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.
Wrobleski
Aaron
A
Department of Medicinal Chemistry, University of Kansas, Room 4070, Malott Hall, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045-7582, USA.
Sahasrabudhe
Kiran
K
Aubé
Jeffrey
J
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry*; D018360:Crystallography, X-Ray; D007212:Indolizines / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D013237:Stereoisomerism
D000470:Alkaloids; D007212:Indolizines; C488519:indolizidine 251F