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Diphenyl phosphonate ester analogues of phenylalanine and peptides derived from these have been prepared and are shown to specifically inhibit chymotrypsin. Phosphonate isosters of serine and tyrosine phosphates appropriately protected for use in peptide synthesis have been prepared.

A 3-step synthesis to the title compounds has been developed which provides them differentially protected at nitrogen. These could then be selectively deprotected using hydrazine hydrate or hydrogenolysis over Pd/C.

Serine phosphonate isosteres (7), suitably protected for direct use in peptide synthesis, have been prepared from vinylphosphonate diesters in three steps and high overall yield.

Pure diasteriomers, obtained simply and directly by reaction of hypophosphorous acid salts of (R)(+) or (S)(−) - N-α-methylbenzylamine with aldehydes, can be simultaneously deprotected and oxidised in one step to provide a highly convenient synthesis of α - aminophosphonic acids in high optical purity.

The synthesis of α-aminophosphonate analogues of tyrosine and tryptophan, e.g. 4 and 5 respectively, and their incorporation into proline-containing dipeptides is reported; of the sequences synthesised, the dipeptide Z-Pro-TrpP(OPh)2 is the only derivative that functions as an irreversible inactivator of the serine proteinase chymotrypsin, in contrast, the tyrosine analogue 4 behaves as a competitive reversible inhibitor of the enzyme and the tryptophan analogue 5 behaves as a slow-binding inhibitor.

The synthesis of diphenyl phosphonate analogues of aspartic and glutamic acid, and their inhibitory activity against S. aureus Vg protease and granzyme B, is described. The study has revealed diiculties with protecting group compatibility in the synthesis of these analogues. Two analogues, Acetyl.AspP(OPh)2 and Acetyl.GluP(OPh)2 were found to function as irreversible inactivators of V8 proteinase, yet exhibit no activity against granzyme B. 0 1998 Elsevier Science Ltd. All rights reserved.

The reaction of sodium methylphenylphosphide with (+)-(R)-1-chloroethylbenzene gives (–)-(SP)-(SC)-α-methylbenzylmethylphenylphosphine oxide after oxidation; the optical purities at phosphorus and carbon have been determined.