Rapid Generation of Complex Molecular Architectures by a Catalytic Enantioselective Dearomatization Strategy

 

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Abstract

A catalytic enantioselective dearomatization strategy can be used to convert readily assembled phenols into complex polycyclic architectures. By combining oxidative dearomatization of phenols bearing a pendent nucleophile with enantioselective secondary amine catalysis, high enantiomeric excesses were obtained for the natural product-like products.

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• 8 Initially, the syn-diastereomer 3 is formed by the desymmetrizing Michael addition; however, this isomer is configurationally unstable and epimerizes to the more stable anti-diastereomer 4a upon standing.
• 9 When this is performed as a one-pot procedure in 2,2,2-trifluoroethanol, tetracycle 4a is obtained in 50% yield and 82% ee.
• 10 Dearomatization of Aromatic Phenols with Intramolecular Carbon Nucleophiles: General Procedure The appropriate phenol (1.0 equiv) was dissolved in F₃CCH₂OH (0.034 M), and the solution was cooled to 0 °C or –40 °C. PhI(OAc)₂ or PhI(O₂CCF₃)₂ (1.1 equiv) was added, and the mixture was stirred at 0 °C or at –40 °C for 30 min. The reaction was quenched by addition of H₂O at 0 °C or at –40 °C, and the mixture was extracted with CH₂Cl₂ (×2). The combined organic layers were washed with brine, dried (MgSO₄), filtered, and concentrated in vacuo to give a crude product that was either used in the crude state or purified by flash chromatography to give the desired cyclohexadienone. Asymmetric Organocatalytic Conjugate Addition: General Procedure The crude cyclohexadienone was dissolved in anhydrous MeCN (0.056 M), and the mixture was cooled to –40 °C. The appropriate organocatalyst (0.1 equiv) and BzOH (0–0.1 equiv) were added, and the mixture was stirred at –40 °C for the appropriate time. The mixture was then concentrated in vacuo and the residue was dissolved in CH₂Cl₂ (0.1 M). Et₃N (0.1 equiv) was added and the mixture stirred at r.t. for 4 h, then concentrated in vacuo to give the crude product that was purified by flash chromatography.
• 11 15,16-Dimethoxy-2,10-dioxoerythrinan-7-carbaldehyde (4a) White solid; yield: 118 mg (0.35 mmol, 60%, >99% ee); mp 169–170 °C; R_f = 0.52 (CH₂Cl₂–MeOH, 9:1); [α]_D ²⁰ +72 (c = 0.04, CHCl₃). IR (film): 3988 (br), 2924, 1630, 1513, 1450, 1411, 1304, 1254, 1233, 1189, 1120, 1100, 1059, 1037 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 9.73 (d, J = 1.9 Hz, 1 H), 6.93 (s, 1 H), 6.68 (s, 1 H), 6.57 (dd, J = 10.2, 2.1 Hz, 1 H), 6.02 (d, J = 10.2 Hz, 1 H), 4.04 (dd, J = 12.6, 7.8 Hz, 1 H), 3.89 (s, 3 H), 3.86 (s, 3 H), 3.80 (dd, J = 12.6, 10.2 Hz, 1 H), 3.74 ( d, J = 20.0 Hz, 1 H), 3.60 (d, J = 20.0 Hz, 1 H), 3.39 (ddd, 10.1, 6.0, 2.1 Hz, 1 H), 3.19 (dd, J = 18.3, 6.0 Hz, 1 H), 3.03 (ddd, 18.1, 10.2, 1.89 Hz, 1 H), 2.90 (br d, J = 18.1 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 197.8, 194.3, 167.2, 149.9, 148.7, 147.6, 127.3, 127.0, 124.1, 110.9, 106.6, 64.9, 56.3, 56.1, 53.1, 43.0, 42.8, 38.7, 36.8. HRMS (APCI⁺): m/z [M + H]⁺calcd for C₁₉H₂₀NO₅: 342.1336; found: 342.1331.
• 12 The analogous para-anisole nucleophile failed to react under the dearomatization conditions, presumably due to its inability to undergo Friedel–Crafts addition at the ortho- and para-positions.
• 13 (4aS,12R,12aS)-8-Methoxy-2-oxo-1,5,6,11,12,12a-hexahydro-2H-naphtho[8a,1,2-de]chromene-12-carbaldehyde (8) Colorless oil; yield: 134 mg (0.45 mmol, 67%, 95% ee) as a colorless oil; [α]_D ²⁵ +123 (c = 1.0, CHCl₃). IR (film): 2954, 1721, 1677, 1585, 1493, 1443 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.59 (d, J = 0.7 Hz, 1 H), 6.93 (dd, J = 10.2, 2.0 Hz, 1 H), 6.74 (d, J = 8.2 Hz, 1 H), 6.67 (d, J = 8.2 Hz, 1 H), 6.07 (dd, J = 10.2, 0.9 Hz, 1 H), 4.51 (ddd, J = 11.5, 4.4, 2.7 Hz, 1 H), 4.25 (ddd, J = 12.9, 11.6, 2.5 Hz, 1 H), 3.86 (s, 3 H), 2.98 (m, 2 H), 2.91 (ddd, J = 15.8, 8.2, 0.7 Hz, 1 H), 2.67 (dt, J = 7.7, 3.6 Hz, 1 H), 2.60 (m, 1 H), 2.54 (ddd, J = 17.2, 3.3, 1.0 Hz, 1 H), 2.43 (dt, J = 13.4, 2.5, 1 H), 2.26 (td, J = 13.1, 4.3 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 201.6, 197.0, 154.3, 147.8, 143.1, 129.5, 127.0, 124.0, 119.7, 110.9, 63.7, 56.4, 50.7, 40.6, 39.8, 36.8, 36.4, 28.1. HRMS (ES⁺): m/z [M + H]⁺calcd for C₁₈H₁₉O₄: 299.1278; found: 299.1277. HPLC: AD-H (15% i-PrOH–hexane, 1.0 mL/min, 210 nm): t_R (major) = 26.6 min, t_R (minor) = 27.9 min (97% ee).
• 14 Tissot M, Phipps RJ, Lucas C, Leon RM, Pace RD. M, Ngouansavanh T, Gaunt MJ. Angew. Chem. Int. Ed. 2014; 53: 13498
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• 15 Liang H, Ciufolini MA. J. Org. Chem. 2008; 73: 4299
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