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DOI: 10.1055/s-2007-967937
Synthesis of Enantiomerically Pure Cyclopentene Building Blocks
Publication History
Publication Date:
07 February 2007 (online)
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Abstract
An efficient synthesis of the enantiomerically pure cis-annulated cyclopentenes 2 and ent-2 was established by the use of an enzymatic transesterification and hydrolysis, respectively, followed by an SN2-type substitution with a benzyloxymethyl cuprate and a sigmatropic rearrangement. The advantage of this approach is the short sequence combined with an excellent overall yield and an enantiomeric excess of 99%.
Key words
cyclopentenes - enzymes - benzyloxymethyl cuprate - spinosyns - Claisen-Ireland rearrangement
-
1a
Hodgson DM.Gibbs AR.Drew MGB. J. Chem. Soc., Perkin Trans. 1 1999, 3579 -
1b
Hodgson DM.Gibbs AR. Synlett 1997, 657 -
1c
Brown B.Hegedus LS. J. Org. Chem. 2000, 65: 1865 - 2
Tietze LF.Brasche G.Stadler C.Grube A.Böhnke N. Angew. Chem. Int. Ed. 2006, 45: 5015 ; Angew. Chem. 2006, 118, 5137 -
3a
Johnson CR.Esker JL.Van Zandt MC. J. Org. Chem. 1994, 59: 5854 -
3b
Zanoni G.Re S.Meriggi A.Castronovo F.Vidari G. Tetrahedron: Asymmetry 2001, 12: 1785 -
3c
Zanoni G.Porta A.Brunoldi E.Vidari G. J. Org. Chem. 2006, 71: 8459 - 4
Crandall JK.Banks DB.Coyler RA.Watkins RJ.Watkins JP. J. Org. Chem. 1968, 33: 423 - 5
Deardorff DR.Myles DC.MacFerrin KD. Tetrahedron Lett. 1985, 26: 5615 - 6
Theil F.Schick H.Winter G.Reck G. Tetrahedron 1991, 47: 7569 -
8a
Johnson CR.Bis SJ. Tetrahedron Lett. 1992, 33: 7287 -
8b
Reetz MT.Eipper A.Tielmann P.Mynott R. Adv. Synth. Catal. 2002, 9: 1008
References and Notes
For the preparation of 7 the following modified procedure was used. A mixture of diol 4 (8.0 g, 80 mmol), Et3N (7.7 mL, 56 mmol), vinyl acetate (11 mL, 0.12 mol) and pancreatin (30 g) in THF (150 mL) was stirred at r.t. until complete consumption of 4 (TLC). The mixture was filtered, the filter pad of the residue washed with EtOAc (3 × 50 mL) and the solvent evaporated under reduced pressure. Purification of the residue by column chromatography (n-pentane-EtOAc, 3:1) afforded acetate 7 as white crystals (8.2 g, 58 mmol, 72%, 99% ee). The diacetate 5 was isolated as by-product in 22% yield; [α]D 20 -69.0 (c 1.00, CHCl3); R f = 0.4 (n-pentane-EtOAc, 1:1). IR (KBr): 3387, 2922, 1726, 1359, 1253, 1087, 1020, 968, 910, 880, 841, 794, 606 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.66 (dt, J = 14.7, 3.8 Hz, 1 H, HB-2), 2.06 (s, 3 H, H-2′), 2.85 (dt, J = 14.7, 7.3 Hz, 1 H, HA-2), 4.70-4.75 (m, 1 H, H-3), 5.47-5.53 (m, 1 H, H-1), 5.97-6.01 (m, 1 H, H-4), 6.10-6.14 (m, 1 H, H-5). 13C NMR (50 MHz, CDCl3): δ = 21.16 (COCH3), 40.46 (C-2), 74.80 (C-1), 77.03 (C-3), 132.60 (C-4), 138.47 (C-5), 170.76 (OCOCH3). MS (EI): m/z (%) = 142.1 (1) [M+], 99 (7) [C5H7O2 +], 82 (100) [C5H6O+], 43 (78) [C2H3O+].
9
Synthesis of ent
-7.
Novo sp 435 lipase (2.0 g) was added to a suspension of diacetate 5 (15.0 g, 81.5 mmol) in a buffer (pH 8, 400 mL) and the mixture was stirred for 18 h at r.t. After that, the reaction was filtered and washed with H2O (100 mL) and EtOAc (2 × 200 mL). The aqueous layer was extracted with EtOAc (3 × 200 mL) and the combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure to afford monoacetate ent-7 as white crystals (11.1 g, 78.1 mmol, 96%, 99% ee); [α]D
20 +66 (c 1.00, CHCl3). IR (film): 3387, 2922, 1726, 1359, 1253, 1087, 1062, 1020, 968, 910, 880, 841, 794, 606 cm-1. 1H NMR (200 MHz, CDCl3): δ = 1.66 (dt, J = 14.7, 3.8 Hz, 1 H, 2-HB), 2.06 (s, 3 H, 2′-H), 2.85 (quint, J = 7.3 Hz, 1 H, 2-HA), 4.70-4.75 (m, 1 H, 3-H), 5.47-5.53 (m, 1 H, 1-H), 5.97-6.01 (m, 1 H, 4-H), 6.10-6.14 (m, 1 H, 5-H). 13C NMR (50 MHz, CDCl3): δ = 21.16, 40.46, 74.80, 77.03, 132.60, 138.47, 170.76. MS (EI, 70 eV): m/z (%) = 142.1 (1) [M+], 99 (7) [C5H7O2
+], 82 (100) [C5H6O+], 43 (78) [C2H3O+].
Synthesis of 8.
Magnesia turnings (575 mg, 23.6 mmol) were dried in vacuo at r.t. for 12 h. After activation with bromine and HgCl2 a solution of benzyl chloromethyl ether (0.5 mL, 0.55 g, 3.5 mmol) in THF (2 mL) was added, whereupon the reaction started. The reaction mixture was then cooled immediately to -5 °C and more benzyl chloromethyl ether (1.5 mL, 1.65 g, 10.5 mmol) was added carefully as a solution in THF (20 mL). After additional stirring for 2.5 h at -5 °C the mixture was transferred into a suspension of CuCN (35 mg, 10 mol%) in THF (20 mL) at -20 °C and stirred for 5 min. Monoacetate 7 (550 mg, 3.90 mmol) was added and the reaction stirred for further 15 min. After addition of sat. NH4Cl (20 mL) and aq NH3 (20 mL) the aqueous layer was separated and extracted with EtOAc (3 × 70 mL). The combined organic layers were dried (Na2SO4) and the solvent removed under reduced pressure. Purification of the residue by column chromatography (n-pentane-EtOAc, 3:1) afforded benzyl ether 8 as a clear liquid (732 mg, 3.59 mmol, 92%); [α]D
20 +146.3 (c 1.00, CHCl3); R
f
= 0.17 (n-pentane-EtOAc, 3:1). IR (KBr): 3380, 3060, 2856, 1651, 1496, 1453, 1361, 1074, 1028, 738, 698 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.75 (s, 1 H, OH), 1.81-2.01 (m, 2 H, H2-5), 3.12-3.24 (m, 1 H, H-4), 3.29-3.41 (m, 2 H, CH2OBn), 4.51 (s, 2 H, CH2Ph), 4.84-4.91 (m, 1 H, H-1), 5.89 (dt, J = 5.6, 2.2 Hz, 1 H, H-2), 5.97-6.01 (m, 1 H, H-3), 7.24-7.38 (m, 5 H, PhH). 13C NMR (75 MHz, CDCl3): δ = 37.3, 44.8, 73.0, 73.9, 76.9, 127.5, 128.3, 134.3, 136.8, 138.3. MS (EI, 70 eV): m/z = 204.1 [M+]. HRMS (EI): m/z [M]+ calcd for C13H16O2: 204.2649; found: 204.2649.
Synthesis of 9.
DIAD (3.94 g, 19.5 mmol) was added dropwise to a stirred solution of benzyl ether 8 (1.98 g, 9.74 mmol), Ph3P (5.12 g, 19.5 mmol) and AcOH (2.23 mL, 2.34 g, 39.0 mmol) in Et2O (60 mL) at 0 °C. After stirring for 30 min at 0 °C the reaction was filtered and the filtrate was washed with cold pentane (4 × 100 mL). The combined extracts were washed with sat. NaHCO3 (100 mL) and the aqueous layer was separated and extracted with pentane (2 × 100 mL). The combined extracts were dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue by column chromatography (PE-EtOAc, 20:1) gave acetate 9 as a colorless oil (4.56 g, 18.5 mmol, 95%); [α]D
20 -1.10 (c 1.00, CHCl3); R
f
= 0.24 (n-pentane-EtOAc, 15:1). UV/Vis (MeOH): λmax (lg ε) = 204.5 (3.926), 251.0 (2.324), 257.0 (2.304), 263.0 (2.140) nm. IR (film): 3391, 3064, 2857, 1732, 1496, 1454, 1364, 1243, 1202, 1092, 1025, 907, 740, 708 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.54 (dt, J = 14.3, 4.1 Hz, 1 H, HA-5), 1.99 (s, 3 H, CH3), 2.46 (dt, J = 14.3, 7.9 Hz, 1 H, HB-5), 2.92 (mc, 1 H, H-4), 3.33-3.46 (m, 2 H, CH2OBn), 4.52 (s, 2 H, CH2Ph), 5.59-5.66 (m, 1 H, H-1), 5.84 (dt, J = 5.7, 2.3 Hz, 1 H, H-2), 6.03-6.07 (m, 1 H, H-3), 7.25-7.37 (m, 5 H, PhH). 13C NMR (50 MHz, CDCl3): δ = 21.26, 33.59, 44.79, 73.08, 74.05, 79.47, 127.55, 127.57, 128.33, 130.49, 138.13, 138.30, 170.85. MS (EI, 70 eV): m/z (%) = 246.2 (1) [M+], 203.1 (4) [M - C2H3O+], 186.1 (12) [M - C2H4O2
+], 91 (100) [C7H7
+]. HRMS (ESI): m/z [M + Na]+ calcd for C8H10NaO2: 269.11482; found: 269.11473.
Synthesis of 10.
n-BuLi (2.5 M in hexane, 12.0 mL, 29.9 mmol) was added dropwise to a stirred solution of DIPA (4.33 mL, 3.10 g, 31.0 mmol) in THF (20 mL) at 0 °C. After 5 min HMPA (5 mL) was added and the reaction was cooled to -78 °C and stirred for further 10 min whereupon a solution of acetate 9 (5.08 g, 20.7 mmol) in THF (35 mL) was added dropwise. The reaction was maintained at -78 °C for additional 20 min. A solution of TBSCl (4.07 g, 27.0 mmol) in THF (5 mL) was added and the reaction was stirred at -78 °C for 5 min before warming to r.t. Then pentane (150 mL) and aq NaOH (0.1 M, 150 mL) were added. The aqueous layer was separated and extracted with pentane (2 × 150 ml). The combined pentane extracts were washed with aq NaOH (0.1 M, 2 × 100 mL), H2O (100 mL), dried (Na2SO4) and the solvent evaporated to give the title compound as a yellow oil (7.45 g, 20.7 mmol, quant.) which was used without further purification steps for the next reaction; [α]D
20 +18.5 (c 1.00, CHCl3). UV/Vis (MeOH): λmax (lg ε) = 251.5 (2.728), 257.5 (2.734), 263.0 (2.666) nm. IR (film): 3426, 3063, 2929, 2855, 1734, 1496, 1454, 1363, 1244, 1093, 1026, 937, 873, 835, 770, 737, 698 cm-1. 1H NMR (300 MHz, CDCl3): δ = 0.24 [s, 6 H, Si(CH3)2], 0.89 [s, 9 H, (SiC(CH3)3], 1.57-1.60 (m, 1 H, HA-5), 2.40-2.52 (m, 1 H, HB-5), 2.80-2.96 (m, 1 H, H-4), 3.25-3.60 (m, 4 H, CH2OBn, H2-2′) 4.51 (s, 2 H, CH2Ph), 5.59-5.65 (m, 1 H, H-1), 5.80-6.08 (m, 2 H, H-2, H-3). 13C NMR (75 MHz, CDCl3): δ = -3.62, 17.94, 25.60, 33.57, 44.78, 69.40 73.08, 74.04, 79.49, 127.56, 128.33, 130.48, 138.13, 138.27, 160.51. MS (DCI): m/z (%) = 378.4 (12) [M + NH4
+], 361.4 (4) [M + H+], 264.2 (100) [C15H18O3 + NH4
+].
Synthesis of 11.
A solution of crude silyl ketene acetal 10 (7.45 g, 20.7 mmol) in dry xylene (50 mL) was heated in a sealed tube to 180 °C for 18 h. After cooling to ambient temperature the solvent was removed under reduced pressure and the residue dissolved in THF (60 mL). Then, aq NaOH (2 M, 60 mL) was added and the reaction stirred vigorously for 2 h. Pentane was then added (100 mL) and the mixture extracted with aq NaOH (2 M, 3 × 150 mL). The combined aqueous layers were acidified to pH 1 with HCl (6 M) and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over Na2SO4 and the solvent evaporated under reduced pressure. Purification of the residue by column chromatography (pentane-EtOAc, 6:1 + 0.5% AcOH) gave acid 11 as a pale yellow oil (4.43 g, 18.0 mmol, 87%); [α]D
20 +76.1 (c 1.00, CHCl3); R
f
= 0.34 (n-pentane-EtOAc, 5:1, 6% AcOH). UV/Vis (MeOH): λmax (lg ε) = 251.5 (2.265), 257.5 (2.321), 263.5 (2.201) nm. IR (film): 3060, 2926, 1706, 1496, 1453, 1410, 1364, 1276, 1200, 1098, 1028, 935, 735, 698 cm-1. 1H NMR (200 MHz, CDCl3): δ = 2.04-2.14 (m, 1 H, HB-4′), 2.21 (dd, J = 15.6, 9.0 Hz, 1 H, HB-2), 2.32-2.46 (m, 1 H, HA-4′), 2.58 (dd, J = 15.6, 6.5 Hz, 1 H, HA-2), 2.70 (mc, 1 H, H-5′), 3.13-3.24 (m, 1 H, H-1′), 3.42-3.52 (m, 2 H, CH2OBn), 4.49 (s, 2 H, CH2Ph), 5.72-5.75 (m, 2 H, H-2′, H-3′), 7.24-7.38 (m, 5 H, Ph-H). 13C NMR (50 MHz, CDCl3): δ = 34.60, 34.89, 40.01, 42.32, 70.58, 73.01, 127.55, 127.65, 128.33, 130.38, 133.71, 138.10, 179.39. MS (EI, 70 eV): m/z (%) = 246.2 (4) [M+], 91 (100) [C7H7
+]. HRMS (ESI): m/z [M + Na]+ calcd for C15H18NaO3: 269.11482; found: 269.11487.
Synthesis of 2.
BCl3 (ca. 1 M in CH2Cl2, 2.0 mL, 2.0 mmol) was added dropwise to a solution of acid 11 (246 mg, 1.00 mmol) in CH2Cl2 (10 mL) at -40 °C. The reaction was allowed to warm to 0 °C while being continuously stirred for 2 h. After being stirred for a further 15 min at 0 °C sat. NH4Cl (5 mL) was added, the aqueous layer was separated and extracted with CH2Cl2 (3 × 50 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated under reduced pressure. After purification of the residue by column chromatography (n-pentane-Et2O, 1:1) 2 was obtained as a white solid (124 mg, 890 µmol, 89%); [α]D
20 +51.0 (c 0.30, CH2Cl2); R
f
= 0.22 (n-pentane-Et2O, 1:1). IR (KBr): 3444, 3052, 2994, 2900, 2854, 1742, 1484, 1435, 1386, 1358, 1340, 1280, 1232, 1078, 991, 950, 861, 758, 724 cm-1. 1H NMR (300 MHz, CDCl3): δ = 2.21-2.31 (m, 1 H, HB-7), 2.25 (dd, J = 15.0, 7.2 Hz, 1 H, HB-4), 2.62-2.86 (m, 2 H, 7-HA, H-7a), 2.66 (dd, J = 15.0, 6.4 Hz, 1 H, HA-4), 3.26-3.40 (m, 1 H, H-4a), 4.10 (dd, J = 11.3, 6.4 Hz, 1 H, HA-1) 4.30 (dd, J = 11.3, 4.3 Hz, 1 H, HB-1), 5.56 and 5.76 (2 × mc, 2 × 1 H, H-5, H-6). 13C NMR (75 MHz, CDCl3): δ = 33.79, 33.87, 41.84, 70.27, 130.88, 131.79, 173.37. MS (EI, 70 eV): m/z = 138 (6) [M+], 66.0(100) [C6H6]+. HRMS (EI): m/z [M]+ calcd for C8H10O2: 138.0681; found: 138.0681.