Fit-for-Purpose Synthesis of an Aza-Cryptophycin Analogue as the Payload for an Antibody-Drug Conjugate

The synthesis of an aza-cryptophycin analogue is described, featuring a highly trans-selective ring-closing metathesis reaction and an asymmetric Corey-Chaykovsky-type reaction to install the epoxide function. This latter reaction is an answer to the long-standing synthetic challenged posed by the efficient formation of the epoxide function of the cryptophycin family of compounds in a diastereoselective manner. It allows for a one-third reduction in the number of steps compared with the previously used synthesis (27 to 19 steps) and increases the overall yield of the longest linear sequence by a factor of 27 (0.6% to 16%). This fit-for-purpose synthesis allowed the production of a steady supply of the material for the early phase of a cryptophycin-based antibody-drug conjugate program.