Synthesis of Macrocyclic Dilactones through Lipases

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.

Candida antarctica B - macrocyclic dilactones - lipases - synthesis - biocatalysis

References

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1c Nicolaou KC. Tetrahedron  1977,  33:  683 

1d Paterson I. Mansuri MM. Tetrahedron  1985,  41:  3569 

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4 Asay RE. Bradshaw JS. Nielsen SF. Thompson MD. Snow JW. Masihdas DRK. Izatt RM. Christensen JJ. J. Heterocycl. Chem.  1977,  14:  85 

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11 Cyclic anhydrides have been used as acylating agents in enzyme-catalyzed reactions. See for instance: de Gonzalo G. Brieva R. Sánchez VM. Bayod M. Gotor V. J. Org. Chem.  2003,  68:  3333 

12 Mori K. Synlett  1995,  1097 

13 Roberts SM. J. Chem. Soc., Perkin Trans. 1  2001,  1475 

14

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].

15

Esterification 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.

16

Spectroscopic 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].

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