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 beta -alanine was converted into the title chiral amid e 1 in 53% overall yield. C-Alkylation of (R,R)-1 required formation of its dianion derivative, (R,R)-1-Li-2, which was best achieved by direct metall ation with two equivalents of n-BuLi in THF solution and at -78 degreesC. T reatment of (R,R)-1-Li-2 with various alkyl halides afforded the monoalkyla ted products 3-6 in 24-85% yield and 65-86% diastereoselectivity. The effec t of LiCl additive or HMPA cosolvent on the diastereoselectivity of the alk ylation reaction was essentially negligible, although reaction yields gener ally improved. Chemical correlation of the major diastereomer from the meth ylation reaction with (S)-alpha -methyl-beta -alanine shows that addition o f the electrophile takes place preferentially on the enolate's Si face. Thi s 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- Li-2 presents a more sterically hindered Re face of the enolate. The theore tical studies also provided useful insight into the importance of hydrogen bonding and attractive pi-pi interactions in (R,R)-1. Furthermore, the calc ulations 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-Li-2.