Enantioselective Synthesis of β-Amino Acids. 12. Experimental and Theoretical Study of the Diastereoselectivity of Alkylation of the Dianion of N′,N′-Bis(α-phenylethyl)-N-carbobenzyloxypropionamide

Abstract

Achiral, inexpensive β-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 cosolvent 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)-α-methyl-β-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 π-π 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.