At the Speed of Light: The Systematic Implementation of Photoredox Cross-Coupling Reactions for Medicinal Chemistry Research.

The adoption of new and emerging techniques in organic synthesis is essential to promote innovation in drug discovery. In this Perspective, we detail the strategy we used for the systematic deployment of photoredox-mediated, metal-catalyzed cross-coupling reactions in AbbVie's medicinal chemistry organization, focusing on topics such as assessment, evaluation, implementation, and accessibility. The comprehensive evaluation of photoredox reaction setups and published methods will be discussed, along with internal efforts to build expertise and photoredox high-throughput experimentation capabilities. We also highlight AbbVie's academic-industry collaborations in this field that have been leveraged to develop new synthetic strategies, along with discussing the internal adoption of photoredox cross-coupling reactions. The work described herein has culminated in robust photocatalysis and cross-coupling capabilities which are viewed as key platforms for medicinal chemistry research at AbbVie.

Nickel-Mediated Alkyl-, Acyl-, and Sulfonylcyanation of [1.1.1]Propellane.

The replacement of traditional functional groups with polycyclic scaffolds has been increasingly rewarding in medicinal chemistry programs. Over the decades, 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs) have demonstrated the potential for being competent bioisosteres for aryl-, alkyl- and alkynyl substructures. Although highly desired, mild and versatile synthetic methods to access synthetically valuable BCP-containing building blocks remain limited. Herein, a versatile way to access bridgehead substituted BCP nitriles, a useful BCP building block, is described, enabled by the unexpected selectivity of nickel in the multi-component radical cyanation. Commodity materials including carboxylic acids, amines, sulfonyl chlorides, and alkyl chlorides are engaged to provide a broad spectrum of substituted BCP nitriles in a single-step, multi-component fashion.

Photoinduced Diastereoselective Aminoalkylation of Cubanes.

The unique properties of rigid, nonconjugated hydrocarbons provide many opportunities to design molecular building blocks for a variety of applications, but the development of suitable conditions for alkylation of cubanes is quite challenging. Herein, a photoinduced method for aminoalkylation of cubanes is reported. The benign conditions reported allow the incorporation of a wide variety of (hetero)arylimine reaction partners with broad functional group tolerance and high diastereoselectivity.

Redefining the Synthetic Logic of Medicinal Chemistry. Photoredox-Catalyzed Reactions as a General Tool for Aliphatic Core Functionalization.

C(sp3)-rich aliphatic motifs in drug molecules are strongly associated with clinical success. Historically, the availability of compound libraries based on C(sp3)-rich cores has been limited due to the challenging direct functionalization of aliphatic rings. Instead, most small molecule drug-like libraries are diversified around central aromatic rings. Herein, we present a general approach to the synthesis of diversified libraries featuring aliphatic core rings via photoredox catalysis under mild conditions.

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.

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.

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.

One step synthesis of unsymmetrical 1,3-disubstituted BCP ketones via nickel/photoredox-catalyzed [1.1.1]propellane multicomponent dicarbofunctionalization.

Bicyclo[1.1.1]pentanes (BCPs), utilized as sp3-rich bioisosteres for tert-butyl- and aryl groups as well as internal alkynes, have gained considerable momentum in drug development programs. Although many elegant methods have been developed to access BCP amines and BCP aryls efficiently, the methods used to construct BCP ketones directly are relatively underdeveloped. In particular, the preparation of unsymmetrical 1,3-disubstituted-BCP ketones remains challenging and still requires multiple chemical steps. Herein, a single-step, multi-component approach to versatile disubstituted BCP ketones via nickel/photoredox catalysis is reported. Importantly, installing a boron group at the carbon position adjacent to the BCP structure bypasses the limitation to tertiary BF3K coupling partners, thus expanding the scope of this paradigm. Further transformation of disubstituted-BCP ketones into a variety of other BCP derivatives demonstrates the synthetic value of this developed method.

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.

Photocatalysis in the Life Science Industry.

In the pursuit of new pharmaceuticals and agrochemicals, chemists in the life science industry require access to mild and robust synthetic methodologies to systematically modify chemical structures, explore novel chemical space, and enable efficient synthesis. In this context, photocatalysis has emerged as a powerful technology for the synthesis of complex and often highly functionalized molecules. This Review aims to summarize the published contributions to the field from the life science industry, including research from industrial-academic partnerships. An overview of the synthetic methodologies developed and strategic applications in chemical synthesis, including peptide functionalization, isotope labeling, and both DNA-encoded and traditional library synthesis, is provided, along with a summary of the state-of-the-art in photoreactor technology and the effective upscaling of photocatalytic reactions.

Nickel-Catalyzed Decarboxylative Cross-Coupling of Bicyclo[1.1.1]pentyl Radicals Enabled by Electron Donor-Acceptor Complex Photoactivation.

The use of bicyclo[1.1.1]pentanes (BCPs) as para-disubstituted aryl bioisosteres has gained considerable momentum in drug development programs. Carbon-carbon bond formation via transition-metal-mediated cross-coupling represents an attractive strategy to generate BCP-aryl compounds for late-stage functionalization, but these typically require reactive organometallics to prepare BCP nucleophiles on demand from [1.1.1]propellane. In this study, the synthesis and Ni-catalyzed functionalization of BCP redox-active esters with (hetero)aryl bromides via the action of a photoactive electron donor-acceptor complex are reported.

Silylium Ions: From Elusive Reactive Intermediates to Potent Catalysts.

The history of silyl cations has all the makings of a drama but with a happy ending. Being considered reactive intermediates impossible to isolate in the condensed phase for decades, their actual characterization in solution and later in solid state did only fuel the discussion about their existence and initially created a lot of controversy. This perception has completely changed today, and silyl cations and their donor-stabilized congeners are now widely accepted compounds with promising use in synthetic chemistry. This review provides a comprehensive summary of the fundamental facts and principles of the chemistry of silyl cations, including reliable ways of their preparation as well as their physical and chemical properties. The striking features of silyl cations are their enormous electrophilicity and as such reactivity as super Lewis acids as well as fluorophilicity. Known applications rely on silyl cations as reactants, stoichiometric reagents, and promoters where the reaction success is based on their steady regeneration over the course of the reaction. Silyl cations can even be discrete catalysts, thereby opening the next chapter of their way into the toolbox of synthetic methodology.

Cyclohexa-1,4-dienes in transition-metal-free ionic transfer processes.

Safe- and convenient-to-handle surrogates of hazardous chemicals are always in demand. Recently introduced cyclohexa-1,4-dienes with adequate substitution fulfil this role as El+/H- equivalents in B(C6F5)3-catalysed transfer reactions of El-H to π- and σ-donors (C[double bond, length as m-dash]C/C[triple bond, length as m-dash]C and C[double bond, length as m-dash]O/C[double bond, length as m-dash]N). Surrogates of Si-H/Ge-H, H-H and even C-H bonds have been designed and successfully applied to ionic transfer hydrosilylation/hydrogermylation, hydrogenation and hydro-tert-butylation, respectively. These processes and their basic principles are summarised in this Minireview. The similarities and differences between these transfer reactions as well as the challenges associated with these transformations are discussed.

Access to Fully Alkylated Germanes by B(C6F5)3-Catalyzed Transfer Hydrogermylation of Alkenes.

Various cyclohexa-2,5-dien-1-yl-substituted germanes are shown to serve as easy-to-handle surrogates of hydrogermanes, including gaseous MeGeH3 and Me2GeH2. The Ge-H functional group is liberated by treatment with catalytic amounts of B(C6F5)3 and participates in situ in the B(C6F5)3-catalyzed hydrogermylation of alkenes. The range of suitable alkenes is broad, and the overall procedure provides a convenient access to tetraalkyl-substituted germanes at room temperature. Transfer hydrogermylation of internal alkynes works equally well and selectively forms the trans or cis diastereomer depending on the electronic bias of the C≡C bond.

3-tert-Butyl-Substituted Cyclohexa-1,4-dienes as Isobutane Equivalents in the B(C6 F5 )3 -Catalyzed Transfer Hydro-tert-Butylation of Alkenes.

Cyclohexa-1,4-dienes with a tert-butyl group at C3 are shown to function as isobutane equivalents when activated by the strong boron Lewis acid tris(pentafluorophenyl)borane. The hitherto unprecedented transfer hydro-tert-butylation from one unsaturated hydrocarbon to another is achieved with 1,1-diarylalkenes as substrates, thereby presenting itself as a new way of incorporating tertiary alkyl groups into carbon frameworks. Transient carbocation intermediates give rise to competing reaction pathways that could not be fully suppressed.