Synthesis and structure of novel (S)-1,6-dialkylpiperazine-2,5-diones and (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones

Eleven (5)-1,6-dialkylpiperazine-2,5-diones and five (35,65)-1,3,6-trialkylpiperazine-2,5-diones were prepared in three steps from the corresponding (S)-alpha-amino acid esters comprising of reductive N-alkylation, N-acylation and cyclisation. The synthesis of (S)-1,6-dialkylpiperazine-2,5-diones has a broad scope allowing preparation of diketopiperazines with primary and secondary alkyl groups at N(1), while the synthesis of (35,6S)-1,3,6-trialkylpiperazine-2,5-diones is limited to compounds with primary alkyl groups at N(1). Reductive alkylation of amino acid ester hydrochlorides by catalytic hydrogenation in the presence of a carbonyl compound proved to be a simple, efficient and general method for the preparation of stable (storable) alpha-alkylamino acid ester hydrochlorides. The structures of the novel compounds were determined by NMR and X-ray diffraction. (C) 2011 Elsevier Ltd. All rights reserved.