Journal of the Brazilian Chemical Society
Print version ISSN 0103-5053
On-line version ISSN 1678-4790
GUTIERREZ-GARCIA, Víctor Manuel; REYES-RANGEL, Gloria; MUNOZ-MUNIZ, Omar and JUARISTI, Eusebio. Enantioselective synthesis of b-Amino acids. 12. experimental and theoretical study of the diastereoselectivity of alkylation of the dianion of N',N'-Bis(a-phenylethyl)-N -carbobenzyloxypropionamide. J. Braz. Chem. Soc. [online]. 2001, vol.12, n.5, pp.652-660. ISSN 0103-5053. http://dx.doi.org/10.1590/S0103-50532001000500008.
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.
Keywords : Amino acids; diastereoselective alkylation; enolates; theoretical studies.