As part of investigations directed toward the determination of the essential/nonessential structural features for the bioactivities of didemnin B, we designed a reduced ring analog in which three moieties, namely the tyrosine side chain, the isostatine hydroxyl, and the side chain (L-lactyl- L-prolyl-N-Me-D-leucine), were in their presumed bioactive conformation. In designing the reduced ring analog, we eliminated the leucine-proline portion of the macrocycle core and replaced it with an n-butyl linker in order to elucidate its role. According to MM2 calculations (MacroModel molecular modeling), this analog was of lower energy than the natural product didemnin B, and both structures were superimposable. The synthetic strategy involved four disconnections. Macrocyclization was accomplished at the activated carboxylic acid of the α-(α-hydroxyisovaleryl)-propionyl unit (HIP) and the protected amine of the n-butyl linker using a modification of Schmidt's protocol. After selective deprotection of the hydroxyl and amino groups of the macrocycle, the peptide side chain was introduced using (benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) as the activating reagent.