https://www.science.org/content/blog-post/i-hadn-t-bet-diazos
I’ve written a number of posts here about weird natural products (and another such roundup is in the works), but I couldn’t resist highlighting this paper. The compounds discussed (which have been found to be produced in bacteria, specifically one human-pathogenic species, Nocardia ninae) are not huge and bewilderingly complex. Natural products have plenty of those kinds of structures, but these are very small molecules indeed. They’re just really unlikely ones.
That’s because they’re diazo compounds - yep, like good ol’ diazomethane, the methyl-ester-seeking-chemist’s friend. The diazo group (as you can see at left) is a funny beast. It has one nitrogen with a formal positive charge and another atom with a formal negative charge, so net neutral. You can put the negative charge either on the terminal carbon or the terminal nitrogen, but the truth is kind of in between. It also really looks like something that could find it in its heart to change to plain old dinitrogen gas. And so it does! Unless stabilized by adjacent functional groups, diazo compounds are known to be reactive and touchy, properties that are most on display with the smaller members of the series.
You don’t get much smaller than diazomethane, and that one is famous for reacting with carboxylic acids to more-or-less instantly form the corresponding methyl ester (and bubbles of nitrogen gas, if you’re working on a large enough scale, and if you are I would consider your life choices carefully). It does a lot of other interesting reactions, but you will always want to have it in dilute solution when you’re trying those, because it is sensitive to friction, heat, strong light, acid, and all sorts of other things, and it will most definitely explode if you push your luck.
It will also poison you without exploding, and this is something that not enough people realize. That’s even more true for the more shelf-stable version (trimethylsilyldiazomethane) because that stability (and the commercial availability of solutions of it) have lead some to thing that it has correspondingly lower toxicity. This is not the case, and there have been fatalities to illustrate it.
Here, the authors demonstrate that this species of bacteria (and likely many others besides) can produce this functional group through the actions of a cluster of enzymes. You start from lysine, and a series of steps goes through a hydroxylamine, disubstituted hydrazine, hydrazone, and then diazo. The authors have recapitulated these steps with isolated enzymes and shown that they occur as a gene cluster as well. The weirdest one (Dob3) is at that final step, and it has an unusual di-iron catalytic center that seems to accept a variety of hydrazone substrates.
By trapping with a cyclooctyne, the paper demonstrates that both 4-diazo-3-oxobutanoic acid and diazoacetone are produced by the bacteria. These would be unlikely to be detected directly in most analytical protocols due to the low amounts and the overall sensitivity of the diazos (see above). Now, just why the organisms are producing these things remains an open question. They are certainly unusual reactive species and might be used in further biosynthetic pathways, or they might deter other bacteria from getting too close and messing around. Maybe both! What’s for sure is that considerable metabolic effort goes into making them, so there must be some reasons that have worked out evolutionarily. We shall see.
So any of you who had diazoacetone on your list of Likely Natural Products, stop by the customer service desk and collect your winnings. The rest of us will be over here shaking our heads and wondering what’s next. . .
https://www.science.org/content/blog-post/i-hadn-t-bet-diazos