Asymmetric reductions using the chiral boronic ester TarB-H: a practical and inexpensive procedure for synthesizing chiral alcohols

Article abstract of DOI:10.1016/j.tetlet.2007.10.075

Chiral alcohols are prepared in high enantiomeric excesses using an inexpensive and easily synthesized tartaric acid derived boronic ester (TarB-H) with sodium borohydride. The phenylboronic acid could be recovered quantitatively using a simple extraction with sodium hydroxide and diethyl ether. The optimized TarB-H system was used to reduce aromatic and aliphatic ketones in an open flask to chiral alcohols with enantiomeric excesses up to 99%.

Full text of DOI:10.1016/j.tetlet.2007.10.075

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Tetrahedron Letters 48 (2007) 9025–9029
Asymmetric reductions using the chiral boronic ester TarB–H:
a practical and inexpensive procedure for synthesizing
chiral alcohols
Scott Eagon, Jinsoo Kim, Katie Yan, Dustin Haddenham and Bakthan Singaram*
Department of Chemistry and Biochemistry, University of California, Santa Cruz, 1156 High Street, Santa Cruz, CA 95064, USA
Received 25 September 2007; accepted 16 October 2007
Available online 22 October 2007
Abstract—Chiral alcohols are prepared in high enantiomeric excesses using an inexpensive and easily synthesized tartaric acid
derived boronic ester (TarB–H) with sodium borohydride. The phenylboronic acid could be recovered quantitatively using a simple
extraction with sodium hydroxide and diethyl ether. The optimized TarB–H system was used to reduce aromatic and aliphatic
ketones in an open flask to chiral alcohols with enantiomeric excesses up to 99%.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The reduction of ketones to optically active secondary
alcohols is a powerful technique in the synthesis of opti-
cally pure compounds.1 A number of boron-derived
reducing agents and catalysts, such as CBS,2 other oxaz-
aborolidine reagents,3–5 and DIP-Clꢁ have proven adept
at reducing aromatic ketones. Both oxazaborolidine-
based reagents and DIP-Clꢁ6 use BH3:L, which in turn
is prepared from NaBH4. Consequently, asymmetric
reductions involving the direct use of NaBH4 are more
desirable. Sodium borohydride has been used with vari-
ous other mediators to reduce ketones to chiral alcohols.
Modifications of NaBH4 to chiral reducing reagents
have been prepared using amino acids,7,8 monosaccha-
rides,9–11 and phase transfer catalysts12 for the reduction
of aromatic and hindered ketones. Mukaiyama et al.
developed a catalyst using alcohol-modified NaBH4
and a chiral b-ketoiminato cobalt(II) complex to reduce
ketones and imines with good enantiomeric excess.13–15
Sodium borohydride modified carboxylic acid systems
using chiral sugars and achiral carboxylic acids have
enantioselectively reduced ketones to chiral alcohols
with ee’s up to 64%.16–18 Chiral carboxylic acid systems
have also been developed to reduce ketones with NaBH4
using mandelic, lactic, and tartaric acid.19–25
We have recently reported that the tartaric acid-derived
reagent TarB–X mediates the asymmetric reduction of
various aliphatic and aromatic ketones using LiBH4.26,27
Since LiBH4 is soluble in THF, the hydride could either
complex with the TarB–X reagent and give chiral reduc-
tion, or react directly with the ketone to give achiral
reduction. Initial screening during these reductions
revealed that TarB–NO2 was the best mediator for
asymmetric induction when used in conjunction with
LiBH4. We later substituted LiBH4 with NaBH4 and
found that it was able to give higher induction. This is
due to the fact that only the acyloxyborohydride, which
is formed by the complexing of carboxylic acid with
NaBH4, is soluble in THF and thus chiral reduction is
favored.28 TarB–NO2 was able to reduce various
ketones under mild conditions; however, meta-nitro
phenylboronic acid is relatively more expensive than
phenyl boronic acid and reductions using TarB–NO2
require a dry and inert atmosphere to maintain high
enantioselectivities.29 We decided to investigate how
different substituents on the phenylboronic acid would
affect the asymmetric induction observed using NaBH4
as our hydride source. In this paper we report our
TarB–X optimization studies for the asymmetric reduc-
tion of ketones using NaBH4 and the first examples of
successful asymmetric reduction of ketones without the
rigorous exclusion of air and moisture.
Keywords: Asymmetric reduction; Sodium borohydride; Acyloxyboro-
hydride; TarB–X.
TarB–X (1) is easily prepared by combining the desired
isomer of tartaric acid with the substituted phenyl-
boronic acid in refluxing THF over CaH2 for 1 h
*
Corresponding author. Tel.: +1 831 459 3154; fax: +1 831 459
2935; e-mail: Singaram@chemistry.ucsc.edu
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.075

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S. Eagon et al. / Tetrahedron Letters 48 (2007) 9025–9029
Table 1. Enantioselective reduction of acetophenone as a function of
phenylboronic acid under inert atmospherea
1
X
% conv.b
% eeb,c
a
b
c
3-NO2
H
4-F
100
100
91
99
85
90
99
Scheme 1. Synthesis of (L)—TarB–X.
d
4-Cl
100
(Scheme 1). The solution is then filtered and stored as a
molar solution in an ampoule.
a See Supplementary data for experimental procedure.
b Determined by GC analysis of the acetylated alcohols on a chiral
Supelco Beta-Dex 120 column.
c Products were of the (R) configuration as determined by optical
rotation.
Reduction is carried out by premixing 1 equiv of TarB–
X with a ketone for 15 min, followed by addition of
2 equiv of NaBH4, which is stirred for 1 h. Computer
modeling supports prior 11B NMR data that reduction
proceeds via a chiral acyloxyborohydride intermediate
species (2), which is formed when NaBH4 reacts with
the carboxylic acid moiety of TarB–X (Scheme 2).30
dry and inert atmosphere, we first examined the stoichi-
ometry of TarB–NO2 and found that 1 and 1.5 equiv of
TarB–NO2 gave lower induction under these conditions.
We attribute this decrease in asymmetric induction to
the hydrolysis of TarB–NO2 by adventitious water. This
is evidenced by the appearance of the methine proton of
free tartaric acid in the 1H NMR spectrum. This was cir-
cumvented by using 2 equiv of TarB–NO2. To determine
if other phenylboronic acids would be effective under
these conditions, we conducted a second substituent
study using the ketone/TarB–X/NaBH4 in a 1:2:2 ratio
and were pleased to find that TarB–H gave excellent
asymmetric induction equal to those observed with
TarB–NO2 and TarB–Cl (Table 2).
Initially we selected various substituted arylboronic
acids, including the parent phenylboronic acid and L-
(+)-tartaric acid, and synthesized several TarB–X deriv-
atives. We then used these TarB–X compounds in the
asymmetric reduction of acetophenone using NaBH4
as our hydride source. For this study we used ketone/
TarB–X/NaBH4 in a 1:1:2 ratio. The reaction was car-
ried out at 25 ꢂC under argon and the enantiomeric
excess of the product alcohol was determined by chiral
GC analysis. The results are summarized in Table 1.
Since phenylboronic acid is significantly less expensive33
than the substituted phenylboronic acids we decided to
employ TarB–H, prepared from phenylboronic acid, in
the reduction of representative aromatic ketones in air
using NaBH4 as the hydride source.34 The results are
summarized in Table 3.
As anticipated, TarB–NO2 mediated reduction gave
superior results, with TarB–Cl also giving comparable
induction. We decided to investigate whether TarB–
NO2 mediated reductions using NaBH4 could maintain
high enantioselectivity in air. Sodium borohydride is
known to be very stable to hydrolysis and oxidation.
However, it was not clear whether TarB–X reagents
are resistant to hydrolysis. Most boron-derived reducing
agents are extremely water sensitive and must be used
under an inert and dry atmosphere. For example, when
using the CBS catalyst Fu et al. reported that an increase
in water concentration from as little as 0.02% to 0.3%
led to a 25% decrease in enantioselection.31 Similarly,
DIP-Clꢁ is also highly susceptible to hydrolysis.32 To
investigate the possibility of using TarB–X without a
The results were excellent with most substrates giving
greater than 95% ee except in the case of o-bromoaceto-
phenone and propiophenone. We then attempted the
reduction of alpha-haloacetophenones using TarB–H
in air. These substrates, after reduction and a basic
workup, provided chiral styrene oxides. However, the
enantiomeric excess of the product epoxide was only
around 50–60%. We then found that 2 equiv of TarB–
Cl (1d) in air gave good results comparable to our
Scheme 2. Asymmetric reduction of a prochiral ketone via the proposed acyloxyborohydride intermediate.

S. Eagon et al. / Tetrahedron Letters 48 (2007) 9025–9029
9027
Table 2. Enantioselective reduction of acetophenone as a function of
phenylboronic acid and amount of TarB–Xa
Table 4. Reduction of a-haloacetophenones in air with TarB–Cla
Ketone
Isolated yieldb
98
% eec
86
Config.d
(S)
1
X
equiv TarB–X
% conv.b
% eeb,c
82
80
(S)
a
a
a
b
b
b
c
3-NO2
3-NO2
3-NO2
H
H
H
1
1.5
2
1
1.5
2
95
100
100
100
100
100
97
88
90
99
80
92
99
93
99
a Reactions carried out as described in Ref. 35.
b All reactions gave 100% conversion to alcohol according to GC and
NMR.
c Determined by GC analysis of the epoxides on a Supelco Beta-Dex
120 column.
d Determined by optical rotation in comparison to the literature values.
See Supplementary data.
4-F
4-Cl
2
2
d
100
a Reactions carried out as described in Ref. 35.
b Determined by GC analysis of the acetylated alcohols on a chiral
Supelco Beta-Dex 120 column.
c Products were of the (R) configuration as determined by optical
rotation.
With our copasetic results from the reduction of aro-
matic ketones, we turned to the reduction of aliphatic
ketones using TarB–H. The tert-alkyl ketones all gave
excellent results, with good to moderate results for sec-
alkyl and n-alkyl ketones (Table 5).
Table 3. Reduction of various aromatic ketones with TarB–H in aira
Ketone
Isolated yieldb (%)
% eec
Config.d
Table 5. Reduction of various aliphatic ketones in air with TarB–Ha
83
99
(R)
Ketone
Isolated yieldb (%)
% eec
Config.d
80
90
99
96
(R)
(R)
80
99
(R)
89
88
96
89
(R)
(R)
81
97
95
95
(R)
(R)
92
89
88
85
(R)
(R)
80
86
86
64
(R)
(R)
68
99
85
67
61
61
(R)
(R)
(R)
a Reactions carried out as described in Ref. 35.
b All reactions gave 100% conversion to alcohol according to GC and
NMR.
c Determined by GC analysis of the acetylated alcohols on a Supelco
Beta-Dex 120 column.
a Reactions carried out as described in Ref. 35.
b All reactions gave 100% conversion to alcohol according to GC and
NMR.
d Determined by optical rotation in comparison to the literature values.
See Supplementary data.
c Determined by GC analysis of the acetylated alcohols on a Supelco
Beta-Dex 120 column.
d Determined by optical rotation in comparison to the literature values.
See Supplementary data.
previous results obtained using TarB–NO2 under dry
and inert conditions (Table 4).27

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S. Eagon et al. / Tetrahedron Letters 48 (2007) 9025–9029
Table 6. Comparison of TarB–H with DIP-Clꢁ and CBS
References and notes
Ketone
% ee
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CBSa
86
DIP-Clꢁb
TarB–H
95
—
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In comparison to DIP-Clꢁ and the CBS catalyst, TarB–
H performed very well. Table 6 compares the three
reagents in the reduction of select ketones. TarB–H
achieved parity with the other two reagents with tert-
alkyl ketones and equal or better results with sec-alkyl
and n-alkyl ketones. It should also be pointed out that
only TarB–H mediated asymmetric reduction can be
carried out in an inert atmosphere without the rigorous
exclusion of water.
19. Nasipuri, D.; Sarkar, A.; Konar, S. K.; Ghosh, A. Indian
J. Chem., Sect. B 1982, 21, 212–215.
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Soc., Perkin Trans. 1 1988, 417–422.
TarB–H provides good to excellent asymmetric reduc-
tion under mild conditions, making it very attractive
for large scale synthesis. TarB–H mediated reductions
proceed smoothly in air without the need for rigorous
drying of the reagents or an inert atmosphere like
DIP-Clꢁ or the CBS catalyst. It is easily prepared using
either enantiomer tartaric acid, both of which are
commercially available and inexpensive. TarB–H can
also reduce ketones using NaBH4 instead of more reac-
tive BH3:L species derived from NaBH4. Additionally,
phenylboronic acid can easily be recovered essentially
quantitatively and recycled using a simple ethereal
extraction. Its ease of preparation and mild reaction
conditions make TarB–H/NaBH4 an excellent asymmet-
ric reducing system for both academic and industrial
endeavors.
21. Adams, C. Synth. Commun. 1984, 14, 955–959.
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Supplementary data
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Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2007.10.075.

S. Eagon et al. / Tetrahedron Letters 48 (2007) 9025–9029
9029
33. Phenylboronic acid costs approximately $430/mol,
4-fluorophenylboronic acid $1400/mol, 4-chlorophenylbo-
ronic acid $1,500/mol, and 3-nitrophenylboronic acid
$1600/mol.
34. On a small scale this reaction can be run in an open flask
in a well-ventilated fume hood to prevent buildup of H2
gas.
35. General procedure for the reduction of ketones with TarB–H
in air. The reduction of acetophenone is representative. A
100 mL oven dried round-bottomed flask was equipped
with a stir bar and a septum and allowed to cool to ambient
temperature in air. A bubbler was connected to the flask,
which was then subsequently charged with the aceto-
phenone (0.58 mL, 5 mmol) and TarB–H (20 mL of a
0.5 M solution in THF, 10 mmol). The ketone and TarB–H
were stirred for 15 min. after which NaBH4 (0.38 g,
10 mmol) was added directly to the solution. The mixture
was allowed to stir for 1 h. The solution was quenched
dropwise with 1 M HCl. CAUTION: H2 gas evolution.
The mixture was brought to pH 12 with 3 M NaOH and
stirred for 30 min. The solution was extracted with pentane
(3 · 10 mL) and the combined organic layers were dried
with MgSO4. Evaporation under reduced pressure yielded
the product alcohol. The enantiomeric excess of the
acetylated alcohol was determined by GC on a Supelco
b-cyclodextrin 120 column (30 m · 0.25 mm). For the
a-haloacetophenone derivatives, the product epoxide was
run without further modification through the GC.