Supporting Information

Supporting Information Chiral Ammonium Hypoiodite Salt-catalyzed Enantioselective xidative Cycloetherification to 2-Acyl Tetrahydrofurans Muhammet Uyanik, Hiroki Hayashi, Hirokazu Iwata, and Kazuaki Ishihara* Graduate School of Engineering, agoya University, Chikusa, agoya, Aichi 464-8603 (Received January 3, 2016; CL-160004; E-mail: ishihara@cc.nagoya-u.ac.jp) Copyright The Chemical Society of Japan

Additional Information Table S1. Investigation of reaction conditions H 2a Catalyst (10 mol%) CHP (2 equiv) Solvent (x M), 25 C 3a Entry Catalyst Solvent (x M) Time (h) Yield (%) a ee (%) b 1 S1 MTBE (0.02) 6 <5 2 S2 MTBE (0.02) 6 43 56 3 S3 MTBE (0.02) 6 37 56 4 4 MTBE (0.02) 2 75 90 5 4 THF (0.02) 6 <5 6 4 EtAc (0.02) 6 <5 7 4 CCl 4 (0.02) 6 36 52 8 4 Et 2 (0.02) 6 67 87 9 4 i-pr 2 (0.02) 6 59 81 10 4 CPME (0.02) 6 40 81 11 4 MTBE (0.2) 2 81 91 (98) c a Isolated yield. b Determined by HPLC analysis. c After a single recrystallization. CHP: Cumene hydroperoxide. MTBE: Methyl tert-butyl ether. THF: Tetrahydrofuran. CPME: Cyclopentyl methyl ether. Ar I + Ar F 3 C CF 3 C 6 F 13 C 6 F 13 CF 3 CF 3 F 3 C CF 3 F 3 C CF 3 Ar = S1 S2 S3 4 S1

Materials and Methods 1 H MR spectra were measured on a JEL ECS-400 (400 MHz) spectrometer at ambient temperature. Data were recorded as follows: chemical shift in ppm from internal tetramethylsilane on the δ scale, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, Q = quintuplet, m = multiplet, brs = broad singlet), coupling constant (Hz), integration, and assignment. 13 C MR spectra were measured on a JEL ECS-400 (100 MHz) spectrometers. Chemical shifts were recorded in ppm from the solvent resonance employed as the internal standard (deuterochloroform at 77.00 ppm). Gas-liquid-phase chromatography (GC) was performed with Shimadzu Model 17A instrument with a flame-ionization detector and a capillary column of CP-Cyclodextrin-β-2,3,6-M-19 (i.d. 0.25 mm 25 m; CHRMPACK; GL Science Inc.) or CHIRALDEX B-DM (i.d., 0.25 mm 20 m; Tokyo Kasei Kogyo Co., LTD). High-performance liquid chromatography (HPLC) analysis was conducted using Shimadzu LC-10 AD coupled diode array-detector SPD-MA-10A-VP and chiral column of Daicel CHIRALCEL AD-H (4.6 mm x 25 cm). ptical rotations were measured on Rudolph Autopol IV digital polarimeter. Melting points were measured on MPA100, Standard Research Systems. For thin-layer chromatography (TLC) analysis throughout this work, Merck precoated TLC plates (silica gel 60 GF 254 0.25 mm) were used. Visualization was accomplished by UV light (254 nm), anisaldehyde, KMn 4, or phosphomolybdic acid. The products were purified by column chromatography on silica gel (E. Merck Art. 9385). High-resolution mass spectral analysis (HRMS) and elemental analysis was performed at Chemical Instrument Center, agoya University. In experiments that required dry solvents, tetrahydrofuran (THF), dichloromethane, and toluene were purchased from Wako as the anhydrous and stored over 4Å molecular sieves. ther solvents were purchased from Kanto Chemical Co., Inc., Aldrich Chemical Co., Inc., Tokyo Chemical Industry (TCI) Co. Ltd., acalai Tesque, Inc. or Wako Pure Chemical Industries, Ltd., and used without further purification. Tetrabutylammonium iodide (Bu 4 I) and cumene hydroperoxide (CHP, contains ca. 20% aromatic hydrocarbon) were purchased from Tokyo Chemical Industry Co. Ltd. and used without further purification. 30-wt% aqueous hydrogen peroxide and anhydrous tert-butyl hydroperoxide (TBHP, 5.5 M nonane solution) were purchased from Aldrich Chemical Co., Inc. and used without further purification. Catalysts 4 and S1 3 are known compounds. 1 ther simple chemicals were commercially obtained as an analytical-grade and used without further purification. S2

Synthesis and Characterization of Starting Materials 2 Isolated γ-hydroxyketones 2 were found to be in equilibrium with the corresponding hemiacetal forms and used as a mixture for the oxidative cycloetherification reactions (2:hemiacetal = ~95:5 to ~80:20). In oxidative cyclization reactions, both 2 and their hemiacetal forms were consumed to give the corresponding 2-acyl THFs 3. Synthesis of 2a d and 2f: R 1 R 1 R 2 R 2 S4a d, S4f (1.5 equiv) n-buli (1.5 equiv) THF, 78 to 25 C, 1 h H R 1 R 1 R 2 R 2 2a d, 2f R 1, R 2 = H, H (2a) H, Me (2b) CH 2 (CH 2 ) 3 CH 2 (2c), (2d) Me, H (2f) 2a d and 2f were synthesized through the nucleophilic ring opening of the corresponding lactones S4a d with lithiated -phenylimidazole. 1 S4a is commercially available. S4b, 2 S4c, 3 S4d 4 and S4f 2 were prepared by following the literature procedure. Synthesis of 2e: H (1 equiv) n-buli (1 equiv) THF, 78 to 25 C, 1 h H S5 Mn 2 (5 equiv) CH 2 Cl 2, 25 C, 12 h S6 Et Et (1.2 equiv) ah (1.2 equiv) THF, 25 to 40 C, 24 h Et Et S7 formaldehyde (1 equiv) ahc 3 (10 mol%) EtH,H 2, 25 C, 24 h H Et 2 C C 2 Et 2e The conditions were not optimized. To a solution of -phenylimidazole (1.26 ml, 10.0 mmol) in THF (33.0 ml) was added n-buli (1.6 M in hexane, 6.25 ml, 10.0 mmol) at 78 C. After stirring at 78 C for 30 min, acrolein (0.667 ml, 10.0 mmol) was added to the reaction mixture at 78 C. The reaction mixture was allowed to warm to 25 C. After stirring for 30 min, the resulting mixture was poured into saturated aqueous H 4 Cl and the aqueous layers were extracted with Et 2 (twice). The combined organic layers were washed with brine and dried over anhydrous MgS 4. The solvents were removed in vacuo to give S5, which was used for next step without further purification. To a crude solution of S5 in CH 2 Cl 2 (20.0 ml) was added Mn 2 (4.35 g, 50.0 mmol) at 25 C. After stirring for 12 h, the S3

reaction mixture was filtered through a plug of tightly packed celite and washed with Et 2. The solvents were removed in vacuo. The residue was purified by flash column chromatography on silica gel (E. Merck Art. 9385, eluent: hexane EtAc = 4:1) to S6 (792 mg, 4.00 mmol) in 40% yield over 2 steps. To a suspension of ah (192 mg, 4.80 mmol) in THF (9.60 ml) was added diethyl malonate (0.732 ml, 4.80 mmol) at 25 C. After stirring for 1 h, the resulting mixture was added to a solution of S6 (792 mg, 4.00 mmol) in THF (8.00 ml) at 25 C. The reaction mixture was warmed to 40 C. After stirring for 24 h, the reaction mixture was poured into saturated aqueous H 4 Cl and the aqueous layers were extracted with EtAc (twice). The combined organic layers were washed with brine and dried over anhydrous MgS 4. The solvents were removed in vacuo. The residue was purified by flash column chromatography on silica gel (E. Merck Art. 9385, eluent: hexane EtAc = 4:1) to give S7 (429 mg, 1.20 mmol) in 30% yield. To a solution of S7 (429 mg, 1.20 mmol) and ahc 3 (11.0 mg) in ethanol (12.0 ml) and water (6.00 ml) was a 37% aqueous solution of formaldehyde (0.0890 ml, 1.20 mmol) at 0 C. The reaction mixture was allowed to warm to 25 C. After stirring for 24 h, the resulting mixture was transferred to a separation funnel and the aqueous layers were extracted with EtAc (twice). The combined organic layers were washed with brine and dried over anhydrous MgS 4. The solvents were removed in vacuo. The residue was purified by flash column chromatography on silica gel (E. Merck Art. 9385, eluent: hexane EtAc = 1:1) to give 2e (324 mg, 0.840 mmol) in 70% yield. Characterization of Starting Materials 2: 5-Hydroxy-1-(1-phenyl-1H-imidazol-2-yl)pentan-1-one (2a): White solid; TLC, R f = 0.32 (hexane EtAc = 1:3); IR (neat) 3500 3000, 2936, 1684, 1494, 1407 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ 1.60 1.67 (m, 2H), 1.74 1.83 (m, 2H), 3.16 3.20 (m, 3H), 3.65 3.69 (m, 2H), 7.18 (m, 1H), 7.26 7.29 (m, 3H), 7.45 7.47 (m, 3H); 13 C MR (CDCl 3, 100 MHz) δ 20.0, 31.9, 38.5, 61.9, 125.8, 126.9, 128.7, 128.9, 129.3, 138.2, 142.7, 191.3; HRMS (FAB) m/z calcd for [C 14 H 17 2 2 +H] + 245.1285, found 245.1290. 5-Hydroxy-4,4-dimethyl-1-(1-phenyl-1H-imidazol-2-yl)pentan-1-one (2b): Colorless oil; TLC, R f = 0.30 (hexane EtAc = 1:3); IR (neat) 3500 300, 2954, 1686, 1598, 1404 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ 0.91 (s, 6H), 1.66 1.72 (m, 2H), 3.01 3.05 (m, 2H), 3.39 (m, 3H), 7.17 (m, 1H), 7.26 7.28 (m, 3H), 7.45 7.47 (m, 3H); 13 C MR (CDCl 3, 100 MHz) δ 24.3, S4

32.6, 34.8, 35.3, 70.2, 125.8, 126.9, 128.8, 129.0, 129.4, 138.2, 142.3, 191.8; HRMS (FAB) m/z calcd for [C 16 H 21 2 2 +H] + 273.1598, found 273.1601. 3-(1-(Hydroxymethyl)cyclohexyl)-1-(1-phenyl-1H-imidazol-2-yl)propan-1-one (2c): Pale yellow oil; TLC, R f = 0.32 (hexane EtAc = 1:3); IR (neat) 3500 3000, 2926, 1686, 1495, 1405 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ 1.17 1.55 (m, 10H), 1.77 1.84 (m, 2H), 2.93 2.97 (m, 2H), 3.41 3.72 (m, 2H), 3.87 3.91 (m, 1H), 7.16 (m, 1H), 7.26 7.29 (m, 3H), 7.39 7.47 (m, 3H); 13 C MR (CDCl 3, 100 MHz) δ 21.5, 26.4, 29.5, 32.8, 34.2, 37.5, 67.9, 125.8, 126.9, 128.8, 128.9, 129.3, 138.2, 142.1, 192.0; HRMS (FAB) m/z calcd for [C 19 H 25 2 2 +H] + 313.1911, found 313.1908. 5-Hydroxy-4,4-diphenyl-1-(1-phenyl-1H-imidazol-2-yl)pentan-1-one (2d): White solid; TLC, R f = 0.50 (hexane EtAc = 1:3); IR (neat) 3500 3000, 3021, 1685, 1495, 1406 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ 2.60 2.64 (m, 2H), 2.92 2.96 (m, 3H), 4.26 4.28 (m, 2H), 7.14 (d, J = 0.92 Hz, 1H), 7.17 7.30 (m, 13H), 7.45 7.47 (m, 3H); 13 C MR (CDCl 3, 100 MHz) δ 30.3, 35.0, 51.1, 68.0, 125.8, 126.2, 126.9, 128.0, 128.1, 128.7, 128.8, 129.3, 138.2, 142.3, 145.6, 191.1; HRMS (FAB) m/z calcd for [C 26 H 25 2 2 +H] + 397.1911, found 397.1905. Diethyl 2-(hydroxymethyl)-2-(3-oxo-3-(1-phenyl-1H-imidazol-2-yl)propyl)malonate (2e): Pale yellow oil; TLC, R f = 0.32 (hexane EtAc = 1:3); IR (neat) 3500 3000, 2981, 1730, 1688, 1495, 1408 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ 1.25 (t, J = 7.2 Hz, 6H), 2.36 (t, J = 7.7 Hz, 2H), 3.15 (t, J = 7.7 Hz, 2H), 4.05 (brs, 1H), 4.18 (m, 2H), 4.21 (q, J = 7.2 Hz, 4H), 7.18 (m, 1H), 7.25 7.29 (m, 3H), 7.46 7.47 (m, 3H); 13 C MR (CDCl 3, 100 MHz) δ 13.9, 25.0, 34.3, 58.9, 61.5, 63.5, 125.8, 127.1, 128.8, 128.9, 129.5, 138.1, 142.1, 170.3, 190.0; HRMS (FAB) m/z calcd for [C 20 H 25 2 6 +H] + 389.1707, found 389.1703. 5-Hydroxy-3,3-dimethyl-1-(1-phenyl-1H-imidazol-2-yl)pentan-1-one (2f): White solid; TLC, R f = 0.31 (hexane EtAc = 1:3); IR (neat) 3500 3000, 2957, 1679, 1495, 1403 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ 1.06 (s, 6H), 1.65 (t, J = 6.6 Hz, 2H), 2.81 2.82 (m, 1H), 3.15 (s, 2H), 3.76 3.81 (m, 2H), 7.16 (d, J = 0.92 Hz, 1H), 7.25 7.27 (m, 3H), 7.46 7.47 (m, 3H); 13 C MR (CDCl 3, 100 MHz) δ 28.6, 33.8, 43.2, 48.7, 59.8, 125.8, 127.2, 128.7, 129.0, 129.3, 138.5, 144.0, 191.5; HRMS (FAB) m/z calcd for [C 16 H 21 2 2 +H] + 273.1598, found 273.1602. S5

General Procedures for the xidative Cycloetherification Synthesis of Authentic Samples: H R 1 R 1 R 2 R 2 2 H n-bu 4 I (20 mol%) CHP (2 equiv) EtAc (0.1 M), 50 C, 24 h R 1 R1 R 2 R 2 3 H To a stirring mixture of 2 (0.100 mmol) and Bu 4 I (7.40 mg, 0.0200 mmol, 20 mol%) in EtAc (1.00 ml) was added cumene hydroperoxide (contains ca. 20% aromatic hydrocarbon, TCI, 0.0370 ml, 0.200 mmol, 2 equiv) at 25 C. The reaction was monitored by TLC analysis. After stirring for 24 h, the resulting mixture was poured into saturated aqueous ahs 3 (1.00 ml), and the aqueous layers were extracted with Et 2 (twice). The combined organic layers were washed with brine and dried over anhydrous MgS 4. The solvents were removed in vacuo. The residue was purified by flash column chromatography on silica gel (E. Merck Art. 9385, eluent: hexane EtAc = 4:1) to give 3 in 30 60% yield. Representative Procedure for Enantioselective xidative Cycloetherification of 2a: H 2a H 4 (10 mol%) CHP (2 equiv) MTBE (0.2 M), 25 C, 2 h 3a H To a stirring mixture of 2a (24.4 mg, 0.100 mmol), (R,R)-4 (17.0 mg, 0.0100 mmol, 10 mol%) in methyl tert-butyl ether (0.500 ml) was added cumene hydroperoxide (contains ca. 20% aromatic hydrocarbon, TCI, 0.0370 ml, 0.200 mmol, 2 equiv) at 25 C. The reaction was monitored by TLC analysis. After stirring for 2 h, the resulting mixture was poured into saturated aqueous ahs 3 (1.00 ml), and the aqueous layers were extracted with Et 2 (twice). The combined organic layers were washed with brine and dried over anhydrous MgS 4. The solvents were removed in vacuo. The residue was purified by flash column chromatography on silica gel (E. Merck Art. 9385, eluent: hexane EtAc = 4:1) to give (R)-3a (19.8 mg, 0.0810 mmol) in 81% yield. Enantiomeric excess of 3a was determined to be 91% ee by HPLC analysis. Procedure for Gram-Scale xidation: To a stirring mixture of 2b (1.12 g, 4.11 mmol), (R,R)-4 (140 mg, 0.0820 mmol, 2 mol%) in methyl tert-butyl ether (206 ml) was added cumene hydroperoxide (contains ca. S6

20% aromatic hydrocarbon, TCI, 1.50 ml, 8.22 mmol, 2 equiv) at 25 C. The reaction was monitored by TLC analysis. After stirring for 6 h, the resulting mixture was poured into saturated aqueous ahs 3 (50 ml), and the aqueous layers were extracted with Et 2 (twice). The combined organic layers were washed with brine and dried over anhydrous MgS 4. The solvents were removed in vacuo. The residue was purified by flash column chromatography on silica gel (E. Merck Art. 9385, eluent: hexane EtAc = 4:1) to give (R)-3b (1.02 g, 3.77 mmol) in 93% yield. Enantiomeric excess of 3b was determined to be 92% ee by HPLC analysis. Characterization of Products 3: (R)-(1H-Imidazol-2-yl)(tetrahydrofuran-2-yl)methanone (3a): The optical purity of 3a could be increased to 98% ee after a single recrystallization from hexane/diethyl ether at 25 C. Colorless crystal; Mp 85.0 C; TLC, R f = 0.56 (hexane EtAc = 1:1); IR (neat) 2975, 1697, 1597, 1492, 1405 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ 1.89 2.00 (m, 2H), 2.01 2.11 (m, 1H), 2.40 2.49 (m, 1H), 3.93 4.03 (m, 2H), 5.59 (dd, J = 5.9 Hz, 1H), 7.21 (s, 1H), 7.27 7.30 (m, 3H), 7.44 7.46 (m, 3H); 13 C MR (CDCl 3, 100 MHz) δ 25.5, 30.2, 69.6, 79.6, 125.8, 127.1, 128.8, 128.9, 130.0, 137.9, 141.9, 190.0; HRMS (FAB) m/z calcd for [C 14 H 15 2 2 +H] + 243.1128, found 243.1128; HPLC (AD H column), Hexane EtH = 4:1 as eluent, 1.0 ml/min, t R = 13.6 min (R), t R = 22.8 min (S); [α] 24.8 D = 107.8 (c 2.14, CHCl 3 ) for 98% ee. (R)-(4,4-Dimethyltetrahydrofuran-2-yl)(1H-imidazol-2-yl)methanone (3b): Colorless oil; TLC, R f = 0.55 (hexane EtAc = 1:1); IR (neat) 2959, 2869, 1698, 1493, 1406 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ 1.08 (s, 3H), 1.19 (s, 3H), 1.80 1.86 (m, 1H), 2.28 2.32 (m, 1H), 3.64 (s, 2H), 5.67 (t, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.27 7.31 (m, 3H), 7.44 7.47 (m, 3H); 13 C MR (CDCl 3, 100 MHz) δ 24.8, 26.3, 40.1, 44.6, 79.9, 81.1, 125.9, 127.1, 128.8, 128.9, 130.0 137.9, 141.3, 189.9; HRMS (FAB) m/z calcd for [C 16 H 19 2 2 +H] + 271.1441, found 271.1439; HPLC (AD H column), Hexane EtH = 4:1 as eluent, 1.0 ml/min, t R = 11.0 min (R), t R = 15.2 min (S); [α] 27.5 D = 131.9 (c 1.11, CHCl 3 ) for 92% ee. (R)-(1H-Imidazol-2-yl)(2-oxaspiro[4.5]decan-3-yl)methanone (3c): Colorless oil; TLC, R f = 0.55 (hexane EtAc = 1:1); IR (neat) 2924, 2851, 1697, 1446, 1405 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ 1.36 1.56 (m, 10H), 1.73 1.78 (m, 1H), 2.37 2.42 (m, 1H), 3.66 (d, J = 8.2 Hz, 1H), 3.79 (d, J = 8.2 Hz, 1H), 5.61 (t, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.27 7.32 (m, S7

3H), 7.44 7.46 (m, 3H); 13 C MR (CDCl 3, 100 MHz) δ 23.4, 24.2, 26.0, 34.9, 35.3, 44.2, 44.3, 79.2, 79.4, 125.8, 127.1, 128.8, 128.9, 130.0, 137.9, 141.3, 190.0; HRMS (FAB) m/z calcd for [C 19 H 23 2 2 +H] + 311.1754, found 311.1754.; HPLC (AD H column), Hexane EtH = 4:1 as eluent, 1.0 ml/min, t R = 14.7 min (R), t R = 16.9 min (S); [α] 26.9 D = 115.1 (c 1.71, CHCl 3 ) for 95% ee. (R)-(4,4-Diphenyltetrahydrofuran-2-yl)(1H-imidazol-2-yl)methanone (3d): Pale yellow solid; TLC, R f = 0.56 (hexane EtAc = 1:1); IR (neat) 3022, 1698, 1597, 1493, 1405 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ 2.74 2.80 (m, 1H), 3.16 3.21 (m, 1H), 4.26 (d, J = 8.7 Hz, 1H), 4.73 (d, J = 8.7 Hz, 1H), 5.65 (dd, J = 7.3 Hz, 1H), 7.16 7.45 (m, 17H); 13 C MR (CDCl 3, 100 MHz) δ 42.8, 56.0, 78.1, 79.7, 125.8, 126.4, 126.5, 127.1, 127.2, 127.3, 128.3, 128.4, 128.8, 128.9, 130.1, 137,8, 141.3, 144.7, 145.6, 189.2; HRMS (FAB) m/z calcd for [C 26 H 23 2 2 +H] + 395.1754, found 395.1759.; HPLC (AD H column), Hexane EtH = 4:1 as eluent, 1.0 ml/min, t R = 16.4 min (R), t R = 35.6 min (S); [α] 25.1 D = 78.6 (c 2.81, CHCl 3 ) for 89% ee. Diethyl (R)-5-(1H-imidazole-2-carbonyl)dihydrofuran-3,3(2H)-dicarboxylate (3e): Pale yellow oil; TLC, R f = 0.56 (hexane EtAc = 1:1); IR (neat) 2982, 1733, 1598, 1446, 1407 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ 1.21 (t, J = 7.3 Hz, 3H), 1.27 (t, J = 7.3 Hz, 3H), 2.76 2.81 (m, 1H), 3.08 3.11 (m, 1H), 4.14 (q, J = 7.3 Hz, 2H), 4.24 (q, J = 7.3 Hz, 2H), 4.36 (d, J = 9.2 Hz, 1H), 4.46 (d, J = 9.2 Hz, 1H), 5.66 (dd, J = 7.6 Hz, 1H), 7.22 (s, 1H), 7.27 7.33 (m, 3H), 7.44 7.46 (m, 3H); 13 C MR (CDCl 3, 100 MHz) δ 13.9, 14.0, 37.3, 60.8, 62.0, 62.1, 74.0, 80.1, 125.8, 127.2, 128.8, 128.9, 130.2, 137.8, 140.1, 169.2, 169.7, 187.7; HRMS (FAB) m/z calcd for [C 20 H 23 2 6 +H] + 387.1551, found 387.1560.; HPLC (AD H column), Hexane EtH = 4:1 as eluent, 1.0 ml/min, t R = 18.2 min (R), t R = 22.6 min (S); [α] 27.7 D = 56.1 (c 1.42, CHCl 3 ) for 78% ee. (R)-(3,3-Dimethyltetrahydrofuran-2-yl)(1H-imidazol-2-yl)methanone (3f): Pale yellow oil; TLC, R f = 0.55 (hexane EtAc = 1:1); IR (neat) 2962, 2873, 1691, 1597, 1406 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ 0.96 (s, 3H), 1.34 (s, 3H), 1.72 7.78 (m, 1H), 1.83 1.91 (m, 1H), 3.97 4.02 (m, 1H), 4.13 4.18 (m, 1H), 5.47 (s, 1H), 7.19 (s, 1H), 7.27 7.31 (m, 3H), 7.45 7.47 (m, 3H); 13 C MR (CDCl 3, 100 MHz) δ 23.8, 28.1, 40.3, 43.7, 68.1, 86.8, 126.0, 127.2, 128.8, 128.9, 129.9, 138.1, 142.6, 191.5; HRMS (FAB) m/z calcd for [C 16 H 19 2 2 +H] + 271.1441, found 271.1443; HPLC (AD H column), Hexane EtH = 4:1 as eluent, 1.0 S8

ml/min, t R = 8.56 min (R), t R = 13.5 min (S); [α] 27.9 D = 60.7 (c 0.42, CHCl 3 ) for 59% ee. Conversion of 3a to (R)-1 1,5 3a (91% ee) 1) MeTf (5 equiv) MS 4Å, CH 2 Cl 2 25 C, 1 h 2) DBU (1.2 equiv) n-buh, 25 C, 30 min (R)-S8 94% yield, 91% ee 1M ah (5 equiv) H THF, MeH 25 C, 2 h (R)-1 93% yield, 91% ee To a stirring mixture of 3a (39.3 mg, 0.160 mmol, 91% ee) and activated 4Å molecular sieves (100 mg) in CH 2 Cl 2 (1.60 ml) was added MeTf (0.0880 ml, 0.810 mmol, 5 equiv) at 25 C. The reaction was stirred at ambient temperature until 3a was all consumed (ca. 1 h). The solvents were removed in vacuo. To the resulting residue were added n-butyl alcohol (12.0 ml) and DBU (0.0280 ml, 0.190 mmol, 1.2 equiv) and the resulting mixture was stirred at ambient temperature. The reaction was monitored by TLC analysis. After stirring for 30 min, the resulting mixture was diluted with CH 2 Cl 2 (5.00 ml) and solids were removed by filtration. The filtrate was poured into brine (10.0 ml), and the aqueous layers were extracted with Et 2 (twice). The combined organic layers were washed with 1 M HCl and brine, and dried over anhydrous MgS 4. The solvents were removed in vacuo. The residue was purified by flash column chromatography on silica gel (E. Merck Art. 9385, eluent: hexane EtAc = 10:1) to give S8 6a (26.4 mg, 0.150 mmol) in 94% yield. Enantiomeric excess of S8 was determined to be 91% ee by GC analysis. To a solution of S8 (26.4 mg, 0.150 mmol) in MeH (0.800 ml) and THF (0.800 ml) was added 1 M ah (0.800 ml) at 0 C. The reaction mixture was allowed to warm to 25 C. After stirring for 30 min, the resulting mixture was acidified with 1 M HCl and the aqueous layers were extracted with EtAc (twice). The combined organic layers were washed with brine and dried over anhydrous MgS 4. The solvents were removed in vacuo to give (R)-1 6 (16.7 mg, 0.140 mmol) in 93% yield without further purification. ptical purity of (R)-1 was determined to be 91% ee by GC analysis of methyl ester derivative. 6b Butyl (R)-tetrahydrofuran-2-carboxylate (S8): 6a Colorless oil; TLC, R f = 0.62 (hexane EtAc = 4:1); 1 H MR (CDCl 3, 400 MHz) δ 0.94 (t, J = 7.5 Hz, 3H), 1.34 1.43 (m, 2H), 1.60 1.67 (m, 2H), 1.89 2.06 (m, 3H), 2.22 2.29 (m, 1H), 3.90 3.95 (m, 1H), 4.00 4.05 (m, 1H), 4.12 4.17 (m, 2H), 4.44 4.47 (m, 1H); 13 C MR (CDCl 3, 100 MHz) δ 13.7, 19.1, 25.2, 30.2, 30.6, 64.7, 69.3, 76.7, 173.5; GC (CHIRALDEX B-DM, 100 C), t R = 7.5 min (S), t R = S9

7.7 min (R); [α] 27.2 D = +2.5 (c 1.45, CHCl 3 ) for 91% ee. (R)-Tetrahydrofuran-2-carboxylic acid (1): 6 Pale yellow oil; 1 H MR (CDCl 3, 400 MHz) δ 1.93 2.00 (m, 2H), 2.06 2.16 (m, 1H), 2.27 2.38 (m, 1H), 3.91 3.98 (m, 1H), 4.01 4.07 (m, 1H), 4.50 4,53 (m, 1H), 10.5 (brs, 1H); 13 C MR (CDCl 3, 100 MHz) δ 25.3, 30.1, 69.6, 76.3, 177.9; [α] 26.6 D = +28.1 (c 1.01, CHCl 3 ) for 91% ee. [lit. 6c +30.4 (c 1.01, CHCl 3 ) for (R)-1, 99% ee]. These data were consistent with those previously reported. 6 References 1. a) M. Uyanik, H. kamoto, T. Yasui, K. Ishihara, Science 2010, 328, 1376. b) M. Uyanik, H. Hayashi, K. Ishihara, Science 2014, 345, 291. 2. D. M. Bailey, R. E. Johnson, J. rg. Chem. 1970, 35, 3574. 3. a) C. A. G. M. Weijers, P. M. Könst, M. C. R. Franssen, E. J. R. Sudhölter, rg. Biomol. Chem. 2007, 5, 3106. b) J. T. S. Yeoman, J. Y. Cha, V. W. Mak, S. E. Reisman, Tetrahedron 2014, 70, 4070. 4. H. E. Zimmerman, S. Shorunov, J. rg. Chem. 2009, 74, 5411. 5. D. A. Evans, K. R. Fandrick, H.-J. Song, K. A. Scheidt, R. Xu, J. Am. Chem. Soc. 2007, 129, 10029. 6. a) Y. Fujima, Y. Hirayama, M. Ikunaka, Y. ishimoto, Tetrahedron: Asymmetry 2003, 14, 1385. b) M. Sebek, J. Holz, A. Börner, K. Jähnisch, Synlett 2009, 461. c) P. C. Bélanger, H. W. R. Williams, Can. J. Chem. 1983, 61, 1383. S10

rac-3a (R)-3a rac-3b (R)-3b S11

rac-3c (R)-3c rac-3d (R)-3d S12

Et 2 C Et 2 C rac-3e Et 2 C Et 2 C (R)-3e rac-3f (R)-3f S13

rac-s8 (R)-S8 rac-1 H Me rac-methyl ester (R)-1 H Me (R)-Methyl ester S14

12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 1.0 2.0 7.4732 7.4640 7.4571 7.4468 7.2865 7.2842 7.2773 7.2693 7.2670 7.2636 7.1754 3.6908 3.6759 3.6610 3.6450 3.2005 3.1822 3.1638 1.8293 1.8156 1.8007 1.7950 1.7767 1.7572 1.7389 1.6678 1.6529 1.6381 1.6323 1.6232 1.6163 1.6048 1.5991 0.0000 X : parts per Million : 1H S15

S16 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0 10.0 20.0 20.0881 31.8633 38.5280 61.9354 77.3146 77.0000 76.6758 129.3067 128.8586 128.6584 126.9421 125.7598 138.2311 142.6933 191.2815 X : parts per Million : 13C

12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 1.0 2.0 7.4709 7.4617 7.4537 7.2807 7.2670 7.2578 7.1685 3.3895 3.0504 3.0310 3.0252 3.0115 1.7022 1.6873 1.6816 1.6781 1.6621 0.9118 0.0000 X : parts per Million : 1H S17

S18 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0 10.0 20.0 24.2833 35.2671 34.7618 32.5975 77.3242 77.2098 77.0000 76.6854 70.2018 129.3639 128.9539 128.8109 126.9517 125.8361 138.2406 142.3309 191.7963 X : parts per Million : 13C

12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 1.0 2.0 7.4743 7.4663 7.4583 7.4308 7.4102 7.3919 7.2865 7.2796 7.2704 7.2624 7.1605 7.0253 6.9760 4.7435 4.0333 3.9061 3.8878 3.8706 3.7240 3.6954 3.5189 3.5018 3.4445 3.4113 2.9748 2.9611 2.9554 2.9485 2.9347 2.5258 1.8408 1.8282 1.8099 1.7961 1.7904 1.7847 1.7698 1.7263 1.6461 1.6358 1.6140 1.5521 1.5430 1.5350 1.5109 1.5017 1.4479 1.4364 1.3391 1.3276 1.2703 1.2532 1.1684 0.0000 0.0080 X : parts per Million : 1H S19

S20 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0 10.0 20.0 21.4515 37.5268 34.1707 32.7691 29.5273 26.4191 67.9040 77.3146 77.0000 76.6854 129.3067 128.9444 128.8300 126.8945 125.8266 138.1834 142.1307 192.0347 X : parts per Million : 13C

12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 1.0 2.0 7.4663 7.4629 7.4594 7.4560 7.4468 7.2979 7.2956 7.2910 7.2796 7.2762 7.2739 7.2636 7.2567 7.2498 7.2452 7.2406 7.2372 7.2315 7.2269 7.2212 7.2097 7.1948 7.1891 7.1845 7.1754 7.1719 7.1376 7.1353 4.2773 4.2635 2.9554 2.9451 2.9359 2.9302 2.9244 2.9153 2.6415 2.6266 2.6209 2.6014 0.0000 X : parts per Million : 1H S21

S22 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0 10.0 20.0 30.3378 35.0383 51.1041 67.9994 77.3242 77.0000 76.6854 138.1739 129.2972 128.8490 128.7251 128.1435 127.9719 126.8563 126.1984 125.8075 145.4583 142.3023 191.1384 X : parts per Million : 13C

12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 1.0 2.0 7.4720 7.4686 7.4640 7.4560 7.2853 7.2819 7.2762 7.2693 7.2613 7.2544 7.1765 4.2326 4.2143 4.1971 4.1788 4.0527 3.1696 3.1501 3.1306 2.3838 2.3643 2.3460 1.2692 1.2520 1.2337 0.0000 X : parts per Million : 1H S23

S24 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0 10.0 20.0 13.9383 24.9889 34.3042 63.4609 61.5063 58.8557 77.3146 77.0000 76.6758 129.4974 128.9158 128.8300 127.1042 125.8170 138.0785 142.0830 170.3054 189.9562 X : parts per Million : 13C

12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 1.0 2.0 7.4743 7.4686 7.4640 7.4571 7.2693 7.2670 7.2647 7.2590 7.2544 7.2475 7.1582 7.1559 3.8019 3.7858 3.7721 3.7561 3.1547 2.8191 2.8053 1.6701 1.6541 1.6369 1.0642 0.0000 X : parts per Million : 1H S25

S26 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0 10.0 20.0 28.6215 33.7798 43.1904 48.7300 59.8187 77.3146 77.0000 76.6854 129.2686 129.0111 128.7442 127.2186 125.7980 138.5266 143.9709 191.5484 X : parts per Million : 13C

12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 1.0 2.0 7.4594 7.4514 7.4434 7.2991 7.2910 7.2876 7.2807 7.2739 7.2132 5.6106 5.5969 5.5900 5.5751 4.0310 4.0115 3.9932 3.9886 3.9726 3.9554 3.9348 2.4914 2.4708 2.4594 2.4536 2.4399 2.4330 2.4216 2.4009 2.1180 2.1031 2.0985 2.0836 2.0676 2.0573 2.0516 2.0367 1.9886 1.9748 1.9588 1.9428 1.9244 1.9084 1.8924 0.0000 X : parts per Million : 1H S27

S28 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0 10.0 20.0 25.4942 30.1852 69.6012 79.6411 77.3242 77.0000 76.6854 129.9550 128.8967 128.7632 127.0661 125.7884 141.1868 137.8878 189.9562 X : parts per Million : 13C

12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 1.0 2.0 7.4709 7.4640 7.4594 7.4560 7.4514 7.4480 7.4445 7.4377 7.3220 7.3117 7.3025 7.2979 7.2945 7.2910 7.2876 7.2658 7.2624 7.2120 7.2097 5.6874 5.6667 5.6461 3.6633 3.6415 3.6381 3.6175 2.3173 2.2990 2.2967 2.2875 2.2669 1.8557 1.8339 1.8248 1.8030 1.1867 1.0756 0.0000 X : parts per Million : 1H S29

12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 1.0 2.0 7.4606 7.4514 7.4445 7.4354 7.3185 7.3082 7.2979 7.2910 7.2842 7.2658 7.2097 5.6312 5.6106 5.5889 3.8019 3.7813 3.6736 3.6530 2.4239 2.4032 2.3918 2.3712 1.7870 1.7663 1.7549 1.7343 1.5567 1.5281 1.4101 1.4021 1.3608 0.0000 X : parts per Million : 1H S31

S32 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0 10.0 20.0 25.9995 24.1594 23.3680 35.2671 34.9430 44.2487 42.2655 79.4218 79.1930 77.3242 77.0000 76.6854 129.9741 128.9349 128.7823 127.0756 125.8361 141.3203 137.9260 189.9657 X : parts per Million : 13C

12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 1.0 2.0 7.4457 7.4388 7.4297 7.4228 7.3838 7.3644 7.3197 7.3002 7.2865 7.2807 7.2590 7.2475 7.2406 7.2177 7.2120 7.2097 7.1994 7.1902 7.1834 7.1799 7.1628 5.6610 5.6427 5.6381 5.6198 4.7458 4.7240 4.2773 4.2555 3.2085 3.1902 3.1776 3.1581 2.7961 2.7732 2.7652 2.7412 0.0000 X : parts per Million : 1H S33

S34 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0 10.0 20.0 42.7518 56.0144 79.6506 78.0869 77.3242 77.0000 76.6854 145.6967 144.7241 141.2726 137.8402 130.1267 128.9539 128.8204 128.4295 128.3914 127.2949 127.2091 127.0756 126.5226 126.3891 125.8075 189.2411 X : parts per Million : 13C

12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 1.0 2.0 7.4629 7.4549 7.4526 7.4468 7.4434 7.3323 7.3289 7.3243 7.3220 7.3185 7.3151 7.3082 7.3059 7.2658 7.2258 7.2235 5.6897 5.6736 5.6679 5.6519 4.4800 4.4571 4.3815 4.3586 4.2715 4.2532 4.2360 4.2177 4.1730 4.1547 4.1375 4.1192 3.1100 3.0882 3.0756 3.0539 2.8145 2.7984 2.7813 2.7652 1.6507 1.2944 1.2761 1.2589 1.2199 1.2028 1.1844 0.0000 X : parts per Million : 1H S35

S36 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0 10.0 20.0 13.9764 13.9002 37.2599 62.0879 61.9354 60.8389 80.0987 77.3146 77.0000 76.6758 74.0347 130.1839 128.9253 128.8395 127.2186 125.8361 140.8817 137.7543 169.7238 169.1803 187.7060 X : parts per Million : 13C

12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 1.0 2.0 7.4652 7.4571 7.4491 7.3025 7.2945 7.2876 7.2796 7.2704 7.2658 7.1948 5.4697 4.1822 4.1707 4.1616 4.1501 4.1409 4.1295 4.0241 4.0058 3.9863 3.9668 1.9050 1.8843 1.8752 1.8637 1.8545 1.8339 1.7744 1.7629 1.7572 1.7457 1.7331 1.7263 1.7159 1.3471 0.9611 0.0000 X : parts per Million : 1H S37

12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 1.0 2.0 7.2636 4.4731 4.4674 4.4605 4.4525 4.4399 4.1662 4.1627 4.1501 4.1455 4.1329 4.1295 4.1192 4.0527 4.0321 4.0149 4.0058 3.9978 3.9497 3.9348 3.9302 3.9164 3.9107 3.8958 2.2944 2.2784 2.2738 2.2635 2.2578 2.2486 2.2429 2.2371 2.2291 2.2223 2.0550 2.0355 2.0218 2.0195 2.0058 1.9886 1.9817 1.9645 1.9496 1.9382 1.9313 1.9221 1.9141 1.9084 1.9050 1.8924 1.8878 1.6747 1.6587 1.6518 1.6403 1.6209 1.6037 1.4319 1.4124 1.3941 1.3746 1.3563 1.3379 0.9565 0.9382 0.9198 0.0000 X : parts per Million : 1H S39

S40 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0 10.0 20.0 13.6713 19.0488 25.2082 30.5952 30.2043 64.7385 77.3146 77.0000 76.7426 76.6854 69.3151 173.5186 X : parts per Million : 13C

12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 1.0 2.0 10.5488 10.4824 7.2830 4.5327 4.5258 4.5190 4.5109 4.4972 4.0745 4.0711 4.0631 4.0573 4.0539 4.0505 4.0413 4.0367 4.0333 4.0207 4.0161 4.0092 3.9771 3.9680 3.9600 3.9577 3.9439 3.9405 3.9233 3.9199 3.9141 2.3769 2.3735 2.3654 2.3563 2.3460 2.3368 2.3242 2.3196 2.3070 2.3036 2.2864 2.2830 2.2749 2.1581 2.1535 2.1409 2.1363 2.1260 2.1226 2.1180 2.1088 2.1043 2.0951 2.0905 2.0825 2.0779 2.0642 2.0023 1.9943 1.9840 1.9668 1.9519 1.9485 1.9359 1.9313 0.0000 X : parts per Million : 1H S41

S42 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0 10.0 20.0 25.2749 30.1280 77.3146 77.0000 76.6758 76.2849 69.6202 177.9426 X : parts per Million : 13C