The Total Synthesis of 20-Deoxyapoptolidinone

The polyketide apoptolidin is an example from a class a class of 20-membered macrolides with potent and selective apoptosis-inducing activity and are believed to be F-ATPase inhibitors. Apoptolidin purportedly targets mitochondrial F0F1-ATPase (F-ATPase) and induces apoptosis selectively in cells transformed with the adenovirus oncogene, leaving normal cells unaffected. Apoptolidin retains activity in concentrations as low as 10nM; normal cells remain unaffected at concentrations as high as 80åµM.

Unfortunately, Wender and Sulikowski independently demonstrated the ring expansion-isomerization of apoptolidin A via an acyl migration of the C20-hydroxyl group to form a less active congener, isoapoptolidin. Isoapoptolidin was found to be considerably less active than apoptolidin and the lack of a C20-hydroxyl group could explain the increased biological activity of apoptolidin C in cell-based assays. We have targeted the total synthesis of 20-deoxyapoptolidin because of the potential of increased chemical stability.

In addition to the increased stability, 20-deoxyapoptolidinone may be a unique chemical entity. Noticeably absent from the family of natural apoptolidin congeners is C20-deoxyapoptolidin. The lack of C20 oxygenation also represents a unique structure that may not be accessible by Nocardiopsis sp., the naturally producing organism. Herein, we present an asymmetric route to the aglycone of 20-deoxyapoptolidinone. The algycone was chosen as an initial target to further explore the biological significance of post-PKS modifications.