Synlett 2021; 32(03): 295-298
DOI: 10.1055/s-0040-1705959
letter

Synthesis of Optically Active Maresin 2 and Maresin 2n-3 DPA

a   Department of Applied Chemistry, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, Japan   Email: narihito@meiji.ac.jp
,
Takahito Amano
a   Department of Applied Chemistry, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, Japan   Email: narihito@meiji.ac.jp
,
Yuichi Kobayashi
b   Organization for the Strategic Coordination of Research and Intellectual Properties, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, Japan
› Author Affiliations
This work was supported by Research Project Grant (B) by Institute of Science and Technology Meiji University (N.O.).
 


Abstract

Maresins are among the most potent antiinflammatory lipid metabolites. We report stereoselective syntheses of maresin 2 and maresin 2n-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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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 2n-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 2n-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 2n-3 DPA by using asymmetric reactions.

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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.

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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.

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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.

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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.

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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]

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Scheme 5 Synthesis of maresin 2 (2)

Next, maresin 2n-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 2n-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]

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

In conclusion, we have accomplished asymmetric syntheses of maresin 2 (2) and maresin 2n-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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Supporting Information

  • References and Notes

  • 2 Deng B, Wang C.-W, Arnardottir HH, Li Y, Cheng C.-YC, Dalli J, Serhan CN. PLoS One 2014; 9: e102362
  • 3 Dalli J, Colas RA, Serhan CN. Sci. Rep. 2013; 3: 1940 ; corrigendum: Sci. Rep. 2014, 4, 6726
    • 4a Wang CW, Yu SH, Fretwurst T, Larsson L, Sugai JV, Oh J, Lehner K, Jin Q, Giannobile WV. J. Dent. Res. 2020; 99: 930
    • 4b Serhan CN, Levy BD. J. Clin. Invest. 2018; 128: 2657
    • 5a Sønderskov J, Tungen JE, Palmas F, Dalli J, Serhan CN, Stenstrøm Y, Hansen TV. Tetrahedron Lett. 2020; 61: 151510
    • 5b Rodriguez AR, Spur BW. Tetrahedron Lett. 2015; 56: 256
    • 6a Ogawa N, Sone S, Hong S, Lu Y, Kobayashi Y. Synlett 2020; 31: 1735
    • 6b Morita M, Tanabe S, Arai T, Kobayashi Y. Synlett 2019; 30: 1351
    • 6c Morita M, Wu S, Kobayashi Y. Org. Biomol. Chem. 2019; 17: 2212
  • 7 Kobayashi Y, Morita M, Ogawa N, Kondo D, Tojo T. Org. Biomol. Chem. 2016; 14: 10667
  • 8 The double bond of the product was obtained with high selectivity. The corresponding olefin isomer could not be detected by 1H NMR spectroscopy.
  • 9 Druais V, Hall MJ, Corsi C, Wendeborn SV, Meyer C, Cossy J. Org. Lett. 2009; 11: 935
  • 10 Banfi L, Basso A, Guanti G, Riva R. Tetrahedron 2006; 62: 4331
  • 11 Matsumura K, Hashiguchi S, Ikariya T, Noyori R. J. Am. Chem. Soc. 1997; 119: 8738
  • 12 Gao Y, Hanson RM, Klunder JM, Ko SY, Masamune H, Sharpless KB. J. Am. Chem. Soc. 1987; 109: 5765
    • 13a Miwa K, Aoyama T, Shioiri T. Synlett 1994; 107
    • 13b Colvin EW, Hamill BJ. J. Chem. Soc., Chem. Commun. 1973; 151
    • 14a Huang Z, Negishi E.-i. Org. Lett. 2006; 8: 3675
    • 14b Spino C, Tremblay M.-C, Godbout C. Org. Lett. 2004; 6: 2801 ; corrigendum: Org. Lett. 2005, 7, 1673
    • 14c Kiyotsuka Y, Igarashi J, Kobayashi Y. Tetrahedron Lett. 2002; 43: 2725
  • 15 Afonso CM, Barros MT, Maycock CD. J. Chem. Soc., Perkin Trans. 1 1987; 1221
  • 16 Boland W, Schroer N, Sieler C, Feigel M. Helv. Chim. Acta 1987; 70: 1025
  • 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); Rf = 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): λmax = 262, 274, 282 nm.

Corresponding Author

Narihito Ogawa
Department of Applied Chemistry, Meiji University
1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571
Japan   

Publication History

Received: 02 September 2020

Accepted after revision: 02 October 2020

Article published online:
02 November 2020

© 2020. Thieme. All rights reserved

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  • References and Notes

  • 2 Deng B, Wang C.-W, Arnardottir HH, Li Y, Cheng C.-YC, Dalli J, Serhan CN. PLoS One 2014; 9: e102362
  • 3 Dalli J, Colas RA, Serhan CN. Sci. Rep. 2013; 3: 1940 ; corrigendum: Sci. Rep. 2014, 4, 6726
    • 4a Wang CW, Yu SH, Fretwurst T, Larsson L, Sugai JV, Oh J, Lehner K, Jin Q, Giannobile WV. J. Dent. Res. 2020; 99: 930
    • 4b Serhan CN, Levy BD. J. Clin. Invest. 2018; 128: 2657
    • 5a Sønderskov J, Tungen JE, Palmas F, Dalli J, Serhan CN, Stenstrøm Y, Hansen TV. Tetrahedron Lett. 2020; 61: 151510
    • 5b Rodriguez AR, Spur BW. Tetrahedron Lett. 2015; 56: 256
    • 6a Ogawa N, Sone S, Hong S, Lu Y, Kobayashi Y. Synlett 2020; 31: 1735
    • 6b Morita M, Tanabe S, Arai T, Kobayashi Y. Synlett 2019; 30: 1351
    • 6c Morita M, Wu S, Kobayashi Y. Org. Biomol. Chem. 2019; 17: 2212
  • 7 Kobayashi Y, Morita M, Ogawa N, Kondo D, Tojo T. Org. Biomol. Chem. 2016; 14: 10667
  • 8 The double bond of the product was obtained with high selectivity. The corresponding olefin isomer could not be detected by 1H NMR spectroscopy.
  • 9 Druais V, Hall MJ, Corsi C, Wendeborn SV, Meyer C, Cossy J. Org. Lett. 2009; 11: 935
  • 10 Banfi L, Basso A, Guanti G, Riva R. Tetrahedron 2006; 62: 4331
  • 11 Matsumura K, Hashiguchi S, Ikariya T, Noyori R. J. Am. Chem. Soc. 1997; 119: 8738
  • 12 Gao Y, Hanson RM, Klunder JM, Ko SY, Masamune H, Sharpless KB. J. Am. Chem. Soc. 1987; 109: 5765
    • 13a Miwa K, Aoyama T, Shioiri T. Synlett 1994; 107
    • 13b Colvin EW, Hamill BJ. J. Chem. Soc., Chem. Commun. 1973; 151
    • 14a Huang Z, Negishi E.-i. Org. Lett. 2006; 8: 3675
    • 14b Spino C, Tremblay M.-C, Godbout C. Org. Lett. 2004; 6: 2801 ; corrigendum: Org. Lett. 2005, 7, 1673
    • 14c Kiyotsuka Y, Igarashi J, Kobayashi Y. Tetrahedron Lett. 2002; 43: 2725
  • 15 Afonso CM, Barros MT, Maycock CD. J. Chem. Soc., Perkin Trans. 1 1987; 1221
  • 16 Boland W, Schroer N, Sieler C, Feigel M. Helv. Chim. Acta 1987; 70: 1025
  • 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); Rf = 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): λmax = 262, 274, 282 nm.

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Figure 1 Structures of maresins
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Scheme 1 Retrosynthetic analysis of maresin 2 (2)
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Scheme 2 Synthesis of terminal alkyne 4
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Scheme 3 Synthesis of epoxy alcohol 19
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Scheme 4 Synthesis of iodoolefin 5
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Scheme 5 Synthesis of maresin 2 (2)
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Scheme 6 Synthesis of maresin 2n-3 DPA (3)