New isonitrile anti-malarial compounds

Abstract

Simple analogs of axisonitrile-3 (1-isocyano-2, 10-dimethyl-7-(1-methylethyl)-spiro[4,5]dec-6-ene), a marine isonitrile natural product, were prepared from menthol employing a Mitsunobu reaction with phthalimide as the key step. The analogs showed moderate activity. The synthesis of more complex analogs was undertaken by formylation and allylation of menthone, followed by a series of reductions and substitution protocols. The effect of steric hindrance of the system on the reaction condition was noted. Parallel chemistry using 4-tert-butyl cyclohexanone was carried out. It was shown that palladium catalyzed allylation is under stereoelectronic control.