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Synlett 2008(10): 1565-1570  
DOI: 10.1055/s-2008-1077789
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© Georg Thieme Verlag Stuttgart · New York

The Effectiveness of Proteinogenic Amino Acids in the Asymmetric Aldol Reaction in DMSO and Aqueous DMSO

Yujiro Hayashi*, Takahiko Itoh, Norio Nagae, Masahiro Ohkubo, Hayato Ishikawa
Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Fax: +81(3)52614631; e-Mail: hayashi@ci.kagu.tus.ac.jp;
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Publication History

Received 2 February 2008
Publication Date:
16 May 2008 (online)

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Abstract

The effects of twenty proteinogenic amino acids have been investigated in the aldol reaction of aldehyde and ketone in DMSO and aqueous DMSO (in the presence of three equivalents of water). Not only proline but also other amino acids promote the aldol reaction enantioselectively. The effect of water varies with amino acid, and water does not affect the enantioselectivity in most cases, the exceptions being Pro, Ser and His. In the case of Pro, large positive effects on diastereo- and enantioselectivities were observed in the reaction of α-substituted methyl ketone, while no effect was observed in that of methyl ketone.

Key words

asymmetric synthesis - aldol reactions - organocatalyst - amino acids - water

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Typical Experimental Procedure (Table 1): To a DMSO solution (0.40 mL [] ) or aq DMSO solution (DMSO: 0.40 mL; H2O: 22 µL [] ) of amino acid (0.12 mmol) were added p-nitrobenzaldehyde (60.5 mg, 0.4 mmol) and cyclohexanone (207 µL, 2.0 mmol) under an argon atmosphere at r.t. When the reaction was complete, it was quenched with pH 7.0 phosphate buffer solution. The organic materials were extracted with EtOAc (3 ×) and the combined organic extracts were dried over anhyd Na2SO4, and concentrated in vacuo after filtration. The residue was purified by flash chromatography to give an aldol product. Diastereoselectivity was determined by 1H NMR (400 MHz). Enantiomeric excess was determined by HPLC analysis with a Chiralpak AS-H column (hexane-2-pro-
panol = 10:1, λ = 231 nm), 1.0 mL/min; major enantiomer t R = 11.5 min, minor enantiomer t R = 18.7 min.