Asymmetric Synthesis of Conformationally Constrained trans-2,3-Piperidinedicarboxylic Acid Derivatives

Jincong Zhuo; David M. Burns; Colin Zhang; Meizhong Xu; Lingkai Weng; Ding-Quan Qian; Chunhong He; Qiyan Lin; Yun-Long Li; Eric Shi; Costas Agrios; Brian Metcalf; Wenqing Yao

doi:10.1055/s-2007-968029

LETTER

Asymmetric Synthesis of Conformationally Constrained trans-2,3-Piperidinedicarboxylic Acid Derivatives

Jincong Zhuo*, David M. Burns, Colin Zhang, Meizhong Xu, Lingkai Weng, Ding-Quan Qian, Chunhong He, Qiyan Lin, Yun-Long Li, Eric Shi, Costas Agrios, Brian Metcalf, Wenqing Yao*
Incyte Corporation, Medicinal Chemistry Division, Experimental Station, Wilmington, DE 19880, USA
Fax: +1(302)4252704; e-Mail: JZhuo@incyte.com; e-Mail: WYao@incyte.com;

Abstract

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Abstract

An efficient asymmetric synthesis of conformationally constrained (2S,3S)-piperidinedicarboxylic acid derivatives starting from l-aspartic acid β-tert-butyl ester and 3-chloro-2-(chloromethyl)-1-propene is described. The key steps involve N-alkylation of the aspartic acid ester followed by a stereoselective enolate intramolecular cyclization (>95:5 dr). Various synthetic strategies were explored to achieve the cyclopropanation of the resulting olefin, including the Simmons-Smith reaction and palladium-catalyzed cyclopropanation.

Key words

cyclopropanation - allylic amine - Simmons-Smith reagent - asymmetric synthesis - spiro piperidine

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References

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