The logic of chemical synthesis

The Ginkgo biloba metabolite bilobalide is widely ingested by humans but its effect on the mammalian central nervous system is not fully understood1-4. Antagonism of γ-aminobutyric acid A receptors (GABAARs) by bilobalide has been linked to the rescue of cognitive deficits in mouse models of Down syndrome5. A lack of convulsant activity coupled with neuroprotective effects have led some to postulate an alternative, unidentified target4; however, steric congestion and the instability of bilobalide1,2,6 have prevented pull-down of biological targets other than the GABAΑRs. A concise and flexible synthesis of bilobalide would facilitate the development of probes for the identification of potential new targets, analogues with differential selectivity between insect and human GABAΑRs, and stabilized analogues with an enhanced serum half-life7. Here we exploit the unusual reactivity of bilobalide to enable a late-stage deep oxidation that symmetrizes the molecular core and enables oxidation states to be embedded in the starting materials. The same overall strategy may be applicable to G. biloba congeners, including the ginkgolides-some of which are glycine-receptor-selective antagonists8. A chemical synthesis of bilobalide should facilitate the investigation of its biological effects and its therapeutic potential.

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Concise asymmetric synthesis of (-)-bilobalide.

2,8-Dioxatricyclo[3.3.3.0 1,5 ]undecane-3,7-dione, C 9 H 10 O 4 , (I), is the dilactone acylal of cyclopentanone-2,2-diacetic acid. Both molecules in the asymmetric unit have conformational chirality and differ principally in the flexing of the carbon ring, which produces a resolvable conformational disorder in one of the molecules. Three intermolecular C-H...O close contacts exist. 7,7'-Oxybis(2,8-dioxatricyclo[3.3.3.0 1,5 ]undecan-3-one), C 18 H 22 O 7 , (II), a racemate, lies on a C 2 axis and is a non-meso furanosyl furanoside dimer derived from the monoacid monoaldehyde corresponding to (I). One intermolecular C-H...O close contact exists. Diminished intramolecular void space in these small propellanoids generates unusually high crystal density in both species, particularly (I).

Sana R. Faruqi

Papers

Two new heterocyclic [3.3.3.01,5]-propellanoid compounds: 2,8-dioxatricyclo[3.3.3.01,5]undecane-3,7-dione and a related dimer.