Synthesis of Optically Active Maresin 2 and Maresin 2_{n-3 DPA}

Abstract

Maresins are among the most potent antiinflammatory lipid metabolites. We report stereoselective syntheses of maresin 2 and maresin 2_{n-3 DPA}. The anti-diol was constructed through epoxide ring opening of an optically active β,γ-epoxy aldehyde, synthesized in situ by Swern oxidation of the corresponding alcohol. Finally, the target compounds were synthesized through a Sonogashira coupling of a C9–C22 iodide and methyl (Z)-oct-4-en-7-ynoate or methyl oct-7-ynoate, respectively.

Key words

maresins - asymmetric synthesis - trienes - Swern oxidation

Publication History

Received: 02 September 2020

Accepted after revision: 02 October 2020

Article published online:
02 November 2020

• References and Notes

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• 17 Maresin 2 (2) Cu(OAc)₂ (101 mg, 0.55 mmol) and AgNO₃ (103 mg, 0.61 mmol) were added to a slurry of Zn (1.08 g, 16.5 mmol) in H₂O (1 mL), and the mixture was stirred for 1 h then filtered by using a Hirsch funnel. The remaining Zn solids were washed successively with H₂O (1 mL), MeOH (1 mL), acetone (1 mL), and Et₂O (1 mL). The activated Zn solids were transferred to 1:1 MeOH–H₂O (2 mL), and a solution of alkyne 25 (30.7 mg, 0.082 mmol) in MeOH (1 mL) was added to the suspension of activated Zn. The mixture was stirred for 11 h then filtered through a plug of cotton that was washed with EtOAc. The mixture was concentrated, and the residue was semi-purified by chromatography (silica gel), ready for the next reaction. To an ice-cold solution of the resulting ester in MeOH (1 mL) and THF (1 mL) was added 2 N aq LiOH (0.82 mL, 1.64 mmol). After 5 h at 0 °C, citrate–phosphate buffer (pH 5.0, 40 mL) was added, and the resulting mixture was extracted with EtOAc (×7). The combined extracts were dried (MgSO₄) and concentrated, and the residue was purified by chromatography (silica gel, hexane–EtOAc) to give maresin 2 (2) as a pale-yellow oil; yield: 18.5 mg (63% from 25); R_f = 0.61 (hexane–EtOAc, 1:2); [α]_D ²⁴ +45.8 (c 0.37, MeOH). IR (neat): 3454, 2064, 1727, 1652 cm^–1. ¹H NMR (400 MHz, CD₃OD): δ = 0.86 (t, J = 7.4 Hz, 3 H), 1.97 (quin, J = 7.4 Hz, 2 H), 2.02–2.13 (m, 1 H), 2.20–2.33 (m, 5 H), 2.70 (t, J = 6.2 Hz, 2 H), 2.89 (t, J = 6.0 Hz, 2 H), 3.47 (dt, J = 8.4, 5.0 Hz, 1 H), 3.92 (dd, J = 7.0, 5.0 Hz, 1 H), 4.84 (s, 3 H, overlapped with the residue from CD₃OD), 5.15–5.43 (m, 7 H), 5.72 (dd, J = 14.8, 7.0 Hz, 1 H), 5.94 (t, J = 11.0 Hz, 1 H), 6.16 (dd, J = 14.8, 11.0 Hz, 1 H), 6.26 (dd, J = 14.8, 11.0 Hz, 1 H), 6.48 (dd, J = 14.8, 11.0 Hz, 1 H). ¹³C NMR (100 MHz, CD₃OD): δ = 14.7, 21.5, 23.8, 26.6, 27.0, 31.8, 35.0, 75.8, 76.3, 127.1, 128.2, 129.1, 129.5, 129.7, 129.8, 131.0, 131.2, 132.7, 133.6, 133.7, 133.8, 177.1. HRMS (FD): m/z [M⁺] calcd for C₂₂H₃₂O₄: 360.23006; found: 360.23029. UV (MeOH): λ_max = 262, 274, 282 nm.