Total Syntheses of (−)-Kopsifoline D and (−)-Deoxoapodine: Divergent Total Synthesis via Late-Stage Key Strategic Bond Formation

Abstract

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.

Total synthesis of (−)-kopsinine and ent-(+)-kopsinine

“…As detailed in preceding studies, 10,11 acid-catalyzed reductive cleavage of the oxido bridge in 1 upon treatment with NaCNBH 3 (20% HOAc/ i -PrOH) provided the alcohol 6 (88%) as a single diastereomer, arising from hydride reduction of an intermediate N -acyliminium ion exclusively from the less hindered convex face (Scheme 1). In efforts that provided improvements in a subsequent Chugaev elimination, 16 6 was first converted to the corresponding Cbz ( N -carboxybenzyl) carbamate 8 via the free indoline 7 .…”

“…7,8 We have subsequently disclosed the use of the common Aspidosperma -like pentacyclic intermediate 1 , assembled using this key cycloaddition cascade and bearing a functionalized C5 ethyl substituent (primary alcohol), in the divergent 9 total synthesis of a series of additional alkaloids. This was accomplished by direct linkage of the C21 primary alcohol oxygen to C19 ( 4 , (+)-fendleridine) 10 and C6 ( 3 , (−)-deoxoapodine) 11 or through linkage of C21 itself to C2 ( 5 , kopsinine) 12 and C3 ( 2 , (−)-kopsifoline D) 11 using the C21 functionality to conduct nucleophilic or electrophilic C–C bond forming reactions (Fig. 1).…”

Tandem Intramolecular Diels–Alder/1,3-Dipolar Cycloaddition Cascade of 1,3,4-Oxadiazoles: Initial Scope and Applications

“…72 This approach mimics what is the likely biosynthesis of the kopsifolines and represents the first total synthesis of a naturally occurring kopsifoline.…”

Chiral Lewis Acid-Catalyzed Enantioselective Cycloadditions between Indoles and Cyclic Carbonyl Ylides Derived from Diazodiketone or Diazoketoester Derivatives

“…Recently, Boger reported on the efficient total syntheses of (−)-vindoline, 2 (−)-vindorosine, 2d vinblastine 3 and its analogues, 2d,4 (−)-kopsifoline D, 5 (+)-fendleridine, 6 and related aspidosperma alkaloids, 7 featuring a powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade reaction of 1,3,4-oxadiazole, 8 which includes the 1,3-dipolar cycloaddition of a cyclic carbonyl ylide with a tethered indole C 2 −C 3 double bond. The total syntheses of optically active alkaloids can either involve the resolution of a key intermediate or employ a highly diastereoselective tandem [4 + 2]/[3 + 2] cycloaddition reaction of the chiral 1,3,4-oxadiazole substrates.…”