Isomeric Amides Research Articles

Proline Analogues.

Within the canonical repertoire of the amino acid involved in protein biogenesis, proline plays a unique role as an amino acid presenting a modified backbone rather than a side-chain. Chemical structures that mimic proline but introduce changes into its specific molecular features are defined as proline analogues. This review article summarizes the existing chemical, physicochemical, and biochemical knowledge about this peculiar family of structures. We group proline analogues from the following compounds: substituted prolines, unsaturated and fused structures, ring size homologues, heterocyclic, e.g., pseudoproline, and bridged proline-resembling structures. We overview (1) the occurrence of proline analogues in nature and their chemical synthesis, (2) physicochemical properties including ring conformation and cis/trans amide isomerization, (3) use in commercial drugs such as nirmatrelvir recently approved against COVID-19, (4) peptide and protein synthesis involving proline analogues, (5) specific opportunities created in peptide engineering, and (6) cases of protein engineering with the analogues. The review aims to provide a summary to anyone interested in using proline analogues in systems ranging from specific biochemical setups to complex biological systems.

The Role of Hydrogen Bonds in Thermally Responsive Crystallization-Driven Template Autocatalysis.

Autocatalysis has been recognized to be involved in the emergence of life and intrinsic to biomolecular replication. Recently, an efficient template autocatalysis driven by solvent-free crystallization has been reported. Herein, we unveil the role of intermolecular hydrogen bonds formed by amides in crystallization-driven template autocatalysis (CDTA), which involves the autocatalytic activity, template selectivity, and thermal responsiveness. We found that the thermal-induced cis-trans isomerization of amides possibly affects the H-bonding-mediated template ability of products for autocatalytic transformation. As a result, CDTA can be reversibly inhibited and activated by tuning the reaction temperatures. Our work sheds light on the significance of noncovalent H-bonding interactions in artificial self-replicators.

The Role of Hydrogen Bonds in Thermally Responsive Crystallization‐Driven Template Autocatalysis

AbstractAutocatalysis has been recognized to be involved in the emergence of life and intrinsic to biomolecular replication. Recently, an efficient template autocatalysis driven by solvent‐free crystallization has been reported. Herein, we unveil the role of intermolecular hydrogen bonds formed by amides in crystallization‐driven template autocatalysis (CDTA), which involves the autocatalytic activity, template selectivity, and thermal responsiveness. We found that the thermal‐induced cis‐trans isomerization of amides possibly affects the H‐bonding‐mediated template ability of products for autocatalytic transformation. As a result, CDTA can be reversibly inhibited and activated by tuning the reaction temperatures. Our work sheds light on the significance of noncovalent H‐bonding interactions in artificial self‐replicators.

A Neutral PCNHCP Co(I)-Me Pincer Complex as a Catalyst for N-Allylic Isomerization with a Broad Substrate Scope.

Earth-abundant-metal catalyzed double bond transposition offers a sustainable and atom-economical route toward the synthesis of internal alkenes. With an emphasis specifically on internal olefins and ethers, the isomerization of allylic amines has been particularly under represented in the literature. Herein, we report an efficient methodology for the selective isomerization of N-allylic organic compounds, including amines, amides, and imines. The reaction is catalyzed by a neutral PCNHCP cobalt(I) pincer complex and proceeds via a π-allyl mechanism. The isomerization occurs readily at 80-90 °C, and it is compatible with a wide variety of functional groups. The in situ formed enamines could additionally be used for a one-pot inverse-electron-demand Diels-Alder reaction to furnish a series of diversely substituted heterobiaryls, which is further discussed in this report.

Smartphone-Based Quantitative Measurement of Cu2+: Fluorescent Turn-on Chemosensor via Radical Cation Formation.

We report a unique radical cation formation-based fluorescent chemosensor (E)-N'-(4-(diphenylamino)benzylidene)thiophene-2-carbohydrazide (DBTC) that quantitatively determines Cu2+ based on the RGB model using a smartphone. DBTC exhibited a weak turquoise fluorescence due to fluorescence suppression by amide isomerization. When Cu2+ was added into DBTC, it showed strong light blue fluorescence with a high quantum yield ([Formula: see text] = 0.470). The detection limit of Cu2+ was determined to be 0.40 µM at the concentration range of 0-7.5 µM. In addition, the detection mechanism of DBTC for Cu2+ was demonstrated to be an oxidative cyclization reaction through 1H NMR titration, ESI-MS analysis, and DFT calculation. Remarkably, DBTC could be applied to the quantitative measurement of Cu2+ using a smartphone and RGB analysis. The detection limit was calculated to be 0.05 µM, which is the lowest detection limit among chemosensors that could detect Cu2+ through smartphone-based fluorescence measurements. Additionally, spike and recovery experiments conducted with different concentrations of Cu2+ showed good recovery values. DBTC exhibited its potential as a chemosensor for determining Cu2+ through the application of a smartphone-based platform capable of real-time monitoring.

Supramolecular liquid crystals from the dimer of L‐shaped molecules with tertiary amide end groups

AbstractSupramolecular liquid crystals (SLCs) are attractive materials for fabricating devices with new optoelectronic functions. Conventional SLCs are made from hydrogen‐bonded mesogens. However, these mesogens suffer from high melting points, and the types of formable aggregates are limited owing to the directionality of the hydrogen bonding. Therefore, to fabricate non‐hydrogen‐bonded SLCs, we hypothesized that the introduction of tertiary amide groups into calamitic molecules would be advantageous because they have an L‐shaped structure with N‐ or C‐alkyl side chains not aligned along the long axis and the flexibility to undergo cis–trans isomerization. In this study, we developed a novel non‐hydrogen‐bonded SLC by assembling an L‐shaped dimer composed of calamitic molecules (phenyltolanes) with tertiary amides at their ends. These molecules exhibited a smectic B phase. The phase transition temperature of the SLCs from crystal to liquid crystal phase was low despite the long π‐conjugated core. Wide‐angle X‐ray diffraction and variable‐temperature Fourier‐transform infrared measurements revealed dimer formation by weak intermolecular interactions, that is, the molecular recognition of L‐shaped molecules, and mobility of the alkyl groups attached to amide driven by cis–trans isomerization in the liquid crystal phase. Thus, cis–trans isomerization of tertiary amides contributed enormously to the formation and lower clearing points of this SLC. The developed method can be used not only to develop non‐hydrogen‐bonded SLCs but also to develop novel soft matter with controlled properties by incorporating the SLCs, as the aggregates can be controlled to impart desired functionalities.

Synthesis, structure and stereodynamics of atropisomeric N-chloroamides.

Atropisomeric N-chloroamides were efficiently accessed by electrophilic halogenation of ortho-substituted secondary anilides. The stereodynamics of atropisomerism in these novel scaffolds was interrogated by detailed experimental and computational studies, revealing that racemization is correlated with amide isomerization. The stereoelectronic nature of the amide was shown to significantly influence racemization rates, with potentially important implications for other C-N atropisomeric scaffolds.

Amide isomerization pathways: Electronic and structural background of protonation- and deprotonation-mediated cis-trans interconversions.

The cis-trans isomerization of amide bonds leads to wide range of structural and functional changes in proteins and can easily be the rate-limiting step in folding. The trans isomer is thermodynamically more stable than the cis, nevertheless the cis form can play a role in biopolymers' function. The molecular system of N-methylacetamide · 2H2O is complex enough to reveal energetics of the cis-trans isomerization at coupled cluster single-double and coupled cluster single-double and perturbative triple [CCSD(T)] levels of theory. The cis-trans isomerization cannot be oversimplified by a rotation along ω, since this rotation is coupled with the N-atom pyramidal inversion, requesting the introduction of a second dihedral angle "α." Full f(ω,α) potential energy surfaces of the different amide protonation states, critical points and isomerization reaction paths were determined, and the barriers of the neutral, O-protonated and N-deprotonated amides were found too high to allow cis-trans interconversion at room temperature: ∼85, ∼140, and ∼110 kJ mol-1, respectively. For the N-protonated amide bond, the cis form (ω = 0°) is a maximum rather than a minimum, and each ω state is accessible for less than ∼10 kJ mol-1. Here we outline a cis-trans isomerization pathway with a previously undescribed low energy transition state, which suggests that the proton is transferred from the more favorable O- to the N-protonation site with the aid of nearby water molecules, allowing the trans → cis transition to occur at an energy cost of ≤11.6 kJ mol-1. Our results help to explain why isomerase enzymes operate via protonated amide bonds and how N-protonation of the peptide bond occurs via O-protonation.

Selective Synthesis of (Z)- and (E)-β-Fluoro-α,β-Unsaturated Amides Using Palladium-Catalyzed Aminocarbonylation.

The selective synthesis of (Z)- and (E)-β-fluoro-α,β-unsaturated amides via the palladium-catalyzed aminocarbonylation of 1-fluoro-2,2-diiodovinylarenes is described in the present study. Using {Pd(allyl)Cl}2 as a catalyst and DBU as a base in DMF, the primary product is (Z)-isomers. Conversely, the use of a Xantphos ligand along with {Pd(allyl)Cl}2 and Et3N as the bases in 1,4-dioxane leads to the selective formation of (E)-isomers. Notably, 1-fluoro-2,2-diiodovinylarenes with various substituents on the phenyl ring react with various secondary amines, producing the corresponding (Z)-isomeric amides with a high yield and selectivity. In contrast, (E)-isomeric amides exhibit lower yields and restricted applicability.

Palladium‐Catalyzed Hydroaminocarbonylation of Olefins with Aliphatic Amines without Additives

AbstractPalladium‐catalyzed hydroaminocarbonylation reactions of olefins using aliphatic amines were performed under carbon monoxide atmosphere. Despite the strong basicity of the applied nucleophiles, the targeted amides were successfully synthesized in the absence of acidic additives. Styrene, oct‐1‐ene and isoprene were transformed to the corresponding amide isomers in moderate to good isolated yields under optimized reaction conditions. Various aliphatic amines were used as N‐nucleophiles. The effect of chiral diphosphines on product distribution, that is, on chemo‐, regio‐ and enantioselectivities was also studied. Plausible explanation was given for the additive‐free hydroaminocarbonylation reaction.

Unmasking the True Identity of Rapamycin's Minor Conformer.

Rapamycin, a well-known macrocyclic natural product with myriad biological activities, has been the subject of intense study since its first isolation and characterization over five decades ago. Rapamycin has been found to adopt a single conformation in the solid state (both when protein bound and uncomplexed) and exists as a mixture of two conformations in solution. Early work established that the major conformer in solution is the trans amide isomer but left the minor conformer mostly uncharacterized. Since that time, it has been widely accepted that the minor conformer of rapamycin is the cis amide, based solely on analogy to FK-506, another potent immunosuppressive compound with some shared key structural elements. To address this long-standing and unresolved question, the solution structure of the minor conformer of rapamycin was investigated using a combination of NMR techniques and computational methods and determined to be a trans amide species with rotation about the ester linkage.

Computation Study on Copper-Catalyzed Aerobic Intramolecular Aminooxygenative C═C Bond Cleavage to Imides: Different Roles of Mononuclear and Dinuclear Copper Complexes

Cu-catalyzed aerobic reactions are a powerful protocol for the synthesis of value-added chemicals based on the ideal oxidant O2. Despite the long research history, the mechanistic studies clarifying the details of the whole catalytic cycle, where Cu-O2 complexes and their derivatives directly participate in the conversion of substrates, are limited, leaving the mechanisms of emerging aerobic reactions far from understanding. Herein, a computational study on the mechanism of Cu-catalyzed aerobic aminooxygenation of alkene-tethered amides to imides is reported. It is found that the Cu(I) precursor is not the active species but can generate two types of Cu(II) complexes LCu(OAc)OH and LCu(OAc)OOR to start the aminooxygenation through the successive formation of dinuclear Cu(III) oxo complex, dinuclear Cu(II) hydroxide complex, and hetero-dinuclear Cu(II)-Cu(I) complex, followed by alkylperoxo radical capture with Cu(I) species. LCu(OAc)OH catalyzes the aminooxygenation via a mononuclear mechanism, while LCu(OAc)OOR is an active intermediate therein. In the initial catalytic stage, LCu(OAc)OH transforms alkene-tethered amides to α-amidated aldehydes through N–H activation, amide isomerization, cyclization, alkyl radical release, alkyl radical capture by O2, alkylperoxo radical capture by in situ-generated Cu(I) species to LCu(OAc)OOR, acetate-assisted proton-coupled electron transfer (PCET), and concerted PCET/O–O bond cleavage. In the second catalytic stage for the generation of imides from α-amidated aldehydes, the previously proposed aldehyde Cα–H pathway is possible, but it is more likely to generate CO2 and H2 as the byproducts. Instead, a more feasible pathway involving C(O)–H activation to acyl radical, decarbonylation, and radical capture to LCu(OAc)OOR′ was discovered. The C(O)–H activation pathway generates CO and H2O as the byproducts and is consistent with the experimental observations. The concerted PCET/O–O bond cleavage steps generating α-amidated aldehydes and imides have close energy barriers and both can be the rate-determining steps. The presented outcome revised and expanded the knowledge of Cu-catalyzed aerobic conversion of C═C bonds and amide N–H bonds, highlighting the different roles of mononuclear and dinuclear copper complexes in the aerobic reactions and the in situ generation of Cu(II) catalysts, respectively.

Understanding the Cis-Trans Amide Bond Isomerization of N,N'-Diacylhydrazines to Develop Guidelines for A Priori Prediction of Their Most Stable Solution Conformers.

N,N'-diacylhydrazines (R1CO-NR3-NR4-COR2) are a class of small molecules with a wide range of applications in chemistry and biology. They are structurally unique in the sense that their two amide groups are connected via a N-N single bond, and as a result, these molecules can exist in eight different isomeric forms. Four of these are amide isomers [trans-trans (t-t), trans-cis (t-c), cis-trans (c-t), and cis-cis (c-c)] arising from C-N bond restricted rotation. In addition, each of these amide isomers can exist in two different isomeric forms due to N-N bond restricted rotation, especially when R3 and R4 groups are relatively bigger. Herein, we have systematically investigated the conformations of 55 N,N'-diacylhydrazines using a combination of solution NMR spectroscopy, X-ray crystallography, and density functional theory calculations. Our data suggest that when the substituents R3 and R4 on the nitrogen atoms are both hydrogens. These molecules prefer twisted trans-trans (t-t) (>90%) geometries (H-N-C═O ∼ 180°), whereas the N-alkylated and N,N'-dialkylated molecules prefer twisted trans-cis (t-c) geometries. Herein, we have analyzed the stabilization of the various isomers of these molecules in light of steric and stereoelectronic effects. We provide a guideline to a priori predict the most stable conformers of the N,N'-diacylhydrazines just by examining their substituents (R1-R4).

A Unique and Stable Polyproline I Helix Sorted out from Conformational Equilibrium by Solvent Polarity.

Polyproline I helical structures are often considered as the hidden face of their most famous geminal sibling, Polyproline II, as PPI is generally spotted only within a conformational equilibrium. We designed and synthesized a stable Polyproline I structure exploiting the striking tendency of (S)-indoline-2-carboxylic acid to drive the peptide bond conformation toward the cis amide isomer, when dissolved in polar solvents. The cooperative effect of only four amino acidic units is sufficient to form a preferential structure in solution. We shed light on this rare secondary structure with a thorough analysis of the spectroscopic and chiroptical properties of the tetramer, supported by X-ray crystallography and computational studies.

The Close Interaction of a C−F Bond with an Amide Carbonyl: Crystallographic and Spectroscopic Characterization

AbstractThe putative interaction of a C−F bond with an amide carbonyl has been an intriguing topic of interest in this century for reasons spanning basic physical organic chemistry to biochemistry. However, to date, there exist no examples of a close, well‐defined interaction in which its unique aspects can be identified and exploited. Herein, we finally present an engineered system possessing an exceptionally tight C−F‐amide interaction, allowing us to obtain spectroscopic, crystallographic, and kinetic details of a distinctive, biochemically relevant chemical system for the first time. In turn, we also explore Lewis acid coordination, C−F bond promotion of amide isomerization, enantiomerization, and ion protonation processes.

The Close Interaction of a C-F Bond with an Amide Carbonyl: Crystallographic and Spectroscopic Characterization.

The putative interaction of a C−F bond with an amide carbonyl has been an intriguing topic of interest in this century for reasons spanning basic physical organic chemistry to biochemistry. However, to date, there exist no examples of a close, well‐defined interaction in which its unique aspects can be identified and exploited. Herein, we finally present an engineered system possessing an exceptionally tight C−F‐amide interaction, allowing us to obtain spectroscopic, crystallographic, and kinetic details of a distinctive, biochemically relevant chemical system for the first time. In turn, we also explore Lewis acid coordination, C−F bond promotion of amide isomerization, enantiomerization, and ion protonation processes.

A predictive journey towards trans-thioamides/amides.

The cis-trans isomerization of (thio)amides was studied by DFT calculations to get the model for the higher preference for the cis conformation by guided predictive chemistry, suggesting how to select the alkyl/aryl substituents on the C/N atoms that lead to the trans isomer. Multilinear analysis, together with cross-validation analysis, helped to select the best fitting parameters to achieve the energy barriers of the cis to trans interconversion, as well as the relative stability between both isomers. Double experimental check led to the synthesis of the best trans candidate with sterically demanding t-butyl substituents, confirming the utility of predictive chemistry, bridging organic and computational chemistry.

Detecting Individual Bond Switching within Amides in a Tunneling Junction.

Amides are essential in the chemistry of life. Detecting the chemical bond states within amides could unravel the nature of amide stabilization and planarity, which is critical to the structure and reactivity of such molecules. Yet, so far, no work has been reported to detect or measure the bond changes at the single-molecule level within amides. Here, we show that a transition between single and double bonds between N and C atoms in an amide can be monitored in real time in a nanogap between gold electrodes via the generation of distinctive conductance features. Density functional theory simulations show that the switching between amide isomers proceeds via a proton transfer process facilitated by a water molecule bridge, and the resulting molecular junctions display bimodal conductance states with a difference as much as nine times.

Influence of N-Methylation and Conformation on Almiramide Anti-Leishmanial Activity.

The almiramide N-methylated lipopeptides exhibit promising activity against trypanosomatid parasites. A structure–activity relationship study has been performed to examine the influences of N-methylation and conformation on activity against various strains of leishmaniasis protozoan and on cytotoxicity. The synthesis and biological analysis of twenty-five analogs demonstrated that derivatives with a single methyl group on either the first or fifth residue amide nitrogen exhibited greater activity than the permethylated peptides and relatively high potency against resistant strains. Replacement of amino amide residues in the peptide, by turn inducing α amino γ lactam (Agl) and N-aminoimidazalone (Nai) counterparts, reduced typically anti-parasitic activity; however, peptide amides possessing Agl residues at the second residue retained significant potency in the unmethylated and permethylated series. Systematic study of the effects of methylation and turn geometry on anti-parasitic activity indicated the relevance of an extended conformer about the central residues, and conformational mobility by tertiary amide isomerization and turn geometry at the extremities of the active peptides.

A Proline Mimetic for the Design of New Stable Secondary Structures: Solvent-Dependent Amide Bond Isomerization of (S)-Indoline-2-carboxylic Acid Derivatives.

A thorough experimental and computational study on the conformational properties of (S)-indoline-2-carboxylic acid derivatives has been conducted. Methyl (S)-1-acetylindoline-2-carboxylate, both a mimetic of proline and phenylalanine, shows a remarkable tendency toward the cis amide isomer when dissolved in polar solvents. This behavior is opposite to the general preference of proline for the trans isomer, making indoline-2-carboxylic acid a good candidate for the design of different secondary structures and new materials.