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1 DOI: /NCHEM.1998 An organic thiyl radical catalyst for enantioselective cyclization Takuya Hashimoto, Yu Kawamata and Keiji Maruoka Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto , Japan Table of Contents 1. General Information.. p Preparation of Catalyst 5h.. p Preparation of Vinylcycloprapanes.. p Diastereo- and Enantioselective Radical Cyclization.. p Determination of the Absolute Configuration of 2a by X-Ray Analysis.. p References.. p Copies of 1 H and 13 C NMR.. p. 33 NATURE CHEMISTRY 1

2 1. General Information Infrared (IR) spectra were recorded on a ThermoFischer Scientific NICOLET is5 spectrometer. 1 H NMR spectra were measured on a JEOL JNM-FX400 (400 MHz) spectrometer. Data were reported as follows: chemical shifts in ppm from tetramethylsilane as an internal standard in CDCl 3, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, app = apparent), coupling constants (Hz), and assignment. 13 C NMR spectra were measured on a JEOL JNM-FX400 (100 MHz) spectrometer with complete proton decoupling. Chemical shifts were reported in ppm from the residual solvent as an internal standard. High performance liquid chromatography (HPLC) was performed on Shimadzu 10A instruments at 210 nm using 4.6 mm x 25 cm Daicel Chiralpak IC-3, IA, IA-3, AD-3, IE, and Chiralcel OZ-H. Optical resolutions of thiols were performed on Shimadzu LC-6AD, CBM-20A, SPD-20A, FRC-10A at 210 nm using 20 mm x 250 mm CHIRALPAK IA. High-resolution mass spectra (HRMS) were performed on Brucker microtof. Optical rotations were measured on a JASCO DIP-1000 digital polarimeter. BLAK-RAY MODEL B 100AP was used as UV-lamp. For thin layer chromatography (TLC) analysis throughout this work, Merck precoated TLC plates (silica gel 60 GF 254, 0.25 mm) were used. The products were purified by flash column chromatography silica gel 60 (Merck, mesh) or preparative thin layer chromatography silica gel (PLC 60 F mm). In experiments requiring dry solvent, CH 2 Cl 2, toluene and THF were purchased from Kanto Chemical Co. Inc. as Dehydrated and further purified by passing through neutral alumina under nitrogen atmosphere. Commercially obtained reagents were used as received. NATURE CHEMISTRY 2

3 2. Preparation of Catalyst 5h 6-Bromo-7-hydroxy-4-methylindanone 7 O OH Me Br purification. To a stirred solution of 7-hydroxy-4-methylindanone 29 6 (3.24 g, 20 mmol) in CH 2 Cl 2 (50 ml) was added bromine (2.05 ml, 40 mmol) at 0 ºC. After 15 min of stirring, the mixture was poured into 1 N Na 2 SO 3 and extracted with CH 2 Cl 2. The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated. The crude product was used to the next reaction without 1 H NMR (400 MHz, CDCl 3 ) 9.40 (1H, s), 7.50 (1H, s), 2.96 (2H, t, J = 5.7 Hz), 2.75 (2H, t, J = 5.7 Hz), 2.24 (3H, s); 13 C NMR (100 MHz, CDCl 3 ) 209.5, 152.9, 152.0, 140.4, 127.8, 123.0, 106.0, 36.0, 24.6, 16.6; IR (neat) 3270, 2923, 1668, 1444, 1413, 1321 cm -1 ; HRMS (ESI) exact mass calcd. for C 10 H 9 BrO 2 : m/z ([M + Na] + ), found: m/z ([M + Na] + ). 6-Bromo-7-((dimethylcarbamothioyl)oxy)-4-methylindanone 8 NATURE CHEMISTRY 3

4 To a stirred solution of the crude mixture of 7 in DMF (60 ml) were added DABCO (5.6 g, 50 mmol) and dimethylthiocarbamoyl chloride (4.9 g, 40 mmol) at room temperature. After stirring for 6 h at 60 ºC, the mixture was poured into 1 N HCl and extracted with CH 2 Cl 2. The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated. The crude residue was then purified by column chromatography on silica gel (hexane/ch 2 Cl 2 /ethyl acetate = 3:3:1) to afford the title compound as a pale yellow crystals in 92% yield. 1 H NMR (400 MHz, CDCl 3 ) 7.61 (1H, s), 3.48 (3H, s), 3.43 (3H, s), (2H, m), (2H, m), 2.33 (3H, s); 13 C NMR (100 MHz, CDCl 3 ) 202.8, 185.6, 154.6, 145.9, 138.7, 134.8, 130.6, 116.3, 43.4, 39.2, 36.7, 24.4, 17.2; IR (neat) 2921, 1712, 1540, 1469, 1396, 1223, 1122 cm -1 ; HRMS (ESI) exact mass calcd. for C 13 H 14 BrNO 2 S: m/z ([M + Na] + ), found: m/z ([M + Na] + ). 6-Bromo-7-((dimethylcarbamoyl)thio)-4-methylindanone 9 The flask containing 8 (1.64 g, 5.0 mmol) was heated at 210 ºC for 30 min. After cooling down to room temperature, the solid was dissolved to CH 2 Cl 2 and purified by column chromatography (hexane/ethyl acetate = 1:4) to afford the title compound as a brown solid in 84% yield. 1 H NMR (400 MHz, CDCl 3 ) 7.68 (1H, s), 3.22 (3H, br), 3.01 (3H, br), 2.90 (2H, m), 2.72 (2H, m), 2.34 (3H, s); 13 C NMR (100 MHz, CDCl 3 ) 203.7, 164.9, 155.1, 138.8, 138.5, 138.1, 130.9, 126.2, 37.4, 36.9, 36.7, 23.4, 17.4; IR (neat) 2919, 1714, 1669, 1437, 1363, 1251, 1201, 1094 cm -1 ; HRMS (ESI) exact mass calcd. for C 13 H 14 BrNO 2 S: m/z ([M + Na] + ), found: m/z ([M + Na] + ). 10h Ar Ar O Si O S tbu Me 2 N Br Me Ar = 4-CF 3 -C 6 H 4 To a stirred solution of 9 (164.1 mg, 0.5 mmol) in THF (5.0 ml) was added KHMDS (0.5 M in toluene, 0.6 mmol, 1.2 ml) at 0 ºC. After stirring at 0 ºC for 30 min, t-butylbis(4-(trifluoromethyl)phenyl)silyl triflate (prepared from procedures indicated below, 0.6 mmol in 2 ml of toluene) was added to this mixture at 0 ºC. After additional 1 h of stirring, the mixture was poured into saturated NH 4 Cl and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NATURE CHEMISTRY 4

5 Na 2 SO 4 and concentrated. The residue was purified by column chromatography (hexane/ethyl acetate = 3:1) to afford the title compound as an amorphous solid in 72% yield. 1 H NMR (400 MHz, CDCl 3 ) 7.67 (4H, d, J = 7.7 Hz), 7.41 (4H, d, J = 7.7 Hz), 6.91 (1H, s), 6.10 (1H, t, J = 2.4 Hz), 3.15 (3H, s), 3.01 (3H, s), 2.88 (2H, d, J = 2.4 Hz), 2.07 (3H, s), 1.13 (9H, s); 13 C NMR (100 MHz, CDCl 3 ) 153.8, 150.2, 143.7, 141.1, 136.7, 136.1, 133.6, (q, 2 J( 13 C, 19 F) = 32 Hz), 131.0, 130.9, (q, 1 J( 13 C, 19 F) = 273 Hz), (q, 3 J( 13 C, 19 F) = 4.1 Hz), 120.0, 117.2, 36.8, 36.6, 32.1, 27.3, 21.0, 16.9; IR (neat) 1724, 1392, 1321, 1161, 1123, 1058 cm -1 ; HRMS (ESI) exact mass calcd. for C 31 H 30 BrF 6 NO 2 SSi: m/z ([M + Na] + ), found: m/z ([M + Na] + ). 6 -(t-butylbis(4-(trifluoromethyl)phenyl)silyl-4-methylindanone 11h To a stirred solution of 10h (0.3 mmol, 211 mg) in Et 2 O (3.0 ml) was added t-buli (1.65 M in pentane, 1.5 mmol, 0.9 ml) at 78 ºC. After stirring for 5 min at 78 ºC, 2 ml of methanol was added at this temperature to quench the reaction. After warming up to room temperature, 1 N HCl was added to the flask. The organic layer was extracted with ethyl acetate, dried over anhydrous Na 2 SO 4 and concentrated. Purification of the residue by column chromatography (hexane/ch 2 Cl 2 = 1:1.5) gave the title compound as an amorphous solid in 79% yield. 1 H NMR (400 MHz, CDCl 3 ) 7.86 (1H, s), 7.75 (4H, d, J = 8.5 Hz), 7.60 (4H, d, J = 8.5 Hz), 2.96 (2H, t, J = 6.0 Hz), 2.76 (2H, t, J = 6.0 Hz), 2.34 (3H, s), 1.21 (9H, s); 13 C NMR (100 MHz, CDCl 3 ) 208.5, 158.1, 143.5, 138.5, 136.3, (q, 2 J( 13 C, 19 F) = 32 Hz), 130.6, 130.2, 129.9, (q, 3 J( 13 C, 19 F) = 3.6 Hz), (q, 1 J( 13 C, 19 F) = 273 Hz), 36.6, 28.7, 23.3, 18.9, 17.6; IR (neat) 1683, 1321, 1164, 1123, 1089 cm -1 ; HRMS (ESI) exact mass calcd. for C 28 H 26 F 6 OSSi: m/z ([M + Na] + ), found: m/z ([M + Na] + ). (R)-5h To a stirred solution of 1-bromo-3,5-bis(10-n-butyl-9-anthryl)benzene (prepared from procedures indicated below, 0.25 mmol, mg) in THF (2.0 ml) was added n-buli (1.5 M in hexane, 0.25 mmol, NATURE CHEMISTRY 5

6 0.17 ml) at 78 ºC. After stirring at this temperature for 30 min, 11h (0.1 mmol, 55.3 mg) was added and then the solution was warmed up to 0 ºC. After 15 min of stirring, the reaction was quenched with 1 N HCl and organic layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated. Purification of the residue by PLC (hexane/ch 2 Cl 2 = 1.5:1) gave (rac)-5h as amorphous solid in 84% yield. Optical resolution of 5h (80 mg) was conducted by using chiral stationary phase column (20 mm x 250 mm CHIRALPAK IA, hexane/etoh = 40:1, flow rate = 15 ml/min, retention time = 19.5 min (S), 21.6 min (R)) to afford both enantiomers quantitatively after two cycles. 1 H NMR (400 MHz, CDCl 3 ) 8.31 (4H, d, J = 8.8 Hz), 7.78 (4H, t, J = 8.4 Hz), 7.66 (2H, d, J = 7.7 Hz), 7.60 (2H, d, J = 7.7 Hz), 7.54(2H, d, J = 8.0 Hz), (7H, m), (7H, m), 3.87 (1H, s), 3.64 (4H, t, J = 8.2 Hz), 3.35 (1H, m), 3.06 (1H, m), 2.88 (1H, m), (2H, m), 2.22 (3H, s), (4H, m), (4H, m), (15H, m); 13 C NMR (100 MHz, CDCl 3 ) 147.3, 147.1, 146.7, 140.3, 139.7, 139.5, 139.3, 136.1, 135.9, 135.6, 135.3, 134.6, 133.5, 132.6, 130.9, 130.1, 130.0, , , 127.4, 127.3, 126.8, , , 125.0, 124.9, 124.6, 124.5, 124.4, 87.3, 44.6, 37.5, 28.9, 28.2, 28.0, 23.4, 18.9, 18.8, 14.0; IR (neat) 2956, 2859, 1323, 1165, 1126, 1059 cm -1 ; HRMS (ESI) exact mass calcd. for C 70 H 64 F 6 OSSi: m/z ([M + Na] + ), found: m/z ([M + Na] + ); [α] 26 D = (c = 1.0, CHCl 3 ; 100% ee, R). Determination of the absolute configuration of the catalyst The absolute configuration of (S)-5b was unambiguously determined by x-ray analysis. The absolute configurations of other catalysts were tentatively assigned by analogy to the enantioselectivity observed in the reaction with (R)-5b. Supplementary Figure S1. X-Ray structure of (S)-5b. Thermal ellipsoids are 50% NATURE CHEMISTRY 6

7 probability level. The crystal structure has been deposited at the Cambridge Crystallographic Data Centre (CCDC ). The data can be obtained free of charge via the Internet at Synthesis of t-butylbis(4-(trifluoromethyl)phenyl)silyl triflate t-butyl(phenyl)bis(4-(trifluoromethyl)phenyl)silane To a stirred solution of trichlorophenylsilane (5.0 mmol, 0.80 ml) in Et 2 O (10 ml) was added t-buli (1.65 M in pentane, 5.5 F 3 C Si CF 3 mmol, 3.3 ml) at 78 ºC. The solution was slowly warmed up to room temperature over 6 h. To another flask containing 1-bromo-4-trifluoromethylbenzene (11 mmol, 1.54 ml) in Et 2 O (20 ml) was added t-buli (1.65 M in pentane, 22 mmol, 13 ml) at 78 ºC. The solution was stirred for 2 h at 78 ºC to give the corresponding aryllithium. This solution was transferred to the first flask at room temperature. After stirring for 12 h at room temperature, saturated NH 4 Cl aq was added to the mixture and organic layer was extracted with hexane. The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated. Purification of the residue by column chromatography (hexane) gave the title compound as a white solid in 85% yield. 1 H NMR (400 MHz, CDCl 3 ) 7.82 (4H, d, J = 8.4 Hz), 7.61 (4H, d, J = 8.4 Hz), 7.53 (2H, d, J = 7.6 Hz), 7.46 (1H, t, J = 7.6 Hz), 7.39 (2H, t, J = 7.6 Hz), 1.20 (9H, s); 13 C NMR (100 MHz, CDCl 3 ) (q, 2 J( 13 C, 19 F) = 32.5 Hz), (q, 3 J( 13 C, 19 F) = 3.6 Hz), (q, 1 J( 13 C, 19 F) = 274 Hz), ; IR (neat) 1321, 1164, 1123, 1103, 1058 cm -1. t-butylbis(4-(trifluoromethyl)phenyl)silyl triflate OTf F 3 C Si CF 3 To a stirred solution of t-butyl(phenyl)bis(4-(trifluoromethyl)phenyl)silane (0.6 mmol, mg) in toluene (2.0 ml) was added TfOH (0.6 mmol, 53 μl) at room temperature. The solution of the corresponding silyl triflate was obtained after NATURE CHEMISTRY 7

8 1 h. The solution was used without isolation. Synthesis of 1-bromo- 3,5-bis(10-n-butyl-9-anthryl)benzene 9-Bromo-10-n-butylanthracene nbu Br To a stirred solution of 9,10-dibromoanthracene (5.0 mmol, 1.68 g) in THF (15 ml) was added n-buli (1.5 M in hexane, 5.0 mmol, 3.2 ml) at 78 ºC. After stirring for 30 min at the same temperature, n-bui (7.5 mmol, 0.93 ml) was added to the solution. The solution was stirred for further 30 min at 0 ºC, then saturated NH 4 Cl aq was added to the solution. The organic layer was extracted with hexane several times and combined organic layers were dried over Na 2 SO 4. After the removal of solvents, purification of the residue by column chromatography (hexane) gave the title compound quantitatively as a yellow liquid. Characterization was performed after the next step. 10-n-Butyl-9-anthrylboronic acid nbu B(OH) 2 To a stirred solution of 9-bromo-10-n-butylanthracene (5.0 mmol, 1.5 g) in THF (15 ml) was added n-buli (1.5 M in hexane, 5.0 mmol, 3.2 ml) at 78 ºC. After stirring for 1 h at the same temperature, trimethyl borate (10 mmol, 1.1 ml) was added to the solution. The solution was stirred for 1.5 h at room temperature. The reaction was quenched with 1 N HCl and the mixture was stirred for additional 1 h at room temperature. The organic layer was extracted with ethyl acetate several times and combined organic layers were dried over Na 2 SO 4. After the removal of solvents, purification of the residue by column chromatography (hexane/ethyl acetate = 4:1 NATURE CHEMISTRY 8

9 to 2:1) gave the title compound as a white solid in 80% yield. 1 H NMR (400 MHz, CDCl 3 ) (2H, m), 8.08 (2H, m), (4H, m), 5.08 (2H, s), 3.61 (2H, t, J = 8.2 Hz), 1.79 (2H, m), 1.61 (2H, q, J = 7.4 Hz), 1.03 (3H, t, J = 7.4 Hz); 13 C NMR (100 MHz, CDCl 3 ) 136.2, 130.4, 130.3, 128.7, 126.6, 125.6, 124.8, 121.6, 33.5, 28.0, 23.4, 14.0; IR (neat) 3342, 2955, 1417, 1355, 1304 cm -1 ; HRMS (ESI) exact mass calcd. for C 18 H 19 BO 2 : m/z ([M + Na] + ), found: m/z ([M + Na] + ). 1-Bromo-3,5-bis(10-n-butyl-9-anthryl)benzene The flask containing 1-bromo-3,5-diiodobenzene 30 (1.2 nbu nbu Br mmol, 490 mg), 10-n-butyl-9-anthrylboronic acid (2.8 mmol, 779 mg), Pd(OAc) 2 (0.12 mmol, 22.5 mg), PPh 3 (0.42 mmol, 111 mg) and Ba(OH) 2 8H 2 O (4.8 mmol, 1.52 g) were added dioxane (10 ml) and water (2 ml). The solution was stirred for 12 h at 50 ºC. The resulting mixture was poured into 1 N HCl and the organic layer was extracted several times with 5:1 mixture of hexane/ch 2 Cl 2. The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated. Purification of the residue by column chromatography (hexane/ch 2 Cl 2 = 10:1) gave the title compound as solid in 70% yield. 1 H NMR (400 MHz, CDCl 3 ) (4H, d, J = 8.5 Hz), 7.90 (4H, d, J = 8.5 Hz), 7.76 (2H, d, J = 1.5 Hz), (9H, m), 3.64 (4H, t, J = 8.1 Hz), 1.83 (4H, m), 1.61 (4H, q, J = 7.4 Hz), 1.03 (6H, t, J = 7.4 Hz); 13 C NMR (100 MHz, CDCl 3 ) 141.5, 136.2, 133.6, 133.3, 130.0, 129.1, 127.3, 125.2, 125.1, 124.7, 122.6, 33.5, 28.0, 23.4, 14.1; IR (neat) 2954, 1552, 1442, 1370, 1026, 905 cm -1. NATURE CHEMISTRY 9

10 3. Preparation of Vinylcyclopropanes General procedure To an argon-purged flask charged with 1,4-dibromo-2-butene and base were added THF and the substrate. The mixture was stirred at room temperature and the reaction progress was monitored by TLC. After the completion of the reaction, the organic layer was washed with saturated NH 4 Cl and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated. Purification of the residue by column chromatography gave the vinylcyclopropane. A little amount of byproduct was included when R 1 is alkyl or aryl 31. Dibenzyl 2-vinylcyclopropane-1,1-dicarboxylate 1a Prepared according to the general procedure with 1,4-dibromo-2-butene BnO 2 C CO 2 Bn (6.0 mmol, 1.28 g), NaH (11.0 mmol, 264 mg) and dibenzyl malonate (5.0 mmol, 1.25 ml) in THF (15 ml) at room temperature for 2 h. The crude material was purified by column chromatography on silica gel (hexane/ch 2 Cl 2 = 1:1, then hexane/ch 2 Cl 2 = 1:4) to give the title compound as a colorless oil in 93% yield. The spectral data were reported in the literature 32. Dimethyl 2-vinylcyclopropane-1,1-dicarboxylate Prepared according to the general procedure with 1,4-dibromo-2-butene MeO 2 C CO 2 Me (2.0 mmol, 428 mg), NaH (4.4 mmol, 106 mg) and dimethyl malonate (2.0 mmol, 0.23 ml) in THF (10 ml) at room temperature for 2 h. The crude material was purified by column chromatography on silica gel (hexane/ch 2 Cl 2 = 1:2) to give the title compound as a colorless oil in 40% yield. The spectral data were reported in the literature 33. Di-t-butyl 2-vinylcyclopropane-1,1-dicarboxylate Prepared according to the general procedure with 1,4-dibromo-2-butene tbuo 2 C CO 2 tbu (2.0 mmol, 428 mg), NaH (4.4 mmol, 106 mg) and di-t-butyl malonate NATURE CHEMISTRY 10

11 (2.0 mmol, 0.45 ml) in THF (10 ml) at room temperature for 2 h. The crude material was purified by column chromatography on silica gel (hexane/ethyl acetate = 6:1) to give the title compound as a white solid in 62% yield. The spectral data were reported in the literature 34. 1,1-Diacetyl-2-vinylcyclopropane Prepared according to the general procedure with 1,4-dibromo-2-butene (6.0 mmol, 1.28 g), K 2 CO 3 (10 mmol, 1.38 g) and acetylacetone (5.0 mmol, 0.45 O O ml) in acetone (15 ml) at room temperature for 10 h. The crude material was purified by column chromatography on silica gel (CH 2 Cl 2 ) to give the title compound as a colorless liquid in 44% yield. The spectral data were reported in the literature 31. Methyl 1-benzoyl-2-vinylcyclopropanecarboxylate Prepared according to the general procedure with 1,4-dibromo-2-butene (6.6 mmol, 1.41 g), K 2 CO 3 (12 mmol, 1.66 g) and methyl benzoylacetate (6.0 mmol, 1.06 g) in methanol (20 ml) under reflux for 4 h. The crude material was purified by column chromatography on silica gel (hexane/ethyl acetate = 3:1) to give the title compound as a colorless liquid in 86% yield as a mixture of diastereomers (dr = 1/0.9) containing 10% of the byproduct reported in the literature H NMR (400 MHz, CDCl 3 ) (3.8H, m), (1.9H, m), (3.8H, m), (1.0H, m), (3.8H, m), 4.99 (0.9H, d, J = 10 Hz), 3.55 (2.7H, s), 3.53 (3.0H, s), 2.92 (0.9H, q, J = 8.4), 2.72 (1.0H, q, J = 8.5 Hz), (1.9H, m), (1.9H, m); 13 C NMR (100 MHz, CDCl 3 ) 193.9, 193.2, 171.4, 169.8, 137.2, 136.8, 133.1, 133.0, 132.9, 128.6, 128.5, 128.4, 128.2, 118.8, 118.5, 52.5, 52.3, 40.4, 39.5, 32.74, 32.70, 30.54, 30.47, 21.6, 19.7; IR (neat) 1727, 1678, 1435, 1311, 1268, 1199, 1148 cm -1 ; HRMS (ESI) exact mass calcd. for C 14 H 14 O 3 : m/z ([M + Na] + ), found: m/z ([M + Na] + ). Methyl 1-(4-bromobenzoyl)-2-vinylcyclopropanecarboxylate Br OMe O O Prepared according to the general procedure with 1,4-dibromo-2-butene (5.5 mmol, 1.18 g), K 2 CO 3 (10 mmol, 1.38 g) and methyl 4-bromobenzoylacetate (5.0 mmol, 1.29 g) in methanol (20 ml) under reflux for 4 h. The crude material was purified by NATURE CHEMISTRY 11

12 column chromatography on silica gel (hexane/ethyl acetate = 5:1) to give the title compound as a colorless liquid in 86% as a mixture of diastereomers (dr = 1/0.9) containing 14% of the byproduct. 1 H NMR (400 MHz, CDCl 3 ) (3.8H, m), (3.8H, m), (1.0H, m), (3.8H, m), 5.00 (0.9H, dd, J = 10 Hz, 2 Hz), 3.58 (2.7H, s), 3.55 (3.0H, s), 2.91 (0.9H, q, J = 8.0), 2.68 (1.0H, q, J = 8.0 Hz), (1.9H, m), 1.66 (1.9H, td, J = 9.1 Hz, 4.7 Hz); 13 C NMR (100 MHz, CDCl 3 ) 192.8, 192.2, 171.1, 169.5, 136.0, 135.5, , , , , 130.0, 129.7, , , 119.0, 118.8, 52.5, 52.4, 40.2, 39.3, 32.9, 32.8, 30.8, 30.7, 21.6, 19.7; IR (neat) 1728, 1679, 1584, 1435, 1312, 1269 cm -1 ; HRMS (ESI) exact mass calcd. for C 14 H 13 BrO 3 : m/z ([M + Na] + ), found: m/z ([M + Na] + ). Methyl 1-(4-methoxybenzoyl)-2-vinylcyclopropanecarboxylate MeO OMe O O Prepared according to the general procedure with 1,4-dibromo-2-butene (6.0 mmol, 1.28 g), K 2 CO 3 (11 mmol, 1.52 g) and methyl 4-methoxybenzoylacetate (5.5 mmol, 1.14 g) in methanol (20 ml) under reflux for 4 h. The crude material was purified by column chromatography on silica gel (hexane/ethyl acetate = 3:1) to give the title compound as a colorless liquid in 83% yield as a mixture of diastereomers (dr = 1/0.8) containing 7% of the byproduct. 1 H NMR (400 MHz, CDCl 3 ) (3.6H, m), (3.6H, m), (1.0H, m), (3.6H, m), (0.8H, m), 3.86 (3.0H, s), 3.85 (2.4H, s), 3.58 (2.4H, s), 3.56 (3.0H, s), 2.87 (0.8H, m), 2.65 (1.0H, q, J = 8.0 Hz), (1.8H, m), (1.8H, m); 13 C NMR (100 MHz, CDCl 3 ) 192.0, 191.3, 171.6, 169.9, , , 133.4, 133.2, 130.9, 130.6, 130.0, 129.3, 118.5, 118.1, 113.6, 113.5, 55.31, 55.27, 55.24, 52.4, 52.3, 40.0, 39.1, 32.24, 32.18, 30.2, 30.1, 21.1, 19.6; IR (neat) 1726, 1670, 1599, 1311, 1256, 1170, 1147 cm -1 ; HRMS (ESI) exact mass calcd. for C 15 H 16 O 4 : m/z ([M + Na] + ), found: m/z ([M + Na] + ). Methyl 1-acetyl-2-vinylcyclopropanecarboxylate Prepared according to the general procedure with 1,4-dibromo-2-butene (5.5 OMe O O mmol, 1.17 g), K 2 CO 3 (10 mmol, 1.38 g) and methyl acetylacetate (5.0 mmol, 0.54 ml) in methanol (15 ml) under reflux for 4 h. The crude NATURE CHEMISTRY 12

13 material was purified by column chromatography on silica gel (hexane/ethyl acetate = 4:1) to give the title compound as a colorless liquid in 75% yield as a mixture of diastereomers (dr = 1/0.7) containing 12% of the byproduct. The 1 H NMR spectrum obtained matched those reported in the literature 35. Methyl 1-pentanoyl-2-vinylcyclopropanecarboxylate Prepared according to the general procedure with 1,4-dibromo-2-butene (4.5 mmol, 0.96 g), K 2 CO 3 (8.2 mmol, 1.13 g) and methyl 3-oxoheptanoate (4.1 mmol, 0.65 g) in methanol (15 ml) under reflux for 4 h. The crude material was purified by column chromatography on silica gel (hexane/ethyl acetate = 6:1) to give the title compound as a colorless liquid in 63% as a mixture of diastereomers (dr = 1/0.4) containing 10% of the byproduct. 1 H NMR (400 MHz, CDCl 3 ) 5.48 (1.0H, ddd, J = 18 Hz, 9.4 Hz, 7.7 Hz), (3.2H, m), 3.76 (3.0H, s), 3.75 (1.2H, s), (1.4H, m), (2.8H, m), 2.38 (0.4H, ddd, J = 17 Hz, 8.6 Hz, 7.5 Hz), 1.85 (0.4H, dd, J = 7.5 Hz, 4.6 Hz), 1.73 (1.0H, dd, J = 7.5 Hz, 4.5 Hz), (3.8H, m), (2.8H, m), (4.2H, m); 13 C NMR (100 MHz, CDCl 3 ) 204.1, 203.2, 171.0, 169.4, 133.2, 133.0, 118.7, 52.4, 52.3, 42.9, 42.5, 42.1, 41.3, 33.5, 33.3, 26.1, 25.7, 22.8, 22.2, 20.0, 13.8; IR (neat) 2957, 1730, 1698, 1436, 1320, 1197, 1164 cm -1 ; HRMS (ESI) exact mass calcd. for C 12 H 18 O 3 : m/z ([M + Na] + ), found: m/z ([M + Na] + ). Methyl 1-isobutyryl-2-vinylcyclopropanecarboxylate Prepared according to the general procedure with 1,4-dibromo-2-butene OMe O O (4.7 mmol, 0.94 g), K 2 CO 3 (8.4 mmol, 1.15 g) and methyl 4-methyl-3-oxopentanoate (4.2 mmol, 0.60 g) in methanol (15 ml) under reflux for 4 h. The crude material was purified by column chromatography on silica gel (hexane/ethyl acetate = 6:1) to give the title compound as a colorless liquid in 76% yield as a mixture of diastereomers (dr = 1/0.5) containing 12% of the byproduct. 1 H NMR (400 MHz, CDCl 3 ) (1.0H, m), (3.5H, m), 3.76 (4.5H, s), (1.5H, m), 2.73 (0.5H, dd, J = 16 Hz, 7.7 Hz), 2.62 (1.0H, dd, J = 16 Hz, 7.5 Hz), 1.92 (0.5H, dd, J = 7.7 Hz, 4.4 Hz), 1.76 (1.0H, dd, J = 7.5 Hz, 4.4 Hz), (1.5H, m), (9H, m); 13 C NMR (100 MHz, CDCl 3 ) 207.9, 206.7, 171.1, 169.5, 133.6, 133.2, 118.7, 118.3, 52.4, 52.3, 42.0, 41.5, 39.7, 39.0, 34.0, 32.7, 22.8, 20.5, 19.4, 18.3, NATURE CHEMISTRY 13

14 18.2, 18.0; IR (neat) 2974, 1729, 1697, 1437, 1319, 1197, 1152 cm -1 ; HRMS (ESI) exact mass calcd. for C 11 H 16 O 3 : m/z ([M + Na] + ), found: m/z ([M + Na] + ). Methyl 1-cyclohexylcarbonyl -2-vinylcyclopropanecarboxylate Prepared according to the general procedure with 1,4-dibromo-2-butene (5.2 mmol, 1.12 g), K 2 CO 3 (9.4 mmol, 1.30 g) and methyl 3-cyclohexyl-3-oxopropanoate (4.7 mmol, 0.86 g) in methanol (15 ml) under reflux for 4 h. The crude material was purified by column chromatography on silica gel (hexane/ethyl acetate = 6:1) to give the title compound as a colorless liquid in 85% yield as a mixture of diastereomers (dr = 1/0.5) containing 13% of the byproduct. 1 H NMR (400 MHz, CDCl 3 ) 5.49 (1.0H, m), (3.5H, m), 3.76 (4.5H, s), (1.5H, m), (0.5H, m), 2.61 (1.0H, m), (9.0H, m), (9.0H, m); 13 C NMR (100 MHz, CDCl 3 ) 206.8, 205.7, 171.2, 169.6, 133.7, 133.2, 118.6, 118.0, 52.3, 52.2, 49.8, 49.1, 42.0, 41.5, 36.7, 34.1, 32.4, 29.8, 28.6, 28.2, 26.0, 25.9, 25.82, 25.77, 25.50, 25.3, 22.6, 20.4; IR (neat) 2931, 2854, 1728, 1693, 1636, 1436, 1319, 1196, 1161 cm -1 ; HRMS (ESI) exact mass calcd. for C 14 H 20 O 3 : m/z ([M + Na] + ), found: m/z ([M + Na] + ). 1-Benzoyl-2-vinylcyclopropanecarboxylic acid Prepared by hydrolysis of the corresponding methyl ester. To the solution of methyl 1-benzoyl-2-vinylcyclopropanecarboxylate (1.0 mmol, 230 mg) in methanol (5.0 ml) was added LiOH H 2 O (5.0 mmol, mg) at room temperature. After 24 h of stirring, the reaction was acidified by 1N HCl. The organic layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated. Purification of the residue by column chromatography (ethyl acetate) gave the title compound as solid in 90% yield as a mixture of diastereomers (dr = 1/0.9). 1 H NMR (400 MHz, CDCl 3 ) (3.8H, m), (1.9H, m), (3.8H, m), 5.30 (1.0H, ddd, J = 17 Hz, 10 Hz, 8.8 Hz), (3.7H, m), 5.00 (1.0H, dd, J = 10 Hz, 1.7 Hz), 2.89 (0.9H, q, J = 8.5 Hz), 2.66 (1.0H, q, J = 8.5 Hz), 1.99 (0.9H, dd, J = 8.5 Hz, 4.8 H), 1.91 (1.0H, dd, J = 8.5 Hz, 4.8 H), 1.78 (1.0H, dd, J = 8.5 Hz, 4.8 H), 1.72 (0.9H, dd, J = 8.5 Hz, 4.8 H); 13 C NMR (100 MHz, CDCl 3 ) 193.6, 192.8, 176.9, 175.2, 137.1, 136.5, , , 132.8, 132.7, 128.8, 128.6, 128.5, 119.5, 119.0, 39.9, 39.1, NATURE CHEMISTRY 14

15 33.9, 32.2, 22.0, 20.4; IR (neat) 3.86, 1674, 1274, 1210, 1157 cm -1 ; HRMS (ESI) exact mass calcd. for C 13 H 12 O 3 : m/z ([M + Na] + ), found: m/z ([M + Na] + ). NATURE CHEMISTRY 15

16 4. Enantioselective Radical Cyclization (Table 2) General procedure To an argon-purged flask were added (R)-5h (0.003 mmol, 3.3 mg), benzoyl peroxide (BPO) (0.006 mmol, 1.5 mg), vinylcyclopropane (0.1 mmol) and alkene (0.2 mmol). The flask was irradiated with a UV-lamp at 0 ºC for 2 h. The resulting solution was concentrated and the residue was purified by preparative thin layer chromatography (PLC). Dibenzyl (3R,4S)-3-t-butoxy-4-vinylcyclopentane-1,1-dicarboxylate 2a Prepared according to the general procedure with dibenzyl 2-vinylcyclopropane-1,1-dicarboxylate 1a ( 0.1 mmol, 34 mg) and t-butyl vinyl ether (0.2 mmol, 27 μl). The crude material (95:5 dr) was purified by PLC (hexane/ch 2 Cl 2 = 1:3) to give the title compound as a colorless liquid in 81% yield [86% ee]. The cis isomer was separated at this stage. 1 H NMR (400 MHz, CDCl 3 ) (10H, m), 5.68 (1H, ddd, J = 18 Hz, 10 Hz, 7.2 Hz), (6H, m), 3.68 (1H, appt q, J = 8.1 Hz), (2H, m), 2.50 (1H, td, J = 18 Hz, 8.3 Hz), 2.06 (1H, dd, J = 14 Hz, 8.3 Hz), 1.83 (1H, dd, J = 14 Hz, 11 Hz), 1.12 (9H, s) ; 13 C NMR (100 MHz, CDCl 3 ) 172.2, 171.5, 138.8, 135.5, 135.4, , , , , , , , 76.4, 73.4, 67.18, 67.17, 56.7, 49.6, 41.8, 35.8, 28.5; IR (neat) 2973, 1729, 1455, 1363, 1237 cm -1 ; HRMS (ESI) exact mass calcd. for C 27 H 32 O 5 : m/z ([M + Na] + ), found: m/z ([M + Na] + ); [α] 26 D = +8.9 (c = 1.0, CHCl 3 ). The enantiomeric purity of the product was determined by HPLC analysis (Daicel CHIRALPAK AD-3, hexane/etoh = 50:1, flow rate = 0.5 ml/min, retention time; 11.6 min (major) and 13.3 min (minor)). NATURE CHEMISTRY 16

17 Supplementary Figure S2. 1 H NMR spectra of the crude mixture of the reaction with (R)-5h (top) and diphenyl disulfide (bottom). Dimethyl (3R,4S)-3-t-butoxy-4-vinylcyclopentane-1,1-dicarboxylate 2b Prepared according to the general procedure with dimethyl 2-vinylcyclopropane-1,1-dicarboxylate ( 0.1 mmol, 18 mg) and t-butyl vinyl ether (0.2 mmol, 27 μl). The crude material (93:7 dr) was purified by PLC (hexane/ch 2 Cl 2 = 1:4) to give the title compound as a colorless liquid in 93% yield [dr = 93:7, 88% ee]. The cis isomer was separated at this stage. 1 H NMR (400 MHz, CDCl 3 ) 5.71 (1H, ddd, J = 18 Hz, 10 Hz, 7.2 Hz), (2H, m), 3.73 (7H, m), (2H, m), 2.50 (1H, m), 2.04 (1H, dd, J = 14 Hz, 8.1 Hz), 1.79 (1H, dd, J = 14 Hz, 11 Hz), 1.15 (9H, s) ; 13 C NMR (100 MHz, CDCl 3 ) 173.0, 172.4, 138.7, 115.5, 76.4, 73.4, 56.5, 52.8, 52.7, 49.7, 41.8, 35.9, 28.6; IR (neat) 2974, 1733, 1250, 1159, 1098 cm -1 ; HRMS (ESI) exact mass calcd. for C 15 H 24 O 5 : m/z ([M + Na] + ), found: m/z ([M + Na] + ); [α] 26 D = +2.7 (c = 1.0, CHCl 3 ). The enantiomeric excess was determined after derivatization to 2b. NATURE CHEMISTRY 17

18 To a stirred solution of 2b (0.1 mmol, 30 mg) in THF (1.0 ml) was added LAH (0.3 mmol, 11 mg) at room temperature. After 2 h of stirring, the mixture was quenched with 1 N HCl and organic layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated. To this mixture were added CH 2 Cl 2 (2.0 ml), 4-bromobenzoyl chloride (0.25 mmol, 50 mg), DMAP (0.05 mmol, 6.1 mg), Et 3 N (0.25 mmol, 35 μl) at room temperature. After 2 h of stirring, the solvent was removed in vacuo. The crude mixture was purified by PLC (hexane/ethyl acetate = 5:1) to give 2b in 69% yield [88% ee]. 1 H NMR (400 MHz, CDCl 3 ) 7.87 (4H, dd, J = 8.6 Hz, 1.6 Hz), 7.56 (4H, dd, J = 8.6 Hz, 3.3 Hz), 5.77 (1H, ddd, J = 18 Hz, 10 Hz, 7.2 Hz), 5.09 (1H, d, J = 18 Hz), 5.04 (1H, d, J = 10 Hz), 4.36 (2H, s), 4.28 (2H, s), 3.78 (1H, appt q, J = 8.0 Hz), 2.61 (1H, m), 2.05 (1H, dd, J = 14 Hz, 7.6 Hz), 1.97 (1H, dd, J = 14 Hz, 7.6 Hz), 1.63 (1H, dd, J = 14 Hz, 7.6 Hz), 1.48 (1H, dd, J = 14 Hz, 11 Hz), 1.15 (9H, s); 13 C NMR (100 MHz, CDCl 3 ) , , 139.3, 131.8, 131.7, 131.1, 131.0, , , 128.3, 128.2, 115.2, 76.6, 73.3, 69.2, 68.6, 49.5, 42.9, 41.0, 34.6, 28.6; IR (neat) 2972, 1717, 1590, 1397, 1261, 1098 cm -1 ; HRMS (ESI) exact mass calcd. for C 27 H 30 Br 2 O 5 : m/z ([M + Na] + ), found: m/z ([M + Na] + ); [α] 26 D = (c = 1.0, CHCl 3 ). The enantiomeric purity of the product was determined by HPLC analysis (Daicel CHIRALPAK AD-H, hexane/iproh =20:1, flow rate = 0.5 ml/min, retention time; 17.6 min (minor) and 19.2 min (major)). Di-t-butyl (3R,4S)-3-t-butoxy-4-vinylcyclopentane-1,1-dicarboxylate 2c Prepared according to the general procedure with di-t-butyl 2-vinylcyclopropane-1,1-dicarboxylate (0.1 mmol, 27 mg) and t-butyl vinyl ether (0.2 mmol, 27 μl). The crude material (94:6 dr) was purified by PLC (hexane/ch 2 Cl 2 = 1:2.5) to give the title compound as a colorless liquid in 94% yield [89% ee]. The cis isomer was separated at this stage. 1 H NMR (400 MHz, CDCl 3 ) 5.71 (1H, ddd, J = 18 Hz, 10 Hz, 7.2 Hz), 5.06 (1H, d, J = 18 Hz), 5.00 (1H, d, J = 10 Hz), 3.66 (1H, appt q, J = 8.8 Hz), (3H, m), 1.87 (1H, NATURE CHEMISTRY 18

19 dd, J = 13 Hz, 8.6 Hz), 1.67 (1H, dd, J = 13 Hz, 10 Hz), 1.45 (9H, s), 1.44 (9H, s), 1.16 (9H, s) ; 13 C NMR (100 MHz, CDCl 3 ) 172.0, 171.0, 139.2, 115.2, 81.1, 80.9, 76.5, 73.3, 57.6, 49.5, 41.6, 35.4, 28.6, 27.8; IR (neat) 2974, 1722, 1366, 1272, 1253, 1169, 1138 cm -1 ; HRMS (ESI) exact mass calcd. for C 21 H 36 O 5 : m/z ([M + Na] + ), found: m/z ([M + Na] + ); [α] 26 D = +0.8 (c = 1.0, CHCl 3 ). The enantiomeric excess was determined after derivatization to 2b. (3R,4S)-1,1-Diacetyl-3-t-butoxy-4-vinylcyclopentane 2d Prepared according to the general procedure with 1,1-diacetyl-2-vinylcyclopropane ( 0.1 mmol, 15 mg) and t-butyl vinyl ether (0.2 mmol, 27 μl). The crude material (>95:5 dr) was purified by PLC (CH 2 Cl 2 ) to give the title compound as a colorless liquid in 99% yield [88% ee]. The cis isomer was separated at this stage. 1 H NMR (400 MHz, CDCl 3 ) 5.66 (1H, ddd, J = 18 Hz, 10 Hz, 7.4 Hz), (2H, m), 3.55 (1H, appt q, J = 7.8 Hz), (2H, m), 2.36 (1H, dt, J = 18 Hz, 8.2 Hz), 2.11 (3H, s), 2.07 (3H, s), 1.78 (1H, dd, J = 13 Hz, 7.9 Hz), 1.53 (1H, dd, J = 13 Hz, 11 Hz), 1.15 (9H, s) ; 13 C NMR (100 MHz, CDCl 3 ) 204.5, 204.4, 138.7, 115.6, 76.1, 73.5, 71.6, 49.6, 38.6, 32.8, 28.5, 26.2, 26.1; IR (neat) 2974, 1698, 1359, 1193, 1094 cm -1 ; HRMS (ESI) exact mass calcd. for C 15 H 24 O 3 : m/z ([M + Na] + ), found: m/z ([M + Na] + ); [α] 26 D = (c = 1.0, CHCl 3 ). The enantiomeric excess was determined after derivatization to 2d. O O O O Br 2d' To a stirred solution of 2d (0.1 mmol, 25 mg) in CH 2 Cl 2 (1.0 ml) was added TFA (0.1 ml) at room temperature. After 2 h of stirring, the solvent and TFA were evaporated and the residue was dissolved to CH 2 Cl 2 (2.0 ml). To this solution were added 4-bromobenzoyl chloride (0.15 mmol, 33 mg), DMAP (0.05 mmol, 6.1 mg), Et 3 N (0.25 mmol, 35 μl) at room temperature. After 2 h of stirring, the solvent was removed. The crude mixture was purified by PLC (hexane/ethyl acetate = 5:1) to give 2d as a colorless oil in 30% yield [88% ee]. 1 H NMR (400 MHz, CDCl 3 ) 7.82 (2H, d, J = 8.7 Hz), 7.58 (2H, d, J = 8.7 Hz), 5.77 (1H, ddd, J = 18 Hz, 10 Hz, 7.0 Hz), (3H, m), 2.85 (1H, dd, J = 14 Hz, 6.8 Hz), (2H, m), 2.29 (1H, dd, J = 14 Hz, 5.7 Hz), 2.13 (3H, s), 2.12 (3H, s), 1.92 (1H, m); 13 C NMR (100 MHz, CDCl 3 ) , , 165.3, 137.2, 131.8, 131.1, 128.9, 128.3, NATURE CHEMISTRY 19

20 116.6, 78.8, 72.7, 48.1, 35.5, 33.5, 26.4, 26.1; IR (neat) 1718, 1699, 1268, 1115, 1103 cm -1 ; HRMS (ESI) exact mass calcd. for C 18 H 19 BrO 4 : m/z ([M + Na] + ), found: m/z ([M + Na] + ); [α] 26 D = -3.5 (c = 1.0, CHCl 3 ). The enantiomeric purity of the product was determined by HPLC analysis (Daicel CHIRALPAK AD-H, hexane/iproh = 30:1, flow rate = 1.0 ml/min, retention time; 21.2 min (minor), 22.8 min (major)). Dibenzyl (3R,4S)-3-triisopropylsiloxy-4-vinylcyclopentane-1,1-dicarboxylate 2e Prepared according to the general procedure with dibenzyl 2-vinylcyclopropane-1,1-dicarboxylate 1a ( 0.1 mmol, 34 mg) and triisopropylsilyl vinyl ether (0.2 mmol, 48 μl). The crude material (>95:5 dr) was purified by PLC (hexane/ch 2 Cl 2 = 1:1.5) to give the title compound as a colorless liquid in 93% yield [90% ee]. 1 H NMR (400 MHz, CDCl 3 ) (10H, m), 5.70 (1H, ddd, J = 18 Hz, 10 Hz, 7.6 Hz), (6H, m), 4.04 (1H, appt q, J = 6.4 Hz), 2.74 (1H, dd, J = 14 Hz, 8.2 Hz), (2H, m), 2.20 (1H, dd, J = 14 Hz, 6.5 Hz), 1.90 (1H, dd, J = 14 Hz, 8.9 Hz), 1.02 (21H, appt s); 13 C NMR (100 MHz, CDCl 3 ) 172.2, 171.5, 139.0, 135.5, 135.4, 128.5, 128.4, , , , , 115.8, 77.7, 67.20, 67.19, 57.2, 52.0, 42.4, 36.4, 18.0, 12.2; IR (neat) 2943, 2866, 1732, 1456, 1241 cm -1 ; HRMS (ESI) exact mass calcd. for C 32 H 44 O 5 Si: m/z ([M + Na] + ), found: m/z ([M + Na] + ); [α] 26 D = +7.6 (c = 1.0, CHCl 3 ). The enantiomeric excess was determined after derivatization to 2e. To a stirred solution of 2e in THF was added TBAF (1.0 M in THF, 0.15 CO 2 Bn mmol, 150 μl) at room temperature. After 15 min of stirring, the solution CO HO 2 Bn 2e' was acidified with acetic acid and concentrated. The residue was purified by PLC (hexane/ethyl acetate = 3:1) to give 2e in 29% yield [>95:5 dr, 90% ee]. 1 H NMR (400 MHz, CDCl 3 ) (10H, m), 5.69 (1H, ddd, J = 18 Hz, 10 Hz, 7.6 Hz), (6H, m), 3.94 (1H, appt q, J = 7.2 Hz), (2H, m), 2.50 (1H, m), 2.21 (1H, dd, J = 14 Hz, 6.9 Hz), (2H, m); 13 C NMR (100 MHz, CDCl 3 ) 172.2, 171.6, 138.2, , , 128.5, 128.3, , , 116.4, 67.5, 67.3, 57.1, 51.7, 41.1, 37.0; IR (neat) 3435, 1727, 1455, 1239, 1167, 1096 cm -1 ; HRMS (ESI) exact mass calcd. for C 23 H 24 O 5 : m/z ([M + Na] + ), found: m/z ([M + Na] + ); [α] 26 D = NATURE CHEMISTRY 20

21 -7.6 (c = 1.0, CHCl 3 ). The enantiomeric purity of the product was determined by HPLC analysis (Daicel CHIRALCEL OZ-H, hexane/etoh =15:1, flow rate = 1.0 ml/min, retention time; 19.1 min (minor) and 21.8 min (major)). Dibenzyl (3R,4S)-3-triisopropylsiloxy-3-methyl-4-vinylcyclopentane-1,1-dicarboxylate 2f Prepared according to the general procedure with dibenzyl 2-vinylcyclopropane-1,1-dicarboxylate 1a ( 0.1 mmol, 34 mg) and triisopropylsilyl 2-propenyl ether (0.2 mmol, 50 μl). The crude material (65:35 dr) was purified by PLC (hexane/ch 2 Cl 2 = 1:1.5) to give the title compound as a colorless liquid in 73% yield [1:0.5 dr, 74%/45% ee]. 1 H NMR (400 MHz, CDCl 3 ) (15H, m), (1.5H, m), (9.0H, m), (6.5H, m), 2.05 (1.0H, dd, J = 14 Hz, 10 Hz), 1.34 (1.5H, s), 1.11 (3.0H, m), (31.5H, m); 13 C NMR (100 MHz, CDCl 3 ) 172.9, 172.1, 171.9, 171.2, 137.0, 136.8, 135.5, , , , , , , , , , 127.8, 117.0, 116.2, 82.6, 81.6, 67.26, 67.17, 67.13, 58.0, 56.6, 56.4, 54.9, 49.3, 48.4, 38.8, 35.9, 26.0, 23.82, 18.44, 18.37, 18.27, 13.4, 13.2; IR (neat) 2943, 2865, 1732, 1456, 1240, 1118 cm -1 ; HRMS (ESI) exact mass calcd. for C 33 H 46 O 5 Si: m/z ([M + Na] + ), found: m/z ([M + Na] + ); [α] 26 D = +8.3 (c = 1.0, CHCl 3 ). The enantiomeric purity of the product was determined by HPLC analysis (Daicel CHIRALPAK IE, hexane/iproh = 100:1, flow rate = 0.5 ml/min, retention time; 15.1 min (major diastereomer/minor), 16.0 min (major diastereomer/major), 17.4 min (minor diastereomer/minor), 19.8 min (minor diastereomer/major)). The relative stereochemistry was determined by the NOE measurement. Dibenzyl (3R,4S)-3-(t-butoxycarbonyl)amino-4-vinylcyclopentane-1,1-dicarboxylate 2g Prepared according to the general procedure with dibenzyl NATURE CHEMISTRY 21

22 2-vinylcyclopropane-1,1-dicarboxylate 1a ( 0.1 mmol, 34 mg) and t-butyl vinyl carbamate (0.2 mmol, 29 mg). The crude material (34:66 dr) was purified by PLC (hexane/ethyl acetate = 3:1) to give the title compound as a colorless liquid in 95% yield [dr = 0.6:1, 51%/12% ee]. 1 H NMR (400 MHz, CDCl 3 ) (16H, m), (1.6H, m), (9.6H, m), 4.77 (1.0H, br), 4.64 (0.6H, br), 4.16 (1.0H, br), 3.84 (0.6H, br), (1.6H, br), (6.4H, br), 1.41 (14.4H, appt s); 13 C NMR (100 MHz, CDCl 3 ) 172.7, 172.1, 171.6, 171.2, , , 137.8, 135.7, , , , , 128.5, , , , , , 117.1, 116.3, 79.2, 67.5, 67.4, 67.3, 57.9, 57.3, 55.6, 54.2, 50.0, 46.9, 40.2, 39.7, 37.8, 36.8, 28.3; IR (neat) 3399, 2977, 1715, 1498, 1243, 1165 cm -1 ; HRMS (ESI) exact mass calcd. for C 28 H 3 NO 6 : m/z ([M + Na] + ), found: m/z ([M + Na] + ); [α] 26 D = +2.7 (c = 1.0, CHCl 3 ). The enantiomeric purity of the product was determined by HPLC analysis (Daicel CHIRALPAK AD-3, hexane/iproh = 5:1, flow rate = 0.5 ml/min, retention time; 18.8 min (cis/major), 19.9 min (cis/minor), 26.1 min (trans/major), 31.3 min (trans/minor)). The relative configuration of the diastereomers were tentatively assigned by the similarity of 1 H NMR with 2a. Methyl (3R,4S)-1-benzoyl-3-t-butoxy-4-vinylcyclopentane-1-carboxylate 2h Prepared according to the general procedure with methyl 1-benzoyl-2-vinylcyclopropanecarboxylate (90% purity, 0.1 mmol, 25 mg) and t-butyl vinyl ether (0.2 mmol, 27 μl). The crude material (93:7 dr (C3:C4)) was purified by PLC (hexane/ch 2 Cl 2 = 1:4) to give the title compound as a colorless liquid in 92% yield [1:0.5 dr (C1:C3-4), 88%/72% ee]. C3:C4 cis isomers were separated at this stage. 1 H NMR (400 MHz, CDCl 3 ) (3.0H, m), (1.5H, m), (3.0H, m), (1.5H, m), (3.0H, m), 3.81 (1.0H, q, J = 8.4 Hz), (5.0H, m), (2.5H, m), 2.74 (0.5H, dd, J = 14 Hz, 8.0 Hz), 2.63 (0.5H, m), 2.42 (1.0H, m), (1.5H, m), 1.92 (0.5H, dd, J = 14 Hz, 11 Hz), 1.82 (1.0H, dd, J = 13 Hz, 12 Hz), 1.17 (4.5H, s), 1.15 (9.0H, s); 13 C NMR (100 MHz, CDCl 3 ) 195.4, 194.4, 180.8, 179.5, 175.0, 174.4, , , , , 133.0, 132.8, , , 128.6, 128.5, 115.7, 76.6, 76.1, 73.5, 73.4, 59.7, 59.5, 52.77, 52.74, 49.7, 49.4, 42.2, 41.9, 36.0, 35.9, 28.61, 28.59; IR (neat) 2973, 1737, 1685, 1251, 1194, 1097 cm -1 ; HRMS (ESI) exact mass NATURE CHEMISTRY 22

23 calcd. for C 20 H 26 O 4 : m/z ([M + Na] + ), found: m/z ([M + Na] + ); [α] 26 D = (c = 1.0, CHCl 3 ). The enantiomeric purity of the product was determined by HPLC analysis (Daicel CHIRALPAK IC-3, hexane/iproh = 100:1, flow rate = 0.5 ml/min, retention time; 13.3 min (minor diastereomer/minor), 14.8 min (minor diastereomer/major), 19.9 min (major diastereomer/major), 24.1 min (major diastereomer/minor)) Supplementary Figure S3. 1 H NMR spectra of the crude mixture (top) and the isolated C3:C4 cis isomers (bottom). Methyl (3R,4S)-1-(4-bromobenzoyl)-3-t-butoxy-4-vinylcyclopentane-1-carboxylate 2i Prepared according to the general procedure with methyl 4-bromobenzoyl-2-vinylcyclopropanecarboxylate (86% purity, 0.1 mmol, 36 mg) and t-butyl vinyl ether (0.2 mmol, 27 μl). The crude material (> 95:5 dr (C3:C4)), was purified by PLC (hexane/ch 2 Cl 2 = 1:3) to give the title compound as a colorless liquid in 99% yield [1:0.6 dr (C1:C3-4), 87%/73% ee]. C3:C4 cis isomers were separated at this stage. NATURE CHEMISTRY 23

24 1 H NMR (400 MHz, CDCl 3 ) (3.2H, m), (3.2H, m), (1.6H, m), (3.2H, m), 3.80 (1.0H, appt q, J = 8.4 Hz), (5.4H, m), (2.6H, m), (1.2H, m), 2.41 (1.0H, m), (1.6H, m), 1.89 (0.6H, dd, J = 13 Hz, 11 Hz), 1.79 (1.0H, dd, J = 13 Hz, 12 Hz), 1.17 (5.4H, s), 1.15 (9H, s); 13 C NMR (100 MHz, CDCl 3 ) 194.4, 193.4, 174.8, 174.2, 138.6, 138.5, 133.4, 133.3, 132.0, 131.9, , , 128.3, 128.1, 115.8, 76.6, 76.0, 73.49, 73.45, 59.7, 59.6, 52.89, 52.87, 49.6, 49.4, 42.1, 41.9, 35.9, 35.8, 28.6; IR (neat) 2973, 1736, 1685, 1584, 1252, 1194 cm -1 ; HRMS (ESI) exact mass calcd. for C 20 H 25 BrO 4 : m/z ([M + Na] + ), found: m/z ([M + Na] + ); [α] 26 D = (c = 1.0, CHCl 3 ). The enantiomeric purity of the product was determined by HPLC analysis (Daicel CHIRALPAK IC-3, hexane/etoh = 100:1, flow rate = 0.75 ml/min, retention time; 8.5 min (minor diastereomer/minor), 9.1 min (minor diastereomer/major), 9.6 min (major diastereomer/ minor), 11.1 min (major diastereomer/minor)). Methyl (3R,4S)-3-t-butoxy-1-(4-methoxybenzoyl)-4-vinylcyclopentane-1-carboxylate 2j Prepared according to the general procedure with methyl 4-methoxybenzoyl-2-vinylcyclopropanecarboxylate (93% purity, 0.1 mmol, 28 mg) and t-butyl vinyl ether (0.2 mmol, 27 μl). The crude material (93:7 dr (C3:C4)) was purified by PLC (hexane/ch 2 Cl 2 = 1:6) to give the title compound as a colorless liquid in 90% yield [1:0.7 dr (C1:C3-4), 90%/71% ee]. C3:C4 cis isomers were separated at this stage. 1 H NMR (400 MHz, CDCl 3 ) (3.4H, m), (3.4H, m), (1.7H, m), (3.4H, m), 3.85 (5.1H, m), 3.79 (1.0H, appt q, J = 8.4 Hz), (5.8H, m), (2.7H, m), 2.74 (0.7H, dd, J = 14 Hz, 8.0 Hz), (0.7H, m), 2.41 (1.0H, m), (1.7H, m), 1.91 (0.7H, dd, J = 14 Hz, 11 Hz), 1.78 (1.0H, dd, J = 13 Hz, 12 Hz), 1.17 (6.3H, s), 1.15 (9H, s); 13 C NMR (100 MHz, CDCl 3 ) 193.9, 193.0, 175.3, 174.7, 163.3, 163.2, 138.9, 138.8, 131.1, , , 115.6, , , 76.6, 76.1, 73.44, 73.35, 59.5, 59.3, 55.4, 52.8, 49.6, 49.4, 42.3, 42.0, 36.0, 35.8, 28.6; IR (neat) 2973, 1734, 1677, 1252, 1168 cm -1 ; HRMS (ESI) exact mass calcd. for C 21 H 28 O 5 : m/z ([M + Na] + ), found: m/z ([M + Na] + ); [α] 26 D = (c = 1.0, CHCl 3 ). The enantiomeric purity of the product was determined by HPLC analysis (Daicel CHIRALCEL OZ-H, hexane/iproh = 100:1, flow rate = 1.0 ml/min, retention time; 8.9 NATURE CHEMISTRY 24

25 min (minor diastereomer/major), 11.1 min (minor diastereomer/minor), 14.1 min (major diastereomer/ minor), 24.0 min (major diastereomer/major)). Methyl (3R,4S)-1-acetyl-3-t-butoxy-4-vinylcyclopentanecarboxylate 2k Prepared according to the general procedure with methyl 1-acetyl-2-vinylcyclopropanecarboxylate (88% purity, 0.1 mmol, 19 mg) and t-butyl vinyl ether (0.2 mmol, 27 μl). The crude material (>95:5 dr (C3:C4)) was purified by PLC (hexane/ch 2 Cl 2 = 1:6) to give the title compound as a colorless liquid in 98% yield [1:0.6 dr (C1:C3-4), 90%/89% ee]. C3:C4 cis isomers were separated at this stage. 1 H NMR (400 MHz, CDCl 3 ) (1.6H, m), (3.2H, m), (5.8H, m), 3.57 (0.6H, appt q, J = 7.8 Hz), (3.8H, m), 2.35 (1.0H, m), 2.15 (3.0H, s), 2.13 (1.8H, s), (1.6H, m), (1.6H, m), (14.4H, m); 13 C NMR (100 MHz, CDCl 3 ) 203.1, 202.4, 173.7, 173.3, , , , , 76.5, 76.2, 73.5, 73.4, 63.1, 62.8, 52.7, 49.8, 49.5, 40.6, 39.9, 34.6, 33.9, 28.6, 26.01, 25.97; IR (neat) 2974, 1715, 1362, 1245, 1193, 1096 cm -1 ; HRMS (ESI) exact mass calcd. for C 15 H 24 O 4 : m/z ([M + Na] + ), found: m/z ([M + Na] + ); [α] 26 D = (c = 1.0, CHCl 3 ). The enantiomeric excess was determined after derivatization to 2k. 2k O O O CO 2 Me Br To a stirred solution of 2k (0.1 mmol, 26 mg) in CH 2 Cl 2 (1.0 ml) was added TFA (0.1 ml) at room temperature. After 2 h of stirring, the solvent and TFA were evaporated and the residue was dissolved to CH 2 Cl 2 (2.0 ml). To this solution were added 4-bromobenzoyl chloride (0.15 mmol, 33 mg), DMAP (0.05 mmol, 6.1 mg), Et 3 N (0.25 mmol, 35 μl) at room temperature. After 2 h of stirring, the solvent was removed in vacuo. The crude mixture was purified by PLC (hexane/ethyl acetate = 5:1) to give 2k as a colorless liquid in 50% yield [dr = 1/0.6, 90%/89% ee]. 1 H NMR (400 MHz, CDCl 3 ) (3.2H, m), (3.2H, m) (1.6H, m), (4.8H, m), 3.77 (3.0H, s), 3.73 (1.8H, s), 2.93 (0.6H, m), (4.2H, m), (1.6H, m), (4.8H, m), (1.6H, m); 13 C NMR (100 MHz, CDCl 3 ) 203.1, 202.4, 173.7, 173.3, , , , , 76.5, 76.2, 73.5, 73.4, 63.1, 62.8, 52.7, 49.8, 49.5, 40.6, 39.9, 34.6, 33.9, 28.6, 26.01, 25.97; IR (neat) 1714, 1268, NATURE CHEMISTRY 25

26 1115, 1103, 1012 cm -1 ; HRMS (ESI) exact mass calcd. for C 18 H 19 BrO 5 : m/z ([M + Na] + ), found: m/z ([M + Na] + ); [α] 26 D = (c = 1.0, CHCl 3 ). The enantiomeric purity of the product was determined by HPLC analysis (Daicel CHIRALCEL OZ-H, hexane/iproh = 40:1, flow rate = 1.0 ml/min, retention time; 12.5 min (major diastereomer/minor), 14.4 min (major diastereomer/major), 17.7 min (minor diastereomer/ minor), 19.1 min (minor diastereomer/major)). Methyl (3R,4S)-3-t-butoxy-1-pentanoyl-4-vinylcyclopentane-1-carboxylate 2l Prepared according to the general procedure with methyl 1-pentanoyl-2-vinylcyclopropanecarboxylate (90% purity, 0.1 mmol, 23 mg) and t-butyl vinyl ether (0.2 mmol, 27 μl). The crude material (>95:5 dr (C3:C4)) was purified by PLC (hexane/ch 2 Cl 2 = 1:6) to give the title compound as a colorless liquid in 95% yield [1:0.9 dr (C1:C3-4), 90%/85% ee]. C3:C4 cis isomers were separated at this stage. 1 H NMR (400 MHz, CDCl 3 ) (1.9H, m), (3.8H, m), (6.6H, m), 3.57 (1.0H, appt q, J = 7.8 Hz), (8.6H, m), (1.9H, m), (6.6H, m), (3.8H, m), (17.1H, m), 0.89 (5.7H, t, J = 7.4 Hz); 13 C NMR (100 MHz, CDCl 3 ) 205.6, 204.8, 173.9, 173.4, 138.9, 138.8, 115.5, 115.4, 76.5, 76.2, 73.42, 73.38, 63.0, 62.6, 52.6, 49.8, 49.5, 40.6, 40.0, 38.1, 38.0, 34.7, 33.9, 28.6, 26.1, 26.0, 22.18, 22.16, 13.8; IR (neat) 2970, 1744, 1714, 1363, 1242, 1193, 1097 cm -1 ; HRMS (ESI) exact mass calcd. for C 18 H 30 O 4 : m/z ([M + Na] + ), found: m/z ([M + Na] + ); [α] 26 D = (c = 1.0, CHCl 3 ). The enantiomeric excess was determined after derivatization to 2l. 2l O nbu O O CO 2 Me Br To a stirred solution of 2l (0.09 mmol, 31 mg) in CH 2 Cl 2 (1.0 ml) was added TFA (0.1 ml) at room temperature. After 2 h of stirring, the solvent and TFA were evaporated and the residue was dissolved to CH 2 Cl 2 (2.0 ml). To this solution were added 4-bromobenzoyl chloride (0.15 mmol, 33 mg), DMAP (0.05 mmol, 6.1 mg), Et 3 N (0.25 mmol, 35 μl) at room temperature. After 2 h of stirring, the solvent was removed in vacuo. The crude mixture was purified by PLC (hexane/ethyl acetate = 5:1) to give 2l as a colorless oil in 43% yield [dr = 1/0.9, 90%/85% ee]. 1 H NMR (400 MHz, CDCl 3 ) (3.8H, m), (3.8H, m), (1.9H, NATURE CHEMISTRY 26