Synthesis Of Indole Alkaloids Research Articles

Recent advances in the oxidative activation of the C2-C3 π bond of indoles and its applications.

The oxidative C2-C3 π bond activation strategy is the most efficient tool to synthesize oxygen-containing indoline, which frequently appears in natural products with various biological activities as structural units. Recently, the oxidation-induced cascade strategy through oxygenation activation of the indolic C2-C3 π bond of indoles has received much attention for its use in efficiently establishing complex indoline with oxygen-containing molecular architectures, and holds tremendous potential in the total synthesis of indole alkaloids. It can be carried out using potential activated indole radical cations or imine cation intermediates produced via oxidative C2-C3 π bond activation of indole with various nucleophiles or ring-forming reagents by employing simple and non-decorated indoles as starting substrates. Herein, we have reviewed recent advances in the oxidation-induced cascade strategies connecting intra-cyclization or inter-annulation reactions, nucleophilic or radical additions and rearrangement via the oxidative C2-C3 π bond activation of indoles over the past two decades, providing diverse oxygen-containing indolines such as indoxyls, indoline oxygen-heterocycles and indolones. The features and mechanisms of different types of oxidation-induced cascade reactions have been summarized and represented, and examples have been given of their asymmetric reactions and applications in the total synthesis of indole alkaloids.

Computation‐Guided Scope Exploration of a Conjugate Addition/Truce‐Smiles Cascade Reaction for Scaffold Diversification

AbstractBased on the successful application of a nitroaryl transfer cascade reaction in the total synthesis of various monoterpene indole alkaloids proceeding via fused bicyclic intermediate, we investigated analogous cascade reactions involving spiro, bridged, and alternatively fused bicyclic intermediates. Unfortunately, none of these was found to afford the desired nitroaryl transfer product. DFT studies of the original cascade process revealed that the Truce‐Smiles rearrangement is the rate‐determining step. In addition, we found that the subsequent SO2 extrusion is accompanied by retro‐Mannich ring opening, resulting in a stabilized enolate that only recyclizes after activation of the cyclic imine moiety. Computation of the reaction profiles of the proposed alternative cascade reactions showed that the barrier for the Truce‐Smiles rearrangement is unreasonably high for the bridged and alternatively fused systems, but only moderately higher for the five‐membered spiro system. Reasoning that even more electron‐deficient arenesulfonamides should have a lower barrier for the Truce‐Smiles rearrangement, we synthesized the corresponding 2,4‐dinitrobenzenesulfonamide precursor and found that it indeed smoothly undergoes the nitroaryl transfer cascade at room temperature. In this case, however, the cascade reaction produces a cyclic imine product, as the intermediate 2,4‐dinitrophenyl‐substituted enolate is insufficiently nucleophilic to undergo the Mannich cyclization.

3-Acetyl Indole in the Synthesis of Natural Bioactive Compounds

Natural products, with their various sources from plants, marine organisms, and microorganisms, are considered a key source and inspiration for medicines and continue to be so. Indole alkaloids are a class of alkaloids and represent a large subunit of natural prod-ucts. Indole alkaloids of biological importance are numerous and cover a wide range of phar-maceutical applications, including anticancer, antiviral, antimicrobial, anti-inflammatory, and antioxidant. Obtaining natural, biologically active indole compounds involves isolating them from their natural sources or preparing them synthetically. 3-Substituted indoles repre-sent an emerging structural class of marine alkaloids based on their high degree of biological activity. 3-Acetyl indole is an important core used as a starting material for synthesizing many bioactive indole alkaloids. (5-Indole)oxazole alkaloids, β-carboline alkaloids, bis-in-dole alkaloids, chuangxinmycin, meridianine, and (±) indolemycin are the most important indole alkaloids that are prepared starting from 3-acety indole. The present review provides comprehensive information on the structures and the synthesis of bioactive indole alkaloids utilizing 3-acetyl indole and its derivatives as starting compounds. Additionally, it also spot-lights the diverse biological activities of these compounds.

Combined physiological, metabolomic and response surface approaches to analyze copper stress resistance mechanisms and repair potential of Epipremnum aureum

Phytoremediation is commonly used to remediate copper (Cu) pollution in water bodies. Epipremnum aureum is often used as a restoration plant because of its rapid reproduction, high population density and high landscape value. However, neither its ability to remediate Cu-polluted water nor its mechanism of resistance to Cu stress has been fully clarified. Therefore, the present study revealed the Cu removal ability and resistance mechanism of E. aureum through physiology and metabolomics. And based on the results of this study, the response surface was applied to the application of plant growth regulator (PGR) to propose a precise restoration program. We first examined the growth physiological indices and repair of Cu in E. aureum under different Cu stress levels and found that the resistance mechanism of E. aureum to Cu was significantly initiated at 400 mg·L-1. And as the level of Cu stress increased, the Cu content in the plant also increased, and the underground part was the main accumulating part. The translocation factor of E. aureum was <1, and the bioconcentration factor was greater than 1 at all different Cu concentrations. Subsequently, metabolomics studies on E. aureum concluded that arginine and proline metabolism, indole alkaloid synthesis and brassinosteroid biosynthesis are the major pathways involved in the mechanism of Cu stress resistance in E. aureum. Based on these results, we proposed that salicylic acid, sodium nitroprusside and 2,4-epibrassinolide could be selected as PGRs, and further optimized the administration of PGRs using response surfaces. The optimized scheme allowed E. aureum to reach a maximum Cu removal of 84.39 % under 400 mg·L-1 Cu stress, which was 35.61 % higher than the non-fortified treatment. This study provides supporting materials and application options for the Cu repair capacity and resistance mechanisms of E. aureum.

Total Synthesis of (-)-Rauvomine B via a Strain-Promoted Intramolecular Cyclopropanation.

We describe the first total synthesis of the unusual cyclopropane-containing indole alkaloid (-)-rauvomine B via a strategy centered upon intramolecular cyclopropanation of a tetracyclic N-sulfonyltriazole. Preparation of this precursor evolved through two generations of synthesis, with the ultimately successful route involving a palladium-catalyzed stereospecific allylic amination, a cis-selective Pictet-Spengler reaction, and ring-closing metathesis as important bond-forming reactions. The key cyclopropanation step was found to be highly dependent on the structure and conformational strain of the indoloquinolizidine N-sulfonyltriazole precursor, the origins of which are explored computationally through DFT studies. Overall, our synthesis proceeds in 11 total steps and 2.4% yield from commercial materials.

Functional characterization of promiscuous tryptophan decarboxylase from indole alkaloids producing Rauvolfia tetraphylla L.

The enzyme Tryptophan decarboxylase (TDC, EC 4.1.1.28) gene facilitates the conversion of tryptophan to tryptamine. A new gene encoding TDC was identified from the alkaloid producing plant Rauvolfia tetraphylla by transcriptome analysis, termed as RtTDC. It contains 1,500 base pair which encodes an open reading frame for 499-amino-acid polypeptide with molecular mass of 55729.29 kDa and isoelectric point of 5.37. Multiple sequence alignment and phylogenetic tree analysis showed the closest similarity (95.3 %) with the TDC from the Rauvolfia verticillata. This enzyme has property of recombinant tryptophan decarboxylase from R. tetraphylla was characterized. The potential activity of tryptophan decarboxylase specific to L-tryptophan may contribute to the biosynthesis of indole alkaloids in R. tetraphylla. The finding of tryptophan metabolites in R. tetraphylla plants is a novel report, lead to hypothesize the existence of TDC enzymatic activity, from which aromatic amino acid decarboxylases is formed. These results support the in-silico annotation of the examined protein sequences of R. tetraphylla as TDC and suggest the involvement of TDC enzymatic activity in this plant. Molecular modeling of the TDC gene evidencing the reliability, stability and the structural similarities of the R. tetraphylla TDC gene with R. verticillata TDC gene. The L-tryptophan used as ligand in docking analysis to verify the TDC gene enzymatic activity for synthesis of Indole alkaloids. High performance liquid chromatography data analyses of RtTDC catalyzed reaction mixture confirmed the catalytically decarboxylative activity of RtTDC.

Genome-Wide Mining of CULLIN E3 Ubiquitin Ligase Genes from Uncaria rhynchophylla.

CULLIN (CUL) protein is a subtype of E3 ubiquitin ligase that is involved in a variety of biological processes and responses to stress in plants. In Uncaria rhynchophylla, the CUL gene family has not been identified and its role in plant development, stress response and secondary metabolite synthesis has not been studied. In this study, 12 UrCUL gene members all contained the typical N-terminal domain and C-terminal domain identified from the U. rhynchophylla genome and were classified into four subfamilies based on the phylogenetic relationship with CULs in Arabidopsis thaliana. They were unevenly distributed on eight chromosomes but had a similar structural composition in the same subfamily, indicating that they were relatively conserved and potentially had similar gene functions. An interspecific and intraspecific collinearity analysis showed that fragment duplication played an important role in the evolution of the CUL gene family. The analysis of the cis-acting elements suggests that the UrCULs may play an important role in various biological processes, including the abscisic acid (ABA) response. To investigate this hypothesis, we treated the roots of U. rhynchophylla tissue-cultured seedlings with ABA. The expression pattern analysis showed that all the UrCUL genes were widely expressed in roots with various expression patterns. The co-expression association analysis of the UrCULs and key enzyme genes in the terpenoid indole alkaloid (TIA) synthesis pathway revealed the complex expression patterns of 12 UrCUL genes and some key TIA enzyme genes, especially UrCUL1, UrCUL1-likeA, UrCUL2-likeA and UrCUL2-likeB, which might be involved in the biosynthesis of TIAs. The results showed that the UrCULs were involved in the response to ABA hormones, providing important information for elucidating the function of UrCULs in U. rhynchophylla. The mining of UrCULs in the whole genome of U. rhynchophylla provided new information for understanding the CUL gene and its function in plant secondary metabolites, growth and development.

Genome-wide identification of Uncaria rhynchophylla bHLH transcription factors and in-vitro validation of UrbHLH1 through interaction with terpenoid indole alkaloid synthesis pathway members

Uncaria rhynchophylla (Gouteng), as an evergreen woody vine belong to Rubiaceae family, is a traditional medicinal herb in China. Its terpenoid indole alkaloids (TIAs), which have good antidepressant and combined therapeutic effects on Alzheimer's disease, have attracted widespread attention. However, the content of TIAs is relatively low in U.rhynchophylla, which is unable to meet the growing market demand. The basic helix loop-helix (bHLH) transcription factor family exists in all three eukaryotic kingdoms and can participate in regulating secondary metabolite pathways. So far, there has been no comprehensive analysis of the bHLH gene in U. rhynchophylla, and their role in TIAs is almost unknown. In this study, a total of 171 UrbHLH genes (UrbHLHs) were unevenly distributed on 22 chromosomes and divided into 23 subfamilies. In addition, the physicochemical properties of UrbHLHs were analyzed. Most UrbHLHs in each subgroup had similar gene structures and conserved motifs. Intraspecific collinearity analysis showed that UrbHLH1 may be related to the biosynthesis of TIAs. Subcellular localization experiments revealed that UrbHLH1 is located in the nucleus; Dual luciferase reporter gene analysis (Dual-LUC) showed that UrbHLH1 could activate the expression of UrG10H and Ur10HGO in the TIAs synthesis pathway of U. rhynchophylla. Finally, using yeast one hybrid (Y1H) it was found that the promoter regions of these two genes both have E-box binding elements, which can be bound by UrbHLH1 and produced strong interactions. Therefore, UrbHLH1 may participate in the synthesis of TIAs pathway. In conclusion, this study provides foundation data on the role of UrbHLH transcription factors in regulating TIAs of U. rhynchophylla.

Synthesis and Activity Evaluation of Vinpocetine-Derived Indole Alkaloids.

This study focuses on the synthesis of novel vinpocetine derivatives (2-25) and their biological evaluation. The chemical structures of the synthesized compounds were fully characterized using techniques such as 1H NMR, 13C NMR, and HRMS. The inhibitory activity of the synthesized compounds on PDE1A was evaluated, and the results revealed that compounds 3, 4, 5, 12, 14, 21, and 25 exhibited superior inhibitory activity compared to vinpocetine. Compound 4, with a para-methylphenyl substitution, showed a 5-fold improvement in inhibitory activity with an IC50 value of 3.53 ± 0.25 μM. Additionally, compound 25, with 3-chlorothiazole substitution, displayed an 8-fold increase in inhibitory activity compared to vinpocetine (IC50 = 2.08 ± 0.16 μM). Molecular docking studies were conducted to understand the binding models of compounds 4 and 25 within the active site of PDE1A. The molecular docking study revealed additional binding interactions, such as π-π stacking and hydrogen bonding, contributing to the enhanced inhibitory activity and stability of the ligand-protein complexes. Overall, the synthesized vinpocetine derivatives demonstrated promising inhibitory activity on PDE1A, and the molecular docking studies provided insights into their binding modes, supporting further development of these compounds as potential candidates for drug research and development.

Dearomative Spirocyclization of Tryptamine-Derived Isocyanides via Iron-Catalyzed Carbene Transfer.

Tryptamine-derived isocyanides are valuable building blocks in the construction of spirocyclic indolenines and indolines via dearomatization of the indole moiety. We report the Bu4N[Fe(CO)3NO]-catalyzed carbene transfer of α-diazo esters to 3-(2-isocyanoethyl)indoles, leading to ketenimine intermediates that undergo spontaneous dearomative spirocyclization. The utility of this iron-catalyzed carbene transfer/spirocyclization cascade was demonstrated by its use as a key step in the formal total synthesis of monoterpenoid indole alkaloids (±)-aspidofractinine, (±)-limaspermidine, (±)-aspidospermidine, and (±)-17-demethoxy-N-acetylcylindrocarine.

Integrated metabolomics and transcriptomics reveals difference involved in flavonoid and indole alkaloids biosynthesis in potato tuber flesh

Colored potatoes have garnered attention due to their higher nutrients compared to regular potatoes. This study describes a combined transcriptomic and metabolomic analysis of potato tubers originating from a single sexual cross between two parents with differing tuber skin and flesh colors. Through the use of RNA-seq, and UPLC-MS/MS metabolomics, this study aimed to elucidate the genetic and metabolic variations involved in the transmission of traits from tetraploid potato parents to hybrid F1 offspring. Our analysis revealed unique genes and metabolites associated with flavonoids and alkaloids within each group of offspring. Phenolic acids, flavonoids, and alkaloids are highlighted as key contributors to the positive heterosis observed in the tubers of potato hybrids, as assessed by calculating mid-parent heterosis for metabolites in three potato hybrids. At the overall metabolites level, hybrid SB (red-skinned and red-fleshed) exhibited a higher mid-parent heterosis than hybrid SA (purple-skinned and purple-fleshed) and SC (yellow-skinned and yellow-fleshed). Within hybrid SB tuber, specific accumulations of luteolin, salicin, isovitexin, and esculeoside B-5 were identified. Moreover, co-expression networks and correlation analysis pinpoint genes related to flavonoid and alkaloid biosynthesis. Notably, StDFR (dihydroflavonol reductase), a gene involved in flavonoid synthesis in potato tuber flesh, exhibits heightened expression in colored potato flesh. Additionally, we identified StYUCCA (indole-3-pyruvate monooxygenase), a gene regulating indole alkaloids synthesis, with elevated expression in yellow potato flesh. These findings provide insights into the utilization of heterosis breeding and the regulation of genes-metabolites in colored potato tuber flesh.

Regulation of P450 TleB catalytic flow for the synthesis of sulfur-containing indole alkaloids by substrate structure-directed strategy and protein engineering

Regulation of P450 TleB catalytic flow for the synthesis of sulfur-containing indole alkaloids by substrate structure-directed strategy and protein engineering

Intramolecular Dearomative Inverse-Electron-Demand Diels Alder Strategy for the Total Synthesis of (+)-Alstonlarsine A.

An evolution of a synthetic route leading to a successful enantioselective total synthesis of monoterpenoid indole alkaloid (+)-alstonlarsine A is represented. The unique 9-azatricyclo[4.3.1.03,8]decane core was assembled through an efficient domino sequence comprising enamine formation in situ, followed by intramolecular dearomative inverse-electron-demand Diels Alder reaction. The preparation of the tricyclic dihydrocyclohepta[b]indole key intermediate via the intramolecular Horner-Wadsworth-Emmons reaction required a development of a new general method for the introduction of the phosphonoacetate moiety into the indole C-2 position, through copper-carbenoid insertion. The modular nature of the represented synthetic approach makes it suitable for the synthesis of analogues with different substituents' patterns.

Modular assembly of indole alkaloids enabled by multicomponent reaction

Indole alkaloids are one of the largest alkaloid classes, proving valuable structural moiety in pharmaceuticals. Although methods for the synthesis of indole alkaloids are constantly explored, the direct single-step synthesis of these chemical entities with broad structural diversity remains a formidable challenge. Herein, we report a modular assembly of tetrahydrocarboline type of indole alkaloids from simple building blocks in a single step while showing broad compatibility with medicinally relevant functionality. In this protocol, the 2-alkylated or 3-alkylated indoles, formaldehyde, and amine hydrochlorides could undergo a one-pot reaction to deliver γ-tetrahydrocarbolines or β-tetrahydrocarbolines directly. A wide scope of these readily available starting materials is applicable in this process, and numerous structural divergent tetrahydrocarbolines could be achieved rapidly. The control reaction and deuterium-labelling reaction are conducted to probe the mechanism. And mechanistically, this multicomponent reaction relies on a multiple alkylamination cascade wherein an unusual C(sp3)–C(sp3) connection was involved in this process. This method could render rapid access to pharmaceutically interesting compounds, greatly enlarge the indole alkaloid library and accelerate the lead compound optimization thus facilitating drug discovery.

Methodological Development and Applications of Tryptamine-Ynamide Cyclizations in Synthesizing Core Skeletons of Indole Alkaloids.

Over the past two decades, synthetic strategies for synthesizing the skeletons of various indole alkaloids based on tryptamine-ynamide have been continuously developed and applied to the total syntheses or formal total syntheses of related molecules. In this synopsis, we summarized the cyclization pathways of tryptamine-ynamide under different catalytic conditions, emphasizing the reaction mechanism and applications in the syntheses of indole alkaloids.

Insights into Stereoselectivity Switch in Michael Addition-Initiated Tandem Mannich Cyclizations and Their Extension from Enamines to Vinyl Ethers.

Both cis- and trans- tetracyclic spiroindolines are the core of many important biologically active indole alkaloids, but the divergent synthesis of these important motifs is largely hampered by the limited stereoselectivity control. A facile stereoinversion protocol is reported here in Michael addition-initiated tandem Mannich cyclizations for constructing tetracyclic spiroindolines, providing an easy access to two diastereoisomeric cores of monoterpene indole alkaloids with high selectivity. The mechanistic studies including in situ NMR experiments, control experiments, and DFT calculations reveal that the reaction undergoes a unique retro-Mannich/re-Mannich rearrangement including a C-C bond cleavage that is very rare for a saturated six-membered carbocycle. Insights into the stereoinversion process have been uncovered, and the major effects were determined to be the electronic properties of N-protecting groups of the indole with the aid of Lewis acid catalysts. By understanding these insights, the stereoselectivity switching strategy is also smoothly applied from enamine substrates to vinyl ether substrates, which are enriched greatly for the divergent synthesis and stereocontrol of monoterpene indole alkaloids. The current reaction also proves to be very practical and was successfully applied to the gram-scale total synthesis of strychnine and deethylibophyllidine in short routes.

Isolation and stereospecific synthesis of indole alkaloids with lipid-lowering effects from the marine-derived fungus Colletotrichum gloeosporioides BB4

Seven undescribed compounds, colletotrichindoles A–E, colletotrichaniline A, and colletotrichdiol A, as well as three known compounds, (−)-isoalternatine A, (+)-alternatine A and 3-hydroxybutan-2-yl 2-phenylacetate were isolated from the marine-derived fungus Colletotrichu gloeosporioides BB4. The racemic mixtures colletotrichindole A，colletotrichindole C, and colletotrichdiol A were further separated by chiral chromatography to give three pairs of enantiomers (10S,11R,13S)/(10R,11S,13R)-colletotrichindole A, (10R,11R,13S)/(10S,11S,13R)-colletotrichindole C, and (9S,10S)/(9R,10R)-colletotrichdiol A, respectively. The chemical structures of seven undescribed compounds and the known compounds, (−)-isoalternatine A, and (+)-alternatine A were determined using a combination of NMR, MS, X-ray diffraction, ECD calculations, and/or chemical synthesis. All possible enantiomers of colletotrichindoles A–E were synthesized and used to determine the absolute configurations of the natural products by comparing their spectroscopic data and HPLC retention times on a chiral column. In addition, the X-ray crystal structures of the known compounds (−)-isoalternatine A and (+)-alternatine A were also obtained to confirm their absolute configurations. (10S,11R,13S)-Colletotrichindole A, colletotrichindole B, and (+)-alternatine A significantly reduced triglyceride levels in 3T3-L1 cells with EC50 values of 5.8, 9.0, and 1.3 μM, respectively.

Total Syntheses of (+)-Villocarine A, (-)-Apogeissoschizine, and (+)-Geissoschizine.

Total syntheses of geissoschizine-type monoterpenoid indole alkaloids (MTIAs) are reported. An intramolecular Pictet-Spengler cyclization was developed for the selective construction of the 3R stereocenter. The first total synthesis of (+)-villocarine A was then achieved. Furthermore, the first total synthesis of the highly strained (-)-apogeissoschizine was also accomplished in an aza-Michael cyclization/E1cB elimination/stereoselective olefin isomerization sequence. Finally, (+)-geissoschizine, a common biosynthetic intermediate of MTIAs, was obtained from apogeissoschizine through ring-opening along with a release of ring strain.

Total Synthesis of (+)-Alstonlarsine A: Old Reactions in Modern Alkaloids Synthesis

Abstract(+)-Alstonlarsine A is a recently isolated monoterpenoid indole alkaloid, possessing a novel pentacyclic skeleton and interesting biological activity, making it an attractive target for synthetic chemists. In this article we focus on its total synthesis, grounded on enamine formation/Diels–Alder reaction domino sequence, as well as a novel methodology for indole C2 functionalization via carbenoid insertion, which could also allow for the synthesis of other indole alkaloids possessing cycloalka[b]indole subunits.1 Introduction2 Diels–Alder Reaction3 Methodology Studies4 Total Synthesis of (+)-Alstonlarsine A by Bihelovic and Ferjancic5 Total Synthesis of (+)-Alstonlarsine A by Zhai6 Summary

Indole-Containing Natural Products 2019-2022: Isolations, Reappraisals, Syntheses, and Biological Activities.

Indole alkaloids represent a large subset of natural products, with more than 4100 known compounds. The majority of these alkaloids are biologically active, with some exhibiting excellent antitumor, antibacterial, antiviral, antifungal, and antiplasmodial activities. Consequently, the natural products of this class have attracted considerable attention as potential leads for novel therapeutics and are routinely isolated, characterized, and profiled to gauge their biological potential. However, data on indole alkaloids, their various structures, and bioactivities are complex due to their diverse sources, such as plants, fungi, bacteria, sponges, tunicates, and bryozoans; thus, isolation methods produce an incredible trove of information. The situation is exacerbated when synthetic derivatives, as well as their structures, bioactivities, and synthetic schemes, are considered. Thus, to make such data comprehensive and inform researchers about the current field's state, this review summarizes recent reports on novel indole alkaloids. It deals with the isolation and characterization of 250 novel indole alkaloids, a reappraisal of previously reported compounds, and total syntheses of indole alkaloids. In addition, several syntheses and semi-syntheses of indole-containing derivatives and their bioactivities are reported between January 2019 and July 2022.