Development of enantioselective synthetic methods promoted by primary amine based organic catalysts

DEVELOPMENT OF ENANTIOSELECTIVE SYNTHETIC METHODS PROMOTED BY PRIMARY AMINE-BASED ORGANIC CATALYSTS LIU CHEN NATIONAL UNIVERSITY OF SINGAPORE 2011 I DEVELOPMENT OF ENANTIOSELECTIVE SYNTHETIC METHODS PROMOTED BY PRIMARY AMINE-BASED ORGANIC CATALYSTS LIU CHEN (BSc. Zhejiang Univ.) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPOR 2011 II Acknowledgements I would like to thank all people who have helped and inspired me during my PhD studies. This thesis could not be possible without their support. I especially want to thank my supervisor, Prof. Lu Yixin, for his guidance during my research and study at National University of Singapore. His perpetual energy and enthusiasm in research had motivated all his students, including me. In addition, he was always accessible and willing to help his students with their research. As a result, research life became smooth and rewarding for me. All my lab mates at Prof. Lu‟s laboratory made it a convivial place to work. In particular, I would like to thank Luo Jie, Cheng Lili, Hu Ruijun, Han Xiao, Jiang Zhaoqin, Zhu Qiang, Liu Xiaoqian, Han Xiaoyu, Chen Guoying, Zhong Fangrui, Dou Xiaowei, Jolin Foo, Dr. Wang Suxi, Dr. Wang Youqing, Dr. Xu Liwen, Dr. Wu Xiaoyu and Dr. Wang Haifei. They had inspired me through our interactions during the long hours in the lab. I am grateful to our collaborators, Prof. Huang Kuo-Wei and his group members, for their assistance in DFT calculations of our experimental findings. I also appreciate the help from the members of instruments tests in NMR and Mass labs. III My deepest gratitude goes to my family for their unflagging love and support throughout my life. I am indebted to my parents, Liu Yuan and Chen Baoxiang, for their care and love. Furthermore, I am grateful to come across all my good friends. You make my life so colorful and wonderful. Finally yet importantly, thanks to the government scholarship and the financial support from National University of Singapore. IV TABLE OF CONTENTS Acknowledgements Table of Contents I III Summary VII List of Tables IX List of Schemes X List of Figures XII List of Abbreviations XIII List of Publications XVI CHAPTER INTRODUCTION 1.1 ASYMMETRIC CATALYSIS 1.2 ASYMMETRIC AMINOCATALYSIS . 1.2.1 Introduction of Iminium Catalysis and Enamine Catalysis 1.2.2 Iminium ion activation of -Unsaturated Ketones . 1.2.2.1 Chiral Primary Amines in Iminium Catalysis 10 1.2.2.2 Asymmetric Counteranion-Directed Catalysis . 14 1.2.2.3 Cinchona Alkaloid Derived Primary Amine Salt for Iminium ion activation of Enones . 16 1.2.3 Direct -Amination Reactions via Enamine Mechanism 20 1.2.3.1 Asymmetric -Amination Catalyzed by Proline, Proline Analogs and Other Secondary Amine Catalysts . 20 1.2.3.2 Asymmetric -Amination Catalyzed by Primary Amine Catalysts 26 V 1.2.4 Aldol Reaction via Enamine Activation 27 1.2.4.1 Asymmetric Aldol Reactions Catalyzed by Proline and Its Analogues 28 1.2.4.2 Asymmetric Aldol Reactions catalyzed by primary amine catalysts 34 1.3 PROJECT OBJECTIVES 39 CHAPTER PRIMARY AMINE/(+)-CSA SALT-PROMOTED ORGANOCATALYTIC CONJUGATE ADDITION OF NITROESTERS TO ENONES .41 2.1 NITROESTERS IN ORGANOCATALYTIC CONJUGATE ADDITION 41 2.2 RESULTS AND DISCUSSION 43 2.2.1 Catalyst and Solvent Screening 43 2.2.2 Reaction Scope .45 2.2.2.1 Nitroesters Screening . 45 2.2.2.2 α,β-Unsaturated Ketones Screening . 47 2.3 SYNTHETIC MANIPULATIONS OF MICHAEL ADDUCTS .49 2.4 CONCLUSION .50 2.5 EXPERIMENTAL SECTION 50 2.5.1 General Information .50 2.5.2 Representative Procedure 52 2.5.3 Determination of Absolute Configurations of the Michael Adducts .52 2.5.4 Synthesis of ethyl 5-methyl-3-phenylpyrrolidine-2-carboxylate .54 2.5.5 Synthesis of ethyl 2-fluoro-2-nitro-5-oxo-3-phenylhexanoate 55 2.5.6 Analytical Data of Michael Adducts .56 CHAPTER PRIMARY AMINE/CSA ION PAIR: A POWERFUL CATALYTIC SYSTEM FOR THE ASYMMETRIC ENAMINE CATALYSIS 66 3.1 INTRODUCTION .66 3.1.1 Primary Amine Chiral Acid Catalytic System 66 3.1.2 Synthesis of-Alkylated Phenylglycine Derivatives by Direct Amination of Branched Aldehydes 68 VI 3.2 RESULTS AND DISCUSSION 70 3.2.1 Catalyst and Solvent Screening 70 3.2.2 Reaction Scope .73 3.2.2.1 Azodicarboxylates Screening . 73 3.2.2.2 Branched Aldehydes Screening 73 3.2.3 Lowing the Catalyst Loading .75 3.3 SYNTHESIS OF -METHYL PHENYLGLYCINE 77 3.4 CONCLUSION .77 3.5 EXPERIMENTAL SECTION 78 3.5.1 General Information .78 3.5.2 Representative Procedure for the Direct Amination Reaction .79 3.5.3 Determination of Absolute Configurations of the Products .80 3.5.4 Analytical Data of the Amination Products 80 CHAPTER ORGANOCATALYTIC ASYMMETRIC ALDOL REACTION OF ACETONE AND HYDROXYACETONE WITH -UNSATURATED -KETO ESTERS: FACILE ACCESS TO CHIRAL TERTIARY ALCOHOLS 92 4.1 INTRODUCTION .92 4.2 RESULTS AND DISCUSSION 94 4.2.1 Catalyst Screening for Acetone as Donor of Aldol Reaction .94 4.2.2 Acid Screening for Acetone as Donor of Aldol Reaction .98 4.2.3 Solvent Screening for Acetone as Donor of Aldol Reaction .100 4.2.4 Reaction Temperature Screening for Acetone as Donor of Aldol Reaction .101 4.2.5 Reaction Scope for Acetone as Donor of Aldol Reaction .102 4.2.6 Catalyst and Acid Screening for Hydroxyacetone as Donor of Aldol Reaction .104 4.2.7 Reaction Scope for Hydroxyacetone as Donor of Aldol Reaction 107 4.2.7.1 -Unsaturated -Keto Esters and Hydroxyacetone Screening . 107 4.2.7.2 -Unsaturated -Keto Esters Screening 110 4.2.7.3 X-Ray Structure of Aldol Adduct 112 VII 4.3 SYNTHESIS OF 2-SUBSTITUTED GLYCEROL DERIVATIVE 113 4.4 CONCLUSION .114 4.5 EXPERIMENTAL SECTION 114 4.5.1 General Information .114 4.5.2 Representative Procedure: Aldol Reaction of Acetone to Ethyl 2-oxo-4-phenylbut-3enoate 115 4.5.3 Representative Procedure: Aldol Reaction of 1-(Naphthalen-2-ylmethoxy)propan-2-one to Ethyl 2-oxo-4-phenylbut-3-enoate 116 4.5.4 Synthesis of (2S,3S)-2-(3-bromophenethyl)pentane-1,2,3,4-tetraol 4-7 .116 4.5.5 Analytical Data and HPLC Chromatogram of Aldol Adducts .118 4.5.6 X-ray crystallographic data for compound 4-5n 136 REFERENCE 149 THESIS DECLARATION 166 VIII Summary This thesis describes the development of enantioselective synthetic methods promoted by primary amine-based organic catalysts. Chapter provides a brief historic overview of asymmetric organocatalysis, especially on the development of asymmetric aminocatalysis via iminium or enamine activation. Moreover, some selected examples of secondary and primary amine catalysts in this field were also illustrated in detailed. Chapter introduces a novel primary amine-based organocatalyst, the combination of 9-amino(9-deoxy)epi-cinchonine and (+)-CSA, for effective conjugated addition via iminium ion activation of nitroesters to -unsaturated ketones. Such a catalytic system could catalyze the conjugate addition in a highly enantioselective manner, affording the desired adducts in high yields and with up to 99% ee. The Michael adducts are rich in functionality and ready to be converted into useful chiral building blocks. Chapter presents that a mixture of 9-amino (9-deoxy) epi-quinine and ()-CSA was found to be the best catalyst with matching chirality, enabling the direct amination of branched aldehydes to proceed in quantitative yields and with nearly perfect enantioselectivities. A 0.5 mol % catalyst loading was sufficient to catalyze the reaction, and a gram scale enantioselective synthesis of biologically important -methyl phenylglycine has been successfully demonstrated. IX Chapter focuses on the effective aldol reaction of acetone and hydroxyacetone to -unsaturated -keto ester catalyzed by the combination of 9-amino(9-deoxy)epicinchonine and trifluoroacetic acid. The desired adducts containing a chiral tertiary alcohol skeleton could be obtained in high yields and up to 99% ee, and an efficient access to 2-substituted glycerol derivatives was also demonstrated. X (43) List, B.; Lerner, R. A.; Barbas, C. F., J. Am. Chem. Soc. 2000, 122, 2395. (44) Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126, 450. (45) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243. (46) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370. (47) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894. (48) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 1999, 121, 6519. (49) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 5139. (50) Ooi, T.; Takeuchi, M.; Maruoka, K. Synthesis 2001, 1716. (51) Ooi, T.; Tayama, E.; Doda, K.; Takeuchi, M.; Maruoka, K. Synlett 2000, 1500. (52) Ooi, T.; Uematsu, Y.; Kameda, M.; Maruoka, K. Angew. Chem., Int. Ed. 2002, 41, 1551. (53) Wynberg, H.; Helder, R. Tetrahedron Lett. 1975, 46, 4057. (54) Hermann, K.; Wynberg, H. J. Org. Chem. 1979, 44, 2238. (55) Wynberg, H.; Smaardijk, A. Tetrahedron Lett. 1983, 24, 5899. (56) Smaardijk, A. A.; Noorda, S.; Vanbolhuis, F.; Wynberg, H. Tetrahedron Lett. 1985, 26, 493. (57) Notz, W.; Tanaka, F.; Watanabe, S.; Chowdari, N. S.; Turner, J. M.; Thayumanavan, R.; Barbas, C. F., J. Org. Chem. 2003, 68, 9624. (58) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bogevig, A.; Jorgensen, K. A. J. Am. Chem. Soc. 2002, 124, 6254. (59) Chen, Y.; Deng, L. J. Am. Chem. Soc. 2001, 123, 11302. (60) Bolm, C.; Gerlach, A.; Dinter, C. L. Synlett 1999, 195. (61) Bolm, C.; Schiffers, I.; Dinter, C. L.; Gerlach, A. J. Org. Chem. 2000, 65, 6984. (62) Bolm, C.; Schiffers, I.; Atodiresei, I.; Hackenberger, C. P. R. Tetrahedron: Asymmetry 2003, 14, 3455. (63) Mizuta, S.; Sadamori, M.; Fujimoto, T.; Yamamoto, I. Angew. Chem., Int. Ed. 2003, 42, 3383. (64) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414. (65) Fu, G. Acc. Chem. Res. 2000, 33, 412. (66) Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794. 151 (67) Tao, B. T.; Ruble, J. C.; Hoic, D. A.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 5091. (68) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901. (69) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964. (70) Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4102. (71) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458. (72) Juhl, K.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1498. (73) Halland, N.; Hansen, T.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 4955. (74) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 1192. (75) Wang, W.; Li, H.; Wang, J. Org. Lett. 2005, 7, 1637. (76) LasterraSanchez, M. E.; Felfer, U.; Mayon, P.; Roberts, S. M.; Thornton, S. R.; Todd, C. J. J. Chem. Soc., Perkin Trans. 1996, 343. (77) Kroutil, W.; Mayon, P.; LasterraSanchez, M. E.; Maddrell, S. J.; Roberts, S. M.; Thornton, S. R.; Todd, C. J.; Tuter, M. Chem. Com. 1996, 845. (78) Julia, S.; Guixer, J.; Masana, J.; Rocas, J.; Colonna, S.; Annuziata, R.; Molinari, H. J. Chem. Soc., Perkin Trans. 1982, 1317. (79) Julia, S.; Masana, J.; Vega, J. C. Angew. Chem., Int. Ed. 1980, 19, 929. (80) Wu, X.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124, 8792. (81) Marigo, M.; Franzen, J.; Poulsen, T. B.; Zhuang, W.; Jorgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964. (82) Brandau, S.; Landa, A.; Franzen, J.; Marigo, M.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2006, 45, 4305. (83) Marigo, M.; Fielenbach, D. I.; Braunton, A.; Kjoersgaard, A.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703. (84) Marigo, M.; Schulte, T.; Franzen, J.; Jorgensen, K. A. J. Am. Chem. Soc. 2005, 127, 15710. (85) Marigo, M.; Bertelsen, S.; Landa, A.; Jorgensen, K. A. J. Am. Chem. Soc. 2006, 128, 5475. (86) Brandau, S.; Maerten, E.; Jorgensen, K. A. J. Am. Chem. Soc. 2006, 128, 14986. (87) Li, H.; Wang, J.; E-Nunu, T.; Zu, L. S.; Jiang, W.; Wei, S.; Wang, W. Chem. Com. 2007, 507. 152 (88) Govender, T.; Hojabri, L.; Moghaddam, F. M.; Arvidsson, P. I. Tetrahedron: Asymmetry 2006, 17, 1763. (89) Enders, D.; Huttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861. (90) Julienne, K.; Metzner, P.; Henryon, V. J. Chem. Soc., Perkin Trans. 1999, 731. (91) Aggarwal, V. K.; Ferrara, M.; O'Brien, C. J.; Thompson, A.; Jones, R. V. H.; Fieldhouse, R. J. Chem. Soc., Perkin Trans. 2001, 1635. (92) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566. (93) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 6751. (94) Sakakura, A.; Suzuki, K.; Nakano, K.; Ishihara, K. Org. Lett. 2006, 8, 2229. (95) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625. (96) Berkessel, A.; Cleemann, F.; Mukherjee, S. Angew. Chem., Int. Ed. 2005, 44, 7466. (97) Hills, I. D.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 3921. (98) Tian, S.; Hong, R.; Deng, L. J. Am. Chem. Soc. 2003, 125, 9900. (99) Wu, X.; Jiang, Z.; Shen, H.; Lu, Y. Adv. Synth. Catal. 2007, 349, 812. (100) Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7, 3873. (101) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (102) Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151. (103) Wilson, R. M.; Jen, W. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 11616. (104) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874. (105) Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240. (106) Yang, J.; Fonseca, M. T. H.; List, B. Angew. Chem., Int. Ed. 2004, 43, 6660. (107) Yang, J.; Fonseca, M. T. H.; Vignola, N.; List, B. Angew. Chem., Int. Ed. 2005, 44, 108. (108) Enders, D.; Seki, A. Synlett 2002, 26. (109) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas, C. F., Tetrahedron Lett. 2001, 42, 4441. (110) Tuttle, J. B.; Ouellet, S. G.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 12662. (111) Gordillo, R.; Houk, K. N. J. Am. Chem. Soc. 2006, 128, 3543. 153 (112) Pulkkinen, J.; Aburel, P. S.; Halland, N.; Jorgensen, K. A. Adv. Synth. Catal. 2004, 346, 1077. (113) Halland, N.; Aburel, P. S.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 1272. (114) Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996, 61, 3520. (115) Halland, N.; Hazell, R. G.; Jorgensen, K. A. J. Org. Chem. 2002, 67, 8331. (116) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975. (117) Halland, N.; Aburel, P. S.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 661. (118) Barbas, C. F. Angew. Chem., Int. Ed. 2008, 47, 42. (119) List, B. Chem. Com. 2006, 819. (120) Marigo, M.; Jorgensen, K. A. Chem. Com. 2006, 2001. (121) Peng, F.; Shao, Z. J. Mol. Catal. A-Chem. 2008, 285, 1. (122) Heine, A.; DeSantis, G.; Luz, J. G.; Mitchell, M.; Wong, C. H.; Wilson, I. A. Science 2001, 294, 369. (123) Clark, R. A.; Parker, D. C. J. Am. Chem. Soc. 1971, 93, 7257. (124) Boyd, D. R.; Jennings, W. B.; Waring, L. C. J. Org. Chem. 1986, 51, 992. (125) Capon, B.; Wu, Z. P. J. Org. Chem. 1990, 55, 2317. (126) List, B. Tetrahedron 2002, 58, 5573. (127) Movassaghi, M.; Jacobsen, E. N. Science 2002, 298, 1904. (128) Bassan, A.; Zou, W.; Reyes, E.; Himo, F.; Cordova, A. Angew. Chem., Int. Ed. 2005, 44, 7028. (129) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F., J. Am. Chem. Soc. 2007, 129, 288. (130) Luo, S.; Xu, H.; Li, J.; Zhang, L.; Cheng, J. J. Am. Chem. Soc. 2007, 129, 3074. (131) Xu, Y.; Cordova, A. Chem. Com. 2006, 460. (132) Xu, Y.; Zou, W.; Sunden, H.; Ibrahem, S.; Cordova, A. Adv. Synth. Catal. 2006, 348, 418. (133) Tsogoeva, S. B.; Wei, S. W. Chem. Com. 2006, 1451. (134) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170. (135) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 6366. (136) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005, 127, 10504. (137) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2007, 129, 8930. 154 (138) Kim, H.; Yen, C.; Preston, P.; Chin, J. Org. Lett. 2006, 8, 5239. (139) Mayer, S.; List, B. Angew. Chem., Int. Ed. 2006, 45, 4193. (140) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368. (141) Zhou, J.; List, B. J. Am. Chem. Soc. 2007, 129, 7498. (142) Wang, X.; List, B. Angew. Chem., Int. Ed. 2008, 47, 1119. (143) Akiyama, T. Chem. Rev. 2007, 107, 5744. (144) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45, 3909. (145) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (146) Marcelli, T.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 7496. (147) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Mazzanti, A.; Sambri, L.; Melchiorre, P. Chem. Com. 2007, 722. (148) Connon, S. J. Chem.-Eur. J. 2006, 12, 5418. (149) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967. (150) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367. (151) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.; Sambri, L.; Melchiorre, P. Org. Lett. 2007, 9, 1403. (152) Chen, W.; Du, W.; Yue, L.; Li, R.; Wu, Y.; Ding, L.; Chen, Y. Org. Biomol. Chem. 2007, 5, 816. (153) Bode, S. E.; Wolberg, M.; Muller, M. Synthesis-Stuttgart 2006, 557. (154) Evans, D. A.; Hoveyda, A. H. J. Org. Chem. 1990, 55, 5190. (155) Ricci, P.; Carlone, A.; Bartoli, G.; Bosco, M.; Sambri, L.; Melchiorre, P. Adv. Synth. Catal. 2008, 350, 49. (156) Bogevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790. (157) List, B. J. Am. Chem. Soc. 2002, 124, 5656. (158) Janey, J. M. Angew. Chem., Int. Ed. 2005, 44, 4292. (159) Guillena, G.; Ramon, D. J. Tetrahedron-Asymmetry 2006, 17, 1465. (160) Jung, S.; Kim, D. Tetrahedron Lett. 2008, 49, 5527. 155 (161) Terada, M.; Nakano, M.; Ube, H. J. Am. Chem. Soc. 2006, 128, 16044. (162) He, R.; Wang, X.; Hashimoto, T.; Maruoka, K. Angew. Chem., Int. Ed. 2008, 47, 9466. (163) Xu, X.; Yabuta, T.; Yuan, P.; Takemoto, Y. Synlett 2006, 137. (164) Chen, Y. Synlett 2008, 1919. (165) Dahlin, N.; Bogevig, A.; Adolfsson, H. Adv. Synth. Catal. 2004, 346, 1101. (166) Franzen, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kjaersgaard, A.; Jorgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296. (167) Nishikawa, Y.; Kitajima, M.; Takayama, H. Org. Lett. 2008, 10, 1987. (168) Vogt, H.; Vanderheiden, S.; Brase, S. Chem. Com. 2003, 2448. (169) Baumann, T.; Vogt, H.; Brase, S. Eur. J. Org. Lett. 2007, 266. (170) Chowdari, N. S.; Barbas, C. F., III. Org. Lett. 2005, 7, 867. (171) Baumann, T.; Bachle, M.; Hartmann, C.; Brase, S. Eur. J. Org. Lett. 2008, 2207. (172) Suri, J. T.; Steiner, D. D.; Barbas, C. F., III. Org. Lett. 2005, 7, 3885. (173) Thomassigny, C.; Prim, D.; Greck, C. Tetrahedron Lett. 2006, 47, 1117. (174) Lacoste, E.; Vaique, E.; Berlande, M.; Pianet, I.; Vincent, J. M.; Landais, Y. Eur. J. Org. Lett. 2007, 167. (175) Hayashi, Y.; Aratake, S.; Imai, Y.; Hibino, K.; Chen, Q. Y.; Yamaguchi, J.; Uchimaru, T. Chem.Asian J. 2008, 3, 225. (176) Kotrusz, P.; Alemayehu, S.; Toma, T.; Schmalz, H. G.; Adler, A. Eur. J. Org. Lett. 2005, 4904. (177) Diner, P.; Kjaersgaard, A.; Lie, M. A.; Jorgensen, K. A. Chem.-Eur. J. 2008, 14, 122. (178) Iwamura, H.; Mathew, S. P.; Blackmond, D. G. J. Am. Chem. Soc. 2004, 126, 11770. (179) Iwamura, H.; Wells, D. H.; Mathew, S. P.; Klussmann, M.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2004, 126, 16312. (180) Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120. (181) Liu, X. -F.; Sun, B.; Deng, L. Synlett 2009, 1685. (182) Liu, X.-F.; Li, H.-M.; Deng, L. Org. Lett. 2005, 7, 167. 156 (183) Melgar-Fernandez, R.; Gonzalez-Olvera, R.; Olivares-Romero, J. L.; Gonzalez-Lopez, V.; Romero-Ponce, L.; Ramirez-Zarate, M. D.; Demare, P.; Regla, I.; Juaristi, E. Eur. J. Org. Lett. 2008, 655. (184) Vogt, H.; Baumann, T.; Nieger, M.; Bräse, S. Eur. J. Org. Lett. 2006, 2006, 5315. (185) Liu, T.; Cui, H.; Zhang, Y.; Jiang, K.; Du, W.; He, Z.; Chen, Y. Org. Lett. 2007, 9, 3671. (186) Groger, H.; Vogl, E. M.; Shibasaki, M. Chem. Eur. J. 1998, 4, 1137. (187) Kleemann, A.; Engels, J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances: Syntheses, Patents, Applications; 4th edition ed. Thieme, Stuttgart, 2001. (188) Kobayashi, S.; Fujishita, Y.; Mukaiyama, T. Chem. Lett. 1990, 1455. (189) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1997, 36, 1871. (190) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168. (191) Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 1997, 119, 7893 and references cited therein. (192) Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187. (193) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003. (194) Shioiri, T.; Bohsako, A.; Ando, A. Heterocycles 1996, 42, 93. (195) Chen, C.; Chao, S.; Yen, K.; Chen, C.; Chou, I.; Hon, S. J. Am. Chem. Soc. 1997, 119, 11341. (196) Danishefsky, S. J.; Masters, J. J.; Young, W. B.; Link, J. T.; Snyder, L. B.; Magee, T. V.; Jung, D. K.; Isaacs, R. C. A.; Bornmann, W. G.; Alaimo, C. A.; Coburn, C. A.; Digrandi, M. J. J. Am. Chem. Soc. 1996, 118, 2843. (197) Nagamitsu, T.; Sunazuka, T.; Obata, R.; Tomoda, H.; Tanaka, H.; Harigaya, Y.; Omura, S.; Smith, A. B. J. Org. Chem. 1995, 60, 8126. (198) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386. (199) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroder, G.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968. 157 (200) Zhou, Y.; Shan, Z. J. Org. Chem. 2006, 71, 9510. (201) Zhou, Y.; Shan, Z. Tetrahedron-Asymmetry 2006, 17, 1671. (202) Suri, J. T.; Mitsumori, S.; Albertshofer, K.; Tanaka, F.; Barbas, C. F. J. Org. Chem. 2006, 71, 3822. (203) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem., Int. Ed. 2003, 42, 2785. (204) Kumar, I.; Rode, C. V. Tetrahedron-Asymmetry 2007, 18, 1975. (205) Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2004, 43, 2152. (206) Thayumanavan, R.; Tanaka, F.; Barbas, C. F. Org. Lett. 2004, 6, 3541. (207) Enders, D.; Gasperi, T. Chem. Com. 2007, 88. (208) Bernard, A. M.; Frongia, A.; Guillot, R.; Piras, P. P.; Secci, F.; Spiga, M. Org. Lett. 2007, 9, 541. (209) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 12911. (210) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 11273. (211) Bahmanyar, S.; Houk, K. N. Org. Lett. 2003, 5, 1249. (212) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475. (213) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16. (214) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H. Y.; Houk, K. N. Acc. Chem. Res. 2004, 37, 558. (215) Nakadai, M.; Saito, S.; Yamamoto, H. Tetrahedron 2002, 58, 8167. (216) Tang, Z.; Jiang, F.; Yu, L.; Cui, X.; Gong, L.; Mi, A.; Jiang, Y.; Wu, Y. J. Am. Chem. Soc. 2003, 125, 5262. (217) Dickerson, T. J.; Janda, K. D. J. Am. Chem. Soc. 2002, 124, 3220. (218) Cordova, A.; Barbas, C. F., Tetrahedron Lett. 2002, 43, 7749. (219) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983. (220) Berkessel, A.; Koch, B.; Lex, J. Adv. Synth. Catal. 2004, 346, 1141. (221) Mase, N.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., Org. Lett. 2004, 6, 2527. 158 (222) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611. (223) Martin, H. J.; List, B. Synlett 2003, 1901. (224) Cordova, A.; Notz, W.; Barbas, C. F., J. Org. Chem. 2002, 67, 301. (225) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798. (226) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84. (227) Krattiger, P.; Kovasy, R.; Revell, J. D.; Ivan, S.; Wennemers, H. Org. Lett. 2005, 7, 1101. (228) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., J. Am. Chem. Soc. 2001, 123, 5260. (229) Pizzarello, S.; Weber, A. L. Science 2004, 303, 1151. (230) Cordova, A.; Zou, W.; Ibrahem, I.; Reyes, E.; Engqvist, M.; Liao, W. Chem. Com. 2005, 3586. (231) Zou, W.; Ibrahem, I.; Dziedzic, P.; Sunden, H.; Cordova, A. Chem. Com. 2005, 4946. (232) Cordova, A.; Zou, W.; Dziedzic, P.; Ibrahem, I.; Reyes, E.; Xu, Y. Chem. Eur. J. 2006, 12, 5383. (233) Dziedzic, P.; Zou, W. B.; Hafren, J.; Cordova, A. Org. Biomol. Chem. 2006, 4, 38. (234) Amedjkouh, M. Tetrahedron-Asymmetry 2007, 18, 390. (235) Deng, D.; Cai, J. Helv. Chim. Acta 2007, 90, 114. (236) Jiang, Z.; Liang, Z.; Wu, X.; Lu, Y. Chem. Com. 2006, 2801. (237) Teo, Y. C. Tetrahedron-Asymmetry 2007, 18, 1155. (238) Wu, X.; Jiang, Z.; Shen, H.; Lu, Y. Adv. Synth. Catal. 2007, 349, 812. (239) Utsumi, N.; Imai, M.; Tanaka, F.; Ramasastry, S. S. V.; Barbas, C. F. Org. Lett. 2007, 9, 3445. (240) Ramasastry, S. S. V.; Albertshofer, K.; Utsumi, N.; Tanaka, F.; Barbas, C. F. Angew. Chem., Int. Ed. 2007, 46, 5572. (241) Demuynck, A. L. W.; Vanderleyden, J.; Sels, B. F. Adv. Synth. Catal. 2010, 352, 2421. (242) Li, J.; Fu, N.; Li, X.; Luo, S.; Cheng, J. J. Org. Chem. 2010, 75, 4501. (243) Hu, S.; Zhang, L.; Li, J.; Luo, S.; Cheng, J. Eur. J. Org. Lett. 2011, 3347. (244) Zheng, B.; Liu, Q.; Guo, C.; Wang, X.; He, L. Org. Biomol. Chem. 2007, 5, 2913. (245) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033. (246) Krause, N.; Hoffmann-Roder, A. Synthesis-Stuttgart 2001, 171. 159 (247) Almasi, D.; Alonso, D. A.; Najera, C. Tetrahedron-Asymmetry 2007, 18, 299. (248) Tsogoeva, S. B. Eur. J. Org. Lett. 2007, 1701. (249) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243. (250) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416. (251) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79. (252) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172. (253) Austin, J. F.; Kim, S. G.; Sinz, C. J.; Xiao, W. J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5482. (254) Xu, L. -W.; Luo, J.; Lu, Y. Chem. Com. 2009, 1807. (255) Xu, L. -W.; Lu, Y. Org. Biomol. Chem. 2008, 6, 2047. (256) Bartoli, G.; Melchiorre, P. Synlett 2008, 1759. (257) Xie, J.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J.; Chen, Y. Org. Lett. 2007, 9, 413. (258) Xie, J.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y.; Wu, Y.; Zhu, J.; Deng, J. Angew. Chem., Int. Ed. 2007, 46, 389. (259) Li, P.; Wang, Y.; Liang, X.; Ye, J. Chem. Com. 2008, 3302. (260) Carlone, A.; Bartoli, G.; Bosco, M.; Pesciaioli, F.; Ricci, P.; Sambri, L.; Melchiorre, P. Eur. J. Org. Lett. 2007, 2007, 5492. (261) Singh, R. P.; Bartelson, K.; Wang, Y.; Su, H.; Lu, X.; Deng, L. J. Am. Chem. Soc. 2008, 130, 2422. (262) Chen, W.; Du, W.; Duan, Y.; Wu, Y.; Yang, S.; Chen, Y. Angew. Chem., Int. Ed. 2007, 46, 7667. (263) Lu, X.; Liu, Y.; Sun, B.; Cindric, B.; Deng, L. J. Am. Chem. Soc. 2008, 130, 8134. (264) Cheng, L.; Han, X.; Huang, H.; Wong, M.; Lu, Y. Chem. Com. 2007, 4143. (265) Cheng, L.; Wu, X.; Lu, Y. Org. Biomol. Chem. 2007, 5, 1018. (266) Zhu, Q.; Cheng, L.; Lu, Y. Chem. Com. 2008, 6315. (267) Han, X.; Kwiatkowski, J.; Xue, F.; Huang, K. -W.; Lu, Y. Angew. Chem., Int. Ed. 2009, 48, 7604. (268) Zhu, Q.; Lu, Y. Chem. Com. 2010, 46, 2235. (269) Jiang, Z.; Lu, Y. Tetrahedron Lett. 2010, 51, 1884. (270) Jiang, Z.; Yang, H.; Han, X.; Luo, J.; Wong, M.; Lu, Y. Org. Biomol. Chem. 2010, 8, 1368. 160 (271) Charette, A. B.; Wurz, R. P.; Ollevier, T. Helv. Chim. Acta 2002, 85, 4468. (272) Fornicola, R. S.; Oblinger, E.; Montgomery, J. J. Org. Chem. 1998, 63, 3528. (273) Shen, B.; Johnston, J. N. Org. Lett. 2008, 10, 4397. (274) Singh, A.; Yoder, R. A.; Shen, B.; Johnston, J. N. J. Am. Chem. Soc. 2007, 129, 3466. (275) Singh, A.; Johnston, J. N. J. Am. Chem. Soc. 2008, 130, 5866. (276) Knudsen, K. R.; Jorgensen, K. A. Org. Biomol. Chem. 2005, 3, 1362. (277) Ikariya, T.; Wang, H.; Watanabe, M.; Murata, K. J. Organomet. Chem. 2004, 689, 1377. (278) Prieto, A.; Halland, N.; Jorgensen, K. A. Org. Lett. 2005, 7, 3897. (279) For a recent book, see: Song, C. E. (Ed.), Cinchoan Alkaloids in Synthesis & Catalysis: Ligands, Immobilization and Organocatalysis, Wiley-VCH, Weinheim, 2009. (280) Han, X.; Luo, J.; Liu, C.; Lu, Y. Chem. Com. 2009, 2044. (281) Ding, C. H.; Maruoka, K. Synlett 2009, 664. (282) Jiang, Z.; Pan, Y.; Zhao, Y.; Ma, T.; Lee, R.; Yang, Y.; Huang, K. -W.; Wong, M.; Tan, C. Angew. Chem., Int. Ed. 2009, 48, 3627. (283) Pan, Y.; Zhao, Y.; Ma, T.; Yang, Y.; Liu, H.; Jiang, Z.; Tan, C. Chem.-Eur. J. 2010, 16, 779. (284) Li, H.; Zhang, S.; Yu, C.; Song, X.; Wang, W. Chem. Com. 2009, 2136. (285) Prakash, G. K. S.; Wang, F.; Stewart, T.; Mathew, T.; Olah, G. A. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 4090. (286) Takeuchi, Y.; Nagata, K.; Koizumi, T. J. Org. Chem. 1989, 54, 5453. (287) Catherine Sylvain; Alain Wagner; Mioskowski, C. Tetrahedron Lett. 1999, 40, 875. (288) Titu, D.; Chadha, A. Tetrahedron: Asymmetry 2008, 19, 1698. (289) Taylor, M. D.; Himmelsbach, R. J.; Kornberg, B. E.; Quin, J.; Lunney, E.; Michel, A. The J. Org. Chem. 1989, 54, 5585. (290) Alza, E.; Cambeiro, X. C.; Jimeno, C.; Pericàs, M. A. Org. Lett. 2007, 9, 3717. (291) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. (292) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. 161 (293) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638. (294) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138. (295) Berkessel, A.; Groger, H. Asymmetric Organocatalysis, Wiley-VCH, Weinheim, 2005. (296) Dalko, P. I. Enantioselective Organocatalysis: Reactions and Experimental Procedures, WileyVCH, Weinheim, 2007. (297) List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395. (298) Davie, E. A. C.; Mennen, S. M.; Xu, Y. J.; Miller, S. J. Chem. Rev. 2007, 107, 5759. (299) Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336. (300) García-García, P.; Lay, F.; García-García, P.; Rabalakos, C.; List, B. Angew. Chem., Int. Ed. 2009, 48, 4363. (301) Liao, S. H.; List, B. Angew. Chem., Int. Ed. 2010, 49, 628. (302) Lifchits, O.; Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2010, 132, 10227. (303) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496. (304) Liu, C.; Lu, Y. Org. Lett. 2010, 12, 2278. (305) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570. (306) Xie, J.; Huang, X.; Fan, L.; Xu, D.; Li, X.; Su, H.; Wen, Y. Adv. Synth. Catal. 2009, 351, 3077. (307) Crommelin, D. J. A.; Storm, G. Eur. J. Pharm. Sci. 1994, 2, 17. (308) Kompella, U. B.; Lee, V. H. L. Adv. Drug Deliv. Rev. 1992, 8, 115. (309) Barrett, G. C. In Amino Acids, Peptides and Proteins; The Royal Society of Chemistry: 1998; Vol. 29. (310) Williams, R. M. Synthesis of Optically Active α-Amino Acids; Pergamon, Oxford, 1989. (311) Baldwin, J. E.; Lee, V.; Schofield, C. J. Heterocycles 1992, 34, 903. (312) Shrader, W. D.; Marlowe, C. K. Bioorg. Med. Chem. Lett. 1995, 5, 2207. (313) Badorrey, R.; Cativiela, C.; Diazdevillegas, M. D.; Galvez, J. A. Tetrahedron-Asymmetry 1995, 6, 2787. (314) Boyce, R. J.; Mulqueen, G. C.; Pattenden, G. Tetrahedron 1995, 51, 7321. (315) Gershonov, E.; Granoth, R.; Tzehoval, E.; Gaoni, Y.; Fridkin, M. J. Med. Chem. 1996, 39, 4833. 162 (316) Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92, 889. (317) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem.-Int. Edit. Engl. 1996, 35, 2708. (318) Wirth, T. Angew. Chem.-Int. Edit. Engl. 1997, 36, 225. (319) Bedingfield, J. S.; Kemp, M. C.; Jane, D. E.; Tse, H. W.; Roberts, P. J.; Watkins, J. C. Brit. J. Phar. 1995, 116, 3323. (320) Sekiyama, N.; Hayashi, Y.; Nakanishi, S.; Jane, D. E.; Tse, H. W.; Birse, E. F.; Watkins, J. C. Brit. J. Phar. 1996, 117, 1493. (321) Hartmann, C. E.; Baumann, T.; Bachle, M.; Brase, S. Tetrahedron-Asymmetry 2010, 21, 1341. (322) Fu, J.; Xu, X.; Li, Y.; Huang, Q.; Wang, L. Org. Biomol. Chem. 2010, 8, 4524. (323) Moteki, S.; Xu, S.; Arimitsu, S.; Maruoka, K. J. Am. Chem. Soc. 2010, 132, 17074. (324) Zhu, Q.; Lu, Y. Angew. Chem., Int. Ed. 2010, 49, 7753. (325) Luo, J.; Xu, L.-W.; Hay, R. A. S.; Lu, Y. Org. Lett. 2009, 11, 437. (326) Han, X.; Zhong, F.; Lu, Y. Adv. Synth. Catal. 2010, 352, 2778. (327) Zhong, F.; Chen, G.; Lu, Y. Org. Lett. 2011, 13, 82. (328) Luo, J.; Wang, H.; Han, X.; Xu, L.-W; Kwiatkowski, J.; Huang, K. -W.; Lu, Y. Angew. Chem., Int. Ed. 2011, 50, 1861. (329) Han, X.; Wang, Y.; Zhong, F.; Lu, Y. J. Am. Chem. Soc. 2011, 133, 1726. (330) Bella, M.; Gasperi, T. Synthesis 2009, 2009, 1583. (331) Extensive decompositions were observed, we suspect the aldehyde substrate may decompose under the reaction conditions. (332) Friest, J. A.; Maezato, Y.; Broussy, S.; Blum, P.; Berkowitz, D. B. J. Am. Chem. Soc. 2010, 132, 5930. (333) Martin, R.; Islas, G.; Moyano, A.; Pericas, M. A.; Riera, A. Tetrahedron 2001, 57, 6367. (334) For a recent book, see: Quaternary Stereocenters (Eds.: J. Christoffers, A. Barw), Wiely-VCH, Weinheim, 2005. (335) Hayashi, Y.; Yamaguchi, H.; Toyoshima, M.; Okado, K.; Toyo, T.; Shoji, M. Chem.-Eur. J. 2010, 16, 10150. 163 (336) Nicewicz, D. A.; Satterfield, A. D.; Schmitt, D. C.; Johnson, J. S. J. Am. Chem. Soc. 2008, 130, 17281. (337) Cuzzupe, A. N.; Di Florio, R.; White, J. M.; Rizzacasa, M. A. Org. Biomol. Chem. 2003, 1, 3572. (338) Narasaka, K.; Sakakura, T.; Uchimaru, T.; Guedinvuong, D. J. Am. Chem. Soc. 1984, 106, 2954. (339) Pasqualotto, A. C.; Thiele, K. O.; Goldani, L. Z. Curr. Opin. Investig. Drugs 2010, 11, 165. (340) Wu, X.; Oehrngren, P.; Ekegren, J. K.; Unge, J.; Unge, T.; Wallberg, H.; Samuelsson, B.; Hallberg, A.; Larhed, M. J. Med. Chem. 2008, 51, 1053. (341) Partridge, J. J.; Shiuey, S. J.; Chadha, N. K.; Baggiolini, E. G.; Blount, J. F.; Uskokovic, M. R. J. Am. Chem. Soc. 1981, 103, 1253. (342) Shintani, R.; Takatsu, K.; Hayashi, T. Org. Lett. 2008, 10, 1191. (343) Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature 2008, 456, 778. (344) Rueping, M.; Theissmann, T.; Kuenkel, A.; Koenigs, R. M. Angew. Chem., Int. Ed. 2008, 47, 6798. (345) Ogawa, S.; Shibata, N.; Inagaki, J.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2007, 46, 8666. (346) Li, H.; Wang, B.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732. (347) Torok, B.; Abid, M.; London, G.; Esquibel, J.; Torok, M.; Mhadgut, S. C.; Yan, P.; Prakash, G. K. S. Angew. Chem., Int. Ed. 2005, 44, 3086. (348) Oisaki, K.; Zhao, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 7164. (349) Dosa, P. I.; Fu, G. J. Am. Chem. Soc. 1998, 120, 445. (350) Harada, T.; Nakajima, H.; Ohnishi, T.; Takeuchi, M.; Oku, A. J. Org. Chem. 1992, 57, 720. (351) Jung, B.; Hong, M. S.; Kang, S. H. Angew. Chem., Int. Ed. 2007, 46, 2616. (352) Jung, B.; Kang, S. H. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 1471. (353) Yanagisawa, A.; Terajima, Y.; Sugita, K.; Yoshida, K. Adv. Synth. Catal. 2009, 351, 1757. (354) Wang, F.; Xiong, Y.; Liu, X.; Feng, X. Adv. Synth. Catal. 2007, 349, 2665. (355) Mikami, K.; Kawakami, Y.; Akiyama, K.; Aikawa, K. J. Am. Chem. Soc. 2007, 129, 12950. (356) Samanta, S.; Zhao, C. J. Am. Chem. Soc. 2006, 128, 7442. (357) Akullian, L. C.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 6532. 164 (358) Tokuda, O.; Kano, T.; Gao, W. G.; Ikemoto, T.; Maruoka, K. Org. Lett. 2005, 7, 5103. (359) Jiang, B.; Chen, Z. L.; Tang, X. Org. Lett. 2002, 4, 3451. (360) Bogevig, A.; Kumaragurubaran, N.; Jorgensen, K. A. Chem. Com. 2002, 620. (361) Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 1997, 119, 7893. (362) Zheng, C.; Wu, Y.; Wang, X.; Zhaoa, G. Adv. Synth. Catal. 2008, 350, 2690. (363) Cao, C.; Sun, X.; Kang, Y.; Tang, Y. Org. Lett. 2007, 9, 4151. (364) Li, P.; Zhao, J.; Li, F.; Chan, A. S. C.; Kwong, F. Y. Org. Lett. 2010, 12, 5616. (365) Li, P.; Chan, S.; Chan, A. S. C.; Kwong, F. Y. Adv. Synth. Catal. 2011, 353, 1179. (366) Melchiorre, P.; Bartoli, G. Synlett 2008, 2008, 1759. (367) Liu, C.; Zhu, Q.; Huang, K. -W.; Lu, Y. Org. Lett. 2011, 13, 2638. (368) When the free hydroxyacetone was used as a donor in the aldol reaction with 2a in the presence of 8/TFA, only [...]... 1.2 Selection of typical organic catalysts Figure 1.3 Steric Factors in iminium ion activation Figure 1.4 Models to explain the opposite enantioselectivity of amination of aldehydes catalyzed by 4 and 32 Figure 1.5 Proline analogues used as organic catalysts Figure 1.6 Some typical examples of chiral primary amine catalysts Figure 3.1 Primary amine chiral acid catalytic system for the enamine catalysis... lysine residues, utilize a primary amine motif in catalysis.122 The chemistry community‟s low level of interest in using primary amines could be explained by the notion of unfavorable imine-enamine equilibrium.123-125 Yet, another reason is that the advent of proline had drawn too much attention to the uses of cyclic secondary amines as organic catalysts. 126,127 With the advent of some recent reports demonstrating... main classes of catalysts for asymmertric chemical reactions.2 In the last century, chemists have rarely employed small organic molecules as catalysts, although some of the very first asymmetric catalysts were purely organic molecules Otswald introduced organic catalyst‟ in 1900 for the first time, in order to differentate organic compounds as catalysts from those based on enzymes and inorganic compounds.3... -amination of -substituted -cyanoacetates Scheme 1.16 -sulfamidation of -branched aldehydes catalyzed by L-proline 4 Scheme 1.17 Direct -amination of aromatic ketones catalyzed by primary amines derived from cinchona alkaloids Scheme 1.18 Early examples of L-Proline-catalyzed aldol reactions reported by List Scheme 1.19 Effects of BINOL on the enantioselectivity of organocatalyzed aldol reactions of acetone... ability of simple natural and unnatural primary amino acid derivatives in promoting important processes such as aldol128-130 and Michael131,132 reactions via the enamine mechanism, primary amines -based catalysis has drawn more and more attention Besides the ability to complement the classical activation modes of proline-derived catalysts, primary amine catalysis offers the unique possibility of participating...List of Tables Table 2.1 Screening of Organic catalysts for the Conjugate Addition of Ethyl Nitro Acetate to trans-4-Phenyl-3-buten-2-one Table 2.2 Conjugate Addition of Ethyl Nitroacetate to α,β-Unsaturated Ketones Table 3.1 Screening of Chiral Primary Amines/Acids for the Amination of 2Phenylpropanal 3-1a with Di-tert-butyl azodicarboxylate 3-2a Table 3.2 The Direct Aminations of Various Branched... context, thiourea 24 was proved to be one of the most useful and general bifunctional organic catalysts. 147-150 Thiourea 24 is easily prepared by a two-step procedure from quinine 1 (Scheme 1.8).149,150 The quinine derived primary amine catalyst 25 was obtained after the Mitsunobu reaction of 1 Triggered by the potential 16 benefit of using a less hindered chiral primary amine catalyst, compound 25 was tested... Aldehydes Table 3.3 Lowing the Catalyst Loading of the Reaction Table 4.1 Screening of Organic catalysts for the Aldol Reaction of acetone 4-1a to methyl 2-oxo-4-phenylbut-3-enoate 4-2a Table 4.2 Cinchona Alkaloid Derived Primary Amine Catalysts Screening for the Aldol Reaction of acetone 4-1a to methyl 2-oxo-4-phenylbut-3-enoate 42a Acid Screening for Aldol Reaction of acetone 4-1a to methyl 2-oxo-4phenylbut-3-enoate... 1.5 Primary amines in iminium catalysis: Diels-Alder reaction of - substituted acroleins Chin and co-workers reported the first example of using primary amines in iminium ion activation of acyclic unsaturated ketones in 2006.138 Interestingly, Chin and coworkers started their studies by making efforts to elucidate the reaction mechanism of the warfarin synthesis, which was previously described by Jorgensen... 1.6 Iminium activators of acyclic enones At the end of 2006, the utilization of chiral primary amines‟ in iminium catalysis and enamine catalysis started to expand rapidly, which in many cases could complement to the existing secondary amine- based catalytic methods 1.2.2.2 Asymmetric Counteranion-Directed Catalysis In 2006, List and co-workers introduced a novel strategy for enantioselective synthesis: . DEVELOPMENT OF ENANTIOSELECTIVE SYNTHETIC METHODS PROMOTED BY PRIMARY AMINE-BASED ORGANIC CATALYSTS LIU CHEN NATIONAL UNIVERSITY OF SINGAPORE 2011 II DEVELOPMENT OF. DEVELOPMENT OF ENANTIOSELECTIVE SYNTHETIC METHODS PROMOTED BY PRIMARY AMINE-BASED ORGANIC CATALYSTS LIU CHEN (BSc. Zhejiang Univ.) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY. enantioselective synthetic methods promoted by primary amine-based organic catalysts. Chapter 1 provides a brief historic overview of asymmetric organocatalysis, especially on the development of asymmetric