Organocatalytic Enantioselective Approach to Spirocyclic Δ^β,γ-Butenolides

Abstract

A novel method for the preparation of the spirocyclic Δ^β,γ-butenolides is presented. The developed strategy is based on a trienamine-mediated [4+2]-cycloaddition between (E)-3-alkylidene-5-arylfuran-2(3H)-ones and 2,4-dienals. Target products containing three contiguous centres including one quaternary are efficiently formed in a highly enantiomerically enriched form in the presence of the silyl-protected diphenylprolinol aminocatalyst.

Key words

asymmetric synthesis - aminocatalysis - trienamines - Δ^β,γ-butenolides - quaternary stereogenic center

• References and Notes


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• 7 Representative Procedure: An ordinary screw-cap vial was charged with a magnetic stirring bar, the corresponding (E)-3-arylidene-5-arylfuran-2(3H)-one 2 (0.2 mmol, 1 equiv), catalyst 3b (0.04 mmol, 0.2 equiv), CH₂Cl₂ (0.4 mL) and the corresponding 2,4-dienal 1 (0.6 mmol, 3 equiv). The reaction mixture was stirred at r.t. and monitored by ¹H NMR spectroscopy. After 24 h the reaction mixture was directly submitted to Ramirez olefination. In a separate screw-cap vial carbon tetrabromide (0.3 mmol, 3.0 equiv) was dissolved in CH₂Cl₂ (0.5 mL) and cooled to –5 °C. Triphenylphosphine (0.6 mmol, 6.0 equiv) was added in one portion and after 5 min the reaction mixture was added dropwise at –5 °C. After 10 min at 0 °C the reaction mixture was directly subjected to flash chromatography on silica gel to afford the target product 5.
• 8 CCDC 1007871 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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• 10 Data for 5a: 6-(3,3-Dibromoallyl)-3,10-diphenyl-2-oxaspiro[4.5]deca-3,7-dien-1-one (Table 2, Entry 1): Following the general procedure, 5a was isolated by flash chromatography on silica (gradient: hexane–Et₂O from 100:0 to 100:6) in 65% yield as a colourless oil (dr = 3.5:1). (5S,6S,10R)-5a: ¹H NMR (700 MHz, CDCl₃): δ = 7.56–7.59 (m, 2 H), 7.38–7.43 (m, 3 H), 7.24–7.31 (m, 5 H), 6.48 (dd, J = 8.2, 6.6 Hz, 1 H), 6.10 (ddt, J = 10.3, 3.7, 1.8 Hz, 1 H), 5.85 (ddd, J = 10.0, 3.8, 2.0 Hz, 1 H), 5.72 (s, 1 H), 3.33 (t, J = 6.6 Hz, 1 H), 2.79 (dddd, J = 16.9, 6.2, 3.9, 2.0 Hz, 1 H), 2.62 (ddd, J = 14.4, 6.6, 4.3 Hz, 1 H), 2.44–2.53 (m, 2 H), 2.36 (ddd, J = 14.3, 10.1, 8.2 Hz, 1 H). ¹³C NMR (176 MHz, CDCl₃): δ = 177.1, 152.2, 140.5, 136.1, 129.9, 128.8 (2 × C), 128.8 (2 × C), 128.3, 128.5 (2 × C), 127.9, 127.6, 126.7, 125.1 (2 × C), 105.8, 90.9, 55.6, 43.1, 39.7, 34.4, 29.6. HRMS: m/z [M + Na]⁺ calcd for C₂₄H₂₀Br₂O₂: 522.9707; found: 522.9710. The ee was determined by HPLC using a Chiralpak IA column [hexane–i-PrOH (98:2)]; flow rate: 1.0 mL/min; t _R (major) = 13.2 min, t _R (minor) = 11.5 min (98% ee); [α]_D ²⁰ +0.8 (c = 1.2, CHCl₃).