Solution-phase synthesis of nucleobase-substituted analogues of triostin A

A synthesis of novel analogues of triostin A presenting two identical or different nucleobases instead of the original quinoxaline substituents has been developed. The DNA bisintercalator triostin A (1) with its rigid backbone provides an optimal scaffold for a parallel preorganization of the intercalating moieties. The bicyclic octadepsipeptide is built up stepwise in solution and modified with various nucleobase-substituted acetic acids at a late stage. The choice of orthogonal protecting groups allows for the synthesis of triostin analogues bearing two different substituents.