Synthesis of 8-HEPE and 10-HDoHE in both (R)- and (S)-Forms via Wittig Reactions with COOH-Ylides

Abstract

Wittig reactions using carboxy (CO₂H) ylides derived from a carboxylic phosphonium salt and NaN(TMS)₂ (NaHMDS) in a 1:1 ratio were applied to the synthesis of 8-HEPE and 10-HDoHE, which are metabolites of eicosapentaenoic acid and docosahexaenoic acid, respectively. The attempted Wittig reaction of 3-(TBS-oxy)pentadeca-4E,6Z,9Z,12Z-tetraenal with the carboxy ylide (2 equiv) derived from Br^– Ph₃P⁺(CH₂)₄CO₂H and NaHMDS (1:1) competed with the elimination of the TBS-oxy group at C3 to give a mixture of the Wittig product and the elimination product in 45–50% and 30–40% yields, respectively. The elimination was suppressed completely by using three equiv of the carboxy ylides in THF/HMPA (7–8:1), and the subsequent desilylation gave 8-HEPE in (R)- and (S)-forms. Similarly, both enantiomers of 10-HDoHE were synthesized.

Key words

lipoxygenase metabolite - 10-HDoHE - 8-HEPE - Wittig reaction - carboxy phosphonium salt

• References and Notes

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• 12 To an ice-cold suspension of 4a (374 mg, 0.844 mmol, 3 equiv) in THF (2.4 mL) and HMPA (0.5 mL) was added NaHMDS (1.0 M in THF, 0.843 mL, 0.843 mmol, 3 equiv). The resulting reddish-orange mixture was stirred at 0 °C for 1 h and cooled to –90 °C. A solution of aldehyde (R)-3 (98 mg, 0.281 mmol, 1 equiv) in THF (0.7 mL) and HMPA (0.1 mL) was added to the mixture dropwise. After 1 h, the mixture was warmed to 0 °C over 2 h before addition of saturated NH₄Cl. The resulting mixture was extracted with EtOAc three times. The combined extracts were dried over MgSO₄ and concentrated to afford a residue, which was purified by chromatography on silica gel to give olefin (R)-27 (102 mg, 84%) as the sole product: liquid; R_f = 0.21 (hexane/EtOAc, 4:1); [α]_D ²⁰ –21 (c 0.86, CHCl₃). IR (neat): 1710, 1255, 836, 776 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 0.04 (s, 3 H), 0.05 (s, 3 H), 0.90 (s, 9 H), 0.97 (t, J = 7.5 Hz, 3 H), 1.69 (quint., J = 7.5 Hz, 2 H), 2.08 (quint., J = 7.5 Hz, 2 H), 2.09 (q, J = 7.5 Hz, 2 H), 2.25 (t, J = 6.0 Hz, 1 H), 2.22–2.31 (m, 2 H), 2.81 (t, J = 6.0 Hz, 2 H), 2.95 (t, J = 6.0 Hz, 2 H), 4.20 (q, J = 6.0 Hz, 1 H), 5.25–5.51 (m, 7 H), 5.66 (dd, J = 15.0, 6.0 Hz, 1 H), 5.98 (t, J = 11.1 Hz, 1 H), 6.48 (dd, J = 15.0, 11.1 Hz, 1 H), 10.2–11.2 (br s, 1 H) ppm. ¹³C-APT NMR (75 MHz, CDCl₃): δ = –4.7 (+), –4.4 (+), 14.3 (+), 18.3 (–), 20.6 (–), 24.5 (–), 25.6 (–), 25.9 (+), 26.1 (–), 26.7 (–), 33.5 (–), 36.4 (–), 73.0 (+), 124.4 (+), 126.8 (+), 127.0 (+), 127.6 (+), 128.2 (+), 128.9 (+), 129.5 (+), 130.2 (+), 132.1 (+), 136.7 (+), 180.3 (+) ppm. HRMS (FAB⁺): m/z calcd for C₂₆H₄₃O₃Si [(M – H)⁺]: 431.2981; found: 431.2990.