Synthesis of the Taxol core using asymmetric 1,4-additions

The topic of this thesis is the synthesis of Taxane derivatives using the asymmetric conjugate addition of alkenes. Taxol is an important anti-cancer drug and owing to its complex structure, remains a subject of fascination by chemists. The asymmetric conjugate addition of alkenes is a power transformation and holds promise in synthesising complex molecules such as Taxol. In Chapter 1, we prove that this is a feasible undertaking by synthesising the C-ring of the Taxol core containing the C8 stereocenter. A complex nucleophile containing a bromide and substituted alkene was successfully synthesised on decagram scale and underwent asymmetric conjugate addition to give this intermediate in 95% yield and 88% ee. In Chapter 2, the trapping of zirconium enolates generated from asymmetric conjugate additions was investigated. Several electrophiles were screened and it was found that only formaldehyde or the Vilsmeier-Haack reagent would give rise to any trapped products. The Vilsmeier-Haack reagent, gave β-chloroaldehydes in modest yields (between 41-60%) and high enantioselectivities (up to 98% ee) for adducts containing quaternary stereocenters. The synthetic utility of these compounds was also demonstrated by synthesising derivatives (Grignard addition and Suzuki-Miyaura couplings). In Chapter 3, we envisged using an unprecedented transannular electrocyclic reaction as a key step to simultaneously form the A and B rings. The precursor 10-membered ring was synthesised by cross metathesis of an intermediate prepared in chapter 2, with a geminal diboron butadiene followed by ring closing Suzuki coupling. Ultimately, we were unsuccessful in carrying out the desired electrocyclic reaction. We discuss possible reasons as to why this was the case. In Chapter 4, the type-II intramolecular Diels–Alder reaction is reviewed in the context of Taxane syntheses and then applied to our model substrate. Using this reaction, we were able to achieve our original objective by synthesising the Taxol core in five steps from simple starting materials in 11% yield, 92% ee and 1:1 d.r. at C1.