Synthesis of <i>gem</i>-Diboromethyl-Substituted Bicyclo[1.1.1]pentanes and Their Application in Palladium-Catalyzed Cross Couplings

We describe the first general transition-metal-free synthesis of gem-diboromethyl-substituted bicyclo[1.1.1]pentane (BCP) and other related C(sp3)-rich carbocyclic benzene bioisosteres from their corresponding p-tosylhydrazones. These novel functionalized benzene bioisosteres demonstrated unique reactivities toward palladium-catalyzed C(sp2)–C(sp3) cross couplings. The overall transformation can be applied to relatively complex substrates with potential utility in drug discovery

Intermolecular Hydropyridylation of Unactivated Alkenes

A general method for the hydropyridylation of unactivated alkenes is described. The transformation connects metal-mediated hydrogen atom transfer to alkenes and Minisci addition reactions. The reaction proceeds under mild conditions with high site-selectivities and allows for the construction of tertiary and quaternary centers from simple alkene starting materials

Synthesis of Ketones and Esters from Heteroatom-Functionalized Alkenes by Cobalt-Mediated Hydrogen Atom Transfer

Cobalt bis­(acetylacetonate) is shown to mediate hydrogen atom transfer to a broad range of functionalized alkenes; in situ oxidation of the resulting alkylradical intermediates, followed by hydrolysis, provides expedient access to ketones and esters. By modification of the alcohol solvent, different alkyl ester products may be obtained. The method is compatible with a number of functional groups including alkenyl halides, sulfides, triflates, and phosphonates and provides a mild and practical alternative to the Tamao–Fleming oxidation of vinylsilanes and the Arndt–Eistert homologation

A Method for the Selective Hydrogenation of Alkenyl Halides to Alkyl Halides

A general method for the selective hydrogenation of alkenyl halides to alkyl halides is described. Fluoro, chloro, bromo, iodo, and <i>gem</i>-dihaloalkenes are viable substrates for the transformation. The selectivity of the hydrogenation is consistent with reduction by a hydrogen atom transfer pathway

Decarboxylative C–N Coupling of 2,2-Difluorobicyclo[1.1.1]pentane (BCP‑F₂) Building Blocks

Described herein is our effort toward achieving the decarboxylative functionalization of 2,2-difluorobicyclo[1.1.1]­pentane (BCP-F2) building blocks. When compared with the nonfluorinated bicyclo[1.1.1]­pentane (BCP) analogues, we discovered divergent reactivities. This is the first successful decarboxylative coupling of BCP-F2 building blocks reported via the photoredox mechanism

Directed C–H Bond Oxidation of (+)-Pleuromutilin

Antibiotics derived from the diterpene fungal metabolite (+)-pleuromutilin (1) are useful agents for the treatment Gram-positive infections in humans and farm animals. Pleuromutilins elicit slow rates of resistance development and minimal cross-resistance with existing antibiotics. Despite efforts aimed at producing new derivatives by semisynthesis, modification of the tricyclic core is underexplored, in part due to a limited number of functional group handles. Herein, we report methods to selectively functionalize the methyl groups of (+)-pleuromutilin (1) by hydroxyl-directed iridium-catalyzed C–H silylation, followed by Tamao–Fleming oxidation. These reactions provided access to C16, C17, and C18 monooxidized products, as well as C15/C16 and C17/C18 dioxidized products. Four new functionalized derivatives were prepared from the protected C17 oxidation product. C6 carboxylic acid, aldehyde, and normethyl derivatives were prepared from the C16 oxidation product. Many of these sequences were executed on gram scales. The efficiency and practicality of these routes provides an easy method to rapidly interrogate structure–activity relationships that were previously beyond reach. This study will inform the design of fully synthetic approaches to novel pleuromutilins and underscores the power of the hydroxyl-directed iridium-catalyzed C–H silylation reaction

C(sp)–C(sp³) Bond Formation through Cu-Catalyzed Cross-Coupling of <i>N</i>-Tosylhydrazones and Trialkylsilylethynes

Copper-catalyzed cross-coupling of <i>N</i>-tosylhydrazones with trialkylsilylethynes leads to the formation of C­(sp)–C­(sp³) bonds. Cu carbene migratory insertion is proposed to play the key role in this transformation

Directed C–H Bond Oxidation of (+)-Pleuromutilin

Antibiotics derived from the diterpene fungal metabolite (+)-pleuromutilin (<b>1</b>) are useful agents for the treatment Gram-positive infections in humans and farm animals. Pleuromutilins elicit slow rates of resistance development and minimal cross-resistance with existing antibiotics. Despite efforts aimed at producing new derivatives by semisynthesis, modification of the tricyclic core is underexplored, in part due to a limited number of functional group handles. Herein, we report methods to selectively functionalize the methyl groups of (+)-pleuromutilin (<b>1</b>) by hydroxyl-directed iridium-catalyzed C–H silylation, followed by Tamao–Fleming oxidation. These reactions provided access to C16, C17, and C18 monooxidized products, as well as C15/C16 and C17/C18 dioxidized products. Four new functionalized derivatives were prepared from the protected C17 oxidation product. C6 carboxylic acid, aldehyde, and normethyl derivatives were prepared from the C16 oxidation product. Many of these sequences were executed on gram scales. The efficiency and practicality of these routes provides an easy method to rapidly interrogate structure–activity relationships that were previously beyond reach. This study will inform the design of fully synthetic approaches to novel pleuromutilins and underscores the power of the hydroxyl-directed iridium-catalyzed C–H silylation reaction