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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Synthetic Studies Toward the MannopeptimycinsM. Morelle, K. Cariou, J. Thierry, and R. H. DoddCentre de Recherche de Gif-sur-Yvette, Institut de Chimie des Substances Naturelles UPR2301, CNRS, Avenue de la terrasse, 91198, Gif-sur-Yvette, FranceIntroductionThe mannopeptimycins are a new family of five glycopeptide antibiotics characterized in2002 by Wyeth laboratories [1]. Some of them exhibit high antibiotic activity againstGram-positive bacteria and more interestinglyOHOROH3 against MRSA and vancomycin-resistantHO OH NH 2HOO OR enterococci via inhibition of cell wall synthesis.HN2NOThey are comprised of a peptidic core of fiveHO OHH 2 N N H OH O OHH ON H NH HNOHO NH HNONH HNOOamino acids: a serine, a glycine, a -methylphenylalanine, a dimannosylated D-tyrosine andtwo enantiomeric non proteinogenic amino acidsbearing a cyclic guanidine, one of which isN-mannosylated.No total synthesis has been achieved so faralthough two papers describing the synthesis of derivatives of the non proteinogenic aminoacids were recently published [2].Three routes to the synthesis of these amino acids were designed, two of which rely onthe intramolecular aziridination of an alkene via the addition of a nitrene generated fromthe oxidation of sulfamates in presence of transition metals [3]. The third one is a moreclassical and convergent approach for the synthesis of -hydroxy -amino acids using analdol reaction between a glycine equivalent and an aldehyde bearing a cyclic guanidine.Results and DiscussionRoute 1: A [5.1.0] bicyclic aziridine could be obtained by the attack of a nitrene generatedfrom the primary sulfamidate A 1 . This sulfamate was prepared and reacted under conditionsdescribed previously [3]. TheHaziridination step gave theNNHObicyclic compound B 1 in aNHP 1 O Nsatisfactory yield in twoO P 1 O OSO 2 NH 2HO OScases with a major productP O O2 HNP 2 HNBocN OH 2 N OHBhaving the desired configurationsat C-2, C-3 and C-4. However, these compounds turned out to be very unstable1A 1making this approach inefficient to pursue the synthesis.OHONBocHORONHR'20°C,10h.Route 2: A [3.1.0]bicyclic aziridine couldbe obtained by the attackof a nitrene generatedfrom the secondary sulfamidateA 2 . The aziridinationstep conductedOHOOHOiOR 1R 1 , R 2 , R 3 = HR 1 = H, R 2 = i-valeryl, R 3 = HR 1 = H, R 2 = H, R 3 = i-valerylR 1 = i-valeryl, R 2 = H, R 3 = HH 2 NO 2 SORONHR'iiROR'HNB 1N OSOOR' = Boc, R = Bn, no reactionR' = Boc, R = Me, no reactionR' = Boc, R = Boc, 66%R' = R= O 80%Reaction conditions : i : cf. ref. [3]; ii : Rh 2 (OAc) 4 (5 mol%), PhIO (1.2 eq), 3 Å m.s., CH 3 CN, -HOH 2 NHNNHOOHNHO OSN OBocNwith rhodium diacetate and iodosobenzene gave the bicyclic aziridine B 2 in a 75%satisfactory yield. Moreover this bicyclic compound B 2 showed good stability. Theconfigurations of the stereogenic centers are still under investigation. The opening of B 2proceeded smoothly in 85% yield to give a mixture of azido compounds.OB 2P 1 NOSO 2 NH 2OA 2P 1 NOHOOP 1 NO152