Mechanism to model: a physical organic chemistry approach to reaction prediction.

The application of mechanistic generalizations is at the core of chemical reaction development and application. These strategies are rooted in physical organic chemistry where mechanistic understandings can be derived from one reaction and applied to explain another. Over time these techniques have evolved from rationalizing observed outcomes to leading experimental design through reaction prediction. In parallel, significant progression in asymmetric organocatalysis has expanded the reach of chiral transfer to new reactions with increased efficiency. However, the complex and diverse catalyst structures applied in this arena have rendered the generalization of asymmetric catalytic processes to be exceptionally challenging. Recognizing this, a portion of our research has been focused on understanding the transferability of chemical observations between similar reactions and exploiting this phenomenon as a platform for prediction. Through these experiences, we have relied on a working knowledge of reaction mechanism to guide the development and application of our models which have been advanced from simple qualitative rules to large statistical models for quantitative predictions. In this feature article, we describe the models acquired to generalize organocatalytic reaction mechanisms and demonstrate their use as a powerful approach for accelerating enantioselective synthesis.

Transferrable selectivity profiles enable prediction in synergistic catalyst space.

Organometallic intermediates participate in many multi-catalytic enantioselective transformations directed by a chiral catalyst, but the requirement of optimizing two catalyst components is a significant barrier to widely adopting this approach for chiral molecule synthesis. Algorithms can potentially accelerate the screening process by developing quantitative structure-function relationships from large experimental datasets. However, the chemical data available in this catalyst space is limited. Herein, we report a data-driven strategy that effectively translates selectivity relationships trained on enantioselectivity outcomes derived from one catalyst reaction systems where an abundance of data exists, to synergistic catalyst space. We describe three case studies involving different modes of catalysis (Brønsted acid, chiral anion, and secondary amine) that substantiate the prospect of this approach to predict and elucidate selectivity in reactions where more than one catalyst is involved. Ultimately, the success in applying our approach to diverse areas of asymmetric catalysis implies that this general workflow should find broad use in the study and development of new enantioselective, multi-catalytic processes.

Guiding Target Synthesis with Statistical Modeling Tools: A Case Study in Organocatalysis.

Practitioners are generally not willing to explore modern reactions where considerable synthetic effort is required to generate materials and the results are not certain. Organocatalysis exemplifies this, in which a broad set of enantioselective reactions have been successfully developed but further applications to include additional substrates are often not performed. Herein we demonstrate how statistical models can be utilized to accurately distinguish between different catalysts and reactions to guide the selection of efficient synthetic routes to obtain a target molecule.