Phosphine-catalyzed Transformations Of ?,?-unsaturated Compounds And Dearomative Cycloaddition Reaction Of Indoles

Over the past decade,phosphine-catalyzed reactions have developed a research hotspot in the field of organic synthesis,which provide highly reliable tools for the construction of important various carbo-and heterocycles.Therefore,the development and application of nucleophilic phosphine-catalyzed reactions have attracted more and more interests of chemists.In particular,different types of novel chiral phosphine catalysts have been developed and employed in cornucopias of organic transformations,leaving a new way to the total synthesis of natural products?pharmaceutically active molecules and other bioactive moleculars.In recent years,we developed several new phosphine catalysts,such as chiral sulfinamide phosphine Xiao-Phos,Chiral sulfinamide bisphosphine Wei-Phos and 3,5-difluoromethylbenzamide phosphine Peng-Phos,which have shown good performance in enantioselective intramolecular Rauhut-Currier reactions,intermolecular Rauhut-Currier reactions and allylation reactions,respectively.Based on our developed chiral phosphine catalysts,we tried to further expand the potential of these catalysts to explore asymmetric new reactions.The main results are divided into the following several aspects:1.Functionalized tetrahydropyridines by enantioselective phosphine-catalyzed aza-[4+2]-cycloaddition of N-Sulfonyl-1-aza-1,3-dienes with vinyl ketonesWe report that the stereoselective aza-[4+2]-cycloaddition process of N-sulfonyl-1-aza-1,3-dienes and vinyl ketones can be realized under the catalysis of chiral bifunctional phosphines P2.6 or P2.7,furnishing functional trifluoromethylated tetrahydropyridines in moderate to good yields?up to 97%?with high diastereo-?up to>20:1 dr?and enantioselectivities?up to 97%ee?.Moreover,in the presence of a chiral sulfinamide phosphine P2.2,chalcone-derived 1,3-azadienes could also undergo the annulation reaction with methyl vinyl ketone,giving the corresponding chiral tetrahydropyridines in moderate yields with excellent enantioselectivities?up to 92%ee?.Mechanistic study indicated that the phosphonium enolate intermediate plays a dual role,acting not only the reaction partner for the cycloaddition but also as a kind of co-precatalyst for the second aza-Michael addition step.2.Ferrocene derived bifunctional phosphine-catalyzed asymmetric oxa-[4+2]-cycloaddition of?-Substituted allenones with enonesWe introduce a highly effective ferrocene derived bifunctional phosphine-catalyzed enantioselective[4+2]-cycloaddition of?-substituted allenones with perfluoroalkyl enones to generate a series of CF₃-containing dihydropyrans in high yields with excellent enantiomeric ratios?90-99%ee?and functional group tolerance.Notably,by employing benzocyclic?,?-enones,a diverse range of optically enriched polycyclic molecular frameworks were constructed in high enantioselectivities.Importantly,the method is also applicable to?,?-unsaturated?-keto ester and?-cyano-enone.3.Catalytic enantiodivergent Michael addition by subtle adjustment of achiral amino moiety of dipeptide phosphinesWe have developed two new chiral dipeptide phosphine catalysts,which showed good performance in enantioselective addition of pyridazinones to?,?-enones.The enantioselectivity could be switched by subtle variation of the amino moiety of chiral dipeptide phosphine catalyst without changing any stereocenter of the phosphine catalyst.Both enantiomers of N²-alkylated pyridazinones can be obtained in high yields?up to 99%?with good to excellent enantioselectivity?up to 99%ee?by the use of P4.5and P4.8,respectively.The detailed reaction mechanism and the origins of the enantioselectivity were investigated by means of DFT calculations.The results suggest that the difference in the relative strength of the N-H…O hydrogen-bonding interactions is responsible for the enantioselectivity reversal observed experimentally.4.Phosphine-catalyzed functionalization of?-fluoroalkyl?,?-enonesA novel phosphine catalyzed the difunctionalization of TMSN₃ to?-fluoroalkyl?,?-enones has been developed which generates a series of?-amino?-diazocarbonyl compounds in moderate to excellent yields?33-94%yield?.In contrast,the corresponding azide compounds would be furnished with the use of?,?-disubstituted enones or 3-aroyl acrylates by the direct azidation reaction.Furthermore,with the use of bifunctional phosphine P2.7 as a chiral catalyst,which providing a facile access to chiral?-amino?-diazocarbonyl compounds in good yields?58-91%?with excellent enantioselectivities?72-85%ee?.Mechanistic studies provide experimental evidence for the key reaction intermediate-triazole.5.Phosphine-catalyzed enantioselective dearomative[3+2]-cycloaddition of 3-nitroindolesWe have disclosed the first example of phosphine-catalyzed enantioselective dearomative[3+2]-cycloaddition between 3-nitroindoles and allenoates which provides a new,facile,and efficient strategy for the construction of chiral cyclopentaindoline alkaloid scaffolds in moderate to excellent yields?up to 98%?with high enantioselectivities?up to 95%ee?.This method is very promising because the versatile transformations of the products into other structurally diverse polycyclic indolines were also feasible.