Yves Blériot

The first synthesis of substituted azepanes mimicking monosaccharides: a new class of potent glycosidase inhibitors

The synthesis of the first examples of seven-membered ring iminoalditols, molecules displaying an extra hydroxymethyl substituent on their seven-membered ring compared to the previously reported polyhydroxylated azepanes, has been achieved from d-arabinose in 10 steps using RCM of a protected N-allyl-aminohexenitol as a key step. While the (2R,3R,4R)-2-hydroxymethyl-3,4-dihydroxy-azepane 10, a seven-membered ring analogue of fagomine, is a weak inhibitor of glycosidases, the (2R,3R,4R,5S,6S)-2-hydroxymethyl-3,4,5,6-tetrahydroxy-azepane 9 selectively inhibits green coffee bean alpha-galactosidase in the low micromolar range (Ki = 2.2 muM) despite a D-gluco relative configuration.

New synthetic seven-membered 1-azasugars displaying potent inhibition towards glycosidases and glucosylceramide transferase

Several members of a new family of seven‐membered azasugars, which can be seen as 1‐azasugar ring homologues, have been obtained by simple chemical transformations starting from a sugar‐derived azidolactol. Unlike their piperidine counterparts, these molecules are chemically stable when they possess a hydroxy group at the pseudo‐C‐2 position. Biological assays with a range of carbohydrate‐processing enzymes have revealed interesting potential for these compounds. A trihydroxymethyl‐substituted azepane displayed strong competitive inhibition on almond β‐glucosidase (Ki=2.5 μM) while a trihydroxylated carboxylic acid derivative proved to be a potent and selective L‐fucosidase inhibitor (Ki=41 nM). N‐Butylation of these seven‐membered 1‐azasugars generated derivatives with some activity towards the Gaucher’s disease‐related glucosylceramide transferase (IC50 75 μM) that did not interact significantly with digestive glucosidases.

Phenylenediamine catalysis of “click glycosylations” in water: practical and direct access to unprotected neoglycoconjugates

Phenylenediamine-catalyzed click chemistry leads to the efficient, practical, and column-free preparation of neoglycoconjugates from unprotected glucosyl azide, in pure water when aglycon solubility permits.

Nucleophilic opening of epoxyazepanes: expanding the family of polyhydroxyazepane-based glycosidase inhibitors

A range of new tetra- and pentahydroxylated seven-membered iminoalditols has been efficiently synthesized from epoxyazepane precursors via nucleophilic opening with hydride or oxygenated species and subsequent hydrogenolysis. One tetrahydroxylated azepane, a ring homologue of deoxymannojirimycin, displays a selective and fairly good inhibition of alpha-L-fucosidase.

Synthesis of seven- and eight-membered carbasugar analogs via ring-closing metathesis and their inhibitory activities toward glycosidases

An expeditious and efficient synthesis of new enantiopure polyhydroxylated seven- and eight-membered carbocycles is described starting from 2,3.5-tri-O-benzyl-D-arabinose. The key cyclization step involves ring closing metathesis of 1,8- and 1,9-dienes using Grubbs catalyst. All of the new carbasugar analogs synthesized were evaluated as glycosidase inhibitors. Contrary to Our expectations, (1 S,2S,3R,4R,5R)-1-(hydroxymethyl)-cyclohepta-1,2,3,4,5-pentol which has the beta-D-mannopyranose configuration for C(1)-C(5) inhibits alpha- and beta-glucosidases, whereas its diepimer (1S,2S,3R,4S,5S)-1-(hydroxymethyl)-cyclohepta-1,2,3,4,5-pentol, which has the alpha-D-glucopyranose configuration, is not recognised by these enzymes

Tandem Staudinger–azaWittig mediated ring expansion: rapid access to new isofagomine-tetrahydroxyazepane hybrids

New seven-membered iminosugars with potent and selective inhibition towards glycosidases have been prepared as 1-N-iminosugar homologues via a tandem Staudinger-azaWittig mediated ring expansion.

Synthesis of novel purine nucleosides towards a selective inhibition of human butyrylcholinesterase

The search for new and potent cholinesterase inhibitors is an ongoing quest mobilizing many organic chemistry groups around the world as these molecules have been shown to treat the late symptoms of Alzheimers disease as well as to act as neuroprotecting agents. In this work, we disclose the synthesis of novel 2-acetamidopurine nucleosides and, for the first time, regioselective N(7)-glycosylation with 2-acetamido-6-chloropurine, promoted by trimethylsilyl triflate, was accomplished by tuning the reaction conditions (acetonitrile as solvent, 65 degrees C, 5h) starting from 1-acetoxy bicyclic glycosyl donors, or by direct coupling of a methyl glucopyranoside with the nucleobase to obtain only N(7) nucleosides in reasonable yield (55-60%). The nucleosides as well as their sugar precursors were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. While none of the compounds tested inhibited AChE, remarkably, some of the N(7) nucleosides and sugar bicyclic derivatives showed potent inhibition towards BChE. Nanomolar inhibition was obtained for one compound competing well with rivastigmine, a drug currently in use for the treatment of Alzheimers disease. Experimental results showed that the presence of benzyl groups on the carbohydrate scaffold and the N(7)-linked purine nucleobase were necessary for strong BChE inactivation. A preliminary evaluation of the acute cytotoxicity of the elongated bicyclic sugar precursors and nucleosides was performed indicating low values, in the same order of magnitude as those of rivastigmine.

Total Synthesis of Calditol: Structural Clarification of this Typical Component of Archaea Order Sulfolobales

The original structure of calditol--that is, an open-chain branched nonitol--has recently been questioned by various research groups and cyclopentane-based structures have been proposed. To unambiguously clear up this confusion, four isomeric cyclopentane candidates 26-29 have been synthesized. Of these, compound 27 was found to be fully identical to the natural product present in Sulfolobus solfataricus (A.T.C.C. 49155). The synthesis of 27 uses a samarium-diiodide-induced pinacolization reaction of the ketoaldehyde 15 as the critical step.

Novel mannosidase inhibitors probe glycoprotein degradation pathways in cells

Multiple isoforms of mammalian α-mannosidases are active in the pathways of N-linked glycoprotein synthesis and catabolism. They differ in specificity, function and location within the cell and can be selectively inhibited by imino sugar monosaccharide mimics. Previously, a series of structurally related novel 7-membered iminocyclitols were synthesised and found to be inhibitors of α-mannosidase using in vitro assays. The present study aimed to delineate α-mannosidases hydrolytic pathways in azepane inhibitor treated cells by the analysis of free oligosaccharides (FOS) as markers of endoplasmic reticulum (ER), Golgi, lysosomal and cytosolic α-mannosidase activities. Two compounds were identified as potent and selective cytosolic α-mannosidase inhibitors. Two related compounds were shown to be potent inhibitors of lysosomal α-mannosidase with different potencies towards α1,6 mannosidase. The specificities of these novel 7-membered imino sugars are related to differences in their structure and d-mannose-like stereochemistry. Specific ER-mannosidase inhibition by kifunensine also reveals significant non-proteasomal degradation following FOS analysis and appears to be cell line dependent. The availability of more selective inhibitors allows the pathways of N-linked oligosaccharide metabolism to be dissected.

Stereochemical Assignment and First Synthesis of the Core of Miharamycin Antibiotics

The relative configuration at C-6 of nucleoside antibiotic miharamycin A has been elucidated by NMR spectroscopy and proved to be S. The total synthesis of miharamycin B has also been investigated, which has led to the unprecedented construction of its core. The bicyclic sugar moiety has been elaborated by means of a SmI(2)-based keto-alkyne coupling. Elongation of its C-6 position towards a bicyclic sugar amino acid and conversion into a suitable glycosyl donor enabled efficient N-glycosylation with 2-aminopurine to take place to afford the nucleosidic part of miharamycin B. Final peptide coupling with arginine afforded the skeleton of miharamycin B. Unfortunately, attempts to deprotect this scaffold failed to afford the complex nucleoside antibiotic.