MPV reduction using AlIII–calix[4]arene Lewis acid catalysts: Molecular-level insight into effect of ketone binding

Catalytic Meerwein–Ponndorf–Verley (MPV) reduction using AlIII–calix[4]arene complexes is investigated as a model system that requires the bringing together of two different chemical species, ketone and alkoxide, within a six-membered transition state. Two-point versus one-point ketone binding is demonstrated to be the most salient feature that controls MPV catalysis rate. A 7.7-fold increase in rate is observed when comparing reactants consisting of a bidentate Cl-containing ketone and sterically and electronically similar but looser-binding ketones, which are substituted with H and F. The one-point and two-point nature of ketone binding for the various ketones investigated is independently assessed using a combination of structural data derived from single-crystal X-ray diffraction and DFT-based molecular modeling. Using MPV catalysis with inherently chiral calix[4]arenes, the effect of multiple point reactant binding on enantioselectivity is elucidated. A higher denticity of ketone binding appears to increase the sensitivity of the interplay between chiral active site structure and MPV reduction enantioselectivity.

Graphical abstractAl(III)–calix[4]arene complexes act as site-isolated Lewis acid catalysts for homogeneous MPV reduction. Two-point versus one-point binding of ketone reactant is a crucial feature that controls the catalytic rate and enantioselectivity.Figure optionsDownload full-size imageDownload high-quality image (91 K)Download as PowerPoint slideHighlights► Al(III)–calix[4]arene complexes are active site-isolated catalysts for MPV reduction. ► Two-point binding of ketone reactant accelerates rate of catalysis versus one-point binding. ► Electronic and steric requirements at the active site are investigated. ► Interplay between calixarene chirality and MPV reduction enantioselectivity is controlled by rigidity of ketone binding.