LETTER
335
Efficient Preparation of 2-Deoxy-3,5-di-O-p-toluoyl-a-D-ribofuranosyl
Chloride
P
reparat
l
2
i
-Deoxy
r
-3,5-di-
i
O
-
p
-tol
a
uoyl-
a
-
D
-ri
n
bofuranosyl Chlor
i
D
de himitruka, John SantaLucia Jr.*
Wayne State University, Department of Chemistry, 5101 Cass Ave., Detroit, MI 48202, USA
Fax +1(313)5778822; E-mail: jsl@chem.wayne.edu
Received 25 August 2003
This work is dedicated to Professor Ray Lemieux.
yields. In the first step, product 2 was not purified by
distillation (Scheme 1).6 In the second step, the product 3
is not typically purified by column chromatography. We,
and others, have found that even with the purification of
product 3 the end product 4 is still not stable. We per-
formed experiments to determine whether these two puri-
fication steps have any influence in the outcome of the
synthesis. Product 2 was distilled under high vacuum and
temperature as described.6
Abstract: An efficient method for the synthesis of 1-O-methyl-3,5-
di-O-p-toluoyl-2-deoxy-a/b-D-ribose is described. Upon treatment
with HCl, 2-deoxy-3,5-di-O-p-toluoyl-a-D-ribofuranosyl chloride,
previously unstable, was produced as a white solid, stable in air
indefinitely.
Key words: 1-O-methyl-3,5-di-O-p-toluoyl-2-deoxy-a/b-D-ribose,
2-deoxy-3,5-di-O-p-toluoyl-a-D-ribofuranosyl chloride, 1-O-meth-
yl-2-deoxy-a/b-D-ribose, hydrogen chloride, p-toluic anhydride
O
2-Deoxy-3,5,-di-O-p-toluoyl-a-D-ribofuranosyl chloride
is widely used in the synthesis of nucleotide analogs.1 The
potential of nucleotide analogs to help understand the
structure and function of RNA and DNA has been well
documented.2 Additionally, many nucleotide analogs ex-
hibit antiviral, antibiotic and anticancer activity.3 There-
fore, the efficient synthesis of 2-deoxy-3,5-di-O-p-
toluoyl-a-D-ribofuranosyl chloride is important. With few
modifications, the method developed by Hoffer in the late
fifties has been used widely.4 Studies dealing with the
anomeric preference of 2-deoxy-3,5-di-O-p-toluoyl-a-D-
ribofuranosyl chloride have appeared frequently, but there
have been few studies on optimizing the preparation.5,7
We recognized the need for such a study considering that
the apparent instability of this product affects the outcome
of a nucleotide analog synthesis especially if performed in
large scale (Scheme 1). In a typical Hoffer procedure, 2-
deoxy-a/b-D-ribose (1) is methylated to give 1-O-methyl-
2-deoxy-a/b-D-ribose (2). According to early studies, 1%
MeOH solution of anhyd HCl is required to affect the de-
sired furanose versus pyranose ring formation.6 Next, es-
terification using 2 equivalents of p-toluoyl chloride per
hydroxyl group in anhyd pyridine, gives the 1-O-methyl-
3,5-di-O-p-toluoyl-2-deoxy-a/b-D-ribose (3). This com-
pound is converted into the product, 2-deoxy-3,5-di-O-p-
toluoyl-a-D-ribofuranosyl chloride (4), by bubbling an-
hyd HCl gas through a solution of 3 in Et2O, HOAc or
adding 4 M HCl in HOAc–dioxane solution.4,7,8 The solid
product is then filtered and kept under high vacuum. Even
under vacuum the product decomposes after two weeks.
The overall yield of the synthesis is 70–80%. In literature
applications of the Hoffer procedure, two key purification
steps were sometimes omitted in order to obtain higher
OH
O
HO
HCl
OMe
HO
1 % in MeOH
HO
O
1
2
HO
Cl
Pyridine
4 Equivalents
O
OMe
O
p-TolO
HCl Gas
Diethyl ether
p-TolO
Cl
p-TolO
3
p-TolO
4
+ p-Toluic anhydride
Scheme 1 The Hoffer synthesis
We repeated the Hoffer procedure using distilled 1-O-me-
thyl-2-deoxy-a/b-D-ribose (2) (Scheme 1). The end prod-
uct 4 was still unstable. MS and NMR analysis revealed
the presence of p-toluic anhydride in the purified 1-O-me-
thyl-3,5-di-O-p-toluoyl-2-deoxy-a/b-D-ribose (3). Appar-
ently, the traditional solvent systems for column
chromatography such as benzene–Et2O and MeOH–
CHCl3 do not give a clean purification. Using hexanes to
remove the p-toluic anhydride or possibly other impuri-
ties, and then using hexanes–EtOAc, we separated out the
pure 1-O-methyl-3,5-di-O-p-toluoyl-2-deoxy-a/b-D-ri-
bose (3). This product was converted upon treatment with
anhyd HCl into 2-deoxy-3,5,-di-O-p-toluoyl-a-D-ribo-
furanosyl chloride (4).8 The product obtained was a white
solid stable in air indefinitely. Apparently, the use of pure
1-O-methyl-3,5-di-O-p-toluoyl-2-deoxy-a/b-D-ribose (3)
results in a stable final product. The formation of toluic
anhydride during the esterification was quite surprising. It
has been commonly assumed that the excess p-toluoyl
chloride would be converted into acid upon aqueous
work-up. The conversion of the aromatic acid chlorides
SYNLETT 2004, No. 2, pp 0335–0337
0
2.
0
2.
2
0
0
4
Advanced online publication: 18.12.2003
DOI: 10.1055/s-2003-45000; Art ID: S08903ST
© Georg Thieme Verlag Stuttgart · New York