Total Synthesis of Patulone: A Natural Xanthonoid Possessing a Geminally Diisoprenylated Structure

Abstract

The first total synthesis of patulone, a plant metabolite possessing a unique 1,1-diisoprenyl-1H-xanthene-2,9-dione structure, is described. Starting from a 1-fluroxanthone derivative with suitable substitution pattern, the pivotal gem-diisoprenylation was efficiently accomplished by implementing twice the sequence of addition of isoprenyl Grignard reagent to the carbonyl at C9 and anion-accelerated oxy-Cope rearrangement.

Key words

total synthesis - xanthone - geminal substitution - isoprenylation - oxy-Cope rearrangement - regioselectivity

Publication History

Received: 28 October 2022

Accepted after revision: 18 November 2022

Article published online:
19 December 2022

• References and Notes


For reviews:
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For applications to the synthesis of natural xanthone, see:
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• 10 Xanthones 13 and 14a and 14b were prepared as shown in Scheme 8. See the Supporting Information for details.
• 11 We previously reported that the oxy-Cope rearrangements of 1-fluoroxanthone derivatives 35a–c gave the corresponding 1-isoprenylxanthones exclusively (Scheme 9, see reference 8). For a discussion on the origin of the higher regioselectivity in these reactions in comparison with the regioselectivity of the reaction of compound 7, see references 8 and 12.
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• 13 Xanthenol 18c, possessing a methoxy substituent at C8, afforded gem-diisoprenylation product 19c and 1,8-diisoprenylxanthone (20) in a ratio of 25:75 (Scheme 10). Compare with the reactions of 18a and 18b.
• 14 Influence of a C6-substituent on the regioselectivity will be reported elsewhere.
• 15 Use of THF as the solvent also effected the reaction, but the product yields were not reproducible (36–65%).
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• 17 Synthesis of Patulone (1); Typical Procedure: To a solution of tomentonone (2) (100 mg, 261 μmol) in cyclopentyl methyl ether (11 mL) was added NaN(SiMe₃)₂ (1.10 M in toluene, 2.20 mL, 2.42 mmol) under an O₂ atmosphere (balloon) at –78 °C, and the mixture was stirred for 8 h at –40 °C. The reaction was quenched with 10% H₂SO₄ aq., and the products were extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, hexane/EtOAc, 2:1) to give patulone (1) (56.4 mg, 54%) as a yellow solid, which was recrystallized from hexane/Et₂O to give yellow prisms (mp 75.5–76.5 °C (dec.)). The ¹H and ¹³C NMR data for patulone (1) are summarized in Table 1.
• 18 CCDC 1545841 (2) and 2215168 (1) contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures