Our main research interest is the synthesis of biologically active natural products, such as taxol, a powerful antitumor agent, or dolabelide C and hexacyclinic acid, molecules with cytotoxic activity. In our approaches towards the target molecules, we uncover problems that cannot be easily solved by known reactions, and to overcome these difficulties we try to develop new methodologies that can also be applied to other syntheses.
TaxolWe envisioned two retrosyntheses for the synthesis 10-deacetylbaccatin III, which is a natural precursor of taxol. They involve a ring-closing metathesis (RCM) to close the eight-membered B ring between C9 and C10 or C10 and C11, and a Shapiro coupling to synthesize the RCM precursors. These two approaches have enabled us to synthesize model BC ring systems of taxoids, and we are exploiting the C10-C11 metathesis route for the synthesis of 10-deacetylbaccatin III.
Dolabelide CDuring the synthesis of Dolabelide C, we have developed new methodologies for the construction of protected allylic syn 1,3-diols. We have reported a diastereoselective intramolecular conjugate addition of a hemiacetal anion, made in situ from a homoallylic alcohol and benzaldehyde in the presence of base, to a vinyl sulfone. The benzylidene acetal was reduced to free the proximal hydroxy group, and addition of the dianion of the β-hydroxy sulfones to aldehydes was successful, but an additional two steps (acetate or benzoate formation followed by reductive elimination) is required to form the alkene, with the issue of differentiating the two hydroxy groups during acylation.
Hexacyclinic acidFinally, we are exploring the synthesis of hexacyclinic acid. The ABC tricycle has been synthesized using a highly diastereoselective Michael addition and a radical cyclization as key steps. The construction of the DEF tricycle is in progress.
Post-polymerisation functionalisation by olefin metathesisThe Prunet group has also been using metathesis reactions for the post-polymerisation functionalisation of a diverse array of polymers with pendent olefin groups. In collaboration with Prof. Christophe Thomas (Chimie ParisTech), the CM of polyesters and diverse small molecule partners was used to afford functionalised polymers with a dramatic increase in their glass-transition temperature compared to the starting polyesters. With Prof. Rob Liskamp (University of Glasgow), three novel polyethers with differently substituted olefinic side chains were prepared, tailored to promote cross metathesis (CM) vs self metathesis (SM), and the first successful CM between a polymer and a coupling partner of biological relevance, the tripeptide RGD, was performed. Insoluble beads of poly(divinylbenzene) prepared in the group of Prof. Peter Cormack (University of Strathclyde) could be functionalised by CM to provide ion-exchange resin materials. Finally, in collaboration with Porf. Michael Shaver (University of Manchester), RCM of isotactic polyepoxybutene (PEB) was used to prepare a stereocontrolled 1,4-linked cis cyclopolyether. Post-polymerisation dihydroxylation (DH) then furnished a poly(ethylene glycol) backbone with sugar-like functionalities (PEGose), which mimics the structure of amylose.