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1 Supporting Information Wiley-VCH Weinheim, Germany

2 Diphenylprolinol Silyl Ether as a Catalyst in an Enantioselective, Catalytic, Formal Aza [3+3] Cycloaddition Reaction for the Formation of Enantioenriched Piperidines Yujiro Hayashi,* Hiroaki Gotoh, Ryouhei Masui, Hayato Ishikawa Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo , Japan. Experimental Section General Remarks: All reactions were carried out under argon atmosphere and monitored by thin-layer chromatography using Merck 60 F254 precoated silica gel plates (0.25 mm thickness). FT-IR spectra were recorded on a JASCO FT/IR-410 spectrometer. 1H and 13 C NMR spectra were recorded on a Brucker AM400 (400 MHz) instrument and Bruker AV-600 (600 MHz). Data for 1 H NMR are reported as chemical shift (δ ppm),multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, bs = broad singlet), coupling constant (Hz), integration, and assignment. Data for 13 C NMR are reported as chemical shift. High-resolution mass spectral analyses (HRMS) were carried out using Bruker ESI-TOF MS. Preparative thin layer chromatography was performed using Wakogel B-5F purchased from Wako Pure Chemical Industries, Tokyo, Japan. Flash chromatography was performed using silica gel 60N of Kanto Chemical Co. Int., Tokyo, Japan. HPLC analysis was performed on a HITACHI Elite LaChrom Series HPLC, UV detection monitered at appropriate wavelength respectively, using Chiralcel OJ-H (0.46 cm x 25 cm), and Chiralpak IA (0.46 cm x 25 cm). S 1

3 General procedure (Table 2, Entry 1) O H OTBS Boc N HN H ClCH 2 CH 2 Cl 10 6a 6a major minor To a dichloroethane (0.33 ml) solution of catalyst 2 (18.3 mg, 10 mol%) and trans-cinnamaldehyde (62.5 µl, 0.5 mmol) was added a dichloroethane (0.66 ml) solution of the enecarbamate 10 (164.5 mg, 0.75 mmol) at room temperature. After stirring the reaction mixture at 70 C for 34 h, the resulting mixture was quenched with 1N-HCl at 0 C and the organic materials were extracted with ethylacetate three times. The combined organic extracts were washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt:hexane = 1:30 ) to afford 6a (158.1 mg, 0.45 mmol, 90%) as a yellow solid. The ratio of α- and β-isomers was determined by 1 H-NMR. A small portion of the mixture was purified by TLC to afford α-and β-isomers, the enantioselectivities of which were determined by HPLC analysis on a chiral phase. (2R, 4R )-N-tert-Butoxycarbonyl-2-hydroxy-4,6-diphenyl-5,6-dehydropiperidine and (2S, 4R )-N-tert-Butoxycarbonyl-2-hydroxy-4,6-diphenyl-5,6-dehydropiperidine major minor Major isomer Rf 0.4 (AcOEt:hexane = 1:3); 1 H-NMR δ 1.03 (9H, s, -COOC(CH3)3), 1.87 (1H, dt, Jd = 2.8 Hz, Jt = 14.0 Hz, -CHCH2-), (1H, m, -CHCH2-), 3.84 (1H, ddd, J = 4.0, 6.4, 10.0 Hz, CH- ), 4.41 (1H, bs, ), 5.33 (1H, d, J = 3.2 Hz, -CH-), 5.99 (1H, bs, -CH=C), (10H, m, overlapped, CHC6H5 and -CH=CC6H5); 13C-NMR δ 27.7(3C, -COOC(CH3)3), 36.7 (-CHCH2-), 38.2 (-CHCH2-), 76.9, 81.5, 117.7, (2C), 126.6, 127.0, (2C), (2C), (2C), 137.2, 141.2, 144.0, 153.7(-COOC(CH3). S 2

4 N Boc Boc N H H β H H noe Minor isomer Rf 0.5 (AcOEt:hexane = 1:3); 1 H-NMR δ 1.04 (9H, s, -COOC(CH3)3), 1.96 (1H, t, J = 12.4 Hz, -CHCH2-), (1H, m, -CHCH2-), 3.36 (1H, dt, Jd = 12.4 Hz, Jt = 3.6 Hz, CH-), 4.26 (1H, bs,, ), 5.66 (1H, d, J = 2.8 Hz, -CH-), 5.91 (1H, t, J = 7.2 Hz, -CH=C), (10H, m, overlapped, CHC6H5 and -CH=CC6H5); 13C-NMR δ 27.7 (3C, -COOC(CH3)3), 38.2 (-CHCH2-), 41.5 (-CHCH2-), 78.6, 81.5, 122.7, (2C), 126.8, 127.3, (2C), (2C), (2C), 138.7, 139.7, 143.8, (-COOC(CH3)3). N Boc Boc N H H H α H noe IR (neat) ν 3438, 2978, 1681, 1645, 1448, 1368, 1165, 1059, 764, 699 cm -1 ; HRMS (ESI): [M+Na] + calculated for C22H25NO3Na: , found: ; Enantiomers were separated by chiral HPLC. Major isomer; tr1 = (minor), tr2 = (major), (Chiralpak IA column, 100/1 hexane/i-pr; flow rate 1.0 ml/min). Minor isomer; tr1 = (minor), tr2 = (major), (Chiralcel OJ-H column, 30/1 hexane/i-pr; flow rate 1.0 ml/min). S 3

5 (2R, 4R )-N-tert-Butoxycarbonyl- 2-hydroxy-4-(2-naphthyl)-6-phenyl-5,6-dehydropiperidine and (2S, 4R )-N-tert-Butoxycarbonyl- 2-hydroxy-4-(2-naphthyl)-6-phenyl-5,6-dehydropiperidine major minor Major isomer Rf 0.5 (AcOEt:hexane = 1:3); 1 H-NMR δ 1.11 (9H, s), (1H, m), 2.43 (1H, ddd, J = 3.2, 5.2, 14.0 Hz), 3.73 (1H, d, J = 2.8 Hz), (1H, m), 5.51 (1H, d, J = 3.2 Hz), (1H, m), (8H, m), (4H, m); 13 C-NMR δ 27.6 (3C), 36.5, 38.0, 76.9, 81.5, 117.6, 125.5, (2C), 125.8, 126.1, 126.2, 127.0, (2C), (2C), 128.4, 132.4, 133.6, 137.7, (2C), Minor isomer Rf 0.3 (AcOEt:hexane = 1:3); 1 H-NMR δ 1.12 (9H, s), (1H, m), 2.65 (1H, ddd, J = 4.0, 6.8, 12.8 Hz), 3.63 (1H, dt, Jd = 12.4 Hz, Jt = 3.2 Hz), (1H, m), 5.81 (1H, d, J = 3.2 Hz), (1H, m), (8H, m), (4H, m); 13 C-NMR δ 27.6 (3C), 38.1, 41.1, 78.9, 81.6, 122.2, (2C), 125.6, 125.7, 126.0, 126.2, 127.3, (2C), (2C), 128.5, 132.4, 133.5, 138.7, 139.5, 141.1, IR (neat) ν 2977, 1680, 1643, 1392, 1368, 1163, 1058, 762, 699, 478 cm -1 ; HRMS (ESI): [M+Na] + calculated for C26H27NO3Na: , found: ; Enantiomers were separated by chiral HPLC. Major isomer; tr1 = (minor), tr2 = (major), (Chiralcel OJ-H column, 30/1 hexane/i-pr; flow rate 1.0 ml/min). Minor isomer; tr1 = 5.55 (minor), tr2 = 7.28 (major), (Chiralpak IA column, 10/1 hexane/i-pr; flow rate 1.0 ml/min). S 4

6 (2R, 4R )-N-tert-Butoxycarbonyl- 2-hydroxy-4-(4-nitrophenyl)-6-phenyl-5,6-dehydropiperidine and (2S, 4R )-N-tert-Butoxycarbonyl- 2-hydroxy-4-(4-nitrophenyl)-6-phenyl-5,6-dehydropiperidine O 2 N major O 2 N minor Major isomer Rf 0.4 (AcOEt:hexane = 1:1); 1 H-NMR δ 1.09 (9H, s), (1H, m), (1H, m), 3.44 (1H, d, J = 2.4 Hz), (1H, m), 5.33 (1H, d, J = 3.2 Hz), (1H, m), (7H, m), (2H, m); 13 C-NMR δ 27.6 (3C), 36.5, 37.8, 76.6, 81.9, 115.5, (2C), (2C), (2C), (2C), (2C), 138.6, 140.5, 146.9, Minor isomer Rf 0.3 (AcOEt:hexane = 1:3); 1 H-NMR δ 1.09 (9H, s), (1H, m), 2.57(1H, ddd, J = 2.0, 6.4, 12.8 Hz), 3.60 (1H, dt, Jd = 11.2 Hz, Jt = 4.0 Hz), 3.81 (1H, d, J = 3.2 Hz), 5.59 (1H, d, J = 3.2 Hz), (1H, m), (7H, m), (2H, m); 13 C-NMR δ 27.6 (3C), 37.9, 40.4, 78.2, 81.9, 119.6, (2C), (2C), (2C), (2C), (2C), 139.3, 139.4, 151.4, IR (neat) ν 3481, 2978, 2932, 1695, 1644, 1518, 1346, 1163, 853, 764, 700 cm -1 ; HRMS (ESI): [M+Na] + calculated for C22H24N2O5Na: , found: ; Enantiomers were separated by chiral HPLC. Major isomer; tr1 = (minor), tr2 = (major), (Chiralcel OJ-H column, 100/1 hexane/i-pr; flow rate 1.0 ml/min). Minor isomer; tr1 = 8.63 (minor), tr2 = (major), (Chiralpak IA column, 100/1 hexane/i-pr; flow rate 1.0 ml/min). S 5

7 (2R, 4R )-N-tert-Butoxycarbonyl- 2-hydroxy-4-(4-bromophenyl)-6-phenyl-5,6-dehydropiperidine and (2S, 4R )-N-tert-Butoxycarbonyl- 2-hydroxy-4-(4-bromophenyl)-6-phenyl-5,6-dehydropiperidine Br major Br minor Major isomer Rf 0.2 (AcOEt:hexane = 1:3); 1 H-NMR δ 0.92 (9H, s), 1.72 (1H, dt, Jd = 3.2 Hz, Jt = 14.0 Hz), (1H, m), (1H, m), 4.38 (1H, bs), 5.15 (1H, d, J = 3.2 Hz), 5.88 (1H, s), (9H, m); 13 C-NMR δ 27.7 (3C), 36.2, 38.0, 76.7, 81.7, 116.9, 120.0, (2C), 127.1, (2C), (2C), (2C), 137.6, 141.0, 143.0, Minor isomer Rf 0.1 (AcOEt:hexane = 1:3); 1 H-NMR δ 0.94 (9H, s), (1H, m), 2.38 (1H, ddd, J = 4.4, 6.8, 12.8 Hz), 3.23 (1H, dt, Jd = 11.6 Hz, Jt = 3.6 Hz), 4.19 (1H, bs), 5.47 (1H, d, J = 3.2 Hz), 5.81 (1H, t, J = 7.2 Hz), (9H, m); 13 C-NMR δ 27.7 (3C), 37.6, 41.2, 78.2, 81.6, 120.5, 121.7, (2C), 127.4, (2C), (2C), (2C), 138.9, 139.5, 142.6, IR (neat) ν 3443, 2978, 2931, 1681, 1487, 1392, 1358, 1164, 1071, 1009, 763 cm -1 ; HRMS (ESI): [M+Na] + calculated for C22H24Br1N1O3Na: , found: ; Enantiomers were separated by chiral HPLC (Chiralcel OJ-H column, 100/1 hexane/i-pr; flow rate 1.0 ml/min). Major isomer; tr1 = (minor), tr2 = (major). Minor isomer; tr1 = (minor), tr2 = (major). S 6

8 (2R, 4R )-N-tert-Butoxycarbonyl- 2-hydroxy-4-(4-methoxyphenyl)-6-phenyl-5,6-dehydropiperidine and (2S, 4R )-N-tert-Butoxycarbonyl- 2-hydroxy-4-(4-methoxyphenyl)-6-phenyl-5,6-dehydropiperidine MeO major MeO minor Major isomer Rf 0.4 (AcOEt:hexane = 1:3); 1 H-NMR δ 1.05 (9H, s), (1H, m), (1H, m), 3.76 (3H, s), (1H, m), 5.35 (1H, d, J = 4.0 Hz), 5.94 (1H, d, J = 2.8 Hz), (2H, m), (7H, m); 13 C-NMR δ 27.6 (3C), 35.6, 38.2, 55.3, 77.0, 81.4, 114.1, 118.1, (2C), (2C), 127.9, (2C), (2C), 137.2, 141.0, 153.6, Minor isomer Rf 0.3 (AcOEt:hexane = 1:3); 1 H-NMR δ 1.06 (9H, s), (1H, m), 2.50 (1H, ddd, J = 4.0, 6.8, 12.8 Hz), 3.36 (1H, dt, Jd = 12.0 Hz, Jt = 3.6 Hz), 3.75 (3H, s), (1H, m), 5.64 (1H, d, J = 3.2 Hz), 5.89 (1H, dt, Jd = 6.8 Hz, Jt = 3.2 Hz), (2H, m), (7H, m); 13 C-NMR δ 27.6 (3C), 37.2, 41.3, 55.3, 78.8, 81.5, 114.1, 122.8, (2C), 127.2, (2C), (2C), (2C), 138.4, 139.6, 154.8, IR (neat) ν 3452, 2978, 2932, 1695, 1644, 1512, 1369, 1247, 1165, 1034, 764 cm -1 ; HRMS (ESI): [M+Na] + calculated for C23H27N1O4Na: , found: ; Enantiomers were separated by chiral HPLC (Chiralcel OJ-H column, 100/1 hexane/i-pr; flow rate 1.0 ml/min). Major isomer; tr1 = (minor), tr2 = (major). Minor isomer; tr1 = (minor), tr2 = (major). S 7

9 (2R, 4R )-N-tert-Butoxycarbonyl- 2-hydroxy-4-(2-furyl)-6-phenyl-5,6-dehydropiperidine and (2S, 4R )-N-tert-Butoxycarbonyl- 2-hydroxy-4-(2-furyl)-6-phenyl-5,6-dehydropiperidine O O major minor Major isomer Rf 0.5 (AcOEt:hexane = 1:3); 1 H-NMR δ 1.04 (9H, s), (1H, m), (1H, m), 3.70 (1H, bs), (1H, m), 5.42 (1H, dd, J = 0.4, 3.2 Hz), 5.97 (1H, d, J = 2.4 Hz), (1H, m), (1H, m), (6H, m); 13 C-NMR δ 27.7 (3C), 30.2, 34.5, 76.7, 81.5, 104.7, 110.1, 114.8, (2C), 127.1, (2C), 137.7, 140.7, 141.5, 153.7, Minor isomer Rf 0.4 (AcOEt:hexane = 1:3); 1 H-NMR δ 1.06 (9H, s), (1H, m), 2.59 (1H, ddd, J = 4.8, 6.0, 13.2 Hz), 3.57 (1H, dt, Jd = 10.4 Hz, Jt = 4.0 Hz), (1H, m), 5.65 (1H, d, J = 3.2 Hz), (1H, m), (1H, m), (1H, m), (6H, m); 13 C-NMR δ 27.6 (3C), 31.4, 37.3, 77.9, 81.5, 104.7, 110.3, 117.9, (2C), 127.4, (2C), 138.6, 139.6, 141.6, 154.3, IR (neat) ν 3443, 2978, 1681, 1645, 1393, 1368, 1252, 1166, 1063, 764 cm -1 ; HRMS (ESI): [M+Na] + calculated for C20H23N1O4Na: , found: ; Enantiomers were separated by chiral HPLC. Major isomer; tr1 = (minor), tr2 = (major), (Chiralpak IA column, 100/1 hexane/i-pr; flow rate 1.0 ml/min). Minor isomer; tr1 = (minor), tr2 = (major), (Chiralcel OJ-H column, 100/1 hexane/i-pr; flow rate 1.0 ml/min). S 8

10 (2R, 4R )-N-tert-Butoxycarbonyl- 2-hydroxy-4-phenyl-6-(4-bromophenyl)-5,6-dehydropiperidine and (2S, 4R )-N-tert-Butoxycarbonyl- 2-hydroxy-4-phenyl-6-(4-bromophenyl)-5,6-dehydropiperidine major Br minor Br Major isomer Rf 0.3 (AcOEt:hexane = 1:10); 1 H-NMR δ 1.10 (9H, s), (1H, m), 2.31 (1H, ddd, J = 3.2, 5.2, 13.2 Hz), 3.61 (1H, bs), 3.81 (1H, ddd, J = 4.0, 6.0, 10.8 Hz), 5.35 (1H, d, J = 3.2 Hz), 5.93 (1H, d, J = 2.4 Hz), (9H, m); 13 C-NMR δ 27.7 (3C), 36.4, 37.9, 76.9, 81.8, 118.3, 120.6, (2C), (2C), (2C), (2C), 131.0, 136.4, 140.0, 143.4, Minor isomer Rf 0.2 (AcOEt:hexane = 1:3); 1 H-NMR δ 1.10 (9H, s), (1H, m), 2.52 (1H, ddd, J = 4.0, 6.8, 12.8 Hz), 3.38 (1H, dt, Jd = 12.0 Hz, Jt = 3.6 Hz), 3.89 (1H, d, J = 2.0 Hz), 5.65 (1H, d, J = 3.6 Hz), 5.88 (1H, dt, Jd = 8.8 Hz, Jt = 2.8 Hz), (9H, m); 13C-NMR δ 27.8 (3C), 38.1, 41.0, 78.8, 81.8, 120.9, 123.0, (2C), (2C), (2C), (2C), 131.2, 137.7, 138.6, 143.5, IR (neat) ν 3444, 2978, 1682, 1644, 1488, 1392, 1350, 1164, 1060, 701 cm -1 ; HRMS (ESI): [M+Na] + calculated for C22H24N1O3Na: , found: ; Enantiomers were separated by chiral HPLC (Chiralpak IA column, 10/1 hexane/i-pr; flow rate 1.0 ml/min). Major isomer; tr1 = (minor), tr2 = (major). Minor isomer; tr1 = (minor), tr2 = (major). S 9

11 (2R, 4R )-N-tert-Butoxycarbonyl- 2-hydroxy-4-phenyl-6-(4-toluenyl)-5,6-dehydropiperidine and (2S, 4R )-N-tert-Butoxycarbonyl- 2-hydroxy-4-phenyl-6-(4-toluenyl)-5,6-dehydropiperidine major minor Major isomer Rf 0.2 (AcOEt:hexane = 1:10); 1 H-NMR δ 1.09 (9H, s), 1.55 (3H, s), (1H, m), (1H, m), 3.44 (1H, d, J = 4.4 Hz), (1H, m), 5.33 (1H, d, J = 4.0 Hz), (1H, m), (5H, m), (2H, m), (2H, m); 13 C-NMR δ 21.1, 27.7 (3C), 36.4, 38.2, 77.0, 81.4, 117.1, (2C), 126.5, (2C), (2C), (2C), 136.6, 137.4, 138.0, 143.8, Minor isomer Rf 0.1 (AcOEt:hexane = 1:3); 1 H-NMR δ 1.05 (9H, s), 1.55 (3H, s), (1H, m), (1H, m), 3.60 (1H, dt, Jd = 11.6 Hz, Jt = 4.0 Hz), 3.81 (1H, d, J = 2.8 Hz), 5.59 (1H, d, J = 4.8 Hz), (1H, m), (5H, m) (2H, m) (2H, m); 13 C-NMR δ 21.1, 27.7 (3C), 38.0, 41.2, 78.9, 81.4, 121.8, (2C), 126.7, (2C), (2C), (2C), 136.6, 137.0, 138.6, 143.8, IR (neat) ν 3445, 2978, 1680, 1643, 1392, 1367, 1165, 1058, 763, 701 cm -1 ; HRMS (ESI): [M+Na] + calculated for C23H27N1O3Na: , found: ; Enantiomers were separated by chiral HPLC (Chiralpak IA column, 10/1 hexane/i-pr; flow rate 1.0 ml/min). Major isomer; tr1 = 5.21 (minor), tr2 = (major). Minor isomer; tr1 = 4.81 (minor), tr2 = 5.52 (major). S 10

12 (2R, 4R )-N-tert-Butoxycarbonyl- 2-hydroxy-4-phenyl-6-(2-furyl)-5,6-dehydropiperidine and (2S, 4R )-N-tert-Butoxycarbonyl- 2-hydroxy-4-phenyl-6-(2-furyl)-5,6-dehydropiperidine O O major minor Major isomer Rf 0.5 (AcOEt:hexane = 1:3); 1 H-NMR δ 1.32 (9H, s), 1.92 (1H, s), 2.38 (1H, dddd, J = 0.8, 2.8, 6.0, 13.6 Hz), (1H, m), 4.13 (1H, s), 5.63 (1H, d, J = 3.6 Hz), 6.03 (1H, bs), 6.31 (1H, d, J = 3.2 Hz), 6.38 (1H, dd, J = 2.0, 3.6 Hz), (6H, m); 13 C-NMR δ 27.7 (3C), 36.2, 37.7, 76.6, 81.3, 105.3, 110.9, 117.2, 126.5, (2C), 128.1, (2C), 140.3, 143.4, 152.8, Minor isomer Rf 0.55 (AcOEt:hexane = 1:3); 1 H-NMR δ 1.34 (9H, s), 2.06 (1H, dt, Jd = 8.0 Hz, Jt = 12.0 Hz), 2.60 (1H, ddd, J = 2.4, 7.6, 13.2 Hz), 3.47 (1H, dt, Jd = 12.0 Hz, Jt = 4.0 Hz), 4.07 (1H, s), 5.92 (1H, d, J = 3.6 Hz), (1H, m), (1H, m), 6.39 (1H, dd, J = 2.0, 3.6 Hz), (6H, m); 13 C-NMR δ 27.7 (3C), 37.6, 41.0, 78.3, 81.4, 105.5, 111.0, 121.4, 126.6, (2C), (2C), 129.3, 140.7, 143.4, 151.6, IR (neat) ν 3437, 2973, 1682, 1346, 1166, 1060, 701 cm -1 ; HRMS (ESI): [M+Na] + calculated for C20H23NO4Na: , found: ; Enantiomeric excess was determined by HPLC (Chiralpak IA column, 20/1 hexane/i-pr; flow rate 1.0 ml/min). major isomer; tr1 = 7.41 (minor), tr2 = 9.16 (major) minor isomer; tr1 = 7.97 (major), tr2 = (minor) S 11

13 (R )-5-Oxo-3,5-diphenylpentanal (5a) O N Boc 2N-HCl H O THF, rt 6a 5a To a THF (0.2 ml) solution of 6a (130 mg, 0.37 mmol) was added 2N-HCl (0.2 ml) at room temperature. After stirring the reaction mixture at room temperature for 39 h, the resulting mixture was quenched with saturated aqueous NaHCO3. The organic materials were extracted with ethylacetate three times, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt:hexane = 1:3) to afford 5a (80.3 mg, 0.37 mmol, 87%). Spectroscopic data are in agreement with the published data 1). (S )-5-Oxo-3,5-diphenylpentanoic acid (11) H O NaH 2 PO 3-2H 2 O O 2-methyl-2-butene NaClO O 2 HO O t Bu-H 2 O 5a 11 To a tert-bu (0.23 ml) and H2O (0.08 ml) solution of 5a (38.6 mg, 0.15 mmol), NaH2PO3-2H2O (71.6 mg, 0.45 mmol) and 2-methyl-2-butene (0.08 ml, 0.61 mmol) was added NaClO2 (55.3 mg, 0.61 mmol) at room temperature and the reaction mixture was stirred for 8.5 h. The resulting mixture was quenched with ph 7.0 phosphate buffer and the organic material were extracted with ethylacetate three times. The combined organic extracts were dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane=1/2) to afford carboxylic acid 11 (20.6 mg, 50%). Spectroscopic data are in agreement with the published data 2). [α]d 22 = (c 1.0, CH2Cl2), Lit. [α]d 20 = (c 1.0, CH2Cl2) S 12

14 (R, 1Z, 5E)-tert-Butyl-6-(ethoxycarbonyl)-1,3-diphenylhexa-1,5-dienylcarbamate O O 3 P OEt N Boc OEt S2 HN Boc toluene, reflux 6a S1 To a toluene (0.44 ml) solution of 6a (78.0 mg, 0.22 mmol) was added wittig reagent S2 (154.9 mg, 0.44 mmol). The reaction mixture was stirred for 5 h under reflux condition. Insoluble materials were removed by filtration with celite pad by the use of AcOEt. The residue was purified by silica gel column chromatography (AcOEt:hexane=1:10) gave S1(74.4 mg, 0.18 mmol, 79%). 1H-NMR δ 1.27 (3H, t, J = 6.8 Hz), 1.32 (9H, bs), 2.70 (2H, t, J = 7.2 Hz), 3.86 ( 1H, q, J = 7.6 Hz), 4.16 (2H, q, J = 7.2 Hz), 5.70 (1H, d, J = 8.8 Hz), 5.74 (1H, s), 5.85 (1H, d, J = 15.6 Hz), 6.89 (1H, dt, Jd = 14.8 Hz, Jt = 7.2 Hz), (10H, m); 13 C-NMR δ 14.2, 28.0 (3C), 39.7, 43.0, 60.2, 77.2, 80.3, 123.3, (2C), 126.8, (2C), 127.7, 127.9, 128.1, (2C), 128.7, (2C), 142.9, 146.0, 166.3; IR (neat) ν 2979, 1719, 1697, 1366, 1163, 702 cm -1 ; HRMS (ESI): [M+Na] + calculated for C26H31NO4Na: , found: ; [α]d (c 0.83, CHCl3). (2S, 4R )-N-tert-Butoxycarbonyl-2-((ethoxycarbonyl)methyl) -4,6-diphenyl-5,6-dehydropiperidine (12) O OEt t BuOK HN Boc THF, 0 S1 12 O OEt N Boc To a THF (0.26 ml) solution of S1(72.9 mg, 0.17 mmol) was added to tert-buok (5.7 mg, mmol) at 0 C. After stirring the reaction mixture at 0 C for 10 min, the resulting mixture was quenched with ph 7.0 phosphate buffer and the organic materials were extracted with ethyl acetate three times. The combined organic materials were dried over anhydrous Na2SO4, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt:hexane=1:6) to afford 12 (67.5 mg, 0.16 mmol) in 93% yield. 1H-NMR δ 1.10 (9H, s), 1.33 (3H, t, J = 7.2 Hz), (1H, m), (1H, m), S 13

15 2.64 (1H, dd, J = 6.4, 14.4 Hz), 2.87 (1H, dd, J = 8.4, 14.4 Hz), 3.64 (1H, ddd, J = 3.6, 7.6, 11.2 Hz), 4.24 (2H, q, J = 7.2 Hz), (1H, m), 5.38 (1H, d, J = 2.8 Hz), (10H, m); 13 C-NMR δ 14.3, 27.7 (3C), 35.9, 36.5, 37.9, 50.4, 60.7, 80.8, 116.9, (2C), 126.6, 127.1, (2C), (2C), (2C), 138.3, 141.1, 143.9, 153.5, 171.4; IR (neat) ν 2979, 2927, 1738, 1699, 1352, 1167 cm -1 ; HRMS (ESI): [M+Na] + calculated for C26H31NO4Na: m/z , found m/z , [α]d (c 0.91, CHCl3). (2S,4R,6S )-N-tert-Butoxycarbonyl-2-((ethoxycarbonyl)methyl) -4,6-diphenyl-piperidine (13) O OEt N Boc Pd() 2, H 2 Me O OEt N Boc To a Me (0.69 ml) solution of 12 (29.4 mg, mmol) was added palladium hydroxide (20% on Carbon, 8.8 mg) at room temperature and the reaction mixture was stirred for 5 h under H2 atmosphere. The reaction mixture was filtered through a pad of Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt:hexane=1:6) to afford 13 (25.0 mg, mmol) in 85% yield. 1H-NMR δ 1.20 (9H, s), 1.27 (3H, t, J = 7.2 Hz), 1.87 (1H, dt, Jd = 13.6 Hz, Jt = 10.0 Hz), (2H, m), 2.29 (1H, dt, Jd = 14.0 Hz, Jt = 4.8 Hz), 2.79 (1H, dd, J = 9.2, 14.4 Hz), 2.86 (1H, dd, J = 5.2, 14.4 Hz), 3.03 (1H, tt, J = 5.2, 10.8 Hz), 4.16 (2H, q, J = 7.2 Hz), 4.67 (1H, dd, J = 4.8, 9.2 Hz), (1H, m), 7.05 (2H, d, J = 7.2 Hz), (8H, m); 13 C-NMR δ 14.2, 28.0 (3C), 34.5, 35.3, 37.0, 41.0, 50.7, 56.6, 60.6, 80.2, (2C), 126.1, 126.4, (2C), (2C), (2C), 145.1, 145.8, 156.2, 171.3; IR (neat) ν 2979, 2931, 1733, 1682, 1166, 1132, 758, 697 cm -1 ; HRMS (ESI): [M+Na] + calculated for C26H33NO4Na: , found m/z , [α]d (c 0.73, CHCl3). H HdH CO 2 Et Ha H Hc Hb noe Ha dd J = 4.8, 9.6 Hz Hb dt J d =13.6Hz,J t =10.0Hz Hc dt J d =14.0Hz,J t =4.8Hz Hd tt J =5.2,10.8 Hz S 14

16 References 1) W. Wang, H. Li, J. Wang., Org. Lett., 2005, 7, ) R. Shintani, G. C. Fu., Angew. Chem., Int. Ed. 2002, 41, S 15

17 S16

18 S17

19 S18

20 S19

21 O 2 N S20

22 S21

23 Br S22

24 S23

25 MeO S24

26 S25

27 O S26

28 S27

29 EtO 2 C S28

30 S29

31 Br S30

32 S31

33 S32

34 S33

35 O S34

36 S35

37 CO 2 Et NHBoc S36

38 S37

39 CO 2 Et S38

40 S39

41 CO 2 Et S40

42 S41