Organocatalytic Asymmetric Conjugate Additions of Oxindoles and Benzofuranones to Cyclic Enones

Abstract

The asymmetric catalytic synthesis of densely functionalized molecules that contain vicinal quaternary and tertiary stereocenters is a challenge for modern chemical methodology. Here we show that a chiral primary amine, derived from natural molecules, efficiently catalyzes the stereoselective conjugate addition of oxindoles to cyclic enones, leading directly to valuable chiral scaffolds. Proof-of-concept for extending the method to benzofuranone derivatives is also provided.

asymmetric catalysis - ketones - Michael addition - quaternary carbon - organocatalysis

References and Notes

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Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre, accession number CCDC 771490(4), and are available free of charge via www.ccdc.cam.ac.uk/data_request/cif.

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<A NAME="RY00310ST-17">17</A>

General Procedure All the reactions were carried out with no precautions to exclude moisture in undistilled toluene. In an ordinary vial equipped with a magnetic stir bar, amine A or B (0.02 mmol, 6.5 mg, 10 mol%) and benzoic acid (0.04 mmol, 4.9 mg, 20 mol%) were dissolved in toluene (1 mL). After stirring at r.t. for 10 min, the cyclic enones 2 (0.2 mmol) was added, followed by the addition of oxindole 1 or benzofuranone 5 (0.24 mmol, 1.2 equiv). The vial was sealed, and the mixture stirred for 1 d at r.t. The crude mixture was diluted with CH₂Cl₂ and flushed through a short plug of silica, using CH₂Cl₂-EtOAc (1:1) as the eluent. Solvent was removed in vacuo, and the Michael adduct 3 or 6 was purified by flash column chromatography (silica gel, hexane-EtOAc). All new compounds gave satisfactory spectroscopic and analytical data. As a typical example, the data of the compound 3a are given. ( R )- tert -Butyl 3-Benzyl-2-oxo-3-[( S )-3-oxocyclohexyl]-indoline-1-carboxylate (3a, Entry 1, Table 2)
Isolated as a mixture of diastereomers (5.2:1 dr) by column chromatography (hexane-acetone = 90:10) in 80% yield. The ee (96% ee) was determined by HPLC on a chiral stationary phase [Chiralpak AD-H; hexane-i-PrOH (98:2); 0.50 mL/min; λ = 214, 254 nm; t _R = 34.1 min(major), 41.7 min (minor, based on the racemic mixture)]; [α]_D ^rt -17.37 (c 0.98, CHCl₃, dr = 5.2:1, 96% ee). ^¹H NMR (400 MHz, CDCl₃): δ = 1.47-1.64 (m, 2 H), 1.55 (s, 9 H), 1.70-1.81 (m, 1 H), 1.97-2.12 (m, 1 H), 2.15-2.32 (m, 1 H), 2.32-2.50 (m, 2 H), 2.55-2.61 (m, 2 H), [CH₂ A-B type spectrum (3.04, d, 1 H, J _gem = -12.8 Hz), (3.30, d, 1 H, J _gem = -12.8 Hz)], 6.72-6.77 (m, 2 H), 6.93-7.06 (m, 3 H), 7.13-7.31 (m, 3 H), 7.52-7.57 (m, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 25.1 (CH₂), 26.4 (CH₂), 28.3 (3× CH₃), 41.4 (CH₂), 42.2 (CH₂), 43.0 (CH₂), 46.2 (CH), 57.4 (C), 84.3 (C), 115.0 (CH), 123.6 (CH), 124.4 (CH), 126.9 (CH), 127.9 (CH), 128.6 (CH), 129.3 (C), 130.0 (CH), 135.1 (C), 140.3 (C), 148.8 (C), 177.2 (C), 210.6 (C). HRMS (EI): m/z calcd for C₂₆H₂₉NO₄: 419.2096; found: 419.2092.