Cubanes! Get Your Cubanes, Here!

A cube of med-chem cubanes**

It's not often you see drug candidates advanced with cubane substructures.* A collaborative group from the UK branch of AstraZeneca and Oxford University aims to change that: a report in Organic Letters indicates they've produced gram-scale quantities of cubane derivatives with common med-chem handles already "baked in."

Starting from a 1,4-cubane diester, Burton, Davies, and Wlochal take turns elaborating each side into thiazoles, beta-diketones, nitriles, amine salts, and ynones. Though more cautious readers might expect the cubed synthons to go up in smoke, they actually seem to survive fairly rigorous conditions - boiling water, phosphoryl and oxalyl chloride, TMS triflate, LDA.

I'd be most interested to hear from any readers who integrate these new building blocks (sorry, couldn't resist!) into their research. It's hip to be...cubic.

* On Twitter, CJ (rightly) points out that the authors could have done some DSC (stability) and solubility assays, just to put minds at ease that these synthons really could be integrated into a drug campaign.

**Not a real substance (but wouldn't that be something???)

Friday Fun: Insane in the Membrane

...CARBORANES in the Brain!*

Source: ACS Chemical Neuroscience | Sydney University 

From the pages of the (relatively new) journal ACS Chemical Neuroscience, comes this report about development of new antidepressants with rather...interesting appendages. The adamantyl (1) and Cookson's diketone (3) molecules shouldn't surprise, but the rest? You're not imagining things - those are blood-brain barrier-penetrant lead molecules based on cubane (2) and closo- and nido-carboranes (4,5). At 20 mg/kg, compounds 2 and 5 restore significant function to mice following stress tests. The authors indicate that, although the caged compounds look pretty huge, they're actually fairly isosteric (similar size) to a phenyl group, yet possess rugged metabolic stability.

*With apologies to Cypress Hill

Pyramid Power!

Atop the energy barrier between hardcore synthetic jocks and dyed-in-the-wool physical chemists lives a dedicated group: the molecular architects. A craving for perfect Platonic shapes, combined with the need to push the limits of bond and orbital theory, drive them towards projects like bullvalenes, cubane, or buckyballs. Despite the obvious challenges - bullvalenes shift and change, cubanes feel some strain - the structures' aesthetic appeal keeps us coming back for more.

Well, another class of shapely compounds seems poised to fall. Enter Pyramidanes*:

Source: JACS | Lee, Sekiguchi

Reported a few days back in JACS by a collaboration between Japanese, French, and Russian scientists, the  near-tetrahedral compounds are within shouting distance of an all-carbon version, never synthesized by human hands. I gotta say, they look pretty awesome. Just staring at it brings up so many questions: what's the hybridization of that top atom? How much strain energy? Could you make some schnazzy ligands from it? How labile is that Sn, anyway? Does this thing blow apart in TBAF?

The crew provides an in-depth discussion of frontier MO theory**, bond orders (fractional all around,
from 0.4-0.7), and NMR properties, concluding that there's a decent structural contribution from the ionic resonance form (see below).

The authors even suggest that the "cyclobutadiene" moiety - the pyramid "base" - can be stuck onto other metals; stable pyramidanes might work as strained-ring storage capsules.

Now I'm excited for the all-carbon version, which (theory predicts) has a lone pair at the apex...crazy!
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*For the absurdly technical or IUPAC-minded, the authors offer alternative names such as tetracyclo-[2.1.0.0.0] pentane, or (my favorite) [3.3.3.3]fenestrane

**N.B. I'm no p-chemist, so someone else can go through the nitty-gritty there...