Preparation of chiral heterocyclic esters of beta-amino acids

Chiral p-amino alcohols were successively prone to N-benzylation, O-allylat ion and oxidation of the resulting benzylamino group to give nitrones 3 whi ch on hydrolysis afforded chiral hydroxylamines HO-NH-CH(R)-CH2-O-CH2-CH=CH 2 ((S)-4: R = Me, Bn, iPr, (R)-4: R = Et). Swern oxidation of methyl 2,2-di methyl-3-hydroxypropionate (16) and treatment of the resulting aldehyde 17 with hydroxylamines (S)-4b (R = Bn) or (R)-4d (R = Et) provided nitrones 18 that underwent an intramolecular 1,3-dipolar cycloaddition on heating yiel ding the bicyclic beta-amino-acid esters 19b and ent-19d, respectively. Red uctive cleavage of the N,O-bond of compounds 19 afforded the eight-membered ring compounds 20b and ent-20d, respectively. N-Benzylalaninol (22) was treated with beta-bromo-methacrylate to give the amino alcohol 23. Swern oxidation and subsequent treatment with N-tert-buty lhydroxylamine provided the bicyclic ester 26a (R = t-Bu) via the correspon ding nitrone 24. Grime 25 was prepared in an analogous way as 24 with unsub stituted hydroxylamine. It underwent an intramolecular 1.3-dipolar cycloadd ition yielding 26b on heating in toluene. Reduction of 26a afforded the pyr rolidine-carboxylic ester 27a.