Innovative reaction methodologies for the synthesis os small compounds
Phone: +49 (231) 755-3870
The research of the group is based on chemical synthesis. We focus on the development of novel methods for the synthesis of small compounds and following application of the developed reaction methodology for the preparation of focused compound libraries. Obtained compounds are studied using cell based assays and chemical genetic approaches to identify possible targets. Furthermore, we are elaborating new synthetic strategies for the preparation of complex molecules with pronounced bioactivity.
The group’s research covers several complementary areas of organic synthesis for the development of novel efficient reaction methodologies, which include (Figure 1):
• C-H bond activation using transition metal catalysis for direct coupling of non-functionalized compounds;
• C-H bond functionalization based on utilization of direct oxidative metal-free methods for the synthesis of compounds of interest;
• Enantioselective catalysis for the synthesis of complex chiral products with multiple stereocenters.
In the last years we developed several transition metal catalyzed reactions for the synthesis of compound collections. In particular, we developed methods for the synthesis of indole derivatives using Rh(III) or Ir (III) catalysis [1, 2]. Furthermore, we developed the first synthesis of indoles using a three-component reaction [3, (Antonchick et al. 2014) Figure 2A]. This method was extended to the synthesis of pyrazoles, pyridazinones and provides a general approach for the synthesis of nitrogen containing heterocyclic compounds. Recently, we developed novel methods for the functionalization of acetophenone derivatives under copper (I) catalyzed reaction conditions. Those methods were used for the synthesis of annulated cyclopropane derivatives and furans [4, 5]. Furthermore, basic principles of those reactions were applied in the development of an extraordinary [1+1+1] cyclotrimerization for cyclopropane synthesis [6, (Antonchick et al. 2016) Figure 2B].
For C-H bond functionalization under metal-free reaction conditions, we developed a hypervalent iodine based transformation [7-9]. We used iodine (III) reagents for the functionalization of various heterocycles under radical reactions condition and for the synthesis of 2-oxidoles derivatives from simple starting materials
[10-13,(Antonchick et al. 2013)
Furthermore, we developed organocatalytic reaction conditions using simple iodobenzene as catalyst in the synthesis of isoquinolone derivatives
[14, (Antonchick et al. 2014) Figure 3B].
Simple organocatalysts offer a novel straightforward approach for the synthesis of isoquinolones. The desired products were formed smoothly and regioselectively at ambient temperature using peracetic acid as oxidant. Using iodosobenzene diacetate, we developed simple conditions for the annulation of benzenes with 2-aminopyridine derivatives
[15, (Manna et al. 2014)].
For the first time, we demonstrated an application of the methyl group in methyl arenes as directing, non-chelating and traceless group in a highly regioselective cross-annulation under metal-free conditions. Using the same reagent, we demonstrated cross coupling of aminopyridines with simple and non-functionalized arenes under metal-free reaction conditions . We used reagent-less conditions for the synthesis of quinoline derivatives and demonstrated an efficient access to various heterocycles by annulation of nitrosopyridines with alkynes [17, 18]. Additionally, we used iodide catalyzed reaction conditions for the synthesis of various heterocycles with pronounced bioactivity [19, 20].
In cooperation with Prof. Waldmann we developed a variety of approaches for the enantioselective synthesis of various compound libraries. In particular, we used enantioselective [2+3] cyclo-addition in Biology-Oriented Synthesis . Using this approach, heterocycles were obtained using copper(I) catalyzed reaction conditions [22-27]. Those studies resulted in the discovery of novel modulators of Wnt and Hedgehog signaling pathways. Recently, we used Rh(II) catalyzed enantioselective 1,3-dipolar cycloaddition in the coupling of tropones with carbonyl ylides to afford troponoids. We demonstrated that α-diazoketone-derived carbonyl ylides, in contrast to carbonyl ylides derived from diazodiketoesters, undergo [6+3] cycloaddition reactions with tropone to yield the corresponding bridged heterocycles with excellent stereoselectivity . The novel organocatalytic methods were developed for the synthesis of natural product inspired compounds. Investigation of the obtained compounds led to the discovery of compounds that promote neurite outgrowth and influence the complexity of neuronal network formation [29, 30].
1. Song, Z., and Antonchick, A.P. (2016). Iridium(III)-catalyzed regioselective C7-sulfonamidation of indoles. Org Biomol Chem 14, 4804-4808. 2. Song, Z., Samanta, R., and Antonchick, A.P. (2013). Rhodium(III)-Catalyzed Direct Regioselective Synthesis of 7-Substituted Indoles. Org Lett 15, 5662-5665. 3 Matcha, K., and Antonchick, A.P. (2014). Cascade Multicomponent Synthesis of Indoles, Pyrazoles, and Pyridazinones by Functionalization of Alkenes. Angew Chem Int Ed 53, 11960-11964. 4. Manna, S., and Antonchick, A.P. (2015). Copper(I)-Catalyzed Radical Addition of Acetophenones to Alkynes in Furan Synthesis. Org Lett 17, 4300-4303. 5. Manna, S., and Antonchick, A.P. (2015). Copper-Catalyzed (2+1) Annulation of Acetophenones with Maleimides: Direct Synthesis of Cyclopropanes. Angew Chem Int Ed 54, 14845-14848. 6. Manna, S., and Antonchick, A.P. (2016). [1+1+1] Cyclotrimerization for the Synthesis of Cyclopropanes. Angew Chem Int Ed 55, 5290-5293. 7. Samanta, R., Matcha, K., and Antonchick, A.P. (2013). Metal-Free Oxidative Carbon-Heteroatom Bond Formation Through C-H Bond Functionalization. Eur J Org Chem 2013, 5769-5804. 8. Narayan, R., Manna, S., and Antonchick, A.P. (2015). Hypervalent Iodine(III) in Direct Carbon-Hydrogen Bond Functionalization. Synlett 26, 1785-1803. 9. Narayan, R., Matcha, K., and Antonchick, A.P. (2015). Metal-Free Oxidative C-C Bond Formation through C-H Bond Functionalization. Chem Eur J 21, 14678-14693. 10. Antonchick, A.P., and Burgmann, L. (2013). Direct Selective Oxidative Cross-Coupling of Simple Alkanes with Heteroarenes. Angew Chem Int Ed 52, 3267-3271. 11. Matcha, K., and Antonchick, A.P. (2013). Metal-Free Cross-Dehydrogenative Coupling of Heterocycles with Aldehydes. Angew Chem Int Ed 52, 2082-2086. 12. Narayan, R., and Antonchick, A.P. (2014). Hypervalent Iodine-Mediated Selective Oxidative Functionalization of (Thio) chromones with Alkanes. Chem Eur J 20, 4568-4572. 13. Matcha, K., Narayan, R., and Antonchick, A.P. (2013). Metal-Free Radical Azidoarylation of Alkenes: Rapid Access to Oxindoles by Cascade C-N and C-C Bond-Forming Reactions. Angew Chem Int Ed 52, 7985-7989. 14. Manna, S., and Antonchick, A.P. (2014). Organocatalytic Oxidative Annulation of Benzamide Derivatives with Alkynes. Angew Chem Int Ed 53, 7324-7327. 15. Manna, S., Matcha, K., and Antonchick, A.P. (2014). Metal-Free Annulation of Arenes with 2-Aminopyridine Derivatives: The Methyl Group as a Traceless Non-Chelating Directing Group. Angew Chem Int Ed 53, 8163-8166. 16. Manna, S., Serebrennikova, P.O., Utepova, I.A., Antonchick, A.P., and Chupakhin, O.N. (2015). Hypervalent Iodine(III) in Direct Oxidative Amination of Arenes with Heteroaromatic Amines. Org Lett 17, 4588-4591. 17. Bering, L., and Antonchick, A.P. (2015). Regioselective Metal-Free Cross-Coupling of Quinoline N-Oxides with Boronic Acids. Org Lett 17, 3134-3137. 18. Manna, S., Narayan, R., Golz, C., Strohmann, C., and Antonchick, A.P. (2015). Regioselective annulation of nitrosopyridine with alkynes: straightforward synthesis of N-oxide-imidazopyridines. Chem Commun 51, 6119-6122. 19. Samanta, R., Narayan, R., Bauer, J.O., Strohmann, C., Sievers, S., and Antonchick, A.P. (2015). Oxidative regioselective amination of chromones exposes potent inhibitors of the hedgehog signaling pathway. Chem Commun 51, 925-928. 20. Song, Z., and Antonchick, A.P. (2016). Catching α-aminoalkyl radicals: cyclization between tertiary alkylanilines and alkenes. Tetrahedron 72, in print, doi:10.1016/j.tet.2016.1004.1052. 21. Narayan, R., Potowski, M., Jia, Z.-J., Antonchick, A.P., and Wadmann, H. (2014). Catalytic Enantioselective 1,3-Dipolar Cycloadditions of Azomethine Ylides for Biology-Oriented Synthesis. Acc Chem Res 47, 1296-1310. 22. Potowski, M., Antonchick, A.P., and Waldmann, H. (2013). Catalytic asymmetric exo-selective 6+3 cycloaddition of iminoesters with fulvenes. Chem Commun 49, 7800-7802. 23. Potowski, M., Golz, C., Strohmann, C., Antonchick, A.P., and Waldmann, H. (2015). Biology-oriented synthesis of benzopyrano 3,4-c pyrrolidines. Biorg Med Chem 23, 2895-2903. 24. Potowski, M., Merten, C., Antonchick, A.P., and Waldmann, H. (2015). Catalytic Aerobic Oxidation and Tandem Enantioselective Cycloaddition in Cascade Multicomponent Synthesis. Chem Eur J 21, 4913-4917. 25. Narayan, R., Bauer, J.O., Strohmann, C., Antonchick, A.P., and Waldmann, H. (2013). Catalytic Enantioselective Synthesis of Functionalized Tropanes Reveals Novel Inhibitors of Hedgehog Signaling. Angew Chem Int Ed 52, 12892-12896. 26. Takayama, H., Jia, Z.-J., Kremer, L., Bauer, J.O., Strohmann, C., Ziegler, S., Antonchick, A.P., and Waldmann, H. (2013). Discovery of Inhibitors of the Wnt and Hedgehog Signaling Pathways through the Catalytic Enantioselective Synthesis of an Iridoid-Inspired Compound Collection. Angew Chem Int Ed 52, 12404-12408. 27. Xu, H., Golz, C., Strohmann, C., Antonchick, A.P., and Waldmann, H. (2016). Enantiodivergent Combination of Natural Product Scaffolds Enabled by Catalytic Enantioselective Cycloaddition. Angew Chem Int Ed 55, in print, doi:10.1002/anie.201602084. 28. Murarka, S., Jia, Z.-J., Merten, C., Daniliuc, C.-G., Antonchick, A.P., and Waldmann, H. (2015). Rhodium(II)-Catalyzed Enantioselective Synthesis of Troponoids. Angew Chem Int Ed 54, 7653-7656. 29. Antonchick, A.P., Lopez-Tosco, S., Parga, J., Sievers, S., Schuermann, M., Preut, H., Hoeing, S., Schoeler, H.R., Sterneckert, J., Rauh, D., et al. (2013). Highly Enantioselective Catalytic Synthesis of Neurite Growth-Promoting Secoyohimbanes. Chem Biol 20, 500-509. 30. Jia, Z.-J., Daniliuc, C.G., Antonchick, A.P., and Waldmann, H. (2015). Phosphine-catalyzed dearomatizing 3+2 annulations of isoquinolinium methylides with allenes. Chem Commun 51, 1054-1057.