Steps Toward the Synthesis of 1,1'-Dideaza-Quinine: A Proof of Concept

Abstract

Quinine is a naturally occurring alkaloid with substantial medicinal relevance due to its historical role as an anti-malarial agent, although it is now used most often for special cases where the organism is resistant to newer drugs. While quinine is easily extracted from the bark of the Cinchona tree, the challenge of engineering a set of reactions to synthesize stereochemically pure quinine has captivated chemists for generations. Due to its four stereocenters, the synthesis of this molecule can yield up to sixteen different stereoisomers. The purpose of this study is to validate the conceptual route proposed by Stotter, Friedman, and Minter for the diastereoselective total synthesis of quinine via the preparation of racemic 1,1'-dideaza-quinine; a quinine analog lacking nitrogen atoms. While the total synthesis of quinine has been completed successfully by several other groups, our proposed route provides a novel process through a tandem, diastereoselective aldol addition and reduction to establish two of the four chiral centers in a single operation. This route avoids overly expensive reagents and provides a more concise synthetic scheme.