Practical synthesis of enantiomerically pure β2-amino acids via proline-catalyzed diastereoselective aminomethylation of aldehydes

Yonggui Chi, Emily P. English, William C. Pomerantz, W. Seth Horne, Leo A. Joyce, Lane R. Alexander, William S. Fleming, Elizabeth A. Hopkins, Samuel H. Gellman

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Abstract

Proline-catalyzed diastereoselective aminomethylation of aldehydes using a chiral iminium ion, generated from a readily prepared precursor, provides α-substituted-β-amino aldehydes with 85:15 to 90: 10 dr. The α-substituted-β-amino aldehydes can be reduced to β-substituted-γ-amino alcohols, the major diastereomer of which can be isolated via crystallization or column chromatography. The amino alcohols are efficiently transformed to protected β2-amino acids, which are valuable building blocks for β-peptides, natural products, and other interesting molecules. Because conditions for the aminomethylation and subsequent reactions are mild, β2-amino acid derivatives with protected functional groups in the side chain, such as β2- homoglutamic acid, β2-homotyrosine, and β2- homolysine, can be prepared in this way. The synthetic route is short, and purifications are simple; therefore, this method enables the preparation of protected β2-amino acids in useful quantities.

Original languageEnglish (US)
Pages (from-to)6050-6055
Number of pages6
JournalJournal of the American Chemical Society
Volume129
Issue number18
DOIs
StatePublished - May 9 2007

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Chi, Y., English, E. P., Pomerantz, W. C., Horne, W. S., Joyce, L. A., Alexander, L. R., Fleming, W. S., Hopkins, E. A., & Gellman, S. H. (2007). Practical synthesis of enantiomerically pure β2-amino acids via proline-catalyzed diastereoselective aminomethylation of aldehydes. Journal of the American Chemical Society, 129(18), 6050-6055. https://doi.org/10.1021/ja070063i