Enantiopure alleno‐acetylenic ligands assemble diastereoselectively upon the addition of a zinc(II) salt to form triple‐stranded helicates, which provide a sufficiently large helical cage ...(“helicage”) for the encapsulation of guests. The inclusion complexation of heteroalicycles is confirmed by ROESY and DOSY NMR spectroscopy and quantified in 1H NMR binding titrations. The ECD spectra of the helicates, which showed strong Cotton effects and exciton coupling, were found to be extremely sensitive to the nature of the guest molecules. Consequently, a series of nonchromophoric, achiral guests of different sizes as well as regioisomers (1,3‐ and 1,4‐dioxane) became distinguishable on the basis of their induced CD (ICD) spectra. Molecular dynamics (MD) simulations show the adaptability of the cavity size to individual guest molecules and support the selective ICD output. Particularly high affinity towards 1,4‐dioxane allowed its selective detection at parts‐per‐million (ppm) levels in aqueous solutions.
Sensory perception: Enantiopure alleno‐acetylenes can be assembled to form triple‐stranded helicates having an internal cavity for the encapsulation of small cyclic guests. Guest‐induced changes in the electronic circular dichroism (ECD) spectra of the helicate allowed the chiroptical detection of nonchromophoric, achiral solutes. Owing to the high affinity for 1,4‐dioxane, this guest could be detected at low ppm levels.
α‐Fluorinated β‐amino thioesters were obtained in high yields and stereoselectivities by organocatalyzed addition reactions of α‐fluorinated monothiomalonates (F‐MTMs) to N‐Cbz‐ and N‐Boc‐protected ...imines. The transformation requires catalyst loadings of only 1 mol % and proceeds under mild reaction conditions. The obtained addition products were readily used for coupling‐reagent‐free peptide synthesis in solution and on solid phase. The α‐fluoro‐β‐(carb)amido moiety showed distinct conformational preferences, as determined by crystal structure and NMR spectroscopic analysis.
Get rid of the middleman: A broad range of α‐fluorinated β‐amino thioesters were formed with high diastereo‐ and enantioselectivity in the presence of 1 mol % of a cinchona‐alkaloid–squaramide catalyst (see scheme; PG=protecting group). The resulting preactivated fluorinated β‐amino acids were readily incorporated into α,β‐peptides without the need for coupling reagents and had a defined conformation that was retained within the peptides.
Collagen model peptides (CMPs), composed of proline–(2S,4R)-hydroxyproline–glycine (POG) repeat units, have been extensively used to study the structure and stability of triple-helical collagenthe ...dominant structural protein in mammalsat the molecular level. Despite the more than 50-year history of CMPs and numerous studies on the relationship between the composition of single-stranded CMPs and the thermal stability of the assembled triple helices, little attention has been paid to the effects arising from their terminal residues. Here, we show that frame-shifted CMPs, which share POG repeat units but terminate with P, O, or G, form triple helices with vastly different thermal stabilities. A melting temperature difference as high as 16 °C was found for triple helices from 20-mers Ac-OGPOG6-NH2 and Ac-POG6PO-NH2, and triple helices of the constitutional isomers Ac-POG7-NH2 and Ac-GPO7-NH2 melt 10 °C apart. A combination of thermal denaturation, circular dichroism and NMR spectroscopic studies, and molecular dynamics simulations revealed that the stability differences originate from the propensity of the peptide termini to preorganize into a polyproline-II helical structure. Our results advise that care must be taken when designing peptide mimics of structural proteins, as subtle changes in the terminal residues can significantly affect their properties. Our findings also provide a general and straightforward tool for tuning the stability of CMPs for applications as synthetic materials and biological probes.
Enteric fermentation from ruminants is a primary source of anthropogenic methane emission. This study aims to add another approach for methane mitigation by manipulation of the rumen microbiome. ...Effects of choline supplementation on methane formation were quantified in vitro using the Rumen Simulation Technique. Supplementing 200 mM of choline chloride or choline bicarbonate reduced methane emissions by 97-100% after 15 days. Associated with the reduction of methane formation, metabolomics analysis revealed high post-treatment concentrations of ethanol, which likely served as a major hydrogen sink. Metagenome sequencing showed that the methanogen community was almost entirely lost, and choline-utilizing bacteria that can produce either lactate, ethanol or formate as hydrogen sinks were enriched. The taxa most strongly associated with methane mitigation were Megasphaera elsdenii and Denitrobacterium detoxificans, both capable of consuming lactate, which is an intermediate product and hydrogen sink. Accordingly, choline metabolism promoted the capability of bacteria to utilize alternative hydrogen sinks leading to a decline of hydrogen as a substrate for methane formation. However, fermentation of fibre and total organic matter could not be fully maintained with choline supplementation, while amino acid deamination and ethanolamine catabolism produced excessive ammonia, which would reduce feed efficiency and adversely affect live animal performance.
Functional group metathesis is an emerging field in organic chemistry with promising synthetic applications. However, no complete mechanistic studies of these reactions have been reported to date, ...particularly regarding the nature of the key functional group transfer mechanism. Unraveling the mechanism of these transformations would not only allow for their further improvement but would also lead to the design of novel reactions. Herein, we describe our detailed mechanistic studies of the nickel-catalyzed functional group metathesis reaction between aryl methyl sulfides and aryl nitriles, combining experimental and computational results. These studies did not support a mechanism proceeding through reversible migratory insertion of the nitrile into a Ni–Ar bond and provided strong support for an alternative mechanism involving a key transmetalation step between two independently generated oxidative addition complexes. Extensive kinetic analysis, including rate law determination and Eyring analysis, indicated the oxidative addition complex of aryl nitrile as the resting state of the catalytic reaction. Depending on the concentration of aryl methyl sulfide, either the reductive elimination of aryl nitrile or the oxidative addition into the C(sp2)–S bond of aryl methyl sulfide is the turnover-limiting step of the reaction. NMR studies, including an unusual 31P–2H HMBC experiment using deuterium-labeled complexes, unambiguously demonstrated that the sulfide and cyanide groups exchange during the transmetalation step, rather than the two aryl moieties. In addition, Eyring and Hammett analyses of the transmetalation between two Ni(II) complexes revealed that this central step proceeds via an associative mechanism. Organometallic studies involving the synthesis, isolation, and characterization of all putative intermediates and possible deactivation complexes have further shed light on the reaction mechanism, including the identification of a key deactivation pathway, which has led to an improved catalytic protocol.
Homochiral strands of alternating alleno-acetylenes and phenanthroline ligands (P)-1 and (P 2)-2, as well as their corresponding enantiomers, selectively assemble with the addition of silver(I) salt ...to yield dinuclear and trinuclear double helicates, respectively. Upon increasing the solvent polarity, the dinuclear and trinuclear helicates interlock to form a 2catenane and bis2catenane, bearing 14 chirality elements, respectively. The solid-state structure of the 2catenane reveals a nearly perfect fit of the interlocked strands, and the ECD spectra show a significant amplification of the chiroptical properties upon catenation, indicating stabilization of the helical secondary structure. Highly selective narcissistic self-sorting was demonstrated for a racemic mixture consisting of both short and long alleno-acetylenic strands, highlighting their potential for the preparation of linear catenanes of higher order.
The implementation of HCN-free transfer hydrocyanation reactions on laboratory scales has recently been achieved by using HCN donor reagents under nickel- and Lewis acid co-catalysis. More recently, ...malononitrile-based HCN donor reagents were shown to undergo the C(sp3)–CN bond activation by the nickel catalyst in the absence of Lewis acids. However, there is a lack of detailed mechanistic understanding of the challenging C(sp3)–CN bond cleavage step. In this work, in-depth kinetic and computational studies using alkynes as substrates were used to elucidate the overall reaction mechanism of this transfer hydrocyanation, with a particular focus on the activation of the C(sp3)–CN bond to generate the active H–Ni–CN transfer hydrocyanation catalyst. Comparisons of experimentally and computationally derived 13C kinetic isotope effect data support a direct oxidative addition mechanism of the nickel catalyst into the C(sp3)–CN bond facilitated by the coordination of the second nitrile group to the nickel catalyst.
Peptides have become valuable as catalysts for a variety of different reactions, but little is known about the conformational properties of peptidic catalysts. We investigated the conformation of the ...peptide H-dPro-Pro-Glu-NH2, a highly reactive and stereoselective catalyst for conjugate addition reactions, and the corresponding enamine intermediate in solution by NMR spectroscopy and computational methods. The combination of nuclear Overhauser effects (NOEs), residual dipolar couplings (RDCs), J-couplings, and temperature coefficients revealed that the tripeptide adopts a single predominant conformation in its ground state. The structure is a type I β-turn, which gains stabilization from three hydrogen bonds that are cooperatively formed between all functional groups (secondary amine, carboxylic acid, amides) within the tripeptide. In contrast, the conformation of the enamine intermediate is significantly more flexible. The conformational ensemble of the enamine is still dominated by the β-turn, but the backbone and the side chain of the glutamic acid residue are more dynamic. The key to the switch between rigidity and flexibility of the peptidic catalyst is the CO2H group in the side chain of the glutamic acid residue, which acts as a lid that can open and close. As a result, the peptidic catalyst is able to adapt to the structural requirements of the intermediates and transition states of the catalytic cycle. These insights might explain the robustness and high reactivity of the peptidic catalyst, which exceeds that of other secondary amine-based organocatalysts. The data suggest that a balance between rigidity and flexibility, which is reminiscent of the dynamic nature of enzymes, is beneficial for peptidic catalysts and other synthetic catalysts.
The C9 position of cinchona alkaloids functions as a molecular hinge, with internal rotations around the C8C9 (τ1) and C9C4′ (τ2) bonds giving rise to four low energy conformers (1; anti‐closed, ...anti‐open, syn‐closed, and syn‐open). By substituting the C9 carbinol centre by a configurationally defined fluorine substituent, a fluorine‐ammonium ion gauche effect (σC−H→σC−F*; Fδ−⋅⋅⋅N+) encodes for two out of the four possible conformers (2). This constitutes a partial solution to the long‐standing problem of governing internal rotations in cinchonium‐based catalysts relying solely on a fluorine conformational effect.
Fixed with fluorine! The C9 position of cinchona alkaloids functions as a molecular hinge, with internal rotations around the C8C9 (τ1) and C9C4′ (τ2) bonds giving rise to four low‐energy conformers. By substituting the C9 carbinol centre by a configurationally defined fluorine, a fluorine‐ammonium gauche effect encodes for two out of the four possible conformers. This constitutes a partial solution to the long‐standing problem of governing internal rotations in cinchonium‐based catalysts.
Conformational changes of amide cavitands A–C were investigated at varied temperatures and in several solvents. While cavitands A and B, with comparatively smaller substituents such as Et and iPr, ...were always in vase conformation in non‐polar solvents such as CDCl3, CD2Cl2, (D8)THF, and C6D6, their thermoswitching (vase to kite) was observed in polar solvents such as (D7)DMF and (D6)DMSO or in the presence of acid (TFA) and H‐bonding inhibitor (TFE). Intra‐ and interannular H‐bonds of A and B were clearly observed by low‐temperature 1H‐NMR spectra in CDCl3. No conformational change of cavitand C with bigger substituent (tBu) was observed under any tested temperature range and in polar or non‐polar solvents; C was always in the kite conformation.
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