Isolation and synthesis of biologically active carbazole alkaloids

140 years ago Adolf von Baeyer proposed the structure of a heteroaromatic compound which revolutionized organic and medical chemistry: indole. After more than a century, indole itself and the complexity of naturally occurring indole derivatives continue to inspire and influence developments in synthetic chemistry. In particular, the ubiquitous presence of indole rings in pharmaceuticals, agrochemicals, and functional materials are testament to the ever increasing interest in the design of mild and efficient synthetic routes to functionalized indole derivatives. This Review emphasizes the achievements in the selective catalytic functionalization of indoles (C-C bond-forming processes) over the last four years.

Catalytic Functionalization of Indoles in a New Dimension

Within 14 years of the seminal experiments of J. D. Roberts
leading to the first proposal of the structure of benzyne (1), synthetic organic chemists recognized the potential to exploit this highly reactive intermediate (and its substituted variants) in the total synthesis of natural products. More specifically, it was recognized that arynes offered the strategic advantage of rapidly functionalizing an aromatic ring by forming multiple carbon− carbon or carbon−heteroatom bonds in a single operation, often in a regioselective manner. Initially, the scope of synthetic
applications was somewhat limited by the harsh conditions
required to produce the aryne species. Many of these methods required strong bases, such as n-BuLi, or high temperatures (Scheme 1). However, with the development of milder methods for the generation of arynes came increased interest in employing them in the synthesis of more complex polycyclic systems. Most recently, the use of o-silyl aryl triflates as aryne precursors has allowed generation of the reactive intermediate under almost neutral conditions.
To date, over 75 individual natural products have been
prepared using arynes to generate key synthetic intermediates. Herein are recounted the reports of total syntheses that utilize arynes in ways that build complexity or introduce motifs essential to the completion of their targets. The methods by which the authors featured in this review accomplish this task reflect the versatility of arynes as reactive intermediates for synthesis (Scheme 2). For the purposes of organization, the syntheses are divided into subgroups on the basis of the type of aryne transformation: (i) nucleophilic additions or multicomponent reactions, (ii) σ-bond insertion reactions, (iii) [4 + 2]- and [2 + 2]-cycloaddition strategies, and (iv) metal-catalyzed aryne reactions.

A Comprehensive History of Arynes in Natural Product Total Synthesis

Vor 140 Jahren schlug Adolf von Baeyer die Struktur fur eine heteroaromatische Verbindung vor, die die organische und medizinische Chemie nachhaltig veranderte: Indol. Nach mehr als einem Jahrhundert beeinflussen Indol selbst, ebenso wie naturliche Indolderivate, weitgehend die Entwicklung in der Synthesechemie. Vor allem die allgegenwartige Prasenz des Indolrings in pharmazeutischen und agrochemischen Verbindungen sowie seine Verwendung in der Materialchemie sind ausschlaggebend fur das anhaltende Interesse an der Entwicklung von neuen milden und effizienten Synthesestrategien fur funktionalisierte Indolderivate. Dieser Aufsatz fasst die Fortschritte hinsichtlich der selektiven katalytischen Funktionalisierung von Indolen (durch C-C-Kupplung) aus den vergangenen vier Jahre zusammen.

Katalytische Funktionalisierung von Indolen in einer neuen Dimension

The union of sodium borohydride and carboxylic acids has yielded an amazingly versatile and efficient set of reducing reagents. These acyloxyborohydride species reduce and N-alkylate indoles, quinolines, isoquinolines, related heterocycles, imines, enamines, oximes, enamides, and similar functional groups. They reduce amides and nitriles, aryl alcohols and ketones, aldehydes in the presence of ketones, and β-hydroxyketones to 1,3-diols stereoselectively. This reagent is also extraordinarily useful for the N-alkylation of primary and secondary amines with aldehydes and ketones in a novel reductive amination process.

Sodium borohydride in carboxylic acid media: a phenomenal reduction system

Synthesis and Diels-Alder reactions of 1,3-dimethyl-4-(phenylsulfonyl)-4H-furo[3,4-b]indole. A new annulation strategy for the construction of ellipticine and isoellipticine

A general and efficient synthesis of these 6H-pyrido[4,3-b]carbazole ring system is described, in which the key steps are (1) regioselective acylation of a 2-lithiol-(phenysulfonyl)indole (14) with 3,4-pyridinedicarboxylic acid anhydride (10), (2) cyclization of the deprotected keto acid 17 to keto lactam 19 with acetic anhydride, and (3) the addition of methyllithium to give, after reduction of the intermediate diol 23 into sodium borohydride, the target ring system

A versatile and efficient construction of the 6H-pyrido[4,3-b]carbazole ring system. Syntheses of the antitumor alkaloids ellipticine, 9-methoxyellipticine, and olivacine, and their analogs

Novel Indole Chemistry in the Synthesis of Heterocycles

The Strychnos dinklagei alkaloid and ellipticine-metabolite 13-oxoellipticine (8) has been synthesized from indole (4) in seven steps and 38% yield.

Judy A. Obaza-Nutaitis

Papers

Synthesis and Diels-Alder reactions of 1,3-dimethyl-4-(phenylsulfonyl)-4H-furo[3,4-b]indole. A new annulation strategy for the construction of ellipticine and isoellipticine

A versatile and efficient construction of the 6H-pyrido[4,3-b]carbazole ring system. Syntheses of the antitumor alkaloids ellipticine, 9-methoxyellipticine, and olivacine, and their analogs

Novel Indole Chemistry in the Synthesis of Heterocycles

Synthesis of 13-oxoellipticine.

Synthesis and Cytotoxicity of Novel Bis-Ellipticines and Bis-Isoellipticines