Download PDF
Synlett 2022; 33(01): 76-79
DOI: 10.1055/s-0040-1719855
letter

Total Synthesis of Resolvin T4

Narihito Ogawa  ∗
a   Department of Applied Chemistry, Meiji University, 1-1-1, Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, Japan
,
Kohei Arai
a   Department of Applied Chemistry, Meiji University, 1-1-1, Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, Japan
,
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 AffiliationsThis work was supported by Research Project Grant B from the Institute of Science and Technology, Meiji University.
› Further Information
    Permissions and Reprints All articles of this category


Abstract

A total synthesis of resolvin T4 was achieved by connecting three intermediates by Wittig reactions. The enal in the C1–C10 part was constructed through reduction of a propargylic alcohol with Red-Al followed by oxidation. The enal moiety in the C11–C16 part was synthesized by a ring-opening reaction of a silyl epoxide followed by a Peterson elimination. The chiral centers at C7 and C13 were constructed by ruthenium-catalyzed asymmetric transfer hydrogenation.

Key words

resolvin T4 - total synthesis - ruthenium catalysis - asymmetric catalysis - Peterson elimination - Wittig reaction

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0040-1719855.
  • Supporting Information


Publication History

Received: 21 September 2021

Accepted after revision: 15 October 2021

Article published online:
12 November 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References and Notes

  • 1 Serhan CN, Levy BD. J. Clin. Invest. 2018; 128: 2657
    CrossrefPubMed
  • 2 Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR, Mirick G, Moussignac R.-L. J. Exp. Med. 2002; 196: 1025
    CrossrefPubMed
  • 3 Hong S, Gronert K, Devchand PR, Moussignac R.-L, Serhan CN. J. Biol. Chem. 2003; 278: 14677
    CrossrefPubMed
  • 4 Serhan CN, Yang R, Martinod K, Kasuga K, Pillai PS, Porter TF, Oh FS, Spite M. J. Exp. Med. 2009; 206: 15
    CrossrefPubMed
  • 5 Dalli J, Chiang N, Serhan CN. Nat. Med. 2015; 21: 1071
    CrossrefPubMed
    • 6a Primdahl KG, Aursnes M, Walker ME, Colas RA, Serhan CN, Dalli J, Hansen TV, Vik A. J. Nat. Prod. 2016; 79: 2693
      CrossrefPubMed
    • 6b Vik A, Dalli J, Hansen TV. Bioorg. Med. Chem. Lett. 2017; 27: 2259
      CrossrefPubMed
  • 7 Rodriguez AR, Spur BW. Tetrahedron Lett. 2020; 61: 151473
    CrossrefPubMed
    • 8a Ogawa N, Sone S, Hong S, Lu Y, Kobayashi Y. Synlett 2020; 31: 1735
      Article in Thieme ConnectPubMed
    • 8b Ogawa N, Sugiyama T, Morita M, Suganuma Y, Kobayashi Y. J. Org. Chem. 2017; 82: 2032
      CrossrefPubMed
    • 8c Kosaki Y, Ogawa N, Kobayashi Y. Tetrahedron Lett. 2010; 51: 1856
      Crossref
    • 8d Ogawa N, Kobayashi Y. Tetrahedron Lett. 2009; 50: 6079
      Crossref
  • 9 Kobayashi Y, Morita M. Cutting-Edge Organic Synthesis and Chemical Biology of Bioactive Molecules: The Shape of Organic Synthesis to Come. Kobayashi Y. Springer Nature Singapore; Singapore: 2019. Chap. 9, 193
    Article in Thieme ConnectGoogle Scholar
    • 10a Bruns H, Herrmann J, Müller R, Wang H, Döbler IW, Schulz S. J. Nat. Prod. 2018; 81: 131
      CrossrefPubMed
    • 10b Ribes C, Falomir E, Murga J, Carda M, Marco JA. Org. Biomol. Chem. 2009; 7: 1355
      CrossrefPubMed
  • 11 Matsumura K, Hashiguchi S, Ikariya T, Noyori R. J. Am. Chem. Soc. 1997; 119: 8738
    Crossref
    • 12a Ogawa N, Tojo T, Kobayashi Y. Tetrahedron Lett. 2014; 55: 2738
      Crossref
    • 12b Hartmann O, Kalesse M. Org. Lett. 2012; 14: 3064
      CrossrefPubMed
  • 13 Suganuma Y, Saito S, Kobayashi Y. Synlett 2019; 30: 338
    Article in Thieme Connect
  • 14 Tungen JE, Aursnes M, Dalli J, Arnardottir H, Serhan CN, Hansen TV. Chem. Eur. J. 2014; 20: 14575
    CrossrefPubMed
  • 15 The 1H and 13C NMR spectra of the Wittig product indicated a high stereoselectivity of the Wittig reaction, as determined by the absence of the corresponding olefin isomers.
  • 16 Resolvin T4 (4) To an ice-cold solution of the methyl ester 27 (18.8 mg, 0.0500 mmol) in THF (0.5 mL) and MeOH (0.5 mL) was added 2 N aq LiOH (0.13 mL). The mixture was stirred at rt for 4 h then diluted with McIlvaine phosphate buffer solution (pH 5.0). The resulting mixture was extracted with CH2Cl2 several times. The combined extracts were dried (MgSO4) and concentrated. The residue was purified by chromatography (silica gel, hexane/EtOAc) to give a crude product [yield; 12.6 mg (70%)] that was further purified by recycling HPLC [LC-Forte/R equipped with YMC-Pack SIL-60, 10ϕ × 250 mm, hexane–EtOAc (33:67), 10 mL/min] to give a colorless liquid; yield: 8.8 mg (49%); Rf = 0.28 (hexane–EtOAc, 1:2); [α]D 27 +13 (c 0.4, MeOH). IR (neat): 3344, 1705, 1412, 984, 949 cm–1. 1H NMR (400 MHz, CD3OD): δ = 0.97 (t, J = 7.6 Hz, 3 H), 1.28–1.66 (m, 8 H), 2.10 (quint, J = 7.6 Hz, 2 H), 2.27 (t, J = 7.2 Hz, 2 H), 2.37–2.51 (m, 2 H), 2.93 (t, J = 7.2 Hz, 2 H), 4.09 (q, J = 6.4 Hz, 1 H), 4.17 (q, J = 6.6 Hz, 1 H), 4.90 (s, 3 H, overlapped with the residue of CD3OD), 5.27–5.50 (m, 4 H), 5.65 (dd, J = 15.2, 6.6 Hz, 1 H), 5.67 (dd, J = 15.2, 6.4 Hz, 1 H), 5.97 (t, J = 11.2 Hz, 1 H), 6.08 (t, J = 11.2 Hz, 1 H), 6.50 (dd, J = 15.2, 11.2 Hz, 1 H), 6.56 (dd, J = 15.2, 11.2 Hz, 1 H). 13C NMR (100 MHz, CD3OD): δ = 14.6, 21.5, 26.1, 26.3, 26.8, 30.2, 34.9, 36.8, 38.2, 73.0, 73.2, 126.49, 126.53, 127.8, 128.1, 129.1, 131.09, 131.11, 133.1, 137.0, 138.0, 177.6. HRMS (FD): m/z [M]+ calcd for C22H34O4: 362.24571; found: 362.24495. UV (MeOH): λmax = 239 nm. The spectroscopic data were consistent with the reported values.7