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Synlett 2009(10): 1631-1634  
DOI: 10.1055/s-0029-1217347
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© Georg Thieme Verlag Stuttgart ˙ New York

Enantioselective Protonation in the Aza-Michael Reaction Using a Combination of Chiral Pd-µ-Hydroxo Complex with an Amine Salt

Yoshitaka Hamashima, Toshihiro Tamura, Shoko Suzuki, Mikiko Sodeoka*
Advanced Science Institute, RIKEN, 2-1 Hirosawa, Wako 351-0198, Japan
Fax: +81(48)4624666; e-Mail: sodeoka@riken.jp;
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Publication History

Received 30 January 2009
Publication Date:
02 June 2009 (online)

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Abstract

A highly enantioselective protonation of enolate intermediates in aza-Michael reaction was achieved by using the combination of a bifunctional chiral Pd-µ-hydroxo complex with aromatic amine salts. The reaction proceeded smoothly to give the desired β-amino carbonyl compounds bearing a stereogenic carbon center at the α-position in good yield with excellent enantioselectivity (up to 97% ee). Although reactions with salts of electron-deficient amines were slow, the introduction of free amine as an additive promoted the reaction to a synthetically useful level.

Key words

asymmetric catalysis - protonations - palladium - aza-Michael additions - β-amino acids

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13

General Procedure
The starting material 9 (0.1 mmol), amine salts 7 (0.15 mmol), and the Pd complex 1 (5 mol%) were dissolved in THF (0.2 mL). In the case of 7c, the additive 15 (0.05 mmol) was included. The resulting solution was stirred at ambient temperature for the time shown in Tables  [¹] -  [³] . For quench-ing, cold sat. aq NaHCO3 (2 mL) was added under ice-bath cooling. Usual workup, followed by flash column chromato-graphy (Si2O, hexane-EtOAc system) gave the pure products.
Analytical Data of 10ca
¹H NMR (400 MHz, CDCl3): δ = 3.38 (dd, J = 5.5, 13.0 Hz, 1 H), 3.74 (s, 3 H), 3.84 (dd, J = 8.7, 13.0 Hz, 1 H), 4.48 (br s, 1 H), 5.08 (s, 2 H), 6.58 (d, J = 8.8 Hz, 2 H), 6.78 (d, J = 8.8 Hz, 2 H), 7.26-7.39 (m, 10 H), 7.55 (br s, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 48.0, 51.2, 55.7, 67.9, 114.7, 115.0, 128.0, 128.4, 128.5, 128.6, 128.7, 129.1, 134.7, 136.0, 141.2, 150.6, 152.5, 172.4. LRMS-FAB (mNBA): m/z = 404 [M+], 405 [M + H]+. HRMS (PEG 400/mNBA): m/z calcd for C24H24N2O4 [M]+ 404.1736; found: 404.1739. [α]D ²5 +64.6 (c 0.82, CHCl3; 93% ee). HPLC (DAICEL CHIRALPAK AD-H, hexane-2-PrOH = 3:1, 1.0 mL/min, 254 mn): t R(minor) = 17.2 min, t R(major) = 20.9 min.