Conformationally locked carbocyclic nucleosides built on a bicyclo[3.1.0]hexane template with a fixed Southern conformation. Synthesis and antiviral activity

Abstract

The construction of carbocyclic nucleosides with a fixed ₃E ring pucker in the Southern hemisphere of the pseudorotational cycle is achieved from a common precursor carbocyclic amine, (1S,3S,4R,5 S )-3-benzyloxy-4-benzyloxymethyl-1-aminobicyclo[3.1.0]hexane 20. This carbocyclic amine is efficiently assembled from optically pure 2-benzyloxymethylcyclopent-3-enol 11 in ten steps. The key cyclopropanation step is performed on (3R,4S )-1-cyano-4-benzyloxy-3-(benzyloxymethyl)cyclopentane 15, and proceeds regio- and stereo-selectively to give the critical cyanocarbocyclic intermediate 17 from which the amine 20 is subsequently obtained. Synthesis of the pyrimidine analogues 6–8 is accomplished via the intermediate acyclic acryloylureas 21 and 22. Preparation of purines 9 and 10 required prior N-formylation of the corresponding 4,6-dichloro-5-aminopyrimidine and 4,6-dichloro-2,5-diaminopyrimidine heterocyclic precursors for efficient coupling with amine 20. Except for (S)-2′-deoxy-methanocarba-A (9, the 2′-deoxyadenosine analogue), all Southern conformers appear to be devoid of antiviral activity.