Asymmetric Synthesis of Protected Unnatural α‑Amino Acids via Enantioconvergent Nickel-Catalyzed Cross-Coupling

• Published in: Journal of the American Chemical Society Vol. 143; no. 23; pp. 8614 - 8618
• Main Authors: Yang, Ze-Peng, Freas, Dylan J, Fu, Gregory C
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 16-06-2021
• Subjects: Amino Acids - chemical synthesis; Amino Acids - chemistry; Catalysis; Molecular Structure; Nickel - chemistry; Stereoisomerism
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.1c03903

Interest in unnatural α-amino acids has increased rapidly in recent years in areas ranging from protein design to medicinal chemistry to materials science. Consequently, the development of efficient, versatile, and straightforward methods for their enantioselective synthesis is an important objective in reaction development. In this report, we establish that a chiral catalyst based on nickel, an earth-abundant metal, can achieve the enantioconvergent coupling of readily available racemic alkyl electrophiles with a wide variety of alkylzinc reagents (1:1.1 ratio) to afford protected unnatural α-amino acids in good yield and ee. This cross-coupling, which proceeds under mild conditions and is tolerant of air, moisture, and a broad array of functional groups, complements earlier approaches to the catalytic asymmetric synthesis of this valuable family of molecules. We have applied our new method to the generation of several enantioenriched unnatural α-amino acids that have previously been shown to serve as useful intermediates in the synthesis of bioactive compounds.