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.

ppp

http://pubs.acs.org/doi/abs/10.1021/ja00331a066

http://www.sciencedirect.com/science/article/pii/S0969212604003879

Making useful contacts

An opportunity to meet people who have made important contributions to science is one of the most rewarding parts of attending a conference, particularly if you are a student. I was glad that my PhD student Sean Liew has been at the MCR conference in Brazil along with me. Sean’s yet to be published total synthesis of one of the ceramide natural products is based on his keen interest in pushing the frontiers of amphoteric reactivity. In his work, Sean has used the Petasis borono-Mannich reaction and, as luck would have it, had a chance to meet the man himself. Below is a photo of Sean together with Professor Nicos Petasis of the USC, which was taken right about time when we were all heading out to a nearby churrasqueira (a Brazilian barbeque). Giving a talk in the same morning session with Nicos was a real treat for Sean, something he will treasure for a long time. One of these days I will ask Sean to explain the key steps of his synthesis on this blog (his talk went great).

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Speaking of the latest trends in that remarkable boronic acid-based process developed by Nicos and his students, here is their neat paper published a couple of weeks ago in Organic Letters. Try to figure out the origin of the difference between the two products before you click on that link. It is an interesting story. I have always been amazed by how many surprises await those who continue to stick to an area of inquiry for many years. The Petasis reaction has led to a treasure trove of discoveries and the paper below demonstrates that one more time. Finally, I really want to thank Professor Carlos Kleber for organizing this event and bringing us all to Brazil.

33

http://pubs.acs.org/doi/full/10.1021/acs.orglett.5b00024

Do it your way

I am in Brasilia, the capital of Brazil, where I am attending the 6th International Conference on Multicomponent Reactions (http://www.mcr2015.unb.br). I have learned a lot of interesting things today and, while I could discuss something that is “hot off the press”, I am going to instead comment on something that is old, yet not well known.

2

https://www.jstage.jst.go.jp/article/bcsj1926/59/1/59_1_179/_article

Take a look at the triazole synthesis shown above. I learned about this reaction from the talk of Professor Bernie Westermann, who shared with us his latest results in the area of biological probe design. This 1986 route to triazoles reported by Sakai is not particularly high-yielding, yet it allows me to relate to a discussion I had with my graduate students several weeks ago. Here is the irony: once some reactions reach a certain level of stardom, they lose their educational value. I refer to azide-alkyne cycloaddition, olefin metathesis, Suzuki reaction, etc. Whenever we have a group meeting where my students try to work on a synthetic problem set, I try to emphatically prohibit them from doing the obvious. In other words, if you see a cyclic alkene – do not make it using metathesis, if you see a triazole – forget that azides exist, and so on. Think about something else.

The example above has been chosen to emphasize that there are alternative ways of looking at the stomping grounds of contemporary synthesis. As a corollary to that, I suppose that it is possible for a reaction to fall victim to its own success. This is the way I see it, at least when it comes to advanced chemistry education when we expect our students to display original thinking. Sakai’s case is also curious as it provides a product with a chain of four nitrogen atoms. It is not clear what to do with the N-Ts “overhang”, but I think this chemistry is really nice.