Functionalization of Highly Oxygenated Xanthones: Unexpected Stereochemistry and Rearrangements

Abstract

Xanthenones were oxidized and explored in terms of stability. Revision and confirmation of stereochemical outcomes have been made. Wagner-Meerwein-type rearrangement of an epoxy­ketone furnished a structurally unusual and stable bicyclic keto­hydrate.

Key words

xanthones - oxidation - Wagner-Meerwein rearrangement

References and Notes

• 1a Shi Y.-L. Shi M. Org. Biomol. Chem.  2007,  5:  1499 
• 1b Bräse S. Encinas A. Keck J. Nising CF. Chem. Rev.  2009,  109:  3903 
• 2a Lesch B. Bräse S. Angew. Chem. Int. Ed.  2004,  116:  118 ; Angew. Chem. 2004, 43, 115
• 2b Nising CF. Ohnemüller UK. Friedrich A. Lesch B. Steiner J. Schnöckel H. Nieger M. Bräse S. Chem. Eur. J.  2006,  12:  3647 
• 2c Gérard EMC. Sahin H. Encinas A. Bräse S. Synlett  2008,  2702 
• 3a Diversonol: Nising CF. Ohnemüller UK. Bräse S. Angew. Chem. Int. Ed.  2006,  45:  307 ; Angew. Chem. 2006, 118, 313
• 3b For an alternative synthesis, see: Titze LF. Spiegl DA. Stecker F. Major J. Raith C. Große C. Chem. Eur. J.  2008,  14:  8956 
• 4a Blennolide: Gérard EMC. Bräse S. Chem. Eur. J.  2008,  14:  8089 
• 4b See also: Nicolaou KC. Li A. Angew. Chem. Int. Ed.  2008,  47:  6579 
• 5 Hemisecalonic acid models: Ohnemüller UK. Nising CF. Encinas A. Bräse S. Synthesis  2007,  2175 
• Synthesis of 7a from 5a:
• 7a

  To a solution of the triol 5a (0.520 g, 2.22 mmol, 1.00 equiv) in CH₂Cl₂ (50 mL) at 0 ˚C were successively added KBr (0.748 g, 6.29 mmol, 2.83 equiv), TEMPO (0.070 g, 0.446 mmol, 0.200 equiv) and NaOCl (2.00 mL, 24.4 mmol, 11.0 equiv). The suspension was stirred for 1 h at 0 ˚C and for 5 h at r.t. After this time the mixture was washed with H₂O (40 mL), 1 M HCl (40 mL) and brine (40 mL). The organic phase was dried over Na₂SO₄ and evaporated under vacuum. The residue was purified by flash column chromatography (cyclohexane-EtOAc, 3:1), yielding 7a (1.77 g, 26%) as a colorless oil.

• 7b

  (b) DMP (5.66 mL, 2.00 mmol, 2.00 equiv, 15% in CH₂Cl₂) was added to a solution of the triol 5a (0.236 g, 1.00 mmol, 1.00 equiv) in CH₂Cl₂ (50 mL). The suspension was stirred for 18 h at r.t. After this time the mixture was quenched with sat. NaHCO₃ solution (50 mL) and extracted with CH₂Cl₂
  (3 × 30 mL). The organic phase was dried over Na₂SO₄, evaporated, and the residue was purified by flash column chromatography (cyclohexane-EtOAc, 3:1), yielding 7a
  (46 mg, 20%) as a colorless oil.
  
  Synthesis of 7a from 9a:

• 7c

  To a solution of the diol 9a (0.372 g, 1.59 mmol, 1.00 equiv) in CH₂Cl₂ (31.5 mL) and MeCN (6.30 mL) were added NMO (0.560 g, 4.75 mmol, 3.00 equiv) and molecular sieve (1.00 g). After stirring for 30 min TPAP (0.112 g, 0.317 mmol 0.200 equiv) was added and the mixture was refluxed for 2 h. The solvent was evaporated and the residue was purified by flash column chromatography (cyclohexane-EtOAc, 3:1), yielding 7a (0.113 g, 22%) as a colorless oil.

• 7d

  (d) DMP (5.66 mL, 2.00 mmol, 2.00 equiv, 15% in CH₂Cl₂) was added to a solution of the diol 9a (0.234 g, 1.00 mmol, 1.00 equiv) in CH₂Cl₂ (10 mL) and the suspension was stirred for 1 h at 0 ˚C and for 5 h at r.t. After this time the mixture was quenched with sat. NaHCO₃ solution (10 mL) and extracted with CH₂Cl₂ (3 × 20 mL). The organic phase was dried over Na₂SO₄ and evaporated under vacuum. The residue was purified by flash column chromatography (cyclohexane-EtOAc, 3:1), yielding 7a (93 mg, 40%) as a colorless oil.

• 11 For some hydrates of nonactivated, cyclic ketones, see, for example: Khartulyari AS. Maier ME. Eur. J. Org. Chem.  2007,  317 
• 12a Cromwell NH. Bambury RE. J. Org. Chem.  1961,  26:  997 
• 12b Buchanan GL. Jhaveri DB. J. Org. Chem.  1961,  26:  4295 
• 12c Watanabe H. Katsuhara J. Yamamoto N. Bull. Chem. Soc. Jpn.  1971,  44:  1328 
• 12d Rehse K. Bienfait R. Arch. Pharm.  1984,  317:  385 
• 12e Bach RD. Klix RC. Tetrahedron Lett.  1985,  26:  985 
• 12f Bach RD. Klix RC. J. Org. Chem.  1985,  50:  5438 
• 12g Elings JA. Lempers HEB. Sheldon RA. Eur. J. Org. Chem.  2000,  1905 
• 12h Majidi L. El Idrissi M. Phys. Chem. News  2003,  9:  122 
• 12i Singh V. Prathap S. J. Ind. Inst. Sci.  2001,  81:  75 
• 13 Sheldrick GM. Acta Crystallogr., Sect. A  2008,  64:  112 

6

Otero, H.; Bräse, S. et al., unpublished results.

8

Characterization Data for 7a: R _f 0.40 (cyclohexane-EtOAc, 3:1). ^¹H NMR (400 MHz, CDCl₃): δ = 1.87-1.98 (m, 1 H, CH₂), 2.07-2.40 (m, 4 H, CH₂), 2.84-2.98 (m, 1 H, CH₂), 4.59 (s, 1 H, OH), 4.63 (dd, ^³ J = 5.5, 2.3 Hz, 1 H, H-4a), 6.96 (dd, ^³ J = 8.4 Hz, ⁴ J = 0.5 Hz, 1 H, H_arom), 7.02-7.06 (m, 1 H, H_arom), 7.47-7.53 (m, 1 H, H_arom), 7.87 (dd, ^³ J = 7.9 Hz, ⁴ J = 1.7 Hz, 1 H, H_arom). ^¹³C NMR (100 MHz, CDCl₃):
δ = 20.7 (CH₂), 25.4 (CH₂), 37.2 (CH₂), 78.1 (C-9a), 83.1 (C-4a), 118.1 (C_arom), 118.6 (C-8a), 121.9 (C_arom), 127.2 (C_arom), 136.9 (C_arom), 160.5 (C-5a), 191.4 (C-9), 207.1 (C-1). IR (KBr): 3415 (w, OH), 1717 (m, C=O) cm^-¹. MS (EI): m/z (%) = 232 (56) [M⁺], 176 (58), 121 (97), 84.0(100). HRMS (EI): m/z calcd for C₁₃H₁₂O₄: 232.0736; found: 232.0733.

9

Synthesis of 7b: To a solution of the triol 5a (0.600 g, 2.25 mmol, 1.00 equiv) in CH₂Cl₂ (10 mL) and sat. aq NaHCO₃ solution at 0 ˚C were successively added Py×HBr₃ (2.44 g, 7.63 mol, 3.00 equiv) and TEMPO-O₂CC₆H₅ (0.14 g, 0.505 mmol, 0.200 equiv). The suspension was stirred for 1 h at
0 ˚C and for 2 h at r.t. After this time Na₂S₂O₃ (ca. 1 g) was added and the mixture was stirred for 1 h. After extraction with CH₂Cl₂ (3 Ž 70 mL) the organic phase was dried over Na₂SO₄ and evaporated under vacuum. The residue was purified by flash column chromatography (cyclohexane-EtOAc, 3:1), yielding 7b (0.293 g, 37%) as a colorless oil; R _f 0.41 (cyclohexane-EtOAc, 3:1). ^¹H NMR (400 MHz, CDCl₃): d = 1.87-2.03 (m, 1 H, CH₂), 2.05-2.27 (m, 2 H, CH₂), 2.27-2.50 (m, 2 H, CH₂), 2.85-3.07 (m, 1 H, CH₂), 4.49 (br s, 1 H, OH), 4.64 (dd, ^³ J = 5.7, 2.8 Hz, 1 H, H-4a), 6.88 (d, ^³ J = 8.9 Hz, 1 H, H_arom), 7.59 (dd, ^³ J = 8.9 Hz, ⁴ J = 2.5 Hz, 1 H, H_arom), 7.98 (d, ⁴ J = 2.5 Hz, 1 H, H_arom). ^¹³C NMR (100 MHz, CDCl₃): d = 20.7 (CH₂), 25.4 (CH₂), 37.2 (CH₂), 78.0 (C_q), 83.3 (C-4a), 114.6 (C_q), 119.9 (C_q), 120.2 (C_arom), 129.5 (C_arom), 139.5 (C_arom), 159.4 (C_q), 190.3 (C-9), 206.7 (C-1). IR (KBr): 3418 (m, OH), 1698 (m, C=O) cm^-¹. MS (EI): m/z (%) = 310/312 (71/70) [M⁺], 254/256 (74/73), 199/201 (94/94), 43 (100). HRMS (EI): m/z calcd for C₁₃H₁₁BrO₄: 309.9841; found: 309.9843.
Synthesis of 10a: To a solution of the epoxide 8a (0.216 g, 1.00 mmol, 1.00 equiv) in toluene (10 mL) was added BF₃×Et₂O (0.532 g, 3.75 mmol, 3.75 equiv). After stirring for 15 min at r.t. the mixture was washed with sat. NaHCO₃ solution (10 mL) and brine (10 mL). The organic phase was dried over Na₂SO₄ and evaporated under vacuum, yielding 10a (158 mg, 73%) as colorless crystals; R _f 0.46 (cyclohexane-EtOAc, 2:1). ^¹H NMR (400 MHz, CDCl₃):
δ = 1.65-1.71 (m, 1 H, CH₂), 1.91-2.07 (m, 2 H, CH₂), 2.26-2.37 (m, 1 H, CH₂), 2.40-2.53 (m, 2 H, CH₂), 4.10 (d, ⁴ J = 1.8 Hz, 1 H, CH), 4.53 (td, ^³ J = 4.5 Hz, ⁴ J = 1.8 Hz, 1 H, CH), 6.88 (d, ^³ J = 8.1 Hz, 1 H, H_arom), 6.93 (dt, ^³ J = 7.5 Hz, ⁴ J = 1.1 Hz, 1 H, H_arom), 7.08 (dd, ^³ J = 7.6 Hz, ⁴ J = 1.6 Hz, 1 H, H_arom), 7.13-7.20 (m, 1 H, H_arom). ^¹³C NMR (100 MHz, CDCl₃): δ = 19.8 (CH₂), 34.0 (CH₂), 43.1 (CH₂), 64.4 (CH), 80.8 (CH), 117.3 (C_arom), 121.0 (C_q), 123.0 (C_arom), 129.9 (C_arom), 130.0 (C_arom), 153.3 (C_q), 202.7 (C = O), 206.3 (C=O). MS (EI): m/z (%) = 216 (10) [M⁺], 133 (100). HRMS (EI): m/z calcd for C₁₃H₁₂O₃: 216.0786; found: 216.0788.

10

Crystal Structure Determinations: All single-crystal X-ray diffraction studies were carried out on a Bruker-Nonius Kappa-CCD diffractometer at 123 (2) K using MoKα radiation (λ = 0.71073 Å). Direct Methods (SHELXS-97)^¹³ were used for structure solution (1b was solved by Patterson methods) and refinement was carried out using SHELXL-97^¹³ (full-matrix least-squares on F ^² ). Hydrogen atoms were localized by difference electron density determination and refined using a riding model [H(O) free]. A semi-absorption correction was applied for 1b and7b.
1b: colorless crystals, C₁₃H₁₁O₂Br, M = 279.13, crystal size: 0.50 × 0.30 × 0.20 mm, triclinic, space group P-1 (No. 2), a = 5.7727 (4) Å, b = 8.4963 (5) Å, c = 11.4856 (9) Å, α = 87.249 (2)˚, β = 79.221 (2)˚, γ = 86.083 (3)˚, V = 551.74 (7) Å^³, Z = 2, ρ(calc) = 1.680 Mg m^-³, F(000) = 280, µ = 3.705 mm^-¹, 3778 reflections (2θ _max = 50˚), 1936 unique [R _int = 0.060], 145 parameters, R1 [I > 2σ(I)] = 0.041, wR2 (all data) = 0.104, S = 1.00, largest diff. peak and hole 0.860 and
-0.663 e Å^-³.
7a: colorless crystals, C₁₃H₁₂O₄, M = 232.23, crystal size: 0.60 × 0.30 × 0.30 mm, monoclinic, space group P2₁/c (No. 14), a = 12.2709 (9) Å, b = 7.1115 (5) Å, c = 13.3525 (12) Å, β = 108.490 (7)˚, V = 1105.05 (15) Å^³, Z = 4, ρ(calc) = 1.396 Mg m^-³, F(000) = 488, µ = 0.104 mm^-¹, 24122 reflections (2θ _max = 55˚), 2534 unique [R _int = 0.026], 157 parameters, 1 restraint, R1 [I > 2σ(I)] = 0.035, wR2 (all data) = 0.097, S = 1.05, largest diff. peak and hole 0.356 and -0.198 e Å^-³.
7b: colorless crystals, C₁₃H₁₁O₄Br, M = 311.13, crystal size: 0.45 × 0.30 × 0.25 mm, monoclinic, space group P2₁/n (No. 14), a = 11.419 (1) Å, b = 8.953 (1) Å, c = 11.685 (1) Å, β = 105.17 (1)˚, V = 1152.98 (19) Å^³, Z = 4, ρ(calc) = 1.792 Mg m^-³, F(000) = 624, µ = 3.569 mm^-¹, 10744 reflections (2θ _max = 55˚), 2631 unique [R _int = 0.036], 166 parameters, 1 restraint, R1 [I > 2σ(I)] = 0.038, wR2 (all data) = 0.100, S = 1.04, largest diff. peak and hole 0.478 and -0.558 e Å^-³.
8a: colorless crystals, C₁₃H₁₂O₃, M = 216.23, crystal size: 0.32 × 0.16 × 0.08 mm, triclinic, space group P-1 (No. 2), a = 8.757 (1) Å, b = 10.018 (1) Å, c = 12.550 (1) Å, α = 101.68 (1)˚, β = 91.88 (1)˚, γ = 102.74 (1)˚, V = 1048.18 (18) Å^³, Z = 4, ρ(calc) = 1.370 Mg m^-³, F(000) = 456, µ = 0.097 mm^-¹, 11652 reflections (2θ _max = 55˚), 4754 unique [R _int = 0.044], 289 parameters, R1 [I > 2σ(I)] = 0.055, wR2 (all data) = 0.122, S = 1.03, largest diff. peak and hole 0.289 and -0.245 e Å^-³.
9a: colorless crystals, C₁₃H₁₄O₄, M = 234.24, crystal size: 0.35 × 0.25 × 0.10 mm, triclinic, space group P-1 (No. 2),
a = 5.670 (1) Å, b = 9.363 (1) Å, c = 11.192 (2) Å, α = 68.76 (1)˚, β = 77.05 (1)˚, γ = 76.84 (1)˚, V = 532.65 (15) Å^³, Z = 2, ρ(calc) = 1.460 Mg m^-³, F(000) = 248, µ = 0.108 mm^-¹, 10734 reflections (2θ _max = 55˚), 2448 unique [R _int = 0.033], 157 parameters, 8 restraints, R1 [I > 2σ(I)] = 0.054, wR2 (all data) = 0.122, S = 1.09, largest diff. peak and hole 0.428 and -0.566 e Å^-³. The atoms C9, O9 are disordered [3:1; s.o.f. (C9, H9, O9, H9O) = 0.760 (3)].
11a: colorless crystals, C₁₃H₁₄O₄, M = 234.24, crystal size: 0.30 × 0.12 × 0.08 mm, triclinic, space group P-1 (No. 2), a = 6.812 (1) Å, b = 7.036 (1) Å, c = 11.865 (1) Å, α = 94.62 (1)˚, β = 99.84 (1)˚, γ = 102.56 (1)˚, V = 542.79 (12) Å^³, Z = 2, ρ(calc) = 1.433 Mg m^-³, F(000) = 248, µ = 0.106 mm^-¹, 4857 reflections (2θ _max = 50˚), 1910 unique [R _int = 0.052], 160 parameters, 2 restraints, R1 [I > 2σ(I)] = 0.058, wR2 (all data) = 0.108, S = 1.06, largest diff. peak and hole 0.200 and -0.284 e Å^-³.
Crystallographic data (excluding structure factors) for the structures reported in this work have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 742582 (1b), CCDC 740940 (7a), CCDC 740941 (7b), CCDC 740942 (8a), CCDC 740943 (9a), and CCDC 740944 (11a). Copies of the data can be obtained free of charge on application to: The Director, CCDC, 12 Union Road, Cambridge DB2 1EZ, UK [Fax: [phone]; e-mail: [e-mail]].