STEREOSELECTIVE APPROACH TO THE Z-ISOMERS OF METHYLENECYCLOPROPANE ANALOGUES OF NUCLEOSIDES: A NEW SYNTHESIS OF ANTIVIRAL SYNGUANOL

摘要

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-carbethoxycyclopropylidene)methyl]purine (>13) were also obtained. Hydrolysis of compounds >11 and >13 and >13 in 80% acetic acid afforded (Z)-9-[2-(carbethoxycyclopropylidene)methyl]guanine (>14) and (Z)-7-[2-(carbethoxycyclopropylidene)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.