Chiral aldehyde catalysis enables direct asymmetric -substitution reaction of N-unprotected amino acids with halohydrocarbons
CHEMICAL SCIENCE(2023)
Abstract
The direct catalytic alpha-hydrocarbylation of readily available amino acids with halohydrocarbons is one of the most straightforward methods leading to alpha,alpha-disubstituted non-proteinogenic alpha-amino acid compounds. However, all the reported methodologies depend on N-protected amino acids as starting materials. Herein, we report on three highly efficient aldehyde-catalyzed direct alpha-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 alpha-arylation, alpha-allylation, and alpha-benzylation of amino acid esters with the corresponding halohydrocarbons proceed smoothly, producing alpha,alpha-disubstituted alpha-amino acids in moderate-to-high yields and good-to-excellent enantioselectivities. The asymmetric alpha-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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Key words
chiral aldehyde catalysis,amino acids,n-unprotected
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