Stereoselective Synthesis Of Para-quinomethanes Derivatives And Bicyclic Cyclopentenes Derivatives

Objective:As important structural fragments,para-quinomethanes and cyclopentenes exist in natural products,drug molecules and even functional materials widely.Therefore,it is crucial to develop new methods to construct above compounds with high stereoselectivity.This paper aims to(1)obtain para-quinomethanes derivatives with higher enantiopurity by designed phase transfer catalysts;(2)construct new bicyclic cyclopentenes with high diastereoselectivity through a one-step tandem reaction.The products were further derivatized to explore the practicality of the reaction.Methods:Enantioselective synthesis of para-quinomethane derivatives:(1)Natural sources of cinchonaine,cyclohexanediamine,cyclopentanol,squarate,bromide and so on were used for starting materials to synthesize the target catalysts through a series of reactions.(2)The phase transfer catalysts were applied to the asymmetric Michael addition reaction of paraquinomethanes and phenacylmalononitrile,and the products with better enantioselectivity was obtained by optimizing the reaction conditions.Squaramide catalysts were used in the asymmetric Michael addition reaction of para-quinomethanes and pyrazolone or nitromethane to establish the reaction path and optimize the reaction conditions.Diastereoselectivie synthesis of bicyclic cyclopentenes:(1)With maleimide and phenacylmalononitrile as model substrates,and highly diastereoselective products were synthesized by a series of Michael/Aldol/Rearrangement reactions and condition optimizations.Further derivatization reaction proved the practicality of the reaction,and the configuration of the product was determined by X-single crystal diffraction.(2)The synthesized organocatalysts of squaramide which were synthesized in the laboratory before were applied to the asymmetric Michael addition reaction of maleimide and phenacylmalononitrile,and the optimal reaction scheme was determined by optimizing the reaction conditions with medium enantioselectivity.Results:Enantioselective synthesis of para-quinomethane derivatives:(1)A total of 17 phase transfer catalysts were synthesized,of which 4 novel bifunctional catalysts(3a-3d)were not reported in literature,and their structures were characterized by 1H-NMR,13CNMR,IR,HRMS;(2)The chiral phase transfer catalyst 2d was used for the asymmetric 1,6conjugated addition reaction of para-quinomethanes and phenacylmalononitrile,and the ee value of the product was up to 26%.Other(thio)squaramide catalysts were used in the asymmetric Michael addition reaction of para-quinomethane to pyrazolone or nitromethane,and the reaction proceeded smoothly with yields of 53%and 22%respectively.Diastereoselectivie synthesis of bicyclic cyclopentenes:(1)Annulation of phenacylmalononitriles with maleimides offered a highly diastereoselective bicyclic cyclopentenes containing a CN-substituted all-carbon quaternary center by cascade Mi chael/aldol/rearrangement reaction.A series of structural analogs with differentsubstituents were synthesized with 99%yield and up to 99:1 dr.The structure of the product was confirmed by 1H-NMR,13C-NMR,HMBC、HSQC,IR,and HRMS,and the possible reaction mechanism was inferred by single crystal diffraction analysis of key intermediate and DFT calculation;(2)Chiral catalyst 4d was used for asymmetric Michael addition reaction of maleimide and phenacylmalononitrile with 43%ee.Conclusion:Enantioselective synthesis of para-quinomethane derivatives:The synthesized squaraine phase transfer catalysts that have not been reported in the literature can provide a reference for the design and synthesis of similar catalysts,and apply them to the asymmetric catalysis of para-quinomethanes and phenacylmalononitrile.Initial effect has been achieved in the synthesis,and a new catalytic system has been obtained,which enriches the types of chiral compounds of para-quinomethanes,but its enantioselectivity needs to be further improved;The asymmetric study of para-quinomethanes and pyrazolone or nitromethane,its enantioselectivity needs to be further improved.Diastereoselectivie synthesis of bicyclic cyclopentenes:the cascade Michael/aldol/rearrangement reaction of maleimide and phenacylmalononitrile can proceed smoothly to obtain bicyclic clocyclopentenes with excellent diastereoselectivity.At the same time,a mild and practical method has been established to quickly prepare such compounds through research.This scheme provides a new idea for the development of drugs with innovative chemical backbones;Squaramide catalyst 4d can be used for the asymmetric Michael addition reaction of maleimide and phenacylmalononitrile well to obtain products with moderate enantioselectivity.