Diversity Oriented Synthesis of Farnesyl Pyrophosphate Analogues as Mechanistic Probes and as Precursors to Modified Natural Products

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Sesquiterpenes are an important class of natural products that exhibit a wide variety of structural variation and biological function with applications ranging from uses as scents and oils to agrochemicals and pharmaceuticals. In contrast to this diversity they are, however, metabolites originating from a single parent compound, farnesyl pyrophospate (FPP). This incredible array of products is generated from FPP by a single class of enzyme, sesquiterpene cyclases, all of which share a common 3D structure. To understand how this stunning diversity of products is formed from one compound with such remarkable fidelity is a major challenge for modern chemical biology. Each sesquiterpene cyclase enzyme must guide neutral or carbocationic intermediates through a series of specific steps whilst preventing reaction with solvent and rearrangement to undesired by-products of very similar energy and conformation.In order to examine and solve this problem we intend to synthesise a series of FPP analogue compounds and challenge sesquiterpene cyclase enzymes with them. The synthesis of these compounds is designed in such a way that a combinatorial approach may be used in the future in order to prepare diverse libraries of these materials. In this study the compounds are designed to test the proposed mechanisms by which sesquiterpene cyclases guide FPP and intermediate materials to the sesquiterpene products. The proposed compounds bear functional groups that are designed to either stabilise or destabilise carbocationic intermediates that have been predicted to form during the formation of sesquiterpene hydrocarbons. They should therefore give predictable products when tested with our range of sesquiterpene cyclase enzymes if the proposed mechanisms of action are true. If this does not prove to be the case then they will give us information allowing us to propose mechanisms that fit all the observed experimental data. FPP analogues that prove to be substrates for these enzymes will inevitably produce sesquiterpenoid materials of novel structure and function. This will expand the range of biologically active compounds that are available to us and moreover, these compounds, which often have complex structures will have been prepared without tedious and expensive total synthesis.