Reaction Of Enolate Research Articles

ChemInform Abstract: Copper‐Catalyzed Oxysulfenylation of Enolates with Sodium Sulfinates: A Strategy to Construct Sulfenylated Cyclic Ethers.

AbstractThe Cu‐catalyzed reaction of enols (I), (VII), and (IX) with sodium sulfinates (II) in the presence of DMF as reducing agent and solvent gives rise to cyclic ethers (III), (VIII), and (X).

Organocatalytic Enantioselective Intramolecular Oxa-Michael Reaction of Enols: Synthesis of Chiral Isochromenes.

An unprecedented enantioselective intramolecular oxa-Michael reaction of enols has been described. A squaramide-containing tertiary amine based bifunctional organocatalyst efficiently activates the o-homoformyl chalcones to provide the chiral isochromenes in moderate yields and good to excellent enantioselectivities. Further, late-stage functionalizations of the vinyl ether moiety of the chiral isochromene products have also been exemplified.

ChemInform Abstract: Theory and Modeling of Asymmetric Catalytic Reactions

AbstractReview: 70 refs.

Scope and mechanism of the highly stereoselective metal-mediated domino aldol reactions of enolates with aldehydes.

A one-pot transformation, which involves the reaction of ketones with aldehydes in the presence of metal halides to furnish tetrahydro-2H-pyran-2,4-diols in a highly diastereoselective manner, is investigated thoroughly by experiments and computations. The reaction was also successfully implemented on a flow micro reactor system.

Determination of thermodynamic parameters for enolization reaction of malonic and metylmalonic acids by using quartz crystal microbalance

We investigated the process of a bromination reaction of malonic acid and methylmalonic acid in the Belousov-Zhabotinsky reaction by using a quartz crystal microbalance (QCM). The process involves an enolization reaction as a rate-determining step. We found that, in the step, the variation of Br2 concentration induced an exactly quantitative shift of a resonant frequency of the QCM, based on the change of the surface mass on the QCM and the solution viscosity and density. This new finding enabled us to estimate the reaction rate constants and the thermodynamic parameters of the enolization reaction due to a QCM measurement. The values measured by the QCM were in good agreement with those measured by a UV-spectrophotometer. As a result, we succeeded to develop a new measurement method of a nonlinear chemical reaction.

Theory and Modeling of Asymmetric Catalytic Reactions.

Modern density functional theory and powerful contemporary computers have made it possible to explore complex reactions of value in organic synthesis. We describe recent explorations of mechanisms and origins of stereoselectivities with density functional theory calculations. The specific functionals and basis sets that are routinely used in computational studies of stereoselectivities of organic and organometallic reactions in our group are described, followed by our recent studies that uncovered the origins of stereocontrol in reactions catalyzed by (1) vicinal diamines, including cinchona alkaloid-derived primary amines, (2) vicinal amidophosphines, and (3) organo-transition-metal complexes. Two common cyclic models account for the stereoselectivity of aldol reactions of metal enolates (Zimmerman-Traxler) or those catalyzed by the organocatalyst proline (Houk-List). Three other models were derived from computational studies described in this Account. Cinchona alkaloid-derived primary amines and other vicinal diamines are venerable asymmetric organocatalysts. For α-fluorinations and a variety of aldol reactions, vicinal diamines form enamines at one terminal amine and activate electrophilically with NH(+) or NF(+) at the other. We found that the stereocontrolling transition states are cyclic and that their conformational preferences are responsible for the observed stereoselectivity. In fluorinations, the chair seven-membered cyclic transition states is highly favored, just as the Zimmerman-Traxler chair six-membered aldol transition state controls stereoselectivity. In aldol reactions with vicinal diamine catalysts, the crown transition states are favored, both in the prototype and in an experimental example, shown in the graphic. We found that low-energy conformations of cyclic transition states occur and control stereoselectivities in these reactions. Another class of bifunctional organocatalysts, the vicinal amidophosphines, catalyzes the (3 + 2) annulation reaction of allenes with activated olefins. Stereocontrol here is due to an intermolecular hydrogen bond that activates the electrophilic partner in this reaction. We have also studied complex organometallic catalysts. Krische's ruthenium-catalyzed asymmetric hydrohydroxyalkylation of butadiene involves two chiral ligands at Ru, a chiral diphosphine and a chiral phosphate. The size of this combination strains the limits of modern computations with over 160 atoms, multiple significant steps, and a variety of ligand coordinations and conformations possible. We found that carbon-carbon bond formation occurs via a chair Zimmerman-Traxler-type transition structure and that a formyl CH···O hydrogen bond from aldehyde CH to phosphate oxygen, as well as steric interactions of the two chiral ligands, control the stereoselectivity.

ChemInform Abstract: Asymmetric Synthesis of β‐Trifluoromethyl‐β‐amino Acids, Including Highly Sterically Constrained α,α‐Dialkyl Derivatives.

AbstractTitle compounds are synthesized via Mannich addition reaction of chiral trifluoroacetaldimine and lithium enolates of alkyl acetates.

Copper-Catalyzed Oxysulfenylation of Enolates with Sodium Sulfinates: A Strategy To Construct Sulfenylated Cyclic Ethers.

A new copper-catalyzed oxysulfenylation reaction of enolates with sodium sulfinates has been disclosed. A series of sulfenylated heterocycles including four- and seven-membered cyclic ether were obtained in mild to good yields. This reaction is proposed to go through a radical process, and the sulfur radical (RS(•)) may be a reactive species.

Oxidation and β-Alkylation of Alcohols Catalysed by Iridium(I) Complexes with Functionalised N-Heterocyclic Carbene Ligands.

The borrowing hydrogen methodology allows for the use of alcohols as alkylating agents for CC bond forming processes offering significant environmental benefits over traditional approaches. Iridium(I)-cyclooctadiene complexes having a NHC ligand with a O- or N-functionalised wingtip efficiently catalysed the oxidation and β-alkylation of secondary alcohols with primary alcohols in the presence of a base. The cationic complex [Ir(NCCH3 )(cod)(MeIm(2- methoxybenzyl))][BF4 ] (cod=1,5-cyclooctadiene, MeIm=1-methylimidazolyl) having a rigid O-functionalised wingtip, shows the best catalyst performance in the dehydrogenation of benzyl alcohol in acetone, with an initial turnover frequency (TOF0 ) of 1283 h(-1) , and also in the β-alkylation of 2-propanol with butan-1-ol, which gives a conversion of 94 % in 10 h with a selectivity of 99 % for heptan-2-ol. We have investigated the full reaction mechanism including the dehydrogenation, the cross-aldol condensation and the hydrogenation step by DFT calculations. Interestingly, these studies revealed the participation of the iridium catalyst in the key step leading to the formation of the new CC bond that involves the reaction of an O-bound enolate generated in the basic medium with the electrophilic aldehyde.

ChemInform Abstract: Synthesis of Functionalized Cyclohexenols via a Domino Michael Addition—Dieckmann Cyclization—Isomerization Reaction Sequence.

Abstract A simple and new protocol for the synthesis of functionalized cyclohexenols via a domino Michael addition followed by Dieckmann cyclization and enolization reaction sequence has been described. A wide variety of activated olefins were utilized in the domino cyclization along with Baylis–Hillman derivatives to afford libraries of functionalized cyclohexenols in good yields.

Evidence for an induced conformational change in the catalytic mechanism of homoisocitrate dehydrogenase for Saccharomyces cerevisiae: Characterization of the D271N mutant enzyme

Homoisocitrate dehydrogenase (HIcDH) catalyzes the NAD+-dependent oxidative decarboxylation of HIc to α-ketoadipate, the fourth step in the α-aminoadipate pathway responsible for the de novo synthesis of l-lysine in fungi. A mechanism has been proposed for the enzyme that makes use of a Lys–Tyr pair as acid-base catalysts, with Lys acting as a base to accept a proton from the α-hydroxyl of homoisocitrate, and Tyr acting as an acid to protonate the C3 of the enol of α-ketoadipate in the enolization reaction. Three conserved aspartate residues, D243, D267 and D271, coordinate Mg2+, which is also coordinated to the α-carboxylate and α-hydroxyl of homoisocitrate. On the basis of kinetic isotope effects, it was proposed that a conformational change to close the active site and organize the active site for catalysis contributed to rate limitation of the overall reaction of the Saccharomyces cerevisiae HIcDH (Lin, Y., Volkman, J., Nicholas, K. M., Yamamoto, T., Eguchi, T., Nimmo, S. L., West, A. H., and Cook, P. F. (2008) Biochemistry47, 4169–4180.). In order to test this hypothesis, site-directed mutagenesis was used to change D271, a metal ion ligand and binding determinant for MgHIc, to N. The mutant enzyme was characterized using initial rate studies. A decrease of 520-fold was observed in V and V/KMgHIc, suggesting the same step(s) limit the reaction at limiting and saturating MgHIc concentrations. Solvent kinetic deuterium isotope effects (SKIE) and viscosity effects are consistent with a rate-limiting pre-catalytic conformational change at saturating reactant concentrations. In addition, at limiting MgHIc, an inverse (SKIE) of 0.7 coupled to a significant normal effect of viscosogen (2.1) indicates equilibrium binding of MgHIc prior to the rate-limiting conformational change. The maximum rate exhibits a small partial change at high pH suggesting a pH-dependent conformational change, while V/KMgHIc exhibits the same partial change observed in V, and a decrease at low pH with a pKa of 6 reflecting the requirement for the unprotonated form of MgHIc to bind to enzyme. However, neither parameter reflects the pH dependence of the chemical reaction. This pH independence of the chemical reaction over the range 5.5–9.5 is consistent with the much slower conformational change that would effectively perturb the observed pK values for catalytic groups to lower and higher pH. In other words, the pH dependence of the chemical reaction will only be observed when chemistry becomes slower than the rate of the conformational change. Data support the hypothesis of the existence of a pre-catalytic conformational change coupled to the binding of MgHIc.

ChemInform Abstract: Organocatalyzed Tandem Process Involving Asymmetric Protonations as a Stereo‐Defining Step

AbstractReview: 127 refs.

Synthesis of functionalized cyclohexenols via a domino Michael addition–Dieckmann cyclization–isomerization reaction sequence

A simple and new protocol for the synthesis of functionalized cyclohexenols via a domino Michael addition followed by Dieckmann cyclization and enolization reaction sequence has been described. A wide variety of activated olefins were utilized in the domino cyclization along with Baylis–Hillman derivatives to afford libraries of functionalized cyclohexenols in good yields.

Understanding the role of the trifluoromethyl group in reactivity and regioselectivity in [3+2] cycloaddition reactions of enol acetates with nitrones. A DFT study.

The mechanism of the [3+2] cycloaddition (32CA) reaction of C-phenyl-N-methylnitrone with ethyl trifluoroacetoacetate has been theoretically studied at the MPWB1K/6-311G(d,p) level. This 32CA reaction, in which the enol form of the β-keto ester participates as the ethylene component, takes place with complete ortho regioselectivity and exo stereoselectivity. The presence of the CF3 group in the β-position in the enol acetate accelerates the 32CA reaction, but it does not modify the regioselectivity, which is controlled by the presence of the ester group. While ortho regioselectivity is reproduced by the MPWB1K calculations, the endo selectivity is not. The inclusion of solvent effects slightly decreases the reactivity but does not modify the gas phase selectivities. Analysis of the DFT global reactivity indices and the Parr functions in reagents provide a rationalization for the participation of ethyl trifluoroacetoacetate and the regioselectivity in this zw-type 32CA reaction.

ChemInform Abstract: Rhenium Complex‐Catalyzed Coupling Reaction of Enol Acetates with Alcohols.

Abstract The reaction of enol acetates with alcohols in the presence of a catalytic amount of a rhenium complex, such as ReBr(CO) 5 , produced the corresponding ketones and aldehydes in moderate to good yields. It was suggested that the preparation of an ether, an intermolecular dehydrated product, was the first step of the reaction.

Synthesis of the all-syn C35–C39 stereopentad of etnangien by the γ-hydroxybutenolide approach

The synthesis of the all-syn C35–C39 stereopentad of etnangien has been achieved using the asymmetric aldol reaction of a γ-hydroxybutenolide (5-hydroxy-4-methylfuran-2(5H)-one) as the key step in the five-step synthesis. The reaction of the titanium enolate of (S)-4-isopropyl-3-propionyl-2-oxazolidinone with 5-hydroxy-4-methylfuran-2(5H)-one gave good yields and diastereoselectivity of corresponding lactone, which was converted into a lactone with an all-syn stereotriad.

Organocatalyzed tandem process involving asymmetric protonations as a stereo-defining step

Enantioselective protonation reactions of enolates, enols, enol ethers, or enol esters have been extensively studied. On the other hand, their applications in tandem or cascade sequence have not been fully explored and examples of such reactions employing organocatalysts are few. This account describes some of the most common synthetic strategies recently developed to address such challenge.

Rhenium complex-catalyzed coupling reaction of enol acetates with alcohols

The reaction of enol acetates with alcohols in the presence of a catalytic amount of a rhenium complex, such as ReBr(CO)5, produced the corresponding ketones and aldehydes in moderate to good yields. It was suggested that the preparation of an ether, an intermolecular dehydrated product, was the first step of the reaction.

Universal tight binding model for chemical reactions in solution and at surfaces. I. Organic molecules.

As is now well established, a first order expansion of the Hohenberg-Kohn total energy density functional about a trial input density, namely, the Harris-Foulkes functional, can be used to rationalize a non self consistent tight binding model. If the expansion is taken to second order then the energy and electron density matrix need to be calculated self consistently and from this functional one can derive a charge self consistent tight binding theory. In this paper we have used this to describe a polarizable ion tight binding model which has the benefit of treating charge transfer in point multipoles. This admits a ready description of ionic polarizability and crystal field splitting. It is necessary in constructing such a model to find a number of parameters that mimic their more exact counterparts in the density functional theory. We describe in detail how this is done using a combination of intuition, exact analytical fitting, and a genetic optimization algorithm. Having obtained model parameters we show that this constitutes a transferable scheme that can be applied rather universally to small and medium sized organic molecules. We have shown that the model gives a good account of static structural and dynamic vibrational properties of a library of molecules, and finally we demonstrate the model's capability by showing a real time simulation of an enolization reaction in aqueous solution. In two subsequent papers, we show that the model is a great deal more general in that it will describe solvents and solid substrates and that therefore we have created a self consistent quantum mechanical scheme that may be applied to simulations in heterogeneous catalysis.

Iridium-catalyzed enantioselective allylic substitution of unstabilized enolates derived from α,β-unsaturated ketones.

We report Ir-catalyzed, enantioselective allylic substitution reactions of unstabilized silyl enolates derived from α,β-unsaturated ketones. Asymmetric allylic substitution of a variety of allylic carbonates with silyl enolates gave allylated products in 62-94% yield with 90-98% ee and >20:1 branched-to-linear selectivity. The synthetic utility of this method was illustrated by the short synthesis of an anticancer agent, TEI-9826.