UC Irvine

The nodulisporic acids comprise a subclass of the paxilline indole diterpene family and express potent insecticidal activity. These natural products have been the targets of synthetic studies since their isolation due to their complex, polycyclic structures. Efficient assembly of these targets has necessitated the development of new chemical transformations to forge bonds otherwise incompatible with retrosynthetic disconnections. This thesis will describe the development of such chemical transformations, culminating in the synthesis of nodulisporic acid C in 12 steps longest linear sequence (LLS) from commercial material as well as the synthesis of an advanced intermediate en route to nodulisporic acid A. A convergent approach utilizing a late stage ketone α-arylation to unite the complex terpene and indenopyran fragments allowed for the brevity of the synthesis. Construction of the indenopyran was accomplished through a diastereo- and regioselective enyne cycloisomerization which afforded the desired stereochemistry and connectivity present in nodulisporic acids A and C. The strategy for the terpene fragment relied on a hydrogen atom transfer (HAT) initiated polycyclization of an α-disubstituted ketone. The synthesis of this intermediate required the selective functionalization of a ketone at the more substituted position to afford a 1,1-disubstituted alkene in an intermolecular fashion. The development of this transformation utilizing a formal ene reaction between an enoxy silane and a terminal alkyne in the presence of catalytic indium(III) bromide is also described herein. Importantly, this reaction is selective for the formation of quaternary centers even in the presence of other enolizable positions. The development of these new chemical transformations has allowed for efficient access to the most complex structural features of the nodulisporic acid family.