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1 Tandem Long Distance Chain-Walking/Cyclization via RuH 2 (CO)(PPh 3 ) 3 /Brønsted Acid Catalysis: Entry to Aromatic Oxazaheterocycles Rodrigo Bernárdez, Jaime Suárez, Martín Fañanás-Mastral, Jesús A. Varela and Carlos Saá* Departamento de Química Orgánica y Centro Singular de Investigación en Química Biológica y Materiales Moleculares (CIQUS), Universidad de Santiago de Compostela, Santiago de Compostela, Spain Supporting Information S1

2 Table of Contents 1. General experimental procedures S3 2. Preparation of starting materials S4 2.1 Synthesis of compounds 1a-f, 1h, 1j, 4 and 5 S4 2.2 Synthesis of compounds (Z)-1g, (E)-1g and 1n S Synthesis of compound 6 S Synthesis of compound 1i S Synthesis of compounds 1k and 1l S Synthesis of compound 1m S Synthesis of compound 10 S Synthesis of compound 11 S Synthesis of compound 12 S Synthesis of compound 16 S25 3. Optimization data S Table S1: General optimization S Table S2: Screening of the acid cocatalyst S27 4. Synthesis and characterization of cycloisomerization products S28 5. Asymmetric cycloisomerization S37 6. NMR Spectra S Starting products S Cyclization products S79 S2

3 1. General experimental procedures All reactions were performed under an inert atmosphere of argon and with anhydrous solvents in glassware oven or flame dried at 80 ºC unless otherwise stated. All chemicals were purchased from Acros Organics Ltd., Aldrich Chemical Co. Ltd., Alfa Aesar, Strem Chemicals Inc., Fluorochem Ltd. or TCI Europe N.V. chemical companies and used without further purification, unless otherwise stated. Analytical thin layer chromatography was carried out on silica-coated aluminium plates (silica gel 60 F 254 Merck) or on aluminium sheets (aluminium oxide 60 F 254 neutral Merck) using UV light as visualizing agent (254 nm) and KMnO 4 (solution of 1.5 g of potassium permanganate, 10 g of potassium bicarbonate and 1.25 ml of 10% sodium hydroxide in 200 ml of water) with heat as developing agents. Flash column chromatography was performed on silica gel 60 (Merck, mesh) or aluminium oxide Camag Brockmann I neutral (Fisher Chemical, mesh) with the indicated eluent. Mass spectrometry was carried out on a Bruker microtof spectrometer. 1 H- and 13 C-NMR experiments were carried out using a Varian Inova 500MHz, a Varian Inova 400MHz or a Varian Mercury 300MHz NMR spectrometers and chemical shifts are reported relative to tetramethylsilane and trichloro-fluoro-methane as internal references. Coupling constants J are given in Hertz (Hz). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p=pentet, m = multiplet or as a combination of them. Multiplicities of 13 C NMR signals were determined by DEPT experiments. All other reagents and solvents: dichloromethane, dichloroethane, tetrahydrofurane, and toluene were used dry, unless otherwise indicated. Acetone was distilled from K 2 CO 3 and storage over 4Å molecular sieves. Yields refer to isolated compounds estimated to be > 95% pure as determined by 1 H NMR analysis. S3

4 2. Preparation of starting materials 2.1 Synthesis of compounds 1a-f, 1h, 1j, 4 and 5. Synthesis of S1a-b: protection with aromatic sulfonyl chloride N-(2-(Hydroxymethyl)phenyl)-4-methylbenzenesulfonamide (S1a). 2- Aminobenzyl alcohol (2.46 g, 20 mmol, 1 equiv) and TsCl (4.2 g, 22 mmol, 1.1 equiv) were dissolved in CHCl 3 (70 ml). Then pyridine (2 ml, 24 mmol, 1.2 equiv) was added to the mixture and the resulting solution was stirred overnight at room temperature. Then, the solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate (60 ml) and washed three times with a 3M solution of aq. HCl (60 ml) and once with saturated aq. NaHCO 3 (60 ml). The organic layer was dried over sodium sulfate, filtered and evaporated. The product S1a was purified by a recristalization in AcOEt and obtained as a white solid in 91% yield (5.03 g, 18.1 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm) : 7.84 (bs, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 1H), (m, 3H), (m, 2H), 4.40 (s, 2H), 2.38 (s, 3H), 2.02 (bs, 1H). N-(2-(Hydroxymethyl)phenyl)-4-nitrobenzenesulfonamide (S1b). 2- Aminobenzyl alcohol (616 mg, 5 mmol, 1 equiv) and p-nscl (1.22 g, 5.5 mmol, 1.1 equiv) were dissolved in CHCl 3 (18 ml). Then pyridine (0.49 ml, 6 mmol, 1.2 equiv) was added to the mixture and the resulting solution was stirred overnight at room temperature. Then, the solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate (15 ml) and washed three times with a 3M solution of aq. HCl (15 ml) and once with saturated aq. NaHCO 3 (15 ml). The organic layer was dried over sodium sulfate, filtered and evaporated. The product S1b was purified by a recristalization in AcOEt and obtained as an orange solid in 82% yield (1.27 g, 4.12 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm) : 8.27 (d, J = 8.4 Hz, 2H), 8.20 (bs, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), (m, 1H), (m, 2H), 4.39 (s, 2H), 2.04 (bs, 1H). S4

5 Synthesis of S1c: protection with mesyl chloride N-(2-(Hydroxomethyl)phenyl)methanesulfonamide (S1c). To a solution of 2-aminobenzylalcohol (1.23 g, 10 mmol, 1 equiv) in 6 ml of CH 2 Cl 2, MsCl (0.81 ml, 10.5 mmol, 1.05 equiv) and pyridine (1.05 ml, 13 mmol, 1.3 equiv) were added dropwise at 0 ºC. The reaction mixture was let to stir overnight at rt. and then transferred to a separatory funnel with 15 ml H 2 O. The aqueous phase was extracted with CH 2 Cl 2 (3x 5 ml) and the combined organic phases were washed with HCl 1M (5 ml), H 2 O (5 ml) and brine (5 ml). The organic phase was dried over Na 2 SO 4, filtered and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane / AcOEt 1:1). S1c was isolated in 48% yield (964 mg, 4.8 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm) : 7.94 (s, 1H), 7.39 (dd, J = 8.0, 1.2 Hz, 1H), 7.24 (td, J = 7.6, 1.8 Hz, 1H), 7.18 (dd, J = 7.6, 1.8 Hz, 1H), 7.09 (td, J = 7.4, 1.3 Hz, 1H), 4.63 (d, J = 4.6 Hz, 2H), 3.73 (t, J = 5.1 Hz, 1H), 2.92 (s, 3H). Synthesis of 1a-f, 1h, 1j, 4 and 5: alkylation of the sulfonamide N-(But-3-en-1-yl)-N-(2-(hydroxymethyl)phenyl)-4-methyl benzenesulfonamide (1a). S1a (3.88 g, 14 mmol, 1 equiv) was dissolved in DMF (140 ml). Then, 4-bromo-1-butene (2.27 ml, 22.4 mmol, 1.6 equiv) and K 2 CO 3 (3.9 g, 28 mmol, 2 equiv) were subsequently added to the solution and the reaction mixture was heated overnight at 80 ºC. Once the reaction was complete, the same amount of water (140 ml) and AcOEt (140 ml) were added to the reaction mixture. The aqueous phase was extracted three times with AcOEt (100 ml) and the combined organic layers were washed three times with H 2 O (100 ml), two times with brine (100 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (hexane / AcOEt 4:1) and the poduct 1a was obtained as a white solid in 81% yield (3.78 g, 11.4 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): 7.62 (dd, J = 7.8, 1.7 Hz, 1H), (m, 2H), 7.36 (td, J = 7.6, 1.3 Hz, 1H), (m, 2H), 7.15 (td, J = 7.8, 1.7 Hz, 1H), 6.45 (dd, J = 8.1, 1.3 Hz, 1H), 5.68 (ddt, J = 17.0, 10.5, 6.6 Hz, 1H), (m, 3H), 4.50 (dd, J = 12.1, 10.1 Hz, 1H), 3.97 (ddd, J = 13.0, 8.7, 7.3 Hz, 1H), 3.16 (ddd, 13.0, 8.7, 5.2 Hz, 1H), (m, 1H), 2.45 (s, 3H), (m, 2H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (CH), (C), (CH), (2xCH), (CH), (CH), (2xCH), (CH), (CH 2 ), 61.0 (CH 2 ), 51.3 (CH 2 ), 32.4 (CH 2 ), 21.6 (CH 3 ). N-Allyl-N-(2-(hydroxymethyl)phenyl)-4-methylbenzenesulfonamide (1b). S1a (1.41g, 5.08 mmol, 1 equiv) was dissolved in DMF (50 ml). Then, allyl bromide (0.66 ml, 7.62 mmol, 1.5 equiv) and K 2 CO 3 (1.4 g, S5

6 10.2 mmol, 2 equiv) were subsequently added to the solution and the reaction mixture was heated overnight at 80 ºC. Once the reaction was complete, the same amount of water (50 ml) and AcOEt (50 ml) were added to the reaction mixture. The aqueous phase was extracted three times with AcOEt (50 ml) and the combined organic layers were washed three times with H 2 O (50 ml), two times with brine (50 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (hexane / AcOEt 4:1) and the poduct 1b was obtained as a white solid in 90% yield (4.56 mmol, 1.45 g). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): (m, 3H), (m, 3H), 7.13 (td, J = 7.7, 1.7 Hz, 1H), 6.44 (dd, J = 8.0, 1.3 Hz, 1H), 5.71 (ddt, J = 17.0, 10.1, 6.9 Hz, 1H), (m, 3H), (m, 2H), (m, 1H), (m, 1H), 2.46 (s, 3H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (C), (CH), (CH), (2xCH), (CH), (CH), (2xCH), (CH), (CH 2 ), 61.2 (CH 2 ), 55.1 (CH 2 ), 21.6 (CH 3 ). N-(2-(Hydroxymethyl)phenyl)-4-methyl-N-(pent-4-en-1-yl)benzene sulfonamide (1c). S1a (1.17 g, 4.2 mmol, 1 equiv) was dissolved in DMF (42 ml). Then, 5-bromo-1-pentene (1 ml, 8.4 mmol, 2 equiv) and K 2 CO 3 (1.2 g, 8.4 mmol, 2 equiv) were subsequently added to the solution and the reaction mixture was heated overnight at 80 ºC. Once the reaction was complete, the same amount of water (40 ml) and AcOEt (40 ml) were added to the reaction mixture. The aqueous phase was extracted three times with AcOEt (40 ml) and the combined organic layers were washed three times with H 2 O (100 ml), two times with brine (40 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (hexane / AcOEt 4:1) and the poduct 1c was obtained as a white solid in 81% yield (1.18g, 3.4 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): 7.57 (dd, J = 7.7, 1.6 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.09 (td, J = 7.7, 1.6 Hz, 1H), 6.43 (d, J = 7.9 Hz, 1H), 5.62 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), (m, 3H), 4.53 (dd, J = 12.3, 7.9 Hz, 1H), 3.81 (ddd, J = 13.0, 9.3, 6.8 Hz, 1H), 3.43 (d, J = 5.7 Hz, 1H), 3.07 (ddd, J = 13.3, 9.1, 4.8 Hz, 1H), 2.37 (s, 3H), 1.96 (p, J = 6.9 Hz, 2H), (m, 1H), (m, 1H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (CH), (C), (CH), (2xCH), (CH), (CH), (2xCH), (CH), (CH 2 ), 60.9 (CH 2 ), 51.6 (CH 2 ), 30.7 (CH 2 ), 27.3 (CH 2 ), 21.5 (CH 3 ). N-(Hex-5-en-1-yl)-N-(2-(hydroxymethyl)phenyl)-4-methylbenzene sulfonamide (1d). S1a (832 mg, 3 mmol, 1 equiv) was dissolved in DMF (30 ml). Then, 6-bromo-1-hexene (0.8 ml, 6 mmol, 2 equiv) and K 2 CO 3 (829 mg, 6 mmol, 2 equiv) were subsequently added to the solution and the reaction mixture was heated overnight at 80 ºC. Once the reaction was complete, the same amount of water (30 ml) S6

7 and AcOEt (30 ml) were added to the reaction mixture. The aqueous phase was extracted three times with AcOEt (30 ml) and the combined organic layers were washed three times with H 2 O (30 ml), two times with brine (30 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (hexane / AcOEt 4:1) and the poduct 1d was obtained as a colorless oil in 75% yield (810 mg, 2.26 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): 7.59 (dd, J = 7.7, 1.6 Hz, 1H), (m, 2H), 7.32 (td, J = 7.5, 1.3 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.12 (td, J = 7.7, 1.7 Hz, 1H), 6.43 (dd, J = 8.0, 1.2 Hz, 1H), 5.67 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.00 (dd, J = 12.2, 3.2 Hz, 1H), (m, 2H), 4.51 (dd, J = 12.2, 9.8 Hz, 1H), (m, 1H), 3.28 (dd, J = 9.8, 3.4 Hz, 1H), (m, 1H), 2.41 (s, 3H), (m, 2H), (m, 4H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (CH), (C), (C), (CH), (2xCH), (CH), (CH), (2xCH), (CH), (CH 2 ), 61.0 (CH 2 ), 51.9 (CH 2 ), 33.1 (CH 2 ), 27.5 (CH 2 ), 25.9 (CH 2 ), 21.6 (CH 3 ). N-(Hept-6-en-1-yl)-N-(2-(hydroxymethyl)phenyl)-4-methylbenzene sulfonamide (1e). S1a (1.11 g, 4 mmol, 1 equiv) was dissolved in DMF (40 ml). Then, 7-bromo-1-heptene (1.2 ml, 8 mmol, 2 equiv) and K 2 CO 3 (1.1 g, 8 mmol, 2 equiv) were subsequently added to the solution and the reaction mixture was heated overnight at 80 ºC. Once the reaction was complete, the same amount of water (40 ml) and AcOEt (40 ml) were added to the reaction mixture. The aqueous phase was extracted three times with AcOEt (30 ml) and the combined organic layers were washed three times with H 2 O (40 ml), two times with brine (40 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (hexane / AcOEt 4:1) and the poduct 1e was obtained as a white solid in 79% yield (1.18 g, 3.16 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): 7.62 (dd, J = 7.7, 1.7 Hz, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.35 (td, J = 7.5, 1.3 Hz, 1H), 7.29 (d, J = 8.1 Hz, 2H), 7.14 (td, J = 7.6, 1.7 Hz, 1H), 6.44 (d, J = 8.0 Hz), 5.73 (ddt, J = 17.1, 10.2, 6.7 Hz, 1H), (m, 3H), 4.51 (t, J = 11.1 Hz, 1H), (m, 1H), (m, 2H), (m, 2H), (m, 6H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (CH), (C), (C), (CH), (2xCH), (CH), (CH), (2xCH), (CH), (CH 2 ), 61.1 (CH 2 ), 52.0 (CH 2 ), 33.5 (CH 2 ), 28.3 (CH 2 ), 28.0 (CH 2 ), 26.1 (CH 2 ), 21.6 (CH 3 ). N-(2-(Hydroxymethyl)phenyl)-4-methyl-N-(undec-10-en-1- yl)benzenesulfonamide (1f). S1a (832 mg, 3 mmol, 1 equiv) was dissolved in DMF (30 ml). Then, 11-bromo-1-undecene (1.32 ml, 6 mmol, 2 equiv) and K 2 CO 3 (829 mg, 6 mmol, 2 equiv) were subsequently added to the solution and the reaction mixture was heated overnight at 80 ºC. Once the reaction was complete, the same S7

8 amount of water (30 ml) and AcOEt (30 ml) were added to the reaction mixture. The aqueous phase was extracted three times with AcOEt (30 ml) and the combined organic layers were washed three times with H 2 O (30 ml), two times with brine (30 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (hexane / AcOEt 4:1) and the poduct 1f was obtained as a white solid in 75% yield (973 mg, 2.26 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): 7.61 (dd, J = 7.7, 1.7 Hz, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.34 (td, J = 7.5, 1.3 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.14 (td, J = 7.7, 1.7 Hz, 1H), 6.44 (dd, J = 8.0, 1.2 Hz, 1H), 5.79 (ddt, J = 16.9, 10.3, 6.6 Hz, 1H), (m, 3H), 4.50 (dd, J = 12.0, 10.0 Hz, 1H), (m, 1H), 3.18 (dd, J = 10.1, 3.3 Hz, 1H), 3.07 (ddd, J = 13.0, 9.4, 3.7 Hz, 1H), 2.44 (s, 3H), 2.01 (q, J = 6.7 Hz, 2H), (m, 14H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm):143.8 (C), (C), (CH), (C), (C), (CH), (2xCH), (CH), (CH), (2xCH), (CH), (CH 2 ), 61.0 (CH 2 ), 52.1 (CH 2 ), 33.7 (CH 2 ), 29.4 (CH 2 ), 29.3 (CH 2 ), 29.1 (CH 2 ), 29.0 (CH 2 ), 28.9 (CH 2 ), 28.1 (CH 2 ), 26.7 (CH 2 ), 21.6 (CH 3 ). N-(2-(Hydroxymethyl)phenyl)-4-methyl-N-(4-phenylbut-3-en- 1-yl)benzenesulfonamide (1h). S1a (832 mg, 3 mmol, 1 equiv) was dissolved in DMF (30 ml). Then, (4-bromo-1-buten-1- yl)benzene (1.09 g, 5.16 mmol, 1.7 equiv, 1:1 mixture of Z and E isomers) and K 2 CO 3 (829 mg, 6 mmol, 2 equiv) were subsequently added to the solution and the reaction mixture was heated overnight at 80 ºC. Once the reaction was complete, the same amount of water (30 ml) and AcOEt (30 ml) were added to the reaction mixture. The aqueous phase was extracted three times with AcOEt (30 ml) and the combined organic layers were washed three times with H 2 O (30 ml), two times with brine (30 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (hexane / AcOEt 4:1) and the poduct 1h was obtained as a white solid in 77% yield (940 mg, 2.3 mmol, 1:1 mixture of Z and E isomers). 1 H NMR for the (E) isomer (300 MHz, CDCl 3 ), δ (ppm): 7.63 (dd, J = 7.7, 1.7 Hz, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.37 (td, J = 7.5, 1.3 Hz, 1H), (m, 6H), (m, 2H), 6.50 (dd, J = 8.0, 1.2 Hz, 1H), 6.29 (d, J = 15.9 Hz, 1H), 6.02 (dt, J = 15.9, 6.9 Hz, 1H), 5.03 (dd, J = 12.2, 2.6 Hz, 1H), 4.51 (dd, J = 12.2, 9.6 Hz, 1H), 4.03 (ddd, J = 12.9, 8.6, 7.2 Hz, 1H), 3.26 (ddd, J = 13.1, 8.2, 5.3 Hz, 1H), 3.12 (dd, J = 9.8, 3.4 Hz, 1H), 2.44 (s, 3H), (m, 2H). 13 C NMR, DEPT for the (E) isomer (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (C), (C), (CH), (CH), (2xCH), (CH), (2xCH), (CH), (2xCH), (CH), (CH), (2xCH), (CH), 61.1 (CH 2 ), 51.5 (CH 2 ), 31.9 (CH 2 ), 21.6 (CH 3 ). S8

9 N-(2-(Hydroxymethyl)phenyl)-4-methyl-N-(2-methylallyl)benzene sulfonamide (1j). S1a (1.11 g, 4 mmol, 1 equiv) was dissolved in DMF (40 ml). Then, 3-Bromo-2-methylpropene (0.61 ml, 6 mmol, 1.5 equiv) and K 2 CO 3 (1.1 g, 8 mmol, 2 equiv) were subsequently added to the solution and the reaction mixture was heated overnight at 80 ºC. Once the reaction was complete, the same amount of water (40 ml) and AcOEt (40 ml) were added to the reaction mixture. The aqueous phase was extracted three times with AcOEt (30 ml) and the combined organic layers were washed three times with H 2 O (40 ml), two times with brine (40 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (hexane / AcOEt 4:1) and the poduct 1j was obtained as a white solid in 88% yield (1.17 g, 3.52 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): 7.60 (dd, J = 7.7, 1.7 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), (m, 3H), (m, 1H), 6.44 (dd, J = 8.1, 1.2 Hz, 1H), 4.99 (d, J = 12.2 Hz, 1H), 4.72 (p, J = 1.5 Hz, 1H), 4.52 (dq, J = 1.7, 0.9 Hz, 1H), (m, 2H), 3.62 (d, J = 13.2 Hz, 1H), (m, 1H), 2.46 (s, 3H), 1.78 (dd, J = 1.5, 0.9 Hz, 3H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (C), (C), (CH), (2xCH), (CH), (2xCH), (CH), (CH), (CH 2 ), 61.0 (CH 2 ), 58.5 (CH 2 ), 21.6 (CH 3 ), 20.4 (CH 3 ). N-(But-3-en-1-yl)-N-(2-(hydroxymethyl)phenyl)-4-nitrobenzene sulfonamide (4). S1b (1.26 g, 4.1 mmol, 1 equiv) was dissolved in DMF (40 ml). Then, 4-bromo-1-butene (0.83 ml, 8.2 mmol, 2 equiv) and K 2 CO 3 (1.13 g, 8.2 mmol, 2 equiv) were subsequently added to the solution and the reaction mixture was heated overnight at 80 ºC. Once the reaction was complete, the same amount of water (40 ml) and AcOEt (40 ml) were added to the reaction mixture. The aqueous phase was extracted three times with AcOEt (30 ml) and the combined organic layers were washed three times with H 2 O (40 ml), two times with brine (40 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (hexane / AcOEt 4:1) and the poduct 4 was obtained as a pale yellow solid in 41% isolated yield (609 mg, 1.68 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): (d, J = 8.8 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.17 (td, J = 7.7, 1.6 Hz, 1H), 5.66 (ddt, J = 17.0, 10.5, 6.6 Hz, 1H), (m, 3H), 4.57 (dd, J = 12.6, 8.7 Hz, 1H), (m, 1H), 3.24 (ddd, J = 13.2, 8.4, 5.3 Hz, 2H), (m, 1H), (m, 2H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (C), (CH), (CH), (CH), (2xCH), (CH), (CH), (2xCH), (CH 2 ), 60.8 (CH 2 ), 51.6 (CH 2 ), 32.3 (CH 2 ). S9

10 N-(But-3-en-1-yl)-N-(2-(hydroxymethyl)phenyl)methane sulfonamide (5). S1c (964 mg, 4.8 mmol, 1 equiv) was dissolved in DMF (48 ml). Then, 4-bromo-1-butene (0.73 ml, 7.2 mmol, 1.5 equiv) and K 2 CO 3 (1.1 g, 19.2 mmol, 4 equiv) were subsequently added to the solution and the reaction mixture was heated overnight at 80 ºC. Once the reaction was complete, the same amount of water (50 ml) and AcOEt (50 ml) were added to the reaction mixture. The aqueous phase was extracted three times with AcOEt (50 ml) and the combined organic layers were washed three times with H 2 O (50 ml), two times with brine (50 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (hexane / AcOEt 4:1) and the poduct 5 was obtained as a white solid in 75% yield (916 mg, 3.6 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): (m, 1H), (m, 2H), (m, 1H), 5.67 (ddt, J = 17.7, 9.7, 6.6 Hz, 1H), (m, 2H), (m, 2H), 4.47 (t, J = 10.8 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), 2.91 (s, 3H), (m, 2H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (CH), (CH), (CH), (CH), (CH), (CH 2 ), 60.8 (CH 2 ), 51.3 (CH 2 ), 36.7 (CH 3 ), 32.7 (CH 2 ). 2.2 Synthesis of compounds (Z)-1g, (E)-1g and 1n Synthesis of S2: protection with tosyl chloride To a solution of TsCl (4.2 g, 22.2 mmol, 1.11 equiv) in 70 ml of CHCl 3 ethyl 2-aminobenzoate (3 ml, 20 mmol, 1 equiv) and pyridine (2 ml, 24.4 mmol, 1.22 equiv) were added. The mixture was stirred 20 h at room temperature. After removal of the solvent, the residue was taken up in AcOEt and then washed with CuSO 4 sat. (2x70mL), and H 2 O (2x70mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The product was purified by a recristalization in AcOEt. Compound S2 was obtained in 90% yield S10

11 (5.75 g, 18 mmol) as a white crystalline solid. 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): (bs, 1H), 7.92 (dd, J = 8.0, 1.7 Hz, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.68 (dd, J = 8.4, 1.1 Hz, 1H), 7.44 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 7.21 (d, J = 8.1 Hz, 2H), 7.02 (ddd, J = 8.3, 7.3, 1.2 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). Synthesis of S3a-c: Mitsunobu reaction Ethyl (Z)-2-((N-(hex-3-en-1-yl)-4-methylphenyl)sulfonamido) benzoate (S3a). To a solution of S2 (1.76 g, 5.5 mmol, 1 equiv), PPh 3 (4.33 g, 16.5 mmol, 3 equiv) and cis-3-hexen-1-ol (1.95 ml, 16.5 mmol, 3 equiv) in 42 ml THF, were added dropwise at 0 ºC DEAD (40% toluene solution, 8.8 ml, 16.5 mmol, 3 equiv). The mixture was stirred 4 h at room temperature. After removal of the solvent the mixture was subjected to column chromatography (hexane/acoet 9:1). S3a was obtained in 81% yield (1.79g, 4.46 mmol) as a white solid. 1 H NMR of the rotameric mixture (300 MHz, CDCl 3 ), δ (ppm): (m, 1H), 7.48 (d, J = 8.4 Hz, 2H), (m, 2H), (m, 2H), (m, 1H), (m, 1H), (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.59 (bs, 2H), 2.39 (s, 3H), 2.33 (bs, 2H), 1.94 (p, J = 7.5 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 7.5 Hz, 3H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (C), (CH), (C), (CH), (CH), (2xCH), (CH), (2xCH), (CH), (CH), 61.3 (CH 2 ), 51.4 (CH 2 ), 26.8 (CH 2 ), 21.5 (CH 3 ), 20.6 (CH 2 ), 14.2 (CH 3 ), 14.1 (CH 3 ). Ethyl (E)-2-((N-(hex-3-en-1-yl)-4-methylphenyl)sulfonamido) benzoate (S3b). To a solution of S2 (1.44 g, 4.5 mmol, 1 equiv), PPh 3 (3.54 g, 13.5 mmol, 3 equiv) and trans-3-hexen-1-ol (1.6 ml, 13.5 mmol, 3 equiv) in 35 ml THF, were added dropwise at 0 ºC DEAD (40% toluene solution, 7.1 ml, 13.5 mmol, 3 equiv). The mixture was stirred 4 h at room temperature. After removal of the solvent the mixture was subjected to column chromatography (hexane/acoet 9:1). S3b was obtained in 75% yield (1.35 g, 3.37 mmol) as a white solid.1h NMR (300 MHz, CDCl 3 ) δ (ppm): (m, 1H), 7.48 (d, J = 8.3 Hz, 2H), (m, 2H), 7.22 (d, J = 8.0 Hz, 2H), (m, 1H), (m, 1H), (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.62 (bs, 2H), 2.40 (s, 3H), 2.28 (bs, 2H), (m, 2H), 1.38 (t, J = 7.1 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (C), (CH), (C), (CH), (CH), (2xCH), (CH), (2xCH), (CH), (CH), 61.3 (CH 2 ), 51.7 (CH 2 ), 32.0 (CH 2 ), 25.5 (CH 2 ), 21.5 (CH 3 ), 14.1 (CH 3 ), 13.6 (CH 3 ). Ethyl 2-((4-methyl-N-(3-methylbut-3-en-1-yl)phenyl)sulfonamido) benzoate (S3c). To a solution of S2 (1.28 g, 4 mmol, 1 equiv), PPh 3 (3.15 g, 12 mmol, 3 equiv) and 3-methyl-3-butene-1-ol (1.22 ml, 12 S11

12 mmol, 3 equiv) in 30 ml THF, were added dropwise at 0 ºC DEAD (40% toluene solution, 5.5 ml, 12 mmol, 3 equiv). The mixture was stirred 4 h at room temperature. After removal of the solvent the mixture was subjected to column chromatography (hexane/acoet 9:1). S3a was obtained as a white solid in 85% yield (1.32 g, 3.4 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): 7.83 (dd, J = 6.9, 2.5 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), (m, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.89 (dd, J = 7.4, 1.9 Hz, 1H), 4.67 (s, 2H), 4.58 (s, 1H), 4.23 (q, J = 7.0 Hz, 2H), (m, 2H), (m, 5H), 1.63 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (C), (C), (C), (CH), (CH), (CH), (2xCH), (CH), (2xCH), (CH 2 ), 61.2 (CH 2 ), 50.3 (CH 2 ), 36.7 (CH 2 ), 22.6 (CH 3 ), 21.4 (CH 3 ), 14.1 (CH 3 ). Synthesis of (Z)-1g, (E)-1g and 1n: reduction with DIBAL-H (Z)-N-(Hex-3-en-1-yl)-N-(2-(hydroxymethyl)phenyl)-4-methyl benzenesulfonamide ((Z)-1g). To a solution of the S3a (1.79 g, 4.45 mmol, 1 equiv) in CH 2 Cl 2 (15 ml) was added at -78 ºC a solution of DIBAL-H 1M in CH 2 Cl 2 (4.9 ml, 4.9 mmol, 1.1 equiv). After 30 min of stirring at this temperature another 1.1 equiv (4.9 ml, 4.9 mmol) of the DIBAL-H 1M solution were added to the reaction mixture. After two more hours at -78 ºC the solution was warmed to R.T. and quenched with MeOH first, and then with a saturated aquous solution of Rochelle's salt. After one hour of stirring the mixture was filtered. The aquous phase was extracted with CH 2 Cl 2 and the combined organic layer were dried over sodium sulfate, filtered and evaporated under reduced pressure. (Z)-1g was obtained after flash chromatography (hexane/acoet 8:2) as a colorles oil in 85% yield (1.36 g, 3.78 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): 7.61 (dd, J = 7.7, 1.7 Hz, 1H), (m, 2H), 7.34 (td, J = 7.5, 1.3 Hz, 1H), (m, 2H), 7.14 (td, J = 7.7, 1.7 Hz, 1H), 6.45 (dd, J = 8.0, 1.3 Hz, 1H), (m, 1H), (m, 1H), 5.02 (dd, J = 12.1, 3.0 Hz, 1H), 4.50 (dd, J = 12.2, 9.9 Hz, 1H), 3.88 (ddd, J = 12.8, 9.0, 7.4 Hz, 1H), (m, 2H), 2.43 (s, 3H), 2.18 (dq, J = 15.3, 7.7 Hz, 2H), (m, 1H), (m, 2H), 0.85 (t, J = 7.5 Hz, 2H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (CH), (C), (CH), (2xCH), (CH), (CH), (2xCH), (CH), (CH), 61.1 (CH 2 ), 51.7 (CH 2 ), 26.1 (CH 2 ),, 21.6 (CH 3 ), 20.5 (CH 2 ), 14.0 (CH 3 ). (E)-N-(Hex-3-en-1-yl)-N-(2-(hydroxymethyl)phenyl)-4- methyl benzenesulfonamide (E)-1g. To a solution of the S3b (800 mg, 2 mmol, 1 equiv) in CH 2 Cl 2 (7 ml) was added at -78 ºC a solution of DIBAL-H 1M in CH 2 Cl 2 (2.2 ml, 2.2 mmol, 1.1 equiv). After 30 min of stirring at this temperature another 1.1 equiv (2.2 ml, 2.2 mmol) of the DIBAL-H 1M solution were added to the reaction S12

13 mixture. After two more hours at -78 ºC the solution was warmed to R.T. and quenched with MeOH first, and then with a saturated aquous solution of Rochelle's salt. After one hour of stirring the mixture was filtered. The aquous phase was extracted with CH 2 Cl 2 and the combined organic layer were dried over sodium sulfate, filtered and evaporated under reduced pressure. (E)-1g was obtained after flash chromatography (hexane /AcOEt 8:2) as a white solid in 82% yield (590 mg, 1.64 mmol). 1 H NMR (500 MHz, CDCl 3 ), δ (ppm): 7.60 (dd, J = 7.7, 1.5 Hz, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.33 (td, J = 7.5, 1.3 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.13 (td, J = 7.6, 1.5 Hz, 1H), 6.45 (dd, J = 8.0, 1.3 Hz, 1H), (m, 1H), (m, 1H), 5.01 (dd, J = 12.4, 2.7 Hz, 1H), 4.51 (dd, J = 12.2, 9.5 Hz, 1H), 3.89 (ddd, J = 12.8, 9.0, 7.1 Hz, 1H), 3.33 (dd, J = 9.6, 3.4 Hz, 1H), (m, 1H), 2.42 (s, 3H), (m, 1H), (m, 2H), 0.90 (t, J = 7.5 Hz, 3H). 13 C NMR, DEPT (125 MHz, CDCl 3 ), δ (ppm):143.9 (C), (C), (C), (CH), (C), (CH), (2xCH), (CH), (CH), (2xCH), (CH), (CH), 61.0 (CH 2 ), 51.8 (CH 2 ), 31.3 (CH 2 ), 25.5 (CH 2 ), 21.6 (CH 3 ), 13.5 (CH 3 ). N-(2-(Hydroxymethyl)phenyl)-4-methyl-N-(3-methylbut-3-en-1- yl)benzenesulfonamide (1n). To a solution of the S3c (1.32 g, 3.4 mmol, 1 equiv) in CH 2 Cl 2 (12 ml) was added at -78 ºC a solution of DIBAL-H 1M in CH 2 Cl 2 (3.75 ml, 3.75 mmol, 1.1 equiv). After 30 min of stirring at this temperature another 1.1 equiv (3.75 ml, 3.75 mmol) of the DIBAL-H 1M solution were added to the reaction mixture. After two more hours at -78 ºC the solution was warmed to R.T. and quenched with MeOH first, and then with a saturated aquous solution of Rochelle's salt. After one hour of stirring the mixture was filtered. The aquous phase was extracted with CH 2 Cl 2 and the combined organic layer were dried over sodium sulfate, filtered and evaporated under reduced pressure. 1n was obtained after flash chromatography (hexane /AcOEt 8:2) as a white solid in 62% yield (730 mg, 2.11 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): 7.58 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.31 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.11 (t, J = 7.6 Hz, 1H), 4.96 (dd, J = 12.4, 3.4 Hz, 1H), 4.70 (s, 1H), 4.54 (s, 1H), (m, 1H), (m, 1H), 3.26 (dd, J = 9.5, 3.7 Hz, 1H), (m, 1H), 2.40 (s, 3H), 2.11 (dt, J = 15.9, 8.3 Hz, 1H), (m, 1H), 1.62 (s, 3H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (C), (C), (CH), (2xCH), (CH), (CH), (2xCH), (CH), (CH 2 ), 61.0 (CH 2 ), 49.9 (CH 2 ), 35.9 (CH 2 ), 22.2 (CH 3 ), 21.6 (CH 3 ). S13

14 2.3 Synthesis of compound 6 Synthesis of S4: alkylation of 2-aminobenzyl alcohol The compound S4 was obtained following a described procedure. 1 Synthesis of 6: aniline protection tert-butyl but-3-en-1-yl(2-(hydroxymethyl)phenyl)carbamate (6). S4 (1 g, 5.6 mmol, 1 equiv) was dissolved in 11 ml EtOH. Boc 2 O (1.9 ml, 8.4 mmol, 1.5 equiv) was then added with a syringe. The solution was stirred at 50 ºC overnight. Once the reaction was complete, the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane / AcOEt 8:2) and the product 6 was obtained in 89% yield (1.39 g, 5 mmol) as a colorless oil. 1 H NMR (300 MHz, 80 ºC, DMSO-d6), δ (ppm): (m, 1H), (m, 2H), 7.10 (dd, J = 7.5, 1.7 Hz, 1H), 5.76 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), (m, 2H), 4.81 (t, J = 5.1 Hz, 1H), 4.44 (d, J = 5.1 Hz, 2H), 3.53 (bs, 2H), 2.25 (q, J = 7.4 Hz, 2H), 1.34 (s, 9H). 13 C NMR, DEPT (75 MHz, 80 ºC, DMSO-d6), δ (ppm): (C), (C), (C), (CH), (CH), (CH), (CH), (CH), (CH 2 ), 79.6 (C), 59.5 (CH 2 ), 49.6 (CH 2 ), 32.8 (CH 2 ), 28.4 (3xCH 3 ). 1 Bar-Haim, G.; Kol, M. Org. Lett.2004, 6, S14

15 2.4 Synthesis of compound 1i Synthesis of S5: alkylation of the sulfonamide To a solution of S1 (1.39 g, 5 mmol, 1 equiv) in 50 ml of DMF were successively added 3-chloropropionaldehyde diethylacetal 90% techn. (2.1 ml, 12.5 mmol, 2.5 equiv), K 2 CO 3 (1.72 g, 12.5 mmol, 2.5 equiv) and KI (415 mg, 2.5 mmol, 0.5 equiv). The reaction mixture was stirred at 80 ºC overnight. Then, 50 ml of H 2 O were added to the solution and the mixture was extracted with AcOEt (3x50 ml). The combined organics extracts were washed with H 2 O (3x50 ml) and brine (2x50 ml). The organic layer was dried with Na 2 SO 4, filtered and the solvent was evaporated under reduced pressure. Column chromatography of the residue (hexane /AcOEt 8:2) afforded the alkylated product S5 (1.73g, 4.25 mmol) as a colorless oil in 85% yield. 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): 7.58 (d, J = 7.7 Hz, 1H), (m, 2H), (m, 3H), 7.11 (t, J = 7.7 Hz, 1H), 6.45 (d, J = 8.0 Hz, 1H), 4.92 (dd, J = 12.4, 3.2 Hz, 1H), 4.58 (dd, J = 12.1, 9.2 Hz, 1H), 4.47 (t, J = 5.4 Hz, 1H), 3.94 (dt, J = 15.0, 7.7 Hz, 1H), (m, 5H), (m, 1H), 2.39 (s, 3H), (m, 1H), (m, 1H), (m, 6H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (C), (CH), (2xCH), (CH), (CH), (2xCH), (CH), (CH), 61.9 (CH 2 ), 61.3 (CH 2 ), 60.8 (CH 2 ), 48.0 (CH 2 ), 32.5 (CH 2 ), 21.5 (CH 3 ), 15.2 (CH 3 ), 15.1 (CH 3 ). Synthesis of S6: acetal hydrolisis The hydrolisis was accomplished following a similar procedure reported by Trost. 2 A 250 ml round bottom flask equiped with a reflux condenser was charged with the diethyl acetetal S5 (1.73 g, 4.25 mmol, 1 equiv) dissolved in a mixture of acetone (150 ml) 2 Trost, B. M.; Weiss, A. H. Angew. Chem. Int. Ed. 2007, 46, S15

16 and water (4 ml). Pyridinium p-toluenesulfonate (327 mg, 1.3 mmol, 30 mol %) was added and the reaction mixture was stirred under reflux overnight. The solution was concentrated under reduced pressure, then water (40 ml) and DCM (40 ml) were added. After separation, the aqueous layer was extracted with 3x DCM (40 ml). The combined organics were dried with Na 2 SO 4, filtered and the solvent was evaporated under reduced pressure. The pure aldehyde S6 was obtained after a short flash chromatography (hexane / AcOEt 1:1) as a white foam in 89% yield (1.26 g, 3.78 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): (m, 1H), (m, 1H), 7.46 (d, J = 8.0 Hz, 2H), (m, 3H), 7.09 (td, J = 7.7, 1.7 Hz, 1H), 6.42 (t, J = 7.6 Hz, 1H), (m, 1H), 4.57 (dd, J = 12.6, 8.0 Hz, 1H), 4.17 (dt, J = 14.5, 7.4 Hz, 1H), (m, 1H), (m, 1H), 2.38 (s, 3H). Synthesis of 1i: Wittig reaction Methyl 5-((N-(2-(hydroxymethyl)phenyl)-4-methyl phenyl)sulfonamido)pent-2-enoate (1i). To a suspension of [Ph 3 PCH 2 CO 2 Me]Br (1.56g, 3.75 mmol, 1.5 equiv) in 18 ml THF and 2 ml of MeOH, NaOMe (203 mg, 3.75 mmol, 1.5 equiv) was added. The mixture was stirred at room temperature during 2 h. Then a solution of the aldehyde S7 (1.1 g, 2.5 mmol, 1 equiv) in 15 ml THF was added dropwise and the reaction mixture was stirred at room temperature overnight. Once the reaction was complete, the solvents were evaporated and the crude residue was purified by column chromatography (hexane / AcOEt 1:1). The product 1i was obtained as a white solid in 76% yield (740 mg, 1.9 mmol) and as a mixture of isomers (4:1 E / Z). 1 H NMR of the major isomer (300 MHz, CDCl 3 ), δ (ppm): 7.57 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.10 (t, J = 8.1 Hz, 1H), 6.72 (dt, J = 15.7, 6.9 Hz, 1H), 6.41 (d, J = 8.0 Hz, 1H), 5.71 (d, J = 15.7 Hz, 1H), 4.87 (d, J = 12.3 Hz, 1H), 4.51 (dd, J = 12.4, 8.5 Hz, 1H), 3.95 (dt, J = 13.0, 7.8 Hz, 1H), 3.63 (s, 3H), (m, 2H), 2.39 (s, 3H), (m, 2H). 13 C NMR, DEPT of the major isomer (75 MHz, CDCl 3 ), δ (ppm): (C), (CH), (C), (C), (C), (C), (CH), (2xCH), (CH), (CH), (2xCH), (CH), (CH), 60.8 (CH 2 ), 51.5 (CH 3 ), 50.3 (CH 2 ), 30.9 (CH 2 ), 21.5 (CH 2 ). S16

17 2.5 Synthesis of compounds 1k and 1l Synthesis of S7a-b: protection with tosyl chloride The corresponding 2-aminophenone was protected with tosyl chloride following a decribed procedure. 3 Synthesis of S8a-b: alkylation of the sulfonamide N-(2-Acetophenone)-N-(but-3-en-1-yl)-4-methylbenzene sulfonamide (S8a). S7a (3.47g, 12 mmol, 1 equiv) was dissolved in DMF (120 ml). Then, 4-bromo-1- butene(2.44 ml, 24 mmol, 2 equiv) and K 2 CO 3 (3.32 g, 24 mmol, 2 equiv) were subsequently added to the solution and the reaction mixture was heated overnight at 80 ºC. Once the reaction was complete, the same amount of water (120mL) and AcOEt (120 ml) were added to the reaction mixture. The aqueous phase was extracted three times with AcOEt (60 ml) and the combined organic layers were washed three times with H 2 O, two times with brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (hexane/acoet 9:1). S8a was obtained as an orange solid in 80% yield (3.16 g, 9.6 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): δ (m, 1H), 7.42 (d, J = 8.3 Hz, 2H), (m, 3H), 7.24 (d, J = 8.5 Hz, 2H), (m, 1H), 5.69 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), (m, 2H), 3.83 (bs, 1H), 3.43 (bs, 1H), 2.65 (s, 3H), 2.41 (s, 3H), 2.33 (bs, 2H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (C), (C), (CH), (CH), (2xCH), 129.1(CH), (CH), (2xCH), (CH), (CH 2 ), 50.8 (CH 2 ), 32.6 (CH 2 ), 30.4 (CH 3 ), 21.5 (CH 3 ). N-(2-Benzophenone)-N-(but-3-en-1-yl)-4-methylbenzene sulfonamide (S8b). S7b (1.76 g, 5 mmol, 1 equiv) was dissolved in DMF (50 ml). Then, 4-bromo-1-butene (1.02 ml, 10 mmol, 2 equiv) and K 2 CO 3 (1.38 g, 2 equiv) were subsequently added to the solution and the reaction mixture was heated overnight at 80 ºC. Once the reaction was complete, the same amount of water (50 ml) and AcOEt (50 ml) were added to the reaction mixture. The aqueous phase was extracted three times with 3 Hari, Y.; Kanie, T.; Miyagi, T.; Aoyama, T. Synthesis 2006, 8, S17

18 AcOEt (25 ml) and the combined organic layers were washed three times with H 2 O, two times with brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (hexane/acoet 9:1). S8b was obtained as a solid in 90% yield (1.82 g, 4.5 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): (m, 2H), (m, 1H), (m, 5H), (m, 2H), (m, 1H), (m, 2H), 5.70 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), (m, 2H), 3.67 (dd, J = 9.8, 6.3 Hz, 2H), 2.38 (q, J = 7.3 Hz, 2H), 2.30 (s, 3H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm):195.1 (C), (C), (C), (C), (C), (C), (CH), (CH), (CH), (2xCH), (CH), (CH), (2xCH), (2xCH), (2xCH), (CH), (CH 2 ), 51.9 (CH 2 ), 32.8 (CH 2 ), 21.5 (CH 2 ). Synthesis of 1k-l: ketone reduction N-(But-3-en-1-yl)-N-(2-(1-hydroxyethyl)phenyl)-4- methylbenzene sulfonamide (1k). S8a (856 mg, 2.5 mmol) was disolved in 30 ml of MeOH. The solution was cooled to 0 ºC and NaBH 4 (280 mg, 7.5 mmol 3 equiv) was added in portions. The reaction mixture was stirred at room temperature for 2 h. The, the reaction was quenched with acetone and the solvents were removed under reduced pressure. The crude was taken up in a AcOEt (25 ml) and water (25 ml). The aqueous phase was washed with 3xAcOEt (25 ml) and the combined organic extracts were washed with 3xH 2 O (25 ml), brine (25 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (hexane / AcOEt 9:1). 1k was obtained as a white solid in 85% yield (735 mg, 2.1 mmol). 1 H NMR of the major rotamer (300 MHz, CDCl 3 ), δ (ppm): 7.68 (dd, J = 7.9, 1.6 Hz, 1H), 7.48 (d, J = 8.3 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.11 (td, J = 7.7, 1.6 Hz, 1H), 5.69 (ddt, J = 17.8, 9.8, 6.5 Hz, 1H), 5.49 (qd, J = 6.7, 2.5 Hz, 1H), (m, 2H), 3.97 (ddd, J = 12.9, 9.0, 7.2 Hz, 1H), (m, 1H), 3.16 (ddd, J = 13.1, 8.7, 5.0 Hz, 1H), 2.44 (s, 3H), (m, 2H), 1.49 (d, J = 6.6 Hz, 3H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (C), (CH), (2xCH), (CH), (2xCH), (CH), (CH), (CH 2 ), 63.1 (CH), 51.1 (CH 2 ), 32.4 (CH 2 ), 21.9 (CH 3 ), 21.6 (CH 3 ). N-(But-3-en-1-yl)-N-(2-(hydroxy(phenyl)methyl)phenyl)-4- methylbenzenesulfonamide (1l). S8b (1.82 g, 4.5 mmol) was disolved in 55 ml of MeOH. The solution was cooled to 0 ºC and NaBH 4 (511 mg, 13.5 mmol 3 equiv) was added in portions. The reaction mixture was stirred at room temperature for 2 h. The, the reaction was quenched with acetone and the solvents were removed under reduced pressure. The crude was taken up in a AcOEt (45 ml) and water (45 S18

19 ml). The aqueous phase was washed with 3xAcOEt (45 ml) and the combined organic extracts were washed with 3xH 2 O (45 ml), brine (45 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (hexane / AcOEt 9:1). 1k was obtained as a colorless solid in 88% yield (1.63g, 4 mmol). 1 H NMR of the rotameric mixture (300 MHz, CDCl 3 ), δ (ppm): (m, 2H), (m, 2H), (m, 7H), (m, 1H), 6.57 (d, J = 2.3 Hz, 1H), 6.49 (dd, J = 8.0, 1.2 Hz, 1H), 5.74 (ddt, J = 16.9, 10.3, 6.5 Hz, 1H), (m, 2H), 4.20 (d, J = 2.4 Hz, 1H), 4.03 (ddd, J = 12.8, 9.7, 6.7 Hz, 1H), 3.26 (ddd, J = 12.8, 9.3, 4.9 Hz, 1H), 2.44 (s, 3H), (m, 2H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (C), (CH), (C), (CH), (2xCH), (CH), (CH), (2xCH), (2xCH), (CH), (2xCH), (CH), (CH 2 ), 68.7 (CH), 51.5 (CH 2 ), 32.5 (CH 2 ), 21.6 (CH 3 ). 2.6 Synthesis of compound 1m: ketone methylation N-(But-3-en-1-yl)-N-(2-(2-hydroxypropan-2-yl)phenyl)-4-methylbenzene sulfonamide (1m). A solution of MeMgBr 3M in Et 2 O (2.1 ml, 6.25 mmol, 2.5 equiv.) was added dropwise to a solution of S8a (820 mg, 2.5 mmol, 1 equiv) in 30 ml of THF at 0 ºC. The mixture was stirred at 0 ºC during 2 h and quenched with a saturated solution of NH 4 Cl. The organic layer was washed with water (30 ml), brine (30 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. Column chromatography of the residue (hexane / AcOEt 9:1) afforded the product 1m as a white solid in 84% yield (760 mg, 2.1 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): 7.57 (d, J = 8.3 Hz, 2H), 7.41 (dd, J = 8.1, 1.6 Hz, 1H), (m, 3H), 7.01 (td, J = 7.6, 1.5 Hz, 1H), 6.47 (dd, J = 8.0, 1.1 Hz, 2H), 5.61 (ddt, J = 17.1, 10.4, 6.7 Hz, 1H), (m, 2H), 4.49 (s, 1H), 3.80 (ddd, J = 12.8, 11.0, 5.5 Hz, 1H), 3.32 (ddd, J = 12.8, 11.0, 5.2 Hz, 1H), (m, 1H), 2.40 (s, 3H), (m, 1H), 1.73 (s, 3H), 1.63 (s, 3H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (CH), (C), (2xCH), (CH), (CH), (3xCH), (CH), (CH 2 ), 74.6 (C), 52.3 (CH 2 ), 33.8 (CH 3 ), 32.7 (CH 3 ), 32.1 (CH 2 ), 21.6 (CH 2 ). S19

20 2.7 Synthesis of compound 10 Synthesis of S9: protection with 2,3-dihydrofuran 2-((tetrahydrofuran-2-yl)oxy)benzonitrile (S9). 2-Hydroxybenzonitrile (1.8 g, 15 mmol, 1 equiv) was dissolved in 36 ml THF. 2,3-dihydrofuran (1.7 ml, 22.5 mmol, 1.5 equiv) and TsOH.H 2 O (29 mg, 0.15 mmol, 1 mol %) were added and the reaction mixture was stirred at room temperature over 24 h. The solvent was evaporated under reduced pressure and the crude residue was purified by flash chromatography on silica gel (hexane / AcOEt 19:1). The product S9 was obtained as a colorless oil in 56% yield (1.6g, 8.5 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): (m, 2H), 7.21 (d, J = 8.4 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 5.79 (d, J = 4.4 Hz, 1H), (m, 2H), (m, 4H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (CH), (CH), (CH), (C), (CH), (CH), (C), 68.6 (CH 2 ), 32.7 (CH 2 ), 23.1 (CH 2 ). Synthesis of S10: reduction and amine protection 4-methyl-N-(2-((tetrahydrofuran-2-yl)oxy)benzyl)benzene sulfonamide (S10). A solution of S9 (1.6 g, 8.5 mmol, 1 equiv) in 10 ml Et 2 O was added to a suspension of LiAlH 4 (638 mg, 16.8 mmol, 2 equiv) in 54 ml Et 2 O at 0 ºC. The reaction mixture was stirred at room temperature overnight and quenched at 0 ºC with H 2 O. The reaction was filtered over Cellite and washed with Et 2 O. The solvent was evaporated under reduced pressure and the corresponding benzylamine (1 g, 5.2 mmol) was used in the next step whitout further purification. The free amine (1g, 5.2 mmol) was dissolved in 16 ml CH 2 Cl 2. Then, TsCl (1.5 g, 7.8 mmol, 1.5 equiv.) and pyridine (1.3 ml, 15.6 mmol, 3 equiv.) were added to the solution. The reaction mixture was stirred at room temperature during 16 h. After this time brine was added to the mixture and the organic phase was separated, dried over Na 2 SO 4, filtered and the solvent removed under reduced pressure. The residue was S20

21 purified by flash chromatography on silica gel (hexane / AcOEt 8:2) and the product S10 was obtained as a white solid in 43% overall yield (1.27g, 3.7 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): 7.65 (d, J = 8.3 Hz, 2H), (m, 3H), (m, 2H), 6.80 (td, J = 7.4, 0.9 Hz, 1H), 5.66 (dd, J = 4.0, 2.0 Hz, 1H), 5.28 (t, J = 6.2 Hz, 1H), 4.07 (d, J = 6.2 Hz, 2H), (m, 2H), 2.36 (s, 3H), (m, 4H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (CH), (2xCH), (CH), (2xCH), (C), (CH), (CH), (CH), 68.3 (CH 2 ), 43.6 (CH 2 ), 32.8 (CH 2 ), 23.5 (CH 2 ), 21.4 (CH 3 ). Synthesis of S11: alkylation of the sulfonamide N-(but-3-en-1-yl)-4-methyl-N-(2-((tetrahydrofuran-2-yl)oxy) benzyl)benzenesulfonamide (S11). The sulfonamide S10 (590 mg, 1.7 mmol, 1 equiv) was dissolved in 18 ml DMF. Then, 4- bromo-1-butene (0.35 ml, 3.4 mmol, 2 equiv.) and K 2 CO 3 (470 mg, 3.4 mmol, 2 equiv.) were subsequently added to the solution and the reaction mixture was heated overnight at 75 ºC. Once the reaction was complete, the same amount of water and AcOEt (20 ml) were added to the reaction mixture. The aqueous phase was extracted three times with AcOEt (20 ml) and the combined organic layers were washed three times with H 2 O (20 ml), two times with brine (20 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (hexane / AcOEt 9:1). The product S11 was obtained as a colorless oil in 60% yield (406 mg, 1 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): (m, 2H), (m, 3H), (m, 1H), 7.13 (dd, J = 8.3, 1.3 Hz, 1H), 6.92 (td, J = 7.4, 1.3 Hz, 1H), 5.76 (dd, J = 4.3, 1.3 Hz, 1H), 5.55 (ddt, J = 17.2, 10.5, 6.8 Hz, 1H), (m, 2H), 4.40 (d, J = 15.0 Hz, 1H), 4.35 (d, J = 15.0 Hz, 1H), (m, 2H), (m, 2H), 2.41 (s, 3H), (m, 6H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (CH), (CH), (2xCH), (CH), (2xCH), (C), (CH), (CH), (CH), (CH), 68.2 (CH 2 ), 47.6 (CH 2 ), 46.5 (CH 2 ), 32.8 (CH 2 ), 32.7 (CH 2 ), 23.5 (CH 2 ), 21.5 (CH 3 ). Synthesis of 10: deprotection of the THF protecting group N-(But-3-en-1-yl)-N-(2-hydroxybenzyl)-4-methylbenzene sulfonamide (10).The THF-protected phenol derivative S11 (400 mg, 1 mmol, 1 equiv) was dissolved in 5 ml MeOH and TsOH.H 2 O (6 mg, 0.03 mmol, 3 mol %) was the added. The reaction mixture was stirred at room temperature during 3 h and the solvent evaporated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (hexane / AcOEt 9:1). The product 10 was obtained as a solid in 99% yield (327 mg, 0.99 mol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), (m, 1H), (m, 2H), 6.93 (dd, J = 8.2, 1.2 Hz, S21

22 1H), 6.83 (td, J = 7.4, 1.2 Hz, 1H), 5.52 (ddt, J = 17.1, 10.3, 6.9 Hz, 1H), (m, 2H), 4.27 (s, 2H), (m, 2H), 2.45 (s, 3H), (m, 2H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (CH), (CH), (CH), (2xCH), (2xCH), (C), (CH), (CH), (CH 2 ), 49.6 (CH 2 ), 48.0 (CH 2 ), 33.0 (CH 2 ), 21.6 (CH 3 ). 2.8 Synthesis of compound 11 Synthesis of S12: alcohol and aniline protection N-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-4-methyl benzenesulfonamide (S12). To a solution of 2-aminophenethyl alcohol (1.73 g, 12.6 mmol, 1 equiv) in 22 ml DMF, TBSCl (2.1 g, 13.9 mmol, 1.1 equiv) and 1H-imidazole (2.15 mmol, 2.5 equiv) were added successively. The reaction mixture was stirred at room temperature during 6 h. Once the reaction over 30 ml of water were added. The aqueous phase was extracted with 2xEt 2 O (30 ml), the combined organic extracts were washed with 3x H 2 O (30 ml), dried over Na 2 SO 4 filtered and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography on silica gel (hexane / AcOEt 30 : 1). The purified TBS protected alcohol (2.34 g, 9.3 mmol, 1 equiv) was dissolved in 30 ml of CHCl 3. TsCl (2 g, 10.4 mmol, 1.12 equiv) and pyridine (0.92 ml, 11.4 mmol, 1.23 equiv) were then added to the solution. The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the crude redissolved in AcOEt, washed with HCl 3N (3x20mL), NaHCO 3 sat. (20mL). The organic layer was dried over Na 2 SO 4, filtered and the solvent was evaporated under reduced pressure. Column chromatography of the residue (hexane / AcOEt 9:1) afforded S12 in 67% overall yield (3.4 g, 8.4 mmol). 1 H NMR (300 MHz, CDCl 3 ), δ (ppm): 8.67 (s, 1H), (m, 3H), (m, 3H), 7.07 (td, J = 7.4, 1.4 Hz, 1H), 6.99 (dd, J = 7.6, 1.7 Hz, 1H), (m, 2H), (m, 5H), 0.87 (s, 9H), 0.02 (s, 6H). 13 C NMR, DEPT (75 MHz, CDCl 3 ), δ (ppm): (C), (C), (C), (C), (CH), (2xCH), (CH), (2xCH), (CH), (CH), 65.9 (CH 2 ), 35.1 (CH 2 ), 26.0 (3xCH 3 ), 21.5 (CH 3 ), 18.4 (C), (2xCH 3 ). S22