Concise asymmetric synthesis of (−)-bilobalide

Abstract

The Ginkgo biloba metabolite bilobalide is widely ingested by humans but its effect on the mammalian central nervous system is not fully understood 1,2,3,4. Antagonism of gammaaminobutyric acid A receptors (GABA A Rs) by bilobalide has been tied to rescue of cognitive deficits in mouse models of Down syndrome 5. A lack of convulsant activity coupled with these neuroprotective effects have led some to postulate an alternative, unidentified target. 4 However, steric congestion and the instability of 1 1,2,6 have prevented pulldown of biological targets other than the GABA A Rs. A concise and flexible synthesis of 1 would provide a platform to generate probes for identification of potential new targets; analogs with differential selectivity between insect and human GABA A Rs; and stabilized analogs with enhanced serum half-life 7. Here we exploit the unusual reactivity of bilobalide to affect a late-stage oxidation that symmetrizes the molecular core and allows oxidation states to be embedded in the starting material. The same overall strategy disclosed here may be applicable to G. biloba congeners including the ginkgolides, some of which are glycine receptor (GlyR)-selective antagonists 8. The therapeutic potential of bilobalide and its incompletely understood effects can now be interrogated through chemical synthesis.

Fe‐Catalyzed Anaerobic Mukaiyama‐Type Hydration of Alkenes using Nitroarenes

“…The hydration of alkenes in the presence of a transition metal catalyst, oxygen and a reductant has been intensively investigated in the past with the first studies being published already in the 1980s (Scheme 1 a). [2–14] In these cascades, mainly first row transition metals (Fe/Co/Mn) have been applied [15] . Moreover, O 2 is generally used as the C‐radical oxygenation reagent in a reaction that proceeds either near the diffusion limit or diffusion‐controlled and accordingly is difficult to run with high stereoselectivity in non‐rigid systems [16–18] .…”

Fungal Endophytes as Efficient Sources of Plant-Derived Bioactive Compounds and Their Prospective Applications in Natural Product Drug Discovery: Insights, Avenues, and Challenges

“…Widely consumed bilobalide (sesquiterpene) has neuroprotective, anti-inflammatory, and analgesic potential and inhibits the diffuse pneumonia caused by Pneumocystis carinii [ 303 , 304 ]. Bilobalide has recently been found to be an antagonistic allosteric modulator of the γ-aminobutyric acid A receptors (GABA A Rs), linking its role in improving cognitive and memory functioning domain in impaired persons [ 305 ]. Recently, Pestalotiopsis uvicola , a foliar endophyte of G. biloba , has been reported to produce bilobalide [ 219 ].…”

Fe‐Catalyzed Anaerobic Mukaiyama‐Type Hydration of Alkenes using Nitroarenes

“…[1] The hydration of alkenes in the presence of at ransition metal catalyst, oxygen and ar eductant has been intensively investigated in the past with the first studies being published already in the 1980s (Scheme 1a). [2][3][4][5][6][7][8][9][10][11][12][13][14] In these cascades, mainly first row transition metals (Fe/Co/Mn) have been applied. [15] Moreover,O 2 is generally used as the C-radical oxygenation reagent in ar eaction that proceeds either near the diffusion limit or diffusion-controlled and accordingly is difficult to run with high stereoselectivity in non-rigid systems.…”