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Divergent total syntheses of the hetero-oligomeric iridoid glycosides mainly found in

A number of alkaloids found in Mitragyna species belonging to the Rubiaceae family have been shown to have potent biological activity such as analgesic properties. Here, we report the asymmetric total syntheses of mitragynine, speciogynine, and 7-hydroxymitragynine, which are classified as corynantheine-type monoterpenoid indole alkaloids, isolated from Mitragyna speciosa. These syntheses were accomplished within 12 steps and in11% total yield from commercial 3-(trimethylsilyl)propanal using an organocatalytic anti-selective Michael reaction and bioinspired transformations.

Ophiorrhiza plants (Family Rubiaceae) are known to produce diverse monoterpenoid indole alkaloids including camptothecin with potent antitumor activity. This review contains a summary of recent chemical studies reported over the past 10 years regarding alkaloids (monoterpenoid indole and tetrahydroisoquinoline alkaloids, and cyclopeptide) in Ophiorrhiza plants. In addition, the alkaloid biosynthetic pathways based on their reported structures were proposed.

The collective and efficient asymmetric total syntheses of five β-carboline-type monoterpenoid indole alkaloid glycosides were achieved in fewer than thirteen steps. A Pictet–Spengler reaction with α-cyanotryptamine followed by the removal of the cyano group and autoxidation (aromatization) efficiently constructed the β-carboline motif. In addition, bioinspired reactions were developed to provide different alkaloid skeletons.

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.

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 S

The first asymmetric total synthesis of new biphenylquinolizidine alkaloids 4″-O-demethyllythridine and 14-epi-4″-O-demethyllythridine isolated from Heimia salicifolia was accomplished. The key steps in the synthesis were a copper(I)-catalyzed asymmetric intramolecular aza-Michael reaction to build a chiral 4-arylquinolizidine unit and an intramolecular Suzuki-Miyaura cross-coupling reaction to construct a macrolactone ring comprising a biphenyl moiety.

The first concise and collective asymmetric total synthesis of six 14-hydroxygelsenicine-related Gelsemium alkaloids, i.e., 14-hydroxygelsedilam, 14-acetoxygelsedilam, gelsefuranidine, gelsemolenin...

Six new biphenyl quinolizidine lactone alkaloids: 14α-hydroxydecodine (1), 14β-hydroxydecodine (2), 4″-O-demethylheimidine (3), 4″-O-demethyl-9β-hydroxyvertine (4), 4″-O-demethylvertine N-oxide (5), and 4″-O-demethyl-9β-hydroxyvertine N-oxide (6) were isolated from so-called “sinicuichi” (origin: Heimia salicifolia) together with 18 known alkaloids. Their structures were determined by spectroscopic analyses and chemical conversions.

One new otonecine-type pyrrolizidine alkaloid secopetasitenine (1), along with petasitenine (fukinotoxine, 2), neopetasitenine (3), and senkirkine (4), was isolated from the whole plant of Petasites japonicus. The structure of 1 was determined by spectroscopic analyses and chemical conversion from the known alkaloid petasitenine (2).

The shortest asymmetric total synthesis of lycopodine (3) and the first asymmetric total synthesis of flabelliformine (4) were accomplished by a strategy that features a cascade cyclization of linear substrate (5) to construct tetracyclic structure (6).

Three new monoterpenoid indole alkaloids, gelsevietmines-A, B, C (1–3), were isolated from Gelsemium elegans seeds collected in Vietnam. Their unique and highly oxidized structures were determined by spectroscopic analyses and chemical means including the asymmetric total synthesis of gelsevietmine-A (1).

Background and Purpose— We recently found that acrolein (CH 2 =CH-CHO) is more strongly involved in brain infarction compared with reactive oxygen species. In this study, we looked for acrolein scavengers with less side effects. Methods— Photochemically induced thrombosis model mice were prepared by injection of Rose Bengal. Effects of N -acetylcysteine (NAC) derivatives on brain infarction were evaluated using the public domain National Institutes of Health image program. Results— NAC, NAC ethyl ester, and NAC benzyl ester (150 mg/kg) were administered intraperitoneally at the time of induction of ischemia, or these NAC derivatives (50 mg/kg) were administered 3× at 24-h intervals before induction of ischemia and 1 more administration at the time of induction of ischemia. The size of brain infarction decreased in the order NAC benzyl ester>NAC ethyl ester>NAC in both experimental conditions. Detoxification of acrolein occurred through conjugation of acrolein with glutathione, which was catalyzed by glutathione S -transferases, rather than direct conjugation between acrolein and NAC derivatives. The level of glutathione S -transferases at the locus of brain infarction was in the order of administration of NAC benzyl ester>NAC ethyl ester>NAC>no NAC derivatives, suggesting that NAC derivatives stabilize glutathione S -transferases. Conclusions— The results indicate that detoxification of acrolein by NAC derivatives is caused through glutathione conjugation with acrolein catalyzed by glutathione S -transferases, which can be stabilized by NAC derivatives. This is a new concept of acrolein detoxification by NAC derivatives.

Three new biphenyl ether quinolizidine lactone alkaloids (1–3) and 13 new biphenyl quinolizidine lactone alkaloids (4–16) were isolated from Heimia salicifolia (Lythraceae) together with seven known alkaloids. Their structures were determined by spectroscopic analyses and chemical conversions.

A new cyclopeptide, ophiorrhisine A (1), a new tetrahydroisoquinoline alkaloid, 7',10-dide-O-methylcephaeline (2), two known β-carboline alkaloids, and four known tetrahydroisoquinoline alkaloids were isolated from Ophiorrhiza nutans (Rubiaceae). Compound 1 is a tetrapeptide possessing a 14-membered paracyclophane ring and a novel N,N,N-trimethyltyrosine residue in the side chain. The stereochemistry at the aryl-alkyl ether bond was different from that of other known 14-membered paracyclophanes. The structure of 2 was established by spectroscopic analysis and semisynthesis.

The first asymmetric total synthesis of andranginine (1) via an asymmetric Morita-Baylis-Hillman reaction and a diastereoselective intramolecular Diels-Alder reaction has revealed that natural andranginine (1) isolated from Kopsia arborea existed as a scalemic mixture and contained predominantly the (16R,21S) form rather than the (16S,21R) form.

A new procedure for the asymmetric total synthesis of lythraceous alkaloids with a 4-arylquinolizidine skeleton was developed, which involved an organocatalyzed asymmetric intramolecular aza -Michael addition.

The first concise and collective asymmetric total synthesis of six 14-hydroxygelsenicine-related

The total syntheses of C-mavacurine-type indole alkaloids, (±)-pleiocarpamine, (±)-normavacurine, and (±)-C-mavacurine, were accomplished. The key step in the syntheses was the cyclization between the metal carbenoid at C16 and the N1 position in a Corynanthe-type compound that was equipped with a diazo function. For this cyclization, the N4 modification of the substrate using an amine–borane complex was indispensable to fix the molecular conformation.

An asymmetric total synthesis of lycopoclavamine-A (1), a structurally unique fawcettimine-type Lycopodium alkaloid, was achieved via a stereoselective Pauson–Khand reaction and a stereoselective conjugate addition to construct a quaternary carbon center at C-12.

Two new indole alkaloids having unusual skeletons were isolated from Yunnan Kopsia arborea. Kopsiyunnanine L has a novel 2,3,4,5-tetrahydro-1H-benzazepine skeleton rearranged from a Strychnos-type monoterpenoid indole alkaloid. Kopsiyunnanine M is a new type of bisindole alkaloid consisting of two Strychnos-type alkaloids.

A new monoterpenoid indole alkaloid, kopsiyunnanine K, was isolated from Kopsia arborea. Its intriguing rearranged structure and absolute configuration, which were inferred from spectral data and a possible biosynthetic pathway, were determined on the basis of a 13-step asymmetric total synthesis.

A total synthesis of indole alkaloids, (±)-conolidine and (±)-apparicine, was accomplished via a gold(I)-catalyzed 6-exo-dig cyclization to construct a piperidine ring bearing an exocyclic (E)-ethylidene appendage.

The structures of new lycopodine-type alkaloids, lycopocarinamines A-F, which were isolated from Lycopodium carinatum, were elucidated by spectroscopic analysis and chemical conversions. The proposed structure of lycocarinatine A was revised.

The first asymmetric total synthesis of ophiorrhisine A (1), a new cyclic tetrapeptide isolated from Ophiorrhiza nutans, was accomplished via an intramolecular aromatic nucleophilic substitution reaction (IMSNAr) of a linear tripeptide to construct a 14-membered paracyclophane ring, resulting in confirmation of its structure and absolute configuration. The structure–activity relationship study of 1 and its derivatives demonstrated that some derivatives possessed cytotoxicity toward human cancer cell lines A549, HT29, and HCT116.

We recently found that acrolein (CHPhotochemically induced thrombosis model mice were prepared by injection of Rose Bengal. Effects ofNAC, NAC ethyl ester, and NAC benzyl ester (150 mg/kg) were administered intraperitoneally at the time of induction of ischemia, or these NAC derivatives (50 mg/kg) were administered 3× at 24-h intervals before induction of ischemia and 1 more administration at the time of induction of ischemia. The size of brain infarction decreased in the order NAC benzyl esterNAC ethyl esterNAC in both experimental conditions. Detoxification of acrolein occurred through conjugation of acrolein with glutathione, which was catalyzed by glutathioneThe results indicate that detoxification of acrolein by NAC derivatives is caused through glutathione conjugation with acrolein catalyzed by glutathione

The total synthesis of (±)-lycoposerramine-R, a novel skeletal type of Lycopodium alkaloid, was accomplished via the Diels–Alder reaction, the stereoselective introduction of a methyl group, the regio- and stereoselective reductive amination, and the construction of a pyridone ring.

Seven new indole alkaloids (aspidofractinine type 1–3, kopsine type 5, strychnos type 6, and vincamine type 7, 8) were isolated from Kopsia jasminiflora (Apocynaceae) collected in Thailand. 5-Oxokopsinic acid (4) was isolated from nature for the first time. The structures of the new alkaloids were determined by spectroscopic analyses and chemical transformation of a known alkaloid. 5,6-Secokopsinine (1) possesses a dialdehyde function that is formed by oxidative cleavage of the C-5–C-6 bond of kopsinine (9). New vincamine-type alkaloid 8 showed potent inhibitory activity toward human cancer cell lines (A549, HT29, HCT116).

Flavonol 3-O-diglucosides with a 1→2 inter-glycosidic linkage are representative pollen-specific flavonols that are widely distributed in plants, but their biosynthetic genes and physiological roles are not well understood. Flavonoid analysis of four Arabidopsis floral organs (pistils, stamens, petals and calyxes) and flowers of wild-type and male sterility 1 (ms1) mutants, which are defective in normal development of pollen and tapetum, showed that kaempferol/quercetin 3-O-β-d-glucopyranosyl-(1→2)-β-d-glucopyranosides accumulated in Arabidopsis pollen. Microarray data using wild-type and ms1 mutants, gene expression patterns in various organs, and phylogenetic analysis of UDP-glycosyltransferases (UGTs) suggest that UGT79B6 (At5g54010) is a key modification enzyme for determining pollen-specific flavonol structure. Kaempferol and quercetin 3-O-glucosyl-(1→2)-glucosides were absent from two independent ugt79b6 knockout mutants. Transgenic ugt79b6 mutant lines transformed with the genomic UGT79B6 gene had the same flavonoid profile as wild-type plants. Recombinant UGT79B6 protein converted kaempferol 3-O-glucoside to kaempferol 3-O-glucosyl-(1→2)-glucoside. UGT79B6 recognized 3-O-glucosylated/galactosylated anthocyanins/flavonols but not 3,5- or 3,7-diglycosylated flavonoids, and prefers UDP-glucose, indicating that UGT79B6 encodes flavonoid 3-O-glucoside:2″-O-glucosyltransferase. A UGT79B6-GUS fusion showed that UGT79B6 was localized in tapetum cells and microspores of developing anthers.

Four new aspidosperma–aspidosperma-type bisindole alkaloids 1–4 were isolated from the seeds and root bark of Voacanga africana (Apocynaceae) and their structures were determined by spectroscopic analysis. Among them, voacandimine A (2) featured a linkage mode new to dimeric monoterpenoid indole alkaloids.

The structures of new lycopodine-type alkaloids, lycopocarinamines A-F, which were isolated from Lycopodium carinatum, were elucidated by spectroscopic analysis and chemical conversions. The proposed structure of lycocarinatine A was revised.

Sarpagine-related indole alkaloids (−)-hydroxygardnerine, (+)-hydroxygardnutine, (−)-gardnerine, (+)-(E)-16-epi-normacusine B, and (−)-koumine were divergently synthesized via a common intermediate possessing a piperidine ring with an exocyclic (E)-ethylidene side chain, which was constructed by a gold(I)-catalyzed 6-exo-dig cyclization strategy.

The structures of new lycopodine-type alkaloids, lycopocarinamines A-F, which were isolated from Lycopodium carinatum, were elucidated by spectroscopic analysis and chemical conversions. The proposed structure of lycocarinatine A was revised.

This chapter covers the literature on bisindole alkaloids consisting of monoterpenoid indoles, published up to June 2015. Bisindole alkaloids isolated from plants belonging to the families Apocynaceae and Loganiaceae, including Iboga-vobasine type, Aspidosperma-Aspidosperma type, eburnan-Aspidosperma type, Strychnos-Strychnos type, macroline-macroline type, and so on, are described. Some recent syntheses of monoterpenoid bisindole alkaloids are outlined as well.

This chapter covers the literature on bisindole alkaloids consisting of monoterpenoid indoles, published up to June 2015. Bisindole alkaloids isolated from plants belonging to the families Apocynaceae and Loganiaceae, including Iboga-vobasine type, Aspidosperma-Aspidosperma type, eburnan-Aspidosperma type, Strychnos-Strychnos type, macroline-macroline type, and so on, are described. Some recent syntheses of monoterpenoid bisindole alkaloids are outlined as well.

A new pyridone-containing Strychnos alkaloid named kopsiyunnanine-I was found in the aerial part of Yunnan Kopsia arborea Blume. The structure of the new alkaloid was elucidated by chemical conversion from strychnine.

The asymmetric total syntheses of some fawcettimine-type Lycopodium alkaloids, utilizing an intramolecular Pauson–Khand reaction as the key step, are described. 1 Introduction 2 First Asymmetric Total Syntheses of Lycoposerramine-C and Phlegmariurine A 3 First Asymmetric Total Synthesis of Huperzine Q 4 Total Syntheses of Fawcettimine and Fawcettidine 5 Conclusion

Voacanga africana (Apocynaceae) is used as an anti-diarrheal medicine in West Africa. In the present study, we investigated the effect of an extract of V. africana and its constituents on smooth muscle contraction induced by capsaicin in mouse rectum, where transient receptor potential vanilloid type 1 (TRPV1)-immunoreactive fibers are abundant. Methanol and alkaloid extracts of the root bark of V. africana were found to inhibit capsaicin-induced contraction in a dose-dependent manner (30-300 μg/ml). Major constituents isolated from the alkaloid extract were then studied for their effects on the capsaicin-induced contraction. The main active constituents were found to be Iboga-type alkaloids, including voacangine (1), 3-oxovoacangine (2), voacristine (3), and (7α)-voacangine hydroxyindolenine (4). The voacangine concentration dependently (3-100 μM) inhibited the capsaicin-induced contraction. The capsaicin-induced contraction was almost completely inhibited by the TRPV1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC). On the other hand, the Iboga-type alkaloids did not inhibit the contractions induced by 3 μM acetylcholine and 300 μM nicotine. These results suggest that Iboga-type alkaloids isolated from V. africana inhibit capsaicin-induced contraction in the mouse rectum, possibly via the inhibition of a TRPV1-mediated pathway. This inhibition may be involved in the anti-diarrheal effect of V. africana.