石川 勇人

There are many indole alkaloids that contain diverse functional groups attached to the benzene ring on the indole core. Promising biological activities of these alkaloids have been reported. Herein, we report the indole C5-selective bromination of indolo[2,3-a]quinolizidine alkaloids by adding nearly equimolar amounts of Br3·PyH and HCl in MeOH. The resulting reaction plausibly proceeds through an indoline intermediate by the nucleophilic addition of MeOH to the C3-brominated indolenine intermediate. Data support the intermediacy of a C3-, C5-dibrominated indolenine intermediate as a brominating agent. These conditions demonstrate excellent selectivity for indole C5 bromination of natural products and their derivatives. Thus, these simple, mild, and metal-free conditions allow for selective, late-stage bromination followed by further chemical modifications. The utility of the brominated product prepared from naturally occurring yohimbine was demonstrated through various derivatizations, including a bioinspired heterodimerization reaction.

The first enantioselective total synthesis of kopsiyunnanine B, which has a unique folded and complex pentacyclic structure containing six contiguous chiral centers, has been achieved along our originally proposed biosynthetic pathway. The key reaction of this synthesis includes a bioinspired cascade that builds three ring structures and three chiral centers in one step and features the stereoselective reduction of a β-acrylate and oxidation to an oxindole.

The aggregation of amyloid-β (Aβ) remains the most acceptable pathological hallmark of Alzheimer's disease (AD). In search for natural products exhibiting anti-amyloidogenic effects, phytochemical analyses were conducted on Uncaria lanosa f. philippinensis leading to the purification of oxindole alkaloid uncarine E (isopteropodine) (1), the phenylethanoid tyrosol (2), the megastigmane vomifoliol (3), and the previously reported alkaloids mitraphylline and isomitraphylline. This is the first report of compounds 1-3 in the title plant, and tyrosol (2) from the genus Uncaria. Assessment of the anti-amyloidogenic potential using Thioflavin T assay showed 91% (at 50 µM) and 70% (at 25 µM) inhibitions for compound 1. Tyrosol (2) gave 76% (at 50 µM) and 63% (at 25 µM) inhibitions. These compounds may be further tested to elucidate their mechanism in the prevention of Aβ aggregation. To the best of our knowledge, this is the first report on the anti-amyloid aggregation activity of compounds 1 and 2.

The enantioselective total syntheses of (-)-silicine and (-)-20-episilicine, which contain a chiral piperidine with three contiguous chiral centers (D-ring) and a strained seven-membered ring (C-ring) attached to an indole, were achieved. The key steps of these syntheses included a chiral secondary amine-catalyzed formal aza-[3 + 3] cycloaddition reaction and Lewis acid-mediated irreversible ring-closing reaction. In addition, the stereochemistry at C20 was controlled at a later stage in the syntheses.

The first asymmetric total synthesis of the Lycopodium alkaloid senepodine F, which contains a decahydroquinoline ring (AB-ring) and a quinolizidine ring (CD-ring) connected by a methylene tether, has been achieved. The key steps of this synthesis include an organocatalytic asymmetric Diels-Alder reaction, a diastereoselective intramolecular aza-Michael reaction, and an intramolecular SN2 cyclization to construct multisubstituted nitrogen-containing heterocycles. In addition, our total synthesis led to the stereochemical reassignment on the decahydroquinoline ring of senepodine F.

Introduction The soil houses a tremendous amount of micro-organisms, many of which are plant parasites and pathogens by feeding off plant roots for sustenance. Such root pathogens and parasites often rely on plant-secreted signaling molecules in the rhizosphere as host guidance cues. Here we describe the isolation and characterization of a chemoattractant of plant-parasitic root-knot nematodes (Meloidogyne incognita, RKN). Methods The Super-growing Root (SR) culture, consisting of excised roots from the legume species Lotus corniculatus L., was found to strongly attract infective RKN juveniles and actively secrete chemoattractants into the liquid culture media. The chemo-attractant in the culture media supernatant was purified using hydrophobicity and anion exchange chromatography, and found to be enriched in carbohydrates. Results Monosaccharide analyses suggest the chemo-attractant contains a wide array of sugars, but is enriched in arabinose, galactose and galacturonic acid. This purified chemoattractant was shown to contain pectin, specifically anti-rhamnogalacturonan-I and anti-arabinogalactan protein epitopes but not anti-homogalacturonan epitopes. More importantly, the arabinose and galactose sidechain groups were found to be essential for RKN-attracting activities. This chemo-attractant appears to be specific to M. incognita, as it wasn’t effective in attracting other Meloidogyne species nor Caenorhabditis elegans. Discussion This is the first report to identify the nematode attractant purified from root exudate of L corniculatus L. Our findings re-enforce pectic carbohydrates as important chemicals mediating micro-organism chemotaxis in the soil, and also highlight the unexpected utilities of the SR culture system in root pathogen research.

Divergent total syntheses of the hetero-oligomeric iridoid glycosides mainly found in Dipsacus asper were achieved. Thus, loganin (1), which is important as a monomer unit, was efficiently synthesized by stereoselective reductive cyclization using secologanin (2) as a substrate. Sequential condensation reactions of derivatives of 1 and 2 as monomer units led to the first enantioselective total syntheses of the heterooligomers cantleyoside, (E)-aldosecologa-nin, dipsaperine, (3R, 5S)-5-carboxyvincosidic acid 22-loganin ester, and dipsanoside A.

A first asymmetric total synthesis of huperzine H has been achieved in a 12% overall yield from commercially available (+)-pulegone. The key steps of this synthesis include a highly diastereoselective Mukaiyama-Michael addition reaction of a pyrrole bearing a silyl enol ether and an intramolecular SN2 cyclization reaction with iodinated pyrrole acting as an effective nucleophile for the formation of the nine-membered ring. As a result, the relative and absolute stereochemistry of huperzine H is established.

Borocyclic radicals with highly conjugated aromatics were generated from orthoquinone-containing polycyclic aromatic compounds by trapping the photoinduced triplet state with simple boron halide under irradiation with light of appropriate wavelength. The picene-based borocyclic radical was remarkably stable when stored at 23 °C in a desiccator for over 1 year. The crystal structure of this stable radical had a stacking structure of a planar π-conjugated system, and the electrical conductivity was higher than those of ordinary organic radical systems.

A series of bioinspired transformations that are applied to convert strictosidine aglycones into monoterpenoid indole alkaloids is reported. The highly reactive key intermediates, strictosidine aglycones, were prepared in situ by simple removal of a silyl protecting group from the silyl ether derivatives, and converted selectively via bioinspired transformations under substrate control into heteroyohimbine- and corynantheine-type, and akagerine and naucleaoral related alkaloids. Thus, concise, divergent total syntheses of 13 monoterpenoid indole alkaloids, (-)-cathenamine, (-)-tetrahydroalstonine, (+)-dihydrocorynantheine, (-)-corynantheidine, (-)-akagerine, (-)-dihydrocycloakagerine, (-)-naucleaoral B, (+)-naucleidinal, (-)-naucleofficines D and III, (-)-nauclefiline, and (-)-naucleamides A and E, were accomplished in fewer than 13 steps.

A new pentacyclic monoterpenoid indole alkaloid glycoside named secorubenine (1) was isolated from the heartwood of Adina rubescens, collected in Indonesia. The structure was elucidated by spectroscopic analysis and chemical modification of isolated secorubenine (1). The bioinspired enantioselective total synthesis of 1 was accomplished in 12 steps, whereafter its structure was determined and the absolute stereochemistry was confirmed.

Root-knot nematodes (RKNs) are plant parasites and major agricultural pests. RKNs are thought to locate hosts through chemotaxis by sensing host-secreted chemoattractants; however, the structures and properties of these attractants are not well understood. Here, we describe a previously unknown RKN attractant from flaxseed mucilage that enhances infection of <italic>Arabidopsis</italic> and tomato, which resembles the pectic polysaccharide rhamnogalacturonan-I (RG-I). Fucose and galactose sidechains of the purified attractant were found to be required for attractant activity. Furthermore, the disaccharide α-<sc>l</sc>-galactosyl-1,3-<sc>l</sc>-rhamnose, which forms the linkage between the RG-I backbone and galactose sidechains of the purified attractant, was sufficient to attract RKN. These results show that the α-<sc>l</sc>-galactosyl-1,3-<sc>l</sc>-rhamnose linkage in the purified attractant from flaxseed mucilage is essential for RKN attraction. The present work also suggests that nematodes can detect environmental chemicals with high specificity, such as the presence of chiral centers and hydroxyl groups.

The discovery and useful application of natural products can help improve human life. Chemicals that inhibit plant growth are broadly utilized as herbicides to control weeds. As various types of herbicides are required, the identification of compounds with novel modes of action is desirable. In the present study, we discovered a novel N-alkoxypyrrole compound, kumamonamide from Streptomyces werraensis MK493-CF1 and established a total synthesis procedure. Resulted in the bioactivity assays, we found that kumamonamic acid, a synthetic intermediate of kumamonamide, is a potential plant growth inhibitor. Further, we developed various derivatives of kumamonamic acid, including a kumamonamic acid nonyloxy derivative (KAND), which displayed high herbicidal activity without adverse effects on HeLa cell growth. We also detected that kumamonamic acid derivatives disturb plant microtubules; and additionally, that KAND affected actin filaments and induced cell death. These multifaceted effects differ from those of known microtubule inhibitors, suggesting a novel mode of action of kumamonamic acid, which represents an important lead for the development of new herbicides.

Root-knot nematodes (RKNs, genus Meloidogyne) are a class of plant parasites that seek out and infect the roots of many plant species. The identification of RKN attractants can be used in agriculture in conjunction with nematode-trapping technology to redirect RKN movements and eventually reduce their prevalence in the field. Here, we discovered that some commercial silica gels can attract nematodes. Silica gels that attract nematodes contain calcium sulfate. Calcium sulfate and calcium carbonate showed strong nematode attraction properties. When plant seeds were surrounded by calcium sulfate or calcium carbonate, nematodes were not attracted to the plant seeds. We propose that calcium sulfate and calcium carbonate can be used in agriculture as a novel material to trap RKN.

© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim A collective synthesis of glycosylated monoterpenoid indole alkaloids is reported. A highly diastereoselective Pictet–Spengler reaction with α-cyanotryptamine and secologanin tetraacetate as substrates, followed by a reductive decyanation reaction, was developed for the synthesis of (−)-strictosidine, which is an important intermediate in biosynthesis. This two-step chemical method was established as an alternative to the biosynthetically employed strictosidine synthase. Furthermore, after carrying out chemical and computational studies, a transition state for induction of diastereoselectivity in our newly discovered Pictet–Spengler reaction is proposed. Having achieved the first enantioselective total synthesis of (−)-strictosidine in just 10 steps, subsequent bioinspired transformations resulted in the concise total syntheses of (−)-strictosamide, (−)-neonaucleoside A, (−)-cymoside, and (−)-3α-dihydrocadambine.

© 2019 Wiley-VCH Verlag GmbH &amp; Co. KGaA, Weinheim The first enantioselective total syntheses of (−)-secologanin (1), (−)-5-carboxystrictosidine (2), and (−)-rubenine (3) were accomplished in 10, 9, and 14 steps, respectively. The key transformation in the synthesis of 1 was a sequential anti-selective organocatalytic Michael reaction/Fukuyama reduction/spontaneous cyclization to form an optically active dihydropyran ring. In addition, the secologanin tetraacetate (16), which is a potential key intermediate for the bioinspired divergent syntheses of monoterpenoid indole alkaloids, was prepared in gram-scale in seven steps. The total syntheses of 2 and 3, which are classified as glycosylated monoterpenoid indole alkaloids, were achieved through bioinspired transformations such as a diastereoselective Pictet–Spengler reaction, a site- and stereoselective epoxidation, and a site-selective epoxide ring-opening followed by a lactonization reaction.

Copyright © 2019 American Chemical Society. A trienamine-mediated asymmetric Diels-Alder reaction using a 5-nitro-2,3-dihydro-4-pyridone derivative as a dienophile in the presence of a secondary amine organocatalyst derived from cis-hydroxyproline was discovered. The reaction provides optically active octahydroquinolines through an endo-selective [4 + 2] cyclization pathway. The following stereoselective denitration, isomerization, and/or hydrogenation generated divergent stereoisomers of decahydroquinolines, which are useful synthons for the total synthesis of Lycopodium alkaloids.

© 2019 The Royal Society of Chemistry. A practical enantioselective total synthesis of the unnatural (+)-quinine and (-)-9-epi-quinine enantiomers, which are important organocatalysts, is reported. The key transformation is a successive organocatalytic formal aza [3 + 3] cycloaddition/Strecker-type cyanation reaction to form an optically active tetrasubstituted piperidine derivative. This organocatalytic reaction proceeded in high yield and gave excellent enantiomeric excess with only 0.5 mol% catalyst loading. In addition, an imidate group, derived from a cyano group, was incorporated in the strategy for site-selective modification of the C4-alkyl chiral piperidine ring of quinine. Furthermore, an efficient coupling between the quinuclidine precursor and dihydroquinoline unit was achieved on a gram scale. The 15-step (LLS) synthetic protocol provided both (+)-quinine and (-)-9-epi-quinine, each with 16% overall yield.

©2018 The Japan Mendel Society. It is widely accepted that a symbiosis involving a cyanobacterium with a peptidoglycan wall led to the origin of plastids of photosynthetic eukaryotes. Recently, we visualized plastid peptidoglycan in a moss species by epifluorescence microscopy using metabolic labeling with click chemistry. In the present study, we applied the same method to visualize plastid peptidoglycan in the filamentous charophyte alga Klebsormidium nitens, as its genome contains a set of genes capable of synthesizing peptidoglycan. To visualize peptidoglycan, the generation of D-alanyl-D-alanine (DA-DA) must be blocked to allow the incorporation of ethynyl-DA-DA (EDA-DA) into peptidoglycan. Because a gene-targeting technique has not been established for K. nitens, we used D-cycloserine, which is an inhibitor of D-Ala: D-Ala ligase. Treatment with 500 µM D-cycloserine arrested cell division and inhibited chloroplast division. The addition of 1 mM EDA-DA restored the rate of cell division to that observed in medium without D-cycloserine, suggesting that EDA-DA can integrate plastid peptidoglycan instead of DA-DA, thus restarting chloroplast division and therefore cell division. Subsequently, cells were subjected to click chemistry to attach an azide-modified Alexa 488 fluorophore to the EDA-DA probe. Microscopic observation indicated that both sides of chloroplasts have strong Alexa 488 fluorescence. Under conditions of no cell growth, the chloroplast peptidoglycan that existed prior to treatment with D-cycloserine might remain in the cell. Therefore, the fluorescence must be indicative of the location of newly synthesized peptidoglycan. Our observations suggest that chloroplast peptidoglycan is built along the chloroplast division plane and serves as an essential system for chloroplast division in K. nitens.

Phytochemical investigation of the roots, stems and leaves of Mostuea thomsonii (Loganiaceae) resulted in the isolation of two new alkaloids of indolic and quinolinic types, named Thomsonines A (1) and B (2) respectively. Eleven additional known compounds, including one alkaloid namely camptothecine 3 and ten triterpene derivatives: 2α,3α,19α-trihydroxy-24-norurs-4(23),12-dien-28-oic acid 4, 3β-acetoxy-2α,19α-dihydroxy-24-norurs-4(23),12-dien-28-oic acid 5, oleanol 6, 3-O-ß-D-glucopyranosideolean-28-oic acid 7, 3-β-acetoxyoleanol 8, 2α 3α 19α-trihydroxy-24-nurs-4(23), 12-dien 9, 3-O-ß-D-glucopyranoside oleanane 10, friedelan-3-ol 11, 3-O-ß-D-glucopyranosylfriedelane 12 and decanol 13, have been isolated from the same sources. The structures of the new compounds were determined by detailed analyses of 1D and 2D NMR spectra, in combination with high-resolution mass spectrometry data and by direct comparison with related data from literature. Compounds 1–4 were evaluated in vitro for their antimicrobial activities against a wide range of micro-organisms using the broth micro-dilution technique, but none of them exhibited noticeable activity.

Copyright © 2018 American Chemical Society. α-Ketocarbenium ions derived from synthesized orthoquinone-containing polycyclic aromatic compounds were generated in the presence of Brønsted acids such as sulfuric acid, trifluoromethanesulfonic acid, and fluorosulfonic acid. The prepared α-ketocarbenium ions were stabilized by conjugation of the aromatic moiety. In addition, unique absorption properties of the α-ketocarbenium ions were observed and identified on the basis of the calculated absorption spectra. It was suggested that the zigzag-shaped architecture stabilizes the newly discovered α-ketocarbenium ions derived from orthoquinone-containing polycyclic aromatic compounds.

Recently, cinchona alkaloids such as quinine and quinidine were re-focused as next generation organocatalysts. Therefore, practical total syntheses of enantiomers of these alkaloids are required in current chemical society. Thus, efficient protocol for preparation of C4-alkyl substituted chiral piperidines using secondary amine catalyzed formal aza [3+3] cycloaddition reaction using aliphatic α, β -unsaturated aldehydes and thiomalonamate derivatives were discovered as key step in total synthesis. In our reaction system, thiomalonamate is excellent nucleophile, and the addition of suitable acid and it's amounts are important factor for the acceleration effect in organocatalytic reaction. These efforts lead to only 0.1 mol% catalyst loading in multi-gram scale synthesis for suitable reaction time.

© 2018 Elsevier Inc. This chapter covers the literature since the advent, in the 21st century, of total syntheses of alkaloids using enantio- or diastereoselective organocatalytic reactions to construct the alkaloid scaffolds. The details of these alkaloid syntheses are described separately for each basic skeleton, including indole, indoline, oxindole, and piperidine alkaloids.

Total syntheses of prenylated pyrrolidinoindoline alkaloids, (−)-mollenines A [(−)-1′] and B (2′), were accomplished via three- and four-step sequences including a bioinspired indole prenylation reaction followed by dioxomorpholine ring formation. Then, the stereochemistry of mollenines A and B was reassigned to 3S,6S,14S,16S by analysis of spectroscopic data and chemical syntheses with different approaches along with the comparison of calculated and experimental ECD spectra. In addition, a thermodynamically controlled epimerization reaction on the dioxomorpholine ring was observed in our synthesis.

Isoprene units derived from dimethylallyl diphosphate (DMAPP) are an important motif in many natural products including terpenoids, carotenoids, steroids, and. natural rubber. Understanding the chemical characteristics of DMAPP is an important topic in natural products chemistry, organic chemistry, and biochemistry. We have developed a direct bioinspired indole prenylation reaction using DMAPP or its equivalents as the electrophile in homogeneous aqueous acidic media in the absence of enzyme to provide prenylated indole products. After establishing the bioinspired indole prenylation reaction, this was then used to achieve the synthesis of a series of natural products, namely, N-prenylcyclo-L-tryptophyl-L-proline, tryprostatins, rhinocladins, and terezine D.

Seven new pentacyclic triterpenoids, including five oleanane-types designated bangwaoleanenes A-E (1)-(5), and two ursane-types, named bangwaursenes A (6) and B (7) together with eight known compounds: 3 beta-acetoxy-urs-12,13-ene-11-one (8), 3 beta-acetoxy-11a-hydroxyurs-12,13-ene (9), 11 alpha, 12 alpha-oxidotaraxeryl acetate (10), beta-amyrin acetate (11), (1R,5S,7S)-7-[2-(4-hydroxyphenyl) ethyl]-2,6dioxabicyclo[ 3.3.1] nonan-3-one (12) 1-desoxyribose (13), myo-inisitol (14), sorbitol (15), were isolated from the seeds of Tapinanthus bangwensis. The structures of the new compounds were elucidated on the basis of extensive spectroscopic analysis including one and two dimensional NMR as well as mass spectral data. The antimicrobial activity of compounds 1, 3, 5-7, 15 were evaluated in vitro against three strains of bacteria Escherichia coli ATCC 25922, Staphylococus aureus NCTC 10652, Salmonella typhi and one isolated fungi, Candida albicans, using the disc diffusion method. The result showed that all the compounds tested were more sensitive to Gram+ bacteria than Gram-bacteria and yeast. Compound 7 present the highest activity, while compound 12 showed no activity. (C) 2016 Phytochemical Society of Europe. Published by Elsevier Ltd. All rights reserved.

Aryl migration reactions of C-3 aryl substituted pyrrolidinoindoline compounds to provide highly conjugated C-2 aryl indole compounds have been discovered. The developed reactions have a wide substrate scope and proceed in high yield under simple acidic conditions. A unique cationic cyclopropane intermediate as the transition state is proposed. (C) 2016 Elsevier Ltd. All rights reserved.

Three new lupan-type triterpernoid derivatives, namely globimetulin A (1), B (2) and C (3), were isolated from the shoot of Globimetula dinklagei (Loranthaceae), a hemiparasitic plant growing on Manihot esculenta, along with five known compounds: friedelin (4), friedelan-3-ol (5), 28-hydroxyfriedelin (6), 4-hydroxy-3,5-dimethoxybenzoic acid (7) and (1R, 5S, 7S)-7-[2-(4-hydroxyphenyl)ethyl]-2,6-dioxabicyclo[3.3.1]nonan-3-one (8). The structures of the new compounds were elucidated by detailed analyses of their MS, IR, 1D and 2D NMR spectral data and chemical evidence. Some of these compounds were evaluated in vitro for their antimicrobial activities against a wide range of microorganisms, but none of them exhibited noticeable activity.

Three new lupan-type triterpernoid derivatives, namely globimetulin A (1), B (2) and C (3), were isolated from the shoot of Globimetula dinklagei (Loranthaceae), a hemiparasitic plant growing on Manihot esculenta, along with five known compounds: friedelin (4), friedelan-3-ol (5), 28-hydroxyfriedelin (6), 4-hydroxy-3,5-dimethoxybenzoic acid (7) and (1R, 5S, 7S)-7-[2-(4-hydroxyphenyl)ethyl]-2,6-dioxabicyclo[3.3.1]nonan-3-one (8). The structures of the new compounds were elucidated by detailed analyses of their MS, IR, 1D and 2D NMR spectral data and chemical evidence. Some of these compounds were evaluated in vitro for their antimicrobial activities against a wide range of microorganisms, but none of them exhibited noticeable activity.

It is believed that the plastids in green plants lost peptidoglycan (i.e., a bacterial cell wall-containing D-amino acids) during their evolution from an endosymbiotic cyanobacterium. Although wall-like structures could not be detected in the plastids of green plants, the moss Physcomitrella patens has the genes required to generate peptidoglycan (Mur genes), and knocking out these genes causes defects in chloroplast division. Here, we generated P. patens knockout lines (Delta Pp-ddl) for a homolog of the bacterial peptidoglycan-synthetic gene encoding D-Ala:D-Ala ligase. Delta Pp-ddl had a macrochloroplast phenotype, similar to other Mur knockout lines. The addition of D-Ala-D-Ala (DA-DA) to the medium suppressed the appearance of giant chloroplasts in Delta Pp-ddl, but the addition of L-Ala-L-Ala (LA-LA), DA-LA, LA-DA, or D-Ala did not. Recently, a metabolic method for labeling bacterial peptidoglycan was established using ethynyl-DA-DA (EDA-DA) and click chemistry to attach an azide-modified fluorophore to the ethynyl group. The Delta Pp-ddl line complemented with EDA-DA showed that moss chloroplasts are completely surrounded by peptidoglycan. Our findings strongly suggest that the moss plastids have a peptidoglycan wall containing D-amino acids. By contrast, no plastid phenotypes were observed in the T-DNA tagged ddl mutant lines of Arabidopsis thaliana.