Rearrangements in the mechanisms of the indole alkaloid prenyltransferases

Mahmoodi, Niusha; Qi, Qian; Luk, Louis Y. P.; Tanner, Martin E.

doi:10.1351/pac-con-13-02-02

Cited by 12 publications

(8 citation statements)

References 63 publications

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“…Importantly, even on a 10 g scale reaction, we could not obtain any C4-prenylated compound. These results support a Cope rearrangement mechanism for the generation of C4-prenylated indoles from C3-reverse-prenylated indoles in biosynthesis, as proposed by Tanner and co-workers …”

Section: Resultsmentioning

confidence: 79%

Bioinspired Indole Prenylation Reactions in Water

2017

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Isoprene units derived from dimethylallyl diphosphate (DMAPP) are an important motif in many natural products including terpenoids, carotenoids, steroids, and natural rubber. Understanding the chemical characteristics of DMAPP is an important topic in natural products chemistry, organic chemistry, and biochemistry. We have developed a direct bioinspired indole prenylation reaction using DMAPP or its equivalents as the electrophile in homogeneous aqueous acidic media in the absence of enzyme to provide prenylated indole products. After establishing the bioinspired indole prenylation reaction, this was then used to achieve the synthesis of a series of natural products, namely, N-prenylcyclo-l-tryptophyl-l-proline, tryprostatins, rhinocladins, and terezine D.

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Section: Resultsmentioning

confidence: 79%

Bioinspired Indole Prenylation Reactions in Water

2017

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“… 21 Few select mutants of wild-type indole prenyltransferases have enabled interesting mechanistic alternatives to this general paradigm to involve Cope rearrangements of alternative intermediates. 22 Similar to DMATS, we envisioned a general-acid–base-promoted regioselective isoprenylation on the Trp core.…”

Section: Resultsmentioning

confidence: 99%

Bioinspired Brønsted Acid-Promoted Regioselective Tryptophan Isoprenylations

et al. 2021

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Tryptophan-containing isoprenoid indole alkaloid natural products are well known for their intricate structural architectures and significant biological activities. Nature employs dimethylallyl tryptophan synthases (DMATSs) or aromatic indole prenyltransferases (iPTs) to catalyze regio- and stereoselective prenylation of l -Trp. Regioselective synthetic routes that isoprenylate cyclo -Trp-Trp in a 2,5-diketopiperazine (DKP) core, in a desymmetrizing manner, are nonexistent and are highly desirable. Herein, we present an elaborate report on Brønsted acid-promoted regioselective tryptophan isoprenylation strategy, applicable to both the monomeric amino acid and its dimeric l -Trp DKP. This report outlines a method that regio- and stereoselectively increases sp 3 centers of a privileged bioactive core. We report on conditions involving screening of Brønsted acids, their conjugate base as salt, solvent, temperature, and various substrates with diverse side chains. Furthermore, we extensively delineate effects on regio- and stereoselection of isoprenylation and their stereochemical confirmation via NMR experiments. Regioselectively, the C3-position undergoes normal -isoprenylation or benzylation and forms exo -ring-fused pyrroloindolines selectively. Through appropriate prenyl group migrations, we report access to the bioactive tryprostatin alkaloids, and by C3- normal -farnesylation, we access anticancer drimentines as direct targets of this method. The optimized strategy affords iso -tryprostatin B-type products and predrimentine C with 58 and 55% yields, respectively. The current work has several similarities to biosynthesis, such as—reactions can be performed on unprotected substrates, conditions that enable Brønsted acid promotion, and they are easy to perform under ambient conditions, without the need for stoichiometric levels of any transition metal or expensive ligands.

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“…Apart from the structural analysis, several observations have led to the speculation that a C-3 prenylation occurs rst, and a rearrangement subsequently produces tryprostatin B. 31,63 The rst such observation, involved the mutation of Gly115 into a threonine in an attempt to revert the active site structure closer to that of 4-DMATS. 62 Surprisingly, the Gly115Thr mutant produced the reverse C-3 prenylated species 17 (Fig.…”

Section: C-2 Prenylation: Normal and Reversementioning

confidence: 99%

Mechanistic studies on the indole prenyltransferases

2015

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Covering: up to 2014. Prenylated indole alkaloids comprise a large and structurally diverse family of natural products that often display potent biological activities. In recent years a large family of prenyltransferases that install prenyl groups onto the indole core have been discovered. While the vast majority of these enzymes are evolutionarily related and share a common protein fold, they are remarkably versatile in their ability to catalyze reverse and normal prenylations at all positions on the indole ring. This highlight article will focus on recent studies of the mechanisms utilized by indole prenyltransferases. While all of the prenylation reactions may follow a direct electrophilic aromatic substitution mechanism, studies of structure and reactivity suggest that in some cases prenylation may first occur at the nucleophilic C-3 position, and subsequent rearrangements then generate the final product.

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Rearrangements in the mechanisms of the indole alkaloid prenyltransferases

Cited by 12 publications

References 63 publications

Bioinspired Indole Prenylation Reactions in Water

Bioinspired Indole Prenylation Reactions in Water

Bioinspired Brønsted Acid-Promoted Regioselective Tryptophan Isoprenylations

Mechanistic studies on the indole prenyltransferases

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