Photoenzymatic Hydrogenation of Heteroaromatic Olefins Using ‘Ene’-Reductases with Photoredox Catalysts

Flavin-dependent ‘ene’-reductases (EREDs) are highly selective catalysts for the asymmetric reduction of activated alkenes. This function is, however, limited to enones, enoates, and nitroalkenes using the native hydride transfer mechanism. Here we demonstrate that EREDs can reduce vinyl pyridines when irradiated with visible light in the presence of a photoredox catalyst. Experimental evidence suggests the reaction proceeds via a radical mechanism where the vinyl pyridine is reduced to the corresponding neutral benzylic radical in solution. DFT calculations reveal this radical to be “dynamically stable”, suggesting it is sufficiently long-lived to diffuse into the enzyme active site for stereoselective hydrogen atom transfer. This reduction mechanism is distinct from the native one, highlighting the opportunity to expand the synthetic capabilities of existing enzyme platforms by exploiting new mechanistic models.     

Photoenzymatic Hydrogenation of Heteroaromatic Olefins Using ‘Ene’‐Reductases with Photoredox Catalysts

Flavin‐dependent ‘ene’‐reductases (EREDs) are highly selective catalysts for the asymmetric reduction of activated alkenes. This function is, however, limited to enones, enoates, and nitroalkenes using the native hydride transfer mechanism. Here we demonstrate that EREDs can reduce vinyl pyridines when irradiated with visible light in the presence of a photoredox catalyst. Experimental evidence suggests the reaction proceeds via a radical mechanism where the vinyl pyridine is reduced to the corresponding neutral benzylic radical in solution. DFT calculations reveal this radical to be “dynamically stable”, suggesting it is sufficiently long‐lived to diffuse into the enzyme active site for stereoselective hydrogen atom transfer. This reduction mechanism is distinct from the native one, highlighting the opportunity to expand the synthetic capabilities of existing enzyme platforms by exploiting new mechanistic models.     

Ligand-controlled regioselectivity in the hydrothiolation of alkynes by rhodium N-heterocyclic carbene catalysts

Rh-N-heterocyclic carbene compounds [Rh(μ-Cl)(IPr)(η(2)-olefin)](2) and RhCl(IPr)(py)(η(2)-olefin) (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-carbene, py = pyridine, olefin = cyclooctene or ethylene) are highly active catalysts for alkyne hydrothiolation under mild conditions. A regioselectivity switch from linear to 1-substituted vinyl sulfides was observed when mononuclear RhCl(IPr)(py)(η(2)-olefin) catalysts were used instead of dinuclear precursors. A complex interplay between electronic and steric effects exerted by IPr, pyridine, and hydride ligands accounts for the observed regioselectivity. Both IPr and pyridine ligands stabilize formation of square-pyramidal thiolate-hydride active species in which the encumbered and powerful electron-donor IPr ligand directs coordination of pyridine trans to it, consequently blocking access of the incoming alkyne in this position. Simultaneously, the higher trans director hydride ligand paves the way to a cis thiolate-alkyne disposition, favoring formation of 2,2-disubstituted metal-alkenyl species and subsequently the Markovnikov vinyl sulfides via alkenyl-hydride reductive elimination. DFT calculations support a plausible reaction pathway where migratory insertion of the alkyne into the rhodium-thiolate bond is the rate-determining step.     

Theoretical study on the mechanism of N-heterocyclic carbene catalyzed transesterification reactions

The mechanism of N-heterocyclic carbene (NHC) catalyzed transesterification reactions have been studied using density functional theory. Our study shows that the role of NHC is to assist proton transfer from alcohol to the carbonyl oxygen, forming the tetrahedral intermediate, which then decomposes to the acylated product. Our predicted activation energies are in fine agreement with the observed reaction rates. An alternative approach, which uses the tetrahedral intermediate as the transition state mimic, provides satisfactory predictions.     

Temporary Intramolecular Generation of Pyridine Carbenes in Metal‐Free Three‐Component C?H Bond Functionalisation/Aryl‐Transfer Reactions

Nucleophilic addition of pyridines to benzyne generates zwitterionic adducts that evolve by a rapid intramolecular proton shift to produce the corresponding pyridine carbenes, N‐phenyl pyrid‐2‐ylidenes. In the presence of electrophilic ketones (isatin derivatives), the pyridylidenes can further react by an original bis‐arylation reaction of the carbonyl compounds involving a formal pyridine C? H bond functionalisation. The overall transformation is an unprecedented three‐component reaction featuring a carbene intermediate. The mechanism of this transformation was examined in detail by using both experimental and theoretical approaches. It was found that the generation of N‐phenyl pyrid‐2‐ylidene from pyridine and benzyne is energetically favoured, and that the corresponding carbene dimer can also form easily. Under the three‐component reaction conditions, the pyridylidene preferentially adds to the ketone group of the isatin derivative to produce a zwitterionic adduct amenable to an intramolecular aryl transfer reaction by a concerted nucleophilic aromatic substitution. This peculiar reactivity for a carbene was compared to possibly competitive known reactions of stable carbenes with carbonyl compounds, and the reaction was found to be under thermodynamic control. The reported method of generation of N‐phenyl pyrid‐2‐ylidenes and their reactivity with carbonyl compounds unlock new perspectives in organic synthesis.     

1,2-Versus 1,4-reduction of α,β-unsaturated carbonyl compounds in the gas phase

The regioselectivity involved in the gas-phase hydride reduction of α,β-unsaturated carbonyl compounds by pentacoordinate silicon hydride ions is investigated. The kinetics and product distributions of the reactions of acrolein, methyl vinyl ketone and cyclohex-2-enone with monoalkoxysiliconate ions of the general composition RSiH₃(OR′)^? were examined with the flowing afterglow–triple quadrupole technique. All three substrates react by hydride transfer and by formation of a siliconate adduct in which hydride reduction of the organic reactant has occurred. The structures of these adducts and the hydride transfer products were identified by various tandem mass spectrometric protocols, including analysis of competitive collision-induced dissociation (CID) reactions and comparisons of CID spectra obtained from reference ions with known structures. 1,4-Reduction forming an enolate ion product is found to be the dominant or exclusive process with all three substrates, i.e. acrolein (70 ± 5%), methyl vinyl ketone (72 ± 5%) and cyclohex-2-enone (100%). Comparisons are made between these gas-phase results and the regioselectivity reported for analogous condensed-phase reactions. The observed behavior is discussed in terms of the reaction thermochemistry.     

Synthesis of unsaturated hydroxy acids by the cobalt carbonyl and phase transfer catalyzed carbonylation of vinyl epoxides

Phase transfer catalyzed reaction of vinyl epoxides with carbon monoxide, methyl iodide, catalytic amounts of cobalt carbonyl and TDA-1, affords β-hydroxy acids. High regioselectivity was observed in some cases.     

Evidence for specific solvation of two halocarbene amides

Laser flash photolysis (LFP, 308 nm) of endo-10-halo-10'-N,N-dimethylcarboxamidetricyclo[4.3.1.0]-deca-2,4-diene (1Cl and 1F) releases indan and halocarbene amide (2Cl and 2F). Although the carbenes are not UV-vis active, they react rapidly with pyridine to form ylides (4Cl, 4F), which are readily detected in LFP experiments (lambda(max) = 450 nm). Dioxane decreases the observed rate of carbene reaction with pyridine in CF(2)ClCFCl(2). Small amounts of THF decrease the observed rate of reaction of carbene 2F with pyridine but increase the rate of reaction of carbene 2Cl with pyridine. LFP (266 nm) of dienes 1Cl and 1F in CF(2)ClCFCl(2) with IR detection produces carbenes 2Cl and 2F with carbonyl vibrations at 1635 and 1650 cm(-1), respectively. In dioxane or THF solvent, LFP produces the corresponding ether ylides (5Cl, 5F) by capture of carbenes 2Cl and 2F. The ylides have broad carbonyl vibrations between 1560 and 1610 cm(-1). The addition of a small amount of dioxane in CFCl(2)CF(2)Cl extends the lifetime of the carbene. This observation, together with the ether-induced retardation of the rates of carbene capture by tetramethylethylene and pyridine, is evidence for solvation of the carbene by dioxane.     

Stereoselective hydride uptake in modelsystems related to the redox-couple nad+/nadh

The present work deals with the mechanistic investigations of the hydride transfer reactions concerning the redox couple NAD⁺/NADH. Based on the theoretical and experimental investigatins of NAD(H) model compounds as 3-carbamoyl pyridinium cations (3-carbamoyl-1,4-dihydropyridine) it was found that the out-of-plane rotation of the carbonyl function controls the stereo-and regiospecificity of the introduced hydride anion. It was found that the hydride anion transfered in the reaction, is always syn-positioned with respect to the carbonyl group. The unique stereoselectivity exhibits a strong coherence with the recent crystallographic 3D-data for the ternary complex of NAD bonded horse liver alcohol dehydrogenase. The results show that the amide group is 30° out of the plane with the carbonyl directed toward the A side. There are observations that the absolute configuration of the introduced chirality in the 3-carbamoyl pyridinium cations selects between the hydride uptake coresponding with the enzymatic A or B specificity.     

Heterocyclic Carbene‐Catalyzed Hydride Transfer in the Hydroboration of Carbonyl Compounds

N‐Heterocyclic carbene (NHC) enabled the highly efficient catalytic hydroboration of a wide range of ketones and aldehydes under mild conditions, and a new mechanism of catalytic hydroboration reaction which involves direct hydride transfer is proposed.     

Remote stereocontrol of intramolecular rhodium carbene addition driven by a small and flexible chiral 2,4-pentanediol tether

Intramolecular rhodium carbenoid additions were studied using 2,4-pentanidiol as a chiral tether between a diazo group, a precursor of the carbene, and an aromatic group to be reacted with the carbene. The reaction was designed to perform the addition at a remote position, conserving the original high stereoselectivity appeared at additions near the tether, in addition to high regioselectivity and sufficient reaction efficiency. Substitution on the near reaction sites, the carbene carbon and aromatic group, in the reactant was effective to relegate the reaction site to a remote position. In the present study, two remote reactions, one dealing with C–H insertion and the other classified in Büchner reaction, were found to give sole products in high yields.     

The Mechanism of Sugar C−H Bond Oxidation by a Flavoprotein Oxidase Occurs by a Hydride Transfer Before Proton Abstraction

Understanding the reaction mechanism underlying the functionalization of C−H bonds by an enzymatic process is one of the most challenging issues in catalysis. Here, combined approaches using density functional theory (DFT) analysis and transient kinetics were employed to investigate the reaction mechanism of C−H bond oxidation in d -glucose, catalyzed by the enzyme pyranose 2-oxidase (P2O). Unlike the mechanisms that have been conventionally proposed, our findings show that the first step of the C−H bond oxidation reaction is a hydride transfer from the C2 position of d -glucose to N5 of the flavin to generate a protonated ketone sugar intermediate. The proton is then transferred from the protonated ketone intermediate to a conserved residue, His548. The results show for the first time how specific interactions around the sugar binding site promote the hydride transfer and formation of the protonated ketone intermediate. The DFT results are also consistent with experimental results including the enthalpy of activation obtained from Eyring plots, as well as the results of kinetic isotope effect and site-directed mutagenesis studies. The mechanistic model obtained from this work may also be relevant to other reactions of various flavoenzyme oxidases that are generally used as biocatalysts in biotechnology applications.     

Cyclodextrin Cavity‐Induced Mechanistic Switch in Copper‐Catalyzed Hydroboration

N ‐heterocyclic carbene‐capped cyclodextrin (ICyD) ligands, α‐ICyD and β‐ICyD derived from α‐ and β‐cyclodextrin, respectively give opposite regioselectivities in a copper‐catalyzed hydroboration. The site‐selectivity results from two different mechanisms: the conventional parallel one and a new orthogonal mechanism. The shape of the cavity was shown not only to induce a regioselectivity switch but also a mechanistic switch. The scope of interest of the encapsulation of a reactive center is therefore broadened by this study.     

Quinoprotein methanol dehydrogenase: a molecular dynamics study and comparison with crystal structure

One of the mechanisms proposed for methanol oxidation by methanol dehydrogenase (MDH) involves a hydride transfer to the quinone carbonyl carbon C5 of 2,7,9-tricarboxy-1H-pyrrolo[2,3-f]-quinoline-4,5-dione (PQQ), initiated by abstraction of a proton from the substrate methanol by a general base. Molecular dynamics studies are performed on MDH-bound to the C5 reduced intermediate (C5RI) of PQQ, for 3 ns. The structural features of the MD and X-ray structures are compared. An interesting feature observed during simulations is the strong hydrogen bond between oxyanion O5 of C5RI and Asp297-CO₂H in the active site. Asp297-CO₂⁻ is suggested to be the general-base catalyst for removing the hydroxyl proton of methanol in concert with the hydride ion transfer from the putative methoxide to C5 carbonyl of PQQ. The formed Asp297-CO₂H acts as the required proton source for the immediate product. Anticorreleated motions observed in the MD structure are not across the active site to influence the reaction mechanism of MDH.     

Hydrogen bonding pathways in human dihydroorotate dehydrogenase

Dihydroorotate dehydrogenase (DHOD) catalyzes the only redox reaction in the pathway for pyrimidine biosynthesis. In this reaction, a proton is transferred from a carbon atom of the substrate to a serine residue, and a hydride is transferred from another carbon atom of the substrate to a cofactor. The deprotonation of the substrate is postulated to involve a proton relay mechanism along a hydrogen bonding pathway in the active site. In this paper, molecular dynamics simulations are used to identify and characterize potential hydrogen bonding pathways that could facilitate the redox reaction catalyzed by human DHOD. The observed pathways involve hydrogen bonding of the active base serine to a water molecule, which is hydrogen bonded to the substrate carboxylate group or a threonine residue. The threonine residue is positioned to enable proton transfer to another water molecule leading to the bulk solvent. The impact of mutating the active base serine to cysteine is also investigated. This mutation is found to increase the average donor-acceptor distances for proton and hydride transfer and to disrupt the hydrogen bonding pathways observed for the wild-type enzyme. These effects could lead to a significant decrease in enzyme activity, as observed experimentally for the analogous mutant in Escherichia coli DHOD.     

Iron-catalyzed, highly regioselective synthesis of α-aryl carboxylic acids from styrene derivatives and CO2

The iron-catalyzed hydrocarboxylation of aryl alkenes has been developed using a highly active bench-stable iron(II) precatalyst to give α-aryl carboxylic acids in excellent yields and with near-perfect regioselectivity. Using just 1 mol % FeCl(2), bis(imino)pyridine 6 (1 mol %), CO(2) (atmospheric pressure), and a hydride source (EtMgBr, 1.2 equiv), a range of sterically and electronically differentiated aryl alkenes were transformed to the corresponding α-aryl carboxylic acids (up to 96% isolated yield). The catalyst was found to be equally active with a loading of 0.1 mol %. Preliminary mechanistic investigations show that an iron-catalyzed hydrometalation is followed by transmetalation and reaction with the electrophile (CO(2)).     

Ruthenium-catalyzed chemoselective N-allyl cleavage: novel Grubbs carbene mediated deprotection of allylic amines

A novel application of the Grubbs carbene complex has been discovered. The first examples of the catalytic deprotection of allylic amines with reagents other than palladium catalysts have been achieved through Grubbs carbene mediated reaction. Significantly, the catalytic system directs the reaction toward the selective deprotection of allylic amines (secondary as well as tertiary) in the presence of allylic ethers. A variety of substrates, including enantiomerically pure multifunctional piperidines, are also usable. The new method is more convenient, chemoselective, and operationally simple than the palladium-catalyzed method. The current mechanistic hypothesis invokes a nitrogen-assisted ruthenium-catalyzed isomerization, followed by hydrolysis of the enamine intermediate. We believe that the reactive species involved in the reaction may be an Rubond;H species rather than the Grubbs carbene itself. Thus, the isomerization may occur according to the hydride mechanism. The synthetic utility of this ruthenium-catalyzed allyl cleavage is illustrated by the preparation of indolizidine-type alkaloids.     

Density functional study on enantioselective reduction of keto oxime ether with borane catalyzed by oxazaborolidine

Chiral amino alcohols have interesting biological activities and are used widely as chiral ligands in metal-mediated organic reactions[1―3]. Although many amino alcohols can be derived from the available amino acids, the asymmetric synthesis is an important method to get novel amino alcohols. Tillyer et al.[4] reported a new, highly stereoselective synthesis of cyclic (1S,2R)-cis amino alcohols A from keto oxime ethers B, via the enantioselective reduction catalyzed by oxazaborolidine C in …     

Selective sp3 C-H activation of ketones at the beta position by Ir(I). Origin of regioselectivity and water effect

The reaction of the cationic (PNP)Ir(I)(cyclooctene) complex (1) (PNP = 2,6-bis-(di-tert-butylphosphinomethyl)pyridine) with 2-butanone or 3-pentanone results in the selective, quantitative activation of a beta C-H bond, yielding O,C-chelated complexes. Calculations show that the selectivity is both kinetically (because of steric reasons in the rate determingin step (RDS)) and thermodynamically controlled, the latter as a result of carbonyl oxygen coordination in the product. The RDS is formation of the eta2-C,H intermediates from the complexed ketone intermediates. Water has a strong influence on the regioselectivity, and in its presence, reaction of 1 with 2-butanone gives also the alpha terminal C-H activation product. Computational studies suggest that water can stabilize the terminal alpha C-H activation product by hydrogen bonding, forming a six-membered ring with the ketone, as experimentally observed in the X-ray structure of the acetonyl hydride aqua complex.     

A DFT study of the mechanism of polymerization of epsilon-caprolactone initiated by organolanthanide borohydride complexes

The mechanisms of polymerization of epsilon-caprolactone (CL) initiated by either the rare-earth hydride [Cp2Eu(H)] or the borohydrides [Cp2Eu(BH4)] or [(N2NN')Eu(BH4)] were studied at the DFT level (Cp=eta5-C5H5; N2NN'=(2-C5H4N)CH2(CH2CH2NMe)2). For all compounds the reaction proceeds in two steps: a hydride transfer from the rare earth initiator to the carbonyl carbon of the lactone, followed by ring-opening of the monomer. In the last step a difference is observed between the hydride and borohydride complexes, because for the latter the ring-opening is induced by an additional B-H bond cleavage leading to a terminal--CH2OBH2 group. This corresponds to the reduction by BH3 of the carbonyl group of CL. Upon reaction of [Cp2Eu(H)] with CL, the alkoxy-aldehyde complex produced, [Cp2Eu(O(CH2)5C(O)H)], is the first-formed initiating species. In contrast, for the reaction of CL with the borohydride complexes [(Lx)Eu(BH4)] (Lx=Cp2 or N2NN'), an aliphatic alkoxide with a terminal--CH2OBH2 group, [(Lx)Eu(O(CH2)6OBH2)] is formed and subsequently propagates the polymerization. The present DFT investigations are fully compatible with previously reported mechanistic studies of experimental systems.