Browse
Submit Data
Databases
API
Help

Dataset Information

32 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Tandem Friedel‐Crafts‐Alkylation‐Enantioselective‐Protonation by Artificial Enzyme Iminium Catalysis

ABSTRACT: Abstract The incorporation of organocatalysts into protein scaffolds holds the promise of overcoming some of the limitations of this powerful catalytic approach. Previously, we showed that incorporation of the non‐canonical amino acid para‐aminophenylalanine into the non‐enzymatic protein scaffold LmrR forms a proficient and enantioselective artificial enzyme (LmrR_pAF) for the Friedel‐Crafts alkylation of indoles with enals. The unnatural aniline side‐chain is directly involved in catalysis, operating via a well‐known organocatalytic iminium‐based mechanism. In this study, we show that LmrR_pAF can enantioselectively form tertiary carbon centres not only during C−C bond formation, but also by enantioselective protonation, delivering a proton to one face of a prochiral enamine intermediate. The importance of various side‐chains in the pocket of LmrR is distinct from the Friedel‐Crafts reaction without enantioselective protonation, and two particularly important residues were probed by exhaustive mutagenesis. BioTrans2021: We created an artificial enzyme consisting of a non‐enzymatic protein (LmrR) containing an unnatural catalytic residue with an aniline side chain (LmrR_pAF). Building on our previous work showing how LmrR_pAF can catalyse a Friedel‐Crafts alkylation of indoles, here we show that when α‐substituted acroleins are applied as substrates the protein scaffold enables enantioselective protonation with good selectivity.

SUBMITTER: Leveson‐Gower R

PROVIDER: S-EPMC9313897 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Unlocking Iminium Catalysis in Artificial Enzymes to Create a Friedel-Crafts Alkylase.

Project description:The construction and engineering of artificial enzymes consisting of abiological catalytic moieties incorporated into protein scaffolds is a promising strategy to realize non-natural mechanisms in biocatalysis. Here, we show that incorporation of the noncanonical amino acid para-aminophenylalanine (pAF) into the nonenzymatic protein scaffold LmrR creates a proficient and stereoselective artificial enzyme (LmrR_pAF) for the vinylogous Friedel-Crafts alkylation between α,β-unsaturated aldehydes and indoles. pAF acts as a catalytic residue, activating enal substrates toward conjugate addition via the formation of intermediate iminium ion species, while the protein scaffold provides rate acceleration and stereoinduction. Improved LmrR_pAF variants were identified by low-throughput directed evolution advised by alanine-scanning to obtain a triple mutant that provided higher yields and enantioselectivities for a range of aliphatic enals and substituted indoles. Analysis of Michaelis-Menten kinetics of LmrR_pAF and evolved mutants reveals that different activities emerge via evolutionary pathways that diverge from one another and specialize catalytic reactivity. Translating this iminium-based catalytic mechanism into an enzymatic context will enable many more biocatalytic transformations inspired by organocatalysis.

| S-EPMC8218303 | biostudies-literature

Synergistic Catalysis of Tandem Michael Addition/Enantioselective Protonation Reactions by an Artificial Enzyme.

Project description:Enantioselective protonation is conceptually one of the most attractive methods to generate an α-chiral center. However, enantioselective protonation presents major challenges, especially in water. Herein, we report a tandem Michael addition/enantioselective protonation reaction catalyzed by an artificial enzyme employing two abiological catalytic sites in a synergistic fashion: a genetically encoded noncanonical p-aminophenylalanine residue and a Lewis acid Cu(II) complex. The exquisite stereocontrol achieved in the protonation of the transient enamine intermediate is illustrated by up to >20:1 dr and >99% ee of the product. These results illustrate the potential of exploiting synergistic catalysis in artificial enzymes for challenging reactions.

| S-EPMC8353628 | biostudies-literature

Enantioselective synthesis of tryptophan derivatives by a tandem Friedel-Crafts conjugate addition/asymmetric protonation reaction.

Project description:The tandem Friedel-Crafts conjugate addition/asymmetric protonation reaction between 2-substituted indoles and methyl 2-acetamidoacrylate is reported. The reaction is catalyzed by (R)-3,3'-dibromo-BINOL in the presence of stoichiometric SnCl(4), and is the first example of a tandem conjugate addition/asymmetric protonation reaction using a BINOL·SnCl(4) complex as the catalyst. A range of indoles furnished synthetic tryptophan derivatives in good yields and high levels of enantioselectivity, even on a preparative scale. The convergent nature of this transformation should lend itself to the preparation of unnatural tryptophan derivatives for use in a broad array of synthetic and biological applications.

| S-EPMC3310256 | biostudies-literature

Artificial Metalloenzymes based on TetR Proteins and Cu(II) for Enantioselective Friedel-Crafts Alkylation Reactions.

Project description:The supramolecular approach is among the most convenient methodologies for creating artificial metalloenzymes (ArMs). Usually this approach involves the binding of a transition metal ion complex to a biomolecular scaffold via its ligand, which also modulates the catalytic properties of the metal ion. Herein, we report ArMs based on the proteins CgmR, RamR and QacR from the TetR family of multidrug resistance regulators (MDRs) and Cu2+ ions, assembled without the need of a ligand. These ArMs catalyze the enantioselective vinylogous Friedel-Crafts alkylation reaction with up to 75 % ee. Competition experiments with ethidium and rhodamine 6G confirm that the reactions occur in the chiral environment of the hydrophobic pocket. It is proposed that the Cu2+-substrate complex is bound via a combination of electrostatic and π-stacking interactions provided by the second coordination sphere. This approach constitutes a fast and straightforward way to assemble metalloenzymes and may facilitate future optimization of the protein scaffolds via mutagenesis or directed evolution approaches.

| S-EPMC7319431 | biostudies-literature

A rational quest for selectivity through precise ligand-positioning in tandem DNA-catalysed Friedel-Crafts alkylation/asymmetric protonation.

Project description:Covalent anchorage of a metallic co-factor to a DNA-based architecture is merely the only way to ensure an accurate positioning of a catalytic site within the chiral micro-environment offered by the DNA double helix. Ultimately, it also allows a fine-tuning of the catalytic pocket through simple synthetic modifications of the DNA sequence. Here, we report highly selective copper(ii)-catalysed asymmetric Friedel-Crafts conjugate addition/enantioselective protonation, which is due to a careful positioning of a bipyridine ligand within a DNA framework. Most importantly, this study unveils specific structural features that account for an optimal chirality transfer from the duplex to the Friedel-Crafts adducts.

| S-EPMC6429601 | biostudies-literature

Lewis Acid-Catalyzed Enantioselective Friedel-Crafts Alkylation of Pyrrole in Water.

Project description:Highly enantioselective Friedel-Crafts alkylation of pyrroles with 2-enoyl-pyridine N-oxides in water/chloroform (10:1) was developed under catalysis of Lewis acid. The Friedel-Crafts alkylation products can be obtained in high yields and excellent enantioselectivities. Moreover, several control experiments were carried out to study the reaction mechanism.

| S-EPMC7271029 | biostudies-literature

Friedel-Crafts Alkylation of Indoles with Trichloroacetimidates.

Project description:Substituted indole scaffolds are often utilized in medicinal chemistry as they regularly possess significant pharmacological activity. Therefore the development of simple, inexpensive and efficient methods for alkylating the indole heterocycle continues to be an active research area. Reported are reactions of trichloroacetimidate electrophiles and indoles to address the challenges of accessing alkyl decorated indole structures. These alkylations perform best when either the indole or the imidate is functionalized with electron withdrawing groups to avoid polyalkylation.

| S-EPMC6720118 | biostudies-literature

The enantioselective construction of tetracyclic diterpene skeletons with Friedel-Crafts alkylation and palladium-catalyzed cycloalkenylation reactions.

Project description:Due to the profound extent to which natural products inspire medicinal chemists in drug discovery, there is demand for innovative syntheses of these often complex materials. This article describes the synthesis of tricarbocyclic natural product architectures through an extension of the enantioselective Birch-Cope sequence with intramolecular Friedel-Crafts alkylation reactions. Additionally, palladium-catalyzed enol silane cycloalkenylation of the tricarbocyclic structures afforded the challenging bicyclo[3.2.1]octane C/D ring system found in the gibberellins and the ent-kauranes, two natural products with diverse medicinal value. In the case of the ent-kaurane derivative, an unprecedented alkene rearrangement converted four alkene isomers to one final product.

| S-EPMC4334740 | biostudies-literature

Catalytic asymmetric tandem Friedel-Crafts alkylation/Michael addition reaction for the synthesis of highly functionalized chromans.

Project description:The enantioselective tandem Friedel-Crafts alkylation/Michael addition reaction of indoles with nitroolefin enoates catalyzed by a diphenylamine-linked bis(oxazoline)-Zn(OTf)2 complex was investigated. This tandem reaction afforded functionalized chiral chromans in good yields with moderate to high stereoselectivities (up to 95:5 dr, up to 99% ee).

| S-EPMC3701415 | biostudies-literature

Electrifying Friedel-Crafts Intramolecular Alkylation toward 1,1-Disubstituted Tetrahydronaphthalenes.

Project description:In this work, we successfully employed electrochemical conditions to promote a Hofer-Moest, intramolecular Friedel-Crafts alkylation sequence. The reaction proceeds under mild conditions, employing carboxylic acids as starting materials. Notably, the electrochemical process performed in batch was adapted to a continuous flow electrolysis apparatus to provide a significant improvement. This catalyst-free, electrochemical approach produces an array of tetrahydronaphthalenes that could be used for API synthesis.

| S-EPMC10729024 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data