Mechanistic studies on carbocation cascades in the biosynthesis of terpene natural products

This dissertation describes mechanistic studies, using modern quantum chemical methods, on carbocationic rearrangements in the biosynthesis of terpene natural products. Chapter 1 is an introduction to carbocation chemistry relevant to the biosynthesis of terpene natural products. Chapter 2 describes quantum chemical studies on complexes of the 2-norbornyl cation with ammonia and benzene. These calculations demonstrate that the delocalized, bridged, nonclassical geometry that is usually favored for this carbocation can be perturbed significantly towards the normally less favorable classical geometry through appropriately oriented noncovalent interactions. Chapter 3 describes examinations of the mechanisms proposed for enzyme-catalyzed formation of the sesquiterpene natural product trichodiene. Two alternative pathways for transformation of the intermediate bisabolyl cation to the cuprenyl cation are discussed. Chapter 4 describes cyclization mechanisms for several sesquiterpene families proposed to be closely related to each other in a biogenic sense (the bisabolene, curcumene, acoradiene, zizaene (zizaene, isozizaene, epi-zizaene and epi -isozizaene), cedrene (alpha/beta-cedrenes and 7-epi-alpha/beta-cedrenes), duprezianene, and sesquithuriferol families). Subtle but important modifications to several of the previous proposals are suggested based on quantum chemical computations. The potential roles of dynamic matching in determining product distributions and enzyme-promoted formation of secondary carbocations are also discussed. Chapter 5 describes evidence for a bifurcating energy surface in a carbocation rearrangement that leads to the diterpene abietadiene. Results presented here point to the potential role that unsymmetrical bifurcating surfaces may play in Nature as a means for controlling the selective production of complex terpene natural products. Chapter 6 describes quantum chemical calculations on the rearrangement of carbocations derived from a cyclopropane-containing analog of farnesyl diphosphate (FPP). These calculations reveal significant differences between the energetics for rearrangement of this analog and FPP itself, suggesting that the behavior of this substrate analog probably does not mirror that of the natural substrate. In addition, our results point to new mechanisms by which this FPP analog inhibits and inactivates trichodiene synthase.