Total syntheses of (9R, 10S)-epi-ustiloxin analogues to probe the inhibition of tubulin polymerization and investigations toward ustiloxin A

The ethynyl aziridine ring-opening reaction with phenol derivatives has proven to be a powerful transformation for total synthesis of ustiloxin congeners and analogues. Detailed investigations of the ethynyl aziridine ring-opening have proven that this reaction is not catalyzed by copper. The ethynyl substituent promotes the ring-opening reaction, but is not a prerequisite for reactivity. Additionally, two diastereomeric N-Boc aziridines have been synthesized for future investigations. Although the reaction mechanism is not known, this transformation is consistent with an SN2 type reaction based on all experimental evidence.; Three ustiloxin analogues, specifically (9R, 10 S)-epi-ustiloxin D, (9R, 10 S)-epi-ustiloxin F, and (9R, 10 S)-epi-6-Ile ustiloxin, have been synthesized in 16 steps by a regio- and stereospecific ethynyl aziridine ring-opening by beta-hydroxytyrosine derivatives. These analogues proved inactive in a purified tubulin binding assay demonstrating for the first time that the spatial arrangement of the 9-methylamino substituent is an essential binding element. Structural changes that alter the macrocyclic conformation likely place this group at a distance too great for contact with the tubulin protein resulting in a loss of activity. Future investigations may reveal other critical binding points to tubulin and advance the understanding of alpha,beta-tubulin binding.; Several methods have been evaluated for alkyl-aryl thioether synthesis towards ustiloxin A. Metal-catalyzed cross-couplings have limited functional group tolerance not amenable for total synthesis. The SNAr reactions examined were successful in introducing the thioether, but subsequent manipulations were problematic and hampered this approach. Identification of a feasible protecting group strategy might enable the total synthesis of ustiloxin A. Finally, investigations of aryl lithiums with sulfur electrophiles provided positive results in model studies, but this reactivity failed to translate to the real system. Hopefully, further investigations will uncover new reactivity and provide an attractive synthetic route culminating in the total synthesis of ustiloxin A.