An efficient synthesis of 1,4-dideoxy-1,4-imino-d- and l-arabinitol and 1,4-dideoxy-1,4-imino-d- and l-xylitol from chiral aziridines

A highly efficient method for the synthesis of 1,4-dideoxy-1,4-imino-d- and l-arabinitol (d-AB1, 1 and l-AB1, 3) and 1,4-dideoxy-1,4-imino-d- and l-xylitol (d-DIX, 2 and l-DIX, 4) starting from commercially available chiral aziridines was developed. The general strategy employs a sequence involving two-carbon homologation, dihydroxylation, and regioselective aziridine ring opening/intramolecular five-membered iminosugar ring formation. The facile use of recrystallization to generate pure diastereomers makes the routes more amenable to large-scale synthesis.     

A facile method for synthesis of (R)-(−)- and (S)-(+)-homocitric acid lactones and related α-hydroxy dicarboxylic acids from d- or l-malic acid

We report here a simple and convenient route for the stereoselective synthesis of (R)-(−)- and (S)-(+)-homocitric acid lactones, which play very important roles in biochemistry. The method involves only three steps, starting from the readily available methyl 3-iodopropionate and d-malic acid or l-malic acid, respectively. The stereoconfiguration of the target molecules has been achieved via a self-regeneration approach with over 98% diastereoselectivity and significantly improved yield over the previous methods.     

Enantioselective synthesis of d- and l-α-methylcysteine with hydantoinase

A scalable and cost-effective synthesis of d- and l-α-methylcysteine is described. A key step is d-selective cyclization of N-carbamoyl S-tert-butyl-d,l-α-methylcysteine catalyzed by hydantoinase. d-5-tert-Butylthiomethyl-5-methylhydantoin and N-carbamoyl S-tert-butyl-l-α-methylcysteine were obtained with excellent yield and optical purity, and these compounds were easily separated by filtration. After hydrolysis and cleavage of the tert-butyl group, d- and l-α-methylcysteine hydrochloride were obtained.     

Inclusion compounds of l,d-dipeptide with small sulfoxides: flexible sheet structure of (S)-phenylglycyl-(R)-phenylglycine

A heterochiral l,d-dipeptide, (S)-phenylglycyl-(R)-phenylglycine (SR-1), formed inclusion compounds with some small dialkyl sulfoxides. By their single-crystal X-ray analyses, we observed monolayer structures, where SR-1 molecules are arranged in parallel to construct a wavy sheet. The sulfoxides were accommodated in a channel cavity between the monolayers of SR-1 by hydrogen bonding with ⁺NH₃ of SR-1. Notably, the sheet of SR-1 is so flexible to change its wavy degree in response to the volume of the included sulfoxides. Furthermore, we could analyze the structure of crystalline SR-1 without any sulfoxide, which has a bilayer structure.     

Synthesis of d-glucose and l-phenylalanine substituted phenylene-thiophene oligomers

Phenylene-thiophene oligomers bearing peracetylated β-d-glucose or N-BOC-l-phenylalanine as chiral substituents were synthesized in good yields by a versatile protocol based on the Suzuki-Miyaura cross-coupling reaction. Aryl iodides bearing the chiral biomolecules as substituents efficiently reacted with pinacol boronates of bi- or terthiophenes leading to the bio-functionalized oligomers in good yields.     

Novel synthesis of 5-thio-hexopyranoside: preparation of 5-thio-d- and l-glucose and 1,6-anhydro-5-thio-l- and d-altrose

Asymmetric synthesis of both d- and l-isomers of 5-thioglucose and 1,6-anhydro-5-thioaltrose are described. The key intermediates, l- and d-threose diethylacetal derivatives, were derived by chemical transformation from d-xylose or d-arabinose and by Sharpless asymmetric dihydroxylation from γ-hydroxycrotylaldehyde diethylacetal. They transformed to γ-thiiranyl diethylacetal via trans-2,3-epoxy alcohol in seven steps. Acetic acid-promoted cyclization of γ-thiiranyl diethylacetal gave 5-thiopyranoside. Removal of the protected groups under the acidic conditions afforded 5-thio-d- and l-glucose and 1,6-anhydro-5-thio-l- and d-altrose, respectively.     

Synthesis of homochiral 2-C-perfluoroalkyl substituted d- and l-riboses

Homochiral 2-C-perfluoroalkyl substituted d- and l-riboses were synthesized via Barbier, Grignard and Ruppert type reactions. The influence of the size of the perfluoroalkyl groups, attached to C-2, on the furanose/pyranose as well as on the α-furanose/β-furanose and α-pyranose/β-pyranose ratio in solution was studied.     

Practical synthesis of d-[1-C]mannose, l-[1-C] and l-[6-C]fucose

The chemical synthesis of ¹³C-labeled mannose and fucose is important for the preparation of molecular probes used in the conformational study of the oligosaccharide portions of glycoproteins. A new method for the synthesis of the title [1-¹³C]-labeled compounds via the corresponding olefin compounds, which are in turn derived from d-mannitol or l-arabinose by efficient introduction of ¹³C, by the Wittig reaction using Ph₃P¹³CH₃I and n-BuLi, is described. The introduction of ¹³CH₃I to produce the [1-¹³C]- and [6-¹³C]-labeled compounds was accomplished in 62%, 56%, and 71% yields, respectively. All mannose and fucose protons, from H-1 to H-6, were observed by the HMQC-TOCSY technique using 1:1 mixtures of [1-¹³C]- and [6-¹³C]-labeled compounds.     

Diastereoselective synthesis of new polyhydroxylated indolizidines from (l)-glutamic acid

A diastereoselective synthesis of two new swainsonine's analogues 1a and 1b with the piperidine ring fused to a phenyl nucleus at C6-C7, namely (1R, 2S, 10R, 10aR)-(+)-1,2,10-trihydroxy-1,2,3,5,10,10a-hexahydrobenzo[f] indolizine (1a) and (1S, 2R, 10R, 10aR)-(+)-1,2,10-trihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[f] indolizine (1b), is described. Throughout this work, the effectiveness of the tricyclic indolizidine dione 5, readily available in three steps from the cheap l-glutamic acid, as an attractive platform for chemo- and stereodivergent transformations is illustrated. The key steps involved totally diastereoselective ketone reduction of compound 5 and catalytic cis-dihydroxylation of the unsaturated amide 10. The synthetic strategy also allowed for the diastereoselective synthesis of benzoanalogues of the 1,8a-di-epi-lentiginosine 3a ((1R, 2S, 10aR)-(+)-1,2-dihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[f]indolizine) and 2,8a-di-epi-lentiginosine 3b ((1S, 2R, 10aR)-(+)-1,2-dihydroxy-1,2,3,5,10,10a-hexahydrobenzo[f]indolizine).     

De novo approach to l-anhydrohexitol nucleosides as building blocks for the synthesis of l-hexitol nucleic acids (l-HNA)

A stereoselective and scalable route to 1,5-anhydrohexitol nucleoside analogues belonging to l-series as building blocks for l-HNA oligonucleotide synthesis has been efficiently tuned. Key to the successful outcome of our approach is the development of a DDQ-mediated domino reaction, which leads to the formation of an unsaturated 1,6-anhydrosugar derivative. Sugar elaborations and base insertion then enable to synthesize six-membered nucleosides.     

Sulfonate protecting groups. Synthesis of O- and C-methylated inositols: d- and l-ononitol, d- and l-laminitol, mytilitol and scyllo-inositol methyl ether

Syntheses of d- and l-ononitol, d- and l-laminitol, mytilitol and scyllo-inositol methyl ether starting from myo-inositol are described. One or two of the myo-inositol 1,3,5-orthoformate hydroxyl groups were protected as tosylates. These mono or ditosylates served as key intermediates for the preparation of O- and C-methyl inositols. Racemic 2,4-di-O-tosyl-myo-inositol 1,3,5-orthoformate was resolved as its diastereomeric camphanates. Use of sulfonate groups for the protection of inositol hydroxyl groups resulted in substantial improvement in the overall yield of O- and C-methyl inositols.     

A general strategy for the stereoselective synthesis of l-1-deoxyallonojirimycin and d-1-deoxygulonojirimycin

A general strategy for the synthesis of deoxyazasugars from d-glucose is described. Ring-closing metathesis and stereoselective dihydroxylation reactions were used as key steps.     

Synthesis of d-gluco-, l-ido-, d-galacto-, and l-altro-configured glycaro-1,5-lactams from tartaric acid

The d-gluco-, l-ido-, d-galacto-, and l-altro-configured glycaro-1,5-lactams 1-4 were prepared from the known tartaric anhydride 5 via the aldehyde 6. These lactams are known (1) or potential (2-4) inhibitors of β-d-glucuronidases and α-l-iduronidases. Olefination of 6 to the (E)- and (Z)-alkenes 7 or 8, followed by reagent or substrate controlled dihydroxylation, lactonization, azidation, reduction, and deprotection led in 10 steps and in overall yields of 11-20% to the title lactams.     

A tethered aminohydroxylation route to l-arabino-[2R,3S,4R] and l-xylo-[2R,3S,4S]-C18-phytosphingosines

A concise and highly efficient synthesis of l-arabino-[2R,3S,4R] and l-xylo-[2R,3S,4S]-C₁₈-phytosphingosines has been achieved. The synthetic strategy features the Sharpless kinetic resolution and tethered aminohydroxylation as the key steps.     

Synthesis of l-aminohomohistidine (l-Ahh)

A short synthesis of l-aminohomohistidine (l-Ahh), which starts from readily available δ-hydroxy-l-lysine is described. The embedding of the basic guanidino moiety in the aromatic imidazole lowers the basicity of the side chain to a pK_a of 8.3. It is proposed that l-Ahh may be employed as an arginine-mimetic in medicinal chemistry.     

Hydrolytic degradation of carbohydrate-based polyamides of the AABB type derived from l-arabinose and d-xylose

The hydrolytic degradation of a series of aregic carbohydrate-based polyamides derived from l-arabinose and d-xylose is described. These polyamides are those that are fully sugar-based (PA-SuSu), those derived from aldaric acids and polyalkylene diamines (PA-mSu), and those derived from diamine sugars and polyalkylene dicarboxylic acids (PA-Sun). Their physical properties and crystal structures depend on their constitution and the configuration of the carbohydrate-based moiety. The feasibility of the hydrolysis of these polyamides was, in general, related with such structural properties. Thus, the fully sugar-based PA-SuSu were amorphous, water-soluble materials, and were hydrolysed in water at 70 °C. PA-mSu were crystalline and more resistant to hydrolysis — they were degraded at pH 2 and 70 °C [T_g(s) 60-90 °C]. PA-Sun were amorphous and highly hygroscopic materials — they were hydrolysed in water at 37 °C [T_g(s) 25-40 °C].     

Henry condensations with 4,6-O-benzylidenylated and non-protected d-glucose and l-fucose via DBU-catalysis

Mechanistic intermediates, and thermodynamically favored side products, in the Henry condensations of partially protected and non-protected pyranoses with a free anomeric hemiacetal function with nitromethane in various solvents for the kinetically controlled syntheses of C-glycopyranosides in the presence of DBU/molecular sieve catalyst system were identified.     

Synthesis of (S)-2-amino-7-methoxytetralin and isoindolo[1,2-a]isoquinolinone derivatives from l-aspartic acid

This paper describes a new total synthesis for (S)-2-amino-7-methoxytetralin, (S)-7-MeO-AT, from l-aspartic acid in an overall yield of 10% over nine steps. The major loss was ascribed to a key intramolecular Friedel–Crafts cyclization step, which afforded up to 36% yield. Attempts to perform a Friedel–Crafts cyclization of an intermediate phthalimide protected amino alcohol 13 did not give the desired protected (S)-7-MeO-AT. On the other hand, two new isoindolo[1,2-a]isoquinolinone derivatives 14 and 15, were isolated in 21 and 11% yield, respectively. The yield of 15 was improved to 70%.     

Stereoselective syntheses of (+)-proto, (−)-gala quercitols and carba-l-rhamnose from d-(−)-quinic acid

Efficient syntheses of (+)-proto, (−)-gala quercitols and carba-l-rhamnose from d-(−)-quinic acid are described.     

Characterization and release of triptolide-loaded poly (d,l-lactic acid) nanoparticles

Triptolide (TP), which has immunosuppressive effect, anti-neoplastic activity, anti-fertility function and severe toxicities on digestive, urogenital, blood circulatory system, was used as a model drug in this study. TP-loaded poly (d,l-lactic acid) (PLA) nanoparticles were prepared by the modified spontaneous emulsification solvent diffusion method (modified-SESD method). Dynamic light scattering system (DLS), transmission electron microscope (TEM), atomic force microscopy (AFM), differential scanning calorimetry (DSC), X-ray powder diffractometry and Fourier transform infra-red spectroscopy (FT-IR) were employed to characterize the nanoparticles fabricated for size and size distribution, surface morphology, the physical state of drug in nanoparticles, and the interaction between the drug and polymer. Encapsulation efficiency (EE) and the in vitro release of TP in nanoparticles were measured by the reverse phase high-performance liquid chromatography (RP-HPLC). The produced nanoparticles exhibited a narrow size distribution with a mean size of approximately 150 nm and polydispersity index of 0.088. The morphology of the nanoparticles exhibited a fine spherical shape with smooth surfaces without aggregation or adhesion. TP-entrapped in nanoparticles was found in the form of amorphous or semicrystalline. It was found that a weak interaction existed between the drug and polymer. In all experiments, more than 65% of EE were obtained. The in vitro release profile of TP from nanoparticles exhibited a typical biphasic release phenomenon, namely initial burst release and consequently sustained release. In this case, the particle size played an important role for the drug release. The modified-SESD method was a potential and advantage method to produce an ideal polymer nanoparticles for drug delivery system (DDS).