Stereoselective total syntheses of (−)-pseudohygrophorone A¹² and (−)-pseudohygrophorone B¹²

Abstract

Stereoselective total syntheses of anti-fungal cyclohexenones (−)-pseudohygrophorone A¹² and (−)-pseudohygrophorone B¹² were achieved. Salient features of these syntheses are the diastereoselective addition of dodecylmagnesium bromide to highly oxygenated ketone derived from (−)-quinic acid and α-oxidation of the enone.

GRAPHICAL ABSTRACT

Keywords:

• Natural products
• total synthesis
• stereoselective Grignard addition
• α-oxidation of enone
• pseudohygrophorones

Disclosure statement

The authors declare no conflict of interest.

Experimental

General: Column chromatography was performed on silica gel, Acme grade 100 − 200 mesh using a proper eluent system. Analytical thin-layered chromatography (TLC) was performed using glass plates pre-coated with silica gel (0.25 mm, 60 Å pore size) impregnated with a fluorescent indicator (254 nm). TLC plates were visualized by exposure to ultraviolet light (UV) and/or submersion in aqueous potassium permanganate solution (KMnO₄), followed by brief heating on a hot plate (120 °C, 10-15 s). Organic solutions were concentrated by rotary evaporation at 30-33 °C. All reagents were purchased from commercial sources and used without additional purification. THF was freshly distilled over Na-benzophenone ketyl. Melting points were uncorrected. NMR spectra were recorded in chloroform-d at 300 or 400 MHz for ¹H NMR spectra and 75 or 100 MHz for ¹³C NMR spectra. Chemical shifts were quoted in parts per million (ppm) referenced to the appropriate solvent peak or 0.0 ppm for tetramethylsilane. The following abbreviations were used to describe peak splitting patterns when appropriate: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, sept = septet, dd = doublet of doublets, td = triplet of doublets, m = multiplet. Coupling constants, J, were reported in Hertz unit (Hz). For ¹³C NMR chemical shifts were reported in ppm referenced to the center of a triplet at 77.0 ppm of chloroform-d. High-resolution mass spectra (HRMS) were recorded on a mass spectrometer using electrospray ionization-time-of-flight (ESI-TOF) reflectron experiments.

(−)-Pseudohygrophorone A¹² (ent-1) and (−)-pseudohygrophorone B¹² (ent-2): To the stirred solution of mixture of α-hydroxy enone 12 and 13 (22 mg, 62.4 µmol) in dichloromethane (2.0 mL), ferric chloride (20 mg, 125 µmol, 2.0 eq) was added at 0 °C and the reaction mixture was stirred for 1 h. The progress of the reaction was monitored by TLC and after the completion of reaction (1 h), the reaction mixture was diluted with ethyl acetate (10.0 mL) and water (10.0 mL). Then the whole reaction mixture was placed in separating funnel and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (2 × 10 mL) and separated. The combined organic layers were washed with brine solution and dried over sodium sulfate. The organics then filtered and concentrated under reduced pressure to afford crude product. The crude residue obtained was purified by column chromatography (eluting with 20% ethyl acetate in hexane) furnished 3.3 mg (17%) of (−)-pseudohygrophorones A¹²(ent-1) as a colorless oil and 12.5 mg (64%) of (−)-pseudohygrophorones B¹²(ent-2) as a colorless oil.

(−)-pseudohygrophorone A¹² (ent-1):R_f = 0.46 (50% ethyl acetate-hexane; UV, KMnO₄). ${\left[\alpha \right]}_D^{24}$ −89.2 (c 0.08, CHCl₃) [(+)-pseudohygrophorone A¹² lit.^[6]${\left[\alpha \right]}_D^{24}$ +87.9 (c 0.070, CHCl₃)]; IR (KBr, cm⁻¹): 3738, 3440, 2923, 2855, 2359, 1740, 1628, 1458, 1380, 1261, 1024, 768, 551, 464; ¹H NMR (400 MHz, CDCl₃): δ 6.83 (dd, J = 10.4, 2.0 Hz, 1 H), 6.15 (dd, J = 10.4, 2.4 Hz, 1 H), 4.49 (br d, J = 11.0, 1 H), 4.16 (s, 1 H), 3.71 (s, 1 H), 2.71 (d, J = 11.0, 1 H), 2.07 (br s, 1 H), 1.96-1.89 (m, 1 H), 1.78-1.72 (m, 1 H)_, 1.46-1.39 (m, 1 H), 1.34-1.21 (m, 19 H), 0.88 (t, J = 6.4 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃): δ 198.3, 151.0, 125.2, 81.5, 75.3, 68.7, 35.1, 31.9, 29.92, 29.63, 29.62, 29.61, 29.54, 29.51, 29.34, 25.1, 22.7, 14.1; HRMS (ESI) m/z calcd for C₁₈H₃₂NaO₄ [M + Na] ⁺, 335.2193; found, 335.2190.

(−)-pseudohygrophorone B¹² (ent-2):R_f = 0.30 (50% ethyl acetate-hexane; UV, KMnO₄). ${\left[\alpha \right]}_D^{24}$ −20.5 (c 0.14, CHCl₃) [(+)-pseudohygrophorone B¹² lit.^[6]${\left[\alpha \right]}_D^{24}$ +19.7 (c 0.120, CHCl₃)]; IR (KBr, cm⁻¹): 3746, 3425, 2922, 2856, 2352, 2352, 1638, 1547, 1454, 1382, 1220, 1088, 1025, 771, 673, 447; ¹H NMR (400 MHz, CDCl₃): δ 6.97 (dd, J = 10.4, 5.6 Hz, 1 H), 6.20 (d, J = 10.0 Hz, 1 H), 4.69 (s, 1 H), 4.44 (d, J = 6.0 Hz, 1 H), 3.35 (br s, 1 H), 3.04 (br s, 1 H), 2.78 (br s, 1 H), 1.74-1.66 (m, 1 H), 1.49-1.41 (m, 1 H)_, 1.34-1.18 (m, 19 H), 1.16-1.11 (m, 1 H), 0.88 (t, J = 6.4 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃): δ 198.1, 145.3, 128.6, 76.8, 76.7, 68.2, 31.9, 31.0, 30.1, 29.63, 29.62, 29.69, 29.51, 29.45, 29.33, 23.10, 22.68, 14.1; HRMS (ESI) m/z calcd for C₁₈H₃₂NaO₄ [M + Na] ⁺, 335.2193; found, 335.2198.

Full experimental detail, ¹H and ¹³C NMR spectra of all compounds. This material can be found via the “Supplementary Content” section of this article’s webpage.

Additional information

Funding

This work was supported by DST-SERB [file no. YSS/2015/000660].