Application of a Dual Fries–Claisen Protocol to Access Pyranonaphthoquinone Natural Products

Abstract

In this paper we describe the application of a recently developed dual Fries–Claisen protocol as a novel synthetic approach to the pyranonaphthoquinone natural products eleutherin and isoeleutherin.

Key words

annelation - pericyclic reaction - rearrangement - Fries - Claisen - cyclisation

• References and Notes

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• 11a X-ray crystal data for 7: C₂₃H₂₁IO₅, M = 504.30, monoclinic, space group P2₁/c, a = 14.3715(5), b = 15.6087(5), c = 9.0761(3) Å, β = 94.3888(5), V = 2029.98(12) ų, T = 150 K, Z = 4, crystal dimensions 0.56 × 0.22 × 0.12 mm³, Mo–Kα monchromated radiation (λ = 0.71073 Å), μ = 1.610 mm^–1, 23393 data measured using a Bruker APEX 2 CCD diffractometer. 6173 data were unique, R _int = 0.022; all unique data used in refinement against F ² values to give final wR = 0.0622 (on F ² for all data), R = 0.0236 {for 5369 data with F ² >4σ(F ²)}. Programs used were Bruker APEX 2 (see ref. 11b), SAINT (see ref. 11b), SHELXTL (see refs. 11c and 11d) and local programs. Crystallographic data (excluding structure factors) for the structure in this paper has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 854341. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [Fax: [phone] or e-mail: [e-mail]].
• 11b APEX 2 and SAINT Software for CCD Diffractometers. Bruker AXS Inc; Madison WI: 2008
• 11c Sheldrick GM. SHELXTL User Manual, Version 5. Bruker AXS Inc; Madison WI: 1994
• 11d Sheldrick GM. Acta Crystallogr., Sect. A 2008; 64: 112
• 12 Synthesis of Eleutherin Precursor, 11a: Step (1): Methyllithium (2.01 mL, 3.23 mmol; 1.6 M solution in decane) was added dropwise to 5,9,10-trimethoxy-3-methyl-3,4-dihydro-1H-benzo[g]isochromen-1-one (9; 813 mg, 2.69 mmol) in anhyd THF–Et₂O (1:1; 50mL) at 0 °C. The reaction mixture was stirred vigorously and allowed to reach r.t. overnight. The reaction was stopped by careful addition of sat. aq NH₄Cl (50 mL) and the aqueous layer was extracted three times with EtOAc (3 × 30 mL). The combined organic phases were dried over anhyd MgSO₄ and concentrated under reduced pressure. The crude white foam recovered (10, 856 mg) was taken forward to the lactol reduction step without purification. Step (2): Lactol 10 (856 mg, 2.69 mmol) was dissolved in anhyd CH₂Cl₂ (20 mL) and cooled to −78 °C before successive dropwise addition of BF₃·OEt₂ (1.02 mL, 8.07 mmol) and TES (1.29 mL). The red solution was stirred vigorously for 1 h at −78 °C before being allowed to warm to r.t. over 2 h. The reaction was carefully quenched with the addition of H₂O (50 mL) and then partitioned between brine (50 mL) and CH₂Cl₂ (50 mL). The organic layer was separated and the aqueous phase was extracted twice more with CH₂Cl₂ (2 × 30 mL). The combined organics were dried over anhyd MgSO₄ and evaporated to dryness under reduced pressure. The crude ¹H NMR spectrum of this material showed a 5:1 cis/trans mixture of (±)-11a and (±)-11b, respectively. The mixture of naphthopyrans was chromatographed on silica using light petroleum (bp 40–60 °C)–EtOAc (6:1) as eluent to yield 11a as a white solid (550 mg, 68% over 2 steps). It was not possible to separate the trans-naphthopyran 11b from the cis-naphthopyran, (±)-11a, at this juncture, only 136 mg (17% over 2 steps) of a mixture (1:1 by ¹H NMR spectroscopy) was isolated (total combined yield 85%). Data for 11a: mp 104–106 °C (Lit.^1a mp 106–107 °C). IR (ATR): 1570, 1071, 1058 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.42 (d, J = 6.0 Hz, 3 H), 1.69 (d, J = 6.0 Hz, 3 H), 2.59 (dd, J = 11.1, 16.2 Hz, 1 H), 3.06 (dd, J = 1.8, 16.2 Hz, 1 H), 3.65–3.71 (m, 1 H), 3.77 (s, 3 H), 3.99 (s, 3 H), 4.01 (s, 3 H), 5.25 (q, J = 6.0 Hz, 1 H), 6.83 (d, J = 7.5 Hz, 1 H), 7.37 (t, J = 8.1 Hz, 1 H), 7.68 (dd, J = 0.6, 8.4 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.9, 23.2, 31.9, 56.1, 61.2, 61.6, 69.4, 71.3, 105.4, 114.5, 119.3, 125.9, 126.1, 129.8, 130.3, 148.5, 149.1, 156.1. MS (EI–CI): m/z [M + H⁺] calcd for C₁₈H₂₂O₄: 303.1591; found: 303.1596.
• 13 Synthesis of Eleutherin (3a): A solution of cerium(IV) ammonium nitrate (1.99 g, 3.64 mmol) in H₂O (2 mL) was added to a solution of the cis-naphthopyran (±)-11a (550 mg, 1.82 mmol) in MeCN (4 mL) at r.t. After stirring for 2 h, the reaction was partitioned between CH₂Cl₂ (50 mL) and H₂O (50 mL). The organic phase was separated and the aqueous phase was re-extracted twice with CH₂Cl₂ (2 × 30 mL). The combined organic fractions were washed with brine, dried over anhyd MgSO₄ and concentrated under reduced pressure. The crude quinone was chromatographed on silica gel using light petroleum (bp 40–60 °C)–EtOAc (2:1) as eluent to give (±)-eleutherin (3a) as a yellow solid (462 mg, 93%). Data for 3a: mp 156–157 °C (Lit.^1a mp 155–156 °C). IR (ATR): 1651, 1584, 1276, 1059 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.37 (d, J = 6.0 Hz, 3 H), 1.54 (d, J = 6.0 Hz, 3 H), 2.20 (ddd, J = 3.6, 10.2, 18.3 Hz, 1 H), 2.75 (dt, J = 2.7, 18.3 Hz, 1 H), 3.56–3.62 (m, 1 H), 4.00 (s, 3 H), 4.83–4.89 (m, 1 H), 7.28 (d, J = 8.1 Hz, 1 H), 7.64 (t, J = 7.8 Hz, 1 H), 7.73 (dd, J = 0.9, 7.5 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.8, 21.3, 29.9, 56.5, 68.7, 70.3, 117.7, 119.0, 120.2, 133.9, 134.6, 139.9, 148.7, 159.4, 183.8, 184.1. MS (EI–CI): m/z [M + H⁺] calcd for C₁₆H₁₆O₄: 273.1121; found: 273.1124.
• 14 Isolation of an Analytical Sample of Isoeleutherin (3b): A solution of cerium(IV) ammonium nitrate (493 mg, 0.90 mmol) in H₂O (1 mL) was added to a solution of 1:1 (±)-11a/b (136 mg, 0.90 mmol) in MeCN (2 mL) at r.t. After 2 h stirring the reaction was partitioned between CH₂Cl₂ (50 mL) and H₂O (50 mL). The organic phase was separated and the aqueous phase was extracted twice more with CH₂Cl₂ (2 × 30 mL). The combined organic fractions were washed with brine, dried over anhyd MgSO₄ and concentrated under reduced pressure. The crude quinone was chromatographed on silica gel using light petroleum (bp 40–60 °C)–EtOAc (4:1) as eluent to give a 1:1 mixture of (±)-eleutherin (3a) and (±)-isoeleutherin (3b) as a yellow solid (109 mg, 89%). It was only possible to isolate an analytical sample (7 mg) of (±)-isoeleutherin (3b) as a yellow solid for characterisation purposes; mp 151–152 °C (Lit.^1a mp 154–155 °C). IR (ATR): 1651, 1584, 1276, 1058 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.35 (d, J = 6.0 Hz, 3 H), 1.54 (d, J = 6.9 Hz, 3 H), 2.24 (ddd, J = 2.1, 10.2, 19.2 Hz, 1 H), 2.70 (dd, J = 3.3, 18.9 Hz, 1 H), 3.96–4.01 (m, 1 H), 4.01 (s, 3 H), 5.02 (q, J = 6.6 Hz, 1 H), 7.29 (d, J = 8.7 Hz, 1 H), 7.66 (t, J = 7.8 Hz, 1 H), 7.76 (dd, J = 0.9, 7.5 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 19.8, 21.5, 29.5, 56.5, 62.4, 67.4, 117.8, 119.1, 119.3, 134.0, 134.8, 139.4, 148.0, 159.7, 182.8, 184.3. MS (EI–CI): m/z [M + H⁺] calcd for C₁₆H₁₆O₄: 273.1121; found: 273.1127.