Studies On Asymmetric Synthesis Of A Series Of Structurally Important Unnatural Chiral Amino Acids And Chiral Heterocyclic Compounds

Chiral unnatural amino acids and heterocyclic compounds are two kinds of important organic synthetic motifs,widely found in biologically active pharmaceuticals.Therefore,considerable efforts have been dedicated to developing efficient methods to access these valuable compounds.This dissertation focused on the efficient asymmetric synthesis of chiral tetrasubstituted 3-indolyl-3-aminooxindole,unnatural ?/?~2/?~2/?~2-amino acids,chiral ?,?-dibenzyl acetate,trans-3,4-disubstituted pyrrolidine,3-aryl phthalide and chromanone via chiral auxiliary and Rh(I)/chiral diene complex catalytic strategies.Highly diastereoselective Friedel-Crafts reaction of indoles with isatin-derived N-sulfinyl ketimines towards the efficient synthesis of chiral tetrasubstituted 3-indolyl-3-aminooxindolesChiral 3-aminooxindoles and indoles are important structural units widely existed in various biologically active compounds,drugs and natural products.The combination of these two valuable fragments into one molecule for drug discovery research is a very meaningful project.Based on the chiral auxiliary strategy,we developed a highly diastereoselective Friedel-Crafts alkylation of indoles with N-tert-butanesulfinyl ketimines.This method provides a new access to tetrasubstituted 3-indolyl-3-aminooxindoles in the presence of Bi(OTf)3 with up to 99% yield and 96% de.The reaction is also compatible with 4,7-dihydroindoles and pyrroles.Furthermore,the N-DMTr and N-sulfinyl groups could be removed with ease under AlCl3 and HCl.This protocol offers opportunities for future applications of this kind of compounds in drug discovery.Rhodium(I)/chiral [3.3.0]diene catalyzed conjugate addition/enantioselective protonation reaction for the concise synthesis of chiral ?~2/?~2/?~2-amino estersChiral unnatural ?~2/?~2/?~2-amino esters are building blocks of great importance for preparing versatile peptides and related drugs.In this chapter,we have successfully developed an efficient Rh(I)/chiral[3.3.0]diene catalyzed 1,4-addition/enantioselective protonation reaction of arylbronic acids to ?-aminoalkyl acrylates with water as proton source to afford a series of optically pure ?~2/?~2/?~2-amino esters in high yields(up to 99% yield,98% ee).The reaction is compatible with a variety of substituents under mild conditions.The synthetic utilities of this approach were demonstrated by the rapid and ingenious construction of corresponding amino acids and other interesting benzo-heterocyclic molecules such as dihydrocoumarins and tetrahydroquinolines.The preliminary mechanism investigation suggests that chiral diene plays a decisive role in the asymmetric protonation process in the presence of water as the proton source.Rhodium(?)/chiral [2.2.2]diene catalyzed conjugate addition/enantioselective protonation reaction: enantioselective synthesis of chiral ?-benzyl amino esters,chiral ?,?-dibenzyl acetates and trans-3,4-disubstituted pyrrolidinesChiral ?-benzyl amino esters,chiral ?,?-dibenzyl acetates and trans-3,4-disubstituted pyrrolidines are common structural motifs found in biologically active molecules in drug discovery research.We successfully developed a highly efficient conjugate addition/enantioselective protonation reaction of arylboronic acids to ?-substituted acrylates with the same strategy,accessing various chiral ?-benzyl amino esters,?,?-dibenzyl acetates and trans-3,4-disubstituted pyrrolidines in high yields with excellent enantioselectivities(up to 99% yield,98% ee).This method utilizes water as the proton source,showing the advantage of mild conditions,high stereocontrol and wide substrate compatibility.Moreover,it provides an important basis for the construction of corresponding bioactive molecules.Rhodium(I)catalyzed asymmetric cascade 1,2-addition/cyclization reaction for the construction of chiral 3-aryl phthalides and chromanone.Chiral 3-aryl phthalides and chromanone have been frequently found in a wide range of biologically active molecules as well as natural products.We have successfully developed a Rhodium(I)catalyzed asymmetric 1,2-addition/esterification reaction of arylboronic acids to o-phthalaldehyde to construct chiral 3-aryl phthalides.Up to 82% yield and 84% ee could be achieved in the preliminary study.We also developed a tandem one-pot 1,2-addition/aza-Micheal reaction of arylboronic acids with ortho-functionalized benzils to generate chiral chromanone in good yields with up to 99% ee.Notably,the two diastereoisomers of the reaction could be separated with ease through flash column chromatography.