Studies towards Phomactin

 

One of My Postdoc Projects

Phomactin APhomactin A, isolated from the marine fungus Phoma sp by Sugano and coworkers in 1991, is a selective inhibitor of platelet-activating factor (PAF). PAF has been associated with inflammatory, respiratory and cardiovascular diseases, and hence, Phomactins might offer an interesting drug template. Phomactin A contains a highly functionalized oxadecalin core which contains six stereocenters, including a quaternary carbon stereocenter and a tertiary ether. An additional tether engages one of the quaternary carbons and the tertiary ether in a 12-membered macrocycle. The challenging structure of Phomactin A and its potential pharmacological use makes it a fundamentally exciting total synthesis target.

Phomactin AWe have investigated ways to efficiently assemble the oxadecaline core of phomactin A, using Diels-Alder cycloadditions as key reaction (of course). Previously, Chemler and Danishefsky have published model studies, which revealed that an intramolecular B-alkyl Suzuki reaction is suitable to close the tether.

Several other research groups have been working in the Phomactin arena, among them the labs of Pattenden, Totah, Maleczka, Halcomb and Leighton. Each of these groups have established their individual “signature approach”, so completion of an “academic” synthesis has to remain focused on reducing to practice the initially laid-out route. Both Pattenden and Halcomb have recently completed their syntheses of Phomactin A, while everyone else is still in the running. Let’s see who finishes next.

Publications

S. R. Chemler, U. Iserloh and S. J. Danishefsky, Enantioselective Synthesis of the Oxadecalin Core of Phomactin A via a Highly Stereoselective Diels-Alder Reaction, Org. Lett 2001, 3, 2949-2951. Download PDF.

Additional Reading