The merger of photoredox catalysis with transition metal catalysis, termed metallaphotoredox catalysis, has become a mainstay in synthetic methodology over the past decade. Metallaphotoredox catalysis has combined the unparalleled capacity of transition metal catalysis for bond formation with the broad utility of photoinduced electron- and energy-transfer processes. Photocatalytic substrate activation has allowed the engagement of simple starting materials in metal-mediated bond-forming processes. Moreover, electron or energy transfer directly with key organometallic intermediates has provided novel activation modes entirely complementary to traditional catalytic platforms. This Review details and contextualizes the advancements in molecule construction brought forth by metallaphotocatalysis.

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The replacement of aryl rings with saturated carbocyclic structures has garnered significant interest in drug discovery due to the potential for improved pharmacokinetic properties upon substitution. In particular, 1,3-difunctionalized bicyclo[1.1.1]pentanes (BCPs) have been widely adopted as bioisosteres for parasubstituted arene rings, appearing in a number of lead pharmaceutical candidates. However, despite the pharmaceutical value of 2-substituted BCPs as replacements for ortho- or meta-substituted arene rings, general and rapid syntheses of these scaffolds remain elusive. Current approaches to 2-substituted BCPs rely on installation of the bridge substituent prior to BCP core construction, leading to lengthy step counts and often nonmodular sequences. While challenging, direct functionalization of the strong bridge BCP C–H bonds would offer a more streamlined pathway to diverse 2-substituted BCPs. Here, we report a generalizable synthetic linchpin strategy for bridge functionalization via radical C–H abstraction of the BCP core. Through mild generation of a strong hydrogen atom abstractor, we rapidly synthesize novel 2-substituted BCP synthetic linchpins in one pot. These synthetic linchpins then serve as common precursors to complex 2-substituted BCPs, allowing one-step access to a number of previously inaccessible electrophile and nucleophile fragments at the 2-position via two new metallaphotoredox protocols. Altogether, this platform enables the expedient synthesis of four pharmaceutical analogues, all of which show similar or improved properties compared to their aryl-containing equivalents, demonstrating the potential of these 2-substituted BCPs in drug development.

The enantioselective dichlorination of alkenes is a continuing challenge in organic synthesis owing to the limitations of selective and independent antarafacial delivery of both electrophilic chlorenium and nucleophilic chloride to an olefin. Development of a general method for the enantioselective dichlorination of isolated alkenes would allow access to a wide variety of polyhalogenated natural products. Accordingly, the enantioselective suprafacial dichlorination of alkenes catalyzed by electrophilic organoselenium reagents has been developed to address these limitations. The evaluation of twenty-three diselenides as precatalysts for enantioselective dichlorination is described, with a maximum e.r. of 76:24 Additionally, mechanistic studies suggest an unexpected Dynamic Kinetic Asymmetric Transformation (DyKAT) process may be operative.

Yndiamides, underexplored cousins of ynamides, offer rich synthetic potential as doubly nitrogenated two carbon building blocks. Here we report a gold-catalyzed oxidative functionalization of yndiamides to access unnatural amino acid derivatives, using a wide range of nucleophiles as a source of the amino acid side chain. The transformation proceeds under mild conditions, is highly functional group tolerant, and displays excellent regioselectivity through subtle steric differentiation of the yndiamide nitrogen atom substituents.