Wednesday, June 4, 2014

An "Ironic" Pauson-Khand

How would you go about making this compound?


Taking a casual glance, I'd offer up at least a few disconnections. An epoxide-opening cascade, starting from that alcohol in the lower left hand corner. Maybe make the oxazole last, after some funky bismuth rearrangement chemistry. Perhaps you think you could stitch together the middle with some new-wave aryne technology?

Well, the Williams group (Indiana) took a completely different tacka 9-iron

Not the reagent in question.
No, not the golf club, but di-iron nonacarbonyl. This dimeric "precatalyst" is thought to dissociate under the reaction conditions to Fe(CO)4, an unsaturated iron species that can complex to a variety of pi groups. It's been used for the Pauson-Khand for about 20 years, but the Williams group uncovered a new wrinkle last year: according to calculations, the iron might be initiating at the allene using a 3-membered metallacyclic ring! 

Very cool.  

Using these results, the Williams group mentally unzips the cyclopentane to this retrosynthetic intermediate (right). This wasn't the first thing they tried - that MOM ether on the oxazole came only after brominated versions of the heterocycle kept falling apart. Amazingly, the diiron complex ignores the alkyne, oxazole, and the MOM, choosing instead to complex to the end of the allene. Alkyne complexation, CO insertion, et voila! Cyclopentanone, coming right up (61% yield). Three more steps (deprotection, Swern, and base-promoted cyclization) produce the desired four-ring core.

The paper possesses blind alleys, full-stop restarts, theoretical underpinnings, and a good mission - anti-tuberculosis activity. Well worth reading the whole thing.


  1. Pretty impressive, given that the entire sequence (with several reiterations) was done by one pair of hands. And risky, to perform the key cyclizations so late in the sequence...

  2. i think it's not so surprising since cationic metals have been documented to bind most strongly to the most strained olefins (the olefins that have the most to gain by alleviating some strain); a preference for allene over alkyne is documented for a similar chromium tricarbonyl complex

    still a cool sequence though.