Solid-phase synthesis of diketopiperazines, useful scaffolds for combinatorial chemistry

Montserrat Del Fresno, Jordi Alsina, Miriam Royo, George Barany, Fernando Albericio

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

Diketopiperazines, which are cyclic dipeptides, are often formed by a side reaction of solid-phase peptide synthesis. Using the new 'Backbone Amide Linker,' this chemistry can be conveniently harnessed for the intentional preparation of diketopiperazines. These products will be useful scaffolds for combinatorial chemistry, since they incorporate three different points of diversity: both amine acid side-chains and one (of the two) amide bonds.

Original languageEnglish (US)
Pages (from-to)2639-2642
Number of pages4
JournalTetrahedron Letters
Volume39
Issue number17
DOIs
StatePublished - Apr 23 1998

Bibliographical note

Funding Information:
functionalities. DKP combinatorial libraries prepared will be suitable for both on-and off-resin screening. Acknowledgments, We thank Drs. Steven A. Kates (PerSeptive Biosystems, USA) and Knud J. Jensen (Technical University of Denmark) for fruitful discussions. This work was partially supported by CICYT (PB96-1490), Generalitat de Catalunya \[Grup Consolidat (1995SGR 494) i Centre de Refer6ncia en Biotecnologia\]a, nd the National Institutes of Health (Grant GM 42722). References and Notes 1. Abbreviations used: AAA, amino acid analysis; Ac20, acetic anhydride; AI, allyl; AIIoc, allyloxycarbonyl; BAL, backbone amide linker; Bu, butyl; Bzl, benzyl; Ddz, 2-(3,5-dimethoxyphenyl)propyl\[2\]oxycarbonyDl;I EA, N,N-diisopropylethylamine; DKP, diketopiperazine, (2,5-piperazinedione);D MF, N,N-dimethylformamide;F moc, 9-fluorenylmethoxycarbonyl;H ATU, N-\[(dimethylamino)-1 H - 1,2,3-triazolo-\[4,5-b\]pyridinl--y l-methylene\]-N-methylmethanaminiumh exafluorophosphate N-oxide; HPLC, high performance liquid chromatography; IRAA, internal reference amino acid; Mtt, 4-methyltrityl; MALDI-TOF, matrix assisted laser desorption ionization, time of flight; PALdehyde, 5-(4-formyl-3,5-dimethoxyphenoxy)valerica cid; PEG-PS, polyethylene glycol-polystyrene grail; PS, polystyrene; PyAOP, 7-azabenzotriazol-l-yl-oxytris(pyrrolidino)phosphonium hexafluorophosphate; TFA, trifluoroacetic acid; THF, tetrahydrofuran; Trt, triphenylmethyl (trityl). Amino acid symbols denote L-configurationu nless otherwise noted. 2. Present address: Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA. 3. (a) Combinatorial Peptide and Nonpeptide Libraries. Jung, G., Ed., VCH: Weinheim, 1996; (b) Combinatorial Libraries. Synthesis, Screening and Application Potential, Cortese, R. Ed., Walter de Gruyter & Co.: Berlin, 1996; (c) Molecular Diversity and Combinatorial Chemistry. Libraries and Drug Discovery, Chaiken, I.M.; Janda, K.D., Eds., ACS Books: Washington, 1996; (d) Combinatorial Chemistry: Synthesis and Applications, Wilson, S.H.; Czarnik, A.W., Eds., Wiley & Sons: New York, 1997; (e) A Practical Guide to Combinatorial Chemistry, DeWitt, S.H.; Czarnik, A.W. Eds., ACS Books: Washington, 1997.

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