Teresa Mancilla, Lourdes Canillo, L. Zamudio-Rivera
Feb 1, 2002
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0
Influential Citations
11
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Journal
Organic Preparations and Procedures International
Abstract
Piperazinediones also known as diketopiperazines, are the smallest cyclic peptides, as well as a common motif in several natural products with therapeutic properties.' It has been shown that bisdiketopiperazines exhibit antitumor activity against Lewis lung carcinoma, sarcoma 180, L12 10 leukemia, P388 leukemia, B 16 myeloma, malignant lymphoma, C-26 colon, C-38 human colon and breast cancer.2-8 They have also been used in clinical trial combination therapy? Further investigations have been directed to establish the mechanism by which these drugs affect cell g r ~ w t h . ' O ' ~ Piperazine-2,6-diones substituted at the 3 and 4 positions have shown hypolipidemic activity, the 3-substituted analogues being more active and clarify efficacious against both normal and induced hyperlipidemia in mice.14 Available methods for the preparation of piperazine-2,6-diones are scarce. They have been prepared from polypeptides,1sl6 iminodiacetic acid and ammonium formate,17 by reduction of 2,6dibenzyloxypyrazineI8 and hydrolysis of 4-benzyl-2,6-bishydroxyiminopiperazine with hydrochloric acid.Iy Our current interest in piperazine-2,6-dione 3 derivatives of a-amino acids prompted us to develop a methodology to obtain them from a-amino acid methyl ester hydrochlorides 2 and 2bromoacetamide. This paper describes a short, high yield synthesis and characterization of six new piperazine-2,6-diones 3b-g, as well as the known piperazine-2,6-dione 3a via 3+3 annulation. This method provides access to the surprisingly rare piperazine subtype derivatives, such as 3b-3f which possess substituents at position 3. The structure of compound 3g was further established by a single crystal X-ray diffraction study. The known a-amino acid methyl ester hydrochlorides 2a-g were prepared by reaction of a-amino acids la-g with thionyl chloride and methanol and were characterized by their 'H NMR spectra. Compounds 3a-3g were obtained by the reaction of bromoacetamide with compounds 2a-2g in the presence of potassium bicarbonate under reflux of acetonitrile. The 'H NMR spectra of