Rational Design of Simple Organocatalysts for the HSiCl Enantioselective Reduction of (E)--(1-Phenylethylidene)aniline.

Prolinamides are well-known organocatalysts for the HSiCl reduction of imines; however, custom design of catalysts is based on trial-and-error experiments. In this work, we have used a combination of computational calculations and experimental work, including kinetic analyses, to properly understand this process and to design optimized catalysts for the benchmark (E)--(1-phenylethylidene)aniline. The best results have been obtained with the amide derived from 4-methoxyaniline and the -pivaloyl protected proline, for which the catalyzed process is almost 600 times faster than the uncatalyzed one. Mechanistic studies reveal that the formation of the component supramolecular complex catalyst-HSiCl-substrate, involving hydrogen bonding breaking and costly conformational changes in the prolinamide, is an important step in the overall process.