Glycosylidene Carbenes. Part 6. Synthesis of alkyl and fluoroalkyl glycosides

The syntheses of glycosides from the diazirine 1 and a range of alcohols under thermal and/or photolytic conditions are described. Yields and diastereoselectivities depend upon the pK_HA values of the alcohols, the solvent, and the reaction temperature. The glycosidation of weakly acidic alcohols (MeOH, EtOH, i-PrOH, and t-BuOH, 1 equiv. each) in CH₂Cl₂ at room temperature leads to the glycosides 2–5 in yields between 60 and 34% (Scheme 1 and Table 1). At ?70 to ?60°, yields are markedly higher. In CH₂Cl₂, diastereoselectivities are very low. In THF, at ?70 to ?60°, however, glycosidation of i-PrOH leads to α-D -/β-D - 4 in a ratio of 8:92. More strongly acidic alcohols, such as CF₃CH₂OH, (CF₃)₂ CHOH, and (CF₃)₂C(Me)OH, and the highly fluorinated long-chain alcohols CF₃(CF₂)₅(CH₂)₂OH ( 11 ) and CHF₂(CF₂)₉CH₂OH ( 13 ) react (CH₂Cl₂, r.t.) in yields between 73 and 85% and lead mainly to the β-D -glucosides β-D - 6 to β-D - 8 , β-D - 12 , and β-D - 14 (d.e. 14–68%). Yields and diastereoselectivities are markedly improved, when toluene, dioxane, 1,2-dimetoxyethane, or THF are used, as examined for the glycosidation of (CF₃)₂C(Me)OH, yielding (1,2-dimethoxyethane, 25°) 80% of α-D -/ β-D - 8 in a ratio of 2:98 (d.e. 96%; Table 4). In EtCN, (CF₃)₂C(Me)OH yields up to 55% of the imidate 10 . Glycosidation of di-O-isopropylideneglucose 15 leads to 16 (CH₂Cl₂, r.t.; 65%, α-D / β-D = 33:67). That glycosidation occurs by initial protonation of the intermediate glycosylidene carbene is evidenced, for strongly acidic alcohols, by the formation of 10 , derived from the attack of (CF₃)₂MeCO^? on an intermediate nitrilium ion (Scheme 4), and for weakly acidic alcohols, by the formation of α-D - 9 and β-D - 9 , derived by attack of i-PrO^? on intermediate tetrahydrofuranylium ions. A working hypothesis is presented (Scheme 3). The diastereoselectivities are rationalized on the basis of a protonation in the σ plane of the intermediate carbene, the stabilization of the thereby generated ion pair by interaction with the BnO? C(2) group, with the solvent, and/or with the alcohol, and the final nucleophilic attack by RO^? in the π plane of the (solvated) oxonium ion.     

The dimeric and polymeric anhydride of 2,3-O-isopropylidene-β-D-ribofuranose. An NMR study

The ¹H- and ¹³C-NMR data of the dimeric anhydride 1 of 2,3-O-isopropylidene-β-D -ribofuranose are reported together with the ¹H-NOE values. The data show that the products of the polymerization of 1,5-anhydro-2,3-O-isopropylidene-β-D -ribofuranose are α- and β-D -ribofuranans and not an α-D -ribofuranan and a β-D -ribofuranan and a β D ribo-pyranan as claimed before [2] [3].     

β-Arylation of Racemic Secondary Benzylic Alcohols to Access Enantioenriched β-Arylated Alcohols

The transformation of alcohols into value-added products is of great importance, as simple alcohols are widespread and can be easily derived from both fossil fuels and biomass. The selective functionalization of a sp³ C−H bond on the alkyl side chain of an alcohol over its hydroxyl group would offer an expedient route to expand the chemical space of alcohols but it remains a challenging task. Harnessing the borrowing hydrogen strategy, the β-arylation of secondary alcohols with aryl bromides has been achieved in this study, which allows for the selective functionalization of a β-Csp³−H bond in an alcohol substrate. Under the catalysis of a Pd complex, secondary alcohols reacted with aryl bromides to afford 1,2-diaryl alcohols with broad substrate scope in the presence of a ketone additive. Furthermore, the enantioconvergent version of the reaction has also been realized, transforming racemic secondary alcohols into enantioenriched chiral 1,2-diaryl alcohols under the cooperative Pd and Ru catalysis. Mechanism studies indicate that the reactions are enabled by borrowing hydrogen catalysis.     

Synthesis of New Nucleosides by coupling of chloropurines with 2- and 3-deoxy derivatives of N-methyl-D-ribofuranuronamide

The synthesis of new deoxyribose nucleosides by coupling chloropurines with modified D -ribose derivatives is reported. The methyl 2-deoxy-N-methyl-3-O-(p-toluoyl)-α-D -ribofuranosiduronamide (α-D - 8 ) and the corresponding anomer β-D - 8 were synthesized starting from the commercially available 2-deoxy-D -ribose ( 1 ) (Scheme 1). Reaction of α-D - 8 with the silylated derivative of 2,6-dichloro-9H-purine ( 9 ) afforded regioselectively the N⁹-(2′-deoxyribonucleoside) 10 as anomeric mixture (Scheme 2), whereas β-D - 8 did not react. Glycosylation of 9 or of 6-chloro-9H-purine ( 17 ) with 1,2-di-O-acetyl-3-deoxy-N-methyl-β-D -ribofuranuronamide ( 13 ) yielded only the protected β-D -anomers 14 and 18 , respectively (Scheme 3). Subsequent deacetylation and dechlorination afforded the desired nucleosides β-D - 11 , β-D - 12,15 , and 16 . The 3′-deoxy-2-chloroadenosine derivative 15 showed the highest affinity and selectivity for adenotin binding site vs. A₁ and A_2A adenosine receptor subtypes.     

Nucleic-Acid Analogs with Restricted Conformational Flexibility in the Sugar-Phosphate Backbone (‘Bicyclo-DNA’). Part 5. Synthesis,Characterization, and Pairing Properties of Oligo-α-D-(bicyclodeoxynucleotides) of the Bases Adenine and Thymine (α-Bicyclo-DNA)

A conformational analysis of the (3′S,5′R)-2′-deoxy-3′,5′-ethano-α-D -ribonucleosides (a-D-bicyclodeoxynucleosides) based on the X-ray analysis of N⁴-benzoyl-α-D -(bicyclodeoxycytidine) 6 and on ¹H-NMR analysis of the α-D -bicyclodeoxynucleoside derivatives 1 - 7 reveals a rigid sugar structure with the furanose units in the l′-exo/2′-endo conformation and the secondary OH groups on the carbocyclic ring in the pseudoequatorial orientation. Oligonucleotides consisting of α-D -bicyclothymidine and α-D -bicyclodeoxyadenosine were successfully synthesized from the corresponding nucleosides by phosphoramidite methodology on a DNA synthesizer. An evaluation of their pairing properties with complementary natural RNA and DNA by means of UV/melting curves and CD spectroscopy show the following characteristics: i) α-bcd(A₁₀) and α-bcd(T₁₀) (α = short form of α-D )efficiently form complexes with complementary natural DNA and RNA. The stability of these hybrids is comparable or slightly lower as those with natural β-d(A₁₀) or β-d(T₁₀)( β = short form ofβ-D ). ii) The strand orientation in α-bicyclo-DNA/β-DNA duplexes is parallel as was deduced from UV/melting curves of decamers with nonsymmetric base sequences. iii) CD Spectroscopy shows significant structural differences between α-bicyclo-DNA/β-DNA duplexes compared to α-DNA/β-DNA duplexes. Furthermore, α-bicyclo-DNA is ca. 100-fold more resistant to the enzyme snake-venom phosphodiesterase with respect to β-DNA and about equally resistant as α-DNA.     

Efficient regio- and stereoselective ring opening of epoxides with alcohols, acetic acid and water catalyzed by ammonium decatungstocerate(IV)

Epoxides can be cleaved in a regio- and stereoselective manner under neutral conditions with alcohols and acetic acid in the presence of catalytic amounts of decatungstocerate(IV) ion, ([CeW₁₀O₃₆]⁸⁻), affording the corresponding β-alkoxy and β-acetoxy alcohols in high yields. In water, ring opening of epoxides occurs with this catalyst to produce the corresponding diols in good yields.     

A 13C-NMR spectral study of cellulose and glucopyranose dissolved in the NH3/NH4SCN solvent system

The ¹³C-NMR chemical shifts of a cellulose with a DP_w of 23 dissolved in the NH₃/NH₄SCN solvent system were found to be very similar to those of cellulose dissolved in DMSO (cellulose oligomers), in the LiCl/DMAC system and in the N-methylmorpholine N-oxide/DMSO system. It was concluded from this that cellulose does not react with the NH₃/NH₄SCN solvent. It was found, however, that glucose reacts with the solvent at C-1 to form β-D -glucopyranosy-lamine. Separation of this compound from the solvent resulted in another compound which was determined to be β,β-di-D -glucopyranosylamine. The compounds β-D -glucopyranosylamine, N-acetyl-2,3,4,6-tetra-O-acetyl-β-D -glucopyranosylamine, β,β-di-D -glucopyranosylamine, α,β-di-D -glucopyranosylamine, 2,3,4,6,2′,3′,4′,6′-octa-O-acetyl-α,β-di-D -glucopyranosylamine were all synthesized and the ¹³C-NMR chemical shifts of these compounds are reported. It was also found that for the low-DP cellulose sample which was used the reducing end group existed and had reacted with the solvent to form an amine at C-1.     

Reactivity of β-amino alcohols against dialkyl oxalate: synthesis and mechanism study in the formation of substituted oxalamide and/or morpholine-2,3-dione derivatives

The reactivity of various β-amino alcohols with dialkyl oxalates, in several reaction conditions, has been investigated. Linear disubstituted oxalamides were obtained with primary β-amino alcohols and linear tetrasubstituted oxalamides, or a mixture of linear tetrasubstituted oxalamides and cyclic morpholine-2,3-diones were obtained with N-substituted β-amino alcohols. A DFT study of the possible mechanism has been made. The theoretical results indicate that these reactions are not kinetically controlled, there is an equilibrium between all species and therefore follow a thermodynamic control. The different behavior between the primary β-amino alcohols and N-methyl β-amino alcohols is due to the greater stability of linear disubstituted oxalamides with respect to linear tetrasubstituted oxalamides. The energy of tetrasubstituted oxalamides is closer to the energy of the corresponding morpholine-2,3-diones.     

Stereoselektive Synthese von 2′-O-(2-Methoxyethyl)ribonucleosiden: Nachbargruppenbeteiligung der Methoxyethoxy-Gruppe bei der Ribosylierung von Heterocyclen

Stereoselective Synthesis of 2′-O-(2-Methoxythyl)ribonucleosides: Neighboring-Group Participation of the Methoxythoxy Group in the Ribosylation Step A new access to 2′-O-(2-methoxyethyl)ribonucleosides, building blocks for second-generation antisense oligonucleotides, is presented. The influence of various reaction parameters on the coupling reaction of 2-O-(2-methoxyethyl)-D -ribose derivatives with heteroaromatic bases as the key step was investigated, and reaction conditions were optimized with regard to formation of the desired β-D -anomers. With Sn²⁺ salts as promotors in polar solvents, these β-D -anomers were formed with a high degree of steroselectivity.     

The Allyl Ester as Carboxy-Protecting Group in the Stereoselective Construction of Neuraminic-Acid Glycosides

The application of the allyl-ester moiety as protecting principle for the carboxy group of N-acetylneuraminic acid is described. Peracetylated allyl neuraminate 2 is synthesized by reacting the caesium salt of the acid 1 with allyl bromide. Treatment of 2 with HCl in AcCl or with HF/pyridine gives the corresponding 2-chloro or 2-fluoro derivatives 3 and 4 , respectively (Scheme 1). In the presence of Ag₂CO₃, the 2-chloro carbohydrate 3 reacts with di-O-isopropylidene-protected galactose 5 to give the 2–6 linked disaccharide with the α-D -anomer 6a predominating (α-D /β-D = 6:1; Scheme 2). Upon activation of the 2-fluoro derivative 4 with BF₃ · Et₂O, the β-D -anomer 6b is formed preferentially (α-D /β-D = 1:5). In further glycosylations of 4 with long-chain alcohols, the β-D -anomers are formed exclusively (see 10 and 11 ; Scheme 4). The allyl-ester moiety can be removed selectively and quantitatively from the neuraminyl derivatives and the neuraminyl disaccharides by Pd(0)-catalyzed allyl transfer to morpholine as the accepting nucleophile (see Scheme 5).     

Synthesis of new chiral keto alcohols by baker’s yeast

Fourteen chiral α- and β-keto alcohols 2a–2r were synthesized by the asymmetric reduction of their corresponding diketones 1a–1r via baker’s yeast. In addition, ten corresponding racemic α-keto alcohols were synthesized by the benzoin condensation of their corresponding aldehydes, which were used for the determination of the ee values through their chiral resolution on chiral HPLC. Amongst the 15 diketones, 1j and chiral α-keto alcohols 2i, 2j and chiral β-keto alcohol 2r are novel compounds. Six keto alcohols 2b, 2c, 2d, 2f, 2h and 2p were synthesized by baker’s yeast for the first time. There are some studies in the literature where baker’s yeast was applied to the diketones 1a, 1g, 1e, 1k and 1n under various conditions different to those reported herein. The yields and the ee values of these studies were not as high as ours. All of the keto alcohols synthesized were characterized by IR, NMR (¹H and ¹³C), and MS. The relationship between the structure of the diketone and the yield, diastereoselectivity and enantiomeric excess is also discussed.     

Manganese(I)-Catalyzed β-Methylation of Alcohols Using Methanol as C1 Source

Highly selective β-methylation of alcohols was achieved using an earth-abundant first row transition metal in the air stable molecular manganese complex [Mn(CO)₂Br[HN(C₂H₄PⁱPr₂)₂]] 1 ([HN(C₂H₄PⁱPr₂)₂]=MACHO-ⁱPr). The reaction requires only low loadings of 1 (0.5 mol %), methanolate as base and MeOH as methylation reagent as well as solvent. Various alcohols were β-methylated with very good selectivity (>99 %) and excellent yield (up to 94 %). Biomass derived aliphatic alcohols and diols were also selectively methylated on the β-position, opening a pathway to “biohybrid” molecules constructed entirely from non-fossil carbon. Mechanistic studies indicate that the reaction proceeds through a borrowing hydrogen pathway involving metal–ligand cooperation at the Mn-pincer complex. This transformation provides a convenient, economical, and environmentally benign pathway for the selective C−C bond formation with potential applications for the preparation of advanced biofuels, fine chemicals, and biologically active molecules     

Étude comparative,par spectroscopie infrarouge,des vibrations v(ch) de quelques alcools et thiols ne comportant qu'un seul vibrateur ch

Infrared spectra of some deuterated alcohols and thiols with only one α-CH or β-CH have been obtained in order to compare α and β heteroatom effects on v(CH). The spectra of RR'CHOH alcohols show two bands (Δv? 50 cm^?1) due to the α-CH bond trans to an oxygen lone-pair and the α-CH bond trans to OH.The α sulphur effect is found very weak or non-existent in thiols. The study of CD₂H-CD ₂OH and CD₂HCD₂SH spectra shows the same β-gauche effect of both the heteroatoms while only the sulphur atom seems to have a β-trans effect.     

Spectrofluorimetric study of the β-cyclodextrin-dapsone-linear alcohol supramolecular system and determination of dapsone

Dapsone (DDS) forms a 1:1 supramolecular complex with β-cyclodextrin (β-CD) both in the absence and presence of linear alcohols. The apparent association constants (K_app) were measured using a steady-state fluorescence method. K_app decreases linearly with an increasing number of carbon atoms in the chain of the alcohol. We attribute this to a competition between dapsone and linear alcohol for the β-CD hydrophobic cavity as detailed analysis of K_app as a function of the concentration of alcohol suggests that the interactions in the β-CD-dapsone-linear alcohol system do not result in the formation of ternary supramolecular complex. Quenching the fluorescence of dapsone with NaI shows that the β-CD cavity acts as a shield against contact between dapsone and this aqueous phase quencher, while addition of alcohols inhibits this protective effect. This again suggests that alcohols occupy the space within the β-CD cavity with the result that dapsone molecules are forced to reside in the aqueous environment. Based on the significant enhancement of the fluorescence intensity of dapsone produced through complex formation, a spectrofluorimetric method for the determination of dapsone in bulk aqueous solution in the presence of β-CD is developed. The linear relationship between the fluorescence intensity and dapsone concentration was obtained in the range of 3.39 to 1.50×10³ ng ml⁻¹, with a correlation coefficient (r) of 0.9998. The detection limit was 1.02 ng ml⁻¹. There was no interference from the excipients normally used in tablet formulations. The application of the present method to the determination of dapsone in tablets and human plasma gave satisfactory results and was compared with the pharmacopoeia method.     

The Reaction of Patchoulol with Lead Tetraacetate,a Regiospecific Fragmentation

Patchoulol (1) forms 2,2,6,8-tetramethylbicyclo [5.3.1]undec-7-en-3-one (5) with lead tetraacetate. This ketone undergoes acid-catalyzed cyclization to 2,6,6,10-tetramethyltricyclo [5.3.1.0^1,5]undec-9-en-5-ol (10) , and is reduced to 2 stereoisomeric alcohols with lithium aluminium hydride. One of these alcohols 8 is readily dehydrated with cyclization to 2,6,6,10-tetramethyltricyclo [5.3.1.0^1,5]undec-9-ene (12) and a double bond isomer 13 , longer treatment with acid resulting in a Wagner-Meerwein rearrangement to a mixture of two 1,3,7,7-tetramethyltricyclo [6.2.1.0^2,6]-undecenes ( 19 and 20 ), isomeric with β-patchoulene ( 23 ). The other alcohol 7 with p-toluenesulfonic acid forms the cyclic ether, 1,3,7,7-tetramethyl-11-oxatricyclo-[4.4.1.1^2,8]dodecane ( 15 ).     

Glycosylidene Carbenes. Part 19. Regioselective glycosidation of allyl 2-deoxy-2-phthalimido-D-allopyranosides

The regio- and stereoselectivity of the glycosidation of the partially protected mono-alcohols 3 and 7 , the diols 2 and 8 , and the triol 4 by the diazirine 1 have been investigated. Glycosidation of the α-D -diol 2 (Scheme 2) gave regioselectively the 1,3-linked disaccharides 11 and 12 (80%, α-D /β-D 9:1), whereas the analogous reaction with the βD -anomer 8 led to a mixture of the anomeric 1,3- and 1,4-linked disaccharides 13 (12.5%), 14 (16%), 15 (13%), and 16 (20.5%; Table 2). Protonation of the carbene by OH–C(4) of 2 is evidenced by the observation that the α-D -mono-alcohol 3 did not react with 1 under otherwise identical conditions, and that the β-D -alcohol 7 yielded predominantly the β-D -glucoside 18 (52%) besides 14% of 17 . Similarly as for the glycosidation of the diol 2 , the influence of the H-bond of HO? C(4) on the direction of approach of the carbene, the role of HO? C(4) in protonating the carbene, and the stereoelectronic control in the interception of the ensuring oxycarbenium cation are evidenced by the reaction of the triol 4 with 1 (Scheme 3), leading mostly to the α-D -configurated 1,3-linked disaccharide 19 (41%), besides its anomer 20 (16%), and some 4-substituted β-D -glucoside 21 (9%). No 1,6-linked disaccharides could be detected. In agreement with the observed reactivity, the ¹H-NMR and IR spectra reveal a strong H-bond between HO? C(3) and the phthalimido group in the α-D -, but not in the β-D -allosides. The different H-bonds in the anomeric phthalimides are in keeping with the results of molecular-mechanics calculations.     

Stereoselective synthesis of pyrrolo[2,3-d]pyrimidine α- and β-D-ribonucleosides from anomerically pure D-ribofuranosyl chlorides: Solid-Liquid Phase-Transfer Glycosylation and 15N-NMR Spectra

Solid-liquid phase-transfer glycosylation (KOH, tris[2-(2-methoxyethoxy)ethye]amine ( = TDA-1), MeCN) of pyrrolo[2,3-d]pyrimidines such as 3a and 3b with an equimolar amount of 5-O-[(1,1 -dimethylethyl)dimethylsilyl]-2,3-O-(1-methylethylidene)-α-D -ribofuranosyl chloride (1) [6] gave the protected β-D -nucleosides 4a and 4b , respectively, stereoselectively (Scheme). The β-D -anomer 2 [6] yielded the corresponding α-D -nucleosides 5a and 5b with traces of the β-D -compounds. The 6-substituted 7-deazapurine nucleosides 6a , 7a , and 8 were converted into tubercidin (10) or its α-D -anomer (11) . Spin-lattice relaxation measurements of anomeric ribonucleosides revealed that T₁ values of H? C(8) in the α-D -series are significantly increased compared to H? C(8) in the β-D -series while the opposite is true for T₁ of H? C(1′). ¹⁵N-NMR data of 6-substituted 7-deazapurine D -ribofuranosides were assigned and compared with those of 2′-deoxy compounds. Furthermore, it was shown that 7-deaza-2′deoxyadenosine ( = 2′-deoxytubercidin; 12 ) is protonated at N(1), whereas the protonation site of 7-deaza-2′-deoxyguanosine ( 20 ) is N(3).     

Highly Enantioselective Synthesis of Linear β-Amino Alcohols

β-Amino alcohols derived from α-amino acids have been extensively used as a powerful source of chirality. Transforming the alcohol moiety into a good leaving group has allowed the rearrangement of these β-amino alcohols and the introduction of a large number of nucleophiles through the anchimeric participation of the nitrogen atom. An overview on the recent progress realized on the rearrangement of these β-amino alcohols in the presence of (CF₃CO)₂O and H₂SO₄ is reported.     

A reasonably stereospecific multistep conversion of Boc-protected α-amino acids to Phth-protected β-amino acids

A method for the synthesis of β³-amino acids starting from α-amino acids is described. This conversion can be effected by an eight-step procedure which involves the transformation of the carboxylic group into an alkyne followed by a selenium-mediated conversion of the carbon-carbon triple bond to a Se-phenyl selenocarboxylate intermediate. The reactive Se-phenyl selenocarboxylate intermediates can be trapped with water, alcohols or the amine of an amino acid derivative to give β³-amino acids, β³-amino esters or mixed peptides, respectively. The whole transformations of the carboxylic group into an alkyne and of the alkyne group into β³-amino acids may not require purification of the intermediate products but a work-up and isolation procedure of crude materials.     

Highly stereoselective ring expansion of enantiopure α-hydroxyalkyl azetidines

Stereodefined α-hydroxyalkyl azetidines, prepared in a few steps from enantiopure β-amino alcohols, are chlorinated or transformed into methanesulfonyloxymethyl derivatives in good yields. Heating of these compounds in chloroform or dimethylformamide induces a stereospecific ring enlargement to give 3-chloro or 3-methanesulfonyloxy pyrrolidines. The ease of this rearrangement depends on the nature of the migrating group (Cl⁻ or MsO⁻), of the class of the starting alcohol (primary or secondary) and of the relative stereochemistry of the starting material.