Strain in dienophiles

I have been on a lookout for the use of the parent cyclobutenone, which was popularized by Danishefsky not too long ago (http://pubs.acs.org/doi/abs/10.1021/ja1056888). This molecule is one of those “functionality-dense”, yet simple entities that beg the following question: “Why wasn’t it discovered and put to good use earlier?” As it turns out, no one thought much about the parent cyclobutenone prior to 2010, which serves as a reminder that some of the simplest things have not been done. It continues to baffle me that chemists are generally quite good in thinking about complex problems, yet overlook (or look down upon?) the ones that are simple. Worse yet, one of the most dangerous mind traps is the idea that complex problems require complex solutions. Nothing can be further from the truth… But this will be a special topic in the future. Coming back to simple, yet amazingly versatile molecules such as cyclobutenone, I enjoyed seeing its application in one of Jeff Aube’s recent works. As part of an approach towards alkaloid-like molecules, this paper documents the use of cyclobutenone in the following sequence.

exp

The last step is non-trivial. I agree with the authors that this previously unknown process is most likely a retro-Michael reaction from the oxonium intermediate shown. While there might be other explanations, this rearrangement is really nifty.

http://www.nature.com/nchem/journal/v6/n2/full/nchem.1844.html

 

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