Study Of Dual Chiral Carbene And Its Cu-complex Catalyzed Asymmetric Boration

Synthesis of single configuration of Chiral compounds is the hotspot in modern organic synthesis field, especially in the pharmaceutical areas. Asymmetric catalysis for optically pure compounds from pro-chiral starting materials is an important method and have thus come into being. N-heterocyclic carbenes is the most popular nucleophilic carbene, due to its nucleophilic and polarity reversal feature, which has been widely applied to organic catalysis and metal catalysis reactions. Introducing a group having chiral center with large steric hindrance on the N-heterocyclic carbene can make it catalyze a variety of asymmetric reactions such as asymmetric benzoin condensation, asymmetric Stetter reaction and asymmetric tandem reaction.Ferrocene-based ligands with planar chirality and [2.2]paracyclophane-based ligands can also be used to catalyze asymmetric reactions in addition to the catalysts with central chirality. Compared with ferrocene, [2.2]paracyclophane has following advantages:(1) convenient to introduce a substituent on the phenyl ring to form planar chirality; (2) high stability, not easy for racemization; (3) high rigidity, providing well asymmetric environment. So, [2.2]paracyclophane-based ligands are increasingly reported in asymmetric catalysis field.We synthesized a series of dual chiral carbene precursors derived from central chiral amino acid and planar chiral [2.2]paracyclophane and applied them in carbene-copper catalyzed asymmetric β-boration of α,β-unsaturated carbonyl compound for the first time. Although products of boration catalyzed by carbene metal complex had been obtained in excellent enantioselectivity, there is still requirement for improvement. We found fluorine-modified binaphthol ligands, triazolium carbene ligands and some other metal complexes showed excellent chemical selectivity and enantioselectivity after checking the relevant literature. So we tried to prepare fluorinated [2.2]paracyclophane-based dual chiral carbene precursors, expecting breakthrough in catalyzing asymmetric conjugate boration.The main content of the thesis was shown as follows:1. Review of the chiral triazolium ligand and [2.2]paracyclophane derivatives in asymmetric catalysis.Rencently, triazolium salts are mainly applied in organocatalytic asymmetric reactions, including benzoin condensation, Stetter reaction,reaetions of α,β-unsaturated aldehydes with various electrophilic reagent, asymmetric hydroacylation, cooperative Lewis acid/N-heterocyclic carbene catalyzed reactions, esterification reactions of enone, asymmetric diethylzinc addition reaction catalyzed by metal complex which is formed by chiral [2.2]paracyclophane-based ligand and transition metal and reactions of aldehydes with phenylboronic acid.2. Synthesis of fluorinated dual chiral triazolium salts(1) Optically pure 4-fluoro-12-formohydrazino[2.2]paracyclophane hydrochloride4,12-dibromo[2.2]paracyclophane was prepared through bromination of [2.2]paracyclo-phane and followed by translocation of 4,16-dibromo[2.2]paracyclophane. Then after reaction with benzophenone imine and acidolysis, 4-amino-12-bromo[2.2]paracyclophane was systhesized, which could be chiral separated to give optically pure diastereomer—Rp-(-)-4-amino-12-bromo[2.2]paracyclophane and Sp-(+)-4-amino-12-bromo[2.2]paracyclophane. Rp-(-)-4-bromo-12-fluoro[2.2]paracyclo-phane was obtained from the diazonium salt prepared by reaction between Rp-(-)-4-amino-12-bromo[2.2]paracyclophane and amyl nitrite, which was then reacted with benzophenone hydrazone to afford Rp-(-)-N-{4-fluoro[2.2]paracyclophane-12-y1} benzophenone hydrazone. Finally, Rp-(-)-4-fluoro-12-formohydrazino[2.2]paracyclo-phane hydrochloride was obtained after formylation and acidolysis.(2) Synthesis of fluorinated dual chiral triazolium saltsChiral amino alcohols prepared by reduction of phenylglycine and tert-leucine reacted with chloroacetic acid to give the amide intermediate. Chiral imino ether was obtained by ring-closed from the amide intermediate in the presence of sodium hydride and followed by reaction with oxonium tetrafluoroborate. Then it was mixed with optically pure 4-fluoro-12-formohydrazino[2.2]paracyclophane hydrochloride in methanol at 50℃. After a while, triethyl orthoformate was added and the mixture was stirred at 110℃ for 3 h, affording the desired fluorinated dual chiral triazolium salts.4. Asymmetric β-boration of acyclic α,β-unsaturated ketone by fluorinated dual chiral N-heterocyclic carbene copper(Ⅰ) catalystsAlthough the catalytic activity of fluorine modified [2.2]paracyclophane-based N-heterocyclic carbene ligand derived from tert-leucine is better than that of phenylglycine derived N-heterocyclic carbene ligand in copper-catalyzed asymmetric boration, the enantioselectivity is lower. Fluorine modified [2.2]paracyclophane-based N-heterocyclic carbene ligand derived from phenylglycine shows better catalytic activity and enantioselectivity than the ligand without fluorine modification. After further study of temperature, solvent and alcohol additives, we eventually found the optimal condition for fluorinated dual chiral N-heterocyclic carbene copper (Ⅰ) complex. Study of applicability of substrates also proved that fluorine modified N-heterocyclic carbene has stronger enantiomeric control. Electron-withdrowning effect of fluorine which resists coordination between copper (Ⅰ) and benzene ring and small radius which does not cause overcrowding of catalytic space make the new catalyst show good catalytic activity and enantioselectivity.5. Asymmetric β-boration of chalcone derivatives by N-heterocyclic carbene catalystsOur group has been committed to the study of asymmetric reactions catalyzed by carbene transition metal complexes, while the asymmetrically organocatalysis is rarely involved except once research on asymmetric Aldol reaction of isatin derivatives with ketones by [2.2]paracyclophane-based thiourea ligand. We try to study on the N-heterocyclic carbene-catalyzed enantioselective β-boration of chalcone derivatives by using a series of N-heterocyclic carbene precursors.The main innovation of this thesis:1. Design and synthesis of fluorine-modified [2.2]paracyclophane-based triazolium salts derived from phenylglycine and tert-leucine for the first time.2. We completed the research on asymmetric β-boration of acyclic a,p-unsaturated ketone by fluorinated dual chiral N-heterocyclic carbene copper(Ⅰ) catalysts, which showes that fluorinated carbene copper(Ⅰ) complex has better catalytic activity and enantiomeric control.3. We study on N-heterocyclic carbene-catalyzed 1,4-boration of chalcone derivatives by using a series of N-heterocyclic carbene precursors. Carbene catalysts exhibited high yields but moderate enantioselectivities. Optimal conditions and good catalysts have not been found after our preliminary studies, further investigation has been conducted in our laboratory.