Mimicking the Aromatic‐Ring‐Cleavage Activity of Gentisate‐1,2‐Dioxygenase by a Nonheme Iron Complex

Gentisate‐1,2‐dioxygenase (GDO), a nonheme iron enzyme in the cupin superfamily, catalyzes the cleavage of the aromatic‐ring of 2,5‐dihydroxybenzoic acid (gentisic acid) to form maleylpyruvic acid in the microbial aerobic degradation of aromatic compounds. To develop a functional model of GDO, we have isolated a nonheme iron(II) complex, [(Tp^Ph2)Fe^II(DHN‐H)] (Tp^Ph2=hydrotris(3,5‐diphenylpyrazole‐1‐yl)borate, DHN‐H=1,4‐dihydroxy‐2‐naphthoate). In the reaction with O₂, the biomimetic complex oxidatively cleaves the aromatic ring of the coordinated substrate with the incorporation of both the oxygen atoms from molecular oxygen into the cleavage product. The presence of para‐hydroxy group on the substrate plays a crucial role in directing the aromatic‐ring cleaving reaction.     

12‐ to 22‐Membered Bridged β‐Lactams as Potential Penicillin‐Binding Protein Inhibitors

As potential inhibitors of penicillin‐binding proteins (PBPs), we focused our research on the synthesis of non‐traditional 1,3‐bridged β‐lactams embedded into macrocycles. We synthesized 12‐ to 22‐membered bicyclic β‐lactams by the ring‐closing metathesis (RCM) of bis‐ω‐alkenyl‐3(S)‐aminoazetidinone precursors. The reactivity of 1,3‐bridged β‐lactams was estimated by the determination of the energy barrier of a concerted nucleophilic attack and lactam ring‐opening process by using ab initio calculations. The results predicted that 16‐membered cycles should be more reactive. Biochemical evaluations against R39 DD‐peptidase and two resistant PBPs, namely, PBP2a and PBP5, revealed the inhibition effect of compound 4d , which featured a 16‐membered bridge and the N‐tert‐butyloxycarbonyl chain at the C3 position of the β‐lactam ring. Surprisingly, the corresponding bicycle, 12d , with the PhOCH₂CO side chain at C3 was inactive. Reaction models of the R39 active site gave a new insight into the geometric requirements of the conformation of potential ligands and their steric hindrance; this could help in the design of new compounds.     

Revised mechanism of carboxylation of ribulose‐1,5‐biphosphate by rubisco from large scale quantum chemical calculations

Here, we describe a computational approach for studying enzymes that catalyze complex multi‐step reactions and apply it to Ribulose 1,5‐bisphosphate carboxylase–oxygenase (Rubisco), the enzyme that fixes atmospheric carbon dioxide within photosynthesis. In the 5‐step carboxylase reaction, the substrate Ribulose‐1,5‐bisphosphate (RuBP) first binds Rubisco and undergoes enolization before binding the second substrate, CO₂. Hydration of the RuBP.CO₂ complex is followed by C C bond scission and stereospecific protonation. However, details of the roles and protonation states of active‐site residues, and sources of protons and water, remain highly speculative. Large‐scale computations on active‐site models provide a means to better understand this complex chemical mechanism. The computational protocol comprises a combination of hybrid semi‐empirical quantum mechanics and molecular mechanics within constrained molecular dynamics simulations, together with constrained gradient minimization calculations using density functional theory. Alternative pathways for hydration of the RuBP.CO₂ complex and associated active‐site protonation networks and proton and water sources were investigated. The main findings from analysis of the resulting energetics advocate major revision to existing mechanisms such that: hydration takes place anti to the CO₂; both hydration and C C bond scission require early protonation of CO₂ in the RuBP.CO₂ complex; C C bond scission and stereospecific protonation reactions are concerted and, effectively, there is only one stable intermediate, the C3‐gemdiolate complex. Our main conclusions for interpreting enzyme kinetic results are that the gemdiolate may represent the elusive Michaelis–Menten‐like complex corresponding to the empirical K_m (=K_c) with turnover to product via bond scission concerted with stereospecific protonation consistent with the observed catalytic rate. © 2018 Wiley Periodicals, Inc.     

Ir‐Catalyzed Asymmetric Hydrogenation of α‐Alkylidene β‐Lactams and Cyclobutanones

Chiral β‐lactams and cyclobutanones are present in numerous natural and pharmaceutical products. The stereoselective construction of chiral four‐membered cyclic compounds is an ongoing challenge for the chemical community. Herein, we report a highly stereocontrolled construction of four‐membered ring (mini‐sized) β‐lactams and cyclobutanones via an Ir/ In‐BiphPHOX ‐catalyzed asymmetric hydrogenation, providing the corresponding optically active four‐membered ring carbonyl products bearing an α‐chiral carbon center with excellent yields (up to 99%) and enantioselectivities (up to 98%) under mild reaction conditions (1.0—2.5 bar H₂ for 1.0—10 h). The reaction presents wide substrate scope. Diverse transformations of the catalyzed products were also conducted to show the potential utility of this protocol.     

Isomeric hexyl‐ketohydroperoxides formed by reactions of hexoxy and hexylperoxy radicals in oxygen

Isomerization reactions of peroxy radicals during oxidation of long‐chain hydrocarbons yield hydroperoxides, and therefore play an important role in combustion and atmospheric chemistry, because of their action as branching agents in these chain reaction processes. Different formation mechanisms and structures are involved. Three isomeric hexyl‐ketohydroperoxides are formed via isomerization reactions in oxygen of either hexoxy RO or hexylperoxy RO₂ radicals. In the temperature range 373–473 K, 2‐hexoxy (C₆H₁₃O) radical in O₂/N₂ mixtures gives 2‐hexanone‐5‐hydroperoxide via two consecutive isomerizations. The second one is a H transfer from a HC(OH) group occurring via a seven‐membered ring intermediate: Its rate constant has been determined at 453 and 483 K, and the general expression can be written as Hexylperoxy C₆H₁₃O₂ radical, present in n‐hexane oxidation by oxygen/nitrogen mixtures in the temperature range 543–573 K, gives 2‐hexanone‐4‐hydroperoxide, 3‐hexanone‐5‐hydroperoxide, and 2‐hexanone‐5‐hydroperoxide. The first two are formed through an isomerization reaction via a six‐membered ring intermediate, and the last through an isomerization reaction via a seven‐membered ring intermediate. The ratio of the rate constant of the isomerization reactions of RO₂ radicals via a seven‐membered ring intermediate to that via a six‐membered ring is found to be 0.795, and the rate constant expression via a seven‐membered ring intermediate is proposed: The role of these reactions in the formation of radicals in the troposphere is discussed. Other products arising in the reactional path, such as ketones, furans, and diketones, are identified. Identification of these ketohydroperoxides was made using gas chromatography/mass spectrometry with electron impact, and with NH₃ (or ND₃) chemical ionization. © 2003 Wiley Periodicals, Inc. Int J Chem Kinet 35: 354–366, 2003     

A One‐Pot Synthesis of N‐Aryl‐2‐Oxazolidinones and Cyclic Urethanes by the Lewis Base Catalyzed Fixation of Carbon Dioxide into Anilines and Bromoalkanes

The multicomponent assembly of pharmaceutically relevant N‐aryl‐oxazolidinones through the direct insertion of carbon dioxide into readily available anilines and dibromoalkanes is described. The addition of catalytic amounts of an organosuperbase such as Barton's base enables this transformation to proceed with high yields and exquisite substrate functional‐group tolerance under ambient CO₂ pressure and mild temperature. This report also provides the first proof‐of‐principle for the single‐operation synthesis of elusive seven‐membered ring cyclic urethanes.     

Base‐Selective Five‐ versus Six‐Membered Ring Annulation in Palladium‐Catalyzed C–C Coupling Cascade Reactions: New Access to Electron‐Poor Polycyclic Aromatic Dicarboximides

Palladium‐catalyzed base‐selective annulation of dibromonaphthalimide to different aryl boronate esters by combined Suzuki–Miyaura cross‐coupling and direct C−H arylation afforded a series of new five‐ and six‐membered ring annulated electron‐poor polycyclic aromatic hydrocarbons. Cesium carbonate (Cs₂CO₃) as auxiliary base in these C−C coupling cascade reactions led exclusively to six‐membered ring annulation, while the use of organic base diazabicycloundecene (DBU) afforded the corresponding five‐membered ring annulated products. This base‐dependent selective mode of annulation is attributed to different mechanistic pathways directed by the applied base. The selective annulation was revealed by single crystal X‐ray analysis of the respective five‐ and six‐membered ring annulated products. The optical and redox properties of the new polycyclic aromatic dicarboximides were characterized by UV/Vis absorption and fluorescence spectroscopy and cyclic voltammetry.     

Pathway from N‐Alkylglycine to Alkylisonitrile Catalyzed by Iron(II) and 2‐Oxoglutarate‐Dependent Oxygenases

N‐alkylisonitrile, a precursor to isonitrile‐containing lipopeptides, is biosynthesized by decarboxylation‐assisted ‐N≡C group (isonitrile) formation by using N‐alkylglycine as the substrate. This reaction is catalyzed by iron(II) and 2‐oxoglutarate (Fe/2OG) dependent enzymes. Distinct from typical oxygenation or halogenation reactions catalyzed by this class of enzymes, installation of the isonitrile group represents a novel reaction type for Fe/2OG enzymes that involves a four‐electron oxidative process. Reported here is a plausible mechanism of three Fe/2OG enzymes, Sav607, ScoE and SfaA, which catalyze isonitrile formation. The X‐ray structures of iron‐loaded ScoE in complex with its substrate and the intermediate, along with biochemical and biophysical data reveal that ‐N≡C bond formation involves two cycles of Fe/2OG enzyme catalysis. The reaction starts with an Fe^IV‐oxo‐catalyzed hydroxylation. It is likely followed by decarboxylation‐assisted desaturation to complete isonitrile installation.     

Anionic ring‐opening polymerization of a five‐membered cyclic urethane derived from d‐glucosamine

The anionic ring‐opening polymerization of a five‐membered cyclic urethane, 2‐amino‐4,6‐O‐benzylidene‐2‐N,3‐O‐carbonyl‐2‐deoxy‐α,d ‐glucopyranoside (MBUG), which was prepared from naturally abundant d ‐glucosamine, was examined. Potassium tert‐butoxide (t‐BuOK) was the most effective initiator among the evaluated bases and produced polyurethane with the Mn of 7800 without any elimination of CO₂. The equimolar reaction of MBUG and t‐BuOK in the presence of CH₃I produced N‐methylated MBUG and suggested that the initiation reaction involves proton abstraction from the NH group. This N‐methylated compound did not undergo the polymerization. Therefore, the mechanism of propagation in the ROP of MBUG should involve the proton abstraction and nucleophilic substitution of the resulting amide anion. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 2491–2497     

Cyclization of a 1,4‐Diborabutadiene Ligand with Both Atoms of CO

A 1,4‐dibora‐1,3‐butadiene iron complex was successfully synthesized through the stoichiometric reaction of an iron bis(borylene) complex with diphenylacetylene. This complex was treated with CO and PMe₃, which led to the formation of an unusual six‐membered B₂C₃O ylidic ring bound to both the PMe₃ group and zerovalent iron center. The reaction is a very rare example of the incorporation of both atoms of CO into a ring system.     

6β‐Methyl‐B‐norandrostenedione

The title compound, C₁₉H₂₆O₂, a B‐norandrogen with a 6β‐methyl group, is a recently identified and experimentally tested potent new aromatase inhibitor. It shares structural and physicochemical similarities both with the natural substrate of the enzyme, androstenedione, and with exemestane, another potent aromatase inhibitor having a 6‐methylidene group. X‐ray diffraction results indicate that the B‐nor molecule and exemestane have nearly the same oxygen–oxygen and methyl–methyl separations, though they have distinct configurations of the hydrophobic groups at the 6‐position. These structural comparisons allow correlations to be inferred between the active site geometry of the molecules and the aromatase inhibition power of the studied compound.     

Formation of High‐Valent Iron–Oxo Species in Superoxide Reductase: Characterization by Resonance Raman Spectroscopy

Superoxide reductase (SOR), a non‐heme mononuclear iron protein that is involved in superoxide detoxification in microorganisms, can be used as an unprecedented model to study the mechanisms of O₂ activation and of the formation of high‐valent iron–oxo species in metalloenzymes. By using resonance Raman spectroscopy, it was shown that the mutation of two residues in the second coordination sphere of the SOR iron active site, K₄₈ and I₁₁₈, led to the formation of a high‐valent iron–oxo species when the mutant proteins were reacted with H₂O₂. These data demonstrate that these residues in the second coordination sphere tightly control the evolution and the cleavage of the O? O bond of the ferric iron hydroperoxide intermediate that is formed in the SOR active site.     

Total Synthesis of 1‐Hydroxytaxinine

1‐Hydroxytaxinine ( 1 ) is a cytotoxic taxane diterpenoid. Its central eight‐membered B‐ring possesses four oxygen‐functionalized centers (C1, C2, C9, and C10) and two quaternary carbon centers (C8 and C15), and is fused with six‐membered A‐ and C‐rings. The densely functionalized and intricately fused structure of 1 makes it a highly challenging synthetic target. Reported here is an efficient radical‐based strategy for assembling 1 from A‐ and C‐ring fragments. The A‐ring bearing an α‐alkoxyacyl telluride moiety underwent intermolecular coupling with the C‐ring fragment by a Et₃B/O₂‐promoted decarbonylative radical formation. After construction of the C8‐quaternary stereocenter, a pinacol coupling reaction using a low‐valent titanium reagent formed the B‐ring with stereoselective installation of the C1,C2‐diol. Subsequent manipulations at the A‐ and C‐rings furnished 1 in 26 total steps.     

Density Functional Studies on Thromboxane Biosynthesis: Mechanism and Role of the Heme‐Thiolate System

Reaction mechanisms for the isomerization of prostaglandin H₂ to thromboxane A₂, and degradation to 12‐L‐hydroxy‐5,8,10‐heptadecatrienoic acid (HHT) and malondialdehyde (MDA), catalyzed by thromboxane synthase, were investigated using the unrestricted Becke‐three‐parameter plus Lee–Yang–Parr (UB3LYP) density functional level theory. In addition to the reaction pathway through Fe^IV‐porphyrin intermediates, a new reaction pathway through Fe^III‐porphyrin π‐cation radical intermediates was found. Both reactions proceed with the homolytic cleavage of endoperoxide O? O to give an alkoxy radical. This intermediate converts into an allyl radical intermediate by a C? C homolytic cleavage, followed by the formation of thromboxane A₂ having a 6‐membered ring through a one electron transfer, or the degradation into HHT and MDA. The proposed mechanism shows that an iron(III)‐containing system having electron acceptor ability is essential for the 6‐membered ring formation leading to thromboxane A₂. Our results suggest that the step of the endoperoxide O? O homolytic bond cleavage has the highest activation energy following the binding of prostaglandin H₂ to thromboxane synthase.     

Total Synthesis of Gelsedilam by Means of a Thiol‐Mediated Diastereoselective Conjugate Addition–Aldol Reaction

The total synthesis of gelsedilam, which features a highly diastereoselective thiol conjugate addition–intramolecular aldol reaction to install the strained and caged [3.2.2] bridged ring system and highly efficient NiCl₂/NaBH₄‐mediated four‐step transformation in one‐pot to construct its five‐membered lactam ring is reported. The synthesis requires only 18 linear steps from the known compounds, providing useful strategies for the construction of the intricate ring system in the synthesis of related gelsedine‐type alkaloids.     

Single‐Atom Iron Boosts Electrochemiluminescence

The traditional luminol–H₂O₂ electrochemiluminescence (ECL) sensing platform suffers from self‐decomposition of H₂O₂ at room temperature, hampering its application for quantitative analysis. In this work, for the first time we employ iron single‐atom catalysts (Fe‐N‐C SACs) as an advanced co‐reactant accelerator to directly reduce the dissolved oxygen (O₂) to reactive oxygen species (ROS). Owing to the unique electronic structure and catalytic activity of Fe‐N‐C SACs, large amounts of ROS are efficiently produced, which then react with the luminol anion radical and significantly amplify the luminol ECL emission. Under the optimum conditions, a Fe‐N‐C SACs–luminol ECL sensor for antioxidant capacity measurement was developed with a good linear range from 0.8 μm to 1.0 mm of Trolox.     

“Extracting” the Key Fragment in ETS‐10 Crystallization and Its Application in AM‐6 Assembly

The mechanism of crystallization of microporous titanosilicate ETS‐10 was investigated by Raman spectroscopy combined with ²⁹Si magic‐angle spinning (MAS) NMR spectroscopy, DFT calculations, and SEM imaging. The formation of three‐membered ring species is shown to be the key step in the hydrothermal synthesis of ETS‐10. They are formed by means of a complex process that involves the interaction of silicate species in the reaction mixture, which promotes the dissolution of TiO₂ particles. These insights into the mechanism of ETS‐10 growth led to the successful development of a new synthesis route to the vanadosilicate AM‐6 that involves the use of intermediates that contain three‐membered ring species as an initiator.     

Electrosynthesis of Dihydropyrano[4,3‐b]indoles Based on a Double Oxidative [3+3] Cycloaddition

Oxidative [3+3] cycloadditions offer an efficient route for six‐membered‐ring formation. This approach has been realized based on an electrochemical oxidative coupling of indoles/enamines with active methylene compounds followed by tandem 6π‐electrocyclization leading to the synthesis of dihydropyrano[4,3‐b]indoles and 2,3‐dihydrofurans. The radical–radical cross‐coupling of the radical species generated by anodic oxidation combined with the cathodic generation of the base from O₂ allows for mild reaction conditions for the synthesis of structurally complex heterocycles.     

Macrodiolide Formation by the Thioesterase of a Modular Polyketide Synthase

Elaiophylin is an unusual C₂‐symmetric antibiotic macrodiolide produced on a bacterial modular polyketide synthase assembly line. To probe the mechanism and selectivity of diolide formation, we sought to reconstitute ring formation in vitro by using a non‐natural substrate. Incubation of recombinant elaiophylin thioesterase/cyclase with a synthetic pentaketide analogue of the presumed monomeric polyketide precursor of elaiophylin, specifically its N‐acetylcysteamine thioester, produced a novel 16‐membered C₂‐symmetric macrodiolide. A linear dimeric thioester is an intermediate in ring formation, which indicates iterative use of the thioesterase active site in ligation and subsequent cyclization. Furthermore, the elaiophylin thioesterase acts on a mixture of pentaketide and tetraketide thioesters to give both the symmetric decaketide diolide and the novel asymmetric hybrid nonaketide diolide. Such thioesterases have potential as tools for the in vitro construction of novel diolides.     

In Pursuit of the PO2+ Cation. The Reaction of KPO2F2 and SbF5 leads to an Eight‐membered Antimony‐Oxygen‐Phosphorus‐bridged Ring

The reaction of KPO₂F₂ with the strong Lewis acid SbF₅ was studied as a potential pathway to the unknown PO₂⁺ cation. The resulting product has the desired PO₂SbF₆ composition but consists of an eight‐membered, antimony‐oxygen‐phosphorus‐bridged ring that was characterized by vibrational and NMR spectroscopy, ab initio methods, and a single crystal x‐ray diffraction study. The preferred formation of the ring and its mechanism are discussed.