Chemistry: Ugi Reaction - Thesis Example

?Running head: UGI REACTION Ugi Reaction 15 July The Ugi reaction is a four-component chemical reaction that has recently gained unprecedented popularity. This paper defines the Ugi reaction and discusses its advantages. Recent advances in chemistry and Ugi reaction applications are discussed. A review of chemical literature is performed. The goal of the paper is to create a complete but dense picture of the Ugi reaction and its place in modern chemistry. Keywords: Ugi reaction, chemistry, four-component, derivatives. Ugi Reaction The Ugi reaction subject has gained unprecedented prominent in recent chemical literature. An explosion of interest toward the Ugi reaction is explained by the rapid development of chemical technologies and the need to solve organic chemistry challenges in a cost-efficient manner. The history of the Ugi reaction dates back to the middle of the 20th century, but it was not before the beginning of the 21st century that its value and benefits for the evolution of organic chemistry were consistently recognized. Ivar Ugi is believed to be the father of all multicomponent reactions [28]. Ugi is also considered the grandfather of the whole combinatorial chemistry [29]. Today’s chemists rely on the advantages of the Ugi reaction, to synthesize diverse collections/ libraries of biologically interesting products. This is particularly the case of the drug industry, which relies on the premise of discovery and innovations and demands fast methods of chemical analysis and synthesis of complex molecules. The Ugi reaction is a popular object of contemporary chemical research. Dozens of studies were performed to understand the hidden benefits of the Ugi reaction and its implications for chemistry. “The Ugi reaction is the one-pot condensation of an amine, aldehyde or ketone, isocyanide, and a nucleophile to afford ?-substitute carboxamide derivatives” [17]. The Ugi reaction is particularly useful in drug and pharmaceutical applications, since it can exemplify a broad range of chemical substitutes and lead to the creation of peptidomimetics of value in the pharmaceutical industry. The mechanism of the Ugi reaction usually involves an imine formation which precedes condensation of the amine and aldehyde [17]. The carboxylic acid is then added together with the imino carbon; acyl transfer rearranges the resulting acylated isoamide, leading to the creation of the desired product [17]. The benefits of the Ugi reaction are numerous. The Ugi reaction is believed to be the most convenient instrument for generating diverse libraries of chemical compounds [8; 9]. That the reaction occurs at room temperature also means that the reaction is relatively simply and cost-effective: it does not require using artificial additions and can be easily held without complex temperature-regulating mechanisms [9]. The Ugi reaction is extremely advantageous for generating pharmacologically active compounds and diverse molecules [9]. For example, it was extensively used to synthesize anti-malarial agents [9]. Most, if not all, Ugi reaction products tend to precipitate in pure form [9; 15; 21]. This is extremely important for the success of other chemical processes, as long as compound mixtures obtained during the Ugi reaction do not require costly purification prior to being used in other chemical procedures [6; 27]. For example, the Ugi reaction does not require the use of costly chromatography and, consequentially, reduces the costs of the process and the final product. Eventually, almost all compounds obtained during the Ugi reaction are quantifiable [6; 38]. No information about potential drawbacks of the Ugi reaction has been available so far. The current state of literature provides extensive information about the Ugi reaction and its practical applications. This is mostly because the Ugi reaction is gradually turning into the key element of chemical research and analysis, especially in the pharmaceutical industry. More and more chemical compounds are obtained by means of multicomponent reactions, which involve more than two educts simultaneously and convert them into the desired product via a one-pot reaction [40]. Fig.1. The graphic mechanism of the Ugi Reaction [8]. In 2001, Nakamura, Inoue and Yamada published the results of their study related to one-pot multicomponent synthesis of N-Pyruvoyl aminoacid derivatives, through the Ugi reaction [33]. Their study also supported other researchers including Baldoli et al, Basso et al, Dyker, Breitenstein and Henkel, and Kennedy, Fryer and Josey, who used the Ugi reaction to generate complex, diverse libraries of molecules with fewer reaction steps [1; 4; 5; 11; 24]. In all those studies, the Ugi reaction proved to be the most representative and comprehensible instrument of chemical synthesis. Other chemists also succeeded in using the Ugi reaction to obtain diverse groups of ?-lactams [2; 12; 25; 34], benzodiazepines [27; 28], imidazoles [18], pyrroles [32; 35], and even piperazinediones [20; 21; 22]. It was shown that repetitive Ugi reactions could result in the creation of various heterocyclic and linear compounds, which would otherwise require developing sophisticated multi-step procedures [7]. Needless to say, all these compounds are extremely valuable for the pharmaceutical industry. Given the current state of competition in the pharmaceutical market, the Ugi reaction has a potential to become the source of sustained competitive advantages for drug manufacturers, making all chemical processes faster and more cost-effective. Oikawa, Ikoma and Sasaki used the Ugi reaction in the parallel synthesis of diverse products with polymer support, later used in the creation of a small molecule library [36]. The researchers also relied on earlier studies, which reported the benefits of using a tandem Ugi-Diels-Alder reaction involving furfural and fumaric acid derivatives instead of aldehyde and carboxylic acid ingredients, correspondingly [25; 26; 31; 44]. The use of the Ugi-Diels-Alder tandem reaction proved to generate a perfect yield of heterotricycles with perfect stereoselectivity [36]. Oikawa et al were the first to extend the cycle of the discussed tandem reaction, to synthesize diverse libraries of small molecules [36]. The tandem reaction, based on the principles of the Ugi reaction, led to the creation of effective small molecule libraries in both solid and liquid phase [36]. The Ugi reaction can be successfully utilized to synthesize quinoline components and isoquinoline [14; 44]. The latter is an important heterocyclic compound which can be readily found in a variety of pharmaceuticals and natural products [44]. The Ugi reaction has proved to be particularly relevant in the medical field, including the production of cytotoxic propynoic acid carbamyl methyl amides and the synthesis of remifentanil and carfentanil [26; 43]. Again, like their colleagues Oikawa et al, Xiang et al were interested in using the Ugi reaction to generate diverse small molecule libraries [36; 44]. The latter would then be used to discover new protein targets to be used in the pharmaceutical industry [12; 36; 37]. That the Ugi reaction is so extensively used in medicine is not surprising, given that the reaction is extremely useful in producing diverse libraries of chemical compounds and particularly cost-effective [8]. Multicomponent reactions do not merely allow for synthesizing diverse natural compounds but guarantee their chemical functionality [26]. These reactions, including the Ugi reaction, are relatively easy to perform. This is why the growing number of studies analyzes the usefulness and applicability of multicomponent reactions in medicine. The fact is in that the future of medical chemistry largely depends upon chemists’ ability to “develop and utilize synthetically accessible scaffolds that are amenable to diverse functional group alterations” [14]. Put simply, for medical chemistry to be innovative and cost-effective, professional chemists must be able to balance complexity with synthetic elegance – use fast multicomponent reactions to produce complex chemical compounds. The Ugi reaction is a common object of professional interest among medical researchers, since it drives diversity-oriented synthesis [14]. It gives pharmaceutical manufacturers a competitive advantage over their rivals. The Ugi reaction can substantially improve the process of synthesizing diverse libraries of chemical compounds without sacrificing their chemical functionality. Obviously, these “medically-oriented” Ugi reaction research trends continue to persist. In the nearest future, the Ugi reaction can readily become the principal source of novelty and efficiency in the pharmaceutical industry and the basis for developing new chemical synthesis mechanisms. Hayes also suggested that the Ugi reaction could be utilized as an important of enhanced microwave synthesis [16]. Actually, Hayes lists the Ugi reaction as one of many microwave-assisted multicomponent reactions currently used in chemistry and pharmaceutical synthesis [16]. This opinion was also supported by Bariwal, Trivedi and Eycken; Ireland, Tye and Whittaker , as well as Tye and Whittaker [3; 18; 39]. Gulevich, Balenkova and Nenaidenko (2007) also provided the first example of a diastereoselectibe thio-Ugi reaction used to synthesize chiral imidazole derivatives [15]. Before their study, no single method for synthesizing functionialized imidazole derivates had been used [15]. Gulevich et al made valuable contribution to the evolution of the Ugi reaction and the development of its novel applications [15]. Ugi, Werner and Domling also investigated the applicability of the Ugi reaction in isocyanides [41], whereas Ziegler et al tried to apply the Ugi reaction in the synthesis of glycopeptides [45]. In 2008, Bradley et al tried to optimize the Ugi reaction in practice, through automated liquid handling and parallel synthesis [6]. Finally, Weber et al sought to describe the mechanism and nature of multicomponent reactions and their relevance in various industries [42]. Apparently, the Ugi reaction is becoming increasingly popular in practical chemistry. Pharmaceutical manufacturers can benefit from using the Ugi reaction, reducing their costs and speeding up the process of synthesizing diverse molecule libraries. Future research must focus on the analysis of its applicability in diverse chemical environments and the effects of various environmental factors on the Ugi reaction outcomes. References 1. C. Baldoli, S. Maiorana, S. Licandro, & G. Zinzalla, Organic Letters, 2002, 4, 4341-4344. 2. L. Banfi, A. Basso, G. Guanti, & R. Riva, Tetrahedron Letters, 2003, 44, 7655-7658. 3. J.B. Bariwal, J.C. Trivedi, & E. Eycken, Topics in Heterocyclic Chemistry, 2010, 25, 169- 230. 4. A. Basso, L. Banfi, R. Riva, & G. Guanti, Journal of Organic Chemistry, 2005, 70, 575- 579. 5. A. Basso, L. Banfi, R. Riva, & G. Guanti, Tetrahedron, 2006, 62, 8830-8837. 6. J.C. Bradley, K.B. Mirza, & K. Owens, Nature Precedings, 2008, August. 7. F. Constabel & I. Ugi, Tetrahedron, 2001, 57, 5785-5789. 8. A. Domling, & I. Ugi, Angew Chemistry International Engineering Edition, 2000, 39, 3168-70. 9. A. Domling, A., Current Opinion in Chemical Biology, 2002, 6, 306-313. 10. A. Domling, A.,Chem Rev, 2006, 106, 17-20. 11. G., Dyker, K. Breitenstein & G. Henkel, Tetrahedron Asymmetry, 2002, 13, 1929-1936. 12. S. Gedey, J. Eycken, & F. Fulop, Organic Letters, 2002, 4, 1967-1969. 13. C.B. Gilley, M.J. Buller, & Y. Kobayashi, Organic Letters, 2007, 9, 3631-3634. 14. C. Gordon, K.A. Young, L. Hizartzidis, F.M. Deane & A. McCluskey, Organic & Biomolecular Chemistry, 2011, 9. 1419-1428. 15. A.V. Gulevich, E.S. Balenkova, & V.G. Nenajdenko, Journal of Organic Chemistry, 2007, 72, 7878-7885. 16. B.L. Hayes, Aldrichimia, 2004, 37, 66-76. 17. C. Hulme, & J. Dietrich, Molecular Diversity, 2009, 13, 195-207. 18. S.M. Ireland, H. Tye, & M. Whittaker, Tetrahedron Letters, 2003, 44, 4369-4371. 19. J. Jack & E.J. Corey. (2009). Name reactions for homologations. John Wiley & Sons. 20. L.E. Kaim, & L. Grimaud, Tetrahedron, 2009, 65, 2153-2171. 21. C. Kalinski, M. Umkehrer, J. Schmidt, G. Ross, & J. Kolb, Tetrahedron Letters, 2006, 47, 4683-4686. 22. U. Kazmaier, & S. Ackermann, Organic Biomolecular Chemistry, 2005, 3, 3184-3187. 23. T.A. Keating, & R.W. Armstrong, Journal of the American Chemical Society, 2000, 118, 2584-2594. 24. A.L. Kennedy, A.M. Fryer, & A. Josey, A, Organic Letters, 2002, 4, 1167-1170. 25. R. Krelaus, & B. Westermann, Tetrahedron Letters, 2004, 45, 5987-5990. 26. S. Malaquin, M. Jida, J.C. Gesquire, R. Deprez-Poulain, B. Deprez & G. Laconde, Tetrahedron Letters, 2010, 51, 2983-2985. 27. S. Marcaccini, R. Pepino, T. Torroba, D. Miguel, & M. Valverde, Tetrahedron Letters, 2002, 43, 8591-8593. 28. S. Marcaccini, M. Miliciani, & R. Pepino, Tetrahedron Letters, 2005, 46, 711-713. 29. S. Marcaccini, & T. Torroba, Nature Protocols, 2007, 2, 632-40. 30. M.A. Mironov, M.N. Ivantsova, & V.S. Mokrushin, Molecular Diversity, 2003, 6, 193- 197. 31. M.A. Mironov. (2010). MCR 2009: Proceedings of the 4th International Conference on Multi-Component Reactions and related chemistry. Springer. 32. V. Nair, & A.U. Vinod, Journal of Organic Chemistry, 2001, 66, 4427-4429. 33. M. Nakamura, J. Inoue, & T. Yamada, Bioorganic & Medicinal Chemistry Letters, 2001, 10, 2807-2810. 34. D. Naskar, A. Roy, & W.L. Seibel, Tetrahedron Letters, 2003, 44, 6297-6300. 35. V.G. Nenajdenko, & A. Reznichenko, Tetrahedron, 2007, 63, 3031-3041. 36. M. Oikawa, M. Ikoma, & M. Sasaki, Tetrahedron Letters, 2005, 46, 415-418. 37. M.C. Pirrung, & K. Sarma, Journal of American Chemical Society, 2004, 126, 444-445. 38. M. Sanudo, S. Marcaccini, S. Basurto, T. Torroba, Journal of Organic Chemistry, 2006, 71, 4578. 39. H. Tye, & M. Whittaker, Organic Biomolecular Chemistry, 2004, 2, 813-815. 40. I. Ugi, I. Pure Appl. Chem, 2001, 73, 187-191. 41. I. Ugi, B. Werner, & A. Domling, Molecules, 2003, 8, 53-66. 42. L. Weber, K. Illgen, & M. Almstetter, New Tools in Synthesis, 2001, 3, 366-374. 43. R. Yamada, X. Cao, A.N. Butkevich, M. Millard, S. Odde, N. Mordwinkin, R. Gunldla et al, Journal of Medicinal Chemistry, 2011, 54, 2902-2914. 44. Z. Xiang, T. Luo, K. Lu, J. Cui, X. Shi, R. Fathi, J. Chen, & Z. Yang, Organic Letters, 2004, 6, 3155-3158. 45. T. Ziegler, H-J. Kaisers, R. Schlomer, & C. Koch, Tetrahedron, 2001, 55, 8397-8408. Read More