Enantioselective tandem conjugate addition elimination reactions 5

Chapter Chapter Experimental 78 Chapter 5.1 General procedures and methods H and 13 C NMR spectra were recorded on a Bruker ACF300 (300 MHz), DPX300 (300 MHz) or AMX500 (500 MHz) spectrometer. Chemical shifts are reported in parts per million (ppm). The residual solvent peak was used as an internal reference. Low resolution mass spectra were obtained on a VG Micromass 7035 spectrometer in EI mode, 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. Infrared spectra were recorded on a BIO-RAD FTS 165 FTIR spectrometer. Enantiomeric excesses were measured via chiral HPLC analysis on Hewlett Packard Ti Series 1050 or a set of Jasco HPLC units, including a Jasco DG-980-50 Degasser, a LG-980-02 Ternary Gradient Unit, a PU-980 Intelligent HPLC Pump, UV-975 Intelligent UV/VIS Detectors, and an AS-950 Intelligent Sampler. Optical rotations were recorded on a Jasco DIP-1000 polarimeter. Melting points were determined on a BÜCHI B-540 melting point apparatus. Analytical thin layer chromatography (TLC) was performed with Merck pre-coated TLC plates, silica gel 60F-254, layer thickness 0.25 mm. Flash chromatography separations were performed on Merck 60 (0.040 - 0.063 mm) mesh silica gel. Toluene was distilled from sodium/benzophenone and stored under N2 atmosphere. THF was freshly distilled from sodium/benzophenone before use. CH2Cl2 was freshly distilled from CaH2. MeOH was refluxed over magnesium turnings together with a small amount of iodine until the iodine disappeared and then distilled off. Other distilled solvents such as CH3CN, ethyl acetate and CHCl3 were 79 Chapter stored under N2. All other reagents and solvents are commercial grade and were used as supplied without further purification, unless otherwise stated. Crystals were grown from hexane and dichloromethane solutions and mounted on glass fibres. X-ray data were collected with a Bruker AXS SMART APEX diffractometer, using Mo-Kα radiation at room temperature, with the SMART suite of Programs(1). Data were processed and corrected for Lorentz and polarisation effects with SAINT(2), and for absorption effect with SADABS(3). Structural solution and refinement were carried out with the SHELXTL, suite of programs (4). The structure was solved by direct methods to locate the heavy atoms, followed by difference maps for the light, non-hydrogen atoms. All non-hydrogen atoms were generally given anisotropic displacement parameters in the final model. All H-atoms were put at calculated positions. 1. SMART version 5.628, 2001. Bruker AXS Inc., Madison, Wisconsin, USA 2. SAINT+ version 6.22a, 2001 Bruker AXS Inc., Madison, Wisconsin, USA 3. SADABS, version 2.10, 2001 G. W. Sheldrick, University of Göttingen 4. SHELXTL, Version 6.14, 2000, Bruker AXS Inc., Madison, Wisconsin, USA 5.2 Typical experimental procedures 5.2.1 Typical procedure for achiral tandem CA-E reactions O O Br t COS Bu CH 2Cl2, rt COStBu eq Et3N + 16f COStBu t BuSOC To a mL round bottom flask containing 2- (bromomethyl) cyclopent-2-enone (18 mg, 0.1 mmol) and S,S-di-tert-butyl dithiomalonate 16f (50 mg, 0.2 mmol, eq.), 80 Chapter anhydrous CH2Cl2 (1 mL) followed by triethylamine (27.9 µL, 0.2 mmol, 2.0 eq.) were added and the mixture was stirred at room temperature. Upon completion, the reaction mixture was directly loaded onto a silica gel column, followed by gradient elution with hexane/EA mixtures (20/1-4/1 ratio). After removing the solvent, the product was obtained as a white crystal in 95% yield. DABCO was not used for this reaction as side products were observed by 1H NMR analysis. t CO2Me COStBu CH 2Cl2 , rt + COStBu eq DABCO Br R 24a-j BuSOC COStBu CO2Me R 16f The same procedure was used to prepare the achiral products of linear substrates. Instead of triethylamine, DABCO was employed as the promoter for the reaction between 24a-j and S,S-di-tert-butyl dithiomalonate 16f. 5.2.2 Typical procedure for asymmetric tandem CA-E reactions O Br + COStBu N COStBu 16f MesO 2S O NH 11h 1.5 eq CH3 CN, rt tBuSOC COStBu 17f To a mL round bottom flask containing 2- (bromomethyl) cyclopent-2-enone (18 mg, 0.1 mmol) and S,S-di-tert-butyl dithiomalonate 16f (50 mg, 0.2 mmol, eq.), anhydrous CH3CN (1 mL) followed by promoter 11h (53 mg, 0.15 mmol, 1.5 eq.) were added and the mixture was stirred at room temperature. Upon completion or after the indicated reaction time, the reaction was quenched by adding M HCl solution (0.5 mL) and extracted with ethyl acetate (2.0 mL × 2). The aqueous layer was basified with M NaOH (0.5 mL) and extracted with CH2Cl2 (2.0 mL × 2) to 81 Chapter recover the promoter 11h. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate as eluent to give the desired product 17f as a white crystal (97% yield, 90% ee). The enantiomeric excess was determined by HPLC analysis using a chiral column. 5.2.3 General procedure for the synthesis of chiral pyrrolidinyl sulfonamides (CPS) 5.2.3.1 Synthesis of CPS from chiral amino alcohols Bn Bn OH NH i ii Bn N Ts N NHTs 11a Reagents and conditions: (i) p-TsCl, Et3N, CH3CN; (ii) pyrrolidine, CH3CN, reflux. (i) Aziridines were prepared according to a reported procedure: W. Ye, D. Leow, L. M. S. Goh, C-T. Tan, C-T. Chian, C-T. Tan, Tetrahedron Lett. 2006, 47, 1007-1010. (ii) General procedure for the ring-opening of aziridines. To a dry sealed tube containing an N-benzyl aziridine (766 mg, 2.7 mmol) was added anhydrous CH3CN (2 mL). Pyrrolidine (0.345 mL, 4.0 mmol, 1.5 eq.) was then added and the reaction mixture was refluxed (85oC oil bath) and monitored by TLC. Upon completion, the solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica gel to yield promoter 11a as pale yellow oil (98% yield). 5.2.3.2 Synthesis of CPS from chiral amino acid The synthesis of CPS from chiral amino acid was achieved according to the 82 Chapter following literatures. O tBu O O i OH 74% NH ii tBu OH NHBoc 78% t Bu t Bu 53% N NH Boc 15 84% v t Bu N NH 13 69% NH iii N 12 iv O tBu 14 N NHTs 11f Reagents and conditions: (i) (Boc)2O, 2M NaOH, 0oC to rt; (ii) pyrrolidine, HOBt, DCC, THF, 0oC to rt; (iii) 3M HCl in EtOAc; (iv) LiAlH4, THF, rt to reflux; (v) p-TsCl, DMAP, Et3N, CH2Cl2, 0oC to rt. (i) A. Boruah, I. N. Rao, J. P. Nandy, S. K. Kumar, A.C. Kunwar and J. Iqbal, J. Org. Chem., 2003, 68, 5006-5008. (ii) E. J. Corey and M. J. Grogan, Org. Lett. 1999, 1, 157-160. (iii) G. L. Stahl, R. Walter and C. W. Smith, J. Org. Chem., 1978, 43, 2285-2286. (iv) E. J. Corey and M. J. Grogan, Org. Lett. 1999, 1, 157-160. (v) L. A. Gandon, A. G. Russell, T. Güveli, A. E. Brodwolf, B. M. Kariuki, N. Spencer and J. S. Snaith, J. Org. Chem., 2006, 71, 5198-5207. 5.2.3.3 Preparation of polymer supported chiral pyrrolidinyl sulfonamide 37 (PS-CPS) N N NH 15 + O CH2 Cl2 , rt S Cl Et3N O O NH S O 37 To a dry round bottom flask containing chiral diamine 15 (85.2 mg, 0.5 mmol, eq.) in CH2Cl2 (1 mL) was added triethylamine (70 µL, 0.5 mmol, eq.) followed by 50 mg polystyrene bound sulfonyl chloride (50 mg, 1.5-2.0 mmol/g). After shaking 83 Chapter for days, the reaction mixture was filtered and washed with CH2Cl2 (2 mL) to recover the chiral diamine 15 (67.1 mg, 0.39 mmol). The beads were washed with DMF (2 mL × 2), H2O (2 mL × 2), EtOH (2 mL × 2), CH2Cl2 (2 mL × 2), diethyl ether (2 mL × 2) and vacumm dried to afford 65.6 mg of 37. 5.2.4 General procedure for the synthesis of chiral imidazoline (53a-j) All chiral imidazoline promoters (53a-j) were synthesized through a reported protocol: N. A. Boland, M. Casey, S. J. Hynes, J. W. Matthews and M. P. Smyth, J. Org. Chem., 2002, 67, 3919-3922. 5.2.5 Typical procedure for asymmetric Baylis-Hillman reactions Typical experimental procedure for chiral imidazoline promoted Baylis-Hillman reaction between aldehydes and acrylates: To an oven-dried vial, promoter 53a (24.4 mg, 0.10 mmol, eq.) was added. This was followed by 4-nitrobenzaldehyde 54a (15.1 mg, 0.10 mmol) and methyl acrylate 55a (0.10 mL). The reaction was stirred at room temperature and monitored by TLC. Upon completion or after the indicated reaction time, the reaction was quenched by adding M HCl solution (1.0 mL) and extracted with ethyl acetate (2.0 mL). The aqueous layer was basified with M NaOH (1.0 mL) and extracted with CH2Cl2 (2.0 mL × 2) to recover the imidazoline 53a. The combined organic layers was dried over anhydrous MgSO4, filtered and concentrated under vacuum. The crude residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate as eluent to give the desired product. The enantiomeric excess was determined by HPLC analysis using a chiral column. 84 Chapter Typical experimental procedure for chiral imidazoline promoted Baylis-Hillman reaction between aldehydes and alkyl vinyl ketones: Similar as the reaction between aldehydes and acrylates, methyl vinyl ketone (30.0 µL, 0.36 mmol, 16 eq.) was added to the toluene solution (0.1 mL) of 4-nitrobenzaldehyde (3.3 mg, 0.02 mmol) and imidazoline promoter 53i (4.0 mg, 0.01 mmol, 50 mol%) at the indicated temperature. Upon completion or after the indicated reaction time, the reaction mixture was purified directly via column chromatography using hexane/ethyl acetate as eluent to yield the product (3.6 mg, 75% yield) and the recovered catalyst. 5.3 Characterization of compounds 5.3.1 Characterization of substrates (3) 2-(bromomethyl)cyclopent-2-enone O Br Pale yellow oil. 1H NMR (300 MHz, CDCl3, ppm) δ 2.46-2.49 (m, 2H), 2.64-2.65 (m, 2H), 4.03 (d, 2H, J = 1.0 Hz), 7.68-7.70 (dd, 1H, J = 2.4, 1.0 Hz); 13C NMR (75 MHz, CDCl3, ppm) δ 21.6, 26.5, 34.6, 120.8, 142.6, 162.0, 206.5. 5.3.2 Characterization of chiral pyrrolidinyl sulfonamides (CPS) (11a) (S)-4-Methyl-N-(1-phenyl-3-(pyrrolidin-1-yl)propan-2-yl)benzenesulfonamide Bn N NHTs Pale yellow oil. 1H NMR (300 MHz, CDCl3, ppm) δ 1.51-1.64 (m, 4H), 2.00-2.08 (m, 2H), 2.11-2.18 (m, 3H), 2.39-2.47 (m, 4H), 2.73-2.80 (dd, 1H, J = 13.5, 7.9 Hz), 3.12-3.25 (m, 2H), 7.12-7.31 (m, 7H), 7.77 (d, 2H, J = 8.2 Hz); 13C NMR (75 MHz, 85 Chapter CDCl3, ppm) δ 21.5, 23.4, 39.6, 53.1, 53.4, 57.4, 126.3, 127.2, 128.2, 129.5, 129.6, 136.6, 137.2, 143.2; IR (film, cm-1) 3375, 2970, 1599, 1475, 1341, 1162, 1092; LRMS (ESI) m/z 359.2 [M+H]+; HRMS (ESI) calcd. for [C20H26N2O2S+H]+ requires m/z 359.1793. Found 359.1796. [α]24 D +83.6 (c = 6.44, CHCl3). (11f) (S)-N-(3,3-Dimethyl-1-(pyrrolidin-1-yl)butan-2-yl)-4-methylbenzenesulfonamide N NHTs Pale yellow crystal. 1H NMR (300 MHz, CDCl3, ppm) δ 0.88 (s, 9H), 1.52 (bs, 4H), 2.20-2.24 (m, 2H), 2.33-2.40 (m, 6H), 2.45-2.53 (m, 1H), 3.21 (dd, 1H, J = 9.1, 4.2 Hz), 7.22 (d, 2H, J = 8.3 Hz), 7.78 (d, 2H, J = 8.3 Hz); 13C NMR (75 MHz, CDCl3, ppm) δ 21.4, 23.4, 26.8, 34.3, 54.0, 56.8, 61.5, 127.0, 128.9, 139.5, 142.3; IR (KBr, cm-1) 3433, 2969, 1600, 1457, 1321, 1153, 1086; LRMS (ESI) m/z 325.2 [M+H]+; HRMS (ESI) calcd. for [C17H28N2O2S+H]+ requires m/z 325.1950. Found 325.1950. [α]24 D +56.4 (c = 4.57, CHCl3). (11g) (S)-N-(3,3-Dimethyl-1-(piperidin-1-yl)butan-2-yl)-4-methylbenzenesulfonamide N NHTs Pale yellow sticky liquid. 1H NMR (300 MHz, CDCl3, ppm) δ 0.84 (s, 9H), 1.33-1.39 (m, 6H), 2.11-2.19 (m, 3H), 2.27-2.34 (m, 3H), 2.38 (s, 3H), 3.27 (dd, 1H, J = 9.0, 4.8 Hz), 7.23 (d, 2H, J = 8.1 Hz), 7.80 (d, 2H, J = 8.1 Hz); 13C NMR (75 MHz, CDCl3, ppm) δ 21.4, 24.1, 25.5, 26.7, 34.3, 54.7, 59.4, 59.7, 127.0, 129.1, 139.5, 142.4; IR (film, cm-1) 3395, 2940, 1600, 1475, 1316, 1155, 1094; LRMS (ESI) m/z 339.3 86 Chapter [M+H]+; HRMS (ESI) calcd. for [C18H30N2O2S+H]+ requires m/z 339.2106. Found 339.2107. [α]24 D +34.1 (c = 5.42, CHCl3). (11h) (S)-N-(3,3-Dimethyl-1-(pyrrolidin-1-yl)butan-2-yl)-2,4,6-trimethylbenzenesulfonamide N MesO 2S NH Pale yellow solid. 1H NMR (500 MHz, CDCl3, ppm) δ 0.83 (s, 9H), 1.50-1.55 (m, 4H), 2.22-2.28 (m, 5H), 2.37 (dd, 1H, J = 12.6, 3.8 Hz), 2.46-2.57 (m, 3H), 2.65 (s, 6H), 3.28 (dd, 1H, J = 10.1, 4.4 Hz), 6.90 (s, 2H); 13C NMR (125 MHz, CDCl3, ppm) δ 20.8, 23.0, 23.5, 26.8, 34.3, 54.1, 56.4, 61.4, 131.5, 136.8, 138.2, 141.1; IR (film, cm-1) 3392, 2958, 1602, 1477, 1338, 1156, 1053; LRMS (ESI) m/z 353.3 [M+H]+; HRMS (ESI) calcd. for [C19H32N2O2S+H]+ requires m/z 353.2263. Found 353.2260. [α]24 D +57.7 (c = 4.79, CHCl3). 5.3.3 Characterization of tandem CA-E products (17f) (S)-S,S'-di-tert-Butyl 2-(2-methylene-3-oxocyclopentyl) propanebis(thioate) O O O StBu St Bu White crystal. 90% ee; Melting point: 100.0-100.6oC; 1H NMR (500 MHz, CDCl3, ppm) δ 1.47 (s, 9H), 1.49 (s, 9H), 1.71-1.78 (m, 1H), 2.06-2.13 (1H, m), 2.27-2.42 (m, 2H), 3.67 (d, 1H, J = 10.0 Hz), 3.69-3.73 (m, 1H), 5.31 (d, 1H, J = 1.9 Hz), 6.06 (d, 1H, J = 1.9 Hz); 13 C NMR (125 MHz, CDCl3, ppm) δ 23.7, 29.5, 29.6, 36.3, 41.3, 49.5, 49.6, 72.4, 119.5, 145.1, 192.4, 192.5, 205.2; IR (film, cm-1); 3021, 2926, 2855, 87 Chapter 216.4; IR (film, cm-1) 3019, 2969, 2400, 1744, 1690, 1366, 1216; LRMS (ESI) m/z 411.0 [M+H]+; HRMS (ESI) calcd. for [C20H30O3N2S2+H]+ requires m/z 411.1776 25 Found 411.1771. [α] D +19.6 ( c = 0.76, CHCl3). (34) S,S'-di-tert-Butyl 2-((1R,2S)-3-oxo-2-(phenylthiomethyl)cyclopentyl)pro panebis(thioate) O SPh O O StBu StBu Et3N (4.0 µL, 0.029 mmol, equiv.) was added dropwise at rt to a stirring CH2Cl2 (0.2 mL) solution of CA-E product 17f (10.0 mg, 0.029 mmol) and thiophenol (6 µL, 0.058 mmol, equiv.). The reaction was monitored by TLC. Upon completion, the mixture was directly purified by silica gel column to give the thio-Michael product 34 as pale yellow oil, which solidified when stored at -20oC (9.2 mg, 70% yield). 1H NMR (500 MHz, CDCl3, ppm) δ 1.44 (s, 9H), 1.45 (s, 9H), 1.70-1.78 (m, 1H), 2.09-2.22 (m, 2H), 2.29-2.37 (m, 2H), 3.01-3.08 (m, 1H), 3.20 (d, 2H, J = 4.4 Hz), 3.73 (d, 1H, J = 8.2 Hz), 7.16 (t, 1H, J = 7.6 Hz), 7.26 (t, 2H, J = 7.6 Hz), 7.37 (d, 2H, J = 7.6 Hz); 13C NMR (125 MHz, CDCl3, ppm) δ 24.5, 29.5 (two peaks), 33.2, 37.4, 41.1, 49.4, 49.5, 52.2, 72.2, 126.3, 128.9, 129.8, 136.1, 192.8, 192.9, 216.5; IR (film, cm-1) 3019, 2967, 2400, 1743, 1690, 1658, 1366, 1217; LRMS (ESI) m/z 451.0 [M-H]-; HRMS (ESI) calcd. for [C23H32O3S3Na]+ requires m/z 475.1411 Found 25 475.1406. [α] D +26.1 ( c = 0.92, CHCl3). (35) S,S'-di-tert-Butyl 2-((1R,2S)-2-methyl-3-oxocyclopentyl)propanebis(thioate) 101 Chapter O O O StBu S Bu t The ethyl acetate (0.2 mL) solution of CA-E product 17f (6.9 mg, 0.02 mmol) and palladium on carbon (2.1 mg, 30% w/w) was stirred at 0oC with a H2 balloon. Upon completion, the reaction mixture was filtered through a silica gel column to yield product 35 as a sticky colorless crystal (5.6 mg, 81% yield). Major diastereomer: 1H NMR (500 MHz, CDCl3, ppm) δ 1.07 (d, 3H, J = 6.9 Hz), 1.49 (s, 18H), 1.59-1.63 (m, 1H), 1.88-1.91 (m, 1H), 2.11-2.18 (m, 2H), 2.32-2.36 (m, 1H), 2.56-2.62 (m, 1H), 3.60 (d, 1H, J = 5.7 Hz); 13C NMR (125 MHz, CDCl3, ppm) δ 14.0, 25.0, 29.5, 29.6 (two peaks), 36.6, 44.9, 48.5, 49.4 (two peaks), 73.7, 192.6, 192.7, 218.8; IR (film, cm-1) 3020, 2400, 1738, 1692, 1216; LRMS (ESI) m/z 367.0 [M+Na]+; HRMS (ESI) calcd. for [C17H28O3S2Na]+ requires m/z 367.1378 Found 367.1372. (36a) S,S'-di-tert-Butyl 2-((1R,2S)-3-oxo-2-pentylcyclopentyl)propanebis(thioate) O O O StBu StBu To a flame-dried rbf containing CuI (22.8 mg, 0.12 mmol, equiv.) was added anhydrous THF (0.5 mL) and the reaction flask was cooled to -78oC. The hexane solution of nBuLi (1.6 M, 0.15 mL, 0.24 mmol, equiv.) was then added and stirred for 30 at -78oC. The mixture of CA-E product 17f (13.7 mg, 0.04 mmol) and TMSCl (30.4 µL, 0.24 mmol, equiv.) was then added slowly to the rbf at -78oC. The 102 Chapter reaction was monitored by TLC. Upon completion, saturated NH4Cl solution (2 mL) was added to rbf and the mixture was extracted by ether (2 mL×2). The crude product was purified by flash chromatography on silica gel to yield compound 36a as a sticky colorless crystal (10.4 mg, 65% yield). 1H NMR (500 MHz, CDCl3, ppm) δ 0.86 (t, 3H, J = 7.6 Hz), 1.12-1.30 (m, 5H), 1.34-1.45 (m, 2H), 1.47 (s, 9H), 1.48 (s, 9H), 1.59-1.67 (m, 2H), 1.92-1.96 (m, 1H), 2.04-2.16 (m 2H), 2.28-2.34 (m, 1H), 2.80-2.87 (m, 1H), 3058 (d, 1H, J = 9.4 Hz); 13C NMR (125 MHz, CDCl3, ppm) δ 14.0, 22.4, 24.7, 25.7, 28.8, 29.5, 29.6, 32.0, 37.2, 41.2, 49.4 (two peaks), 52.9, 73.5, 192.6, 192.8, 219.2; IR (film, cm-1) 3021, 2966, 2928, 2401, 1737, 1693, 1660, 1457, 1216; LRMS (ESI) m/z 423.2 [M+Na]+; HRMS (ESI) calcd. for [C21H36O3S2Na]+ requires 25 m/z 423.2004 Found 423.1998. [α] D +31.7 ( c = 0.06, CHCl3). HPLC conditions: Chiralcel AS-H column (Diacel); 98/2 hexane/2-propanol; Flow rate 0.5 mL/min; λ = 210 nm; 7.3 (minor), 12.5 (major). 5.3.5 Determination of absolute configuration The absolute configuration was determined by comparing with the literature values1 and further verified with single crystal X-ray analysis of compound 36b (see Appendices). T. Perrard, J.-C. Plaquevent, J.-R. Desmurs and D. Hébrault, Org. Lett., 2000, 2, 2959. 103 Chapter O H O COSt Bu + neat, rt Cl OHPh O K2CO3 (0.14 eq.) COS Bu PTC (0.11 eq.) N N t t S Bu O StBu (+)-36b OMe PTC N-benzylquininium chloride 25 [α] D +35.0 (c = 0.10, CHCl3), 93% ee O O n O BuLi, CuI, TMSCl O o THF,-78 C O StBu O StBu 17f StBu StBu (+)-36b 25 [α] D +31.7 ( c = 0.06, CHCl3), 88% ee 5.3.6 Characterization of chiral imidazoline 53a-j. (53a) (S)-4-tert-Butyl-1-isopropyl-2-phenyl-4, 5-dihydro-1H-imidazole N N Ph Pale yellow oil. 1H NMR (500 MHz, CDCl3, ppm) δ 0.92 (d, 3H, J = 6.5 Hz), 0.93 (s, 9H), 1.07 (d, 3H, J = 6.5 Hz), 3.16 (dd, 1H, J = 9.7, 9.2 Hz), 3.33 (dd, 1H, J = 11.1, 9.7 Hz), 3.69 (septet, 1H, J = 6.5 Hz), 3.78 (dd, 1H, J = 11.1, 9.2 Hz), 7.32-7.41 (m, 5H); 13 C NMR (500 MHz, CDCl3, ppm) δ 19.1, 20.7, 25.9, 34.3, 43.8, 46.5, 73.3, 128.0, 128.1 (two peaks), 128.2, 129.1, 132.4, 165.4; IR (film, cm-1) 2954, 2868, 25 1596, 1497; [α] D -37.5 (c 6.22, CHCl3); LRMS (FAB) m/z 245.1 (M+H+); HRMS (FAB) [C16H24N2+H] + requires m/z 245.2018. Found 245.2014. 104 Chapter (53b) (S)-4-Benzyl-1-isopropyl-2-phenyl-4, 5-dihydro-1H-imidazole Bn N N Ph Yellow oil. 1H NMR (500 MHz, CDCl3, ppm) δ 0.78 (d, 3H, J = 6.9 Hz), 0.94 (d, 3H, J = 6.9 Hz), 2.75 (dd, 1H, J = 13.4, 8.3 Hz), 3.05-3.13 (m, 2H), 3.36 (t, 1H, J = 9.9 Hz), 3.63 (septet, 1H, J = 6.9 Hz), 4.32-4.39 (m, 1H), 7.14-7.32 (m, 10H); 13C NMR (500 MHz, CDCl3, ppm) δ 19.6, 20.2, 25.3, 41.3, 46.8, 61.5, 126.4,128.1, 128.3,128.6, 25 129.9, 130.7, 137.2, 165.5; IR (film, cm-1) 3325, 3156, 1613, 1591; [α] D +4.7 ( c 0.23, CHCl3); LRMS (FAB) m/z 279.1 (M+H+); HRMS (FAB) calcd. for [C19H22N2+ H] + requires m/z 279.1861. Found 279.1866. (53c) (S)-1-Isopropyl-2, 4-diphenyl-4, 5-dihydro-1H-imidazole Ph N N Ph Colorless oil. 1H NMR (300 MHz, CDCl3, ppm) δ 1.01 (d, 3H, J = 6.6 Hz), 1.13 (d, 3H, J = 6.6 Hz), 3.34 (t, 1H, J = 9.2 Hz), 3.84-3.94 (m, 2H), 5.18 (dd, 1H, J = 11.2, 8.8 Hz), 7.25-7.60 (m, 10H); 13 C NMR (300 MHz, CDCl3, ppm) δ 19.6, 20.6, 46.8, 51.2, 66.9, 126.6, 126.9, 128.2, 128.4, 128.5, 129.7, 131.6, 144.8, 166.8; IR (film, 25 cm-1) 2975, 2934, 1644, 1621; [α] D -37.8 ( c 0.66, CHCl3); LRMS (FAB) m/z 265.1 (M+H+); HRMS (FAB) calcd. for [C18H20N2+H]+ requires m/z 265.1705. Found 265.1700. (53d) (S)-4-tert-Butyl-1, 2-diphenyl-4, 5-dihydro-1H-imidazole 105 Chapter N Ph N Ph Menges, F.; Neuburger, M.; Pfaltz, A. Org. Lett. 2002, 4, 4713-4716. (53e) (4S, 5S)-1-Isopropyl-2, 4, 5-triphenyl-4, 5-dihydro-1H-imidazole Ph Ph N N Ph Pale yellow oil. 1H NMR (300 MHz, CDCl3, ppm) δ 0.82 (d, 3H, J = 6.8 Hz), 0.95 (d, 3H, J = 6.8 Hz), 4.01 (septet, 1H, J = 6.8 Hz), 4.51 (d, 1H, J = 6.8 Hz), 4.92 (d, 1H, J = 6.8 Hz), 7.25-7.51 (m, 13H), 7.80-7.83 (m, 2H); 13C NMR (300 MHz, CDCl3, ppm) δ 19.6, 22.6, 48.4, 69.1, 126.3, 127.3, 127.6, 128.6, 128.7, 128.9, 130.7, 143.9, 145.1, 25 167.5; IR (film, cm-1) 3020, 2934, 2401, 2097, 1615, 1216; [α] D +1.1 ( c 0.10, CHCl3); LRMS (FAB) m/z 341.2 (M+H+); HRMS (FAB) calcd. for [C24H24N2+H]+ requires m/z 341.2018. Found 341.2026. Stereochemistry of 3i was determined based on literature: Boland, N. A.; Casey, M.; Hynes, S. J.; Matthews, J. W.; Smyth, M. P. J. Org. Chem. 2002, 67, 3919-3922. (53f) (S)-4-tert-butyl-2-phenyl-1-[-(S)-1-phenylethyl)-4, 5-dihydro-1H-imidazole] N N Ph Ph Pale yellow oil. 1H NMR (300 MHz, CDCl3, ppm) δ 0.75 (s, 9H), 1.54 (d, 3H, J = 7.0 Hz), 2.85 (t, 1H, J = 9.4 Hz), 3.37 (dd, 1H, J = 11.5, 9.4 Hz), 3.81 (dd, 1H, J = 11.5, 9.4 Hz), 4.87 ( q, 1H, J = 7.0 Hz), 7.10-7.13 (m, 2H), 7.23-7.31 (m, 3H), 7.42-7.45 (m, 106 Chapter 3H), 7.56-7.59 (m, 2H); 13C NMR (300 MHz, CDCl3, ppm) δ 17.3, 25.9, 30.2, 34.2, 44.6, 53,3, 73.6, 125.7, 127.0, 127.2, 127.4, 128.2, 128.3, 128.5, 129.6, 132.3, 140.3, 25 165.2; IR (film, cm-1) 2959, 2869, 1593, 1495; [α] D -4.7 ( c 18.2, CHCl3); LRMS (FAB) m/z 307.2 (M+H+); HRMS (FAB) calcd. for [C21H26N2+H]+ requires m/z 307.2174. Found 307.2174. (53g) (S)-4-tert-Butyl-2-phenyl-1-[-(R)-1-phenylethyl)-4, 5-dihydro-1H-imidazole] N N Ph Ph Pale yellow solid. Melting point 111.6-112.4 oC H NMR (300 MHz, CDCl3, ppm) δ 0.96 (s, 9H), 1.43 (d, 3H, J = 6.8 Hz), 3.07-3.24 (m, 2H), 3.79 (dd, 1H, J = 11.2, 9.4 Hz), 4.83 (q, 1H, J = 6.8 Hz), 7.24-7.58 (m, 10H); 13C NMR (300 MHz, CDCl3, ppm) δ 16.5, 26.0, 34.5, 44.9, 53.3, 73.5, 126.7, 127.1, 128.2, 128.5 (two peaks), 129.6, 25 132.1, 141.4, 165.4; IR (film, cm-1) 3021, 2965, 1620, 1216; [α] D -1.5 ( c 2.59, CHCl3); LRMS (FAB) m/z 307.1 (M+H+); HRMS (FAB) calcd. for [C21H26N2+H]+ requires m/z 307.2174. Found 307.2174. (53h) (S)-1-Benzhydryl-4-tert-butyl-2-phenyl-4, 5-dihydro-1H-imidazole Ph N N Ph Ph Colorless oil. 1H NMR (300 MHz, CDCl3, ppm) δ 0.79 (s, 9H), 3.01 (t, 1H, J = 9.6 Hz), 3.37 (t, 1H, J = 10.4 Hz), 3.85 (m, 1H), 6.01 (s, 1H), 7.02-7.05 (m, 2H), 7.21-7.42 (m, 13H), 7.53-7.56 (m, 2H); 13 C NMR (300 MHz, CDCl3, ppm) δ 25.9, 107 Chapter 34.2, 46.2, 63.3, 73.9, 126.9 (two peaks), 127.3 (two peaks), 127.4, 127.5, 128.1, 128.2, 128.4, 128.6, 129.0, 129.9, 131.8, 139.1, 139.7, 165.6; IR (film, cm-1) 2958, 25 2925, 2866, 1618, 1596; [α] D -33.8 (c 1.27, CHCl3); LRMS (FAB) m/z 369.1 (M+H+); HRMS (FAB) calcd. for [C26H28N2+H]+ requires m/z 369.2331. Found 369.2334. (53i) (S)-4-tert-Butyl-1-((R)-1-(naphthalen-2-yl) ethyl)-2-phenyl-4, 5-dihydro-1Himidazole N N Ph White solid. Melting point 112.7-112.9 oC 1H NMR (300 MHz, CDCl3, ppm) δ 0.97 (s, 9H), 1.54 (d, 3H, J = 7.0 Hz), 3.09 (t, 1H, J = 10.5 Hz), 3.23 (t, 1H, J = 9.6 Hz), 3.80 (m, 1H), 4.99 (q, 1H, J = 7.0 Hz), 7.43-7.85 (m, 12H); 13C NMR (300 MHz, CDCl3, ppm) δ 16.2, 26.0, 34.4, 44.9, 53.3, 73.7, 124.9. 125.5, 125.9, 126.2, 127.5, 127.9, 128.2 (two peaks), 128.5, 129.5, 132.3, 132.5, 133.2, 139.0, 165.3; IR (film, 25 cm-1) 2954, 2869, 1615, 1594, 1409; [α] D +7.9 (c 4.28, CHCl3); LRMS (FAB) m/z 357.3 (M+H+); HRMS (FAB) calcd. for [C26H28N2+H]+ requires m/z 357.2321. Found 357.2324. (53j) (S)-4-tert-Butyl-1-isopropyl-2-(naphthalen-2-yl)-4, 5-dihydro-1H-imidazole N N 108 Chapter Yellow oil. 1H NMR (300 MHz, CDCl3, ppm) δ 1.01 (s, 9H), 1.04 (d, 3H, J = 6.6 Hz), 1.17 (d, 3H, J = 6.6 Hz), 3.34 (t, 1H, J = 9.4 Hz), 3.52 (t, 1H, J = 10.1 Hz), 3.83-3.97 (m, 2H), 7.50-7.55 (m, 3H), 7.83-7.91 (m, 3H), 8.05 (s, 1H); 13 C NMR (300 MHz, CDCl3, ppm) δ 19.5, 20.6, 25.8, 34.6, 44.2, 47.0, 71.6, 125.0, 126.5, 127.0, 127.7, 128.2, 128.3, 128.5, 132.8, 133.9, 165.8; IR (film, cm-1) 2959, 2869, 1591; 25 [α] D -13.2 (c 0.19, CHCl3); LRMS (FAB) m/z 295.3 (M+H+); HRMS (FAB) calcd. for [C26H28N2+H]+ requires m/z 295.2174. Found 295.2170. 5.3.7 Characterization of Baylis-Hillman adducts. (56a) Methyl 2-(hydroxy (4-nitrophenyl) methyl) acrylate OH O O O2N 60% ee. Yang, K. S.; Lee, W. D; Pan, J. F. J. Org. Chem. 2003, 68, 915-919. HPLC conditions: Chiralcel OD-H column (Diacel); 96/4 hexane/2-propanol; Flow rate 0.5 mL/min; λ = 254 nm; 46.7 (major, R), 50.6 (minor, S) 2. (56b) Butyl 2-(hydroxyl (4-nitrophenyl) methyl) acrylate OH O O O2N 41% ee. Basavaiah, D.; Krishnamacharyulu, M.; Rao, A. J. Syn. Comm. 2000, 30, 2061-2069. HPLC conditions: Chiralcel OB-H column (Diacel); 95/5 hexane/2-propanol; Flow rate 1.0 mL/min; λ = 254 nm; 23.4 (minor), 26.2 Absolute configuration of 56a was assigned by comparing with the literature data: Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219. 109 Chapter (major). (56c) Benzyl 2-(hydroxy (4-nitrophenyl) methyl) acrylate OH O OBn O2N 48% ee. Yang, K. S.; Lee, W. D; Pan, J. F. J. Org. Chem. 2003, 68, 915-919. HPLC conditions: Chiralcel OD-H column (Diacel); 80/20 hexane/2-propanol; Flow rate 0.5 mL/min; λ = 254 nm; 15.4 (major), 17.5 (minor). (56d) Benzyl 2-(hydroxyl (3-nitrophenyl) methyl) acrylate OH O OBn NO 47% ee. Colorless oil. 1H NMR (300 MHz, CDCl3, ppm) δ 3.05 (bs, 1H), 5.14 (s, 2H), 5.64 (s, 1H), 5.95 (s, 1H), 6.46 (s, 1H), 7.24-7.34 (m, 5H), 7.48 (t, 1H, J = 8.0 Hz), 7.70 (d, 1H, J = 7.7 Hz), 8.11 (dd, 1H, J = 8.4, 1.1 Hz), 8.22 (s, 1H); 13C NMR (300 MHz, CDCl3, ppm) δ 66.9, 72.3, 121.5, 122.7, 127.4, 128.1, 128.4, 128.5, 129.3, 132.7, 135.0, 141.0, 143.5, 148.2, 165.6; IR (film, cm-1) 3498, 3020, 1712, 1531, 1351, 1216; LRMS (ESI) m/z 348.5 (M+Cl-); HRMS (ESI) calcd. for [C17H15NO5+Cl]- requires m/z 348.0639. Found 348.0640. HPLC conditions: Chiralcel OD-H column (Diacel); 95/5 hexane/2-propanol; Flow rate 1.0 mL/min; λ = 254 nm; 22.9 (major), 33.7 (minor). (56e) Benzyl 2-(hydroxy (2-nitrophenyl) methyl) acrylate 110 Chapter OH O OBn NO2 14% ee. Pale yellow oil. 1H NMR (300 MHz, CDCl3, ppm) δ 3.24 (bs, 1H), 5.15 (dd, 2H, J = 22.0, 12.2 Hz), 5.78 (s, 1H), 6.21 (s, 1H), 6.43 (s, 1H), 7.22-7.34 (m, 5H), 7.41-7.47 (1H, m), 7.57-7.63 (dt, 1H, J = 7.7, 1.1 Hz), 7.72 (dd, 1H, J = 7.7, 1.1 Hz), 7.9 (dd, 1H, J = 8.4, 1.1 Hz); 13C NMR (300 MHz, CDCl3, ppm) δ 66.8, 67.6, 124.6, 126.8, 128.0, 128.2, 128.5, 128.6, 128.8, 133.4, 135.3, 136.1, 140.6, 148.2; IR (film, cm-1) 3469, 3020, 1718, 1527, 1350, 1217; LRMS (ESI) m/z 336.1 (M+Na+); HRMS (ESI) calcd. for [C17H15NO5+Na]+ requires m/z 336.0848. Found 336.0855. HPLC conditions: Chiralcel OD-H column (Diacel); 95/5 hexane/2-propanol; Flow rate 1.0 mL/min; λ = 254 nm; 23.4 (minor), 29.9 (major). (56f) Benzyl 2-((4-cyanophenyl) (hydroxy) methyl) acrylate OH O OBn NC 48% ee. Colorless oil. 1H NMR (300 MHz, CDCl3, ppm) δ 3.15 (bs, 1H), 5.14 (s, 2H), 5.58 (s, 1H), 5.91 (s, 1H), 6.43 (s, 1H), 7.23-7.35 (m, 5H), 7.47 (d, 2H, J = 8.4 Hz), 7.58 (d, 2H, J = 8.4 Hz); 13 C NMR (300 MHz, CDCl3, ppm) δ 66.8, 72.5, 111.3, 118.6, 127.1, 127.2, 128.1, 128.4, 128.5, 132.1, 135.1, 141.1, 146.6, 165.6; IR (film, cm-1) 3473, 3020, 2231, 1716, 1630, 1500, 1456, 1317; LRMS (ESI) m/z 328.5 (M+Cl-); HRMS (ESI) calcd. for [C18H15NO3+Cl]- requires m/z 328.0740. Found 328.0741. HPLC conditions: Chiralcel OD-H column (Diacel); 95/5 hexane/2-propanol; Flow rate 1.0 mL/min; λ = 254 nm; 28.5 (major), 36.6 111 Chapter (minor). (56g) Benzyl 2-((2-chloro-5-nitrophenyl) (hydroxy) methyl) acrylate OH O O 2N OBn Cl 31% ee. Colorless oil. 1H NMR (300 MHz, CDCl3, ppm) δ 3.57 (bs, 1H), 5.21 (dd, 2H, J = 16.0, 12.2 Hz), 5.67 (s, 1H), 5.99 (s, 1H), 6.45 (s, 1H), 7.30-7.37 (m, 5H), 7.50 (d, 1H, J = 8.7 Hz), 8.09 (dd, 1H, J = 8.7, 2.8 Hz), 8.45 (d, 1H, J = 2.8 Hz); 13C NMR (300 MHz, CDCl3, ppm) δ 67.0, 69.0, 123.6, 123.7, 128.0, 128.1, 128.4, 128.6, 130.4, 135.1, 139.4, 139.6, 140.5, 146.8, 165.8; IR (film, cm-1) 3483, 3020, 1718, 1527, 1462, 1348; LRMS (ESI) m/z 382.2 (M+Cl-); HRMS (ESI) calcd. for [C17H14ClNO5+Cl]- requires m/z 382.0249. Found 382.0252. HPLC conditions: Chiralcel OD-H column (Diacel); 95/5 hexane/2-propanol; Flow rate 1.0 mL/min; λ = 254 nm; 19.3 (major), 23.3 (minor). (58a) 3-(Hydroxy (4-nitrophenyl) methyl) but-3-en-2-one OH O O2 N 60% ee. Shi, M.; Jiang, J. K. Tetrahedron: Asymmetry 2002, 13, 1941-1497. HPLC conditions: Chiralcel OJ-H column (Diacel); 96/4 hexane/2-propanol; Flow rate 1.0 mL/min; λ = 254 nm; 71.6 (minor, S), 75.6 (major, R).3 Absolute configuration of 58a was assigned by comparing with the literature data: Shi, M.; Jiang, J. K. Tetrahedron: Asymmetry 2002, 13, 1941. 112 Chapter (58b) 3-(Hydroxy (3-nitrophenyl) methyl) but-3-en-2-one OH O NO2 67% ee. Shi, M.; Li, C. Q.; Jiang, J. K. Chem.Comm. 2001, 9, 833-834. HPLC conditions: Chiralcel OD-H column (Diacel); 96/4 hexane/2-propanol; Flow rate 0.5 mL/min; λ = 254 nm; 49.3 (major), 53.0 (minor). (58c) 4-(1-Hydroxy-2-methylene-3-oxobutyl) benzonitrile OH O NC 54% ee. Colorless oil. 1H NMR (300 MHz, CDCl3, ppm) δ 2.34 (s, 3H), 5.62 (s, 1H), 6.01 (s, 1H), 6.25 (s, 1H), 7.49 (d, 2H, J = 8.4 Hz), 7.63 (d, 2H, J = 8.4 Hz); 13 C NMR (300 MHz, CDCl3, ppm) δ 26.3, 72.1, 111.3, 118.7, 127.1, 127.4, 132.1, 147.0, 149.1, 200.0; IR (film, cm-1) 3466, 3020, 2230, 1674, 1217; LRMS (FAB) m/z 202.1 (M+H+); HRMS (FAB) calcd. for [C12H11NO2+H]+ requires m/z 202.0868. Found. 202.0866. HPLC conditions: Chiralcel AS-H hexane/2-propanol; Flow rate 0.75 mL/min; λ = column (Diacel); 90/10 254 nm; 33.4 (major), 40.5 (minor). (58d) 3-(Hydroxy (4-(trifluoromethyl) phenyl) methyl) but-3-en-2-one OH O F3C 47% ee. Lin, Y. S.; Liu, C. W.; Tsai, T. Y. R. Tetrahedron Lett. 2005, 46, 1859-1861. 113 Chapter HPLC conditions: Chiralcel AS-H column (Diacel); 90/10 hexane/2-propanol; Flow rate 0.75 mL/min; λ = 254 nm; 8.5 (major), 9.9 (minor). (58e) 2-(Hydroxy (4-nitrophenyl) methyl) pent-1-en-3-one OH O O2N 77% ee. Shi, M.; Li, C. Q.; Jiang, J. K. Tetrahedron 2003, 59, 1181-1189. HPLC conditions: Chiralcel OD-H column (Diacel); 90/10 hexane/2-propanol; Flow rate 0.75 mL/min; λ = 254 nm; 13.1 (major), 15.2 (minor). (58f) 2-(Hydroxyl (3-nitrophenyl) methyl) pent-1-en-3-one OH O NO2 75% ee. Shi, M.; Li, C. Q.; Jiang, J. K. Tetrahedron 2003, 59, 1181-1189. HPLC conditions: Chiralcel OD-H column (Diacel); 95/5 hexane/2-propanol; Flow rate 0.75 114 Chapter mL/min; λ = 254 nm; 22.1 (major), 24.8 (minor). (58g) 1-Cyclohexyl-2-(hydroxy (4-nitrophenyl) methyl) prop-2-en-1-one4 OH O O2N 78% ee. Colorless oil. 1H NMR (300 MHz, CDCl3, ppm) δ 1.13-1.31 (m, 5H), 1.60-1.75 (m, 5H), 2.93-2.99 (m, 1H), 3.49 (d, 1H, J = 5.8 Hz), 5.62 (d, 1H, J = 5.8 Hz), 5.99 (s, 1H), 6.22 (s, 1H), 7.53 (d, 2H, J = 8.7 Hz), 8.18 (d, 2H, J = 8.7 Hz); 13C NMR (300 MHz, CDCl3, ppm) δ 25.5, 25.6, 25.7, 29.1, 29.2, 45.5, 73.2, 123.5, 125.8, 127.1, 128.4, 147.5, 149.1, 206.2; IR (film, cm-1) 3445, 3021, 2936, 1665, 1523, 1349, 1216; LRMS (ESI) m/z 288.5 (M-H-); HRMS (ESI) calcd. for [C16H18NO4-H]requires m/z 288.1236. Found 288.1228. HPLC conditions: Chiralcel AD-H column (Diacel); 95/5 hexane/2-propanol; Flow rate 0.75 mL/min; λ = 254 nm; 24.8 (major), 27.8 (minor). (58h) 1-Cyclohexyl-2-(hydroxy (3-nitrophenyl) methyl) prop-2-en-1-one OH O NO2 68% ee. Colorless oil. 1H NMR (500 MHz, CDCl3, ppm) δ 1.14-1.31 (m, 5H), 1.66-1.77 (m, 5H), 2.95-2.99 (m, 1H), 3.49 (bs, 1H), 5.62 (s, 1H), 6.02 (s, 1H), 6.24 (s, 1H), 7.50 (t, 1H, J = 8.2 Hz), 7.72 (d, 1H, J = 7.6 Hz), 8.11-8.13 (m, 1H), 8.20 (s, 1H); The starting material cylcohexyl vinyl ketone was synthesized through a reported protocol: Hammen, P. D., Braisted, A. C., Northrup, D. L. Syn. Comm. 1991, 21, 2157-2163. 115 Chapter 13 C NMR (500 MHz, CDCl3, ppm) δ 25.5, 25.6, 25.7, 29.1, 29.2, 45.5, 73.1, 121.2, 122.5, 125.8, 129.3, 132.5, 144.1, 147.4, 206.3; IR (film, cm-1) 3413, 1020, 2934, 1532; LRMS (FAB) m/z 289.1 (M+); HRMS (FAB) calcd. for [C16H19NO4]+ requires m/z 289.1314. Found 289.1322. HPLC conditions: Chiralcel AD-H column (Diacel); 95/5 hexane/2-propanol; Flow rate 1.0 mL/min; λ = 254 nm; 17.5 (minor), 24.8 (major). (58i) 4-[2-(Cyclohexanecarbonyl)-1-hydroxyallyl] benzonitrile OH O NC 69% ee. Colorless oil. 1H NMR (300 MHz, CDCl3, ppm) δ 1.13-1.34 (m, 5H), 1.67-1.75 (m, 5H), 2.92-2.98 (m, 1H), 5.58 (s, 1H), 5.96 (s, 1H), 6.19 (s, 1H), 7.47 (d, 2H, J = 8.4 Hz), 7.61 (d, 2H, J = 8.4 Hz); 13C NMR (500 MHz, CDCl3, ppm) δ 25.5, 25.6, 25.7, 29.1, 29.2, 45.5, 73.3, 111.3, 118.7, 125.5, 127.0, 132.1, 147.1, 147.6, 206.2; IR (film, cm-1) 3439, 3020, 2936, 2231, 1663, 1216; LRMS (EI) m/z (M-H-) 268.1; HRMS (EI) calcd. for [C17H18NO2]- requires m/z 268.1338. Found 268.1336. HPLC conditions: Chiralcel OJ-H column (Diacel); 90/10 hexane/2-propanol; Flow rate 0.75 mL/min; λ = 254 nm; 16.6 (minor), 20.7 (major). 116 [...]... 6H); 13 C NMR ( 75 MHz, CDCl3, ppm) δ 23.7, 24.3, 29 .5, 36.2, 36.6, 41 .5, 41.6, 49.7, 66.1, 66.8, 119.0, 119.4, 128.8, 128.9, 133.9 (two peaks), 136.4, 136 .5, 1 45. 5, 1 45. 9, 192.6, 192.8, 193.4 (two peaks), 2 05. 4, 2 05. 5; IR (film, cm-1) 3021, 17 25, 1693, 1 657 , 1216; LRMS (ESI) m/z 353 .0 [M+Na]+; HRMS (ESI) calcd 25 for [C19H22O3SNa]+ requires m/z 353 .1187 Found 353 .1183 [α] D -108 ( c = 0 .54 , CHCl3); HPLC... 4 .55 (d, 1H, J = 9.4 Hz, major diastereomer), 4.61 (d, 1H, J = 10.1 Hz, minor diastereomer), 5. 02 (d, 1H, J = 2 .5 Hz, major diastereomer), 5. 38 (d, 1H, J = 1.9 Hz, minor diastereomer), 5. 90 (d, 1H, J = 2 .5 Hz, major diastereomer), 6.09 (d, 1H, J = 2 .5 Hz, minor diastereomer), 6.94-6.97 (m, 5H), 8.01-8.04 (m, 5H); 13C NMR (1 25 MHz, CDCl3, ppm) δ 23.8, 24.3, 29 .5, 36.3, 36.6, 41 .5, 41.6, 49.6, 55 .5 (two... 73.7, 124.9 1 25. 5, 1 25. 9, 126.2, 127 .5, 127.9, 128.2 (two peaks), 128 .5, 129 .5, 132.3, 132 .5, 133.2, 139.0, 1 65. 3; IR (film, 25 cm-1) 2 954 , 2869, 16 15, 159 4, 1409; [α] D +7.9 (c 4.28, CHCl3); LRMS (FAB) m/z 357 .3 (M+H+); HRMS (FAB) calcd for [C26H28N2+H]+ requires m/z 357 .2321 Found 357 .2324 (53 j) (S)-4-tert-Butyl-1-isopropyl-2-(naphthalen-2-yl)-4, 5- dihydro-1H-imidazole N N 108 Chapter 5 Yellow oil 1H... Hz), 3 .52 (t, 1H, J = 10.1 Hz), 3.83-3.97 (m, 2H), 7 .50 -7 .55 (m, 3H), 7.83-7.91 (m, 3H), 8. 05 (s, 1H); 13 C NMR (300 MHz, CDCl3, ppm) δ 19 .5, 20.6, 25. 8, 34.6, 44.2, 47.0, 71.6, 1 25. 0, 126 .5, 127.0, 127.7, 128.2, 128.3, 128 .5, 132.8, 133.9, 1 65. 8; IR (film, cm-1) 2 959 , 2869, 159 1; 25 [α] D -13.2 (c 0.19, CHCl3); LRMS (FAB) m/z 2 95. 3 (M+H+); HRMS (FAB) calcd for [C26H28N2+H]+ requires m/z 2 95. 2174 Found... 1 .51 -1 .59 (m, 1H), 1. 85- 1. 95 (m, 2H), 2.03-2.49 (m, 9H), 3.90-3. 95 (m, 1H each for two diastereomers), 4.61 (d, 1H, J = 9.8 Hz, major diastereomer), 4.73 (d, 1H, J = 9.8 Hz, minor diastereomer), 5. 03 (d, 1H, J = 2.4 Hz, major diastereomer), 5. 39 (d, 1H, J = 1 .5 Hz, minor diastereomer), 5. 92 (d, 1.5H, J = 2.4 Hz), 6.10 (d, 1H, J = 2 .5 Hz), 7.46-7 .52 (m, 6H), 7 .58 -7.61 (m, 3H), 90 Chapter 5 8.01-8. 05. .. 13C NMR (1 25 MHz, CDCl3, ppm) δ 21.9, 29.8 (two peaks), 31.9, 33.9, 36.2, 41.4, 41 .5, 43.0, 45. 0, 45. 4, 50 .6, 52 .1, 52 .4, 62.7, 70.9, 133.3, 140.8, 192.8, 193 .5, 219.3; IR (film, cm-1) 2911, 2 852 , 1727, 1679, 1 452 , 1 253 ; LRMS (ESI) m/z 56 5.2 [M+H]+; HRMS (ESI) calcd for [C34H44O3S2Na]+ 25 requires m/z 58 7.2630 Found 58 7.2624 [α] D -14.2 ( c = 0.86, CHCl3) (33) S,S'-di-tert-Butyl 2-((1R,2R)-2-((1H-pyrazol-1-yl)methyl)-3-oxocyclopentyl)... 3. 15 (bs, 1H), 5. 14 (s, 2H), 5. 58 (s, 1H), 5. 91 (s, 1H), 6.43 (s, 1H), 7.23-7. 35 (m, 5H), 7.47 (d, 2H, J = 8.4 Hz), 7 .58 (d, 2H, J = 8.4 Hz); 13 C NMR (300 MHz, CDCl3, ppm) δ 66.8, 72 .5, 111.3, 118.6, 127.1, 127.2, 128.1, 128.4, 128 .5, 132.1, 1 35. 1, 141.1, 146.6, 1 65. 6; IR (film, cm-1) 3473, 3020, 2231, 1716, 1630, 150 0, 1 456 , 1317; LRMS (ESI) m/z 328 .5 (M+Cl-); HRMS (ESI) calcd for [C18H15NO3+Cl]- requires... 132.4, 1 65. 4; IR (film, cm-1) 2 954 , 2868, 25 159 6, 1497; [α] D -37 .5 (c 6.22, CHCl3); LRMS (FAB) m/z 2 45. 1 (M+H+); HRMS (FAB) [C16H24N2+H] + requires m/z 2 45. 2018 Found 2 45. 2014 104 Chapter 5 (53 b) (S)-4-Benzyl-1-isopropyl-2-phenyl-4, 5- dihydro-1H-imidazole Bn N N Ph Yellow oil 1H NMR (50 0 MHz, CDCl3, ppm) δ 0.78 (d, 3H, J = 6.9 Hz), 0.94 (d, 3H, J = 6.9 Hz), 2. 75 (dd, 1H, J = 13.4, 8.3 Hz), 3. 05- 3.13... Chapter 5 1H), 3 .50 (d, 1H, J = 10.1 Hz), 4.41 (d, 1H, J = 6.3 Hz), 5. 03 (t, 1H, J = 1.9 Hz), 5. 20 (t, 1H, J = 1.9 Hz); 13C NMR (1 25 MHz, CDCl3, ppm) δ 25. 6, 29.8, 33.8, 36.2, 41 .5, 42.2, 52 .2 (two peaks), 73 .5, 74.6, 109.8, 154 .3, 192.6, 192.9; IR (film, cm-1) 3446, 3021, 2914, 2401, 1703, 1216; LRMS (ESI) m/z 50 1.2 [M+H]+; HRMS (ESI) calcd 25 for [C29H40O3S2+Na]+ requires m/z 52 3.2317 Found 52 3.2314... 1H NMR (50 0 MHz, CDCl3, ppm) δ 1.00 (s, 9H), 1.02 (s, 9H), 1 .53 -1 .59 (m, 14H), 1.70-1.80 (m, 3H), 1.87-1.91 (dd, 2H, J = 15. 2, 5. 7 Hz), 2.06-2.12 (m, 1H), 2.27-2.42 (m, 2H), 3.66 (d, 1H, J = 10.1 Hz), 3.69-3.74 (m, 1H), 5. 31 (d, 1H, J = 1.9 Hz), 6. 05 (d, 1H, J = 2 .5 Hz); 13C NMR (1 25 MHz, CDCl3, ppm) δ 23.7, 29.1, 29.2, 29 .5, 31.6, 32.6 (two peaks), 36.3, 41.3, 53 .2, 53 .3, 54 .7 (two 88 Chapter 5 peaks), . 8.1 Hz); 13 C NMR ( 75 MHz, CDCl 3 , ppm) δ 21.4, 24.1, 25. 5, 26.7, 34.3, 54 .7, 59 .4, 59 .7, 127.0, 129.1, 139 .5, 142.4; IR (film, cm -1 ) 33 95, 2940, 1600, 14 75, 1316, 1 155 , 1094; LRMS (ESI). 1.9 Hz); 13 C NMR (1 25 MHz, CDCl 3 , ppm) δ 23.7, 29 .5, 29.6, 36.3, 41.3, 49 .5, 49.6, 72.4, 119 .5, 1 45. 1, 192.4, 192 .5, 2 05. 2; IR (film, cm -1 ); 3021, 2926, 2 855 , Chapter 5 88 2401, 1690,. 49.6, 55 .5 (two peaks), 65. 8, 66 .5, 114.1 (two peaks), 119.0, 119.3, 129.4, 129.6, 131.3, 131.3, 1 45. 7, 146.0, 164.2 (two peaks), 190.8, 191.0, 193.6, 193.7, 2 05. 5, 2 05. 6; IR (film, cm -1 ) 30 15,