Asymmetric Synthesis Of Chromanes By Transition-Metal-Catalyzed Reactions

Chiral chromane is a privileged structural motif found in amounts of natural products and biologically active molecules.Considering the prevalence of this structural unit,there has been considerable interest and challenge in developing methods for accessing chiral chromanes in organic synthesis and pharmaceutical chemistry.Asymmetric catalysis is one of the most important parts of modern organic synthesis,and also one of the most efficient methods to prepare optically active compounds.This dissertation is mainly focused on the development of transition-metal-catalyzed asymmetric functionalizations of C=C bonds of 2H-chromenes to access chiral chromanes with excellent enantioselectivities,including hydroarylation,hydroboration and hydroamination.Meanwhile,the cobalt-catalyzed cross-dehydrogenative coupling reaction of isochromanes with imidazo[1,2-a]-pyridines was explored.A kinetic resolution of chromenes with arylboronic acids has been developed by [Rh?cod?Cl]₂/?R?-Difluorphos-catalyzed asymmetric arylation.Under the mild reaction conditions,various chiral chromanes that contained two vicinal stereogenic centers could be obtained in 92%-99% enantioselectivities with 24%-47% yields,and the recovered chromenes were afforded in 28%-44% yields with 74%-99% enantioselectivities.The s factor is up to 532.The absolute configuration of arylation product was proved as?2S,3R?by X-ray crystally structural analysis.A possible mechanism of the reaction was proposed on the base of the literature reports and deuterium-labeling experiment.Initially,[Rh?cod?Cl]₂ and?R?-Difluorphos generates hydroxorhodium species in the present of potassium hydroxide.Then,the phenylrhodium species,generated by transmetalation of phenylboronic acid to hydroxorhodium?Ph-Rh?species,following 2H-chromene coordination and insertion into the Ar-Rh generates alkylrhodium intermediate.1,4-Rh migration occurs from alkylrhodium intermediate to generates Ar-Rh intermediate,which then reacts with water to liberate the product and generate hydroxorhodium species.In addition,a dynamic kinetic resolution of chromene acetals was further developed by [Rh?cod?OH]₂/?R?-Xyl-P-phos-catalyzed asymmetric arylation.The chiral chromanes was obtained in 48%-85% yields with 71%-98% enantioselectivities.The absolute configuration of arylation product was proved as?2S,3R?by X-ray crystally structural analysis.The products obtained could be easily converted to either chiral isoflavane or hydrocoumarin successfully.The kinetic resolution of flavenes with B2pin2 via CuCl/?R,R?-Ph-BPEcatalyzed asymmetric hydroboration has also been developed.This reaction provides a feasible one-pot method for the synthesis of chiral flavanols with excellent enantioselectivies.Under the optimal reaction conditions,vari ous optically active flavanols with two vicinal sterogenic centers could be obtained in 95%->99% enantiomeric excesses with 35%-48% yields,and the recovered chiral flavenes were afforded in 35%-47% yields with 92%->99% enantioselectivities.The s factor is up to 1060.The absolute configuration of flavanol was determined via X-ray crystally structural analysis,which is?2R,3S?.The obtained product could be converted into?-?-catechin gallates in 63% yield by two steps.Then,the Cu?OAc?₂/?R?-DTBM-Segphos-catalyzed enantioselective hydroamination of chromenes with hydroxylamine benzoates has been developed employing methyldimethoxylsilane as hydride source.4-Aminochromanes were obtained in high yields?50%-88%?and enantioselectivities?59%-99%?.The absolute configuration of amination product was proved as?S?by X-ray crystally structural analysis.The newly developed synthesis protocol of chiral molecules with a chromane core will facilitate their bioactivity study in medicinal chemistry.At last,an efficient Co Cl2·6H₂O catalyzed oxidative cross-dehydrogenative coupling reaction of isochromanes with 2-aryl imidazo[1,2-a]pyridines has been developed to achieve the isochromane derivatives containing imidazo[1,2-a]pyridine core using molecular oxygen as the oxidant.A broad range of 2-aryl imidazo[1,2-a]pyridines reacted smoothly to afford the coupling products in 52%-85% yields.The advantages of this method are inexpensive catalysts used,environmentally benign conditions and operational convenience.Then,the asymmetric cross-dehydrogenative coupling of isochromane with 2-phenyl imidazo[1,2-a]pyridine has been explored.A possible mechanism of the reaction was proposed on the base of the literature reports and the control experiments.Initially the reaction of isochromane with oxygen and Co Cl2 generates oxonium ion,the nucleophile imidazo[1,2-a]pyridine trap oxonium ion to generate product and water.The other pathway is the isochromane react ion with oxygen and Co Cl2 to form a radical cation by single electron transfer?SET?.Then,the oxonium ion is formed by another SET and deprotonation,which reacts with imidazo[1,2-a]pyridine to generate the product.