Approaches towards the synthesis of gem-difluorinated monosaccharides analogues
thesisposted on 15.12.2014, 10:35 by Stéphane Pintat
This thesis describes the synthesis of gem-difluorinated cyclic molecules using building block approaches based mainly on ring-closing metathesis (RCM) using commercially available ruthenium catalysts such as Grubbs' catalyst. In the first instance, 1-bromo-1,1-difluoroprop-2-ene was used to synthesise difluorinated dihydropyrans in order to demonstrate that the unprecedented RCM of a substrate containing two fluorine atoms in the allylic position could be achieved. A similar approach allowed the highly diastereoselective synthesis of new 4,4-difluoro-4-deoxyhexoses using a RCM-dihydroxylation sequence. In order to widen the range of available difluorinated monosaccharide analogues, a potentially highly enantioselective, non-RCM based route was developed. This approach relied on the use of (3-bromo-3,3-difluoro-prop-1-ynyl)-benzene as the fluorinated building block and Sharpless asymmetric dihydroxylations to introduce hydroxyl groups enantioselectively. Unfortunately, a poor choice of protecting group prevented access to the desired difluorinated monosaccharide analogues, even if the asymmetric dihydroxylation proved successful and enantioselective. RCM was also used to synthesise different types of difluorocyclooctenones from trifluoroethanol. These difluorinated 8-membered carbocycles showed interesting and unusual conformational behaviour and were investigated by NMR experiments and a simple computational study. These difluorocyclooctenones were also used to synthesise new bicyclic structures, which are effectively conformationally restrained difluorinated monosaccharide analogues.