Importance of Electrostatically Driven Non-Covalent Interactions in Asymmetric Catalysis

Computational chemistry has become a powerful tool for understanding the principles of physical organic chemistry and rationalizing and even predicting the outcome of catalytic and non-catalytic organic reactions. Non-covalent interactions are prevalent in organic systems and accurately capturing their impact is vital for the reliable description of myriad chemical phenomena. These interactions impact everything from molecular conformations and stability to the outcome of stereoselective organic reactions and the function of biological macromolecules. Driven by the emergence of density functional theory (DFT) methods that can account for dispersion-driven noncovalent interactions, there has been a renaissance in terms of computational chemistry shaping modern organic chemistry. DFT Studies of the origins of stereoselectivity in asymmetric organocatalytic reactions can not only provide key information on the mode of asymmetric induction, but can also guide future rational catalyst design. We start with an overview of weak intermolecular interactions and aromatic interactions. Special emphasis is given to the methods that one can use to study these ephemeral interactions. We next provide a brief account how computational chemistry has aided our understanding of chiral phosphoric acid (CPA) catalyzed reactions. Thereafter, three case studies showcasing the importance of non-covalent interactions in chiral NHC catalysis, CPA catalysis, and chiral nucleophilic catalysis has been elaborated. Each of these studies highlights the importance of electrostatically-driven non-covalent interactions in controlling reactivity and selectivity. Moreover, unprecedented activation modes are identified and new predictive selectivity models developed that can be used to rationalize the outcome of future reactions. Studying these reactions using state of art DFT methods, we aimed not only to contribute to the understanding of their selectivity and the importance of noncovalent interactions in catalysis, but also to bring a sound understanding that will enable the design of new reactions and better catalysts. Overall, this dissertation highlights the underappreciated role of electrostatic interactions in controlling reactivity and selectivity in asymmetric catalysis

Importance of Electrostatically Driven Non-Covalent Interactions in Asymmetric Catalysis

Computational chemistry has become a powerful tool for understanding the principles of physical organic chemistry and rationalizing and even predicting the outcome of catalytic and non-catalytic organic reactions. Non-covalent interactions are prevalent in organic systems and accurately capturing their impact is vital for the reliable description of myriad chemical phenomena. These interactions impact everything from molecular conformations and stability to the outcome of stereoselective organic reactions and the function of biological macromolecules. Driven by the emergence of density functional theory (DFT) methods that can account for dispersion-driven noncovalent interactions, there has been a renaissance in terms of computational chemistry shaping modern organic chemistry. DFT Studies of the origins of stereoselectivity in asymmetric organocatalytic reactions can not only provide key information on the mode of asymmetric induction, but can also guide future rational catalyst design. We start with an overview of weak intermolecular interactions and aromatic interactions. Special emphasis is given to the methods that one can use to study these ephemeral interactions. We next provide a brief account how computational chemistry has aided our understanding of chiral phosphoric acid (CPA) catalyzed reactions. Thereafter, three case studies showcasing the importance of non-covalent interactions in chiral NHC catalysis, CPA catalysis, and chiral nucleophilic catalysis has been elaborated. Each of these studies highlights the importance of electrostatically-driven non-covalent interactions in controlling reactivity and selectivity. Moreover, unprecedented activation modes are identified and new predictive selectivity models developed that can be used to rationalize the outcome of future reactions. Studying these reactions using state of art DFT methods, we aimed not only to contribute to the understanding of their selectivity and the importance of noncovalent interactions in catalysis, but also to bring a sound understanding that will enable the design of new reactions and better catalysts. Overall, this dissertation highlights the underappreciated role of electrostatic interactions in controlling reactivity and selectivity in asymmetric catalysis

Electrostatic Interactions in Asymmetric Organocatalysis

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

Generalized Lambert series, Raabe's integral and a two-parameter generalization of Ramanujan's formula for ζ(2m+1)

A comprehensive study of the generalized Lambert series ∑n=1∞nN−2hexp(−anNx)1−exp(−nNx),00, N∈N and h∈Z, is undertaken. Two of the general transformations of this series that we obtain here lead to two-parameter generalizations of Ramanujan's famous formula for ζ(2m+1), m>0 and the transformation formula for logη(z). Numerous important special cases of our transformations are derived. An identity relating ζ(2N+1),ζ(4N+1),⋯,ζ(2Nm+1) is obtained for N odd and m∈N. Certain transcendence results of Zudilin- and Rivoal-type are obtained for odd zeta values and generalized Lambert series. A criterion for transcendence of ζ(2m+1) and a Zudilin-type result on irrationality of Euler's constant γ are also given. New results analogous to those of Ramanujan and Klusch for N even, and a transcendence result involving ζ(2m+1−1N), are obtained.by Atul Dixit, Rajat Gupta, Rahul Kumar and Bibekananda Maj

Importance of Electrostatic Effects in the Stereoselectivity of NHC-Catalyzed Kinetic Resolutions

Three <i>N</i>-heterocyclic carbene (NHC) catalyzed kinetic resolutions (KR) and one dynamic kinetic resolution (DKR) were examined using modern density functional theory methods to identify the origin of catalytic activity and selectivity and the role of cocatalysts in these reactions. The results reveal electrostatic interactions as the common driver of selectivity. Furthermore, in the case of a recently described KR of BINOL-derivatives, a computational examination of the full catalytic cycle reveals that a benzoic acid byproduct changes the turnover limiting transition step, obviating the need for an added cocatalyst. Together, these data provide key insights into the activity and selectivity of NHC-catalyzed kinetic resolutions, and underscore the importance of electrostatic interactions as a driver of selectivity

Design of an Organocatalytic Asymmetric (4+3) Cycloaddition of2-Indolylalcohols with Dienolsilanes

Here we present the design of a highly enantioselective, catalytic (4 + 3) cycloaddition ofgem-dialkyl 2-indolylalcohols and dienolsilanes, enabled by strong and confined IDPi Lewis acids. The method furnishes novel bicyclo[3.2.2]cyclohepta-[b]indoles with up to three stereogenic centers, one of which is quaternary. A broad substrate scope is accompanied by versatiledownstream chemical modifications. Density functional theory-supported mechanistic studies shed light on the importance of the insitu generated silylium species in an overall concerted yet asynchronous cycloaddition

Catalytic Asymmetric Additions of Enol Silanes to In Situ Generated Cyclic, Aliphatic N-Acyliminium Ions

Strong and confined imidodiphosphorimidate (IDPi) catalysts enable highly enantioselective substitutions of cyclic, aliphatic hemiaminal ethers with enol silanes. 2-Substituted pyrrolidines, piperidines, and azepanes are obtained with high enantioselectivities, and the method displays a broad tolerance of various enol silane nucleophiles. Several natural products can be accessed using this methodology. Mechanistic studies support the intermediacy of non-stabilized, cyclic N-(exo-acyl)iminium ions, paired with the confined chiral counteranion. Computational studies suggest transition states that explain the observed enantioselectivity