Organocatalyst Mediated Pot‐Economical Total Synthesis of (−)‐Quinine and its Derivatives

Abstract

Abstract(−)‐Quinine was synthesized in high enantio‐ and diastereoselectivity using an organocatalytic reaction as a key step. The piperidine skeleton was constructed using a diphenylprolinol silyl ether‐mediated Michael reaction, aza‐Henry reaction, and hemiacetalization in one‐pot. A reduction furnished the tri‐substituted piperidine with the correct stereochemistry in excellent diastereoselectivity. Introduction of a quinoline moiety and several transformations afforded (−)‐quinine. Using a stop‐and‐go method, (−)‐quinine was synthesized in 13 % yield with 12 pots. We further optimized the reactions for pot economy and achieved a synthesis of (−)‐quinine in 14 % yield using only five reaction vessels. Using 2,4‐dibromo‐6‐methoxyquinoline as a starting material enabled the preparation of C2′‐(−)‐quinine derivatives.