Study Of The Green Synthesis Of Chiral Nine-membered Heterocycles And Chiral Acyclic Nucleosides Via The Asymmetric Catalysis

Nine-membered ring skeletons are widely found in natural products and possess different kinds of biological activities.At this stage,the researches on the synthesis of nine-membered rings are progressing slowly,and the synthesis remains a formidable challenge.The lack of efficient methods for synthesizing medium-sized rings has become a bottleneck for developing medium-sized ring chemistry.The appearance of the [5+4] cycloaddition reaction brings in a new idea for the synthesis of ninemembered rings.As a novel five-membered synthon,vinylethylene carbonate has aroused great interest among scientists from the moment it appeared.Our research group has also developed a new catalyzing asymmetric [5+4] cycloaddition reaction in this scientific research wave.We choose substituted vinylethylene carbonates and ortho-quinone methides as substrates and try to carry out [5+4] cycloaddition reaction.Since both substrates have high reactivity,in theory,various cycloaddition products will appear,such as [3+2],[3+4],[5+2],and [5+4],and even the chain products.Through arduous screening of conditions,we finally find suitable reaction conditions.Through the asymmetric [5+4] cycloaddition reaction catalyzed by palladium,the high regioselectivity and enantioselectivity of the reaction are achieved.The reaction allows for the efficient synthesis of various nine-membered benzodioxonines in good yields(up to 88%)with high enantioselectivity(up to 98%).Preliminary research on the machine indicates that the [5+4] annulation occurs through an unusual action of chiral phosphine and achiral palladium catalysts.Intensely worked in nucleoside chemistry for many years,we have blazed a path with our advantages in the field of nucleoside modification and asymmetric catalytic synthesis.We have completed the synthesis of multiple series of different types of chiral nucleosides and have also carried out researches on biological activities,which have contributed to the development of nucleoside chemistry.After the asymmetric [5+4]cycloaddition reactions are realized,we tried to combine the subject with the characteristics of our research group.We hope to use vinylethylene carbonate and ortho-quinone methides to react with N-heteroaromatics such as purines and pyrimidines to obtain chiral acyclic nucleosides.Firstly,we choose vinylethylene carbonate as the allylation reagent and try to carry out asymmetric allylation reactions on purines,pyrimidines,and other N-heteroaromatics.During the reaction process,we need to control the reaction to occur at the C-3 position of the ?-allyl palladium intermediate,and at the same time,need to improve the enantioselectivity of the products.Finally,we find the best ligand for the reaction and completed the asymmetric allylic amination of N-heteroaromatics.The employed procedure allows for the efficient synthesis of various acyclic nucleoside analogs in good yields(up to 96%)and with high enantioselectivities(up to 99%)at a Pd catalyst amount of 0.5 mol%.In addition,these acyclic nucleosides are demonstrated to undergo rapid transformation to a variety of interesting structurally diverse chiral acyclic nucleosides and isonucleosides.Next,we used ortho-hydroxybenzyl alcohols as the precursor of ortho-quinone methides.Under the action of Br?nsted acid,the alcoholic hydroxyl group is removed to generate the ortho-quinone methide intermediates in situ in the reaction.Further,the intermediates undergo a conjugate addition reaction with purines to generate a series of purine acyclic nucleosides.The reaction allows for efficient synthesis of various acyclic nucleoside analogs,with excellent yields of up to 95%,across a broad range of substrates,and the yields were maintained as the reactions were scaled up.Simultaneously,the reaction avoids the use of metal catalysts and reduces the risk of environmental pollution.Increasing the regioselectivity and enantioselectivity of the reaction can improve the atomic economy of the reaction,and reduce waste and avoid pollution,which is what green chemistry advocates.Based on the requirements of green chemistry,we develop a new method for the synthesis of chiral nine-membered heterocycles through asymmetric [5+4] cycloaddition reactions,and then combine with nucleoside chemistry and synthesize chiral acyclic nucleosides.These works promote the development of medium-sized ring chemistry,and accelerate the progress of nucleoside chemistry.