Enantioselective transition-metal catalysis via an anion-binding approach.

Asymmetric transition-metal catalysis represents a powerful strategy for accessing enantiomerically enriched molecules1-3. The classical strategy for inducing enantioselectivity with transition-metal catalysts relies on direct complexation of chiral ligands to produce a sterically constrained reactive metal site that allows formation of the major product enantiomer while effectively inhibiting the pathway to the minor enantiomer through steric repulsion4. The chiral-ligand strategy has proven applicable to a wide variety of highly enantioselective transition-metal-catalysed reactions, but important scenarios exist that impose limits to its successful adaptation. Here, we report a new approach for inducing enantioselectivity in transition-metal-catalysed reactions that relies on neutral hydrogen-bond donors (HBDs)5,6 that bind anions of cationic transition-metal complexes to achieve enantiocontrol and rate enhancement through ion pairing together with other non-covalent interactions7-9. A cooperative anion-binding effect of a chiral bis-thiourea HBD is demonstrated to lead to high enantioselectivity (up to 99% enantiomeric excess) in intramolecular ruthenium-catalysed propargylic substitution reactions10. Experimental and computational mechanistic studies show the attractive interactions between electron-deficient arene components of the HBD and the metal complex that underlie enantioinduction and the acceleration effect.

Catalytic Enantioselective Synthesis of Difluorinated Alkyl Bromides.

We report an iodoarene-catalyzed enantioselective synthesis of ß,ß-difluoroalkyl bromide building blocks. The transformation involves an oxidative rearrangement of α-bromostyrenes, utilizing HF-pyridine as the fluoride source and m-CPBA as the stoichiometric oxidant. A catalyst decomposition pathway was identified, which, in tandem with catalyst structure-activity relationship studies, facilitated the development of an improved catalyst providing higher enantioselectivity with lower catalyst loadings. The versatility of the difluoroalkyl bromide products was demonstrated via highly enantiospecific substitution reactions with suitably reactive nucleophiles. The origins of enantioselectivity were investigated using computed interaction energies of simplified catalyst and substrate structures, providing evidence for both CH-π and π-π transition state interactions as critical features.

Oxidative functionalisation of alcohols and aldehydes via the merger of oxoammonium cations and photoredox catalysis.

We present a new paradigm for nitroxyl-mediated processes via the merger of oxoammonium cation-mediated oxidation with visible-light photoredox catalysis. The integration of these two forms of catalysis has been realised for the oxidative amidation of aldehydes, furnishing N-acylated heterocycles. Extension of this process to the oxidative amidation of alcohols via the intermediacy of an aldehyde was successfully pursued, thus proffering a general oxidation platform. The activated amides synthesised here are excellent synthetic handles for acylation.

Accessing N-Acyl Azoles via Oxoammonium Salt-Mediated Oxidative Amidation.

An operationally simple, robust, metal-free approach to the synthesis of N-acyl azoles from both alcohols and aldehydes is described. Oxidative amidation is facilitated by a commercially available organic oxidant (4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate) and proceeds under very mild conditions for an array of structurally diverse substrates. Tandem reactions of these activated amides, such as transamidation and esterification, enable further elaboration. Also, the spent oxidant can be recovered and used to regenerate the oxoammonium salt.

A combined computational and experimental investigation of the oxidative ring-opening of cyclic ethers by oxoammonium cations.

The propensity of oxoammonium cations to facilitate the oxidative ring-opening of cyclic ethers to their corresponding distal hydroxy ketones is investigated. The reaction has been evaluated using experimental and computational methods to gain deeper insight into trends in reactivity.

Toward a Unified Mechanism for Oxoammonium Salt-Mediated Oxidation Reactions: A Theoretical and Experimental Study Using a Hydride Transfer Model.

A range of oxoammonium salt-based oxidation reactions have been explored computationally using density functional theory (DFT), and the results have been correlated with experimentally derived trends in reactivity. Mechanistically, most reactions involve a formal hydride transfer from an activated C-H bond to the oxygen atom of the oxoammonium cation. Several new potential modes of reactivity have been uncovered and validated experimentally.

Oxidative cleavage of allyl ethers by an oxoammonium salt.

A method to oxidatively cleave allyl ethers to their corresponding aldehydes mediated by an oxoammonium salt is described. Using a biphasic solvent system and mild heating, cleavage proceeds readily, furnishing a variety of α,ß-unsaturated aldehydes and ketones.

Access to nitriles from aldehydes mediated by an oxoammonium salt.

A scalable, high yielding, rapid route to access an array of nitriles from aldehydes mediated by an oxoammonium salt (4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate) and hexamethyldisilazane (HMDS) as an ammonia surrogate has been developed. The reaction likely involves two distinct chemical transformations: reversible silyl-imine formation between HMDS and an aldehyde, followed by oxidation mediated by the oxoammonium salt and desilylation to furnish a nitrile. The spent oxidant can be easily recovered and used to regenerate the oxoammonium salt oxidant.