Electrostatic Interactions in Asymmetric Organocatalysis

01 February 2023, Version 2
This content is a preprint and has not undergone peer review at the time of posting.


Electrostatic interactions are ubiquitous in catalytic systems and are often decisive in determining reactivity and stereoselectivity. However, a lack of understanding of the fundamental underlying principles has long stymied our ability to fully harness the power of these interactions. Fortunately, advances in affordable computing power together with new quantum chemistry methods have increasingly enabled a detailed atomic-level view. Empowered by this more nuanced perspective, synthetic practitioners are now adopting these techniques with growing enthusiasm. In this review, we narrate our recent results rooted in state-of-the-art quantum chemical computations, describing pivotal roles for electrostatic interactions in the organization of transition state (TS) structures to direct reactivity and selectivity in the realm of asymmetric organocatalysis. To provide readers with a fundamental foundation in electrostatics, we first introduce a few guiding principles, beginning with a brief discussion of electrostatic interactions and electrostatics-dominated non-covalent interactions as well as and their modulating factors. We then describe computational approaches to capture these effects, primarily through representative case studies. Subsequently, we cover some general strategies that have been utilized to impart stereocontrol in asymmetric organocatalysis, presenting our own results along with selected highlights from other groups. We then briefly cover our most significant recent computational investigations in three specific branches of asymmetric organocatalysis, beginning with chiral phosphoric acid (CPA) catalysis. We disclose how CPA-catalyzed asymmetric ring openings of meso-epoxides are driven by stabilization of a transient partial positive charge in the SN2-like TS by the chiral electrostatic environment of the catalyst. We also report on substrate-dependent electrostatic effects from our study of CPA-catalyzed intramolecular oxetane desymmetrizations. For non-chelating oxetane substrates, electrostatic interactions with the catalyst confers stereoselectivity, whereas oxetanes with chelating groups adopt a different binding mode that overrides this electrostatic stereodetermination and erodes selectivity. In another example, computational approaches revealed a pivotal role of CH···O and NH···O hydrogen bonding in CPA-catalyzed asymmetric synthesis of 2,3-dihydroquinazolinones. These interactions control selectivity during the enantiodetermining intramolecular amine addition step, and their strength is modulated by substrate positioning within the electrostatic environment created by the catalyst, allowing us to rationalize the effect of introducing o-substituents. Next, we describe our efforts to understand selectivity in a series of NHC-catalyzed kinetic resolutions. We discovered that electrostatic interactions are the common driver of selectivity. Finally, we discuss our breakthrough in understanding asymmetric silylium ion-catalyzed Diels–Alder cycloaddition of cinnamate esters to cyclopentadienes. The diastereoselectivity of these transformations is guided by CH···O electrostatic interactions that selectively stabilize the endo-transition state. Additionally, we deduced the geometry of the preferred binding mode to explain the requirement for a 9-fluorenylmethyl ester to achieve high selectivity. We conclude with a brief overview of the outstanding challenges and the potential roles of computational chemistry in enabling the exploitation of electrostatic interactions in asymmetric organocatalysis.


electrostatic interactions
density functional theory


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