ArticlePDF Available

Fischer indole synthesis applied to the total synthesis of natural products

Authors:

Abstract and Figures

One of the oldest and most useful reactions in organic chemistry is the Fischer indole synthesis (FIS). It is known to have a wide variety of applications including the synthesis of indole rings, often present as the framework in the total synthesis of natural products, particularly those found in the realm of alkaloids, which comprise a ring system known as an indole alkaloid. In this review, we are trying to emphasize the applications of FIS as an old reaction, which is currently applied to the total synthesis of biologically active natural products and some other complex targets.
Content may be subject to copyright.
Source: Heravi, M.M., Rohani, S., Zadsirjan, V., Zahedi, N. (2017), Fischer indole synthesis applied to the total
synthesis of natural products, Journal of RSC Advances, 7(83), doi: 10.1039/c7ra10716a
Fischer indole synthesis applied to the total synthesis of
natural products
Nazli Zahedi ,Vahideh Zadsirjan ,Sahar Rohani,
1
Majid M. Heravi
Department of Chemistry, Faculty of Physics &Chemistry Alzahra University, Vanak, Tehran, Iran.
1
Abstract
One of the oldest and most useful reactions in organic chemistry is the Fischer
indole synthesis (FIS). It is known to have a wide variety of applications
including the synthesis of indole rings, often present as the framework in the total
synthesis of natural products, particularly those found in the realm of alkaloids,
which comprise a ring system known as an indole alkaloid. In this review, we are
trying to emphasize the applications of FIS as an old reaction, which is currently
applied to the total synthesis of biologically active natural products and some
other complex targets.
Keywords
Alkaloids, Chemical compounds, Metabolites, Synthesis (chemical), A-RINGS,
Complex targets, Fischer Indole synthesis, Indole alkaloids, Indole rings, Natural
products, Organic Chemistry, Total synthesis,Polycyclic aromatic hydrocarbons
... A lot of strategy available for the preparation of 1,2,3,4-tetrahydrocarabzole scaffold in literature. However, Fischer indole synthesis approach is most common synthetic method used for the preparation of tetrahydrocarbazole scaffold and also play important role in preparation of various natural products [5,[16][17][18]. Various research groups synthesized tetrahydrocarbazoles based on Fischer indole method using starting material phenyl hydrazine and cyclohexanone using conventional, microwave and catalyst approach. ...
... Reaction of unsubstituted or substituted phenyl hydrazine (7 or 16) with substituted cyclohexane (17)(18)(19) gave substituted `1,2,3,4-tetrahydrocarbazoles (20-23) [27] (Scheme 6). The yield of the product (20-23) was found 28-89%. ...
Article
Full-text available
In this review article, we discussed old to new synthetic methods used for the preparation of 1,2,3,4-Tetrahydrocarbazole (THCz) based on reported literature. Around the worldwide, various researchers energetically reported new synthetic methods for tetrahydrocarbazoles preparation using conventional method or microwave method or use of catalyst. This review will be helpful to synthetic and medicinal chemist to find selective method for the preparation of 1,2,3,4-Tetrahydrocarbazoles with good percentage yield and less time. This review will also useful to medicinal chemist to design new biologically active tetrahydrocarbazoles based on reported synthetic methods.
... This is because of the generally favorable kinetics and thermodynamics of such systems. As such, there is a rich variety of "heteroatomic 1,5-diene" substrates classes reported in ( Figure 1A), 1-20 including many "named reactions" (aromatic Claisen-21 and Sommelet-Hauser-22 rearrangements; Fischer indole synthesis 23 ). The allcarbon analogs (1,5-dienes; Cope rearrangement substrates 24 ) are more challenging, energetically speaking. ...
Preprint
Full-text available
Reported herein is the discovery of a diastereoselective indole-dearomative Cope rearrangement. A suite of minor driving forces (substrate destabilizing effects; product stabilizing effects) are what promote this otherwise unfavorable dearomatization reaction. These include the following that work in concert to overcome the penalty for dearomatization: (i.) steric congestion in the starting material, (ii.) alkylidene malononitrile and stilbene conjugation events in the product, and (iii.) an unexpected intramolecular p–p* stack on the product side of the equilibrium. The key substrates are rapidly assembled from alkylidenemalononitriles and indole-phenylmethanol derivatives resulting in many successful examples (high yields and diastereoselectivity). The products are structurally complex bearing vicinal stereocenters generated by the dearomative Cope rearrangement. They also contain a variety of functional groups for interconversion to complex architectures. On this line, also described herein are proof-of-concept strategies for achieving enantioselectivity and conversion of the dearomative products to valuable and functionalized small drug-like molecules.
Article
Herein, we report a strategically novel method for the efficient construction of indole skeletons using 2-phenylisoxazol-5-ones as the starting material. This reaction proceeds via Brønsted acid-promoted α-iminyl cation generation by N-O bond cleavage and a subsequent intramolecular cyclization to afford 1H-indole-3-carboxylic acid, which further undergoes decarboxylation to yield the final product. Control experiments show that N-O bond cleavage and intramolecular cyclization proceed so fast that the 1H-indole-3-carboxylic acid could be isolated in high yields even after 5-10 min. The substrate scope of this transformation is broad, and the desired products are obtained in moderate to good yields. The transition-metal-free reaction condition, CO2 as the sole byproduct, and good practicability add to the synthetic potential of this transformation in the pharmaceutical and flavor industries.
Article
Natural product-inspired compound collections serve as excellent sources for the identification of new bioactive compounds to treat disease. However, such compounds must necessarily be more structurally-enriched than traditional screening compounds, therefore inventive synthetic strategies and reliable methods are needed to prepare them. Amongst the various possible starting materials that could be considered for the synthesis of natural product-inspired compounds, ketones can be especially valuable due to the vast variety of complexity-building synthetic transformations that they can take part in, their high prevalence as commercial building blocks, and relative ease of synthesis. With a view towards developing a unified synthetic strategy for the preparation of next generation bioactive compound collections, this review considers whether ketones could serve as general precursors in this regard, and summarises the opulence of synthetic transformations available for the annulation of natural product ring-systems to ketone starting materials.
Chapter
Paal–Knorr (P–K) synthesis is an old name reaction in organic chemistry that generates either furans, pyrroles, or thiophenes, starting from 1,4-dicarbonyl compounds in acidic media. It is one of the most significant methodologies for the preparation of these five membered aromatic heterocycles. P–K synthesis has found several applications in the total synthesis of natural products. In this chapter, we update our previous chapter published in Advances in Heterocyclic Chemistry in 2014. It covers the advances made in the applications of P–K reaction in the synthesis of pyrroles, furans and thiophenes from 2015 till date. It also underscores the applications of P–K reaction in the total synthesis of natural products.
Article
Natural product synthesis remains a field in which new synthetic methods and reagents are continually being evaluated. Due to the demanding structures and complex functionality of many natural products, only powerful and selective methods and reagents will be highlighted in this proceeding. Since its introduction by Henri Kagan, samarium(ii) iodide (SmI2, Kagan's reagent) has found increasing use in chemical synthesis. Over the years, many reviews have been published on the application of SmI2 in numerous reductive coupling procedures as well as in natural product total synthesis. This review highlights recent advances in SmI2-mediated synthetic strategies, as applied in the total synthesis of natural products since 2004.
Article
3‐Methylindole, as an important N‐heterocycle compound, is widely applied in the fields of medicine, agriculture and industry for synthesizing momentous drugs and plant growth regulators as well as the production of spices. Therefore, the efficient synthesis of 3‐methylindole is very important and has attracted much attention from chemists. In this paper, the synthetic methods of 3‐methylindole were classified into Fischer proton rearrangement, radical reaction, coupling cyclization, electrophilic reaction, nucleophilic reaction, reduction reaction and oxidation reaction. Also, the recent advances in the synthetic method and mechanism were reviewed, in which the most promising method for the green and cheap synthesis of 3‐methylindole from biomass‐derived glycerol and aniline was proposed.
Article
Hantzsch reaction, leading to the synthesis of 1,4‐dihydropyridines (1,4‐DHPs) with momentous biological activities and pharmacological properties is a well‐known MCR. In recent years, microwave irradiation (MWI) has been successfully used as the unconventional and green source of energy to promote organic transformations including Hantzsch 1,4‐dihydropyridines. Literature survey disclosed that construction of 1,4‐DHPs as well as their aromatization can be successfully performed under MWI in solution as well as in dry media. In this review, we try to underscore recent advances in the synthesis and aromatization of Hantzsch 1,4‐DHPs under MWI as green approach. In recent years, microwave irradiation (MWI) has been successfully used as the unconventional and green source of energy to promote organic transformations including Hantzsch 1,4‐dihydropyridines. Literature survey disclosed that construction of 1,4‐DHPs as well as their aromatization can be successfully performed under MWI in solution as well as in dry media. In this review, we try to underscore recent advances in the synthesis and aromatization of Hantzsch 1,4‐DHPs under MWI as green approach.
Book
Of the myriad of heterocycles known to man, the indole ring stands foremost for its remarkably versatile chemistry, its enormous range of biological activities, and its ubiquity in the terrestrial and marine environments. The indole ring continues to be discovered in natural products and to be employed in man-made pharmaceuticals and other materials. Given the enormous resurgence in indole ring synthesis over the past decade - highlighted by the power of transition metal catalysis - this authoritative guide addresses the need for a comprehensive presentation of the myriad of methods for constructing the indole ring, from the ancient to the modern, and from the obscure to the well-known. Following presentation of the classic indole ring syntheses and many newer methods, coverage continues with indole ring syntheses via pyrroles, indolines, oxindoles, isatins, radical and photochemical reactions, aryne cycloadditions. This extensive volume concludes with the modern transition metal-catalyzed indole ring syntheses that utilize copper, palladium, rhodium, gold, ruthenium, platinum, and other metals to fashion the indole ring. Indole Ring Synthesis is a comprehensive, authoritative and up-to-date guide to the synthesis of this important heterocycle for organic chemists, pharmaceutical researchers and those interested in the chemistry of natural products.
Article
A new approach for the divergent total syntheses of (±)-vincaminorine, (±)-N-methylquebrachamine, (±)-quebrachamine, (±)-minovine and (±)-vincadifformine, each in less than 10 linear steps starting from a single δ-lactam building block, is reported. Key to our route design is the late-stage generation of reactive enamine functionality from stable indole-linked δ-lactams via a highly chemoselective iridium(I)-catalyzed reduction. The efficiently formed secodine intermediates subsequently undergo either a formal Diels-Alder cycloaddition or a competitive Michael addition/reduction to access aspidosperma-type alkaloids in excellent diastereoselectivities. Product selectivity could be controlled by changing the indole N-protecting group in the reductive cyclization precursors. An asymmetric variant of this synthetic strategy for the synthesis of (+)-20-epi-ibophyllidine is also described.
Article
Aryl hydrazides with a ketone or aldehyde containing side chains linked to the meta-position of the aromatic ring undergo acid-promoted intramolecular Fischer indole synthesis to generate 3,4-fused tricyclic indoles. The preparative utility of this conceptually new synthetic approach, which does not require prefunctionalization of the indole ring, was demonstrated by its application to a concise total synthesis of (-)-aurantioclavine.
Article
Reductive cyclization of the 2,4,5-trisubstituted cyclohexenone 16 using dihydogen in the presence of Raney cobalt afforded compound 17 (60%) that could be elaborated over a further five steps, including one involving a cationic cyclization process, into the racemic modification of the unusual uleine alkaloid gilbertine. Single-crystal X-ray analyses of compounds (+/-)-1, 16 and a derivative of 17 are reported.
Article
Total synthesis of the bismacrocyclic thiopeptide antibiotic nosiheptide was achieved through the assembly of a fully functionalized linear precursor followed by consecutive macrocyclizations. Key features are a critical macrothiolactonization and a mild deprotection strategy for the 3-hydroxypyridine core. The natural product was identical to isolated authentic material in terms of spectral data and antibiotic activity.
Article
Generally, heterocycles occupy a prominent place in chemistry due to their wide range of applications in the fields of drug design, photochemistry, agrochemicals, dyes and so on.Among them, indole scaffolds have been found in most of the important synthetic drug molecules and paved a faithful way to develop effective targets.Privileged structures bind to multiple receptors with high affinity, thus aiding the development of novel biologically active compounds.Among the indole class of compounds, 2-arylindoles appear to be a most promising lead for drug development.The derivatives of 2-arylindoles exhibits antibacterial, anticancer, anti-oxidants, anti-inflammatory, anti-diabetic, antiviral, antiproliferative, antituberculosis activity, etc.This article would provide a clear knowledge on the wide-ranging biological activities of 2-arylindoles over the past two decades, which would be beneficial for the designing of more potent drug targets in order to compete with the existing drugs.
Article
This review highlights noteworthy synthetic and biological aspects of the clavine subfamily of ergot alkaloids. Recent biosynthetic insights have laid the groundwork for a better understanding of the diverse biological pathways leading to these indole derivatives. Ergot alkaloids were among the first fungal-derived natural products identified, inspiring pharmaceutical applications in CNS disorders, migraine, infective diseases, and cancer. Pergolide, for example, is a semi-synthetic clavine alkaloid that has been used to treat Parkinson's disease. Synthetic activities have been particularly valuable to facilitate access to rare members of the Clavine family and empower medicinal chemistry research. Improved molecular target identification tools and a better understanding of signaling pathways can now be deployed to further extend the biological and medical utility of Clavine alkaloids.
Article
In this review, we update our previous presentation, underscoring the recent applications of isocyanides as privileged synthons in the synthesis of various heterocyclic compounds, especially focused on those synthesized via multicomponent reactions.
Article
An efficient and highly stereoselective intramolecular [3 + 2] cycloaddition of nonstabilized azomethine ylide generated from a designed bicyclic aminal precursor is reported for the synthesis of both (-)- and (+)-octahydropyrroloquinolinone. One of the enantiomers is further advanced to accomplish the total synthesis of (+)-aspidospermidine.