Chapter Chapter Introduction Chapter 1.1 BrØnsted-Base Catalyzed Diels-Alder Reactions The Diels-Alder (DA) reaction is unarguably one of the most powerful bond forming reactions in organic chemistry as it creates as many as contiguous chiral centres in one single reaction. Since its discovery, it has brought about much advancement in contemporary synthetic organic chemistry.1 The methods whereby DA reactions are traditionally and conventionally carried out included reflux and the use of Lewis acids as catalysts.2 On the other hand, the use of BrØnsted bases as catalysts is a relatively rarer approach.3 Rickborn and Koerner were the first to observe that anthrones can behave as dienes and able to take part in DA reactions with several dienophiles.4 However, it was Kagan and Riant who reported the first enantioselective reaction of anthrones catalyzed by Cinchona alkaloids (Scheme 1.1).5 Excellent yields were obtained, nevertheless, there is still much room for improvement in the enantioselectivity. O O N Me O O + N Me O 2a 10 mol% cat. CHCl3, -50oC OMe OH N H HO 97% yield, 61% ee N quinidine as catalyst Scheme 1.1 Diels-Alder reaction of anthrone and N-methyl maleimide catalyzed by quinidine. Yamamoto et al. attempted to improve this anthrone DA reaction using pyrrolidine derivatives as catalysts. Chiral maleimides were used and great results were Chapter obtained (Scheme 1.2).6 The diastereoselectivity was 80%. Pyrrolidine derivatives with a pyridyl group proved to be the best catalysts giving an enantiomeric excess of 87% (Scheme 1.3).7 A transition state model between the catalyst and the substrates held together by ionic interactions and hydrogen bondings was also proposed by the authors. OH NH O O H + N O Me R1 R1 OH H 10mol% cat. Me O N O CHCl3, rt OH major isomer Scheme 1.2 DA reaction of anthrone and a chiral maleimide catalyzed by C2-symmetric pyrrolidine diol. Scheme 1.3 DA reaction of anthrone and N-aryl maleimide catalyzed by N-pyridyl methyl pyrrolidine diol. This anthrone DA reaction was further improved by our group when a BrØnsted– basic bicyclic guanidine was used as the catalyst (Scheme 1.4).8 Good yields of the cycloadducts were obtained and excellent enantioselectivities were achieved. The regioselectivity was also excellent. The absolute configuration of the compound was determined using X-ray analysis. Chapter Scheme 1.4 DA reaction of anthrone and N-aryl maleimide catalyzed by C2-symmetric bicyclic guanidine. Scheme 1.5 Michael reaction of dithranol and N-benzyl maleimide catalyzed by C2symmetric bicyclic guanidine. In addition, it was also found that when the structure of anthrone was slightly altered to include hydroxy groups, i.e. dithranol, the reaction between dithranol and maleimides will give a Michael product (Scheme 1.5). No Diels-Alder product was obtained. Okamura et al. was the first group to report that BrØnsted bases such as triethylamine (NEt3) can catalyze the Diels-Alder reactions of 3-hydroxy-2-pyrone and electron deficient dienophiles giving cycloadducts in good yields.9 The use of the base varied from a catalytic amount of 0.1 equivalent to 1.0 equivalent and in all cases good yields were obtained (Scheme 1.6). Chapter Scheme 1.6 DA reaction of 3-hydroxy-2-pyrone 1. The enantioselective version was explored by the same group using Cinchona alkaloids (Figure 1.1).10 Enantiomeric excess as high as 77% was obtained and the selectivity was good. H HO N R2 OR1 R N N R = H, cinchonidine R = OMe, quinine N H R1 = R2 = H, cinchonine R1 = CH3CO, R2 = H R1 = PhCO, R2 = H R1 = H, R2 = OMe, quinidine Figure 1.1 Cinchona alkaloids used. The best results were obtained when cinchonidine and cinchonine were used and the products were obtained in opposite hands. Following the above results, Deng et al. reported the first highly diastereoselective and enantioselective and DA reactions of 3-hydroxy-2-pyrones (Scheme 1.7).11 The catalysts used were still Cinchona alkaloids. However, the structures were modified and fine tuned to deliver high enantiomeric excesses in the cycloadducts. Chapter Scheme 1.7 DA reaction of and α,β-unsaturated ketone esters. Ph R2 OH OR1 6' N PHN = Cl PYR = N H modified Cinchona alkaloid scaffold Ph A : R1 = PHN, R2 = Et B : R1 = Ac, R2 = -CH=CH2 C : R1 = Bn, R2 = -CH=CH2 D : R1 = PYR, R2 = -CH=CH2 Cinchona alkaloid derivatives as catalysts Table 1.1: Diels Alder reaction of and ester catalyzed by Cinchona alkaloid derivatives. Entry Catalyst dra (exo:endo) ee (%) of exo isomer 85:15 82 D 87:13 80 C 90:10 57 B 88:12 88 A 93:7 89 A a In crude reaction mixture. bReaction run in Et2O They also found that the 6’ position hydroxyl group was essential for improving the catalytic efficiency compared to when natural Cinchona alkaloids were used. Several protecting groups for R1 (PHN, Ac, Bn and PYR) were explored. However, the authors found that the best catalyst was A, in which R1 is the phenanthrene group (PHN) as the Chapter exo product can be obtained in 88% ee. Further optimization by conducting the reaction in Et2O improved the diastereoselectivity, as well as the enantiomeric excess (Table 1, entry 5). In a separate communication, the same authors also reported the use of the modified alkaloid with a primary amine moiety, together with the use of an organic acid in the Diels-Alder reaction of and α,β-unsaturated ketones (Scheme 1.8).12 Scheme 1.8 DA reaction of catalyzed by a Cinchona alkaloid bearing a primary amine moiety. The diastereomeric ratio of the products was 80:20 (exo:endo) with the major product (exo) achieving an enantiomeric excess of 98%. Okamura’s group also reported the Diels-Alder reaction of N-tosyl-3-hydroxy-2pyridone which is the nitrogen analogue of 3-hydroxy-2-pyrone (Scheme 1.9).13 O NTs O OH + N Me O NEt3 (1.0 eq.) CH2Cl2 O 2a Ts N O HO O N (99% yield) Me Scheme 1.9 DA reaction of N-tosyl-3-hydroxy-2-pyridone with N-methyl maleimide. Similar to pyrone, triethylamine was used as the promoter for the reaction. A single product was obtained which was determined to be the endo product. They reasoned that Chapter the bulky tosyl group might have discouraged the approach to yield the exo product which resulted in the excellent regioselectivity. Another possible reason could be the bulkier base might have blocked an exo attack as it was observed that a lower endo selectivity was obtained when a primary amine like tBuNH2 was used as the catalyst. Other electron deficient dienophiles (methyl acrylate and methyl vinyl ketone) were also tested in the DA reactions with N-tosyl-3-hydroxy-2-pyridone and a more sluggish reaction was observed (Scheme 1.10). The diastereoselectivity was starkly different for the case of acrylate or vinyl ketone as the selectivity was better for the former. Scheme 1.10 Terminal olefins used for the DA reaction with N-tosyl-3-hydroxy-2pyridone. Even when 1.0 equivalent of NEt3 was employed as the promoter, the reaction did not proceed to completion. Chapter Scheme 1.11 DA reaction of 2(1H)-pyridones with N-phenyl maleimide under neat conditions. A recent report by Fujita and co-workers made use of 2(1H)-pyridones as dienes for the DA reactions with N-phenyl maleimide under neat conditions.14 Thermal conditions were used and there was no investigation of applying a catalyst to conduct the reaction using milder conditions. With many of the parameters remaining to be changed and tested, there is much room for the improvement and development of this reaction. In addition, it was soon discovered that there is much synthetic use for the cycloadducts obtained from the DA reaction of N-substituted-3-hydroxy-2-pyridone. With all these information, we are sure that there is more research that can be done on the enantioselective reactions of 3-hydroxy-2-pyrone and N-substituted-3hydroxy-2-pyridone. Chapter References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem. Int. Ed. 2002, 41, 1668-1698. Corey, E. J. Angew. Chem. Int. Ed. 2002, 41, 1650-1667. Shen, J.; Tan, C. H. Org. Biomol. Chem. 2008, 6, 3229-3236. (a) Koerner, M.; Rickborn, B. J. Org. Chem. 1989, 54, 6-9. (b) Koerner, M.; Rickborn, B. J. Org. Chem. 1990, 55, 2662-2672. (a) Riant, O.; Kagan, H. B. Tetrahedron Lett. 1989, 30, 7403-7406. (b) Riant, O.; Kagan, H. B.; Ricard, L. Tetrahedron 1994, 50, 4543-4554. Tokioka, K.; Masuda, S.; Fujii, T.; Hata, Y.; Yamamoto, Y. Tetrahedron: Asymmetry 1997, 8, 101-107. Uemae, K.; Masuda, S.; Yamamoto, Y. J. Chem. Soc., Perkin Trans. 2001, 9, 1002-1006. Shen, J.; Nguyen, T. T.; Goh, Y. P.; Ye, W. P.; Fu, X.; Xu, J. Y.; Tan, C. H. J. Am.Chem. Soc. 2006, 128, 13692-13693. Okamura, H.; Iwagawa, T. Nakatani, M., Tetrahedron Lett. 1995, 36, 5939-5942. Okamura, H.; Nakamura, Y.; Iwagawa, T.; Nakatani, M. Chem. Lett. 1996, 3, 193194. Wang, Y.; Li, H. M.; Wang, Y. Q.; Liu, Y.; Foxman, B. M.; Deng, L. J. Am.Chem. Soc. 2007, 129, 6364-6365. Singh, R. P.; Bartelson, K.; Wang, Y.; Su, H.; Lu, X.; Deng, L. J. Am.Chem. Soc. 2008, 130, 2422-2423. Okamura, H.; Nagaike, H.; Iwagawa, T.; Nakatani, M. Tetrahedron Lett. 2000, 41, 8317-8321. Hoshino, M.; Matsuzaki, H.; Fujita, R. Chem. Pharm. Bull. 2008, 56, 480-484. 10 . done on the enantioselective reactions of 3- hydroxy- 2- pyrone and N- substituted -3- hydroxy- 2- pyridone. Chapter 1 10 References 1. Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.;. Vassilikogiannakis, G. Angew. Chem. Int. Ed. 20 02, 41, 16 68 -16 98. 2. Corey, E. J. Angew. Chem. Int. Ed. 20 02, 41, 16 50 -16 67. 3. Shen, J.; Tan, C. H. Org. Biomol. Chem. 20 08, 6, 32 29 - 32 36. 4 quinine R 1 =R 2 = H, cinchonine R 1 =CH 3 CO, R 2 =H R 1 =PhCO,R 2 =H R 1 =H,R 2 = OMe, quinidine H N HN OR 1 R 2 Figure 1. 1 Cinchona alkaloids used. The best results were obtained when