Credit: © 2008 ACS

Natural product synthesis provides an ideal testing ground for any new synthetic methodology, particularly asymmetric catalysis. It is almost always possible to create a simple natural product from a compound prepared during development of the methodology, but a tougher test involves applying this to the synthesis of an entirely new natural product.

In their synthesis1 of clavirolide C, Kevin Brown and Amir Hoveyda, from Boston College, identified the opportunity to test no less than three methodologies developed in their lab. Retrosynthetic analysis of the target led to two fragments each with a single stereocentre. The first fragment required the formation of a quaternary stereocentre — known to be a tough task — and was achieved by a 1,4-addition using a copper catalyst in combination with an N-heterocyclic carbene (NHC) ligand. Hoveyda and Brown had to modify the design of their NHC ligand to achieve the desired high level of selectivity. The second fragment was also prepared using a copper-catalysed 1,4-addition, this time in combination with a chiral amino-acid-derived Schiff base–phosphine ligand.

The combination of these two fragments was achieved using an intramolecular aldol reaction. The diene produced underwent ring-closing metathesis to form an 11-membered ring — again, a challenging structure to obtain — and a reaction that required significant optimization of the conditions and catalyst. Elaboration of this intermediate to the natural product was then relatively straightforward. The synthesis has shown the utility of three methodologies — two 1,4-additions and a ring-closing metathesis — but has also provided a new problem: the intramolecular aldol reaction proceeded with low selectivity and it is on such reactions that Hoveyda and Brown will now focus their attention.