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

Maitotoxin (MTX) is a ladder-​shaped polyether produced by the epiphytic dinoflagellate Gambierdiscus toxicus. It is known to elicit potent toxicity against mammals and induce influx of Ca2+ into cells. An artificial ladder-​shaped polyether possessing a 6​/7​/6​/6​/7​/6​/6 heptacyclic ring system, which was designed for elucidating interactions with transmembrane proteins, was found to be the most potent inhibitor against MTX-​induced Ca2+ influx that has ever been reported.

DOI： 10.1016/j.bmcl.2012.04.053

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

Language：Japanese   Publisher：The Society of Synthetic Organic Chemistry, Japan  

DOI： 10.5059/yukigoseikyokaishi.82.953

CiNii Research

Publisher：Chemistry Letters  

The unified synthesis of the NOPQ and STUV rings of brevisulcenal-F was achieved from a common intermediate based on a convergent strategy via 2-ring construction. The STUV ring was synthesized via radical reduction of an O,S-acetal, and the NOPQ ring was constructed via ring expansion giving a 7-membered ring ketone, methylation of an O,S-acetal, and introduction of the cis-1,2-diol moiety at C60–C61.

DOI： 10.1093/chemle/upae179

Web of Science

Scopus

Publisher：Tetrahedron Letters  

A scalable method for synthesizing the L/N ring of maitotoxin corresponding to an unnatural L-glucose derivative was developed via the MacMillan method and C-glycosylation under flow conditions. The longest linear sequence from Z-2-buten-1,4-diol was 7 steps with 10 total steps.

DOI： 10.1016/j.tetlet.2024.155221

Web of Science

Scopus

Language：English   Publisher：Organic Letters  

The MN ring of Caribbean ciguatoxin C-CTX-1 was synthesized from a meso-syn-2,7-dimethyloxepane derivative corresponding to the M ring via desymmetrization by acetal formation with a camphor derivative, followed by construction of the N ring via the Horner-Wadsworth-Emmons reaction and acetal formation. The meso-syn-2,7-dimethyloxepane derivative was synthesized via photoinduced electrocyclization of a conjugated exo-diene under flow conditions, giving a cyclobutene derivative, followed by ring expansion via oxidative cleavage and diastereoselective reduction of a β-hydroxy ketone.

DOI： 10.1021/acs.orglett.3c04013

Web of Science

Scopus

PubMed

Language：English   Publisher：Bioorganic and Medicinal Chemistry Letters  

Here we examined the membrane binding and pore formation of amphidinol 3 (AM3) and its truncated synthetic derivatives. Importantly, both of the membrane affinity and pore formation activity were well correlated with the reported antifungal activity. Our data clearly demonstrated that the C1-C30 moiety of AM3 plays essential roles both in sterol recognition and stable pore formation. Based on the current findings, we updated the interacting model between AM3 and sterol, in which the moiety encompassing from C21 to C67 accommodates a sterol molecule with forming hydrogen bonds with the sterol hydroxy group and van der Waals contact between AM3 polyol and sterol skeleton. Although the conformation of the C1-C20 moiety of AM3 is hard to specify due to its flexibility, the region likely contributes to stabilization of pore structure.

DOI： 10.1016/j.bmcl.2023.129594

Web of Science

Scopus

PubMed

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

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

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

Language：Japanese   Publisher：The Society of Synthetic Organic Chemistry, Japan  

<p>Maitotoxin (MTX) is a ladder-shaped polyether produced by the dinoflagellate <i>Gambierdiscus toxicus</i>. MTX comprises of 32 cyclic ethers and 98 stereogenic centers with the molecular weight of 3422. The molecule can be divided in two parts, hydrophobic (northern hemisphere) and hydrophilic (southern hemisphere) regions. MTX elicits potent acute toxicity and Ca²⁺ influx activity. The unique giant structure and potent biological activity of MTX has attracted great deal of interest among synthetic chemists. During the course of our structure-activity relationship studies based on chemical synthesis of partial structure of MTX, we synthesized the C'D'E'F' and WXYZA'B'C' ring systems corresponding to partial structures of the hydrophobic region of MTX, and found that they inhibited MTX-induced Ca²⁺ influx with IC₅₀ values of 59µM and 30µM, respectively. With the expectation that a more extended partial structure would inhibit MTX-induced Ca²⁺ influx in a more potent manner, the WXYZA'B'C'D'E'F' ring corresponding to the hydrophobic region was synthesized. We have developed a convergent method for synthesizing ladder-shaped polyethers via α-cyano ethers, therefore we planned to synthesize the WXYZA'B'C'D'E'F' ring from the WXYZ ring and the C'D'E'F' ring systems via construction of the A'B' ring system. The C'D'E'F' ring was synthesized from the E' ring via successive construction of the D' and C' rings by using SmI₂ induced reductive cyclization, and Suzuki-Miyaura coupling to introduce a side chain, and Pd catalyzed cyclization to construct the F' ring. The WXYZ ring was synthesized from the W and Z rings via aldehyde-alkyne coupling, cyclodehydration, ring-expansion of a six-membered ring ketone to a seven-membered one, and methylation of an <i>O</i>, <i>S</i>-acetal. The WXYZ ring aldehyde and the C'D'E'F' ring diol was combined by acetal formation, and regioselective opening of the resulting seven-membered ring acetal afforded an α-cyano ether. Reduction of the nitrile followed by Grignard reaction afforded a diene, which was subjected to ring closing metathesis to furnish eight-membered cyclic ether. Oxidation of the secondary alcohol followed by base induced epimerization afforded an enone corresponding to the B' ring. Although reductive etherification of a methyl acetal to construct the A' ring was unsuccessful giving an undesired diastereomer at C117, that via radial reduction of an <i>O</i>, <i>S</i>-acetal resulted in the formation of the desired one. Introduction of the terminal olefin via Wittig reaction afforded the WXYZA'B'C'D'E'F' ring in 16 steps. The molecular weight of the synthesized compound is 1140, and the longest linear sequence from commercially available starting material is 53 steps with 104 total steps. Although a number of synthetic studies on partial structure of MTX have been reported, this is the first example of the synthesis of the WXYZA'B'C'D'E'F' ring segment of MTX. The NMR data for the synthetic compound are in good accordance with those for the natural product except for the W ring terminus due to the structure difference from MTX. Contrary to our expectation, the WXYZA'B'C'D'E'F' ring segment did not inhibit MTX-induced Ca²⁺ influx, presumably due to its poor solubility in aqueous media. These results provide potential clues to understanding the mode of action of MTX, and will aid in the design of biologically active molecules based on the partial structure of the natural product.</p>

DOI： 10.5059/yukigoseikyokaishi.81.35

Scopus

CiNii Research

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

Web of Science

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Science Advances  

Amphotericin B, an antifungal drug with a long history of use, forms fungicidal ion-permeable channels across cell membranes. Using solid-state nuclear magnetic resonance spectroscopy and molecular dynamics simulations, we experimentally elucidated the three-dimensional structure of the molecular assemblies formed by this drug in membranes in the presence of the fungal sterol ergosterol. A stable assembly consisting of seven drug molecules was observed to form an ion conductive channel. The structure is somewhat similar to the upper half of the barrel-stave model proposed in the 1970s but substantially different in the number of molecules and in their arrangement. The present structure explains many previous findings, including structure-activity relationships of the drug, which will be useful for improving drug efficacy and reducing adverse effects.

DOI： 10.1126/sciadv.abo2658

Web of Science

Scopus

PubMed

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

DOI： 10.3987/com-21-14545

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

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

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

DOI： doi.org/10.1246/bcsj.20200151

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

DOI： doi.org/10.1002/ajoc.202000264

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

Amphidinol 3 (AM3) is a potent antifungal produced by the dinoflagellate Amphidinium klebsii. It was difficult to determine the absolute configuration of AM3 by using the scarce natural product due to the presence of numerous stereogenic centers on the acyclic carbon chain. Since the absolute configuration was partially determined on the basis of insufficient evidence, the originally proposed structure has been revised three times. Although recent progress on structure determination by computational analysis is remarkable, total synthesis is still the most reliable way to confirm structures. The first total synthesis of AM3 was achieved via expeditious assembly of three components in five steps, confirming the revised structure of AM3 after more than 20 years since its first discovery. The established synthetic route would be a general strategy for synthesizing amphidinol congeners. An artificial and simplified analogue of AM3, which elicited antifungal activity comparable to that of AM3, was designed and synthesized. This is the first example of a biologically active artificial analogue possessing a shorter polyol moiety, providing insight on the antifungal mode-of-action.

DOI： 10.1021/jacs.9b11789

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

Chemotaxis of sperm toward an egg is a critical step in reproduction, particularly in aquatic environments, where sperm frequently travel long distances to contact an egg. Chemoattractants called sperm activating and attracting factors (SAAFs) were isolated from eggs of the ascidians Ciona intestinalis and Ascidia sydneiensis, and the structures of SAAFs were determined to be novel polyhydroxysterol sulfates, Ciinte-SAAF and Assydn-SAAF, respectively. However, the absolute configuration at C25 of the side chain remained unknown. For the complete structure elucidation of SAAFs, their two possible diastereomers with respect to C25 were synthesized. Ciinte-SAAF was synthesized starting from chenodeoxychoric acid. The steroid backbone was constructed via reductive 1,3-transposition of an allylic alcohol and the axial opening of an epoxide as key steps, and the side chain was introduced by Wittig olefination. Assydn-SAAF was synthesized starting from ergosterol. The steroid backbone was constructed by using an intramolecular pinacol coupling reaction and stereoselective reduction of a hydroxyketone as key steps, and the side chain was introduced by Julia-Kocienski olefination. Comparison of the NMR data of the synthetic specimens with those of the natural products, Ciinte-SAAF and Assydn-SAAF, led to the elucidation of the both absolute configurations at C25 as S. Thus, the complete structures were determined and the first syntheses of Ciinte-SAAF and Assydn-SAAF were achieved. Furthermore, structure-activity relationship studies of Ciinte-SAAF was carried out by using synthetic analog molecules, and molecular probes were prepared for elucidating the mode-of-action.

DOI： 10.5059/yukigoseikyokaishi.78.213

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

Addition of reactants under an inert atmosphere is a fundamental but extremely important technique in synthetic chemistry. Although this is achievable in many cases by using a glove box or a Schlenk-and-syringe technique, the direct addition of powder (solid) materials without contamination by air or moisture has been difficult, especially in the later stages of a reaction. Here, we offer a simple and small apparatus to realize powder addition with easy handling. Use of this apparatus permitted one-pot glycosylation reactions that required extremely dry conditions to be performed in a highly reproducible manner.

DOI： 10.1055/s-0039-1690689

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

Unified synthesis of 6/6/6-tricyclic ethers corresponding to the DEF and GHI ring systems of maitotoxin was achieved from a common intermediate prepared from a furan derivative and a terminal olefin via FujiwaraMoritani reaction, followed by Sharpless asymmetric dihydroxylation, and Achmatowicz reaction. The DEF ring was synthesized from the common intermediate via regio- and stereoselective borylation of an enone, and methylation of an S, O-acetal. On the other hand, the GHI ring was synthesized from the common intermediate via reductive etherification, Sharpless asymmetric dihydroxylation, and BartonMcCombie deoxygenation.

DOI： 10.1246/cl.190479

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

Ladder-shaped polyethers (LSPs) are marine natural products produced by dinoflagellates. The unique molecular structure and interesting biological activities have attracted considerable attention of the synthetic community. On the other hand, artificial ladder-shaped polyethers (ALPs) have been designed and synthesized for exploring biological functions. In this review, design and synthesis of ALPs are summarized focusing on the development of synthetic strategies and methodologies.

DOI： 10.3987/REV-18-SR(F)1

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

The use of 2-O-alkoxymethyl groups as effective stereodirecting substituents for the construction of 1,2-trans glycosidic linkages is reported. The observed stereoselectivity arises from the intramolecular formation of a five-membered cyclic architecture between the 2-O-alkoxymethyl substituent and the oxocarbenium ion, which provides the expected facial selectivity. Furthermore, the observed stereocontrol and the extremely high reactivity of 2-O-alkoxymethyl-protected donors allowed development of a one-pot sequential glycosylation strategy that should become a powerful tool for the assembly of oligosaccharides.

DOI： 10.1021/acs.orglett.9b00220

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

The first synthesis of anti-tubercular marine alkaloids denigrins A and B were accomplished in three and five steps and 62% and 31% overall yields respectively, from maleic anhydride. The key features of the synthesis include efficient Mizoroki-Heck reaction, geometry-controlled vinylogous aldol condensation, and one-pot lactamization. The synthesis first demonstrates the serviceability of maleic anhydride in palladium-catalyzed cross-coupling reactions with diaryliodonium salt.

DOI： 10.1016/j.tetlet.2018.06.013

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

Amphidinol 3 (AM3) is a marine natural product produced by the dinoflagellate Amphidinium klebsii. Although the absolute configuration of AM3 was determined in 1999 by extensive NMR analysis and degradation of the natural product, it was a daunting task because of the presence of numerous stereogenic centers on the acyclic carbon chain and the limited availability from natural sources. Thereafter, revisions of the absolute configurations at C2 and C51 were reported in 2008 and 2013, respectively. Reported herein is the revised absolute configuration of AM3: 32S, 33R, 34S, 35S, 36S, and 38S based on the chemical synthesis of partial structures corresponding to the C31–C67 fragment of AM3 in combination with degradation of the natural product. The revised structure is unique in that both antipodal tetrahydropyran counterparts exist on a single carbon chain. The structural revision of AM3 may affect proposed structures of congeners related to the amphidinols.

DOI： 10.1002/anie.201712167

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

For the complete structure elucidation of an endogenous sperm-activating and -attracting factor isolated from eggs of the ascidian Ascidia sydneiensis (Assydn-SAAF), its two possible diastereomers with respect to C-25 were synthesized. Starting from ergosterol, the characteristic steroid backbone was constructed by using an intramolecular pinacol coupling reaction and stereoselective reduction of a hydroxy ketone as key steps, and the side chain was introduced by Julia-Kocienski olefination. Comparison of the NMR data of the two diastereomers with those of the natural product led to the elucidation of the absolute configuration as 25S; thus the complete structure was determined and the first synthesis of Assydn-SAAF was achieved.

DOI： 10.1021/acs.jnatprod.7b01052

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

Over 40 years have passed since a well-known hypothesis of a channel-like amphotericin B (AmB) assembly with ergosterol (Erg) was proposed as the mode of action accounting for its selective fungal toxicity. However, no reliable or direct experimental evidence had been obtained until recently mainly because of significant difficulties in structural analysis of the self-assembly of small molecules specifically formed inside a membrane. In this study, we describe the accomplishments in the chemical synthesis of two AmB derivatives with fluorine labeling in the molecular skeleton for applying solid-state NMR techniques. The interatomic distance measurements using these chemically prepared probes have successfully shown the detailed AmB-Erg bimolecular interaction in the channel structure for the first time. The latest solid-state NMR analysis backed by synthetic chemistry is expected to achieve a breakthrough in elucidating the long-unsolved AmB channel architecture.

DOI： 10.5059/yukigoseikyokaishi.76.1197

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

An artificial analog corresponding to the C31-C67 section of amphidinol 3 (AM3) was designed as a part of the structure-activity relationship studies to elucidate structure requirements for eliciting antifungal activity. To reduce the number of synthetic steps, the 43-deoxy-51-epi derivative containing common tetrahydropyran ring system was designed and synthesized from a pivotal intermediate in 17 steps. The analog elicited no antifungal activity, suggesting that not only the two tetrahydropyran rings, but also polyol section of AM3 are necessary to elicit antifungal activity.

DOI： 10.3987/COM-18-13927

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

Synthesis of 6/6/6-tricyclic ethers possessing 1,3-diaxial methyl groups was examined via Achmatowicz reaction and intramolecular oxa-Michael reaction. A key precursor was prepared via coupling of an aldehyde with a furyllithium derivative followed by radical deoxygenation of the resulting secondary alcohol. The intramolecular oxa-Michael reaction proceeded in a stereoselective manner to afford cis-fused product as a single isomer.

DOI： 10.3987/COM-17-S(T)10

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

A concise procedure to prepare optically active (3R)- and (3S)-(E)-1-iodohexa-1,5-dien-3-ol was developed. Ethyl (E)-3-iodoacrylate was converted to racemic (E)-1-iodohexa-1,5-dien-3-ol under flow and batch conditions via successive half reduction followed by Grignard reaction. Kinetic resolution of the racemic alcohol was achieved under flow conditions by using lipase packed in a column to afford (3S)-(E)-1-iodohexa-1,5-dien-3-ol and corresponding (3R)-acetate. Removal of the acetyl group was also carried out under flow conditions by using ion exchange resin packed in a column and (3R)-(E)-1-iodohexa-1,5-dien-3-ol was obtained after simple evaporation of the eluent.

DOI： 10.1246/cl.180475

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

A convergent method to construct the 6/7/6/6-tetracyclic ether system possessing contiguous angular methyl groups was developed. The key steps of the synthesis involve coupling of a lithium acetylide and an aldehyde, cyclodehydration of a hydroxy ketone to form a dihydropyran, ring expansion of a six-membered ring ketone into a seven-membered one, and methylation of a mixed-thioacetal. Based on this strategy, syntheses of the WXYZ ring of maitotoxin and the HIJK ring of brevisulcenal-F were achieved, and the stereochemistry of the HIJK ring of brevisulcenal-F was confirmed.

DOI： 10.1246/cl.171056

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

1-Naphthylmethyl (NAP^I) and 1-naphthylmethoxymethyl (NAPOM^I) protecting groups were developed as new members of the benzyl- and benzyloxymethyl-type family. NAP^I and NAPOM^I can be introduced under conventional conditions, such as NAP^IBr/NaH/room temperature (rt), or NAPOM^ICl/i-Pr₂EtN/rt. They can also be removed under conventional conditions, e.g., by dichlorodicyanobenzoquinone (DDQ)- or ceric ammonium nitrate (CAN)-mediated oxidation, or by hydrogenolysis. The specific advantages of these new protecting groups are: i) a less costly synthesis of NAPOM^ICl compared to NAPOM^IICl, ii) the possibility to remove NAPOM^II selectively in the presence of NAPOM^I by DDQ-mediated oxidation, and iii) the compatibility with strong acids even in the presence of hard nucleophiles.

DOI： 10.1016/j.tetlet.2017.04.046

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

As a part of structureactivity relationship studies to elucidate structure requirements for eliciting antifungal activity, an artificial analog of amphidinol 3 (AM3) was designed. A truncated analog corresponding to the C21C39/C52C67 section was synthesized by using SuzukiMiyaura coupling and JuliaKocienski olefination as key steps. An expeditious and versatile method to construct the C53C67 polyene section was also developed based on a linchpin strategy via successive cross-coupling reactions. The analog elicited no antifungal activity, suggesting that the two tetrahydropyran rings of AM3 are necessary to elicit antifungal activity.

DOI： 10.1246/cl.170050

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

Structure-activity relationship studies of maitotoxin (MTX), a marine natural product produced by an epiphytic dinoflagellate, were conducted using chemically synthesized model compounds corresponding to the partial structures of MTX. Both enantiomers of the LMNO ring system were synthesized via aldol reaction of the LM ring aldehyde and the NO ring ketone. These fragments were derived from a common cis-fused pyranopyran intermediate prepared through a sequence involving Nozaki-Hiyama-Kishi reaction, intramolecular oxa-Michael addition, and Pummerer rearrangement. The NOPQR(S) ring system, in which the original seven-membered S ring was substituted with a six-membered ring, was also synthesized through the coupling of the QR(S) ring alkyne and the NO ring aldehyde and the construction of the P ring via 1,4-reduction, dehydration, and hydroboration. The inhibitory activities of the synthetic specimens against MTX-induced Ca²⁺ influx were evaluated. The LMNO ring system and its enantiomer induced 36 and 18% inhibition, respectively, at 300 μM, whereas the NOPQR(S) ring system elicited no inhibitory activity.

DOI： 10.1021/acs.joc.7b01658

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

Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti-estrogenic agents. Derivatives with a hydroxy group at the molecular edge exhibit potent binding affinity to the estrogen receptor α (ERα) and ERβ (IC₅₀ < μM), while binding to the estrogen-related receptor γ (ERRγ), i.e., an orphan nuclear receptor on which estrogens often trigger unfavorable events, was not observed. These findings offer valuable insights into 12-arylbenzoacridines as a novel platform for the development of selective estrogen-receptor modulators (SERMs).

DOI： 10.1016/j.bmc.2017.07.067

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

Amphotericin B (AmB) is a polyene macrolide antibiotic isolated from Streptomyces nodosus. The antifungal activity of AmB can be attributed to the formation of an ion-channel assembly in the presence of ergosterol (Erg), in which there are two different AmB-Erg orientations, parallel and antiparallel, as reported previously. In this study, to elucidate the structures of those AmB-Erg complexes based on solid-state nuclear magnetic resonance, a ¹⁹F-labeled AmB derivative was newly prepared by a hybrid synthesis that utilized degradation products from the drug. Using the 2-(trimethylsilyl)ethoxymethyl (SEM) group as the protecting group for the carboxylic acid moiety of AmB, the fully deprotected labeled AmB compounds were obtained successfully. Then, these labeled AmBs were subjected to ¹³C{¹⁹F} rotational-echo double-resonance (REDOR) experiments in hydrated lipid bilayers. The results indicated the coexistence of parallel and antiparallel orientations for AmB and Erg pairing, at a ratio of 7:3. A total of six distances between AmB and Erg were successfully obtained. Geometry analysis using the distance constraints derived from the REDOR experiments provided the plausible AmB-Erg complex structure for both the parallel and antiparallel interactions. The flat macrolide of AmB and the tetracyclic core of Erg closely contacted in a face-to-face manner, thus maximizing the van der Waals interaction between the two molecules. This interaction can be attributed to the coexistence of both the parallel and antiparallel orientations.

DOI： 10.1021/acs.biochem.6b00193

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

The diversity-​oriented doubling strategy, which generates two 12-​arylbenzoacridines from a single triarylmethanol precursor was developed to construct a library of drug candidates for the identification of biol. active compds. Exploration of this 12-​arylbenzoacridine library furnished a 4'-​OH deriv. as an estrogenic compd.

DOI： 10.1055/s-0035-1560521

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

The diversity-oriented doubling strategy, which generates two 12-arylbenzoacridines from a single triarylmethanol precursor was developed to construct a library of drug candidates for the identification of biologically active compounds. Exploration of this 12-arylbenzoacridine library furnished a 4′-OH derivative as an estrogenic compound.

DOI： 10.1055/s-0035-1560521

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

The 2-​naphthylmethoxymethyl (NAPOM) group was developed as a protecting group for alcs., phenols, carboxylic acids, and thiols. The NAPOM group can be introduced in extremely mild conditions using 2-​naphthylmethoxymethyl chloride either with diisopropylethylamine as a base or with 2,​6-​lutidine as a base in the presence of tetrabutylammonium iodide at room temp.; under the latter conditions, a monoacetylated diol was protected with minimal concomitant acyl migration. Selective removal of the NAPOM protecting group in the presence of 2-​naphthylmethyl and p-​methoxybenzyl (PMB) groups and, conversely, selective removal of a PMB group in the presence of a NAPOM group were realized. The solvent compatibility of the installation and removal of the NAPOM group was studied; most solvents were compatible with its installation, while deprotections in THF and DMF gave product in reduced yields.

DOI： 10.1021/acs.orglett.5b01408

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

The interaction of amphotericin B (AmB) with fungal ergosterol (Erg) is stronger than its interaction with mammalian cholesterol (Cho), and this property of AmB as an antifungal drug is thought to be responsible for its selective toxicity toward fungi. However, the mechanism by which AmB recognizes the structural differences between sterols, particularly minor difference in the sterol alicyclic portion, is largely unknown. Thus, to investigate the mode of interaction between AmB and the sterol core, we assessed the affinity of AmB to various sterols with different alicyclic structures. Ion flux assays and UV spectral measurements clearly revealed the importance of the Δ7-double bond of the sterol B-ring for interaction with the drug. AmB showed lower affinity for triene sterols, which have double bonds at the Δ5, Δ7, and Δ9 positions. Intermolecular distance measurements by 13C{19F} rotational echo double resonance (REDOR) revealed that the AmB macrolide ring is in closer contact with the steroid core of Erg than it is with the Cho core in the membrane. Conformational analysis suggested that an axial hydrogen atom at C7 of Δ5-sterol (2, 6) and the protruded A-ring of Δ5,7,9-sterol (4, 8) sterically hampered face-to-face contact between the van der Waals surface of the sterol core and the macrolide of AmB. These results further suggest that the α-face of sterol alicycle interacts with the flat macrolide
structure of AmB.

DOI： 10.1021/bi5012942

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

Lipid rafts have attracted much attention because of their significant functional roles in membrane-​assocd. processes. It is thought that sphingomyelin and cholesterol are essential for forming lipid rafts; however, their motion characteristics are not fully understood despite numerous studies. Here the authors show accurate local motions encompassing an entire sphingomyelin mol., which were captured by measuring quadrupole splittings for 19 kinds of site-​specifically deuterated sphingomyelins (i.e., mol. motion capture of sphingomyelin)​. The quadrupole splitting profiles, which are distinct from those reported from perdeuterated sphingomyelins or simulation studies, reveal that cholesterol enhances the order in the middle parts of the alkyl chains more efficaciously than at the shallow positions. Comparison with dimyristoylphosphocholine bilayers suggests that cholesterol is deeper in sphingomyelin bilayers, which likely explains the so-​called umbrella effect. Also (i) the C2'-​C3' bond predominantly takes the gauche conformation, (ii) the net ordering effect of cholesterol in sphingomyelin bilayers is not larger than that in phosphatidylcholine bilayers, (iii) cholesterol has no specific preference for the acyl or sphingosine chain, (iv) the acyl and sphingosine chains seem mismatched by about two methylene lengths, and (v) the motion of the upper regions of sphingomyelin chains is less temp. dependent than that of lower regions probably due to intermol. hydrogen bond formation among SM mols. These insights into the at.-​level dynamics of sphingomyelin provide crit. clues to understanding the mechanism of raft formation.

DOI： 10.1021/bi3009399

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

To implement specific guest responsivity, a hydrophobic cholesterol-based co-ligand, cholest-5-en-3-yl-4-isonicotinate (Cholpy), was incorporated into a two-dimensional Hofmann-type Co(ii)Ni(ii) coordination polymer. The chemically programmed structure successfully demonstrated the unique guest response with remarkable chromatic changes.

DOI： 10.1039/c3dt51465j

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

To implement specific guest responsivity, a hydrophobic cholesterol-based co-ligand, cholest-5-en-3-yl-4-isonicotinate (Cholpy), was incorporated into a two-dimensional Hofmann-type Co(II)Ni(II) coordination polymer. The chemically programmed structure successfully demonstrated the unique guest response with remarkable chromatic changes.

DOI： 10.1039/C3DT51465J

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

Stereoselective synthesis of the C43-​C67 part of amphidinol 3 (AM3) and its C51-​epimer, I (R1 = OH, R2 = H; R1 = H, R2 = OH)​, was achieved starting from a common intermediate corresponding to the tetrahydropyran moiety of AM3, via asym. oxidns. and Julia-​Kocienski olefination. By comparing NMR data of the synthetic specimens with those of AM3, the abs. configuration at C51 of AM3 was revised from R to S.

DOI： 10.1021/ol401176a

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

A novel SAAF was isolated from the title ascidian. The structure was elucidated using the entire sample of 4 nmol, suggesting that the position of the OH group confers genus-​specificity to sperm chemotaxis in ascidians. This study not only provides insight into the chem. tactics in sperm chemotaxis but demonstrates that the innovative techniques allow structure detn. of natural products in trace amts.

DOI： 10.1021/ol303172n

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

Ladder-shaped polyether (LSP) toxins attract considerable attention among synthetic organic chemists due to their potent biological activities coupled with their unique molecular structures. Although a number of methods for synthesizing LSPs have been reported, developments of convergent and practical methods are necessary for efficient synthesis of LSPs in order to reveal their biological function at the molecular level and because of their limited availability from natural sources. During the course of our synthetic studies of LSPs, we developed a convergent method via α-cyano ethers (α-cyano ether method). An additional two rings can be constructed through the coupling of fragments, which is an advantage of this strategy for the construction of polycyclic systems. Medium-sized cyclic ethers are formed by ring-closing metathesis, and tetrahydropyran rings are stereoselectively constructed by reductive etherification or thioacetal formation followed by alkylation. The α-cyano ether method was successfully applied to the synthesis of the partial structure corresponding to the ABCDEFGHIJ ring system of yessotoxin, where utilization of a microflow reactor was found to be effective for reductive etherification. The α-cyano ether method was also applicable for synthesizing the WXYZA-B-C-ring system of maitotoxin, and designed artificial tetra-, hepta-, and decacyclic LSPs.

DOI： 10.5059/yukigoseikyokaishi.70.1170

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

Amphidinol 3 (AM3), a membrane-active agent isolated from the dinoflagellate Amphidinium klebsii, consists of a long carbon chain containing twenty five stereogenic centers. Although the absolute configuration of AM3 was determined by extensive NMR analysis and degradation of the natural product, the partial structure corresponding to the tetrahydropyran ring system was found to be antipodal to that of karlotoxin 2, a structurally related compound recently isolated from the dinoflagellate Karlodinium veneficum. By extensive degradation of the natural product and conversion of the resulting alcohol to an MTPA ester, the absolute configuration at C45 of AM3 was confirmed to be R, supporting the originally proposed structure.

DOI： 10.1021/np300604w

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

Lipid rafts have attracted much attention because of their significant functional roles in membrane-​assocd. processes. It is thought that sphingomyelin and cholesterol are essential for forming lipid rafts; however, their motion characteristics are not fully understood despite numerous studies. Here the authors show accurate local motions encompassing an entire sphingomyelin mol., which were captured by measuring quadrupole splittings for 19 kinds of site-​specifically deuterated sphingomyelins (i.e., mol. motion capture of sphingomyelin)​. The quadrupole splitting profiles, which are distinct from those reported from perdeuterated sphingomyelins or simulation studies, reveal that cholesterol enhances the order in the middle parts of the alkyl chains more efficaciously than at the shallow positions. Comparison with dimyristoylphosphocholine bilayers suggests that cholesterol is deeper in sphingomyelin bilayers, which likely explains the so-​called umbrella effect. Also (i) the C2'-​C3' bond predominantly takes the gauche conformation, (ii) the net ordering effect of cholesterol in sphingomyelin bilayers is not larger than that in phosphatidylcholine bilayers, (iii) cholesterol has no specific preference for the acyl or sphingosine chain, (iv) the acyl and sphingosine chains seem mismatched by about two methylene lengths, and (v) the motion of the upper regions of sphingomyelin chains is less temp. dependent than that of lower regions probably due to intermol. hydrogen bond formation among SM mols. These insights into the at.-​level dynamics of sphingomyelin provide crit. clues to understanding the mechanism of raft formation.

DOI： 10.1021/bi3009399

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

Sphingomyelin (SM) is a common sphingolipid in mammalian membranes and is known to be substantially involved in cellular events such as the formation of lipid rafts. Despite its biol. significance, conformation of SM in a membrane environment remains unclear because the noncryst. property and anisotropic environment of lipid bilayers hampers the application of x-​ray crystallog. and NMR measurements. In this study, to elucidate the conformation of SM in membranes, the authors utilized bicelles as a substitute for a lipid bilayer membrane. First, the authors demonstrated through 31P NMR, 2H NMR, and dynamic light scattering expts. that SM forms both oriented and isotropic bicelles by changing the ratio of SM​/dihexanoyl phosphatidylcholine. Then, the authors detd. the conformation of SM in isotropic bicelles on the basis of coupling consts. and NOE correlations in 1H NMR and found that the C2-​C6 and amide groups of SM take a relatively rigid conformation in bicelles.

DOI： 10.1016/j.bmc.2011.11.001

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

Amphotericin B (AmB) is thought to exert its antifungal activity by forming an ion-​channel assembly in the presence of ergosterol. In the present study we aimed to elucidate the mode of mol. interactions between AmB and ergosterol in hydrated phospholipid bilayers using the rotational echo double resonance (REDOR) spectra. We first performed 13C{19F}​REDOR expts. with C14-​19F-​labeled AmB and biosynthetically 13C-​labeled ergosterol and implied that both "head-​to-​head" and "head-​to-​tail" orientations occur for AmB-​ergosterol interaction in the bilayers. To further confirm the "head-​to-​tail" pairing, 13C-​labeled ergosterol at the di-​Me terminus (C26​/C27) was synthesized and subjected to the REDOR measurements. The spectra unambiguously demonstrated the presence of a "head-​to-​tail" orientation for AmB-​ergosterol pairing. In order to obtain information on the position of the di-​Me terminus of ergosterol in membrane, 13C{31P}​REDOR were carried out using the labeled ergosterol and the phosphorus atom of a POPC headgroup. Significant REDOR dephasing was obsd. at the C26​/C27 signal of ergosterol in the presence of AmB, but not in the absence of AmB, clearly indicating that the side-​chain terminus of ergosterol in the AmB complex comes close to the bilayer surface.

DOI： 10.1021/bi2012542

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

A lipid raft is a cholesterol (Chol)-rich microdomain floating in a sea of lipid bilayers. Although Chol is thought to interact preferentially with sphingolipids such as sphingomyelin (SM), rather than with glycerophospholipids, the origin of the specific interaction has remained unresolved, primarily because of the high mobility of lipid mols. and weak intermol. interactions. In this study, we synthesized SM-Chol conjugates with functionally designed linker portions to restrain Chol mobility and examd. their formation of ordered membranes by a detergent insoly. assay, fluorescence anisotropy expts., and fluorescence-quenching assay. In all of the tests, membranes prepd. from the conjugates showed properties of ordered domains comparable to a SM-Chol (1:1) membrane. To gain insight into the structure of bilayers composed from the conjugates, we performed mol. dynamics simulations with 64 mols. of the conjugates, which suggested that the conjugates form a stable bilayer structure by bending at the linker portion and, mostly, reproduce the hydrogen bonds between the SM and Chol portions. These results imply that the mol. recognition between SM and Chol in an ordered domain is essentially reproduced by the conjugated mols. and, thus, demonstrates that these conjugate mols. could potentially serve as mol. probes for understanding mol. recognition in lipid rafts.

DOI： 10.1002/chem.201100849

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

Selectively 2H- and 13C-labeled spermines (SPM) were efficiently synthesized and analyzed by NMR spectroscopy to det. the spin-spin coupling consts. for 6 conformationally relevant bonds. SPM that is composed of 3 alkyl moieties, a butanylene, and 2 propanylene chains underwent a conformational change when interacting with multivalent anions (e.g., ATP, ATP-Mg2+, and tripolyphosphate). Upon interaction with ATP, the C-C bonds, which affect the distance between the neighboring pairs of NH4+ groups (i.e., N1/N5 and N5/N5'), increased the population of gauche rotamers by 17-20% relative to those in the 4 HCl salt of SPM. However, the trend in increments of the gauche conformers for the SPM-ATP complex profoundly differed from that of the spermidine (SPD)-ATP complex. This implied that SPM may preferentially recognize the adenylyl group of ATP rather than the tripolyphosphate moiety. This may account for the higher affinity of SPM to ATP-Mg2+ than with that of SPD, which chiefly interacts with β- and γ-phosphates and is easily replaced by Mg2+. These results may provide a clue for the further understanding of the structural basis of polyamine biol. functions.

DOI： 10.1002/chem.201002759

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

Among other homologues, amphidinol 3 (AM3) is the most potent antifungal compd. isolated from the dinoflagellate Amphidinium klebsii. AM3 undergoes conformational changes in org. solvents while it takes relatively fixed configuration in a membrane model. By using NMR data of peracetyl AM3, we were able to confirm the configuration of C50-C51 of AM3 which remained uncertain in our previous study.

DOI： 10.3987/COM-10-S(E)86

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

Two well-known antifungals, amphotericin B (AmB) and amphidinol 3 (AM3), are thought to exert antifungal activity by forming ion-permeable channels or pores together with sterol mols. However, detailed mol. recognitions for AmB-sterol and AM3-sterol in lipid bilayers have yet to be detd. Toward 19F NMR-based investigation of the mol. recognition underlying their potent antifungal activity, we synthesized 6-fluoro-ergosterol I in five steps via ring opening of (5α,6α)-epoxide of ergosterol acetate using a novel combination of TiF4 and n-Bu4N+Ph3SiF2-. Then we evaluated its activity of promoting pore formation of AmB and AM3, and found that pore formation of AmB was barely promoted by 6-F-ergosterol in clear contrast to the dramatic promotion effect of unmodified ergosterol, whereas AM3 activity was markedly enhanced in the presence of 6-F-ergosterol, which was comparable to that of unmodified ergosterol. These results indicate that the introduction of an F atom at C6 position of ergosterol plays an inhibitory role in interacting with AmB, but it is not the case with AM3.

DOI： 10.1039/c0ob00685h

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

The affinity of amphidinol 3 (AM3) to phospholipid membranes in the presence and absence of sterol was examd. by surface plasmon resonance (SPR) expts. The results showed that AM3 has 1000 and 5300 times higher affinity for cholesterol- and ergosterol-​contg. liposomes, resp., than those without sterol. The two-​state reaction model well reproduced the sensor grams, which indicated that the interaction is composed of two steps, which correspond to binding to the membrane and internalization to form stable complexes.

DOI： 1016/j.bmcl.2010.02.025

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

DOI： 10.1016/j.bmcl.2010.02.025

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

DOI： 10.1246/cl.2010.108

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

DOI： 10.1016/j.tetlet.2010.03.011

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

DOI： 10.1016/j.bmcl.2010.09.080

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

Ladder-shaped polyether (LSP) toxins are thought to bind to transmembrane (TM) proteins. To elucidate the interactions of LSPs with TM proteins, artificial ladder-shaped polyethers (ALPs) possessing simple iterative structure with different number of rings were synthesized based on the convergent method via α-cyano ethers. The interaction of these ALPs with TM proteins was evaluated, and we found that the difference of activities among the ALPs can be accounted for by the concept of "hydrophobic matching" i. e. lengths of the hydrophobic region including the side chains of ALPs are ca. 25 Å, which match the lengths of the hydrophobic region of α-helical TM proteins. The partial structure corresponding to the WXYZA'B'C' ring system of maitotoxin (MTX) was synthesized based on the convergent method via α-cyano ethers, and we found that hemolysis of human red blood cells induced by MTX was blocked by the fragment The hydrophobic portion of MTX is expected to be promising molecular probes for identifying the target proteins of MTX.

DOI： 10.5059/yukigoseikyokaishi.67.1250

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

(Chemical Equation Presented) A concise synthesis of a tetrahydropyran ring system corresponding to the C31-C40 and C43-C52 units of amphidinol 3 is described. Successive chemoselective reactions, i.e., cross-metathesis to differentiate the iodoolefin from the terminal olefin and Sharpless asymmetric dihydroxylation on the resulting E-olefin, resulted in expeditious synthesis of an intermediate that was then cross-coupled to afford an E,E-diene system. Four contiguous stereogenic centers were installed via construction of the tetrahydropyran ring by means of Katsuki-Sharpless asymmetric epoxidation, 6-endo-tet cyclization, and Sharpless asymmetric dihydroxylation.

DOI： 10.1021/jo901793f

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

Although amphotericin B (AmB) is thought to exert its antifungal activity by forming transmembrane ion-permeable self-assemblies together with ergosterol, no previous study has directly proven AmB-ergosterol interaction. To establish the interaction, we measured ²H NMR using deuterium-labeled sterols and AmB. The ²H NMR spectra of deuterated ergosterol in palmitoyloleoylphosphatidylcholine (POPC) bilayers showed that fast axial diffusion of erogosterol was almost completely inhibited by the coexistence of AmB. Conversely, cholesterol mobility in POPC membrane was essentially unchanged with or without AmB. These results unequivocally demonstrate that ergosterol has significant interaction with AmB in POPC bilayers. In addition, we examined the mobility of AmB using deuterium-labeled AmB, and found that, although AmB is almost immobilized in sterol-free and cholesterol-containing POPC membranes, a certain ratio of AmB molecules acquires mobility in the presence of ergosterol. The similar mobility of AmB and ergosterol in POPC bilayers confirmed the idea of the direct intermolecular interaction between ergosterol and AmB.

DOI： 10.1021/ja9033473

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

Amphotericin B (AmB) exerts its pharmacological effects by forming a barrel-stave assembly in fungal membranes. To examine the interaction between AmB and ergosterol or cholesterol, ¹³C- and ¹⁹F-labeled covalent conjugates were prepared and subjected to solidstate NMR measurements. Using rotor-synchronous double-resonance experiments such as rotational echo double resonance (REDOR) and RDX, we estimated the distance between the fluorine atom and its nearest carbon in the heptaene moiety to be less than 8.6 A ̊, indicating that the B ring of ergosterol comes close to the AmB polyene moiety. Conformational search of the AmB-ergosterol conjugate using the NMR-derived constraints suggested that ergosterol molecules surround the AmB assembly in contrast to the conventional image where ergosterol is inserted into AmB molecules. AmB-AmB bimolecular interaction was examined by using ¹³C- and ¹⁹F-labeled AmBs in dimyritoylphosphatidylcholine (DMPC) membrane without sterols. ¹³C- and ¹⁹F dipolar interactions deriving from both head-to-head and head-to-tail orientations were observed in the REDOR experiments. The interactions between AmB and acyl chains of the phospholipid were also detected.

DOI： 10.1351/PAC-CON-08-08-37

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

The photoactive and biotinylating ligand was prepared from MTX and maleimide-conjugated Hatanaka reagent with use of Diels-Alder reaction. Blood cells were subjected to affinity labelling experiments using the ligand thus obtained. The labelled band on SDS-PAGE was replaced not by MTX but by brevetoxin B (PbTx2), which suggested the presence of binding proteins in blood 2+ cells. Screening of polyether compounds for MTX inhibitory activity using Ca flux assays in C6 cells disclosed that a synthetic fragment of the hydrophilic portion of MTX inhibited the MTX activity.

DOI： 10.3987/COM-08-S(D)78

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

Ladder-shaped polyether (LSP) compounds represented by brevetoxins and ciguatoxins were largely discovered in association with seafood poisoning. Thus, a quick quantification method for LSPs is potentially important. We examined a surface plasmon resonance method using desulfated-yessotoxin (dsYTX) immobilized on a sensor chip and phosphodiesterase PDEII in a inhibition detection mode. Yessotoxin, brevetoxin B and synthetic LSP derivatives showed clear inhibition against PDEII binding to the immobilized dsYTX, by which their half inhibitory concentrations were successfully estimated. This inhibition method appeared to be superior in specificity to direct binding assays where binding proteins to LSP was immobilized on a sensor chip.

DOI： 10.1016/j.bmcl.2009.03.103

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

Endogenous polyamines, represented by putrescine, spermidine, and spermine, are known to exert their physiological functions by interacting with polyanionic biomolecules such as DNA, RNA, adenosine triphosphate (ATP), and phospholipids. Very few examples of conformation analysis have been reported for these highly flexible polymethylene compounds, mainly due to the lack of appropriate methodologies. To understand the molecular basis of the weak interaction between polyamines and polyanions that underlies their physiological functions, we aimed to elucidate the solution conformation of spermidine by using diastereospecifically deuterated and
¹³
C-labeled derivatives (1-7), which were designed to diagnose the orientation of seven conformationally relevant bonds in spermidine. 1H-1H and
¹³
C-1H NMR coupling constants (
³
J
_H,H
and
³
J
_C,H
) were successfully determined for a spermidine-ATP complex. The relevant coupling constants markedly decreased upon complexation. The results reveal that spermidine, when interacting with ATP, undergoes changes that make the conformation more bent and forms the complex with the triphosphate part of ATP in an orientation-sensitive manner.

DOI： 10.1002/chem.200801961

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

Salicylihalamide A (SA), a benzolactone enamide compound, possesses potent cytotoxicity against human tumor cell lines. SA is a selective inhibitor of mammalian vacuolar type H⁺-ATPase (V-ATPase), and is distinct from previously known V-ATPase inhibitors such as bafilomycins and concanamycins that do not discriminate between mammalian and nonmammalian V-ATPases. Because of its potent antitumor activity and structural simplicity, SA is a promising candidate for an anticancer drug. Although a number of structure-activity relation studies using synthetic analogues have been reported, no fluorinated derivative of SA has been evaluated even though selective addition of a fluorine atom into a therapeutic small molecule candidate often enhances pharmacokinetic and physicochemical properties. We designed and synthesized fluorinated analogues of SA and evaluated their V-ATPase inhibitory activities. Compared to the natural product, the synthetic analogues were potent V-ATPase inhibitors, suggesting that these analogues are potential drug candidates and potential molecular probes for mode-of-action studies using fluorine-based analytical methods such as ¹⁹F-NMR spectroscopy.

DOI： 10.1021/jm801265e

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

Publishing type：Research paper (scientific journal)  

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

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

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

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

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

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

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

A ¹³C-labeled amphotericin B (AmB) derivative was synthesized based on a hybrid strategy combining chemical synthesis with degradation of a natural product through successive cross-coupling reactions and macrolactonization. The specimen regiospecifically ¹³C-labeled (99% enrichment) at C25 position corresponding to the polyene moiety would be a powerful tool for structural analysis of the molecular assembly formed by AmB based on solid-state NMR measurements.

DOI： 10.1246/cl.2009.114

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

(Chemical Equation Presented) Combinatorial synthesis of a 1,5-polyol system corresponding to the C1-C14 unit of amphidinol 3 (AM3) and its diastereomers was achieved via chemoselective cross metathesis as the key step. Comparison of ¹³C NMR data of the synthetic specimens with that of AM3 led to a controversy regarding the originally proposed structure. From GC-MS analysis of the degradation product, the absolute configuration at C2 of AM3 has been revised to be R.

DOI： 10.1021/ol802168r

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

Marine dinoflagellates are a rich source of structurally and biologically intriguing secondary metabolites. Among those, maitotoxin may be one of the best known examples, which is the largest natural product known to date and possesses the most potent toxicity known amongst non-proteinaceous compounds. Structural studies of maitotoxin are reviewed with a particular focus on the configuration and mode of action of this unique toxin. In addition, there are many marine natural products which bind to biomembranes to exert their biological activities. To gain a better understanding of their mode of action, conformation, and bimoleeular interaction occurring in biomembranes are particularly important. Recent results from NMR studies of membrane systems in the authors' group are reviewed briefly.

DOI： 10.1246/bcsj.81.307

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

Ladder-shaped polyether (LSP) compounds are thought to interact with transmembrane α-helices, but direct evidence has scarcely obtained for these interactions. We adopted a transmembrane α-helix of glycophorin A, and quantitatively evaluated its interaction with LSPs such as yessotoxin (YTX), desulfated YTX and artificial LSPs, using surface plasmon resonance and saturation transfer difference NMR. As a result, dissociation constants (K_D) of YTX and desulfated YTX to a transmembrane domain peptide of glycophorin A were determined to be in the submillimolar range. Furthermore, in saturation transfer difference NMR, the signals at the polyene side chain and the angular methyl groups of YTX were significantly attenuated, which probably comprised an interacting interface of LSPs with a transmembrane α-helix. These results suggest that hydrophobic interaction plays an important role in molecular recognition of the α-helix peptide by LSPs.

DOI： 10.1016/j.bmcl.2008.10.020

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

Amphotericin B (AmB) exerts its antifungal activity by forming ion-permeable assemblies across lipid bilayers. To investigate AmB-AmB bimolecular interactions in the assembly, we carried out ¹³C{ ¹⁹F}REDOR experiments using 14-¹⁹F- and ¹³C41-labeled AmBs in sterol-containing and sterol-free palmitoyloleoylphosphatidylcholine (POPC) membranes and measured the average distance between the labeled sites of AmBs in membrane-bound forms. The REDOR results suggested that the intermolecular distance of AmB molecules is significantly increased in the ergosterol membrane as compared with the cholesterol membrane. This sterol-dependent change was supported by the UV spectra of AmB in lipid bilayers, in which the excitonic absorption band arising from the aggregated state of AmB shifted to longer wavelength in ergosterol-containing POPC membrane. The REDOR experiments also disclosed that the head-to-head orientation of AmB is predominant in both of the sterol-containing membranes and AmB-POPC interaction was detected only in the ergosterol membrane. Ergosterol significantly influences the interactions between AmB molecules as well as those between AmB and POPC, which may facilitate formation of ion-permeable channels in ergosterol-containing membrane.

DOI： 10.1021/bi801875y

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

(Chemical Equation Presented) The WXYZA′B′C′ ring system (1) of maitotoxin (MTX) was synthesized in a convergent manner via successive coupling of the W, Z, and C′ ring fragments through construction of the XY and A′B′ ring systems. The synthetic segment 1 blocked the hemolytic activity elicited by MTX.

DOI： 10.1021/ol801369g

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

The sperm activating and attracting factor (SAAF) from the eggs of the ascidian Ciona intestinalis was identified as the sulfated polyhydroxysterol,3α,4β,7α,26-tetrahydroxy-5α-cholestane-3,26-disulfate. We present a functional analysis of SAAF derivatives that reveals the roles of the various SAAF functional groups. Optical isomerism does not affect SAAF activities. Hydrolysis on one side, i.e. at the sulfate groups of SAAF, decreases the sperm-activating and sperm-attracting activities, while hydrolysis on both sides resulted in the loss of both activities. Biotinylated-SAAF lost its sperm-activating ability, but retained sperm-binding and chemotactic abilities. Thus, the sulfate groups of SAAF are responsible for these activities.

DOI： 10.1016/j.febslet.2008.09.006

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

Sperm chemotaxis toward an egg is observed in many animals, and the control of sperm-attracting activity is thought to play an important role in ensuring fertilization. However, the mechanism underlying the release of a sperm attractant from an egg is still obscure. In this study, we examined the systems involved in the release of sperm-activating and sperm-attracting factor (SAAF), which is the sperm attractant of the ascidian Ciona intestinalis. Here, we show that the egg acquires sperm-attracting activity after germinal vesicle breakdown. Further, since the cytoplasmic extracts of immature oocytes exhibit no sperm-attracting activity, the SAAF in oocytes may be activated after germinal vesicle breakdown. We found 13 SAAF-binding proteins in an egg plasma membrane extract and identified five proteins by proteomic analysis: valosin-containing protein (VCP)/p97, proteasome alpha 2 subunit, MGC97756 protein, proteasome subunit Y, and beta-tubulin. In particular, the interaction between VCP/p97 and SAAF was confirmed by a pull-down assay. VCP/p97 is initially localized in the germinal vesicle, and during oocyte maturation, it shifts to the endoplasmic reticulum in the cortical regions. Thus, VCP/p97 is a potential modulator of SAAF release from the egg.

DOI： 10.1111/j.1440-169X.2008.01064.x

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

A highly convergent synthesis of the A-J ring system of yessotoxin was achieved. A convergent strategy via α-cyano ethers was extensively applied in the assembly of the F and IJ ring fragments to afford the FGHIJ ring unit, followed by coupling with the ABC ring unit.

DOI： 10.1055/s-2008-1078266

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

Ladder-shaped polyether (LSP) toxins represented by brevetoxins and Ciguatoxins are thought to bind to transmembrane (TM) proteins. To elucidate the interactions of LSPs with TM proteins, we have synthesized artificial ladder-shaped polyethers (ALPs) containing 6/7/6/6 tetracyclic, 6/7/6/6/7/6/6 heptacyclic, and 6/7/6/6/7/6/6/7/6/6 decacyclic systems, based on the convergent method via α-cyano ethers. The ALPs possessing the simple iterative structure with different numbers of rings would be useful for structure-activity relationship studies on the molecular length, which is supposed to be important when naturally occurring LSPs elicit their toxicity. Two series of ALPs were prepared to evaluate the hydrophilic or hydrophobic effects of the side chains: (i) both sides were functionalized as diols (A series), and (ii) one side remained as diol and the other side was protected as benzyl ethers (B series). To examine the interaction of these ALPs with TM proteins, dissociation of glycophorin A (GpA) dimers into monomers was evaluated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The heptacyclic ether (ALP7B) elicited the most potent activity in the presence of 2% SDS buffer, whereas the decacyclic ether (ALP10A) exhibited an intriguing phenomenon to induce precipitation of GpA in a dose-dependent manner, under the low concentration of SDS (0.03%). ALP10A also induced precipitation of integrin α ₁β₁, a TM protein known to form heterodimers in the lipid bilayer membranes. The different activities among the ALPs can be accounted for by the concept of "hydrophobic matching" that is, lengths of the hydrophobic region including the side chains of ALP7B and ALP10A are ca. 25 Å, which match the lengths of the hydrophobic region of α-helical TM proteins, as well as the hydrophobic thickness of lipid bilayer membranes. The concept of the hydrophobic matching would be a clue to understanding the interaction between LSPs and TM proteins, and also a guiding principle to design ALPs possessing potent affinities with TM proteins.

DOI： 10.1021/ja801576v

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

Amphotericin B (AmB) is a membrane-active antibiotic that increases the permeability of fungal membranes. Thus, the dynamic process of its interaction with membranes poses intriguing questions, which prompted us to elaborate a quick and reliable method for real-time observation of the drug's binding to phospholipid liposomes. We focused on surface plasmon resonance (SPR) and devised a new modification method of sensor chips, which led to a significant reduction in the level of nonspecific binding of the drug in a control lane. With this method in hand, we examined the affinity of AmB for various membrane preparations. As expected, AmB exhibited much higher affinity for sterol-containing palmitoyloleoylphosphatidylcholine membranes than those without sterol. The sensorgrams recorded under various conditions partly fitted theoretical curves, which were based on three interaction models. Among those, a two-state reaction model reproduced well the sensorgram of AmB binding to an ergosterol-containing membrane; in this model, two states of membrane-bound complexes, AB and AB*, are assumed, which correspond to a simple binding to the surface of the membrane (AB) and formation of another assembly in the membrane (AB*) such as an ion channel complex. Kinetic analysis demonstrated that the association constant in ergosterol-containing POPC liposomes is larger by 1 order of magnitude than that in the cholesterol-containing counterpart. These findings support the previous notion that ergosterol stabilizes the membrane-bound assembly of AmB.

DOI： 10.1021/bi800334p

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

Amphidinols (AMs) are a group of dinoflagellate metabolites with potent antifungal activity. As is the case with polyene macrolide antibiotics, the mode of action of AMs is accounted for by direct interaction with lipid bilayers, which leads to formation of pores or lesions in biomembranes. However, it was revealed that AMs induce hemolysis with significantly lower concentrations than those necessary to permeabilize artificial liposomes, suggesting that a certain factor(s) in erythrocyte membrane potentiates AM activity. Glycophorin A (GpA), a major erythrocyte protein, was chosen as a model protein to investigate interaction between peptides and AMs such as AM2, AM3 and AM6 by using SDS-PAGE, surface plasmon resonance, and fluorescent-dye leakages from GpA-reconstituted liposomes. The results unambiguously demonstrated that AMs have an affinity to the transmembrane domain of GpA, and their membrane-permeabilizing activity is significantly potentiated by GpA. Surface plasmon resonance experiments revealed that their interaction has a dissociation constant of the order of 10 μM, which is significantly larger than efficacious concentrations of hemolysis by AMs. These results imply that the potentiation action by GpA or membrane integral peptides may be due to a higher affinity of AMs to protein-containing membranes than that to pure lipid bilayers.

DOI： 10.1016/j.bbamem.2008.01.018

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

6-F-cholesterol was reported to exhibit biological and interfacial properties similar to unmodified cholesterol. We have also found that 6-F-cholesterol mimicked the cholesterol activity observed in the systems of amphotericin B and lipid rafts. However, to use 6-F-cholesterol as a molecular probe to explore molecular recognition in membranes, it is indispensable to have detailed knowledge of the dynamic and orientation properties of the molecule in membrane environments. In this paper, we present the molecular orientation of 6-F-cholesterol (30 mol %) in dimyristoylphosphatidylcholine (DMPC) bilayers revealed by combined use of ¹⁹F chemical shift anisotropy (CSA), ²H NMR, and C-F rotational echo double resonance (REDOR) experiments. The axis of rotation of 6-F-cholesterol was shown to be in a similar direction to that of cholesterol in DMPC bilayers, which is almost parallel to the long axis of the molecular frame. The molecular order parameter of 6-F-cholesterol was determined to be ca. 0.85, which is within the range of reported values of cholesterol. These findings suggest that the dynamic properties of 6-F-cholesterol in DMPC are quite similar to those of unmodified cholesterol; therefore, the introduction of a fluorine atom at C6 has virtually no effect on cholesterol dynamics in membranes. In addition, this study demonstrates the practical utility of theoretical calculations for determining the ¹⁹F CSA principal axes, which would be extremely difficult to obtain experimentally. The combined use of quantum calculations and solid-state ¹⁹F NMR will make it possible to apply the orientation information of ¹⁹F CSA tensors to membrane systems.

DOI： 10.1021/ja077580l

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

Amphidinols (AMs) are a new class of polyhydroxyl polyene compounds with potent antifungal activity. Membrane-permeabilizing activities of AM2, AM3, and AM6 were examined using fluorescent-dye leakage experiments with various phosphatidylcholines (PCs) and sterols. All the AMs tested showed the potent activity to cholesterol-containing liposomes. In the absence of the sterol, AM2, AM3, and AM6 had no membrane-permeabilizing activities to membranes of saturated PC. In liposomes consisting of unsaturated PC, AM2, which possesses an additional ether ring in a polyhydroxyl chain, showed membrane-permeabilizing activities with a moderate efficacy, while AM3 or AM6 did not. The potentiation by sterols was prominent even at 0.5% (wt/wt) and structure-dependent, which ruled out the possibility that alteration of the membrane physical properties induced by sterol was chiefly responsible for this sterol effect. The finding that their activity was not affected by membrane thickness implies that AMs permeabilized membrane by a different mechanism from that of polyene macrolide antibiotics.

DOI： 10.1016/j.bmc.2007.12.029

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

Amphotericin B (AmB) is thought to exert its pharmacological effects by forming a barrel-stave assembly with ergosterol in fungal membranes. To examine the interaction between AmB and ergosterol (Erg) or cholesterol (Cho), ¹³C- and ¹⁹F-labelled covalent conjugales were prepared as reported previously (N. Matsumori et al. Chem. Biol. 2004, 11, 673-679). The CD spectra of the conjugates in a membrane-bound form suggested that the distance between the heptaene moieties of the ergosterol conjugates AmB-C ₂-(6-F)Erg 2 and AmB-C₂Erg 3 is similar to that of AmB in ergosterol-containing membranes, but significantly larger than that of AmB in nonsterol or cholesterol-containing mem branes. These observations suggest that, as is the case with ergosterol-containing membranes, the conjugated sterol moiety prevents the close contact between the heptaene moieties within the membrane that would reduce channel conductivity of the AmB assemblies. To further investigate this bimolecular interaction, we recorded the solid-state NMR spectra of conjugates 2 and AmB-C₂-(6-F)Cho 4. which are composed of uniformly ¹³C-labelled AmB and 6-fluorinuted ergosterol or cholesterol; the conjugates were expected to facilitate the estimation of distances between the fluorine and carbon atoms. By using rotor-synchronous double resonance (rotational echo double resonance of X cluster; RDX) experiments, we deduced the distance between the fluorine atom and its nearest carbon atom in the heptaene moiety of 2 to be less than 8.6 Å. This indicates that the B ring of ergosterol comes close to the AmB polyene moiety. A conformational search of the AmB-ergosterol conjugate by using distance constraints derived from the RDX results suggested that ergosterol molecules possibly surround the AmB assembly, which is in contrast with the conventional image in which ergosterol is inserted into AmB molecules.

DOI： 10.1002/chem.200701256

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

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

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

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

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

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

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

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

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

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

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

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

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

Based on an amphotericin B (AmB) ion-channel model where the close proximity of neighboring molecules is effected by interaction between carboxyl and amino groups, we prepared covalent dimers of AmB connected between these functionalities. While directly connected and short-tethered derivatives (2 and 3) lacked the activities, dimer 4 with a longer linker revealed K⁺ ion flux activity, suggesting that some distance and/or flexibility between the carboxyl and amino groups in adjacent molecules is required for the formation of ion-permeable complex in biomembranes.

DOI： 10.1016/j.tetlet.2007.03.058

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

The JK ring fragment (7) of 42,43,44,45,46,47,55-heptanor-41-oxoyessotoxin was synthesized via enyne metathesis and 6-exo cyclization of a hydroxy epoxide. Conversion of 7 into the JK ring fragment (6) of yessotoxin was achieved in a single step by treatment with an alkenyllithium.

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

Heme oxygenase (HO) catalyzes the regiospecific cleavage of the porphyrin ring of heme using reducing equivalents and O₂ to produce biliverdin, iron, and CO. Because CO has a cytoprotective effect through the p38-MAPK pathway, HO is a potential therapeutic target in cancer. In fact, inhibition of the HO isoform HO-1 reduces Kaposi sarcoma tumor growth. Imidazole-dioxolane compounds have recently attracted attention because they have been reported to specifically inhibit HO-1, but not HO-2, unlike Cr-containing protoporphyrin IX, a classical inhibitor of HO, that inhibits not only both HO isoforms but also other hemoproteins. The inhibitory mechanism of imidazole-dioxolane compounds, however, has not yet been characterized. Here, we determine the crystal structure of the ternary complex of rat HO-1, heme, and an imidazole-dioxolane compound, 2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-1,3- dioxolane. This compound bound on the distal side of the heme iron, where the imidazole and 4-chlorophenyl groups were bound to the heme iron and the hydrophobic cavity in HO, respectively. Binding of the bulky inhibitor in the narrow distal pocket shifted the distal helix to open the distal site and moved both the heme and the proximal helix. Furthermore, the biochemical characterization revealed that the catalytic reactions of both HO-1 and HO-2 were completely stopped after the formation of verdoheme in the presence of the imidazole-dioxolane compound. This result should be mainly due to the lower reactivity of the inhibitor-bound verdoheme with O₂ compared to the reactivity of the inhibitor-bound heme with O₂.

DOI： 10.1021/bi062264p

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

The synthesis of the CDEF ring fragment of yessotoxin, a marine ladder polyether, has been achieved. Union of three components, the C ring aldehyde, the F ring diol, and trimethylsilyl cyanide, was accomplished by treatment with Sc(OTf)
₃
to afford the α-cyano ether both in stepwise and one-pot reactions. The DE ring system was constructed through a ring closing metathesis reaction and reductive etherification sequence.

DOI： 10.3987/COM-06-S(O)23

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

Ladder-shaped tetracyclic and heptacyclic ethers containing a 6/7 cis-fused ring system have been synthesized. The synthesis features convergent coupling of monocyclic building blocks through esterification, ring-closing reaction using a low-valent titanium complex, and hydroxy dithioacetal cyclization. The double reaction strategy enabled expeditious synthesis of the heptacyclic ether in only thirteen steps from the building blocks.

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

Ladder-shaped polyether (LSP) compounds, such as brevetoxins and ciguatoxins, are thought to interact with transmembrane (TM) proteins. As a model LSP compound, we designed and synthesized an artificial tetracyclic ether (1) and evaluated its interaction with glycophorin A (GpA), a membrane protein known to dimerize or oligomerize between membrane-integral α-helical domains. Model compound 1 was found to induce the dissociation of oligomeric GpA in a similar manner to natural LSPs when examined by SDS-PAGE. The results suggest that even an artificial tetracyclic ether possesses the ability to interact with TM proteins, presumably through the intermolecular hydrogen bonds (C_α-H ⋯ O) with the GXXXG motif.

DOI： 10.1016/j.bmcl.2006.09.004

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

Two new homologues of amphidinols (AM14 and AM15) were isolated from the cultured dinoflagellate Amphidinium klebsii. The structures were elucidated on the basis of 2D NMR and collision-induced dissociation MS/MS and turned out to be closely related homologues of AM7. Their weak membrane-disrupting activity indicates that the hydrophobic polyene chain is essential for the potent biological activities. Structure-activity relationship for the polyhydroxyl part was then examined with use of AM homologues possessing various chain lengths, indicating that the pore size of the channel/lesion formed by AMs was not greatly affected by the length of the polyhydroxyl chain.

DOI： 10.1016/j.bmc.2006.06.012

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

A fluorinated amphotericin B (AmB) derivative, 28-
¹⁹
F-AmB methyl ester (3), labeled at the polyene moiety, was synthesized by combining chemical synthesis with degradation of a natural product via cross-coupling reactions and macrolactonization. The fluorinated derivative 3 showed antifungal activity similar to that of AmB, and is expected to be a powerful tool for NMR-based investigation of the mechanism of ion-channel formation.

DOI： 10.1016/j.tetlet.2006.06.159

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

Synthesis of a 6/6/6 tricyclic ether system (3) corresponding to the ABC ring fragment of yessotoxin (1) has been achieved via coupling of a triflate and a 2-lithiofuran followed by intramolecular hetero-Michael addition. The IJ ring fragment (4) of 1 was readily synthesized via successive Sharpless epoxidation and 6-endo cyclization of the resulting vinyl epoxide.

DOI： 10.1016/j.tetlet.2006.04.018

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

Amphotericin B (AmB) is known to assemble together and form an ion channel across biomembranes. The selective toxicity is generally accounted for by its higher affinity for ergosterol than cholesterol. To better understand the ion-channel structure and intermolecular interactions, we prepared various AmB derivatives and measured their activities. AmB dimers which are covalently linked between the amino groups by short chains showed more potent ion-channel activity than that of AmB, indicating that the mutual topology of AmB molecules is a head-to-head orientation. AmB-sterol conjugates were also designed and examined for ion-channel activities. AmB-ergosterol conjugates showed more powerful ion-channel activity than AmB-cholesterol congeners, suggesting that stronger van der Waals interaction between AmB and ergosterol contributes to the higher ion-channel activity. Finally, we prepared conformation-restricted derivatives of AmB, in which the amino and carboxyl groups were bridged with various lengths of alkyl chains. The derivatives successfully gave us information on the active-conformation of the sugar moiety of AmB in membrane. These derivatives are now labeled by ¹³C and/or ¹⁹F to probe the molecular structure of AmB ion channel using solid-state NMR.

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

Structure elucidation studies on natural products are reviewed emphasizing extremely small sample amounts. Previous studies on insect pheromones, periplanones, and bean-originating kairomones, glycinoeclepins, are described briefly. Recent examples are selected from marine natural products such as ciguatoxin, dolastatin-3, and aurisides. A more detailed description is given of a sperm-activating and attracting factor (SAAF), which may be the smallest sample amount used in the structure elucidation of novel non-peptidic natural products. SAAF was isolated from the eggs of the ascidian, Ciona intestinalis, and its structure was deduced with only approximately 4 microg (6 nmol) of sample. Based upon the proposed structure, two epimers were synthesized from chenodeoxycholic acid in 17 steps, leading to the identification of SAAF as a novel sterol sulfate.

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

Ladder-shaped polyether compounds, represented by brevetoxins, ciguatoxins, maitotoxin, and prymnesins, are thought to possess the high affinity to transmembrane proteins. As a model compound of ladder-shaped polyethers, we adopted desulfated yessotoxin (2) and examined its interaction with glycopholin A, a membrane protein known to form a dimer or oligomer. Desulfated yessotoxin turned out to interact with the α-helix so as to induce the dissociation of glycopholin oligomers when examined by SDS and PFO gel electrophoresis. The results provided the first evidence that lapper-shaped polyethers interact with transmembrane helix domains.

DOI： 10.1016/j.bmc.2005.05.039

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

The first stably fluorinated derivative of amphotericin B (2) with a fluorine atom in the macrolide skeleton was synthesized using an electrophilic fluorination reagent, Selectfluor®. The derivative 2 showed hemolytic, K⁺ permeable, and antifungal activities similar to those of AmB and thus was expected to be a powerful tool for NMR-based investigations on the mechanism of ion-channel formation by amphotericin B.

DOI： 10.1016/j.bmcl.2005.05.058

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

A convergent synthetic route to the FGHI ring system of yessotoxin, a marine ladder polyether, has been developed. The synthesis features convergent coupling of the diol and the aldehyde to form α-cyano ethers via acetal formation followed by ring closing metathesis and reductive etherification to construct the oxocane ring G and tetrahydropyran ring H, respectively. The β-methyl group on the G ring was stereoselectively introduced by alkylation of the corresponding ketone.

DOI： 10.1016/j.tetlet.2005.04.040

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

We have reported previously that glycoglycerolipids derived from the membranes of Acholeplasma laidlawii, 3-O-[2′-O-(α-D-glucopyranosyl)- 6′-O-acyl-α-glucopyranosyl]-1,2-di-O-acyl-sn-glycerols (GAGDGs) bind to human cell lines. In addition, the GAGDGs were found to augment HIV-1 infection in human cell lines. Here we show that GAGDG binds to HIV-1 and facilitates the entry of HIV-1 into cells. The binding ability of GAGDG to HIV-1 was blocked by anti-GAGDG serum. Binding assay with synthetic GAGDGs and related compounds showed that the presence of branching form of acyl chains at the C14 or C16 position, glucose, and the acyl chain binding to the glucose were critical for efficient binding. GAGDG efficiently augmented the entry of HIV-1 into cells in a single-cycle replication assay. These results indicate that GAGDG of A. laidlawii membranes participates in the facilitation of HIV-1 infection.

DOI： 10.1007/s00284-003-4101-x

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

Glycation reactions using a model peptide of collagen and glucose or ribose resulted in detection of carboxylmethyl-lysine in the peptide; and treatment with glyoxal provided a dimer of the peptide linked with glyoxal lysine dimer (GOLD). Advanced glycation end products (AGE) are accumulated in human tissues when long-lived proteins are glycated due to hyperglycemia and/or aging. In this study, we synthesized a collagen model peptide, Ac-(Pro-Hyp-Gly) ₅-Pro-Lys-Gly-(Pro-Hyp-Gly) ₅-Ala-NH ₂ to investigate intact AGEs in peptides. The peptide formed a stable triple helix structure, and was subjected to glycation reactions with glucose, ribose and glyoxal. Besides carboxymethyl-lysine in the peptide, a conjugated form linked with glyoxal lysine dimer (GOLD) was detected upon treatment with glyoxal. This is the first example of intact glycation-derived dimers of peptides retaining intrinsic protein structures.

DOI： 10.1016/j.bmcl.2004.08.044

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

The ABCDE ring moiety of ciguatoxin CTX3C, a major causative agent of ciguatera poisoning, was stereoselectively synthesized. The key transformations are a chiral auxiliary-based asymmetric alkylation and an asymmetric aldol condensation, which controlled the formation of the C11 and C21-stereocenters, respectively. A highly practical and efficient route to the ABCD ring fragment, a common precursor for the divergent synthesis of the left wings of ciguatoxins, was also established. Graphical Abstract.

DOI： 10.1016/j.tet.2004.07.010

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

A sperm-activating and attracting factor (SAAF) was isolated from the eggs of the ascidian Ciona intestinalis, and its structure was deduced with only approximately 4 μg of the specimen. Based upon the proposed structure, two epimers were synthesized from chenodeoxycholic acid in 16 steps. Comparison between synthetic and natural compounds led to the unambiguous structure determination of SAAF to be (3R,4R,7R,25S)-3,4,7,26-tetrahydroxycholestane-3,26- disulfate. The synthetic pure specimen was also utilized to confirm that both sperm-activation and attraction were elicited by a single compound.

DOI： 10.1016/j.tet.2004.02.075

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

Polyamines such as spermidine and spermine are known to interact with polyanionic biomolecules under physiological conditions. Conformation analysis of these highly flexible acycles is virtually unprecedented due to the lack of appropriate methodologies. Spin-spin coupling constants, which are often utilized for acyclic systems, are rather uninformative for polyamines due to unresolved ¹H NMR signals of their tri- and tetra-methylene moieties. We attempted to solve this problem by synthesizing diastereospecifically deuterated spermidine, (1S^*,2S^*)-1,8-diamino- 4-azaoctane-1,2,3,3,5,5,6,6,7,7,8,8-d₁₂. To evaluate its utility, ¹H-¹H spin coupling constants were measured as trihydrochloride or tripolyphosphate salt. The relevant coupling constant markedly decreased upon complexation to tripolyphosphate. Under neutral pH, where the net charge of tripolyphosphate became tetravalent, the coupling constant was small; as pH was lowered to 1.4, where the charge was divalent, the constant increased significantly. These data clearly indicate that, when interacting with polyanions, spermidine undergoes conformational changes to increase bent conformation, which could be effectively monitored by the deuterated spermidine.

DOI： 10.1016/j.tet.2004.04.056

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

Amphotericin B-sterol conjugates were synthesized and examined for their membrane permeabilizing activity. Ergosterol and cholesterol, each connected with amphotericin B via an ethylenecarbamate or hexamethylenecarbamate linker, were examined by K⁺ flux assays using liposomes and by single-channel recording across phospholipid membrane. Among four conjugates tested, AmB-ergosterol bearing an ethylenecarbamate linker exhibited the most powerful activity, which substantially exceeded that of the cholesterol homolog. Single-channel recording clearly exhibited that the ergosterol conjugate elicited channel current with the conductance of 28 pS, which was comparable with those by AmB, and revealed a higher channel open probability than the cholesterol conjugate. These results imply that direct interaction between amphotericin B and ergosterol is reproduced by their conjugate, which may serve as a model compound for understanding the drug's selective toxicity.

DOI： 10.1016/j.chembiol.2004.02.027

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

A convergent method for synthesizing 6/n/6/6 (n=7, 8) tetracyclic ether system via two-rings construction of the central n/6 ring system was developed. The key steps of the present synthesis involve a ring-closing metathesis reaction for the construction of the seven- and eight-membered rings, and reductive etherification for the tetrahydropyrans. Unification of the two fragments through acetal formation, followed by regioselective cleavage of the acetal using TMSCN/TMSOTf in the presence of 2,6-di-tert-butyl-4-methylpyridine, afforded the α-cyano ether, of which the nitrile group was manipulated to give the precursors of the ring-closing reactions.

DOI： 10.1016/S0040-4039(03)01862-8

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

A chemoattractant candidate named sperm-activating and attracting factor (SAAF) from the eggs of ascidian Ciona intestinalis, was synthesized from chenodeoxycholic acid in 16 steps. The present synthesis led to the unambiguous structure determination of SAAF to be (3R,4R,7R,25S)-3,4,7,26-tetrahydroxycholestane-3,26-disulfate. The synthetic pure specimen was also used to confirm the dual sperm-activating and attracting activity.

DOI： 10.1016/S0040-4039(03)01598-3

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

Ciguatoxins are the causative neurotoxins of ciguatera seafood poisoning, and more than 20,000 people suffer annually from ciguatera disease in subtropical and tropical regions. The extremely low content of ciguatoxins in fish has hampered the isolation and detailed biological studies. The complicated and huge, 3 nm long, molecular structure of ciguatoxins has impeded synthetic chemists from completing their total syntheses, which are formidable synthetic challenge in modern organic synthesis. Our highly convergent strategic approach featuring the chemoselective ring closing metathesis (RCM) reaction as a key tactics, (i) alkylative coupling and RCM, (ii) intramolecular carbonyl olefination and reductive etherification, (iii) chemo- and regioselective radical cyclization and RCM, has enabled the first total synthesis of ciguatoxin CTX 3 C, which will provide the practical supply for further studies.

DOI： 10.5059/yukigoseikyokaishi.61.562

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

Ciguatoxin CTX3C is a representative congener of the ciguatoxins, which are known to be the principal causative agents of ciguatera food poisoning. The structure of CTX3C spans more than 3nm and is characterized by 13 ether rings. To attain a practical construction of this molecule, efficient supplies of the structural fragments are crucial. Herein we report the convergent synthesis of the HIJKLM ring fragment and present a new carbonyl olefination protocol to cyclize the J ring using low-valent titanium.

DOI： 10.1016/S0040-4020(02)00660-9

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

(Matrix Presented) Covalently linked dimers of amphotericin B were prepared by cross-linking its carboxylic acid. Among these, a dimer with a linkage of 1,6-hexanediamine revealed potent hemolytic activity (EC₅₀,0.25 μM) while its N-acetyl derivative gave rise to large K⁺ ion flux in phosphatidylcholine liposomes, regardless of the presence or absence of sterols, suggesting that the dimers may serve as a tool for elucidating the structure of the ion channel assemblage formed by amphotericin B.

DOI： 10.1021/ol025982m

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

Polyenemacrolides such as amphotericin B (AmB) were thought to assemble together and form an ion channel across plasma membranes. Their antimicrobial activity has been accounted for by this assemblage, whose stability and activity are dependent on sterol constituents of lipid bilayer membranes. The structure of this channel-like assemblage formed in biomembranes has been a target of extensive investigations for a long time. For the first step to this goal, we prepared several AmB dimers with various linkers and tested for their channel-forming activity. Among these, AmB dimers that bore an aminoalkyl-dicarboxylate tether covalently linked between amino groups of AmB showed potent hemolytic activity. Furthermore, K⁺ influx actions monitored by measuring the pH of the liposome lumen by ³¹P NMR revealed that the dimers formed the molecular assemblage similar to that of AmB in phospholipid membrane. Judging from changes in ³¹P NMR spectra, the dimers appeared to induce "all-or-none"-type ion flux across the liposome membrane in the presence of ergosterol, which suggested that the ion channel formed by ergosterol/dimer is similar to that of AmB. With these data in hand, we are now trying to elucidate the structure of the ion-channel complex by making the labeled conjugates of AmB for NMR measurements.

DOI： 10.1021/ja012026b

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

Ciguatoxin CTX3C is a representative congener of the ciguatoxins, which are known to be the principal causative-agents of ciguatera seafood poisoning. The structure of CTX3C spans over three nanometers and is characterized by thirteen ether rings. To attain a practical construction of this molecule, efficient supplies of the structural fragments are crucial. Herein we report the convergent synthesis of the ABCDE ring fragment featuring (i) alkylative coupling of the AB ring and E ring, and (ii) ring-closing olefin metathesis.

DOI： 10.1016/S0040-4020(02)00041-8

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

More than 20,000 people suffer annually from ciguatera seafood poisoning in subtropical and tropical regions. The extremely low content of the causative neurotoxins, designated as ciguatoxins, in fish has hampered the isolation, detailed biological studies, and preparation of anti-ciguatoxin antibodies for detecting these toxins. The large (3 nanometers long) and complicated molecular structure of ciguatoxins has impeded chemists from completing their total synthesis. Our highly convergent strategic approach featuring the chemoselective ring-closing metathesis reaction as a key tactic has enabled the total synthesis of ciguatoxin CTX3C, which will provide a practical supply for further studies.

DOI： 10.1126/science.1065757

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

Monoclonal antibodies (mAbs), 4H2 and 6H7, were prepared previously using a protein conjugate of a 1:1 epimeric mixture of the synthetic ABC-ring fragments of ciguatoxin (CTX), 3 and 4. Here, the interactions of these mAbs with the fragments of CTX and CTX3C, 3 and 5, were investigated by surface plasmon resonance (SPR) spectroscopy in an attempt to clarify an antigenic determinant. Compared with the previous synthesis, the fragment 3 possessing the 2S configuration was synthesized from tri-O-acetyl-D-glucal much more effectively. The mAb 4H2 was already known to show a dose-dependent binding to the bovine serum albumin (BSA) conjugate of 3, but not to that of 5. The present SPR study of 4H2 demonstrates that the A-ring side chain of 3 plays a decisive role as an epitope. Therefore, SPR can effectively replace the ELISA method for the analysis of mAbs.

DOI： 10.1016/S0960-894X(01)00358-4

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

A stereoselective synthesis of the EFGH ring fragment of ciguatoxin CTX3C has been achieved through: (i) selective cleavage of a dioxepane acetal C-O bond; (ii) radical cyclization to form the oxepane G ring; and (iii) chemoselective ring-closing metathesis of a triene yielding the hexahydrooxonin F ring.

DOI： 10.1016/S0040-4039(01)01219-9

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

An enantioselective synthesis of an epoxybicyclo[7.3.0]dodecenediyne core system of the neocarzinostatin chromophore has been achieved via intramolecular acetylide addition and palladium-mediated coupling of iodocyclopentene 5 with alkyne 6. The key cyclopentene moiety, trans-4,5-dihydroxy-2-cyclopenten-1-one 7, was conveniently prepared in both enantiomerically pure forms via enzymatic desymmetrization of meso-3,4,5-trans,trans-trihydroxycyclopentene derivatives.

DOI： 10.1246/bcsj.74.997

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

A combination of asymmetric alkylation using (1R,2S)-1-amino-2-indanol derivative as a chiral auxiliary and the ring-closing metathesis reaction was shown to be an efficient method for synthesizing the ABCD ring fragment of ciguatoxin CTX3C.

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

The HIJKLM ring segment (27) of the right half portion of ciguatoxin CTX3C (1) has been synthesized using a ring-closing reaction mediated by a low-valent titanium reagent.

DOI： 10.1039/b009506k

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

The ABCDE ring fragment of CTX3C, the most important member of the ciguatoxin family, was concisely synthesized by extensive use of ring-closing olefin metathesis.

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

A versatile synthetic route to 3-O(2-O-α-D-glucopyranosyl-6-O-acyl-α-D-glucopyranosyl)-1,2-di-O-acyl-sn-gl ycerols, which should provide various acyl derivatives, has been developed. (C) 2000 Elsevier Science Ltd.

DOI： 10.1016/S0040-4020(00)00793-6

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

DOI： 10.1021/jo000068x

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

The functionalized AB-ring moiety of ciguatoxin has been synthesized in a highly convergent manner via transition metal catalysis. (C) 2000 Elsevier Science Ltd.

DOI： 10.1016/S0040-4039(99)02185-1

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

A component that binds to human lymphoid cells was isolated from the membranes of Acholeplasma laidlawii PG8. The component was extracted using the Bligh-Dyer method and purified using a silica-gel column and TLC. The active component was identified as 3-O-[2'-O- (α-D-glucopyranosyl)-6'-O-acyl-α-D-glucopyranosyl]-1, 2-di-O-acyl-sn-glycerol (GAGDG) using ¹H- and ¹³C-NMR and GC-MS. The compositions of the major saturated fatty acids were nC₁₄ (17·8%), isoC₁₄ (10·7%) and nC₁₆ (34·9%) as determined by GC-MS. The amounts of unsaturated species were less than 10% of those of the corresponding saturated acids. GAGDGs which have three tetradecanoyl groups were synthesized. These synthetic GAGDGs, as well as GAGDGs derived from A. laidlawii membranes, had a high binding affinity for MOLT-4 and HUT-78 (human T cell lines), Raji (a B cell line), HL-60 (a monoblastoid cell line) and primary cultured human T cells. The binding affinities of GAGDGs with an isoC₁₄ acyl group was higher than those with nC₁₄ and nC₁₆ acyl groups. The binding to lymphoid cells reveals a novel biological activity of GAGDGs.

DOI： 10.1099/00221287-146-9-2317

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

The marine antibiotic korormicin, isolated from the culture filtrate of marine bacterial strain Pseudoalteromonas sp. F-420, specifically inhibits the growth of marine Gram-negative bacteria without affecting terrestrial species. The absolute configuration of korormicin was determined by the combination of a CD exciton chirality method and chemical degradation. Convergent total synthesis of korormicin has been also achieved.

DOI： 10.1016/S0040-4039(99)01812-2

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

The IJKLM ring fragment of CTX3C, an important member of the ciguatoxin family, was synthesized via ring-closing metathesis using the Tebbe reagent and an improved method of reductive hydroxy ketone cyclization.

DOI： 10.1039/a906834a

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

The AB-ring fragment of ciguatoxin was synthesized in ten steps from tri-O-benzyl-D-glucal based on a highly diastereoselective ring-closing metathesis and subsequent cross metathesis.

DOI： 10.1016/S0040-4039(99)01017-5

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

An alkylation-metathesis sequence is shown to be a powerful method to synthesize the ABCDE ring framework of ciguatoxin 1.

DOI： 10.1039/a903063h

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

The extensive ring-expansion strategy for the synthesis of tetrahydrooxepin, oxocane, and hexahydrooxonin, which correspond to the D(E), I and F rings of ciguatoxin (CTX1B, 1). respectively, has been established. Chemoenzymatic acylation of the meso alcohols using a lipase provides an expeditious entry for the enantiomeric building blocks.

DOI： 10.1016/S0040-4020(99)00370-1

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

The ABC-ring fragment of ciguatoxin was synthesized as a C2 epimeric mixture (1:1). The mixture, which was designed as a possible hapten for preparing an anti-ciguatoxin monoclonal antibody was conjugated with a carrier protein (KLH) and then used for immunization of mice. The three monoctonal antibodies (mAbs) obtained have shown an appreciable reactivity to the hapten. Each mAb discriminated configuration of the C2 hydroxy group of the ABC-ring fragment. The mAb which showed reactivity to the 2S-fragment was cross-reacted with ciguatoxin.

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

A convergent synthesis of the trans-fused 6-n-6-6 (n = 7-10) tetracyclic ether system was achieved via stereoselective alkylation and ring-closing metathesis reaction.

DOI： 10.1039/a801678j

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

The absolute stereochemistry of the secondary alcohol of the 1,2-dihydroxybutenyl substituent of ciguatoxin (1) was shown to be S by comparing (he split CD curve of ciguatoxin tetra-p-bromobenzoate (2) with those of di- and tri-p-bromobenzoates of AB ring fragments that were synthesized enaotioselectively.

DOI： 10.1016/S0040-4020(97)00071-9

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

Synthesis of a trans-fused 6-7-6 tricyclic ether system was achieved via stereoselective acetal formation, reductive cleavage of the acetal, and a ring-closing metathesis reaction.

DOI： 10.1055/s-1997-969

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

DOI： 10.1021/ja972482t

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

Stereoselective synthesis of the LM ring moiety of ciguatoxin was achieved from (R)-(E)-1-benzyloxy-2-hydroxy-3-pentene via Ireland-Claisen rearrangement, iodolactonization, and reagent-controlled asymmetric dihydroxylation.

DOI： 10.1246/cl.1997.845

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

Divergent synthesis of the HIJ ring framework 21 of ciguatoxin 1 starting with oxocane 10 is achieved using the palladium- and acid-catalysed cyclization reactions of hydroxy epoxides.

DOI： 10.1039/a702158e

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

The extensive ring-expansion strategy for the synthesis of oxepene 19, oxocane 23, and oxonene 28, which correspond to the D (E), I and F ring fragments of ciguatoxin (1), respectively, has been established. Chemoenzymatic asymmetric acylation of the meso alcohols using lipase AK provided a simple entry of the enantiomeric building blocks.

DOI： 10.1055/s-1996-5729

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

The AB ring fragment 15 of ciguatoxin (1) has been synthesized enantioselectively from D-glucose.

DOI： 10.1055/s-1995-5259

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

A short-step synthesis of (-)-(4R,5S)- and (+)-(4S,5R)-trans-4,5-dihydroxy-2-cyclopenten-1-one derivatives (14) has been achieved via the enzymatic asymmetric transformations of meso-3,4,5-trans,trans-trihydroxycyclopentene derivatives 12 and 15, respectively.

DOI： 10.1055/s-1995-5261

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

(+)-Swainsonine 2 and (-)-8,8a-di-epi-swainsonine 3 were stereoselectively synthesized from L-glutamic acid via a highly diastereoselective intramolecular conjugate addition of amide 20 and carbamate 8, respectively. Another key step is a stereoselective osmium-catalyzed dihydroxylation of indolizidine double bond.

DOI： 10.1055/s-1995-5002

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

Chiral C₂-symmetric 2,3-disubstituted 1,4-diazabicyclo[2.2.2]octanes (DABCOs) (1) have been utilized as catalysts for asymmetric Baylis-Hillman reactions. Optically active α-methylene-β-hydroxyalkanone was obtained in up to 47% ee. Under high pressure conditions, a remarkable enhancement of both reaction rate and enantioselectivity has been observed.

DOI： 10.1016/0957-4166(95)00153-G

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

An enantiomeric pair of (S,S)- and (R,R)-bipyrrolidine derivatives has been prepared from D- and L-tartaric acids or D-mannitol as optically active starting materials. Taking advantage of the C₂-symmetric nature of these chiral sources, the synthetic sequence has been established by using efficient side chain elongation, stereospecific conversion of a vicinal diol into a diazido group via S_N2 inversion, and pyrrolidine ring formation via intramolecular substitution as the key steps.

DOI： 10.1016/0957-4166(95)00297-3

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

New neocarzinostatin chromophore analogs of 10-membered ring are synthesized. Generation of σ,σ-biradical via a cumulene intermediate has been demonstrated. The DNA-cleaving activity of the hybrid 4 is found to be 50-fold more potent than 1.

DOI： 10.1016/S0040-4039(00)60739-6

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

Highly diastereoselective dihydroxylation of 4,5-dihydroxy-2-pentenoate with osmium tetroxide using chiral N,N'-dialkyl-2,2′-bipyrrolidine ligands (1) is described. Either syn or anti selection was achieved for acetate (2d) and methyl ether (2e) by employing the enantiomeric ligands.

DOI： 10.1016/S0040-4039(00)73639-2

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

Chiral 2,3-disubstituted 1,4-diazabicyclo[2.2.2]octane (DABCO) derivatives have been synthesized and utilized as a chiral ligand for the osmium-catalyzed asymmetric dihydroxylation of olefins. Optically active diols in up to 41%ee are obtained in good yields.

DOI： 10.1016/S0040-4039(00)92331-1

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

Optically pure 2,2'-bipyrrolidine (1) and its 1,1'-disubstituted derivatives have been synthesized from pyrrole and 2-pyrrolidone.

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

DOI： 10.5059/yukigoseikyokaishi.48.1006

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

Extremely high levels of asymmetric induction have been achieved in osmium tetraoxide oxidation of trans-disubstituted and monosubstituted olefins by using chiral N,N'-dineohexyl-2,2'-bipyrrolidine ligand.

DOI： 10.1021/jo00286a002

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

Asymmetric osmylation of alkenes by using N,N′-dialkyl-2,2′- bipyrrolidines as the chiral ligands shows a high asymmetric induction and a marked dependence of the enantioselectivity on both the N-alkyl group and the reaction solvent.

DOI： 10.1039/C39890000665

Event date： 2023.12

Language：English  

Venue：淡路夢舞台国際会議場   Country：Japan  

Event date： 2023.11

Language：English  

Venue：リーガロイヤルホテル京都   Country：Japan  

Event date： 2023.11

Language：English   Presentation type：Oral presentation (general)  

Venue：リーガロイヤルホテル京都   Country：Japan  

Event date： 2023.11

Language：English  

Venue：リーガロイヤルホテル京都   Country：Japan  

Event date： 2023.11

Language：English   Presentation type：Oral presentation (general)  

Venue：Pusan National University   Country：Korea, Republic of  

Event date： 2023.11

Language：English  

Venue：沖縄コンベンションセンター   Country：Japan  

Event date： 2023.11

Language：English  

Venue：沖縄コンベンションセンター   Country：Japan  

Event date： 2023.11

Language：Japanese  

Venue：早稲田大学国際会議場   Country：Japan  

Event date： 2023.10

Language：Japanese  

Venue：タワーホール船堀   Country：Japan  

Event date： 2023.10

Language：Japanese  

Venue：タワーホール船堀   Country：Japan  

Event date： 2023.9

Language：Japanese  

Venue：東京大学 本郷キャンパス 安田講堂   Country：Japan  

Event date： 2023.8 - 2023.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：九州大学病院キャンパス　コラボ・ステーションⅠ　2階視聴覚ホール   Country：Japan  

Event date： 2023.8

Language：Japanese  

Venue：タワーホール船堀   Country：Japan  

Event date： 2023.7

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2023.7

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2023.7

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Venue：九州大学   Country：Japan  

Event date： 2023.5

Language：Japanese  

Venue：大阪大学   Country：Japan  

Event date： 2023.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京理科大学・野田キャンパス   Country：Japan  

Event date： 2023.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京理科大学・野田キャンパス   Country：Japan  

Event date： 2023.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京理科大学・野田キャンパス   Country：Japan  

Event date： 2023.1

Language：English   Presentation type：Oral presentation (general)  

Venue：びわ湖大津プリンスホテル   Country：Japan  

Event date： 2022.11

Language：English   Presentation type：Oral presentation (general)  

Venue：The Magellan Sutera Resort, Sabah, Malaysia   Country：Malaysia  

Event date： 2022.11

Language：English   Presentation type：Oral presentation (general)  

Venue：The Magellan Sutera Resort, Sabah, Malaysia   Country：Malaysia  

Event date： 2022.11 - 2023.11

Language：Japanese  

Venue：早稲田大学国際会議場   Country：Japan  

Event date： 2022.9

Language：Japanese  

Venue：アクティブリゾーツ福岡八幡   Country：Japan  

Event date： 2022.9

Language：Japanese  

Venue：アクティブリゾーツ福岡八幡   Country：Japan  

Event date： 2022.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：九州大学病院キャンパス・コラボステーションI   Country：Japan  

Event date： 2022.7

Language：English   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2022.7

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2022.7

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2022.6 - 2023.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2022.6

Language：Japanese  

Venue：九州大学　椎木講堂   Country：Japan  

Event date： 2021.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2021.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2021.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2021.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2021.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2020.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2020.11

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2020.11

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2020.10 - 2021.10

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2020.10

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2020.10

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2020.10

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2020.9 - 2021.9

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2019.3

Language：English   Presentation type：Oral presentation (general)  

Venue：甲南大学理工学部　岡本キャンパス   Country：Japan  

Event date： 2019.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：甲南大学理工学部　岡本キャンパス   Country：Japan  

Event date： 2019.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：甲南大学理工学部　岡本キャンパス   Country：Japan  

Event date： 2019.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：甲南大学理工学部　岡本キャンパス   Country：Japan  

Event date： 2019.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：甲南大学理工学部　岡本キャンパス   Country：Japan  

Event date： 2019.3

Language：English   Presentation type：Oral presentation (general)  

Venue：甲南大学理工学部　岡本キャンパス   Country：Japan  

Event date： 2019.3

Language：English   Presentation type：Oral presentation (general)  

Venue：甲南大学理工学部　岡本キャンパス   Country：Japan  

Event date： 2019.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：西鉄イン福岡およびアクロス福岡   Country：Japan  

Event date： 2018.11

Language：English   Presentation type：Oral presentation (general)  

Venue：Rihga Royal Hotel KYOTO   Country：Japan  

Event date： 2018.11

Language：English  

Venue：Rihga Royal Hotel KYOTO   Country：Japan  

Event date： 2018.11

Language：English  

Venue：Rihga Royal Hotel KYOTO   Country：Japan  

Event date： 2018.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：タワーホール船堀   Country：Japan  

Event date： 2018.10

Language：Japanese  

Venue：タワーホール船堀   Country：Japan  

Event date： 2018.10

Language：Japanese  

Venue：タワーホール船堀   Country：Japan  

Event date： 2018.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：久留米シティプラザ   Country：Japan  

Event date： 2018.6

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2018.6

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2018.6

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2018.6

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2018.6

Language：English  

Venue：Riva del Garda (Lake Garda)   Country：Italy  

Event date： 2018.6

Language：Japanese  

Venue：志賀島休暇村   Country：Japan  

Event date： 2018.6

Language：Japanese  

Venue：志賀島休暇村   Country：Japan  

Event date： 2018.6

Language：Japanese  

Venue：仙台国際センター   Country：Japan  

Event date： 2018.6 - 2019.6

Language：Japanese  

Country：Japan  

Event date： 2018.5

Language：Japanese  

Venue：九州大学馬出キャンパス百年記念講堂   Country：Japan  

Event date： 2018.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：日本大学理工学部　船橋キャンパス   Country：Japan  

Event date： 2018.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：日本大学理工学部　船橋キャンパス   Country：Japan  

Event date： 2018.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：日本大学理工学部　船橋キャンパス   Country：Japan  

Event date： 2018.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：日本大学理工学部　船橋キャンパス   Country：Japan  

Event date： 2018.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：日本大学理工学部　船橋キャンパス   Country：Japan  

Event date： 2018.1

Language：Japanese  

Country：Japan  

Event date： 2017.11

Language：Japanese  

Venue：淡路夢舞台国際会議場   Country：Japan  

Event date： 2017.11

Language：Japanese  

Venue：淡路夢舞台国際会議場   Country：Japan  

Event date： 2017.11

Language：Japanese  

Venue：淡路夢舞台国際会議場   Country：Japan  

Event date： 2017.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：Kimdaejung Convention Center, Gwangju   Country：Korea, Republic of  

Event date： 2017.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：KAIST   Country：Korea, Republic of  

Event date： 2017.10

Language：Japanese  

Venue：タワーホール船堀   Country：Japan  

Event date： 2017.10

Language：Japanese  

Venue：タワーホール船堀   Country：Japan  

Event date： 2017.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：わくわくホリデーホール，札幌   Country：Japan  

Event date： 2017.7

Language：Japanese  

Venue：Melbourne   Country：Australia  

Event date： 2017.7

Language：Japanese  

Venue：熱川ハイツ   Country：Japan  

Event date： 2017.7

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2017.7

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2017.7

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2017.7

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2017.7

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2017.6

Language：Japanese  

Venue：プサン大学   Country：Korea, Republic of  

Event date： 2017.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：Hotel Continental Saigon, Ho Chi Minh City   Country：Viet Nam  

Event date： 2017.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：Hotel Continental Saigon, Ho Chi Minh City   Country：Viet Nam  

Event date： 2017.6

Language：Japanese  

Venue：九州大学馬出キャンパス百年記念講堂   Country：Japan  

Event date： 2017.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：九州大学薬学部第一講堂   Country：Japan  

Event date： 2017.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：慶應義塾大学　日吉キャンパス   Country：Japan  

Event date： 2017.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：慶應義塾大学　日吉キャンパス   Country：Japan  

Event date： 2017.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：慶應義塾大学　日吉キャンパス   Country：Japan  

Event date： 2017.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：慶應義塾大学　日吉キャンパス   Country：Japan  

Event date： 2016.11

Language：Japanese  

Venue：淡路夢舞台国際会議場   Country：Japan  

Event date： 2016.11

Language：Japanese  

Country：Japan  

Event date： 2016.10

Language：Japanese  

Venue：KAIST   Country：Korea, Republic of  

Event date： 2016.10

Language：Japanese  

Venue：九州大学先導物質化学研究所   Country：Japan  

Event date： 2016.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：九州大学，伊都キャンパス   Country：Japan  

アンフィジノール3(AM3, 1)は，渦鞭毛藻Amphidinium klebsiiから単離されたポリエンポリオール化合物であり，強力な抗真菌活性 (4μg/disk, Aspergliius niger)ならびに溶血活性 (EC50 = 9.4 nM)を有する。AM3の絶対配置は1999年に決定されたが3、合成化学的な構造確認の結果，C2位およびC51位の立体化学が構造式(1)の様に改訂された。また，AM3の改定された構造式(1)に基づきC31-C67部分の合成を行い，合成品と天然物のNMRスペクトルの比較を行った結果，C32-C38位の絶対立体配置が構造式(1)とは異なる構造式(2)である可能性が示唆された。本研究ではこの可能性を検証するため，構造式(2)のC31-C67に相当する化合物9の合成研究を行った。

Event date： 2016.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：九州大学，伊都キャンパス   Country：Japan  

マイトトキシン（MTX）やブレビスルセナール－Ｆ（KBT-F）などの梯子状ポリエーテル天然物は，エーテル環がトランス-シン-トランスに縮環した特徴的な構造を有する。当研究室ではα-シアノエーテルを経由する二環構築型収束的合成法を開発し，この方法を用いたMTXのWXYZ環部の合成に成功した。本研究では，新奇二環構築型収束的合成法の開発を目指し，MTXのWXYZ環部およびKBT-FのHIJK環部の合成を検討した。

Event date： 2016.7

Language：Japanese  

Venue：湯沢東映ホテル   Country：Japan  

Event date： 2016.7

Language：Japanese  

Venue：湯沢東映ホテル   Country：Japan  

Event date： 2016.7

Language：Japanese  

Venue：湯沢東映ホテル   Country：Japan  

Event date： 2016.7

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2016.7

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2016.7

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2016.7

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2016.7

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2016.7

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2016.7

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2016.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：九州大学薬学部1 号館5 階 第1 講堂 （病院地区 馬出キャンパス）   Country：Japan  

Event date： 2016.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：同志社大学　京田辺キャンパス   Country：Japan  

Event date： 2016.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：同志社大学　京田辺キャンパス   Country：Japan  

Event date： 2016.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：同志社大学　京田辺キャンパス   Country：Japan  

Event date： 2016.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：同志社大学　京田辺キャンパス   Country：Japan  

Event date： 2016.3

Language：Japanese  

Venue：サントリー生命科学財団研究所   Country：Japan  

Event date： 2016.1

Language：Japanese  

Venue：名古屋大学   Country：Japan  

Event date： 2016.1

Language：Japanese  

Venue：名古屋大学   Country：Japan  

Event date： 2015.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：Hawaii   Country：Armenia  

Event date： 2015.12

Language：Japanese  

Venue：Hawaii   Country：Armenia  

Event date： 2015.12

Language：Japanese  

Venue：Hawaii   Country：Armenia  

Event date： 2015.12

Language：Japanese  

Venue：Hawaii   Country：Armenia  

Event date： 2015.12

Language：Japanese  

Venue：Hawaii   Country：Armenia  

Event date： 2015.10

Language：Japanese  

Venue：タワーホール船堀   Country：Japan  

Event date： 2015.10

Language：Japanese  

Venue：タワーホール船堀   Country：Japan  

Event date： 2015.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：九州大学馬出キャンパス   Country：Japan  

Event date： 2015.8

Language：Japanese  

Venue：九州大学馬出キャンパス   Country：Japan  

Event date： 2015.8

Language：Japanese  

Venue：九州大学馬出キャンパス   Country：Japan  

Event date： 2015.7

Language：Japanese  

Venue：グリーンピア岩沼 モンタナリゾート   Country：Japan  

Event date： 2015.7

Language：Japanese  

Venue：グリーンピア岩沼 モンタナリゾート   Country：Japan  

Event date： 2015.7

Language：Japanese  

Venue：グリーンピア岩沼 モンタナリゾート   Country：Japan  

Event date： 2015.7

Language：Japanese  

Venue：グリーンピア岩沼 モンタナリゾート   Country：Japan  

Event date： 2015.6

Language：Japanese  

Country：Japan  

Event date： 2015.6

Language：Japanese  

Country：Japan  

Event date： 2015.6

Language：Japanese  

Country：Japan  

Event date： 2015.6

Language：Japanese  

Country：Japan  

Event date： 2015.6

Language：Japanese  

Country：Japan  

Event date： 2015.6

Language：Japanese  

Country：Japan  

Event date： 2015.6

Language：Japanese  

Country：Japan  

Event date： 2015.6

Language：Japanese  

Country：Japan  

Event date： 2015.6

Language：Japanese  

Venue：仙台国際センター   Country：Japan  

Event date： 2015.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：仙台国際センター   Country：Japan  

Event date： 2015.5

Language：Japanese  

Venue：九州大学百年記念講堂   Country：Japan  

Event date： 2014.7

Language：English  

Venue：京都大学宇治キャンパス   Country：Japan  

Recently, an endogenous sperm activating and attracting factor (SAAF, 1) from eggs of ascidian Ascidia sydneiensis was isolated. SAAF was estimated to be a sulfated polyhydroxysterol: 3,7,8,26-tetrahydroxycholestane-3,26-disulfate by NMR and ESI/TOF-MS analysis using approximately 2.6 µg of the sample.
Although the stereochemistry of steroidal backbone moiety was determined, the configuration at C25 remains unknown. For elucidation of the complete structure, 25S-SAAF was synthesized and NMR data of synthetic specimen were compared with those of the natural product.

Event date： 2014.7

Language：English  

Venue：京都大学宇治キャンパス   Country：Japan  

Amphidinol 3 (AM3, 1) is a marine natural product produced by the dinoflagellate Amphidinium klebsii. AM3 has attracted considerable attention of synthetic chemists because of the unique structure and potent antifungal activity. It was difficult to determine the absolute configuration of AM3 because of the presence of a number of stereogenic centers on the acyclic long carbon chain, therefore revisions of stereochemistry at C2 and C51 have been made. In order to confirm the absolute configuration, synthetic studies toward total synthesis of AM3 were performed.

Event date： 2014.7

Language：Japanese  

Venue：せとうち児島ホテル，岡山   Country：Japan  

Event date： 2014.7

Language：Japanese  

Venue：せとうち児島ホテル，岡山   Country：Japan  

Event date： 2014.7

Language：Japanese  

Venue：せとうち児島ホテル，岡山   Country：Japan  

Event date： 2014.7

Language：Japanese  

Venue：せとうち児島ホテル，岡山   Country：Japan  

Event date： 2014.6

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

アンフィジノール３（AM3, 1）は渦鞭毛藻が産生する抗真菌物質である。最近51位の立体化学が改訂された1) 。AM3の生物活性発現メカニズムは未解明であるが、細胞膜中に疎水性ポリエン部分を挿入し分子複合体を形成することで細胞膜に穴をあけると考えられている。近年、耐性菌の出現が問題となっている中、AM3は新規抗菌剤のリード化合物として注目されている。当研究室では、AM3のポリエン部分と膜との相互作用をより詳細に解析するため、蛍光標識化プローブの合成を目指している。今回、AM3のC43-C67部分に蛍光基を導入した分子プローブの合成を検討した。目的の分子プローブは、化合物2のアジド基を利用して、蛍光基と連結することにした。化合物2は、4つのフラグメント3 ~ 6から収束的に合成した。すなわち、3と 4を右田–小杉–Stilleカップリングを用いて、また、既知のテトラヒドロピラン1)から誘導したアルデヒド6とスルホン5をJulia–Kocienskiオレフィン化を用いてそれぞれ連結した。最後に得られたフラグメントを鈴木–宮浦カップリングを用いて連結した。

Event date： 2014.6

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

アンフィジノール3 (AM3, 1) は渦鞭毛藻が産生する抗真菌物質である。AM3は細胞膜に直接作用して活性を発現するため、従来にはない新しいタイプの抗菌剤として注目されている。当研究室では、AM3の効率的な合成法を開発し、正確な立体配置の確認および構造活性相関を基にした簡略化アナログ分子の創成を目指している。本研究ではC1-C29部分に相当する化合物2の合成研究を行った。まず、Weinrebアミド 4へのリチウムアセチリド5およびビニルリチウム3の付加と立体選択的還元を順次行い、7を合成した。さらに、6とのクロスメタセシスを行うことでC1-C20部分に相当するアルデヒド8を合成した。続いて、C21-C29部分のPTスルホン9とのJulia-Kocienskiオレフィン化を用いたフラグメントの連結、続くSharpless不斉ジヒドロキシ化を経由してC1-C29部分2を最長直線工程数18段階で合成した。

Event date： 2014.6

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

受精の際、精子が卵に遭遇する確率を高める仕組みのひとつとして、卵から放出される物質により精子の運動能が高められる精子活性化現象や、精子を卵の方へ引き寄せる精子誘引現象が知られている。ホヤの一種であるスジキレボヤの卵から精子活性化誘因物質 (Sperm Activating and Attracting Factor, 以下SAAFと略す) が単離・構造決定されたが、7, 8, 25位の立体化学が未確定であった1)。7, 8位に関しては、対応する4つのジアステレオメリックなモデル化合物を合成し、天然物のNMRスペクトルデータと比較することで決定されたが、25位は未確定である。本研究では、SAAFの25位に関する2つの可能なジアステレオマー (1, 2) を化学合成し、天然物のNMRスペクトルデータと比較することでスジキレボヤSAAFの全立体配置を決定することにした。まず、市販のエルゴステロール3から8段階でオレフィン4を合成し、立体選択的ジヒドロキシ化、四酢酸鉛による酸化的開裂、ヨウ化サマリウムを用いたピナコールカップリングを経由し、-ジオール5へと誘導した。ジオール5に対して酸化、立体選択的還元を行うことで7位の立体化学を反転し、保護基の変換、第1級アルコールの酸化を行い、アルデヒド6を合成した。このアルデヒド6と別途調製したスルホン7とのJulia-Kocienski反応を行い、オレフィン8 (E/Z = 7:1)を得た後、さらに4段階で(25S)-SAAF (1)を合成した。現在、天然物のNMRスペクトルデータとの比較を行っている。

Event date： 2014.6

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

マイトトキシン(MTX)は、渦鞭毛藻類Gambierdiscus toxicusによって生産される両親媒性の梯子状ポリエーテルである。強力な致死毒性を持ち、溶血活性や細胞内Ca2+濃度上昇作用などの様々な生物活性を持つことが知られている。しかし、その作用標的分子や活性発現機構については未だ解明されていない。
MTXの合成フラグメントを用いた構造活性相関研究では、疎水性部分であるW-C’環部や親水性部分に対応するLMNO環部のエナンチオマーがMTXの引き起こすCa2+流入活性を阻害することが見出されている1),2)。本研究ではMTXのLMNO環部に着目し、生物活性の比較を行うためにLMNO環部とそのエナンチオマーの合成の検討を行った。
　まず、Nicolaouらの合成3)を参考に、グリコール酸から16段階で化合物2を合成した。次にヨウ化アルケニル3を用いた野崎-檜山-岸(NHK)反応を行うことによりアリルアルコール4を得た。TBS基の除去、続く分子内オキサMichael反応によりスルホン5を得た後、Pummerer転位を行うことでLM環部6へと誘導した。さらにLM環部6から7段階を経てNO環部7へと変換し、6と7のアルドール反応、続くβ-ヒドロキシケトンのアンチ選択的な還元によってLMNO環部8を合成した。

Event date： 2014.6

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

マイトトキシン(MTX)は渦鞭毛藻Gambierdiscus toxicusが生産する梯子状ポリエーテル化合物である。MTXは極低濃度でCa2+流入活性を示すことで知られているが、未だその作用機構は解明されていない。当研究室ではMTXの作用標的分子の同定を目指し、化学合成に基づいたMTXの構造活性相関研究を行っている1)。本研究ではMTXのアゴニストとなる部分構造の探索を目的とし、その疎水性部分と親水性部分の境界領域に相当するNOPQRS環部の合成を計画した。まず、Weinrebアミド1とフリルリチウム2とのカップリング反応を経てアルコール3を合成した。続いてAchmatowicz反応および化学選択的メチル化によって化合物4へと変換後、立体選択的ジヒドロキシ化を経てQ環部に存在する5連続不斉中心を構築した。得られた三環性化合物5は環拡大反応によってQRS環部6へと変換した。QRS環部6を末端アルキンへと誘導後、NO環部7とのカップリング反応を経てNOPQRS環部8を合成する予定である。

Event date： 2014.6

Language：Japanese  

Venue：大阪大学　豊中キャンパス　大阪大学会館   Country：Japan  

マイトトキシン(MTX)は渦鞭毛藻Gambierdiscus toxicusが生産する梯子状ポリエーテル化合物であり、32個のエーテル環と98個の不斉中心を有し、疎水性部分と親水性部分を併せ持つ巨大な天然物である。MTXは強力な毒性を示すほか、極低濃度でCa2+流入活性を示すことが知られているが、その作用機構は未解明である1)。疎水性の梯子状ポリエーテル化合物であるブレベトキシンが、膜貫通タンパク質である電位依存性Na+チャネルに作用することが知られていることから、MTXも同様に疎水性部分が膜の中に入り、標的タンパク質に作用しているという仮説を立てた。当研究室では、この仮説をもとに化学合成したMTXの疎水性部分構造を用いた構造活性相関研究を行っており、WXYZA’B’C’環部がMTXのCa2+流入活性をIC50 = 30 μMで阻害することを見出した2)。本研究では、MTXのCa2+流入活性に対してより強い阻害活性を示す部分構造の探索を目指し、同じく疎水性部分に含まれるQRS環部およびC’D’E’F’環部を合成し、生物活性試験を行った。その結果、C’D’E’F’環部がMTXのCa2+流入活性をIC50 = 60 μMで阻害することが分かった。なお、QRS環部に対して同様の活性試験を行った結果についても報告する予定である。

Event date： 2014.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京工業大学（大岡山キャンパス）ディジタル多目的ホール   Country：Japan  

アンフィジノール3（以下、AM3、1）は渦鞭毛藻 Amphidinium klebsiiから単離されたポリエンポリオール化合物であり1、強力な抗真菌活性（4 g/disk, Aspergillus niger）ならびに溶血性（EC50 = 9.4 nM）を有する2。AM3の活性発現機構は明らかになっていないが、複数のAM3が凝集しトロイダル型のポアを形成して膜機能を破壊すると考えられている。また、AM3の絶対配置は1999年に決定されたが3、合成化学的な構造確認の結果C2位およびC51位の立体化学が改訂された4-6。今回我々はAM3の全立体配置を確認することを目的として全合成研究を行った。

Event date： 2014.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：和光純薬工業㈱ 湯河原研修所   Country：Japan  

Event date： 2014.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：タワーホール船堀   Country：Japan  

アンフィジノール3(AM3)は渦鞭毛藻Amphidinium klebsiiから単離された天然物であり1)、強力な溶血活性、抗真菌活性を有する。AM3は、直鎖のポリオール部分と2つのTHP環、およびポリエン部分からなる特徴的な構造を有するが、不斉炭素の約7割が鎖状炭素上に存在するため絶対配置の決定が困難である。これまで部分構造の合成によってC2位およびC51位の絶対配置が訂正された2, 3)。そこで、本研究では、全合成による正確なAM3の絶対配置の確認を指向してC1-C20部分の合成研究を行った。まず、Weinrebアミド 2へのリチウムアセチリド3およびビニルリチウム1の付加と立体選択的還元を順次行い、5を合成した。さらに、4とのクロスメタセシスを行うことでC1-C20部分6を総工程数18で合成した。

Event date： 2014.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：タワーホール船堀   Country：Japan  

マイトトキシン(MTX)は渦鞭毛藻Gambierdiscus toxicusが生産する梯子状ポリエーテル化合物であり、低濃度で細胞内Ca2+濃度上昇作用を示す。当研究室では化学合成したMTXの部分構造を用いた構造活性相関研究を行っている1)。本研究ではまずQRS環部(5)の合成を行った。Weinrebアミド1とフリルリチウム3とのカップリング、化学選択的メチル化、立体選択的ジヒドロキシ化を経由して3環性化合物4を得た後、環拡大反応を経てQRS環部5を合成した。次いでC’D’E’F’環部(9)の合成を行った。C’D’F’環部に相当する末端オレフィン6と側鎖部分であるヨードオレフィン7の鈴木－宮浦反応によるカップリング2)を経て化合物8を得た。続いて上西らの報告3)に従い、Pd(II)を用いた触媒的環化反応によりF’環部を立体選択的に構築することに成功した。さらにSharpless不斉ジヒドロキシ化および末端オレフィンの導入を経てC’D’E’F’環部(9)を合成した。合成した2つの部分構造に関して生物活性試験を行った結果についても報告する予定である。

Event date： 2014.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：タワーホール船堀   Country：Japan  

アンフィジノール３（AM3）は渦鞭毛藻 Amphidinium krebsiiから単離された海洋天然物であり、ポリエン鎖、２つのTHP環、ポリオール鎖で構成されている。強力な抗真菌活性および溶血性を有するが、その詳細な分子機構は未だ解明されていない。脂質膜と直接的に相互作用し会合して膜に孔を開けることでその生物活性を発現するとされており、その際に疎水性ポリエン部分が重要な役割を果たすと考えられている。
我々は、AM3の活性発現に必要な最小構造単位を知るための構造類縁体の一つとしてTHP環およびポリオール部分を短縮した化合物1を設定し、合成および生物活性試験を行うこととした。すなわち、AM3のC21-C29 部分に相当するアルキルボラン2とC30-C40部分に相当するヨードオレフィン3とを鈴木―宮浦カップリングにより連結後、C53-C67部分に相当するポリエン鎖をJulia-Kocienskiオレフィン化を用いて導入することで、短縮類縁体1の合成を検討した。発表ではその詳細を報告する。

Event date： 2014.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：タワーホール船堀   Country：Japan  

マイトトキシンは渦鞭毛藻Gambierdiscus toxicusが生産する梯子状ポリエーテルであり、強力な毒性や細胞内Ca2+濃度上昇作用を示す。当研究室では合成フラグメントを用いたMTXの構造活性相関研究を行なっており、本研究ではMTXのLMNO環部(1)に着目し、その合成を検討した。まずNicolaouらの報告1)を参考に、フラン2を出発原料としてL/N環部3を合成した。次にヨウ化アルケニル4を用いた野崎-檜山-岸反応を行うことでアリルアルコール5を得た。アリルアルコール5に対しTBAFを作用させるとTBS基の除去および分子内オキサMichael反応が連続して起こり、LM/NO環部6を与えた。さらにPummerer転位によりLM環部7へと誘導し、LM環部7から7段階を経てNO環部8を得た。アルドール反応によるLM環部7とNO環部8の連結についても報告する予定である。

Event date： 2014.1 - 2011.1

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：早稲⽥⼤学国際会議場   Country：Japan  

複雑な構造を有する天然物の合成にもフローマイクロ合成は有用である。以下の反応においてフラスコを用いる従来法ではスケールアップを行うと低収率であるが、フローマイクロ合成により再現性良くスケールアップが可能になった。

Event date： 2014.1

Language：Japanese  

Venue：Nishijin Plaza, Kyushu University, Fukuoka   Country：Japan  

Amphidinol 3 (AM3, 1) is a marine natural product produced by the dinoflagellate Amphidinium klebsii. AM3 has attracted considerable attention of synthetic chemists because of the unique structure and potent antifungal activity. As a part of our studies on total synthesis of AM3, the C1-C20 part of AM3 (5) has been synthesized.

Event date： 2014.1

Language：Japanese  

Venue：Nishijin Plaza, Kyushu University, Fukuoka   Country：Japan  

Maitotoxin (MTX) is a ladder shaped polyether compound produced by dinoflagellate Gambierdiscus toxicus, and it was found as one of the causative toxins of ciguatera seafood poisoning. MTX elicits remarkable biological activities at extremely low concentrations, for instance, MTX causes hemolysis of red blood cells and a profound influx of Ca2+ into cells. As a part of our structure-activity relationship studies based on chemical synthesis of the partial structures of MTX[1], the QRS ring system (3) of MTX was designed. The synthesis of 3 from Weinreb amide 1 and furyl lithium 2 was achieved via selective methylation and ring expansion as key steps.

Event date： 2014.1

Language：Japanese  

Venue：Nishijin Plaza, Kyushu University, Fukuoka   Country：Japan  

Chemotaxis of sperm toward an egg is a critical step in reproduction, particularly in aquatic environments, where sperm frequently travel long distances to contact an egg. A non-peptidic chemoattractant called sperm-activating and attracting factor (SAAF, 1) was isolated from eggs of the ascidian Ciona intestinalis. To identify its target protein(s), molecular probes of SAAF were synthesized.

Event date： 2014.1

Language：Japanese  

Venue：Nishijin Plaza, Kyushu University, Fukuoka   Country：Japan  

Amphidinol 3 (AM3) is a marine natural product isolated from dinoflagellate Amphidinium klebsii. AM3 elicits potent antifungal activity (MIC = 4.0 g/disk), but its mode of action remains to be elucidated. Because of the presence of a number of stereogenic centers on the acyclic long carbon chain, it was difficult to determine the molecular structure of AM3. Although the stereochemistry of AM3 was determined by extensive NMR analysis and degradation of the natural product, total synthesis of AM3 is necessary for the structure confirmation. Our recent approach toward total synthesis of AM3 will be discussed.

Event date： 2013.11 - 2013.12

Language：English   Presentation type：Oral presentation (general)  

Venue：Todaiji Temple Cultural Center, Nara   Country：Japan  

Event date： 2013.11

Language：English  

Country：Japan  

Amphidinol 3 (AM3, 1) is a marine natural product isolated from dinoflagellate Amphidinium klebsii.1 AM3 elicits potent antifungal activity (MIC = 4.0 g/disk),2 but its mode of action remains to be elucidated. Because of the presence of a number of stereogenic centers on the acyclic long carbon chain, it was difficult to determine the molecular structure of AM3. Although the stereochemistry of AM3 was determined by extensive NMR analysis and degradation of the natural product,3 total synthesis of AM3 is necessary for the structure confirmation. As a part of our studies on structure confirmation of AM3 based on the chemical synthesis of the partial structures,4,5 the C31-C67 part of AM3 has been synthesized. Both the C43-C52 and the C31-C42 THP fragments were prepared from common THP intermediate.6 Coupling of these fragments and introduction of the polyene group via Julia-Kocienski olefination successfully afforded the C31-C67 part of AM3.

Event date： 2013.10 - 2013.11

Language：Japanese  

Venue：北海道大学創成科学研究棟   Country：Japan  

Event date： 2013.10

Language：English  

Venue：The Ritz-Carlton Seoul, Seoul   Country：Korea, Republic of  

Maitotoxin (MTX) is a causative toxin of ciguaetra seafood poisoning produced by the dinoflagellate Gambierdiscus toxicus. MTX is one of the largest non-biopolymer (MW 3422) and most toxic against mammals (50 ng/kg) known to date. MTX elicits remarkable biological activities at extremely low concentration, for instance, hemolysis of red blood cells (15 nM) and calcium ion influx in various cell lines (0.3 nM). Despite a large number of investigations, the precise mode of action at the molecular level has not been elucidated. During the course of our synthetic studies of MTX for developing its antagonists, partial structure of MTX corresponding to the WXYZA’B’C’ ring system was synthesized based on the -cyano ether method via successive coupling of the W- and Z-ring giving the WXYZ-ring fragment, followed by coupling with the C’-ring through the construction of the A’B’-ring systems. Syntheses of the C’D’E’F’ ring and the QRS ring system will be also reported.

Event date： 2013.10

Language：Japanese  

Venue：タワーホール船堀   Country：Japan  

アンフィジノール3 (AM3) は渦鞭毛藻が産生する天然有機化合物であり、強力な溶血活性、抗真菌活性を有する。AM3は細胞膜に直接作用して活性を発現するため、従来にはない新しいタイプの抗菌剤として注目されている。また、連続した１，５―ポリオール部分と官能基化された2つのTHP環、およびポリエン部分を有する構造が特徴的である。AM3には25個の不斉炭素が含まれるが、その約７割が鎖状炭素鎖に存在するため立体配置の決定が困難な化合物である。当研究室では、AM3の部分構造を化学合成し、合成フラグメントと天然物のNMRを比較することによって、C2位およびC51位の立体化学の訂正した。本研究では、全合成によるAM3の正確な立体配置の確認、および効率的合成法の開発を指向して、C1-C20部分の合成を行った結果について報告する。

Event date： 2013.10

Language：English  

Venue：Niigata University, Niigata   Country：Japan  

Amphidinol 3 (AM3, 1) is a marine natural product isolated from dinoflagellate Amphidinium klebsii.1 AM3 elicits potent antifungal activity (MIC = 4.0 g/disk),2 but its mode of action remains to be elucidated. Because of the presence of a number of stereogenic centers on the acyclic long carbon chain, it was difficult to determine the molecular structure of AM3. Although the stereochemistry of AM3 was determined by extensive NMR analysis and degradation of the natural product,3 total synthesis of AM3 is necessary for the structure confirmation. As a part of our studies on structure confirmation of AM3 based on the chemical synthesis of the partial structures,4,5 the C31-C67 part of AM3 has been synthesized. Both the C43-C52 and the C31-C42 THP fragments were prepared from common THP intermediate.6 Coupling of these fragments and introduction of the polyene group via Julia-Kocienski olefination successfully afforded the C31-C67 part of AM3.

Event date： 2013.10

Language：English  

Venue：Niigata University, Niigata   Country：Japan  

Maitotoxin (MTX) is a ladder shaped polyether compound produced by dinoflagellate Gambierdiscus toxicus, and it was found as one of the causative toxins of ciguatera seafood poisoning. MTX elicits remarkable biological activities at extremely low concentrations, for instance, MTX causes hemolysis of red blood cells and a profound influx of Ca2+ into cells. As a part of our structure-activity relationship studies based on chemical synthesis of the partial structures of MTX,1 the QRS ring system (1) of MTX was designed. The synthesis of 1 began with coupling reaction of Weinreb amide 2 with furyllithium 3, followed by Achmatowicz reaction and methylation to afford pyranone 4. Chemoselective methylation on the methoxy group of 4 was achieved in a stereoselective manner, and then tricyclic compound 6 was synthesized via methylation. After conversion of compound 6 to ketone 7, the synthesis of the QRS ring system 1 was achieved via ring expansion.

Event date： 2013.8

Language：Japanese  

Venue：九州大学 馬出キャンパス　 コラボステーション   Country：Japan  

Event date： 2013.8

Language：Japanese  

Venue：九州大学 馬出キャンパス　 コラボステーション   Country：Japan  

Event date： 2013.8

Language：Japanese  

Venue：九州大学 馬出キャンパス　 コラボステーション   Country：Japan  

Event date： 2013.8

Language：Japanese  

Venue：九州大学 馬出キャンパス　 コラボステーション   Country：Japan  

Event date： 2013.8

Language：Japanese  

Venue：九州大学 馬出キャンパス　 コラボステーション   Country：Japan  

Event date： 2013.7

Language：Japanese  

Venue：九州大学医学部百年講堂   Country：Japan  

アンフィジノール3 (AM3, 1) は渦鞭毛藻が産生する抗真菌物質である。AM3は細胞膜に直接作用して活性を発現するため、従来にはない新しいタイプの抗菌剤として注目されている。当研究室では、AM3の効率的な合成法を開発し、正確な立体配置の確認および構造活性相関を基にした簡略化アナログ分子の創成を目指している。本研究ではC1-C20部分に相当する化合物2の合成研究を行った。当研究室では、化学選択的なクロスメタセシスを用いたAM3のC1-C10部分の合成1に成功しているので、その方法を応用することにした。すなわち、ワインレブアミド 3とリチウムアセチリド4から6段階で誘導可能なエノン5とヨードオレフィン6との化学選択的クロスメタセシス、CBS還元を経由してオレフィン7を得た。続いてオレフィン7と8とのクロスメタセシスによりC1-C20部分に相当する2を合成した。

Event date： 2013.7

Language：Japanese  

Venue：九州大学医学部百年講堂   Country：Japan  

マイトトキシン(MTX)は、渦鞭毛藻Gambierdiscus toxicusが生産する梯子状ポリエーテル化合物であり、細胞内Ca2+濃度上昇作用や溶血活性を示す。しかし、MTXは非特異的吸着が強く、また天然から極微量しか得られないことから、作用標的タンパク質や詳細な作用機構は解明されていない。当研究室ではマイトトキシンの構造活性相関研究を視野に入れた部分構造の合成を行っている1)。今回C’D’E’F’環部(7)の合成を計画し、側鎖の導入には鈴木―宮浦カップリング反応2)を用いることにした。まず、側鎖部分であるヨードオレフィン1とC’D’E’環部に相当する末端オレフィン2から鈴木―宮浦反応によりカップリング成績体3を合成した。さらにTBS基の除去を行ってジオール4に変換した後、上西らの報告3)に従いPd(II)を用いた触媒的環化反応によりF’環部を立体選択的に構築することに成功した。続いてオレフィン5に対しSharpless不斉ジヒドロキシ化を行うことでジオール6 (α : β = 3 : 1)を得た。さらに末端オレフィンを導入し、C’D’E’F’環部7の合成に成功した。

Event date： 2013.7

Language：Japanese  

Venue：九州大学医学部百年講堂   Country：Japan  

マイトトキシン(MTX)は渦鞭毛藻Gambierdiscus toxicusが生産する梯子状ポリエーテルである。当研究室では化学合成した部分構造を用いたMTXの構造活性相関研究を行っている1)。本研究ではQRS環部2とNO環部3とのカップリングによるNOPQRS環部(1)の合成を検討した。S環部に相当するWeinrebアミド4とフリルリチウム5とのカップリング反応により得られたケトン6に対し、不斉還元、Achmatowicz反応を経由して7を合成した。ピラノン7に対してBF3・OEt2存在下、Me2Znを作用させることでケトン存在下、メチルアセタールのみをメチル化することに成功した。R環を構築後、オレフィン8に対し四酸化オスミウム酸化を行うことで望む三環性化合物9を単一の生成物として得ることに成功した。QRS環部2への変換についても報告する予定である。

Event date： 2013.7

Language：Japanese  

Venue：九州大学医学部百年講堂   Country：Japan  

近年、抗生物質が効かない耐性菌の出現が問題となっている。アンフィジノール3は渦鞭毛藻が産生する抗真菌物質である。AM3は細胞膜に直接作用して活性を発現するため、耐性菌が出現しにくい新しいタイプの抗菌剤として注目されている。当研究室では、AM3の効率的な合成法の開発および構造活性相関を基にした簡略化アナログ分子の創生を目指している。1) 本研究ではC19-C40部分に相当する化合物1の合成研究を行った。化合物1はC29とC30の間で鈴木―宮浦カップリングを行うことにより合成することにした。オレフィン2とアクロレイン(3)とのクロスメタセシスを行った後、分子内oxa-Michael反応によりC27位の立体化学を構築し化合物4へと変換した。続いてDess-Martin酸化、Brown不斉クロチル化を行いC21-C29部に相当する化合物5を得た。一方、文献既知の化合物62) から大平-Bestmann反応を経由してアルキン7を得た。化合物7から誘導したヨードオレフィンと化合物8から誘導したアルキルボランを用いた鈴木―宮浦カップリングを検討中である。

Event date： 2013.6

Language：English  

Venue：Vienna   Country：Austria  

Amphidinol 3 (AM3) is a marine natural product isolated from dinoflagellate Amphidinium klebsii. AM3 elicits potent antifungal activity (MIC = 4.0 g/disk), but its mode of action remains to be elucidated. Because of the presence of a number of stereogenic centers on the acyclic long carbon chain, it was difficult to determine the molecular structure of AM3. Although the stereochemistry of AM3 was determined by extensive NMR analysis and degradation of the natural product, total synthesis of AM3 is necessary for the structure confirmation.
As a part of our studies on structure confirmation of AM3, synthesis of the C31-C67 part of AM3 was achieved. Both the C31-C42 (3) and the C43-C52 (4) fragments were prepared from common THP intermediate 2. Coupling of these fragments and introduction of the polyene unit via Julia-Kocienski olefination using sulfone 5 successfully afforded the C31-C67 part of AM3 (6).

Event date： 2013.6

Language：English  

Venue：Pukyong National University Jangbogo Hall   Country：Korea, Republic of  

Amphidinol 3 (AM3, 1) is a marine natural product produced by the dinoflagellate Amphidinium klebsii. AM3 has attracted considerable attention of synthetic chemists because of the unique structure and potent antifungal activity. As a part of our studies on total synthesis of AM3, the C1-C20 part of AM3 (5) has been synthesized via chemoselective cross metathesis1 as a key step.

Event date： 2013.6

Language：English  

Venue：Pukyong National University Jangbogo Hall   Country：Korea, Republic of  

Maitotoxin (MTX) is a biotoxin produced by dinoflagellate Gambierdiscus toxicus and it was found as one of the causative toxins of ciguatera seafood poisoning. As a part of our structure-activity relationship studies based on chemical synthesis of the partial structures of MTX,1 the QRS ring system of MTX was designed and synthesized via chemoselective methylation of a pyranone and ring expansion giving seven-membered S-ring.

Event date： 2013.6

Language：Japanese  

Venue：九州大学医学部百年講堂   Country：Japan  

マイトトキシン(MTX)は、渦鞭毛藻Gambierdiscus toxicusが生産する梯子状ポリエーテル化合物であり、細胞内Ca2+濃度上昇作用や溶血活性を示す。MTXは非特異的吸着が強く、また天然から極微量しか得られないことから、作用標的タンパク質や詳細な作用機構は解明されていない。当研究室ではマイトトキシンの構造活性相関研究を視野に入れた部分構造の合成を行っている1)。今回C’D’E’F’環部(7)の合成を計画し、側鎖の導入には鈴木―宮浦カップリング反応2)を用いることにした（Scheme 1）。まず、側鎖部分であるヨードオレフィン1とC’D’E’環部に相当する末端オレフィン2から鈴木―宮浦反応によりカップリング成績体3を合成した。さらにTBS基の除去を行ってジオール4に変換した後、上西らの報告3)に従いPd(II)を用いた触媒的環化反応によりF’環部を立体選択的に構築することに成功した。続いてオレフィン5に対しSharpless不斉ジヒドロキシ化を行うことでジオール6 (α : β = 5 : 1)を得た。末端オレフィン導入による7への変換についても報告する予定である。

Event date： 2013.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：和光純薬工業㈱ 湯河原研修所   Country：Japan  

Event date： 2013.5

Language：English  

Venue：Crown Plaza ANA Nagasaki Gloverhill, Nagasaki   Country：Japan  

Amphidinol 3 (AM3, 1) is a marine natural product isolated from dinoflagellate Amphidinium klebsii.1) AM3 elicits potent antifungal activity (MIC = 4.0 g/disk),2) but its mode of action remains to be elucidated. Because of the presence of a number of stereogenic centers on the acyclic long carbon chain, it was difficult to determine the molecular structure of AM3. Although the stereochemistry of AM3 was determined by extensive NMR analysis and degradation of the natural product,3) total synthesis of AM3 is necessary for the structure confirmation.
As a part of our studies on structure confirmation of AM3, the C31-C67 part of AM3 has been synthesized. Both the C43-C52 and the C31-C42 THP fragments were prepared from common THP intermediate. Coupling of these fragments and introduction of the polyene group via Julia-Kocienski olefination successfully afforded the C31-C67 part of AM3. In the poster presentation, we will present a synthesis and structure analysis of the C31-C67 part of AM3.

Event date： 2013.4

Language：English  

Venue：Tokyo Institute of Technology, Tokyo   Country：Japan  

Event date： 2013.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：立命館大学びわこ・くさつキャンパス   Country：Japan  

Event date： 2013.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：立命館大学びわこ・くさつキャンパス   Country：Japan  

Event date： 2013.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：立命館大学びわこ・くさつキャンパス   Country：Japan