Studies towards the synthesis of the bicyclic 3,8-secotaxane diterpenoid system using a ring closing metathesis strategy

Molecular modelling studies on the interations between taxanes and tubulins, developed by us, revealed that modified Taxuspines U and X could adopt a conformation similar to that of the bioactive conformation of paclitaxel and could be well accommodated within the proposed model. Accordingly, simplified Taxuspine U and X analogues have been rationally designed and their bicyclic 3,8-secotaxane diterpenoids intermediates have been synthesized through an approach that involves ring closing metathesis (RCM) as the key step for the macrocycle formation. Extensive studies on RCM have been performed using chemically diverse substrates, outlining the influence in the macrocyclization of the presence and position of functionalities, the molecular constraints and the importance of the site of ring closure.