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The synthesis of the ABCDEF-ring of ciguatoxin 3C was achieved via a route that included anion coupling of a dimethyldithioacetal mono-S-oxide derivative corresponding to the AB-ring and an aldehyde corresponding to the EF-ring, followed by cyclization using reductive etherification. The AB-ring was synthesized from a known d -glucose derivative based on ring-closing olefin metathesis, and the EF-ring was prepared by a process employing chirality-transferring Ireland-Claisen rearrangement and ring-closing olefin metathesis.

Pectenotoxin-2 (PTX2) is a shellfish toxin and has a non-anomeric spiroacetal, which is not stabilized by an anomeric effect. The selective construction of the non-anomeric spiroacetal has been a major problem in the synthesis of PTX2. Described herein is the stereoselective total synthesis of PTX2 via the isomerization of anomeric spiroacetal pectenotoxin-2b (PTX2b). The synthesis of PTX2b was achieved by a simple process including sulfone-mediated assembly of spirocyclic and bicyclic acetals and subsequent macrocyclization by ring-closing olefin metathesis. Finally, the selective construction of PTX2 was accomplished by the early termination of a dynamic transition process to equilibrium in the acid-catalyzed isomerization of anomeric PTX2b. [6,6]-Spiroacetal pectenotoxin-2c (PTX2c) was also synthesized from PTX2b. The cytotoxicity assay of the synthetic compounds against HepG2 and Caco2 cancer cells showed a potency of the order: PTX2≫PTX2b>PTX2c.

The C8–C20 segment of pectenotoxin-2 was efficiently synthesized in 16% overall yield in 22 steps from l -malic acid via an improved route.

In this study, we synthesized the C8–C20 and C21–C30 segments of the diarrhetic shellfish toxin pectenotoxin 2. The C8–C20 segment was assembled from a phosphonate corresponding to the C8–C15 segment (prepared from l -malic acid in 19 steps) and an aldehyde corresponding to the C16–C20 segment (synthesized from 3-methyl-3-butenol in nine steps) by a twelve-step process including the Horner–Wadsworth–Emmons reaction, regio- and stereoselective reduction of the resulting enone, diastereoselective epoxidation, and 5-exo epoxide cleavage forming the C-ring. The C21–C30 segment was constructed in 13 steps from (S)-glycidol via a route involving E-ring formation by 5-exo epoxide cleavage and stereoselective methylation at C27 by the Evans method.

Convergent synthesis of the common FGHI-ring part (54) of ciguatoxins was achieved via the following key steps: (i) the Nozaki–Hiyama–Kishi reaction connecting the F-ring part (6) with the I-ring part (7); (ii) regio- and stereoselective epoxidation; (iii) the 6-exo-epoxide opening reaction forming simultaneously the H-ring and the quaternary asymmetric center at C30; (iv) inversion of the C29 stereocenter by a two-step oxidation/reduction process, where the successful inversion depended on proper management of the steric environment of the substrate; and (v) final reductive cyclization constructing the G-ring.

The common FGHI-ring part ( 2 ) of ciguatoxins has been synthesized from the F- and I-ring parts ( 6 and 5 , respectively). The Nozaki–Hiyama–Kishi coupling of 6 with 5 followed by regio- and stereoselective epoxidation at C29 and C30 afforded an epoxide ( 4 ), which was transformed into a tricyclic compound ( 3 ) corresponding to the F-HI-ring part by 6- exo -epoxide opening and the subsequent inversion of the C29 stereocenter. Reductive cyclization of 3 forming the C31–O26 bond of the G-ring successfully produced 2 .

Convergent synthesis of the IJKLM-ring part ( 2 ) of ciguatoxin CTX3C has been achieved from the I-ring and the L-ring parts ( 4 and 5 ) in total eight steps in 27% overall yield. The carbanion derived from 4 , stabilized by a dimethyldithioacetal S-oxide group, was readily reacted with aldehyde 5 to give an adduct, which was facilely transformed into the corresponding α,e-dihydroxy ketone 3 . The JK-ring formation from 3 under reductive conditions followed by oxidative M-ring cyclization efficiently led to the pentacyclic ether 2 . Improved synthesis of 6 , a synthetic intermediate for 4 , was also established.

Aiming at a convergent total synthesis of ciguatoxin CTX1B, its EF-ring segment has been synthesized. During the synthesis, a novel method for the construction of branched ethers, based on regioselective reduction of γ-alkoxy β,γ-unsaturated α-silyloxy nitriles with borontrifluoride etherate and trialkyl silane or tributyltin hydride, has been developed. Combination use of the method and ring-closing olefin metathesis successfully provided medium-sized cyclic ethers. Efficient site-selective reduction of vinyl epoxides into homoallyl alcohols has also been developed.

ペルチェ効果を利用して雪結晶を生成する装置を考案した.本装置は,大型のペルチェ素子を多段化し水冷方式で使用する事により,室内で-30℃程度までの低温環境を実現しながら,電圧を調節することで,結晶生成領域の温度と水温,すなわち水面から発生する水蒸気量を変化させ,簡単に雪結晶を生成することができる対流型の人工雪発生装置である.筐体に発泡スチロールを使用するなどの工夫によって,装置の製作が容易であり,同時に小型で移動もできるという利点を持つ.これは,従来の対流型や拡散型装置のように低温室など大がかりな装置や,冷媒を使用する複雑な付加装置が不要である.本論文では,この装置の基本原理およびその構成を述べ,本装置によって作られた雪結晶のいくつかを紹介する.

Natural trans-fused polycyclic ethers, produced by marine sources such as dinoflagellates, are hypothesized to be constructed efficiently from the corresponding polyepoxide precursors by a cascade ...

A synthetic method for a branched ether system was developed. The method was based on Lewis-acid-promoted γ-position selective reduction of a γ-alkoxy β,γ-unsaturated α-silyloxy nitrile, prepared through a process including intermolecular hetero-Michael reaction of a 2-butynoate ester derivative with an alcohol. The method was efficiently applied to the synthesis of fused medium-ring ethers involving the EF-ring segment ( 2 ) of ciguatoxin ( 1 ).

Convergent synthesis of the ABCDE-ring part (2) of ciguatoxin CTX3C (1) has been achieved. A carbanion stabilized by a dimethyldithioacetal S-oxide group in the AB-ring part (4) readily reacted with an aldehyde group in the E-ring part (5). The resulting adduct was facilely converted to the corresponding β,γ-unsaturated α,e-dihydroxy ketone (3). The subsequent reductive hydroxy-ketone-cyclization reactions constructed the CD-ring part efficiently. Thus, the ABCDE-ring part (2) was concisely synthesized in 10 steps in 11% overall yield from the AB-ring and the E-ring parts (4 and 5).

Concise construction of the trans-fused 7/7/6/6 tetracyclic ether part of hemibrevetoxin B (1) was achieved by a convergent strategy based on coupling reaction of an acyl anion equivalent, reductive cyclization of an α,e-dihydroxyketone, and introduction of a methyl group at the central ring junction by the Nicolaou method. The resultant tetracyclic ether was transformed into the known intermediate, which was already converted to 1 by the Yamamoto group, thereby completing the formal total synthesis of 1.

Azadirachtin is a C-seco limonoid, derived from the neem tree. Previously, we reported the synthesis of the right and left segments of azadirachtin, in addition to the coupling reaction of the modeled ester utilizing Claisen rearrangement. Herein we report the transformation of the modeled rearrangement product into a tricyclic dihydrofuran, which would be expected to have bioactivity against insects.

The synthesis of the AB-ring segment aiming at the convergent construction of the left half in ciguatoxin (CTX1B) has been achieved by a strategy based on ring-closing metathesis (RCM) and diastereocontrolled hydroboration to cyclic vinyl ethers.

In the course of the synthetic studies on gymnodimine, a potent shellfish toxin, the asymmetric construction of the azaspirocyclic part was achieved by the (-)-siam.Cu(SbF 6 ) 2 complex catalyzed intermolecular Diels-Alderreaction in high exo- and enantioselectivities.

The BCDE-ring part of ciguatoxin has been convergent-ly synthesized by a sequence of reactions involving coupling of the E-ring part having a Z-enal group with the B-ring part as an acyl anion equivalent, selective removal of a p-bromobenzyl protective group using Miyaura's conditions, and reductive cyclization.

Chiral medium-sized monocyclic ethers corresponding to the D-, E-, F-, and I-ring parts of ciguatoxin have been synthesized from tri-O-acetyl-D-glucal through a common synthetic route involving ring-closing olefin metathesis.

The asymmetric formation of azaspiro[5.6]dodec-9-ene system is described. The Diels-Alder reactions of an α-methylene caprolactam and diene in the presence of a Cu(II) and (S,S)-tBu-BOX complex afford the desired spirocyclic compounds with good exo-selectivity as well as excellent enantioselectivity. These exoadducts would be applicable to the synthesis of marine natural toxins including the corresponding cyclic imine moiety.

We previously showed that zooxanthellatoxin-B, isolated from dinoflagellate, caused a sustained contraction of the aorta in an external Ca2+-dependent manner. To clarify the role of Ca2+in this action, we examined the effects of zooxanthellatoxin-B as well as a depolarizing stimulus (60 mM KCl), using the simultaneous recording for cytosolic Ca2+level (fura-2) and developed tension in the rabbit aorta. KCl (60 mM) elicited a rapid cytosolic Ca2+elevation followed by a pronounced contraction, and time required for half-maximum contraction was 2 min. Zooxanthellatoxin-B caused an increase in cytosolic Ca2+followed by a gradual contraction, with a time for half-maximum contraction of 5–10 min in a concentration-dependent manner. We found a strong correlation between Ca2+elevation and the contraction in zooxanthellatoxin-B action. In a Ca2+-free solution, zooxanthellatoxin-B caused neither the contraction nor the increase in cytosolic Ca2+. Furthermore, both pre- and post-treatment with verapamil, a voltage-operated Ca2+-channel blocker, partially suppressed both an increase in cytosolic Ca2+and the contraction by zooxanthellatoxin-B. Zooxanthellatoxin-B-induced contraction was also inhibited by other voltage-operated Ca2+-channel blockers: nifedipine or diltiazem. These results suggest that zooxanthellatoxin-B-elicited contraction is caused by a Ca2+influx into the smooth muscle cells, partially via voltage-operated Ca2+channels.Key words: zooxanthellatoxin, Ca2+imaging, rabbit aorta, contraction, voltage-operated Ca2+-channels.

The bioluminescence reaction of coelenterazine involves an oxidative process. To investigate the reaction mechanism, we synthesized three mechanism-based inhibitors with an indanone core structure. The inhibitors exhibited the competitive inhibition of the Renilla luciferase reaction. The (−)-4-benzyl-2-(4-hydroxybenzyl)-2-hydroxymethyl-6-(4-hydroxyphenyl)-indan-1-one showed the significant enantio-selectivity of the inhibition and its absolute configuration was assigned as the R -configuration. These inhibitors could be useful probes to study the catalytic environment in the coelenterazine–luciferase reaction.

The chemiliminescent compound coelenterazine is involved in various bioluminescence reactions as the substrates, causing the luminescence with an emission peak in the range of 450–475 nm. Anticipating the introduction of a bathochromicshift of the luminescence, several new coelenterazine analogues that have conjugated olefins or aromatic groups at the 8-position of imidazopyrazinone ring were synthesized. In the chemiluminescence reaction, the emission spectra of a majority of the compounds synthesized showed a bathochromic shift, giving an emission peak in the range of 520–580 nm. In the bioluminescence catalyzed by Oplophorus luciferase, the bisthienyl analogue of coelenterazine emitted a moderate intensity of luminescence (5% of coelenterazine) with an emission maximum at 528 nm, which was the longest wavelength of all the analogues tested.

We previously showed that zooxanthellatoxin-B, isolated from dinoflagellate, caused a sustained contraction of the aorta in an external Ca2+-dependent manner. To clarify the role of Ca2+ in this action, we examined the effects of zooxanthellatoxin-B as well as a depolarizing stimulus (60 mM KCl), using the simultaneous recording for cytosolic Ca2+ level (fura-2) and developed tension in the rabbit aorta. KCl (60 mM) elicited a rapid cytosolic Ca2+ elevation followed by a pronounced contraction, and time required for half-maximum contraction was 2 min. Zooxanthellatoxin-B caused an increase in cytosolic Ca2+ followed by a gradual contraction, with a time for half-maximum contraction of 5-10 min in a concentration-dependent manner. We found a strong correlation between Ca2+ elevation and the contraction in zooxanthellatoxin-B action. In a Ca2+-free solution, zooxanthellatoxin-B caused neither the contraction nor the increase in cytosolic Ca2+. Furthermore, both pre- and post-treatment with verapamil, a voltage-operated Ca2+-channel blocker, partially suppressed both an increase in cytosolic Ca2+ and the contraction by zooxanthellatoxin-B. Zooxanthellatoxin-B-induced contraction was also inhibited by other voltage-operated Ca2+-channel blockers: nifedipine or diltiazem. These results suggest that zooxanthellatoxin-B-elicited contraction is caused by a Ca2+ influx into the smooth muscle cells, partially via voltage-operated Ca2+ channels.

Various halogenated organic compounds, originated from marine livings, have been well-known over five decades. Particularly, cyclic bromo-ether have attracted many chemists to study their existence, biogenetic syntheses and artificial syntheses, owing to their unique structures. Laurencia species produce eight-membered ethers as major products, although their syntheses by chemical procedures are generally difficult. These compounds are divided into laurenan and lauthisan groups based on the type of ring formation. The laurenan compounds are characteristic in respect of C6-S and C7-S configurations, while the lauthisan series haveR and R at the requisite positions. It has been proposed without any proof that the bromine atoms in the marine compounds could be introduced via bromo cationic species, generated by the two-electron oxidation of bromide ion with bromoperoxidase (BPO) and hydrogen peroxide. We studied on the enzymatic formation of these bromo-ethers, and found that both series of laurenan and lauthisan compounds could be biosynthesized directly from linear C15 compounds, laurediols. Herein, we mention our study of these natural products, and the recent studies around this field.

To determine the absolute configuration of the common C25 long chain acid part (L) of zooxanthellatoxins, the degradation product derived from the terminal carboxylic acid portion of L was synthesized from glucose and used to establish that the total absolute configuration of L was 3 R ,4 R ,5 S ,7 S ,11 S ,12 S ,13 R ,14 S ,15 R ,17 R ,18 R .

dl -Cypridina luciferin and its analogues were synthesized from 2-aminopyrazine by an eight-step method that included two regio-selective Pd-mediated cross couplings, and their chemi- and bioluminescent activities were compared. Analogues having a 3-benzofuranyl or a 3-benzothienyl group in the place of a 3-indolyl group showed luciferase affinities similar to Cypridina luciferase but with a lower luminescent efficiency, suggesting that the NH group is unimportant for molecular recognition whereas the indolyl group is crucial for efficient luminescence.

Introduction of an alkoxymethyl group at the C1 position in the 6,8-dioxabicyclo[3.2.1]octane system enabled novel formation of oxepane compounds in TiCl4-catalyzed acetal cleavage reactions.

Construction of the left segment of azadirachtin in naturally occurring enantiomer is described. The key reaction is an intramolecular Diels-Alder reaction, which was performed under thermal conditions to afford the highly functionalized decalin compounds selectively.

An asymmetric synthesis of the tricyclic dihydrofuran moiety of azadirachtin is reported. The Diels-Alder adduct, which was catalyzed by Evans' chiral Cu-bisoxazoline complex, was easily converted to the tricyclic portion via SmI 2 reductive cleavage and selective functionalization.

The absolute configuration of the exomethylene portion of zooxanthellatoxin-A (ZT-A) was established as 71 R ,73 R ,74 S ,75 R by comparing an MTPA ester of an acyclic degradation product of ZT-A with those of the compound synthesized from methyl-α-D-glucopyranoside.

Superoxide-triggered chemiluminescence of five new imidazopyrazinone derivatives was investigated using the hypoxanthine-xanthine oxidase system as the source of superoxide anion. The results showed that they are highly sensitive and have favorable properties in measuring superoxide anion. With those new probes, the generation of superoxide anion from the bacteria Listeria monocytogenes was examined. The results confirmed the previous report that L. monocytogenes is an unusual organism that extracellularly and continuously generates a high level of superoxide anion in the presence of acetaldehyde. The data indicated that two of the probes, 3,7-dihydro-2-methyl-6-phenylethynylimidazo[1,2-a]pyrazin-3- one (4) and its methoxy derivative (5), are highly sensitive and useful in the measurements of superoxide anion and are clearly superior to 3,7-dihydro-2-methyl-6-(4-methoxyphenyl)imidazo[1,2-a]pyrazin-3-on e (MCLA), which-has been generally considered the most sensitive superoxide probe in the past. When tested at a probe concentration of 3.3 microM, the luminescence response and the signal-background ratio of compound 4 were 1.5 and 2.5 times those of MCLA, respectively, and the signal-background ratio of compound 5 was almost 15 times that of MCLA, though the luminescence response of this compound was slightly lower than that of MCLA. The low probe concentration used enhances the usefulness of probes in the measurements of superoxide in functioning biological systems.

In studies on the biogenesis of vasocontrictive macrolides, zooxanthellatoxins isolated from a symbiotic dinoflagellate Symbiodinium sp., we have investigated metabolites of the dinoflagellate cultured under different conditions. Four new compounds were isolated from 70% EtOH extract of the cells cultured in f/2 medium. Two betaines (zooxanthellabetaine-A and -B) were obtained from a neutral fraction of n-BuOH soluble portion and the structure of zooxanthellabetaine-A was determined as 4-(4-hydroxybenzoyloxy)-3-(trimethylammonio)butyrate. The EtOAc soluble portion afforded a new C-30 alkaloid, zooxanthellamine, and a new ceramide, symbioramide-C16. The structural similarity of zooxanthellamine to zoanthid alkaloids, zoanthamines, suggested an algal origin of these zoanthamines. Zooxanthellamine might be derived biogenetically from a polyketide chain presumably started from a glycine unit, like other marine toxins such as zooxanthellatoxin and palytoxin.

The spiro acetal part (C46–C55) of ciguatoxin was synthesized stereoselectively.

The synthesis of the A,B,C-ring system having all the natural substituents of ciguatoxin was achieved from D-glucose.

Endo selective intramolecular cyclization has been achieved in 5, 6-epoxy-5-methoxymethyl-1-heptanol and 6, 7-epoxy-6-methoxymethyl-3-octen-1-ol systems by the chelation of La(OTf) 3 between the oxygen atoms of the epoxide and methoxymethyl groups, affording 3-hydroxyoxepane and 3-hydroxy-5-oxocene derivatives, respectively.

3,7-Dihydro-8-chlorostyryl-6-phenylethynyl-2-imidazo[1,2- a ]pyrazin-3-one ( 5a ) prepared from 2-amino-3,5-diphenylethynylpyrazine by condensation with methylglyoxal showed bimodal luminescence in DMSO, i.e., orange-colored luminescence under acidic to neutral conditions and yellow-colored luminescence under basic conditions. The large bathochromic shift of chemiluminescence caused by a styryl group at the 8 position was established by synthesizing 3,7-dihydro-8-styryl-6-phenylethynyl-2-imidazo[1,2- a ]pyrazin-3-one ( 5b ).

The first construction of the A,B,C-ring system having all of the natural substituents in ciguatoxin was achieved from d -glucose. © 1997 Elsevier Science Ltd.

An asymmetric synthesis of syringolide 1, one of the elicitors produced by Pseudomonas syringae pv. tomato, is described. It was synthesized from 2-(1-oxoethyl)-2-buten-4-olide via 1,4-addition of alkenyl cuprate, asymmetric dihydroxylation, and intramolecular Michael reaction.

The synthesis of the B,C,D-ring fragment of pinnatoxins is described. The highly stereocontrolled construction of the 6,5,6-tris-spiroacetal core was achieved on treatment of compound 3 with aqueous HF in CH 3 CN. The anomeric effect at C 16 enhanced by neighboring carbonyl group led to form the tris-spiroacetal having the natural configuration.

The formation of fused cyclic ethers by biomimetic synthesis was demonstrated. The one-pot successive ring-expansion reactions of bromo diepoxides were investigated by regarding the epoxy groups as the nucleophiles for the intramolecular cationic carbons to obtain the fused cyclic ethers.

Feeding experiments of 13C-labeled compounds to dinoflagellates have unveiled existence of methionine cascade pathway from methionine to sulfonium compounds such as 3-dimethylsulfoniopropionate, gonyauline and gonyol in a dinoflagellate.