Based on some discussions with my graduate students, I decided to look at bicycles containing diketopiperazinone sub-structures. As it turns out, there is not a whole lot of simple natural products with this architecture. By “simple” I imply a fairly uncomplicated connection between the alpha-carbons in the structure. This is somewhat surprising given the facility with which structures with diketopiperazinone cores are biosynthesized. Bicyclomycin is one molecule of this class that comes to mind. It was made several times in the past, with perhaps the most notable contribution coming from Bob Williams of Colorado State University. To me, the intermediacy of the bridgehead organolithium species shown below is one of the highlights of that synthesis. At that time, bicyclomycin’s mode of action was not fully established, although there were some good clues about the antibiotic nature of this natural product. It is now known that bicyclomycin inhibits the transcription termination factor Rho. There is a fairly unusual mode of noncompetitive inhibition in this case. The structure was determined by Berger and colleagues in 2005, which provided a rare view of this non-nucleotide inhibitor bound to a hexameric helicase/translocase (the yellow sphere you see is magnesium ion).
Still, given the fact that there are so many bioactive diketopiperazinones, it is interesting that nature has not come up with too many structures in which the two alpha carbons are linked by 4-5 atoms in a fairly uncomplicated way.