An Enantioselective Cross-Dehydrogenative Coupling Catalysis Approach to Substituted Tetrahydropyrans

Abstract

An enantioselective cross-dehydrogenative coupling (CDC) reaction to access tetrahydropyrans has been developed. This process combines in situ Lewis acid activation of a nucleophile in concert with the oxidative formation of a transient oxocarbenium electrophile, leading to a productive and highly enantioselective CDC. These advances represent one of the first successful applications of CDC for the enantioselective couplings of unfunctionalized ethers. This system provides efficient access to valuable tetrahydropyran motifs found in many natural products and bioactive small molecules.

Recent Advances on Copper-Catalyzed C–C Bond Formation via C–H Functionalization

“…The key step in this transformation was the in situ Lewis acid activation of the nucleophile with the formation of an oxocarbenium electrophile under oxidative conditions (Scheme 3). 35 A Cu(II)-bisoxazoline (BOX) complex was used as the catalyst and DDQ as the oxidant. Interestingly, increasing the steric demand of the ester moiety on the substrates did not improve the stereoselectivity of the reaction.…”

Catalytic enantioselective oxidative coupling of saturated ethers with carboxylic acid derivatives

“…Although impressive progress has been made in enantioselective CDC during the last decade, current studies predominantly focused on N -arylated amine 7–19 and xanthese substrates 20–25 . In contrast, enantioselective CDC of ethers has remained scarce, and the unique existing two examples still focused on specific, activated benzylic and allylic ethers 26,27 . Our group described an enantioselective bimolecular CDC of cyclic benzylic ethers and aldehydes with high enantioselectivity 26 .…”

“…Our group described an enantioselective bimolecular CDC of cyclic benzylic ethers and aldehydes with high enantioselectivity 26 . Scheidt reported a delicate asymmetric intramolecular CDC of allylic ethers with appended β-keto esters, providing substituted tetrahydropyran-4-ones with excellent diastereo- and enantioselectivities 27 . On the other hand, optically pure saturated ethers with diverse α-alkyl substitutions represent ubiquitous structural motifs in numerous bioactive natural products and synthetic pharmaceuticals 28–30 .…”

Catalytic Asymmetric Cross‐Dehydrogenative Coupling of 2H‐Chromenes and Aldehydes

“…To the best of our knowledge, only two examples of enantioselective CDC of ethers have been reported to date. [5,6] In 2014, our group disclosed the first catalytic asymmetric bimolecular CDC of cyclic benzylic ethers with aldehydes with excellent enantiocontrol (Figure 1a). [5] In 2018, Scheidt and co-workers described an elegant Cu(OTf) 2 -catalyzed enantioselective intramolecular CDC of allylic ethers with appended β-ketoesters, furnishing substituted tetrahydropyrones with high yields and enantioselectivity ( Figure 1b).…”

“…[5] In 2018, Scheidt and co-workers described an elegant Cu(OTf) 2 -catalyzed enantioselective intramolecular CDC of allylic ethers with appended β-ketoesters, furnishing substituted tetrahydropyrones with high yields and enantioselectivity ( Figure 1b). [6] Therefore, developing a catalytic asymmetric CDC process of other types of ether skeletons would still be an attractive project to pursue.…”