Electrophilic substitution in indoles—II

Jackson, Anthony H.; Smith, Alice Emily

doi:10.1016/0040-4020(68)89038-6

Cited by 92 publications

(27 citation statements)

References 24 publications

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“…[87] iminium ion can occur either directly at position 2 or at position 3 of the indole to form a spiroindolenine. [105] Evidence for the involvement of the spiro intermediate was obtained by employing isotopic labeling. [106] The study demonstrated that the formation of the spiroindolenine is fast and reversible, and that the formation of the pentahydrob-carboline carbonium ion is the rate-limiting step of the reaction.…”

Section: The Mechanism Of the Non-enzymatic Pictetspengler Reactionmentioning

confidence: 99%

The Pictet–Spengler Reaction in Nature and in Organic Chemistry

et al. 2011

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Alkaloids are an important class of natural products that are widely distributed in nature and produced by a large variety of organisms. They have a wide spectrum of biological activity and for many years were used in folk medicine. These days, alkaloids also have numerous applications in medicine as therapeutic agents. The importance of these natural products in inspiring drug discovery programs is proven and, therefore, their continued synthesis is of significant interest. The condensation discovered by Pictet and Spengler is the most important method for the synthesis of alkaloid scaffolds. The power of this synthesis method has been convincingly proven in the construction of stereochemicaly and structurally complex alkaloids.

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Section: The Mechanism Of the Non-enzymatic Pictetspengler Reactionmentioning

confidence: 99%

The Pictet–Spengler Reaction in Nature and in Organic Chemistry

et al. 2011

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“…Since the aromaticity is broken during the cyclization step ( Figure 1, step 4), it might be reasonable to assume that cyclization would be rate controlling 42 and that no primary isotope effect would be observed with [2-2 H]-tryptamine 1b. While it is true that some nonenzymatic electrophilic aromatic substitution reactions do exhibit small KIE values, there are in fact many examples that exhibit primary KIE values for the replaced proton at the site of electrophilic aromatic substitution.…”

Section: Enzymatic Kinetic Isotope Effect: Rate-controlling Stepmentioning

confidence: 99%

Strictosidine Synthase: Mechanism of a Pictet−Spengler Catalyzing Enzyme

et al. 2007

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The Pictet-Spengler reaction, which yields either a β-carboline or a tetrahydroquinoline product from an aromatic amine and an aldehyde, is widely utilized in plant alkaloid biosynthesis. Here we deconvolute the role that the biosynthetic enzyme strictosidine synthase plays in catalyzing the stereoselective synthesis of a β-carboline product. Notably, the rate-controlling step of the enzyme mechanism, as identified by the appearance of a primary kinetic isotope effect (KIE), is the rearomatization of a positively charged intermediate. The KIE of a nonenzymatic Pictet-Spengler reaction indicates that rearomatization is also rate-controlling in solution, suggesting that the enzyme does not significantly change the mechanism of the reaction. Additionally, the pH dependence of the solution and enzymatic reactions provides evidence for a sequence of acid-base catalysis steps that catalyze the Pictet-Spengler reaction. An additional acid-catalyzed step, most likely protonation of a carbinolamine intermediate, is also significantly rate controlling. We propose that this step is efficiently catalyzed by the enzyme. Structural analysis of a bisubstrate inhibitor bound to the enzyme suggests that the active site is exquisitely tuned to correctly orient the iminium intermediate for productive cyclization to form the diastereoselective product. Furthermore, ab initio calculations suggest the structures of possible productive transition states involved in the mechanism. Importantly, these calculations suggest that a spiroindolenine intermediate, often invoked in the Pictet-Spengler mechanism, does not occur. A detailed mechanism for enzymatic catalysis of the β-carboline product is proposed from these data.

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“…For the former case, it is reported that strong electrophiles prefer to perform the substitution reaction at the 2-position on 3-alkylindoles. [22,23] On the other hand, both the PictetϪSpengler type cyclization to form tetrahydro-β-carbolines [24] and the Plancher rearrangement of 3,3-dialkyl-3H-indolinium ions to give 2,3-dialkylindoles are believed to occur through migration of an alkyl moiety at the level of an indoline intermediate. [25,26] Also, tetrahydrocarbazoles are reported to rearrange to 2,2-spirocycloalkyl-3-oxoindole derivatives under photo-oxygenation conditions.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Cycloalkanoindoles by an Unusual DAST‐Triggered Rearrangement Reaction

et al. 2004

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A series of 1,1‐bis(indol‐3‐yl) and 1‐(indol‐2‐yl)‐1‐(indol‐3‐yl)‐ψ‐hydroxyalkanes, prepared from the corresponding indole derivatives and suitable hydroxyaldehydes via routine coupling reactions, were treated with DAST (diethylaminosulfur trifluoride) under mild conditions, to generate a small library of cycloalkanoindoles. Irrespective of the substitution pattern, i.e. whether they are symmetrical or unsymmetrical derivatives, the same mixture of products is produced, in which the tetrahydro‐1H‐carbazole and hexahydrocyclohepta[b]indole scaffolds are substituted by a indol‐3‐yl nucleus on one of the two α‐carbon atoms of the cycloalkane moieties. Thus, speculations on the reaction mechanism with the prediction of a common reaction intermediate are presented. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

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Electrophilic substitution in indoles—II

Cited by 92 publications

References 24 publications

The Pictet–Spengler Reaction in Nature and in Organic Chemistry

The Pictet–Spengler Reaction in Nature and in Organic Chemistry

Strictosidine Synthase: Mechanism of a Pictet−Spengler Catalyzing Enzyme

Synthesis of Cycloalkanoindoles by an Unusual DAST‐Triggered Rearrangement Reaction

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