The synthesis of Nauclea indole-pyridine alkaloids. 3,4-Disubstituted and 3,4,5-trisubstituted pyridines as synthetic intermediates; a total synthesis of (±)-decarbomethoxy-3α- and -3β-nauclechine

Abstract

Synthetic routes to a number of 3,4-disubstituted and 3,4,5-trisubstituted pyridines have been explored. These pyridines, designed to be used in the synthesis of Nauclea indole-pyridine alkaloids, are potentially useful intermediates in a number of syntheses. Particular attention has been paid to more highly substituted derivatives of 4-pyridineacetic acid, and the experimental limitations associated with their synthesis and use in subsequent reactions such as the Bischler–Napieralski cyclization have been described and explained. A synthesis of decarbomethoxynauclechine from 4-methylnicotinaldehyde avoiding these difficulties was then designed and executed. Both diastereoisomers, (±)-decarbomethoxy-3α-nauclechine and (±)-decarbomethoxy-3β-nauclechine, were obtained; the structure and stereochemistry of each was rigorously established, but it was not possible to demonstrate which corresponded to the natural alkaloid, decarbomethoxynauclechine, reported previously.