Enantioselective additions of fluorocarbon nucleophiles using bifunctional organic catalysts

ENANTIOSELECTIVE ADDITIONS OF FLUOROCARBON NUCLEOPHILES USING BIFUNCTIONAL ORGANIC CATALYSTS HAN XIAO NATIONAL UNIVERSITY OF SINGAPORE 2010 ENANTIOSELECTIVE ADDITIONS OF FLUOROCARBON NUCLEOPHILES USING BIFUNCTIONAL ORGANIC CATALYSTS HAN XIAO (BSc. Soochow Univ.) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2010 Acknowledgements I would like to express my gratitude to those people who have helped and inspired me during my PHD studies in Department of Chemistry, National University of Singapore (NUS). This thesis could not be completed without their support. First of all, I would like to thank my supervisor Prof. Lu Yixin for giving me an opportunity to study in NUS, and offering all his enthusiasm and guidance during my five years of research. He is not only an extraordinary supervisor, a complete mentor, but a truly friend. It was from him that I have learned a lot which will aid me greatly throughout my life. I am deeply grateful to our collaborators, Prof. Huang Kuo-wei and his group members from KAUST Catalysis Center (KCC) & Division of Chemical and Life Sciences and Engineering, Kingdom of Saudi Arabia, for their assistance in the computational calculations of our experimental findings. I would also like to thank my colleagues: Dr. Animesh Ghosh, Dr. Wu Xiaoyu, Dr. Wang Youqing, Dr. Yuan Qing, Dr. Xie Xiaoan, Dr. Wang Haifei, Dr. Cheng Lili, Dr. Jiang Zhaoqin, Luo Jie, Liu Xiaoqian, Zhu Qiang, Zhong Fangrui, Jacek Kwiatkowski，Han Xiaoyu, Chen Guoying, Liu Chen and other labmates. They had helped me a lot not only in chemistry but also in life. I also want to express my appreciation to the members of instruments tests in NMR, Mass lab. They gave me too much help during my research work. My deepest appreciation goes to my family for their unflagging love and support throughout my studies. Without their help, I cannot complete this work. The financial support from National University of Singapore is gratefully acknowledged. i Table of Contents Acknowledgements i Table of Contents ii Summary vi List of Tables vii List of Schemes ix List of Figures xii List of Abbreviations xiv List of Publications xvii Chapter Introduction 1.1 Asymmetric Organocatalysis 1.2 Chiral Brønsted Acids Organocatalysis 1.2.1 Introduction 1.2.2 Hydroxyl-containing Organocatalysts 1.2.3 Thiourea-based Catalysts 12 1.2.3.1 Monofunctional Thiourea-based Catalysts 12 1.2.3.2 Bifunctional Thiourea-based Catalysts 16 1.3 1.2.4 Guandium Salts 23 1.2.5 Chiral Phosphoric Acids 25 Project Objectives 28 Chapter Asymmetric Generation of Fluorine-containing Quaternary Carbons Adjacent to Tertiary Stereocenters: Uses of Fluorinated Methines as Nucleophiles 2.1 29 Chiral Fluorinated Moleculars 29 ii 2.2 Results and Discussion 32 2.2.1 Preliminary Studies 32 2.2.2 Catalyst and Solvent Screening 34 2.2.3 Substrate Scope 35 2.2.3.1 Michael Acceptors 35 2.2.3.2 α-Fluorinated β-Ketoesters Screening 37 2.2.4 Chiral Pyrrrolidine and Lactam Synthesis 38 2.2.5 Postulated Catalyst Mode of Action 39 2.3 Conclusion 40 2.4 Experimental Section 40 2.4.1 General Information 40 2.4.2 Representative Procedure 41 2.4.3 Determination of Absolute Configurations of the Michael Products 2.4.4 2.4.5 42 Conversion of Michael Adduct to Chiral Lactam and Pyrrolidine 47 Analytical Data of Substrates and Michael Adducts 48 Chapter Asymmetric Mannich Reaction of Fluorinated Ketoesters with a Tryptophan-Derived Bifunctional Thiourea Catalyst 71 3.1 Introduction 71 3.2 Synthesis of Catalysts 73 3.3 Results and Discussion 74 3.3.1 Catalyst Screening 74 3.3.2 Solvent Screening 75 iii 3.3.3 3.3.4 Reaction Scope 76 3.3.3.1 α-Fluorinated β-Ketoesters Screening 76 3.3.3.2 Mannich Acceptors 78 3.3.3.3 None-fluorinated 1,3-Dicarbonyl Substrates 79 Chiral β-Amino Acid and β-Lactam Synthesis 80 3.4 Kinetic Studies 81 3.5 Conclusion 92 3.6 Experimental Section 93 3.6.1 General Information 93 3.6.2 Preparation of Catalysts 94 3.6.3 Representative Procedure 3.6.4 Conversion of Mannich Adduct to Chiral β-Amino Acid, β- 100 Lactam and β-Lactone 100 3.6.5 Analytical Data of Substrates and Mannich Adducts 105 3.6.6 DFT Calculations 129 Chapter Highly Enantioselective Amination Reactions of Fluorinated Ketoesters Mediated by Novel Chiral Guanidines Derived from Cinchona Alkaloids 138 4.1 Introduction 138 4.2 Synthesis of Catalysts 139 4.3 Results and Discussion 140 4.3.1 Catalyst Screening 140 4.3.2 Solvent Screening 141 4.3.3 Reaction Scope 142 iv 4.4 Modification of Amination Product 144 4.5 Conclusion 146 4.6 Experimental Section 147 4.6.1 General Information 147 4.6.2 Preparation of Catalysts 148 4.6.3 Representative Procedure 153 4.6.4 Analytical Data of Amination Adducts 154 4.6.5 NMR Spectra of Products 161 Reference Appendices: Appendix One: X-ray Crystallographic Data for β-Lactam 3-8 175 I I Appendix Two: X-ray Crystallographic Data for Amination Adduct 4-3e XI v Summary This thesis describes development of enantioselective additions of fluorocarbon nucleophiles using bifunctional organic catalysts. A brief historic overview of asymmetric organocatalysis was provided in Chapter 1, in particular, chiral Brønsted acid organocatalysis was discussed. A selection of examples showing recent advancements in this field of catalysis was described in detail. In Chapter 2, α-fluorinated β-ketoesters were employed as nucleophiles, and their conjugate addition to nitroolefin could be effectively catalyzed by cinchona alkaloidbased bifunctional thiourea organocatalysts. The products containing adjacent quaternary fluorinated and tertiary chiral centers were obtained in high yield and with up to 19:1 diastereomeric ratio and excellent enantioselectivity, and synthetic useful chiral structural scaffolds with three contiguous stereogenic centers were also derived. In Chapter 3, we introduced a novel tryptophan-based bifunctional thiourea catalyst that was remarkable effective in promoting the asymmetric Mannich reaction of α-fluorinated β-ketoesters. The resulting compounds with fluorinated quaternary and tertiary stereocenters were converted readily into α-fluoro-β-lactams. We have also shown that tertiary amine-thiourea bifunctional catalysts can be easily derived from natural amino acids, this strategy may lead to the discovery of various novel multifunctional organic catalysts. In Chapter 4, an enantioselective, organocatalytic asymmetric route was chosen for the preparation of α-fluoro-α-hydrazino β-ketoesters, potential precursors for αfluoro-α-amino acids. Towards this end, novel bifunctional chiral guanidine catalysts were synthesized and used. vi List of Tables Table 2.11 Screening of different ketoesters for the asymmetric Michael addition to nitroolefin 33 Table 2.12 Screening of organocatalysts for the asymmetric Michael addition to nitroolefin 35 Table 2.13 Diastereoselective and enantioselective Michael addition of αfluorinated β-ketoester 2-1f to various nitroolefins 36 Table 2.14 Asymmetric Michael addition of different α-fluorinated β-ketoesters 37 Table 3.11 Catalyst screening for the asymmetric Mannich reaction of 3-1a and 32a 75 Table 3.12 Solvent screening for the asymmetric Mannich reaction of 3-1a and 32a 76 Table 3.13 Asymmetric Mannich reaction of different α-fluorinated β-ketoesters 77 Table 3.14 Asymmetric Mannich reaction of different Boc-imines Table 3.15 Mannich reaction of imine and a large excess of fluorinated ketoester carried out in the presence of 10 mol% catalyst 82 Table 3.16 Mannich reaction of fluorinated ketoester and a large excess of imine carried out in the presence of 10 mol% catalyst 83 Table 3.17 Mannich reaction of imine and fluorinated ketoester carried out in the presence of 10 mol% catalyst 85 Table 3.18 Mannich reaction of imine and fluorinated ketoester carried out in the presence of 15 mol% Catalyst 86 Table 3.19 Mannich reaction of imine and fluorinated ketoester carried out in the presence of 20 mol% catalyst 87 Table 3.20 Mannich reaction of imine and fluorinated ketoester carried out in the presence of 25 mol% catalyst 88 Table 3.21 Observed reaction rate constant based on imine A 90 Table 3.22 Observed reaction rate constant based on ketoester B 90 Table 4.11 Catalyst screening for the Amination reaction of 3-1a and 4-2 141 Table 4.12 Solvent screening for the Amination reaction of 3-1a and 4-2 142 78 vii Table 4.13 Asymmetric Amination reaction of different α-fluorinated β-ketoesters 143 viii Table 5. Hydrogen coordinates (x 104) and isotropic displacement parameters (Å2 x 103) for jhl7 ________________________________________________ x y z U(eq) ________________________________________________ H(3) -624 5987 3739 53 H(1) -831 8244 5057 62 H(4) 4443 6583 3701 57 H(2) 4140 4323 4507 89 H(6) 1255 2934 3021 81 H(7) -41 2024 1569 111 H(8) 341 3927 382 121 H(9) 2144 6643 631 110 H(10) 3486 7571 2070 81 H(12) -1498 6563 2072 74 H(13) -3227 8311 911 89 H(15) -4151 12303 2634 91 H(16) -2308 10634 3794 74 H(17A) -4333 11560 368 194 H(17B) -5020 12956 1048 194 IX H(17C) -6234 11142 711 194 ________________________________________________ X Appendix Two: X-ra ay crystalloographic da ata for Amiination Addduct 4-3e Table 1. Crystal C data and structuure refinemeent for 9366 6A (4-3e) Identificatioon code 9366a Empirical formula f C21 C H28 Brr F N2 O7 Formula weeight 519.36 Temperaturre 223(2) K Wavelengthh 0.71073 Å Crystal systtem Monoclinic M Space grouup P2(1) P Unit cell diimensions a = 9.1606(4 4) Å α= 90° b = 10.4979 9(5) Å ββ= 96.0080(10)° c = 12.5357(6) Å γ= = 90° XI Volume 1198.90(10) Å3 Z Density (calculated) 1.439 Mg/m3 Absorption coefficient 1.764 mm-1 F(000) 536 Crystal size 0.40 x 0.30 x 0.20 mm3 Theta range for data collection 1.63 to 27.50°. Index ranges -11[...]... robust, inexpensive, readily available, and non-toxic Organic catalyst’ was first introduced by Otswald in 1900, with the purpose of distinguishing organic compounds as catalysts from that of enzymes and inorganic compounds.27 A few years later, Bredig reported the first example of an asymmetric reaction using organic catalysts. 28 The hydrocyanation of benzaldehyde was catalyzed by the Cinchona alkaloids... Cleavage of N-N bond 146 xi List of Figures Figure 1.11 Three modes of electrophilic activation of carbonyl compounds 6 Figure 1.12 Brønsted acid family 7 Figure 1.13 Kelly and Jørgensen’s activation models 8 Figure 1.14 Structures of orgnaocatalysts TADDOL 8 and derivatives of BINOL 9, 10 9 Figure 1.15 Double hydrogen bonding monofunctional urea and thiourea catalysts 12 Figure 1.16 Jacobsen’s monofunctional... resulted from uses of transition metals and tedious product contamination.26 2 In contrast, organocatalysts are purely organic molecules which are mainly composed of carbon, hydrogen, oxygen, sulfur, and phosphorus The catalytic activity of organocatalysts resides in the low molecular weight organic molecule itself, and no transition metals are required The advantages of organocatalysts are notable:... thiourea catalysts Figure 1.17 Takemoto’s activation model of the Michael reaction between malonate esters and nitro alkenes 17 Figure 1.18 Pápai’s activation model for the Michael reaction 18 Figure 1.19 Jacobsen’s bifunctional thiourea catalysts 19 Figure 1.20 Proposed transition state model of the thiourea-catalyzed addition of indole to nitroalkene 21 Figure 1.21 Chiral bifunctional thiourea catalysts. .. the hydrolysis and formation of esters, acetals, etc The synthetic utility of Brønsted acids as catalysts for carbon-carbon bond-forming reactions has been quite limited until recently Chiral Brønsted acids as a new class of organocatalysts for 60-63 enantioselective reactions has gained great development quite recently There are three modes of electrophilic activation of carbonyl compounds: single... Lewis acid catalysts A number of metal-centered Lewis acid catalysts have been developed and a wide range of center metals such as Ti, Zr, Cu, Al, Zn and others have been studied so far.59 The proton is the smallest element of the Lewis acid, that is Brønsted acid While Lewis acids have been widely employed as catalysts for carbon-carbon bond formations, Brønsted acids have been used as catalysts mainly... trimethylsilyl triflate Ts toluenesulfonyl Tr trityl xvi List of Publications 1 "Apparent Negative Activating Enthaphy: Elucidation of the Role of Bifunctional Thiourea Catalysts" Xiao Han, Jie Luo, Tao Chen, Kuo-Wei Huang,* Yixin Lu* (Manuscript in preparation) 2 "Chiral Guanidine as Highly Active and Enantioselective Catalyst for Asymmetric Amination of Fluorinated Ketoesters" Xiao Han, Fangrui Zhong, Yixin... Figure 1.16 Jacobsen’s monofunctional thiourea catalysts In 1998, a library of Schiff base derived thiourea catalysts were synthesized and reported by Jacobsen (Figure 1.16).81 These catalysts were initially designed as potential ligands for Lewis acidic metals However, high enantioselectivity was observed in the absence of the metal ion when tested in the Strecker reaction of hydrogen cyanide with... reaction of hydrogen cyanide with N-allylaldimine 14 Scheme 1.21 Reactions catalyzed by Jacobsen’s monofunctional thiourea catalysts 14 Scheme 1.22 Chiral bis-thiourea catalyzed Baylis-Hillman addition 15 Scheme 1.23 Friedel-Crafts addition catalyzed by bis-thiourea 16 Scheme 1.24 Enantioselective Michael Addition reaction catalyzed by a tertiary amine thiourea 17 Scheme 1.25 Enantioselective 1,4 -additions. .. C O 5 93% yield 94% ee OMe H N OAc N 4 Scheme 1.11 Examples of asymmetric reactions using organic catalysts in the early age Organocatalysts can be broadly classified into four catagories: Lewis acids, Lewis bases, Brønsted acids, and Brønsted bases.58 The corresponding catalytic cycles are shown below (Scheme 1.12) Accordingly, Lewis acid catalysts (A) 4 initiates the catalytic cycle via electrophilic . This thesis describes development of enantioselective additions of fluorocarbon nucleophiles using bifunctional organic catalysts. A brief historic overview of asymmetric organocatalysis was. ENANTIOSELECTIVE ADDITIONS OF FLUOROCARBON NUCLEOPHILES USING BIFUNCTIONAL ORGANIC CATALYSTS HAN XIAO (BSc. Soochow Univ.) A THESIS SUBMITTED FOR THE DEGREE OF. ENANTIOSELECTIVE ADDITIONS OF FLUOROCARBON NUCLEOPHILES USING BIFUNCTIONAL ORGANIC CATALYSTS HAN XIAO NATIONAL UNIVERSITY OF SINGAPORE