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

Publikationsverlauf

Eingereicht: 28. Oktober 2022

Angenommen nach Revision: 18. November 2022

Artikel online veröffentlicht:
19. Dezember 2022

• References and Notes


For reviews:
• 1a Pinto MM. M, Castanheiro RA. P. In Natural Products: Chemistry, Biochemistry and Pharmacology . Brahmachari G. Alfa Science; Oxford: 2009: 520
• 1b Genovese S, Fiorito S, Taddeo VA, Epifano F. Drug Discovery Today 2016; 21: 1814
• 1c Klein-Júnior LC, Campos A, Niero R, Correa R, Vander Heyden Y, Filho VC. Chem. Biodivers. 2020; 17: e1900499
• 2 Ishiguro K, Nagareya N, Suitani A, Fukumoto H. Phytochemistry 1997; 44: 1065
• 3 Li Z, Luo L, Ma G, Huang R, Hu Z. Chin. Tradit. Herb. Drugs (Zhongcaoyao) 2004; 35: 131
• 4a Oku H, Ueda Y, Iinuma M, Ishiguro K. Planta Med. 2005; 71: 90
• 4b Yamakuni T, Aoki K, Nakatani K, Kondo N, Oku H, Ishiguro K, Ohizumi Y. Neurosci. Lett. 2006; 394: 206
• 5 Nagia M, Gaid M, Biedermann E, Fiesel T, El-Awaad I, Hänsch R, Wittstock U, Beerhues L. New Phytol. 2019; 222: 318
• 6 For tomentonene (2), see: Banerji A, Deshpande AD, Prabhu BR, Pradhan P. J. Nat. Prod. 1994; 57: 396
• 7a For hyperixanthone A, see: Xiao ZY, Shiu WK. P, Zeng YH, Mu Q, Gibbons S. Pharm. Biol. 2008; 46: 250
• 7b For apetalinone D, see: Iinuma M, Ito T, Tosa H, Tanaka T, Miyake R, Chelladurai V. Phytochemistry 1997; 46: 1423
• 7c For zeyloxanthone, see: Banerji A, Deshpande AD, Pradhan P. Tetrahedron Lett. 1991; 32: 4995
• 8 Fujimoto Y, Watabe Y, Yanai H, Taguchi T, Matsumoto T. Synlett 2016; 27: 848

For applications to the synthesis of natural xanthone, see:
• 9a Fujimoto Y, Yanai H, Matsumoto T. Synlett 2016; 27: 2229
• 9b Fujimoto Y, Takahashi K, Kobayashi R, Fukaya H, Yanai H, Matsumoto T. Synlett 2020; 31: 1378
• 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.
• 12 Chambers RD, Martin PA, Sandford G, Williams DL. H. J. Fluorine Chem. 2008; 129: 998 ; and references cited therein
• 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%).
• 16a For a review on cyclopentyl methyl ether (CPME), see: Watanabe K, Yamagiwa N, Torisawa Y. Org. Process Res. Dev. 2007; 11: 251
• 16b For the use of CPME as a solvent in oxidation through carbanion formation under O₂ atmosphere, see: Yang F, Zhou B, Chen P, Zou D, Luo Q, Ren W, Li L, Fan L, Li J. Molecules 2018; 23: 1922
• 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