Skip to main content
eScholarship
Open Access Publications from the University of California

Synthesis of Natural and Designed Antitumor Agents: Epothilones and Thailanstatin A

  • Author(s): Rhoades, Derek
  • Advisor(s): Nicolaou, Kyriacos C
  • et al.
Abstract

The epothilones are an intriguing class of natural products and a classic in total synthesis. Their remarkable biological properties have been under investigation for the last two decades and endeavors into their synthesis reached levels of global intensity. Clinical trials of natural and designed epothilones are currently ongoing, and one derivative is approved by the U.S. Food and Drug Administration (FDA). In spite of the massive attention that the epothilones, in particular epothilone B, have enjoyed over the years, the excitement has waned since its initial burst in the mid 1990’s. This was mostly due to their generally narrow therapeutic window. However, the continuing maturation of various selective drug delivery systems, such as antibody drug conjugates (ADCs), has provoked a renaissance for designed analogues of the epothilones and other natural products that were originally pursued but ultimately abandoned because of undesired side effects stemming from their potency and their specific formulation. Thus, Chapter 1 of this dissertation describes the molecular design and synthesis of epothilone B analogues that possess attachment sites suitable for conjugation to ADCs or related systems. These analogues were synthesized utilizing a Stille coupling protocol with the historically successful macrocyclic vinyl iodide 1.33 and novel N-arylpyrazolyl stannanes as the coupling partners. As a further development, the use of an aziridine functional group as an isosteric replacement for the epoxide moiety of epothilone B was investigated. These efforts culminated in the discovery of a convenient, commercially viable route for accessing a plethora of novel aziridinyl epothilone B analogues in seven steps from natural epothilone B. Highlights of this synthesis include the recently developed Ess–Kürti–Falck aziridination, and an in-depth survey of the Horner–Wadsworth–Emmons reaction and its related Still–Gennari modification as it relates to β-heteroaryl phosphonates, an understudied yet highly valuable class of compounds for the synthesis of complex heterocycles.

Thailanstatin A is a recently isolated natural product with impressive therapeutic potential. Its unique mechanism of action as a potent inhibitor of the spliceosome, as well as its structural features which are naturally tailored to accommodate ADCs or related technologies, prompted its total synthesis. Chapter 2 of this dissertation describes the total synthesis of thailanstatin A, which was accomplished in a longest linear sequence of 9 steps from readily available starting materials. The tetrahydropyran components of this molecule conveniently derive from cheap chiral pool materials, L-threonine and D-glucal, and a final stage Suzuki coupling between advanced vinyl iodide and vinyl boronate pinacol ester intermediates was employed to deliver the target molecule in a reliable manner. A key methodological development realized en route to the target was the oxa-Michael/hydrogenation sequence of an α,β,γ,δ-unsaturated aldehyde to enable diastereodivergent access to highly substituted tetrahydropyrans. The high utility of this approach is currently guiding the exploration of designed analogues of this natural product, the results of which will provide potential lead compounds for therapeutic candidates and add new insights into the SARs of this intriguing class of bioactive compounds.

Main Content
Current View