Directed Heterodimerization: Total Synthesis of (−)-Folicangine, (−)-Voafolidine, (−)-Isovoafolidine, and (−)-Tabernaesine B

We report the first total synthesis of heterodimeric aspidosperma-aspidosperma alkaloids (-)-folicangine, (-)-voafolidine, (-)-isovoafolidine, and (-)-tabernaesine B. Our biosynthesis-inspired stereoselective directed union of complex fragments derived from (-)-mehranine (northern half) and (-)-deoxoapodine (southern half) provided a methylene-bridged heterodimer, serving as a key precursor to these structurally related bisindole alkaloids. Methylenation of this versatile heterodimeric intermediate resulted in a stereodivergent ring closure to give (-)-tabernaesine B alongside its C7 diastereomer, enabling our stereochemical revision of this alkaloid. The corresponding C2'-hemiaminal alkaloids (-)-voafolidine and (-)-isovoafolidine were obtained via an analogous spirocyclization-reduction sequence from a hydrated derivative of the methylene-bridged heterodimeric precursor. Our biosynthesis-inspired heterodimerization strategy allowed for the assembly of the intricate double hemiaminal alkaloid (-)-folicangine via C8-iminium ion capture by the C2'-hemiaminal of an intermediate en route to (-)-isovoafolidine.