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
› InstitutsangabenThis work was supported by Research Project Grant B from the Institute of Science and Technology, Meiji University.
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.
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
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.
16Resolvin 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]D27 +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
