Structural evidence that alkoxy substituents adopt electronically preferred pseudoaxial orientations in six-membered ring dioxocarbenium ions

Nucleophilic substitution reactions of monosubstituted tetrahydropyran acetals give opposite selectivities when a remote alkyl or alkoxy substituent is present at C-4. Coupled with earlier computational reports on the intermediates of glycosylation reactions, these results are consistent with the preference for the oxocarbenium ion intermediate derived from alkoxy-substituted tetrahydropyran acetals to occupy a pseudoaxial conformation. Theoretical, spectroscopic, and X-ray crystallographic evidence of this conformational preference in an analogous and more stable dioxocarbenium ion are provided. This contrasteric preference for an axial orientation of an alkoxy substituent likely derives from the electronically favored pseudoaxial orientation of remote electronegative substituents in neutral six-membered rings possessing electron-deficient carbon atoms.     

Nucleophilic substitution reactions of sulfur-substituted cyclohexanone acetals: an analysis of the factors controlling stereoselectivity

The reactions of cyclohexanone acetals substituted with thiophenyl groups (and other heteroatoms) at C-2 demonstrate the powerful influence that these substituents have on the stereoselectivity of nucleophilic substitution reactions. The trans selectivities of these reactions correlate with the behavior of the corresponding ketones. These experiments lend support to the possibility that the reactions of the acetals, which proceed via oxocarbenium ions, are operating under Felkin-Anh control.     

Stereoselective C-glycosylation reactions of pyranoses: the conformational preference and reactions of the mannosyl cation

A systematic study of C-glycosylations of acetals related to mannose and other pyranoses was conducted. The C-5 alkoxyalkyl group provides only a modest influence on stereoselectivity. On the other hand, studies of pentopyranoses bearing alkoxy groups at C-2, C-3, and C-4 showed that the alkoxy groups exerted powerful influences on selectivity. In the case of mannose, the high alpha selectivity observed with C-mannosylation was reversed to high beta selectivity if the C-5 alkoxyalkyl group were removed. An analysis of the conformational preferences of the intermediate oxocarbenium ions, including the mannosyl cation, as well as consideration of steric effects that develop in the transition states for nucleophilic attack provide explanations for these phenomena.     

Enantioselective thiourea-catalyzed additions to oxocarbenium ions

Asymmetric, catalytic reactions of oxocarbenium ions are reported. Simple, chiral urea and thiourea derivatives are shown to catalyze the enantioselective substitution of silyl ketene acetals onto 1-chloroisochromans. A mechanism involving anion binding by the chiral catalyst to generate a reactive oxocarbenium ion is invoked. Catalysts bearing tertiary benzylic amide groups afforded highest enantioselectivities, with the optimal structure being derived from enantioenriched 2-arylpyrrolidine derivatives.     

Investigations into the role of ion pairing in reactions of heteroatom-substituted cyclic oxocarbenium ions

[reaction: see text] The O-to-C rearrangement of vinyl acetals is used to demonstrate that tight ion pairing is not involved in the stereoselective nucleophilic addition reactions of alkoxy-substituted cyclic oxocarbenium ions.     

The NMR spectra and conformations of dihydropyran derivatives—I: The conformations of 2-alkoxy-5,6-dihydro-α-pyran-6-carboxylic esters

On the basis of NMR spectra of trans- and cis-2-alkoxy-5,6-α-pyran-6-carboxylic esters it was found that, at room temperature, the trans-compounds exist exclusively in the conformation with equatorial carbalkoxy and pseudoaxial alkoxy groups. The cis-isomers appear to be in conformational equilibrium between a form with equatorial carbalkoxy and pseudoequatorial alkoxy groups and that with axial and pseudoaxial substituents. In the latter case, the axial carbalkoxy group is bent out off its normal position by about 15°.     

Oxidatively generated electrophiles as initiators of epoxide cascade cyclization processes

Oxidatively generated oxocarbenium ions are shown to be effective promoters of polyepoxide cascade cyclization reactions to form polyether compounds. The reaction conditions are neutral, ensuring that background acid-mediated processes are not operative and that other acid-sensitive functional groups, such as acetals, can be incorporated into cyclization substrates. While 5-exo pathways are more common that 6-endo pathways, a rational design has been employed to access tetrahydropyranyl ethers.     

Chiral Brønsted acid-catalyzed enantioselective ionic [2+4] cycloadditions

The first asymmetric chiral N-triflylphosphoramide-catalyzed ionic [2+4] cycloaddition reaction of unsaturated acetals is described. This reaction proceeds through the intermediacy of a vinyl oxocarbenium/chiral anion pair, and the chiral N-triflylphosphoramide anion controls the stereoselectivity of the cycloaddition step. Moderate enantioselectivities (up to 80:20 e.r.) have been obtained when α,β-unsaturated dioxolanes were employed as the dienophiles. These reactions demonstrate strong dependence on the counterion coordinating properties and solvent polarity, a behavior characteristic of oxocarbenium ions.     

Surveying approaches to the formation of carbon-carbon bonds between a pyran and an adjacent ring

We have examined several methods for the stereoselective formation of carbon-carbon bonds between contiguous rings where a stereogenic center is already present. The approaches investigated were a [1,3] oxygen to carbon rearrangement of cyclic vinyl acetals, an intermolecular enolsilane addition into an in situ generated oxocarbenium ion, an intramolecular conjugate addition of tethered alkoxy enones, and epimerization of several α-pyranyl cycloalkanones. These routes have been found to be complementary in several cases and have enabled formation of both the trans:anti and cis:anti stereoisomers in good to excellent yields and varying diastereoselectivities. We have proven C2-C2′ relative stereochemistry of 1-2 via a chemical correlation.     

Synthesis and structure analysis of cyclic furfural acetals

Quantum chemical calculations and the PMR method are used to show that the preferable conformation of cyclic furfural acetals is a chair with an axial orientation of the furyl substituent. In 2-(furyl-2′)-5-ethyl-5-oxymethyl-1,3-dioxane, the conformation equilibrium is shifted toward the transisomer with diaxial positions of the furyl and oxymethyl groups. The results of calculations suggest that the synthesis can lead to a cisisomer with an axial orientation of the furyl and equatorial oxymethyl groups. It was shown experimentally that the synthesis leads to a mixture of trans-and cis-isomers. Mild conditions (room temperature, aqueous medium) lead to formation of the transisomer and small amounts of the cisisomer (less than 2%). In rigid conditions (boiling in aromatic hydrocarbons), up to 20% of the cisisomer is formed. Translated fromZhurnal Struktumoi Khimii, Vol. 38, No. 6, pp. 1083–1091, November–December, 1997.     

Reductive openings of benzylidene acetals revisited: a mechanistic scheme for regio- and stereoselectivity

Despite the importance of regioselective reductive openings of cyclic acetals, mechanistic details are scarce. In this study 4,6-O-benzylidene acetals were used as model compounds for deciphering the mechanism of regioselective openings using a variety of reducing agents. Competitive isotopic studies aiming at primary and secondary isotope effects, as well as an electron-deficient substrate, were used to evaluate stereo- and regioselectivity. We show that there are three distinctly different mechanistic pathways. In nonpolar solvents, such as toluene, the acetal is activated by the very reactive naked Lewis acid to give a fully developed oxocarbenium ion that is then reduced by the borane, with low stereoselectivity. In THF the reactivity of the Lewis acid is moderated by complex formation with the solvent. These reactions are thus much slower and proceed through an intimate ion pair and thereby show high stereoselectivities. The regioselectivity in these reactions is directed by the interaction between the Lewis acid and the most nucleophilic oxygen of the acetal, thus yielding a free 6-hydroxyl group. Finally, boranes such as BH(3)·NMe(3) are activated by Lewis acid, which results in the borane being the most electrophilic species, and consequently the reaction shows inversed regioselectivity to give a free 4-hydroxyl group. These reactions proceed through an oxocarbenium ion and thus show low stereoselectivity.     

Stereochemistry of nucleophilic substitution reactions depending upon substituent: evidence for electrostatic stabilization of pseudoaxial conformers of oxocarbenium ions by heteroatom substituents

Lewis acid-mediated nucleophilic substitution reactions of substituted tetrahydropyran acetates reveal that the conformational preferences of six-membered-ring cations depend significantly upon the electronic nature of the substituent. Nucleophilic substitutions of C-3 and C-4 alkyl-substituted tetrahydropyran acetates proceeded via pseudoequatorially substituted oxocarbenium ions, as would be expected by consideration of steric effects. Substitutions of C-3 and C-4 alkoxy-substituted tetrahydropyran acetates, however, proceeded via pseudoaxially oriented oxocarbenium ions. The unusual selectivities controlled by the alkoxy groups were demonstrated for a range of other heteroatom substituents, including nitrogen, fluorine, chlorine, and bromine. It is believed that the pseudoaxial conformation is preferred in the ground state of the cation because of an electrostatic attraction between the cationic carbon center of the oxocarbenium ion and the heteroatom substituent. This analysis is supported by the observation that selectivity diminishes down the halogen series, which is inconsistent with electron donation as might be expected during anchimeric assistance. The C-2 heteroatom-substituted systems gave moderately high 1,2-cis selectivity, while small alkyl substituents showed no selectivity. Only in the case of the tert-butyl group at C-2 was high 1,2-trans selectivity observed. These studies reinforce the idea that ground-state conformational effects need to be considered along with steric approach considerations.     

Determination of the Influence of Side‐Chain Conformation on Glycosylation Selectivity using Conformationally Restricted Donors

The synthesis of a series of conformationally locked mannopyranosyl thioglycosides in which the C6?O6 bond adopts either the gauche,gauche, gauche,trans, or trans,gauche conformation is described, and their influence on glycosylation stereoselectivity investigated. Two 4,6‐O‐benzylidene‐protected mannosyl thioglycosides carrying axial or equatorial methyl groups at the 6‐position were also synthesized and the selectivity of their glycosylation reactions studied to enable a distinction to be made between steric and stereoelectronic effects. The presence of an axial methoxy group at C6 in the bicyclic donor results in a decreased preference for formation of the β‐mannoside, whereas an axial methyl group has little effect on selectivity. The result is rationalized in terms of through‐space stabilization of a transient intermediate oxocarbenium ion by the axial methoxy group resulting in a higher degree of S_N1‐like character in the glycosylation reaction. Comparisons are made with literature examples and exceptions are discussed in terms of pervading steric effects layered on top of the basic stereoelectronic effect.     

The "aqueous" Prins reaction

[reaction: see text] In this communication we demonstrate that Prins cyclization reactions occur under very mild conditions when cyclic alpha,beta-unsaturated acetals are employed as oxocarbenium ion progenitors and allylsilanes are used as nucleophiles. Cyclizations proceed efficiently inside Lewis acidic micelles in water, demonstrating that colloidal suspensions can protect highly electrophilic intermediates from hydrolysis. Reactions are experimentally facile and useful in the preparation of a variety of vinyl- and aryl-substituted tetrahydropyrans with excellent stereocontrol.     

Recognition of cyclic, acyclic, exocyclic, and spiro acetals via structurally diagnostic ion/molecule reactions with the (CH3)2N-C(+)=O acylium ion

Reactions of the model acylium ion (CH3)2N-C(+)=O with acyclic, exocyclic, and spiro acetals of the general formula R(1)O-CR(3)R(4)-OR(2) were systematically evaluated via pentaquadrupole mass spectrometry. Characteristic intrinsic reactivities were observed for each of these classes of acetals. The two most common reactions observed were hydride and alkoxy anion [R(1)O(-) and R(2)O(-)] abstraction. Other specific reactions were also observed: (a) a secondary polar [4(+) + 2] cycloaddition for acetals bearing alpha,beta-unsaturated R(3) or R(4) substituents and (b) OH(-) abstraction for exocyclic and spiro acetals. These structurally diagnostic reactions, in conjunction with others observed previously for cyclic acetals, are shown to reveal the class of the acetal molecule and its ring type and substituents and to permit their recognition and distinction from other classes of isomeric molecules.     

Acceleration of Acetal Hydrolysis by Remote Alkoxy Groups: Evidence for Electrostatic Effects on the Formation of Oxocarbenium Ions

In contrast to observations with carbohydrates, experiments with 4‐alkoxy‐substituted acetals indicate that an alkoxy group can accelerate acetal hydrolysis by up to 20‐fold compared to substrates without an alkoxy group. The acceleration of ionization in more flexible acetals can be up to 200‐fold when compensated for inductive effects.     

Medium-sized rings versus macrocycles through rhodium-catalyzed ring-expansion reactions of cyclic acetals

α-Diazo β-ketoesters and diketones react with cyclic acetals under Rh(II) catalysis to yield unprecedented polyoxygenated 8- and 9-membered rings in one pot. The reactions occur under mild conditions with yields up to 90%. A perfect regioselectivity is obtained, which can be rationalized through a mechanistic hypothesis that considers 1) the formation of an oxonium ylide, 2) its transformation into an unsaturated acyclic oxocarbenium electrophilic intermediate, and 3) an intramolecular nucleophilic attack in a direct application of Baldwin's rules.     

Why are silyl ethers conformationally different from alkyl ethers? Chair-chair conformational equilibria in silyloxycyclohexanes and their dependence on the substituents on silicon. The wider roles of eclipsing, of 1,3-repulsive steric interactions, and of attractive steric interactions

An NMR study of the diaxial/diequatorial chair equilibrium in a range of silylated derivatives of trans-1,4- and trans-1,2-dihydroxycyclohexane is reported and discussed with a view to explaining unusually large populations of chair conformations with axial substituents, noted previously for some monosilyloxycyclohexanes and in some silylated sugars. X-ray diffraction studies of three bis-triphenylsilyloxycyclohexanes are reported and show both axial and equatorial silyloxy groups with the exocyclic bonds eclipsed. Eclipsing is also suggested by molecular mechanics (MM3) calculations on such derivatives. Both axial and equatorial tertiary silyl groups have 1,3-repulsive interactions with whatever substituents or hydrogen atoms are at the two adjacent equatorial positions, and these are relieved by rotation toward the eclipsed conformation of the exocyclic C-O bond. The three substituents on silicon interact attractively with the nine atoms at the 3, 4, and 5-positions of the cyclohexane ring and calculations suggest that these stabilizing interactions are significantly greater in the axial than in the equatorial conformation. An equatorial C-OSiR(3) bond with one or two equatorial neighbors has a restricted potential energy well that becomes much broader when the bond is axial without any equatorial neighbors in the alternative chair. Adjacent silyl groups in the 1,2-disubstituted series interact in a stabilizing way overall in all conformations, this being particularly marked in the diaxial conformation of the more complex ethers. These factors lead to unusually large axial populations.     

C-glycosylation reactions of sulfur-substituted glycosyl donors: evidence against the role of neighboring-group participation

Nucleophilic substitution reactions of C-4 sulfur-substituted tetrahydropyran acetals revealed that neighboring-group participation does not control product formation. Spectroscopic evidence for the formation of an intermediate sulfonium ion is provided, as are data from nucleophilic substitution reactions demonstrating that products are formed from oxocarbenium ion intermediates. The selectivity was not sensitive to solvent or to which Lewis acid was employed. The identity of the heteroatom at the C-4 position also did not significantly impact diastereoselectivity. Consequently, neighboring-group participation was not responsible for the formation of either the major or the minor products. These studies implicate a Curtin-Hammett kinetic scenario in which the formation of a low-energy intermediate does not necessitate its involvement in the product-forming pathway.     

Medium‐Sized Rings versus Macrocycles through Rhodium‐Catalyzed Ring‐Expansion Reactions of Cyclic Acetals

α‐Diazo β‐ketoesters and diketones react with cyclic acetals under Rh^II catalysis to yield unprecedented polyoxygenated 8‐ and 9‐membered rings in one pot. The reactions occur under mild conditions with yields up to 90 %. A perfect regioselectivity is obtained, which can be rationalized through a mechanistic hypothesis that considers 1) the formation of an oxonium ylide, 2) its transformation into an unsaturated acyclic oxocarbenium electrophilic intermediate, and 3) an intramolecular nucleophilic attack in a direct application of Baldwin’s rules.