Kiral Diazadioksokaliks[2]aren[2]triazin Bazlı Organokatalizörün Nitrostirenler ile Antronun Enantiyoselektif Michael Tepkimesinde Kullanılması

Year 2024, , 58 - 68, 30.04.2024

Ummu Ozgun , Hayriye Nevin Genç , Abdulkadir Sırıt

https://doi.org/10.47112/neufmbd.2024.32

Abstract

Kiral, stereoseçici ya da enantiyoseçici sentez olarak tanımlanan asimetrik sentez bir veya daha fazla stereojenik merkez bulunduran kiral bileşiklerin sentezlenmesini sağlayan organik sentez türüdür. Bir molekülün farklı enantiyomerleri genellikle birbirlerinden farklı biyolojik aktivite gösterdiklerinden dolayı, asimetrik sentez konusu ilaç kimyası ve organik kimyada oldukça önemli bir konudur. Kiral özellik göstermeyen bileşiklerden kiral bir bileşik sentezleme yöntemleri arasında en çok tercih edilen yöntemlerden biri kiral katalizör kullanımıdır. Bu çalışmada anthron ve farklı nitrostiren türevlerinin kullanıldığı asimetrik Michael tepkimesinde kullanılmak üzere literatürde bulunmayan bir kiral katalizör sentezlenmiştir. Öncelikle kiral katalizörün başlangıç maddesi olarak literatürde bulunan diazadioksookaliks[2]aren[2]triazin sentezlenmiştir. Sentezlenen başlangıç maddesi ile (S)-(+)-1-siklohekziletilamin tepkimeye sokularak enantiyoselektif tepkimede kiral katalizör olarak kullanılacak olan madde elde edilmiştir. Çalışma süresince yapılan tüm reaksiyonlar ince tabaka kromatografisi ile izlenmiş ve elde edilen maddeler kolon kromatografisi ile saflaştırılmıştır. Saflaştırılan ürünler FTIR, 1H NMR ve 13C NMR ile aydınlatılmış ve optik çevirme açıları ölçülmüştür. Sentezlenen katalizör asimetrik Michael reaksiyonunda denenmiş, yüksek verim ve yüksek enantiyoseçicilik elde edilmiştir (%95 verim ve %98 ee).

Keywords

Organokataliz, Asimetrik sentez, Michael reaksiyonu

Chiral Diazadioxocalix[2]arene[2]triazine-Based Derivative as Organocatalyst for Enantioselective Michael Reaction of Nitrostyrenes with Anthrone

Abstract

Asymmetric synthesis, also known as chiral, enantioselective or stereoselective synthesis, is an organic synthesis which allows the formation of chiral compounds containing one or more stereogenic centers. Since different enantiomers of a molecule usually show different biological activity from each other, asymmetric synthesis is a very important topic in the pharmaceutical industry and organic chemistry. One of the most preferred methods to obtain a chiral compound from non-chiral compounds is the use of chiral catalysts. In this study, a chiral catalyst, which is not available in the literature, was synthesized for use in the asymmetric Michael reaction using anthrone and different nitrostyrene derivatives. First, diazadioxocalix[2]arene[2]triazine, which is available in the literature, was synthesized as the starting material of the chiral catalyst. (S)-(+)-1-cyclohexylethylamine was reacted with the synthesized starting material to obtain the substance to be used as a chiral catalyst in the enantioselective reaction. During the study, all reactions were monitored by thin layer chromatography and the obtained substances were purified by column chromatography. The structures of the purified products were elucidated by FTIR, 1H NMR and 13C NMR techniques and optical rotation angles were measured. The synthesized catalyst was tested in asymmetric Michael reaction and high yields and high enantioselectivity were obtained (95% yield and 98% ee).

Keywords

Asymmetric synthesis, Michael reaction, Organocatalysis

References

• M.W. Ha, S.M. Paek, Recent advances in the synthesis of ibuprofen and naproxen, Molecules. 26 (2021), 4792-4814. doi:10.3390/molecules26164792
• L. Albrecht, H. Jiang, K.A. Jørgensen, Hydrogen-bonding in aminocatalysis: From proline and beyond, Chemistry–A European Journal. 20 (2014), 358-368. doi:10.1002/chem.201303982
• B.T. Kumpuga, S. Itsuno, Synthesis of chiral polyesters of cinchona alkaloid catalysts for enantioselective Michael addition of anthrone to nitroalkenes, Journal of Catalysis. 361 (2018), 398–406. doi:10.1016/j.jcat.2018.03.020
• B. Kasprzyk-Hordern, Pharmacologically active compounds in the environment and their chirality, Chemical Society Reviews. 39 (2010), 4466-4503. doi:10.1039/C000408C
• M. Tsakos, C.G. Kokotos, Primary and secondary amine-(thio)ureas and squaramides and their applications in asymmetric organocatalysis, Tetrahedron. 69 (2013), 10199-10222. doi:10.1016/j.tet.2013.09.080
• Y. Wang, X. Xu, G. Wu, B. Pang, S. Liao, Y. Ji, Ligand-enabled C–H olefination and lactonization of benzoic acids and phenylacetic acids via palladium catalyst, Organic Letters. 24(3) (2022), 821-825. doi:10.1021/acs.orglett.1c04000
• Q. Zhang, B.F. Shi, 2-(Pyridin-2-yl)isopropyl (PIP) amine: An enabling directing group for divergent and asymmetric functionalization of unactivated methylene C(sp3)–H bonds, Accounts of Chemical Research. 54(12) (2021), 2750-2763. doi:10.1021/acs.accounts.1c00168
• R. Chang, Y. Chen, W. Yang, Z. Zhang, Z. Guo, Y. Li, Unveiling the mechanism, origin of stereoselectivity, and ligand-dependent reactivity in the Pd(II)-catalyzed unbiased methylene C(sp3)–H Alkenylation–Aza-Wacker Cyclization reaction, The Journal of Organic Chemistry. 85(20) (2020), 13191-13203. doi:10.1021/acs.joc.0c01906
• M. Borgini, P. Wipf, Stereoselective synthesis of δ-fluorinated isoleucines exploiting consecutive C(sp3)-H bond activations, Tetrahedron. 120 (2022), 132876. doi:10.1016/j.tet.2022.132876
• S. Garai, K.G. Ghosh, A. Biswas, S. Chowdhury, D. Sureshkumar, Diastereoselective palladium-catalyzed C(sp3)–H cyanomethylation of amino acid and carboxylic acid derivatives, Chemical Communications. 58(56) (2022), 7793-7796. doi:10.1039/D2CC03106J
• J. Sheng, D.R.S. Pooler, B.L. Feringa, Enlightening dynamic functions in molecular systems by intrinsically chiral light-driven molecular motors, Chemical Society Reviews. 29 (2023), 52(17), 5875-5891. doi: 10.1039/d3cs00247k.
• G.T.M. Bitchagno, V.A. Nchiozem-Ngnitedem, D. Melchert, S.A. Fobofou, Demystifying racemic natural products in the homochiral world, Nature Reviews Chemistry. 6(11) (2022), 806-822. doi: 10.1038/s41570-022-00431-4.
• R. Tamatam, D. Shin, Asymmetric synthesis of US-FDA approved drugs over five years (2016-2020): A recapitulation of chirality, Pharmaceuticals (Basel). 16(3) (2023), 339. doi: 10.3390/ph16030339.
• S. Orlandini, G. Hancu, Z.I. Szabó, A. Modroiu, L.A. Papp, R. Gotti, S. Furlanetto, New trends in the quality control of enantiomeric drugs: Quality by design-compliant development of chiral capillary electrophoresis methods, Molecules. 27(20) (2022), 7058. doi: 10.3390/molecules27207058.
• D. Ghislieri, N.J. Turner, Biocatalytic approaches to the synthesis of enantiomerically pure chiral amines. opics in Catalysis. 57 (2014), 284–300. doi:10.1007/s11244-013-0184-1
• D. Koszelewski, I. Lavandera, D. Clay, D. Rozzell, W. Kroutil, Asymmetric synthesis of optically pure pharmacologically relevant amines employing ω-transaminases, Advanced Synthesis & Catalysis. 350 (2008), 2761-2766. doi:10.1002/adsc.200800496
• C.J. Dunsmore, R. Carr, T. Fleming, N.J. Turner, A chemo-enzymatic route to enantiomerically pure cyclic tertiary amines, Journal of the American Chemical Society. 128 (2006), 2224–2225. doi:10.1021/ja058536d
• H.N. Genc, U. Ozgun, A. Sirit, Chiral tetraoxacalix[2]arene[2]triazine-based organocatalysts for enantioselective Aldol reactions, Tetrahedron Letters. 60 (2019), 1763–1768. doi:10.1016/j.tetlet.2019.05.051
• H.N. Genc, U. Ozgun, A. Sirit, Design, synthesis and application of chiral tetraoxacalix[2]arene[2]triazine‐based organocatalysts in asymmetric Michael addition reactions, Chirality. 31 (2019), 293–300. doi:10.1002/chir.23055
• H.N. Genc, Enantioselective Michael reaction of anthrone catalyzed by chiral tetraoxacalix[2]arene[2]triazine derivatives, RSC Advances. 9 (2019), 21063–21069. doi:10.1039/C9RA03029H
• H.N. Genc, Effective asymmetric Michael addition of anthrone to nitroalkenes using chiral tetraoxacalix[2]arene[2]triazines as organocatalysts, Chirality. 31 (2019), 711–718. doi:10.1002/chir.23108
• M.X. Wang, H.B. Yang, A general and high yielding fragment coupling synthesis of heteroatom‐bridged calixarenes and the unprecedented examples of calixarene cavity fine‐tuned by bridging heteroatoms, Journal of the American Chemical Society. 126(47) (2004), 15412‐15422. doi:10.1021/ja0465092
• H.B. Yang, D.X. Wang, Q.Q. Wang, M.X. Wang, Efficient functionalizations of heteroatom‐bridged calix[2]arene[2]triazines on the larger rim, The Journal of Organic Chemistry. 72(10) (2007), 3757‐3763. doi:10.1021/jo070001a
• M. Shi, Z.Y. Lei, M.X. Zhao, J.W. Shi, A highly efficient asymmetric Michael addition of anthrone to nitroalkenes with cinchona organocatalysts, Tetrahedron Letters. 48 (2007), 5743-5746. doi:10.1016/j.tetlet.2007.06.107
• Y.H. Liao, H. Zhang, Z.J. Wub, L.F. Cun, X.M. Zhang, W.C. Yuan, Enantioselective Michael addition of anthrone to nitroalkenes catalyzed by bifunctional thiourea‐tertiary amines, Tetrahedron Asymmetry. 20(20) (2009), 2397‐2402. doi:10.1016/j.tetasy.2009.09.023