Stereoselective Pudovik reaction of aldehydes, aldimines, and nitroalkenes with CAMDOL-derived H-phosphonate

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Optically pure phosphonates featuring an α-functional motif serve as core structures of versatile pharmaceuticals. Pudovik reaction employing P-stereogenic H-phosphonates derived from recyclable chiral auxiliary (CA) is one of the most practical and efficient asymmetric synthetic strategies. Although several centre and axial CAs have been investigated in this field, the development of novel chiral H-phosphonates has remained largely unexplored over the past 25 years. Here, we developed a kind of H-phosphonate (CAMDOL-PHO) derived from camphor-derived 2,3-diol (CAMDOL). Stereoselective Pudovik reactions of CAMDOL-PHO with diverse aldehydes, aldimines, and nitroalkenes were well developed, affording a library of molecules of α-hydroxyl, α-amino, and β-nitro phosphonates respectively with high dr values (up to 99:1) and yields (up to 97%) as well as broad scopes. Comparative DFT and experimental studies demonstrated that CAMDOL-PHO possessed significant superiority to install the P-adjacent C-stereogenic centre, mainly benefiting from its unique diphenyl-substituted camphor skeleton with an angular methyl group.