Thirteen-Step Chemoenzymatic Synthesis of Gedunin

The limonoids have attracted significant attention from the synthetic community owing to their striking structural complexity and medicinal potential. Recent efforts notwithstanding, synthetic access to many intact or ring-D seco limonoids still remains elusive. Here, we report the first de novo synthesis of gedunin, a ring-D seco limonoid with HSP90 inhibitory ac-tivity, that proceeds in thirteen steps. Two enabling features in our strategy are the application of modern catalytic transformations to set the key quaternary centers in the carbocyclic core and the application of site- and chemoselective enzymatic oxidation to establish the requisite oxidation pattern on the A ring. This work lays the foundation for efficient synthetic access to other limonoids and unnatural analogs to facilitate further pharmacological investigation of the family.