Kinetic resolution of diarylmethanols using a mutated variant of lipase CALB

Article abstract of DOI:10.1016/j.tet.2012.06.040

An enzymatic kinetic resolution of diarylmethanols via acylation has been developed. This was achieved by the use of a mutated variant of CALB that accepts larger substrates compared to the wild type. By the use of diarylmethanols with two differently sized aryl groups, enantioselective transformations were achieved. A larger size-difference led to a higher enantioselectivity. In addition, substrates with electronically different aryl groups, such as phenyl and pyridyl, also gave an enantioselective reaction. The highest E value was observed with a substrate where steric and electronic effects were combined.

Full text of DOI:10.1016/j.tet.2012.06.040

Tetrahedron 68 (2012) 7613e7618
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Kinetic resolution of diarylmethanols using a mutated variant of lipase CALB
a
b
b
a,
*
€
€
Karin Engstrom , Michaela Vallin , Karl Hult , Jan-E. Backvall
a Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
b Department of Biochemistry, School of Biotechnology, Royal Institute of Technology (KTH), AlbaNova University Center, SE-106 91 Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
An enzymatic kinetic resolution of diarylmethanols via acylation has been developed. This was achieved
by the use of a mutated variant of CALB that accepts larger substrates compared to the wild type. By the
use of diarylmethanols with two differently sized aryl groups, enantioselective transformations were
achieved. A larger size-difference led to a higher enantioselectivity. In addition, substrates with elec-
tronically different aryl groups, such as phenyl and pyridyl, also gave an enantioselective reaction. The
highest E value was observed with a substrate where steric and electronic effects were combined.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 9 March 2012
Received in revised form 30 May 2012
Accepted 8 June 2012
Available online 15 June 2012
Keywords:
Kinetic resolution
Diarylmethanols
Biotransformation
Candida antarctica lipase B
Enzymatic resolution
1. Introduction
drawback, the substrate specificity. Even though the enzyme ac-
cepts substrates where one of the substituents on the alcohols is
Enantiomerically enriched diarylmethanols are important con-
stituents and precursors of biologically active compounds. For
example, they are versatile building blocks in the synthesis of
compounds with antihistaminic, antiarrhythmic, diuretic, anti-
depressive, laxative, local-anaesthetic and anticholinergic activi-
ties.1 Because of their use as intermediates for obtaining
pharmaceutically relevant products, further development of
enantioselective catalytic methods for preparing diarylmethanols
are of importance. The reported methods for enantioselective
synthesis of diarylmethanols have mainly employed one of two
different approaches: (i) arylation of aldehydes by addition of or-
ganometallic compounds1 and (ii) reduction of diaryl ketones via
transfer hydrogenation2e4 or via a biocatalytic transformation.5,6
The latter biocatalytic reductions involve the use of bakers yeast5
or a ketoreductase.6
Another biocatalytic reaction commonly employed in the
preparation of enantiomerically enriched secondary alcohols, apart
from the reduction of ketones, is kinetic resolution (KR). In KR, one
of the enantiomers of the substrate alcohol is selectively trans-
formed by e.g., an enzyme, leaving the other enantiomer un-
touched. One of the most widely used enzymes for these reactions
is Candida antarctica lipase B (CALB).7,8 This enzyme shows excel-
lent enantioselectivity for many substrates, but it has one
relatively large, the other group is limited to a rather small group.
This limits the substrate scope, and as a result diarylmethanols are
not accepted as substrates by CALB.
The limitation in the substrate acceptance is due to the size of
the so-called stereospecificity pocket of CALB. In its catalytically
active binding mode, the fast-reacting enantiomer is placing its
medium-sized substituent in the stereospecificity pocket and its
large substituent towards the active site entrance (Fig. 1A).9 The
side chains of three residues, Thr42, Ser47 and Trp104 set the steric
limits of this pocket, where Trp104 in the bottom of this pocket
blocks it for larger groups than ethyl. This is the reason for the
excellent enantioselectivity for substrates with differently sized
groups attached to the alcohol, as well as the reason for the limi-
tations in substrate scope.
A mutated variant of CALB where Trp104, the residue in the
bottom of the stereospecificity pocket, was changed into an alanine,
was published in 2005.10,11 Since the large tryptophan (W) was
changed into the much smaller alanine (A), the W104A variant
accepts substrates with larger side-chains,12 as was also predicted
by modelling.13 Interestingly, substrates such as 1-phenylethanol
actually showed (S)-selectivity. This enantiopreference is opposite
to that of CALB wild type, which is a result of the substrate being
positioned the other way around, i.e., with the methyl group to-
wards the opening and with the phenyl group in the stereospeci-
ficity pocket (Fig. 1B). This was used in an (S)-selective dynamic
kinetic resolution of 1-phenylalkanols.14
* Corresponding author. Tel.: þ46 8 6747178; fax: þ46 8 154908; e-mail address:
€
jeb@organ.su.se (J.-E. Backvall).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.040

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K. Engstrom et al. / Tetrahedron 68 (2012) 7613e7618
7614
A
B
C
Fig. 1. The positioning of the substrate in the catalytically active binding mode. A. CALB
wild type: the large group is positioned towards the active site entrance and the
medium-sized substituent points into the stereospecificity pocket. B. CALB W104A: the
large group is positioned in the stereospecificity pocket and the medium group is
pointing towards the enzyme opening, resulting in reversed enantioselectivity com-
pared to the wild type enzyme (unless the large group is too large to fit in this pocket).
C. CALB W104A: Both pockets can accommodate a large group, such as phenyl, and
therefore it is possible for CALB W104A to accommodate substrates with two such
groups, something that wild type CALB does not.
2. Results and discussion
Fig. 2. Diphenylmethyl acetate as tetrahedral intermediate in the active site of CALB
W104A after 1 ns dynamics at 298 K. The size of the stereospecificity pocket is shown
by using the molecular surface of its surrounding amino acids. The pro-(S)-phenyl
group of the substrate is shown in balls, coloured magenta, to show how well it fills the
pocket. The rest of the substrate and the catalytic histidine are shown in sticks.
Since two pockets are available in CALB W104A that are large
enough to fit a phenyl, it seemed probable that the enzyme could
accept diarylmethanols, compounds that have two large groups, as
substrates (Fig.1C). A test reaction with benzhydrol proved that this
was the case. The question was how well-designed the enzyme was
to perform these transformations in an enantioselective manner.
substrates. By changing the substituent, the size difference be-
tween the groups was varied, and its effect could be analyzed.
The first substrate to be tested was (p-methylphenyl) phenyl-
methanol (1a), where a methyl group in the para position of one of
the phenyl substituents is the only difference between the two
groups. The reaction was stereoselective, the enantiomeric excess
of the product (eep) being 55% (Table 1, entry 1). This result shows
that the enzyme can distinguish between a phenyl and a para-
methylphenyl group. The E value of this reaction, however, was
moderate (E¼4). The (R)-enantiomer of the product was formed in
excess, indicating that the catalytically most favourable binding
mode of the substrate is formed when the smaller phenyl group is
placed in the stereospecificity pocket and the larger p-methyl-
phenyl group points towards the enzyme opening, as predicted
from the modelling.
2.1. Molecular dynamics simulation
To get an indication of if and how well the enzyme could dis-
criminate between two differently sized aryl groups, CALB W104A
was studied with molecular dynamics.
A model of the transition state for the formation of diphe-
nylmethyl acetate was built as the tetrahedral intermediate in the
active site of CALB W104A (Fig. 2). In the transition state the active
site serine 105 is linked to the reacting carbonyl carbon while the
carbonyl oxygen, as an oxygen anion, has hydrogen bonds to T40
and E106. Furthermore, H224 forms hydrogen bonds to the alcohol
and S105 oxygens. These interactions fix the substrate in the active
site. In Fig. 2 it can be seen that the pro-(S)-phenyl group of the
substrate fully occupies the stereospecificity pocket, while the pro-
(R)-phenyl group is situated in the alcohol binding site, which is
open to the surrounding.
To test the hypothesis that a larger para-substituent would
give higher enantioselectivity, the KR of (p-ethylphenyl)phenyl-
methanol 1b was carried out (Table 1, entry 2). As expected,
a higher enantioselectivity was observed for this substrate (E¼26),
suggesting that a larger substituent makes it harder for the aryl
group to fit in the stereospecificity pocket.
Next, the group was extended to a p-propylphenyl (1c), but this
resulted in no higher selectivity (E¼16) but only a slower reaction
(entry 3). In agreement with the steric trend seen for the p-alkyl
substituents, p-OMe (1d, E¼11) and p-Br (1e, E¼11) were trans-
formed with a higher selectivity than p-Cl (1f, E¼2) (Table 1, entries
4e6).
From the modelling results it was predicted that even small
substituents on one of the phenyl groups would induce a significant
enantioselectivity. The experiment with a methyl substituent
showed a lower enantioselectivity than expected. With slightly
larger substituents the enantioselectivity could be increased up to
E¼26. Further modelling showed that with substituted phenyl
groups situated in the stereospecificity pocket (that is, the (S)-en-
antiomer) the enzyme could change conformation and expand the
pocket. Only when very large substituents were used a high
enantioselectivity would be expected.
2.2. Kinetic resolution
The observation from the modelling was that the stereospeci-
ficity pocket of CALB W104A is fully occupied by the phenyl group
and that it therefore is less likely that a phenyl with a substituent
can fit in the pocket. To study if this discrimination can result in
enantioselectivity, kinetic resolutions were performed with diaryl
methanols in which one of the aryl groups was a phenyl and the
other was a substituted phenyl. In these reactions, the substrate
alcohols were acylated by the enzyme with isopropenyl acetate as
acyl donor. Toluene was chosen as the solvent, since KRs with CALB
W104A had previously proven to be efficient in this solvent.14
2.2.1. Steric effects on enantioselectivity. Diphenylmethanols with
a substituent on one of the phenyl groups were first evaluated as

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K. Engstrom et al. / Tetrahedron 68 (2012) 7613e7618
7615
Table 1
the enzyme opening, resulting in low activity. (2-Naphthyl)phe-
nylmethanol (1i) reacted faster, this substrate probably fits better
since it is less wide, but unfortunately it gave a lower selectivity
(E¼10, Table 1, entry 9).
Kinetic resolution of diarylmethanols with a substituent on (one of) the phenyl
groupsa
Methyl groups were also introduced in the ortho- and meta-
positions. (m-Methylphenyl)phenylmethanol (1j) reacted fast but
with low selectivity (E¼4), and in contrast to all the other sub-
strates the (S)-product was formed (Table 1, entry 10). (o-Methyl-
phenyl)phenylmethanol (1k) reacted much slower but with
a higher selectivity (E¼15) (Table 1, entry11).
Entry
1
R
Substrate Time (h) eepb (%) Conv.c (%) Ed
Another related substrate with a size-difference between the
two groups is 1,2-diphenylethanol (1l). A lipase from Pseudomonas
stutzeri has previously been used in enantioselective trans-
esterification of this substrate.15 In the latter study the authors
obtained 99% ee and an E value of >200. The enantioselectivity with
CALB W104A was lower (93% ee and E¼34, Table 1, entry 12) than
that obtained with P. stutzeri.
1a
1b
1c
1d
6
6
55
91
86
73
24e
18e
21
4 (R)e
,
f
2
3
4
26e
12
24
16f
2.2.2. Enantiodiscrimination by electronic effects. Apart from steric
effects, electronic effects can also affect the binding of the substrates
in the enzyme. Electronic interaction of the substrate with one or
more residues of the enzyme can affect the reaction. Previous
results with wild type CALB suggest that electronic interactions of
the substrate with residues in the enzyme stereospecificity pocket
affect substrate binding. To evaluate electronic effects on enantio-
selectivity with CALB W104A, diarylmethanols with one phenyl and
one pyridyl group were studied. These two groups are of approxi-
mately the same size, but the pyridine nitrogen has a free electron
pair, and thereby the possibility to interact through hydrogen
bonding with residues close by.
45e
11 (R)e
11 (R)
2 (R)
5
6
7
1e
1f
24
24
24
76
34
96
38
38
27
1g
69 (R)
The 2-, 3- and 4-pyridyl(phenyl)methanols were investigated
separately, since the position of the nitrogen is most probably
crucial for the possibility to bind a side chain in the enzyme. Kinetic
resolution of 2- and 4-pyridyl(phenyl)methanol (1m and 1n) gave
distinct enantioselectivities (E¼6 and E¼10, respectively, Table 2,
entries 1e2), whereas the reaction with 3-pyridyl(phenyl)metha-
nol (1o) showed almost no selectivity with an E value of 2 (Table 2,
entry 3).
8
1h
24
96
4
51 (R)
9
1i
1j
24
12
80
55
27e
32
10 (R)e
4 (S)
The enzyme was (S)-selective for all pyridyl(phenyl)methanols.
This stereochemical outcome indicates that the substrate binds
with the pyridyl group positioned in the stereospecificity pocket,
10
11
1k
1l
24
24
87
93
9
15 (R)
34 (R)
Table 2
Kinetic resolution of pyridyl phenylmethanolsa
12
20
a
Reaction conditions: alcohol (0.25 mmol), isopropenyl acetate (1.5 equiv) and
CALB W104A (45 mg) dissolved in toluene (1 mL) and heated at 70 ꢀC.
b
Determined by chiral HPLC.
c
Determined by 1H NMR spectroscopy.
d
Calculated from eep and conv. unless otherwise noted.
Calculated from eep and ees.
The absolute configuration could not be explicitly determined but is assumed to
Entry
1
R
Substrate
Time (h)
12
eepb (%)
65
Conv.c (%)
33
Ed
e
f
be R.
1m
6 (S)
The size difference between the groups was therefore increased
further. (4-Biphenyl)phenylmethanol (1g) reacted only slightly
slower than the para-propyl, but the selectivity was much higher,
with an E value of 69 (Table 1, entry 7). This indicates that the large
biphenyl group definitely does not fit in the stereospecificity pocket.
(1-Naphthyl)phenylmethanol (1h) reacted slowly, but with
good selectivity (E¼51, Table 1, entry 8). This substituent points
more towards the side compared to the para-substituents that
points more straight back, which may be a reason that this sub-
strate does not fit as well in the long but not so wide tunnel towards
2
1n
1o
24
12
74
27
38
46
10 (S)
2 (S)
3
a
Reaction conditions: alcohol (0.25 mmol), isopropenyl acetate (1.5 equiv) and
CALB W104A (45 mg) dissolved in toluene (1 mL) and heated at 70 ꢀC.
b
Determined by chiral HPLC.
c
Determined by 1H NMR spectroscopy.
d
Calculated from eep and conv. unless otherwise noted.

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K. Engstrom et al. / Tetrahedron 68 (2012) 7613e7618
7616
and suggests that the pyridyl group can interact with something in
the pocket.
In addition to the steric effects, electronic effects also had an
impact on the enantioselectivity. With a pyridyl as one of the aryl
groups and phenyl as the other, selective transformations were
achieved, and in combination with a bulky substituent on the
phenyl group the highest enantioselectivity (E¼180) of all sub-
strates tested was obtained.
2.2.3. Combining steric and electronic effects. When a para-sub-
stituent is attached to one of the phenyls, this group is positioned by
the enzyme in the cavity towards the entrance, since it does not really
fit in the stereospecificity pocket. This arrangement results in (R)-
selectivity. On the contrary, when a pyridyl group is present, it is
bound in the stereospecificity pocket, giving the (S)-product. One
might argue that there could be a synergy between steric and elec-
tronic effects to give an even higher enantioselectivity, with a para
substituted phenyl as one of the aryls and a pyridyl as the other.
To test if this is the case, 2-pyridyl(4-chlorophenyl)methanol
(1p) was synthesized. Compound 1p is a precursor of an active
histamine antagonist,16 and therefore a highly interesting sub-
strate. The selectivity of this substrate was higher (E¼24) than that
for the substrates where a phenyl group is combined with p-chloro
(E¼2) or 2-pyridyl (E¼6) groups, indicating a cooperative effect
(Table 3, entry 1).
4. Experimental section
4.1. General
Unless otherwise noted, all materials were obtained from
commercial suppliers and used without further purification. Iso-
propenyl acetate was dried over CaCl2, distilled and stored over
molecular sieves. Column chromatography was performed on silica
gel (Acros, 40e60 mm).
1H and 13C NMR spectra were recorded on a Bruker Avance II
spectrometer at 400 MHz and 100 MHz, respectively. Chemical
shifts (d) are reported in parts per million, using the residual solvent
peak in CDCl3 (dH 7.26 and dC 77.0) as internal standard. Chiral HPLC
was performed using either a Chiralcel OJ or Chiracel OD-H column
(0.46 cm ꢁ 25 cm), flowrate of 0.5 mL/min. High resolution mass
spectra were recorded on a Bruker MicroTOF ESI-TOF mass spec-
trometer. Optical rotation was obtained on a PerkineElmer 241
Polarimeter. The absolute configuration of the reaction products
was assigned from the optical rotation of the product acetate or the
remaining alcohol based on comparison to previously reported
data.
Table 3
Kinetic resolution of p-substituted (2-pyridyl)phenylmethanolsa
b
Entry
1
R
Substrate
Time (h)
12
eep (%)
Conv.c (%)
38
Ed
4.2. Preparation of CALB W104A
CALB W104A was prepared as previously described.12 The
amount of active immobilized lipase on the support was de-
termined to 0.07% by active-site titration with the inhibitor methyl
4-methylumbelliferyl hexylphosphonate as described previously.11
1p
87
24(S)
2
1q
1r
12
24
73
98
41
38
10e
4.3. Preparation of diarylmethanols
3
180e
Diarylmethanols 1a, 1e and 1k were commercially available.
Compounds 1b, 1d, 1f, 1g, 1i, 1j, 1l, 1m, 1n and 1o were obtained by
reduction of the corresponding ketones with NaBH4 in EtOH, and
the spectral properties were in accordance with previously pub-
lished data.17e21 Alcohol 1h was obtained by lithiation of the cor-
responding aldehyde with phenyllithium according to a published
procedure.22 Compound 1p was prepared via a Grignard reaction.23
a
Reaction conditions: alcohol (0.25 mmol), isopropenyl acetate (1.5 equiv) and
CALB W104A (45 mg) dissolved in toluene (1 mL) and heated at 70 ꢀC.
b
Determined by chiral HPLC.
c
Determined by 1H NMR spectroscopy.
d
Calculated from eep and conv.
The absolute configuration could not be explicitly determined but is assumed to
e
be S.
4.3.1. Preparation of phenyl(4-propylphenyl)methanol (1c). 4-Propyl-
benzaldehyde (398 mL, 2.70 mmol) was dissolved in THF under an
The enantioselectivity for (4-bromophenyl)(2-pyridyl)methanol
(1q), was expected to be even higher, since a bromide is larger than
a chloride (cf. also Table 1, entry 5 vs entry 6). However, the enzyme
had an E value of 10 towards 1q, which is lower than that for the
chloride analogue (Table 3, entry 2).
4-Biphenyl(phenyl)methanol reacted, as discussed above, with
high selectivity (E¼69, Table 1, entry 7). When the phenyl sub-
stituent was changed into a 2-pyridyl, the 4-biphenyl(2-pyridyl)
methanol (1r) reacted with high enantioselectively, giving the
product 2r in 98% ee at 38% conversion after 24 h (Table 3, entry 3).
This corresponds to an E value of 180.
argon atmosphere. Phenyllithium (7.1 mL of a 1.9 M solution in THF,
13.5 mmol) was added under stirring at 0 ꢀC. The reaction mixture
was allowed to reach ambient temperature, and was then stirred for
4 h. The reaction was quenched by addition of water (20 mL). The
mixture was extracted with EtOAc (2ꢁ20 mL). The combined or-
ganic phases were washed with brine, dried over MgSO4 and con-
centrated. The crude product was purified by flash column
chromatography (pentane/ethyl acetate 8:1), to give 1c (280 mg,
46%) as a colourless oil. 1H NMR: 0.94 (t, 3H, J¼7.3), 1.58e1.68 (m,
2H), 2.57 (t, 2H, J¼7.7), 5.84 (d, 1H, J¼3.5), 7.13e7.18 (m, 2H),
7.25e7.40 (m, 7H). 13C NMR: 13.8, 24.5, 37.7, 76.1, 126.5, 126.5, 127.4,
128.4, 128.6, 141.2, 142.1, 143.9. IR (liquid film, cmꢂ1): 3500e3050
(br), 2958, 2929, 1453, 1175, 1015. MS(ESI-TOF): calcd for [MþNa]þ:
249.1250; Found: 249.1248.
3. Conclusion
CALB W104A catalyses enantioselective transesterification of
diarylmethanols, and the degree of enantioselectivity is dependent
on the size difference between the aryl groups. Only when large
substituents were used was a good enantioselectivity obtained.
4.3.2. (4-Bromphenyl)(2-pyridyl)methanol (1q). A solution of
2-bromopyridine (0.48 mL, 5.0 mmol) in THF (4 ml) was added
slowly to Mg turnings (0.32 g, 12.5 mmol) and the mixture was

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K. Engstrom et al. / Tetrahedron 68 (2012) 7613e7618
7617
refluxed for
2
h. The solution was cooled to
0
ꢀC,
128.8, 131.6, 139.3, 139.6, 169.9. IR (liquid film, cmꢂ1): 1742, 1488,
1370, 1231, 1024, 1011. MS(ESI-TOF): calcd for [MþNa]þ: 326.9991;
Found: 326.9986. HPLC: Chiralpak OJ column, i-hexane/i-PrOH,
95:5, tR1: 17.9 min (S)-2e, tR2: 19.5 min (R)-2e.
4-bromobenzaldehyde (1.0 g, 5.5 mmol) in THF (4 ml) was added
slowly, and the solution was allowed to reach ambient temperature
and then stirred for 2 h. The reaction was quenched by addition of
saturated NH4Cl and extracted with EtOAc. The combined organic
phases were washed with brine, dried over MgSO4 and concen-
trated. The crude product was purified by flash column chroma-
tography (pentane/ethyl acetate 8:1) to give 1q (530 mg, 40%).
Spectral data were in accordance with those previously reported.24
4.4.6. (4-Chlorophenyl)(phenyl)methyl acetate (2f). White solid. 1H
NMR: 2.19 (s, 3H), 6.87 (s, 1H), 7.25e7.40 (m, 9H). 13C NMR: 21.2,
76.1, 127.0, 128.1, 128.5, 128.6, 128.7, 133.8, 138.8, 139.7, 169.9. IR
(liquid film, cmꢂ1): 1742, 1490, 1370, 1230, 1014. MS(ESI-TOF): calcd
for [MþNa]þ: 283.0496; Found: 283.0487. HPLC: Chiralpak OJ col-
umn, i-hexane/i-PrOH, 95:5, tR1: 17.0 min (S)-2f, tR2: 18.9 min
(R)-2f.
4.3.3. 4-Biphenyl(2-pyridyl)methanol (1r). Prepared by the same
procedure as 1q. Yielded a sticky solid (478 mg, 37%). 1H NMR: 5.81
(s, 1H), 7.19e7.24 (m, 2H), 7.31e7.36 (m, 1H), 7.40e7.48 (m, 4H),
7.54e7.60 (m, 4H), 7.62e7.67 (m, 1H), 8.57e8.61 (m, 1H). 13C NMR:
74.7, 121.4, 122.5, 127.1, 127.3, 127.4, 127.5, 128.7, 136.9, 140.8, 140.8,
142.2, 147.9, 160.8. IR (liquid film, cmꢂ1): 3500e2900 (br), 1595,
1487, 1435, 1056, 1007. MS(ESI-TOF): calcd for [MþNa]þ: 284.1046;
Found: 284.1035.
4.4.7. 4-Biphenyl(phenyl)methyl acetate (2g). White solid. 1H NMR:
2.20 (s, 3H), 6.94 (s, 1H), 7.28e7.47 (m, 10H), 7.54e7.61 (m, 4H). 13C
NMR: 21.3, 77.2, 127.1, 127.1, 127.3, 127.4, 127.6, 128.0, 128.5, 128.8,
139.2, 140.1, 140.6, 140.9, 170.0. IR (liquid film, cmꢂ1): 1739, 1370,
1231, 1020. MS(ESI-TOF): calcd for [MþNa]þ: 325.1199; Found:
325.1190. HPLC: Chiralpak OJ column, i-hexane/i-PrOH, 95:5, tR1
:
4.4. General procedure for the kinetic resolution of
diarylmethanols
26.8 min (S)-2g, tR2: 31.7 min (R)-2g.
4.4.8. 1-Naphthyl(phenyl)methyl acetate (2h). White solid. 1H NMR:
2.19 (s, 3H), 7.25e7.40 (m, 5H), 7.42e7.52 (m, 3H), 7.56e7.60
(m,1H), 7.63 (s,1H), 7.82e7.90 (m, 2H), 7.98e8.03 (m, 1H). 13C NMR:
21.3, 74.4, 123.9, 125.2, 125.5, 125.7, 126.4, 127.4, 128.0, 128.5, 128.8,
128.9, 130.7, 133.9, 135.3, 139.7, 170.1. IR (liquid film, cmꢂ1): 1737,
1369, 1229, 1020. MS(ESI-TOF): calcd for [MþNa]þ: 299.1043;
Found: 299.1033. HPLC: Chiralpak OJ column, i-hexane/i-PrOH,
90:10, tR1: 41.1 min (S)-2h, tR2: 47.8 min (R)-2h.
Diarylmethanol (0.25 mmol), isopropenyl acetate (0.38 mmol,
41 ml) and CALB W104A (45 mg) were mixed in toluene (1 mL) and
stirred at 70 ꢀC for 6e24 h. The conversion was determined by 1H
NMR. The enantiomeric excess (ee) of the products, and in some
cases also of the remaining substrates were determined by chiral
HPLC. E values were calculated from eep and conversion unless
otherwise noted.25
4.4.1. Phenyl(p-tolyl)methyl acetate (2a). White solid. 1H NMR: 2.17
(s, 3H), 2.35 (s, 3H), 6.88 (s, 1H), 7.14e7.18 (m, 2H), 7.23e7.40
(m, 7H). 13C NMR: 21.1, 21.3, 76.8, 126.9, 127.1, 127.8, 128.4, 129.2,
137.3, 137.7, 140.3, 170.0. IR (liquid film, cmꢂ1): 1741, 1370, 1232,
1019. MS(ESI-TOF): calcd for [MþNa]þ: 263.1043; Found: 263.1038.
HPLC: Chiralpak OJ column, i-hexane/i-PrOH, 97:3, tR1: 28.2 min
(S)-2a, tR2: 30.9 min (R)-2a.
4.4.9. 2-Naphthyl(phenyl)methyl acetate (2i). White solid. 1H NMR:
2.21 (s, 3H), 7.07 (s, 1H), 7.28e7.55 (m, 8H), 7.79e7.88 (m, 4H). 13C
NMR: 21.3, 77.0, 125.0, 126.0, 126.2, 126.3, 127.2, 127.7, 128.0, 128.4,
128.5, 132.9, 133.1, 137.5, 140.1, 170.0. IR (liquid film, cmꢂ1): 1740,
1369, 1230, 1022. MS(ESI-TOF): calcd for [MþNa]þ: 299.1043;
Found: 299.1032. HPLC: Chiralpak OJ column, i-hexane/i-PrOH,
90:10, tR1: 22.1 min (R)-2i, tR2: 24.6 min (S)-2i.
4.4.2. (4-Ethylphenyl)(phenyl)methyl acetate (2b). White solid. 1H
NMR: 1.24 (t, 3H, J¼7.6), 2.17 (s, 3H), 2.65 (q, 2H, J¼7.6), 6.89 (s, 1H),
7.16e7.22 (m, 2H), 7.25e7.44 (m, 7H). 13C NMR: 15.4, 21.3, 28.5, 76.8,
127.0, 127.2, 127.8, 128.0, 128.4, 137.5, 140.4, 144.0, 170.0. IR (liquid
film, cmꢂ1): 1741, 1370, 1232, 1019. MS(ESI-TOF): calcd for
[MþNa]þ: 277.1199; Found: 277.1204. HPLC: Chiralpak OJ column, i-
hexane/i-PrOH, 95:5, tR1: 17.6 min, tR2: 20.9 min (major).
4.4.10. Phenyl(o-tolyl)methyl acetate (2j). White solid. 1H NMR:
2.16 (s, 3H), 2.31 (s, 3H), 7.06 (s, 1H), 7.15e7.19 (m, 1H), 7.20e7.25
(m, 2H), 7.28e7.37 (m, 5H), 7.39e7.44 (m, 1H). 13C NMR: 19.5, 21.2,
74.2, 126.1, 126.8, 127.6, 127.9, 127.9, 128.4, 130.6, 135.7, 138.1, 139.4,
170.0. IR (liquid film, cmꢂ1): 1741, 1370, 1233, 1020. MS(ESI-TOF):
calcd for [MþNa]þ: 263.1043; Found: 263.1033. HPLC: Chiralpak
OJ column, i-hexane/i-PrOH, 95:5, tR1: 18.1 min (R)-2j, tR2: 20.3 min
(S)-2j.
4.4.3. Phenyl(4-propylphenyl)methyl acetate (2c). White solid. 1H
NMR: 0.94 (t, 3H, J¼7.3), 1.60e1.70 (m, 2H), 2.16 (s, 3H), 2.57 (t, 2H,
J¼7.6), 6.87 (s, 1H), 7.13e7.18 (m, 2H), 7.23e7.38 (m, 7H). 13C NMR:
13.9, 21.3, 24.5, 37.7, 76.8, 127.0, 127.1, 127.8, 128.5, 128.6, 137.5,
140.4, 142.5, 170.1. IR (liquid film, cmꢂ1): 2958, 2929, 1741, 1370,
1231, 1019. MS(ESI-TOF): calcd for [MþNa]þ: 291.1356; Found:
4.4.11. Phenyl(m-tolyl)methyl acetate (2k). White solid. 1H NMR:
2.18 (s, 3H), 2.35 (s, 3H), 6.87 (s, 1H), 7.09e7.19 (m, 3H), 7.20e7.40
(m, 6H). 13C NMR: 21.3, 21.4, 76.9, 124.1, 127.0, 127.8, 127.8, 128.4,
128.5, 128.7, 138.2, 140.1, 140.3, 170.0. IR (liquid film, cmꢂ1): 1743,
1370, 1232, 1024. MS(ESI-TOF): calcd for [MþNa]þ: 263.1043;
Found: 263.1033. HPLC: Chiralpak OJ column, i-hexane/i-PrOH,
95:5, tR1: 25.0 min (R)-2k, tR2: 33.0 min (S)-2k.
291.1345. HPLC: Chiralpak OJ column, i-hexane/i-PrOH, 98:2, tR1
:
17.6 min, tR2: 20.8 min (major).
4.4.4. (4-Methoxyphenyl)(phenyl)methyl acetate (2d). White solid.
1H NMR: 2.17 (s, 3H), 3.81 (s, 3H), 6.86e6.92 (m, 3H), 7.26e7.33
(m, 2H), 7.34e7.40 (m, 5H). 13C NMR: 21.3, 55.2, 76.5, 113.8, 126.8,
127.7, 128.4, 128.7, 132.4, 140.4, 159.2, 170.0. IR (liquid film, cmꢂ1):
1739,1610,1512,1370,1248,1234,1174,1032. MS(ESI-TOF): calcd for
[MþNa]þ: 279.0992; Found: 279.0983. HPLC: Chiralpak OJ column,
i-hexane/i-PrOH, 90:10, tR1: 38.6 min (S)-2d, tR2: 51.6 min (R)-2d.
4.4.12. 1,2-Diphenylethyl acetate (2l). Spectroscopic data in accor-
dance with those previously published.15 HPLC: Chiralpak OJ col-
umn, i-hexane/i-PrOH, 90:10, tR1: 22.9 min (S)-2l, tR2: 34.2 min
(R)-2l.
4.4.13. Phenyl(2-pyridyl)methyl acetate (2m). White solid. 1H NMR:
2.21 (s, 3H), 6.88 (s, 1H), 7.19 (ddd, 1H, J¼1.1, 4.8, 7.7), 7.27e7.38
(m, 3H), 7.40e7.46 (m, 3H), 7.69 (ddd, 1H, J¼1.8, 7.7, 7.7), 8.59 (ddd,
1H, J¼0.9, 1.8, 4.8). 13C NMR: 21.3, 77.9, 120.9, 122.7, 127.4, 128.2,
128.6, 136.8, 139.0, 149.6, 159.2, 169.9. IR (liquid film, cmꢂ1): 1742,
1591, 1434, 1369, 1229, 1026. MS(ESI-TOF): calcd for [MþNa]þ:
4.4.5. (4-Bromophenyl)(phenyl)methyl acetate (2e). White solid. 1H
NMR: 2.16 (s, 3H), 6.82 (s,1H), 7.19e7.24 (m, 2H), 7.28e7.39 (m, 5H),
7.43e7.49 (m, 2H). 13C NMR: 21.1, 76.2, 121.9, 127.0, 128.1, 128.6,

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K. Engstrom et al. / Tetrahedron 68 (2012) 7613e7618
7618
250.0838; Found: 250.0832. HPLC: Chiralpak ODH column, i-hex-
ane/i-PrOH, 95:5, tR1: 26.8 min (R)-2m, tR2: 32.6 min (S)-2m.
1370, 1230, 1032. MS(ESI-TOF): calcd for [MþNa]þ: 326.1151;
Found: 326.1146. HPLC: Chiralpak OJ column, i-hexane/i-PrOH,
95:5, tR1: 70.1 min, tR2: 77.8 min (major).
4.4.14. Phenyl(4-pyridyl)methyl acetate (2n). Colourless oil. 1H
NMR: 2.20 (s, 3H), 6.82 (s, 1H), 7.23e7.28 (m, 2H), 7.30e7.40
(m, 5H), 8.55e8.65 (m, 2H). 13C NMR: 21.1, 75.5, 121.4, 127.4, 128.6,
128.8, 138.6, 148.9, 149.9, 169.7. IR (liquid film, cmꢂ1): 1744, 1599,
1372, 1230, 1026. MS(ESI-TOF): calcd for [MþNa]þ: 250.0838;
Found: 250.0833. HPLC: Chiralpak OJ column, i-hexane/i-PrOH,
95:5, tR1: 38.5 min (R)-2n, tR2: 56.7 min (S)-2n.
Acknowledgements
Financial support from the Swedish Research Council and the
Knut and Alice Wallenberg Foundation is gratefully acknowledged.
References and notes
4.4.15. Phenyl(3-pyridyl)methyl acetate (2o). Colourless oil. 1H
NMR: 2.18 (s, 3H), 6.91 (s, 1H), 7.27e7.40 (m, 6H), 7.63 (d, 1H, J¼7.7),
8.4e8.8 (m, 2H). 13C NMR: 21.1, 74.8, 123.4, 127.0, 128.3, 128.7, 134.8,
135.9, 139.1, 148.6, 149.1, 169.8. IR (liquid film, cmꢂ1): 1741, 1427,
1371, 1231, 1023. MS(ESI-TOF): calcd for [MþNa]þ: 250.0838;
Found: 250.0835. HPLC: Chiralpak OJ column, i-hexane/i-PrOH,
95:5, tR1: 43.4 min (R)-2o, tR2: 58.5 min (S)-2o.
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1H NMR: 2.21 (s, 3H), 6.84 (s, 1H), 7.21 (ddd, 1H, J¼1.1, 4.9, 7.5),
7.29e7.40 (m, 4H), 7.40e7.44 (m, 1H), 7.70 (ddd, 1H, J¼1.8, 7.7, 7.7),
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95:5, tR1: 19.5 min (S)-2p, tR2: 31.5 min (R)-2p.
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4.4.17. (4-Bromophenyl)(2-pyridyl)methyl acetate (2q). Colourless
oil. 1H NMR: 2.21 (s, 3H), 6.83 (s, 1H), 7.18e7.24 (m, 1H), 7.29e7.34
(m, 2H), 7.39e7.44 (m, 1H), 7.45e7.50 (m, 2H), 7.66e7.74 (m, 1H),
8.57e8.61 (m, 1H). 13C NMR: 21.3, 77.0, 120.8, 122.2, 122.9, 129.0,
131.6, 137.1, 137.9, 149.3, 158.4, 169.7. IR (liquid film, cmꢂ1): 1744,
1371, 1228, 1032. MS(ESI-TOF): calcd for [MþNa]þ: 327.9944;
Found: 327.9933. HPLC: Chiralpak ODH column, i-hexane/i-PrOH,
98:2, tR1: 29.7 min, tR2: 54.4 min (major).
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4.4.18. 4-Biphenyl(2-pyridyl)methyl acetate (2r). Colourless oil. 1H
NMR: 2.23 (s, 3H), 6.93 (s, 1H), 7.20 (ddd, 1H, J¼0.8, 4.8, 7.5),
7.30e7.37 (m, 1H), 7.39e7.60 (m, 9H), 7.71 (td, 1H, J¼1.7, 7.7) 8.61 (d,
1H). 13C NMR: 21.2, 77.7, 120.9, 122.7, 127.3, 127.4, 127.8, 128.7, 136.8,
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