Total synthesis of Amphidinol 3 – AMPHI3

The amphidinols (AMs) are a fascinating group of biologically active polyketide matabolites isolated in 1991 from the marine dinoflagellates of the Amphidinium species. Among them amphidinol 3, isolated by Yamumoto (12mg from 440L in culture) has emerged as an important synthetic target because of its antifungal and hemolytic activities and its challenging structure bearing 67 carbon atoms whose 25 stereogenic centers, polyhydroxylated linear structure and a hairpin conformation. To date, no total synthesis of amphidinol 3 has been reported in the literature but only synthesis of fragments have been performed. Two years ago three teams (J. Cossy, F. Colobert, I. Marko) decided to join their efforts to embark on the journey to synthesise this molecule using some of the methodologies developed in their laboratories: - The synthesis of the polyene fragment C53-C67 was achieved and published using either a sequence of reduction, benzoylation and reductive elimination starting from acetylenic precursors or from sorbic acid by employing a chemioselective cross-metathesis applied to a Weinreb amide and the Julia-Kocienski olefination as the key steps. - Lot of work has been done concerning the synthesis of the polyol chain C1-C30 by disconnection in two parts C1-C18, C19-C30 or C1-C17, C18-C30 but all attempts to connect the corresponding fragments failed in our hands, especially the selective reduction of the C18-C19 double bond after Julia-Kociensky olefination. We did not find conditions to reduce this double bond chemioselectively in presence of protected allylic alcohols. The present project consists in pursuing the total synthesis of Amphidinol 3. The challenge of being in competition with talented and well-world recognized US groups for the total synthesis of this natural product is an exciting goal. Furthermore, the choice for a convergent and modulable synthesis that opens the route to many synthetic homologues of AM3 will allow some links with biologists and formation of a network to have a better understanding of the mode of action of this intriguing family of molecules. We proposed for this project four complementary tasks: - The 1st task of this project is to prepare fragment C1-C30 by the connexion of two or three parts; in the last case a linker will be used in order to connect the polyhydroxylated fragment C19-C30 and the fragment bearing the homoallylic alcohols C1-C8. - The second task focuses on the stereoselective synthesis of the tetrahydropyranic part C31-C52 starting from D-mannose. - The third task concerns the coupling reactions between fragments C1-C30, C31-C52 and C53-C67 that have been prepared in tasks one and two and subsequent overall deprotection of hydroxyl groups. - The selected strategy will be compatible with a convenient access to C20-C52 central core of amphidinols and the last task will deal with the preparation of analogues of AM3 with structural variations of the two antipodal sites (C1-C20 and especially C53-C67) which are important for the biological activity of the molecule. Two international recognized academic teams from Paris (Pr. Janine Cossy, Laboratoire de Chimie Organique, ESPCI) and Strasbourg (Pr. Françoise Colobert, laboratoire de stéréochimie, ECPM) will continue and join the task. This association offers the unique opportunity to combine complementary expertise of total synthesis. Both partners involves synthetic chemists specialized in total synthesis and development of new and efficient methodologies. The goal of this working group is to gather various synthetic methodologies in organic synthesis to focus on the total synthesis of Amphidinol 3 and, if possible, synthetic homologues. We plan to attack this objective through several research pathways.