Giving Up Benzyne

From Rolf Huisgen's highly detailed and comprehensive biography The Adventure Playground of Mechanisms and Novel Reactions comes this rather eyebrow-lifting passage:

"I had several reasons for abandoning benzyne chemistry at the beginning of the 1960s. Many groups were active in the field, and other areas like 1,3-dipolar cycloaddition began to blossom in Munich. In addition, Georg Wittig, my venerated senior colleague, signaled in print and word that he regarded dehydrobenzene as his domain."

Left, benzyne, in one of its (many) accepted resonance forms
Right: Emeritus professor Rolf Huisgen, of dipolar cycloaddition fame

I wonder: Given the advances in benzyne chemistry over the past 112 years, and that up-and-coming groups make its study a central piece of their research portfolios, would this choice be made in today's research landscape? Readers, have you ever been asked to cease your studies in a certain area because someone more prestigious laid claim?

An "Ironic" Pauson-Khand

How would you go about making this compound?

(+)-ileabethoxazole

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 tack: a 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.