Construction Of Quaternary Carbon Containing Cyclobutanes Via Asymmetric Enamine-formation Reaction Of 1,3-cyclobutanediones

Chiral quaternary carbon containing cyclobutanes are important structural units in many bioactive natural products,as well as the characteristic structural units for the discovery of new drugs and dominant framework for drug molecular design.Therefore,it is of great significance and broad application prospect to develop novel methods for the efficient and enantioselective construction of structural units.This thesis aims to provide a new asymmetric catalytic method for the construction of chiral quaternary carbon containing cyclobutanes via the catalytic enamine-formation reaction of prochiral cyclobutane-1,3-dione and primary amine.Starting from the prochiral 2,2-disubstituted cyclobutane-1,3-dione,the amine component of the reaction was firstly investigated.It was found that when 2,4,6-trimethylaniline,which with moderate nucleophilic and steric hindrance,was used as the amine source,the reaction could obtain the target product with good yield and enantioselectivity.After the investigation of a series of chiral phosphoric acids,the chiral binaphthol skeleton derived catalyst(R)-TRIP was found to be the best choice.The solvent effect investigation revealed that the reaction showed the best reactivity and enantioselectivity in toluene.As the reaction temperature had no significant effect on the enantioselectivity of the reaction,so we chose 25 ℃ as the optimal temperature for the reaction.After the investigation of different molecular sieve additives,it was found that the reaction rate was obviously accelerated when 5(?)molecular sieves was added.Under the optimal conditions,we investigated the substrate scope of the reaction.A series of methyl-substituted cyclobutane-1,3-dione could be well tolerated and yield the target products with the highest yield of 99%and 92%ee values,but the reaction is not very compatible with non-methyl-substituted cyclobutane-1,3-diones.At the same time,we have also tried to elaborate the thus obtained products to give a series of fully substituted cyclobutenone derivatives,which vividly demonstrated the synthetic potential of the current method.It is worth mentioning that the chiral phosphoric acid catalyzed condensation of1,3-cyclobutanedione with the carbony-amine of primary amine developed in this paper represents the first catalytic desymmetric reaction of prochiral 2,2-disubstituted cyclobutane-1,3-dione.