Around 100 tons of the potent antimalarial artemisinin is produced annually; a remarkable quantity given its very unusual and fragile looking molecular structure (below). When I looked at this, I was immediately struck by a thought: surely this is a classic molecule for analyzing stereoelectronic effects (anomeric and gauche). Here this aspect is explored.
I start by listing the bonds around which interesting things might happen:
The crystal structure is shown below, annotated with pertinent bond lengths (trivial atom numbering). The dihedral 2-3-4-6 and 2-3-4-6 are respectively -51 and 72° (hence a double gauche at the 3-4 bond).
First, an exploration of what might be happening around C4. The following is a search of the Cambridge crystal structure database, plotted for the two C-O bond lengths common to C4.
Where such stereoelectronic interactions are asymmetric, one might expect enhanced reactivity. A good example of this are two stereoisomeric of a 7-ring herbicide[1] where one anomer with equal anomeric C-O lengths is a stable soil-persistent species, whereas the other with asymmetric lengths has a very short soil residency due to rapid hydrolysis. It might be tempting to speculate that some aspect of the activity of artemisinin may be due to such stereoelectronic asymmetries.
Finally, because it is virtually free to do so in a computational sense, I show the computed VCD spectrum[2] (covering the possibility that it is measured at some point). The calculated[3] optical rotation ([α]589 is +93° (obs ~+76°). Whilst the absolute configuration is not in any doubt, it is always nice to have further confirmations.
This post has DOI: 10.14469/hpc/12766
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