Asymmetric[4+2]-Cycloaddition Reaction Of Ortho-Alkenyl Naphthols/Phenols And Ortho-Quinone Methides To Synthesize 2,3,4-Trisubstituted Chromans

Chromans constitute the core of numerous natural products and synthetic analogs displaying an extensive array of biological activities.Chiral chromans have played an important role in various therapeutic areas including cardiovascular diseases,hypertension,diabetes,obesity,cancer,central nerve system and endocrine disorders,and infectious diseases.Because their saturated heterocycle,chroman compounds have up to three consecutive chiral centers,named 2,3,4-trisubstituted chroman compounds,which are existed with diverse stereo structural forms in natural products and biologically active molecules.But different enantiomers and diastereomers usually have different or even opposite biological activity.Therefore,it is necessary to develop an efficient and convenient method for the synthesize of stereospecific chromans.Ortho?alkenyl phenols,as an excellent two-carbon synthon,have been exploited for the asymmetric synthesis of various(hetero-)cyclic compounds through the corresponding intermolecular stereoselective catalytic cycloaddition.The new strategy has received widespread attention in recent years.In this work,chiral phosphoric acids are used to catalyze ortho?alkenyl naphthols/phenols with in-situ generated orthoquinone methides(o-QMs)in a [4+2]-cycloaddition reaction to synthesize 2,3,4-trisubstituted chromans in high yields with excellent enantio-and diastereoselectivities(33 examples,up to 99% yield,98% ee,>20:1 dr).Notably,this methodology not only enabled access to the trans-cis chiral trisubstituted chromans from 1-alkenyl-2-naphthols,but also is compatible with 2-alkenyl-1-naphthols and phenols to deliver trans-trans chiral trisubstituted chroman.This strategy has validated the compatibility of the [4+2]-cycloaddition for 2-alkenyl-1-naphthols with ortho-quinone methides,which expand the substrate scope of the [4+2]-cycloaddition.Meanwhile,it provides a new method to construct chroman compounds with different configuration by adjusting the substrate and catalyst.