Rationale on the abnormal effect of temperature on the enantioselectivity in the asymmetric borane reduction of ketones catalyzed by L-prolinol

Article abstract of DOI:10.1002/hlca.200490292

The effect of temperature on the enantioselectivity of the oxazaborolidine-catalyzed asymmetric borane reduction of ketones was investigated in the presence of (5S)-3-oxa-1-aza-2-borabicyclo[3.3.0]octane (=(3aS)-tetrahydro-1H,3H-pyrolo[1,2-c][1,3,2]oxazaborole; 1a) and its 2-methoxy derivative (1b) as catalysts, which were synthesized from L-prolinol with borane and trimethyl borate, respectively. The results indicate that the two catalysts induce a different temperature-dependent enantioselectivity. The enantioselectivity of the B-unsubstituted (5S)-3-oxa-1-aza-borabicyclo[3.3.0] octane (1a) increases with increasing temperature, while its B-methoxy-substituted derivative 1b shows the highest enantioselectivity at ca. 50°. (5S)-3-Oxa-1-aza-2-borabicyclo[3.3.0]octane (1a) is more likely to dimerize than its 2-methoxy derivative 1b. The conversion rates of L-proline to L-prolinol in the presence of different amounts of borane were also determined in this study.

Full text of DOI:10.1002/hlca.200490292

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Rationale on the Abnormal Effect of Temperature on the Enantioselectivity
in the Asymmetric Borane Reduction of Ketones Catalyzed by l-Prolinol
by Jiaxi Xu*, Tiezheng Wei, Shrong-Shi Lin, and Qihan Zhang
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of
Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871,
Peopleꢀs Republic of China
(phone: ‡86-10-6275-1497; fax: ‡86-10-6275-1708; e-mail: jxxu@pku.edu.cn)
The effect of temperature on the enantioselectivity of the oxazaborolidine-catalyzed asymmetric borane
reduction of ketones was investigated in the presence of (5S)-3-oxa-1-aza-2-borabicyclo[3.3.0]octane (ˆ(3aS)-
tetrahydro-1H,3H-pyrolo[1,2-c][1,3,2]oxazaborole; 1a) and its 2-methoxy derivative (1b) as catalysts, which
were synthesized from l-prolinol with borane and trimethyl borate, respectively. The results indicate that the
two catalysts induce a different temperature-dependent enantioselectivity. The enantioselectivity of the B-
unsubstituted (5S)-3-oxa-1-aza-borabicyclo[3.3.0]octane (1a) increases with increasing temperature, while its
B-methoxy-substituted derivative 1b shows the highest enantioselectivity at ca. 508. (5S)-3-Oxa-1-aza-2-
borabicyclo[3.3.0]octane (1a) is more likely to dimerize than its 2-methoxy derivative 1b. The conversion rates
of l-proline to l-prolinol in the presence of different amounts of borane were also determined in this study.
1. Introduction. ± Enantioselective 1,3,2-oxazaborolidine-catalyzed borane reduc-
tion of prochiral ketones to chiral secondary alcohols is one of the most-often applied
reactions in asymmetric syntheses and has been widely used in the preparation of
various secondary alcohols during the past two decades (for recent reviews, see [1]).
Numerous new efficient oxazaborolidines have been developed and applied until now.
In comparison with the numerous attempts to search for new catalysts, in only some of
the papers was attention paid to the factors that affect enantioselectivity in the
asymmetric reduction, such as the structure [1][2] and stability [3] (including
dimerization) of the catalyst, the borane source [4], the reduction of temperature
[5], the solvent [3a][4c], the additive [6], the electronic effect [7], etc. Although a few
papers have reported the effects of temperature on enantioselectivity, different 1,3,2-
oxazaborolidines seem to show obviously different effects on the enantioselectivity, and
the effect of B-unsubstituted 1,3,2-oxazaborolidine has not been investigated in detail.
Herein, we wish to report our observations and rationale on the effects of prolinol-
derived, B-unsubstituted and B-methoxy-substituted 1,3,2-oxazaborolidine catalysts in
the asymmetric borane reduction of acetophenone.
2. Results and Discussion. ± Many chiral 1,3,2-oxazaborolidines derived from chiral
vicinal amino alcohols have been prepared and evaluated in the asymmetric borane
reduction of ketones, and some excellent enantioselectivities have been achieved with
them [1]. (5S)-3-Oxa-1-aza-2-borabicyclo[3.3.0]octane (ˆ(3aS)-tetrahydro-1H,3H-
pyrrolo[1,2-c][1,3,2]oxazaborol; 1a), derived from (2S)-pyrrolidine-2-methanol (ˆl-
ꢁ 2005 Verlag Helvetica Chimica Acta AG, Zürich

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prolinol), was reported by Buono and co-workers to be an effective catalyst in the
asymmetric reduction of ketones in refluxing toluene, giving excellent yields and
enantioselectivities [5a]. However, a year later, Martens and co-workers found that
only moderate enantioselectivities were obtained under the same conditions and
argued against the results of Buono and co-workers [8]. According to [5], the effect of
temperature on the enantioselectivity of B-unsubstituted chiral 1,3,2-oxazaborolidines
has not been investigated in detail at temperatures > 558. Recently, we found that (5S)-
2-methoxy-4,4-diphenyl-3-oxa-1-aza-2-borabicyclo[3.3.0]octane (2b) is a better cata-
lyst than the B-unsubstituted (5S)-4,4-diphenyl-3-oxa-1-aza-2-borabicyclo[3.3.0]oc-
tane (2a) [9]. Employing (5S)-3-oxa-1-aza-2-borabicyclo[3.3.0]octane (1a) as a simple
catalyst easily prepared from l-prolinol, even in situ from l-proline, we now
investigated the effects of temperature on the enantioselectivity of acetophenone
reduction in the presence of 1a or of its 2-methoxy derivative 1b, aiming at finding a
simple and efficient catalyst (Scheme 1) and at settling the argument on the
enantioselectivity in refluxing toluene.
Scheme 1. Asymmetric Borane Reduction of Acetophenone Catalyzed by l-Prolinol
In our asymmetric reduction, catalyst 1a (0.1 equiv. rel. to acetophenone) was
prepared first by addition of borane ´ dimethyl sulfide (BH3 ´ Me2S; 1.5 equiv. rel. to l-
prolinol) to a solution of l-prolinol in toluene and heating at 458 for 14 h or at 1108 for
15 min. After adjustment to the desired temperature and after addition of an additional
amount of BH3 ´ Me2S (1.0 equiv. rel. to acetophenone), acetophenone (1.0 equiv.) was
added dropwise within 0.5 h1). Catalyst 1b was prepared in situ by addition of trimethyl
borate to a solution of l-prolinol in toluene and stirred at 258 for 2 h. Then, at the
desired temperature and after addition of BH3 ´ Me2S (1.0 equiv. rel. to acetophenone),
acetophenone (1 equiv.) was added dropwise within 0.5 h. The enantiomer excesses
were determined after usual workup (see Exper. Part) by means of HPLC on a chiral
OD column. The results revealed different temperature-dependent enantioselectivities
1
)
The experimental results established that no obvious difference in enantioselectivity was observed
between the two modes used for the preparation of catalyst 1a.

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for the two catalysts (see Figs. 1 and 2). With catalyst 1b, the highest enantioselectivity
(60%) in the asymmetric reduction of acetophenone was achieved at ca. 508 (Fig. 2),
similarly to catalyst 2b reported previously [5b,g]. In contrast, with catalyst 1a, the
enantioselectivities increased almost linearly (r2 ˆ 0.98) with increasing temperature
(Fig. 1). Compared with the traditional dependence of enantioselectivity on temper-
ature, the results with catalyst 1a are abnormal.
Fig. 1. The effect of temperature on the enantioselectivity of catalyst 1a
Fig. 2. The effect of temperature on the enantioselectivity of catalyst 1b
As we suggested previously [5g], dimerization is an important factor in temper-
ature-dependent enantioselectivities for B-unsubstituted catalysts, while noncatalytic
reduction is a non-negligible factor for B-substituted catalysts.
Based on literature data [5] and our results, the different temperature-dependent
enantioselectivities can be rationalized by the dimerization of catalyst 1a at lower
temperatures and the formation of the monomer with increasing temperature. Thus, the
monomer/dimer ratio is highest at 1108, close to the boiling point of toluene. We suggest
that catalyst 1a tends to dimerize more easily than catalyst 1b because of the different
substituents at the B-atom. The electron-donating MeO group in 1b decreases the
Lewis acidity of the B-atom so that it cannot coordinate with the N-atom of another
molecule, thus preventing 1b from dimerizing. That is the reason why chiral 1,3,2-

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oxazaborolidines substituted at the B-atom by an electron-rich alkyl, aryl, or alkoxy
group usually show better enantioselectivities than the corresponding B-unsubstituted
chiral 1,3,2-oxazaborolidines under reduction conditions (cf. also [3]).
Thus, we presumed that, energetically, the dimer 3, as suggested by Nevalainen on
the basis of quantum-chemical calculations [10], should be the most-favored one of the
possible dimers, rather than dimer 4 (Scheme 2), which is still a chiral reducing reagent
and could also reduce ketones asymmetrically. Thus, 3 should be one of the active
species in the asymmetric reduction. The equilibrium between monomer 1 (monomer-
borane complex) and the postulated dimer 3 (dimer-borane complex) in the reduction
system is shown in Scheme 2.
Scheme 2. Equilibrium between the Monomer (monomer-borane complex) and the Postulated Dimer (dimer-
borane complex)
To interpret the abnormal effect of temperature on the enantioselectivity in the
reduction, we decided to determine the monomer/dimer ratios for catalysts 1a and 1b at
different temperatures. 11B-NMR Tracing experiments were designed and carried out at
different temperatures; unfortunately, we could not observe clear monomer/dimer
ratios for 1a at different temperatures (25 ± 1108) due to the complexity of the 11B-
NMR spectrum. Moreover, the EI-MS of 1a showed a monomer peak at m/z 111 and a
dimer peak at m/z 222. For catalyst (1b), only one 11B-NMR signal was observed at
8.13 ppm, which should arise from monomeric 1b; no dimer was detected in the
reducing system. The 11B-NMR results are in accordance with our rationale mentioned
above.
Buono and co-workers reported that l-proline could also be used as a catalyst in
asymmetric borane reduction of ketones and found that enantioselectivity increased
with increasing reduction temperature [5a]. These authors and the Martens group also
found that l-proline always gave lower enantioselectivities than l-prolinol in the
asymmetric reduction [5a][8]. Another factor affecting the enantioselectivity is the
amount of catalyst in the reduction mixture, which depends on the amount of l-
prolinol. The latter is related to the conversion of l-proline in the reduction system.
Thus, we determined the conversion rate of l-proline to l-prolinol at different
temperatures in the presence of 1.5 or 10 equiv. of borane, which are related to the
amounts of borane in the preparation of catalysts and reduction of ketone, respectively
(Figs. 3 and 4). The results established increasing conversion rates with increasing
temperature or amount of borane. l-Proline seems to be an inactive species in the
catalytic reduction but l-proline could also be used as a catalyst in the asymmetric
borane reduction of ketones because it is reduced to l-prolinol. However, l-proline
always gave lower enantioselectivity than l-prolinol in asymmetric reductions, due to

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its incomplete reduction. Nevertheless, its induced enantioselectivity increased with
increasing reduction temperature because the reduction rate of l-proline increased
with increasing temperature.
Our results established that the enantioselectivities reported by Martens and co-
workers are reliable, and (5S)-2-methoxy-3-oxa-1-aza-2-borabicyclo[3.3.0]octane (1b)
shows indeed a better enantioselectivity than (5S)-3-oxa-1-aza-3-borabicyclo[3.3.0]oc-
tane (1a). However, the enantioselectivities induced by both 1a and 1b are not as good
as those reported by Buono and co-workers [5a].
Fig. 3. Conversion of l-proline to l-prolinol with 1.5 equiv. of borane at different temperatures
Fig. 4. Conversion of l-proline to l-prolinol with 10 equiv. of borane at different temperatures
3. Conclusions. ± In conclusion, the effect of temperature on the enantioselectivity
of the asymmetric borane reduction of acetophenone catalyzed by the B-unsubstituted
(5S)-3-oxa-1-aza-2-borabicyclo[3.3.0]octane (1a) and its B-methoxy-substituted de-
rivative 1b, which are derived from l-prolinol with borane and trimethyl borate,
respectively, was investigated. The results indicate that the enantioselectivity in the
presence of 1a increases with increasing temperature, which represents an abnormal
effect of temperature on the enantioselectivity, while that of 1b shows the highest
enantioselectivity around 508. The different temperature-dependent enantioselectiv-

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ities were caused by the different substituents at the B-atom of the catalysts. The B-
unsubstituted 1a tends to dimerization, which is not observed for the B-methoxy-
substituted 1b.
The project was supported in part by the National Natural Science Foundation of China (No. 20272002 and
20472005), the Ministry of Education of P. R. China (SRF for ROCS and EYTP), and Peking University
(President Grant).
Experimental Part
1. General. Trimethyl borate and the borane ´ dimethyl sulfide complex were purchased from Acros
Organics. Toluene was heated under reflux over Na and distilled prior to use. CC ˆ Column chromatography.
HPLC: HP-1100 HPLC equipment, e.e. values: Chiralcel OD column (4.6 Â 250 mm), eluent hexane/iPrOH
9 :1, flow 0.5 ml/min, detection at 228 nm; conversion rates of l-proline to l-prolinol: Vydac RP-C18 column
(4.6 Â 250 mm) eluent H2O/MeOH 9 :1, flow 1.0 ml/min, detection at 214 nm. NMR spectra: Mercury Plus-300
(300 MHz) spectrometer; CDCl3 solns. with SiMe4 as an internal standard for 1H and 13C; in toluene solns. with
BF3 ´ Et2O (47%) as external standard for 11B; chemical shifts d in ppm.
2. Asymmetric Reduction of Acetophenone by Using (5S)-2-Methoxy-3-oxa-1-aza-2-borabicyclo[3.3.0]oc-
tane (1b): General Procedure. To a soln. of l-prolinol (5.1 mg, 0.05 mmol) in dry toluene (2.5 ml) was added
trimethyl borate (6.0 mg, 0.06 mmol), and the mixture was stirred under N2 at r.t. for 2 h. After the addition of
2m BH3 ´ Me2S in THF (0.25 ml, 0.5 mmol), a soln. of acetophenone (60 mg, 0.5 mmol) in dry toluene (2.5 ml)
was added dropwise at the desired temp. with 0.5 h. The resulting mixture was stirred at the same temp. until the
acetophenone was consumed (GLC monitoring). The resulting mixture was quenched with MeOH in an ice-
water bath and evaporated. The residue was purified by CC (siliga gel, petroleum ether (60 ± 908/AcOEt 5 :1)):
chiral a-methylbenzenemethanol. Colorless oil.
3. Asymmetric reduction of Acetophenone by Using (5S)-3-Oxa-1-aza-2-borabicyclo[3.3.0]octane (1a).
General Procedure. To a soln. of l-prolinol (5.1 mg, 0.05 mmol) in dry toluene (2.5 ml) was added 2m BH3 ´ Me2S
in THF (38 ml, 0.075 mmol), and the mixture was stirred under N2 at 458 for 14 h or 1108 for 15 min. After the
mixture was adjusted to the desired temp. and after the addition of 2m BH3 ´ Me2S in THF (0.25 ml, 0.5 mmol), a
soln. of acetophenone (60 mg, 0.5 mmol) in dry toluene (2.5 ml) was added dropwise within 0.5 h. The mixture
was stirred until the acetophenone was consumed (GLC monitoring). Workup and purification as described in
Exper. 2: chiral a-methylbenzenemethanol.
4. Asymmetric reduction of Acetophenone by Using the Catalyst 1a Generated from l-Proline. General
Procedure. l-Proline (5.75 mg, 0.05 mmol) was suspended in dry toluene (2.5 ml), and 2m BH3 ´ Me2S in THF
(38 ml, 0.075 mmol) was added via syringe under N2. The mixture was stirred at r.t. for 10 min and then heated to
reflux (1108) for 0.5 h. After the mixture was cooled to the desired temp. and after the addition of 2m BH3 ´ Me2S
in THF (0.25 ml, 0.5 mmol), a soln. of acetophenone (60 mg, 0.5 mmol) in dry toluene (2.5 ml) was added
dropwise within 0.5 h. The mixture was stirred until the acetophenone was consumed (GLC monitoring).
Workup and purification as described in Exper. 2: chiral a-methylbenzenemethanol.
5. Conversion Rate of the Reduction of l-Proline by Using Borane. General Procedure. l-Proline (5.75 mg,
0.05 mmol) was suspended in dry toluene (2.5 ml), and 2m BH3 ´ Me2S in THF (38 ml, 0.075 mmol; or 0.25 ml,
0.5 mmol) was added via a syringe under N2. The mixture was stirred, and a sample (25 ml) of the soln. was taken
periodically by syringe, quenched with MeOH (2 ml), and the resulting soln. (20 ml) analyzed by HPLC (C18,
H2O/MeOH 9 :1). The remaining reduction mixture was kept stirring to complete reduction. A sample (25 ml) of
the final soln. was diluted with MeOH (2 ml) and analyzed as described above. The conversion rate was
calculated with the following equation: Conversion rate ˆ (absorbance of the sample at the indicated time)/
(absorbance of the complete reduction sample) ´ 100%.
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Received September 16, 2004