The Research Of Chiral Hydantoin Auxiliary Reagent In Asymmetric Mannich Reaction

Due to the simple synthesis method and stable structure, chiral hydatoin was widely used in the asymmetric Michael addition reaction, Aldol condensation reaction, etc, and obtained good induced effect. We applied it in asymmetric Mannich reaction first, discussed the asymmetric induced effect.Four kinds of natural amino acid methyl ester hydrochloride as the chiral material, reacted with phenyl isocyanate, then refluxed in HCl solution and synthesized four kinds of5-substituent chiral hydatoin auxiliary, the chiral hydatoin respectively obtained the N-propionyl hydatoin, then reacted with the benzaldimine to induce asymmetric Mannich reaction. When5-methyl or benzyl substitued of hydatoin with benzaldimine, we got the side chain and ring Mannich adducts. When5-isopropyl or isobutyl substituted hydatoin with benzaldimine, we only got the side chain Mannich adducts. In order to improve the regional selective, asymmetric Mannich reaction used5-isopropyl substituted hydatoin as the chiral auxiliary.The effect of reaction of asymmetric Mannich reaction induced by chiral hydantoin, found that the best reaction condition was1equiv TiCl4and2.5equiv DIPEA,0℃. The reaction of5-isopropyl substituted different N-acylation hydantoin and benzaldimine afforded22%-75%yield with99:1diastereoselectivity, the yield decreased as the acylation substituent steric hindrance increased. The reaction of5-isopropyl substituted N-propionyl hydantoin and different aldimines afforded58%-82%yield with91:9-96:4diastereoselectivity. We got thirteen kinds of(anti,5S,2’R,3’S) configuration of Mannich adducts.The Mannich adducts were refluxed in DMAP/CH3OH for8h, which resulted in the quantitative recovery of the chiral hydantoin auxiliary, and afforded twelve (2R,3S)-β-amino esters with99%enantiomeric excess, the chiral hydantoin chemical configuration did not change.To determine the absolute configuration of the Mannich adducts, P-amino esters were treated with LiHMDS to afford the known β-lactams. Comparison of the observed coupling constants and specific rotation revealed that the newly prepared β-lactams were (anti,3R,4S), which should be extended to the Mannich adducts as (5S,2’R,3’S). The products were characterized by NMR, infrared spectroscopy, high resolution mass spectrometry, high performance liquid chromatograph, melting point apparatus, automatic polarimeter, and the structure consistented with the data.Chiral hydantoin auxiliary was successfully applied in the asymmetric Mannich reaction, asymmetric Mannich adducts had high diastereoselectivity. The chiral hydantoin auxiliary could be recycled, which will be applied to induce asymmetric reactions.