The Research Of Microgel Supported Hydantoin As Chiral Auxiliaries For Asymmetric Mannich Reaction

Polymer supported chiral auxiliary has been widely applied in asymmetric Mannich reaction,aldol reaction,alkylation reaction and Diels-Alder reaction with a good asymmetric induction and purification effect.In this thesis,we successfully synthesized soluble microgel supported hydantoin chiral auxiliary and investigated its asymmetric induction effect in Mannich reaction for the first time.L-tyrosine methyl ester hydrochloride,which was used as a chiral material,was firstly reacted with phenyl isocyanate under pyridine as the base,and then refluxed in hydrochloric acid to give a chiral hydantoin.The chiral hydantoin was then reacted with 4-vinylbenzyl chloride in the presence of K₂CO₃ to obtain the hydantoin monomer,and then treated with propionyl chloride to give N-acylated hydantoin monomer.Finally,N-acylated hydantoin monomer was copolymerized with styrene and different crosslinkers with AIBN as the initiator in THF to give four kinds of microgel supported hydantoin chiral auxiliaries with different internal structures,78?92%yield,and 0.9?1.01 mmol/g loading capacity.The solubility of microgel supported hydantoin chiral auxiliaries was investigated,and found that they are soluble in THF,CH₂Cl₂,DMF,CH₃CO₂Et,but insoluble in MeOH,EtOH,H₂O and other strong polar protic solvents.Thus microgel supported chiral auxiliaries can be carried out homogeneous reaction in THF,CH₂Cl₂ and monitored on line by IR,¹H NMR,¹³C NMR during.the reaction.After the reaction,the solvent was removed and precipitated in ice-methanol,filtered,washed until no small molecule impurity detected by TLC.The effect of asymmetric Mannich reaction induced by microgel supported hydantoin chiral auxiliaries was investigated.Four kinds of microgel supported hydantoin chiral auxiliaries were reacted with benzaldimine under the condition of 0?,TiCl₄ as Lewis acid,DIPEA as base to induce asymmetric Mannich reaction,then cleaved with CH₃OH/DMAP to give the Mannich adducts.And from the yield and enantiomeric excess of Mannich adducts,we inferred that microgel supported hydantoin 6c was the best chiral auxiliary.Thus microgel supported hydantoin chiral auxiliary 6c was reacted with other five different kinds of aldimines,and then cleave with CH₃OH/DMAP to give five Mannich adducts with high stereoselectivity?99%?and good yields?61 to 82%?.To determine the absolute configuration of the Mannich adducts,?-amino esters were treated with LiHMDS to afford the known ?-lactams.Comparison with the observed coupling constants and specific rotation revealed that the newly prepared ?-lactams were?anti,3R,4S?,which should be extended to the Mannich adducts as?5S,2'R,3'S?.The recycling and reuse of microgel supported hydantoin chiral auxiliary was studied.The results indicated that the stereoselectivity of the recovered chiral auxiliary remained almost intact for at least four reaction cycles,and the yield decreased slightly in each cycle.All the products and intermediates were characterized by infrared spectroscopy,NMR,high resolution mass spectrometry,high performance liquid chromatograph,melting point apparatus,automatic polarimeter,thermo gravimetric analyzer,gel permeation chromatography,transmission electron microscope,and the structure was consistent with the data.