A 5- and 7-membered lactams formation reaction through the treatment of 3-aminoalkanoates with t-BuLi was discovered. This unexpected reaction could be accounted initial beta-lactam formation followed by aza-[1,2]- and [2,3]-sigmatropic rearrangement. 5-Membered lactams were obtained in trans form and 7-membered lactams were obtained in cis form.
Expecting chirality transfer from 3-aminoalkanoates to 5- and 7-membered lactams, we used chiral 3-aminoalkanoates. Unfortunately, 5- and 7-membered lactams were obtained with significant loss of enantioselectivity. We assumed that the loss of the enantioselectivity is due to opening 4-membered rings of beta-lactams, and we introduced a Me group to alpha position of the carbonyl group to keep the enantioselectivity even if the 4-membered rings opened. As we expected, we can finally obtained the 7-membered lactam with high enantioselectivity.

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Propargylic esters undergo a number of transition metal-mediated intramolecular cyclization and related reactions. Compared with the impressive evolution of reactions using Au and Pt catalysts, reactions using Pd(II) species have received only scant attention. Herein, we report a palladium(II) catalyzed tandem carbonylative cyclization of 1,2-diethynyl acetates controlled by the phbox ligand. The reaction of acetate in the presence of phbox (7.5 mol %) / Pd(TFA)2 (5 mol %) and p-benzoquinone (1.2 equiv.) in methanol under carbon monoxide atmosphere (balloon) afforded bicyclic lactone in 89% yield. On the other hands, in the absence of the phbox ligand, two kinds of orthoesters were obtained in 51 and 15% yield. Based on a ligand screening, the role of the phbox ligand will be discussed.

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The total synthesis of (+)-magellaninone, (-)-magellanine, and (+)-paniculatine, isolated from Lycopodium Paniculatum and Lycopodium magellanicum in the mid to late 1970s, was completed from diethyl L-tartrate via the common intermediate in a stereoselective fashion. The crucial steps in this synthesis involved the dual intramolecular Pauson-Khand reaction of enynes: the first Pauson-Khand reaction provided the bicyclo[4.3.0]nonenone framework, the corresponding A- and B-rings of these three alkaloids, in a highly stereoselective manner, whereas the second Pauson-Khand reaction enabled us to stereoselectively construct the additional bicyclo[3.3.0]skeleton, which could be successfully converted into the C- and D-rings of the target natural products.

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Development of potent proteasome inhibitors based on the stereochemical diversity-oriented strategy using a conformationally rigid cyclopropane structure was investigated. Thus, a series of stereo- and regio-isomeric analogues of belactosin A, a cyclopropane amino acid-containing tripeptidic proteasome inhibitor, were designed. The target compounds including belactosin A were systematically synthesized. Biological evaluation showed that the activities of the compounds are changed dependent on the stereochemistry of the central cyclopropane amino acid part. Also, a newly developed compound, which is 20-times as potent as belactosin A and is even more potent than the well-known inhibitor lactacystin, may be an effective lead for developing anticancer drugs. These results show that the stereochemical diversity-oriented approach can be a powerful strategy in medicinal chemistry.

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Halichondrin B (HB) has received much attention due to its intriguing structure and extraordinary in vitro and in vivo antitumor activity. E7389 is a fully synthetic macrocyclic ketone analog of HB, with antitumor activity matching or even surpassing those of HB. Since the first and only total synthesis of HB in 1992, the continuing effort of our group is to establish a practical synthesis to HB (particularly right half of HB, which exhibits the same antitumor activity as HB) and E7389. This presentation will report recent progress toward practical synthesis toward this aim:
(1) Catalytic asymmetric Ni/Cr coupling reaction at C26-C27.
(2) Catalytic Ni/Cr macrocyclization without use of high dilution conditions.
(3) Use of ion-exchange resins for workup of TBAF-mediated desilylation reaction and ketal formation.
(4) Selective ammonolysis reaction of terminal epoxide.

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The total synthesis of the cyclodepsipeptide halipeptin A, a potent anti-inflammatory agent from marine sponge, has been achieved by proline-catalyzed enantioselective oxiamination and asymmetric aldol reaction using chiral oxazaborolidinone reagent in the highly substituted decanoic acid residue as key steps. The introduction of (S)-Ala residue to highly hindered the secondary alcohol at C3 position of HTMMD was accomplished in high yield without epimerization using the trans esterification method from less hindered site to hindered one. The condensation of (ala)Thz and (2S,3S)-NMeOHIIle was carried out using BMTB reagent. The coupling of the ester segment and the amide was attained by acid chloride strategy. A HATU method was effective for the macrolactamization step

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Tumor necrosis factor (TNF) receptor superfamily members transmit signals that promote diverse cellular responses. Cell growth, differentiation, migration, and apoptosis are regulated by growth factors or cytokines which exert their effects via ligand-induced dimerization or trimerization of cell surface receptors.
Abnormalities in such signal transduction pathways cause for pathological conditions and diseases such as arthritis, cancer, AIDS and diabetes. To study ligand-induced activation of TNF receptor superfamily as well as subsequent downstream effects, we tried to design and synthesis compound to be capable of trimerizing GST-fused signal transducing protein.
We report herein synthesis of novel compounds in which three glutathione appendages are symmetrically placed around the central benzene, assembling GST-fused proteins.

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4-[3,5-Bis(trimethylsilyl)benzamido]benzoic acid (TAC-101, 1) is an anticancer drug and now under clinical trials. In pre-clinical and clinical studies, the metabolism of 1 has been investigated in rats, dogs, and human. The structure of the metabolites of 1 were proposed on the basis of liquid chromatography-mass spectrometry (LC-MS) analysis to be the compounds which are hydroxylated at the silyl group (M-1, 1a : M-2, 1b : M-3, 1c).
Here, we wish to report the convenient and efficient synthesis of 1a and 1b using 3,5-dibromobenzoic acid as a starting material. And we also wish to demonstrate the novel oxidation reaction by which silylmethanols can be converted into silanols. Using this reaction, we accomplished the synthesis of 1c which had been considered difficult to synthesize.

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Depollution of water contaminating toxic substance has been very serious environmental problems to be solved. Bisguanidinobenzene is designed as a potential scavenger for toxic substances, such as metal salts or arsenic acid, because of its strongly basic multi-nitrogen functionality. Mixing of it with several kinds of metal salts under aqueous conditions suggested wide ranges of possible coordination, from which the host was quantitatively recovered from the complex by extraction. Job's plot and tituration experiment in the NMR study indicated that arsenic and phosphoric acids could be also scavenged with bisguanidinobenzene. The same host-guest interaction was, as expected, observed after structural modification of bisguanidinobenzenes to recyclable polymer-supported derivatives.

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Miraziridine A isolated from the marine sponge is composed of (2R, 3R)-aziridine-2,3-dicarboxylic acid, L-leucine, (3S, 4S)-statine, (S)-a-aminobutyric acid, and (S)-vinylogous arginine. Miraziridine A is reported to inhibit cathepsin B (IC50 = 1.4 mg/mL). We report syntheses of miraziridine A and its analogues and identification of the reaction site for cathepsin B. The necessary three unusual amino acids, EtO-Azd-OH, Fmoc-Sta-OH, and H-vArg-OEt, were synthesized. Coupling of H-vArg-OEt with EtO-Azd-Leu-Sta-Abu-OH prepared by Fmoc-based SPPS was achieved by HATU/HOAt to give miraziridine A diethyl ester. Enzyme-assisted hydrolysis was conducted to afford miraziridine A. Comparing IC50 and Ki values of analogues, the major reaction site was estimated to be the N-terminal aziridine.

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In chemo-enzymatic synthesis of 1-β-O-acyl glucuronides from their methyl acetyl derivatives, LAS and CSR are efficient enzymes for O-deacetylation while PLE and CALB are efficient for the subsequent hydrolysis of methyl ester. The nature of 1-β-O-acyl groups influenced chemoselectivity and catalytic activity of the enzymes. Of substrates with o-, m- or p-phenylbenzoic acid as a 1-β-O-acyl group, LAS and CSR showed high chemoselectivity toward the o-isomer and m-isomer, respectively. The p-isomer was O-deacetylated only by LAS plus CSR. LAS showed a high activity toward fully acetylated substrates, while CSR preferred partially deacetylated intermediates. CALB showed higher chemoselectivity than PLE. LAS showed a regioselectivity in the O-deacetylation, which was also found for 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside of N-phenylacetohydroxamic acid.

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To develop effective chemical catalysts is one of the biggest concerns in organic chemistry. Recent progress in combinatorial chemistry has generated large libraries of candidate catalysts, but their activities and the optimized reaction conditions are still examined by using HPLC and GC, which take a lot of time. Therefore, high-throughput screening (HTS) systems for catalysts are urgently required.
Here we present a rationally designed fluorescence probe as a HTS tool for evaluation of the activities of candidate catalysts and for optimizing reaction conditions in the Michael addition as shown below. Our novel HTS tool allows evaluation of the activity of chemical catalysts simply by measuring the fluorescence of the reaction mixture.

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Akabori reported that the reaction of N-methylalanine (1) with benzaldehyde at 130 ^oC for 1 h in pyridine gave pseuido-ephedrine in 16% yield (Nipponkagakukaishi 1942, 64, 608-611). We have already reported on this symposium (last year) that the reaction of 1,3-benzodioxole-5-carbaldehyde (piperonal) with 1 gave the amino alcohol derivative in good yield (87% yield as a mixture of diastereomer) via unstable 3,4-dimethyl-2,5-diphenyl-oxazolidine as an intermediate. We further investigated the reaction condition of this reaction in detail. As a result, we could improve the reaction as follows: 1) The molar ratio of 1 could be decreased to 2 mol eq. from 6.5 mole eq. 2) DMSO or cyclopentyl methyl ether (CPME) could be used as a solvent. 3) The reaction temperature could be decreased to 85 ^oC from 130 ^oC. The present results are very useful information in order to develop the diastereo- and stereo-selective reactions.

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In the course of our study, the required beta-tetralones were newly synthesized by the Cross-Methathesis reaction using the Grubbs catalyst. Subsequently, their pinacol borates were derived from beta-tetralones in two steps. In addition, total syntheses of benzo[c]phenanthridine alkaloids, nornitidine, noravicine, norchelerythrine, and norsanguinarine were established by the microwave-assisted thermal electrocyclic reaction of 1-azahexatriene system involving the benzene double bond, followed by oxidation.

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Conventional DNA-templated organic synthesis (DTS) involves hybridization of two oligonucleotide probes with each other or with a template strand, followed by a bond-forming reaction between reactive substituents conjugated on each strand. Bond cleavage reactions promoted by hybridization of DNA templates comprise a new class of DTS and should be useful for novel genome technologies. Here, we report the site-specific bond cleavage of the oligonucleotide probe triggered by hybridization with a dsDNA template. Oligonucleotides bearing a P3'-N5' phosphoramidate linkage are well known to undergo P-N bond cleavage under acidic conditions. We found that the acid-mediated P-N bond cleavage is significantly accelerated by sequence-selective triplex formation with the dsDNA template. By incorporation of a fluorophore and a quencher into the oligonucleotide probe, we successfully achieved sequence-specific dsDNA sensing.

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Transition metal-catalyzed cross-coupling reactions are of great importance in organic synthesis. In this area, N-heterocyclic carbenes (NHCs) have attracted an attention as alternatives to phosphine ligands recently. In 2006, we demonstrated that a novel NHC-derived pincer-type nickel(II) complex, which can be readily prepared and is also stable to air and moisture, serves as an effective catalyst in the Heck reaction. In an attempt to further evaluate the catalytic activities of this complex, we carried out the Suzuki-Miyaura and Kumada-Tamao-Corriu coupling reactions. As a result, variously substituted aryl bromides, chlorides, and fluorides reacted smoothly with arylboronic acid or Grignard reagents in the presence of our nickel complex and the corresponding biaryls were obtained in high yields. Further studies, involving the syntheses of other nickel-pincer complexes and their application to a range of cross-coupling reactions, are underway.

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Delivering molecules of biological interest to a target location is a key technology in the field of chemical biology. Recent developments of peptidyl vectors enable us to transfer various molecules to desired location in one direction; however, controlled shuttling of the vector-tethered molecule has yet to be achieved. Previously, we reported a stimulus-responsive amino acid which induces a processing (peptide bond cleavage) reaction by an exposure to a stimulus such as photo-irradiation. In the present study, we applied the photo-responsive amino acid to a nucleocytoplasmic shuttle peptide which could initially localize in the nuclei and could then return to the cytoplasm upon photo-irradiation. Details of synthesis of the nucleocytoplasmic shuttle peptide, photo-processing reaction and localization assay in living cells will be discussed.

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We describe the one-pot synthesis by Michael-aldol reaction of chromone and flavonoid derivatives bearing pyridine units. 4'-Benzyloxy-2'-hydroxyacetophenone (1) reacted with various pyridinecarboxaldehyde (2) to give intermediate chalcone derivatives, which underwent intramolecular cyclization followed by aldol reaction with another aldehyde. The endo 2,3-disubstituted chromones were obtained in one step as the only or major product. Furthermore, use of substituted benzaldehydes (Aldehyde A) and subsequent addition of 2 (Aldehyde B) gave 3-pyridyl-substituted flavones. Some of synthesized compounds showed the inhibition of GLI-mediated transcription, and cell growth inhibitory activity against HeLa cells.

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In photosynthetic organisms, carotenoids are acting as antenna by transferring light-energy to chlorophyll to promote photosynthesis. Toward the fabrication of dye-sensitized solar cells, we tried to synthesize hybrid compounds of chlorophyll and polyenes having several conjugated systems and SH group, which is utilized for connecting polyene parts to an electrode made from gold.
As a preliminary experiment, we have established a synthetic procedure for the hybrid compound by use of a model compound having a shorter conjugated system. A conjugated allyl alcohol possessing a triisopropylsilylthio group was derived from commercially available methyl 4-hydroxymethylbenzoate via elongation of conjugated double bonds and transformation of the benzyl alcohol part to a benzyl silylthio group. This ally alcohol was condensed with porphyrin-carboxylic acid by Mukaiyama's method, and then desilylated to give a desired hybrid compound.

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Carbenoids are reactive intermediates that are useful in organic synthesis because they have both electrophilic and nucleophilic reactivities. Magnesium cyclopropylidenes were generated from 1-chlorocyclopropyl phenyl sulfoxides with i-PrMgCl in THF at -78 temperature by sulfoxide-magnesium exchange reaction. Reaction of the magnesium cyclopropylidenes with N-lithio arylamines was investigated and it was found that the reaction gave ortho-cyclopropylation of arylamines in moderate to good yields. This is the first example of direct cyclopropylation of arylamines on the aromatic ring. The magnesium cyclopropylodenes having at least one substitutent was found to be essential to this C-cyclopropylation.

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Conjugate addition of lithium carbanion of dichloromethyl aryl sulfoxide to a,b- unsaturated carbonyl compounds at low temperature gave adducts in high yields. The adducts were treated with trifluoroacetic anhydride in the presence of sodium iodide to give 2-thiofurans in good yields. This is a good procedure for a synthesis of highly substituted furans having arylsulfanyl group at the 2-position from a,b- unsaturated carbonyl compounds in only two steps.
When the temperature of the conjugate addition was allowed to warm to room temperature, cyclopropanes were obtained in high yields with excellent stereoselectivity. Elimination of the arylsulfinyl group on the cyclopropane ring with Grignard reagent gave chlorocyclopropane having a carbonyl group as a substituent. This is an effective one-step synthesis of high substituted cyclopropanes from a,b- unsaturated carbonyl compounds.

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We had already succeeded to develop Michael addition reactions between the silyl ketene acetal and 2-pyridinone derivatives in the presence of Lewis acid to afford the 4-substitued products. Introduction of methoxycarbonyl group at C3-positon of 2-pyridinone derivatives did not affect the regioselectivity. However, when the same reaction was applied to the substrate having methoxycarbonyl group at C5-position, either C6-substitued product or azabicyclo-compound was afforded depending on the amount of Lewis acid.
These reactions were applied to the synthetic studies of awajanomycin, which is a new anti-tumor natural product isolated from marine-derived fungus in 2006. Since the absolute configuration of this compound has not been determined yet, we planed to the stereoselective synthesis of awajanomycin as an optically active form.
The detail of the regioselective Michael reactions and the synthetic studies of awajanomycin will be presented.

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Indium reagents including indium metal have become of attention due to the moderate reactivity attained under mild conditions. Here are presented indium-mediated transformations such as the tetrahydropyranylation of alcohols and depyranylation, and methyl esterification of carboxylic acids, which are smoothly catalyzed by indium(III) triflate and indium(III) chloride, respectively. Indium metal serves for exclusive deprotection and reductive demonochlorination of 2,2,2-trichloroethyl esters, highly depending on structural features of the substrates.

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A new and efficient method was developed for a stereocontrolled synthesis of a-aminophosphinic acid derivatives, which were useful intermediates for biologically active aminophosphinyl peptides, starting with a-amino-H-phosphinates possessing defined relative configuration. The method was based upon stereospecific Michael addition of a-amino-H-phosphinates to acrylates, affording adducts with retention of phosphorous chirality, followed by diastereoselective alkylation of their corresponding lithium enolates. The diastereoselectivty depended upon steric factor of protective group on the nitrogen atom. Excellent selectivity (>17:1) was observed using a trisyl group as the nitrogen protective group. The feature of this method is a high diastereoselectivity partially controlled by the asymmetric center at the phosphorus atom.

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Treatment of magnesium alkylidene carbenoids, which were generated from 1-chlorovinyl p-tolyl sulfoxides with isopropylmagnesium chloride at low temperture in toluene, with N-lithio nitrogen-containing heterocycles gave N-alkenylated products in moderate to good yields. Reaction of the magnesium alkylidene carbenoids with 2-lithio thiophenes gave 2-alkenylated thiophenes in good to high yields. The intermediate of these two reactions was found to be an alkenylmagnesium, which could be trapped with several electrophiles. These procedures offer novel and efficient one-pot synthesis of N-alkenylated nitrogen-containing heterocycles and thiophenes having a trisubstituted olefin on the nitrogen and at the 2-position, respectively.

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Raft domain is the lipid microdomain, which consist of sphingomyelin and cholesterol as major components. Generally, this particular domain is considered to play a key role in processes such as membrane trafficking and signal transduction. However, the effective role of sphingomyelin to construct the raft domain has not been understood. We designed three types of sphingomyelin analogues, in which the oxygen atom connecting the phosphocholine head group to the sphingosine backbone was replaced with CH2, NH, and S groups, and examined their physical properties. In this symposium, we report the syntheses of three sphingomyelin analogues by our own olefin cross methathesis protocol, which can provide various kinds of sphingomyelin delivatives, as a key step. We also report their physical properties, in particular their packing phenomena of raft domain comparing with the natural one.

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An interesting substituent effect on ring-closing enyne metathesis has been found. An allylic hydroxy group on enyne substrates accelerates ring-closing enyne metathesis of terminal alkynes and the reaction proceeds smoothly without ethylene atmosphere and/or more reactive newer generation Ru-carbene catalysts, which are generally necessary to promote the reaction. This efficient reaction was applied to the synthesis of isofagomine. Mechanistic studies on the acceleration effect have suggested acceleration of the regeneration step of Ru-carbene species from Ru-vinylcarbene species in the catalytic cycle.

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We are initially going to report the first one-pot vicinal double C-acylation of styrenes by electroreduction in the presence of aliphatic acid anhydrides or N-acylimidazoles using an undivided cell equipped with Zn-plates as the electrodes to afford the corresponding 1,4-diketones. Secondly, one-pot vicinal double carboalkoxylation of styrenes has been developed by electroreduction in the presence of N-carboalkoxyimidazoles to give the corresponding phenylsuccinates while electroreduction of aromatic imines under the similar conditions brought about one-pot geminal double carboalkoxylation to give the corresponding 2-amino-2-arylmalonic acid esters. We finally wish to present novel regio- and stereoselective double cross coupling between styrenes and diphenyl succinate or glutarate as a bifunctional electrophile by electroreduction using an undivided cell to afford the corresponding five- and six-membered spiro-lactones, possessing cyclopropane rings.

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In the presence of Pd(OAc)₂-(R)-SEGPHOS catalyst, the intramolecular N-arylation (intramolecular Buchwald-Hartwig amination) of achiral ortho-tert-butyl NH-anilides possessing an iodophenyl group proceeded with high enantioselectivities (up to 93% ee) to afford atropisomeric lactams having an N-C chiral axis. The reaction of the lithium enolate prepared from the atropisomeric lactam product with alkyl halides gave alpha-alkylation products with high diastereoselectivities. The further alpha-alkylation with alpha-alkylated lactams also proceeded in a highly diastereoselctive manner to give double alkylation products. These alpha-alkylated lactams were efficiently converted to synthetic intermediates for norepinephrine transporter inhibitors (NET inhibitors).

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Skytanthine-type alkaloids having an azabicyclo[4.3.0]nonane skeleton as a core framework have been isolated from a number of Tecoma and Skytanthus species. Among them, incarvillateine bearing a characteristic stereochemical feature has been recognized to exhibit significant antinociceptive activity in formaline-induced pain model mice. As part of our continuing effort to synthesize biologically active natural products, we are interested in a diastereoselective synthesis of (-)-incarvilline as a key precursor of (-)-incarvillateine. Delavayine A showing a significant level of antinociceptive activity would also be synthesized by the application of similar methodology. Thus, we decided to exploit an intramolecular Pauson-Khand reaction of the corresponding enyne amide as a key step. We believe that the synthesis developed here should be a useful tool for finding potenthial analgesic compounds.

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Stemonamide, isostemonamide, stemonamine and isostemonamine were isolated from the roots of Stemona japonica, which have been used as Chinese and Japanese folk medicine. We achieved the total synthesis of stemonamide and related alkaloids based on the radical cascade as a key step. Treatment of enamide, which was readily prepared from 1,2-cyclopentanedione, with Bu₃SnH/ACN (1,1-azobiscyclohexanecarbonitrile) caused radical cascade involving 7-endo-trig/5-endo-trig cyclization to afford the tricyclic cores of stemonamides. Synthesis of stemonamide and isostemonamide was accomplished by elaboration of the tricyclic cores including construction of methyl tetronate moiety and introductions of the ketone, the methyl group and double bond, respectively. Stemonamine and isostemonamine were synthesized from stemonamide and isostemonamide by selective reduction of lactam via thioamidation.

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The regioselective a-arylation reactions of substituted ketones with alkenyl bromide have been achieved using palladium catalyst. The reaction of 2-phenylcyclopentanone with b-bromostyrene in the presence of palladium catalyst affords the a-styryl-substituted ketone having a quaternary carbon center in high yield. Various aryl- and alkenyl-substituted ketones at the a position reacted with alkenyl bromide to produce the correesponding a-alkenyl-substituted ketones. No reaction proceeded when alkyl-substituted ketone was examined, which indicates that the formation of thermodynamically stable conjugate enolate intermediate is important in this regioselective arylation process. The application toward the synthesis of eptazocine, an antagonistic analgesic which is used for therapeutic purposes, was also attempted.

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Sulfides can be selectively oxidized into sulfoxides by 30% hydrogen peroxide in the presence of 2 mol% of tantalum(V) chloride in i-propanol or t-butanol. On the other hand, sulfides were oxidized into sulfones by 30% hydrogen peroxide in the presence of 2 mol% of tantalum(V) chloride in methanol. The reaction of sulfides with 3~4 eq. of 30% hydrogen peroxide in methanol in the presence of 2 mol% of niobium(V) ethoxide provides the corresponding sulfones in high yields. This reaction is highly chemoselective, because alcohols and alkenes did not react under the reaction condition. Thioacetals can be converted to carbonyl compounds by 30% hydrogen peroxide in the presence of 10 mol% of tantalum(V) chloride and 10 mol% sodium iodide.

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Discorhabdin alkaloids show strong cytotoxicities and are of interest as new types of antitumor drugs. We recently have accomplished the first total synthesis of discorhabdin A, which shows especially potent activity in vitro but does not in vivo due to its instability. This time, we planned to synthesize more stable discorhabdins, discorhabdin B which shows some antitumor effect in vivo and prianosin B which has stabilized pyrroloiminoquinone unit. For their syntheses, two kinds of dehydrogenation reactions have been developed. One is the conversion of the ketone function to the enone unit by using LDA, N-tert-butyl phenylsulfinimidoyl chloride and 15-crown-5, and discorhabdin B naphthoquinone model was synthesized. The other is dehydrogenation of the pyrroloiminoquinone unit by using catalytic amount of NaN₃, and prianosin B was synthesized. In the reactions, usual oxidative reagents such as MnO₂ and CAN etc. gave poor results.

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A novel synthetic approach to Phe-Gly type (Z)-trifluoromethylalkene dipeptide isosteres (CF3-ADIs) is described. Starting from N-Boc-L-phenylalanine, Phe-Gly type CF3-ADIs were obtained in good to excellent yields through palladium-catalyzed carbonylation of allylic carbonate as a key reaction. The method was expanded to the stereoselective synthesis of several Phe-Gly type trisubstituted alkene dipeptide isosteres (TADIs). This divergent synthetic route enables facile evaluation of CF3-ADIs and several TADIs as peptidomimetics.

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We have achieved a highly stereoselective reduction of a-enononesulfoxides to a-allylhydroxysulfoxides using YbCl₃ 6H₂O and NaBH₄ in MeOH. This system, various optically active a-enonesulfoxides were led to highly optically active a-allylic alcohol type sulfoxides without racemization. Moreover, these a-allylalcohol type sulfoxides were led to a-allylalcohols in good stereoselective yield and excellent enantiomeric excess with Li / n-PrNH₂.

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Plants of Lycopodium species produce a number of structually diverse alkaloids, which possess complex structure and a variety of biological activities. In continuation of our chemical study on Lycopodium alkaloids, we have isolated a new quinolizidine alkaloid, cermizine C N-oxide, together with its related alkaloids from Lycopodium cernuum. We planned the asymmetric total synthesis to establish their absolute configulation and efficient synthetic route to these quinolizidine-type alkaloids. The common intermediate was synthesized from (+)-citronellal by 11 steps, including proline-catalyzed asymmetiric amination. From this compound, the total syntheses of cermizine C N-oxide and D were accomplished by utilizing asymmetric allylation to sulfinimine as a key step. Transformation toward cernuine is under investigation.

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Hajos-Parrish-Eder-Sauer-Wiechert reaction has been well-kwown as a successful intramolecular asymmetric aldol reaction mediated by an amino acid to synthesize Wieland-Miescher ketone derivatives. However, we have found that an amino acid has decomposed to a corresponding achiral amine by decarboxylation during the reaction. We report here a detailed study to assess the enantioselectivity of intramolecular asymmetric aldol reactions of a 1,3-cyclohexane- or 1,3-cycloheptane- dione derivative. The cyclizations were mediated by a series of chiral amines in the presence of Brønsted acid. Strikingly, we have observed that the process was characterized by an inversion of enantioselectivity when compared the reactions with or without Brønsted acid.

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We investigated the practical method to attain the selective N-dealkylation of secondary and tertiary amines in L-phenylalanine derivatives. Debenzylation of a secondary amine in N-benzyl-L-phenylalanine derivatives was accomplished by oxidation of the C-N bond using the N-iodosuccinimide (NIS) or N-bromosuccinimide (NBS) in acetonitrile. Moreover, we performed the selective dealkylation of a tertiary amine in N-benzyl-N-methyl-L-phenylalanine derivatives by this method and followed by treatment with O-methylhydroxylamine hydrochloride for transoximation of imine intermediates. Surprisingly, the reaction performed with NBS predominantly gave the debenzylated product. In contrast, the reaction with NIS afforded the demethylated product accompanied with a small amount of debenzylated product.

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FK228, isolated from the culture broth of Chromobacterium violaceum, is a novel histone deacetylase inhibitor and possesses great potential as a new drug for cancer therapy. In addition to its promising biological properties, the unique depsipeptide structure of FK228 presents an intriguing synthetic challenge. We report herein the total synthesis of FK228 based on the convergent methodology. We envisioned that FK228 would be constructed efficiently from the coupling reaction of two segments followed by macrolactonization and disulfide bond formation. The coupling reaction of two segments proceeded smoothly by using HATU and HOAt to provide a linear compound. After removal of the protecting groups in sequence, macrolactonization of the resulting seco acid under the Mitsunobu condition gave a desired 16-membered depsipeptide. Finally disulfide bond formation using iodine produced the target FK228, whose spectroscopic properties were identical with those of natural product.

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Synthesis of linear and cyclic chiral oligothiazolines is described. Linear oligothiazolines were synthesized by the iterative formation of thiazoline ring and the two-directional block condensation. Construction of 24- to 36-membered cyclic oligothiazolines could be achieved by the head-to-tail cyclooligomerization of linear fragments. Linear oligomers have proved to inhibit cell growth of several cancer cell lines. Studies on the structure-activity-relationships indicated that the IC₅₀ values clearly depend on both the length and the terminal functionalities. Longer derivatives showed more potent activity. In addition, thiazoline-thiazole hybrid macrocycles were synthesized via synthesized the iterative protocol and head-to-tail cyclooligomerization. The macrocycles consisting of eight heterocyclic subunits displays high binding affinity to the heavy metal toxins Pd²⁺ and Cd²⁺.

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Formylporphyrins are among the most useful precursors for subsequent transformations to synthesize more complicated porphyrin derivatives. However, there have so far been very limited methods available for the introduction of formyl group to the porphyrin core, with the exception of classic Vilsmeier formylation and related reactions that require use of strong acidic conditions and usually work well only with Ni(II) and Cu(II) complexes. Here we report an efficient direct conversion of 5,15-disubstituted porphyrins to the corresponding meso-formylporphyrins utilizing a facile one-pot protocol that involves SNAr reactions with (2-pyridyldimethylsilyl)methyl lithium followed by hydrolysis and oxidation with DDQ. Also described here is the preparation of meso-hydroxymethylporphyrins that can be attained by the same protocol with oxygen or air as an oxidant instead DDQ.

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The aim of our research is to develop a simple Ullmann-type N-arylation by use of organoantimony compound as an aryl donor. Search for suitable reaction conditions involving Cu reagent, solvents, and additives by using the reaction between Ph₃Sb and p-toluidine was made and the best result was obtained when the reaction was carried out by use of 2.2 eq of Cu(OAc) ₂ and 4.4 eq of Et₃N in acetonitrile at 60˚C under aerobic condition. Similar reactions between a variety of triarylstibanes and amines gave the corresponding N-arylated products in moderate to good yields. When Ar₅Sb was used as an aryl donor instead of Ar₃Sb, the N-arylated products were isolated over 100% (~ 179%) yields based on Ar₅Sb. The result shows that two of the five aryl groups on Ar₅Sb were involved in the present reaction.

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A simple and efficient method has been developed for the stereoselective synthesis of thiochromans from unsaturated aldehydes and arylthiols by using a base- and an acid-supported reagents system "Na₂CO₃/SiO₂-PPA/SiO₂" in one-pot. Micheal addition of arylthiol to unsaturated aldehyde was promoted by Na₂CO₃/SiO₂. The product, which adducted another arylthiol, was cyclized in the presence of PPA/SiO₂ to afford a thiochroman.
This method using supported reagents gave preferentially the trans-thiochromans. When unsupported PPA was used as an acid catalyst, no stereo selective products were observed.

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Difluorovinylsilane (1) can be synthesized through four steps from 2,2,2-trifluoroethanol in moderate yield. Highly functionalized structure of 1 is expected to show the unusual reactivity. We have disclosed its useful character allowing easy conversion to α,α-difluoro tetrahydrofuran derivatives. Electrophilic difluorovinyl group realized the intramolecular cyclization of 1 to the THF ring. Triethylsilyl group would stabilize the carbanion generated by the cyclization to avoid defluorination to dihydrofuran. Remarkably, the carbanion was able to add to a co-existing aldehyde and subsequent Peterson olefination was induced spontaneously. Finally, this reaction gave α,α-difluoro-β-vinylidene-tetrahydrofuran (2) that has never isolated.

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7,20-Diisocyanoadociane, isolated from the marine sponge Adocia sp. by Wells et al. in 1976, is a diterpenoid containing all-trans-perhydropyrene ring with two isocyano and four methyl groups. 7,20-Diisocyanoadociane has been shown to exhibit antimalarial activity. Its unique structural features and biological activity prompted the authors to undertake the synthesis of 7,20-diisocyanoadociane. The authors achieved construction of all-trans-perhydropyrene ring system, which is the fundamental skeleton in 7,20-diisocyanoadociane, by the continual reaction of isomerization and intramolecular Diels-Alder reaction as the key step. Total synthesis of 7,20-diisocyanoadociane of from tetracyclic compound having all-trans-perhydropyrene ring system is in progress now.

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We have previously reported the synthesis of chiral cyclic a,a-disubstituted a-amino acid {(3S,4S)-1-amino-3,4-dimethoxycyclopentanecarboxylic acid; (S,S)-Ac(5)c(dOM)}, in which the a-carbon atom is not a chiral center but the asymmetric centers exist at the side-chain cyclopentane, and disclosed that the chiral centers on the side chain of cyclic a,a-disubstituted a-amino acid (S,S)-Ac(5)c(dOM) could control the helical-screw sense of its homopeptides.
Herein we designed and synthesized a chiral cyclic a,a-disubstituted a-amino acid {(3R,4R)-1-amino-3,4-diazidocyclopentanecarboxylic acid; (R,R)-Ac(5)c(dN3)}.
The cyclic amino acid (R,R)-Ac(5)c(dN3) has been efficiently synthesized starting from dimethyl L-(+)-tartrate. Conversion of the amino acid (R,R)-Ac(5)c(dN3) into various chiral cyclic amino acids having several functional groups, and conformational analysis of their peptides have been studied.

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Sticher et al. isolated (+)-adunctin E (1) from leaves of Piper aduncum L. (Piperaceae) collected in Papua New Guinea, and determined its structure as [(5aR*,6S*,9R*,9a S*)-3,6-dihydroxy-1-methoxy-6-methyl-9-(1-methylethyl)-4-(3-phenylpropionyl)-5a,6,7,8,9,9a-hexahydrodibenzofuran (2)]. The compound 2 was prepared in five steps in 55% overall yield from (5a RS,6 SR,9 RS,9a SR)-5a,6,7,8,9,9a-hexahydro-3-hydroxy-1-methoxy-9-(1-methylethyl)dibenzofuran-6-one; however, the spectral data including ¹H- and ¹³C-NMR spectra of the prepared 2 were inconsistent with the literature data for adunctin E (1). Thus, we suggest that either the proposed structure by Sticher for adunctin E or the reported NMR spectral data was incorrect.

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Axially chiral binaphthyls have been well recognized as powerful chiral sources in asymmetric synthesis and molecular recognition. On the other hand, biaryl ethers in which two of aromatic rings connected via an oxygen atom have not been well documented as an axially chiral compound. Herein, we report the design, synthesis and stereostructure of novel biphenanthryl ethers as promising candidate for axially chiral polycyclic aromatic compounds. Upon photo-irradiation of stylene derivative in the presence of iodine, cyclization-aromatization reaction proceeded smoothly to give desired biphenanthryl ether, containing fluoro substituents at bay positions, in excellent yield. The crystal structure of biphenanthryl ether derivative clearly showed axial chirality.

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4H-1,2-Benzoxazines are very simple, but quite new, heterocyclic compounds that afford substituted o-quinone methides (o-QMs) through retro Diels-Alder reaction under mild thermal conditions. The resultant o-QMs undergo Diels-Alder reaction in situ with dienophiles to chroman derivatives. The mechanism of generation of o-QMs has been little studied. Our experimental and DFT studies have yielded the following results. 1) The generation of o-QMs, i.e., the retro hetero-Diels-Alder reaction of 4H-1,2-benzoxazines is rate-determining. 2) The reaction rate is strongly influenced by the electronic features of substituents and the polarity of the solvent. 3) The reactions show characteristic positional effects of substitution on the benzene ring. All these data support the involvement of polarized TS structures, in which the O-N bond cleavage precedes the C-C bond cleavage.

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