Transition metal-catalyzed cross-coupling reactions have become one of the most utilized carbon–carbon and carbon–heteroatom bond-forming reactions in chemical synthesis. More 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. In this manuscript, 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 significantly, 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 (SET) catalysts.

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 a-amino and a-oxy sp3 C–H bonds in both cyclic and acyclic systems.

A catalytic, enantioselective method for the C-H functionalization of indoles by diazo compounds has been achieved. With catalytic amounts of Rh 2 (S-NTTL) 4 , the putative Rh-carbene intermediates from α-alkyl-α-diazoesters react with indoles at C(3) to provide α-alkyl-α-indolylacetates in high yield and enantioselectivity. From DFT calculations, a mechanism is proposed that involves a Rh-ylide intermediate with oxocarbenium character.Indoles are important structural motifs in a myriad of biologically interesting natural products and pharmaceutical targets. 1 Accordingly, several methods have been developed for the generation of highly functionalized indoles. 2 Among these strategies is the selective functionalization by metal carbenes derived from α-diazocarbonyl compounds, 3 a reactivity pattern that has been utilized in various total syntheses 4 as well as selective tryptophan modification in peptides and proteins. 5 However, the only catalytic enantioselective reaction of indoles and transient metal carbenes is Davies' [3+2] annulation of indoles with styryldiazoacetates (eq. 1). 6 While indol-3-yl acetate derivatives with stereogenic centers positioned α-to C-3 have high medicinal value, 1e,f only one example of an enantioselective C-H functionalization reaction of an indole has been reported, and the ee was < 5%. 6 Described herein is a general Rh-catalyzed method for enantioselective C-H functionalization of indoles by carbenoids derived from α-alkyl-α-diazoesters (eq. 2).(1) (2) jmfox@udel.edu . Supporting Information Available: Full experimental details, 1 H and 13 C-NMR spectra, stereochemical assignments, computational details and crystallographic (CIF) data are provided. This material is available free of charge via the Internet at http://pubs.acs.org. 4 ]. 10,11 Models for asymmetric induction based on chiral crown conformations have been proposed 7a,9 and debated, 12 and factors that create bias for the chiral crown configuration over competing conformations have been discussed. 7a,9,10 With this foundation, we hypothesized that enantioselective reactions between indoles and α-alkyl-α-diazoesters could be catalyzed by Rh-complexes proposed to adopt chiral crown conformations. NIH Public AccessWe began our investigation with the reaction of 1,2-dimethylindole with a 2-fold excess of ethyl 2-diazohexanoate (Table 1). A variety of Rh-complexes derived from t-leucine were screened, as were Rh 2 (S-DOSP) 4 and Rh 2 (S-PTAD) 4 . While many of the catalysts screened gave 1 with good enantioselectivity, it was found that Rh 2 (S-NTTL) 4 in toluene at −78 °C was optimal both in terms of yield and enantioselectivity, as 1 was formed in 95% yield and 95% ee. In line with our previous observations, 7 the use of low temperature was critical to the success of the reaction: the analogous reaction at higher temperature (0 °C) gave 1 in only 36% yield and 85% ee (entry 7).With the optimized reaction conditions in hand, the scope of this transformation was then explored, and the results are summarized in T...

An efficient route towards biologically relevant pentose derivatives is described. The de novo 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 C-nucleosides and fluorinated pentoses. Finally, this work has facilitated expedient syntheses of pharmaceutically active compounds currently in clinical use.

Nucleoside analogues have been and continue to be extremely important compounds in drug discovery. Despite the significant effort dedicated to their synthesis, medicinal chemistry campaigns around these structures are often hampered by synthetic challenges. We describe a strategy for the functionalization of purine nucleosides via photoredox and nickel-catalyzed sp2–sp3 cross-coupling. The conditions described herein allow for coupling of unprotected nucleosides with readily available alkyl bromides, providing opportunities for their application to parallel medicinal chemistry.