Total Synthesis of TANDEM on Solid Phase

Significance

The total synthesis of N-demethylated triostin A (TANDEM), a C ₂-symmetric bicyclic octadepsipeptide, on solid phase was successfully achieved in 22 steps (19 steps on solid phase) in an overall yield of 18%. Starting from N-Fmoc-alanine attached to Wang resin, seven amino acids and two chromophore moieties were successively incorporated in an alphabetical order [(a)-(i)]. The octadepsipeptide chain was then released from the resin by acidolysis using TFA (j), and macrolactamization of the resulting octadepsipeptide (k) followed by disulfide bond formation (l) gave TANDEM. DNase I footprinting analyses showed the ability of TANDEM to bind to DNA with a preference for 5′-TpA sequences.