Synlett 2006(20): 3399-3402  
DOI: 10.1055/s-2006-956454
LETTER
© Georg Thieme Verlag Stuttgart · New York

Asymmetric Organocatalytic Synthesis of cis-Substituted ­Dihydrobenzofuranols via Intramolecular Aldol Reactions

Dieter Enders*a, Oliver Niemeiera, Leo Straverb
a Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax: +49(241)8092127; e-Mail: enders@rwth-aachen.de;
b Bruker AXS B. V., Application SCD, Oostsingel 209, 2600AV Delft, The Netherlands
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Publikationsverlauf

Received 28 September 2006
Publikationsdatum:
08. Dezember 2006 (online)

Abstract

The diastereo- and enantioselective synthesis of 3-hydroxy 2,3-dihydrobenzofurans via an intramolecular cis-selective aldol reaction employing proline-type organocatalysts is described enabling a new entry to coumarine natural products.

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Aldehyde ketones of type 4 can be synthesized by reaction of the corresponding salicyl aldehydes, K2CO3 and α-bromo ketones in DMF at r.t.

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CCDC 617162 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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All new compounds were fully characterized (IR, NMR, MS, elemental analysis, optical rotation, melting point).
Asymmetric Organocatalytic Intramolecular cis -Aldol Reaction to 5b - Typical Procedure.
To a suspension of (S)-proline (17.3 mg, 0.15 mmol, 30 mol%) in DMF (0.5 mL) was added the aldehyde-ketone 4b (96 mg, 0.5 mmol) and stirred at r.t. for 24 h. The mixture was quenched with a pH 7 buffer solution, extracted with Et2O (3 ×) and dried over MgSO4. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel (Et2O-n-pentane, 1:2) to yield 5b (71 mg, 74%) as a colorless solid; mp. 106 °C; de 88% (99% after recrystallization, determined by GC); ee 77% [99% after recrystallization, determined by chiral stationary phase HPLC (Daicel Chiralpak IA)]; [α]D 23 -149.5 (c 1.7, CHCl3). IR (KBr): 3363, 2971, 2927, 1720, 1601, 1469, 1394, 1311, 1237, 1166, 1024, 981, 939, 847, 748, 634, 490 cm-1. 1H NMR (400 MHz, CDCl3, TMS): δ = 1.09 (t, 3 H, J = 7.3 Hz, CH3), 2.58 (s, 1 H, OH), 2.63 (dq, 1 H, J = 7.2, 18.7 Hz, CHH), 2.80 (dq, 1 H, J = 7.2, 18.7 Hz, CHH), 4.98 (d, 1 H, J = 6.6 Hz, CH), 5.54 (d, 1 H, J = 6.6 Hz, CH), 6.95-6.97 (m, 1 H, ArH), 6.98-7.01 (m, 1 H, ArH), 7.29-7.33 (m, 1 H, ArH), 7.40-7.42 (m, 1 H, ArH). 13C NMR (100 MHz, CDCl3): d = 6.7 (CH3), 34.1 (CH2), 73.0, 89.9, 110.6, 121.6, 125.7 (CH), 126.6 (C), 131.0 (CH), 159.3 (C), 208.7 (CO). MS (EI): m/z (%) 192 (25) [M+], 121 (7), 119 (9), 118 (100), 107 (7), 79 (10), 77 (11), 57 (13). Anal. Calcd for C11H12O3: C, 68.74; H, 6.29. Found: C, 68.96; H, 6.65.