Synthesis of a Carbon-Linked Acyldepsipeptide Derivative

We report the synthesis and conformational analysis of a methylene-linked acyldepsipeptide (ADEP). The convergent approach hinged on the generation of a protected vinylglycine synthon, a versatile noncanonical amino acid building block. A rationally optimized Grubbs metathesis and a new mode for macrocyclization to provide critical intermediates are also featured. NMR and in silico studies revealed an unusual trans–trans proline orientation for this new unnatural analog, advancing the understanding of ADEP structure–activity relationships and cyclic peptidomimetics in general.