Synthesis and Applications of Carbohydrate-Based Organocatalysts.

Organocatalysis is a very useful tool for the asymmetric synthesis of biologically or pharmacologically active compounds because it avoids the use of noxious metals, which are difficult to eliminate from the target products. Moreover, in many cases, the organocatalysed reactions can be performed in benign solvents and do not require anhydrous conditions. It is well-known that most of the above-mentioned reactions are promoted by a simple aminoacid, l-proline, or, to a lesser extent, by the more complex cinchona alkaloids. However, during the past three decades, other enantiopure natural compounds, the carbohydrates, have been employed as organocatalysts. In the present exhaustive review, the detailed preparation of all the sugar-based organocatalysts as well as their catalytic properties are described.

Formation of Tetrahydrothiophenes via a Thia-Paternò-Büchi-Initiated Domino Photochemical Reaction.

We have established photochemical access to thietane or tetrahydrothiophene compounds from thiobenzophenone derivatives and acrylonitrile, wherein the product selectivity is controlled by a simple adjustment of the reagent concentration in solution. Small libraries of five-membered ring sulfur-containing compounds were prepared through a thia-Paternò-Büchi reaction, followed by a previously unknown regioselective photochemical ring enlargement reaction in a domino process or a stepwise fashion. A mechanism is proposed to rationalize this ring enlargement reaction via a carbene species provided from photoexcited thiocarbonyl compounds.

A Greener and Efficient Method for Nucleophilic Aromatic Substitution of Nitrogen-Containing Fused Heterocycles.

A simple and efficient methodology for the nucleophilic aromatic substitution of nitrogen-containing fused heterocycles with interesting biological activities has been developed in an environmentally sound manner using polyethylene glycol (PEG-400) as the solvent, leading to the expected compounds in excellent yields in only five minutes.

Cooperative 5- and 10-membered ring interactions in the 10-helix folding of oxetin homo-oligomers.

Homo-oligomers of the natural product oxetin (cis-3-amino-2-oxetanecarboxylic acid) were prepared and their conformational behaviour studied in solution and solid state and by molecular modelling. The predominant secondary structure was a 10-helix, propiciously stabilized by a network of 5-membered ring H-bonds implicating ring oxygens and neighboring amide hydrogen atoms.

Synthetic Access to All Four Stereoisomers of Oxetin.

A short synthesis of all four stereoisomers of 3-amino-2-oxetanecarboxylic acid (oxetin) is described. The oxetane core is built using a Paternò-Büchi photochemical [2 + 2] cycloaddition; from the key intermediates, complementary resolution protocols provide access to enantiomerically pure oxetin and epi-oxetin on gram-scale.

Synthesis and antiproliferative activity of a natural like glycoconjugate polycyclic compound.

A natural like O-glycoconjugate polycyclic compound 4 was obtained by a multistep procedure starting from N-(3-methyl-1-(4-nitrophenyl)-1H-pyrazol-5-yl)acetamide. The glycosyl derivative 4 showed antiproliferative activity against all the tumoral cell lines of the NCI panel in the range 0.47-5.43 µM. Cytofluorimetric analysis performed on MDA-MB231, a very aggressive breast cancer cell line, which does not express estrogen, progesterone and HER-2/neu receptors, showed that 4 is able to induce prolonged cell cycle arrest at G2/M phase and morphological signs of differentiation. These events are correlated with down-regulation of both cyclin B1 and cdc2, the cyclins involved in G2/M transition, as well as up-regulation of cyclin-dependent kinase (CDK) inhibitor p21 Cip1/Waf1.

The weight of flash chromatography: A tool to predict its mass intensity from thin-layer chromatography.

Purification by flash chromatography strongly impacts the greenness of a process. Unfortunately, due to the lack of the relevant literature data, very often this impact cannot be assessed thus preventing the comparison of the environmental factors affecting the syntheses. We developed a simple mathematical approach to evaluate the minimum mass intensity of flash chromatography from the retention factor values determined by thin-layer chromatography.

SENSASS NMR: New NMR techniques for enhancing the sensitivity and the spectral resolution of polymer supported chemicals.

The use of polyethylene glycols (PEGs) as organic polymer soluble supports for synthesis has been receiving growing interest. The main advantages of using PEGs as support are related to their non-toxicity, their commercial availability and their solubility properties allowing easy recovery and analysis of compounds linked to the polymer. The NMR characterization of PEG-branched products could however be difficult due to the presence of huge signals of the polymeric support. In order to overcome this problem, we developed new NMR experiments named SENSitivity increAsed and resolution enhanced by Signal Suppression or SENSASS NMR. These experiments implement either semi-selective pulses or Water Gate sequences for reducing signals of the polymer as well as fast pulsing techniques optimizing the recycling delay for enhancing the sensitivity of signals. They have been successfully implemented in classical NMR characterization experiments namely, COSY, HSQC and HMBC experiments.

Knoevenagel reaction of unprotected sugars.

The Knoevenagel reaction of unprotected sugars was investigated in the 1950s using zinc chloride as promoter. The so-called Garcia Gonzalez reaction had been almost forgotten for 50 years, until the emergence of new water tolerant catalysts having Lewis acid behavior. The reaction was thus reinvestigated and optimal conditions have been found to prepare trihydroxylated furan derivatives from pentose or beta-tetrahydrofuranylfuran from hexoses with non-cyclic beta-keto ester or beta-diketones. Other valuable compounds such as beta-linked tetrahydrobenzofuranyl glycosides or hydroxyalkyl-3,3,6,6,-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione can be obtained using cyclic beta-dicarbonylic derivatives. Apart from one report in the 1950s, the Knoevenagel reaction of unprotected carbohydrate in basic condition has been studied only in the mid-1980s to prepare C-glycosyl barbiturates from barbituric acids and, later on, from non-cyclic beta-diketones, beta-C-glycosidic ketones. The efficient method exploited to prepare such compounds has found an industrial development in cosmetics.

Diastereoselective addition of sugar radicals to camphorsultam glyoxilic oxime ether: a route toward C-glycosylthreonine and allothreonine.

C-glucosyl, mannosyl and galactosyl 2-iodopropane, readily obtained from the corresponding C-glycosyl ketones, were coupled with (+)- or (-)-camphorsultam glyoxylic oxime ether with diastereoselectivity ranging from 70:30 to 80:20. C-glucosyl allothreonine was obtained by cleavage of the camphorsultam moiety.

Synthesis of C-disaccharides via a hetero-Diels-Alder reaction and further stereocontrolled transformations.

The partial de novo synthesis of two new C-disaccharides containing D-glucosamine is described. The strategy is based on a hetero-Diels-Alder reaction leading to a 1:1 mixture of separable cycloadducts, which have been stereoselectively functionalized and converted into alpha-D-Galp-(1-->3)-C-D-GlcpNAc and alpha-l-Galp-(1-->3)-C-D-GlcpNAc.

Investigation of the aqueous transmetalation of pi-allylpalladium with indium salt: the use of the Pd(OAc)2-TPPTS catalyst.

pi-Allylpalladium complexes could be generated in water by the palladium(0) water soluble catalyst prepared in situ from palladium acetate and TPPTS. These complexes were transmetalated with indium to react with benzaldehyde. The aqueous solution of Pd(0)(TPPTS)(n) could be reused without deterioration of the catalyst in the first and second recycling. The system proved to be efficient with primary and secondary allylic substrates. The stereochemical outcome of the allylation through umpolung of allylpalladium, was also studied using models with a restraint conformation.

One-step synthesis of beta-C-glycolipid derivatives from unprotected sugars.

Condensations of nonsymmetrical or symmetrical beta-diketones and unprotected sugars in aq NaHCO3 soln were explored. C-glucosyl and C-maltosyl derivatives bearing lipophilic residue of 8 or 11 carbon atoms were prepared efficiently using this one-step procedure. The amphiphilic properties of these compounds were demonstrated by measuring their CMC.