Deep tunneling dominates the biologically important hydride transfer reaction from NADH to FMN in morphinone reductase

The temperature dependence of the primary kinetic isotope effect (KIE), combined temperature-pressure studies of the primary KIE, and studies of the alpha-secondary KIE previously led us to infer that hydride transfer from nicotinamide adenine dinucleotide to flavin mononucleotide in morphinone reductase proceeds via environmentally coupled hydride tunneling. We present here a computational analysis of this hydride transfer reaction using QM/MM molecular dynamics simulations and variational transition-state theory calculations. Our calculated primary and secondary KIEs are in good agreement with the corresponding experimental values. Although the experimentally observed KIE lies below the semiclassical limit, our calculations suggest that approximately 99% of the reaction proceeds via tunneling: this is the first "deep tunneling" reaction observed for hydride transfer. We also show that the dominant tunneling mechanism is controlled by the isotope at the primary rather than the secondary position: with protium in the primary position, large-curvature tunneling dominates, whereas with deuterium in this position, small-curvature tunneling dominates. Also, our study is consistent with tunneling being preceded by reorganization: in the reactant, the rings of the nicotinamide and isoalloxazine moieties are stacked roughly parallel to each other, and as the system moves toward a "tunneling-ready" configuration, the nicotinamide ring rotates to become almost perpendicular to the isoalloxazine ring.     

Formation of the active species of cytochrome p450 by using iodosylbenzene: a case for spin-selective reactivity

The generation of the active species for the enzyme cytochrome P450 by using the highly versatile oxygen surrogate iodosylbenzene (PhIO) often produces different results compared with the native route, in which the active species is generated through O(2) uptake and reduction by NADPH. One of these differences that is addressed here is the deuterium kinetic isotope effect (KIE) jump observed during N-dealkylation of N,N-dimethylaniline (DMA) by P450, when the reaction conditions change from the native to the PhIO route. The paper presents a theoretical analysis targeted to elucidate the mechanism of the reaction of PhIO with heme, to form the high-valent iron-oxo species Compound I (Cpd I), and define the origins of the KIE jump in the reaction of Cpd I with DMA. It is concluded that the likely origin of the KIE jump is the spin-selective chemistry of the enzyme cytochrome P450 under different preparation procedures. In the native route, the reaction proceeds via the doublet spin state of Cpd I and leads to a low KIE value. PhIO, however, diverts the reaction to the quartet spin state of Cpd I, which leads to the observed high KIE values. The KIE jump is reproduced here experimentally for the dealkylation of N,N-dimethyl-4-(methylthio)aniline, by using intra-molecular KIE measurements that avoid kinetic complexities. The effect of PhIO is compared with N,N-dimethylaniline-N-oxide (DMAO), which acts both as the oxygen donor and the substrate and leads to the same KIE values as the native route.     

Measuring the kinetic isotope effect at natural isotopic abundances for discriminating between the homogeneous and heterogeneous catalytic mechanisms in the Heck and Suzuki reactions

The kinetic isotope effect (KIE) at the natural abundances of bromine and carbon isotopes in the substrates of the Heck and Suzuki reactions have been investigated to determine the true nature of catalyst in these reactions. Data processing has demonstrated that statistically significant differences between KIE values for the Suzuki reaction of nonactivated bromobenzene are observed upon the replacement of the soluble catalyst precursor with the insoluble one. This finding unambiguously indicates that the reaction takes place on heterogeneous palladium species. Similar experiments on the Heck reaction have demonstrated that the KIE values are insensitive to the nature of the catalyst precursor, which is consistent with the true homogeneous mechanism of catalysis.     

Probing the transition states of four glucoside hydrolyses with 13C kinetic isotope effects measured at natural abundance by NMR spectroscopy

Kinetic isotope effects (KIEs) were measured for methyl glucoside (4) hydrolysis on unlabeled material by NMR. Twenty-eight (13)C KIEs were measured on the acid-catalyzed hydrolysis of alpha-4 and beta-4, as well as enzymatic hydrolyses with yeast alpha-glucosidase and almond beta-glucosidase. The 1-(13)C KIEs on the acid-catalyzed reactions of alpha-4 and beta-4, 1.007(2) and 1.010(6), respectively, were in excellent agreement with the previously reported values (1.007(1), 1.011(2): Bennet and Sinnott, J. Am. Chem. Soc. 1986, 108, 7287). Transition state analysis of the acid-catalyzed reactions using the (13)C KIEs, along with the previously reported (2)H KIEs, confirmed that both reactions proceed with a stepwise D(N)A(N) mechanism and showed that the glucosyl oxocarbenium ion intermediate exists in an E(3) sofa or (4)H(3) half-chair conformation. (13)C KIEs showed that the alpha-glucosidase reaction also proceeded through a D(N)*A(N) mechanism, with a 1-(13)C KIE of 1.010(4). The secondary (13)C KIEs showed evidence of distortions in the glucosyl ring at the transition state. For the beta-glucosidase-catalyzed reaction, the 1-(13)C KIE of 1.032(1) demonstrated a concerted A(N)D(N) mechanism. The pattern of secondary (13)C KIEs was similar to the acid-catalyzed reaction, showing no signs of distortion. KIE measurement at natural abundance makes it possible to determine KIEs much more quickly than previously, both by increasing the speed of KIE measurement and by obviating the need for synthesis of isotopically labeled compounds.     

Metal–Organic Frameworks as Efficient Heterogeneous Catalysts for the Regioselective Ring Opening of Epoxides

An iron‐based metal–organic framework, [Fe(BTC)] (BTC: 1,3,5‐benzenetricarboxylate) is an efficient catalyst in the ring opening of styrene oxide with alcohols and aniline under mild reaction conditions. Out of the various alcohols tested for ring opening of styrene oxide, methanol was found to be the most reactive in terms of percentage conversion and reactivity. The rate of the ring‐opening reaction of styrene oxide decreases as the size of the alcohol is increased, suggesting the location of active sites in micropores. [Fe(BTC)] was a truly heterogeneous catalyst and could be reused without loss of activity. The analogous compound [Cu₃(BTC)₂] was also found to be effective, although with somewhat lower activity than [Fe(BTC)]. The present heterogeneous protocol is compared with a homogeneous catalyst to give an insight into the reaction mechanism.     

Quantum-classical Liouville dynamics of proton and deuteron transfer rates in a solvated hydrogen-bonded complex

Proton and deuteron transfer reactions in a hydrogen-bonded complex dissolved in a polar solution are studied using quantum-classical Liouville dynamics. Reactive-flux correlation functions that involve quantum-classical Liouville dynamics for species operators and quantum equilibrium sampling are used to calculate the rate constants. Adiabatic and nonadiabatic reaction rates are computed, compared, and analyzed. Large variations of the kinetic isotope effect (KIE) for this reaction have been observed in the literature, which depend on the nature of the approximate calculation used to estimate the proton and deuteron transfer rates. Our estimate of the KIE lies at the low end of the range of previously observed values, suggesting a rather small KIE for this reaction.     

Synthetic studies on stevastelins. 1. Total synthesis of stevastelins B and B3

[Chemical reaction: See text] The synthesis of stevastelin B3 (2) and B (5) are described. In a first approach, epoxy cyclodepsipeptide 8 was considered as a promising candidate for the synthesis of the [15]-membered ring members of the stevastelins; however, the oxirane ring opening, required for the completion of the natural stevastelin synthesis, failed. Thus, we synthesized stevastelin B (5), carrying out the oxirane ring opening earlier in the synthesis and following a synthetic scheme capable of delivering analogues. On the other hand, a translactonization reaction of the [15]-membered ring derivative 59 led to the total synthesis of the natural [13]-membered ring component of the stevastelins family, stevastelin B3 (2).     

Ribosyl geometry in the transition state of Streptococcus pneumoniae methylthioadenosine nucleosidase from the 3'-(2)H kinetic isotope effect

Synthesis of [3'-2H]-labeled 5'-methylthioadenosine (MTA) derivatives permitted measurement of the [3'-2H] KIE of the reaction catalyzed by Streptococcus pneumoniae methylthioadenosine nucleosidase (spMTAN). The key [3'-2H] KIE revealed the partial 3'-OH polarization and H3'-endo-->exo ribosyl configuration at the spMTAN transition state. A new understanding of the transition state stabilization of spMTAN-catalyzed hydrolysis is uncovered in structural features at the spMTAN transition state.     

Kinetic Isotope Effect as a Tool To Investigate the Oxygen Reduction Reaction on Pt-based Electrocatalysts – Part I: High-loading Pt/C and Pt Extended Surface

Kinetic isotope effect (KIE) was used to study the rate-determining step for oxygen reduction reaction (ORR) on dispersed Pt/C electrocatalyst and polycrystalline Pt (Pt-poly). KIE is defined as the ratio of the kinetic current measured in protonated electrolyte versus deuterated electrolyte, with KIE values larger than one indicating proton participation in the rate-determining step. The effect of poisoning anions on the platinum rate determining step is investigated by assessing the KIE in perchloric (non-poisoning) and sulfuric acid-based electrolytes. The kinetics currents were calculated using the Koutechy-Levich and Tafel analysis. A KIE of 1 was observed for Pt/C (with a 40 wt.% Pt loading) and Pt-poly, thus indicating that, on 40 wt. % Pt/C and Pt-poly, the rate determining step is proton independent.     

Conrotatory photochemical ring opening of alkylcyclobutenes in solution. A test of the hot ground-state mechanism.

Quantum yields for photochemical ring opening of six alkylcyclobutenes have been measured in hexane solution using 228-nm excitation, which selectively populates the lowest pi,R(3s) excited singlet states of these molecules and has been shown previously to lead to ring opening with clean conrotatory stereochemistry. The compounds studied in this work-1,2-dimethylcyclobutene (1), cis- and trans-1,2,3,4-tetramethylcyclobutene (cis- and trans-5), hexamethylcyclobutene (8), and cis- and trans-tricyclo[6.4.0.0(2,7)]dodec-1(2)-ene (cis- and trans-9)-were selected so as to span a broad range in molecular weight and as broad a range as possible in Arrhenius parameters for thermal (ground-state) ring opening. RRKM calculations have been carried out to provide estimates of the rate constants for ground-state ring opening of each of the compounds over a range of thermal energies from 20 000 to 49 000 cm(-1). These have been used to estimate upper limits for the quantum yields of ring opening via a hot ground-state mechanism, assuming a value of k(deact) = 10(11) s(-1) for the rate constant for collisional deactivation by the solvent, that internal conversion to the ground state from the lowest Rydberg state occurs with close to unit efficiency, and that ergodic behavior is followed. The calculated quantum yields are significantly lower than the experimental values in all cases but one (1). This suggests that the Rydberg-derived ring opening of alkylcyclobutenes is a true excited-state process and rules out the hot ground-state mechanism for the reaction.     

Asymmetric synthesis of the highly methylated tryptophan portion of the hemiasterlin tripeptides

[reaction: see text] The asymmetric synthesis of the methylated tryptophan portion of hemiasterlin peptides is described. The key reactions are a SnCl4-mediated ring opening of epoxynitriles or epoxysulfones by N-methylindole followed by an asymmetric Strecker reaction. A second approach involving opening of glycidic esters by indoles is also described.     

Palladium-mediated ring opening of hydroxycyclopropanes

[reaction: see text] The palladium-mediated ring opening of substituted cyclopropanols has been found to take place predominantly at the less substituted C-C bond. Thus, sequential application of the titanium-mediated cyclopropanation of esters and the palladium-mediated ring opening of the resulting cyclopropanols provides a convenient method for functionalizing monosubstituted olefins.     

Reactions of PhSCH(2)Li and NCCH(2)Li with benzaldehyde and benzophenone: when does the mechanism change from ET to polar?

The carbonyl-carbon kinetic isotope effect (KIE) and the substituent effect were measured for the reaction of phenylthiomethyllithium (PhSCH(2)Li, 1) with benzaldehyde and benzophenone, and cyanomethyllithium (NCCH(2)Li, 2) with benzaldehyde, and the results were compared with those for other lithium reagents such as MeLi, PhLi, CH(2)=CHCH(2)Li, and CH(2)=C(OLi)C(CH(3))(3). It was previously shown that the reactions of MeLi, PhLi, and CH(2)=CHCH(2)Li proceed via a rate-determining electron transfer (ET) process whereas the reaction of lithium pinacolone enolate goes through the polar (PL) mechanism. The reaction of 1 with benzaldehyde gave no carbonyl-carbon KIE ((12)k/(13)k = 0.999 +/- 0.004), similar to that measured previously for the MeLi reaction with benzophenone ((12)k/(14)k = 1.000). The effect of substituents of the aromatic ring of benzaldehyde and benzophenone on the reactivity gave very small Hammett rho values of 0.17 +/- 0.03 and 0.26 +/- 0.05, respectively. These small rho values are again similar to that observed for the reaction of MeLi. Likewise the reactions of 2 with benzaldehydes gave small KIE and the rho value ((12)k/(13)k = 0.996 +/- 0.004, rho = 0.14 +/- 0.02). Dehalogenation and enone-isomerization probe experiments for 2 showed no evidence for the presence of radical-ion pair of sufficient lifetime during the course of the reaction. It is concluded that the reactions of 1 and 2 with the aromatic carbonyl compounds proceed via the electron transfer-radical coupling mechanism with rate-determining ET as in the reactions of MeLi, PhLi, and CH(2)=CHCH(2)Li.     

Structural effects on the beta-scission reaction of alkoxyl radicals. Direct measurement of the absolute rate constants for ring opening of benzocycloalken-1-oxyl radicals

[reaction: see text] The absolute rate constants for beta-scission of a series of benzocycloalken-1-oxyl radicals and of the 2-(4-methylphenyl)-2-butoxyl radical have been measured directly by laser flash photolysis. The benzocycloalken-1-oxyl radicals undergo ring opening with rates which parallel the ring strain of the corresponding cycloalkanes. In the 1-X-indan-1-oxyl radical series, ring opening is observed when X = H, Me, whereas exclusive C-X bond cleavage occurs when X = Et. The factors governing the fragmentation regioselectivity are discussed.     

二环丁烷[1.1.0]开环反应的量子化学研究

本文用MNDO方法研究了二环丁烷[1.1.0]开环反应的反应途径, 并优化了该反应的反应物、产物和过渡态的结构, 在理论上证明了此开环反应的反应机理。     

A one-pot sequence for the efficient synthesis of highly functionalized macrocarbocycles or bridged 2,8-dioxabicyclo[3.2.1]octanes from 1-nitrobicyclic compounds

The reaction of 1-nitrobicyclo[n.3.1]alkane-(6 + n)ones with sodium borohydride followed by acidic workup led to ring opening via a one-pot sequence comprising the retro-Dieckmann-type opening of the α-nitroketone structural fragment, followed by aldehyde reduction and a final Nef reaction, leading to highly functionalized 12 to 14-membered carbocyclic ketones bearing three stereocenters, which are adjacent in some of the compounds. The reactions starting from 1-nitrobicyclo[9.3.1]pentadecan-15-ones could be adjusted to give macrocyclic 2,8-dioxabicyclo[3.2.1]octanes containing an additional bridge by diastereoselective formation of a third ring and a fourth stereocenter through acid-promoted intramolecular ketal formation. This is a very interesting ring system related to the core of the zaragozic acid family of natural products.     

Electrocyclic ring opening of cis-bicyclo[m.n.0]alkenes: the anti-Woodward-Hoffmann quest

The dubbed anti-Woodward-Hoffmann ring-opening reaction of cis-bicyclo[4.2.0]oct-7-ene to yield cis,cis-cycloocta-1,3-diene has been intensively studied with robust, high-level computational methods. This reaction has been found to proceed through a conrotatory allowed pathway to afford cis,trans-cycloocta-1,3-diene followed by E to Z isomerization, instead of a disrotatory forbidden pathway, as suggested. Computational calculations of kinetic isotope effects are consistent with this interpretation and the experimental values. The study of lower bicyclic homologues with [3.2.0], [2.2.0] and [2.1.0] skeletons indicates the feasibility of a mechanistic change towards the anti-Woodward-Hoffmann disrotatory path. This is clearly favored for the ring opening of the highly strained cis-bicyclo[2.1.0]pent-2-ene and is highly competitive with the conrotatory path for cis-bicyclo[2.2.0]hex-2-ene. Therefore, the rearrangement of the smallest bicyclic cyclobutene is predicted computationally to be an anti-Woodward-Hoffmann disrotatory electrocyclic ring-opening reaction.     

Isotope Separation Factor and Kinetic Isotopic Effect of the Hydrogen Evolution Reaction

The hydrogen isotope separation factor decreases with increasing overvoltage on mercury-like electrodes in acid solutions. This dependence qualitatively differs from that for the ratio between hydrogen evolution rates in light and heavy water, which increases with polarization. The reason for the difference is that the isotope separation factor depends on the kinetic isotopic effect (KIE) in two reaction stages: discharge and electrochemical desorption. Experimental data show that a decrease in KIE with potential in the latter stage outweighs the increase in KIE in the former. The KIE decreases in the desorption reaction because this process is activationless; therefore, there is no potential dependence of the relative contribution made by vibrationally excited states of the product in this case, i.e. no dependence that is responsible for the increase in KIE at the discharge stage. The same factor has no effect on KIE for a barrierless discharge, which also decreases with increasing overvoltage. Thus, all experimentally observed dependences of KIE on potential are explained in the framework of a unified approach.     

Highly diastereoselective formation of 1,2,3-trisubstituted cyclopropane derivatives

A highly diastereoselective formation of cyclopropane derivatives was reported. When the chiral phenylvinyl epoxide reacted with lithiated 2-alkyl-1,3-dithiane or lithiated alkyl carbonanion in the presence of HMPA, cyclopropanes bearing stereochemistry at all three positions on the ring were readily obtained in high yields of 80-97% and high dr values of 68:32-99:1. This reaction was supposed to be a tandem conjugation addition-epoxide opening sequence. [reaction: see text]     

Intramolecular cyclopropanation of glycals: studies toward the synthesis of canadensolide, sporothriolide, and xylobovide

[reaction: see text] The first examples of copper-catalyzed intramolecular cyclopropanations of glycal-derived diazoacetates are reported. The new cyclopropanes are converted into advanced intermediates for the synthesis of bislactone natural products. Synthetic highlights include the selective monodeprotection of a di-tert-butylsilylene ether and a zinc-mediated ring opening cascade reaction.