Synthesis Of Indole Alkaloids Research Articles

Construction of Spirocyclic Oxindoles for Indole Alkaloid Synthesis

Key words spirocycles - oxindoles - Ullmann coupling - Claisen rearrangement

Biogenetically inspired synthesis and skeletal diversification of indole alkaloids

To access architecturally complex natural products, chemists usually devise a customized synthetic strategy for constructing a single target skeleton. In contrast, biosynthetic assembly lines often employ divergent intramolecular cyclizations of a polyunsaturated common intermediate to produce diverse arrays of scaffolds. With the aim of integrating such biogenetic strategies, we show the development of an artificial divergent assembly line generating unprecedented numbers of scaffold variations of terpenoid indole alkaloids. This approach not only allows practical access to multipotent intermediates, but also enables systematic diversification of skeletal, stereochemical and functional group properties without structural simplification of naturally occurring alkaloids. Three distinct modes of [4+2] cyclizations and two types of redox-mediated annulations provided divergent access to five skeletally distinct scaffolds involving iboga-, aspidosperma-, andranginine- and ngouniensine-type skeletons and a non-natural variant within six to nine steps from tryptamine. The efficiency of our approach was demonstrated by successful total syntheses of (±)-vincadifformine, (±)-andranginine and (-)-catharanthine.

Diastereoselective Synthesis of Bridged Polycyclic Alkaloids via Tandem Acylation/Intramolecular Diels–Alder Reaction

A mild and efficient stereoselective synthesis of hexacyclic indole alkaloids with a tetrahydro-β-carboline motif has been developed by utilizing the Pictet-Spengler reaction and tandem N-acylation followed by intramolecular Diels-Alder cyclization. Initially, a diene unit was installed in the tetrahedron β-carboline skeleton through Pictet-Spengler cyclization of the corresponding aldehyde with tryptophan ester. The dienophile moiety was introduced by N-acylation of tetrahydro-β-carboline. Successive, in situ, [4 + 2] intramolecular Diels-Alder cycloaddition of the activated dienophile and conjugated diene containing intermediate furnished bridged polycyclic heterocycles with high diastereoselectivity. Formation of four new rings, five new covalent bonds, and five new chiral centers with excellent stereoselectivity is the key feature of this strategy. The diastereoselective formation of product was attributed to intramolecular chirality transfer through a chiral amino acid. The stereoselective outcome of this tandem reaction was confirmed by X-ray crystallographic studies. The developed synthetic strategy was also explored on a soluble polymer support to incorporate the advantage of rapid synthesis and a high-throughput workup process toward the development of a green synthetic protocol for polycyclic alkaloids.

Direct Olefination at the C-4 Position of Tryptophan via C–H Activation: Application to Biomimetic Synthesis of Clavicipitic Acid

The first Pd-catalyzed method for direct olefination at the C4 position of tryptophan derivatives has been developed via C-H activation to prepare 4-substituted tryptophans, which could be used for the synthesis of many hemiterpenoid indole alkaloids. This reaction proceeds under mild reaction conditions and with exceptional tolerance to a variety of functional groups. Furthermore, the efficiency of this method is demonstrated by the rapid and biomimetic synthesis of clavicipitic acid.

Silver-Catalyzed Carboazidation of Arylacrylamides

A novel and inexpensive method of nontoxic, silver-salt-catalyzed carboazidation of arylacrylamides to afford corresponding azide oxindoles is reported. This reaction system exhibits great functional group tolerance. All products form a crucial skeleton for the synthesis of various indole alkaloids.

SYNTHESIS OF SOME ALKALOIDS USING THE ALLYL DERIVATIVES OF BORON

Data on the application of the allylic derivatives of boron for the synthesis of piperidine, indolizine, pyrrolizidine, and indole alkaloids are reviewed. Authors: Yu. N. Bubnov and E. V. Klimkina. English Translation in Chemistry of Heterocyclic Compounds , 1999, 35 (8), pp 888-899 http://link.springer.com/article/10.1007/BF02252156

Diastereoselective construction of continuous all-carbon quaternary centers via intramolecular oxidative coupling reaction

Construction of continuous all-carbon quaternary centers via intramolecular oxidative coupling was described. Intramolecular oxidative coupling of bisoxindole linked by diol derived from d-tartaric acid diastereoselectively produced C1 or C2 isomers of the annulation product. The selectivity was realized by judiciously choosing base and solvent employed in the reaction. As key intermediates for the synthesis of cyclotryptamine alkaloids, the resulting bisoxindole should be applicable to the total syntheses of complex indole alkaloids with continuous all-carbon quaternary centers.

MARINE INDOLE ALKALOIDS CONTAINING AN 1-(INDOL-3-YL)ETHANE-1,2-DIAMINE FRAGMENT

Data on the isolation from natural sources, biological properties, and synthesis of indole alkaloids containing an 1-(indol-3-yl)ethane-1,2-diamine fragment are reviewed. Authors: N. E. Golantsov, A. A. Festa, A. V. Karchava, and M. A. Yurovskaya English Translation in Chemistry of Heterocyclic Compounds, 2013, 49 (2), pp 203-225 http://link.springer.com/article/10.1007/s10593-013-1238-9

Marine indole alkaloids containing an 1-(indol-3-yl)ethane-1,2-diamine fragment (Review)

Data on the isolation from natural sources, biological properties, and synthesis of indole alkaloids containing an 1-(indol-3-yl)ethane-1,2-diamine fragment are reviewed.

Synthesis of cleavamine-type indole alkaloids and their 5-nor derivatives by a ring-closing metathesis–vinyl halide Heck cyclization strategy

An indole-templated RCM has been used to assemble the central medium-sized rings of the indole upper-half of vinorelbine and the cleavamine-type alkaloids. From these key intermediates, the bridged tetracyclic framework of the alkaloids is completed with the insertion of a 2-ethylpropeno unit, by N-alkylation followed by a challenging endocyclic vinyl halide Heck cyclization. The usefulness of the approach is illustrated with the synthesis of (±)-cleavamine and (±)-dihydrocleavamine.

Oxidative Coupling Strategy in the Total Syntheses of Complex Indole Alkaloids

* E-mail: qinyong@cqu.edu.cn; Tel.: 0086-023-65678456; Fax: 0086-023-65678456 Received December 11, 2012; published January 4, 2013. Project supported by National Basic Research Program of China (973 program, No. 2010CB833200), the Natural Science Foundation of China (Nos. 21202209, 21132006), the Fundamental Research Funds for the Central Universities (CQDXWL-2012-131), and the Natural Science Foundation Project of CQ CSTC (No. cstc2012jjA10087). 项目受科技部 973 计划(No. 2010CB833200)、国家自然科学基金(Nos. 21202209, 21132006)、中央高校基本科研业务费(CQDXWL-2012-131)以及重庆 市自然科学基金(No. cstc2012jjA10087)资助.

Synthesis of Indole Compounds Using Multifunctional Synthons

This review describes a synthesis of indole compounds using multifunctional synthons. The multifunctional synthons, trienes and gramines, were respectively synthesized using Pd-catalyzed tandem cyclization/cross-coupling reaction of indolylborate with vinyl bromide, and reaction of indolylcuprate with iminium chloride. As an application of the multifunctional synthons to the indole alkaloids synthesis, we accomplished the total synthesis of ellipticine, 9-methoxyellipticine, 9-hydroxyellipticine, tetrahydroellipticine, μ-alkaloid B, μ-alkaloid D, calothrixin A, calothrixin B, tubifoline, and yuehchukene. We have also developed 6π-electrocyclization of hexatrienes catalyzed by Cu(I) trifluoromethanesulfonate toluene complexe, which is unprecedented.

Quick access to the core of mersicarpine through an SNAr strategy

A quick access to the core of dihydroindole alkaloid mersicarpine was developed based on straightforward transformations from readily available and inexpensive starting materials. The synthetic route features an aldol reaction, a Beckmann rearrangement for the synthesis of the δ-lactam, an intramolecular SNAr strategy for indoxyl heterocycle formation, and in situ autoxidation of indoxyl intermediate. The new strategy offered an alternative approach for the formation of an oxidized indoxyl moiety, which could potentially have a wider application in the total synthesis of indole alkaloids containing apparent or masked indoxyl moieties.

Enantioselective Cyclopropanation of Indoles: Construction of All-Carbon Quaternary Stereocenters

The first enantioselective copper-catalyzed cyclopropanation of N-acyl indoles is described. Using carbohydrate-based bis(oxazoline) ligands (glucoBox), the products were obtained in up to 72% ee. Cyclopropanation of N-Boc 3-methyl indole yielded a product with an all-carbon quaternary stereocenter, which is a valuable building block for the synthesis of indole alkaloids: Deprotection and rearrangement gave a tricyclic hemiaminal ester in 96% ee, which was subsequently employed as a key intermediate for the synthesis of (-)-desoxyeseroline.

ChemInform Abstract: Diastereoselective Synthesis of C3‐Quaternary Indolenines Using α,β‐Unsaturated N‐Aryl Ketonitrones and Activated Alkynes.

AbstractTitle compounds, obtained by reaction of readily available α,β‐unsaturated N‐aryl ketonitrones and activated alkynes, are potentially applicable to the synthesis of complex indole alkaloids and related compounds.

Indole Alkaloids Synthesis via a Selective Cyclization of Aminocyclopropanes

The continuous progress in medicinal chemistry requires more versatile synthetic strategies for the generation of large libraries of active compounds and their analogues. As a result, the research for new effective cyclization and cycloaddition reactions is an essential task in organic chemistry. In 2008 we developed the first catalytic formal homo-Nazarov reaction starting from activated cyclopropanes. Herein we report the extension of the catalytic formal homo-Nazarov cyclization to aminocyclopropanes. Highly diastereoselective cyclizations were obtained via an acyliminium intermediate generated through opening of the cyclopropane. An excellent control over the regioselectivity of either the C-C or C-N cyclization in the case of free indoles as nucleophilic partners was achieved. The utility of the developed methodology was demonstrated by the generation of the polycyclic scaffolds of Aspidosperma and Gonioma natural products starting from a common intermediate. Based on this method, a formal total synthesis of the alkaloid aspidospermidine and the total synthesis of the alkaloid goniomitine are presented. Finally, the scope and limitations of our methodology are discussed on an extended range of vinyl-cyclopropyl ketones with cyclic or acyclic carbamates, as well as ethers as donor groups on the cyclopropane.

Diastereoselective Synthesis of C3‐Quaternary Indolenines Using α,β‐Unsaturated N‐Aryl Ketonitrones and Activated Alkynes

Title compounds, obtained by reaction of readily available α,β-unsaturated N-aryl ketonitrones and activated alkynes, are potentially applicable to the synthesis of complex indole alkaloids and related compounds.

Diastereoselective Synthesis of C3-Quaternary Indolenines Using α,β-UnsaturatedN-Aryl Ketonitrones and Activated Alkynes

Title compounds, obtained by reaction of readily available α,β-unsaturated N-aryl ketonitrones and activated alkynes, are potentially applicable to the synthesis of complex indole alkaloids and related compounds.

A Concise and Versatile Double‐Cyclization Strategy for the Highly Stereoselective Synthesis and Arylative Dimerization of Aspidosperma Alkaloids

The monoterpene indole alkaloids represent the largest family of alkaloid natural products whose more than 2,000 members display a broad range of chemical diversity and potent biological activity.1 The structural challenges presented by this family have long been a source of interest, resulting in the development of a variety of inventive synthetic strategies to access various family members. The biogenetically related natural alkaloids N-methylaspidospermidine (1), N-methylquebrachamine (2), and tabernaebovine (3) represent the aspidosperma subfamily of monoterpene indole alkaloids (Figure 1).2-5 The dimeric alkaloid 3, isolated from Tabernaemontana bovina in 1998,2e has a fascinating molecular constitution that exhibits a unique C2–C15′ linkage between two pentacyclic aspidosperma skeletons. While elegant strategies for synthesis of other dimeric monoterpene indole alkaloids have been reported,5 no synthetic solution to the distinctive C2–C15′ union present in 3 exists. As an outgrowth of our laboratory's studies concerning electrophilic amide activation,6 we report a concise and convergent strategy for the enantioselective synthesis of alkaloids (–)-1, (+)-2, and dimeric (+)-dideepoxytabernaebovine (4).

A Concise and Versatile Double‐Cyclization Strategy for the Highly Stereoselective Synthesis and Arylative Dimerization of Aspidosperma Alkaloids

The monoterpene indole alkaloids represent the largest family of alkaloid natural products whose more than 2,000 members display a broad range of chemical diversity and potent biological activity.1 The structural challenges presented by this family have long been a source of interest, resulting in the development of a variety of inventive synthetic strategies to access various family members. The biogenetically related natural alkaloids N-methylaspidospermidine (1), N-methylquebrachamine (2), and tabernaebovine (3) represent the aspidosperma subfamily of monoterpene indole alkaloids (Figure 1).2-5 The dimeric alkaloid 3, isolated from Tabernaemontana bovina in 1998,2e has a fascinating molecular constitution that exhibits a unique C2–C15′ linkage between two pentacyclic aspidosperma skeletons. While elegant strategies for synthesis of other dimeric monoterpene indole alkaloids have been reported,5 no synthetic solution to the distinctive C2–C15′ union present in 3 exists. As an outgrowth of our laboratory's studies concerning electrophilic amide activation,6 we report a concise and convergent strategy for the enantioselective synthesis of alkaloids (–)-1, (+)-2, and dimeric (+)-dideepoxytabernaebovine (4).