[88733-39-5]  · C11H18N2O  · (S)-4-Anilino-3-methylamino-1-butanol  · (MW 194.27)

(tridentate chiral ligand to modify LiAlH4 for the enantioselective reduction of alkyl phenyl ketones2 and a,b-unsaturated ketones3)

Physical Data: bp 139-140 °C; [a]23D -13.7° (c 1.0, CHCl3).

Solubility: sol THF.

Preparative Methods: b-benzyl N-benzyloxycarbonylaspartate4 is treated with ethyl chloroformate, N-methymorpholine, and aniline. Subsequent reduction of the corresponding anilide with LiAlH4 gives the title reagent in overall 80% yield.2

Chiral Ligand of LiAlH4 for the Enantioselective Reduction of Alkyl Phenyl Ketones.

Optically active alcohols are important synthetic intermediates. There are two major chemical methods for synthesizing optically active alcohols from carbonyl compounds. One is asymmetric (enantioselective) reduction of ketones.1 The other is asymmetric (enantioselective) alkylation of aldehydes.5 Extensive attempts have been reported to modify Lithium Aluminum Hydride with chiral ligands in order to achieve enantioselective reduction of ketones.1 However, most of the chiral ligands used for the modification of LiAlH4 are unidentate or bidentate, such as alcohol, phenol, amino alcohol, or amine derivatives.

Unlike many other chiral ligands, (S)-4-amilino-3-methylamino-1-butanol (1) is designed as a tridentate chiral ligand anticipating a more rigid complex formation with LiAlH4. The chiral reducing reagent is prepared in situ by mixing LiAlH4 and (1) in THF. To this chiral reducing reagent is added alkyl phenyl ketone at -100 °C. Optically active (S)-s-alcohols with 51-88% ee's are obtained in 84-93% yields (eq 1). The results are summarized in Table 1.

The ee's of the obtained alcohols increase according to the increase in steric bulkiness of the alkyl substituents of prochiral ketones. Thus the reduction of t-butyl phenyl ketone occurs with 86% ee whereas reduction of acetophenone gives 51% ee. The enantioselective reduction of t-butyl phenyl ketone and a-tetralone (86 and 88% ee, respectively) are among the most selective of those reported.6

After quenching the reaction, the amino alcohol (1) is recovered in a yield of over 85% without any racemization.

Chiral Ligand of LiAlH4 for the Enantioselective Reduction of a,b-Unsaturated Ketones.

Enantioselective reductions of a,b-unsaturated ketones afford optically active allylic alcohols which are useful intermediates in natural product synthesis.7 Enantioselective reduction of a,b-unsaturated ketones with LiAlH4 modified with chiral amino alcohol (1) affords optically active (S)-allylic alcohols with high ee's. When 2-cyclohexen-1-one is employed, (S)-2-cyclohexen-1-ol with 100% ee is obtained in 95% yield (eq 2). This is comparable with the results obtained using LiAlH4-chiral binaphthol8 and chiral 1,3,2-oxazaborolidine.9

When (S)-4-(2,6-xylidino)-3-methylamino-1-butanol (2) is used instead of (1), (R)-2-cyclohexen-1-ol is obtained with less enantioselectivity (13% ee) (eq 3).

1. Grandbois, E. R.; Howard, S. I.; Morrison, J. D. In Asymmetric Synthesis, Morrison, J. D., Ed.; Academic: New York, 1983; Vol. 2, Chapter 3.
2. Sato, T.; Goto, Y.; Fujisawa, T. TL 1982, 23, 4111.
3. Sato, T.; Goto, Y.; Wakabayashi, Y.; Fujisawa, T. TL 1983, 24, 4123.
4. Benoiton, L. CJC 1962, 40, 570.
5. Soai, K.; Niwa, S. CRV 1992, 92, 833.
6. (a) Landor, S. R.; Miller, B. J.; Tatchell, A. R. JCS(C) 1967, 197. (b) Noyori, R.; Tomino, I.; Tanimoto, Y. JACS 1979, 101, 3129. (c) Terashima, S.; Tanno, N.; Koga, K. CL 1980, 981. (d) Yamaguchi, S.; Mosher, H. S. JOC, 1973, 38, 1870. (e) Asami, M.; Mukaiyama, T. H 1979, 12, 499.
7. (a) Terashima, S.; Tanno, N.; Koga, K. TL, 1980, 21, 2753. (b) Suzuki, M.; Sugiura, S.; Noyori, R. TL, 1982, 23, 4817.
8. Noyori, R.; Tomino, I.; Nishizawa, M. JACS 1979, 101, 5843.
9. Corey, E. J.; Bakshi, R. K. TL 1990, 31, 611.

Kenso Soai

Science University of Tokyo, Japan

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