Synthesis of Two Stereoisomers of Potentially Bioactive 13,19,20-Trihydroxy Derivative of Docosahexaenoic Acid

Abstract

The C16–C22 fragment with the acetylene terminus was constructed through the asymmetric dihydroxylation of the corresponding olefin, while the 15-iodo-olefin corresponding to the C11–C15 part was prepared via the asymmetric transfer hydrogenation of the corresponding acetylene ketone followed by hydrozirconation/iodination. Both pieces were joined by a Sonogashira coupling, and the product was further converted into the title compound via a Wittig reaction with the remaining C1–C10 segment and Boland reduction using Zn with TMSCl.

Key words

DHA metabolite - trihydroxylated DHA - organic synthesis - enyne - Boland reduction - TMSCl - Hansen protocol

• References and Notes

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• 30 To an argon-bubbled suspension of Zn powder (4.30 g, 65.8 mmol) in H₂O (20 mL) were added Cu(OAc)₂ (436 mg, 2.40 mmol) and, after 20 min, AgNO₃ (442 mg, 2.60 mmol). The suspension was stirred for 45 min and filtered by suction, and the remaining solids were washed with H₂O, MeOH, acetone, and Et₂O, sequentially. A solution of triol 5aa (129 mg, 0.330 mmol) in H₂O/MeOH (1:1, 20 mL) was added to the above solids. Subsequently, TMSCl (0.410 mL, 3.28 mmol) was added. The mixture was stirred at rt for 18 h and filtered through a pad of Celite. The filtrate was concentrated, and the residue was purified first by chromatography on silica gel (hexane/EtOAc) and second by recycling HPLC (LC-Forte/R equipped with YMC-Pack SIL-60, ø 20 × 250 mm, hexane/EtOAc 30:70, 25 mL/min) to afford methyl ester 25 (104 mg, 81%) as a colorless liquid: R_f  = 0.22 (hexane/EtOAc = 1:2); [α]_D ²¹ –2.3 (c 1.0, CHCl₃). IR (neat): 3480, 1733, 1652, 759 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.99 (t, J = 7.4 Hz, 3 H), 1.44–1.66 (m, 2 H), 1.77 (br s, 1 H), 2.22–2.52 (m, 10 H), 2.77–2.90 (m, 4 H), 3.40 (dt, J = 8.4, 4.2 Hz, 1 H), 3.53 (q, J = 5.8 Hz, 1 H), 3.68 (s, 3 H), 4.25 (q, J = 6.0 Hz, 1 H), 5.31–5.60 (m, 7 H), 5.77 (dd, J = 15.2, 6.0 Hz, 1 H), 6.16 (t, J = 11.2 Hz, 1 H), 6.55 (dd, J = 15.2, 11.2 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 10.1, 22.9, 25.7, 25.9, 26.6, 32.3, 34.1, 35.4, 51.7, 71.9, 73.5, 75.1, 125.0, 125.3, 127.5, 127.9, 128.0, 128.3, 129.4, 130.8, 131.2, 136.5, 173.8. HRMS (FD): m/z calcd for C₂₃H₃₆O₅ [M]⁺: 392.25627; found: 392.25781.