Synthesis of Star-Shaped Aromatic Derivatives with Chirality Predetermined by Bicyclo[3.3.1]nonane Framework

Dedicated to Professor Viktoras A. Sniečkus on the occasion of his 80th anniversary

Abstract

Star-shaped aromatic derivatives of bicyclo[3.3.1]nonane with predetermined chirality were synthesized by employing the Suzuki and Sonogashira reactions. The C ₃-symmetric trifunctional aromatic derivatives based on the lateral bicyclo[3.3.1]nonene moiety possess unique molecular structures. The chiroptical properties of the star-shaped compounds and the corresponding monomeric derivatives were studied, and the absolute configuration was confirmed by using the empirical octant rule for the carbonyl chromophore and the sector rule for the aromatic chromophore.

Key words

bicyclononanes - cross-coupling - silver - Sonogashira reaction - Suzuki reaction - chiroptical properties - circular dichroism

• References and Notes

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• 10 6-Oxobicyclo[3.3.1]non-2-en-2-yl Derivatives 1–3; General Procedure A solution of LiHMDS (1.2 equiv) in toluene was added dropwise over 20 min to a solution of bicyclo[3.3.1]nonane-2,6-dione (1 equiv) in anhyd THF (5 mL) under argon at –40 °C, and the mixture was stirred at –40 °C for 40 min. The mixture was then cooled to –70 °C, and N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide), Ts₂O, or (EtO)₂POCl (1.1 equiv) was added as appropriate. The mixture was stirred at a low temperature for 2 h, then allowed to warm slowly to r.t. over 12 h. Sat. aq NH₄Cl (10 mL) was added, and the mixture was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated. The residue was purified by flash column chromatography.
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• 12 Suzuki Reaction: Typical ProcedureA mixture of monotriflate 3 (1 equiv), PhB(OH)₂ (1.5 equiv), Pd(PPh₃)₄ (3 mol%), and CsF (2 equiv) was dissolved in dry DMF (2 mL) under argon. The solution was stirred at r.t. in the closed vessel for 24 h. The mixture was then filtered through a Celite pad that was washed with CH₂Cl₂. The combined organic phases were washed with H₂O (2 × 10 mL) and brine (2 × 10 mL), dried (Na₂SO₄), filtered, and concentrated. The residue was purified by flash column chromatography.Sonogashira Reaction: General ProcedureA mixture of monotriflate 3 (1 equiv), Pd(PPh₃)₄ (3 mol%) and AgOTf (15 mol%) was dissolved in dry THF (2 mL) under argon. Ethynylbenzene (2 equiv) or 1,3,5-triethynylbenzene (0.3 equiv) and Et₃N (5 equiv) were added, and the mixture was stirred at 50 °C for 12 h. The mixture was then filtered through a Celite pad that was washed with CH₂Cl₂. The combined organic phases were washed with H₂O (2 × 10 mL) and brine (2 × 10 mL), dried (Na₂SO₄), filtered, and concentrated. The residue was purified by flash column chromatography.
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• 15 Characterization Data for Representative Compounds(+)-(S, 5)-6-Oxobicyclo[3.3.1]non-2-en-2-yl Triflate (3)Colorless oil; yield: 163 mg (81%); [α]_D +48.1 (c 1.04, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 5.91 (dd, J = 4.8, 2.8 Hz, 1 H), 2.73 (dd, J = 6.7, 3.4 Hz, 2 H), 2.57 (ddd, J = 19.2, 7.0, 2.8 Hz, 1 H), 2.47–2.35 (m, 2 H), 2.21–1.87 (m, 5 H). ¹⁹F NMR (282 MHz, CDCl₃): δ = –74.49. ¹³C NMR (75 MHz, CDCl₃): δ = 212.1, 149.5, 118.6 (q, J = 320 Hz), 117.5, 43.0, 35.9, 32.7, 31.6, 28.4, 27.8. HRMS (EI): m/z calcd for C₁₀H₁₁F₃O₄S: 284.2521; found: 284.2532.(+)-(1S,5S)-6-Phenylbicyclo[3.3.1]non-6-en-2-one (4)Colorless crystals; yield: 36 mg (91%); mp 37–38 °C; [α]_D +29.4 (c 1.09, CHCl₃); IR: 2932, 1708, 1446, 761, 735, 699 cm^–1; ¹H NMR (300 MHz, CDCl₃): δ = 7.52 – 7.21 (m, 5 H), 6.19 (dd, J = 4.5, 2.9 Hz, 1 H), 3.10–3.06 (m, 1 H), 2.76–2.78 (m, 1 H), 2.71–2.04 (m, 6 H), 2.04–1.84 (m, 2 H); ¹³C NMR (75 MHz, CDCl₃): δ = 215.0, 141.0, 140.0, 128.8, 127.5, 125.9, 123.5, 44.2, 36.4, 32.2, 31.0, 30.9, 30.1. UV (EtOH): λ_max (log ε) = 244 (4.09). CD (EtOH): λ_max (Δε) = 247 (–3.0), 289 (1.5).(+)-(1S,5S)-6-(Phenylethynyl)bicyclo[3.3.1]non-6-en-2-one (5)Yellow oil; yield: 43 mg (88) [α]_D +28.9 (c 1.14, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.55–7.28 (m, 5 H), 6.31 (dd, J = 4.6, 3.0 Hz, 1 H), 2.79–2.71 (m, 1 H), 2.71–2.63 (m, 1 H), 2.62–1.85 (m, 8 H). ¹³C NMR (75 MHz, CDCl₃): δ = 214.1, 133.2, 131.6, 128.4, 124.1, 123.4, 89.6, 88.5, 43.7, 36.0, 33.4, 30.9, 30.4. HRMS (EI): m/z calcd for C₁₇H₁₆O: 236.1201; found: 236.1224. UV (CH₂Cl₂): λ_max (log ε) = 291 (3.90), 275 (3.99). CD (EtOH): λ_max (Δε) = 299 (5.0), 270 (–0.50). (+)-(1S,1′S,1′′S,5S,5′S,5′′S)-6,6′,6′′-(Benzen-1,3,5-triyl)tris(bicyclo[3.3.1]non-6-en-2-one) (6)Colorless amorphous material; yield: 34 mg (70%); mp > 250 °C (dec.); [α]_D +18.7 (c 1.07, CHCl₃); IR: 3406, 1707, 1589, 1447, 1186, 1106, 1066 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.36 (s, 3 H), 6.22 (dd, J = 4.3, 2.8 Hz, 3 H), 3.10 (m, 3 H), 2.80 (m, 3 H), 2.72 – 2.07 (m, 18 H), 1.98 (m, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 214.6, 141.4, 140.0, 124.1, 122.4, 77.6, 77.2, 76.7, 44.1, 36.2, 32.1, 31.2, 30.8, 30.0. HRMS (EI): m/z calcd for C₃₃H₃₆O₃: 480.2664; found: 480.2668. UV (CH₂Cl₂): λ_max (log ε) = 249 (4.41), 314 (3.42). CD (CH₂Cl₂): λ_max (Δε) = 245 (–3.0), 308 (4.1).(+)-(1S,1′S,1′′S,5S,5′S,5′′S)-6,6′,6′′-(Benzen-1,3,5-triyltris(ethyn- 1,2-diyl))tris(bicyclo[3.3.1]non-6-en-2-one) (8)Colorless amorphous material; yield: 97 mg (86%); mp > 250 °C (dec.); [α]_D +145 (c 1.23, CHCl₃). IR: 2200, 1709, 1576, 1104 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.43 (s, 3 H), 6.32 (dd, J = 4.3, 3.1 Hz, 3 H), 3.74–3.68 (m, 3 H), 2.81–2.70 (m, 3 H), 2.69–1.70 (m, 24 H). ¹³C NMR (75 MHz, CDCl₃): δ = 213.6, 134.2, 133.8, 124.1, 123.8, 86.9, 43.6, 36.0, 33.3, 30.8, 30.3, 29.9. HRMS (EI): m/z calcd for C₃₉H₃₆O₃: 552.2664; found: 552.2659. UV (CH₂Cl₂): λ_max (log ε) = 297 (4.63), 281 (4.63), 268 (shoulder, 4.49). CD (CH₂Cl₂): λ_max (Δε) = 303 (20.5), 274 (–4.4).(+)-(1S,1′S,1′′S,5S,5′S,5′′S)-6,6′,6′′-(Benzen-1,3,5-triyltris(phenyl-1,4-diyl))tris(bicyclo[3.3.1]non-6-en-2-one) (10)Colorless amorphous material; yield: 20 mg (49%); mp > 250 °C (dec.); [α]_D +81.8 (c 1.98, CHCl₃); IR: 1708, 1512, 813 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.80 (s, 3 H), 7.63 (dd, J = 41.7, 8.5 Hz, 12 H), 6.30 (dd, J = 4.4, 2.9 Hz, 3 H), 3.21–3.08 (m, 3 H), 2.88–2.77 (m, 3 H), 2.68 (dd, J = 18.1, 5.7 Hz, 3 H), 2.58–1.40 (m, 21 H). ¹³C NMR (75 MHz, CDCl₃): δ = 214.8, 142.0, 140.0, 139.9, 139.3, 127.5, 126.2, 124.9, 123.7, 44.1, 36.2, 32.1, 30.8, 30.8, 30.1. HRMS (EI): m/z calcd for C₅₁H₄₈O₃: 708.3603; found: 708.3605. UV (CH₂Cl₂): λ_max (log ε) = 287 (4.86). CD (CH₂Cl₂): λ_max (Δε) = 308 (18.9), 277 (–23.7).
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