Dataset Information

Sterically Controlled C-H Olefination of Heteroarenes.

ABSTRACT: The regioselective functionalization of heteroarenes is a highly attractive synthetic target due to the prevalence of multiply substituted heteroarenes in nature and bioactive compounds. Some substitution patterns remain challenging: While highly efficient methods for the C2-selective olefination of 3-substituted five-membered heteroarenes have been reported, analogous methods to access the 5-olefinated products have remained limited by poor regioselectivities and/or the requirement to use an excess of the valuable heteroarene starting material. Herein we report a sterically controlled C-H olefination using heteroarenes as the limiting reagent. The method enables the highly C5-selective olefination of a wide range of heteroarenes and is shown to be useful in the context of late-stage functionalization.

SUBMITTER: Chen H

PROVIDER: S-EPMC7384109 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Sterically Controlled C-H Olefination of Heteroarenes.

Chen Hao H Farizyan Mirxan M Ghiringhelli Francesca F van Gemmeren Manuel M

Angewandte Chemie (International ed. in English) 20200514 29

The regioselective functionalization of heteroarenes is a highly attractive synthetic target due to the prevalence of multiply substituted heteroarenes in nature and bioactive compounds. Some substitution patterns remain challenging: While highly efficient methods for the C2-selective olefination of 3-substituted five-membered heteroarenes have been reported, analogous methods to access the 5-olefinated products have remained limited by poor regioselectivities and/or the requirement to use an ex ...[more]

PMID: 32267990

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Project description:BackgroundRecently we reported a nanocontainer based reduction triggered release system through an engineered transmembrane channel (FhuA Delta1-160; Onaca et al., 2008). Compound fluxes within the FhuA Delta1-160 channel protein are controlled sterically through labeled lysine residues (label: 3-(2-pyridyldithio)propionic-acid-N-hydroxysuccinimide-ester). Quantifying the sterical contribution of each labeled lysine would open up an opportunity for designing compound specific drug release systems.ResultsIn total, 12 FhuA Delta1-160 variants were generated to gain insights on sterically controlled compound fluxes: Subset A) six FhuA Delta1-160 variants in which one of the six lysines in the interior of FhuA Delta1-160 was substituted to alanine and Subset B) six FhuA Delta1-160 variants in which only one lysine inside the barrel was not changed to alanine. Translocation efficiencies were quantified with the colorimetric TMB (3,3',5,5'-tetramethylbenzidine) detection system employing horseradish peroxidase (HRP). Investigation of the six subset A variants identified position K556A as sterically important. The K556A substitution increases TMB diffusion from 15 to 97 [nM]/s and reaches nearly the TMB diffusion value of the unlabeled FhuA Delta1-160 (102 [nM]/s). The prominent role of position K556 is confirmed by the corresponding subset B variant which contains only the K556 lysine in the interior of the barrel. Pyridyl labeling of K556 reduces TMB translocation to 16 [nM]/s reaching nearly background levels in liposomes (13 [nM]/s). A first B-factor analysis based on MD simulations confirmed that position K556 is the least fluctuating lysine among the six in the channel interior of FhuA Delta1-160 and therefore well suited for controlling compound fluxes through steric hindrance.ConclusionsA FhuA Delta1-160 based reduction triggered release system has been shown to control the compound flux by the presence of only one inner channel sterical hindrance based on 3-(2-pyridyldithio)propionic-acid labeling (amino acid position K556). As a consequence, the release kinetic can be modulated by introducing an opportune number of hindrances. The FhuA Delta1-160 channel embedded in liposomes can be advanced to a universal and compound independent release system which allows a size selective compound release through rationally re-engineered channels.

Dataset Information

Sterically Controlled C-H Olefination of Heteroarenes.

Publications

Sterically Controlled C-H Olefination of Heteroarenes.

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