The combined catalytic systems derived from organocatalysts and transition metals exhibit powerful activation and stereoselective-control abilities in asymmetric catalysis. This work describes a highly efficient chiral aldehyde-nickel dual catalytic system and its application for the direct asymmetric α−propargylation reaction of amino acid esters with propargylic alcohol derivatives. Various structural diversity α,α−disubstituted non-proteinogenic α−amino acid esters are produced in good-to-excellent yields and enantioselectivities. Furthermore, a stereodivergent synthesis of natural product NP25302 is achieved, and a reasonable reaction mechanism is proposed to illustrate the observed stereoselectivity based on the results of control experiments, nonlinear effect investigation, and HRMS detection.
The direct catalytic α−hydrocarbylation of readily available amino acids with halohydrocarbons is one of the most straightforward methods leading to α,α−disubstituted non-proteinogenic α−amino acid compounds. However, all the reported methodologies...
Chiral α-amino ketones are common structural motifs in natural products and pharmaceuticals, as well as important synthons in organic synthesis. Thus, establishing efficient methods for preparing compounds with these privileged...
The direct catalytic hydrocarbylation of readily available amino acids with halohydrocarbons is one of the most straightforward methods leading to disubstituted non-proteinogenic amino acid compounds. However, all the re-ported methodologies depend on N-protected amino acids as starting materials. Herein, we report on three highly efficient aldehyde-catalyzed direct hydrocarbylations of N-unprotected amino acid esters with aryl-, allyl-, and benzyl halides. By promoting a simple chiral BINOL-aldehyde catalyst or combining catalysts of a chiral aldehyde and Lewis acid ZnCl2, the asymmetric arylation, allylation, and benzylation of amino acid esters with the corresponding halohydrocarbons proceed smoothly, producing disubstituted amino acids in moderate-to-high yields and good-to-excellent enantioselectivities. The asymmetric arylation reaction can be applied in the formal synthesis of the clinical candidate compound (+)-AG-041R. Based on the results given by control experiments, three reaction models are proposed to illustrate the stereoselective-control outcomes.
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