Total synthesis of N14-desacetoxytubulysin H

[GRAPHICS] The N-14-desacetoxy analogue of tubulysin H was prepared in 20 steps and 2.1% overall yield. Our strategy features a thiazole anion addition to assemble the tubuvaline residue at the C(10)-C(11) bond, as well as acylations at N-5, N-14, and N-17. This iterative coupling approach, as well as the removal of the labile N,O-acetal at N-14, enables the synthesis of analogues for detailed studies of structure-activity relationships in this family of potent tubulin disrupters.