Development of Sclareol- and Sclareolide-Based Chemoenzymatic Approaches to Ring Intact and Seco Limonoids

The limonoids are a family of tetranortriterpenoids that share a steroid-like ring system with a conserved 3'-substituted furan moiety. The family exhibits a high degree of structural diversity arising from extensive oxidations and skeletal rearrangements. This account chronicles the evolution of our chemoenzymatic strategy toward various limonoids from two feedstock terpenes, sclareol and sclareolide. An initial route starting from sclareol successfully delivered the limonoid tetracyclic skeleton but was deemed to lack the versatility to access more oxidized family members. A second-generation strategy that commenced from sclareolide was conceived to allow convergent access to gedunin, Corey's protolimonoid, nimbocinol and azadiradione. Finally, the strategy was further extended to the synthesis of two ring-seco limonoids, methyl angolensate and mexicanolide.