Sm(OTf)3 as a highly efficient catalyst for the synthesis of 2,3-unsaturated O- and S-pyranosides from glycals and the temperature-dependent formation of 4-O-acetyl-6-deoxy-2,3-unsaturated S-pyranosides and 4-O-acetyl-6-deoxy-3-alkylthio glycals

By using Sm(OTf)₃ as the catalyst, synthesis of 2,3-unsaturated-glycosides has been performed. A series of 2,3-unsaturated glycosides were obtained from 3,4,6-tri-O-acetyl–d-glucal or 3,4-di-O-acetyl-l-rhamnal under mild reaction conditions in good yield and high anomeric selectivity. It was found that under certain conditions, reaction of 3,4-di-O-acetyl-l-rhamnal with thiol leads to temperature-dependent formation of C-1-S and C-3-S product. A temperature-dependent profile of the yield of these two products is given.     

A new synthesis of key intermediates for the assembly of polycyclic ethers: Yb(OTf)3-promoted formation of O,S-acetals from α-fluorosulfides and alcohols

We report a new reaction for the direct construction of O,S-acetals, key intermediates in the assembly of fused polycyclic ethers. α-Fluorosulfides and secondary alcohols were coupled by the action of Yb(OTf)₃ to generate O,S-acetals in high yield. The neutral and selective nature of the reaction should be useful for synthesizing natural and artificial polyethers with multisensitive functionalities.     

Synthesis of modified Weinreb amides: N-tert-butoxy-N-methylamides as effective acylating agents

An efficient preparation of N-methyl-O-tert-butylhydroxylamine hydrochloride has been settled, which allowed the synthesis of modified Weinreb amides. Nucleophilic addition of organolithium and Grignard reagents on these N-tert-butoxy-N-methylamides afforded efficiently the corresponding ketones and reduction with DIBAL furnished the corresponding aldehydes in good yields up to 97%.     

Y(OTf)3 as a highly efficient catalyst in Ferrier Rearrangement for the synthesis of O- and S-2,3-unsaturated glycopyranosides

By using Y(OTf)₃ as the catalyst, a series of 2,3-unsaturated-glucosides have been synthesized from 3,4,6-tri-O-acetyl-d-glucal, 3,4-di-O-acetyl-l-rhamnal, and 3,4,6-tri-O-benzyl-d-glucal under mild reaction conditions in good yields with high anomeric selectivities. It was found that, in this reaction, 3,4,6-tri-O-benzyl-d-glucal behaved differently from the other two glucals when it was reacted with phenol, O-benzyl glucoside instead of O-phenyl glucoside formed as the sole product. An explanation is given for this phenomenon.     

Imidomethylation of C-nucleophiles using O-phthalimidomethyl trichloroacetimidate and catalytic amounts of TMSOTf

The O-phthalimidomethyl trichloroacetimidate (1), as a latent aminomethylating agent, exhibits high electrophilicity towards a variety of C-nucleophiles in the presence of catalytic amounts of TMSOTf and mild reaction conditions. The nucleophiles include aromatics, alkenes and active methylene compounds 2-11 whereby a phthalimidomethyl group could be introduced to give compounds 12-22. Removal of the phthaloyl group gave the respective amines, β-amino ketones, and β-amino acids. The O-(trichloroacetamido)methyl trichloroacetimidate (35) was also found to be a good amidomethylating agent.     

An efficient chemoenzymatic method to prepare optically active O-methyl-d-serine

Lacosamide is an important anti-epilepsy drug and O-methyl-d-serine is a relevant intermediate in the synthesis of lacosamide. Optically active O-methyl-d-serine was prepared by using a chemoenzymatic method from inexpensive acrylamide. Our method is a four-step reaction sequence: bromination of acrylamide; etherification of dibromopropionamide; ammonolysis of α-bromo-β-methoxy-propionamide; enzymatic racemization and selective hydrolysis. The double-enzyme catalyst system, which consists of α-amino-ε-caprolactam racemase (Locus, E01594) and d-stereospecific amino-acid amidase (Locus, AB026907), was successfully applied to produce enantiopure O-methyl-d-serine (ee >99.8%) in high yield (>98.5%). Optically active O-methyl-d-serine was obtained with a total yield of 81.3%.     

BF3·Et2O catalyzed diastereoselective nucleophilic reactions of 3-silyloxypiperidine N,O-acetal with silyl enol ether and application to the asymmetric synthesis of (+)-febrifugine

The asymmetric BF₃·Et₂O catalyzed nucleophilic reactions of 3-silyloxypiperidine N,O-acetal 10 with silyl enol ethers derived from ketones are described. (+)-Febrifugine 1, an antimalarial alkaloid, was successfully synthesized based on this nucleophilic substitution. In addition, N,O-acetal 10 was synthesized from l-benzyl glutamate in 11 steps.     

Practical synthesis of gem-difluorides from cyclohexanone: Synthesis of gem-bistrifluoroacetates and their reactions with fluoride nucleophiles

Formation of ketone acylals bearing trihaloacetoxy groups and their nucleophilic geminal disubstitution by fluoride ions were investigated. Cyclohexanone reacted with trifluoroacetic anhydride without catalyst to give gem-bistrifluoroacetates via a concerted bimolecular reaction. Treatment with hydrogen fluoride under mild conditions efficiently yielded the corresponding gem-difluorides. In this reaction process, trifluoroacetic acid was recovered and converted to trifluoroacetic anhydride using P₂O₅. Since gem-difluorides were derived from ketones, HF and P₂O₅, this constitutes a practical synthesis of gem-difluorides.     

Per-O-methylation reaction for structural analysis of carbohydrates by mass spectrometry

Per-O-methylation of carbohydrates is an important sample preparation step in structural analysis of complex carbohydrates, which has generated considerable interest as shown by thousands of citations in the last 10 years. This article provides a critical overview of the per-O-methylation methods applied for structural analysis of carbohydrates by mass spectrometry. The understanding of the O-methylation mechanism can help the researchers to apply the adequate O-methylation method and can generate new ideas in the effort of improving this reaction. The per-O-methylation of carbohydrates is relied upon stepwise reactions. The parameters that affect the reaction are discussed for the most important methods and are critically commented for each reaction step. The limits of each method are emphasized. The improvements of the per-O-methylation reaction are described in detail with their advantages and disadvantages and some illustrative examples are given. The methods that give complete O-methylation in non-hazardous conditions with high yields within minutes at room temperature with a very low amount of side-products are especially highlighted.     

Truncated diastereoselective Passerini reaction, a rapid construction of polysubstituted oxazole and peptides having an α-hydroxy-β-amino acid component

The reaction of aldehydes and ketones, including aliphatic and aromatic ones, with amides of α-isocyano-β-phenylpropionic acid in toluene in the presence of lithium bromide gives 2,4,5-trisubstituted oxazoles in good to excellent yield. Protected chiral α-amino aldehydes participate in this reaction to give, after hydrolysis of the oxazoles, norstatine-containing peptides in good overall yield. The nucleophilic addition of isonitriles to N,N-dibenzylphenylalanal is investigated for the first time and is found to be stereoselective leading predominantly to the anti-adduct (dr=9/1). On the other hand, the reaction between the N-Boc phenylalanal and isonitrile is non-stereoselective.     

Nano-ferrous ferric oxide (nano-Fe3O4): Powerful,reusable, and stable catalyst for N-Boc protection of amines

Nano-ferrous ferric oxide (nano-Fe₃O₄) efficiently catalyzed N-boc protection of amines in high yields and acceptable reaction times. Nano-Fe₃O₄ was applied as an efficient, green, heterogeneous and reusable magnetite catalyst. Clean reaction, simple purification, short reaction time and high yield were some other advantages of this compound.     

An unexpected migration of O-silyl group under Mitsunobu reaction conditions

A 1,4 O→O silyl migration followed by nucleophilic substitution with phthalimide was observed under Mitsunobu reaction conditions. This one step secondary alcohol protection and primary alcohol substitution with N-nucleophiles was extended to a variety of 2-hydroxyethyl trialkylsilylether derivatives. A possible mechanism has been postulated based on the pK_a values of the alcohol and nucleophile. The present one-pot silyl migration and substitution reaction might find application in the stereoselective synthesis of novel iminosugar derived anti diabetic agents.     

A facile one-pot synthesis of 7-substituted pyrazolo[1,5-a]pyrimidines by base induced three-component reaction

The preparation of steroid/nonsteroid fused 7-substituted pyrazolo[1,5-a]pyrimidines is described by a one-pot reaction of steroidal/nonsteroidal ketones, aromatic aldehydes and 3-amino-1H-pyrazoles/5-amino-1H-pyrazoles in the presence of potassium tert-butoxide in good yield under reflux condition in ethanol.     

Bi(III) halides as efficient catalysts for the O-acylative cleavage of tetrahydrofurans: an expeditious entry to tetralins

The mild (DCM/20 °C), quantitative, regioselective, O-acylative cleavage of tetrahydrofurans using organic acid halides with catalytic Bi(III) halides is reported. X-ray crystallography is used to rationalise the failure of the reaction in the case of certain crowded acid chlorides, and a useful aspect of chemoselectivity is revealed. The synthetic potential of this reaction is illustrated with a highly efficient O-acylative cleavage/intramolecular alkylation approach to tetralins.     

Convenient synthesis of N-isobutyryl-2′-O-methyl guanosine by efficient alkylation of O-trimethylsilylethyl-3′,5′-di-tert-butylsilanediyl guanosine

We present a novel route for the synthesis of N²-isobutyryl-2′-O-methyl guanosine, introducing 3′,5′-di-tert-butylsilyl and O⁶-trimethylsilylethyl groups as efficient protections during the 2′-O-methylation step with NaH/CH₃I. These protections were then removed simultaneously in a single step with TBAF. The eight-step synthesis is easy to perform, employing convenient commercially available reagents; crude mixtures are of satisfying purity, so only three chromatography purifications were required. Title compound was obtained in 25% overall yield from guanosine.     

Synthetic studies of erythromycin derivatives: 6-O-methylation of (9S)-12,21-anhydro-9-dihydroerythromycin A derivatives

Synthetic studies on methylation of erythromycin derivatives were conducted. Methylation of 6 resulted in the formation of the C-3′ quaternary ammonium salts with a rate faster than 6-O-methylation. In dipolar aprotic solvent and under strong base conditions, 6-O-methylation, C-3′ quaternary ammonium salts formation and 2-C-methylation proceeded simultaneously to yield a mixture of three different products 7, 8 and 9. The quaternary ammonium salts were converted back to the corresponding tertiary amines 2, 10 and starting material 6 by employing sodium 4-pyridinethiolate as a N-demethylation reagent. The 6-O-methylation was eventually achieved in a good yield when a carbobenzyloxy (Cbz) group was utilized to protect the C-3′-dimethylamino group of 4. In this report, we will discuss the details of different reaction courses in the methylation of (9S)-12, 21-anhydro-9-dihydroerythromycin A derivatives.     

An efficient multicomponent stereoselective synthesis of 1,2,4-trisubstituted 1,3-thiazetidines

The first one-pot three-component coupling reaction of O,O-diethyl hydrogen phosphorodithioate, aldehydes, and aldimines affording 1,2,4-trisubstituted 1,3-thiazetidines is reported. The product is obtained in moderate to high yields (45-94%) and has excellent diastereoselectivity (90-96%) in favour of the cis isomer. Shorter reaction times, ambient temperature, operational simplicity, and high yields are the salient features of the present procedure.     

Convenient and efficient Suzuki-Miyaura cross-coupling reactions catalyzed by palladium complexes containing N,N,O-tridentate ligands

N,N,O-Tridentate ligands 1-9 were prepared from the condensation of amines with nine aromatic aldehydes or ketones. These ligands are thermally stable and neither air- nor moisture-sensitive. Combination of either 2-methoxy-6-[(pyridine-2-ylmethylimino)-methyl]-phenol, 1 or 2-(benzothiazol-2-yl-hydrazonomethyl)-4,6-di-tert-butyl-phenol, 6 with Pd(OAc)₂ furnished an excellent catalyst precursor for the Suzuki-Miyaura cross-coupling of various aryl bromides with arylboronic acids. The effects of varying solvents, bases, and ligand/palladium ratios on the performance of the coupling reaction were investigated. The molecular structures of both free ligand 1 and its palladium acetate complex 10 were determined by single-crystal X-ray diffraction methods. The DFT studies revealed that the catalytic performance of palladium complexes involving this type of a ligand may differ greatly upon a small variation in its structure.     

1→2 Migration and concurrent glycosidation of phenyl 1-thio-α-mannopyranosides via 2,3-O-cyclic dioxonium intermediates

Treatment of phenyl 2,3-O-cyclic ketene acetal- and 2,3-O-thionocarbonyl-1-thio-mannopyranosides with TMSOTf and MeOTf, respectively, gave the corresponding 2,3-O-cyclic dioxonium intermediates, which proceeded via 1→2 migration and concurrent glycosidation in the presence of alcohols to provide the corresponding 2-S-phenyl glycosides stereoselectively. While the former donors were too labile, the latter donors have proved superior for the present purpose. The X-ray crystallographic structures of phenyl 4-O-methyl-2,3-O-thiocarbonyl-1-thio-α-l-rhamnopyranoside (1), a typical donor for the present reaction, and its anomeric azide analogue (6), which could not undergo the present reaction under similar conditions, are provided.     

Hetero-Diels-Alder reaction of photochemically generated α-hydroxy-o-quinodimethanes with trifluoromethyl ketones

Hetero-Diels-Alder reaction of α-hydroxy-o-quinodimethanes photochemically generated from o-tolualdehydes with trifluoromethyl ketones gave a mixture of hemiacetals and hydroxyaldehydes in fairly good yields. Their subsequent oxidation with PCC provided 1-isochromanones as formal oxidative [4+2] cycloaddition products. In contrast, similar reaction of aromatic ketones such as o-methylbenzophenone, 1-indanone, and α-tetralone gave exclusively the corresponding ketones having (trifluoromethyl)methylol groups at the o-position.