Direct Catalytic Asymmetric Aldol Reaction of Thioamide with an α-Vinyl Appendage.

The direct catalytic asymmetric aldol reaction is an emerging catalytic methodology that provides atom-economical access to functionalized chiral building blocks. Thioamides are useful aldol donors due to their high-fidelity chemoselective enolization and divergent post-aldol transformations. Herein we describe the incorporation of an α-vinyl appendage on a thioamide, which expands the utility of aldol adducts for natural product synthesis. This vinylated thioamide was not accommodated under the previously identified catalyst settings, but the newly developed catalytic conditions furnished aldol products containing the pendant vinyl group.

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 ß-hydrogen elimination. The overall driving force of the reaction is the reductive elimination to form the carbon-carbon bond.

Nickel/N-Heterocyclic Carbene-Catalyzed Suzuki-Miyaura Type Cross-Coupling of Aryl Carbamates.

The utility of N-heterocyclic carbene ligands in nickel-catalyzed Suzuki-Miyaura cross-coupling of aryl esters and carbamates is investigated. Imidazol-2-ylidene bearing 2-adamantyl groups at its nitrogen atoms generates the most active nickel species among the ligands examined, allowing cross-coupling of a range of aryl carbamates and pivalates. Unlike the previously reported system using tricyclohexylphosphine, this protocol is suitable for the cross-coupling using arylboronic esters in addition to arylboronic acids.

Photocontrolled Organocatalyzed Living Radical Polymerization Feasible over a Wide Range of Wavelengths.

Photocontrolled organocatalyzed living radical polymerization was conducted over a wide range of irradiation wavelengths (350-750 nm). The polymerization was induced and controlled at the desired wavelengths by exploiting suitable organic catalysts. This system was finely responsive to the irradiation wavelength; the polymerization was instantly switched on and off, and the polymerization rate was sensitively modulated by altering the irradiation wavelength. The polymer molecular weight and its distribution (M(w)/M(n) = 1.1-1.4) were well controlled for methacrylate monomers up to fairly high conversions in many cases. The monomer scope encompassed various functional methacrylates, and their block copolymers were obtained. The feasibility of such a wide range of wavelengths and the fine response to the wavelength are unprecedented features. As a unique application of the wavelength-responsive nature of this system, we demonstrated "one-pot" selective regulation of living radical polymerization and another type of polymerization (ring opening polymerization), where the regulation was achieved by simply altering the irradiation wavelength. Facile operation and applicability to a wide range of polymer designs are advantages of this polymerization.

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.

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.

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.

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.

Requirement of beta-alanine components in sequence-specific DNA alkylation by pyrrole-imidazole conjugates with seven-base pair recognition.

To investigate the effect of incorporation of beta-alanine in alkylating N-methylpyrrole (Py)-N-methylimidazole (Im) polyamide, seco-CBI conjugates 2-8 were synthesized by an Fmoc solid-phase method and subsequent coupling with an alkylating moiety. DNA-alkylating activities of conjugates 2-8 were evaluated by high-resolution denaturing gel electrophoresis with 202-base pair (bp) DNA fragments. Alkylation by conjugates 2 and 3, which have antiparallel pairings of beta-alanine (beta) opposite beta (beta/beta) and Py/beta, occurred mainly at the adenine (A) of the matching sequences, 5'-AGCTCCA-3' (site 1) and 5'-AGCACCA-3' (site 3). However, conjugate 4, with beta/Py, did not show any DNA-alkylating activities. Similarly, conjugate 5, which possessed a Py/Py pair, weakly alkylated the matching sites at micromolar concentrations. Conjugates 6 and 7, which possessed beta/beta and Py/beta pairs, respectively, alkylated at the A of the matching sequences, 5'-ACTACCA-3' (site 2) and 5'-ACAACCA-3' (site 4). In contrast, conjugated 8, with a Py/Py pair, showed lower activity and less alkylated DNA at sites 2 and 4 with mismatched alkylation at site 1 at a higher concentration than that of 6 and 7. These results demonstrate that incorporation of beta-alanine is required for the sequence-specific alkylation by seco-CBI Py-Im conjugates with a seven-base pair sequence.

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.

Nickel-catalyzed reductive cleavage of aryl alkyl ethers to arenes in absence of external reductant.

The reductive cleavage of the C-O bonds of aryl ethers has great potential in organic synthesis. Although several catalysts that can promote the reductive cleavage of aryl ethers have been reported, all such systems require the use of an external reductant, e.g., hydrosilane or hydrogen. Here, we report the development of a new nickel-based catalytic system that can cleave the C-O bonds of ethers in the absence of an external reductant. The hydrogen atom required in this new reductive cleavage reaction is provided by the alkoxy group of the substrate, which serves as an internal reductant. The absence of an external reductant enables the unique chemoselectivity, i.e., the selective reduction of an alkoxy group over alkenes and ketones.