Asymmetric synthesis of P-stereogenic phosphindane oxides via kinetic resolution and their biological activity

Long Yin, Jiajia Li, Changhui Wu, Haoran Zhang, Wenchao Zhao, Zhiyuan Fan, Mengxuan Liu, Siqi Zhang, Mengzhe Guo (), Xiaowei Dou () and Dong Guo ()
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Long Yin: Xuzhou Medical University
Jiajia Li: Xuzhou Medical University
Changhui Wu: China Pharmaceutical University
Haoran Zhang: Xuzhou Medical University
Wenchao Zhao: Xuzhou Medical University
Zhiyuan Fan: Xuzhou Medical University
Mengxuan Liu: Xuzhou Medical University
Siqi Zhang: Xuzhou Medical University
Mengzhe Guo: Xuzhou Medical University
Xiaowei Dou: China Pharmaceutical University
Dong Guo: Xuzhou Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract The importance of P-stereogenic heterocycles has been widely recognized with their extensive use as privileged chiral ligands and bioactive compounds. The catalytic asymmetric synthesis of P-stereogenic phosphindane derivatives, however, remains a challenging task. Herein, we report a catalytic kinetic resolution of phosphindole oxides via rhodium-catalyzed diastereo- and enantioselective conjugate addition to access enantiopure P-stereogenic phosphindane and phosphindole derivatives. This kinetic resolution method features high efficiency (s factor up to >1057), excellent stereoselectivities (all >20:1 dr, up to >99% ee), and a broad substrate scope. The obtained chiral phosphindane oxides exhibit promising therapeutic efficacy in autosomal dominant polycystic kidney disease (ADPKD), and compound 3az is found to significantly inhibit renal cyst growth both in vitro and in vivo, thus ushering in a promising scaffold for ADPKD drug discovery. This study will not only advance efforts towards the asymmetric synthesis of challenging P-stereogenic heterocycles, but also surely inspire further development of P-stereogenic entities for bioactive small-molecule discovery.

Date: 2024
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DOI: 10.1038/s41467-024-46892-7

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