Efficient synthesis of beta-D-mannosides and beta-D-talosides by double parallel or double serial inversion

A neighboring equatorial ester group plays a highly important role in the Lattrell-Dax (nitrite-mediated) carbohydrate epimerization reaction, inducing the formation of inversion compounds in good yields. On the basis of this effect, efficient synthetic routes to beta-D-mannosides and beta-D-talosides, from the corresponding beta-D-galactosides and beta-D-glucosides, have been designed. The present routes are based on multiple regioselective acylation via the respective stannylene intermediates, followed by inversions to the corresponding manno- and talopyranoside structures by nitrite or acetate substitution. It was found that the ester group was able to induce the inversion of its two neighboring groups in high yields following either a double parallel or a double serial inversion process. By combination of direct inversion, and neighboring- as well as remote-group participation, several beta-d-mannoside and beta-D-taloside derivatives were very conveniently obtained in good yields.     

Beiträge zur Kenntnis des chromophoren Systems der Corrine: XII [1]. Chemische Eigenschaften des Reaktionsproduktes aus Dicyanocobyrinsäure-heptamethylester mit hypochloriger Säure

Contributions to the Knowledge of the Corrin Chromophore: XII [1]. Chemical Behaviour of the Reaction Product of Heptamethyl Dicyano-cobyrinate with Hypochlorous Acid Heptamethyl chloro-cyano-5α, 10, 15-trichloro-6α, 14-dihydroxy-5,6,14,15-tetrahydrocobyrinate ( 2 ) in CH₃OH/H₂SO₄ yields with RuO₂ under 50 bar hydrogen and at 100° during 2 h a mixture of heptamethyl dicyanocobyrinate ( 1 ) with an epimeric ester. Using deuterium instead of hydrogen in this reaction, C(13) comes out as the probable epimerization center.     

Axial and equatorial hydrogen shifts in methyl substituted cyclohexylidenes. Stereochemically-dependent isotope effects and bystander assistance

Carbenes were generated from 4-t-butyl-cis-2-methylcyclohexanone (4a) and from 4-t-butyl-cis-2-trans-6-dimethylcyclohexanone (8a, and its corresponding 2,6-d₂ analog 8b) by conventional Bamford-Stevens reactions. Product analysis revealed that an equatorial CH₃ assists migration of a geminal H more efficiently than does an axial CH₃ by a factor of about 4.6. The primary deuterium isotope effect (k_H/k_D) for axial shift (I_ax) is ca. 1.5 times greater than for equatorial shift (I_eq) in the anchored dimethyl substituted carbene 9.     

An improved synthesis of aziridine-2,3-dicarboxylates via azido alcohols—epimerization studies

The reasons for epimerization of 3-azido-2-hydroxysuccinates observed during the ring opening of epoxides or cyclic sulfites with sodium azide is now clarified. It is caused by the high acidity of the proton at the 3-position. This is proven by a proton deuterium exchange in assays with either D₂O or DCl containing solvents. The anti-3-azido-2-hydroxysuccinates serve as intermediates for enantiomerically pure trans-aziridine-2,3-dicarboxylates for which an optimized synthetic pathway is presented. The first example of an enantiomerically pure mixed diester of the aziridine-2,3-dicarboxylic acid the synthesis of the allyl ethyl ester is reported herein.     

An improved procedure for N- to C-directed (Inverse) solid-phase peptide synthesis

A method for solid-phase peptide synthesis in the N- to C-direction that delivers good coupling yields and a low degree of epimerization is reported. The optimized method involves the coupling, without preactivation, of the resin-bound C-terminal amino acid with excess amounts of amino acid tri-tert-butoxysilyl (Sil) esters, using HATU as coupling reagent and 2,4,6-trimethylpyridine (TMP, collidine) as a base. For the amino acids investigated, the degree of epimerization was typically 5%, except for Ser(t-Bu) which was more easily epimerized (ca. 20%). Five tripeptides (AA(1)-AA(2)-AA(3)) with different properties were used as representative model peptides in the development of the synthetic method: Asp-Leu-Glu, Leu-Ala-Phe, Glu-Asp-Val, Asp-Ser-Ile, and Asp-D-Glu-Leu. The study used different combinations of HATU and TBTU as activating agents, N, N-diisopropylethylamine (DIEA) and TMP as bases, DMF and dichloromethane as solvents, and cupric chloride as an epimerization suppressant. The epimerization of AA(2) in the coupling of AA(3) was further reduced in the presence of cupric chloride. However, the use of this reagent also resulted in a decrease in loading onto the resin and significant cleavage between AA(1) and AA(2). Experiments indicated that the observed suppressing effect of cupric chloride on epimerization in the present system merely seemed to be a result of a base-induced cleavage of the oxazolone system, the key intermediate in the epimerization process. Consequently, the cleavages were most pronounced in slow couplings. An improved synthesis of fully characterized amino acid tri-tert-butoxysilyl (Sil) ester hydrochloride building blocks is presented. The amino acid Sil esters were found to be stable as hydrochlorides but not as free bases. Although only a few peptides have been used in this study, we believe that the facile procedure devised herein should provide an attractive alternative for the solid-phase synthesis of short (six residues or less) C-terminally modified peptides, e.g., in library format.     

Peptide cysteine thiyl radicals abstract hydrogen atoms from surrounding amino acids: the photolysis of a cystine containing model peptide

Peptide cysteine thiyl radicals were generated through UV-photolysis of disulfide precursors, in order to follow intramolecular reactions of those radicals with neighboring amino acids. When reactions were carried out in D(2)O, there was a significant incorporation of deuterium specifically into the C(alpha)-H bonds of glycine residues in positions i+1 and i-1 to the Cys residue, indicating a fast reversible H-atom transfer. This H-atom transfer occurred prior to the formation of final, nonradical products including free thiol, thioaldehyde, and aldehyde. Such fast H-atom transfer is relevant to biologic conditions of oxidative stress and to the stabilization of proteins against oxidation, where the formation of carbon-centered radicals in proteins may lead to fragmentation, intramolecular cross-linking, aggregation and/or epimerization.     

Stereochemistry of nitrogenous heterocycles. 71. Isomerization — Equilibration of stereoisomeric ethinylcarbinols epimeric at the carbinol center

Equilibration of stereoisomeric cyclic ethinylcarbinols, epimeric at the carbinol center, was conducted for the first time and it was shown that the equilibrium is shifted toward the equatorial alcohol (at 50C for 2e-methyl-4-hydroxy-4-phenylethinyl-trans-decahydroquinoline, 2e-methyl-4-hydroxy-4-ethinyl-trans-decahydroquinoline, 4-hydroxy-4-ethinyl-trans-decahydroquinoline —(78±1)% equatorial and (22±1)% axial alcohol, for 1,2e,5e-trimethyl-4-ethinylpiperidol-4 (74±1)% equatorial and (26±1)% axial alcohol). The epimerization of stereoisomeric ethinylcarbinols can be used as a method for determination of the configuration of the quaternary carbinol center.See [1] for Communication 70.The data was presented at the VI International IUPAC Conference on Organic Synthesis [2].Translated from Khimi-ya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1072–1076, August, 1991.     

Stereoelectronic effects in cyclic sulfoxides, sulfones, and sulfilimines: application of the Perlin effect to conformational analysis

The 1JC--H coupling constants in conformationally constrained sulfoxides, bissulfoxides, sulfoxide-sulfones, and sulfilimines derived from 2-benzylidene-1,3-dithiane and 2-(2,2-dimethylpropylidene)-1,3-dithiolane were measured by means of HMQC and HSQC NMR experiments and the Perlin effects were calculated. The type and the relative configuration of S==X groups (X= O, NTos) in these compounds have a strong influence on the magnitude of coupling constants for axial and equatorial C--H bonds, respectively. Axial S==O bonds give rise to a stereoelectronic effect on antiperiplanar axial C--H bonds. The resultant weakening of the respective C--H bonds leads to a smaller coupling constant than for a respective equatorial C--H bond. Equatorial S==O groups have an influence on beta-C--H bonds through a homoanomeric effect. Here, the axial C--H bond is weakened and a smaller coupling constant is measured. Sulfilimine groups show similar effects to sulfoxide groups.     

Epimerization and racemization of some chiral drugs in the presence of cyclodextrin and liposomes

The effects of alpha-, beta-, gamma- and dimethyl-beta-cyclodextrins (alpha-, beta-, gamma- and DM-beta-CyDs) and liposomes on epimerization or racemization of etoposide, ethiazide and carbenicillin were examined kinetically. alpha- and beta-CyDs accelerated both epimerization and hydrolysis of carbenicillin. They had no effect on epimerization of etoposide, and did not affect racemization and hydrolysis of ethiazide. DM-beta-CyD retarded epimerization of etoposide, hydrolysis of picroetoposide (which is an epimer of etoposide), and racemization and hydrolysis of ethiazide, but had no effect on epimerization and hydrolysis of carbenicillin. gamma-CyD retarded epimerization of etoposide and hydrolysis of picroetoposide. On the other hand, gamma-CyD accelerated epimerization of carbenicillin. It is suggested that the formation of inclusion complexes between CyDs and etoposide, picroetoposide and ethiazide inhibited the attack of bases such as OH- and buffer components, thereby retarding epimerization, racemization and hydrolysis. On the other hand, alpha-, beta- and gamma-CyDs increased the reactivity of carbenicillin through the OH group, accelerating its epimerization and hydrolysis. Liposomes retarded epimerization of etoposide, hydrolysis of picroetoposide and racemization of ethiazide. Liposomes did not affect epimerization and hydrolysis of carbenicillin. These differences in the effect of liposomes on reactivity may be interpreted in terms of the solubility of the drugs.     

Base induced rearrangements of α-halosulfones α-sulfonyl carbanions with bridgehead electrofugal centre

The KOtBu-induced Ramberg-Bäcklund reaction of the trans bicyclic halosulfones 1 and 2 is studied in DME and DMSO. Strong indications are obtained that the reaction proceeds via the intermediate Z-episulfone with retention-inversion (involving exo-S-geometry).¹ Base induced epimerization at the nucleofugal centre (from axial to equatorial halogen) is demonstrated in DMSO.     

Reduction of nitriles to amines in positive ion electrospray ionization mass spectrometry

Some compounds readily form [M+46]+ adduct ions during positive ion electrospray ionization mass spectrometry ((+)ESI-MS) analysis. These [M+46]+ ions were characterized as [M+CH3CH2NH2+H]+ by accurate mass determination. Ethylamine involved in the adduct was proposed to be the reduction product of acetonitrile and this was confirmed using deuterated acetonitrile. Other nitrile-containing compounds tested, including isobutyronitrile and benzonitrile, also formed the adduct ions of the respective amine forms under (+)ESI-MS conditions. Hydrogen/deuterium exchange experiments demonstrated that the reductive hydrogen originated from water. Reduction of nitriles (R-CN) to their respective amines (R-CH2NH2) under (+)ESI-MS conditions expands the ability to identify nitrile-containing chemical unknowns.     

The fate of C5' radicals of purine nucleosides under oxidative conditions

The factors that influence the reactivity of C5' radicals in purine moieties under aerobic conditions are unknown not only in DNA, but also in simple nucleosides. 5',8-Cyclopurine lesions are the result of a rapid C5' radical attack to the purine moieties before the reaction with oxygen. These well-known lesions among the DNA modifications were suppressed by the presence of molecular oxygen in solution. Here we elucidate the chemistry of three purine-substituted C5' radicals (i.e., 2'-deoxyadenosin-5'-yl, 2'-deoxyinosin-5'-yl, and 2'-deoxyguanosin-5'-yl) under oxidative conditions using gamma-radiolysis coupled with product studies. 2'-Deoxyadenosin-5'-yl and 2'-deoxyinosin-5'-yl radicals were selectively generated by the reaction of hydrated electrons (e(aq)(-)) with 8-bromo-2'-deoxyadenosine and 8-bromo-2'-deoxyinosine followed by a rapid radical translocation from the C8 to the C5' position. Trapping these two C5' radicals with Fe(CN)6(3-) gave corresponding hydrated 5'-aldehydes in good yields that were isolated and fully characterized. When an oxygen concentration in the range of 13-266 microM (typical oxygenated tissues) is used, the hydrated 5'-aldehyde is accompanied by the 5',8-cyclopurine nucleoside. The formation of 5',8-cyclopurines is relevant in all experiments, and the yields increased with decreasing O2 concentration. The reaction of HO(*) radicals with 2'-deoxyadenosine and 2'-deoxyguanosine under normoxic conditions was also investigated. The minor path of C5' radicals formation was found to be ca. 10% by quantifying the hydrated 5'-aldehyde in both experiments. Rate constants for the reactions of the 2'-deoxyadenosin-5'-yl with cysteine and glutathione in water were determined by pulse radiolysis to be (2.1 +/- 0.5) x 10(7) and (4.9 +/- 0.6) x 10(7) M(-1) s(-1) at 22 degrees C, respectively.     

Langsame Inversion am pyramidal gebundenen Stickstoff: Isolierung und Epimerisierung diastereomerer N-Methoxy-3,3-di-methoxycarbonyl-5-cyan-1, 2-oxazolidine. Vorläufige Mitteilung

Two crystalline diastereomeric N-methoxy-3, 3-di-methoxycarbonyl-5-cyano-1, 2-oxazolidines (II and III) have been isolated. The pyramidal arrangement at the respective nitrogen atoms does not invert at room temperature. The ARRHENIUS activation energy for the epimerization of the thermodynamically less stable isomer to the more stable one in bromoform solution is 29,2 ± 0,5 kcal/Mol (log A = 14,2 ± 0,3).     

Removal of Acyl Protective Groups from Glycopeptides: Base Does Not Epimerize Peptide Stereocenters, and beta-Elimination Is Slow

Epimerization of glycopeptide stereocenters and beta-elimination have been considered as important potential side reactions on deacylation of glycopeptides which have the carbohydrate moieties protected with O-acyl groups. Since no systematic investigation of these side reactions has been reported, a model acetylated, O-linked glycotripeptide and its three epimers at the alpha-carbon stereocenters were prepared. The model glycopeptide did not undergo any epimerization (<1%) or beta-elimination, as determined by (1)H NMR spectroscopy, under various conditions which are in common use for deacetylation of glycopeptides. Under more severe conditions, which are required for removal of O-benzoyl groups, beta-elimination occurred slowly and was accompanied by slight (<5%) epimerization. The surprisingly low tendency of glycopeptides to undergo base catalyzed epimerization and beta-elimination is most likely due to protection of the alpha-carbon stereocenters by deprotonation of the adjacent amide groups.     

Enantioselective synthesis of six-membered palladacycles having metal-bound stereogenic carbons: isolation and reactivity of palladacycles containing readily accessible beta-hydrogens

Five enantiopure palladacycles containing palladium bonded to a stereogenic carbon and an N-coordinated oxindole were synthesized by the reaction of alkenyl aryl triflates 2 and 9 with Pd(0) bisphosphine complexes. Two palladacyclic complexes, 3beta and 10alpha, were characterized by single-crystal X-ray crystallography. The reactivity of neutral palladacycles 3beta and 10beta was studied in detail. These unusual palladium alkyls, which have three accessible beta-hydrogens, are thermally stable at temperatures as high as 120 degrees C. At higher temperature, or at room temperature in the presence of weak acids, these complexes epimerize at the stereogenic carbon bonded to palladium. The mechanism of the acid-promoted epimerization was studied in detail. During this epimerization, cationic palladium alkyls 13/14 and 33 and cationic palladium hydride alkene complexes 31 and 32 are in rapid equilibrium.     

The First Synthesis of a Ribo-Hexos-5-Ulose: the L-Enantiomer

ABSTRACT

The title compound, previously unreported in either enantioform, and its 2,6-di-O-benzyl derivative have been synthesized through a stereocontrolled epimerization at C-2 of 6-O-protected methyl 3,4-O-isopropylidene-5-C-methoxy-β-D-galactopyranosides. The epimerization, performed through a high yielding sequence of oxidation-reduction owing to the cooperative role of the equatorial C-1 aglycon and the steric hindrance of the isopropylidene group, turned out to be completely diastereoselective. Whereas the unprotected L-ribo-hexos-5-ulose exists, as proved by NMR in D₂O, in five main tautomeric forms in a ratio of about 4:2:2:1:1, only two anomeric 1,4-furanosic forms are present at equilibrium in its 2,6-di-O-benzyl derivative, in ratios ranging from 10:1 to 7:3, depending on the prevalence of D₂O or CD₃CN in the solvent mixture.     

Mutual influence of axial and equatorial P-Cl bonds in the molecular forms of pentachlorophosphorane,their lengths in gaseous and crystalline states

The quantum-chemical calculations by RHF/6-31G(d), MR2/6-31G(d) and MP2/6-31+G(d) methods of molecular forms of pentachlorophosphorane with the complete geometry optimization at the different lengths of P-Cl bonds are performed. The results of the calculations are used for estimation of respective ³⁵Cl NQR frequencies. The lengths of axial (2.05 Å) and equatorial (2.01 Å) P-Cl bonds are found, when the calculated NQR frequencies of Cl atoms practically coincide with the obtained experimentally at 77 K. These bonds are a little shorter than in the gaseous state of the matter. In contrast to the ratio of the lengths of the experimental P-Cl bonds and NQR frequencies of respective Cl atoms, at the use of increased lengths of these bonds in the quantum-chemical calculations of the molecule, the ³⁵Cl NQR frequencies of Cl atoms calculated from the results of these calculations, increase. Therewith, the change in the length of the equatorial P-Cl bonds with unchanged length of axial bonds leads to a significantly greater change in the NQR frequencies of axial chloroine atoms than of the equatorial, and vice versa.     

Über Pterinchemie. 73. Mitteilung [1]. Zum Verlauf der katalytischen Reduktion von 7-Methylpterin

On the Pathway of the Catalytic Reduction of 7-Methylpterin The catalytic hydrogenation of 7-methylpterin (VII) in a neutral solution occurs first by the reduction of the 7,8-double bond (thermodynamically-controlled reaction) followed by the reduction of the 5,6-double bond. On the contrary, in an acidic medium like CF₃COOH, the 5,6-double bond is reduced first (kinetically-controlled reaction). The dihydro-intermediate then undergoes a [1,2]-H-rearrangement leading to the formation of the thermodynamically more stable 7-methyl-7,8-dihydropterin (XV) which on further reduction gives 7-methyl-5,6,7,8-tetrahydropterin (VIII). The catalytic reduction of 7-methyl-7,8-dihydropterin (XV) with deuterium gives stereoselectively a sole product with D at C(6) in the equatorial position.     

QCT study of isotopic effects in H + HBr abstraction and exchange reactions

The method of quasi-classical trajectories on an LEPS hypersurface was used for studying the influence of the exchange of one or both of the hydrogen atoms for deuterium in the reaction H¹ + H²Br. As expected, the reaction cross sections of the exchange and abstraction reactions were found to increase if H¹ was replaced by D and decrease if H² was replaced by deuterium. A similar change in the reaction cross sections have also been observed for vibrationally excited reactants. The distribution of vibrational (rotational) energy is related to the ω_e (B_e) values of the respective reactants and products.     

Phenylsulfanylation of 3',4'-unsaturated adenosine employing thiophenol-N-iodosuccinimide leads to 4'-phenylsulfanylcordycepin: synthesis of 4'-substituted cordycepins on the basis of substitution of the phenylsulfanyl leaving group

Upon reaction of the 3',4'-unsaturated adenosine derivative 2 with N-iodosuccinimide (NIS) and thiophenol, an unexpected electrophilic hydrophenylsulfanylation proceeded to provide 4'-phenylsulfanylcordycepin 7 in 79% yield with the ratio 7a/7b = 6.6/1. A study of the reaction mechanism revealed that hydrogen iodide (HI) generated from NIS and PhSH acted as an active species. On the basis of a deuterium experiment using PhSD, initial protonation occurred at the β face of the double bond to furnish the β-π complex III, which underwent anti addition of PhSH as a major pathway. Nucleophilic substitution of N(6)-pivaloylated 9 with various alcohols in the presence of N-bromosuccinimide (NBS) gave the respective 4'-α-alkoxycordycepins 15a-21a as the major stereoisomers. Use of DAST in place of an alcohol gave the 4'-α-fluoro analogue 23a stereoselectively. Radical-mediated carbon-carbon bond construction was also applicable to 7, giving 4'-α-allylcordycepin (24a) and 4'-α-cyanoethylcordycepin (25) derivatives.