An Efficient Synthesis of Chiral Catalyst: Application in Enantioselective Michael Addition Reactions

Abstract

Asymmetric synthesis, also called stereoselective synthesis, chiral synthesis or enantioselective synthesis, is a form of organic synthesis which presentes one or more new elements of chirality. Use of catalysts is one of the most effective methods preferred by the researchers in recent years. It causes to the preferential formation of a stereoisomer rather than a constitutional isomer. In this study, tetraoxocalix[2]arene[2]triazine was synthesized firstly by using resorcinol and cyanuric chloride and then this starting material was derivatized with (R)-(-)-2-phenylglycinol to obtain tetraoxocalix[2]arene[2]triazine based chiral compound. Characterization of tetraoxocalix[2]arene[2]triazine was done by 1H and 13C NMR spectroscopy which is depicted in literature. Then, new organocatalyst, which possess an amino and a hydroxyl group, was designed and synthesized. The structure of the receptor characterized by FTIR, 1H spectroscopy, 13C NMR spectroscopy, optical rotation and elemental analysis measurement was also included. The newly prepared tetraoxocalix[2]arene[2]triazine derivative was employed as a chiral ligand in the enantioselective Michael addition of dimethylmalonate to conjugated nitroalkenes and good to excellent enantioselectivities were obtained. Various factors, (solvent, temperature, catalyst %) were examined and the reactions were optimized. The best condition for the Michael addition reaction was determined as room temperature, toluene as solvent and 10 mol% of heteroatom-bridged calixaromatic based chiral catalyst as organocatalyst loading. The catalytic efficiency of the chiral catalyst was analyzed by HPLC using chiral columns. The corresponding adducts were generally obtained in (S)-forms with great yields (up to 93%) and enantioselectivities (up to 95% ee).

Keywords

• Asymmetric synthesis
• Organocatalysis
• Michael addition
• Stereoselectivity

Etkili Bir Kiral Katalizör Sentezi: Enantiyoselektif Michael Reaksiyonlarında Kullanılması

Öz

Kiral sentez, enantioselektif sentez veya stereoselektif sentez olarak da adlandırılan asimetrik sentez, stereoseçici olarak bir veya daha fazla kiral bileşiklerin oluşturulmasını sağlayan organik sentez biçimidir. Bir molekülün farklı enantiyomerleri veya diastereomerleri çoğu zaman farklı biyolojik aktiviteye sahip olduğu için asimetrik sentez özellikle ilaç endüstrisinde ve organik kimya alanında önemlidir. Kiral katalizör kullanımı ise, son yıllarda araştırmacılar tarafından tercih edilen en etkili yöntemlerden birisi olup; normal şartlarda rasemik karışım şeklinde ürün veren bir tepkimeye etki ederek, ağırlıklı olarak bir stereoizomeri elde etmeye yönelik bir stratejidir. Bu çalışmada ilk önce tetraoksakaliks[2]aren[2]triazin resorsinol ve siyanürik klorid kullanılarak sentezlendi ve sonra bu başlangıç maddesi (R)-(-)-2-fenilglisinol ile reaksiyona sokularak tetraoksakaliks[2]aren[2]triazin bazlı kiral bir bileşik elde edildi. Tetraoksakaliks[2]aren[2]triazinin karakterizasyonu, literatürde bulunan 1H ve 13C NMR spektroskopi değerleri ile karşılaştırılarak yapıldı. Daha sonra, hidroksil ve amino grubuna sahip yeni bir organokatalizör tasarlandı ve sentezlendi. Yeni katalizörün yapısı 1H ve 13C NMR spektroskopisi, elemental analiz ve çevirme açısı teknikleriyle aydınlatıldı. Sentezlenen kiral bileşik dimetilmalonatın farklı nitroalkenlerle olan enantiyoselektif Michael katılma reaksiyonlarında katalizör olarak kullanıldı ve çok iyi enantiyoselektivite elde edildi. Reaksiyonu etkileyen farklı faktörler (çözücü, sıcaklık, katalizör yüzdesi) incelenerek reaksiyon şartları optimize edildi. En iyi reaksiyon şartları oda sıcaklığı, çözücü olarak toluen ve %10 mol katalizör olarak bulundu. Kiral katalizörün katalitik etkisi HPLC’de kiral kolonlar kullanılarak belirlendi. Reaksiyon sonucunda oluşan ürünler yüksek verim (%93) ve yüksek enantiyomerik fazlalık (%95) ile (S) formunda elde edildi.

Anahtar Kelimeler

• Asimetrik sentez
• Organokatalizör
• Michael katılma
• Stereoselektivite

References

1. Almasi, D., Alonso, D. A., Najera, C. (2007). Organocatalytic asymmetric conjugate additions. Tetrahedron Asymmetry, 18, 299–365.
2. Bozkurt, S., Türkmen, M. B. (2016). New chiral oxo-bridged calix[2]arene[2]triazine for the enantiomeric recognition of α-racemic carboxylic acids. Tetrahedron Asymmetry, 27, 443-447.
3. Comelles, J., Moreno-Mañas, M., Vallribera, A. (2005). Michael additions catalyzed by transition metals and lanthanides species. A review. Part 1. Transition metals. ARKIVOC, 9, 207–238.
4. Dong, Z., Qiu, G., Zhou, H-B., Dong, C. (2012). Chiral squaramide as multiple H-bond donor organocatalysts for the asymmetric Michael addition of 1,3-dicarbonyl compounds to nitroolefins. Tetrahedron Asymmetry, 23, 1550-1556.
5. Enders, D., Saint-Dizier, A., Lannou, M-I., Lenzen, A. (2006). The phospha‐Michael addition in organic synthesis. European Journal of Organic Chemistry, 29–49.
6. Genc, H. N,, Sirit, A, (2018). Novel and highly efficient bifunctional calixarene thiourea derivatives as organocatalysts for enantioselective Michael reaction of nitroolefins with diketones. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 90, 39-49.
7. Genc, H. N. (2019). Enantioselective Michael reaction of anthrone catalyzed by chiral tetraoxacalix[2]arene[2]triazine derivatives. RSC Advances, 9, 21063-21069.
8. Genc, H. N., Ozgun, U., Sirit, A. (2019). Chiral tetraoxacalix[2]arene[2]triazine-based organocatalysts for Enantioselective Aldol reactions. Tetrahedron Letters, 60, 1763-1768.

9. Genc, H. N., Ozgun, U., Sirit, A. (2019). Design, synthesis and application of chiral tetraoxacalix[2]arene[2]triazine‐based organocatalysts in asymmetric Michael addition reactions. Chirality, 31, 293–300.
10. Harutyunyan, S. R., Hartog, T. D., Geurts, K., Minnaard, A. J., Feringa, B. L. (2008). Catalytic asymmetric conjugate addition and allylic alkylation with grignard reagents. Chemical Reviews, 108, 2824–2852.
11. Hayashi, Y., Gotoh, H., Hayashi, T., Shoji, M. (2005). Diphenylprolinol silyl ethers as efficient organocatalysts for the asymmetric Michael reaction of aldehydes and nitroalkenes. Angewandte Chemie International Edition, 44, 4212–4215.
12. Li, B-L., Wang, Y-F., Luo, S-P., Zhong, A-G., Li, Z-B., Du, X-H., Xu, D-Q. (2010). Enantioselective michael addition of aromatic ketones to nitroolefins catalyzed by bifunctional thioureas and mechanistic insight. European Journal of Organic Chemistry, 656–662.
13. Liu, B., Han, X., Dong, Z., Lv, H., Zhou, H-B., Dong, C. (2013). Highly enantioselective Michael addition of 1,3-dicarbonyl compounds to nitroalkenes catalyzed by designer chiral BINOL–quinine–squaramide: efficient access to optically active nitro-alkanes and their isoxazole derivatives. Tetrahedron Asymmetry, 24, 1276-1280.
14. Lu, A., Hu, K., Wang, Y., Song, H., Zhou, Z., Fang, J., Tang, C. (2012). Enantioselective synthesis of trans-dihydrobenzofurans via primary amine-thiourea organocatalyzed intramolecular Michael addition. The Journal of Organic Chemistry, 77, 6208–6214.
15. Ma, H., Liu, K., Zhang, F-G., Zhu, C-L., Nie, J., Ma, J-A. (2010). Chiral bifunctional thiourea-catalyzed enantioselective Michael addition of ketones to nitrodienes. The Journal of Organic Chemistry, 75, 1402–1409.
16. Mase, N., Thayumanavan, R., Tanaka, F., Barbas III, C. F. (2004). Direct asymmetric organocatalytic Michael reactions of α,α-disubstituted aldehydes with β-nitrostyrenes for the synthesis of quaternary carbon-containing products. Organic Letters, 6, 2527–2530.
17. Mase, N., Watanabe, K., Yoba, H., Takabe, K., Tanaka, F., Barbas III, C. F. (2006). Organocatalytic direct Michael reaction of ketones and aldehydes with β-nitrostyrene in brine. Journal of the American Chemical Society, 128, 4966–4967.
18. Naziroglu, H. N., Durmaz, M., Bozkurt, S., Demir, A. S., Sirit, A. (2012). Application of L-prolinamides as highly efficient organocatalysts for the asymmetric Michael addition of unmodified aldehydes to nitroalkenes. Tetrahedron Asymmetry, 23, 164-169.
19. Naziroglu, H. N., Sirit, A. (2016). Novel efficient bifunctional calixarene thiourea organocatalysts: synthesis and application in the direct enantioselective aldol reactions. Tetrahedron Asymmetry, 27, 201-207.
20. Nugent, T. C., Shoaib, M., Shoaib, A. (2011). Practical access to highly enantioenriched quaternary carbon Michael adducts using simple organocatalysts. Organic & Biomolecular Chemistry, 9, 52–56.
21. Palomo, C., Vera, S., Mielgo, A., Go´mez-Bengoa, E. (2006). Highly efficient asymmetric Michael addition of aldehydes to nitroalkenes catalyzed by a simple trans-4-hydroxyprolylamide. Angewandte Chemie International Edition, 45, 5984–5987.
22. Pansare, S. V., Pandya, K. (2006). Simple diamine and triamine-protonic acid catalysts for the enantioselective Michael addition of cyclic ketones to nitroalkenes. Journal of the American Chemical Society, 128, 9624–9625.
23. Sulzer-Mossé, S., Alexakis, A. (2007). Chiral amines as organocatalysts for asymmetric conjugate addition to nitroolefins and vinyl sulfonesviaenamine activation. Chemical Communications, 30, 3123–3135.
24. Tsakos, M., Kokotos, C. G., Kokotos, G. (2012). Primary amine‐thioureas with improved catalytic properties for “difficult” Michael reactions: Efficient organocatalytic syntheses of (S)‐Baclofen, (R)‐Baclofen and (S)‐Phenibut. Advanced Synthesis & Catalysis, 354, 740–746.
25. Tsandi, E., Kokotos, C. G., Kousidou, S., Ragoussis, V., Kokotos, G. (2009). Sulfonamides of homoproline and dipeptides as organocatalysts for Michael and aldol reactions. Tetrahedron, 65, 1444–1449.
26. Tsogoeva, S. B. (2007). Recent advances in asymmetric organocatalytic 1,4‐conjugate additions. European Journal of Organic Chemistry, 11, 1701–1716.
27. Wang, M-X., Yang, H-B. (2004). 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, 15412-15422.
28. Yalalov, D.A., Tsogoeva, S. B., Schmatz, S. (2006). Chiral thiourea‐based bifunctional organocatalysts in the asymmetric nitro‐Michael addition: A joint experimental‐theoretical study. Advanced Synthesis & Catalysis, 348, 826–832.
29. Yoshida, M., Sato, A., Hara, S. (2010). Asymmetric Michael addition of aldehydes to nitroalkenes using a primary amino acid lithium salt. Organic & Biomolecular Chemistry, 8, 3031–3036.