CONSPECTUS. Implementation of any chemical reaction in a structurally complex setting (King, S. M., J. Org. Chem., 2014, 79, 8937) confronts structurally-defined barriers: steric environment, functional group reactivity, product instability, and through-bond electronics. But there are also practical barriers. Late stage reactions conducted on small quantities of material are run inevitably at lower than optimal concentrations. Access to late stage material limits extensive optimization. Impurities from past reactions can interfere, especially with catalytic reactions. Therefore, chemical reactions that can be relied upon at the front lines of a complex synthesis campaign emerge from the crucible of total synthesis as robust, dependable, and widely applied. Trost conceptualized ‘chemoselectivity’ as a reagent’s selective reaction of one functional group or reactive site in preference to others (Trost, B. M., Science, 1983, 219, 245). Chemoselectivity and functional group tolerance can be evaluated quickly using robustness screens (Collins, K. D., Nat. Chem., 2013, 5, 597). A reaction may also be characterized by its ‘chemofidelity’, its reliable reaction with a functional group in any molecular context. For example, ketone reduction by an electride (dissolving metal conditions) exhibits high chemofidelity, but low chemoselectivity: it usually works, but many other functional groups are reduced at similar rates. Conversely, alkene coordination chemistry effected by π Lewis acids can exhibit high chemoselectivity (Trost, B. M., Science, 1983, 219, 245), but low chemofidelity: it can be highly selective for alkenes, but sensitive to substitution patterns (Larionov, E., Chem Comm., 2014, 50, 9816). In contrast, alkenes undergo reliable, robust, and diverse hydrogen atom transfer reactions from metal hydrides to generate carbon-centered radicals. Although there are many potential applications of this chemistry, its functional group tolerance, high rates, and ease of execution have led to its rapid deployment in complex synthesis campaigns. Its success derives from high chemofidelity; its dependable reactivity in many molecular environments and with many alkene substitution patterns. Metal hydride H-atom transfer (MHAT) reactions convert diverse, simple building blocks to more stereochemically and functionally dense products (Crossley, S. W. M., Chem. Rev., 2016, 116, 8912). When hydrogen is returned to the metal, MHAT can be considered the radical equivalent of Brønsted acid catalysis—itself a broad reactivity paradigm. This Account summarizes our group’s contributions to method development, reagent discovery, and mechanistic interrogation. Our earliest contribution to this area—a stepwise hydrogenation with high chemoselectivity and high chemofidelity—has found application to many problems. More recently, we reported the first examples of a dual-catalytic cross-couplings that rely on the merger of MHAT cycles and nickel catalysis. With time, we anticipate MHAT will become a staple of chemical synthesis.

Metal-hydride hydrogen atom transfer (MHAT) functionalizes alkenes with predictable branched (Markovnikov) selectivity. The breadth of these transformations has been confined to π-radical traps; no sp3 electrophiles have been reported. Here we describe a Mn/Ni dual catalytic system that hydroalkylates unactivated olefins with unactivated alkyl halides, yielding aliphatic quaternary carbons.

DNA Encoded Libraries have proven immensely powerful tools for lead identification. The ability to screen billions of compounds at once has spurred increasing interest in DEL development and utilization. Although DEL provides access to libraries of unprecedented size and diversity, the idiosyncratic and hydrophilic nature of the DNA tag severely limits the scope of applicable chemistries. It is known that biomacromolecules can be reversibly, non-covalently adsorbed and eluted from solid supports, and this phenomenon has been utilized to perform synthetic modification of biomolecules in a strategy we have described as reversible adsorption to solid support (RASS). Herein, we present the adaptation of RASS for a DEL setting, which allows reactions to be performed in organic solvents at near anhydrous conditions opening previously inaccessible chemical reactivities to DEL. The RASS approach enabled the rapid development of C(sp 2 )-C(sp 3 ) decarboxylative cross-couplings with broad substrate scope, an electrochemical amination (the first electrochemical synthetic transformation performed in a DEL context), and improved reductive amination conditions. The utility of these reactions was demonstrated through a DEL-rehearsal in which all newly developed chemistries were orchestrated to afford a compound rich in diverse skeletal linkages. We believe that RASS will offer expedient access to new DEL reactivities, expanded chemical space, and ultimately more drug-like libraries.