Synthesis of the Reported Structure of Crassiflorone, a Pentacyclic Naphthoquinone Isolated from the African Ebony Diospyros crassiflora

Abstract

A short synthesis of the furocoumarin naphthoquinone structure reported for the natural product crassiflorone is described, in which the key steps are a Diels-Alder reaction to form 2-bromo-8-hydroxy-6-methylnaphthoquinone, followed by O-protection and copper(II)-mediated coupling to 4-hydroxy-5-methylcoumarin to establish the pentacyclic framework.

Key words

quinones - natural products - fused ring systems - Diels-Alder reaction - copper

References and Notes

• 1a Thomson RH. Naturally Occurring Quinones   Butterworths; London: 1957. 
• 1b Thomson RH. Naturally Occurring Quinones   2nd ed.:  Academic Press; London: 1971. 
• 1c Thomson RH. Naturally Occurring Quinones III. Recent Advances   3rd ed.:  Chapman and Hall; London: 1987. 
• 1d Thomson RH. Naturally Occurring Quinones IV. Recent Advances   4th ed.:  Blackie; London: 1997. 
• 2 Tangmouo JG. Meli AL. Komguem J. Kuete V. Ngounou FN. Lontsi D. Beng VP. Choudhary MI. Sondengam BL. Tetrahedron Lett.  2006,  47:  3067 
• 3 Kuete V. Tangmouo JG. Meyer JJM. Lall N. Int. J. Antimicrob. Agents  2009,  34:  322 
• 4 Savard J. Brassard P. Tetrahedron  1984,  40:  3455 
• 5 Perumal PT. Bhatt MV. Synthesis  1979,  205 
• 6 Bringmann G. Gotz R. Keller PA. Walter R. Boyd MR. Lang FR. Garcia A. Walsh JJ. Tellitu I. Bhaskar KV. Kelly TR. J. Org. Chem.  1998,  63:  1090 
• 7 Appendino G. Cravotto G. Giovenzana GB. Palmisano G. J. Nat. Prod.  1999,  62:  1627 
• 8 For some recent examples, see: Bolognesi ML. Lizzi F. Perozzo R. Brun R. Cavalli A. Bioorg. Med. Chem. Lett.  2008,  18:  2272 
• 9 Luly JR. Rapoport H. J. Am. Chem. Soc.  1983,  105:  2859 
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11-Benzyloxy-1,9-dimethyl-6 H -naphtho[2′,3′:4,5]furo[3,2- c ]-chromene-6,7,12-trione (6)
To a mixture of 2-bromo-8-benzyloxy-6-methyl-1,4-naphthoquinone (4, 0.20 g, 0.56 mmol), Cu(OAc)₂ (0.30 g, 1.67 mmol), 4-hydroxy-5-methylcoumarin (3, 0.10 g, 1.67 mmol), and K₂CO₃ (0.20 g, 1.67 mmol) was added MeCN (10 mL). The reaction mixture was heated to reflux for 8 h with constant stirring. After 8 h, the mixture was diluted with CH₂Cl₂ (100 mL), and filtered through Celite, washing with CH₂Cl₂-MeOH (9:1; 100 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography to give the title compound (0.14 g, 56%); mp 236-238 ˚C. HRMS: m/z calcd for C₂₈H₁₈O₆ + Na⁺: 473.0996; found: 473.0985 [M + Na⁺]. IR (CHCl₃): ν_max = 2985, 1731, 1446, 1374, 1249, 1045 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.71 (1 H, s, ArH), 7.62 (2 H, d, J = 7.4 Hz, ArH), 7.52 (1 H, dd, J = 8.0, 7.8 Hz, ArH), 7.42 (2 H, dd, J = 7.4, 7.8 Hz, ArH), 7.33 (2 H, d, J = 7.6 Hz, ArH), 7.22 (1 H, d, J = 7.5 Hz, ArH), 7.18 (1 H, s, ArH), 5.28 (2 H, s, CH₂), 2.94 (3 H, s, Me), 2.50 (3 H, s, Me). ^¹³C NMR (100 MHz, CDCl₃): δ = 177.9 (C), 172.2 (C), 162.0 (C), 159.8 (C), 155.2 (C), 154.9 (C), 154.3 (C), 147.4 (C), 136.0 (C), 135.9 (C), 136.6 (C), 132.5 (CH), 128.7 (CH), 127.9 (CH), 127.1 (CH), 126.7 (CH), 124.2 (C), 121.9 (C), 120.1 (CH), 117.2 (C), 115.2 (CH), 110.7 (C), 107.3 (C), 70.8 (CH₂), 22.5 (Me), 21.5 (Me).

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11-Hydroxy-1,9-dimethyl-6 H -naphtho[2′,3′:4,5]furo[3,2- c ]-chromene-6,7,12-trione (1, ‘crassiflorone’) The benzyl ether 6 (0.10 g,) was dissolved in EtOAc (10 mL), and Pearlman’s catalyst (20 mg) was added. The reaction mixture was flushed carefully with nitrogen followed by hydrogen, then stirred for 16 h under a hydrogen atmosphere. The reaction mixture was filtered through Celite, washing with 5% MeOH in CH₂Cl₂ (100 mL). The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography to give the title compound (0.09 g, 93%); mp 230 ˚C (decomp.). HRMS: m/z calcd for C₂₁H₁₂O₆ + H⁺: 361.0707; found: 361.0700 [M + H⁺]; m/z calcd for C₂₁H₁₂O₆ + Na⁺: 383.0526; found: 383.0537 [M + Na⁺]. IR (CHCl₃): ν_max = 3689, 3604, 3043, 1755, 1644, 1603, 1239 cm^-¹. UV/Vis (MeOH):
λ_max = 305 (log ε 4.056), 440 (log ε 3.54) nm. ^¹H NMR (400 MHz; CDCl₃): δ = 11.84 (1 H, s, 11-OH), 7.66 (1 H, s, H-8), 7.58 (1 H, dd, J = 8.2, 7.6 Hz, H-3), 7.38 (1 H, d, J = 8.2 Hz, H-4), 7.26 (1 H, d, J = 7.6 Hz, H-2), 7.14 (1 H, s, H-10), 2.96 (3 H, s, Me-14), 2.51 (3 H, s, Me-15). ^¹³C NMR (125 MHz; CDCl₃): δ = 177.7 (C), 177.3 (C), 162.83 (C), 162.80 (C), 155.1 (C), 154.7 (C), 152.9 (C), 149.4 (C), 136.0 (C), 133.2 (C), 133.1 (CH), 127.3 (CH), 127.2 (C), 124.7 (CH), 122.5 (CH), 115.4 (CH), 112.4 (C), 110.5 (C), 107.9 (C), 22.4 (Me), 21.4 (Me).

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