What about simple amino acid-based bicycles?

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.




4 thoughts on “What about simple amino acid-based bicycles?

  1. I faintly remember seeing some fairly potent marine-derived diketopiperazine antibiotics linked by polysulfide through alpha carbons, and it can be synthesized by deprotonation with a strong base like LDA followed by quench with S8

  2. Yes indeed, this is correct and is something Mo Movassaghi has been working on. But I was referring to substantially more mundane natural products that are not only small but contain bridges that are mainly carbon-based… Movassaghi gave a great talk here several weeks ago…

  3. I think this is one of the best applications of bridgehead enolates in complex molecule synthesis (recently there were some more work on bridgehead enolate chemistry from Prof. Simpkins also).
    I noticed a mistake in the structure of bicyclomycin – a hydroxy group is missing at the second bridgehead position. Also, the first deprotonation takes place not at the shown position but at the bridgehead position adjacent to the exo-double bond.

    • Oh wait – you are right – I used the “non-OH” model system for the post, but you are correct about the natural product structure. In fact the second deprotonation would be at the OH. Cheers, Andrei

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