Asymmetric synthesis of beta-amino acids via the Michael addition of chiral metal amides

A lithium amide conjugate addition approach to the synthesis of beta-amino acid derivatives is described. Lithium amides derived from alpha-methylbenzylamine, such as lithium (alpha-methylbenzyl) benzylamide undergo highly diastereoselective 1,4-conjugate addition to a variety of alpha,beta-unsaturated carbonyl compounds. The benzyl substituents on the amino group can be readily removed by hydrogenolysis to afford a wide range of beta-amino acid derivatives. The enolate intermediate can be trapped by electrophiles such as alkylhalides and (camphorsulphonyl)oxaziridine to give alpha-alkyl and alpha-hydroxy-beta-amino beta-amino acids in a highly stereocontroled fashion. The synthetic utility of the methodology is demonstrated by the syntheses of numbers of natural products and other important synthetic intermediates such as taxol C-13 side chain, cispentacin, and (+)-negamycin. The origin of the stereoselectivity is briefly discussed.