Stereoselective Approach to the Z-Isomers of Methylenecyclopropane Analogues of Nucleosides: A New Synthesis of Antiviral Synguanol

Abstract

Stereoselective synthesis of antiviral synguanol (1) is described. Reaction of 6-benzyloxy-2-(dimethylaminomethyleneamino)purine (10) with ethyl (cis,trans)-2-chloro-2-(chloromethyl) cyclopropane-1-carboxylate (2c) under the conditions of alkylation-elimination gave (Z)-6- benzyloxy-2-formylamino-9-[(2-carbethoxycyclopropylidene)methyl]purine (11) but no E,N⁹-isomer. Minor amounts of (Z)-6-benzyloxy-2-formylamino-7-[(2-carbethoxy-cyclopropylidene)methyl]purine (13) were also obtained. Hydrolysis of compounds 11 and 13 in 80% acetic acid afforded (Z)-9-[2-(carbethoxycyclopropylidene)methyl]guanine (14) and (Z)-7-[2-(carbethoxy- cyclopropylidene)methyl]guanine (15). Reduction of 14 furnished synguanol (1). Reaction of N⁴-acetylcytosine (7) with ester 2c led to (Z,E)-1-(2-carbethoxycyclopropropylidenemethyl)cytosine (8, Z/E ratio 6.1:1). Basicity of purine base, lower reactivity of alkylation intermediates as well as interaction of the purine N³ or cytosine O² atoms with the carbonyl group of ester moiety seem to be essential for the observed high stereoselectivity of the alkylation-elimination. The Z-selectivity is interpreted in terms of E1cB mechanism leading to a transitory “cyclic” cyclopropenes which undergo a cyclopropene-methylenecyclopropane rearrangement.

Keywords:

• Methylenecyclopropanes
• nucleoside analogues
• alkylation-elimination
• Z-stereoselectivity
• antivirals
• synguanol

We thank Hongwang Zhang for some initial experiments and L. M. Hrihorczuk from the Central Instrumentation Facility (D. M. Coleman, Director) for mass spectra. The work described herein was supported by SBIR Grant 5 R44 AI0554135 to Microbiotix, Inc., Worcester, MA, USA and Research Grant 1 RO1 CA32779 from the National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.