Synlett 2007(6): 0885-0888  
DOI: 10.1055/s-2007-970787
LETTER
© Georg Thieme Verlag Stuttgart · New York

Organocatalytic Asymmetric Conjugate Nucleophilic Glyoxylation

Dieter Enders*, Maurice Hubert Bonten, Gerhard Raabe
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax: +49(241)8092127; e-Mail: enders@rwth-aachen.de;
Further Information

Publication History

Received 10 January 2007
Publication Date:
26 March 2007 (online)

Abstract

Organocatalytic nucleophilic glyoxylation reactions have been developed for the first time in asymmetric Michael additions of aminonitriles to α,β-unsaturated aldehydes employing iminium activation with a diphenylprolinol catalyst. After reduction and TBS protection or conversion into camphanoyl derivatives of the resulting alcohols, the final 3-substituted 2-ketoesters were ­obtained in acceptable yields over four steps (ee = 83-87%, de = 49-88%). Recrystallisation of the camphanoyl derivatives ­afforded the pure diastereomers (de ³ 98%)

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CCDC 631143 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.

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All new compounds were fully characterised (IR, NMR, MS, elemental analysis, optical rotation, melting point).
Organocatalytic Asymmetric Nucleophilic Glyoxylation to 8a - Typical Procedure To a solution of the aminonitrile 1 (840 mg, 4 mmol) in toluene (4.0 mL) were added the aldehyde 3a (280 mg, 0.33 mL, 4 mmol) and the catalyst (S)-2 (293 mg, 20 mol%). The reaction mixture was stirred at r.t. for 2 d, quenched with brine and extracted three times with Et2O (10 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product 4a was dissolved in anhyd THF (8.0 mL), cooled to 0 °C and NaBH4 (453 mg, 12 mmol) was added. The suspension was slowly treated with MeOH (2 mL), using a syringe pump. After stirring for 1 h, the mixture was quenched with sat. NH4Cl solution, the organic phase separated and the aqueous phase extracted three times with Et2O (10 mL). The combined organic phases were washed with brine and H2O, respectively, dried over MgSO4 and the solvent was evaporated. The crude product 5a was subsequently dissolved in anhyd THF (32 mL) and TBSCl (0.9 g, 6.0 mmol) was added. The mixture was cooled to 0 °C and slowly treated with a solution of imidazole (0.54 g, 8 mmol) in anhyd THF (8.0 mL). After stirring for 15 min, the mixture was quenched with brine and extracted three times with Et2O (10 mL). The combined organic phases were washed with H2O, dried over MgSO4, and the solvent was evaporated. The crude product 6a was dissolved in THF (40 mL) and aq 2 N AgNO3 (2.72 g, 16 mmol) was added. After stirring for 2 h, Et2O (40 mL) was added and the mixture stirred for an additional 30 min. The Ag residues were removed by filtration and washed with Et2O and H2O. The aqueous phase was extracted three times with Et2O (10 mL). The combined organic layers were subsequently washed with brine, dried over MgSO4 and the solvent was evaporated. The crude product was purified by flash chromatography on silica gel (Et2O-n-pentane, 1:10) to yield 8a (480 mg, 38%) as a colourless oil; ee 83% (determined by 1H-shift NMR); [α]D 20 -4.3 (c 0.65, CHCl3). IR (CHCl3): 2933, 2886, 2859, 1724, 1558, 1465, 1370, 1290, 1257, 1168, 1099, 1027, 837, 779 cm-1. 1H NMR (300 MHz, CDCl3, TMS): δ = 0.03 [s, 6 H, Si(CH3)2], 0.88 [s, 9 H, SiC(CH3)3], 1.14 (d, 3 H, J = 7.10 Hz, CHCH 3), 1.55 [s, 9 H, OC(CH3)3], 1.63 (m, 1 H, CH 2CH2O), 1.94 (m, 1 H, CH 2CH2O), 3.32 (m, 1 H, CHCH3), 3.65 (t, 3 H, J = 7.05 Hz, CH2O). 13C NMR (75 MHz, CDCl3): d = -5.42 [Si(CH3)2], 15.24 (CHCH3), 18.32 [SiC(CH3)3], 25.94 [SiC(CH3)3], 27.88 [OC(CH3)3], 34.76 (CH2CH2O), 38.93 (CHCH3), 60.34 (CH2O), 83.67 [OC(CH3)3], 161.28 (CO2 t-Bu), 198.50 (COCH). MS (CI): m/z (%) = 316 (0.7) [M+], 295 (9), 261 (54), 259 (3), 215 (2) [M+ - C5H9O2]. Anal. Calcd for C16H32O4Si: C, 60.72; H, 10.19. Found: C, 60.91; H, 10.08.