Concise total synthesis of Enigmazole A & studies towards the total synthesis of Rhizoxin D

Abstract

The successful total synthesis of enigmazole A was achieved and an important key intermediate towards rhizoxin D was prepared. The benefit of ring closing alkyne metathesis was demonstrated on a highly functionalized substrate in a late stage during the synthesis of enigmazole A. This metathesis was reliable on a multigram scale unprecedented for such a complex substrate. The densely functionalized macrocycle, the propargylic acetate and the oxazole heterocyclic sidechain had no major impact on the stability of the Furstner metathesis catalysts. Post-metathesis functionalization of the obtained alkyne by π-acid catalysis afforded a syn-tetrahydropyran ring via a complex gold-catalyzed [3,3]-sigmatropic rearrangement of the propargylic acetate alongside the alkyne followed by a transannular hydroalkoxylation of the intermediately formed allene. This key transformation showed an interesting catalyst/substrate chirality match/mismatch case. Furthermore, the recently reported ring closing diyne metathesis was applied in the synthesis towards rhizoxin D and gave promising preliminary results. Further investigations are necessary to optimize the yield and finish the total synthesis of rhizoxin D. Due to the concise syntheses presented in this thesis, new derivatives of enigmazole A and rhizoxin D could be obtained in the future, which may provide pharmacological insights on new cancer therapeutics.