A facile and effective synthesis of lipophilic 2,6-diketopiperazine analogues Christos Fytas, Grigoris Zoidis, George Fytas * Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupoli-Zografou, GR-15771 Athens, Greece article info Article history: Received 4 February 2008 Received in revised form 10 April 2008 Accepted 1 May 2008 Available online 3 May 2008 Keywords: 2,6-Diketopiperazines Base-induced cyclization Potassium bis(trimethylsilyl)amide NMR abstract Adamantane and cyclooctane lipophilic 2,6-diketopiperazines (2,6-DKPs) have been prepared by a sim- ple and effective method, including the synthesis of the corresponding iminodiacetic amido-ester de- rivatives and their intramolecular cyclization. In this method, the key step of the imide formation was accomplished by a novel base-induced cyclization protocol, which involved the treatment of amido-ester 2,6-DKP precursors with potassium bis(trimethylsilyl)amide. Moreover, the cyclization methodology used allowed the synthesis of the respective 1-functionalized 2,6-DKPs in one pot and in excellent yields when the same primary amido-esters were treated with the previous base and the intermediate po- tassium imidate salts were then reacted with the electrophile benzyl bromoacetate. Hydrogenolysis of the benzyl 2,6-diketopiperazine acetates afforded the respective carboxylic acids, which constitute versatile intermediates in the synthesis of peptidomimetics and other bioactive molecules concerning our pharmacological studies. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction The head to head cyclic dipeptide framework of the 2,6-dike- topiperazine (2,6-DKP) is present in several biologically active compounds, and it serves as an effective template for construction of conformationally constrained analogues. Among the 2,6-dike- topiperazine structures, the bis(2,6-diketopiperazine) derivatives ICRF-154, ICRF-159, and ICRF-193 (Fig. 1) have been proved to be promising antitumor agents, through the inhibition of DNA top- oisomerase II, 1 whereas some 1,4-disubstituted 2,6-DKP derivatives were found to display potent in vitro inhibition of leukemia and Hep cells’ growth. 2 Additionally, flutimide 3 (a fungus-derived en- donuclease inhibitor of influenza virus) is a structural 2,6-diketo- D3-piperazine motif (Fig. 1). On the other hand, adamantane is frequently found in bi- ologically active compounds across a number of different phar- macological activities (antiviral, antibacterial, trypanocidal, anticancer, and anti-Parkinsonic activity). 4 The cage-like structure of the adamantane, present in bioactive compounds, improves their lipophilicity. 5 Therefore, during last years the adamantane de- rivatives have attracted considerable attention. As part of our research, concerning pharmacological studies, we were interested in preparing analogues incorporating the bulky lipophilic adamantane or cyclooctane ring to the 2,6-DKP core structure. Thus, we synthesized the novel adamantane and cyclo- octane spiro heterocycles 10a,b and 11 , and their 1-substituted derivatives 13a,b, 14, 16a,b, and 17 , as well as the 3-adamantyl-2,6- diketopiperazine derivatives 12, 15, and 18 (Table 1), by a new ef- fective synthetic procedure outlined in Scheme 1 . Particularly, carboxylic acids 16–18 appeared as useful building blocks in the preparation of our target compounds. 2. Results and discussion The synthesis of 2,6-diketopiperazines (2,6-DKPs) by intra- molecular cyclization of iminodiacetic acid derivatives (amido-es- ters or amido-carboxylic acids) is well established. 6 Acyclic 2,6-DKP precursors commonly contain a primary or secondary amide group, as a nucleophilic nitrogen source, and a carboxyl or ester group, as the electrophilic moiety. Several variations of the reaction condi- tions, depending on the nature of the iminodiacetic derivative and the demands of the 2,6-DKP ring substitution, have appeared in the literature. 2,3,6,7 In the case of amido-ester 2,6-DKP precursors, the base-catalyzed intramolecular cyclization reaction is the most preferred route in producing 2,6-DKPs. HN N O O R 1 R 2 N NH O O N N OH O O Flutimide ICRF-154 : R 1 =H, R 2 =H ICRF-159 : R 1 =H, R 2 =CH 3 ICRF-193 : R 1 =CH 3 , R 2 =CH 3 Figure 1. Structures of ICRF-154, ICRF-159, ICRF-193, and flutimide. * Corresponding author. Tel.: þ30 210 7274810; fax: þ30 210 7274747. E-mail address: gfytas@pharm.uoa.gr (G. Fytas). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.05.005 Tetrahedron 64 (2008) 6749–6754