Nickel-catalyzed cross-coupling reactions have recently been receiving significant attention from the synthetic community as a way to construct carbon-carbon or carbon-heteroatom bonds, because nickel catalysts are less expensive and less toxic than palladium catalysts.
We herein describe our recent developments in nickel-catalyzed biaryl coupling methodology, along with mechanistic studies and applications to the synthesis of natural products and pharmaceuticals. In particular, we focus on nickel-catalyzed direct coupling reactions in which “unreactive” bonds such as C-H, C-O, and C-C bonds are converted into biaryl moieties.

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Direct functionalization of unreactive bonds catalyzed by transition metal complexes has become a powerful tool in organic synthesis and has been studied extensively by many researchers. Our research group has been exploring regioselective functionalization via chelation-assisted cleavage of unreactive bonds by transition metal catalysts. Here we describe our recent efforts toward development of efficient methods for construction of π-conjugated systems by catalytic substitution via chelation-assisted cleavage of unreactive aromatic carbon-hydrogen and -heteroatom bonds. Ruthenium catalysts were employed to cleave aromatic carbon-hydrogen, carbon-oxygen, carbon-nitrogen, and carbon-fluorine bonds (aromatic carbon bonds) at ortho positions of directing groups and to introduce aryl, alkenyl, and carbonyl groups onto the aromatic rings. Application of these methods for short syntheses of substituted fused aromatic compounds such as twisted anthracenes, pentacenes, dibenzo[a,h]anthracenes, and picenes is also described.

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This review focuses on the development of metathesis polymerization-based polymers for medical application including therapeutic and diagnostic agents. The feature of metathesis polymerization, ring-opening metathesis polymerization (ROMP) and acyclic diene metathesis (ADMET) polymerization, is briefly outlined. The modification methods to synthesize highly functionalized polymers as well as the functional group tolerance under the polymerization conditions are described. The delivery of antitumor drugs, genes, and contrast agents utilizing polymeric nanoparticles is discussed. Recent application of metathesis polymerization-based ionic polymers to antimicrobial materials, cell-penetrating materials, antifouling materials, and signal transducers is also summarized.

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1,2-cis amino glycosides are often found in biologically active oligosaccharides. For the stereoselective formation of 1,2-cis aminoglycosides, glycosyl donors with 2,3-trans carbamate group were developed. The first synthesis of anti-Helicobacter pylori oligosaccharide was achieved by using the novel glycosyl donor in an effective manner. Furthermore, the pyranosides with 2,3-trans carbamate groups were found to undergo endocyclic cleavage reactions, which are rarely found in pyranosides. The endocyclic cleavage reaction was confirmed both from experimental and computational approaches.
As an additional example of cooperative work of experimental and computational chemistry, understanding of the solvent effect in glycosylation reactions was also described.

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Aqueous solubility is essential for drug candidates, and improvement of the aqueous solubility of bioactive compounds is a major issue for medicinal chemists. The strategy of introducing hydrophilic group(s) into molecules is generally used for this purpose, but is not universally effective. We proposed an alternative strategy for improving aqueous solubility, that is, modification of bicyclic molecules in ways that would disrupt molecular planarity by increasing the dihedral angle or that would disrupt the molecular symmetry. Such planarity-or symmetry-disruption has the effect of decreasing the efficiency of crystal packing, which in turn results in an increase of aqueous solubility. Improvement of aqueous solubility by 350-fold was achieved in one example. Furthermore, to clarify the mechanisms of improvement of aqueous solubility, we examined the changes in physicochemical properties of the compounds.

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Aplyviolene (1) is a diterpene isolated from marine sponge, it has characteristic structures of cis-perhydroazulene and 6-acetoxy-2,7-dioxabicyclo[3.2.1]-octan-3-one moieties. One of the synthetic challenges of 1 is a stereoselective construction of continuous carbon centers at C8 (quaternary carbon) and C14. In this mini review, a total synthesis of aplyviolene by Overman was discussed focusing on the control of those stereocenters by using prochiral nucleophiles of 6 or 10 with electrophiles.

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The answer will be published in the next issue.

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