Diastereomeric aziridine carbinol catalyzed enantioselective arylation reaction: Toward the asymmetric synthesis of both enantiomers of chiral 3-aryl phthalide

Article abstract of DOI:10.1021/jo500796w

The diastereomeric aziridine carbinols are applied, respectively, as efficient chiral ligand in the catalysis of asymmetric arylation and sequential arylation-lactonization cascade. The two diastereomers, which are facilely synthesized from the same chiral source, function as pseudo enantiomers in arylation of aromatic aldehydes providing the different enantiomers of the diarylmethanols with almost the same excellent enantioselectivities. The arylation method is also carried out in tandem with lactonization process to afford a concise synthetic approach to both enantiomers of optically active 3-aryl phthalide.

Full text of DOI:10.1021/jo500796w

Article
pubs.acs.org/joc
Diastereomeric Aziridine Carbinol Catalyzed Enantioselective
Arylation Reaction: Toward the Asymmetric Synthesis of Both
Enantiomers of Chiral 3‑Aryl Phthalide
Xixi Song, Yuan-Zhao Hua, Jing-Guo Shi, Ping-Ping Sun, Min-Can Wang,* and Junbiao Chang*
The College of Chemistry and Molecular Engineering, Zhengzhou University, No. 75 Daxue Road, Zhengzhou, Henan Province
450052, P. R. China
S
* Supporting Information
ABSTRACT: The diastereomeric aziridine carbinols are applied,
respectively, as efficient chiral ligand in the catalysis of asymmetric
arylation and sequential arylation-lactonization cascade. The two
diastereomers, which are facilely synthesized from the same chiral
source, function as pseudo enantiomers in arylation of aromatic
aldehydes providing the different enantiomers of the diary-
lmethanols with almost the same excellent enantioselectivities.
The arylation method is also carried out in tandem with
lactonization process to afford a concise synthetic approach to
both enantiomers of optically active 3-aryl phthalide.
ligand (e.g., 1a in eq 2, Scheme 1), just by interchanging the
aryl groups of arylboronic acid and aldehyde (Ar1 and Ar2 in eq
2, Scheme 1). However, the aryl moiety bearing strong
electronic withdrawing group, such as ester or amide, is not
suitable for swapping, because of the insufficient nucleophil-
icity. Additionally, the applicability of the strategy in
complicated synthetic process, such as a tandem sequence, is
also limited by the requirement of two different sets of
reactants.
Recently in our research group, a pair of diastereomeric
aziridine carbinols (Scheme 2, 3a and 3b) was facilely
synthesized in two steps from the same starting materials,
with (S)-α-methylbenzyl amine 2 as the only chiral source.6
The two ligands share the same chiral N-(S)-phenylethyl
moiety, but bear the β-amino alcohol backbones of the opposite
absolute configurations. Each diastereomer catalyzed asym-
metric alkylation of various aldehydes, and afforded opposite
enantiomers of alkylation products in almost identical excellent
enantioselectivities. To broaden the applicability of the pseudo
enantiomeric ligand pair, we directly apply them in the
asymmetric arylation of aromatic aldehyde by using the
boron to zinc transmetalation protocol, and each enantiomer
of diarylmethanol is produced from the same set of reactants
(Scheme 2, eq 1).
INTRODUCTION
■
The catalytic enantioselective addition of arylzinc species to
aromatic aldehydes in the presence of chiral ligand is one of the
powerful asymmetric arylation methods, which produces
biologically and pharmacologically valuable diarylmethanols.1
As early as in 2002, Bolm and co-workers introduced an
important arylation protocol for the catalyzed synthesis of
optically active diarylmethanols with excellent enantioselectiv-
ities.2 The reactive arylalkylzinc species, which was the real
arylating agent, was generated from arylboronic acid and
dialkylzinc reagent via the boron to zinc transmetalation. Since
various commercially available and readily prepared arylboronic
acids could be used as aryl source, the scope of transferable aryl
groups has been extensively broadened. Following the early
pioneering work, the arylation protocol is well studied, and
many efficient chiral ligands have been developed.3 However,
compared to the intensive practical application of the protocol,
the strategy for asymmetric synthesis of each enantiomer of the
arylation product has not been fully developed.4
Traditionally, in order to prepare each enantiomer of
diarylmethanol, all two enantiomers of a chiral ligand are
usually required for asymmetric catalysis (Scheme 1, eq 1). One
enantiomer (e.g., 1a in eq 1, Scheme 1) can often be
synthesized from natural chiral sources, such as L-amino
acids, which are available in only one absolute configuration,
but the other enantiomer (e.g., 1b in eq 1, Scheme 1) may be
not equally accessible. To overcome the limitation, a strategy
based on the swapping of aryl groups has been developed
(Scheme 1, eq 2).1,5 Each enantiomer of diarylmethanol can be
selectively accessed by using the same enantiomer of chiral
In another aspect, the 3-functionalized phthalides are widely
distributed in a large population of natural products, and
possess broad physiological and biological activities, which
Received: April 8, 2014
© XXXX American Chemical Society
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Scheme 1. Previous Strategies for the Construction of Both Enantiomers of Diarylmethanol
Scheme 2. Access to Each Enantiomer of Diarylmethanol and Its Derivative by Using Diastereomeric Aziridine Carbinol as
Chiral Ligand
render them important structural motifs for natural product
syntheses and pharmaceutical elaborations.7 Although various
catalytic strategies have been developed for the asymmetric
synthesis of chiral phthalides, most of these methods require
expensive transition-metals as well as laboriously accessible
chiral ligands, some of them do not give satisfactory
stereoselectivity, and neither of them could facilely construct
each enantiomer of the chiral framework.8 In this context,
considering the readily availability of cheap organozinc
reagents, arylboronic acids and our diastereomeric aziridine
carbinol ligands, we develop the asymmetric tandem approach
to construct each enantiomer of chiral 3-aryl phthalide by using
the Bolm’s arylation protocol (Scheme 2, eq 2).
framework, few studies have focused on the behavior of
different diastereomeric β-amino alcohols in the asymmetric
arylation.5b,i
Recently, the two diastereomeric triphenylprolinols (Figure
1, 5a and 5b) were synthesized by Correia and Ludtke and co-
̈
Figure 1. Examples of β-amino alcohol ligands for asymmetric
arylation.
RESULTS AND DISCUSSION
■
workers, and were used as effective chiral ligands in the
asymmetric arylation of aldehydes.5b Because the diarylprolinol
ligand 4 and the two diastereomeric analogues (Figure 1, 5a
and 5b), respectively, afforded chiral diarylmethanol product in
the same absolute configuration and comparable enantiose-
lectivity, it is assumed that the chiral center outside the β-amino
alcohol backbone does not provide decisive contribution to
stereoselective induction. Besides the five-membered frame-
Consideration of Diastereomeric Ligands. During the
development of suitable chiral ligands for the Bolm’s
asymmetric arylation, it is found that most of the effective
ligands share the bidentate backbone with two different
heteroatoms as donors, and the successful catalytic results
have been acquired predominantly by using β-amino alcohol as
chiral backbone.5a,b Despite efforts in developing novel ligand
B
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work, aziridine-2-methanol analogues (Figure 1, 6 and 7) were
also examined in the Bolm’s arylation reaction by Braga and
Wessjohann and co-workers.5i However, compared to ligand 6,
which gave excellent enantioselectivity, the ligand 7 with an
extra methyl substituent on the aziridine ring produced a poor
stereoselectivity of 17% ee.
diarylmethanol was afforded in 78% yield without sacrifice of
stereoselectivity (Table 1, entry 3). Further lowering the
temperature to −20 °C decreased the reaction yield to 27%
(Table 1, entry 4). Additionally, when the catalyst loading was
decreased to 5 mol %, the yield was brought down to 50%
(Table 1, entry 5). The increase of catalyst loading to 20 mol %
could significantly boost the reaction yield to 83% and the
enantioselectivity to 80% ee (Table 1, entry 6). To our delight,
when the organozinc reagent was changed from diethylzinc to
dimethylzinc, the enantiomeric excess increased to 96% (Table
1, entry 7). With dimethylzinc as the selected reagent, reaction
temperature and catalyst loading were screened again (data not
shown in Table 1), and the optimal conditions remained the
same as of diethylzinc.
Scope of Asymmetric Arylation Reaction. Encouraged
by the results obtained in the template reaction, substrate scope
was further expanded to test the generality of the method
(Table 2). Under the optimal reaction conditions, when
another diastereomer 3b was used as chiral ligand, the (R)-
phenyl(m-tolyl)methanol 11a-R, which is the opposite
enantiomer of 11a-S, was afforded in 72% yield and 98% ee
(Table 2, entry 2). It was found that the arylation reactions of
various aromatic aldehydes were complete after 2 days with
good to high yields (72−96%) and moderate to excellent
enantioselectivities (80−98% ee), irrespective of the position
and electronic nature of the substituents on the phenyl ring
(Table 2). Meanwhile, various substituted arylboronic acids
were also well-tolerated in the catalytic system (Table 2, entries
11−18).
On the basis of these examples, we speculated that an extra
chiral center outside the enantiopure aziridine ring might not
interfere with stereoselective induction in asymmetric catalysis.
As for the diastereomeric aziridine carbinols (Scheme 2, 3a and
3b), the N-(S)-phenylethyl moiety originated from the chiral
source (S)-α-methylbenzyl amine 2 and served as a chiral
auxiliary during the preparation of diastereomers.6 In this
context, we proposed that the N-(S)-phenylethyl moiety should
simply function as a steric hindrance group, and make little
decisive contribution to the stereoselective induction in the
catalysis of asymmetric arylation reaction. As a result, the
diastereomers (3a and 3b in Scheme 2) would behave as
pseudo enantiomers (such as 1a and 1b in Scheme 1).
Optimization of Reaction Conditions. Initially, the
optimization of reaction conditions was carried out, and one
diastereomer of aziridine carbinols was directly used in the
template reaction (Table 1). On the basis of the boron to zinc
Table 1. Optimization of Reaction Conditions of the
Catalytic Asymmetric Arylation of 3-Methylbenzaldehyde
a
In most of these cases, each enantiomer of a chiral
diarylmethanol was produced in similar good yield and almost
identical excellent enantioselectivity of more than 90% ee. Each
diastereomeric aziridine carbinol ligand demonstrated almost
the same ability in enantioselective induction. On the basis of
our previous conformational analysis of the ligands, we
proposed that the ligand 3a should control the addition of
arylmethylzinc species to the Si-face of the prochiral aromatic
aldehydes, and the ligand 3b should control the addition to the
Re-face.6
Design of Cascade Process. Considering that the
organozinc reagents possess the appropriate balance between
nucleophilicity and basicity, and the high functional-group
tolerance, we envision that the diastereomeric aziridine carbinol
catalyzed arylation can be carried out in conjunction with
lactonization to stereoselectively produce each enantiomer of
chiral 3-aryl phthalide (Scheme 3). The bifunctional substrate,
methyl 2-formylbenzoate 12, was chosen for the sequential
processes. As shown in the proposed mechanism, the reactive
arylalkylzinc species is in situ generated by using the boron to
zinc transmetalation. After the enantioselective aryl transfer to
the electronic deficient aldehyde 12, the resulting diary-
lmethoxy alkyl zinc intermediate 13 would proceed with
intramolecular cyclization to generate 3-aryl phthalide 14. The
similar strategies based on addition−lactonization cascade have
been reported by using different catalytic systems.8b,c
Comparing with those works, our method would provide a
more practical approach from the following aspects: (i) the use
of a cheap transition metal, (ii) a broad range of transferable
aryl group, and (iii) the accessibility to each enantiomer of
chiral 3-aryl phthalide product.
b
entry
R
3a (mol %)
temp. (°C)
yield (%)
ee (%)
c
1
Et
Et
Et
Et
Et
Et
Me
10
10
10
10
5
20
20
0
22
26
78
27
50
83
76
43
48
49
51
66
80
96
2
3
4
5
6
7
−20
0
20
20
0
0
a
Reaction conditions: The mixture of phenylboronic acid 8a (0.5
mmol) and dialkylzinc (2.4 mmol) was heated at 60 °C for 12 h, and
substrate 10a (0.25 mmol) together with chiral ligand 3a (mol %
relative to 10a) were added to the reaction mixture and stirred for 2
b
days at designated temperature. The ee value was determined by
HPLC using Chiralcel OD column, and the absolute configuration of
11a-S was assigned as S by correlation to literature data.9 The 3-fold
c
excess of dialkylzinc (1.5 mmol) comparing with 8a was used.
transmetalation protocol, phenylboronic acid 8a was treated
with diethylzinc in toluene at 60 °C. After the phenylalkylzinc
species 9a was prepared, the chiral ligand 3a and 3-
methylbenzaldehyde 10a were added into the reaction mixture.
When the arylation process was carried out at 20 °C, the (S)-
phenyl(m-tolyl)methanol 11a-S was obtained as desired
product in only 22% yield and 43% ee (Table 1, entry 1). In
Bolm’s classical protocol, the 3-fold excess of dialkylzinc
reagent comparing with arylboronic acid was usually used.2,3,5
After optimization, it was found that the increase of the usage
of diethylzinc to nearly 5-fold excess would give improved
results in both yield and enantioselectivity (Table 1, entry 2). If
the reaction temperature was decreased to 0 °C, the
Scope of Asymmetric Arylation−Lactonization Cas-
cade. On the basis of the above proposition, the methyl 2-
formylbenzoate 12 was directly applied into the well-developed
C
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Table 2. Catalytic Asymmetric Arylation of Aromatic Aldehydes with Arylboronic Acid by Using Diastereomeric Aziridine
a
Carbinol as Chiral Ligand
b
c
entry
R1
R2
ligand
11
yield (%)
ee (%)
configuration
1
H
H
H
H
H
H
H
H
H
H
3-Me
3-Me
2-Me
2-Me
4-MeO
4-MeO
2-Br
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
11a-S
11a-R
11b-S
11b-R
11c-S
11c-R
11d-S
11d-R
11e-S
11e-R
11f-S
76
72
79
86
84
78
87
90
88
90
94
96
90
95
84
83
89
94
96
98
80
96
96
98
97
97
96
96
96
97
94
96
97
98
97
89
S
2
R
S
3
4
R
S
5
6
R
S
7
8
2-Br
R
S
9
4-Cl
10
11
12
13
14
15
16
17
18
4-Cl
R
S
4-Me
4-Cl
4-Me
4-Cl
11f-R
11g-R
11g-S
11c-R
11c-S
11h-S
11h-R
R
R
S
4-Me
2-MeO
2-MeO
H
4-Me
4-MeO
4-MeO
4-MeO
4-MeO
R
S
H
4-Cl
S
4-Cl
R
a
Reaction conditions: The mixture of arylboronic acid 8 (0.5 mmol) and dimethylzinc (2.4 mmol) was heated at 60 °C for 12 h, and substrate 10
(0.25 mmol) together with chiral ligand 3a or 3b (mol % relative to 10) were added to the reaction mixture and stirred for 2 days at 0 °C.
b
c
Determined by chiral HPLC. The absolute configuration of 11 was assigned by correlation to literature data.5,9,10
Scheme 3. Proposed Reaction Mechanism for the Asymmetric Arylation−Lactonization Cascade
arylation conditions without further optimization, and each
enantiomer of chiral 3-aryl phthalide 14 was efficiently
produced in enantiomerically enriched form (Table 3). Various
substituted arylboronic acids were inspected in the cascade
process to broaden the substrate scope. Good yields were
obtained, and enantioselectivities of opposite enantiomers were
nearly identical in most cases (Table 3, entries 1 vs 2, 3 vs 4,
etc.).
The pattern of enantioselectivities implied a strong electronic
dependency. The phenylboronic acid (Table 3, entries 11 and
12) and substituted arylboronic acids bearing electronic
donating groups (Table 3, entries 1−10) gave moderate to
excellent enantioselectivities ranging from 77% to 97% ee. And
the arylboronic acids bearing weak electronic withdrawing
groups (Table 3, entries 13−18) provided poor to mediocre
enantioselectivities from 7% to 56% ee. Comparing with the
strong electronic effect, the steric hindrance effect was weak. As
for the same substituent, such as methyl, methoxyl, or chlorine,
on arylboronic acid, different substituted positions gave similar
enantioselective outcomes (Table 3, entries 1, 3 and 5, etc.).
CONCLUSION
■
In summary, we reported the application of the diastereomeric
aziridine carbinol in the catalytic asymmetric arylation reaction
and the sequential arylation−lactonization cascade. The two
diastereomeric ligands, which were facilely synthesized from the
same chiral source, functioned as pseudo enantiomers in the
asymmetric arylation of aromatic aldehydes, and each
enantiomer of chiral diarylmethanol product was furnished in
almost identical excellent enantioselectivity. The diastereomer
catalyzed arylation method was directly applied to the
arylation−lactonization process to develop a concise synthetic
approach to both enantiomers of optically active 3-aryl
phthalides. The usefulness of the diastereomeric aziridine
carbinol ligands in asymmetric catalysis was broadened.
EXPERIMENTAL SECTION
■
General Methods. NMR spectra (1H and 13C) were performed on
a commercial spectrometer (400 MHz for H and 100 MHz for 13C)
1
using solution in CDCl3 (referenced internally to Me4Si); J values are
given in Hz; the 13C NMR was proton-decoupled carbon NMR
(13C{1H} NMR). TLC was performed on dry silica gel plates
developed with petroleum ether (60−90 °C) and ethyl acetate
(EtOAc). The diastereomeric aziridine carbinol ligands (3a and 3b)6
D
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144.1, 144.0, 138.4, 128.7, 128.6, 127.7, 127.4, 126.7, 123.8, 76.5, 21.7
ppm.
Table 3. Catalytic Asymmetric Synthesis of Both
Enantiomers of 3-Aryl Phthalides by Using Diastereomeric
a
(S)-Phenyl(o-tolyl)methanol (11b-S). Purified by column
chromatography (petroleum ether/EtOAc = 9:1) to give the product
in 79% yield (39.2 mg) and 80% ee. HPLC (Chiralcel OD, hexane/i-
PrOH = 100/2, flow rate = 0.5 mL/min, λ = 216 nm): tR(S) = 69.1
Aziridine Carbinols
1
min, tR(R) = 63.8 min. H NMR (400 MHz, CDCl3): δ = 7.50−7.48
(m, 2H), 7.34−7.28 (m, 4H), 7.26−7.17 (m, 3H), 7.12 (d, J = 7.2 Hz,
1H), 5.96 (s, 1H), 2.31 (br, 1H), 2.22 (s, 3H) ppm. 13C NMR (100
MHz, CDCl3): δ = 143.0, 141.6, 135.6, 130.7, 128.7, 127.8, 127.7,
127.3, 126.5, 126.3, 73.6, 19.6 ppm.
b
c
(S)-(4-Methoxyphenyl)(phenyl)methanol (11c-S). Purified by
column chromatography (petroleum ether/EtOAc = 9:1) to give the
product in 84% yield (45.0 mg) and 96% ee. HPLC (Chiralcel AD,
hexane/i-PrOH = 100/2, flow rate = 0.5 mL/min, λ = 216 nm): tR(S)
entry
R
ligand
14
yield (%) ee (%)
configuration
1
4-Me
4-Me
3-Me
3-Me
2-Me
2-Me
4-MeO
4-MeO
3-MeO
3-MeO
H
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
14a-S
14a-R
14b-S
14b-R
14c-S
14c-R
14d-S
14d-R
14e-S
14e-R
14f-S
93
96
88
93
93
95
93
80
85
98
94
92
85
87
85
79
75
69
96
93
91
84
94
92
86
77
89
84
97
91
44
7
S
2
R
S
1
3
= 102.7 min, tR(R) = 94.3 min. H NMR (400 MHz, CDCl3): δ =
4
R
S
7.35−7.28 (m, 4H), 7.25−7.22 (m, 3H), 6.83 (d, J = 8.7 Hz, 2H), 5.74
(s, 1H), 3.75 (s, 1H), 2.42 (br, 1H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.2, 144.2, 136.4, 128.6, 128.1, 127.5, 126.6, 114.0,
75.9, 55.4 ppm.
5
6
R
S
7
(S)-(2-Bromophenyl)(phenyl)methanol (11d-S). Purified by
column chromatography (petroleum ether/EtOAc = 9:1) to give the
product in 87% yield (57.2 mg) and 97% ee. HPLC (Chiralcel OD,
hexane/i-PrOH = 98/2, flow rate = 1.0 mL/min, λ = 216 nm): tR(S) =
45.6 min, tR(R) = 29.4 min. 1H NMR (400 MHz, CDCl3): δ = 7.56−
7.50 (m, 2H), 7.38−7.22 (m, 6H), 7.24−7.09 (m, 1H), 6.14 (s, 1H),
2.58 (br, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 142.7, 142.3,
133.0, 129.3, 128.6, 127.9, 127.8, 127.2, 123.0, 74.9 ppm.
8
R
S
9
10
11
12
13
14
15
16
17
18
R
S
H
14f-R
14g-S
14g-R
14h-S
14h-R
14i-R
14i-S
R
S
4-Cl
4-Cl
R
S
3-Cl
33
56
21
14
(S)-(4-Chlorophenyl)(phenyl)methanol (11e-S). Purified by
column chromatography (petroleum ether/EtOAc = 9:1) to give the
product in 88% yield (48.1 mg) and 96% ee. HPLC (Chiralcel OB,
hexane/i-PrOH = 90/10, flow rate =1.0 mL/min, λ = 216 nm): tR(S)
3-Cl
R
R
S
2-Cl
2-Cl
1
a
= 21.6 min, tR(R) = 14.5 min. H NMR (400 MHz, CDCl3): δ =
Reaction conditions: The mixture of arylboronic acid 8 (0.5 mmol)
7.32−7.29 (m, 4H), 7.27−7.26 (m, 5H), 5.74 (s, 1H), 2.50 (br, 1H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 143.6, 142.4, 133.4, 128.8,
128.7, 128.1, 128.0, 126.7, 75.7 ppm.
and dimethylzinc (2.4 mmol) was heated at 60 °C for 12 h, and
substrate 12 (0.25 mmol) together with chiral ligand 3a or 3b (mol %
relative to 12) were added to the reaction mixture and stirred for 2
days at 0 °C. Determined by chiral HPLC. The absolute
configuration of 14 was assigned by correlation to literature data
and considering the similarity in the stereochemical reaction
pathway.8,11
b
c
(S)-(4-Chlorophenyl)(p-tolyl)methanol (11f-S). Purified by
column chromatography (petroleum ether/EtOAc = 9:1) to give the
product in 94% yield (54.7 mg) and 96% ee. HPLC (Chiralcel OD-H,
hexane/i-PrOH = 98/2, flow rate = 0.5 mL/min, λ = 216 nm): tR(S) =
72.6 min, tR(R) = 65.4 min. 1H NMR (400 MHz, CDCl3): δ = 7.28−
7.27 (m, 4H), 7.20−7.11 (m, 4H), 5.72 (s, 1H), 2.37 (br, 1H), 2.32 (s,
3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 142.6, 140.8, 137.8,
133.3, 129.5, 128.7, 128.0, 126.7, 75.6, 21.3 ppm.
(R)-(2-Methoxyphenyl)(p-tolyl)methanol (11g-R). Purified by
column chromatography (petroleum ether/EtOAc = 9:1) to give the
product in 90% yield (51.4 mg) and 94% ee. HPLC (Chiralcel OD-H,
hexane/i-PrOH = 98/2, flow rate = 1.0 mL/min, λ = 216 nm): tR(S) =
41.6 min, tR(R) = 37.6 min. 1H NMR (400 MHz, CDCl3): δ = 7.27−
7.22 (m, 4H), 7.11 (d, J = 8 Hz, 2H), 6.95−6.86 (m, 2H), 6.02 (s,
1H), 3.79 (s, 3H), 2.32 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 156.8, 140.4, 136.8, 132.1, 128.7, 127.8, 126.6, 120.9, 110.8, 72.1,
55.5, 21.2 ppm.
and the substrate 12 were synthesized according to reported
procedures. All other reagents were commercially available and used
as received.
General Procedure for the Asymmetric Syntheses of Chiral
Diarylmethanols 11 and 3-Aryl Phthalides 14. The mixture of 0.5
mmol arylboronic acid 8 and 2.4 mmol dimethylzinc (1.2 M in
hexane) was stirred in 1.5 mL of anhydrous toluene at 60 °C for 12 h.
After the reaction vessel was cooled to room temperature of 25 °C, 20
mol % chiral ligand 3a or 3b was added, and the reaction mixture was
stirred at room temperature for 15 min. After the mixture was cooled
to 0 °C, 0.25 mmol benzaldehyde substrate 10 or 12 was added into
the reaction flask. After stirring for 2 days at 0 °C, the reaction mixture
was quenched by 10 mL of saturated NH4Cl aqueous solution and was
extracted with 20 mL of diethyl ether three times. The combined
organic phase was washed by brine, and was dried with anhydrous
Na2SO4. The solvent was evaporated, and the crude residue was
purified by column chromatography (petroleum ether/EtOAc).
Absolute configurations of products 11 and 14 were assigned by
correlation to literature data and considering the similarity in the
stereochemical reaction pathway.5,8−12
(S)-(4-Chlorophenyl)(4-methoxyphenyl)methanol (11h-S).
Purified by column chromatography (petroleum ether/EtOAc = 9:1)
to give the product in 89% yield (55.3 mg) and 97% ee. HPLC
(Chiralcel OD, hexane/i-PrOH = 100/2, flow rate = 0.5 mL/min, λ =
1
216 nm): tR(S) = 94.1 min, tR(R) = 103.9 min. H NMR (400 MHz,
CDCl3): δ = 7.26−7.20 (m, 6H), 6.82 (d, J = 8.5 Hz, 2H), 5.74 (s,
1H), 3.75 (s, 3H), 2.11 (br, 1H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 159.3, 142.4, 135.8, 133.1, 128.5, 127.9, 127.8, 114.0, 75.2, 55.3
ppm.
(S)-3-p-Tolylisobenzofuran-1(3H)-one (14a-S). Purified by
column chromatography (petroleum ether/EtOAc = 4:1) to give the
product in 93% yield (52.1 mg) and 96% ee. HPLC (Chiralcel OD,
hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm): tR(S)
= 5.82 min, tR(R) = 6.92 min. 1H NMR (400 MHz, CDCl3): δ = 7.93
(d, J = 7.5 Hz, 1H), 7.64−7.51 (m, 2H), 7.31 (d, J = 7.5 Hz, 1H),
7.18−7.12 (m, 4H), 6.36 (s, 1H), 2.33 (s, 3H) ppm. 13C NMR (100
(S)-Phenyl(m-tolyl)methanol (11a-S). Purified by column
chromatography (petroleum ether/EtOAc = 9:1) to give the product
in 76% yield (37.3 mg) and 96% ee. HPLC (Chiralcel OD, hexane/i-
PrOH = 100/2, flow rate = 1.0 mL/min, λ = 216 nm): tR(S) = 22.0
1
min, tR(R) = 32.6 min. H NMR (400 MHz, CDCl3): δ = 7.38−7.30
(m, 4H), 7.27−7.14 (m, 4H), 7.07 (d, J = 7.3 Hz, 1H), 5.78 (s, 1H),
2.32 (s, 3H), 2.27 (br, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ =
E
dx.doi.org/10.1021/jo500796w | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
MHz, CDCl3): δ = 170.7, 149.9, 139.4, 134.4, 133.5, 129.7, 129.4,
127.1, 125.7, 125.6, 123.0, 82.8, 21.3 ppm.
δ = 170.7, 149.7, 134.8, 134.7, 133.1, 130.4, 130.3, 129.7, 127.8, 127.7,
126.0, 125.6, 123.1, 79.3 ppm.
(S)-3-m-Tolylisobenzofuran-1(3H)-one (14b-S). Purified by
column chromatography (petroleum ether/EtOAc = 4:1) to give the
product in 88% yield (49.3 mg) and 93% ee. HPLC (Chiralcel OD,
hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm): tR(S)
ASSOCIATED CONTENT
■
S
* Supporting Information
1
The H and 13C NMR spectra of diastereomeric aziridine
1
= 5.82 min, tR(R) = 7.8 min. H NMR (400 MHz, CDCl3): δ = 7.95
carbinols 3a and 3b, diarylmethanols 11, methyl 2-formylben-
zoate 12, and 3-aryl phthalides 14; chiral HPLC spectra of
chiral diarylmethanols 11, and chiral 3-aryl phthalides 14. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(d, J = 7.5 Hz, 1H), 7.66−7.52 (m, 2H), 7.32 (d, J = 7.5 Hz, 1H),
7.28−7.16 (m, 2H), 7.08−7.06 (m, 2H), 6.36 (s, 1H), 2.32 (s, 3H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 170.8, 150.0, 139.0, 136.5,
134.5, 130.2, 129.4, 129.0, 127.6, 125.7, 124.2, 123.0, 83.0, 21.5 ppm.
(S)-3-o-Tolylisobenzofuran-1(3H)-one (14c-S). Purified by
column chromatography (petroleum ether/EtOAc = 4:1) to give the
product in 93% yield (52.1 mg) and 94% ee. HPLC (Chiralcel OD,
hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm): tR(S)
= 7.03 min, tR(R) = 9.01 min. 1H NMR (400 MHz, CDCl3): δ = 7.96
(d, J = 7.5 Hz, 1H), 7.68−7.54 (m, 2H), 7.34−7.10 (m, 4H), 6.90 (d, J
= 7.5 Hz, 1H), 6.67 (s, 1H), 2.48 (s, 3H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.6, 149.3, 137.1, 134.2, 134.1, 131.1, 129.3, 129.0,
127.2, 126.4, 125.6, 123.0, 80.5, 19.3 ppm.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: wangmincan@zzu.edu.cn.
*E-mail: changjunbiao@zzu.edu.cn.
■
Notes
The authors declare no competing financial interest.
(S)-3-(4-Methoxyphenyl)isobenzofuran-1(3H)-one (14d-S).
Purified by column chromatography (petroleum ether/EtOAc = 4:1)
to give the product in 93% yield (55.9 mg) and 86% ee. HPLC
(Chiralcel OD, hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ =
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (NSFC: 81330075, 21272216
and 21302173) and the China Postdoctoral Science Founda-
tion (2013M541984). We express our gratitude to Professor
Wei Wang (University of New Mexico), Professor Gregory
Cook (North Dakota State University) and Dr. Narayanaga-
nesh Balasubramanian (North Dakota State University) for
editing and giving comments on this manuscript.
1
254 nm): tR(S) = 9.31 min, tR(R) = 11.37 min. H NMR (400 MHz,
CDCl3): δ = 7.96 (d, J = 7.5 Hz, 1H), 7.67−7.53 (m, 2H), 7.31 (d, J =
7.5 Hz, 1H), 7.32−6.88 (m, 4H), 6.37 (s, 1H), 3.80 (s, 3H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.7, 160.6, 150.0, 134.4, 129.5, 129.0,
128.5, 126.1, 125.8, 123.1, 114.6, 82.9, 55.5 ppm.
(S)-3-(3-Methoxyphenyl)isobenzofuran-1(3H)-one (14e-S).
Purified by column chromatography (petroleum ether/EtOAc = 4:1)
to give the product in 85% yield (51.1 mg) and 89% ee. HPLC
(Chiralcel OD, hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ =
REFERENCES
1
■
254 nm): tR(S) = 8.73 min, tR(R) = 13.20 min. H NMR (400 MHz,
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127.1, 126.0, 125.5, 125.2, 123.0, 81.8 ppm.
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dx.doi.org/10.1021/jo500796w | J. Org. Chem. XXXX, XXX, XXX−XXX