Studies On Construction Of Quaternary Stereogenic Centers And Spiro/Bridged Skeletons By Addition To Imines

The nucleophilic addition to imines represents one of the most important ways to synthesize complex nitrogenous compounds.However,preparation and purification of unstable imine substrates usually limit the application scope of this type of reaction.Furthermore,efficient methods to construct adjacent quaternary stereogenic centers and spiro/bridged skeletons remain scarce.Therefore,the development of novel nucleophilic reagents,new ways to form imine intermediates in situ,and unprecedented stereoselective strategies,which allow highly efficient construction of the challenging adjacent quaternary stereogenic centers and spiro/bridge skeletons in an asymmetric manner,would be highly valued.In this thesis,we have studied the asymmetric addition of multi-functionalized allylboronic acids and cyclopropanols as the novel nucleophiles to ketimines and iminium ions formed in situ by using the inexpensive chiral amino acids or their derivatives as the chiral pool.Highly stereoselective construction of the adjacent quaternary stereogenic centers and the spiro/bridge skeletons have been achieved.1)The allylation of ketimines with?,?-disubstituted allylboronic acids to construct adjacent quaternary stereogenic centersThe diastereoselective nucleophilic addition to ketimines,which were prepared by condensation of chiral amino alcohols and isatins,with achiral?,?-disubstituted allylboronic acids has been successfully achieved,furnishing a series of3-aminooxindole derivatives with adjacent quaternary stereogenic centers in high yield with excellent diastereoselectivity.Mechanism studies showed that this reaction proceeds in an intramolecular manner after a ligand exchange between the amino-alcohol moiety of the ketimines and allylboronic acids.The ligand exchange not only dramatically enhances the reaction rate,but also effectively controls the stereoselectivity,thereby solving the typical problems of low reactivity and stereoselectivity in adjacent quaternary stereogenic center construction.The advantages of this work include:inexpensive chiral amino alcohols were used as the source of chirality and nitrogen;ketimines were formed in situ to avoid the tedious preparation and purification procedures;broad application scope of allylboronic acids and isatins were tolerated;all four stereoisomers of a particular product could be synthesized by choosing an appropriate E/Z isomer of the allylboronic acid and an L/D enantiomer of the amino alcohol.This reaction represents the first allylation of ketimines with achiral?,?-disubstituted allylboronic acids,which would enrich the construction of the adjacent quaternary stereogenic centers.2)The cyclization of ketimines with cyclopropanols to construct the piperidine spiroindolone skeletonsUsing chiral amino acid as the chiral pool,the first copper-catalyzed cyclopropane ring-opening addition of?-amino-cyclopropanols to ketimines formed in situ has been realized,furnishing piperidine spiroindolone skeletons in high efficiency.Mechanism studies showed that the active catalyst copper(?)complex of this reaction was formed by in-situ oxidation of the Cu Cl-?-diketiminate complex,and the process of free radical ring-opening of cyclopropanol may be involved.This method represents the first nucleophilic addition of cyclopropanol to ketimine,which would expand the application range of cyclopropanol as the nucleophilic synthon.3)Copper-catalyzed tandem C-H oxidation/cyclopropanol ring-opening cyclization to construct the azabicyclo[3.3.1]nonane bridged skeletonsBased on the success of ring-opening addition of cyclopropanol to ketimine,a new tandem reaction involving C-H oxidation and ring-opening cyclization of cyclopropanol to the in-situ formed iminium ions has been developed using the cheap chiral amino acids as starting materials and copper as the catalyst.This reaction allows a highly efficient construction of azabicyclo[3.3.1]nonane skeleton,which is widespread in natural products and medicines.Using this reaction as the key step,a 9-step enantioselective total synthesis of indole alkaloid(-)-suaveoline has been achieved.Mechanism studies showed that Cu Cl₂ catalyzed the initial C-H oxidation and the subsequent cyclopropanol ring-opening addition.The advantages of this work include:1)inexpensive chiral starting materials(amino acids),catalyst(Cu Cl₂),and oxidant(air)were used;2)besides the diverse substituted types of cyclopropanols,azabicyclo[3.3.1]nonane bridged skeletons with a bridgehead quaternary stereogenic center as well as an azabicyclo[4.3.1]decane bridged skeleton have been constructed.Therefore,this study not only provides an efficient,low-cost,and environmentally benign method for constructing such bridged frameworks but also enriches the realm of C-H functionalization...