substituted nucleosides 45 including a D4T derivative 56
prompted us to investigate the preparation of 4′-substituted
2′,3′-dideoxyisonucleosides 6 as a potential anti-HIV agent.
To our knowledge, the synthesis of 4′-substituted 2′,3′-
dideoxyisonucleosides 6 is quite limited, and a report by Nair
et al. concerning the synthesis of D- and L-enantiomers of
2′,3′-dideoxy-4′-hydroxymethylisonucleosides 7 was par-
ticularly interesting.7 Although the compounds themselves
were inactive against HIV, they represent a key intermediate
in the synthesis of various 4′-substituted 2′,3′-dideoxyiso-
nucleosides 6. In this report, we describe a novel and
convenient synthesis of 4′-hydroxymethylisonucleosides 7.
Synthesizing new compounds in racemic form would have
the advantage that the antiviral activities of both enantiomers
can be assayed in one procedure. Therefore, we decided to
synthesize a racemic mixture of 4′-substituted nucleosides
6 by a method that can potentially be applied to a chiral
synthesis. Following this concept, we attempted to synthesize
(()-7, the key intermediate for synthesizing 6, from achiral
2,2-dimethyl-1,3-dioxan-5-one 10 by the method shown in
Scheme 1.
these dianions to 10 gave diol 11 in moderate yields
(30-40% yields). The use of an organocerium reagent,9
prepared from the magnesium salt of the dianion and
anhydrous cerium chloride, greatly improved the yield of
11 (84%). The semi-hydrogenation of 11 in the presence of
a Lindlar catalyst gave a (Z)-allyl alcohol derivative 12 in
91% yield. Cyclization of the allyl alcohol derivative 12 to
a dihydrofuran derivative 13 was achieved by the Mistunobu
reaction in 58% yield. However, the epoxidation of the
dihydrofuran 13 to give dioxabicyclohexane 14 gave a
complex and troublesome mixture (Scheme 2).
Scheme 2. Synthesis of the Dihydrofuran Derivative 13
Scheme 1. Retro Synthesis of 4′-Substituted Isonucleosides
Failure to obtain the dioxabicyclohexane derivative led us
to synthesize an epoxy alcohol derivative 17 which should
be a precursor to 14. The allyl alcohol derivative 12 was
silylated at the primary hydroxyl group to give 15. Com-
pound 15 was treated with m-chloroperoxybenzoic acid
(mcpba) to give the epoxide 16 which was desilylated to
afford the epoxy alcohol 17. As in the case of the synthesis
of the dihydrofuran derivative 13, the epoxy alcohol 17 was
subjected to intramolecular SN2 cyclization via the Mitsunobu
reaction. Thus, treatment of the epoxy alcohol 17 with PPh3
and DEAD in THF gave the desired dioxabicyclohexane
derivative 14 in excellent yield. It is noteworthy that the
oxirane ring of 14 remained intact under the reaction
conditions employed. We next attempted the direct introduc-
tion of a nucleobase unit into 14 via the nucleophilic opening
of the oxirane ring.
When 14 was treated with 6-chloropurine and potassium
carbonate in DMF, the reaction was too sluggish. Even under
harsh conditions (heating at reflux), the same reaction gave
none of the desired isonucleosides (data not shown). It is
likely that the weak nucleophilicity of the purine base
resulted in the unsuccessful reaction.
To circumvent this difficulty, we attempted to cleave the
oxirane ring of 14 by an appropriate thiol derivative which
is more nucleophilic. The tactics also include the possibility
A key intermediate of this synthesis should be the dioxa-
bicyclohexane derivative 8 which can serve as an acceptor
for a nucleobase to construct an isonucleoside skeleton. The
dioxabicyclohexane derivative 8 can be obtained from allyl
alcohol 9 which can be prepared from 2,2-dimethyl-1,3-
dioxan-5-one 10. Therefore, we first investigated the addition
reaction of a dianion of propargyl alcohol to 10.
The starting material 10 was readily obtained from tris-
(trihydroxyethyl)amine hydrochloride as described in the
literature.8 After a lithium or magnesium salt of a propargyl
alcohol dianion was prepared by the reaction with n-
butyllithium or n-butylmagnesium chloride, the addition of
(5) Ohrui, H.; Kohgo, S.; Kitano, K.; Sakata, S.; Kodama, E.; Yoshimura,
K.; Matsuoka, M.; Shigeta, S.; Mitsuya, H. J. Med. Chem. 2000, 43, 4516-
4525.
(6) (a) Dutschman, G. E.; Grill, S. P.; Gullen, E. A.; Haraguchi, K.;
Takeda, S.; Tanaka, H.; Baba, M.; Cheng, Y.-C. Antimicrob. Agents
Chemother. 2004, 48, 1640-1646. (b) Nitada, T.; Wang, X.; Kumamoto,
H.; Haraguchi, K.; Tanaka, H.; Cheng, Y.-C.; Baba, M. Antimicrob. Agents
Chemother. 2005, 49, 3355-3360.
(7) (a) Zintek, L. B.; Jeon, G. S.; Nair, V. Heterocycles 1994, 37, 1853-
1864. (b) Nair, V.; Zintek, L. B.; Jeon, G. S. Nucleosides Nucleotides 1995,
14, 389-391.
(8) Hoppe, D.; Schmincke, H.; Kleeman, H.-W. Tetrahedron 1989, 45,
687-694.
(9) Inamoto, T.; Takiyama, N.; Nakamura, K. Tetrahedron Lett. 1985,
26, 4763-4766.
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Org. Lett., Vol. 8, No. 26, 2006