| Abstract
| - In this article, the first solid-phase-based total synthesis of TANDEM, a synthetic analogue oftriostin A, is described. In initial studies, the synthesis incorporated depsipeptide formation,introduction of chromophores, and disulfide bond formation on the solid phase, prior to a finalsolution-phase macrolactamization, to give the target molecule. Although pure TANDEM wasobtained in an overall yield comparable to those for all syntheses to date, the yield of the finalcyclization was low (11%). A more efficient approach involved removal from the solid phase priorto disulfide bond formation. The resulting linear peptide underwent macrolactamization under mildconditions and high dilution. Final disulfide bond formation was essentially quantitative and gavethe target molecule, TANDEM, in an overall yield of 18%. The final compound was assessed for itsability to bind to 5‘-TpA sequences on DNA by DNase I footprinting. This efficient synthesis setsthe stage for a study of the structure−activity relationship of TANDEM and the natural producttriostin A, with analogues containing “point mutations” at every site within the cyclic compounds.
|
