Total Synthesis of the Allenic Macrolide (+)-Archangiumide.

Archangiumide is the first known macrolide natural product comprising an endocyclic allene. For the ring strain that this linear substructure might entail, it was planned to unveil the allene at a very late stage of the projected total synthesis; in actual fact, this was achieved as the last step of the longest linear sequence by using an otherwise globally deprotected substrate. This unconventional timing was made possible by a gold catalyzed rearrangement of a macrocyclic propargyl benzyl ether derivative that uses a -PMB group as latent hydride source to unveil the signature cycloallene; the protecting group therefore gains a strategic role beyond its mere safeguarding function. Although the gold catalyzed reaction per se is stereoablative, the macrocyclic frame of the target was found to impose high selectivity and a stereoconvergent character on the transformation. The required substrate was formed by ring closing alkyne metathesis (RCAM) with the aid of a new air-stable molybdenum alkylidyne catalyst.