Semi-synthetic approaches towards analogues of Paclitaxel, from Brevifoliol and Taxchinin A

This thesis describes our approaches towards the construction of a new taxol analogue, beginning with brevifoliol 1 or taxchinin A 2 both isolated, here in Leicester, from an Indian Yew resin. (Fig. 8728A).;Attempts to selectively protect either OH(5) or OH(13), or construct the oxetane ring across positions C-4/C-5, directly on brevifoliol 1, were unsuccessful. Hence, we hydrolysed all three ester groups, affording compound 3 for further investigations. On treating this derivative with di-tert-butylsilyl ditriflate, then triethylsilyl chloride, we achieved the successful formation of compounds 4 and 5. Conformational analysis of derivatives 3, 4, and 5, using 2-D, NOESY and 29Si-iH NMR spectroscopy, allowed us to determine the twist-boat/chair conformation of both these compounds. Assignment of these conformations, containing the unusual hydroxysilyl ether groups, strengthened our knowledge of 11(15-1)abeo-taxanes, allowing us to continue work towards oxetane ring construction. (Fig. 8728B).;In addition, hydrolysis of taxchinin A 2, furnished compound 6. Variable temperature NMR analysis showed this derivative exists, in solution, in conformational equilibrium. Treatment with di-tert-butylsilyl ditriflate then triethylsilyl chloride, gave compounds 7 and 8 in the twist-boat/chair and twist-chair/boat conformations respectively. This was again confirmed using 2-D and NOESY NMR spectroscopy. (Fig. 8728C).;We have shown, that in carrying out work on these rearranged taxanes, conformational behaviour is crucial to the outcome of the reaction and, as such, must be taken into account when constructing a new taxol analogue.