Enantioselective Synthesis of β‐Amino Acids, Part 13

Abstract

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.

Molecular Modeling of Salt (Lithium Chloride) Effects on the Enantioselectivity of Diethylzinc Addition to Benzaldehyde in the Presence of Chiral β-Amino Alcohols

“…Salient features in the catalytic cycle advanced in Figure are (1) the lowest-energy structures I − M , presenting ion-triplet configuration of the dilithium salts, and (2) in contrast with the mechanism presented in Figure , only 1 equiv of dialkylzinc should be required for the alkyl addition to take place.…”

β2‐amino acids—syntheses, occurrence in natural products, and components of β‐peptides1,2

“…In contrast, precursor (R)-V affords low selectivity in the absence of additives and complete inversion of selectivity in the presence of 3 equivalents of HMPA (Scheme 16). As a further extension toward the preparation of enantiopure ␤ 2 -amino acids, the stereoselective alkylation of ␤-homoglycine dianion derivatives I-2Li 139 and IV-2Li 140 has also been tested (Scheme 17). Previous work of several groups has, indeed, demonstrated that alkylation of chiral dianion derivatives proceeds with high stereoselectivity.…”

Reversible Enolization of β-Amino Carboxamides by Lithium Hexamethyldisilazide

“…As an adjunct to investigations of the enolization and alkylation of β-amino esters, we had occasion to study the enolization and alkylation of β-amino carboxamides (eq 1) . The protocol, using an unprotected amino group, − is synthetically interesting given the biochemical and pharmaceutical importance of β-amino amides and β-amino acids . Furthermore, the reversible enolization suggests an underlying complexity that piqued our interest.…”