Concise Total Synthesis of Elliptoxanthone A by Utilizing Aromatic Oxy-Cope Rearrangement for Efficient C-Isoprenylation of Xanthone Skeleton

Abstract

The first total synthesis of elliptoxanthone A, a naturally occurring isoprenylated xanthone, has been accomplished in 28% overall yield in 12 steps from commercially available 3′,4′-difluoroacetophenone by utilizing the novel C-isoprenylation of xanthone skeleton via the anion-accelerated aromatic oxy-Cope rearrangement.

Key words

natural product synthesis - xanthone - S_NAr reaction - isoprenylation - oxy-Cope rearrangement

• References and Notes


For recent reviews on natural xanthones, see:
• 1a El-Seedi HR, El-Barbary MA, El-Ghorab DM, Bohlin L, Borg-Karlson AK, Göransson U, Verpoorte R. Curr. Med. Chem. 2010; 17: 854
• 1b Pinto MM. M, Sousa ME, Nascimento MS. J. Curr. Med. Chem. 2005; 12: 2517
• 2 For naturally occurring prenylated xanthones, see: Pinto MM. M, Castanheiro RA. P. In Natural Products: Chemisry, Biochemistry and Pharmacology . Brahmachari G. Alpha Science; Oxford: 2009: 520

For recent reviews on the synthesis of xanthones, see:
• 3a Masters K.-S, Bräse S. Chem. Rev. 2012; 112: 3717
• 3b Sousa ME, Pinto MM. M. Curr. Med. Chem. 2005; 12: 2447
• 4 Fujimoto Y, Watabe Y, Yanai H, Taguchi T, Matsumoto T. Synlett 2016; 27: 848
• 5 For elliptoxanthone A, see: Manning K, Petrunak E, Lebo M, González-Sarrías A, Seeram NP, Henry GE. Phytochemistry 2011; 72: 662

This work represents the first example of the synthesis of naturally occurring 1-isoprenylxanthone derivative possessing a substituent at C2 that was achieved by installation of the isoprenyl moiety to a pre-constructed xanthone framework by using a five-carbon precursor. For previous reports on the synthesis of naturally occurring 1-prenylxanthones, see:
• 6a Quillinan AJ, Scheinmann F. J. Chem. Soc., Perkin Trans. 1 1972; 1382
• 6b Quillinan AJ, Scheinmann F. J. Chem. Soc., Perkin Trans. 1 1975; 241
• 6c Lee H.-H. J. Chem. Soc., Perkin Trans. 1 1981; 3205
• 6d Iikubo K, Ishikawa Y, Ando N, Umezawa K, Nishiyama S. Tetrahedron Lett. 2002; 43: 291
• 6e Hamada M, Iikubo K, Ishikawa Y, Ikeda A, Umezawa K, Nishiyama S. Bioorg. Med. Chem. Lett. 2003; 13: 3151
• 6f Jeso V, Nicolaou KC. Tetrahedron Lett. 2009; 50: 1161
• 6g Xu D, Nie Y, Liang X, Ji L, Hu S, You Q, Wang F, Ye H, Wang J. Nat. Prod. Commun. 2013; 8: 1101
• 7a Knudsen RD, Snyder HR. J. Org. Chem. 1974; 39: 3343
• 7b Liu C, Yin X, Chang J, Tang X, Zhang B. J. Fluorine Chem. 2014; 165: 101
• 8a Fujimoto Y, Itakura R, Hoshi H, Yanai H, Ando Y, Suzuki K, Matsumoto T. Synlett 2013; 24: 2575
• 8b Chuzel O, Roesch A, Genet J.-P, Darses S. J. Org. Chem. 2008; 73: 7800
• 8c O’Keefe BM, Simmons N, Martin SF. Org. Lett. 2008; 10: 5301
• 8d Lampe JW, Hughes PF, Biggers CK, Smith SH, Hu H. J. Org. Chem. 1994; 59: 5147
• 9 The γ preference was a little lower than those of the related examples cited in our previous report (97:3 to >99:<1).⁴ Though the detailed reason is not clear, this would be ascribed to the nonprotected phenolic hydroxy group because the selectivity was considerably improved by protecting the hydroxy by a MOM group (>99:<1, 93% yield).¹⁰ Nonetheless, we opted for the route shown in Scheme 5, by giving priority to reducing the number of synthetic steps and also because of the easiness of separation of the isomers.
• 10 See Supporting Information.
• 11 Typical Procedure of the Aromatic Oxy-Cope Rearrangement of 12 To a solution of alcohol 12 (50.6 mg, 120 μmol) in THF (3.0 mL) in a two-necked, brown-glass flask was added KHMDS (0.5 M solution in toluene, 0.72 mL, 0.36 mmol) followed by a solution of 18-crown-6 (98.0 mg, 371 µmol) in THF (1.0 mL) at –78 °C. After carefully purging air with argon (3×), the reaction mixture was quickly warmed up to 0 °C by replacing the dry ice/acetone bath with the ice-cold water bath, and the stirring was continued for 10 min. The reaction was quenched with sat. aq NH₄Cl solution, and the products were extracted with EtOAc (3×). The combined organic extracts were washed with brine and dried over Na₂SO₄. Removal of the solvents in vacuo and purification by preparative TLC (silica gel, hexane–EtOAc = 2:1) gave xanthone 14 (36.0 mg, 75%) as yellow solids, which were recrystallized from hexane–EtOAc to give yellow needles. Compound 14: mp 77.8–79.0 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.69 (s, 3 H), 1.86 (s, 3 H), 3.51 (s, 3 H), 3.60 (s, 3 H), 4.17 (d, 2 H, J = 6.8 Hz), 5.22 (s, 2 H), 5.22 (s, 2 H), 5.22–5.26 (m, 1 H), 6.68 (d, 1 H, J = 9.2 Hz), 7.38 (d, 1 H, J = 9.2 Hz), 7.43 (d, 1 H, J = 9.2 Hz), 7.56 (d, 1 H, J = 9.2 Hz), 12.62 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 18.1, 25.89, 25.91, 56.1, 56.4, 95.3, 97.3, 108.8, 109.7, 116.5, 118.9, 122.4, 123.2, 126.0, 132.2, 132.8, 136.4, 146.5, 151.4, 152.6, 156.7, 184.3. IR (ATR): 2914, 1646, 1589, 1468, 1350, 1318, 1267, 1243, 1200, 1177, 1148, 1070, 1029, 946, 926, 917, 820, 789, 759, 720, 671, 627, 611 cm^–1. Anal. Calcd for C₂₂H₂₄O₇: C, 65.99; H, 6.04. Found: C, 65.72; H, 6.07.
• 12 Amano S, Takemura N, Ohtsuka M, Ogawa S, Chida N. Tetrahedron 1999; 55: 3855
• 13 The MOM group at C4 was resistant to hydrolysis in aqueous acid solution (e.g., aq HCl or H₂SO₄ of varied concentrations in THF or 1,4-dioxane) as compared with that at C7. Liberation of the C4 hydroxy group required a prolonged reaction time, and in the meantime, the cyclization gradually proceeded between the C7 hydroxy group and the C8 isoprenyl group to give 15 (Figure 2) as the major product. In contrast, anhydrous HCl in MeOH effected a rapid cleavage of both MOM groups, while an addition of MeOH to the isoprenyl moiety was accompanied. Then, we employed 2-PrOH, instead of MeOH, for retarding the addition to the double bond.
• 14 CCDC 1456398 contains the supplementary X-ray crystallographic data of elliptoxanthone A (1) for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.