Oxidative Rearrangement via in situ generated N-Chloroamine: Synthesis of Fused Tetrahydroisoquinolines

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1 Oxidative Rearrangement via in situ generated N-Chloroamine: Synthesis of Fused Tetrahydroisoquinolines Kenichi Murai*, Kei Matsuura, Hiroshi Aoyama, Hiromichi Fujioka* Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamada-oka, Suita, Osaka, (Japan) Tel: (+81) , Fax: (+81) Supporting Information Table of Contents 1. Page S2 General 2. Page S2 Preparation of compound 1 3. Page S9 Reaction in Table 2 (Oxidative rearrangement reaction with NaBH4) 4. Page S13 Reactions in Table 3 (Reaction with carbon nucleophiles) 5. Page S16 Reactions in Scheme 3 (Synthesis of crispine A and analogues) 6. Page S18 Reactions in Scheme 4 (Reaction with the norcamphor derivative) 7. Page S20 X-ray crystallographic analysis of 6a TsOH 8. Page S22 NMR study 9. Page S24 1 H and 13 C NMR Data 10. Page S90 2D NMR data for 1f-CHO, 1g, 2f, 2g, and 5-CHO S1

2 1. General Melting points were measured by BÜCHI B-545 and all melting points were uncorrected. 1 H-NMR and 13 C-NMR spectra were measured by JEOL JNM-ECS 400, JEOL ECS 300 or JEOL JNM-LA 500 spectrometers with tetramethylsilane as an internal standard. IR spectra were recorded by Shimadzu FTIR 8400 using a diffuse reflectance measurement of samples dispersed in KBr powder. High resolution mass spectra and elemental analysis were performed by the Elemental Analysis Section of Osaka University. Column chromatography was performed with SiO 2 (Merck Silica Gel 60 ( mesh) or Kanto Chemical Silicagel 60 (spherical, m). Microwave irradiations were performed in Biotage Initiator+. Unless otherwise noted, materials were purchased from Aldrich Inc., Kanto Kagaku, Wako Chemicals, and other commercial suppliers and were used without purification. 2-(3,4-Methylenedioxyphenyl)ethylamine, cyclobutanone 7a, 7b, and 7c were prepared according to the literature Preparation of compound 1 General Method A A 20 ml or 5 ml microwave vial was charged with arylethylamine (1.0 equiv), cyclobutanone (1.1 equiv), trifluoroacetic acid (8 equiv), and toluene (0.3 M) at rt. The reaction vial was placed in the microwave reactor and heated to 140 o C for 4 h. The reaction mixture was poured into sat. NaHCO 3 aq. and the solution was basified with 10% NaOH aq.. The mixture was extracted with CH 2 Cl 2. The organic layer was dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by SiO 2 column chromatography to give compound 1. 1 For 2-(3,4-Methylenedioxyphenyl)ethylamine ; F. Crestey, A. A. Jensen, M. Borch, J. T. Andreasen, J. Andersen, T. Balle, J. L. Kristensen, J. Med. Chem. 2013, 56, 9673.; for 7a: H.-J. Xu, F.-F. Zhu, Y.-Y. Shen, X. Wan, Y.-S. Feng, Tetrahedron, 2012, 68, 4145.; for 7b: Y. L. Bennani, B. Huck, M. J. Robarge, PCT Int. Appl. (2006), WO ; for 7b: A. Rioz-Martínez1, G. Gonzalo1, D. E. Torres Pazmiño, M. W. Fraaije, V. Gotor, Eur. J. Org. Chem. 2009, ; for 7c: B. M. Trost, J. Xie, J. Am. Chem. Soc. 2008, 130, S2

3 General Method B (2 step preparation) 2 X NH 2 R O Ti(OiPr) 4 HCOOH R' Ac 2 O X R 1-CHO NCHO R' NaOH 1st step: Under N 2, the mixture of ketone (1.0 equiv), arylethylamine (1.5 equiv), and Ti(OiPr) 4 was heated at 80 o C for 3 h. After the reaction mixture was cooled to 0 o C, the mixture of HCOOH (100 equiv) and Ac 2 O (100 equiv) was added to the reaction mixture and the resulting solution was heated at 70 o C for 2 h. After trifluoroacetic acid (200 equiv) was added to the reaction mixture, the resulting solution was heated at 70 o C overnight. After the completion of the reaction, the solution was diluted with AcOEt and the reaction was quenched with NaHCO 3 aq.. The organic layer was washed with NaHCO 3 aq. and brine, dried over Na 2 SO 4, and evaporated in vacuo. The residue was roughly purified by SiO 2 column chromatography to give 1-CHO. 2nd step: The solution of 1-CHO and NaOH in EtOH/H 2 O (1/1) was heated under reflux. After the completion of the reaction, the solution was diluted with H 2 O. The mixture was extracted with CH 2 Cl 2. The organic layer was dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by SiO 2 column chromatography to give compound 1. X R 1 NH R' Compound 1a Reaction was carried out according to the general method A with 2-(3-methoxyphenyl)-ethylamine (0.29 ml, 1.98 mmol), cyclobutanone (0.17 ml, 2.18 mmol), and trifluoroacetic acid (1.2 ml, 15.9 mmol) in toluene (6.6 ml) to give 1a (332.5 mg, 82%) as pale yellow oil. Column chromatography: SiO 2, AcOEt/triethylamine = 20/1 1 H NMR (500 MHz, CDCl 3 ): δ= 7.41 (d, J = 8.6 Hz, 1H), 6.79 (dd, J = 8.6, 2.9 Hz, 1H), 6.57 (d, J = 2.9 Hz, 1H), 3.78 (s, 3H), 3.06 (t, J = 5.8 Hz, 2H), 2.76 (t, J = 5.8 Hz, 2H), (m, 2H), (m, 3H), ppm (m, 1H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 157.5, 135.6, 135.3, 126.5, 113.1, 112.5, 59.1, 55.2, 39.5, 37.3, 30.5, 14.5 ppm; IR (KBr): 3280, 2930, 1609 cm -1 ; HRMS (MALDI-TOF): calcd for C 13 H 18 NO [M+H] + : , found Y. Horiguchi, H. Kodama, M. Nakamura, T. Yoshimura, K. Hanezi, H. Hamada, T. Saitoh, T. Sano, Chem. Pharm. Bull. 2002, 50, 253. S3

4 Compound 1b Reaction was carried out according to the general method A with 2-(3,4-methylenedioxyphenyl)ethylamine (170.8 mg, 1.03 mmol), cyclobutanone (0.10 ml, 1.30 mmol), and trifluoroacetic acid (0.64 ml, 8.36 mmol) in toluene (3.5 ml) to give 1b (42.8 mg, 19 %) as pale yellow oil. Column chromatography: SiO 2, AcOEt/triethylamine = 20/1 1 H NMR (300 MHz, CDCl 3 ): δ= 6.98 (s, 1H), 6.50 (s, 1H), 5.91 (s, 2H), 3.03 (t, J = 5.8 Hz, 2H), 2.68 (t, J = 5.8 Hz, 2H), (m, 2H), ppm (m, 4H); 13 C NMR (100.5 MHz, CDCl 3 ): δ= 146.1, 145.6, 136.4, 127.3, 108.3, 105.5, 100.6, 59.5, 39.5, 37.3, 30.3, 14.5 ppm; IR (KBr): 3283, 2933, 1503, 1484 cm -1 ; HRMS (MALDI-TOF): calcd for C 13 H 16 NO 2 [M+H] + : , found Compound 1c Title compound was prepared according to the general method B. 1st reaction was carried out with 2-(3-methylphenyl)ethylamine (0.24 ml, 1.61 mmol), cyclobutanone (0.08 ml, 1.08 mmol), Ti(OiPr) 4 (0.51 ml, 1.62 mmol), HCOOH (4.6 ml, 110 mmol), Ac 2 O (10.4 ml, 110 mmol) and trifluoroacetic acid (16.8 ml, 220 mmol) to give 1c-CHO (181.9 mg, 78%) as pale yellow oil. Column chromatography: SiO 2, AcOEt/triethylamine = 20/1. 2nd reaction was carried out with 1c-CHO (181.9, mmol) and NaOH (2.1 g, 53 mmol) in EtOH/H 2 O (1/1, 4.2 ml) to give 1c (45.5 mg, 29%) as pale yellow oil. Column chromatography: SiO 2, AcOEt/triethylamine = 20/1 1 H NMR (500 MHz, CDCl 3 ): δ= 7.39 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.86 (s, 1H), 3.05 (t, J = 5.8 Hz, 2H), 2.74 (t, J = 5.8 Hz, 2H), (m, 2H), 2.29 (s, 3H), (m, 3H), ppm (m, 2H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 140.2, 135.4, 133.8, 129.3, 127.0, 125.3, 59.1, 39.5, 37.2, 30.1, 20.9, 14.5 ppm; IR (KBr): 3285, 2930, 1662 cm -1 ; HRMS (MALDI-TOF): calcd for C 13 H 18 N [M+H] + : , found Synthesis of 1d 1d was prepared from 1e as following scheme. S4

5 Compound 1e-Tf To a solution of 1e (83.4 mg, mmol) in CH 2 Cl 2 (4.4 ml) was added Et 3 N (0.14 ml, 0.97 mmol) at rt and the reaction mixture was cooled to -78 o C. Tf 2 O (0.16 ml, 0.97 mmol) was added to the resulting solution at -78 o C and the resulting mixture was stirred for 1 h. The reaction was quenched with sat. NaHCO 3 aq.. The mixture was extracted with CH 2 Cl 2. The organic layer was dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by SiO 2 column chromatography (AcOEt/Hexane = 1/8) to give compound 1e-Tf (189.3 mg, 95%) as colorless solid. Mp: o C; 1 H NMR (300 MHz, CDCl 3 ): δ= 7.60 (d, J = 8.8 Hz, 1H), 7.18 (dd, J = 8.8, 2.4 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), (m, 2H), (m, 2H), (m, 2H), (m, 2H), ppm (m, 2H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 148.6, 140.8, 135.3, 124.7, 122.4, 119.4, (q, J = 321 Hz), (q, J = 320 Hz), 62.7, 42.3, 34.9, 28.6, 13.7 ppm; IR (KBr): 2966, 1490, 1424, 1381 cm -1 ; HRMS (MALDI-TOF): calcd for C 14 H 13 NO 5 F 6 NaS 2 [M+H] + : , found Compound 1d-Tf To a solution of 1e-Tf (168.6 mg, mmol) in MeOH (3.7 ml) were added 10% Pd/C (17.5 mg, 10 wt%), Mg (48.4 mg, 1.99 mmol) and NH 4 OAc (307.0 mg, 3.98 mmol) at rt 3 and the resulting solution was stirred at rt for 17 h. The reaction mixture was filtered through a celite (eluent: AcOEt) and the filtrate was evaporated in vacuo. The residue was purified by SiO 2 column chromatography (AcOEt/Hexane = 1/12) to give compound 1d-Tf (97.1 mg, 86%) as colorless oil. 1 H NMR (400 MHz, CDCl 3 ): δ= (m, 1H), (m, 2H), (m, 1H), (m, 2H), (m, 2H), (m, 2H), (m, 2H), ppm (m, 2H); 13 C NMR (100.5 MHz, CDCl 3 ): δ= 140.3, 132.1, 129.8, 127.6, 126.6, 122.6, (q, J = 322 Hz), 63.2, 42.8, 34.9, 28.4, 13.8 ppm; IR (KBr): 2970, 1382 cm -1 ; HRMS (MALDI-TOF): calcd for C 13 H 14 NO 2 F 3 NaS [M+H] + : , found H. Sajiki, A. Mori, T. Mizusaki, T. Ikawa, T. Maegawa, K. Hirota, Org. Lett., 2006, 8, 987. S5

6 Compound 1d To a solution of 1d-Tf (97.1 mg, mmol) in toluene (3.7 ml) was added Red-Al (0.9 ml, 3.18 mmol) and the resulting solution was heated to 50 o C. After being stirred for 15 h, the solution was cooled to rt and the reaction was quenched with sat. Rochell's salt aq.. The mixture was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by SiO 2 column chromatography (AcOEt/triethylamine = 20/1) to give compound 1d (39.8 mg, 72%) as pale yellow oil. 1 H NMR (500 MHz, CDCl 3 ): δ= 7.50 (d, J = 8.3 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 7.12 (td, J = 7.4, 1.1 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 3.07 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 2H), (m, 2H), (m, 3H), ppm (m, 2H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 143.1, 134.0, 128.8, 126.2, 125.9, 125.3, 59.3, 39.5, 37.3, 30.1, 14.6 ppm; IR (KBr): 3276, 2931 cm -1 ; HRMS (MALDI-TOF): calcd for C 12 H 16 N [M+H] + : , found Compound 1e To a solution of 1a (128.3 mg, mmol) in CH 2 Cl 2 was added BBr 3 (1.0 M in CH 2 Cl 2, 3.2 mmol), at -20 o C and the resulting solution was stirred at the same temperature for 18 h. The reaction was quenched with MeOH and the resulting solution was concentrated in vacuo. The residue was purified by SiO 2 column chromatography (AcOEt/MeOH/trimethylamine = 15/1/0.8) to give compound 1e (107.9 mg, 90%) as colorless solid. Mp: o C; 1 H NMR (500 MHz, CD 3 OD): δ= 7.34 (d, J = 8.8. Hz, 1H), 6.65 (dd, J = 8.8, 2.8 Hz, 1H), 6.45 (d, J = 2.8 Hz, 1H), 2.97 (t, J = 6.0 Hz, 2H), 2.73 (t, J = 6.0 Hz, 2H), (m, 2H), (m, 2H), ppm (m, 2H); 13 C NMR (125.8 MHz, CD 3 OD): δ= 157.0, 135.3, 133.4, 127.3, 115.6, 115.2, 60.4, 39.8, 37.2, 29.5, 14.6 ppm; IR (KBr): 3269, 2940, 1612 cm -1 ; HRMS (MALDI-TOF): calcd for C 12 H 16 NO [M+H] + : , found Compound 1f Title compound was prepared according to the general method B. 1st reaction was carried out with 2-(3-methoxyphenyl)ethylamine (0.43 ml, 2.93 mmol), cyclobutanone 7a (242.6 mg, 1.95 mmol), Ti(OiPr) 4 (0.92 ml, 2.93 mmol), HCOOH (8.2 ml, 195 mmol), Ac 2 O (18.7 ml, 195 mmol) and trifluoroacetic acid (29.9 ml, 391 mmol) to give 1f-CHO (408.6 mg, 73%) as S6

7 yellow solid. Column chromatography: SiO 2, Hexane/AcOEt = 2/1. 2nd reaction was carried out with 1f-CHO (258.6 mg, mmol) and NaOH (3.2 g, 54.4 mmol) in EtOH/H 2 O (1/1, 7.7 ml) to give 1f (182.5 mg, 78%) as pale yellow oil. Column chromatography: SiO 2, Hexane/AcOEt = 1/1 to AcOEt/triethylamine = 20/1. 1f-CHO: Mp: o C; 1 H NMR (500 MHz, CDCl 3 ): δ= 8.25 (s, 1H), 7.39 (d, J = 8.6 Hz, 1H), 6.78 (dd, J = 8.6, 2.3 Hz, 1H), 6.75 (d, J = 2.3 Hz, 1H), (m, 1H), 3.81 (s, 3H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 1H), (m, 3H), (m, 2H), ppm (m, 1H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 161.2, 158.7, 136.7, 134.3, 123.0, 114.1, 111.2, 59.8, 55.3, 45.0, 39.3, 29.5, 27.4, 25.7, 25.5, 23.9, 22.4, 21.1 ppm; IR (KBr): 2930, 1652, 1612 cm -1 ; HRMS (MALDI-TOF): calcd for C 18 H 24 NO 2 [M+H] + : , found H NMR (500 MHz, CDCl 3 ): δ= 7.47 (d, J = 8.6 Hz, 1H), 6.77 (dd, J = 8.6, 2.9 Hz, 1H), 6.58 (d, J = 2.9 Hz, 1H), 3.78 (s, 3H), (m, 1H), (m, 1H), (m, 1H), 2.69 (td, J = 16.1, 5.1 Hz,1H), (m, 2H), (m, 1H), (m, 2H), (m, 4H), (m, 3H), ppm (m, 1H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 157.4, 136.8, 135.7, 125.5, 113.3, 112.1, 58.2, 55.2, 44.8, 41.2, 40.2, 30.1, 27.0, 25.5, 21.5, 21.2, 20.8 ppm; IR (KBr): 3320, cm -1 ; HRMS (MALDI-TOF): calcd for C 17 H 24 NO [M+H] + : , found Stereochemistry was determined by NOESY of 1f-CHO. Compound 1g Title compound was prepared according to the general method B. 1st reaction was carried out with 2-(3-methoxyphenyl)ethylamine (0.32 ml, 2.20 mmol), cyclobutanone 7b (222.2 mg, 1.40 mmol), Ti(OiPr) 4 (0.65 ml, 2.07 mmol), HCOOH (5.8 ml, 138 mmol), Ac 2 O (13.2 ml, 138 mmol) and trifluoroacetic acid (21.2 ml, 276 mmol) to give 1g-CHO (367.5 mg, 83%) as pale yellow oil. Column chromatography: SiO 2, Hexane/AcOEt = 5/4. 2nd reaction was carried out with 1g-CHO (367.5, 1.15 mmol) and NaOH (4 g, 100 mmol) in EtOH/H 2 O (1/1, 6.5 ml) to give 1g (298.1 mg, 89%) as pale yellow solid. Column chromatography: SiO 2, Hexane/AcOEt = 1/1 to 1/3. Mp: o C; 1 H NMR (500 MHz, CDCl 3 ): δ= 7.53 (d, J = 8.6 Hz, 1H), (m, 1H), (m, 3H), 6.87 (dd, J = 8.6, 2.9 Hz, 1H), 6.57 (d, J = 2.9 Hz, 1H), (m, 1H), 3.80 (s, 3H), (m, 1H), (m, 1H), 3.12 (dd, J = 17.8, 9.7 Hz, 1H), (m, 2H), (m, S7

8 1H), (m, 2H), ppm (m, 1H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 157.4, 148.2, 144.4, 136.8, 135.3, , , 126.6, 124.8, 124.3, 112.9, 57.7, 55.2, 50.2, 47.2, 39.9, 39.0, 32.8, 30.3 ppm; IR (KBr): 3335, 2925, 1610 cm -1 ; HRMS (MALDI-TOF): calcd for C 20 H 22 NO [M+H] + : , found Stereochemistry was determined by NOESY. MeO NH H H 1g Compound 1h Title compound was prepared according to the general method B. 1st reaction was carried out with 2-(3-methoxyphenyl)ethylamine (0.32 ml, 2.16 mmol), cyclobutanone 7c (320.5 mg, 1.44 mmol), Ti(OiPr) 4 (0.68 ml, 2.16 mmol), HCOOH (5.7 ml, 144 mmol), Ac 2 O (13.6 ml, 144 mmol) and trifluoroacetic acid (22.1 ml, 288 mmol) to give 1h-CHO (401.6 mg, 73%) as pale yellow solid. Column chromatography: SiO 2, Hexane/AcOEt = 5/4. 2nd reaction was carried out with 1h-CHO (401.6 mg, 1.05 mmol) and NaOH (4.0 g, 100 mmol) in EtOH/H 2 O (1/1, 6.5 ml) to give 1h (307.9 mg, 83%) as colorless solid. Column chromatography: SiO 2, Hexane/AcOEt = 1/3 Mp: o C; 1 H NMR (400 MHz, CDCl 3 ): δ= (m, 2H), (m, 6H), (m, 2H), 7.02 (d, J = 8.7 Hz, 1H), 6.64 (dd, J = 8.7, 2.7 Hz, 1H), 6.54 (d, J = 2.7 Hz, 1H), 3.74 (s, 3H), (m, 2H), (m, 2H), 2.97 (t, J = 6.0 Hz, 2H), 2.76 (t, J = 6.0 Hz, 2H); 13 C NMR (100.5 MHz, CDCl 3 ): δ= 157.5, 150.6, 150.0, 136.0, 134.8, 128.6, 128.4, 127.2, 126.3, 125.9, 125.6, 125.5, 113.0, 112.4, 55.1, 55.0, 51.0, 44.4, 39.4, 30.5 ppm; IR (KBr): 3331, 2935, 1609 cm -1 ; HRMS (MALDI-TOF): calcd for C 25 H 26 NO [M+H] + : , found S8

9 3. Reaction in Table 2 (Oxidative rearrangement reaction with NaBH4) General Procedure A To a solution of 1 (1.0 equiv) in MeOH ( M) was added NCS (1.1 equiv) at 0 o C and the reaction mixture was stirred at rt. After the disappearance of N-chloroamine (checked by TLC), NaBH 4 was added to the resulting solution at 0 o C and stirred for 1 h. The reaction was quenched with sat. NH 4 Cl aq. and the solution was basified with 10% NaOH aq.. The mixture was extracted with CH 2 Cl 2. The organic layer was dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by SiO 2 column chromatography to give compound 2. General Procedure B To a solution of 1 (1.0 equiv) in CF 3 CH 2 OH ( M) was added NCS (1.1 equiv) at 0 o C and the reaction mixture was stirred at rt. After the disappearance of N-chloroamine (checked by TLC), CF 3 CH 2 OH was evaporated in vacuo and to the residue was added MeOH ( M). NaBH 4 was added to the resulting solution at 0 o C and stirred for 1 h. The reaction was quenched with sat. NH 4 Cl aq. and the solution was basified with 10% NaOH aq.. The misxture was extracted with CH 2 Cl 2. The organic layer was dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by SiO 2 column chromatography to give compound 2. Compound 2a Reaction was carried out according to the general procedure A with 1a (21.5 mg, mmol), NCS (15.7 mg, mmol), and NaBH 4 (12.3 mg, mmol) in MeOH (1.1 ml) to give 2a (21.0 mg, 98%) as colorless oil. Reaction time for rearrangement: 10.5 h; Column chromatography: SiO 2, AcOEt/triethylamine = 25/1 1 H NMR (500 MHz, CDCl 3 ): δ= 6.99 (d, J = 8.3 Hz, 1H), 6.71 (dd, J = 8.3, 2.3 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H), 3.77 (s, 3H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), 2.62 (ddd, J = 10.8, 10.8, 4.6 Hz, 1H), 2.52 (q, J = 8.4 Hz, 1H), (m, 1H), (m, 2H), ,65 ppm (m, 1H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 157.7, 135.5, 131.3, 126.5, 113.2, 111.8, 63.0, 55.2, 53.3, 48.4, 30.3, 28.9, 22.1 ppm; IR (KBr): 2939, 1611 cm -1 ; HRMS (MALDI-TOF): calcd for C 13 H 18 NO [M+H] + : , found Compound 2b O O N Reaction was carried out according to the general procedure A with 1b (22.2 mg, mmol), NCS (15.2 mg, mmol), and NaBH 4 (12.0 mg, mmol) in MeOH (1.0 ml) to give 2b (21.4 mg, 96%) as pale yellow oil. Reaction time for rearrangement: 24 h; Column chromatography: SiO 2, S9

10 AcOEt/triethylamine = 20/1 1 H NMR (500 MHz, CDCl 3 ): δ= 6.58 (s, 1H), 6.55 (s, 1H), 5.88 (s, 2H), (m, 1H), 3.16 (ddd, J = 11.2, 6.3, 3.2 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), 2.51 (q, J = 8.6 Hz, 1H), (m, 1H), (m, 2H), ppm (m, 1H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 145.7, 145.6, 131.9, 127.2, 108.3, 105.8, 100.5, 63.4, 53.2, 48.4, 30.4, 28.7, 22.0 ppm; IR (KBr): 2904 cm -1 ; HRMS (MALDI-TOF): calcd for C 13 H 16 NO 2 [M+H] + : , found Compound 2c Reaction was carried out according to the general procedure A with 1d (23.7 mg, mmol), NCS (18.5 mg, mmol), and NaBH 4 (14.7 mg, mmol) in MeOH (1.3 ml) to give 2d (21.6 mg, 91%) as pale yellow oil. Reaction time for rearrangement: 12 h; Column chromatography: SiO 2, AcOEt/triethylamine = 20/1 1 H NMR (400 MHz, CDCl 3 ): δ= (m, 3H), (m, 1H), 3.10 (ddd, J = 11.0, 6.0, 2.7 Hz, 1H), (m, 2H), (m, 1H), (m, 1H), 2.45 (q, J = 8.7 Hz, 1H), (m, 1H), 2.22 (s, 3H), (m, 2H), ppm (m, 1H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 135.8, 135.4, 134.0, 129.0, 126.5, 125.5, 63.0, 53.2, 48.3, 30.4, 28.4, 22.2, 21.0 ppm; IR (KBr): 2966 cm -1 ; HRMS (MALDI-TOF): calcd for C 13 H 18 N [M+H] + : , found Compound 2d Reaction was carried out according to the general procedure A with 1d (20.0 mg, mmol), NCS (17.1 mg, mmol), and NaBH 4 (14.4 mg, mmol) in MeOH (2.0 ml) to give 2d (11.7 mg, 59%) as colorless oil. Reaction time for rearrangement: 24 h; Column chromatography: SiO 2, AcOEt/triethylamine = 20/1 1 H NMR (300 MHz, CDCl 3 ): δ= (m, 4H), (m, 1H), (m, 1H) (m, 2H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), ppm (m, 1H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 138.8, 134.1, 128.4, 126.0, 125.7, 125.6, 63.4, 53.4, 48.5, 30.2, 28.6, 22.2 ppm; IR (KBr): 2952 cm -1 ; HRMS (MALDI-TOF): calcd for C 12 H 16 N [M+H] + : , found S10

11 Compound 2e To a solution of 1e (20.6 mg, mmol) in MeOH (1.1 ml) was added NCS (16.4 mg, mmol) at 0 o C and the reaction mixture was stirred at rt for 7 h. NaBH 4 (12.4 mg, mmol) was added to the resulting solution at 0 o C and stirred for 1 h. The solution was concentrated in vacuo and the residue was purified by SiO 2 column chromatography to give compound 2e (11.7 mg, 57%) as colorless solid. Mp: o C; 1 H NMR (500 MHz, CD 3 OD): δ= 6.91 (d, J = 8.0 Hz, 1H), 6.59 (dd, J = 8.0, 2.3 Hz, 1H), 6.55 (d, J = 2.3 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), 2.80 (td, J = 16.6, 4.6 Hz, 1H), (m, 2H), (m, 1H), (m, 2H), ppm (m, 1H); 13 C NMR (125.8 MHz, CD 3 OD): δ= 156.9, 136.0, 130.0, 127.8, 115.6, 114.4, 64.3, 54.3, 49.2, 31.3, 29.4, 22.9 ppm; IR (KBr): 2935 cm -1 ; HRMS (MALDI-TOF): calcd for C 12 H 16 NO [M+H] + : , found Compound 2f Reaction was carried out according to the general procedure A with 1f (29.1 mg, mmol), NCS (17.0 mg, mmol), and NaBH 4 (13.8 mg, mmol) in MeOH (1.1 ml) at -78 o C to give 2f (22.5 mg, 77%) as pale yellow oil. Reaction time for rearrangement: 1 h; Column chromatography: SiO 2, Hexane/AcOEt = 1/2 1 H NMR (400 MHz, CDCl 3 ): δ= 6.95 (d, J = 8.3 Hz, 1H), 6.69 (dd, J = 8.3, 2.3 Hz, 1H), 6.66 (d, J = 2.3 Hz, 1H), 3.77 (s, 3H), (m, 1H), (m, 2H), 2.83 (dd, J = 16.7, 4.8 Hz, 1H), (m, 1H), (m, 1H), 2.22 (ddd, J = 11.0, 11.0, 5.0 Hz, 1H), (m, 1H), (m, 1H), (m, 4H), ppm (m, 4H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 157.8, 135.9, 132.7, 125.7, 113.4, 111.3, 64.5, 63.1, 55.2, 47.4, 36.0, 30.7, 30.0, 29.7, 25.0, 24.0, 20.2 ppm; IR (KBr): 2927, 1610 cm -1 ; HRMS (MALDI-TOF): calcd for C 17 H 24 NO [M+H] + : , found Stereochemistry was determined by NOESY. MeO H N H S11

12 Compound 2g Reaction was carried out according to the general procedure A with 1g (29.4 mg, mmol), NCS (15.2 mg, mmol), and NaBH 4 (12.2 mg, mmol) in MeOH (2.0 ml) to give 2g (21.9 mg, 75%) as colorless solid. Reaction time for rearrangement: 22 h; Column chromatography: SiO 2, Hexane/AcOEt = 1/3 Mp: o C; 1 H NMR (500 MHz, CDCl 3 ): δ= (m, 4H), 6.96 (d, J = 8.6 Hz, 1H), 6.66 (dd, J = 8.6, 2.9 Hz, 1H), 6.60 (d, J = 2.9 Hz, 1H), (m, 1H), 3.73 (s, 3H), (m, 2H), 3.21 (t, J = 6.9 Hz, 1H), (m, 3H), (m, 1H), 2.82 (dd, J = 17.2, 4.6 Hz, 1H), 2.46 (ddd, J = 11.4, 11.4, 4.6 Hz, 1H), 1.68 ppm (ddd, J = 11.4, 11.4, 6.3 Hz, 1H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 157.9, 147.2, 141.8, 135.7, 131.1, 126.7, 126.5, 125.8, 125.2, 124.4, 113.3, 111.5, 68.2, 65.0, 55.2, 48.3, 48.0, 37.2, 36.6, 30.0 ppm; IR (KBr): 2904, 1611 cm -1 ; HRMS (MALDI-TOF): calcd for C 20 H 22 NO [M+H] + : , found Stereochemistry was determined by NOESY. Compound 2h MeO N Ph Ph Reaction was carried out according to the general procedure B with 1h (16.2 mg, mmol), NCS (7.2 mg, mmol), and NaBH 4 (5.7 mg, mmol) in CF 3 CH 2 OH (1.8 ml) and MeOH (1.0 ml) to give 2h (16.2 mg, 100%) as colorless solid. Reaction time for rearrangement: 22 h; Column chromatography: SiO 2, Hexane/AcOEt= 1/2 Mp: o C; 1 H NMR (500 MHz, CDCl 3 ): δ= (m, 2H), (m, 2H), (m, 5H), ,12 (m, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.73 (dd, J = 8.3, 2.3 Hz, 1H), 6.66 (d, J = 2.3 Hz, 1H), (m, 1H), 3.78 (s, 3H), (m, 1H), 3.47 (d, J = 9.1 Hz, 1H), (m, 2H), (m, 2H), (m, 1H), 2.32 ppm (dd, J = 12.0, 10.3 Hz, 1H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 157.6, 136.3, 128.3, 128.1, 127.3, , , 126.0, 125.9, 113.2, 112.2, 65.1, 59.9, 55.2, 53.3, 48.2, 47.0, 27.2 ppm; IR (KBr): 2931, 1611 cm -1 ; HRMS (MALDI-TOF): calcd for C 25 H 26 NO [M+H] + : , found S12

13 4. Reactions in Table 3 (Reaction with carbon nucleophiles) Compound 3a To a solution of 1a (21.4 mg, mmol) in MeOH (1.1 ml) was added NCS (15.6 mg, mmol) at 0 o C and the reaction mixture was stirred at rt for 28 h. MeOH was removed in vacuo and to the residue were added CH 2 Cl 2 (0.6 ml) and THF (0.6 ml). AllylMgBr solution (0.7 M in THF, 1.5 ml, 1.05 mmol) was added to the resulting solution at 0 o C and the reaction mixture was stirred for 3 h at rt. The reaction was quenched with sat. NH 4 Cl aq. and the solution was basified with 10% NaOH aq.. The mixture was extracted with CH 2 Cl 2. The organic layer was dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by SiO 2 column chromatography (AcOEt/triethylamine = 20/1) to give compound 3a (21.9 mg, 86%) as pale yellow oil. 1 H NMR (500 MHz, CDCl 3 ): δ= 7.05 (d, J = 8.6 Hz, 1H), 6.74 (dd, J = 8.6, 2.9 Hz, 1H), 6.59 (d, J = 2.9 Hz, 1H), (m, 1H), (m, 2H), 3.78 (s, 3H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), ppm (m, 1H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 157.2, , , 135.2, 128.2, 116.6, 112.8, 112.4, 64.8, 55.1, 51.2, 46.8, 43.6, 37.8, 24.7, 22.6 ppm; IR (KBr): 2932, 1609 cm -1 ; HRMS (MALDI-TOF): calcd for C 16 H 22 NO [M+H] + : , found Compound 3b To a solution of 1a (20.9 mg, mmol) in MeOH (1.0 ml) was added NCS (15.1 mg, mmol) at 0 o C and the reaction mixture was stirred at rt for 9 h. MeOH was removed in vacuo and to the residue was added CH 2 Cl 2 (0.5 ml). MeMgBr solution (0.91 M in THF, 1.1 ml, 1.03 mmol) was added to the resulting solution at 0 o C and the reaction mixture was stirred for 2.5 h at rt. The reaction was quenched with sat. NH 4 Cl aq. and the solution was basified with 10% NaOH aq.. The mixture was extracted with CH 2 Cl 2. The organic layer was dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by SiO 2 column chromatography (AcOEt/triethylamine = 20/1) to give compound 3b (12.2 mg, 55%) as pale yellow oil. 1 H NMR (500 MHz, CDCl 3 ): δ= 7.10 (d, J = 8.6 Hz, 1H), 6.75 (dd, J = 8.6, 2.3 Hz, 1H), 6.58 (d, J = 2.3 Hz, 1H), 3.78 (s, 3H), (m, 1H), (m, 3H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), 1.41 ppm (s, 3H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 157.2, 136.1, 135.0, 127.8, 112.8, 112.7, 62.4, 55.1, 50.6, 43.1, 40.2, 30.1, 24.5, 22.3 ppm; IR (KBr): 2963, 1609, 1500 cm -1 ; HRMS (MALDI-TOF): calcd for C 14 H 20 NO [M+H] + : , found S13

14 Compound 3c To a solution of 1a (22.6 mg, mmol) in MeOH (1.1 ml) was added NCS (16.5 mg, mmol) at 0 o C and the reaction mixture was stirred at rt for 11 h. MeOH was removed in vacuo and to the residue was added CH 2 Cl 2 (1.1 ml). EtMgBr solution (1.0 M in THF, 1.1 ml, 1.11 mmol) was added to the resulting solution at 0 o C and the reaction mixture was stirred for 2 h at rt. The reaction was quenched with sat. NH 4 Cl aq. and the solution was basified with 10% NaOH aq.. The mixture was extracted with CH 2 Cl 2. The organic layer was dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by SiO 2 column chromatography (AcOEt/triethylamine = 20/1) to give compound 3c (22.3 mg, 87%) as pale yellow oil. 1 H NMR (500 MHz, CDCl 3 ): δ= 7.06 (d, J = 8.6 Hz, 1H), 6.74 (dd, J = 8.6, 2.8 Hz, 1H), 6.59 (d, J = 2.8 Hz, 1H), 3.78 (s, 3H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), 2.58 (td, J = 16.2, 4.7 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 3H), 0.80 ppm (t, J = 7.4 Hz, 3H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 157.0, 136.0, 135.5, 128.1, 112.7, 112.3, 65.5, 55.1, 51.8, 44.6, 38.0, 35.0, 25.5, 22.8, 9.3 ppm; IR (KBr): 2959, 1609 cm -1 ; HRMS (MALDI-TOF): calcd for C 15 H 22 NO [M+H] + : , found Compound 3d To a solution of 1a (22.4 mg, mmol) in MeOH (1.1 ml) was added NCS (16.7 mg, mmol) at 0 o C and the reaction mixture was stirred at rt for 8 h. MeOH was removed in vacuo and to the residue was added CH 2 Cl 2 (1.1 ml). iprmgbr solution (1.0 M in THF, 1.1 ml, 1.10 mmol) was added to the resulting solution at 0 o C and the reaction mixture was stirred for 6 h at rt. The reaction was quenched with sat. NH 4 Cl aq. and the solution was basified with 10% NaOH aq.. The mixture was extracted with CH 2 Cl 2. The organic layer was dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by SiO 2 column chromatography (AcOEt/triethylamine = 20/1) to give compound 3d (22.7 mg, 84%) as pale yellow oil. 1 H NMR (500 MHz, CDCl 3 ): δ= 7.09 (d, J = 8.6 Hz, 1H), 6.73 (dd, J = 8.6, 2.9 Hz, 1H), 6.59 (d, J = 2.9 Hz, 1H), 3.78 (s, 3H), (m, 1H), (m, 1H), (m, 2H), 2.76 (ddd, J = 16.6, 7.4, 7.4 Hz, 1H), 2.55 (td, J = 17.2, 5.6 Hz, 1H), 2.15 (ddd, J = 12.6, 8.6, 4.6 Hz, 1H), (m, 2H), (m, 1H), (m, 1H), 0.93 (d, J = 6.9 Hz, 3H), 0.84 ppm (d, J = 6.9 Hz, 3H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 157.0, 136.2, 135.1, 128.7, 112.7, 111.8, 67.4, 55.1, 52.3, 44.7, 37.9, 35.9, 24.8, 22.9, 18.7, 18.4 ppm; IR (KBr): 2954, 1608 cm -1 ; HRMS (MALDI-TOF): calcd for C 16 H 24 NO [M+H] + : , found S14

15 Compound 3e MeO N To a solution of 1a (21.0 mg, mmol) in MeOH (1.0 ml) was added NCS (15.2 mg, mmol) at 0 o C and the reaction mixture was stirred at rt for 17 h. MeOH was removed in vacuo and to the residue was added CH 2 Cl 2 (1.0 ml). VinylMgBr solution (1.0 M in THF, 1.0 ml, 1.03 mmol) was added to the resulting solution at 0 o C and the reaction mixture was stirred for 4 h at rt. The reaction was quenched with sat. NH 4 Cl aq. and the solution was basified with 10% NaOH aq.. The mixture was extracted with CH 2 Cl 2. The organic layer was dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by SiO 2 column chromatography (AcOEt/triethylamine = 20/1) to give compound 3e (19.0 mg, 80%) as pale yellow oil. 1 H NMR (500 MHz, CDCl 3 ): δ= 7.03 (d, J = 8.6 Hz, 1H), 6.74 (dd, J = 8.6, 2.9 Hz, 1H), 6.60 (d, J = 2.9 Hz, 1H), 5.94 (dd, J = 17.2, 10.3 Hz, 1H), 5.05 (dd, 10.3, 1.4 Hz, 1H), 4.70 (dd, J = 17.2, 1.4 Hz, 1H), 3.78 (s, 3H), (m, 1H), (m, 3H), (m, 1H), (m, 1H), 2.21 (ddd, J = 12.6, 9.2, 5.7 Hz, 1H), 2.13 (ddd, J = 12.6, 8.6, 6.3 Hz, 1H), (m, 1H), ,66 ppm (m, 1H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 157.5, 145.7, 136.3, 131.4, 129.3, 114.3, 112.8, 112.3, 66.9, 55.1, 49.8, 42.5, 38.5, 24.4, 22.6 ppm; IR (KBr): 2933, 1608 cm -1 ; HRMS (MALDI-TOF): calcd for C 15 H 20 NO [M+H] + : , found Compound 3f To a solution of 1a (18.7 mg, mmol) in MeOH (1.0 ml) was added NCS (13.9 mg, mmol) at 0 o C and the reaction mixture was stirred at rt for 11 h. MeOH was removed in vacuo and to the residue was added CH 2 Cl 2 (1.0 ml). PhenylethynylMgBr solution (1.0 M in THF, 0.9 ml, mmol) was added to the resulting solution at 0 o C and the reaction mixture was stirred for 3.5 h at rt. The reaction was quenched with sat. NH 4 Cl aq. and the solution was basified with 10% NaOH aq.. The mixture was extracted with CH 2 Cl 2. The organic layer was dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by SiO 2 column chromatography (AcOEt/triethylamine = 20/1) to give compound 3f (24.1 mg, 86%) as pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ= (m, 2H), (m, 4H), 6.68 (dd, J = 8.2, 2.7 Hz, 1H), 6.57 (d, J = 2.7 Hz, 1H), 3.71 (s, 3H), (m, 4H), (m, 1H), (m, 1H), (m, 1H), ppm (m, 3H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 158.1, 135.0, 132.4, 131.8, 131.7, 128.0, 127.7, 127.1, 123.4, 113.3, 112.3, 91.0, 85.7, 61.6, 55.2, 50.1, 43.8, 39.1, 27.6, 21.4 ppm; IR (KBr): 2938, 1608 cm -1 ; HRMS (MALDI-TOF): calcd for C 21 H 22 NO [M+H] + : , found S15

16 Comparison of solvent 5. Reactions in Scheme 3 (Synthesis of crispine A and analogues) Compound 1i Reaction was carried out according to the general method A with 2-(3,4-dimethoxyphenyl)ethylamine (0.52 ml, 3.0 mmol), cyclobutanone (0.254 ml, 3.3 mmol), and trifluoroacetic acid (1.84 ml, 24 mmol) in toluene (10 ml) to give 1i (551.3 mg, 79%) as pale yellow oil. Column chromatography: SiO 2, AcOEt/triethylamine = 20/1 1 H NMR (500 MHz, CDCl 3 ): δ= 6.98 (s, 1H), 6.52 (s, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.06 (t, J = 6.3 Hz, 2H), 2.70 (t, J = 6.3 Hz, 2H), (m, 2H), (m, 3H), ppm (m, 1H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 147.5, 147.4, 135.1, 126.4, 111.3, 108.6, 59.2, 56.1, 55.8, 39.7, 37.1, 29.8, 14.8 ppm; IR (KBr): 3304, 2934 cm -1 ; HRMS (MALDI-TOF): calcd for C 14 H 20 NO 2 [M+H] + : , found Compound 4a (crispine A) 4 MeO MeO N Reaction was carried out according to the general procedure A with 1i (24.2 mg, mmol), NCS (15.4 mg, mmol), and NaBH 4 (12.2 mg, mmol) in MeOH (1.0 ml) to give 4a (22.3 mg, 92%) as pale yellow solid. Reaction time for rearrangement: 15.5 h; Column chromatography: SiO 2, 4 Q. Zhang, G. Tu, Y. Zhao, T. Cheng, Tetrahedron 2002, 58, S16

17 AcOEt/triethylamine = 20/1 Mp: o C (lit o C); 1 H NMR (500 MHz, CDCl 3 ): δ= 6.61 (s, 1H), 6.57 (s, 1H), 3.85 (s, 3H), 3.84 (s, 3H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 147.3, 147.2, 130.9, 126.2, 111.3, 108.8, 62.9, 56.0, 55.8, 53.1, 48.3, 30.5, 28.0, 22.2 ppm; IR (KBr): 2936, 1507 cm -1 ; HRMS (MALDI-TOF): calcd for C 14 H 20 NO 2 [M+H] + : , found Compound 4b MeO MeO N To a solution of 1i (27.0 mg, mmol) in MeOH (1.2 ml) was added NCS (17.4 mg, mmol) at 0 o C and the reaction mixture was stirred at rt for 15.5 h. MeOH was removed in vacuo and to the residue was added CH 2 Cl 2 (1.2 ml). AllylMgCl solution (1.0 M in THF, 1.1 ml, 1.16 mmol) was added to the resulting solution at 0 o C and the reaction mixture was stirred for 3 h at rt. The reaction was quenched with sat. NH 4 Cl aq. and the solution was basified with 10% NaOH aq.. The mixture was extracted with CH 2 Cl 2. The organic layer was dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by SiO 2 column chromatography (AcOEt/triethylamine = 20/1) to give compound 4b (24.7 mg, 78%) as pale yellow oil. 1 H NMR (500 MHz, CDCl 3 ): δ= 6.61 (s, 1H), 6.54 (s, 1H), (m, 1H), (m, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.22 (ddd, J = 13.2, 10.3, 4.6 Hz, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 3H), (m, 1H), 1.98 (ddd, J = 16.6, 12.6, 8.0 Hz, 1H), (m, 1H), ppm (m, 1H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 147.2, 146.9, 135.7, 134.9, 126.3, 116.6, 110.9, 110.1, 64.9, 56.0, 55.7, 50.8, 46.6, 43.3, 37.7, 23.4, 22.5 ppm; IR (KBr): 2928, 1512 cm -1 ; HRMS (MALDI-TOF): calcd for C 17 H 24 NO 2 [M+H] + : , found Compound 4c To a solution of 1i (24.8 mg, mmol) in MeOH (1.1 ml) was added NCS (15.7 mg, mmol) at 0 o C and the reaction mixture was stirred at rt for 17 h. MeOH was removed in vacuo and to the residue was added CH 2 Cl 2 (1.1 ml). BnMgCl solution (0.96 M in THF, 1.1 ml, 1.06 mmol) was added to the resulting solution at 0 o C and the reaction mixture was stirred for 4 h at rt. The reaction was quenched S17

18 with sat. NH 4 Cl aq. and the solution was basified with 10% NaOH aq.. The mixture was extracted with CH 2 Cl 2. The organic layer was dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by SiO 2 column chromatography (AcOEt/triethylamine = 20/1) to give compound 4c (25.7 mg, 75%) as pale yellow oil. 1 H NMR (500 MHz, CDCl 3 ): δ= (m, 3H), (m, 2H), 6.53 (s, 1H), 6.17 (s, 1H), 3.85 (s, 3H), 3.62 (s, 3H), 3.20 (ddd, J = 12.6, 9.7, 4.6 Hz, 1H), (m, 1H), (m, 5H), 2.38 (td, J = 16.0, 4.3 Hz, 1H), 2.25 (ddd, J = 12.6, 8.0, 4.6 Hz, 1H), 1.93 (ddd, J = 16.0, 12.6, 8.0 Hz, 1H) (m, 1H), ppm (m, 1H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 146.9, 146.5, 138.8, 133.6, 131.0, 127.4, 127.0, 125.9, 110.8, 110.7, 65.9, 55.70, 55.65, 51.4, 48.5, 43.9, 38.1, 24.1, 22.5 ppm; IR (KBr): 2935, 1609, 1512 cm -1 ; HRMS (MALDI-TOF): calcd for C 21 H 26 NO 2 [M+H] + : , found Reactions in Scheme 4 (Reaction with the norcamphor derivative) Compound 5 Title compound was prepared according to the general method B. 1st reaction was carried out with 2-(3-methoxyphenyl)ethylamine (0.44 ml, 2.96 mmol), norcamphor (233.1 mg, 1.40 mmol), Ti(OiPr) 4 (0.95 ml, 3.03 mmol), HCOOH (8.4 ml, 0.2 mol), Ac 2 O (19.1 ml, 0.2 mol) and trifluoroacetic acid (30.6 ml, 0.4 mol) to give 5-CHO (333.4 mg, 59%) as pale yellow oil. Column chromatography: SiO 2, Hexane/AcOEt = 1/1. 2nd reaction was carried out with 5-CHO (195.5 mg, 0.72 mmol) and NaOH (2.32 g, 58 mmol) in EtOH/H 2 O (3.6 ml) to give 5 (112.5 mg, 64%) as pale yellow oil. Column chromatography: SiO 2, AcOEt/triethylamine = 20/1 5-CHO: 1 H NMR (500 MHz, CDCl 3 ): δ= 8.44 (s, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.69 (dd, J = 8.6, 2.9 Hz, 1H), 6.64 (d, J = 8.6 Hz, 1H), (m, 1H), 3.77 (s, 3H), (m, 1H), (m, 1H), 2.83 (ddd, J = 16.9, 7.5, 2.3 Hz, 1H), (m, 2H), (m, 1H), 2.01 (dd, J = 14.0, 2.3 Hz, 1H), (m, 1H), (m, 2H), 1.53 (td, J = 12.6, 4.5 Hz, 1H), (m, 1H), ppm (m, 1H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 163.3, 158.3, 136.1, 135.6, 125.9, 114.5, 110.7, 66.9, 55.2, 47.9, 37.5, 37.1, 36.3, 35.0, 29.8, 27.3, 22.8 ppm; IR (KBr): 2960, 1657, 1608 cm -1 ; HRMS (MALDI-TOF): calcd for C 17 H 22 NO 2 [M+H] + : , found : 1 H NMR (500 MHz, CDCl 3 ): δ= 7.19 (d, J = 8.6 Hz, 1H), 6.68 (dd, J = 8.6, 2.9 Hz, 1H), 6.61 (d, J = 2.9 Hz, 1H), 3.77 (s, 3H), (m, 2H), (m, 1H), (m, 1H), (m, 3H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), 1.18 ppm (dd, J = 13.2, 2.8 Hz, 1H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 157.5, 137.8, 135.7, 127.2, 114.1, 110.7, 62.1, 55.1, 46.9, 46.4, 40.0, 37.0, 36.5, 29.3, 29.1, 23.5 ppm; IR (KBr): 3324, cm -1 ; HRMS (MALDI-TOF): calcd for C 16 H 22 NO [M+H] + : , found Stereochemistry was determined by NOESY of 5f-CHO. S18

19 Compound 6a Reaction was carried out according to the general procedure B with 5 (29.8 mg, mmol), NCS (18.4 mg, mmol), and NaBH 4 (13.9 mg, mmol) in CF 3 CH 2 OH (1.2 ml) and MeOH (1.2 ml) to give 6a (18.5 mg, 62%) as colorless oil. Reaction time for rearrangement: 8 h; Column chromatography: SiO 2, Hexane/AcOEt= 4/1 1 H NMR (500 MHz, CDCl 3 ): δ= 7.11 (d, J = 8.6 Hz, 1H), 6.70 (dd, J = 8.6, 2.3 Hz, 1H), 6.61 (d, J = 2.3 Hz, 1H), 3.77 (s, 3H), (m, 1H), 3.06 (s, 1H), 2.80 (dd, J = 11.8, 6.3 Hz, 1H), (m, 2H), (m, 1H), 2.49 (ddd, J = 11.8, 11.8, 4.1 Hz, 1H), 2.36 (d, J = 10.3 Hz, 1H), (m, 1H), (m, 4H), ppm (m, 2H); 13 C NMR (125.8 MHz, CDCl 3 ): δ= 157.4, 137.5, 130.5, 125.4, 113.5, 111.4, 66.9, 62.3, 55.1, 51.8, 38.41, 38.38, 35.6, 30.1, 29.0, 25.6 ppm; IR (KBr): 2935, 1502 cm -1 ; HRMS (MALDI-TOF): calcd for C 16 H 22 NO [M+H] + : , found Compound 6b MeO N To a solution of 5 (26.4 mg, mmol) in CF 3 CH 2 OH (1.1 ml) was added NCS (16.1 mg, mmol) at 0 o C and the reaction mixture was stirred at rt for 10 h. CF 3 CH 2 OH was removed in vacuo and to the residue was added CH 2 Cl 2 (0.6 ml) and THF (0.6 ml). AllylMgBr solution (1.0 M in Et 2 O, 1.1 ml, 1.1 mmol) was added to the resulting solution at 0 o C and the reaction mixture was stirred for 0.5 h at rt. The reaction was quenched with sat. NH 4 Cl aq. and the solution was basified with 10% NaOH aq.. The mixture was extracted with CH 2 Cl 2. The organic layer was dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by SiO 2 column chromatography (Hexane/AcOEt = 4/1) to give compound 6b (18.5 mg, 60%) as pale yellow oil. 1 H NMR (500 MHz, CDCl 3 ): δ= 7.01 (d, J = 8.6 Hz, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 1H), 3.77 (s, 3H), (m, 2H), 2.84 (d, J = 10.3 Hz, 1H), (m, 2H), (m, 2H), (m, 1H), 2.29 (dd, J = 14.1, 7.4 Hz, 1H), (m, 1H), 1.90 (d, J = 11.5 Hz, 1H), (m, 2H), ppm (m, 3H); 13 C NMR (125.8 MHz, S19

20 CDCl 3 ): δ= 157.2, 136.8, 135.6, 134.7, 126.1, 117.0, 113.7, 110.2, 61.6, 57.4, 55.0, 45.0, 40.4, 35.6, 34.8, 32.2, 29.3, 28.8, 26.4 ppm; IR (KBr): 2933, 1609, 1502 cm -1 ; HRMS (MALDI-TOF): calcd for C 19 H 26 NO [M+H] + : , found X-ray crystallographic analysis of 6a TsOH 6a TsOH was prepared 6a and TsOH H 2 O (1.0 equiv). Crystallization Method:Re-crystallization from AcOEt and Hexane. Single crystal X-ray diffraction data were collected under nitrogen gas flow on Rigaku AFC-7R diffractometer and Mercury CCD detector equipped with graphite-monochoromatic Mo K radiation ( Å), installed at the institute of scientific and industrial research, Osaka University. A transparent block of crystal was mounted on LithoLoops (Moleclular Deimensions, USA) with vacuum grease under an optical microscope. The intensity data sets were integrated by CrystalClear software. 5 The absorption corrections were carried out by the empirical method. The structures were solved by direct methods using SIR2004 program 6 and refined by full-matrix least squares on F 2 using SHELXL-97 program 7, implemented in program package WinGX. 8 The final models include anisotropic refinement for the non-hydrogen atoms and an isotropic riding model for H atoms. Further details of the refinements are given table S1. Crystallographic data for the structures reported in this paper have been deposited at the Cambridge Crystallographic Data Centre (CCDC ). Table S2. Crystallographic data and structure refinement for 6a TsOH: Compound 6a TsOH Moiety formula C 16 H 22 NO, C 7 H 7 O 3 S Sum formula C 23 H 29 NO 4 S Formula weight Temperature (K) 123(2) Crystal system triclinic Space group P-1 a (A ) (1) b (A ) (17) c (A ) (3) ( ) (4) ( ) (3) 5 CrystalClear Rigaku Corporation, The Woodlands, Texas, USA, M. C. Burla, R. Caliandro, M. Camalli, B. Carrozzini, G. L. Cascarano, L. De Caro, C. Giacovazzo, G. Polidori, R. Spagna, J. Appl. Crystallogr. 2005, 38, G. M. Sheldrick. Acta Cryst. 2008, A64, L. J. Farrugia J. Appl. Crystallogr. 1999, 32, S20

21 ( ) (4) V (A 3 ) (3) Z 2 D calcd (g/cm 3 ) Data completeness Data / parameters 4,504 / 263 R wr Goodness-of-fit c Full structure 6a TsOH S21

22 8. NMR Study S22

23 13 C NMR of the intermediate single pulse decoupled gated NOE DFILE carbon_carbon-1-1 COMNT single pulse decoupled gate DATIM :32:06 OBNUC 13C EXMOD carbon.jxp OBFRQ MHz OBSET 7.87 KHz OBFIN 4.21 Hz POINT FREQU Hz SCANS 439 ACQTM sec PD sec PW usec CTEMP 20.5 c SLVNT CD3OD EXREF ppm RGAIN S23

24 9. 1 H and 13 C NMR Data of 2a 1 H NMR chart of 1a single_pulse DFILE _proton-1-1.als COMNT single_pulse DATIM :16:42 OBNUC 1H EXMOD proton.jxp OBFRQ MHz OBSET 2.41 KHz OBFIN 6.01 Hz POINT FREQU Hz SCANS 16 ACQTM sec PD sec PW usec CTEMP 20.0 c EXREF 0.00 ppm RGAIN S24

25 13 C NMR chart of 1a single pulse decoupled gated NOE DFILE carbon_carbon-1-1 COMNT single pulse decoupled gate DATIM :19:57 OBNUC 13C EXMOD carbon.jxp OBFRQ MHz OBSET 7.87 KHz OBFIN 4.21 Hz POINT FREQU Hz SCANS 500 ACQTM sec PD sec PW usec CTEMP 20.5 c EXREF ppm RGAIN S25

26 1 H NMR chart of 1b single_pulse F:\NMR\140275_proton-1-1.als DFILE _proton-1-1.als COMNT single_pulse DATIM :56:09 OBNUC 1H EXMOD proton.jxp OBFRQ MHz OBSET 1.15 KHz OBFIN 8.57 Hz POINT FREQU Hz SCANS 16 ACQTM sec PD sec PW usec CTEMP 17.9 c EXREF 0.00 ppm RGAIN S26

27 13 C NMR chart of 1b single pulse decoupled gated NOE F:\NMR\ for data_carbon-1-1.als DFILE for data_carbon-1- COMNT single pulse decoupled gate DATIM :12:29 OBNUC 13C EXMOD carbon.jxp OBFRQ MHz OBSET 5.35 KHz OBFIN 5.86 Hz POINT FREQU Hz SCANS 1000 ACQTM sec PD sec PW usec CTEMP 20.7 c EXREF ppm RGAIN S27

28 1 H NMR chart of 1c single_pulse DFILE for data_proton-1-1 COMNT single_pulse DATIM :19:52 OBNUC 1H EXMOD proton.jxp OBFRQ MHz OBSET 2.41 KHz OBFIN 6.01 Hz POINT FREQU Hz SCANS 16 ACQTM sec PD sec PW usec CTEMP 17.3 c EXREF 0.00 ppm RGAIN S28

29 13 C NMR chart of 1c single pulse decoupled gated NOE DFILE for data_carbon-1- COMNT single pulse decoupled gate DATIM :23:09 OBNUC 13C EXMOD carbon.jxp OBFRQ MHz OBSET 7.87 KHz OBFIN 4.21 Hz POINT FREQU Hz SCANS 512 ACQTM sec PD sec PW usec CTEMP 18.0 c EXREF ppm RGAIN S29

30 1 H NMR chart of 1e-Tf single_pulse DFILE _proton-1-1.als COMNT single_pulse DATIM :42:11 OBNUC 1H EXMOD proton.jxp OBFRQ MHz OBSET 1.15 KHz OBFIN 8.57 Hz POINT FREQU Hz SCANS 16 ACQTM sec PD sec PW usec CTEMP 19.5 c EXREF 0.00 ppm RGAIN S30

31 13 C NMR chart of 1e-Tf single pulse decoupled gated NOE DFILE _Carbon-1-1.al COMNT single pulse decoupled gate DATIM :08:24 OBNUC 13C EXMOD carbon.jxp OBFRQ MHz OBSET 7.87 KHz OBFIN 4.21 Hz POINT FREQU Hz SCANS 7500 ACQTM sec PD sec PW usec CTEMP 21.2 c EXREF ppm RGAIN S31

32 1 H NMR chart of 1d-Tf single_pulse DFILE d.p._proton-1-1.als COMNT single_pulse DATIM :04:22 OBNUC 1H EXMOD proton.jxp OBFRQ MHz OBSET 4.19 KHz OBFIN 7.29 Hz POINT FREQU Hz SCANS 16 ACQTM sec PD sec PW usec CTEMP 20.1 c EXREF 0.00 ppm RGAIN S32

33 13 C NMR chart of 1d-Tf single pulse decoupled gated NOE DFILE d.p._carbon-1-1.als COMNT single pulse decoupled gate DATIM :09:41 OBNUC 13C EXMOD carbon.jxp OBFRQ MHz OBSET 5.35 KHz OBFIN 5.86 Hz POINT FREQU Hz SCANS 9300 ACQTM sec PD sec PW usec CTEMP 19.9 c EXREF ppm RGAIN S33

34 1 H NMR chart of 1d single_pulse DFILE _proton-1-1.als COMNT single_pulse DATIM :07:51 OBNUC 1H EXMOD proton.jxp OBFRQ MHz OBSET 2.41 KHz OBFIN 6.01 Hz POINT FREQU Hz SCANS 16 ACQTM sec PD sec PW usec CTEMP 19.7 c EXREF 0.00 ppm RGAIN S34