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Remote amide bonds in simple N-acyl amino acid amide or peptide derivatives 1 can be surprisingly unstable hydrolytically, affording, in solution, variable amounts of 3 under mild acidic conditions, such as trifluoroacetic acid/water mixtures at room temperature. This observation has important implications for the synthesis of this class of compounds, which includes N-terminal-acylated peptides. We describe the factors contributing to this instability and how to predict and control it. The instability is a function of the remote acyl group, R(2)CO, four bonds away from the site of hydrolysis. Electron-rich acyl R(2) groups accelerate this reaction. In the case of acyl groups derived from substituted aromatic carboxylic acids, the acceleration is predictable from the substituent's Hammett σ value. N-Acyl dipeptides are also hydrolyzed under typical cleavage conditions. This suggests that unwanted peptide truncation may occur during synthesis or prolonged standing in solution when dipeptides or longer peptides are acylated on the N-terminus with electron-rich aromatic groups. When amide hydrolysis is an undesired secondary reaction, as can be the case in the trifluoroacetic acid-catalyzed cleavage of amino acid amide or peptide derivatives 1 from solid-phase resins, conditions are provided to minimize that hydrolysis.

Reacting imine derivatives of resin-bound amino acids with alpha,omega-dihaloalkanes provides highly versatile intermediates to racemic alpha,alpha-disubstituted amino acids with a wide variety of side-chain functionality. Two strategies were developed to convert the intermediate omega-chloro or omega-bromo derivatives to the desired products. Together, they allow the creation of amino acids with diverse functionalities (omega-chlorides, nitriles, azides, acetates, thioacetates, thioethers, secondary and tertiary aliphatic amines, and anilines) placed at varying chain lengths (2-5) from the alpha-center of the amino acid.

The enantioselective alkylation of Schiff base acetates 1 with malonate types of stabilized carbon nucleophiles in the presence of a stable palladium source Pd(OAc)2 and the chiral ligand (+)-BINAP was developed. The product 2, a protected β-carboxyaspartic acid (ASA), was obtained in up to 85% enantiomeric excess by varying the ester protecting group on the substrate. The nature of the nucleophile has a significant effect on the enantioselectivity in this (2-aza-π-allyl)palladium system. While a rapid chemical conversion was achieved with Schiff base benzoates 5, the enantioselectivity was insensitive to the leaving group used. An optically active substrate (51% ee) gave the same level of enantioselectivity as that obtained from the racemate. Temperature effects on the reaction were also studied; the best selectivity was obtained at 0 °C. A laboratory-scale reaction of the reactive nucleophile KCH(COOCH3)2 with the tert-butyl ester substrate 1c gave, following a single recrystallization, product 2c with ...