Photochemical Methods Applied to DNA Encoded Library (DEL) Synthesis.

DNA-encoded library technology (DELT) is a new screening modality that allows efficient, cost-effective, and rapid identification of small molecules with potential biological activity. This emerging technique represents an enormous advancement that, in combination with other technologies such as high-throughput screening (HTS), fragment-based lead generation, and structure-based drug design, has the potential to transform how drug discovery is carried out. DELT is a hybrid technique in which chemically synthesized compounds are linked to unique genetic tags (or "barcodes") that contain readable information. In this way, millions to billions of building blocks (BBs) attached on-DNA via split-and-pool synthesis can be evaluated against a biological target in a single experiment. Polymerase chain reaction (PCR) amplification and next-generation sequencing (NGS) analysis of the unique sequence of oligonucleotides in the DNA tag are used to identify those ligands with high affinity for the target. This innovative fusion of genetic and chemical technologies was conceived in 1992 by Brenner and Lerner (Proc. Natl. Acad. Sci. 1992, 89, 5381-5383) and is under accelerated development with the implementation of new synthetic techniques and protocols that are compatible with DNA. In fact, reaction compatibility is a key parameter to increasing the chances of identification of a drug target ligand, and a central focus has been the development of new transformations and the transition to robust protocols for on-DNA synthesis. Because the sole use of the DNA tag is as an amplifiable identification barcode, its structural integrity during a new chemical process is mandatory. As such, the use of these sensitive, polyfunctional biological molecules as substrates typically requires aqueous solutions within defined pH and temperature ranges, which is considered a notable challenge in DEL synthesis.Using low-energy visible light as the driving force to promote chemical transformations represents an attractive alternative to classical synthetic methods, and it is an important and well-established synthetic tool for forging chemical bonds in a unique way via radical intermediates. Recent advances in the field of photocatalysis are extraordinary, and this powerful research arena is still under continuous development. Several applications taking advantage of the mild reaction conditions of photoinduced transformations have been directed toward DEL synthesis, allowing the expansion of chemical space available for the evaluation of new building blocks on-DNA. There are no doubts that visible-light-driven reactions have become one of the most powerful approaches for DELT, given the easy way they provide to construct new bonds and the challenges to achieve equal success via classical protocols.Key characteristics of photocatalytic synthesis include the short reaction times and efficiency, which translate into retention of DNA integrity. In this Account, we describe recent advances in the photoinduced diversification of building blocks prepared on-DNA, highlighting the amenability of the techniques employed for preserving the genetic structure of the molecules. We demonstrate with recent research from our group the applicability of photocatalysis to the field and include in the summary a table containing all the photoinduced methods reported to date for DELT, demonstrating their key aspects such as scope, applications, and DNA compatibilities. With this information, practitioners are provided with compelling reasons for developing/choosing photocatalytic methods for DELT applications.

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.

A General and Modular Approach to BCP Alkylamines via Multicomponent Difunctionalization of [1.1.1]Propellane.

Over the past decade, bicyclo[1.1.1]pentane (BCP) motifs have come to the fore as valuable pharmaceutical bioisosteres of para-disubstituted benzenes. However, the limited approaches and requisite multistep syntheses of useful BCP building blocks are hampering early discovery research in medicinal chemistry. Herein we report the development of a modular strategy for the divergent preparation of functionalized BCP alkylamines. In this process, a general method to introduce fluoroalkyl groups to BCP scaffolds using readily available and easy-to-handle fluoroalkyl sulfinate salts was also developed. Moreover, this strategy can also be extended to S-centered radicals for incorporation of sulfones and thioethers into the BCP core. Overall, this multicomponent strategy enables rapid construction of BCP-type bioisosteres for applications in drug discovery.

A General and Practical Route to Functionalized Bicyclo[1.1.1]Pentane-Heteroaryls Enabled by Photocatalytic Multicomponent Heteroarylation of [1.1.1]Propellane.

1-Aryl-substituted bicyclo[1.1.1]pentanes (BCPs) are an important class of BCP derivatives with widespread application in drug development. Most syntheses of these materials require multiple chemical steps via BCP electrophiles or nucleophiles derived from [1.1.1]propellane. Although one-step, multicomponent radical cross-coupling reactions could provide a more sustainable and rapid route to access diverse heteroarylated BCPs, current approaches are limited to tertiary alkyl radicals, leading to a decrease in their practical value. In this study, a conceptually different approach enabled by a radical multicomponent heteroarylation of [1.1.1]propellane to access functionalized heteroarylated BCPs is described. Importantly, this protocol is compatible with primary-, secondary-, and tertiary aliphatic radicals, as well as various fluoroalkyl radical sources, thus enabling rapid library generation of sought-after BCP derivatives for drug development.

Dicarbofunctionalization of [1.1.1]Propellane Enabled by Nickel/Photoredox Dual Catalysis: One-Step Multicomponent Strategy for the Synthesis of BCP-Aryl Derivatives.

Bicyclo[1.1.1]pentane (BCP) motifs as para-disubstituted aryl bioisosteres are playing an emerging role in pharmaceutical, agrochemical, and materials chemistry. The vast majority of these structures is obtained from a BCP electrophile or nucleophile, which are themselves derived from [1.1.1]propellane via cleavage of the internal C-C bond through the addition of either radicals or metal-based nucleophiles. Compared with the current stepwise approaches, a multicomponent reaction that provides direct access to complex and diverse disubstituted BCP products would be more attractive. Herein, we report a single-step, multicomponent approach to synthetically versatile arylated BCP products via nickel/photoredox catalysis. Importantly, this three-component process allows two C-C bonds to be formed in a single step and sets three quaternary centers, unprecedented in any previously reported methods. The method has been demonstrated to allow access to complex BCP architectures from aryl halide and radical precursor substrates.

Photochemical Intermolecular [3σ + 2σ]-Cycloaddition for the Construction of Aminobicyclo[3.1.1]heptanes.

The development of synthetic strategies for the preparation of bioisosteric compounds is a demanding undertaking in medicinal chemistry. Numerous strategies have been developed for the synthesis of bicyclo[1.1.1]pentanes (BCPs), bridge-substituted BCPs, and bicyclo[2.1.1]hexanes. However, progress on the synthesis of bicyclo[3.1.1]heptanes, which serve as meta-substituted arene bioisosteres, has not been previously explored. Herein, we disclose the first photoinduced [3σ + 2σ] cycloaddition for the synthesis of trisubstituted bicyclo[3.1.1]heptanes using bicyclo[1.1.0]butanes and cyclopropylamines. This transformation not only uses mild and operationally simple conditions but also provides unique meta-substituted arene bioisosteres. The applicability of this method is showcased by simple derivatization reactions.

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.

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.

Nickel-Mediated Synthesis of Non-Anomeric C-Acyl Glycosides through Electron Donor-Acceptor Complex Photoactivation.

The preparation of nonanomeric C-acyl-saccharides has been developed from two different carboxylic acid feedstocks. This transformation is driven by the synergistic interaction of an electron donor-acceptor complex and Ni catalysis. Primary-, secondary-, and tertiary redox-active esters are incorporated as coupling partners onto preactivated pyranosyl- and furanosyl acids, preserving their stereochemical integrity. The reaction occurs under mild conditions, without stoichiometric metal reductants or exogenous catalysts, using commercially available Hantzsch ester as the organic photoreductant.

Sustainable Thioetherification via Electron Donor-Acceptor Photoactivation Using Thianthrenium Salts.

The synthesis of sulfides has been widely studied because this functional subunit is prevalent in biomolecules and pharmaceuticals, as well as being a useful synthetic platform for further elaboration. Thus, various methods to build C-S bonds have been developed, but typically they require the use of precious metals or harsh conditions. Electron donor-acceptor (EDA) complex photoactivation strategies have emerged as versatile and sustainable ways to achieve C-S bond formation, avoiding challenges associated with previous methods. This work describes an open-to-air, photoinduced, site-selective C-H thioetherification from readily available reagents via EDA complex formation that tolerates a wide range of different functional groups. Moreover, C(sp2 )-halogen bonds remain intact using this protocol, allowing late-stage installation of the sulfide motif in various bioactive scaffolds, while allowing yet further modification through more traditional C-X bond cleavage protocols. Additionally, various mechanistic investigations support the envisioned EDA complex scenario.

Photochemical C-H Activation Enables Nickel-Catalyzed Olefin Dicarbofunctionalization.

Alkenes, ethers, and alcohols account for a significant percentage of bulk reagents available to the chemistry community. The petrochemical, pharmaceutical, and agrochemical industries each consume gigagrams of these materials as fuels and solvents each year. However, the utilization of such materials as building blocks for the construction of complex small molecules is limited by the necessity of prefunctionalization to achieve chemoselective reactivity. Herein, we report the implementation of efficient, sustainable, diaryl ketone hydrogen-atom transfer (HAT) catalysis to activate native C-H bonds for multicomponent dicarbofunctionalization of alkenes. The ability to forge new carbon-carbon bonds between reagents typically viewed as commodity solvents provides a new, more atom-economic outlook for organic synthesis. Through detailed experimental and computational investigation, the critical effect of hydrogen bonding on the reactivity of this transformation was uncovered.

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.

Catalyst-Free Decarbonylative Trifluoromethylthiolation Enabled by Electron Donor-Acceptor Complex Photoactivation.

A catalyst- and additive-free decarbonylative trifluoromethylthiolation of aldehyde feedstocks has been developed. This operationally simple, scalable, and open-to-air transformation is driven by the selective photoexcitation of electron donor-acceptor (EDA) complexes, stemming from the association of 1,4-dihydropyridines (donor) with N-(trifluoromethylthio)phthalimide (acceptor), to trigger intermolecular single-electron transfer events under ambient- and visible light-promoted conditions. Extension to other electron acceptors enables the synthesis of thiocyanates and thioesters, as well as the difunctionalization of [1.1.1] propellane. The mechanistic intricacies of this photochemical paradigm are elucidated through a combination of experimental efforts and high-level quantum mechanical calculations [dispersion-corrected (U)DFT, DLPNO-CCSD(T), and TD-DFT]. This comprehensive study highlights the necessity for EDA complexation for efficient alkyl radical generation. Computation of subsequent ground state pathways reveals that SH2 addition of the alkyl radical to the intermediate radical EDA complex is extremely exergonic and results in a charge transfer event from the dihydropyridine donor to the N-(trifluoromethylthio)phthalimide acceptor of the EDA complex. Experimental and computational results further suggest that product formation also occurs via SH2 reaction of alkyl radicals with 1,2-bis(trifluoromethyl)disulfane, generated in-situ through combination of thiyl radicals.

Selectivity in the Elaboration of Bicyclic Borazarenes.

Among aromatic compounds, borazarenes represent a significant class of isosteres in which carbon-carbon bonds have been replaced by B-N bonds. Described herein is a summary of the selective reactions that have been developed for known systems, as well as a summary of computationally-based predictions of selectivities that might be anticipated in reactions of yet unrealized substructures.

Stereoinduction in Metallaphotoredox Catalysis.

Metallaphotoredox catalysis has evolved into an enabling platform to construct C(sp3 )-hybridized centers under remarkably mild reaction conditions. The cultivation of abundant radical precursor feedstocks has significantly increased the scope of transition-metal-catalyzed cross-couplings, especially with respect to C(sp2 )-C(sp3 ) linkages. In recent years, considerable effort has been devoted to understanding the origin of stereoinduction in dual catalytic processes. In this context, Ni- and Cu-catalyzed transformations have played a predominant role exploiting this mode of catalysis. Herein, we provide a critical overview on recent progress in enantioselective bond formations enabled by Ni- and Cu-catalyzed manifolds. Furthermore, selected stereochemical control elements within the realm of diastereoselective transformations are discussed.

On the Nature of C(sp3)-C(sp2) Bond Formation in Nickel-Catalyzed Tertiary Radical Cross-Couplings: A Case Study of Ni/Photoredox Catalytic Cross-Coupling of Alkyl Radicals and Aryl Halides.

The merger of photoredox and nickel catalysis has enabled the construction of quaternary centers. However, the mechanism, role of the ligand, and effect of the spin state for this transformation and related Ni-catalyzed cross-couplings involving tertiary alkyl radicals in combination with bipyridine and diketonate ligands remain unknown. Several mechanisms have been proposed, all invoking a key Ni(III) species prior to undergoing irreversible inner-sphere reductive elimination. In this work, we have used open-shell dispersion-corrected DFT calculations, quasi-classical dynamics calculations, and experiments to study in detail the mechanism of carbon-carbon bond formation in Ni bipyridine- and diketonate-based catalytic systems. These calculations revealed that access to high spin states (e.g., triplet spin state tetrahedral Ni(II) species) is critical for effective radical cross-coupling of tertiary alkyl radicals. Further, these calculations revealed a disparate mechanism for the C-C bond formation. Specifically, contrary to the neutral Ni-bipyridyl system, diketonate ligands lead directly to the corresponding tertiary radical cross-coupling products via an outer-sphere reductive elimination step via triplet spin state from the Ni(III) intermediates. Implications to related Ni-catalyzed radical cross-couplings and the design of new transformations are discussed.

Radical-Polar Crossover Annulation: A Platform for Accessing Polycyclic Cyclopropanes.

Photoredox-mediated radical/polar crossover (RPC) processes provide unique solutions to challenging annulations. Herein, we describe an approach to the cyclopropanation of olefins that are embedded within bicyclic scaffolds. Whereas these systems are notoriously recalcitrant toward classical cyclopropanation approaches, RPC cyclopropanation can be executed with ease, leading to polycarbocyclic and polyheterocyclic cyclopropanes. The cyclopropanation proceeds through a photoredox-enabled Giese-type radical addition followed by an intramolecular anionic substitution reaction on a neopentyl leaving group.

Photoredox-Mediated Net-Neutral Radical/Polar Crossover Reactions.

Radical/Polar Crossover (RPC) chemistry is a rapidly growing subset of photoredox catalysis that is characterized by transformations featuring both radical and ionic modes of reactivity. Net-neutral RPC is particularly interesting in that both the single-electron oxidation and reduction steps occur through interaction with the photocatalyst, thus precluding the need for exogenous oxidants or reductants. As such, these transformations facilitate rapid incorporation of molecular complexity while maintaining mild reaction conditions. This review covers recent advances in photoredox-mediated net-neutral RPC synthetic methods, with a particular emphasis on C-C bond-forming reactions.

Three-Component Olefin Dicarbofunctionalization Enabled by Nickel/Photoredox Dual Catalysis.

An intermolecular, photocatalytic dicarbofunctionalization (DCF) of olefins enabled by the merger of Giese-type addition with Ni/photoredox dual catalysis has been realized. Capitalizing on the rapid addition of 3° radicals to alkenes and their reluctance toward single electron metalation to Ni complexes, regioselective alkylation and arylation of olefins is possible. This dual catalytic method not only permits elaborate species to be assembled from commodity materials, but also allows quaternary and tertiary centers to be installed in a singular, chemoselective olefin difunctionalization. This multicomponent process occurs under exceptionally mild conditions, compatible with a diverse range of functional groups and synthetic handles such as pinacolboronate esters. This technology was directly applied to the synthesis of an intermediate to a preclinical candidate (TK-666) and its derivatives.