Oxocarbenium Ion Research Articles

Hydrosilylation of Carbonyl-Containing Substrates Catalyzed by an Electrophilic η1-Silane Iridium(III) Complex

Hydrosilation of a variety of ketones and aldehydes using the cationic iridium catalyst, (POCOP)Ir(H)(acetone)(+), 1, (POCOP = 2,6-bis(di-tert-butyl phosphinito)phenyl) is reported. With triethyl silane, all but exceptionally bulky ketones undergo quantitative reactions employing 0.5 mol% catalyst in 20-30 min at 25 °C. Hydrosilation of esters and amides results in over-reduction and cleavage of C-O and C-N bonds, respectively. The diastereoselectivity of hydrosilation of 4-tert-butyl cyclohexanone has been examined using numerous silanes and is highly temperature dependent. Using EtMe(2)SiH, analysis of the ratio of cis:trans hydrosilation products as a function of temperature yields values for ΔΔH(‡) (ΔH(‡) (trans) - ΔH(‡) (cis)) and ΔΔS(‡) (ΔS(‡) (trans) - ΔS(‡)(cis)) of -2.5 kcal/mol and -6.9 e.u., respectively. Mechanistic studies show that the ketone complex, (POCOP)Ir(H)(ketone)(+), is the catalyst resting state and is in equilibrium with low concentration of the silane complex, (POCOP)Ir(H)(HSiR(3))(+). The silane complex transfers R(3)Si(+) to ketone forming the oxocarbenium ion, R(3)SiOCR'(2) (+), which is reduced by the resulting neutral dihydride 3, (POCOP)Ir(H)(2), to yield product R(3)SiOCHR'(2) and (POCOP)IrH(+) which closes the catalytic cycle.

On the mechanism of the N-glycosydic bond hydrolysis of 2′-deoxyguanosine: insights from first principles calculations

The effect of the activation of the nucleobase (leaving group) or the activation of the water molecule (nucleophile) by a general acid or a general base on the hydrolysis of the N-glycosydic bond of 2′-deoxyguanosine has been analyzed by means of density functional methods. First, we have considered two limiting cases: (1) the activation of the guanine by protonation at N7 and (2) the nucleophile attack by a hydroxyl ion, to separately evaluate the two kinds of activation. Next, we have studied the simultaneous activation of the leaving group and the nucleophile by introducing models of amino acid residues such as a formic acid (HCOOH) and imidazolium (C3N2H5 +), methylammonium (CH3NH3 +) and formate (HCOO−) ions in the system. It is shown that protonation of the nucleobase greatly catalyzes the hydrolysis of the N-glycosydic bond, the reaction occurring through a stepwise (DN*AN) mechanism with a discrete oxocarbenium ion intermediate. However, when a H2O nucleophile molecule is activated by a formate anion, the reaction mechanism is a concerted ANDN but with different degrees of dissociative character of the transition structure depending on the acid that is activating the nucleobase.

Microwave-Assisted Domino Hydroformylation/Cyclization Reactions: Scope and Limitations

Hydroformylation of alkenes can be carried out in short time and with low syngas pressure under microwave (MW) dielectric heating. Alkenes, carrying O-, N-, or C-nucleophilic fragments, can be designed for domino reactions, mainly cyclocondensations. Allyl and homoallyl alcohols are excellent substrates for cyclizative hydroformylation to lactols under MW heating. In the presence of NaOAc as an additional nucleophile, a domino reaction occurs giving 2-acetoxytetrahydrofurans, suitable to introduce a C-nucleophile on tetrahydrofuran rings through an oxocarbenium ion. The synthesis of the furanopiperidine substructure of cyclopamine is described as an application. With alkene amides, the domino process collapsed to a transient acyliminium ion that further cyclized with an additional C-nucleophile. To perform domino hydroformylation Pictet-Spengler or aza-Sakurai reactions, an autoclave under conventional heating is essential. Syntheses of (±)-epilupinine and of a homoberberine alkaloid are reported to illustrate each sequence. Although apparently more versatile, hydroformylation of alkenes using MW heating is sensitive to the nature of the nucleophiles present in the substrates, evidencing that the conventional heating process cannot be completely replaced by MW irradiation.

Stereoselective synthesis of tertiary ethers through geometric control of highly substituted oxocarbenium ions.

Oxocarbenium ions are intermediates in a number of synthetic processes including Prins cyclizations,[1] acid-mediated additions to acetals,[2] allyl group transfers,[3] and additions of carbonyls to electrophiles.[4] Stereocontrol in these transformations can be quite high as a result of the strong preference, calculated at approximately 2 kcalmol−1,[5] for monosubstituted oxocarbenium ions to exist in E configurations. However, reports of geometric control for 1,1-disubstituted oxocarbenium ions are rare[6] because the steric difference between the alkyl groups is generally smaller than the steric difference between an alkyl group and a hydrogen atom. General models that predict the geometry of disubstituted oxocarbenium ions would be valuable for designing syntheses of natural products or natural-product-like libraries[7] that contain tertiary ether groups. Recently, our research group reported[8] that intramolecular nucleophilic additions to alkynyl-substituted oxocarbenium ions proceed with minimal stereocontrol to provide cis- and trans-2,6-disubstituted tetrahydropyrans. This unusual lack of stereo-control results from the approximate energetic equivalence of the E and Z oxocarbenium ions, which is a result of the small steric difference between an alkynyl group and a hydrogen atom (Scheme 1). Herein, we describe a rare application of carbon–hydrogen bond functionalization for stereoselective syntheses of molecules that contain fully substituted carbon atoms. The approach is based on the development of a model that is able to predict the geometries of 1,1-disubstituted oxocarbenium ions involved in nucleophilic additions that form tertiary ethers with high stereocontrol. We also report a model that illustrates stereocontrol in intramolecular additions to monosubstituted oxocarbenium ions relative to a tertiary ether.

Stereoselective Synthesis of Tertiary Ethers through Geometric Control of Highly Substituted Oxocarbenium Ions

Vollständig substituiert heißt vollständig kontrolliert: Die Geometrie in 1,1-disubstituierten Oxocarbeniumionen und die Konformation von Oxocarbeniumionen, die ein tertiäres Stereozentrum enthalten, lassen sich mithilfe einfacher Modelle vorhersagen. Auf diesen Modellen beruhen hoch stereoselektive Synthesen von Tetrahydropyran-Derivaten mit tertiären Ethergruppen (siehe Schema; RL, RS und RN sind große, kleine bzw. nucleophile Gruppen).

Synthesis of 3,5-diazabicyclo [5.1.0] octenes. A new platform to mimic glycosidase transition states

All- cis 1-hydroxymethyl 2,3 bis-aminomethyl cyclopropane was used to construct the first 3,5-diazabicyclo [5.1.0]-3-octenes. This system has the interesting ability to exist in a conformation that resembles a snapshot of a glycoside hydrolysis reaction with respect to charge and geometric analogy to an oxocarbenium ion, and the positioning of the departing aglycon. The cis-configured cyclopropane core was synthesized by Cu-catalyzed intramolecular cyclopropanation of benzyl protected cis-2-butene-1,4-diol diazoacetate ester. Serial functionalization to bis-aminomethyl cyclopropanes and subsequent cyclization to amidines lead to the target bicyclic compounds in good overall yields. Several glycosidases were surveyed for the inhibitory potential of these transition state analogs, and amongst them, selective competitive inhibitors with micromolar K i values were identified.

Mechanism of a Chemical Glycosylation Reaction

Glycosylation is arguably the most important reaction in the field of glycochemistry, yet it involves one of the most empirically interpreted mechanisms in the science of organic chemistry. The beta-mannopyranosides, long considered one of the more difficult classes of glycosidic bond to prepare, were no exception to this rule. A number of logical but circuitous routes for their preparation were described in the literature, but they were accompanied by an even greater number of mostly ineffective recipes with which to access them directly. This situation changed in 1996 with the discovery of the 4,6-O-benzylidene acetal as a control element permitting direct entry into the beta-mannopyranosides, typically with high yield and selectivity. The unexpected nature of this phenomenon demanded study of the mechanism, leading first to the demonstration of the alpha-mannopyranosyl triflates as reaction intermediates and then to the development of alpha-deuterium kinetic isotope effect methods to probe their transformation into the product glycosides. In this Account, we assemble our observations into a comprehensive assessment consistent with a single mechanistic scheme. The realization that in the glucopyranose series the 4,6-O-benzylidene acetal is alpha- rather than beta-directing led to further investigations of substituent effects on the stereoselectivity of these glycosylation reactions, culminating in their explanation in terms of the covalent alpha-glycosyl triflates acting as a reservoir for a series of transient contact and solvent-separated ion pairs. The function of the benzylidene acetal, as explained by Bols and co-workers, is to lock the C6-O6 bond antiperiplanar to the C5-O5 bond, thereby maximizing its electron-withdrawing effect, destabilizing the glycosyl oxocarbenium ion, and shifting the equilibria as far as possible toward the covalent triflate. beta-Selective reactions result from attack of the nucleophile on the transient contact ion pair in which the alpha-face of the oxocarbenium ion is shielded by the triflate counterion. The alpha-products arise from attack either on the solvent-separated ion pair or on a free oxocarbenium ion, according to the dictates of the anomeric effect. Changes in selectivity from varying stereochemistry (glucose versus mannose) or from using different protecting groups can be explained by the shifting position of the key equilibria and, in particular, by the energy differences between the covalent triflate and the ion pairs. Of particular note is the importance of substitutents at the 3-position of the donor; an explanation is proposed that invokes their evolving torsional interaction with the substituent at C2 as the chair form of the covalent triflate moves toward the half-chair of the oxocarbenium ion.

A propos of glycosyl cations and the mechanism of chemical glycosylation

Abstract A critical overview of the current state of the art regarding the mechanism of chemical glycosylation reactions is presented. Particular emphasis is placed on the glycosyl oxocarbenium ions and the evidence for and against their existence and their intermediacy in glycosylation reactions. The various factors influencing the mechanism of a glycosylation reaction are commented.

Scanning the Potential Energy Surface of Furanosyl Oxocarbenium Ions: Models for Reactive Intermediates in Glycosylation Reactions

A new scanning method with complementary graph to describe the ring potential energy surface of furanoses is introduced. Density functional theory at the B3LYP level of theory with the 6-311G(d,p) basis set is used to calculate the energy of the partially minimized structures. The method is used to determine the correlation between the preferred conformation of oxocarbenium ions that are model intermediates for a glycosylation reaction and recent experimental results. Key disagreements between the predicted geometry and the minima based on the scans described herein indicate that the preferred oxocarbenium ion conformation is not a consistent predictor of preferred stereochemistry of the products.

Total synthesis of neopeltolide and analogs

Neopeltolide, a potent cytotoxin from a Carribean sponge, was synthesized through a brief sequence that highlights the use of ethers as oxocarbenium ion precursors. Other key steps include an acid-mediated etherification and sequence that features a Sonogashira reaction, an intramolecular alkyne hydrosilylation reaction, and a Tamao oxidation. The alkene that is required for the oxidative cyclization can be hydrogenated to provide access to the natural product or an epimer, or can be epoxidized or dihydroxylated to form polar analogs.

Erosion of Stereochemical Control with Increasing Nucleophilicity: O-Glycosylation at the Diffusion Limit

Nucleophilic substitution reactions of 2-deoxyglycosyl donors indicated that the reactivity of the oxygen nucleophile has a significant impact on stereoselectivity. Employing ethanol as the nucleophile resulted in a 1:1 (alpha:beta) ratio of diastereomers under S(N)1-like reaction conditions. Stereoselective formation of the 2-deoxy-alpha-O-glycoside was only observed when weaker nucleophiles, such as trifluoroethanol, were employed. The lack of stereoselectivity observed in reactions of common oxygen nucleophiles can be attributed to reaction rates of the stereochemistry-determining step that approach the diffusion limit. In this scenario, both faces of the prochiral oxocarbenium ion are subject to nucleophilic addition to afford a statistical mixture of diastereomeric products. Control experiments confirmed that all nucleophilic substitution reactions were performed under kinetic control.

Infrared spectra and quantum chemical characterization of weakly bound clusters of the benzoyl cation with Ar and H2O

Weakly-bound clusters of the closed-shell benzoyl cation (C(6)H(5)CO(+), PhCO(+)) with Ar and H(2)O are investigated by infrared (IR) spectroscopy, mass spectrometry, and quantum chemical calculations in order to characterize the interaction of a closed shell aromatic cation with a nonpolar and a polar ligand. PhCO(+)-L dimers are produced by electron ionization of benzaldehyde in a supersonic plasma expansion. IR photodissociation (IRPD) spectra of PhCO(+)-L with L = Ar and H(2)O are analyzed in the C-O, C-H, and O-H stretch ranges (2000-3900 cm(-1)). The potential energy surface of the PhCO(+)-L dimers is characterized at the MP2/6-311++G(2df,2pd) level to locate the various minima and determine their energetic and vibrational properties. PhCO(+)-Ar prefers intermolecular π-bonding to the aromatic ring with a bond energy of D(0) = 6 kJ mol(-1). The weak interaction implies that the IRPD spectrum of PhCO(+)-Ar is very close to the IR spectrum of bare PhCO(+). The detection of the C-H and C-O stretch fundamentals provides valuable information about the C-O and C-H bond strengths in this prototypical aromatic acylium ion. Moreover, a variety of weak combination and overtone bands are assigned. The global minimum on the PhCO(+)-H(2)O potential has a planar charge-dipole configuration with D(0) = 41 kJ mol(-1) (with only the two H(2)O protons being out-of-plane), in which the lone pairs of H(2)O interact with the positive partial charges on the carbonyl carbon atom and the proton of the CH group in ortho position. The experimental IRPD spectra are in accord with the calculated global minima. The analysis of the charge distribution shows that the PhCO(+) cation is best represented as an oxocarbenium ion (Ph-C(+)[double bond, length as m-dash]O) with smaller contributions of the ketene structure (Ph(+)[double bond, length as m-dash]C[double bond, length as m-dash]O). This view is supported by the geometrical and vibrational properties of PhCO(+) as well as the shape of the intermolecular PhCO(+)-L dimer potentials.

Origin of Stereocontrol in the Construction of the 12-Oxatricyclo[6.3.1.02,7]dodecane Ring System by Prins−Pinacol Reactions

Polycyclic products containing the 12-oxatricyclo[6.3.1.0(2,7)]dodecane moiety having either the trans (8a-e) or cis (9a-e) relative configuration of the oxacyclic bridge and the cis angular substituents are formed stereospecifically by Prins-pinacol cyclizations of unsaturated alpha-dithianyl acetals 14a-e or 15a-e. These results show that the topography (boat or chair) of the Prins cyclization of the sulfur-stabilized oxocarbenium ions generated from acetals 14a-e or 15a-e is controlled by the stereoelectronic influence of the allylic substituents, with steric effects playing a minor role. A complex molecular rearrangement that is terminated by a thio-Prins-pinacol reaction is also identified.

Catalytic Reaction Mechanism Based on α-Secondary Deuterium Isotope Effects in Hydrolysis of Trehalose by European Honeybee Trehalase

Trehalase, an anomer-inverting glycosidase, hydrolyzes only alpha,alpha-trehalose in natural substrates to release equimolecular beta-glucose and alpha-glucose. Since the hydrolytic reaction is reversible, alpha,alpha-[1,1'-(2)H]trehalose is capable of synthesis from [1-(2)H]glucose through the reverse reaction of trehalase. alpha-Secondary deuterium kinetic isotope effects (alpha-SDKIEs) for the hydrolysis of synthesized alpha,alpha-[1,1'-(2)H]trehalose by honeybee trehalase were measured to examine the catalytic reaction mechanism. Relatively high k(H)/k(D) value of 1.53 for alpha-SDKIEs was observed. The data imply that the catalytic reaction of the trehalase occurs by the oxocarbenium ion intermediate mechanism. In addition, the hydrolytic reaction of glycosidase is discussed from the viewpoint of chemical reactivity for the hydrolysis of acetal in organic chemistry. As to the hydrolytic reaction mechanism of glycosidases, oxocarbenium ion intermediate and nucleophilic displacement mechanisms have been widely recognized, but it is pointed out for the first time that the former mechanism is rational and valid and generally the latter mechanism is unlikely to occur in the hydrolytic reaction of glycosidases.

β-Directing Effect of Electron-Withdrawing Groups at O-3, O-4, and O-6 Positions and α-Directing Effect by Remote Participation of 3-O-Acyl and 6-O-Acetyl Groups of Donors in Mannopyranosylations

Mannosylations of various acceptors with donors possessing an electron-withdrawing o-trifluoromethylbenzenesulfonyl, benzylsulfonyl, p-nitrobenzoyl, benzoyl, or acetyl group at O-3, O-4, or O-6 positions were found to be beta-selective except when donors had 3-O-acyl and 6-O-acetyl groups, which afforded alpha-mannosides as major products. The alpha-directing effect of 3-O-acyl and 6-O-acetyl groups was attributed to their remote participation, and the isolation of a stable bicyclic trichlorooxazine ring resulting from the intramolecular trapping of the anomeric oxocarbenium ion by 3-O-trichloroacetimidoyl group provided evidence for this remote participation. The triflate anion, counteranion of the mannosyl oxocarbenium ion, was essential for the beta-selectivity, and covalent alpha-mannosyl triflates with an electron-withdrawing group at O-3, O-4, or O-6 were detected by low-temperature NMR. The strongly electron-withdrawing sulfonyl groups, which exhibited a higher beta-directing effect in the mannosylation, made the alpha-mannosyl triflates more stable than the weakly electron-withdrawing acyl groups. We therefore proposed the mechanism for the beta-mannosylation and the origin of the beta-directing effect: the electron-withdrawing groups would stabilize the alpha-mannosyl triflate intermediate, and the subsequent reaction of the alpha-triflate (or its contact ion pair) with the acceptor would afford the beta-mannoside. The beta-selective mannosylation of a sterically demanding acceptor was achieved by employing a donor possessing two strongly electron-withdrawing benzylsulfonyl groups at O-4 and O-6 positions.

Correlations Between Nucleophilicities and Selectivities in the Substitutions of Tetrahydropyran Acetals

Selectivities that deviate from S(N)1 stereoelectronic models in the nucleophilic substitutions of tetrahydropyran acetals were investigated. When weak nucleophiles were employed, stereoselectivities conformed to known S(N)1 stereoelectronic models. In contrast, stereoselectivities in the substitutions of acetals with strong nucleophiles depended on reaction conditions. Erosions in selectivities were observed when strong nucleophiles were employed in the absence of coordinating counterions. These erosions in selectivities are attributed to rates of nucleophilic additions to oxocarbenium ion intermediates that approach the diffusion limit. When triflate counterions were present, however, S(N)2-like pathways became accessible with strong nucleophiles. In most cases examined, the major stereoisomers formed from reactions that proceeded through S(N)2-like pathways were opposite to the major stereoisomers formed from the analogous reactions that proceeded through S(N)1 pathways.

Theoretical analysis of kinetic isotope effects on proton transfer reactions between substituted alpha-methoxystyrenes and substituted acetic acids.

Primary kinetic isotope effects (KIEs) on a series of carboxylic acid-catalyzed protonation reactions of aryl-substituted alpha-methoxystyrenes (X-1) to form oxocarbenium ions have been computed using the second-order Kleinert variational perturbation theory (KP2) in the framework of Feynman path integrals (PI) along with the potential energy surface obtained at the B3LYP/6-31+G(d,p) level. Good agreement with the experimental data was obtained, demonstrating that this novel computational approach for computing KIEs of organic reactions is a viable alternative to the traditional method employing Bigeleisen equation and harmonic vibrational frequencies. Although tunneling makes relatively small contributions to the lowering of the free energy barriers for the carboxylic acid catalyzed protonation reaction, it is necessary to include tunneling contributions to obtain quantitative estimates of the KIEs. Consideration of anharmonicity can further improve the calculated KIEs for the protonation of substituted alpha-methoxystyrenes by chloroacetic acid, but for the reactions of the parent and 4-NO(2) substituted alpha-methoxystyrene with substituted carboxylic acids, the correction of anharmonicity overestimates the computed KIEs for strong acid catalysts. In agreement with experimental findings, the largest KIEs are found in nearly ergoneutral reactions, DeltaG(o) approximately 0, where the transition structures are nearly symmetric and the reaction barriers are relatively low. Furthermore, the optimized transition structures are strongly dependent on the free energy for the formation of the carbocation intermediate, that is, the driving force DeltaG(o), along with a good correlation of Hammond shift in the transition state structure.

Structure-reactivity effects on primary deuterium isotope effects on protonation of ring-substituted alpha-methoxystyrenes.

Primary product isotope effects (PIEs) on L(+) and carboxylic acid catalyzed protonation of ring-substituted alpha-methoxystyrenes (X-1) to form oxocarbenium ions X-2(+) in 50/50 (v/v) HOH/DOD were calculated from the yields of the alpha-CH(3) and alpha-CH(2)D labeled ketone products, determined by (1)H NMR. A plot of PIE against reaction driving force shows a maximum PIE of 8.7 for protonation of 4-MeO-1 by Cl(2)CHCOOH (DeltaG(o) = 1.0 kcal/mol). The PIE decreases to 8.1 for protonation of 4-MeO-1 by L(3)O(+) (DeltaG(o) = -2.8 kcal/mol) and to 5.1 for protonation of 3,5-di-NO(2)-1 by MeOCH(2)COOH (DeltaG(o) = 13.1 kcal/mol). The PIE maximum is around DeltaG(o) = 0. Arrhenius-type plots of PIEs on protonation of 4-MeO-1 and 3,5-di-NO(2)-1 by L(3)O(+) and on protonation of X-1 by MeOCH(2)COOH in 50/50 (v/v) HOH/DOD give similar slopes and intercepts. These were used to calculate values of [(E(a))(H) - (E(a))(D)] = -1.2 kcal/mol and (A(H)/A(D)) = 1.0 for the difference in activation energy for reactions of A-H and A-D and for the limiting PIE at infinite temperature, respectively. These parameters are consistent with reaction of the hydron over an energy barrier. There is no evidence for quantum mechanical tunneling of the hydron through the barrier. These PIEs suggest that the transferred hydron at the transition state lies roughly equidistant between the acid donor and base acceptor and contrast with the recently published Brønsted parameters [Richard, J. P.; Williams, K. B. J. Am. Chem. Soc. 2007, 129, 6952-6961], which are consistent with a product-like transition state. An explanation for these seemingly contradictory results is discussed.

Probing Synergy between Two Catalytic Strategies in the Glycoside Hydrolase O-GlcNAcase Using Multiple Linear Free Energy Relationships

Human O-GlcNAcase plays an important role in regulating the post-translational modification of serine and threonine residues with beta-O-linked N-acetylglucosamine monosaccharide unit (O-GlcNAc). The mechanism of O-GlcNAcase involves nucleophilic participation of the 2-acetamido group of the substrate to displace a glycosidically linked leaving group. The tolerance of this enzyme for variation in substrate structure has enabled us to characterize O-GlcNAcase transition states using several series of substrates to generate multiple simultaneous free-energy relationships. Patterns revealing changes in mechanism, transition state, and rate-determining step upon concomitant variation of both nucleophilic strength and leaving group abilities are observed. The observed changes in mechanism reflect the roles played by the enzymic general acid and the catalytic nucleophile. Significantly, these results illustrate how the enzyme synergistically harnesses both modes of catalysis; a feature that eludes many small molecule models of catalysis. These studies also suggest the kinetic significance of an oxocarbenium ion intermediate in the O-GlcNAcase-catalyzed hydrolysis of glucosaminides, probing the limits of what may be learned using nonatomistic investigations of enzymic transition-state structure and offering general insights into how the superfamily of retaining glycoside hydrolases act as efficient catalysts.

2,3-Anhydrosugars in Glycoside Bond Synthesis: Mechanism of 2-Deoxy-2-thioaryl Glycoside Formation

A series of investigations probing the mechanism of the 2,3-anhydrosugar migration-glycosylation reaction were performed using a thioglycoside with the D-lyxo stereochemistry as the substrate. Among the work reported are the results of quantum mechanical calculations, NMR studies, the measurement of alpha-deuterium kinetic isotope effects, and the synthesis of a series of substrate analogues. All studies point to a consistent finding: that the reaction proceeds through an oxocarbenium ion intermediate, not an episulfonium ion as previously suggested. It is proposed that the high stereoselectivity of the reaction arises from a preferred "inside attack" of the nucleophile onto the oxocarbenium ion intermediate.