Highly enantioselective carbonyl reduction with borane catalyzed by chiral spiroborate esters derived from chiral 1,2-aminoalcohols

Article abstract of DOI:10.1016/j.tetasy.2005.12.005

Novel spiroborate esters derived from nonracemic 1,2-amino alcohols were examined as chiral catalysts in the borane reduction of acetophenone and other aromatic ketones at room temperature. The optically active alcohols were obtained in excellent chemical yields and enantioselectivities up to 99% ee with 10% of catalyst.

Full text of DOI:10.1016/j.tetasy.2005.12.005

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 17 (2006) 112–115
Highly enantioselective carbonyl reduction with borane catalyzed
by chiral spiroborate esters derived from chiral 1,2-aminoalcohols
*
Viatcheslav Stepanenko, Margarita Ortiz-Marciales, Wildeliz Correa, Melvin De Jes u´ s,
Sandraliz Espinosa and Lymaris Ortiz
Department of Chemistry, University of Puerto Rico-Humacao, CUH Station, Humacao, PR 00791, USA
Received 28 October 2005; accepted 1 December 2005
Abstract—Novel spiroborate esters derived from nonracemic 1,2-amino alcohols were examined as chiral catalysts in the borane
reduction of acetophenone and other aromatic ketones at room temperature. The optically active alcohols were obtained in excellent
chemical yields and enantioselectivities up to 99% ee with 10% of catalyst.
Ó 2006 Published by Elsevier Ltd.
1
. Introduction
steps to eliminate traces of boronic acid and their esters.
Therefore, the commercially available reagents are very
expensive.
Asymmetric reduction of prochiral ketones to obtain
enantiomerically pure alcohols is one of the most impor-
tant transformations in organic synthesis. Over the last
Masui and Shioiri11 obtained excellent enantioselectivi-
ties in the borane–DMS reduction of acetophenone
and nitrogen containing prochiral ketones using a mix-
ture of diphenylprolinol and trimethylborate as catalyst.
They postulated the in situ formation of a very reactive
B-methoxy oxazaborolidine.
2
5 years, a large variety of asymmetric catalysts have
been prepared from alumino- or borohydrides and
chiral diols or amino alcohols, which are highly useful
for the enantioselective reduction of carbonyl com-
1
,2
pounds.
In particular, the 1,3,2-oxazaborolidines
derived from chiral amino alcohols have been recog-
nized as exceptional catalysts in the reduction of
aromatic ketones and in other enantioselective reac-
Recently, Brown et al.12 reported a new enantioselective
reducing reagent system, in which the chiral catalyst is a
tight amino-borane complex 1 and borane is the external
hydride donor to reduce hindered and substituted aryl
alkyl ketones, with good to high enantioselectivities, as
shown in Scheme 1.
3
–5
tions.
The B-H oxazaborolidine–borane complexes
are frequently reported as catalysts for carbonyl reduc-
tions since they are conveniently prepared from the
corresponding amino alcohol and either borane–THF
or borane dimethyl sulfide (DMS) complexes. However,
the extreme sensitivity of these reagents to atmospheric
moisture makes them difficult to isolate and purify. Con-
sequently, they are prepared in situ prior to the use in
asymmetric reductions. Moreover, B-H oxazaboroli-
dines can form dimers and other species which can alter
Ph
Ph
HO
Ar
82-99.2%ee
H
O
1.0 ºC, 15 min
H
O
B
+
BH3-THF
+
R
Ar
2. H2O, work-up
R
N
H
6
–8
the nature of the catalyst.
Impurities present in the
catalysts may lead to diminished selectivity and lead to
1
9
,10
5
irreproducible results.
On the other hand, B-substi-
Scheme 1.
tuted oxazaborolidines show excellent enantioselectiv-
ity and synthetic utility but require careful purification
Boronic and borate esters form stable complexes with
1
3,14
amino groups
also well documented.
acetophenone at 0 °C in THF in good yield and with
and intramolecular coordination is
1
5,16
14
*
Corresponding author. Tel.: +1 787 852 3222; fax: +1 787 850
422; e-mail: mr_ortiz@webmail.uprh.edu
Thormeier et al. reduced
9
0957-4166/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2005.12.005

V. Stepanenko et al. / Tetrahedron: Asymmetry 17 (2006) 112–115
113
low to moderate enantioselectivity using 2 equiv of an
in situ prepared chiral biarylhydroborate–aniline com-
plex and in the presence of boron trifluoride–ethylether.
results, other aromatic ketones were reduced enantio-
selectively in different solvents and the results are pre-
sented in Table 1. Modest to high enantioselectivities
were achieved for all the substrates in THF. The selec-
tivity decreases to 60% ee for the reduction of acetoph-
enone in dichloromethane (entry 2), but is comparable
in dioxane (86% ee, entry 3). Reduction of other sub-
strates gave similar results to that of acetophenone
(entries 4–6).
1
7,18
More recently, Shan et al.
developed a new class of
catalyst for the borane reduction of prochiral aliphatic
and aromatic ketones based on spiroborate esters
0
derived from chiral 1,1 -bi-2-naphthyl borate esters
and chiral 1,2-amino alcohols or 2-amino acids. These
gave modest to high enantioselectivities with 0.1 equiv
of catalyst. The stereochemistry of the chiral diol-
derived part of the catalyst did not influence the alcohol
configuration. Our interest in new reagents for catalytic
asymmetric synthesis led us to develop a new chiral
spiroborate ester system, which offers great potential
for the borane-based catalytic asymmetric synthesis of
Table 1. Enantioselective reduction of aromatic ketones with spiro-
a
borate 2 (0.2 equiv)
b
c
Entry Ketone
Solvent
THF
CH Cl
2 2
Dioxane 72
Yield (%) ee%
1
2
3
4
5
6
Acetophenone
Acetophenone
Acetophenone
4-Chloro-acetophenone THF
4-Methoxy-1-tetralone
3-Acetylpyridine
98
79
88
60
86
87
85
82
d
d
1
9,20
enantiopure alcohols.
74
70
90
THF
THF
e
2
. Results and discussion
a
b
c
1
equiv of ketone:1.4 equiv of borane:0.2 equiv of cat. at rt, 1 h.
Initially, we investigated the synthesis and properties of
borate 2 (Scheme 2). This was prepared by the addition
of (1R,2S)-(ꢀ)-norephedrine to catecholborane in ether
Purified by Kugelrohr distillation.
Determined by GC on a chiral column (CP-Chiralsil-DexCB).
Crude product.
d
e
1
5
at 0 °C for 1 h. The white crystalline solid was washed
2 equiv of borane and a 24 h workup with methanol.
1
1
with ether and isolated in 83% yield. By B NMR, the
characteristic signal for the central boron atom was
Next, we were interested in studying borate ester 3
(Scheme 2) with a diphenylprolinol-derived fragment,
analogous to the CBS reagent and Brown’s complex 1.
This compound was prepared from catecholborane
and diphenylprolinol in 75% yield and about 80% purity
1
5
observed at d 11.6 ppm. Other signals at d 14.2 and
.9 ppm, were also observed due to by-products, pre-
sumably belonging to the complexed spiro dicatechol-
7
1
7
borate and its borate amino complex, respectively,
1
13
1
13
11
which were estimated at ꢁ20% by H and C NMR.
Unfortunately, all attempts to remove these impurities
by recrystallization of the sample did not improve the
purity of the compound. Similar results were obtained
when the reaction was carried out at a lower tempera-
ture (ꢀ40 °C). At ꢀ78 °C, the reaction did not take
place. The synthesis of 2 in THF and dichloromethane
gave lower chemical yields of 42% and 46%, respectively,
again in low purity. An alternative method for the prep-
aration of 2 from catechol, triisopropyl borate, and
by H and C NMR. By B NMR, the characteristic
signal for the central boron atom was observed at d
11.7 ppm. The reduction of acetophenone with borane
and 20% catalyst 3 afforded (R)-1-phenylethanol in
93% yield and 92% ee. Change of the amino alcohol
moiety in the catalyst increased the enantioselectivity
slightly.
Further modification of the catalytic system was envis-
aged through a change in the structure of the chiral spiro-
borate ester by employing a less strained diol ring
system. We felt that this would make the compounds
more stable. A series of new reagents 4–12, shown in
Figure 1, were conveniently prepared from ethylene gly-
col, triisopropyl borate, and readily available enantio-
pure amino alcohols according to the method reported
(
1R,2S)-(ꢀ)-norephedrine also afforded a product with
low purity.
O
o
1
. THF/25 C,1 h
H
OH
Me
+
BH -DMS
+ Cat.
3
Me
Ph
2. MeOH
Ph
1
6
(
1.4 equiv)
(0.2 equiv)
O
by Huskens and Reetz.
The borate esters were
(
1.0 equiv)
(R)
obtained in essentially quantitative yields with only
minor amounts (<10%) of impurities, as assessed by
Ph
O
Cat.:
B
98% yield, 88% ee
1
1
1
13
O
B, H, and C NMR. No further purification was
attempted. Their characteristic mp, specific rotation,
H N Me
2
2
1
1
and B NMR signals are presented in Table 2. The
white crystalline borate amino complexes were easy to
handle under nitrogen, and exhibit little decomposition
over prolonged storage (4–6 months) at rt. However,
Ph
Ph
H
O
O
O
9
3% yield, 92% ee
B
N
H
10 did show some susceptibility to light.
3
Scheme 2.
To assess the enantioselectivity obtained by employing
these chiral spiroborate esters 4–12 in the catalytic
reduction of aromatic ketones, acetophenone was used
as a model compound. The reduction was carried out
with 1 M equiv of borane–DMS complex and 2.5–20%
of the different catalysts at room temperature in THF.
The borane reduction of acetophenone was carried out
in the presence of 20% of 2 (prepared in ether), obtain-
ing the (R)-1-phenyl ethanol in quantitative yield and
with 88% ee, as indicated in Scheme 2. Based on these

114
V. Stepanenko et al. / Tetrahedron: Asymmetry 17 (2006) 112–115
Table 3. Enantioselective borane reduction of acetophenone with
spiroborate esters 4–12 as catalysts
Ph
Ph
Ph
Ph
O
O
O
O
N
O
O
O
O
O
a
B
B
B
b
c
Entry
Cat.
mol %
Yield (%)
ee%
Conf.
H C
3
NH2
H3C
NH2
1
2
3
4
5
6
7
8
9
4
4
20
10
5
92
75
92
90
88
75
0
90
82
98
96
98
98
95
94
83
99
98
R
R
R
R
—
R
S
4
5
6
d
4
84
85
85
Ph
Ph
Ph
4
2.5
10
10
10
20
10
10
5
10
5
10
10
5
Ph
Ph
Ph
O
O
O
O
O
O
d,e
O
B
NH O
O
5
B
B
6
87
94
75
99
89
97
75
96
93
98
95
Ph
NH2
NH2
2
7
8
R
R
S
7
8
9
8
1
1
0
1
9
9
S
H O
N
2
O
N
O
Ph
O
N
O
O
12
13
14
10
10
11
12
12
S
B
O
B
B
H
S
H
O
O
H
R
R
R
H
1
1
5
6
1
0
1
1
12
a
b
c
1
equiv of ketone:1 equiv of borane at rt, 1 h.
Purified by Kugelrohr distillation.
Determined by GC on a chiral column (CP-Chiralsil-DexCB).
Crude product.
Traces of ketone was left after 3 h.
Figure 1. Spiroborate esters derived from chiral amino alcohols.
d
e
Table 2. Representative properties of spiroborates 4–12
2
D
0
11
Cat. Mp (°C)
½aꢂ
B NMR d (ppm)
4
5
6
7
8
9
1
1
1
176–179
70–75
ꢀ37.5 (c 0.056, DMSO) 10.0 (s) (DMSO-d
6
)
the reaction mechanism of asymmetric induction and
applications of the catalytic system in the reduction of
a variety of ketones and their imino analogues.
ꢀ5.0 (c 0.024, CHCl
3
)
10.9 (s) (CDCl
3
)
183 (dec) +5.0 (c 0.029, DMSO)
161 (dec) ꢀ38.7 (c 0.062, CHCl
207–209 +98.0 (c 0.05, CHCl
194 (dec) +43.0 (c 0.023, DMSO) 10.5 (s) (DMSO-d
151 (dec) +28.6 (c 0.018, CHCl
115–116 +13.0 (c 0.049, CHCl
10.5 (s) (DMSO-d
6
)
)
3
)
10.3 (s) (DMSO-d
6
3
)
3
9.6 (s) (CDCl )
6
)
)
0
1
2
3
)
)
10.3 (s) (CDCl
9.9 (s) (CDCl
3
)
)
4. Experimental
3
3
274 (dec) ꢀ110.0 (c 0.03, DMSO) 10.3 (s) (DMSO-d
6
4.1. Optimized procedure for the borane reduction of
acetophenone using catalyst 12
Table 3 summarizes these results. Catalyst 4 showed
higher enantioselectivity (Table 3, entry 1) than borate
ester 2. To establish the correlation between the amount
of catalyst and enantioselectivity, systematic studies
were carried out using borate ester 4 prepared from an
inexpensive aminoalcohol. Decreasing the catalyst from
Borane–DMS complex (10 M, 1.0 mL, 10.0 mmol) was
added to a solution of catalyst 12 (0.323 g, 1.00 mmol)
in dry THF (30 mL) and stirred at rt, under nitrogen
for 15 min.
A solution of acetophenone (1.2 g,
10.0 mmol) in THF (10 mL) was added to the reaction
mixture for 1 h using an infusion pump. After 15 min,
the reaction was monitored by GC, indicating that ace-
tophenone was consumed. The solution was stirred at rt
over 1 h, then cooled to 0 °C and quenched with metha-
nol (10 mL). After stirring for 1 h at rt the solvents were
removed under vacuum. The residue was dissolved in
DCM (40 mL), washed with a saturated solution of
ammonium chloride (25 mL), water (25 mL), and dried
with sodium sulfate. The solvents were removed under
vacuum and the residue was distilled in Kugelrohr appa-
ratus under vacuum (59 °C/0.25 mmHg) to give the
2
0 to 5 mol % slightly decreased the ee of the alcohol
(
Table 3, entries 1–3), and with 2.5 mol % the enantio-
selectivity was substantially lower (Table 3, entry 4).
In almost all studies, the reactions were very fast. The
reduction of acetophenone using 5% of catalysts 4 and
1
2 was complete within 15 min after the substrate was
added, as shown by GC analysis. With the exception
of the less reactive 5, moderate to excellent enantioselec-
tivities were achieved. In particular, catalysts 8, 9, and
1
2 were highly effective. In all cases, the reactions took
20
place with excellent reproducibility. In addition, the
amino alcohols could be recovered.
final product as a colorless oil (1.20 g, 98%), ½aꢂ ¼
D
þ43:8 (c 0.039, MeOH). Chiral GC indicates ratio of
enantiomers as 99.53:0.47, 99% ee.
3. Conclusion
Acknowledgements
With the exception of 5, spiroborate esters 2–12 are
particularly stable and exhibit comparable enantioselec-
tivities to those observed for the corresponding B-substi-
tuted oxazaborolidines (CBS reagent). These catalysts
offer an excellent alternative for asymmetric reduction.
Further studies are currently in progress to elucidate
Financial support by the National Institute of Health
through their MBRS (GM 08216) and NIH-IMBRE
(NC P20 RR-016470) Grants is greatly appreciated.
The NIH-IMBRE and NSF-AMP undergraduate sup-
port is also gratefully acknowledged.

V. Stepanenko et al. / Tetrahedron: Asymmetry 17 (2006) 112–115
11. Masui, M.; Shioiri, T. Synlett 1997, 273–274.
115
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