12,13-Aziridinyl Epothilones. Stereoselective Synthesis of Trisubstituted Olefinic Bonds from Methyl Ketones and Heteroaromatic Phosphonates and Design, Synthesis, and Biological Evaluation of Potent Antitumor Agents

The synthesis and biological evaluation
of a series of 12,13-aziridinyl
epothilone B analogues is described. These compounds were accessed
by a practical, general process that involved a 12,13-olefinic methyl
ketone as a starting material obtained by ozonolytic cleavage of epothilone
B followed by tungsten-induced deoxygenation of the epoxide moiety.
The attachment of the aziridine structural motif was achieved by application
of the Ess–Kürti–Falck aziridination, while the
heterocyclic side chains were introduced via stereoselective phosphonate-based
olefinations. In order to ensure high (E) selectivities
for the latter reaction for electron-rich heterocycles, it became
necessary to develop and apply an unprecedented modification of the
venerable Horner–Wadsworth–Emmons reaction, employing
2-fluoroethoxyphosphonates that may prove to be of general value in
organic synthesis. These studies resulted in the discovery of some
of the most potent epothilones reported to date. Equipped with functional
groups to accommodate modern drug delivery technologies, some of these
compounds exhibited picomolar potencies that qualify them as payloads
for antibody drug conjugates (ADCs), while a number of them revealed
impressive activities against drug resistant human cancer cells, making
them desirable for potential medical applications.