Chiral Proton Shuttle Catalysts:Design & Applications On Asymmetric Insertion Reactions

Hydrogen shift widely exists in organic transformations.Due to the features of small sizes,fast rates and uncertain pathways,asymmetric hydrogen shift is hard to be achieved.Although some asymmetric proton transfers have been realized by enzymes,it is still very difficult to directly induce the asymmetric proton transfers of active intermediates by artificial chiral catalysts nowadays.Transition-metal-catalyzed asymmetric carbene insertion reaction into X?H(X=N,O,S,P,etc.)bonds is an efficient method of constructing C?X bonds.The chirality-determining step of such transformation is an asymmetric proton transfer of highly active and sensitive ylide intermediates,which could rarely be well-catalyzed by traditional chiral metal complexes.Thus,taking asymmetric X?H insertion reactions as a starting point,we tried to clarify the mechanism of asymmetric proton transfers in the insertion reaction.With the insights,we developed a series of novel chiral proton shuttle catalysts,which could directly induce the asymmetric proton transfers of several challenging insertion reactions.We firstly investigated the asymmetric N?H insertion reactions catalyzed by copper complexes of chiral spiro bisoxazolines.The asymmetric N–H insertion reactions of numerous?-alkyl-?-diazoacetates and anilines were achieved with excellent enantioselectivities(up to 98%ee).The detailed mechanism study supports that asymmetric N–H insertion reaction is a stepwise transformation,and the proton transfer of ylide intermediates is the rate-determining step.We came up a concept of chiral proton shuttle catalysts,and proposed that the asymmetric proton transfers of active intermediates could be directly induced through the proton-trapping and proton-releasing of chiral proton shuttle catalysts.We designed and synthesized a series of spiro phosphoric acids(SPAs)as the first generation of chiral proton shuttle catalysts.The P=O part was proposed as proton-acceptor while the P?OH part can serve as proton-donor.Meanwhile,the6,6'-positions of SPAs could be derived by introducing substituents,which could tune SPAs'chiral inducing abilities.Using SPAs as chiral proton shuttle catalysts,we accomplished the rhodium(II)catalyzed asymmetric N?H insertion reactions of?-diazoesters and Boc NH₂ with high enantioselectivities(90?95%ee),high yields(85?97%yield),fast reaction rate(in 1 min)at low catalyst loading(as low as to 0.1 mol%).The achiral dirhodium carboxylates is responsible for decomposition of diazo substrates and generation of ammonium ylide intermediates,while the SPAs catalyze the asymmetric 1,2-proton transfer of ylides and afforded high enantioselectivities.Comparing to the tranditional chiral complex catalysts,the cooperative catalysts involving chiral proton shuttles could significantly improve the reactivities and enantioselectivities.We developed the first highly enantioselective N?H insertion reaction of?-diazoketones by the cooperative catalysis of dirhodium(II)carboxylates and chiral spiro phosphoric acids.The insertion reaction provides a new access to versatile chiral?-aminoketones with fast reaction rates(in 1 min),good yields(up to 97%yield)and high enantioselectivities(86?95%ee)under mild and neutral conditions.Chiral proton shuttle catalysts significantly expanded the substrate scope of asymmetric insertion reactions.We developed the first highly enantioselective S–H insertion reaction by cooperative catalysis of dirhodium(II)carboxylates and chiral spiro phosphoric acids(SPAs)under mild and neutral reaction conditions with fast reaction rates,high yields(77–97%yields),and excellent enantioselectivities(up to 98%ee).The catalytic S–H bond insertion reaction provides a highly efficient method for the synthesis of chiral sulfur-containing compounds and advances the synthesis of sulfur-containing drug(S)-Eflucimibe.Taking the asymmetric S–H inserton as model reaction,we investigated the mechanism of the asymmetric proton transfer catalysed by chiral proton shuttle catalysts.Firstly,a systematical study using ³¹P NMR and in situ FT-IR spectroscopy excluded the possibility of in situ generated chiral dirhodium(II)spiro-phosphates,verified that the SPAs performed as independent chiral proton shuttle catalysts.Secondly,DFT calculations showed that the activation energy of the proton transfer could be remarkably reduced by SPAs,so that the SPAs could catalyze the asymmetric proton transfers efficiently.Besides the asymmetric X?H insertion reactions,we further introduced the chiral proton shuttle catalysts into the rhodium(II)catalyzed intermolecular asymmetric C(sp²)?H insertion reactions of?-diazoesters and substituted benzene rings.High enantioselectivities(up to 97%ee)were achieved,and a range of chiral?-biarylesters were obtained.