BICYCLIC GUANIDINE CATALYZED ENANTIOSELECTIVE ALLYLIC ADDITION REACTIONS WANG JIANMIN NATIONAL UNIVERSITY OF SINGAPORE 2011 BICYCLIC GUANIDINE CATALYZED ENANTIOSELECTIVE ALLYLIC ADDITION REACTIONS WANG JIANMIN 2011 BICYCLIC GUANIDINE CATALYZED ENANTIOSELECTIVE ALLYLIC ADDITION REACTIONS WANG JIANMIN (BSc., Hunan University) (MSc., Beijing University of Chemical Technology) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE To my parents and my grandmother, for their love, support, and encouragement Acknowledgements First and foremost, I would like to take this opportunity to thank my supervisor, Associate Professor Tan Choon-Hong, for his guidance and encouragement throughout my PhD research and study. I would like to thank all my labmates for creating such a harmonious, encouraging, and helpful working environment. My special thanks go to Dr. Chen Jie for her great contribution to the γ-selective allylic addition project. I would also like to thank Mr. Choon Wee Kee for his computational study on the γ-selective allylic addition project, Mr. Hongjun Liu for his pioneer work on the allylic addition of N-aryl alkylidene-succinimides project. I thank Mdm Han Yanhui, and Mr. Wong Chee Ping 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 during my Ph.D. study here. Table of Contents Summary List of Schemes List of Tables List of Figures List of Abbreviations Chapter Asymmetric Allylic Addition and Substitution reactions---------------------------1 1.1 Overview of Enantioselective Allylic Addition Reactions------------------- 1.2 Stoichiometric Asymmetric Allylic Addition Reactions ------------------ 1.3 Catalytic Enantioselective Addition of Allylic Organometallic Reagents to Carbonyl Compound------------------------------------------------------ 10 1.4 Metal-Catalyzed Enantioselective Allylation Reactions----------------- 16 1.4.1 Novel Ligands in Transition Metal Catalyzed Asymmetric Allylic Substitution and Addition Reactions -------------------------------------- 17 1.4.2 Molybdenum-Catalyzed Asymmetric Allylic Alkylations--------------- 21 1.5 Organocatalyst Catalyzed Enantioselective Allylic Addition----------- 27 Chapter Bicyclic Guanidine Catalyzed Direct Asymmetric Allylic Addition of N-Aryl Alkylidene-Succinimides----------------------------------------------------------- 35 2.1 Introduction to Guanidine Catalyst --------------------------------------- 36 2.2 Bicyclic Guanidine Catalyzed Direct Allylic Addition---------------- 41 2.2.1 Deuteration Study on N-phenyl Itaconimides---------------------------- 41 2.2.2Bicyclic Guanidine Catalyzed Direct Michael Addition to Nitrostyrenes----------------------------------------------------------------- 43 2.2.3 Bicyclic Guanidine Catalyzed Direct Mannich Type Addition to Imines-------------------------------------------------------------------------- 43 2.2.4 Isotopic Labelling Study and the Proposed Mechanism----------------- 48 Chapter Bicyclic Guanidine Catalyzed Direct γ-Selective Asymmetric Allylic Amination---------------------------------------------------------------------------- 54 3.1 Introduction to γ-selective Allylic Addition--------------------------------- 55 3.2 Introduction to Enantiodivergent Asymmetric Synthesis----------------- 62 3.3 γ-Selective Enantioselective Allylic Amination ----------------------------66 Chapter Experimental Procedures------------------------------------------------------------- 77 4.1 General Procedures and methods--------------------------------------------- 78 4.1.1 Instrumentations--------------------------------------------------------78 4.1.2 Materials ---------------------------------------------------------------------- 81 4.2 Preparation and Characterization of Substrates and Products---------- 82 4.3 The Synthetic Application of Allylic Addition Products--------------- 129 Publications------------------------------------------------------------------------- 133 Conference presentations--------------------------------------------------------- 134 Appendix---------------------------------------------------------------------------- CD Summary The aim of this study is to develop highly enantioselective allylic addition reactions catalyzed by chiral bicyclic guanidines. A chiral bicyclic guanidine was found to catalyze a direct asymmetric allylic addition reaction to imines. This reaction provides enantio-enriched maleimides and succinimides that can be used to prepare aza-heterocycles with multiple chiral centers. NMR studies and deuterium-exchange experiments were used to study the intermediates in the reaction We have also found that the chiral bicyclic guanidine was also efficient to catalyze enantiodivergent -selective allylic amination of β,γ-unsaturated carbonyl compounds. Both enantiomers with high enantioselectivity and yield were achieved. The computational studied revealed the possible originality of the inversed enantioselectivity and diastereoselectivity. The methodology was elegantly utilized in the synthesis of biologically and pharmaceutically important g-Aminobutyric (+)-Zwittermicin A core structure. acid derivatives and List of Schemes Scheme 1.1 Allylic addition of allylmetal reagents to aldehydes. Scheme 1.2 Diastereoselective addition of crotylboronates to aldehydes. Scheme 1.3 Diastereoselective addition of allylic boronates to α-chiral aldehydes. Scheme 1.4 Diastereoselective addition of allylchromium to chiral aldehydes. Scheme 1.5 Lewis acid mediated addition of allyltrimethylsilane to aldehyde. Scheme 1.6 Stereocontrolled additions α-hydroxyaldehyde derivatives. Scheme 1.7 Enantioselective addition of diisopinocampheylboranes to aldehyde. Scheme 1.8 Asymmetric allylation of aldehydes with allyltrichlorosilane. Scheme 1.9 Asymmetric allylation of aldehydes with allysilane. Scheme 1.10 Asymmetric allylation of aromatic aldehydes using chiral tin reagents. Scheme 1.11 Three types of allylic addition of organometallic reagents to aldehydes. Scheme 1.12 Addition of allylsilanes catalyzed by CAB. Scheme 1.13 Addition of allylic organometallic reagents to aldehydes catalyzed by BINOL/Ti(IV) Complexes. Scheme 1.14 Chromium-Mediated allylation reaction. Scheme 1.15 Addition of allylic trichlorosilanes to aldehydes catalyzed by 17. Scheme 1.16 Addition of allyltrichlorosilane catalyzed by N-Oxide. Scheme 1.17 Mo-catalyzed asymmetric allylic alkylation. Scheme 1.18 Mo-catalyzed asymmetric allylic alkylation in the synthesis of drug intermediate. of allyltri-n-butylstannane to Scheme 1.19 Mo-catalyzed asymmetric allylic alkylation in the synthesis of Tipranavir. Scheme 1.20 Mo-catalyzed asymmetric allylic alkylation in the synthesis of (R)-baclofen. Scheme 1.21 Mannich-Type reaction/isomerization sequence with a β,γ-unsaturated esters or cyanides. Scheme 1.22 Orgnocatalytic γ-amination of α,β-unsaturated aldehydes. Scheme 1.23 Organocatalytic allylic amination. Scheme 2.1 Bicyclic guanidine 60 catalyzed enantioselective Strecker reaction. Scheme 2.2 Enantioselective transamination reactions of an imine catalyzed by bicyclic guanidine 60. Scheme 2.3 Bicyclic guanidine 65 catalyzed enantioselective and diastereo-selective reactions between α-fluoro-β-ketoester 66 and N-alkyl maleimides. Scheme 2.4 Bicyclic guanidine 65 catalyzed phospha-Michael reaction of various diaryl phosphine oxides to conjugated aryl nitroalkenes. Scheme 2.5 Bicyclic guanidine 65 catalyzed enantioselective protonation /deuteration reactions of various 2-(substituted-phthalimido) acrylates. Scheme 2.6 Bicyclic guanidine 60 catalyzed Diels-Alder reaction between substituted anthrones and maleimides. Scheme 2.7 Bicyclic guanidine 65 catalyzed Mannich reaction between β-keto acyloxazolidinone 75 and N-Eoc imines. Scheme 2.8 Bicyclic guanidine 65 catalyzed Enantioselective protonation of itaconimides with thiol donor. Scheme 2.9 Bicyclic Scheme 2.10 Bicyclic guanidine catalyzed -selective direct allylation reaction of 2-methylene-N-aryl succinimide 80a with N-Eoc protected imine 83d. Scheme 2.11 Proposed reaction sequences of -selective direct allylation reaction of succinimide 77. Scheme 3.1 Organocatalytic asymmetric allylic addition system. guanidine catalyzed -selective direct allylic Michael addition of 2-methylene-N-aryl succinimide 80a with nitrostyrene 81. Chapter Appendices 228 Chapter Appendices 229 Chapter Appendices 230 Chapter Appendices 231 Chapter Appendices 232 Chapter Appendices 233 Chapter Appendices 234 Chapter Appendices 235 Chapter Appendices 236 Chapter Appendices \ 237 Chapter Appendices 238 Chapter Appendices 239 Chapter Appendices 240 Chapter Appendices X-ray Structure Analysis. 241 Chapter Appendices 242 Chapter Appendices 243 [...]... Introduction to Enantioselective Allylic Addition and Substitution Reaction Scheme 1.11 Three types of allylic addition of organometallic reagents to aldehydes Type I reactions: chiral Lewis bases catalyzed addition of allylic trichlorosilanes; type II reactions: Lewis acids catalyzed addition of allylic organometallic reagents (Si, Sn, B), predominantly syn diastereoselectivity observed; type III reactions: ... significance of the methodology Transition metal catalyzed enantioselective allylic addition and substitution reactions are the most widely studied asymmetric allylic reactions and many reviews and books were published on this topic These transition metal catalyzed enantioselective allylic addition and substitution reactions, in particular the asymmetric allylic alkylations, were employed in the asymmetric... Ns 2-nitrobenzensulfonyl M mol∙l-1 mM mmol∙l-1 Chapter 1 Introduction to the Enantioselective Allylic Addition and Substitution Reactions 1 Chapter 1 Introduction to Enantioselective Allylic Addition and Substitution Reaction 1.1Overview of Enantioselective Allylic Addition and Substitution Reactions The fast development of enantioselective transformation methodologies enables efficient synthesis of... aminoalcohol catalyzed enantioselective reduction reactions Scheme 3.15 Influence of double bond geometry on the copper catalyzed asymmetric conjugated addition List of Tables Table 1.1 Addition of allylic trichlorosilanes to benzaldehyde promoted by (R,R)-14 Table 1.2 Summary of the best results for the Pd -catalyzed allylic substitution using diphosphite ligands Table 1.3 Mo -catalyzed allylic alkylations... Enantioselective Allylation Reactions The transition metal -catalyzed enantioselective allylic addition and substitution, typically the asymmetric allylic alkylation reaction (AAA reaction), occupies a significant position among the asymmetric allylic functionalizations Quite a few reviews were published based on this topic In contrast to most metal -catalyzed enantioselective processes, asymmetric allylic. .. asymmetric γ -addition Scheme 3.3 Phosphine -catalyzed asymmetric γ -addition of nitromethane to allenamides Scheme 3.4 Phosphine -catalyzed asymmetric γ -addition of malonate esters to γ-substituted allenoates Scheme 3.5 Phosphine -catalyzed enantioselective synthesis of tetrahedrofurans and tetrahydropyrans Scheme 3.6 Phosphine -catalyzed asymmetric γ -addition of thiols to allenoates Scheme 3.7 Enantioselective. .. is effective for the addition of substituted allylic silanes to aromatic aldehydes Up to 98/2 er and 97/3 syn/anti selectivities of the 11 Chapter 1 Introduction to Enantioselective Allylic Addition and Substitution Reaction homoallylic alcohols were observed regardless of the geometry of the starting silane Scheme 1.13 Addition of allylic organometallic reagents to aldehydes catalyzed by BINOL/Ti(IV)... diastereoselectivity observed; type III reactions: in situ generated allylic organometallic reagents (Cr, Zn, In) from allylic halides addition catalyzed by chelating ligands, predominantly anti-selective independent of starting allylic geometry Scheme 1.12 Addition of allylsilanes catalyzed by CAB The first example of type II reactions catalyzed by chiral Lewis acid were reported by Yamamoto in 1991 using... well developed before 1.4.1 Novel Ligands in Transition Metal Catalyzed Asymmetric Allylic Substitution and Addition Reactions In general, for the Pd catalyzed asymmetric substitution reactions, high enantioselectivities were observed in unhindered disubstituted linear substrates and 17 Chapter 1 Introduction to Enantioselective Allylic Addition and Substitution Reaction low in hindered substrates... of chiral auxiliary promoted asymmetric addition to carbonyl compounds; (b) the catalytic enantioselective addition of allylic organometallic reagents to carbonyl compounds; (C) the transition metal catalyzed enantioselective allylic substitution reaction; (d) the organocatalyst promoted enantioselective allyic addition reaction Significant attentions have been paid on the first three methodologies . GUANIDINE CATALYZED WANG JIANMIN 2011 ENANTIOSELECTIVE ALLYLIC ADDITION REACTIONS BICYCLIC GUANIDINE CATALYZED ENANTIOSELECTIVE ALLYLIC ADDITION REACTIONS WANG JIANMIN (BSc.,. Asymmetric Allylic Addition and Substitution reactions 1 1.1 Overview of Enantioselective Allylic Addition Reactions 2 1.2 Stoichiometric Asymmetric Allylic Addition Reactions 4 1.3 Catalytic Enantioselective. BICYCLIC GUANIDINE CATALYZED ENANTIOSELECTIVE ALLYLIC ADDITION REACTIONS WANG JIANMIN NATIONAL UNIVERSITY OF SINGAPORE 2011 BICYCLIC GUANIDINE CATALYZED