Amino protecting groups with phthaloyl function

While the Al -phthaloyl (Phth)P 9 and Al -dithiasuccinoyl (Dts)t derivatives of amino acids are used as reversible protecting groups, the aliphatic N-maleoyl groupt is mainly exploited as a reactive handle for postsynthetic modifications of peptides with thiol-functionalized labels and probes, e.g. carbohydrates, lipids, and chromophores. These N -diacyl derivatives are highly stable to even strong acids, but are cleaved under basic conditions. 

Melphalan and the racemic analog have been prepared by two general routes (Scheme I). In Approach (A) the amino acid function is protected, and the nitrogen mustard moiety is prepared by conventional methods from aromatic nitro-derivatives. Thus, the ethyl ester of N-phthaloyl-phenylalanine was nitrated and reduced catalytically to amine I. Compound I was reacted with ethylene oxide to form the corresponding bis(2-hydroxyethyl)amino derivative II, which was then treated with phosphorus oxychloride or thionyl chloride. The blocking groups were removed by acidic hydrolysis. Melphalan was precipitated by addition of sodium acetate and was recrystallized from methanol. No racemization was detected [10,28—30]. The hydrochloride was obtained in pure form from the final hydrolysis mixture by partial neutralization to pH 0.5 [31]. Variants of this approach, used for the preparation of the racemic compound, followed the same route via the a-acylamino-a-p-aminobenzyl malonic ester III [10,28—30,32,33] or the hydantoin IV [12]. 

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