Catalytic asymmetric Tsuji–Trost α−benzylation reaction of N-unprotected amino acids and benzyl alcohol derivatives

Jian-Hua Liu, Wei Wen (), Jian Liao, Qi-Wen Shen, Yao Lin, Zhu-Lian Wu, Tian Cai and Qi-Xiang Guo ()
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Jian-Hua Liu: School of Chemistry and Chemical Engineering, Southwest University
Wei Wen: School of Chemistry and Chemical Engineering, Southwest University
Jian Liao: School of Chemistry and Chemical Engineering, Southwest University
Qi-Wen Shen: School of Chemistry and Chemical Engineering, Southwest University
Yao Lin: School of Chemistry and Chemical Engineering, Southwest University
Zhu-Lian Wu: School of Chemistry and Chemical Engineering, Southwest University
Tian Cai: School of Chemistry and Chemical Engineering, Southwest University
Qi-Xiang Guo: School of Chemistry and Chemical Engineering, Southwest University

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Catalytic asymmetric Tsuji–Trost benzylation is a promising strategy for the preparation of chiral benzylic compounds. However, only a few such transformations with both good yields and enantioselectivities have been achieved since this reaction was first reported in 1992, and its use in current organic synthesis is restricted. In this work, we use N-unprotected amino acid esters as nucleophiles in reactions with benzyl alcohol derivatives. A ternary catalyst comprising a chiral aldehyde, a palladium species, and a Lewis acid is used to promote the reaction. Both mono- and polycyclic benzyl alcohols are excellent benzylation reagents. Various unnatural optically active α-benzyl amino acids are produced in good-to-excellent yields and with good-to-excellent enantioselectivities. This catalytic asymmetric method is used for the formal synthesis of two somatostatin mimetics and the proposed structure of natural product hypoestestatin 1. A mechanism that plausibly explains the stereoselective control is proposed.

Date: 2022
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DOI: 10.1038/s41467-022-30277-9

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