Chiral Amide Research Articles

Supramolecular Assembly of Edge Functionalized Top‐Down Chiral Graphene Quantum Dots

AbstractThe construction of supramolecular assemblies of heterogeneous materials at the nanoscale is an open challenge in science. Herein, new chiral graphene quantum dots (GQDs) prepared by amidation reaction introducing chiral amide groups and pyrene moieties into the periphery of GQDs are described. The analytical and spectroscopic data show an efficient chemical functionalization and the morphological study of the supramolecular ensembles using SEM and AFM microscopies reveals the presence of highly ordered fibers of several micrometers length. Fluorescence studies, using emission spectroscopy and confocal microscopy, reveal that the fibers stem from the π‐π stacking of both pyrenes and GQDs, together with the hydrogen bonding interactions of the amide groups. Circular dichroism analysis supports the chiral nature of the supramolecular aggregates.

Copper-catalyzed hydroamination of polyfluoroalkyl substituted alkenes via asymmetric radical cross-coupling access to α-chiral tertiary alkylamines

α-Chiral tertiary alkylamines are quintessential scaffolds in pharmaceuticals, bioactive molecules, and organic materials. Although there has been substantial advancement in the synthesis of chiral amides or sulfonamides through open-shell pathway in recent years, it remains problematic to efficiently obtain optically active aliphatic amines, especially α -chiral tertiary alkylamines. Herein, we have demonstrated, by means of density functional theory calculations jointly with experimental studies, that the chiral C–N bond can be forged through a mechanically unprecedented radical cross-coupling of a Cu(I)-bounded dialkyl amine radical species with a carbon-based radical species. Consequently, by virtue of this protocol, a diversity of important optically active β -polyfluoroalkyl substituted α -chiral tertiary alkylamines have been efficiently constructed with high enantioselectivity. • CuH-catalyzed asymmetric reversal hydroamination • Cu-catalyzed enantioselective radical cross-coupling • Efficient construction of β-polyfluoroalkyl-substituted α-chiral tertiary alkylamines • Theoretical mechanistic insight and experimental synthesis A Cu-catalyzed radical cross-coupling of in-situ -generated Cu(I)-bounded dialkyl amine radical species with a carbon-based radical species to create a chiral C–N bond has been disclosed for the first time to our knowledge. By virtue of this approach, asymmetric radical hydroamination of β-aryl substituted polyfluoroalkyl alkenes with hydroxylamine derivatives have been successfully implemented to access an array of important β-polyfluoroalkyl substituted α-chiral tertiary alkylamines in an excellent regio-and enantioselective manner. A Cu-catalyzed radical cross-coupling of in-situ -generated Cu(I)-bounded dialkyl amine radical species with a carbon-based radical species to create a chiral C–N bond has been disclosed for the first time to our knowledge. By virtue of this approach, asymmetric radical hydroamination of β-aryl substituted polyfluoroalkyl alkenes with hydroxylamine derivatives has been successfully implemented to access an array of important β-polyfluoroalkyl substituted α-chiral tertiary alkylamines in an excellent regio- and enantioselective manner.

Natural Product-Inspired Chiral Ligand Design: Aloperine and N-Substituted Aloperines-Induced Pd-Catalyzed Asymmetric Hydroarylation of Ketimines.

A naturally occurring alkaloid aloperine was utilized as a chiral skeleton for the development of new ligands/catalysts in asymmetric synthesis. A number of N-substituted aloperines have been prepared, and a Pd-catalyzed asymmetric hydroarylation of ketimines using these chiral 1,3-diamine ligands was reported. A range of chiral sulfonyl amides were prepared in high yields and enantioselectivities. The stereoselectivity and structure relationships of aloperines have been studied. In addition, preliminary studies on the desymmetrization of meso-anhydride have also shown that these diamines have good potential in organocatalysis. These discoveries would provide a new future development for natural product-inspired chiral ligand design and developments.

Impact of Host Flexibility on Selectivity in a Supramolecular Host-Catalyzed Enantioselective aza-Darzens Reaction.

A highly enantioselective aza-Darzens reaction (up to 99% ee) catalyzed by an enantiopure supramolecular host has been discovered. To understand the role of host structure on reaction outcome, nine new gallium(III)-based enantiopure supramolecular assemblies were prepared via substitution of the external chiral amide. Despite the distal nature of the substitution in these catalysts, changes in enantioselectivity (61 to 90% ee) in the aziridine product were observed. The enantioselectivities were correlated to the flexibility of the supramolecular host scaffold as measured by the kinetics of exchange of a model cationic guest. This correlation led to the development of a best-in-class catalyst by substituting the gallium(III)-based host with one based on indium(III), which generated the most flexible and selective catalyst.

Synthesis of 2-chloropurine ribosides with chiral amino acid amides at C6 and their evaluation as A1 adenosine receptor agonists

A series of purine ribonucleosides bearing chiral amino acid amides at the C6 position of 2-chloropurine was synthesized. Molecular docking of the synthesized analogs of 2-chloroadenosine by their affinity for A1 adenosine receptors (A1ARs) was conducted. The investigation of A1AR stimulating activity of synthesized nucleosides was carried out in a model of an isolated mouse atrium. We have shown that derivatives with tyrosine, valine, and serine residues exhibit the properties of A1AR partial agonists. Animal experiments in the open field test have shown that these compounds have different profiles of psychoactive action. These nucleosides have an ophthalmic hypotensive effect and reduce intraocular pressure in a manner slightly inferior to that of timolol and brimonidine. The synthesized nucleosides can be the basis for further design and synthesis of new A1AR agonists.

NiH-catalyzed asymmetric hydroalkynylation of α,β-unsaturated amides

An enantioselective NiH-catalyzed hydroalkynylation of α,β-unsaturated amides is reported. A wide range of α,β-unsaturated amides and bromoalkynes are suitable substrates for this reaction, which proceeds under mild conditions, allowing access to a variety of enantioenriched chiral β-alkynyl amides. β,γ-Unsaturated amides can also be used as substrates and undergo the β-selective hydroalkynylation with a slightly lower enantiomeric excess.

Merging enzymes with chemocatalysis for amide bond synthesis

Amides are one of the most fundamental chemical bonds in nature. In addition to proteins and other metabolites, many valuable synthetic products comprise amide bonds. Despite this, there is a need for more sustainable amide synthesis. Herein, we report an integrated next generation multi-catalytic system, merging nitrile hydratase enzymes with a Cu-catalysed N-arylation reaction in a single reaction vessel, for the construction of ubiquitous amide bonds. This synergistic one-pot combination of chemo- and biocatalysis provides an amide bond disconnection to precursors, that are orthogonal to those in classical amide synthesis, obviating the need for protecting groups and delivering amides in a manner unachievable using existing catalytic regimes. Our integrated approach also affords broad scope, very high (molar) substrate loading, and has excellent functional group tolerance, telescoping routes to natural product derivatives, drug molecules, and challenging chiral amides under environmentally friendly conditions at scale.

Orientational Chirality, Its Asymmetric Control, and Computational Study.

Orientational chirality was discovered and characterized by a C(sp)-C(sp3) axis-anchored chiral center and a remotely anchored blocker. X-ray structural analysis proved that orientatiomers are stabilized by through-space functional groups, making it possible for 1 R- or S-chiral center to exhibit 3 orientational isomers simply by rotating operations. A new model system was proposed, fundamentally different from the traditional Felkin-Ahn-type or Cram-type models. In these traditional models, chiral C(sp3) center and blocking C(sp2) carbons are connected adjacently, and there exist 6 energy barriers during rotating along the C(sp2)-C(sp3) axis. In comparison, the present orientational chirality model shows that a chiral C(sp)-C(sp3) carbon is remotely located from a blocking group. Thus, it is focused on the steric dialog between a chiral C(sp3) center and a remotely anchored functional group. There exist 3 energy barriers for either (R)- or (S)-C(sp)-C(sp3) stereogenicity in the new model. Chiral amide auxiliary was proven to be an excellent chiral auxiliary in controlling rotations of orientatiomers to give complete stereoselectivity. The asymmetric synthesis of individual orientatiomers was conducted via multistep synthesis by taking advantage of the Suzuki-Miyaura cross-coupling and Sonogashira coupling reactions. Density functional theory computational study presented optimized conformers and relative energies for individual orientatiomers. This discovery would be anticipated to result in a new stereochemistry topic and have a broad impact on chemical, biomedical, and material sciences in the future.

Catalyst- and solvent-free aminolysis of the asymmetric derivatives of Evans’ chiral N-acyloxazolidinones: enantioselective synthesis of chiral amides and its applications

We report a convenient method for the aminolysis of N-acyloxazolidinone-derived asymmetric products and the direct conversion of the resulting secondary amides into diverse classes of compounds.

Synthesis and properties of helical polystyrene derivatives with amino acid side groups

A series of polystyrene derivatives with chiral amide groups with a controlled molecular weight and narrow molecular weight distribution were synthesized by reversible addition–fragmentation chain transfer (RAFT) radical polymerization.

Asymmetric C–H Activation for the Synthesis of P- and Axially Chiral Biaryl Phosphine Oxides by an Achiral Cp*Ir Catalyst with Chiral Carboxylic Amide

Asymmetric C–H Activation for the Synthesis of P- and Axially Chiral Biaryl Phosphine Oxides by an Achiral Cp*Ir Catalyst with Chiral Carboxylic Amide

Combined Theoretical and Experimental Studies Unravel Multiple Pathways to Convergent Asymmetric Hydrogenation of Enamides.

We present a highly efficient convergent asymmetric hydrogenation of E/Z mixtures of enamides catalyzed by N,P–iridium complexes supported by mechanistic studies. It was found that reduction of the olefinic isomers (E and Z geometries) produces chiral amides with the same absolute configuration (enantioconvergent hydrogenation). This allowed the hydrogenation of a wide range of E/Z mixtures of trisubstituted enamides with excellent enantioselectivity (up to 99% ee). A detailed mechanistic study using deuterium labeling and kinetic experiments revealed two different pathways for the observed enantioconvergence. For α-aryl enamides, fast isomerization of the double bond takes place, and the overall process results in kinetic resolution of the two isomers. For α-alkyl enamides, no double bond isomerization is detected, and competition experiments suggested that substrate chelation is responsible for the enantioconvergent stereochemical outcome. DFT calculations were performed to predict the correct absolute configuration of the products and strengthen the proposed mechanism of the iridium-catalyzed isomerization pathway.

The Application of 1,2-Oxazinanes as Chiral Cyclic Weinreb Amide-Type Auxiliaries Leading to a Three-Component, One-Pot Reaction

Abstract1,2-Oxazines were synthesised via a copper-catalysed aerobic acyl nitroso Diels–Alder reaction from 1,4-disubstituted 1,3-dienes and N-Boc-hydroxylamine. From this, 1,2-oxazinanes were obtained in a novel follow-up reaction path. The stability of several 1,2-oxazines and 1,2-oxazinanes towards organometallic compounds was tested to rate their operability as cyclic chiral Weinreb amide auxiliaries. 3,6-Di-tert-butyl-1,2-oxazinane gave the best results and was introduced as a chiral Weinreb amide-type auxiliary to yield chiral α-substituted ketones in a diastereomeric ratio of up to 98:2. The removal of the auxiliary can be performed with BuLi to form unsymmetrical α-chiral ketones. Thereafter, the chiral auxiliary can be re-isolated and purified by sublimation under vacuum.

Fluorescence Spectroscopy of Enantiomeric Amide Compounds Enforced by Chiral Light

Chirality, the absence of mirror symmetry, governs behavior in most biologically important molecules, thus making the chiral recognition of great importance in the pharmaceutical and agrochemical industries, as well as medicine. Chiral molecules can be characterized by means of optical experiments based on chiro-optical excitation of molecules. Specifically, chiral absorptive materials differently absorb left- and right-circular polarized light, i.e., they possess circular dichroism (CD). Unfortunately, the natural CD of most molecules is very low and lies in the ultraviolet range. Fluorescence-detected CD is a fast and sensitive tool for investigation of chiral molecules which emit light; ultralow CD in absorption can be detected as the difference in emission. In this work, we perform fluorescence-detected CD on novel chiral amide compounds, designed specifically for visible green emission; we synthesize two enantiomeric fluorescent compounds using low-cost starting compounds and easy purification. We investigate different solutions of the enantiomers at different concentrations, and we show that the fluorescence of the intrinsically chiral compounds depends on the polarization state of the penetrating light, which is absorbed at 400 nm and emits across the green wavelength range. We believe that these compounds can be coupled with plasmonic nanostructures, which further shows promise in applications regarding chiral sensing or chiral emission.

Enantioselectivity of Chiral Derivatives of Xanthones in Virulence Effects of Resistant Bacteria.

Antimicrobial peptides are one of the lines of defense produced by several hosts in response to bacterial infections. Inspired by them and recent discoveries of xanthones as bacterial efflux pump inhibitors, chiral amides with a xanthone scaffold were planned to be potential antimicrobial adjuvants. The chiral derivatives of xanthones were obtained by peptide coupling reactions between suitable xanthones with enantiomerically pure building blocks, yielding derivatives with high enantiomeric purity. Among 18 compounds investigated for their antimicrobial activity against reference strains of bacteria and fungi, antibacterial activity for the tested strains was not found. Selected compounds were also evaluated for their potential to inhibit bacterial efflux pumps. Compound (R,R)-8 inhibited efflux pumps in the Gram-positive model tested and three compounds, (S,S)-8, (R)-17 and (R,S)-18, displayed the same activity in the Gram-negative strain used. Studies were performed on the inhibition of biofilm formation and quorum-sensing, to which the enantiomeric pair 8 displayed activity for the latter. To gain a better understanding of how the active compounds bind to the efflux pumps, docking studies were performed. Hit compounds were proposed for each activity, and it was shown that enantioselectivity was noticeable and must be considered, as enantiomers displayed differences in activity.

A relay catalysis strategy for enantioselective nickel-catalyzed migratory hydroarylation forming chiral α-aryl alkylboronates

A relay catalysis strategy for enantioselective nickel-catalyzed migratory hydroarylation forming chiral α-aryl alkylboronates

Biocatalytic, Intermolecular C-H Bond Functionalization for the Synthesis of Enantioenriched Amides.

Directed evolution of heme proteins has opened access to new-to-nature enzymatic activity that can be harnessed to tackle synthetic challenges. Among these, reactions resulting from active site iron-nitrenoid intermediates present a powerful strategy to forge C-N bonds with high site- and stereoselectivity. Here we report a biocatalytic, intermolecular benzylic C-H amidation reaction operating at mild and scalable conditions. With hydroxamate esters as nitrene precursors, feedstock aromatic compounds can be converted to chiral amides with excellent enantioselectivity (up to >99 % ee) and high yields (up to 87 %). Kinetic and computational analysis of the enzymatic reaction reveals rate-determining nitrenoid formation followed by stepwise hydrogen atom transfer-mediated C-H functionalization.

Biocatalytic, Intermolecular C−H Bond Functionalization for the Synthesis of Enantioenriched Amides

AbstractDirected evolution of heme proteins has opened access to new‐to‐nature enzymatic activity that can be harnessed to tackle synthetic challenges. Among these, reactions resulting from active site iron‐nitrenoid intermediates present a powerful strategy to forge C−N bonds with high site‐ and stereoselectivity. Here we report a biocatalytic, intermolecular benzylic C−H amidation reaction operating at mild and scalable conditions. With hydroxamate esters as nitrene precursors, feedstock aromatic compounds can be converted to chiral amides with excellent enantioselectivity (up to >99 % ee) and high yields (up to 87 %). Kinetic and computational analysis of the enzymatic reaction reveals rate‐determining nitrenoid formation followed by stepwise hydrogen atom transfer‐mediated C−H functionalization.

Facile Synthesis of Chiral Arylamines, Alkylamines and Amides by Enantioselective NiH‐Catalyzed Hydroamination

AbstractRegio‐ and enantioselective hydroarylamination, hydroalkylamination and hydroamidation of styrenes have been developed by NiH catalysis with a simple bioxazoline ligand under mild conditions. A wide range of enantioenriched benzylic arylamines, alkylamines and amides can be easily accessed by nitroarenes, hydroxylamines and dioxazolones, respectively as amination reagents. The chiral induction in these reactions is proposed to proceed through an enantiodifferentiating syn‐hydronickellation step.

Facile Synthesis of Chiral Arylamines, Alkylamines and Amides by Enantioselective NiH-Catalyzed Hydroamination.

Regio- and enantioselective hydroarylamination, hydroalkylamination and hydroamidation of styrenes have been developed by NiH catalysis with a simple bioxazoline ligand under mild conditions. A wide range of enantioenriched benzylic arylamines, alkylamines and amides can be easily accessed by nitroarenes, hydroxylamines and dioxazolones, respectively as amination reagents. The chiral induction in these reactions is proposed to proceed through an enantiodifferentiating syn-hydronickellation step.