Supplementary Information

Transcription

1 FeCl 3 -catalyzed highly diastereoselective synthesis of substituted piperidines and tetrahydropyrans Amandine Guérinot, Anna Serra-Muns, Christian Gnamm, Charlélie Bensoussan, Sébastien Reymond* and Janine Cossy* Supplementary Information Table of contents General experimental methods Experimental section Compounds of Table 1 Compounds of Table 2 Compounds of Table 3 Page S2 Pages S2-S30 Pages S2-S9 Pages S9-S19 Pages S20-S30

2 General experimental methods Infrared (IR) spectra were recorded on a Bruker TENSR TM 27 (IRFT), wave-numbers are indicated in cm 1. NMR spectra were recorded on a Bruker AVANCE H NMR spectra were recorded at 400 MHz and data are reported as follows: chemical shift in ppm from tetramethylsilane as an internal standard with the residual solvent peak as an internal indicator (CDCl 3 δ: 7.26), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or overlap of non-equivalent resonances), integration. 13 C NMR spectra were recorded at 100 MHz and data are reported as follows: chemical shift in ppm from tetramethylsilane with the solvent as an internal indicator (CDCl 3 δ 77.1 ppm), multiplicity with respect to proton (deduced from DEPT experiments, s = quaternary C, d = CH, t = CH 2, q = CH 3 ). CH 2 Cl 2 was distilled from CaH 2. THF and Et 2 were dried over Na/benzophenone prior to distillation. TLC was performed on silica gel plates visualized either with a UV lamp (254 nm), or using solutions of p-anisaldehyde sulfuric acid acetic acid in EtH followed by heating. Filtration was performed on silica gel (Merck-Kieselgel 60, mesh). Mass spectra with electronic impact (MS-EI) were recorded on a GC/MS (70 ev). HRMS were performed at the Laboratoire de Spectrométrie de Masse SM 3 E de l Université Pierre et Marie Curie in Paris. Table 1. FeCl 3 -catalyzed synthesis of 2-alkenylpiperidines. General procedure A : cross-metathesis between amines of type 8/13 and allylic acetates of type 9 : To a solution of amine of type 8 or 13 (1 equiv) and allylic acetates of type 9 (3 equiv) in CH 2 Cl 2 (0.1 M) was added Grubbs-Hoveyda catalyst (0.05 equiv). The reaction mixture was stirred overnight at 40 C and the solvent was removed under reduced pressure. A flash chromatography on silica gel previously neutralized by NEt 3 afforded compounds of type 1 and 3. Acetate 9a 1, amines 8a-8b 2 and 8c 3 were prepared following reported procedures. 1 Marion, N.; Gealageas, R.; Nolan, S. P. rg. Lett. 2007, 9, Michael, F. E.; Cochran, B. M. J. Am. Chem. Soc. 2006, 128, Marcotullio, M. C.; Campagna, V.; Sternativo, F.; Curini, M. Synthesis 2006, 16, S2

3 Acetic acid 1-methyl-allyl ester (9b) But-3-en-2-ol (1.6 ml, 40 mmol, 1 equiv) was dissolved in CH 2 Cl 2 (80 ml) and the solution was cooled to 0 C. NEt 3 (6.7 ml, 48 mmol, 1.2 equiv), DMAP (488 mg, 4 mmol, 0.1 equiv) and Ac 2 (4.9 ml, 52 mmol, 1.3 equiv) were added and the resulting mixture was stirred overnight. It was then poured into water (50 ml), the two phases were separated, the organic layer was washed with a saturated solution of NaHC 3 in water (50 ml), dried over MgS 4 and filtered. Dichloromethane was distilled thanks to a distillation apparatus. The residue was also distilled (P atm, T = 120 C) to afford a 2.4/1 mixture of allylic acetate 9b and acetic anhydride. IR (neat) : 2954, 2926, 2856, 2359, 1826, 1738, 1458, 1369, 1241, 1123, 1049 cm H NMR (400 MHz, CDCl 3 ) δ : 5.82 (ddd, J = 16.6, 10.6, 6.0 Hz), (m), 5.22 (dt, J = 17.3, 1.3 Hz), 5.11 (dt, J = 10.5, 1.3 Hz, 1H), 2.03 (s, 3H), 1.29 (d, J = 6.5 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (d), (t), 71.0 (d), 21.3 (q), 19.9 (q). Acetic acid 1-(2,4,6-trimethyl-phenyl)-allyl ester (9c) To a solution of mesitaldehyde (10 mmol, 1.4 ml, 1 equiv) in THF (100 ml) at -78 C was added a solution of vinylmagnesium bromide (13 mmol, 1 M in THF, 1.3 equiv). After 1 h at -78 C, the reaction media was warmed to room temperature and stirred until complete conversion. The reaction mixture was then cooled to 0 C and acetic anhydride (1.4 ml, 15 mmol, 1.5 equiv) was added. After one night at room temperature, the reaction mixture was quenched with a saturated solution of ammonium chloride in water (80 ml). The two phases were separated and the aqueous phase was extracted with diethyl ether (3 x 50 ml). The organic layers were combined, dried over MgS 4, filtered and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography on silica gel previously neutralized by NEt 3 (PE/Et 2 : 97/3 to 9/1) to give 9c (90%). IR (neat) : 2922, 1738, 1612, 1448, 1371, 1235, 1018 cm H NMR (400 MHz, CDCl 3 ) δ : 6.83 (s, 2H), 6.70 (m, 1H), 6.07 (ddd, J = 17.3, 10.6, 4.5 Hz, 1H), 5.18 (dd, J = 10.6, 2.0 Hz, 1H), 5.09 (dd, J = 17.3, 2.0 Hz, 1H), 2.39 (s, 6H), 2.26 (s, 3H), 2.08 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (s), (2s), (d), (s), (d), (t), 73.1 (d), 21.2 (q), 21.0 (q), 20.6 (2q). HRMS (ESI) : Calculated for C 14 H 18 Na 2 [M+Na] + : Found : S3

4 Acetic acid (E)-7-tert-butoxycarbonylamino-1- phenyl-hept-2-enyl ester (1a, mixture of rotamers (60/40)) N H Prepared according to the general procedure A with amine 8a 2 and allylic acetate 9a 1 (37% yield). IR (neat) : 3362, 2931, 1698, 1517, 1453, 1391, 1366, 1237, 1170, 1019 cm H NMR (400 MHz, C 6 D 6 ) δ : (m, 1H), (m, 2H), (m, 2H), 6.60 (d, J = 15.7 Hz, 0.6H), 6.45 (m, 0.4H), 6.05 (dd, J = 16.9, 8.2 Hz, 0.6H), (m, 0.8H), 5.48 (q, J = 6.9 Hz, 0.6H), (m, 1H), (m, 2H), 1.74 (s, 1.8H), 1.70 (s, 1.2H), (m, 0.6H), 1.45 (s, 9H), (m, 4.4H, H 4β -H 2 -H 3 ). 13 C NMR (100 MHz, C 6 D 6 ) δ : (s), (s), (s), (s), (s), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), 78.4 (s), 76.4 (d), 74.6 (d), 40.5 (t), 34.6 (t), 32.1 (t), 30.2 (t), 29.8 (t), 28.6 (q), 26.2 (t), 22.7 (t), 20.9 (2q). MS (EI) m/z : 339 (18), 268 (20), 267 (88), 199 (8), 183 (9), 69 (100). HRMS (ESI) : Calculated for C 20 H 29 NNa 4 [M + Na] + : Found : H NMR (400 MHz, C 6 D 6 ) δ : 7.37 (d, J = 7.4 Hz, 2H), 7.27 (d, J = 7.3 Hz, 2H), (m, 6H), 6.48 (d, J = 4.8 Hz, 1H), (m, 2H), 5.10 (m, 2H), 4.05 (br s, 1H), (m, 2H), (m, 2H), 1.70 (s, 3H), (m, 4H). 13 C NMR (100 MHz, C 6 D 6 ) δ : (s), (s), (s), (s), (d), (d), (d), (d), (d), (d), (d), 76.4 (d), 66.6 (t), 40.9 (t), 32.0 (t), 29.7 (t), 26.1 (t), 20.9 (q). HRMS (ESI) : Calculated for C 23 H 27 NNa 4 [M + Na] + : Found : Acetic acid (E)-7-benzyloxycarbonylamino-1- phenyl-hept-2-enyl ester (1b, mixture of rotamers) N H Prepared according to the general procedure A with amine 8b 2 and allylic acetate 9a 1 (46% yield). IR (neat) : 3338, 2922, 2856, 1700, 1524, 1455, 1370, 1232, 1135, 1018 cm -1. Ac (2E)-7-{[(4-Methylphenyl)sulfonyl]amino}-1-phenylhept-2- en-1-yl acetate (1c) NHTos Prepared according to the general procedure A with amine 8c 3 and allylic acetate 9a 1 (70% yield). IR (neat) : 3275, 2923, 1731, 1598, 1494, 1427, 1370, 1323, 1231, 1155, 1092, 1018 cm H NMR (400 MHz, C 6 D 6 ) δ : 7.88 (d, J = 8.3 Hz, 2H), (m, 2H), (m, 2H), (m, 1H), 6.88 (d, J = 7.8 Hz, 2H), (m, 1H), (m, 2H), 5.12 (t, J = 6.0 Hz, 1H), 2.71 (dt, J = 6.9, 6.6 Hz, 2H), 1.95 (s, 3H), (m, 2H), 1.73 (s, 3H), (m, 2H), (m, 2H). S4

5 13 C NMR (100 MHz, C 6 D 6 ) δ : (s), (s), (s), (s), (d), (2d), (d), (2d), (d), (2d), (2d), 76.4 (d), 43.2 (t), 31.8 (t), 29.2 (t), 25.9 (t), 21.2 (q), 21.0 (q). HRMS (ESI) : Calculated for C 22 H 27 NNa 4 S [M+Na] + : Found : Ac (2E)-1-Methyl-7-{[(4-methylphenyl)sulfonyl]amino}hept-2-en-1- yl acetate (1d) NHTos Prepared according to the general procedure A with amine 8c 3 and acetate 9b (30% yield). IR (neat) : 3273, 2927, 1729, 1598, 1428, 1370, 1324, 1239, 1155, 1092, 1039 cm H NMR (400 MHz, C 6 D 6 ) δ : 8.01 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.3 Hz, 2H), (m, 4H), 2.87 (dt, J = 6.8, 6.7 Hz, 2H), 2.07 (s, 3H), (m, 2H), 1.83 (s, 3H), (m, 2H), 1.28 (d, J = 6.3 Hz, 3H), (m, 2H). 13 C NMR (100 MHz, C 6 D 6 ) δ : (s), (s), (s), (d), (d), (2d), (2d), 71.1 (d), 43.2 (t), 31.8 (t), 29.2 (t), 26.0 (t), 21.2 (q), 21.1 (q), 20.5 (q). HRMS (ESI) : Calculated for C 17 H 25 NNa 4 S [M+Na] + : Found : (2E)-7-{[(4-Methylphenyl)sulfonyl]amino}hept-2-en-1-yl Ac NHTos acetate (1e, E/Z = 89/11) Prepared according to the general procedure A with amine 8c 3 and acetic acid (Z)-4-acetoxy-but-2- enyl ester (E/Z : 89/11, 97% yield). IR (neat) : 3280, 2935, 2864, 1736, 1431, 1326, 1234, 1158, 1094, 1024, 971, 815, 663 cm H NMR (400 MHz, C 6 D 6 ) δ : 7.91 (d, J = 7.6 Hz, 2H), 6.94 (d, J = 7.3 Hz, 2H), 5.60 (br s, 1H), (m, 2H), 4.42 (d, J = 5.6 Hz, 2H), 2.79 (dt, J = 6.2 Hz, 6.2 Hz, 2H), 2.00 (s, 3H), (m, 2H), 1.74 (s, 3H), (m, 2H), (m, 2H). 13 C NMR (100 MHz, C 6 D 6 ) δ : (s), (s), (s), (d), (2d), (2d), (d), 65.2 (t), 43.2 (t), 31.8 (t), 29.2 (t), 25.9 (t), 21.2 (q), 20.7 (q). MS (EI) m/z : = 265 ([M-AcH] +, 1),184 ([TosNHCH 2 ] +, 14), 170 ([M-Tos] +, 3), 155 ([M-TosNH] +, 26), 110 (30), 92 (12), 91 (100), 82 (10.2), 79 (20), 67 (11), 65 (36), 54 (13). HRMS (ESI) : Calculated for C 16 H 23 NNa 4 S [M+Na] + : Found : H N-[(5E)-7-Hydroxy-7-phenylhept-5-en-1-yl]-4- methylbenzenesulfonamide (1f) NHTos K 2 C 3 (243 mg, 2.5 mmol, 5 equiv) was added to a solution of acetate 1c (197 mg, 491 µmol, 1 equiv) in methanol (6 ml). The mixture was stirred at room temperature for 15 h. Water (5 ml) was added and the mixture was extracted with ethyl acetate (3 x 10 ml). The combined organic layers were dried over Na 2 S 4 and S5

6 concentrated in vacuo. Purification by flash column chromatography on silica gel (PE/EtAc : 4/1 to 2/1) gave alcohol 1f (157 mg, 89 %) as a colorless oil. IR (neat) : 3270, 2921, 2859, 1598, 1450, 1320, 1152, 1092 cm H NMR (400 MHz, C 6 D 6 ) δ : 7.86 (d, J = 8.3 Hz, 2H), (m, 2H), (m, 2H), (m, 1H), 6.86 (d, J = 8.0 Hz, 2H), (m, 2H), (m, 2H), 2.71 (dt, J = 6.7, 6.6 Hz, 2H), 2.19 (m, 1H), 1.93 (s, 3H), 1.73 (dt, J = 6.7, 6.5 Hz, 2H), (m, 2H), (m, 2H). 13 C NMR (100 MHz, C 6 D 6 ) δ : (s), (s), (s), (d), (d), (2d), (2d) (2d), (d), (2d), 75.1 (d), 43.2 (t), 31.8 (t), 29.2 (t), 26.0 (t), 21.2 (q). HRMS (ESI) : Calculated for C 20 H 25 NNa 3 S [M+Na] + : Found : N-[(5E)-7-Hydroxyhept-5-en-1-yl]-4-methylbenzenesulfonamide H NHTos (1g, E/Z = 89/11) K 2 C 3 (340 mg, 3.43 mmol, 5 equiv) was added to a solution of acetate 1e (223 mg, mmol, 1 equiv) in methanol (5 ml). The mixture was stirred at room temperature for 16 h. Water (5 ml) was added and the mixture was extracted with ethyl acetate (3 x 10 ml). The combined organic layers were dried over Na 2 S 4 and concentrated in vacuo. Purification by flash column chromatography on silica gel (PE/EtAc : 4/1 to 3/1 to 2/1) gave alcohol 1g (186 mg, 96 %) as an inseparable mixture of stereoisomers (E/Z = 89/11 according to 1 H NMR) as a colorless oil. IR (neat) : 3270, 2921, 2858, 1722, 1598, 1427, 1320, 1243, 1153, 1091, 1043 cm H NMR (400 MHz, C 6 D 6 ) δ : (m, 2H), (m, 2H), (m, 1H), (m, 2H), 4.07 (m, 2H), 3.30 (m, 1H), 2.86 (m, 2H), 2.05 (s, 3H), (m, 2H), (m, 2H), (m, 2H). 13 C NMR (100 MHz, C 6 D 6 ) δ : (s), (s), (d), (d), (2d), (2d), 63.5 (t), 43.4 (t), 31.9 (t), 29.2 (t), 26.3 (t), 21.3 (q). MS (EI) m/z : 238 (2), 155 ([Tos] +, 23), 128 ([M-Tos] +, 8), 110 (15), 92 (12), 91 ([C 7 H 7 ] +, 100), 84 (11), 79 (18), 67 (13), 65 (42), 55 (16). HRMS (ESI) : Calculated for C 14 H 21 NNa 3 S [M+Na] + : Found : S6

7 General procedure B : iron-catalyzed cyclizations : To a solution of substrate A in CH 2 Cl 2 (0.1 M) at room temperature was added FeCl 3.6H 2 (5 mol %). After the required time (see Tables for details), the resulting mixture was directly filtered through a pad of silica gel (CH 2 Cl 2 ) and the volatiles were removed under reduced pressure to yield the corresponding cyclized product B without any further purification. FeCl 3.6H 2 (cat.) XH R 1 CH 2 Cl 2 X R 1 R 3 R 2 A 1a-1g 3a-3g 5a-5i X=NPG, R 1,R 2 =H,Alk,Ar R 3 =H,Ac R 2 B 2a-2e 4a-4g 6a-6i 2-((E)-Styryl)-piperidine-1-carboxylic acid tert-butyl ester (2a) Prepared according to general procedure B using 1a (72%). N IR (neat) : 2931, 2857, 1687, 1599, 1542, 1496, 1449, 1407, 1364, 1322, Boc 1269, 1250, 1161, 1092, 1072, 1039 cm -1 1 H NMR (400 MHz, CDCl 3 ) δ : (m, 4H), (m, 1H), 6.32 (dd, J = 16.1, 1.9 Hz, 1H), 6.11 (dd, J = 16.1, 4.9 Hz, 1H), 4.89 (bs, 1H), 3.93 (d, J = 14.1 Hz, 1H), 2.84 (td, J = 12.7, 2.4 Hz, 1H), (m, 2H), (m, 4H), 1.40 (s, 9H) 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (s), (d), (d), (2d), (d), (2d), 79.6 (s), 52.4 (d), 40.0 (t), 29.7 (t), 28.6 (q), 25.7 (t), 19.8 (t); MS (EI) m/z : 232 (8), 231 (51), 230 ([M-tBu] +, 5), 214 (5), 187 (21), 186 (100), 170 (14), 158 (7), 145 (6), 144 (6), 143 (5), 141 (5), 140 (22), 130 (18), 129 (17), 128 (15), 117 (9), 115 (22), 110 (8), 104 (5), 103 (7), 96 (5), 91 ([C 7 H 7 ] +,18), 84 (5), 83 (5), 82 (10), 77 ([C 6 H 5 ] +,8), 57 (63), 56 (13), 55 (11), 54 (8). HRMS (ESI) : Calculated for C 18 H 25 NNa 2 [M+Na] + : Found : ((E)-Styryl)-piperidine-1-carboxylic acid benzyl ester (2b) Prepared according to general procedure B using 1b (65%). N IR (neat) : 2936, 1806, 1756, 1694, 1497, 1448, 1419, 1371, 1311, 1252, CBz 1212, 1170, 1116, 1067 cm H NMR (400 MHz, CDCl 3 ) δ : (m, 9H), (m, 1H), 6.33 (d, J = 16.2 Hz, 1H), 6.13 (dd, J = 16.2, 4.8 Hz, 1H), 5.12 (d, J = 13.1 Hz, 1H), 5.07 (d, J = 12.4 Hz, 1H), 4.98 (bs, 1H), 4.02 (d, J = 13.5 Hz, 1H), 2.92 (td, J = 13.0, 2.4 Hz, 1H), (m, 2H), (m, 4H); 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (s), (s), (d), (d), (d), (d), (2d), (2d), (d), (2d), 67.2 (t), 52.6 (d), 40.4 (t), 29.6 (t), 25.7 (t), 19.7 (t) ; S7

8 MS (EI) m/z : 321 ([M] +., 0.5), 230 ([M- Ph-CH 2 ] +, 50), 186 (29), 129 (7), 128 (7), 115 (11), 92 (8), 91 (100), 82 (27), 65 (12). HRMS (ESI) : Calculated for C 21 H 23 NNa 2 [M + Na] + : Found : ((E)-Styryl)-1-(toluene-4-sulfonyl)-piperidine (2c) Prepared according to general procedure B using 1c (99%). N IR (neat) : 3058, 2933, 2852, 1597, 1494, 1446, 1335, 1184, 1154, 1091, 1055 Ts cm H NMR (400 MHz, CDCl 3 ) δ : 7.68 (d, J = 8.4 Hz, 2H ar ), (m, 7H ar ) 6.40 (dd, J = 16.1, 1.6 Hz, 1H), 5.99 (dd, J = 15.9, 6.4 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), 2.35 (s, 3H), (m, 2H), (m, 4H). 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (s), (s), (d), (2d), (2d), (1d), (2d), (d), (2d), 55.2 (d), 42.1 (t), 30.7 (t), 25.2 (t), 21.5 (q), 19.3 (t). MS (EI) m/z : 341 ([M] +., 0.1), 277 (12), 238 ([M-{PhCH=CH}] +, 2), 186 ([M-Tos] +,62), 185 (13), 184 (29), 155 ([Tos] +,6), 130 (17), 129 (22), 128 (15), 117 (13), 115 (35), 91 ([C 7 H 7 ] +, 100), 82 (46), 77 ([C 6 H 5 ] +, 14), 65 (29), 55 (20). HRMS (ESI) : Calculated for C 20 H 23 NNa 2 S [M+Na] + : Found: N Ts (2-((E)-Propenyl)-1-(toluene-4-sulfonyl)-piperidine (2d) Prepared according to general procedure B using 1d (96%). IR (neat) : 2920, 2854, 1736, 1597, 1445, 1335, 1239, 1154, 1091, 1045 cm H NMR (400 MHz, CDCl 3 ) δ : 7.58 (d, J = 8.5 Hz, 2H), (m, 2H), (m, 1H), 5.27 (ddd, J = 15.6, 6.5, 1.9 Hz, 1H), 4.47 (br s, 1H), (m, 1H), (m, 1H), 2.34 (s, 3H), (m, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (s), (2d), (d), (3d), 54.9 (d), 41.8 (t), 30.6 (t), 25.3 (t), 21.6 (q), 19.2 (t), 17.9 (q). MS (EI) m/z : ([M] +., 4), 264 ([M-Me] +, 2), 238 ([M-{CH=CHCH 3 }] +, 14, 155 ([Tos] +, 18), 124 ([M-Tos] +, 100), 108 (24), 97 (10), 91 ([C 7 H 7 ] +, 71), 82 (20), 68 (28), 67 (14), 65 (24), 55 (33). HRMS (ESI) : Calculated for C 15 H 21 NNa 2 S [M+Na] + : Found: N Ts 1-(Toluene-4-sulfonyl)-2-vinyl-piperidine (2e) Prepared according to general procedure B using 1e (61%). IR (neat) : 2925, 2857, 1731, 1598, 1453, 1336, 1154, 1093, 1053 cm H NMR (400 MHz, CDCl 3 ) δ : 7.69 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 7.9 Hz, 2H), 5.70 (ddd, J = 17.2, 10.6, 5.2 Hz, 1H), 5.14 (ddd, J = 17.3, 1.6, 1.6 Hz, 1H), 5.13 (ddd, J = 10.4, 1.6, 1.6 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), 2.41 (s, 3H), (m, 2H), (m, 4H). S8

9 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (s), (d), (2d), (2d), (t), 55.1 (d), 41.7 (t), 29.7 (t), 25.1 (t), 21.6 (q), 19.1 (t). MS (EI) m/z : 265 ([M] +., 3), 238 ([M-{CH=CH 2 }] +, 18), 155 ([Tos] +, 18), 110 ([M-Tos] +, 80), 108 (10), 92 (11), 91 ([C 7 H 7 ] +, 100), 82 (12), 68 (18), 65 (46), 55 (39), 54 (32), 53 (11). Table 2. FeCl 3 -catalyzed synthesis of cis-2,6-piperidines. General procedure C : preparation of primary amines 12a-12d To a solution of 1-hexenol (1 equiv) and Celite (900 wt%) in CH 2 Cl 2 (0.05 M) was added at 0 C pyridinium chlorochromate (2.25 equiv). The reaction mixture was stirred for 30 min at 0 C and then allowed to warm to room temperature. After 2 h, the suspension was filtered through a pad of silica gel (CH 2 Cl 2 ). Due to the volatility of the product, the resulting filtrate was carefully evaporated to afford 1- hexenal. The latter (1 equiv) was dissolved in Et 2 (0.5 M) and cooled to - 78 C before a solution of the Grignard reagent was added. After 1 h of stirring at - 78 C and 2 h at room temperature, the reaction mixture was poured onto a saturated solution of ammonium chloride in water. The two phases were separated, the aqueous phase was extracted with Et 2, the combined organic layers were dried over MgS 4, filtered and volatiles were carefully removed to give the alcohol 10. A solution of 10 (1 equiv) and Celite (900 wt%) was cooled to 0 C and pyridinium chlorochromate (2.25 equiv) was added. The resulting mixture was stirred for 30 min at 0 C and for 3 h at room temperature. It was then filtered through a pad of silica gel which was washed with CH 2 Cl 2 and the filtrate was evaporated to afford 11. The ketone 11 (1 equiv) was dissolved in methanol (0.4 M) and treated with ammonium formate (10 equiv) and sodium borohydride (0.7 equiv) in presence of molecular sieves 4Å. The resulting mixture was stirred overnight at room temperature and a solution of sodium hydroxyde (5 M in water) was added. The aqueous phase was extracted with Et 2 and the combined organic layers were dried over Na 2 S 4, filtered and concentrated carefully. In order to remove any trace of water, CH 2 Cl 2 and anhydrous potassium carbonate were added. After 2 h at room temperature, the mixture S9

10 was filtered through a pad of Celite and the filtrate was carefully concentrated to give amines 12. These compounds were used without any further purification. General procedure D : tosylation of primary amines 12a-12d Crude amine 12a-12d were dissolved in CH 2 Cl 2 (0.1 M) and NEt 3 (2 equiv), DMAP (0.1 equiv) and TosCl (1.1 equiv) were added. The mixture was stirred at room temperature overnight and water was added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over Na 2 S 4 and concentrated in vacuo. The crude product was purified by flash column chromatography to give tosylamide 13a-13d. Tosylamide 13c was prepared following a reported procedure. 4 NHTs N-(1-Isopropylhex-5-en-1-yl)-4-methylbenzenesulfonamide (13a) Prepared according to general procedures C and D using iso-propylmagnesium chloride (2 M in THF) (35% overall yield from 1- hexenol). IR (neat) : 3283, 2925, 1598, 1428, 1322, 1157, 1093, 1003 cm H NMR (400 MHz, CDCl 3 ) δ : 7.75 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 5.64 (ddt, J = 18.0, 11.4, 5.7 Hz, 1H), (m, 2H), 4.31 (d, J = 8.9 Hz, 1H), 3.09 (m, 1H), 2.42 (s, 3H), (m, 2H), 1.72 (d{hept}, J = 6.7, 5.4 Hz, 1H), (m, 4H), 0.78 (d, J = 6.8 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (s), (d), (2d), (2d), (t), 59.3 (d), 33.4 (t), 31.3 (d), 31.2 (t), 24.9 (t), 21.6 (q), 18.4 (q), 17.7 (q,). MS (EI) m/z : 295 ([M] +., 0.1), 252 ([M-i-Pr] +, 17), 226 ([M-{CH 2 CH 2 CH 2 CH=CH 2 }] +, 6), 172 (11), 155 ([Tos] +, 38), 140 ([M-Tos] +, 1), 91 ([C 7 H 7 ] +, 100), 81 (23), 65 (21.4). HRMS (ESI) : Calculated for C 16 H 25 NNa 2 S [M+Na] + : Found : NHTs 4-Methyl-N-(1-pentyl-hex-5-enyl)-benzenesulfonamide (13b) Prepared according to general procedures C and D using pentylmagnesium bromide (0.5 M in THF) (29% overall yield from 1-hexenol). IR (neat) : 3273, 2924, 2858, 1640, 1599, 1496, 1424, 1379, 1322, 1304, 1157, 1094, 1034 cm Gribkov, D. V.; Hultzsch, K. C.; Hampel, F. J. Am. Chem. Soc. 2006, 128 (11), S10

11 1 H NMR (400 MHz, CDCl 3 ) δ : 7.56 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 7.5 Hz, 2H), (m, 1H), (m, 2H), 3.19 (m, 1H), 2.41 (s, 3H), 1.90 (m, 2H), (m, 12H), 0.80 (t, J = 6.9 Hz, 3H) 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (s), (d), (2d), (2d), (t), 54.0 (d), 35.0 (t), 34.5 (t), 33.4 (t), 31.5 (t), 24.9 (t), 24.4 (t), 22.5 (t), 21.5 (q), 13.9 (q). MS (EI) m/z : 255 (7), 254 (45), 252 (24), 172 (16), 155 (54), 154 ([M-Ts] +, 8), 92 (9), 91 (100), 81 (16), 65 (15), 55 (8). HRMS (ESI) : Calculated for C 18 H 29 NNa 2 S [M + Na] + : Found : NHTs 4-Methyl-N-(1-phenylhex-5-en-1-yl)benzenesulfonamide (13d) Prepared according to general procedures C and D using phenylmagnesium bromide 3 M in Et 2 (39% overall yield from 1-hexenol). IR (neat) : 3267, 2921, 1639, 1598, 1494, 1424, 1319, 1154, 1092 cm -1 1 H NMR (400 MHz, CDCl 3 ) δ : (m, 2H), (m, 5H), (m, 2H), 5.67 (ddt, J = 16.9, 11.9, 5.9 Hz, 1H), (m, 3H), 4.26 (dt, J = 7.4, 7.3 Hz, 1H), 2.35 (s, 3H), 1.96 (dtt, J = 7.3, 7.1, 1.1 Hz, 2H), (m, 2H), (m, 1H), (m, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (s), (d), (s), (2d), (2d), (d), (2d), (2d), (t), 58.3 (d), 37.1 (t), 33.2 (t), 25.1 (t), 21.5 (q). MS (EI) m/z : 328 ([M-H] +, 0.1), 260 ([M-{CH 2 CH 2 CH 2 CH=CH 2 ]] +, 60), 174 ([M-Tos] +, 4), 158 ([M- TosNH 2 ] +, 7), 155 ([Tos] +, 46), 91 ([C 7 H 7 ] +, 100), 77 ([C 6 H 5 ] +, 8). HRMS (ESI) : Calculated for C 19 H 23 NNa 2 S [M + Na] + : Found : (1-Isopropyl-hex-5-enyl)-carbamic acid tert-butyl ester (13e) Primary amine 12a (407 mg, 2.89 mmol, 1 equiv) prepared according to HN general procedure C was dissolved in CH 2 Cl 2 (8 ml) and NEt 3 (885 µl, 6.36 mmol, 2.2 equiv) and di-tert-butylcarbonate (1.9 g, 8.67 mmol, 3 equiv) were added. The reaction mixture was stirred overnight at room temperature and a 10% solution of citric acid (5 ml) was added. The phases were separated and the aqueous phase was extracted with CH 2 Cl 2 (3 x 10 ml). The combined organic layers were dried over MgS 4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE/EtAc 100/2) to give 13e as a colorless oil (134 mg, 6% overall yield from 1-hexenol). IR (neat) : 3340, 2961, 2930, 1686, 1641, 1503, 1456, 1389, 1365, 1307, 1244, 1170, 1080, 1045, 1016 cm H NMR (400 MHz, CDCl 3 ) δ : (m, 1H), (m, 2H), 4.26 (m, 1H), 3.43 (m, 1H), (m, 2H), (m, 2H), (m, 2H), 1.43 (s, 9H), (m, 1H), 0.88 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 7.0 Hz, 3H). S11

12 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (d), (t), 78.9 (s), 55.5 (d), 33.7 (t), 32.2 (d), 32.0 (t), 28.5 (q), 25.6 (t), 19.2 (q), 17.7 (q). MS (EI) m/z : 199 (1, [M-iPr] + ), 142 (29), 116 (8), 98 (42), 81 (28), 72 (22), 69 (8), 57 (100, [t-bu] + ), 56 (58), 55 (25). HRMS (ESI) : Calculated for C 14 H 27 NNa 2 [M + Na] + : Found : NH (1-Isopropyl-hex-5-enyl)-carbamic acid benzyl ester (13f) The primary amine 12a (65 mg, 0.46 mmol, 1 equiv) prepared according to general procedure C was dissolved in CH 2 Cl 2 (2 ml) before Et 3 N (140 µl, 1.01 mmol, 2.2 equiv) and benzylchloroformate (72 µl, 0.51 mmol, 1.1 equiv) were added. The reaction mixture was stirred overnight at room temperature and a 10% solution of citric acid in water (2 ml) was added. The phases were separated and the aqueous phase was extracted with CH 2 Cl 2 (3 x 2 ml). The combined organic layers were dried over MgS 4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE/EtAc 9/1) to give 13f as a colorless oil (28 mg, 18% overall yield from 1-hexenol). IR (neat) : 3325, 2930, 1692, 1640, 1531, 1455, 1388, 1369, 1342, 1239, 1091, 1046, 1026 cm H NMR (400 MHz, CDCl 3 ) δ : (m, 5H), (m, 1H), 5.10 (s, 2H), (m, 2H), 4.50 (br s, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 3H), (m, 1H), 0.90 (d, J = 6.7 Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (d), (s), (2d), (2d), (t), 66.7 (t), 56.3 (d), 33.7 (t), 32.2 (d), 32.0 (t), 25.6 (t), 19.3 (q), 17.7 (q). HRMS (ESI) : Calculated for C 17 H 25 NNa 2 [M + Na] + : Found : NHNs N-(1-Isopropyl-hex-5-enyl)-2-nitro-benzenesulfonamide (13g) To the amine 12a prepared according to the general procedure C (591 mg, 4.19 mmol, 1 equiv) in CH 2 Cl 2 (20 ml) were added at 0 C NEt 3 (1.2 ml, mmol, 2 equiv), DMAP (51 mg, mmol, 0.1 equiv) and 2-nitrobenzenesulfonyl chloride (1.023 g, mmol, 1.1 equiv). After 20 h, water (10 ml) and brine (5 ml) were added. The two phases were separated and the aqueous phase was extracted with CH 2 Cl 2 (3 x 10 ml). The combined organic layers were dried over MgS 4, filtered and the solvent was removed in vacuo. A flash chromatography on silica gel (PE/Et 2 : 8/2) afforded 13g as a colorless oil (972 mg, 71%, 30% overall yield from 1-hexenol). IR (neat) : 3344, 3079, 2963, 1640, 1594, 1539, 1442, 1417, 1361, 1301, 1167, 1124, 1061, 1023 cm H NMR (400 MHz, CDCl 3 ) δ : (m, 1H), (m, 1H), (m, 2H), (m, 1H), 5.12 (d, J = 9.2 Hz, 1H), (m, 1H), (m, 1H), 3.33 (dq, J = 8.8, 4.7 Hz, 1H), 1.92 S12

13 (td, J = 6.5, 6.5 Hz, 2H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), 0.84 (d, J = 7.0 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (d), (s), (d), (d), (d), (d), (t), 60.9 (d), 33.3 (t), 32.0 (d), 31.7 (t), 25.1 (t), 18.8 (q), 17.7 (q). MS (EI) m/z : 285 (1), 283 (15), 186 (63, [Nos] + ), 96 (9), 92 (9), 82 (10), 81 (100), 78 (10), 77 (11), 71 (8), 70 (10), 55 (14), 51 (15). HRMS (ESI) : Calculated for C 15 H 22 N 2 Na 4 S [M + Na] + : Found : (2E)-8-Methyl-7-{[(4-methylphenyl)sulfonyl]amino}-1- phenylnon-2-en-1-yl acetate (3a, mixture of NHTs diastereoisomers) Prepared according to general procedure A using allylic acetate 9a (5 equiv) and tosylamide 13a, 10 mol % of Grubbs-Hoveyda second-generation catalyst were necessary (65% yield). IR (neat) : 3280, 2930, 1735, 1447, 1371, 1323, 1232, 1157, 1043, 1018 cm -1 1 H NMR (400 MHz, C 6 D 6 ) δ : 7.93 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 7.7 Hz, 2H), (m, 2H), (m, 1H), 6.88 (d, J = 8.1 Hz, 2H), 6.43 (d, J = 4.8 Hz, 1H), (m, 2H), (m, 1H), (m, 1H), 1.97 (m, 3H), (m, 5H), (m, 1H), (m, 4H), 0.77 (d, J = 6.8 Hz, 3H), 0.70 (d, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, C 6 D 6 ) δ : (s), (s), (s), (s), (d), (d), (2d), (2d), (2d), (d), (2d), (2d), 76.4 (2d), 59.3 (d), 32.1 (2t), 31.8 (2d), 31.1 (2t), 25.2 (t), 25.1 (t), 21.2 (q), 20.9 (q), 18.5 (q), 18.0 (2q). MS (EI) m/z : 228 ([M-Tos-{AcH}] +, 12), 155 ([Tos] +, 12), 143 (14), 141 (10), 128 (28), 115 (19), 92 (1), 91 ([C 7 H 7 ] +, 100), 72 (90), 65 (25). HRMS (ESI) : Calculated for C 25 H 33 NNa 4 S [M+Na] + : Found : Acetic acid (E)-1-phenyl-7-(toluene-4-sulfonylamino)- NHTs dodec-2-enyl ester (3b, mixture of diastereoisomers) Prepared according to general procedure A using allylic acetate 9a and tosylamide 13b (53% yield). IR (neat) : 3283, 2929, 2859, 1736, 1599, 1495, 1453, 1426, 1371, 1324, 1235, 1158, 1094, 1020 cm H NMR (400 MHzZ, C 6 D 6 ) δ : 7.84 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 7.0 Hz, 2H), (m, 2H), (m, 1H), 6.83 (m, 2H), (m, 1H), (m, 2H), 4.41 (d, J = 8.4 Hz, 1H), (m, 1H), 1.94 (s, 3H), (m, 2H), 1.72 (s, 1.5H), 1.71 (s, 1.5H), (m, 12H), 0.81 (t, J = 7.3 Hz, 3H). S13

14 13 C NMR (100 MHz, C 6 D 6 ) δ : (s), (s), (s), (s), (d), (d), (2d), (d), (2d), (2d), (2d), 76.4 (d), 54.0 (d), 35.4 (t), 34.9 (t), 34.8 (t), 32.2 (t), 31.9 (t), 25.3 (t), 24.8 (2t), 22.9 (t), 21.1 (q), 20.9 (q), 14.2 (q). HRMS (ESI) : Calculated for C 27 H 37 NNa 4 S [M + Na] + : Found : Acetic acid (E)-1-phenyl-7-(toluene-4-sulfonylamino)-oct-2-enyl NHTs ester (3c, mixture of diastereoisomers) Prepared according to general procedure A using allylic acetate 9a and tosylamide 13c 4 (56% yield). IR (neat) : 3275, 2932, 1735, 1599, 1495, 1454, 1428, 1372, 1324, 1305, 1236, 1160, 1092, 1020 cm H NMR (400 MHz, C 6 D 6 ) δ : 7.83 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 7.6 Hz, 2H), (m, 1H), (m, 2H), 6.82 (d, J = 7.9 Hz, 2H), (m, 1H), (m, 2H), 4.40 (d, J = 8.2 Hz, 1H), 3.19 (sext, J = 6.7 Hz, 1H), 1.92 (s, 3H), (m, 5H), (m, 4H), 0.74 (d, J = 2.4 Hz, 1.5H), 0.72 (d, J = 2.5 Hz, 1.5H). 13 C NMR (100 MHz, C 6 D 6 ) δ : (s), (s), (s), (s), (d), (d), (2d r ), (d), (d), (d), (d), (3d), 76.4 (d), 49.7 (d), 36.9 (t), 32.0 (t), 25.0 (t), 21.7 (q), 21.1 (q), 20.8 (q). HRMS (ESI) : Calculated for C 23 H 29 NNa 4 S [M + Na] + : Found : Ac NHTs (2E)-7-{[(4-Methylphenyl)sulfonyl]amino}-1,7- diphenylhept-2-en-1-yl acetate (3d, mixture of diastereomers) Prepared according to general procedure A using allylic acetate 9a (9 equiv) and tosylamide 13d (65% yield). IR (neat) : 3272, 2924, 1734, 1599,1454, 1371, 1325, 1233, 1092, 1044 cm H NMR (400 MHz, CD 2 Cl 2 ) δ : (d, J = 8.2 Hz, 2H), (m, 5H), (m, 5H), (m, 2H), (m, 1H), (m, 2H), (m, 1H), (dt, J = 7.6, 7.6 Hz, 1H), 2.33 (s, 3H), 2.04 (s, 3H), (m, 2H), (m, 2H), (m, 1H), (m, 1 H). 13 C NMR (100 MHz, CD 2 Cl 2 ) δ : (s), (s), (s), (s), (s), (d), (d), (2d), (d), (d), (2d), (2d), (d), (d), (2d), (2d), (2d), 76.2 (d), 58.2 (d), 58.1 (d), 37.2 (d), 37.1 (d), 31.6 (t), 31.5 (t), 25.1 (t), 21.2 (q, 21.2 (q). HRMS (ESI) : Calculated for C 28 H 31 NNa 4 S [M + Na] + : Found : S14

15 HN Acetic acid (E)-7-tert-butoxycarbonylamino-8-methyl-1- phenyl-non-2-enyl ester (3e, mixture of diastereoisomers) To a solution of 13e (458 mg, 1.9 mmol, 1 equiv) in CH 2 Cl 2 (15 ml) was added acrolein (380 µl, 5.7 mmol, 3 equiv) and Grubbs-Hoveyda catalyst (35 mg, mmol, 0.03 equiv). The mixture was stirred for 20 h at 40 C and the solvent was removed under reduced pressure. A filtration on silica gel (PE/EtAc : 6/4) gave the expected α,β-unsaturated aldehyde (222 mg, 43%). The latter (222 mg, mmol, 1 equiv) was subsequently dissolved in THF (5 ml) and a solution of phenyllithium (1.8 M in di-butylether, 1.1 ml, 1.98 mmol, 2.4 equiv) was added dropwise at -78 C. After 2 h at -78 C, an additional portion of phenyllithium was added (1.8 M in di-butylether, 550 µl, 0.99 mmol, 1.2 equiv). After 2 h, the mixture was quenched by addition of a saturated aqueous solution of NH 4 Cl (5 ml) and warmed to room temperature. The two phases were separated, the aqueous layer was extracted with Et 2 (3 x 5 ml) and the combined organic layers were dried over MgS 4, filtered and evaporated in vacuo. After filtration on silica gel (PE/EtAc : 8/2 ) the obtained alcohol was dissolved in a 3/1 mixture of CH 2 Cl 2 /pyridine (5.4 ml) and treated at 0 C by acetic anhydride (82 µl, mmol, 1.5 equiv) and DMAP (3.5 mg, mmol, 0.05 equiv). The mixture was stirred overnight at room temperature and a solution of CuS 4 (10% in water) was added (5 ml). The phases were separated and the aqueous layer was extracted with Et 2 (3 x 5 ml). The combined organic layers were washed with the aqueous solution of CuS 4 (3 x 5 ml), dried over MgS 4 and the solvents were evaporated under reduced pressure. A flash chromatography on silica gel previously neutralized by NEt 3 (PE/EtAc : 95/5 to 9/1 ) afforded amine 3e (165 mg, 54%). IR (neat) : 3345, 2929, 1695, 1497, 1454, 1389, 1365, 1232, 1167, 1081, 1017 cm H NMR (400 MHz, C 6 D 6 ) δ : (m, 2H), (m, 2H), (m, 1H), 6.48 (br d, J = 4.6 Hz, 1H), (m, 2H), 3.91 (m, 1H), 3.55 (m, 1H), (m, 2H), (m, 3H), 1.47 (s, 9H), (m, 3H), (m, 2H), 0.78 (d, J = 6.6 Hz, 1.4H), 0.77 (d, J = 6.6 Hz, 1.6H), 0.66 (d, J = 6.8 Hz, 1.4H), 0.65 (d, J = 6.8 Hz, 1.6H). 13 C NMR (100 MHz, C 6 D 6 ) δ : (s), (s), (s), (d), (d), (d), (d), (d), (d), (d), (2d), 78.3 (s), 76.5 (d), 76.4 (d), 55.2 (d), 32.6 (2d), 32.3 (t), 32.2 (t), 32.0 (t), 28.6 (3q), 25.8 (t), 25.7 (t), 20.9 (q), 19.4 (q), 17.7 (2q). MS (EI) m/z : 274 ([M-NHBoc] +, 6), 273 (34), 230 (59), 186 (47), 169 (10), 144 (13), 143 (100), 130 (13), 129 (16), 128 (28), 115 (24), 91 (34), 82 (13), 62 (24), 57 (73), 56 (28), 55 (28). HRMS (ESI) : Calculated for C 23 H 35 NNa 4 [M + Na] + : Found : Acetic acid (E)-7-benzyloxycarbonylamino-8- methyl-1-phenyl-non-2-enyl ester (3f, mixture of diastereomers) To a solution of 13f (169 mg, mmol, 1 equiv) in CH 2 Cl 2 (5 ml) was added acrolein (137 µl, HN S15

16 mmol, 3 equiv) and Grubbs-Hoveyda catalyst (21 mg, mmol, 0.05 equiv). The mixture was stirred for 20 h at 40 C and the solvent was removed under reduced pressure. The residue was filtered on silica gel (PE/AcEt : 8/2) to give the α,β-unsaturated aldehyde. The latter (78 mg, mmol, 1 equiv) was subsequently dissolved in THF (2 ml) and a solution of phenyllithium (1.8 M in dibutylether, 350 µl, mmol, 2.2 equiv) was added dropwise at -78 C. After 1.5 h at this temperature, the mixture was quenched by addition of a saturated aqueous solution of NH 4 Cl (2 ml) and warmed to room temperature. The two phases were separated, the aqueous layer was extracted with Et 2 (3 x 2 ml) and the combined organic layers were dried over MgS 4, filtered and evaporated in vacuo. A filtration on silica gel (PE/Et 2 : 4/6 ) afforded the desired alcohol (24 mg, mmol) which was dissolved in a 5/1 mixture of CH 2 Cl 2 /pyridine (1 ml/0.2 ml) and treated at 0 C with acetic anhydride (10 µl, mmol, 1.5 equiv) and DMAP (4 mg, 0.03 mmol, 0.05 equiv). The mixture was stirred overnight at room temperature and a solution of CuS 4 (10% in water, 1 ml) was added. The phases were separated and the aqueous layer was extracted with Et 2 (3 x 2 ml). The combined organic layers were washed with an aqueous solution of CuS 4 (3 x 2 ml), dried over MgS 4 and the solvents were evaporated under reduced pressure to give 3f (28 mg, 10%) which was used without any further purification in the cyclization step. IR (neat) : 3320, 3033, 2927, 1693, 1530, 1455, 1388, 1369, 1304, 1232, 1154, 1089, 1019 cm -1 1 H NMR (400 MHz, C 6 D 6 ) δ : (m, 2H), (d, J = 7.2 Hz, 2H), (m, 6H), (m, 1H), (m, 2H), (m, 2H), 4.10 (t, J = 10.0 Hz, 1H), (m, 1H), (m, 2H), 1.69 (s, 3H), (m, 3H), 0.98 (m, 2H), 0.76 (d, J = 6.8 Hz, 1.5H), 0.75 (d, J = 6.9 Hz, 1.5H), 0.65 (d, J = 6.8 Hz, 1.5H), 0.64 (d, J = 6.7 Hz, 1.5H). 13 C NMR (100 MHz, C 6 D 6 ) δ : (s), (s), (s), (s), (d), (d), (d), (d), (d), (d), (2d), (d), (d), (d), (2d), 76.5 (d), 66.6 (t), 56.1 (d), 32.5 (d), 32.3 (t), 32.2 (t), 31.8 (t), 25.7 (t), 20.9 (q), 19.3 (q), 17.8 (q), 17.7 (q). MS (EI) m/z : 264 (28), 263 (41), 235 (29), 212 (25), 150 (25), 141 (31), 128 (36), 96 (43), 95 (31), 93 (21), 91 (49), 83 (23), 82 (45), 81 (44), 80 (57), 79 (46), 70 (22), 69 (46), 67 (60), 56 (37), 55 (100), 54 (20). HRMS (ESI) : Calculated for C 26 H 33 NNa 4 [M + Na] + : Found : Acetic acid (E)-8-methyl-7-(2-nitro-benzenesulfonylamino)-1- NHNs phenyl-non-2-enyl ester (3g, mixture of diastereoisomers) Prepared according to the general procedure A using allylic acetate 9a and sulfonamide 13g (57% yield). IR (neat) : 2931, 1640, 1593, 1538, 1441, 1416, 1358, 1300, 1165, 1124, 1060 cm H NMR (400 MHz, C 6 D 6 ) δ : 7.80 (ddd, J = 7.8, 2.8, 1.4 Hz, 1H), (m, 2H), (m, 2H, (m, 1H), 6.98 (dd, J = 7.9, 1.4 Hz, 0.5H), 6.93 (dd, J = 8.0, 1.4 Hz, 0.5H), 6.69 (td, J = 7.6, 1.4 Hz, 0.5H), 6.66 (td, J = 6.7, 1.4 Hz, 0.5H), (m, 1H), ( m, 1H), (m, S16

17 2H), 5.04 (m, 1H), (m, 1H), 1.71 (M, 3H), (m, 2H), (m, 4H), 0.62 (d, J = 6.8 Hz, 3H), 0.60 (d, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, C 6 D 6 ) δ : (s), (s), (s), (s), (d), (d), (d), (d), (d), (2d), (2d), (d), (d), 76.2 (d), 60.5 (d), 32.2 (d), 31.8 (2t), 31.6 (t), 25.1 (t), 20.8 (q), 18.7 (q), 17.7 (q), 17.6 (q). MS (EI) m/z : 283 (16), 257 (8), 187 (5), 186 ([Nos] +,61), 96 (9), 92 (11), 82 (10), 81 (100), 78 (11), 77 (10), 71 (8), 70 (10), 65 (6), 64 (7), 56 (7), 55 (15), 51 (16), 50 (5). HRMS (ESI) : Calculated for C 24 H 30 N 2 Na 6 S [M + Na] + : Found : cis-2-isopropyl-6-((e)-styryl)-1-(toluene-4-sulfonyl)-piperidine (4a) Prepared from 3a according to general procedure B (99%). N IR (neat) : 2934, 2869, 1598, 1494, 1447, 1334, 1216, 1161, 1095, 1035 Ts cm H NMR (CDCl 3, 400 MHz) δ : 7.69 (d, J = 8.4 Hz, 2H), (m, 6H), (m, 1H), 6.45 (dd, J = 16.3, 1.6 Hz, 1H), 6.30 (dd, J = 16.4, 5.3 Hz, 1H), (m, 1H), 3.60 (dd, J = 10.8, 4.7 Hz, 1 H), 2.34 (s, 3H), (m, 1H), (m, 2H), (m, 1H), (m, 3H), 1.02 (d, J = 6.6 Hz, 3H), 0.78 (d, J = 6.8 Hz, 3H). 13 C NMR (CDCl 3, 100 MHz) δ : (s), (s), (s), (d), (d), (2d), (2 d), (1d), (2d), (2d), 59.8 (d), 52.8 (d), 29.0 (d), 26.2 (t), 25.1 (t), 21.5 (q), 20.8 (q)), 20.7 (q), 14.5 (t). MS (EI) m/z : 340 ([M-i-Pr] +, 11), 228 ([M-Tos] +, 3), 172 (11), 155 ([Tos] +, 15), 144 (12), 143 (84), 129 (165), 128 (39), 115 (26), 91 ([C 7 H 7 ] +, 100), 77 ([C 6 H 5 ] +, 8), 65 (28), 55 (15). HRMS (ESI) : Calculated for C 23 H 29 NNa 2 S [M + Na] + : Found : cis-2-pentyl-6-((e)-styryl)-1-(toluene-4-sulfonyl)-piperidine (4b) N Prepared from 3b according to general procedure B (70%). Ts IR (neat) : 3027, 2928, 2858, 1598, 1494, 1448, 1393, 1331, 1304, 1219, 1160, 1100, 1084, 1042, 1018 cm H NMR (400 MHz, CDCl 3 ) δ : 7.67 (d, J = 8.4 Hz, 2H), (m, 7H), 6.45 (d, J = 16.9 Hz, 1H), 6.24 (dd, J = 16.3, 5.1 Hz, 1H 7 ), (m, 1H), 3.96 (m, 1H), 2.34 (s, 3H), (m, 1H), (m, 2H), (m, 1H), (m, 10H), 0.74 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (s), 137,1 (s), (d), (d), (2d), (2d), (d), (2d), (2d), 53.3 (d), 52.5 (d), 34.2 (t), 31.8 (t), 27.6 (t), 27.1 (t), 26.8 (t), 22.7 (t), 21.6 (q), 14.5 (t), 14.1 (q). MS (EI) m/z : 347 ([M-S 2 ] +., 11), 340 ([M-Pent] + 19), 256 ([M-Tos] +, 30), 255 (30), 199 (5), 198 (15), 185 (13), 184 (7), 172 (11), 169 (9), 155 ([Tos] +, 14), 143 (100), 141 (6), 130 (12), 129 (17), 128 (35), 115 (22), 91 (C 7 H + 7, 70), 77 (6), 65 (12), 55 (10). S17

18 HRMS (ESI) : Calculated for C 25 H 33 NNa 2 S [M + Na] + : Found : cis-2-methyl-6-((e)-styryl)-1-(toluene-4-sulfonyl)-piperidine (4c) Prepared from 3c according to general procedure B (80%). N IR (neat) : 3027, 2936, 2868, 1598, 1494, 1448, 1393, 1327, 1303, 1260, Ts 1223, 1180, 1162, 1140, 1102, 1075, 1020 cm H NMR (400 MHz, CDCl 3 ) δ : (d, J = 8.3 Hz, 2H), (m, 7H), 6.45 (dd, J = 16.3, 1.9 Hz, 1H), 6.22 (dd, J = 16.3, 4.8 Hz, 1H), (m, 1H), (m, 1H), 2.31 (s, 3H), (m, 1H), (m, 2H), (m, 4H), 1.18 (d, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ : (s, C ar ), (s, C ar ), (s, C ar ), (d, C 7 ), (d, C 8 ), (2d, C ar ), (2d, C ar ), (d, C ar ), (2d, C ar ), (2d, C ar ), 52.6 (d, C 6 ), 48.5 (d, C 2 ), 29.6 (t, C 3 ), 27.7 (t, C 5 ), 21.5 (q, C 10 ), 21.4 (q, C 9 ), 14.1 (t, C 4 ). MS (EI) m/z : 291 ([M-S 2 ] +.,31), 201 (11), 200 ([M-Tos] +, 78), 199 (46), 198 (49), 184 (27), 170 (5), 157 (9), 156 (7), 155 ([Tos] +, 11), 143 (28), 130 (27), 129 (36), 128 (28), 122 (13), 117 (13), 116 (6), 115 (33), 105 (13), 103 (10), 102 (5), 92 (10), 91 ([C 7 H 7 ] +,100), 89 (5), 79 (5), 77 (13), 69 (10), 65 (23), 63 (5), 55 (13), 51 (5). HRMS (ESI) : Calculated for C 21 H 25 NNa 2 S [M + Na] + : Found : cis-2-phenyl-6-((e)-styryl)-1-(toluene-4-sulfonyl)-piperidine (4d) Prepared from 3d according to general procedure B (80%). N IR (neat) : 3026, 2922, 2869, 1597, 1494, 1447, 1336, 1222, 1158, Ts 1095, 1058 cm H NMR (400 MHz, CDCl 3 ) δ : 7.76 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), (m, 8H), 6.77 (m, 2H), 6.22 (d, J = 15.9 Hz, 1H), 5.64 (dd, J = 15.9, 7.3 Hz, 1H), 5.26 (d, J = 5.1 Hz, 1H), 4.72 (m, 1H), 2.38 (s, 3H), (m, 1H), (m, 1H), (m, 4H). 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (s), (s), (s), (d), (d), (2d), (2d), (2d), (2d), (d), (2d), (d), (2d), 54.7 (d), 53.6 (d), 27.8 (t), 25.3 (t), 21.7 (q), 15.2 (t). HRMS (ESI) : Calculated for C 26 H 27 NNa 2 S [M+Na] + : Found : cis-2-isopropyl-6-((e)-styryl)-piperidine-1-carboxylic acid tert-butyl ester (4e), mixture of rotamers (50/50) N Prepared from 3e according to general procedure B (66%). Boc IR (neat) : 3026, 2970, 2933, 2870, 1682, 1600, 1578, 1495, 1474, 1449, 1402, 1386, 1364, 1325, 1274, 1255, 1175, 1127, 1109, 1095, 1075, 1064, 1052 cm H NMR (400 MHz, CDCl 3 ) δ : (m, 4H), (m, 1H), 6.57 (dd, J = 16.2, 1.4 Hz, 1H), 6.36 (dd, J = 16.1, 7.0 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 2H), (m, 1H), (m, 1H), 1.48 (s, 9H), 0.91 (d, J = 6.7 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H). S18

19 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (s), (d), (d), (2d), (d), (2d), 79.4 (s), 56.8 (d), 51.3 (d), 30.4 (d), 28.7 (3q), 26.5 (t), 21.0 (q), 20.2 (q), 15.2 (2t). MS (EI) m/z : 273 (30), 272 ([M-tBu] +, 0.9), 231 (8), 230 (47), 186 (47), 169(7), 156 (5), 144 (13), 143 (100), 141 (6), 130 (14), 129 (17), 128 (30), 127 (8), 117 (9), 115 (24), 103 (5), 91 ([C 7 H 7 ] +, 30), 82 (11), 62 (18), 57 (78), 56 (44), 55 (28), 54 (6), 51 (7), 50 (6). HRMS (ESI) : Calculated for C 21 H 31 NNa 2 [M + Na] + : Found : cis-2-isopropyl-6-((e)-styryl)-piperidine-1-carboxylic acid benzyl ester (4f), mixture of rotamers 70/30 N Prepared from 3f according to general procedure B (66%). CBz IR (neat) : 3335, 3030, 2935, 2870, 1684, 1599, 1531, 1497, 1448, 1410, 1386, 1352, 1300, 1269, 1232, 1142, 1095, 1073, 1051, 1029 cm H NMR (400 MHz, CDCl 3 ) δ : (m, 10H), 6.50 (d, J = 16.4 Hz, 0.7H), (m, 1.3H), (m, 2.7H), 4.31 (bs, 0.3H), (m, 0.7H), (m, 0.3H), (m, 1H), (m, 2H), (m, 2H), (m, 2H), 0.90 (d, J = 6.8 Hz, 1.7H), (d, J = 6.6 Hz, 4.3H). 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (s), (s), (s), (s), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), 67.3 (t), 67.0 (t), 59.5 (d), 57.4 (d), 54.9 (d), 51.8 (d), 30.5 (d), 30.3 (d), 28.6 (t), 28.0 (t), 26.5 (t), 20.9 (q), 20.8 (q), 20.0 (q), 19.7 (q), 15.1 (t); MS (EI) m/z : 363 ([M] +., 0.2), 320 ([M-i-Pr] +, 5), 276 (14), 272 ([M-C 7 H 7 ] +, 34), 143 (29), 129 (6), 128 (9), 115 (8), 91 ([C 7 H 7 ] +, 100), 82 (10), 65 (7), 55 (6). HRMS (ESI) : Calculated for C 24 H 29 NNa 2 [M + Na] + : Found : cis-2-isopropyl-1-(2-nitro-benzenesulfonyl)-6-((e)-styryl)-piperidine (4g) N Prepared from 3g according to general procedure B (90%). Ns IR (neat) : 3025, 2960, 2871, 1591, 1542, 1495, 1447, 1371, 1344, 1295, 1261, 1216, 1169, 1141, 1125, 1035 cm H NMR (400 MHz, CDCl 3 ) δ : (m, 1H), (m, 2H), (m, 1H), (m, 4H), (m, 1H), 6.53 (d, J = 16.3 Hz, 1H), 6.37 (ddd, J = 16.3, 5.5, 1.9 Hz, 1H), (m, 1H), 3.65 (dd, J = 10.5, 5.2 Hz, 1H), (m, 1H), (m, 2H), (m,1h), (m, 3H), 0.96 (d, J = 6.5 Hz, 3H), 0.82 (d, J = 6.5 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (s), (s), (d), (d), (d), (d), (d), (2d), (d), (2d), (d), 60.9 (d), 53.4 (d), 29.2 (d), 27.2 (t), 25.8 (t), 20.8 (q), 20.7 (q), 14.5 (t). MS (EI) m/z : 414 ([M] +., 3), 371 ([M-i-Pr] +, 26), 226 (10), 186 ([Nos] +, 22), 185 (11), 184 (13), 169 (26), 144 (13), 143 (100), 130 (10), 129 (18), 128 (43), 115 (24), 91 (29), 55 (13). HRMS (ESI) : Calculated for C 22 H 26 N 2 Na 4 S [M + Na] + : Found : S19

20 Table 3. FeCl 3 -catalyzed synthesis of cis-2,6-tetrahydropyrans. Acetic acid 1-pentyl-hex-5-enyl ester (14a) Pyridinium chlorochromate (2.48 g, 11.3 mmol, 1.5 equiv) was added to a stirred solution of 5-hexen-1-ol (0.91 ml, 7.5 mmol, 1.0 equiv) and Celite (6 g) in CH 2 Cl 2 (170 ml) at room temperature under argon. The mixture was stirred for 2 h and an additional portion of pyridinium chlorochromate (0.74 g, 3.4 mmol, 0.4 equiv) was added. This mixture was stirred for 2 h was then filtered through a pad of silica.the solvent was evaporated at atmospheric pressure. The resulting oil was diluted in diethyl ether (15 ml) and the solution was cooled to -78 C. Pentylmagnesium bromide (2 M in THF, 5.6 ml,11.2 mmol, 1.5 equiv) was added and the solution was stirred at room temperature overnight. Saturated ammonium chloride solution (10 ml) was added and the aqueous phase was extracted with diethyl ether (3 x 10 ml). The organic layer was washed with brine, dried over MgS 4 and the solvents were evaporated at atmospheric pressure. The obtained oil was diluted in dichloromethane (11 ml) and pyridine (5.5 ml) and cooled at 0 C. 4-(dimethylamino)pyridine (46.3 mg, 0.37 mmol, 0.05 equiv) and acetic anhydride (1.06 ml, mmol, 1.5 equiv) were added. After 1.5 h at room temperature the mixture was washed with a 10% copper sulfate solution (4 x 10 ml) and the aqueous phase was extracted with diethyl ether (3 x 20 ml). The combined organic layers were washed with brine (50 ml), dried over MgS 4, filtered and concentrated under reduced pressure to give 14a (1.192 g, 75 %). IR (neat) : 2934, 2863, 1739, 1642, 1460, 1375, 1245, 1023, 914 cm H NMR (400 MHz, CDCl 3 ) δ : 5.78 (ddt, J = 17.1, 10.3, 6.7 Hz, 1H), 5.01 (dm, J = 17.1 Hz, 1H), 4.95 (dm, J = 10.3 Hz, 1H), 4.86 (quint, J = 6.2 Hz, 1H), (m, 2H), 2.03 (s, 3H), (m, 4H), 1.40 (m, 2H), 1.28 (m, 6H), 0.88 (t, J = 6.7 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ : (s), (d), (t), 74.4 (d), 34.2 (t), 33.7 (2t), 31.8 (t), 25.1 (t), 24.7 (t), 22.6 (t), 21.4 (q), 14.1 (q). MS (EI) m/z : 170 (10), 124 (25), 110 (18), 99 (32), 96 (45), 95 (30), 83 (25), 82 (58), 81 (100), 69 (42), 68 (36), 67 (47), 55 (58), 54 (65). HRMS (ESI) : Calculated for C 13 H 24 Na 2 [M+Na] + : Found : General procedure E : cross-metathesis between acetates or alcohol of type 9 and acetates of type 14 S20

21 To a solution of 14 (1 equiv) and 9 (3 equiv) in CH 2 Cl 2 was added Grubbs-Hoveyda catalyst (0.05 equiv). The mixture was stirred overnight at 40 C and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel previously neutralized by NEt 3 to afford diacetates of type 15. Acetate 14b was prepared following reported procedure using (R)-propylene oxide. 5 General procedure F : preparation of diols of type 5 from diacetates 15 To a solution of diacetate 15 (1 equiv) in MeH (0.3 M) was added sodium methoxide (1 M in MeH, 1.2 equiv). The mixture was stirred at room temperature for 20 h and an additional portion of sodium methoxide (1 M in MeH, 1.2 equiv) was added. Water was then added and the aqueous phase was extracted with EtAc, the organic layers were washed with brine, dried with MgS 4, filtered and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel furnished diol 5. H H (E)-1-Phenyl-dodec-2-ene-1,7-diol (5b, mixture of diastereomers) Prepared according to general procedures E and F acetates 9a and 14a (15%, 2 steps). IR (neat) : 3338, 2928, 2857, 1453, 1276 cm H NMR (400 MHz, C 6 D 6 ) δ : 7.51 (m, 2H), 7.30 (m, 2H), 7.20 (m, 1H), 5.77 (m, 2H), 5.15 (m, 1H), 3.46 (m, 1H), 2.45 (br s, 1H), (m, 2H), (m, 12H), 1.02 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, C 6 D 6 ) δ : (s), (d), (d), (2d), (d), (2d), 75.1 (d), 71.5 (d), 38.0 (t), 37.3 (t), 32.5 (t), 25.8 (t), 25.5 (t), 23.1 (t), 32.5 (t), 14.3 (q). HRMS (ESI) : Calculated for C 18 H 28 Na 2 [M+Na] + : Found : Lin, W.; Zercher, C. K. J. rg. Chem. 2007, 72, S21