Chiral guanidine catalyzed enantioselective protonation reactions

      CHIRAL GUANIDINE CATALYZED ENANTIOSELECTIVE  PROTONATION REACTIONS        LEOW DASHENG JACKSON              NATIONAL UNIVERSITY OF SINGAPORE  2009    CHIRAL GUANIDINE CATALYZED  ENANTIOSELECTIVE PROTONATION REACTIONS    LEOW DASHENG JACKSON  2009  CHIRAL GUANIDINE CATALYZED ENANTIOSELECTIVE  PROTONATION REACTIONS          LEOW DASHENG JACKSON  (B.Sc., National University of Singapore)        A THESIS SUBMITTED    FOR THE DEGREE OF DOCTOR OF PHILOSOPHY    DEPARTMENT OF CHEMISTRY    NATIONAL UNIVERSITY OF SINGAPORE      To my family and Su Ying,  for their love, support, and encouragement    Acknowledgements The completion of this work would not have been possible without the support and contribution of the individuals to whom I would like to dedicate this section. Firstly, I would like to express my gratitude to my advisor, Assistant Professor Tan Choon-Hong. He was the role model for me to follow in my development as an organic chemist. He introduced me to research when I was an undergraduate and motivated me to stay on for Ph.D. He was always willing to listen to my problems when the project was not going well and gave suggestions to solve them. It has been a privilege to work under his guidance for more than five years. I would also like to thank the Chemistry department for the Kiang Ai Kim scholarship. Also without the constant support and encouragements from fellow members of the Tan’s group, my work might not have completed fast and smoothly. I would like to collectively thank the group for the enjoyable and harmonious work atmosphere. A few of them had worked with me in the past and their names deserved to be mentioned here. Special thanks went to Ms Lin Shishi, Dr Santhosh Kumar Chittimalla, and Mr Liu Hongjun. Special mentions went to Ms Loh Weitian, Ms Fan Yitian, and Mr Eey Tze Chiang Stanley for providing critiques for this thesis. I would like to thank Mdm Han Yanhui and Mr. Wong Chee Ping for providing their technical expertises in NMR. Mdm Wong Lai Kwai and Mdm Lai Hui Ngee were gratefully acknowledged for mass spectroscopic analysis. In addition, I would like to acknowledge Dr Koh Lip Lin, Ms Tan Geok Kheng and Ms Woo Su Fen for solving the X-Ray crystal structures. Lastly, I would like to thank other staff in the department that had rendered me help from time to time. I would like to take this opportunity to thank my parents Chet Men and Poi Khim for all their sacrifices and pains to educate and bring me up. They were the greatest people in my life. Last but not least, I would like to thank my wife, Su Ying, for her encouragements and support. Table of Contents  Abstract  List of Schemes  List of Tables  List of Figures  List of Abbreviations  Chapter 1 Chiral Guanidines Catalyzed Enantioselective Reactions  1. Chiral Guanidines Catalyzed Enantioselective Reactions  1  1.1. Introduction  2  1.2. Chiral Guanidines as Asymmetric Catalysts  3  1.2.1. Henry reaction  3  1.2.2. Michael reaction of nitroalkanes  6  1.2.3. Michael reaction  9  1.2.4. Aza‐Michael reaction  20  1.2.5. Phospha‐Michael reaction  21  1.2.6. Oxa‐Michael reaction  23  1.2.7. Diels‐Alder reaction  24  1.2.8. Electrophilic amination reaction  26  1.2.9. Nucleophilic epoxidation reaction  27    1.2.10. Mannich reaction  30  1.2.11. Strecker reaction  31  1.2.12. Trimethylsilylcyanation reaction  32  1.2.13. Reduction reaction  33  1.2.14. Alkylative esterification reaction  34  1.2.15. Alkylation reaction  34  1.2.16. Silylation reaction  35  1.2.17. Azidation reaction  36  1.2.18. Transamination reaction  36  1.2.19. Claisen rearrangement reaction  37  1.3. Conclusions  38  1.4. References  38  Chapter 2 Enantioselective Protonation Reactions Catalyzed by Chiral  Bicyclic Guanidine  2. Enantioselective Protonation Reactions Catalyzed by Chiral Bicyclic Guanidine  2.1. Catalytic Enantioselective Protonation Reactions  42  43  2.1.1. Introduction  43  2.1.2. Enantioselective protonation of pre‐formed enolates  46  2.1.3. Enantioselective protonation of silyl enol ethers and ketene silyl acetals  47  2.1.4. Enantioselective tautomerization of enols  50  2.1.5. Enantioselective protonation of transient enolate via addition to ketenes 51  2.1.6. Enantioselective protonation of transient enolate via conjugate additions 53    2.1.7. Conclusions  2.2. Preparation of a New Bulky Chiral Bicyclic Guanidine  60  60  2.3. Enantioselective Protonation Reactions of Phthalimidoacrylates with  Thiols Catalyzed by Chiral Bicyclic Guanidine  62  2.3.1. Introduction  62  2.3.2. Preparation of substrates  63  2.3.3. Reaction conditions optimization studies  64  2.3.4. Substrates scope  70  2.3.5. Enantioselective deuteration of phthalimidoacrylate with thiol  82  2.3.6. Chemoselective deprotection strategies  83  2.4. Enantioselective Protonation Reactions of Itaconimides with Secondary  Phosphine Oxides Catalyzed by Chiral Bicyclic Guanidine  89  2.4.1. Reaction conditions optimization studies  89  2.4.2. Substrate scope  92  2.5. Enantioselective Protonation Reactions of Itaconimides with Thiols  Catalyzed by Chiral Bicyclic Guanidine  97  2.5.1. Introduction  97  2.5.2. Reaction optimizations  97  2.5.3. Reaction scope  99  2.5.4. Proposed reaction model for the origin of axial chirality  102  2.6. Conclusions  104  2.7. References  104    Chapter 3 Kinetic Studies of Enantioselective Protonation Reactions  Catalyzed by Chiral Bicyclic Guanidine  3. Kinetic Studies of Enantioselective Protonation Reactions Catalyzed by Chiral Bicyclic  Guanidine  108  3.1. Introduction  109  3.2. Kinetic Analysis  112  3.2.1. Overall reaction order  112  3.2.2. Reaction  order  with  respect  to  itaconimide  and  secondary  phosphine  oxide  113  3.2.3. Reaction order with respect to guanidine catalyst  116  3.2.4. Kinetic isotope effect (KIE)  118  3.3. Mechanistic Possibilities  121  3.4. Conclusions  124  3.5. References  124  Chapter 4 Enantioselective Synthesis of Chiral Allenoates by  Guanidine­Catalyzed Isomerization of 3­Alkynoates  4. Enantioselective Synthesis of Chiral Allenoates by Guanidine‐Catalyzed Isomerization of  3‐Alkynoates  126  4.1. Synthesis of Allenes by Isomerization Reactions  127  4.1.1. Introduction  127  4.1.2. Catalytic synthesis of chiral allenes through isomerization reactions  128    4.2. Enantioselective Synthesis of Chiral Allenes by Guanidine‐Catalyzed  Isomerization of Alkynes  132  4.2.1. Preparation of substrates  132  4.2.2. Reaction optimizations  133  4.2.3. Reaction scope  137  4.2.4. Reaction reversibility  141  4.3. Conclusions  142  4.4. References  142  Chapter 5 Experimental Procedures  5. Experimental Procedures  144  5.1. General Information  145  5.1.1. General procedures and methods  145  5.1.2. Instrumentations  146  5.1.3. Materials  148  5.2. Procedures for the Synthesis of Chiral Bicyclic Guanidines  149  5.3. Syntheses and Characterizations of Starting Materials for  Enantioselective Protonation Reactions  153  5.3.1. Representative procedure for synthesis of 2‐phthalimidoacrylates  153  5.3.2. Representative procedure for synthesis of itaconimides  155  5.3.3. Representative procedure for synthesis of benzhydryl mercaptan  156  5.3.4. Representative procedure for synthesis of secondary phosphine oxides  156  5.4. Representative Procedures for Enantioselective Protonation Reactions  160      160 062008 #31 [m odified by TCH] m AU LDS9119(u) UV_VIS_2 WVL:254 nm - .0 140 - .7 120 100 80 60 40 20 -20 0.0 300 m in 5.0 10.0 15.0 20.0 062008 #33 [m odified by TCH] m AU 25.0 30.0 35.0 LDS9120(u) 40.0 48.3   UV_VIS_2 WVL:254 nm - .9 3 250 200 150 100 - .6 50 -50 0.0 m in 2.0 4.0 6.0 8.0 10.0 12.0 14.0 15.8   373      350 062008 #30 [m odified by TCH] m AU LDS9119(l) UV_VIS_2 WVL:254 nm 300 - 1 .6 250 200 - .6 150 100 50 -50 0.0 400 m in 5.0 10.0 062008 #32 [m odified by TCH] m AU 15.0 20.0 LDS9120(L) 25.3   UV_VIS_1 WVL:210 nm - .7 350 300 250 200 - 1 .8 150 100 50 -50 0.0   m in 5.0 10.0 15.0 20.0 25.5     374      4,000 062008 #221 m AU LDS10097 UV_VIS_1 WVL:210 nm 3,000 - 12.780 2,000 1,000 -100 0.0 m in 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0     3,000 062008 #230 [m odified by TCH LAB] m AU LDS10121 UV_VIS_1 WVL:210 nm 2,500 2,000 1,500 - 11.620 - 15.507 1,000 500 -100 0.0 4,000 m in 2.5 5.0 7.5 062008 #219 [m odified by TCH LAB] m AU 10.0 12.5 15.0 17.5 LDS100115 20.0   UV_VIS_1 WVL:210 nm 3,000 2,000 - 11.513 1,000 - 15.293 -100 0.0 m in 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0   375      2,500 062008 #225 [m odified by TCH LAB] m AU LDS10015 UV_VIS_1 WVL:210 nm 2,000 1,500 - 38.460 1,000 500 -100 0.0 m in 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0     900 062008 #224 [m odified by TCH LAB] m AU LDS10120 UV_VIS_1 WVL:210 nm 600 400 - 28.887 - 31.180 200 -100 0.0 2,500 m in 5.0 10.0 15.0 062008 #223 [m odified by TCH LAB] m AU 20.0 25.0 30.0 35.0 LDS10116 40.0 45.0   UV_VIS_1 WVL:210 nm 2,000 1,500 - 28.867 1,000 500 - 31.227 -100 0.0 m in 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0   376      4,000 062008 #235 m AU LDS10114 UV_VIS_1 WVL:210 nm 3,000 - 11.013 2,000 1,000 -100 0.0 m in 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0     3,500 062008 #237 [m odified by TCH LAB] m AU LDS10128 UV_VIS_1 WVL:210 nm 3,000 2,500 2,000 - 9.653 - 11.707 1,500 1,000 500 -100 0.0 7,000 m in 2.5 5.0 7.5 062008 #241 [m odified by TCH LAB] m AU 10.0 12.5 15.0 LDS10131 17.5 20.0   UV_VIS_1 WVL:210 nm 6,000 5,000 4,000 - 9.460 3,000 2,000 1,000 - 11.267 -100 0.0 2.5 5.0 7.5 10.0 12.5 m in 15.0 17.5 20.0   377      1,500 062008 #233 m AU LDS9156 UV_VIS_1 WVL:210 nm 1,250 1,000 750 - 17.973 500 250 -100 0.0 m in 5.0 10.0 15.0 20.0 25.0 30.0 35.0     1,000 062008 #232 [m odified by TCH LAB] m AU LDS10124 UV_VIS_1 WVL:210 nm 800 600 400 - 19.740 - 28.927 200 -100 0.0 2,000 m in 5.0 10.0 062008 #226 [m odified by TCH LAB] m AU 15.0 20.0 25.0 LDS10118 30.0 35.0   UV_VIS_1 WVL:210 nm 1,500 1,000 - 19.973 500 - 28.407 -100 0.0 m in 5.0 10.0 15.0 20.0 25.0 30.0 35.0   378    CO2tBu   MeO 2,000 062008 #192 m AU LDS10063 UV_VIS_1 WVL:210 nm 1,500 - 19.093 1,000 500 -100 0.0 m in 5.0 10.0 15.0 20.0 25.0 30.0     2,500 062008 #234 [m odified by TCH LAB] m AU LDS10122 UV_VIS_2 WVL:254 nm 2,000 1,500 - 17.547 1,000 - 23.460 500 -100 0.0 m in 5.0 10.0 15.0 20.0 25.0 30.0   379    400 062008 #242 [m odified by TCH LAB] m AU LDS10129 UV_VIS_1 WVL:210 nm 300 200 - 17.520 100 - 23.293 -30 0.0 m in 5.0 10.0 15.0 20.0 25.0 30.0   380      4,000 062008 #222 m AU LDS10065 UV_VIS_2 WVL:254 nm 3,000 2,000 - 14.800 1,000 -100 0.0 m in 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0     2,000 062008 #231 [m odified by TCH LAB] m AU LDS10123 UV_VIS_1 WVL:210 nm 1,500 1,000 - 13.120 - 17.513 500 -100 0.0 2,000 m in 2.5 5.0 7.5 062008 #220 [m odified by TCH LAB] m AU 10.0 12.5 15.0 LDS100117 17.5 20.0   UV_VIS_1 WVL:210 nm 1,500 1,000 - 13.053 500 - 17.287 -100 0.0 m in 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0   381      3,000 062008 #238 m AU LDS10126 UV_VIS_1 WVL:210 nm 2,500 2,000 1,500 - 12.587 - 15.147 1,000 500 -100 0.0 3,500 m in 2.5 5.0 7.5 062008 #244 [m odified by TCH LAB] m AU 10.0 12.5 15.0 LDS10135 17.5 20.0   UV_VIS_1 WVL:210 nm 3,000 2,500 2,000 - 12.953 1,500 1,000 500 - 16.013 -30 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 m in 20.0   382    Br H CO2tBu H 3,000   062008 #239 [m odified by TCH LAB] m AU LDS10133 UV_VIS_1 WVL:210 nm 2,500 2,000 1,500 - 11.140 1,000 - 14.847 500 -100 0.0 3,500 m in 2.5 5.0 7.5 062008 #245 [m odified by TCH LAB] m AU 10.0 12.5 15.0 LDS10136 17.5 20.0   UV_VIS_1 WVL:210 nm 3,000 2,500 2,000 - 12.180 1,500 1,000 500 - 16.720 -30 0.0   m in 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0     383      1,000 062008 #255 [m odified by TCH LAB] m AU LDS10138(2) UV_VIS_1 WVL:210 nm 800 600 400 - 29.467 - 36.047 200 -30 0.0 750 m in 5.0 10.0 15.0 062008 #262 [m odified by TCH LAB] m AU 20.0 25.0 30.0 35.0 LDS10148 40.0 45.0   UV_VIS_1 WVL:210 nm 600 500 400 300 - 31.660 200 100 - 38.893 -30 0.0 m in 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0   384    O O H Br tBu   2,000 062008 #272 [m odified by TCH LAB] m AU LDS10155 UV_VIS_1 WVL:210 nm 1,500 1,000 - 22.760 - 26.980 500 -100 0.0 1,500 m in 5.0 10.0 062008 #275 [m odified by TCH LAB] m AU 15.0 20.0 25.0 30.0 LDS10157 35.0   UV_VIS_1 WVL:210 nm 1,250 1,000 750 - 25.813 500 250 - 21.920 -100 0.0 m in 5.0 10.0 15.0 20.0 25.0 30.0 35.0   385      1,000 062008 #258 [m odified by TCH LAB] m AU LDS10144 UV_VIS_1 WVL:210 nm 800 600 400 - 13.087 - 14.713 200 -100 0.0 m in 5.0 10.0 15.0 20.0 25.0     1,000 062008 #251 [m odified by TCH LAB] m AU LDS10140 UV_VIS_1 WVL:210 nm 800 600 400 - 10.667 200 - 19.593 - 13.387 - 15.100 -100 0.0 m in 5.0 10.0 15.0 20.0 25.0     386    4,500 062008 #279 [m odified by TCH LAB] m AU LDS10159 UV_VIS_1 WVL:210 nm 3,000 - 12.600 2,000 1,000 - 10.280 - 14.427 - 18.447 -100 0.0   5.0 10.0 15.0 20.0 m in 25.0     387    List of Publications  Research publications  (6) Brønsted-Base Catalyzed Tandem Isomerization oxy-Michael Reactions of Alkynes Org. Lett. 2009, Manuscript submitted. Liu, H.; Leow, D.; Loh, W.-T.; Tan, C.-H. (5) Enantioselective Protonation of Itaconimides with Thiols and the Rotational Kinetics of the Axially Chiral C–N Bond Chem. Asian. J. 2009, DOI: 10.1002/asia.200900331. Lin, S.*; Leow, D.*; Huang, K.-W.; Tan, C.-H. (*These authors contributed equally to this work.) (4) Enantioselective Synthesis of Chiral Allenoates by Guanidine-Catalyzed Isomerization of 3-Alkynoates J. Am. Chem. Soc. 2009, 131 , 7212–7213. (1 citations) Liu, H.*; Leow, D.*; Huang, K.-W.; Tan, C.-H. (*These authors contributed equally to this work.)  Highlighted in Synfacts 2009, , 0794-0794. (3) Enantioselective Protonation Catalyzed by a Chiral Bicyclic Guanidine Derivative Angew. Chem. Int. Ed. 2008, 47 , 5641–5645. (20 citations) Leow, D.; Lin, S.; Chittimalla, S. K.; Fu, X.; Tan, C.-H.  Highlighted in Synfacts 2008, , 0993-0993.  Highlighted in ChemInform 2008, 39 , DOI: 10.1002/chin.200847194. (2) Chiral Bicyclic Guanidine as a Versatile Brønsted Base Catalyst for the Enantioselective Michael Reactions of Dithiomalonates and β -Keto Thioesters Adv. Synth. Catal. 2007, 349 , 2454–2458. (16 citations) Ye, W.; Jiang, Z.; Zhao, Y.; Goh, S. L. M.; Leow, D.; Soh, Y.-T.; Tan, C.-H. (1) Chiral Bicyclic Guanidines: a Concise and Efficient Aziridine-Based Synthesis Tetrahedron Lett. 2006, 47 , 1007–1010. (19 citations) Ye, W.; Leow, D.; Goh, S. L. M.; Tan, C.-T.; Chian, C.-H.; Tan, C.-H.  Highlighted in ChemInform 2006, 37, DOI: 10.1002/chin. 200620062. Reviews  (1) Chiral Guanidine Catalyzed Enantioselective Reactions Chem. Asian. J. 2008, , 488–507. (8 citations) Leow, D.; Tan, C.-H.  Top most accessed article from 10/2008–9/2009. Conferences  (1) Enantioselective Protonation Catalyzed by a Chiral Bicyclic Guanidine Derivative 237 th ACS National Meeting, Salt Lake City, UT, March 22-26, 2009 Leow, D.; Lin, S.; Chittimalla, S. K.; Fu, X.; Tan, C.-H. 388    [...]... Deracemization of amino acid derivatives by enantioselective protonation of the enolate.  Scheme 2.5  Enantioselective protonation of lithium enolate 28.  Scheme 2.6  Enantioselective protonation with chiral Kemp’s acid imide 32.  Scheme 2.7  Enantioselective protonation with chiral amine 34.  Scheme 2.8  Lewis acid‐assisted chiral Brønsted acid (LBA) system.  Scheme 2.9  New  Brønsted  acid  catalyzed enantioselective protonation ... Enantioselective Mannich reactions of various N‐Boc protected imines  catalyzed by guanidine ent‐13a.  Scheme 1.42  Asymmetric Strecker reactions of N‐benzhydryl imines catalyzed by  dipeptide 25.  Scheme 1.43  Asymmetric Strecker reactions of N‐benzhydryl imines catalyzed by bicyclic  guanidine 7e.  Scheme 1.44  Enantioselective trimethylsilylcyanation reactions of various carbonyl  compounds catalyzed by bicyclic guanidine 7g. ... Asymmetric Henry reactions.   Scheme 1.3  Diastereoselective Henry reaction catalyzed by guanidine 3a.  Scheme 1.4  Guanidine 4a catalyzed asymmetric Henry reactions.   Scheme 1.5  Asymmetric Henry reactions of various aldehydes and nitroalkanes  catalyzed by guanidine thiourea 5.  Scheme 1.6  Diastereoselective Henry reaction catalyzed by guanidine thiourea 5.  Scheme 1.7  Asymmetric Henry reactions of various α‐ketoesters and nitroalkanes ... protonation of  catalyzed by chiral poly Gd complex.  Scheme 2.34  Chiral aluminum‐thiol  complex  conjugate  addition  and  enantioselective protonation of various α‐substituted acryalates.  Scheme 2.35  Synthesis of chiral bicyclic guanidine.   Scheme 2.36  Enantioselective synthesis  of  a  new  chiral bicyclic  guanidine bearing  adamantanyl appendage.  Scheme 2.37  Enantioselective protonation ... Asymmetric Henry reactions of various α‐ketoesters and nitroalkanes  catalyzed by guanidine thiourea 5.  Scheme 1.8  Guanidine 6 catalyzed asymmetric Michael reactions of nitroalkanes.  Scheme 1.9  Conjugate addition of 2‐nitropropane to chalcone catalyzed by guanidine 4a.  Scheme 1.10  Tripeptides 8a‐b catalyzed Michael reactions of 2‐nitropropane to 2‐ cyclohexene‐1‐one.  Scheme 1.11  Guanidine 3b catalyzed Michael reaction between anthrone and ... Scheme 1.12  Guanidine 13a catalyzed Michael reactions between 2‐cyclopenten‐1‐one  and dibenzyl malonates.  Scheme 1.13  Asymmetric Michael reactions of various 1,3‐dicarbonyl compounds with  conjugated nitroalkenes catalyzed by guanidine 15a.  Scheme 1.14  Enantioselective Michael reactions of various nitrocarbonyls to vinyl  ketones catalyzed by pentapeptide 17.  Scheme 1.15  Enantioselective Michael reactions of dithranol to various maleimides ... Representative  procedures  for  enantioselective protonation reaction  of  itaconimide with thiol catalyzed by chiral bicyclic guanidine 188  5.4.7 Procedures  for  enantioselective protonation reaction  of  axially  chiral itaconimide 126h catalyzed by chiral bicyclic guanidine 7c  195  5.4.8 Determination of the relative configuration of axially chiral imides 129d  and 131a by 1H‐1H 2D COSY NMR and 1H NOE NMR ... by chiral bicyclic guanidine.  The first chapter is a review on the chiral guanidines catalyzed enantioselective reactions.  Guanidines have been successfully employed as Brønsted base in  important asymmetric reactions.  They have also been shown to be effective Brønsted acids  as well as phase transfer catalysts.  Chiral bicyclic guanidine 7c is found to catalyze protonation and deuteration reactions with  high  ees.  This  is ... by  enantioselective tautomerization by chiral β‐amino alcohol catalyst.  Scheme 2.15  Addition of methanol to ketene catalyzed by O‐acetylquinine.  Scheme 2.16  Various enantioselective protonation reactions of ketenes catalyzed planar  chiral azaferrocenes.  Scheme 2.17  Asymmetric protonation of ketene using catalytic amount of amino alcohol  no and lithium thiolate.  Scheme 2.18  Chiral carbene catalyzed enantioselective protonation.  ... Representative  procedure  for  enantioselective protonation reaction  of  tert‐butyl  2‐phthalimidoacrylates  56b  with  aromatic  thiols  catalyzed by  chiral bicyclic guanidine 7c  5.4.2 Procedure  for  enantioselective 160  protonation reaction  of  phthalimidoacrylate  56b  with  alkyl  thiol  114  catalyzed by  chiral bicyclic  guanidine 7c  171  5.4.3 Procedure  for  enantioselective deuteration  . 38 Chapter2 Enantioselective Protonation Reactions Catalyzed by Chiral Bicyclic Guanidine 2. Enantioselective Protonation Reactions Catalyzed by Chiral Bicyclic Guanidine 42 2.1. Catalytic Enantioselective Protonation Reactions .  TableofContents Abstract ListofSchemes ListofTables ListofFigures ListofAbbreviations Chapter1 Chiral Guanidines Catalyzed Enantioselective Reactions 1. Chiral Guanidines Catalyzed Enantioselective Reactions 1 1.1. Introduction 2 1.2. Chiral GuanidinesasAsymmetricCatalysts. 104  Chapter3KineticStudiesof Enantioselective Protonation Reactions Catalyzed by Chiral Bicyclic Guanidine 3. KineticStudiesof Enantioselective Protonation Reactions Catalyzed by Chiral Bicyclic Guanidine