Download PDF
Synthesis
DOI: 10.1055/s-0040-1720114
paper

A Novel Methodology for the Asymmetric Synthesis of 2,3,5-Trisubstituted Piperazine Derivatives

Nurzhan Beksultanova
a   Department of Chemistry, Middle East Technical University, Dumlupınar Bulvarı No 1, 06800 Çankaya, Ankara, Turkey
,
Özge Özdemir
a   Department of Chemistry, Middle East Technical University, Dumlupınar Bulvarı No 1, 06800 Çankaya, Ankara, Turkey
,
Sıdıka Polat Çakır
b   Department of Chemical Engineering, Çanakkale Onsekiz Mart University, 17100, Çanakkale, Turkey
,
Muhittin Aygün
c   Department of Physics, Dokuz Eylül University, Cumhuriyet Bulvarı No 144, 35210 Alsancak, Izmir, Turkey
,
Özdemir Doğan  ∗
a   Department of Chemistry, Middle East Technical University, Dumlupınar Bulvarı No 1, 06800 Çankaya, Ankara, Turkey
› Author AffiliationsWe thank the Scientific and Technological Research Council of Turkey (Türkiye Bilimsel ve Teknolojik Araştırma Kurumu; TUBITAK, Grant No. 221Z173) and the Middle East Technical University (METU; Orta Doğu Teknik Üniversitesi) for financial support.
› Further Information
    Permissions and Reprints All articles of this category


Abstract

Piperazines constitute an important structural feature of many pharmaceuticals. For the discovery of new drugs, the ability to modify the lead compound’s structure is crucial. Herein, we provide an efficient method for the synthesis of chiral 2,3,5-trisubstituted piperazine structures. Our route enables the synthesis of several novel chiral aryl aziridinyl ketones that could be converted into aziridine-fused bicyclic imines. The reduction of these imines and the nucleophilic ring-opening reaction of the aziridine ring allowed us to synthesize highly functionalized piperazine derivatives.

Key words

piperazines - asymmetric synthesis - aziridines - Staudinger reaction - intramolecular cyclization

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0040-1720114.
  • Supporting Information


Publication History

Received: 19 February 2024

Accepted after revision: 26 March 2024

Article published online:
10 April 2024

© 2024. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Brito AF, Moreira LK. S, Menegatti R, Costa EA. Fundam. Clin. Pharmacol. 2019; 33: 13
    PubMed
  • 2 Zhou Q, Tang X, Chen S, Zhan W, Hu D, Zhou R, Sun N, Wu Y, Xue W. J. Agric. Food Chem. 2022; 70: 1029
    PubMed
  • 3 Patel S, Chapman AG, Graham JL, Meldrum BS, Frey P. Epilepsy Res. 1990; 7: 3
    PubMed
  • 4 Ryckebusch A, Deprez-Poulain R, Maes L, Debreu-Fontaine MA, Mouray E, Grellier P, Sergheraert C. J. Med. Chem. 2003; 46: 542
    PubMed
  • 5 Rohde KH, Michaels HA, Nefzi A. Bioorg. Med. Chem. Lett. 2016; 26: 2206
  • 6 McCombie SW, Tagat JR, Vice SF, Lin SI, Steensma R, Palani A, Neustadt BR, Baroudy BM, Strizki JM, Endres M, Cox K, Dan N, Chou CC. Bioorg. Med. Chem. Lett. 2003; 13: 567
  • 7 Sultan SM, Abdennabi AM. S, Almuaibed AM. Talanta 1999; 49: 1051
    PubMed
  • 8 Ennis MD, Ghazal NB. Tetrahedron Lett. 1992; 33: 6287
  • 9 Lin JC, Ho YS, Lee JJ, Liu CL, Yang TL, Wu CH. Food Chem. Toxicol. 2007; 45: 935
    PubMed
  • 10 Rathi AK, Syed R, Shin HS, Patel RV. Expert Opin. Ther. Pat. 2016; 26: 777
    PubMed
  • 11 Elliott S. Drug Test. Anal. 2011; 3: 430
    PubMed
  • 12 Shaquiquzzaman M, Verma G, Marella A, Akhter M, Akhtar W, Khan MF, Tasneem S, Alam MM. Eur. J. Med. Chem. 2015; 102: 487
    PubMed
  • 13 Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257
    CrossrefPubMed
  • 14 Gettys KE, Ye Z, Dai M. Synthesis 2017; 49: 2589
  • 15 Ye Z, Gettys KE, Dai M. Beilstein J. Org. Chem. 2016; 12: 702
    CrossrefPubMed
  • 16 Durand C, Szostak M. Organics 2021; 2: 337
  • 17 Mickelson JW, Belonga KL, Jacobsen EJ. J. Org. Chem. 1995; 60: 4177
  • 18 Schanen V, Cherrier MP, de Melo SJ, Quirion JC, Husson HP. Synthesis 1996; 833
  • 19 Nakhla JS, Wolfe JP. Org. Lett. 2007; 9: 3279
    PubMed
  • 20 Zhai H, Borzenko A, Lau YY, Ahn SH, Schafer LL. Angew. Chem. Int. Ed. 2012; 51: 12219
    PubMed
  • 21 Lau YY, Zhai H, Schafer LL. J. Org. Chem. 2016; 81: 8696
    PubMed
  • 22 Chamakuri S, Tang SA, Tran KA, Guduru SK. R, Bolin PK, Mackenzie KR, Young DW. Molecules 2022; 27: 3419
    PubMed
  • 23 Dick CR. J. Org. Chem. 1967; 32: 72
  • 24 Manna SK, Panda G. RSC Adv. 2013; 3: 18332
  • 25 Smalley AP, Cuthbertson JD, Gaunt MJ. J. Am. Chem. Soc. 2017; 139: 1412
    CrossrefPubMed
  • 26 Sorto NA, Painter PP, Fettinger JC, Tantillo DJ, Shaw JT. Org. Lett. 2013; 15: 2700
    PubMed
  • 27 Dogan Ö, Zeytinci S, Bulut A. Synth. Commun. 2005; 35: 1067
  • 28 Jhang YJ, Zhelavskyi O, Nagorny P. Org. Lett. 2023; 25: 7721
    PubMed
  • 29 Polat-Cakir S, Beksultanova N, Dogan Ö. Helv. Chim. Acta 2019; 102: 1
  • 30 Weglarz-Tomczak E, Berlicki Ł, Pawełczak M, Nocek B, Joachimiak A, Mucha A. Eur. J. Med. Chem. 2016; 117: 187
    PubMed
  • 31 Jeong H, Yadav NN, Ha HJ. Synthesis 2017; 49: 1264
  • 32 Dolence EK, Roylance JB. Tetrahedron: Asymmetry 2004; 15: 3307
  • 33 Eröksüz S, Dogan Ö, Garner PP. Tetrahedron: Asymmetry 2010; 21: 2535