Nitrone dipolar cycloaddition routes to piperidines and indolizidines. Part 9. Formal synthesis of (−)-pinidine and total synthesis of (−)-histrionicotoxin, (+)-histrionicotoxin and (−)-histrionicotoxin 235A

Abstract

An intramolecular hydroxylamine-alkyne cyclisation is used for the enantioselective synthesis of the cyclic nitrones 36 and 44. We have demonstrated the use of a novel nitrone protection strategy by cycloaddition of styrene to the cyclic nitrone 44 in the synthesis of the spirocyclic core of the histrionicotoxin family of alkaloids. Deprotection by dipolar cycloreversion of the styrene adduct (the bicyclic isoxazolidine 39) and in situ intramolecular dipolar cycloaddition of a pendant (Z)-α,β-unsaturated nitrile to the intermediate nitrone 50 gave the isoxazolidine 51 in high yield with a surprising degree of regioselectivity compared with the corresponding (Z)-enyne 36. The method is amenable to the synthesis of both enantiomers 51 and 62 of the tricyclic core structure which can be converted by way of the common intermediates (e.g.53 and ent-53) respectively into the natural configuration of alkaloids (−)-histrionicotoxin 1 and (−)-histrionicotoxin 235A 65 as well as the unnatural (+)-histrionicotoxin 63.