Catalytic Enantioselective Oxidative Cross-Coupling Of Benzylic Ethers With Aldehydes

The development of a efficient method towards C-C bond-formation prcesses is of great interest to chemists. The cross-dehydrogenative coupling (CDC) of two C-H bonds is a particularly elegant process.The nucleophilic addition to a prochiral cyclic oxocarbeniumion provides aefficient strategy to synthesis a-substituted oxygen heterocycles, which are common structural motifs in complex natural products and biologically active molecules. Although various reliable methods have been developed for diastereoselective additions to oxocarbeniumions, only a few catalytic enantioselective variants have been reported.Oxocarbeniumions are usually generated in situ through the acid-mediated collapse of cyclic acetals; however, these methods suffer from extra steps that are required for substrate construction. On the other hand, the formation of oxocarbenium ions can be initiated by the selective oxidation of a C-H bond adjacent to an oxygen atom. This strategy provides excellent opportunities to access a target compound from readily accessible precursors with a minimal amount of intermediary refunctionalizations and with high atom economy.Given the importance of O-heterocyclic motifs in biologically relevant molecules and the fact that the asymmetric alkylation of aldehydes would afford heterocycles with multiple stereogenic centers, we herein describe the enantioselective oxidative cross-coupling of cyclic benzylic ethers with aldehydes.The enantioselective oxidative cross-coupling CDC of isochroman with valeraldehyde was selected as the model reaction for optimization, and the researh mainly contains five fields as follows:type of catalyst, type of acid, type of additive, different temperature and type of solvent. Then we got the optimized conditions. With the optimized conditions for the one-pot reaction inhand, the scope of the enantioselective oxidative coupling of isochroman with various aldehydes was extensively investigatedIn summary, we have developed the one-pot oxidative and enantioselective cross-coupling reaction of cyclic benzylic ethers with aldehydes. The reaction features high enantioselectivity, good yields, excellent functional-group tolerance, wide compatibility of structurally and electronically varied benzylic ethers, making it applicable to structurally complex compounds.