Organocatalytic asymmetric Michael addition reaction of aldehydes with 2-furanones: experimental, applications and DFT studies

Xiao You; Wenning Zhu; Jiacheng Du; Yuehua Liu; Fumin Chen; Yongshuai Chai; Qiang Zhang; Jingxiang Pang; Aiqin Liu; Zhushuang Bai

doi:10.1039/D2QO01891H

Organocatalytic asymmetric Michael addition reaction of aldehydes with 2-furanones: experimental, applications and DFT studies†

Xiao You,‡^a Wenning Zhu,‡^a Jiacheng Du,‡^a Yuehua Liu,^a Fumin Chen,^a Yongshuai Chai,^a Qiang Zhang,^a Jingxiang Pang,*^b Aiqin Liu*^a and Zhushuang Bai

*^a

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* Corresponding authors

^a School of Pharmacy and Pharmaceutical Science & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Jinan 250117, Shandong, China
E-mail: baizhushuang@sdfmu.edu.cn

^b Shandong Medicinal Biotechnology Centre, Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Key Lab for Biotechnology Drugs of Ministry of Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China

Abstract

Organocatalytic asymmetric Michael addition of aldehydes to 2-furanones are successfully conducted. This study provides an efficient approach to produce highly functionalized chiral γ-lactones, with three consecutive stereogenic carbons accompanied by good yields (up to 89%) and high stereoselectivities (up to 9.2 : 1 dr and 99% ee), which have been applied to the synthesis of vorapaxar's analogues. The results of mechanistic studies using DFT explained the high stereoselectivity. The protonation of anionic malonate with water by a hydrogen bond bridge is the rate-determining step to obtain the main product.

Organic Chemistry Frontiers

Organocatalytic asymmetric Michael addition reaction of aldehydes with 2-furanones: experimental, applications and DFT studies†

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Organocatalytic asymmetric Michael addition reaction of aldehydes with 2-furanones: experimental, applications and DFT studies

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