We'll start things off with our lab's recent synthesis of ouabagenin. We'll skip the biological relevance of the molecule for the purpose of this blog and go straight to the actual synthesis.
We knew that the C19-OH and the butenolide installations would be trouble when we first walked into this project, and this suspicion was proven to be true as these 2 transformations took the longest time to achieve. As alluded in the paper, we initially tried to effect a porphyrin-catalyzed direct C19 hydroxylation, but this unfortunately didn't work in our hands. Thus, after months of experiments, we eventually settled on a Norrish type II photochemistry/oxidative fragmentation route to install this alcohol. The next few steps that followed proved to be rather straightforward.
We did not, however, expect the diepoxide fragmentation to be as difficult as it turned out to be. Shown here is a small sampling of conditions that we tried:
As you can see, the only reagent that could consistently give our desired product was aluminum amalgam, and even then we had to play around extensively with the condition to get satisfactory yield.
The last thing that I would like to highlight is the butenolide installation as this took more than 6 months to achieve (including going back and forth between our estrone model system and the real system and endless procrastination on Facebook :)). We started with our estrone model system and did a Stille coupling to arrive at the corresponding dienoate. Initial reduction screening, however, gave only the undesired epimeric product at C17, which led us to consider a different strategy. We decided to try Barluenga's hydrazone/boronic acid cross-coupling (Nature Chem. 2009, 1, 494), and while we could get it to go on the estrone model system, it just wouldn't work on the actual substrate. In the end, desperation kicked in, as I really need to graduate. To reinvent my exit, we decided to go back to the Stille coupling route (directly on the model system this time). As was observed in the model system, the penultimate reduction of the dienoate proved to be difficult, but we were fortunate to find the right condition—specifically by heating with Barton's base—that eventually delivered synthetic ouabagenin.