Total Synthesis of (+)-Gliocladin C Based on One-Pot Construction of a 3a-(3-Indolyl)pyrroloindoline Skeleton by Sulfonium-Mediated Cross-Coupling of Tryptophan and Indole.

Total synthesis of (+)-gliocladin C has been achieved on the basis of one-pot construction of the 3a-(3-indolyl)pyrroloindoline core structure by the cross-coupling of a tryptophan derivative and an indole promoted by a sulfonium species generated from dialkylsulfoxide and triflic anhydride.

Direct C2-Functionalization of Indoles Triggered by the Generation of Iminium Species from Indole and Sulfonium Salt.

An indole core bearing a functional group on the C2 position is often found as a key structure in biologically active natural products and pharmaceuticals. Here, we report direct C2-functionalization of indoles triggered by the formation of an iminium species generated from indole and a sulfonium reagent. The reaction proceeded under very mild conditions to give the corresponding C2-substituted indole derivatives in good to high yields.

Design and Synthesis of Non-peptide RGD Mimics for Evaluation of Their Utility as Anti-platelet Agents.

Arg-Gly-Asp (RGD) mimics were synthesized and their anti-platelet activity was evaluated. A concise method was developed for the synthesis of the target compounds from dehydroepiandrosterone and Wieland-Miescher and Hajos-Parrish ketones, which are suitable for readily available platform. Among the synthesized compounds, the perhydronaphthalene framework with a 3-(4-piperidinyl)propoxyl structure 3e possessed the highest anti-aggregative activity. The IC50 values of 3e were 0.91 mM (ADP initiation) and 0.54 mM (collagen initiation).

Synthesis and ABCG2 inhibitory evaluation of 5-N-acetylardeemin derivatives.

An efficient and versatile synthesis of 5-N-acetylardeemin (1a) and sixteen 2-, 3- and 13-substituted derivatives 1b-q was achieved through Ugi three-component reaction of 3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole and cyclization/epimerization. Their inhibitory activity on the drug efflux of breast cancer resistance protein (ABCG2) was evaluated by flow cytometric analysis of accumulation of Hoechst 33342 stain in Flp-In-293/ABCG2 cells. Most of the derivatives exhibited a stronger ABCG2 inhibitory effect compared with natural product 1a. The derivative 1m with a 4-tolyl substituent at the C-13 position exhibited the most potent ABCG2 inhibition. This preliminary structure-activity relationship study indicates that an electron-rich aryl moiety as the 13-substituent is key to increasing the inhibitory activity.

DMSO/Tf2O-mediated cross-coupling of tryptamine with substituted aniline to access C3a-N1'-linked pyrroloindoline alkaloids.

The cross-coupling of tryptamine with substituted aniline to access C3a-nitrogen-linked pyrroloindolines has been developed via the consecutive cyclization of tryptamine with DMSO/Tf2O and the substitution of 3a-pyrroloindolylthionium intermediate with aniline. The use of 2,3-dihydrotryptamine instead of aniline enabled easy access to 3a-(1-indolyl)pyrroloindoline and the concise synthesis of C3a-N1'-linked pyrroloindoline alkaloid (±)-psychotriasine was accomplished.

Asymmetric total synthesis of (-)-leuconoxine via chiral phosphoric acid catalyzed desymmetrization of a prochiral diester.

The asymmetric total synthesis of (-)-leuconoxine has been achieved. The desymmetrization of a prochiral diester using a chiral phosphoric acid catalyst produced a highly enantioenriched lactam with excellent yield. The ring construction featuring an intramolecular N-acyliminium cyclization and the one-step pyrrolidone formation using Bestmann's ylide was successfully accomplished.

Thionium-based one-pot construction of homo-/heterodimeric pyrroloindoline from tryptamine.

We report a one-pot procedure for forming a dimeric pyrroloindoline framework with a thionium reagent. The cyclization of tryptamine with DMSO and Tf(2)O, followed by substitution with indole derivatives, produced racemic 3a-indolylpyrroloindolines. The method enables rapid access to heterodimeric pyrroloindolines as well as to homodimeric pyrroloindolines.

Sulfoxide-TFAA and nucleophile combination as new reagent for aliphatic C-H functionalization at indole 2α-position.

Aliphatic C-H functionalization at indole 2α-position mediated by acyloxythionium species 1 generated from sulfoxide and acid anhydride has been developed. The combination of sulfoxide and TFAA with O-, N- and C-nucleophiles enabled introduction of various substituents in a one-pot procedure. Especially on utilizing DMSO, the combination provided a practical and efficient method for the synthesis of a wide range of 2α-substituted indoles.

Synthesis of phenserine analogues and evaluation of their cholinesterase inhibitory activities.

Phenserine is a potentially attractive drug for Alzheimer's disease. In order to further expand SAR study for inhibitions of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), the methyl group at the 3a-position of phenserine was replaced with an alkyl or alkenyl group, and its phenylcarbamoyl moiety was substituted at the o- or p-position. The synthetic methodology for these phenserine analogues includes the efficient cascade reactions for introduction of the 3a-substituent and assembly of the quaternary carbon center followed by reductive cyclization to the key pyrroloindoline structure. The bulkiness of the substituent at 3a-position of phenserine derivatives tends to reduce the inhibitory effect on AChE activity in the following order: methyl > ethyl > vinyl > propyl ≈ allyl > reverse-prenyl groups. Among the series synthesized, the 3a-ethyl derivative demonstrated the highest AChE selectivity. In construct, the 3a-reverse-prenyl derivative indicated modest BuChE selectivity.

Active thionium species mediated functionalization at the 2α-position of indole derivatives.

A combination of dimethyl sulfoxide (DMSO) and trifluoroacetic anhydride (TFAA) mediates functionalization at the 2α-position of indole derivatives. Carbon and heteroatom nucleophiles were directly introduced via a one-pot procedure in excellent yields.

Distribution of deoxynivalenol and nivalenol in milling fractions from fusarium-infected Japanese wheat cultivars.

The fate of the Fusarium mycotoxins deoxynivalenol and nivalenol during the milling of Japanese wheat cultivars artificially infected with Fusarium was investigated. Grain samples with different mycotoxin concentrations were milled using a laboratory-scale test mill to produce eight fractions: three breaking flours (1B, 2B, and 3B), three reduction flours (1M, 2M, and 3M), wheat bran, and wheat shorts. Patent flour for human consumption was made from the 1B, 2B, 1M, and 2M flours, and low-grade flour was made from 3B and 3M flours. The four resulting samples (patent flour, low-grade flour, bran, and shorts) were analyzed for deoxynivalenol and/or nivalenol with an in-house validated analytical method using high-performance liquid chromatography with UV absorbance detection. In samples with different mycotoxin concentrations, the distribution of those toxins differed among the milling fractions. Grains with a lower level of contamination produced bran and shorts samples with a high relative concentration of nivalenol. A high percentage of nivalenol was found in patent flour, followed by bran. Contrary to the less-contaminated sample, the concentration of nivalenol in moderately contaminated grain was high only in the shorts sample. The highest percentage of deoxynivalenol and nivalenol was observed in the patent flour. The results of this study indicate that the distribution of deoxynivalenol and nivalenol in milled Japanese wheat could be influenced by the contamination level of the original grain, and the milling process is not always effective for removal of toxins from wheat grains.

Total syntheses of (-)-fructigenine A and (-)-5-N-acetylardeemin.

The first total synthesis of (-)-fructigenine A and a novel approach to (-)-5-N-acetylardeemin through a common imine intermediate (+)-3 are described. The key steps include highly enantioselective preparation of (+)-3 via domino olefination/isomerization/Claisen rearrangement (OIC) of 5, reductive cyclization (RC), and regioselective oxidation of (-)-4 and a novel assembly of the pyrazino ring of these alkaloids via Ugi three-component reaction/cyclization of (+)-3 with the corresponding amino acid and isonitrile.

First total synthesis of hinckdentine A.

We have accomplished the first total synthesis of (+/-)-hinckdentine A (1). The key steps are m-CPBA oxidation of 2-arylindole followed by acid-mediated Mannich-type C-C bond formation of 2-hydroxyindolin-3-one, seven-membered ring closure, and regioselective tribromination.

Preparation of an in-house reference material containing fumonisins in Thai rice and matrix extension of the analytical method for Japanese rice.

Mycotoxin contamination in rice is less reported, compared to that in wheat or maize, however, some Fusarium fungi occasionally infect rice in the paddy field. Fumonisins are mycotoxins mainly produced by Fusarium verticillioides, which often ruins maize. Rice adherent fungus Gibberella fujikuroi is taxonomically near to F. verticillioides, and there are sporadic reports of fumonisin contamination in rice from Asia, Europe and the United States. Therefore, there exists the potential risk of fumonisin contamination in rice as well as the need for the validated analytical method for fumonisins in rice. Although both natural and spiked reference materials are available for some Fusarium mycotoxins in matrices of wheat and maize, there are no reference materials for Fusarium mycotoxins in rice. In this study, we have developed a method for the preparation of a reference material containing fumonisins in Thai rice. A ShakeMaster grinding machine was used for the preparation of a mixed material of blank Thai rice and F. verticillioides-infected Thai rice. The homogeneity of the mixed material was confirmed by one-way analysis of variance, which led this material to serve as an in-house reference material. Using this reference material, several procedures to extract fumonisins from Thai rice were compared. Accordingly, we proved the applicability of an effective extraction procedure for the determination of fumonisins in Japanese rice.

Cell surface glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of Lactobacillus plantarum LA 318 recognizes human A and B blood group antigens.

Lactobacillus plantarum LA 318 is a potential probiotic strain isolated from normal human intestinal tissue that shows high adhesion to human colonic mucin mediated by the bacterial cell surface glyceraldehyde-3-phosphate dehydrogenase (GAPDH). We report the adhesion mechanism of the lactobacilli is in part due to GAPDH binding to human ABO-type blood group antigens expressed on human colonic mucin (HCM). After periodate oxidation of HCM, adhesion of L. plantarum LA 318 bacterial cells significantly decreased compared to normal HCM. A BIACORE binding assay of GAPDH to blood group antigens was then performed. High binding was observed to A and B group antigens, while binding to H group antigen was lower (P<0.01). No interaction was observed between GAPDH and various monosaccharides. Furthermore, GAPDH binding to the B-trisaccharide biotinyl polymer (BP)-probe [Galalpha1-3 (Fucalpha1-2) Gal-] was significantly higher as compared to B-disaccharide, Lewis D-trisaccharide, 3-fucosyl-N-acetylglucosamine and alpha-N-acetylneuraminic acid BP-probes. The data suggests the trisaccharide structure is important in binding to the blood group antigens. The binding of GAPDH to HCM significantly decreased after incubation with NAD+. This suggests that the NAD binding domain on GAPDH may be related to binding to HCM.

Total synthesis of (+/-)-flustramines A and C, (+/-)-flustramide A, and (-)- and (+)-debromoflustramines A.

Here we describe the efficient total synthesis of the three title hexahydropyrrolo[2,3-b]indole alkaloids and debromo derivative from readily available indolin-3-ones using key domino reactions, olefination-isomerization-Claisen rearrangement (OIC), and reductive cyclization (RC). (+/-)-Flustramine C (5) was synthesized in five steps from 6-bromoindolin-3-one 9 via a key intermediate 13a. (+/-)-Flustramine A (1) has been obtained by reduction of flustramide A (6), which has been prepared in five steps from 13a. (+/-)-Debromoflustramine A (19) was provided in a similar manner from 13b. The (-)- and (+)-enantiomers of 19 were synthesized through optical resolution of (+/-)-carboxylic acid 17b using (R)-4-phenyloxazolidin-2-one.

Simple indole alkaloids and those with a nonrearranged monoterpenoid unit.

This review covers the literature on simple indole alkaloids and those with a nonrearranged monoterpenoid unit. Newly isolated alkaloids, structure determinations, total syntheses and biological activities are included.

Enantioselective total synthesis of (-)-flustramines A, B and (-)-flustramides A, B via domino olefination/isomerization/Claisen rearrangement sequence.

The concise total synthesis of marine alkaloids, (-)-flustramines A and B, and (-)-flustramides A and B has been achieved through the domino olefination/isomerization/Claisen rearrangement (OIC) for highly enantioselective construction of the asymmetric quaternary carbon center and the chemoselective reduction-cyclization (RC) for pyrrolidine formation as key steps.

Simple indole alkaloids and those with a nonrearranged monoterpenoid unit.

This review covers the literature on simple indole alkaloids and those with a nonrearranged monoterpenoid unit from the beginning up to the end of 2004. Newly isolated alkaloids, structure determinations, total synthesis and biological activities are included.

Synthesis of diversely functionalized hexahydropyrrolo[2,3-b]indoles using domino reactions, olefination, isomerization and Claisen rearrangement followed by reductive cyclization.

Hexahydropyrrolo[2,3-b]indoles 6 were synthesized in five steps from indolin-3-one 8 by a general and efficient method, in which elements of molecular diversity were readily added onto the 3a-position of the pyrrolo[2,3-b]indole ring system. Horner-Wadsworth-Emmons reaction of 2-allyloxyindolin-3-ones 7, derived from indolin-3-one 8 and a variety of allylic alcohols, smoothly proceeded with successive Claisen rearrangement to give the corresponding 3-allyl-3-cyanomethylindolin-2-ones 15. Indolin-2-ones 15 were converted into pyrrolo[2,3-b]indoles 6 using partial hydrolysis followed by reductive cyclization with LiAlH(4). Synthesis of N-methylated pyrrolo[2,3-b]indole derivatives 23 and 26 is also described.