A Highly Enantioselective Amino Acid-Catalyzed Route to Functionalized α-Amino Acids

• Published in: Journal of the American Chemical Society Vol. 124; no. 9; pp. 1842 - 1843
• Main Authors: Córdova, Armando, Notz, Wolfgang, Zhong, Guofu, Betancort, Juan M, Barbas, Carlos F
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 06.03.2002; Amer Chemical Soc
• Subjects: Aliphatic compounds; Amino Acids - chemical synthesis; Amino Acids - chemistry; Catalysis; Chemistry; Chemistry, Multidisciplinary; Exact sciences and technology; Organic chemistry; Physical Sciences; Preparations and properties; Science & Technology; Stereoisomerism; ETHERS; ASYMMETRIC-SYNTHESIS; STEREOSELECTIVE-SYNTHESIS; IMINES; α-Aminoacid; Catalytic reaction; Enantioselectivity; Functionalization; Regioselectivity; Mannich reaction; Proline; Enantiomeric excess; Chemical synthesis; Ketone; Diastereoselectivity
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja017270h

The development of syntheses providing enantiomerically pure α-amino acids has intrigued generations of chemists and been the subject of intense research. This report describes a general approach to functionalized α-amino acids based on catalytic asymmetric synthesis. Proline catalyzed Mannich-type reactions of N-PMP-protected α-imino ethyl glyoxylate with a variety of unmodified ketones to provide functionalized α-amino acids in high yields with excellent regio-, diastereo-, and enantioselectivities. Study of seven examples yielded six with product ee values of ≥99%. 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. Significantly, this methodology utilizes readily available and rather inexpensive starting materials, does not require any preactivation of substrates or metal ion assistance, and can be carried out on a gram scale under operationally simple reaction conditions. The keto-functionality present in the products provides a particularly attractive site for versatile modifications. This study compliments and extends our bioorganic approach to asymmetric synthesis to a versatile synthon class. Given that we have shown that a variety of optically active amino acids can be synthesized with proline catalysis, where an l-amino acid begets other l-amino acids, our results may stimulate thoughts concerning prebiotic syntheses of optically active amino acids based on this route.