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Total Synthesis of (+)-Gracilamine Based on Oxidative Phenolic Coupling Reaction and Determination of its Absolute Configuration.

Research paper by Kazuo K Nagasawa, Minami M Odagi, Yoshiharu Y Yamamoto

Indexed on: 21 Sep '17Published on: 21 Sep '17Published in: Angewandte Chemie International Edition



Abstract

The Amaryllidaceae alkaloid (+)-gracilamine (1), isolated from Galanthus gracilis, contains a characteristic pentacyclic ring system with seven consecutive stereogenic centers, including an all-carbon quaternary stereocenter. Herein, we report the first enantioselective total synthesis of (+)-gracilamine (1), featuring a diastereoselective phenolic coupling reaction followed by a regioselective intramolecular aza-Michael reaction to construct the ABCE ring system. The stereochemistry at C3a in 1 is controlled by the stereocenter at C9a, which was selectively generated (91% ee) by utilizing an organocatalytic enantioselective aza-Friedel-Crafts reaction developed by our group. This synthesis reveals that the absolute configuration of (+)-gracilamine (1) is (3aR, 4S, 5S, 6R, 7aS, 8R, 9aS).