M.Sc Thesis

M.Sc StudentSinha Mantosh
SubjectTotal Synthesis of a Photoactive Derivative of Asimicin
for Affinity Labeling of Complex I
DepartmentDepartment of Chemistry
Supervisor PROFESSOR EMERITUS Ehud Keinan


The naturally occurring Annonaceous acetogenins are powerful inhibitors of the electron-transport system mediated by the mitochondrial NADH-ubiquinone oxidoreductase (Complex I). These fatty acid derivatives are known not only for their antitumor activity, but also for being potent antimalarial, immunosuppressive, pesticidal, and antifeedant agents. More than 350 acetogenins have already been isolated from 37 species in the Annonaceae, a family of tropical trees and shrubs that accommodates over 2300 species. While most of them exhibit remarkable structural diversity, they share very similar carbon skeletons, with the main variations being the relative and absolute configuration of the various stereogenic oxygen functions. For example, a dominant structural feature that appears in the most active Annonaceous acetogenins, including asimicin, is a ten-carbon fragment that contains two adjacent tetrahydrofuran rings flanked by either one or two hydroxyl groups. A long alkyl chain tethers this fragment to a butenolide group, which represents the conserved part of almost all acetogenins. The asymmetric total synthesis of the 34-hydroxyasimicin and its 3- (4-benzoylphenyl)propionate ester was achieved by means of a convergent synthetic strategy. This ester, which contains eight asymmetric centers, represents the first photoaffinity-labeling agent that is derived from an Annonaceous acetogenin. The key transformations in the synthesis include the Sharpless asymmetric dihydroxylation reaction, the Wittig olefination reaction, an oxidative cyclization reaction with rhenium(vii) oxide, the Williamson etherification reaction, and a palladium-catalyzed cross-coupling reaction. Use of the target molecule for photoaffinity-labelingstudies of bovine mitochondrial NADH-ubiquinone oxidoreductase (Complex I) may shed light on the structure/function of this intricate enzyme and on the origin of the high antitumor activity exhibited by the Annonaceous acetogenins.