Catalytic Enantioselective Cross-Dehydrogenaive Coupling Of 3,6-Dihydro-2H-pyrans With Aldehydes

Enantiopure ?-substituted 3,6-dihydro-2H-pyrans(DHPs)and tetrahydropyrans(THPs)are ubiquitous structural motifs in numerous biologically active natural products and synthetic pharmaceuticals.How to efficiently construct photoactive?-substituted 3.6-dihydro-2H-pyran and tetrahydropyran is a problem that organic chemists around the world need to solve.The conventional synthesis method mainly uses a multi-step conversion with an optically active intermediate to obtain a chiral?-substituted oxygen-containing heterocyclic compound.This multi-step synthesis method does not satisfy the step economics of the organic synthesis method,and in some cases,the method also has significant limitations on the universality of the substrate.Therefore,the development of simpler,more direct and more efficient methods for the synthesis of chiral a-substituted 3,6-dihydro-2H-pyrans and tetrahydropyrans has attracted much attention from many organic chemists.The catalytic asymmetric synthesis of existing chiral alpha-substituted 3,6-dihydro-2H-pyran and tetrahydropyrans relies primarily on the enantioselective cyclization of the pre-functionalized olefmic substrate.Heterocyclic building strategies such as asymmetric intramolecular olefin alkoxylation,asymmetric Prins cyclization,and asymmetric[4 + 2]cycloaddition reactions.In view of the fact that the six-membered cyclic ether skeleton can be rapidly prepared by many methods,it is simple and easy to obtain.Therefore,many organic chemists can more easily and rapidly synthesize chiral a-substituted 3.6-dihydro-2H-pyran and tetrahydropyran compounds by asymmetric nucleophilic addition reaction of oxonium ions..It is fascinating to obtain chiral a-substituted oxygen-containing heterocyclic compounds with different structures by using various core nucleophilic strategies using various nucleophilic diversification strategies,because it not only rapidly increases the complexity of the molecule.It will also increase the diversity of stereochemistry.In recent years,the catalytic asymmetric oxidation functionalization strategy of C(sp3)-H bonds adjacent to heteroatoms has become a powerful tool for the new C-C bond forging process.In this case,the advantage of the enantioselective cross-dehydrogenation coupling(CDC)reaction is particullarly pronounced,especially in terms of economic issues.In the past decade,the asymmetric CDC reaction of N-arylated cyclic amines has yielded impressive results.However,the catalytic asymmetric CDC reaction of the corresponding ethers remains a daunting challenge.The range of cyclic ethers is limited to benzopyrans.To the best of our knowledge,the catalytic asymmetric CDC reaction of 3,6-dihydro-2H-pyran and tetrahydropyrans has never been reported so far.Therefore,we studied and achieved a catalytic asymmetric cross-dehydro coupling reaction of the first 3,6-dihydro-2H-pyran skeleton and aldehyde.In this paper,optically active ?-substituted 3,6-dihydro-2H-pyran is obtained mainly by catalytic asymmetric oxidation functionalization strategy of ?-position C(sp3)-H bond of hetero atom.First,the ?-position C(sp3)-H bond of the hetero atom in the substrate is oxidized,and then the unstable oxidized intermediate is captured by the "acetal pool" strategy to form a relatively stable acetal,and then The asymmetric nucleophilic addition of the acetal intermediates enables the efficient synthesis of asymmetric ?-substituted 3,6-dihydro-2H-pyrans as follows:At present,there are few articles on the catalytic enantioselective synthesis of cyclic ether molecular skeletons.In 2018,Scheidt reported the enantioselective intramolecular CDC reaction of allyl ethers with additional ?-ketoesters.A substituted-controlled substituted tetrahydropyran-4-one compound.Our group also previously reported the intermolecular CDC reaction of 2-H benzopyrans.However,the substrate range of the intermolecular reaction process is limited to benzopyrans.Therefore,we want to directly use the 3,6-dihydro-2H-pyran skeleton as a substrate to achieve chiral synthesis of ?-substituted 3,6-dihydro-2H-pyrans.Our model reaction is 4-phenyl-3,6-dihydro-2H-pyran as a substrate,using DDQ as the oxidant,a chiral secondary amine as the catalyst,and an aldehyde as the nucleophile.Under the above conditions,we screened the catalyst,additive,solvent,temperature,oxidant and other conditions to determine the optimal reaction conditions.Next,we expanded the range of the substrate and found that different 4-position aryl substituents:phenyl,thiophene,etc.can be converted with high ef'ficiency and selectivity;when the 4-position is phenyl,different The aldehyde as a nucleophilic reagent has good adaptability to the reaction,and can obtain a photoactive product with high yield and high selectivity.The above proves that the substrate of the method has a wide application range.Finally,we verified the reaction mechanism by separation of the reaction intermediates and further experiments.In summary,we achieved the chiral synthesis of ?-substituted 3,6-dihydro-2H-pyrans by oxidation of the "acetal pool" strategy for the first time.In this process,DDQ acts as an oxidant to oxidize the ?-position C(sp3)-H bond of the oxygen atom,and then,under the catalysis of a chiral secondary amine,achieves an asymmetric nucleophilic addition reaction to the oxonium ion,and finally obtains a photoactive activity.Product.The reaction has a simple operation,mild reaction conditions,good functional group tolerance,and wide compatibility of various 3,6-dihydro-2H-pyran and aldehyde components,thereby synthesizing optically pure?-The substituted 3.6-dihydro-2H-pyran provides a practical and economical process.