Monday, July 7, 2014

A Cage-y Déjà Vu

I love finding molecular "diamonds in the rough." Especially when they look, well, a bit like diamonds.

While strolling through the literature, I did a double-take at this polycyclic caged structure reported by Santiago Vázquez  (Universitat de Barcelonaand coworkers. Wow!



Source: ACIEE 2014, Vasquez et. al.

Spawned from a "highly pyramidalized" (nonplanar) olefin dimerization, it features three cyclobutanes, four "envelope" cyclopentanes, and four cyclohexanes locked in their "boat" conformations (Even worse? All those eclipsing methyl groups on each end . . .jeepers). One might expect a thing like that to fall apart in a minute with a little heat, but, amazingly, the compound remains stable up to 500 degrees Celsius.


Model of the "highly-pyramidalized" olefin monomer.
Phil Baran used to say that you could judge the strain based
on how badly your model's bonds bent...

A little reference digging proved that similar caged olefins were first produced almost half a century ago at Smith Kline & French, using a seven-step prep reliant on chloroketals and long-duration sulfuric acid stirs (yuck). A major step forward came in 1970, when Avila and Silva (San Fernando Valley State U) realized that blasting UV light at a double-Diels Alder adduct of acetylene dicarboxylic acid led to a symmetric anhydride precursor.

Vázquez extended this little gem of a starting material towards finding active antiviral analogues of amantadine. Using the imide version of Silva's anhydride, Vázquez produced a caged secondary amine (see right) that exhibits activity against mutant versions of the H1N1 flu virus. His compound also inhibits the influenza A wild-type proton channel; molecular dynamics simulations indicate that it performs a "flip" relative to bound amantadine that plugs up this pore more effectively.

Let's just hope that these new polycycles get an easier-to-pronounce nickname. 

Octopane? Rocketane? Congestane? I'm open to suggestions!

5 comments:

  1. Reminds me of these sentinel things in "the matrix". There's something about these four methyl groups sticking out like tentacles in the back.

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  2. Interestingly enough, I expect there to be only 3 proton signals in this molecule. I work with somewhat similar structures (polycyclics) and that kind of degeneracy from high symmetry is common. At times it can be hard to see what you're looking at, but when a reacton goes wrong, often times you lose symmetry which is very visible. All in all, I think it's a good thing because it's a case of a relatively large molecule that doesn't have a messy spectrum.

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