Asymmetric synthesis of alpha amino acids and their phosphorus analogues via sulfinimine chemistry

α,α-Disubstituted α-amino acids and cyclic α-amino acids are of interest because their incorporation into peptides provides molecules that are useful in determining structure-activity relationship and have improved therapeutic profiles. The object of this research was to explore the application of the sulfinimine-mediated asymmetric Strecker synthesis in the preparation of α,α-disubstituted α-amino acids, proline, and pipecolic acid derivatives. A second goal was to develop efficient methodologies for the enantioselective syntheses of α-amino phosphonic acid derivatives via sulfinimine chemistry.; Sulfinimines (N-sulfinyl imines), are versatile chiral imine building blocks that have provided a general solution to the problem of the addition of organometallic reagents to chiral imines. Keto- and masked oxo sulfinimines were prepared in good to excellent yields from ( S)- and (R)-p-toluenesulfinamide or from the Andersen reagent, and the corresponding ketones or aldehydes.; The sulfinimine-mediated asymmetric Strecker synthesis, which involved addition of “EtAl(O-i-Pr)CN,” generated in situ from Et₂AlCN and i-PrOH, to ketone-derived sulfinimines was employed to prepare α,α-disubstituted α-amino acids in 50–98% de's and 48–69% yields. The diastereoselectivity was largely dependent on the E/Z isomer ratio of the ketosulfinimine that was dependent upon the size difference of the two substituents attached to the imino carbon. Similarly, the addition of Et₂AlCN/i-PrOH to masked oxo sulfinimines afforded the corresponding α-amino nitriles in excellent de's. Hydrolysis resulted in the formation of intermediate oxo α-amino acids that underwent intramolecular cyclization to imines. Subsequently, hydrogenation of the cyclic imines afforded cis-proline and pipecolic acid derivatives in 95–98% ee's and 48–85% yields.; Analogous to the asymmetric Strecker synthesis, the addition of metallo phosphites to enantiopure ketosulfinimines provided the first examples of quaternary α-alkyl α-amino (arylmethyl) phosphonates with remarkable diastereoselectivity (>95%). In a similar manner, masked oxo sulfinimines were employed in the asymmetric synthesis of cis-proline, cis-piperidine, and cis-azepane phosphonates with ee's >95%. Moreover, the confusion in the literature regarding the absolute stereochemistry of N-sulfinyl α-amino phosphonates, prepared by addition of metal phosphites to sulfinimines, was resolved.