Stereocontrolled Synthesis of Paracentrone

Abstract

The stereocontrolled total synthesis of the C31 apocarotenoid paracentrone was achieved by sequential cross-coupling reactions using C5 boronic acid ester and iodo-substituted dienes, which were newly developed building blocks for elongation of the conjugated polyene systems at both their terminals.

Key words

apocarotenoid - paracentrone - fucoxanthin - cross-coupling - C5 diene - allene

• References and Notes

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• 20 The tin- and boronate-substituted diene 16 is also a new bidirectionally extensible C5 building block.
• 21 When lower amount of the Hoveyda–Grubbs I catalyst (5 mol%) was employed, the cross-metathesis reaction of 13 with 15 was very slow (CH₂Cl₂, reflux, 19 h, >50% recovery of 13). The Grubbs I catalyst (15 mol%) was also effective for the cross-metathesis reaction of both 13 and 14 with 15 (CH₂Cl₂, reflux, 41 h) to give 16 and 18, which upon treatment with iodine, furnished 17 (51%, 2 steps) and 10 (52%, 2 steps), respectively.
• 22 The E geometries of the C1–C2 olefin in both 10 and 17 were supported by the J values in the ¹H NMR spectra (17.4 Hz in 10, 17.8 Hz in 17, Scheme 2).
• 23 Synthesis of 10 To a solution of 14 (813 mg, 2.28 mmol) and vinylboronic acid pinacol ester (15, 702 mg, 4.56 mmol) in dry CH₂Cl₂ (11.4 mL) was added Hoveyda–Grubbs I catalyst (205 mg, 342 μmol). The brick red solution was refluxed for 19 h. The mixture was then concentrated in vacuo to give 18 ²⁾ as a dark yellow oil. A solution of the resulting 18 in CH₂Cl₂ (5.0 mL) was added dropwise to a solution of I₂ (1.16 g, 4.56 mmol) and Na₂CO₃ (966 mg, 9.12 mmol) in CH₂Cl₂ (17.8 mL) at 0 °C. The mixture was stirred at 0 °C for 15 min and quenched with sat. aq Na₂S₂O₃. The mixture was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were washed with brine (1 × 20 mL), dried over Mg₂SO₄, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexane–EtOAc = 100:1) to give 10 (426 mg, 2 steps, 58%) as a dark yellow oil. IR (neat): 2978, 2929, 1614, 1379, 1357, 1328 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.07 (dd, J = 10.7, 17.4 Hz, 1 H), 6.87 (br d, J = 10.7 Hz, 1 H), 5.49 (d, J = 17.4 Hz, 1 H), 2.60 (d, J = 1.3 Hz, 3 H), 1.27 (s, 12 H). ¹³C NMR (75 MHz, CDCl₃): δ = 143.1, 142.6, 103.1, 83.4, 28.7, 24.7 [note: the carbon attached to boron was not observed due to quadrupole broadening caused by the ¹¹B nucleus]. HRMS (APCI): m/z [M + H]⁺ calcd for [C₁₁H₁₉BIO₂]⁺: 321.0519; found: 321.0519.
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• 26 Compound 4: IR (neat): 3007, 2958, 1755, 1611, 1457, 1336, 1292, 1259, 1237, 1158, 1113, 1087, 1030, 1004, 990, 956 cm^–1. ¹H NMR (400 MHz, acetone-d ₆): δ = 6.71 (d, J = 17.8 Hz, 1 H), 6.64 (s, 1 H), 5.83 (d, J = 17.8 Hz, 1 H), 4.23 (d, J = 17.0 Hz, 2 H), 4.05 (d, J = 17.0 Hz, 2 H), 3.02 (s, 3 H), 1.99 (s, 3 H). ¹³C NMR (100 MHz, acetone-d ₆): δ = 168.8, 147.2, 142.7, 85.9, 62.1, 47.2, 19.8 [note: the carbon attached to boron was not observed].²³ ESI-HRMS: m/z [M – H]^– calcd for [C₁₀H₁₂BINO₄]^–: 347.9904; found: 347.9908.
• 27 Synthesis of 8 – Sonogashira Coupling Procedure To a solution of epoxyacetylene 9 (200 mg, 1.11 mmol) and vinyl iodide 10 (352 mg, 1.11 mmol) in i-Pr₂NH (5.5 mL) was added Pd(PPh₃)₄ (64.0 mg, 55.4 μmol) and CuI (21.0 mg, 110 μmol) at r.t. The mixture was stirred at r.t. for 1 h, and quenched with sat. aq NH₄Cl. The mixture was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (1 × 5 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexane–EtOAc = 85:15) to give 8 (314 mg, 77%) as a yellow oil: [α]_D ²⁰.⁰ –2.67 (c 2.00, CHCl₃). IR (neat): 2978, 2929, 1611, 1384, 1353, 1335 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.22 (dd, J = 17.5, 11.3 Hz, 1 H), 6.42 (d, J = 11.3 Hz, 1 H), 5.59 (d, J = 17.5 Hz, 1 H), 3.83 (m, 1 H), 2.36 (ddd, J = 14.2, 5.0, 1.6 Hz, 1 H), 1.97 (d, J = 1.0 Hz, 3 H), 1.95–1.90 (br, 1 H), 1.64 (dd, J = 14.2, 8.7 Hz, 1 H), 1.60 (m, 1 H), 1.50 (s, 3 H), 1.27 (s, 12 H), 1.26 (s, 3 H), 1.23 (m, 1 H), 1.12 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 143.9, 137.7 122.0, 89.2, 87.6, 83.3, 67.2, 63.9, 63.8, 45.9, 39.9, 34.5, 29.9, 25.6, 24.7, 21.6, 17.9 [note: the carbon attached to boron was not observed].²³ ESI-HRMS: m/z [M + Na]⁺ calcd for [C₂₂H₃₃BNaO₄]⁺: 395.2368; found: 395.2365.
• 28 Widmer E. Pure Appl. Chem. 1985; 57: 741
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• 30 The incompatibility of MIDA boronate with DIBAL-H was reported. See: Gillis EP, Burke MD. J. Am. Chem. Soc. 2008; 130: 14084
• 31 Kajikawa T, Iguchi N, Katsumura S. Org. Biomol. Chem. 2009; 7: 40586
• 32 Synthesis of 1 – Suzuki–Miyaura Coupling Procedure To a solution of 24 (10 mg, 18.7 μmol) and methyl ketone 5 (4.0 mg, 18.7 μmol) in (THF–H₂O = 5:1, 374 μL) was added NaOH (5.6 mg, 140 μmol), Pd(OAc)₂ (0.2 mg, 0.935 μmol), and SPhos (0.8 mg, 1.87 μmol) at r.t. The mixture was stirred at r.t. for 20 min and quenched with H₂O. The mixture was extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with brine (1 × 2 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by preparative TLC on silica gel (hexane–EtOAc = 1:2) to give paracentrone (1, 6.8 mg, 65%, all-trans form) as a red solid; mp 145–149 °C. IR (neat): 3361, 2922, 2853, 1923, 1734, 1653, 1647, 1606, 1368, 1278, 1229, 1154, 956 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.14 (d, J = 10.8 Hz, 1 H), 6.75–6.55 (m, 5 H), 6.39 (d, J = 11.2 Hz, 1 H), 6.36 (d, J = 15.2 Hz, 1 H), 6.26 (d, J = 10.8 Hz, 1 H), 6.12 (d, J = 11.6 Hz, 1 H), 6.03 (s, 1 H), 4.32 (m, 1 H), 2.36 (s, 3 H), 2.26 (br d, J = 11.8 Hz, 1 H), 1.992 (s, 3 H), 1.985 (s, 3 H), 2.00–1.95 (m, 1 H), 1.94 (s, 3 H), 1.81 (s, 3 H), 1.55 (br s, 2 H), 1.45–1.30 (m, 2 H), 1.35 (s, 3 H), 1.34 (s, 3 H), 1.07 (s, 3 H). ¹H NMR (400 MHz, C₆D₆): δ = 6.94 (d, J = 12.4 Hz, 1 H), 6.79–6.70 (m, 2 H), 6.66–6.55 (m, 1 H), 6.54–6.45 (m, 3 H), 6.33 (d, J = 13.5 Hz, 1 H), 6.32 (d, J = 12.6 Hz, 1 H), 6.23 (d, J = 10.8 Hz, 1 H), 6.05 (s, 1 H), 4.22 (m, 1 H), 2.14 (ddd, J = 12.8, 4.0, 2.1 Hz, 1 H), 2.09 (s, 3 H), 1.99 (s, 3 H), 1.88 (s, 3 H), 1.85–1.75 (m, 1 H), 1.81 (s, 3 H), 1.77 (s, 3 H), 1.37 (s, 3 H), 1.26–1.20 (m, 2 H), 1.21 (s, 3 H), 1.12 (s, 3 H), 0.74 (br s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 202.4, 199.4, 144.5, 140.0, 137.9, 137.0, 136.2, 135.6, 132.6, 132.2, 132.1, 129.4, 128.4, 125.6, 123.7, 117.7, 103.2, 73.0, 64.3, 49.5, 49.0, 35.8, 32.1, 31.4, 29.3, 25.6, 14.0, 12.9, 12.7, 11.7. ESI-HRMS: m/z [M + Na]⁺ calcd for [C₃₁H₄₂NaO₃]⁺: 485.3032; found: 485.3039.
• 33 Other geometric isomers were not detected by ¹H NMR spectroscopy.
• 34 Pure paracentrone (1) was obtained by crystallization from Et₂O and n-hexane without purification by HPLC.
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