Indole Natural Products Research Articles

Oxidative Coupling Approach to Sarpagine Alkaloids: Total Synthesis of (-)-Trinervine, Vellosimine, (+)-Normacusine B, and (-)-Alstomutinine C.

Sarpagine alkaloids are bioactive indole natural products that contain a highly rigid indole-fused 1-azabicyclo[2.2.2]octane, more than 100 members of which have been identified. Herein, a detailed examination of the intramolecular oxidative coupling between a ketone and a Weinreb amide for assembling the complex 1-azabicyclo[2.2.2]octane core structure of sarpagine family alkaloids is described. Precise late-stage manipulations of the ketone and Weinreb amide enable the divergent syntheses of (-)-trinervine, (+)-vellosimine, (+)-normacusine B, and (-)-alstomutinine C. Other notable transformations of the synthesis featured an aza-Achmatowicz/indole cyclization cascade to generate the azabicyclo[3.3.1]nonane structure, a regioselective elimination reaction to form the ethylidene motif embedded in the (+)-vellosimine and (+)-normacusine B structures, and a diastereoselective indole oxidative rearrangement to form the spirooxindole structure in (-)-alstomutinine C.

Oxidative Coupling Approach to Sarpagine Alkaloids: Total Synthesis of (−)‐Trinervine, Vellosimine, (+)‐Normacusine B, and (−)‐Alstomutinine C

AbstractSarpagine alkaloids are bioactive indole natural products that contain a highly rigid indole‐fused 1‐azabicyclo[2.2.2]octane, more than 100 members of which have been identified. Herein, a detailed examination of the intramolecular oxidative coupling between a ketone and a Weinreb amide for assembling the complex 1‐azabicyclo[2.2.2]octane core structure of sarpagine family alkaloids is described. Precise late‐stage manipulations of the ketone and Weinreb amide enable the divergent syntheses of (−)‐trinervine, (+)‐vellosimine, (+)‐normacusine B, and (−)‐alstomutinine C. Other notable transformations of the synthesis featured an aza‐Achmatowicz/indole cyclization cascade to generate the azabicyclo[3.3.1]nonane structure, a regioselective elimination reaction to form the ethylidene motif embedded in the (+)‐vellosimine and (+)‐normacusine B structures, and a diastereoselective indole oxidative rearrangement to form the spirooxindole structure in (−)‐alstomutinine C.

Recent Advances of Marine Natural Indole Products in Chemical and Biological Aspects.

The ocean has always been one of the important sources of natural products. In recent years, many natural products with different structures and biological activities have been obtained, and their value has been clearly recognized. Researchers have been deeply engaged in the field of separation and extraction, derivative synthesis, structural studies, biological evaluation, and other fields of research for marine natural products. Thus, a series of marine indole natural products which have structural and biological prospect have caught our eyes. In this review, we summarize some of these marine indole natural products with relatively good pharmacological activity and research value, and discuss issues concerning chemistry, pharmacological activity, biological evaluation, and synthesis, including monomeric indoles, indole peptides, bis-indoles, and annelated indoles. Most of the compounds have cytotoxic, antiviral, antifungal, or anti-inflammatory activities.

The application of C–H bond functionalization in the total syntheses of indole natural products

The recent advances in total synthesis of indole natural products focusing on the application of C–H bond functionalization are summarized.

First discovery of pimprinine derivatives and analogs as novel potential herbicidal, insecticidal and nematicidal agents

Pimprinine and streptochlorin are indole natural products produced by many species of organisms, and they are reported to possess a wide range of biological activities, such as anticancer, antiviral, antifungal activity and so on. In this study, three series of pimprinine derivatives or analogs were efficiently synthesized under the optimized methods. Biological assays conducted at Syngenta firstly indicated the pimprinine derivatives or analogs possessed potential herbicidal and insecticidal activity, and this is highlighted by compounds 21g, 21h, 21i, 21j, 21l, 22h, 22i and 23h, they possessed significant biological activity as well as broad spectrum. Meanwhile, compounds with benzothiophene-oxazole core (21h, 22h and 23h), showed effective nematicidal activity in primary screening. Compounds 21g and 21i were identified as the most promising lead structures for further study.

Biological Activities of 3-(5-Oxazolyl)indole Natural Products and Advances on Synthesis of Its Derivatives

Biological Activities of 3-(5-Oxazolyl)indole Natural Products and Advances on Synthesis of Its Derivatives

Facile in Vitro Biocatalytic Production of Diverse Tryptamines.

Tryptamines are a medicinally important class of small molecules that serve as precursors to more complex, clinically used indole alkaloid natural products. Typically, tryptamine analogues are prepared from indoles through multistep synthetic routes. In the natural world, the desirable tryptamine synthon is produced in a single step by l-tryptophan decarboxylases (TDCs). However, no TDCs are known to combine high activity and substrate promiscuity, which might enable a practical biocatalytic route to tryptamine analogues. We have now identified the TDC from Ruminococcus gnavus as the first highly active and promiscuous member of this enzyme family. RgnTDC performs up to 96 000 turnovers and readily accommodates tryptophan analogues with substituents at the 4, 5, 6, and 7 positions, as well as alternative heterocycles, thus enabling the facile biocatalytic synthesis of >20 tryptamine analogues. We demonstrate the utility of this enzyme in a two-step biocatalytic sequence with an engineered tryptophan synthase to afford an efficient, cost-effective route to tryptamines from commercially available indole starting materials.

Total Synthesis of Paspaline A and Emindole PB Enabled by Computational Augmentation of a Transform-Guided Retrosynthetic Strategy.

We report the total syntheses of two indole diterpenoid natural products, paspaline A and emindole PB. Paspaline A is synthesized in a 9-step sequence from commercially available materials. The first total synthesis of emindole PB is accomplished in 13 steps and confirms a previously ambiguous structural assignment. Density functional theory calculations are utilized to interrogate the key carbocationic rearrangement in a predictive capacity to aid in the selection of the most favorable precursor substrate. This work highlights how retrosynthetic design can be augmented with quantum chemical calculations to reveal energetically feasible synthetic disconnections, minimizing time-consuming and expensive empirical evaluation.

FgaPT2, a biocatalytic tool for alkyl-diversification of indole natural products.

Aromatic prenyltransferases from natural product biosynthetic pathways display relaxed specificity for their aromatic substrates. While a growing body of evidence suggests aromatic prenyltransferases to be more tolerant towards their alkyl-donor substrates, most studies aimed at probing their donor-substrate specificity are limited to only a small set of alkyl pyrophosphate donors, restricting their broader utility as biocatalysts for synthetic applications. Here, we assess the donor substrate specificity of an l-tryptophan C4-prenyltransferase, also known as C4-dimethylallyltryptophan synthase, FgaPT2 from Aspergillus fumigatus, using an array of 34 synthetic unnatural alkyl-pyrophosphate analogues, and demonstrate FgaPT2 can catalyze the transfer of 25 of the 34 non-native alkyl groups from their corresponding synthetic alkyl-pyrophosphate analogues at N1, C3, C4 and C5 position of tryptophan in a normal and reverse manner. The kinetic studies and regio-chemical analysis of the alkyl-l-tryptophan products suggest that the alkyl-donor transfer by FgaPT2 is a function of the stability of the carbocation and the steric factors in the active site of the enzyme. Further, to demonstrate the biocatalytic utility of FgaPT2, this study also highlights the FgaPT2-catalyzed synthesis of a small set of alkyl-diversified indolocarbazole analogues. These results reveal FgaPT2 to be more tolerant to diverse non-native alkyl-donor substrates beyond their known acceptor substrate promiscuity and set the stage for its development as a novel biocatalytic tool for the differential alkylation of natural products for drug discovery and other synthetic applications.

Cyclohepta[b]indoles: A Privileged Structure Motif in Natural Products and Drug Design.

Seven-membered rings fused with an indole are termed cyclohepta[b]indoles. Compounds exhibiting this structure motif display a broad spectrum of biological activities, ranging from inhibition of adipocyte fatty-acid-binding protein (A-FABP), deacetylation of histones, inhibition of leukotriene production p53, antituberculosis activities, and anti-HIV activities. These biological profiles are found in natural products containing the cyclohepta[b]indole motif, as well as in pharmaceuticals that contain this structure motif. Therefore, the biology of molecules derived from the skeleton of cyclohepta[b]indoles, as well as cyclopenta- and cyclohexa[b]indoles, has attracted considerable interest from the pharmaceutical industry as potential therapeutics in recent years. This is reflected by more than two dozen patents that have been issued in the past decade, solely based on the cyclohepta[b]indole structure motif. The efficient preparation of highly functionalized and unsymmetrically substituted cyclohepta[b]indoles has therefore become of central interest for synthetic organic chemists. Historically, this structure motif most often has been prepared by means of a Fischer indole synthesis. Although very robust and useful, this reaction poses certain limitations. Especially unsymmetrically functionalized cyclohepta[b]indoles are not suitable for a Fischer indole type synthesis, since product mixtures are inevitable. Therefore, novel methodologies to overcome these synthetic obstacles have been developed in recent years. This Account introduces all natural products and pharmaceutical compounds exhibiting the cyclohepta[b]indole motif. The structural variability within cyclohepta[b]indole alkaloids in combination with the broad range of organisms where these alkaloids have been isolated from, strongly suggests that the cyclohepta[b]indole is somehow a "privileged" structure motif. The organisms producing these compounds range from evergreen trees (actinophyllic acid) to cyanobacteria (ambiguinines). The synthetic methodologies to construct these molecular scaffolds (natural and unnatural in origin) are in turn highlighted and discussed with regard to their potential to access highly functionalized and unsymmetrical cyclohepta[b]indoles, for which they specifically have been designed. The methods are classified with respect to reaction type and whether or not they are enantioselective. Finally, the syntheses of cyclohepta[b]indole natural products are presented, thereby in each case, focusing on the construction of this structure motif in the course of the respective total synthesis. As a conclusion, we end by contrasting the methodological progress in the field with the actual successful application of the newly developed methods to the synthesis of complex structures to pinpoint the urgent requirement for further synthetic development for efficient synthetic design of this "privileged" structure motif.

Expanding indole diversity: direct 1-step synthesis of 1,2-fused indoles and spiroindolines from 2-halo anilines for fast SAR antiviral elucidation against tobacco mosaic virus (TMV).

To systematically investigate the influence of the variation of the original skeletons and spatial configuration of 2,3-fused indole natural products on antiviral activities, two types of structurally novel and potent pseudo-indole natural product derivatives, 1,2-fused indole and spiroindoline, with different substituents were direct synthesized from 2-halo anilines, and their antiviral activities against tobacco mosaic virus (TMV) were evaluated. The results showed that these compounds exhibited good anti-TMV activity, especially 3f, 3g, 3i, 5e, 5h, and 5l, which were more potent than the commercial anti-virus agent ribavirin. An SAR investigation demonstrates that the original ring size, arrangement, and planarity are not optimal; their anti-TMV activities can be improved by skeleton modification and spatial configuration variation. Both of the structurally novel skeletons provide a new template for antiviral studies, which may also provide some useful information for antiviral mechanism elucidation.

Synthesis and antifungal activity of novel streptochlorin analogues

Streptochlorin, first isolated as a new antibiotic in 1988 from the lipophilic extracts of the mycelium of a Streptomyces sp, is an indole natural products with a variety of biological activities. Based on the methods developed for the synthesis of pimprinine in our laboratory, we have synthesized a series of indole-modified streptochlorin analogues and measured their activities against seven phytopathogenic fungi. Some of the analogues displayed good activity in the primary assays, and the seven compounds 10b, 10c, 11e, 13e, 21, 22c and 22e (shown in Figure 1) were identified as the most promising candidates for further study. Structural optimization is still ongoing with the aim of discovering synthetic analogues with improved antifungal activity.

Scalable total syntheses of (−)-hapalindole U and (+)-ambiguine H

The Stigonemataceae family of cyanobacteria produces a class of biogenetically related indole natural products that include hapalindoles and ambiguines. In this full account, a practical route to the tetracyclic hapalindole family is presented by way of an eight-step, enantiospecific, protecting-group-free total synthesis of (−)-hapalindole U that features an oxidative indole–enolate coupling. With gram-scale access to hapalindole U, the first total synthesis of an ambiguine alkaloid, (+)-ambiguine H, was completed via an isonitrile-assisted prenylation of an indole followed by a photofragmentation cascade.

ChemInform Abstract: Enantioselective Synthesis of 3‐Substituted Tryptamines as Core Components of Central Nervous System Drugs and Indole Natural Products.

AbstractThe reaction of indole (I) with unsaturated aldehyde (II) in the presence of MacMillan′s catalyst leads to 3‐substituted indole adduct (III), which is readily converted into late‐stage intermediate (VI) of migraine drug prototype NXN274.

ChemInform Abstract: A Variation of the Fischer Indolization Involving Condensation of Quinone Monoketals and Aliphatic Hydrazines.

The indole ring system is one of the most ubiquitous heterocycles in nature. Many indole-containing natural products show a wide scope of biological activities, in particular because they bind to many receptors with high affinity. Since Baeyer s first synthesis of indole from oxindole in 1866 (indigo!isatin!oxindole!indole), numerous methods for the synthesis of indoles have been reported. One of the most efficient and widely employed syntheses is the Fischer indolization discovered in 1883. Compared with other indole syntheses, the importance of Fischer indolization lies in its simplicity and convenience, that is, formation of a critical C C bond to an unactivated aromatic carbon through a [3,3] sigmatropic rearrangement of enolizable Narylhydrazones. After more than a century of development, the Fischer indole synthesis remains a reliable and versatile method for the preparation of a variety of indole natural products and medicinal compounds. Many new variations have been developed in recent years. Most recently, the first catalytic asymmetric version of Fischer indole synthesis was reported by the group of List. Although the Fischer indole synthesis is widely used, several disadvantages still remain. The classical Fischer indole synthesis starts with arylhydrazines, which are generally made either from anilines through diazonium salts, or from aryl halides through transitionmetal-mediated coupling reactions. These processes involve the use of aniline precursors and toxic reagents (nitrous acid, stannous chloride, etc.) and potentially explosive diazonium intermediates, or expensive transition metals. We report herein a novel variation of the Fischer indolization involving a one-pot condensation of quinone monoketals with aliphatic hydrazines (Scheme 1). To the best of our knowledge, this is the first Fischer-type indole synthesis using an aliphatic hydrazine as the nitrogen source and a quinone monoketal as a masked benzene ring. We envisioned that condensation of quinone monoketal 1 and aliphatic hydrazine 2 would ultimately lead to an indole via alkylaryldiazene 5 and arylhydrazone intermediate 6, as illustrated in Scheme 2. The feasibility of this method relies on the initial formation of alkylaryldiazene 5 from a 1,2addition/dehydration sequence. It should be noted that there has been no report on the synthesis of alkylaryldiazenes 5 from quinone derivatives and aliphatic hydrazines, although arylaryldiazenes (azobenzenes) have been synthesized from condensations of arylhydrazines with quinones, quinols, quinone monoketals, and quinone bisketals. There is a single report on the condensation of an aliphatic hydrazine (N,N-dimethylhydrazine) with naphthoquinone monoketal, which, however, gave a 1,4-addition product in high yield. Therefore, our first object was to test the practicality of the Scheme 1. Strategies for the synthesis of indoles.

A Variation of the Fischer Indolization Involving Condensation of Quinone Monoketals and Aliphatic Hydrazines

The indole ring system is one of the most ubiquitous heterocycles in nature. Many indole-containing natural products show a wide scope of biological activities, in particular because they bind to many receptors with high affinity. Since Baeyer s first synthesis of indole from oxindole in 1866 (indigo!isatin!oxindole!indole), numerous methods for the synthesis of indoles have been reported. One of the most efficient and widely employed syntheses is the Fischer indolization discovered in 1883. Compared with other indole syntheses, the importance of Fischer indolization lies in its simplicity and convenience, that is, formation of a critical C C bond to an unactivated aromatic carbon through a [3,3] sigmatropic rearrangement of enolizable Narylhydrazones. After more than a century of development, the Fischer indole synthesis remains a reliable and versatile method for the preparation of a variety of indole natural products and medicinal compounds. Many new variations have been developed in recent years. Most recently, the first catalytic asymmetric version of Fischer indole synthesis was reported by the group of List. Although the Fischer indole synthesis is widely used, several disadvantages still remain. The classical Fischer indole synthesis starts with arylhydrazines, which are generally made either from anilines through diazonium salts, or from aryl halides through transitionmetal-mediated coupling reactions. These processes involve the use of aniline precursors and toxic reagents (nitrous acid, stannous chloride, etc.) and potentially explosive diazonium intermediates, or expensive transition metals. We report herein a novel variation of the Fischer indolization involving a one-pot condensation of quinone monoketals with aliphatic hydrazines (Scheme 1). To the best of our knowledge, this is the first Fischer-type indole synthesis using an aliphatic hydrazine as the nitrogen source and a quinone monoketal as a masked benzene ring. We envisioned that condensation of quinone monoketal 1 and aliphatic hydrazine 2 would ultimately lead to an indole via alkylaryldiazene 5 and arylhydrazone intermediate 6, as illustrated in Scheme 2. The feasibility of this method relies on the initial formation of alkylaryldiazene 5 from a 1,2addition/dehydration sequence. It should be noted that there has been no report on the synthesis of alkylaryldiazenes 5 from quinone derivatives and aliphatic hydrazines, although arylaryldiazenes (azobenzenes) have been synthesized from condensations of arylhydrazines with quinones, quinols, quinone monoketals, and quinone bisketals. There is a single report on the condensation of an aliphatic hydrazine (N,N-dimethylhydrazine) with naphthoquinone monoketal, which, however, gave a 1,4-addition product in high yield. Therefore, our first object was to test the practicality of the Scheme 1. Strategies for the synthesis of indoles.

Enantioselective synthesis of 3-substituted tryptamines as core components of central nervous system drugs and indole natural products

Application of the MacMillan iminium ion Michael and Friedel–Crafts type reactions to γ-amino α,β-unsaturated butanals led to the corresponding β-substituted butanals in good yields and high enantioselectivities. The products could be useful intermediates in the synthesis of indole-based central nervous system (CNS) drugs and natural products.

Rearrangement Reaction of 1-Ethoxy- and 1-Hydroxy-2-phenylindole

Photoirradiation of 1-ethoxy-2-phenylindole in methanol and the reaction of 1-hydroxy-2-phenylindole with tosyl chloride produced 6-ethoxyand 6-tosyloxy-2-phenylindoles, respectively, as minor products. The latter was derived to 6-ethoxy-2-phenylindole. The structure is determined by direct comparison of the spectral data with those of the authentic 4-, 5-, 6-, and 7ethoxy-2-phenylindoles whose syntheses are reported in detail. We speculated that indole natural products having 3-, 4-, and/or 6-methoxy (or hydroxy) substituent could be produced in plant leaves by the sun light from the corresponding 1-alkoxyor 1hydroxyindoles. In order to examine this 1-hydroxyindole hypotheses, we attempted the photochemical reaction of 1-ethoxy-2-phenylindole (2), derived from 1-hydroxy-2-phenylindole (1). Upon irradiation of 2 with Hannovia UV lamp in MeOH, we characterized 2-phenylindole (3) and 3ethoxy-2-phenylindole (4) in 35 and 12% yields, respectively, from the closely overlapped eight products monitored on tlc (Scheme 1). At the same time, we isolated a 3% yield of product X (5), which was a 2phenylindole carrying an ethoxy group in the benzene ring. On the other hand, upon reaction of 1 with tosyl chloride, we isolated a 6% yield of product Y (6), which has a tosyloxy group on the benzene ring, in addition to 2-phenyl-3-tosyloxyindole (7), 2,2’-diphenyl-3,3’-bisindolyl (8), and 3 in 53, 2, and 5% † Dedicated to Prof. Dr. Albert Padwa. ‡ Professor Emeritus of Kanazawa University. Present address: 56-7 Matsuhidai, Matsudo-shi, Chiba 270-2214, Japan. yields, respectively. At that time, we employed H-NMR spectrum in order to determine the position of substituent on the indole ring utilizing the anisotropy effect of 1-acyl group (Scheme 2). Thus, the unknown indole having R-group (9) is led to the corresponding 1-acyl derivative (10), where the C(7)-proton shifts to lower magnetic field and becomes clearly discernible from other aromatic protons. Based on its coupling pattern, we can determine the position of the R-group unequivocally. In cases of product X (5) and product Y (6) the above structural determination method was impossible because the phenyl group at the 2position blocked the introduction of an acyl group into the 1-position under various reaction conditions (Ac2O reflux or NaH, AcCl). Moreover, the low resolving power of 60 MHz H-NMR apparatus at that time was of no use for analyzing the coupling pattern of aromatic protons. Although we could later utilize a 270 and a 500 MHz H-NMR instruments, they have still not enough resolving power to judge the coupling pattern of the indole benzenoid protons due to the overlapping protons of 2-phenyl group. The left course for the structure determination of product X (5) and product Y (6) was the only one, direct comparison with the authentic 4(11), 5(12), 6(13), and 7-ethoxy-2-phenylindoles (14). Their syntheses required new reactions such as regioselective thallation-palladation method for the preparation of 4-substituted, and 7-substituted indoles, general preparation method for 1-hydroxyindoles, and selective 2-lithiation method of 1-methoxyindoles. After discovering these essential new methods, we succeeded at last in the syntheses of authentic 11, 12, 13, and 14 in 1998. Consequently, structures of N

Concise Total Synthesis of (±)-cis-Trikentrin A and (±)-Herbindole A via Intermolecular Indole Aryne Cycloaddition

An efficient nine-step total synthesis of the annulated indole natural products (+/-)-cis-trikentrin A and (+/-)-herbindole A was accomplished via an intermolecular Diels-Alder cycloaddition using our recently developed indole aryne (indolyne) methodology as the key step. This strategy provides rapid access into the trikentrins and the related herbindoles and represents the first application of this methodology to natural products total synthesis. The required 6,7-indolyne precursor was readily constructed by means of the Bartoli indole synthesis with substituted nitrobenzenes and vinyl magnesium bromide.

Reaction of (dimethylvinylidene)carbene with indole-3-carbaldehyde and its application in the synthesis of β-(dehydroprenyl)indole-based natural products

Reaction of (dimethylvinylidene)carbene with indole-3-carbaldehyde gives various dehydroprenyl-based indoles. Efficient synthesis of the indole natural products yuehchukene and murrapanine, using this reaction as a key step, is also described.