A straightforward and efficient synthesis of praziquantel enantiomers and their 4′-hydroxy derivatives

A new method for the synthesis of praziquantel enantiomers via resolution of praziquanamine with (S)-(+)-naproxen was developed. The four 4′-hydroxy derivatives were obtained through each single praziquanamine enantiomer, coupling with cis- and trans-4-(benzyloxy)cyclohexanecarboxylic acids and subsequent hydrogenolysis for the deprotection of the 4′-OH cyclohexane residue. Additionally, the in vitro cysticidal activity of the compounds was tested, finding that (R)-(−)-praziquantel is the eutomer.     

A highly efficient and straightforward stereoselective synthesis of novel chiral α-acetylenic ketones

A very efficient and straightforward synthesis of novel chiral α-acetylenic ketones of type 3 has been developed. Starting from commercially available l-(−)-serine 4, and through the Garner's aldehyde 5, ethynyloxazolidine 2 was formed in good overall yield. Condensation of the corresponding lithium acetylide 7 with different aliphatic and aromatic aldehydes 5 and 8a–h at low temperatures yielded the respective propargylic alcohols 9a–i. Subsequent mild oxidation of 9a–i with 10-I-4-iodinane oxide (IBX) 12 afforded chiral α-acetylenic ketones 3a–i almost quantitatively.     

A microbially based approach for the asymmetric synthesis of both enantiomers of R-and S-fluoxetine

Both enantiomers of fluoxetine were synthesized in five steps from ethyl benzoylacetate(1)using microbial-chemical approach with overall yields of 59% and 62% respectively.(S)-Enan-tiomer can be obtained in >99% e.e.by resting cell of baker's yeast and the R form was produced in 81 %e.e.by immobilized Geotrichum sp.G 38.     

A straightforward synthesis of N-monosubstituted α-keto amides via aerobic benzylic oxidation of amides

An efficient sodium bicarbonate promoted aerobic oxidation reaction to prepare N-monosubstituted α-keto amides in the presence of n-tetrabutylammonium hydrogensulfate (TBAHS) was described. This reaction provides a very simple and convenient synthetic route to N-monosubstituted α-keto amides from easily available aryl- or heteroarylacetamides in good to high yields without using toxic reagents and harsh conditions.     

Stereoselective hydrofluorination of ynamides: a straightforward synthesis of novel α-fluoroenamides

α-Fluoroenamides, potent rigid fluorinated bioisosters of ureas, have been synthesized by a highly regio- and stereo-selective hydrofluorination of ynamides in anhydrous HF. This reaction provides the first general entry to α-fluoroenamides and can easily be applied to a wide range of substrates.     

A chemoenzymatic approach to the synthesis of enantiomerically pure aza analogues of paraconic acid methyl ester and both enantiomers of methyl β-proline

Enantiopure methyl esters of 1-alkyl-5-oxo-3-pyrrolidinecarboxylic acids were obtained by enzymatic resolution of the corresponding chiral racemic mixtures. A particularly favourable interaction, also supported by molecular mechanics calculations, was observed between the 1-benzyl derivative and α-chymotrypsin, for which the enantiomeric ratio, E, exceeded 200. The absolute configurations of the lactams were determined by means of CD spectroscopy. From the resulting enantiomerically pure (99% e.e.) (S)-(+)-1-benzyl-3-pyrrolidinecarboxylic acid and methyl (R)-(−)-1-benzyl-3-pyrrolidinecarboxylate, the methyl esters of (+) and (−)-β-proline were synthesised in 99% e.e. and 18 and 22% overall yield, respectively.     

A practical synthesis of novel α-dibromoalkyl- and trimethylsilylmethyl-aminoboranes and derivatives

Addition of LDA to a mixture of trimethylborate and dibromomethane in THF at a temperature of -78°C leads to the formation of dibromomethyllithium and its capture by borate ester. ClB(OMe)(2) converts the resulting borate salt to dimethoxy(dibromomethyl)borane 2. N,N-Dimethylamino(methoxy)(dibromomethyl)borane 3 and N,N-bis(dimethylamino)(dibromomethyl)borane 4 were prepared by an amination reaction between N,N-dimethylaminotrimethylsilane and dimethoxy(dibromomethyl)borane 2. To obtain dichlorotrimethylsilylmethylborane 7 not containing the α-halomethyl group, N,N-bis(dimethylamino)(trimethylsilylmethyl)borane 5 was first obtained from the reaction of ClB(NMe(2))(2) with an organolithium reagent. Dimethoxy(trimethylsilylmethyl)borane 6 was then prepared by methoxylation of compound 5. Finally, compound 7 was prepared by chlorination of 6 using BCl(3). The chemical structures of these compounds were determined using (13)C, (1)H, (11)B NMR and GC/MS/MS techniques.     

Organocatalytic synthesis of α-hydroxy and α-aminophosphonates

A new and highly flexible procedure is described for the synthesis of α-amino- and α-hydroxy phosphonates. In the presence of a catalytic amount of oxalic acid (10 mol %), trimethyl phosphite reacts with aldehydes or imines (generated in situ from an aldehyde and an amine) to yield the corresponding coupled products in good yield.     

Biological activities of α-pinene and β-pinene enantiomers

The antimicrobial activities of the isomers and enantiomers of pinene were evaluated against bacterial and fungal cells. The agar diffusion test showed that only the positive enantiomers of the α- and β-isomers of pinene were active. The minimal inhibitory concentration (MIC) and minimal microbicidal concentration (MMC) of these monoterpenes were also determined, confirming that the positive enantiomers exhibited microbicidal activity against all fungi and bacteria tested with MICs ranging from 117 to 4,150 μg/mL. However, no antimicrobial activity was detected with the negative enantiomers up to 20 mg/mL. Time-kill curves showed that (+)-α-pinene and (+)-β-pinene were highly toxic to Candida albicans, killing 100% of inoculum within 60 min. By contrast, the bactericidal effect occurred after 6 h in methicillin-resistant Staphylococcus aureus (MRSA). In combination with commercial antimicrobials, ciprofloxacin plus (+)-α-pinene or (+)-β-pinene presented synergistic activity against MRSA whereas an indifferent effect against all fungi was detected when amphotericin B was combined with the positive enantiomers of pinene. The potential of (+)-α-pinene and (+)-β-pinene to inhibit phospholipase and esterase activities was also evaluated, and the best inhibition results were obtained with Cryptococcus neoformans. C. albicans biofilm formation was prevented with the MIC concentration of (+)-α-pinene and twice the MIC value of (+)-β-pinene. Finally, the cytotoxicity of the positive enantiomers of pinene to murine macrophages was evaluated, and 250 μg/mL of (+)-α-pinene and (+)-β-pinene reduced the cell viability to 66.8% and 57.7%, respectively.     

A facile and straightforward synthesis of 1,2,3-thiadiazoles from α-enolicdithioesters via nitrosation/reduction/diazotization/cyclization cascade in one-pot

An operationally simple, economical, and straightforward synthesis of diverse 4,5-disubstituted 1,2,3-thiadiazoles from α-enolicdithioesters has been achieved via nitrosation/reduction/diazotization/cyclization sequence in one-pot through the formation of cascade 1–2 (N–S) and 3–4 (C–N) bonds. Importantly, this is the first straightforward entry to highly functionalized 1,2,3-thiadiazoles from dithioesters.     

Design and synthesis of α-carboxy phosphononucleosides

Rhodium catalyzed O-H insertion reactions employing α-diazophosphonate 20 with appropriately protected thymidine, uridine, cytosine, adenosine and guanosine derivatives leads to novel 5'-phosphononucleoside derivatives. Deprotection led to a novel series of phosphono derivatives bearing a carboxylic acid moiety adjacent to the phosphonate group with potential antiviral and/or anticancer activity. The phosphononucleosides bearing an α-carboxylic acid group are envisaged as potential diphosphate mimics. Conversion to mono- and diphosphorylated phosphononucleosides has been effected for evaluation as nucleoside triphosphate mimics. Most of the novel phosphononucleosides proved to be inactive against a variety of DNA and RNA viruses. Only the phosphono AZT derivatives 56-59 showed weak activity against HIV-1 and HIV-2.     

A direct synthesis of α-(hydroxymethyl) and α-alkyl-vinyl alkyl ketones

Reaction of 2,4-diketoesters 3a-c with aqueous formaldehyde using potassium carbonate solution as base affords the corresponding α-methylene-β-hydroxyalkanones 4a-c which provide a route to α,β-unsaturated alkyl ketones 6a-e via coupling of α-acetoxymethyl alkyl vinyl ketone 5a with Grignard reagents in the presence of a catalytic amount of LiCuBr₂ at low temperature.     

Regiospecific synthesis of α-chloro- and α-fluoro-1,2-diones

α-Chloro-1,2-diones and α-fluoro-1,2-diones were prepared from the corresponding α-chloroaldimines by a sequence of reactions involving cyanation to α-cyanoenamines, α-halogenation to form α-chloro- or α-fluoroimidoyl cyanides and addition of organolithium reagents across the nitrile moiety, followed by acidic hydrolysis. All steps are straightforward and occur without side reactions finally leading to regiospecifically chlorinated and fluorinated 1,2-diones in good yields.     

A simple synthesis of α-methylene-β-hydroxyalkanones

Reaction of methyl vinyl ketone with a variety of aldehydes, catalyzed by 1,4-diazabicyclo (2.2.2)octane (DABCO) in tetrahydrofuran, conveniently provides the corresponding α-methylene-β-hydroxyalkanones in good yields.     

A practical asymmetric synthesis of homochiral α-arylglycines

Enantioselective reduction of a series of substituted aryl trichloromethyl ketones with the CBS-catecholborane reagent afforded homochiral aryl trichloromethyl carbinols which have been elaborated to give homochiral α-arylglycines in high e.e.     

A catalyst-free synthesis of α-aminophosphonates in glycerol

A simple and efficient method is described using glycerol as a solvent in the catalyst-free synthesis of α-aminophosphonates in high purity. Products are prepared by the Kabachnik–Fields reaction from amines, phosphites, and carbonyl compounds. The method does not require a toxic catalyst.     

Methods of synthesis and synthetic application of α-diazomethylphosphonates

Data on methods of synthesis and reactivity of α-diazomethylphosphonic acid esters are classified. Main approaches to obtain diazomethylphosphonate ester (the Seyferth—Gilbert reagent) as well as α-substituted diazomethylphosphonates are considered. The most important reactions of α-diazomethylphosphonates are discussed: [1+2] cycloaddition to alkenes, insertion into heteroatom—heteroatom bonds, reactions with aldehydes and ketones, being of interest as preparative methods to obtain cyclopropane phosphonates, α-substituted methylphosphonic esters and alkynes, correspondingly.