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Synlett 2008(1): 73-76  
DOI: 10.1055/s-2007-992412
LETTER
© Georg Thieme Verlag Stuttgart · New York

Asymmetric Bisprolinamide-Catalyzed Cross-Aldol Reaction of Aldehydes

Yan Xionga, Fei Wanga, Shunxi Donga, Xiaohua Liua, Xiaoming Feng*a,b
a Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, P. R. of China
b State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, P. R. of China
Fax: +86(28)85418249; e-Mail: xmfeng@scu.edu.cn ;
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Publication History

Received 26 September 2007
Publication Date:
11 December 2007 (online)

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Abstract

A C 2-symmetric para-orientation bisprolinamide catalyst has been designed to effectively promote the enantioselective coupling reactions of aldehydes, which delivered the systematic investigation on amine-amide catalysis. Transforming the monoprolinamide 1a into the bisprolinamide 2a improved not only the stereoselectivities but also the reactivities. With this strategy, the functionalized β-hydroxyaldehydes could be furnished in high yields (up to 99%) with good selectivities (up to 8:92 syn/anti and 99% ee) even in the presence of 5 mol% of catalyst 2a. Based on the preliminary experiment and the absolute configuration of cross-aldol adduct, a rational transition state A was proposed to explain the origin of reactivity and selectivity.

Key words

asymmetric catalysis - bisprolinamide - cross-aldol reactions - hydroxyaldehydes - nonlinear effect

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Typical Procedure for the Preparation of Bisprolinamides 2a-d:(i) To a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (678.0 mg, 3.15 mmol) in CH2Cl2, dicyclohexylcarbodiimide (DCC; 649.9 mg, 3.15 mmol) and benzotriazol-1-ol (HOBt; 425.6 mg, 3.15 mmol) were added at r.t. under stirring. After 10 min, benzene-1,4-diamine (162.2 mg, 1.5 mmol) was added. The mixture was allowed to be stirred for 10 h and filtered. The filtrate was washed with 1 M KHSO4, sat. NaHCO3 and brine and was then dried over anhyd Na2SO4 and concentrated.(ii) To the residue in CH2Cl2, TFA (3.15 mL) was added and stirring was continued for an hour. Then the solution was concentrated in vacuo to a glutinous phase and H2O (4 mL) was added. The pH of the mixture was brought into the range of 8-10 by the addition of 2 M NaOH. The aqueous phase was extracted with EtOAc. The EtOAc extracts were pooled, washed with brine, dried over anhyd Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography using MeOH-EtOAc (1:2) as eluent to afford the bisprolinamide 2a as a white solid (390.1 mg, 86% yield). 1H NMR (400 MHz, CDCl3): δ = 9.71 (s, 2 H), 7.56 (s, 4 H), 3.86 (dd, J 1 = 9.2 Hz, J 2 = 5.2 Hz, 2 H), 3.06-3.12 (m, 2 H), 2.96-3.02 (m, 2 H), 2.38 (s, 2 H), 2.17-2.26 (m, 2 H), 2.00-2.08 (m, 2 H), 1.80-1.82 (m, 4 H).

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Typical Procedure for the Catalytic Asymmetric Cross-Aldol Reaction of Aldehydes:To the mixture of bisprolinamide 2a (1.5 mg, 0.005 mmol) and 4-nitrobenzaldehyde (15.1 mg, 0.1 mmol) in NMP (0.2 mL) was added hexanal (24.5 µL, 0.2 mmol) at 0 °C. The mixture was stirred for 30 h and purified by flash column chromatography using EtOAc-PE (1:2) as eluent to afford (2S)-2-[(1R)-hydroxy(4-nitrophenyl)methyl]hexanal (3a; 24.8 mg, 99% yield, 8:92 syn/anti, 99% ee).Typical Procedure for Determining the Enantiomeric Excess of 3a-e (Table 2):To a solution of (2S)-2-[(1R)-hydroxy(4-nitrophenyl)methyl]hexanal (3a; 24.8 mg) in CH2Cl2 (1 mL) were added 2,2-dimethyl-1,3-propanediol (10.4 mg, 0.10 mmol), triethyl orthoformate (13.3 µL, 0.08 mmol) and p-toluenesulfonic acid (catalytic amount) in this sequence at r.t. After 2 h of stirring, the reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (PE-EtOAc, 15:1) to afford (1R,2S)-2-(5,5-dimethyl-1,3-dioxan-2-yl)-1-(4-nitrophenyl)hexan-1-ol quantitatively as a colorless oil; [α]D 25 +9.5 (c = 0.50, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.22 (d, J = 8.8 Hz, 2 H), 7.54 (d, J = 8.8 Hz, 2 H), 5.00 (dd, J 1 = 6.0 Hz, J 2 = 4.8 Hz, 1 H), 4.47-4.48 (m, 2 H), 3.64-3.71 (m, 2 H), 3.37-3.41 (m, 2 H), 1.97-1.99 (m, 1 H), 1.23-1.26 (m, 9 H), 0.84-0.86 (m, 3 H), 0.75 (m, 3 H). HPLC (Chiralcel OJ-H, hexane-i-PrOH, 96:4; flow rate: 0.5 mL/min, 23 °C, UV: λ = 215 nm): t R(minor) = 20.665 min, t R(major) = 22.750 min.