Asymmetric Total Synthesis of Dendrobatid Alkaloids: Preparation of Indolizidine 251F and Its 3-Desmethyl Analogue Using an Intramolecular Schmidt Reaction Strategy

Total syntheses of alkaloid 251F (1), a natural product detected from the skin extracts of the
dendrobatid frog species Minyobates bombetes, and its racemic 3-desmethyl derivative (2) are reported.
A Diels−Alder reaction initiated both syntheses and established four consecutive stereogenic centers.
Important to the synthesis of 2 was a first-generation ozonolysis/olefination/aldol strategy to convert a [2.2.1]
bicyclic acid to the [3.3.0]bicyclooctane diquinane 4b. Further elaboration to an appropriate keto azide
allowed for a key intramolecular Schmidt reaction to deliver the tricyclic core of the target molecule. In a
second-generation approach, a tandem ring-opening/ring-closing metathesis reaction effected an overall
[2.2.1] → [3.3.0] skeletal rearrangement to deliver diquinane 4a. In similar fashion, 4a was manipulated to
an appropriate keto azide, and an intramolecular Schmidt reaction generated the core cyclic architecture
of 251F.