Yeni Bisiklik Pirol Türevlerinin Sentezi için Etkili Sentetik Yöntem

Year 2025, Volume: 25 Issue: 4, 720 - 728, 04.08.2025

Nuriye Tuna Subaşı

https://doi.org/10.35414/akufemubid.1564932

Abstract

Bir dizi yeni bisiklik pirol türevi (pirolizin ve indolizin benzeri yapılar) iki aşamalı bir prosedürle başarıyla sentezlenmiştir. Dimetoksitetrahidrofuran ve amino asit esterlerinden başlayarak, sübstitüe olmayan pirol türevleri ve amino asit esterlerinin uygun kloroenonlarla muamelesi ile 1,2-disübstitüe ve 1,2,4-trisübstitüe pirol türevleri rasemizasyon olmaksızın sentezlendi. Daha sonra çalışmaya, sentezlenen bu sübstitüe ve sübstitüe olmayan pirol türevlerinin BBr3 ile siklizasyon reaksiyonu ile devam edilerek yeni bisiklik pirol türevleri iyi verimle elde edildi.

Keywords

Sübstitüe pirol türevi , Kloroenon , BBr3 siklizasyonu , İndolizin , Pirolizin

Ethical Statement

Yazar tüm etik standartlara uyduklarını beyan eder.

Thanks

Dr. Ayhan S. Demir'in (Orta Doğu Teknik Üniversitesi) finansal desteğine minnetle teşekkür ederim. Bu makale Dr. Ayhan S. DEMİR'in (1950-2012) anısına ithaf edilmiştir.

Efficient Synthetic Methodology for the Synthesis of New Bicyclic Pyrrole Derivatives

Abstract

A series of novel bicyclic pyrrole derivatives (pyrrolizine and indolizine like structures) were successfully synthesized in a two-step procedure. Starting from dimethoxytetrahydrofuran and amino acid esters, unsubstituted pyrrole derivatives and 1,2-disubstituted and 1,2,4-trisubstituted pyrrole derivatives were synthesized without racemization through the reaction of amino acid esters with suitable chloroenones. Subsequently, these substituted and unsubstituted pyrrole derivatives were subjected to cyclization reactions with BBr₃ (boron tribromide), resulting in the formation of new bicyclic pyrrole derivatives with good yields. This synthesis strategy stands out by providing a broader substrate scope and improved yields compared to existing methods in the literature..

Keywords

Substituted pyrrole derivative , Chloroenone , BBr3 cyclisation , Indolizine , Pyrrolizine

Ethical Statement

This study is derived from doctorate thesis (thesis number: 286194) under the supervision of Prof. Dr. Ayhan S. DEMİR completed in 2011 by Nuriye Tuna SUBAŞI entitled “Novel synthetic methodologies for heterocycles as building blocks in drug synthesis”. The author declares that she complies with all ethical standards.

Thanks

I gratefully acknowledge the financial support of Prof. Dr. Ayhan S. Demir (Middle East Technical University). This article is dedicated to the memory of Prof. Dr Ayhan S. DEMİR (1950-2012).

References

• Almerico, A.M., Diana, P., Barraja, P., Dattolo, G., Mingoia, F., Loi, A.D., Scintu, F., Millia, C., Puddu, I. and La Colla, P., 1998. Glycosidopyrroles Part 1. Acyclic derivatives: 1-(2-hydroxyethoxy) methylpyrroles as potential anti-viral agents. Farmaco, 53, 33-40. https://doi.org/10.1016/S0014-827X(97)00002-5
• Barbry, D., Faven, C. and Ajana, A., 1993. Acylation of Unsaturated Halides, Alcohols, Esters and Ketones. Synth. Commun., 23(19), 2647-2658. https://doi.org/10.1080/00397919308013794
• Bond, T.J., Jenkins, R., Ridley, A.C. and Taylor, P.C. 1993. Efficient asymmetric synthesis of indolizidine building blocks. J. Chem. Soc., Perkin Trans. 1, 2241-2242. https://doi.org/10.1039/P19930002241
• Caldarelli, M., Habermann, J. and Ley, S.V., 1999. Clean five-step synthesis of an array of 1,2,3,4-tetra-substituted pyrroles using polymer-supported reagents. J. Chem. Soc., Perkin Trans. 1, 107-110. https://doi.org/10.1039/A809345H
• Chadwick, D.J. and Hodgson, S.T., 1983. The protecting–directing role of the trityl group in syntheses of pyrrole derivatives: efficient preparations of 1-H-pyrrole-3-carboxylic acid and 3-acyl-, 3-amino-, and 3-bromo-1-tritylpyrroles. J. Chem. Soc. Perkin Trans. 1, 93-102. https://doi.org/10.1039/P19830000093
• Chen, L., Huang, S., Li, C.Y., Gao, F. and Zhou, X.L., 2018. Pyrrolizidine alkaloids from Liparis nervosa with antitumor activity by modulation of autophagy and apoptosis. Phytochemistry, 147-155. https://doi.org/10.1016/j.phytochem.2018.06.001
• Corvo, M.C. and Pereira, M.A., 2002. A radical approach towards indolizidine 167B. Tetrahedron Lett., 43, 455-458. https://doi.org/10.1016/S0040-4039(01)02189-X
• Daidone, G., Maggio, B. and Schillari, D., 1990. Salicylanilide and its heterocyclic analogs: comparative study of their antimicrobial activity. Pharmazie., 45, 441-442. Daly, J.W., 1982. Alkaloids of Neotropical Poison Frogs (Dendrobatidae). Fortschr. Chem. Naturst., 41, 205. https://doi.org/10.1007/978-3-7091-8656-5_6
• Daly, J.W., Myers, C.W. and Whittaker, N., 1987. Further classification of skin alkaloids from neotropical poison frogs (dendrobatidae), with a general survey of toxic/noxious substances in the amphibia. Toxicon, 25, 1023-1095. https://doi.org/10.1016/0041-0101(87)90265-0
• Daly, J.W., Nishizawa, Y., Padgett, W.L., Tokuyama, T., Smith, A.L., Holmes, A.B., Kibayashi, C. and Aronstam, R.S., 1991. 5,8-Disubstituted indolizidines: A new class of noncompetitive blockers for nicotinic receptor-channels. Neurochem. Res., 16, 1213-1218. https://doi.org/10.1007/BF00966698
• Demir, A.S., Akhmedov, I.M., Sesenoglu, O., Alpturk, O., Apaydin, S., Gercek, Z. and Ibrahimzade, N., 2001. Conversion of homochiral amines, β-amino alcohols and α-amino acids to their chiral 2-substituted pyrrole derivatives. J. Chem. Soc. Perkin Trans. 1, 1162-1167. https://doi.org/10.1039/B008317H
• Demir, A.S., Subasi, N.T. and Sahin, E., 2006. Intermolecular one-pot cyclization of formyl-pyrroles of amino acid esters with norephedrine: stereoselective routes to new tricyclic pyrrole–pyrazine–oxazole fused structures. Tetrahedron:Asymmetry, 17, 2625-2631. https://doi.org/10.1016/j.tetasy.2006.09.020
• Dieter, R.K. and Yu, H., 2000. A Facile Synthesis of Polysubstituted Pyrroles. Org. Lett., 2, 2283-2286. https://doi.org/10.1021/ol006050q
• Fu, P.P., Xia, Q., Lin, G. and Chou, M.W., 2004. Pyrrolizidine Alkaloids—Genotoxicity, Metabolism Enzymes, Metabolic Activation, and Mechanisms. Drug Metab. Rev., 36, 1-55. https://doi.org/10.1081/DMR-120028426
• Gossauer, A., 2003. Monopyrrolic Natural Compounds Including Tetramic Acid Derivatives. Prog. Chem. Org. Nat. Prod., 86, 9-16. https://doi.org/10.1007/978-3-7091-6029-9_1
• Harit, V.K. and Ramesh, N.G., 2016. Amino-functionalized iminocyclitols: synthetic glycomimetics of medicinal interest. RSC Adv., 6, 109528- 109607. https://doi.org/10.1039/C6RA23513A
• Hartmann, T. and Witte, L., 1995. Alkaloids: Chemical and Biological Perspectives. Pelletier, S.W. (Ed.), Pergamon, pp. 155-233. Haubmann, C., Hubner, H. and Gmeiner, P., 1999. Piperidinylpyrroles: Design, synthesis and binding properties of novel and selective dopamine D4 receptor ligands. Bioorg. Med. Chem. Lett., 21, 3143-3146. https://doi.org/10.1016/S0960-894X(99)00540-5
• Jefford, C.W., Thornton, S.R. and Sienkiewicz, K., 1994. An enantiospecific entry to indolizidines by intramolecular acylation of N-pyrrole esters. Tetrahedron Letters, 35(23), 3905-3908. https://doi.org/10.1016/S0040-4039(00)76698-6
• Jefford, C.W., de Villedon de N.F., and Sienkiewicz, K., 1996. The synthesis of chiral 1-(1H-pyrrole) derivatives. Tetrahedron:Asymmetry, 7(4), 1069-1076. https://doi.org/10.1016/0957-4166(96)00111-5
• Jones R.A., 1992. In Pyrroles Part II, The synthesis, Reactivity and Physical Properties of Substituted Pyrroles. Wiley and Sons, New York. Kaiser, D.G. and Glenn, E.M., 1972. Correlation of Plasma 4,5-Bis (p-methoxyphenyl)-2-phenylpyrrole-3- acetonitrile Levels with Biological Activity. Journal of Pharmaceutical Sciences, 61, 1908-1911. https://doi.org/10.1002/jps.2600611205
• Lehuede, J., Fauconneau, B., Barrier, L., Ourakow, M., Piriou, A. and Vierfond, J.M., 1999. Synthesis and antioxidant activity of new tetraarylpyrroles. Eur. J. Med. Chem., 34, 991-996. https://doi.org/10.1016/S0223-5234(99)00111-7
• Liu, J., Yang, Q., Mak, T.C. and Wong, H.N.C., 2000. Highly Regioselective Synthesis of 2,3,4-Trisubstituted 1H-Pyrroles: A Formal Total Synthesis of Lukianol A. J. Org. Chem., 65, 3587-3595. https://doi.org/10.1021/jo9915224
• Massicot, F., Messire, G., Vallee, A., Vasse, J.L., Py, S. and Behr, J.B., 2019. Regiospecific formation of sugar-derived ketonitrone towards unconventional C-branched pyrrolizidines and indolizidines. Org. Biomol. Chem., 17, 7066-7077. https://doi.org/10.1039/C9OB01419E
• Mattocks, A.R., 1986. Chemistry and Toxicology of Pyrrolizidine Alkaloids. Academic Press. Michael, J.P., 2004. Indolizidine and quinolizidine alkaloids. Nat. Prod. Rep., 21, 625. https://doi.org/10.1039/B413748P
• Ragno, R., Marshall, G., Di Santo, R., Costi, R., Massa, S., Rompei, R. and Artico M., 2000. Antimycobacterial pyrroles: synthesis, anti-Mycobacterium tuberculosis activity and QSAR studies. Bioorg. Med. Chem., 8, 1423-1432. https://doi.org/10.1016/S0968-0896(00)00061-4
• Raub, M.F. and Cardellina, J. H., 1992. The piclavines, antimicrobial indolizidines from the tunicate Clavelina picta. Tetrahedron Lett., 33, 2257-2260. https://doi.org/10.1016/S0040-4039(00)74183-9
• Rizk, A.F., 1990. Naturally Occurring Pyrrolizidine Alkaloids, CRC Press. Tamariz, J., Burgueno-Tapia, E., Vazquez, M.A. and Delgado, F., 2018. The Alkaloids: Chemistry and Biology. Knolker, H.J. (Ed.), Academic Press, vol. 80, pp. 1-314.
• Tanaka, T., Oba, T., Okamure, N., Watanabe, K., Kurozumi, S. and Naruchi, T., 1980. A Convenient Synthesis of 1, 2, 5-Trisubstituted 3-Benzoylpyrroles. Synthetic Commun., 10(10), 773-789. https://doi.org/10.1080/00397918008061842
• Tokuyama, T., Nishimori, N., Shimada, A., Edwards, M.W. and Daly J.W., 1987. New classes of amidine, indolizidine and quinolizidine alkaloids from a poison-frog, dendrobates pumilio (dendrobatidae). Tetrahedron, 43, 643-652. https://doi.org/10.1016/S0040-4020(01)89998-1
• Tokuyama, T., Tsujita, T., Garraffo, H.M., Spande, T.F. and Daly, J.W., 1991. Alkaloids from dendrobatid poison frogs: Further pumiliotoxins and allopumiliotoxins and a reassignment of the keto function in pumiliotoxin 307F. Tetrahedron, 47, 5415-5424. https://doi.org/10.1016/S0040-4020(01)80975-3
• Wiedenfeld, H., Roeder, E., Bourauel, T. and Edgar, J., 2008. Pyrrolizidine Alkaloids: Structure and Toxicity. V&R Unipress. Yates, F.S., 1984. In Comprehensive Heterocyclic Chemistry Boulton. A.J., McKillop, A., Eds., Pergamon: Oxford, Vol 2, Part 2A, pp 511.