Enantioselective synthesis of beta-Amino acids. 12. experimental and theoretical study of the diastereoselectivity of alkylation of the dianion of N',N'-Bis(alpha-phenylethyl)-N -carbobenzyloxypropionamide

achiral, inexpensive b-alanine was converted into the title chiral amide 1 in 53% overall yield. c-alkylation of (r,r)-1 required formation of its dianion derivative, (r,r)-1-li2, which was best achieved by direct metallation with two equivalents of n-buli in thf solution and at -78°c. treatment of (r,r)-1-li2 with various alkyl halides afforded the monoalkylated products 3-6 in 24-85% yield and 65-86% diastereoselectivity. the effect of licl additive or hmpa co-solvent on the diastereoselectivity of the alkylation reaction was essentially negligible, although reaction yields generally improved. chemical correlation of the major diastereomer from the methylation reaction with (s)-a-methyl-b-alanine shows that addition of the electrophile takes place preferentially on the enolate's si face. this conclusion is also supported by molecular modelling studies (ab initio hf/3-21g), which indicate that the conformation of lowest energy for (r,r)-1-li2 presents a more sterically hindered re face of the enolate. the theoretical studies also provided useful insight into the importance of hydrogen bonding and attractive p-p interactions in (r,r)-1. furthermore, the calculations predict a determining role for n-li-o chelation in (r,r)-1-li, as well as an interesting ion triplet configuration for dilithium dianion (r,r)-1-li2.