Reaction of 1-Trimethylsilyl-1,2-epoxy-3-alkanols with Alkynes and Application to the Synthesis of 18-HEPE

Abstract

A reaction of epoxy alcohols (anti and/or syn isomers) ­derived from (E)-TMS-CH=CHCH(OH)R with TMS-C≡CLi in THF/HMPA s­tereoselectively afforded (E)-TMS-C≡C-CH=CHCH(OH)R. The (E) stereo­chemistry was independent of the anti/syn stereochemistry, but the syn isomers showed higher reactivity than the anti isomers. The reaction was applied to the synthesis of (18R)- and (18S)-HEPE.

Key words

alkynes - epoxide ring opening - silicon - stereoselective synthesis - Castro–Stephens coupling - eicosapentaenoic acid

• References and Notes

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Previous syntheses of 18-HEPE:
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• 11 To an ice-cold solution of 2a (0.40 mL, 2.89 mmol) and n-BuLi (1.55 M in hexane, 1.60 mL, 2.48 mmol) in THF (0.1 mL) were added HMPA (0.95 mL, 5.44 mmol) and a solution of 1a (anti) (65 mg, 0.30 mmol) in THF (0.2 mL). After being stirred at rt for 3 h, the solution was diluted with saturated NH₄Cl. The mixture was extracted with EtOAc and the crude product was purified by chromatography on silica gel (hexane/EtOAc) to afford enyne rac-3a (41 mg, 60%). Liquid, R_f = 0.43 (hexane/EtOAc 9:1). ¹H NMR (300 MHz, CDCl₃): δ = 0.19 (s, 9 H), 0.88 (t, J = 6.9 Hz, 3 H), 1.20–1.66 (m, 9 H), 4.08–4.22 (m, 1 H), 5.72 (dd, J = 15.9 Hz, 1.5 Hz, 1 H), 6.20 (dd, J = 15.9, 6.3 Hz, 1 H) ppm. ¹³C–APT NMR (75 MHz, CDCl₃): δ = –0.05 (+), 14.1 (+), 22.6 (–), 25.0 (–), 31.8 (–), 36.9 (–), 72.3 (+), 95.1 (–), 103.2 (–), 109.8 (+), 147.0 (+) ppm. HRMS (FAB⁺): m/z [M + Na]⁺ calcd for C₁₃H₂₄OSiNa: 247.1494; found: 247.1490.
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• 15 Castro–Stephens coupling of rac-7 (1.2 equiv) with Z-allylic bromide i (1 equiv) using CuI (2 equiv), NaI (2 equiv), and K₂CO₃ (1.5 equiv) at rt in DMF gave a mixture of rac-12 and the regioisomer ii in a 3:1 ratio (¹H NMR), which were hardly separated by chromatography on silica gel (Scheme 6). The mixture was converted into 18-HEPE and the regioisomer by a sequence of reactions: 1) TBAF; 2) Zn (Cu/Ag); 3) LiOH; an attempted separation at each step was hardly successful.