Aldolase Cascade Facilitated by Self‐Assembled Nanotubes from Short Peptide Amphiphiles

Early evolution benefited from a complex network of reactions involving multiple C?C bond forming and breaking events that were critical for primitive metabolism. Nature gradually chose highly evolved and complex enzymes such as lyases to efficiently facilitate C?C bond formation and cleavage with remarkable substrate selectivity. Reported here is a lipidated short peptide which accesses a homogenous nanotubular morphology to efficiently catalyze C?C bond cleavage and formation. This system shows morphology‐dependent catalytic rates, suggesting the formation of a binding pocket and registered enhancements in the presence of the hydrogen‐bond donor tyrosine, which is exploited by extant aldolases. These assemblies showed excellent substrate selectivity and templated the formation of a specific adduct from a pool of possible adducts. The ability to catalyze metabolically relevant cascade transformations suggests the importance of such systems in early evolution.     

Predictable Selectivity in Remote C−H Oxidation of Steroids: Analysis of Substrate Binding Mode

Predictability is a key requirement to encompass late-stage C−H functionalization in synthetic routes. However, prediction (and control) of reaction selectivity is usually challenging, especially for complex substrate structures and elusive transformations such as remote C(sp³)−H oxidation, as it requires distinguishing a specific C−H bond from many others with similar reactivity. Developed here is a strategy for predictable, remote C−H oxidation that entails substrate binding to a supramolecular Mn or Fe catalyst followed by elucidation of the conformation of the host-guest adduct by NMR analysis. These analyses indicate which remote C−H bonds are suitably oriented for the oxidation before carrying out the reaction, enabling prediction of site selectivity. This strategy was applied to late-stage C(sp³)−H oxidation of amino-steroids at C15 (or C16) positions, with a selectivity tunable by modification of catalyst chirality and metal.     

Selenocysteine as a Substrate,an Inhibitor and a Mechanistic Probe for Bacterial and Fungal Iron-Dependent Sulfoxide Synthases

Sulfoxide synthases are non-heme iron enzymes that participate in the biosynthesis of thiohistidines, such as ergothioneine and ovothiol A. The sulfoxide synthase EgtB from Chloracidobacterium thermophilum (CthEgtB) catalyzes oxidative coupling between the side chains of N-α-trimethyl histidine (TMH) and cysteine (Cys) in a reaction that entails complete reduction of molecular oxygen, carbon–sulfur (C−S) and sulfur–oxygen (S−O) bond formation as well as carbon–hydrogen (C−H) bond cleavage. In this report, we show that CthEgtB and other bacterial sulfoxide synthases cannot efficiently accept selenocysteine (SeCys) as a substrate in place of cysteine. In contrast, the sulfoxide synthase from the filamentous fungus Chaetomium thermophilum (CthEgt1) catalyzes C−S and C−Se bond formation at almost equal efficiency. We discuss evidence suggesting that this functional difference between bacterial and fungal sulfoxide synthases emerges from different modes of oxygen activation.     

Exploring The Sequence of Electron Density Along The Chemical Reactions Between Carbonyl Oxides And Ammonia/Water Using Bond Evolution Theory

The molecular mechanism of the reactions between four carbonyl oxides and ammonia/water are investigated using the M06-2X functional together with 6-311++G(d,p) basis set. The analysis of activation and reaction enthalpy shows that the exothermicity of each process increased with the substitution of electron donating substituents (methyl and ethenyl). Along each reaction pathway, two new chemical bonds C−N/C−O and O−H are expected to form. A detailed analysis of the flow of the electron density during their formation have been characterized from the perspective of bonding evolution theory (BET). For all reaction pathways, BET revealed that the process of C−N and O−H bond formation takes place within four structural stability domains (SSD), which can be summarized as follows: the depopulation of V(N) basin with the formation of first C−N bond (appearance of V(C,N) basin), cleavage of N−H bond with the creation of V(N) and V(H) monosynaptic basin, and finally the V(H,O) disynaptic basin related to O−H bond. On the other hand, in the case of water, the cleavage of O−H bond with the formation of V(O) and V(H) basins is the first stage, followed by the formation of the O−H bond as a second stage, and finally the creation of C−O bond.     

Water-Promoted Carbon-Carbon Bond Cleavage Employing a Reusable Fe Single-Atom Catalyst

The development of methods for selective cleavage reactions of thermodynamically stable C−C/C=C bonds in a green manner is a challenging research field which is largely unexplored. Herein, we present a heterogeneous Fe−N−C catalyst with highly dispersed iron centers that allows for the oxidative C−C/C=C bond cleavage of amines, secondary alcohols, ketones, and olefins in the presence of air (O₂) and water (H₂O). Mechanistic studies reveal the presence of water to be essential for the performance of the Fe−N−C system, boosting the product yield from <1 % to >90 %. Combined spectroscopic characterizations and control experiments suggest the singlet ¹O₂ and hydroxide species generated from O₂ and H₂O, respectively, take selectively part in the C−C bond cleavage. The broad applicability (>40 examples) even for complex drugs as well as high activity, selectivity, and durability under comparably mild conditions highlight this unique catalytic system.     

Molecular Dynamics Simulations Guide Chimeragenesis and Engineered Control of Chemoselectivity in Diketopiperazine Dimerases

In the biosynthesis of the tryptophan-linked dimeric diketopiperazines (DKPs), cytochromes P450 selectively couple DKP monomers to generate a variety of intricate and isomeric frameworks. To determine the molecular basis for selectivity of these biocatalysts we obtained a high-resolution crystal structure of selective Csp²−N bond forming dimerase, AspB. Overlay of the AspB structure onto C−C and C−N bond forming homolog NzeB revealed no significant structural variance to explain their divergent chemoselectivities. Molecular dynamics (MD) simulations identified a region of NzeB with increased conformational flexibility relative to AspB, and interchange of this region along with a single active site mutation led to a variant that catalyzes exclusive C−N bond formation. MD simulations also suggest that intermolecular C−C or C−N bond formation results from a change in mechanism, supported experimentally through use of a substrate mimic.     

seco-Labdanes: A Study of Terpenoid Structural Diversity Resulting from Biosynthetic C−C Bond Cleavage

The cleavage of a C−C bond is a complexity generating process, which complements oxidation and cyclisation events in the biosynthesis of terpenoids. This process leads to increased structural diversity in a cluster of related secondary metabolites by modification of the parent carbocyclic core. In this review, we highlight the diversifying effect of C−C bond cleavage by examining the literature related to seco-labdanes—a class of diterpenoids arising from such C−C bond cleavage events.     

Al/P- and Ga/P-Based Frustrated Lewis Pairs and Electronically Unsaturated Substrates: Ring Cleavage and Ring Closure,C−C and C−N Bond Formation

Al/P- and Ga/P-based frustrated Lewis pairs (FLPs) reacted with an azirine under mild conditions under cleavage of the heterocycle on two different positions. Opening of the C−C bond yielded an unusual nitrile–ylide adduct in which a C−N moiety coordinated to the FLP backbone. Cleavage of a C−N bond afforded the thermodynamically favored enamine adduct with the N atom bound to P and Al or Ga atoms. Ring closure was observed upon treatment of an Al/P FLP with electronically unsaturated substrates (4-(1-cyclohexenyl)-1-aza-but-1-en-3-ynes) and yielded by C−N bond formation hexahydroquinoline derivatives, which coordinated to the FLP through P−C and Al−C bonds. Diphenylcyclopropenone showed a diverse reactivity, which depending on steric shielding and the polarizing effect of Al or Ga atoms afforded different products. An AltBu₂/P FLP yielded an adduct with the C=O group coordinated to P and Al. The dineopentyl derivative gave an equilibrium mixture consisting of a similar product and a simple adduct with O bound to Al and a three-coordinate P atom. Both compounds co-crystallize. The Ga/P FLP only formed the simple adduct with the same substrate. Rearrangement resulted in all cases in C₃-ring cleavage and migration of a mesityl group from P to a former ring C atom by C−C bond formation. Diphenylthiocyclopropenone (evidence for the presence of P=C bonds) and an imine derivative afforded similar products.     

Frontispiece: Photocatalytic Terminal C−C Coupling Reaction Inside Water Soluble Nanocages

Developing methods that activate C−H bonds directly with high selectivity for C−C bond formation in complex organic synthesis has been a major chemistry challenge. Recently it has been shown that photoactivation of weakly polarized C−H bonds can be carried out inside a cationic water-soluble nanocage with visible light-mediated host-guest charge transfer (CT) chemistry. Using this novel photoredox activation paradigm, here we demonstrate C−C bond formation to photo-generate 1,3-diynes at room temperature in water from terminal aromatic alkynes for the first time. The formation of cavity-confined alkyne radical cation and the proton-removed neutral radical species highlight the unique C−C coupling step driven by supramolecular preorganization.     

Aminoacyl-SNACs as small-molecule substrates for the condensation domains of nonribosomal peptide synthetases

BACKGROUND: Nonribosomal peptide synthetases (NRPSs) are large multidomain proteins that catalyze the formation of a wide range of biologically active natural products. These megasynthetases contain condensation (C) domains that catalyze peptide bond formation and chain elongation. The natural substrates for C domains are biosynthetic intermediates that are covalently tethered to thiolation (T) domains within the synthetase by thioester linkages. Characterizing C domain substrate specificity is important for the engineered biosynthesis of new compounds. RESULTS: We synthesized a series of aminoacyl-N-acetylcysteamine thioesters (aminoacyl-SNACs) and show that they are small-molecule substrates for NRPS C domains. Comparison of rates of peptide bond formation catalyzed by the C domain from enterobactin synthetase with various aminoacyl-SNACs as downstream (acceptor) substrates revealed high selectivity for the natural substrate analog L-Ser-SNAC. Comparing L- and D-Phe-SNACs as upstream (donor) substrates for the first C domain from tyrocidine synthetase revealed clear D- versus L-selectivity. CONCLUSIONS: Aminoacyl-SNACs are substrates for NRPS C domains and are useful for characterizing the substrate specificity of C domain-catalyzed peptide bond formation.     

Reductive Coupling of (Fluoro)pyridines by Linear 3d-Metal(I) Silylamides of Cr–Co: A Tale of C−C Bond Formation,C−F Bond Cleavage and a Pyridyl Radical Anion

Herein, we disclose the facile reduction of pyridine (and its derivatives) by linear 3d-metal(I) silylamides (M=Cr–Co). This reaction resulted in intermolecular C−C coupling to give dinuclear metal(II) complexes bearing a bridging 4,4′-dihydrobipyridyl ligand. For iron, we demonstrated that the C−C coupling is reversible in solution, either directly or by reaction with substrates, via a presumed monomeric metal(II) complex bearing a pyridyl radical anion. In the course of this investigation, we also observed that the dinuclear metal(II) complex incorporating iron facilitated the isomerisation of 1,4-cyclohexadiene to 1,3-cyclohexadiene as well as equimolar amounts of benzene and cyclohexene. Furthermore, we synthesised and structurally characterised a non-3d-metal-bound pyridyl radical anion. The reactions of the silylamides with perfluoropyridine led to C−F bond cleavage with the formation of metal(II) fluoride complexes of manganese, iron and cobalt along with the homocoupling or reductive degradation of the substrate. In the case of cobalt, the use of lesser fluorinated pyridines led to C−F bond cleavage but no homocoupling. Overall, in this paper we provide insights into the multifaceted behaviour of simple (fluoro)pyridines in the presence of moderately to highly reducing metal complexes.     

Rare-Earth Catalyzed C−H Bond Alumination of Terminal Alkynes

Organoaluminum reagents’ application in catalytic C−H bond functionalization is limited by competitive side reactions, such as carboalumination and hydroalumination. Herein, rare-earth tetramethylaluminate complexes are shown to catalyze the exclusive C−H bond metalation of terminal alkynes with the commodity reagents trimethyl-, triethyl-, and triisobutylaluminum. Kinetic experiments probing alkyl-group exchange between rare-earth aluminates and trialkylaluminum, C−H bond metalation of alkynes, and catalytic conversions reveal distinct pathways of catalytic aluminations with triethylaluminum versus trimethylaluminum. Most significantly, kinetic data point to reversible formation of a unique [Ln](AlR₄)₂⋅AlR₃ adduct, followed by turnover-limiting alkyne metalation. That is, C−H bond activation occurs from a more associated organometallic species, rather than the expected coordinatively unsaturated species. These mechanistic conclusions allude to a new general strategy for catalytic C−H bond alumination that make use of highly electrophilic metal catalysts.     

Direct N−H Activation to Generate Nitrogen Radical for Arylamine Synthesis via Quantum Dots Photocatalysis

Represented herein is the first example of N-radical generation direct from N−H bond activation under mild and redox-neutral conditions. The in situ generated N-radical intercepts a reduced heteroarylnitrile/aryl halide for C−N bond formation under visible-light irradiation of quantum dots (QDs). A series of aryl and alkylamines with heteroarylnitriles/aryl halides exhibit high efficiency, site-selectivity and good functional-group tolerance. Moreover, consecutive C−C and C−N bond formation using benzylamines as substrates is also achieved, producing N-aryl-1,2-diamines with H₂ evolution. The redox-neutral conditions, broad substrate scope, and efficiency of N-radical formation are advantageous for organic synthesis.     

A DFT Study on the Binuclear Copper(I)-Catalyzed Synthesis Mechanism of 1,2,3-Triazolo[1,5-c]Pyrimidine via Interrupted Click and Ketenimine Rearrangement

In this paper, the mechanism of the full catalytic cycle for binuclear Cu(I)-catalyzed sulfonyl azide-alkyne cycloaddition reaction for the synthesis of triazolopyrimidines was rationalized by density functional theoretical (DFT) calculations. The computed reaction route consists of: (a) formation of dicopper intermediates, including C−H activation of terminal alkyne, 3+2 ring cycloaddition and ring-reducing reaction and transmetalation, (b) interrupted CuAAC reaction, including di-copper catalyzed ring-opening of 2H-azirines and C−C bond formation to generate the copper-triazoles and -ketenimines, (c) two-step C−N cross-coupling and following (d) multi-step hydrogen transfer by the hydrogen bonding chain of water to promote the C−N formation and another C−N cleavage through the removal of p-tolyl sulfonamides. Our DFT results indicate that the multi-step hydrogen transfer process is the rate-determining step along the potential energy surface profile. The explicit water model was used for systematic determination of barrier for C−C cross-coupling, C−N bond formation and cleavage, and p-tolylsulfonamide removal. A critical insight in the interrupted CuAAC reaction was proposed. Further prediction interprets H₂O hydrogen bond chain plays an important role in C−N bond formation and cleavage, and the removal of p-tolylsulfonamide. This may have fundamental guidance on the design of 1, 5-herterocyclic functionalized triazolopyrimidines via interrupted CuAAC rearrangement reaction, as well as hydrogen bond chain of water.     

Distal‐Bond‐Selective C−C Activation of Ring‐Fused Cyclopentanones: An Efficient Access to Spiroindanones

A site‐selective rhodium‐catalyzed C−C activation of ring‐fused cyclopentanones was achieved to afford efficient access to a range of spiroindanones. The use of bulky 2‐amino‐6‐picoline as a cocatalyst is key to the excellent selectivity of this C−C bond cleavage in cyclopentanones.     

Radical-Pair Formation in Hydrocarbon (Aut)Oxidation

The reaction profiles for the uni- and bimolecular decomposition of benzyl hydroperoxide have been studied in the context of initiation reactions for the (aut)oxidation of hydrocarbons. The unimolecular dissociation of benzyl hydroperoxide was found to proceed through the formation of a hydrogen-bonded radical-pair minimum located +181 kJ mol⁻¹ above the hydroperoxide substrate and around 15 kJ mol⁻¹ below the separated radical products. The reaction of toluene with benzyl hydroperoxide proceeds such that O−O bond homolysis is coupled with a C−H bond abstraction event in a single kinetic step. The enthalpic barrier of this molecule-induced radical formation (MIRF) process is significantly lower than that of the unimolecular O−O bond cleavage. The same type of reaction is also possible in the self-reaction between two benzyl hydroperoxide molecules forming benzyloxyl and hydroxyl radical pairs along with benzaldehyde and water as co-products. In the product complexes formed in these MIRF reactions, both radicals connect to a centrally placed water molecule through hydrogen-bonding interactions.     

Mechanistic Insight into Peptidyl-Cysteine Oxidation by the Copper-Dependent Formylglycine-Generating Enzyme

The copper-dependent formylglycine-generating enzyme (FGE) catalyzes the oxygen-dependent oxidation of specific peptidyl-cysteine residues to formylglycine. Our QM/MM calculations provide a very likely mechanism for this transformation. The reaction starts with dioxygen binding to the tris-thiolate Cu^I center to form a triplet Cu^II-superoxide complex. The rate-determining hydrogen atom abstraction involves a triplet-singlet crossing to form a Cu^II−OOH species that couples with the substrate radical, leading to a Cu^I-alkylperoxo intermediate. This is accompanied by proton transfer from the hydroperoxide to the S atom of the substrate via a nearby water molecule. The subsequent O−O bond cleavage is coupled with the C−S bond breaking that generates the formylglycine and a Cu^II-oxyl complex. Moreover, our results suggest that the aldehyde oxygen of the final product originates from O₂, which will be useful for future experimental work.     

Chemoenzymatic Platform for Synthesis of Chiral Organofluorines Based on Type II Aldolases

Aldolases are C?C bond forming enzymes that have become prominent tools for sustainable synthesis of complex synthons. However, enzymatic methods of fluorine incorporation into such compounds are lacking due to the rarity of fluorine in nature. Recently, the use of fluoropyruvate as a non‐native aldolase substrate has arisen as a solution. Here, we report that the type II HpcH aldolases efficiently catalyze fluoropyruvate addition to diverse aldehydes, with exclusive (3S)‐selectivity at fluorine that is rationalized by DFT calculations on a mechanistic model. We also measure the kinetic parameters of aldol addition and demonstrate engineering of the hydroxyl group stereoselectivity. Our aldolase collection is then employed in the chemoenzymatic synthesis of novel fluoroacids and ester derivatives in high stereopurity (d.r. 80–98 %). The compounds made available by this method serve as precursors to fluorinated analogs of sugars, amino acids, and other valuable chiral building blocks.     

Palladium‐Catalyzed Carbon–Fluorine and Carbon–Hydrogen Bond Alumination of Fluoroarenes and Heteroarenes

Through serendipitous discovery, a palladium bis(phosphine) complex was identified as a catalyst for the selective transformation of sp²C−F and sp²C−H bonds of fluoroarenes and heteroarenes to sp²C−Al bonds (19 examples, 1 mol % Pd loading). The carbon–fluorine bond functionalization reaction is highly selective for the formation of organoaluminium products in preference to hydrodefluorination products (selectivity=4.4:1 to 27:1). Evidence is presented for a tandem catalytic process in which hydrodefluorination is followed by sp²C−H alumination.     

Site-Selective Alkoxylation of Benzylic C−H Bonds by Photoredox Catalysis

Methods that enable the direct C−H alkoxylation of complex organic molecules are significantly underdeveloped, particularly in comparison to analogous strategies for C−N and C−C bond formation. In particular, almost all methods for the incorporation of alcohols by C−H oxidation require the use of the alcohol component as a solvent or co-solvent. This condition limits the practical scope of these reactions to simple, inexpensive alcohols. Reported here is a photocatalytic protocol for the functionalization of benzylic C−H bonds with a wide range of oxygen nucleophiles. This strategy merges the photoredox activation of arenes with copper(II)-mediated oxidation of the resulting benzylic radicals, which enables the introduction of benzylic C−O bonds with high site selectivity, chemoselectivity, and functional-group tolerance using only two equivalents of the alcohol coupling partner. This method enables the late-stage introduction of complex alkoxy groups into bioactive molecules, providing a practical new tool with potential applications in synthesis and medicinal chemistry.