Enantioselective Synthesis of β‐Amino Acids,Part 13

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.