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Some dipeptides of threo-P-hydroxyaspartic acid were synthesised, by use of a-benzyl N-benzyloxycarbonyl-threo-P-hydroxyaspartate, with carbodi-imides as condensing agents.Jerusalem, Israel THE synthesis of peptides containing amino-acids with an alcoholic hydroxy-group , such as serine or threonine , presents certain difficulties due to the reactivity of the hydroxy-group, the lability of the peptide bonds (in the case of serine l), and the tendency for p-elimination reactions and N-0 (or 0-N) acyl shifts.2 Further complications are encountered in the synthesis of peptides containing the p-hydroxyaspartic acids ; these possess an additional carboxy-group which makes them tetrafunctional. Only the erythro-form of phydroxyaspartic acid has been isolated from natural sources,3 but both the threo-and erythro-isomers, first synthesized by Dakin,4 can now be prepared stereospecifically. 6 We have attempted to synthesise dipeptides containing the threo-isomer, with a view to preparing the p-hydroxy-L-aspartyl analogue of the physiologically active oligopeptide angiotensin I1 , an octapeptide with L-aspartic acid at its N-terminal end. We first used the more readily available racemic form to test the methods and then the L-isomer, obtained by resolution of N-benzyl-threo-p-hydroxy-DL-aspartic acid with L-ephedrine.6The synthesis of peptides containing hydroxy-aminoacids does not necessarily require protection of the hydroxy-group. On the contrary, the use of acyl groups for this purpose increases the possibility of p-elimination. Etherification does not suffer from this disadvantage, but the benzyl ethers cannot be prepared readily from the hydroxy-amino-acids themselves. The hydroxygroup was therefore not protected in this work.One of the classical methods for the production of CCand P-aspartyl peptides is based on the cyclic anhydride obtained when N-benzyloxycarbonylaspartic acid reacts with acetic anhydride.' This procedure , when applied

The N-carboxy-anhydrides derived from either rhreo-or eryrhrop-hydroxy-DL-aspartic acid in which the hydroxygroup is protected by an acetyl group and the p-carboxy-group by a benzyl or methyl ester do not undergo polymerisation in solution by basic catalysts or in bulk. This is due to an 0 --t N-acetyl shift. Polymerisation does take place after methylation of the hydroxy-group. a-AMINO-ACIDS possessing one additional functional group have been polymerised by means of suitably protected N-carboxy-anhydrides1 However, the preparation of a polymer from a tetrafunctional cc-aminoacid has not yet been reported.? It therefore seemed of interest to synthesise N-carboxy-anhydrides from threoand erythrop-hydroxyaspartic acid with the p-carboxyand hydroxy-groups reversibly masked, and investigate their polymerisation. In order to pave the way for the preparation of the much less readily obtainable optically active substances, we restricted ourselves to the use of racemic threoand erythro-8-hydroxyaspartic acids prepared stereo~pecifically.~ In the threo-series, we first aimed at protecting the p-carboxy-group by the t We do not include dihydroxy-phenylalanines among tetrafunctional amino-acids since the second hydroxy-function does not create additional synthetic problems.

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An asymmetric synthesis of N-benzyl-D-aspartic acid was achieved by addition of benzylarnine to N-D-cr-methylbenzylmaleamic acid and hydrolysis of the resulting N1-benzyl-N2-D-cr-methylbenzylasparagine with 48% hydrobromic acid. Attempts to carry out asymmetric syntheses from crotonic or maleic acids and asymmetric bases were unsuccessful.