I haven’t had to think about looking for 7-membered ring construction for some time. And if it doesn’t have a nitrogen I look the other way, lol! So you can imagine looking for a microwave method seems even a bit out there for it. Let me assure you — it is. Unlike 5/6-membered rings, these systems sometimes avoid the traditional intramolecular attack we like to think about and careful considerations of different processes come into play.

I’m going to point you in the direction of a moderately recent paper from a guy I have followed at Conn College (a local guy) during my years at Bayer. Timo Ovaska comes up with some pretty creative research projects so i always like to see what they are doing. So Timo’s paper is on the construction of 7-membered rings through a microwave assisted tandem oxoanionic 5-exo dig cyclization-claisen rearrangement — wow, better not have a drink before that one. He does go after some difficult stuff.

Like most total synthesis projects — we here about how the structures are difficult to make and are found in many natural products of interest and should be of interest to medicinal chemists — sounds like a sports interview, right? However in this case, there are many concepts that need to be kept in check so that the methodology works — both useful synthetically but also important for our strategic thought. Below I show the basic [3,3] claisen followed by their approach to fused systems containing a 7-membered ring.

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3,3-claisen for fused 7-membered rings

Their strategy to 5/7  hydroazulenone carbon rings systems used a microwave method step with very high diastereocontrol ([3.2.0] system for the purists in the audience). While I get the polar process in a non-polar medium is a long established belief — this is something I would want to find an alternative for — 210 in phenetole, ouch….for 45 minutes. In their hands, this was considered a good process so what do I know — maybe the MeLi and ionic mechanism was good enough to get to that temp in a microwave, but I think it probably needed help. Although not their problem, this is something that screams DOE with reaction screening – because the process chemists in the back are snickering again. So we know we need high temp and maybe a non-polar environment. Everyone put on your hats and let’s go to the white board. I would like to have seen a conventional reaction to see what parameters I would try — sometimes it is too easy to jump into a microwave without this discussion first — did I say that out loud? lol!

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Selective anionic cyclization 3,3 claisen catalytic MeLi
mw 210C with high boiling ether

Looking closer into this paper the huge step forward is in the alpha-arylation of the fused system — very difficult to do once you have the fused system in place — or even with a 7-membered ring for that matter. Take a look through the work to get an appreciation for the strategy and the microwave step.

 

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