Prodrugs of Vitamin C: The reaction of 1-acyloxyalkyl-1-iodides with Vitamin C 5,6-acetonide

Article abstract of DOI:10.1016/j.tetlet.2015.08.023

The reaction of 2 equiv of 1-acyloxyalkyl-1-iodides with vitamin C 5,6-acetonide gave mixtures of products that were O-alkylated on the 3-position and either O-alkylated, 7, or O-acylated, 8, on the 2-position. The 8 products comprised the majority of the mixtures: 56:54 to 94:6. The 3-alkylated-2-acylated prodrugs, 8, hydrolyzed to vitamin C 5,6-acetonide chemically at pH 7.4 with half-lives of 6-12 h.

Full text of DOI:10.1016/j.tetlet.2015.08.023

Tetrahedron Letters 56 (2015) 5441–5444
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Prodrugs of vitamin C: the reaction of 1-acyloxyalkyl-1-iodides
with vitamin C 5,6-acetonide
⇑
Jennifer McGowan, Nikki Thiele, Kenneth B. Sloan
Department of Medicinal Chemistry, PO Box 100485, University of Florida, Gainesville, FL 32610, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of 2 equiv of 1-acyloxyalkyl-1-iodides with vitamin C 5,6-acetonide gave mixtures of prod-
ucts that were O-alkylated on the 3-position and either O-alkylated, 7, or O-acylated, 8, on the 2-position.
The 8 products comprised the majority of the mixtures: 56:54 to 94:6. The 3-alkylated-2-acylated pro-
drugs, 8, hydrolyzed to vitamin C 5,6-acetonide chemically at pH 7.4 with half-lives of 6–12 h.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 23 June 2015
Revised 7 August 2015
Accepted 8 August 2015
Available online 13 August 2015
Keywords:
Vitamin C
Vitamin C 5,6-acetonide
Prodrugs
O-alkylation
Soft alkyl derivatives
Introduction
of the 3-OH position (or the 2-OH position) are capable of undergo-
ing typical acyl hydrolysis initiated by the attack of a nucleophile
ꢀ
00
Vitamin C (ascorbic acid, 1) contains a unique set of connected
functional groups that give 1 its unique antioxidant properties. The
(HO ) on the carbon of the polarized C@X functional groups to
0
00
cleave the X –(C@X ) bond and to generate an unstable intermedi-
0
0
1
-one-2,3-diol-2-ene system in 1 is highly ionized, exhibiting two
ate (drug-X–CHR –X –H) which subsequently spontaneously
decomposes to drugX and CHR @X . In the present examples
X@X @X @O, R = alkyl or alkyloxy and R = H or CH .
3
values (4.1 and 11.8).1 These sorts of acidic pK
ꢀ
0
0
acidic pK values
a
a
0
00
0
are normally observed for a carboxylic acid and a phenol substi-
tuted with electron donating groups, respectively. Because 1 exists
predominately as a charged species at physiological pH and con-
tains two additional polar hydroxy groups at 5-C and 6-C, vitamin
C, 1, does not cross biological membranes efficiently by passive dif-
fusion; it is not sufficiently lipid soluble to partition into the lipid
phases of the membrane. As part of a general program to design
more lipid soluble prodrugs of polar molecules/drugs to increase
0
0
00
drugX ꢀ CHR ꢀ X ꢀ ðC ¼ X Þ ꢀ R
ð1Þ
a-alkyl) iodides,
2
The reaction of alkylcarbonyloxymethyl (and
ACOM (and ACOA) iodides, or alkyloxycarbonyloxymethyl (and
a-alkyl) iodides, AOCOM (and AOCOA) iodides, 3, with oxygen cen-
tered acidic functional groups has been known for at least 50 years,
dating to their reactions with the carboxylic acid groups of peni-
cillins to give prodrugs with improved bioavailability.4 Similarly,
the reaction of ACOM iodides with nitrogen centered acidic func-
tional groups (amides and imides) to give soft N-alkyl prodrugs that
transiently masked those polar functional groups to increase their
lipid solubility and topical delivery of the molecule have been
their topical delivery, we have become interested in synthesizing
novel soft alkyl prodrugs2 of 1 that would transiently mask the
highly ionized polar functional groups in 1 while maintaining ade-
3
quate water solubility to optimize their topical delivery.
2
Soft alkyl prodrugs take the generic form of 2 in Eq. 1. 2 soft
alkyl derivatives exhibit stability toward hydrolysis of the bond
0
0
0
connecting drugX– to –CHR – in the promoiety (–CHR –X –
3
,5,6
0
0
known for over 40 years.
More recently the reaction of ACOM,
(
C@X )–R) that is characteristic of a typical alkyl derivative of
3
ACOA, and AOCOM iodides, 3, with less highly ionized oxygen cen-
tered functional groups such as phenols has been reported.7 As
opposed to the other reactions of ACOM, ACOA, and AOCOM iodides
with acidic functional groups which give exclusively alkylated
products, their reaction with phenols gave a mixture of O-acylated,
4, and O-alkylated, 5, products (Eq. 2). This result was attributed to
the ability of the more nucleophilic phenolic anion to react with the
drugX–H. 3-Ethyl vitamin C is an example of such an O-alkyl
derivative of vitamin C. However, 3-ethyl vitamin C does not revert
to vitamin C by hydrolysis. On the other hand, soft alkyl derivatives
–9
⇑
Corresponding author.
E-mail address: sloan@cop.ufl.edu (K.B. Sloan).
http://dx.doi.org/10.1016/j.tetlet.2015.08.023
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

5
442
J. McGowan et al. / Tetrahedron Letters 56 (2015) 5441–5444
0
0
carbon of the polarized C@X group to give 4, or the carbon of the
leaving group which contributes to the formation of a tight transi-
tion state which is necessary to produce nucleophilic attack on the
0
CHR –I group to give 5, depending on how tight the transition state
7
0
7
was (Eq. 2).
–CHR –I that would result in O-alkylation. Thus, it was expected
that the reaction of 3 with the acidic oxygen centered functional
groups in vitamin C 5,6-acetonide may give products where the
3-OH anion was O-alkylated but the 2-OH anion was either O-alky-
lated, 7, or O-acylated, 8, depending on the steric bulk in R.7
O
O
O
R'
R
base
R
O
,8
OH
O
O
R'
However, although the 3-OH has an acidic pK
a carboxylic acid and the 2-OH has an acidic pK
a
similar to that of
similar to that
R
O
I
a
3
4
5
of a phenol, the interaction of the 2-OH with the 3-alkylated
intermediate, or vice versa, in the stepwise formation of the
disubstituted derivative of the complex 1-one-2,3-diol-2-ene set
of connected functional groups makes it difficult to predict the
course of the reaction with certainty.
ð2Þ
Results and discussion
When 2 equiv of the ACOM pivaloyloxymethyl iodide were
To date no one has reported the results from attempts to soft
alkylate the complex 1-one-2,3-diol-2-ene set of connected func-
tional groups in vitamin C. Here we would like to report some
preliminary results from the reaction of 2 equiv of ACOM, ACOA
and AOCOM iodides (3), respectively, with vitamin C 5,6-ace-
tonide (6), in an acetone suspension containing 2 equiv of
allowed to react with 6 in the presence of 2 equiv of K CO3 sus-
2
pended in acetone, unexpectedly, an apparent equimolar mixture
of two products was obtained based on the appearance of two
1
equally intense 4C-H absorptions in the H NMR spectrum of the
crude mixture at about d 4.6 and d 4.7 (7e and 8e, Table 1).
The reaction of other ACOM, ACOA, and AOCOM iodides with 6 in
the presence of 2 equiv of K CO suspended in acetone gave
K
2
CO
tiary amine as an acid scavenger or ionizing agent instead of the
heterogeneous K CO /acetone conditions led to formation of the
.7,8 Previous attempts to use an organic base such as a ter-
3
2
3
mixtures where the intensity of the absorptions at d 4.7, 8, were
much greater than the one at d 4.6, 7, (94:6 to 74:26, Table 1).
There did not appear to be any trends in the ratios of the intensities
of the absorptions at d 4.7 to those at d 4.6 based on steric
considerations. Flash column chromatography was able to separate
the two products with varying degrees of success since their TLC Rf
values were always quite close (0.85 vs 0.80 for 7e and 8e, respec-
tively). In the case of 7e and 8e, reasonable total yields (Table 1)
were obtained while in the other cases, regardless that 1H NMR
spectra of the crude products suggested high conversion to the
two products, usually only very poor yields of the pure major
product, 8, were isolated after chromatography. In our hands all
the isolated products were oils or soft waxes except for 8a (white
solid, mp 87–89 °C) and 8f (hard wax which started melting at
about 70 °C).
2
3
corresponding quaternary salt of the soft alkylating agent, 3,
and no further reaction with the phenol-OH. 6 was used in the
reactions instead of 1 to prevent potential off target reactions of
the ACOM, ACOA, and AOCOM iodides with the 5- or 6-hydroxy
groups.
Previously it had been shown that the reaction of pivaloy-
loxymethyl (an ACOM) iodide with phenol in the presence of a
2 3
K CO suspension in acetone gave exclusively the O-alkylated
product, 5, with no detectable O-acylated product, 4. On the other
hand, if pivaloyloxymethyl chloride was used in the reaction, only
the O-acylated product, 4, was obtained.10 Furthermore, reaction of
normal alkyl ACOM iodides with phenol in the presence of a K
2 3
CO
suspension in acetone gave about 70% O-alkylated, 5, and 30% O-
1
0
acylated product, 4. The pivaloyloxymethyl iodide alkylating
agent exhibits properties expected to give exclusively O,O-dialky-
lated products, 7, from its reaction with 6. It includes significant
steric bulk around its carbonyl group which hinders nucleophilic
attack that would result in O-acylation, and the iodide is a good
The assigned structures of 7 and 8 were initially based on the
1
13
correlation between the H and C NMR spectra of pure 7 and 8
and those of the known 2,3-dialkyl (9–11), 2-acyl-3-alkyl
(12–14) and 2-alkyl-3-acyl (15, 16) derivatives of vitamin C
5,6-acetonide reported by Olabisi and Olabisi and Wimalasena.1
11
Table 1
Synthesis of ACOM, ACOA, and AOCOM derivatives of vitamin C 5,6-acetonide
O
O
O
O
O
O
O
O
R
R'
O
O
O
O
O
O
O
O
2
x base
R'
R'
O
R
O
O
O
O
O
R'
2x
O
O
HO
OH
R
R
R
O
I
6
3
8
7
0
Crude ratio 8:7a
Yield 8b (%)
Yield 7b (%)
Compounds
R
R
8
8
8
8
8
8
8
a, 7a
b, 7b
c, 7c
d, 7d
e, 7e
f, 7f
CH
CH
CH
CH
3
3
3
3
–
H–
H–
H–
H–
H–
CH
H–
94:6
90:10
74:26
87:13
56:54
92:8
59
14
20
38
36
57
18
—
3
1
2
CH –
(CH
(CH
2
)
3
–
–
)
2 4
8
(CH
3
)
3
C–
38
—
—
CH
CH
3
–
(CH
3
–
g, 7g
3
)
2 2
–O–
77:23
a
Based on integrations of peaks at d 4.6 (7) and at d 4.7 (8) in 1H NMR spectra.
Elemental analysis was correct for all isolated structures.
b

J. McGowan et al. / Tetrahedron Letters 56 (2015) 5441–5444
5443
Table 2
2
eotopic –CH – protons appear as one set of doublet of doublets
NMR spectra of 2,3-dialkyl, 2-acyl-3-alkyl and 2-alkyl-3-acyl derivatives of vitamin C
with one diastereotopic proton centered at d 5.86 and the other
at d 5.87 (J = 5.7 Hz). The HMBC-2D spectrum of 7e shows cou-
5
,6-acetonide
1
3
pling of the upfield –CH
2
1
– absorptions with the 2C C absorption
O
3
O
O
at d 120 and the (C@O) C absorption of its promoiety at about d
O
1
2
73, and coupling of the downfield –CH – absorptions with the
1
3
13
R3
O
O
2R
3C C absorption at d 154 and the (C@O) C absorption of its
promoiety at about d 172. The HMBC-2D spectrum of 8e shows
coupling of the single set of –CH
absorption at d 156.3–157.2 and the (C@O) C absorption of its
promoiety at about d 176.5.
13
9
-16
2
– absorptions with the 3C
C
1
3
Compounds 2R
9–16
13C NMR
d 2C d 3C
1H NMR
Attempts to soft alkylate vitamin C itself produced complex
mixtures of products that did not contain discernable signature
4C-H absorptions at about d 4.6 and d 4.7 or the two sets of
3
R
d 4C-H
9a
CH
3
–
CH
C
CH
CH
CH
C H CH –
6 5 2
CH
CH
2
@CHCH
CH
2
–
123.0 155.1 4.53
121.2 156.4 4.53
121.5 155.7 4.55
114.6 159.5 4.69
114.5 160.7 4.67
114.8 159.8 4.71
131.2 142.3 5.15
130.1 144.6 5.15
0a
1
1
1
1
1
1
1
C
6
H
5
CH
2
–
6
H
5
2
–
a
a
a
a
a
a
1
2
3
4
5
6
CH
2
CH
3
CH
3
CH
3
CH
3
@CHCH
(C@O)–
(C@O)–
(C@O)–
–
2
–
2
2
3
@CHCH
@CHCH
–
2
–
–
2
–CH – doublet of doublets absorptions between d 5.94 and d 5.78
2
representative of 7 or 8 or mixtures of 7 and 8. In some reactions
of soft alkylating agents 3 with 6, the same side product 17 was
obtained, regardless of the R in 3. 17 exhibited a complex set of
two doublet of doublets absorptions between about d 5.02–5.32
integrating for a total of 4 protons and a doublet for the 4C-H at
3
(C@O)–
(C@O)–
6 5 2
C H CH –
3
Rb
0
b
R
1
13
7b
7d
7e
CH
CH
3
CH
(CH
C–
2
–
H–
H–
H–
120.4 154.4 4.60(d)
120.4 154.3 4.60(d)
120.4 154.6 4.60(d)
d 4.67 in its H NMR spectrum. The C NMR spectrum of 17 exhib-
ited absorptions at d 123.29 and d 143.68 for the 2C and 3C car-
3
2
)
4
–
–
(CH
3
)
3
13
bons, respectively, which did not fit the C NMR absorption
8a
8b
8d
8e
8f
CH
3
CH
3
CH
3
–
H–
H–
H–
H–
CH
116.1 157.2 4.72(d)
116.2 157.0 4.73(d)
116.2 156.9 4.72(d)
116.1 156.6 4.71(d)
115.9 156.3 4.75, 4.70
patterns for any of the characterized products, but only one
CH
(CH
C–
2
–
13
carbonyl C absorption at d 166.53, which corresponds to the
2
)
4
carbonyl carbon in the 1-position of 6. Since there are no
(CH
3
)
3
1
3
other carbonyl C absorptions and the chemical shift of the two
CH
3
–
3
–
1
(
dd)
sets of doublet of doublets absorptions in the H spectra is charac-
8
g
CH
3
(CH
2
)
2
O–
H–
116.9 156.7 4.76(d)
teristic of a –O–CH
fits those facts is 17. The elemental analysis of 17 is consistent with
the given structure. The presence of two –O–CH –O–, but missing
2
–O– absorption, the one logical structure that
a
Refs. 1,11.
R and R from Table 1.
b
0
2
their corresponding acyl groups in 3, suggests that a mono substi-
tuted intermediate formed during the stepwise synthesis of 7 or 8
rearranged to give 17. Attempts to synthesize mono substituted
soft alkyl derivatives at the 3-OH or 2-OH positions of 6 were
unsuccessful, which supports the formation of rearrangement
products such as 17 during the synthesis of 7 and 8.
In Table 2 we have reproduced the chemical shifts of the perti-
nent absorptions in the 13C and 1H NMR spectra of 9–16 that
had previously been reported. The absorptions for 2C (d 121–
13
1
23) and 3C (d 155–157) in the C NMR and 4C-H (d 4.5) in
1
the H NMR spectra of the 2,3-alkyl derivatives, 9–11, correspond
closely to the absorptions for 2C (d 120.4) and 3C (d 154.3–154.6)
in the C NMR and 4C-H (d 4.60) in the H NMR spectra of 2,3-
soft dialkyl derivatives (7b, d and e). Similarly, the absorptions for
O
O
1
3
1
O
O
13
2
C (d 114.5–114.8) and 3C (d 159.5–160.7) in the C NMR and
O
O
4
C-H (d 4.67–4.71) in the 1H NMR spectra of the 2-acyl-3-alkyl
O
derivatives, 12–14, correspond closely to the absorptions for 2C
1
3
17
(
d 116.6–116.9) and 3C (d 156.3–157.2) in the C NMR and 4C-
1
H (d 4.70–4.75) in the H NMR spectra of 2-acyl-3-soft alkyl
derivatives (8a,b,d–g). On the other hand, the absorptions for
13
2
4
C (d 130.1–131.2) and 3C (d 142.3–144.6) in the C NMR and
As expected, the reaction of optically pure L-ascorbic acid 5,6-ace-
C-H (d 5.15) in the 1H NMR spectra of the 2-alkyl-3-acyl deriva-
tonide with a mixture of R and S soft alkylating agent 3, where
13
1
tives, 15 and 16, do not match the absorptions in the C and
H
0
R = CH
3
, gave an equimolar mixture of the two possible diastere-
1
NMR spectra of any of the isolated products from the soft alkyla-
tion reactions.
omers of 8f by H NMR spectroscopy. This conclusion was based
on the fact that integration of the 4C-H H NMR peaks for the indi-
1
Additional support for the assigned structures of 7 and 8
vidual diastereomers centered at d 4.70 and d 4.75 were equal and
1
1
derives from an analysis of the remaining H NMR absorptions,
that of the O–CH(CH
3
)–O H NMR peaks centered at d 6.65 and d
0
especially of the –CHR – groups in 7e and 8e, and their coupling
6
.66 were equal in the crude reaction mixture and in the isolated
13
with the 2C and 3C (for 7e) or 3C (for 8e) C NMR absorptions
product. 7f was present in the crude reaction mixture in too small
an amount to be isolated and characterized.
and their respective (C@O) 13C absorptions in HMBC-2D spectra.
2
In 7e the two sets of diastereotopic –CH – protons appear as
Chemical hydrolysis of 7 or 8 to 6 is expected to proceed in an A
to B to C stepwise fashion. However, the inability to synthesize
potential intermediates in their hydrolysis (see above) makes it
impossible to determine individual rates of each step. Thus, instead
we determined the macro half-lives of 8 based on the loss of the UV
two sets of doublet of doublets with one diastereotopic proton
centered at d 5.94 and the other at d 5.87 (J = 5.2 Hz) for the
downfield set of doublet of doublets, and with one diastereotopic
proton centered at d 5.81 and the other at d 5.78 (J = 5.6 Hz) for
the upfield set of doublet of doublets. In 8e the one set of diaster-
absorption of 8 at 224 nm (e = 10,340 L/mol) and the appearance of

5
444
J. McGowan et al. / Tetrahedron Letters 56 (2015) 5441–5444
the UV absorption of 6 at 255 nm (
e
= 14,591 L/mol). For 8a the
References and notes
half-life was 6.8 h. Similarly, the half-life of 8g was 12.25 h. Thus,
the prodrugs 8 hydrolyze to 6 at a reasonable rate: they are
prodrugs.
1
2
.
.
Olabisi, A. O.; Wimalasena, K. J. Org. Chem. 2004, 69, 7026–7032.
Sloan, K. B.; Hashida, M.; Alexander, J.; Bodor, N.; Higuchi, T. J. Pharm. Sci. 1983,
7
2, 372–378.
Some of the results presented here are contained in patent WO
3. Sloan, K. B. Adv. Drug Deliv. Rev. 1989, 3, 67–101.
1
2
4.
5.
6.
Jansen, A. B. A.; Russell, T. J. J. Chem. Soc. 1965, 2127–2132.
Sloan, K. B.; Bodor, N. Int. J. Pharm. 1982, 12, 299–313.
Mollgaard, B.; Hoelgaard, A.; Bundgaard, H. Int. J. Pharm. 1982, 12, 153–162.
2
015/048121A1.
Supplementary data
7. Sloan, K. B.; Koch, S. A. M. J. Org. Chem. 1983, 48, 3777–3783.
8
9
.
.
Thomas, J. D.; Sloan, K. B. Tetrahedron Lett. 2006, 47, 8785–8787.
Thomas, J. D.; Sloan, K. B. Tetrahedron Lett. 2007, 48, 109–112.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.08.
1
0. Thomas, J. D.; Sloan, K. B. Synthesis 2008, 272–278.
11. Olabisi, A. O. Dissertation, Wichita State, Kansas, 2005.
2. Sloan, K. B. Int. Publication Number WO 2015/048121.
1
0
23.