The Organocatalytic Asymmetric Synthesis Of Dihydro-Coumarins And ?,?-Disubstituted Unnatural ?-Amino Ester

Part 1The dihydrocoumarin skeleton is present as a structural core in numerous naturally occurring products which have attracted considerable interest because of their various structural and biological activities.Different classes of dihydrocoumarin derivatives have shown biological activities,some have been used as drug candidates.Therefore,the synthesis of these compounds have very important significance.Many methods for the synthesis of dihydrocoumarin derivatives,especially in an asymmetric manner,have been developed,among which organocatalysis has recently been used as an efficient and mild approach.Guided by the donor/acceptor concept,[4+2] cycloaddition reactions of phenol derivatives bearing electrophilic carbon atoms on the ortho-position are most commonly used strategies to generate the dihydrocoumarin core.Despite these advances,the development of new strategies allowing the direct and efficient construction of optically pure dihydrocoumarins bearing versatile functionalities remains a challenging task.Herein,we report our recent advance in this area by applying a novel [3+3] protocol for the synthesis of dihydrocoumarins through an organocatalytic Friedel-Crafts alkylation/lactonization cascade of naphthols with 3-trifluoroethylidene oxindoles.This reaction catalyzed by only 2.5 mol% of a quininederived squaramide catalyst,to afford the corresponding ?-aryl-?-trifluoromethyl dihydrocoumarin derivatives in high yields(up to 99%)with excellent enantio-and diastereoselectivities(up to 98% ee,>20:1 d.r.).Importantly,the lactonization proceeded by nucleophilic attack of the naphthol hydroxyl group at the amide motif of the oxindoles under mild reaction conditions.This protocol represents a new strategy for the formation of dihydrocoumarins by an efficient intramolecular amide C-N bond-cleavage and esterification process.More importantly,the incorporation of a pharmaceutically interesting CF3 group,which can often increase the metabolic stability and bioavailability of the parent compounds into a biologically important dihydrocoumarin skeleton makes this protocol useful in the field of drug discovery.To further exploit the use of the asymmetric Friedel-Crafts alkylation/lactonization protocol,some representative transformations of the products were carried out,these compounds all have potential biological activities.Part 2Enantio-enriched ?,?-disubstituted unnatural ?-amino acid unit presents widely in natural products,drug candidates and multi-functional materials,as an important building block,also has a wide application in organic synthesis.The catalytic enantioselective nucleophilic addition of ?-ketimino esters provides an efficient approach to generate optically active ?-quaternary amino acid derivatives.In the case of asymmetric aza-Friedel-Crafts alkylation of indoles with ?-ketimino esters,a series of indole-containing ?-amino acids bearing tetrasubstituted ?-stereogenic centers could be obtained.Those compounds can be used as potential intermediates for the synthesis of many biologically active natural products and pharmaceutical drugs.Herein,A highly enantioselective aza-Friedel-Crafts alkylation of indoles with cyclic aryl ?-ketimino esters catalyzed by a chiral phosphoric acid has been developed,the corresponding ?,?-disubstituted unnatural ?-amino ester derivatives were obtained in moderate to high yields(up to 85% yield)with high enantioselectivities(up to 93% ee)under mild reaction conditions.Finally,a representative transformation of the addition product was carried out and it can be used to synthesis of ?-amino ester.