A Highly Enantioselective Amino Acid-Catalyzed Route to Functionalized α-Amino Acids
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, III, J. Am. Chem. Soc., 2002, 124, 1842-1843.
DOI: 10.1021/ja017270h
Abstract
Proline-catalyzed Mannich-type reactions of N-PMP-protected α-imino ethyl glyoxylate with a variety of unmodified ketones provided functionalized α-amino acids in high yields with excellent regio-, diastereo-, and enantioselectivities. In reactions involving ketone donors where diastereoisomeric products could be formed, two adjacent stereogenic centers were created simultaneously upon carbon-carbon bond formation with complete syn-stereocontrol. Reactions were typically performed using 20 vol-% of the donor ketone and 20 mol-% proline catalyst, however, reduction of the donor ketone used to 2 eq. and reduction of catalyst loading to 5 mol-% provided the desired products without loss in yield or enantioselectivity.
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Details
The document discusses a highly enantioselective method for synthesizing functionalized α-amino acids using amino acid catalysis. The research, conducted by Armando Co´rdova and colleagues at The Scripps Research Institute, focuses on the Mannich-type reaction involving N-PMP-protected α-imino ethyl glyoxylate and various ketones, catalyzed by L-proline. This method yields α-amino acids with excellent regio-, diastereo-, and enantioselectivities. Initial experiments showed promising results, with the reaction of N-PMP-protected α-imino ethyl glyoxylate and L-proline in acetone/DMSO producing α-amino acid 1a in 82% yield and 95% ee. Further exploration with different ketones consistently produced high yields and selectivities. The study also found that environmentally friendly solvents could be used without compromising yield or selectivity. The methodology is operationally simple, does not require preactivation of substrates or metal ion assistance, and can be performed on a gram scale. The research highlights the potential for further modifications of the Mannich products and the broad applicability of this approach in synthesizing enantiomerically pure α-amino acids. The study was supported by the NIH and The Skaggs Institute for Chemical Biology.
H. Zhang, M. Mifsud, F. Tanaka, C. F. Barbas, III, J. Am. Chem. Soc., 2006, 128, 9630-9631.
Key Words
Organocatalysis, Mannich Reaction, β-Amino Ketones, α-Amino Acids
ID: J48-Y2002-1060
