Chapter Chapter Experimental 93 Chapter 4.1 General information 4.1.1 General procedures and methods Experiments involving moisture and/or air sensitive components were performed under a positive pressure of nitrogen in oven-dried glassware equipped with a rubber septum inlet. Air sensitive reagents were weighed in a glovebox. Dried solvents and liquid reagents were transferred by oven-dried syringes or hypodermic syringe cooled to ambient temperature in a desiccator. Reactions mixtures were stirred in round bottle flasks or 4mL sample vials with Teflon-coated magnetic stirring bars unless otherwise stated. Moisture in non-volatile reagents/compounds was removed in high vacuo by means of an oil pump and subsequent purging with nitrogen. Solvents were removed in vacuo under ~30 mmHg and heated with a water bath using Heidolph or Büchi rotary evaporator with Eyela A-3S aspirator. The condenser was cooled with running water at °C. Reactions requiring temperatures −20 °C were stirred in either Thermo Neslab CB-60 with Cryotrol temperature controller or Eyela PSL-1400 with digital temperature controller cryobaths. Technical grade isopropanol was used as the bath medium. All experiments were monitored by analytical thin layer chromatography (TLC). TLC was performed on pre-coated plates, Merck 60 F254. After elution, plate was visualized under UV illumination at 254 nm for UV active material. Further visualization was achieved by staining KMnO4, ceric molybdate, or anisaldehyde solution. For those using the aqueous stains, the TLC plates were heated on a hot plate. Columns for flash chromatography (FC) contained silica gel 60 (0.040 mm - 0.063 mm, Merck). Columns were packed as slurry of silica gel in hexane and 94 Chapter equilibrated with the appropriate solvent/solvent mixture prior to use. The analyte was loaded neat or as a concentrated solution using the appropriate solvent system. The elution was assisted by applying pressure with an air pump. 4.1.2 Instrumentations Proton nuclear magnetic resonance (1H NMR), carbon NMR (13C NMR), phosphorous NMR (31P NMR), and fluorine NMR (19F NMR) spectra were recorded in CDCl3 otherwise stated. 1H (500 MHz or 300 MHz), with complete proton decoupling, 31 13 C (125 MHz or 75 MHz) P (202 MHz) with complete proton decoupling, and 1H Nuclear Overhauser Effect (NOE) NMRs were performed on a 500 MHz Bruker AMX NMR spectrometer. 19F NMR (282 MHz) was performed on a 300 MHz Bruker ACF spectrometer. Chemical shifts were reported as δ in units of parts per million (ppm) downfield from tetramethylsilane (δ 0.00), using the residual solvent signal as an internal standard: CDCl3 (1H NMR: δ 7.26, singlet; 13 C NMR: δ 77.0, triplet). Multiplicities were given as: s (singlet), d (doublet), t (triplet), q (quartet), quintet, m (multiplets), dd (doublet of doublets), dt (doublet of triplets), and br (broad). Coupling constants (J) were recorded in Hertz (Hz). The number of proton atoms (n) for a given resonance was indicated by nH. The number of carbon atoms (n) for a given resonance was indicated by nC. High resolution Electrospray Ionization (ESI) mass spectra were obtained by Chemical and Molecular Analysis Centre (CMAC) of the National University of Singapore. MS and HRMS were reported in units of mass of charge ratio (m/z). Mass samples were dissolved in MeCN (HPLC Grade) unless otherwise stated. Melting points were determined on a BÜCHI B-540 melting point 95 Chapter apparatus. Enantiomeric excesses were determined by chiral High Performance Liquid Chromatography (HPLC) analysis on Dionex HPLC UltiMate® 3000 series, including a variable wavelength UV/VIS detector VWD-3400 and LPG-3400A pump with manual injection valve. Data acquisitions were done using Chromeleon® software. HPLC samples were dissolved in HPLC grade isopropanol (IPA) unless otherwise stated. 4.1.3 Materials All commercial reagents were purchased from Sigma-Aldrich, Fluka, Alfa Aesar, Merck, TCI, and Acros of the highest purity grade. They were used without further purification unless specified. All solvents used, mainly hexane (Hex) and ethyl acetate (EtOAc), were distilled. Anhydrous DCM was freshly distilled from CaH2. Anhydrous THF was freshly distilled from Na/benzophenone. MeCN and CHCl3 were distilled from CaH2. Anhydrous hexane was purchased from Sigma-Aldrich. All compounds synthesized were stored in a −34 °C freezer and light-sensitive compounds were protected with aluminium foil. 4.2 Experimental procedures related in the conjugate addition reaction. 4.2.1 Synthesis of chiral pentanidium and characterizations Representative procedure for the synthesis of chiral pentanidium 80a: 96 Chapter Step 1: To a solution of chiral diamine 81 (2.12 g, 10 mmol) and Et3N (4.1 ml, 30 mmol) in CH2Cl2 (25 mL), triphosgene (977 mg, 3.3 mmol, dissolved in mL CH2Cl2) was added in a dropwise manner, keeping the temperature lower than oC all the time. After allowing the temperature to rise to room temperature, an additional 4-5 hours of stirring was required to allow the reaction to complete (monitored by TLC). After diamine 81 was completely consumed, reaction was quenched by water (20 mL) and extracted using CH2Cl2 times (30 mL x 3). The combined organic layer was washed by brine and dried by Na2SO4. Solvent was removed under reduced pressure. Product 82 was pale yellow solid, which can be used in the next step without any further purification. Step 2: To a suspension of NaH (720 mg, 30 mmol, 3.0 equiv) in THF (15 mL) was added a solution of 82 (from step 1) in THF (20 mL). After 0.5h, MeI (2.3 mL, 37 mmol, 3.7 equiv) was added in one portion. After completion of the reaction (monitored by TLC), the mixture was filtered through a short pad of Celite. Solvent was removed under reduced pressure and C was obtained by flash chromatography (silica gel, hexane-ethyl acetate 3:1), as a white solid, 2.10 g (2 steps, 80% overall yield). 97 Chapter Step 3: A 100 mL RBF was charged with a solution of 83 (1.60 g, mmol, equiv) in toluene (40 mL) with a condenser under N2 atmosphere. (COCl)2 (5.2 mL, 60 mmol, 10 equiv) was added via syringe in one portion. The mixture was refluxed overnight until 83 was completely reacted. Toluene was removed under reduced pressure and solid 84 (1.93 g) was obtained for the next step without any purification. (84 is air and moisture sensitive, which should be stored under nitrogen atmosphere or vacuum.) Step 4: Separate half of 84 for the step 5. The other part (960mg) was dissolved in dry MeCN/MeOH (volume ratio 1:1, 20 mL), NH3 was bubbled into the solution at oC for 0.5 h. After the introduction of NH3, the seal tube was sealed and placed in 60 oC oil bath. After stirring overnight to complete reaction, pressure was released and water was added (40 mL). The mixture was extracted by CH2Cl2 times (20 mL x 3). The combined organic layer was dried by Na2SO4. After removing solvent under reduced pressure, guanidine 85 was obtained as a brown solid, 801 mg, >99% yield. Step 5: To a solution of 85 (800 mg, 3.06 mmol) and Et3N (0.45 mL, 3.24 mmol) in MeCN (15 mL) was added a solution of 84 (from step 4, 970 mg, 1.0 equiv) in dry MeCN (10 mL) was added in a dropwise manner. The reaction mixture was stirred until the reaction was completed. Reaction was quenched by water (20 mL), and extracted using CH2Cl2 times (20 mL x 3). The combined organic layer was dried by Na2SO4. Solvent was removed under reduced pressure. The brown solid obtained was re-crystallized by CH2Cl2/ethyl acetate solvent system. Chiral pentanidium chloride 80a was isolated as a white solid, 820mg, 48% yield. 98 Chapter (S, S)-4, 5-Diphenylimidazolidin-2-one (82): white solid; 1H NMR (300 MHz, CDCl3): δ 7.38-7.34 (m, 6H), 7.27-7.30 (m, 4H), 5.83 (s, 2H), 4.57 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 163.1, 140.2, 128.7, 128.2, 126.4, 65.9, LRMS (ESI) m/z 239.1 (M + H+), HRMS (ESI) m/z 239.1185 ([M + H+]), calc. for [C15H14N2O+H+] 239.1179. (S, S)-1,3-Dimethyl-4,5-diphenylimidazolidin-2-one (83): white solid; 80% yield for steps; 1H NMR (300 MHz, CDCl3): δ 7.34-7.32 (m, 6H), 7.14-7.11 (m, 4H), 4.07 (s, 2H), 2.69 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 161.7, 137.9, 128.7, 128.3, 127.2, 70.2, 29.9; LRMS (ESI) m/z 267.1 (M + H+), HRMS (ESI) m/z 267.1497 ([M + H+]), calc. for [C17H18N2O +H+] 267.1492. (4S, 5S)-1,3-Dimethyl-4,5-diphenylimidazolidin-2-imine (85): brown solid; 99% yield; 1H NMR (300 MHz, CDCl3): δ 7.17-7.14 (m, 6H), 6.99-6.97 (m, 4H), 4.48 (b, 1H), 3.87 (s, 2H), 2.52 (s, 6H); 13 C NMR (125.77 MHz, CDCl3): δ 163.3, 137.9, 128.6, 128.2, 127.4, 72.1, 31.4; LRMS (ESI) m/z 266.1 (M + H+), HRMS (ESI) m/z 266.1664 ([M + H+]), calc. for [C17H19N3 + H+] 266.1652. 99 Chapter (S,S)-Tetraphenyl-tetramethyl-pentanidium chloride (80a): white solid, mp 276-278 oC; 48% yield; 1H NMR (500 MHz, CDCl3): δ 7.35-7.34 (m, 12H), 7.24-7.21 (m, 8H), 4.67 (s, 4H), 2.93 (s, 12H); 13 C NMR (126 MHz, CDCl3) δ 159.5, 135.4, 129.3, 129.3, 127.6, 72.6, 32.5; LRMS (ESI) m/z 514.5 ([M-Cl-])+, HRMS (ESI) m/z 514.2970 ([M-Cl-])+, calc. for [C34H36N5+] 514.2965. [α]29D = +171.2 (c 1.18, CHCl3); For the synthesis of 80b, the following step is required: transformation to thiourea1. 1.0 eq 86 and 1.0 eq Lawesson’s reagent were reflux in O-xylene under N2 condition for overnight. Full conversion and 90% yield was achieved. The following steps are the same with 80a. (S, S)-Tetraphenyl-tetraethyl-pentanidium chloride (80b): white solid; 1H NMR (500 MHz, CDCl3) δ 7.42-7.40 (m, 12H), 7.17-7.15 (m, 8H), 4.53 (s, 4H), 4.31-4.24 (m, 4H), 3.05-3.03 (m, 4H), 1.16 (t, J=7.5, 12H); 100 13 C NMR (126 MHz, CDCl3) δ Chapter 157.1, 136.5, 129.4, 129.4, 127.0, 69.8, 39.0, 11.3; LRMS (ESI) m/z 570.5 ([M-Cl-])+, HRMS (ESI) m/z 570.3586 ([M-Cl-])+, calc. for [C38H44N5+] 570.3591. (S, S)-Tetra-4-methoxy-phenyl-tetraethyl-pentanidium chloride (80c): white solid; 56% yield; 1H NMR (300 MHz, CDCl3) δ 7.19 (d, J=8.7 Hz, 8H), 6.89 (d, J=8.7 Hz, 8H), 4.60 (s, 4H), 3.79 (s, 12H), 2.90 (s, 12H); 13C NMR (75 MHz, CDCl3) δ 160.2, 159.2, 129.0, 127.3, 114.6, 72.2, 55.2, 32.3; LRMS (ESI) m/z 634.5 ([M-Cl-])+, HRMS (ESI) m/z 634.3403 ([M-Cl-])+, calc. for [C38H44N5O4+] 634.3388. Chiral pentanidium salt 80d and 80e were prepared in the following manner: (S, S)-Tetraphenyl-tetramethyl-pentanidium tetrafluoroborate (80d): white solid; 98% yield; 1H NMR (300 MHz, CDCl3) δ 7.40-7.37 (m, 12H), 7.26-7.22 (m, 8H), 4.62 (s, 4H), 2.91 (s, 12H); 13C NMR (75 MHz, CDCl3) δ 159.5, 135.5, 129.30, 129.2, 127.6, 104.9, 72.7, 32.2; 19F NMR (282 MHz, CDCl3) δ -76.59. 101 Chapter (S, S)-Tetraphenyl-tetramethyl-pentanidium hexafluorophosphate (80e): white solid; 99% yield; 1H NMR (300 MHz, CDCl3) δ 7.43-7.40 (m, 12H), 7.27-7.24 (m, 8H), 4.63 (s, 4H), 2.92 (s, 12H); 129.3, 127.6, 72.7, 32.2; 19 13 C NMR (75 MHz, CDCl3) δ 159.4, 135.4, 129.4, F NMR (282 MHz, CDCl3) δ 3.32 (d, 710Hz). 31 P NMR (121 MHz, CDCl3) δ -143.6 (tt, J1=709Hz, 1418Hz). Chiral pentanidium salt 80f is colorless oil, thus flash chromatography was required for purification step (silica gel, CH2Cl2/MeOH, 50:1). (S, S)-Dicyclohexyl-tetramethyl-pentanidium chloride (80f): colorless oil; H NMR (300 MHz, CDCl3) δ 3.01-2.99 (m, 4H), 2.79 (s, 12H), 2.19-2.10 (m, 8H), 1.93 (d, J = 6.2 Hz, 4H), 1.45-1.42 (m, 4H); 13 C NMR (75 MHz, CDCl3) δ 162.7, 66.2, 31.4, 27.8, 23.8; LRMS (ESI) m/z 318.5 ([M-Cl-])+, HRMS (ESI) m/z 318.2659 ([M-Cl-])+, calc. for [C18H32N5+] 318.2652. 2-(((4S,5S)-1,3-dimethyl-4,5-diphenylimidazolidin-2-ylidene)amino)-1,3-dimethyl -4,5-dihydro-1H-imidazol-3-ium chloride (80g): pale yellow oil; 1H NMR (300 MHz, MeOD) δ 7.42-7.44 (m, 6H), 7.30-7.34 (m, 4H), 4.69 (s, 2H), 3.82-3.67 (m, 102 Chapter Solvent ether was removed in vacuo and the crude product was directly loaded onto a short silica gel column, followed by gradient elution with hexane/ethyl acetate (15:1-12:1 ratio). Product 90 (61.2 mg) was obtained as pale yellow solid in 91% yield. Absolute configuration of 90 was verified by X-Ray diffraction analysis. To a solution of 90 (61.2 mg, 0.17 mmol) in MeOH (2 mL) at oC, NaBH4 (20 mg x 3, 1.5 mmol, 9.0 equiv) was added in three portions. The reaction was stirred at oC and allowed to warm to room temperature with monitoring by TLC. After stirring for 10 h, reaction mixture was added mL H2O, and extracted by diethyl ether (5 mL + mL). Solvent ether was removed in vacuo and the crude product was directly loaded onto a short silica gel column, followed by gradient elution with hexane/ethyl acetate (15:1 ratio). Product 91 (48.5 mg) was obtained as colorless oil in 80% yield. (2R,3S)-tert-Butyl-3-(4-chlorophenyl)-5-phenyl-3,4-dihydro-2H-pyrrole-2-carbox ylate (90): pale yellow solid; 91% yield; mp 79-81 oC 1H NMR (500 MHz, CDCl3) δ 7.93-7.87 (m, 2H), 7.50-7.38 (m, 3H), 7.31-7.26 (m, 2H), 7.19-7.12 (m, 2H), 4.79 (dt, J = 5.9, 1.6 Hz, 1H), 3.75 (dt, J = 9.6, 6.2 Hz, 1H), 3.62 (ddd, J = 17.1, 9.6, 1.9 Hz, 1H), 3.10 (ddd, J = 17.1, 6.4, 1.5 Hz, 1H), 1.48 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 174.5, 171.2, 142.0, 133.7, 132.6, 131.1, 128.9, 128.5, 128.4, 128.1, 83.2, 81.6, 46.3, 44.5, 28.1; LRMS (ESI) m/z 356.0 (M + H+), HRMS (ESI) m/z 356.1428 ([M + H+]), 123 Chapter calc. for [C21H22ClNO2+H+] 356.1412; [α]29D = -32.7 (c 5.81, CHCl3); HPLC analysis: Chiralpak AD-H (Hex/IPA = 92/8, 0.8 mL/min, 254 nm, 23°C), 13.3 (minor), 17.9 (major), 92% ee. (2R,3S,5R)-tert-Butyl-3-(4-chlorophenyl)-5-phenylpyrrolidine-2-carboxylate (91): colorless oil; 80% yield; 1H NMR (500 MHz, CDCl3) δ 7.46-7.44 (m, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.30-7.24 (m, 5H), 4.50 (dd, J = 10.5, 5.6 Hz, 1H), 3.85 (d, J = 7.5 Hz, 1H), 3.37 (dt, J = 11.1, 7.3 Hz, 1H), 2.70 (d, J = 61.8 Hz, 1H), 2.57 (ddd, J = 12.6, 7.1, 5.7 Hz, 1H), 1.94 (dd, J = 23.1, 10.9 Hz, 1H), 1.40 (s, 9H); 13 C NMR (126 MHz, CDCl3) δ 174.1, 143.8, 141.4, 132.3, 128.9, 128.6, 128.4, 127.1, 126.5, 81.5, 67.8, 62.3, 50.2, 44.9, 28.0; LRMS (ESI) m/z 358 (M + Na+), HRMS (ESI) m/z 358.1566 ([M + Na+]), calc. for [C32H31NO3S + Na+] 358.1568; [α]29D = -6.5 (c 1.42, CHCl3); HPLC analysis: Chiralpak IA (Hex/IPA = 92/08, 0.8 mL/min, 210 nm, 23°C), 7.7 (major), 11.8 min, 92% ee. 4.2.7 Synthesis of Benzophenone Imines of Phosphoglycine Ester7 124 Chapter (i) Toluene reflux, Na2SO4, 95%, (ii) Diisopropylphosphite, 92%; (iii) DDQ, Å Molecular Sieves, Toluene, 99%. To a solution of diphenylmethanamine (2.20 g, 12 mmol, 1.0 equiv) in toluene 24 mL, was added formaldehyde solution (1.14 mL, 37% wt, 1.2 equiv), and Na2SO4 (8.5 g, 60 mmol, 5.0 equiv). Reaction mixture was refluxed and monitored by TLC. After 1.5 h, reaction reached full conversion. After filtration and removing toluene under reduced pressure, the crude product was re-crystallized to yield a white solid, 2.2 g, 95% yield. The white solid (1.30 g, 5.1 mmol, 1.0 equiv) was redissolved in toluene 20 mL, and diisopropyl phosphite (846 mg, 5.1 mmol, 1.0 equiv) was added. The reaction mixture was kept stirring at 100 oC for h. After consuming all the starting material, solvent was removed under reduced pressure, and the crude product was purified by flash chromatography (silica gel, hexane/ethyl acetate 5/1-4/1). Product was obtained as yellow oil in 92% yield. The yellow oil product was oxidized by DDQ (1.3 g, 5.8 mmol) in toluene (30 mL) at 60 oC in the presence of crushed Å molecular sieves (2.0 g) for h to give the benzophenone imines of phosphoglycine ester, 1.87 g, yellow oil, 86% yield for 3steps. 125 Chapter Diisopropyl ((diphenylmethylene)amino) methyl)phosphonate (92a): yellow oil; 86% yield; 1H NMR (500 MHz, CDCl3) δ 7.64-7.62 (m, 2H), 7.49-7.41 (m, 3H), 7.40-7.36 (m, 1H), 7.34-7.30 (m, 2H), 7.24-7.22 (m, 2H), 4.78 (ddd, J = 12.4, 6.2, 1.4 Hz, 2H), 3.88 (d, J = 17.4 Hz, 2H), 1.33 (dd, J = 8.2, 6.2 Hz, 12H); 13 C NMR (75 MHz, CDCl3) δ 171.4 (d, J = 18.5 Hz), 137.5 (d, J = 288.4 Hz), 128.6 (d, J = 5.7 Hz), 128.0 (d, J = 6.3 Hz), 70.8 (d, J = 6.7 Hz), 52.2 (d, J = 161.9 Hz), 24.0 (dd, J = 7.8, 4.2 Hz); 31 P NMR (121 MHz, CDCl3) δ 21.89; LRMS (ESI) m/z 382 (M + Na+), HRMS (ESI) m/z 382.1536 ([M + Na+]), calc. for [C20H26NO3P + Na+] 382.1543; 4.2.8 Procedure for Phase Transfer Michael Addition Reactions of 92a with Benzyl Acrylate Benzophenone imines of phosphoglycine ester 92a (190 mg, 0.52 mmol, 1.0 equiv), (S, S)-80a (5.8 mg, 0.01 mmol, 0.02 equiv) and CsOH·H2O (170 mg, 1.1 mmol, 2.0 equiv) were placed in mesitylene and diether ether (3 mL + mL) and stirred at -78 o C for 10 min, then benzyl acrylate 54f (162 mg, 1.1 mmol, 2.0 equiv) was added through syringe. The reaction mixture was stirred at -50 oC and monitored by TLC. After 24 h, upon complete consumption of 92a, the reaction mixture was directly loaded onto a short silica gel column, followed by gradient elution with hexane/ethyl acetate (4:1-2:1 ratio). After removing the solvent, product 96a (225.2 mg) was obtained as colorless oil in 93% yield. 126 Chapter (S)-benzyl4-(diisopropoxyphosphoryl)-4-((diphenylmethylene)amino)butanoate (96a): colorless oil; 93% yield; 1H NMR (300 MHz, CDCl3) δ 7.64-7.61 (m, 2H), 7.43-7.24(m, 13H), 5.05-4.95 (m, 2H), 4.80-4.60 (m, 2H), 3.92-3.79 (m, 1H), 2.40-2.18 (m, 4H), 1.41-1.19 (m, 12H); 13C NMR (126 MHz, CDCl3) δ 172.7, 171.1 (d, J = 16.4 Hz), 139.5, 135.9 (d, J = 12.9 Hz), 130.2, 128.8, 128. 6, 128.5, 128.4, 128.4, 128.1, 128.0, 71.1 (dd, J = 56.0, 7.0 Hz), 66.2, 61.1 (d, J = 160.5 Hz,), 31.3 (d, J = 14.9 Hz), 26.5 (d, J = 4.8 Hz), 24.1 (ddd, J = 11.0, 7.1, 2.7 Hz); 31 P NMR (121 MHz, CDCl3) δ 22.40; LRMS (ESI) m/z 544.1 (M + Na+), HRMS (ESI) m/z 544.2232 ([M + Na+]), calc. for [C30H36NO5P + Na+] 544.2223; [α]29D = -2.6 (c 2.9, CHCl3); HPLC analysis: Chiralpak AD-H (Hex/IPA = 70/30, 1.0 mL/min, 254 nm, 23°C), 5.5 (major), 14.6 min, 85% ee. Absolute configuration of 96a was determined to be S, by comparing similar compound with former work.8 4.2.9 Procedures for cyclization and reduction of 96a to afford phosphonic analogues of (S)-proline 98 127 Chapter To a THF solution of adduct 96a (255 mg, 0.49 mmol in mL THF) was added 2M HCl solution (2 mL) at oC. The reaction mixture was stirred room temperature and monitored by TLC. After h, upon complete consumption of 96a, THF was removed in vacuo. The reaction mixture was washed by Et2O three times (10 mL x 3). After the aqueous phase was neutralized by NaHCO3 saturated solution, the mixture was extracted by CH2Cl2 times (10mL x 3). The combined organic layer was dried over Na2SO4. Solvent was removed in vacuo and the residue was dissolved in toluene and refluxed overnight. Solvent was removed in vacuo and product 97 was obtained by flash chromatography on silica gel (CH2Cl2: MeOH 10/1), as a white solid, 84 mg, 71% yield. BF·OEt2 (454 mg, 3.2 mmol, 10 eq) was added dropwisely to a stirred solution of the lactam 97 (80 mg, 0.32 mmol, eq) in THF (5 ml) at oC. This mixture was added dropwisely to a solution of LiBH4 (28 mg, 1.28 mmol, 4eq) in THF (5 ml) under N2 atmosphere through syringe.9 The reaction was kept stirring at room temperature for 36h. Then NaHCO3 saturated solution (5 ml) was added and the reaction mixture were refluxed for 1-2h. The mixture was extracted by CH2Cl2 times (10 ml x 3). After the solvent was removed in vacuo, the crude product was treated by Pd/C (10%) in MeOH for 0.5h. After filtration with cilite and removing solvent, pyrrolidine 98 was obtained by flash chromatography on silica gel (CH2Cl2:MeOH 10:1), as a pale yellow oil. Enantiomeric excess of 98 was determined as the form of N-Cbz 98. 128 Chapter (S)-diisopropyl (5-oxopyrrolidin-2-yl)phosphonate (97): white solid; 71% yield; 1H NMR (300 MHz, CDCl3) δ 6.33 (s, 1H), 4.79-4.65 (m, 2H), 3.75 (t, J = 6.3 Hz, 1H), 2.45-2.25 (m, 4H), 1.31-1.28 (m, 12H). 13C NMR (75 MHz, CDCl3) δ 178.0, 71.5(dd), 50.40(d), 29.3, 24.0(m), 21.6(d); 31 P NMR (121 MHz, CDCl3) δ 22.1. LRMS (ESI) m/z 250.1 (M + H+), calc. for [C10H20NO4P + H+] 250.1. [α]29 D = -5.3 (c 1.5, CHCl3, 83% ee); (S)-diisopropyl pyrrolidin-2-ylphosphonate(98): pale yellow oil; 62% yield; 1H NMR (500 MHz, CDCl3) δ 4.76-4.69 (m, 2H), 3.77 (s, 1H), 3.36-3.32 (m, 1H), 3.12-3.07 (m, 1H), 3.01-2.97 (m, 1H), 2.01-1.77 (m, 4H), 1.31 (d, J = 6.2 Hz, 6H); 13 C NMR (126 MHz, CDCl3) δ 71.0(dd), 54.4(d), 47.5(d), 26.7, 25.6(d), 24.1(m); 31P NMR (121 MHz, CDCl3) δ 25.6. HRMS (ESI) m/z 236.1340 ([M + H+]), calc. for [C10H22NO3P + H+] 236.1337; [α]29D = +14.5 (c 1.2, CHCl3); ee was determined as the form of N-Cbz 12, HPLC analysis: Chiralpak IC (Hex/IPA = 70/30, 1.0 mL/min, 210 nm, 23°C), 9.5 (minor), 15.2 (major) min, 83% ee. 4.2.10 Protocol for the synthesis of proline-derived pentanidium 129 Chapter The synthesis starts from Boc-protected L-proline 99. In the amide coupling reaction, two method both afford 100 with similar yield, 83%. After deprotection of Boc and reduction, chiral diamine 102 was obtained in 75% yield.12 Guanidine 106 was obtained by treating 102 with BrCN in full conversion and imidazoline salt 105 was achieved through urea, thiourea with the previous method. The coupling of 105 and 106 gives the pentanidium 107 with 53% yield. 107 was purified with flash chromatography (CH2Cl2: MeOH = 50:1 to 20: 1). (R)-2-benzyltetrahydro-1H-pyrrolo[1,2-c]imidazol-3(2H)-one (103): colorless oil; 60% yield; 1H NMR (500 MHz, CDCl3) δ 7.31-7.18 (m, 5H), 4.35 (s, 2H), 3.70-3.52 (m, 2H), 3.35 (t, J =8.7 Hz, 1H), 3.08-3.00 (m, 2H), 1.92-1.82 (m, 2H), 1.82-1.74 (m, 1H), 1.30-1.22 (m, 1H). 13 C NMR (126 MHz, CDCl3) δ 163.7, 136.9, 128.5, 127.8, 127.3, 56.4, 47.6, 46.7, 45.7, 30.7, 25.0; 130 Chapter (R)-2-benzyltetrahydro-1H-pyrrolo[1,2-c]imidazole-3(2H)-thione (104): white solid; 68% yield; 1H NMR (500 MHz, CDCl3) δ 7.34-7.24 (m, 5H), 4.82 (d, J = 6.4, 2H), 4.13-4.04 (m, 1H), 3.88-3.80 (m, 1H), 3.57 (t, J = 9.8Hz, 1H), 3.38-3.28 (m, 2H), 2.04-1.84 (m, 3H), 1.33-1.6 (m, 1H). 13 C NMR (126 MHz, CDCl3) δ 185.9, 136.1, 128.6, 127.9, 127.6, 59.5, 51.2, 50.8, 48.2, 30.8, 24.6; (S)-2-benzyl-3-((Z)-((R)-2-benzyltetrahydro-1H-pyrrolo[1,2-c]imidazol-3(2H)-yli dene)amino)-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-2-ium chloride (107): brown liquid; 53% yield; 1H NMR (500 MHz, CDCl3) δ 7.23-7.10 (m, 5H), 4.45 (dd, J = 18Hz, 2H), 4.07-4.02 (m, 1H), 3.76 (t, J = 9.9hz, 1H), 3.39-3.34 (m,1H), 3.20-3.15 (m,1H), 2.82-2.73 (m,1H), 2.03-1.86 (m,3H), 1.32-1.26 (m,1H); 13C NMR (126 MHz, CDCl3) δ 161.5, 134.8, 128.7, 128.0, 127.9, 60.0, 53.5, 49.6, 49.0, 47.3, 31.4, 25.5; 4.2.11 Synthesis axially chiral pantanidium bearing non chiral center 131 Chapter 4.3 Procedure for the amination reaction 4.3.1 Procedure for asymmetric α-amination of glycinate Schiff base tert-butyl glycinate-benzophenone Schiff base (15 mg, 0.05 mmol, equiv.), pentanidium (1.2 mg, 0.0025 mmol, 0.05 equiv.) and CsF (90 mg, 0.5 mol, 10 equiv.) was placed in mesitylene (0.5 mL) and stirred at room temperature, before di-tert-butyl azodicarboxylate 125c (13 mg, 0.05 mmol, equiv.) was added in one portion. The mixture was stirred at room temperature and monitored by TLC. Upon reaction completion, the reaction mixture was loaded onto a silica gel column and product isolated by hexane:ether (10:1 ratio). Solvent was removed under reduced pressure to obtain product 155 as colorless oil. 132 Chapter di-tert-butyl-1-(3-(tert-butoxy)-1-((diphenylmethylene)amino)-2,3-dioxopropyl)h ydrazine-1,2-dicarboxylate (155): Colorless oil; Rf = 0.58 (Hexane : EA = 4:1); 88% yield, 74% ee, [α]25D = +28.8 (c 1.65, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.78 – 7.68 (m, 4H), 7.52 (d, J = 7.3 Hz, 2H), 7.42 (t, J = 7.4 Hz, 5H), 7.20 (s, 1H), 5.97 (s, 1H), 1.40 (s, 18H); ESI-MS calculated for C29H40N3O6 [M+H]+ 526.2917, found 526.2909; HPLC: Chiralpak AD-H column, i-PrOH/hexane 8/92, detector: 254 nm, 25 o C, 0.8 mL/min, tR = 6.98 min, 8.16 (major). 4.3.2 Procedure for the ee enrichment To a solution of adduct 155 (24 mg, 0.044mmol, 74% ee) in THF (1 mL) was added 1mL 15% Citric acid. The reaction mixture was stirred for 12 h. After removing THF under reduced pressure, the residue was neutralized by NaHCO3 (sat) solution and extracted by EA times (5 mL x 3). Solvent EA was removed in vacuo. Crude product was dissolved in DCM, Et3N (10 uL, 1.5eq) and PhCOCl (6.16 uL, 1.2 eq) were added sequently. The reaction mixture was stirred for h at room temperature. After extraction by EA and washing by brine, 156 (20 mg, 95%) was isolated by flash chromatography (silica gel, hexane/ethyl acetate 12:1-10:1), as pale yellow liquid. 156 was dissolved in 1mL hexane and placed in -34 oC freezer. After 12h, optical active pure 156, 96% ee, was isolate by filtration, which was in the filtrate. 133 Chapter di-tert-butyl 1-(1-benzamido-2-(tert-butoxy)-2-oxoethyl)hydrazine-1,2-dicarboxylate (156): Colorless oil; 96% ee, 1H NMR (300 MHz, CDCl3) δ 7.87-7.85 (d, J = 7.9Hz, 2H), 7.50-7.30 (m, 3H), 6.86-6.74 (d, J = 19 Hz, 1H), 6.42 (s, 1H), 6.09 (s, 1H), 1.05-1.43 (m, 27H); 13C NMR (126 MHz, CDCl3) δ 166.4, 156.5, 153.7, 133.5, 132.9, 131.7, 129.8, 128.4, 128.2, 127.2, 83.2, 82.3, 82.0, 81.3, 27.9, 27.7. LRMS (ESI) m/z 488.1 (M + Na+), HRMS (ESI) m/z 488.2350 ([M + Na+]), calc. for [C23H35N3O2+Na+] 488.2367; [α]25D = -48.4 (c 5.7, CHCl3); HPLC analysis: Chiralpak OD-H (Hex/IPA = 85/15, 1.0 mL/min, 254 nm, 23°C), 4.3 (major), 5.9 (min), 96% ee. 134 Chapter Reference 1. Ryoda, A; Yajima, N; Haga, T; Kumamoto, T; Nakanishi, W; Kawahata, M; Yamaguchi, K; Ishikawa, T. J. Org. Chem. 2008, 73, 133-141. 2. Hernandez-T., J; Gomez A.R.; Carretero, J.C. Chem. Eur. J. 2010, 16, 1153-1157. 3. Lichtenstein, B. R.; Cerda, J. F.; Koder, R. L.; Dutton, P. L. Chem. Commun. 2009, 2, 168-170. 4. An, X.; Chen, J.; Li, C.; Zhang, F.; Zou, Y.; Guo, Y.; Xiao, W. Chem. Asia. J. 2010, 5, 2258-2265. 5. Vavrecka, M.; Hesse, M. Helvetica Chimica Acta 1999, 74, 438-44. 6. Rateb, N. M.; Zohdi, H. F. Synth. Commun. 2009, 39, 2789-2794. 7. Peter B. S.; John F. H. Org. Lett. 1999, 1, 1395-1397. 8. Jaszaya, Z. M.; Nemeth, G.; Pham, T. S.; Petnehazy, I.; Grun, I.; Toke, L. Tetrahedron: Asymmetry 2005, 16, 3837–3840. 9. Uhich G., Lutz R., and Uhich S. Tetrahedron 1992, 48, 117-122. 10. Sankhavasi, W.; Yamamoto, M.; Kohmoto, S.; Yamada, K. Bull. Chem. Soc. Jpn. 1991, 64, 1425-1427. 11. Matsumoto, H.; Kato, E. Jpn. Kokai Tokkyo Koho 2006, Application: JP 2005-135908 20050509. Priority: JP 2005-135908 20050509. 12.Held, I.; Larionov, E.; Bozler, C.; Wagner, F.; Zipse, H. Synthesis 2009, 13, 2267-2277. 135 Chapter 4.4 X‐Ray Crystallographic Analysis Single-crystal structure of (S, S)-80a Single-crystal structure of 90 136 Chapter H NOESY analysis of 91 137 Chapter 138 [...]... 7 .47 -7 .41 (m, 3H), 7.38-7.37 (m, 1H), 7.32 (t, J = 7.5 Hz, 2H), 7.19-7.13 (m, 2H), 3.95 (t, J=12.1 Hz,1H), 2.55-2 .42 (m, 2H), 2 .41 -2.33 (m, 2H), 2. 14 (dd, J = 13.8, 7.5 Hz, 2H), 1. 54- 1 .47 (m, 2H), 1 .43 (s, 9H), 1.27 (dd, J = 15.0, 7 .4 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H); 13C NMR 107 Chapter 4 (75 MHz, CDCl3) δ 210.6, 171.0, 170.3, 139 .4, 136 .4, 130.2, 128.7, 128.5, 128 .4, 127.9, 127.6, 81.0, 64. 7, 42 .4, ... 137.3, 136 .4, 133 .4, 132.8, 130.3, 129.5, 128.9, 128.5, 128 .4, 128.2, 128.2, 128.0, 127.6, 113.5, 81.2, 71.1, 55.2, 44 .2, 40 .4, 27.9; LRMS (ESI) m/z 556.1 (M + Na+), HRMS (ESI) m/z 556. 244 4 ([M + Na+]), calc for [C35H35NO4 + Na+] 556. 245 8; [α]29 = +52.7 (c 2. 34, CHCl3); HPLC analysis: Chiralcel D OD-H (Hex/IPA = 90/10, 1.0 mL/min, 2 54 nm, 23° 5 .4 (major), 9.2 min, 85% ee C), 116 Chapter 4 (2R,3S)-tert-Butyl-5- (4- chlorophenyl)-2-((diphenylmethylene)amino)-5-oxo-3-phe... 7 .42 - 7.29 (m, 6H), 7.17-7.10 (m, 6H), 6. 74 (d, J = 6.9 Hz, 2H), 6 .47 (dd, J = 3.5, 1.6 Hz, 1H), 4. 21 -4. 15 (m, 1H), 4. 16 (d, J = 5 .4 Hz, 1H), 3.57 (dd, J = 16.3, 9.8 Hz, 1H), 3 .42 (dd, J = 16.3, 4. 2 Hz, 1H), 1.31 (s, 9H); 13 C NMR (126 MHz, CDCl3) δ 187.8, 171.1, 169.9, 153.0, 146 .0, 141 .1, 139 .4, 136.3, 130.3, 128.9, 128.6, 128 .4, 128.2, 128.1, 128.0, 127.6, 126.6, 116.9, 112.1, 81.3, 70.9, 44 .7, 40 .1,... (d, J = 6.9 Hz, 2H), 4. 19 -4. 10 (m, 2H), 3.79-3.69 (m, 1H), 3.65-3.56 (m, 1H), 1. 34 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 198 .4, 171 .4, 169 8, 140 .6, 139.2, 137.1, 136.2, 133.0, 131.2, 130.5, 130.3, 128.8, 128.5, 128 .4, 128.3, 128.2, 128.1, 127.5, 120 .4, 81.6, 70.6, 44 .2, 39.7, 27.9; LRMS (ESI) m/z 6 04. 0 (M + Na+), HRMS (ESI) m/z 6 04. 1262 ([M + Na+]), calc for [C34H32BrNO3 + Na+] 6 04. 145 8; [α] 29 = +36.7... 2H), 7 .42 -7.29 (m, 6H), 7.20-7.11 (m, 5H), 6.71 (d, J = 7.1 Hz, 2H), 4. 07 (d, J = 5.5 Hz, 1H), 4. 00 120 Chapter 4 (dt, J = 9.9, 4. 9 Hz, 1H), 3.09 (ddd, J = 21.1, 16.5, 7.2 Hz, 2H), 2.08 (s, 3H), 1.32 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 207 .4, 171.1, 169.9, 141 .2, 139 .4, 136.3, 130 .4, 128.8, 128.6, 128 .4, 128.2, 128.2, 128.0, 127.5, 126.7, 81.3, 70.8, 45 .3, 44 .6, 30.3, 27.9; LRMS (ESI) m/z 44 2.2 (M... CDCl3) δ 7. 64- 7.61 (m, 2H), 7 .43 -7. 24( m, 13H), 5.05 -4. 95 (m, 2H), 4. 80 -4. 60 (m, 2H), 3.92-3.79 (m, 1H), 2 .40 -2.18 (m, 4H), 1 .41 -1.19 (m, 12H); 13C NMR (126 MHz, CDCl3) δ 172.7, 171.1 (d, J = 16 .4 Hz), 139.5, 135.9 (d, J = 12.9 Hz), 130.2, 128.8, 128 6, 128.5, 128 .4, 128 .4, 128.1, 128.0, 71.1 (dd, J = 56.0, 7.0 Hz), 66.2, 61.1 (d, J = 160.5 Hz,), 31.3 (d, J = 14. 9 Hz), 26.5 (d, J = 4. 8 Hz), 24. 1 (ddd,... 128.5, 128.5, 128.3, 128.2, 128.1, 127.5, 115.0, 1 14. 8, 81 .4, 70.9, 44 .1, 40 .2, 27.9; LRMS (ESI) m/z 544 .1 (M + Na+), HRMS (ESI) m/z 544 .2258 ([M + Na+]), calc for [C34H32FNO3+Na+] 544 .2258; [α]29 = + 54. 5 (c D 1.26, CHCl3); HPLC analysis: Chiralcel OD-H (Hex/IPA = 95/5, 0.5 mL/min, 2 54 nm, 23° 10.2 (major), 19.9 min, 90% ee C), (2R,3S)-tert-Butyl-3- (4- chlorophenyl)-2-((diphenylmethylene)amino)-5-oxo-5-phe... Hz, 2H), 7. 74- 7. 54 (m, 5H), 7.60 (s, 1H), 7.55-7.52 (m, 1H), 111 Chapter 4 7 .45 -7.30 (m, 9H), 7.22-7.19 (m, 2H), 6. 64 (d, J = 7.0 Hz, 2H), 4. 40 -4. 37 (m, 1H), 4. 29 (d, J = 5.0 Hz, 1H), 3.89 (dd, J = 17.0, 10.2 Hz, 1H), 3.72 (dd, J = 17.0, 3.8 Hz, 1H), 1.31 (s, 9H).; 13C NMR (126 MHz, CDCl3) δ 198.7, 171.2, 170.0, 141 .1, 140 .6, 139 .4, 137.2, 136.3, 132.8, 130 .4, 129.0, 128.9, 128.7, 128.5, 128 .4, 128.2,... CDCl3) δ 8. 04 -7. 94 (m, 2H), 7.72-7.65 (m, 2H), 7.56-7.51 (m, 3H), 7 .48 -7. 34 (m, 10H), 7.30 (t, J = 7 .4 Hz, 3H), 7.21 (d, J = 8.2 Hz, 2H), 6.73 (d, J = 7.1 Hz, 2H), 4. 26 -4. 20 (m, 2H), 3.81 (dd, J = 17.0, 10.0 Hz, 1H), 3.66 (dd, J = 17.0, 3.6 Hz, 1H), 1. 34 (s, 9H); 13 C NMR (126 MHz, CDCl3) δ 198.7, 171.2, 170.0, 141 .1, 140 .6, 139 .4, 137.2, 136.3, 132.8, 130 .4, 129.0, 128.9, 128.7, 128.5, 128 .4, 128.2,... 2H), 7 .44 -7.39 (m, 3H), 7.39-7.36 (m, 1H), 7.36-7.27 (m, 7H), 7.18-7.13 (m, 2H), 5. 04 (s, 2H), 3.98 (dd, J = 7 .4, 5.2 Hz, 1H), 2 .43 (dd, J = 11.3, 5.2 Hz, 2H), 2.31-2.20 (m, 2H), 1 .44 (s, 9H) 13 C NMR (75 MHz, CDCl3) δ 172.9, 170.7, 139 .4, 136 .4, 135.9, 130.2, 128.7, 128.5, 128 .4, 128.3, 128.1, 127.9, 127.6, 81.1, 66.1, 64. 8, 30.7, 28.5, 28.0; LRMS (ESI) m/z 48 0.1 (M + Na+), HRMS (ESI) m/z 48 0.2165 . S)-Tetraphenyl-tetraethyl -pentanidium chloride (80b): white solid; 1 H NMR (500 MHz, CDCl 3 ) δ 7 .42 -7 .40 (m, 12H), 7.17-7.15 (m, 8H), 4. 53 (s, 4H), 4. 31 -4. 24 (m, 4H), 3.05-3.03 (m, 4H), 1.16 (t, J=7.5,. 2-(((4S,5S)-1,3-dimethyl -4, 5-diphenylimidazolidin-2-ylidene)amino)-1,3-dimethyl -4, 5-dihydro-1H-imidazol-3-ium chloride (80g): pale yellow oil; 1 H NMR (300 MHz, MeOD) δ 7 .42 -7 .44 (m, 6H), 7.30-7. 34 (m, 4H), 4. 69 (s, 2H), 3.82-3.67 (m, Chapter 4 103 4H), 3. 04 (s,. 159.2, 129.0, 127.3, 1 14. 6, 72.2, 55.2, 32.3; LRMS (ESI) m/z 6 34. 5 ([M-Cl - ]) + , HRMS (ESI) m/z 6 34. 340 3 ([M-Cl - ]) + , calc. for [C 38 H 44 N 5 O 4 + ] 6 34. 3388. Chiral pentanidium salt 80d