Tetrahedron Letters
Regioselective synthesis of 2-O-acyl-3-O-(1-acyloxyalkyl) prodrugs of
5,6-isopropylidene-L-ascorbic acid
⇑
John Prybylski, Nikki A. Thiele, Kenneth B. Sloan
Department of Medicinal Chemistry, P. O. 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:
An efficient regioselective synthesis of 2-O-acyl-3-O-(1-acyloxyalkyl) prodrugs of vitamin C 5,6-acetonide
Received 17 February 2016
Revised 26 February 2016
Accepted 29 February 2016
Available online xxxx
has been developed which does not involve tedious column chromatographic separation of the desired
products from contaminants exhibiting very similar R values. Vitamin C 5,6-acetonide is first acylated
f
with one equivalent of acyl halide in the presence of two equivalents of pyridine. The crude 2-O-acylated
product is then alkylated with one equivalent of 1-acyloxyalkyl-1-iodide in the presence of one
equivalent of triethylamine. The 2-O-acyl-3-O-(1-acyloxyalkyl) vitamin C 5,6-acetonides are obtained
in moderate yields.
Keywords:
Prodrugs
Soft alkyl drug
Alkylation
Acylation
Ó 2016 Elsevier Ltd. All rights reserved.
Regioselective
Vitamin C
Introduction
(2, Fig. 1). Also produced in variable amounts was a product tenta-
tively identified as 3 (Fig. 1), which was presumably formed from
It is well known that topically applied
L
-ascorbic acid (VC) can
intermediates during the formation of 1 and 2, and was not
expected to function as a prodrug. The conversion of VCA to the
various products was complete: no VCA remained when the reac-
tion was stopped. However, the separation of the various products
was very difficult and sometimes required a second chromato-
graphic separation to obtain analytically pure 1 and 2 in low yields.
Since substantial amounts of 1 or 2 were required for further char-
exhibit photoprotective effects based on its ability to scavenge free
radicals and reduce oxidative damage.1 VC can also exhibit anti-
aging effects based on its ability to increase collagen production
and reduce the appearance of wrinkles.2 However, VC is very
hydrophilic so it does not effectively cross biological membranes
3
such as skin. It is also not stable to premature oxidation in formu-
3
lations unless the pH is maintained well below its pK
a
of 4.2. In
acterization of the physicochemical and biological properties of
5
addition, the known derivatives of VC either do not protect the vul-
nerable, unique 1-one-2,3-diol-2-ene system from premature oxi-
dation, do not enhance the lipophilicity of VC to enhance its ability
to cross skin, or do not revert to VC in vivo. Thus, there is a need
for a transient, more lipophilic derivative of L-ascorbic acid that
this type of soft alkyl prodrug of
L-ascorbic acid (or VCA), and
the attachment of the 1-acyloxyalkyl group to the phenolic 2-O
position in 2 without competitive acylation of the 2-O position
was not possible, we focused on a practical synthesis of 1 that
would not involve the separation of 1 from 2 and 3. In this Letter
we report the regioselective synthesis of 1 (Fig. 1).
2
protects the unique 1-one-2,3-diol-2-ene system that is responsi-
ble for its antioxidant properties in vivo.
Regioselective synthesis of derivatives of VCA where the 2-O
position was acylated and the 3-O position was alkylated (similar
In a recent paper we have described results from the reaction of
6
1
-acyloxyalkyl-1-iodides
with
5,6-isopropylidene-
L-ascorbic
to 1) or vice versa have been reported recently. VCA was chosen
acid (vitamin C acetonide, VCA) in acetone in the presence of
as the starting point for the synthesis of transient, more lipophilic
derivatives to prevent off target reactions with the 5- or 6-hydroxy
groups in VC. The synthesis of 2-O-alkyl-3-O-acyl derivatives of VCA
relied on the selective and greater nucleophilicity of the anion of the
4
two equivalents of K
the complex 1-one-2,3-diol-2-ene set of connected functional
groups were obtained: 2-O-acyl-3-O-(1-acyloxyalkyl)-5,6-
isopropylidene- -ascorbic acid (1, Fig. 1), the major product, and
-O, 3-O-di-(1-acyloxyalkyl)-5,6-isopropylidene- -ascorbic acid
2
CO
3
.
Two novel prodrug derivatives of
7
L
weaker acid in the reactions of the 2,3-O-dianion of VCA with one
2
L
equivalent of alkyl halides to introduce the 2-O-alkyl group. Acyla-
tion of the 3-O position then gave the desired product. The synthesis
of the 2-O-acyl-3-O-alkyl derivative of VCA (similar to 1) required
only the alkylation of the 3-O-monoanion of VCA with an alkyl
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