An Anionic Polycondensation Strategy for the Synthesis of Dibenzo­xanthenones: Progress Toward the Synthesis of Hypoxyxylerone

Abstract

An anionic polycondensation has been used as the key step in a highly convergent strategy for the preparation of hypoxy­xylerone derivatives.

Key words

antitumor agents - condensation - heterocycles - natural products - total synthesis

References

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• 1b Gimbert Y, Chevenier E, Greene AE, Massardier C, and Piettre A. inventors; EP  014025514. 
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• 3c

  To the best of our knowledge, bikaverin is the only natural product prepared to date through the use of this chemistry.

• 5a Chiarello J. Joullié M. Tetrahedron  1988,  44:  41 
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• 7 For an excellent review of modern methods for the synthesis of naphthalenes, see: de Koning CB. Rousseau AL. van Otterlo WAL. Tetrahedron  2003,  59:  7 
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• 9 For similar transformations, see: Lewis CN. Spargo PL. Staunton J. Synthesis  1986,  944 
• 10 Weinreb amides are superior to acid chlorides for this type of reaction. See: Carpenter TA. Evans GE. Leeper FJ. Staunton J. Wilkinson MR. J. Chem. Soc., Perkin Trans. 1  1984,  1043 ; see also ref. 6c
• 11 Matsumoto N. Nakashima T. Isshiki K. Kuboki H. Hirano S.-I. Kumagai H. Yoshioka T. Ishizuka M. Takeuchi T. J. Antibiotics  2001,  54:  285 
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• 16a

  Although acetonaphthone 17a was known, [16b] the reported yield was only 3.5%. Therefore, a new route was developed (Scheme [8] , R = H; 30% overall yield). Acetonaphthone 17b [16c] could be prepared through a route analogous to that used for the preparation of acetonaphthone 15b (Scheme [5] , N-methoxy-N-methylacetamide replaces 12); however, a route analogous to that used for 17a proved superior (Scheme [8] , R = OMe; 52% overall yield).

• 16b Yang NC. Lin LC. Shani S. Yang SS. J. Org. Chem.  1969,  34:  1845 
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• 19 The corresponding unprotected derivatives 19b-d (R¹, R² = H, OH) could also be secured in moderate yield through treatment of the xanthones 18b-d with boron tribromide prior to reduction-hydrolysis

4

Crystal data for 8: C₂₁H₁₂O₃ monoclinic. P2₁/n; a = 7.729 (1) Å, b = 8.127 (3) Å, c = 23.067 (3) Å; β = 95.95 (1)°; V = 1441.1 (5) ų; D = 1.44 gcm^-3; µ = 0.96 cm^-1; λ = 0.71073 Å. 2θ _max = 48°. 2501 measured reflections, 2440 independent reflections; 220 parameters. Reflections/parameters ratio: 6.8; R [I>1.1σ(I)] = 5.8%; wR [all data] = 5.8%. G. O. F. (all data) = 1.54. Full lists of fractional atomic co-ordinates, bond lengths and angles, and thermal parameters have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-247512.

15

Procedure for the Preparation of 4 - Polycondensation of 11 and 15b: To a stirred suspension of pentane-washed NaH (79 mg, 3.29 mmol, from a 60% dispersion in mineral oil) in anhyd THF (2.5 mL) under argon at 0 °C was added dropwise a solution of 15b (130 mg, 0.45 mmol) in THF (5.0 mL). The mixture was stirred at 25 °C for 1 h before the addition of a solution of homophthalate 11 (204 mg, 0.76 mmol) in THF (3.5 mL). The resultant mixture was stirred at 25 °C for 2 h and then heated at 80 °C for 20 h (pressure tube). The solution was cooled and aq HCl (6 N) was added, and the resultant mixture was extracted with CHCl₃. After the usual workup, the product was flash chromatographed (SiO₂, EtOAc in pentane, 30-50%) to give a mixture of 4 and 16 (12% and 25%, respectively, NMR), which was heated in H₂O-toluene 5:1 (12 mL) at 180 °C for 16 h (pressure tube). The cooled solution was worked up in the usual way with CHCl₃ to afford a solid product, which was triturated with Et₂O and filtered to give 4 (79 mg, 37%) as an orange solid. Mp 268-269 °C (CHCl₃). IR (neat): 3411, 1649, 1620, 1602 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.62 (s, 3 H), 3.89 (s, 3 H), 3.90 (s, 3 H), 3.98 (s, 3 H), 4.04 (s, 3 H), 5.16 (s, 2 H), 6.32 (d, J = 2.2 Hz, 1 H), 6.52 (d, J = 2.2 Hz, 1 H), 6.57 (d, J = 2.2 Hz, 1 H), 6.70 (d, J = 2.2 Hz, 1 H), 6.98 (s, 1 H), 7.65 (s, 1 H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 55.5 (CH₃), 55.6 (CH₃), 56.3 (CH₃), 56.4 (CH₃), 59.1 (CH₃), 73.6 (CH₂), 96.9 (CH), 97.9 (CH), 99.6 (CH), 99.8 (CH), 100.8 (CH), 104.4 (C), 108.2 (C), 109.7 (C), 112.4 (C), 119.7 (CH), 137.5 (C), 140.4 (C), 141.8 (C), 152.0 (C), 157.2 (C), 159.8 (C), 161.0 (C), 161.7 (C), 161.8 (C), 163.9 (C), 183.8 (C). MS (DCI, NH₃ + isobutane): m/z (%) = 477 (100) [MH⁺]. HRMS: m/z calcd for C₂₇H₂₄O₈: 476.1471. Found: 476.1479 (M ⁺). Xanthone 4 was identical in all respects with the material prepared earlier [2] through the homo-Fries route.

17

Crystal data for 18d: C₂₆H₂₂O₇ triclinic. P-1; a = 10.404 (3) Å, b = 11.124 (3) Å, c = 15.392 (6) Å; α = 67.91 (2)°, β = 77.29 (2)°, γ = 66.97 (2)°. V = 1513.5 (9) ų; D = 1.49 gcm^-3; µ = 1.97 cm^-1, λ = 0.56083 Å; 2θ _max = 35.7°. 3863 measured reflections, 3863 independent reflections. 424 parameters. Reflections/parameters ratio: 5; R [I>2σ(I)] = 9.7%; wR [all data] = 9.9%. G. O. F. = 2.22. The poor resolution is due to problems associated with severely disordered CHCl₃ molecules in the asymmetric cell and desolvation (capillary tube). Full lists of fractional atomic co-ordinates, bond lengths and angles, and thermal parameters have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-247513.

18

This procedure for accessing the o-quinone methides was found to be more convenient than that previously used [2] based on Saegusa dehydrosilylation.