Bioactive Indole Alkaloids Research Articles

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.

Estimating Anticancer Effects of Yohimbine in DMBA-Induced Oral Carcinogenesis Hamster Model: Utilizing Biochemical and Immunohistochemical Techniques.

Yohimbine is a potent bioactive indole alkaloid, isolated from a variety of biological sources and has long been used as a natural stimulant and aphrodisiac, particularly to treat erectile dysfunction. However, some literature also points toward its anticancer effect in different experimental models. The current study aimed to address a clinical concern on the therapeutic utilization of yohimbine as a repurposed drug. We employed 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis model juxtaposed with biochemical investigation of several detoxification and antioxidant markers, such as Cyt p450, Cyt b5, thiobarbituric acid reactive substance (TBARS), glutathione (GSH), glutathione reductase (GR), glutathione S transferase (GST), DT-diaphorase, vitamin C, vitamin E, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). The immunohistochemical assessment of cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), proliferating cell nuclear antigen (PCNA), and cyclin D1 expression were also performed to observe the effect of yohimbine on these markers. The hamsters treated with DMBA presented the growth of tumors in the buccal pouches, accompanied by significant changes in the liver and buccal mucosa levels of Phase I & II detoxification enzymes and lipid peroxidation (LPO). A significant rise in the range of 2- to 3.5-fold was observed in Cyt p450, Cyt b5, and LPO in DMBA-treated animals. However, oral administration of yohimbine significantly restored the LPO, antioxidant, and detoxifying enzyme activities. Additionally, the levels of COX-2, IL-6, PCNA, and cyclin D1 were also found to be downregulated by yohimbine treatment. In conclusion, yohimbine improved the biochemical and immunohistochemical markers of DMBA-induced oral cancer and reverted to near normal values via ameliorating the underlying inflammation and oxidative stress conditions. Our study highlighted the potential of yohimbine as anticancer agent, especially against oral cancer and suggested its possible use as repurposed drug.

Discovery and Heterologous Expression of Functional 4-O-Dimethylallyl-l-tyrosine Synthases from Lichen-Forming Fungi.

Fungal aromatic prenyltransferases are a family of biosynthetic enzymes that catalyze the prenylation of a range of aromatic substrates during the biosynthesis of bioactive indole alkaloids, diketopiperazines, and meroterpenoids. Their broad substrate scope and soluble nature make these enzymes particularly adept for applications in biocatalysis; for example, the enzymatic derivatization of aromatic drugs improves their bioactivity. Here, we investigated four putative aromatic prenyltransferases from lichen-forming fungi, an underexplored group of organisms that produce more than 1,000 unique metabolites. We successfully expressed two enzymes, annotated as dimethylallyltryptophan synthases, from two lichen species in the heterologous host A. oryzae. Based on their in vivo activity, we hypothesize that these enzymes are in fact 4-O-dimethylallyl-l-tyrosine synthases. Our extensive bioinformatic analysis further confirmed that these and related lichen aromatic prenyltransferases are likely not active on indoles but rather on aromatic polyketides and phenylpropanoids, major metabolites in lichens. Overall, our work provides new insights into fungal aromatic prenyltransferases at the family level and enables future efforts aimed at identifying new candidates for biocatalytic transformations of aromatic compounds.

Preclinical pharmacokinetic studies of villocarine A, an active Uncaria alkaloid.

Villocarine A is a bioactive indole alkaloid isolated from the Uncaria genus. It has demonstrated vasorelaxation activity and potential to protect the central nervous system. To identify the pharmacokinetic properties of villocarine A, a series of in vitro and in vivo studies have been performed. Villocarine A was found to be highly permeable (15.6 ± 1.6*10-6cm/s) across human colorectal adenocarcinoma cell monolayer with high protein binding (>91%) in both rat and human plasma. Hepatic extraction ratio of villocarine A was 0.1 in pooled rat liver and 0.2 in human liver microsomes and was found stable in rat plasma at 37°C. Due to the high permeability and low rate of metabolism properties, villocarine A was initially considered suitable for preclinical development and an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantification (linearity: 1-150 ng/ml) in rat plasma was developed and validated for in vivo studies. Essential pharmacokinetic parameters included the volume of distribution and clearance of villocarine A, which were found to be 100.3 ± 15.6L/kg and 8.2 ± 1.1L/h/kg, respectively, after intravenous administration in rats. Following oral dosing, villocarine A exhibited rapid absorption as the maximum plasma concentration (53.2 ± 10.4ng/ml) occurred at 0.3 ± 0.1h, post-dose. The absolute oral bioavailability of villocarine A was 16.8 ± 0.1%. To our knowledge, this was the first pharmacokinetic study of villocarine A, which demonstrated the essential pharmacokinetic properties of villocarine A: large volume distribution, high clearance, and low oral bioavailability in rats.

Formation, Identification, and Occurrence of the Furan-Containing β-Carboline Flazin Derived from l-Tryptophan and Carbohydrates.

β-Carbolines (βCs) are bioactive indole alkaloids found in foods and in vivo. This work describes the identification, formation, and occurrence in foods of the βC with a furan moiety flazin (1-[5-(hydroxymethyl)furan-2-yl]-9H-pyrido[3,4-b]indole-3-carboxylic acid). Flazin was formed by the reaction of l-tryptophan with 3-deoxyglucosone but not with 5-hydroxymethylfurfural. Its formation was favored in acidic conditions and heating (70-110 °C). The proposed mechanism of formation occurs through the formation of intermediates 3,4-dihydro-β-carboline-3-carboxylic acid (imines), followed by the oxidation to C═O in the carbohydrate chain and aromatization to βC ring with subsequent dehydration steps and cyclization to afford the furan moiety. Flazin is generated in the reactions of tryptophan with carbohydrates. Its formation from fructose was higher than from glucose, whereas sucrose gave flazin under acidic conditions and heating owing to hydrolysis. Flazin was identified in foods by HPLC-MS, and its content was determined by HPLC-fluorescence. It occurred in numerous processed foods, such as tomato products, including crushed tomato puree, fried tomato, ketchup, tomato juices, and jams, but also in soy sauce, beer, balsamic vinegar, fruit juices, dried fruits, fried onions, and honey. Their concentrations ranged from not detected to 22.3 μg/mL, with the highest mean levels found in tomato concentrate (13.9 μg/g) and soy sauce (9.4 μg/mL). Flazin was formed during the heating process, as shown in fresh tomato juice and crushed tomatoes. These results indicate that flazin is widely present in foods and is daily uptaken in the diet.

Mechanistic investigation into the binding property of Yohimbe towards natural polymeric DNAs

DNA interactions with multivalent ligand(s) have increasingly become the subject of substantial research. For several small molecules with therapeutic potential, nucleic acids serve as their primary molecular target. Such interaction has been shown to affect transcription or replication, ultimately leading to apoptotic cell death. As a result, researchers are becoming increasingly interested in understanding how small molecules interact with DNA making it possible to develop new, DNA-specific drugs. The bioactive indole alkaloid, Yohimbe (Yohimbine; Yh) has been broadly studied in pharmacological properties while its binding mode to DNA has not been explicated so far. This study adopted molecular modelling and multi-spectroscopic methods to investigate the interaction between Yohimbine and herring testes (HT DNA) in physiological conditions. Minor hypochromic and bathochromic shifts of fluorescence intensity were observed, suggesting the binding of Yh to HT DNA. The Scatchard plot analyses using the McGhee-von Hipple method revealed non-cooperative binding and affinities in the range of 105 M−1. The thermodynamic parameters suggested exothermic binding, which was favoured by negative enthalpy and positive entropy changes from temperature-dependent fluorescence experiments. Salt-dependent fluorescence suggested that the interaction between the ligand and DNA was governed by non-polyelectrolytic forces. The results of iodide quenching, urea denaturation assay, dye displacement, and in silico molecular docking, suggested groove binding of Yh to HT DNA. Thus, the groove binding mechanism of interaction was validated by both biophysical and computational techniques. The structural elucidation and energetic profiling of Yh's interaction with naturally occurring polymeric DNA can be useful to the development of DNA-targeted therapeutics.

Two Novel Iboga-Type and an Oxindole Glucuronide Alkaloid from Tabernaemontana peduncularis Disclose Related Biosynthetic Pathways to Tabernaemontana divaricata.

Phytochemical investigation of the two Tabernaemontana species (Apocynaceae) T. peduncularis Wall. and T. divaricata (L.) R.Br. ex Roem. & Schult. indicated closely related biosynthetic pathways leading to lipophilic and hydrophilic alkaloids. In total, 18 specialized metabolites comprising indole-derived alkaloid aglycones, three oxindole-derived alkaloid glycosides, and two iridoid glucosides could be identified in the studied species. Among the alkaloids, the two Iboga-type alkaloids 3,7-coronaridine isoindolenine, coronaridine 3,4-iminium and a javaniside derivative bearing a glucuronic acid, named javanuronic acid, could be described by spectroscopic and spectrometric methods for the first time. A docking experiment using alpha-fold was performed to generate a protein model of the enzyme 7-deoxyloganetic acid glucosyl transferase. Performed bioassays exhibited a growth reduction of neonate Spodoptera littoralis larvae and reduced cell viability of HepG2 cells of the extracts containing Iboga alkaloids, whilst the javaniside derivatives containing hydrophilic fraction did not show any effects. These findings indicate a high flexibility in the formation of bioactive indole alkaloid aglycones by Tabernaemontana species and also evidence similar accumulation trends in both species as well as indicate that biosynthetic routes leading to oxindole alkaloids like javanisides are more widespread than reported. Furthermore, the incorporation of the three novel compounds into potential biosynthetic pathways is discussed.

Bioactive Indole Alkaloid from Aspergillus amoenus TJ507 That Ameliorates Hepatic Ischemia/Reperfusion Injury.

Hepatic ischemia/reperfusion injury (IRI) is a major factor contributing to the failure of hepatic resection and liver transplantation. As part of our ongoing investigation into bioactive compounds derived from fungi, we isolated eight indole alkaloids (1-8) from the endophytic fungus Aspergillus amoenus TJ507. Among these alkaloids, one previously undescribed compound, amoenamide D (1), was identified. The planar structure of 1 was elucidated by extensive spectroscopic analysis, including HRESIMS and NMR spectra. The absolute configuration of 1 was elucidated by using electronic circular dichroism calculations. Notably, in the CoCl2-induced hepatocyte damage model, notoamide Q (3) exhibited significant anti-hypoxia injury activity. Furthermore, in a murine hepatic ischemia/reperfusion injury model, treatment with 3 prevents IRI-induced liver damage and hepatocellular apoptosis. Consequently, 3 might serve as a potential lead compound to prevent hepatic ischemia/reperfusion injury.

Bioactive Indole Alkaloids from the Tobacco-Derived Endophytic Fungus Aspergillus fumigatus

Bioactive Indole Alkaloids from the Tobacco-Derived Endophytic Fungus Aspergillus fumigatus

Deciphering binding affinity, energetics, and base specificity of plant alkaloid Harmane with AT and GC hairpin duplex DNA.

Insights into binding efficacy and thermodynamic aspects of small molecules are important for rational drug designing and development. Here, the interaction of Harmane (Har), a very important bioactive indole alkaloid, with AT and GC hairpin duplex-DNAs has been reported using various biophysical tools. Detailed molecular mechanism with special emphasis on binding nature, base specificity, and thermodynamics have been elucidated via probing nucleic acids with varying base compositions. Har bound to both the DNA strands exhibited hypochromic effect in absorbance whereas bathochromic and hypochromic effects in fluorescence spectra. The binding constants estimated were in the order of 105 M-1 (higher for GC sequence compared with AT) with 1:1 stoichiometry. Noncooperative binding mode has been observed via intercalation in both the cases. The thermodynamic profile was obtained from temperature-dependent fluorescence experiments. Both Har-AT and Har-GC complexations were exothermic in nature associated with positive entropy and negative enthalpy changes. Salt-dependent studies revealed that the binding interaction was governed by nonpolyelectrolytic and hydrophobic interaction forces. The ligand-induced structural perturbation of the DNA structures was evident from the circular dichroism data. Molecular modelling data indicated towards the involvement of hydrophobic forces and hydrogen bonding.

Targeting Natural Polymeric DNAs with Harmane: An Insight into Binding and Thermodynamic Interaction Through Biophysical Approach.

DNA is one of the major molecular targets for a broad range of anticancer drugs. Hence, interaction studies involving cellular DNA and small molecules can be highly beneficial as they often lead to rational and efficient drug design. In this study, the binding interaction of Harmane (a naturally occurring, bioactive indole alkaloid) with two natural polymeric DNAs, that is, Calf thymus (CT) DNA and Herring testis (HT) DNA has been elucidated using biophysical techniques. A ground state, 1:1 complexation, was revealed by steady-state fluorescence spectroscopy. The thermodynamic profile and energetics of the associated reaction were evaluated by temperature-dependent fluorescence spectroscopy. The spontaneity of the binding was confirmed by the negative ΔG° values in both cases. Negative enthalpy change, along with stronger positive entropic contribution, indicated the dominant electrostatic nature of the interaction and finally the entropy-driven exothermic binding process throughout. Salt-dependent studies further demonstrated the significant contribution of electrostatic interactions in ligand binding toward DNA. Infrared data substantiated the structural information of the said interactions, leading to the exploration of the structure-function relationship.

Research progress in pharmacology and toxicology of evodiamine

Evodiamine, a bioactive indole alkaloid from Evodia rutaecarpa, E. rutaecarpa var. officinalis, or E. rutaecarpa var. bodinieri, has been extensively investigated due to its pharmacological activities in recent years. At present, evodiamine is proved to significantly suppress the proliferation of a variety of cancer cells and mediate cell processes such as cell cycle arrest and cell migration. In addition, evodiamine displays significant pharmacological activities against cardiovascular diseases(hyperlipidemia, etc.), and tinea manus and pedis. Recently, evodiamine has been found to have potential toxic effects, such as hepatotoxicity, nephrotoxicity, and cardiotoxicity. However, the pharmacological and toxicological mechanism of evodiamine is not clear, and its toxicity in vitro and in vivo has been rarely reported. Therefore, this study reviewed the pharmacological and toxicological articles of evodiamine in recent years, aiming at providing new ideas and references for future research.

Bioactive indole alkaloids from insect derived endophytic Aspergillus lentulus

As part of our program to discover new bioactive agents from endophytic fungi, three new indole alkaloids (1–2, 4) along with twelve known compounds were isolated from an inset derived endophytic strain Aspergillus lentulus. Their structures were determined by comprehensive spectroscopic analyses of 1D/2D NMR and HR-ESI-MS data. The absolute configurations were confirmed by ECD calculation using Time-dependent Density functional theory (TD-DFT) at the B3LYP/6–31 + g (d, p) level and Rh2(OCOCF3)4-induced ECD experiments. Compounds 2, 4, 5, 13 and 15 exhibited moderate cytotoxic effects on A549 cell line with IC50 in the range of 17.92–48.29 μM. Compounds 1, 2 and 13–15 displayed the anti-bacterial activity against Xanthomonas oryzae pv. oryzae and Xanthomonas oryzae pv. oryzicola with MIC values ranging from 25 to 100 μg/mL.

Accelerated Solvent Extractions (ASE) of Mitragyna speciosa Korth. (Kratom) Leaves: Evaluation of Its Cytotoxicity and Antinociceptive Activity.

Mitragyna speciosa Korth (kratom) is known for its psychoactive and analgesic properties. Mitragynine is the primary constituent present in kratom leaves. This study highlights the utilisation of the green accelerated solvent extraction technique to produce a better, non-toxic and antinociceptive active botanical extract of kratom. ASE M. speciosa extract had a dry yield (0.53–2.91 g) and showed a constant mitragynine content (6.53–7.19%) when extracted with organic solvents of different polarities. It only requires a shorter extraction time (5 min) and a reduced amount of solvents (less than 100 mL). A substantial amount of total phenolic (407.83 ± 2.50 GAE mg/g and flavonoids (194.00 ± 5.00 QE mg/g) were found in ASE kratom ethanol extract. The MTT test indicated that the ASE kratom ethanolic leaf extract is non-cytotoxic towards HEK-293 and HeLa Chang liver cells. In mice, ASE kratom ethanolic extract (200 mg/kg) demonstrated a better antinociceptive effect compared to methanol and ethyl acetate leaf extracts. The presence of bioactive indole alkaloids and flavonols such as mitragynine, paynantheine, quercetin, and rutin in ASE kratom ethanolic leaf extract was detected using UHPLC-ESI-QTOF-MS/MS analysis supports its antinociceptive properties. ASE ethanolic leaf extract offers a better, safe, and cost-effective choice of test botanical extract for further preclinical studies.

Marine-derived fungi as a source of bioactive indole alkaloids with diversified structures.

Marine-derived fungi are well known as rich sources of bioactive natural products. Growing evidences indicated that indole alkaloids, isolated from a variety of marine-derived fungi, have attracted considerable attention for their diverse, challenging structural complexity and promising bioactivities, and therefore, indole alkaloids have potential to be pharmaceutical lead compounds. Systemic compilation of the relevant literature. In this review, we demonstrated a comprehensive overview of 431 new indole alkaloids from 21 genera of marine-derived fungi with an emphasis on their structures and bioactivities, covering literatures published during 1982-2019.

Deletion of the Histone Deacetylase HdaA in Endophytic Fungus Penicillium chrysogenum Fes1701 Induces the Complex Response of Multiple Bioactive Secondary Metabolite Production and Relevant Gene Cluster Expression.

Epigenetic regulation plays a critical role in controlling fungal secondary metabolism. Here, we report the pleiotropic effects of the epigenetic regulator HdaA (histone deacetylase) on secondary metabolite production and the associated biosynthetic gene clusters (BGCs) expression in the plant endophytic fungus Penicillium chrysogenum Fes1701. Deletion of the hdaA gene in strain Fes1701 induced a significant change of the secondary metabolite profile with the emergence of the bioactive indole alkaloid meleagrin. Simultaneously, more meleagrin/roquefortine-related compounds and less chrysogine were synthesized in the ΔhdaA strain. Transcriptional analysis of relevant gene clusters in ΔhdaA and wild strains indicated that disruption of hdaA had different effects on the expression levels of two BGCs: the meleagrin/roquefortine BGC was upregulated, while the chrysogine BGC was downregulated. Interestingly, transcriptional analysis demonstrated that different functional genes in the same BGC had different responses to the disruption of hdaA. Thereinto, the roqO gene, which encodes a key catalyzing enzyme in meleagrin biosynthesis, showed the highest upregulation in the ΔhdaA strain (84.8-fold). To our knowledge, this is the first report of the upregulation of HdaA inactivation on meleagrin/roquefortine alkaloid production in the endophytic fungus P. chrysogenum. Our results suggest that genetic manipulation based on the epigenetic regulator HdaA is an important strategy for regulating the productions of secondary metabolites and expanding bioactive natural product resources in endophytic fungi.

A Co-Culturing Approach Enables Discovery and Biosynthesis of a Bioactive Indole Alkaloid Metabolite.

Whole-genome sequence data of the genus Streptomyces have shown a far greater chemical diversity of metabolites than what have been discovered under typical laboratory fermentation conditions. In our previous natural product discovery efforts on Streptomyces sp. MA37, a bacterium isolated from the rhizosphere soil sample in Legon, Ghana, we discovered a handful of specialised metabolites from this talented strain. However, analysis of the draft genome of MA37 suggested that most of the encoded biosynthetic gene clusters (BGCs) remained cryptic or silent, and only a small fraction of BGCs for the production of specialised metabolites were expressed when cultured in our laboratory conditions. In order to induce the expression of the seemingly silent BGCs, we have carried out a co-culture experiment by growing the MA37 strain with the Gram-negative bacterium Pseudomonas sp. in a co-culture chamber that allows co-fermentation of two microorganisms with no direct contact but allows exchange of nutrients, metabolites, and other chemical cues. This co-culture approach led to the upregulation of several metabolites that were not previously observed in the monocultures of each strain. Moreover, the co-culture induced the expression of the cryptic indole alkaloid BGC in MA37 and led to the characterization of the known indolocarbazole alkaloid, BE-13793C 1. Neither bacterium produced compound 1 when cultured alone. The structure of 1 was elucidated by Nuclear Magnetic Resonance (NMR), mass spectrometry analyses and comparison of experimental with literature data. A putative biosynthetic pathway of 1 was proposed. Furthermore, BE-13793C 1 showed strong anti-proliferative activity against HT-29 (ATCC HTB-38) cells but no toxic effect to normal lung (ATCC CCL-171) cells. To the best of our knowledge, this is the first report for the activity of 1 against HT-29. No significant antimicrobial and anti-trypanosomal activities for 1 were observed. This research provides a solid foundation for the fact that a co-culture approach paves the way for increasing the chemical diversity of strain MA37. Further characterization of other upregulated metabolites in this strain is currently ongoing in our laboratory.

The indole-based subincanadine alkaloids and their biogenetic congeners.

The tryptamine-derived polycyclic bridged bioactive indole alkaloids subincanadines A-G were isolated in 2002 by Ohsaki and coworkers from the bark of the Brazilian medicinal plant Aspidosperma subincanum. Kobayashi proposed that subincanadines D-F could be biosynthetically resulting from stemmadenine via two different pathways and, furthermore, that the subincanadines A-C could be biogenetically resulting from subincanadines D and E. Kam and coworkers, in their focused efforts, isolated five indole alkaloids from Malaysian Kopsia arborea species, namely valparicine, apparicine, arboridinine, arborisidine, and arbornamine in combination with subincanadine E. On the basis of structural features, it has been proposed and proved in some examples that subincanadine E is a biogenetic precursor of these five different bioactive indole alkaloids bearing complex structural architectures. All important information on isolation, characterization, bioactivity, probable biogenetic pathways, and more specifically racemic and enantioselective total synthesis of subincanadine alkaloids and their biogenetic congeners are summarized in the present chapter. Special importance is given to the total synthesis and the synthetic strategies intended therein, comprising a set of main reactions.

Utilization of 1H-Indole-3-carboxaldehyde as a Precursor for the Synthesis of Bioactive Indole Alkaloids

Indole alkaloids constitute a large class of natural products and their diverse and complex structures have been attributed to potent biological activities such as anticancer, anti-inflammatory, antimicrobial, antimalarial, antiplasmodial and protein kinase inhibition. The isolation of bioactive compounds from natural sources is difficult, costly and an extremely time-consuming process, therefore synthetic pathways are more convenient than natural separation to deliver such compounds in considerable amounts. In this respect, this review provides comprehensive information on the structures and the synthesis of bioactive indole alkaloids utilizing 1H-indole-3-carboxaldehyde and its derivatives as starting compounds. 1 Overview2 Phytoalexins2.1 Brassinin, Cyclobrassinin and Brassitin2.2 1-Methoxybrassinin, 1-Methoxyspirobrassinol and 1-Methoxyspirobrassinin2.3 4-Methoxybrassinin and 4-Methoxycyclobrassinin2.4 Cyclobrassinone2.5 Brassilexin2.6 (S)-(–)-Spirobrassinin2.7 Camalexin3 Bis(indole) Alkaloids: Rhopaladines A–D4 Coscinamides A and B5 α-Cyclopiazonic Acid6 Dipodazine7 Isocryptolepine8 Apparicine9 Carbazole Alkaloids: Mukonine and Clausine E10 Indolmycin11 Conclusion

Total Synthesis of Sarpagine-Related Bioactive Indole Alkaloids.

Extension of the asymmetric Pictet-Spengler reaction to bulkier Nb -alkylated tryptophan derivatives resulted in an improved stereospecific access to the key bicyclo[3.3.1]nonane core of bioactive C-19 methyl substituted sarpagine/macroline/ajmaline indole alkaloids with excellent diastereoselectivity by internal asymmetric induction. Complete stereocontrol of the C-19 methyl function in either the α- or β-configuration was achieved, which enables the total synthesis of any member from this group of thirty alkaloids. We report herein, the total synthesis of macrocarpines (A-C) 1-3, talcarpine 4, N(4)-methyl-N(4),21-secotalpinine 5, dihydroperaksine 8 and deoxyperaksine 9.