Biocatalytic Strategy for the Highly Stereoselective Synthesis of Fluorinated Cyclopropanes.

Fluorinated cyclopropanes are highly desired pharmacophores in drug discovery owing to the rigidity nature of the cyclopropane ring and the beneficial effects of C-F bonds on the pharmacokinetic properties, cell permeability, and metabolic stability of drug molecules. Herein a biocatalytic strategy for the stereoselective synthesis of mono-fluorinated and gem-difluoro cyclopropanes is reported though the use of engineered myoglobin-based catalysts. In particular, this system allows for a broad range of gem-difluoro alkenes to be cyclopropanated in the presence of diazoacetonitrile with excellent diastereo and enantiocontrol (up to 200:1 d.r. and 99% e.e.), thereby enabling a transformation not currently accessible with chemocatalytic methods. The synthetic utility of the present approach is further exemplified through the gram-scale synthesis of a key gem-difluorinated cyclopropane intermediate useful for the preparation of fluorinated bioactive molecules.

Recent Discovery, Development, and Synthetic Applications of Formic Acid Salts in Photochemistry.

The advancement of sustainable photoredox catalysis in synthetic organic chemistry has evolved immensely because of the development of versatile and cost-effective reagents. In recent years, a substantial effort has been dedicated to exploring the utility of formic acid salts in various photochemical reactions. In this context, formates have demonstrated diverse capabilities, functioning as reductants, sources of carbonyl groups, and reagents for hydrogen atom transfer. Notably, the CO2 ⋅- radical anion derived from formate exhibits strong reductant properties for cleaving both C-X and C-O bonds. Moreover, these salts play a pivotal role in carboxylation reactions, further highlighting their significance in a variety of photochemical transformations. The ability of formates to serve as reductants, carbonyl sources, and hydrogen atom transfer reagents reveal exciting possibilities in synthetic organic chemistry. This minireview highlights an array of captivating discoveries, underscoring the crucial role of formates in diverse and distinctive photochemical methods, enabling access to a wide range of value-added compounds.

Photochemical Deoxygenative Hydroalkylation of Unactivated Alkenes Promoted by a Nucleophilic Organocatalyst.

The direct utilization of simple and abundant feedstocks in carbon-carbon bond-forming reactions to embellish sp3 -enriched chemical space is highly desirable. Herein, we report a novel photochemical deoxygenative hydroalkylation of unactivated alkenes with readily available carboxylic acid derivatives. The reaction displays broad functional group tolerance, accommodating carboxylic acid-, alcohol-, ester-, ketone-, amide-, silane-, and boronic ester groups, as well as nitrile-containing substrates. The reaction is operationally simple, mild, and water-tolerant, and can be carried out on multigram-scale, which highlights the utility of the method to prepare value-added compounds in a practical and scalable manner. The synthetic application of the developed method is further exemplified through the synthesis of suberanilic acid, a precursor of vorinostat, a drug used for the treatment of cutaneous T-cell lymphoma. A novel mechanistic approach was identified using thiol as a nucleophilic catalyst, which forms a key intermediate for this transformation. Furthermore, electrochemical studies, quantum yield, and mechanistic experiments were conducted to support a proposed catalytic cycle for the transformation.

Transition metal-free photochemical C-F activation for the preparation of difluorinated-oxindole derivatives.

The development of strategies for single and selective C-F bond activation represents an important avenue to overcome limitations in the synthesis of valuable fluorine-containing compounds. The synthetic and medicinal research communities would benefit from new routes that access such relevant molecules in a simple manner. Herein we disclose a straightforward and mechanistically distinct pathway to generate gem-difluoromethyl radicals and their installation onto N-arylmethacrylamides for the preparation of valuable difluorinated oxindole derivatives. To achieve operational simplicity, the use of a readily available benzenethiol as a photocatalyst under open-to-air conditions was developed, demonstrating the facile multigram preparation of the targeted fluorinated molecules. Additionally, dispersion-corrected density functional theory (DFT) and empirical investigations provide a new basis to support the proposed reaction pathway, indicating that arene thiolate is an efficient organophotocatalyst for this transformation.

Practical, scalable, and transition metal-free visible light-induced heteroarylation route to substituted oxindoles.

The synthetic application of (hetero)aryl radicals in organic synthesis has been known since the last century. However, their applicability has significantly suffered from ineffective generation protocols. Herein, we present a visible-light-induced transition metal-free (hetero)aryl radical generation from readily available (hetero)aryl halides for the synthesis of 3,3'-disubstituted oxindoles. This transformation is amenable to a wide range of (hetero)aryl halides as well as several easily accessible acrylamides, and it is also scalable to multigram synthesis. Finally, the versatility of the oxindole products is demonstrated through their conversion to a variety of useful intermediates applicable to target-directed synthesis.

1,2-Radical Shifts in Photoinduced Synthetic Organic Transformations: A Guide to the Reactivity of Useful Radical Synthons.

The exploration of 1,2-radical shift (RS) mechanisms in photoinduced organic reactions has provided efficient routes for the generation of important radical synthons in many chemical transformations. In this Review, the basic concepts involved in the traditional 1,2-spin-center shift (SCS) mechanisms in recently reported studies are discussed. In addition, other useful 1,2-RSs are addressed, such as those proceeding through 1,2-group migrations in carbohydrate chemistry, via 1,2-boron shifts, and by the generation of α-amino radicals. The discussion begins with a general overview of the basic aspects of 1,2-RS mechanisms, followed by a demonstration of their applicability in photoinduced transformations. The sections that follow are organized according to the mechanisms operating in combination with the 1,2-radical migration event. This contribution is not a comprehensive review but rather aims to provide an understanding of the topic, focused on the more recent advances in the field, and establishes a definition for the nomenclature that has been used to describe such mechanisms.

Visible-Light-Induced C-F Bond Activation for the Difluoroalkylation of Indoles.

An aryl disulfide mediated C-F bond activation of the trifluoromethyl group to generate valuable gem-difluoroalkylindoles is described. This method relies on readily available commodity reagents under mild reaction conditions and represents the first transition-metal-free redox-neutral C-F bond activation strategy. The reaction employs various substituted indoles and α-fluoro-substituted esters. Further, this mode of C-F activation was also amenable to the activation of trifluoromethylated arenes for the preparation of bis-benzylic gem-difluoromethylenes between indole and arene substructures, providing access to a unique chemical space.

Metal-Free Photochemical Imino-Alkylation of Alkenes with Bifunctional Oxime Esters.

The concurrent installation of C-C and C-N bonds across alkene frameworks represents a powerful tool to prepare motifs that are ubiquitous in pharmaceuticals and bioactive compounds. To construct such prevalent bonds, most alkene difunctionalization methods demand the use of precious metals or activated alkenes. We report a metal-free, photochemically mediated imino-alkylation of electronically diverse alkenes to install both alkyl and iminyl groups in a highly efficient manner. The exceptionally mild reaction conditions, broad substrate scope, excellent functional group tolerance, and facile one-pot reaction protocol highlight the utility of this method to prepare privileged motifs from readily available alkene and acid feedstocks. One key and striking feature of this transformation is that an electrophilic trifluoromethyl radical is equally efficient with both electron-deficient and electron-rich alkenes. Additionally, dispersion-corrected density functional theory (DFT) and empirical investigations provide detailed mechanistic insight into this reaction.

A three-component difunctionalization of N-alkenyl amides via organophotoredox radical-polar crossover.

Herein, we report a three-component organophotoredox coupling of N-alkenyl amides with α-bromocarbonyls and various nucleophiles. This transition metal-free difunctionalization protocol installs sequential C-C and C-Y (Y = S/O/N) bonds in alkenes. This reaction works with terminal and internal alkenes containing both cyclic and acyclic amides via radical-polar crossover.

A practical and sustainable two-component Minisci alkylation via photo-induced EDA-complex activation.

An operationally simple, open-air, and efficient light-mediated Minisci C-H alkylation method is described, based on the formation of an electron donor-acceptor (EDA) complex between nitrogen-containing heterocycles and redox-active esters. In contrast to previously reported protocols, this method does not require a photocatalyst, an external single electron transfer agent, or an oxidant additive. Achieved under mildly acidic and open-air conditions, the reaction incorporates primary-, secondary-, and tertiary radicals, including bicyclo[1.1.1]pentyl (BCP) radicals, along with various heterocycles to generate Minisci alkylation products in moderate to good yields. Additionally, the method is exploited to generate a stereo-enriched, hetereoaryl-substituted carbohydrate.

From Styrenes to Fluorinated Benzyl Bromides: A Photoinduced Difunctionalization via Atom Transfer Radical Addition.

An operationally simple and practical method is disclosed to achieve the difunctionalization of styrenes, generating fluorinated benzyl bromides via a photoinduced atom transfer radical addition process. The developed method is mild, atom-economical, cost-effective, employs very low photocatalyst loading (1000 ppm), and is highly compatible with a broad range of functional groups on styrene. The versatility of the fluorinated benzyl bromides is demonstrated through their derivatization to a variety of valuable compounds.

On-DNA Hydroalkylation to Introduce Diverse Bicyclo[1.1.1]pentanes and Abundant Alkyls via Halogen Atom Transfer.

DNA-encoded libraries have proven their tremendous value in the identification of new lead compounds for drug discovery. To access libraries in new chemical space, many methods have emerged to transpose traditional mol-scale reactivity to nmol-scale, on-DNA chemistry. However, procedures to access libraries with a greater fraction of C(sp3) content are still limited, and the need to "escape from flatland" more readily on-DNA remains. Herein, we report a Giese addition to install highly functionalized bicyclo[1.1.1]pentanes (BCPs) using tricyclo[1.1.1.01,3]pentane (TCP) as a radical linchpin, as well as other diverse alkyl groups, on-DNA from the corresponding organohalides as non-stabilized radical precursors. Telescoped procedures allow extension of the substrate pool by at least an order of magnitude to ubiquitous alcohols and carboxylic acids, allowing us to "upcycle" these abundant feedstocks to afford non-traditional libraries with different physicochemical properties for the small-molecule products (i.e., non-peptide libraries with acids). This approach is amenable to library production, as a DNA damage assessment revealed good PCR amplifiability and only 6% mutated sequences for a full-length DNA tag.

Photochemical C-F Activation Enables Defluorinative Alkylation of Trifluoroacetates and -Acetamides.

The installation of gem-difluoromethylene groups into organic structures remains a daunting synthetic challenge despite their attractive structural, physical, and biochemical properties. A very efficient retrosynthetic approach would be the functionalization of a single C-F bond from a trifluoromethyl group. Recent advances in this line of attack have enabled the C-F activation of trifluoromethylarenes, but limit the accessible motifs to only benzylic gem-difluorinated scaffolds. In contrast, the C-F activation of trifluoroacetates would enable their use as a bifunctional gem-difluoromethylene synthon. Herein, we report a photochemically mediated method for the defluorinative alkylation of a commodity feedstock: ethyl trifluoroacetate. A novel mechanistic approach was identified using our previously developed diaryl ketone HAT catalyst to enable the hydroalkylation of a diverse suite of alkenes. Furthermore, electrochemical studies revealed that more challenging radical precursors, namely trifluoroacetamides, could also be functionalized via synergistic Lewis acid/photochemical activation. Finally, this method enabled a concise synthetic approach to novel gem-difluoro analogs of FDA-approved pharmaceutical compounds.

Dynamic Kinetic Resolution of Alkenyl Cyanohydrins Derived from α,ß-Unsaturated Aldehydes: Stereoselective Synthesis of E-Tetrasubstituted Olefins.

A novel dynamic kinetic resolution (DKR) of tetrasubstituted alkenyl cyanohydrins prepared from the corresponding α,ß-unsaturated aldehydes is described. The deprotonation of a geometrical mixture of tetrasubstituted alkenyl cyanohydrins with sodium diisopropylamide (NaDA) affords the allylic anions, which enables the equilibration of the E- and Z-olefins to permit the selective functionalization of the E-adduct. Theoretical studies indicate that the nature of the alkali metal cation is a critical component to lowering the barrier for interconversion between the two geometrical isomers, which provides the mechanistic basis for the DKR reaction. In addition, we demonstrate that the DKR reaction can be combined with a transition metal-catalyzed allylic substitution to generate a stereodefined E-tetrasubstituted olefin and quaternary center in a single cross-coupling reaction.

Synthesis of a tricyclic lactam via Beckmann rearrangement and ring-rearrangement metathesis as key steps.

A tricyclic lactam is reported in a four step synthesis sequence via Beckmann rearrangement and ring-rearrangement metathesis as key steps. Here, we used a simple starting material such as dicyclopentadiene.