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.
We 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.
During 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.
Finally, 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.