DIAL-A-TERPENE: NEW CHEMICAL PROTOCOLS ALLOWING FOR THE ITERATIVE SYNTHESIS OF TERPENOIDS

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Terpenoids, comprised of 'head-to-tail' and 'head-to-head' arrangements of five-carbon atom containing (C5) units, are a very large and diverse class of linear and (poly)cyclic natural occuring biomolecules and account for 60% of known natural products (estimated as more than 40 000 distinct chemical structures). Their vital biological functions include lipid membrane modulation, light harvesting and photooxidative protection, electron transport, intercellular signaling as hormones, and interspecies defence amongst others. Their medicinal benefits have been recognised for centuries, initially as traditional herbal remedies from plants, and subsequent development of e.g., steroidal medicines as blockbuster drugs in the 20th century through to the present day (budesonide was the number 1 prescribed drug of 2013). It is well understood that the (poly)cyclic terpenoids all arise from linear (C5)n precursors, and nature constructs the linear precusors by sequential addition of activated C5 phosphate-containing units. These linear terpenoids are important in their own right, being constituents of nearly every living cell, and play vital roles in peptide modification. A very great deal of chemical, biochemical and biological research has been directed towards the understanding of all of the above, and scientific database searches at the time of writing on "terpen*" (as a catch-all for terpene and terpenoid) reveals > 94 000 manuscripts have been published in this area. However, despite the long-term recognition that these linear compounds are essentially C5-repeating units, a general and iterative chemical protocol for their synthesis - using naturally occuring terpenoid building blocks - does not exist. This is in stark contrast to the state of affairs for synthesis of the other main classes of biologically important compounds (peptides, RNA and oligosaccharides) where use of of solid-phase synthesis, iterative coupling protocols and automated methods has revolutionised these research areas. It is thefore the aim of this proposal to develop such chemical protocols for terpenoids.