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A molecular-modeling study using x-ray analysis of the didemnins indicated the three structural features crucial for biological activity. The structural features were the side chain attached to the amino group of threonine, the isostatine hydroxyl group, and the tyrosine side chain. The synthesis of macrocycle was accomplished through reductive amination using sodium triacetoxyborohydride, stereoselective reduction of the beta-keto ester, and the in situ deprotection of the amino group.

Synthesis of didemnin B analogs that contain the modified L-lactyl-L-propyl portion of the side chain helps analyze structure-activity relationships in this region and the factors responsible for bioactivities of this natural product. Use of a Dess-Martin periodinane reagent and a coupling reagent helps produce gram quantities of the didemnin B macrocycle. Threonine, N-methyl-D-leucine and proline influence the bioactivity of this compound.