In most modern organic chemistry reports, including many of ours, reaction optimization schemes are typically presented to showcase how reaction conditions have been tailored to augment the reaction's yield and selectivity. In asymmetric catalysis, this often involves evaluation of catalyst, solvent, reagent, and, sometimes, substrate features. Such an article will then detail the process's scope, which mainly focuses on its successes and briefly outlines the "limitations". These limitations or poorer-performing substrates are occasionally the result of obvious, significant changes to structure (e.g., a Lewis basic group binds to a catalyst), but frequently, a satisfying explanation for inferior performance is not clear. This is one of several reasons such results are not often reported. These apparent outliers are also commonplace in the evaluation of catalyst structure, although most of this information is placed in the Supporting Information. These practices are unfortunate because results that appear at first glance to be peculiar or poor are considerably more interesting than ones that follow obvious or intuitive trends. In other words, all of the data from an optimization campaign contain relevant information about the reaction under study, and the "outliers" may be the most revealing. Realizing the power of outliers as an entry point to entirely new reaction development is not unusual. Nevertheless, the concept that no data should be wasted when considering the underlying phenomena controlling the observations of a given reaction is at the heart of the strategy we describe in this Account. The idea that one can concurrently optimize a reaction to expose the structural features that control its outcomes would represent a transformative addition to the arsenal of catalyst development and, ultimately, de novo design. Herein we outline the development of a recently initiated program in our lab that unites optimization with mechanistic interrogation by correlating reaction outputs (e.g., electrochemical potential or enantio-, site, or chemoselectivity) with structural descriptors of the molecules involved. The ever-evolving inspiration for this program is rooted in outliers of classical linear free energy relationships. These outliers encouraged us to ask questions about the parameters themselves, suggest potential interactions at the source of the observed effects, and, of particular applicability, identify more sophisticated physical organic descriptors. Throughout this program, we have integrated techniques from disparate fields, including synthetic methodology development, mechanistic investigations, statistics, computational chemistry, and data science. The implementation of many of these strategies is described, and the resulting tools are illustrated in a wide range of case studies, which include data sets with simultaneous and multifaceted changes to the reagent, substrate, and catalyst structures. This tactic constitutes a modern approach to physical organic chemistry wherein no data are wasted and mec...

Although asymmetric catalysis is universally dependent on spatial interactions to impart specific chirality on a given substrate, examination of steric effects in these catalytic systems remains empirical. Previous efforts by our group and others have seen correlation between steric parameters developed by Charton and simple substituents in both substrate and ligand; however, more complex substituents were not found to be correlative. Here, we review and compare the steric parameters common in quantitative structure activity relationships (QSAR), a common method for pharmaceutical function optimization, and how they might be applied in asymmetric catalysis, as the two fields are undeniably similar. We re-evaluate steric/enantioselection relationships, which we previously analysed with Charton steric parameters, using the more sophisticated Sterimol parameters developed by Verloop and co-workers in a QSAR context. Use of these Sterimol parameters led to strong correlations in numerous processes where Charton parameters had previously failed. Sterimol parameterization also allows for greater mechanistic insight into the key elements of asymmetric induction within these systems.

Visible-light-promoted organic reactions can offer increased reactivity and selectivity via unique reaction pathways to address a multitude of practical synthetic problems, yet few practical solutions exist to employ these reactions for multikilogram production. We have developed a simple and versatile continuous stirred tank reactor (CSTR) equipped with a high-intensity laser to drive photochemical reactions at unprecedented rates in continuous flow, achieving kg/day throughput using a 100 mL reactor. Our approach to flow reactor design uses the Beer–Lambert law as a guideline to optimize catalyst concentration and reactor depth for maximum throughput. This laser CSTR platform coupled with the rationale for design can be applied to a breadth of photochemical reactions.

Carbohydrates are involved in nearly all aspects of biochemistry, but their complex chemical structures present long-standing practical challenges to their synthesis. In particular, stereochemical outcomes in glycosylation reactions are highly dependent on the steric and electronic properties of coupling partners, and thus, carbohydrate synthesis is not easily predictable. Here, we report the discovery of a macrocyclic bis-thiourea derivative that catalyzes stereospecific invertive substitution pathways of glycosyl chlorides. The utility of the catalyst is demonstrated in the synthesis of 1,2-trans-, 1,2-cis-, and 2-deoxy-β-glycosides. Mechanistic studies are consistent with a cooperative mechanism in which an electrophile and a nucleophile are simultaneously activated to effect a stereospecific substitution reaction.

Chemical reaction outcomes are often rationalized on the basis of independent analyses of steric and electronic effects. We applied three-dimensional free energy relationships correlating steric and electronic effects to design and optimize a ligand class for the enantioselective Nozaki-Hiyama-Kishi propargylation of ketones. The resultant mathematical model describing the steric and electronic parameter relationship is highly reliant on the synergistic interactions of these two effects.