Kinetic and dynamic kinetic resolution of secondary alcohols with ionic-surfactant-coated Burkholderia cepacia lipase: Substrate scope and enantioselectivity

Article abstract of DOI:10.1021/jo3027627

Forty-four different secondary alcohols, which can be classified into several types (II-IX), were tested as the substrates of ionic surfactant-coated Burkholderia cepacia lipase (ISCBCL) to see its substrate scope and enantioselectivity in kinetic and dynamic kinetic resolution (KR and DKR). They include 6 boron-containing alcohols, 24 chiral propargyl alcohols, and 14 diarylmethanols. The results from the studies on KR indicate that ISCBCL accepted most of them with high enantioselectivity at ambient temperature and with useful to high enantioselectivity at elevated temperatures. In particular, ISCBCL displayed high enantioselectivity toward sterically demanding secondary alcohols (types VIII and IX) which have two bulky substituents at the hydroxymethine center. DKR reactions were performed by the combination of ISCBCL with a ruthenium-based racemization catalyst at 25-60 C. Forty-one secondary alcohols were tested for DKR. About half of them were transformed into their acetates of high enantiopurity (>90% ee) with good yields (>80%). It is concluded that ISCBCL appears to be a superb enzyme for the KR and DKR of secondary alcohols.

Full text of DOI:10.1021/jo3027627

Article
pubs.acs.org/joc
Kinetic and Dynamic Kinetic Resolution of Secondary Alcohols with
Ionic-Surfactant-Coated Burkholderia cepacia Lipase: Substrate Scope
and Enantioselectivity
Cheolwoo Kim,‡ Jusuk Lee,‡ Jeonghun Cho,‡ Yeonock Oh,‡ Yoon Kyung Choi, Eunjeong Choi,
Jaiwook Park,* and Mahn-Joo Kim*
Department of Chemistry, Pohang University of Science and Technology, San-31 Hyojadong, Pohang 790-784, Republic of Korea
S
* Supporting Information
ABSTRACT: Forty-four different secondary alcohols, which
can be classified into several types (II-IX), were tested as the
substrates of ionic surfactant-coated Burkholderia cepacia lipase
(ISCBCL) to see its substrate scope and enantioselectivity in
kinetic and dynamic kinetic resolution (KR and DKR). They
include 6 boron-containing alcohols, 24 chiral propargyl
alcohols, and 14 diarylmethanols. The results from the studies
on KR indicate that ISCBCL accepted most of them with high
enantioselectivity at ambient temperature and with useful to
high enantioselectivity at elevated temperatures. In particular,
ISCBCL displayed high enantioselectivity toward sterically
demanding secondary alcohols (types VIII and IX) which have two bulky substituents at the hydroxymethine center. DKR
reactions were performed by the combination of ISCBCL with a ruthenium-based racemization catalyst at 25−60 °C. Forty-one
secondary alcohols were tested for DKR. About half of them were transformed into their acetates of high enantiopurity (>90%
ee) with good yields (>80%). It is concluded that ISCBCL appears to be a superb enzyme for the KR and DKR of secondary
alcohols.
INTRODUCTION
■
Enantioselective transformations by lipases provide convenient
routes to a wide range of nonracemic compounds, particularly
optically active alcohols, carboxylic acids, amines, amino acids,
and their derivatives.1 Most of them employ racemic substrates
and usually provide a pair of separated enantiomers via kinetic
resolution (KR). These processes thus suffer from a serious
limitation that the theoretical maximum yield for a wanted
enantiomer is 50%. Over the past decade, several groups
including ours have developed more practical processes
employing a lipase and a ruthenium-based racemization catalyst
in combination for dynamic kinetic resolution (DKR)2−5 to
overcome the limitations of classical enzymatic KR. The scope
of chemoenzymatic DKR is determined largely by the substrate
specificity and enantioselectivity of enzyme employed. Accord-
ingly, enzymes with both broad substrate specificity and high
enantioselectivity are needed for the wide applications of
chemoenzymatic DKR. Lately, we communicated that ionic-
surfactant-coated Burkholderia cepacia lipase (ISCBCL), which
was prepared by coating an aqueous extract of a commercial
lipase (lipase PS) with an ionic surfactant (1), had great
potential as such an enzyme.6 We now wish to report a full
account on the substrate scope and enantioselectivity of
ISCBCL examined with a wider range of new substrates.
We could classify secondary alcohols into nine types (I−IX,
Figure 1) according to the nature of two substituents at the
hydroxymethine center to show the substrate specificity of a
lipase. Among commercially available lipases, few accept all
nine types of substrates with good activity and high
enantioselectivity. The most popular Candida antarctica lipase
B (CALB; brand name Novozym 435) has been known to
accept only three types (I, II, and V) of secondary alcohols and
carries a small and a relatively large substituent at the
hydroxymethine center, with good to high enantioselectivity
at synthetically useful rates.7 Recent studies, however, revealed
that CALB could be engineered by site-directed mutagenesis to
accept sterically more demanding types. A mutant of CALB
accepted the substrates of type VI, VII,8a and IX8b with useful
enantioselectivity. In our previous communication,6 we
demonstrated that ISCBCL accepted the substrates of three
types (VI−VIII) in DKR with good results. The results
encouraged us to explore further the substrate scope and
enantioselectivity of ISCBCL. It was found that ISCBCL could
Received: December 21, 2012
Published: February 13, 2013
© 2013 American Chemical Society
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Article
a TMS-ethynyl substituent at the hydroxymethine center, thus
representing three types (II−IV) of substrates. Six boron-
containing secondary alcohols 3a−f with an alkyl (C1−C6) and
an aryl substituent at the hydroxymethine center can be
considered as another three types, V−VII. Seventeen
disubstituted propargyl alcohols 4a−q carrying an aryl and a
phenyl- or tert-butylethynyl substituent at the stereocenter
belong to the type VIII. Fourteen diarylmethanols 5a−n are the
type IX substrates. To the best of our knowledge, none of them
(2a−5n) has been tested before as the substrates of lipase for
DKR. It is noted that the CALB mutant has been used in the
DKR of substrates of types VI and VII with good results.8a In
this case, however, the substrates were 1-phenylalkanols
(RCH(OH)Ph, R = butyl and hexyl).
Active-Site Model and Enantioselectivity of ISCBCL. It
is possible to predict the enantioselectivity of ISCBCL using the
active-site model based on the X-ray structure of BCL10 (Figure
3). BCL has three binding pockets (HA, HB, and HH) at its
Figure 1. Types of secondary alcohols as the substrates of lipases: RS,
small aliphatic; RM, medium-sized aliphatic; RL, long aliphatic; RB,
branched and bulky aliphatic; Ar, aromatic; ArS, small or simple
aromatic; ArB, branched and bulky aromatic.
accept all eight types (II−IX) of secondary alcohols with useful
to high enantioselectivity.
BCL may be coated with commercially available surfactants
(such as PEG and AOT) or ionic liquids for enhancing its
activity in organic solvent. We observed that commercial
surfactants were weakly activating. The coating of BCL with 1,
however, enhanced its activity in organic solvent by 1000-fold
relative to its commercial precursor.6 ISCBCL thus was more
active than Novozym 435 and displayed an excellent perform-
ance in the DKR of substrates of type VI−VIII. Recently, Itoh
et al. reported that some synthetic ionic liquids enhanced the
activity of BCL by orders of magnitude,9 but the application of
ionic-liquid-coated BCL to DKR has not been reported yet.
RESULTS AND DISCUSSION
■
Types of Secondary Alcohols Tested As the Sub-
strates of ISCBCL. The 44 secondary alcohols tested as the
substrates of ISCBCL are described in Figure 2. Seven TMS-
protected propargyl alcohols 2a−g have an alkyl (C1∼C6) and
Figure 3. Active-site model of ISCBCL showing the binding of more
reactive enantiomers.
active site for anchoring three substituents at the stereocenter
of substrate. Among them, the HH binding pocket appears to
play an essential role in determining the substrate specificity
and enantioselectivity. It has two rooms, a hydrophilic trench
and its entrance (a space of 4.5 Å in diameter), which are
separated by a contraction.10a It can accept small, medium, or
long aliphatic groups. It can also accommodate flat aromatic
rings. However, branched and bulky aliphatic and aromatic
groups are difficult to fit into the pocket owing to severe steric
repulsion around the contraction of the pocket. Therefore, the
enantiomers shown in Figure 3 should bind more favorably and
thus react more rapidly than their antipodes11 (Figure 3). And
it is also expected that the enantioselectivity should be high.
Enantioselectivity of ISCBCL in Kinetic Resolution. The
enantioselectivity of ISCBCL for each of the secondary alcohols
was examined with the ISCBCL-catalyzed transesterification. In
typical procedures, the reactions were performed with solutions
containing a substrate (0.1 mmol), ISCBCL6 (10−30 mg/
mmol), and isopropenyl acetate (IPA, 1.5 equiv) in toluene at
25−60 °C. The reactions at elevated temperatures (40−60 °C)
were done for the applications to the higher temperature DKR.
After the reactions reached near 50% completion, the acylated
Figure 2. Secondary alcohols tested as the substrates of ISCBCL.
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Table 1. Enantioselectivity of ISCBCL in Transesterification
a
a
a
entry
substrate
T (°C)
E
entry
substrate
T (°C)
E
entry
substrate
T (°C)
E
1
2b
2g
3a
3b
3c
3d
3e
3f
25
25
25
25
40
40
40
40
25
25
25
25
25
>200
>200
>200
>200
118
14
15
16
17
18
19
20
21
22
23
24
25
26
4f
25
25
60
60
60
60
60
60
60
60
60
60
25
65
27
28
29
30
31
32
33
34
35
36
37
38
39
5b
5c
5d
5e
5f
60
60
60
60
60
60
60
60
60
60
60
60
60
29
17
18
22
19
23
103
94
44
43
70
69
37
2
4g
4h
4i
>200
>200
>200
>200
>200
65
3
4
5
4j
6
58
4k
4l
5g
5h
5i
7
50
8
50
4m
4n
4o
4p
4q
5a
60
9
4a
4b
4c
4d
4e
>200
>200
>200
>200
>200
51
5j
10
11
12
13
43
5k
5l
>200
20
5m
5n
>200
a
The enantioselectivity was calculated using the equation: E = ln[1 − c(1 + eep)]/ln[1 − c(1 − eep)] where c = ees/(ees + eep).
products and remaining substrates were isolated and analyzed
by HPLC or GC for determining their enantiomeric excesses.
The enantioselectivity (E) of ISCBCL for each substrate was
then calculated using the equation: E = ln[1 − c(1 + eep)]/ln[1
− c(1 − eep)] where c = ees/(ees + eep). The results are
described in Table 1.
cally acceptable in most cases. In general, the enantioselectivity
of ISCBCL is in good agreement with our prediction based on
the active-site model of ISCBCL.
Dynamic Kinetic Resolution with ISCBCL. The secon-
dary alcohols described in Figure 2 were subjected to the
ISCBCL-catalyzed DKR in toluene. The DKR reactions were
performed at three different temperatures (rt, 40, and 60 °C)
depending on the reactivity of substrate. In all the DKR
reactions, isopropenyl acetate (IPA) was employed as the acyl
donor, and in most of them, ruthenium complex 614b was
employed as the racemization catalyst.
The enantioselectivity of ISCBCL toward TMS-protected
propargyl alcohols12 was examined for two substrates (2b and
2g) at 25 °C. Both of them were accepted with high
enantioselectivity (E = >200) (entries 1 and 2). The high
enantioselectivity for 2g is particularly noteworthy because it
has two bulky substituents at the stereocenter. These results
thus indicate that ISCBCL can accept the three types of
substrates (II−IV) with high enantioselectivity. The enantiose-
lectivity of ISCBCL toward the boron-containing substrates13
(3a−f) was high at 25 °C (entries 3 and 4) and good at 40 °C
(entries 5−8). These results prove that the three types of
substrates (V−VII) are accepted by ISCBCL enantioselectively.
The enantioselectivity of ISCBCL toward α-arylpropargyl
alcohols (4a−q) was generally good to high but dependent
on the substitution pattern of α-aromatic ring. It was high (E =
>200) for those having no substituent (entries 9 and 15) or a
para-substituent on the α-aromatic ring (entries 10−13 and
16−19) but lower (E = 43−60) for those having a meta-
substitutent on the α-aromatic ring (entries 14, 21−23). It is
notable that the enantioselectivities for some substrates were
high even at 60 °C (entries 16−19). The size of the α-aromatic
ring also affected the enantioselectivity. It was high (E = >200)
if the α-aromatic ring was furyl but modest (E = 20) if the α-
aromatic ring was naphthyl (entries 24 and 25).
The enantioselectivity of ISCBCL toward diarylmethanols
was surprisingly high (E = >200) at 25 °C (entry 26). The
enantioselectivity at 60 °C was significantly lower but increased
if p-isopropylphenyl was replaced by p-tert-butylphenyl
(compare entries 27−32 with entries 34−39). The results
indicate that diarylmethanols can be accepted by ISCBCL with
good to high enantioselectivity if they have a simple and a bulky
aromatic substituent.
Overall, ISCBCL displayed high enantioselectivity (E =
>200) toward all the substrates except one tested at 25 °C and
some substrates tested at elevated temperatures. The lower
enantioselectivities at elevated temperatures are still syntheti-
The DKR reactions of TMS-propargyl alcohols 2a−g were
performed with solutions containing substrate (0.3 mmol),
ISCBCL (3 mg), 6 (5 mol %), K2CO3 (0.3 mmol), and IPA
(1.5 equiv) in toluene at 60 °C. Here, the elevated temperature
was needed to promote the ruthenium-catalyzed racemization
of substrate. The DKR reactions of 2a−c were complete in 24 h
to give good yields and excellent enantiomeric excesses (Table
2). Those of 2d−f required a longer reaction time (36 h) for
the completion and provided good yields but slightly reduced
enantiopurities. The DKR reaction of 2g was rather sluggish
due to the increased bulkiness of α-substituent (c-Hex) and
thus needed a much longer reaction time (72 h). In this case,
the enantiopurity was relatively lower probably due to the slow
racemization. Overall, the results indicate that the DKR of α-
alkyl-TMS-propargyl alcohols was successful. This DKR
complements the DKR of α-aryl-TMS-propargyl alcohols
reported in the previous communication.6
It is noted that the acylated products from these DKRs can
be readily converted to TMS-free acetates or alcohols by
treatment with TBAF or K2CO3, respectively, without any loss
in enantiopurity (Scheme 1).6,12b Accordingly, the DKR of
TMS-protected α-chiral propargyl alcohols provides a practical
route to enantioenriched α-chiral propargyl alcohols and
acetates which are useful building blocks in asymmetric
synthesis.15 Recently, Ariza et al. reported that enantiopure α-
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was used instead of 6 as the racemization catalyst because 6
catalyzed the isomerization of substrate to the corresponding
ketone via dehydrogenation of hydroxy group and hydro-
genation of allylic group. In the case of 3f, the DKR reaction
was sluggish and thus required a long reaction time. Overall, the
results indicate that the DKR of boron-containing alcohols was
successfully achieved. It is noted that the DKR products can be
utilized as chiral building blocks for the enantioselective
synthesis of more complex compounds via the well-known
Suzuki cross coupling reaction.17
The DKR reactions of α-arylpropargyl alcohols 4a−q were
carried out with solutions containing substrate (0.1 mmol),
ISCBCL (1−3 mg), 6 (4 mol %), K2CO3 (0.1 mmol), and IPA
(1.5 equiv) in toluene. The DKR reaction of 4a at room
temperature was sluggish and provided modest enantiopurity
(entry 1, Table 4). The reactions of 4b and 4d performed at 60
Table 2. DKR of TMS-propargyl Alcohols with ISCBCL
a
entry
substrate
product
time (h)
yield (%)
ee (%)
b
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
8a
24
24
24
36
36
36
72
92
92
93
94
97
97
91
99
99
b
8b
c
8c
8d
8e
8f
98
c
97
c
92
c
92
d
2g
8g
84
a
b
Isolated yield. Absolute configurations were confirmed by
comparing their optical rotations with the literature data (see the
c
Experimental Section). Determined after TMS was removed.
a
d
Table 4. DKR of α-Arylpropargyl Alcohols with ISCBCL
Determined after TMS and acyl were removed.
Scheme 1. Deprotection of TMS-propargyl Acetates
b
entry
substrate
product
time (h)
yield (%)
ee (%)
c
1
4a
4b
4d
4g
4h
4i
10a
72
24
24
24
48
48
48
48
48
48
48
48
48
48
65
90
95
97
97
96
97
96
98
97
96
93
95
96
68
19
24
99
95
95
92
95
66
88
83
74
2
10b
10d
3
c
4
10g
5
10h
10i
6
7
4j
10j
chiral propargyl acetate was particularly useful as the building
block for the stereoselective construction of polyhydroxylated
chains.16
8
4k
4l
10k
10l
9
10
11
12
13
14
4m
4n
4o
4p
4q
10m
10n
10o
10p
10q
The DKR reactions of boron-containing substrates 3a,b were
carried out with solutions containing substrate (0.1 mmol),
ISCBCL (1 mg), ruthenium complex 6 (4 mol %), K2CO3 (0.1
mmol), and IPA (1.5 equiv) in toluene at room temperature to
give the products with good yields and high enantiomeric
excesses (entries 1 and 2, Table 3). The DKR of less reactive
3c−f was done with a larger amount (2 mg) of enzyme at 40
°C to obtain good yields and good enantiomeric excesses
(entries 3−6). In the case of 3c (entry 3), ruthenium complex 7
d
61
71
a
The reaction of 4a was performed at 25 °C and those of the rest at 60
°C. Isolated yield. Absolute configurations were confirmed by
comparing their optical rotations with the literature data (see the
b
c
d
Experimental Section). Determined after being deacetylated.
a
Table 3. DKR of Boron-Containing Alcohols with ISCBCL
°C gave disappointedly low enantiopurity (entries 2 and 3,
Table 4). It was found that spontaneous chemical acylation
took place significantly in these cases. These results indicate
that the DKR of diarylpropargyl alcohols is less than satisfactory
and thus needs more efforts for improvement. In contrast to
this, the DKR of α-aryl-tert-butylpropargyl alcohols 4g−q at 60
°C provided better results. The high enantiopurities with good
yields were obtained for the DKR of 4g−k (entries 4−8, Table
4). In case of 4l−q, the enantiopurity was substantially lowered
due to minor chemical acylation (entries 9−14). These results
indicate that the enantioselectivity was apparently dependent
on the nature of α-aryl ring. In general, the para-substituted α-
aryl rings led to good enantioselectivity relative to their meta-
substituted counterparts.
b
entry
substrate
product
time (h)
yield (%)
ee (%)
c
1
2
3a
3b
3c
3d
3e
3f
9a
24
24
89
92
78
85
87
88
98
99
94
94
94
94
9b
9c
9d
9e
9f
d
3
72
4
5
6
60
60
108
a
The DKR of diarylmethanols 5a−n was performed with
solutions containing substrate (0.1 mmol), ISCBCL (3 mg), 6
(5 mol %), K2CO3 (0.1 mmol), and IPA (1.5 equiv) in toluene
at 60 °C. The DKR of three substrates (5a, 5h, and 5i)
provided satisfactory results in both yield and enantiopurity
The reactions of 3a,b were performed at 25 °C and those of the rest
b
c
at 40 °C. Isolated yield. Absolute configuration was confirmed by
comparing its optical rotation with the literature value (see the
Experimental Section). Compound 7 was employed as the
racemization catalyst instead of 6.
d
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then shaken at 25−60 °C until the reaction reached 40−50%
conversion. After being diluted with methylene chloride, the reaction
mixture was filtered through a Celite pad, concentrated, and then
analyzed by HPLC or GC to determine the enantiomeric excesses of
remaining substrate and acetylated product. The enantioselectivity (E)
of ISCBCL was then calculated using the equation: E = ln[1 − c(1 +
eep)]/ln[1 − c(1 − eep)] where c = ees/(ees + eep).
(entries 1, 8, and 9, Table 5). In other cases, the yields were
significantly reduced owing to the oxidation of substrates to the
Table 5. DKR of Diaryl Carbinols with ISCBCL
DKR of 2a−g. The DKR reactions were performed with solutions
containing substrate (0.3 mmol), ISCBCL (3 mg), 6 (5 mol %),
K2CO3 (41 mg, 0.3 mmol), and IPA (1.5 equiv) in toluene at 60 °C
for 24−72 h according to the standard procedure described
previously.6
a
entry
substrate
product
time (h)
yield (%)
ee (%)
(R)-3-Acetoxy-1-(trimethylsilyl)-1-butyne (8a): 51 mg (92% yield,
b
1
5a
5b
5c
5d
5e
5f
11a
36
36
36
36
48
48
48
36
48
48
60
48
60
60
93 (86)
65 (57)
61
91
91
85
61
75
79
83
95
95
94
87
71
86
93
99% ee); [α]17D = +117 (c = 1.0, CHCl3) [lit.19 [α]20D = +119 (c = 2.2,
2
11b
11c
11d
11e
11f
1
CHCl3, 99% ee)]; H NMR (300 MHz, CDCl3, ppm) δ 5.47 (q, J =
3
6.72 Hz, 1H), 2.08 (s, 3H), 1.48 (d, J = 6.72 Hz, 3H), 0.17 (s, 9H);
13C NMR (75 MHz, CDCl3, ppm) 170.0, 103.8, 89.7, 60.9, 21.7, 21.4,
0.0; GC conditions: β-dex 120, inlet temp 250 °C, FID detector temp
300 °C, oven initial temp 60 °C (2 min), rate 1 °C/min, oven final
temp 70 °C (30 min), retention times 33.42 min (S), 34.09 min (R).
(R)-3-Acetoxy-1-(trimethylsilyl)-1-pentyne (8b): 55 mg (92% yield,
99% ee); [α]18 = +123 (c = 0.9, CHCl3) [lit.20 [α]20 = +126.5 (c =
4
19
5
75
6
65
7
5g
5h
5i
11g
11h
11i
46
8
89 (87)
84 (76)
55
D
D
9
1.0, CHCl3, 99% ee)]; 1H NMR (300 MHz, CDCl3, ppm) δ 5.34 (t, J
= 6.50 Hz, 1H), 2.09 (s, 3H), 1.83−1.71 (m, 2H), 1.00 (t, J = 7.45 Hz,
3H), 0.17 (s, 9H); 13C NMR (75 MHz, CDCl3, ppm) 170.1, 102.7,
90.5, 65.7, 28.3, 21.3, 9.5, 0.0; GC conditions: β-dex 120, inlet temp
250 °C, FID detector temp 300 °C, oven initial temp 60 °C (2 min),
rate 1 °C/min, oven final temp 75 °C (35 min), retention times 44.07
min (S), 44.83 min (R).
10
11
12
13
14
5j
11j
5k
5l
11k
11l
42
76
5m
11m
11n
69
5n
68
a
1
Determined by H NMR. Isolated yields are given in parentheses.
b
(R)-3-Acetoxy-1-(trimethylsilyl)-1-hexyne (8c): 59 mg (93% yield,
Absolute configuration was confirmed by comparing the optical
1
98% ee); [α]18 = +101 (c = 1.0, CHCl3); H NMR (300 MHz,
rotation of its hydrolyzed product with the literature value (see the
Experimental Section).
D
CDCl3, ppm) δ 5.39 (t, J = 6.65 Hz, 1H), 2.08 (s, 3H), 1.78−1.68 (m,
2H), 1.50−1.38 (m, 2H), 0.95 (t, J = 7.31 Hz, 3H), 0.17 (s, 9H); 13C
NMR (75 MHz, CDCl3, ppm) 170.1, 102.9, 90.4, 64.4, 37.1, 21.3,
18.5, 13.8, 0.0. Enantiomeric excess (ee) was determined by GC after
deprotecting TMS with TBAF. GC conditions: β-dex 120, inlet temp
250 °C, FID detector temp 300 °C, oven initial temp 60 °C (2 min),
rate 2 °C/min, oven final temp 90 °C (0 min), retention times 14.27
min (R), 14.76 min (S); TOF-MS (ESI+) calcd for [C11H20O2Si +
Na]+ 235.1130, found 235.1130.
corresponding ketones. In particular, p-methoxy-substituted
diarylmethanol 5d was highly susceptible to oxidation, thus
resulting in the lowest yield (entry 4).18 As expected, the DKR
reactions of p-tert-butyl-substituted substrates (entries 8−14) in
general provided the products of higher enantiopurity than
those of their para-isopropyl-substituted counterparts (entries
1−7).
(R)-3-Acetoxy-1-(trimethylsilyl)-1-heptyne (8d): 64 mg (94% yield,
1
97% ee); [α]17 = +92.7 (c = 1.0, CHCl3); H NMR (300 MHz,
D
CDCl3, ppm) δ 5.38 (t, J = 6.72 Hz, 1H), 2.08 (s, 3H), 1.79−1.70 (m,
2H), 1.47−1.27 (m, 4H), 0.95−0.88 (m, 3H), 0.17 (s, 9 H); 13C NMR
(75 MHz, CDCl3, ppm) 170.1, 103.0, 90.4, 64.6, 34.7, 27.3, 22.4, 21.3,
14.1, 0.0. Enantiomeric excess (ee) was determined by GC after
deprotecting TMS with TBAF. GC conditions: β-dex 120, inlet temp
250 °C, FID detector temp 300 °C, oven initial temp 60 °C (2 min),
rate 4 °C/min, oven final temp 100 °C (10 min), retention times 14.6
min (R), 15.09 min (S); TOF-MS (ESI+) calcd for [C12H22O2Si +
Na]+ 249.1287, found 249.1265.
CONCLUSION
■
More than 40 secondary alcohols, which can be classified into
eight different types (II−IX) according to the nature of two
substituents at the hydroxymethine center, were examined as
the substrates of ISCBCL for KR and DKR. They include
boron-containing alcohols, α-chiral propargyl alcohols, and
diarylmethanols. Most of them were accepted by ISCBCL with
useful to high enantioselectivity. The results prove that
ISCBCL is particularly useful in the resolution of sterically
demanding substrate types (VIII and IX) with two bulky
substituents at the hydroxymethine center. The DKR reactions
of 41 secondary alcohols performed by the combination of
ISCBCL and a ruthenium-based racemization catalyst provided
good yields and high enantiopurities for about half of them. We
thus conclude that ISCBCL is a superb enzyme for the KR and
DKR of secondary alcohols.
(R)-3-Acetoxy-1-(trimethylsilyl)-1-octyne (8e): 70 mg (97% yield,
1
92% ee); [α]18 = +71.0 (c = 1.0, CHCl3); H NMR (300 MHz,
D
CDCl3, ppm) δ 5.38 (t, J = 6.65 Hz, 1H), 2.08 (s, 3H), 1.79−1.68 (m,
2H), 1.49−1.37 (m, 2H), 1.35−1.27 (m, 4H), 0.94−0.86 (m, 3H),
0.17 (s, 9H); 13C NMR (75 MHz, CDCl3, ppm) 170.1, 103.0, 90.4,
64.6, 34.9, 31.4, 24.8, 22.6, 21.3, 14.1, 0.0. Enantiomeric excess (ee)
was determined by GC after deprotecting TMS with TBAF. GC
conditions: β-dex 120, inlet temp 250 °C, FID detector temp 300 °C,
oven initial temp 60 °C (2 min), rate 4 °C/min, oven final temp 100
°C (20 min), retention times 20.99 min (R), 21.65 min (S); TOF-MS
(ESI+) calcd for [C13H24O2Si + Na]+ 263.1443, found 263.1426.
EXPERIMENTAL SECTION
(R)-3-Acetoxy-1-(trimethylsilyl)-1-nonyne (8f): 74 mg (97% yield,
■
1
92% ee); [α]17 = +74.3 (c = 1.0, CHCl3); H NMR (300 MHz,
Determination of the Enantioselectivity of ISCBCL. ISCBCL
was prepared according to the procedure described previously.6 The
enantioselectivity of ISCBCL for each substrate was determined with
its ISCBCL-catalyzed transesterification in the presence of IPA in
toluene. In a typical procedure, isopropenyl acetate (1.5 equiv) was
added to a 4 mL vial containing ISCBCL (1 mg), substrate (0.2
mmol), and anhydrous toluene (0.2 M). The resulting solution was
D
CDCl3, ppm) δ 5.38 (t, J = 6.65 Hz, 1H), 2.08 (s, 3H), 1.79−1.69 (m,
2H), 1.48−1.36 (m, 2H), 1.35−1.24 (m, 6H), 0.93−0.85 (m, 3H),
0.17 (s, 9H); 13C NMR (75 MHz, CDCl3, ppm) 170.1, 103.0, 90.4,
64.6, 35.0, 31.8, 28.9, 25.1, 22.7, 21.3, 14.2, 0.0. Enantiomeric excess
(ee) was determined by GC after deprotecting TMS with TBAF. GC
conditions: β-dex 120, inlet temp 250 °C, FID detector temp 300 °C,
2575
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The Journal of Organic Chemistry
Article
oven initial temp 60 °C (2 min), rate 4 °C/min, oven final temp 100
°C (25 min), retention times 32.44 min (R), 33.69 min (S); TOF-MS
(ESI+) calcd for [C14H26O2Si + Na]+ 277.1600, found 277.1580.
retention times 5.28 min (S), 15.2 min (R); TOF-MS (ESI+) calcd for
[C19H29BO4 + Na]+ 355.20566, found 355.20604.
(R)-1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-
heptyl acetate (9f): 32 mg (88% yield, 94% ee), [α]16 = +37.4 (c =
(R)-3-Acetoxy-3-cyclohexyl-1-(trimethylsilyl)-1-propyne (8g): 69
D
1.0, CHCl3); 1H NMR (300 MHz, CDCl3, ppm) δ 7.79 (d, J = 8.0 Hz,
2H), 7.32 (d, J = 7.9 Hz, 2H), 5.72 (t, J = 6.9 Hz, 1H), 2.06 (s, 3H),
1.95−1.69 (m, 2H), 1.36−1.24 (m, 20H), 0.86 (t, J = 4.7 Hz, 3H); 13C
NMR (75 MHz, CDCl3, ppm) 170.4, 144.0, 134.9, 125.8, 83.8, 76.1,
36.3, 31.7, 29.0, 25.4, 24.9, 22.6, 21.3, 14.0. HPLC conditions: (R,R)-
Whelk-O1, n-hexane/2-propanol = 95/5, flow rate = 1.0 mL/min, UV
= 217 nm, retention times 5.44 min (S), 17.6 min (R); TOF-MS (ESI
+) calcd for [C21H33BO4+Na]+ 383.23696, found 383.23644.
DKR of 4a−q. The DKR reactions were performed with solutions
containing substrate (0.1 mmol), ISCBCL (1−3 mg), 6 (4 mol %),
K2CO3 (14 mg, 0.1 mmol), and IPA (1.5 equiv) in toluene at 25−60
°C for 24−48 h according to the standard procedure described
previously.6 The DKR reaction of 4a was carried out 25 °C and the
rest at 60 °C.
1
mg (91% yield, 84% ee); [α]17 = +69.2 (c = 1.0, CHCl3); H NMR
D
(300 MHz, CDCl3, ppm) δ 5.24 (d, J = 6.14 Hz, 1H), 2.09 (s, 3H),
1.88−1.59 (m, 6H), 1.34−0.99 (m, 5H), 0.17 (s, 9H); 13C NMR (75
MHz, CDCl3, ppm) 170.2, 101.9, 91.0, 68.7, 42.0, 28.7, 28.2, 26.4,
25.9, 25.8, 21.2, 0.0. Enantiomeric excess (ee) was determined after
deprotection of TMS and acetyl with K2CO3. GC conditions: β-dex
120, inlet temp 250 °C, FID detector temp 300 °C, oven initial temp
80 °C (2 min), rate 1 °C/min, oven final temp 130 °C (0 min),
retention times 37.86 min (S), 38.48 min (R); TOF-MS (ESI+) calcd
for [C14H24O2Si + Na]+ 275.1443, found 275.1412.
DKR of 3a−f. The DKR reactions were performed with solutions
containing substrate (0.1 mmol), ISCBCL (1−2 mg), 6 (4 mol %) or
7 (4 mol %), K2CO3 (14 mg, 0.1 mmol), and IPA (1.5 equiv) in
toluene at 25−40 °C for 24−108 h according to the standard
procedure described previously.6 Ruthenium catalyst 6 was employed
in most cases except DKR of 3c, in which 7 was used instead. The
DKR reactions of 3a,b were carried out 25 °C and the rest at 40 °C.
(R)-1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-
ethyl acetate (9a): 26 mg (89% yield, 98% ee); [α]25D = +103.8 (c =
(R)-1,3-Diphenylprop-2-ynyl acetate (10a): 16 mg (65% yield,
1
68% ee), [α]25 = +2.48 (c = 1.0, CHCl3); H NMR (300 MHz,
D
CDCl3, ppm) δ 7.59 (d, J = 1.58 Hz, 2H), 7.48−7.46 (m, 2 H), 7.40−
7.39 (m, 3 H), 7.38−7.32 (m, 3 H), 6.70 (s, 1H), 2.13 (s, 3H); 13C
NMR (75 MHz, CDCl3, ppm) 169.9, 137.2, 131.9, 129.0, 128.8, 128.7,
128.3, 127.8, 122.1, 87.1, 85.6, 66.1, 21.2. HPLC conditions: (R,R)-
Whelk-O1, n-hexane/2-propanol = 95/5, flow rate = 0.5 mL/min, UV
= 217 nm, retention times 14.6 min (S), 15.8 min (R); TOF-MS (ESI
+) calcd for [C17H14O2 − OAc]+ 191.08608, found 191.08575. The
product was hydrolyzed by the treatment with K2CO3 in water-MeOH
0.5, CHCl3) [lit.21 [α]24 = +81.8 (c = 1.0, CHCl3, >99% ee)]; H
1
D
NMR (300 MHz, CDCl3, ppm) δ 7.80 (d, J = 8.0 Hz, 2H), 7.35 (d, J =
7.9 Hz, 2H), 5.88 (q, J = 6.6 Hz, 1H), 2.07 (s, 3H), 1.52 (d, J = 6.6 Hz,
3H), 1.34 (s, 12H); 13C NMR (75 MHz, CDCl3, ppm) 170.3, 144.8,
135.0, 125.3, 83.8, 72.3, 24.8, 22.2, 21.3. HPLC conditions: (R,R)-
Whelk-O1, n-hexane/2-propanol = 95/5, flow rate = 1.0 mL/min,
UV=217 nm, retention times 5.92 min (S), 19.5 min (R); TOF-MS
(ESI+) calcd for [C16H23BO4 + Na]+ 313.15871, found 313.15532.
(R)-1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-
propyl acetate (9b): 28 mg (92% yield, >99% ee); [α]25D = +118.4 (c
to give the corresponding alcohol: [α]25 = +3.32 (c = 1.0, CHCl3)
D
[lit.22 [α]22 = +5.1 (c = 0.5, CHCl3, 88% ee)].
D
(R)-1-(4-Fluorophenyl)-3-phenylprop-2-ynyl acetate (10b): 24 mg
(90% yield, 19% ee), [α]27D = +2.95 (c = 1.0, CHCl3); 1H NMR (300
MHz, CDCl3, ppm) δ 7.58−7.56 (m, 2H), 7.48−7.46 (m, 2H), 7.33−
7.31 (m, 3H), 7.09 (t, J = 8.62 Hz, 2H), 6.67 (s, 1H), 2.12 (s, 3H); 13C
NMR (75 MHz, CDCl3, ppm) 169.8, 164.6, 131.9, 129.9, 128.9, 128.3,
121.9, 115.8, 115.5, 87.3, 85.3, 65.4, 21.1. HPLC conditions: (R,R)-
Whelk-O1, n-hexane/2-propanol = 95/5, flow rate = 1.0 mL/min, UV
= 217 nm, retention times 6.38 min (S), 7.00 min (R); TOF-MS (ESI
+) calcd for [C17H13FO2 − OAc]+ 209.07665, found 209.07613.
(R)-3-Phenyl-1-p-tolylprop-2-ynyl acetate (10d): 25 mg (95%
yield, 24% ee), [α]27D = +3.19 (c = 1.0, CHCl3); 1H NMR (300 MHz,
CDCl3, ppm) δ 7.50−7.46 (m, 4H), 7.32−7.30 (m, 3H), 7.21 (d, J =
7.89 Hz, 2H), 6.67 (s, 1H), 2.37 (s, 3H), 2.11 (s, 3H); 13C NMR (75
MHz, CDCl3, ppm) 169.9, 139.0, 134.3, 131.9, 129.4, 128.8, 128.3,
127.8, 122.2, 86.9, 85.8, 66.0, 21.3, 21.2. HPLC conditions: (R,R)-
Whelk-O1, n-hexane/2-propanol = 95/5, flow rate = 1.0 mL/min, UV
= 217 nm, retention times 7.17 min (S), 7.36 min (R); TOF-MS (ESI
+) calcd for [C18H16O2 − OAc]+ 205.10173, found 205.10191.
(R)-4,4-Dimethyl-1-phenylpent-2-ynyl acetate (10g): 22 mg (97%
yield, 99% ee), [α]25D = +28.7 (c = 1.0, CHCl3); 1H NMR (300 MHz,
CDCl3, ppm) δ 7.50 (dd, J = 7.60, 1.90 Hz, 2H), 7.37−7.35 (m, 3H),
6.49 (s, 1H), 2.08 (s, 3H), 1.25 (s, 9H); 13C NMR (75 MHz, CDCl3,
ppm) 169.9, 137.8, 128.6, 127.8, 126.5, 96.3, 75.2, 65.9, 30.8, 27.5,
21.3. HPLC conditions: (R,R)-Whelk-O1, n-hexane/2-propanol = 96/
4, flow rate = 0.5 mL/min, UV = 217 nm, retention times 4.35 min
(R), 4.73 min (S). The product was hydrolyzed by the treatment with
1
= 0.5, CHCl3); H NMR (300 MHz, CDCl3, ppm) δ 7.79 (d, J = 7.7
Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 5.66 (t, J = 6.8 Hz, 1H), 2.07 (s,
3H), 1.93−1.78 (m, 2H), 1.33 (s, 12H), 0.87 (t, J = 7.5 Hz, 3H); 13C
NMR (75 MHz, CDCl3, ppm) 170.4, 143.6, 134.9, 125.9, 83.8, 76.6,
29.2, 24.9, 21.2, 9.82. HPLC conditions: (R,R)-Whelk-O1, n-hexane/2-
propanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm, retention
times 18.5 min (R); TOF-MS (ESI+) calcd for [C17H25BO4 + Na]+
327.17436, found 327.17210.
(R)-1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-
but-3-enyl acetate (9c): 25 mg (78% yield, 94% ee), [α]16D = +59.7 (c
1
= 1.0, CHCl3); H NMR (300 MHz, CDCl3, ppm) δ 7.79 (d, J = 7.9
Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 5.80 (t, J = 6.8 Hz, 1H), 5.75−5.61
(m, 1H), 5.09−5.02 (m, 2H), 2.69−2.52 (m, 2H), 2.07 (s, 3H), 1.33
(s, 12H); 13C NMR (75 MHz, CDCl3, ppm) 170.2, 143.1, 134.9,
133.2, 125.8, 118.1, 83.8, 75.1, 40.7, 24.9, 21.2. HPLC conditions:
(R,R)-Whelk-O1, n-hexane/2-propanol = 95/5, flow rate = 1.0 mL/
min, UV = 217 nm, retention times 5.45 min (S), 13.7 min (R); TOF-
MS (ESI+) calcd for [C18H25BO4+Na]+ 339.17436, found 339.17345.
(R)-1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-
butyl acetate (9d): 27 mg (85% yield, 94% ee), [α]14 = +76.2 (c =
D
0.5, CHCl3); 1H NMR (300 MHz, CDCl3, ppm) δ 7.79 (d, J = 8.0 Hz,
2H), 7.33 (d, J = 8.0 Hz, 2H), 5.74 (t, J = 6.9 Hz, 1H), 2.06 (s, 3H),
1.94−1.67 (m, 2H), 1.33 (s, 14H), 0.90 (t, J = 7.4 Hz, 3H); 13C NMR
(75 MHz, CDCl3, ppm) 170.3, 144.0, 134.9, 125.8, 83.8, 75.9, 38.4,
24.9, 21.3, 18.7, 13.8. HPLC condition: (R,R)-Whelk-O1, n-hexane/2-
propanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm, retention
times 5.58 min (S), 16.0 min (R); TOF-MS (ESI+) calcd for
[C18H27BO4 + Na]+ 341.19001, found 341.18906.
K2CO3 in water−MeOH to give the corresponding alcohol: [α]25
=
D
+31.0 (c = 1.0, CHCl3) [lit.22 [α]28 = +21.3 (c = 0.5, CHCl3), 75%
D
ee].
(R)-1-(4-Fluorophenyl)-4,4-dimethylpent-2-ynyl acetate (10h): 24
mg (97% yield, 95% ee), [α]25 = +29.6 (c = 0.5, CHCl3); H NMR
1
D
(300 MHz, CDCl3, ppm) δ 7.51 (dd, J = 8.77, 5.41 Hz, 2H), 7.05 (t, J
= 8.70 Hz, 2H), 6.45 (s, 1H), 2.08 (s, 3H), 1.25 (s, 9H); 13C NMR
(75 MHz, CDCl3, ppm) 168.8, 163.5, 128.6, 128.0, 114.5, 95.5, 74.0,
64.2, 29.7, 26.5, 20.2. HPLC conditions: (R,R)-Whelk-O1, n-hexane/2-
propanol = 97/3, flow rate = 0.5 mL/min, UV = 217 nm, retention
times 8.88 min (R), 9.68 min (S).
(R)-1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-
pentyl acetate (9e): 29 mg (87% yield, 94% ee), [α]20 = +52.3 (c =
D
0.5, CHCl3); 1H NMR (300 MHz, CDCl3, ppm) δ 7.79 (d, J = 8.0 Hz,
2H), 7.32 (d, J = 8.0 Hz, 2H), 5.72 (t, J = 6.9 Hz, 1H), 2.06 (s, 3H),
1.95−1.70 (m, 2H), 1.39−1.12 (m, 16H), 0.86 (t, J = 4.7 Hz, 3H); 13C
NMR (75 MHz, CDCl3, ppm) 170.4, 143.9, 134.9, 125.8, 83.8, 76.1,
36.0, 27.6, 24.9, 22.4, 21.3, 13.9. HPLC conditions: (R,R)-Whelk-O1,
n-hexane/2-propanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm,
(R)-1-(4-Chlorophenyl)-4,4-dimethylpent-2-ynyl acetate (10i): 25
1
mg (96% yield, 95% ee), [α]25 = +27.3 (c = 1.0, CHCl3); H NMR
D
(300 MHz, CDCl3, ppm) δ 7.45 (d, J = 8.46 Hz, 2H), 7.33 (d, J = 8.55
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Article
Hz, 2H), 6.44 (s, 1H), 2.08 (s, 3H), 1.24 (s, 9H); 13C NMR (75 MHz,
CDCl3, ppm) 169.8, 136.5, 134.6, 129.2, 128.7, 96.7, 74.8, 65.2, 30.7,
27.5, 21.2. HPLC conditions: (R,R)-Whelk-O1, n-hexane/2-propanol
= 95/5, flow rate =0.5 mL/min, UV = 217 nm, retention times 8.86
min (R), 10.4 min (S).
7.50 (d, J = 3.15 Hz, 1H), 7.49−7.47 (m, 2H), 6.64 (s, 1H), 2.10 (s,
3H), 1.27 (s, 9H); 13C NMR (75 MHz, CDCl3, ppm): 169.9, 135.2,
133.4, 128.4, 128.3, 127.7, 127.1, 126.5, 126.2, 125.7, 124.4, 96.1, 76.3,
66.1, 30.8, 27.7, 22.5. Enantiomeric excess (ee) was determined after
hydrolysis of acetate. HPLC conditions: Chiralcel-OD, n-hexane/2-
propanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm, retention
times 9.36 min (S), 10.5 min (R).
(R)-1-(4-Bromophenyl)-4,4-dimethylpent-2-ynyl acetate (10j): 30
1
mg (97% yield, 92% ee), [α]25 = +33.7 (c = 1.0, CHCl3); H NMR
D
(300 MHz, CDCl3, ppm) δ 7.50 (d, J = 8.53 Hz, 2H), 7.38 (d, J = 8.42
Hz, 2H), 6.42 (s, 1H), 2.08 (s, 3H), 1.24 (s, 9H); 13C NMR (75 MHz,
CDCl3, ppm) 169.8, 137.0, 137.1, 129.5, 122.8, 96.7, 74.8, 65.2, 30.7,
27.5, 21.2. HPLC conditions: (R,R)-Whelk-O1, n-hexane/2-propanol
= 95/5, flow rate = 0.5 mL/min, UV = 217 nm, retention times 9.02
min (R), 10.8 min (S).
DKR of 5a−n. The DKR reactions were performed with solutions
containing substrate (0.1 mmol), ISCBCL (3 mg), 6 (5 mol %),
K2CO3 (14 mg, 0.1 mmol), and IPA (1.5 equiv) in toluene at 60 °C
for 36−60 h according to the standard procedure described
previously.6 The products from the DKR reactions of 5a, 5b, 5h,
and 5i were isolated and characterized.
(R)-(4-Isopropylphenyl)(phenyl)methyl acetate (11a): 23 mg
(R)-4,4-Dimethyl-1-p-tolylpent-2-ynyl acetate (10k): 23 mg (96%
yield, 95% ee), [α]25D = +31.4 (c = 0.5, CHCl3); 1H NMR (300 MHz,
CDCl3, ppm) δ 7.41 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.95 Hz, 2H),
6.45 (s, 1H), 2.35 (s, 3H), 2.06 (s, 3H), 1.25 (s, 9H); 13C NMR (75
MHz, CDCl3, ppm) 169.9, 138.6, 134.9, 129.2, 127.8, 96.1, 75.3, 65.8,
30.1, 27.5, 22.4, 21.3. HPLC conditions: (R,R)-Whelk-O1, n-hexane/2-
propanol = 96/4, flow rate = 1.0 mL/min, UV = 217 nm, retention
times 4.54 min (R), 5.07 min (S).
1
(86% yield, 91% ee), [α]25 = +18.5 (c = 1.0, CHCl3); H NMR
D
(300 MHz, CDCl3, ppm) δ 7.34−7.16 (m, 9H), 6.86 (s, 1H), 2.95−
2.81 (m, 1H), 2.14 (s, 3H), 1.23 (d, J = 6.9 Hz, 6H); 13C NMR (75
MHz, CDCl3, ppm) 170.0, 148.5, 140.3, 137.5, 128.4, 127.7, 127.1,
126.9, 126.5, 33.7, 23.9, 21.3. HPLC conditions: (R,R)-Whelk-O1, n-
hexane/2-propanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm,
retention times 6.9 min (R), 7.6 min (S); TOF-MS (ESI+) calcd for
[C18H20O2−OAc]+ 209.1330, found 209.1306. The absolute config-
uration was confirmed by comparing the optical rotation of the
hydrolyzed product with the literature value. (R)-(4-Isopropylphenyl)-
(R)-1-(4-Methoxyphenyl)-4,4-dimethylpent-2-ynyl acetate (10l):
1
26 mg (98% yield, 66% ee), [α]25 = +19.1 (c = 1.0, CHCl3); H
D
NMR (300 MHz, CDCl3, ppm) δ 7.45 (d, J = 8.64 Hz, 2H), 6.89 (d, J
= 8.51 Hz, 2H), 6.44 (s, 1H), 3.81 (s, 3H), 2.06 (s, 3H), 1.25 (s, 9H);
13C NMR (75 MHz, CDCl3, ppm) 170.0, 159.9, 130.1, 129.3, 113.8,
96.1, 75.4, 65.6, 55.3, 30.8, 27.5, 21.3. Enantiomeric excess (ee) was
determined after hydrolysis of acetate. HPLC conditions: Chiralcel-
OD, n-hexane/2-propanol = 95/5, flow rate = 1.0 mL/min, UV = 217
nm, retention times 8.85 min (S), 10.5 min (R).
(phenyl)methanol, [α]25 = +6.3 (c = 1.0, CHCl3) [lit.23 [α]24
=
D
D
+11.2 (c = 0.8, CHCl3, 86% ee)].
(R)-(4-Fluorophenyl)(4-isopropylphenyl)methyl acetate (11b): 16
1
mg (57% yield, 91% ee), [α]25 = +12.8 (c = 1, CHCl3); H NMR
D
(300 MHz, CDCl3, ppm) δ 7.33−7.17 (m, 6H), 7.01 (t, J = 8.7 Hz,
2H), 6.83 (s, 1H), 2.93−2.84 (m, 1H), 2.14 (s, 3H), 1.23 (d, J = 6.9
Hz, 6H); 13C NMR (75 MHz, CDCl3, ppm) 170.0, 163.9, 160.6,
148.7, 137.3, 136.2, 136.2, 128.9, 128.8, 127.0, 126.6, 115.5, 115.2,
76.1, 33.8, 23.9, 21.2. HPLC conditions: (R,R)-Whelk-O1, n-hexane/2-
propanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm, retention
times 6.3 min (R), 6.8 min (S); TOF-MS (ESI+) calcd for
[C18H19FO2 − OAc]+ 227.1236, found. 227.1199
(R)-1-(3-Bromophenyl)-4,4-dimethylpent-2-ynyl acetate (10m):
1
30 mg (97% yield, 88% ee), [α]25 = +34.1 (c = 1.0, CHCl3); H
D
NMR (300 MHz, CDCl3, ppm) δ 7.66 (t, J = 1.83 Hz, 1H), 7.45−7.42
(m, 2H), 7.26−7.23 (m, 1H), 6.43 (s, 1H), 2.10 (s, 3H), 1.25 (s, 9H);
13C NMR (75 MHz, CDCl3, ppm) 169.7, 140.1, 131.7, 130.8, 130.1,
126.3, 122.5, 96.9, 74.6, 65.0, 30.7, 27.5, 21.2. Enantiomeric excess
(ee) was determined after hydrolysis of acetate. HPLC conditions:
Chiralcel-OD, n-hexane/2-propanol = 95/5, flow rate = 0.5 mL/min,
UV = 217 nm, retention times 12.4 min (S), 13.4 min (R).
(R)-4,4-Dimethyl-1-m-tolylpent-2-ynyl acetate (10n): 23 mg (96%
yield, 83% ee), [α]25D = +32.3 (c = 1.0, CHCl3); 1H NMR (300 MHz,
CDCl3, ppm) δ 7.34−7.26 (m, 3H), 7.16−7.14 (m, 1H), 6.45 (s, 1H),
2.37 (s, 3H), 2.08 (s, 3H), 1.25 (s, 9H); 13C NMR (75 MHz, CDCl3,
ppm) 169.9, 138.2, 137.7, 129.4, 128.5, 128.4, 124.8, 96.2, 75.3, 65.9,
30.8, 27.5, 21.4, 21.3. Enantiomeric excess (ee) was determined after
hydrolysis of acetate. HPLC conditions: Chiralcel-OD, n-hexane/2-
propanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm, retention
times 6.65 min (S), 9.55 min (R).
(R)-(4-tert-Butylphenyl)(phenyl)methyl acetate (11h): 25 mg
1
(87% yield, 95% ee), [α]25 = +21.8 (c = 1.0, CHCl3); H NMR
D
(300 MHz, CDCl3, ppm) δ 7.36−7.24 (m, 9H), 6.86 (s, 1H), 2.15 (s,
3H), 1.29 (s, 9H); 13C NMR (75 MHz, CDCl3, ppm) 170.0, 150.8,
140.3, 137.1, 128.4, 127.7, 127.0, 126.8, 125.4, 34.5, 31.2, 21.3. HPLC
conditions: (R,R)-Whelk-O1, n-hexane/2-propanol = 95/5, flow rate =
1.0 mL/min, UV = 217 nm, retention times 6.3 min (R)), 7.3 min (S);
TOF-MS (ESI+) calcd for [C19H22O2 − OAc]+ 223.1487, found
223.1467.
(R)-(4-tert-Butylphenyl)(4-fluorophenyl)methyl acetate (11i): 23
1
mg (76% yield, 93% ee), [α]25 = +14.1 (c = 1.0, CHCl3); H NMR
D
(300 MHz, CDCl3, ppm) δ 7.36−7.21 (m, 6H), 7.02 (t, J = 8.6 Hz,
2H), 6.84 (s, 1H), 2.14 (s, 3H), 1.29 (s, 9H); 13C NMR (75 MHz,
CDCl3, ppm) 170.0, 163.9, 160.6, 150.9, 136.9, 136.2, 128.9, 128.8,
126.7, 125.4, 115.5, 115.2, 34.1, 31.2, 21.3. HPLC conditions: (R,R)-
Whelk-O1, n-hexane/2-propanol = 95/5, flow rate = 1.0 mL/min, UV
= 217 nm, retention times 6.0 min (R), 6.9 min (S); TOF-MS (ESI+)
calcd for [C19H21FO2 − OAc]+ 241.1392, found 241.1377.
(R)-1-(3-Methoxyphenyl)-4,4-dimethylpent-2-ynyl acetate (10o):
1
24 mg (93% yield, 74% ee), [α]26 = +16.5 (c = 0.5, CHCl3); H
D
NMR (300 MHz, CDCl3, ppm): δ 7.28−7.25 (m, 1H), 7.10−7.08 (m,
2H), 6.90−6.87 (m, 1H), 6.46 (s, 1H), 3.82 (s, 3H), 2.09 (s, 3H), 1.25
(s, 9H); 13C NMR (75 MHz, CDCl3, ppm): 169.9, 159.6, 139.3, 129.5,
120.1, 114.4, 113.2, 96.3, 76.0, 65.7, 55.2, 30.8, 29.7, 21.2. HPLC
conditions: (R,R)-Whelk-O1, n-hexane/2-propanol = 95/5, flow rate =
1.0 mL/min, UV = 217 nm, retention times 5.48 min (R), 6.30 min
(S).
ASSOCIATED CONTENT
* Supporting Information
NMR spectra and GC/HPLC chromatograms. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
(R)-1-(Furan-2-yl)-4,4-dimethylpent-2-ynyl Acetate (10p). This
product was unstable so it was converted by the treatment with K2CO3
in water−MeOH to the corresponding alcohol: 21 mg (95% yield,
1
61% ee), [α]26 = +12.7 (c = 1.0, CHCl3); H NMR (300 MHz,
D
AUTHOR INFORMATION
Corresponding Author
*E-mail: (M.-J.K.) mjkim@postech.ac.kr, (J.P.) pjw@postech.
ac.kr.
■
CDCl3, ppm) δ 7.39 (dt, J = 1.75, 0.88 Hz, 1 H), 6.43 (d, J = 0.75 Hz,
1 H), 6.33 (d, J = 1.34 Hz, 1 H), 5.43 (s, 1 H), 2.50 (s, 1H), 1.26 (s, 9
H); 13C NMR (75 MHz, CDCl3, ppm) 153.9, 142.8, 110.2, 107.5,
94.8, 76.1, 58.2, 30.8, 27.4. HPLC conditions: Chiralcel-OD, n-
hexane/2-propanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm,
retention times 8.60 min (S), 10.0 min (R).
Author Contributions
‡These authors contributed equally.
(R)-4,4-Dimethyl-1-(naphthalen-2-yl)pent-2-ynyl acetate (10q):
1
27 mg (96% yield, 71% ee), [α]26 = +10.9 (c = 0.5, CHCl3); H
Notes
D
NMR (300 MHz, CDCl3, ppm): δ 7.97 (s, 1H), 7.86−7.81 (m, 3H),
The authors declare no competing financial interest.
2577
dx.doi.org/10.1021/jo3027627 | J. Org. Chem. 2013, 78, 2571−2578

The Journal of Organic Chemistry
Article
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ACKNOWLEDGMENTS
■
We are grateful to the National Research Foundation of Korea
(project nos. 2012R1A1A2006595 and 2012-007235) and the
POSTECH Basic Science Research Institute for financial
support of this work. We thank Dr. Hirose (Amano
Pharmaceutical Co.) for providing technical information on
Burkholderia cepacia lipase.
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