Base-Free Dynamic Kinetic Resolution of Secondary Alcohols with a Ruthenium-Lipase Couple

Article abstract of DOI:10.1021/acs.joc.9b02510

We report the dynamic kinetic resolution (DKR) of various secondary alcohols by the combination of a ruthenium catalyst and an anionic surfactant-activated lipoprotein lipase. The DKR reactions performed under totally base-free conditions at room temperature provided the products of excellent enantiopurities (91-99% ee or greater) in high yields (92-99%). More importantly, the DKR of α-arylallyl alcohols was achieved for the first time with high yields (87-91%).

Full text of DOI:10.1021/acs.joc.9b02510

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Note
Base-free Dynamic Kinetic Resolution of Secondary
Alcohols with a Ruthenium-Lipase Couple
Inyeol Yun, Jin Yong Park, Jaiwook Park, and Mahn-Joo Kim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02510 • Publication Date (Web): 28 Nov 2019
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The Journal of Organic Chemistry
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Base-free Dynamic Kinetic Resolution of Secondary Alcohols with a
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RutheniumLipase Couple
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Inyeol Yun, Jin Yong Park, Jaiwook Park*, and Mahn–Joo Kim*
Department of Chemistry, Pohang University of Science and Technology 77 Cheongam-ro, Pohang
37673, Republic of Korea
E-mail: mjkim@postech.ac.kr
OH
OAc
Ru catalyst
Lipoprotein lipase
MeO
OC
isopropenyl acetate
toluene, 25 oC, 6 h
O
Ru
(91% yield, 93% ee)
Racemic
OC
Ru catalyst
OMe
Dynamic kinetic resolution
(16 additional examples)
ABSTRACT
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We report the dynamic kinetic resolution (DKR) of various secondary alcohols by the combination of
a ruthenium catalyst and an anionic surfactant-activated lipoprotein lipase. The DKR reactions
performed under totally base-free conditions at room temperature provided the products of excellent
enantiopurities (9199% ee or greater) in high yields (92−99%). More importantly, the DKR of -
arylallyl alcohols was achieved for the first time with high yields (87−91%).
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Dynamic kinetic resolution (DKR) provides a powerful methodology for the transformations of
racemic substrates to enantiomerically-enriched products.1 Since the first report by the Williams group
on the coupling of a metal-catalyzed racemization and an enzymatic kinetic resolution for DKR,2
various metal complexes have been reported to be useful as racemization catalysts for the
chemoenzymatic DKR of secondary alcohols.3 Among them, cyclopentadienylruthenium complexes
1
2
3
4
5
6
7
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13 were most widely utilized in DKR4 (Scheme 1). The Shvo’s dimeric ruthenium complex 1 needs
thermal activation into two active monomeric forms, thus requiring a thermally stable enzyme such as
Candida antarctica lipase B (CALB) as the partner for the efficient DKR.5 Ruthenium catalysts 2a-d
reported by our group6 display good activities at ambient temperature, which are thus compatible with
a wider range of enzymes in DKR. The ruthenium catalyst 3 also displays a good activity at ambient
temperature. 7 Ru catalysts 2 and 3, however, require a base (KOtBu or K2CO3) for the activation,
which makes the DKR process less practical. Thus, we have tried to develop a ruthenium catalyst
undergoing base-free activation at ambient temperature. The first example was a dimeric Ru complex
4 displaying good racemization activity under the base-free conditions if photoactivated.8 However,
the DKR with 4 needed still a weak base to remove acid formed as byproduct. We now report that
ruthenium catalyst 59 is a good alternative for the base-free racemization and DKR of secondary
alcohols at ambient temperature.10 In particular, this ruthenium catalyst is useful for the DKR of -
substituted allyl alcohols that was previously difficult to achieve with other Ru catalysts.6b, 11
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Scheme 1. Dynamic kinetic resolution of secondary alcohols and ruthenium catalysts
OAcyl
OH
OH
Ar
Lipase
Ru catalyst
R
Ar
R
Ar
R
Acyl donor
Ph
Ru
Ar
O
O
Ph
Ph
Ph
Ph
Ar
Ar
OC
OC
X
H
H
Ph
Ph
Ph
Ph
Ph
Ru
Ar
Ph
Ru
OC
Cl
Ph
Ph
Cl
Ru
OC
OC
CO
OC
CO
i
3
1
2a
2b
2c
2d
Ar = Ph, X = NH Pr
Ar = Ph, X = OBn
Ar = Ph, X = OBz
Ar = Ph-p-OMe,
X = OBz-p-OMe
NHiPr
O
CO
Ph
Ph
Ph
Ru Ru
MeO
Ph
O
Ru
OC
OC
OC
O
OMe
iPrHN
4
5
At first, we examined the racemization of (S)-1-phenylethanol with 5 in the absence of base. The
racemization in the presence of 4 mol% 5 proceeded to completion within 30 min at room temperature
(Scheme 2). At the early stage of racemization, the color of solution was changed from yellow to red.
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This color change implies the formation of new ruthenium complex 7 as the active catalyst form
leading to racemization (Scheme 3). The active catalyst 7 then reacts with nonracemic alcohol to give
ruthenium-alkoxide complex 8, which undergoes decarbonylation and reductive elimination to yield
ruthenium-ketone complex 10 via 9. The subsequent reduction of ketone coordinated to ruthenium
leads to racemic alkoxide complex 11. The alkoxide exchange then gives ruthenium-alkoxide complex
9 with release of racemic alcohol.12 It is noted that the racemization activity of 5 is rather surprising
because the Bäckvall group reported that the pentaphenylcyclopentadienylruthenium analogue of 5
was thermally stable and displayed no racemization activity.12 As a rationale of the racemization
activity of 5, we suggest that the conversion of 5 into its active catalyst form 7 via 16-electron complex
6 could take place owing to the presence of electron-rich cyclopentadienyl ring.
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Scheme 2. Racemization of (S)-1-phenylethanol with Ru catalyst
OH
OH
5
Ru catalyst (4 mol%)
toluene (0.5 M)
30 min, RT
0.1 mmol
>99% ee
less than 1 % ee
Scheme 3. Proposed pathway for the racemization of (S)-1-phenylethanol
CO
MeO
OC
OC
MeO
OC
MeO
OC
OC
O
O
Ru
Ru
Ru
OMe
OMe
OMe
7
6
5
OH
Ph
MeOH
MeO
OC
MeO
OC
MeO
OC
Ru
Ru
Ru
O
O
O
CO
Ph
Ph
H
Ph
OC
10
8
9
OH
Ph
OH
Ph
MeO
OC
Ru
O
Ph
11
Scheme 4. DKR of 1-phenylethanol
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5
Ru catalyst (4 mol%)
OH
OAc
1
1
LPL-D (20 mg/mmol)
2
3
4
5
isopropenyl acetate (1.5 eq)
MS 4Ao (300 mg/mmol)
toluene, 25 oC, 5 h
12a
13a
(96% yield, 99% ee)
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7
8
The successful racemization of (S)-1-phenylethanol with 5 encouraged us to explore the base-free
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DKR of racemic 1-phenylethanol 12a by the combination of 5 and an (R)-selective lipoprotein lipase
(LPL) from Burkholderia species. LPL was treated with anionic surfactant before use to ensure its
high activity in organic solvent. In our earlier study,13 it was found that the anionic surfactant-treated
LPL (LPL-D1) was three orders of magnitude more active than its native counterpart in toluene. The
DKR reaction of racemic 1-phenylethanol was then performed with a solution containing substrate
(0.2 mmol), LPL-D1 (20 mg/mmol), 5 (4 mol%), isopropenyl acetate (0.3 mmol), and MS 4Å (60 mg)
in toluene (0.5 M) at room temperature. The DKR was complete in 5 h and gave the product of
excellent enantiopurity (99 % ee ) with high yield (96 %) (Scheme 4). The results thus proved that the
base-free DKR was successful.
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Other secondary benzylic alcohols, 12b-f with a para-substituent on the benzene ring, were also
subject to DKR under base-free conditions. All of them were transformed into the products of excellent
enantiopurities (99 % ee or greater) with high yields (95−97 %), although two of them, 12e and 12f,
required a longer reaction time (entries 2−6, Table 1). The need for a longer reaction time implies that
electron-poor substrates are less reactive in both Ru-catalyzed racemization and lipase-catalyzed
acylation. The results from the DKR of 12g with an electron-withdrawing meta-substituent were
similar to those from the DKR of 12e (compare entries 5 and 7, Table 1). It is expected that other
secondary benzylic alcohols with a meta-substituent also should react similarly to their para-
substituted counterparts in DKR. Secondary benzylic alcohols with an ortho-substituent were not
tested for DKR because they are poor substrates of LPL. The chloroethyl carbinol 12h reacted even
more slowly owing to the presence of an electron-withdrawing, relatively larger alkyl substituent at
the hydroxymethine center, thus requiring the use of a larger amount of enzyme and much longer
reaction time (entry 8, Table 1). Although the yield of 13h was high, the enantioselectivity was slightly
lower. On the other hand, non-benzylic alcohols, 12i and 12j, were as good as benzylic alcohols in
DKR (entries 9 and 10, Table 1). Excellent yields and enantioselectivities were obtained. The DKR of
naphthyl carbinol 12k was also successful with excellent yield and enantioselectivity (entry 11, Table
1).
In the previous study,6b we found that -phenylallyl alcohol 12l was poor substrate in the DKR
employing 2a as the racemization catalyst. This DKR performed in the presence of one equivalent of
Na2CO3 provided 62% yield with a relatively large amount of saturated ketone (38% yield) as the side
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product. In the present work, we also found that a significant amount of saturated ketone (23% yield)
was produced in the DKR of 12l employing 2d as the racemization catalyst in the presence of one
equivalent of K2CO3. It is noted that 2d requires one equivalent of K2CO3 for pre-activation and DKR.
It was previously reported that the rates in the Ru-catalyzed isomerization of allylic alcohols to
saturated ketone were dramatically enhanced by K2CO3.14 We also observed such a dramatic rate
enhancement by K2CO3 in the Ru-catalyzed isomerization of 12l. In the presence of ruthenium catalyst
2d (4 mol%) and K2CO3 (1 equiv) in toluene at room temperature, 12l was isomerized almost
quantitatively to saturated ketone within 6 h. Under the same conditions without base, however, no
significant isomerization took place. These results thus suggest that the use of base-free racemization
catalyst system should lead to the successful DKR of 12l. As expected, the base-free DKR of 12l with
5 provided high yield (91%) with a small amount of ethyl phenyl ketone (7%) (entry 12, Table 1). To
the best of our knowledge, this is the first successful DKR of 12l that has been reported up to date.
This success encouraged us to further test the p-substituted derivatives of 12l in DKR. Allylic alcohols
with an electron-donating substituent, 12m and 12n, displayed also satisfactory performance. Products,
13m and 13n, were obtained in high yields (9091% yield) with good enantiopurities (9596% ee)
(entries 13 and 14, Table 1). In contrast to these results, allylic alcohols with an electron-withdrawing
substituent, 12o and 12p, were problematic and required a lower amount of enzyme for giving a good
enantioselectivity. The DKR reactions of these alcohols thus proceeded rather slowly and provided
relatively lower yields and enantiomeric excesses (entries 15 and 16, Table 1). Finally, the DKR of -
substituted allyl alcohol 12q proceeded successfully and provided enantiomerically pure 13q in 94%
yield (entry 17, Table 1).
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Table 1. DKR of secondary alcoholsa
LPL-D1
t
Yieldc
(%)
eed
Entry
1
Substrate
Productb
(mg/mmol) (h)
(%)
OH
OAc
12a
12b
12c
12d
20
20
20
20
5
6
6
6
13a
13b
13c
13d
96
96
95
97
99
>99
99
OH
OH
OAc
2
3
4
OAc
OMe
OMe
OH
OAc
99
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OH
OH
OAc
1
2
3
4
5
6
7
8
5
6
7
12e
12f
12g
20
20
20
12
12
12
13e
13f
13g
95
97
93
>99
>99
>99
Cl
Br
Cl
Br
OAc
OH
OAc
9
Cl
Cl
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11
12
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OH
OAc
Cl
8
9
12h
12i
12j
40
20
20
24
6
13h
13i
13j
95
92
94
95
>99
97
Cl
OAc
OH
OH
OAc
10
12
OH
OAc
11
12
13
12k
12l
20
20
20
9
6
9
13k
13l
99
91
90
>99
93
OH
OAc
OH
OAc
12m
13m
96
OH
OAc
OAc
OAc
OAc
14
15
12n
12o
20
10
9
13n
13o
91
89
95
91
OMe
OMe
OH
OH
48
Cl
Br
Cl
Br
16
17
12p
12q
10
20
48
12
13p
13q
87
94
91
OH
>99
a Alcohol (0.2 mmol), LPL-D1 (10‒40 mg/mmol), Ru catalyst 5 (4 mol%), isopropenyl acetate (0.3
mmol), and MS 4Å (60 mg) were stirred in toluene (0.5 M) at room temperature under an argon
atmosphere. b The signs of optical rotations and the chromatogram patterns from chiral HPLC analyses
indicate that all the products have (R)-stereochemistry. c Isolated yield. d Determined by chiral HPLC.
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In summary, we explored the DKR of various secondary alcohols employing ruthenium complex 5
as the racemization catalyst and LPL-D1 as the resolution catalyst under totally base-free conditions.
The DKR reactions of simple secondary alcohols proceeded smoothly and provided high yields and
excellent enantiomeric excesses. Furthermore, we have demonstrated for the first time that the DKR
of -arylallyl alcohols provided good to high yields. Our DKR process is simpler and easier to perform
compared to those requiring base for the pre-activation of racemization catalyst. Thus, we have
established a useful protocol for the base-free DKR of a wider range of secondary alcohols, leading to
the synthesis of enantiomerically-enriched esters.15
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EXPERIMENTAL SECTION
General procedure for dynamic kinetic resolution. In a flame-dried Schlenk flask, substrate (0.2
mmol), LPL-D116 (10−20 mg/mmol), ruthenium catalyst 517 (4 mol%), and molecular sieves (4Å,
powder, 60 mg) were added under an argon atmosphere, followed by addition of distilled toluene (400
μL) and isopropenyl acetate (0.3 mmol, 34 μL). The reaction mixture was stirred at room temperature
for 5–48 h. After the reaction was completed, the mixture was filtered through a celite pad and
concentrated under reduced pressure, and purified by column chromatography (n-hexane/EtOAc =
10:1).
Analytical data of DKR products. (R)-1-Phenylethyl acetate (13a): 31.6 mg (96% yield, 99% ee);
[α]25D = + 96.3 (c = 1.0, CHCl3) [lit.18 [α]25D = + 102 (c = 1, CHCl3, >99% ee)]; 1H NMR (CDCl3, 300
MHz): δ 7.41-7.27 (m, 5H), 5.92-5.85 (q, J = 6.6 Hz, 1H), 2.07 (s, 3H), 1.55-1.53 (d, J = 6.6 Hz, 3H);
13C{1H} NMR (CDCl3, 75 MHz): 170.3, 141.7, 128.5, 127.0, 125.3, 72.3, 22.2, 21.4; HPLC conditions:
(R,R)-Whelk-O1, n-hexane/2-propanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm; retention times:
4.91 min (S), 8.59 min (R). The NMR data are in good agreement with those reported in the literature.18
(R)-1-(p-Tolyl)ethyl acetate (13b): 34.4 mg (96% yield, >99% ee); [α]25D = + 111.5 (c = 1.0, CHCl3)
[lit.17 [α]25D = + 113 (c = 0.87, CHCl3, 98% ee)]; 1H NMR (CDCl3, 300 MHz): δ 7.23-7.16 (m, 2H),
7.09-7.02 (m, 2H), 5.81-5.75 (q, J = 6.6 Hz, 1H), 2.28 (s, 3H), 2.05 (s, 3H), 1.46-1.43 (d, J = 6.6 Hz,
3H);13C{1H} NMR (CDCl3, 75 MHz): 170.4, 138.7, 137.6, 129.5, 125.7, 72.4, 22.2, 21.4, 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: 4.91 min (S), 10.04 min (R). The NMR data are in good agreement with those reported
in the literature.18
(R)-1-(4-Methoxyphenyl)ethyl acetate (13c): 36.9 mg (95% yield, 99% ee); [α]25D = + 107.1 (c = 1.0,
CHCl3) [lit.18 [α]25D = + 121.7 (c = 1, CHCl3, 99% ee)]; 1H NMR (CDCl3, 300 MHz): δ 7.30-7.20 (m,
2H), 6.83-6.78 (m, 2H), 5.80-5.74 (q, J = 6.6 Hz, 1H), 3.79 (s, 3H), 2.04 (s, 3H), 1.46-1.44 (d, J = 6.6
Hz, 3H); 13C{1H} NMR (CDCl3, 75 MHz): 170.4, 159.3, 133.8, 127.6, 113.8, 72.0, 55.3, 22.0, 21.4;
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HPLC conditions: (R,R)-Whelk-O1, n-hexane/2-propanol = 95/5, flow rate = 1.0 mL/min, UV = 217
nm; retention times: 6.81 min (S), 19.10 min (R). The NMR data are in good agreement with those
reported in the literature.18
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2
3
4
5
6
7
8
(R)-1-(4-Fluorophenyl)ethyl acetate (13d): 37.3 mg (97% yield, 99% ee); [[α]25D = + 103.6 (c = 1.0,
CHCl3) [lit.18 [α]25D = + 113 (c = 0.9, CHCl3, 99% ee)]; 1H NMR (CDCl3, 300 MHz): δ 7.34-7.29 (m,
2H), 7.06-6.99 (m, 2H), 5.89-5.82 (q, J = 6.6 Hz, 1H), 2.06 (s, 3H), 1.46-1.44 (d, J = 6.6 Hz, 3H);
13C{1H} NMR (CDCl3, 75 MHz): 169.2, 162.9, 159.7, 136.5, 127.2, 114.5, 114.2, 70.6, 21.2, 20.4;
HPLC conditions: (R,R)-Whelk-O1, n-hexane/2-propanol = 95/5, flow rate = 1.0 mL/min, UV = 217
nm; retention times: 4.85 min (S), 8.30 min (R). The NMR data are in good agreement with those
reported in the literature.18
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(R)-1-(4-Chlorophenyl)ethyl acetate (13e): 37.7 mg (95% yield, >99% ee); [α]25D = + 71.2 (c = 1.0,
CHCl3) [lit.18 [α]25D = + 80 (c = 1.25, CHCl3, 99% ee)]; 1H NMR (CDCl3, 300 MHz): δ 7.37-7.24 (m,
4H), 5.87-5.80 (q, J = 6.6 Hz, 1H), 2.05 (s, 3H), 1.48-1.46 (d, J = 6.6 Hz, 3H);13C{1H} NMR (CDCl3,
75 MHz): 170.2, 140.2, 133.6, 128.7, 127.5, 71.6, 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: 4.95 min (S), 10.62
min (R). The NMR data are in good agreement with those reported in the literature.18
(R)-1-(4-Bromophenyl)ethyl acetate (13f): 47.3 mg (97% yield, >99% ee); [α]25D = + 94.3 (c = 1.0,
CHCl3) [lit.18 [α]25D = + 91 (c = 1, CHCl3, 99% ee)]; 1H NMR (CDCl3, 300 MHz): δ 7.48-7.45 (m,
2H), 7.24-7.21 (m, 2H), 5.85-5.79 (q, J = 6.6 Hz, 1H), 2.06 (s, 3H), 1.52-1.49 (d, J = 6.6 Hz, 3H);
13C{1H} NMR (CDCl3, 75 MHz): 170.2, 140.8, 131.6, 127.9, 121.7, 71.6, 22.1, 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:
5.00 min (S), 11.81 min (R). The NMR data are in good agreement with those reported in the
literature.18
(R)-1-(3-Chlorophenyl)ethyl acetate (13g): 37.2 mg (93% yield, >99% ee); [α]25D = + 95.3 (c = 1.0,
CHCl3) [lit.19 [α]25D = + 103.0 (c = 1.05, CHCl3, 95% ee)]; 1H NMR (CDCl3, 300 MHz): δ 7.36-7.22
(m, 4H), 5.88-5.82 (q, J = 6.6 Hz, 1H), 2.06 (s, 3H), 1.55-1.52 (d, J = 6.6 Hz, 3H); 13C{1H} NMR
(CDCl3, 75 MHz): 172.0, 145.6, 136.3, 131.7, 129.9, 128.1, 126.1, 73.4, 24.1, 23.1; HPLC conditions:
(R,R)-Whelk-O1, n-hexane/2-propanol = 90/10, flow rate = 0.5 mL/min, UV = 217 nm; retention times:
8.01 min (S), 12.13 min (R). The NMR data are in good agreement with those reported in the
literature.19
(R)-3-Chloro-1-phenylpropyl acetate (13h): 40.6 mg (95% yield, 95% ee); [α]25D = + 53.8 (c = 1.0,
CHCl3) [lit.6g [α]25D = - 58.2, (S)-form (c = 1.34, CHCl3)]; 1H NMR (CDCl3, 300 MHz): δ 7.31-7.18
(m, 5H), 5.88-5.83 (m, 1H), 3.50-3.35 (m, 2H), 2.36-2.28 (m, 1H), 2.15-2.01 (m, 1H), 1.97 (s, 3H);
13C{1H} NMR (CDCl3, 75 MHz): 170.0, 129.7, 127.5, 125.3, 72.8, 42.6, 40.6, 38.7, 21.2; HPLC
conditions: (R,R)-Whelk-O1, n-hexane/2-propanol = 95/5, flow rate = 1.0 mL/min, UV = 217 nm;
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retention times: 5.64 min (S), 9.43 min (R). The NMR data are in good agreement with those reported
in the literature.6g
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(R)-1-Phenylpropan-2-yl acetate (13i): 32.9 mg (92% yield, >99% ee); [α]25D =  14.1 (c = 1.0, CHCl3)
[lit.18 [α]D25 =  5.6 (c = 1, CHCl3, 99% ee)]; 1H NMR (CDCl3, 300 MHz): δ 7.35-7.18 (m, 5H), 5.16-
5.10 (m, 1H), 2.96-2.89 (m, 1H), 2.78-2.71(m, 1H), 2.06 (s, 3H), 1.22-1.20 (d, J = 6.3 Hz, 3H);13C{1H}
NMR (CDCl3, 75 MHz): 170.4, 137.6, 129.4, 128.3, 126.4, 71.4, 42.3, 21.2, 19.4; HPLC conditions:
(R,R)-Whelk-O1, n-hexane/2-propanol = 98/2, flow rate = 1.0 mL/min, UV = 217 nm; retention times:
5.14 min (S), 5.70 min (R). The data are in good agreement with those reported in the literature.18
(R)-4-Phenylbutan-2-yl acetate (13j): 36.0 mg (94% yield, 97% ee); [α]25D = + 12.2 (c = 1.0, CHCl3)
[lit.18 [α]25D = + 7.82 (c = 1, CHCl3, 99% ee)]; 1H NMR (CDCl3, 300 MHz): δ 7.28-7.08 (m, 5H), 4.91-
4.81 (m, 1H), 2.61-2.53 (m, 2H), 1.96 (s, 3H), 1.86-1.53 (m, 2H), 1.19-1.17 (d, J = 6.3 Hz, 3H);
13C{1H} NMR (CDCl3, 75 MHz): 170.8, 141.6, 129.3, 128.5, 125.0, 71.2, 37.6, 31.9, 21.4, 20.1; HPLC
conditions: (R,R)-Whelk-O1, n-hexane/2-propanol = 99/1, flow rate = 0.5 mL/min, UV = 217 nm;
retention times: 12.11 min (S), 13.56 min (R). The NMR data are in good agreement with those
reported in the literature.18
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(R)-1-(Naphthalen-2-yl)ethyl acetate (13k): 42.3 mg (99% yield, >99% ee); [α]25D = + 121.6 (c = 1.0,
CHCl3) [lit.18 [α]22D = + 122 (c = 1, CHCl3, >99% ee)]; CHCl3)]; 1H NMR (CDCl3, 300 MHz): δ 7.90-
7.80 (m, 4H), 7.50-7.43 (m, 3H), 6.08-6.02 (q , J = 6.6 Hz, 1H), 2.04 (s, 3H), 1.41-1.39 (d, J = 6.6 Hz,
3H); 13C{1H} NMR (CDCl3, 75 MHz): 170.4, 139.0, 133.0, 128.6, 126.9, 126.3, 125.4, 124.1, 123.3,
71.4, 22.2, 21.4; HPLC conditions: Chiracel-OD, n-hexane/2-propanol = 99/1, flow rate = 0.5 mL/min,
UV = 217 nm; retention times: 20.27 min (S), 16.64 min (R). The NMR data are in good agreement
with those reported in the literature.18
(R)-1-Phenylallyl acetate (13l): 31.9 mg (91% yield, 93% ee); [α]25D = + 37.0 (c = 1.0, CHCl3) [lit.20
[α]25 = + 30.42(c = 0.48, CHCl3), 96% ee]; 1H NMR (CDCl3, 300 MHz): δ 7.27-7.25 (m, 5H), 6.19
D
(d, J = 5.9 Hz, 1H), 6.00-5.88 (m, 1H), 5.25-5.16 (m, 2H), 2.03 (s, 3H); 13C{1H} NMR (CDCl3, 75
MHz): 168.9, 138.0, 135.4, 127.5, 127.1, 126.1, 115.9, 75.2, 20.2; HPLC conditions: (R,R)-Whelk-
O1, n-hexane/2-propanol = 98/2, flow rate = 0.5 mL/min, UV = 217 nm; retention times: 9.79 min (S),
13.45 min (R). The NMR data are in good agreement with those reported in the literature.20
(R)-1-(p-Tolyl)allyl acetate (13m): 34.2 mg (90% yield, 96% ee); [α]25D = + 56.4 (c = 1.0, CHCl3)
[lit.21 [α]25 = - 224 (c = 0.17, CHCl3), 97% ee for (S)-enantiomer]; 1H NMR (CDCl3, 300 MHz): δ
D
7.35-7.15 (m, 4H), 6.23 (d, J = 5.8 Hz, 1H), 6.06-5.95 (m, 1H), 5.31-5.21 (m, 2H), 2.34 (s, 3H), 2.08
(s, 3H); 13C{1H} NMR (CDCl3, 75 MHz): 169.9, 138.0, 136.5, 136.0, 129.2, 127.1, 116.6, 76.1, 21.2,
21.1; HPLC conditions: (R,R)-Whelk-O1, n-hexane/2-propanol = 98/2, flow rate = 0.5 mL/min, UV =
217 nm; retention times: 9.85 min (S), 14.65 min (R); HRMS (EI, magnetic sector) m/z: M+ Calcd for
[C12H14O2]+ 190.0994; Found 190.0994.
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(R)-1-(4-Methoxyphenyl)allyl acetate (13n): 37.5 mg (91% yield, 95% ee); [α]25D = + 67.6 (c = 1.0,
1
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3
CHCl3) [lit.22 [α]25 = + 55.42(c = 1.43, CHCl3), 99% ee]; 1H NMR (CDCl3, 300 MHz): δ 7.30-7.26
D
(m, 2H), 6.91-6.86 (m, 2H), 6.22 (d, J = 5.6 Hz, 1H), 6.06-5.95 (m, 1H), 5.30-5.21 (m, 2H), 3.80 (s,
3H), 2.09 (s, 3H); 13C{1H} NMR (CDCl3, 75 MHz): 169.9, 159.6, 136.5, 131.1, 128.7, 116.4, 114.0,
75.8, 55.3, 21.2; HPLC conditions: (R,R)-Whelk-O1, n-hexane/2-propanol = 98/2, flow rate = 0.5
mL/min, UV = 217 nm; retention times: 13.83 min (S), 25.95 min (R). The NMR data are in good
agreement with those reported in the literature.22
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(R)-1-(4-Chlorophenyl)allyl acetate (13o): 37.2 mg (89% yield, 91% ee); [α]25D = + 33.5 (c = 1.0,
CHCl3) [lit.22 [α]25 = + 28.0 (c = 1.25, CHCl3), 99% ee]; 1H NMR (CDCl3, 300 MHz): δ 7.34-7.27
D
(m, 4H), 6.22 (d, J = 5.8 Hz, 1H), 6.02-5.91 (m, 1H), 5.31-5.24 (m, 2H), 2,11 (s, 3H); 13C{1H} NMR
(CDCl3, 75 MHz): 169.7, 137.5, 135.9, 134.0, 129.4, 128.8, 117.3, 75.4, 21.1; HPLC conditions:
(R,R)-Whelk-O1, n-hexane/2-propanol = 98/2, flow rate = 0.5 mL/min, UV = 217 nm; retention times:
10.36 min (S), 17.73 min (R). The NMR data are in good agreement with those reported in the
literature.22
(R)-1-(4-Bromophenyl)allyl acetate (13p): 44.6 mg (87% yield, 91% ee); [α]25D = + 36.2 (c = 1.0,
25
CHCl3) [lit.21 [α]D = + 5 (c = 1.43, CHCl3), 53% ee]; 1H NMR (CDCl3, 300 MHz): δ 7.84-7.81 (m,
2H), 7.25-7.21 (m, 2H), 6.20 (d, J = 5.9 Hz, 1H), 5.98-5.93 (m, 1H), 5.31-5.24 (m, 2H), 2.11 (s, 3H);
13C{1H} NMR (CDCl3, 75 MHz): 169.7, 138.0, 135.8, 131.7, 128.8, 122.1, 117.3, 75.4, 21.1; HPLC
conditions: (R,R)-Whelk-O1, n-hexane/2-propanol = 98/2, flow rate = 0.5 mL/min, UV = 217 nm;
retention times: 10.82 min (S), 17.94 min (R). The NMR data are in good agreement with those
reported in the literature.20
(R,E)-4-Phenylbut-3-en-2-yl acetate (13q): 35.8 mg (94% yield, >99% ee); [α]25D = +139.2 (c = 1.0,
CHCl3) [lit.6b [α]25D = + 144.5 (c = 1, CHCl3, 98% ee)]; 1H NMR (CDCl3, 300 MHz): δ 7.39-7.24 (m,
5H), 6.63-6.57 (m, 1H), 6.22-6.15 (m, 1H), 5.55-5.50 (m, 1H), 2.06 (s, 3H), 1.42-1.40 (d, J = 6.5 Hz,
3H); 13C{1H} NMR (CDCl3, 75 MHz): 170.3, 136.4, 131.7, 128.8, 128.6, 127.9, 126.7, 71.0, 21.4,
20.4; 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 (S), 13.66 min (R). The NMR data are in good agreement with those
reported in the literature.6b
ASSOCIATED CONTENT
Supporting Information
The supporting information is available free of charge on the ACS Publication website at DOI:
NMR spectra and HPLC chromatograms of products (PDF)
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AUTHOR INFORMATION
Corresponding Author
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*E-mail: mjkim@postech.ac.kr (mjk); pjw@postech.ac.kr (JP)
ORCID
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Mahn-Joo Kim: 0000-0002-5292-6249
Jaiwook Park: 0000-0002-1135-3317
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This work was supported by grant (2018R1D1A1B07044423) from the National Research Foundation
of Korea.
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