S_NAr Reaction/Claisen Rearrangement Approach to 2,4-Diisoprenylxanthones: Total Synthesis of Garcinone A

Abstract

A total synthesis of garcinone A, a natural xanthone possessing a 2,4-diisoprenylated structure, was accomplished by utilizing a readily available 1,3-difluoroxanthone derivative as the key intermediate through the installation of two isoprenyl side chains by an S_NAr reaction with the alkoxide of 1,1-dimethylallyl alcohol followed by a Claisen rearrangement. The strategy also permitted the selective installation of mutually different allylic moieties at the C2 and C4 positions.

Key words

natural product synthesis - xanthones - isoprenylation - S_NAr reaction - Claisen rearrangement - garcinone A

• References and Notes


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• 11 The model reaction with 4 (Scheme 3) was not completely regio­selective (96:4). Fortunately, however, this was not a problem in the actual reaction of 16 (Scheme 7), because migration of the C₅ unit from C1–O to C2 took place easily at 25 °C and was completed before the migration from C3–O (70 °C) began; see also ref. 16.
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• 16 At this stage, neither of the byproducts 30 nor 31 that might possibly arise through prenyl migration from C3–O was detected (Scheme 10).
• 17 S_NAr Reaction/Claisen Rearrangement for the Synthesis of 17; Typical ProcedureA 1.0 M solution of the potassium alkoxide of 1,1-dimethylallyl alcohol 3 in DMF (0.74 mL, 0.74 mmol) was added dropwise to a solution of 1,3-difluoroxanthone 12 (103 mg, 352 μmol) in DMF (1.0 mL), and stirring was continued for 13 h at 25 °C. The reaction was quenched with phosphate buffer (0.1 M, pH 7), and the products were extracted with Et₂O (×3). The combined extracts were washed with H₂O and brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was azeotropically dried with toluene and the crude product 16 was used for the next step without further purification.Silica gel (452 mg, 300 wt% based on the theoretical yield of 16), in a two-necked round-bottomed flask, was dried in vacuo by heating it with a heating gun and then suspended in toluene (0.5 mL). To this suspension was added a solution of the crude product 16 in toluene (1.2 mL) at 0 °C, and the mixture was stirred for 4.5 h at 70 °C. After removal of the silica gel by filtration through a sintered glass filter, the filtrate was concentrated in vacuo. The residue was purified by column chromatography [silica gel, hexane–EtOAc (20:1)] to give xanthone 17 as a yellow solid; yield: 130 mg (87%, 2 steps). Crystallization from hexane–EtOAc gave 17 as yellow needles; mp 125.6–126.1 °C.IR (ATR): 2986, 2911, 1647, 1618, 1604, 1566, 1487, 1446, 1416, 1390, 1307, 1289, 1258, 1236, 1218, 1208, 1166, 1154, 1134, 1115, 1079, 1003, 978, 949, 919, 864, 833, 816, 792, 701, 663, 626, 607, 563, 524, 500, 468, 455, 442, 421, 404 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.63 (s, 6 H), 1.67 (s, 3 H), 1.80 (s, 3 H), 3.35 (d, J = 7.2 Hz, 2 H), 3.50 (s, 3 H), 5.27 (br t, J = 7.2 Hz, 1 H), 5.31 (d, J = 11.2 Hz, 1 H), 5.395 (d, J = 17.6 Hz, 1 H), 5.396 (s, 2 H), 6.26 (dd, J = 17.6, 11.2 Hz, 1 H), 6.71 (s, 1 H), 7.09 (d, J = 9.6 Hz, 1 H), 7.10 (s, 1 H), 8.12 (d, J = 9.6 Hz, 1 H), 13.13 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 17.9, 22.1, 25.6, 27.5 (2 C), 56.4, 82.0, 95.1, 96.2, 103.4, 103.6, 114.47, 114.55, 114.9, 115.4, 123.2, 127.7, 131.3, 144.7, 155.7, 158.3, 160.3, 162.2, 163.6, 180.7. Anal. Calcd for C₂₅H₂₈O₆: C, 70.74; H, 6.65. Found: C, 70.83; H, 6.66.
• 18 The original papers on isolation of garcinone A (1) by Sen et al.^{8a , b} did not record any NMR data for the natural product, but instead gave spectral data for the natural product-derived triacetate 21 (IR, ¹H NMR). We identified 1 and 21, which we synthesized, by comparing their data with those of the respective synthetic materials reported by Sen et al.^{8a , b} and Ahluwalia et al.^9a (for 21) and by Ahluwalia et al.^9a, Zhang et al.^9b and Lim et al.^9d (for 1). Furthermore, the structures were fully characterized by an extensive NMR study. See the Supporting Information for details.