Efficient synthesis of phosphonodepsipeptides derived from norleucine

In the present work, we describe in detail an efficient solution synthesis of norleucine-derived phosphonopeptides mimicking the peptide sequences Nle-Gly(Ala) and Nle-Gly(Ala)-Val. The most efficient strategy involved use of the benzyl group. The synthesis was achieved through BOP-catalysed coupling of the monobenzyl ester of the N-Cbz-protected phosphonate derivative of norleucine with the hydroxyl moieties of derivatised l-lactic or glycolic acid. Subsequently, complete deprotection of the products was achieved in good yields by one-step Pd-catalysed hydrogenolysis. We also prepared the Fmoc-Nle-Ψ[PO(OH)O]-CH2-COOH synthon and demonstrated that this precursor is a suitable building block for the solid-phase synthesis of cysteine-containing phosphonopeptides.