The synthesis of isoquinolines by site-selective CH activation of O-acyl oximes with a Cp*Co^III catalyst is described. In the presence of this catalyst, the CH activation of various unsymmetrically substituted O-acyl oximes selectively occurred at the sterically less hindered site, and reactions with terminal as well as internal alkynes afforded the corresponding products in up to 98 % yield. Whereas the reactions catalyzed by the Cp*Co^III system proceeded with high site selectivity (15:1 to 20:1), use of the corresponding Cp*Rh^III catalysts led to low selectivities and/or yields when unsymmetrical O-acyl oximes and terminal alkynes were used. Deuterium labeling studies indicate a clear difference in the site selectivity of the CH activation step under Cp*Co^III and Cp*Rh^III catalysis.

Two new biotin analogues, biotin carbonate 5 and biotin carbamate 6, have been synthesized. These molecules were designed to reversibly bind with streptavidin by replacing the hydrogen-bond donor NH group(s) of biotin’s cyclic urea moiety with oxygen. Biotin carbonate 5 was synthesized from L-arabinose (7), which furnishes the desired stereochemistry at the 3,4-cis-dihydroxy groups, in 11 % overall yield (over 10 steps). Synthesis of biotin carbamate 6 was accomplished from L-cysteine-derived chiral aldehyde 33 in 11 % overall yield (over 7 steps). Surface plasmon resonance analysis of water-soluble biotin carbonate analogue 46 and biotin carbamate analogue 47 revealed that K_D values of these compounds for binding to streptavidin were 6.7×10⁻⁶ M and 1.7×10⁻¹⁰ M, respectively. These values were remarkably greater than that of biotin (K_D=10⁻¹⁵ M), and thus indicate the importance of the nitrogen atoms for the strong binding between biotin and streptavidin.

Synthesis of heteroatom-containing ladder-type π-conjugated molecules was successfully achieved via a palladium-catalyzed intramolecular oxidative CH/CH cross-coupling reaction. This reaction provides a variety of π-conjugated molecules bearing heteroatoms, such as nitrogen, oxygen, phosphorus, and sulfur atoms, and a carbonyl group. The π-conjugated molecules were synthesized efficiently, even in gram scale, and larger π-conjugated molecules were also obtained by a double CH/CH cross-coupling reaction and successive oxidative cycloaromatization.

The synthesis of isoquinolines by site-selective CH activation of O-acyl oximes with a Cp*Co^III catalyst is described. In the presence of this catalyst, the CH activation of various unsymmetrically substituted O-acyl oximes selectively occurred at the sterically less hindered site, and reactions with terminal as well as internal alkynes afforded the corresponding products in up to 98 % yield. Whereas the reactions catalyzed by the Cp*Co^III system proceeded with high site selectivity (15:1 to 20:1), use of the corresponding Cp*Rh^III catalysts led to low selectivities and/or yields when unsymmetrical O-acyl oximes and terminal alkynes were used. Deuterium labeling studies indicate a clear difference in the site selectivity of the CH activation step under Cp*Co^III and Cp*Rh^III catalysis.

Alzheimer’s disease (AD), a progressive severe neurodegenerative disorder, is currently incurable, despite intensive efforts worldwide. Herein, we demonstrate that catalytic oxygenation of amyloid-β peptides (Aβ) might be an effective approach to treat AD. Aβ1–42 was oxygenated under physiologically-relevant conditions (pH 7.4, 37 °C) using a riboflavin catalyst and visible light irradiation, with modifications at the Tyr¹⁰, His¹³, His¹⁴, and Met³⁵ residues. The oxygenated Aβ1–42 exhibited considerably lower aggregation potency and neurotoxicity compared with native Aβ. Photooxygenation of Aβ can be performed even in the presence of cells, by using a selective flavin catalyst attached to an Aβ-binding peptide; the Aβ cytotoxicity was attenuated in this case as well. Furthermore, oxygenated Aβ1–42 inhibited the aggregation and cytotoxicity of native Aβ.

Treatment of 2-phenylpyridines with amino(1,3,2-dioxaborolan-2-yl)diphenylsilane produced fluorosilylated 2-phenylpyridines in good to excellent yields under palladium catalysis. This reaction is the first example of CH fluorosilylation. Single-crystal X-ray structure analysis revealed a Lewis acid–base interaction between the silicon and nitrogen atoms, and the obtained fluorosilylated products are silafluorene equivalents. The fluorosilylated products showed stronger fluorescence than the corresponding silafluorene derivative.

Inhibition of amyloid-β (Aβ) aggregation could be a target of drug development for the treatment of currently incurable Alzheimer's disease. We previously reported that a head-to-tail cyclic peptide of KLVFF (cyclic-KLVFF), a pentapeptide fragment corresponding to the Aβ16–20 region (which plays a critical role in the generating Aβ fibrils), possesses potent inhibitory activity against Aβ aggregation. Here we found that the inhibitory activity of cyclic-KLVFF was significantly improved by incorporating an additional phenyl group at the β-position of the Phe4 side chain (inhibitor 3). Biophysical and biochemical analyses revealed the rapid formation of 3-embedded oligomer species when Aβ1–42 was mixed with 3. The oligomer species is an “off-pathway” species with low affinity for cross-β-sheet-specific dye thioflavin T and oligomer-specific A11 antibodies. The oligomer species had a sub-nanometer height and little capability of aggregation to amyloid fibrils. Importantly, the toxicity of the oligomer species was significantly lower than that of native Aβ oligomers. These insights will be useful for further refinement of cyclic-KLVFF-based aggregation inhibitors.

Inhibition of pathogenic protein aggregation may be an important and straightforward therapeutic strategy for curing amyloid diseases. Small-molecule aggregation inhibitors of Alzheimer’s amyloid-β (Aβ) are extremely scarce, however, and are mainly restricted to dye- and polyphenol-type compounds that lack drug-likeness. Based on the structure-activity relationship of cyclic Aβ16–20 (cyclo-[KLVFF]), we identified unique pharmacophore motifs comprising side-chains of Leu², Val³, Phe⁴, and Phe⁵ residues without involvement of the backbone amide bonds to inhibit Aβ aggregation. This finding allowed us to design non-peptidic, small-molecule aggregation inhibitors that possess potent activity. These molecules are the first successful non-peptidic, small-molecule aggregation inhibitors of amyloids based on rational molecular design.

Treatment of 2-phenylpyridines with amino(1,3,2-dioxaborolan-2-yl)diphenylsilane produced fluorosilylated 2-phenylpyridines in good to excellent yields under palladium catalysis. This reaction is the first example of CH fluorosilylation. Single-crystal X-ray structure analysis revealed a Lewis acid–base interaction between the silicon and nitrogen atoms, and the obtained fluorosilylated products are silafluorene equivalents. The fluorosilylated products showed stronger fluorescence than the corresponding silafluorene derivative.

The first copper-catalyzed intramolecular C(sp³)H and C(sp²)H oxidative amidation has been developed. Using a Cu(OAc)₂ catalyst and an Ag₂CO₃ oxidant in dichloroethane solvent, C(sp³)H amidation proceeded at a terminal methyl group, as well as at the internal benzylic position of an alkyl chain. This reaction has a broad substrate scope, and various β-lactams were obtained in excellent yield, even on gram scale. Use of CuCl₂ and Ag₂CO₃ under an O₂ atmosphere in dimethyl sulfoxide, however, leads to 2-indolinone selectively by C(sp²)H amidation. Kinetic isotope effect (KIE) studies indicated that CH bond activation is the rate-determining step. The 5-methoxyquinolyl directing group could be removed by oxidation.

The site-specific cleavage of peptide bonds is an important chemical modification of biologically relevant macromolecules. The reaction is not only used for routine structural determination of peptides, but is also a potential artificial modulator of protein function. Realizing the substrate scope beyond the conventional chemical or enzymatic cleavage of peptide bonds is, however, a formidable challenge. Here we report a serine-selective peptide-cleavage protocol that proceeds at room temperature and near neutral pH value, through mild aerobic oxidation promoted by a water-soluble copper–organoradical conjugate. The method is applicable to the site-selective cleavage of polypeptides that possess various functional groups. Peptides comprising D-amino acids or sensitive disulfide pairs are competent substrates. The system is extendable to the site-selective cleavage of a native protein, ubiquitin, which comprises more than 70 amino acid residues.