Designing Secondary-Sphere Modifications in Organocatalysis

Introduction

Our group has been involved in the design, in-situ modification, and mechanistic interrogation of secondary-sphere interactions in organocatalysis. As proof-of-concept, we modified the secondary sphere of N-heterocyclic carbenes (NHCs) using boronic acids under reaction conditions. This strategy allowed us to control the reactivity and selectivity of the benzoin reaction and probe its mechanism.[1-3] We recently reported the implications of this strategy on amino catalysts in a proline-catalyzed aldol reaction.[4] By modifying proline with boronic acids in situ, we were able to rapidly access different organocatalyst derivatives without any synthetic effort. Taking advantage of the broad spread of data stemming from our secondary-sphere modifications, we set out to study the influence of solvent effects on the aldol reaction.[5] Solvent effects are of particular interest in secondary-sphere-modified catalysts, not only because of the additional degrees of structural freedom the modifier confers, but also due to the required binding stability under different reaction conditions. Whereas the concept of secondary-sphere modifications is inspired by enzymatic catalysis, the modifiers impart less spatial constrains than an enzymatic microenvironment. Therefore, the role of solvent molecules is paramount in controlling the intermediates and transition states that determine reactivity and selectivity.

References:
[1] Dhayalan, V.; Gadekar, S. C.; Alassad, Z.; Milo, A. Nat. Chem. 2019, 11, 543-551.
[2] Zak, I. L.; Gadekar, S. C.; Milo, A. Synlett 2021, 32, 329-336.
[3] Alassad, Z.; Nandi, A.; Kozuch, S.; Milo, A. J. Am. Chem. Soc. 2023, 145, 89-98.
[4] Domb, I.; Lustosa, D. M.; Milo, A. Chem. Comm. 2022, 58, 1950-1953.
[5] Lustosa, D. M.; Barkai, S.; Domb, I.; Milo, A. J. Org. Chem. 2022, 87, 1850-1857.

Anat Milo

received her B.Sc./B.A. in Chemistry and Humanities from the Hebrew University of Jerusalem, her M.Sc. from UPMC Paris with Bernold Hasenknopf, and Ph.D. from the Weizmann Institute of Science with Ronny Neumann. Her postdoctoral studies at the University of Utah with Matthew Sigman focused on physical organic descriptors and data science approaches in chemistry. She then joined the Department of Chemistry at Ben-Gurion University of the Negev, where her research group develops experimental, statistical, and computational strategies for identifying molecular design principles in catalysis, with particular focus on intercepting reactive intermediates in organocatalysis by second sphere interactions.