Dynamic kinetic resolution of diarylmethanols with an activated lipoprotein lipase

Article abstract of DOI:10.1021/cs501629m

We explored the kinetic resolution of 31 different diarylmethanols with an activated lipoprotein lipase (LPL-D1) which was about 3000-fold more active than its native counterpart in organic solvent. Most of the substrates tested were accepted by LPL-D1 with good to high enantioselectivity in the kinetic resolution. Next, we explored the dynamic kinetic resolutions (DKRs) of these substrates (24 out of 31) using LPL-D1 and a ruthenium-based racemization catalyst in combination, which provided satisfactory yields (71-96%) and high enantiopurities (90-99% ee). As an illustrative example for the synthetic applications of the DKR procedure, we synthesized L-cloperastine, an antitussive drug, from phenyl-(p-trimethylsilylphenyl)methanol via DKR. (Chemical Equation Presented).

Full text of DOI:10.1021/cs501629m

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Article
Dynamic Kinetic Resolution of Diarylmethanols
with an Activated Lipoprotein Lipase
Jusuk Lee, Yeonock Oh, Yoon Kyung Choi, Eunjeong Choi, Kyungwoo Kim, Jaiwook Park, and Mahn-Joo Kim
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/cs501629m • Publication Date (Web): 12 Dec 2014
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Dynamic Kinetic Resolution of Diarylmethanols
with an Activated Lipoprotein Lipase
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Jusuk Lee, Yeonock Oh, Yoon Kyung Choi, Eunjeong Choi, Kyungwoo Kim, Jaiwook Park* and
MahnꢀJoo Kim*
Department of Chemistry, Pohang University of Science and Technology, 77 Cheongamꢀro,
Pohang 790ꢀ784, Republic of Korea
ABSTRACT
We explored the kinetic resolution of 31 different diarylmethanols with an activated
lipoprotein lipase (LPLꢀD1) which was about 3000ꢀfold more active than its native counterpart
in organic solvent. Most of the substrates tested were accepted by LPLꢀD1 with good to high
enantioselectivity in the kinetic resolution. Next, we explored the dynamic kinetic resolutions
(DKRs) of these substrates (24 out of 31) using LPLꢀD1 and a rutheniumꢀbased racemization
catalyst in combination, which provided satisfactory yields (71ꢀ96%) and high enantiopurities
(90ꢀ99% ee). As an illustrative example for the synthetic applications of the DKR procedure, we
synthesized Lꢀcloperastine, an antitussive drug, from phenylꢀ(pꢀtrimethylsilylphenyl)methanol
via DKR.
KEYWORDS: diarylmethanol, dynamic kinetic resolution, lipase, ruthenium, catalysis
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INTRODUCTION
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Dynamic kinetic resolution (DKR) provides a powerful methodology for the complete
transformations of racemates to single enantiomers.1 Over the past decade, the procedures
employing an enzyme as the resolution catalyst and a metal (complex) as the racemization
catalyst have been intensively explored for the efficient DKR.2ꢀ6 Several useful procedures now
are available for the DKR of alcohols,7ꢀ22 amines,23ꢀ33 and amino acids.34ꢀ38 The wider
applications of the DKR procedures, however, are limited by the low activity, narrow substrate
specificity or modest enantioselectivity of enzyme employed. For example, Candida antarctica
lipase B (CALB; brand name, Novozym 435), which has been most frequently employed in the
DKR of alcohols, has good activity in organic solvent but does not accept sterically demanding
substrates such as diarylmethanols.39 Recently, we reported that an ionicꢀsurfactantꢀcoated
Burkholderia cepacia lipase (ISCBCL) was highly active in organic solvent40 and accepted a
wider range of secondary alcohols in the DKR.41 Unfortunately, the DKR of diarylmethanols
with this enzyme was not satisfactory. Later, we communicated that a lipoprotein lipase42 (LPL)
from Burkholderia species was also highly active in organic solvent if it was coated with both
dextrin (D) and ionic surfactant (1) via lyophilization.43 We now wish to report a successful
application of this LPL preparation (LPLꢀD1) to the DKR of diarylmethanols including aryl
heteroarylmethanols (Scheme 1).
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Scheme 1. DKR of diarylmethanols with LPLꢀD1 and a Ru complex
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Enantiomericallyꢀenriched diarylmethanols are useful as the precursors or building blocks for
the synthesis of pharmaceutically important compounds such as antihistaminic, antiarrhythmic,
and anticholinergic agents.44 Several chemical procedures have been explored to provide the
routes to them. Two common approaches include the enantioselective additions of aryl
nucleophiles to aromatic aldehydes45,46 and the asymmetric hydrogenations of diaryl ketones.47ꢀ49
The enzymatic methods are available as well. They include the asymmetric reduction of ketones
employing ketoreductases50,51 and the lipaseꢀcatalyzed kinetic resolution of racemic alcohols.39
All of these chemical and enzymatic methods have advantages and disadvantages. In particular,
the enzymatic kinetic resolution has a serious limitation that the theoretical maximum yield is
50% for the wanted enantiomer. The DKR procedure described in this manuscript provides
higher yields.
RESULTS AND DISCUSSION
Activity of LPL-D1. LPLꢀD1 was prepared by freezeꢀdrying a solution containing LPL (52%
protein),52 dextrin (D), and 1 at a 1 : 2 : 1 weight ratio in 1 : 1 (v/v) waterꢀdioxane. The activities
of LPLꢀD1 were measured for the hydrolysis and alcoholysis of pꢀnitrophenyl acetate (AcOPNP)
to compare with those of its native counterpart in water and organic solvent. The data (kcat/Km)
from Table 1 indicate that LPLꢀD1 were as active as its native counterpart in water (compare the
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entries 1 and 4) but about 3000ꢀfold more active than the latter in organic solvent (compare the
entries 2 and 5 or the entries 3 and 6). It is particularly noteworthy that, in the reaction of
AcOPNP with benzyl alcohol in toluene, the turnover frequency (TOF, kcat) of LPLꢀD1 reached
the aqueousꢀlevel (entry 5). To the best of our knowledge, LPLꢀD1 is the first lipase preparation
that has displayed the aqueousꢀlevel TOF in anhydrous organic solvent. We guess that dextrin
and 1 induced such a dramatic activation in organic solvent by providing both waterꢀmimicking
and oilꢀlike microenvironments around the enzyme. Despite the aqueousꢀlevel TOF, the overall
catalytic efficiency (kcat/Km) in organic solvent was still below the aqueous level owing to the
relatively large Km (compare the entries 4 and 5). So, further improvements in the Km are needed
to realize the aqueousꢀlevel catalytic efficiency in organic solvent.
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Table 1. The kinetic parameters of LPL and LPLꢀD1 for the hydrolysis and alcoholysis of pꢀ
nitrophenyl acetate
kcat/Km
entry
lipase
ROH
kcat (sꢀ1) a
Km (M) a
(sꢀ1/M)
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LPL
H2O
2.8 x 102
6.4 x 10ꢀ2
4.8 x 10ꢀ4
2.5 x 10ꢀ1
8.7 x 10ꢀ2
4.7 x 10ꢀ4
6.4 x 10ꢀ1
1.0 x 10ꢀ1
5.7 x 105
2.6 x 10ꢀ1
2.0 x 10ꢀ1
6.3 x 105
8.8 x 102
5.5 x 102
LPL
PhCH2OH
LPL
PhCH(CH3)OH 1.7 x 10ꢀ2
LPLꢀD1
LPLꢀD1
LPLꢀD1
H2O
3.0 x 102
5.7 x 102
PhCH2OH
PhCH(CH3)OH 5.5 x 10
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a The Vmax and Km values were obtained using the nonꢀlinear curve fitting of average rates per 1
mg of LPL (52% protein) measured in duplicate. Each kcat was then calculated using the equation
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V
max = kcat[E]0, where [E]0 is total concentration of enzyme (MW 33,000).
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Enantioselectivity of LPL-D1 in the Kinetic Resolution of Diarylmethanols. Total 31
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different diaryl and aryl heteroarylmethanols were chosen as the substrates of LPLꢀD1 to
examine the enantioselectivity in the kinetic resolution (Chart 1). The enantioselectivity of LPLꢀ
D1 for each substrate was determined by performing the transesterification of each substrate in
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the presence of isopropenyl acetate (IPA) as the acyl donor in toluene at 40 C. It is noted that
the elevated temperature was chosen because most DKR reactions were performed at this
temperature. The reaction of each substrate was carried out with a solution containing substrate
(0.1 mmol), LPLꢀD1 (20 mg/mmol of substrate; enzyme content: ca 13%, w/w), and IPA (1.5
equiv) in toluene. The enantioselectivity in each reaction was determined as the E value, E = ln
[1 – c (1 + eep)] / ln [1 – c (1 – eep)] where c = ees / (ees + eep),53 by analyzing the enantiomeric
excesses (ees, eep) of acetylated product and remaining substrate when the reaction approached
near 50% conversion (c). The E value for each substrate is described on the right side of each
substrate number in Chart 1.
The E values from Chart 1 indicate that, in general, the enantioselectivity of LPLꢀD1 increased
with increasing the difference in size between two aryl groups at the hydroxymethine center of
substrate. The enantioselectivity was low for monohalogenated 3 but increased significantly in
i
the case that the halogen was substituted by a bulkier substituent such as Pr, tꢀBu or
trimethylsilyl (TMS) (compare 3a, 4a, 5a, and 6a): here, the order of increasing the
i
enantioselectivity was X < TMS < Pr < tꢀBu. It was rather surprising that the steric effect of a
TMS group was less significant than that of an isopropyl group in enhancing the
enantioselectivity. The presence of a second substituent on the other aromatic ring reduced the
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Chart 1. The enantioselectivity of LPLꢀD1 in the kinetic resolution of diarylmethanolsa
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aThe E value on the right side of each substrate number indicates the enantioselectivity.
enantioselectivity. In this case, the enantioselectivity decreased as the size of second substituent
increased (E = H > F > Cl > OMe > NO2; compare 4aꢀg or 5aꢀg). As expected, the replacement
of a phenyl ring by a smaller heteroaromatic ring increased the enantioselectivity (compare
4a,h,i. or 5a,h,i or 6a,b). Interestingly, the change of a phenyl ring to a similar size of pyridyl
ring also increased the enantioselectivity (compare between 4a and 4l,m or 5a and 5l,m or 6a,c),
suggesting that the basic pyridine ring seems to bind to the active site of enzyme more favorably.
The enantioselectivity for aryl heteroarylmethanols was also dependent on the nature of a
i
substituent on the aryl ring: it increased in an order of TMS < Pr < tꢀBu as observed for
diarylmethanols (compare between 4j, 5j, and 6b or between 4l, 5l, and 6c). On the basis of this
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similarity, we think that, for all the substrates tested, LPLꢀD1 should have the same
stereopreference which is controlled largely by the steric difference between two aromatic rings
of substrate (see the scheme in Chart 1). Overall, most of the substrates tested (26 out of 31)
were accepted by LPLꢀD1 with synthetically useful enantioselectivity (E = >20) and six of them
with high enantioselectivity (E = >100). These results thus encouraged us to explore the DKR of
diarylmethanols with LPLꢀD1.
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Dynamic Kinetic Resolution of Diarylmethanols with LPL-D1. We explored the DKR of 24
diarylmethanols which were accepted by LPLꢀD1 with good to high enantioselectivity. The DKR
reactions were carried out under the optimized conditions: substrate (0.1 mmol), LPLꢀD1 (30 ꢀ
50 mg/mmol of substrate), ruthenium complex 254 (5 mol%), isopropenyl acetate (1.5 equiv), and
K2CO3 (1 equiv) in toluene at 40 oC. It is noted that the ruthenium complex 2 as the racemization
catalyst was chosen because it had displayed a good performance in the previous DKR.41 The
DKR reactions of 4a and its pꢀFꢀsubstituted analog 4d were complete in 48 h and provided good
enantiopurities (91ꢀ94% ee) and satisfactory yields (88–91%) (entries 1 and 4, Table 2). Those of
mꢀsubstituted derivatives 4b,c needed a longer time due to lower enzymatic activity and provided
lower yields (entries 2 and 3). The DKR reactions of furyl or thiophenylꢀcontaining substrates
4hꢀk proceeded more rapidly. These reactions were complete in 24ꢀ36 h to afford better
enantiopurities (95ꢀ97% ee) (entries 5ꢀ8). To the contrary, those of pyridylꢀcontaining substrates
4l,m were sluggish due to slower racemization so that they were performed at higher temperature
(60 oC) for longer time (72 h). The yields and enantiopurities were satisfactory (entries 9 and 10).
The DKR reactions of 5 (carrying a tꢀbutyl substituent), in general, took longer times (48ꢀ96 h)
compared to those of 4 (carrying an isopropyl substituent) but provided higher enantiopurities
(94ꢀ99% ee) as expected. The yields ranged from 74ꢀ92% (entries 11ꢀ21). The DKR reactions of
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6 (carrying a TMS substituent) also required rather long times (60ꢀ72 h) to provide high
enantiopurities (94ꢀ96% ee) with satisfactory yields (82ꢀ92%) (entries 22ꢀ24). Overall, all the
DKR reactions were successful and provided high enantiomeric excesses with satisfactory yields.
It is noted that the lower yields (71ꢀ79%) in some cases were partly due to the oxidation of
substrates to the corresponding ketones.
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Table 2. DKR of diarylmethanols with LPLꢀD1 and ruthenium catalyst 2
entry
1
substrate
4a
product
8a
time (h)
48
yielda (%)
88
eeb ( %)
94
2
72
79
90
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4c
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8c
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91
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91
91
4d
4h
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96
96
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89
95
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80
97
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36
72
97
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72c
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95
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76
92
4m
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98
72
88
97
5b
5c
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90
97
72
92
96
5d
5e
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>99
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96c
96c
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5k
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9l
5m
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a Isolated yield. b Determined by HPLC. c 60 °C.
Scheme 2. Synthesis of Lꢀcloperastinea
a
Reagents and conditions: (i) 2 (5 mol%), LPLꢀD1 (2 mg), isopropenyl acetate (1.5 equiv),
o
K2CO3 (1 equiv), toluene 0.3 M, 40 C, 72 h, 82%, 96% ee. (ii) K2CO3 (3 equiv), MeOHꢀH2O,
r.t., 2 h, 92%, 96% ee. (iii) KCl (1.2 equiv), Nꢀchlorosuccinimide (1.2 equiv), MeOH, 60 oC, 2 h,
81%, 96% ee. (vi) 1ꢀ(2ꢀchloroethyl)piperidine hydrochloride (1.5 equiv), NaOH (3 equiv),
CH2Cl2, r.t., overnight, 94%, 96% ee.
The Synthesis of L-Cloperastine. To show a synthetic application of our DKR procedure, we
synthesized Lꢀcloperastine (11), an antitussive drug, from (R)ꢀ10a (96% ee) which had been
obtained from the DKR of 6a. In the first step, (R)ꢀ10a was deacetylated by the treatment with
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K2CO3 in MeOHꢀH2O to yield (R)ꢀ6a, which in turn was subject to chlorodesilylation with KCl
and Nꢀchlorosuccinimide (NCS) to obtain (R)ꢀ3a. Finally, the reaction of (R)ꢀ3a with 1ꢀ(2ꢀ
chloroethyl)piperidine gave 11. All the reactions from (R)ꢀ10a proceeded without loss in the
enantiopurity and the overall yield was 57% from 6a (Scheme 2).
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CONCLUSION
We have demonstrated that LPL displayed about 3000ꢀfold enhanced activity in organic
solvent, if it was formulated with dextrin (D) and ionic surfactant (1), and its TOF in organic
solvent reached the aqueousꢀlevel. The activated LPL (LPLꢀD1) accepted a wider range of
diarylmethanols with useful to high enantioselectivity in the kinetic resolution. The DKR
reactions of these substrates with the LPLꢀD1 were successful and provided high enantiopurities
and satisfactory yields. We thus have developed a useful protocol for the DKR of
diarylmethanols which was difficult to achieve with other enzymes. In addition, we synthesized
Lꢀcloperastine, a chiral drug for the treatment of cough, from a racemic diarylmethanol via the
DKR.
EXPERIMENTAL SECTION
Determination of Enzymatic Activity. The kinetic parameters (Vmax and Km) of LPL and
LPLꢀD1 for the alcoholysis of AcOPNP with 1ꢀphenylethanol were obtained through two sets of
experiments to determine Vmax and Vmax/Km separately. The Vmax value of LPL was determined
with solutions containing AcOPNP (0.075ꢀ0.25 M), lipase (10 mg), and 1ꢀphenylethanol (2.0
o
equiv) in toluene (1 mL) at 25 C. The Vmax/Km value of LPL was determined with solutions
containing AcOPNP (0.075ꢀ0.25 M), lipase (10 mg), and 1ꢀphenylethanol (0.5 M) in toluene (1
o
mL) at 25 C. The Vmax of LPLꢀD1 was determined with solutions containing AcOPNP (0.11ꢀ
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0.75 M), LPLꢀD1 (1 mg), and 1ꢀphenylethanol (0.67 equiv) in toluene (1 mL). The Vmax/Km
value of LPLꢀD1 was determined with solutions containing AcOPNP (0.3ꢀ0.75 M), LPLꢀD1 (1.0
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mg), and 1ꢀphenylethanol (0.5 M) in toluene (1 mL) at 25 C. The rate measurement at each
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substrate concentration was performed twice as follows. The solution was shaken at 250 rpm. An
aliquot was sampled periodically, filtered through a short silica gelꢀpad, and analyzed by HPLC
to determine the conversion % against time. The kcat and Km values were then obtained using the
nonlinear curve fitting for the average rates.
Determination of the Enantioselectivity of LPL-D1. According to the procedure reported
previously,43 LPLꢀD1 was prepared by freezeꢀdrying a solution containing LPL (52% protein),
dextrin (D), and 1 at a 1 : 2 : 1 weight ratio in 1 : 1 (v/v) waterꢀdioxane. The enantioselectivity of
LPLꢀD1 for each substrate was determined by performing the transesterification of each
o
substrate in the presence of isopropenyl acetate (IPA) as the acyl donor in toluene at 40 C. In a
typical procedure, IPA (1.5 equiv) was added to a 4mLꢀvial containing LPLꢀD1 (30 mg/mmol),
substrate (0.1 mmol), and anhydrous toluene (0.3 M, 330 µL). The resulting solution was then
o
shaken at 40 C until the reaction reached near 50% conversion (c). After being diluted with
methylene chloride, the reaction mixture was filtered through a silica gelꢀpad, concentrated, and
then analyzed by HPLC to determine the enantiomeric excesses of remaining substrate (ees) and
acetylated product (eep). The enantioselectivity (E) of LPLꢀD1 was then calculated using the
equation: E = ln [1 ꢀ c (1 + eep)] / ln [1ꢀ c (1 ꢀ eep)] where c = ees / (ees + eep).53
Dynamic Kinetic Resolution of Diarylmethanols. As the representative procedure, the DKR
of 4a is described. Freshly dried and degassed toluene (0.3 M, 330 µL) was added to a pearꢀ
shaped Schlenk flask containing the ruthenium catalyst 2 (4 mg, 5 mol%), LPLꢀD1 (30
mg/mmol), K2CO3 (13.82 mg, 0.1 mmol), alcohol (0.1 mmol) under argon. The resulting
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solution was stirred for 30 min at 60 C. After stirred for 30 min, isopropenyl acetate (16 µL,
0.15 mmol) was added into the flask and the solution was stirred at 40 oC for 48 h. The solution
diluted with methylene chloride, and filtered through a celite pad. The filtrate was concentrated
and purified by silica gel chromatography to give product.
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(R)-(4-Isopropylphenyl)(phenyl)methyl acetate (8a): 88% yield, 94% ee; The analytical data
were in good agreement with the literature values.41
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(R)-(3-Fluorophenyl)(4-isopropylphenyl)methyl acetate (8b): 79% yield, 90% ee; [α]D
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+26.5 (c = 0.5, CHCl3); H NMR (300 MHz, CDCl3, ppm): δ 7.30ꢀ7.18 (m, 4H), 7.12ꢀ7.07 (m,
2H), 6.96ꢀ6.92 (m, 2H), 6.82 (s, 1H), 2.93ꢀ2.84 (m, 1H), 2.16 (s, 3H), 1.24ꢀ1.21 (d, J = 6.9 Hz,
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6H); C NMR (75 MHz, CDCl3, ppm): 169.9, 164.4, 161.2, 148.9, 142.9, 136.9, 130.0, 127.2,
126.6, 122.5, 114.8, 114.5, 113.9, 113.6, 76.1, 33.8, 23.8, 21.2; HPLC conditions (hydrolysis
product: alcoholꢀform): WhelkꢀO1, nꢀhexane/2ꢀpropanol = 95/5, flow rate = 1.0 mL/min, UV =
217 nm, retention times 6.7 min (R), 8.4 min (S); TOFꢀMS (ESI+) calcd for [C18H19FO2ꢀOAc]+
227.12360, found 227.12167.
(R)-(4-Isopropylphenyl)(m-tolyl)methyl acetate (8c): 71% yield, 91% ee; [α]D25 +15.5 (c =
0.9, CHCl3); 1H NMR (300 MHz, CDCl3, ppm): δ 7.26ꢀ7.05 (m, 8H), 6.81 (s, 1H), 2.92ꢀ2.83 (m,
1H), 2.33 (s, 3H), 2.15 (s, 3H), 1.23ꢀ1.21 (d, J = 6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3, ppm):
170.1, 148.5, 140.2, 138.1, 137.6, 128.5, 128.3, 127.6, 127.1, 126.5, 124.0, 76.5, 33.7, 23.9, 21.4,
21.3; HPLC conditions (hydrolysis product: alcoholꢀform): WhelkꢀO1, nꢀhexane/2ꢀpropanol =
95/5, flow rate = 1.0 mL/min, UV = 217 nm, retention times 7.9 min (R), 9.0 min (S); TOFꢀMS
(ESI+) calcd for [C19H22O2ꢀOAc]+ 223.14868, found 223.14671.
(R)-(4-Fluorophenyl)(4-isopropylphenyl)methyl acetate (8d): 91% yield, 91% ee; The
analytical data were in good agreement with the literature values.41
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(S)-Furan-2-yl(4-isopropylphenyl)methyl acetate (8h): 96% yield, 96% ee; [α]D25 ꢀ36.8 (c =
1.25, CHCl3); 1H NMR (300 MHz, CDCl3, ppm): δ 7.37ꢀ7.34 (m, 3H), 7.23ꢀ7.20 (d, J = 8.05 Hz
, 2H), 6.86 (s, 1H), 6.30ꢀ6.28 (m, 1H), 6.18ꢀ6.17 (m, 1H), 2.96ꢀ2.83 (m, 1H), 2.10 (s, 3H), 1.24ꢀ
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1.22 (d, J = 6.86 Hz, 6H); C NMR (75 MHz, CDCl3, ppm): 169.9, 152.6, 149.1, 143.0, 134.7,
127.3, 126.6, 110.2, 109.4, 70.4, 33.8, 23.9, 21.1; HPLC conditions: WhelkꢀO1, nꢀhexane/2ꢀ
propanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm, retention times 6.6 min (R), 8.9 min (S);
TOFꢀMS (ESI+) calcd for [C16H18O3ꢀOAc]+ 199.11229, found 119.11009.
(S)-Furan-3-yl(4-isopropylphenyl)methyl acetate (8i): 89% yield, 95% ee; [α]D25 +10.8 (c =
1.0, CHCl3); 1H NMR (300 MHz, CDCl3, ppm): δ 7.36ꢀ7.28 (m, 4H), 7.23ꢀ7.19 (m, 2H), 6.80 (s,
1H), 6.33ꢀ6.32 (m, 1H), 2.94ꢀ2.85 (m, 1H), 2.11 (s, 3H), 1.25ꢀ1.22 (d, J = 6.9 Hz, 6H); 13C NMR
(75 MHz, CDCl3, ppm): 170.1, 148.9, 143.3, 140.7, 136.6, 127.0, 126.5, 125.6, 109.6, 70.3, 33.8,
23.9, 21.2; HPLC conditions: WhelkꢀO1, nꢀhexane/2ꢀpropanol = 95/5, flow rate = 1.0 mL/min,
UV = 217 nm, retention times 6.2 min (R), 7.9 min (S); TOFꢀMS (ESI+) calcd for [C16H18O3ꢀ
OAc]+ 199.11229, found 119.11089.
(S)-(4-Isopropylphenyl)(thiophen-2-yl)methyl acetate (8j): 80% yield, 97% ee; [α]D25 ꢀ32.7
1
(c = 1.0, CHCl3); H NMR (300 MHz, CDCl3, ppm): δ 7.36ꢀ7.33 (m, 2H), 7.28ꢀ7.25 (m, 3H),
7.06 (s, 1H), 6.95ꢀ6.92 (m, 2H), 2.97ꢀ2.83 (m, 1H), 2.13 (s, 3H), 1.25ꢀ1.23 (d, J = 6.9 Hz, 6H);
13C NMR (75 MHz, CDCl3, ppm): 169.9, 149.0, 143.8, 136.9, 126.8, 126.5, 126.4, 125.9, 72.7,
33.8, 23.9, 21.2; HPLC conditions: WhelkꢀO1, nꢀhexane/2ꢀpropanol = 95/5, flow rate = 1.0
mL/min, UV = 217 nm, retention times 6.4 min (R), 7.9 min (S); TOFꢀMS (ESI+) calcd for
[C16H18O2SꢀOAc]+ 215.08945, found 215.09132.
(S)-(4-Isopropylphenyl)(thiophen-3-yl)methyl acetate (8k): 72% yield, 97% ee; [α]D25 +3.5
1
(c = 0.75, CHCl3); H NMR (300 MHz, CDCl3, ppm): δ 7.30ꢀ7.15 (m, 6H), 7.0ꢀ6.98 (m, 1H),
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6.92 (s, 1H), 2.92ꢀ2.87 (m, 1H), 2.13 (s, 3H), 1.24ꢀ1.22 (d, J = 6.9 Hz, 6H); 13C NMR (75 MHz,
CDCl3, ppm): 170.1, 148.7, 141.4, 137.0, 127.1, 126.7, 126.5, 126.0, 122.8, 73.3, 33.8, 23.9,
21.3; HPLC conditions: WhelkꢀO1, nꢀhexane/2ꢀpropanol = 95/5, flow rate = 1.0 mL/min, UV =
217 nm, retention times 7.3 min (R), 8.8 min (S); TOFꢀMS (ESI+) calcd for [C16H18O2SꢀOAc]+
215.08945, found 215.09327.
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(S)-(4-Isopropylphenyl)(pyridin-3-yl)methyl acetate (8l): 89% yield, 95% ee; [α]D25 +24.8(c
= 0.5, CHCl3); 1H NMR (300 MHz, CDCl3, ppm): δ 8.63ꢀ8.62 (d, J = 2.2 Hz, 1H), 8.54ꢀ8.52 (m,
1H), 7.65ꢀ7.61(m, 1H), 7.28ꢀ7.19 (m, 5H), 6.87 (s, 1H), 2.96ꢀ2.82 (m, 1H), 2.16 (s, 3H), 1.24ꢀ
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1.22 (d, J = 6.9 Hz, 6H); C NMR (75 MHz, CDCl3, ppm): 169.9, 149.2, 149.1, 148.6, 136.4,
136.0, 134.6, 127.1, 126.8, 123.3, 74.8, 33.8, 23.9, 21.2; HPLC conditions: WhelkꢀO1, nꢀ
hexane/2ꢀpropanol = 90/10, flow rate = 1.0 mL/min, UV = 217 nm, retention times 25.4 min (R),
28.3 min (S); TOFꢀMS (ESI+) calcd for [C17H19NO2ꢀOAc]+ 210.12827, found 210.12573.
(S)-(4-Isopropylphenyl)(pyridin-4-yl)methyl acetate (8m): 76% yield, 92% ee; [α]D25 +58.6
1
(c = 0.5, CHCl3); H NMR (300 MHz, CDCl3, ppm): δ 8.58ꢀ8.56 (m, 2H), 7.26ꢀ7.21 (m, 7H),
6.79 (s, 1H), 2.93ꢀ2.82 (m, 1H), 2.17 (s, 3H), 1.24ꢀ1.21 (d, J = 6.9 Hz, 6H); 13C NMR (75 MHz,
CDCl3, ppm): 169.8, 150.0, 149.4, 149.0, 136.0, 127.5, 126.8, 121.3, 75.5, 33.8, 23.8, 21.1;
HPLC conditions: WhelkꢀO1, nꢀhexane/2ꢀpropanol = 95/5, flow rate = 1.0 mL/min, UV = 217
nm, retention times 54.2 min (R), 57.6 min (S); TOFꢀMS (ESI+) calcd for [C17H19NO2ꢀOAc]+
210.12827, found 210.12929.
(R)-(4-tert-Butylphenyl)(phenyl)methyl acetate (9a): 92% yield, 98% ee; The analytical data
were in good agreement with the literature values.41
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(R)-(4-tert-Butylphenyl)(3-fluorophenyl)methyl acetate (9b): 88% yield, 97% ee; [α]D
1
+28.3 (c = 1.0, CHCl3); H NMR (300 MHz, CDCl3, ppm): δ 7.42ꢀ7.26 (m, 5H), 7.13ꢀ7.07 (m,
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2H), 7.04ꢀ6.96 (m, 1H), 6.82 (s, 1H), 2.16 (s, 3H), 1.29(s, 9H); 13C NMR (75 MHz, CDCl3, ppm):
169.9, 164.4, 161.2, 151.2, 142.9, 136.5, 130.0, 126.9, 125.5, 122.5, 114.8, 114.5, 114.0, 113.7,
76.0, 34.5, 31.2, 21.2; HPLC conditions (hydrolysis product: alcoholꢀform): WhelkꢀO1, nꢀ
hexane/2ꢀpropanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm, retention times 6.6 min (R),
8.7 min (S); TOFꢀMS (ESI+) calcd for [C19H21FO2ꢀOAc]+ 241.13925, found 241.13765.
(R)-4-tert-Butylphenyl)(m-tolyl)methyl acetate (9c): 90% yield, 97% ee; [α]D25 +14.5 (c =
0.8, CHCl3); 1H NMR (300 MHz, CDCl3, ppm): δ 7.36ꢀ7.07 (m, 8H), 6.82 (s, 1H), 2.33 (s, 3H),
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2.15 (s, 3H), 1.29 (s, 9H); C NMR (75 MHz, CDCl3, ppm): 170.0, 150.7, 140.2, 138.1, 137.2,
128.5, 128.3, 127.6, 126.8, 125.4, 124.0, 76.5, 34.5, 31.3, 21.4, 21.3; HPLC conditions: Whelkꢀ
O1, nꢀhexane/2ꢀpropanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm, retention times 7.5 min
(R), 10.8 min (S); TOFꢀMS (ESI+) calcd for [C20H24O2ꢀOAc]+ 237.16433, found 237.16287.
(R)-(4-tert-Butylphenyl)(4-fluorophenyl)methyl acetate (9d): 92% yield, 96% ee; The
analytical data were in good agreement with the literature values.41
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(R)-(4-tert-Butylphenyl)(4-chlorophenyl)methyl acetate (9e): 84% yield, 95% ee; [α]D
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+14.7 (c = 1.0, CHCl3); H NMR (300 MHz, CDCl3, ppm): δ 7.36ꢀ7.21 (m, 8H), 6.81 (s, 1H),
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2.14 (s, 3H), 1.29(s, 9H); C NMR (75 MHz, CDCl3, ppm): 169.9, 151.1, 138.9, 136.6, 133.6,
128.6, 128.4, 126.8, 125.5, 76.0, 34.5, 31.2, 21.2; HPLC conditions: WhelkꢀO1, nꢀhexane/2ꢀ
propanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm, retention times 6.8 min (R), 9.3 min (S);
TOFꢀMS (ESI+) calcd for [C19H21ClO2ꢀOAc]+ 257.10970, found 257.10836.
(S)-(4-(tert-Butyl)phenyl)(furan-2-yl)methyl acetate (9h): 91% yield, 97% ee; [α]D25 ꢀ34.7 (c
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= 1.0, CHCl3); H NMR (300 MHz, CDCl3, ppm): δ 7.40ꢀ7.34 (m, 5H), 6.87 (s, 1H), 6.32ꢀ6.30
(m, 1H), 6.20ꢀ6.19 (m, 1H), 2.12 (s, 3H), 1.31 (s, 9H); 13C NMR (75 MHz, CDCl3, ppm): 169.9,
152.5, 151.3, 143.0, 134.2, 126.9, 125.4, 110.2, 109.4, 70.3, 34.6, 31.2, 21.1; HPLC conditions:
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WhelkꢀO1, nꢀhexane/2ꢀpropanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm, retention times
6.2 min (R), 7.7 min (S); TOFꢀMS (ESI+) calcd for [C17H20O3ꢀOAc]+ 213.12794, found
213.12393.
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(S)-(4-(tert-Butyl)phenyl)(furan-3-yl)methyl acetate (9i): 85% yield, 98% ee; [α]D25 +10.3 (c
= 0.65, CHCl3); 1H NMR (300 MHz, CDCl3, ppm): δ 7.39ꢀ7.22 (m, 5H), 6.81 (s, 1H), 6.34ꢀ6.33
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(m, 1H), 2.11 (s, 3H), 1.31 (s, 9H); C NMR (75 MHz, CDCl3, ppm): 170.1, 151.1, 143.3,
140.7, 136.2, 126.7, 125.5, 125.4, 109.6, 70.2, 34.5, 31.3, 21.3; HPLC conditions: WhelkꢀO1, nꢀ
hexane/2ꢀpropanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm, retention times 6.1 min (R),
7.3 min (S); TOFꢀMS (ESI+) calcd for [C17H20O3ꢀOAc]+ 213.12794, found 213.12358.
(S)-(4-(tert-Butyl)phenyl)(thiophene-2-yl)methyl acetate (9j): 81% yield, 98% ee; [α]D25 ꢀ
1
26.2 (c = 0.8, CHCl3); H NMR (300 MHz, CDCl3, ppm): δ 7.40ꢀ7.33 (m, 4H), 7.25ꢀ7.23 (m,
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1H), 7.07 (s, 1H), 6.92ꢀ6.90 (m, 2H), 2.11 (s, 3H), 1.30 (s, 9H); C NMR (75 MHz, CDCl3,
ppm): 169.8, 151.2, 143.7, 136.5, 126.5, 126.5, 126.4, 125.9, 125.4, 72.6, 34.5, 31.2, 21.2; HPLC
conditions: WhelkꢀO1, nꢀhexane/2ꢀpropanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm,
retention times 7.8 min (R), 9.3 min (S); TOFꢀMS (ESI+) calcd for [C17H20O2SꢀOAc]+ 229.1051,
found 229.10368.
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+1.5 (c = 0.45, CHCl3); H NMR (300 MHz, CDCl3, ppm): δ 7.38ꢀ7.35 (m, 2H), 7.30ꢀ7.25 (m,
2H), 7.16ꢀ7.15 (m, 1H), 7.01ꢀ6.99 (m, 1H), 6.92 (s, 1H), 2.13 (s, 3H), 1.30 (s, 9H); 13C NMR (75
MHz, CDCl3, ppm): 170.1, 151.0, 141.4, 136.7, 126.8, 126.7, 126.0, 125.4, 122.8, 73.2, 34.5,
31.3, 21.3; HPLC conditions: WhelkꢀO1, nꢀhexane/2ꢀpropanol = 95/5, flow rate = 1.0 mL/min,
UV = 217 nm, retention times 7.2 min (R), 8.1 min (S); TOFꢀMS (ESI+) calcd for [C17H20O2Sꢀ
OAc]+ 229.1051, found 229.10378.
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(S)-(4-(tert-Butyl)phenyl)(pyridin-3-yl)methyl acetate (9l): 76% yield, 94% ee; [α]D25 +18.2
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(c = 0.7, CHCl3); H NMR (300 MHz, CDCl3, ppm): δ 8.63ꢀ8.62 (m, 1H), 8.54ꢀ8.52 (m, 1H),
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7.65ꢀ7.61 (m, 1H), 7.38ꢀ7.36 (m, 2H), 7.28ꢀ7.24 (m, 3H), 6.88 (s, 1H), 2.16 (s, 3H), 1.30 (s, 9H);
13C NMR (75 MHz, CDCl3, ppm): 169.9, 151.3, 149.1, 148.6, 136.0, 135.9, 134.6, 126.8, 125.6,
123.3, 74.7, 34.5, 31.2, 21.2; HPLC conditions: WhelkꢀO1, nꢀhexane/2ꢀpropanol = 95/5, flow
rate = 1.0 mL/min, UV = 217 nm, retention times 62.9 min (R), 67.4 min (S); TOFꢀMS (ESI+)
calcd for [C18H21NO2ꢀOAc]+ 224.14392, found 224.14281.
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(S)-(4-(tert-Butyl)phenyl)(pyridin-4-yl)methyl acetate (9m): 75% yield, >99% ee; [α]D
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+70.3 (c = 0.4, CHCl3); H NMR (300 MHz, CDCl3, ppm): δ 8.58ꢀ8.56 (m, 2H), 7.39ꢀ7.35 (m,
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2H), 7.26ꢀ7.22 (m, 4H), 6.79 (s, 1H), 2.18 (s, 3H), 1.29 (s, 9H); C NMR (75 MHz, CDCl3,
ppm): 169.8, 151.6, 150.0, 149.0, 135.6, 127.2, 125.7, 121.3, 75.4, 34.6, 31.2, 21.1; HPLC
conditions (hydrolysis product: alcohol-form): WhelkꢀO1, nꢀhexane/2ꢀpropanol = 90/10, flow
rate = 1.0 mL/min, UV = 217 nm, retention times 39.1 min (R), 46.1 min (S); TOFꢀMS (ESI+)
calcd for [C18H21NO2ꢀOAc]+ 224.14392, found 224.14029.
(R)-Phenyl(4-(trimethylsilyl)phenyl)methyl acetate (10a): 82% yield, 96% ee; [α]D25 +17.1
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(c = 0.9, CHCl3); H NMR (300 MHz, CDCl3, ppm): δ 7.50ꢀ7.47 (m, 2H), 7.34ꢀ7.26 (m, 7H),
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6.86 (s, 1H), 2.14 (s, 3H), 0.24 (s, 9H); C NMR (75 MHz, CDCl3, ppm): 171.1, 141.8, 141.3,
134.6, 129.6, 129.0, 128.2, 127.5, 78.0, 22.4, 0.0; HPLC conditions: WhelkꢀO1, nꢀhexane/2ꢀ
propanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm, retention times 7.3 min (R), 8.2 min (S);
TOFꢀMS (ESI+) calcd for [C18H22O2Siꢀ OAc]+ 239.12560, found 239.12369.
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(S)-Thiophen-2-yl(4-(trimethylsilyl)phenyl)methyl acetate (10b): 82% yield, 96% ee; [α]D
ꢀ18.3 (c = 1.3, CHCl3); 1H NMR (300 MHz, CDCl3, ppm): δ 7.52 (d, J = 8.1 Hz, 2H), 7.40 (d, J
= 8.1 Hz, 2H), 7.27ꢀ7.24 (m, 1H), 7.07 (s, 1H), 6.95ꢀ6.91 (m, 1H), 2.14 (s, 3H), 0.26 (s, 9H); 13C
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NMR (75 MHz, CDCl3, ppm) 171.0, 144.7, 141.8, 141.2, 134.7, 129.7, 127.7, 127.2, 73.9, 22.3,
0.0; HPLC conditions: WhelkꢀO1, nꢀhexane/2ꢀpropanol = 96/4, flow rate = 1.0 mL/min, UV =
217 nm, retention times 5.5 min (R), 6.4 min (S); TOFꢀMS (ESI+) calcd for [C16H20O2SSiꢀ
OAc]+ 245.08202, found 245.07877.
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(S)-Pyridin-3-yl(4-(trimethylsilyl)phenyl)methyl acetate (10c): 92% yield, 94% ee; [α]D
+19.4 (c = 1.0, CHCl3); 1H NMR (300 MHz, CDCl3, ppm): δ 8.63(d, J = 2.1 Hz, 1H), 8.54ꢀ8.52
(m, 1H), 7.64ꢀ7.61 (m, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.27ꢀ7.23 (m, 1H),
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6.88 (s, 1H), 2.16 (s, 3H), 0.25 (s, 9H); C NMR (75 MHz, CDCl3, ppm): 171.0, 150.5, 149.9,
142.1, 140.7, 137.0, 135.9, 134.9, 127.5, 124.5, 76.1, 22.3, 0.0; HPLC conditions: WhelkꢀO1, nꢀ
hexane/2ꢀpropanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm, retention times 21.4 min (R),
24.1 min (S); TOFꢀMS (ESI+) calcd for [C17H21NO2Siꢀ OAc]+ 240.12085, found 240.11560.
Synthesis of L-Cloperastine (11). To a solution containing (R)ꢀ10a (0.5 mmol, 96% ee) in
MeOHꢀH2O (5.0 mL, 0.1 M) was added K2CO3 (240 mg, 1.5 mmol). The resulting solution was
stirred at room temperature for 2 h and then concentrated by removing solvent under reduced
pressure. The residue was purified through a silica gel column chromatography to provide (R)-6a
1
(0.46 mmol, 92% yield, 96% ee); H NMR (300 MHz, CDCl3, ppm): δ 7.52ꢀ7.45 (m, 2H), 7.39ꢀ
13
7.20 (m, 7H), 5.88ꢀ5.82 (m, 1H), 2.22ꢀ2.18 (m, 1H), 0.24 (s, 9H); C NMR (75 MHz, CDCl3,
ppm): 145.4, 144.8, 140.9, 134.7, 129.6, 128.7, 127.6, 126.9 77.3. 0.0; HPLC condition: Whelkꢀ
O1, nꢀhexane/2ꢀpropanol = 96/4, flow rate = 1.0 mL /min, UV = 217 nm; retention times 7.2 min
(R), 8.3 min (S); TOFꢀMS (ESI+) calcd for [C16H20OSiꢀOH]+ 239.12560, found 239.12656.
To a solution containing (R)ꢀ6a (0.5 mmol, 96% ee) in MeOH (5 mL, 0.1 M) was added KCl
(0.6 mmol, 45 mg) and NCS (0.6 mmol, 83 mg). The resulting solution was stirred at 60 oC for 2
h, then quenched with H2O, and extracted with CH2Cl2 .The organic layer was washed with
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brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was
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purified by silica gel chromatography to give (R)ꢀ3a (0.41 mmol, 81% yield, 96% ee): [α]D25 ꢀ
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18.1 (c = 0.6, CHCl3) (lit.55 [α]D25= ꢀ20 (c = 1.0, AcOEt, 90% ee)); H NMR (300 MHz, CDCl3,
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ppm): δ 7.38ꢀ7.23 (m, 9H), 5.80ꢀ5.83 (m, 1H), 2.25ꢀ2.22 (m, 1H); C NMR (75 MHz, CDCl3,
ppm): 143.4, 142.2, 133.2, 128.6, 127.8, 126.5, 75.6; HPLC conditions: ChiralcelꢀOD, nꢀ
hexane/2ꢀpropanol = 98/2, flow rate = 1.0 mL/min, UV = 217 nm, retention times 56.8 min (S),
63.0 min (R); TOFꢀMS (ESI+) calcd for [C13H11ClOꢀOH]+ 201.04710, found 201.04921.
To a solution containing (R)ꢀ3a (0.4 mmol, 96% ee) in methylene chloride (4.0 mL, 0.1 M)
was added 1ꢀ(2ꢀchloroethyl)piperidine hydrochloride (120 mg, 0.6 mmol). The resulting solution
was cooled at 0 oC followed by the addition of NaOH (48 mg, 1.2 mmol). After the mixture had
been stirred for 20 min at 0 °C and then overnight at room temperature, it was quenched with
H2O and extracted with CH2Cl2 .The organic layer was washed with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel
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chromatography to give 11 (0.38 mmol, 94% yield, 96% ee): [α]D ꢀ6.29 (c = 1.0, CHCl3)
(lit.56[α]D ꢀ 6 ~ ꢀ 6.5); 1H NMR (300 MHz, CDCl3, ppm): δ 7.35ꢀ7.21 (m, 9H), 5.34 (1H), 3.57 (t,
J = 6.27 Hz, 2H), 2.63 (t, J = 6.27 Hz, 2H), 2.47ꢀ2.40 (m, 4H), 1.59ꢀ1.52 (m, 4H), 1.51ꢀ1.32 (m,
13
2H); C NMR (75 MHz, CDCl3, ppm): 141.8, 140.9, 133.0, 128.4, 128.3, 127.6, 126.9, 83.2,
67.1, 58.6, 55.0, 26.0, 24.2; HPLC condition: Chiralcel ODꢀH, nꢀhexane/2ꢀpropanol = 80/20,
flow rate = 0.5 mL /min, UV = 254 nm; retention times 7.44 min (S), 7.74 min (R); TOFꢀMS
(ESI+) calcd for [C20H24ClNOꢀ C7H14NO]+ 201.04710, found 201.04303.
ASSOCIATED CONTENT
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Supporting Information
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NMR spectra and HPLC chromatograms of products. This material is available free of charge
via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: mjkim@postech.ac.kr (mjk)
*Eꢀmail: pjw@postech.ac.kr (jp)
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Research Foundation of Korea (project numbers,
2012R1A1A2006595 and 2012ꢀ007235) for financial support of this work. We thank Amano for
the generous supply of the LPL sample used in this work and specially Dr. Hirose for proving the
technical information.
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