We have been working on finding new bioactive microbial metabolites at the Kitasato Institute. Their microbial natural products have a variety of unique and complex skeletones with many chiral centers and functional groups, and biological activities. We also have been working on synthetic study of them, which is effective and concise convergent approach, designed to afford easy access to both the natural products and a variety of analogs to clarify the structure-activity relationships. We have succeeded in the efficient total syntheses of bioactive microbial metabolites; pyripyropene (1), arisugacin (2), lactacystin (3), macrosphelide (4), and madindoline (5), and the construction of indoline spiroaminal moiety of neoxaline (6). We also have succeeded in creating better analogs of pyripyropene (1) and lactacystin (3). Furthermore, we have also been working on synthetic study of macrolides which have a variety of biological activities and also clarifying the mode of action in order to develop novel medicines. We have succeeded in creating novel macrolides, a motilide (EM574) and an anti-inflammatory agent (EM905).
Electrochemical approaches have proven to be effective for regulating either one or two electron transfers at the surface of the electrodes that afford not only various functional group transformations, but also a wide variety of carbon-carbon bond forming reactions. Especially, the anodic oxidation of electron-rich olefins generates their radical cations, which are then trapped by a variety of nucleophiles, leading to a number of interesting cyclizations. These anodic transformations are initiated by the umpolung processes that normally nucleophilic electron-rich olefins are anodically oxidized to give electrophilic radical cations to react with second nucleophiles. Meanwhile, unactivated olefins have been found to act as carbon nucleophiles in lithium perchlorate/nitromethane electrolyte solutions that can be used to construct intermolecular carbon-carbon bonds. The use of enol ethers as electron-rich olefins has led to the formation of cyclobutane-like intermediates through which intermolecular olefin cross-coupling and -metathesis are achieved.
Heterogeneous palladium catalysts have drawn much attention in organic synthetic and process chemistry from sustainable and industrial points of view due to their air-stability, recoverability, reusability, rare-residual property, and so on. Palladium on charcoal (Pd/C), which has been used as a common hydrogenation catalyst, is finding various applications including cross-coupling and deuterium (tritium) labeling reactions. However, the catalyst activity is sometimes supplier-or even lot-dependent, since the charcoal is derived from natural resources such as peat and sawdust, which produce difference in ultra-trace amount of inorganic impurities, pore sizes and surface areas. We demonstrate the development of a novel heterogeneous Pd and Cu catalysts supported on a commercial synthetic adsorbent, DIAION® HP20, and their application to the hydrogenation of a wide range of reducible functionalities, ligand-free cross-coupling reactions, such as Suzuki-Miyaura, Mizoroki-Heck and Sonogashira-type reactions and the azide-alkyne Huisgen cycloaddition. The distinct features of catalysts is the simple preparation, strong and efficient catalyst activity based on the lipotropy or hydrophobic effect of the support, wide applicability, recoverability by a simple filtration, and reusability.
We have been investigating a computer aided synthetic route development, i.e., “in silico synthetic route developments (ISSRD)”. Our TSDB (transition state data base) together with remarkable developments of computer technologies made it possible to screen potential synthetic routes from synthetic route design systems (SRDSs) and/or organic chemists before executing trial- and-error experimental works. In the present paper, we summarized the studies concerning with the ISSRD such as successful application to 2,6-dimethylchroman-4-one, usage of TSDB and a method predicting experimental yields of organic reactions. Futures of ISSRD are also discussed.
Whereas biradicals are generally observed only under cryogenic inert conditions, highly stabilized 1,3-diphosphacyclobutane-2,4-diyls, phosphorus congeners of cyclobutane-1,3-diyl, can be stored at room temperature and even in air. We succeeded in establishing a promising synthetic protocol for the extremely stable biradicals by utilizing a bulky phosphaalkyne Mes*C≡P(Mes*=2,4,6-tri-t-butylphenyl). The singlet ground state biradicals were characterized by spectroscopies including NMR, and the X-ray structural parameters indicated effects of the phosphorus atoms and sterically encumbered aryl substituents. Conversion into the cyclic phosphorane and thermal ring-expansion were facilitated by the presence of amino- and acyl substituents, respectively. Dual hydrogen loadings on the biradical skeleton were accomplished to afford cyclobutadiene-like P-heterocycles. Most of the air-stable P-heterocyclic biradicals showed high electron-donating properties, and catenation of two or three biradical units induced unique intramolecular through-space interactions between the biradical chromophores. Stable P-heterocyclic neutral monoradical was successfully obtained by utilizing the biradical synthetic procedures.
Polyglycerols are oligomers of glycerol (glycerin). Their fatty acid esters (PGE) are generally dispersible in water and soluble in oil. They are widely using in food additives, cosmetic materials and toiletries as surfactants. We are interested in developing chemically modified linear and cyclic polyglycerols and their esters that have a single polymerization degree and fine structure. In this study, we synthesized authentic standards of linear and cyclic polyglycerol with well-defined structures and degrees. Linear oligomers polymerized from 2 to 10 were synthesized by means of a convergent approach based on the coupling of tosylate with protected glycerol units in good yields. Cyclic polyglycerols polymerized from 3 to 6 were also synthesized by intramolecular cyclization conditions. Triglyceryl di-, tri-, and tetra-fatty acid esters were also synthesized from common substrate as new prominent gelators. These triglyceryl esters were capable of gelling up a wide variety of oils. A comparison of the gelation ability of structurally related compounds clarified that the introduction of alkyl chains of suitable length is required for effective gelation. The measurement of transmittance at 500 nm could be the appraisal standard for the aggregation level.
Cu(I)-catalyzed azide-alkyne cycloaddition, considered as a “click chemistry”, has been used in many fields of chemistry, including chemical biology. But, because of cytotoxicity of Cu(I), applications of this reaction for living systems have been restricted. Cyclooctyne which has high ring strain energy reacts with azide without Cu(I) catalyst. This reaction is often called “copper-free click chemistry (CFCC)”. This short review summarizes the recent advance in CFCC using cyclooctynes.
Trifluoromethyl group is one of the important groups in medicinal chemistry. In 2010, Yu and Sanford reported the Pd-catalyzed aromatic C-H bond trifluoromethylation with the aid of directing groups. With these reports as a turning point, the studies on this field have been developed in a couple of years. This review describes the recent advances in aromatic C-H bond trifluoromethylation catalyzed/mediated by transition metal reagents.