Details of Grant 

EPSRC Reference:	EP/C542169/1
Title:	Biosynthetically-Inspired Synthesis of Marine Natural Products: The Obtusallenes
Principal Investigator:	Braddock, Professor DC
Other Investigators:
Researcher Co-Investigators:
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Department:	Chemistry
Organisation:	Imperial College London
Scheme:	Standard Research (Pre-FEC)
Starts:	03 October 2005	Ends:	02 October 2007	Value (£):	147,814
EPSRC Research Topic Classifications:	Biological & Medicinal Chem. Chemical Synthetic Methodology
EPSRC Industrial Sector Classifications:	Chemicals Pharmaceuticals and Biotechnology
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Panel History:
Summary on Grant Application Form
The myriad aquatic organisms of planet earth's oceans are a rich source of diverse novel chemical structures. Many of these compounds show structural motifs (i.e. particular arrangements of atoms) that have never previously been seen before, and often have potent biological properties that make them excellent candidates for the design of new drugs to combat cancer and other diseases threatening to human health. Over the past twenty years, different researchers around the world have isolated and identified a series of new compounds with common chemical characteristics from seaweeds and red algae of the species Laurencia. Other structurally similar compounds have been isolated from the digestive tracts of sea slugs that feed on these algae, bringing the total number of these particular compounds isolated to ten. On the basis of the isolation of the first compound from a red algae of Laurencia obtusa, and the common bromoallene structural sub-unit in their structures, this family of compounds has been named the Obtusallenes. Because of their manner of isolation from rarely occurring and limited supplies of the marine organisms, these compounds have only been isolated in microgram quantities - rendering extensive studies o these compounds impossible. One solution to the lack of availability of these compounds is to instead make them via chemical synthesis. To date, however, no syntheses of partial syntheses of these compounds have been reported.The Obtusallenes are particularly structurally interesting, because they consist of a double ring structure where the small ring (consisting of five atoms) is incorporated into a larger ring - technically termed a macrocycle - consisting of twelve contiguous atoms; they also contain bromine atoms and an extremely rare bromoallene sub-unit. Of particular interest is how the Obtusallenes are manufactured - biosynthesised - by the organisms themselves. To date, no such bisoynthesis has been proposed for the Obtusallenes and no chemical synthesis has been attempted. In this proposal we identify a self-consistent biosynthetic pathway that interrelates all the Obtusallenes. This predicts that some of the Obtusallenes isolated from natural sources have had their structures incorrectly assigned in the literature. It also predicts that the macrocyclic ring is formed by a ring-closing event controlled by several subtle factors called the gauche effect and 1,3-allylic strain to deliver both the macrocycle and the bromoallene in an aesthetically pleasing single step. Crucial to this proposal, is the recognition that species of the family Laurencia contain an enyme that is capable of converting bromide (negative charged bromine atoms) ions from sea-water into highly reactive positively charged bromine atoms. We propose that it is these positively charged bromine ions that drive the biosynthesis of the ObtusallenesIn this proposal we intend to synthesise the Obtusallene family of natural products by a biosynthetically-inspired route. Using chemically available sources of positively charged bromine we intend to produce compounds - termed substrates - that will undergo the desired positively charged bromine mediated macrocyclisation to produce the macrocyclic ring. Model substrates have already been synthesised and exposed to the positively charged bromine to give the predicted bromoallene subunit and thereby confirm the validity of this idea. Subsequent to formation of the macrocycle, chemically available sources of positive bromine will be further used to drive the rearrangement to the other members of the Obtusallene family by consideration of the biosynthetic pathways proposed. This will enable us to confirm or correct the published structures of the entire Obtusallene family and firmly elucidate the biosynthetic pathway.
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