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Toward the Total Synthesis of 20-Deoxyapoptolidin

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posted on 2006-04-13, 00:00 authored by William David Paquette
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.

History

Date Modified

2017-06-02

Defense Date

2006-04-07

Research Director(s)

Richard E. Taylor

Committee Members

Richard E. Taylor Seth Brown Paul Helquist Marvin J. Miller

Degree

  • Doctor of Philosophy

Degree Level

  • Doctoral Dissertation

Language

  • English

Alternate Identifier

etd-04132006-164505

Publisher

University of Notre Dame

Program Name

  • Chemistry and Biochemistry

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