Supporting Information
Lipase-catalyzed kinetic resolution of boron-containing chiral alcohols Leandro H. Andrade* and Thiago Barcellos Institute of Chemistry, University of São Paulo Av. Prof. Lineu Prestes, 748, CEP 05508-900, São Paulo, SP, Brasil. *
[email protected] Table of Contents General Techniques Synthetic Procedures Enzymatic Procedures and Chromatograms 1 H, 13C and 11B NMR Spectra of new compounds
S1
S2 S4 S16 S35
1
General Techniques
Unless otherwise noted, commercially available materials were used without further purification. Lipase from Candida antarctica (lipase B, CAL-B) immobilized and commercially available as Novozym® 435 was kindly donated by Novozymes Latin America Ltda. Others enzymes was purchased from the Sigma-Aldrich Chemical Company and stored at 4 °C. All solvents were HPLC or ACS grade. Solvents used for moisture sensitive operations were distilled from drying reagents under a nitrogen atmosphere: THF was distilled from Na/benzophenone. CH2Cl2 was distilled from CaH2. Analytical thin-layer chromatography (TLC) was performed by using aluminum-backed silica plates coated with a 0.25 mm thickness of silica gel 60 F254 (Merck), visualized with an ultraviolet light (λ = 254 nm), followed by exposure to p-anisaldehyde solution, potassium permanganate solution, or vanillin solution and heating. Standard chromatographic purification procedures were followed using 35-70 μm (240400 mesh) silica gel purchased from Acros Organics®. Nuclear magnetic resonance (NMR) spectra were recorded on a Varian Gemini 200 or Bruker DRX 500 spectrometer at operating frequencies of 200 and 500 MHz (1H NMR) or 50 and 125 MHz (13C NMR). The 1H NMR chemical shifts are reported in ppm relative to TMS peak. Data are reported as follows: chemical shift (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, sext = sextuplet, m = multiplet, br = broadened signal), and coupling constant (J) in Hertz and integrated intensity. The 13C NMR chemical shifts are reported in ppm relative to CDCl3 or DMSO-d6 signal. The 11B NMR spectra were obtained on a Varian Inova 300 spectrometer equipped with the appropriate decoupling accessories. All 11B chemical shifts were referenced to external BF3.OEt2 (0.00 ppm). A note about 13C NMR spectra: Due to the boron quadrupole, carbons directly attached to this element are often not detected in 13C spectra.1 Melting points were determined on a Buchi melting point apparatus, model B-545 and are uncorrected. Infrared spectra were recorded from KBr discs or from a thin film between NaCl plates on a Bomem Michelson model 101 FTIR spectrometer with internal referencing. Absorption maxima (νmax) are reported in wavenumbers (cm-1). Low-resolution mass spectra were obtained on a GC/MS Shimadzu spectrometer, operating at 70 eV. High-resolution mass spectra (HRMS) were acquired using a Bruker Daltonics MicroTOF instrument, operating electrospray ionization (ESI) mode. Optical rotations were measured on a Perkin Elmer-343 digital polarimeter in a 1 mL cuvette with a 1 dm pathlength. All values are reported in the following format: [α]D(temperature of measurement) = specific rotation (concentration of the solution reported in units of 10 mg sample per 1 mL solvent used). Gas chromatography (GC) analyses for measurement of enantiomeric excesses were obtained using a Shimadzu 17-A Gas Chromatograph, equipped with autosampler, Flame 1
Wrackmeyer, B. Prog. In NMR espectroscopy 1979, 12, 227.
S2
Ionization Detector (FID), and a chiral column Varian CP-Chirasil-DEX CB β-ciclodextrin (25 m x 0.32 mm x 0.25μm). Temperature of the detector and injector was 220 º C; flow = 100 kPa, H2. High performance liquid chromatograph (HPLC) analyses for measurement of enantiomeric excesses were performed on a Shimadzu, LC-10AD liquid chromatograph equipped with autosampler and a variable wavelength UV detector (deuterium lamp 190-600 nm). Chiral columns: Chiralcel® OJ-H (0.46 cmφ x 25 cm) or Chiralcel® OD (0.46 cmφ x 25 cm) from Daicel Chemical Ind. i-PrOH and hexane (60% n-hexane) HPLC grade purchased from J. T. Baker were used as the eluting solvents. The enantioselectivity of the lipase-catalyzed reaction can be described by enantiomeric ratio (E, E-value). The E-value is defined as the ratio of specificity constant for the two enantiomers and can be expressed in terms of eeS and eeR (Equation 1).2
⎛ ⎜ 1 − eeS ln⎜ ⎜ eeS ⎜1+ ⎝ eeR
⎞ ⎟ ⎟ ⎟ ⎟ ⎠ E= ⎛ ⎞ ⎜ ⎟ 1 + eeS ⎟ ⎜ ln ⎜ eeS ⎟ ⎜1+ ⎟ ⎝ eeR ⎠
Equation 1
Reference 4b: Dorsey, B. D.; Iqbal, M.; Chatterjee, S.; Menta, E.; Bernardini, R.; Bernareggi, A.; Cassara, P. G.; D’Arasmo, G.; Ferretti, E.; De Munari, S.; Oliva, A.; Pezzoni, G.; Allievi, C.; Strepponi, I.; Ruggeri, B.; Ator, M. A.; Williams, M.; Mallamo, J. P. J. Med. Chem. 2008, 51, 1068.
2
(a) Chen, C-S., Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294. (b) Straathof, A. J. J.; Jongejan, J. A. Enzyme Microb. Technol. 1997, 21, 559.
S3
Synthetic Procedures 1.1
General procedure for esterification reaction of acetylphenyl boronic acids.
To a 50 mL, two-necked, round-bottomed flask containing anhydrous THF (30 mL) were added the appropriate acetylphenyl boronic acid (6 mmol, 983 mg) and the appropriate diol (6 mmol). The resultant solution was evaporated under reduced pressure at 40 ºC. This procedure was repeated (3 times) until TLC analysis indicated a complete conversion. The crude product was purified by column chromatography using hexanes/EtOAc (8:2) as eluent. 1.1.1 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone (4a).3 Yield: 1.447 g (98%), white solid (mp = 66.3 - 67.7 °C). 1 H NMR (200 MHz, CDCl3) δ = 1.36 (s, 12H), 2.61 (s, 3H), 7.92 (s, 4H). 13 C NMR (50 MHz, CDCl3) δ = 24.81, 26.69, 84.16, 127.22, 134.87, 138.95, 198.37. 11 B NMR (96 MHz, CDCl3) δ = 30.59. FT-IR (KBr) νmax = 2986, 1661, 1509, 1398, 1358, 1267, 1142, 1092,959, 857, 830, 654 cm-1. LRMS (EI) m/z (%) = 246(2, M+), 231(15), 160(16), 147(48), 131(17), 85(16), 77(15), 42(100). 1.1.2 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone (4b).4 Yield: 1.461 g (99%), white solid (mp = 50.7 - 52.5 °C). 1 H NMR (200 MHz, CHCl3) δ = 1.36 (s, 12H), 2.63 (s, 3H), 7.47 (t, J=7.4Hz, 1H), 7.97-8.09 (m, 2H), 8.36 (s, 1H). 13 C NMR (50 MHz, CDCl3) δ = 25.07, 26.92, 84.34, 130.94, 134.99, 136.72, 139.58, 142.62, 198.56. 11 B NMR (96 MHz, CDCl3) δ = 30.69. FT-IR (KBr) νmax = 2967, 1685, 1596, 1357, 1322, 1250, 1149, 959, 862, 702, 593 cm-1. LRMS (EI) m/z (%) = 246 (15) [M+], 231(100), 203(42), 185(14), 160(4), 147(55), 131(12), 85(7), 77(4).
3
(a) Claudel, S.; Gosmini, C.; Paris, J. M.; Périchon, J. Chem. Commun 2007, 3667. (b) Ma, Y.; Song, C.; Jiang, W.; Xue, G.; Cannon, J. F.; Wang, X.; Andrus, M. B. Org. Lett. 2003, 5, 4635. (c) Murata, M.; Oyama, T.; Watanabe, S., Masuda, Y. J. Org. Chem. 2000, 65, 164. (d) Ishiyama, I. Murata, M., Miyaura, N. J. Org. Chem. 1995, 60, 7508. 4 Murata, M.; Oyama, T.; Watanabe, S., Masuda, Y. J. Org. Chem. 2000, 65, 164.
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1.1.3 1-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)ethanone (4c).5 Yield: 1.351 g (97%), white solid (mp = 89.2 – 90.7 °C). 1 H NMR (200 MHz, CHCl3) δ = 1.03 (s, 6H), 2.61 (s, 3H), 3.78 (s, 4H), 7.90 (s, 4H). 13 C NMR (50 MHz, CDCl3) δ = 23.63, 26.86, 33.06, 72.55, 127.60, 134.40, 138.77, 198.77. 11 B NMR (96 MHz, CDCl3) δ = 26.54. FT-IR (KBr) νmax = 2962, 1678, 1477, 1250, 1133, 835, 694, 644 cm-1. LRMS (EI) m/z (%) = 232(20, M+), 217(100), 189(6), 147(10), 121(15), 103(12), 77(11), 69(27). 1.1.4 1-(3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)ethanone (4d).6 Yield: 1.337 g (96%), white solid (mp = 56.7 – 57.5 °C). 1 H NMR (200 MHz, CHCl3) δ = 1.03 (s, 6H), 2.63 (s, 3H), 3.78 (s, 4H), 7.44 (t, J = 7.2 Hz, 1H), 8.01 (t, J = 7.2 Hz, 2H), 8.37 (s, 1H). 13 C NMR (50 MHz, CDCl3) δ = 22.17, 26.97, 32.08, 72.52, 128.03, 130.58, 134.42, 136.56, 138.91, 198.81. 11 B NMR (96 MHz, CDCl3) δ = 26.63. FT-IR (KBr) νmax = 2971, 1677, 1484, 1426, 1255, 1136, 811, 700, 595 cm-1. LRMS (EI) m/z (%) = 232(10, M+), 217(100), 189(2), 147(7), 121(13), 102(7), 77(8), 69(30). 1.2
General procedure to reduction of pinacolyl and neopentyl acetylphenyl boronate esters.
To a 100 mL round-bottomed flask containing anhydrous methanol (1.5 mL) cooled at 0 °C with an ice bath, was added NaBH4 (4 mmol, 160 mg) followed by slow addition of a solution of the boronate ester (2 mmol in methanol, 1.5 mL). The mixture was stirred for 0.5 h at 0 °C, and additional 4 h at room temperature. The mixture was cooled to 0 °C and treated with 1N HCl until pH = 7. The mixture was then extracted with EtOAc (3 x 5 mL), dried with anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography using hexanes/EtOAc (8:2) as eluent.
5 6
(a) Shi, B.; Boyle, R. W. J. Chem. Soc., Perkin Trans. 1 2002, 1397. (b) Kabalka, G. W.; Akula, M. R.; Zhang, J. Nucl. Med. Biol. 2002, 29, 841. Kitamura, Y.; Sakurai, A.; Udzu, T.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Tetrahedron 2007, 63, 10596.
S5
1.2.1 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol (1a). Yield: 486 mg (98%), white solid (mp = 79.6 – 81.2 °C). 1 H NMR (200 MHz, CDCl3) δ = 1.33 (s, 12H), 1.47 (d, J = 6.4 Hz, 3H), 1.99 (s, 1H), 4.90 (q, J = 6.4 Hz, 1H), 7.37 (d, J = 8 Hz, 2H), 7.79 (d, J = 8 Hz, 2H). 13 C NMR (50 MHz, CDCl3): δ = 25.0, 25.33, 70.53, 83.95, 124.83, 135.20, 149.16. 11 B NMR (96 MHz, CDCl3) δ = 30.87. FT-IR (KBr) νmax = 3330, 2978, 1516, 1362, 1323, 1144, 1093, 859, 661 cm-1. LRMS (EI) m/z (%) = 248(7) [M+], 233(100), 165(35), 149(67), 133(28), 101(24), 84(28). HRMS (ESI): Calculated for C14H21BO3Na [M + Na]+ = 271.1481; found: 271.1474. 1.2.2 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol (1b). Yield: 486 mg (98%), colourless oil. 1 H NMR (200 MHz, CHCl3) δ = 1.34 (s, 12H); 1.49 (d, J = 6.4 Hz, 3H), 2.00 (br, 1H), 4.91 (q, J = 6.4 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H) 7.92 (s, 1H). 13 C NMR (50 MHz, CDCl3): δ = 25.00, 25.30, 70.47, 83.98, 128.10, 128.48, 131.93, 134.07, 145.30. 11 B NMR (96 MHz, CDCl3) δ = 30.91. FT-IR (KBr) νmax = 3232, 2978, 1358, 1200, 1144, 864, 710 cm-1. LRMS (EI) m/z (%) = 248(6) [M+], 233(100), 165(31), 149(39), 133(27), 101(27), 84(24). HRMS (ESI): Calculated for C14H21BO3Na [M + Na]+ = 271.1481; found: 271.1472. 1.2.3 1-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)ethanol (1c) Yield: 224 mg (48%), white solid (mp = 61.2 – 63.5 °C). 1 H NMR (200 MHz, CDCl3) δ = 1.01 (s, 6H), 1.47 (d, J = 6.4 Hz, 3H), 2.01 (br, 1H), 3.75 (s, 4H), 4.88 (q, J = 6.4 Hz, 1H), 7.34 (d, J = 7.8 Hz, 2H), 7.78 (d, J = 7.8 Hz, 2H). 13 C NMR (50 MHz, CDCl3): δ = 22.07, 25.27, 32.05, 70.61, 72.48, 124.75, 134.31, 148.50. 11 B NMR (96 MHz, CDCl3) δ = 26.79. FT-IR (KBr) νmax = 3289, 2974, 1609, 1479, 1425, 1316, 1249, 1133, 1091, 834, 647 cm-1. LRMS (EI) m/z (%) = 234(10) [M+], 219(100), 133(15), 104(52), 91(29), 77(13), 69(56). HRMS (ESI): Calculated for C13H19BO3Na [M + Na]+ = 257.1325; found: 257.1319 1.2.4 1-(3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)ethanol (1d) Yield: 253 (54%), white solid (mp = 88 - 89 °C). 1 H NMR (200 MHz, CHCl3) δ = 1.01 (s, 6H), 1.49 (d, J = 6.4 Hz, 3H), 2.02 (s, 1H), 3.76 (s, 4H), 4.88 (q, J = 6.4 Hz, 1H), 7.29 – 7.49 (m, 2H), 7.68 – 7.78 (m, 2H). 13 C NMR (50 MHz, CDCl3): δ = 22.07, 25.26, 32.04, 70.72, 72.48, 127.94, 128.00, 131.02, 133.23, 145.05. 11 B NMR (96 MHz, CDCl3) δ = 26.78 FT-IR (KBr) νmax = 3409, 2971, 1601, 1485, 1428, 1310, 1251, 1195, 1129, 1086, 1007, 813, 711 cm-1. S6
LRMS (EI) m/z (%) = 234(3) [M+], 219(38), 133(23), 104(65), 91(37), 77(20), 69(70). HRMS (ESI): Calculated for C13H19BO3Na [M + Na]+ = 257.1325; found: 257.1319.
1.3
General procedure to acetylation of boronate esters (RS)-3a-d.7
A 25 mL, two-necked, round-bottomed flask was charged with boronate ester 1 (0.5 mmol, 124 mg for 1a,b or 117 mg for 1c,d), N-bromosuccinamide (10 mol%; 50 μmol, 8.8 mg) and anhydrous dichloromethane (3 mL) under dry nitrogen atmosphere. Acetic anhydride (1 mmol, 100 μL) was then added and the mixture was stirred for 12 h. Dichloromethane (10 mL) was added and the resulting solution was washed with 5% NaHCO3 (2 x 2 mL). The organic layer was dried over anhydrous MgSO4, filtrated and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography using hexanes/EtOAc (9:1) as eluent. 1.3.1 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl acetate (2a). Yield: 139 mg (96%), white solid (mp = 82.7 - 83.7 °C). 1 H NMR (200 MHz, CDCl3) δ = 1.33 (s, 12H), 1.52 (d, J = 6.6 Hz, 3H), 2.07 (s, 3H), 5.88 (q, J = 6,6 Hz,1H), 7.35 (d, J = 7.8 Hz, 2H), 7.80 (d, J = 7.8 Hz, 2H). 13 C NMR (50 MHz, CDCl3): δ = 21.46, 22.36, 25.00, 72.43, 83.96, 125.48, 135.19, 144.93, 170.42. 11 B NMR (96 MHz, CDCl3) δ = 30.81. FT-IR (KBr) νmax = 2984, 1750, 1359, 1233, 1140, 1090, 1019, 855, 654 cm-1. LRMS (EI) m/z (%) = 290(2) [M+], 275(2), 248(17), 231(5), 215(7), 165(15), 144(46), 131(56), 105(18), 83(42), 58(37), 42(100). HRMS (ESI): Calculated for C16H23BO4Na [M + Na]+ = 313.1587; found: 313.1578. 1.3.2 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl acetate (2b). Yield: 130 mg (90%), colourless oil. 1 H NMR (200 MHz, CDCl3) δ = 1.34 (s, 12H), 1.53 (d, J = 6.6 Hz, 3H), 2.06 (s, 3H), 5.89 (q, J = 6.6 Hz, 1H), 7.31-7.48 (m, 2H), 7.71-7.80 (m, 2H).
7
Babak, K.; Hassan, S. Synlett 2001, 519.
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C NMR (50 MHz, CDCl3): δ = 21.54, 22.37, 25.06, 72.60, 84.04, 128.07, 129.23, 132.58, 134.57, 141.11, 170.50. 11 B NMR (96 MHz, CDCl3) δ = 30.81. FT-IR (KBr): νmax = 2980, 1742, 1371, 1241, 1145, 709 cm-1. LRMS (EI) m/z (%) = 290(24) [M+], 275(16), 248(96), 231(41), 215(39), 204(20), 190(19), 165(37), 144(82), 131(100), 105(36), 84(40). HRMS (ESI): Calculated for C16H23BO4Na [M + Na]+ = 313.1587; found: 313,1579. 13
1.3.3 1-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)ethyl acetate (2c). Yield: 126 mg (92%), colourless oil. 1 H NMR (200 MHz, CDCl3) δ = 1.00 (s, 6H), 1.52 (d, J = 6.8 Hz, 3H), 2.06 (s, 3H), 3.75 (s, 4H), 5.88 (q, J = 6.8 Hz, 1H), 7.33 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 8.2 Hz, 2H). 13 C NMR (50 MHz, CDCl3): δ = 21.17, 21.71, 22.02, 31.71, 72.14, 125.05, 133.94, 143.91, 170.13. 11 B NMR (96 MHz, CDCl3) δ = 26.66. FT-IR (KBr) νmax = 2958, 1735, 1613, 1478, 1422, 1247, 1135, 1068, 1021, 948, 831, 706, 643 cm-1. LRMS (EI) m/z (%) = 276(12) [M+], 261(2), 234(57); 216(74), 173(15), 146(17), 130(86), 117(15), 104(64), 77(16), 56(84). HRMS (ESI): Calculated for C15H21BO4Na [M + Na]+ = 299.1430; found: 299.1428. 1.3.4 1-(3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)ethyl acetate (2d). Yield: 123 mg (89%), colourless oil. 1 H NMR (200 MHz, CDCl3) δ = 1.02 (s, 6H), 1.54 (d, J = 6.6 Hz, 3H), 2.06 (s, 3H), 3.76 (s, 4H), 5.89 (q, J = 6.6 Hz, 1H), 7.29-7.45 (m, 2H), 7.70-7.82 (m, 2H). 13 C NMR (50 MHz, CDCl3): δ = 21.58. 22.10, 22.36, 32.05, 72.49, 72.72, 127.94, 128.71, 131.75, 133.67, 140.86, 170.53. 11 B NMR (96 MHz, CDCl3) δ = 26.83. FT-IR (KBr) νmax = 2963, 1732, 1605, 1478, 1432, 1376, 1318, 1242, 1200, 1133, 1066, 944, 804, 710 cm-1. LRMS (EI) m/z (%) = 274(2) [M]+, 261(2), 233(87), 216(100), 173(18), 146(19), 130(72), 117(13), 104(42), 91(6), 77(9), 56(21). HRMS (ESI): Calculated for C15H21BO4Na [M + Na]+ = 299.1430; found: 299.1429.
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1.4
Reduction of acetylphenylboronic acids 3a,b The title compounds were prepared by adapting previously described procedure8 A 25 mL, two-necked, round-bottomed flask was charged with acetylphenylboronic acid
(1.00 g, 6.10 mmol), anhydrous EtOH (5.0 mL), and cooled at 0 °C with an ice bath, NaBH4 (579 mg, 15.2 mmol) was added portionwise. After stirring for 16 h, additional EtOH (5.0 mL) was added and the mixture was stirred for 4 h. The solution was cooled to 0 °C and treated with 1N HCl (30 mL, 30 mmol). The mixture was then extracted with EtOAc (3 X 15 mL), dried over anhydrous MgSO4, filtrated and concentrated under reduced pressure. The dried solids were triturated with THF (20 mL) and filtered to remove insoluble salts. 1.4.1 4-(1-hydroxyethyl)phenylboronic acid (1g) Yield: 942 mg (93 %), white waxy solid. 1 H NMR (200 MHz, DMSO-d6) δ = 1.33 (d, J = 6.4 Hz, 3H), 4.73 (q, J = 6.4 Hz, 1H), 7.33 (d, J = 8 Hz, 2H), 7.75 (d, J = 8 Hz, 2H). 13 C NMR (50 MHz, DMSO-d6): δ = 26.02, 68.46, 124.77, 134.28, 149.45. 11 B NMR (96 MHz, DMSO-d6) δ = 19.83. 1.4.2 3-(1-hydroxyethyl)phenylboronic acid (1h) Yield: 952 mg (94 %), white solid (mp = 98.2ºC) 1 H NMR (200 MHz, DMSO-d6) δ = 1.30 (d, J = 6.4 Hz, 3H), 4.68 (q, J = 6.4 Hz, 1H), 7.227.38 (m, 2H), 7.61 (d, J = 7 Hz, 1H), 7.72 (s, 1H). 13 C NMR (50 MHz, DMSO-d6): δ = 26.11, 68.71, 127.62, 127.66, 131.59, 132.84, 146.28. 11 B NMR (96 MHz, DMSO-d6) δ = 19.84. 1.5
Synthesis of 3-tert-butyldimethylsiloxy-1-butyne (5).9
A 25 mL, two-necked, round-bottomed flask was charged with anhydrous dichloromethane (20 mL) and propargylic alcohol 5 (10 mmol, 700 mg, 0.78 mL) under dry nitrogen atmosphere. Imidazole (11 mmol, 749 mg) was added at 0 ºC followed by addition of tert-butyldimethylchloride (11 mmol, 1,65 g). The mixture was stirred for 5 h. Water (5 mL) was added followed by extraction with hexanes (4 x 15 mL). The combined organic layers were dried over anhydrous MgSO4, filtrated and concentrated under reduced pressure. The
8 9
Molander, G. A.; Petrillo, D. E. J. Am. Chem Soc. 2006, 128, 9634. Schone, N.; Pietrszka, J. Eur. J. Org. Chem. 2004, 5011.
S9
crude product was purified by column chromatography using hexanes as eluent. The compound 5 was obtained as colourless oil. Yield: 1.509 mg (82%). H NMR (200 MHz, CHCl3) δ = 0.08 (s, 3H), 0.12 (s, 3H), 0.9 (s, 9H); 1.44 (d, J = 6.6 Hz, 3H), 2.38 (d, J = 2 Hz , 1H), 4.52 (qd, J = 6.6 and 2 Hz, 1H). 13 C NMR (50 MHz, CDCl3): δ = -4.3, -3,2, 18.3, 25.6, 58.8, 70.9, 86.3. LRMS (EI) m/z (%) = 184(0.3) [M]+, 169(3), 125(87), 113(5), 101(27), 83(100). 1
S10
1.6
Synthesis of (E)-tert-butyldimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)but-3-en-2-yloxy)silane3-tert-butyldimethylsiloxy-1-butyne (6).10
A 25 mL, two-necked, round-bottomed flask was charged with pinacol (6.25 mmol, 799 mg) and anhydrous dichloromethane (2 mL) under dry nitrogen atmosphere. The solution was cooled at 0 °C with an ice bath, and BH3.SMe2 (5M in Et2O, 6.25 mmol, 1.25 mL) was added dropwise. The resultant solution was stirred for 3 h at 0 ºC.10a The protected propargylic alcohol 5 (5 mmol, 920 mg) was added slowly at 0 ºC. The reaction mixture was allowed to warm to room temperature, and stirred for an additional 12 h. Et2O (20 mL) was added followed by saturated aqueous NH4Cl solution (4 mL). The aqueous phase was extracted with Et2O (2 x 10 mL). The combined organic phases were washed with saturated aqueous NH4Cl solution (2 x 4 mL), brine (4 mL) and dried over anhydrous MgSO4, filtrated and concentrated under reduced pressure. The crude product was purified by column chromatography using hexanes/EtOAc (8:2) as eluent. The resulting product 6 was obtained as colourless oil. Yield: 1.263 g (81%).10b,c H NMR (200 MHz, CDCl3) δ = 0.05 (s, 9H), 0,90 (s, 9H), 1,21 (d, J = 6.6 Hz, 3H), 1.27 (s, 12H), 4.27 (m, 1H), 5.57 (dd, J = 18, 1.8 Hz, 1H), 6.55 (dd, J = 18, 3.8 Hz, 1H). 13 C NMR (50 MHz, CDCl3): δ = -4.63, -4.48, 18.49, 23.09, 24.95, 25,01, 26.12, 70.06, 83.31, 157.22. FT-IR (KBr) νmax = 2930, 28,57, 1642, 1369, 1337, 1254, 1146, 835, 775 cm-1. LRMS (EI) m/z (%) = 297(2) [M+- CH3], 255(30), 197(2), 155(100); 113(64), 75(92). HRMS (ESI): Calculated for C16H33BO3Si Na [M + Na]+ = 335.2189; found: 335.2193. 1
10
(a) Tucker, C. E.; Davidson, J.; Knochel, P. J. Org. Chem, 1992, 57, 3482. (b) Movassaghi, M.; Hunt, D. K.; Tjandra, M. J. Am. Chem. Soc. 2006, 128, 8126 (c) Fortineau, A.; Robert, M.; Guégan, J.; Carrié, D.; Mortier, J.; Vaultier, M. C. R. Acad. Sci. Paris, t.I 1998, 253.
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1.7
Synthesis (1e).10b
of
(E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-ol
OTBS
OH B
O
citric acid MeOH
B
3h, rt 78%
O
O
O (RS)-1e
(RS)-6
A 25 mL, two-necked, round-bottomed flask was charged with boronate ester 6 (2 mmol; 622 mg) and anhydrous MeOH (2 mL) under dry nitrogen atmosphere. To this solution was added anhydrous citric acid (2 mmol; 420 mg), and stirred for 3 h. To the reaction mixture was added EtOAc (5 mL). The organic layer was washed with water (2 x 1 mL) and dried over anhydrous MgSO4, filtrated and concentrated under reduced pressure. The crude product was purified by column chromatography using hexanes/EtOAc (4:1) as eluent. The resulting product 1e was obtained as colourless oil. Yield: 309 mg (78%). H NMR (200 MHz, CDCl3) δ = 1.24 (d, J = 5.6 Hz, 3H); 1.28 (s, 12H), 2.29 (br, 1H), 4.33 (m, 1H), 6.61 (dd, J = 18, 1.8 Hz, 1H), 6.65 (dd, J = 18, 3.8 Hz, 1H). 13 C NMR (50 MHz, CDCl3): δ = 22.77, 24.89, 69.68, 83.48, 156.46. 11 B NMR (96 MHz, CDCl3) δ = 29.97. FT-IR (KBr) νmax = 3438, 2978, 1644, 1361, 1326, 970, 849 cm-1. LRMS (EI) m/z (%) = 183(22) [M+- CH3], 155(4), 141(10), 98(100), 83(41), 55(80). HRMS (ESI): Calculated for C10H19BO3Na [M + Na]+ = 221.1325; found: 221.1315. 1
1.8
Synthesis of acetate (2e).
(E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-yl
O OH B O (RS)-1e
O
Ac2O NBS (10 mol%) CH2Cl2, 12h, rt 92%
O B
O
O (RS)-2e
The title compound was prepared according to the general procedure described in item 1.3, from boronate ester (RS)-1e (0.5 mmol, 99 mg). The crude product was purified by column chromatography using hexanes/EtOAc (9:1) as eluent. The resulting product (RS)-2e was obtained as colourless oil. Yield: 109 mg (92%).
S12
H NMR (200 MHz, CDCl3) δ = 1.27 (s, 12H), 1.32 (d, J = 6.6 Hz, 3H), 2.06 (s, 3H), 5.39 (m, 1H), 5.58 (dd, J = 18, 1.8Hz, 1H), 6.55 (dd, J = 18, 4.8Hz, 1H). 13 C NMR (50 MHz, CDCl3): δ = 19.75, 21.34, 24.92, 71.43, 83.57, 151.38, 170.38. 11 B NMR (96 MHz, CDCl3) δ = 29.84. FT-IR (KBr) νmax = 2980, 1741, 1645, 1371, 1333, 1238, 1146, 850 cm-1. LRMS (EI) m/z (%) = 225(2) [M+- CH3], 197(8), 140(27), 97(19), 83(20). HRMS (ESI): Calculated for C12H21BO4Na [M + Na]+ = 263.1430; found: 263.1420. 1
1.9
Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexan-2-ol (1f).
A 25 mL, two-necked, round-bottomed flask was charged with pinacol (15 mmol, 1.772 g) and anhydrous dichloromethane (10 mL) under dry nitrogen atmosphere. The solution was cooled with an ice bath, and BH3.SMe2 (5 M in Et2O, 15 mmol, 3 mL) was added dropwise. The resulting solution was stirred for 3 h at 0 ºC.10a 5-hexen-2-one (7) (5 mmol, 294 mg, 345 μl) was dropwise added and stirred for 1 h at 0 ºC. The reaction mixture was allowed to warm to room temperature, and stirred for an additional 24 h. Et2O (20 ml) and saturated aqueous NH4Cl solution (4 mL) was added. The aqueous phase was extracted with Et2O (2 x 10 mL). The combined organic phases were washed with saturated aqueous NH4Cl solution (2 x 4 mL), brine (4 mL) and dried over anhydrous MgSO4, filtrated and concentrated under reduced pressure. The crude product was purified by column chromatography using hexanes/EtOAc (4:1) as eluent. The resulting product (RS)-1f was obtained as colourless oil. Yield: 947 mg (83%). H NMR (500 MHz, CDCl3) δ = 0.79 (t, J = 7.6 Hz, 2H), 1.17 (d, J = 6.2 Hz, 3H ), 1.24 (s, 12H), 1.34-1.48 (m, 6H), 1.86 (br, 1H), 3.79 (sext, J = 6.2 Hz, 1H). 13 C NMR (125 MHz, CDCl3): δ = 23.49, 23.94, 24.71, 28.50, 39.17, 67.97, 83.07. 11 B NMR (96 MHz, CDCl3) δ = 35.15. FT-IR (KBr) νmax = 3442, 2977, 2931, 1463, 1373, 1320, 1146, 967, 847 cm-1. LRMS (EI) m/z (%) = 213(0,2) [M+- CH3], 195(0,9), 169(14), 154(10), 127(44), 101(27), 83(36), 58(100). HRMS (ESI): Calculated for C12H25BO3Na [M + Na]+ = 251.1794; found: 251.1792. 1
S13
1.10 Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexan-2-yl acetate (2f).
A 25 mL, two-necked, round-bottomed flask was charged with boronate ester (RS)-1f (0.5 mmol, 124 mg), Et3N (1.5 equiv.; 1.5 mmol, 210 μL), DMAP (10 mol%; 50 μmol, 8.8 mg) and anhydrous dichloromethane (3 mL) under dry nitrogen atmosphere. Acetic anhydride (1 mmol, 100 μL) was then added and the mixture was stirred for 12 h. Dichloromethane (10 mL) was added and the organic phase was washed with 5% NaHCO3 (2 x 2 mL). The organic layer was dried over anhydrous MgSO4, filtrated and concentrated under reduced pressure. The crude product was purified by column chromatography using hexanes/EtOAc (9:1) as eluent. The resulting product (RS)-2f was obtained as colourless oil. Yield: 120 mg (89%). H NMR (500 MHz, CDCl3) δ = 0.77 (t, J = 7.6 Hz, 2H), 1.19 (d, J = 6.2 Hz, 3H ), 1.24 (s, 12H), 1.28-1.61 (m, 6H), 2.01 (s, 3H), 4.88 (sext, J = 6.2 Hz, 1H). 13 C NMR (125 MHz, CDCl3): δ = 20.10, 21.54, 24.03, 24.98, 28.20, 35.87, 71.21, 83.06, 170.91. 11 B NMR (96 MHz, CDCl3) δ = 34.07. FT-IR (KBr) νmax = 2978, 2934, 1737, 1373, 1320, 1244, 1146, 968, 847 cm-1. LRMS (EI) m/z (%) = 255(2) [M+- CH3], 212(17), 169(52), 153(21), 129(42), 101(28), 87(46), 83(42), 69(28). HRMS (ESI): Calculated for C14H27BO4Na [M + Na]+ = 293.1900; found: 293.1902. 1
1.11 Suzuki-Miyaura cross-coupling reactions: Preparation of 1-(biphenyl-yl)ethanols 8a,b.
The title compounds were prepared by adapting a previously described procedure.11 A 10 mL round-bottomed flask equipped with reflux condenser was charged with appropriate boronate ester (RS)-1a,b (1 mmol, 248 mg), bromobenzene (1 mmol, 157 mg, 104 μL) and degassed i-PrOH (4 mL) under dry nitrogen atmosphere. After 15 min, palladium(II) acetate (10 μmol, 2.2 mg), Ph3P (20 μmol, 5.2 mg), degassed 2 M aqueous Na2CO3 (0,64 mL) 11
(a) Callam, C. S.; Lowary, T. L. J. Chem. Ed. 2001, 78, 947. (b) Kourist, R.; Gonzáles-Sabín, J.; Liz, R.; Rebolledo, F. Adv. Synth. Catal. 2005, 347, 695.
S14
and degassed water (0.4 mL) were added, and the mixture was refluxed for 2.5 h. After cooling to room temperature, the mixture was stirred under air for 10 min. EtOAc (10 mL) was added and transferred to a separatory funnel. The aqueous layer was extract with EtOAc (4 x 2 mL). The combined organic layer was, successively, washed with 5% aqueous Na2CO3 (3 x 4 mL) and brine (2 x 4 mL), and dried over anhydrous MgSO4. The organic layer was stirred for 20 min in the presence of activated carbon (100 mg). The resulting suspension was filtrated and concentrated under reduced pressure. The crude product was purified by column chromatography using chloroform/MeOH (98:2) as eluent. 1.11.1 1-(biphenyl-4-yl)ethanol (8a).11 Yield: 164 mg (83%), white solid (mp = 96.5-97.5 °C). 1 H NMR (200 MHz, CDCl3) δ = 1.52 (d, J = 6.6 Hz, 3H), 1.97 (br, 1H), 4.93 (q, J = 6.4 Hz, 1H), 7.33-7.62 (m, 9H). 13 C NMR (50 MHz, CDCl3): δ = 25.35, 70.35, 126.05, 127.28, 127.47, 128.97, 137.71, 140.65, 141.06, 145.02. LRMS (EI) m/z (%) = 198(47) [M+], 183(79), 180(48), 155(100), 152(36), 91(18), 77(40). 1.11.2 1-(biphenyl-3-yl)ethanol (8b).11 Yield: 156 mg (79%), colourless oil. 1 H NMR (200 MHz, CDCl3) δ = 1.49 (d, J = 6.4 Hz, 3H), 2.29 (br, 1H), 4.89 (q, J = 6.4 Hz, 1H), 7.27-7.60 (m, 9H). 13 C NMR (50 MHz, CDCl3): δ = 25.38, 70.55, 112.17, 124.42, 126.40, 127.33, 127.50, 128.92, 129.07, 141.26, 141.59, 146.52. LRMS (EI) m/z (%) = 198(50) [M+], 183(42), 155(100), 152(23), 91(16), 77(22).
S15
2 2.1
Enzymatic Procedures General procedure for small scale enzymatic reactions
A 50 mL flask was charged with the appropriate boronate ester (1a-f, 0.2 mmol), 10 mL of nhexane (HPLC grade) and CAL-B (enzyme amount as indicate in the tables 1 to 5) and vinyl acetate (3 equiv., 0.6 mmol, 55 μL). The reaction mixture was sealed with a rubber stopper and stirred on a rotary shaker (30 ºC, 150 rpm) until the appropriate time. After that, the mixture was filtered and the solvent evaporated under reduced pressure.
2.2
General procedure for preparative-scale enzymatic reactions
A 250 mL Erlenmeyer flask was charged with appropriate boronate ester (1a-f, 1.5 mmol), 75 mL of n-hexane (HPLC grade), CAL-B (150 mg), and vinyl acetate (3 equiv., 4.5 mmol, 412 μL). The reaction mixture was sealed with a rubber stopper and stirred on a rotary shaker (30 ºC, 150 rpm) until the appropriate time (Table 1-5). After that, the mixture was filtered and the solvent evaporated under reduced pressure. The ester (2) was separated from the remaining alcohol (1) by column chromatography using hexanes/EtOAc as eluent.
S16
2.2.1 Enzymatic kinetic resolution of (RS)-1a. The enantioenriched compounds (S)-1a and (R)-2a were prepared according to the method described in item 2.2. (S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol, [(S)-1a] Yield: 161 mg (43%), >99% ee, [α]D24 = -31.4 (c 1.0, CHCl3). HPLC condition: Chiralcel® OJ-H column, n-hexane/i-PrOH (95:5), 1.0 mL/min, 227 nm UV detector, tR = 10.6 min for (R) and tR = 12.6 min for (S).
OH
O
B O
(RS)-1a
OH
O
B O
(S)-1a
S17
(R)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl acetate, [(R)-2a] Yield: 186 mg (42.6%), >99% ee, [α]D24 = +81.8 (c 1.0, CHCl3). GC condition: oven 150-180 ºC, rate 1 ºC/min, tR = 18.1 min for (S) and tR = 18.7 min for (R).
O O
O
B O
(RS)-2a
O O
O
B O
(R)-2a
S18
2.2.2 Enzymatic kinetic resolution of (RS)-1b. The enantioenriched compounds (S)-1b and (R)-2b were prepared according to the method described in item 2.2. (S)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol, [(S)-1b] Yield: 159 mg (42.6%), >99% ee, [α]D24 = -27.2 (c 1.14, CHCl3) HPLC condition: Chiralcel® OJ-H column, n-hexane/i-PrOH (95:5), 1.0 mL/min, 227 nm UV detector, tR = 8,6 min for (S) and tR = 22.5 min for (R).
OH
B O
(RS)-1b O
OH
(S)-1b O
B
O
S19
(R)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl acetate [(R)-2b] Yield: 186 mg (42.6%), >99% ee, [α]D24 = +66.8 (c 1.0, CHCl3). GC condition: oven 150-180 ºC, rate 1 ºC/min, tR = 14.2 min for (S) and tR = 14.8 min for (R).
O O
(RS)-1b O
B
O
O O
(R)-1b O
B
O
S20
2.2.3 Enzymatic kinetic resolution of (RS)-1c. The enantioenriched compounds (S)-1c and (R)-2c were prepared according to the method described in item 2.2 (S)-1-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)ethanol, [(S)-1c] Yield: 137 mg (39%), >99% ee, [α]D23 = -27.9 (c 1.0, CHCl3). HPLC condition: Chiralcel® OJ-H column, n-hexane/i-PrOH (95:5), 1.0 mL/min, 227 nm UV detector, tR = 23.3 min for (S) and tR = 25.4 min for (R).
OH
O
B
(RS)-1c
O
OH
O
B O
(S)-1c
S21
(R)-1-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)ethyl acetate, [(R)-2c] Yield: 174 mg (42%), >99% ee, [α]D23 = +95.8 (c 1.0, CHCl3). GC condition: isotherm 170 ºC, tR = 17.2 min for (S) and tR = 17.9 min for (R).
O O
O
B O
(RS)-2c
O O
O
B
(R)-2c
O
S22
2.2.4 Enzymatic kinetic resolution of (RS)-1d. The enantioenriched compounds (S)-1d and (R)-2d were prepared according to the method described in item 2.2 (S)-1-(3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)ethanol, [(S)-1d] Yield: 123 mg (35%), >99% ee, [α]D23 = -22.1 (c 1.0, CHCl3). HPLC condition: Chiralcel® OJ-H column, n-hexane/i-PrOH (95:5), 1.0 mL/min, 227 nm UV detector, tR = 14.9 min for (S) and tR = 24.3 min for (R).
OH
O
B
(RS)-1d O
OH
O
B
(S)-1d O
S23
(R)-1-(3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)ethyl acetate, [(R)-2d] Yield: 170 mg (41%), >99% ee, [α]D23 = +67.4 (c 1.0, CHCl3). GC condition: isotherm 160 ºC, tR = 22.5 min for (S) and tR = 23.4 min for (R).
O O
(RS)-2d O
B
O
O O
(R)-2b O
B
O
S24
2.2.5 Enzymatic kinetic resolution of (RS)-1e. The enantioenriched compounds (S)-1e and (R)-2e were prepared according to the method described in item 2.2. (S)-(E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-ol, [(S)-1e] Yield: 136 mg (45%) >99% ee, [α]D24 = +11.8 (c 1.0, MeOH). Lit.10c [α]D25 = +5.4 (c 1.0, MeOH). HPLC condition: Chiralcel® OJ-H column, n-hexane/i-PrOH (99.5:0.5), 0.5 mL/min, 220 nm UV detector, tR = 13.3 min for (R) and tR = 15.8 min for (S).
OH O
B O
(RS)-1e
OH O
B O
(S)-1e
S25
(R)-(E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-ol, [(R)-2e] Yield: 155 mg (43%) >98% ee, [α]D24 = +42.5 (c 1.0, MeOH). GC condition: oven 100-150 ºC, rate 2 ºC/min,, tR = 19.4 min for (S) and tR = 19.8 min for (R).
O
O O
B O
(RS)-2e
O
O O
B O
(RS)-2e
S26
2.2.6 Enzymatic kinetic resolution of (RS)-1f The enantioenriched compounds (S)-1f and (R)-2f were prepared according to the method described in item 2.2. (S)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexan-2-ol, [(S)-1f] Yield: 156 mg (45%) >99% ee, [α]D22 = +3.1 (c 1.08, CHCl3). GC condition: oven 100-180 ºC, rate 3 ºC/min, tR = 14.9 min for (S) and tR = 15.4 min for (R).
O O O
B O
(RS)-2f
O O
OH O
acetylation
O
B O
B O
(S)-1f
S27
(S)-2f
(R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexan-2-yl acetate, [(R)-2f] Yield: 192 mg (47%) >99% ee, [α]D22 = -0.5 (c 1.0, CHCl3). GC condition: oven 100-180 ºC, rate 3 ºC/min, tR = 14.9 min for (S) and tR = 15.4 min for (R).
O O O
B O
(RS)-2f
O O O
B O
(R)-2f
S28
2.3 Determination of absolute configuration of 1a and 1b The enantioenriched compounds (S)-8a and (S)-8b were prepared according to the method described in item 1.11. (S)-1-(biphenyl-4-yl)ethanol, [(S)-8a] Yield: 78 mg (79%), 96% ee, [α]D24 = -46.6 (c 1.0, CH3Cl). Lit,12 [α]D28 = -43.7 (c 0.75, CHCl3). HPLC condition: Chiralcel® OD column, n-hexane/i-PrOH (95:5), 0.8 mL/min, 254 nm UV detector, tR = 15,6 min for (S) and tR = 18.0 min for (R).
OH
(RS)-8a
OH
(S)-8a
12
Salvi, N. A.; Chattopadhyay, S. Tetrahedron 2001, 57, 2833.
S29
(S)-1-(biphenyl-3-yl)ethanol, [(S)-8b] Yield: 79 mg (80%) >99% ee, [α]D24 = -37.8 (c 1.0, CH3Cl). Lit,11b [α]D20 = -38.0 (c 1.09, CHCl3). HPLC condition: Chiralcel® OD column, n-hexane/i-PrOH (95:5), 0.8 mL/min, 254 nm UV detector, tR = 14.9 min for (S) and tR = 29.5 min for (R).
OH
(RS)-8b
OH
(S)-8b
S30
2.4
Determination of the absolute configuration of 1c and 1d As we have attributed the absolute configuration to the esters 1a and 1b, we carried out the transesterification reaction of 1c and 1d optically pure with pinacol to afford the corresponding pinacoyl esters 1a and 1b.
A 25 mL round-bottomed flask was charged with anhydrous THF (3 mL), boronate 1c or 1d (0.2 mmol; 46.8 mg) optically pure, and pinacol (0.2 mmol; 23.6 mg). The resulting solution was evaporated under reduced pressure at 40 °C. This procedure was repeated (3 times). The resulting products (pinacoyl and neopentyl esters) were analyzed by HPLC. Absolute configuration of 1c: OH
OH
OH
pinacol
O
THF
B O
O
+ O
(S)-1c
O
B
B O
(S)-1c
(S)-1a
HPLC condition: Chiralcel® OJ-H column, n-hexane/i-PrOH (95:5), 1 mL/min, 227 nm UV detector, tR = 9.8 min for (R)-1a, tR = 11.7 min for (S)-1a, tR = 24.3 min for (S)-1c, tR = 26.1 min for (R)-1c.
(R)-1a
(S)-1c (S)-1a
S31
(R)-1c
(S)-1c
(S)-1a
Absolute configuration of 1d:
HPLC condition: Chiralcel® OJ-H column, n-hexane/i-PrOH (95:5), 1 mL/min, 227 nm UV detector, tR = 8.7 min for (S)-1b, tR = 22.7 min for (R)-1b, tR = 14.7 min for (S)-1d, tR = 23.6 min for (R)-1d.
S32
(S)-1d (R)-1d
(S)-1b (R)-1b
(S)-1b (S)-1d
S33
2.5
Determination of the absolute configuration of 1f
The title compound was prepared by adapting a previously described procedure.13 To a 25 mL, round-bottomed flask containing the boronate ester (S)-1f (0.5 mmol, 114 mg) and 2 M aqueous NaOH (10 equiv., 5 mmol, 2.5 mL) was added dropwise 30% H2O2 solution (10 equiv., 270 mg, 566 μL) at 0 °C. The reaction mixture was stirred for 30 min. Et2O (10 mL) was added and transferred to a separatory funnel. The organic layer was washed, sequentially, with saturated aqueous NaHCO3 (2 mL) and brine (2 mL). The aqueous layers were extract with EtOAc (5 x 5 mL). The combined organic layers were dried over anhydrous MgSO4, filtrated and concentrated under reduced pressure. The crude product was purified by column chromatography using hexanes/EtOAc (1:4) as eluent. The resulting product (S)-9 was obtained as colourless oil. Yield: 28 mg (58%), >99% ee, [α]D22 = +6.3 (c 1.1, MeOH). Lit,14 [α]D20 = +12.9 (c 1.0, MeOH). 1 H NMR (200 MHz, CHCl3) δ = 1.12 (d, J = 6.2 Hz, 3H), 1.33 – 1.55 (m, 6H), 1.78 (br, 2H), 3.58 (t, J = 6.2 Hz, 2H), 3.73 (quint, J = 6.2 Hz, 1H) . 13 C NMR (50 MHz, CDCl3): δ = 22.05, 23.71, 32.68, 38.99, 62.84, 68.14. LRMS (EI) m/z (%) = 118(1) [M+], 103(6), 87(10), 75(22), 56(60), 45 (100).
13 14
Molander, G. A.; Bobbit, K. L. J. Am. Chem. Soc. 1993, 115, 7517. Barua, N. C.; Schmidt, R. R. Synthesis 1986, 1067.
S34
OH
O
B O
1
H NMR (200 MHz, CDCl3) Spectrum of compound 1a
S35
1a
OH
O
B O
13
C NMR (50 MHz, CDCl3) Spectrum of compound 1a S36
1a
OH
O
B O
11
B NMR (96 MHz, CDCl3) Spectrum of compound 1a S37
1a
OH
O
1
O
1b
H NMR (200 MHz, CDCl3) Spectrum of compound 1b S38
B
OH
O
13
O
1b
C NMR (50 MHz, CDCl3) Spectrum of compound 1b S39
B
OH
O
11
O
1b
B NMR (96 MHz, CDCl3) Spectrum of compound 1b S40
B
OH
O
B O
1
1c
H NMR (200 MHz, CDCl3) Spectrum of compound 1c S41
OH
O
B O
13
1c
C NMR (50 MHz, CDCl3) Spectrum of compound 1c S42
OH
O
B O
11
B NMR (96 MHz, CDCl3) Spectrum of compound 1c
S43
1c
OH
O
1
B
O
1d
H NMR (200 MHz, CDCl3) Spectrum of compound 1d S44
OH
O
13
B
O
1d
C NMR (50 MHz, CDCl3) Spectrum of compound 1d S45
OH
O
11
O
1d
B NMR (96 MHz, CDCl3) Spectrum of compound 1d
S46
B
O O
O
B O
1
H NMR (200 MHz, CDCl3) Spectrum of compound 2a S47
2a
O O
O
B O
13
C NMR (50 MHz, CDCl3) Spectrum of compound 2a S48
2a
O O
O
B O
11
B NMR (96 MHz, CDCl3) Spectrum of compound 2a
S49
2a
O O
O
1
B
O
H NMR (200 MHz, CDCl3) Spectrum of compound 2b S50
2b
O O
O
13
B
O
2b
C NMR (50 MHz, CDCl3) Spectrum of compound 2b S51
O O
O
11
O
2b
B NMR (96 MHz, CDCl3) Spectrum of compound 2b
S52
B
O O
O
B O
1
2c
H NMR (200 MHz, CDCl3) Spectrum of compound 2c S53
O O
O
B
2c
O
13
C NMR (50 MHz, CDCl3) Spectrum of compound 2c S54
O O
O
B O
11
B NMR (96 MHz, CDCl3) Spectrum of compound 2c
S55
2c
O O
O
1
B
O
2d
H NMR (200 MHz, CDCl3) Spectrum of compound 2d S56
O O
O
13
B
O
2d
C NMR (50 MHz, CDCl3) Spectrum of compound 2d S57
O O
O
11
O
2d
B NMR (96 MHz, CDCl3) Spectrum of compound 2d
S58
B
OH B O
O
1e
1
H NMR (200 MHz, CDCl3) Spectrum of compound 1e S59
OH B O
O
1e
13
C NMR (50 MHz, CDCl3) Spectrum of compound 1e S60
OH B O
O
1e
11
B NMR (96 MHz, CDCl3) Spectrum of compound 1e
S61
O
O B O
O
2e
1
H NMR (200 MHz, CDCl3) Spectrum of compound 2e S62
O
O B O
O
2e
13
C NMR (50 MHz, CDCl3) Spectrum of compound 2e S63
O
O B O
O
2e
11
B NMR (96 MHz, CDCl3) Spectrum of compound 2e
S64
OH B
1f
1
O
O
H NMR (500 MHz, CDCl3) Spectrum of compound 1f S65
OH B
1f
1
O
H NMR (500 MHz, CDCl3) Spectrum of compound 1f (expansion) S66
O
OH B
1f
O
O
13
C NMR (125 MHz, CDCl3) Spectrum of compound 1f S67
OH B
1f
13
O
O
C NMR (125 MHz, CDCl3) Spectrum of compound 1f (expansion) S68
OH B
1f
11
O
B NMR (96 MHz, CDCl3) Spectrum of compound 1f
S69
O
O O B
2f
1
O
H NMR (500 MHz, CDCl3) Spectrum of compound 2f S70
O
O O B
2f
1
O
O
H NMR (500 MHz, CDCl3) Spectrum of compound 2f (expansion) S71
O O B
2f
1
O
H NMR (500 MHz, CDCl3) Spectrum of compound 2f (expansion) S72
O
O O B
2f
13
O
O
C NMR (125 MHz, CDCl3) Spectrum of compound 2f S73
O O B
2f
13
O
C NMR (125 MHz, CDCl3) Spectrum of compound 2f (expansion) S74
O
O O B
2f
11
O
B NMR (96 MHz, CDCl3) Spectrum of compound 2f
S75
O
