1,2-Asymmetric induction in dianionic functionalization reactions of L-aspartic acid diesters

Functionalization of the dianions derived from N-protected aspartic acid es ters is a simple route to the preparation of novel alpha-amino acids and pe ptidomimetic precursors. We have demonstrated previously that high levels o f 1,2-asymmetric induction may be obtained in this reaction under the appro priate conditions (I.B. Parr, rt al., J. Med. Chem., 1996, 39, 2367). The o bserved diastereoselectivity results from the complicated interaction of a number of experimental factors. We now report that the nature of the electr ophile and the work-up protocol both influence the level of stereocontrol i n the alkylation of N-benzyloxycarbonyl aspartic acid esters. In addition, the stereo-chemical preference for high anti selectivity in the reaction ca n be reversed by increasing the steric bulk of the alpha-ester. Application of these observations has allowed the stereocontrolled preparation of two novel, N-protected, chimeric alpha-amino acids and a peptidomimetic precurs or. The molecular basis for 1,2-asymmetric induction in the alkylation reac tion can be rationalized on the basis of the configurational preferences of the lithium ester enolate formed from the N-protected aspartate diester us ed in these studies.