Asymmetric dehydration of β-hydroxy esters and application to the syntheses of flavane derivatives

Article abstract of DOI:10.1016/j.tet.2007.11.026

Catalytic asymmetric dehydration of β-aryl or alkyl substituted β-hydroxy esters via kinetic resolution has been investigated. A brief survey of 10 different chiral ligands is conducted to examine the effects of chiral ligand structure on selectivity of t

Full text of DOI:10.1016/j.tet.2007.11.026

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1515e1522
www.elsevier.com/locate/tet
Asymmetric dehydration of b-hydroxy esters
and application to the syntheses of flavane derivatives
*
Eui Ta Choi, Min Hee Lee, Yongtae Kim, Yong Sun Park
Department of Chemistry and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea
Received 20 October 2007; received in revised form 7 November 2007; accepted 7 November 2007
Available online 12 November 2007
Abstract
Catalytic asymmetric dehydration of b-aryl or alkyl substituted b-hydroxy esters via kinetic resolution has been investigated. A brief survey
of 10 different chiral ligands is conducted to examine the effects of chiral ligand structure on selectivity of the dehydration. The kinetic reso-
lution of a variety of rac-b-hydroxy tert-butyl esters in the presence of prolinol chiral ligand 2 and BrZnCH2CO2-t-Bu can provide highly enan-
tioenriched b-hydroxy esters 14e21 with selectivity factors ranging from 11 to 66. Also, application of this asymmetric synthetic methodology
to the preparation of enantioenriched flavane derivatives 25e29 is demonstrated.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Kinetic resolution; Asymmetric syntheses; Chiral catalyst; Flavonoids; Dehydration
1. Introduction
preliminary results of the novel alcohol resolution prompted
us to investigate the asymmetric dehydration in more detail.
Herein we describe our recent progress to optimize reaction
condition with 10 different prolinol chiral ligands and to
extend the scope of the methodology to various b-alkyl sub-
stituents. Application of this methodology to highly enantio-
selective preparation of flavane derivatives 25e29 is also
presented.
Kinetic resolution of a racemic mixture with a chiral cata-
lyst is presently an area of great importance in organic chem-
istry.1 In particular, significant advances have been made
recently in nonenzymatic kinetic resolution of alcohols by
enantioselective oxidation and acylation.2,3 Earlier we have
been able to introduce first example for the enantioselective
catalytic asymmetric dehydration of b-aryl-b-hydroxy
esters via kinetic resolution as shown in Scheme 1.4 The
2. Results and discussion
HO
Ar
HO
Ar
Ar
Ligand 2
We have found that chiral ligand 2 is efficient for the asym-
metric dehydration of b-aryl-b-hydroxy esters in the presence
of excess amount of BrZnCH2CO2-t-Bu as a base. Treatment
of racemic b-hydroxy ester 1 (Ar¼p-MeO-Ph) in the presence
of 2 (20 mol %) and BrZnCH2CO2-t-Bu (8 equiv) in anhy-
drous THF at reflux for 2 h afforded a mixture of trans-
cinnamate and b-hydroxy ester (R)-1. At 53% conversion,
trans-cinnamate was isolated in 43% yield and the uncon-
verted (R)-1 was obtained in 39% yield with 89% ee. In the
absence of either ligand 2 or BrZnCH2CO2-t-Bu no elimina-
tion occurred at all. It was found that the kinetic resolution
worked best when carried out in refluxing THF and the
+
BrZnCH2CO2t-Bu
t-BuO2C
rac-1
t-BuO2C
(R)-1
t-BuO2C
THF, Reflux
Ph Ph
N
s = 15-42
Ph
N
H
HO
Scheme 1.
2
* Corresponding author. Tel.: þ822 450 3377; fax: þ822 3436 5382.
E-mail address: parkyong@konkuk.ac.kr (Y.S. Park).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.026

1516
E.T. Choi et al. / Tetrahedron 64 (2008) 1515e1522
elimination of b-hydroxy ester did not proceed at lower
temperatures.
difference in reactivities of the two enantiomers of b-hydroxy
ester 1 (s¼kS/kR¼24, an average of five runs), dehydration will
slow as most of (S )-1 is converted to the cinnamate.5 Conse-
quently, there is a wide range of time during which the reac-
tion can be stopped without compromising the yield of
recovered b-hydroxy ester 1.
During the course of our studies toward the development of
the efficient chiral ligand 2 for asymmetric dehydration, we
have prepared nine different chiral ligands 5e13 as shown
in Figure 2. D-Phg-L-Pro dipeptide-derived chiral ligands
5e10 were prepared using the methodology, which we have
recently developed for asymmetric syntheses of dipeptide
Therefore, an investigation was carried out to establish if
there was a relationship between the extent of cinnamate for-
mation and enantiopurity of unreacted b-hydroxy ester. We
have closely monitored the progress of the reaction in terms
of the conversion and enantioselectivity of 1 (Ar¼p-MeO-
Ph) by NMR analysis of crude reaction mixture with
5 mol % of chiral ligand 2, 8 equiv of BrZnCH2CO2-t-Bu,
and hexamethylbenzene as an internal integration standard.
The results shown in Figure 1 clearly indicate a direct relation-
ship between dehydration of b-hydroxy ester to cinnamate and
enantiomeric excess of the remaining b-hydroxy ester. Figure 1
also shows that the rate of dehydration decreased drastically as
they approach 50% conversion. Because of the large
Ph Ph
Ph Ph
Ph Ph
N
N
N
H3C
N
H
H3C
N
H
N
H
HO
HO
HO
5
6
7
a
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
Ph Ph
N
Ph
Ph
N
N
N
H
N
N
H
HO
HO
Ph
HO
10
8
9
Ph Ph
Ph
Ph
Ph
cinnamate formation (%)
ee (%) of hydroxy ester
H
N
N
N
Ph
N
H
Ph
N
H
Ph
N
H
HO
HO
HO
0
1
2
3
4
5
6
11
12
13
time (h)
Figure 2.
b
analogs as shown in Scheme 2.6 The treatment of two diastereo-
meric mixtures (ca. 50:50) of N-(a-bromo-a-phenylacetyl)-
(L)-proline methyl ester 3 with an amine nucleophile in the
presence of tetrabutylammonium iodide (TBAI) and diisopro-
pylethylamine (DIEA) in CH2Cl2 at room temperature gave
the D-Phg-L-Pro dipeptide analogs 4 in 93e40% yields with
99:1e81:19 diastereomeric ratios (drs). The subsequent
Ph
Ph
N
N
Br
Br
TBAI
DIEA
CO2Me
CO2Me
R)-3
O
O
(
(
S)-3
R
NH
R
Ph
Ph
(
BH3-THF
R
N
R
N
N
R
N
R
Figure 1. (a) Relationship between cinnamate formation and the enantiopurity
of unreacted b-hydroxy ester 1 (Ar¼p-MeO-Ph). (b) Representative 1H NMR
spectra (400 MHz, CDCl3, 293 K) of the crude reaction mixture after acidic
extractive work-up during the dehydration of 1 with 5 mol % of ligand 2
and 8 equiv of BrZnCH2CO2-t-Bu.
CO2Me
O
HO
2, 5-10
R)-4
Scheme 2.

E.T. Choi et al. / Tetrahedron 64 (2008) 1515e1522
1517
reduction of 4 using an excess of BH3eTHF (5 equiv) in THF
furnished the expected chiral ligands as a mixture of two
isomers. In all cases, the optically pure N-alkylated (N-(R)-2-
amino-2-phenylethyl)-(S )-prolinols 5e10 were easily isolated
in 70e49% yields by flash column chromatographic separation.
Also, preparation of chiral ligands 11, 12, and 13 was
successfully achieved by the reduction of corresponding
N-diphenylmethylene dipeptide derivatives. Treatments of
N-diphenylmethylene-Gly-L-Pro methyl ester, N-diphenyl-
methylene-L-Phg-L-Pro methyl ester, and N-diphenylmethyl-
ene-D-Phg-L-Leu methyl ester with BH3eTHF in THF
furnished ligands 11, 12, and 13 in 78, 82, and 66% yields,
respectively.
We then explored asymmetric dehydration reactions as
a preliminary evaluation of the catalytic properties of nine chi-
ral ligands 5e13. The results of the kinetic resolution of race-
mic b-hydroxy ester 1 with chiral ligands 5e13 are
summarized in Table 1, entries 1e13. With 20 mol % of chiral
ligand and 8 equiv of BrZnCH2CO2-t-Bu, the reaction with
N-(R)-1-phenethylated ligand 5 gave a comparable level of
selectivity (s¼26) relative to N-diphenylmethylated ligand 2,
while N-benzylated ligand 6 and N-(S )-1-phenethylated ligand
7 produced modest and poor level of selectivities, respectively
(entries 2e4). These results indicate that subtle N-alkyl group
modifications of D-Phg-L-Pro-derived structure can lead to
substantial variations in reactivity and enantioselection.
Much lower level of selectivities were observed with chiral
ligands 8e10, which have different N-alkyl groups such as
N-fluorenyl, N-naphthyl, and N,N-dibenzyl groups (entries
5e7). To gain an insight into the effect of the phenyl substit-
uent of D-Phg-L-Pro-derived core structure, we have also tested
two different prolinol ligands 11 and 12. Considerable loss of
selectivity was observed in both reactions with L-Phg-L-Pro-
derived ligand 12 and Gly-L-Pro-derived ligand 11 having no
phenyl substituent (entries 8 and 9). Notably, leucine-derived
chiral ligand 13 gave no selectivity (entry 10). The brief sur-
vey of various chiral ligands shown in Figure 2 indicates
that D-Phg-L-Pro dipeptide-derived N-(R)-aminophenylethyl-
(S )-prolinol skeleton is catalytic core structure and the other
structural component, N-benzyl substituent of ligand, has
been shown to be vital for both reactivity and selectivity and
thus appear to function cooperatively.
The high selectivities obtained with chiral ligands 2, 5, and
6 prompted us to test the possibility of lowering the ligand
loading of them. As shown in entries 11e13, with 5 mol %
of ligand loading, the selectivity dropped sharply with chiral
ligands 5 and 6, while the selectivity did not change signifi-
cantly with chiral ligand 2 showing the superior reactivity of
the catalyst of ligand 2. However, further decreasing ligand
loading to 3 mol % of 2 was not satisfactory with a selectivity
of 11 (entry 14). When the reaction was carried out with
1 mol % of ligand 2, only 4% conversion was observed after
4 h. Taking reactivity and selectivity into account, 5 mol %
of ligand 2 was deemed to be the best for dehydration and it
was used for the subsequent investigations. Next, the influence
of the organozinc reagent on enantioselectivtity was investi-
gated. The use of 4 or 2 equiv of BrZnCH2CO2-t-Bu in the
presence of 5 mol % of chiral ligand 2 gave lower conversions
and lower selectivities after 6 h (entries 16 and 17). The pre-
liminary results indicate that the selectivity and rate of dehy-
dration is substantially influenced by the amount of the base,
BrZnCH2CO2-t-Bu.
Table 1
L*
HO
Ar
Ar
HO
Ar
BrZnCH2CO2t-Bu
+
t-BuO2C
t-BuO2C
t-BuO2C
(R)-1
THF, reflux
rac-1
(Ar = p-MeO-Ph)
Next, we initiated investigations into the reaction’s scope
with various b-hydroxy tert-butyl esters and chiral ligand 2.
For convenience, most reactions were performed with
5 mol % of 2 and 8 equiv of BrZnCH2CO2-t-Bu. As shown
in Table 2, the kinetic resolution with chiral ligand 2 provided
excellent levels of asymmetric induction with three b-aryl-b-
hydroxy esters 14e16. Most reactions reached 55e57% con-
version after 1e1.5 h with the selectivities ranging from 19
to 28. Thus, the unconverted b-hydroxy esters (R)-14e16
with 93e98% ee were obtained in 40e32% isolated yields.
The high selectivity and high activity of this catalyst enabled
us to successfully perform a resolution of b-hydroxy esters
14e16 on a multigram scale, which have been used in asym-
metric syntheses of flavane derivatives 25e29 as shown in
Scheme 3. Additionally, the resolutions of b-vinyl substituted
ester 17 and b-pentadienyl substituted ester 18 gave a high
level of selectivities (entries 4 and 5). Higher selectivities
were observed in the kinetic resolution of b-(E )-styryl
substituted b-hydroxy esters 19e21 (entries 6e8). Our most
impressive results were obtained with b-o-methoxystyryl
b-hydroxy ester 20, affording a krel of 66 (entry 7). When
R was an aliphatic group (R¼CH3 or PhCH2CH2), no
Entry Ligand
BrZnR
(mol %) (equiv)
Time (h) Conv.a (%) % eeb s (kS/kR)c
1
2 (20)
5 (20)
6 (20)
7 (20)
8 (20)
9 (20)
10 (20)
11 (20)
12 (20)
13 (20)
2 (5)
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
4
2
2
53
51
47
44
53
46
39
50
39
56
56
26
51
51
4
89
87
68
37
59
18
4
22
26
13
5
2
3
3
0.5
2
4
5
4
5
6
6
2
1.2
7
20
0.5
20
8
65
28
12
97
18
58
72
d
51
20
6
9
4
1.3
10
11
12
13
14
15
16
17
a
3
1
2
2
2
4
6
6
24
6 (5)
7 (5)
4
6
2 (3)
2 (1)
11
d
17
11
2 (5)
2 (5)
38
21
Determined based on consumption of starting b-hydroxy ester substrate by
1H NMR analysis of characteristic signals directly on the crude mixture with
hexamethylbenzene as an internal integration standard.
b
The % ee of 1 is determined by CSP-HPLC.
c
Selectivity (s) values represent an average of at least three experiments,
while conversion and ee value are for specific cases.

1518
E.T. Choi et al. / Tetrahedron 64 (2008) 1515e1522
Table 2
The dehydration of b-hydroxy isopropyl or ethyl ester also
proceeded with ligand 2 and BrZnCH2CO2-t-Bu, but the effi-
ciency of the kinetic resolution was lower than the reaction of
b-hydroxy tert-butyl ester. Kinetic resolutions of b-( p-methoxy-
phenyl)-b-hydroxy isopropyl and ethyl esters with 5 mol % of
2 and 8 equiv of BrZnCH2CO2-t-Bu gave lower selectivities
of 9 and 10, respectively. When using b-hydroxy esters, which
have an a-substituent or two b-substituents as substrates, no
dehydration occurred under the same reaction condition. Evi-
dently, the efficiency of kinetic resolution is strongly sub-
strate-dependent. Subtle steric and electronic factors result in
efficient kinetic resolution of b-hydroxy tert-butyl ester.
To extend the utility of this methodology, we decided to
take advantage of the functional groups present in b-aryl-b-hy-
droxy ester for subsequent synthetic elaboration. In particular,
the opportunity to prepare enantioenriched flavane derivatives
25e29 was provided from the enantioenriched b-aryl-b-hy-
droxy esters 14e16 as shown in Scheme 3. Reduction of
14e16 (95e96% ee) with LiAlH4 provided the corresponding
1,3-diols and subsequent selective iodination of primary alco-
hols gave 3-iodo-propanols 22e24 in 68e50% yields over the
two steps. When 22e24 were treated with a phenol under stan-
dard Mitsunobu inversion condition, the reaction provided the
(S )-aryl ethers in 87e77% yields. After the addition of
2 equiv of n-butyl lithium to the aryl ether in THF at 0 ꢀC,
the reaction was allowed to warm to room temperature.7 Under
these conditions, the bromineelithium exchange of the aryl
bromide and subsequent cyclization gave (S )-chromans 25e
29 in 67e55% yields with 90e96% ee. The sign of rotation
and optical purities of 25e29 confirmed that the Mitsunobu re-
action occurred with inversion and the four-step transforma-
tion from enantioenriched 14e16 proceeded without
significant racemization.
HO
R
R
5 mol% 2
HO
R
BrZnCH2CO2t-Bu
+
t-BuO2C
rac-14-21
t-BuO2C
THF, reflux
t-BuO2C
(R)-14-21
Time (h) Conv.a (%) % eeb s (kS/kR)c
Entry
R
1
2
3
1.5
1
57
55
57
93
93
98
19
28
22
(14)
Me
(15)
Cl
1
(16)
4
5
5
4
62
57
97
81
20
11
(17)
(18)
6
7
1.5
1
55
52
97
95
38
66
(19)
MeO
(20)
8
1.5
53
94
42
(21)
a
Determined based on consumption of starting b-hydroxy ester substrate by
1H NMR analysis of characteristic signals directly on the crude mixture with
hexamethylbenzene as an internal standard.
b
The % ee of 14e21 is determined by CSP-HPLC.
Selectivity (s) values represent an average of at least three experiments,
while conversion and ee value are for specific cases.
c
dehydration occurred under the same reaction condition and
racemic b-hydroxy ester was quantitatively recovered. These
results imply that the primary driving force for dehydration
is the formation of a double bond, which is conjugated with
both the carbonyl group and R group.
3. Conclusion
We have developed conceptually novel enantioselective de-
hydration of b-hydroxy esters via kinetic resolution. This
study introduces D-Phg-L-Pro dipeptide-derived N-(R)-amino-
phenylethyl-(S )-prolinol ligand for asymmetric dehydration
and may ultimately lead to new dehydration catalysts with
higher selectivity and broad synthetic utility. In addition, we
have established the applicability of this method as exempli-
fied by the preparation of enantioenriched flavane derivatives.
While the effective chiral catalyst for dehydration was found
in this work, the substrate scope is still quite limited and the
precise structure of the zinc enolateechiral ligand complex
is unclear. Further studies to resolve them as well as to show
more synthetic utility are now in progress.
R1
R1
1. LiAlH4
HO
HO
2. PPh3, I2
I
t-BuO2C
22 (R1=H)
(R)-14 (R1=H) 95% ee
(R)-15 (R1= Me) 96% ee
(R)-16 (R1= Cl) 96% ee
23 (R1= Me)
24 (R1= Cl)
R1
1. DEAD, Ph3P
OH
O
4. Experimental
R2
R2
Br
2. n-BuLi
(S)-25 (R1= H, R2=H) 94% ee
(S)-26 (R1=Me, R2=H) 92% ee
(S)-27 (R1=H, R2=Me) 90% ee
(S)-28 (R1= H, R2=Cl) 93% ee
4.1. General procedure for the preparation of chiral
ligands 2 and 5e10
(S)-29 (R1= Cl, R2=Cl) 96% ee
To a solution of N-(a-bromo-a-phenylacetyl) (S )-proline
methyl ester in dry CH2Cl2 (0.1 M) at room temperature
Scheme 3.

E.T. Choi et al. / Tetrahedron 64 (2008) 1515e1522
1519
were added an amine (1.2 equiv), TBAI (1.0 equiv), and DIEA
(1.2 equiv). The resulting reaction mixture was stirred at room
temperature for 24 h. The solvent in mixture was evaporated
and the crude product was purified by column chromatography
on silica gel. The substituted products were obtained in 85%
yield with 99:1 dr (with benzhydrylamine), 43% yield with
90:10 dr (with (R)-a-methylbenzylamine), in 89% yield with
81:19 dr (with benzylamine), in 40% yield with 81:19 dr
(with (S )-a-methylbenzylamine), in 79% yield with 91:9 dr
(with 9-fluorenamine), in 80% yield with 85:15 dr (with 1-
naphthylamine), and in 93% yield with 99:1 dr (with dibenzyl-
amine), respectively.6 To a solution of product in THF (0.5 M)
was added BH3eTHF (1.0 M, 5.0 equiv), and the mixture was
refluxed for 12 h. The reaction was quenched by adding
MeOH (0.5 mL) under ice-water cooling, and the solvents
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 mLꢁ3). The combined organic ex-
tracts were dried with anhydrous MgSO4, filtered, and concen-
trated in vacuo. Chromatographic separation on silica gel
afforded the ligands with >99:1 dr.
(dd, J¼12.5 and 3.5 Hz, 1H), 2.23 (m, 1H), 1.89e1.58 (m,
4H); 13C NMR (CDCl3, 100 MHz) 142.7, 140.9, 128.9,
128.8, 128.5, 127.9, 127.8, 127.3, 65.7, 64.3, 63.2, 61.2,
54.8, 51.7, 27.7, 24.2. HRMS calcd for C20H27N2O
(Mþþ1): 311.2123, found: 311.2149.
4.1.4. N-[(R)-N-((S )-1-Phenylethyl)-2-amino-2-
phenylethyl]-(S )-prolinol (7)
A pale yellow oil was obtained in 49% yield. H NMR
1
(CDCl3, 400 MHz) 7.33e7.17 (m, 10H), 3.67 (dd, J¼11.1
and 3.7 Hz, 1H), 3.50 (m, 2H), 3.41 (dd, J¼11.2 and 3.1 Hz,
1H), 3.30 (br, 1H), 2.90 (t, 1H), 2.74 (m, 1H), 2.60 (m, 1H),
2.30 (dd, J¼12.5 and 3.1 Hz, 1H), 2.05 (m, 1H), 1.90e1.60
(m, 4H), 1.33 (d, J¼6.8 Hz, 3H); 13C NMR (CDCl3,
100 MHz) 145.8, 143.0, 128.9, 128.8, 127.9, 127.7, 127.3,
127.0, 65.5, 64.2, 62.9, 59.1, 55.2, 54.6, 27.8, 25.0, 24.2.
HRMS calcd for C21H29N2O (Mþþ1): 325.2280, found:
325.2251. [a]2D0 ꢂ125.5 (c 0.1, CHCl3).
4.1.5. N-[(R)-N-(9H-Fluoren-9-yl)-2-amino-2-phenylethyl]-
(S )-prolinol (8)
A colorless oil was obtained in 66% yield. 1H NMR
(CDCl3, 400 MHz) 7.63e7.13 (m, 13H), 4.73 (s, 1H), 4.24
(dd, J¼10.8 and 3.6 Hz, 1H), 3.58 (dd, J¼11.1 and 3.5 Hz,
1H), 3.34 (dd, J¼11.1 and 3.6 Hz, 1H), 2.98 (m, 4H), 2.57
(m, 1H), 2.43 (dd, J¼12.5 and 3.5 Hz, 1H), 2.25 (m, 1H),
1.83e1.50 (m, 4H); 13C NMR (CDCl3, 100 MHz) 147.2,
146.8, 142.9, 141.0, 140.6, 128.9, 128.4, 128.2, 128.1,
127.8, 127.7, 127.3, 125.9, 125.8, 120.3, 119.9, 65.7, 64.4,
63.7, 61.0, 59.8, 54.7, 27.6, 24.2. HRMS calcd for
C26H29N2O (Mþþ1): 385.2280, found: 385.2254.
4.1.1. N-((R)-N-Diphenylmethyl-2-amino-2-phenylethyl)-
(S )-prolinol (2)
A colorless oil was obtained in 70% yield. 1H NMR
(CDCl3, 400 MHz) 7.31e7.11 (m, 15H), 4.62 (s, 1H), 3.60
(m, 2H), 3.45 (dd, J¼11.0 and 4.0 Hz, 1H), 3.12 (br, 1H),
2.94 (t, J¼12.1 Hz, 1H), 2.77 (m, 1H), 2.54 (m, 1H), 2.34
(dd, J¼12.5 and 3.2 Hz, 1H), 2.04 (m, 1H), 1.80e1.63 (m,
4H); 13C NMR (CDCl3, 100 MHz) 140.5, 138.6, 129.6,
129.3, 128.7, 128.5, 127.7, 127.4, 65.4, 62.8, 61.4, 57.1,
55.1, 54.5, 28.3, 24.4. Anal. Calcd for C26H30N2O: C, 80.79;
H, 7.82; N, 7.25. Found: C, 80.77; H, 8.00; N, 7.51. [a]D20
ꢂ75.5 (c 0.1, CHCl3).
4.1.6. N-[(R)-N-(1-Naphthyl)-2-amino-2-phenylethyl]-(S )-
prolinol (9)
A colorless oil was obtained in 57% yield. 1H NMR
(CDCl3, 400 MHz) 8.05e7.10 (m, 11H), 6.27 (d, J¼8.0 Hz,
1H), 5.80 (br, 1H), 4.43 (dd, J¼11.2 and 3.6 Hz, 1H), 3.73
(dd, J¼10.8 and 4.0 Hz, 1H), 3.58 (dd, J¼10.7 and 2.8 Hz,
1H), 3.07 (m, 2H), 2.66 (m, 2H), 2.31 (m, 2H), 1.95e1.58
(m, 4H); 13C NMR (CDCl3, 100 MHz) 143.7, 142.8, 134.7,
129.2, 129.1, 127.8, 127.0, 126.8, 126.2, 125.5, 124.8,
120.7, 118.1, 107.2, 65.4, 63.8, 63.2, 58.0, 54.3, 27.9, 24.2.
HRMS calcd for C23H27N2O (Mþþ1): 347.2123, found:
347.2107.
4.1.2. N-[(R)-N-((R)-1-Phenylethyl)-2-amino-2-
phenylethyl]-(S )-prolinol (5)
A pale yellow oil was obtained in 63% yield. H NMR
1
(CDCl3, 400 MHz) 7.33e7.16 (m, 10H), 3.84 (dd, J¼10.5
and 3.4 Hz, 1H), 3.78 (q, J¼6.5 Hz, 1H), 3.61 (dd, J¼11.0
and 3.4 Hz, 1H), 3.41 (dd, J¼11.0 and 4.9 Hz, 1H), 3.21 (m,
1H), 3.00 (br, 1H), 2.97 (dd, J¼12.7 and 10.8 Hz, 1H), 2.68
(m, 1H), 2.52 (dd, J¼12.8 and 3.5 Hz, 1H), 2.36 (q,
J¼8.2 Hz, 1H), 1.90e1.60 (m, 4H), 1.36 (d, J¼6.6 Hz, 3H);
13C NMR (CDCl3, 100 MHz) 146.4, 143.4, 128.8, 128.7,
127.6, 127.5, 127.1, 127.0, 65.8, 64.8, 63.6, 60.5, 55.8, 55.3,
27.9, 24.6, 22.5. HRMS calcd for C21H29N2O (Mþþ1):
325.2280, found: 325.2309.
4.1.7. N-((R)-N,N-Dibenzyl-2-amino-2-phenylethyl)-(S )-
prolinol (10)
A colorless oil was obtained in 68% yield. 1H NMR
(CDCl3, 400 MHz) 7.42e7.18 (m, 15H), 3.89 (m, 1H), 3.87
(d, J¼13.6 Hz, 2H), 3.57 (dd, J¼10.7 and 3.5 Hz, 1H), 3.40
(dd, J¼12.8 and 8.7 Hz, 1H), 3.32 (dd, J¼10.7 and 2.1 Hz,
1H), 3.15 (d, J¼13.6 Hz, 2H), 2.80 (br, 1H), 2.79 (m, 1H),
2.62 (dd, J¼12.8 and 5.5 Hz, 1H), 2.56 (m, 1H), 2.03 (q,
J¼8.6 Hz, 1H), 1.81e1.58 (m, 4H); 13C NMR (CDCl3,
100 MHz) 144.8, 144.2, 142.9, 129.0, 128.9, 128.7, 128.4,
127.9, 127.8, 127.7, 127.5, 127.1, 65.3, 64.0, 63.5, 62.9,
59.3, 54.6, 27.9, 24.2. Anal. Calcd for C27H32N2O: C, 80.96;
4.1.3. N-((R)-N-Benzyl-2-amino-2-phenylethyl)-(S )-
prolinol (6)
A colorless oil was obtained in 69% yield. 1H NMR
(CDCl3, 400 MHz) 7.39e7.25 (m, 10H), 3.75 (m, 2H), 3.63
(dd, J¼11.1 and 3.5 Hz, 1H), 3.51 (d, J¼13.6 Hz, 1H), 3.42
(dd, J¼11.1 and 4.2 Hz, 1H), 3.01 (m, 1H), 2.92 (dd,
J¼11.3 and 12.3 Hz, 1H), 2.76 (br, 1H), 2.62 (m, 1H), 2.43

1520
E.T. Choi et al. / Tetrahedron 64 (2008) 1515e1522
H, 8.05; N, 6.99. Found: C, 80.83; H, 8.04; N, 6.89. [a]D20
ꢂ93.8 (c 0.1, CHCl3).
4.3. General procedure for asymmetric dehydration
reactions of 1 and 14e21
Trimethylchlorosilane (0.3 equiv) was added to a suspen-
sion of zinc metal (8.0 equiv) in anhydrous THF (5 mL). After
the mixture was refluxed for 40 min, the heating was stopped,
and a solution of ligand (5 mol %), tert-butyl bromoacetate
(8.0 equiv) and racemic b-hydroxy ester (0.5 mmol,
1.0 equiv), and hexamethylbenzene (internal standard, 0.3e
0.5 equiv) in THF (5 mL) was slowly added. The mixture
was stirred at reflux for 1e5 h and then quenched with satu-
rated NH4Cl solution. The resulting mixture was extracted
with methylene chloride (3ꢁ5 mL) and the combined extracts
were washed with brine. The solvents were removed under re-
duced pressure and the residue purified by flash column chro-
matography to give enantioenriched b-hydroxy esters 1 and
14e21.
4.2. General procedure for the preparation of chiral
ligands 11e13
To a solution of N-diphenylmethylene dipeptide methyl es-
ter in THF (0.5 M) was added BH3eTHF (1.0 M, 5.0 equiv),
and the mixture was refluxed for 12e24 h. The reaction was
quenched by adding MeOH (0.5 mL) under ice-water cooling,
and the solvents 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 mLꢁ3). The com-
bined organic extracts were dried with anhydrous MgSO4, fil-
tered, and concentrated in vacuo. Chromatographic separation
on silica gel afforded the ligands 11e13.
4.3.1. tert-Butyl (R)-3-(4-methoxyphenyl)-3-hydroxy-
propanoate (1)
The product was recovered in 35% yield based on 56%
4.2.1. N-(N-Diphenylmethyl-2-aminoethyl)-(S )-prolinol (11)
A pale yellow oil was obtained in 78% yield from N-diphe-
nylmethylene-Gly-L-Pro methyl ester. 1H NMR (CDCl3,
400 MHz) 7.40e7.18 (m, 10H), 4.82 (s, 1H), 3.64 (dd,
J¼11.1 and 3.6 Hz, 1H), 3.43 (m, 2H), 3.10 (m, 1H), 2.97
(m, 1H), 2.72 (m, 3H), 2.49 (m, 1H), 2.28 (m, 1H), 1.84e
1.55 (m, 4H); 13C NMR (CDCl3, 100 MHz) 144.4, 144.2,
129.0, 128.9, 127.7, 127.6, 127.3, 127.4, 68.0, 65.9, 64.0,
55.4, 55.1, 47.0, 27.9, 24.2. HRMS calcd for C20H27N2O
(Mþþ1): 311.2123, found: 311.2118.
1
conversion. H NMR (CDCl3, 400 MHz) 7.26 (d, J¼8.4 Hz,
2H), 6.85 (d, J¼8.4 Hz, 2H), 5.00 (br, 1H), 3.76 (s, 3H),
3.51 (br, 1H), 2.61 (m, 2H), 1.43 (s, 9H); 13C NMR (CDCl3,
100 MHz) 172.2, 159.5, 135.4, 127.4, 114.2, 81.7, 70.4,
55.6, 44.8, 28.5. Anal. Calcd for C14H20O4: C, 66.65; H,
7.99. Found: C, 66.56; H, 7.87. [a]2D0 þ28.0 (c 0.15,
CHCl3); CSP-HPLC (Chiralcel OJ-H column; 5% 2-propanol
in hexane; 0.5 mL/min): 97% ee, 33.3 min (R), 30.7 min (S ).
4.3.2. tert-Butyl (R)-3-phenyl-3-hydroxypropanoate (14)
The product was recovered in 32% yield based on 57%
conversion. The analytical data is in accordance with the liter-
ature.8a 1H NMR (CDCl3, 400 MHz) 7.35e7.22 (m, 5H), 5.05
(br, 1H), 3.57 (br, 1H), 2.62 (m, 2H), 1.38 (s, 9H). [a]2D0 þ7.8
(c 0.05, CHCl3); CSP-HPLC; tert-butyl ester 14 was converted
to methyl ester for better chromatographic separation (Chiral-
cel OD column; 10% 2-propanol in hexane; 0.5 mL/min): 93%
ee, 26.8 min (R), 19.0 min (S ).
4.2.2. N-((S )-N-Diphenylmethyl-2-amino-2-phenylethyl)-
(S )-prolinol (12)
A pale yellow oil was obtained in 82% yield from N-diphe-
nylmethylene-L-Phg-L-Pro methyl ester. 1H NMR (CDCl3,
400 MHz) 7.40e7.16 (m, 15H), 4.66 (s, 1H), 3.64 (m, 1H),
3.40 (dd, J¼11.1 and 3.9 Hz, 1H), 3.21 (dd, J¼11.0 and
4.2 Hz, 1H), 3.03 (dd, J¼12.8 and 7.7 Hz, 1H), 2.92 (br,
1H), 2.80e2.60 (m, 4H), 2.24 (m, 1H), 1.73e1.51 (m, 4H);
13C NMR (CDCl3, 100 MHz) 144.9, 143.6, 143.2, 129.0,
128.9, 128.8, 128.1, 127.7, 127.6, 127.5, 127.4, 127.3, 66.1,
64.2, 64.0, 62.8, 60.2, 56.4. Anal. Calcd for C26H30N2O: C,
80.79; H, 7.82; N, 7.25. Found: C, 80.67; H, 7.86; N, 7.23.
4.3.3. tert-Butyl (R)-3-(4-methylphenyl)-3-hydroxy-
propanoate (15)
The product was recovered in 40% yield based on 55%
conversion. The analytical data is in accordance with the liter-
ature.8b 1H NMR (CDCl3, 400 MHz) 7.23 (d, J¼8.1 Hz, 2H),
7.11 (d, J¼8.1 Hz, 2H), 5.01 (m, 1H), 3.51 (br, 1H), 2.67e
2.54 (m, 2H), 2.31 (s, 3H), 1.43 (s, 9H); CSP-HPLC (Chiralcel
OB-H column; 5% 2-propanol in hexane; 0.5 mL/min): 93%
ee, 10.8 min (R), 12.8 min (S ).
4.2.3. N-((R)-N-Diphenylmethyl-2-amino-2-phenylethyl)-
(S )-leucinol (13)
A pale yellow oil was obtained in 66% yield from N-diphe-
nylmethylene-D-Phg-L-Leu methyl ester. 1H NMR (CDCl3,
400 MHz) 7.35e7.13 (m, 15H), 4.64 (s, 1H), 3.60 (dd,
J¼7.8 and 5.5 Hz, 1H), 3.53 (dd, J¼10.6 and 3.8 Hz, 1H),
3.19 (dd, J¼10.6 and 6.5 Hz, 1H), 2.83 (m, 1H), 2.77 (m,
1H), 2.60 (m, 1H), 1.52 (m, 1H), 1.22 (m, 1H), 1.13 (m,
1H), 0.83 (d, J¼6.5 Hz, 6H); 13C NMR (CDCl3, 100 MHz)
144.9, 143.6, 142.7, 129.0, 128.9, 128.8, 128.2, 127.9,
127.7, 127.6, 127.4, 127.3, 64.0, 63.8, 60.9, 57.3, 53.8, 41.5,
25.3, 23.4, 23.1. HRMS calcd for C27H35N2O (Mþþ1):
403.2749, found: 403.2718.
4.3.4. tert-Butyl (R)-3-(4-chlorophenyl)-3-hydroxy-
propanoate (16)
The product was recovered in 37% yield based on 57%
conversion. The analytical data is in accordance with the liter-
ature.8c 1H NMR (CDCl3, 400 MHz) 7.29 (m, 4H), 5.03 (m,
1H), 3.68 (m, 3H), 2.61 (m, 2H), 1.44 (s, 9H). [a]2D0 þ13.8
(c 0.18, CHCl3); CSP-HPLC (Chiralcel OB-H column; 5%

E.T. Choi et al. / Tetrahedron 64 (2008) 1515e1522
1521
2-propanol in hexane; 0.5 mL/min): 98% ee, 11.5 min (R),
13.2 min (S ).
(Chiralcel OJ-H column; 5% 2-propanol in hexane; 0.5 mL/
min): 94% ee, 20.5 min (R), 14.8 min (S ).
4.4. General procedure for the preparation of 22e24
4.3.5. tert-Butyl (R)-3-hydroxy-4-pentenoate (17)
The product was recovered in 31% yield based on 62%
conversion. The analytical data is in accordance with the lit-
erature.8d 1H NMR (CDCl3, 400 MHz) 5.88 (m, 1H), 5.31
(m, 1H), 5.13 (m, 1H), 4.49 (br, 1H), 3.54 (br, 1H), 2.44 (m,
2H), 1.47 (s, 9H); CSP-HPLC; b-hydroxy ester 17 was con-
verted to O-(3,5-dimethoxyphenyl)derivative (Chiralcel OJ-H
column; 5% 2-propanol in hexane; 0.5 mL/min): 97% ee,
11.5 min (R), 12.4 min (S ).
From the reactions of racemic b-hydroxy esters 14, 15, and
16 (10.0 mmol) under the standard asymmetric dehydration
condition described in Section 4.3, enantioenriched 14, 15,
and 16 were obtained with 95% ee (32% yield at 60% conver-
sion), 96% ee (30% yield at 62% conversion), and 96% ee
(30% yield at 63% conversion), respectively. After the addi-
tion of LiAlH4 (1.5 equiv) to enantioenriched b-hydroxy esters
14e16 in THF, the mixture was stirred at rt for 1 h and then
quenched with EtOAc and 10% HCl. Extractive work-up and
flash chromatography gave 1,3-diols in 85e79% yields. To
a stirred solution of a 1,3-diol (1.0 equiv) in benzene was
added imidazole (1.0 equiv), PPh3 (2.0 equiv), and iodine
(2.0 equiv). After stirring for 1 h, saturated sodium thiosulfate
solution and EtOAc were added. The resulting mixture was ex-
tracted with ethyl acetate (3ꢁ5 mL) and the combined extracts
were washed with brine. The solvents were removed under
reduced pressure and the residue purified by flash column
chromatography to give 3-iodo-1-propanols 22e24.
4.3.6. tert-Butyl (3R,4E,6E )-3-hydroxy-4,6-octadienoate(18)
The product was recovered in 35% yield based on 57%
conversion. 1H NMR (CDCl3, 400 MHz) 6.22 (dd, J¼16.1
and 10.4 Hz, 1H), 6.02 (m, 1H), 5.70 (m, 1H), 5.55 (dd,
J¼15.3 and 6.4 Hz, 1H), 4.50 (br, 1H), 3.20 (br, 1H), 2.46
(m, 2H), 1.74 (d, J¼5.9 Hz, 3H), 1.45 (s, 9H); 13C NMR
(CDCl3, 100 MHz) 172.0, 131.4, 131.1, 130.9, 130.5, 81.7,
69.2, 43.0, 28.5, 18.4. HRMS calcd for C12H21O3 (Mþ):
212.1412, found: 212.1405; CSP-HPLC (Chiralcel OJ-H
column; 5% 2-propanol in hexane; 0.5 mL/min): 81% ee,
15.5 min (R), 14.5 min (S ).
4.4.1. (R)-3-Iodo-1-phenyl-1-propanol (22)
A pale yellow oil was obtained in 62% overall yield. The
analytical data is in accordance with the literature.8e 1H
NMR (CDCl3, 400 MHz) 7.38e7.25 (m, 5H), 4.79 (m, 1H),
3.29 (m, 1H), 3.16 (m, 1H), 2.21 (m, 2H), 2.10 (d,
J¼3.4 Hz, 2H).
4.3.7. tert-Butyl (3R,4E )-3-hydroxy-5-phenyl-4-
pentenoate (19)
The product was recovered in 37% yield based on 55%
conversion. The analytical data is in accordance with the liter-
ature.8c 1H NMR (CDCl3, 400 MHz) 7.23 (m, 5H), 6.62 (d,
J¼16.0 Hz, 1H), 6.18 (dd, J¼17.0 and 6.0 Hz, 1H), 4.66 (br,
1H), 3.44 (d, J¼3.8 Hz, 1H), 2.54 (m, 2H), 1.45 (s, 9H).
[a]2D0 þ7.2 (c 0.12, CHCl3); CSP-HPLC (Chiralcel OD col-
umn; 10% 2-propanol in hexane; 0.5 mL/min): 97% ee,
17.4 min (R), 25.9 min (S ).
4.4.2. (R)-3-Iodo-1-(4-methylphenyl)-1-propanol (23)
A pale yellow oil was obtained in 50% overall yield. H
1
NMR (CDCl3, 400 MHz) 7.23 (d, J¼7.9 Hz, 2H), 7.15 (d,
J¼7.9 Hz, 2H), 4.73 (m, 1H), 3.27 (m, 1H), 3.13 (m, 1H),
2.33 (s, 3H), 2.18 (m, 3H); 13C NMR (CDCl3, 100 MHz)
140.9, 138.1, 129.8, 126.2, 74.4, 42.7, 21.6, 3.2. Anal. Calcd
for C10H13IO: C, 43.50; H, 4.75. Found: C, 43.43; H, 4.84.
4.3.8. tert-Butyl (3R,4E )-3-hydroxy-5-(2-methoxyphenyl)-4-
pentenoate (20)
The product was recovered in 38% yield based on 52%
4.4.3. (R)-3-Iodo-1-(4-chlorophenyl)-1-propanol (24)
A pale yellow oil was obtained in 68% overall yield. H
1
1
conversion. H NMR (CDCl3, 400 MHz) 7.40 (d, J¼7.6 Hz,
1H), 7.21 (m, 1H), 6.88 (m, 3H), 6.22 (dd, J¼16.1 and
6.0 Hz, 1H), 4.68 (br, 1H), 3.82 (s, 3H), 3.18 (d, J¼4.0 Hz,
1H), 2.57 (m, 2H), 1.46 (s, 9H); 13C NMR (CDCl3,
100 MHz) 172.1, 157.2, 131.3, 129.2, 127.4, 126.0, 121.0,
111.3, 81.7, 69.9, 55.8, 43.1, 28.5. HRMS calcd for
C16H22O4 (Mþ): 278.1518, found: 278.1518; CSP-HPLC
(Chiralcel OJ-H column; 10% 2-propanol in hexane; 0.5 mL/
min): 95% ee, 21.4 min (R), 17.4 min (S ).
NMR (CDCl3, 400 MHz) 7.35e7.26 (m, 5H), 4.80 (m, 1H),
3.29 (m, 1H), 3.15 (m, 1H), 2.21e2.11 (m, 3H); 13C NMR
(CDCl3, 100 MHz) 142.4, 134.0, 129.2, 127.6, 73.9, 42.6,
2.7. Anal. Calcd for C9H10ClIO: C, 36.45; H, 3.40. Found:
C, 36.49; H, 3.46.
4.5. General procedure for the preparation of 25e29
To a stirred solution of PPh3 (1.5 equiv) and DIAD
(1.5 equiv) in THF at 0 ꢀC was added a solution of 2-bromo-
phenol (2 equiv) and iodopropanols 22e24 (1.0 equiv) in
THF. After stirring for 2 h at 0 ꢀC, the reaction mixture was
concentrated under reduced pressure, and the residue was sub-
jected to flash chromatography to obtain O-phenyl derivatives
in 87e77% yields. For intramolecular cyclization, a solution
of O-phenyl derivatives (1.0 equiv) in THF was added
4.3.9. tert-Butyl (3R,4E )-3-hydroxy-4-methyl-5-phenyl-4-
pentenoate (21)
The product was recovered in 34% yield based on 53%
conversion. The analytical data is in accordance with the liter-
ature.8a 1H NMR (CDCl3, 400 MHz) 7.24 (m, 5H), 6.59 (s,
1H), 4.55 (br, 1H), 3.22 (d, J¼3.6 Hz, 1H), 2.58 (d,
J¼6.4 Hz, 2H), 1.88 (s, 3H), 1.47 (s, 9H); CSP-HPLC

1522
E.T. Choi et al. / Tetrahedron 64 (2008) 1515e1522
dropwise to a stirred solution of n-BuLi (2.5 M in hexane,
1 equiv) in THF at 0 ꢀC. After an additional n-BuLi (1 equiv)
was introduced, the reaction mixture was slowly warmed to
room temperature. After stirring at rt for 3 h, the reaction
was quenched by pouring into saturated aqueous ammonium
chloride. The resulting mixture was extracted with methylene
chloride (3ꢁ5 mL) and the combined extracts were washed
with brine. The solvents were removed under reduced pressure
and the residue purified by flash column chromatography to
give flavane derivatives 25e29.
4.5.5. (S )-6-Chloro-3,4-dihydro-2-(4-chlorophenyl)-2H-1-
benzopyran (29)
A pale yellow oil was obtained in 46% overall yield. The
analytical data is in accordance with the literature.7a 1H
NMR (CDCl3, 400 MHz) 7.37e7.28 (m, 4H), 7.07 (m, 2H),
6.80 (d, J¼8.4 Hz, 1H), 4.97 (dd, J¼10.1 and 1.8 Hz, 1H),
2.88 (m, 1H), 2.72 (m, 1H), 2.15 (m, 1H), 1.97 (m, 1H).
[a]2D0 ꢂ7.8 (c 0.16, CHCl3); CSP-HPLC (Chiralcel OJ-H
column; 10% 2-propanol in hexane; 0.5 mL/min): 96% ee,
22.4 min (S ), 14.2 min (R).
Acknowledgements
4.5.1. (S )-3,4-Dihydro-2-phenyl-2H-1-benzopyran (25)
A white solid was obtained in 57% overall yield. The ana-
lytical data is in accordance with the literature.7a 1H NMR
(CDCl3, 400 MHz) 7.43e7.31 (m, 5H), 7.12 (m, 2H), 6.90
(m, 2H), 5.06 (dd, J¼10.1 and 2.4 Hz, 1H), 2.98 (m, 1H),
2.80 (m, 1H), 2.20 (m, 1H), 2.10 (m, 1H). [a]2D0 ꢂ10.6 (c
0.06, CHCl3); CSP-HPLC (Chiralcel OJ-H column; 10%
2-propanol in hexane; 0.5 mL/min): 94% ee, 23.4 min (S ),
17.3 min (R).
This work was supported by a grant from Korea Research
Foundation (KRF-2006-005-J03402).
References and notes
1. (a) Robinson, D. E. J. E.; Bull, S. D. Tetrahedron: Asymmetry 2003, 14,
1407; (b) Keith, J. M.; Larrow, J. F.; Jacobson, E. N. Adv. Synth. Catal.
2001, 343, 5.
2. (a) For leading references on catalytic oxidation, see: Chen, T.; Jiang, J.-J.;
Xu, Q.; Shi, M. Org. Lett. 2007, 9, 865; (b) Mueller, J. A.; Cowell, A.;
Chandler, B. D.; Sigman, M. S. J. Am. Chem. Soc. 2005, 127, 14817; (c)
Trend, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 4482; (d)
Radosevich, A. T.; Musich, C.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 1090; (e) Nishibayashi, Y.; Yamauchi, A.; Onodera, G.; Uemura, S.
J. Org. Chem. 2005, 46, 2239; (f) Masutani, K.; Uchida, T.; Irie, R.;
Katsuki, T. Tetrahedron Lett. 2003, 68, 5875.
4.5.2. (S )-3,4-Dihydro-2-(4-methylphenyl)-2H-1-
benzopyran (26)
A pale yellow oil was obtained in 48% overall yield. The
analytical data is in accordance with the literature.8f 1H
NMR (CDCl3, 400 MHz) 7.31 (d, J¼8.0 Hz, 2H), 7.23e7.06
(m, 4H), 6.91e6.83 (m, 2H), 5.02 (dd, J¼10.0 and 2.0 Hz,
1H), 2.97 (m, 1H), 2.80 (m, 1H), 2.35 (s, 3H), 2.18 (m, 1H),
2.10 (m, 1H); CSP-HPLC (Chiralcel OJ-H column; 10%
2-propanol in hexane; 0.5 mL/min): 92% ee, 26.8 min (S ),
18.3 min (R).
3. Catalytic acylation: (a) Mazet, C.; Roseblade, S.; Kohler, V.; Pfaltz, A. Org.
¨
Lett. 2006, 8, 1879; (b) Yamada, S.; Misono, T.; Iwai, Y. Tetrahedron Lett.
2005, 46, 2239; (c) Suzuki, Y.; Yamauchi, K.; Muramatsu, K.; Sato, M.
Chem. Commun. 2004, 2770; (d) Vedejs, E.; Daugulis, O. J. Am. Chem.
Soc. 2003, 125, 4166; (e) Tao, B.; Ruble, J. C.; Hoic, D. A.; Fu, G. C.
J. Am. Chem. Soc. 1999, 121, 5091; (f) Miller, S. J.; Copeland, G. T.;
Papaioannou, N.; Horstmann, T. E.; Ruel, E. M. J. Am. Chem. Soc. 1998,
120, 1629.
4.5.3. (S )-6-Methyl-3,4-dihydro-2-phenyl-2H-1-
benzopyran (27)
4. Kim, Y.; Choi, E. T.; Lee, M. H.; Park, Y. S. Tetrahedron Lett. 2007, 48,
2833.
A pale yellow oil was obtained in 45% overall yield. The
analytical data is in accordance with the literature.7a 1H
NMR (CDCl3, 400 MHz) 7.43e7.31 (m, 5H), 6.93e6.80 (m,
3H), 5.02 (dd, J¼10.0 and 2.3 Hz, 1H), 2.95 (m, 1H), 2.76
(m, 1H), 2.27 (s, 3H), 2.18 (m, 1H), 2.09 (m, 1H); CSP-
HPLC (Chiralcel OJ-H column; 10% 2-propanol in hexane;
0.5 mL/min): 90% ee, 23.9 min (S ), 17.1 min (R).
5. The selectivity factor (s) was estimated using the equation, s¼kS/kR¼
ln[(1ꢂC)(1ꢂee)]/ln[(1ꢂC)(1þee)], where ee is the enantiomeric excess of
unconverted b-hydroxy ester and the conversion (C ) determined by 1H
NMR of reaction mixture using internal standard.
6. (a) Shin, E.-k.; Kim, H. J.; Kim, Y.; Kim, Y.; Park, Y. S. Tetrahedron Lett.
2006, 47, 1933; (b) Shin, E.-k.; Chang, J.-y.; Kim, H. J.; Kim, Y.; Park,
Y. S. Bull. Korean Chem. Soc. 2006, 27, 447; (c) Chang, J.-y.; Shin,
E.-k.; Kim, H. J.; Kim, Y.; Park, Y. S. Tetrahedron 2005, 61, 2743; (d)
Nam, J.; Chang, J.-y.; Shin, E.-k.; Kim, H. J.; Kim, Y.; Jang, S.; Park,
Y. S. Tetrahedron 2004, 60, 6311; (e) Nam, J.; Chang, J.-y.; Hahm,
K.-S.; Park, Y. S. Tetrahedron Lett. 2003, 44, 7727.
4.5.4. (S )-6-Chloro-3,4-dihydro-2-phenyl-2H-1-
benzopyran (28)
7. (a) Hodgetts, K. J. Tetrahedron 2005, 61, 6860; (b) Hodgetts, K. J. Tetra-
hedron Lett. 2000, 41, 8655.
A white solid was obtained in 52% overall yield. The ana-
lytical data is in accordance with the literature.7a 1H NMR
(CDCl3, 400 MHz) 7.40e7.26 (m, 5H), 7.08e6.82 (m, 3H),
5.04 (dd, J¼10.0 and 2.4 Hz, 1H), 2.92 (m, 1H), 2.75 (m,
1H), 2.20 (m, 1H), 2.08 (m, 1H); CSP-HPLC (Chiralcel
OJ-H column; 5% 2-propanol in hexane; 0.5 mL/min): 93%
ee, 33.9 min (S ), 18.3 min (R).
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Soc. 2005, 127, 3774; (b) Uccello-Barretta, G.; Pini, D.; Mastantuono, A.;
´
Salvadori, P. Tetrahedron: Asymmetry 1995, 6, 1965; (c) Andres, J. M.;
´
Martin, Y.; Pedrosa, R.; Perez-Encabo, A. Tetrahedron 1997, 53, 3787;
(d) Bauer, M.; Maier, M. E. Org. Lett. 2002, 4, 2205; (e) Robertson,
D. W.; Krushinski, J. H.; Fuller, R. W.; Leander, J. D. J. Med. Chem.
´
´
1988, 31, 1412; (f) Delgado, J.; Espinos, A.; Jimenez, M. C.; Miranda,
M. A.; Tormos, R. Tetrahedron 1997, 53, 681.