Native functionality in triple catalytic cross-coupling: sp3 C-H bonds as latent nucleophiles

The use of sp3 C–H bonds—which are ubiquitous in organic molecules—as latent nucleophile equivalents for transition metal–catalyzed cross-coupling reactions has the potential to substantially streamline synthetic efforts in organic chemistry while bypassing substrate activation steps. Through the combination of photoredox-mediated hydrogen atom transfer (HAT) and nickel catalysis, we have developed a highly selective and general C–H arylation protocol that activates a wide array of C–H bonds as native functional handles for cross-coupling. This mild approach takes advantage of a tunable HAT catalyst that exhibits predictable reactivity patterns based on enthalpic and bond polarity considerations to selectively functionalize α-amino and α-oxy sp3 C–H bonds in both cyclic and acyclic systems

A General and Enantioselective Approach to Pentoses: A Rapid Synthesis of PSI-6130, the Nucleoside Core of Sofosbuvir

An efficient route towards biologically relevant pentose derivatives is described. The <i>de novo</i> synthetic strategy features an enantioselective α-oxidation reaction enabled by a chiral amine in conjunction with copper­(II) catalysis. A subsequent Mukaiyama aldol coupling allows for the incorporation of a wide array of modular two-carbon fragments. Lactone intermediates accessed via this route provide a useful platform for elaboration, as demonstrated by the preparation of a variety of <i>C</i>-nucleosides and fluorinated pentoses. Finally, this work has facilitated expedient syntheses of pharmaceutically active compounds currently in clinical use

Switching on elusive organometallic mechanisms with photoredox catalysis

Transition-metal-catalysed cross-coupling reactions have become one of the most used carbon–carbon and carbon–heteroatom bond-forming reactions in chemical synthesis. Recently, nickel catalysis has been shown to participate in a wide variety of C−C bond-forming reactions, most notably Negishi, Suzuki–Miyaura, Stille, Kumada and Hiyama couplings1,2. Despite the tremendous advances in C−C fragment couplings, the ability to forge C−O bonds in a general fashion via nickel catalysis has been largely unsuccessful. The challenge for nickel-mediated alcohol couplings has been the mechanistic requirement for the critical C–O bond-forming step (formally known as the reductive elimination step) to occur via a Ni(iii) alkoxide intermediate. Here we demonstrate that visible-light-excited photoredox catalysts can modulate the preferred oxidation states of nickel alkoxides in an operative catalytic cycle, thereby providing transient access to Ni(iii) species that readily participate in reductive elimination. Using this synergistic merger of photoredox and nickel catalysis, we have developed a highly efficient and general carbon–oxygen coupling reaction using abundant alcohols and aryl bromides. More notably, we have developed a general strategy to ‘switch on’ important yet elusive organometallic mechanisms via oxidation state modulations using only weak light and single-electron-transfer catalysts