We all know that because of the difference in ground states, diastereoselectivity is inherently more complicated that enantioselectivity. Of course, there are reagent- and catalyst-controlled reactions that override the ground state effects, but they are still largely underdeveloped. In efforts to rationalize and predict reaction outcomes, we are left with various devices that help us build models. When it comes to relative stereochemistry and diastereoselection, organic chemists are the creatures of habit who are trained to recognize conformations and factors that control them. Things such as the Felkin-Ahn model are ingrained in our understanding of reactivity. It makes it ever more amusing when we see exceptions to the rules we are used to, particularly when an example with some ridiculously high level of selectivity comes up. While in France, I heard a great talk by Dr. Kai Rossen from Sanofi-Aventis, detailing the painstaking efforts on behalf of his company to bring artemisinin to market. There are many insightful lessons in the chemistry of this important antimalarial agent. Those of you who know its structure, might think that any attempt to scale up the synthesis of this peroxide is akin to an attempted suicide. Yet, there is a special plant in Italy that handles artemisinin production on a multi-kilogram scale for Sanofi-Aventis. But this will be the subject of a separate post in the future… Today I want to talk about diastereoselectivity. There is one particular step in the synthesis of artemisinin that has some serious “wow” factor attached to it. I refer to the hydrogenation shown below (I drew this based on the data in the paper). This example comes back to my original point about the inherent bias one might expect in a diastereoselective process. It is simply NOT possible to explain the amazing selectivity you see by doodling out some routine rotamers. No way. They are very similar in energy. Instead, the factor that operates in this case appears to be weak non-covalent interactions between the carboxylate group and the olefinic CH bonds of the artemisinate’s cis-decalene system in the transition state. I think I am developing a growing appreciation of weak interactions…
amphoteros 