Development of novel amino acid derived multifunctional phosphines for enantioselective reactions

DEVELOPMENT OF NOVEL AMINO ACID-DERIVED MULTIFUNCTIONAL PHOSPHINES FOR ENANTIOSELECTIVE REACTIONS ZHONG FANGRUI NATIONAL UNIVERSITY OF SINGAPORE 2012 DEVELOPMENT OF NOVEL AMINO ACID-DERIVED MULTIFUNCTIONAL PHOSPHINES FOR ENANTIOSELECTIVE REACTIONS ZHONG FANGRUI (B.Sc., Zhejiang Univ.) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2012 To my parents, sisters, and Yuzhou, for their endless love, support and encouragement PHD DISSERTATION 2012 ZHONG FANGRUI Acknowledgements It is my great pleasure to take this opportunity to express my gratitude and thanks to all the people who have helped and encouraged me during my PhD studies This thesis could not have been accomplished without their supports Foremost, my deepest appreciation and respect go to my supervisor, Prof Lu Yixin, for his constant support and guidance throughout my PhD research His intensity, passion, motivation and profound knowledge make it a privilege for me to work under your supervision Prof Lu has allowed me great freedom in developing projects to work on in the lab and has always been ready for providing valuable advice when there is a need There is no doubt that what I have benefited from Prof Lu, a professional chemist and supervisor, will have an extraordinary impact to my future life Among all the past and present members in Prof Lu’s group, I would like to extend my special thanks to Prof Wang Youqing I really appreciate his efforts and kind help as my mentor at the initial stage of my PhD studies Meanwhile, one person in particular I need to express my gratitude is Dr Han Xiaoyu, whose effective collaboration, helpful discussion and friendship have greatly helped in my PhD years My thanks also go to Dr Wang Tianli and Wu Wenqin for proofreading of my thesis draft I am truly grateful to all other colleagues: Dr Yuan Qing, Dr Xie Xiaoan, Dr Wang Haifei, Dr Jiang Zhaoqin, Dr Wang Suxi, Dr Zhu Qiang, Dr Han Xiao, Dr Liu Xiaoqian, Dr Yao Weijun, Dr Luo Jie, Dr Liu Chen, Jolin Foo, Guoying, Xiaowei, Jacek, Guannan, Chunhui, Wen Shan, Vicknesh, and others labmates It is my great pleasure to study in such a harmonious and encouraging environment i PHD DISSERTATION 2012 ZHONG FANGRUI I also want to thank the research scholarship provided by National University of Singapore Thanks also go to the staff in department of chemistry for all their help: Suriawati Bte Sa'Ad (administrative office), Ms Tan Geok Kheng and Ms Hong Yimian (X-ray crystallography analysis), Madam Han Yanhui (NMR analysis), Madam Wong Lai Kwai and Madam Lai Hui Ngee (Mass analysis) Last but not least, I am extremely grateful to my parents who have unconditionally loved and nurtured me through my life I am indebted to my sisters for taking care of my parents all these years when I have been studying away from home They have been my pillar of support through happiness and woes in my endeavors Finally, I thank my beloved fiancée, Wu Yuzhou, for always being there for me and being my soul mate It was extremely fortunate for me to meet her, her endless love, support, and encouragement have helped me make key developments in my life, both professionally and socially My gratitude also goes to my parentsinlaw for their endless love, for believing in us, and allowing us to pursue our dreams ii PHD DISSERTATION 2012 ZHONG FANGRUI Thesis Declaration The work in this thesis is the original work of Zhong Fangrui, performed independently under the supervision of A/P Lu Yixin, Chemistry Department, National University of Singapore, between 08/2008 and 07/2012 The contents of the thesis have been partly published in: Fangrui Zhong, Xiaowei Dou, Xiaoyu Han, Weijun Yao, Qiang Zhu, YueZhong Meng, Yixin Lu Angew Chem Int Ed 2013, DOI: 10.1002/anie.201208285 Fangrui Zhong, Jie Luo, Guo-Ying Chen, Xiaowei Dou, Yixin Lu J Am Chem Soc 2012, 134, 10222 Fangrui Zhong, Xiaoyu Han, Youqing Wang, Yixin Lu Chem Sci 2012, 3, 1231 Fangrui Zhong, Guoying Chen, Xiaoyu Han, Weijun Yao, Yixin Lu Org Lett., 2012, 14, 3764 Fangrui Zhong, Xiaoyu Han, Youqing Wang, Yixin Lu Angew Chem Int Ed 2011, 50, 7837 Fangrui Zhong, Youqing Wang, Xiaoyu Han, Kuo-Wei Huang, Yixin Lu Org Lett 2011, 13, 1310 Fangrui Zhong, Guo-Ying Chen, Yixin Lu Org Lett 2011, 13, 82 Zhong Fangrui Name Signature Date iii PHD DISSERTATION 2012 ZHONG FANGRUI Table of Contents Acknowledgements i Thesis Declaration iii Table of Contents iv Summary x xiii List of Tables List of Schemes xv List of Figures xx List of Abbreviations xxii List of Publications xxv Chapter Lewis Base Catalysis Employing Nucleophilic Phosphines 1.1 Lewis Base Catalysis and Nucleophilic Phosphine Catalysis 1.2 Phosphine-catalyzed Organic Reactions 1.2.1 The MBH Reaction and Its Aza-Counterpart 1.2.2 [3+2] Annulations with Allenoates and Alkynoates 11 1.2.3 [4+2] Annulations with Allenoates 17 1.2.4 Other Phosphine-catalyzed [m+n] Annulation Reactions 22 1.2.5 Allylic Substitutions and Annulations with MBH Adducts 30 1.2.6 Umpolung Additions and Michael Additions 39 1.2.7 Acylation Reactions and Kinetic Resolution 44 1.3 Chiral Mono- and Bicyclic Phosphines 48 1.3.2 iv 47 1.3.1 1.4 Recent Advances of Chiral Phosphine Catalysis Chiral Phosphines with H-Bond Functionalities 54 Project Objectives and Overall Design 60 PHD DISSERTATION 2012 ZHONG FANGRUI 8.3 Conclusions In summary, we have successfully demonstrated the first asymmetric MBH reaction of isatins with acrylates The reactions proceeded efficiently at room temperature, yielding the desired adducts in high yields and with excellent enantioselectivities The method reported represents a novel approach to access structurally challenging and biologically important chiral 3-hydroxy-2-oxindoles Additive studies performed suggested that the C6′-OH group of -ICD facilitates the proton transfer step via its participation in an intramolecular proton relay process We anticipate the methodology described here will find wide applications in the synthesis of novel 3-hydroxy-2-oxindoles and mechanistic insights gained in this study may facilitate the rational design of novel catalytic systems for the asymmetric MBH reactions 8.4 Experimental Section 8.4.1 Material and General Methods All the starting materials were obtained from commercial sources and used without further purification unless otherwise stated THF and diethyl ether were dried and distilled from sodium benzophenone ketyl prior to use CHCl3 and CH2Cl2 were distilled from CaH2 prior to use Dioxane was dried and distilled from Na prior to use All the solvents used in reactions involving phosphorous-containing compounds were de-gassed by dry N2 1H and 13C NMR spectra were recorded on a Bruker ACF300 or AMX500 (500 MHz) spectrometer Chemical shifts were reported in parts per million (ppm), and the residual solvent peak was used as an internal reference: proton - 341   Chapter Enantioselective MBH Reaction of Isatins with Acrylates (chloroform δ 7.26), carbon (chloroform δ 77.0) Multiplicity was indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet), br (broad singlet) Coupling constants were reported in Hertz (Hz) Low resolution mass spectra were obtained on a Finnigan/MAT LCQ spectrometer in ESI mode, and a Finnigan/MAT 95XL- T mass spectrometer in FAB mode All high resolution mass spectra were obtained on a Finnigan/MAT 95XL-T spectrometer For thin layer chromatography (TLC), Merck pre- coated TLC plates (Merck 60 F254) were used, and compounds were visualized with a UV light at 254 nm Further visualization was achieved by staining with iodine, or ceric ammonium molybdate followed by heating on a hot plate Flash chromatographic separations were performed on Merck 60 (0.040-0.063 mm) mesh silica gel The enantiomeric excesses of products were determined by chiral-phase HPLC analysis, using a Daicel Chiralcel IC-H column (250 x 4.6 mm), or Chiralpak OD-H ncolumn, or IA column (250 x 4.6 mm) All the isatin derivatives 8-5 were prepared following the literature procedures.18 β-ICD and β-isocinchonine were prepared according to methods.19 8.4.2 Representative Procedure for the MBH Reaction O O O + OBn N Bn 8-5a β - ICD (10 mol%) Å MS CHCl3, RT, 72 h 8-6f HO CO2Bn O N Bn 8-7a                                                                 18 19 (a) Itoh, T.; Ishikawa, H.; Hayashi, Y Org Lett., 2009, 11, 3854 (b) M T Chan, D M T.; Monaco, K L.; Wang, R.-P.; Winters, M P Tetrahedron Lett 1998, 39, 2933 Waldmann, H.; Khedkar, V.; Dückert, H.; Schürmann, M.; OppeI M.; Kumar, K Angew Chem Int Ed 2008, 47, 6869.  - 342   PHD DISSERTATION 2012 ZHONG FANGRUI To a flame-dried round bottle flask with a magnetic stirring bar were added catalyst β-ICD (1.6 mg, 0.005 mmol), N-benzyl isatin 8-5a (12.9 mg, 0.05 mmol) and Å molecular sieve under Ar, followed by the addition of dry CHCl3 (100 L) After the 8-5a was dissolved, benzyl acrylate 8-6f (15 L, 0.1 mmol) was then added The flask was sealed, and the reaction was stirred at room temperature for 72 hrs The reaction mixture was purified directly by column chromatography on silica gel using hexane/ethyl acetate (8:1 to 3:1) as an eluent to afford 8-7a as a white solid (16.6 mg, 83% yield) 8.4.3 Analytical Data of MBH Adducts (R)-Benzyl 2-(1-benzyl-3-hydroxy-2-oxoindolin-3-yl)acrylate 8-7a HO CO2 Bn O N 8-7a Bn A white solid; [α]25D = -34.5 (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) δ 3.83 (br, 1H), 4.53 (d, J = 15.8 Hz, 1H), 4.86 (d, J = 15.8 Hz, 1H), 4.93 (d, J = 12.6 Hz, 1H), 5.07 (d, J = 12.6 Hz, 1H), 6.48 (s, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.66 (s, 1H), 7.00 (t, J = 7.6 Hz, 1H), 7.12-7.14 (m, 2H), 7.18-7.21 (m, 2H), 7.24 (d, J = 7.0 Hz, 1H),7.23-7.33 (m, 7H); 13 C NMR (125 MHz, CDCl3) δ 43.84, 66.88, 76.19, 109.82, 122.97, 123.87, 127.30, 127.58, 128.29, 128.31, 128.43, 128.51, 128.72, 129.40, 130.03, 135.14, 135.47, 139.07, 143.66, 164.38, 176.31; HRMS (ESI) m/z calcd for C25H21NO4 [M+Na]+ = 422.1363, found = 422.1356; The ee value was 96%, tR (minor) = 13.7 min, tR (major) = 18.1 (Chiralcel IC-H, λ = 254 nm, 20% i-PrOH/hexanes, flow rate = 1.0 mL/min) - 343   Chapter Enantioselective MBH Reaction of Isatins with Acrylates (R)-Benzyl 2-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)acrylate 8-7b A white solid; [α]25D = -27.8 (c 0.94, CHCl3); 1H NMR (500 MHz, CDCl3) δ 3.77 (s, 3H), 4.08 (br, 1H), 4.50 (d, J = 15.8 Hz, 1H), 4.81 (d, J = 15.8 Hz, 1H), 4.93 (d, J = 12.6 Hz, 1H), 5.08 (d, J = 12.0 Hz, 1H), 6.52 (s, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.68 (s, 1H), 6.84 (d, J = 8.7 Hz, 2H), 7.02 (t, J = 7.6 Hz, 1H), 7.13-7.15 (m, 2H), 7.20 (d, J = 7.6 Hz, 1H), 7.23 (dd, J = 1.3 Hz, 7.6 Hz, 1H), 7.28 (d, J = 8.2 Hz, 2H), 7.35 (dd J = 3.8 Hz, 6.3 Hz, 3H); 13 C NMR (125 MHz, CDCl3) δ 43.24, 55.17, 66.80, 76.13, 109.82, 114.07, 122.90, 123.77, 127.43, 128.24, 128.30, 128.47, 128.52, 128.64, 129.43, 129.94, 135.08, 138.95, 143.58, 158.98, 164.31, 176.33; HRMS (ESI) m/z calcd for C26H23NO5 [M+Na]+ = 452.1468, found = 452.1463; The ee value was 95%, tR (minor) = 19.7 min, tR (major) = 20.1 (Chiralcel IC-H, λ = 254 nm, 20% i-PrOH/hexanes, flow rate = 1.0 mL/min) (R)-Benzyl 2-(1-benzhydryl-3-hydroxy-2-oxoindolin-3-yl)acrylate 8-7c A white solid; [α]25D = -30.3 (c 0.95, CHCl3); 1H NMR (500 MHz, CDCl3) δ 3.62 (br, 1H), 4.92 (d, J = 12.6 Hz, 1H), 5.16 (d, J = 12.6 Hz, 1H), 6.44 (s, 1H), 6.45 (d, J = 8.2 Hz, 1H), 6.61 (s, 1H), 6.96 (t, J = 7.6 Hz, 2H), 7.05 (dt, J = 1.3 Hz, 7.6 Hz, 1H), - 344   PHD DISSERTATION 2012 ZHONG FANGRUI 7.13-7.15 (m, 2H), 7.18 (d, J = 6.3 Hz, 1H), 7.28-7.36 (m, 11H), 7.41 (dd, J = 1.3 Hz, 8.9 Hz, 2H); 13 C NMR (125 MHz, CDCl3) δ 58.61, 66.63, 75.82, 112.43, 122.68, 123.84, 127.71, 127.79, 127.84, 128.12, 128.30, 128.46, 128.47, 128.50, 128.58, 128.65, 129.50, 129.61, 135.44, 137.30, 137.57, 139.02, 143.34, 164.40, 176.34; HRMS (ESI) m/z calcd for C31H25NO4 [M+Na]+ = 498.1676, found = 498.1671; The ee value was 93%, tR (minor) = 7.7 min, tR (major) = 12.7 (Chiralcel IC-H, λ = 254 nm, 20% i-PrOH/hexanes, flow rate = 1.0 mL/min) (R)-Benzyl 2-(3-hydroxy-2-oxo-1-tritylindolin-3-yl)acrylate 8-7d HO CO2 Bn O N Trt 8-7d A white solid; [α]25D = -10.7 (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) δ 3.28 (br, 1H), 5.03 (d, J = 12.6 Hz, 1H), 5.25 (d, J = 12.7 Hz, 1H), 6.38 (d, J = 7.6 Hz, 1H), 6.43 (s, 1H), 6.62 (s, 1H), 6.93-6.99 (m, 2H), 7.16 (dd, J = 1.3 Hz, 6.3 Hz, 1H), 7.21-7.29 (m, 12H), 7.35 (dd, J = 1.9 Hz, 5.1 Hz, 3H), 7.56-7.57 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 66.62, 74.58, 76.14, 116.40, 122.47, 123.31, 126.82, 127.58, 127.94, 128.14, 128.49, 128.54, 129.35, 129.42, 135.51, 139.42, 141.91, 144.36, 164.49, 177.10; HRMS (ESI) m/z calcd for C37H29NO4 [M+Na]+ = 574.1989, found = 574.1977; The ee value was 92%, tR (minor) = 11.1 min, tR (major) = 13.9 (Chiralcel IC-H, λ = 254 nm, 10% i-PrOH/hexanes, flow rate = 1.0 mL/min) (R)-Benzyl 2-(3-hydroxy-2-oxo-1-phenylindolin-3-yl)acrylate 8-7e - 345   Chapter Enantioselective MBH Reaction of Isatins with Acrylates A white solid; [α]25D = -20.5 (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) δ 3.97 (br, 1H), 5.01 (d, J = 12.6 Hz, 1H), 5.16 (d, J = 12.6 Hz, 1H), 6.57 (s, 1H), 6.70 (s, 1H), 6.79 (d, J = 7.6 Hz, 1H), 7.09-7.15 (m, 3H), 7.26-7.34 (m, 6H), 7.41 (t, J = 7.6 Hz, 2H), 7.50 (t, J = 7.6 Hz, 2H); 13 C NMR (125 MHz, CDCl3) δ 66.86, 76.15, 109.98, 123.33, 124.11, 126.39, 128.06, 128.22, 128.47, 129.00, 129.48, 130.01, 134.05, 135.09, 139.24, 144.61, 164.35, 175.66; HRMS (ESI) m/z calcd for C24H19NO4 [M+Na]+ = 408.1206, found = 408.1202; The ee value was 90%, tR (minor) = 18.6 min, tR (major) = 21.3 (Chiralcel IC-H, λ = 254 nm, 20% i-PrOH/hexanes, flow rate = 0.8 mL/min) (R)-Benzyl 2-(3-hydroxy-1-(4-methoxyphenyl)-2-oxoindolin-3-yl)acrylate 8-7f A white solid; [α]25D = -42.6 (c 1.10, CHCl3); 1H NMR (500 MHz, CDCl3) δ 3.70 (br, 1H), 3.85 (s, 3H), 5.00 (d, J = 12.7 Hz, 1H), 5.14 (d, J = 12.0 Hz, 1H), 6.54 (s, 1H), 6.68 (s, 1H), 6.71 (d, J = 7.6 Hz, 1H), 6.97-7.00 (m, 2H), 7.07 (t, J = 7.6 Hz, 1H), 7.11-7.13 (m, 2H), 7.22 (dd, J = 1.9 Hz, 8.8 Hz, 1H), 7.24-7.29 (m, 6H); 13 C NMR (125 MHz, CDCl3) δ 55.49, 66.86, 76.15, 109.92, 114.84, 123.19, 124.06, 126.76, 127.84, 128.06, 128.24, 128.50, 128.93, 130.07, 134.91, 135.18, 139.37, 145.15, 159.21, 164.39, 175.79; HRMS (ESI) m/z calcd for C25H21NO5 [M+Na]+ = 438.1312, - 346   PHD DISSERTATION 2012 ZHONG FANGRUI found = 438.1308; The ee value was 92%, tR (minor) = 23.3 min, tR (major) = 28.3 (Chiralcel IC-H, λ = 254 nm, 20% i-PrOH/hexanes, flow rate = 1.0 mL/min) (R)-Benzyl 2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)acrylate 8-7g HO CO2 Bn O N 8-7g A white solid; [α]25D = -50.2 (c 1.50, CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.93 (s, 3H), 4.60 (br, 1H), 4.92 (d, J = 12.6 Hz, 1H), 4.97 (d, J = 12.6 Hz, 1H), 6.54 (s, 1H), 6.66 (s, 1H), 6.70 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 7.08-7.09 (m, 2H), 7.18 (d, J = 7.6 Hz, 1H), 7.31-7.34 (m, 4H); 13 C NMR (125 MHz, CDCl3) δ 25.84, 66.72, 75.87, 108.58, 122.77, 123.51, 128.16, 128.25, 128.33, 128.54, 129.44, 129.79, 134.72, 138.88, 144.14, 164.13, 176.21; HRMS (ESI) m/z calcd for C19H17NO4 [M+Na]+ = 346.1050, found = 346.1046; The ee value was 95%, tR (minor) = 18.1 min, tR (major) = 21.1 (Chiralcel IC-H, λ = 254 nm, 20% i-PrOH/hexanes, flow rate = 1.0 mL/min) (R)-Benzyl 2-(1-benzyl-7-chloro-3-hydroxy-2-oxoindolin-3-yl)acrylate 8-7h HO CO2 Bn O Cl N Bn 8-7h A white solid; [α]25D = -57.6 (c 0.50, CHCl3); 1H NMR (500 MHz, CDCl3) δ 3.78 (br, 1H), 4.98 (d, J = 12.6 Hz, 1H), 5.04 (d, J = 16.4 Hz, 1H), 5.10 (d, J = 12.0 Hz, 1H), 5.21 (d, J = 16.4 Hz, 1H), 6.50 (s, 1H), 6.69 (s, 1H), 6.97 (t, J = 7.6 Hz, 1H), 7.11 (dd, - 347   Chapter Enantioselective MBH Reaction of Isatins with Acrylates J = 1.3 Hz, 7.6 Hz, 1H), 7.17-7.20 (m, 3H), 7.21 (d, J = 1.3 Hz, 1H), 7.24-7.33 (m, 4H), 7.35-7.37 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 44.92, 67.10, 75.46, 115.88, 122.52, 123.93, 126.48, 127.10, 128.33, 128.43, 128.50, 128.65, 128.85, 132.13, 132.68, 134.86, 137.24, 138.71, 139.80, 164.13, 177.01; HRMS (ESI) m/z calcd for C25H20ClNO4 [M+Na]+ = 456.0973, found = 456.0978; The ee value was 96%, tR (minor) = 17.7 min, tR (major) = 26.4 (Chiralcel IC-H, λ = 254 nm, 20% i-PrOH/hexanes, flow rate = 1.0 mL/min) (R)-Benzyl 2-(1-benzyl-7-fluoro-3-hydroxy-2-oxoindolin-3-yl)acrylate 8-7i A white solid; [α]25D = -43.9 (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.07 (br, 1H), 4.64 (d, J = 15.7 Hz, 1H), 4.85 (d, J = 12.0 Hz, 1H), 4.97 (d, J = 12.0 Hz, 1H), 5.06 (d, J = 12.0 Hz, 1H), 6.48 (s, 1H), 6.65 (s, 1H), 6.92-6.99 (m, 3H), 7.09-7.11 (m, 2H), 7.23-7.36 (m, 8H); 13 C NMR (125 MHz, CDCl3) δ 45.31, 66.95, 76.03 (d, J = 2.8 Hz), 118.30 (d, J = 20.0 Hz), 119.72 (d, J = 2.7 Hz), 123.74 (d, J = 6.4 Hz), 127.47 (d, J = 7.3 Hz), 128.33 (d, J = 10.0 Hz), 128.50, 128.54, 128.84, 130.14 (d, J = 8.2 Hz), 132.23, 134.87, 136.60, 138.64, 146.46, 148.41, 164.10, 158.03 (d, J = 107.5 Hz), 176.14; HRMS (ESI) m/z calcd for C25H20FNO4 [M+Na]+ = 440.1269, found = 440.1260; The ee value was 92%, tR (minor) = 8.4 min, tR (major) = 11,0 (Chiralcel IC-H, λ = 254 nm, 20% i-PrOH/hexanes, flow rate = 1.0 mL/min) (R)-Benzyl 2-(1-benzyl-5-fluoro-3-hydroxy-2-oxoindolin-3-yl)acrylate 8-7j - 348   PHD DISSERTATION 2012 ZHONG FANGRUI HO CO 2Bn F O N 8-7j Bn A white solid; [α]25D = -81.1 (c 1.15, CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.20 (br, 1H), 4.56 (d, J = 15.8 Hz, 1H), 4.87 (d, J = 15.8 Hz, 1H), 4.97 (d, J = 12.0 Hz, 1H), 5.12 (d, J = 12.0 Hz, 1H), 6.52 (d, J = 3.6 Hz, 1H), 6.54 (d, J = 3.8 Hz, 1H), 6.69 (s, 1H), 6.89 (dt, J = 2.5 Hz, 8.8 Hz, 1H), 6.95 (dd, J = 2.6 Hz, 6.4 Hz, 1H), 7.18-7.20 (m, 2H), 7.26-7.39 (m, 8H); 13C NMR (125 MHz, CDCl3) δ 43.97, 66.99, 76.22, 110.47 (d, J = 8.2 Hz), 112.08 (d, J = 24.6 Hz), 116.12 (d, J = 22.8 Hz), 127.23, 127.69, 128.41, 128.55, 128.78, 128.97, 131.01 (d, J = 6.4 Hz), 135.03 (d, J = 10.9 Hz), 138.64, 139.42, 159.28 (d, J = 240.5 Hz), 164.16, 176.28; HRMS (ESI) m/z calcd for C25H20FNO4 [M+Na]+ = 440.1269, found = 440.1260; The ee value was 92%, tR (minor) = 8.3 min, tR (major) = 11.0 (Chiralcel IC-H, λ = 254 nm, 20% i-PrOH/hexanes, flow rate = 1.0 mL/min) (R)-Benzyl 2-(1-benzyl-5-chloro-3-hydroxy-2-oxoindolin-3-yl)acrylate 8-7k HO Cl CO 2Bn O N Bn 8-7k A white solid; [α]25D = -38.7 (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.12 (br, 1H), 4.55 (d, J = 16.4 Hz, 1H), 4.86 (d, J = 15.8 Hz, 1H), 4.95 (d, J = 12.0 Hz, 1H), 5.12 (d, J = 12.0 Hz, 1H), 6.52 (s, 1H), 6.53 (d, J = 5.1 Hz, 1H), 6.70 (s, 1H), 7.15-7.19 (m, 4H), 7.29-7.37 (m, 8H); 13 C NMR (125 MHz, CDCl3) δ 43.92, 67.00, 76.00, 110.81, 124.39, 127.22, 127.72, 128.40, 128.42, 128.56, 128.79, 129.02, - 349   Chapter Enantioselective MBH Reaction of Isatins with Acrylates 129.82, 131.07, 134.93, 138.55, 142.07, 164.08, 176.08; HRMS (ESI) m/z calcd for C25H20ClNO4 [M+Na]+ = 456.0973, found = 456.0978; The ee value was 91%, tR (minor) = 18.8 min, tR (major) = 29.1 (Chiralcel IC-H, λ = 254 nm, 10% i-PrOH/hexanes, flow rate = 1.0 mL/min) (R)-benzyl 2-(1-benzyl-5-bromo-3-hydroxy-2-oxoindolin-3-yl)acrylate 8-7l A white solid; [α]25D = -22.3 (c 1.00, CHCl3); 1H NMR (500 MHz，CDCl3) δ 3.62 (br, 1H), 4.53 (d, J = 15.8 Hz, 1H), 4.85 (d, J = 15.8 Hz, 1H), 4.94 (d, J = 12.0 Hz, 1H), 5.09 (d, J = 12.6 Hz, 1H), 6.47 (d, J = 8.2 Hz, 1H), 6.49 (s, 1H), 6.69 (s, 1H), 7.14-7.16 (m, 2H), 7.28-7.33 (m, 8H), 7.34 (d, J = 3.2 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 43.93, 67.07, 75.97, 111.31, 115.63, 127.20, 127.24, 127.28, 127.79, 128.40, 128.43, 128.59, 128.84, 128.89, 131.25, 132.84, 134.96, 138.59, 142.68, 164.11, 175.80; HRMS (ESI) m/z calcd for C25H2079BrNO4 [M+Na]+ = 500.0468, found = 500.0460; C25H2081BrNO4 [M+Na]+ = 502.0463, found = 502.0439; The ee value was 94%, tR (minor) = 9.5 min, tR (major) = 13.1 (Chiralcel IC-H, λ = 254 nm, 20% i-PrOH/hexanes, flow rate = 1.0 mL/min) (R)-Benzyl 2-(1-benzyl-3-hydroxy-5-nitro-2-oxoindolin-3-yl)acrylate 8-7m A white solid; [α]25D = -48.6 (c 0.80, CHCl3); 1H NMR (500 MHz, CDCl3) δ 3.67 (br, - 350   PHD DISSERTATION 2012 ZHONG FANGRUI 1H), 4.66 (d, J = 15.8 Hz, 1H), 4.92 (d, J = 15.8 Hz, 1H), 4.93 (d, J = 12.6 Hz, 1H), 5.10 (d, J = 16.0 Hz, 1H), 6.59 (s, 1H), 6.68 (d, J = 8.8 Hz, 1H), 6.76 (s, 1H), 7.16-7.17 (m, 2H), 7.30-7.36 (m, 8H), 8.03 (d, J = 2.5 Hz, 1H), 8.13 (dd, J = 1.9 Hz, 8.8 Hz, 1H); 13 C NMR (125 MHz, CDCl3) δ 44.27, 67.17, 75.40, 109.70, 119.70, 126.93, 127.25, 128.08, 128.45, 128.57, 128.60, 128.99, 129.53, 130.51, 134.32, 134.80, 138.17, 143.60, 149.28, 163.94, 176.60; HRMS (IT-TOF) m/z calcd for C25H20N2O6 [M+Na]+ = 467.1214, found = 467.1215; The ee value was 85%, tR (minor) = 15.4 min, tR (major) = 18.8 (Chiralcel IC-H, λ = 254 nm, 20% i-PrOH/hexanes, flow rate = 1.0 mL/min) (R)-Benzyl 2-(1-benzyl-3-hydroxy-5-methyl-2-oxoindolin-3-yl)acrylate 8-7n HO CO2 Bn O N Bn 8-7n A white solid; [α]25D = -27.0 (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.28 (s, 3H), 3.72 (br, 1H), 4.55 (d, J = 15.8 Hz, 1H), 4.86 (d, J = 15.8 Hz, 1H), 4.95 (d, J = 12.0 Hz, 1H), 5.10 (d, J = 12.0 Hz, 1H), 6.50 (s, 1H), 6.53 (d, J = 8.2 Hz, 1H), 6.69 (s, 1H), 7.01 (d, J = 8.8 Hz, 2H), 7.15-7.17 (m, 2H), 7.25-7.35 (m, 8H); 13C NMR (125 MHz, CDCl3) δ 20.94, 43.81, 66.87, 76.29, 109.60, 124.65, 127.27, 127.52, 128.29, 128.35, 128.40, 128.49, 128.69, 129.26, 130.29, 132.63, 135.12, 135.54, 139.07, 141.14, 164.38, 176.24; HRMS (ESI) m/z calcd for C26H23NO4 [M+Na]+ = 436.1519, found = 436.1518; The ee value was 92%, tR (minor) = 15.4 min, tR (major) = 22.5 (Chiralcel IC-H, λ = 254 nm, 20% i-PrOH/hexanes, flow rate = 1.0 mL/min) - 351   Chapter Enantioselective MBH Reaction of Isatins with Acrylates (R)-Benzyl 2-(1-benzyl-3-hydroxy-5-methoxy-2-oxoindolin-3-yl)acrylate 8-7o A white solid; [α]25D = -25.6 (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) δ 3.70 (s, 3H), 3.98 (br, 1H), 4.50 (d, J = 15.8 Hz, 1H), 4.83 (d, J = 15.8 Hz, 1H), 4.93 (d, J = 12.6 Hz, 1H), 5.07 (d, J = 12.0 Hz, 1H), 6.48 (s, 1H), 6.51 (d, J = 8.2 Hz, 1H), 6.65 (s, 1H), 6.70 (dd, J = 2.6 Hz, 8.2 Hz, 1H), 6.79 (d, J = 2.6 Hz, 1H), 7.13-7.15 (m, 2H), 7.24-7.33 (m, 8H); 13C NMR (125 MHz, CDCl3) δ 43.92, 55.77, 66.93, 76.56, 110.41, 110.93, 114.68, 127.32, 127.58, 128.34, 128.41, 128.54, 128.60, 128.75, 130.60, 135.16, 135.56, 136.90, 139.02, 156.24, 164.38, 176.19; HRMS (ESI) m/z calcd for C26H23NO5 [M+Na]+ = 452.1468, found = 452.1461; The ee value was 91%, tR (minor) = 18.4 min, tR (major) = 22.8 (Chiralcel IC-H, λ = 254 nm, 20% i-PrOH/hexanes, flow rate = 1.0 mL/min) (R)-benzyl 2-(1-benzyl-3-hydroxy-5,7-dimethyl-2-oxoindolin-3-yl)acrylate 8-7p A white solid; [α]25D = -53.0 (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.10 (s, 3H), 2.23 (s, 3H), 3.68 (br, 1H), 4.73 (d, J = 17.0 Hz, 1H), 4.99 (d, J = 12.6 Hz, 1H), 5.09 (d, J = 17.0 Hz, 1H), 5.10 (d, J = 12.0 Hz, 1H), 6.49 (s, 1H), 6.68 (s, 1H), 6.77 (s, 1H), 6.86 (s, 1H), 7.16-7.18 (m, 2H), 7.21-7.23 (m, 3H), 7.27-7.30 (m, 2H), 7.33-7.34 - 352   PHD DISSERTATION 2012 ZHONG FANGRUI (m, 3H); 13C NMR (125 MHz, CDCl3) δ 18.43, 20.61, 45.05, 66.91, 75.65, 120.10, 122.55, 125.75, 127.05, 128.30, 128.32, 128.52, 128.75, 129.78, 129.97, 132.66, 134.51, 135.15, 137.48, 139.12, 139.29, 164.42, 177.40; HRMS (ESI) m/z calcd for C27H25NO4 [M+Na]+ = 450.1676, found = 450.1668; The ee value was 95%, tR (minor) = 13.3 min, tR (major) = 24.6 (Chiralcel IC-H, λ = 254 nm, 30% i-PrOH/hexanes, flow rate = 1.0 mL/min) 8.4.4 X-Ray Crystallographic Analysis and Determination of Configurations of MBH Adducts The absolute configuration of the product 8-7h (R) was assigned by X-ray crystallographic analysis of a single crystal of 8-7h (Figure 8.4) The configurations of other MBH products were assigned by analogy Figure 8.4 X-ray structure of 8-7h Table 8.5 Crystal Data and Structure Refinement for A398 Identification code a398 Empirical formula C25 H20 Cl N O4 Formula weight 433.87 Temperature 100(2) K - 353 -   Chapter Enantioselective MBH Reaction of Isatins with Acrylates Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1) Unit cell dimensions a = 8.6429(12) Å = 90° b = 27.752(4) Å =107.440(4)° c = 9.2865(14) Å  = 90° Volume 2125.0(5) Å3 Z Density (calculated) 1.356 Mg/m3 Absorption coefficient 0.212 mm-1 F(000) 904 Crystal size 0.40 x 0.36 x 0.20 mm3 Theta range for data collection 2.41 to 27.50° Index ranges -10