Expedient and divergent synthesis of unnatural peptides through cobalt-catalyzed diastereoselective umpolung hydrogenation

Author:

Song Xinjian1ORCID,Bai Shuangyi1,Li Yuan1,Yi Tong1,Long Xinyu1,Pu Qinghua1,Dang Ting1,Ma Mengjie1,Ren Qiao1ORCID,Qin Xurong12ORCID

Affiliation:

1. Engineering Research Center of Coptis Development and Utilization, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, 2 Tiansheng Road, Chongqing, 400715, P. R. China.

2. State Key Laboratory of Medicinal Chemical Biology, Nankai University, No. 94 Wei Jin Road, Tianjin, 300071, P. R. China.

Abstract

The development of a reliable method for asymmetric synthesis of unnatural peptides is highly desirable and particularly challenging. In this study, we present a versatile and efficient approach that uses cobalt-catalyzed diastereoselective umpolung hydrogenation to access noncanonical aryl alanine peptides. This protocol demonstrates good tolerance toward various functional groups, amino acid sequences, and peptide lengths. Moreover, the versatility of this reaction is illustrated by its successful application in the late-stage functionalization and formal synthesis of various representative chiral natural products and pharmaceutical scaffolds. This strategy eliminates the need for synthesizing chiral noncanonical aryl alanines before peptide formation, and the hydrogenation reaction does not result in racemization or epimerization. The underlying mechanism was extensively explored through deuterium labeling, control experiments, HRMS identification, and UV-Vis spectroscopy, which supported a reasonable Co I /Co III catalytic cycle. Notably, acetic acid and methanol serve as safe and cost-effective hydrogen sources, while indium powder acts as the terminal electron source.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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