The Research Of Auxiliary Reagent (S)-Imidazolidin-2-thione Induced Asymmetric Mannich Reaction

Chiral auxiliary reagents used in induction of asymmetric synthesis has been extensively studied in recent years and has a good prospect in the synthesis of chiral natural products and pharmaceutical intermediates.Due to the readily available raw materials,simple synthesis methods,structural stability and ease of product separation and purification,(S)-imidazolidin-2-thione as a new chiral auxiliary reagents development in recent years and inducing performance good in the asymmetric Aldol addition reaction,and has good application prospects in asymmetric synthesis.(S)?imidazole-2-thione will applied to induce asymmetric Mannich reactions in this paper,and preparation of chiral ?-amino ester,explore its induction in asymmetric synthesis reactions.1.Preparation of chiral auxiliary reagentsRespectively in five chiral natural amino acids as raw materials,in a mixed solvent of 1,4-dioxane and water to generate thiourea reaction with phenyl isothiocyanate,in the presence of triethylamine and concentrated hydrochloric acid,the intramolecular cyclization to give the(S)-2-thiohydantoin,and then reductive the carbonyl group on the 4-position to give the five(S)-imidazolidin-2-thione auxiliary reagents.2.Induced asymmetric Mannich ReactionFive chiral imidazolidine-2-thione auxiliary agents having different substituents in 4-position respectively react with seven kinds of acyl chloride,to give eleven kinds of post-acylated N-(S)-imidazolidine-2-thione auxiliary agents,the chiral auxiliary with N-acylated and then reacted with six kinds of benzaldiinine to induce asymmetric Mannich reaction.First,With N-propionyl-4-isopropyl-imidazolidin-2-thione and benzaldehyde imine asymmetric Mannich reaction as a template to investigate the optinmum reaction conditions.Which investigate the affect of the type of Lewis acid-base and the equivalent,the reaction temperature and other conditions of asymmetric reactions,Found that under the condition of 1.05 equiv TiCl4,1-1 equiv DIPEA,-78?,asymmetric Mannich reaction afforded 88%yield with 88:12 dr.In order to further improve the diastereoselectivity of the reaction,we then were discussed on the thirteen kinds of achiral additives of the effects on Mannich reaction When Ph3P as a non-chiral additive,Mannich reaction obtained the best effect,afforded 90%yield with 98:2 dr.Thus,(S)-imidazole-2-thione in asymmetric Mannich reaction and the optimal reaction conditions was 1.05equiv TiCl4?1.lequiv DIPEA?-78 ? and PPh3 as additives.Under the optimal reaction conditions,we were explored aldimine,N-acylated with different groups,different substituents,and the 4-position of imidazolidin-2-thione affect the asymmetric Mannich reaction.We got sixteen kinds of(anti,5S,2'R,3'S)configuration of Mannich adducts:The reaction of N-propionyl-4-isopropyl-imidazolidin-2-thione and different aldimines afforded 78%-91%yield with 91:9-98:2 diastereoselectivity.When the steric hindrance of N-acylated groups increases,it has little effect on the dr,afforded 65%-94%yield with>94:6 dr,Wherein when N-acylated groups was tert-butyl acetyl there no Mannich reaction product.Different substituted 4-position of imidazolidin-2-thione is reacted with benzene carbaldehyde imine,when the substituent sterically is increased and no big impact on the dr value and the yield,afforded>87%yield with>97:3 dr.3.The chiral auxiliary reagents reliefThe Mannich adducts were refluxed in DMAP/CH3OH,which resulted in the quantitative recovery of the(S)-imidazolidin-2-thione auxiliary,and afforded with a higher yield(2R,3S)-(3-amino esters and both having a value ?97%ee,the chiral imidazolidin-2-thione chemical configuration did not change.The P-amino ester synthesized as a composition of known configuration ?-lactam,Comparison of the observed coupling constants and specific rotation with the literature,the newly prepared ?-lactams were(anti,3R,4,S),then extended to the major Mannich reaction products absolute configuration as(5S,2'R,3'S).4.Structural analysisAll Mannich products and intermediates were characterized by IR,1H NMR,13C NMR,LC-MS and other analytical instruments,the results of spectral analysis data structure consistented with the compound,dr values measured by 1H NMR,ee value by HPLC determination,separation and purification process using TLC detection.(S)-imidazolidin-2-thione was applied in the asymmetric Mannich reaction,and the product has a good chemical yield and stereoselectivity,The(S)-imidazolidin-2-thione auxiliary could be recycled,the chiral auxiliary chemical configuration did not change,and which will be applied to induce more asymmetric synthesis reactions.