A Highly Enantioselective Route to Either Enantiomer of Both α- and β-Amino Acid Derivatives
Armando Córdova, Wolfgang Notz, Guofu Zhong, Juan M. Betancort and Carlos F. Barbas III*
*The Skaggs Institute for Chemical Biology and the Department of Molecular
Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla,
California 92037, Email: carlos
scripps.edu
A. Cordova, W. Notz, G. Zhong, J. M. Betancort, C. F. Barbas, J. Am. Chem. Soc., 2002, 124, 1866-1867.
DOI: 10.1021/ja017833p
Abstract
This is the first report concerning the use of unmodified aldehydes as a nucleophiles in direct catalytic asymmetric Mannich reactions.
Proline-catalyzed Mannich-type reactions of N-PMP-protected α-imino ethyl glyoxylate with a variety of unmodified aliphatic aldehydes provided functionalized α-amino acids in high yields with excellent enantioselectivities. The diastereoselectivity of the reaction increased with the bulkiness of the substituents of the aldehyde donor.
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Details
The document discusses a novel method for the enantioselective synthesis of amino acid derivatives using the Mannich reaction. Researchers from The Scripps Research Institute developed a catalytic asymmetric Mannich-type reaction using unmodified aldehydes and N-PMP-protected α-imino ethyl glyoxylate, catalyzed by L-proline. This method provides a highly enantioselective route to β-amino acids, β-lactams, and β-amino alcohol derivatives with excellent yields and diastereoselectivities. The reaction was tested with various solvents, with dioxane yielding the highest enantioselectivity (93% ee). The study also demonstrated that the reaction works efficiently with different aliphatic aldehydes, achieving high diastereoselectivities, especially with bulkier aldehyde donors. The products can be further modified into valuable pharmaceutical synthons, such as aspartic acid derivatives and carbapenem antibiotic precursors. This methodology is significant for its atom economy, use of inexpensive materials, and ability to produce either enantiomer of amino acid derivatives with high stereocontrol. The research was supported by the NIH and the Skaggs Institute for Chemical Biology, and further studies are ongoing to explore the scope and applicability of this method.
Key Words
Organocatalysis, Mannich Reaction, β-Amino Aldehydes, α-Amino Acids
ID: J48-Y2002-1070
