Homologing reactions

Tonight I want to talk about reaction homologs. This is one of those enduring ideas in chemistry, representing what is consistently coming to the minds of those who are interested in developing new reactions. “Homologing” is when you have a process that gives a product that differs from its established predecessor by formal insertion of a one-carbon unit somewhere in the framework. For instance, in the case of a Diels-Alder reaction, a version that results in a seven-membered ring would be a homolog. Paul Wender did some really nice work in this regard, resorting to vinyl cyclopropanes in place of dienes. In the case of a pericyclic process, there is just no way that the homolog formation proceeds by the same mechanism as its “origin”. It just can’t happen. However, polar reactions are not that stringent and one-carbon “insertions” are often tolerated. The caveat is that those are almost obvious and not that interesting.

I have always been attracted to interesting workaround solutions to homologing reactions that proceed via polar mechanisms. I do not see too many of them these days, but there are many examples that were developed in the past. Below is an example of a homo-Robinson annulation. The venerable Robinson annulation to make fused rings is the permanent fixture in advanced undergraduate classes, but what if you want to form a seven-membered ring instead? About a decade ago, Sam Danishefsky developed a really nice way to carry out this transformation. Below is the way it works. The reaction served Sam well in the synthesis of guanacastepene.