A solution-phase total synthesis of argifin using 3,4,5-tris(octadecyloxy)benzyl (TAGa) tag as a hydrophobic protective group of carboxylic acid was developed in 44% overall yield for 16 linear steps. Because a novel class of natural product chitinase inhibitor, argifin, was a highly water-soluble cyclic pentapeptide, solid-phase synthesis techniques can only be acceptable to conveniently prepare argifin and its derivatives. TAGa alcohol (HO-TAGa) and its esters were highly crystalline materials and favorable to dissolve into less-polar solvents such as dichloromethane, benzene, THF etc., but insolvable into polar solvents such as methanol and DMSO. The combination of HO-TAGa and Fmoc-based peptide synthesis with simple purification by the mainly recrystallization from MeOH solution furnished an efficient and practical route of argifin in the solution-phase.

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Chloropupukeananin (1) was isolated from Pestalotiopsis fici by Che and colleagues as a new inhibitor against HIV-1 replication. The array of functional groups in a rigid tricyclic structure of 1 has provided us with a strong motive to construct the pupukeanane core based on biosynthetic hypothesis. We proposed a biosynthetic pathway for chloropupukeananin via maldoxin involving a reverse electron-demand Diels-Alder (REDDA) reaction and an intramolecular carbonyl-ene reaction. Herein, we report the investigation of REDDA and carbonyl-ene reaction with a model of maldoxin and vinylallene.
The precursors of REDDA were subjected to high pressure conditions to give a major product and other isomers. The X-ray crystallographic analysis of the major product revealed that the precursors underwent the REDDA reaction and the intramolecular carbonyl-ene reaction to construct the pupukeanane core in a single operation.

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Palladium-catalyzed N-allylation of anthranilic acids with allyl alcohol in the presence of Pd(OAc)2, sodium diphenylphosphinobenzene-3-sulfonate (TPPMS) in THF:H2O at room temperature gave only mono-N-allylated anthranilic acids in good yields (70-98%). The reactions of 4-bromoanthranilic acid with 2-methyl-3-buten-2-ol showed complete chemoselectivity in N-allylation (neutral conditions) and C-vinylation (basic conditions). In our catalytic system, the keys to success are use of an unprotected anthranilic acid as a starting material and water as a solvent. The carboxyl group of anthranilic acid and water may play important roles for the smooth generation of the π-allyl palladium species by activation of the hydroxyl group of the allylic alcohol.

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Since epoxides are versatile intermediates for a variety of chemicals, epoxidation of alkenes is a most important functional-group transformation in organic synthesis. Generally epoxidations of alkenes have been carried out with peracids instead of their explosivility. Molecular oxygen is thought to be the most desirable oxidant with respect to environmental and economic consideration, and much effort has been made to develop direct epoxidation of alkenes with molecular oxygen as an oxygen donor. Although there have been many reports on the metal-catalyzed epoxidation of alkenes with molecular oxygen as a terminal oxidant, only a limited number of metal-free methods have been reported. As a result of our effort to develop more economic and effective methods, we have found a new convenient synthetic method for metal-free one-pot epoxidation of alkenes using molecular oxygen and benzaldehyde under visible light irradiation.

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Chiral γ-hydroxy-α,β-acetylenic esters are attractive building blocks containing three functionalities: a hydroxyl group, an alkyne, and an ester, in a small molecule. Although asymmetric alkynylation of aldehydes with propiolates is one of the useful syntheses of chiral γ-hydroxy-α,β-acetylenic esters, previous reports required excess amounts of reagents and additives such as Ti(Oi-Pr)₄. Herein, we disclose an asymmetric alkynylation of aliphatic and aromatic aldehydes with propiolates mediated by dialkylzinc and a novel prolinol catalyst without high reagent loading and any additives, to give the corresponding γ-hydroxy-α,β-acetylenic esters with high enantiomeric excess of up to 95%.

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We have developed a regio- and stereoselective cohalogenation of alkynylbenezenes, which have electron-donating groups at the para-position on the aromatic ring. The stereoselectivity of the reaction is dependent upon the substituent on the acetylene terminus. Alkyl-substituted alkynylbenzene proceeded via anti-addition, affording E-iodoalkene, while aryl-substituted alkynylbenzene exhibited a preference for syn-selectivity. The resulting iodoalkene was utilized for the transformation through a Pd-catalyzed coupling reaction. A one-pot regio- and stereoselective cohalogenation/Suzuki-coupling reaction was also achieved.

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2,4,6-Tri-tert-butyl anilide derivatives are unique compounds which can be isolated rotational isomers based on amide bond at rt. Recently, we succeeded in the highly selective stereodivergent synthesis of E- and Z-rotamers of these anilide derivatives using Pd chemistry. We report here on the novel structural property of 2,4,6-tri-tert-butylanilide. Namely, interconversion between the separable 2,4,6-tri-tert-butylanilide rotamers was found to easily occur at rt through formation of the lithium enolate. Protonation of the anilide enolate gave the anilide rotamer mixture of E-major. On the other hand, reactions of lithium enolate prepared from 2,4,6-tri-tert-butylpropionanilide with alkyl bromides preferentially afforded a Z-rotamer of alkylated products. In particular, n-propylation with the enolate from E-rotamer occurred with almost complete inversion of the rotational isomerism.

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Enantiomer enrichment of non-racemic compounds through achiral chromatography has been so far found by many groups. However, as far as we know, study on generalization of such enrichment has not been reported. We report here on the methodology for enantiomer enrichment which can be applied to various non-racemic chiral amine derivatives. Excess enantiomers of various non-racemic chiral amines were efficiently separated through the conversion to N-acetamide derivatives and subsequent MPLC using an achiral silica gel column. MPLC chart of these N-acetamide derivatives has a clear boundary and the less polar fractions contain almost optically pure N-acetamide. The efficiency of the present enantiomer enrichment remarkably depends on the substituent on nitrogen atom. For examples, in N-tosyl and N-benzoyl derivatives, such separation was not observed.

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Reduction on TiO₂ are applicable to organic reactions, because electrons photogenerated in the conduction band (CB) or those trapped at defect sites on TiO₂ can transfer into an substrate adsorbed on TiO₂. We report the results of photo-hydrogenation of acetophenone (AC) and its fluorinated derivatives occurred upon UV irradiated TiO₂ surface. AC gave the secondary alcohol with 98% yield, in which electrons trapped at the shallow sites located just below the CB edge transferred into AC. However, electrons trapped at the deep levels remained on the TiO₂ surface. Ratio of the amount of remained/transferred electrons was estimated to be ca. 1/4. Trifluoromethyl acetophenone (TFAC) also gave the corresponding secondary alcohol, where all of the trapped electrons transferred into TFAC upon the TiO₂ surface. The photo-hydrogenation mechanism for acetophenone derivatives is compared and discussed.

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Sodium alkoxide- and aryloxide-mediated cyclization reactions of
1-sulfanyl-4-oxohepta-1,6-diynes have been developed. The reactions with diverse sodium
alkoxides produced 4-alkoxymethylfurans in good to high yields. The reactions of
4-oxohepta-1,6-diynes with aryloxides, which have higher nucleophilicities than alkoxides,
and the successive desulfanylation using tributyltin hydride/AIBN, provided 3-methylfurans.
While, the cyclizations of 4-oxohepta-1,6-diynes with sodium thiolate and the following
desulfanylations gave the 3,4-dimethylfurans. We further investigated the tyrosine-mediated
cyclizations of the 4-oxohepta-1,6-diynes and the syntheses of tetrahydronaphthyl derivatives,
which have interesting biological activities.

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Flavonoids are plant secondary metabolites and have various biological activities. Additionally, more attractive bioactivities of the prenylated derivatives than those of original flavonoids have been frequently discovered. Therefore, development of the efficient and general prenylating procedure of flavonoids was desirable. We report here an efficient method for C-prenylation of flavonoids, and their evaluation of suppressive effect on disused muscular atrophy based on our recent report. Our procedure for prenylation of flavonoids is selective protection and/or deprotection of hydroxyl groups, palladium-catalyzed O-1,1-dimethyl-2-propenylation and the following regioselective Claisen rearrangement for the carbon-carbon bond formation as the key steps.

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Marine eicosanoid hybridalactone was isolated from an extract of the red alga Laurencia hybrida in 1981 by Higgs and co-workers. Its unique structure, such as a tetracyclic ring system containing cyclopropane, cyclopentane, 13-membered macrolactone and epoxide, contains seven contiguous stereogenic centers and a skipped Z,Z-configured 1,4-diene motif. We report here the enantioselective total synthesis of hybridalactone. The synthetic strategy involves a ring-closing metathesis, an our developed tandem intermolecular/intramolecular dialkylation-lactonization using epoxyiodide and methyl phenylsulfonylacetate, and a Shiina macrolactonization. Consequently, hybridalactone was synthesized in 21.9% overall yield via 21 steps linear sequence.

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Magnevist^® has been used for the medical diagnosis to enhance magnetic resonance imaging (MRI). Diethylenetriaminepentaacetic acid (DTPA) is a major component of Magnevist^®, and chelates gadolinium (III) cation (Gd³⁺) which dramatically changes the relaxation parameters of hydrogen atoms.
We have developed a new method for the synthesis of a C-allylated DTPA derivative at the central glycinate moiety in high chemical yield with high site-selectivity. This key reaction is based on Stevens rearrangement. The resulting compound was converted to a versatile intermediate, which was derived to DTPA-Cholestanol derivatives.
Imaging ability of the DTPA-Cholestanol derivative was higher than that of Magnevist^®.

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Double-helix forming ologomers have attracted much interest. However, the relationship between the primary structure and the double-helix forming ability is not well understood. We synthesized and examined aggregation of sulfonamidohelicene oligomers (M)-1 and aminomethylhelicene oligomers (P)-2 in order to compare their property with ethynylhelicene and amidohelicene oligomers previously obtained. (M)-1 (n = 2-7, 9, 11) were synthesized by stepwise method of coupling reaction with building block and deprotection of Boc moieties. (P)-2 (n = 2-5) were obtained by repeating a reductive amination and deprotection of Boc moieties. CD spectra of tetramer (M)-1 (n = 4) and pentamer (P)-2 (n = 5) exhibited a strong cotton effect in m-difluorobenzene. Vapor pressure osmometry in m-difluorobenzene showed bimolecular formation. These results indicated that both formed helix dimer structures.

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Insertion reaction is very interesting, because the reaction enables the formation of a carbon-carbon bond between a carbenoid carbon and a non-activated carbon. Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were derived from cyclobutanones and chloromethyl p-tolyl sulfoxide, with lithium enolate of tert-butyl carboxylates, amides, and lithium α-sulfonyl carbanions gave adducts in high to quantitative yields. The adducts were treated with Grignard regents in toluene to afford 1-substituted cyclopentenes in good to high yields with one-carbon ring-expansion via 1,2-carbon-carbon (1,2-CC) insertion reaction of the generated magnesium carbenoid intermediates. On the other hand, treatment of the adducts of 1-chlorovinyl p-tolyl sulfoxides with lithium enolate of N,N-dibenzylglycine tert-butyl ester with i-PrMgCl afforded not only cyclopentenes but also bicyclo[2.1.0]pentanes via 1,3-carbon- hydrogen (1,3-CH) insertion reaction.

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Cyclobutyl magnesium carbenoid were generated from 1-chlorocyclobutyl p-tolyl sulfoxides were treated with 2.5 equivalents of ethylmagnesium chloride in THF at -90C° by sulfoxide-magnesium exchange reaction. These carbenoids were found to be stable at -78C°. Treatment of the cyclobutyl magnesium carbenoid with Grignard reagents at low temperature gave cyclobutanes. Moreover, the alkylated intermediate, derived from the cyclobutyl magnesium carbenoid with Grignard reagents, could be trapped with various electrophiles to give multi-substituted cyclobutanes with quaternary carbon center. This procedure provides a new method for a synthesis of multi-substituted cyclobutanes. Treatment of the cyclobutyl magnesium carbenoid reacted with 3 equivalents of lithium α- sulfonyl carbanion generated from vinyl sulfone with n-BuLi or LDA gave allylidenecyclobutanes.

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Chiral sulfoxides have been recognized to be one of the most important chiral auxiliaries in asymmetric synthesis. Treatment of α,β-unsaturated carbonyl compounds with lithium α-sulfinyl carbanions of enantiopure dichloromethyl p-tolyl sulfoxides gave 1-chlorocyclopropyl p-tolyl sulfoxides bering the carbonyl group. The carbonyl group of the adducts was reduced to give alcohols by NaBH₄ in quantitative yields.
Finaly, treatment of the alcohols with i-PrMgCl gave cyclopropylmagnesium carbenoids through the sulfoxide-magnesium exchange reaction. Doering-LaFlamme type rearrangement of the unstable carbenoids took place to afford enantiopure allenes. The asymmetric induction to the allenes from the enantiopure carbenoids was proved to proceed completely.

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A coordination bond was made use of construction for various metal complexes. Coordination polymer is one of the most attractive materials to achieve molecular recognition, molecular sieve, and reaction field. Although monitoring for synthesis process of isolated metal complex was established by several spectroscopies such as NMR, UV-vis and ESR, monitoring for construction process of coordination polymer could not be succeeded. In this work, cold-spray ionization mass spectrometry (CSI-MS) was applied to detection for soluble chemical species of coordination poly. Complexation of organic ligands, L_P, L_Q and Co(NO₃)₂ gave complex [Co(L_P)₂(L_Q)] and polymer [Co(L_P)(L_Q)(NO₃)]_n determined by X-ray analysis. In their solution, CSI-MS detected chemical species corresponding to coordination polymer components with solvent or fragmentation.

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We have developed an enantioselective oxidative coupling of 2-naphthol derivatives using vanadium(V) catalysts possessing (S)-tert-leucine moieties at the 3,3'-positions of the (R)-binaphthyl skeleton. This time we investigated a coupling of chrysen-5-ol and found a mononuclear vanadium(V) catalyst having naphthyl skeleton promoted the reaction to produce 6,6'-bi(chrysen-5-ol) in 83% yield with 73% ee. Optically pure coupling product was obtained after a recrystallization. We will report the applications of the coupling product to enantioselective organocatalysis.

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Quinolizidine skeleton is found in natural products. Since it often possesses significant biological activities, development of synthetic methods for this skeleton is important. Reductive cyclization of acylpyridinium cation, which was derived from carboxylic acid and Ghosez's reagent was investigated for construction of quinolizidine skeletons. Several functional groups, including electron withdrawing groups, silyl and acetal groups, were tolerated under these conditions. The resultant compounds, highly oxidized quinolizidines, were converted into several natural products having quinolizidine skeletons.

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Novel base-free Hirao-type P-arylation by the use of triarylantimony diacetates and H-phosphonate diesters in the presence of Pd(PPh₃)₂ (5 mol%) catalyst led to the formation of arylphosphonates in moderate to excellent yields. This reaction is first example for carbon-phosphorus bond formation by the use of palladium-catalyzed cross-coupling reaction of organoantimony compound.

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Vinylazetidine is a stained and reactive compound and various cycloaddition reactions have been reported. We have been interested in the reactivity of vinylazetidines and reported that vinylazetidine reacted with tosyl isocyanate to give eight-membered cyclic urea without catalyst under mild conditions. We extended our study and found that a new cycloaddition reaction of vinylazetidine with benzyne.
When a solution of 2-trimethylsilylphenyl triflate and N-benzyl-2-vinylazetidine was added dropwise to a suspension of cesium fluoride in toluene-CH₃CN, a benzazocine derivative was obtained in high yield. A series of vinylazetidine derivatives reacted similarly, providing the corresponding benzazocine derivatives in good to high yields. The detail of this reaction, as well as the mechanism of this reaction, will be presented.

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We developed both syn- and anti-cyanopalladation that were applicable for various alkyne substrates and their syn-selectivity was strongly dependent on the substituent on propargylic position. The substrates could be effectively activated by Pd(II) and nucleophilic cyanation at terminal carbon would predominantly occur (syn-cyanopalladation). Anti-cyanopalladation would be triggered by direct nucleophilic cyanation into internal carbon but steric bulk easily prevents this pathway. Following reductive elimination would afford the corresponding dicyanated products together with Pd(0) that could be quickly oxidized to Pd(II). When further application for new cyclization and cycloaddition protocol was investigated, we observed that the enyne cyclization was promoted via 5-exo and 6-endo mode. In case of ene-enynes, [4+2] cycloaddition was accomplished via four CC bond formations through single operation with critical control of maximum 5 stereocenters.

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Recently, we reported that dirhodium(II) carboxylates incorporating N-tetrahalophthaloyl-(S)-tert-leucinates as chiral bridging ligands are highly efficient catalysts for enantioselective aminations with pNsN=IPh or NsN=IPh. As a logical extension of our studies in this area, we herein report enantioselective intramolecular C-H amination of sulfamate esters catalyzed by chiral Rh(II) carboxylates. We found that the enantioselective intramolecular C-H amination of sulfamate esters derived from 3-(indole-3-yl)propan-1-ol using chiral dirhodium(II) carboxylate catalysts, PhI(OAc)₂, and MgO at room temperature provides the corresponding cyclic sulfamidates in high yield and with up to 93% ee. In this process, the use of Rh₂(S-TCPTTL)₄ as well as installation of tert-butoxycarbonyl group as a N-substituent proved to be crucial in terms of both product yield and enantioselectivity.

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Phaeosphaeride A is a nitrogen-containing natural product isolated from an endophytic fungus in 2006 by Clardy and co-workers. Phaeosphaeride A inhibits the growth of STAT3-dependent U266 multiple myeloma cells in vitro. Although the relative stereochemistry of phaeosphaeride A was deduced on the basis of NOE experiments, the absolute configurations remained unknown. This unique molecular structure and promising biological activity prompted us to a synthetic study of phaeosphaeride A. Here, the first total synthesis of the proposed structure of phaeosphaeride A has been achieved via six-membered-ring formation by means of intramolecular vinyl-anion aldol reaction as a key step. This synthesis suggests a revised configurational assignment for phaeosphaeride A.

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The phenol nucleus is found in numerous biologically active compounds, ranging from natural products to medical supplies. In laboratory-scale synthesis of phenols, transition metal-catalyzed hydroxylation of aryl halides has recently been widely used. However, such a process requires the use of a rather toxic phosphine ligand and the harsh reaction conditions, thus there is still a room for improvement. Hu, Wang and co-workers recently reported the copper-catalyzed, base-mediated transformation of arylboronic acids for the preparation of phenols. The process employs a copper catalyst and a phenanthroline ligand along with 3 equiv. of KOH as a base, affording variously substituted phenols. Herein, we describe our finding that various arylboronic acids are efficiently converted into the corresponding phenols in the presence of a copper catalyst. The reactions efficiently proceed under mild, ligand- and base-free conditions in water containing an amphiphilic surfactant.

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1,3-Methyleneglycerol (1,3-mG) is a versatile compound which was used as a variety of aims such as 1) an increase of water-solubility or efficacy of medicine; 2) starting material of monomer to synthesize functional polymer; and 3) starting material for fine chemistry. However, 1,3-mG is only purchased as a mixture contained 44 mol% of unwanted 1,2-methyleneglycerol 1,2-mG). Moreover, it is difficult to separate both isomers that have very similar properties such as boiling point and polarity.
In this paper, we describe development of the method for the preparation of 1,3-mG with ≥99% purity, via acid-catalyzed equilibrium to increase 1,3-mG and selective protection of unwanted 1,2-mG, which was removed by facile procedure such as distillation or extraction. We newly report herein that tritylation with 2,4,6-collidine in dichloromethane as the final step to afford the best purity of 1,3-mG.

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A spiroiridal triterpenoid, 28-Deacetylbelamcandal was isolated from the rhizomes of Belamcanda chinensis in 1991. This natural product possesses a spiro[4.5]decane framework including five contiguous stereogenic centers and a tetrasubstituted olefin.
Our strategy towards 28-Deacetylbelamcandal features Claisen rearrangement in alkenyl dihydropyran system for construction of a highly functionalized spiro[4.5]decane framework and stereoselective synthesis of tetrasubstituted olefin via intramolecular Heck reaction, subsequent deprotonation at bisallylic position and Rubottom oxidation.
Alkenyl dihydropyran was prepared in 8 steps involving asymmetric aldol reaction and acid-catalyzed cyclization. The Claisen rearrangement (in triglyme, 0.05 M, 230 ^oC, 4 hr.) gave the desired product in 84% yield. Conversion of the Claisen product to the precursor for Heck reaction is currently under way.

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Rocaglamide derivatives, which are one of the cyclopenta[b]benzofuran compounds including in plants of Asian and Western Pacific region, are counted on bioactivities. We isolated two rocaglamide derivatives from leaves of Amoora cucullata (Meliaceae). They showed very strong activity in sensitizing to TRAIL, which leads to apoptosis of cancer cells. In this research, we aim to synthesize rocaglamide derivatives with heterocyclic units to discover their extraordinary potential. As first, we succeed the efficient synthesis of 2-furanyl-3-hydroxy-chromone. A phtochemical [3+2]-cycloaddition between the furanylchromone and methyl cinnamate smoothly proceeded. Base-induced rearrangement and reduction gave a 3a-furanyl-rocaglamide derivative in 6 steps 11% yield.

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Bongkrekic acid (BKA) is a toxic antibiotic produced by the bacterium Burkholderia cocovenenans. The high toxicity of BKA has been attributed to its affinity for the adenine nucleotide translocator protein (ANT), thus preventing oxidative phosphorylation. Recently, BKA has been found to inhibit mitochondria-induced apoptosis. Although BKA is now a very important and useful biochemical tool for investigation of apoptosis, the biochemistry of BKA has not been extensively studied, due to its limited availability from fermentation or chemical synthesis. Thus, BKA and its analogues are required to be synthesized on large scale in pure form. Although several total synthesis of BKA have been reported, these were not suitable for enough amount of its preparation. Here, we report the second-generation synthesis of BKA using a three-component convergent strategy involving a Julia-Kocienski olefination and a Suzuki-Miyaura coupling. The SAR study of BKA will also be presented.

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Recently, we have established a novel synthetic method for triplet drugs with 1,3,5-trioxazatriquinane skeletons using a nitrogen clamp. The useful synthetic method led us to examine its application to compound library. Totally we synthesized 42 homo- and heterotrimers and 4 of them bound to opioid receptor in several μM (Ki value), another 4 compounds bound in hundreds nM. Especially, SYK-146 showed highly selective for κ opioid receptor ((Ki = 6.093 nM (κ), >1000 nM (μ), >1000 nM (δ)). The representative κ selectivity of SYK-146 was almost same as that of U-50,488H, selective κ opioid ligand. These results suggested that these obtained trimers would be a valuable compound library in drug screening for opioid receptor. Furthermore, this library expected to be applicable for general GPCRs by changing phenol moieties to other hetero aromatic rings. On this symposium, we will report the synthesis of the heterotrimers and their pharmacologies.

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We developed Nalfurafine Hydrochloride as an antipruritic drug for kidney dialysis Patients, which was released in Japan in 2009. This was the first kappa opioid agonist which had no addiction nor aversion. However, Nalfurafine was applied to an antipruritic, but not analgestic because of serious sedation. Since then, we are examining to design and synthesis of a potent analgestic without addiction, aversion and sedation. We postulated the active conformation of Nalfurafine for binding to kappa receptor whose 6-side chain was oriented to upper side of C-ring of nalfurafine. On the other hand, we synthesized novel propellane derivatives whose 7-amide chain was oriented to upper side of C-ring of molecules. Then we synthesized a novel pentacyclic ketone derivatives 6,7 from iminium 8 via 6 steps using Reformatsky reaction as a key reaction. In this symposium, we will report SARS of propellane derivatives with 7-amide side chain and synthesis of a pentacyclic ketone 6,7.

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We have been studying the design and synthesis of opioid ligands using the opioid antagonist naltrexone (2). In the cource of these studies, we observed the similarities of the structure between (-)-galanthamine (1) and naltrexone (2). (-)-Galanthamine (1) is aprescription drug for the treatment of Alzheimer's disease in Europe and the United States. Some of the derivatives exhibited higher inhibitory activity than (-)-galanthamine itself. We were interested in the influence of ring expantion of (-)-galanthamine (1) on the pharmacological synthesis of (-)-homogalanthamine 3 from naltrexone (2) and the results of inhibitory activity of homogalanthamine 3 and the derivatives against AChE.

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Based on the postulated active conformation of TRK-820(Nalfurafine hydrochloride: kappa agonist), we designed and synthesized a novel kappa agonist KNT-63 with oxabicyclo[2.2.2]octane skeleton. KNT-63 showed profound antinociceptive effect via the kappa receptor.
In the course of investigating the synthesis of KNT-63 derivatives, we found a novel rearrangement providing morphinan derivative with an oxazatricyclodecane structure. The rearrangement product showed moderate affinities for three opioid receptor types. This result led us to attempt to synthesize rearrangement product derivatives to obtain novel useful ligands for opioid receptor. Designed compounds, SYK-40 and -89, prepared from rearrangement product, showed high affinity for delta opioid receptor.
SYK-89 derivatives are expected to a useful lead compound for a novel delta ligand.

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Scillascillosides, eucosterol oligoglycosides isolated from the bulbs of Scilla Scilloides by Kawasaki and co-workers in 1985, were found to exhibit cytotoxicity against several tumor cells. Having completed the synthesis of the tetrasaccharide subunit of scillascilloside E-1, we addressed the synthesis of its aglycon moiety.
We envisioned that the B ring would be constructed at a late stage of the synthesis, and disconnections of this ring afford the A and the CDE ring units. The A ring unit has been synthesized from the known aldehyde via a twelve-step sequence involving an intramolecular Diels–Alder reaction. With regard to the synthesis of the CDE ring unit, we found that the contiguous quaternary stereocenters at C13 and C17 could be formed simultaneously by an Ireland–Claisen rearrangement, albeit with 1:5 stereoselectivity favoring the undesired isomer.

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Oxidation is a most important transformation in organic synthesis. Many methods and reagents have been developed to date; however, these reactions typically involve the use of large quantities of heavy metals and complex organic compounds, which generate large amount of waste, and are not environmentally benign. Molecular oxygen has received much attention as an ultimate oxidant, since it is photosynthesized by plants, produces little waste, is inexpensive and of large atom efficiency than that of other oxidants. With this perspectives, we have found that methyl aromatics effectively oxidized to benzoic acids by photooxidation with molecular oxygen as terminal oxidant in the presence of 2-chloroanthraquinone. In the course of further our study, vicinal -diols were found to be oxidatively cleaved to corresponding carboxylic acids with molecular oxygen as terminal oxidant in the presence of 2-chloroanthraquinone under irradiation with a 400 W high-pressure mercury lamp.

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The oxidation from alcohol to aldehyde or ketone is one of the important reactions in the organic synthesis. 2, 2, 6, 6-Tetramethyl- piperidine-1-oxyl (TEMPO) was used on the oxidation as an oxidant of low toxicity. We found that 4-hydroxy TEMPO was easily adsorbed by silica gel in nonpolar solvent such as toluene, 1,2-dichloroethane, and chloroform. Aerobic oxidation of alcohols using supported reagent ([4-hydroxy TEMPO + NaCl]/SiO₂) and Fe(NO₃)₃•9H₂O was achieved high yield of corresponding carbonyl compound in a short time. [4-hydroxy TEMPO + NaCl]/SiO₂ was easily prepared, and can be easily separated by filtration.

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The reaction of 1,3-dithianes with electrophiles is one of the most important synthetic methods for the selective construction of C–C bonds. Removal of a dithioacetal protecting group often requires harsh conditions or the use of stoichiometric toxic reagents such as Hg(II) salts.
Gold compounds generally have a strong affinity for a sulfur atom. We anticipated that gold compounds have an ability to activate a sulfur atom and hydrolyze 1,3-dithianes. Herein, we report the hydrolysis of 1,3-dithianes promoted by a catalytic amount of gold(I) iodide under O₂ atmosphere in acetonitrile-water at room temperature, affording the corresponding aldehydes or ketones. Additionally, reducing the amount of the catalyst can be successfully achieved by carrying out the reaction under high oxygen pressure. We also present the scope, limitations and mechanistic insights into this reaction.

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Enantioselective 1,4- and 1,2-additions of boronic acids to conjugated enones, ketones, or imines constitute effective C–C bond forming reactions in organic synthesis. Although numerous efficient chiral transition metal catalysts are known, few organocatalysts (chiral biphenol and thiourea derivatives) have been successful in these transformations. Herein we have demonstrated that O-monoacylated tartaric acids are capable of activating boronic acids and catalyze the asymmetric conjugate addition of boronic acids to conjugated enones with good enantioselectivity (68-88% ee). The 3,5-di(tert-butyl)benzoyl group provides the best results among the acyl groups examined. Addition of methanol effectively prevents the non-catalyzed reaction increasing the enantioselectivity.

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Simple and efficient procedure for the carbon-carbon bond formation has been developed from alcohol and active methylenes using silica-gel supported sodium hydrogensulfate (NaHSO₄/SiO₂) under mild conditions and short times. For instance a mixture of acetyl acetone (2 mmol), benzhydrol (2 mmol) and NaHSO₄/SiO₂ (2.1 mmol) was stirred in dichloroethane (DCE) at 60 °C for 30 min, corresponding 3-benzhydryl pentane-2,4-dione was given in 98 % yield. NaHSO₄/SiO₂ can be reused without loss of catalytic activity at least 10 times.

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UCS1025A was isolated from the fungus Acremonium sp. KY4917 in 2000. Due to its potent telomerase inhibitory activity and antimicrobial activity, UCS1025A is expected to be a lead compound for the drug development. The structure of UCS1025A is composed of a pyrrolizidinone (azabicyclo[3.3.0]octanone) skeleton cross-linked by γ-lactone and the hemiaminal at ring juncture. Herein, we will report the total synthesis of optically active UCS1025A which involves new strategies of the construction of pyrrolizidinone skeleton and the stereocontrolled hemiaminal moiety.

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Pachastrissamine (jaspin B) was isolated from the Okinawan marine sponge Pachastrissa sp. by Higa and co-workers in 2002 and shortly after from a different sponge, Jaspis sp., by the Debitus group in 2003 as a naturally occurring novel anhydrophytosphingosine derivative. It exhibited cytotoxic activities against several human carcinoma cell lines. Because of the impressive biological activity and its novel structural features, pachastrissamine has attracted much attention from synthetic chemists. Although we reported the first enantioselective total synthesis of pachastrissamine using rhodium(II)-catalyzed C–H amination as a key step in 2007, it is not suitable for large scale synthesis due to low yield step included. We now report here an improved synthetic route that would be more flexible for the synthesis of its analogues.

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Here, we will present our studies that have led to the development of new acyclic 1,3-diamine-tethered guanidine/bisthiourea organocatalysts 1. Analysis of these processes shows that the catalytic effect resides in a trade off between enthalpies and entropies of activation and reveals the existence of dramatic concentration effects. This effort has uncovered a unique catalytic stereodiscrimination process controlled only by differences in activation entropies. Furthermore, we have successfully developed the cycle-specific catalysis with guanidine/bisthiourea 1 and external achiral base combination, facilitating the effective one-flask syntheses of N,N-bis-dihydrofuranyl-hydroxyamines 5 from phenols 2 and nitroolefins 3. Mechanistic studies on these organocatalytic reactions are also discussed.

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We have developed three sp³ C-H functionalization methodologies; 1) intramolecular C-H acylation utilizing the Norrish-Yang photocyclization and ring-opening sequence, 2) intermolecular C-H carbamoylation using pentafluorophenyl isocyanate, 3) intermolecular C-H cyanation using tosyl cyanide. The developed reactions proceed in a highly efficient and chemoselective manner at ambient temperature through hydrogen abstraction of the photo-excited carbonyl groups. These transformations provide powerful tools for the direct introduction of the functionalized carbon units onto the saturated carbocyclic or heterocyclic compounds. The details of scope and limitations of each reaction will be presented.

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Carbon dioxide is a cheap, abundant, and readily available C1 source. Carboxylation of carbon nucleophiles with carbon dioxide to form new C-C bonds therefore represents an attractive method for the synthesis of carboxylic acid derivatives. To meet this purpose, we have developed a one-pot synthesis of amino acids from imine precursors, amino sulfones derived from aryl aldehydes, using carbon dioxide as a C1 source. In the presence of TMSSnBu₃, CsF, and carbon dioxide (1 MPa), amino sulfones were transformed into the corresponding arylglycine derivatives in moderate-to-high yields. Various substituted amino benzyl sulfones were tolerated in this one-pot amino synthesis. It is believed that the one-pot transformation consists of three sequential reactions, such as imine formation, stannylation, and carboxylation. CsF plays different roles for each step (base, silicon activator, and stannane activator).

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An addition of nitrogen nucleophiles to intramolecular carbon–carbon multiple bond (i.e., hydroamination) is one of the most powerful method to synthesize nitrogen-containing heterocycles. Since olefins are electron-rich in nature, it is important to enhance the electrophilicity of olefins by a coordination of Lewis acids or a reaction with electrophiles, and/or, increase the nucleophilicity of nitrogen by converting amino N–H to metal amide. An addition of organometallic reagents to C=N double bonds is an alternative to generate metal amides, whose addition to intramolecular C=C double bonds enables to synthesize nitrogen-containing heterocycles in a one-pot. The utility of this approach is unnecessity of the preparation of the cyclization precursor for heterocycles. We report herein a carbamoylation of ω-alkenylmagnesium bromide with N-tosylisocyanate and subsequent bromolactamization by an oxidation of magnesium amide intermediate.

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A direct catalytic asymmetric addition of allyl cyanide to ketones and aldehydes with a cooperative catalytic system comprising (R,R)-Ph-BPE/[Cu(MeCN)₄]ClO₄/LiOR is described. In case of ketones, exclusive γ-addition of allyl cyanide was observed, affording optically enriched tertiary alcohols bearing Z-configured α,β-unsaturated nitriles. On the other hand α-adduct was produced using aldehydes as substrate, which was a kinetic product and eventually converged to Z-configured α,β-unsaturated nitriles. The reaction proceeded under proton-transfer conditions, utilizing soft Lewis acid/hard Brønsted base cooperative catalysis. The applicability of the reaction to synthesis of key intermediate of (+)-fostriecin was disclosed.

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During the study of the synthesis of 14-epi-19-norprevitamin D₃, we found 14-epi-19-nortachysterol formation through C6,7-cis/trans isomerization. Also, we succeeded in their chemical synthesis including their 2-substituted (methyl, hydroxypropyl, and hydroxypropoxy) analogs, and revealed their marked stability and potent VDR binding affinity and, to the best of our knowledge, this is the first example to isolate stable tachysterol analogs. Surprisingly, 14-epi-19-nortachysterol derivatives exhibited an unprecedented binding configurations for the ligand binding pocket in hVDR, C5,6-s-trans and C7,8-s-trans triene configurations, which were opposite the natural triene-configuration of 1&alpha,25(OH) ₂D₃.

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The diketopiperazine containing derivative plinabulin was found to have potential anti-microtubule activity and phase II clinical trials with intravenous injection were undertaken in the US as a promising vascular disrupting agent. However, the low water-solubility had to be improved for the requirement of drug. Recently, we designed and synthesized the water-soluble prodrug of plinabulin using click chemistry. Our strategy produced a unique monolactim skeleton, high water solubility, and regeneration of the parent compound upon esterase hydrolysis. The safe and stable prodrug was transformed in three steps from the parent compound. In addition, alkyne intermediate is able to be functionalized with various aqueous azide substituents. Higher-order functional assessment and investigation of water-solubilizing group are now in progress.

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Nemorosone is a polycyclic polyprenylated acylphloroglucinol (PPAP). PPAPs
have diverse and complex structures with intriguing biological activities.
Their fascinating structure and wide-ranging biological activities have
made PPAPs attractive synthetic targets, and many synthetic studies
including total synthesis have been reported. We have developed
a synthetic strategy for constructing the common scaffold of PPAPs.
Our strategy features the intramolecular cyclopropanation (Step I), subsequent
alkylation (Step II), and a regioselective ring-opening reaction (Step III). This
sequential process includes the desymmetrization step (Step I) which was
devised after considering the hidden symmetry in PPAPs; hence,
the process would be enantioselective by use of a chiral catalyst, and
could be applied to the enantioselective synthesis of other PPAPs.

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