Indolactam-V (IL-V), bryostatin 1 (Bryo-1), and aplysiatoxin (ATX) are structurally diverse natural products that potently activate protein kinase C (PKC). Although they exhibit scientifically and therapeutically attractive bioactivities through PKC activation, their application for research and therapeutic uses has been limited by poor synthetic accessibility and complex biological profile. Recognizing this issue, we have designed structurally simpler and thus synthetically more accessible analogs of these PKC activators that can emulate or even improve biological performance of the parent natural products. IL-V analog was proved to be a useful tool for tracing PKC-mediated cellular signal transduction. Bryo-1 and ATX analogs have become promising leads for anti-cancer drugs. This study demonstrates that structural simplification of natural products provides biologically and therapeutically valuable molecules that are better suitable for human use.
Effective synthesis of ethynylanthracene derivatives as novel π-conjugated compounds and their applications to the synthesis of anthracene-acetylene oligomers are described. Ethynyl groups were introduced into anthracene moieties by cross-coupling reactions (Kumada-Tamao and Sonogashira couplings), addition-aromatization reactions, or double-elimination reactions from suitable starting materials. In some cases, the reaction integration techniques such as one-pot or one-shot processes were useful to simplify the experimental procedures. Diacetylene derivatives were synthesized by oxidative coupling of terminal alkynes or Sonogashira coupling. The desilylation and silylation of ethynylanthracene derivatives under appropriate conditions are important processes on preparation of unsymmetrical building units. Thus prepared building units were accumulated by Sonogashira coupling or oxidative coupling to synthesize cyclic oligomers ranging from trimers to dodecamers as well as 9,10-bis(phenylethynyl)anthracene oligomers. Each oligomer shows characteristic structural, stereochemical, and electronic properties depending on the number of anthracene units, the mode of connections, and the shape of anthracene units. Enantiomers of some chiral cyclic oligomers were successfully resolved by chiral HPLC.
The polyaromatic ketone compounds having non-coplanarly aromatic-ring-accumulated structure have been studied from the viewpoint of uniqueness and specificity in reaction behavior and characteristics in spatial organization. Synthesis of 1-aroylated and 1,8-diaroylated derivatives of 2,7-dimethoxynaphthalene was successfully performed by the action of arenecarboxylic acids or their chlorides with the aid of adequate acidic mediator: Lewis/Brønsted acid or direct condensation reagent. The aroylation shows distinct dependence on acidic mediator employed. The product distribution among 1-aroyl-, 1,8-diaroyl-, and 3-aroylnaphthalenes is strongly affected by the kind of acidic mediator. With the aid of the monitoring of the time-course of the product distribution, interconversion from the 1-aroylated- and 1,8-diaroylated derivatives to the 3-aroylated one is revealed. These reaction behaviors including acid-strength-dependent reversibility are well interpreted from the nature of highly congested non-coplanar geometry of the polyaromatic ketone products. By the separate reaction of the isolated aryl-aryl ketones, the acid-mediated retro-aroylation of aromatic ketone molecules is confirmed. Moreover, the aroylated 2,7-dimethoxynaphthalene homologues/analogues show susceptible ether scission of the methyl ether moiety adjacent to aroyl substituents. These unique and specific reaction behavior compared to conventional aromatic ketones and aromatic methyl ether is interpreted due to the non-coplanarly situated carbonyl group of the aroyl moieties against naphthalene ring with essentially perpendicular situation. The spatial organization of these compounds has been investigated with expectation of useful information for clarification of reactivity-structure relationship analysis and elucidation of structure determining factors. On the basis of the X-ray crystal structure analysis of about 80 homologous/analogous compounds and NMR spectroscopic study including variable temperature measurement, both the protocols of determination of single molecular and packing structures in crystal and analysis of bond rotation behavior in solution were undertaken. The structure characteristics about symmetric nature of the single molecule, stabilizing intermolecular interaction, and alignment of molecules in crystal and the rotation capability of the bonds in solution were discussed to clarify the determining factors for spatial organization and reaction behavior of the non-coplanarly aromatic-ring-accumulated compounds and to design the molecular materials having such type of spatial organization in the future.
Effective ligand design for metal-catalyzed reactions is highly important to control catalyst performance. Especially, readily-synthesized and easy-to-handle ligands with the ability to realize high reaction efficiency and substrate tolerance have been still desired. We have developed novel N-heterocyclic carbene ligands on the basis of the concept of hemilabile coordination, whose precursors were prepared in short steps and obtained as crystalline solids stable enough to handle and store under the air. The thioether-imidazolinium chlorides achieved excellent catalyst activity in the palladium-catalyzed arylation of aldehydes. On the other hand, the ether-imidazolium carbenes were found to be highly effective in the Suzuki-Miyaura reaction. In both cases, remarkable substrate tolerance was observed, which realized the efficient transformation of heterocycle-containing compounds.
Hydrogen peroxide is one of the ideal oxidants in organic synthesis and green chemistry because the waste produced from hydrogen oxide-oxidation is nontoxic water. We have developed several synthetic reactions using hydrogen peroxide as the oxidant catalyzed by transition metals or combinations of transition metals and halide ions (halogen anions). Electrophilic bromination and oxidation of organosulfur compounds (dithioacetals, thiols and sulfides) can be achieved and be selectively obtained the desired products in high yields. Selective oxidation of sulfides to sulfoxides using hydrogen peroxide has also been achieved under catalyst-free conditions using a T-shaped microreactor.
Within recent years, anion recognition catalysis has become a powerful tool in organic synthesis. Silanediols are known to undergo molecular recognition with suitable anions via the formation of two successive hydrogen bonds. This short review covers the initial successes of silanediols as hydrogen-bond donor catalysts, their structural and mechanistic aspect and application in asymmetric catalysis.
Carbohydrates bind proteins multivalently to enhance the affinity between them. This multivalent interaction called a glycoside cluster effect has received much attention from not only carbohydrate chemists but also medicinal and natural product chemists. Herein the recent progress of the drug discovery research using a cluster effect is reviewed.
Catalytic asymmetric reaction is important for the syntheses of optically active medicines and bioactive natural products, because chiral catalysts enable acceleration of reaction and chiral amplification at the same time. Recently, the asymmetric reaction systems based on stimuli-responsive supramolecular catalyst are drawing attention. Such catalysts realize switchability of catalytic properties to control reaction rate and selectivity. This short review focuses on the asymmetric reactons using chirality-switchable catalysts whose structures are dynamically changed by external stimuli such as light, temperature, solvent, and pH.