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.