5652 J. Org. Chem. 2009, 74, 5652–5655 Published on Web 06/11/2009 DOI: 10.1021/jo900441s r 2009 American Chemical Society pubs.acs.org/joc Expedite Protocol for Construction of Chiral Regioselectively N-Protected Monosubstituted Piperazine, 1,4-Diazepane, and 1,4-Diazocane Building Blocks Franc -ois Crestey, † Matthias Witt, § Jerzy W. Jaroszewski, † and Henrik Franzyk* ,† † Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark, and § Bruker Daltonik GmbH, Fahrenheitstrasse 4, D-28359 Bremen, Germany hf@farma.ku.dk Received February 26, 2009 This paper describes the first study of solution-phase synthesis of chiral monosubstituted piperazine building blocks from nosylamide-activated aziridines. The proto- col, involving aminolysis of the starting aziridines with ω-amino alcohols and subsequent Fukuyama-Mitsunobu cyclization, offers the advantage of mild conditions as well as short reaction times, and it leads to optically pure N-Boc- or N-Ns-protected piperazines. This four-step sequence, requiring only a single final chromatographic purification, was extended to include novel diazepane and diazocane derivatives. Piperazines, diazepanes, and diazocanes are structural motifs of important pharmacophores found in a large number of drugs; e.g., N-arylpiperazines are considered “privileged structures” in medicinal chemistry. Thus, the piperazine moiety is present in antimicrobial agents such as pefloxacin and related quinolones, 1 in antipsychotics such as trifluoperazine, 2 in dopaminergic D3 agents, 3 in HIV-protease inhibitors, 4 and in the antidepressant agent clozapine. 5 While the 1,4-diazepane scaffold is present in several marketed drugs, 6 pharmacologically active com- pounds containing a diazocane nucleus, such as novel inter- leukine-1B converting inhibitors 7 and high-affinity ligands for the R4β2 nicotinic receptor, 8 have been reported only recently. A major constraint when incorporating such saturated heterocyclic scaffolds into biologically active compounds is that introduction of structural diversity via substituents on their carbon backbones often is quite tedious. Due to the limited commercial large-scale availability of this type of monosubstituted chiral building blocks, their potential for applications in novel therapeutics appears to be poorly explored. Thus, there is an apparent lack of general stereo- selective routes to chiral monosubstituted piperazines and their homologues, whereas the development of syn- thetic methods for preparation of the corresponding oxo-derivatives has progressed considerably during the past decade. 9 A synthesis of N-Boc-protected (2-hydroxymethyl)- piperazine from optically pure, commercial piperazine-2- carboxylic acid in four steps with good overall yield has recently been published by Gao and co-workers, but this route is strongly restricted in terms of possibilities for side chain variation. 10 Commonly, chiral piperazine building blocks are prepared by reduction of substituted mono- and diketopiperazines, which may be obtained by using either chiral building blocks or via asymmetric synthesis employing a chiral auxiliary. 11 However, this methodology generally involves the use of high temperatures, extended reaction times, and harsh reducing agents, and elaborate changes of the N-protection scheme are usually required to pro- duce synthetically useful compounds. Finally, Berkheij and co-workers have recently described the synthesis of 2-substituted, but racemic, piperazines by a direct *To whom correspondence should be addressed. Phone: +45-35336255. Fax: +45-35336041. (1) Lu, S.; Zhang, Y.; Liu, J.; Zhao, C.; Liu, W.; Xi, R. J. Agric. Food. Chem. 2006, 54, 6995–7000. (2) Madrid, P. B.; Polgar, W. E.; Toll, L.; Tanga, M. J. Bioorg. Med. Chem. Lett. 2007, 17, 3014–3017. (3) Leopoldo, M.; Lacitiva, E.; Colabufo, N. A.; Contino, M.; Berardi, F.; Perrone, R. J. Med. Chem. 2005, 48, 7919–7922. (4) Askin, D.; Eng, K. K.; Rossen, K.; Purick, R. M.; Welss, K. M.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1994, 35, 673–676. (5) Su, J.; Tang, H.; McKittrick, B. A.; Burnett, D. A.; Zang, H.; Smith-Torhan, A.; Fawzi, A.; Lachowicz, J. Bioorg. Med. Chem. Lett. 2006, 16, 4548–4553. (6) For tetrazepam, see: (a) Piek, T.; van Weeren-Kramer, J.; van Wilgenburg, H.; Zeegers, A.; Leeuwin, R. S. Neurosci. Res. Comm. 2001, 28, 85–93. 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