Dataset Information

Macrocyclization of peptidoarylacetamides with self-assembly properties through late-stage palladium-catalyzed C(sp²)?H olefination.

ABSTRACT: Peptide macrocycles often display diverse bioactivities and self-assembly properties, which lead to a variety of applications in medicinal and material sciences. Transition metal-catalyzed C?H activations are emerging strategies for site-selective functionalization of amino acids and peptides, as well as the construction of cyclic peptides. Here, we report the development of a peptide-directed method for the macrocyclization of peptidoarylacetamides by Pd(II)-catalyzed late-stage C(sp²)?H olefination. In this protocol, peptide backbones act as internal directing groups and enable facile preparation of diverse cyclic peptides that are difficult to synthesize by conventional macrolactamization. Furthermore, we show that the incorporation of aryl-alkene cross-link in the backbone constrains cyclic peptides into conformations for self-assembly.

SUBMITTER: Tan J

PROVIDER: S-EPMC6408153 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Macrocyclization of peptidoarylacetamides with self-assembly properties through late-stage palladium-catalyzed C(sp<sup>2</sup>)▬H olefination.

Tan Jiantao J Wu Jie J Liu Shu S Yao Hequan H Wang Huan H

Science advances 20190308 3

Peptide macrocycles often display diverse bioactivities and self-assembly properties, which lead to a variety of applications in medicinal and material sciences. Transition metal-catalyzed C▬H activations are emerging strategies for site-selective functionalization of amino acids and peptides, as well as the construction of cyclic peptides. Here, we report the development of a peptide-directed method for the macrocyclization of peptidoarylacetamides by Pd(II)-catalyzed late-stage C(sp<sup>2</sup ...[more]

PMID: 30873434

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Project description:Frequently referred to as the 'magic methyl effect', the installation of methyl groups-especially adjacent (α) to heteroatoms-has been shown to dramatically increase the potency of biologically active molecules1-3. However, existing methylation methods show limited scope and have not been demonstrated in complex settings1. Here we report a regioselective and chemoselective oxidative C(sp3)-H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site-selective and chemoselective C-H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst, Mn(CF3PDP), at low loading (at a substrate/catalyst ratio of 200) affords targeted C-H hydroxylation on heterocyclic cores, while preserving electron-neutral and electron-rich aryls. Fluorine- or Lewis-acid-assisted formation of reactive iminium or oxonium intermediates enables the use of a mildly nucleophilic organoaluminium methylating reagent that preserves other electrophilic functionalities on the substrate. We show this late-stage C(sp3)-H methylation on 41 substrates housing 16 different medicinally important cores that include electron-rich aryls, heterocycles, carbonyls and amines. Eighteen pharmacologically relevant molecules with competing sites-including drugs (for example, tedizolid) and natural products-are methylated site-selectively at the most electron rich, least sterically hindered position. We demonstrate the syntheses of two magic methyl substrates-an inverse agonist for the nuclear receptor RORc and an antagonist of the sphingosine-1-phosphate receptor-1-via late-stage methylation from the drug or its advanced precursor. We also show a remote methylation of the B-ring carbocycle of an abiraterone analogue. The ability to methylate such complex molecules at late stages will reduce synthetic effort and thereby expedite broader exploration of the magic methyl effect in pursuit of new small-molecule therapeutics and chemical probes.

Dataset Information

Macrocyclization of peptidoarylacetamides with self-assembly properties through late-stage palladium-catalyzed C(sp²)?H olefination.

Publications

Macrocyclization of peptidoarylacetamides with self-assembly properties through late-stage palladium-catalyzed C(sp<sup>2</sup>)▬H olefination.

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Dataset Information

Macrocyclization of peptidoarylacetamides with self-assembly properties through late-stage palladium-catalyzed C(sp2)?H olefination.

Publications

Macrocyclization of peptidoarylacetamides with self-assembly properties through late-stage palladium-catalyzed C(sp<sup>2</sup>)▬H olefination.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Macrocyclization of peptidoarylacetamides with self-assembly properties through late-stage palladium-catalyzed C(sp²)?H olefination.