Efficiency in nonenzymatic kinetic resolution

Abstract

The Walden memorial at the Technical University in Riga is pictured in the frontispiece to mark the recent centennial of the Walden inversion. This is a rare public monument to key events from the first era of exploration in stereocontrolled synthesis, and may be the only such monument to use the language of organic chemistry expressed at the molecular level. The reaction of racemic substrates with chiral nucleophiles is one of many methods currently known to achieve kinetic resolution, a phenomenon that ranks as the oldest and most general approach for the synthesis of highly enantioenriched substances. The first nonenzymatic kinetic resolutions as well as the original forms of the Walden inversion were studied in the 1890s. All of these investigations were conducted within the first generation following the demonstration that carbon is tetrahedral, and provided abundant evidence that the principles and importance of enantiocontrolled syntheses were understood. However, a reliable, rapid technique to quantify results and guide the optimization process was still lacking. Many decades passed before this problem was solved by the advent of HPLC and GLPC assays on chiral supports, which stimulated explosive growth in the synthesis of nonracemic substances by kinetic resolution. The Walden monument is accessible to passers-by for hands-on inspection as well as for contemplation and learning. In a similar way, kinetic resolution is experimentally accessible and can be thought-provoking at several levels. We follow the story of kinetic resolution from the early discoveries through fascinating historical milestones and conceptual developments, and close with a focus on modern techniques that maximize efficiency.