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

DOI： 10.1038/s41467-023-44401-w

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1021/acs.orglett.3c03002

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry (RSC)  

A stereodivergent synthesis of 2,5-disubstituted pyrrolidines from readily available amino alkynes was made possible under Au catalysis.

DOI： 10.1039/d3cc02453a

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

DOI： 10.1021/acs.orglett.3c01932

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1021/acs.orglett.3c00551

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1246/bcsj.20220340

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Chemical Society of Japan  

DOI： 10.1246/bcsj.20220253

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

DOI： 10.1021/acs.orglett.2c02007

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

DOI： 10.1021/acs.orglett.2c01429

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

DOI： 10.3390/toxins14040254

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-VCH  

DOI： 10.1002/anie.202202549

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

DOI： 10.1016/j.fct.2022.112812

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Chemical Society of Japan  

DOI： 10.1246/bcsj.20210178

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

DOI： 10.1021/acs.joc.1c00443

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

DOI： 10.1021/acs.joc.1c00508

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

DOI： 10.1021/acs.joc.1c00085

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

© The Royal Society of Chemistry 2020. Amphirionin-2 is a linear polyketide metabolite that exhibits potent and selective cytotoxic activity against certain human cancer cell lines. We disclose herein the first total synthesis of amphirionin-2 and determination of its absolute configuration. Our synthesis featured an extensive use of cobalt-catalyzed Mukaiyama-type cyclization of γ-hydroxy olefins for stereoselective formation of all the tetrahydrofuran rings found in the natural product, and a late-stage Stille-type coupling for convergent assembly of the entire carbon backbone. Four candidate diastereomers of amphirionin-2 were synthesized in a unified, convergent manner, and their spectroscopic/chromatographic properties were compared with those of the authentic material. The present study culminated in the reassignment of the C5/C7 relative configuration, assignment of the C12/C18 relative configuration, and determination of the absolute configuration of amphirionin-2.

DOI： 10.1039/D0SC06021F

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-VCH  

DOI： 10.1002/asia.202001015

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

DOI： 10.1016/j.neuroscience.2019.06.024

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-VCH  

DOI： 10.1002/asia.201901660

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-VCH  

Iriomoteolide-2a is a marine macrolide metabolite isolated from a cultured broth of the benthic dinoflagellate Amphidinium sp. HYA024 strain. This naturally occurring substance was reported to show remarkable cytotoxic activity against human cancer cell lines HeLa and DG-75 and in vivo antitumor activity against murine leukemia P388 cell line. Herein, the total synthesis, stereochemical revision, and biological assessment of iriomoteolide-2a are reported in detail. Total synthesis of the proposed structure 1 of iriomoteolide-2a featured a late-stage convergent assembly of three components by a Suzuki-Miyaura coupling, an esterification, and a ring-closing metathesis. However, the NMR data of synthetic 1 were not identical to those of the natural product. Careful analysis of the NMR data of the authentic material and synthesis/NMR analysis of appropriately designed model compounds led to consideration of four possible stereoisomers 2-5 as candidates for the correct structure. Accordingly, total syntheses of 2-5 were achieved by taking advantage of the convergent strategy, and comparison of the NMR spectra of synthetic 2-5 with those of the natural product led to the conclusion that 5 shows the correct relative configuration of iriomoteolide-2a. The absolute configuration of this natural product was finally established through chiral HPLC analysis of synthetic 5/ent-5 with the authentic sample. The antiproliferative activity of the synthetic compounds was assessed against HeLa and A549 cells to show that, in contrast to expectation, synthetic 5 and ent-5 were only marginally active in these cell lines. This work clearly underscores the vital role of total synthesis in the establishment of the structure and biological activity of natural products.

DOI： 10.1002/chem.201900813

PubMed

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

Design, synthesis and functional analysis of fluorescent derivatives of neopeltolide, an antiproliferative marine macrolide, are reported herein. Live cell imaging using the fluorescent derivatives showed rapid cellular uptake and localization within the endoplasmic reticulum as well as the mitochondria.

DOI： 10.1039/C9OB01276A

PubMed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society  

DOI： 10.1021/acs.orglett.9b01182

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

DOI： 10.1021/acs.orglett.8b03368

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-VCH  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-VCH  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Neopeltolide, an antiproliferative marine macrolide, is known to specifically inhibit complex III of the mitochondrial electron transport chain (mETC). However, details of the biological mode-of-action(s) remain largely unknown. This work demonstrates potent cytotoxic activity of synthetic neopeltolide analogue, 8,9-dehydroneopeltolide (8,9-DNP), against starved human pancreatic adenocarcinoma PANC-1 cells and human non-small cell lung adenocarcinoma A549 cells. 8,9-DNP induced rapid dissipation of the mitochondrial membrane potential and depletion of intracellular ATP level in nutrient-deprived medium. Meanwhile, in spite of mTOR inhibition under starvation conditions, impairment of cytoprotective autophagy was observed as the lipidation of LC3-I to form LC3-II and the degradation of p62 were suppressed. Consequently, cells were severely deprived of energy sources and underwent necrotic cell death. The autophagic flux inhibited by 8,9-DNP could be restored by glucose, and this eventually rescued cells from necrotic death. Thus, 8,9-DNP is a potent anti-austerity agent that impairs mitochondrial ATP synthesis and cytoprotective autophagy in starved tumor cells.

DOI： 10.3390/md15100320

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

Gambierol and its two, tetra- and heptacyclic, analogues have been previously proved as promising molecules for the modulation of Alzheimer's disease (AD) hallmarks in primary cortical neurons of 3xTg-AD fetuses. In this work, the effect of the tetracyclic analogue of gambierol was tested in vivo in 3xTg-AD mice (10 months old) after 1 month of weekly treatment with 50 mu g/kg. Adverse effects were not reported throughout the whole treatment period and no pathological signs were observed for the analyzed organs. The compound was found in brain samples after intraperitoneal injection. The tetracyclic analogue of gambierol elicited a decrease of amyloid beta(1-42) levels and a dose-dependent inhibition of beta-secretase enzyme-1 activity. Moreover, this compound also reduced the phosphorylation of tau at the 181 and 159/163 residues with an increase of the inactive isoform of the glycogen synthase kinase-3 beta. In accordance with our in vitro neuronal model, this compound produced a reduction in the N2A subunit of the N-methyl-D-aspartate (NMDA) receptor. The combined effect of this compound on amyloid beta(1-42) and tau phosphorylation represents a multitarget therapeutic approach for AD which might be more effective for this multifactorial and complex neurodegenerative disease than the current treatments.

DOI： 10.1021/acschemneuro.7b00012

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Language：English   Publishing type：Part of collection (book)   Publisher：Academic Press Inc.  

This account describes our endeavors on the total synthesis and structure elucidation of a marine macrolide glycoside, (−)-lyngbyaloside B. This natural product was isolated as a moderately cytotoxic constituent from the Palauan cyanobacterium Lyngbya sp. Our investigation started with the total synthesis of a nonnatural analog, (−)-13-demethyllyngbyaloside B, which was completed by exploiting an esterification/ring-closing metathesis strategy for the construction of the macrocyclic framework. Our efforts toward (−)-lyngbyaloside B were frustrated by the difficulties associated with the construction of the macrocycle involving an acylated tertiary alcohol. Eventually, the first total synthesis of the proposed structure of (−)-lyngbyaloside B was completed via an acyl ketene macrocyclization to forge the macrocyclic backbone. Because the proposed structure turned out to be erroneously assigned, we deduced the correct structure of (−)-lyngbyaloside B on the basis of the NMR data of the authentic material and molecular modeling. Ultimately, our revised structure was unambiguously verified through total synthesis.

DOI： 10.1016/B978-0-08-100756-3.00005-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：日本化学会  

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

This paper describes a concise synthesis of six- to eight-membered alpha,alpha'-substituted cyclic ethers by exploiting diastereoselective ring-closing metathesis (RCM) of 1,4-pentadien-3-yl ether derivatives. The RCM precursors could be efficiently prepared via a vinylation of the corresponding a-acetoxy ether derivatives using divinylzinc. Diastereoselective RCM of 1,4-pentadien-3-yl ether derivatives afforded a series of six- to eight-membered alpha,alpha'-substituted cyclic ethers with moderate to good diastereoselectivity. The stereochemical consequence of the diastereoselective RCM appeared to be dependent on the structure of the ring being forged. The diastereoselectivity of six- and seven-membered cyclic ethers appeared to be largely under kinetic control irrespective of the catalyst reactivity, whereas that of an eight-membered cyclic ether could be controlled by the catalyst reactivity. Finally, the diastereoselective RCM chemistry was applied to the synthesis of a biotin-tagged photoactivatable derivative of gambierol.

DOI： 10.1021/acs.joc.6b01302

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

Okadaic acid (OA), a product of dinoflagellate Prorocentrum spp., is transformed into 7-O-acyl OA in various bivalve species. The structural transformation proceeds enzymatically in vitro in the presence of the microsomal fraction from the digestive gland of bivalves. We have been using LC-MS/MS to identify OA-transforming enzymes by detecting 7-O-acyl OA, also known as dinophysistoxin 3 (DTX3). However, an alternative assay for DTX3 is required because the OA-transforming enzyme is a membrane protein, and surfactants for solubilizing membrane proteins decrease the sensitivity of LC-MS/MS. The present study examined saturated fatty acyl CoAs with a carbon chain length of 10 (decanoyl), 12 (dodecanoyl), 14 (tetradecanoyl), 16 (hexadecanoyl) and 18 (octadecanoyl) as the substrate for the in vitro acylation reaction. Saturated fatty acyl CoAs with a carbon chain length of 14, 16 and 18 exhibited higher yields than those with a carbon chain length of 10 or 12. Acyl CoAs with carbon chain lengths from 14 to 18 and containing either a diene unit, an alkyne unit, or an azide unit in the carbon chain were synthesized and shown to provide the corresponding DTX3 with a yield comparable to that of hexadecanoyl CoA. The three functional units can be conjugated with fluorescent reagents and are applicable to the development of a novel assay for DTX3. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2016.05.027

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

We have described in detail the total synthesis of both the proposed and correct structures of (-)-lyngbyalosideB, which facilitated the elucidation of the complete stereostructure of this natural product. Our study began with the total synthesis of 13-demethyllyngbyalosideB, in which an esterification/ring-closing metathesis (RCM) strategy was successfully used for the efficient construction of the macrocycle. We also established reliable methods for the introduction of the conjugated diene side chain and the l-rhamnose residue onto the macrocyclic framework. However, the esterification/RCM strategy proved ineffective for the parent natural product because of the difficulties in acylating the sterically encumbered C-13 tertiary alcohol; macrolactionization of a seco-acid was also extensively investigated under various conditions without success. We finally completed the total synthesis of the proposed structure of (-)-lyngbyalosideB by means of a macrolactonization that involves an acyl ketene as the reactive species. However, the NMR spectroscopic data of our synthetic material did not match those of the authentic material, which indicated that the proposed structure must be re-examined. Inspection of the NMR spectroscopic data of the natural product and molecular mechanics calculations led us to postulate that the configuration of the C-10, C-11, and C-13 stereogenic centers had been incorrectly assigned in the proposed structure. Finally, our revised structure of (-)-lyngbyalosideB was unambiguously verified through total synthesis.

DOI： 10.1002/chem.201600341

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

Campechic acids A and B are anti-invasive polyketide antibiotics isolated from Streptomyces sp. CHI93 strain. Herein we describe stereoselective synthesis of the C-16-C-30 fragment of campechic acids A and B via a biosynthesis-inspired epoxide-opening cascade and its NMR spectroscopic comparison with the authentic degradation product, resulting in configurational assignment of the C-21, C-24, C-25, and C-28 stereogenic centers and reassignment of the C-18 stereogenic center.

DOI： 10.1021/acs.joc.6b00290

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

A synthesis of the C8-C29 fragment of amphidinolide N, a potent cytotoxic macrolide isolated from the marine dinoflagellate Amphidinium sp., has been achieved. The key features of the synthesis involve a convergent union of the C9-C15 and C16-C29 fragments by Steglich esterification and the construction of a pyran unit through a Tebbe methylenation/ring-closing metathesis sequence.

DOI： 10.1021/acs.orglett.6b00871

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Tetrahydropyrans are structural motifs that are abundantly present in a range of biologically important marine natural products. As such, significant efforts have been paid to the development of efficient and versatile methods for the synthesis of tetrahydropyran derivatives. Neopeltolide, a potent antiproliferative marine natural product, has been an attractive target compound for synthetic chemists because of its complex structure comprised of a 14-membered macrolactone embedded with a tetrahydropyran ring, and twenty total and formal syntheses of this natural product have been reported so far. This review summarizes the total and formal syntheses of neopeltolide and its analogues, highlighting the synthetic strategies exploited for constructing the tetrahydropyran ring.

DOI： 10.3390/md14040065

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

Goniodomin A is a marine polyether macrolide natural product isolated from the dinoflagellate Alexandrium hiranoi. In this paper, we report stereocontrolled, convergent synthesis of a fully functionalized C12-C36 fragment of goniodomin A. The synthesis of the C12-C25 vinylstannane involved a Wittig reaction and a reductive cycloetherification for the construction of the dihydropyran ring. The C26-C36 thioester was synthesized via a Nozaki-Hiyama-Kishi reaction of an aldehyde and an iodoalkyne, the former of which was easily prepared from (R)-malic add as a chiral source by taking advantage of substrate-controlled diastereoselective reactions. Finally, a palladium-catalyzed coupling of the C12-C25 vinylstannane and the C26-C36 thioester completed the synthesis of the target compound.

DOI： 10.1021/acs.joc.5b02650

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Language：English   Publisher：PACIFICHEM2015  

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

A marine polyether natural product okadaic acid is known to be a potent and specific inhibitor of protein phosphatases 1 and 2A. Herein, concise synthesis of the C15-C38 fragment of okadaic acid is reported. We investigated two different strategies for the construction of two spiroacetal substructures found in the target compound. The first strategy involved Suzuki Miyaura coupling for the synthesis of endocyclic enol ethers and subsequent spiroacetalization. The second strategy exploited Suzuki-Miyaura coupling for the synthesis of exo-olefins as the precursor of spiroacetals. An alkynylaluminum-anomeric sulfone coupling effectively assembled the key spiroacetal substructures and completed the target compound. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2015.04.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER HEIDELBERG  

Gambierol is a marine polycyclic ether toxin, produced along with ciguatoxin congeners by the dinoflagellate Gambierdiscus toxicus. We have recently reported that two truncated skeletal analogs of gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound showed similar potency to gambierol on voltage-gated potassium channels (Kv) inhibition in neurons. Gambierol and its truncated analogs share the main crucial elements for biological activity, which are the C28=C29 double bond within the H-ring and the unsaturated side chain. Since Kv channels are critical for the regulation of calcium signaling, proliferation, secretion and migration in human T lymphocytes, we evaluated the activity of both the tetracyclic and heptacyclic analogs of gambierol on potassium currents in resting T lymphocyte and their effects on interleukin-2 (IL-2) release and gene expression in activated T lymphocytes. The results presented in this work clearly demonstrate that both truncated analogs of gambierol inhibit Kv channels present in resting T lymphocytes (Kv1.3) and prevented lymphocyte activation by concanavalin A. The main effects of the heptacyclic and tetracyclic analogs of gambierol in human T cells are: (1) inhibition of potassium channels in resting and concanavalin-activated T cells in the nanomolar range, (2) inhibition of IL-2 release from concanavalin-activated T cells and (3) negatively affect the expression of genes involved in cell proliferation and immune response observed in concanavalin-activated lymphocytes. These results together with the lack of toxicity in this cellular model, indicates that both analogs of gambierol have additional potential for the development of therapeutic tools in autoimmune diseases.

DOI： 10.1007/s00204-014-1299-2

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

Gambierol and its heptacyclic and tetracyclic analogs were tested for inhibitory activity against the human voltage-gated potassium channel Kv1.2 (hKv1.2), which was stably expressed in Chinese hamster ovary (CHO) cells. Gambierol, the heptacyclic analog, and the tetracyclic analog inhibited the potassium current evoked by a step pulse from -80 mV to 40 mV. The IC50 values for the three compounds were 0.75 +/- 0.15 nM, 7.6 +/- 1.2 nM, and 28 +/- 4.0 nM (the mean +/- SEM, n = 3), respectively. The cytotoxic activity was examined in order to assess a relationship between cytotoxicity and inhibition of the hKv1.2. The IC50 values for gambierol, the heptacyclic analog, and the tetracyclic analog in the wild-type CHO cells were 95 +/- 7.1 lM, 6.5 +/- 0.8 lM(the mean +/- SEM, n = 3), and > 100 lM (n = 3), respectively, whereas those in the CHO cells stably expressing hKv1.2 were 78 +/- 5.8 lM, 6.0 +/- 1.0 lM (the mean +/- SEM, n = 3), and > 100 lM (n = 3). These results suggested that cytotoxicity is not triggered by inhibition of the human Kv1.2. The electrophysiological recording at the resting potential in the presence of gambierol, the heptacyclic analog, and the tetracyclic analog revealed the dose-dependent leak current, which was largest when the heptacyclic analog was administered to the cells. We thus propose that the leak current induced by these compounds might cause a fatal effect on the cultured cells. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2014.12.022

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FRONTIERS MEDIA SA  

Gambieric acid A (GAA) and its congeners belong to the family of marine polycyclic ether natural products. Their highly complex molecular architecture and unique biological activities have been of intense interest within the synthetic community. We have previously reported the first total synthesis, stereochemical reassignment, and preliminary structure activity relationships of GAA. Here we disclose a concise synthesis of the A/BCD-ring fragment of GAA. The synthesis started from our previously reported synthetic intermediate that represents the A/B-ring. The C-ring was synthesized via an oxiranyl anion coupling and a 6-endo cyclization, and the D-ring was forged by means of an oxidative lactonization and subsequent palladium-catalyzed functionalization of the lactone ring. In this manner, the number of linear synthetic steps required for the construction of the C- and D-rings was reduced from 22 to 11.

DOI： 10.3389/fchem.2014.00116

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

(-)-Lyngbyaloside B is a 14-membered macrolide glycoside isolated from the marine cyanobacterium Lyngbya sp. as a cytotoxic substance by Moore and co-workers. The first total synthesis of (-)-lyngbyaloside B and the reassignment of its stereostructure is described. The synthesis features an Abiko-Masamune aldol reaction, a vinylogous Mukaiyama aldol reaction, and a macrocyclization involving an acyl ketene intermediate for the construction of the macrocyclic backbone, which contains an acylated tertiary alcohol. The antiproliferative activity of selected compounds against a small panel of human cancer cell lines is also reported.

DOI： 10.1002/anie.201409629

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

A stereocontrolled synthesis of the C13-C29 segment of amphidinolide N, a marine macrolide natural product that is extremely potent cytotoxic, is described.

DOI： 10.3987/COM-14-S(K)66

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

(+)-Neopeltolide is a marine macrolide natural product that exhibits potent antiproliferative activity against several human cancer cell lines. Previous study has established that this natural product primarily targets the complex III of the mitochondrial electron transport chain. However, the biochemical mode-of-actions of neopeltolide have not been investigated in detail. Here we report that (-)-8,9-dehydroneopeltolide (8,9-DNP), a more accessible synthetic analogue, shows potent cytotoxicity against human promyelocytic leukemia HL-60 cells preferentially under energy stress conditions. Nuclear morphology analysis, as well as DNA ladder assay, indicated that 8,9-DNP induced significant nuclear condensation/fragmentation and DNA fragmentation, and these events could be suppressed by preincubating the cells with a pan-caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD). Immunoblot analysis demonstrated the release of cytochrome c from the mitochondria and the cleavage of full-length caspase-3 and poly(ADP-ribose) polymerase (PARP). These results indicated that 8,9-DNP induced caspase-dependent apoptotic programmed cell death under energy stress conditions. It was also found that 8,9-DNP induced non-apoptotic cell death in the presence/absence of zVAD under energy stress conditions. Immunoblot analysis showed the intracytosolic release of apoptosis-inducing factor (AIF), although it did not further translocate to the nucleus. It appears most likely that, in the presence of zVAD, 8,9-DNP triggered necrotic cell death as a result of severe intracellular ATP depletion.

DOI： 10.3390/md12115576

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Language：English   Publisher：新学術領域研究（研究領域提案型）「天然物ケミカルバイオロジー」  

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

More than thirty years after the discovery of polycyclic ether marine natural products, they continue to receive intense attention from the chemical, biological, and pharmacological communities because of their potent biological activities and highly complex molecular architectures. Gambieric acids are intriguing polycyclic ethers that exhibit potent antifungal activity with minimal toxicity against mammals. Despite the recent advances in the synthesis of this class of natural products, gambieric acids remain unconquered due to their daunting structural complexity, which poses a formidable synthetic challenge to organic chemists. This paper reviews our long-term studies on the total synthesis, complete configurational reassignment, and structure-activity relationships of gambieric acid A over the last decade.

DOI： 10.1002/tcr.201402052

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

We describe the synthesis and biological evaluation of (+)-neopeltolide analogues with structural modifications in the oxazole-containing side chain. Evaluation of the antiproliferative activity of newly synthesized analogues against A549 human lung adenocarcinoma cells and PANC-1 human pancreatic carcinoma cells have shown that the C19-C20 and C26-C27 double bonds within the oxazole-containing side chain and the terminal methyl carbamate group are essential for potent activity. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2014.04.031

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

Stereoselective synthesis of alpha,alpha'-substituted medium-sized cyclic ethers has been achieved by means of nucleophilic substitution of the corresponding lactone-derived thioacetals and their sulfone counterparts. Nucleophilic substitution of medium-sized lactone-derived thioacetals could be achieved efficiently either by (i) activation with NIS/TMSOTf in the presence of allyltrimethylsilane or TMSCN or by (ii) oxidation to the corresponding sulfones followed by treatment with an appropriate organometallic species such as divinylzinc or dimethyl(2-phenylethynyl)aluminum. Interestingly, the stereochemical consequence was found to be largely dependent on the local structure of substrates. In some cases, the gauche steric interaction developed in the transition state was considered to be responsible for the observed diastereoselectivity. The present method enables an efficient synthesis of a variety of alpha,alpha'-substituted seven- to nine-membered cyclic ethers from readily accessible lactone precursors.

DOI： 10.1021/jo4025545

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

Didemnaketal B, a structurally complex spiroacetal that exhibits potent HIV-1 protease inhibitory activity, was originally discovered by Faulkner and his colleagues from the ascidian Didemnum sp. collected at Palau. Its absolute configuration was proposed on the basis of degradation/derivatization experiments of the authentic sample. However, our total synthesis of the proposed structure of didemnaketal B questioned the stereochemical assignment made by Faulkner et al. Here we describe in detail our first total synthesis of the proposed structure 2 of didemnaketal B, which features 1) a convergent synthesis of the C7-C21 spiroacetal domain by means of a strategy exploiting Suzuki-Miyaura coupling, 2) an Evans syn-aldol reaction and a vinylogous Mukaiyama aldol reaction for the assembly of the C1-C7 acyclic domain, and 3) a Nozaki-Hiyama-Kishi reaction for the construction of the C21-C28 side chain domain. The NMR spectroscopic discrepancies observed between synthetic 2 and the authentic sample as well as careful inspection of the Faulkner's stereochemical assignment led us to postulate that the absolute configuration of the C10-C20 domain of 2 has been erroneously assigned. Accordingly, the total synthesis of the revised structure 65 was achieved to show that the NMR spectroscopic properties of synthetic 65 were in good agreement with those of the authentic sample. Furthermore, application of the phenylglycine methyl ester ( PGME) method to the C7-C21 spiroacetal domain enabled us to establish the absolute configuration of didemnaketal B.

DOI： 10.1002/chem.201303713

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Language：English   Publisher：新学術領域研究（研究領域提案型）「天然物ケミカルバイオロジー」  

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

In this study, stereoisomeric aspergillide A/neopeltolide chimeras were synthesized in a parallel manner, and their antiproliferative activity was evaluated to demonstrate the potential utility of the 14-membered macrolactone structure embedded with a tetrahydropyran substructure as a template for developing natural product-like antiproliferative agents.

DOI： 10.1246/cl.130322

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Language：English   Publisher：日本化学会東北支部  

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

Total synthesis of the proposed structure of didemnaketal B has been accomplished. The C7-C21 spiroacetal domain was synthesized by exploiting our Suzuki-Miyaura coupling/spiroacetalization strategy. The C1-C7 acyclic domain was constructed via an Evans syn-aldol reaction and a vinylogous Mukaiyama aldol reaction. Finally, the C22-C28 side chain was introduced by means of a Nozaki-Hiyama-Kishi reaction. Comparison of the NMR spectroscopic data of our synthetic material with those of the authentic sample revealed that the proposed structure requires stereochemical reassignment.

DOI： 10.1021/ol4017518

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

We describe herein a concise synthesis of (+)-neopeltolide, a marine macrolide natural product that elicits a highly potent antiproliferative activity against several human cancer cell lines. Our synthesis exploited the powerful bond-forming ability and high functional group compatibility of olefin metathesis and esterification reactions to minimize manipulations of oxygen functionalities and to maximize synthetic convergency. Our findings include a chemoselective olefin cross-metathesis reaction directed by H-bonding, and a ring-closing metathesis conducted under non-high dilution conditions. Moreover, we developed a 16-member stereoisomer library of 8,9-dehydroneopeltolide to systematically explore the stereostructure-activity relationships. Assessment of the antiproliferative activity of the stereoisomers against A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma, HT-1080 human fibrosarcoma, and P388 murine leukemia cell lines has revealed marked differences in potency between the stereoisomers. This study provides comprehensive insights into the structure-activity relationship of this important antiproliferative agent, leading to the identification of the pharmacophoric structural elements and the development of truncated analogues with nanomolar potency. SAR of (+)-neopeltolide: A modular synthetic route to (+)-neopeltolide, a potent antiproliferative marine macrolide, was established by exploiting the esterification/olefin metathesis strategy, and a 16-member stereoisomer library of 8,9-dehydeoneopeltolide was developed to elucidate the stereostructure- activity relationships (see figure). Copyright © 2013 WILEY-VCH Verlag GmbH &amp
Co. KGaA, Weinheim.

DOI： 10.1002/chem.201300664

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PubMed

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

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

Total synthesis of 13-demethyllyngbyaloside B, an unnatural analogue of a marine macrolide glycoside lyngbyaloside B, has been achieved. The 14-membered macrocyclic backbone was constructed in a convergent manner via esterification and ring-closing metathesis. The bromodiene side chain was introduced by means of a Stille-type reaction and a subsequent bromodesilylation. Finally, the rhamnopyranose unit was stereoselectively introduced by glycosylation under Schmidt conditions.

DOI： 10.1021/ol400408w

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

(-)-Exiguolide (1), isolated from the marine sponge Geodia exigua, has been shown to inhibit the growth of the A549 human lung adenocarcinoma and NCI-H460 human lung large cell carcinoma cells in vitro. In this study, we synthesized structural analogues of 1 to explore its skeletal structure-activity relationships and found that the C18 methyl group and the configuration of the C16-C17 double bond of 1 are important for the potent antiproliferative activity. Furthermore, we prepared a series of side-chain analogues of 1 by diversification of a late-stage intermediate of our total synthesis, and found that the triene side chain of 1 could be modified to some extent without significant loss of activity, provided a Lewis basic heteroatom is placed at the terminus.

DOI： 10.1039/c3ob40131f

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

We describe herein a concise synthesis of the AB-ring fragment of gambierol, wherein silver(I) trifluoromethanesulfonate-catalyzed 6-endo cyclization of a hydroxy ynone was exploited for the formation of the A-ring.

DOI： 10.3987/COM-12-S(N)21

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

Herein, we describe the concise synthesis of 2,6-cis-substituted tetrahydropyran derivatives based on a domino olefin cross-metathesis/intramolecular oxa-conjugate cyclization (CM/IOCC) reaction. We have found that the domino CM/IOCC of delta-hydroxy olefins with alpha,beta-unsaturated carbonyl compounds (e.g., trans-crotonaldehyde or N-acryloyl-2,5-dimethylpyrrole) could be efficiently achieved in the presence of the second-generation Hoveyda-Grubbs catalyst under elevated temperature conditions, directly affording 2,6-cis-substituted tetrahydropyrans in excellent yields with synthetically useful diastereoselectivity ("auto-tandem catalysis"). In addition, we have found that the domino CM/IOCC of delta-hydroxy olefins with alpha,beta-unsaturated carbonyl compounds could be achieved simply by performing CM in the presence of a Bronsted acid in CH2Cl2 at 25-35 degrees C, which delivered 2,6-cis-substituted tetrahydropyrans in good yields with excellent diastereoselectivity ("orthogonal-tandem catalysis"). To understand the mechanism of auto-tandem catalysis in the domino CM/IOCC reaction, we have investigated the role of ruthenium hydride complexes in the IOCC of a zeta-hydroxy alpha,beta-unsaturated ketone as a model case.

DOI： 10.1039/c2ob26189h

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Language：English   Publisher：新学術領域研究（研究領域提案型）「天然物ケミカルバイオロジー」  

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

Gambierol (1), a polycyclic ether natural neurotoxin isolated from the ciguatera causative dinoflagellate, Gambierdiscus toxicus has been reported to be a potent and subtype-selective blocker of voltage-gated potassium channels (VGPCs). Previous studies of marine polycyclic ether molecules have suggested the importance of the whole skeleton of polycyclic ether for potent biological activity. We have previously investigated the peripheral structure-activity relationships of Gambierol, however, it remained unclear whether the full length of polycyclic ether skeleton is essential for its toxicity. In this presentation, we designed and synthesized two structurally simplified analogues of Gambierol comprising BCDEFGH- and EFGH- rings of the parent compound (2 and 3). Surprisingly, both analogues showed comparable potency to Gambierol on VGPCs inhibition in cerebellar granule cells of mice. These results indicated that we obtained the easily synthesized analogues of Gambierol that have potent biological activity. Moreover, to investigate the additional functions of truncated analogues, we examined the effect of these compounds in a model of Alzheimer's disease (AD) obtained from triple transgenic mice, which expresses amyloid beta (An) accumulation and tau hyperphosphorylation. In vitro preincubation of the neurons of these mice with Gambierol or analogues decreased steady-state level of the NMDA receptor subunit 2A without affecting the 2B subunit. In addition, treatment of these compounds reduced the intra- and extracellular levels of Aβ and the levels of hyperphosphorylated tau. This study constitutes the first discovery of designed structurally simplified analogues of polycyclic ether compound possessing potent biological activity. Furthermore, it suggested the practicality of gambierol and analogues as chemical probes for understanding the function of VGPCs and the mechanism of modulation of the accumulation of Aβ and hyperphosphorylated tau by NMDA receptors.

DOI： 10.24496/tennenyuki.54.0_633

CiNii Books

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

Gambieric acid A (1) is a marine polycyclic ether natural product that was isolated from the ciguatera causative dinoflagellate Gambierdiscus toxicus. Despite its structural similarity to ciguatoxins and brevetoxins, 1 only weakly binds to voltage-gated sodium channels and does not exhibit lethal toxicity against mice at 1 mg/kg (ip). Instead, 1 displays extraordinary potent antifungal activity against Aspergillus niger. Our previous studies on the synthesis and NMR analysis of suitably designed model compounds have strongly suggested that the stereochemical assignment of the originally proposed structure of 1 is questionable and led us to propose that the absolute configuration of the polycyclic ether domain of 1 is opposite to that of the natural product. Here, we disclose the first total synthesis and complete stereostructure of 1. The B-ring was first synthesized based on our methodology for the synthesis of medium-sized cyclic ethers. The A-ring was next forged via stereoselective bromoetherification. Suzuki-Miyaura coupling of the A/B-ring exo-olefin with an acetate-derived enol phosphate followed by ring-closing metathesis (RCM) constructed the D-ring, and mixed-thioacetalization and one-pot oxidation/methylation methodologies were used to close the C-ring. The A/BCD- and F'GHIJ-ring fragments were coupled by means of Suzuki-Miyaura coupling. After establishment of the C25 stereogenic center by exploiting the conformational bias of the F'-ring, oxidative cleavage of the F'-ring followed by elaboration of the E-ring via stereoselective allylation of a mixed thioacetal by using glycosylation chemistry, and ensuing closure of the F-ring furnished the entire polycyclic ether backbone. Finally, the J-ring side chain was introduced by means of modified Julia-Kocienski olefination to complete the first total synthesis of gambieric acid A (1). The spectroscopic data, optical rotation value, and antifungal activity of synthetic 1 matched those of the natural product. Thus, our total synthesis confirmed the correctness of our revised structure and unambiguously established the complete stereostructure of 1.

DOI： 10.24496/tennenyuki.54.0_187

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

The polycyclic ether class of marine natural products has attracted the attention of researchers due to their complex and large chemical structures and diverse biological activities. Gambierol is a marine polycyclic ether toxin, first isolated along with ciguatoxin congeners from the dinoflagellate Gambierdiscus toxicus. The parent compound gambierol and the analogues evaluated in this work share the main crucial elements for biological activity, previously described to be the C28=C29 double bond within the H ring and the unsaturated side chain [Fuwa, H., Kainuma, N., Tachibana, K., Tsukano, C., Satake, M., and Sasaki, M. (2004) Diverted total synthesis and biological evaluation of gambierol analogues: Elucidation of crucial structural elements for potent toxicity. Chem. Eur. J. 10, 4894-4909]. With the aim to gain a deeper understanding of the cellular mechanisms involved in the biological activity of these compounds, we compared its activity in primary cultured neurons. The three compounds inhibited voltage-gated potassium channels (Kv) in a concentration-dependent manner and with similar potency, caused a small inhibition of voltage-gated sodium channels (Nay), and evoked cytosolic calcium oscillations. Moreover, the three compounds elicited a "loss of function" effect on Kv channels at concentrations of 0.1 nM. Additionally, both the tetracyclic and the heptacyclic derivatives of gambierol elicited synchronous calcium oscillations similar to those previously described for gambierol in cultured cerebellar neurons. Neither gambierol nor its tetracyclic derivative elicited cell toxicity, while the heptacyclic analogue caused a time-dependent decrease in cell viability. Neither the tetracyclic nor the heptacyclic analogues of gambierol exhibited lethality in mice after ip injection of 50 or 80 mu g/kg of each compound. Altogether, the results presented in this work support an identical mechanism of action for gambierol and its tetracyclic and heptacyclic analogues and indicate a "loss of function" effect on potassium channels even after administration of the three compounds at subnanomolar concentrations. In addition, because gambierol is known to stabilize the closed state of Kv3 channels, the results presented in this paper may have implications for understanding of channel functions and for future development of therapies against ciguatera poisoning and potassium channel-related diseases.

DOI： 10.1021/tx300242m

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

Stereoselective synthesis of the C1-C16 fragment of the antifungal marine polyether macrolide goniodomin A is described. A Stille-type coupling of organostannanes and thioesters was exploited as the key carbon carbon bondforming process, namely for the formation of the C7-C8 and C11-C12 bonds. Construction of the spiroacetal domain via acid-catalyzed acetalization of a triol-enone 30 unexpectedly provided a mixture of natural 11S spiroacetal 2, unnatural 11R spiroacetal 32, and constitutional isomer 33. Fortunately, it was eventually found that protection of the C5 hydroxy group as its acetate facilitated the isolation of natural 11S isomer 47 via acid-catalyzed equilibration of unnatural 11R isomer 48 and avoided the formation of a constitutional isomer, thereby increasing the efficacy of the spiroacetalization process.

DOI： 10.1246/bcsj.20120152

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

Total synthesis of gambieric acid A, a potent antifungal polycyclic ether metabolite, has been accomplished for the first time, which firmly established the complete stereostructure of this natural product.

DOI： 10.1021/ja305864z

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

A growing number of tetrahydropyran-containing biologically active substances are being discovered from nature. Intramolecular oxa-conjugate cyclization (IOCC) is known as one of the most powerful methodologies for the stereoselective synthesis of substituted tetrahydropyran derivatives, although there is clearly room for methodological improvement. In this review, we describe our successful total synthesis of tetrahydropyran-containing natural products by exploiting IOCC and the discoveries that we have made during the course of the synthetic campaigns.

DOI： 10.3987/REV-12-730

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Language：Japanese   Publisher：日本農芸化学会  

DOI： 10.1271/kagakutoseibutsu.50.404

CiNii Books

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

Gambierol is a potent neurotoxin that belongs to the family of marine polycyclic ether natural products and primarily targets voltage-gated potassium channels (K-v channels) in excitable membranes. Previous work in the chemistry of marine polycyclic ethers has suggested the critical importance of the full length of polycyclic ether skeleton for potent biological activity. Although we have previously investigated structure-activity relationships (SARs) of the peripheral functionalities of gambierol, it remained unclear whether the whole polycyclic ether skeleton is needed for its cellular activity. In this work, we designed and synthesized two truncated skeletal analogues of gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound, both of which surprisingly showed similar potency to gambierol on voltage gated potassium channels (K-v) inhibition. Moreover, we examined the effect of these compounds in an in vitro model of Alzheimer's disease (AD) obtained from triple transgenic (3xTg-AD) mice, which expresses amyloid beta (A beta) accumulation and tau hyperphosphorylation. In vitro preincubation of the cells with the compounds resulted in significant inhibition of K+ currents, a reduction in the extra- and intracellular levels of A beta, and a decrease in the levels of hyperphosphorylated tau. In addition, pretreatment with these compounds reduced the steady-state level of the N-methyl-D-aspartate (NMDA) receptor subunit 2A without affecting the 2B subunit. The involvement of glutamate receptors was further suggested by the blockage of the effect of gambierol on tau hyperphosphorylation by glutamate receptor antagonists. The present study constitutes the first discovery of skeletally simplified, designed polycyclic ethers with potent cellular activity and demonstrates the utility of gambierol and its synthetic analogues as chemical probes for understanding the function of K-v channels as well as the molecular mechanism of A beta metabolism modulated by NMDA receptors.

DOI： 10.1021/ja300565t

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

Intramolecular oxa-conjugate cyclization (IOCC) of alpha,beta-unsaturated carbonyl compounds, triggered by deprotonation with a base, represents a straightforward method for the synthesis of tetrahydropyrans. However, it has been known that stereochemical outcome of IOCC depends on the local structure substrates and sometimes requires harsh reaction conditions and/or prolonged reaction times for selective formation of 2,6-cis-substituted tetrahydropyrans. These shortcomings limit the feasibility of IOCC in the context of complex natural product synthesis. In this paper, we describe Bronsted acid-catalyzed IOCC of alpha,beta-unsaturated ester surrogates (e.g., alpha,beta-unsaturated thioesters, oxazolidinone imides, and pyrrole amides) under mild reaction conditions, which affords a series of synthetically versatile 2,6-cis-substituted tetrahydropyran derivatives with good to excellent stereoselectivity (dr from 7:1 to >20:1). These alpha,beta-unsaturated carbonyl compounds were found to be more reactive than the corresponding oxoesters that are generally unreactive toward Bronsted acid-catalyzed intramolecular oxa-conjugate additions. The product tetrahydropyrans could be transformed into various derivatives in an efficient manner, highlighting the usefulness of our methodology.

DOI： 10.1021/jo202179s

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

We describe a streamlined strategy for the practical synthesis of trans-fused polycyclic ethers and its application to a concise total synthesis of (-)-brevenal, a new pentacyclic polyether natural product with intriguing biological activities. The B-, D-, and E-rings were constructed by TEMPO/PhI(OAc)2-mediated oxidative lactonization of the corresponding 1,6-diols, with minimal need for manipulation of oxygen functionalities. The B- and E-ring lactones were appropriately functionalized by SuzukiMiyaura coupling of lactone-derived enol phosphates and subsequent stereoselective hydroboration. The A-ring was formed by our mixed thioacetalization methodology. The AB- and DE-ring fragments were assembled through SuzukiMiyaura coupling, and the C-ring was forged in the same manner as that for the A-ring. More than two grams of the pentacyclic polyether core of (-)-brevenal have been synthesized by the synthetic route developed in this study.

DOI： 10.1002/chem.201101437

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

The ladder-shaped polycyclic ether marine natural products present formidable and challenging synthetic targets due to their structural complexity, and exceptionally potent biological activities. Over the past decade, however, the limited availability of these substances from natural sources has precluded detailed biological studies. There has been an urgent need for means to supply useful quantities of these natural products and their analogues by total synthesis. We have developed a highly convergent strategy for the rapid and efficient assembly of polycyclic ether arrays, which relies on the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of cyclic enol triflates or phosphates. The utility of this strategy has been demonstrated by its application to the convergent total synthesis of the polycyclic ether class of natural products.

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

A stereocontrolled synthesis of a fully elaborated GHIJ-ring fragment of gambieric acids, which are potent antifungal polycyclic ether natural products, has been accomplished. The synthesis features convergent assembly of the tetracyclic polyether skeleton through aldol coupling/cyclodehydration/reductive etherification processes and stereoselective construction of the J-ring side chain by a CeCl(3)-promoted Julia-Kocienski olefination. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2011.05.082

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

In this paper, we describe a new strategy for the synthesis of substituted dihydropyrones and tetrahydropyrones. By exploiting palladium-catalyzed coupling of thioesters with terminal alkynes or alkenylboronic acids, a variety of beta-hydroxy ynones or enones, respectively, could be prepared in an efficient manner under mild conditions. AgOTf-promoted intramolecular oxa-conjugate cyclization of beta-hydroxy ynones provided 2,6-substituted dihydropyrones in excellent yields. On the other hand, acid-catalyzed cyclization of beta-hydroxy enones caused racemization of the product 2,6-substituted tetrahydropyrones due to its reversible nature. Eventually, stereoselective hydrogenation of substituted dihydropyrones was found to be a solid and efficient approach for the synthesis of 2,6-cis-substituted tetrahydropyrone derivatives. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2011.03.114

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

Many microalgae produce compounds that exhibit potent biological activities. Ingestion of marine organisms contaminated with those toxins results in seafood poisonings. In many cases, the lack of toxic material turns out to be an obstacle to make the toxicological investigations needed. In this study, we evaluate the cytotoxicity of several marine toxins on neuroblastoma cells, focusing on gambierol and its effect on cytosolic calcium levels. In addition, we compared the effects of this toxin with ciguatoxin, brevetoxin, and gymnocin-A, with which gambierol shares a similar ladder-like backbone, as well as with polycavernoside A analogue 5, a glycosidic macrolide toxin. For this purpose, different fluorescent dyes were used: Fura-2 to monitor variations in cytosolic calcium levels, Alamar Blue to detect cytotoxicity, and Oregon Green 514 Phalloidin to quantify and visualize modifications in the actin cytoskeleton. Data showed that, while gambierol and ciguatoxin were successful in producing a calcium influx in neuroblastoma cells, gymnocin-A was unable to modify this parameter. Nevertheless, none of the toxins induced morphological changes or alterations in the actin assembly. Although polycavernoside A analogue 5 evoked a sharp reduction of the cellular metabolism of neuroblastoma cells, gambierol scarcely reduced it, and ciguatoxin, brevetoxin, and gymnocin-A failed to produce any signs of cytotoxicity. According to this, sharing a similar polycyclic ether backbone is not enough to produce the same effects on neuroblastoma cells; therefore, more studies should be carried out with these toxins, whose effects may be being underestimated.

DOI： 10.1021/tx200038j

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

Intramolecular oxa-conjugate cyclization of alpha,beta-unsaturated thioesters under Bronsted acid catalysis, inspired by biosynthesis of polyketide natural products, provides a variety of 2,6-cis-substituted tetrahydropyran derivatives with excellent diastereoselectivities. An added bonus of this methodology is that the product tetrahydropyrans could be readily elaborated to various derivatives by exploiting the unique reactivity of the thioester group.

DOI： 10.1021/ol200333p

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

A convergent synthesis of the C1-C16 segment of goniodomin A, an actin-targeting marine polyether macrolide natural product, has been achieved via a 2-fold application of palladium-catalyzed organostannane-thioester coupling.

DOI： 10.1021/ol1031409

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Language：English   Publisher：日本化学会  

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

We describe herein an enantioselective total synthesis of (-)-exiguolide, the natural enantiomer. The methylene bis(tetrahydropyran) substructure was efficiently synthesized by exploiting olefin cross-metathesis for the assembly of readily available acyclic segments and intramolecular oxa-conjugate cyclization and reductive etherification for the formation of the tetrahydropyran rings. The 20-membered macrocyclic framework was constructed in an efficient manner by means of Julia-Kocienski coupling and Yamaguchi macrolactonization. Finally, the (E,Z,E)-triene side chain was introduced stereoselectively via Suzuki-Miyaura coupling to complete the total synthesis. Assessment of the growth inhibitory activity of synthetic (-)-exiguolide against a panel of human cancer cell lines elucidated for the first time that this natural product is an effective antiproliferative agent against the NCI-H460 human lung large cell carcinoma and the A549 human lung adenocarcinoma cell lines. Moreover, we have investigated structure-activity relationships of (-)-exiguolide, which elucidated that the C5-methoxycarbonylmethylidene group and the length of the side chain are important for the potent activity.

DOI： 10.1002/chem.201003135

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

Metastasis is responsible for most cancer deaths. Here, we show that Aes (or Grg5) gene functions as an endogenous metastasis suppressor. Expression of Aes was decreased in liver metastases compared with primary colon tumors in both mice and humans. Aes inhibited Notch signaling by converting active Rbpj transcription complexes into repression complexes on insoluble nuclear matrix. In tumor cells, Notch signaling was triggered by ligands on adjoining blood vessels, and stimulated transendothelial migration. Genetic depletion of Aes in Apc(Delta 716) intestinal polyposis mice caused marked tumor invasion and intravasation that were suppressed by Notch signaling inhibition. These results suggest that inhibition of Notch signaling can be a promising strategy for prevention and treatment of colon cancer metastasis.

DOI： 10.1016/j.ccr.2010.11.008

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

In this Account, we describe our efforts in the development of new synthetic strategies for the construction of N- and O-heterocycles by exploiting palladium-catalyzed reactions using enol phosphates as an electrophilic component.

DOI： 10.1055/s-0030-1259104

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

A stereocontrolled convergent synthesis of the C15-C36 segment of goniodomin A, a potent anti-angiogenic marine polyether macrolide, has been achieved using Stille-type cross-coupling reaction of a vinylstannane and a thioester as a key segment assembly process. (C) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2010.11.017

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

A stereocontrolled synthesis of the GHIJ-ring fragment having a side chain of gambieric acids, which are potent antifungal polycyclic ether natural products, has been achieved. The synthesis features convergent assembly of the tetracyclic polyether skeleton by using aldol coupling and stereoselective construction of the J-ring side chain by a cerium chloride-promoted Julia-Kocienski reaction. (C) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2010.11.127

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

Total synthesis of structurally complex marine oxacyclic natural products, (-)-gambierol, (-)-brevenal, and (+)-neopeltolide, has been accomplished by exploiting Suzuki-Miyaura coupling of enol phosphates, paving the way for biological investigations on these scarcely available substances.

DOI： 10.1246/bcsj.20100209

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

A highly convergent synthesis of the C9-C28 spiroacetal subunit of didemnaketal B has been accomplished. Assembly of the C9-C15 alkylborate and C16-C21 enol phosphate by means of Suzuki-Miyaura coupling and acid-catalyzed cyclization of the derived dihydroxy enol ether enabled a rapid and efficient construction of the spiroacetal subunit. The C22-C28 side chain was incorporated via Nozaki-Hiyama-Kishi coupling to complete the synthesis.

DOI： 10.1021/ol1024713

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

Gambierol is a complex marine toxin first isolated with ciguatoxins from cell cultures of the toxic dinoflagellate Gambierdiscus toxicus. Despite the chemical complexity of the polycyclic ether toxin, the total successful synthesis of gambierol has been achieved by different chemical strategies. In the present work the effects of synthetic gambierol on mouse and frog skeletal neuromuscular preparations and Xenopus skeletal myocytes have been studied. Gambierol (0.1-5 mu M) significantly increased isometric twitch tension in neuromuscular preparations stimulated through the motor nerve. Less twitch augmentation was observed in directly stimulated muscles when comparing twitch tension-time integrals obtained by nerve stimulation. Also, gambierol induced small spontaneous muscle contraction originating from presynaptic activity that was completely inhibited by D-tubocurarine. Gambierol slowed the rate of muscle action potential repolarization, triggered spontaneous and/or repetitive action potentials, and neither affected action potential amplitude nor overshoot in skeletal muscle fibers. These results suggest that gambierol through an action on voltage-gated K+ channels prolongs the duration of action potentials, enhances the extent and time course of Ca2+ release from the sarcoplasmic reticulum, and increases twitch tension generation. Further evidence is provided that gambierol at sub-micromolar concentrations blocks a fast inactivating outward K+ current that is responsible for action potential prolongation in Xeno pus skeletal myocytes. (C) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.toxicon.2010.06.001

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

(-)-Exiguolide was isolated from the sponge Geodia exigua collected off Amami-Oshima, Japn, by Ohta, Ikegami, and co-workers. The gross structure including the relative stereochemistry was established through extensive 2D NMR studies, conformational analysis on the basis of ^3J_<H,H> values and NOE correlations, and JBCA method. The molecular structure, characterized by the 20-membered macrolactone core embedded with a methylene bis(tetrahydropyran) substructure, is related to that of bryostains. (-)-Exiguolide inhibits fertilization of the sea urchin gametes but not embryogenesis of the fertilized egg. These structural and biological aspects led to an assumption that (-)-exiguolide may represent a simplified analogue of the bryostatins by Nature and render this natural product an intriguing target for organic chemists. Herein, we present the enantioselective total synthesis of (-)-exiguolide, the nturally occurring enantiomer, for the first time. The methylene bis(tetrahydropyran) substructure was efficiently constructed in a convergent fashion. Thus, the readily available C1-C7 and C8-C16 segments were assembled through olefin cross-metathesis, and two tetrahydreopyran rings were successively forged via intramolecular oxa-conjugate cyclization and reductive etherification. Stereoselective formation of the sterically encumbered C16-C17 double bond was achieved via Julia-Kocienski olefination. The 20-membered macrolactone framework was constructed in an excellent yield by means of Yamaguchi macrolactonization. An alternative approach toward the macrocycle based on ring-closing metathesis was less effecient than the macrolactonization approach. Finally, the (E,Z,E)-triene side chain was introduced in a stereoselective manner via Suzuki-Miyaura coupling under exceptionally mild conditions.

DOI： 10.24496/tennenyuki.52.0_181

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

An enantioselective total synthesis of aspergillides A and B has been accomplished on the basis of a unified synthetic strategy that exploits stereodivergent intramolecular oxa-conjugate cyclization and Yamaguchi macrolactonization. (C) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2010.07.062

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

A stereocontrolled convergent synthesis of a DEFG-ring model compound of gambieric acids, highly potent antifungal marine polycyclic ether natural products, has been achieved based on Suzuki-Miyaura coupling. Conformational analysis of the model compound revealed that the nine-membered F-ring exists exclusively as a single stable conformer, as opposed to that of ciguatoxins.

DOI： 10.1021/jo1008146

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：日本複素環化学研究所  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Gambierol is a marine polyether ladder toxin derived from the dinoflagellate Gambierdiscus toxicus. To date, gambierol has been reported to act either as a partial agonist or as an antagonist of sodium channels or as a blocker of voltage-dependent potassium channels. In this work, we examined the cellular effect of gambierol on cytosolic calcium concentration, membrane potential and sodium and potassium membrane currents in primary cultures of cerebellar granule cells. We found that at concentrations ranging from 0.1 to 30 mu M, gambierol-evoked [Ca(2+)]c oscillations that were dependent on the presence of extracellular calcium, irreversible and highly synchronous. Gambierol-evoked [Ca(2+)]c oscillations were completely eliminated by the NMDA receptor antagonist APV and by riluzole and delayed by CNQX. In addition, the K(+) channel blocker 4-aminopyridine (4-AP)-evoked cytosolic calcium oscillations in this neuronal system that were blocked by APV and delayed in the presence of CNQX. Electrophysiological recordings indicated that gambierol caused membrane potential oscillations, decreased inward sodium current amplitude and decreased also outward IA and IK current amplitude. The results presented here point to a common mechanism of action for gambierol and 4-AP and indicate that gambierol-induced oscillations in cerebellar neurons are most likely secondary to a blocking action of the toxin on voltage-dependent potassium channels and hyperpolarization of sodium current activation. J. Cell. Biochem. 110: 497-508, 2010. (C) 2010 Wiley-Liss, Inc.

DOI： 10.1002/jcb.22566

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

An efficient strategy for the synthesis of 2,6-disubstituted 2,3-dihydro-4H-pyran-4-ones has been developed, which relied on Sonogashira coupling of alkynes and p-toluenethiol esters and AgOTf-promoted 6-endo-dig cyclization of the derived beta-hydroxy ynones.

DOI： 10.1055/s-0029-1219794

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DOI： 10.1055/s-0029-1219794

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

An enantioselective total synthesis of aspergillides A and B has been accomplished based on a unified strategy, wherein a hydroxy-directed, highly chemoselective olefin cross-metathesis and a diastereoselective intramolecular oxa-conjugate cyclization were employed to forge the 2,6-substituted tetrahydropyran substructure.

DOI： 10.1021/ol100463a

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

A novel strategy for the stereoselective synthesis of substituted tetra hydropyrans has been developed on the basis of a domino olefin cross-metathesis/intramolecular oxa-conjugate cyclization catalyzed by the Hoveyda-Grubbs second-generation catalyst.

DOI： 10.1021/ol100431m

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

Total synthesis of (-)-exiguolide, the natural enantiomer, has been accomplished for the first time. The bis(tetrahydropyran) subunit was efficiently synthesized via consecutive olefin cross-metathesis/intramolecular oxa-conjugate addition/reductive etherification. Construction of the 20-membered macrocycle was achieved by Yamaguchi macrolactonization. Stereoselective introduction of the (E,Z,E)-triene side chain via Suzuki-Miyaura coupling completed the total synthesis.

DOI： 10.1021/ol902778y

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

A catalytic amount of TEMPO in the presence of PhI(OAc)(2) effected oxidative lactonization of 1,6- and 1,7-diols, directly affording seven- and eight-membered lactones, respectively, in good yields.

DOI： 10.1039/b919673k

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

DOI： 10.1002/anie.201000624

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

DOI： 10.1002/anie.201000624

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

Stereoselective convergent synthesis of the C15-C36 segment of goniodomin A, an actin-targeting marine polyether macrolide natural product, has been achieved. The present synthesis features palladium(0)-catalyzed, copper(I)-mediated Liebeskind-Srogl cross-coupling as the fragment assembly process.

DOI： 10.1021/ol902217q

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

Gambieric acids (GAs) are marine polycyclic ether natural products, isolated from the ciguatera causative dinoflagellate Gambierdiscus toxicus by Nagai, Yasumoto, and co-workers. The molecular architecture of GAs is composed of a nonacyclic polyether core and a side chain including a tetrahydrofuran. GAs show minimal toxocity against mammalians but display extraordinary potent antifungal activity against Aspergillus niger. The highly complicated structures coupled with the interesting biological activity make GAs attractive synthetic targets. We have previously reported the synthesis of the B-J-ring polycyclic ether core of gambieric acid A (GAA). Herein we report our efforts toward the total synthesis of GAA, which culminated in the stereochemical reassignment of the nonacyclic polyether core and the synthesis of the A/B-, DEFG-, and GHJI-ring fragments. The synthesis and NMR analysis of the A/BC-ring fragment of gambieric acid B confirmed that the absolute configuration of the polycyclic ether core of GAs is opposite to that of the originally proposed structure. Accordingly, we synthesized the A/B-ring fragment of GAA wigh the correct stereochemistry, wherein the A-ring was constructed via a Suzuki-Miyaura coupling and a diastereoselective iodoetherification. We devised a new strategy for the stereocontrolled synthesis of the DEFG-ring fragment of GAs, wherein a Suzuki-Miyaura coupling was implemented as the fragment assembly process and a seven-membered cyclic ether was utilized as a template for controlling the C25 stereogenic center. We also completed the synthesis of the GHIJ-ring fragment of GAs in a convergent manner. The G- and J-rings were assembled through an aldol coupling and the H- and I-rings were constructed by cyclodehydration and reductive etherification, respectively.

DOI： 10.24496/tennenyuki.51.0_359

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

A stereocontrolled entry to the DEFG-ring skeleton of gambieric acids, potent antifungal polycyclic ether natural products, has been developed based on the Suzuki-Miyaura coupling as the fragment assembly process and the use of an oxepane as a template for controlling the C25 stereogenic center.

DOI： 10.1246/cl.2009.866

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

We have used proteomic analyses to probe the responses induced by a pair of marine biotoxins, okadaic acid (OA) and gambierol (GB), added alone or in combination to a cultured cell line and carried out a preliminary investigation into the possible interactions between toxins possessing two different molecular mechanisms of action at a cellular level. When MCF-7 cells were treated with OA, we found that cellular levels of 30 proteins were significantly affected, including several isoforms of nonphosphorylated and phosphorylated hsp 27, as well as enzymes involved in the maintenance of nucleoside triphosphate pools and the control of redox states of the cell. When we repeated our analysis using GB, nine proteins were significantly affected, including some isoforms of nonphosphorylated hsp 27, as well as semenogelin-1, myosin-7, and the ATP synthase subunit delta. The combined addition of OA and GB to MCF-7 cells, in turn, affected 14 proteins, including some isoforms of nonphosphorylated and phosphorylated hsp 27, as well as myosin-7, the ATP synthase subunit delta, and enzymes involved in the control of redox states of the cell. If components affected by either OA or GB, as well as by the combined treatment, were classified according to the detected changes, two sets of data were obtained, including the components whose levels were found affected by the combined treatment, regardless of the effect observed after addition of only one agent, and those that had been found affected in cells that had been challenged with only one toxin but not when cells had been subjected to the combined treatment. Multiple patterns of responses to the toxin mixture were recorded in the two sets, consisting of both independent and interacting actions, among which we detected synergistic, similar, and antagonistic effects.

DOI： 10.1021/tx900044p

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

A highly stereocontrolled, convergent synthesis of the A/B-ring fragment of gambieric acids (GAs) has been developed on the basis of (i) a Suzuki-Miyaura coupling of the C1-C6 alkylborate and the C7-C17 vinyl iodide and (ii) a diastereoselective haloetherification for the construction of the A-ring tetrahydrofuran as key steps. Inspection of the (1)H and (13)C NMR chemical shifts of the synthesized A/B-ring model compounds led to a stereochemical reassignment of the absolute configuration of the polycyclic ether core of GAS. This structure revision was further supported by a synthesis of the A/BC-ring model compound of gambieric acid B and a comparison of its (1)H and (13)C NMR data with those of the natural product.

DOI： 10.1021/jo900332q

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本薬学会  

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

New strategies for the synthesis of 2-substituted indoles and indolines using acyclic, imide-derived enol phosphates which were readily prepared from o-haloanilides have been developed based on Suzuki-Miyaura coupling-cyclization sequences. A highly chemoselective cross-coupling of imide-derived enol phosphates with boron nucleophiles under Suzuki-Miyaura conditions allowed for the efficient preparation of various N-(o-halophenyl)enecarbamates that served as useful precursors for subsequent 5-endo-trig Heck or 5-endo-trig aryl radical cyclizations to furnish 2-substituted indoles or indolines, respectively. Furthermore, a one-pot Suzuki-Miyaura Coupling-cyclization cascade starting from enol phosphates has been developed, which was Successfully applied to the efficient synthesis of an indol-2-yl-1H-quinolin-2-one KDR inhibitor.

DOI： 10.1021/jo801985a

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

The stereocontrolled total synthesis of the originally proposed (1) and correct (2) structures of (+)-neopeltolide, a novel marine macrolide natural product with highly potent anti-proliferative activity against several cancer cell lines as well as potent antifungal activity, has been achieved by exploiting a newly developed Suzuki-Miyaura coupling/ring-closing metathesis strategy. Alkylborate 44, which was generated in situ from iodide 34, was coupled with enol phosphate 8 by a Suzuki-Miyaura coupling. Ring-closing metathesis of the derived diene 45 followed by stereoselective hydrogenation afforded tetrahydropyran 47 as a single stereoisomer in high overall yield from 34. Our convergent strategy enabled us to construct the 14-membered macrolactone core structure of 2 in a rapid and efficient manner. Total synthesis and biological evaluation of synthetic intermediates and designed synthetic analogues, performed to establish the structure-activity relationships of 2, led to the discovery of a structurally simple yet potent cytotoxic analogue, 9-demethylneopeltolide (54).

DOI： 10.1002/chem.200901675

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

Brevenal is a pentacyclic polyether natural product isolated from the red tide dinoflagellate Karenia brevis. This natural product competitively displaces tritiated dihydrobrevetoxin-B ([^3H]-PbTx3) from voltage-sensitive sodium channels in a dose dependent manner, whereas it showed no toxicity in a fish bioassay. Moreover, brevenal increased tracheal mucus velocity in picomolar concentrations in an animal model of asthma. Thus, brevenal represents a potential lead for the development of novel therapeutic agents for treatment of mucociliary dysfunction associated with cystic fibrosis and other lung disorders. Toward elucidation of the biological mode of action at the molecular level and establishment of the structure-activity relationships, it is essential to develop an efficient, scalable, and flexible synthetic route to brevenal; however, our first-generation total synthesis involved lengthy fragment syntheses and tedious and capricious manipulations unsuitable for scale-up. Herein, we describe a highly convergent and efficient synthesis of the pentacyclic polyether core 2, which is a key intermediate in the previous synthesis. The present synthesis features i) highly efficient and scalable synthesis of the AB- and DE-ring fragments and ii) two-fold use of our Suzuki-Miyaura coupling/mixed thioacetalization-based convergent strategy for the synthesis of polycyclic ether frameworks. Our second-generation synthesis (total number of steps: 59; longest linear sequence: 32) is considerably more efficient than the original one (total number of steps: 73; longest linear sequence: 50).

DOI： 10.24496/tennenyuki.50.0_641

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

In modern organic synthesis, the Suzuki-Miyaura coupling has been extensively utilized in the synthesis of structurally complex natural products and pharmaceuticals due to the powerful C-C bond forming ability, mild reaction conditions, and compatibility with virtually all functional groups. Although aryl and alkenyl halides and their triflate counterparts are generally used as an electrophilic component in the Suzuki-Miyaura coupling, α-heteroatom substituted alkenyl halides and triflates, potentially useful precursors for the synthesis of heterocycles, are difficult to prepare and handle because of their inherent instability. During the course of our synthetic studies on marine polycyclic ether natural products, we found that lactone-derived enol phosphates are stable enough for isolation/purification and are sufficiently reactive under the Suzuki-Miyaura conditions to yield cross-coupled products in high yields. Our continuous efforts to broaden the scope of the alkenyl phosphate-based palladium chemistry have culminated in the development of several efficient methods for the synthesis of heterocycles such as dihydropyrans and indoles. Here we report the total synthesis of cytotoxic marine metabolites, attenols A and B and (+)-neopeltolide, exploiting our recently developed strategy for the synthesis of dihydropyrans based on a sequential Suzuki-Miyaura coupling/ring-closing metathesis.

DOI： 10.24496/tennenyuki.50.0_755

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

A new method for the generation of indole-2,3-quinodi-methanes based on a palladium-catalyzed cascade process starting from N-(o-iodophenyl)allenamides has been developed.

DOI： 10.1246/cl.2008.904

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

An efficient method for the synthesis of enol ethers and enecarbamates has been developed based on palladium(0)-catalyzed chemoselective reduction of alkenyl phosphates. This method has been applied successfully to the total synthesis of two isoindolobenzazepine alkaloids, lennoxamine and chilenine.

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

An efficient strategy for the synthesis of endocyclic enol ethers based on a Suzuki-Miyaura coupling/ring-closing metathesis sequence has been developed. The strategy has successfully been applied to the synthesis of spiroacetals, including cytotoxic marine metabolites attenols A and B.

DOI： 10.1021/ol800815t

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

Total synthesis of (-)-brevenal, a novel marine polycyclic ether natural product, is described. Highly efficient and scalable entries to the AB-ring exo-olefin and the DE-ring enol phosphate and a rapid construction of the C-ring by means of our Suzuki-Miyaura coupling-based strategy realized a concise synthesis of the pentacyclic skeleton of (-)-brevenal. The present synthesis is considerably more efficient than our previous synthesis (longest linear sequence: 50 steps from 2-deoxy-D-ribose).

DOI： 10.1021/ol800685c

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

Stereocontrolled synthesis of the A/B-ring fragment of the originally assigned structure of gambieric acid B and its possible diastereomers has been accomplished. Detailed comparison of their (1)H and (13)C NMR data with those of the corresponding moiety of the natural product culminated in a stereochemical reassignment of the absolute configuration of the polycyclic ether region of gambieric acid B.

DOI： 10.1021/ol800642t

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

Marine polycyclic ether natural products continue to fascinate chemists and biologists due to their exceptionally large and complex molecular architectures and potent and diverse biological activities. Tremendous progress has been made over the past decade toward the total synthesis of marine polycyclic ether natural products. In this area, a convergent strategy for assembling small fragments into an entire molecule always plays a key role in successful total synthesis. This review describes our efforts to develop convergent strategies for the synthesis of polycyclic ethers and their application to the total synthesis of gambierol, gymnocin-A, and brevenal, and to the partial synthesis of the central part of ciguatoxins and the nonacyclic polyether skeleton of gambieric acids.

DOI： 10.1039/b705664h

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

DOI： 10.1002/anie.200801399

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：THOMSON SCIENTIFIC  

For more than twenty years, chemists and biologists have been fascinated by the highly complex molecular architectures and the diverse and potent biological activities of marine polycyclic ether natural products. Given the scarce availability of these intriguing substances from natural sources, total chemical synthesis is the only way to obtain sufficient quantities for biological investigation. This review describes recent synthetic advances in the field of marine polycyclic ether natural products and their successful implementation in total synthesis endeavors.

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

Strategies have been developed for the synthesis of 2-substituted indoles and indolines starting from acyclic alpha-phosphoryloxy enecarbamates. A highly chemoselective cross-coupling of N-(o-bromophenyl)-alpha-phosphoryloxyenecarbamates with boron nucleophiles enabled the efficient preparation of various N-(o-bromophenyl)enecarbamates, which served as useful precursors for subsequent Heck-type cyclization or 5-endo-trig aryl radical cyclization to furnish 2-substituted indoles or indolines, respectively.

DOI： 10.1021/ol071312a

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

Divergent synthesis of multifunctional molecular probes based on caprolactam-derived dipeptidic -secretase inhibitors (GSIs), Compound E (CE) and LY411575 analogue (DBZ), was efficiently accomplished by means of Cu(I)-catalyzed azide/alkyne fusion reaction. Photoaffinity labeling experiments using these derivatives coupled to photoactivatable and biotin moieties provided direct evidence that the molecular targets of CE and DBZ are the N-terminal fragment of presenilin 1 within the -secretase complex. Moreover, these photoprobes directly targeted signal peptide peptidase. These data suggest that the divergent synthesis of molecular probes has been successfully applied to characterize the interaction of GSIs with their molecular targets and define the structural requirements for inhibitor binding to intramembrane-cleaving proteases.

DOI： 10.1021/cb700073y

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

Stereoselective synthesis of the AB-ring fragment of gambieric acid A has been accomplished, wherein (i) an acetylide-aldehyde coupling for fragment assembly and (ii) construction of the tetrahydrofuran A-ring via a diastereoselective bromoetherification were successfully employed as key transformations.

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

An efficient method for the synthesis of enol ethers and enecarbamates has been developed based on catalytic hydrosilane reduction of alpha-phosphonoxy enol ethers and alpha-phosphonoxy enecarbamates. This method has been applied to the total syntheses of two isoindolobenzazepine alkaloids, lennoxamine and chilenine.

DOI： 10.1039/b706087d

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

A strategy for the synthesis of 2,3-disubstituted indole derivatives based on an intramolecular carbopalladation-anion capture cascade has been developed, wherein construction of the pyrrole ring and functionalisation of the indole C2 and C3 positions were achieved by extensive use of palladium( 0)catalysed coupling reactions.

DOI： 10.1039/b707338k

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

An intramolecular Heck/Diels-Alder cycloaddition cascade starting from acyclic alpha-phosphono enecarbamates has been developed to prepare nitrogen heterocycles via indole-2,3-quinodimethanes and 2-(N-alkoxycarbonylamino)-1,3-dienes.

DOI： 10.1039/b704374k

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

A concise and short synthetic entry to 5,6-dihydropyridin-2-one derivatives has been developed by means of palladium(0)-catalyzed cross-coupling of cyclic ketene aminal phosphates.

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

Total synthesis of structure 1 originally proposed for brevenal, a nontoxic polycyclic ether natural product isolated from the Florida red tide dinoflagellate, Karenia brevis, was accomplished. The key features of the synthesis involved (i) convergent assembly of the pentacyclic polyether skeleton based on our developed Suzuki-Miyaura coupling chemistry and (ii) stereoselective construction of the multi-substituted (E,E)-dienal side chain by using copper(I) thiophen-2-carboxylate (CuTC)-promoted modified Stille coupling. The disparity of NMR spectra between the synthetic material and the natural product required a revision of the proposed structure. Detailed spectroscopic comparison of synthetic 1 with natural brevenal, coupled with the postulated biosynthetic pathway for marine polyether natural products, suggested that the natural product was most likely represented by 2, the C26 epimer of the proposed structure 1. The revised structure was finally validated by completing the first total synthesis of (-)-2, which also unambiguously established the absolute configuration of the natural product.

DOI： 10.1021/ja066772y

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

Brevenal is a polyether natural product isolated from laboratory cultures of the Florida red tide-forming dinoflagellate, Karenia Brevis. Its gross structure, including relative stereochemistry, was disclosed based on extensive 2D NMR studies. It has been reported that brevenal competitively displaces tritiated dihydrobrevetoxin from voltage-sensitive Na^+ channels and acts as a natural brevetoxin antagonist in vivo. More importantly, brevenal improved tracheal mucus velocity in picomolar concentrations in an animal model of asthma. Thus, it may be a source of novel therapeutic agents for treatment of cystic fibrosis and other respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD). Intrigued by these biological profiles of brevenal, we embarked on the total synthesis of brevenal by means of our developed convergent methodology. Suzuki-Miyaura coupling of the AB ring enol phosphate 6 and an alkylborane derived from the DE ring exo-olefin 7 proceeded smoothly to afford coupling product 23. The C ring was then constructed by mixed-thioacetalization followed by one-pot oxidation/methylation. After construction of the left-hand (E,E)-diene side chain by means of CuTC-mediated Stille coupling, the total synthesis was completed by installing the right-hand (Z)-diene chain via Wittig reaction. However, ^1H and ^<13>C NMR spectra of synthetic 1 were not identical with those of the natural product. Detailed NMR studies suggested that the true structure of brevenal is the C26-epimer of the originally proposed structure. This notion is also supported by the postulated biosynthetic pathway of marine polyether natural products. In the event, this proved to be correct as the spectroscopic data of synthetic 2 were completely identical with those of the natural product. In addition, the optical rotation of synthetic 2 matched the value for the natural product. Thus, we succeeded in unambiguous determination of the absolute configuration of brevenal through our total synthesis endeavor.

DOI： 10.24496/tennenyuki.48.0_229

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

The marine dinoflagellate Gambierdiscus toxicus produces highly lipophilic, polycyclic ether toxins that cause a seafood poisoning called ciguatera. Ciguatoxins (CTXs) and gambierol represent the two major causative agents of ciguatera intoxication, which include taste alterations (dysgeusiae). However, information on the mode of action of ciguatera toxins in taste cells is scarce. Here, we have studied the effect of synthetic CTX3C (a CTX congener) on mouse taste cells. By using the patch-clamp technique to monitor membrane ion currents, we found that CTX3C markedly affected the operation of voltage-gated Na+ channels but was ineffective on voltage-gated K+ channels. This result was the exact opposite of what we obtained earlier with gambierol, which inhibits K+ channels but not Na+ channels. Thus, CTXs and gambierol affect with high potency the operation of separate classes of voltage-gated ion channels in taste cells. Our data suggest that taste disturbances reported in ciguatera poisoning might be due to the ability of ciguatera toxins to interfere with ion channels in taste buds.

DOI： 10.1093/chemse/bjl008

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

Synthesis and biological evaluation of an arylsulfonamide class of gamma-secretase inhibitors are described. Design, synthesis, and biological evaluation of multifunctional molecular probes harboring a benzophenone photophore as a cross-linking group and a biotin tag are also reported. (c) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2006.05.091

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

DOI： 10.1021/ja062524q

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

Synthesis of the JK/LM-ring model of prymnesins, polycyclic ether toxins isolated from the red tide phytoflagellate, Pryninesilun parvian, is described. Comparison of the H-1 and C-13 NMR data of the synthetic model with those reported for prymnesins confirmed the reported configurational assignment of the K/L-ring juncture. (c) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2006.06.032

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

DOI： 10.24496/intnaturalprod.2006.0__P-561_

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

Screening of our in-house compound library comprised of intermediates of natural product synthesis projects resulted in discovering two novel gamma-secretase inhibitors, which coincidently had similar moieties, that is, cyclohexenone and two aryl groups arranged on the core six-membered ring. Structure-activity relationship studies of these compounds were also developed. (c) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2006.04.025

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Language：English   Publisher：International Union of Pure and Applied Chemistry  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

gamma-Secretase is a multimeric membrane protein complex composed of presenilin (PS), nicastrin, Aph-1 and, Pen-2 that is responsible for the intramembrane proteolysis of various type I transmembrane proteins, including amyloid beta-precursor protein and Notch. The direct labeling of PS polypeptides by transition-state analogue gamma-secretase inhibitors suggested that PS represents the catalytic center of gamma-secretase. Here we show that one of the major gamma-secretase inhibitors of dipeptidic type, N-[N-( 3,5- difluorophenacetyl)-L-alanyl]-S- phenylglycine t-butyl ester (DAPT), targets the C-terminal fragment of PS, especially the transmembrane domain 7 or more C-terminal region, by designing and synthesizing DAP-BpB (N-[N-(3,5- difluorophenacetyl)-L-alanyl]-(S)-phenylglycine4-(4-(8-biotinamido) octylamino)benzoyl)benzyl) methylamide), a photoactivable DAPT derivative. We also found that DAP-BpB selectively binds to the high molecular weight gamma-secretase complex in an activity-dependent manner. Photolabeling of PS by DAP-BpB is completely blocked by DAPT or its structural relatives (e.g. Compound E) as well as by arylsulfonamides. In contrast, transition-state analogue inhibitor L-685,458 or alpha-helical peptidic inhibitor attenuated the photolabeling of PS1 only at higher concentrations. These data illustrate the DAPT binding site as a novel functional domain within the PS C-terminal fragment that is distinct from the catalytic site or the substrate binding site.

DOI： 10.1074/jbc.M513012200

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

Background: Gambierol is a polycyclic ether toxin with the same biogenetic origin as ciguatoxins. Gambierol has been associated with neurological symptoms in humans even though its mechanism of action has not been fully characterized. Methods: We studied the effect of gambierol in human neuroblastoma cells by using bis-oxonol to measure membrane potential and FURA-2 to monitor intracellular calcium. Results: We found that this toxin: i) produced a membrane depolarization, ii) potentiated the effect of veratridine on membrane potential iii) decreased ciguatoxin-induced depolarization and iv) increased cytosolic calcium in neuroblastoma cells. Conclusion: These results indicate that gambierol modulate ion fluxes by acting as a partial agonist of sodium channels. Copyright (c) 2006 S. Karger AG, Basel.

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Language：English   Publisher：PACIFICHEM2005  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Ciguatera is a food poisoning caused by toxins of Gambierdiscus toxicus, a marine dinoflagellate. The neurological features of this intoxication include sensory abnormalities, such as paraesthesia, heightened nociperception, and also taste alterations. Here, we have evaluated the effect of gambierol, one of the possible ciguatera toxins, on the voltage-gated ion currents in taste cells. Taste cells are excitable cells endowed with voltage-gated Na+, K+, and Cl- currents (I-Na, I-K, and I-Cl, respectively). By applying the patch-clamp technique to single cells in isolated taste buds obtained from the mouse vallate papilla, we have recorded such currents and determined the effect of bath-applied gambierol. We found that this toxin markedly inhibited I-K in the nanomolar range (IC50 of 1.8 nM), whereas it showed no significant effect on I-Na or I-Cl even at high concentration (1 mu M). The block of I-K was irreversible even after a 50-min wash. In addition to affecting the current amplitude, we found that gambierol significantly altered both the activation and inactivation processes of I-K. In conclusion, unlike other toxins involved in ciguatera, such as ciguatoxins, which affect the functioning of voltage-gated sodium channels, the preferred molecular target of gambierol is the voltage-gated potassium channel, at least in taste cells. Voltage-gated potassium currents play an important role in the generation of the firing pattern during chemotransduction. Thus, gambierol may alter action potential discharge in taste cells and this could be associated with the taste alterations reported in the clinical literature.

DOI： 10.1093/toxsci/kfi097

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

The general synthesis and a novel intramolecular nucleophilic aromatic substitution (SNAr) reaction of 2-carboxamido-3-arylquinazolin-4-ones, a potentially useful scaffold in the field of medicinal chemistry, are described. The synthetic utility of the SNAr reaction as a tool for the synthesis of secondary aryl amines, including diaryl amines, is also demonstrated. (c) 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2005.02.038

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

A novel intramolecular nucleophilic aromatic substitution reaction of 2-carboxamido-3-arylquinazolin-4-one derivatives induced by base treatment and its application to the expeditious synthesis of secondary aryl amines, including diaryl amines, are described.

DOI： 10.1055/s-2004-8354805

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

Marine polycyclic ether class of natural products, brevetoxins and ciguatoxins being representative, has attracted a great deal of attention of chemists and biologists due to the unusually complex and gigantic molecular architecture as well as potent and diverse biological activities. Gambierol is a marine polycyclic ether isolated as a toxic constituent from the cultured cells of the ciguatera causative dinoflagellate Gambierdiscus toxicus. It is known that gambierol exerts potent toxicity against mice (MLD 50 μg/kg, ip) and the symptoms caused in mice resemble those shown by ciguatoxins, implying that gambierol is also relevant to the ciguatera seafood poisoning. Recently, Inoue et al. have disclosed that gambierol inhibits competitively the binding of brevetoxin PbTx-3 to the voltage-sensitive sodium channel in excitable membranes. However, extremely limited availability of this toxin from natural sources has prevented further detailed biological studies. We have accomplished the first total synthesis of gambierol based on our developed Suzuki-Miyaura coupling-based strategy. Herein we report the structure-activity relationships of gambierol aiming at establishment of a rational basis for the development of probe molecules useful for biochemical studies. There exist only a few precedents of structure-activity relationship studies on marine polyether natural products, probably due to the difficulties of providing ample quantities of these natural products as well as altering the structure of highly gigantic and complex molecules by chemical means. We surmised that these difficulties could be overcome by synthesizing a diverse set of analogues from a simple yet advanced intermediate of the total synthesis (diverted total synthesis). We have synthesized up to 18 structural analogues and evaluated their biological activity. MLD value against mice (ip) was used as an index. It has been shown that the presence of the C28-C29 and C32-C33 double bonds and an appropriate length of the side chain are crucial structural elements for exerting potent toxicity. The C30 axial methyl group was found to enhance the toxicity, but it is not an essential functional group. Partial reduction of the conjugated diene system within the side chain resulted in a great decrease in toxicity. On the other hand, analogues possessing isomeric conjugated diene still displayed significant activity. These suggest that the planar nature of the conjugated diene system would be an important structural feature. Interestingly, modification of the C1 or C6 hydroxyl groups has almost no influence on the toxicity. In the case of 1-deoxy and 1-O-methylgambierol, however, mice death occurred in 45-140 min (3-10 times longer than gambierol and other active analogues), suggesting the possibility that Cl hydroxyl group is relevant to the bioavailability of the molecule.

DOI： 10.24496/tennenyuki.46.0_359

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

Gambierol is a polycyclic ether toxin, which has been isolated from the marine dinoflagellate Gambierdiscus toxicus. A series of gambierol analogues have been prepared from an advanced intermediate of our total synthesis of gambierol and investigated for their toxicity against mice, thus providing the first systematic structure-activity relationships (SAR) of this polycyclic ether class of marine toxin. The SAR studies described herein clearly indicate that 1) the C28=C29 double bond within the H ring and the unsaturated side chain are the crucial structural elements required for exerting potent biological activity and 2) the C1 and C6 hydroxy groups, the C30 methyl group, and the C37=C38 double bond have little influence on the degree of neurotoxicity against mice.

DOI： 10.1002/chem.200400355

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

The polycyclic ether class of marine natural products presents formidable and challenging synthetic targets due to their structural complexity and exceptionally potent biological activities. We have developed a highly convergent strategy for the assembly of a huge polycyclic ether array, which features Suzuki-Miyaura cross-coupling of alkylboranes, generated from exocyclic enol ethers, with cyclic ketene acetal triflates or phosphates combined with reductive ring-closure. The utility of this strategy was demonstrated by its application to synthetic studies on ciguatoxins, and the total syntheses of gambierol and gymnocin-A.

DOI： 10.1055/s-2004-830860

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

Synthesis of the ABCDE ring fragment of ciguatoxins has been achieved in a highly stereocontrolled and convergent manner via the B-alkyl Suzuki-Miyaura conpling-based approach. (C) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2004.04.083

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

Stereoselective synthesis of the C18-C34 fragment of antascomicin A is described. Construction of the C27-C34 carbocycle moiety was achieved via catalytic Ferrier carbocylization and Johnson-Claisen rearrangement, which was converted to iodide 2 by use of asymmetric alkylation and Sharpless epoxidation as key transformations. Coupling of iodide 2 and sulfone 3 furnished the C18-C34 fragment. (C) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2004.04.072

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

A highly efficient method for the synthesis of medium-sized lactams based on intramolecular Staudinger-aza-Wittig reaction of omega-azido pentafluorophenyl ester has been developed. A variety of 7-10 membered lactams were synthesized in excellent yields. Application of the method to the synthesis of analogues of a potent gamma-secretase inhibitor LY411575 and their biological evaluation are also described. (C) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2004.01.087

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

Gambierol was isolated from Gambierdiscus toxicus, which causes ciguatera fish poisoning. The acute toxicological effects induced in mice by synthesized gambierol were studied. The lethal doses were about 80 mug/kg by i.p. and i.v., and 150 mug/kg by p.o. The main injury by this toxin was observed in the lung, and secondary in the heart, resulting in systemic congestion. Another toxic effect was seen in the stomach, inducing hypersecretion and ulceration. With survival from the severe stage during the initial 3 h, recovery was favorable, especially after 4 days. Additional effects were not evident during 1-week post-administration observation. (C) 2003 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.toxicon.2003.09.011

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

Gambierol is a polycyclic ether toxin, isolated as a toxic constituent from the marine dinoflagellate Gambierdiscus toxicus. We describe here the synthesis and biological evaluation of structural analogues of gambierol. The present preliminary structure-activity relationship studies clearly indicate that the H ring functionality and the unsaturated side chain of gambierol are crucial for its potent toxicity. (C) 2003 Elsevier Ltd. All rights reserved.

DOI： 10.1016/S0960-894X(03)00467-0

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Language：Japanese   Publisher：学会出版センター  

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Language：Japanese   Publisher：日本薬学会  

CiNii Books

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Language：Japanese   Publisher：化学同人  

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

The first total synthesis of (-)-gambierol (1), a marine polycyclic ether toxin, has been achieved. Key features of the successful synthesis include (1) a convergent union of the ABC and EFGH ring fragments (5 and 6, respectively) via our developed B-alkyl Suzuki-Miyaura cross-coupling strategy leading to the octacyclic polyether core 4 and (2) a late-stage introduction of the sensitive triene side chain by use of Pd(PPh3)(4)/CuCl/LiCl-promoted Stille coupling. The ABC ring fragment 5 was synthesized in a linear manner (B - AB - ABC), wherein the A ring was formed by intramolecular hetero-Michael reaction and the C ring was constructed via 6-endo cyclization of hydroxy epoxide 7. An improved synthetic entry to the EFGH ring fragment 6 is also described, in which Sml(2)-induced reductive cyclization methodology was applied to the stereoselective construction of the F and H rings, leading to 6 with remarkable overall efficiency. Stereoselective hydroboration of 5 and subsequent Suzuki-Miyaura coupling with 6 provided endocyclic enol ether 45 in high yield, which was then converted to octacyclic polyether core 4. Careful choice of the global deprotection stage was a key element for the successful total synthesis. Functionalization of the H ring and global desilylation gave (Z)-vinyl bromide 2. Finally, cross-coupling of 2 with (Z)-vinyl stannane 3 under Corey's Pd(PPh3)(4)/CuCl/LiCl-promoted Stille conditions completed the total synthesis of (-)-gambierol (1).

DOI： 10.1021/ja028167a

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

Gambierol (1) is a marine polycyclic ether toxin isolated from the ciguatera causative dinoflagellate Gambierdiscus toxicus. The toxin exhibits potent toxicity against mice (LD_<50> 50μg/kg, ip), and the symptoms caused in mice resemble those shown by ciguatoxins, implying that gambierol is also responsible for ciguatera fish poisoning. However, extremely limited availability from natural sources hampered further detailed biological studies, and therefore, sample supply by practical chemical synthesis is strongly demanded. The chemical structure is characterized by the octacyclic polyether core with 18 stereogenic centers and labile triene side chain that includes conjugated (Z,Z)-diene. Herein we report the first total synthesis of gambierol, featuring convergent synthesis of the octacyclic polyether core via our B-alkyl Suzuki-Miyaura coupling strategy and stereoselective construction of the sensitive triene side chain through the Pd(PPh_3)_4/CuCl/LiCl promoted Stille coupling. The ABC ring fragment 5 was synthesized from the known olefin 7, representing the B ring. The C6 hydroxy group was installed stereoselectively by Sharpless asymmetric epoxidation of allylic alcohol 8 and subsequent reductive cleavage of the derived hydroxy epoxide. Intramolecular hetero-Michael reaction of 10 was utilized for stereoselective formation of the A ring to give 11 as a single stereoisomer. The C ring was constructed via 6-endo cyclization of vinyl epoxide 14 to afford tricyclic compound 15, which was then converted to 5 without incident. Synthesis of the EFGH ring fragment 6 started from the known ester 16. Construction of the H ring was performed by use of a SmI_2-mediated reductive cyclization methodology developed by Nakata. 6-Endo cyclization of vinyl epoxide 19 cleanly afforded the GH ring fragment 20, which was readily converted to methyl ketone 21. Reductive cyclization of 21 under Nakata conditions gave the FGH ring fragment 22, which was then transformed into the targeted fragment 6 by standard chemistry. The convergent union of the ABC and EFGH ring fragments (5 and 6, respectively) was successfully achieved by using the B-alkyl Suzuki-Miyaura coupling to yield the cross-coupled product 23 in gratifying 86% yield. Subsequent elaboration to the octacyclic polyether core 4 of gambierol was accomplished from 23 in only six steps. Compound 4 was converted to tertiary alcohol 26 in six steps via an introduction of the double bond within the H ring by Ito-Saegusa protocol. An array of careful protective group manipulations and installation of a (Z)-vinyl bromide unit led to triol 29. Cross-coupling of 29 with the known (Z)-vinyl stannane 3 under the Pd(PPh_3)_4/CuCl/LiCl promoted Stille conditions furnished gambierol 1. Spectroscopic data (^1H and ^<13>C NMR, FIRMS, CD) and mouse lethality of synthetic 1 were identical with those of authentic natural sample.

DOI： 10.24496/tennenyuki.44.0_157

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

The first total synthesis of gambierol, a marine polycyclic ether toxin, has been achieved. The synthesis features the Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille coupling for the stereoselective construction of the sensitive triene side chain that includes a conjugated (Z,Z)-diene moiety.

DOI： 10.1021/o1026394b

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

A new method for convergent coupling of fused polycyclic ethers has been developed, which relies on B-alkyl Suzuki cross-coupling of lactone-derived enol triflates or phosphates. The strategy was successfully applied to a convergent synthesis of the ABCD ring fragment 4 of ciguatoxins, the causative toxin for ciguatera fish poisoning. The synthetic route includes a convergent union of the B and D rings (18 and 29c, respectively) by the B-alkyl Suzuki coupling, introduction of a double bond into the D ring followed by reductive closure of the tetrahydropyran C ring to afford the BCD ring system 51, and, finally, ring-closing metathesis reaction to construct the oxepene A ring. (C) 2002 Elsevier Science Ltd. All rights reserved.

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

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A convergent synthetic route to the octacyclic polyether core of gambierol, a marine polycyclic ether toxin, has been developed, The synthesis involves construction of two fragments representing the ABC and EFGH ring systems followed by their coupling via a B-alkyl Suzuki reaction.

DOI： 10.1021/ol0166597

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

A synthetic route to the EFGH ring system (3) of gambierol (1), a marine polyether toxin isolated from the dinoflagellate Gambierdiscus toxicus, has been developed. The present synthesis features convergent coupling of the F and H rings followed by ring-closure of the G ring based on the B-alkyl Suzuki reaction of lactone-derived enol phosphates. An angular methyl group at C23 was stereoselectively introduced by treatment of sulfone 32 with trimethylaluminum. Installation of a tertiary alcohol at C21 was accomplished through stereo-selcetive dihydroxylation of exo-methylene 36 followed by selective formation of the primary p-toluensulfonate and treatment of the resultant monotosylate 40 with lithium aluminum hydride. Finally, formation of the E ring as a lactone form completed the synthesis of 3. (C) 2001 Elsevier Science Ltd. All rights reserved.

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

A synthetic route to the FGH ring system of gambierol, a marine polyether toxin isolated from the dinoflagellate Gambierdiscus toxicus, has been developed. The present synthesis features B-alkyl Suzuki coupling of the F and H rings, followed by ring-closure of the G ring and stereoselective installation of 1,3-diaxial methyl groups at C21 and C23. (C) 2000 Elsevier Science Ltd. All rights reserved.

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

Convergent synthesis of HIJK ring model compound 1 of ciguatoxin is described. The present synthesis relied on a palladium-catalyzed Suzuki cross-coupling reaction between eight-membered ketene acetal phosphate 2 and seven-membered alkylborane 6. (C) 2000 Elsevier Science Ltd. All rights reserved.

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

[GRAPHICS]
A general method for convergent assembly of polyether structure has been developed based on palladium(0)-mediated Suzuki cross-coupling reaction of alkylboranes with cyclic ketene acetal phosphates. The present method allowed for coupling of medium-sited ether rings and thus a concise synthesis of the ABCD ring system of ciguatoxins has been achieved.

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

A new strategy for convergent synthesis of trans-fused polyethers based on palladium(0)-catalyzed Suzuki cross-coupling reaction of alkylboranes with cyclic enol triflates has been developed. The present method allows to construct polyether frameworks rapidly and efficiently. (C) 1998 Elsevier Science Ltd. All rights reserved.

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Responsible for pages：348-412   Language：English   Book type：Scholarly book

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Responsible for pages：48-49   Language：Japanese   Book type：Scholarly book

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Language：Japanese  

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Language：English   Publisher：ROYAL SOC CHEMISTRY  

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Language：English   Publisher：ROYAL SOC CHEMISTRY  

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J-GLOBAL

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：The International Pharmaceutical Federation  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (other)   Publisher：The Society of Synthetic Organic Chemistry, Japan  

The first total synthesis of gambierol, a marine polycyclic ether toxin, has been achieved. Highly efficient synthesis of the ABC and EFGH ring fragments allowed us to prepare those two advanced intermediates in multi-gram quantities. The key feature of the present total synthesis is the B-alkyl Suzuki-Miyaura coupling tactics, which culminated in the union of the advanced intermediates and convergent synthesis of the octacyclic polyether core. Introduction of the sensitive triene side chain via Pd (PPh₃) 4/CuCl/LiCl-promoted Stille coupling was conducted at the final step of the synthesis.<BR>The present total synthesis supplied useful quantities of gambierol and its structural analogues for detailed biological studies : an interesting observation was gained through pathological studies. Also, preliminary structure-activity relationship studies revealed that the functionalities present in the H ring and unsaturated side chain are crucial for potent toxicity against mice.

DOI： 10.5059/yukigoseikyokaishi.61.742

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Other Link： https://jlc.jst.go.jp/DN/JALC/00230309041?from=CiNii

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