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

(-)-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. Enantioselective total synthesis of (-)-quinine has been accomplished using an organocatalytic reaction as a key step. The reactions were optimized for pot economy and (-)-quinine was synthesized in 14 % yield only in 5 pots. This synthesis is efficient, environmentally benign, and easy to synthesize quinine derivatives.image

Automated summary

(-)-Quinine was synthesized in high enantio- and diastereoselectivity using an organocatalytic reaction as a key step. The reactions were optimized for pot economy and (-)-quinine was synthesized in 14 % yield only in 5 pots. This synthesis is efficient, environmentally benign, and important for the preparation of quinine derivatives.