A Unified Approach to ent-Atisane Diterpenes and Related Alkaloids: Synthesis of (−)-Methyl Atisenoate, (−)-Isoatisine, and the Hetidine Skeleton

A unified approach to ent-atisane diterpenes and related atisine and hetidine alkaloids has been developed from ent-kaurane (−)-steviol (1). The conversion of the ent-kaurane skeleton to the ent-atisane skeleton features a Mukaiyama peroxygenation with concomitant cleavage of the C13–C16 bond. Conversion to the atisine skeleton (9) features a C20-selective C–H activation using a Suárez modification of the Hofmann–Löffler–Freytag (HLF) reaction. A cascade sequence involving azomethine ylide isomerization followed by Mannich cyclization forms the C14–C20 bond in the hetidine skeleton (8). Finally, attempts to form the N–C6 bond of the hetisine skeleton (7) with a late-stage HLF reaction are discussed. The synthesis of these skeletons has enabled the completion of (−)-methyl atisenoate (3) and (−)-isoatisine (4).