Lipase-catalyzed doubly enantioselective ring-opening resolution between alcohols and lactones: Synthesis of chiral hydroxyl esters with two stereogenic centers

Article abstract of DOI:10.1002/cctc.201402672

A novel lipase B from Candida antarctica-catalyzed doubly enantioselective ring-opening resolution between racemic alcohols and lactones was developed. By using this strategy, three optically pure compounds including hydroxyl esters with two stereogenic centers and recovered alcohols and lactones were obtained simultaneously in high yields and ee. This process was used for the resolution of various racemic alcohols with different substituent groups and lactones with different ring sizes (four- and seven- membered lactones). The scale-up experiments were also successful. Moreover, molecular docking was performed to explain the molecular basis of this doubly enantioselective ring-opening resolution. As an attractive and efficient strategy, lipase-catalyzed doubly enantioselective ring-opening resolution will be widely used in the synthesis of optically pure hydroxyl esters with two stereogenic centers. Opening new doors: A novel lipase B from Candida antarctica-catalyzed doubly enantioselective ring-opening resolution between racemic alcohols and lactones is developed.

Full text of DOI:10.1002/cctc.201402672

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DOI: 10.1002/cctc.201402672
Lipase-Catalyzed Doubly Enantioselective Ring-Opening
Resolution between Alcohols and Lactones: Synthesis of
Chiral Hydroxyl Esters with Two Stereogenic Centers
Bo Xia, Yanyan Li, Guilin Cheng, Xianfu Lin, and Qi Wu*[a]
A novel lipase B from Candida antarctica-catalyzed doubly
enantioselective ring-opening resolution between racemic al-
cohols and lactones was developed. By using this strategy,
three optically pure compounds including hydroxyl esters with
two stereogenic centers and recovered alcohols and lactones
were obtained simultaneously in high yields and ee. This pro-
cess was used for the resolution of various racemic alcohols
with different substituent groups and lactones with different
ring sizes (four- and seven- membered lactones). The scale-up
experiments were also successful. Moreover, molecular docking
was performed to explain the molecular basis of this doubly
enantioselective ring-opening resolution. As an attractive and
efficient strategy, lipase-catalyzed doubly enantioselective ring-
opening resolution will be widely used in the synthesis of opti-
cally pure hydroxyl esters with two stereogenic centers.
Introduction
Lipase-catalyzed kinetic resolution (KR) is an important tool for
chemists in creating enantiopure compounds, such as chiral al-
cohols (or amines) and esters (or amides), owing to its high
stereoselectivity and operation under mild reaction condi-
tions.[1–3] In the classical KR process via transesterification,
esterification, interesterification, and amidation, only one of
the components, either the alcohol (amine) or the acylating
agent, is chiral or prochiral. In the mechanism of the lipase-cat-
alyzed KR process, such as transesterification between the alco-
hol and the acylating agent, two binding sites for the alcohol
and the carboxylic acid in the catalytic structure of some lipas-
es are responsible for the chiral discrimination of both racemic
partners.[4] However, only a few examples describing lipase-cat-
alyzed KR of racemic acyl donors and alcohols (or amines)
have been reported so far.[5] The first example of lipase-cata-
lyzed double KR process was reported by Gotor and coworkers
in 1990, which described the enantioselective aminolysis of
ethyl (Æ)-2-chloropropionate with racemic amines, producing
amides with two newly generated chiral centers.[5a] In most
cases of the double KR process, conversions of both racemic
partners could not exceed 50%, sometimes leading to moder-
ate ee values of the recovered acyl donor or nucleophiles.[5h]
Our group recently reported a dynamic double KR strategy
that combines a metal-catalyzed racemization reaction with
the classical double KR process for the simultaneous resolution
of primary amines and secondary alcohols in one pot.[6] This
dynamic double KR strategy efficiently provided chiral amides
and alcohols (esters) in high yields and ee.
An alternative to lipase-catalyzed KR is the selective ring
opening of substituent lactones. Optically pure hydroxyl acids
are prepared by using either the selective ring-opening pro-
cess or another strategy.[7] Optically pure hydroxyl acids are im-
portant biologically active compounds found in lipopeptides
that demonstrate antimicrobial, insecticidal, and antiviral activi-
ties.[8] R-b-Hydroxyalkanoic acid exists in the fatty acid synthe-
sis pathway as an adduct of the acyl carrier protein, and S-b-
hydroxyalkanoic acid exists as an ester of coenzyme A. R-(À)-b-
Hydroxytetradecanoic acid, found in many microorganisms,
plays the main role of lipid A that is associated with the toxici-
ty of endotoxin.[9] Achiral alcohols were usually used for the
ring-opening KR or the selective ring-opening polymerization
of substituent lactones.[10] To our knowledge, no examples of
double KR of racemic alcohols and substituent lactones have
been reported. Therefore, the interest in these reactions is ob-
vious. If racemic alcohols were used for the resolution of sub-
stituent lactones, multiple optically pure products could be ob-
tained through a one-step reaction and easily separated by
using simple column chromatography owing to their different
polarities. The one-step reaction could also produce a hydroxyl
acid with two stereogenic centers that could not be obtained
easily. Baker’s yeast was used for preparing this kind of hydrox-
yl acid; however, the results were not satisfactory because the
ee values of hydroxyl acids with two stereogenic centers were
low (from 14 to 77%).[11]
[a] Dr. B. Xia,+ Y. Li,+ Dr. G. Cheng, Prof. X. Lin, Dr. Q. Wu
Department of Chemistry
Our group studied the lipase-catalyzed resolution of alcohols
and amines, especially the resolution of multicomponents in
one pot.[6,12] On the basis of our earlier studies, herein we re-
ported a doubly enantioselective ring-opening resolution be-
tween racemic alcohols and substituted lactones that was
used to synthesize optically pure hydroxyl esters with two ste-
Zhejiang University
Hangzhou, 310027 Zhejiang (P.R. China)
E-mail: Wuqi1000@163.com
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201402672.
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tones. The ee values and conver-
sions of both the recovered sub-
strates were low with PS-IM as
a catalyst (Table 1, entry 2) even
after increasing the reaction
time to 120 h. With CAL-B as the
catalyst, the yields and ee values
of both obtained hydroxyl esters
and recovered lactones are satis-
factory whereas conversions and
ee values of alcohols were low
(Table 1, entry 1). To improve this
doubly enantioselective ring-
opening resolution, further opti-
Scheme 1. Process of doubly enantioselective ring-opening resolution.
mization of reactions conditions
was required.
reogenic centers as well as recovered chiral lactones and alco-
hols (Scheme 1). We chose 3-methyl propiolactone as the
model compound and used it to investigate substituted lac-
tones with different sizes (five-, six-, and seven-membered lac-
tones). Both hydroxyl esters and recovered alcohols or lactones
were obtained in high yields and ee. In addition, molecular
docking was performed to explain the molecular basis of this
doubly enantioselective ring-opening resolution.
According to some previous studies,[13] solvents have a signif-
icant effect on the activity of lipases. Herein, five polar and
nonpolar solvents were investigated, and the results are sum-
marized in Table 2. Highly polar solvents, such as DMF, were
not suitable for enzymatic resolution, and conversions and ee
values of the two reactants were the lowest (Table 2, entry 2).
THF and acetonitrile with moderate polarity were better sol-
vents than DMF, nonetheless, their use provided non-satisfac-
tory results. As also reported by many studies of CAL-B-cata-
lyzed KR, toluene was the best solvent for the reaction cata-
lyzed by CAL-B and its use led to (R)-2a and 3a in high yields
and ee.[13a]
Results and Discussion
We selected the KR reaction between 1-phenylethanol (1a)
and 3-methyl propiolactone (2a) as the model reaction. Six en-
zymes were chosen for this doubly enantioselective ring-open-
ing resolution, which are listed in Table 1. Among these en-
zymes, only two lipases—lipase B from Candida antarctica
(CAL-B) and Amano lipase PS-IM (PS-IM)—could catalyze this
reaction. Other enzymes showed low activities for this process,
possibly because in doubly enantioselective ring-opening reso-
lution, lipase is suitable not only for alcohols but also for lac-
Under the reaction conditions listed in Tables 1 and 2, it was
difficult to obtain satisfactory ee values of both reactants and
products because CAL-B catalyzed the polymerization of lac-
tones and produced some dimers or trimers. These oligomers
could not be detected by using chiral GC or HPLC. To inhibit
the polymerization, we decreased the reaction temperature
from 50 to 378C and increased the reaction time to 72 h. The
ee values of alcohols and lactones were monitored for the
entire reaction period (Fig-
ure S1). However, the findings in-
Table 1. Results of resolution of different lipases.[a,b,c]
dicated that the ee values of al-
cohols were still low. All the
above optimizations indicated
that other reaction parameters
may have significantly affected
the stereoselectivity output.
Considering that the lactone was
Entry
Enzyme
(S)-1a
Conv.[d] [%]
(R)-2a
Conv.[e] [%]
3a
ee [%]
ee [%]
ee[f] [%]
Yield[d] [%]
overconsumed in the undesired
polymerization, which led to
a lower lactone to alcohol ratio
than the required value, we eval-
uated the molar ratio of lactones
to alcohols; the results are pre-
sented in Figure 1. If the molar
ratio was 1:1.5, high ee values of
alcohols and lactones could be
obtained simultaneously. As
pointed out in the Introduction,
we aimed to develop a doubly
1
2
3
4
5
6
CAL-B
PS-IM
MJL
CAL
PPL
57
45
38
30
–
–
–
99
56
–
–
–
50
36
–
–
–
98
98
–
–
–
37
32
–
–
–
[g]
–
–
–
–
PCL
–
–
–
–
–
[a] Reaction conditions: 0.5 mmol of the alcohol, 0.5 mmol of the lactone, 2.0 mL of toluene, 31 mg of lipases,
T=508C, and t=60 h; [b] All ee values and yields were mean values of two to four determinations; [c] Unless
otherwise indicated, all ee values were determined from chiral GC analysis; [d] Isolated conversions and yields
after column chromatography; [e] Conversions of lactones were determined from GC analysis using n-dodec-
ane as an internal standard; [f] The obtained optically pure product 3a was a diastereomer, and the ee values
of 3a were determined from chiral HPLC analysis; [g] –: No reaction.
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scaled up this process further.
First, we scaled it twofold (from
0.1 to 0.2 mmol of the alcohol;
Table 3, entry 5), and all three
products were obtained in high
yields and ee values. Then, we
further increased the reaction
scale (to 10 mmol of the alco-
hol), which continued to provide
Table 2. Results of resolution of different solvents.[a]
Entry
Solvent
(S)-1a
Conv.[b] [%]
(R)-2a
Conv.[c] [%]
3a
ee [%]
ee [%]
ee[d] [%]
Yield[b] [%]
1
2
3
4
5
THF
DMF
acetonitrile
n-hexane
toluene
15
1
37
10
57
12
1
25
10
38
71
21
30
17
99
42
15
24
13
50
98
96
98
99
98
13
3
24
9
satisfactory
entry 6).
results
(Table 3,
To gain some insight into the
enantioselectivity of CAL-B used
as catalysts for the doubly enan-
tioselective ring-opening resolu-
tion of racemic lactone and alco-
hols, molecular docking was per-
formed with AutoDock 4.0 by
using the X-ray crystal structure
37
[a] Reaction conditions: 0.5 mmol of the alcohol, 0.5 mmol of the lactone, 31 mg of CAL-B, 2.0 mL of the sol-
vent, T=508C, and t=60 h; [b] Isolated conversions and yields after column chromatography; [c] Conversions
of lactones were determined from GC analysis using n-dodecane as an internal standard; [d] The obtained opti-
cally pure product 3a was a diastereomer, and the ee values of 3a were determined from chiral HPLC analysis.
of CAL-B (PDB code 1TCA) as the starting point.[15,16] The quan-
tum chemical software Gaussian 03 was used to optimize the
structures of four possible products with different configura-
tions obtained at the 6-31+G(d) basis set level by using Becke
3-parameter Lee–Yang–Parr hybrid DFT.[17] For each possible
product, the configuration with the lowest energy was chosen
as the docking ligand structure.
Wild-type CAL-B is an excellent catalyst for the hydrolytic or
transesterification KR of chiral secondary alcohols, such as 1a
substrate, which preferentially formed the R enantiomer;[18] this
result was also confirmed by results of molecular docking per-
formed herein. In the case of the preferential product (R)-1-
phenylethyl (S)-3-hydroxybutanoate (R/S-3a) obtained with
CAL-B, the large substituent (phenyl group) of the (R)-1a
moiety was oriented toward the active site entrance and the
medium-sized substituent (methyl group) was positioned in
the stereospecificity pocket surrounded by residues Trp104,
Ser47, Thr40, and Ala281. Meanwhile, the acyl moiety of the
product R/S-3a was sterically accommodated in the acid-bind-
ing pocket surrounded by residues Val189, Thr138, Leu140,
and Gln157, whereas the carbonyl oxygen atom was efficiently
stabilized by the oxyanion hole defined, inter alia, by residues
Gln106 and Thr40. All the hydrogen bonds required for cataly-
sis were spatially arranged (Figure 2a), and the distance be-
tween the serine in the catalytic triad and the carbonyl func-
tion of R/S-3a was suitable for effective nucleophilic attack. In
the case of the nonpreferential product (R)-1-phenylethyl (R)-3-
hydroxybutanoate (R/R-3a), the docking experiment revealed
the presence of a hydrogen bond in the (S)-3-hydroxybuta-
noate moiety and Asp134 residue [(R/R-3a)ÀOHÀO=CÀ
Asp134], which pulled the acyl moiety of R/R-3a far away from
the oxyanion hole and thus led to the lack of the stability
effect of the oxyanion hole on the carbonyl oxygen atom of
the substrate (Figure 2b). Moreover, the analysis of two other
nonpreferential products, S/S-3a and S/R-3a, revealed that
CAL-B could not accommodate these two enantiomers in a cat-
alytically active configuration as easily as R/S-3a owing to
steric considerations (Figure 2c and d). Although the large sub-
&
*
Figure 1. ee Values of lactone ( ) and alcohol ( ) substrates in reactions with
different molar ratios of alcohols to lactones.
enantioselective ring-opening resolution, and all ee values of
both reactants and products are important factors that made
this strategy more attractive and efficient.
After completing the optimization and obtaining some good
results with the model reaction, we were interested in expand-
ing the substrate scope. With 2a as the lactone, various race-
mic alcohols with different substituent groups could efficiently
participate in this doubly enantioselective ring-opening resolu-
tion, and excellent results for all three chiral compounds were
obtained (Table 3, entries 1–4). Moreover, we compared lac-
tones with different ring sizes (four-, five-, six-, and seven-
membered lactones) for the doubly enantioselective ring-
opening resolution process. The ee values of both substrates
and products were high with use of four- and seven-mem-
bered lactones for this ring-opening process. Most ee values
were greater than 90% (Table 3, entries 1–4 and 9). However,
with five- and six-membered lactones, this process failed, pos-
sibly owing to their high thermodynamic stability and unfavor-
able ring–chain equilibrium; this result was consistent with
previous reports (Table 3, entries 7 and 8).[14]
To demonstrate the application potential of this enzymatic
doubly enantioselective ring-opening resolution strategy, we
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carbonyl moiety of the substrate
(4.27 and 4.09 ꢁ) were too long
for rapid nucleophilic attack to
occur. Furthermore, the stability
effect of the oxyanion hole on
the carbonyl oxygen atom of the
substrate (S/S-3a or S/R-3a) was
reduced partly or fully owing to
undesirable orientations. These
results explained the high enan-
tioselectivity of wild-type CAL-B
in the doubly enantioselective
ring-opening resolution of race-
mic lactones and secondary alco-
hols.
Table 3. Results of doubly enantioselective ring-opening resolution of lactones[a,b,c]
Entry
X
n
(S)-1a–d[d]
Conv. [%]
(R)-2a–d[e]
Conv. [%]
3a–e[d]
Yield [%]
ee [%]
ee [%]
ee[c] [%]
1
2
3
4
5[f]
6[g]
7
8
9
H
1
1
1
1
1
1
2
3
4
98
95
89
85
92
93
n.d.[h]
n.d.
70
46
48
45
43
45
46
n.d.
n.d.
40
97
96
98
92
98
98
n.d.
n.d.
87
48
48
49
46
49
49
n.d.
n.d.
45
96 (97)
93 (95)
92 (94)
90 (92)
97 (94)
96 (98)
n.d.
47
45
48
43
45
42
n.d.
n.d.
40
4-OMe
4-Br
4-NO2
H
H
Conclusions
4-Br
4-Br
4-OMe
n.d.
95 (93)
We have reported a highly effi-
cient double kinetic resolution
reaction between racemic alco-
hols and substituent lactones,
namely, lipase-catalyzed doubly
[a] Reaction conditions: 0.5 mmol of the alcohol, 0.75 mmol of the lactone, 5% (with respect to the quality of
alcohols) CAL-B, 2.0 mL of toluene, T=378C, and t=60 h; [b] ee Values of alcohols and lactones were deter-
mined from chiral GC analysis; [c] The obtained optically pure product 3a–e was a diastereomer. The obtained
hydroxyl esters were hydrolyzed to determine its ee values. The ee values outside parentheses were that of the
alcohol moiety, and the ee values within parentheses were that of the ethyl ester of the hydroxyl acid; [d] Iso-
lated yields and conversions after column chromatography; [e] Conversions of lactones were determined from
GC analysis using n-dodecane as an internal standard; [f] Reaction scale was 1.0 mmol of the alcohol; [g] Reac-
tion scale was 10 mmol of the alcohol. [h] Not detected.
enantioselective
ring-opening
resolution, used for preparing
optically pure hydroxyl esters
with two stereogenic centers as
well as recovered chiral lactones
and alcohols. Among various re-
action parameters, the molar
ratio of lactones to alcohols had
the most significant effect on
the reaction results, and lactones
were needed in excess as com-
pared with alcohols because of
the overconsumption of lactones
by the undesired polymerization.
After optimization, this strategy
could be used for the resolution
of various racemic alcohols with
different substituent groups as
well as lactones with different
ring sizes (four- and seven-mem-
bered lactones). Optically pure
alcohols, lactones, and (R/S)-hy-
droxyl esters were obtained si-
multaneously in high yields and
ee. Each of the optically pure
compounds was easily separated
by using column chromatogra-
phy. The scale-up experiments
were also successful. Moreover,
molecular docking was per-
Figure 2. Optimized positions of the hydroxyl ester product 3a with different configurations in CAL-B and
Cys105–His224–Asp187 as the catalytic triad: a) (R/S)-3a, b) (R/R)-3a, c) (S/S)-3a, and d) (S/R)-3a. g: Hydrogen
bonds required for catalysis and the stabilization of the oxyanion hole (a). c: Oxyanion-stabilizing hydrogen
bonds in the nonproductive complex of CAL-B and (R/R)-3a, (S/S)-3a, or (S/R)-3a break and the distances be-
tween the catalytically active serine and the carbonyl function of the products or between histidine and the ester
bond are too long (b–d).
stituent (phenyl group) and medium-sized substituent (methyl
group) of the (S)-1a moiety could be positioned similarly in
both the active site entrance and the stereospecificity pocket,
the distances between the hydroxyl group of Cys105 and the
formed to explain the molecular basis of this doubly enantio-
selective ring-opening resolution. As lipase-catalyzed doubly
enantioselective ring-opening resolution is a more atom eco-
nomical and efficient strategy than the use of kinetic resolution
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J=8 Hz, 3H); 13C NMR (400 MHz, CDCl3): d=153.0, 147.1, 126.1,
123.8, 69.5, 25.5 ppm.
and ring-opening as two separate processes, this strategy will
be widely used in the synthesis of optically pure hydroxyl
esters with two stereogenic centers.
(R)-4-Methyloxetan-2-one, (R)-2a: 1H NMR (400 MHz, CDCl3): d=
4.74–4.70 (m, 1H), 3.62–3.56 (dd, 1H), 3.11–3.06 (dd, 1H), 1.60–
1.59 ppm (dd, 3H); 13C NMR (400 MHz, CDCl3): d=168.1, 67.9, 44.3,
20.6 ppm.
Experimental Section
The 1H and 13C NMR spectra were recorded with a Bruker AMX-
400 MHz spectrometer using TMS as an internal standard. Chiral
HPLC was performed with a Chiralpak AD-H column (250 mmꢂ
4.6 mm; n-hexane/2-propanol=99:1 as the mobile phase; flow
rate: 0.5 mLminÀ1) and a UV detector (220 or 254 nm). Chiral GC
was performed with an Agilent CP-Chirasil-Dex CB 25ꢂ0.25
(R)-7-Methyloxepan-2-one, (R)-2d: 1H NMR (400 MHz, CDCl3): d=
4.48–4.44 (m, 1H), 2.71–2.58 (m, 2H), 1.96–1.88 (m, 3H), 1.68–1.57
(m, 3H), 1.37–1.36 ppm (d, J=4 Hz, 3H); 13C NMR (400 MHz, CDCl3):
d=175.8, 36.2, 35.0, 28.3, 22.9, 22.6 ppm.
(R)-1-Phenylethyl-(S)-3-hydroxybutanoate,
(R/S)-3a:
1H NMR
(400 MHz, CDCl3): d=7.39–7.36 (m, 5H), 5.97–5.92 (m, 1H), 4.25–
4.24 (m, 1H), 3.06 (brs, 1H), 2.52–2.49 (m, 2H), 1.59–1.57 (d, J=
8 Hz, 2H), 1.24–1.22 ppm (d, J=8 Hz, 2H); 13C NMR (400 MHz,
CDCl3): d=172.2, 141.3, 128.6, 128.0, 126.0, 72.8, 64.2, 43.0, 22.3,
22.2 ppm.
column (heating rates: 50–608C, 18CminÀ1; 60–1408C, 408CminÀ1
;
140–2008C, 108CminÀ1, 2008C maintained for 7 min). All the
known products were characterized by comparison 1H and
13C NMR data with those reported in the literature. Absolute ster-
eochemistries of amines, alcohols, amides, and esters were deter-
mined by comparison with literature values.
(R)-1-(4-Methoxyphenyl)ethyl-(S)-3-hydroxybutanoate,
(R/S)-3b:
1H NMR (400 MHz, CDCl3): d=7.23–7.19 (m, 2H), 6.83–6.80 (m, 2H),
5.84–5.79 (q, J=20 MHz, 1H), 4.11–4.06 (m, 1H), 3.73 (s, 3H), 2.39–
2.37 (m, 2H), 1.47–1.46 (d, J=4 Hz, 3H), 1.13–1.12 ppm (d, J=
4 MHz, 3H); 13C NMR (400 MHz, CDCl3): d=172.2, 159.4, 133.4,
127.6, 113.9, 64.2, 55.3, 43.0, 22.3, 21.9 ppm.
Materials
All enzymes were purchased from Sigma–Aldrich, including CAL-B,
PS-IM, lipase from porcine pancreas (PPL), Amano lipase M from
Mucor javanicus (MJL), lipase acrylic resin from C. antarctica (CAL),
and Amano lipase G from Penicillium camemberti (PCL). All re-
agents were obtained from commercial sources and were used as
received, except toluene. Toluene (99%) was purchased from Sino-
pharm Chemical Reagent Co. Ltd (China) and was distilled over
sodium. All alcohols and lactones were purchased from Sigma–
Aldrich.
(R)-1-(4-Bromophenyl)ethyl-(S)-3-hydroxybutanoate,
(R/S)-3c:
1H NMR (400 MHz, CDCl3): d=7.51–7.49 (d, J=8 Hz, 2H), 7.25–7.23
(m, 2H), 5.90–5.86 (m, 1H), 4.21–4.19 (m, 1H), 2.93 (brs, 1H), 2.50–
2.48 (m, 2H), 1.54–1.52 (d, J=8 Hz, 3H), 1.22–1.21 ppm (d, J=4 Hz,
3H); 13C NMR (400 MHz, CDCl3): d=140.3, 131.7, 127.8, 72.1, 64.2,
42.9, 22.3 ppm.
1
(R)-1-(4-Nitrophenyl)ethyl-(S)-3-hydroxybutanoate, (R/S)-3d: H NMR
(400 MHz, CDCl3): d=8.23–8.21 (d, J=8 Hz, 2H), 7.53–7.51 (d, J=
8 Hz, 2H), 5.99–5.94 (m, 1H), 4.23–4.18 (m, 1H), 2.54–2.52 (m, 2H),
1.59–1.57 (d, J=8 Hz, 3H), 1.25–1.23 ppm (d, J=8 Hz, 3H);
13C NMR (400 MHz, CDCl3): d=171.9, 148.6, 147.5, 126.7, 123.9,
71.6, 64.2, 42.9, 22.5, 22.2 ppm.
Syntheses
Process of doubly enantioselective ring-opening resolution
A solution of an alcohol (0.5 mmol) and a lactone (0.75 mmol) in
freshly distilled toluene (2 mL) was added to 5% (with respect to
the quality of alcohols) CAL-B. Then, the mixture was shaken at
378C (200 rpm) for 60 h. After the chiral GC analysis showed that
the reaction was complete, the mixture was filtered and the lipase
was washed thrice with dichloromethane (3 mL). The combined or-
ganic phase was concentrated in vacuo, and the residue was sepa-
rated by using column chromatography (petroleum ether 60-90/
EtOAc=10:1 to 5:1).
(R)-1-(4-Methoxyphenyl)ethyl-(S)-6-hydroxyheptanoate,
(R/S)-3e:
1H NMR (400 MHz, CDCl3): d=7.22–7.20 (d, J=8 Hz, 2H), 6.81–6.79
(d, J=12 Hz, 2H), 5.79–5.77 (m, 1H), 4.82–4.80 (m, 1H), 3.73 (s,
3H), 2.26–2.17 (m, 4H), 1.56–1.52 (m, 5H), 1.13–1.08 ppm (m, 5H);
13C NMR (400 MHz, CDCl3): d=173.4, 159.2, 133.8, 127.5, 113.8,
71.8, 70.5, 67.8, 55.2, 38.8, 34.5, 24.9, 23.5, 22.0, 19.9 ppm.
Scale-up of doubly enantioselective ring-opening resolution
(S)-1-Phenylethan-1-ol, (S)-1a: 1H NMR (400 MHz, CDCl3): d=7.42–
7.19 (m, 5H), 4.96–4.90 (m, 1H), 1.92–1.90 (brs, 1H), 1.54–1.52 ppm
(d, J=8 Hz, 3H); 13C NMR (400 MHz, CDCl3): d=145.8, 128.5, 127.5,
125.4, 70.4, 25.1 ppm.
First increase: A solution of an alcohol (1.0 mmol) and a lactone
(1.5 mmol) in freshly distilled toluene (6 mL) was added to 5%
(with respect to the quality of alcohols) CAL-B. Then, the mixture
was shaken at 378C (200 rpm) for 60 h. After the chiral GC analysis
showed that the reaction was complete, the mixture was filtered
and the lipase was washed thrice with dichloromethane (5 mL).
The combined organic phase was concentrated in vacuo, and the
residue was separated by using column chromatography (petrole-
um ether 60-90/EtOAc=10:1 to 5:1).
(S)-1-(4-Methoxyphenyl)ethan-1-ol, (S)-1b: 1H NMR (400 MHz,
CDCl3): d=7.33–7.31 (d, J=8 Hz, 2H), 6.92–6.89 (m, 2H), 4.88–4.86
(m, 1H), 3.83 (s, 3H), 1.96–1.92 (m, 1H), 1.51–1.49 ppm (d, J=8 Hz,
3H); 13C NMR (400 MHz, CDCl3): d=158.9, 138.0, 126.6, 113.8, 69.9,
55.3, 25.0 ppm.
(S)-1-(4-Bromophenyl)ethan-1-ol, (S)-1c: 1H NMR (400 MHz, CDCl3):
d=7.50–7.48 (d, J=8 Hz, 2H), 7.28–7.26 (d, J=8 Hz, 2H), 4.91–4.87
(m, 1H), 1.90 (brs, 1H), 1.50–1.48 ppm (d, J=8 Hz, 3H); 13C NMR
(400 MHz, CDCl3): d=144.7, 131.5, 127.1, 121.1, 69.8, 25.2 ppm.
Second increase: A solution of an alcohol (10 mmol) and a lactone
(15 mmol) in freshly distilled toluene (20 mL) was added to 5%
(with respect to the quality of alcohols) CAL-B. Then, the mixture
was shaken at 378C (200 rpm) for 60 h. After the chiral GC analysis
showed that the reaction was complete, the mixture was filtered
and the lipase was washed thrice with dichloromethane (20 mL).
The combined organic phase was concentrated in vacuo, and the
(S)-1-(4-Nitrophenyl)ethan-1-ol, (S)-1d: 1H NMR (400 MHz, CDCl3):
d=8.15–8.12 (d, J=12 Hz, 2H), 7.49–7.47 (d, J=8 Hz, 2H), 7.98–
7.93 (m, 1H), 4.97–4.95 (m, 1H), 1.97 (brs, 1H), 1.46–1.44 ppm (d,
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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We acknowledge the financial support received from the National
Natural Science Foundation of China (21272208), the Zhejiang
Provincial Natural Science Foundation (LY14B020006), and the
Ph.D. Programs Foundation of Ministry of Education of China
(20110101110008).
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Keywords: alcohols · enantioselectivity · enzyme catalysis ·
lactones · lipases
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