Overman, Martin and Rohde. JACS, 2008, ASAP. DOI: 10.1021/ja803158y.
Can a target scream ‘Overman’ any more?! And, yet again, his approach to this little beastie is as smart and unique as ever. But before we get into the synthesis, let’s find out if it’s go well with the morning aspirin… Turn’s out it’s ‘…an inhibitor of carboxypeptidase U (CPU)…’; this is interesting, as CPU itself inhibits the removal of fibrin clots, so one might expect actinophyllic acid to favour the fibrinolysis process. Certainly more interesting than the usual ‘cytotoxic…’.
Synthesis-wise, Overman’s taken an unusual approach too – building the key eight-membered ring via an amazing intramolecular oxidative coupling of the malonate with the enolate of the piperidone… And with quite a strange metal oxidant; the cited papers are here and here, but there’s not an abundance of detail. However, other papers cited show that both Paquette and Baran have managed this type of chemistry with slightly less exotic reagents. Nice result!
If you thought that was good… After a bit of vinyl-Grignard, removal of the Boc group (and saponification / mono-decarboxylation of the t-butyl esters) left the basic nitrogen ready for a bit of action. Formaldehyde gave the iminium ion, which immediately did the [3+3] thing to give ten-membered ring interemediate. This was then set to do the Mannich part of the aza-Copeâˆ’Mannich.
Only two further steps were required to get to product in this short, but very sweet paper. Top banana!
Martin, C.L., Overman, L.E., Rohde, J.M. (2008). Total Sythesis of (Ã‚Â±)-Actinophyllic Acid. Journal of the American Chemical Society DOI: 10.1021/ja803158y