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Synlett 2012(3): 453-357  
DOI: 10.1055/s-0031-1290316
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Stereoselective Synthesis of vic-Halohydrins via l-tert-Leucine-Catalyzed syn-Selective Aldol Reaction

Atsushi Umehara, Takuya Kanemitsu, Kazuhiro Nagata, Takashi Itoh*
School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Fax: +81(3)37845982; e-Mail: itoh-t@pharm.showa-u.ac.jp;
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Publication History

Received 9 November 2011
Publication Date:
19 January 2012 (online)

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Abstract

l-tert-Leucine was found to be an effective organocatalyst for the asymmetric aldol reaction of chloroacetone. The stereoselective synthesis of vic-halohydrins was accomplished with excellent regioselectivity (>99%) to generate α-chloro-β-hydroxy ketones with high syn selectivity (syn/anti = 16:1) and enantioselectivity (up to 95% ee).

Key words

aldol reaction - amino acids - asymmetric synthesis - chloroacetone - organocatalysis

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11

Optimized Procedure for the Synthesis of 3a To a mixture of chloroacetone (1a, 400 µL, 5 mmol) and l-tert-leucine (13 mg, 0.1 mmol), 4-nitrobenzaldehyde (2a, 76 mg, 0.5 mmol) was added, and the mixture was stirred at r.t. The reaction was monitored by TLC analysis. After 7 d, H2O was added and extracted with CH2Cl2 (3×), dried over MgSO4, and concentrated in vacuo. To determine the regioselectivity and the diastereomeric ratio, the remaining residue was analyzed by ¹H NMR. Moreover, the ee value of the product 3a was determined by chiral-phase HPLC analysis of the residue. Then, the residue was purified by column chromatography on silica gel in gradient elution with hexane-EtOAc to give a 7:1 inseparable mixture of the desired products 3a and 4a (108 mg, 89%).
Analytical Data for Compound 3a
¹H NMR (400 MHz, CDCl3): δ = 8.24-8.20 (m, 2 H), 7.61-7.58 (m, 2 H), 5.47 (t, J = 3.6 Hz, 1 H), 4.46 (d, J = 3.2 Hz, 1 H), 3.43 (d, J = 4.0 Hz, 1 H), 2.40 (s, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 203.4, 147.6, 146.2, 127.3, 123.5, 72.0, 67.3, 28.3. HPLC: 83% ee [Daicel CHRALCEL OJ-H, hexane-iPrOH (9:1), flow rate 1.0 mL/min, λ = 254 nm]: t R(major) = 34.7 min; t R(minor) = 39.1 min.