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A concise preparative method for the tetracyclic core of platensimycin in an optically active form was developed through a nine-step sequence from p-anisaldehyde without the use of protecting groups.

Novel fluorescent compounds based on quinolinecarboxylic acid were developed. These compounds were easily prepared in two or three steps from commercially available compounds. Compound 2 showed a ratiometric response to zinc(II) salt in aprotic solvent.

Four new briarane-type diterpenoids, brianodins A-D ( 1- 4), were isolated from a soft coral, Pachyclavularia sp., and the structures and relative stereochemistry of 1- 4 were elucidated on the basis of spectroscopic data. The absolute configurations of 3 and 4 were assigned by the MTPA method. Brianodin A ( 1) showed a modest cytotoxicity.

Five new briarane-type diterpenoids, pachyclavulides E (5), F (6), G (7), H (8) and I (9), were isolated from the Okinawan soft coral Pachyclavularia violacea. The structures of these compounds were elucidated based on the results of spectroscopic analysis. Compound 5 showed a weak growth-inhibitory activity in vitro toward cancer cells.

Enantioselective short formal synthesis of (+)-precapnelladiene (1) was achieved from a bicyclo[3.2.0]heptane derivative, which was prepared enantioselectively by chiral copper-catalyzed [2+2]-cycloaddition reaction of 2-methoxycarbonyl-2-cyclopenten-1-one with phenylthioacetylene developed by us.

The enantioselective total synthesis of preclavulone-A methyl ester and its diastereomer was achieved from enantiomerically pure 5 in a stereocontrolled manner. The absolute stereochemistry of naturally occurring preclavulone-A methyl esters was determined by comparison of the [α]D value.

A new catalytic system for enantioselective [2+2]-cycloaddition reaction of 2-methoxycarbonyl-2-cyclopenten-1-one with thioacetylene derivatives is described. The use of a catalytic amount (20–30 mol%) of copper(II) salt with chiral bis-pyridine ligand was found to be effective in promoting the [2+2]-cycloaddition reaction, furnishing the corresponding bicyclic compound in good yield and good enantioselectivity.

The solid-phase synthesis of a combinatorial cross-conjugated dienone library based on the structure of clavulones and their biological activity are reported. Clavulones are a family of marine prostanoids, and are composed of a cross-conjugated dienone system bearing two alkyl side-chains. The cross-conjugated dienone system irreversibly reacted with two nucleophiles. Our strategy for the solid-phase synthesis of the cross-conjugated dienones involves the Sonogashira-coupling reaction of a solid-supported cyclopentenone 10 bearing an acetylene group, followed by aldol condensation with aldehydes. The diphenyl derivative 7 aA was prepared from the solid-supported cyclopentenone 10 in 56% total yield. Combinatorial synthesis of a small library using twelve halides and eight aldehydes resulted in the production of 74 desired compounds from 98 candidates, and were detected by their mass spectra. Antiproliferative effects of the crude compounds against HeLaS3 cells showed that eleven samples showed strong antitumor activity (IC50

Four new briarane-type diterpenoids, pachyclavulides A (1), B (2), C (3), and D (4), were isolated from the Okinawan soft coral Pachyclavularia violacea. The structures of these compounds were elucidated on the basis of the results of spectroscopic analysis. The absolute configuration of pachyclavulide A (1) was determined by the X-ray crystallographic analysis of its p-bromobenzoyl ester.

Tributylphosphine or dimethylphenylphosphine (1-5 mol%) catalyzed the Morita-Baylis-Hillman reaction of 2-cyclopenten-1-one (1) with 1.2 equivalents of formalin proceeded nicely to give 2-hydroxymethyl-2-cyclopenten-1-one(2) within a short period and in an excellent yield. The efficiency of the reaction (yield and time) was strongly dependent on the solvent and the best result was obtained in the case of an aqueous MeOH-CHCl 3 solvent system.

A novel terpenoid-related compound, stolonilactone (1), was isolated from the Okinawan soft coral Clavularia koellikeri. The structure of 1 was elucidated on the basis of spectroscopic analysis. A possible biogenesis of 1 through the [4 + 2]-cycloaddition of a trisnorsesquiterpenoid-type diene and a cembranolide-type dienophile is proposed.

We describe an efficient solid-phase synthesis of clavulones via the sequential coupling of the alpha- and omega-chains, involving two separate carbon-carbon bond-forming steps. The tetrahydropyranyl linker survived these reaction conditions and was cleaved without decomposing the unstable cross-conjugated dienones. Our methodology has allowed us to prepare six clavulone derivatives that are varied within the alpha-chain.

Six new terpenoids (two maaliane-type sesquiterpenoids, 1 and 2, one aromadendrane-type sesquiterpenoid, 3, one noraromadendrane-type sesquiterpenoid, 4, and two neodolabellane-type diterpenoids, 5 and 6) were isolated from the Okinawan soft coral Clavularia koellikeri. The structures of these compounds were determined on the basis of the results of spectroscopic analysis, chemical conversion, and X-ray crystallographic analysis. Compound 6 exhibited modest growth-inhibition effect in vitro toward tumor cells.

Various molecules, in which heterocyclic aromatics are linked with phenyl or benzyl groups, were converted to their corresponding cis -dihydrodiols by recombinant Escherichia coli cells expressing modified biphenyl dioxygenase genes. Heterocyclic aromatic compounds with substituted phenyl or aliphatic moieties were also biotransformed to the hydroxylated products by the cells. Many of the converted products were novel compounds. These compounds are potentially useful as versatile starting materials for the chemical synthesis of pharmaceuticals and biologically active organic molecules.

Chemical investigation of the Okinawan soft coral Clavularia koellikeri resulted in the isolation of two new cembrane diterpenoids (1 and 2) and one new dollabelane diterpenoid, 3. Their structures were determined on the basis of the results of spectroscopic analysis. Compounds 1 and 3 were examined for in vitro growth-inhibition effects toward tumor cells.

Two new diterpenoids, 2 and 4, having a dolabellane skeleton were isolated from the Okinawan soft coral of the genus Clavularia. Their structures were determined based on spectroscopic analysis, chemical conversion and X-ray crystallographic analysis. One of these diterpenoids showed cytotoxic activity against tumor cells.

Stereoselective construction of the tricyclic core of yonarolide (1), a marine norditerpenoid, was achieved. This synthetic route includes a Diels–Alder reaction and an intramolecular aldol condensation. It also involves efficient epimerization through a retro-Michael reaction–Michael addition and will be applicable to the total synthesis of 1.

Five new halogenated prostanoids 1-4 and 6 were isolated from the Okinawan soft coral Clavularia viridis. The gross structure of 1 was elucidated mainly on the basis of NMR spectral data. The relative and absolute configurations were determined by analysis of NOESY and CD data, chemical conversion, and the modified Mosher's method. The structures of 2-4 and 6 were deduced by comparison of their spectral data with those of 1. Compound 1 demonstrated cytotoxic activity.

Bioconversion (biotransformation) experiments on arenes (aromatic compounds), including various tricyclic fused aromatic compounds such as fluorene, dibenzofuran, dibenzothiophene, carbazole, acridene, and phenanthridine, were done using the cells of Escherichia coli transformants expressing several arene dioxygenase genes. E. coli carrying the phenanthrene dioxygenase (phdABCD) genes derived from the marine bacterium Nocardioides sp. strain KP7 converted all of these tricyclic aromatic compounds, while E. coli carrying the Pseudomonas putida F1 toluene dioxygenase (todC1C2BA) genes or the P. pseudoalcaligenes KF707 biphenyl dioxygenase (bphA1A2A3A4) genes was not able to convert these substrates. Surprisingly, E. coli carrying hybrid dioxygenase (todC1::bphA2A3A4) genes with a subunit substitution between the toluene and biphenyl dioxygenases was able to convert fluorene, dibenzofuran, and dibenzothiophene. The cells of a Streptomyces lividans transformant carrying the phenanthrene dioxygenase genes were also evaluated for bioconversion of various tricyclic fused aromatic compounds. The ability of this actinomycete in their conversion was similar to that of E. coli carrying the corresponding genes. Products converted from the aromatic compounds with these recombinant bacterial cells were purified by column chromatography on silica gel, and identified by their MS and 1H and 13C NMR analyses. Several products, e.g., 4-hydroxyfluorene converted from fluorene, and cis-1,2-dihydroxy-1,2-dihydrophenanthridine, cis-9,10-dihydroxy-9,10-dihydrophenanthridine, and 10-hydroxyphenanthridine, which were converted from phenanthridine, were novel compounds.

Three new cytotoxic long-chain acetylenic alcohols, strongylodiols A, B and C, were isolated from the Okinawan marine sponge of the genus Strongylophora. Their gross structures were elucidated based on spectroscopic analysis. During the process for determination of the absolute stereochemistry at C-6 using the modified Mosher's method, these acetylenic alcohols were each found to be an enantiomeric mixture with a different ratio; 91:9 for strongylodiol A, 97:3 for strongylodiol B and 84:16 for strongylodiol C. The R configuration for each major enantiomer was established by the modified Mosher's method. Each enantiomer was separated and fully characterized.

A new maleic anhydride derivative 1 (FR222398) was isolated from fermentations with the fungus Talaromyces sp. No. 10092. The structure of 1 was determined based on spectroscopic analysis and chemical conversion. The sodium salt of 1 exhibited a dispersant activity toward kaolin suspension.

Six new marine steroids, yonarasterols A through F, were isolated from the Okinawan soft coral, Clavularia viridis. Their structures were determined based on the results of spectroscopic analysis.

Aragusterol A (YTA0040), isolated from the Okinawan marine sponge of the genus Xestospongia, is a potent anti-tumor marine steroid that possesses a unique structural component. This compound showed broad-spectrum anti-proliferative activity against a panel of 14 human cancer cell lines (IC50 = 0.01–1.6 μM). P-glycoprotein–mediated, multidrug-resistant cells showed cross-resistance to YTA0040 cells, whereas cisplatin-resistant non-small-cell lung-cancer (NSCLC) sublines showed a collateral sensitivity to YTA0040. In transplantable murine tumor models, YTA0040 displayed a broad spectrum and high degree of anti-tumor activity when administered i.p. or p.o. (life span T/C = 135–234%). In P388 murine leukemia cells, YTA0040 caused dose- and time-dependent suppression of nucleic acid and protein synthesis, with protein synthesis being more potently and rapidly inhibited than nucleic acid synthesis. Flow-cytometric analysis revealed that YTA0040 blocked the entry of human NSCLC-derived A549 cells into S phase, leading to arrest in the G1 phase of the cell cycle. Western blot analysis demonstrated that YTA0040 caused a dose-dependent decrease in the levels of expression of hyperphosphorylated pRb and cyclin A in A549 cells. The level of p53 protein expression was decreased by YTA0040 treatment. A higher concentration of YTA0040 down-regulated the levels of expression of CDK2, CDK4, cyclin D1 and cyclin E. These findings indicated that YTA0040 arrested human NSCLC cells in late G1 phase of the cell cycle through inhibition of pRb phosphorylation. Inhibition of pRb phosphorylation by YTA0040 resulted from down-regulation of levels of expression of the CDKs and cyclins involved in the G1/S transition and not from induction of p53 and/or the CDK inhibitor p21. Int. J. Cancer 88:810–819, 2000. © 2000 Wiley-Liss, Inc.

Three new xenicane diterpenoids, xeniaol, xeniadiol and xeniatriol, were isolated from the Okinawan soft coral of the genus, Xenia . Their structures were elucidated by spectroscopic analysis.

Two new marine carbocyclic oxylipins, clavirin I (1) and II (2), were isolated from the Okinawan soft coral, Clavularia viridis. Their structures containing unique α-side chains were determined, based on spectroscopic analysis and stereoselective total synthesis. Clavirins showed growth-inhibitory activity toward HeLa S3 cells.

A new method has been developed for determining the absolute configurations of acyclic β- or γ-methyl substituted secondary alcohols using their 2NMA esters. The 1 H-NMR spectra of ( R )- and ( S )-2NMA esters of model compounds were measured, and Δδ values (δ R-ester - δ S-ester ) for the corresponding protons were compared between syn and anti compounds. Threshold values important for judging the relative stereochemistry of the two chiral centers bearing methyl and hydroxy groups were obtained. The absolute configuration of the chiral center bearing a secondary hydroxy group is easily determined based on the sign of Δδ values as in the MTPA method and thus in the present study it was also possible to clearly determine the absolute configuration of the chiral center bearing a methyl group.

A new unsaturated fatty acid with unique vicinal dimethyl branches was isolated from the Okinawan soft coral of the genus Sinularia. The structure of the compound was determined based on the results of spectroscopic analysis and chemical conversion. The absolute configuration was deduced by applying the Ohrui-Akasaka method.

[reaction: see text] The total synthesis of racemic clavubicyclone (1), which was isolated from Okinawan soft coral by our group, is described. The bicyclo[3.2.1]octane skeleton was prepared by Cope rearrangement of a divinylcyclopropane derivative. Three functional groups on the skeleton were constructed by Barton decarboxylation, Wittig reaction, and alkylation.

Two new marine prostanoids, preclavulone lactones I (1) and II (2) were isolated from the Okinawan soft coral, Clavularia viridis . Their structures were determined based on spectroscopic analysis and chemical synthesis from ( S )-malic acid. Preclavulone lactones with side chains having absolute configurations opposite to those of mammalian prostanoids could be recognized as key intermediates in biosynthesis of clavulones.

New 26, 27-cyclosterols, aragusterols E-H, were isolated from the Okinawan marine sponge of the genus Xestospongia . Their structures were determined by spectroscopic measurement and chemical conversion. The absolute configurations of xestokerols A and B were determined by chemical conversion.

Eight new marine steroids were isolated from the Okinawan soft coral Clavularia viridis Quoy and Gaimard. Their structures were determined based on spectroscopic analysis, chemical conversion, and X-ray crystallographic analysis. Steroids 5 and 6 showed growth inhibition activity toward HeLa S3 cells and human diploid cells in vitro.

The tricyclic ring system of tricycloclavulone was synthesized from 2-methoxycarbonyl-2-cyclopenten-1-one (2). Key reactions include Lewis acid-catalyzed [2+2]-cycloaddition of α,β-unsaturated ester 2 with thioacetylene derivatives and construction of the A-ring by using the Grubbs catalyst.

Acetylenic enol ether glycerides, 1 and 3, were found in the Okinawan marine sponge of the genus Petrosia. The plane structures of these glycerides were deduced from spectroscopic analysis. Their complete structures were established by enantioselective total synthesis of all possible stereoisomers using (R)-1-O-benzylglycerol and its (S)-enantiomer, prepared from D-mannitol and L-ascorbic acid, respectively, as chiral building blocks. The synthesis involves the palladium(0)-catalyzed coupling reaction of bromo enol ether 9 with enediyne 21 as a key step. It became evident from the synthesis that the natural product 1 consisted of a mixture of (7R,2'S)-24 (petrosyne Ia) and (7S,2'S)-24 (petrosyne Ib), and the natural product 3 consisted of a mixture of (7R,2'S)-28 (petrosyne IIa) and (7S,2'S)-28 (petrosyne IIb)

Aragusterol A, a new marine steroid possessing potent antitumor activity, was isolated from the Okinawan sponge of the genus Xestospongia and its structure was determined by spectroscopic analysis and chemical evidence. The compound strongly inhibited the cell proliferation of KB, HeLaS3, P388 and LoVo cells in vitro , and also showed potent in vivo antitumor activity toward P388 in mice and L1210 in mice.

A new marine norditerpenoid, sinulariadiolide, was isolated from Okinawan soft coral of the genus, Sinularia. Its structure was determined by spectroscopic analysis and chemical reaction. This compound is structurally characterized by a new carbon skeleton and two lactonic moieties, five-membered and nine-membered, the latter being conjugated to a 2-hydroxylated carbon−carbon double bond. A possible biogenesis of sinulariadiolide is briefly discussed.

Two novel lactonic steroids, stoloniolide I and II, were isolated from the Okinawan soft coral, Clavularia viridis Quoy and Gaimard. Their structures were determined by spectroscopic analysis. They each possessed a unique 1,10-secoergostane skeleton unprecedented in the field steroids.

Yonarolide, a new marine norditerpenoid possessing a novel tricyclic skeleton, was isolated from the Okinawan soft coral of the genus, Sinularia. The structure of yonarolide was determined by spectroscopic analysis.

New 26, 27-cyclosterols, aragusterols E-H, were isolated from the Okinawan marine sponge of the genus Xestospongia . Their structures were determined by spectroscopic measurement and chemical conversion. The absolute configurations of xestokerols A and B were determined by chemical conversion.

Two new marine prostanoids, preclavulone lactones I (1) and II (2) were isolated from the Okinawan soft coral, Clavularia viridis . Their structures were determined based on spectroscopic analysis and chemical synthesis from ( S )-malic acid. Preclavulone lactones with side chains having absolute configurations opposite to those of mammalian prostanoids could be recognized as key intermediates in biosynthesis of clavulones.

A new method has been developed for determining the absolute configurations of acyclic β- or γ-methyl substituted secondary alcohols using their 2NMA esters. The 1 H-NMR spectra of ( R )- and ( S )-2NMA esters of model compounds were measured, and Δδ values (δ R-ester - δ S-ester ) for the corresponding protons were compared between syn and anti compounds. Threshold values important for judging the relative stereochemistry of the two chiral centers bearing methyl and hydroxy groups were obtained. The absolute configuration of the chiral center bearing a secondary hydroxy group is easily determined based on the sign of Δδ values as in the MTPA method and thus in the present study it was also possible to clearly determine the absolute configuration of the chiral center bearing a methyl group.

Two new marine carbocyclic oxylipins, clavirin I (1) and II (2), were isolated from the Okinawan soft coral, Clavularia viridis. Their structures containing unique α-side chains were determined, based on spectroscopic analysis and stereoselective total synthesis. Clavirins showed growth-inhibitory activity toward HeLa S3 cells.

A method has been developed for determining the absolute configurations of acyclic tertiary alcohols using their 2NMA [methoxy-(2-naphthyl)acetic acid] esters. The 1H NMR spectra of (R)- and (S)-2NMA esters of model compounds were measured, and Δδ values (δR-ester − δS-ester) were calculated. The absolute configuration for tertiary hydroxy group is determined based on the sign of Δδ values like that for secondary hydroxy group.