Acetal Carbon Atom Research Articles

Experimental observations on the reductive cleavage of endo and exo 3,4-O-benzylidene fucopyranoside derivatives

Reductive cleavage of methyl 3,4-O-benzylidene-α-L-fucopyranosides with BH3·THF-TfOH and NaCNBH3-TfOH systems resulted in enhanced reaction rates and selectivity compared to BH3·THF-Bu2BOTf. With this latter system, the nature of the O-2 substituent exerted a clear control on the reactivity but practically did not affect the regioselectivity. With TfOH the direction of cleavage was determined, as expected, by the configuration of the acetal carbon atom, but slightly influenced by its competitive epimerization. Protic conditions provided higher regioselectivity in the openings of the exo isomers, affording a useful approach to the practical synthesis of 3-O-benzyl ethers.

Hydrolysis of Hydroxypropyl Methylcellulose by Trifluoromethanesulfonic Acid and Subsequent Determination of Chemical Structure by 13C NMR Spectroscopy

The hydrolysis of three hydroxypropyl methylcellulose samples with varying degrees of polymerization by aqueous solutions of trifluoromethanesulfonic acid with a concentration of 1, 2, 3, and 4% at a temperature of 80, 90, 100, and 110°C in a microwave reactor is studied. The completeness of hydrolysis is estimated by 13C NMR spectroscopy of the disappearance of the signal the acetal carbon atom. It is shown that the concentration of acid has the greatest influence on the hydrolysis rate, the effect of temperature increase is not so strong, and the effect of reaction time is even smaller. Using 13C NMR spectroscopy, substitution parameters at the second, third, and sixth positions (DSC-2, DSC-3, and DSC-6) are determined, the amount of methyl (DSMe) and hydroxypropyl groups (DSHP) is estimated, and the total degree of substitution (DStotal) is calculated.

Influence of alkoxy groups on rates of acetal hydrolysis and tosylate solvolysis: electrostatic stabilization of developing oxocarbenium ion intermediates and neighboring-group participation to form oxonium ions.

The hydrolysis of 4-alkoxy-substituted acetals was accelerated by about 20-fold compared to that of sterically comparable substrates that do not have an alkoxy group. Rate accelerations are largest when the two functional groups are linked by a flexible cyclic tether. When controlled for the inductive destabilization, an alkoxy group can accelerate acetal hydrolysis by up to 200-fold. The difference in rates of acetal hydrolysis between a substrate where the alkoxy group was tethered to the acetal group by a five-membered ring compared to one where it was tethered by an eight-membered ring was less than 100-fold, suggesting that fused-ring intermediates were not formed. By comparison, the difference in rates of solvolysis of structurally related tosylates were nearly 10(6)-fold between the five- and eight-membered ring series. This observation implicates neighboring-group participation in the solvolysis of tosylates but not in the hydrolysis of acetals. The acceleration of acetal hydrolysis by an alkoxy group is better explained by electrostatic stabilization of intermediates that accumulate positive charge at the acetal carbon atom.

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.

Bis-phosphonium salts of pyridoxine: The relationship between structure and antibacterial activity

A series of 23 novel bis-phosphonium salts based on pyridoxine were synthesized and their antibacterial activities were evaluated in vitro. All compounds were inactive against gram-negative bacteria and exhibited the structure-dependent activity against gram-positive bacteria. The antibacterial activity enhanced with the increase in chain length at acetal carbon atom in the order n-Pr>Et>Me. Further increasing of length and branching of alkyl chain leads to the reduction of antibacterial activity. Replacement of the phenyl substituents at the phosphorus atoms in 5,6-bis(triphenylphosphonio(methyl))-2,2,8-trimethyl-4H-[1,3]-dioxino[4,5-c]pyridine dichloride (compound 1) with n-butyl, m-tolyl or p-tolyl as well as chloride anions in the compound 1 with bromides (compound 14a) increased the activity against Staphylococcus aureus and Staphylococcus epidermidis up to 5times (MICs=1–1.25μg/ml). But in practically all cases chemical modifications of compound 1 led to the increase of its toxicity for HEK-293 cells. The only exception is compound 5,6-bis[tributylphosphonio(methyl)]-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine dichloride (10a) which demonstrated lower MIC values against S. aureus and S. epidermidis (1μg/ml) and lower cytotoxicity on HEK-293 cells (CC50=200μg/ml). Compound 10a had no significant mutagenic and genotoxic effects and was selected for further evaluation. It should be noted that all bis-phosphonium salt based on pyridoxine were much more toxic than vancomycin.

ChemInform Abstract: One‐Pot Synthesis of Tetrahydroindolizines by Catalytic Intra‐ and Intermolecular Alkylation of 1,2‐Disubstituted Pyrroles.

Tetrahydroindolizine fragment is a structural unit of many natural and unnatural compounds possessing diverse biological activity [1–3]. Known methods for the preparation of tetrahydroindolizine derivatives are tedious, and the yields of the target products are poor [4, 5]. Therefore, development of new procedures for their synthesis is an important problem in medicinal and organic chemistry. In the present communication we report on a new convenient one-step procedure for the synthesis of tetrahydroindolizines via successive intraand intermolecular alkylations of 2-methyland 2-phenyl-1(4,4-diethoxybutyl)pyrroles I and II in the presence of a catalytic amount of Yb(OTf)3 (Scheme 1). The yields of compounds III and IV were 40–45% when the reactions were carried out in tetrahydrofuran at room temperature over a period of three days. A probable mechanism of formation of tetrahydroindolizines III and IV (Scheme 2) involves intramolecular nucleophilic addition of C in the pyrrole ring at the acetal carbon atom in the side chain, which bears a partial positive charge enhanced by interaction with the catalyst. Intramolecular ring closure in intermediate complex A gives complex B which reacts with the second substrate molecule, and subsequent elimination of ethanol yields the final product.

One-pot synthesis of tetrahydroindolizines by catalytic intra- and intermolecular alkylation of 1,2-disubstituted pyrroles

Tetrahydroindolizine fragment is a structural unit of many natural and unnatural compounds possessing diverse biological activity [1–3]. Known methods for the preparation of tetrahydroindolizine derivatives are tedious, and the yields of the target products are poor [4, 5]. Therefore, development of new procedures for their synthesis is an important problem in medicinal and organic chemistry. In the present communication we report on a new convenient one-step procedure for the synthesis of tetrahydroindolizines via successive intraand intermolecular alkylations of 2-methyland 2-phenyl-1(4,4-diethoxybutyl)pyrroles I and II in the presence of a catalytic amount of Yb(OTf)3 (Scheme 1). The yields of compounds III and IV were 40–45% when the reactions were carried out in tetrahydrofuran at room temperature over a period of three days. A probable mechanism of formation of tetrahydroindolizines III and IV (Scheme 2) involves intramolecular nucleophilic addition of C in the pyrrole ring at the acetal carbon atom in the side chain, which bears a partial positive charge enhanced by interaction with the catalyst. Intramolecular ring closure in intermediate complex A gives complex B which reacts with the second substrate molecule, and subsequent elimination of ethanol yields the final product.

Structure of dihydroxyacetone phosphate dimethyl acetal, a stable dihydroxyacetone phosphate precursor, in the crystalline state

Crystal and molecular structures of four different salts of a dihydroxyacetone phosphate (DHAP) precursor, its dimethyl acetal [2,2-dimethoxy-1,3-propanediol phosphate, C 5H 13O 7P, (MeO) 2DHAP]: (cha) 2[(MeO) 2DHAP]·H 2O ( 6a), (cha)[(MeO) 2DHAP] ( 6b), Na 2[(MeO) 2DHAP]·5.75H 2O ( 6c) and K 2[(MeO) 2DHAP]·H 2O ( 6d), along with the cyclohexylammonium (cha) salt of its phenyl ester (cha)[(MeO) 2DHAP(Ph)] ( 6e) are described. In the (MeO) 2DHAP mono- and dianions, slightly different orientation of the phosphate group in relation to the acetal carbon atom is observed, with a delicate tendency of phosphate group to be located antiperiplanar in the monoanions and anticlinal in the dianions. The 2,2-dimethoxy-1,3-propandiol moiety, (MeO) 2DHA, seems to be very rigid and its conformation is independent of phosphorylation, the ionization state of the inserted phosphate group and its additional substitution. The overall structures of the cyclohexylammonium ( 6a, b) and potassium salts ( 6d) have a double-layered architecture, while the sodium cation network in 6c forms the system of channels, which are filled up with the [(MeO) 2DHAP] 2− ions. The different architectures of 6c and 6d crystals result from the different ways in which the relevant dianions coordinate to sodium and potassium ions and affect also the hydrogen bonding system observed in 6c and 6d crystals.

Stereochemistry of Seven-Membered Heterocycles: XLIII. Steric Structure of Diastereoisomeric 8,8-Dichloro(dibromo)-4-R-3,5-dioxabicyclo[5.1.0]octanes

Dichloro- and dibromocyclopropanation of 2-substituted 1,3-dioxacyclohept-5-enes according to Makosza resulted in formation of the corresponding 4-substituted 8,8-dichloro(dibromo)-3,5-dioxabicyclo[5.1.0]octanes in good yields. Ultrasonic activation of the process considerably shortened the reaction time. According to the 13C NMR spectra, the chair-twist equilibrium is essentially displaced toward the chair conformer for the exo isomers and toward the twist conformer for the endo structures. Similar results were obtained by AM1 semiempirical calculations which indicated that the CCl···O interaction largely determines the conformational equilibrium. The state of the diastereoisomer epimerization equilibrium depends on the size of the substituent at the acetal carbon atom.

The presence of water improves reductive openings of benzylidene acetals with trimethylaminoborane and aluminium chloride

The acidic reagent formed in situ from anhydrous AlCl 3 and H 2O in 3:1 ratio is much more efficient for the reductive openings of the cyclic benzylidene acetals with Me 3N·BH 3 in tetrahydrofurane than the AlCl 3 alone. Under proposed conditions, the dioxane-type 4,6- O-bezylidene acetals of hexopyranosides give regioselectively the corresponding 4-hydroxy,6- O-benzyl derivatives in excellent yields. Reductive openings of the dioxolane-type 3,4- O-benzylidene acetals of galactopyranoside are also very efficient and regioselective and give either 3- O-benzyl derivative (from 3,4- O- exo-benzylidene acetal) or 4- O-benzyl derivative (from 3,4- O- endo-benzylidene acetal) depending on the configuration of the acetal carbon atom.

Stereochemistry of Seven-Membered Heterocycles: XLII. A Theoretical Study of Stereochemistry of H Complexes Formed by Conformationally Nonuniform 2-R-1,3-Dioxacyclohept-5-enes with Some Proton Donors

According to semiempirical AM1 calculations, the stability of the boat and twist forms of 2-R-1,3- dioxacyclohept-5-enes depends on the size of substituents at the acetal carbon atom. The twist form gives diastereomeric H complexes with chloroform and methanol of the cis and trans structure, containing monocentered hydrogen bonds, whereas the chair conformation preferably forms complexes with a two-centered hydrogen bond. Based on theoretical data (θO H, ΔH, geometry of complexes), the specific features of H complexes of the conformers in electrophilic addition and cycloaddition were revealed. Considerable preferableness of the exo attack of the diastereotopic double bond in the H complex having the chair form is due to the steric accessibility of the exo side, whereas in the complexes of the twist form the facial selectivity is appreciably lower.

EPR and computational studies of the formation and β-scission of cyclic and acyclic dialkoxyalkyl radicals

EPR spectroscopy and density functional theory have been applied to study the formation and subsequent β-scission of a series of dialkoxyalkyl radicals. Abstraction of hydrogen by photochemically-generated tert-butoxyl radicals from acyclic acetals R1O(R2O)CHR3, and from cyclic analogues derived from diols, takes place mainly from the acetal carbon atom to give radicals of the type R1O(R2O)ĊR3 and relative rates of abstraction have been determined in competition experiments. When R3 = phenyl or vinyl, the activating influence of these substituents on hydrogen-atom abstraction is smaller than might be expected, probably because delocalisation of the unpaired electron on to the unsaturated group comes at the expense of planarisation at Cα, in opposition to the natural pyramidalising tendency of the two α-alkoxy groups. Absolute rate constants and Arrhenius activation parameters for β-scission of R1O(R2O)ĊR3 have been determined by a steady-state EPR method and the results can be understood in terms of angle-strain and stereoelectronic effects. β-Scission of selected cyclic dialkoxyalkyl radicals that carry a phenyl or vinyl substituent at the radical centre has been investigated using density functional theory at the UB3LYP/6-31G(d,p) level. Computed activation parameters are in good agreement with the experimental results, where comparison is possible. Both experiment and theory indicate that benzylic 2-phenyl-1,3-dioxan-2-yl radicals undergo β-scission more readily than the corresponding allylic 2-vinyl-1,3-dioxan-2-yl radicals.

Tricarbonylrhenium(I) halide complexes of 2-[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]pyridine (L1) and 2,6-bis[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]pyridine (L2): structure and solution stereodynamics

The non-racemic chiral ligands 2-[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]pyridine (L¹) and 2,6-bis[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]pyridine (L²) reacted with the [ReX(CO)₅] compounds (X = Cl, Br, or I) to form fac-[ReX(CO)3(L¹)] and fac-[ReX(CO)₃(L²)], respectively. The ligands co-ordinate to the metal moiety in a bidentate fashion via the N donor of the pyridine ring and one of the acetal O atoms. The bonding modes are confirmed by the molecular structures of [ReI(CO)₃(L¹)] and [ReBr(CO)₃(L²)]. There are four possible diastereoisomers, depending on the configuration at the metal and the acetal carbon atom. In the solid state [ReI(CO)₃(L¹)] and [ReBr(CO)₃(L²)] exist exclusively as the RR and SR diastereoisomers, respectively. In solutions of the complexes of L¹ all four diastereoisomers are observed in varying concentrations, with the SR species being dominant. Only two of the four possible species are observed in solutions of the complexes of L², with the SR diastereoisomer being present in ca. 96% diastereomeric excess over the RR diastereoisomer. Above ambient temperatures both series of complexes are fluxional. A reversible flip of the acetal ring in the complexes [ReX(CO)₃(L¹)] leads to the pair-wise exchange of diastereoisomers as a result of the formal inversion of configuration at the acetal carbon atom; the free energies of activation are in the range 78–82 kJ mol⁻¹. The ring flip process appears to occur via a pseudo seven-co-ordinate transition state, in which both O atoms of the acetal ring are loosely bound to the metal. The pendant and co-ordinated acetal rings in the complexes of L² are exchanged via the tick-tock mechanism; the free energies of activation are in the range 75–79 kJ mol⁻¹.

Stereochemical rearrangements in tricarbonylrhenium(I) halide complexes of the nonracemic chiral ligand 2-[(4R,5R)-dimethyl-1,3-dioxan-2-yl]pyridine (L): a dynamic NMR study

Tricarbonylrhenium(I) halide complexes of the nonracemic chiral ligand 2-[(4R,5R)-dimethyl-1,3-dioxan-2-yl]pyridine (L), namely fac-[ReX(CO)3L] (X = Cl, Br, or I), have been prepared and their latent fluxionality studied by dynamic NMR techniques in the slow and intermediate exchange regimes. In solution, these complexes give rise to four diastereoisomers, depending on the configuration at the metal and at the acetal-carbon atom, respectively; the relative populations are in the order SR > RR >>; RS > SS. At moderate temperatures, a reversible "acetal ring flip" leads to formal inversion of configuration at the acetal-carbon atom; the free energies of activation are in the range 84-88 kJ mol-1 at 298 K. Above ca. 370 K, reversible ligand dissociation also occurs, leading to an exchange of all four diastereoisomers on the NMR chemical shift time-scale.Key words: dynamic NMR, fluxionality, tricarbonylrhenium(I) complexes, chiral acetal ligands.

Stereochemical rearrangements in tricarbonylrhenium(I) halide complexes of the nonracemic chiral ligand 2-[(4<i>R</i>,5<i>R</i>)-dimethyl-1,3-dioxan-2-yl]pyridine (L): a dynamic NMR study

Tricarbonylrhenium(I) halide complexes of the nonracemic chiral ligand 2-[(4R,5R)-dimethyl-1,3-dioxan-2-yl]pyridine (L), namely fac-[ReX(CO)3L] (X = Cl, Br, or I), have been prepared and their latent fluxionality studied by dynamic NMR techniques in the slow and intermediate exchange regimes. In solution, these complexes give rise to four diastereoisomers, depending on the configuration at the metal and at the acetal-carbon atom, respectively; the relative populations are in the order SR > RR >>; RS > SS. At moderate temperatures, a reversible "acetal ring flip" leads to formal inversion of configuration at the acetal-carbon atom; the free energies of activation are in the range 84-88 kJ mol-1 at 298 K. Above ca. 370 K, reversible ligand dissociation also occurs, leading to an exchange of all four diastereoisomers on the NMR chemical shift time-scale.Key words: dynamic NMR, fluxionality, tricarbonylrhenium(I) complexes, chiral acetal ligands.

A detailed NMR study of the solution stereodynamics in tricarbonylrhenium(I) halide complexes of the non-racemic chiral ligand 2,6-bis[(4R,5R)-dimethyl-1,3-dioxan-2-yl]pyridine (L1) and the molecular structure of fac-[ReBr(CO)3(L1)] †

Tricarbonylrhenium(I) halide complexes of the non-racemic chiral ligand 2,6-bis[(4R,5R)-dimethyl-1,3-dioxan-2-yl]pyridine (L1), namely fac-[ReX(CO)3(L1)] (X = Cl, Br or I), have been prepared. In these complexes the ligand is bound in a bidentate fashion, with the N atom of the pyridine ring and an O atom of one of the acetal rings co-ordinated to the octahedral metal centre. The bidentate mode is confirmed by the crystal structure of fac-[ReBr(CO)3(L1)]. There are four possible diastereoisomers, depending on the configuration at the metal centre and at the acetal-carbon atom of the co-ordinated ring; the crystal structure of fac-[ReBr(CO)3(L1)] shows that the SR diastereoisomer is present in the solid-state. In solution, three of the four possible diastereoisomers are observed, namely SR, RR and SS; their relative populations are in the order SR > RR > SS. Above ambient temperature the complexes are stereochemically non-rigid. The fluxional kinetics have been measured by a combination of standard band shape analysis and selective inversion experiments. Two distinct processes are present: an acetal ring flip and exchange of the pendant and co-ordinated acetal rings. The latter process occurs via two independent mechanisms, namely tick-tock and rotation pathways. The activation energies for the stereodynamics are in the ranges 72–73 kJ mol–1 (tick-tock), 77–78 kJ mol–1 (acetal ring flip) and 83–90 kJ mol–1 (rotation) at 298 K.

REACTIONS OF ACYLFORMYLKETENE S,S-AND S,N-ACETALS WITH AMINES

Abstract Acylformylketene S,S-and S,N-acetals 1 and 12 react with amines substituting one or both donor groups at the acetal carbon atom leading to 2–5, 7, 9–11, 13, 14 and 18 and also yielding azomethines 6–9, 11, 17 and 21. Obviously, the reaction at the acetal carbon proceeds by thermodynamic control and at the aldehyde carbon by kinetic control, 1,4-Dinucleophiles are appropriate building blocks for heterocycles 19, 20 and 22.

ChemInform Abstract: Catalytic‐Transfer Hydrogenolysis of Benzylidene Acetals with Palladium‐Carbon and Ammonium Formate or Hydrazine Hydrate.

AbstractThe direction of the hydrogenolytic ring‐cleavage of 2‐phenyl‐1,3‐dioxolanes (I) and (III) is determined by the configuration of the acetal carbon atom.

The crystal structure of 2,4:3,5-di- O-benzylidene- d-arabinose diethyl dithioacetal, and related molecular-mechanics calculations

A new di- O-benzylidene derivative of d-arabinose diethyl dithioacetal, obtained by benzylidenation with α,α-dimethoxytoluene, was shown by X-ray crystallography to have the 2,4:3,5-di- O-benzylidene structure. The two O-benzylidene rings are trans-fused, and the CH(SEt) 2 group adopts an axial orientation at C-4 of a 2-phenyl-1,3-dioxane ring. The axial group is twisted, and there is some distortion of the chair conformation of the ring. 1H-N.m.r. coupling-constants showed that the conformation is similar in solution. Molecular-mechanics calculations using a modified MM2 program indicated that the distortions are caused by intramolecular interactions. They also suggest that rotation about the bond from the acetal carbon atom to the phenyl ring in 2-phenyl-1,3-dioxanes is not free, as previously calculated. The parallel conformation was calculated to be a minimum, and the perpendicular conformation a saddlepoint 0.95 kcal.mol −1 higher on the potential-energy surface. The 1H- and 13C-n.m.r. parameters of this system and other trans-fused 3,7-diphenyl-2,4,6,8-tetraoxa[4,4]bicyclodecanes do not fit the ranges previously proposed for structural assignment of benzylidene acetals. The ranges have been revised to include this type of compound.

Mass spectrometry of oligosaccharides by chloride-attachment reactions: The origin of fragment loss

The direct exposure, negative chemical ionisation, chloride-attachment mass spectrometry of trehalose and sucrose gave abundant chloride-attached molecular ions. The same feature was observed when these sugars were subjected to fast-atom bombardment (f.a.b.) in a glycerol matrix containing ammonium chloride. No characteristic fragment ion was found when trehalose was analysed by either method. In contrast, sucrose gave intense chloride-containing fragments, arising by glycosidic cleavage, when analysed by the first method, whereas such cleavage was not detectable by f.a.b.-ammonium chloride analysis. However, the mass-analysed ion kinetic energy (m.i.k.e.) spectra of the (M + Cl) − ions from either trehalose and sucrose, generated under f.a.b.-ammonium chloride conditions, showed glycosidic cleavage reactions in addition to a large loss of HCl. These cleavage reactions might be attributed to S N2-like reactions on the acetal carbon atom and to base-induced eliminations, and they were enhanced by collision-induced dissociations. However, the relative abundance of such glycosidic cleavages from the ionic state would be too weak to explain the presence of the large chloride-containing fragments in the direct exposure spectra of sucrose. Thus, these ions were mainly produced by a thermal cleavage followed by chloride-attachment reactions.