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Three steps to potential anticancer drugs
21 May 2010
A simple three-step synthesis of a naturally occurring compound with anticancer properties has been developed by US scientists.
(+)-Frondosin B is a member of a family of compounds isolated from the marine sponge Dysidea frondosa, and displays anti-inflammatory properties that have potential for anticancer and HIV therapies. Despite the compound's relative simplicity, synthetic methods to produce it are long and complicated - up to 20 steps with low yields. The major stumbling block is controlling the configuration of the single chiral centre.
However, David MacMillan and colleagues from Princeton University have devised a route to synthesise the compound in only three steps, with a 50 per cent overall yield. Macmillan identified a key intermediate, which could be obtained from three simple building blocks, with a variant of his group's well established oxazolidinone catalyst providing the stereochemical control via an iminium ion.
Shortest ever route to the therapeutically interesting natural product frondosin B
After their initial five-step synthesis attempt, the group realised that the final three steps of their route - closing the seven-membered ring of frondosin; shuffling a double bond around the ring; and demethylating the aromatic methoxy group - were all catalysed by acid. By carefully selecting their acid (boron tribromide), they managed to get all three processes to go in a single step.
'Previous syntheses have ranged from 10-20 steps for this molecule,' says MacMillan, 'and as such, a three step synthesis allows rapid access to this structure and potentially even more interesting analogues.'
Derrick Clive, an expert in natural product synthesis at the University of Alberta, Canada, called the work 'a remarkable solution to a difficult synthetic problem - it demonstrates in a spectacular way the power of LUMO [lowest unoccupied molecular orbital]-lowering iminium catalysis and the approach has the simplicity of genius'. Macmillan's team hope to continue their work in finding ways 'to build any and all natural products in 12 steps or less'.
Link to journal article
The organocatalytic three-step total synthesis of (+)-frondosin B
Maud Reiter, Staffan Torssell, Sandra Lee and David W. C. MacMillan, Chem. Sci., 2010, 1, 37
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