Catalytic Asymmetric 1,6-conjugate Addition Of Para-quinone Methides(p-QMs)

Chiral diarylmethane derivatives are widely found in medicines and natural products,such as histamine H1 receptor antagonist clomastine,(S)-neobenodine and so on.In the past few decades,the development of asymmetric synthesis of chiral diarylmethane derivatives with simple starting materials has attracted considerable attention.para-Quinone methides(p-QMs)units exist in a variety of natural products such as fungal metabolites,terpenes,and plant pigments.As a result of the existence of zwitterionic resonance structure and have intrinsic electrophilic reactivity of p-QMs,highly reactive transient p-QMs species generated in situ are implicated in many chemical,medicinal,and biological processes such as lignin biosynthesis,enzyme inhibition,and DNA alkylation and cross-linking.Due to the high reactivity of p-QMs,the asymmetric 1,6-conjugate addition of p-QMs to synthesize chiral diarylmethane derivatives is an effective way.At present,studies on 1,6-conjugate addition reactions of p-QMs have been reported,but most of these reported reactions have focused on the formation of tertiary stereocenters and have strict requirements on the substrate.p-QMs must have two identical electron-donating substituents at the α-position of the oxygen atom(mostly tert-butyl)in order to obtain good yield and enantiomeric excess(ee),these limitations severely limit the the diverse construction of diarylmethane derivatives.Therefore,it is of great significance to break through this limitation and develop an asymmetric catalytic simple substrate p-QMs to construct a quaternary stereocenters to achieve the diverse construction of diarylmethane derivatives.In this paper,we mainly use p-QMs to catalyze asymmetric 1,6-conjugate addition to synthesize diarylmethane derivatives bearing all-carbon quaternary stereocenters.Compared with the common asymmetric 1,4-conjugated addition of ortho-quinone methides(o-QMs),the stereoselective control of 1,6-conjugated addition of p-QMs is relatively difficult,mainly because the reaction center of the substrate is far away from the stereocenter.In addition,compared with the asymmetric formation of tertiary stereocenters,the formation of all-carbon quaternary stereocenter has the problems of low reactivity and difficulty in stereocontrol due to the larger steric hindrance.Therefore,the catalytic asymmetric 1,6-conjugate addition of p-QMs to construct all-carbon quaternary stereocenters is still full of challenges.Initially,our model reaction selected δ-phenyl-δ-cyano disubstituted p-QMs as the substrate and diphenyl malonate as the nucleophile.Under the above conditions,we screened the reaction temperature,solvent,catalyst,additives and other conditions to determine the best conditions for the reaction.With the optimized conditions in hand,the scope of malonates was next explored.It was found that the system is well compatible with p-QMs substrates with different substitution positions and different electron substitution effects.The diphenyl malonate with different substitution effects on the benzene ring also has good adaptability to this reaction,and has achieved relatively high yield and ee.In addition,dibenzyl phthalate can also obtain high yield and ee value under this condition,which proves that the method has a wide application range.Subsequently,we studied the reaction mechanism through a control experiment and prepared an N-methylated catalyst.It was found through experiments that the amide N-H bond is very important for the stereoselectivity of the reaction.Finally,combined with the relevant literature,a plausible transition state is proposed.In summary,we have successfully developed a new method for the construction of chiral diarylmethane derivatives through the catalytic asymmetric 1,6-conjugate addition of simple substrate p-QMs.This method has good substrate universality and strong functional group tolerance,and provides a direct and effective way for the synthesis of drugs or drug intermediates containing chiral diaryl stereocenters.