Totally Synthetic by Paul H. Docherty, 8 October 2007
Total Synthesis of Pasteurestin A
M. Kögl, L. Brecker, R. Warras, J. Mulzer, Angew. Chem. Int. Ed. 2007, 46, 9320-9322.
A second paper in Angewandte from the Mulzer lab in a few weeks, this synthesis shares a little with the previous post on Platensimycin. Both natural products contain tightly functionalised polycyclic systems, and both are potent antibiotics. However Pasteurestin A&B are only active against bovine illness. This synthetic work consists of the first synthesis and also confirmation of assignment, so let's get into the chemistry.
The chemistry really gets going with an auxiliary controlled Reformatsky addition, using an unsaturated aldehyde. This tin-mediated process gave them an interesting result, in that the stereochemistry of the hydroxyl was (S-), not (R-) as in the aldol reaction with this system. They presumed that this must be due to the low temperature at which they ran the reaction, so they repeated it at RT, and found that the product rearranged before they could isolate it.
A few simple synthetic transformations then gave them the starting materials for the interesting Vollhardt [2+2+2] cycloaddition, which went in moderate yield to form three rings in one reaction. Very efficient! The next step was interesting too, but for different reasons… the selectivity here is impressive, maybe based on delivery of one electron to give the allyl anion, which is then protonated to give the most stable alkene.
The next few transformations are far more easily understood, and complete Pasteurestin B in a synthetically pleasing manner. Hydroboration of the remaining alkene and oxidation gave the ketone shown, which was selectively deprotonated, trapped with carbon dioxide and methylated to give the methyl ester. This was then deprotonated again, selenated and the selenide eliminated to give the desired enone.
Deprotection then gave Pasteurestin B in what was admittedly a rather linear route, but they were able to use a similar approach to get Pasteurestin A, showing the flexibility of the chemistry. Neat work.