posted on 2024-01-19, 16:39authored byJack L. Sutro, Alois Fürstner
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.