Enzyme- and ruthenium-catalyzed dynamic kinetic resolution of functionalized cyclic allylic alcohols

Article abstract of DOI:10.1021/jo402086z

Enantioselective synthesis of functionalized cyclic allylic alcohols via dynamic kinetic resolution has been developed. Cyclopentadienylruthenium catalysts were used for the racemization, and lipase PS-IM or CALB was employed for the resolution. By optimization of the reaction conditions the formation of the enone byproduct was minimized, making it possible to prepare a range of optically active functionalized allylic alcohols in good yields and high ee's.

Full text of DOI:10.1021/jo402086z

Article
pubs.acs.org/joc
Enzyme- and Ruthenium-Catalyzed Dynamic Kinetic Resolution of
Functionalized Cyclic Allylic Alcohols
Richard Lihammar, Renaud Millet, and Jan-E. Backvall*
̈
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
S
* Supporting Information
ABSTRACT: Enantioselective synthesis of functionalized cyclic allylic alcohols
via dynamic kinetic resolution has been developed. Cyclopentadienylruthenium
catalysts were used for the racemization, and lipase PS-IM or CALB was
employed for the resolution. By optimization of the reaction conditions the
formation of the enone byproduct was minimized, making it possible to prepare a
range of optically active functionalized allylic alcohols in good yields and high
ee’s.
Scheme 1. Two Examples of Ruthenium-Based Racemization
Catalysts (A and B) and a Schematic Picture of an (R)-
Selective Dynamic Kinetic Resolution
INTRODUCTION
■
Enantiomerically pure allylic alcohols are versatile intermediates
and building blocks in the synthesis of pharmaceuticals,
agrochemicals, and natural products; hence, the enantioselec-
tive synthesis of allylic alcohols has been the subject of many
studies.1 Cyclic allylic alcohols have attracted considerable
interest and are important in connection with Claisen
technology,2 epoxidations,3 and various SN2′ substitution
reactions.4 Cyclic allylic alcohols are also found as common
starting materials and intermediates in various synthetic
applications.5 Traditional protocols for the production of
enantiopure allylic alcohols often include asymmetric reduction
of vinyl ketones by the use of chiral catalysts6 or enzymes,7
enantioselective addition of alkenyl metal reagents to
aldehydes,8 and kinetic resolution or dynamic kinetic resolution
of racemic allylic alcohols.9 One problem associated with
several of the enantioselective reactions of cyclic allylic alcohols
is the need of a large group at the 2-position in order to achieve
a high enantiomeric excess (ee). If a large group is not present
it has to be introduced before the enantioselective reaction and
then removed, thus creating two additional steps.6b
Enzymatic kinetic resolution (KR) is a highly chemo- and
stereoselective method in organic synthesis. For the KR of
secondary alcohols and amines a hydrolase can be employed as
a transesterification or hydrolysis catalyst reacting with the
substrate enantiomers with two different rates. This makes it
possible to selectively convert one of the enantiomers into
product while leaving enantiomerically enriched starting
material behind. A drawback with a KR is that the yield of
the enantiomerically pure compounds (retained starting
material or converted product) can never exceed 50%. To
overcome this limitation a racemization catalyst can be
introduced to the system, thus turning it into a dynamic
kinetic resolution (DKR). In the latter process the substrate is
continuously racemized, making it possible to obtain the
product in a theoretical yield of 100% and with an ee of up to
100% (Scheme 1). To this date, a wide range of enantiomeri-
cally pure alcohols and amines have been prepared according to
this method.10−12 Two racemization catalysts that have been
used extensively for secondary alcohols are dimeric catalyst A,
also known as Shvo’s catalyst, which is activated by heat,13 and
monomeric catalyst B, activated by base.14 The aim of the
present study was to utilize these transition metal complexes to
extend the protocol of enzymatic DKR to also include
functionalized cyclic allylic alcohols.
In the course of the in situ racemization of allylic alcohols
with catalysts A and B a conjugated enone-intermediate
(noncoordinated or coordinated) is formed together with a
ruthenium hydride. In order to achieve racemization the α,β-
unsaturated carbonyl intermediate must be reduced by the
metal hydride at the carbonyl position. However, competing
hydride addition may occur at the olefin bond resulting in an
isomerization of the starting material to the saturated ketone.15
Also, the α,β-unsaturated carbonyl intermediate may escape
reduction leading to an oxidized side product.
Received: September 26, 2013
Published: November 18, 2013
© 2013 American Chemical Society
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a
Table 1. KR of Cyclic Allylic Alcohols Bearing a C3-Substituent
a
Reaction conditions: 1 (0.2 mmol), isopropenyl acetate (2 equiv), Na2CO3 (1 equiv), and enzyme (25 mg/mmol) stirred in dry toluene (0.8 mL)
b
c
at room temperature. Determined by 1H NMR Determined by chiral GC or HPLC (see the Supporting Information for further details). nd: not
determined. calculated by eeOH and eeOAc according to formula.16
d
together with CALB (25 mg/mmol) as the enzyme. The
reaction with catalyst A was performed at 60 °C with p-
chlorophenyl acetate (2 equiv) as acyl donor and afforded 2a in
90% yield and 80% ee after 24 h (Table 2, entry 1).17 DKR with
catalyst B, activated by 5 mol % of t-BuOK and using
isopropenyl acetate as acyl donor, gave 47% yield of the desired
acetate 2a in 86% ee with the remaining components being
14% of unreacted 1a, 10% of oxidation product 3-phenyl-
cyclohex-2-enone (3a), and 29% of ether 4a (Table 2, entry 2).
The origin of ether 4a is not clear, but previous studies on 3-
arylcyclohex-2-enols have shown that compounds with
electron-rich substituents at C3 give spontaneous ether
formation even at room temperature.18 However, compound
1a could be stored for several weeks without any signs of 4a.
Clearly, one or several of the components in the DKR with
catalyst B induced this undesired reaction. To establish the
origin of 4a a racemization test was conducted mixing only (S)-
3-phenylcyclohex-2-enol ((S)-1a) and the activated ruthenium
catalyst B in toluene. Within 1 h all of the alcohol had been
converted to ether 4a. This undesired side reaction makes B a
less suitable catalyst for DKR of these substrates. Catalyst A was
therefore chosen for the further studies of the DKR protocol,
and the rate of the racemization was increased by increasing the
temperature. This did not deliver (R)-2a in significant higher
ee; however, the ketone formation increased (Table 2, entries 3
and 4). Lowering the enzyme loading with the aim of obtaining
a better match between the transesterification rate and
racemization rate did raise the ee to 90%, but again the ketone
formation increased due to the slower reaction (Table 2, entry
5).
RESULTS AND DISCUSSION
■
Our study started with a screening of lipases to find the most
suitable enzyme for the KR. Five immobilized enzymes were
tested for the transesterification of 3-phenylcyclohex-2-enol
(1a) employing isopropenyl acetate as acyl donor and toluene
as solvent. Both Candida antarctica lipase B (CALB) and lipase
PS from Burkholderia cepacia (previously named Pseudomonas
cepacia) immobilized on Celite (PS-IM) were found to catalyze
the reaction with high enantioselectivity giving E values of 160
and 170, respectively.16 CALB was the faster of the two lipases
with a conversion of 46% after 4 h compared to 23% for PS-IM
(Table 1, entries 1 and 2). Lipase AK Amano 20 and PS
immobilized on ceramics (PS-C1) or coated with ionic liquid
(IL1-PS) delivered the acetate with a poor rate, and therefore,
these enzymes were not considered suitable for further studies
(Table 1, entries 3−5). Encouraged by the high selectivity
displayed by CALB and PS-IM for substrate 1a, kinetic
resolutions of cyclohexenyl alcohols with smaller groups in the
C-3 position were performed. For substrate 1b having a methyl
substituent at the vinylic position, the selectivity displayed by
CALB was still rather high with an E value of 63 (Table 1, entry
6). For PS-IM on the other hand, the methyl was too small for
the enzyme to catalyze the formation of (R)-2b in high
enantioselectivity and a moderate E value of 11 was obtained
(Table 1, entry 7). Surprisingly, even for an unsubstituted olefin
like 1c the enzymes were capable of showing enantioselectivity,
however the E values were too low for the substrate to be
practical for a DKR.
Having identified two suitable lipases for the DKR protocol,
we investigated the suitability of racemization catalysts A and B
by subjecting 1a to a DKR with 5 mol % of either catalyst
By changing to the slower biocatalyst PS-IM, which had
shown a slightly higher selectivity in the KR, it was possible to
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plausible explanation for the formation of racemic acetate is
racemization of the product via the stabilized carbocation.20
Next, we turned our attention to various allylic alcohols with
scaffolds of interest for further transformation to more
functionalized molecules. (R)-3-(Phenylsulfonyl)cyclohex-2-
enyl acetate ((R)-2f) was obtained in full conversion with an
ee of 94%. Compound (R)-2f is highly interesting due to the
electrophilic site that the sulfonyl creates in the 2-position of
the cyclic allylic alcohol derivative. This structural feature has
been used extensively and has made it possible to reach a wide
range of useful products.21
3-Iodocyclohex-2-enol (1g) gave 71% of the corresponding
acetate 2g, with an ee of 96%. However, by using racemization
catalyst B the yield could be further increased to 99% (90%
isolated) with 99% ee. No ether formation was observed for this
substrate, plausibly due to the electron-withdrawing nature of
the iodine. Enantiomerically pure 2g is a useful synthetic
intermediate. By performing an iodine−metal exchange this
intermediate can be trapped by various electrophiles, making it
possible to reach a wide range of optically active 3-subsituted
allylic alcohols.22 Also, a transition-metal-catalyzed cross
coupling of 2g allows for the introduction of a variety of
substituents in the 3-position. Herein we demonstrate the
possibility to acquire enantiomerically pure allylic alcohol 1c by
lithium−hydrogen exchange and diene 5 by Stille coupling. In
both reactions, the stereochemistry is fully retained (Scheme
2).
Table 2. Optimization of Dynamic Kinetic Resolution of 3-
Phenylcyclohex-2-enol (1a) with Lipase and Ruthenium
Catalyst A or B
a
b
c
c
c
temp eeOAc
1a
2a
3a
4a
entry catalyst
enzyme
(°C)
(%)
(%) (%) (%) (%)
1
2
3
4
5
6
7
8
9
A
B
A
A
A
A
A
A
A
A
CALB (25
mg/mmol)
60
80
90
47
88
86
74
91
92
70
62
86
10
10
12
14
26
9
CALB (25
mg/mmol)
rt
70
80
60
60
60
60
60
60
86
80
84
90
97
96
95
94
91
14
29
CALB (25
mg/mmol)
CALB (25
mg/mmol)
CALB (2
mg/mmol)
PS-IM (50
mg/mmol)
d
e
f
PS-IM (50
mg/mmol)
8
PS-IM (50
mg/mmol)
17
12
13
26
14
PS-IM (50
mg/mmol)
(R)-3-Undecylcyclohex-2-enol (1h) was transformed into
(R)-2h in 87% yield (79% isolated) and an ee of 91%. As
previously shown this substrate can be used in the synthesis of
the antifungal Tanikolide.23
g
10
PS-IM (50
mg/mmol)
a
Conditions using catalyst A: 1a (0.25 mmol), A (13.6 mg), lipase,
When the DKR was performed on 3-(phenylsulfonyl)-
cyclopent-2-enol (1i) a considerable amount of ketone was
formed. Even after further elaboration the result could not be
improved. The ee of (R)-2i was 88%, which can be considered
reasonable due to the selectivity displayed by the enzyme.24 By
changing the 3-substituent to cyanide (1j), the ketone
formation was completely suppressed, but the ee of the acetate
2j was as low as 26%. Again, a full screening of available
enzymes was performed, showing that none of the enzymes
gave good enantioselectivity.
PCPA (2 equiv) stirred in dry toluene (1 mL) for 24 h. Conditions
using catalyst B: 1a (0.25 mmol), B (8 mg), t-BuOK (1.7 mg),
Na2CO3 (26.5 mg), lipase, isopropenyl acetate (2 equiv) stirred in dry
b
toluene (1 mL) for 24 h Determined by GC analysis with chiral
c
d
stationary phase. Determined after 24 h by NMR analysis. 20 mol %
e
of degassed 2,6-dimethylheptan-4-ol added. Reaction performed in
cyclohexane. Reaction performed in acetonitrile. Reaction performed
in diisopropyl ether.
f
g
(R)-3-Methylcyclohex-2-enyl acetate ((R)-2b), used in the
total synthesis of dysidiolide,25 was acquired by the same
protocol and was delivered in full conversion with an ee of 60%.
Due to the similarity of the acyl donor p-chlorophenyl
acetate and some of the products a slow column chromatog-
raphy with low polarity of the solvent was required in order to
yield a pure product. In those cases where this was not possible,
selective hydrolysis of the acyl donor was performed, prior to
the chromatography.26
In summary, a DKR of cyclic allylic alcohols has been
described. Most of the substrates are transformed to their
corresponding acetates in high yields and high enantioselectiv-
ity. Electron-rich compounds are not suitable for this DKR
protocol due to the formation of ether products. 3-
Iodocyclohex-2-enyl acetate (2g), obtained by this method, is
a useful synthetic intermediate, and its transformation toward
chiral alcohol derivatives 1c and 5 was demonstrated.
obtain (R)-3-phenylcyclohex-2-enyl acetate ((R)-2a) in 97% ee
and 91% yield (Table 2, entry 6). Addition of 2,6-
dimethylheptan-4-ol as a hydride donor gave similar results
(entry 7), and therefore, this additive was later omitted to keep
the protocol as simple as possible.19 Other hydrophobic
solvents were investigated, but none managed to compete
with the results from the reaction made in toluene. In
cyclohexane, the reaction reached 83% conversion after 24 h,
where 70% was (R)-2a with an ee of 95% (Table 2, entry 8). In
acetonitrile, the reaction rate was higher converting 88% of 1a;
however, the product ee was lower (94%) and ketone
formation higher than in both toluene and cyclohexane
(entry 9). In diisopropyl ether the reaction reached full
conversion within 24 h and furnished acetate (R)-2a in 86%
yield with an ee of 91% (entry 10).
3-(4-Chlorophenyl)cyclohex-2-enol (1d) was converted into
(R)-3-(4-chlorophenyl)cyclohex-2-enyl acetate ((R)-2d) in
90% yield and 96% ee (Figure 1). However, with a p-methoxy
substituent on the phenyl group (1e) a considerable amount of
ketone was formed along with ether dimer 4e. The acetate that
was formed was racemic, even though the enzyme was
supposed to be selective for 1e showing an E value of 146. A
EXPERIMENTAL SECTION
General Procedures. All reactions were carried out using dry
conditions in flame-dried glassware. DKR and KR were carried out
under dry argon atmosphere using standard Schlenk techniques. Dry
■
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Figure 1. Substrate scope for the dynamic kinetic resolution of cyclic allylic alcohols. The conversion was measured by NMR with remaining material
consisting of oxidation product 3 unless otherwise noted. Isolated yields in parentheses. n.i. = not isolated. Enantiomeric excess was determined by
chiral GC or HPLC analysis. (a) Method A: substrate (0.25 mmol), A (5 mol %), PS-IM (50 mg/mmol), p-chlorophenyl acetate (2 equiv) stirred in
dry toluene (1 mL) for 24 h. (b) Method B: substrate (0.25 mmol), B (5 mol %), t-BuOK (5 mol %), Na2CO3 (1 equiv), PS-IM (25 mg/mmol),
isopropenyl acetate (2 equiv) stirred in dry toluene (1 mL) for 24 h. (c) 31% ketone, 28% ether 4e. (d) CALB (5 mg/mmol) used instead of PS-IM
and 2,6-dimethylpentan-4-ol (1 equiv) added.
a
Scheme 2. Alteration of Substrate 2g by Reduction of the Iodine to Compound 1c and Stille coupling yielding 5
a
In both reactions the stereochemistry is fully retained.
solvents were obtained from VAC solvent purifier. Isopropenyl acetate
was dried over CaCl2 and distilled before use. Na2CO3 was dried for 1
h in vacuo at 220 °C before use. All other chemicals and solvents were
used as purchased. The enantiomeric excess of the compounds was
determined by chiral HPLC or chiral GC using racemic compounds as
references. Racemic acetates 2 were obtained from the corresponding
alcohols by standard acylation. Shvo’s complex A27 and catalyst B11c
were synthesized according to literature procedures. CALB (Novo-
zyme 435), PS-IM, AK Amano 20, PS-C1 are commercially available.
IL1-PS can be prepared according to literature procedures.28
1H and 13C NMR spectra, respectively. HRMS spectra were recorded
with either a TOF-ESI detector or using CI with methane as carrier
gas. Microwave reactions were performed in a Biotage Initiator 2.5.3,
with an external IR sensor for temperature monitoring.
3-Phenylcyclohex-2-enol (1a). Compound 1a was prepared
according to a literature procedure.29 1H NMR (CDCl3, 400 MHz)
δ: 7.35−7.22 (m, 5H); 3.84−3.78 (m, 1H); 3.50 (s, 1H); 2.56−2.48
(m, 4H); 2.30−2.20 (m, 1H); 1.85−1.74 (m, 1H); 1.65−1.46 (m,
3H). HPLC: Chiralpak OB column, 5% i-PrOH/isohexane, 1 mL·
min−1, 35 °C, 211 nm, tR1 = 10 min (R), tR2 = 18 min (S).
Alcohol 1b and 1c were both commercial available.
The remaining alcohols 1d−j were prepared by reduction of the
corresponding ketone. The ketones were prepared according to the
following methods: ref 30 (ketones for 1d and 1e), ref 21b (ketones
for 1f and 1i), ref 31 (ketone for 1g), ref 32 (ketone for 1h), ref 33
(ketone for 1j).
Silica column chromatography was performed with Davisil
chromatographic silica media for separation and purification
applications (35−70 μm). HPLC samples were analyzed by UV
detection. GC samples were run on an IVADEX-1 chiral column with
1
FID detector and N2 as a carrier gas with a flow of 1.8 mL/min. H
1
and 13C NMR were recorded at 400 and 100 MHz, respectively. H
NMR data are presented as follows: chemical shift δ (in ppm)
[multiplicity, coupling constant(s) J, relative integral]. The signal due
to residual CHCl3 appearing at δH 7.26 and the central resonance of
the CDCl3 “triplet” appearing at δC 77.16 were used to reference the
General Procedure for Ketone Reduction. Synthesis of 1d−j.
CeCl3·7H2O (1.2 equiv) was dissolved in MeOH (10 mL/mmol).
After addition of the corresponding ketone (1 equivalent), the mixture
was cooled to 0 °C. NaBH4 (1.2 equiv) was added in one portion, and
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the reaction mixture was allowed to stir for 3 h. After addition of a satd
NH4Cl (aq), the product was extracted twice with Et2O. The
combined organic layers were washed with brine, dried over MgSO4,
and concentrated in vacuo. Purification through flash chromatography
(SiO2, pentane/EtOAc) gave the corresponding allylic alcohol in
approximately quantitative yields.
3-(4-Chlorophenyl)cyclohex-2-enol (1d). Experimental data were
in accordance with those reported in the previous literature.34 1H
NMR (CDCl3, 400 MHz): δ = 7.35−7.28 (m, 4H), 6.14−6.09 (m,
1H), 4.40 (s, 1H), 2.47−2.29 (m, 2H), 2.00−1.87 (m, 2H), 1.79−1.64
(m, 2H). No chiral separation found on GC or HPLC.
3-(4-Methoxyphenyl)cyclohex-2-enol (1e). Experimental data were
in accordance with those reported in the previous literature.29 1H
NMR (CDCl3, 400 MHz): δ = 7.35 (d, 2H, J = 8.9 Hz), 6.86 (d, 2H, J
= 8.9 Hz), 6.09−6.02 (m, 1H), 4.43−4.33 (m, 1H), 3.81 (s, 3H),
2.50−2.40 (m, 1H), 2.38−2.29 (m, 1H), 1.98−1.85 (m, 2H), 1.79−
1.63 (m, 2H). Chiral separation: GC: IVADEX-I, 100−1 °C/min−180
°C, tR1 = 79.8 min (S), tR2 = 80.3 min (R).
3-(Phenylsulfonyl)cyclohex-2-enol (1f). Experimental data were in
accordance with those reported in the previous literature.21b 1H NMR
(CDCl3, 400 MHz): δ = 7.44−7.39 (m, 2H), 7.36−7.28 (m, 3H),
5.74−5.71 (m, 1H), 4.28−4.21 (m, 1H), 2.20−2.03 (m, 2H), 1.90−
1.74 (m, 2H), 1.68−1.58 (m, 2H). Chiral separation: HPLC:
Chiralpak OJ column, 95:5 isohexane/i-PrOH, 0.5 mL·min−1, 30 °C,
211 nm, tR1 = 23 min (R), tR2 = 24.6 min (S).
3-Iodocyclohex-2-enol (1g). Experimental data were in accordance
with those previous reported.35 1H NMR (CDCl3, 400 MHz): δ =
6.46−6.42 (m, 1H), 4.19−4.13 (m, 1H), 2.60−2.41 (m, 2H), 1.95−
1.87 (m, 2H), 1.86−1.76 (m, 1H), 1.69−1.57 (m, 2H). Chiral
separation: GC: IVADEX-I, 70−1 °C/min−140 °C, tR1 = 57.1 min
(R), tR2 = 60.2 min (S).
3-Undecylcyclohex-2-enol (1h). Experimental data were in
accordance with those reported in the previous literature.32 1H
NMR (CDCl3, 400 MHz): δ = 5.52−5.48 (m, 1H), 4.21−4.17 (m,
1H), 2.05−1.89 (m, 4H), 1.86−1.70 (m, 2H), 1.64−1.55 (m, 2H),
1.47−1.36 (m, 2H), 1.34−1.24 (m, 16H), 0.92−0.89 (m, 3H). No
chiral separation found on GC or HPLC.
3-(Phenylsulfonyl)cyclopent-2-enol (1i). Experimental data were in
accordance with those reported in the previous literature.21b 1H NMR
(CDCl3, 400 MHz): δ = 7.96−7.91 (m, 2H), 7.72−7.65 (m, 1H),
7.61−7.55 (m, 2H), 6.69−6.65 (m, 1H), 5.05−4.97 (m, 1H), 2.73−
2..63 (m, 1H), 2.56−2.44 (m, 2H), 1.97−1.82 (m, 2H). HPLC:
Chiralpak IA column, 10% i-PrOH/isohexane, 0.5 mL·min−1, 30 °C,
211 nm, tR1 = 50 min (R), tR2 = 57 min (S).
3-Hydroxycyclopent-1-enecarbonitrile (1j). Experimental data
were in accordance with those reported in the previous literature.33
1H NMR (CDCl3, 400 MHz): δ = 6.63−6.60 (m, 1H), 5.04−4.96 (m,
1H), 2.81−2.71 (m, 1H), 2.60−2.49 (m, 1H), 2.46−2.36 (m, 1H),
1.88−1.78 (m, 2H). HPLC: Chiralpak IA column, 5% i-PrOH/
isohexane, 0.5 mL·min−1, 30 °C, 211 nm, tR1 = 30 min (R), tR2 = 33
min (S).
THF, 0.0125 mmol) was added to the reaction mixture. The reaction
turned orange. After approximately 5 min of stirring, racemic alcohol 1
(0.25 mmol) dissolved in dry toluene (0.5 mL) was added to the
reaction mixture. After an additional 5 min, isopropenyl acetate (110
μL, 2 mmol) was added. The reaction was heated to indicated
temperature. After 24 h, the reaction mixture was filtered and
concentrated.
(R)-3-Phenylcyclohex-2-enyl Acetate (2a). The reaction was
performed according to method A using the enzyme preparation
Amano PS-IM. Excess p-chlorophenyl acetate was hydrolyzed by
stirring the concentrated residue in a NaHCO3-saturated 4:1 mixture
of MeOH/H2O for 1 h. SiO2 chromatography (pentane/EtOAc 20:1)
was performed to obtain pure product in 87% yield (47 mg) and 97%
ee. Experimental data were in accordance with those reported in the
previous literature.36 1H NMR (CDCl3, 400 MHz): δ = 7.44−7.40 (m,
2H), 7.37−7.28 (m, 3H), 6.10−6.04 (m, 1H), 5.48 (s, 1H), 2.59−2.36
(m, 2H), 2.07 (s, 3H), 1.95−1.85 (m, 2H), 1.82−1.74 (m, 2H). Chiral
separation: GC: IVADEX-I, 100−1 °C/min−180 °C, tR1 = 55.5 min
(S), tR2 = 56.4 min (R), 97% ee.
The NMR data for side product 4a were in accordance with those
reported in the previous literature.37 Mixture of two diastereomers. 1H
NMR (CDCl3, 400 MHz): δ = 7.46−4.42 (m, 4H), 7.36−7.30 (m,
4H), 6.21−6.14 (m, 2H), 4.34−4.24 (m, 2H), 2.55−2.46 (m, 2H),
2.44−2.35 (m, 2H), 2.06−1.91 (m, 4H), 1.86−1.72 (m, 4H).
(R)-3-(4-Chlorophenyl)cyclohex-2-enyl Acetate (2d). The reaction
performed according to method A using the enzyme preparation
Amano PS-IM. Compound isolated after column chromatography
1
(SiO2, pentane/EtOAc 19:1) in 84% yield (53 mg) and 96% ee. H
NMR (CDCl3, 400 MHz): δ = 7.39−7.27 (m, 4H), 6.09−6.05 (m,
1H), 5.47−5.41 (m, 1H), 2.51−2.45 (m, 1H), 2.39−2.30 (m, 1H) 2.08
(s, 3H), 1.95−1.90 (m, 2H), 1.79−1.75 (m, 2H). 13C NMR (CDCl3,
100 MHz): δ = 171.0, 141.2, 139.6, 133.6, 128.6, 126.7, 122.3 69.0,
28.0, 27.4, 21.5, 19.5. HR-MS (ESI): calcd for C14H15ClO2+ 273.0652,
found 273.0653 [M + Na]+. Chiral separation: GC: IVADEX-I, 100−1
°C/min−180 °C, tR1 = 75.7 min (S), tR2 = 76.2 min (R), [α]22
+85.4 (c 0.80, CHCl3), 96% ee.
=
D
(R)-3-(4-Methoxyphenyl)cyclohex-2-enyl Acetate (2e). The reac-
tion was performed according to method A using the enzyme
preparation Amano PS-IM. After 24 h, the reaction mixture consisted
of 41% 2e, 31% of the ketone adduct, and 28% of ether dimer. No
enantiomeric excess was obtained. The compound was not isolated. 1H
NMR (CDCl3, 400 MHz): δ = 7.38−7.33 (m, 2H), 6.88−6.83 (m,
2H), 6.03−6.00 (m. 1H), 5.47−5.42 (m, 1H), 3.81 (s, 3H), 2.54−2.46
(m, 1H), 2.39−2.30 (m, 1H), 2.07 (s, 3H), 1.94−1.87 (m, 2H), 1.82−
1.75 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ = 171.0, 159.4, 141.6,
133.6, 126.6, 120.7, 113.8, 69.2, 55.4, 28.1, 27.5, 21.6, 19.5. HR-MS
(CI): calcd for C15H18O3 246.1256, found 246.1255 [M]+. Chiral
separation: GC: IVADEX-I, 100−1 °C/min−200 °C, tR1 = 81.1 min
(S), tR2 = 82.5 min (R), 0% ee.
(R)-3-(Phenylsulfonyl)cyclohex-2-enyl Acetate (2f). The reaction
was performed according to method A using the enzyme preparation
Amano PS-IM. The compound was isolated after column chromatog-
General Procedure for Kinetic Resolution. Substrate (0.2
mmol), isopropenyl acetate (2 equiv), lipase (25 mg/mmol), and
Na2CO3 (1 equiv) was dissolved in dry toluene (0.8 mL) and stirred at
room temperature. Aliquots (50 μL) were taken by syringe at the
indicated time and filtered with EtOAc through a Celite plug. After
evaporation of the solvent, the enantiomeric excess and conversion
were check by HPLC and NMR spectroscopy, respectively.
General Procedure Dynamic Kinetic Resolution. Method A.
Shvo’s complex (A) (13.6 mg, 0.0125 mmol), lipase (12.5 mg, 50 mg/
mmol substrate), and the racemic alcohol 1 (0.25 mmol) were added
to a dry Schlenk tube under argon atmosphere. Dry toluene (1 mL)
and then p-chlorophenyl acetate (0.875 mmol) were added. The
reaction was heated to 60 °C. After 24 h, the mixture was filtered
through cotton and concentrated under vacuum.
1
raphy (SiO2, pentane/EtOAc 4:1) in 82% yield (27 mg), 94% ee. H
NMR (CDCl3, 400 MHz): δ = 7.90−7.84 (m, 2H), 7.67−7.61 (m,
1H), 7.58−7.51 (m, 2H) 6.93−6.88 (m, 1H), 5.46−5.40 (m, 1H),
2.32−2.22 (m, 1H), 2.19−2.11 (m, 1H), 2.08 (s, 3H), 1.93−1.59 (m,
4H). 13C NMR (CDCl3, 100 MHz): δ = 170.4, 144.5, 138.7, 134.7,
133.7, 129.4, 128.4, 67.4, 27.2, 23.0, 21.2, 19.2. HR-MS (ESI): calcd
for C14H16NaO4S+ 303.0671, found 303.0662 [M + Na]+. Chiral
separation: HPLC: Chiralpak OJ column, 97:3 isohexane/i-PrOH, 0.5
mL·min−1, 30 °C, 211 nm, tR1 = 22 min (R), tR2 = 23 min (S). [α]20
+95.0 (c 0.92, CHCl3), 94% ee.
=
D
(R)-3-Iodocyclohex-2-enyl Acetate (2g). The reaction was
performed at 30 °C according to method B using the enzyme
preparation Amano PS-IM. Compound isolated after column
chromatography (SiO2, pentane/EtOAc 20:1) in 90% yield (58 mg).
>99% ee. Experimental data were in accordance with those previous
reported.35 1H NMR (CDCl3, 400 MHz): δ = 6.46−6.42 (m, 1H),
4.19−4.13 (m, 1H), 2.60−2.41 (m, 2H), 1.95−1.87 (m, 2H), 1.86−
1.76 (m, 1H), 1.69−1.57 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ =
Method B. Ruthenium complex B (η5C5Ph5)Ru(CO)2Cl (8 mg,
0.0125 mmol), lipase (6.25 mg, 25 mg/mmol substrate), and Na2CO3
(26.5 mg, 0.25 mmol) were added to a dry Schlenk tube under argon
atmosphere. Dry toluene (0.5 mL) was added, and the resulting yellow
solution was stirred. A THF solution of t-BuOK (25 μL, 0.5 M in dry
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The Journal of Organic Chemistry
Article
170.4, 135.7, 103.8, 69.4, 39.4, 26.9, 21.5, 21.4. Chiral separation: GC:
−78 °C for 20 min and then allowed to reach rt for 2 h. The reaction
was quenched by addition of 3 mL of NH4Cl (aq) followed by wash of
the organic phase by 3 mL of H2O. The organic phase was separated
and dried with MgSO4. The solvent was reduced by evaporation at 50
mbar pressure. The product was isolated with 15 mol % of the
remaining diethyl ether that could not be evaporated without losing
large amounts of product. Yield: 1c + 15% Et2O: 28 mg (71%) 99% ee.
1H NMR (CDCl3, 400 MHz): δ = 5.87−5.81 (m, 1H), 5.78−5.72 (m,
1H), 4.20 (br s, 1H), 2.10−1.95 (m, 2H), 1.94−1.83 (m, 1H), 1.79−
1.68 (m, 1H), 1.66−1.50 (m, 3H). Chiral separation: GC: IVADEX-I,
70 °C-1 °C/min-140 °C, tR1 = 12.4 min (S), tR2 = 13.0 min (R), 99%
ee.
IVADEX-I, 70−1 °C/min−140 °C, tR1 = 52 min (S), tR2 = 54 min (R).
[α]20 = +127.9 (c 1.90, THF), >99% ee.
D
(R)-3-Undecylcyclohex-2-enyl Acetate (2h). The reaction was
performed according to method A using the enzyme preparation
Amano PS-IM. The compound was isolated after column chromatog-
raphy (SiO2, pentane/EtOAc 19:1) in 79% yield (59 mg). 91% ee.
Experimental data were in accordance with those previous reported.36
1H NMR (CDCl3, 400 MHz): δ = 5.46−5.43 (m, 1H), 5.28−5.24 (m,
1H), 2.04 (s, 3H), 2.01−1.88 (m, 4H), 1.83−1.59 (m, 4H), 1.44−1.36
(m, 2H), 1.29−1.23 (m, 16H), 0.91 (t, 3H J = 6.5). Chiral separation:
HPLC: Chiralpak ID column, 100% isohexane, 0.5 mL·min−1, 22 °C,
211 nm, tR1 = 54 min (R), tR2 = 61 min (S). [α]20 = +90.2 (c 0.58,
D
CHCl3), 91% ee.
ASSOCIATED CONTENT
■
(R)-3-(Phenylsulfonyl)cyclopent-2-enyl Acetate (2i). The reaction
was performed according to method A using the enzyme preparation
Amano PS-IM. The compound was isolated after column chromatog-
S
* Supporting Information
Mechanism for formation of racemic 2e and 4e, additional
kinetic resolution data, and copies of 1H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org/.
1
raphy (SiO2, pentane/EtOAc 4:1) in 40% yield (27 mg). 88% ee. H
NMR (CDCl3, 400 MHz): δ = 7.94−7.89 (m, 2H), 7.69−7.63 (m,
1H), 7.60−7.53 (m, 2H), 6.62−6.57 (m, 1H), 5.75−5.68 (m, 1H),
2.76−2.64 (m, 1H), 2.56−2.42 (m, 2H), 2.03 (s, 3H), 1.98−1.83 (m,
1H). 13C NMR (CDCl3, 100 MHz): δ = 170.5, 150.0, 138.8, 138.2,
134.0, 129.5, 128.4, 78.3, 30.7, 29.5, 21.1. HR-MS (ESI): calcd for
C13H14O4S+ 289.0498, found 289.0505 [M + Na]+. Chiral separation:
HPLC: Chiralpak IA column, 10% i-PrOH/isohexane, 0.5 mL·min−1,
30 °C, 211 nm, tR1 = 24 min (R), tR2 = 26 min (S), 88% ee.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jeb@organ.su.se.
Notes
(R)-3-Cyanocyclopent-2-enyl Acetate (2j). The reaction was
performed according to method A using the enzyme preparation
Amano PS-IM. The compound was isolated after column chromatog-
The authors declare no competing financial interest.
1
raphy (SiO2, pentane/EtOAc 4:1) in 92% yield (35 mg). H NMR
ACKNOWLEDGMENTS
■
(CDCl3, 400 MHz): δ = 6.63−6.59 (m, 1H), 5.77−5.71 (m, 1H),
2.82−2.72 (m, 1H), 2.64−2.54 (m, 1H), 2.49−2.38 (m, 1H), 2.05 (s,
3H), 1.88−1.78 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ = 170.5,
144.8, 120.3, 115.7, 78.7, 33.2, 29.7, 21.0. HR-MS (CI): calcd for
C8H10NO2 152.0712, found 152.0718 [M + H]+. Chiral separation:
HPLC: Chiralpak IA column, 1% i-PrOH/isohexane, 0.5 mL·min−1, 30
°C, 211 nm, tR1 = 20.6 min (R), tR2 = 21.9 min (S), 26% ee.
Financial support from the Swedish Research Council and the
Knut and Alice Wallenberg Foundation is gratefully acknowl-
edged. We also thank Dr. Yoshihiko Hirose, Amano Enzyme
Inc., and Gifu R&D Center for kindly providing us with
enzymes (PS-IM, PS-C) and Prof. T. Itoh for providing IL1-PS.
(R)-3-Methylcyclohex-2-enyl Acetate-3 (2b). Reaction performed
according to method A with 2,6-dimethylheptan-4-ol (1 equiv) and
Candida antarctica lipase B, enzyme preparation Novozyme-435 (5
mg/mmol). The product was obtained in 60% ee but not isolated.
Experimental data in accordance with those previous reported.38 1H
NMR (CDCl3, 400 MHz): δ = 5.49−5.45 (m, 1H), 5.27−5.21 (m,
1H), 2.04 (s, 3H), 2.00−1.89 (m, 2H), 1.82−1.59 (m, 4H), 1.71 (s,
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