Studies On Catalytic Enantioselective Diels

Tetrahydrocarbazole has received considerable interest as a building block for the construction of bioactive natural products that often exhibit significant biological activity.Carbazoles and derivatives are also frequently found in organic functional materials as the primary scaffold.It is therefore of particular interest to develop or improve synthetic methods for the controlled synthesis of tetrahydrocarbazole derivatives.Diels-Alder type reactions are one of the most powerful transformations for the construction of six-membered ring structures in organic chemistry,rapidly giving access to cyclic and polycyclic compounds that contain multiple stereocenters.We based our work on the[4+2]cycloaddition reactions of benzoquinones and3-vinylindoles,and report an efficient asymmetric Diels-Alder reaction for the formation of tetrahydrocarbazole derivatives.Chiral phosphoric acid based catalysts derived from substituted BINOL have been previously successfully employed in enantioselective Diels-Alder reactions.In2006,Akiyama developed tan aza-Diels-Alder reaction catalyzed by a chiral phosphoric acid derived from BINOL,using 2-hydroxyphenyl imines with Brassard’s diene.In the same year,he also extended his results utilizing imine substrates.Terada also showed a hetero-Diels-Alder reaction of ethyl glyoxylate and dienes to synthesize dihydropyrans in 2009.However,when one considers the use of chiral phosphate metal catalysts with multiple coordination sites being possible,often as alkali and alkaline-metal salts,one can realize why chiral phosphates as ligands for asymmetric catalysis could be attractive.Inanaga’s group pioneered the utilization of chiral lanthanide phosphates and a series of other chiral phosphates in asymmetric Diels-Alder reactions.Later,Feng and Zhu reported the hetero-Diels-Alder reactions with other chiral BINOL derived catalysts.In addition,our group used metal phosphates as catalysts to develop new enantioselective Diels-Alder Reactions.In addition,chiral thioureas,a very successful bifunctional acid-base organocatalyst,has been reported to catalyze DA reactions of3-vinylindoles with different representative dienophiles for obtaining optically active tetrahydrocarbazole derivatives.However,effective catalysts have rarely been reported for the generation of optically active tetrahydrocarbazole derivatives in DA reactions.This inspired our exploration of a catalytic system for preparing enantioselective tetrahydrocarbazole skeletons utilizing the Diels-Alder reaction.We synthesized some efficient catalysts by chiral（R）-BINOL phophoric acids and their metal complexes to catalyze asymmetric Diels-Alder reaction for obtaining tetrahydrocarbazole deriviates.We initiated our study for the asymmetric Diels-Alder reaction by screening various chiral metal BINOL phosphate catalysts.After optimization of reaction conditions for this reaction,the best condition was obtained showing 96%ee when using methylcyclohexane as the solvent and chiral magnesium phosphate salt Mg[P4]₂as the catalyst at-25 ^oC.With the optimum reaction conditions in hand,we explored the substrate scope of benzoquinones and3-vinylindoles.As shown in data,this transformation features wide substrate scope,excellent enantioselectivities and mild conditions.Especially,an electron-withdrawing group（F,Br,Cl）and electron-donating group（Me,OMe）at the 4,5,6,7-position of the indole nucleus was well tolerated.On the basis of above study and the catalyst structural information,we speculated a possible transition state for the asymmetric Diels-Alder reaction catalyzed by chiral magnesium phosphate salt.Beyond that,since the product is easy to be aromatized in air,its derivative was obtained directly by reduction reaction to make the tetrahydrocarbazole skeleton more stable.In conclusion,a mild Diels-Alder reaction catalyzed by a chiral metal magnesium phosphate complex in high enantioselectivity and efficiency was established.It provides a basic method for the formation of tetrahydrocarbazole derivatives.Simultaneously,mono activation is also proven to be effective on benzoquinones substrates for affording highly asymmetric DA reaction.We can apply this reaction to synthesis and application of various natural products and organic materials.Further study is in progress and will be reported in due course.