) 3.1 Hz), 4.73 (2H,
m), 5.62 (1H, dtq, J ) 15.4, 6.5, 1.6 Hz), 5.87 (1H, dtq, J )
15.4, 6.5, 1.6 Hz); 13C NMR (75 MHz, CDCl3) δ 17.7, 20.2, 25.5,
25.7, 65.2, 72.6, 73.7, 75.3, 110.5, 114.4, 124.0, 133.2, 159.7,
167.0, 167.6.
5,6-O-Isop r op ylid en e-3-O-a llyl-2-O-a cet yl-L-a scor b ic
Acid (5d ). This was synthesized from 2d and acetyl chloride
in 70% yield as a colorless semisolid using the standard
procedure for 5a : 1H NMR (300 MHz, CDCl3) δ 1.37 (3H, s),
1.41 (3H, s), 2.27 (3H, s), 4.08 (1H, dd, J ) 8.6, 6.6 Hz), 4.16
(1H, dd, J ) 8.6, 6.6 Hz), 4.38 (1H, dt, J ) 6.6, 3.0 Hz), 4.69
(1H, d, J ) 3.0 Hz), 4.81 (2H, two ddt), 5.35 (1H, dq, J ) 10.6,
1.6 Hz), 5.40 (1H, dq, J ) 17.7, 1.6 Hz), 5.95 (1H, ddt, J )
17.7, 10.6, 5.5 Hz); 13C NMR (75 MHz, CDCl3) δ 20.3, 25.5,
25.8, 65.2, 72.5, 73.7, 75.3, 110.6, 114.6, 119.6, 131.0, 159.5,
166.8, 167.6.
5,6-O-Isop r op ylid en e-3-O-tr a n s-cin n a m yl-2-O-a cet yl-
L-a scor bic Acid (5e). A mixture of 6 (1 g, 3.87 mmol) and
1.2 equiv of K2CO3 (0.64 g, 4.65 mmol) in DMSO/THF (9:8)
was stirred for 20 min at room temperature. Then 1.2 equiv
of cinnamyl bromide (0.92 g, 4.65 mmol) in the same solvent
was added dropwise, and the mixture was vigorously stirred
for 4-6 h at room temperature. The reaction mixture was
diluted (4-fold) with water and extracted with ethyl acetate.
The organic layer was thoroughly washed with water and dried
over anhydrous Na2SO4, and the solvents were removed under
reduced pressure. The product was purified by conventional
silica gel column chromatography using 7:1 n-hexane/ethyl
acetate to give 76% yield as a colorless crystals: 1H NMR (300
MHz, CDCl3) δ 1.36 (3H, s), 1.41 (3H, s), 2.28 (3H, s), 4.09
(1H, dd., J ) 8.6, 6.6 Hz), 4.17 (1H, dd., J ) 8.6, 6.6 Hz), 4.40
(1H, d t, J ) 6.6, 2.9 Hz), 4.70 (1H, d, J ) 2.9 Hz), 4.90-5.03
(2H, m), 6.29 (1H, dt, J ) 15.9, 6.3 Hz), 6.71 (1H, d, J ) 15.9
Hz), 7.23-7.36 (3H, m), 7.37-7.42 (2H, m); 13C NMR (75 MHz,
CDCl3) δ 20.2, 25.5, 25.7, 65.2, 72.6, 73.6, 75.3, 110.6, 114.7,
121.6, 126.7, 128.6, 128.7, 129.3, 135.5, 159.7, 166.9, 167.6.
5,6-O-Isop r op ylid en e-2-O-m et h yl-3-O-a cet yl-L-a scor -
bic Acid (4b). This was synthesized from 3b and acetyl
chloride in 80% yield as a transparent viscous oil using the
standard procedure for 4a : 1H NMR (300 MHz, CDCl3) δ 1.36
(3H, s), 1.39 (3H, s), 2.32 (3H, s), 4.00 (3H, s), 4.04 (1H, dd, J
) 9.0, 6.9 Hz), 4.16 (1H, dd, J ) 9.0, 6.9 Hz), 4.30 (1H, dt, J
) 6.9, 2.3 Hz), 5.15 (1H, d, J ) 2.3 Hz); 13C NMR (75 MHz,
CDCl3) δ 20.5, 25.3, 25.6, 58.4, 65.1, 72.8, 74.4, 110.5, 131.2,
142.3, 166.2, 166.4; HRMS (FAB+) m/z exact mass calcd for
C
12H17O7 (M + 1) 273.0970, found m/z 273.0974.
5,6-O-Isop r op ylid e n e -2-O-tr a n s-cr ot yl-3-O-a ce t yl-L-
a scor bic Acid (4c). This was synthesized from 3c and acetyl
chloride in 84% yield as a light yellow oil using the standard
procedure for 4a : 1H NMR (400 MHz, CDCl3) δ 1.36 (3H, s),
1.38 (3H, s), 1.73 (3H, dq, J ) 6.4, 1.8 Hz), 2.31 (3H, s), 4.01
(1H, dd, J ) 8.5, 6.6 Hz), 4.14 (1H, dd, J ) 8.5, 6.6 Hz), 4.28
(1H, dt, J ) 6.6, 2.4 Hz), 4.70 (2H, dt, J ) 6.4, 1.7 Hz), 5.18
(1H, d, J ) 2.4 Hz), 5.64 (1H, dtq, J ) 16.8, 6.4, 1.7 Hz), 5.83
(1H, dtq, J ) 16.8, 6.4, 1.7 Hz); 13C NMR (100 MHz, CDCl3) δ
17.7, 20.5, 25.3, 25.6, 65.0, 71.4, 72.9, 74.4, 110.5, 125.4, 130.1,
132.2, 143.8, 166.3, 166.5. Anal. Calcd for C15H20O7: C, 57.69;
H, 6.45; O, 35.86. Found: C, 57.74; H, 6.54; O, 35.72.
5,6-O-Isop r op ylid en e-2-O-b en zyl-3-O-a cet yl-L-a scor -
bic Acid (4d ). This was synthesized from 3d and acetyl
chloride in 82% yield as a light yellow oil using the standard
procedure for 4a : 1H NMR (400 MHz, CDCl3) δ 1.33 (3H, s),
1.34 (3H, s), 2.21 (3H, s), 3.96 (1H, dd, J ) 8.4, 6.8 Hz), 4.11
(1H, dd, J ) 8.4, 6.8 Hz), 4.25 (1H, dt, J ) 6.8, 2.4 Hz), 5.15
(1H, d, J ) 2.4 Hz), 5.28 (1H, d, J ) 11.6 Hz), 5.33 (1H, d, J
) 11.6 Hz) 7.31-7.39 (5H, m); 13C NMR (100 MHz, CDCl3) δ
20.6, 25.3, 25.6, 65.0, 72.5, 72.8, 74.40, 110.5, 127.8, 128.4,
128.5, 130.1, 135.9, 144.6, 166.1, 166.5; HRMS (FAB+) m/z
exact mass calcd for C18H21O7 (M + 1) 349.1290, found m/z
349.1298.
5,6-O-Isop r op ylid en e-2-O-cin n a m yl-3-O-a cetyl-L-a scor -
bic Acid (4e). This was synthesized from 3e and acetyl
chloride in 76% yield as viscous oil using the standard
procedure for 4a : 1H NMR (300 MHz, CDCl3) δ 1.30 (3H, s),
1.32 (3H, s), 2.30 (3H, s), 4.02 (1H, dd, J ) 8.4, 6.6 Hz), 4.13
(1H, dd, J ) 8.4, 6.6 Hz), 4.29 (1H, dt, J ) 6.6, 2.4 Hz), 4.89-
5.00 (2H, m), 5.17 (1H, d, J ) 2.4 Hz), 6.33 (1H, dt, J ) 13.6,
6.5 Hz), 6.08 (1H, d, J ) 13.6 Hz), 7.19-7.41 (5H, m); 13C NMR
(75 MHz, CDCl3) δ 25.3, 25.4, 25.6, 65.1, 71.3, 72.9, 74.5, 110.6,
123.4, 126.7, 128.3, 128.6, 128.8, 134.8, 136.0, 144.6, 166.3,
166.6; HRMS (FAB +) m/z exact mass calcd for C20H23O7
(M + 1) 375.1440, found m/z 375.1444.
5,6-O-Isop r op ylid en e-3-O-m et h yl-2-O-a cet yl-L-a scor -
bic Acid (5a ). This compound was synthesized according to
the procedure of Wimalasena and Mahindaratne.32 2a (1 g,
4.34 mmol) and 1.4 equiv of pyridine (0.481 g, 6.1 mmol) in
5,6-O-Isop r op ylid en e-2-O-a cetyl-L-a scor bic Acid (6).
This was synthesized by stirring a suspension of 1 (1 g, 4.63
mmol) and 1.4 equiv of pyridine (0.51 g, 6.48 mmol) in CH2Cl2
at room temperature for 10 min. Then 1.2 equiv of acetyl
J . Org. Chem, Vol. 69, No. 21, 2004 7031

Olabisi and Wimalasena
chloride (0.44 g, 5.55 mmol) was added dropwise. The mixture
was vigorously stirred until the solution became homogeneous
and was further stirred for 2 h at room temperature. The
reaction was diluted (4-fold) with water and extracted with
ethyl acetate. The organic layer was thoroughly washed with
water and dried over anhydrous Na2SO4, and the solvents were
removed under reduced pressure. The product was purified
with conventional silica gel column chromatography using 5:2
n-hexane/ethyl acetate to give 90% yield as a white solid: 1H
NMR (300 MHz, CDCl3) δ 1.38 (3H, s), 1.41 (3H, s), 2.36 (3H,
s), 4.10 (1H, dd, J ) 8.71, 6.74 Hz), 4.20 (1H, dd, J ) 8.71,
6.74 Hz), 4.44 (1H, dt, J ) 6.74, 2.81 Hz), 4.70 (1H, d, J )
2.81 Hz), 9.70-9.80 (1H, s); 13C NMR (75 MHz, CDCl3) δ 20.68,
25.54, 25.72, 65.28, 73.40, 74.57, 110.72, 115.39, 155.13,
166.23, 171.29.
Ack n ow led gm en t. This work was supported by a
grant from the National Institutes of Health (NS 39423).
We thank Bob Drake and Lawrence Seib of the Mass
Spectrometry laboratory at University of Kansas for the
help in exact mass (FAB) analyses.
Su p p or tin g In for m a tion Ava ila ble: 1H, 13C, and selected
2D NMR spectra for compounds 2a -d , 3a -f, 4a -e, and 5a -e
and the calculated electrostatic potential diagram of the
neutral, monoanionic, and dianionic forms of 5, 6-O-Isoprop-
ylidene-L-ascorbic acid (1). This material is available free of
charge via the Internet at http://pubs.acs.org.
J O049319I
7032 J . Org. Chem., Vol. 69, No. 21, 2004