Enantioselective Synthesis of β-Amino Acids, Part 13

• Published in: Helvetica chimica acta 2002-12, Vol.85 (12), p.4189-4199
• Main Authors: Gutiérrez-García, Víctor Manuel, Reyes-Rangel, Gloria, Muñoz-Muñiz, Omar, Juaristi, Eusebio
• Format: Article
• Language: English
• ISSN: 0018-019X; 1522-2675
• DOI: 10.1002/hlca.200290004

Inexpensive acryloyl chloride was converted in 91% overall yield to two derivatives of β‐alanine, (R,R,R)‐6 and (R,R,S)‐6, containing two chiral auxiliaries. C‐Alkylation of (R,R,R)‐ and (R,R,S)‐6 via a dianion derivative, was performed by direct metallation with 2.2 equiv. of lithium hexamethyldisilazane (LHMDS) in THF at −78°. C‐Alkylation of (R,R,S)‐6‐Li2 (‘matched' pair of chiral auxiliaries) afforded the mono‐alkylated products 8–11 in 29–96% yield and 54–95% stereoselectivity. Employment of LiCl as an additive generally increased stereoselectivities, whereas the effect of HMPA as a cosolvent was erratic. Chemical correlation of the major diastereoisomer from the alkylation reactions with (S)‐α‐alkyl‐β‐alanine (12–15) showed that addition of the electrophile preferentially takes place on the enolate's Si‐face. This conclusion is also supported by molecular‐modeling studies (ab initio HF/3‐21G), which indicate that the lowest‐energy conformation for (R,R,S)‐6‐Li2 presents the more sterically hindered Re‐face of the enolate. The theoretical studies also predict a determining role for NLiO chelation in (R,R,S)‐6‐Li2, giving rise to an interesting ‘ion‐triplet' configuration for the dilithium dianion.