Phil Baran upon learning about electrochemistry
UPDATE: Our paper was highlighted on Deadspin!
UPDATE 2: Support from the San Diego Chargers!
Our paper on the total synthesis of dixiamycin B is now live in the JACS ASAP section, which means it's my turn to write a blog post. When we initiated this project, we had no idea we'd turn to electrochemistry; we just thought making the N–N bond would be interesting. In fact, I remember it like it was yesterday...
UPDATE 2: Support from the San Diego Chargers!
Our paper on the total synthesis of dixiamycin B is now live in the JACS ASAP section, which means it's my turn to write a blog post. When we initiated this project, we had no idea we'd turn to electrochemistry; we just thought making the N–N bond would be interesting. In fact, I remember it like it was yesterday...
[Professor enters from stage left]
Professor: How would you make this?!
Student: Probably from hydrazine.
Professor: That's not interesting!
[Professor exits stage left]
With this retrosynthesis in mind, we set out to discover the magic [#interesting] reagent. This work was carried out with a post-doc in my group, Erik Werner. We spent a long time trying to oxidize carbazole and carboline to forge the N–N bond; the best we could do was an inconsistent crappy yield from a crappy purple reaction (potassium permanganate). But then...
[Professor enters from stage left]
Professor: Have you thought about using elecrochemistry?
[Professor exits stage left]
Student: Well... I guess we should look into that.
And thus, our heroes ventured into the unknown depths of the electrochemical literature, only to find exactly what they were looking for. Unfortunately, that paper lacked several important attributes, like explorations on functional group tolerance (obviously important if we wanted a free alcohol or carboxylic acid), different substitution patterns or heteroatoms, or coherent structure. Fortunately for us, some optimization and a little bit of imagination got us to a point where we felt like we were making interesting molecules in reasonable yields. I'm not going to put up the substrate scope, because you can go look at the paper, but I do think the crystal structure of the carbazole dimer is pretty cool, especially for something so small.
[Professor enters from stage left]
Professor: Welcome to the dark side!
[Professor exits state left]
Student: One day I will understand that man.
Post-doc: No, you will never understand him.
This left us with the daunting task of dimerizing xiamycin A to make dixiamycin, which in turn left us with the considerably less daunting task of preparing xiamycin A. We turned to the time-tested cation-olefin cyclization to prepare the core, and a few oxidations and protecting group manipulations gave us xiamycin A, and using that sequence we could easily make more than a gram of xiamycin A. It took us a few tries, but after a little bit more optimization (mostly in workup and purification), we were able to reproducibly fish out dixiamycin B in about 30% yield along with bromoxiamycin in about 20% yield. For some reason that escapes me, the other atropisomer (dixiamycin A), is nowhere to be seen in the crude mixture. We do, however, see other N–C-linked dimers, but their isolation and purification from one another is quite challenging.
So that's that. We finished some natural products, and we used electrochemistry. I welcome discussion, questions, and criticisms in the comments section, and I leave you with visual representations of the rest of team dixiamycin.
why did you use Bu4N Br as the electrolyte at the potentials you employed? oxidation of Br- to form Br2 becomes an issue. also did you consider protecting the acid and forming the amide to favor the radical at the nitrogen?
ReplyDeleteIn general, our reactions employed either tetraethylammonium bromide or tetraethylammonium perchlorate as electrolytes, as these were the electrolytes that worked the best. You can see in our key step that bromination does in fact occur, but generally it was a non-issue. We only thought about protecting the carboxylic acid if the key step did not work - part of what made this exciting to us was that we were able to effect the dimerization on the completely unprotected monomer (xiamycin A) in a somewhat biomimetic sense.
DeletePaper I read, yes. Questions I will now ask, hmm?
ReplyDelete1. Where do you suppose the N-C linked dimers, well...link? At the site of Br add'n, or elsewhere?
2. I know it's pronounced "DI-zhiamycin" or something, but couldn't you just humour me and call it "DIXIE-amycin?"
I'm glad you read it! We saw multiple N–C dimers, including at the site of Br addition, and at the position "para" to the nitrogen. We didn't have trouble seeing diagnostic peaks in crude NMR spectra, but separating some of those regioisomers was very challenging. It would also be reasonable to suspect that some of the remaining mass balance was C–C dimers, but I don't have good hard evidence to back that up right now.
DeleteAround the lab, we sometimes call it "DIXIE-amycin", but in moments of rage we call it something less suitable for the viewers of this blog!
Dixamycin, penisporolide, dictazole, dictyodendrin. You get the idea.
DeleteGiven the professor in context, the more appropriate caption would be "professor CHARGES from stage left" :)
ReplyDeleteit reminds me of: "Dr. Van Helsing rushed into the room, ejaculating furiously", from Bram Stoker's Dracula (1897)
ReplyDeleteWell there's an image of Big Phil that will stay with me for a while.
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