Ruthenium-Catalyzed Reactions
Olefin metathesis has become one of the most powerful synthetic arsenals for carbon-carbon formation and the impact of which has been recognized by the 2005 Novel prize in chemistry “For the development of the metathesis method in organic synthesis”. Among metal-carbene complexes that can catalyze the metathesis reactions, ruthenium-alkylidene carbenes known as “Grubbs catalyst” have shown wide range of application in organic synthesis due to their relatively high stability to air and moisture as well as polar functional groups. Most pronounced applications of metathesis chemistry range from synthesis of natural products, pharmaceuticals, and polymers of novel properties. Additionally, the greener nature of metathesis compared to other synthetic methods has additional benefits especially considering the environmental issues. While many different types of metathesis involving alkenes such as ring-closing metathesis (RCM), cross metathesis (CM), ring-opening metathesis (ROM), ring-rearrangement metathesis (RRM), ring-opening metathesis polymerization (ROMP), and non-metathetic transformations catalyzed by ruthenium carbenes (G-I, G-II, GH-II) have been studied extensively, the corresponding metathesis involving both alkenes and alkynes known as enyne metathesis have been underdeveloped. However, significant advances in RCM and its extension to metallotropic [1,3] shift bodes well for the further development of enyne metathesis.
Arguably, the first enyne RCM reaction was reported by Katz and coworkers in 1985 using tungsten Fisher carbene complexes. Since then a variety of low-valent transition metals have been used to catalyze this reaction. However, it was not until the development of ruthenium carbene in the 1990’s that the enyne metathesis is considered to be a viable metathesis tool, yet it still has a narrow substrate scope due to its mechanistic complexity compared to alkene metathesis. In light of this, we have been exploring the tandem bond-forming capacity of enyne metathesis. These endeavors have led to significant advances in our understanding of the reactivity and selectivity of various substrate platforms in RCM and CM reactions. Furthermore, the highly effective metallotropic [1,3] shift of propargylic ruthenium carbene allows for a series of sequential enyne metathesis, which can form molecules of extended conjugation with both double and triples bonds. Tandem metathesis of multiynes with a sequence of enyne metathesis and metallotropic [1,3] shift has led to the discovery of many unprecedented transformations and hidden catalytic activities of Ru-alkylidene carbenes. These novel transformations include the formation of highly conjugated oligo-enynes (A), 1,4-hydrovinylative cyclization of triynes and tetraynes (B), benzyne formation via the hexedehydro Diels-Alder reaction of multiynes followed by transfer of hydrohalogen from common halogenated organic solvents (C), and metallotropic shift-driven formation of ruthenium-alkyne chelate (D). The prowess of the tandem bond-forming nature of enyne metathesis in tandem with metallotropic 1,3-shift has been applied to the synthesis of 1,3-diyne- and 1,3-enyne-containng natural products (E, F). Also, relying on enyne RCM and CM as the key step for the construction of 1,3-diynes, an efficient total synthesis of amphidinolide V was achieved (G). Our current research focuses on the development of new ruthenium alkylidene complexes to further expand and discover novel reactivities of these complexes and their application to the synthesis of natural products and conjugated oligomers.
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Based on the facile formation of halogen-containing arenes from acyclic tetraynes, our research explores the reactivity of arynes generated via hexadehydro Diels-Alder reactions towards various nucleophiles, encompassing both intra- and intermolecular reaction pathways. This investigation includes metal-catalyzed reactions involving poor and good nucleophiles, as well as non-catalyzed reactions. Representative transformations include:
Metal-catalyzed reactions: These involve C–H insertion, inter- and intramolecular hydroarylation, intramolecular hydride transfer, hydrohalogenation, hydrofluorination, mono- and double-addition of nitriles, and mixed addition of nitrile and isonitrile to form diverse products.
Thermal reactions: Arynes, due to alkyne bond distortion, participate in Diels-Alder reactions, Alder-ene reactions, 1,3-dipolar cycloadditions, and nucleophile additions. Reactions include Type-I and Type-II Alder-ene reactions, intermolecular Alder-ene reactions with functionalized alkenes, addition of α,β-unsaturated aldehydes, steric pressure-driven ene-reactions, regioselective addition of weak nucleophiles, and addition of nucleophiles containing silver cations.
Application to natural product synthesis: Aryne-based methods were key in synthesizing herbindole B, an antifeedant and cytotoxic compound. The synthesis involved HDDAR followed by hydrobromination, Sonogashira coupling, gold-catalyzed rearrangement, and other steps culminating in a formal synthesis of herbindole B. Further applications include the aryne-based synthesis of selaginpulvilins, valuable for their PDE4 inhibitory activity. The synthesis strategy involved Sonogashira coupling, Cadiot-Chodkiewicz reaction, aryne intermediate formation, and Friedel-Crafts arylation to achieve selaginpulvilin C in a multi-step process.
Aryne Chemistry
Trimethylsilyldiazomethane Chemistry
Trimethylsilyldiazomethane (TMSCHN2) has been engaged in various synthetic transformations and we have been exploring the novel reactivity of TMSCHN2 especially in carbon-carbon bond forming reactions, which are graphically outlined. As opposed to a common Lewis acid-catalyzed one-carbon homologation withTMSCHN2, the corresponding lithiated reagent TMSC(Li)N2 is a much stronger nucleophile, thus it reacts readily with a broader range carbonyl compounds to generate one-carbon homologation product with high selectivity (Path A). On the other hand, the same intermediate can undergo an intramolecular cyclization with tethered alkene to generate Δ1-pyrazolines (Path B). By controlling the reaction temperature, the adducts between carbonyl compounds and TMSC(Li)N2 undergo elimination of LiOSiMe3 followed by N2 to generate alkylidene carbenes. This highly reactive unsaturated carbene species can participate in an insertion reaction with a C–H bond to generate cyclopentene derivatives (Path C). The insertion of alkylidene carbene onto a bridgehead C–H was also possible, which was employed as a key strategy in the novel construction of platensimycin core. α-Silyl ketones react with TMSC(Li)N2 to generate an alkylidene carbene intermediate, which readily undergo C–Si bond insertion to generate silyl cyclopropenes, treatment of which with PtCl2 efficiently rearrange the cyclopropene moiety to generate silyl allenes (Path D). Alkylidene carbenes generated from γ,δ-unsaturated ketones undergo addition onto the π-bond to generate highly strained bicyclo[3.1.0]hex-1-ene systems, which readily undergo dimerization (Path E). It was discovered that alkylidene carbenes generated from various acyclic and cyclic ketones readily react withTMSCHN2, providing silyl allenes, which are prone to react with molecular oxygento generate the corresponding propargylic peroxides (Path F). α,β-Unsaturated cyclic ketones react with TMSC(Li)N2 in a 1,4-addition mode followed by cyclization to generate pyrazolines, which lead to non-reductive N–N bond cleavage to generate α,β-aminocyanation products upon treating with TsOH (Path G). These α,β-unsaturated cyclic ketones also react sequentially with 2 equivalents of TMSC(Li)N2. With appropriate structural elements, alkylidene carbenes generated from lithium pyrazolinate intermediate can undergo fragmentation to form pyrazoles containing a tethered alkyne moiety, or alternatively undergo N–L bond insertion followed by cycloreversion of the azete intermediate to provide 1,2-diazepines.
RESEARCH AREAS
Our research involves new synthetic method development and their application to the synthesis of structurally novel and biologically active natural products. Metal-catalyzed reactions to merge alkenes and alkynes to construct multiply unsaturated molecular structures are one of the major research interests. Aryne formation from tri- and tetraynes followed by exploiting their reactivity to develop novel transformation is another active area of our research. The reaction between lithiated trimethylsilyldiazomethane and unsaturated carbonyl compound followed by proteolytic cleavage of N–N bond constitutes a formal 1,2-aminocyanation, which is under investigation for the construction of amino quaternary carbon-containing molecules including amathspiramides and massadine.
2024