Chiral Aldehyde Catalysis Enables Direct Asymmetric Substitution Reaction of N-Unprotected Amino Acids with Halohydrocarbons

20 February 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


asymmetric catalysis
chiral aldehyde catalysis
asymmetric alkylation
asymmetric arylation
asymmetric benzylation
asymmetric allylation
amino acid

Supplementary materials

Supporting Information for Chiral Aldehyde Catalysis Enables Direct Asymmetric α-Substitution Reaction of N-Unprotected Amino Acids with Halohydrocarbons
Complete experimental procedures, characterization of new products, NMR and HRMS spectra and HPLC chromatograms, and DFT calculation details.


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