A system of RhH(PPh₃)₄, trifluoromethanesulfonic acid, and triarylphosphine catalyzes disulfide exchange reaction. Treatment of two symmetrical disulfides with the catalyst provides an equilibrium mixture of three disulfides within 15 min in acetone. The use of 4 mol equivalent excess of one of the disulfides provides the unsymmetrical disulfide in a yield exceeding 80%. Disulfide-containing amino acid and peptide also undergo the exchange reaction without racemization. The reaction of a diaryl disulfide and a dialkyl disulfide is even faster, and reaches equilibrium within 5 min at room temperature. This system is active after reaching the equilibrium, and addition of a disulfide to the mixture changes the ratio of the products. The catalyst turned out to be active also in water.

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We found that unusual sulfinylation proceeds on treatment of 1-alkynyl sulfoxides with a Pd(0)-catalyst and Et₂Zn, wherein a sulfinylzinc (or zinc sulfenate) species is assumed to be generated in situ to undergo highly syn-selective conjugate addition to the 1-alkynyl sulfoxides. Using 3,3-dimethyl-1-butynyl sulfoxides, formation of the bis-sulfinyl alkenes was completely suppressed and the sulfinylzincation of activated alkynes was accomplished. The reaction tolerates various functionalities, and the resulting vinylzinc intermediate was trapped stereoselectively on treatment with CuCN·2LiCl and electrophiles. Stereodivergent synthesis of (E/Z)-isomers of the vinylic sulfoxides, selective sulfinylation of bis-alkynoate by neighboring group participation, and intramolecular sulfinylzincation were examined. Asymmetric sulfinylzincation of alkynoates was also investigated and selectivity of ca. 9:1 dr was achieved.

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Zincophorin, which was isolated from Streptomyces griseus, exhibits strong in vitro activity against Grampositive bacteria.Toward the stereoselective total synthesis of Zincophorin, we designed a convergent synthetic strategy which involves two segments, C₁-C₁₅ segment (segment A) and C₁₆-C₂₅ segment (segment B). Segment A was highly stereoselectively synthesized through stereospecific S_N2- and S_N2'-type methylation reactions of γ,δ-epoxy-α,β-unsaturated esters and C-glycosylation using an optically active allylsilane. Segment B was also obtained via a S_N2' methylation reaction of a diene monoepoxyde. These two segments were connected by the Suzuki–Miyaura coupling reaction, and asymmetric total synthesis of Zincophorin was accomplished.

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The first total synthesis of (−)-nalanthalide (1), a novel blocker of the voltage-gated potassium channel Kv 1.3, was achieved starting from the known Wieland–Miescher ketone analogue 5. Our synthesis commenced with the conversion of alcohol 6, readily derived from 5, to stannylmethyl ether 4 by elongation of allyl group to homoprenyl group followed by elaboration of allyl stannylmethyl ether. The crucial [2,3]-Wittig rearrangement proceeded smoothly by exposure of 4 to n-BuLi in hexane, affording the desired alcohol 8 with complete stereoselectivity. The second key coupling reaction between aldehyde 3, obtained from 8, and the lithium reagent 2, prepared from γ-pyrone 10 with n-BuLi, was accomplished to give rise to alcohol 11, which was successfully converted to (−)-nalanthalide (1) through deoxygenation of the resulting hydroxy group.

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(+)-Brefeldin C was isolated as biosynthetic precursor of (+)-brefeldin A, which possessed a wide range of biological activity such as antifungal, antiviral, and antitumor effects. Having an interest in biological activities of Brefeldin family, we synthesized (−)-brefeldin C, which was the antipode of the natural brefeldin C. Amide 4 derived from 1-cyclopentenylmethanol in 4 steps was subjected to asymmetric aza-Claisen rearrangement in order to construct the asymmetric stereocenters around five-membered ring in brefeldin C. The rearranged product was converted to (−)-brefeldin C by multistep procedures including Wittg olefination, Kocienski–Julia olefination, lactonization, and so on.

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We developed a practical route for the synthesis of optically active cyclic α,α-disubstituted α-amino acid, (3S,4S)-1-amino-3,4-bis(alkoxy)cyclopentanecarboxylic acid. That is to say, the diol moiety in dimethyl tartrate was first protected as ether, and subsequently the methyl esters were reduced to a diol and then converted into a chiral iodide. The alkylation of dimethyl malonate with the iodide gave a cyclic diester. Monohydrolysis of the ester, followed by Curtius rearrangement afforded the cyclic α,α-disubstituted α-amino acid. The peptides composed of the chiral cyclic α,α-disubstituted α-amino acid were prepared by solution-phase methods, and their conformation was studied by using X-ray crystallographic analysis, ¹H NMR, IR, and CD spectra.

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Triplex forming oligonucleotides (TFOs) may be used to control gene expression at a specific site of duplex DNA. However, a TA and a CG base pairs in the homopurine:homopyrimidine regions interrupt the formation of stable triplexes. We have previously developed a novel nucleoside analog (WNA: W-shape nucleoside analog) with a bicyclic skeleton. In a systematic search for selective WNA analogs for a TA or a CG interrupting site, we have determined the two useful WNA analogs. The WNA-βT analog containing a thymine exhibited selective stabilization at a TA site. In contrast, the WNA-βC analog with a cytosine showed selectivity to a CG interrupting site. It should be noted that the triplexes with these new base analogs are more stable than the corresponding natural triplexes, and they would be useful to expand the target sequences for triplex formation.

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Artificial fluorescence probes for small organic signal molecules have been little explored in contrast with those for inorganic signal molecules (Ca²⁺ , NO, Zn²⁺ , phosphate). As the first step for the development of a fluorescence probe for 3',5'-cAMP, this paper presents our efforts for the design and synthesis of host 1 based on bisoxazolylpyridine having two amide substituents. This host is capable of highly selective 1:1 complexation with adenine nucleobase by multiple hydrogen bonds. The involvement of both Watson–Crick and Hoogsteen type hydrogen bondings was supported by ¹H NMR. Host 1 displayed a high complexation selectivity for adenine, the association constant for adenine derivative (Ks = 6.5 x 10³ M^-1) being 100 times greater than those for other nucleoside derivatives. Host 2, which is also based on bisoxazolylpyridine but has only one urea substituent, showed selectivity for cytosine derivative.

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Molecular design to develop a stable biochemical probe for a study of the role of prostacyclin (PGI₂) in the brain led to the discovery of 15R-TIC that binds selectively to a novel PGI₂ receptor, IP₂, expressed in the central nervous system and exhibits distinct neuroprotective effect under high oxygen condition and ischemic treatment. The IP₂ receptors in monkey and human brains were imaged by positron emission tomography (PET) using a short-lived ¹¹C-incorporated 15R-TIC methyl ester, which was synthesized by the newly developed Stille type rapid methylation between sp² and sp³ carbons. Another type rapid methylation between sp and sp³ carbons is also described toward the image of a PGI₂ receptor, IP₁, in peripheral system.

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Stereospecific preparation of 5-thiohexoaldopyranoside, in which the ring oxygen atom is replaced with a sulfur atom in hexoaldopyranoside, is described. The four key intermediates, erythrose and threose derivatives, were derived by chemical transformation from commercially available D-xylose, D-ribose, D-arabinose, and D-lyxose respectively, and also by Sharpless asymmetric dihydroxylation from γ-hydroxycrotylaldehyde diethylacetal. Two-carbon extension of terminal aldehyde and functionalization to γ-thiiranyl diethylacetal via cis-, or trans-2,3-epoxy alcohol in 6 steps followed by acetic acid-promoted cyclization of γ-thiiranyl diethylacetal gave 5-thioaldopyranoside. Finally, removal of the protected groups afforded 5-thiopyranose.

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Cocaine abuse prevails as a major public health concern, causing direct adverse medical consequences and contributing to grave social problems. Nicotine is the most widely used addictive drug in the world. Despite substantial multidisplinary research, an effective treatment against these illnesses remains elusive. Immunopharmacotherapy provides a novel way for potentially treating various drug addictions. We have developed catalytic antibodies that provide a strategy for not only binding, but also degrading cocaine, which offers a broad-based therapy. We will also present the foundation for our investigations into the relationship between the conformational constraint of nicotine and its immunogenicity, and therefore the development of new nicotine vaccines.

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Paclitaxel 1, one of the most important chemotherapeutic agents with promising antitumor activity, has a sparing water-solubility. This is one of the major drawbacks of 1, since the detergent required for solubilization of 1 causes hypersensitivity reaction. Previously, we have developed a novel class of "O–N intramolecular acyl migration" -type water-soluble prodrugs of HIV-1 protease inhibitors. Hencewe designed novel water-soluble paclitaxel prodrug, isotaxel 2, which is a 2'-O-benzoyl isoform of paclitaxel. Isotaxel was synthesized via coupling of an oxazolidine derivative of phenylisoserine with a Baccactin III derivative and showed 1,800-fold higher water-solubility than paclitaxel. Parent drug 1 was released promptly and completely through simple pH-dependent chemical mechanism,by means of O-N intramolecular acyl migration, under physiological conditions. Since 2 has no additional functional auxiliaries released during the conversion to 1, this would be a great advantage in toxicology and medical economics.

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The lipase-catalyzed kinetic resolution of racemic alcohols has been widely employed. However, few examples on the effective use of the installed acyl moiety as a part of the constituent structure of the subsequent reactions have been reported. We present here the lipase-catalyzed domino reactions in which the dynamic kinetic resolution of racemic 3-vinylcyclohex-2-en-1-ols using ethoxyvinyl maleates was followed by the intramolecular Diels–Alder reaction of the installed maleoyl group. The finding of the highly effective catalyst, [RuCl₂(mesitylene)]₂ for the racemization of optically active alcohols at room temperature was the key to success, and thus the one-pot asymmetric synthesis of the polysubstituted decalines was achieved with up to 95% ee in 81% yield.

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γ-Substituted γ-hydroxyglutamic acid is a common structure of a monatin (1) (high-intensity sweetener), dysiherbaine (2) (strong agonist of non-NMDA type glutamate receptor), and lycoperdic acid (3). To explore the method for the common structure, cycloadditions of nitrone 4 with allyl alcohols 5a-e or α,β-unsaturated esters 7a-c were examined. Treatment of nitrone 4 with alcohol 5a-e in the presence of MgBr₂·OEt₂ gave 6a-e with a high stereoselectivity. Cycloadducts 6b and 6e having correct stereochemistries for the natural γ-substituted γ-hydroxyglutamic acids 1 and 3 were readily transformed into monatin (1) and lycoperdic acid (3), respectively. On the other hand, cycloaddition of 4 with ester 7a-c afforded 8a-c. 4-epi-Monatin (13) was synthesized from cycloadduct 8b.

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When 6-(tosylamino)hex-2-ynyl benzoate was stirred in the presence of a catalytic amount of 2 equiv. of Cs₂CO₃ ,Pd₂dba₃·CHCl₃ and P(o-tol)₃ in toluene at 70 °C for 3 h,2,3-dihydro-1-tosyl-5-vinyl-1H-pyrrole (5-membered ring heterocycle) was obtained in 85% yield. On the other hand, the same substrate was treated with Pd₂dba₃·CHCl₃ and DPPF under same reaction conditions to give 1,2,5,6-tetrahydro-2-methylene-1-tosylpyridine and 2-methylene-1-tosylpiperidin-3-yl benzoate (6-membered ring heterocycles) in 53% and 36% yields, respectively. The former product should be formed by attacking of the tosylamide nitrogen to the palladium metal on η¹-allenylpalladium complex generated from propargyl ester and Pd(0), and the latter compound should be formed by attacking to the central carbon of η³-propargylpalladium complex, which is in a state of equilibrium with η¹-allenylpalladium complex.

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The mission of process chemists is to contribute toward human health care by synthetic chemistry and chemical technologies. Speed, quality, cost, safety, and robustness are the key words. Though the candidate API molecules are becoming more complex in recent years, the time to develop good chemical process is becoming short to minimize the loss of resources and to maximize returns. Process chemists play an important role not only for early clinical introduction and NDA filing, but also for reduction of commercial production cost. However, unlike in other area of organic chemistry, process chemistry of active pharmaceutical ingredients has not been discussed systematically. I'm going to talk about the strategy and technology of the process research at early stage and some of our results.The mission of process chemists is to contribute toward human health care by synthetic chemistry and chemical technologies. Speed, quality, cost, safety, and robustness are the key words. Though the candidate API molecules are becoming more complex in recent years, the time to develop good chemical process is becoming short to minimize the loss of resources and to maximize returns. Process chemists play an important role not only for early clinical introduction and NDA filing, but also for reduction of commercial production cost. However, unlike in other area of organic chemistry, process chemistry of active pharmaceutical ingredients has not been discussed systematically.I'm going to talk about the strategy and technology of the process research at early stage and some of our results.

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Two novel synthesis methods for 1-hydroxy-5-nitroindole-3-carbaldehyde (A) have been developed from indoline through ether cleavage with BBr₃ either of 1-methoxy- (B) or of 1-benzyloxy-5-nitroindole-3-carbaldehyde. Compound (B) has been disclosed to be the most reactive substrate for the nucleophilic substitution reactions. In the reactions of B with nitrogen centered nucleophiles, interesting site selectivity has been found. Thus, the nitrogen anions attacked the 2-position regioselectively giving 2-substituted indoles, while tertiary amine such as DABCO attacked the 1-methoxy methyl carbon culminating in the quantitative formation of A. On the other hand, free primary amine (methylamine) attacked B at the 3-position and underwent ring transformation to furnish 3-methyl-7-nitroquinazoline-4-one. Utilizing A, preparations of various derivatives of B and investigations of their reactions with nucleophiles are in progress.

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[in Japanese]

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Samarium(II)-mediated spirocyclization onto an aromatic ring was achieved by the reaction of methyl 4-(4-oxoalkyl)benzoates with SmI₂ in the presence of i-PrOH and HMPA, yielding methyl 1-alkyl-1-hydroxyspiro[4.5]dec-6-ene-8-carboxylates in moderate to high yields. Utilizing this chemistry, spiro[3.5] and [5.5] systems, and sterically congested spiro[4.5] systems were easily synthesized. For the successful conversion, appropriate activation of the aromatic ring has proven to be extremely important: while an ester or amide functionality on the aromatic ring can promote the spirocyclization, a sulfonamide substituent causes ortho cyclization.

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We have shown for the first time that the β-ICD-catalyzed Baylis–Hillman reaction of aromatic imines with HFIPA proceeds with S-selectivity, in contrast to the reaction of aldehydes, which afford R-selectivity. We propose a reaction mechanism where the phenolic OH of β-ICD plays a crucial role on enantioselectivity. This work provides an effective method for the preparation of aryl substituted α-methylene β-amino acid derivatives in >93% ee by the reaction of diphenylphosphinoyl imines followed by recrystallization. The synthetic utility of the β-ICD-catalyzed Baylis–Hillman reaction of imines was successfully demonstrated by the conversion of the Baylis–Hillman adduct to the β-lactam.

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Recently, salen complexes have been receiving a great deal of attention as highly efficient catalysts for many asymmetric reactions. We are interested in salen ligands having a pyridoxal structure in place of an o-salicylaldehyde structure from the following viewpoints; 1) difference of their reactivity 2) possibility that the pyridoxal-type salen complexes could be applied to solid-phase reaction and/or hydrophilic reaction via quarternalization. We have synthesized salen ligands having a pyridoxal structure and found that the corresponding complex prepared with Red-Al catalyze Michael reaction. Optically active pyridoxal derivative having a cyclophane structure was also synthesized. Although, so far, the stereoselectivity was moderate, asymmetric Michael reaction was also found to proceed.

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We studied a metal-halogen exchange reaction using O-protected 5-iodo-2'-dU (1) to prepare 5-lithiated species. Treatment of 1 with 2 eq. of n-BuLi followed by the reaction with MNP gave 5-N-tert-butylhydroxylamino derivative (2) in 19 % yield and deiodinated dU in 80 % yield. This result suggested that abstraction of imide proton and metal–halogen exchange were competitive at the early stage of the reaction. Thus, treatment of 1 with NaH for in situ imide protection and the following lithiation of the resulted 5-iodo-2'-dU sodium salt and the reaction with MNP afforded the desired 2 in good yield. Synthesis of 5-substituted 2'-dUs via the same method proceeded easily to give 5-substituted products in improved yields. 5-N-tert-Butylhydroxylamino-2'-dU derivative was converted to aminoxyl radical, which was confirmed by ESR spectroscopy. This method was also used to the synthesis of 5-substituted 2'-dC derivative.

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Synthesis of carboxylic esters and amides is one of the most fundamental and important process for producing natural and unnatural useful compounds in organic chemistry. Accordingly, a variety of condensing reagents for esterification and amidation have been developed. Simple methods for the esterification and amidation under mild condition are still very desirable. In this paper, we present a novel condensing reagent including base: 1-tert-butoxy-2-tert-butoxycarbonyl-1, 2-dihydroisoquinoline (BBDI) readily available from Boc₂O and isoquinoline. Treatment of N-protected amino acids with alcohols and amines in the absence of a base gave the corresponding esters and amides, respectively, in good yields.

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We established the simple and efficient synthesis of solid-supported barbituric acid from commercially available aminomethyl polystyrene resin. This solid-supported reagent as well as soluble N, N'-dimethylbarbituric acid can be used for the palladium(0)-catalyzed deprotection of allyl amines, carbamates, carbonates, esters and ethers to release the corresponding amines, acids and alcohols in excellent yields. In comparison with the soluble one, the solid-supported reagent facilitates isolation and purification of the deallylated compounds, especially highly polar compounds. We have also shown bromination of anilines and carbonyl compounds such as aldehydes and ketones using the solid-supported 5, 5-dibromobarbituric acid.

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Reductive amination of an aldehyde in the presence of an aromatic amine using Hantzsch dihydropyridine and a catalytic amount of Sc(OTf)₃ was established, and applied to the alkylation of phenylenediamines. In the case of o-phenylenediamine, however, 2-phenylbenzimidazole was obtained in the presence of O₂ and a catalytic amount of Sc(OTf)₃. The result suggests that Sc(OTf)₃ was a catalyst for an oxidation by O₂, and this presumption was supported by the oxidation of benzothiazoline under the same conditions. The reaction was applied to the synthesis of 2-arylbenzothiazoles from 2-aminobenzenthiol and aryl aldehydes.

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We have developed the stereoselective Horner–Wadsworth–Emmons (HWE) reaction of aldehydes with 2-fluoro-2-diethylphosphonoacetic acid (1) employing i-PrMgBr for the synthesis of (Z)-α-fluoro-α,β-unsaturated carboxylic acids as the major products. (E)-α,β-unsaturated carboxylic acids were obtained by the HWE reactions of aryl alkyl ketones with bis(2,2,2-trifluoroethyl)phosphonoacetic acid (2) utilizing lithium hexamethyldisilazide in N,N-dimethylformamide. Phosphonoacetic acid 2 was prepared by enzymatic hydrolysis of the corresponding methyl ester with porcine liver esterase (PLE). In addition, a novel P-chiral HWE reagent was synthesized by the PLE-promoted kinetic resolution of racemic phosphonates.

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Mesityllithium is recognized as one of chemoselective metalating reagents. The hydrogen–lithium exchange reaction of the immobilized indole derivatives using mesityllithium proceeded smoothly at −40 °C, and the subsequent reaction with 1,2-diiodoethane followed by cleavage with TBAF gave the 2-iodoindole derivtives in excellent yields. LTBZ (lithium tri-tert-butylzincate) also has been used as a chemoselective metalating reagent. The halogen–zinc exchange reaction of the immobilized 3-iodoindole derivatives using LTBZ proceeded, and the palladium-catalyzed cross-coupling reaction of the immobilized indolylzincate with various aryl halides gave unsymmetrical biaryls. Solid phase synthesis of bis-indole alkaloids is in progress using the immobilized indolylzincate.

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Recently, we have reported that intramolecular alkoxy-carbonylation of terminal acetylenes and the first example of an asymmetric version of this type reactions by using Pd(II)-p-benzoquinone catalyst. Although these reactions proceeded under mild conditions and afforded the β-alkoxyacrylates in good yields, undesirable hydroquinone is also produced. Now we wish to report here the above reaction by using aqueous H₂O₂ as a terminal oxidant. Na₂WO₄, VO(acac)₂, (NH₄)₆Mo₇O₂₄•6H₂O, CuCl₂ and FeCl₃•6H₂O were found to be useful for the co-oxidant of Pd(0). An asymmetric reaction of 2-propargyl-2-methyl-1,3-cyclohexanediol in the presence of Pd(CF₃CO₂)₂ / chiral ligand / FeCl₃•6H₂O / 30%H₂O₂ aq. in methanol under CO atmosphere afforded 58% ee of β-alkoxyacrylate in 90% yield.

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Synthesis of pentasubstituted tetrahydropyrans and related compounds via radical cyclization is reported. Intramolecular radical cyclization of 3-[2-(1-alkoxy-prop-2-ynyl)-tetrahydropyran-3-yloxy]-acrylic acid methyl esters by tributyltin hydride–AIBN in toluene at 110°C gave the bicyclic tetrahydropyrans having an exo-methylene group in good yields after protonolysisof vinylstannanes. The configuration of the alkoxy group of the propargyl side chain has little influence on the yield and stereochemistry of the products. Radical cyclizations proceeded in 70–80% and the diastereoselectivity of the newly formed stereogenic center was 94:6.

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We noticed that a methyl group at the aromatic nucleus was oxidized to the corresponding carboxylic acid directly in the presence of LiBr under photoirradiation. In executing our ongoing project involving oxidation reactions under photoirradiation, we found that dodecanol (1) was oxidized to dodecanoic acid (2) in the presence of LiBr under photoirradiation (Scheme). By considering both the promoting effect of oxygen and a catalytic amount of LiBr, aerobic oxidation via hydroperoxide, which is thought to be generated by abstraction of a hydrogen abstraction with a bromo radical from LiBr, proceeded. Now we report our study on the generality and the mechanism of this oxidation with alkali metal halides under photoirradiation.

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N-Phenylacetohydroxamic acid O-(tetra-O-acetyl)glucoside was selectively O-deacetylated to give the fully deacetylated glucoside by a carboxylesterase purified from Taka-diastase. In the reaction, seven partially deacetylated intermediates, all of which retain acetyl group at least at 6-position of the sugar moiety, were identified. From the isotope experiment using 6-[¹³C-acetyl]-labeled 3 and kinetics of non-enzymatic acetyl migrations of the possible fourteen kinds of deacetylated derivatives, the enzymatic hydrolysis was shown to proceed with intramolecular acetyl migrations. The migrations of 4→6 and 6→4 were the fastest and slowest ones, respectively, within the each tri-O-, di-O-, or mono-O-acetyl derivatives.

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Novel and specific reactivity is expected from the structure of cumulenes, one of the accumulated polyenes possessing multiply successive double bonds. Furthermore, starting from prochiral cumulene derivatives, selective transformation to optically active compounds having central and/or axial chirality can open a new way to interesting and useful chiral building blocks. In this study, reactivity of some [3]cumulene derivatives, 5,5-diarylpenta-2,3,4-trienal, toward nucleophiles and dienes was investigated. Successive treatment with Grignard reagent and Pd reagent in the presence of electrophile gave a tetrasubstituted furan derivative through two carbon-carbon bond formations consisting of 1,2-addition and Pd-mediated cyclization. Using this tandem reaction, preparation of tetrasubstituted furan with four different substituents is feasible. Cycloaddition of cumulene derivatives with dienes is also described.

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We reported that Rh-catalyzed intermolecular hydroacylation between salicylaldehydes and 1,5-hexadienes proceeded under mild reaction conditions to afford a mixture of iso- and normal-hydroacylated products in good yield.¹⁾ Here we examined the Rh-catalyzed hydroacylation between salicylaldehyde and norbornenes. The hydroacylation of norbornylene with salicylaldehyde in the presence of RhCl(PPh₃)₃ (0.2 equiv) proceeded at 80°C to give an exo-acylated product in quantitative yield, while that of norbornadiene proceeded to give an endo- product preferentially (endo : exo= 15 : 1) in good yield. “Double-chelation” and “chelation”salicylaldehyde and norbornenes to the Rh-complex might play vital roles in the stereoselective intermolecular hydroacylation.

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We have already revealed iodine-catalyzed aziridination of olefins using commercially available Chloramine-T (CT) as a nitrogen source. Here we report that a phase transfer catalyst or silica was found to be effective for the aziridination of olefins in water. In the reactions, a variety of olefins were converted to the corresponding aziridines under mild conditions. Especially, the combination of silica and water showed unique results that the efficiency of the reaction depends on the pore size of silica.

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We noticed that the direction of oxirane ring cleavage in epoxides (1) having olefinic groups at C-6 depended upon the length of conjugated double bond system and the electron-withdrawing ability of the substituents adjacent to the double bond. Treatment of 3-hydroxy-epoxydienonitrile and epoxydienoate possessing weak electron-withdrawing groups with an aminium salt predominantly gave the 3,6-furanoids (2) by opening of C-6-bond of oxirane ring (route a) and subsequent ring closing from C-3-hydroxy group. On the other hand, treatment of 3-silyloxy-epoxydienal having the strong electron-withdrawing formyl group with SnCl₄ only provided the cyclopentyl ketone (3) by cleavage of the oxirane ring at the C-5 position (route b) and successive stereoselective ring contraction. Deriving from compounds (2) and (3), total synthesis of capsanthin and cucurbitaxanthin A was accomplished.

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Stereoselective total synthesis of preclavulone-A methyl ester and its diastereomer, which were isolated from the soft coral Clavularia viridis by our group was achieved. Both natural products were synthesized from vinyl lactone as a common intermediate. Diastereoselective Mukaiyama-aldol reaction and α-alkylation of vinyl lactone were important for the stereoselective total synthesis of both diastereomers. The ring-closing olefin metathesis was employed for the construction of cyclopentene ring.

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Agardhilactone, isolated from the marine red alga Agardhiella subulata by Gerwick et al. in 1996, is a tricyclic eicosanoid containing δ-lactone, cyclopentane and epoxide rings and a conjugated diene. The relative configuration (C-6, C-8, C-9 and C-10) of agardhilactone was determined by spectroscopic analysis of derivative compounds and the absolute configuration of hydroxy group at C-18 was determined by chemical conversions. However, the relative configuration at C-5 remains to be elucidated. The relative configuration (C-5, C-6, C-9, C-10 and C-11) was revised by direct comparison with four synthesized model compounds. On the basis of the relative configuration, synthesis of agadhilactone was carried out. The structure of agardhilactone was revised by this synthesis.

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Polyamines constitute a class of DNA binding molecules and there is an increasing interest in hybrid molecules composed by polyamines and known DNA-cleavable reagents in order to enhance their activity and specificity.In the course of our studies, we have engaged with regulating the reactivity of the α,3-didehydrotoluene biradicals generated from enediynes, and reported that the α,3-didehydrotoluene biradicals possessing the electron withdrawing group at benzylic position exhibited enhanced DNA-cleaving activity.Here, we report the synthesis and DNA-cleaving activity of the polyamine-enediyne conjugates and other enediynes bearing cationic moieties.

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Novel lipophilic benzo[b]furan derivatives with alkylcarbamoylvinyl groups were designed based on possible conformers of LTB₄. Introductions of alkylcarbamoylvinyl groups to benzo[b]furan ring were accomplished by Heck reaction and/or Horner–Wadsworth–Emmons reaction. The structure of novel compounds was examined by ¹H-, ¹³H-NMR and MS. Several compounds among these show potent LTB₄ receptor antagonistic activity.

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Treatment of 2-acetylbenzo[b]furan-3-alkylcarboxamides with DMF-POCl₃ complex in dry DMF gave novel products having exo-formylmethylene group. Structure of the products was identified as (E or Z )-4-(formylmethylene)-2-(E)-(2-phenylvinyl)-(5-bromobenzofuro)[3, 2-d]-3, 1-oxazine by ¹H-NMR,¹³C-NMR and MS. Tentative mechanism of the new ring closure reactions was proposed. These compounds suggested that new ring closure reactions was found under the Vilsmeier conditions.

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Influenza sialidase offers an attractive site for the therapeutic intervention in influenza infections. A variety of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (Neu5Ac2en) analogs has been synthesized as competitve sialidase inhibitors. We found that Neu5Ac2en analog having thiocarbamoylmethyl group had most potent inhibitory activity towards human parainfluenza virus type 1(hPIV-1) sialidase. The fluorous tag allows us ready purification by a single chromatographic method, greatly reducing time for isolation. As a part of our ongoing program aimed at the synthesis of new sialidase inhibitors, we wish to present here the Neu5Ac aldolase-catalyzed synthesis of novel sialic acid derivatives from N-acetyl-D-mannosamine derivative bearing (perfluorohexyl)ethyl group as a fluorous tag at the C-6 position.

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In connection with our search for new metabolites via isolation and characterization of biologically active compounds from Thai marine animals, we found a blue sponge, Xestospogia sp. growing around Sichang Island in the Gulf of Thailand. We present the isolation and structure elucidation of renieramycins M–O, and Q–S, pretreated with potassium cyanide in methanolic buffer solution. Renieramycin E, prepared by treating renieramycin M with silver nitrate in aqueous acetonitrile was transformed into simple isoquinoline quinones, such as mimosamycin and renierone by treatment with a catalytic amount of TFA in chloroform. This strategy is the first example of the gram-scale preparation of this series of compounds, and presents a potential solution for increasing the gram-scale supply of novel natural products from marine sources.

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We report a new method for the synthesis of olefin-containing cyclic peptide using the Horner–Emmons reaction on solid support. The linear peptide alcohol was anchored to CLEAR (Cross Linked Ethoxylate Acrylate Resin) through the γ-carboxyl group of Glu. Dess–Martin periodinane mediated oxidation was employed to prepare the peptide aldehyde resin. Horner–Emmmons reaction of the aldehyde resin with diethyl phosphonoate yielded the olefin-containing linear precursor. Head-to-tail cyclization was achieved by EDC-mediated amide bond formation. Cyclization by olefin bond formation also gave the same product, but the yield was fairly low. Using the synthetic procedure established above, olefin-peptide libraries were constructed by “split & mix” or “parallel” synthesis.

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A general method was developed for introducing a wide variety of 2α-substituents on 1α,25-dihydroxyvitamin D₃. 2α-Substituents could be introduced via addition reaction of Grignard reagent towards the known sugar epoxide, easily obtained from D-glucose. In the reaction, the solvent effect was remarkable and the use of toluene gave higher chemical yield and chemical reactivity as compared with ethereal solvents. Using this methodology, novel 1α,25-dihydroxyvitamin D₃ analogues, which possess aromatic ring on the 2α-position, could be synthesized.

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We previously reported that a 14-residue peptide, T140, is a highly potent antagonist for CXCR4, which is related to HIV-infection, cancer metastasis and rheumatoid arthrists. Recently, alanine scanning on T140 have revealed that four amino acid residues, Arg², Nal³, Tyr⁵ and Arg¹⁴, are essential for its bioactivity. In our present report, two orthogonal convergent libraries of cyclic pentapeptides containing these four residues and an extra Gly residues were designed by combination of “confomation-based” and “sequence-based” libraries for the purpose of molecular-size reduction and identification of spatial disposition of these indispensable residues of T140. As a result, FC131 (8k), cyclo(–L-Nal–Gly–D-Tyr–L-Arg–L-Arg–) , equipotent to T140 in terms of CXCR4 antagonism and anti-HIV activity, was discovered.

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[in Japanese]

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Since utilization of niobium in organic synthesis has been reported for these two decades, however, its application was focused on limited area such as reaction of low valent Nb (III) with aldehydes or alkynes. On the other hand, niobium(V) itself exibits strong Lewis acid property and its application in organic synthesis are one of the challenging goal. We have revealed that niobium (V) promotes highly selective dealkylation of dialkoxyaromatics to give mono alkoxyphenols in excellent yields. The possible intermediate was assumed as a Nb alkoxide with substrates as bidentate ligands to decrease the Lewis acidity and the following second dealkylation does not proceed at all. Furthermore, homocoupling of imine was also observed. We have succeeded in the synthesis of chiral bistetrahydroisoquinoline using Nb and its application is under progress.

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Betulin 1 is a unique triterpene which has a reducing effect against the toxicity of cadmium. Although we have already clarified some structure-activity relationships of 1, we decided to synthesize 1 as an optical active form to progress the further studies. For this purpose, we designed a convergent synthetic plan and selected Wieland–Miescher type compound 2a and 2b as the starting materials. At first, we investigated to synthesize optically active 2a. Acetal 14, which was prepared from 11 by the sequential regioselective alkylations followed by several standard procedures, was subjected to the tandem acetal-cleavage and cyclization reaction to afford 15. The TBS ether of 15 was subjected to the reductive alkylation to provide 17 as a single diastereomer. The further studies synthesizing the both enantiomers are in progress. And also, the synthetic studies of racemic DE ring system of 1 will be presented.

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Chiral phosphinooxazolizine ligands 7a,b were synthesized by the condensation of pyrrolidinylmethanols 6a,b with 2-(diphenylphosphino)benzaldehyde, and the obtained 7a,b were attached to polystylene-diethylsilyl (PS–DES) resin, giving rise to the PS–DES-supported chiral ligands 8a,b. These were derived to PS–DES-supported chiral PdCl₂-phosphinooxazolidine complexes 10a,b, and the reaction with AgSbF₆ gave chiral cationic PS–DES-supported catalysts 11a,b. Furthermore, the catalysts 11a,b were successfully applied to the enantioselective Diels–Alder reaction of cyclopentadiene with acryloyl-N-oxazolidinone to give the DA adduct 12 in good chemical yield and enantioselectivity.

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[in Japanese]

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