Compound 4aA

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Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.

General procedure for organocatalytic stereoselective [8 + 2] and [6 + 4] cycloadditions: a small glass vial equipped with a magnetic stirring bar was charged with the catalyst 1 (0.02 mmol, 0.2 equiv.) in the specified solvent (0.1 mL). The acid (0.2 to 0.6 equiv) was added followed by the cyclic vinyl ketone 2 (0.2 mmol, 2 equiv.) and the heptafulvene/tropone 3 (0.1 mmol, 1 equiv.). The reaction mixture was stirred at the stated temperature for 18 h and then directly purified by FC on silica gel to afford the corresponding product. The catalysts 1a-d (Liu, Y. et al. Enantioselective [4+2] cycloaddition of cyclic N-sulfimines and acyclic enones or ynones: a concise route to sulfamidate-fused 2,6-disubstituted piperidin-4-ones. Org. Lett. 15, 6090–6093 (2013)) and 2-cyclohexenones 7a-d (Dauvergne, J., Happe, A. M. & Roberts, S. M. Titanium mediated alkylidenation of substituted cycloalkenones: scope and limitations. Tetrahedron 60, 2551–2557 (2004)) were prepared according to literature procedures.

The title compound was prepared according to the general procedure outlined above; 1c (0.02 mmol, 0.2 equiv.), (-)-CSA (0.04 mmol, 0.4 equiv.), 2a (0.2 mmol, 2 equiv.), 3A (0.1 mmol, 1 equiv.) in 1,4-dioxane (0.1 mL) at 60 ˚C for 18 h. Cycloadduct 4aA was obtained after FC on silica gel (CH₂Cl₂) in 51% yield and >20:1 dr as a white solid. [α]²⁵_D -258.5 (c 0.88, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 6.08 – 5.98 (m, 2H), 5.72 (dd, J = 11.7, 7.4 Hz, 1H), 5.59 (dd, J = 11.3, 7.6 Hz, 1H), 3.33 – 3.28 (m, 1H), 3.25 – 3.20 (m, 1H), 2.83 (br s, 1H), 2.68 – 2.62 (m, 2H), 2.57 (dd, J = 19.0, 7.0 Hz, 1H), 2.36 (dd, J = 19.0, 3.7 Hz, 1H), 1.83 (dt, J = 13.0, 4.6 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 215.5, 207.1, 127.8, 127.2, 126.6, 125.2, 59.7, 57.7, 54.9, 47.4, 40.8, 26.8. HRMS calc. for C₁₂H₁₂O₂ 211.0730 [M+Na]⁺, found 211.0728. UPC² IA, CO₂/MeOH, gradient 99:1 to 60:40, 3 mL·min^-1, 40 °C, 120 bar; t_major = 3.11 min; t_minor = 2.92 min (95% ee). Crystal data for 4aA: C₁₂H₁₂O₂, M = 188.22, monoclinic, space group P 1 21/n 1 (no. 82), a = 12.1951(17) Å, b = 6.6707(5) Å, c = 12.487(16) Å, β = 115.639(16)°, V = 915.8(2) ų, T = 100 K, Z = 4, d_c = 1.365 g cm^-3, μ(Mo Kα, λ = 0.71073 Å) = 0.092 mm^-1, 4624 reflections collected, 2216 unique [R_int = 0.0568], which were used in all calculations. Refinement on F², final R(F) = 0.0905, R_w(F2) = 0.1605. CCDC number 1434123. The crystal was obtained after recrystallization from CHCl₃.