Total synthesis of the xyloketal natural products and alboatrin

The isolation and structural characterization of seven closely related natural products, the xyloketals, from a mangrove fungus of the Xylaria species have been reported recently by Lin and co-workers. Of these natural products, all of which incorporate identical chiral nonracemic 5,6-bicyclic acetal moieties, xyloketal A has a unique and aesthetically pleasing C3-symmetric molecular structure that was elucidated by detailed spectroscopic studies and by X-ray crystallography. Xyloketal A, B, C and D have also been shown to be potent inhibitors of acetylcholine esterase and so represent important lead compounds for the treatment of neurological diseases. In addition, xyloketal A, B and F have been shown to have L-calcium channel blocking activity. Thus, the total synthesis of these natural products, and structural analogues thereof, is of notable significance. Towards these ends, a series of novel synthetic routes to prepare these compounds were developed. The initial route, in which the key synthetic transformation involved an inverse electron demand hetero Diels-Alder reaction between appropriately substituted ortho-quinone methides and dihydrofurans, afforded (±)-, (+)- and (–)-xyloketal D. In addition, demethyl analogues of xyloketal A and D were prepared. However, the application of this synthetic route to prepare the more structurally complex xyloketals was unsuccessful. A second route, utilizing a phenylboronic acid-mediated condensation reaction as the key synthetic transformation, afforded a series of novel tris-2H-chromenes that represent structural analogues of the natural product xyloketal A. However, due to the instability of a key reaction intermediate, the total synthesis of xyloketal A was not completed by this route. A third route was also investigated that featured a boron trifluoride diethyl etherate-promoted electrophilic aromatic substitution reaction as a key step. This synthetic route was used to complete total syntheses of xyloketal A, B, D, E, F and G. Moreover, demethyl analogues of xyloketal A, B, C, D, E and G were also prepared. The application of the electrophilic aromatic substitution reaction towards the total synthesis of the structurally related and biologically active natural product alboatrin was also investigated. This led to the first asymmetric total synthesis of this natural product as well as a demethyl analogue.