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Abstract

A concise synthesis of the pyrrolizidine alkaloid epohelmin B (1) and a series of analogues is described. The key steps en route to this lanosterol synthase (oxidosqualene cyclase) inhibitor comprise a highly practical “azonia–Cope rearrangement”, which sets the chiral amine center with excellent optical purity, a ring-closing metathesis (RCM) reaction catalyzed by a readily prepared and now also commercially available ruthenium–indenylidene complex, a manganese-catalyzed epoxidation of the resulting eight-membered cycloalkene derivative, and a nosyl-deprotection/transannular-epoxide-opening cascade to forge the pyrrolizidine core. Digression from the route leading to the natural product in the final stages allowed for the preparation of several “epohelmin-like” compounds with modified side chains, which is necessary for investigations into a possible functional relationship with other known lanosterol synthase inhibitors.