Enantioselective Total Syntheses of Methanoquinolizidine-Containing Akuammiline Alkaloids and Related Studies

The akuammiline alkaloids are a structurally
diverse class of bioactive
natural products isolated from plants found in various parts of the
world. A particularly challenging subset of akuammiline alkaloids
are those that contain a methanoquinolizidine core. We describe a
synthetic approach to these compounds that has enabled the first total
syntheses of (+)-strictamine, (−)-2­(S)-cathafoline,
(+)-akuammiline, and (−)-Ψ-akuammigine. Our strategy
relies on the development of the reductive interrupted Fischer indolization
reaction to construct a common pentacyclic intermediate bearing five
contiguous stereocenters, in addition to late-stage formation of the
methanoquinolizidine framework using a deprotection–cyclization
cascade. The total syntheses of (−)-Ψ-akuammigine and
(+)-akuammiline mark the first preparations of akuammiline alkaloids
containing both a methanoquinolizidine core and vicinal quaternary
centers. Lastly, we describe the bioinspired reductive rearrangements
of (+)-strictamine and (+)-akuammiline to ultimately provide (−)-10-demethoxyvincorine
and a new analogue thereof.