The Study On Asymmetric Ring Opening Reaction Of Epoxides Catalyzed By Chiral Lewis Acids

The asymmetric ring-opening aminolysis of meso-epoxides represents one of the most important reactions in organic synthesis,giving rise to enantio-enriched aminoalcohol products with two chiral centers.The research work in the dissertation was focused on the study of catalytic asymmetric ring-opening of meso-epoxides by amines.Three highly efficient and enantioselective Lewis acidic catalyst systems, including a variety of titanium(â…£)complexes of B1NOL derivatives(BINOL-Ti), magnesium(â…¡)complexes of BINOL derivatives(BINOL-Mg),and magnesium(â…¡) complexes of some dinucleating chiral ligands with semi-crown prolinol skeletons (semi-crown prolinol-Mg),have been developed for the titled reactions.1.Mechanistic study on the asymmetric ring-opening aminolysis of 4,4-dimethyl-3,5,8-trioxabieydo[5.1.0]octane catalyzed by titaniumBINOLate-water system.The mechanism of the enantioselective ring-opening aminolysis of 4,4-dimethyl-3,5,8 -trioxabicyclo[5.1.0]octane with benzylamine,catalyzed by the titanium-BINOLate species generated in situ from a mixture of enantiopure BINOL (1,1'-bi-2-naphthol),Ti(OPrⁱ)₄ and H₂O in toluene,has been elucidated in detail and progressively uncovered on the basis of reaction profile studies,nonlinear effect(NLE) investigation,¹H NMR,as well as ESI-MS analysis.The titanium species bearing Ti(BINOLate)₂ moiety is established as the active species responsible for the catalysis. The epoxide competes with BnNH₂ for coordination to the metal site to achieve an adequate activation,followed by backward attack of the amine on the epoxide.Water is found to facilitate the catalytic turnover by acting as a proton shuttle between the reactants.Moreover,ESI-MS studies revealed that the BINOL ligands with same type of absolute configurations display a stronger tendency to form the homochiral ML₂ type complexes in the present reaction system,whereas analogous heterochiral ML₂ type complexes bearing BINOL ligands with opposite absolute configurations were not observed.Based on this result,a new model has been proposed to rationalize the pronounced(+)-NEE.Furthermore,highly efficient and enantioselective catalysts for the ring-opening reactions of epoxide 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane with amines have been developed by combinatorial screening the dynamic Ti-L₁-L₂ type catalyst libraries,constructed on the basis of the mechanistic understanding the reaction as well as the concept of asymmetric activation.At a catalyst loading of 0.5 mol%,the target compound 3,an important chiral intermediate for the synthesis of Nelfinavir(a potent HIV-protease inhibitor),could be obtained in 97%yield with 99%ee.Further extension of the protocol to the ring-opening of epoxide 1 using aliphatic amines nBuNH₂,iPrNH₂ or tBuNH₂ was also successful,affording the corresponding amino alcohol products in moderate to high yields with excellent enantioselectivities (95-99%ee)under mild reaction conditions.2.BINOL-Mg-catalyzed asymmetric ring-opening aminolysis of epoxides with aromatic and aliphatic aminesA new chiral catalyst system based on the magnesium complexes of BINOL derivatives was developed for the asymmetric ring-opening aminolysis of meso epoxides with both aromatic and aliphatic amines as nucleophiles.The amount of water present in the reaction system was found to exert a significant effect on the enantioselectivity of catalysis.With a slight modification of catalyst composition(1% loading of BINOL-Mg,with or without the MeLi additive),both aromatic and aliphatic amines can be used as effective nucleophiles in the ring-opening of a variety of meso-epoxides,affording the corresponding amino alcohol in moderate to excellent ee's.The BINOL-Mg system developed in this work should represent the first successful example of achieving good enantioselectivity for the asymmetric catalytic ring-opening of some meso-epoxides with both of aliphatic amines and aromatic amines,which might facilitate further research on the challenging topic of the asymmetric ring opening of meso-epoxides using aliphatic amines. 3.Asymmetric ring-opening aminolysis of meso epoxides with aromatic amines catalyzed by magneium complexes of Trost-type ligandsThe chiral magnesium complexes,generated in situ from combinations of the enantiopure dinucleating Trost-type ligands with dibutylmagnesium,were found to efficiently catalyze the asymmetric ring-opening of meso-epoxides by aromatic amines.Under the optimized reaction conditions,good yields and up to 88%ee were achieved in the asymmetric ring-opening of cyclohexene oxide by aromatic amines.A plausible catalyst cycle involving dinuclear Mg complex as the active species,has been proposed on the basis of a previous structural study of an analogous complex reported by our group as well as the ligand structure-enantioselectivity-reactivity relationship studies in the present system.