Synthesis of TMC-95A analogues. Structure-based prediction of cyclization propensities of linear precursors

Cyclization of a TMC-95A related tripeptide precursor with the preformed C6-indole/phenol junction was found to produce exclusively the related dimer, whereas under identical conditions from the tripeptide precursor with the built-in natural C7-oxindole/phenol junction only the desired monomeric cyclic species was obtained. These experimental results were fully consistent with structure-based computations of the cyclization propensities. However, by extending these computations to the analogous complestatin molecule, a consistency was not observed, thus confirming the severe limitations of such predicting procedures, even when applied to homologous systems.