Efficient Organocatalytic Construction of C4-Alkyl Substituted Piperidines and Their Application to the Synthesis of (+)-α-Skytanthine

Chemistry : a European Journal
Shinya ShiomiHayato Ishikawa

Abstract

Chiral piperidines which contain an alkyl group at C4 positions are one of the important architectures because it is appeared in several natural products. An efficient protocol for the preparation of C4-alkyl substituted chiral piperidines using secondary amine catalyzed formal aza [3+3] cycloaddition reaction with aliphatic α,β-unsaturated aldehydes and thiomalonamate derivatives is reported. In our reaction system, thiomalonamate is an excellent nucleophile and the addition of suitable acid and its amount is an important factor for the acceleration effect in organocatalytic reaction. Furthermore, water and MeOH also have an acceleration effect. These efforts lead to only 0.1 mol % catalyst loading in multigram scale synthesis for suitable reaction time. In addition, the efficient enantioselective total synthesis of (+)-α-skytanthine by using our developed reaction as key step was achieved in total 15 % yield. All carbon and nitrogen units were introduced by one step with high enantioselectivity.

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Citations

Dec 3, 2015·Organic & Biomolecular Chemistry·Hayato Ishikawa, Shinya Shiomi
Feb 29, 2020·Chemical Science·Shinya ShiomiHayato Ishikawa
Sep 25, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Zhonglei Wang
Sep 7, 2016·Chemistry : a European Journal·Bruno Matos PazKarl Anker Jørgensen
Feb 13, 2019·Chemical Reviews·Gabriel J Reyes-RodríguezKarl Anker Jørgensen

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