Endoannular interactions in cysteine-containing cyclotripeptides: one-step synthesis and crystal structure of a tetracyclic aza-cyclol

Abstract

Mild unmasking of the thiol group of the linear tripeptide N-chloroacetyl-S-t-butylthio-L-cysteinyl-L-phenylalanyl-L-proline p-nitrophenyl ester (8) with tributylphosphine in aqueous solution at room temperature gave, in one step, the tetrahedral adduct (aza-cyclol)(13). The same adduct was obtained starting from (R)-5-oxothiomorpholin-3-ylcarbonyl-L-phenylalanyl-L-proline p-nitrophenyl ester (12). The conformationally rigid polycyclic skeleton stabilizes the structure of the aza-cyclol (13) which is an example of a tetrahedral adduct derived from amide–amide interaction. Relevant conformational details, as revealed by an X-ray crystallographic analysis, are: the proline ring adopts a C_s-C_βendo conformation; the phenylalanine side-chain is extended towards its nitrogen; the proline H_α and hydroxylic hydrogen atom are in the characteristic planar W conformation.