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DOI: 10.1055/s-2005-917099
Synthesis of Macrocyclic Dilactones through Lipases
Publication History
Publication Date:
05 October 2005 (online)
Abstract
We report herein a selective and efficient method to prepare macrocyclic dilactones in good yields from diols and succinic anhydride through a biocatalytic condensation reaction.
Key words
Candida antarctica B - macrocyclic dilactones - lipases - synthesis - biocatalysis
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References
As a typical example, in a 25 mL Erlenmeyer flask was placed a mixture of 0.118 g (1 mmol) of hexanediol, 0.100 g (1 mmol) of succinic anhydride, 15 mL of toluene and 0.100 g of Candida antarctica B lipase. The Erlenmeyer flask was capped, placed in a tempered bath at 30 °C, and shaken at 80 U. The reaction was monitored by GC and when the transformation was complete (24 h reaction), the mixture was filtered and the enzyme washed with Et2O and MeOH. The solvent was stripped off and the resulting crude purified by column chromatography on silica gel eluting with hexane-Et2O mixtures to furnish 0.337 g (84%) of lactone 4d. Mp 96-98 °C. IR (KBr): 2984, 2945, 2864, 1728, 1268, 1172 cm-1. 1H NMR (300 MHz): δ = 4.06 (t, J = 6.6 Hz, 8 H, 4 CH2O), 2.58 (s, 8 H, 4 CH2CO), 1.54 (m, 8 H, 4 CH2), 1.34 (m, 8 H, 4 CH2). 13C NMR (75 MHz): δ = 172.01 (CO), 64.51 (OCH2), 29.42, 29.28, 28.44, 28.37, 25.47. Anal. Calcd for C20H32O8: C, 59.98; H, 8.05. Found: C, 60.12; H, 8.08. MS (CI): m/z (%) = 401 (100) [M+ + 1], 429 (8) [M+ + 29], 441 (5) [M+ + 41].
15Esterification was achieved by addition of anhyd DMF (0.90 mL) and K2CO3 (93 mg, 0.65 mmol) to the crude lipase-catalyzed reaction (52 mg). The suspension was magnetically stirred for 20 min, then MeI (0.300 mL, 4.81 mmol) was added and the mixture stirred for 16 h. After conventional work up, a mixture of the methyl esters 6d and 7d, starting material 1d, and dilactone 4d were obtained in almost quantitatively yield.
16Spectroscopic and analytical data of compounds 4a-f.
Compound 4a: mp 84 -87 °C. IR (KBr): 2963, 1727, 1265, 1182 cm-1. 1H NMR (300 MHz): δ = 4.28 (s, 8 H, 4 CH2O), 2.66 (s, 8 H, 4 CH2CO). 13C NMR (75 MHz): δ = 171.53 (CO), 62.46 (CH2O), 29.31. Anal. Calcd for C12H16O8: C, 50.00; H, 5.59. Found: C, 49.89; H, 5.47. MS (CI):
m/z (%) = 289 (100) [M+ + 1].
Compound 4b: mp 86-88 °C. IR (KBr): 2967, 1722, 1275, 1193 cm-1. 1H NMR (300 MHz): δ = 4.14 (t, J = 5.7 Hz, 8 H, 4 CH2O), 2.62 (s, 8 H, 4 CH2CO), 1.94 (q, J = 6.0 Hz, 4 H, 2 CH2). 13C NMR (75 MHz): δ = 171.77 (CO), 60.83 (CΗ2O), 29.59, 27.67. Anal. Calcd for C14H20O8: C, 53.16; H, 6.37. Found: C, 53.05; H, 6.22. MS (CI): m/z (%) = 317 (100) [M+ + 1].
Compound 4c: mp 88-92 °C. IR (KBr): 2964, 1716, 1265, 1176 cm-1. 1H NMR (300 MHz): δ = 4.09 (m, 8 H, 4 CH2O), 2.62 (s, 8 H, 4 CH2CO), 1.68 (m, 8 H, 4CH2). 13C NMR (75 MHz): δ = 171.94 (CO), 64.36 (CΗ2O), 29.53, 25.24. Anal. Calcd for C16H24O8: C, 55.81; H, 7.02. Found: C, 55.82; H, 7.11. MS (CI): m/z (%) = 345 (100) [M+ + 1].
Compound 4e: mp 87-91 °C. IR (KBr): 2948, 1726, 1265, 1173 cm-1. 1H NMR (300 MHz): δ = 4.06 (t, J = 6.0 Hz, 8 H, 4 CH2O), 2.60 (s, 8 H, 4 CH2CO), 1.52 (m, 8 H, 4 CH2), 1.30 (s, 16 H, 8 CH2). 13C NMR (75 MHz): δ = 177.11 (CO), 64.71 (CH2O), 29.54, 29.10, 28.54, 25.75. Anal. Calcd for C24H40O8: C, 63.14; H, 8.83. Found: C, 63.24; H, 8.94. MS (CI): m/z (%) = 457 (100) [M+ + 1].
Compound 4f: mp 69-72 °C. IR (KBr): 2923, 1729, 1266, 1172 cm-1. 1H NMR (300 MHz): δ = 4.08 (t, J = 6.6 Hz, 8 H, 4 CH2O), 2.62 (s, 8 H, 4 CH2CO), 1.60 (m, 8 H, 4 CH2), 1.29 (s, 24 H, 12 CH2). 13C NMR (75 MHz): δ = 172.15 (CO), 64.79 (CH2O), 29.51, 29.38, 29.30, 29.18, 28.56, 25.83. Anal. Calcd for C28H48O8: C, 65.60; H, 9.44. Found: C, 65.66; H, 9.41. MS (CI): m/z (%) = 513 (100) [M+ + 1].