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Type of Document Dissertation Author Paquette, William Danny URN etd-04132006-164505 Title Toward the Total Synthesis of 20-Deoxyapoptolidin Degree Doctor of Philosophy Department Chemistry and Biochemistry Advisory Committee
Advisor Name Title Marvin J. Miller Committee Member Paul Helquist Committee Member Richard E. Taylor Committee Member Seth Brown Committee Member Keywords
- apoptolidin
- thionyl chloride
- aldol
- stereoselective
Date of Defense 2006-04-07 Availability unrestricted Abstract 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 F0F1-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.
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