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The replacement of aryl rings with C(sp3)-rich 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 para-substituted arene rings, appearing in a number of lead pharmaceutical candidates. Due to their medicinal importance, multiple methods have been developed to efficiently synthesize these 1,3-difunctionalized BCPs. 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 non-modular 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 analogs, 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 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.

Over the past three decades, considerable progress has been made in the development of methods to construct sp2 carbon-nitrogen (C-N) bonds using palladium, copper or nickel catalysis1,2. However, the incorporation of alkyl substrates to form sp3 C-N bonds remains one of the major challenges in the field of cross-coupling chemistry. Here we demonstrate that the synergistic combination of copper catalysis and photoredox catalysis can provide a general platform from which to address this challenge. This cross-coupling system uses naturally abundant alkyl carboxylic acids and commercially available nitrogen nucleophiles as coupling partners. It is applicable to a wide variety of primary, secondary and tertiary alkyl carboxylic acids (through iodonium activation), as well as a vast array of nitrogen nucleophiles: nitrogen heterocycles, amides, sulfonamides and anilines can undergo C-N coupling to provide N-alkyl products in good to excellent efficiency, at room temperature and on short timescales (five minutes to one hour). We demonstrate that this C-N coupling protocol proceeds with high regioselectivity using substrates that contain several amine groups, and can also be applied to complex drug molecules, enabling the rapid construction of molecular complexity and the late-stage functionalization of bioactive pharmaceuticals.

The functionalization of carbon–hydrogen (C–H) bonds is one of the most attractive strategies for molecular construction in organic chemistry. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in organic molecules and its availability for functionalization at almost any stage in a synthetic sequence1. Although many C–H functionalization reactions involve C(sp3)–C(sp2) coupling, there is a growing demand for C–H alkylation reactions, wherein sp3 C–H bonds are replaced with sp3 C–alkyl groups. Here we describe a polarity-match-based selective sp3 C–H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodology simultaneously uses three catalytic cycles to achieve hydridic C–H bond abstraction (enabled by polarity matching), alkyl halide oxidative addition, and reductive elimination to enable alkyl–alkyl fragment coupling. The sp3 C–H alkylation is highly selective for the α-C–H of amines, ethers and sulphides, which are commonly found in pharmaceutically relevant architectures. This cross-coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chemistry.

A wide array of cross-coupling methods for the formation of C–C bonds from unactivated alkyl electrophiles have been described in recent years. In contrast, progress in the development of methods for the construction of C–heteroatom bonds has lagged; for example, there have been no reports of metal-catalyzed cross-couplings of unactivated secondary or tertiary alkyl halides with silicon nucleophiles to form C–Si bonds. In this study, we address this challenge, establishing that a simple, commercially available nickel catalyst (NiBr_2·diglyme) can achieve couplings of alkyl bromides with nucleophilic silicon reagents under unusually mild conditions (e.g., −20 °C); especially noteworthy is our ability to employ unactivated tertiary alkyl halides as electrophilic coupling partners, which is still relatively uncommon in the field of cross-coupling chemistry. Stereochemical, relative reactivity, and radical-trap studies are consistent with a homolytic pathway for C–X bond cleavage.

In this report, we establish that a readily available nickel/bis(oxazoline) catalyst accomplishes a wide array of enantioconvergent cross-couplings of arylzinc reagents with CF_3-substituted racemic secondary alkyl halides, a process that necessitates that the chiral catalyst be able to effectively distinguish between a CF_3 and an alkyl group in order to provide good ee. We further demonstrate that this method can be applied without modification to the catalytic asymmetric synthesis of other families of fluorinated organic compounds.

Over the last three decades, significant progress has been made in the development of methods to construct sp2 C–N bonds using palladium, copper, or nickel catalysis1,2. However, the incorporation of alkyl substrates to form sp3 C–N bonds remains one of the major challenges in the field of cross-coupling chemistry. Here, we demonstrate that the synergistic combination of copper catalysis and photoredox catalysis can provide a general platform to address this challenge. This cross-coupling system employs naturally abundant alkyl carboxylic acids and commercially available N-nucleophiles as coupling partners, and is applicable to a wide variety of primary, secondary, and tertiary alkyl carboxylic acids (via iodonium activation). At the same time, a vast array of N-nucleophiles, including N-heterocycles, amides, sulfonamides, and anilines, can undergo C–N coupling to provide N-alkyl products in good to excellent efficiency at room temperature and in short order (5 minutes to 1 hour). We have also demonstrated that this C–N coupling protocol can be applied to substrates bearing multiple amines with high regioselectivity, as well as complex drug molecules, enabling the rapid construction of molecular complexity and the late stage functionalization of bioactive pharmaceuticals.

The development of new approaches to the construction of fluorine-containing target molecules is important for a variety of scientific disciplines, including medicinal chemistry. In this Article, we describe a method for the catalytic enantioselective synthesis of tertiary alkyl fluorides through Negishi reactions of racemic α-halo-α-fluoroketones, which represents the first catalytic asymmetric cross-coupling that employs geminal dihalides as electrophiles. Thus, selective reaction of a C-Br (or C-Cl) bond in the presence of a C-F bond can be achieved with the aid of a nickel/bis(oxazoline) catalyst. The products of the stereoconvergent cross-couplings, enantioenriched tertiary α-fluoroketones, can be converted into an array of interesting organofluorine compounds.

For the first time, the use of metal catalyst NiBr2·diglyme for the title reaction is described to yield a wide range of silylated compounds.

Silver hexafluroantimonate was identified as a highly efficient agent to reverse the facial selectivity of the titanium chloride-mediated vinylogous Mukaiyama aldol reaction (VMAR), and this unprecedented reaction provides a concise, diastereoselective synthesis of δ-hydroxy-α,γ-dimethyl-α,β-unsaturated carbonyl units from readily available chiral vinylketene silyl N,O-acetal 6 and ethyl glyoxylate 8.

In this report, we establish that a readily available nickel/bis(oxazoline) catalyst accomplishes a wide array of enantioconvergent cross-couplings of arylzinc reagents with CF3-substituted racemic secondary alkyl halides, a process that necessitates that the chiral catalyst be able to effectively distinguish between a CF3 and an alkyl group in order to provide good ee. We further demonstrate that this method can be applied without modification to the catalytic asymmetric synthesis of other families of fluorinated organic compounds.

Fluorinated organic molecules are of interest in fields ranging from medicinal chemistry to polymer science. Described herein is a mild, convenient, and versatile method for the synthesis of compounds bearing a perfluoroalkyl group attached to a tertiary carbon atom by using an alkyl–alkyl cross-coupling. A nickel catalyst derived from NiCl_2⋅glyme and a pybox ligand achieves the coupling of a wide range of fluorinated alkyl halides with alkylzinc reagents at room temperature. A broad array of functional groups is compatible with the reaction conditions, and highly selective couplings can be achieved on the basis of differing levels of fluorination. A mechanistic investigation has established that the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) inhibits cross-coupling under these conditions and that a TEMPO–electrophile adduct can be isolated.

Fluorinated organic molecules are of interest in fields ranging from medicinal chemistry to polymer science. Herein, we describe a mild, convenient, and versatile method for the synthesis of compounds that bear a perfluoroalkyl group attached to a tertiary carbon, via an alkyl–alkyl cross-coupling. Thus, a nickel catalyst derived from commercially available components (NiCl2·glyme and a pybox ligand) achieves the coupling of a wide range of fluorinated alkyl halides with alkylzinc reagents at room temperature. A broad array of functional groups (e.g., alkyne, aryl iodide, carbamate, furan, ketone, nitrile, phosphonate, primary alkyl bromide, and primary alkyl tosylate) are compatible with the reaction conditions, and highly selective couplings can be achieved on the basis of differing levels of fluorination. A mechanistic investigation has established that the presence of TEMPO inhibits cross-coupling under these conditions and that a TEMPO–electrophile adduct can be isolated.

The development of new approaches to the construction of fluorine-containing target molecules is important for a variety of scientific disciplines, including medicinal chemistry. In this Article, we describe a method for the catalytic enantioselective synthesis of tertiary alkyl fluorides through Negishi reactions of racemic α-halo-α-fluoroketones, which represents the first catalytic asymmetric cross-coupling that employs geminal dihalides as electrophiles. Thus, selective reaction of a C–Br (or C–Cl) bond in the presence of a C–F bond can be achieved with the aid of a nickel/bis(oxazoline) catalyst. The products of the stereoconvergent cross-couplings, enantioenriched tertiary α-fluoroketones, can be converted into an array of interesting organofluorine compounds.