Synthesis of Selectively gem-Difluorinated Molecules; Chiral gem-Difluorocyclopropanes via Chemo-Enzymatic Reaction and gem-Difluorinated Compounds via Radical Reaction.

The incorporation of fluorine atoms into an organic compound can alter the chemical reactivity or biological activity of the resulting compound due to the strong electron withdrawing nature of the fluorine atom. We have synthesized many original gem-difluorinated compounds and described the results in four sections. The first section describes the synthesis of optically active-gem-difluorocyclopropanes via the chemo-enzymatic reaction; we applied these compounds to liquid crystalline molecules, then further discovered a potent DNA cleavage activity for the gem-difluorocyclopropane derivatives. The second section describes the synthesis of selectively gem-difluorinated compounds via a radical reaction; we synthesized fluorinated analogues of a sex pheromone of the male African sugarcane borer, Eldana saccharina, and used the compounds as proof for investigating the origin of pheromone molecule recognition on the receptor protein. The third involves the synthesis of 2,2-difluorinated-esters by visible light-driven radical addition of 2,2-difluoroacetate with alkenes or alkynes in the presence of an organic pigment. The last section describes the synthesis of gem-difluorinated compounds via the ring-opening of gem-difluorocyclopropanes. We further developed a novel method of synthesizing gem-difluorohomoallylic alcohols via the ring-opening of gem-difluorocyclopropane and aerobic oxidation by photo-irradiation in the presence of an organic pigment. Since gem-difluorinated compounds that were prepared by the present method have two olefinic moieties with a different reactivity at the terminal position, we accomplished the synthesis of four types of gem-difluorinated cyclic alkenols via the ring-closing-metathesis (RCM) reaction.

Synthesis of gem-Difluoromethylene Containing Cycloalkenes via the Ring-Opening Reaction of gem-Difluorocyclopropanes and Subsequent RCM Reaction.

The radical-type ring-opening reaction of gem-difluorocyclopropanes and subsequent regioselective monoepoxidation of the products were demonstrated. Introduction of a vinyl or allyl group to the epoxide produced the diene derivatives that were subjected to the ring closing metathesis reaction to furnish the gem-difluoromethylene containing cyclopentene, cycloheptene, and cyclooctene derivatives in good to excellent yields.

Rational optimization of the mannoside building block for automated electrochemical assembly of the core trisaccharide of GPI anchor oligosaccharides.

We have developed a carbohydrate building block of mannosides based on DFT calculations, electrochemical analysis, and automated solution-phase synthesis. The optimized building block in hand was used to prepare the core trisaccharide of GPI anchor oligosaccharides.

The ß-Silyl Effect on the Memory of Chirality in Friedel-Crafts Alkylation Using Chiral α-Aryl Alcohols.

Iron salt-catalyzed Friedel-Crafts alkylation of chiral α-aryl alcohols with a trimethylsilyl group was found to proceed with retention of the configuration of the hydroxyl group as a leaving group. The memory of chirality of this system stems from the ß-silyl effect of the trimethylsilyl group on the carbocation intermediate.

Development of n-Type Semiconductor Based on Cyclopentene- or Cyclohexene-Fused [C60]-Fullerene Derivatives.

Properties of cyclopentene- or cyclohexene-fused [C60]-fullerene derivatives as the acceptor in photovoltaic cells have been investigated by use of poly(3-hexylthiophene) (P3HT) as the model donor polymer. Several cyclopentene- or cyclohexene-fused [C60]-fullerene derivatives show high power conversion efficiency (PCE). The highest PCE was obtained for 3',6'-dihydro-4'-phenoxycarbonyl-6'-methylbenzo[1,9][5,6](C60-Ih)fullerene (3.2%); this is superior to that of [C60]-PCBM with the P3HT polymer under the same experimental conditions. PCE of the OPV devices with alkyl-substituted cyclohexene-fused [C60]-fullerenes depended on the alkyl substituent on the cyclohexene ring; compounds with substituents of odd-number alkyl groups showed better PCE than those compounds possessing even-number alkyl groups.

Automated electrochemical assembly of the protected potential TMG-chitotriomycin precursor based on rational optimization of the carbohydrate building block.

The anomeric arylthio group and the hydroxyl-protecting groups of thioglycosides were optimized to construct carbohydrate building blocks for automated electrochemical solution-phase synthesis of oligoglucosamines having 1,4-ß-glycosidic linkages. The optimization study included density functional theory calculations, measurements of the oxidation potentials, and the trial synthesis of the chitotriose trisaccharide. The automated synthesis of the protected potential N,N,N-trimethyl-d-glucosaminylchitotriomycin precursor was accomplished by using the optimized building block.

Possible origin of modified EAG activity by point-fluorination of insect pheromones.

Fluorine closely mimics the steric requirement of hydrogen at enzyme receptor sites, but its strong electronegativity significantly alters the reactivity of neighboring centers. Therefore, point-fluorination of biologically active molecules is an important technology with which to investigate the relationship between a biologically active compound with a receptor protein. We synthesized point-fluorinated pheromone analogues of eldanolide and measured their biological activity by electroantennography (EAG) to understand the importance of conformation in the specificity of ligand recognition by the olfactory receptor. By comparing EAG activities and conformational analysis of these molecules using density functional theory calculations, significant differences were found in the population of preferable conformers between EAG-active compounds and EAG-inactive compounds. Based on these results, we propose a working hypothesis for the possible origin of the diversity of relationship between enantiomer and activity in pheromone perception response. These results obtained in the investigation of the mechanism of chemical communication through pheromone molecules among insects should be useful to expand the horizons of medicinal chemists.

Linker-oriented design of binaphthol derivatives for optical resolution using lipase-catalyzed reaction.

Candida antarctica lipase B (CAL-B) is one the most frequently used enzymes in organic synthesis for the preparation of optically active alcohols. However, it has not been used for the optical resolution of (+/-)-2,2'-binaphthol. We established an efficient linker-oriented design of 2,2'-binaphthol derivatives that is appropriate for optical resolution using CAL-B-catalyzed hydrolysis reaction. Methyl 4-(1-(6-bromo-2-methoxymethoxynaphthalen-1-yl)-6-bromonaphthalen-2-yloxy)butanoate was hydrolyzed by CAL-B to afford a corresponding acid with excellent enantioselectivity ( E > 200). Two types of optically active binaphthol derivatives, 1-(2-hydroxy-6-(naphthalen-1-yl)naphthalen-1-yl)-6-(naphthalen-1-yl)naphthalen-2-ol and 6-butyl-1-(6-butyl-2-hydroxynaphthalen-1-yl)naphthalen-2-ol, were prepared by this chemo-enzymatic reaction protocol and were used as chiral templates for symmetric reactions.

Ruthenium-catalysed linear-selective allylic alkylation of allyl acetates.

The regioselectivity in the ruthenium-catalysed allylic alkylation of mono substituted allyl acetates with the malonate anion was highly controlled by Ru3(CO)12 with 2-(diphenylphosphino)benzoic acid, and the linear-type alkylated product was obtained.

Retention of regiochemistry of monosubstituted allyl acetates in the ruthenium catalysed allylic alkylation with malonate anion.

In the RuCl2(p-cymene)/PPh3 catalysed regioselective allylic alkylation of monosubstituted allyl acetates with malonate anion, the selective substitution at the position originally substituted with acetate was observed.

Increased enantioselectivity and remarkable acceleration of lipase-catalyzed transesterification by using an imidazolium PEG-alkyl sulfate ionic liquid.

Several types of imidazolium salt ionic liquids were prepared derived from poly(oxyethylene)alkyl sulfate and used as an additive or coating material for lipase-catalyzed transesterification in an organic solvent. A remarkably increased enantioselectivity was obtained when the salt was added at 3-10 mol % versus substrate in the Burkholderia cepacia lipase (lipase PS-C)-catalyzed transesterification of 1-phenylethanol by using vinyl acetate in diisopropyl ether or a hexane solvent system. In particular, a remarkable acceleration was accomplished by the ionic liquid coating with lipase PS in an iPr(2)O solvent system while maintaining excellent enantioselectivity; it reached approximately 500- to 1000-fold acceleration for some substrates with excellent enantioselectivity. A similar acceleration was also observed for IL 1-coated Candida rugosa lipase. MALDI-TOF mass spectrometry experiments of the ionic-liquid-coated lipase PS suggest that ionic liquid binds with lipase protein.

A B3LYP study of the effects of phenyl substituents on 1,5-hydrogen shifts in 3-(Z)-1,3-pentadiene provides evidence against a chameleonic transition structure.

The effects of one or two phenyl substituents on the activation enthalpy for a 1,5-hydrogen shift in 3-(Z)-1,3-pentadiene (1) and on the geometry of the transition structure (TS) have been investigated by B3LYP/6-31G calculations. The phenyl-substituent effects on the experimentally measured activation enthalpies are predicted to be sizable, spanning a range of nearly 10 kcal/mol. However, if differences between steric effects in the transoid isomers of the reactants are factored out by comparing the activation enthalpies in the cisoid conformers, the electronic components of the phenyl-substituent effects on both the barrier heights and the TS geometries are found to be quite modest in size. Unlike the TS in the Cope rearrangement, the TS for a 1,5-hydrogen shift in 1 is not highly variable in nature, and the reason the 1,5-hydrogen shift TS is not chameleonic is discussed.