Approaches to pseudopeptidic ergopeptines. Synthesis and molecular structure of an α-aza-phenylalanine-containing oxa-cyclol

Abstract

A synthesis of the tetrahedral adduct (oxa-cyclol)6 structurally related to the peptide portion of ergotamine and possessing an α-aza-phenylalanine residue in place of the central phenylalanine is described. The reaction sequence comprises acylation of cyclo-(-azaPhe-Pro-) with (S)-2-benzyloxypropionyl chloride, followed by chemoselective hydrogenolytic removal of the O-benzyl protecting group. The intermediate N-(α-hydroxyacyl)-cyclo-(-azaPhe-Pro-) undergoes spontaneous ring enlargement leading stereospecifically to the tetrahedral adduct 6 tautomeric with the 9-membered cyclodepsitripeptide cyclo-(-Lac-azaPhe-Pro-)7. The stereochemistry of 6 has been confirmed by an X-ray crystallographic analysis which provides, in addition, detailed information on the structural and conformational features of the newly formed pseudopeptide system.