A new and high yielding synthesis of unstable pyrroles via a modified Clauson-Kaas reaction

An investigation of the reaction requirements to effect the Clauson-Kaas pyrrole synthesis led to the formulation of a new procedure that avoids the contact of pyrroles to heat or strongly acidic conditions that cause decomposition of the desired products. The procedure involves mild hydrolysis of 2,5-dimethoxytetrahydrofuran in water to the activated species 2,5-dihydroxytetrahydrofuran that reacts with primary amines in an acetate buffer at room temperature to give N-substituted pyrroles in high yield. In the case of chiral amines, pyrrole formation proceeds with no detectable epimerisation. Acidor heat-sensitive pyrroles are also obtained in high yield and purity. 2005 Elsevier Ltd. All rights reserved. Recently we reported the synthesis of 5-alkyl substituted indolizidine alkaloids such as indolizidine 209D from the ring opening of c-lactones with pyrrole to give cpyrrolic ester derivatives 2 (Scheme 1). This approach is somewhat limited by the difficulty of the ring opening reaction with substituted lactones and an asymmetric synthesis was not viable due to the prohibitive cost and lack of availability of enantiopure lactones. To overcome these limitations, we turned to the Clauson-Kaas pyrrole synthesis that utilises the condensation 0040-4039/$ see front matter 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.11.104 * Corresponding author. Tel.: +61 3 6226 2182; fax: +61 3 6226 2858; e-mail: [email protected] N