CHIRAL BICYCLIC GUANIDINE CATALYZED MICHAEL REACTIONS YE WEIPING (BSc., Peking University) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE To my parents, sisters, and Junye, for their love, support, and encouragement Acknowledgements First and foremost, I would like to take this opportunity to thank my supervisor, Assistant Professor Tan Choon-Hong, for his guidance and encouragement throughout my PhD research and study. I appreciate Mr. Goh Kunli’s help in proofreading this manuscript. Mr. Soh Ying Teck and Dr. Jiang Zhiyong’s suggestions and comments also helped improve this thesis. I would also like to thank all my labmates for creating such a harmonious, encouraging, and helpful working environment. My special thanks go to Miss Serena Goh, Mr. Leow Dasheng, Mr. Chian Chee-Hoe, Mr. Tan Chin-Tong, and Dr. Jiang Zhiyong for their participation in different stages of this project. I thank Mdm Han Yanhui and Miss Ler Peggy for their assistance in NMR analysis, and Mdm Wong Lai Kwai and Mdm Lai Hui Ngee for their assistance in Mass analysis as well. I also owe my thanks to many other people in NUS chemistry department, for their help and assistance from time to time. Last but not least, I thank all my friends in Singapore who helped me settle down at the beginning. Singapore is a great place and I enjoy the life here. Table of Contents Summary List of Schemes List of Tables List of Figures List of Abbreviations Chapter Chiral Guanidines and Guanidinium Derivatives as Asymmetric Catalysts------------14 Chapter 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD) Catalyzed Michael Reactions 2.1 The Synthetic Utility of TBD----------------------------------------------------------31 2.2 TBD Catalyzed Michael Reactions---------------------------------------------------32 Chapter Chiral Bicyclic Guanidines Catalyzed Michael Reaction 3.1 An Aziridine-Based Synthesis of Chiral Bicyclic Guanidines --------------------47 3.2 Michael Reaction between 2-Cyclopenten-1-one and 1,3-Dicarbonyl Compounds-------------------------------------------------------------------------------49 3.3 Michael Reactions of Acyclic Michael Acceptors-----------------------------------66 Chapter Michael Reaction between N-Alkyl Maleimides and 1,3-Dicarbonyl Compounds 4.1 Michael Reaction of N-Alkyl Maleimides--------------------------------------------73 4.2 Enantioselective Synthesis of (S)-(+)-homo-β-Proline------------------------------78 Chapter Proposed Stereochemical Model for the Origin of Enantioselectivity-------------------82 Chapter Experimental Procedures 6.1 General Procedures----------------------------------------------------------------------91 6.2 Preparation of S,S’-Dialkyl Dithiomalonates----------------------------------------92 6.3 General Procedures for the Synthesis of Chiral Bicyclic Guanidines------------94 6.4 Typical Experimental Procedures for the Michael Reactions--------------------101 6.5 Characterization of Michael Adducts------------------------------------------------102 6.6 Synthesis of (S)-(+)-β-Proline -------------------------------------------------------141 References ------------------------------------------------------------------------------------146 Appendix--------------------------------------------------------------------------------------156 Publications-----------------------------------------------------------------------------------226 Summary The aim of this study is to develop a highly enantioselective Michael reaction catalyzed by chiral bicyclic guanidines. 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD), a bicyclic guanidine base, was found to be an excellent catalyst for Michael and Michael-type reactions. A wide variety of Michael donors and acceptors can participate in these reactions using 10 - 20 mol% of TDB. These reactions are mild, fast, easy to perform, and proceed with high yields. They can occur in several solvents without the need for strictly anhydrous conditions. A series of chiral bicyclic guanidines, both symmetrical and non-symmetrical, were synthesized using a concise and efficient aziridine-based synthetic methodology. One of the synthesized chiral bicyclic guanidine was found to be a highly enantioselective organocatalyst for the Michael reactions between 2-cyclopenten-1-one and various 1,3-dicarbonyl compounds, including dialkyl malonates, benzoylactetates, and S,S’-dialkyl dithiomalonates. The enantioselectivities generally range from 86-96%, with yields between 84-99%. The substrate scope of the chiral bicyclic guanidine catalyzed Michael reaction was expanded to include N-alkyl maleimides. The enantioselectivities generally range from 90-96%, with yields between 91-99%. The methodology has been applied to the first enantioselective synthesis of (S)-(+)-homo-β-proline, which is a potent GABA agonist and uptake inhibitor. A stereochemical model was proposed to explain the origin of the high enantioselectivity obtained. List of Schemes Scheme 1.1 Ma and Cheng’s chiral guanidine catalyzed Michael reaction of glycinate. Scheme 1.2 Ishikawa’s chiral guanidine catalyzed Michael reaction of glycinate. Scheme 1.3 Ma’s chiral guanidine catalyzed Michael reaction and Diels-Alder reaction between anthrone and maleimide. Scheme 1.4 Chiral bicyclic guanidinium salt catalyzed aza-Michael reaction. Scheme 1.5 Chiral guanidine or guanidinium catalyzed nitro Michael reaction. Scheme 1.6 Terada’s axially chiral guanidine catalyzed Michael reaction of nitroalkene. Scheme 1.7 Lipton’s cyclic dipeptide catalyzed Strecker reaction. Scheme 1.8 Corey’s bicyclic guanidine catalyzed Strecker reaction. Scheme 1.9 Guanidinium slat catalyzed phase transfer epoxidation. Scheme 1.10 Guanidine promoted epoxidation of chalcone. Scheme 1.11 Guanidine promoted epoxidation. Scheme 1.12 Chiral guanidine catalyzed asymmetric silylation of secondary alcohol. Scheme 1.13 Chiral guanidine catalyzed TMS cyanation of aliphatic aldehydes 45. Scheme 1.14 Chiral guanidine mediated azidation of (±)-1-indanol 41a. Scheme 1.15 Isolated complex between TBD and phenyl nitromethane. Scheme 1.16 Henry reaction catalyzed by homochiral guanidine. Scheme 1.17 Diastereoselective Henry reaction catalyzed by chiral guanidines. Scheme 1.18 Diastereoselective Henry reaction catalyzed by a guanidine-thiourea catalyst. Scheme 1.19 Chiral pentacyclic guanidinium salt catalyzed phase transfer alkylation. Scheme 1.20 Chiral tetracyclic guanidinium salt catalyzed phase transfer alkylation. Scheme 2.1 Organobase catalyzed Michael reaction between 2-cyclopenten-1-one 64 and dimethyl malonate 65a. Scheme 2.2 Several organobase catalyzed Michael reaction between Michael acceptors 67 and dimethyl malonate 65a. Scheme 2.3 TBD (10 mol%) catalyzed Michael addition of various carbon nucleophiles to 2-cyclopenten-1-one 64 in toluene at rt. Scheme 2.4 TBD catalyzed Michael reaction between various Michael acceptors 67 and dimethyl malonate 65a. Scheme 2.5 TBD (10 mol%) catalyzed Michael reactions between 2-acetyl-cyclopentanone 65f and various activated terminal alkenes 69a-d. Scheme 3.1 Synthesis of symmetrical chiral bicyclic guanidines. Scheme 3.2 Synthesis of non-symmetrical or hindered chiral bicyclic guanidines. Scheme 3.3 Various chiral bicyclic guanidines catalyzed Michael reaction of 2-cyclopenten-1-one 64 and dimethyl malonate 65a. Scheme 3.4 Chiral bicyclic guanidines 79b catalyzed Michael reaction of 2-cyclopenten-1-one 64 and dimethyl malonate 65a in different conditions. Scheme 3.5 Determination of the absolute configuration of 65y. Scheme 3.6 Bicyclic guanidines catalyzed Michael reaction of nitroalkanes with trans-chalcone 35a. Scheme 3.7 Bicyclic guanidines catalyzed Michael reaction of dimethyl malonate with fumaric derivatives. Scheme 3.8 Bicyclic guanidines catalyzed Michael reaction of dimethyl malonate 65a with fumaric derivatives 84. Scheme 4.1 Cyclic Michael acceptors that resemble 2-cyclopenten-1-one 64 tested in the reaction with dimethyl malonate 65a in the presence of 10 mol% TBD in toluene. Scheme 4.2 Chiral guanidine 79b catalyzed Michael reaction between N-substituted maleimides 87a-b and dimethyl malonate 65a. Scheme 4.3 Chiral guanidine 79b catalyzed Michael reaction between N-alkyl maleimides and S,S’-dialkyl dithiomalonates. Scheme 4.4 Chiral Guanidine 79b catalyzed Michael reaction between N-alkyl maleimides and 1,3-diketones. Scheme 4.5 Derivatization of Michael adducts 90f-h for HPLC analyses. Scheme 4.6 The first enantioselective synthesis of (S)-(+)-homo-β-proline. Scheme 5.1 Proposed catalytic cycle in the chiral bicyclic guanidine catalyzed Michael reaction. List of Tables Table 2.1 The influence of catalyst amount and solvents on the reaction between 2-cyclopenten-1-one 64 and dimethyl malonate 65a. Table 2.2 The influence of different organobases (10 mol%) on the reaction between 2-cyclopenten-1-one 64 and dimethyl malonate 65a in toluene as solvent. Table 2.3 Comparision of TBD with other organobases as catalyst (10 mol%) in the reactions of various substrates 67 and dimethyl malonate 65a (Scheme 2.2). Table 2.4 TBD catalyzed Michael addition of various carbon nucleophiles to 2-cyclopenten-1-one 64 (Scheme 2.3). Table 2.5 TBD (10 mol%) catalyzed Michael reaction between dimethyl malonate and various substrates in toluene. Table 2.6 The reaction times and yields of the reactions in Scheme 2.5. Table 3.1 Various chiral bicyclic guanidines catalyzed Michael addition of dimethyl malonate 65a to 2-cyclopenten-1-one 64 (Scheme 3.3). Table 3.2 Solvent effect on the Michael addition of dimethyl malonate 65a to 2-cyclopenten-1-one 64 catalyzed by 79b (Scheme 3.4). Table 3.3 Concentration and temperature effects on the Michael addition of dimethyl malonate 65a to 2-cyclopenten-1-one 64 catalyzed by 79b in toluene as solvent. Table 3.4 Additive effect on the Michael addition of dimethyl malonate 65a to 2-cyclopenten-1-one 64 catalyzed by 79b. Table 3.5 Chiral guanidine 79b catalyzed Michael addition of various dialkyl malonates to 2-cyclopenten-1-one 64. Table 3.6 Chiral guanidine 79b catalyzed Michael addition of various ethyl benzoylacetates 65l-r to 2-cyclopenten-1-one 64. Table 3.7 Chiral guanidine 79b catalyzed Michael addition of 1,3-diketones 65s-u and 65f to 2-cyclopenten-1-one 64. various 220 210 200 190 n-C6 H 13 N O O 180 170 160 150 140 130 120 110 4.0 100 90 3.0 80 70 2.0 60 50 40 30 20 13.9691 5.0 (ppm) 31.9743 31.3176 29.5245 27.4730 26.4031 22.4404 6.0 40.4530 39.0731 7.0 49.9574 49.7729 8.0 66.1104 3.0140 8.0617 9.0307 9.0687 0.9991 1.0046 O 0.9987 O 1.9954 1.0000 n-C6 H 13 N 77.4080 76.9874 76.5594 9.0 176.9679 175.9939 192.8775 Integral 0.8666 0.8446 1.2717 1.4992 1.4354 2.9490 2.9304 2.8875 2.8689 2.8120 2.7818 2.7517 2.7203 3.5050 3.4818 3.4562 3.3425 3.3239 3.3111 3.2926 3.2740 4.2154 4.1968 7.2612 ja13ywp.2.1 ywp8088 O O St Bu 89c StBu 1.0 0.0 ja13ywp.3.1 ywp8088 13c O O St Bu 89c StBu (ppm) 10 211 220 210 200 Bn N O 190 O 180 7.6 170 7.2 160 6.8 150 6.4 140 6.0 130 5.6 5.2 120 4.8 110 4.4 100 4.0 90 3.6 80 3.2 70 2.8 60 2.4 50 2.0 40 32.2525 29.7433 29.7070 8.0 42.7693 40.7692 8.4 50.1805 50.0059 8.8 66.1593 9.2 77.6215 77.1997 76.7778 9.6 9.0199 9.0436 2.0000 0.9991 0.9999 O 2.0022 O 135.7183 128.8889 128.7435 128.0162 5.4591 Bn N 176.8035 175.7707 193.0805 Integral 1.4934 1.3878 3.3680 3.3495 3.3367 3.3309 3.3181 3.2995 2.9908 2.9722 2.9293 2.9107 2.8410 2.8097 2.7795 2.7482 4.2281 4.2096 4.7075 4.6599 4.6530 4.6054 7.3796 7.3738 7.3540 7.3146 7.3053 7.2867 7.2612 7.2449 de15ywp.2.1 ywp8045-2 O O StBu St Bu 89d (ppm) 1.6 1.2 30 0.8 20 0.4 10 0.0 13C Standard AV300 de16ywp1.1.1 ywp8045-2 O O StBu St Bu 89d (ppm) -10 212 220 210 O 200 8.0 Me N O 190 7.6 180 7.2 170 6.8 160 6.4 150 6.0 140 5.6 130 5.2 120 4.8 110 4.4 100 4.0 3.6 90 3.2 80 2.8 70 2.4 60 2.0 50 1.6 40 1.2 30 25.0158 22.4847 8.4 36.1583 36.0477 32.1293 8.8 40.4973 9.2 12.008 2.0120 3.0075 1.0144 O 2.0058 Me N 65.3135 9.6 1.3681 1.3565 1.3448 1.3344 1.3054 1.2868 1.2822 1.2636 2.9943 2.9409 2.9211 2.8805 2.8608 2.8492 2.8190 2.7877 2.7575 4.3129 4.2943 3.7905 3.7673 3.7441 3.7209 3.7093 3.6988 3.6861 3.6629 3.6408 3.6176 3.3866 3.3680 3.3576 3.3495 3.3378 3.3193 7.2600 O 77.4154 76.9874 76.5668 1.0000 O 176.8868 175.8537 192.5602 Integral ja25ywp.4.1 ywp8112-1 O SiPr SiPr 89e (ppm) 0.8 20 0.4 10 0.0 ja27ywp.2.1 ywp8112-1 O O SiPr SiPr 89e (ppm) 213 220 9.2 210 8.8 8.4 O 200 8.0 Et N O 190 7.6 180 7.2 170 6.8 160 6.4 150 6.0 140 5.6 130 5.2 120 4.8 110 4.4 4.0 100 90 3.6 (ppm) 3.2 80 2.8 ja21ywp.2.1 ywp8090 13c O O SiPr SiPr 89e 70 2.0 60 50 1.2 40 30 0.8 20 12.7147 22.5659 22.4773 1.6 36.1214 36.0181 33.9372 32.0850 2.4 40.4087 2.9969 6.0461 6.0071 1.9993 1.0447 2.0266 O 2.0098 Et N 65.2914 9.6 1.3657 1.3530 1.3425 1.3298 1.3031 1.2833 1.2613 1.1800 1.1556 1.1313 2.9339 2.9142 2.8724 2.8538 2.8248 2.7935 2.7633 2.7319 4.3198 4.3024 3.7859 3.7627 3.7406 3.7174 3.7058 3.6942 3.6826 3.6594 3.6362 3.6141 3.5920 3.5677 3.5433 3.5201 3.3553 3.3367 3.3251 3.3193 3.3065 3.2879 7.2600 O 77.4154 76.9874 76.5668 1.0000 O 176.6506 175.6618 192.6044 192.4864 Integral ja19ywp.2.1 ywp8090 O SiPr SiPr 89e 0.4 0.0 (ppm) 10 214 220 210 O 200 Et N 190 O 180 170 6.8 160 6.4 150 6.0 140 5.6 130 5.2 120 4.8 110 4.4 4.0 100 3.6 90 3.2 80 2.8 70 2.4 60 2.0 50 1.6 40 1.2 30 12.6040 7.2 33.9889 31.4504 7.6 39.8627 8.0 54.2890 8.4 77.4154 76.9947 76.5668 8.8 3.0016 0.9975 0.9997 1.0129 2.0004 1.0000 2.0306 2.9996 O 129.4091 128.8483 128.6786 128.4129 9.2 0.9966 Et N 135.3789 134.5155 133.8292 9.6 2.0021 1.9825 O 177.7280 175.9644 195.1355 194.7223 Integral 1.1493 1.1342 1.1203 3.5951 3.5800 3.5662 3.5510 3.3972 3.3884 3.3783 3.3695 3.3594 3.0152 3.0039 2.9787 2.9673 2.6345 2.6156 2.5979 2.5790 6.0170 6.0082 8.0783 8.0619 7.8249 7.8224 7.8085 7.6976 7.6824 7.6686 7.5765 7.5614 7.5501 7.5463 7.5349 7.5198 7.4076 7.3925 7.3761 7.2613 1H AV500 wp0118.1.1. ywp8084 O O Ph Ph 90a (ppm) 0.8 20 0.4 10 0.0 ja14ywp.3.1 ywp8084 13c O O Ph Ph 90a (ppm) 215 220 210 200 O 190 Me N 180 O 170 160 6.8 150 6.4 140 6.0 5.6 130 5.2 120 4.8 110 4.4 100 4.0 90 3.6 80 3.2 70 2.8 60 2.4 2.0 50 1.6 40 30 25.1304 7.2 31.5287 7.6 39.9966 8.0 54.2872 8.4 77.3153 77.0602 76.8052 8.8 1.0265 4.0362 1.0224 1.0000 2.0527 3.0152 O 129.4929 128.9026 128.7423 128.4289 9.2 1.0132 O 2.0260 2.0071 Me N 135.3300 134.6450 134.5066 133.9163 9.6 178.0122 176.2341 195.1594 194.8606 Integral 3.4203 3.4033 3.3885 3.3721 3.3567 3.0543 3.0357 3.0100 2.9935 2.9754 2.6539 2.6226 2.5936 2.5618 6.0231 6.0094 8.0869 8.0628 8.0590 7.8124 7.7883 7.7845 7.7149 7.7111 7.6892 7.6656 7.6618 7.5900 7.5642 7.5374 7.5314 7.5067 7.5029 7.4092 7.3835 7.3588 7.3566 7.2607 7.2569 1H normal range AV300 de05ywp.1.1 ywp8036-1 O O Ph Ph 90b (ppm) 1.2 0.8 20 0.4 10 0.0 13C AV500 wp1206.2.1 ywp8036-1 13c O O Ph Ph 90b (ppm) -10 216 220 210 200 190 180 n-C6 H13 N O 170 O 160 150 140 130 120 110 100 4.0 90 3.0 80 70 60 2.0 50 40 30 20 13.9054 5.0 (ppm) 31.3897 31.2516 27.3096 26.3350 22.3785 6.0 39.8337 39.1064 7.0 54.1979 8.0 3.0256 6.2360 2.1062 1.0299 1.0314 1.0535 O 2.0255 1.0000 2.0325 O 3.0108 1.0217 2.0105 2.0008 n-C6 H13 N 77.3624 76.9406 76.5187 9.0 135.3646 134.5428 134.4119 133.7573 129.3353 128.7753 128.6153 128.3898 177.8462 176.0716 195.0396 194.5741 Integral 0.8877 0.8680 0.8455 1.5238 1.5090 1.5002 1.2641 3.5201 3.4955 3.4708 3.4095 3.3914 3.3777 3.3602 3.3459 3.0424 3.0238 2.9816 2.9630 2.6518 2.6200 2.5910 2.5592 6.0183 6.0046 8.0761 8.0514 7.8301 7.8060 7.7035 7.6778 7.6542 7.5786 7.5529 7.5337 7.5096 7.4143 7.3880 7.3633 7.2603 7.2581 1H normal range AV300 de05ywp.2.1 ywp8036-2 O O Ph Ph 90c 1.0 0.0 13C Standard AV300 de06ywp.2.1 ywp8036-2 13c O O Ph Ph 90c (ppm) 10 -10 217 220 210 200 Bn N O 190 7.6 O 180 7.2 170 6.8 160 6.4 150 6.0 140 5.6 130 5.2 120 4.8 110 4.4 100 4.0 90 3.6 3.2 80 2.8 70 2.4 60 2.0 50 40 31.5316 8.0 42.6151 40.0177 8.4 54.1267 8.8 77.4227 77.0021 76.5741 9.2 1.0144 1.0109 1.0147 2.0043 1.0000 7.1428 3.0044 O 1.0380 O 2.0622 2.0019 Bn N 135.6002 135.2755 134.5302 133.8661 129.4091 128.8483 128.6786 128.5310 128.5015 128.4350 127.7488 9.6 177.5435 175.6913 195.0396 194.5599 Integral 3.4435 3.4249 3.4110 3.3970 3.3936 3.3785 3.0860 3.0674 3.0256 3.0070 2.6774 2.6460 2.6170 2.5857 4.7748 4.7273 4.6599 4.6123 6.0168 6.0029 7.8125 7.7881 7.7847 7.7011 7.6767 7.6523 7.5711 7.5583 7.5455 7.5339 7.5270 7.5200 7.5096 7.4063 7.3807 7.3552 7.3343 7.3296 7.3099 7.2983 7.2913 7.2809 7.2693 7.2600 7.2461 ja25ywp.2.1 ywp8099 O O Ph Ph 90d (ppm) 1.6 1.2 30 0.8 20 0.4 10 0.0 ja25ywp.3.1 ywp8099 13c O O Ph Ph 90d (ppm) 218 220 210 200 O 190 iBu N 180 O 170 160 6.4 150 140 6.0 130 5.6 5.2 120 4.8 110 4.4 100 4.0 90 3.6 80 3.2 70 2.8 60 2.4 50 2.0 40 1.6 30 20.0948 20.0438 6.8 27.1199 7.2 31.4267 7.6 39.9238 8.0 46.4533 8.4 54.1487 8.8 6.0280 1.0240 1.0266 1.0148 3.0259 1.0000 1.9576 2.9859 O 77.2715 77.0165 76.7614 9.2 0.9767 O 2.0037 2.0027 iBu N 135.4685 134.6232 134.5211 133.8434 129.4346 128.8734 128.7131 128.4799 9.6 178.0996 176.3434 195.1521 194.6492 Integral 3.4066 3.3978 3.3952 3.3877 3.3789 3.3763 3.3675 3.3524 3.3499 3.3373 3.3347 3.3234 3.3083 3.0687 3.0574 3.0322 3.0208 2.6451 2.6262 2.6085 2.5896 2.0551 2.0412 2.0274 2.0135 1.9996 1.9857 1.9719 0.8977 0.8851 0.8763 0.8637 6.0239 6.0163 8.0776 8.0625 7.8318 7.8166 7.6969 7.6817 7.6666 7.5758 7.5607 7.5456 7.5342 7.5191 7.4069 7.3918 7.3754 7.2606 1H AV500 wp0110.1.1. ywp8067 O O Ph Ph 90e (ppm) 1.2 0.8 20 0.4 10 0.0 13C AV500 WP0110.2.1 YWP8067 13C O O Ph Ph 90e (ppm) -10 219 Et 220 210 N 200 H O 190 O 180 7.2 170 6.8 160 6.4 150 6.0 140 5.6 130 5.2 120 4.8 110 4.4 4.0 100 3.6 90 3.2 80 2.8 70 2.4 60 2.0 50 1.6 40 1.2 30 0.8 O O Ph 90f Me 20 0.9744 7.6 12.6261 12.5745 8.0 39.7299 39.4421 33.9667 33.8634 32.3581 31.5168 29.5023 29.2071 8.4 61.2402 59.0928 8.8 77.4596 77.0390 76.6110 9.2 2.3719 3.0233 3.0829 2.3482 3.6969 1.0036 1.5733 2.9759 0.7700 1.0000 O 5.4107 O 135.8954 135.0911 134.5745 134.2794 129.3058 128.9885 128.7302 128.7154 9.6 H 1.5257 2.0118 N 177.7354 177.6837 175.8168 175.5954 Et 195.8070 194.8108 202.2933 201.7030 Integral 3.1939 3.1753 3.1614 3.1486 3.1301 2.8956 2.8643 2.8341 2.8027 2.7795 2.7598 2.7192 2.6994 2.6751 2.6565 2.6135 2.5950 2.5625 2.5335 2.5021 2.2758 2.1376 1.1974 1.1742 1.1498 1.0512 1.0268 1.0024 3.6013 3.5770 3.5537 3.5387 3.5294 3.5015 3.4771 3.4528 3.4295 5.2090 5.1950 5.0488 5.0291 7.2600 8.0249 7.9994 7.9193 7.8938 7.6895 7.6651 7.6407 7.6245 7.5989 7.5676 7.5409 7.5165 7.4933 7.4678 7.4434 ja19ywp.1.1 tct3091 O O Ph Me 90f (ppm) 0.4 0.0 ja21ywp.3.1 tct3091 13c (ppm) 10 220 Et 220 210 N O 200 H O 190 180 7.2 170 6.8 160 6.4 150 6.0 140 5.6 130 5.2 120 4.8 110 4.4 100 4.0 3.6 90 3.2 80 2.8 70 2.4 2.0 O O Ph OEt 90g 60 50 1.6 40 1.2 30 13.8437 13.8363 12.7073 12.6704 7.6 39.6044 39.4126 33.9520 32.4245 32.1810 8.0 53.3076 51.9941 8.4 62.1921 62.0593 8.8 77.4301 77.0021 76.5815 9.2 11.240 3.6142 1.0000 0.7406 4.0377 3.6140 0.6898 1.0033 O 5.3571 O 135.7331 135.4822 134.0949 133.9694 128.9368 128.7597 128.7154 128.4867 9.6 H 168.1646 167.7661 N 1.2837 1.9258 Et 177.6542 177.4845 176.0308 175.9422 193.9991 193.1948 Integral 5.1324 5.1184 4.9060 4.8886 4.2096 4.2038 4.1852 4.1805 4.1550 4.1295 4.1063 3.6292 3.6048 3.5944 3.5816 3.5700 3.5572 3.5468 3.5224 3.4783 3.4597 3.4481 3.4412 3.4295 3.4110 3.3239 3.3111 3.2995 3.2856 3.2740 3.2612 2.9409 2.9211 2.8805 2.8596 2.8422 2.8260 2.8167 2.7958 2.7656 1.2114 1.1870 1.1684 1.1626 1.1580 1.1452 1.1348 1.1208 7.2600 7.9948 7.9704 7.9263 7.9007 7.6535 7.6291 7.6047 7.5873 7.5618 7.5339 7.5072 7.4829 7.4573 7.4318 de15ywp.3.1 ywp8045-3 O O Ph OEt 90g (ppm) 0.8 20 0.4 10 0.0 dpx300 de15ywp.4.1 ywp8045-3 13c (ppm) 221 220 210 t Bu N 200 O 190 O 180 7.2 170 6.8 160 6.4 150 6.0 140 5.6 130 5.2 120 4.8 110 4.4 100 4.0 90 80 3.8729 0.7592 3.6976 0.7396 1.0000 3.6650 0.9678 3.6 3.2 2.8 70 2.4 60 50 9.0015 5.0262 2.0 1.6 1.2 40 30 13.8953 13.8511 7.6 32.6827 32.4319 28.2183 28.1814 8.0 39.6044 39.3830 8.4 62.0593 61.9486 58.5689 53.3887 52.2745 8.8 77.4080 76.9874 76.5668 9.2 135.9470 135.5338 133.9989 133.8440 128.9147 128.7228 128.6859 128.4793 9.6 2.0017 O 168.3933 167.8915 O 1.4060 2.0038 t Bu N 178.7463 178.6356 177.0934 194.1614 193.3645 Integral 5.0821 5.0733 4.8690 4.8589 4.1870 4.1844 4.1819 4.1794 4.1731 4.1681 4.1580 4.1555 4.1529 4.1504 4.1441 4.1416 4.1391 4.1365 3.3562 3.3435 3.3360 3.3322 3.3246 3.3133 3.2250 3.2162 3.2112 3.2061 3.2036 3.1973 3.1923 3.1847 2.8292 2.8166 2.7939 2.7813 2.7762 2.7636 2.7409 2.7308 2.7270 2.7220 2.7119 2.7056 2.6943 2.6854 2.6754 1.5949 1.5546 1.1839 1.1700 1.1537 1.1385 7.2606 7.9276 7.9137 7.9112 7.6376 7.6225 7.6099 7.6073 7.6048 7.5998 7.5846 7.5720 7.5695 7.5670 7.5556 7.5216 7.5052 7.4901 7.4762 7.4598 7.4485 7.4447 1H AV500 wp0118.3.1 ywp8092 O H O Ph 90h OEt (ppm) 0.8 20 0.4 10 0.0 ja19ywp.4.1 ywp8092 13c O H O Ph OEt 90h (ppm) 222 220 210 Bn N O 200 190 180 170 160 150 140 130 120 110 100 90 3.0 80 70 60 50 40 29.7237 4.0 36.5052 34.0258 5.0 43.8179 42.5561 6.0 48.9243 7.0 77.4080 76.9800 76.5594 8.0 9.0354 1.0000 2.0352 2.0241 2.0097 O 128.6933 128.5752 127.8595 5.6955 Bn N 135.6297 9.0 178.2593 175.6471 197.0836 Integral 3.1463 3.1301 3.1161 3.1022 3.0918 3.0848 3.0709 3.0569 3.0372 3.0244 2.9420 2.9107 2.8805 2.8550 2.8271 2.7993 2.5439 2.5276 2.4835 2.4673 1.4365 4.7215 4.6739 4.6657 4.6181 7.3900 7.3703 7.3656 7.3250 7.3064 7.2832 7.2612 fe28ywp.3.1 ywp8168 O O StBu 92 (ppm) 2.0 1.0 30 0.0 fe28ywp.4.1 ywp8168 13c O O StBu 92 (ppm) 20 10 223 220 210 200 190 180 170 160 6.5 CH OH 150 6.0 140 5.5 130 5.0 120 4.5 110 100 4.0 90 3.5 80 3.0 70 2.5 60 2.0 50 40 29.0227 7.0 34.2619 7.5 37.6637 8.0 60.4063 60.1554 60.0964 53.5437 8.5 77.5777 77.1497 76.7217 9.0 128.9590 128.3317 127.1880 9.5 3.0322 1.0038 1.9893 1.0000 2.0301 4.0747 1.5978 4.4707 3.6478 3.6060 3.5886 3.5781 3.5712 3.5514 3.5329 3.5131 3.4957 3.4760 2.6936 2.6762 2.6646 2.6460 2.6344 2.6170 2.6008 2.5358 2.5126 2.5056 2.4835 2.4534 2.3721 2.3547 2.3350 2.3025 2.0355 2.0146 2.0065 1.9902 1.9751 1.9635 1.9461 1.9345 1.7024 1.6815 1.6559 1.6362 1.6107 1.6025 1.5828 1.5642 1.5445 1.5375 1.5178 1.4992 1.4830 1.4540 7.2971 7.2832 7.2635 7.2507 7.2391 7.2229 CH OH 138.1239 5.1661 Integral ma01ywp.2.1 ywp8170-1 N Bn 93 (ppm) 1.5 1.0 30 20 0.5 10 0.0 ma01ywp.3.1 ywp8170-1 13c N Bn 93 (ppm) 224 220 210 200 8.0 CO2 H 190 7.5 180 170 7.0 160 6.5 150 6.0 140 5.5 130 5.0 120 4.5 110 100 4.0 90 3.5 80 3.0 70 2.5 60 2.0 50 40 29.3719 8.5 1.0000 3.0908 1.0609 0.9703 0.9889 1.0044 1.0229 4.8809 3.4602 3.4346 3.4219 3.3963 3.3801 3.3662 3.3557 3.3418 3.3279 3.3104 3.3046 3.3000 3.2942 3.2362 3.2106 3.1979 3.1804 3.1723 3.1421 2.9413 2.9135 2.9030 2.8752 2.8485 2.6732 2.6581 2.6477 2.6233 2.5989 2.5734 2.4260 2.3958 2.3749 2.3459 2.3250 2.2925 2.2658 2.2426 2.2240 2.2159 2.1822 2.1671 2.1567 2.1427 1.7318 1.7028 1.6877 1.6738 1.6587 1.6448 1.6297 1.6007 CO2 H 35.0022 9.0 49.6278 48.0486 47.7682 47.4804 47.2000 46.9122 46.6318 46.3440 44.4328 39.7913 9.5 177.8705 Integral ma18ywp.1.1 ywp8219 in MeOD N H 97 (ppm) 1.5 1.0 30 20 0.5 10 0.0 ma18ywp.6.1 ywp8219 in MeOD N H 97 (ppm) 225 Publications Ye, Weiping; Xu, Junye; Tan, Chin-Tong; Tan, Choon-Hong. 1,5,7-Triazabicyclo[4.4.0]- -dec-5-ene (TBD) Catalyzed Michael Reactions. Tetrahedron Lett. 2005, 46, 6875. Ye, Weiping; Leow, Dasheng; Goh, Serena Li Min; Tan, Chin-Tong; Chian, Chee-Hoe; Tan, Choon-Hong. Chiral Bicyclic Guanidines: A Concise and Efficient Aziridine-Based Synthesis. Tetrahedron Lett. 2006, 47, 1007. Ye, Weiping; Goh, Serena Li Min; Leow, Dasheng; Jiang, Zhiyong; Soh, Ying-Teck; Tan, Choon-Hong. Chiral Bicyclic Guanidine Catalyzed Michael Reaction; Application to the Enantioselective Synthesis of (S)-(+)-homo-β-Proline. Submitted for publication. Ye, Weiping; Tan, Choon-Hong. Enantioselective Michael Reaction of 1,3-Dicarbonyl Compounds to Cyclopentenone Catalyzed by Chiral Bicyclic Guanidines. Manuscript in preparation. Shen, Juan; Nguyen, Thanh Truc; Goh Yong-Peng; Ye, Weiping; Fu Xiao; Xu Junye; Tan Choon-Hong. Enantioselective Reactions of Anthrone Derivatives Catalyzed by Chiral Bicyclic Guanidine. Manuscript in preparation. 226 [...]... Chiral guanidine 79b catalyzed Michael addition of S,S’-dialkyl dithiomalonates 65v-y to 2-cyclopenten-1-one 64 Table 3.9 Chiral guanidine 79b catalyzed Michael addition between other cyclic enones and 1,3-dicarbonyl compounds Table 3.10 The influence of different guanidine catalysts on the Michael reaction of nitroalkanes with trans-chalcone 35a (Scheme 3.6) Table 3.11 Chiral bicyclic guanidines catalyzed. .. Scheme 1.5 Chiral guanidine or guanidinium catalyzed nitro Michael reaction The chiral guanidine catalysts discussed above are either acyclic guanidine (eg 4a-c) with chiral side chains or mono-to-polycyclic systems (eg 4d, 7, 15, 16, 20, and 24) with central chiralities Recently, Terada3 et al developed a new type of chiral guanidine catalysts, such as (R)-28, which introduced an axially chiral binaphthyl... guanidinium salt catalyzed phase transfer alkylation Summary: Chiral guanidines function as effective Brønsted base catalyst for a variety of reactions It is best demonstrated in Terada’s axially chiral guanidine (R)-28 catalyzed Michael reaction of nitroalkenes, Lipton’s dipeptide 31 and Corey’s bicyclic guanidine 33 catalyzed Strecker reaction Chiral guanidinium salts are also effective phase transfer... conjugate addition reactions In contrast, organobases such as DBU35 (Fig 2.1) and TBD26, 36 are less extensively documented as catalysts for Michael reactions We embarked on a search for the range of substrates and carbon nucleophiles that are suitable for Michael and Michael- type reactions using TBD as the catalyst 2.2 TBD Catalyzed Michael Reactions 2.2.1 Various organobases catalyzed Michael reaction... yield, 97% ee) 8 R = CN (79% yield, 55% ee) Scheme 1.2 Ishikawa’s chiral guanidine catalyzed Michael reaction of glycinate 15 Chapter 1 Ma also reported that chiral guanidine 4a catalyzed the Michael reaction and Diels-Alder reaction between anthrone 9 and N-methylmaleimide 10 (Scheme 1.3).6 Up to 70% ee and 67% yield was obtained for the Michael addition product 12, while the Diels-Alder product 11 was... asymmetric catalytic ability of chiral guanidine or guanidinium has been demonstrated in several reactions, including the Michael reaction, Strecker reaction, enone epoxidation, asymmetric silylation of secondary alcohol, TMS cyanation, azidation, Henry reaction, and phase transfer alkylation Michael reactions: In 1999, Ma reported that chiral guanidines 4a-b catalyze the Michael reaction of glycinate... yield) Scheme 1.3 Ma’s chiral guanidine catalyzed Michael reaction and Diels-Alder reaction between anthrone and maleimide O 0.3 M in CDCl3 , r.t N H 14 13 O O 17 N TBSO N guanidinium salt 15 or 16 O N N H Cl- 15 8 fold rate increase Mendoza et al N OTBDPS N O H R N O BF4 - R 16 1.25 - 11 fold rate increase Murphy et al Scheme 1.4 Chiral bicyclic guanidinium salt catalyzed aza -Michael reaction Knowing... de) Scheme 1.17 Diastereoselective Henry reaction catalyzed by chiral guanidines Ma also studied the diastereoselective Henry reactions of N,N-dibenzyl α-amino aldehydes 56 with nitromethane 53 catalyzed by guanidines (Scheme 1.17).15 Among the various chiral guanidines tested, including acyclic, monocyclic, and bicyclic ones, acyclic guanidine 57 afforded the product 58-anti with the best diastereoselectivity... (TBD) Catalyzed Michael Reactions Chapter 2 2.1 The Synthetic Utility of TBD Non -chiral bicyclic guanidine bases18 such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene (49, TBD, pKa(MeCN) = 26, Fig 2.1) and 1,3,4,6,7,8-hexahydro-1-methyl-2H-pyrimido- [1,2-a]-pyrimidine (7-methyl-TBD or MTBD, pKa(MeCN) = 25, Fig 2.1) are known as superbases due to their high pKa values.19 They have been shown to promote various reactions. .. tol., quanti 45 R CN 46 R = CH 2CH 2Ph (70% ee) R = Cyclohexyl (60% ee) Scheme 1.13 Chiral guanidine catalyzed TMS cyanation of aliphatic aldehydes 45 Azidation reaction: Chiral bicyclic guanidines 47a-b were also found to promote the kinetic azidation of (±)-1-indanol 41a (Scheme 1.14).5a Stoichiometric amount of the guanidine was used and the product was obtained in 26-30% ee 23 Chapter 1 Ph N HN N . 31 2.2 TBD Catalyzed Michael Reactions 32 Chapter 3 Chiral Bicyclic Guanidines Catalyzed Michael Reaction 3.1 An Aziridine-Based Synthesis of Chiral Bicyclic Guanidines 47 3.2 Michael Reaction. Cheng’s chiral guanidine catalyzed Michael reaction of glycinate. Scheme 1.2 Ishikawa’s chiral guanidine catalyzed Michael reaction of glycinate. Scheme 1.3 Ma’s chiral guanidine catalyzed Michael. hindered chiral bicyclic guanidines. Scheme 3.3 Various chiral bicyclic guanidines catalyzed Michael reaction of 2-cyclopenten-1-one 64 and dimethyl malonate 65a. Scheme 3.4 Chiral bicyclic guanidines