Kinetics, Thermodynamics, and Emergence in Stereoediting Reactions

Conspectus The selective formation of one stereoisomer over another is a long-standing challenge in organic chemistry. Conventionally, the configuration of a stereogenic center is defined during bond forming molecular assembly steps and thereafter treated as a static component of the molecular structure. One isomer is often more accessible than others, because it can be obtained directly from natural sources, because synthetic strategies to access certain stereochemical patterns are more efficient than others, or because substrate-based steric and electronic biases preclude certain reaction outcomes. In such cases, the ability to revise the stereochemistry without altering the underlying molecular skeleton could parlay more accessible products directly into more challenging targets. In this Account, we describe our efforts to develop stereocenter editing tools to enable the interconversion of stereoisomers with a predictable and tunable selectivity. Stereoediting methods developed by our lab leverage radical intermediates accessed by sequential H atom abstraction and donation steps promoted by a range of different H atom transfer reagents. Modern photoredox methods enable access to reactive radical intermediates under mild reaction conditions, serve as an orthogonal stimulus to induce dynamic character from otherwise static structures, and provide ample fuel to drive contra -thermodynamic product composition when mechanistically feasible. The first methods developed by our lab targeted secondary alcohol stereogenic centers located ubiquitously in complex chiral molecules. By varying catalyst identity and reaction conditions, product distributions can either reflect a thermodynamic equilibrium or reach an out-of-equilibrium steady state defined by kinetic factors. In the latter case, catalyst control enables contra -thermodynamic product distributions to form and offers the best prospects for tunable site- and stereocontrol. Our laboratory has been particularly interested in applications of stereoediting in rare sugar synthesis where innovative solutions are required to address the site-selectivity challenges presented by minimally protected glycan substrates. Subsequent efforts in our laboratory have led to the development of stereoediting methods targeting unactivated tertiary stereogenic centers for which there are few other methods or synthetic routes for stereorevision. Here, stereoediting methods offer substantial flexibility for molecular construction and can formally extend the scope of stereochemical outcomes accessible from powerful existing synthetic methodologies. Finally, we have sought to extend the mechanistic principles governing catalyst-controlled stereocenter isomerization into more general classes of constitutional isomerization, including a synthetically versatile contra -thermodynamic positional alkene isomerization reaction leveraging many of the same elementary steps. Like other transformations within the “editing” superfamily, stereoediting methods are designed for surgical precision and with a late-stage application in mind. Although a structurally minimalist perturbation, stereoediting can profoundly alter synthetic access to certain complex chiral targets and has the potential to fundamentally transform the logic of stereodefined synthesis.