Catalytic Enantioselective Synthesis of 1,1-Disubstituted Isochromans

In the presence of a newly developed conjugate-base-stabilized carboxylic acid (CBSCA) catalyst, β-aryl ethanols containing a hydrogen bond donor site undergo enantioselective oxa-Pictet-Spengler reactions with ketals to provide 1-aryl,1-alkyl-isochromans in good to excellent yields and enantioselectivities. The minimization of catalyst aggregation was identified as a critical factor in the overall reaction, with lower catalyst loadings resulting in significant improvements in enantioselectivity. Detailed kinetic, nonlinear effect, and DFT studies reveal that catalyst aggregation plays a key role in modulating reactivity and enantioselectivity, and that C-C bond formation via an intramolecular addition to a catalyst-bound oxocarbenium ion constitutes the enantiodetermining step. Energy decomposition and noncovalent interaction analyses further delineate the steric and electronic factors governing asymmetric induction. These findings establish a general platform for the catalytic asymmetric synthesis of tertiary ether-containing heterocycles and offer fundamental insight into the mechanism of chiral Bro̷nsted acid catalysis.