Supporting Information

Supporting Information Wiley-VCH 2006 69451 Weinheim, Germany

Catalytic, Enantioselective Crossed Aldehyde Ketone Benzoin Cyclization Hiroshi Takikawa, Yoshifumi Hachisu, Jeffrey W. Bode, and Keisuke Suzuki * [*] Department of Chemistry, Tokyo Institute of Technology, SRST JST Agency, 2-12-1 -okayama, guro-ku, Tokyo 152-8551 (Japan) [ Present address] Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106-9510, (USA) Experimental Section General thods: All reactions utilizing air- or moisture-sensitive reagents were performed in dried glassware under an atmosphere of dry Ar and N 2. Substrates 3, 14, 15 were prepared by our previously reported methods. [1] Substrates 8 13 were prepared by literature procedures. [2] Catalysts 5, 7, 2a, 2b were prepared by literature methods. [3,4] Ethereal solvents (anhydrous; Kanto Chemical Co., Inc.) were used as received. t-buh was distilled prior to use. CH 2 Cl 2 was distilled successively from P 2 5 and CaH 2, and stored over 4A molecular sieves. DBU was distilled from Ba. Kt-Bu was purified by sublimation. Et 3 N was distilled from KH. ther reagents were used without further purification. Thin layer chromatography (TLC) was performed on rck precoated plates (silica gel 60 F254, Art 5715, 0.25 mm) and were visualized by fluorescence quenching under UV light or by staining with phosphomolybdic acid. Silica-gel preparative thin-layer chromatography (PTLC) was [1] a) J. W. Bode, T. Matsuura, Y. Hachisu, K. Suzuki, Tetrahedron Lett. 2003, 44, 3555 3558; b) T. Matsuura, J. W. Bode, Y. Hachisu, K. Suzuki, Synlett 2003, 11, 1746 1748; c) Y. Hachisu, J. W. Bode, K. Suzuki, J. Am. Chem. Soc. 2003, 125, 8432 8433. [2] Y. Hachisu, J. W. Bode, K. Suzuki, Adv. Synth. Catal. 2004, 346, 1097 1100. [3] R. L. Knight, F. J. Leeper, Tetrahedron Lett. 1997, 38, 3611 3614. [4] R. L. Knight, F. J. Leeper, J. Chem. Soc., Perkin Trans. 1 1998, 1891 1893. Page 1

performed using plates prepared from rck Kieselgel 60 PF 254 (Art 7747). Column chromatography was performed on E. rck Silica Gel 60 (230 400 sh) using a forced flow of 0.5 1.0 bar. lting point (m.p.) determinations were performed using a Yanaco MP-S3 instrument and are uncorrected. 1 H NMR and 13 C NMR were measured on a JEL JMN Lambda-300 or Lambda-400 spectrometer. Chemical shifts are expressed in parts per million (PPM) downfield from internal tetramethylsilane (δ = 0), and coupling constants are reported as hertz (Hz). Splitting patterns are indicated as follows: br, broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. Infrared (IR) spectra were recorded on a Jasco IRA-202 spectrophotometer and are reported as wavenumbers (cm 1 ). High performance liquid chromatography (HPLC) analyses were performed using a JASC C-2060 plus for intelligent column thermostat, UV-2077 plus for intelligent UV/VIS detector, PU-1580 for intelligent HPLC pump, DG-2080-53 for 3-line degasser and LG-2080-02 for ternary gradient unit. Gas chromatography (GC) analyses were performed using a SHIMADZU gas chromatograph GC-17A. Enantiomeric excesses were assessed by HPLC analysis on chiral columns, CHIRALPAK AD-H or CHIRALCEL D-H (Daicel Chemical Ind., Ltd.) and GC analysis on a capillary column, CHRMPACK Chirasil-Dex CB (GL Sciences Inc. Japan). General Procedure for Benzoin Cyclization of a Keto-aldehyde: The reaction of 3 is representative. A mixture of 3 (934 mg, 3.10 mmol) and triazolium salt 2b (101 mg, 0.310 mmol) in anhydrous THF (8.75 ml) was degassed by three cycles of freeze-pumpthaw. To the mixture was added a degassed 0.40 M THF solution of DBU (0.78 ml, 0.31 mmol) dropwise at room temperature under a nitrogen atmosphere. After stirring at this temperature for 12 h, the reaction was cooled to 0 C, and water was added. The products were extracted with CH 2 Cl 2 (30 ml x 1) and EtAc (30 ml x 2). The combined organic extracts were dried over Na 2 S 4 and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (EtAc/CH 2 Cl 2 /hexane = 3/4/3) to give benzoin product 4 (92%, 99% ee) as a yellow solid. Recrystallization from EtAc gave enantiomerically pure 4 (75%, >99% ee) as Page 2

colorless needles. The enantiomeric excess was assessed by HPLC analysis on a chiral column: CHIRALPAK AD-H. (eluent: 2-propanol:hexane = 13:87, flow rate: 1.0 ml/min, 25 C) MM N H 4 Spectroscopic data of 4: colorless solid, m.p. 224 225 C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.75 (dd, 1 H, J = 6.6, 2.4 Hz), 7.47 7.55 (m, 2 H), 5.37 (d, 1 H, J = 7.1 Hz), 5.34 (d, 1 H, J = 7.1 Hz), 3.53 (s, 3 H), 2.99 (dd, 1 H, J = 16.3, 6.4 Hz), 2.62 2.74 (m, 1 H), 2.58 (bs, 1 H), 2.18 2.46 (m, 3 H), 1.64 (td, 1 H, J = 14.2, 3.2 Hz); 13 C NMR (100 MHz, CDCl 3 ) δ 195.1, 171.1, 154.0, 153.3, 133.3, 131.5, 122.9, 120.4, 117.8, 113.6, 94.4, 67.1, 56.4, 28.9, 22.3, 17.8; IR (KBr) 3484, 2957, 1702, 1665, 1576, 1264, 1155, 1012, 911, 801 cm 1 ; Anal. Calc d for C 16 H 15 N 5 : C, 63.78; H, 5.02; N, 4.65, Found: C, 63.74; H, 5.25; N, 4.43; HPLC (CHIRALPAK AD-H, eluent: 2-propanol:hexane = 13:87, flow rate: 1.0 ml/min, 25 C): (R)-4: t 1 = 21.4 min; (S)-4: t 2 = 32.9 min; [α] 21 D +30.5 (CHCl 3, c 0.50) for >99% ee. MM N 26 To a solution of 4 (34.2 mg, 0.114 mmol) in CH 2 Cl 2 (1.1 ml) at 0 C was added (S)- camphanic chloride (36.9 mg, 0.170 mmol) and DMAP (22.2 mg, 0.182 mmol). The reaction mixture was warmed to room temperature and stirred for 15 min. The reaction was quenched by addition of saturated aq NH 4 Cl solution, and the products were extracted with EtAc (10 ml x 3). The combined organic extracts were washed with brine, dried over Na 2 S 4 and concentrated under reduced pressure. The residue was purified by silica-gel preparative thin-layer chromatography (EtAc/CH 2 Cl 2 /hexane = 5/3/2) to afford (S)-camphanyl derivative 26 as colorless solid (53.0 mg, 97 %). Page 3

Recrystallization from EtAc gave a single crystal of 26 for the X-ray analysis. The spectroscopic data of 26; colorless solid, m.p. 167 C (decomp.); 1 H NMR (300 MHz, CDCl 3 ) δ 7.64 (dd, 1 H, J = 6.6, 2.4 Hz), 7.49 7.54 (m, 2 H), 5.43 (d, 1 H, J = 7.1 Hz), 5.40 (d, 1 H, J = 7.1 Hz), 3.54 (s, 3 H), 2.97 3.05 (m, 1 H), 2.58 2.80 (m, 2 H), 2.25 2.34 (m, 3 H), 1.75 1.97 (m, 3 H), 1.56 1.65 (m, 1 H), 1.03 (s, 3 H), 0.85 (s, 3 H), 0.55 (s, 3 H); 13 C NMR (75 MHz, CDCl 3 ) δ 192.5, 177.9, 171.7, 166.2, 154.1, 153.7, 134.9, 131.7, 122.3, 120.6, 118.0, 111.3, 94.8, 90.4, 76.1, 56.5, 54.8, 54.5, 30.3, 28.8, 27.7, 22.1, 18.0, 16.5, 16.0, 9.6; IR (KBr) 2970, 2943, 2879, 1782, 1751, 1689, 1654, 1574, 1485, 1281, 1207, 1109, 1057, 939, 885, 835, 768, 729 cm 1 ; Anal. Calc d for C 26 H 27 N 8 : C, 64.86; H, 5.65; N, 2.91, Found: C, 65.12; H, 5.67; N, 2.72; [α] 22 D +14.0 (CHCl 3, c 1.00). CCDC 245398 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or deposit@ccdc.cam.ac.uk). Spectroscopic data of chiral triazolium salts N N + N Cl 2a Spectroscopic data of 2a: light tan solid, m.p. 142 145 C; 1 H NMR (400 MHz, CDCl 3 ) δ 13.2 (s, 1 H), 8.11 (d, 2 H, J = 9.2 Hz), 8.07 (d, 1 H, J = 7.2 Hz), 7.28 7.35 (m, 2 H), 7.20 (d, 1 H, J = 6.8 Hz), 6.94 (d, 2 H. J = 9.2 Hz), 6.38 (bd, 1 H, J = 3.6 Hz), 5.05 (s, 2 H), 5.02 (brd, 1 H, J = 3.6 Hz), 3.82 (s, 3 H), 3.10 (brs, 2 H); 13 C NMR (75 MHz, CDCl 3 ) δ 160.8, 149.0, 140.7, 139.8, 135.0, 129.4, 128.1, 127.7, 125.10, 125.06, 121.8, 114.9, 77.6, 62.1, 60.2, 55.5, 37.2; IR (KBr) 3417, 2935, 1606, 1579, 1537, 1508, 1392, 1259, 1176, 1101, 1053, 1022, 972, 837, 769, 742 cm 1 ; Anal. Calc d for C 19 H 18 ClN 3 2 : C, Page 4

64.13; H, 5.10; N, 11.81, Found: C, 64.06; H, 5.38; N, 11.51; [α] D 28 +263 (CHCl 3, c 1.00). N N + N Cl 2b Spectroscopic data of 2b: colorless solid, m.p. 243 244 C; 1 H NMR (300 MHz, CDCl 3 ) δ 13.5 (s, 1 H), 8.18 8.22 (m, 2 H), 8.11 (bd, 1 H, J = 6.6 Hz), 7.39 7.50 (m, 3 H), 7.27 7.35 (m, 2 H), 7.19 (bd, 1 H, J = 6.6 Hz), 6.41 (d, 1 H, J = 4.5 Hz), 5.06 (s, 2 H), 5.03 (td, 1 H, J = 4.5, 1.5 Hz), 3.08 (brd, 1 H, J = 16.8 Hz), 3.00 (dd, 1 H, J = 16.8, 4.5 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 149.3, 141.9, 139.9, 135.02, 134.96, 130.3, 130.0, 129.5, 127.7, 125.2, 125.1, 120.2, 77.7, 62.3, 60.3, 37.2; IR (KBr) 3420, 3022, 2910, 1587, 1531, 1462, 1390, 1252, 1101, 1053, 970, 769, 744, 687 cm 1 ; Anal. Calc d for C 18 H 16 ClN 3: C, 66.36; H, 4.95; N, 12.90, Found: C, 66.10; H, 5.01; N, 12.67; [α] 23 D +316 (CHCl 3, c 1.00). Benzoin cyclization for keto-aldehyde substrates. Table 2, entry 1 8 Spectroscopic data of 8 [5] : colorless liquid; 1 H NMR (400 MHz, CDCl 3 ) δ 9.77 (t, 1 H, J = 1.6 Hz), 2.42 2.52 (m, 4 H), 2.15 (s, 3 H), 1.57 1.70 (m, 4 H); 13 C NMR (100 MHz, CDCl 3 ) δ 208.4, 202.2, 43.6, 43.2, 29.9, 23.1, 21.4; IR (neat) 1712 cm 1 (C=). [5] a) J. -X. Chen, K. Sakamoto, A. rita, J. tera, J. rg. Chem. 1998, 63, 9739 9745.; b) Ref. 2. Page 5

H 16 Spectroscopic data of 16 [6] : colorless liquid; 1 H NMR (400 MHz, CDCl 3 ) δ 3.94 (s, 1 H), 2.45 2.62 (m, 2 H), 2.05 2.20 (m, 2 H), 1.56 1.88 (m, 4H), 1.41 (s, 3 H); 13 C NMR (CDCl 3 ) δ 214.4, 76.4, 42.0, 37.7, 27.8, 25.0, 23.0; IR (neat) 3483, 2939, 2866, 1714, 1450, 1373, 1185, 1120 cm 1 ; GC (CHRMPACK Chirasil-Dex CB, flow rate: 50.0 ml/min, 150 C): (S)-16: t 1 = 5.6 min; (R)-16: t 2 = 5.8 min; [α] 28 D +106 (CHCl 3, c 0.96) for 96% ee; Lit. [7] [α] 22 D +100.5 (CHCl 3, c 0.962) for 95% ee. 27 Spectroscopic data of 27: colorless solid, m.p. 139 140 C; 1 H NMR (400 MHz, CDCl 3 ) δ 2.37 2.56 (m, 4 H), 1.67 2.07 (m, 8 H), 1.51 (s, 3 H), 1.12 (s, 3 H), 1.11 (s, 3 H), 1.04 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ 206.3, 177.9, 166.1, 90.6, 85.2, 54.8, 54.3, 39.0, 38.9, 30.5, 28.9, 27.0, 21.83, 21.79, 16.7, 16.6, 9.6; IR (KBr) 2966, 2937, 2871, 1782, 1753, 1718, 1441, 1381, 1313, 1284, 1228, 1171, 1109, 1062, 1020, 939 cm 1 ; Anal. Calc d for C 17 H 24 5 : C, 66.21; H, 7.84, Found: C, 65.94; H, 7.89; [ ] 29 D +27.8 (CHCl 3, c 1.04). CCDC 290474 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or deposit@ccdc.cam.ac.uk). [6] B. K. Bettadaiah, K. N. Gurudutt, P. Srinivas, J. rg. Chem. 2003, 68, 2460 2462. [7] T. Fujisawa, M. Watanabe, T. Sato, Chem. Lett. 1984, 2055 2058. Page 6

Table 2, entry 2 9 Spectroscopic data of 9: colorless liquid; 1 H NMR (400 MHz, CDCl 3 ) δ 10.2 (s, 1 H), 7.80 (dd, 1 H, J = 7.5, 1.5 Hz), 7.51 (td, 1 H, J = 7.5, 1.5 Hz), 7.41 (td, 1 H, J = 7.5, 1.2 Hz), 7.32 (d, 1 H, J = 7.5 Hz), 3.29 (t, 2 H, J = 7.5 Hz), 2.77 (t, 2 H, J = 7.5 Hz), 2.15 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ 207.5, 192.9, 143.5, 133.83, 133.80, 133.76, 131.4, 126.9, 44.8, 29.9, 27.1; IR (neat) 3073, 2942, 2899, 2747, 1708, 1694, 1599, 1574, 1362, 1207, 1191, 1158, 761 cm 1. H 17 Spectroscopic data of 17: colorless liquid; 1 H NMR (400 MHz, CDCl 3 ) δ 8.04 (d, 1 H, J = 8.0 Hz), 7.52 (dd, 1 H, J = 7.7, 7.5 Hz), 7.35 (t, 1 H, J = 7.7, 8.0 Hz), 7.26 (d, 1 H, J = 7.5 Hz), 3.87 (s, 1 H), 2.97 3.18 (m, 2 H), 2.17 2.31 (m, 2 H), 1.40 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ 201.8, 143.4, 134.0, 129.9, 129.0, 128.0, 126.9, 73.6, 35.8, 26.8, 23.9; IR (neat) 3489, 3066, 3026, 2972, 2933, 2864, 1689, 1603, 1455, 1371, 1290, 1222, 1155, 1097, 971, 796, 742 cm 1 ; HPLC (CHIRALCEL D-H, eluent: 2- propanol:hexane = 0.25:99.75, flow rate: 1.0 ml/min, 25 C): (R)-17: t 1 = 22.2 min; (S)- 17: t 2 = 26.3 min; [α] 30 D +16.4 (CHCl 3, c 2.00) for 96% ee; Lit. [8] [α] D +17.3 (CHCl 3, c 2.00) for =95% ee. 28 [8] a) F. A. Davis, M. C. Weismiller, C. K. Murphy, R. T. Reddy, B. C., Chen, J. rg. Chem. 1992, 57, 7274 7285; b) F. A. Davis, M. C. Weismiller, J. rg. Chem. 1990, 55, 3715 3717. Page 7

Spectroscopic data of 28: colorless solid, m.p. 187 188 C; 1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, 1 H, J = 7.6 Hz), 7.49 7.52 (m, 1 H), 7.32 7.36 (m, 1 H), 7.23 7.26 (m, 1 H), 3.02 3.11 (m, 3 H), 2.42 2.49 (m, 1 H), 2.04 2.17 (m, 2 H), 1.89 1.96 (m, 1 H), 1.65 1.72 (m, 1 H), 1.61 (s, 3 H), 1.11 (s, 6 H), 0.99 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ 193.7, 178.1, 165.7, 141.8, 133.8, 130.8, 128.6, 128.3, 127.0, 90.8, 82.7, 54.9, 54.5, 33.2, 30.6, 29.1, 26.8, 21.7, 16.6, 16.4, 9.7; IR (KBr) 2978, 2947, 2883, 1785, 1751, 1697, 1603, 1456, 1315, 1289, 1224, 1171, 1113, 1065, 937, 744 cm 1 ; Anal. Calc d for C 21 H 24 5 : C, 70.77; H, 6.79, Found: C, 70.50; H, 6.91; [ ] 29 D +24.8 (CHCl 3, c 1.00). CCDC 290472 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or deposit@ccdc.cam.ac.uk). Table 2, entry 3 H 18 Spectroscopic data [9] of 18: colorless oil; 1 H NMR (CDCl 3 ) 7.78 (d, 1 H, J = 7.7 Hz), 7.64 (t, 1 H, J = 7.7 Hz), 7.44 (d, 1 H, J = 7.3 Hz), 7.41 (dd, 1 H, J = 7.7, 7.3 Hz), 3.28 (d, 1 H, J = 16.8 Hz), 3.22 (d, 1 H, J = 16.8 Hz), 2.81 (s, 1 H), 1.45 (s, 3 H); 13 C NMR (CDCl 3 ) 208.0, 151.1, 135.8, 133.5, 127.9, 126.7, 124.9, 77.4, 42.2, 25.7; IR (neat) 3434, 3072, 2970, 2925, 1716, 1608, 1468, 1431, 1367, 1300, 1219, 1092, 958, 893, 739 cm 1 ; HPLC (CHIRALCEL D-H, eluent: 2-propanol:hexane = 1:99, flow rate: 1.0 ml/min, 25 C): (S)-18: t 1 = 26.0 min; (R)-18: t 2 = 29.9 min; [ ] 30 D +24.9 (CHCl 3, c 1.40) for 60% ee; Lit.* [ ] D +33.4 (CHCl 3, c 1.4) for 78% ee. [9] H. Ziehe, R. Wartchow, H. Butenschoen, Eur. J. rg. Chem. 1999, 823 835. Page 8

29 Spectroscopic data of 29: colorless solid, m.p. 211 212 C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (d, 1 H, J = 7.2 Hz), 7.65 (t, 1 H, J = 7.2 Hz), 7.41 7.44 (m, 2 H), 3.58 (d, 1 H, J = 16.4 Hz), 3.23 (d, 1 H, J = 16.4 Hz), 2.42 2.49 (m, 1 H), 2.05 2.12 (m, 1 H), 1.90 1.98 (m, 1 H), 1.66 1.73 (m, 1 H), 1.53 (s, 3 H), 1.13 (s, 3 H), 1.12 (s, 3 H), 1.01 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ 201.3, 177.8, 166.2, 148.6, 135.6, 133.6, 127.9, 126.4, 124.6, 90.4, 83.4, 54.8, 54.6, 39.9, 30.5, 29.0, 23.4, 16.7, 16.5, 9.7; IR (KBr) 3033, 2979, 2929, 1790, 1740, 1724, 1608, 1354, 1321, 1269, 1219, 1173, 1092, 1016, 968, 933, 889, 791, 733 cm 1 28 ; Anal. Calc d for C 20 H 22 5 : C, 74.24; H, 5.98, Found: C, 73.96; H, 6.23; [ ] D +22.7 (CHCl 3, c 0.96). CCDC 290477 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or deposit@ccdc.cam.ac.uk). Table 2, entry 4 11 Spectroscopic data of 11: colorless liquid; 1 H NMR (400 MHz, CDCl 3 ) δ 9.84 (s, 1 H), 7.98 8.05 (m, 1 H), 7.75 7.83 (m, 1 H), 7.49 7.64 (m, 4 H), 7.22 7.32 (m, 2 H), 2.25 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ 201.1, 191.5, 144.6, 139.4, 137.3, 133.8, 133.4, 131.8, 131.0, 130.5, 128.6, 128.3, 128.2, 128.1, 29.4; IR (neat) 3060, 2843, 2750, 1691, 1594, 1250, 827, 762 cm 1. H 19 Page 9

Spectroscopic data of 19: colorless solid, m.p. 81 82 C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (dd, 1 H, J = 7.8, 1.5 Hz), 7.95 (d, 1 H, J = 8.3 Hz), 7.83 7.88 (m, 1 H), 7.77 7.81 (m, 1 H), 7.70 (dt, 1 H, J = 1.5, 7.8 Hz), 7.37 7.46 (m, 3 H), 4.03 (bs, 1 H), 1.56 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ 204.0, 141.5, 137.5, 135.1, 129.5, 128.6, 128.3, 128.1, 127.9, 127.6, 125.6, 124.0, 123.2, 76.9, 32.6; IR (KBr) 3481, 3068, 2977, 2923, 1694, 1601, 1452, 1207, 1077, 757, 732 cm 1 ; Anal. Calc d for C 15 H 12 2 : C, 80.34; H, 5.39; Found: C, 80.57; H, 5.57; HPLC (CHIRALCEL D-H, eluent: 2-propanol:hexane = 1:99, flow rate: 1.0 ml/min, 25 C): (R)-19: t 1 = 21.4 min; (S)-19: t 2 = 30.4 min; [α] 24 D 121 (CHCl 3, c 1.00) for 33% ee. 30 Spectroscopic data of 30: m.p. 233 234 C; 1 H NMR (400 MHz, CDCl 3 ) δ 8.13 8.15 (m, 1 H), 8.00 8.07 (m, 2 H), 7.70 7.74 (m, 1 H), 7.37 7.52 (m, 4 H), 2.30 2.37 (m, 1 H), 1.85 1.98 (m, 2 H), 1.63 1.70 (m, 4 H), 1.29 (s, 3 H), 1.15 (s, 3 H), 1.04 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ 194.8, 178.6, 166.0, 139.9, 136.6, 135.0, 129.6, 128.6, 128.39, 128.38, 128.35, 127.8, 124.4, 123.8, 123.2, 90.8, 81.7, 55.1, 54.8, 30.3, 28.7, 28.2, 16.7, 16.5, 9.9; IR (KBr) 3062, 2976, 2889, 1778, 1760, 1707, 1604, 1452, 1311, 1263, 1168, 1106, 1018, 764, 737 cm 1 ; Anal. Calc d for C 25 H 24 5 : C, 74.24; H, 5.98, Found: C, 74.08; H, 6.22; [ ] 29 D 126 (CHCl 3, c 0.97). CCDC 290476 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or deposit@ccdc.cam.ac.uk). Table 2, entry 5 Page 10

Et 12 Spectroscopic data of 12: yellow liquid; 1 H NMR (300 MHz, CDCl 3 ) δ 9.84 (s, 1 H), 7.99 8.02 (m, 1 H), 7.71 7.74 (m, 1 H), 7.50 7.60 (m, 4 H), 7.22 7.31 (m, 2 H), 2.54 2.62 (m, 2 H), 0.96 (t, 3 H, J = 7.2 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 204.4, 191.5, 144.6, 139.7, 136.9, 133.8, 133.3, 131.7, 130.6, 130.5, 128.2, 128.02, 127.99, 127.95, 34.9, 8.1; IR (neat) 3060, 2978, 2937, 2843, 2750, 1693, 1597, 1250, 1215, 949, 827, 760 cm 1. HEt 20 Spectroscopic data of 20: colorless solid, m.p. 92 93 C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.91 7.94 (m, 2 H), 7.81 7.85 (m, 1 H), 7.72 7.75 (m, 1 H), 7.66 7.70 (m, 1 H), 7.38 7.43 (m, 3 H), 4.03 (bs, 1 H), 1.70 1.87 (m, 2 H), 0.80 (t, 3 H, J = 7.2 Hz); 13 C NMR (100 MHz, CDCl 3 ) δ 203.9, 140.7, 137.5, 134.9, 128.96, 128.95, 128.4, 128.3, 127.9, 127.0, 126.1, 124.0, 123.1, 80.0, 37.8, 8.2; IR (KBr) 3489, 3068, 2972, 2935, 2875, 1689, 1601, 1452, 1282, 1259, 1201, 1097, 976, 750, 733 cm 1 ; Anal. Calc d for C 16 H 14 2 : C, 80.65; H, 5.92; Found: C, 80.60; H, 6.21; HPLC (CHIRALCEL D-H, eluent: 2- propanol:hexane = 5:95, flow rate: 1.0 ml/min, 25 C): (R)-20: t 1 = 10.1 min; (S)-20: t 2 = 15.5 min; [α] 27 D 265 (CHCl 3, c 1.15) for 90% ee. Et 31 Spectroscopic data of 31: m.p. 172 173 C; 1 H NMR (400 MHz, CDCl 3 ) δ 8.09 8.11 (m, 1 H), 7.98 8.04 (m, 2 H), 7.69 7.72 (m, 1 H), 7.36 7.46 (m, 4 H), 2.33 2.39 (m, 1 H), 2.10 2.19 (m, 1 H), 1.85 2.02 (m, 3 H), 1.63 1.70 (m, 1 H), 1.30 (s, 3 H), 1.15 (s, 3 H), 1.05 (s, 3 H), 0.79 (t, 3 H, J = 7.2 Hz); 13 C NMR (100 MHz, CDCl 3 ) δ 194.6, 178.7, 166.0, 138.8, 136.7, 134.9, 129.3, 128.9, 128.4, 128.3, 127.9, 124.7, 123.8, 123.2, 91.1, Page 11

84.8, 77.2, 55.1, 54.8, 31.9, 30.3, 28.7, 16.8, 16.5, 9.9, 7.7; IR (KBr) 2968, 2933, 2877, 1784, 1751, 1689, 1597, 1574, 1450, 1263, 1171, 1103, 1018, 897, 760, 731 cm 1 ; Anal. Calc d for C 26 H 26 5 : C, 74.62; H, 6.26, Found: C, 74.48; H, 6.08; [ ] 23 D 178 (CHCl 3, c 1.06). CCDC 260890 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or deposit@ccdc.cam.ac.uk). Table 2, entry 6 i-pr 13 Spectroscopic data of 13: colorless liquid; 1 H NMR (300 MHz, CDCl 3 ) δ 9.86 (s, 1 H), 8.03 (dd, 1 H, J = 7.5, 1.8 Hz), 7.49 7.66 (m, 5 H), 7.21 7.33 (m, 2 H), 2.80 2.93 (m, 1 H), 0.95 (d, 3 H, J = 1.5 Hz), 0.93 (d, 3 H, J = 1.5 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 208.7, 191.5, 144.4, 139.9, 136.7, 134.0, 133.3, 131.8, 130.6, 130.2, 128.24, 128.16, 127.9, 127.8, 39.0, 18.9, 18.0; IR (neat) 3060, 2971, 2871, 2751, 1693, 1594, 1467, 1250, 1214, 977, 827, 758 cm 1. Hi-Pr 21 Spectroscopic data of 21: colorless solid, m.p. 72 74 C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (d, 1 H, J = 8.0 Hz), 7.86 (dd, 1 H, J = 8.0, 1.6 Hz), 7.77 7.81 (m, 1 H), 7.66 7.70 (m, 2 H), 7.34 7.43 (m, 3 H), 3.95 (s, 1 H), 1.89 1.99 (m, 1 H), 0.83 (d, 3 H, 6.8 Hz), 0.74 (d, 3 H, 6.8 Hz) ; 13 C NMR (100 MHz, CDCl 3 ) δ 205.1, 139.9, 137.8, 134.8, 129.6, 129.1, 128.31, 128.27, 127.9, 127.2, 126.8, 124.2, 123.0, 82.1, 38.9, 17.2, 16.6; IR (KBr) 3489, 3068, 2968, 2933, 2873, 1693, 1601, 1452, 1288, 1201, 1109, 1004, 771, 733 cm 1 ; Anal. Calc d for C 17 H 16 2 : C, 80.93; H, 6.39; Found: C, 80.83; H, 6.47; HPLC Page 12

(CHIRALCEL D-H, eluent: 2-propanol:hexane = 5:95, flow rate: 1.0 ml/min, 25 C): (R)-21: t 1 = 9.7 min; (S)-21: t 2 = 13.5 min; [α] D 29 232 (CHCl 3, c 1.04) for 85% ee. i-pr 32 Spectroscopic data of 32: colorless solid, m.p. 164 165 C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 8.06 (m, 3 H), 7.67 7.71 (m, 1 H), 7.34 7.45 (m, 4 H), 2.25 2.39 (m, 2 H), 1.86 1.99 (m, 2 H), 1.63 1.69 (m, 1 H), 1.31 (s, 3 H), 1.15 (s, 3 H), 1.05 (s, 3 H), 0.94 (d, 3 H, J = 6.8 Hz), 0.77 (d, 3 H, J = 7.1 Hz); 13 C NMR (100 MHz, CDCl 3 ) δ 194.5, 178.8, 166.0, 137.8, 137.0, 134.7, 130.2, 129.9, 128.8, 128.4, 128.3, 127.4, 125.4, 123.7, 123.1, 91.2, 87.0, 55.2, 54.8, 39.1, 30.4, 28.7, 16.94, 16.91, 16.7, 16.5, 9.9; IR (KBr) 2972, 2937, 2877, 1784, 1751, 1695, 1600, 1452, 1396, 1265, 1171, 1101, 1065, 903, 735 cm 1 ; Anal. Calc d for C 27 H 28 5 : C, 74.98; H, 6.53, Found: C, 75.16; H, 6.76; [ ] 29 D 139 (CHCl 3, c 0.93). CCDC 290470 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or deposit@ccdc.cam.ac.uk). Table 2, entry 7 N 14 Spectroscopic data of 14: colorless solid, m.p. 155 156 C; 1 H NMR (400 MHz, CDCl 3 ) δ 10.16 (d, 1 H, J = 0.7 Hz), 7.58 7.62 (m, 3 H), 7.38 7.44 (m, 2 H), 7.26 7.29 (m, 2 H), 6.87 (dd, 1 H, J = 8.3, 0.7 Hz), 3.51 (s, 3 H), 2.58 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ 191.1, 189.3, 172.7, 156.8, 156.3, 137.2, 136.3, 132.9, 131.1, 128.6, 128.1, 120.4, 119.8, Page 13

119.6, 117.8, 115.32, 115.28, 55.3, 12.9; IR (KBr) 3062, 3008, 2976, 2943, 2862, 2750, 1693, 1666, 1593, 1473, 1448, 1421, 1389, 1273, 1167, 1074, 903, 700 cm 1 ; Anal. Calc d for C 19 H 15 N 4 : C, 71.02; H, 4.71; N, 4.36, Found: C, 70.98; H, 4.83; N, 4.06. N H 22 Spectroscopic data of 22: colorless solid, m.p. 180 182 C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.52 (dd, 1 H, J = 7.8, 1.2 Hz), 7.47 (t, 1 H, J = 7.8 Hz), 7.29 (dd, 1 H, J = 7.8, 1.2 Hz), 7.24 (bs, 5 H), 4.56 (brs, 1 H), 4.09 (s, 3 H), 2.50 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ 198.8, 167.6, 156.8, 154.4, 139.8, 131.6, 131.3, 128.8, 128.5, 125.7, 121.2, 117.8, 117.4, 113.6, 76.5, 56.4, 11.8; IR (KBr) 3424, 2985, 2942, 1695, 1637, 1278, 1248, 1000, 890, 772, 725, 706 cm 1 ; Anal. Calc d for C 19 H 15 N 4 : C, 71.02; H, 4.71; N, 4.36, Found: C, 70.74; H, 4.74; N, 4.12; HPLC (CHIRALPAK AD-H, eluent: 2-propanol:hexane = 24 15:85, flow rate: 1.0 ml/min, 25 C): (R)-22: t 1 = 20.8 min; (S)-22: t 2 = 30.3 min; [α] D 97.9 (CHCl 3, c 1.00) for >99% ee. N Ph 33 The spectroscopic data of 33; colorless solid, m.p. 230 C (decomp.); 1 H NMR (300 MHz, CDCl 3 ) δ 7.66 (d, 1 H, J = 7.6 Hz), 7.50 (t, 1 H, J = 7.6 Hz), 7.29 7.38 (m, 6 H), 4.11 (s, 3 H), 2.49 2.58 (m, 1 H), 2.27 (s, 3 H), 1.94 2.03 (m, 1 H), 1.71 1.80 (m, 1 H), 2.17 1.71 (m, 1 H), 1.21 (s, 3 H), 1.14 (s, 3 H), 0.99 (s, 3 H); 13 C NMR (75 MHz, CDCl 3 ) δ 191.1, 177.8, 166.1, 165.9, 157.3, 154.6, 135.2, 131.5, 131.0, 129.2, 128.9, 126.3, 121.7, 117.4, 117.2, 113.3, 90.4, 80.0, 56.5, 54.8, 54.5, 31.0, 28.9, 16.7, 16.4, 11.5, 9.6; IR (KBr) 2972, 2937, 2841, 1793, 1753, 1699, 1579, 1482, 1311, 1281, 1169, 1109, 1059, 935, 760, 723 cm 1 ; Anal. Calc d for C 29 H 27 N 7 : C, 69.45; H, 5.43; N, 2.79, Found: C, 69.17; H, 5.20; N, 2.57; [α] 22 D 78.8 (CHCl 3, c 1.00). Page 14

CCDC 260889 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or deposit@ccdc.cam.ac.uk). Table 2, entry 8 N 15 Spectroscopic data of 15: pink solid, m.p. 162 C; 1 H NMR (400 MHz, CDCl 3 ) δ 9.78 (s, 1 H), 7.57 (d, 1 H, J = 8.1 Hz), 7.03 (d, 1 H, J = 8.1 Hz), 6.10 (brs, 2 H), 3.11 (brd, 2 H, J = 3.4 Hz), 2.52 (t, 2 H, J = 6.6 Hz), 2.28 (brs, 2 H); 13 C NMR (100 MHz, CDCl 3 ) δ 191.6, 189.1, 181.1, 153.1, 152.4, 147.6, 129.8, 128.4, 115.6, 109.3, 109.2, 102.6, 37.9, 23.2, 22.1; IR (KBr) 3365, 3091, 2956, 2908, 2729, 1695, 1595, 1506, 1468, 1356, 1265, 1066, 935, 829, 623 cm 1 ; Anal. Calc d for C 15 H 11 N 5 : C, 63.16; H, 3.89; N, 4.91, Found: C, 63.07; H, 4.05; N, 4.85. N Ac 34 To a suspension of the crude benzoin product 23 (135 mg) in pyridine (1.0 ml) at 0 C was added Ac 2 (0.75 ml) and DMAP (11 mg, 0.090 mmol). The reaction mixture was warmed to room temperature and then stirred for 1 h. The reaction was quenched by addition of saturated aq NH 4 Cl solution. The products were extracted with CH 2 Cl 2 (20 ml x 3), and the combined organic extracts were washed with brine, dried over Na 2 S 4 and concentrated under reduced pressure. The residue was purified by silicagel preparative thin-layer chromatography (CHCl 3 /H = 97/3) to afford the acetylated product 34 as yellow amorphous solid (72.3 mg, 73 %, 2 steps). The spectroscopic data of 34; 1 H NMR (400 MHz, CDCl 3 ) δ 7.73 (d, 1 H, J = 8.0 Hz), 6.94 (d, 1 H, J = 8.0 Hz), 6.30 (d, 1 H, J = 1.2 Hz), 6.25 (d, 1 H, J = 1.2 Hz), 3.02 (dd, 1 H, J = 18.4, 6.8 Hz), 2.57 2.80 (m, 2 H), 2.19 2.45 (m, 2 H), 1.96 (s, 3 H), 1.41 1.49 (m, 1 H); 13 C NMR (75 Page 15

MHz, CDCl 3 ) δ 190.8, 171.6, 169.5, 152.8, 143.8, 126.8, 125.0, 112.9, 109.7, 109.4, 103.3, 77.2, 73.3, 29.3, 22.0, 20.6, 17.5; IR (CHCl 3 ) 3026, 3012, 2964, 2910, 1743, 1689, 1518, 1491, 1454, 1362, 1230, 1124, 1074, 1034, 1011, 972, 829, 779 cm 1 ; Anal. Calc d for C 17 H 13 N 6 : C, 62.39; H, 4.00; N, 4.28, Found: C, 62.14; H, 4.26; N, 3.99; HPLC (CHIRALCEL D-H, eluent: 2-propanol:hexane = 15:85, flow rate: 1.0 ml/min, 25 C): t 1 = 36.7 min; t 2 = 52.4 min; [α] 23 D +11.5 (CHCl 3, c 1.00) for 99% ee. Scheme 2 24 Spectroscopic data of 24: colorless solid, m.p. 109 110 C; 1 H NMR (300 MHz, CDCl 3 ) δ 10.5 (s, 1 H), 7.87 (dd, 1 H, J = 7.5, 1.8 Hz), 7.46 7.51 (m, 1 H), 7.22 7.37 (m, 5 H), 7.08 (t, 1 H, J = 7.5 Hz), 6.70 (d, 1 H, J = 8.4 Hz), 4.75 (s, 2 H), 3.92 (s, 2 H); 13 C NMR (75 MHz, CDCl 3 ) δ 203.3, 189.2, 159.7, 135.8, 132.6, 129.4, 129.1, 128.9, 127.5, 125.2, 121.8, 112.3, 72.1, 46.5; IR (KBr) 3028, 2898, 2863, 2767, 1722, 1685, 1599, 1483, 1284, 1246, 1061, 769, 704 cm 1.; Anal. Calc d for C 16 H 14 3 : C, 75.57; H, 5.55; Found: C, 75.57; H, 5.57 H 25 Spectroscopic data of 25 [10] : colorless liquid; 1 H NMR (300 MHz, CDCl 3 ) δ 7.89 (dd, 1 H, J = 7.8, 2.1 Hz), 7.54 7.60 (m, 1 H), 7.04 7.33 (m, 7 H), 4.30 (d, 1 H, J = 11.3 Hz), 4.11 (d, 1 H, J = 11.3), 3.58 (bs, 1 H), 3.04 (d, 1 H, J = 13.8 Hz), 2.97 (d, 1 H, J = 13.8 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 196.0, 161.4, 136.7, 134.3, 130.6, 128.2, 127.6, 127.1, 122.0, 118.4, 118.0, 73.0, 72.2, 40.9; IR (neat) 3475, 3062, 3029, 2920, 2871, 1695, 1608, 1477, 1306, 1217, 1093, 1036, 1018, 764, 700 cm 1 ; Anal. Calc d for C 16 H 14 3 : C, 75.57; H, 5.55; Found: C, 75.50; H, 5.59; HPLC (CHIRALPAK AD-H, eluent: 2- [10] Ref. 8b. Page 16

propanol:hexane = 2:98, flow rate: 1.0 ml/min, 25 C): (S)-25: t 1 = 23.8 min; (R)-25: t 2 = 28.8 min; [α] D 30 11.0 (CHCl 3, c 3.04) for 88% ee; Lit. [8] [α] D 20 10.0 (CHCl 3, c 3.00) for 91% ee. 35 Spectroscopic data of 35: colorless solid, m.p. 160 161 C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (dd, 1 H, J = 8.0, 2.0 Hz), 7.54 7.58 (m, 1 H), 7.28 7.38 (m, 5 H), 7.11 7.15 (m, 1 H), 7.05 7.07 (m, 1 H), 4.98 (d, 1 H, J = 10.8 Hz), 4.14 (d, 1 H, J = 10.8 Hz), 3.25 (d, 1 H, J = 14.4 Hz), 3.13 (d, 1 H, J = 14.4 Hz), 2.38 2.46 (m, 1 H), 1.92 2.05 (m, 2 H), 1.67 1.74 (m, 1 H), 1.13 (s, 6 H), 0.97 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ 188.9, 177.8, 165.5, 160.6, 136.5, 133.2, 130.9, 128.3, 128.1, 127.5, 122.4, 119.5, 117.9, 90.7, 81.2, 68.0, 54.9, 54.8, 38.9, 30.4, 29.1, 16.7, 16.4, 9.8; IR (KBr) 3070, 3037, 2966, 2935, 2877, 1780, 1761, 1701, 1610, 1475, 1456, 1313, 1259, 1173, 1111, 1049, 1014, 937, 764 cm 1 28 ; Anal. Calc d for C 26 H 26 6 : C, 71.87; H, 6.03, Found: C, 72.17; H, 6.28; [ ] D +10.0 (CHCl 3, c 1.01). CCDC 290471 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or deposit@ccdc.cam.ac.uk). Page 17