Kinetic resolution of β-alkenyl-, β-alkynyl- and β-flavenyl-substituted β-hydroxy esters in asymmetric dehydration

Article abstract of DOI:10.1002/ejoc.200800807

Catalytic asymmetric dehydration of β-alkenyl- or alkynyl-substituted β-hydroxy esters by kinetic resolution has been investigated with five different chiral ligands 3-7. The kinetic resolution of a variety of racemic β-hydroxy tert-butyl esters in the presence of a prolinol chiral ligand and BrZnCH₂CO₂tBu provided highly enantio-enriched β-hydroxy esters 9-22 with selectivity factors ranging from 11 to 59. In addition, the application of this asymmetric synthetic methodology to the preparation of enantio-enriched flavene derivatives 23-29 is demonstrated. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800807

FULL PAPER
DOI: 10.1002/ejoc.200800807
Kinetic Resolution of β-Alkenyl-, β-Alkynyl- and β-Flavenyl-Substituted
β-Hydroxy Esters in Asymmetric Dehydration
Min Hee Lee,[a] Eui Ta Choi,[a] Dajung Kim,[a] Yoon Min Lee,[a] and Yong Sun Park*[a]
Keywords: Kinetic resolution / Asymmetric catalysis / Dehydration / Chiral ligands / Flavonoids
Catalytic asymmetric dehydration of β-alkenyl- or alkynyl-
substituted β-hydroxy esters by kinetic resolution has been
investigated with five different chiral ligands 3–7. The ki-
netic resolution of a variety of racemic β-hydroxy tert-butyl
esters in the presence of a prolinol chiral ligand and
droxy esters 9–22 with selectivity factors ranging from 11 to
59. In addition, the application of this asymmetric synthetic
methodology to the preparation of enantio-enriched flavene
derivatives 23–29 is demonstrated.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
BrZnCH2CO2tBu provided highly enantio-enriched β-hy- Germany, 2008)
tion provided a mixture of tert-butyl (E,E)-5-phenylpen-
Introduction
tadienoate (2) and β-hydroxy ester (R)-1. At 55% conver-
sion, pentadienoate 2 was isolated in 40% yield, and the
unconverted (R)-1 was obtained in 37% yield with 97% ee
[selectivity s = kS/kR = 38].[5] A significantly high enantio-
selectivity was noted in the elimination of the secondary
alcohols with an excess amount of organozinc reagent as
base in refluxing THF.
The nonenzymatic kinetic resolution of racemic com-
pounds with a chiral catalyst is presently an area of great
importance in asymmetric organic synthesis.[1] Highly ef-
ficient kinetic resolution in the oxidation and acylation of
secondary alcohols has been developed by several research
groups.[2,3] We have also explored the catalytic asymmetric
dehydration of β-hydroxy esters by kinetic resolution.[4] Al-
though the catalytic dehydration provides a synthetic ap-
proach to enantio-enriched β-aryl- and β-styryl-substituted
β-hydroxy esters, the substrate scope explored was some-
what limited. Application of this methodology to more
complex and highly functionalized β-hydroxy esters and the
development of more efficient catalytic systems are desir-
able. Herein we describe the results of our recent investiga-
tion to assess the substrate scope and limitation of the
asymmetric dehydration methodology with five different
chiral ligands. In addition, the versatility of this kinetic res-
olution is further demonstrated with β-flavenyl-substituted
β-hydroxy esters bearing an additional chiral center.
Scheme 1. Asymmetric dehydration of β-hydroxy-β-styryl ester 1.
To develop a more efficient catalytic system, we initially
examined the effect of excess organozinc reagent on the
enantioselectivity and conversion, as shown in Figure 1.
The dehydration did not proceed with 1 equiv. of
BrZnCH2CO2tBu, and proceeded only slowly in the pres-
ence of 2 equiv. of BrZnCH2CO2tBu and with low selectiv-
ity. Although a comparable conversion was attained with
4 equiv. of BrZnCH2CO2tBu in 2 h, the selectivity was
much lower than was obtained in the reaction with 8 equiv.
of BrZnCH2CO2tBu. Preliminary results indicate that the
selectivity and rate of dehydration is significantly influenced
by the amount of BrZnCH2CO2tBu. Importantly, 8 equiv.
of BrZnCH2CO2tBu is essential to achieve a highly efficient
dehydration, and smaller quantities of BrZnCH2CO2tBu
gave lower selectivities. When a mixture of β-hydroxy ester
1 and chiral ligand 3 (5 mol-%) in THF was added to pre-
formed BrZnCH2CO2tBu in THF (8 equiv.), no significant
difference in selectivity or conversion was observed. With
BrZnCH2CO2Me or BrZnCH2CO2Et, the dehydration took
Results and Discussion
We have previously reported the kinetic resolution of β-
hydroxy-β-styryl tert-butyl ester 1 in the presence of the -
Phg--Pro dipeptide derived chiral ligand
3
and
BrZnCH2CO2tBu[4a] (Scheme 1). When a mixture of race-
mic β-hydroxy ester 1, tert-butyl bromoacetate (8 equiv.),
and chiral ligand 3 (5 mol-%) in THF was added to acti-
vated zinc (8 equiv.) in THF and refluxed for 2 h, the reac-
[a] Department of Chemistry, Bio/Molecular Informatics Center,
Konkuk University,
Seoul 143-701, Korea
Fax: +822-3436-5382
E-mail: parkyong@konkuk.ac.kr
5630
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5630–5637

Kinetic Resolution of Substituted β-Hydroxy Esters
place slowly, and the selectivity was much lower in both
cases. The use of BrZnCH2CO2Me in the reaction of 1 gave
25% conversion after 10 h and a selectivity value of 10 un-
der the same reaction conditions. When tBuLi was used as
base in the presence of chiral ligand 3, the reaction gave the
eliminated product 2 with no detectable enantioselectivity.
However, the reaction of 1 with Et2Zn, BrZnCH2CH2-
CH2(CH3)2, or tBuMgCl did not provide the dehydrated
product 2 under the same reaction conditions.
Scheme 2. Asymmetric preparation of chiral ligands 3–7.
To examine the substrate scope of the methodology we
carried out the dehydration of various α- and β-substituted
β-hydroxy esters 8a–g with chiral ligand 3 (Figure 2). β-
Phenethyl-β-hydroxy ester 8a and β-hydroxy-β-methyl ester
8b did not undergo dehydration to yield α,β-unsaturated
esters, which indicates that the dehydration is not likely to
occur if the resulting conjugation does not extend through-
out the molecule. Conjugation of the newly formed double
bond with both a β-alkenyl group and the carbonyl group
stabilizes the α,β-unsaturated product and provides the
thermodynamic driving force for the dehydration process.
Interestingly, β-phenyl-β-styryl-disubstituted ester 8c, which
is anticipated to exhibit more extended conjugation, did not
produce the eliminated product, and the racemic β-hydroxy
ester was quantitatively recovered. Also, dehydration of the
β-methyl-β-styryl-disubstituted ester 8d did not occur at all,
from which it was concluded that the catalyst system was
not suitable for the dehydration of β,β-disubstituted β-hy-
droxy esters, probably due to the steric bulk associated with
the β-position of the substrate. Under the same reaction
conditions, the reactions of α-phenyl-substituted ester 8e
(mixture of two diastereomers) and α-methyl-substituted es-
ter 8f (mixture of two diastereomers) did not produce the
corresponding α,β-unsaturated ester. Instead, the two reac-
tions led to β-hydroxy-β-styryl ester 1 and the α,β-unsatu-
rated ester 2, which might be produced by retro-aldol reac-
tions of 8e and 8f and subsequent addition of
BrZnCH2CO2tBu to cinnamaldehyde. Once again, this de-
hydration system is not successful for the dehydration of α-
phenyl-substituted ester 8g bearing no β-substituent. Un-
fortunately, the substrate scope of this asymmetric method-
ology is limited to β-hydroxy esters with a β-conjugated
substituent and no α-substituent.
Figure 1. Dependence of converison and selectivity on the amount
of BrZnCH2CO2tBu used in the reaction of 1 with 5 mol-% of chi-
ral ligand 3 for 2 h in THF.
Our previous studies towards the development of an ef-
ficient chiral ligand for asymmetric dehydration revealed
that the (S)-N-[(R)-2-amino-2-phenylethyl]prolinol skeleton
of chiral ligand 3 is the catalytic core structure and the di-
phenylmethyl substituent is vital for both reactivity and
selectivity.[4a] On the basis of these facts, we have attempted
to modify the catalytic properties of 3 by introducing dif-
ferent phenyl substituents, such as chlorine, fluorine, and
methyl groups, as shown in Scheme 2. The chiral ligands 4–
7 were prepared according to the synthetic methodology
that we recently developed for the asymmetric synthesis of
dipeptide analogues.[6] The treatment of two diastereomeric
mixtures (ca. 50:50) of N-(α-bromo-α-phenylacetyl)--pro-
line methyl ester with a corresponding amine nucleophile
in the presence of tetrabutylammonium iodide (TBAI) and
diisopropylethylamine (DIEA) in CH2Cl2 at room tempera-
ture gave the -Phg--Pro dipeptide analogues in 45–71%
yields with diastereomeric ratios (drs) Ͼ95:5. The subse-
quent reduction with excess BH3·THF (5 equiv.) in THF
furnished chiral ligands 4–7 in 53–62% yields by flash col-
umn chromatographic separation. We then explored the
asymmetric dehydration of β-hydroxy ester 1 as a prelimi-
nary evaluation of the catalytic properties of the chiral li-
gands 4–7. After 2 h at reflux under the standard reaction
conditions, the p-chloro-, p-fluoro-, m-fluoro-, and p-
methyl-substituted ligands 4–7 gave selectivity values of 29,
25, 34, and 30, respectively, with 50–55% conversion. In
the reactions of β-hydroxy ester 1, the introduction of a
substituent on to the diphenylmethyl group of the ligand in
Figure 2. β-Hydroxy esters 8a–g used in the dehydration reactions.
As shown in Table 1, we have investigated the asymmet-
all cases slightly decreased the selectivity without affecting ric dehydration of a variety of β-alkenyl-β-hydroxy esters 9–
the reactivity.
20 bearing a β-substituent and no α-substituent. For conve-
Eur. J. Org. Chem. 2008, 5630–5637
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M. H. Lee, E. Ta Choi, D. Kim, Y. M. Lee, Y. S. Park
FULL PAPER
nience, all reactions were performed with 5 mol-% of the Table 1. Asymmetric dehydration of β-alkenyl-β-hydroxy esters 9–
20.
chiral ligand and 8 equiv. of BrZnCH2CO2tBu. The kinetic
resolution of the β-(p-methoxystyryl)-substituted ester 9
with chiral ligand 3 provided an excellent level of asymmet-
ric induction (s = 58). In an examination of the effects of
the modified chiral ligands 4–6, m-fluoro-substituted ligand
6 produced a comparable level of selectivity (s = 53) relative
to chiral ligand 3, whereas chiral ligands 4 and 5 produced
modest levels of selectivity in the dehydration of β-alkenyl-
β-hydroxy esters 9 (Entry 1). On the other hand, in the reac-
tions of 10 and 11, p-chloro-substituted ligand 4 gave
slightly higher selectivities than chiral ligand 3 (Entries 2
and 3). With the identification of chiral ligand 3 as gen-
erally the most efficient ligand for the asymmetric dehy-
dration of β-alkenyl-β-hydroxy esters, we set out to examine
the scope of the asymmetric dehydration with β-alkenyl-
substituted esters 12–20. As shown in Entries 4–7, β-alk-
enyl-β-hydroxy esters 12–15 gave high levels of selectivity in
the presence of 3 (s = 33–39). We were pleased to observe
that excellent selectivities (s = 54–59) were obtained in the
kinetic resolution of highly functionalized β-hydroxy esters
16, 17, 19, and 20 (Entries 8, 9, 11, and 12). Curiously, β-
(3-furanyl)-substituted ester 18 showed a much lower selec-
tivity (s = 17) with chiral ligand 3 compared with the dehy-
dration of β-(2-furanyl)-substituted ester 17 (Entry 10).
We have also extended the reaction’s scope to β-alkynyl-
substituted β-hydroxy esters. As shown in Table 2, the ki-
netic resolution of β-hydroxy-β-propargyl ester 21 provided
a selectivity value of 29 with 5 mol-% of chiral ligand 3 and
8 equiv. of BrZnCH2CO2tBu (Entry 1). Slightly lower levels
of selectivity were observed with chiral ligands 4, 5, and 7
(Entries 2–4). In contrast, the kinetic resolution of β-hep-
tynyl-substituted β-hydroxy ester 22 with chiral ligands 3
and 4 gave similar levels of selectivity (Entries 5 and 6).
Given the remarkably high levels of enantioselectivity at-
tainable in the asymmetric dehydration of β-alkenyl- and β-
alkynyl-substituted β-hydroxy esters, we evaluated whether
β-flavenyl-β-hydroxy esters 23a–28a bearing an additional
chiral center might be good substrates for kinetic resolu-
tion. The flavene (2-phenyl-2H-chromene) structural core is
a widespread element in natural flavonoids, and the devel-
opment of synthetic strategies for highly functionalized
flavenes is of considerable interest because a wide range of
[a] Based on the consumption of the starting β-hydroxy ester sub-
biological activities associated with the scaffold have been
strate, as determined by 1H NMR analysis of characteristic signals
identified.[7] Efficient kinetic resolution in the dehydration
directly in the crude mixture with hexamethylbenzene as the in-
of β-flavenyl-β-hydroxy esters bearing an additional chiral
center at the 2-position of the flavene framework can allow
both unconverted substrate 23a–28a and the eliminated
product 23b–28b to be obtained in a highly enantio-en-
riched form.
ternal integration standard. [b] The ee values were determined by
CSP-HPLC. [c] Selectivity (s) values represent an average of at least
two experiments; the conversion and ee values are for specific cases.
3. Similar results were obtained with flavenes 25a and 26a,
When racemic 6-chloro-2-(o-methoxyphenyl)flavene de- whereas poor selectivities were observed with flavenes 24a,
rivative 23a was treated with BrZnCH2CO2tBu and chiral 27a, and 28a (Entries 2–6). These limited results suggest
ligand 3, the dehydration provided 3-alkenyl-substituted fla- that the selectivity is sensitive to the substitution pattern on
vene derivative (R)-23b with 68% ee in 42% yield and the both aryl rings of the flavene framework. Next, other chiral
unreacted 3-(1Ј-hydroxyalkyl)flavene derivative (2S,1ЈR)- ligands 4–6 were examined to identify a more efficient cata-
23a with 98% ee in 30% yield (s = 23), as shown in Table 3, lytic system for the dehydration of β-flavenyl-β-hydroxy es-
Entry 1.[8] With five different flavenes 24a–28a, the scope of ters 23a–28a. The reaction of 23a with p-chloro-substituted
the asymmetric dehydration was explored with chiral ligand chiral ligand 4 produced the dehydrated product (R)-23b
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Eur. J. Org. Chem. 2008, 5630–5637

Kinetic Resolution of Substituted β-Hydroxy Esters
Table 2. Asymmetric dehydration of β-alkynyl-β-hydroxy esters 21 Exceptionally high efficiency in the kinetic resolution was
and 22.
obtained with 6-methyl-substituted 27a, affording a selec-
tivity value of 41 (Entry 14). Chiral ligand 6 afforded a sim-
ilar selectivity in the reaction of 23a (Entry 16). In addition,
the experimental procedure for dehydration was applied to
the kinetic resolution of 8-methoxy-2-phenyl-substituted
flavene derivative 29, which is a diastereomeric isomer of
26a.[8] The reaction of 29 with chiral ligand 5 produced the
dehydrated product (S)-26b in 53% conversion and the un-
reacted flavene derivative (2R,1ЈR)-29 with 88% ee and with
a comparable selectivity to that of the diastereomeric iso-
mer 26a, as shown in Entry 17 (s = 23). These limited re-
sults reflect a highly effective discrimination between the
(1ЈS) and (1ЈR) chiral centers in the dehydration process,
but little effect of the chiral center at the 2-position of the
flavene framework. Consequently, the successful asymmet-
ric dehydration of the flavene derivatives 23a–28a,29 bear-
ing two stereocenters resulted in the isolation of enantio-
enriched 3-(1Ј-hydroxyalkyl)- and 3-alkenyl-substituted fla-
vene derivatives.
Entry
R
Ligand Time [h] Conv.[a] [%] ee[b] [%] s[c]
1
2
3
4
5
6
Ph (21)
Ph (21)
Ph (21)
3
4
5
7
3
4
1.5
1
1
2
1.5
2
55
54
59
58
58
55
97
86
97
96
97
91
29
18
20
20
22
21
Ph (21)
CH3(CH2)4 (22)
CH3(CH2)4 (22)
[a] Based on the consumption of the starting β-hydroxy ester sub-
strate, as determined by 1H NMR analysis with hexamethylbenzene
as the internal integration standard. [b] The ee values were deter-
mined by CSP-HPLC. [c] Selectivity (s = kS/kR) values represent
an average of at least two experiments; the conversion and ee value
are for specific cases.
with a lower selectivity (s = 14; Entry 7) than the reaction
with chiral ligand 3. Furthermore, the chiral ligand 4 gave
disappointing results in the dehydration of 24a and 26a with
much lower selectivities (Entries 8 and 9). On the other
hand, p-fluoro-substituted chiral ligand 5 exhibited higher
Conclusions
We have reported the successful catalytic kinetic resolu-
selectivities (s = 21–41) than both chiral ligands 3 and 4 tion of β-alkenyl-, β-alkynyl-, and β-(2H-3-flavenyl)-substi-
with all substrates examined, as shown in Entries 10–15. tuted β-hydroxy esters in asymmetric dehydration. The en-
Table 3. Asymmetric dehydration of β-flavenyl-β-hydroxy esters 23a–28a,29.[a]
Entry
Starting material
R
Ar
Ligand
ee[b] [%] of a
ee [%] of b
Conv.[c] [%]
s[c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
23a
24a
25a
26a
27a
28a
23a
24a
26a
23a
24a
25a
26a
27a
28a
23a
29[d]
6-Cl
8-MeO
H
8-MeO
6-Me
6-Cl
o-MeOC6H4
p-MeOC6H4
o-MeOC6H4
Ph
3
3
3
3
3
3
4
4
4
5
5
5
5
5
5
6
5
98
30
96
89
79
50
76
96
88
68
91
60
94
66
52
96
88
68
74
70
77
73
74
74
32
41
86
75
88
74
91
87
70
77
59
29
58
54
52
40
51
75
68
44
55
41
56
42
37
58
53
23
9
21
22
15
11
14
7
Ph
Ph
6-Cl
o-MeOC6H4
p-MeOC6H4
Ph
o-MeOC6H4
p-MeOC6H4
o-MeOC6H4
Ph
8-MeO
8-MeO
6-Cl
8-MeO
H
8-MeO
6-Me
6-Cl
6
28
21
25
23
41
26
21
23
Ph
Ph
6-Cl
8-MeO
o-MeOC6H4
Ph
[a] All reactions were carried out in refluxing THF for 2–6 h. [b] The ee values of 23–29 were determined by CSP-HPLC. [c] Determined
from the ee values of 23a–29 and 23b–28b, as given in ref.[5] [d] Flavene derivative 29 is a diastereomer of 26a.
Eur. J. Org. Chem. 2008, 5630–5637
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. H. Lee, E. Ta Choi, D. Kim, Y. M. Lee, Y. S. Park
FULL PAPER
NMR (CDCl3, 400 MHz): δ = 7.34–7.20 (m, 9 H), 7.03 (m, 2 H),
6.92 (m, 2 H), 4.59 (s, 1 H), 3.68 (m, 1 H), 3.57 (m, 1 H), 3.47 (m,
1 H), 2.94 (t, J = 12.2 Hz, 1 H), 2.80 (br., 2 H), 2.64 (br., 1 H),
2.41 (d, J = 12.6 Hz, 1 H), 2.13 (m, 1 H), 1.85–1.69 (m, 4 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 162.4 (d, J = 244.2 Hz), 162.1
(d, J = 243.5 Hz), 142.5, 140.3, 139.6, 129.7 (d, J = 7.9 Hz), 129.2
(d, J = 7.9 Hz), 129.1, 127.9, 127.8, 115.8 (d, J = 21.2 Hz), 115.4
(d, J = 21.2 Hz), 65.3, 63.9, 62.8, 62.2, 59.4, 54.6, 27.8, 24.2 ppm.
HRMS: calcd. for C26H28F2N2O [M]+ 423.2248; found 423.2260.
antio-enriched products contain several functionalities that
allow further transformation to more complex molecules.
The kinetic resolution in the dehydration reaction is a con-
ceptually new and efficient method for the preparation of
highly enantio-enriched β-hydroxy esters, but this method
is also prone to limitations. Examples of asymmetric dehy-
dration demonstrated thus far are restricted to β-hydroxy
esters bearing a conjugated β-substituent and no α-substitu-
ent, and the efficiency of the chiral ligand is strongly sub-
strate-dependent. A challenge for future development is to
tailor the chiral ligand for a broader scope of substrates.
Further investigations to provide detailed mechanistic in-
sights into the origin of the enantioselectivity and applica-
tion to the syntheses of biologically interesting molecules
are underway.
(S)-N-{(R)-2-[Bis(m-fluorophenyl)methyl]amino-2-phenylethyl}pro-
1
linol (6): A pale-yellow oil was obtained in 35% overall yield. H
NMR (CDCl3, 400 MHz): δ = 7.34–6.97 (m, 13 H), 4.60 (s, 1 H),
3.66 (m, 1 H), 3.60 (dd, J = 11.0 and 3.1 Hz, 1 H), 3.49 (dd, J =
10.9 and 3.9 Hz, 1 H), 2.95–2.80 (m, 4 H), 2.62 (br., 1 H), 2.41 (dd,
J = 12.5 and 3.1 Hz, 1 H), 2.12 (m, 1 H), 1.87–1.72 (m, 4 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 163.4 (d, J = 244.2 Hz), 163.2
(d, J = 244.3 Hz), 146.8, 146.4, 142.4, 130.4 (d, J = 7.9 Hz), 130.1
(d, J = 7.9 Hz), 129.1, 127.8, 127.7, 123.9 (d, J = 2.2 Hz), 123.2 (d,
J = 2.7 Hz), 114.9 (d, J = 21.6 Hz), 114.7 (d, J = 22.4 Hz), 114.6
(d, J = 21.1 Hz), 114.2 (d, J = 21.0 Hz), 65.3, 63.9, 62.8, 62.7,
59.4, 54.6, 27.8, 24.1 ppm. HRMS: calcd. for C26H28F2N2O [M]+
423.2248; found 423.2245.
Experimental Section
General: All reactions were carried out under nitrogen. Chemicals
were purchased from Aldrich and Fluka and, unless otherwise
noted, were used without further purification. Analytical chiral sta-
tionary phase HPLC was performed with a pump system coupled
to an absorbance detector (215 nm). Chiral columns
(25 cmϫ4.6 mm i.d.) with 2-propanol/hexane as mobile phase were
used to determine the enantiomeric ratios. 1H and 13C NMR spec-
tra were acquired with a Bruker AV 400 (400 MHz 1H, 100.6 MHz
13C) spectrometer. Mass spectrometric data were acquired at the
Korea Basic Science Institute, Mass Spectrometry Laboratory.
(S)-N-{(R)-2-[Bis(p-methylphenyl)methyl]amino-2-phenylethyl}pro-
linol (7): A colorless oil was obtained in 39 % overall yield. 1H
NMR (CDCl3, 400 MHz): δ = 7.33–7.03 (m, 13 H), 4.56 (s, 1 H),
3.68 (dd, J = 11.1 and 3.6 Hz, 1 H), 3.63 (dd, J = 11.0 and 3.2 Hz,
1 H), 3.47 (dd, J = 11.1 and 4.0 Hz, 1 H), 3.05 (br., 2 H), 2.97 (t,
J = 12.1 Hz, 1 H), 2.83 (m, 1 H), 2.62 (m, 1 H), 2.40 (dd, J = 12.6
and 3.2 Hz, 1 H), 2.33 (s, 3 H), 2.26 (s, 3 H), 2.13 (m, 1 H), 1.72–
1.69 (m, 4 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 142.9, 142.1,
141.2, 136.8, 136.6, 129.6, 129.3, 129.0, 128.1, 127.9, 127.7, 127.6,
65.5, 63.9, 62.9, 59.3, 54.6, 53.9, 27.8, 24.2, 21.5, 21.4 ppm. HRMS:
calcd. for C28H34N2O [M]+ 415.2749; found 415.2768.
General Procedure for the Preparation of Chiral Ligands 4–7: The
corresponding
diphenylmethylamine
(1.2 equiv.),
TBAI
(1.0 equiv.), and DIEA (1.2 equiv.) were added to a solution of N-
(α-bromo-α-phenylacetyl)-(S)-proline methyl ester in dry CH2Cl2
(0.1 ) at room temperature. The resulting reaction mixture was
stirred at room temperature for 24 h. The solvent in the mixture
was evaporated and the crude product was purified by column
chromatography on silica gel. The substituted products were ob-
tained in 45–71% yield with dr Ͼ 95:5. BH3·THF (1.0 , 5.0 equiv.)
was added to a solution of the substituted product in THF (0.5 ),
and the mixture was refluxed for 12 h. The reaction was quenched
by adding MeOH (0.5 mL) under ice/water cooling, and the sol-
vents were evaporated. Aqueous 5% HCl (2 mL) was added to the
residue, and the mixture was refluxed for 1 h. The reaction mixture
was basified with K2CO3, saturated with NaCl, and extracted with
CHCl3 (5 mLϫ3). The combined organic extracts were dried with
anhydrous MgSO4, filtered, and concentrated in vacuo. Chromato-
graphic separation on silica gel afforded the chiral ligands 4–7 with
dr Ͼ 99:1.
General Procedure for Asymmetric Dehydration: Chlorotrimethylsil-
ane (0.5 equiv.) was added to a suspension of zinc metal (8 equiv.)
in anhydrous THF (5 mL). After the mixture had been heated at
reflux for 40 min, a solution of the chiral ligand (5 mol-%), tert-
butyl bromoacetate (8 equiv.), and racemic β-hydroxy ester in THF
was slowly added. The mixture was stirred at reflux for 2–6 h and
then quenched with a saturated NH4Cl aqueous solution. The re-
sulting mixture was extracted with CH2Cl2 (5 mL ϫ2), and the
combined extracts were washed with brine. The solvents were re-
moved under reduced pressure, and the residue was purified by
flash column chromatography to give the enantio-enriched prod-
ucts.
tert-Butyl (3R,4E)-3-Hydroxy-5-(p-methoxyphenyl)-4-pentenoate
(9): The product was recovered in 37% yield based on 50% conver-
1
sion. H NMR (CDCl3, 400 MHz): δ = 7.26 (d, J = 8.6 Hz, 1 H),
6.81 (d, J = 8.6 Hz, 1 H), 6.54 (d, J = 16.0 Hz, 1 H), 6.05 (dd, J =
16.0 and 6.4 Hz, 1 H), 4.63 (m, 1 H), 3.75 (s, 3 H), 3.60 (br., 1 H),
2.53 (d, J = 6.7 Hz, 2 H), 1.44 (s, 9 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 171.9, 159.6, 130.4, 129.7, 128.6, 128.1, 114.3, 81.6,
69.6, 55.6, 43.3, 28.5 ppm. C16H22O4 (278.4): calcd. C 69.04, H
7.97; found C 69.12, H 7.79. CSP-HPLC (Chiralcel OD column;
10% 2-propanol in hexane; 0.5 mL/min): 90% ee; 17.0 min (major
enantiomer), 18.8 min (minor enantiomer).
(S)-N-{(R)-2-[Bis(p-chlorophenyl)methyl]amino-2-phenylethyl}pro-
linol (4): A colorless oil was obtained in 41 % overall yield. 1H
NMR (CDCl3, 400 MHz): δ = 7.34–7.17 (m, 13 H), 4.57 (s, 1 H),
3.68 (dd, J = 11.0 and 3.7 Hz, 1 H), 3.57 (dd, J = 11.0 and 3.1 Hz,
1 H), 3.47 (dd, J = 11.0 and 3.8 Hz, 1 H), 2.95 (m, 1 H), 2.83 (br.,
1 H), 2.65 (br., 2 H), 2.41 (dd, J = 12.6 and 3.1 Hz, 1 H), 2.15 (m,
1 H), 1.87–1.72 (m, 4 H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
142.8, 142.3, 142.2, 133.4, 133.1, 129.5, 129.2, 129.1, 129.0, 128.8,
128.0, 127.7, 65.3, 63.8, 62.8, 62.3, 59.4, 54.6, 27.8, 24.2 ppm.
HRMS: calcd. for C26H29Cl2N2O [M + 1]+ 455.1657; found
455.1659.
tert-Butyl (R)-3-Hydroxy-4-pentenoate (10): The product was reco-
vered in 41% yield based on 51% conversion. The analytical data
is in accordance with that in the literature.[4a] 1H NMR (CDCl3,
400 MHz): δ = 5.88 (m, 1 H), 5.31 (m, 1 H), 5.13 (m, 1 H), 4.49
(br., 1 H), 3.54 (br., 1 H), 2.44 (m, 2 H), 1.47 (s, 9 H) ppm. CSP-
HPLC: β-hydroxy ester 10 was converted into the O-(3,5-dini-
(S)-N-{(R)-2-[Bis(p-fluorophenyl)methyl]amino-2-phenylethyl}pro-
1
linol (5): A pale-yellow oil was obtained in 32% overall yield. H
5634
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5630–5637

Kinetic Resolution of Substituted β-Hydroxy Esters
trobenzoyl) derivative for better chromatographic analysis (Chi-
ralpak AD-H column; 10% 2-propanol in hexane; 0.5 mL/min):
82% ee; 22.2 min (major enantiomer), 33.5 min (minor enantio-
mer).
60.1, 41.1, 28.4, 15.5, 14.6 ppm. C12H20O5 (244.3): calcd. C 59.00,
H 8.25; found C 58.77, H 8.43. CSP-HPLC (Chiralcel OD column;
10% 2-propanol in hexane; 0.5 mL/min): 97% ee; 0.9 min (major
enantiomer), 10.1 min (minor enantiomer).
tert-Butyl (3R,4E,6E)-3-Hydroxy-4,6-octadienoate (11): The prod-
uct was recovered in 35% yield based on 57% conversion. The
analytical data is in accordance with that in the literature.[4a] 1H
NMR (CDCl3, 400 MHz): δ = 6.22 (dd, J = 16.1 and 10.4 Hz, 1
H), 6.02 (m, 1 H), 5.70 (m, 1 H), 5.55 (dd, J = 15.3 and 6.4 Hz, 1
tert-Butyl (R)-3-(2-Furanyl)-3-hydroxypropanoate (17): The product
was recovered in 39% yield based on 52% conversion. 1H NMR
(CDCl3, 400 MHz): δ = 7.35 (s, 1 H), 6.31–6.24 (m, 2 H), 5.06 (m,
1 H), 3.78 (br., 1 H), 2.75 (m, 2 H), 1.44 (s, 9 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 171.4, 155.6, 142.3, 110.5, 106.4, 81.7, 64.6,
H), 4.50 (br., 1 H), 3.20 (br., 1 H), 2.46 (m, 2 H), 1.74 (d, J = 41.4, 28.3 ppm. C11H16O4 (212.2): calcd. C 62.25, H 7.60; found C
5.9 Hz, 3 H), 1.45 (s, 9 H) ppm. CSP-HPLC (Chiralcel OJ-H col-
umn; 5% 2-propanol in hexane; 0.5 mL/min): 81% ee; 15.5 min
(major enantiomer), 14.5 min (minor enantiomer).
62.20, H 7.52. CSP-HPLC (Chiralcel OD column; 10% 2-propanol
in hexane; 0.5 mL/min): 95% ee; 12.4 min (major enantiomer),
10.9 min (minor enantiomer).
tert-Butyl (3R,4E)-3-Hydroxy-4-hexenoate (12): The product was
recovered in 39% yield based on 52% conversion. The analytical
data is in accordance with that in the literature.[9] 1H NMR
(CDCl3, 400 MHz): δ = 5.69 (m, 1 H), 5.48 (m, 1 H), 4.42 (m, 1
tert-Butyl (R)-3-(3-Furanyl)-3-hydroxypropanoate (18): The product
was recovered in 39% yield based on 50% conversion. 1H NMR
(CDCl3, 400 MHz): δ = 7.37 (m, 2 H), 6.39 (s, 1 H), 5.04 (m, 1 H),
3.78 (d, J = 4.4 Hz, 1 H), 2.65 (m, 2 H), 1.45 (s, 9 H) ppm. 13C
H), 3.61 (br., 1 H), 2.42 (m, 2 H), 1.63 (d, J = 6.5 Hz, 3 H), 1.45 NMR (CDCl3, 100 MHz): δ = 172.0, 143.6, 139.4, 128.0, 108.9,
(s, 9 H) ppm. CSP-HPLC: β-Hydroxy ester 12 was converted into
the O-(3,5-dinitrobenzoyl) derivative for better chromatographic
analysis (Chiralcel OD column; 10% 2-propanol in hexane; 0.5 mL/
min): 91% ee; 35.5 min (major enantiomer), 47.5 min (minor en-
antiomer).
81.9, 63.9, 43.4, 28.4 ppm. C11H16O4 (212.2): calcd. C 62.25, H
7.60; found C 62.24, H 7.77. CSP-HPLC (Chiralcel OD column;
10% 2-propanol in hexane; 0.5 mL/min): 76% ee; 11.4 min (major
enantiomer), 10.5 min (minor enantiomer).
tert-Butyl (R)-3-Hydroxy-3-(2-thiophenyl)propanoate (19): The
1
tert-Butyl (3R,4E)-3-Hydroxy-4-methyl-4-hexenoate (13): The prod- product was recovered in 30% yield based on 52% conversion. H
uct was recovered in 39% yield based on 53% conversion. 1H NMR
(CDCl3, 400 MHz): δ = 5.10 (m, 1 H), 4.63 (m, 1 H), 3.28 (br., 1
H), 2.38 (dd, J = 15.5 and 8.1 Hz, 1 H), 2.26 (dd, J = 15.5 and
4.9 Hz, 1 H), 1.63 (s, 3 H), 1.61 (s, 3 H), 1.37 (s, 9 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 171.8, 135.3, 126.6, 81.0, 65.5, 43.4,
28.3, 25.9, 18.4 ppm. C11H20O3 (200.3): calcd. C 65.97, H 10.07;
found C 65.97, H 10.00. CSP-HPLC: β-hydroxy ester 13 was con-
verted into the O-(3,5-dinitrobenzoyl) derivative for better chroma-
tographic analysis (Chiralcel OD column; 10% 2-propanol in hex-
ane; 0.5 mL/min): 94% ee; 24.1 min (major enantiomer), 33.8 min
(minor enantiomer).
NMR (CDCl3, 400 MHz): δ = 7.20 (d, J = 4.6 Hz, 1 H), 6.92 (m,
2 H), 5.27 (m, 1 H), 3.90 (d, J = 4.6 Hz, 1 H), 2.73 (m, 2 H), 1.43
(s, 9 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 171.5, 147.2,
127.0, 125.0, 123.9, 81.9, 67.0, 44.7, 28.4 ppm. C11H16O3S (228.3):
calcd. C 57.87, H 7.06, S 14.04; found C 57.85, H 6.89, S 13.68.
CSP-HPLC (Chiralcel OD column; 10 % 2-propanol in hexane;
0.5 mL/min): 96 % ee; 12.8 min (major enantiomer), 11.6 min
(minor enantiomer).
tert-Butyl (R)-3-(2-Benzofuranyl)-3-hydroxypropanoate (20): The
1
product was recovered in 37% yield based on 52% conversion. H
NMR (CDCl3, 400 MHz): δ = 7.50–7.16 (m, 4 H), 6.61 (s, 1 H),
5.20 (m, 1 H), 3.90 (d, J = 5.4 Hz, 1 H), 2.85 (d, J = 6.3 Hz, 2 H),
1.43 (s, 9 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 171.6, 158.3,
155.2, 128.5, 124.6, 123.2, 121.5, 111.6, 103.2, 82.1, 65.3, 41.4,
tert-Butyl (R)-3-(1-Cyclohexen-1-yl)-3-hydroxypropanoate (14): The
product was recovered in 41% yield based on 52% conversion. The
analytical data is in accordance with that in the literature.[9] 1H
NMR (CDCl3, 400 MHz): δ = 5.71 (br., 1 H), 4.33 (m, 1 H), 3.18 28.5 ppm. C15H18O4 (262.3): calcd. C 68.68, H 6.92; found C 68.68,
(d, J = 4.0 Hz, 1 H), 2.45 (m, 2 H), 2.02 (m, 4 H), 1.61 (m, 4 H),
1.45 (s, 9 H) ppm. CSP-HPLC: β-hydroxy ester 14 was converted
H 6.99. CSP-HPLC (Chiralpak AD-H column; 10% 2-propanol in
hexane; 0.5 mL/min): 95 % ee; 24.9 min (major enantiomer),
into the O-(3,5-dinitrobenzoyl) derivative for better chromato- 28.7 min (minor enantiomer).
graphic analysis (Chiralcel OD column; 10% 2-propanol in hexane;
0.5 mL/min): 91 % ee; 26.7 min (major enantiomer), 43.9 min
(minor enantiomer).
tert-Butyl (R)-3-Hydroxy-5-phenyl-4-pentynoate (21): The product
was recovered in 35% yield based on 55% conversion. 1H NMR
(CDCl3, 400 MHz): δ = 7.42–7.26 (m, 5 H), 4.93 (m, 1 H), 3.45 (d,
J = 6.3 Hz, 1 H), 2.75 (d, J = 6.0 Hz, 2 H), 1.48 (s, 9 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 171.0, 132.1, 128.8, 128.6, 122.9,
tert-Butyl (R)-5-(2-Furanyl)-3-hydroxy-4-pentenoate (15): The prod-
uct was recovered in 38% yield based on 50% conversion. 1H NMR
(CDCl3, 400 MHz): δ = 7.33 (s, 1 H), 6.49–6.12 (m, 4 H), 4.64 (m, 89.0, 85.2, 82.1, 59.8, 43.6, 28.5 ppm. C15H18O3 (246.3): calcd. C
1 H), 3.60 (br., 1 H), 2.51 (m, 2 H), 1.45 (s, 9 H) ppm. 13C NMR 73.15, H 7.37; found C 73.19, H 7.17. CSP-HPLC (Chiralcel OD
(CDCl3, 100 MHz): δ = 171.8, 152.6, 142.3, 129.3, 119.0, 111.7, column; 10% 2-propanol in hexane; 0.5 mL/min): 97% ee; 13.1 min
108.6, 81.7, 68.8, 43.0, 28.4 ppm. C13H18O4 (238.3): calcd. C 65.53,
H 7.61; found C 65.47, H 7.59. CSP-HPLC (Chiralcel OD column;
2% 2-propanol in hexane; 0.5 mL/min): 85% ee; 36.5 min (major
enantiomer), 39.9 min (minor enantiomer).
(major enantiomer), 18.9 min (minor enantiomer).
tert-Butyl (R)-3-Hydroxy-4-decynoate (22): The product was reco-
1
vered in 30% yield based on 58% conversion. H NMR (CDCl3,
400 MHz): δ = 4.68 (m, 1 H), 3.28 (d, J = 6.0 Hz, 1 H), 2.62 (d, J
= 6.0 Hz, 2 H), 2.18 (m, 2 H), 1.51–1.30 (m, 6 H), 1.47 (s, 9 H),
0.89 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
171.3, 86.0, 81.8, 79.9, 59.5, 43.8, 31.3, 28.6, 28.4, 22.5, 19.0,
tert-Butyl (R)-5-(Ethoxycarbonyl)-3-hydroxy-4-methyl-4-pentenoate
(16): The product was recovered in 39% yield based on 53% con-
1
version. H NMR (CDCl3, 400 MHz): δ = 6.02 (s, 1 H), 4.45 (m,
1 H), 4.16 (q, J = 7.0 Hz, 2 H), 3.49 (d, J = 3.8 Hz, 1 H), 2.56 (dd, 14.3 ppm. C14H24O3 (240.3): calcd. C 69.96, H 10.07; found C
J = 16.0 and 3.2 Hz, 1 H), 2.42 (dd, J = 16.1 and 9.0 Hz, 1 H),
2.12 (s, 3 H), 1.46 (s, 9 H), 1.27 (t, J = 7.0 Hz, 3 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 171.9, 167.1, 157.9, 116.0, 82.2, 72.8,
69.93, H 9.77. CSP-HPLC (Chiralpak AD-H column; 10% 2-pro-
panol in hexane; 0.5 mL/min): 96% ee; 20.6 min (major enantio-
mer), 23.7 min (minor enantiomer).
Eur. J. Org. Chem. 2008, 5630–5637
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5635

M. H. Lee, E. Ta Choi, D. Kim, Y. M. Lee, Y. S. Park
tert-Butyl (R)-3-[(S)-6-Chloro-2-(o-methoxyphenyl)-2H-chromen-3- NMR (CDCl3, 100 MHz): δ = 166.6, 157.1, 153.2, 141.5, 131.2,
FULL PAPER
yl]-3-hydroxypropanoate (23a): The product was recovered in 30%
yield based on 59% conversion. H NMR (CDCl3, 400 MHz): δ =
131.0, 130.9, 130.7, 128.8, 127.9, 126.3, 122.1, 121.7, 121.1, 120.3,
117.1, 111.5, 80.8, 70.1, 56.2, 28.5 ppm. HRMS: calcd. for
C23H24O4 [M]+ 364.1675; found 364.1666. CSP-HPLC (Chiralpak
AD-H column; 10% 2-propanol in hexane; 0.5 mL/min): 70% ee;
29.6 min (major enantiomer), 14.2 min (minor enantiomer).
1
7.27–7.19 (m, 2 H), 7.02–6.82 (m, 4 H), 6.60 (m, 2 H), 6.48 (s, 1
H), 4.43 (m, 1 H), 3.89 (s, 3 H), 3.21 (d, J = 4.8 Hz, 1 H), 2.43 (m,
2 H), 1.42 (s, 9 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 171.9,
157.2, 151.1, 137.7, 130.7, 129.3, 129.0, 126.5, 126.4, 126.0, 123.5,
121.1, 119.7, 118.0, 111.7, 82.1, 71.4, 70.9, 68.3, 56.3, 41.0,
28.5 ppm. HRMS: calcd. for C23H25ClO5 [M]+ 416.1391; found
416.1383. CSP-HPLC (Chiralpak AD-H column; 10% 2-propanol
in hexane; 0.5 mL/min): 98% ee; 70.0 min (major enantiomer),
63.5 min (minor enantiomer).
tert-Butyl (R)-3-Hydroxy-3-[(S)-8-methoxy-2-phenyl-2H-chromen-
3-yl]propanoate (26a): The product was recovered in 35 % yield
based on 54% conversion. 1H NMR (CDCl3, 400 MHz): δ = 7.44–
7.26 (m, 5 H), 6.83–6.69 (m, 3 H), 6.60 (s, 1 H), 6.05 (s, 1 H), 4.47
(m, 1 H), 3.72 (s, 3 H), 3.21 (d, J = 4.8 Hz, 1 H), 2.52 (m, 2 H),
1.42 (s, 9 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 172.1, 148.5,
tert-Butyl 3-[(R)-6-Chloro-2-(o-methoxyphenyl)-2H-chromen-3-yl]- 141.5, 139.2, 136.4, 129.1, 129.0, 128.2, 122.7, 121.2, 120.1, 119.6,
propenoate (23b): The product was recovered in 42% yield based
113.4, 82.1, 77.1, 68.3, 56.7, 41.0, 28.5 ppm. C23H26O5 (382.5): C
72.23, H 6.85; found C 72.18, H 6.89. CSP-HPLC (Chiralcel-OD
on 59% conversion. 1H NMR (CDCl3, 400 MHz): δ = 7.29–6.62
(m, 10 H), 5.61 (d, J = 16.0 Hz, 1 H), 3.96 (s, 3 H), 1.48 (s, 9 H) column; 10% 2-propanol in hexane; 0.5 mL/min): 89% ee; 52.0 min
ppm. 13C NMR (CDCl3, 100 MHz): δ = 166.3, 157.1, 151.7, 140.9,
132.1, 131.0, 130.7, 129.5, 128.7, 127.2, 126.4, 125.7, 123.4, 121.3,
121.1, 118.4, 111.6, 81.0, 70.4, 56.2, 28.5 ppm. HRMS: calcd. for
C23H23ClO4 [M]+ 398.1285; found 398.1286. CSP-HPLC (Chi-
ralpak AD-H column; 10% 2-propanol in hexane; 0.5 mL/min):
68% ee; 39.3 min (major enantiomer), 42.8 min (minor enantio-
mer).
(major enantiomer), 37.4 min (minor enantiomer).
tert-Butyl 3-[(R)-8-Methoxy-2-phenyl-2H-chromen-3-yl]propenoate
(26b): The product was recovered in 41% yield based on 54% con-
version. 1H NMR (CDCl3, 400 MHz): δ = 7.43–7.26 (m, 6 H), 6.95
(s, 1 H), 6.80 (m, 3 H), 6.16 (s, 1 H), 5.64 (d, J = 16.0 Hz, 1 H),
3.76 (s, 3 H), 1.47 (s, 9 H) ppm. 13C NMR (CDCl3, 100 MHz): δ
= 166.5, 148.8, 142.1, 141.8, 138.1, 131.1, 130.8, 129.2, 129.0, 128.0,
123.1, 121.7, 120.7, 120.4, 114.4, 81.0, 76.5, 56.7, 28.5 ppm.
HRMS: calcd. for C23H24O4 [M]+ 364.1675; found 364.1681. CSP-
HPLC (Chiralpak AD-H column; 10 % 2-propanol in hexane;
0.5 mL/min): 77 % ee; 24.4 min (major enantiomer), 21.7 min
tert-Butyl (R)-3-Hydroxy-3-[(S)-2-(p-methoxyphenyl)-8-methoxy-
2H-chromen-3-yl]propanoate (24a): The product was recovered in
36% yield based on 55% conversion. 1H NMR (CDCl3, 400 MHz):
δ = 7.36 (d, J = 11.4 Hz, 2 H), 6.81–6.69 (m, 5 H), 6.61 (s, 1 H),
5.97 (s, 1 H), 4.47 (m, 1 H), 3.77 (s, 3 H), 3.73 (s, 3 H), 3.23 (br., (minor enantiomer).
1 H), 2.47 (m, 2 H), 1.42 (s, 9 H) ppm. 13C NMR (CDCl3,
tert-Butyl (R)-3-Hydroxy-3-[(S)-6-methyl-2-phenyl-2H-chromen-3-
100 MHz): δ = 172.1, 160.3, 148.6, 141.4, 136.6, 131.3, 129.7, 122.9,
121.1, 120.0, 119.6, 114.3, 113.3, 82.1, 77.1, 68.5, 56.7, 55.6, 41.2,
28.5 ppm. HRMS: calcd. for C24H28O6[M]+ 412.1886; found
412.1876. CSP-HPLC (Chiralpak AD-H column; 10% 2-propanol
in hexane; 0.5 mL/min): 91% ee; 74.2 min (major enantiomer),
90.9 min (minor enantiomer).
yl]propanoate (27a): The product was recovered in 33% yield based
on 52% conversion. 1H NMR (CDCl3, 400 MHz): δ = 7.39–7.26
(m, 5 H), 6.85 (m, 2 H), 6.58 (d, J = 8.0 Hz, 1 H), 6.55 (s, 1 H),
5.96 (s, 1 H), 4.43 (m, 1 H), 3.17 (d, J = 4.9 Hz, 1 H), 2.50 (m, 2
H), 2.24 (s, 3 H), 1.43 (s, 9 H) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 172.1, 150.2, 139.4, 136.3, 130.7, 130.5, 129.1, 129.0, 128.2,
tert-Butyl 3-[(R)-2-(p-Methoxyphenyl)-8-methoxy-2H-chromen-3-yl]- 127.6, 121.6, 120.3, 116.3, 82.1, 77.6, 68.2, 40.9, 28.5, 21.0 ppm.
propenoate (24b): The product was recovered in 45% yield based
on 55% conversion. H NMR (CDCl3, 400 MHz): δ = 7.35 (m, 3
C23H26O4 (366.5): C 75.38, H 7.15; found C 75.33, H 6.98. CSP-
HPLC (Chiralpak AD-H column; 10 % 2-propanol in hexane;
0.5 mL/min): 79 % ee; 27.9 min (major enantiomer), 32.4 min
1
H), 6.94 (s, 1 H), 6.81 (m, 5 H), 6.11 (s, 1 H), 5.61 (d, J = 15.9 Hz,
1 H), 3.76 (s, 3 H), 3.75 (s, 3 H), 1.46 (s, 9 H) ppm. 13C NMR (minor enantiomer).
(CDCl3, 100 MHz): δ = 166.5, 160.4, 148.8, 142.1, 141.7, 131.0,
tert-Butyl 3-[(R)-6-Methyl-2-phenyl-2H-chromen-3-yl]propenoate
130.9, 130.2, 129.5, 123.1, 121.6, 120.6, 120.3, 114.4, 114.3, 81.0,
76.3, 56.7, 55.6, 28.5 ppm. HRMS: calcd. for C24H26O5 [M]+
394.1780; found 394.1781. CSP-HPLC (Chiralcel OD column; 10%
2-propanol in hexane; 0.5 mL/min): 75% ee; 17.7 min (major en-
antiomer), 20.1 min (minor enantiomer).
(27b): The product was recovered in 41% yield based on 52% con-
version. 1H NMR (CDCl3, 400 MHz): δ = 7.39–7.26 (m, 6 H), 6.91
(m, 3 H), 6.64 (m, 1 H), 6.03 (s, 1 H), 5.59 (d, J = 15.9 Hz, 1 H),
2.23 (s, 3 H), 1.46 (s, 9 H) ppm. 13C NMR (CDCl3, 100 MHz): δ
= 166.6, 150.8, 141.9, 138.3, 132.0, 131.4, 131.2, 130.7, 129.1, 129.0,
tert-Butyl (R)-3-Hydroxy-3-[(S)-2-(o-methoxyphenyl)-2H-chromen- 128.4, 128.1, 122.1, 120.3, 116.9, 81.0, 76.5, 28.5, 20.9 ppm.
3-yl]propanoate (25a): The product was recovered in 35 % yield
based on 58% conversion. H NMR (CDCl3, 400 MHz): δ = 7.25
HRMS: calcd. for C23H24O3 [M]+ 348.1725; found 348.1728. CSP-
HPLC (Chiralpak AD-H column; 10 % 2-propanol in hexane;
0.5 mL/min): 73 % ee; 14.2 min (major enantiomer), 19.5 min
(minor enantiomer).
1
(m, 2 H), 7.04 (m, 2 H), 6.91 (d, J = 8.4 Hz, 1 H), 6.82 (m, 2 H),
6.68 (m, 2 H), 6.49 (s, 1 H), 4.42 (m, 1 H), 3.90 (s, 3 H), 3.10 (d, J
= 4.8 Hz, 1 H), 2.46 (m, 2 H), 1.41 (s, 9 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 172.0, 157.2, 152.6, 136.3, 130.5, 129.8, 129.1, 127.2,
127.1, 122.1, 121.4, 121.1, 120.7, 116.7, 111.6, 81.9, 70.6, 68.5, 56.3,
41.1, 28.5 ppm. C23H26O5 (382.5): calcd. C 72.23, H 6.85; found
C 72.31, H 6.67. CSP-HPLC (Chiralpak AD-H column; 10% 2-
propanol in hexane; 0.5 mL/min): 96 % ee; 40.9 min (major
enantiomer), 51.8 min (minor enantiomer).
tert-Butyl (R)-3-[(S)-6-Chloro-2-phenyl-2H-chromen-3-yl]-3-hy-
droxypropanoate (28a): The product was recovered in 44% yield
based on 37% conversion. 1H NMR (CDCl3, 400 MHz): δ = 7.37–
7.30 (m, 5 H), 7.00 (m, 2 H), 6.61 (d, J = 8.2 Hz, 1 H), 6.54 (s, 1
H), 5.96 (s, 1 H), 4.42 (m, 1 H), 3.29 (d, J = 4.8 Hz, 1 H), 2.49 (m,
2 H), 1.43 (s, 9 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 172.0,
150.9, 138.8, 137.8, 129.5, 129.4, 129.2, 128.2, 126.6, 126.2, 123.3,
119.3, 117.9, 82.3, 77.9, 68.0, 40.7, 28.5 ppm. C22H23ClO4 (386.9):
C 68.30, H 5.99; found C 68.50, H 5.75. CSP-HPLC (Chiralpak
tert-Butyl 3-[(R)-2-(o-Methoxyphenyl)-2H-chromen-3-yl]propenoate
(25b): The product was recovered in 41% yield based on 58% con-
version. 1H NMR (CDCl3, 400 MHz): δ = 7.27–6.65 (m, 11 H), AD-H column; 10% 2-propanol in hexane; 0.5 mL/min): 52% ee;
5.58 (d, J = 16.0 Hz, 1 H), 3.97 (s, 3 H), 1.45 (s, 9 H) ppm. 13C 34.2 min (major enantiomer), 38.1 min (minor enantiomer).
5636
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Eur. J. Org. Chem. 2008, 5630–5637

Kinetic Resolution of Substituted β-Hydroxy Esters
2239–2242; d) Y. Suzuki, K. Yamauchi, K. Muramatsu, M.
Sato, Chem. Commun. 2004, 2770–2771; e) E. Vedejs, O. Daug-
ulis, J. Am. Chem. Soc. 2003, 125, 4166–4173; f) B. Tao, J. C.
Ruble, D. A. Hoic, G. C. Fu, J. Am. Chem. Soc. 1999, 121,
5091–5092.
a) E. T. Choi, M. H. Lee, Y. Kim, Y. S. Park, Tetrahedron 2008,
64, 1515–1522; b) Y. Kim, E. T. Choi, M. H. Lee, Y. S. Park,
Tetrahedron Lett. 2007, 48, 2833–2835; c) E.-k. Shin, H. J. Kim,
Y. Kim, Y. Kim, Y. S. Park, Tetrahedron Lett. 2006, 47, 1933–
1935.
The selectivity factor (s) was estimated by using the equation s
= kS/kR = ln[(1 – C)(1 – ees)]/ln[(1 – C)(1 + ees)], where ees is
the enantiomeric excess of unconverted β-hydroxy esters and C
is the conversion determined by 1H NMR analysis of the reac-
tion mixture using hexamethylbenzene as an internal standard
for 1 and 9–22. For the reactions of 23a–28a and 29 the conver-
sion (C) was calculated by using the equation C = 100ϫees/
(ees + eep), where eep is the enantiomeric excess of the elimin-
ated product. H. B. Kagan, J. C. Fiaud, Top. Stereochem. 1988,
18, 249–330.
a) J.-y. Chang, E.-k. Shin, H. J. Kim, Y. Kim, Y. S. Park, Tetra-
hedron 2005, 61, 2743–2750; b) J. Nam, J.-y. Chang, E.-k. Shin,
H. J. Kim, Y. Kim, S. Jang, Y. S. Park, Tetrahedron 2004, 60,
6311–6318.
a) Y. Satoh, J. L. Stanton, A. J. Hutchison, A. H. Libby, T. J.
Kowalski, W. H. Lee, D. H. White, E. F. Kimble, J. Med. Chem.
1993, 36, 3580–3594; b) J.-F. Cheng, A. Ishikawa, Y. Ono, T.
Arrhenius, A. Nadzan, Bioorg. Med. Chem. Lett. 2003, 13,
3647–3650; c) K. Hajela, J. Pandey, A. Dwivedy, J. D. Dhar, S.
Sarkhel, P. R. Maulik, D. Velumurugan, Bioorg. Med. Chem.
1999, 7, 2083–2090; d) N. Ishizuka, K.-i. Matsumura, J. Kiku-
chi, H. Nakai, Bioorg. Med. Chem. 2002, 10, 3965–3972; e)
O. F. Funk, V. Kettmann, J. Drimal, T. Langer, J. Med. Chem.
2004, 47, 2750–2760; f) N. Ishizuka, K.-i. Matsumura, K.
Sakai, M. Fujimoto, S.-i. Mihara, T. Yamamori, J. Med. Chem.
2002, 45, 2041–2055.
Racemic β-flavenyl-β-hydroxy esters 23a–28a have been pre-
pared by the substrate-controlled diastereoselective addition of
a Reformatsky reagent to flavene-3-carbaldehyde with dr ≈
90:10. M. H. Lee, E. T. Choi, Y. M. Lee, D. Kim, Y. S. Park,
Bull. Korean Chem. Soc. 2008, 29, 1299–1300. The major dia-
stereomers 23a–28a were separated from minor diastereomers
by column chromatography on silica gel and subjected to asym-
metric dehydration.
tert-Butyl 3-[(R)-6-Chloro-2-phenyl-2H-chromen-3-yl]propenoate
(28b): The product was recovered in 29% yield based on 37% con-
version. H NMR (CDCl3, 400 MHz): δ = 7.33 (m, 6 H), 7.06 (m,
1
2 H), 6.90 (s, 1 H), 6.67 (d, J = 8.6 Hz, 1 H), 6.06 (s, 1 H), 5.63 (d,
J = 16.0 Hz, 1 H), 1.46 (s, 9 H) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 166.2, 151.4, 141.1, 137.6, 131.8, 130.8, 129.7, 129.5, 129.2,
128.1, 127.3, 126.7, 123.6, 121.6, 118.5, 81.2, 76.8, 28.5 ppm.
HRMS: calcd. for C22H21ClO3 [M]+ 368.1179; found 368.1182.
CSP-HPLC (Chiralpak AD-H column; 10% 2-propanol in hexane;
0.5 mL/min): 87 % ee; 22.0 min (major enantiomer), 44.0 min
(minor enantiomer).
[4]
[5]
tert-Butyl (R)-3-Hydroxy-3-[(R)-8-methoxy-2-phenyl-2H-chromen-
3-yl]propanoate (29): The product was recovered in 35% yield based
on 53% conversion. 1H NMR (CDCl3, 400 MHz): δ = 7.49–7.26
(m, 5 H), 6.82–6.71 (m, 3 H), 5.85 (s, 1 H), 4.43 (m, 1 H), 3.72 (s,
3 H), 3.34 (d, J = 3.9 Hz, 1 H), 2.55 (dd, J = 16.3 and 3.0 Hz, 1
H), 2.41 (dd, J = 16.3 and 8.8 Hz, 1 H), 1.43 (s, 9 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 172.1, 148.5, 141.6, 138.9, 136.7,
129.3, 129.1, 128.4, 122.9, 121.3, 120.3, 119.6, 113.3, 82.3, 77.1,
68.4, 56.7, 41.5, 28.5 ppm. C23H26O5 (382.5): C 72.23, H 6.85;
found C 72.18, H 6.89. CSP-HPLC (Chiralpak-AD-H column;
10% 2-propanol in hexane; 0.5 mL/min): 88% ee; 52.2 min (major
enantiomer), 43.2 min (minor enantiomer).
[6]
[7]
Acknowledgments
This work was supported by a grant from the Korea Research
Foundation (KRF-2006-005-J03402).
[1] a) D. E. J. E. Robinson, S. D. Bull, Tetrahedron: Asymmetry
2003, 14, 1407–1446; b) J. M. Keith, J. F. Larrow, E. N. Jacob-
son, Adv. Synth. Catal. 2001, 343, 5–26.
[2] For recent reviews on asymmetric oxidation, see: a) M. Wills,
Angew. Chem. Int. Ed. 2008, 47, 4264–4267; b) S. Arita, T.
Koike, Y. Kayaki, T. Ikariya, Angew. Chem. Int. Ed. 2008, 47,
2447–2449; c) T. Chen, J.-J. Jiang, Q. Xu, M. Shi, Org. Lett.
2007, 9, 865–868; d) J. A. Mueller, A. Cowell, B. D. Chandler,
M. S. Sigman, J. Am. Chem. Soc. 2005, 127, 14817–14824; e)
R. M. Trend, B. M. Stoltz, J. Am. Chem. Soc. 2004, 126, 4482–
4483; f) A. T. Radosevich, C. Musich, F. D. Toste, J. Am.
Chem. Soc. 2005, 127, 1090–1091.
[3] For recent reviews on asymmetric acylation, see: a) C. Mazet,
S. Roseblade, V. Köhler, A. Pfaltz, Org. Lett. 2006, 8, 1879–
1882; b) V. B. Birman, H. Jiang, Org. Lett. 2005, 7, 3445–3447;
c) S. Yamada, T. Misono, Y. Iwai, Tetrahedron Lett. 2005, 46,
[8]
[9]
J.-F. Lavallée, C. Spino, R. Ruel, K. T. Hogan, P. Deslongch-
amps, Can. J. Chem. 1992, 70, 1406–1426.
Received: August 21, 2008
Published Online: October 13, 2008
Eur. J. Org. Chem. 2008, 5630–5637
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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