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Synlett 2003(12): 1910-1914  
DOI: 10.1055/s-2003-41486
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© Georg Thieme Verlag Stuttgart · New York

The First Organocatalytic Hetero-Domino Knoevenagel-Diels-Alder-Epimerization Reactions: Diastereoselective Synthesis of Highly Substituted Spiro[cyclohexane-1,2′-indan]-1′,3′,4-triones

D. B. Ramachary, Naidu S. Chowdari, Carlos F. Barbas III*
The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, California 92037, USA
Fax: +1 (858)7842583; e-Mail: carlos@scripps.edu;
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Publication History

Received 4 June 2003
Publication Date:
19 September 2003 (online)

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Abstract

l-Proline and pyrrolidine catalyzed the three component hetero-domino Knoevenagel-Diels-Alder-Epimerization reactions of readily available precursors enones 1a-i, arylaldehydes 2a-i and 1,3-indandione 3 to furnish highly substituted prochiral spiro[cyclohexane-1,2′-indan]-1′,3′,4-triones 5a-i in a highly diastereo­selective fashion with excellent yields. We demonstrate the first l-proline and pyrrolidine catalyzed epimerization reactions of trans-spiranes 6a-i to cis-spiranes 5a-i. Prochiral spiranes 5a-i are excellent­ starting materials for the synthesis of benzoannelated centro­polyquinanes.

Key words

2-amino-1,3-butadiene - Diels-Alder reaction - domino reactions - organocatalysis - organic Lewis acid

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General Experimental Procedure for the Preparation of Prochiral Spiro[cyclohexane-1,2′-indan]-1′,3′,4-triones by Using l -Proline and Pyrrolidine Catalyzed Hetero-Domino Knoevenagel-Diels-Alder-Epimerization Reaction: Method A. In an ordinary glass vial equipped with a magnetic stirring bar, to 0.5 mmol of the aldehyde and 0.5 mmol of 1,3-indandione was added 1.0 mL of solvent, and then the catalyst l-proline (0.1 mmol) or pyrrolidine (0.15 mmol) was added and the reaction mixture was stirred at ambient temperature for 15-30 min. When the reaction mixture solidified, more solvent was added, 0.5 mL. Then 0.5 mmol of the enone was added and the reaction stirred at 70 °C for 1-2 h (Table [2] ). The crude reaction mixture was treated with saturated aq NH4Cl solution, the layers were separated, and the organic layer was extracted three to four times with CH2Cl2 (10 mL), dried with anhyd Na2SO4, and evaporated. The pure Domino products were obtained by flash column chromatography (silica gel, mixture of hexane/EtOAc). Method B. In an ordinary glass vial equipped with a magnetic stirring bar, to 0.5 mmol of aldehyde, 0.5 mmol of enone, 0.5 mmol of 1,3-indandione was added 1.0 mL of solvent, and then the catalyst l-proline (0.1 mmol) or pyrrolidine (0.15 mmol) was added and the reaction mixture was heated slowly to 70 °C with stirring for 1-h. the Domino products were isolated as in Method A. Both methods gave identical results. (2β,6β)-2,6-Diphenylspiro[cyclohexane-1,2′-indan]-1′,3′,4-trione(5aa). Plane of symmetry with chair conformation. 1H NMR (399 MHz, CDCl3): δ = 7.64 (1 H, td, J = 7.6 and 1.2 Hz), 7.48 (1 H, m), 7.41 (2 H, m), 7.08-6.90 (10 H, m, 2 × Ph-H), 3.81 (4 H, m), 2.66 (2 H, ABq, J = 17.1 Hz). 13C NMR (100 MHz, CDCl3): δ = 208.4 (C, C=O), 203.4 (C, C=O), 201.8 (C, C=O), 142.7 (C, C-8′), 141.9 (C, C-9′), 137.3 (2 × C), 135.2 (2 × CH), 128.3 (4 × CH), 128.0 (4 × CH), 127.6 (2 × CH), 122.4 (CH), 122.0 (CH), 62.0 (C, C-1 or C-2′), 48.7 (2 × CH), 43.4 (2 × CH2). HRMS (MALDI-FTMS): m/z = 381.1492 [M + H+], calcd for C26H20O3H+ 381.1485. (2β,6α)-2,6-Diphenyl-spiro[cyclohexane-1,2′-indan]-1′,3′,4-trione(6aa).
C2-Symmetry with twist conformation. 1H NMR (399 MHz, CDCl3): δ = 7.57 (2 H, m), 7.52 (2 H, m), 7.08-6.90 (10 H, m, 2 × Ph-H), 3.99 (2 H, dd, J = 13.5 and 3.2 Hz, H-2 and 6), 3.62 (2 H, dd, J = 16.3 and 13.5 Hz, H-3β and 5β), 2.78 (2 H, dd, J = 16.7 and 3.2 Hz, H-3α and 5α). 13C NMR (100 MHz, CDCl3): δ = 210.0 (C, C=O), 202.8 (2 × C, C=O), 142.0 (2 × C, C-8′ and 9′), 137.2 (2 × C), 135.3 (2 × CH,
C-7′ and 4′), 128.3 (4 × CH), 128.1 (4 × CH), 127.3 (2 × CH), 122.4 (2 × CH, C-5′ and 6′), 61.5 (C, C-1 or 2′), 43.4 (2 × CH, C-6 and 2), 41.5 (2 × CH2, C-3 and 5). HRMS (MALDI-FTMS): m/z = 403.1300 [M + Na+], calcd for C26H20O3Na+ 403.1305.

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Formation of the kinetic product, trans-spirane 6aa as the major isomer in ionic liquids, as opposed to the cis-spirane 5aa through the endo-transition state in the classical Diels-Alder route is likely explained by unique solvation in the ionic liquid of the 2-amino-1,3-butadiene 9a and dienophile 8a in the transition states shown below. Asymmetric solvation in the ionic liquids may produce a steric hindrance with the phenyl group on the dienophile, in the endo-transition state, thereby disfavoring it (Figure [1] ).