Anion-Accelerated Aromatic Oxy-Cope Rearrangement in Geranylation/Nerylation of Xanthone: Stereochemical Insights and Synthesis of Fuscaxanthone F

Abstract

An efficient installation of a 3,7-dimethylocta-2,6-dien-1-yl (geranyl or neryl) side chain at the C(1) position of a xanthone core by utilizing an anion-accelerated aromatic oxy-Cope rearrangement is described. Experiments revealed that this uncommon rearrangement takes place in a stereospecific manner through a chair-like transition-state structure. An application to the syntheses of the natural xanthone fuscaxanthone F, possessing a geranyl side chain, and its neryl analogue is also described.

Key words

natural product synthesis - xanthones - oxy-Cope rearrangement - isoprenoids - geranylation - nerylation

• References and Notes


For reviews on natural xanthones, see:
• 1a Klein-Júnior LC, Campos A, Niero R, Corrêa R, Vander Heyden Y, Cechinel Filho V. Chem. Biodivers. 2020; 17: e1900499
• 1b El-Seedi HR, El-Barbary MA, El-Ghorab DM. H, Bohlin L, Borg-Karlson A.-K, Göransson U, Verpoorte R. Curr. Med. Chem. 2010; 17: 854
• 1c Pinto MM. M, Sousa ME, Nascimento MS. J. Curr. Med. Chem. 2005; 12: 2517

For recent examples of biological studies on prenylated xanthones, see:
• 2a Natrsanga P, Jongaramruong J, Rassamee K, Siripong P, Tip-pyang S. J. Nat. Med. 2020; 74: 467
• 2b Li P, Yang Z, Tang B, Zhang Q, Chen Z, Zhang J, Wei J, Sun L, Yan J. ACS Omega 2020; 5: 334
• 2c Jin S, Shi K, Liu L, Chen Y, Yang G. Int. J. Mol. Sci. 2019; 20: 4803

For a review, see:
• 2d Pinto MM. M, Castanheiro RA. P. In Natural Products: Chemistry, Biochemistry and Pharmacology . Brahmachari G. Alpha Science; Oxford: 2009: 520

For a review on the synthesis of prenylxanthones, see:
• 3a Pinto MM. M, Castanheiro RA. P. Curr. Org. Chem. 2009; 13: 1215

For reviews on the synthesis of xanthones, see:
• 3b Masters K.-S, Bräse S. Chem. Rev. 2012; 112: 3717
• 3c Azevedo CM. G, Afonso CM. M, Pinto MM. M. Curr. Org. Chem. 2012; 16: 2818
• 4a Fujimoto Y, Itakura R, Hoshi H, Yanai H, Ando Y, Suzuki K, Matsumoto T. Synlett 2013; 24: 2575
• 4b Fujimoto Y, Watabe Y, Yanai H, Taguchi T, Matsumoto T. Synlett 2016; 27: 848
• 4c Fujimoto Y, Yanai H, Matsumoto T. Synlett 2016; 27: 2229

For other examples of syntheses of naturally occurring 1-prenylxanthones, see:
• 5a Quillinan AJ, Scheinmann F. J. Chem. Soc., Perkin Trans. 1 1972; 1382
• 5b Quillinan AJ, Scheinmann F. J. Chem. Soc., Perkin Trans. 1 1975; 241
• 5c Lee H.-H. J. Chem. Soc., Perkin Trans. 1 1981; 3205
• 5d Iikubo K, Ishikawa Y, Ando N, Umezawa K, Nishiyama S. Tetrahedron Lett. 2002; 43: 291
• 5e Xu D, Nie Y, Liang X, Ji L, Hu S, You Q, Wang F, Ye H, Wang J. Nat. Prod. Commun. 2013; 8: 1101
• 5f Ito S, Kitamura T, Arulmozhiraja S, Manabe K, Tokiwa H, Suzuki Y. Org. Lett. 2019; 21: 2777

For other reports on anion-accelerated aromatic oxy-Cope rearrangement, see:
• 6a Jung ME, Hudspeth JP. J. Am. Chem. Soc. 1978; 100: 4309
• 6b Marvell EN, Almond SW. Tetrahedron Lett. 1979; 20: 2779
• 6c Seki K, Tooya M, Sato T, Ueno M, Uyehara T. Tetrahedron Lett. 1998; 39: 8673
• 7 To avoid confusing discussion, we opted not to record the results from the use of the parent compound 1-fluoroxanthone (20) as the starting material in the main text because of the formation of the byproducts (Z)- and (E)-23 as a result of the migration of the C₁₀ unit to the C(8) position (Scheme 11). Such migration to the undesired position did not occur when the starting xanthone was substituted by an inductively electron-withdrawing group at C(2) or C(3), as in 2 and 5, or by an alkyl group at C(8), as in 7 (see ref. 4b). Nonetheless, it is worth noting that the reactions of alcohols 21a and 21b were both stereospecific: neither (Z)-22 nor (E)-23 was obtained from 21a and, likewise, neither (E)-22 nor (Z)-23 was obtained from 21b.
• 8 Throughout this paper, ‘more polar isomer’ refers to the isomer of lower mobility on silica-gel TLC with hexane–EtOAc as eluent, and ‘less polar isomer’ refers to the isomer with a higher mobility.
• 9 All the oxy-Cope rearrangements described in this paper were conducted in darkness in a brown-glass flask. Otherwise, many side reactions occurred, leading to irreproducible results. See ref. 4b.
• 10a Dorman DE, Jautelat M, Roberts JD. J. Org. Chem. 1971; 36: 2757
• 10b Bohlmann F, Zeisberg R, Klein E. Org. Magn. Reson. 1975; 7: 426
• 11 CCDC 1989869 and 1989870 contain the supplementary crystallographic data for compounds 6b and 8a, respectively. The data can be obtained free of charge from Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 12 Grignard Addition/Aromatic Oxy-Cope Rearrangement Sequence: Synthesis of (E)-9; Typical Procedure A 1.0 M solution of geranyl Grignard reagent in THF (0.5 mL, 0.5 mmol) was added dropwise to a suspension of xanthone 5 (101 mg, 341 μmol) in THF (1.7 mL) at –78 °C, and the resulting mixture was stirred for 10 min at the same temperature. The reaction was then quenched with sat. aq NH₄Cl, and the products were extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by column chromatography [silica gel, hexane–EtOAc (7:1)] to give alcohol 6 as a mixture of diastereomers; yield: 134 mg (91%; 6a/6b = 1.1:1). Further chromatographic separation [silica gel, hexane–EtOAc (40:1)] permitted the isolation of each of the isomers. To a solution of 6a (48.1 mg, 112 μmol) in THF (3.5 mL) in a two-necked brown-glass flask was added a 0.5 M solution of KHMDS in toluene (0.50 mL, 0.25 mmol), followed by a solution of 18-crown-6 (91.1 mg, 335 μmol) in THF (1.0 mL) at –78 °C. The reaction mixture was quickly warmed to 0 °C by replacing the dry ice–acetone bath with an ice-cold water bath, and stirring was continued for 10 min. The reaction was quenched with sat. aq NH₄Cl, and the products were extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by preparative TLC [silica gel, hexane–EtOAc (15:1)] to give xanthone (E)-9 as a colorless oil; yield: 40.1 mg (87%). IR (neat): 2975, 2925, 2850, 1660, 1615, 1580, 1460, 1440 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.55 (s, 3 H), 1.61 (d, J = 0.8 Hz, 3 H), 1.88 (d, J = 0.8 Hz, 3 H), 1.98–2.02 (m, 2 H), 2.04–2.10 (m, 2 H), 4.36 (d, J = 6.0 Hz, 2 H), 5.04–5.11 (m, 2 H), 7.24 (d, J = 8.8 Hz, 1 H), 7.34 (ddd, J = 8.0, 7.2, 0.8 Hz, 1 H), 7.41 (dd, J = 8.4, 0.8 Hz, 1 H), 7.68 (ddd, J = 8.4, 7.2, 1.6 Hz, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 8.28 (dd, J = 8.0, 1.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 16.8, 17.7, 25.6, 26.7, 33.1, 39.8, 117.3, 117.9, 121.1 (2 C), 121.3, 122.6, 124.0, 124.4, 127.1, 131.1, 134.6, 136.3, 138.3, 143.9, 154.9, 156.9, 177.6. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₃H₂₃BrNaO₂ : 433.0779; found: 433.0780.
• 13 As additional information in this regard, a crossover experiment employing model compounds 24 and 25 demonstrated that the rearrangement occurred in an intramolecular manner, at least for the migration of C₅ (isoprenyl) moieties (Scheme 12).
• 14 Preliminary theoretical calculations for the migration of a C₅ unit as a model (Scheme 13) were carried out by density functional theory methods at the B3LYP/6–311+G(df,p)/THF(PCM) level of theory (Gaussian 09 package). A very shallow bifurcation appeared on the potential-energy surface, suggesting that the rearrangement is not completely concerted. Accurate analysis indicated that bond dissociation precedes bond formation, and that a short-lived intermediate exists between them. See Supporting Information.
• 15 Ito C, Itoigawa M, Takakura T, Ruangrungsi N, Enjo F, Tokuda H, Nishino H, Furukawa H. J. Nat. Prod. 2003; 66: 200

For other examples of isolation of prenylxanthones from G. fusca Pierre, see:
• 16a Nontakham J, Charoenram N, Upamai W, Taweechotipatr M, Suksamrarn S. Arch. Pharmacal Res. 2014; 37: 972
• 16b Nguyen NK, Truong XA, Bui TQ, Bui DN, Nguyen HX, Tran PT, Nguyen L.-HD. Chem. Biodivers. 2017; 14: e1700232
• 17 See Supporting Information for the preparation of 12.
• 18 Amano S, Takemura N, Ohtsuka M, Ogawa S, Chida N. Tetrahedron 1999; 55: 3855