Methods for the catalytic enantioselective synthesis of alpha-amino and beta-aspartic acid derivatives

Methodology for the catalytic asymmetric synthesis of α-amino and β-aspartic acids is presented. The first approach relies on the use of catalytic quantities (1–5 mol%) of chiral, transition metal-based phosphine complexes as Lewis acid catalysts for the addition of enol silanes, ketene acetals, alkenes, and allylsilanes to α-amino esters and N,O acetals to afford α-amino acids. The alkylation products of these reactions were prepared with high enantioselectivity (up to 99% ee) and diastereoselectivity (up to 25:1/anti:syn). Currently, the final α-amino acid products prepared by this approach are of interest as potential precursors of natural products and pharmaceuticals. Following a fundamentally different approach, we have developed methodology for the preparation of β-aspartic acid derivatives using the Lewis basic catalyst benzoylquinine, acid chlorides and α-chloroamines. In this reaction, the catalyst benzoylquinine serves up to four distinct catalytic roles. The mechanism of this reaction was investigated through 1H, 19F NMR and the catalytic role of benzoylquinine established by a series of control experiments. The products, substituted β-aspartic acids, were selectively formed with high diastereoselectively (dr up to 12:1/syn:anti) and enantioselectivity (up to 96% ee). Utilizing this approach, protected L-threo-β-hydroxyasparagine, a key constituent of the antibiotic lysobactin, as well as other potent antibiotics, was prepared.