Akimichi Ohtsuki

Nickel-catalyzed alkynylation of anisoles via C-O bond cleavage.

A new cross-coupling reaction has been developed for the introduction of an alkyne moiety to an anisole derivative through C-O bond activation using an NHC ligand. This method has been used for direct alkynylation of a broad range of anisole derivatives and provided rapid access to compounds with potential applications in biological and materials science.

Reversible generation of a carbon-centered radical from alkyl iodide using organic salts and their application as organic catalysts in living radical polymerization.

A new method of producing carbon-centered radicals was discovered through the reaction of an alkyl iodide (R-I) with organic salts to reversibly generate the corresponding alkyl radical (R(•)). Via this new reaction, the organic salts were used as new and highly efficient organic catalysts in living radical polymerization. The catalysts included common and inexpensive compounds such as tetrabutylammonium iodide and methyltributylphosphonium iodide. Notably, the catalysts were highly reactive. They enabled the synthesis of high-molecular-weight polymers (up to Mn = 140,000) and the control of acrylate polymerization, which had been difficult with other organic catalysts. The organic salt catalysts were highly versatile, reacting with methacrylate, acrylate, styrene, acrylonitrile, and functional methacrylate monomers. Well-defined block copolymers were also prepared by using this method. A kinetic study quantitatively confirmed the high reactivity of these catalysts. Attractive features of this system include its low cost, its ease of operation, and its ability to access a wide range of polymer designs.

Synthetic small molecules for epigenetic activation of pluripotency genes in mouse embryonic fibroblasts.

Considering the essential role of chromatin remodeling in gene regulation, their directed modulation is of increasing importance. To achieve gene activation by epigenetic modification, we synthesized a series of pyrrole–imidazole polyamide conjugates (PIPs) that can bind to predetermined DNA sequences, and attached them with suberoylanilide hydroxamic acid (SAHA), a potent histone deacetylase inhibitor. As histone modification is associated with pluripotency, these new types of conjugates, termed SAHA–PIPs, were screened for their effect on the expression of induced pluripotent stem cell (iPSC) factors. We found certain SAHA–PIPs that could differentially up‐regulate the endogenous expression of Oct‐3/4, Nanog, Sox2, Klf4 and c‐Myc. SAHA and other SAHA–PIPs did not show such induction; this implies a role for PIPs and their sequence specificity in this differential gene activation. Chromatin immunoprecipitation analysis suggested that SAHA–PIP‐mediated gene induction proceeds by histone H3 Lys9 and Lys14 acetylation and Lys4 trimethylation, which are epigenetic features associated with transcriptionally active chromatin.

Development of programmable small DNA-binding molecules with epigenetic activity for induction of core pluripotency genes.

Epigenetic modifications that govern the gene expression are often overlooked with the design of artificial genetic switches. N-Methylpyrrole-N-methylimidazole (PI) hairpin polyamides are programmable small DNA binding molecules that have been studied in the context of gene regulation. Recently, we synthesized a library of compounds by conjugating PI polyamides with SAHA, a chromatin-modifier. Among these novel compounds, PI polyamide-SAHA conjugate 1 was shown to epigenetically activate pluripotency genes in mouse embryonic fibroblasts. Here, we report the synthesis of the derivatives of conjugate 1 and demonstrate that these epigenetically active molecules could be developed to improve the induction of pluripotency factors.

The Distance Between Donor and Acceptor Affects the Proportion of C1′ and C2′ Oxidation Products of DNA in a BrU-Containing Excess Electron Transfer System

We have investigated the products of (Br)U in excess electron transfer and have demonstrated that in DNA the proportion of products changes with the distance between the donor and acceptor. On the basis of a labeling experiment using H(2)(18)O, we have shown that hole migration from Py(•+) formed after charge separation is involved in the reaction.

Combined Theoretical and Experimental Studies of Nickel-Catalyzed Cross-Coupling of Methoxyarenes with Arylboronic Esters via C–O Bond Cleavage

Nickel(0)-catalyzed cross-coupling of methoxyarenes through C-O bond activation has been the subject of considerable research because of their favorable features compared with those of the cross-coupling of aryl halides, such as atom economy and efficiency. In 2008, we have reported nickel/PCy3-catalyzed cross-coupling of methoxyarenes with arylboronic esters in which the addition of a stoichiometric base such as CsF is essential for the reaction to proceed. Recently, we have also found that the scope of the substrate in the Suzuki-Miyaura-type cross-coupling of methoxyarenes can be greatly expanded by using 1,3-dicyclohexylimidazol-2-ylidene (ICy) as the ligand. Interestingly, a stoichiometric amount of external base is not required for the nickel/ICy-catalyzed cross-coupling. For the mechanism and origin of the effect of the external base to be elucidated, density functional theory calculations are conducted. In the nickel/PCy3-catalyzed reactions, the activation energy for the oxidative addition of the C(aryl)-OMe bond is too high to occur under the catalytic conditions. However, the oxidative addition process becomes energetically feasible when CsF and an arylboronic ester interact with a Ni(PCy3)2/methoxyarene fragment to form a quaternary complex. In the nickel/ICy-catalyzed reactions, the oxidative addition of the C(aryl)-OMe bond can proceed more easily without the aid of CsF because the nickel-ligand bonds are stronger and therefore stabilize the transition state. The subsequent transmetalation from an Ar-Ni-OMe intermediate is determined to proceed through a pathway with lower energies than those required for β-hydrogen elimination. The overall driving force of the reaction is the reductive elimination to form the carbon-carbon bond.