Over the last half-century, transition metal-mediated cross-coupling reactions have changed the way in which complex organic molecules are synthesized. Indeed, the predictable and chemoselective nature of these transformations has led to their widespread adoption across a vast array of chemical research areas1. However, the construction of sp3–sp3 bonds, a fundamental unit of organic chemistry, remains an important yet elusive objective for cross-coupling reaction engineering2. In comparison to related procedures with sp2-hybridized species, the development of methods for sp3–sp3 bond formation via transition metal catalysis has been historically hampered by deleterious side-reactions, such as β-hydride elimination with Pd-catalysis, and the reluctance of alkyl halides to undergo oxidative addition3,4. To address this issue, a number of research groups have demonstrated the feasibility of nickel-catalyzed cross-coupling processes to form sp3–sp3 bonds that utilize organometallic nucleophiles and alkyl electrophiles5–7. In particular, the coupling of alkyl halides with pregenerated organozinc8–10, Grignard11,12, and organoborane13 species has been used to furnish diverse molecular structures. However, the poor step and atom economies along with the operational difficulties associated with making, carrying, and using these sensitive coupling partners has hindered their widespread adoption. The prospect of establishing a generically useful sp3–sp3 coupling technology that employs bench-stable, native organic functional groups, without the need for pre-functionalization or substrate derivatization, would therefore be a valuable addition to fields of research that rely on organic molecule construction. Here, we demonstrate that the synergistic merger of photoredox and nickel catalysis enables the direct formation of sp3–sp3 bonds using only simple carboxylic acids and alkyl halides as the nucleophilic and electrophilic coupling partners, respectively. The outlined protocol is suitable for a wide array of primary and secondary carboxylic acids and does not require the presence of radical stabilizing groups. The merit of this coupling strategy is illustrated by the expedient synthesis of the pharmaceutical tirofiban in four steps from commercially available starting materials.

Multicomponent reactions (MCRs) have become a mainstay in both academic and industrial synthetic organic chemistry due to their step- and atom-economy advantages over traditional synthetic sequences 1 . Recently, bicyclo[1.1.1]pentane (BCP) motifs have come to the fore as valuable pharmaceutical bioisosteres of benzene rings, and, in particular, 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para -phenyl ring replacements 2 . Often these structures are generated from [1.1.1]propellane via opening of the internal C─C bond, either through the addition of radicals or metal-based nucleophiles 3 - 13 . The resulting propellane-addition adducts are subsequently transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. While this approach has been effective to date, it is clear that a multicomponent reaction that enables single-step access to complex and diverse polysubstituted BCP products would be synthetically advantageous over the current stepwise approaches. Herein we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicycles using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. The reaction operates on short time scales (five minutes to one hour) across multiple (>10) nucleophile classes and can accommodate a diverse array of radical precursors, including those which generate alkyl, α-acyl, trifluoromethyl, and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which has substantially different pharmacokinetic properties to those of its commercial progenitor.

A strategy for the installation of small alkyl fragments onto pharmaceutically relevant aliphatic structures has been established via metallaphotoredox catalysis. Herein, we report that tris(trimethylsilyl)silanol can be employed as an effective halogen abstraction reagent that, in combination with photoredox and nickel catalysis, allows a generic approach to Csp3─Csp3 cross-electrophile coupling. In this study, we demonstrate that a variety of aliphatic drug-like groups can be successfully coupled with a number of commercially available small alkyl electrophiles, including methyl tosylate and strained cyclic alkyl bromides. Moreover, the union of two secondary aliphatic carbon centers, a long-standing challenge for organic molecule construction, has been accomplished with a wide array of structural formats. Last, this technology can be selectively merged with Csp2─Csp3 aryl–alkyl couplings to build drug-like systems in a highly modular fashion.

The merger of open- and closed-shell elementary organometallic steps has enabled the selective intermolecular addition of nucleophilic radicals to unactivated alkynes. A range of carboxylic acids can be subjected to a CO extrusion, nickel capture, migratory insertion sequence with terminal and internal alkynes to generate stereodefined functionalized olefins. This platform has been further extended, via hydrogen atom transfer, to the direct vinylation of unactivated C-H bonds. Preliminary studies indicate that a Ni-alkyl migratory insertion is operative.

The marine roseobacter Phaeobacter sp. strain Y4I synthesizes the blue antimicrobial secondary metabolite indigoidine when grown in a biofilm or on agar plates. Prior studies suggested that indigoidine production may be, in part, regulated by cell-to-cell communication systems. Phaeobacter sp. strain Y4I possesses two luxR and luxI homologous N-acyl-L-homoserine lactone (AHL)-mediated cell-to-cell communication systems, designated pgaRI and phaRI. We show here that Y4I produces two dominant AHLs, the novel monounsaturated N-(3-hydroxydodecenoyl)-L-homoserine lactone (3OHC 12:1 -HSL) and the relatively common N-octanoyl-L-homoserine lactone (C 8 -HSL), and provide evidence that they are synthesized by PhaI and PgaI, respectively. A Tn5 insertional mutation in either genetic locus results in the abolishment (pgaR::Tn5) or reduction (phaR::Tn5) of pigment production. Motility defects and denser biofilms were also observed in these mutant backgrounds, suggesting an overlap in the functional roles of these systems. Production of the AHLs occurs at distinct points during growth on an agar surface and was determined by isotope dilution high-performance liquid chromatography-tandem mass spectrometry (ID-HPLC-MS/MS) analysis. Within 2 h of surface inoculation, only 3OHC 12:1 -HSL was detected in agar extracts. As surface-attached cells became established (at ϳ10 h), the concentration of 3OHC 12:1 -HSL decreased, and the concentration of C 8 -HSL increased rapidly over 14 h. After longer (>24-h) establishment periods, the concentrations of the two AHLs increased to and stabilized at ϳ15 nM and ϳ600 nM for 3OHC 12:1 -HSL and C 8 -HSL, respectively. In contrast, the total amount of indigoidine increased steadily from undetectable to 642 M by 48 h. Gene expression profiles of the AHL and indigoidine synthases (pgaI, phaI, and igiD) were consistent with their metabolite profiles. These data provide evidence that pgaRI and phaRI play overlapping roles in the regulation of indigoidine biosynthesis, and it is postulated that this allows Phaeobacter sp. strain Y4I to coordinate production of indigoidine with different growth-phase-dependent physiologies. Bacteria are in constant competition for niches in the environment, and the ability to coordinate gene expression may provide a competitive advantage (1). Some bacteria are able to synchronize gene expression in a cell-density-dependent manner by sensing and responding to small diffusible molecules synthesized by individuals; in proteobacteria, members of the broadly distributed and chemically diverse class of N-acyl-L-homoserine lactones (AHLs) are among the best-characterized signaling molecules (2). Proteobacterial AHL synthases are fairly well conserved and form the LuxI protein family. Members of the LuxR protein family are cytoplasmic transcriptional regulators that can modulate gene expression, most typically when bound to the corresponding cognate AHL (3-7). It has been shown that luxI-luxR (luxIR) pairs are frequently colocalized within chromosomes and constitutively exp...