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Totally Synthetic by Paul H. Docherty, 27 May 2008

Total Synthesis of Actinophyllic Acid


C. L. Martin, L. E. Overman, J. M. Rohde, J. Am. Chem. Soc. 2008, 130, 7568-7569.

DOI: 10.1021/ja803158y

Actinophyllic Acid is 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. Regarding the total synthesis, Overman has taken an unusual approach: building the key eight-membered ring via an amazing intramolecular oxidative coupling of the malonate with the enolate of the piperidone with quite a strange metal oxidant; the cited papers are here and here. However, other papers cited show that both Paquette and Baran have managed this type of chemistry with slightly less exotic reagents. Nice result!

After addition of vinyl Grignard reagent, removal of the Boc group (and saponification / mono-decarboxylation of the t-butyl esters), the basic nitrogen was reacted with formaldehyde to give the iminium ion, which immediately underwent a [3+3] cycloaddition (aza-Cope rearrangement) to give a ten-membered ring interemediate. This sequence was followed by a Mannich reaction.

Only two further steps were required to get to product in this short, but very sweet paper. A very interesting total synthesis!