Sylvain Favre

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Publications associées (11)

Synthesis of branched seven-membered 1-N-iminosugars and their evaluation as glycosidase inhibitors

Sylvain Favre, Pierre Vogel

Four branched tetra- and pentahydroxylated azepanes have been synthesized from a common azepane precursor through dihydroxylation followed by deoxygenation. They have been assayed as glycosidase inhibitors on a panel of 22 glycosidases and one methylated azepane displayed selective, competitive, and moderate inhibition toward bovine kidney alpha-L-fucosidase. (C) 2011 Elsevier Ltd. All rights reserved.

2012

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Synthetic studies toward the CD spiroketal of spongistatins

Sylvain Favre, Sandrine Gerber, Pierre Vogel

Starting from the readily available meso-methylenedi(8-oxa-3-oxobicyclo[3.2.1]hept-6-en-1-yl) (1), meso-1,1'-methylidene [(4R,4'S,6R,6'S)-4,6-dioxycyclohept-1-en-1-yl]tetrasilylethers (7, 8) were obtained and transformed into all-syn 1,3,5,11,13,15-hexahydroxypentadeca-7,9-dione derivatives (9, 10). The conversion of these intermediates into spiroketals was not met with success. An alternative strategy based on the sequential and stereoselective functionalization of 1 afforded a 1-(1,3,5,7-tetrahydroxyoctyl)cyclohept-1-ene-4,6-diol derivative ((+)-15, 94 % ee). Ozonolysis of the cycloheptene moiety of (+)-19 provided equatorial/axial spiroketal (+)-21 ((+)-(2R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[(2S,4S,6R,8S,10S)-10-{[tert-butyl(dimethyl) silyl]oxy}-4-hydroxy-8-(2-hydroxyethyl)-1,7-dioxaspiro[5.5]undec-2-yl]butan-2-yl 4-methoxybenzoate). Pivaloylation of its primary alcohol moiety and Meerwein's methylation of the remaining secondary alcohol unit furnished (−)-24, a potential precursor of a ketal-isomer of the CD fragment found in spongistatins 1 and 2.

Wiley-Blackwell2010

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For thousands of years, nature provided us remedies to treat diseases and its biologically active molecules inspired chemists for the development of new drugs. In 1993, three research groups independently reported the isolation, from sponges, of spongistatin 1. This 42-membered macrolactone, comprises 24 stereogenic centres, a chloro triene side chain, two spiroketals (AB and CD) and two tetrahydropyranyl units (E and F rings). This molecule was found to be among the most potent cancer cells' growth inhibitors tested to date by the U.S. National Cancer Institute. This compound inhibits the microtubule polymerisation with nanomolar to picomolar activities but further biological investigations were precluded by the extremely low quantities that were obtained from the marine organism. This scarce abundance, together with the remarkable structural complexity, prompted many research groups to address this challenge and seven of them reported a total synthesis. Vogel's methodology for the synthesis of 15 carbons polyolic chains was extended to the preparation of highly advanced intermediates of the AB and CD-spiroketals of spongistatin 1. This non-iterative synthesis started with the meso-1,1'-methylenedi[(1R,1'S,5S,5'R)-3-oxo-8-oxabicyclo[3.2.1]oct-6-ene-1-yl] derivative. The diene, obtained after an endo-reduction and the opening of the oxa-bridges, was resolved by mean of Sharpless asymmetric dihydroxylation. After an oxidative cleavage of the first cycle and a 1,3-anti reduction, ozonolysis was used to open the second cycloheptene. Acid catalysed spirocyclisation furnished the rigid core needed for the diastereoselective methylation and the inversion of an hydroxyl group. Finally, the axial/axial configuration of the AB-spiroketal was confirmed by two dimensional NMR analyses. Similar methodology was applied to the synthesis of the CD-fragment. An exo-reduction of the same starting diketone followed by Sharpless asymmetric dihydroxylation and a sequential cleavage of the cycloheptene rings furnished the equatorial/axial spiroketal with all the functionalities of the CD-fragment of spongistatin 1.

EPFL2009

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EPFL2009