Chiral terpene auxiliaries II. Spiroborate esters derived from α-pinene - New catalysts for asymmetric borane reduction of prochiral ketones

Article abstract of DOI:10.1016/j.tetlet.2011.05.095

New spiroborate esters derived from (1R,2R,3S,5R)-3-aminopinan-2-ol and ethylene glycol, propane-1,3-diol, pinacol, catechol, (1S,2S,3R,5S)-pinane-2,3- diol, and (1R,2R,3S,5R)-pinane-2,3-diol were used as catalysts in the borane reduction of acetophenone and other prochiral aryl alkyl ketones producing the corresponding alcohols in high yields. The influence of the spiroborate structure on the enantioselectivity and configuration of the product alcohols was examined.

Full text of DOI:10.1016/j.tetlet.2011.05.095

Tetrahedron Letters 52 (2011) 3919–3921
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Chiral terpene auxiliaries II. Spiroborate esters derived from a-pinene—new
catalysts for asymmetric borane reduction of prochiral ketones
⇑
´
´
´
Marek P. Krzeminski , Marta Cwiklinska
´
Faculty of Chemistry, Nicolaus Copernicus University, 7 Gagarin St., Torun, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
New spiroborate esters derived from (1R,2R,3S,5R)-3-aminopinan-2-ol and ethylene glycol, propane-1,3-
diol, pinacol, catechol, (1S,2S,3R,5S)-pinane-2,3-diol, and (1R,2R,3S,5R)-pinane-2,3-diol were used as
catalysts in the borane reduction of acetophenone and other prochiral aryl alkyl ketones producing the
corresponding alcohols in high yields. The influence of the spiroborate structure on the enantioselectivity
and configuration of the product alcohols was examined.
Received 4 April 2011
Revised 6 May 2011
Accepted 20 May 2011
Available online 27 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric reduction
Borane
a-Pinene
Aminoalcohols
Spiroborate esters
The transformation of ketones into enantiomerically pure or
highly enriched chiral alcohols plays a key role in modern asym-
metric organic synthesis. This step is often employed in the total
synthesis of natural products.1 Among many useful chiral promot-
amino alcohols8d,9 and diols. Both types of spiroborates exhibit
high catalytic activity in the borane reduction of ketones,8d,9b–d,10
oxime ethers,8b,9a,11 and in the asymmetric aldol condensation.8a
In particular, spiroborate esters synthesized from 1,1-diphenylpro-
linol and ethylene glycol,9c,10 and from 1,1-diphenylvalinol and
ethylene glycol,9a,11 proved to be very active catalysts. These two
compounds were utilized in the syntheses of mexiletine10c,11a
and nicotine,11b and their analogues—a group of ligand-gated ion
channel receptors that play a vital role in biological processes, for
example, neurotransmission.
ers,
a-pinene is a convenient natural source of chirality, readily
available in both enantiomeric forms. Its numerous derivatives,
such as Alpine-Borane and DIP-chloride,2 pinane-derived oxaz-
aborolidines,3 a pinane-type tridentate modifier of LAH,4 and
diphosphine ligands with a pinane core complexed with transition
metals,5 have been utilized successfully in asymmetric reduction of
ketones. On the other hand, pinane derivatives have turned out to
be very useful chiral promoters for the asymmetric addition of
diethylzinc to aldehydes,4 and for the asymmetric allylation of
aldehydes with allyltrichlorosilane,6 leading to chiral alcohols with
high enantiomeric excess.
Herein, we describe pinanyl spiroborate esters as a new class of
boron compounds exhibiting catalytic activity in the reduction of
ketones with borane. Spiroboranes contain a characteristic O3BN
framework, in which the B–N coordinate bond enhances the stabil-
ity of the molecule toward moisture and air. This is an advantage
compared to other boron catalysts, for example, oxazaborolidines
used in asymmetric syntheses. The first chiral spiroborate esters
were discovered by Shan and used for the resolution of 1,10-bi-2-
naphthol enantiomers.7 Later, two general pathways for the syn-
thesis of this class of compounds were developed; the esters are
derived either from chiral amino acids7,8 and diols, or from chiral
Our interest in new reagents for catalytic asymmetric synthesis
led us to develop a new chiral spiroborate ester system derived
from (1R,2R,3S,5R)-3-amino-pinan-2-ol12 (2), conveniently pre-
pared from (–)-a
-pinene3a,12 (1) (Fig. 1), and widely used as a chiral
auxiliary, a ligand, and as the component of oxazaborolidines.3 This
system offers an interesting alternative and significant potential
for the borane-based catalytic asymmetric synthesis of enantio-
pure alcohols.
Terpene spiroborate esters 3–8 (Fig. 2) were prepared by the
reaction of (1R,2R,3S,5R)-3-aminopinan-2-ol (2), triisopropyl
OH
NH2
1
2
⇑
Corresponding author.
E-mail address: mkrzem@chem.umk.pl (M.P. Krzemin´ ski).
Figure 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.095

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M. P. Krzeminski, M. Cwiklinska / Tetrahedron Letters 52 (2011) 3919–3921
3920
the reaction mixture was cooled to room temperature to precipi-
O
O
O
N
O
O
O
N
tate the spiroborate product.14
B
B
Products 3–8 were isolated in high yields by recrystallization
from toluene. The 11B NMR spectra showed characteristic signals
for the central boron atom (about 4–12 ppm) for each spiroborate
ester confirming the O3BN framework. Minor signals at 16.5 and
14.5 ppm, for 4 and 6 respectively, and for 3, 5, 7 and 8 around
21 ppm, were also observed. Two signals in the 11B NMR spectra
of compounds 3–8 recorded in THF-d8 came from the co-existing
forms: spiroborate and the borate lacking complexation between
the nitrogen and boron atoms. The results are summarized in Table
1. The terpene spiroborate esters were stable after being exposed
H2
H2
3
4
O
O
O
N
O
B
B
N
O
O
H2
H2
5
6
O
O
O
N
O
O
B
B
N
O
H2
H2
Table 3
7
8
Borane reduction of prochiral ketones catalyzed by spiroborate ester 3
3
1.
Figure 2. Spiroborate esters 3–8.
O
OH
*
.
BH3 SMe2 / THF, r.t
R1
R2
R1
R2
Table 1
2. MeOH
Synthesis of spiroborate esters 3–814
Entry Ketone
3 (mol %) Yielda (%) ee (%) Conf.d
½ ꢀ
a 2D0
Product
Yield (%)
Mp (°C)
11B NMRa,b (d ppm)
O
3
4
5
6
7
8
84
54
87
85
45
84
161–163
147–150
221–224
200 (dec.)
241–242
220–222
8.44
3.83
7.26
11.8
8.50
8.34
+7.96 (c 1, THF)
–8.33 (c 1, THF)
+2.12 (c 0.9, THF)
+31.8 (c 0.9, THF)
+12.3 (c 0.9, THF)
ꢁ14.7 (c 1, THF)
10
5
94
90
96b
93
R
1
O
10
5
91
92
93b
90
a
R
Spectra were recorded in THF-d8.
Co-existing signals in the 11B NMR spectra and their percentage: 3 (21.5 ppm,
b
2
3%), 4 (16.5 ppm, 36%), 5 (20.5 ppm, 8%), 6 (14.1 ppm, 4%), 7 (20.6 ppm, 13%), 8
(20.6 ppm, 45%).
OMe
O
10
5
88
93
98b
95
R
R
borate, and diols (ethylene glycol, propan-1,3-diol, pinacol, cate-
chol, (1S,2S,3R,5S)-pinane-2,3-diol,13 and (1R,2R,3S,5R)-pinane-
2,3-diol,13 respectively) in dry toluene under reflux. After partial
evaporation of the toluene together with the evolved isopropanol,
3
OMe
O
10
5
91
87
97b
96
4
Table 2
Borane reduction of acetophenone into 1-phenylethanol catalyzed by spiroborate
esters 3–8
MeO
1. 3-8
O
O
.
O
OH
BH3 SMe2 / THF, r.t
10
5
94
93
92b
90
5
6
R
Ph
Ph
2. MeOH
Entry
Catalyst (mol %)
Yielda (%)
eeb,c (%)
1
2
3
3 (10)
3 (5)
94
90
93
94
92
92
90
93
81
88
86
91
94
90
96
93
92
96
81
66
92
89
77
7
10
5
95
91
65c
60
e
—
3 (1)
O
4
5
6
7
4 (10)
4 (5)
4 (1)
O
5 (10)
5 (5)
8
9
e
7
10
87
4c
—
5 (1)
10
11
12
13
14
6 (10)
7 (10)
7 (5)
8 (10)
8 (5)
95
86
90
88
a
Isolated yield.
b
Determined by GC analysis on
a
chiral column, Supelco b-DEX 325™,
a
30 m ꢂ 0.25 mm.
Isolated yield.
ee determined by GC analysis on
c
b
Determined by HPLC analysis on
a
chiral column, Daicel Chiralcel OD-H,
a chiral column, Supelco b-DEX 325™,
250 ꢂ 4.6 mm, 5
lm.
30 m ꢂ 0.25 mm.
d
c
Assigned by comparison of the sign of rotation with literature data.
The R configuration was assigned by comparison of the sign of rotation with the
literature data.
e
Absolute configuration not determined.

´
´
´
3921
M. P. Krzeminski, M. Cwiklinska / Tetrahedron Letters 52 (2011) 3919–3921
7. (a) Shan, Z.; Xiong, Y.; Li, W.; Zhao, D. Tetrahedron: Asymmetry 1998, 9, 3985–
3989; (b) Shan, Z.; Xiong, Y.; Zhao, D. Tetrahedron 1999, 55, 3893–3896.
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74, 4195–4202.
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cited therein.
to air for a short period of time as was evidenced by the unchanged
11B NMR spectra, and can be stored under an inert atmosphere for
prolonged periods.
The catalytic activity of the spiroborate esters was examined in
the asymmetric borane reduction of prochiral ketones.15 Initially,
acetophenone was reduced with 1 molar equivalent of borane–
dimethyl sulfide adduct and 0.1, 0.05 and 0.01 molar equivalent
of 3–8 as the catalyst in dry THF, at room temperature. The THF
solution of acetophenone was added dropwise to the reaction flask
using a syringe pump. The reaction was quenched by the addition
of methanol, and the product was isolated by column chromatog-
raphy. The results are summarized in Table 2.
In all cases, reduction of acetophenone was very fast (>1 h) and
gave good yields of (R)-1-phenylethanol. Each terpene spiroborate
ester, except 6, led to the product (R)-1-phenylethanol with high
enantiomeric excess, and catalyst 3 gave the highest enantioselec-
tivity (Table 2). Interestingly, when the amount of 3 was lowered
from 10 to 1 mol % only a slight decrease in the enantioselectivity
was observed (Table 2, entries 1 vs 3). However, lowering the
amount of 4 from 10 to 1 mol % resulted in a sharp fall in the
enantioselectivity (from 96% to 66%, Table 2, entries 4–6). This
could be caused by the presence of a 1,3,2-dioxaborinane in cata-
lyst 4, which is less stable than the five-membered 1,3,2-dioxa-
borolane in 3. The change of the diol part in the spiroborate ester
molecule did not affect the configuration of the product alcohol.
The chiral pinane diols exerted only a small effect on the enanti-
oselectivity of the reduction (Table 2, entries 11–14). It seems that
the size of the diol moiety and not its chirality is an important fac-
tor in these reductions, thereby explaining the highest selectivity
obtained in the presence of spiroborate ester 3.
Consequently, catalyst 3 was employed in the borane reduction
of other prochiral ketones (Table 3). The corresponding optically
active alcohols were obtained in excellent yields and with high
enantiomeric excess, except for naphthalen-2-yl(phenyl)methanol
(Table 3, entry 7). Interestingly, the reduction of benzofuryl phenyl
ketone provided benzofuran-2-yl-(phenyl)methanol in moderate
enantioselectivity (Table 3, entry 6).
In conclusion, terpene spiroborate esters have been synthesized
via a simple method in good yields, and are stable solids. The bo-
rate esters, except 6, exhibited high catalytic activity in the asym-
metric borane reduction of acetophenone and other prochiral
ketones. For the reduction of acetophenone, the size of the diol
moiety, not its chirality, was the dominant factor affecting the
enantioselective reduction by the spiroborate catalyst. The de-
scribed spiroborate ester 3 is a highly efficient and stable catalyst
for the asymmetric reduction of various prochiral ketones.
14. General procedure for the synthesis of terpene spiroborate esters 3–8: To
a
solution of the corresponding diol (5 mmol) in dry toluene (10 mL), under a
nitrogen atmosphere, was added triisopropyl borate (1.17 mL, 5.1 mmol) via
syringe and the mixture stirred under mild reflux conditions for about 20 min.
When the mixture became homogeneous, a solution of (1R,2R,3S,5R)-3-amino-
pinan-2-ol (0.845 g, 5 mmol) in dry toluene (10 mL) was added. The mixture
was refluxed for 20 min and during this time a portion of toluene along with
evolving isopropanol was removed by distillation (about 10 mL). Next, toluene
(10 mL) was added to the distillation flask and the contents evaporated again
to make sure all the isopropanol had been removed. After stirring for 20 min,
the mixture was cooled to room temperature and a white precipitate of the
spiroborate ester appeared. The product was filtered and recrystallized from
toluene as a white crystalline powder. 3: 1H NMR (400 MHz, THF-d8) d 0.91 (s,
3H), 1.24 (s, 3H), 1.26 (s, 3H), 1.77–1.84 (m, 2H), 1.84–1.91 (m, 2H), 1.97–2.05
(m, 1H), 2.31–2.36 (m, 1H), 3.27 (m, 1H), 3.65 (m, 4H), 5.02–5.56 (m, 2H), 13C
NMR (100 MHz, THF-d8) d 24.59, 28.03, 28.44, 30.64, 35.04, 39.20, 41.70, 53.06,
54.79, 64.97, 65.01, 79.74. Anal. Calcd for C12H22BNO3: C, 60.27; H, 9.27; N,
5.86. Found: C, 60.41; H, 9.45; N, 5.97. 4: 1H NMR (400 MHz, THF-d8) d 0.90 (s,
3H), 1.25 (s, 3H), 1.26 (s, 3H), 1.53 (quin, J = 5.5 Hz, 2H), 1.78–1.86 (m, 4H),
1.97–2.04 (m, 1H), 2.27–2.35 (m, 1H), 3.28 (m, 1H), 3.74 (t, J = 5.5 Hz, 4H), 5.24
(br s, 2H), 13C NMR (100 MHz, THF-d8) d 24.64, 27.95, 28.44, 30.87, 30.92,
35.20, 40.04, 41.78, 53.59, 54.93, 62.22 (2 ꢂ C), 79.96. Anal. Calcd for
C13H24BNO3: C, 61.68; H, 9.56; N, 5.53. Found: C, 61.92; H, 9.65; N, 5.78. 5:
1H NMR (400 MHz, THF-d8) d 0.90 (s, 3H), 1.02–1.05 (m, 12H), 1.23 (s, 3H), 1.25
(s, 3H), 1.77–1.82 (m, 2H), 1.86 (t, J = 5.6 Hz, 1H), 1.91 (m, 1H), 1.98 (m, 1H),
2.25–2.34 (m, 1H), 3.22 (m, 1H), 5.10 (br s, 2H), 13C NMR (100 MHz, THF-d8) d
24.64, 25.16 (2 ꢂ C), 25.89 (2 ꢂ C), 28.08, 28.48, 30.82, 35.14, 39.15, 41.73,
53.20, 54.89, 79.00 (2 ꢂ C), 79.26. Anal. Calcd for C16H30BNO3: C, 65.09; H,
10.24; N, 4.74. Found: C, 65.26; H, 10.08; N, 4.92. 6: 1H NMR (400 MHz, THF-d8)
d 0.93 (s, 3H), 1.30 (s, 3H), 1.33 (s, 3H), 1.80–1.90 (m, 2H), 1.92 (d, J = 10.5 Hz,
1H), 2.01 (t, J = 5.7 Hz, 1H), 2.09–2.18 (m, 1H), 2.32–2.41 (m, 1H), 3.44 (m, 1H),
5.51 (m, 1H), 6.31 (m, 1H), 6.42–6.52 (m, 4H), 13C NMR (100 MHz, THF-d8) d
24.50, 28.29, 28.37, 30.37, 34.77, 39.26, 41.60, 53.75, 54.45, 81.57, 109.24,
109.36, 118.62, 118.74, 153.10, 153.24. Anal. Calcd for C16H22BNO3: C, 66.92; H,
7.72; N, 4.88. Found: C, 67.19; H, 7.51; N, 5.01. 7: 1H NMR (400 MHz, THF-d8) d
0.82 (s, 3H), 0.91 (s, 3H), 1.17 (s, 3H), 1.20 (s, 3H), 1.22 (s, 3H), 1.26 (s, 3H),
1.75–1.83 (m, 5H), 1.85–1.97 (m, 3H), 1.97–2.01 (m, 2H), 2.12–2.19 (m, 1H),
2.26–2.33 (m, 1H), 3.24 (dq, J = 10.4, 5.4Hz, 1H), 3.89 (m, 1H), 5.06 (br s, 2H),
13C NMR (100 MHz, THF-d8) d 24.59, 24.91, 27.71, 28.20, 28.28, 28.54, 30.69,
30.78, 35.06, 39.03, 39.13, 39.23, 41.61, 41.75, 53.11, 54.56, 54.98, 76,47, 79.38,
81.31. Anal. Calcd for C20H34BNO3: C, 69.17; H, 9.87; N, 4.03. Found: C, 69.38;
H, 9.96; N, 4.18. 8: 1H NMR (400 MHz, THF-d8) d 0.82 (s, 3H), 0.91 (s, 3H), 1.17
(s, 3H), 1.20 (s, 3H), 1.22 (s, 3H), 1.26 (s, 3H), 1.75–1.83 (m, 5H), 1.85–1.97 (m,
3H), 1.97–2.01 (m, 2H), 2.12–2.19 (m, 1H), 2.26–2.33 (m, 1H), 3.24 (dq, J = 10.4,
5.4 Hz, 1H), 3.89 (m, 1H), 5.06 (br s, 2H), 13C NMR (100 MHz, THF-d8) d 24.64,
24.92, 27.69, 27.98, 28.28, 28.43, 29.28, 30.75, 35.33, 39.09, 39.13, 39.30, 41.67,
41.71, 53.14, 54.52, 54.85, 76.55, 79.18, 81.26. Anal. Calcd for C20H34BNO3: C,
69.17; H, 9.87; N, 4.03. Found: C, 69.43; H, 9.92; N, 4.21.
Acknowledgments
Financial support from the Ministry of Science and Higher Edu-
´
cation, Warsaw, grant 2683/B/H03/2010/38, is acknowledged. M.C.
is grateful for financial support from the European Social Fund and
National Budget, grant ‘Stypendia dla doktorantów 2008/2009–
ZPORR’.
References and notes
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the corresponding catalyst 3–8 (0.1–0.01 mmol) in dry THF (3 mL), BH3ꢃSMe2
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(10 M, 100 lL, 1 mmol) was added at room temperature with stirring. Next, a
solution of ketone (1 mmol) in THF (2 mL) was added at a rate of 3 mL per hour
using a syringe pump. The solution was stirred for 20 min and quenched by the
addition of MeOH (1 mL) at room temperature. After stirring for 30 min at rt,
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column chromatography using hexane/EtOAc (4:1) as eluent.
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