Studies On Synthesis Of Chiral β-Amino Alcohols And Their Application In Asymmetric Henry Reactions

Asymmetric synthesis is a hot field in modern organic synthesis. Development of high effective and enantionselective synthesis is a highlight in modern synthetic chemistry.The Henry reaction is one of the mostuseful methodologies for carbon-carbon bond formation.Asymmetric Henry reaction using chiral ligands has become one of the standard tools for the synthetic chemist,allowing access to enantiomerically enriched secondary nitroalcohol with excellent enantiomeric excess.The resulting secondary nitroalcohol is typically further transformations involving the newly formedβ-nitroalkanol functionality such as reduction to amines,the oxidation to carbonyl compounds,dehydration to nitroalkenes,etc.,which is a versatile intermediate in synthetic organic chemistry.Enantiomerically pureβ-amino alcohols have been extensively used aschiral building blocks for the syntheses of chiral pharmaceuticals,such as adrenergic drugs,β-adrenergic blockers and unnatural amino acids, etc.They have also been extensively used as chiral catalysts in asymmetric reactions,such as asymmetric addition of dialkylzinc to aldehydes, asymmetric epoxidation,asymmetric Henry reaction and asymmetric reduction of prochiral ketone.We have prepared two groups of enantiomerically pureβ-amino alcohols from L-phenylalanin and L-phenylglycine in a simplified way and used them as chiral catalysts in the asymmetric Henry reaction and asymmetric reduction of prochiral ketone.This thesis mainly focuses on the following three aspects: 1.The synthesis of chiralβ-Aminoa lcohols(1).Synthesis of chiralβ-amino alcohols from L-phenylalaninA series of new chiralβ-amino alcohols were synthesized with L-phenylalanin used as raw material,by four-step process——esterization, Griganard reaction,aldehyde condensation and reduction.It was confirmed that the structures of aminoalcohol were in agreement with the corresponding molecular structures of MS,IR,¹HNMR,¹³CNMR,and specific rotation.This approach has advantages such as easier operation, higher yield,low price and easy availability.(2).Synthesis of chiralβ-amino alcohols from L-phenylglycineThe chiralβ-amino alcohols were synthesized with L- phenylglycine used as raw material,by three steps——NaBH₄/I₂ reduction,aldehyde condensation and reduction in a simplified way.Their sructures were characterized by MS,IR,¹HNMR,and specific rotation.2.Application of chiralβ-amino alcohols in the catalytic asymmetric Henry reactionChiralβ-amino alcohols have been used as chiral catalysts in the asymmetric addition of nitromethane to aldehydes.Various factors have also been thoroughly studied in relation to the a mount of catalysts and copper salt,the structure of catalysts,solvent and reaction temperature on enantioselectivity.When the amount of catalyst and CuCl was 10 mol% relative to aldehyde,and reaction temperature was 18℃,the chiral ligand, 2-(furan-2-ylmethylamino)-2-phenylethanol LBG-3,had excellent performance in the catalytic enantioselective addition of aldehydes,which gavesβ-nitroalcohols with the yield up to 95%and enantiomeric excess up to 89%in ethanol.In addition,We supposed the possible mechanism for this catalytic reaction. 3 Asymmetric organocatalytic reduction of acetophenone with chiralβ-amino alcohosUsing the I₂/NaBH₄ system,unexpectedly,the chiralβ-amino alcohos were found not to be efficiency in asymmetric reduction of acetophenone, the yield were 80%-89%and enantiomeric excesses were only 5.0%.This application need to be found in further research.