Oxidative Kinetic Resolution-Claisen Rearrangement Sequence to ­Enantioenriched Arylcycloalkenes

Abstract

The Pd-catalyzed oxidative kinetic resolution of secondary alcohols afforded enantioenriched allylic alcohols with high ­selectivity. These alcohols were transformed into arylcycloalkenes with enantioenriched tertiary and quaternary stereocenters through a two-step vinylation and Lewis acid promoted Claisen rearrangement. Subsequent Pd-catalyzed oxidative cyclization of a Claisen product afforded a 5,5-fused tetrahydrofuran.

oxidative kinetic resolution - Claisen rearrangement - oxidative cyclization - secondary alcohols - palladium catalysis

References and Notes

For oxidative kinetic resolutions, see:

1a Ferreira EM. Stoltz BM. J. Am. Chem. Soc.  2001,  123:  7725 

1b Bagdanoff JT. Ferreira EM. Stoltz BM. Org. Lett.  2003,  5:  835 

1c Bagdanoff JT. Stoltz BM. Angew. Chem. Int. Ed.  2004,  43:  353 

1d Trend RM. Stoltz BM. J. Am. Chem. Soc.  2004,  126:  4482 

1e Nielson RJ. Keith JM. Stoltz BM. Goddard WA. J. Am. Chem. Soc.  2004,  126:  7967 

For oxidative cyclizations, see:

2a Trend RM. Ramtohul YK. Ferreira EM. Stoltz BM. Angew. Chem. Int. Ed.  2003,  42:  2892 

2b Ferreira EM. Stoltz BM. J. Am. Chem. Soc.  2003,  125:  9578 

2c Zhang H. Ferreira EM. Stoltz BM. Angew. Chem. Int. Ed.  2004,  43:  6144 

2d Trend RM. Ramtohul YK. Stoltz BM. J. Am. Chem. Soc.  2005,  127:  17778 

Simultaneous to our publication, a related system was reported, see:

3a Jensen DR. Pugsley JS. Sigman MS. J. Am. Chem. Soc.  2001,  123:  7475 

3b Mueller JA. Jensen DR. Sigman MS. J. Am. Chem. Soc.  2002,  124:  8202 

3c Mandal SK. Jensen DR. Pugsley JS. Sigman MS. J. Org. Chem.  2003,  68:  4600 

3d Mandal SK. Sigman MS. J. Org. Chem.  2003,  68:  7535 

3e Mueller JA. Sigman MS. J. Am. Chem. Soc.  2003,  125:  7005 

3f Jensen DR. Sigman MS. Org. Lett.  2003,  5:  63 

3g Mueller JA. Cowell A. Chandler BD. Sigman MS. J. Am. Chem. Soc.  2005,  127:  14817 

3h Sigman MS. Jensen DR. Acc. Chem. Res.  2006,  39:  221 

4 For application to natural product synthesis, see: Tambar UK. Ebner DC. Stoltz BM. J. Am. Chem. Soc.  2006,  128:  11752 

5 For application to the synthesis of pharmaceutical intermediates, see: Caspi DD. Ebner DC. Bagdanoff JT. Stoltz BM. Adv. Synth. Catal.  2004,  346:  185 

6a Ruel FS. Braun MP. Johnson CR. Org. Synth., Coll. Vol. X   Wiley and Sons; New York: 2004.  p.467 

6b Padwa A. Blacklock TJ. Getman D. Hatanaka N. Loza R. J. Org. Chem.  1978,  43:  1481 

7 Ireland RE. Mueller RH. Willard AK. J. Am. Chem. Soc.  1976,  98:  2868 

8 Johnson WS. Werthemann L. Bartlett WR. Brocksom TJ. Li T.-t. Faulker DJ. Petersen MR. J. Am. Chem. Soc.  1970,  92:  741 

9 Kraus GA. Frazier K. J. Org. Chem.  1980,  45:  2579 

10 Ito S. Kasai M. Ziffer H. Silverton JV. Can. J. Chem.  1987,  65:  574 

11

The decreased ee for this substrate is presumably due to competing 1,3-rearrangement, leading to partial racemization.

12

General Procedure for the Oxidative Kinetic Resolution of Allylic Alcohols [1b]
To an oven-dried reaction tube with stir bar was added oven-dried powdered 3 Å MS (500 mg). After cooling, Pd(nbd)Cl₂ (13.5 mg, 0.05 mmol), followed by toluene (2 mL) and then (-)-sparteine (46.9 mg, 46 µL, 0.20 mmol) were added. The reaction vessel was then cooled to -78 °C, vacuum evacuated, and purged with O₂ (3×). The reaction was then heated to 60 °C with vigorous stirring under O₂ (1 atm) for 20 min. Finely powdered anhyd Cs₂CO₃ (162.9 mg, 0.50 mmol) was added, followed by a solution of allylic alcohol (1.0 mmol), t-BuOH (111.2 mg, 143 mL, 1.5 mmol) and toluene (2 mL). Reaction progress was monitored by GC analysis of an aliquot filtered through silica gel (Et₂O as eluent). When the reaction was complete, the reaction was cooled to r.t., filtered through silica gel (Et₂O as eluent), concentrated under reduced pressure, and purified by flash chromatography to afford enantioenriched alcohol and ketone.
2-Phenylcyclopent-2-enol [(+)-1]
R _f = 0.20 (4:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.60-7.54 (comp. m, 2 H), 7.39-7.22 (comp. m, 3 H), 6.32 (t, J = 2.5 Hz, 1 H), 5.29-5.21 (m, 1 H), 2.74-2.60 (m, 1 H), 2.51-2.34 (m, 2 H), 2.02-1.90 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 144.8, 135.1, 130.2, 128.8, 127.8, 126.4, 77.4, 34.3, 30.7. IR (thin film/NaCl): 3220, 2883, 1496, 1322, 1050, 759, 691 cm^-1. HRMS-EI: m/z [M]⁺ calcd for [C₁₁H₁₂O]⁺: 160.0888; found: 160.0881. [α]_D ²⁵ +14.0 (c 1.4, CHCl₃; 99% ee). HPLC: Chiralcel OD-H column, 3% EtOH-hexane, 1 mL/min flow rate, major peak t _R = 21.1 min, minor peak t _R = 16.9 min.
2-(4-Methylphenyl)cyclopent-2-enol [(+)-2]
R _f = 0.35 (7:3 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.46 (d, J = 8.0 Hz, 2 H), 7.16 (d, J = 8.1 Hz, 2 H), 6.26 (t, J = 2.5 Hz, 1 H), 5.22 (m, 1 H), 2.73-2.59 (m, 1 H), 2.49-2.32 (m, 2 H), 2.34 (s, 3 H), 2.01-1.88 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 144.7, 137.3, 132.2, 129.5, 129.2, 126.3, 77.4, 34.2, 30.7, 21.4. IR (thin film/NaCl): 3337, 2921, 1512, 1043, 813 cm^-1. HRMS-EI: m/z [M]⁺ calcd for [C₁₂H₁₄O]⁺: 174.1045; found: 174.1042. [α]_D ²⁵ +4.5 (c 1.6, CHCl₃; 98.5% ee). HPLC: Chiralcel OB-H column, 8% EtOH-hexane, 1 mL/min flow rate, major peak t _R = 15.3 min, minor peak t _R = 7.8 min.
2-(4-Methoxyphenyl)cyclopent-2-enol [(+)-3]
R _f = 0.30 (7:3 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.51 (d, J = 8.8 Hz, 2 H), 6.88 (d, J = 8.8 Hz, 2 H), 6.18 (t, J = 2.4 Hz, 1 H), 5.19 (m, 1 H), 3.81 (s, 3 H), 2.72-2.56 (m, 1 H), 2.48-2.31 (m, 2 H), 2.00-1.87 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 159.1, 144.2, 128.1, 127.8, 127.6, 114.2, 77.5, 55.5, 34.3, 30.6. IR (thin film/NaCl): 3249, 2958, 2892, 2846, 1052, 1033, 824 cm^-1. HRMS-EI: m/z [M]⁺ calcd for [C₁₂H₁₄O₂]⁺: 190.0994; found: 190.0995. [α]_D ²⁵ +10.6 (c 1.9, CHCl₃; 99% ee); HPLC: Chiralpak AS column, 4% EtOH-hexane, 1 mL/min flow rate, major peak t _R = 11.5 min, minor peak t _R = 15.9 min.
2-{Benzo[1,3]dioxol-5-yl}cyclopent-2-enol [(+)-4]
R _f = 0.27 (7:3 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.08-7.03 (comp. m, 2 H), 6.82-6.76 (m, 1 H), 6.16 (t, J = 2.5, 1 H), 5.95 (s, 2 H), 5.15 (m, 1 H), 2.71-2.57 (m, 1 H), 2.47-2.30 (m, 2 H), 1.99-1.87 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 148.1, 147.1, 144.3, 129.5, 128.8, 120.0, 108.5, 106.8, 101.2, 77.5, 34.3, 30.6. IR (thin film/NaCl): 3354, 2894, 1490, 1503, 1226, 1041, 937 cm^-1. HRMS-EI: m/z [M]⁺ calcd for [C₁₂H₁₂O₃]⁺: 204.0787; found: 204.0793. [α]_D ²⁵ +9.6 (c 1.6, CHCl₃; 99% ee). HPLC: Chiralcel OB-H column, 10% EtOH-hexane, 1 mL/min flow rate, major peak t _R = 27.1 min, minor peak t _R = 12.0 min.
2-[4-(Trifluoromethyl)phenyl]cyclopent-2-enol [(+)-5]
R _f = 0.34 (7:3 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.67 (d, J = 8.5 Hz, 2 H), 7.58 (d, J = 8.5 Hz, 2 H), 6.43 (t, J = 2.6 Hz, 1 H), 5.24 (m, 1 H), 2.77-2.62 (m, 1 H), 2.54-2.37 (m, 2 H), 2.02-1.86 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 143.4, 138.4, 132.6, 127.7, 126.3, 125.4 (q, J _F = 3.8 Hz), 77.1, 34.1, 30.5. ¹⁹F NMR (282 MHz, CDCl₃): δ = -63.5. IR (thin film/NaCl): 3239, 1326, 1112, 827 cm^-1. HRMS-EI: m/z [M]⁺ calcd for [C₁₂H₁₁OF₃]⁺: 228.0762; found: 228.0752. [α]_D ²⁵ +16.0 (c 2.5, CHCl₃; 99% ee). HPLC: Chiralcel OD-H column, 2% EtOH-hexane, 1 mL/min flow rate, major peak t _R = 15.0 min, minor peak t _R = 13.7 min.
2-(2-Naphthyl)cyclopent-2-enol [(+)-6]
R _f = 0.37 (7:3 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 8.00 (s, 1 H), 7.87-7.67 (comp. m, 4 H), 7.50-7.40 (comp. m, 2 H), 6.45 (t, J = 2.5 Hz, 1 H), 5.37 (m, 1 H), 2.80-2.65 (m, 1 H), 2.56-2.38 (m, 2 H), 2.07-1.95 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 144.7, 133.9, 133.0, 132.4, 130.9, 128.5, 128.4, 127.9, 126.4, 126.1, 125.0, 124.8, 77.4, 34.4, 30.9. IR (thin film/NaCl): 3385, 1044, 819, 476 cm^-1. HRMS-EI: m/z [M]⁺ calcd for [C₁₅H₁₄O]⁺: 210.1045; found: 210.1043. [α]_D ²⁵ +46.4 (c 2.0, CHCl₃; 99% ee); HPLC: Chiralpak AS column, 3% EtOH-hexane, 1 mL/min flow rate, major peak t _R = 11.5 min, minor peak t _R = 13.3 min.
2-(2-Furyl)cyclopent-2-enol [(+)-7]
R _f = 0.26 (7:3 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.38 (d, J = 1.6 Hz, 1 H), 6.43 (d, J = 3.4 Hz, 1 H), 6.40 (dd, J = 3.3, 1.7 Hz, 1 H), 5.11 (m, 1 H), 2.74-2.60 (m, 1 H), 2.49-2.30 (m, 2 H), 1.95-1.84 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 151.2, 142.0, 135.7, 128.4, 111.4, 106.8, 77.3, 55.9, 30.8. IR (thin film/NaCl): 3344, 2934, 2849, 1044, 928, 733 cm^-1. HRMS-EI: m/z [M]⁺ calcd for [C₉H₁₀O₂]⁺: 150.0681; found: 150.0680. [α]_D ²⁵ +30.9 (c 1.1, CHCl₃; 99% ee). HPLC: Chiralcel OB-H column, 4% EtOH-hexane, 1 mL/min flow rate, major peak t _R = 17.0 min, minor peak t _R = 10.5 min.
3-Methyl-2-phenylcyclopent-2-enol [(-)-8]
R _f = 0.24 (4:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.41-7.22 (comp. m, 5 H), 5.16 (br d, J = 5.5 Hz, 1 H), 2.74-2.58 (m, 1 H), 2.44-2.30 (m, 2 H), 1.87-1.75 (m, 1 H), 1.85 (d, J = 1.1 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 139.8, 138.5, 136.7, 128.6, 128.5, 126.9, 80.5, 36.9, 32.7, 15.9. IR (thin film/NaCl): 3370, 2930, 1442, 699 cm^-1. HRMS-EI: m/z [M]⁺ calcd for [C₁₂H₁₄O]⁺: 174.1045; found: 174.1037. [α]_D ²⁵ -2.4 (c 1.2, CHCl₃; 99% ee). HPLC: Chiralcel OB-H column, 2% EtOH-hexane, 1 mL/min flow rate, major peak t _R = 13.2 min, minor peak t _R = 10.4 min.
2-Phenylcyclohex-2-enol [(-)-9]
Characterization data matched that in the literature; [9] [a]_D ²⁵ -109.5 (c 1.3, CHCl₃; 99% ee) {lit. [10] [α]_D +114.5 (c 1.6, CHCl₃)}. HPLC: Chiralpak AD column, 3% EtOH-hexane, 1 mL/min flow rate, major peak t _R = 22.5 min, minor peak t _R = 17.3 min.
General Procedure for the Vinylation of Allylic Alcohols To a flame-dried 1-dram vial was added allylic alcohol (0.23 mmol), freshly distilled ethyl vinyl ether (3 mL), and then Hg(OAc)₂ (20.3 mg, 0.64 mmol, 0.28 equiv). The reaction mixture was stirred at 40 °C for 120 h. After cooling to 23 °C, K₂CO₃ (173 mg, 1.25 mmol, 5.4 equiv) was added, and the suspension was stirred for 30 min. Then, the mixture was filtered, and the solution was concentrated under reduced pressure. Purification by preparative TLC (10:1 hexane-EtOAc as eluent) afforded the vinyl ether and starting allylic alcohol.
3-Methyl-2-phenyl-1-vinyloxy-2-cyclopentene [(+)-11]
R _f = 0.75 (10:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.38-7.36 (comp. m, 4 H), 7.31-7.24 (m, 1 H), 6.45 (dd, J = 13.8, 6.3 Hz, 1 H), 5.25 (br d, J = 6.9 Hz, 1 H), 4.31 (dd, J = 14.4, 1.8 Hz, 1 H), 4.04 (dd, J = 6.6, 1.5 Hz, 1 H), 2.79-2.68 (m, 1 H), 2.48-2.22 (m, 2 H), 2.06-1.97 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 150.5, 142.3, 136.4, 134.7, 128.2, 128.1, 126.6, 88.0, 87.1, 37.1, 28.9, 15.7. IR (thin film/NaCl): 3055, 3029, 2975, 2938, 2912, 2845, 1631, 1608, 1492, 1444, 1379, 1350, 1317, 1189, 1099, 1058, 1016, 989, 964, 872, 816 cm^-1. HRMS-ES: m/z [M]⁺ calcd for [C₁₄H₁₆O]⁺: 200.1201; found: 200.1213. [α]_D ²⁶ +6.1 (c 0.80, CH₂Cl₂).
2-Phenyl-1-vinyloxy-2-cyclopentene
R _f = 0.75 (10:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.49-7.46 (comp. m, 2 H), 7.35-7.22 (comp. m, 3 H), 6.50-6.43 (m, 2 H), 5.37 (dt, J = 6.9, 2.4 Hz, 1 H), 4.35 (dd, J = 14.4, 1.8 Hz, 1 H), 4.11 (dd, J = 6.6, 1.5 Hz, 1 H), 2.76-2.64 (m, 1 H), 2.54-2.26 (m, 2 H), 2.15-2.12 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 150.1, 141.1, 134.6, 132.0, 128.4, 127.3, 125.9, 88.3, 83.1, 31.0, 30.1. IR (thin film/NaCl): 3057, 2934, 2846, 1632, 1610, 1496, 1447, 1358, 1318, 1188, 1048, 1032, 962, 822 cm^-1. HRMS-ES: m/z [M]⁺ calcd for [C₁₃H₁₄O]⁺: 186.1045; found: 186.1042. [α]_D ²⁵ +32.5 (c 0.38, CH₂Cl₂).
2-(4-Methylphenyl)-1-vinyloxy-2-cyclopentene
R _f = 0.75 (10:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.41 (d, J = 6.3 Hz, 2 H), 7.17 (d, J = 8.1 Hz, 2 H), 6.52 (dd, J = 14.4, 6.9 Hz, 1 H), 6.42 (t, J = 2.4 Hz, 1 H), 5.37 (dt, J = 7.2, 2.4 Hz, 1 H), 4.37 (dd, J = 14.4, 1.8 Hz, 1 H), 4.12 (dd, J = 6.6, 1.8 Hz, 1 H), 2.74-2.65 (m, 1 H), 2.54-2.43 (m, 1 H), 2.36 (s, 3 H), 2.39-2.27 (m, 1 H), 2.16-2.09 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 150.1, 141.0, 137.0, 131.8, 131.0, 129.1, 125.9, 88.3, 83.1, 31.0, 30.1, 21.2. IR (thin film/NaCl): 2921, 2849, 1631, 1609, 1513, 1449, 1352, 1317, 1187, 1048, 1030, 963, 813 cm^-1. HRMS-ES: m/z [M]⁺ calcd for [C₁₄H₁₆O]⁺: 200.1201; found: 200.1201. [α]_D ²⁵ +20.8 (c 0.16, CH₂Cl₂).
2-(4-Methoxyphenyl)-1-vinyloxy-2-cyclopentene R _f = 0.75 (10:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.44 (d, J = 8.7 Hz, 2 H), 6.89 (d, J = 9.0 Hz, 2 H), 6.51 (dd, J = 14.4, 6.9 Hz, 1 H), 6.33 (t, J = 2.7 Hz, 1 H), 5.37 (dt, J = 7.2, 2.1 Hz, 1 H), 4.36 (dd, J = 14.4, 2.1 Hz, 1 H), 4.11 (dd, J = 6.6, 1.8 Hz, 1 H), 3.81 (s, 3 H), 2.75-2.62 (m, 1 H), 2.52-2.42 (m, 1 H), 2.38-2.56 (m, 1 H), 2.14-2.05 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 158.9, 150.1, 140.5, 129.9, 127.4, 127.2, 113.8, 88.3, 83.3, 55.2, 30.9, 30.1. IR (thin film/NaCl): 2918, 2848, 2359, 2340, 1632, 1609, 1512, 1463, 1353, 1317, 1269, 1257, 1180, 1112, 1036, 963, 891, 824 cm^-1. HRMS-ES: m/z [M]⁺ calcd for [C₁₄H₁₆O₂]⁺: 216.1150; found: 216.1155. [α]_D ²⁶ +18.8 (c 0.43, CH₂Cl₂).
2-{Benzo[1,3]dioxol-5-yl}-1-vinyloxy-2-cyclopentene
R _f = 0.75 (10:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.00 (d, J = 1.8 Hz, 1 H), 6.97 (dd, J = 13.8, 1.5 Hz, 1 H), 6.79 (d, J = 7.8 Hz, 1 H), 6.49 (q, J = 6.9 Hz, 1 H), 6.30 (t, J = 2.4 Hz, 1 H), 5.94 (s, 2 H), 5.29 (dt, J = 7.2, 2.4 Hz, 1 H), 4.35 (dd, J = 14.4, 2.1 Hz, 1 H), 4.11 (dd, J = 6.9, 1.8 Hz, 1 H), 2.73-2.61 (m, 1 H), 2.51-2.40 (m, 1 H), 2.37-2.25 (m, 1 H), 2.13-2.04 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 150.0, 147.7, 146.9, 140.6, 130.6, 119.7, 108.2, 106.4, 100.9, 88.4, 83.2, 30.9, 30.0. IR (thin film/NaCl): 2898, 2849, 2359, 2340, 1632, 1610, 1503, 1490, 1447, 1366, 1317, 1227, 1187, 1106, 1040, 969, 936, 889, 808 cm^-1. HRMS-ES: m/z [M]⁺ calcd for [C₁₄H₁₄O₃]⁺: 230.0943; found: 230.0933. [α]_D ²⁶ +20.8 (c 0.075, CH₂Cl₂).
2-[4-(Trifluoromethyl)phenyl]-1-vinyloxy-2-cyclopentene
R _f = 0.75 (10:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.58 (m, 4 H), 6.58 (t, J = 2.7 Hz, 1 H), 6.50 (dd, J = 14.4, 6.6 Hz, 1 H), 5.37 (dt, J = 7.2, 2.1 Hz, 1 H), 4.37 (dd, J = 14.1, 1.8 Hz, 1 H), 4.15 (dd, J = 6.6, 1.8 Hz, 1 H), 2.80-2.67 (m, 1 H), 2.58-2.47 (m, 1 H), 2.42-2.30 (m, 1 H), 2.17-2.08 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 149.9, 140.2, 134.6, 126.2, 125.5, 125.4, 125.3, 125.3, 88.8, 82.9, 31.2, 30.0. IR (thin film/NaCl): 2917, 2846, 2141, 1731, 1660, 1633, 1614, 1507, 1414, 1365, 1317, 1246, 1190, 1164, 1122, 1071, 1033, 1016, 963, 829, 733 cm^-1. HRMS-ES: m/z [M]⁺ calcd for [C₁₄H₁₃OF₃]⁺: 254.0919; found: 254.0913. [α]_D ²⁶ +31.0 (c 0.32, CH₂Cl₂).
2-(2-Naphthyl)-1-vinyloxy-2-cyclopentene
R _f = 0.75 (10:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.87-7.80 (comp. m, 4 H), 7.70-7.67 (m, 1 H), 7.51-7.43 (comp. m, 2 H), 6.61 (t, J = 2.7 Hz, 1 H), 6.58 (dd, J = 14.4, 6.9 Hz, 1 H), 5.51 (dt, J = 7.2, 2.7 Hz, 1 H), 4.43 (dd, J = 14.1, 1.8 Hz, 1 H), 4.18 (dd, J = 6.9, 1.8 Hz, 1 H), 2.83-2.71 (m, 1 H), 2.60-2.49 (m, 1 H), 2.44-2.32 (m, 1 H), 2.23-2.13 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 150.1, 141.1, 133.5, 1327, 131.9, 128.3, 127.9, 127.5, 126.0, 125.8, 124.7, 124.3, 88.5, 83.1, 31.2, 30.1. IR (thin film/NaCl): 3282, 3055, 2929, 2848, 1632, 1610, 1507, 1449, 1317, 1187, 1048, 1030, 963, 947, 894, 815, 746, 665 cm^-1. HRMS-ES: m/z [M]⁺ calcd for [C₁₇H₁₆O]⁺: 236.1201; found: 236.1207. [α]_D ²⁶ +48.7 (c 0.53, CH₂Cl₂).
2-(2-Furyl)-1-vinyloxy-2-cyclopentene
R _f = 0.75 (10:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.38 (d, J = 1.8 Hz, 1 H), 6.49 (q, J = 6.6 Hz, 1 H), 6.39 (dd, J = 3.6, 2.1 Hz, 1 H), 6.36 (t, J = 3.0 Hz, 1 H), 6.30 (d, J = 3.3 Hz, 1 H), 5.23 (dt, J = 7.2, 2.7 Hz, 1 H), 4.34 (dd, J = 14.4, 1.8 Hz, 1 H), 4.10 (dd, J = 6.9, 1.8 Hz, 1 H), 2.75-2.63 (m, 1 H), 2.53-2.42 (m, 1 H), 2.37-2.25 (m, 1 H), 2.09-1.99 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 150.5, 150.2, 141.9, 132.2, 130.1, 111.1, 106.9, 88.5, 83.3, 31.1, 30.1. IR (thin film/NaCl): 2924, 2850, 1633, 1611, 1487, 1349, 1317, 1189, 1153, 1051, 1028, 962, 916, 884, 806 cm^-1. HRMS-ES: m/z [M]⁺ calcd for [C₁₁H₁₂O₂]⁺: 176.0837; found: 176.0842. [α]_D ²⁵ +39.1 (c 0.35, CH₂Cl₂).
2-Phenyl-1-vinyloxy-2-cyclohexene R _f = 0.75 (10:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.43-7.22 (comp. m, 5 H), 6.43 (dd, J = 14.1, 6.6 Hz, 1 H), 6.35 (t, J = 3.3 Hz, 1 H), 4.78 (t, J = 3.0 Hz, 1 H), 4.41 (dd, J = 14.1, 1.5 Hz, 1 H), 4.08 (dd, J = 6.6, 1.8 Hz, 1 H), 2.40-2.30 (m, 1 H), 2.25-2.14 (m, 2 H), 1.91-1.64 (comp. m, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 150.5, 140.4, 135.6, 130.6, 128.3, 126.9, 125.6, 88.5, 72.5, 27.6, 25.9, 16.8. IR (thin film/NaCl): 3023, 2933, 2865, 2829, 2359, 2340, 1632, 1610, 1496, 1445, 1376, 1355, 1330, 1312, 1260, 1185, 1094, 1062, 1011, 977, 946, 917, 870, 813, 756, 695 cm^-1. HRMS-ES: m/z [M]⁺ calcd for [C₁₄H₁₆O]⁺: 200.1201; found: 200.1207. [α]_D ²⁵ -115.8 (c 0.17, CH₂Cl₂).
General Procedure for Claisen Rearrangement of Vinyl Ethers
To a flame-dried 1-dram vial was added vinyl ether (0.041 mmol) and CH₂Cl₂ (0.5 mL). The solution was cooled to -40 °C, and DIBAL-H (1 M in toluene, 45 µL, 0.045 mmol) was added dropwise. The reaction mixture was allowed to warm to 23 °C and stir for 2 h, after which it was quenched with excess Na₂SO₄·10H₂O. After 30 min stirring, the cloudy suspension was filtered, and the solution was concentrated under reduced pressure. Purification by preparative TLC (9:2 hexane-EtOAc as eluent) afforded the primary alcohol.
1-(2-Hydroxyethyl)-1-methyl-2-phenyl-2-cyclopentene [(+)-12] R _f = 0.16 (10:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.35-7.20 (comp. m, 5 H), 5.80 (t, J = 2.4 Hz, 1 H), 3.75-3.58 (m, 2 H), 2.42-2.35 (m, 2 H), 2.10-2.01 (m, 1 H), 1.89-1.77 (comp. m, 3 H), 1.34 (s, 1 H), 1.25 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 150.6, 137.9, 128.9, 128.1, 127.3, 126.6, 60.7, 48.7, 48.5, 39.2, 30.1, 26.8. IR (thin film/NaCl): 3369, 3054, 2951, 2866, 1598, 1492, 1453, 1376, 1099, 1054, 1020, 759, 700 cm^-1. HRMS-ES: m/z [M]⁺ calcd for [C₁₄H₁₈O]⁺: 202.1358; found: 202.1355. [α]_D ²⁵ +27.5 (c 0.66, CH₂Cl₂; 87% ee). HPLC: Chiralcel OD-H column, 3% EtOH-hexane, 1 mL/min flow rate, major peak t _R = 13.1 min, minor peak t _R = 10.7 min.
1-(2-Hydroxyethyl)-2-phenyl-2-cyclopentene [(+)-13] R _f = 0.13 (5:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.42-7.19 (comp. m, 5 H), 6.07-6.05 (m, 1 H), 3.75-3.63 (m, 2 H), 3.29 (m, 1 H), 2.53-2.21 (m, 2 H), 2.20-2.14 (m, 1 H), 1.94-1.75 (m, 2 H), 1.55-1.45 (m, 1 H), 1.42 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 146.3, 136.2, 128.4, 126.9, 126.7, 126.1, 61.7, 41.5, 36.5, 31.5, 29.8. IR (thin film/NaCl): 3350, 3053, 2935, 2847, 1598, 1494, 1445, 1330, 1055, 755, 694 cm^-1. HRMS-ES: m/z [M]⁺ calcd for [C₁₃H₁₆O]⁺: 188.1201; found: 188.1208. [α]_D ²⁴ +62.3 (c 0.27, CH₂Cl₂; 97.9% ee). HPLC: Chiralcel OJ column, 2% EtOH-hexane, 1 mL/min flow rate, major peak t _R = 32.6 min, minor peak t _R = 22.8 min.
1-(2-Hydroxyethyl)-2-(4-methylphenyl)-2-cyclopentene [(+)-14] R _f = 0.15 (5:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.32 (d, J = 7.8 Hz, 2 H), 7.14 (d, J = 8.1 Hz, 2 H), 6.02-6.00 (m, 1 H), 3.73-3.65 (m, 2 H), 3.26 (m, 1 H), 2.52-2.44 (m, 2 H), 2.34 (s, 3 H), 2.26-2.13 (m, 1 H), 1.94-1.74 (m, 2 H), 1.55-1.43 (m, 1 H), 1.34 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 146.1, 136.6, 129.1, 126.0, 125.8, 61.7, 41.5, 36.5, 31.5, 29.8, 21.1. IR (thin film/NaCl): 3337, 3048, 3023, 2936, 2844, 1901, 1617, 1566, 1511, 1437, 1379, 1335, 1307, 1185, 1111, 1056, 1019, 981, 879, 803 cm^-1. HRMS-ES: m/z [M]⁺ calcd for [C₁₄H₁₈O]⁺: 202.1358; found: 202.1353. [α]_D ²⁴ +51.5 (c 0.075, CH₂Cl₂; 96.8% ee). HPLC: Chiralcel OJ column, 2% EtOH-hexane, 1 mL/min flow rate, major peak t _R = 13.4 min, minor peak t _R = 15.3 min.
1-(2-Hydroxyethyl)-2-(4-methoxyphenyl)-2-cyclopentene [(+)-15] R _f = 0.15 (5:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.36 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 5.94 (s, 1 H), 3.80 (s, 3 H), 3.72-3.64 (m, 2 H), 3.26 (br s, 1 H), 2.50-2.44 (m, 2 H), 2.24-2.11 (m, 1 H), 1.92-1.73 (m, 2 H), 1.54-1.42 (m, 1 H), 1.44 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 158.5, 145.6, 128.9, 127.2, 124.7, 113.7, 61.7, 55.2, 41.6, 36.4, 31.4, 29.8. IR (thin film/NaCl): 3392, 2934, 2836, 1607, 1510, 1462, 1441, 1294, 1252, 1178, 1037, 804 cm^-1. HRMS-ES: m/z [M]⁺ calcd for [C₁₄H₁₈O₂]⁺: 218.1307; found: 218.1299. [α]_D ²⁵ +66.9 (c 0.27, CH₂Cl₂; 98.6% ee). HPLC: Chiralcel OJ column, 4% EtOH-hexane, 1 mL/min flow rate, major peak t _R = 13.6 min, minor peak t _R = 16.2 min.
1-(2-Hydroxyethyl)-2-{2-Benzo[1,3]dioxol-5-yl}-2-cyclopentene [(+)-16] R _f = 0.15 (5:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 6.92 (s, 1 H), 6.89 (dd, J = 8.4, 1.2 Hz, 1 H), 6.78 (d, J = 8.4 Hz), 5.94 (s, 2 H), 5.93 (s, 1 H), 3.72-3.64 (m, 2 H), 3.32 (br s, 1 H), 2.49-2.43 (m, 2 H), 2.23-2.11 (m, 1 H), 1.92-1.73 (m, 2 H), 1.54-1.42 (m, 1 H), 1.49 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 147.7, 146.5, 145.8, 130.6, 125.4, 119.6, 108.1, 106.6, 100.9, 61.6, 41.7, 36.3, 31.3, 29.7. IR (thin film/NaCl): 3350, 3041, 2935, 2888, 2777, 2063, 1850, 1604, 1503, 1489, 1443, 1356, 1223, 1126, 1104, 1040, 986, 937, 862, 806 cm^-1. HRMS-ES: m/z [M]⁺ calcd for [C₁₄H₁₆O₃]⁺: 232.1100; found: 232.1091. [α]_D ²⁴ +62.2 (c 0.27, CH₂Cl₂; 93.1% ee). HPLC: Chiralcel OJ column, 4% EtOH-hexane, 1 mL/min flow rate, major peak t _R = 17.8 min, minor peak t _R = 21.1 min.
1-(2-Hydroxyethyl)-2-[4-(trifluoromethyl)phenyl]-2-cyclopentene [(+)-17]
R _f = 0.15 (5:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.58 (dd, J = 8.4, 21.6 Hz, 4 H), 6.17 (s, 1 H), 3.72-3.67 (m, 2 H), 3.30 (br s, 1 H), 2.52-2.50 (m, 2 H), 2.29-2.16 (m, 1 H), 1.90-1.78 (m, 2 H), 1.52-1.42 (m, 1 H), 1.37 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 145.3, 139.8, 129.4, 126.3, 125.4, 125.4, 125.3, 61.5, 41.5, 36.3, 31.6, 29.7. IR (thin film/NaCl): 3368, 2937, 2846, 1615, 1412, 1326, 1164, 1123, 1110, 1069, 1015, 850, 831, 815 cm^-1. HRMS-ES: m/z [M]⁺ calcd for [C₁₄H₁₅OF₃]⁺: 256.1075; found: 256.1073. [α]_D ²⁶ +48.5 (c 0.20, CH₂Cl₂; 97.1% ee). HPLC: Chiralcel OJ column, 2% i-PrOH-hexane, 1 mL/min flow rate, major peak t _R = 21.6 min, minor peak t _R = 18.5 min. 1-(2-Hydroxyethyl)-2-(2-naphthyl)-2-cyclopentene [(+)-18] R _f = 0.15 (5:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.83-7.78 (comp. m, 4 H), 7.63 (d, J = 8.7 Hz, 1 H), 7.49-7.41 (m, 1 H), 6.22 (s, 1 H), 3.80 (s, 3 H), 3.72 (t, J = 5.1 Hz, 2 H), 3.41 (br s, 1 H), 2.62-2.46 (m, 2 H), 2.31-2.18 (m, 1 H), 2.10-1.81 (m, 2 H), 1.61-1.49 (m, 1 H), 1.44 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 146.2, 133.6, 133.5, 132.5, 128.0, 127.9, 127.52, 127.46, 126.1, 125.6, 124.8, 124.5, 61.7, 41.5, 36.4, 31.6, 29.8. IR (thin film/NaCl): 3369, 3055, 2933, 2847, 1627, 1595, 1505, 1435, 1354, 1273, 1197, 1145, 1128, 1056, 989, 962, 946, 893, 858, 812, 747 cm^-1. HRMS-ES: m/z [M]⁺ calcd for [C₁₇H₁₈O]⁺: 238.1358; found: 238.1354. [α]_D ²⁵ +25.4 (c 0.47, CH₂Cl₂; 98.8% ee). HPLC: Chiralcel OJ column, 4% EtOH-hexane, 1 mL/min flow rate, major peak t _R = 12.7 min, minor peak t _R = 14.1 min.
1-(2-Hydroxyethyl)-2-(2-furyl)-2-cyclopentene [(+)-19] R _f = 0.15 (5:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.35 (d, J = 1.5 Hz, 1 H), 6.38 (dd, J = 3.3, 1.8 Hz, 1 H), 6.26 (d, J = 3.3 Hz, 1 H), 6.07 (s, 1 H), 3.77-3.67 (m, 2 H), 3.09 (br s, 1 H), 2.60-2.37 (m, 2 H), 2.19-2.09 (m, 1 H), 2.02-1.91 (m, 1 H), 1.83-1.74 (m, 1 H), 1.68-1.54 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 151.9, 141.4, 136.6, 125.4, 110.9, 105.8, 61.6, 41.6, 36.7, 31.3, 29.8. IR (thin film/NaCl): 3368, 2938, 2873, 1654, 1487, 1459, 1329, 1056, 1008, 920, 885, 800, 733, 681 cm^-1. HRMS-ES: m/z [M]⁺ calcd for [C₁₁H₁₄O₂]⁺: 178.0994; found: 178.0995. [α]_D ²⁴ +23.4 (c 0.29, CH₂Cl₂; 48.6% ee). [11] HPLC: Chiralcel OJ column, 4% EtOH-hexane, 1 mL/min flow rate, major peak t _R = 12.3 min, minor peak t _R = 10.9 min.
1-(2-Hydroxyethyl)-2-phenyl-2-cyclohexene [(+)-20] R _f = 0.15 (5:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.32-7.21 (comp. m, 5 H), 5.92 (t, J = 4.2 Hz, 1 H), 3.59 (t, J = 6.0 Hz, 2 H), 2.89 (br s, 1 H), 2.21-2.15 (m, 2 H), 1.87-1.43 (comp. m, 7 H). ¹³C NMR (75 MHz, CDCl₃): δ = 142.6, 141.7, 128.3, 126.5, 126.5, 126.2, 61.2, 36.5, 30.0, 27.3, 26.0, 18.5. IR (thin film/NaCl): 3351, 3021, 2930, 2861, 2832, 1639, 1598, 1493, 1443, 1430, 1058, 1032, 1013, 986, 757, 698 cm^-1. HRMS-ES: m/z [M]⁺ calcd for [C₁₄H₁₈O]⁺: 202.1358; found: 202.1358. [α]_D ²⁵ +107.2 (c 0.050, CH₂Cl₂; 97.0% ee). HPLC: Chiralcel OJ column, 2% EtOH-hexane, 1 mL/min flow rate, major peak t _R = 14.2 min, minor peak t _R = 19.2 min.
Tetrahydrofuran (-)-21 To an oven-dried reaction tube with stir bar was added oven-dried powdered 3 Å MS (120 mg). After cooling, Pd(TFA)₂ (4.1 mg, 0.012 mmol), anhyd Na₂CO₃ (52.6 mg, 0.50 mmol), followed by toluene (2.5 mL), pyridine (3.9 mg, 4.0 µL, 0.050 mmol), and alcohol (+)-12 (25.1 mg, 0.12 mmol). The reaction vessel was then cooled to -78 °C, vacuum evacuated, and purged with O₂ (3×). The reaction was then heated to 80 °C with vigorous stirring under O₂ (1 atm). After 15.5 h, the reaction was complete by TLC analysis. The reaction was cooled to r.t., filtered through silica gel (EtOAc as eluent), and concentrated under reduced pressure to afford tetrahydrofuran (-)-21 (21.0 mg, 85% yield) as a colorless oil. Further purification by preparative TLC (4:1 hexane-EtOAc as eluent) afforded an analytically pure sample: R _f = 0.62 (4:1 hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.34-7.20 (comp. m, 5 H), 6.07 (ddd, J = 5.8, 2.4, 2.4 Hz, 1 H), 5.65 (ddd, J = 5.8, 2.1, 2.1 Hz, 1 H), 4.07 (ddd, J = 8.6, 6.8, 4.3 Hz, 1 H), 3.82 (ddd, J = 8.6, 8.6, 6.2 Hz, 1 H), 2.53 (ddd, J = 17.3, 2.2, 2.2 Hz, 1 H), 2.34 (ddd, J = 17.3, 2.2, 2.2 Hz, 1 H), 1.96 (ddd, J = 12.0, 6.1, 4.4 Hz, 1 H), 1.89 (ddd, J = 11.9, 8.6, 6.8 Hz, 1 H), 0.69 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 142.7, 134.6, 133.4, 128.0, 127.0, 126.2, 100.0, 65.9, 51.4, 47.6, 43.6, 25.5. IR (thin film/NaCl): 2956, 1722, 1492, 1448, 1047 cm^-1. HRMS-EI: m/z [M]⁺ calcd for [C₁₄H₁₆O]⁺: 200.1201; found: 200.1203. [α]_D ²⁶ -16.1 (c 1.6, CH₂Cl₂; 86% ee). Chiral GC: G-TA column, 100 °C initial temperature, ramp 1 °C/min, 1 mL/min carrier gas flow, major peak t _R = 28.8 min, minor peak t _R = 29.2 min.