Adenoviruses is a common pathogen associated to multiple diseases. Carbohydrates containing a diversely substituted urea moiety were synthesized from the corresponding isocyanate and used on Human adenovirus as target. The structure with phenyl ring as substituent provides a potential anti- Ads with an inhibition about 50%.

MAO inhibitors have increased their importance as a result of the high incidence of neurodegenerative diseases such as Parkinson or Alzheimer. Herein, we report the synthesis and characterization of coumarin glycosides by reaction of a glycosyl halide with coumarin derivatives as well as mechanistic considerations based on DFT calculations. Additionally, the determination of the enzymatic parameters has shown that the carbohydrate-coumarin derivative is an efficient drug-releasing system.

The reaction of phenylhydrazine with a sugar dialdehyde in water, as a key step for the synthesis of the 3-amino-3-deoxy-d-glucose moiety contained in kanamycin, has been revisited. Structural studies (IR and NMR as well as a simple theoretical model based on energy-minimization calculations and MD calculations) reported herein support the observed stereo- and regioselectivity. Efforts to improve the reproducibility and viability of the process as part of a convenient approach towards fluorinated kanamycin are also now presented.

A general approach to enantiopure conformationally constrained sugar derived α/β- and α/γ-peptides has been established. Five-membered ring α/β-peptides were synthesized via formyl C-glycofuranosides, easy available from hexose-derived azido-2-equatorial-OH-glycopyranosides by DAST-promoted ring contraction. By means of a regioselective oxidation with TEMPO at C-6 of hexose-derived 3-azido glycopyranosides as the key step, two- and three-residue α/γ-peptides having a six-membered ring were obtained in good yields and under very simple experimental conditions.

The interest of fluorescent carbohydrates is due to wide applications in biology and environmental technology. For example, water soluble glucose based imino-anthracenyl derivatives have been shown to recognize specifically Hg2+ (which is highly toxic and causes DNA damage and impair mitosis) by switch-on fluorescence.[1] Fluorescence is a powerful technique as a consequence of its highly sensible and specific detection methods. [2],[3] With the aim to generate new derivatives with biological, pharmacological and technological properties, we design the here presented compounds using as diversity point (see Scheme), the amino group. We have selected coumarins as chromophore units (CU), due to their demonstrated anticoagulant activity and easy availability. On the other hand, fluorescent aldehydes have been chosen as fluorescence sources for their chemosensor potential activity in a wide variety of fields. We report here on new fluorescent derivatives of D-glucosamine (1) previous protection of its hydroxyl groups. These derivatives having general structures 2 and 3, have been prepared in good yields by: a) nucleophilic attack of the amino group to activated carboxycoumarins, and b) by reductive amination, respectively. We thank the AECID (Projects A/023577/09 and A/040322/10) and the \'Junta de Andalucía\' (FQM 142 and Project P09-AGR-4597) for financial support. [1] Mitra, A.; Mittal, K. A. and Rao, P. C. Chem. Comm., 2011, 47, 2565 and references therein. [2] Lee, D.Y.; Singh, N. and Jang, D. O. Tetrahedron Lett. 2010, 51, 1103 [3] a) Rettig, W. Applied Fluorescence in Chemistry, Biology and Medicine; Springer: New York, 1999. b) Christensen, L.; Norgaard, R.; Bro, S. and Engelsen, B. Chem. Rev. 2006, 106, 1979.

Today the aminoglycosides are still the most commonly used antibiotics worldwide thanks to the combination of their high efficacy with low cost. The interest of aminoglycoside antibiotics is due to their use in treatment of wide variety infections. These compounds act on gram-positive and gram-negative bacteria as protein synthesis inhibitors.[1] However, they are nephrotoxic and ototoxic in some cases, thus limiting its use. Kanamycin is an aminoglycoside antibiotic with multiple therapeutic applications. A previous step of their synthesis is the formation of 3-amino-3-deoxy-D-glucose from commercial available products. Integration of phenylhydrazine with a sugar derived dialdehyde (2) in water, as a key step, has been used[2] as an elegant and easy strategy synthesis. However, a low reproducibility of this method makes synthetic chemists reluctant to its use, in such a way that other routes of synthesis of 3-amino-3-deoxy-D-glucose are preferred.[3] All this, despite the fact that the above mentioned integration reaction can be considered as a representative example of green chemistry.[4] We have revisited this process and we report herein new NMR and IR data of compounds 2 and 3 that they confirm the structures proposed in literature. In addition, we describe novel different conditions for their synthesis that reduce the time of reactions, especially in case of dialdehyde 2. We thank the AECID (Projects A/023577/09 and A/040322/10) and the \'Junta de Andalucía\' (FQM 142 and Project P09-AGR-4597) for financial support. [1] a) Li, J.; Chang. T., Anti-Infec. Agents in Med. Chem. 2006, 5, 255.; b) Corey, E. J.; Czakó, B.; Kürti, L., Molecules and Medicine. John Wiley & Sons, New Jersey, 2007 [2] Patroni, J.; Stick, R. Aust. J. Chem, 1985, 38, 947 and reference therein. [3] Faghih, R.; Cabrera-Escribano, F. et al, J. Org. Chem. 1986, 51, 4558 [4] Anastas, Y.; Warner, J.C. Green Chemistry: theory and practice.Oxford University Press, New York, 1998

A route for the preparation of five- and six-membered ring α/β - and α/γ-glycoamino acids is described starting from D-Glucose. The α/β glycoamino acids were synthesized using a DAST-promoted ring contraction as a key step followed by hydrolysis, acetylation, oxidation and attachment of the α-amino acid. The α/γ-glycoamino acids were synthesized by cleavage of the benzylidene protecting group as the first step, accompanied with subsequent oxidation, acetylation and attachment of the α-amino acid. At the present, we are focusing our attention in synthesizing these α/β-glycoamino acids at a higher scale by using other non-corrosive fluorinating agents.

A general approach to enantiopure C-glycofuranoside-based hybrid α/β-amino acids and nitrones, among other valuable building blocks, has been established via formyl C-glycofuranosides, easily available from hexose-derived equatorial-2-OH-glyco-pyranosides by DAST-promoted ring contraction.

The dipolar cycloaddition of (Z)-N-benzyl-(3-O-benzyl-1,2-O-isopropylidene-α-d-ribofuranos-5-ylidene)amine N-oxide to methyl acrylate gives a 53:16:26:5 diastereomeric mixture of isoxazolidine derivatives. The dipolar cycloaddition of the xylo analogue to methyl acrylate is more diastereoselective, producing a 44:13:43 mixture of only three diastereomers. The ribo-configured adducts have been converted (4 steps only) into the new (2R,6S,7S,8R,8aR)-, (2S,6S,7S,8R,8aR)-, (2S,6S,7S,8R,8aS)- and (2R,6S,7S,8R,8aS)-2,6,7,8-tetrahydroxyindolizidines. Similarly, the two xylo-configured major isoxazolidine derivatives were converted into the known derivatives (2R,6S,7R,8R,8aS)- and (2S,6S,7R,8R,8aR)-2,6,7,8-tetrahydroxyindolizidines. The six isomeric indolizidine derivatives obtained have been evaluated for their inhibiting activities towards 15 glycosidases. Only the (2R,6S,7S,8R,8aR)-configured isomer is a selective inhibitor of amyloglucosidases from Aspergillus niger (IC50=350μM) and from Rhizopus mold (IC50=90μM, Ki=195μM, non-competitive), the other indolizidines show very little inhibitory activity at 1mM concentration.

Reductive amination of formyl C-glycofuranosides, easily available from hexose-derived equatorial-2-OH-glycopyrano-sides by DAST-promoted ring contraction, afforded N-substituted 1-C-aminomethyl glycofuranosides in most cases in high yields.

Ready access to constrained, multifunctionalized, hydrolytically stable amino acids has been established by the synthesis of their direct precursors using 2,5-anhydro-3-azido-3-deoxy-d-altrose (a ‘formyl azido-C-glycofuranoside’), or its readily available, stable synthetic equivalent [(1R) and (1S)-2,5-anhydro-3-azido-4,6-O-benzylidene-3-deoxy-1-fluoro-1-O-methyl-d-altritol], as novel molecular scaffolds.

A short and efficient route to enantiomerically pure hexahydroxy- and pentahydroxy-perhydroazaazulenes, ring-homologues of castanospermine, starting from the sole isoxazolidine derivative obtained in the 1,3-dipolar cycloaddition of a d-galactose-derived nitrone and methyl acrylate, is established. The procedure allows both backbone and stereochemical modulation of the products by choice of the starting monosaccharide. Structural assignment was based on crystallographic analysis of the starting isoxazolidine and NMR techniques. The products were tested for inhibitory activity against several glycosidases.

Graphic

Regio- and stereoselective cycloaddition of methyl acrylate to C-glycosyl nitrones derived from d-galactose and d-glucose, giving 5-methoxycarbonyl-3-(pentoglycos-5-yl or pentitol-1-yl)isoxazolidines, is reported. Transformation of one of them into a 4-hydroxy-2-(pentoglycos-5-yl)pyrrolidine derivative, potentially useful in a route to polyhydroxy-perhydroazaazulenes, was achieved.

Reaction of diversely configured and substituted, unbranched methyl d -hexopyranosides with the DAST in dichloromethane or acetonitrile led to normal substitution products and/or rearranged fluoro compounds (ring-contracted 2,5-anhydro-1-fluoro-1- O -methylhexitol derivatives, 2-methoxy- d -hexopyranosyl fluorides, and, for some 3-azido substrates, rearranged 2-azido-3-fluoro- d -hexopyranosides). When the reaction was performed in acetonitrile, the solvent participation as a nucleophile (Ritter reaction) was observed in one case. For a 2,4-unprotected 3-azido substrate, 2,3-dehydration and fluorination at C(4), the latter with epimerization, took place. 19 F/ 1 H and 19 F/ 13 C coupling constant values were systematically applied to discriminate between isomeric structures for fluorinated products, and for some, previously described, coming from five 3-branched-chain d - or l -hexopyranosides, thus discarding the previously reported structural assignment. From the synthetic point of view, the most outstanding result was the preparation of 2,5-anhydro-1-fluoro-1- O -methylhexitols, showing a latent formyl group functionality, a transformation, which was achieved in one case. A rationalization for the formation of the different types of product is also proposed.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Protected C7 and C8 aminodialdoses were prepared stereoselectively from readily available C5 and C6 monosaccharide N-benzyl nitrones, by regio- and diastereoselective 1,3-dipolar cycloaddition reactions with vinyl trimethylsilane, followed by acetyl chloride-mediated cleavage of the 5-(trimethylsilyl)isoxazolidine formed. The cycloaddition reaction took place in moderate to good global yields (67–74%); estimation of diastereoselectivities from isolated yields showed total endo preference for the reaction of the d-galacto configured nitrone and high endo preference for the d-ribo analogue, but exo preference for the d-xylo configured substrate. Attack on the re face of the nitrone was predominant in all cases. The absolute configuration of one of the protected 3-(α-d-galacto-pentopyranos-5-yl)isoxazolidine products was assigned by X-ray crystallographic analysis, allowing correlation of the configuration at the new stereogenic centre in the corresponding aminodialdose. For non-crystalline isoxazolidines, configurations were assigned on the basis of NOESY experiments and/or chemical correlation. Combined yields of aminodialdoses coming from isoxazolidines having identical configuration at C(3) sometimes reached high values (up to 90%). These compounds are precursors of higher-chain glycosamino acids.

Novel, potentially bioactive, fluorinated branched-chain monosaccharides were obtained by reaction of diethylaminosulphur trifluoride (DAST) with a series of methyl 3-C-cyano-3-ethoxycarbonyl-β-d-glucopyranoside derivatives, including the 4,6-O-benzylidene derivative and their 3-C-(N-protected aminomethyl) reduction products, as well as the phenyl 3-C-cyano-3-ethoxycarbonyl-1-thio-α-d-(and β-d-)glucopyranosides. The absolute configuration at C(3) was unambiguously assigned for all compounds on the basis of X-ray crystallographic analysis of methyl 4,6-O-benzylidene-3-C-cyano-3-deoxy-3-ethoxycarbonyl-β-d-glucopyranoside, corroborating the previous tentative assignment by other authors for the 4,6-unprotected compound. The course of the fluorination depended on the reaction temperature and the substitution pattern of the substrate. Thus, for methyl 3-C-cyano-3-ethoxycarbonyl-β-d-glucopyranoside, fluorination occurred exclusively at C(6), but for the phenylthio analogue, a 2-deoxy-2-phenylthio-α-d-manno-configured glycosyl fluoride and its 6-fluoro derivative were obtained, resulting from the expected rearrangement reaction, whilst starting from the phenylthio α anomer, only the unrearranged 6-fluoro compound was formed. Rearrangement was also observed in the fluorination of methyl 4,6-O-benzylidene-3-C-(N-protected aminomethyl)-β-d-glucopyranoside, which led to the 2-O-methyl-α-d-mannopyranosyl fluoride derivative as the sole product. This methodology may constitute a simple route to enantiopure conformationally constrained cyclic fluorinated β-amino acids having the α carbon atom shared with a pyranose ring, although only moderate yields were achieved, particularly in the fluorination step.

Fluorination of diverse 3-deoxy-3-C-methyl-3-nitro-hexopyranosides and hexo-1-thiopyranosides of the d- and l-series by the DAST reagent was studied in order to establish, on this 3-branched-chain sugar domain, the influence of the stereochemical relationship of the substituents at positions 1 and 2, as well as the protection of the HO-4, on the kinds of rearrangement reaction promoted by this fluorinating agent. Three classes of pyranosidic substrate were employed: (a) 1,2-trans configured, irrespective of whether HO-4 is protected or not; (b) 4-O-protected 1,2-cis configured; and (c) 4-O-unprotected 1,2-cis configured. They were prepared starting from simple glycosides through routes involving a Baer reaction and subsequent transformations by known methodology. All the substrates of class a essayed underwent, on treatment with DAST at room or higher temperatures, a rearrangement involving a 1,2-shift to give both the anomeric 2-inverted pyranosyl fluorides (or, for the 1-thioglycosides, only the α fluoride). Substrates of class b led, through a mechanism similar to that proposed for transformations of related substrates, to ring-contracted 2,5-anhydro-1-fluoro-1-O-methyl- (or 1-deoxy-1-phenylthio-)hexitol derivatives (sometimes as 1-epimers), which are precursors of 2,5-anhydro-aldehydo-sugars. Substrates of class c led to 4,5-anhydro-1-fluoro-1-O-methylalditol derivatives in all cases, together with a ring-contracted 5-fluoro-hexofuranoside in only one case; a rationalisation for their formation is proposed.

Mixed crystals of methyl 3-deoxy-3-C-methyl-3-nitro-α-d- and β-l-glucopyranosides (1:1), easily available from d-glucose by means of the Baer reaction, were completely characterised by X-ray diffraction analysis. These diastereomeric components, separation of which could be achieved through their 4,6-O-benzylidene derivatives, were selectively fluorinated at position 6 by treatment with DAST and stereoselectively transformed into phenyl 3-deoxy-3-C-methyl-3-nitro-1-thio-β-d-glucopyranoside and phenyl 3-deoxy-3-C-methyl-3-nitro-1-thio-β-l-glucopyranoside, respectively. Fluorination with DAST of each pure enantiomer afforded, depending on the conditions, the corresponding enantiomeric phenyl 3,6-dideoxy-6-fluoro-3-C-methyl-3-nitro-1-thio-β-d- and β-l-glucopyranosides or the respective rearranged 2,3,6-trideoxy-6-fluoro-3-C-methyl-3-nitro-2-phenylthio-α-d- and α-l-mannopyranosyl fluorides. This route constitutes a simple method for obtaining fair-to-good yields of 6-fluorinated branched-chain d- and l-sugar derivatives, potentially useful as glycosyl donors, starting from d-glucose.