Proton-assisted activation of a MnIII-OOH for aromatic C-H hydroxylation through a putative [MnVO] species.

Adding HClO4 to [(BnTPEN)MnIII-OO]+ in MeOH generates a short-lived MnIII-OOH species, which converts to a putative MnVO species. The potent MnVO species in MeCN oxidizes the pendant phenyl ring of the ligand in an intramolecular fashion. The addition of benzene causes the formation of (BnTPEN)MnIII-phenolate. These findings suggest that high valent Mn species have the potential to catalyze challenging aromatic hydroxylation reactions.

Altering the Localization of an Unpaired Spin in a Formal Ni(V) Species.

The participation of both ligand and the metal center in the redox events has been recognized as one of the ways to attain the formal high valent complexes for the late 3d metals, such as Ni and Cu. Such an approach has been employed successfully to stabilize a Ni(III) bisphenoxyl diradical species in which there exist an equilibrium between the ligand and the Ni localized resultant spin. The present work, however, broadens the scope of the previously reported three oxidized equivalent species by conveying the approaches that tend to affect the reported equilibrium in CH3 CN at 233 K. Various spectroscopic characterization revealed that employing exogenous N-donor ligands like 1-methyl imidazole and pyridine favors the formation of the Ni centered localized spin though axial binding. In contrast, due to its steric hinderance, quinoline favors an exclusive ligand localized radical species. DFT studies shed light on the novel intermediates' complex electronic structure. Further, the three oxidized equivalent species with the Ni centered spin was examined for its hydrogen atom abstraction ability stressing their key role in alike reactions.

Mechanism of a Dually Catalyzed Enantioselective Oxa-Pictet-Spengler Reaction and the Development of a Stereodivergent Variant.

Enantioselective oxa-Pictet-Spengler reactions of tryptophol with aldehydes proceed under weakly acidic conditions utilizing a combination of two catalysts, an indoline HCl salt and a bisthiourea compound. Mechanistic investigations revealed the roles of both catalysts and confirmed the involvement of oxocarbenium ion intermediates, ruling out alternative scenarios. A stereochemical model was derived from density functional theory calculations, which provided the basis for the development of a highly enantioselective stereodivergent variant with racemic tryptophol derivatives.

Electrostatic Interactions in Asymmetric Organocatalysis.

ConspectusElectrostatic interactions are ubiquitous in catalytic systems and can be decisive in determining the reactivity and stereoselectivity. However, difficulties quantifying the role of electrostatic interactions in transition state (TS) structures have 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 Account, we narrate our recent results rooted in state-of-the-art quantum chemical computations, describing pivotal roles for electrostatic interactions in the organization of TS structures to direct the 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 how electrostatic interactions can be harnessed to tune the strength of noncovalent interactions. We then describe computational approaches to capture these effects followed by examples in which electrostatic effects impact structure and reactivity. We then cover some of our 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 nonchelating oxetane substrates, electrostatic interactions with the catalyst confer stereoselectivity, whereas oxetanes with chelating groups adopt a different binding mode that leads to electrostatic effects that erode selectivity. In another example, computations revealed a pivotal role of CH···O and NH···O hydrogen bonding in the 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 electrostatic effects, 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, where we discovered that the electrostatic stabilization of key proton(s) is 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 endo:exo of these transformations is guided by electrostatic interactions that selectively stabilize the endo-transition state.We conclude with a brief overview of the outstanding challenges and potential roles of computational chemistry in enabling the exploitation of electrostatic interactions in asymmetric organocatalysis.

Stereospecific Nickel-Catalyzed Cross-Electrophile Coupling Reaction of Alkyl Mesylates and Allylic Difluorides to Access Enantioenriched Vinyl Fluoride-Substituted Cyclopropanes.

Cross-electrophile coupling reactions involving direct C-O bond activation of unactivated alkyl sulfonates or C-F bond activation of allylic gem-difluorides remain challenging. Herein, we report a nickel-catalyzed cross-electrophile coupling reaction between alkyl mesylates and allylic gem-difluorides to synthesize enantioenriched vinyl fluoride-substituted cyclopropane products. These complex products are interesting building blocks with applications in medicinal chemistry. Density functional theory (DFT) calculations demonstrate that there are two competing pathways for this reaction, both of which initiate by coordination of the electron-deficient olefin to the low-valent nickel catalyst. Subsequently, the reaction can proceed by oxidative addition of the C-F bond of the allylic gem-difluoride moiety or by directed polar oxidative addition of the alkyl mesylate C-O bond.

Enzymatic Nitrogen Insertion into Unactivated C-H Bonds.

Selective functionalization of aliphatic C-H bonds, ubiquitous in molecular structures, could allow ready access to diverse chemical products. While enzymatic oxygenation of C-H bonds is well established, the analogous enzymatic nitrogen functionalization is still unknown; nature is reliant on preoxidized compounds for nitrogen incorporation. Likewise, synthetic methods for selective nitrogen derivatization of unbiased C-H bonds remain elusive. In this work, new-to-nature heme-containing nitrene transferases were used as starting points for the directed evolution of enzymes to selectively aminate and amidate unactivated C(sp3)-H sites. The desymmetrization of methyl- and ethylcyclohexane with divergent site selectivity is offered as demonstration. The evolved enzymes in these lineages are highly promiscuous and show activity toward a wide array of substrates, providing a foundation for further evolution of nitrene transferase function. Computational studies and kinetic isotope effects (KIEs) are consistent with a stepwise radical pathway involving an irreversible, enantiodetermining hydrogen atom transfer (HAT), followed by a lower-barrier diastereoselectivity-determining radical rebound step. In-enzyme molecular dynamics (MD) simulations reveal a predominantly hydrophobic pocket with favorable dispersion interactions with the substrate. By offering a direct path from saturated precursors, these enzymes present a new biochemical logic for accessing nitrogen-containing compounds.

Probing the Free Energy Landscape of Organophotoredox-Catalyzed Anti-Markovnikov Hydrofunctionalization of Alkenes.

Experimental 13C kinetic isotope effects (KIEs) provide unprecedented mechanistic insight into three intermolecular anti-Markovnikov alkene hydrofunctionalization reactions─hydroesterification, hydroamination, and hydroetherification─enabled by organophotoredox catalysis. All three reactions are found to proceed via initial oxidation of the model alkenes to form a radical cation intermediate, followed by sequential nucleophilic attack and hydrogen-atom transfer to deliver the hydrofunctionalized product. A normal 13C KIE on the olefinic carbon that undergoes nucleophilic attack provides qualitative evidence for rate-limiting nucleophilic attack in all three reactions. Comparison to predicted 13C KIE values obtained from density functional theory (DFT) calculations for this step reveals that alkene oxidation has partial rate-limiting influence in hydroesterification and hydroamination, while the nucleophilic attack is solely rate-limiting in the hydroetherification reaction. The basic additive (2,6-lutidine) activates the nucleophile via deprotonation and is an integral part of the transition state for nucleophilic attack on the radical cation, providing an important design principle for the development of asymmetric versions of these reactions. A more electron-rich pyridine base (2,6-dimethoxypyridine) exhibits considerable rate enhancements in both inter- and intramolecular hydrofunctionalization reactions.

Enantioselective Catalytic Synthesis of α-Halogenated α-Aryl-ß2,2-amino Acid Derivatives.

The enantioselective synthesis of a broad variety of novel differently functionalized α-halogenated α-aryl-ß2,2-amino acid derivatives by means of an ammonium-salt-catalyzed asymmetric α-halogenation of isoxazolidin-5-ones was accomplished. Key to success to obtain high levels of enantioselectivities was the use of Maruoka's spirocyclic binaphthyl-based ammonium salts, and detailed accompanying mechanistic studies using density functional theory methods revealed the key features for the catalyst-substrate interactions.

Biocatalytic, Intermolecular C-H Bond Functionalization for the Synthesis of Enantioenriched Amides.

Directed evolution of heme proteins has opened access to new-to-nature enzymatic activity that can be harnessed to tackle synthetic challenges. Among these, reactions resulting from active site iron-nitrenoid intermediates present a powerful strategy to forge C-N bonds with high site- and stereoselectivity. Here we report a biocatalytic, intermolecular benzylic C-H amidation reaction operating at mild and scalable conditions. With hydroxamate esters as nitrene precursors, feedstock aromatic compounds can be converted to chiral amides with excellent enantioselectivity (up to >99 % ee) and high yields (up to 87 %). Kinetic and computational analysis of the enzymatic reaction reveals rate-determining nitrenoid formation followed by stepwise hydrogen atom transfer-mediated C-H functionalization.

Chiral phosphoric acid catalysis: from numbers to insights.

Chiral phosphoric acids (CPAs) have emerged as powerful organocatalysts for asymmetric reactions, and applications of computational quantum chemistry have revealed important insights into the activity and selectivity of these catalysts. In this tutorial review, we provide an overview of computational tools at the disposal of computational organic chemists and demonstrate their application to a wide array of CPA catalysed reactions. Predictive models of the stereochemical outcome of these reactions are discussed along with specific examples of representative reactions and an outlook on remaining challenges in this area.

Enantioselective Synthesis of Chiral Oxime Ethers: Desymmetrization and Dynamic Kinetic Resolution of Substituted Cyclohexanones.

Axially chiral cyclohexylidene oxime ethers exhibit unique chirality because of the restricted rotation of C=N. The first catalytic enantioselective synthesis of novel axially chiral cyclohexylidene oximes has been developed by catalytic desymmetrization of 4-substituted cyclohexanones with O-arylhydroxylamines and is catalyzed by a chiral BINOL-derived strontium phosphate with excellent yields and good enantioselectivities. In addition, chiral BINOL-derived phosphoric acid catalyzed dynamic kinetic resolution of α-substituted cyclohexanones has been performed and yields versatile intermediates in high yields and enantioselectivities.