Asymmetric oxazaborolidine-catalyzed reduction of prochiral ketones with N-tert-butyl-N-trimethylsilylamine-borane

Article abstract of DOI:10.1016/S0040-4039(03)01036-0

Employing N-tert-butyl-N-trimethylsilylamine-borane (1) as the borane source and 5-10% (R)-Me-CBS (2), the oxazaborolidine-catalyzed reduction of representative aryl and aliphatic ketones was carried out obtaining the corresponding alcohols (3) in 83-89% isolated yields and 69-98% ee.

Full text of DOI:10.1016/S0040-4039(03)01036-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4435–4437
Asymmetric oxazaborolidine-catalyzed reduction of prochiral
ketones with N-tert-butyl-N-trimethylsilylamine–borane
Ramo´n E. Huertas,a Joseph A. Corellab and John A. Soderquista,*
aDepartment of Chemistry, University of Puerto Rico, Rio Piedras, PR 00931, USA
bCallery Chemical Company, 1420 Mars-Evans City Road, Evans City, PA 16033, USA
Received 10 April 2003; revised 21 April 2003; accepted 22 April 2003
Abstract—Employing N-tert-butyl-N-trimethylsilylamine-borane (1) as the borane source and 5–10% (R)-Me-CBS (2), the
oxazaborolidine-catalyzed reduction of representative aryl and aliphatic ketones was carried out obtaining the corresponding
alcohols (3) in 83–89% isolated yields and 69–98% ee. © 2003 Elsevier Science Ltd. All rights reserved.
The oxazaborolidine-catalyzed (CBS) reduction of
prochiral ketones with borane provides a convenient
access to a wide variety of optically active alcohols,
which are valuable chiral building blocks for the syn-
thesis of natural products.1 Since the initial use of
BH3–THF as the stoichiometric reducing agent in this
important asymmetric process,2 a number of alternative
borane reagents have been employed which include:
BH3–SMe2,3 BH3–1,4-thioxane,4 catecholborane5 and
several phenylamine-BH3 complexes.6 These borane
reagents however, each suffer from disadvantages such
as low concentration, low thermal stability, obnoxious
odors and difficulties in separating the borane ligand
from the desired alcohol, which often require the use of
an acidic or chromatographic workup.6
isolation through the hydrolysis of the silylamine upon
aqueous work-up producing the water-soluble primary
t-butylamine and volatile silicon by-products.7a We
envisaged that this unique feature of these reagents
could also facilitate the isolation of the alcohol prod-
ucts from a CBS reduction.
The asymmetric oxazaborolidine-catalyzed reduction of
some representative aromatic and aliphatic prochiral
ketones were examined employing 1 as the borane
source and (R)-Me-CBS (2)2b as the catalyst (Eq. (1)).
These results are summarized in Table 1.
Employing acetophenone as a model substrate, the
effect of reaction temperature, 1/ketone ratio and the
amount of catalyst were briefly explored. Using a
1:1:0.05 ratio of acetophenone/1/2 at room tempera-
ture, (1S)-phenylethanol was obtained in 84% yield and
97% ee (Table 1, entry 1). By 11B NMR analysis of the
reaction mixture taken 20 min after the addition of the
ketone, the reaction was complete revealing the pres-
ence of the expected dialkoxyborane (RO)2BH (l 27),
unreacted 1 (l −20), traces of borate ester (RO)3B (l
18) and a triplet centered at 42 ppm which we attribute
Several years ago, we prepared a series silylamine–
borane complexes which proved to be highly useful
borane sources for both hydroboration/oxidation and
for the efficient synthesis of common mono- and
dialkylborane hydroborating agents.7 In these studies, it
was demonstrated that N-tert-butyl-N-trimethylsilyl-
amine-borane (1) was the most reactive of these com-
plexes in the hydroboration reaction.7a This silylamine–
borane complex offered the advantage of easy product
(1)
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01036-0

4436
R. E. Huertas et al. / Tetrahedron Letters 44 (2003) 4435–4437
Table 1. Asymmetric Me-CBS (2)-catalyzed reduction of prochiral ketones with 1
Entry
RL
RS
Temperature (°C)
3 (%)
ee (%)c
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Et
23
21
23
0
22
23
20
22
22
3a 84a
3a 88a
3a 85a
3a 83a
3b 83a
3c 89a
3d 86a
3e 100b
3f 98b
97d
98e
90f
80d
94d
93d
79d
69d
97d
a-Tetralone
c-Hx
i-Pr
t-Bu
Me
Me
Me
a Isolated yield of analytically pure material.
b GC-yield using internal standard.
c % ee Determined by chiral GC with a CDX-B 30 m×0.25 mm column (J and W Scientific) or Mosher Ester.
d Ketone/1/2 ratio of 1:1:0.05.
e Ketone/1/2 ratio of 1:1:0.1.
f Ketone/1/2 ratio of 1.7:1:0.05.
aryl and alkyl ketones. The corresponding chiral alco-
hols were isolated in excellent yields with enantiomeric
excesses comparable to those reported employing other
combinations of borane reagents with the attractive
feature that an acidic workup is not required. The fact
that the N-tert-butyl-N-trimethylsilylamine ligand
undergoes hydrolysis during the neutral aqueous work-
up step to give volatile and/or water-soluble products
also greatly facilitates the isolation of the CBS reduc-
tion product when compared to bulky 3°-amine–borane
complexes.6
to the alkoxyborane ROBH2 partially complexed to the
catalyst. Increasing the catalyst to 10 mol% did not
significantly improve the ee in the alcohol product (see
entry 2). Lowering the reaction temperature decreased
the enantioselectivity (0°C, 80% ee, entry 4). A decrease
in the optimal enantioselectivity was also observed
when a 1.7:1:0.05 ratio of acetophenone/1/2 was
employed (90% ee, entry 3).
Since the conditions employed in entry 1 gave the best
results for this substrate, these conditions were selected
for the other prochiral ketones examined. All of the
reductions were complete in 51 h. As indicated in
Table 1 acetophenone, propiophenone, a-tetralone and
pinacolone were reduced to the corresponding alcohols
in excellent enantioselectivities which are comparable to
those reported using other borane reagents.1b As
expected, lower enantioselectivities were obtained for
the isopropyl (69%) and cyclohexyl (79%) methyl
ketones, consistent with the results from other borane
sources. These less Lewis acidic aliphatic ketones are
thought to possibly undergo a non-catalyzed borane
reduction.1b,8 However, we view this as simply a steri-
cally based syn versus anti 2/ketone complexation prob-
lem which disappears for the isotropically bulkier
pinacolone (98% ee).
Acknowledgements
The support of the NIH (S06GM8102) and the US
Department of Education GAANN Program
(P200A70219-97A) is gratefully acknowledged.
References
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All of the nonvolatile chiral alcohols were isolated in
excellent yields (83–89%) (entries 1–7)9 and GC analysis
showed quantitative conversion for the pinacolone and
isopropyl methyl ketone cases (entries 8–9). As in the
hydroboration–oxidation process, the isolation of the
alcohols does not require acidic extractions, as is the
case when N,N-diethylaniline-borane or other 3°-
amines are employed as stoichiometric reagents.6a,10 GC
and NMR analysis of the crude non-volatile alcohols
prior to purification by vacuum distillation revealed
only trace amounts of hexamethyldisiloxane (TMS2O)
and toluene.
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In summary, N-tert-butyl(trimethylsilyl)amine-borane
(1) acts as an efficient borane source in the oxazaboro-
lidine-catalyzed asymmetric reduction of representative

R. E. Huertas et al. / Tetrahedron Letters 44 (2003) 4435–4437
4437
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8. The non-catalyzed reduction of acetophenone at room
temperature with 1 was carried out employing a 2:1
ketone/silylamine–borane stoichiometry. The reaction
was completed after 4 h. This reaction time was consider-
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butyl-N-methyl-isopropylamine–borane (18 h).10
9. General procedure: A dry 100 mL thee-necked round-bot-
tomed flask equipped with an addition funnel, magnetic
stirring bar, thermocouple and septum inlet was charged
with 1 (1.59 g, 10.0 mmol) inside a glove box. The vessel
was charged with 10 mL of dry toluene and a 1.0 M
solution of 2 in toluene (1.0 mL, 1.0 mmol). The flask
was immersed in a water bath to moderate the tempera-
ture. Acetophenone (1.20 g, 10.0 mmol) in 5 mL of
toluene was placed in the addition funnel and slowly
added to the reaction flask over 1 h (four drops/min).
The temperature was maintained between 20 and 22°C
during the course of the addition. After the addition of
the ketone was complete, stirring was continued for an
additional 1 h. The reaction mixture was quenched with
methanol (5 mL), heated at reflux for 0.5 h, and allowed
to reach room temperature. A short path distillation
apparatus was connected to the flask and the contents
were distilled to remove most of the volatiles. To the
remaining oil residue was added water (10 mL) and the
aqueous layer was washed with ether (3×10 mL). The
combined organic portions were washed with water (3×10
mL) and brine (10 mL). The organic layer was analyzed
for the optical purity by GC with a CDX-B 30 m×0.25
mm column (J and W Scientific) and found to be 98% ee
(S)-sec-phenethyl alcohol. The ether was distilled off
under atmospheric pressure and the crude sec-phenethyl
alcohol was distilled under reduced pressure to obtain
1.07 g (88%) of pure product. The enantiomeric purity
and absolute configuration of the alcohol was also cor-
roborated by its optical rotation ([h]2D3 −40.5 (neat), lit.11
−41.3 (neat).
10. (a) Brown, H. C.; Kanth, J. V. B.; Zaidlewicz, M. J. Org.
Chem. 1998, 63, 5154; (b) Brown, H. C.; Kanth, J. V. B.;
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Sigma-Aldrich Corp.; Milwaukee, WI, 1998; p. 1306; (b)
See also: Imai, T.; Tamura, T.; Yamamuro, A.; Sato, T.;
Wollmann, T. A.; Kennedy, R. M.; Masamune; S. J. Am.
Chem. Soc. 1986, 108, 7402 (97.3% ee, ([h]2D0 −40.7 (c
2.45, C6H6).