Highly enantioselective reduction of achiral ketones with NaBH4/Me3SiCl catalyzed by (S)-α,α-diphenylpyrrolidinemethanol

Article abstract of DOI:10.1016/S0040-4039(00)01848-7

The reducing agent prepared from sodium borohydride, trimethylsilyl chloride and a catalytic amount of (S)-α,α-diphenylpyrrolidinemethanol has been successfully applied to the enantioselective reduction of ketones. The optically active secondary alcohols were obtained in excellent enantiomeric excess and almost quantitative chemical yield. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01848-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10281–10283
Highly enantioselective reduction of achiral ketones with
NaBH /Me SiCl catalyzed by
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(S)-a,a-diphenylpyrrolidinemethanol
Biao Jiang,* Yan Feng and Jian Zheng
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai,
00032, PR China
2
Received 18 August 2000; revised 13 October 2000; accepted 19 October 2000
Abstract
The reducing agent prepared from sodium borohydride, trimethylsilyl chloride and a catalytic amount
of (S)-a,a-diphenylpyrrolidinemethanol has been successfully applied to the enantioselective reduction of
ketones. The optically active secondary alcohols were obtained in excellent enantiomeric excess and
almost quantitative chemical yield. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric reduction; enantioselective catalysis; NaBH /Me SiCl combination.
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Much attention has been devoted to the enantioselective synthesis of optically active alcohols
1
which are important starting materials for many biologically active compounds. The chiral
oxazaborolidine-catalyzed reduction (CBS reduction) of prochiral ketones developed by Corey
and co-workers is one of the most important methods for generation of chiral secondary
2
alcohols. However, the CBS reduction commonly requires expensive borane–dimethyl sulfide
3
2f,4
complex, borane–tetrahydrofuran, borane–1,4-thioxane or catecholborane,
which are toxic
and rather expensive. Moreover, due to the air and moisture sensitivity of the BꢀH oxazaboro-
lidine, the method for generation of the oxazaborolidine using a,a-diphenylpyrrolidine methanol
2a
and borane suffers from a complicated preparation procedure. The expanding utility of the
CBS reduction in the pharmaceutical industries has created a need for development of more
convenient processes for reduction of prochiral ketones to chiral secondary alcohols. Herein we
report an enantioselective reduction of ketones with the combined reagent of NaBH /Me SiCl
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and a catalytic amount of (S)-a,a-diphenylpyrrolidinemethanol.
*
Corresponding author.
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01848-7

10282
Sodium borohydride has become one of the most widely used reagents for both laboratory
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and industrial scale application in chemistry. It was reported that the combination reagent of
LiBH (NaBH ) and Me SiCl was used for the reduction of the carboxyl group of amino acids.
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The reaction mechanism proposed that a borane–tetrahydrofuran complex was formed when
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LiBH (NaBH ) was treated with Me SiCl in THF, and this inspired us to investigate the
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possibility of carrying out the CBS asymmetric reductions of ketones by formation of the
oxazaborolidine in situ from NaBH /Me SiCl and (S)-a,a-diphenylpyrrolidinemethanol.
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Typically a mixture of 1.2 equivalents of NaBH and Me SiCl in THF was allowed to react
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at 70°C for one hour, then 0.1 equivalents of (S)-a,a-diphenylpyrrolidinemethanol was added to
give a reducing mixture to which the ketone was slowly added for reduction at room
temperature. We have found that the reduction of ketones using the combined reagent of
NaBH /Me SiCl catalyzed by (S)-a,a-diphenylpyrrolidinemethanol yielded the corresponding
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3
alcohols almost quantitatively with excellent enantiomeric excess. The reduction of several
ketones was examined by using the new reduction conditions (Table 1). In each case, the
2
a
enantioselective reduction gave almost the same result as a CBS reduction. Reduction of
acetophenone (entry 1) offered (R)-1-phenylethanol in 96% ee (97% in CBS reduction). In the
Table 1
Asymmetric reduction of prochiral ketones using the combination of NaBH and Me SiCl catalyzed by (S)-a,a-
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a
diphenylpyrrolidinemethanol
a
All reactions were carried out using 1.2 mmol of NaBH , 1.2 mmol of Me SiCl, 1.0 mmol ketone and 0.1 mmol
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3
b
c
of (S)-a,a-diphenylpyrrolidinemethanol; Isolated yields; Ee determined by HPLC on chiralcel OD column with 5%
isopropanol in hexane as solvent; Absolute configurations were determined by the comparison of optical rotation
d
with literature values.

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reduction of a-bromoacetophenone and 2-acetonaphthenone (entries 4 and 6), the highest
enantiomeric excesses (98%) were observed. After reaction, the chiral auxiliary (S)-a,a-
diphenylpyrrolidinemethanol was easily recovered in 86% yield by extraction into aqueous acid
and precipitation with ammonium hydroxide. The results suggest that the catalyst, the BꢀH
oxazaborolidine, is generated in situ on treatment of (S)-a,a-diphenylpyrrolidinemethanol with
the combined reagent of NaBH /Me SiCl.
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The following procedure for the asymmetric reduction of acetophenone is representative. Freshly
distilled trimethylsilyl chloride (130 mg, 1.2 mmol) was added to a suspension of NaBH (45 mg,
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1
.2 mmol) in dry THF (5 mL). After the mixture was heated at 70°C for 1 h and allowed to cool
to room temperature, a solution of (S)-a,a-diphenylpyrrolidinemethanol (25 mg, 0.1 mmol) in
THF (2 mL) was added. When there was no gas emitted, a solution of acetophenone (120 mg,
1
mmol) in THF (2 mL) was added slowly with a gas-tight syringe controlled by a syringe pump
to the reductive system at a rate of 0.6 mL/h. After the addition was complete, the mixture was
hydrolyzed with 2N HCl (5 mL) and extracted with ether (3×10 mL). The combined organic
layers were washed with brine, and dried with sodium sulfate. After removal of the solvent by
distillation, the residue was distilled under vacuum to afford (R)-1-phenylethanol (120 mg) in
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8% yield. The optical purity of (R)-1-phenylethanol was checked by HPLC on a Chiralcel OD
column to be 96% ee.
In summary, a highly practical enantioselective reduction of prochiral ketones with NaBH4/
Me SiCl catalyzed by (S)-a,a-diphenylpyrrolidinemethanol is demonstrated. The results of our
3
research of asymmetric reduction are favorably comparable to the reported CBS reduction. This
in situ procedure eliminates to use of toxic borane complexes and the necessity of isolating
unstable air and moisture sensitive BꢀH oxazaborolidines, providing a cost-effective and simple
manipulation method for enantioselective reduction of prochiral ketones.
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