Enantioselective synthesis of unprotected 2-quinolinone-based cyclic amino acids via sequential palladium-catalyzed asymmetric allylation/desymmetrization

Chiral unprotected 3-amino-2-quinolinone and 2-quinolinone-based cyclic amino acids have been recognized as important scaffolds in the structures of various drugs and bioactive molecules. However, a direct asymmetric method for the synthesis of these structures remains elusive. In this study, we report a Pd(0)-catalyzed enantioselective sequential decarboxylative allylation/desymmetrization protocol. Various vinyl benzoxazinanones can be used as substrates to react with unprotected amino esters, affording enantioenriched 2-quinolinone-based cyclic amino acids with high enantioselectivities (up to 96% ee) and good diastereoselectivities (up to 15:1 dr). Moreover, the products could be successfully transformed to chiral 3-amino-2-quinolinone derivatives after treatment with aqueous HCl. Mechanistic studies revealed that the double-hydrogen-bond-directing effect between the enolate (2-aminomalonate) and pi-allyl Pd(II) complex plays an important role in the control of regioselectivity, and the steric hindrance between tert-butyl group on the ligand and allyl group on the substrate is responsible for the high enantioselectivity. (C) 2023, Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Published by Elsevier B.V. All rights reserved.

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English Summary: Chiral unprotected 3-amino-2-quinolinone and 2-quinolinone-based cyclic amino acids are important in the structures of drugs and bioactive molecules. A Pd(0)-catalyzed enantioselective sequential decarboxylative allylation/desymmetrization protocol is reported for the synthesis of these structures. The reaction exhibits high enantioselectivities (up to 96% ee) and good diastereoselectivities (up to 15:1 dr), and the products can be further transformed into chiral 3-amino-2-quinolinone derivatives.