Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/ajoc.202000603

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

α/β-Tubulin inhibitors that alter microtubule (MT) dynamics are commonly used in cancer therapy, however, these inhibitors also cause severe side effects such as peripheral neuropathy. γ-Tubulin is a possible target as antitumor drugs with low side effects, but the antitumor effect of γ-tubulin inhibitors has not been reported yet. In this study, we verified the antitumor activity of gatastatin, a γ-tubulin specific inhibitor. The cytotoxicity of gatastatin was relatively weak compared with that of the conventional MT inhibitors, paclitaxel and vinblastine. To improve the cytotoxicity, we screened the chemicals that improve the effects of gatastatin and found that BI 2536, a Plk1 inhibitor, greatly increases the cytotoxicity of gatastatin. Co-treatment with gatastatin and BI 2536 arrested cell cycle progression at mitosis with abnormal spindles. Moreover, mitotic cell death induced by the combined treatment was suppressed by the Mps1 inhibitor, reversine. These findings suggest that co-treatment with Plk1 and γ-tubulin inhibitors causes spindle assembly checkpoint-dependent mitotic cell death by impairing centrosome functions. These results raise the possibility of Plk1 and γ-tubulin inhibitor co-treatment as a novel cancer chemotherapy.

DOI： 10.3389/fphar.2020.620185

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Georg Thieme Verlag {KG}  

<title>Abstract</title>
C
1-Symmetric chiral ammonium salt catalysts induced a kinetic resolution of racemic α-nitrolactones through an asymmetric ester–amide exchange reaction. The corresponding amides were obtained with high enantioselectivities and high S (= k
fast/k
slow) values. This reaction system is a useful approach for obtaining carbocyclic quaternary α-nitroamides as chiral building blocks.

DOI： 10.1055/s-0040-1707303

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Georg Thieme Verlag {KG}  

<title>Abstract</title>An enantioselective Diels–Alder reaction of 3-nitrocoumarins has been developed. A tryptophan-derived C
1-symmetric organoammonium thiourea catalyst promoted the reaction of 3-nitrocoumarins with Danishefsky’s diene to give the corresponding adducts with good enantioselectivity (up to 94% ee). One of the resulting adducts was converted into a chiral carbocyclic quaternary β-amino alcohol.

DOI： 10.1055/s-0040-1707302

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Gatastatin (O-7-benzyl glaziovianin A) is a gamma-tubulin-specific inhibitor that is used to investigate gamma-tubulin function in cells. We have previously reported that the unsubstituted phenyl ring of the O-7-benzyl group in gatastatin is important for gamma-tubulin inhibition. To obtain further structural information regarding gamma-tubulin inhibition, we synthesized several gatastatin derivatives containing a fixed O-7-benzyl moiety. Modifications of the B-ring resulted in drastic decrease in cytotoxicity, abnormal spindle formation activity, and inhibition of microtubule (MT) nucleation. In contrast, various O-6-alkylated gatastatin derivatives showed potent cytotoxicity, induced abnormal spindle formation, and inhibited MT nucleation. We had previously reported that O-6-benzyl glaziovianin A is a potent alpha/beta-tubulin inhibitor; thus, these new results suggest that the O-6-position restricts affinity for alpha/beta- and gamma-tubulin. Considering that an O-7-benzyl group increases specificity for gamma-tubulin, more potent and specific gamma-tubulin inhibitors can be generated through O-6-modifications of gatastatin.

DOI： 10.1021/acsmedchemlett.9b00526

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A formal total synthesis of manzacidin B is described. beta,beta-Disubstituted gamma-hydroxy-beta-aminoalcohol, the key structure of manzacidin B, is stereoselectively constructed via sequential Henry reactions. By taking advantage of noncovalent interactions, such as intramolecular hydrogen bonding and chelation, we could diastereodivergently control the stereoselectivity of the Henry reaction.

DOI： 10.1021/acs.joc.9b02811

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<p>A procedure converting tribromocyclopropane to densely functionalized β-selenocyclopropylboronic ester using the 1,2-metallate rearrangement of a boron ate-complex has been developed.</p>

DOI： 10.1039/d0cc07134j

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DOI： 10.1021/acs.joc.9b02627

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Georg Thieme Verlag {KG}  

Organoammonium salts of dipeptide-derived chiral triamines or diamines with TfOH catalyzed the enantioselective 1,3-dipolar cycloaddition reactions of α-acyloxyacroleins with nitrones to give the corresponding adducts in good yields (up to 96%) and with high diastereo- and enantioselectivities (up to 89% ee). Although α-(p-methoxybenzoyloxy)acrolein is rather unstable under the reaction conditions, α-(3-pyrroline-1-carbonyloxy)acrolein is stable enough to be smoothly converted into the corresponding adducts with the aid of the chiral organoammonium salt catalysts.

DOI： 10.1055/s-0039-1690133

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The heterocyclic portions of yuzurimine-type alkaloids, such as deoxyyuzurimine and macrodaphnine, were synthesized by using a stereoselective hydroboration-oxidation reaction to install the C20 methyl group, the intramolecular Mitsunobu reaction to construct the E-ring portion, and the intramolecular SN2 reaction to construct the F-ring portion as key steps.

DOI： 10.1021/acs.orglett.9b02232

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PubMed

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DOI： 10.1021/acs.orglett.9b00352

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<p>The first catalytic enantioselective Hosomi−Sakurai reaction of α-ketoesters.</p>

DOI： 10.1039/C9CC01159E

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Georg Thieme Verlag {KG}  

Chiral BINOL-derived pyrophosphoric acid catalysts were developed and used for the regio- and enantioselective aza-Friedel–Crafts reaction of phenols with aldimines. ortho/para-Directing phenols could react at the para-position selectively with moderate to good enantioselectivities. Moreover, the gram-scale transformation of a product into the key intermediate for the antifungal agent (R)-bifonazole was demonstrated.

DOI： 10.1055/s-0037-1610250

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<p>Chiral <italic>C</italic>₂- and <italic>C</italic>₁-symmetric BINOL-derived bis(phosphoric acid) catalysts facilitated the enantioselective aza-Friedel–Crafts reaction of 2-methoxyfuran with α-ketimino esters.</p>

DOI： 10.1039/C8SC02290A

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The reaction of silyl dienol ether of gamma-pyrone with dimethyl acetylenedicarboxylate (DMAD) gives the regioselective insertion product in 66% yield. This DMAD-insertion reaction is thought to include a three-step sequence: (1) thermal [2+2]-type cycloaddition reaction of silyl dienol ether of gamma-pyrone with DMAD, (2) ring-opening electrocyclic reaction of the cyclobutene skeleton, and (3) hydrolysis of the silyl dienol ether. The present reaction proceeds under mild conditions without any catalysts or heating. In addition, the [2+2]-type cycloaddition reaction proceeds regioselectively at the C3-C4 double bond in the silyl dienol ether of gamma-pyrone.

DOI： 10.3987/COM-17-13820

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

beta,beta,-Disubstituted -amino alcohols has been synthesized in a diastereodivergent manner from chiral secondary nitroalkanes as starting materials. In this key Henry reaction, the use of different protecting groups resulted in the diastereoselective construction of the tetrasubstituted carbon stereocenter with different configuration. Based on this methodology, a total synthesis of manzacidins A and C has been achieved.

DOI： 10.1002/ajoc.201700568

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG KG  

The intramolecular dehydro-Diels-Alder reaction of 1-indolyl-1,6-heptadiynes proceeds smoothly under rather mild heating conditions to give substituted carbazoles in moderate to good yields. The reaction of 7-aryl-1-indolyl-1,6-heptadiynes under heating gives the corresponding carbazoles chemoselectively in high yields, whereas the reaction under basic conditions gives naphthalenes as major products.

DOI： 10.1055/s-0036-1588461

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The biomimetic cyclization of 3,5-diketo esters was reinvestigated for the synthesis of alpha-methoxy-gamma-pyrones. 3,5-Diketo esters were selectively synthesized via the aldol reaction of commercially available methyl 2-methyl-3-oxopentanoate with an aldehyde followed by the oxidation with AZADOL (R) and PhI(OAc)(2). The DBU-promoted intramolecular transesterification of 3,5-diketo esters showed excellent reactivity in MeOH, to give the corresponding gamma-hydroxy-alpha-pyrones in high yields under mild reaction conditions. Based on the present cyclization scheme, the total synthesis of cyercene A was achieved.

DOI： 10.1055/s-0036-1588795

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We have discovered O-6-benzyl glaziovianin A, which showed stronger inhibition of microtubule polymerization (IC50 = 2.1 mu M) than known alpha,beta-tubulin inhibitors, such as colchicine and glaziovianin A. Also, we performed competition binding experiments of O-6-benzyl glaziovianin A and revealed that O-6-benzyl glaziovianin A binds to the colchicine binding site with high affinity. It is interesting that glaziovianin A derivatives change their mode of action in benzylation at the O-6 (alpha,beta-tubulin inhibitor) or O-7 (gamma-tubulin-specific inhibitor) position. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmc.2016.09.026

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A simple procedure for the synthesis of chiral 3,5-disubstituted piperazinones is described. The aza-Michael addition of alpha-amino esters to beta-substituted nitroalkenes in an organic/aqueous biphasic solvent system followed by reduction of a nitro group with zinc nanopowder in acidic media and intramolecular ester-amide exchange under heating conditions gives piperazinones in good overall yields. This novel three-step process can provide a short access to a variety of chiral 3,5-disubstituted piperazinones simply by changing the combination of starting nitroalkenes and alpha-amino esters. This process can be applied to the concise synthesis of the piperazinone-containing natural product 6',6 ''-didebromo-cis-3,4-dihydrohamacanthin B. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2016.09.015

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Chiral phosphite-urea bifunctional catalysts have been developed for the enantioselective bromocyclization of 2-geranylphenols with N-bromophthalimide (NBP) for the first time. The chiral triaryl phosphite moiety activates NBP to generate a bromophosphonium ion. On the other hand, the urea moiety interacts with a hydroxyl group of the substrate through hydrogen bonding interactions. Enantioselectivity is effectively induced through two-point attractive interactions between the catalyst and the substrate.

DOI： 10.1039/c6cc00229c

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Authorship：Lead author,　Corresponding author   Language：English   Publisher：WILEY-V C H VERLAG GMBH  

Electrophilic cyclizations of unactivated alkenes play highly important roles in the synthesis of useful building blocks. This account describes our contributions to the rational design of monofunctionalized chiral Lewis base catalysts for enantioselective iodo- and protocyclizations. For the stereoselective promotion of electrophilic bromocyclizations, nucleophilic phosphite-urea cooperative catalysts have been designed.

DOI： 10.1002/tcr.201500005

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We developed 1,3-dipolar cycloadditions of azomethine imines with propioloylpyrazoles catalyzed by a chiral copper(II) complex of 3-(2-naphthyl)-L-alanine amide. The asymmetric environment created by intramolecular pi-cation interaction and the N-alkyl group of the chiral ligand gives the corresponding adducts in high yields with excellent enantioselectivity. This is the first successful method for the catalytic enantioselective 1,3-dipolar cycloaddition of azomethine imines with internal alkyne derivatives to give fully substituted pyrazolines.

DOI： 10.1021/ja508441t

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Nucleophilic phosphite-urea cooperative catalysts are highly efficient for the bromonium-induced cyclization of 2-geranylphenols. Phosphite-N,N'-dimethylurea catalysts also show moderate activity, probably due to the steric effect of their bent conformation. Chirality 26:355-359, 2014. (c) 2014 Wiley Periodicals, Inc.

DOI： 10.1002/chir.22297

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Chiral triaryl phosphates promote the enantioselective iodolactonization of 4-substituted 4-pentenoic acids to give the corresponding iodolactones in high yields with high enantioselectivity. N-Chlorophthalimide (NCP) is employed as a Lewis acidic activator and oxidant of I-2 for the present iodolactonization. In combination with 1.5 equivalents of NCP, only 0.5 equivalents of I-2 are sufficient to generate the iodinating reagent.

DOI： 10.1002/anie.201400946

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The first diastereo- and enantioselective inverse electron demand hetero-Diels-Alder reaction of beta,gamma-unsaturated alpha-ketoesters with allylsilanes is described. Chiral copper( II) catalysts successfully activate the beta,gamma-unsaturated alpha-ketoesters and promote the reaction with allylsilanes with excellent enantioselectivities. This process represents a new entry to chiral oxanes.

DOI： 10.1002/anie.201402934

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DOI： 10.1002/anie.201303572

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Primary alkylboronic acids such as methyl boronic acid and butylboronic acid are highly active catalysts for the dehydrative amide condensation of alpha-hydroxycarboxylic acids. The catalytic activities of these primary alkylboronic acids are much higher than those of the previously reported arylboronic acids. The present method was easily applied to a large-scale synthesis, and 14 g of an amide was obtained in a single reaction.

DOI： 10.1021/ol401537f

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Chiral phosphonium salts induce the kinetic resolution of racemic a-substituted unsaturated carboxylic acids through asymmetric protolactonization. Both the lactones and the recovered carboxylic acids are obtained with high enantioselectivities and high S (=k(fast)/k(slow)) values. Asymmetric protolactonization also leads to the desymmetrization of achiral carboxylic acids. Notably, chiral phosphonous acid diester not only induced the enantioselectivity but also promoted protolactonization.

DOI： 10.1021/ol401313d

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Nucleophilic phosphite-urea cooperative high-turnover catalysts have been designed for the highly selective bromocyclization of homogeranylarenes. The introduction of a urea moiety and bulky aryl groups in the catalyst inhibits decomposition of the catalyst and the generation of byproducts. Only 0.5 mol% of the catalyst successfully promotes the bromocyclization of 4-homogeranyltoluene to give the desired product in 96% yield.

DOI： 10.1039/c3sc51432c

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

DOI： 10.1002/ajoc.201200054

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

A catalytic and enantioselective Diels-Alder reaction of alpha-(carbamoylthio)acroleins induced by an organoammonium salt of chiral triamine is described. alpha-(Carbamoylthio)acroleins are designed and synthesized as new sulfur-containing dienophiles for the first time. The Diels-Alder reaction affords chiral tertiary thiol precursors with up to 91% ee.

DOI： 10.1021/ol300921f

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Reverse micelle-type N,N-diarylammonium pyrosulfate (3-5 mol %) efficiently catalyzes the hydrolysis of esters (up to 100 mmol scale) under organic solvent-free conditions. The present method is successfully applied to the hydrolysis of various esters without the decomposition of the base-sensitive moieties and without any loss of optical purity for alpha-heterosubstituted carboxylic acids.

DOI： 10.1021/ol301290c

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Oil-soluble N,N-diarylammonium pyrosulfates as nonsurfactant-type catalysts for the dehydrative ester condensation under aqueous conditions are described. Preheat treatment of dibasic sulfuric acid with bulky N,N-diarylamines generates water-tolerant salts of pyrosulfuric acid as active catalyst species. The present catalysts in water can also widely be applied to unusual selective esterifications and dehydrative glycosylation.

DOI： 10.1021/ol2027366

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Five cytotoxic macrolides. aplyronines D-H (4-8), were isolated from the Japanese sea hare Aplysia kurodai. They are new congeners of the antitumor compound aplyronine A (1), which was previously isolated from the same organism. Their structures were determined by spectroscopic analysis (NMR and MS). The cytotoxicity of these new compounds was evaluated in comparison with that of aplyronines A C (1-3), suggesting the importance of the 7-O-seryl ester group for mediating the potent cytotoxicity of aplyronines. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2011.11.095

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

The desymmetrization of meso-glycerol derivatives bearing a 3-pyrroline-1-carbonyl (Pyroc) directing group is demonstrated through an enantioselective acylation reaction promoted by L-histidine-derived bifunctional catalysts. The desired monoacylated products are obtained in good yields (up to 74%) with high enantioselectivities (up to 99% ee).

DOI： 10.1002/adsc.201100252

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Authorship：Lead author   Language：English   Publisher：AMER CHEMICAL SOC  

DOI： 10.1021/ol201032t

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Bronsted base-assisted boronic acid catalysis for the dehydrative self-condensation of carboxylic acids is described. Arylboronic acid bearing bulky (N,N-dialkylamino)methyl groups at the 2,6-positions can catalyze the intramolecular dehydrative condensation of di- and tetracarboxylic acids. This is the first successful method for the catalytic dehydrative self-condensation of carboxylic acids.

DOI： 10.1021/ol102926n

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：CSIRO PUBLISHING  

Bifunctional Bronsted base-assisted boronic acid catalysts, arylboronic acids bearing two sterically bulky (N,N-dialkylamino)methyl groups at the 2,6-positions, exhibit remarkable activities for the dehydrative intramolecular condensation of dicarboxylic acids. The steric bulkiness of the (N,N-dialkylamino) methyl groups of 1, which prevents the formation of less active species such as the N -> B chelated species and triarylboroxines 3, is crucial for the high catalytic activity. This is the first successful method for the catalytic dehydrative self-condensation of di- and tetracarboxylic acids.

DOI： 10.1071/CH11301

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The rational design of small but highly functional artificial catalysts is very important for practical organic synthesis. Asymmetric Lewis acid catalyses with non-covalent secondary interactions have been developed for enantioselective reactions. This tutorial review describes the concept, design and examples of asymmetric Cu(II) catalyses for cycloaddition reactions based on intramolecular pi-cation or pi-cation interactions between the copper( II) cation and auxiliary Lewis basic sites of the chiral ligands.

DOI： 10.1039/b924478f

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The nucleophilic phosphine-catalyzed diastereoselective iodocyclization of linear isoprenoids bearing an oxygen terminal group was investigated. TBDMS ether of homogeraniol and TBDMS ester of homogeranic acid were successfully converted to the corresponding iodopolycyclic products in the presence of a catalytic amount of triphenylphosphine with complete diastereoselectivity.

DOI： 10.3987/COM-09-S(E)1

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A chiral copper(II) complex of 3-(2-naphthyl)-L-alanine amide successfully catalyzes the enantioselective 1,3-dipolar cycloaddition reaction of nitrones with propioloylpyrazole and acryloylpyrazole derivatives. The asymmetric environment created by intramolecular pi-cation interaction gives the corresponding adducts in high yields with excellent enantioselectivity. This is the first successful method for the catalytic enantioselective 1,3-dipolar cycloaddition of nitrones with acetylene derivatives. The 1,3-dipolar cycloadducts can be stereoselectively converted to beta-lactams via reductive cleavage of the N-O bond using SmI2.

DOI： 10.1021/ja1081603

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Authorship：Lead author   Language：English   Publisher：CHEMICAL SOC JAPAN  

The rational design of small-molecule chiral catalysts is an important subject in the development of practical organic syntheses. We have designed primary ammonium salt catalysts for enantioselective cycloaddition reactions with alpha-substituted acroleins such as alpha-(acyloxy)acroleins and alpha-diacylaminoacroleins. Ammonium salts of an aliphatic triamine derived from H-L-Phe-L-Leu-N(CH2CH2)(2) successfully promote the Diels-Alder reaction of alpha-(acyloxy)acroleins and alpha-(N,N-diacylamino)acroleins, and the [2 + 2] cycloaddition reaction of alpha-(acyloxy)acroleins with high enantioselectivity. An ammonium salt of a C-2-symmetric aromatic diamine, 1,1'-binaplithy1-2,2'-diamine, with a superacid is also an efficient catalyst and shows high activity and enantioselectivity for the Diels Alder reaction of cyclic dienes with alpha-(acyloxy)acroleins.

DOI： 10.1246/bcsj.20090345

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DOI： 10.1021/ja906098b

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG KG  

The O-3-pyrroline-1-carbonyl (O-Pyroc) group and 3-pyrrolinamide are useful removable protecting groups for the kinetic resolution of racemic alpha-hydroxycarboxylic acids, beta-hydroxycarboxylic acids, 1,2-dicarboxylic acids, and 1,2-diols using the L-histidine-derived bifunctional catalysts. The Pyroc group can be easily introduced from Pyroc chloride. Selective deprotection of the Pyroc group and 3-pyrrolinamide can be carried out via DDQ oxidation followed by hydrolysis using sodium hydroxide, without epimerization.

DOI： 10.1055/s-0029-1217321

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Commercially available molybdenum(VI) oxides such as (NH4)(2)MoO4, (NH4)(6)Mo7O24 center dot 4H(2)O, MoO2(acac)(2), and MoO2(TMHD)(2) are highly effective dehydrative cyclization catalysts for the synthesis of a variety of oxazolines. The reaction proceeds with a complete retention of configuration at the beta-position. For the dehydrative cyclization of cysteine derivatives, bis(2-ethyl-8-quinolinolato)dioxomolybdenum(VI) shows remarkable catalytic activity and gives thiazolines without a significant loss of stereochemical integrity at the C2-exomethine positions. (C) 2008 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2008.12.074

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Authorship：Corresponding author   Language：Japanese   Publisher：SOC SYNTHETIC ORGANIC CHEM JPN  

The design of highly functionalized artificial catalysts is very important for practical organic synthesis. We have succeeded in the rational design of high-performance catalysts based on acid-base combined salts. Acid-base combined salt catalysts can be classified into three types: (1) Metal oxide-Lewis base combined salts, (2) Bronsted acid-Bronsted base combined salts, and (3) Lewis acid-Lewis base combined salts. Here we report our recent studies on development of highly selective cyclization reactions for the synthesis of key intermediates of bioactive natural products. Molybdenum(VI) oxide-bis(quinolinolato) complexes (class 1) efficiently catalyze biomimetic dehydrative cyclization of serine, threonine and cysteine derivatives to give oxazolines and thiazolines. Chiral 1,1'-binaphthyl-2,2'-diammonium salts (class 2) are useful catalysts for enantioselective Diels-Alder reaction of alpha-acyloxyacroleins. We also have developed the first enantioselective biomimetic iodocyclization of isoprenoids using a chiral nucleophilic promoter (class 3).

DOI： 10.5059/yukigoseikyokaishi.66.942

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The selective synthesis of phosphoric acid diesters has been achieved through the direct catalytic dehydrative condensation of phosphoric acid with two equivalents of alcohols. The present method works especially well for the synthesis of cyclic phosphoric acid diesters. The combination of perrhenic acid and N-methylbenzylamine efficiently catalyzes the dehydrative condensation of phosphoric acid with equimolar amounts of diols to give cyclic phosphoric acid diesters in excellent yields.

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The direct and catalytic kinetic resolution of racemic carboxylic acids bearing a Bronsted base such as O-protected alpha-hydroxy carboxylic acids and N-protected alpha-amino acids has been accomplished through an L-histidine-derived sulfonamide-induced enantioselective esterification reaction with tert-butyl alcohol for the first time. Highly asymmetric induction [S(k(fast)/k(slow)) = up to 56] has been achieved under the equilibrium between a chiral catalyst and two diastereomeric acylammonium salts through an intramolecular hydrogen-bonding interaction.

DOI： 10.1021/ol801007m

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Ester condensation is one among the most fundamental organic transformations, and more environmentally benign alternatives to current esterification processes are needed. Under solvent-free and drying agent-free conditions, catalytic amounts of sulfonic acids promote ester condensation between an equimolar mixture of carboxylic acids and alcohols. In particular, p-toluenesulfonic acid (TsOH) and 10-camphorsulfonic acid (CSA), which have appropriate acidities, efficiently catalyze the ester condensation of secondary alcohols without their decomposition. Since the present protocol does not require solvents under simple open-air conditions, a large amount of esters can be synthesized in a rather small apparatus. (c) 2008 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2008.06.058

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Neighboring-group participation of an acyl protecting group efficiently promotes the Bronsted acid-catalyzed dehydrative cyclization of 1,3,5-triketones to gamma-pyrones, whereas a bulky silyloxy group in the beta-position retards the cyclization. This reaction provides an efficient synthetic route for a common intermediate for the synthesis of gamma-pyrone-containing bioactive natural products.

DOI： 10.1021/ol800860p

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

Efficient total syntheses of fluvibactin and vibriobactin have been achieved via molybdenum(VI) oxide-catalyzed dehydrative cyclization, Sb(OEt)(3)-catalyzed ester-amide transformation, and WSCI and HOAt-promoted dehydrative amide formation.

DOI： 10.1039/b805880f

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

With regard to atom economy and E-factor, catalytic condensation of carboxylic acids with equimolar amounts of alcohols is the most desirable. Although several highly active dehydration catalysts have been reported, more efficient alternatives are still strongly needed because the dehydrative esterification of tertiary alcohols, phenols, acid-sensitive alcohols, amino acids, and hardly soluble alcohols has never proceeded satisfactorily. Here we report new insights into the classical DMAP-catalyzed acylation of alcohols: surprisingly, only a 0.05-2 mol % of DMAP can efficiently promote acylation of alcohols with acid anhydrides under auxiliary base- and solvent-free conditions to give the corresponding esters in high yields. Furthermore, we achieved the recovery and reuse of Commercially available polystyrene-supported DMAP without using any solvents. These serendipitous findings provide widely useful and environmentally benign esterification methods, which might be more practical and reliable than catalytic dehydrative condensation methods, in particular, for the less reactive alcohols which hardly condense with carboxylic acid directly.

DOI： 10.1021/ja075824w

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：TEKNOSCIENZE PUBL  

Enantioselective biomimetic polyene cyclizations of polyprenoids have been studied for a long time. Very recently, we have developed the first "chiral iodonium ion"-induced enantioselective polyene cyclization of polyprenoids using a nucleophilic promoter. Achiral nucleophilic phosphorus compounds catalytically promote the diastereoselective halocyclization in dichloromethane to give a halogenated cyclic product in excellent yield. Moreover, chiral phosphoramidites stoichiometrically promote the enantioselective halocyclization of simple polyprenoids with N-iodosuccinimide in toluene to give iodinated cyclic products in up to 99 percent ee and 99 percent ds. Some enantioselective polycyclizations have been reported in addition to this halocyclization. One of the advantages of these biomimetic polycyclizations is the simultaneous formation of several carbon-carbon bonds with the relative and absolute stereocontrol. Enantioselective biomimetic domino reactions would be highly useful for the practical synthesis of natural products and related compounds.

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

Bis(2-ethyl-8-quinolinolato)dioxomolybdenum(VI) (9) (1 mol%) shows remarkable catalytic activity for the dehydrative cyclization of cysteine-containing dipeptides 1 to give the corresponding thiazolines 2 with less than 6% epimerization at the C2-exomethine position. For the dehydrative cyclization of threonine-containing dipeptides 4, 1 mol% of bis(2-phenyl-8-quinolinolato)dioxomolybdenum(VI) (10) gives the corresponding oxazolines 5 with retention of configuration at the 5-position.

DOI： 10.1002/adsc.200700068

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

The dehydrative cyclization of N-(o-hydroxybenzoyl)threonine derivative la is efficiently promoted by the combined use of molybdenum(VI) oxides and benzoic acids bearing electron-withdrawing substituents. In the presence of ammonium molybdate [(NH4)(2)MoO4, 10 mol %] and pentafluorobenzoic acid (C6F5CO2H; 10 mol %), dehydrative cyclization of la was conducted in toluene under azeotropic reflux conditions to give 2-(o-hydroxyphenyl)oxazoline 2a in 76 % yield. Furthermore, the first total synthesis of the antitumour substance BE-70016 was achieved using the catalytic dehydrative cyclization of la as a key reaction.

DOI： 10.1002/adsc.200600550

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG KG  

The design of small but highly functional artificial catalysts is very important for practical organic synthesis. We have succeeded in the rational design of small and simple catalysts and related reactions based on acid-base combination chemistry. Acid-base combined catalysts can be classified into three types: (i) acid-base combined salt catalysts, (ii) conjugate acid-base catalysts, and (iii) nonconjugate acid-base catalysts. We have systematically developed acid-base combined salt catalysts such as ammonium salts, ate complexes, ion pairs and cation-pi complexes, acid-base conjugate catalysts such as metal oxides (monoconjugation) and zinc(Il)3,3'-diphosphinol-BINOLates (triconjugation), and acid-base nonconjugate catalysts like L-histidine-derived sulfonamides.

DOI： 10.1055/s-2007-970776

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Polycyclic bio-active natural products that contain halogen atoms have been isolated from a number of different marine organisms(1). The biosynthesis of these natural products appears to be initiated by an electrophilic halogenation reaction at a carbon - carbon double bond(2-4) via a mechanism that is similar to a proton-induced olefin polycyclization(5-8). Enzymes such as haloperoxidases generate an electrophilic halonium ion ( or its equivalent), which reacts with the terminal carbon - carbon double bond of the polyprenoid, enantioselectively inducing a cyclization reaction that produces a halogenated polycyclic terpenoid. Use of an enantioselective halocyclization reaction is one possible way to chemically synthesize these halogenated cyclic terpenoids; although several brominated cyclic terpenoids have been synthesized via a diastereoselective halocyclization reaction that uses stoichiometric quantities of a brominating reagent(9-12), the enantioselective halocyclization of isoprenoids induced by a chiral promoter has not yet been reported. Here we report the enantioselective halocyclization of simple polyprenoids using a nucleophilic promoter. Achiral nucleophilic phosphorus compounds are able to promote the diastereoselective halocyclization reaction to give a halogenated cyclic product in excellent yields. Moreover, chiral phosphoramidites promote the enantioselective halocyclization of simple polyprenoids with N-iodosuccinimide to give iodinated cyclic products in up to 99% enantiomeric excess and diastereomeric excess. To the best of our knowledge, this is the first successful example of the enantioselective halopolycyclization of polyprenoids.

DOI： 10.1038/nature05553

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

Bulky diarylammonium pentafluorobenzenesulfonates effectively promote dehydration reactions, such as condensation reactions to give esters and the dehydrative cyclization of 1,3.5-triketones. In particular, N-(2,6-diphenylphenyl)-N-mesitylammonium pentafluorobenzenesulfonate shows much higher catalytic activity than C6F5SO3H under reaction conditions without the removal of generated water, even though the former is a weaker acid. Its crystallization gives an aggregated cyclic ion pair, which is composed of two diarylammonium cations, four pentafluorobenzenesulfonate anions, and two oxonium cations. This ion pair is strongly stabilized by four intermolecular and two intramolecular pi-pi attractive interactions and 10 hydrogen bonds. The extremely high catalytic activity of N-(2,6-diphenylphenyl)-N-mesitylammonium pentafluorobenzenesulfonate in the dehydration reactions may be ascribed to the local hydrophobic environment of the tightly aggregated ammonium salts.

DOI： 10.1002/asia.200600380

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

DOI： 10.1002/anie.200604333

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

A protocol for ester condensation between equimolar amounts of carboxylic acids and alcohols catalyzed by bulky diarylammonium pentafluorobenzenesulfonate is described. We also present procedures for the synthesis of N-(2,6-diisopropylphenyl)-N-mesitylammonium pentafluorobenzenesulfonate. The present ester condensation proceeds well under mild conditions even without the removal of generated water. The synthesis of N-(2,6-diisopropylphenyl)-N-mesitylammonium pentafluorobenzenesulfonate will take similar to 5 days. The ester condensation reactions will take similar to 6 h to 3 days.

DOI： 10.1038/nprot.2007.254

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

A metal-free phosphazenium cation-catalyzed direct dehydrative condensation of phosphoric acid with alcohols has been developed for the environmentally benign synthesis of phosphoric acid monoesters.

DOI： 10.1039/b707974e

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

A diammonium salt of chiral 1,1'-binaphthyl-2,2'-diamine (2a) and trifluoromethanesulfonimide (Tf2NH) shows excellent catalytic activity and enantioselectivity for the Diels-Alder reaction of alpha-acyl-oxyacroleins. For example, in the presence of 5 mol % of 2a and 9.5 mol % of Tf2NH, the Diels-Alder reaction of alpha-(cyclohexanecarbonyloxy)acrolein with cyclopentadiene proceeded in EtCN at -75 degrees C to give the adducts in 88 % yield with 92 % exo and 91 % ee. The electron-donating property of the acyl group of the alpha-acyloxyacroleins increases the enantioselectivity due to the formation of strong intramolecular hydrogen bonding of the acyl group with a proton of the ammonium group in the transition state. This catalyst can be easily prepared in situ by mixing the commercially available chiral diamine and Tf2NH.

DOI： 10.1002/adsc.200600322

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

Aurisides A (1) and B (2) are macrolide glycosides isolated from Japanese sea hare Dolabella auricuralia, which exhibit cytotoxicity against HeLa S_3 cells with IC_<50> values of 0.17 and 1.2μg/mL, respectively. The main structural features of aurisides are a bromine-substituted conjugated diene, a 14-membered lactone, and a cyclic hemiacetal. We achieved the enantioselective synthesis of aurisides A and B by a convergent approach. The C1-C9 segment 4 was prepared from (R)-pantolactone using a reaction of dithiane carbanion with epoxide, stereoselective reduction of β-hydroxyketone with Me_4NBHOAc, and rhodium-catalyzed Reformatsky-type reaction as key steps. The C10-C17 segment 12 was synthesized from (R)-glycidyl trityl ether. The Nozaki-Hiyama-Kishi reaction between 4 and 12 and subsequent reactions including construction of bromine-substituted conjugated diene gave seco acid 10, which was converted into the aglycon (3) of aurisides by construction of the 14-membered lactone. The Mukaiyama glycosylation reaction of the aglycon 3 provided aurisides A (1) and B (2).

DOI： 10.24496/tennenyuki.48.0_205

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

The interaction between actin and aplyronine A, a potent antitumor and actin-depolymerizing substance of marine origin, was investigated by photoaffinity labeling experiments and X-ray structure analysis of actin complex with aplyronine A. Photoaffinity probes consisting of a side-chain portion of aplyronine A as a ligand, a diazirine moiety as a photoaffinity group, and a fluorophor as a detecting group were synthesized. Photolabeling experiments between actin and the probe were carried out. Actin was successfully photolabeled by the fluorescent probe and visualized clearly. The present results provide the first chemical evidence for the direct interaction between actin and the side-chain portion of aplyronine A. X-ray structure analysis of actin-aplyronine A complex was carried out. The analysis showed that Aplyronine A bound to a hydrophobic cleft between subdomains 1 and 3 of actin. The structural feature is that the trimethylserine moiety protrudes toward the bulk solvent region.

DOI： 10.24496/tennenyuki.48.0_43

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The enantioselective synthesis of aurisides A and B, macrolide glycosides of marine origin, was achieved by a convergent approach. The C1-C9 segment 4 was prepared from (R)-pantolactone, and the C10-C17 segment 14 was synthesized from (R)-glycidyl trityl ether. The Nozaki-Hiyama-Kishi reaction between 4 and 14 and subsequent reactions gave seco acid 10, which was converted into the aglycon (3) of aurisides by construction of the 14-membered lactone and bromine-substituted conjugated diene. The glycosylation reaction of the aglycon provided aurisides A and B. (c) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2006.05.077

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Mycalolide analog 4, consisting only of the side chain of mycalolide B (2), a trisoxazole macrolide of marine origin, was stereoselectively synthesized using Roush crotylboration, an Evans aldol reaction, and a Paterson aldol reaction as key steps. The analog 4 was found to have strong actin-depolymerizing activity. (c) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2006.06.046

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DOI： 10.24496/intnaturalprod.2006.0__P-81_

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：SOC SYNTHETIC ORGANIC CHEM JPN  

More environmentally benign alternatives to current chemical processes, especially large-scale fundamental reactions, are highly desirable for many reactions. We have developed bulky diary-lammonium pentafluorobenzenesulfonates la and 2a as mild and extremely active dehydration catalysts. In the presence of the catalysts, dehydrative cyclization of 1, 3, 5-triketones and ester condensation of carboxylic acids with equimolar amounts of alcohols are performed in heptane by heating at 80 V without the removal of water. We have also developed an efficient molybdenum oxide-catalyzed dehydrative cyclization of serine, threonine, and cysteine derivatives, which gives oxazolines and thiazolies. In the presence of molybdenum oxides, the reaction is carried out by heating at azeotropic reflux with the removal of water. Phosphate monoesters are synthesized from a mixture of phosphoric acid and alcohols in the presence of tributylamine. The reaction is promoted by nucleophilic bases such as N-butylimidazole. The hydroxyl groups of amino alcohols, such as 5'-hydroxyl group of 2, 3'-O-isopropylidene ribonucleosides, are phosphorylated selectively.

DOI： 10.5059/yukigoseikyokaishi.64.651

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

A diammonium salt of chiral 1,1'-binaphthyl-2,2'-diamine and trifluoromethanesulfonimide (Tf2NH) shows excellent catalytic activity and enantioselectivity for the Diels-Alder reaction of alpha-acyloxyacroleins with cyclic dienes. For example, in the presence of 5 mol % of the ammonium catalyst, the Diels-Alder reaction of alpha-(cyclohexanecarbonyloxy) acrolein with cyclopentadiene proceeded in EtCN at -75 degrees C to give the adducts in 88% yield with 92% exo and 91% ee. This catalyst can be easily prepared in situ by mixing the commercially available chiral diamine and Tf2NH.

DOI： 10.1021/ol060490l

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The interaction between actin and aplyronine A, a potent antitumor and actin-depolymerizing substance of marine origin, was investigated by photoaffinity labeling experiments. Photoaffinity probes consisting of a side-chain portion of aplyronine A as a ligand, a diazirine moiety as a photoaffinity group, and a fluorophore as a detecting group were synthesized. Photolabeling experiments between actin and the probe were carried out. Actin was successfully photolabeled by the fluorescent probe and visualized clearly. The present results provide the first chemical evidence for the direct interaction between actin and the side-chain portion of aplyronine A. © 2006 American Chemical Society.

DOI： 10.1021/bc050324i

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More environmentally benign alternatives to current chemical processes, especially large-scale, fundamental reactions like ester condensations, are highly desirable for many reactions. Bulky diarylammonium pentafluorobenzenesulfonates and tosylates serve as extremely active dehydration catalysts for the ester condensation reaction of carboxylic acids with equimolar amounts of sterically demanding alcohols and acid-sensitive alcohols. Typically, the esterification reaction is performed in heptane by heating at 80°C in the presence of 1 mol% of the catalyst without removing water. Esterification with primary alcohols proceeds without solvents even at room temperature. Furthermore, 4-(N-mesitylamino)polystyrene resin-bound pentafluorobenzenesulfonate can be recycled more than 10 times without a loss of activity. © 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2005.09.059

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

Oxazoline, oxazole, thiazoline, and thiazole rings are important constituents of numerous bioactive natural products and pharmaceuticals. The biosynthesis of many naturally occurring oxazolines and thiazolines appears to involve the dehydrative cyclization of serine, threonine, and cysteine residues. Oxazoles and thiazoles are synthesized by the oxidation of oxazolines and thiazolines, respectively. We describe here a biomimetic synthesis of oxazolines and thiazolines catalyzed by molybdenum (IV or VI) oxides, their mode of cyclization is retentive at the β-position. In the course of screening various metal oxides as catalysts for the dehydrative cyclization of dipeptides 1a and 1b, we found that molybdenum oxides had good catalytic activities. Interestingly, the ammonium salts of molybdenum(VI) oxides, (NH_4)_6Mo_7O_<24>・4H_2O and (NH_4)_2MoO_4, exhibited remarkable catalytic activities and gave oxazolines 2a and 2b in a short reaction time, along with small amounts of 3a and 3b. Next, we examined the dehydrative cyclization of cysteine derivatives 4a and 4b to thiazolines 5a and 5b using molybdenum oxides as catalysts. In the case of the dehydrative cyclization of 4a, (NH_4)_6Mo_7O_<24>・4H_2O, (NH_4)_2MoO_4 and MoO_2(acac)_2 showed excellent catalytic activities. MoO_2(acac)_2 could catalyze the dehydrative cyclization of 4b, to give 5b in 70% yield along with 5c (15%). To the best of our knowledge, this is the first example of the catalytic dehydrative cyclization of dipeptide substrates that include serine, threonine, and cysteine residues. A key synthetic intermediate 11 of hennoxazole A and bis(oxazoline)s 13a and 13b were synthesized by the dehydrative cyclization using molybdenum oxide catalysts. In addition, polyaniline-supported MoO_2(acac)_2 could easily be recovered and reused.

DOI： 10.24496/tennenyuki.47.0_475

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(Chemical Equation Presented) Phosphate monoesters are synthesized from a mixture of phosphoric acid (1 or 2 equiv) and alcohols (1 equiv) in the presence of tributylamine. The reaction is promoted by nucleophilic bases such as N-alkylimidazole and 4-(N,N-dialkylamino)pyridine. 2′,3′-I- Isopropylidene ribonucleosides are selectively converted to their 5′-monophosphates without the protection of amino groups in nucleobases. © 2005 American Chemical Society.

DOI： 10.1021/ol0504796

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(Chemical Equation Presented) In the presence of molybdenum oxide the dehydrative cyclization of N-acylserines, N-acylthreonines, and N-acylcysteines can be carried out under Dean-Stark conditions in toluene to give oxazolines and thiazolines. The ammonium salts (NH4)6Mo 7O24·4H2O and (NH4) 2MoO4 have excellent catalytic activities for the dehydrative cyclization of serine and threonine derivatives, and the acetylacetonate complex MoO2(acac)2 has a remarkable catalytic activity for the dehydrative cyclization of cysteine derivatives. In addition, polyaniline-supported MoO2(acac)2 can easily be recovered and reused. © 2005 American Chemical Society.

DOI： 10.1021/ol050543j

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More environmentally benign alternatives to current chemical processes, especially large-scale, fundamental reactions such as ester condensations, are highly desirable for many reactions. Bulky diarylammonium pentafluorobenzenesulfonates and tosylates serve as extremely active dehydration catalysts for the ester condensation reaction of carboxylic acids with equimolar amounts of sterically demanding alcohols and acid-sensitive alcohols. Typically, the esterification reaction is performed in heptane by heating at 80 °C in the presence of 1 mol % of the catalyst without removing water. Esterification with primary alcohols proceeds without solvents even at room temperature. Furthermore, 4-(N-mesitylamino)polystyrene resin-bound pentafluorobenzenesulfonate can be recycled more than 10 times without activity loss. Copyright © 2005 American Chemical Society.

DOI： 10.1021/ja050223v

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

The construction of strained carbon skeletons by ring-closing olefin metathesis (RCM) was investigated. With well-designed diene 4, RCM was found to be applicable to the formation of a highly strained inside-outside bicyclo[4.4.1]undecane skeleton of ingenol, a bioactive diterpenoid, and formal total synthesis of optically active ingenol (1) was achieved. The key features of this synthesis are construction of an A-ring by spirocyclization of the ketone with an allylic chloride unit, 26, and ring closure of a B-ring by olefin metathesis. Starting from Funk's keto ester 6, the key intermediate aldehyde 9 in Winkler's total synthesis was synthesized in eight steps in 12.5% overall yield. This strategy of direct cyclization of a strained inside-outside skeleton provided the first easy access to optically active ingenol.

DOI： 10.1021/jo048833l

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A novel cysteine derivative, spongiacysteine (1), was isolated from marine sponge Spongia sp. The gross structure was elucidated by detailed spectroscopic analysis, and the absolute stereostructure was established by its total synthesis. This compound showed moderate antimicrobial activity against rice blast fungus Pyricularia oryzae.

DOI： 10.1246/cl.2004.1262

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

Ingenol is a diterpenoid isolated from Euphorbia ingens, possessing a bicyclo[4.4.1]undecane skeleton with a highly strained inside, outside-intrabridgehead stereochemistry. Several strategies for construction of the unique skeleton have been reported, however, direct cyclization to the inside, ousidet-bicyclo[4.4.1]undecane system has not been reported. Recently, two total syntheses in a racemic form using the aforementioned strategies were reported by Winkler and Tanino-Kuwajima. We would like to report the construction of strained carbon skeletons of ingenol by direct cyclization with ring-closing olefin metathesis (RCM). With well-designed diene compounds 4, 23, and 24, RCM was found to be applicable to the formation of a highly strained skeleton of ingenol, and formal total synthesis of optically active ingenol (1) was achieved. The key features of this synthesis are construction of an A-ring by spirocyclization of ketone 21 with an allylic chloride unit and ring closure of a B-ring by olefin metathesis. Starting from Funk's keto ester 17, the key intermediate aldehyde 27 in Winkler's total synthesis was synthesized in eight steps in 12.5% overall yield. This strategy of direct cyclization of a strained inside-outside skeleton provided the first easy access to optically active ingenol.

DOI： 10.24496/tennenyuki.46.0_569

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Aplyronine A (1) is a potent antitumor macrolide isolated from the sea hare Aplysia kurodai, and mycalolide B (2) is a cytotoxic and antifungal macrolide isolated from a sponge of the genus Mycale. These macrolides interact with actin, one of the major proteins in cytoskeleton. We achieved total synthesis of aplyronine A (1) and its analogs and investigated the structure-activity relationships. We improved the synthesis of the side chain portion of aplyronine A (1) by using the Paterson aldol reaction and subsequent stereoselective reduction with Me_4NBH(OAc)_3 as key steps. The synthetic analogs 3 and 4 that only consists of the side chain part of aplyronine A (1) and mycalolide B (2) turned out to exhibit a strong actin depolymerizing activity, considering the size of the molecule. This result revealed that the side chain portion in aplyronine A (1) and mycalolide B (2) was responsible for the potent activity of 1 and 2. Analysis of the interaction of aplyronine analogs, such as 30 and 31, with actin by a photoaffinity labeling method has been carried out. Crystallization and X-ray structure analysis of actin complex with aplyronine A (1) also are in progress.

DOI： 10.24496/tennenyuki.46.0_323

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

To obtain information on the chemical modification of biomolecules with jolkinolide D, a bioactive diterpenoid of plant origin, jolkinolide D pharmacophore was synthesized, and its reactivity toward amino acids, nucleosides, and DNA was investigated. © 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2003.08.080

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Mycalolide analog 4, consisting only of the side chain of mycalolide B (2), was stereoselectively synthesized and was found to have strong actin-depolymerizing activity. © 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2004.05.078

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The all-or-none type DNA folding transition from a coil to globule can be differentiated by the chirality of the triamines. The fluorescent microscope observation on single DNA molecules makes it clear that the tripeptides obtained from naturally occurring basic amino acids (L-lysine or L-arginine) can compact DNA molecules at concentrations lower than those from D-isomers. Nanometer-sized beads are found in the AFM images on the folded DNA molecule. Copyright © 2003 American Chemical Society.

DOI： 10.1021/ja036745x

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Jolkinolide D (1) is a diterpenoid isolated from Euphorbia jolkini Boiss in 1974, and its stereostructure was recently determined by X-ray crystallographic analysis. It inhibited tumor invasion into the basement membrane and induced apoptosis in tumor cells. Jolkinolide D (1) has a γ,δ-unsaturated-β-hydroxy-α-methylene lactone unit as the pharmacophore structure, which suggests that jolkinolide D (1) might alkylate biomolecules such as proteins and DNA irreversibly. Since there are no other compounds that have the pharmacophore, reactivities of the unit toward nucleophiles have not hitherto been investigated. For the purpose of obtaining preliminary information on the chemical modification of biomolecules with jolkinolide D (1), jolkinolide D pharmacophore (2) was synthesized from 6-(tert-butyldimethylsilyloxy)-3-methyl-2-cyclohexenone (3) and 2-iodoallylalcohol (4), and its reactivity toward amino acids, nucleosides, and DNA was investigated. It was found that the order of reactivity of jolkinolide D pharmacophore (2) toward the nucleophiles in the amino acids at pH 7.5 is the thiol group in L-cysteine and glutathione > the imidazolyl group in L-histidine, the α-amino groups in amino acids > the carboxyl groups in amino acids. Jolkinolide D pharmacophore (2) alkylated 2'-deoxyguanosine at the N-1 position (pH 7.5) and thymidine at the N-3 position (pH 8.7), and modified DNA at the same sites in lower yields.

DOI： 10.24496/tennenyuki.44.0_623

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For the purpose of obtaining preliminary information on the chemical modification of biomolecules with jolkinolide D, a bioactive diterpenoid of plant origin, jolkinolide D pharmacophore, was synthesized and its reactivity toward amino acids, nucleosides, and DNA was investigated. © 2002 Published by Elsevier Science Ltd.

DOI： 10.1016/S0040-4039(02)01195-4

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It is demonstrated that the reaction of a nucleoside phosphoramidite and a nucleoside aided by a suitable promoter in the presence of molecular sieves 3A or 4A in a liquid phase is efficiently performed by the use of stoichiometric amounts of the reactants to give the desired coupling product in an excellent yield. © 2001 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4020(01)00880-8

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Language：English   Publishing type：Research paper (scientific journal)  

It is demonstrated that not only N2- but also O 6-protection of the guanine base is necessary for obtaining the oligodeoxyribonucleotides in high yields and at a high purity in the solid-phase synthesis via the (5′ → 3′)-chain elongated phosphoramidite approach.

DOI： 10.1081/NCN-100002082

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PubMed

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Language：English   Publishing type：Research paper (scientific journal)  

The utility of various kinds of acid salts of azole derivatives as promoters for the condensation of a nucleoside phosphoramidite and a nucleoside is investigated. Among the salts, N-(phenyl)imidazolium triflate, N-(p-acetylphenyl)imidazolium triflate, N-(methyl)benzimidazolium triflate, benzimidazolium triflate, and N-(phenyl)imidazolium perchlorate have shown extremely high reactivity in a liquid phase. These reagents serve as powerful activators of deoxyribonucleoside 3′-(allyl N,N-diisopropylphosphoramidite)s or 3′-(2-cyanoethyl N,N-diisopropylphosphoramidite)s employed in the preparation of deoxyribonucleotides, and 3′-O-(tert-butyldimethylsilyl)ribonucleoside 2′-(N,N-diisopropylphosphoramidite)s or 2′-O-(tert-butyldimethylsilyl)-ribonucleoside 3′-(N,N-diisopropylphosphoramidite)s used for the formation of 2′-5′ and 3′-5′ internucleotide linkages between ribonucleosides, respectively. The azolium salt has allowed smooth and high-yield condensation of the nucleoside phosphoramidite and a 5′-O-free nucleoside, in which equimolar amounts of the reactants and the promoter are employed in the presence of powdery molecular sieves 3A in acetonitrile. It has been shown that some azolium salts serve as excellent promoters in the solid-phase synthesis of oligodeoxyribonucleotides and oligoribonucleotides. For example, benzimidazolium triflate and N-(phenyl)imidazolium triflate can be used as effective promoters in the synthesis of an oligodeoxyribonucleotide, 5′CGACACCCAATTCTGAAAAT3′ (20mer), via a method using O-allyl/N-allyloxycarbonyl-protected deoxyribonucleoside 3′-phosphoramidites or O-(2-cyanoethyl)/N-phenoxyacetyl-protected deoxyribonucleotide 3′-phosphoramidite as building blocks, respectively, on high-cross-linked polystyrene resins. Further, N-(phenyl)imidazolium triflate is useful for the solid-phase synthesis of oligoribonucleotides, such as 5′AGCUACGUGACUACUACUUU3′ (20mer), according to an allyl/allyloxycarbonyl-protected strategy. The utility of the azolium promoter has been also demonstrated in the liquid-phase synthesis of some biologically important substances, such as cytidine-5′-monophosphono-N-acetylneuraminic acid (CMP-Neu5Ac) and adenylyl(2′-5′)adenylyl(2′-5′)adenosine (2-5A core).

DOI： 10.1021/ja010078v

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PubMed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ltd  

An efficient synthesis of base-labile nucleotide-peptide conjugates has been accomplished, in which the two components are directly linked between the terminal hydroxyl of a nucleotide and the hydroxyl of a serine or threonine residue of a peptide by a phosphodiester bond. This synthesis utilizes the phosphoramidite method with allyl for the phosphate linkages and the C-terminal of the peptide and allyloxycarbonyl for the nucleoside bases and the N-terminal of the peptide. In this synthesis, the removal of the allylic protecting groups and the detachment of the products was achieved under non-basic or mild basic conditions to bring about no conspicuous decomposition of the labile phosphate linker, and thus the target conjugates were obtained at a high purity and in high yields. (C) 2000 Elsevier Science Ltd.

DOI： 10.1016/S0040-4020(00)00376-8

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Language：English   Publishing type：Research paper (scientific journal)  

A new method for synthesis of 3'-end-phosphorylated DNA oligomers via the phosphoramidite method with allyl protection has been developed. This method is particularly useful for the preparation of derivatives with base- labile structures such as oligoDNA-OPO(OH)OCH2CH(R)Z, in which Z is an electron-withdrawing function. For example, a oligonucleotide-amino acid conjugate, 5'TGTCGACACCCAATT3'-OPO(OH)OCH2CH(NH2)COOH, and a oligonucleotide-peptide conjugate, 5'TGTCGACACCCAATT3'- OPO(OH)OCH2CH(NH2)CONHCH2COOH, have been obtained in high purity.

DOI： 10.1016/S0040-4039(99)00748-0

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Language：English   Publishing type：Research paper (scientific journal)  

The enantioselective total synthesis of aplyronine A (1), a potent antitumor substance of marine origin, was achieved by a convergent approach. Three segments 4, 5, and 6, corresponding to the C5-C11, C21-C27, and C28-C34 portions of aplyronine A (1), were prepared using the Evans aldol reaction and the Sharpless epoxidation as key steps. The coupling reaction of 4 with iodide 7 followed by Julia olefination with sulfone 8 gave the C5-C20 segment 9, while the Julia coupling reaction between segments 5 and 6 provided the C21-C34 segment 10. Julia olefination between segments 9 and 10 and the subsequent four-carbon homologation reaction led to seco acid 83, which was converted into aplyronine A (1) by Yamaguchi lactonization followed by the introduction of two amino acids. The use of the [(3,4-dimethoxybenzyl)oxy]methyl group as a protecting group for the hydroxyl at C29 was crucial for this synthesis. The enantioselective synthesis of two natural congeners, aplyronines B (2) and C (3), was also carried out using the intermediates for the synthesis of 1, which determined the absolute stereostructures of 2 and 3 unambiguously. To study the structure-cytotoxicity relationships of aplyronines, artificial analogues of 1 were synthesized and their cytotoxicities were evaluated: the trimethylserine moiety, two hydroxyl groups, and the side chain portion in 1 turned out to be important in the potent cytotoxicity shown by 1. Biological studies with aplyronine A (1) showed that 1 inhibited polymerization of G-actin to F-actin and depolymerized F-actin to G-actin.

DOI： 10.1021/jo9606113

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Language：English   Publishing type：Research paper (scientific journal)  

Synthesis of aplyronines B and C, the congeners of aplyronine A, was achieved enantioselectively, which established their stereostructures. © 1995.

DOI： 10.1016/0040-4039(95)00921-X

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Language：English  

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Language：English   Publishing type：Research paper (scientific journal)  

The C21-C34 segment 2 of aplyronine A (1), a potent antitumor substance of marine origin, was synthesized enantioselectively in 25 steps (17% overall yield) from imide 11. © 1994.

DOI： 10.1016/0040-4039(94)88035-2

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

Aplyronine A (1) is a potent antitumor macrolide isolated as a minute component from the sea hare Aplysia kurodai. The gross structure of 1 was determined by the spectral analysis and chemical degradation. We report herein the absolute stereostructure of 1 and the result of the synthetic study. Chemical degradation of 1 afforded five fragments 2-6. Enantioselective syntheses of the fragments 4a and 5a were performed to disclose the absolute stereochemistry of seven chiral centers (C7-C10, C13, C17, and C19). HPLC analyses of the fragments 2 and 3 using chiral columns disclosed that N,N,O-trimethylserine and N,N-dimethylalanine moieties of 1 were scalemic mixtures (S:R=52:48 for 2; 72:28 for 3). On the basis of the result of the previous and present studies, the absolute stereostructure of aplyronine A (1) was elucidated unambiguously. The synthetic study of 1 was carried out using the Evans aldol reaction and the Sharpless epoxidation reaction as key steps. Starting from N-propionylurethane 11, the C5-C20 segment 13 and the C21-C34 segment 16 were synthesized. The Julia coupling reaction of 13 with 16 followed by four-carbons homologation and lactonization provided 24-membered lactone 17.

DOI： 10.24496/tennenyuki.35.0_174

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Language：English   Publisher：ACAD SCI CZECH REPUBLIC, INST ORGANIC CHEM & BIOCHEMISTRY  

Utility of benzimidazolium triflate as a promoter in the solid-phase synthesis of oligodeoxyribonucleotides and their amino acid conjugates via the phosphoramidite method with allyl protection has been demonstrated.

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Event date： 2018.9.26 - 2018.9.28

Presentation type：Poster presentation  

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Country：Japan

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