Pyrrolizidine alkaloid analogues. Synthesis of macrocyclic diesters of (±)-synthanecine A from (±)-3-chloromethyl-2-hydroxymethyl-1-methyl-2,5-dihydropyrrolium chloride

Abstract

Reaction of 2,3-bis(hydroxymethyl)-1-methyl-2,5-dihydropyrrole [(±)-synthanecine A](3) with thionyl chloride produces (±)-3-Chloromethyl-2-hydroxymethyl-1-methyl-2,5-dihydropyrrolium chloride (11), which was treated with a series of anhydrides and base at room temperature to give the corresponding 6-monoesters of (±)-synthanecine A. Intramolecular nucleophilic substitution of the chlorine by carboxylate anion in the presence of base (DBU) gives the corresponding macrocyclic diesters of (±)-synthanecine A. The pyrrolizidine alkaloid analogues [(6), (7), and (16)–(20)] are prepared in better yields than using Corey–Nicolaou lactonisation conditions. A range of new 10-membered [(8)–(10) and (12)–(14)] and 11-membered [(15) and (21)] macrocyclic diesters of (±)-synthanecine A has been prepared.