| Apoptolidin is a polyketide natural product isolated from the bacteria, Nocardiopsis sp. It is a selective apoptotic inducer of cells transformed with the adenovirus E1A oncogene, leaving normal cells unaffected. Its mode of action has been proposed to be inhibition of the mitochondrial F0 F1-ATPase through the study of various molecular and cell-based assays. Along with its exciting biological activity, the structural features of apoptolidin have attracted vast interest in the synthetic community. As a research group interested in molecules of biological importance combined with unique structural motifs, we found this target attractive.; Apoptolidin's skeleton possesses a polyunsaturated 20-membered lactone containing separate conjugated triene and diene units along with a monosaccharide. Appended from the macrolactone is a highly oxygenated fragment that contains a stereo-enriched pyran moiety with a proximal disaccharide. While apoptolidin exhibits unique biological properties, it is known to undergo a ring expansion under cell assay conditions to afford a less active compound, isoapoptolidin. Therefore, our synthetic approach is toward the 20-deoxy analogue, the compound that will eliminate the ring expansion. It relies on the synthesis of three distinct fragments.; The conjugated (E,E,E)-triene portion of 20-deoxyapoptolidin represented a synthetic target where we could take advantage of an allylic rearrangement method. We were able to construct the contiguous (E,E,E )-triene moiety in an iterative fashion utilizing a thionyl chloride rearrangement/oxidation sequence. The thionyl chloride rearrangement was highly E-selective (E:Z > 20:1 by NMR), which illustrated its utility to construct trisubstituted olefins efficiently.; The highly oxygenated side chain of 20-deoxyapoptolidin was constructed using oxazolidinethione chiral auxiliaries to install the important syn propionate units. With two key fragments complete, the coupling of fragment A and B was investigated using copper and palladium-catalyzed reactions to effect the desired transformation. Following successful formation of the C11-C12 bond through the Stille reaction, forming the 20-membered macrolide through Yamaguchi macrolactonization was attempted. |
