Nucleosides, Nucleotides, and Nucleic Acids, 26:835–839, 2007
Copyright ꢀ Taylor & Francis Group, LLC
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ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701503969
AN ALTERNATIVE SYNTHETIC METHOD FOR
4ꢀ-C-ETHYNYLSTAVUDINE BY MEANS OF NUCLEOPHILIC
SUBSTITUTION OF 4ꢀ-BENZOYLOXYTHYMINE NUCLEOSIDE
Kazuhiro Haraguchi, Masanori Sumino, and Hiromichi Tanaka
School of
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Pharmaceutical Sciences, Showa University, Shinagawa-ku, Tokyo, Japan
For the synthesis of 2ꢁ,3ꢁ-didehydro-3ꢁ-deoxy-4ꢁ-C-ethynylthymidine (8: 4ꢁ-Ed4T), a recently
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reported promising anti-HIV agent, a new approach was developed. Since treatment of 1-(2,5-
dideoxy-β-L-glycero-pent-4-enofuranosyl)thymine with Pb(OBz)4 allowed the introduction of a 4’-
benzoyloxy leaving group, nucleophilic substitution at the 4ꢁ-position became feasible for the first
time. Thus, reaction between the 4’-benzoyloxy derivative (11) and Me3SiC≡CAl(Et)Cl as a nucle-
ophile led to the isolation of the desired 4’-“down”-ethynyl derivative (15) stereoselectively in 62%
yield.
Keywords Anti-HIV; diacyloxylation; 4ꢁ,5ꢁ-unsaturated nucleoside; nucleophilic substi-
tution; ethynylation; 4ꢁ-substituted nucleosides; didehydro-3ꢁ-deoxythymidine; organoa-
luminum reagents; organosilicon reagents
INTRODUCTION
Recently, 4ꢁ-substituted nucleosides have attracted much attention be-
cause of the discovery of the potent anti-HIV agents 4ꢁ-C-cyano (1) and
4ꢁ-C-ethynyl (2) analogs of thymidine (Figure 1). Synthesis of these 4ꢁ-
carbon-substituted nucleosides has mostly relied on manipulation of the
4ꢁ-hydroxymethyl derivatives of nucleosides or sugars that can be pre-
pared by the well known aldol-Cannizzaro reaction of the corresponding
aldehyde.[1]
We have already carried out ring-opening of 4ꢁ,5ꢁ-epoxynucleosides with
organosilicon[2] or an organoaluminum[3] reagent. Thus, oxidation of the
4ꢁ,5ꢁ-unsaturated derivative 3 with an acetone solution of dimethyldioxirane
(DMDO) gave 4, which was then reacted with organoaluminum reagents
(R3Al) to furnish the 4ꢁ-carbon-substituted products (5–7) (Scheme 1).
Financial support from the Japan Society for the Promotion of Science (KAKENHI No. 17590093
to K. H. and No. 17590094 to H. T.), the Research Foundation of Pharmaceutical Sciences (to K. H.),
and the Japan Health Sciences Foundation (SA14804 to H. T.) are gratefully acknowledged.
Address correspondene to Dr. Kazuhiro Haraguchi, School of Pharmaceutical Sciences, Showa Uni-
versity, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. E-mail: harakazu@pharm.showa-u.ac.jp
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