Total syntheses of (-)-kopsifoline D and (-)-deoxoapodine: divergent total synthesis via late-stage key strategic bond formation.
Divergent total syntheses of (-)-kopsifoline D and (-)-deoxoapodine are detailed from a common pentacyclic intermediate 15, enlisting the late-stage formation of two different key strategic bonds (C21-C3 and C21-O-C6) unique to their hexacyclic ring systems that are complementary to its prior use in the total syntheses of kopsinine (C21-C2 bond formation) and (+)-fendleridine (C21-O-C19 bond formation). The combined efforts represent the total syntheses of members of four classes of natural products from a common intermediate functionalized for late-stage formation of four different key strategic bonds uniquely embedded in each natural product core structure. Key to the first reported total synthesis of a kopsifoline that is detailed herein was the development of a transannular enamide alkylation for late-stage formation of the C21-C3 bond with direct introduction of the reactive indolenine C2 oxidation state from a penultimate C21 functionalized Aspidosperma-like pentacyclic intermediate. Central to the assemblage of the underlying Apidosperma skeleton is a powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole that provided the functionalized pentacyclic ring system 15 in a single step in which the C3 methyl ester found in the natural products served as a key 1,3,4-oxadiazole substituent, activating it for participation in the initiating Diels-Alder reaction and stabilizing the intermediate 1,3-dipole.
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Kiyoun
K
Lee
Dale L
DL
Boger
D000470:Alkaloids / Q000138:chemical synthesis*; D061565:Cycloaddition Reaction / Q000379:methods*; D015394:Molecular Structure; D013237:Stereoisomerism
D000470:Alkaloids