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Late-stage C(sp²)-H and C(sp³)-H glycosylation of C-aryl/alkyl glycopeptides: mechanistic insights and fluorescence labeling.

ABSTRACT: C(sp³)-H and C(sp²)-H glycosylations of structurally complex amino acids and peptides were accomplished through the assistance of triazole peptide-isosteres. The palladium-catalyzed peptide-saccharide conjugation provided modular access to structurally complex C-alkyl glycoamino acids, glycopeptides and C-aryl glycosides, while enabling the assembly of fluorescent-labeled glycoamino acids. The C-H activation approach represents an expedient and efficient strategy for peptide late-stage diversification in a programmable as well as chemo-, regio-, and diastereo-selective fashion.

SUBMITTER: Wu J

PROVIDER: S-EPMC8152807 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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Late-stage C(sp2)-H and C(sp3)-H glycosylation of C-aryl/alkyl glycopeptides: mechanistic insights and fluorescence labeling.

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Late-stage C(sp²)-H and C(sp³)-H glycosylation of C-aryl/alkyl glycopeptides: mechanistic insights and fluorescence labeling.