Empirical method for predicting enantioselectivity in catalytic reactions: demonstration with lipase and oxazaborolidine

Article abstract of DOI:10.1016/j.tet.2009.09.058

We derived a novel equation capable of predicting the degree of enantioselectivity in a catalytic reaction without any knowledge of the reaction mechanism and/or the transition-state structure, and tested the validity of this equation by changing substrates systematically in the lipase or oxazaborolidine-catalyzed reactions. A good correlation was observed between the predicted and observed E values, and the stereochemistry of the products could be predicted correctly in most cases (28 out of 30).

Full text of DOI:10.1016/j.tet.2009.09.058

Tetrahedron 65 (2009) 9583–9591
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Empirical method for predicting enantioselectivity in catalytic reactions:
demonstration with lipase and oxazaborolidine
*
*
Tadashi Ema , Norichika Ura, Masataka Yoshii, Toshinobu Korenaga, Takashi Sakai
Division of Chemistry and Biochemistry, Graduate School of Natural Science and Technology, Okayama University, Tsushima, Okayama 700-8530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We derived a novel equation capable of predicting the degree of enantioselectivity in a catalytic reaction
without any knowledge of the reaction mechanism and/or the transition-state structure, and tested the
validity of this equation by changing substrates systematically in the lipase or oxazaborolidine-catalyzed
reactions. A good correlation was observed between the predicted and observed E values, and the
stereochemistry of the products could be predicted correctly in most cases (28 out of 30).
Ó 2009 Elsevier Ltd. All rights reserved.
Received 2 September 2009
Received in revised form
12 September 2009
Accepted 15 September 2009
Available online 18 September 2009
Keywords:
Enantioselectivity
Prediction
Lipase
Oxazaborolidine
1. Introduction
2. Results and discussion
In general, predicting the degree of enantioselectivity in a cata-
lytic reaction without any knowledge of a reaction mechanism and/
or a transition-state structure is almost impossible. Even if the
mechanism of enantioselectivity of the catalytic reaction is clear,
the quantitative prediction of enantioselectivity is still difficult
because the magnitudes of the steric and/or electronic effects that
the chiral catalyst experiences in the transition state are hard to
predict. Although it is well-known that the essence of chemical
reactions lies in the transition state, only a limited number of
methods are available for investigating the transition state, which
has a lifetime of femto-second order: kinetic constants, the Eyring
plot giving the activation enthalpy and entropy, Hammett’s sub-
stituent constants, isotope effects, spectroscopic detection of re-
action intermediates, estimation based on a series of derivatives of
catalyst and substrate, and theoretical calculations.1 Although the
Es value, defined by Taft, is a useful measure of the magnitude of the
steric effect,2 the Es values cannot address this issue because dif-
ferent catalysts have different steric effects on the same substituent
and because the electronic property and solvent can also affect the
transition state. Here we report an empirical method for predicting
the degree of enantioselectivity without any knowledge of a re-
action mechanism and/or a transition-state structure.
During our mechanistic study on the lipase-catalyzed kinetic
resolution,3 we noticed that the E value4 (EAB) for substrate AB
having two substituents R1 and R2 can be predicted by using the
E values (EA and EB) experimentally determined for two reference
substrates A and B having substituent R1 and R2, respectively, as
shown in Scheme 1.
Scheme 1. Empirical prediction of the E value for the lipase-catalyzed kinetic reso-
lution of alcohols.
The equation for the prediction is quite simple:
* Corresponding authors. Tel.: þ81 86 251 8091; fax: þ81 86 251 8092.
E-mail address: ema@cc.okayama-u.ac.jp (T. Ema).
E
ABzEA=EB
(1)
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.058

9584
T. Ema et al. / Tetrahedron 65 (2009) 9583–9591
As shown in Experimental section and Supplementary data, this
equation can be applied to various reactions where the approxima-
tion of additivity and substitution is fulfilled. Eq. 1 means that infor-
mation needed to predict the degree of enantioselectivity for AB is
included in the EA and EB values involving the steric and electronic
effects that a chiral catalyst experiences in the transition state. In
this method, the steric effect is not separated from the electronic ef-
fect, but both of them are involved in the substituent effect. To test
the validity of our hypothesis Eq.1, we examined two types of enan-
tioselective reactions: (i) the lipase-catalyzed kinetic resolution of
secondary alcohols and (ii) the oxazaborolidine-catalyzed reduc-
tion of ketones.
We initially carried out the lipase-catalyzed kinetic resolution of
alcohols 1a–10a (Scheme 2).5 The lipase-catalyzed reactions were
conducted with vinyl acetate in dry i-Pr2O or Et2O at 30 ꢀC, and the
E values were calculated according to the literature.4b Based on the
results obtained with reference substrates 1a–4a, the E values for
5a–10a, which possess two substituents out of the chloromethyl, n-
butyl, cyclohexyl, and phenyl groups, were predicted. The results
are summarized in Table 1. The correlation between the predicted
and observed E values is plotted in Figure 1a.
value exceeding 200 is less reliable. Nevertheless, Figure 1a clearly
indicates that the data are scattered around a line inclined 45ꢀ. This
means that the predicted E values are qualitatively in good agree-
ment with the observed E values and that the equation, EABzEA/EB,
is valid as the first approximation. In other words, the approxi-
mation of additivity and substitution is valid to some extent. (The
good correlation in Fig. 1a does not justify the use of the E values
greater than 200 and the E values less than 200 should be used for
a reliable prediction.)
It should be noted that the enantiopreference for 10a, having the
cyclohexyl and phenyl substituents of similar sizes, could be pre-
dicted correctly in all cases. Because of the similar bulkiness of the
two substituents, it would be impossible to unambiguously predict,
which enantiomer reacts faster a priori. The lipases did discrimi-
nate both the difference and order of the bulkiness of the two
substituents correctly.
Lipase PS-C II exhibited very low enantioselectivities for 5a in i-
Pr2O (E¼1.53, R-preference) and Et2O (E¼1.18, S-preference), and low
E values were predicted (E¼1.29, 2.14, S-preference). This enzyme
experiences or ‘feels’ a similar degree of steric hindrance against the
chloromethyl and n-butyl groups, leading to a wrong prediction
under condition 1 (Table 1). Changing the enzyme was found to be
more effective for improving reliability than changing the solvent;
both the predicted and observed E values were enhanced by using
lipase LIP or Chirazyme L-2 (see conditions 3 and 4 in Table 1).
We next examined the oxazaborolidine-catalyzed reduction of
ketones 11a–25a.6,7 The outline of the method is shown in Scheme 3.
The asymmetric reduction was conducted with (S)-5,5-diphenyl-2-
methyl-3,4-propano-1,3,2-oxazaborolidine and H3B$SMe2 in dry
THF at 30 ꢀC and the Eobsd value was calculated from
Eobsd¼(100þ%ee)/(100ꢁ%ee). Based on the results obtained with
reference ketones 11a–15a, the E values for 16a–25a, which possess
two substituents out of the benzyl, n-butyl, 2-phenylethyl, cyclo-
hexyl, and phenyl groups, were predicted, which were then con-
verted to the %ee values. The results are summarized in Figure 2.
The correlation between the predicted and observed E values is
plotted in Figure 1b. (Note that although compounds 12b, 14b, 15b,
21b, 22b, and 25b (Fig. 2) are identical to 2a, 3a, 4a, 8a, 9a, and 10a
(Scheme 2), respectively, different compound numbers are used
intentionally to avoid confusion. The characterization of them is
also described separately in Experimental section.)
Scheme 2. Alcohols used for the lipase-catalyzed kinetic resolution.
Although the E values could not be predicted precisely, the
enantiopreferences (R/S) were predicted successfully in most cases
(19 out of 20; see Table 1); only the kinetic resolution of 5a medi-
ated by lipase PS-C II in i-Pr2O did not give a correct enantiopre-
ference. A tendency can be seen that the E values predicted by using
an E value of >200, such as that for 4a, deviate considerably from
the observed E values (Table 1), which is partly because a high E
The sense of enantioselectivity (R/S) could be predicted correctly
in most cases (9 out of 10; see Fig. 2), and a good correlation can be
seen in Figure 1b. The E values for the reference ketones decreased
Table 1
Empirical prediction of the E value and enantiopreference for the lipase-catalyzed kinetic resolution of secondary alcohols
Alcohol
Condition 1a
Condition 2b
Condition 3c
Condition 4d
R/Sf
Epred
R/Sh
Eobsd
R/S
Epred
R/S
Eobsd
R/S
Epred
R/S
Eobsd
R/S
Epred
R/S
e
g
Eobsd
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
12.0
15.5
164
2321
1.53
47.5
783
1.89
37.5
47.6
R
R
R
R
R
S
d
d
d
d
d
S
S
S
R
R
10.6
22.7
279
2397
1.18
63.5
706
3.91
53.1
54.2
R
R
R
R
S
S
S
R
R
R
d
d
d
d
d
S
S
S
R
R
4.70
52.7
334
1102
11.5
462
2453
14.6
43.7
28.2
R
R
R
R
S
S
S
R
R
R
d
d
d
d
d
S
S
S
R
R
117
1976
>6961
8493
13.6
237
74.5
di
R
R
R
R
S
S
S
d
d
d
d
d
d
d
d
S
S
S
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
1.29
13.7
193
10.6
150
14.2
2.14
26.3
226
12.3
106
8.59
11.2
71.1
234
6.34
20.9
3.30
16.9
>59
72.6
d
S
R
R
R
di
d
R
R
R
di
d
a
Conditions: lipase, alcohol (0.82 mmol), vinyl acetate (1.63 mmol), dry solvent (5 mL), 30 ꢀC. Lipase PS-C II (180 mg), i-Pr2O.
Conditions: lipase, alcohol (0.82 mmol), vinyl acetate (1.63 mmol), dry solvent (5 mL), 30 ꢀC. Lipase PS-C II (180 mg), Et2O.
Conditions: lipase, alcohol (0.82 mmol), vinyl acetate (1.63 mmol), dry solvent (5 mL), 30 ꢀC. Lipase LIP (80 mg), i-Pr2O.
Conditions: lipase, alcohol (0.82 mmol), vinyl acetate (1.63 mmol), dry solvent (5 mL), 30 ꢀC. Chirazyme L-2 (120 mg), i-Pr2O.
Observed E value. E¼ln[1ꢁc(1þee(b))]/ln[1ꢁc(1ꢁee(b))], where c¼ee(a)/(ee(a)þee(b)).
Observed absolute configuration of the ester.
Predicted E value. For the method of prediction, see Scheme 1 and text.
Predicted absolute configuration of the ester.
No reaction.
b
c
d
e
f
g
h
i

T. Ema et al. / Tetrahedron 65 (2009) 9583–9591
9585
Figure 2. The optically active alcohols 11b–25b obtained by the oxazaborolidine-cat-
alyzed reduction of the corresponding ketones 11a–25a are shown. The observed and
predicted % ee values of 16b–25b are shown in blue and red, respectively. The Eobsd
value was calculated from Eobsd¼(100þ%ee)/(100ꢁ%ee), while the Epred value was
calculated as shown in Scheme 3. The Epred value was then converted to the predicted
%ee value according to the equation, %eepred¼100ꢂ(Epredꢁ1)/(Epredþ1). Conditions: (S)-
a,a-diphenyl-2-pyrrolidinemethanol (0.22 mmol), trimethylboroxine (0.14 mmol),
H3B+9$SMe2 (0.6 mmol), ketone (1.0 mmol, slow addition via a syringe pump over 2 h),
dry THF (3 mL), 30 ꢀC.
in the following order: 15a>14a>13a>12a>11a. This order reflects
the magnitude of steric hindrance that the catalyst feels. The ex-
cellence of the present method can be seen from the fact that the
absolute configuration of 16b could be predicted correctly, where
the n-butyl group is recognized to be bulkier than the benzyl group,
which would be impossible to predict a priori. On the other hand, in
the reduction of 25a, the predicted sense of enantioselectivity was
found to be wrong (Figs. 1b and 2). This type of deviation can help
us gain an insight into the reaction mechanism. For example, we
can suppose that the two bulky substituents (phenyl and cyclo-
hexyl) connected to the carbonyl group interfere with each other to
rotate and strain the two substituents and that the ground-state
and transition-state structures should be very crowded and dif-
ferent from those of reference substrates 14a and 15a, which may
disrupt the approximation of additivity and/or substitution.
Figure 1. Correlation plots for the ln Eobsd and ln Epred values. When the sense of the
observed enantioselectivity was opposite to that of the predicted one, the sign of the
ln Eobsd value was set to negative. Note that multiplying ln E by ꢁRT gives the differ-
ential free energy of activation, DDGz. (a) Lipase-catalyzed kinetic resolution of alco-
hols. The data obtained under conditions 1, 2, 3, and 4 in Table 1 are plotted by red
circle, pink diamond, green circle, and blue circle, respectively. (b) Oxazaborolidine-
catalyzed reduction of ketones. The data in Figure 2 are plotted.
3. Conclusion
In summary, we derived an equation, EABzEA/EB, capable of
predicting the degree of enantioselectivity without any knowledge
of a reaction mechanism and/or a transition-state structure, and
tested the validity of this equation by changing the structure of
substrates systematically in the enzymatic and nonenzymatic
reactions. As a result, the degree of enantioselectivity and the ste-
reochemistry of the product could be predicted correctly in most
cases (28 out of 30). The same analysis was also applied to the
reported data on the enantioselective hydrosilylation of ketones to
give a good correlation as shown in Supplementary data. Such
a quantitative relationship as characterized by Eq. 1 has been un-
known. This type of analysis can afford a hint to gain an insight into
the event occurring in the transition state of an enantioselective
reaction.
Scheme 3. Empirical prediction of the
reduction of ketones.
E value for the oxazaborolidine-catalyzed

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T. Ema et al. / Tetrahedron 65 (2009) 9583–9591
4. Experimental
to asymmetric synthesis if the approximation of additivity and
substitution is fulfilled.
4.1. Derivation of Eq. 1 based on thermodynamics
Eq. 1 can be derived as described below, assuming the two ap-
proximations shown in Figure 3.
4.2. Lipase-catalyzed kinetic resolution
ThedifferentialfreeenergyofactivationforAB canbeexpressedby
4.2.1. Materials and methods. Lipase PS-C II (Burkholderia cepacia
lipase) purchased from Amano Enzyme Inc., lipase LIP (Pseudomo-
nas aeruginosa lipase) purchased from Toyobo Co., and Chirazyme
L-2 (Candida antarctica lipase B) provided by Boehringer Mannheim
GmbH were used. Alcohols 1a, 7a, and 10a were prepared by the
reduction of the corresponding ketones commercially available, as
shown below. Alcohols 5a and 6a were prepared by the reduction of
the corresponding ketones synthesized as shown below. Alcohols
2a, 3a, 4a, 8a, and 9a were purchased. All the alcohols were purified
by distillation or column chromatography before use in the lipase-
catalyzed reactions. Acetates 1b,8 2b,9 3b,10 4b,11 5b,12 7b,13 8b,14
9b,15 and 10b16 were characterized according to the literature.
DDGzAB
[
GzRABL GzSAB
D D
When additivity is assumed for both substituents (R1 and R2), the
free energy of activation can be divided as follows (approximation
of additivity):
ꢀ
ꢁ
ꢀ
ꢁ
DDGzABz
D
GzRABðR1Þ þ
D
GzRABðR2Þ
ꢁ
D
GzSABðR1Þ þ
D
GzSABðR2Þ
ꢁ
ꢀ
ꢁ
ꢀ
¼
D
GzRABðR1Þ ꢁ
D
GzSABðR1Þ
ꢁ
D
GzSABðR2Þ ꢁ
D
GzRABðR2Þ
If the effects of R1 in RAB and SAB are equal to those of R1 in RA
and SA, respectively, and if the effects of R2 in RAB and SAB are
equal to those of R2 in SB and RB, respectively (approximation of
substitution), then
4.2.2. Synthesis of a-chloro ketones 5c and 6c. a-Chloro ketones 5c
and 6c were prepared from ethyl pentanoate and methyl cyclo-
hexylacetate, respectively, which are commercially available,
according to the literature.17 A mixture of Mg (2.71 g, 111 mmol)
and I2 (one piece) in dry Et2O (10 mL) was stirred under N2 at room
temperature for several minutes, and a small amount of tert-butyl
chloride (0.8 mL, 7.4 mmol) was added. After the reaction had been
initiated, a solution of tert-butyl chloride (7.4 mL, 68 mmol) in dry
Et2O (30 mL) was added dropwise to the suspended solution over
1 h in a water bath. After the mixture had been stirred for a few
hours, the mixture was added dropwise to a mixture of ester
(15.0 mmol), sodium chloroacetate (3.50 g, 30.0 mmol), and Et3N
(2.5 mL, 18 mmol) in dry Et2O (15 mL) under N2 over 1 h in an ice
bath. After the mixture had been stirred at room temperature
overnight, the reaction was stopped by adding 10% HCl in an ice
bath. After brine (3 mL) had been added, the product was extracted
with Et2O (10 mLꢂ2), and the solution was neutralized with satu-
rated aqueous NaHCO3 (3 mLꢂ5). The mixture was dried over
MgSO4, filtered, and concentrated. The product was purified by
silica gel column chromatography.
ꢀ
ꢁ
ꢀ
ꢁ
DDGzABz
D
GzRA
ꢁ
D
GzSA
ꢁ
D
GzRB
ꢁ
D
GzSB
(The effect of the methyl group in A and B is cancelled out and
eliminated.)
¼
DDGzA ꢁ DDGzB
¼ ꢁRTln EA þ RTln EB ¼ ꢁRTln EA=EB
(For the formula of DDGz ¼ –RT ln E, see Refs. 5a,b.)
On the other hand, the differential free energy of activation for
AB is given by
DDGzAB ¼ ꢁRTln EAB
Therefore,
4.2.2.1. 1-Chloro-2-hexanone (5c)18. 44% yield; colorless oil; 1H
E
ABzEA=EBðif EA>EBÞ
(2)
NMR (200 MHz)
d
0.91 (t, J¼7.2 Hz, 3H), 1.34 (sext, J¼7.4 Hz, 2H),
To meet the above conditions, all the reactions must be con-
1.61 (quint, J¼7.0 Hz, 2H), 2.59 (t, J¼7.2 Hz, 2H), 4.07 (s, 2H); 13C
ducted under the same conditions. Although the above derivation is
done for kinetic resolution, the same derivation can also be applied
NMR (50 MHz) d 13.7, 22.2, 25.7, 39.4, 48.2, 202.6; IR (neat) 2959,
2936, 2874, 1732, 1466, 1404, 1381 cmꢁ1
.
4.2.2.2. Chloromethyl cyclohexyl ketone (6c)19. The product was
used in the next reaction without purification.
OH
OH
R1
E
A
4.2.3. Typical procedure for the preparation of racemic alcohols
(1a, 5a–7a, 10a). To a solution of ketone (20 mmol) in EtOH
(30 mL) was added NaBH4 (0.38 g, 10 mmol) in an ice bath. The
mixture was stirred at room temperature for a few hours and then
acidified with 3% HCl. After the solvent had been removed under
reduced pressure, brine (3 mL) was added. The product was
extracted with Et2O (5 mLꢂ3), and the solution was neutralized
with saturated aqueous NaHCO3 (3 mL). The mixture was dried
over MgSO4, filtered, and concentrated. Alcohol 1a was purified by
distillation (60–61 ꢀC/55 mmHg). Alcohols 5a–7a were purified by
silica gel column chromatography and distillation (5a: 71–72 ꢀC/12
mmHg, 6a: 75–77 ꢀC/4 mm Hg, 7a: 85 ꢀC/3 mm Hg). Alcohol 10a
was purified by silica gel column chromatography.
R1
Me
Me
experimental value
SA
RA
references
A, B
OH
OH
E
B
R2
Me
Me
R1
R2
experimental value
RB
SB
OH
OH
target
AB
E
AB
R2
SAB
R1
RAB
R2
predicted value
Figure 3. Two approximations for the derivation of Eq. 1. The (R)-enantiomers (RA and
RB) are assumed to be the faster-reacting enantiomers in the derivation. The R/S
descriptor for AB is arbitrary (It depends on the priority of R1 and R2 in the IUPAC
nomenclature). When EA is greater than EB, RAB is predicted to be the faster-reacting
enantiomer, and the magnitude of EAB is predicted by EA/EB. Red arrow: approximation
of substitution; green arrow: approximation of additivity.
4.2.3.1. (ꢃ)-1-Chloro-2-propanol (1a)8. 50% yield; colorless oil;
1H NMR (200 MHz)
3.45 (dd, J¼7.0, 11.0 Hz, 1H), 3.60 (dd, J¼3.6, 11.0 Hz, 1H), 3.94–4.10
d
1.27 (d, J¼6.4 Hz, 3H), 2.19 (d, J¼4.6 Hz, 1H),

T. Ema et al. / Tetrahedron 65 (2009) 9583–9591
9587
(m, 1H); 13C NMR (50 MHz)
2957, 1456, 1429, 1375 cmꢁ1
d
20.2, 51.4, 67.6; IR (neat) 3369, 2978,
Det. 220 ꢀC, 1b 6.2 min, 1a 6.7 min. Reaction time 7 min. (S)-1a:
43.2% ee. (R)-1b: 75.0% ee; GC: CP-cyclodextrin-b-2,3,6-M-19, Inj.
250 ꢀC, Col. 70 ꢀC, Det. 220 ꢀC, (S) 11.5 min, (R) 12.3 min.
.
4.2.3.2. (ꢃ)-1-Chloro-2-hexanol (5a)18. 86% yield; colorless oil;
1H NMR (200 MHz)
d
0.91 (t, J¼7.0 Hz, 3H), 1.24–1.62 (m, 6H), 2.14
4.2.4.2. Kinetic resolution of 2-hexanol (2a). GC for monitoring
the reaction: PEG-20 M (3 m), Inj. 250 ꢀC, Col. 100 ꢀC, Det. 220 ꢀC,
2b 3.9 min, 2a 4.6 min. Reaction time 6 min. (S)-2a: 88.4% ee. (R)-
(d, J¼4.8 Hz, 1H), 3.48 (dd, J¼7.3, 11.1 Hz, 1H), 3.65 (dd, J¼3.3,
11.1 Hz, 1H), 3.74–3.89 (m, 1H); 13C NMR (50 MHz)
13.9, 22.6, 27.7,
33.9, 50.5, 71.4; IR (neat) 3381, 2957, 2934, 2862, 1468, 1433,
1379 cmꢁ1
d
27
2b: 16% yield; colorless oil; 99.7% ee; [
a
]
¼–6.8 (c 0.82, CHCl3);
D
20
.
lit.9
[a
]
¼þ4.8 (c 1, CHCl3) for (S)-2b with 99% ee; 1H NMR
D
(200 MHz)
d
0.89 (t, J¼6.6 Hz, 3H), 1.20 (d, J¼6.2 Hz, 3H), 1.20–1.40
4.2.3.3. (ꢃ)-2-Chloro-1-cyclohexylethanol (6a)20. 41% yield;
(m, 4H),1.40–1.64 (m, 2H), 2.03 (s, 3H), 4.89 (sext, J¼6.2 Hz,1H); 13C
colorless oil; 1H NMR (200 MHz)
d
0.93–1.98 (m, 11H), 2.10 (d,
NMR (50 MHz) d 14.0, 20.0, 21.4, 22.6, 27.6, 35.6, 71.1, 170.7; IR
J¼4.6 Hz, 1H), 3.47–3.76 (m, 3H); 13C NMR (50 MHz)
d
25.9, 26.0,
(neat) 2959, 2936, 2862, 1740, 1456, 1371, 1244 cmꢁ1; GC: CP-cy-
clodextrin-
-2,3,6-M-19, Inj. 250 ꢀC, Col. 80 ꢀC, Det. 220 ꢀC, (S)
26.3, 28.3, 29.0, 41.3, 49.2, 75.6; IR (neat) 3391, 2926, 2853, 1450,
b
1435 cmꢁ1
.
7.7 min, (R) 8.7 min.
4.2.3.4. (ꢃ)-2-Chloro-1-phenylethanol (7a)21. 60% yield; color-
4.2.4.3. Kinetic resolution of 1-cyclohexylethanol (3a). GC for
less oil; 1H NMR (200 MHz)
d
2.65 (d, J¼3.0 Hz, 1H), 3.65 (dd, J¼8.5,
monitoring the reaction: PEG-20 M (3 m), Inj. 250 ꢀC, Col. 120 ꢀC,
11.3 Hz, 1H), 3.76 (dd, J¼3.7, 11.3 Hz, 1H), 4.87–4.95 (m, 1H), 7.28–
7.41 (m, 5H); 13C NMR (50 MHz)
50.8, 74.0, 125.9, 128.3, 128.5,
139.8; IR (neat) 3391, 3063, 3031, 2955, 1495, 1454, 1427 cmꢁ1
Det. 220 ꢀC, 3b 8.1 min, 3a 9.5 min. Reaction time 20 min. (S)-3a:
29
d
52% yield; colorless oil; 81.0% ee; [
a]
¼þ2.90 (c 1.00, CHCl3); lit.23
D
.
[a
]D¼ꢁ3.3 (c 0.4, CHCl3) for (R)-3a with 80% ee; 1H NMR (200 MHz)
d
0.90–1.39 (m, 10H), 1.62–1.93 (m, 5H), 3.55 (quint, J¼6.2 Hz, 1H).
4.2.3.5. (ꢃ)-Cyclohexylphenylmethanol (10a)22. 93% yield; white
(R)-3b: 43% yield; Colorless oil; 97.0% ee; [
a
]
¼þ7.45 (c 1.02,
29
D
solid; mp 49 ꢀC (lit.22 46–48 ꢀC); 1H NMR (200 MHz)
d
0.84–1.48
CHCl3); 1H NMR (200 MHz)
d 0.90–1.55 (m, 9H), 1.55–1.85 (m, 5H),
(m, 6H), 1.54–1.86 (m, 5H), 1.96–2.02 (m, 1H), 4.37 (d, J¼7.2 Hz, 1H),
7.24–7.42 (m, 5H); 13C NMR (50 MHz)
26.0, 26.1, 26.4, 28.8, 29.3,
44.9, 79.3,126.5, 127.3,128.1, 143.5; IR (KBr) 3408, 3086, 3061, 3032,
2915, 2846, 1493, 1442, 1323 cmꢁ1
2.03 (s, 3H), 4.72 (quint, J¼6.3 Hz, 1H); 13C NMR (50 MHz)
d 17.1,
d
21.4, 26.0, 26.1, 26.4, 28.5, 42.6, 74.6, 170.7; IR (neat) 2980, 2928,
2855, 1736, 1450, 1371, 1248 cmꢁ1; GC: CP-cyclodextrin-
b-2,3,6-M-
.
19, Inj. 250 ꢀC, Col. 100 ꢀC, Det. 220 ꢀC, (S) 21.0 min, (R) 23.4 min.
4.2.4. General procedure for lipase-catalyzed kinetic resolutions.
After a mixture of lipase (180 mg for lipase PS-C II, 80 mg for lipase
LIP, or 120 mg for Chirazyme L-2) and alcohol (0.82 mmol) in dry i-
Pr2O (5 mL) or dry Et2O (5 mL) had been stirred in a test tube with
a rubber septum in a thermostat at 30 ꢀC for 30 min, vinyl acetate
4.2.4.4. Kinetic resolution of 1-phenylethanol (4a). Reaction time
26
1.5 h. (S)-4a: 43% yield; colorless oil; 97.0% ee; [
a
]
¼ꢁ55.1 (c 1.02,
D
23
CHCl3); lit.24
[
a
]
¼ꢁ43.7 (c 0.90, CHCl3) for (S)-4a with 69% ee; 1H
1.51 (d, J¼6.4 Hz, 3H), 1.81 (br s, 1H), 4.85–4.94
D
NMR (200 MHz)
d
(m, 1H), 7.26–7.42 (m, 5H); GC: CP-cyclodextrin-b-2,3,6-M-19, Inj.
250 ꢀC, Col. 100 ꢀC, Det. 220 ꢀC, (R) 24.6 min, (S) 26.1 min. (R)-4b:
(150
mL, 1.63 mmol) was added to start the reaction. The progress of
25
the reaction for 4a, 7a, 9a, and 10a was monitored by TLC, and that
for 1a–3a, 5a, 6a, and 8a was monitored by GC. For sluggish re-
41% yield; colorless oil; 99.9% ee; [
a
]
¼þ112 (c 1.00, CHCl3); 1H
D
NMR (200 MHz)
d
1.54 (d, J¼6.6 Hz, 3H), 2.07 (s, 3H), 5.88 (q,
actions, vinyl acetate (150
mL, 1.63 mmol) was added every two
J¼6.6 Hz, 1H), 7.26–7.40 (m, 5H); 13C NMR (50 MHz)
d 21.4, 22.2,
days. The reaction was stopped by filtration at an appropriate
conversion. After the solvent had been removed under reduced
pressure, alcohol and ester were separated by silica gel column
chromatography. In Chirazyme L-2-catalyzed resolution of 6a and
7a, after removal of the lipase powder, unknown white precipitate
probably originating from supporting material was formed, which
was removed by centrifugation (3000 rpm, 5 min) before column
chromatography. In the case of 1 and 2, which are very volatile, the
chromatographic fractions containing the products were found by
GC, and the solvent was not removed completely because of vola-
tility. In the case of 4a and 7a, the enantiomeric purities of both
alcohol and acetate were determined by chiral GC with a CP-cy-
72.3, 126.0, 127.8, 128.4, 141.6, 170.2; IR (neat) 3065, 3033, 2982,
2934, 1732, 1495, 1456, 1371, 1240 cmꢁ1; GC: CP-cyclodextrin-
b-
2,3,6-M-19, Inj. 250 ꢀC, Col. 100 ꢀC, Det. 220 ꢀC, (S) 21.6 min, (R)
23.6 min.
4.2.4.5. Kinetic resolution of 1-chloro-2-hexanol (5a). GC for
monitoring the reaction: PEG-20 M (3 m), Inj. 250 ꢀC, Col. 120 ꢀC,
Det. 220 ꢀC, 5b 8.7 min, 5a 10.4 min. Reaction time 35 min. (R)-5a:
13
44% yield; 4.2% ee; [
a
]
¼ꢁ0.19 (c 1.03, CHCl3); lit.25
[
a
]D¼ꢁ1.1 (c
D
2.0, CHCl3) for (R)-5a with 80% ee. (S)-5b: 24% yield; colorless oil;
13
6.7% ee; [
a
]
¼ꢁ1.33 (c 1.05, CHCl3); 1H NMR (200 MHz)
d 0.90 (t,
D
J¼6.6 Hz, 3H),1.23–1.46 (m, 4H),1.60–1.74 (m, 2H), 2.09 (s, 3H), 3.55
(dd, J¼5.4, 11.7 Hz, 1H), 3.64 (dd, J¼4.6, 11.7 Hz, 1H), 4.96–5.10 (m,
clodextrin-
b
-2,3,6-M-19 column (Varian,
4
0.25 mmꢂ25 m). In the
case of 1a–3a, 5a, and 6a, the alcohol was converted to the corre-
sponding acetate to determine the enantiomeric purities by means
of chiral GC. In the case of 8a–10a, the ester was converted to the
corresponding alcohol to determine the enantiomeric purity. That
of 8a was then determined by chiral GC, and those of 9a and 10a
were determined by HPLC using Chiralcel OB-H and Chiralpak AS-H
columns (Daicel Chemical Industries), respectively. The absolute
configurations of optically active 2b, 3a–5a, and 7a–10a were de-
termined by comparing the sign of their specific rotations with that
of the reported specific rotations. The absolute configurations of
optically active 1a and 6a were determined after conversion to the
corresponding MTPA esters.
1H); 13C NMR (50 MHz)
d 13.9, 21.0, 22.4, 27.2, 31.2, 45.7, 72.8,170.4;
IR (neat) 2959, 2934, 2862, 1747, 1468, 1435, 1373, 1236 cmꢁ1; GC:
CP-cyclodextrin-
-2,3,6-M-19, Inj. 250 ꢀC, Col. 80 ꢀC, Det. 220 ꢀC,
b
(R) 39.2 min, (S) 44.5 min.
4.2.4.6. Kinetic resolution of 2-chloro-1-cyclohexylethanol
(6a). GC for monitoring the reaction: PEG-20 M (3 m), Inj. 300 ꢀC,
Col. 145 ꢀC, Det. 220 ꢀC, 6b 15.7 min, 6a 17.2 min. Reaction time
30
1.5 h. (R)-6a: 44% yield; 62.7% ee; [
a
]
¼ꢁ6.70 (c 1.00, CHCl3). (S)-
D
30
6b: 38% yield; colorless oil; 92.3% ee; [
1H NMR (200 MHz)
0.90–1.40 (m, 6H), 1.62–1.84 (m, 5H), 2.10 (s,
3H), 3.60 (dd, J¼5.7, 11.9 Hz, 1H), 3.69 (dd, J¼4.1, 11.9 Hz, 1H), 4.83–
4.93 (m, 1H); 13C NMR (50 MHz)
20.9, 25.7, 25.8, 26.1, 28.1, 28.7,
a
]
¼ꢁ0.50 (c 1.01, CHCl3);
D
d
d
4.2.4.1. Kinetic resolution of 1-chloro-2-propanol (1a). GC for
monitoring the reaction: PEG-20 M (3 m), Inj. 250 ꢀC, Col. 100 ꢀC,
38.8, 44.3, 76.4, 170.5; IR (neat) 2929, 2854, 1734, 1451, 1371,
1228 cmꢁ1; Anal. Calcd for C10H17O2Cl: C, 58.68; H, 8.37. Found: C,

9588
T. Ema et al. / Tetrahedron 65 (2009) 9583–9591
58.59; H, 8.17. GC: CP-cyclodextrin-
b
-2,3,6-M-19, Inj. 300 ꢀC, Col.
NaOH (1 mL). The mixture was stirred at room temperature over-
120 ꢀC, Det. 220 ꢀC, (R) 33.5 min, (S) 35.4 min.
night and then acidified with 3% HCl. After the solvent had been
removed under reduced pressure, the product was extracted with
Et2O (1 mLꢂ3), and the solution was neutralized with saturated
aqueous NaHCO3 (1 mL). The mixture was dried over Na2SO4, fil-
tered, and concentrated. The product was purified by silica gel
column chromatography.
4.2.4.7. Kinetic resolution of 2-chloro-1-phenylethanol (7a).
14
Reaction time 2.5 h. (R)-7a: 50% yield; 86.6% ee; [
a]
¼ꢁ50.4 (c 1.01,
D
25
CHCl3); lit.21
[a
]
¼ꢁ56.2 (c 1.1, CHCl3) for (R)-7a with >99% ee; GC:
D
CP-cyclodextrin-
b
-2,3,6-M-19, Inj. 250 ꢀC, Col.120 ꢀC, Det. 220 ꢀC, (S)
47.6 min, (R) 50.3 min. (S)-7b: 43% yield; colorless oil; 99.2% ee;
14
[
a
]
¼þ82.8 (c 1.01, CHCl3); 1H NMR (200 MHz)
d
2.15 (s, 3H), 3.72
4.2.7. Typical procedure for the synthesis of MTPA ester of alcohols 1a
and 6a. To a mixture of alcohol (0.05 mmol), DMAP (7.6 mg,
0.062 mmol), and pyridine (0.1 mL, 1.2 mmol) in dry toluene
D
(dd, J¼4.8, 11.5 Hz, 1H), 3.80 (dd, J¼7.8, 11.5 Hz, 1H), 5.96 (dd, J¼4.8,
7.8 Hz, 1H), 7.30–7.43 (m, 5H); 13C NMR (50 MHz)
126.5,128.6,128.7,137.0,169.8; IR (neat) 3065, 3034, 2961,1747,1495,
d 21.0, 46.5, 75.0,
(0.5 mL) was added (S)-MTPA-Cl (28 mL, 0.15 mmol, acyl chloride
1456, 1429, 1373, 1229 cmꢁ1; GC: CP-cyclodextrin-
b
-2,3,6-M-19, Inj.
of (R)-MTPA) under N2. After the mixture had been stirred at room
temperature overnight, water (1 mL) was added. The product
was extracted with EtOAc (1 mLꢂ4). The mixture was washed
with 10% HCl, and then neutralized with saturated aqueous
NaHCO3 (1 mL). The mixture was dried over Na2SO4, filtered, and
concentrated. The product was purified by silica gel column
chromatography.
250 ꢀC, Col. 130 ꢀC, Det. 220 ꢀC, (R) 25.8 min, (S) 26.8 min.
4.2.4.8. Kinetic resolution of 1-cyclohexyl-1-pentanol (8a). GC
for monitoring the reaction: PEG-20 M (3 m), Inj. 300 ꢀC, Col.
145 ꢀC, Det. 220 ꢀC, 8b 10.5 min, 8a 12.9 min. Reaction time 17 h.
26
(S)-8a: 56% yield; colorless oil; 15.0% ee; [
a
]
¼ꢁ2.87 (c 1.01,
D
MeOH); lit.26
[
a
]D¼ꢁ10.2 (c 1.0, MeOH) for (S)-8a with 62% ee; 1H
NMR (200 MHz)
d
0.91 (t, J¼6.7 Hz, 3H), 1.02–1.90 (m, 18H), 3.30–
3.42 (m, 1H); GC: CP-cyclodextrin-
105 ꢀC, Det. 220 ꢀC, (S) 62.3 min, (R) 64.5 min. (R)-8b: 37% yield;
colorless oil; 24.6% ee; [
b
-2,3,6-M-19, Inj. 300 ꢀC, Col.
4.3. Oxazaborolidine-catalyzed reduction
26
a
]
¼þ6.73 (c 1.04, MeOH); 1H NMR
4.3.1. Materials and methods. Ketones 11a and 21a were prepared
by the Swern oxidation of the corresponding alcohols commercially
available. Ketones 17a,28 18a,28 20a,29 and 23a30 were prepared by
the Grignard reaction according to the literature, followed by the
Swern oxidation. Ketones 12a–16a, 19a, 22a, 24a, and 25a were
purchased. All the liquid ketones were purified by distillation be-
fore use in the oxazaborolidine-catalyzed reactions. All alcohols
and ketones 11a,31 17a,32 18a,33 20a,34 21a,35 and 23a30 were
characterized according to the literature.
D
(200 MHz)
d
0.88 (t, J¼6.8 Hz, 3H), 0.91–1.81 (m, 17H), 2.05 (s, 3H),
4.73 (q, J¼6.6 Hz, 1H); 13C NMR (50 MHz)
d 14.0, 21.1, 22.6, 26.1,
26.4, 27.6, 28.1, 29.0, 30.8, 41.2, 77.9, 170.8; IR (neat) 2929, 2855,
1732, 1450, 1370, 1243 cmꢁ1
.
4.2.4.9. Kinetic resolution of 1-phenyl-1-pentanol (9a). Reaction
23
time 34 h. (S)-9a: 53% yield; colorless oil; 75.7% ee; [
a]
¼ꢁ33.3 (c
D
1.03, CHCl3); lit.24
[
a]
¼ꢁ39.3 (c 0.57, CHCl3) for (S)-9a with 92%
24
D
ee; 1H NMR (200 MHz)
d
0.89 (t, J¼6.8 Hz, 3H), 1.20–1.52 (m, 4H),
1.65–1.90 (m, 3H), 4.67 (t, J¼6.6 Hz, 1H), 7.28–7.40 (m, 5H); HPLC:
Chiralcel OB-H, hexane/i-PrOH¼20:1, flow rate 0.5 mL/min, de-
4.3.2. Typical procedure for the Swern oxidation of alcohols. DMSO
(0.84 mL, 12 mmol) was added dropwise to a stirred solution of
oxalyl chloride (0.6 mL, 7.0 mmol) in dry CH2Cl2 (60 mL) at –78 ꢀC
under N2. After 5 min, alcohol (5.9 mmol) was added to the reaction
mixture, and stirring was continued for 30 min. Et3N (3.2 mL,
23 mmol) was added dropwise and the reaction mixture was
allowed to warm to room temperature. After 30 min, water was
added to the reaction mixture. The solution was acidified (pH 3)
and the product was extracted with CH2Cl2 three times. The
combined organic layers were washed with brine and dried
over MgSO4. The product was purified by silica gel column
chromatography.
tection 254 nm, (S) 15.5 min, (R) 18.1 min. (R)-9b: 45% yield; col-
23
orless oil; 90.1% ee;
(200 MHz)
[
a
]
¼þ76.7 (c 1.01, CHCl3); 1H NMR
D
d
0.87 (t, J¼6.7 Hz, 3H), 1.14–1.42 (m, 4H), 1.66–2.00 (m,
2H), 2.07 (s, 3H), 5.72 (t, J¼7.0 Hz, 1H), 7.26–7.40 (m, 5H); 13C NMR
(50 MHz) d 13.9, 21.3, 22.4, 27.6, 36.0, 76.1, 126.4, 127.7, 128.3, 140.7,
170.2; IR (neat) 3065, 3034, 2957, 2934, 2862, 1736, 1495, 1456,
1371, 1240 cmꢁ1
.
4.2.4.10. Kinetic
resolution
of
cyclohexylphenylmethanol
(10a). Reaction time 91 h. (S)-10a: 55% yield; 59.4% ee;
31
25
[
a
]
¼ꢁ22.5 (c 1.00, Et2O); lit.27
[
a
]
¼ꢁ36.0 (c 2.25, Et2O) for
D
D
(S)-10a with 80% ee; HPLC: Chiralpak AS-H, hexane/i-PrOH¼20:1,
4.3.2.1. Phenylacetone (11a)31. 77% yield; colorless oil; 1H NMR
flow rate 0.5 mL/min, detection 254 nm, (R) 13.9 min, (S) 15.6 min.
(300 MHz)
(m, 3H).
d 2.16 (s, 3H), 3.70 (s, 2H), 7.19–7.23 (m, 2H), 7.25–7.37
32
(R)-10b: 37% yield; colorless oil; 92.6% ee; [
a]
¼þ58.4 (c 1.01,
D
Et2O); 1H NMR (200 MHz)
d 0.82–1.46 (m, 6H), 1.58–1.93 (m, 5H),
2.06 (s, 3H), 5.48 (d, J¼8.0 Hz, 1H), 7.25–7.38 (m, 5H); 13C NMR
4.3.2.2. 1,4-Diphenyl-2-butanone (17a)32. 55% yield; white
solid; mp 44–46 ꢀC; 1H NMR (500 MHz)
(50 MHz)
d
21.2, 25.8, 26.3, 29.0, 42.9, 80.2, 127.1, 127.6, 128.1, 139.6,
d
2.77 (t, J¼7.8 Hz, 2H), 2.87
170.3; IR (neat) 3031, 2928, 2852, 1729, 1370, 1237 cmꢁ1
.
(t, J¼7.8 Hz, 2H), 3.67 (s, 2H), 7.12–7.20 (m, 5H), 7.24–7.33 (m, 5H).
4.3.2.3. Benzyl cyclohexyl ketone (18a)33. 44% yield; colorless
4.2.5. Typical procedure for the acetylation of alcohol. To a mixture
of alcohol (0.15 mmol) and DMAP (22 mg, 0.18 mmol) in dry Et2O
oil; 1H NMR (500 MHz)
d 1.17–1.40 (m, 5H), 1.64–1.84 (m, 5H), 2.46
(1 mL) was added acetic anhydride (60
m
L, 0.63 mmol) under N2.
(tt, J¼3.5, 11.5 Hz, 1H), 3.73 (s, 2H), 7.17–7.33 (m, 5H).
The mixture was stirred at room temperature for a few hours and
then acidified with 3% HCl. The product was extracted with Et2O
(1 mLꢂ3), and the solution was neutralized with saturated aqueous
NaHCO3 (1 mL). The mixture was dried over Na2SO4, filtered, and
concentrated. The product was purified by silica gel column
chromatography.
4.3.2.4. 1-Phenyl-3-heptanone (20a)34. 62% yield; colorless oil;
1H NMR (200 MHz)
d
0.88 (t, J¼7.2 Hz, 3H), 1.28 (sext, J¼7.2 Hz, 2H),
1.53 (quint, J¼7.2 Hz, 2H), 2.38 (t, J¼7.2 Hz, 2H), 2.68–2.76 (m, 2H),
2.86–2.94 (m, 2H), 7.16–7.32 (m, 5H).
4.3.2.5. n-Butyl cyclohexyl ketone (21a)35. 88% yield; colorless
4.2.6. Typical procedure for the hydrolysis of acetate. To a solution of
acetate (0.20 mmol) in EtOH (1 mL) was added 1.0 M aqueous
oil; 1H NMR (200 MHz)
2.31–2.33 (m, 1H), 2.42 (t, J¼7.3 Hz, 2H).
d
0.89 (t, J¼7.1 Hz, 3H), 1.20–1.84 (m, 14H),

T. Ema et al. / Tetrahedron 65 (2009) 9583–9591
9589
4.3.2.6. 1-Cyclohexyl-3-phenyl-1-propanone (23a)30. 91% yield;
colorless oil; 1H NMR (500 MHz)
1.15–1.36 (m, 5H), 1.64–1.82 (m,
1.83 (m, 2H), 2.65–2.70 (m, 1H), 2.74–2.79 (m, 1H), 3.83 (sext,
d
J¼6.0 Hz, 1H), 7.18–7.21 (m, 3H), 7.28–7.30 (m, 2H); 13C NMR
5H), 2.28–2.34 (m, 1H), 2.75 (t, J¼7.6 Hz, 2H), 2.88 (t, J¼7.6 Hz, 2H),
(150 MHz) d 23.6, 32.1, 40.8, 67.4, 125.8, 128.3, 142.0; IR (KBr) 3364,
7.17–7.20 (m, 3H), 7.26–7.29 (m, 2H).
3024, 2963, 2924, 2862, 1605, 1497, 1458, 1373, 1312, 1180, 1126,
1057, 957, 856, 748, 702 cmꢁ1; GC: CP-cyclodextrin-
b-2,3,6-M-19,
4.3.3. General procedure for the asymmetric reduction of ketones. A
Inj. 300 ꢀC, Col. 110 ꢀC, Det. 220 ꢀC, (S) 37.9 min, (R) 38.8 min.
20 mL Schlenk tube was charged with (S)-a,a-diphenyl-2-pyrroli-
dinemethanol (55.5 mg, 0.22 mmol) and dry toluene (2 mL) under
Ar. The suspended solution was heated at 50 ꢀC to afford a colorless
solution, which was cooled to room temperature. To the solution
4.3.3.4. Reductionofcyclohexylmethylketone(14a). Reaction time
26
13 h. (R)-14b: 36% yield; colorless oil; 72.6% ee; [
0.515, CHCl3); lit.23
1H NMR (500 MHz)
a
]
¼ꢁ2.91 (c
D
[
a
d
]D¼ꢁ3.3 (c 0.4, CHCl3) for (R)-14b with 80% ee;
was added trimethylboroxine (20
mL, 0.14 mmol). After the solution
0.93–1.05 (m, 2H), 1.16 (d, J¼6.5 Hz, 3H), 1.17–
had been stirred at room temperature for 2 h, the solution was
concentrated to 1 mL by distillation. To the reaction mixture was
added dry toluene (1 mL), and then the solution was concentrated
to 1 mL again. After this cycle had been repeated three times, the
remaining toluene was removed in vacuo to give (S)-5,5-diphenyl-
2-methyl-3,4-propano-1,3,2-oxazaborolidine as a colorless solid:
1.31 (m, 5H), 1.65–1.84 (m, 5H), 3.54 (quint, J¼6.5 Hz, 1H); 13C NMR
(125 MHz)
d 20.2, 26.1, 26.2, 26.4, 28.3, 28.6, 45.0, 72.0; IR (neat)
3364, 2970, 2924, 2851, 2669,1447,1373,1312,1265,1188,1126,1088,
1061, 1042, 999, 937, 891, 833, 733 cmꢁ1; the corresponding acetate:
1H NMR (500 MHz)
d
0.87–1.76 (m, 11H), 1.16 (d, J¼6.5 Hz, 3H), 2.03
(s, 3H), 4.72 (quint, J¼6.5 Hz,1H); GC: CP-cyclodextrin-
b-2,3,6-M-19,
1H NMR (500 MHz)
d
0.42 (s, 3H), 0.82–0.90 (m, 1H), 1.61–1.67 (m,
Inj. 250 ꢀC, Col. 100 ꢀC, Det. 220 ꢀC, (S) 18.2 min, (R) 20.3 min.
1H), 1.77–1.84 (m, 2H), 3.05–3.10 (m, 1H), 3.36–3.41 (m, 1H), 4.39
(dd, J¼6.0, 9.5 Hz, 1H), 7.22–7.39 (m, 8H), 7.57 (d, J¼7.5 Hz, 2H).7a To
a solution of oxazaborolidine in dry THF (2 mL) was added
4.3.3.5. Reduction of acetophenone (15a). Reaction time 13 h.
26
(R)-15b: 58% yield; colorless oil; 98.0% ee; [
a
]
¼þ75.1 (c 1.05,
D
23
H3B$SMe2 (57
m
L, 0.6 mmol), and the solution was stirred at 30 ꢀC
CHCl3); lit.24
[
a
]
¼ꢁ43.7 (c 0.90, CHCl3) for (S)-15b with 69% ee;
D
for 15 min. A solution of ketone (1.0 mmol) in dry THF (1 mL) was
added via a syringe pump over 2 h, and then the reaction mixture
was stirred at 30 ꢀC for 12–13 h. To the mixture was added MeOH
(1.5 mL), and then the solvent was removed under reduced pres-
sure. The product was purified by silica gel column chromatogra-
phy. In the case of 12b and 14b, the alcohol was converted to the
corresponding acetate to determine the enantiomeric purity. En-
antiomeric excesses of 12b (acetate form), 13b, 14b (acetate form),
15b, and 21b were determined by chiral GC, and those of 11b, 16b–
20b, and 22b–25b were determined by chiral HPLC. The absolute
configurations of optically active 11b–15b, 19b, and 21b–25b were
determined by comparing the sign of their specific rotations with
that of the reported values. The absolute configurations of optically
active 16b–18b, and 20b were determined by retention times of
HPLC as reported previously.
1H NMR (500 MHz)
d
1.51 (d, J¼6.5 Hz, 3H), 1.80 (br s, 1H), 4.91 (q,
J¼6.5 Hz, 1H), 7.26–7.40 (m, 5H); 13C NMR (125 MHz)
d 25.1, 70.4,
125.4, 127.4, 128.5, 145.8; IR (neat) 3364, 3086, 3063, 3021, 2970,
2924, 2878, 1952, 1882, 1805, 1605, 1489, 1450, 1366, 1304, 1204,
1080, 1011, 895, 764, 702 cmꢁ1; GC: CP-cyclodextrin-
b-2,3,6-M-19,
Inj. 250 ꢀC, Col. 97 ꢀC, Det. 220 ꢀC, (R) 24.9 min, (S) 29.2 min.
4.3.3.6. Reduction of 1-phenyl-2-hexanone (16a). Reaction time
28
13 h. (S)-16b: 43% yield; colorless oil; 36.0% ee; [
a]
¼þ6.3 (c 1.0,
D
CHCl3); 1H NMR (500 MHz)
d
0.92 (t, J¼6.8 Hz, 3H),1.30–1.57 (m, 7H),
2.65 (dd, J¼8.3, 13.8 Hz, 1H), 2.84 (dd, J¼4.3, 13.8 Hz, 1H), 3.81–3.85
(m, 1H), 7.21–7.26 (m, 3H), 7.30–7.33 (m, 2H); 13C NMR (125 MHz)
d
14.0, 22.7, 27.9, 36.5, 44.0, 72.7, 126.4, 128.5, 129.4, 138.7; IR (neat)
3395, 3063, 3028, 2932, 2858, 1601, 1497, 1454,1126, 1080,1030, 745,
698 cmꢁ1; HPLC: Chiralcel OD-H, hexane/i-PrOH¼99.5:0.5, flow rate
1.0 mL/min, detection 254 nm, (S) 12.2 min, (R) 15.8 min.28
4.3.3.1. Reduction of phenylacetone (11a). Reaction time 12.5 h.
28
(R)-11b: 76% yield; colorless oil; 50.7% ee; [
a
]
¼ꢁ20.7 (c 1.08,
4.3.3.7. Reduction of 1,4-diphenyl-2-butanone (17a). Reaction
D
27
CHCl3); lit.36
[
a
]
¼þ41.8 (c 2.15, CHCl3) for (S)-11b with >95% ee;
time 13 h. (S)-17b: 26% yield; white solid; mp 38–40 ꢀC (lit.28 43–
D
1H NMR (500 MHz)
d
1.25 (d, J¼6.1 Hz, 3H), 1.51 (br s, 1H), 2.70 (dd,
44 ꢀC); 39.5% ee; [
a
]
¼ꢁ8.3 (c 1.2, CHCl3); 1H NMR (500 MHz)
29
D
J¼8.0, 13.5 Hz,1H), 2.80 (dd, J¼5.0, 13.5 Hz,1H), 4.03 (sext, J¼6.1 Hz,
d
1.51 (d, J¼4.0 Hz, 1H), 1.82–1.89 (m, 2H), 2.67–2.75 (m, 2H), 2.83–
1H), 7.20–7.26 (m, 3H), 7.31–7.33 (m, 2H); 13C NMR (150 MHz)
2.88 (m, 2H), 3.83–3.87 (m, 1H), 7.17–7.33 (m, 10H); 13C NMR
(125 MHz) 32.1, 38.4, 44.1, 71.9, 125.8, 126.5, 128.37, 128.43, 128.6,
d
22.6, 45.7, 68.8, 126.5, 128.6, 129.4, 138.6; IR (neat) 3364, 3063,
d
3024, 2970, 2932, 1605, 1497, 1450, 1373, 1312, 1196, 1111, 1080,
1065, 941, 841, 741, 702 cmꢁ1; HPLC: Chiralcel AD-H, hexane/
i-PrOH¼20:1, flow rate 0.3 mL/min, detection 254 nm, (S) 26.2 min,
(R) 27.9 min.
129.4, 138.3, 142.0; IR (KBr) 3302, 3063, 3025, 2928, 1601, 1497,
1454, 1084, 1030, 926, 856, 748, 698 cmꢁ1; HPLC: Chiralcel OD-H,
hexane/i-PrOH¼95:5, flow rate 1.0 mL/min, detection 254 nm, (S)
10.8 min, (R) 15.5 min.28
4.3.3.2. Reduction of 2-hexanone (12a). Reaction time 13 h. (R)-
4.3.3.8. Reduction of benzyl cyclohexyl ketone (18a). Reaction time
13 h. (R)-18b: 61% yield; white solid; mp 58–60 ꢀC (lit.28 55–57 ꢀC);
20
12b: 77% yield; colorless oil; 64.5% ee; [
a
]
¼ꢁ12.4 (c 1.09, CHCl3);
D
25
28
1
lit.37
[a
]
¼þ10.39 (CHCl3) for (S)-12b with 96% ee; 1H NMR
55.9% ee; [
a
]
¼þ21.8 (c 0.73, CHCl3); H NMR (500 MHz)
d 1.06–
D
D
(500 MHz)
d
0.91 (t, J¼7.0 Hz, 3H), 1.19 (d, J¼6.1 Hz, 3H), 1.18–1.46
1.31 (m, 5H), 1.40–1.46 (m, 2H), 1.68–1.93 (m, 5H), 2.60 (dd, J¼9.4,
13.5 Hz, 1H), 2.89 (dd, J¼3.5, 13.5 Hz, 1H), 3.57–3.60 (m, 1H), 7.22–
(m, 7H), 3.79 (sext, J¼6.1 Hz, 1H); 13C NMR (125 MHz)
d 13.9, 22.6,
23.3, 27.9, 38.9, 67.9; IR (neat) 3348, 2963, 2932, 2862, 1458, 1373,
7.33 (m, 5H); 13C NMR (125 MHz)
d 26.1, 26.3, 26.5, 27.9, 29.3, 40.7,
1327, 1146, 1111, 1053, 1018, 941, 841 cmꢁ1; the corresponding ace-
43.1, 76.8, 126.2, 128.4, 129.3, 139.2; IR (KBr) 3317, 3028, 2928, 2889,
2855, 1493, 1447, 1404, 1339, 1292, 1188, 1084, 1061, 1034, 1003, 748,
698 cmꢁ1; HPLC: Chiralcel OD-H, hexane/i-PrOH¼99.6:0.4, flow rate
1.0 mL/min, detection 254 nm, (R) 16.7 min, (S) 23.5 min.28
tate: 1H NMR (200 MHz)
d
0.89 (t, J¼6.6 Hz, 3H), 1.20 (d, J¼6.2 Hz,
3H), 1.20–1.40 (m, 4H), 1.40–1.64 (m, 2H), 2.03 (s, 3H), 4.89 (sext,
J¼6.2 Hz, 1H); GC: CP-cyclodextrin-
b
-2,3,6-M-19, Inj. 250 ꢀC, Col.
85 ꢀC, Det. 220 ꢀC, (S) 6.36 min, (R) 7.16 min.
4.3.3.9. Reduction of benzyl phenyl ketone (19a). Reaction time
12.5 h. (R)-19b: 22% yield; white solid; mp 67–68 ꢀC (lit.28 64–
4.3.3.3. Reduction of benzylacetone (13a). Reaction time 12.5 h.
25
32
25
(R)-13b: 46% yield; white solid; mp 49 ꢀC; 67.7% ee; [
a
]
¼ꢁ12.6 (c
66 ꢀC); 90.4% ee; [
a
]
¼ꢁ51.6 (c 0.940, EtOH); lit.39
[
a
]
¼þ54.8
D
D
D
0.532, CHCl3); lit.38
[a
]
¼ꢁ1.19 (c 1.13, CHCl3) for (R)-13b with 6%
(c 3.52, EtOH) for (S)-19b with 98% ee; 1H NMR (500 MHz)
d
1.56 (br
15
D
ee; 1H NMR (600 MHz)
d
1.24 (d, J¼6.0 Hz, 3H), 1.34 (br s, 1H), 1.73–
s,1H), 2.99 (dd, J¼8.5,13.8 Hz,1H), 3.05 (dd, J¼5.0,13.8 Hz,1H), 4.91

9590
T. Ema et al. / Tetrahedron 65 (2009) 9583–9591
29
25
(dd, J¼5.0, 8.5 Hz, 1H), 7.20–7.36 (m, 10H); 13C NMR (125 MHz)
66 ꢀC); 59.3% ee; [
a]
¼ꢁ16.4 (c 1.04, Et2O); lit.27
[
a
]
¼–36.0 (c
D
D
d
46.0, 75.3, 125.9, 126.6, 127.6, 128.4, 128.5, 129.5, 138.0, 143.8; IR
2.25, Et2O) for (S)-25b with 80% ee; 1H NMR (500 MHz)
d
0.90–1.27
(KBr) 3333, 3024, 2916, 2862, 1497, 1454, 1072, 1022, 760, 745,
698 cmꢁ1; HPLC: Chiralcel OD-H, hexane/i-PrOH¼9:1, flow rate
0.5 mL/min, detection 254 nm, (R) 17.0 min, (S) 19.4 min.
(m, 5H), 1.36–1.40 (m, 1H), 1.58–1.68 (m, 3H), 1.75–1.80 (m, 2H),
1.97–2.00 (m, 1H), 4.37 (dd, J¼3.3, 7.3 Hz, 1H), 7.25–7.35 (m, 5H);
13C NMR (150 MHz)
d 25.96, 26.0, 26.4, 28.8, 29.2, 44.9, 79.3, 126.6,
127.4, 128.1, 143.6; IR (KBr) 3348, 2970, 2924, 2855, 1450, 1373,
1312, 1265, 1188, 1126, 1096, 1065, 1042, 941, 887 cmꢁ1; HPLC:
Chiralcel OD-H, hexane/i-PrOH¼9:1, flow rate 0.3 mL/min, de-
tection 254 nm, (S) 18.2 min, (R) 20.3 min.
4.3.3.10. Reduction of 1-phenyl-3-heptanone (20a). Reaction
34
time 13 h. (R)-20b: 68% yield; colorless oil; 5.2% ee; [
a
]
¼ꢁ1.53 (c
D
25
1.05, CHCl3); lit.40
[a
]
¼ꢁ11.6 (c 3.9, CHCl3) for (R)-20b with 97%
D
ee; 1H NMR (500 MHz)
d
0.91 (t, J¼7.0 Hz, 3H), 1.26–1.52 (m, 6H),
1.54 (br s, 1H), 1.70–1.84 (m, 2H), 2.65–2.71 (m, 1H), 2.77–2.83 (m,
Acknowledgements
1H), 3.61–3.66 (m, 1H), 7.17–7.21 (m, 3H), 7.27–7.30 (m, 2H); 13C
NMR (125 MHz) d 14.0, 22.7, 27.8, 32.0, 37.3, 39.1, 71.4, 125.7, 128.35,
This work was supported in part by a Grant-in-Aid for Scientific
Research from Japan Society for the Promotion of Science (JSPS). We
are grateful to the SC-NMR Laboratory of Okayama University for
the measurement of NMR spectra.
128.37, 142.2; IR (neat) 3364, 3063, 3028, 2932, 2858, 1940, 1605,
1558, 1497, 1454, 1126, 1042, 999, 934, 903, 748, 698 cmꢁ1; HPLC:
Chiralcel OD-H, hexane/i-PrOH¼20:1, flow rate 0.5 mL/min, de-
tection 254 nm, (R) 15.7 min, (S) 21.4 min.40
Supplementary data
4.3.3.11. Reduction of n-butyl cyclohexyl ketone (21a). Reaction
32
time 13 h. (R)-21b: 97% yield; colorless oil; 25.8% ee; [
(c 1.06, MeOH); lit.26
ee; 1H NMR (500 MHz)
3.33–3.37 (m, 1H); 13C NMR (125 MHz)
27.7, 28.1, 29.3, 33.8, 43.6, 76.2; IR (neat) 3364, 2924, 2855, 1450,
a
]
¼þ5.83
D
Detailed explanation of Eq. 1, detailed data for the lipase-cata-
lyzed kinetic resolution, anda correlationplotfor thehydrosilylation
of ketones reported by other researchers.42 The supplementary data
associated with this article can be found in the on-line version at
doi:10.1016/j.tet.2009.09.058.
[
a
]D¼ꢁ10.2 (c 1.0, MeOH) for (S)-21b with 62%
0.91 (t, J¼7.0 Hz, 3H), 0.96–1.81 (m, 18H),
14.0, 22.8, 26.2, 26.4, 26.6,
d
d
895 cmꢁ1
; GC: CP-cyclodextrin-b
-2,3,6-M-19, Inj. 300 ꢀC, Col.
105 ꢀC, Det. 220 ꢀC, (S) 59.1 min, (R) 60.9 min.
References and notes
1. (a) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, 3rd ed.; Plenum:
New York, NY, 1990; Chapter 4 in Part A: Structure and Mechanisms; (b)
Gawley, R. E.; Aube´, J. Principles of Asymmetric Synthesis; Elsevier: Oxford,
1996; (c) Smith, M. B.; March, J. March’s Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure, 5th ed.; John Wiley & Sons: New York, NY, 2001;
Chapter 6.
4.3.3.12. Reduction of valerophenone (22a). Reaction time
31
12.5 h. (R)-22b: 53% yield; colorless oil; 95.6% ee; [
a
]
¼þ39.2 (c
D
0.536, CHCl3); lit.24
92% ee; 1H NMR (500 MHz)
4H), 1.60–1.67 (m, 1H), 1.69–1.76 (m, 2H), 4.58 (t, J¼6.8 Hz, 1H),
7.17–7.29 (m, 5H); 13C NMR (125 MHz)
14.0, 22.6, 28.0, 38.8, 74.7,
[
a]
¼ꢁ39.3 (c 0.57, CHCl3) for (S)-22b with
24
D
d
0.81 (t, J¼7.3 Hz, 3H), 1.15–1.35 (m,
2. Taft, R. W., Jr. In Steric Effects in Organic Chemistry; Newman, M. S., Ed.; John
Wiley & Sons: New York, NY, 1956.
d
125.9, 127.5, 128.4, 144.9; IR (neat) 3364, 3063, 3032, 2932, 2862,
1944, 1882, 1805, 1605, 1458, 1335, 1204, 1111, 1034, 910, 756,
702 cmꢁ1; HPLC: Chiralcel OB-H, hexane/i-PrOH¼20:1, flow rate
0.3 mL/min, detection 254 nm, (S) 23.8 min, (R) 27.3 min.
3. (a) Ema, T.; Kobayashi, J.; Maeno, S.; Sakai, T.; Utaka, M. Bull. Chem. Soc. Jpn.
1998, 71, 443–453; (b) Ema, T.; Jittani, M.; Furuie, K.; Utaka, M.; Sakai, T. J. Org.
Chem. 2002, 67, 2144–2151; (c) Ema, T.; Fujii, T.; Ozaki, M.; Korenaga, T.; Sakai, T.
Chem. Commun. 2005, 4650–4651.
4. The E value is the enantiomeric ratio defined by the ratio of the kinetic con-
stants of the two enantiomers, k/k0. (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.;
Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237–6240;
(b) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104,
7294–7299.
5. (a) Wong, C.-H.; Whitesides, G. M. Enzymes in Synthetic Organic Chemistry;
Elsevier: Oxford, 1994; (b) Enzymatic Reactions in Organic Media; Koskinen, A.
M. P., Klibanov, A. M., Eds.; Blackie Academic: Glasgow, 1996; (c) Bornscheuer,
U. T.; Kazlauskas, R. J. Hydrolases in Organic Synthesis; Wiley-VCH: Weinheim,
1999; (d) Industrial Biotransformations, 2nd ed.; Liese, A., Seelbach, K.,
Wandrey, C., Eds.; Wiley-VCH: Weinheim, 2006.
4.3.3.13. Reduction
of
1-cyclohexyl-3-phenyl-1-propanone
(23a). Reaction time 13 h. (R)-23b: 34% yield; white solid; mp 75–
77 ꢀC (lit.41 96 ꢀC, The discrepancy in the melting point may be due
to the difference in the enantiomeric purity.); 9.3% ee;
32
20
[
a]
¼þ5.89 (c 1.04, CHCl3); lit.41
[
a
]
¼þ28.7 (c 0.91, CHCl3) for
D
D
(R)-23b with >95% ee; 1H NMR (500 MHz)
d 0.98–1.28 (m, 5H),
1.31–1.38 (m, 2H), 1.65–1.83 (m, 7H), 2.62–2.68 (m, 1H), 2.81–2.87
6. For a review, see: Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–
2012.
(m, 1H), 3.39 (q, J¼4.2 Hz, 1H), 7.17–7.22 (m, 3H), 7.27–7.30 (m, 2H);
13C NMR (125 MHz)
d 26.2, 26.3, 26.5, 27.8, 29.1, 32.3, 35.9, 43.8,
7. (a) Mathre, D. J.; Jones, T. K.; Xavier, L. C.; Blacklock, T. J.; Reamer, R. A.; Mohan,
J. J.; Jones, E. T. T.; Hoogsteen, K.; Baum, M. W.; Grabowski, E. J. J. J. Org. Chem.
1991, 56, 751–762; (b) Mathre, D. J.; Thompson, A. S.; Douglas, A. W.; Hoogs-
teen, K.; Carroll, J. D.; Corley, E. G.; Grabowski, E. J. J. J. Org. Chem. 1993, 58,
2880–2888; (c) Stone, G. B. Tetrahedron: Asymmetry 1994, 5, 465–472; (d)
Douglas, A. W.; Tschaen, D. M.; Reamer, R. A.; Shi, Y.-J. Tetrahedron: Asymmetry
1996, 7, 1303–1308; (e) Price, M. D.; Sui, J. K.; Kurth, M. J.; Schore, N. E. J. Org.
Chem. 2002, 67, 8086–8089; (f) Liu, H.; Du, D.-M.; Xu, J. Helv. Chim. Acta 2006,
89, 1067–1074.
75.6, 125.7, 128.3, 128.4, 142.4; IR (KBr) 3206, 3024, 2912, 2851,
1605, 1497, 1454, 1346, 1319, 1265, 1088, 1061, 1030, 961, 918, 891,
745, 694 cmꢁ1; HPLC: Chiralcel AD-H, hexane/i-PrOH¼9:1, flow
rate 0.5 mL/min, detection 254 nm, (S) 12.1 min, (R) 13.1 min.
4.3.3.14. Reduction of 1,3-diphenyl-1-propanone (24a). Reaction
time 13 h. (R)-24b: 52% yield; white solid; mp 50 ꢀC; 93.3% ee;
´
8. Izquierdo, I.; Plaza, M. T.; Rodrıguez, M.; Tamayo, J. Tetrahedron: Asymmetry
2000, 11, 1749–1756.
9. Nunno, L. D.; Franchini, C.; Nacci, A.; Scilimati, A.; Sinicropi, M. S. Tetrahedron:
Asymmetry 1999, 10, 1913–1926.
26
20
[
a]
¼þ27.3 (c 0.506, CHCl3); lit.38
[a
]
¼þ13.4 (c 0.22, CHCl3) for
D
D
(R)-24b with 47% ee; 1H NMR (600 MHz)
d 1.83 (br s, 1H), 2.01–2.07
10. Meyers, A. I.; Ford, M. E. J. Org. Chem. 1976, 41, 1735–1742.
11. Hayashi, T.; Hirate, S.; Kitayama, K.; Tsuji, H.; Torii, A.; Uozumi, Y. J. Org. Chem.
2001, 66, 1441–1449.
12. Iranpoor, N.; Zeynizadeh, B. J. Chem. Res., Synop. 1998, 582–583.
13. Pa`mies, O.; Ba¨ckvall, J.-E. J. Org. Chem. 2002, 67, 9006–9010.
14. Schleppnik, A. A. 2650602 Ger. Offen. 1977, .
15. Adam, W.; Lukacs, Z.; Viebach, K.; Humpf, H.-U.; Saha-Mo¨ller, C. R.; Schreier, P.
J. Org. Chem. 2000, 65, 186–190.
16. Ramsden, C. A.; Rose, H. L. Synlett 1997, 27–28.
17. Nishiyama, A.; Sugawa, T.; Manabe, H.; Inoue, K.; Yoshida, N. PCT Int. Appl. WO
96/23756 1996.
(m, 1H), 2.11–2.17 (m, 1H), 2.65–2.70 (m, 1H), 2.73–2.78 (m, 1H),
4.70 (t, J¼6.6 Hz,1H), 7.17–7.36 (m,10H); 13C NMR (150 MHz)
d 32.0,
40.4, 73.8, 125.8, 125.9, 127.5, 128.3, 128.38, 128.43, 141.7, 144.5; IR
(KBr) 3271, 3086, 3063, 3024, 2939, 2924, 2878, 2862, 1952, 1882,
1605, 1489, 1450, 1350, 1312, 1281, 1211, 1150, 1065, 1018, 1003, 934,
764, 733, 694 cmꢁ1; HPLC: Chiralcel OD-H, hexane/i-PrOH¼95:5,
flow rate 0.5 mL/min, detection 254 nm, (S) 16.1 min, (R) 18.2 min.
4.3.3.15. Reduction of cyclohexyl phenyl ketone (25a). Reaction
time 13 h. (S)-25b: 74% yield; white solid; mp 62–65 ꢀC (lit.27
18. Ema, T.; Sugiyama, Y.; Fukumoto, M.; Moriya, H.; Cui, J.-N.; Sakai, T.; Utaka, M.
J. Org. Chem. 1998, 63, 4996–5000.

T. Ema et al. / Tetrahedron 65 (2009) 9583–9591
9591
19. House, H. O.; Fischer, W. F., Jr.; Gall, M.; McLaughlin, T. E.; Peet, N. P. J. Org. Chem.
1971, 36, 3429–3437.
20. Shapiro, S. L.; Soloway, H.; Freedman, L. J. Am. Chem. Soc. 1958, 80, 6060–
6064.
21. Kamal, A.; Sandbhor, M.; Ramana, K. V. Tetrahedron: Asymmetry 2002, 13, 815–
820.
22. Screttas, C. G.; Steele, B. R. J. Org. Chem. 1989, 54, 1013–1017.
23. Ileby, N.; Kuzma, M.; Heggvik, L. R.; Sørbye, K.; Fiksdahl, A. Tetrahedron:
Asymmetry 1997, 8, 2193–2198.
24. Salvi, N. A.; Chattopadhyay, S. Tetrahedron 2001, 57, 2833–2839.
25. Sakai, T.; Wada, K.; Murakami, T.; Kohra, K.; Imajo, N.; Ooga, Y.; Tsuboi, S.;
Takeda, A.; Utaka, M. Bull. Chem. Soc. Jpn. 1992, 65, 631–638.
26. Weber, B.; Seebach, D. Tetrahedron 1994, 50, 7473–7484.
27. Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P. J. Org. Chem.
1996, 61, 8229–8243.
30. Taylor, S. K.; Bischoff, D. S.; Blankespoor, C. L.; Deck, P. A.; Harvey, S. M.;
Johnson, P. L.; Marolewski, A. E.; Mork, S. W.; Motry, D. H.; Eenenaam, R. V.
J. Org. Chem. 1990, 55, 4202–4207.
31. Li, L.; Cai, P.; Guo, Q.; Xue, S. J. Org. Chem. 2008, 73, 3516–3522.
32. Angle, S. R.; Neitzel, M. L. J. Org. Chem. 2000, 65, 6458–6461.
33. Inaba, S.; Rieke, R. D. J. Org. Chem. 1985, 50, 1373–1381.
34. Richey, H. G., Jr.; Erickson, W. F. J. Org. Chem. 1983, 48, 4349–4357.
35. Crawford, J. J.; Henderson, K. W.; Kerr, W. J. Org. Lett. 2006, 8, 5073–5076.
36. Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1991, 113, 6129–6139.
37. Keinan, E.; Hafeli, E. K.; Seth, K. K.; Lamed, R. J. Am. Chem. Soc. 1986, 108, 162–169.
38. Node, M.; Nishide, K.; Shigeta, Y.; Shiraki, H.; Obata, K. J. Am. Chem. Soc. 2000,
122, 1927–1936.
39. Yamamoto, K.; Fukushima, H.; Nakazaki, M. J. Chem. Soc., Chem. Commun. 1984,
1490–1491.
40. Sumida, S.; Ohga, M.; Mitani, J.; Nokami, J. J. Am. Chem. Soc. 2000, 122,1310–1313.
41. Beckmann, E.; Desai, V.; Hoppe, D. Synlett 2004, 2275–2280.
42. Wu, J.; Ji, J.-X.; Chan, A. S. C. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 3570–3575.
28. Blakemore, P. R.; Marsden, S. P.; Vater, H. D. Org. Lett. 2006, 8, 773–776.
29. Liang, X.; Bols, M. J. Chem. Soc., Perkin Trans. 1 2002, 503–508.