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.

 

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Key words

maresins - asymmetric synthesis - trienes - Swern oxidation

Resolvins and protectins, metabolized from polyunsaturated fatty acids, are specialized pro-resolving mediators (SPMs).[1] SPMs have been reported to actively promote the resolution of inflammation. In 2014, Serhan isolated maresin 2 from human macrophages as a metabolite derived from docosahexaenoic acid (Figure [1]).[2] This compound shows a strong antiinflammatory effect at 1 ng per mouse in a mouse peritonitis model.[2] Maresin 2_{n-3 DPA}, possessing a single bond at the C4–C5 position of maresin 2, also shows an antiinflammatory effect.[3] Several SPMs are undergoing initial clinical trials, and maresin 1 has recently been reported to possess wound-healing activity.[4] Consequently, maresin 2 and maresin 2_{n-3 DPA} are also of interest as candidates for drug-discovery research. However, maresins are available only in minute amounts from natural sources. In addition, commercially available maresin 2 is expensive, making it difficult to obtain sufficient amounts. The groups of Spur and Hansen have reported syntheses of these compounds through the chiral-pool method with 2-deoxy-d-ribose as a starting material.[5] However, drug-discovery research requires a flexible synthetic method that can efficiently supply the desired chiral centers. We have previously synthesized various lipid mediators by constructing chiral centers by asymmetric reactions.[6] Here, we report stereoselective syntheses of maresin 2 and maresin 2_{n-3 DPA} by using asymmetric reactions.

Figure 1 Structures of maresins

Scheme [1] outlines our retrosynthetic analysis of maresin 2 (2). We planned to construct the triene of 2 by connecting two components, the terminal alkyne 4 and the iodoalkene 5, by a Sonogashira coupling reaction, followed by acetylene reduction.[6] The internal cis-olefin 4 would be obtained from γ-butyrolactone by a Wittig reaction. The vicinal diol at C13–C14 would be constructed stereoselectively by a Sharpless asymmetric epoxidation, followed by an epoxide ring opening of the β,γ-epoxy aldehyde.

Scheme 1 Retrosynthetic analysis of maresin 2 (2)

The first step in our synthesis of maresin 2 (2) involved the preparation of enyne 4 (Scheme [2]). Phosphonium salt 9 was synthesized from but-3-yn-1-ol (8) by a previously reported procedure.[7] The ring-opening reaction of γ-butyrolactone (10) with Et₃N/MeOH generated the corresponding alcohol, which was then oxidized with sulfur trioxide/pyridine (SO₃·py) to yield aldehyde 11. Wittig reaction of 11 with phosphonium salt 9 in the presence of NaHMDS afforded the terminal alkyne 4 [8] in 64% yield over the three steps.

Scheme 2 Synthesis of terminal alkyne 4

Next, the iodoolefin 5 was prepared via the epoxy alcohol 19. Propane-1,3-diol (12) was converted into the silyl ether 13 by a reported procedure (Scheme [3]).[9] Oxidation of 13 by SO₃·py was followed by the addition of alkyne 14 [10] to the resulting aldehyde to give alcohol rac-15 in 65% yield. Oxidation of rac-15 followed by asymmetric transfer hydrogenation[11] produced the optically active alcohol (S)-15 in 69% yield with 98% ee, as determined by ¹H NMR analysis of its α-methoxy-α-(trifluoromethyl)phenylacetic (MTPA) ester derivative. Treatment of (S)-15 with Red-Al not only reduced the triple bond, but also promoted deprotection of the TBDPS group. As a result, the resulting primary hydroxy group was protected once again with TBDPSCl to give allylic alcohol 17 [8] in 51% yield. This was then converted into the epoxy alcohol 18 by a Sharpless asymmetric epoxidation[6c] [12] in 75% yield with >99% ee, as determined by ¹H NMR analysis of the MTPA ester derivative. In this reaction, the enantiomeric purity was improved by kinetic resolution of 17 (98% ee). Protection of epoxy alcohol 18 followed by deprotection using DDQ afforded alcohol 19 in 58% yield.

Scheme 3 Synthesis of epoxy alcohol 19

Enal 20,[8] containing a vicinal diol, was prepared in 69% yield by oxidation of epoxy alcohol 19 followed by cleavage of the epoxide ring (Scheme [4]). Protection of 20 with TBSOTf in the presence of 2,6-lutidine gave the disilyl ether 21 in 83% yield; this was subsequently converted into enyne 22 (76% yield) by treatment with TMSCHN₂ and LDA.[13] The (E)-stereoselectivity of the olefin in 22 was >99%, as determined by ¹H NMR spectroscopy. Hydrozirconation of 22 with Cp₂Zr(H)Cl, generated in situ from Cp₂ZrCl₂ and DIBAL,[14] followed by iodination of the resulting vinylzirconium species with I₂ produced vinyl iodide 23.[8] The TBS and TBDPS groups in 23 were then replaced by TES groups in a two-step reaction to produce 24. Swern oxidation[15] of 24 occurred regioselectively at the terminal carbon to afford an aldehyde that, upon Wittig reaction with phosphonium salt 7 [5a] followed by desilylation, afforded iodoolefin 5 [8] in 59% yield over three steps.

Scheme 4 Synthesis of iodoolefin 5

In the last stage, the synthesis of maresin 2 (2) was completed, as shown in Scheme [5]. Polyene 25 was synthesized in 61% yield by Sonogashira coupling of the alkyne 4 and iodoolefin 5.[6] Finally, reduction of 25 by Zn(Cu/Ag),[6b] [c] ^, [16] followed by hydrolysis with aqueous LiOH afforded maresin 2 (2) in 63% yield.[17] The spectral data (NMR and UV) of 2 were in good agreement with those reported previously.[5b]

Scheme 5 Synthesis of maresin 2 (2)

Next, maresin 2_{n-3 DPA} (3) was synthesized according to the method shown in Scheme [6]. Alkyne 28 was obtained by Sonogashira coupling of iodoolefin 5 with alkyne 27, prepared from oct-7-yn-1-ol (26) in three steps. Maresin 2_{n-3 DPA} (3) was then synthesized in a two-step reaction by using the same method as used for 2. The spectral data (NMR and UV) and [α] _d of 3 were consistent with those reported previously.[5a]

Scheme 6 Synthesis of maresin 2_{n-3 DPA} (3)

In conclusion, we have accomplished asymmetric syntheses of maresin 2 (2) and maresin 2_{n-3 DPA} (3). Alkyne 4 was synthesized from γ-butyrolactone (10) and phosphonium salt 7 in three steps. Meanwhile, vicinal diol 20 was constructed by a Sharpless asymmetric epoxidation and a Swern oxidation. Diol 20 was then converted into iodoolefin 5 by a multistep reaction. Finally, reaction of 4 with 5 gave maresin 2 (2) in 22 steps from propane-1,3-diol (12) with a total yield of 0.79%. We also synthesized 3 by using the same approach as that described for 2 in 22 steps from 12, with a total yield of 0.58%. The spectral data for 2 and 3 were consistent with those previously reported.[5]

 

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• 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.

Publication History

Received: 02 September 2020

Accepted after revision: 02 October 2020

Article published online:
02 November 2020