Total Synthesis and Structural Investigations of Didemnins A, B, and C

Didemnins A, B, and C, cyclodepsipeptides isolated from a marine tunicate of the family Didemnidae, were efficiently prepared in a stereocontrolled manner, producing the common macrocycle and, in a separate step, introducing the substituents on the amino group of L-threonine as optically pure units. We envisaged that disconnections between L-leucine and the HIP group (25,45) and between L-threonine and isostatine (35,42?,55) would afford two units: a HIP-isostatine unit (I) and a tetrapeptide unit (II). The HIP-isostatine unit was synthesized stereoselectively, and a convergent strategy was used to construct the tetrapeptide. The two units were coupled to afford a linear precursor which was cyclized after appropriate functionalization. Macrocyclization was accomplished at the carboxylic acid of the HIP unit and the free amino group of leucine by using diphenylphosphoryl azide (DPPA). After selective deprotection of the hydroxyl and amino groups of the macrocycle, the substituents attached to the amino group of L-threonine were introduced by using benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP).