posted on 2019-09-05, 22:13authored byXirui Hu, Andrew J. Musacchio, Xingyu Shen, Yujia Tao, Thomas J. Maimone
With hundreds of
unique members isolated to date, guaianolide lactones
represent a particularly prolific class of terpene natural products.
Given their extensive documented therapeutic properties and fascinating
chemical structures, these metabolites have captivated the synthetic
chemistry community for many decades. As a result of divergent biosynthetic
pathways, which produce a wide array of stereochemical and oxidative
permutations, a unifying synthetic pathway to this broad family of
natural products is challenging. Herein we document the evolution
of a chiral-pool-based synthetic program aimed at accessing an assortment
of guaianolides, particularly those from the plant family Apiaceae
as well as Asteraceae, members of which possess distinct chemical
substructures and necessitate deviating synthetic platforms. An initial
route employing the linear monoterpene linalool generated a lower
oxidation state guaianolide but was not compatible with the majority
of family members. A double-allylation disconnection using a carvone-derived
fragment was then developed to access first an Asteraceae-type guaianolide
and then various Apiaceae congeners. Finally, using these findings
in conjunction with a tandem polyoxygenation cascade, we developed
a pathway to highly oxygenated nortrilobolide. A variety of interesting
observations in metal-mediated aldehyde allylation and alkene polyoxygenation
are reported and discussed.