Synthesis of a New Bivalent Hirudin Analog (hirufos), which includes a stable 4′‐phosphono‐ L ‐phenylalanine mimic of ( L ‐tyrosine O 4 ‐sulfate)‐63

The synthesis on solid phase of a new derivative of the anticoagulant protein hirudin is described (see Scheme and Fig.1 , I ). The henicosapeptide is a bivalent conjugate of the C‐terminus of hirudin and of the active‐site‐binding tetrapeptide D ‐Phe‐Pro‐Arg‐Pro linked via a tetraglycine spacer. The peptide, for which the name hirufos was coined, incorporates a stable phosphono derivative of L ‐phenylalanine which, combined with the other structural modifications, leads to a potent anticoagulant agent. Synthesis was readily achieved by the (9 H ‐fluoren‐9‐yl)‐methoxycarbonyl (Fmoc) strategy followed by acidolytic cleavage from the resin and deprotection, including the liberation of the crucial phosphonic group on L ‐phenylalanine.