Total Synthesis of Linoxepin

Key words

linoxepin - Catellani reaction - domino reaction - palladium catalysis - C–H functionalization

Significance

Lautens and co-workers report the synthesis of linoxepin, a lignin isolated from Linum perennne L. (Linaceae). The elegant strategy relies on the Catellani reaction, in which a strained olefin (norbornene) is used to couple an iodoarene, an alkyl halide, and a terminal olefin using palladium catalysis. This is the first application of the Catellani reaction in the synthesis of a natural product and underscores the power of processes that form multiple bonds in a single step. In this context, it is worth highlighting the recent synthesis of linoxepin by Tietze and co-workers (Angew. Chem. Int. Ed. 2013, 52, 3191), which relies on a different palladium-catalyzed domino reaction.

Comment

Alkylation of phenol A with benzyl iodide B gave Catellani precursor C in 94% yield. The norbornene-mediated domino process involving aryl iodide C, enantiopure alkyl iodide D and acrylate E delivered key intermediate F in 89% yield. Oxidative cleavage of the olefin followed by TiCl₄-promoted aldol condensation furnished G, which in the presence of catalytic amounts of a palladium catalyst underwent a Mizoroki–Heck reaction to give (+)-linoxepin in 76% yield.