Valorisation des concepts de stéréosélection acyclique et cyclique en synthèse totale: borrelidine, longicine et épothilone I2

Description

This thesis is composed of two parts. The first presents the synthesis of bioactive oligosaccharides. The second presents the total synthesis of cyclodepsipeptide (−)-doliculide.In the first part, we are primarily interested in two compounds which each carry an epitope Galaα(1→3)Gal. This epitope plays a very important role in the phenomenon of hyperacute rejection which happens with heart xenotransplantations from pigs to primates. The synthesis of these two compounds was carried out using the glycosylation method based on the remote activation concept, which uses 3-methoxy-2-pyridyloxy glycosyl donors (MOP donors). We next present the synthesis of a potential antagonist of E-selectin which offers interesting perspectives concerning the treatment of chronic inflammatory diseases. Our synthesis is based on the use of 2-thiopyridylcarbonate glycosyl donors (TOPCAT donors) to carry out the glycosylation reactions.The second part consists of the total synthesis of the natural product (−)-doliculide which is a strong antineoplasic agent. In order to establish the syn/syn-deoxypropionate part of the polyketide chain, we used an iterative sequence based on the addition of Me2CuLi in the presence of TMSCl to chiral non-racemic δ-methyl-α,β-unsaturated esters. The syn/syn nature of this subunit was established by synthesizing the natural product (+)-siphonarienal.Our approach permitted us to carry out the total synthesis of (−)-doliculide in 28 steps (for the longest linear sequence), which is the shortest synthesis carried out up until now. We also report a qualitative interpretation to explain the diastereoselectivities observed in the 1,4-additions used in the synthesis. This led us to study the conformational properties of some deoxypropionate units and to propose several models using a virtual diamond lattice to visualize them. Last, we dwell on interesting correlations observed by 1H and 13C NMR between enoates harboring a syn - or an anti-deoxypropionate unit.