The Claisen rearrangement of allyl vinyl ethers has been accepted as a versatile synthetic protocol for the preparation of γ,δ-unsaturated carbonyl compounds. The stereoselectivities of the rearrangement, including the E/Z selectivity, are usually high, and virtually all cases proceed with high selectivity for the products with E configuration. However, there is amazingly limited precedent for the rearrangement with the opposite Z-selectivity. Reported herein is the first example of catalytic Z-selective Claisen rearrangement of simple aliphatic allyl vinyl ethers: the use of a chromium(III) porphyrin complex, Cr(TPP)Cl, as a catalyst significantly enhances reversal of E–Z selectivity in the thermal Claisen rearrangement of allyl vinyl ethers, especially, 4,5- and 4,6-disubstituted derivatives, at low catalyst loading (5 mol %).

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A chiral synthesis of α-hydroxy-H-phosphinates was achieved via lipase-catalyzed hydrolysis of the corresponding racemic acetates. The reactions provided diastereomerically pure α-hydroxy-H-phosphinates in high optical purity starting from not only diastereomerically pure racemic acetates but also a mixture of diastereomers. A new utility of a pseudo-C₂-symmetric α,α'-dihydroxyphosphinate, derived from α-hydroxy-H-phosphinate, for a chiral ligand of Lewis acid was examined. In the presence of catalytic amounts of Zr(O-t-Bu)₄ and α,α'-dihydroxyphosphinate, the reaction of benzaldehyde with allyltri-n-butylstannane provided the allylation product in 36% ee.

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Asymmetric conjugate addition of nitrogen nucleophiles to α,β-unsaturated esters has been one of the most powerful methods for the synthesis of chiral β-aminoester. Previously we have reported chiral ligand-controlled asymmetric conjugate addition of lithium amide. For improvement of reactivity and selectivity of a lithium amide, steric modification of lithium amide was carried out. Addition of toluene solution of enoates 3 to a mixture of lithium amide 2, which had a bulky mesitylmethyl group on nitrogen, and chiral diether ligand 1 in toluene gave conjugate adducts 4 in high yield and enantioselectivity up to 99% ee. Conjugate adduct 4 were converted to primary amine 5 without racemization through the removal of mesitylmethyl group with successive reactions of N-chlorination–dehydrochloride–transimination.

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Formaldehyde is one of the most important C1 electrophiles in organic synthesis. However, it has been difficult to realize catalytic asymmetric aldol reactions of formaldehyde (catalytic asymmetric hydroxymethylation) with silicon enolates with high enantioselectivity. Here we report the highly selective asymmetric hydroxymethylation using Sc(OTf)₃ and a chiral ligand having bipyridine moiety. It is noteworthy that a commercial aqueous solution of formaldehyde can be directly used for this reaction. X-ray analysis of a complex of the ligand with ScBr₃ has revealed a pentagonal bipyramidal structure in which the OH groups of the ligand coordinate to the Sc cation. We assume that this type of structure is a key for the high enantioselectivity in the asymmetric hydroxymethylation.

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An efficient synthesis of optically active N-protected 5-hydroxy-3-piperidenes used as a promising chiral building block for synthesis of biologically active compounds such as alkaloids and azasugars has been investigated by palladium-catalyzed deracemization. Treatment of racemic N-protected 5-methoxycarbonyloxy-3-piperidenes with 2 mol % of Pd₂(dba)₃•CHCl₃ and 8 mol % of BPA in CH₂Cl₂–H₂O (9:1) gave N-protected 5-hydroxy-3-piperidenes in high ees (86–99% ee) and chemical yields (72–90%). Employing DMSO–H₂O (9:1) as homogeneous solvent system instead of CH₂Cl₂–H₂O as heterogeneous solvent system also resulted in high ees and chemical yields.

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A new concept of dual activation catalysis for the enantioselective homolytic coupling reaction of 2-naphthol derivatives is described. The novel dinuclear vanadium(IV) complexes, bearing two active metal sites attached to the 3,3'-position on binaphthyl, biphenyl and octahydro binaphthyl skeletons, promote the oxidative coupling reaction of 2-naphthols to afford BINOL derivatives in good yield with up to 94% ee. This “dual activation” mechanism was supported by kinetic analysis of the catalytic reaction and the effect of catalyst loading.

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The optically active α-chloro α-sulfonyl ketones were easily synthesized in a four-step conversion from optically active 4-tolyl alkyl sulfoxide in good overall yield. Treatment of the ketones with NaH and BnNH₂ gives β-sulfonyl amides via asymmetric Favorskii rearrangement. The sulfonyl group of β-sulfonyl amides was reduced to afford optically active α-alkyl amides. The amides were converted to acetoxypivalimides, and then the imides were hydrolyzed to yield (+)-, (–)-2-ethylhexanoic acid without epimerization. The process to (+)-, (–)-2-ethylhexylamine will be presented.

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We have already found exo- and enantioselective cycloaddition of azomethine ylides catalyzed by Cu(II)–BINAP complexes. Herein, the corresponding cycloaddition of polymer-supported azomethine ylides were examined. The solid-phase reaction afforded higher diastereoselectivity as well as nearly the same enantioselectivity compared with those of liquid-phase reaction. For example, the reaction of N-benzylidene glycine methyl ester on Wang resin with N-phenylmaleimide in the presence of catalytic amounts of (S)-BINAP and copper(II) triflate gave the corresponding exo-cycloadduct in 35% ee. Linkers, resins, and reaction conditions were also examined.

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As an efficient tool for preparing a variety of chiral synthon necessary in medicinal chemistry, we developed a new solid-supported chiral auxiliary, i.e., Wang resin-supported Evans' oxazolidine-2-one, which is anchored at the 5-position of the oxazolidinone ring. Solid-phase asymmetric alkylation on this resin proceeded in high diastereoselectivity comparable to that of conventional solution-phase model experiments. In the present study, we newly developed a simple synthetic route of this solid-supported chiral auxiliary using Fmoc-based solid-phase chemistry. In addition, the ability of Sm(OTf)₃ mediated chemoselective cleavage of products from the solid-supported chiral auxiliary was examined. The ester- and amide-forms of corresponding chiral synthon were obtained with a reasonable yield. Further study to expand the utility of this auxiliary revealed that asymmetric alkylation, hydrazination and fluorination were achieved successfully in high stereoselective manner.

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(S)-1,1'-binaphthalene-2,2'-disulfinic acid (1) was prepared from (S)-1,1'-binaphthalene-2,2'-diol and evaluated as a chiral discrimination reagent of alcohols. Enantiomers of 2-butanol and menthol were esterified with 1 in the presence of N-methylimidazole (10 eq) and DCC (1.5 eq). Each reaction was completed within 1–2 h at room temperature to yield a single diastereomeric ester. The ¹H NMR analyses (270 MHz, CDCl₃) of reaction products revealed the large chemical shift difference between diastereomers derived from enantiomers of alcohol. For example, 0.93 ppm was observed in the chemical shift difference of 1-methyl proton between derivatives prepared from (+)-2-butanol and (–)-2-butanol. For the purpose of a detailed study of a reaction mechanism, crystallization of monoesters followed by X-ray analysis for the determination of absolute configuration at a sulfur atom is now on going.

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We previously showed that the CFTA method using α-cyano-α-fluoro-p-tolylacetic acid is much more reliable for ¹H NMR determination of the absolute configurations of chiral molecules than the existing methods including the modified Mosher's method. This method was based on the formation of the highly stable conformers of CFTA derivatives. As the part of our study to show the versatility of the CFTA method, we here report that this procedure is applicable for determination of the absolute configuration of chiral benzhydrols and α-monodeutrated benzyl alcohols, which have two quite similar substituents. We also report the application for determination of the absolute configuration of chiral primary amines. Moreover, using ab initio calculation, we demonstrate for the first time that a hyperconjugation can play an important role in the determination of conformational preference of CFTA derivatives.

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Novel optically pure α-imino acids bearing a fluorescent coumarin nuclei at an N position have proven to be the quite reliable and useful chiral derivatizing agents (CDAs) for enantiomeric amines and alcohols involving the tertiary ones by inspecting a diastereotopic nonequivalence [Δδ (ppm) in CDCl₃] of the specific sharp-singlet proton at coumarin C-3 in the resulting crude diastereomeric amides and esters.

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Nitric oxide (NO) donors are now very useful and important reagents for the research field of NO physiology and pathology including various diseases. We have found that 6-nitrobenz[a]pyrene can release NO in response to the photoirradiation. This interesting property of the compound was suggested due to the non-planar conformation of its nitro function. In the light of this finding, we developed 4-substituted-2,6-dimethylnitrobenzene derivatives, which are also expected to have non-planar conformations of the nitro group in their simple structures, and compared their NO releasing activity in response to the visible light irradiation. Among the 15 various synthesized dimethylnitrobenzene derivatives, 8 compounds showed the potent NO releasing activity. The simulation study of their molecular structures suggested that the NO releasing activity were closely related to the conformation of the aromatic nitro group.

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We previously reported that an aminofullerene can deliver extra-cellular gene into mammalian cells, and that an appropriately designed amphiphilic fullerene functions as a new transfection reagent. Here we report synthesis of a newly designed fullerene transfection reagent. Using a new method for the synthesis of tetraaminofullerene epoxides, several kinds of aminofullerene were synthesized in high yield and selectivity. The DNA binding ability was estimated by exclusion of ethidium bromide from DNA and the transfection efficiency by luciferase activity. Most of the aminofullerene had high DNA binding ability. We found one of aminofullerene had high transfection ability as lipofectin, which was prepared in good yield by two-step transformation of C₆₀.

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Homochiral oligoesters such as an oligolactate preferentially forms a helical structure. On the other hand, D,L-oligoesters, consisting of alternating D- and L- lactic acid, favorably adopt a higher-ordered cyclic structure when lactic units are in the range of 6~8. Structural analysis indicated that the cyclic structure of D,L-oligoesters is not the result from intramolecular hydrogen-bonding, but from their D,L-chirality. Ion-transport experiments were performed with octaesters consisting of 2-hydroxy-3-phenylpropionic units. The D,L-octaester showed the higher rate of ion transport both for Na⁺ and K⁺ than the corresponding homochiral octaester. The D,L-octaester selectively transported potassium ion and the rate was as fast as that for sodium-ion transport by well-known ionophore, monensin.

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In order to develop a prototype of synthetic channels capable of forming a stable channel structure, a series of thiacalix[4]arene derivatives were synthesized as “half channels”, and their ion-selective channel functions in bilayer membranes were examined for alkali and alkaline earth cations (Li⁺, Na⁺, K⁺, Mg²⁺, Ca²⁺). Among the channel molecules appended with long alkyl chains, the ester type channels (Li⁺-selective) showed channel currents with a large conductance (60 pS) and a long duration time (up to 6 s). Furthermore, the channel appended with oligoethereal chains displayed K⁺-selective channel currents with largest conductance (70 pS) and longest duration time (up to 16.8 s). These results indicate the importance of “cationophilicity” of the channel chains in addition to the suitable thiacalix[4]arene structure.

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We developed a new synthetic route for (Z)-alkene-containing diketopiperazine mimetics as promising scaffolds for drug discovery. Alkylations of γ-phosphoryloxy-α,β-unsaturated lactams synthesized as key synthetic intermediates with various organocopper reagents which were prepared from organometallic reagent (Li, Mg, Zn) and Cu(I) salt in the presence of LiCl proceeded in an anti-S_N2' manner with very high regio- and stereoselectivity to yield desired α-alkylated products in good yields. In this study we found that addition of LiCl dramatically increased α-regioselectivity of the reaction of MeCuI•MgCl. We presume that change of cluster structure of MeCuI•MgCl induced by LiCl is responsible for the determination of regioselectivity. In other words MeCuI•MgCl•2LiCl can form a stable reaction intermediate exclusively leading to anti-S_N2' products.

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Annonaceous acetogenins have attracted much attention due to a wide variety of biological activities. Whereas these compounds is thought to inhibit the complex I (NADH–ubiquinone oxidoreductase), there still remains to verify whether they bind to the ubiquinone reduction site. As such, structure–activity relationship study is important to elucidate their essential structural requirements and inhibitory mechanism against the terminal electron transport system of complex I. In the present study, we achieved the synthesis of a series of acetogenins including reticulatain-1, cis-solamin, dihydroxy-cohibin A and diepomuricanin-A. Our synthesis proceeded through the following major transformations; (i) asymmetric dihydroxylation to construct most of the chiral centers, (ii) Sonogashira coupling of core unit and γ-lactone. The inhibitory action of compounds was examined with bovine heart mitochondrial complex I.

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It is known that some benzophenanthridine alkaloids show antitumor activity. We also found that a 2-aryl-1,4-napthoquinone-1-oxime, which was prepared as a key synthetic intermediate for macarpine, a 12-alkoxybenzophenanthridine base, by the regioselective nitrosation of 3-aryl-1-naphthol under basic conditions (isoamyl nitrite–potassium carbonate–DMF), showed strong antitumor activity. Thus, the structure–activity relationship of the naphthoquinone monooxime derivatives was examined for the development of a new anticancer drug. Chemical modification of the naphthoquinone skeleton suggested that the quinine oxime function was essential for the activity, whereas the substitution system of the 2-aryl group was tolerant.

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In order to find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, a series of compounds modeled after suberoylanilide hydroxamic acid (SAHA) were designed as follows. (1) structure-based drug design; (2) design applying the thiophilicity of zinc ion; (3) design based on the structure of the transition state; (4) mechanism-based drug design; (5) irreversible inhibition-oriented design. In this series, compounds in which the hydroxamic acid of SAHA was replaced by a thiol (4) and a mercaptoacetamide (9) were found to be as potent as SAHA. In small molecule HDAC inhibitors, thiol and mercaptoacetamide are the first zinc-binding group that has comparable activity to hydroxamic acid. These compounds could be new leads for anticancer agents free of the problems of hydroxamic acids.

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A novel and efficient “O-acyl isopeptide method” for the synthesis of difficult sequence-containing peptides was successfully applied to the synthesis of amyloid β peptide (Aβ) 1-42 via a novel water-soluble isopeptide of Aβ1-42, i.e., “26-O-acyl isoAβ1-42”. It is noteworthy that only one insertion of the isopeptide structure into the sequence of 42-residue peptide can suppress the unfavorable nature of its difficult sequence. In addition, rapid migration of O-acyl isopeptide to intact Aβ1-42 under physiological conditions (pH 7.4) via O–N intramolecular acyl migration reaction was observed while it was stable under storage conditions. Hence, our strategy not only overcomes the solubility problem in the synthesis of Aβ1-42, but also provides a novel tool for the biological evaluation system in Alzheimer's disease research, in which 26-O-acyl isoAβ1-42 can be stored in a solubilized form before use and rapidly produces intact Aβ1-42 in situ during biological experiments.

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Calnexin (CNX), and its soluble homologue calreticurin (CRT) are molecular chaperones that lead newly synthesized glycoproteins to correct folding structure in the endoplasmic reticulum (ER). To investigate the mechanism of protein quality control, we have synthesized structurally defined high-mannose-type oligosaccharides related to this ER system. Moreover, an undecasaccharide was designed and synthesized as a CNX/CRT inhibitor that possess key structural features of CNX/CRT binding without a recognized unit by a Glucosidase II, which removes glucose residue from the CNX/CRT binding structure to release from this chaperones. Their binding properties to CRT and inhibition activities of CRT's suppression of thermal aggregation of malate dehydrogenase (MDH) were investigated. Synthesized inhibitor showed the binding property to CRT and showed inhibition of CRT.

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In 1997, coyolosa was isolated from the Acrocomia mexicana root. It is worth noting that coyolosa, which is a new carbohydrate connected by an ether-linkage, shows a significant effect on the fasting blood glucose level. So far, no studies on the sugar linkage by ether bonding have ever been reported. Thus, we examined a novel synthesis of 6,6'-ether-connected pyranoses. Also, we reconsidered the proposed structure of coyolosa based on the structure–activity relationship (SAR) studies.

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Azasugars are rare natural products such as nojirimycin, and many derivatives have been reported. In those cases, researchers have focused on chemistry of mono-azasugars, and their interests mainly have directed to glycosidase-inhibitory activities. As a result, few research efforts were expended on azaoligosaccharides and some examples of oligosaccharides containing azasugars are reported. Azasugars, however, might have some properties which are not given to sugars. First, azasugars can make a covalent bond from the ring-nitrogen to the outside of the sugar ring. By this unique bond, azaoligosaccharides are expected to have various structures and new functions. Secondly, a hydroxyl group at the C-1 position of an azasugar is so reactive that the elongation of azasugar chains will be easier than that of sugar chains. In this time we report the synthesis of azaoligosaccharides using their unique properties.

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We previously synthesized cyclic ADP-carbocyclic-ribose (cADPcR) which was designed as a stable mimic of cyclic ADP-ribose (cADPR), an intracelleular Ca²⁺-mobilizing second messenger. cADPcR is actually very stable under chemical and biological conditions and exhibits 3 times more potent Ca²⁺-releasing activity than cADPR in sea urchin egg homogenates. In this study, we focused on SAR of the N-1-carbocyclic-ribose moiety of cADPcR. We designed and synthesized several cADPcR analogs modified in this group. We estimated their Ca²⁺-releasing activity in sea urchin egg homogenates and calculated the stable conformation of these analogs based on the NOESY constraints, to find a relationship between their biological activity and stable conformation.

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Leustroducsin B, a metabolite of S. platensis, exhibits a variety of interesting biological activities such as colony-stimulating activity, thrombopoiesis, and inhibition against protein phosphatase 2A. We planned to synthesize leustroducsin B by taking a convergent route in which the molecule is divided into three segments A, B, and C. Segment A was synthesized from trans-2-pentenol via an asymmetric epoxidation reaction as a crucial step. Segment B bearing a series of stereogenic centers was synthesized from (R)-malic acid; the stereogenic centers at C-8 and C-9 were prepared by a combination of Wittig reaction and asymmetric dihydroxylation reaction. Segment C was prepared by means of an asymmetric Diels–Alder reaction as a key reaction. We have accomplished the construction of the carbon framework of leustroducsin B by Julia coupling reaction of segments A and B, followed by Stille coupling reaction of segment C.

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A cytotoxic macrolide, amphidinolide A, has been isolated from the dinoflagellate Amphidimium sp., and the gross structure and the relative strereochemistry have been proposed as 1 on the basis of extensive 2D NMR experiment by our group. However, recent total syntheses of 1 by three other groups indicated that the proposed stereochemistry of 1 might be incorrect. Since two possible diastereomers, 2 and 3, for amphidinolide A came up by our reexamination of the 2D NMR data, we have tried to synthesize the two diastereomers, 2 and 3. On the other hand, NMR data of diastereomer 3 synthesized quite recently by Trost's group were almost identical with those of natural specimen. In this symposium, our synthetic studies of compounds 2 and 3 will be described.

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Formal synthesis of tautomycin showing proteinphosphatase inhibitor activity was achieved on the basis of regioselective enzymatic acetylation of spiroketal diol 3 as segment C5–C16 of tautomycin. The diol 3 was synthesized from 7 in 5 steps, including a coupling reaction with sulfone 13. Compound 7 was synthesized from meso-diol 4 in 8 steps through a process that included enantioselective enzymatic acetylation of 4. We also synthesized 7 from alcohol 8 in 9 steps based on Sharpless epoxidation and stereoselective hydrogenation catalyzed by palladium. The regioselective enzymatic acetylation of 3 with lipase Amano PS afforded the desired monoacetate 17 in 90% yield. The monoacetate 17 was converted into Oikawa's intermediate as segment C1–C18 of tautomycin based on Julia coupling and Wittig homologation.

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We developed a new method to construct chiral quaternary carbons utilizing aza-Claisen rearrangement of amide enolate. For example, the treatment of (S,E)-N-(3-methyl-2-pentenyl)-N-(1-phenylethyl)propanamide with 5 equiv. of LHMDS at 120 °C afforded (1'S,2R,3S)-3-ethyl-2,3-dimethyl-N-(1-phenylethyl)-4-pentenamide in high yield with high stereoselectivity. The method was applied to the synthesis of (+)-(α)-cuparenone. Furthermore, the addition of Li salts was quite effective to save the usage of LHMDS without the decrease of chemical yield and stereoselectivity.

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Antimycin A (AA) family was isolated from Streptomyces sp. as antibiotics possessing antifungal activity. AA family has been widely used for biological and biochemical studies because of its unique inhibitory activity against electron transfer system of ubiquinol–cytochrome c oxidoreductase. We accomplished a total synthesis of AA family for large scale preparations utilizing an asymmetric aldol reaction as a key step this time. The aldol reaction of hexanoylsultam with O-protected lactaldehyde proceeded with excellent stereoselectivity.

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Many of the novel bromoindole alkaloids such as flustramines were isolated from marine bryozoan Flustra foliacea. These compounds exhibit various biological activities, for example, antibacterial activity and muscle relaxant activity. Here we wish to report the asymmetric total synthesis of (–)-flustramines A and B and (–)-flustramide A, contained some key steps such as tandem cascade of 2-allyloxyindolin-3-one, olefination, isomerization, and asymmetric Claisen rearrangement to 3-cyanomethyl-3-allylindolin-2-one, transformations of allylic moieties to prenyl and reversed prenyl groups, and reductive cyclization.

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Febrifugine is an antimararial agent that was isolated from Dichroa febrifuga and Hydrangea umbellate. Racemic compound of febrifugine was synthesized using a Wittig reaction of 2,3-dihydroxypiperidine (1) followed by the Michael reaction of open-ring enone. We could prepare dl-febrifugine by the short steps. This method was applied to the synthesis of 3'-methyl febrifugine. A reaction of 1 with a Wittig reagent introduced a methyl group finely proceeded to afford the open-ring methyl enone (2). The Michael reaction of 2 by acid afforded a 2-(1-methyl-2-oxopropyl)piperidine (3) diastereoselectively introduced a methyl group. A coupling reaction of 3 with 4(3H)-quinazolinone followed by deprotection is under investigation.

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Amaryllidaceae family is an attractive source of alkaloids, which are valuable as targets for total synthesis because of their unique structures, limited supply, and promising bioactivities such as cholinesterase inhibition which has being found in (–)-galanthamine. The alkaloids are, in the metabolic pathways, synthesized by different types of intramoecular phenol coupling. Here, we would like to report the asymmetric synthesis of (–)-galanthamine and the short-step synthesis of buflavine and siculine by using PIFA-mediated intramolecular diphenol coupling as a common key step.

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The conversion of the message site of the skeleton of naltrexone was carried out to improve the selectivity of ligands binding to opioid κ,δ receptors. Wittig reaction with methoxymethyltriphenylphosphonium ylides followed by hydrolysis was performed to convert the 6-keto-group of naltrexone to the aldehyde, but an unanticipated α,β-unsaturated aldehyde which 4,5-epoxy ring was cleaved was obtained. In this report, to prepare a high selective agonist for opioid receptors using this novel reaction, we designed a 7-membered ring ether derivative which was bridged at OCH₂ group between 4- and 6-position of naltrexone. We will also report the application of the novel reaction to syntheses of new κ,δ opioid ligands for analgesics without addiction.

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In the process of synthesis of ε opioid receptor selective ligands, we found a new synthetic method of novel orthoester derivative. When 17-(cyclopropylmethyl)-4,5α-epoxy-3-methoxy-6α,14-dihydroxy-6β-(1,3-dithian-2-yl)- morphinan was hydrolyzed with CuO/CuCl₂, the unexpected 17-(cyclopropylmethyl)-4,5α-epoxy-6α-hydroxy-3,7,7-trimethoxy-8-oxa-6,14-endoethanomorphinan was obtained. The compound was converted to an ester with hydrochloric acid. The structure of the orthoester was determined by 2D NMR and mass spectra. We will examine whether the reaction is general or specific for naltrexone derivatives. We also try to synthesize ε receptor selective ligands by use of this intermediate and the details will be reported.

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A novel and stereo-controlled synthesis of tetrodotoxin (TTX) is described. A polyfunctionalized key cyclitol compound containing three branched-chains for the synthesis of TTX was prepared from D-glucose employing the Ferrier reaction and the nitro aldol (Henry) reaction as key transformations (Method B and C), and myo-inositol (Method A). Stereo-controlled construction of the branched-chains was achieved by our original method via spiro α-chloroepoxide derivatives.

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Our laboratory have been developed that C₂-asymmetric bisoxazolidine, obtained easily from (R)-2,4,6-trimethoxybenzylphenylglicinol and dialdehyde, was reacted with Grignard reagent to afford diamine with high diastereoselectivity. Recently, we achieved that asymmetric synthesis of (–)-dihydrocuscohygrine, C₂-asymmetric pyrrolidine alkaloid, using diastereoselective addition of Grignard reagent to bisoxazolidine prepared from known 3-cyclopenten-1-ol. Thereupon, we tried that synthesis of dipiperidinylpropanol was similar to synthetic route of (–)-dihydrocuscohygrine. Now, we have studied that asymmetric synthesis of (+)-isosparteine by the same method.

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Dysiherbaine, a glutamic acid derivative bearing an amino-sugar moiety, exhibits strong non-NMDA-glutamate receptor agonist activity. In this study, the amino sugar moiety of dysiherbaine was synthesized by using addition reaction to a nitrone with 2-trimethylsilyloxyfuran. The starting nitrone was readily prepared from 2,3-isopropylidene-D-glyceraldehyde and 2,3:5,6-O-diisopropylidene-L-gulofuranose oxime. The nitrone, on treatment with 2-trimethylsilyloxyfuran in the presence of a catalytic amount of TMSOTf at –78 °C, underwent nucleophilic addition reaction to give bicyclic adduct as a single stereoisomer after work-up with TBAF. The bicyclic adduct was elaborated to the key synthetic intermediate having a protected amino-sugar moiety of dysiherbaine in 11 steps which involved reductive N-methylation, sequential reductive N–O bond-cleavage and formation of oxazolidinone ring.

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The strong affinity of t-Bu-P4 base to proton has been well investigated. Recently it was found that t-Bu-P4 base strongly activates alkynyl carbon–silicon σ bond. Catalytic alkynylations were accomplished using alkynylsilanes in the presence of catalytic amount of t-Bu-P4 base. Nucleophilic substitution of nitroaryl fluoride was performed using the acetylide anion generated by t-Bu-P4 base. Not only carbon–silicon bond but also oxygen–silicon bond was found to be activated by using t-Bu-P4 base. As a preliminary NMR experiment on the interaction of alkynylsilane and t-Bu-P4 base, a significant change was observed on silicon attached terminal carbon signal of phenylethynyltrimethylsilane in the ¹³C NMR spectrum.

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Recently, we reported a chiral copper ion-catalyzed asymmetric carbon–carbon bond forming reaction between N-acyl-β,γ-unsaturated iminium ions generated from β,γ-unsaturated-α-methoxypiperidine derivatives and dimethyl malonate with moderate enantioselectivities. Now, we found that using methyl phenyl malonate or some diaryl malonates in place of dimethyl malonate afforded α-substituted piperidine derivatives with high enantioselectivities being affected by the kind of the aryl group. For example, the reaction using di-p-chlorophenyl malonate proceeded with the highest enantioselectivity (93% ee) among examined malonates, while di-o-chlorophenyl malonyl group did with low efficiency (16% yield, 35% ee).

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The design and synthesis of 1-methyl-2-azaadamantane N-oxyl (1-Me-2-AZADO), as a precursor of robust oxoammonium ion type-catalyst with expanded applicability for eco-friendly oxidation of alcohols to carbonyl compounds, are described. 1-Me-2-AZADO was synthesized from 1-adamantanol in 15% yield by employing a seven-step sequence. The catalyst exhibited superiority of catalytic efficiency over 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) under the typical reaction conditions using either NaOCl or PhI(OAc)₂ as terminal oxidants. The novel utility of 1-Me-2-AZADO-catalyzed oxidation system is highlighted by demonstrating the remarkable efficiency towards oxidation of a panel of sterically hindered alcohols to the corresponding carbonyl compounds, which TEMPO-catalyzed systems suffered from poor yields.

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A short and efficient synthesis of (+)-aureol (1), a structurally novel and biologically important marine natural product, was achieved starting from readily available optically active 5-methyl-Wieland–Mischer ketone (2). (+)-Arenarol (3) (cis-fused decalin) and (–)-neoavarol (4) (trans-fused decalin) were prepared from (–)-2 and (+)-2, respectively, through the introduction of aromatic moiety and salcomine oxidation of the phenolic derivative as the crucial steps. The key acid-induced rearrangement/cyclization reaction proceeded smoothly by exposure of both (+)-3 and (–)-4 to boron trifluoride etherate to give (+)-aureol (1) with complete stereoselectivity in high yield. The reaction involves the tandem migration of the angular methyl group and hydrogen, followed by intramolecular etheration.

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The palladium-catalyzed intramolecular α-arylation of formyl group was successfully applied to a total synthesis of (±)-nominine, a heptacyclic hetisine-type aconite alkaloid isolated from Aconitum sanyoense Nakai in 1956. The synthesis consists of forty-steps from 2-bromo-5-methoxyphenethyl iodide, and constitutes the first total synthesis of a hetisine-type aconite alkaloid, the sole representative aconite skeleton whose total synthesis has remained unsuccessful. Key steps other than the above α-arylation are (i) acetal ene-reaction to form the C14–C20 bond, (ii) LiAlH₄ reduction of cyano-enol silyl ether to form the N–C6 bond, (iii) radical cyclization from enyne precursor to construct the methylenebicyclo[2.2.2]octane framework, and (iv) allylic oxidation with SeO₂–tert-BuOOH to introduce 15β-OH. Completion of the synthesis was verified unequivocally by single crystal X-ray analysis of (±)-nominine.

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The selective alkylation of primary amines to secondary amines represent an important class of chemical transformations that have found extensive use in the construction of a tremendous range of natural products, bioactive molecules and industrial materials. We have developed the selective and reductive mono-N-alkylation method of aromatic and aliphatic both amines using nitriles as an alkylating agent. This method is particularly attractive to provide alkyl halides or carbonyl compounds free, environmentally benign and applicable alkylation method of amines.

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Synthesis of bisubstrate type inhibitor for N-acetylglucosaminyltransferases (GnTs), which are involved in cancer metastasis and neuronal development, was achieved. It utilized polymer resin hybrid capture–release strategy for the construction of the acceptor trisaccharide component, which was employed low molecular weight PEG and cysteine loading resin. Bromoacetamide having GlcNAc phosphate derivative was synthesized independently as a donor component. Chemoselective ligation procedure was applied for the selective coupling between donor and thiol induced acceptor component in aqueous media. After SepPak^TM C-18 purification based on hydrophobic tag, it was converted to the target compound using UMP-morpholidate for the instruction of UDP component. Inhibitory activities toward GnT-V and IX were evaluated to reveal its potency toward the latter enzyme (Ki = 7.2 μM).

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Diversity-oriented synthesis entails the development of pathways leading to efficient synthesis (3–5 steps) of collections of small molecules having skeletal and stereochemical diversity with high appending potential. Inspired by the skeletal diversity of naturally occurring indole alkaloids, we have developed a versatile pathway entailing six modes of intramolecular reactions to construct indole alkaloid-like skeletons having complex molecular architectures. In this context, an efficient folding pathway via a rhodium-catalyzed tandem cyclization–cycloaddition has been developed, which affords densely functionalized compounds with distinct skeletons in a stereo-controlled manner. It is hoped that the pathways discussed here will provide a valuable illustration of diversity-oriented synthesis and also effective probes for chemical genetic studies aimed at exploring biology and medicine with chemistry.

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