Isosterically designed chiral catalysts: Rationale, optimization and their application in enantioselective nucleophilic addition to aldehydes

Article abstract of DOI:10.1016/j.tet.2020.131648

Proline-based N,N′-dioxide ligands were designed on the basis of isosteric approach, and were successfully applied in enantioselective nucleophilic addition to aldehydes. In the presence of 10 mol% of chiral ligand 1b, enantioselective addition of diethylzinc to aldehydes provided the corresponding secondary alcohols in up to 90% isolated yield and up to 99% ee. Similarly, using 3e as chiral ligand, enantioselective arylation and alkynylation of aldehydes also proceeded readily, leading to the desired chiral alcohols in up to 92% isolated yield at 99% ee and 80% isolated yields and up to 84% ee, respectively. The current work would shed light on expanding the structure diversity in the design of chiral ligands and chiral catalysts.

Full text of DOI:10.1016/j.tet.2020.131648

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Isosterically designed chiral catalysts: Rationale, optimization and
their application in enantioselective nucleophilic addition to
aldehydes
a
a
a
a
a, b, *
En Gao , Qiao Li , Lili Duan , Lin Li , Yue-Ming Li
a
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University,
Tianjin, People’s Republic of China
b
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032,
People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
0
Article history:
Received 8 July 2020
Received in revised form
Proline-based N,N -dioxide ligands were designed on the basis of isosteric approach, and were suc-
cessfully applied in enantioselective nucleophilic addition to aldehydes. In the presence of 10 mol% of
chiral ligand 1b, enantioselective addition of diethylzinc to aldehydes provided the corresponding sec-
ondary alcohols in up to 90% isolated yield and up to 99% ee. Similarly, using 3e as chiral ligand,
enantioselective arylation and alkynylation of aldehydes also proceeded readily, leading to the desired
chiral alcohols in up to 92% isolated yield at 99% ee and 80% isolated yields and up to 84% ee, respectively.
The current work would shed light on expanding the structure diversity in the design of chiral ligands
and chiral catalysts.
29 August 2020
Accepted 22 September 2020
Available online xxx
Keywords:
Enantioselective addition
Diethylzinc
©
2020 Elsevier Ltd. All rights reserved.
0
Chiral N,N -dioxide
Aldehyde
Chiral zinc catalyst
1
. Introduction
Our attention has been driven by the successful application of
proline-based chiral ligands in a variety of asymmetric organic
reactions [7], and it is our interest in expanding the structure di-
versity of proline-based chiral ligands using conventional strate-
gies. Herein, we wish to present a detailed strategy for expanding
the structure diversity in the design of chiral ligands, and the
application of these chiral ligands/catalysts in a variety of enan-
tioselective nucleophilic addition reactions.
Asymmetric catalysis has been proven to be the most efficient
method for the preparation of enantiomerically pure chiral com-
pounds, and has played important roles in organic synthesis and
drug synthesis [1]. To this end, significant efforts have been devoted
towards the development of new type of chiral ligands/catalysts
[
2]. Among the variety of chiral catalysts developed, binaphthyl-
based [3] and amino acid-based [4] chiral ligands have drawn
considerable attention due to their excellent performance in
different asymmetric organic reactions. Especially worthy of
mentioning are the chiral catalyst systems derived from proline and
related structures [5] which have been successfully applied in a
good amount of asymmetric transformation reactions varying from
asymmetric hydrogenation, to organocatalytic reactions as well as
different Lewis acid-catalyzed asymmetric organic reactions [6].
2
. Results and discussion
Previous report indicated that isosteric strategy was a viable
method for the design of chiral ligands. This led to the preparation
of different N,N -dioxide ligands 1a-1e which gave up to 83% ee in
Cu(II)-catalyzed asymmetric Henry reactions [8].
0
1a
1b
1c
1d
1e
*
Corresponding author. State Key Laboratory of Medicinal Chemical Biology,
i
College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai
University, Tianjin, People’s Republic of China.
E-mail address: ymli@nankai.edu.cn (Y.-M. Li).
https://doi.org/10.1016/j.tet.2020.131648
0
040-4020/© 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: E. Gao, Q. Li, L. Duan et al., Isosterically designed chiral catalysts: Rationale, optimization and their application in
enantioselective nucleophilic addition to aldehydes, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131648

E. Gao, Q. Li, L. Duan et al.
Tetrahedron xxx (xxxx) xxx
These results compared unfavorably with Feng’s catalyst sys-
tems [9]. A preliminary DFT calculation suggested that central
metal adopted a distorted square pyramidal structure (Fig. 1), and
was highly crowded comparing to the chiral catalyst model pro-
posed by Feng et al. [9c].
The calculation result suggested that in the catalyst system with
1a-1e as the chiral ligands, the presence of counter anion has to be
considered when assessing the performance of the catalysts. Given
that coordination of aldehyde to copper is weaker than that of ac-
etate anion, chirality transfer may not be so efficient due to the
weak coordination of benzaldehyde as compared with the counter
Fig. 1. Calculated model of copper catalyst. Hydrogen atoms were hidden for clarity.
ꢀ
anion AcO . In this regard, it should be a good idea to design a
catalyst without the participation of counter anion, and carefully
designed zinc complex would be quite suitable for this purpose. On
the basis of this assumption, reaction of the chiral ligands 1a-1e
with diethylzinc was proposed to in situ generate the chiral zinc
catalysts (Scheme 1).
Chiral ligand 1c which gave the most promising result in
asymmetric Henry reactions was then chosen for further molecular
modelling study at M062X/SDD level [10]. Reaction of tetradentate
ligands 1 with diethylzinc would produce different species con-
taining either one metal or two metal atoms, and mononuclear
species could also form a dimer as proposed by Noyori [11]. Pre-
liminary calculation at M062X/SDD level suggested that mono-
nuclear species Zn-1b was the preferred structure when 1b was
allowed to react with diethylzinc, and a mixture of mononuclear
Scheme 1. Proposed formation of zinc catalysts.
2 2
species Zn-1c and dinuclear species Et Zn -1c may exist when 1c
was allowed to react with diethylzinc (Fig. 2). The dimer form of the
mono-metal complex was less likely due to the steric hindrance
between two monomer species [10].
The molecular model in Fig. 2 suggested that the structure of
zinc complex differed significantly from that of copper complex,
and showed enough space for benzaldehyde coordination. This
preliminary structure suggested that the catalyst system should be
suitable for further reactions such as enantioselective alkylation of
carbonyl compounds.
Fig. 2. The optimized models of possible Zn-1 species. Hydrogen atoms were hidden
for clarity.
Studies such as enantioselective addition of diethylzinc, diphe-
nylzinc, and alkynylzinc to carbonyl substrates have been well
Table 1
a
Enantioselective addition of diethylzinc to benzaldehyde .
entry
ligand
yield (%)b
ee (%)c
configd
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
trace
65
75
81
85
e
e
R
R
S
S
S
77
67
60
35
65
18
30
20
1g
S
a
All reactions were performed with benzaldehyde (0.25 mmol), Et
Isolated yield.
Determined by chiral HPLC.
2
Zn (0.5 mmol), ligand (10 mol %) in toluene for 12 h.
b
c
d
Absolute configurations were determined by comparison of the HPLC elution order with that of the literature data and the direction of optical rotation [13].
2

E. Gao, Q. Li, L. Duan et al.
Tetrahedron xxx (xxxx) xxx
Table 2
Table 3
a
Optimization of reaction conditions .
Scope and limitation of substrates in the catalytic asymmetric addition of diethylzinc
to aldehydes using 1b as chiral ligand .
a
1
b
1b
2
a
2
entry
solvent
yield (%)b
ee (%)c
configd
1
2
3
4
5
toluene
xylene
benzene
n-hexane
xylene:benzene ¼ 3:1
xylene:benzene ¼ 3:1
xylene:benzene ¼ 3:1
61
50
80
70
80
75
65
85
91
93
89
97
95
95
R
R
R
R
R
R
R
entry Aldehyde
product yield (%)b ee (%)c configc
1
benzaldehyde
2a
2b
2c
2d
2e
2f
86
75
79
80
65
60
59
85
60
74
81
83
90
85
86
84
e
99
94
96
92
99
91
92
88
83
95
90
94
95
96
97
94
e
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
e
e
2
3
4
5
4-methylbenzaldehyde
3-methylbenzaldehyde
2-methylbenzaldehyde
4-methoxybenzaldehyde
3-methoxybenzaldehyde
f
f,g
6
7
f,h
6
a
All reactions were conducted with PhCHO (0.25 mmol), Et
L; 0.5 mmol), and solvent in the presence of 1b (10 mol%) at 0 C for 24 h.
Isolated yields based on PhCHO.
Enantiomeric excesses were determined by chiral HPLC analysis.
Absolute configurations were determined by comparison of the HPLC elution
2
Zn (1 M in toluene,
7
3,4-dimethylbenzaldehyde 2g
ꢁ
5
00
m
8
cinnamaldehyde
2h
2i
2j
2k
2l
b
9
1-naphthaldehyde
c
10
11
12
13
14
15
16
2-naphthaldehyde
d
4-formylbenzonitrile
3-fluorobenzaldehyde
3-chlorobenzaldehyde
2-chlorobenzaldehyde
4-bromobenzaldehyde
2-bromobenzaldehyde
4-nitrobenzaldehyde
order and the direction of optical rotations with that of the literature data.
e
f
ꢁ
The reaction was carried at 20 C.
2m
2n
2o
2p
2q
ꢁ
The reaction was carried out at ꢀ20 C.
g
h
The reaction was carried out at 1 mmol scale.
(
R,R)-1b was used as chiral ligand.
17
a
2
All reactions were conducted with RCHO (0.25 mmol), Et Zn(1 M in toluene, 2
developed [12], and can be used as ideal models for the assessment
of the performance of chiral ligands as well as ideal models for the
evaluation of chiral ligands design strategies. To this end, chiral
ligands 1a-1g were first treated with 2.0 equiv of diethyl zinc to
allow the in situ generation of the chiral catalysts, and benzalde-
hyde was added in an attempt to get the nucleophilic addition
product. The results are summarized in Table 1.
equiv) and xylene and benzene as a solvent (xylene: benzene ¼ 3:1) in the presence
ꢁ
of 1b (10 mol%) at ꢀ20 C for 24 h. Unless otherwise mentioned, the aldehydes were
added to the reaction systems as solutions in corresponding solvent.
b
Isolated yields based on RCHO.
Enantiomeric excesses were determined by chiral HPLC analysis, and absolute
c
configurations were determined by comparison of the HPLC elution order and the
direction of optical rotations with that of the literature data [14].
These results showed that, different degrees of enantiose-
lectivity were obtained when these chiral ligands were used, and
chiral ligand 1b gave the most promising result.
withdrawing substituents on the phenyl group exhibited higher
reactivity than that with electron-donating groups (Table 3, entries
12e16 vs entries 2e7). The chemical yield depended on the elec-
Encouraged by these preliminary results, the reaction condi-
tions were then optimized using 1b as the chiral ligands. The results
are summarized in Table 2. Preliminary results showed that better
results were obtained in less polar solvents such as xylene, toluene
or benzene, and a mixture of xylene and benzene (the ratio of
xylene-to-benzene ¼ 3:1) gave the most promising results when
trophilicity of the carbonyl carbon atom of the substrates. Bulky
substrates such as naphthalenealdehydes could also give the
desired products in acceptable results (2i-2j, 60% and 74% yields,
83% and 95% ee). Reactions of heteroaromatic aldehydes were less
successful, possibly due to the coordination of heteroatoms with
the central metal. The absolute configurations were assigned to be
R based on previous reports [13b,14].
After the successful enantioselective addition of diethylzinc to
different aromatic aldehydes, a closely related reaction, namely,
enantioselective aryl transfer reaction was also studied to extend
the application scope of the catalyst system. This reaction, first
exemplified by Bolm [15], can also be a viable method for the
preparation of substituted benzohydrols.
ꢁ
the reactions were carried out at ꢀ20 C, possibly due to good
solubility of the reactants in such mixture [10]. We reasoned that
polar solvents such as diethyl ether or tetrahydrofuran may exist
competitive interaction with central metal of the active catalyst,
thus diminishing the interaction of the substrate with the catalyst,
and finally weakening the chirality transfer of the reaction. This
condition was also suitable for scale-up, and similar result was
observed when the reaction was carried out at 1 mmol scale
Chiral ligands 1a-1g, which showed high potential in
(
Table 2, entry 6). Further, similar level of stereoselectivity was
observed when the enantiomer of 1b was used as the chiral ligand
under otherwise identical conditions (Table 2, entry 7).
After establishing the reaction conditions, the scope and limi-
tation of the substrates were investigated using 1b as the chiral
ligand. The results are summarized in Table 3. As shown in Table 3,
excellent yields and ee values were obtained when 1b was used as
the chiral ligand regardless of the electronic nature of the alde-
hydes. Benzaldehydes bearing various substituents on the phenyl
2
group reacted smoothly with Et Zn and produced the addition
products 2a-2q in 59e90% yields, with up to 99% ee except for 4-
nitrobenzaldehyde. When 4-nitrobenzaldehyde was used, the
products were very complex that the expected product was un-
detectable (Table 3, entry 17). The substrates with electron-
2
Fig. 3. Computed structures of Zn -3e. Hydrogen atoms were hidden for clarity.
3

E. Gao, Q. Li, L. Duan et al.
Tetrahedron xxx (xxxx) xxx
Table 4
a
Optimization of conditions of phenyl transfer reactions .
To get structural insights of the chiral catalysts, the structures of
the zinc complexes were studied using computation methods with
chiral ligand 3e as a model. Different species containing either one
metal or two metal atoms may form during the reaction of tetra-
dentate ligand 3e with diethylzinc. Preliminary calculation at
M062X/SDD level suggested that dinuclear catalyst Et
favored over the mononuclear one. Further, under the phenyl
transfer conditions, the diphenyl dinuclear structures Ph Zn -3e
was favored over the diethyl dinuclear structure Et Zn -3e [10].
The computer model suggested that in Ph Zn -3e, one Zn atom
possessed a distorted pyramidal structure, and another Zn atom
possessed a three-coordinate planar structure (Fig. 3). The latter
zinc atom would provide enough space for the orientation of the
aldehydes.
2 2
Zn -3e was
yield (%)b
ee (%)c
configd
2
2
entry
ligand
2
2
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
5
e
e
R
S
S
S
R
R
R
2
2
60
61
45
73
20
35
36
12
47
67
88
5
3g
3h
5.2
23
Encouraged by the computation results, enantioselective addi-
tion of phenyl group to 4-chlorobenzaldehyde was studied at room
temperature in toluene using 10 mol% of 3a-3h as the chiral ligands.
a
The mol ratio of PhB(OH)
2
:Et
m
2
Zn:aldehyde ¼ 1:3:1. All reactions were per-
ꢁ
formed with benzaldehyde (125
2 h.
mol), ligand (10 mol %), in toluene at 20 C for
Comparing with Ph
easy to handle, rendering this compound an ideal surrogate for
Ph Zn in several phenyl transfer reactions. Therefore, phenyl
2
Zn, phenylboronic acid is easy to access and is
1
b
Isolated yield.
Determined by chiral HPLC.
c
2
d
Absolute configuration assigned by comparison with known elution order from
Chiralcel columns and the direction of optical rotations according to the literature
16].
transfer reactions were carried out using phenylboronic acid as the
phenyl source. The preliminary results are shown in Table 4. As
these results showed, all compounds except 3a were able to pro-
mote the phenyl transfer reactions, and the products were obtained
with some extent of enantiomeric excesses. Compound 3a was
unable to promote the reaction, possibly due to its unfavorable
steric feature.
[
enantioselective addition of diethylzinc to aldehydes, were first
tested in aryl transfer reactions. However, preliminary results
showed that the performance of the catalyst system was not
satisfactory. We reasoned that a big nucleophile such as phenyl
would have different steric demand during the chirality transfer
process. After carefully examining the structure model, our atten-
tion turned to the tetradentate ligands 3a-3h which were the
The enantioselectivity could be increased when gradually
increasing the steric hindrance of the ligands (Table 4, entries 3a-
3e), and proline-based ligands generally gave better results than
homoproline-based ligands. In particular, 3e gave the most prom-
ising result, and further optimization of the reaction conditions was
focused on 3e-involved reactions.
0
precursors of the N,N -dioxide ligands 1.
3
3
3
3
3
3
3
a
b
c
d
e
f
i
3
h
g
Table 5
Phenyl transfer to 4-chlorobenzaldehyde catalyzed by Zn-3e .
a
3e
4n
ꢁ
yield (%)b
ee (%)c
configd
Entry
3e (mol%)
solvent
temp ( C)
1
2
3
4
5
10
10
10
10
10
5
xylene
benzene
n-hexane
3:1
3:1
3:1
0
10
0
74
85
72
90
89
79
92
90
92
91
95
95
S
S
S
S
S
S
e
0
e
ꢀ20
e
6
ꢀ20
a
The mol ratio of PhB(OH)
2
:Et
2
Zn:aldehyde ¼ 1:3:1. All reactions were performed with benzaldehyde (125
mmol), ligand (10 mol%), in solvent for 24 h.
b
c
Isolated yields.
Enantiomeric excesses were determined by chiral HPLC analysis.
Absolute configurations were determined by comparison of the HPLC elution order and the direction of optical rotations with that of the literature data.
Ratio of xylene and benzene.
d
e
4

E. Gao, Q. Li, L. Duan et al.
Tetrahedron xxx (xxxx) xxx
Table 6
Table 8
a
a
Asymmetric arylation of aldehydes catalyzed by Zn-3e .
Enantioselective addition of alkynylzinc to benzaldehyde catalyzed by Zn-3e .
3e
3e
4
5a
yield (%)b
ee (%)c
configd
entry aldehyde
product yield (%)b ee (%)c configd
entry
3e (mol%)
solvent
ꢁ
temp ( C)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
4-methylbenzaldehyde
4a
4b
4c
4d
4e
4f
4g
4h
4i
79
76
80
65
75
85
87
70
60
85
81
50
55
89
92
88
45
55
98
97
97
98
95
99
94
86
98
98
96
95
93
95
97
96
96
99
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
R
R
1
2
3
4
5
6
10
10
10
10
10
10
10
xylene
benzene
n-hexane
dioxane
3:1
ꢀ10
20
41
61
60
73
55
51
75
78
58
44
4
70
80
80
R
R
R
R
R
R
R
3-methylbenzaldehyde
2-methylbenzaldehyde
4-methoxybenzaldehyde
3-methoxybenzaldehyde
2-methoxybenzaldehyde
3,4-dimethylbenzaldehyde
cinnamaldehyde
4-isopropylbenzaldehyde
4-phenylbenzaldehyde
4-trifluotomethylbenzaldehyde 4k
ꢀ10
20
e
ꢀ10
ꢀ20
ꢀ20
e
3:1
3:1
e,f
7
a
The mol ratio of phenylacetylene: Et
2
Zn: benzaldehyde ¼ 2:2:1. All reactions
mol), ligand (10 mol %), in solvent for
were performed with benzaldehyde (125
2 h.
m
0
1
2
3
4
5
6
7
8
4j
1
b
Isolated yields.
1-naphthaldehyde
2-naphthaldehyde
4l
c
Determined by HPLC using a Chiralcel OD-H column. The product chromato-
4m
4n
4o
4p
4q
4r
grams were compared with the corresponding racemate.
4-chlorobenzaldehyde
4-bromobenzaldehyde
2-bromobenzaldehyde
2-furanphenaldehyde
2-thiophenaldehyde
d
Absolute configuration assigned by the direction of optical rotations and known
elution order from a Chiralcel OD-H column according to the literature.
e
Ratio of xylene and benzene ¼ 3:1.
f
Reaction time ¼ 24 h.
a
The mol ratio of PhB(OH)
2
:Et
2
Zn:aldehyde ¼ 1:3:1. All reactions were per-
mol), ligand (10 mol%), in solvent for 24 h.
formed with aromatic aldehyde (125
m
most promising results. Temperature also showed some impact on
b
Isolated yields.
c
the reaction, and the reaction temperature was finally fixed
Determined by HPLC using Chiralcel columns. In all cases, the product chro-
matograms were compared with the corresponding racemates.
ꢁ
at ꢀ20 C (Table 5, entry 4 vs entry 5). The amount of chiral ligand
d
Absolute configurations were assigned by comparison with known elution or-
was also important. Both the yield and enantioselectivity were
influenced by catalyst loading, and the most suitable catalyst
loading was found to be 10 mol% (Table 5, entry 5 vs entry 6) [10].
After the optimization of reaction conditions, the scope of al-
dehydes was studied using 3e as the chiral ligand. The results are
summarized in Table 6. As showed in Table 6, the corresponding
products were obtained in up to 99% ee. 2-Furanaldehyde and 2-
thiophenaldehyde exhibited low reactivity under the optimal re-
action conditions possibly due to a competitive side catalytic cycle
involving the heteroatoms (Table 6, entry 17 and 18) [18]. Reaction
of cinnamaldehyde gave product with moderate ee (86% ee). The
electronic properties or steric hindrance of the substituents on the
aromatic ring showed less effect on the enantioselectivity of the
reactions. The substrates bearing electron-withdrawing sub-
stituents at the 4-position of the aromatic groups exhibited higher
reactivity than those with electron-donating groups (Table 6, en-
tries 11, 14, 15 vs entries 1 and 9). Reactions of 1- or 2-
naphthalenealdehyde also gave satisfactory results (95% ee and
der and the direction of optical rotations from chiral columns according to the
literatures.
Table 7
a
Enantioselective addition of alkynyl group to aromatic aldehydes .
5
yield (%)b
ee (%)c
configd
entry
ligand
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
trace
trace
63%
65%
59%
trace
11
e
e
e
e
R
R
e
e
0
45
55
e
9
3% ee, Table 6, entries 12 and 13). Such results also compared
favorably with reactions induced by similar simple amino alcohols
19].
Finally, enantioselective addition of alkynyl group to aldehydes
3g
3h
14
8.8
R
R
23
[
a
The mol ratio of phenylacetylene: Et
2
Zn: benzaldehyde ¼ 2:2:1. All reactions
mol), ligand (10 mol %), in toluene
were performed with benzaldehyde (125
m
ꢁ
at ꢀ10 C for 12 h.
were also studied to further expand the application scope of the
chiral ligands [20]. The alkynylzinc reagent was formed in situ via
deprotonation of phenylacetylene with dialkylzinc at room tem-
perature [21]. Again, chiral ligand 3e gave the most promising re-
sults. In the presence of catalytic amounts of chiral ligand 3e
b
Isolated yield.
Determined by chiral HPLC.
Absolute configuration assigned by comparing the elution order from Chiralcel
c
d
OD-H column with known compounds reported in the literature [16].
(10 mol%), enantioselective addition of alkynylzinc to benzaldehyde
Next, asymmetric phenylation of 4-chlorobenzaldehyde was
studied in details using 3e as the chiral ligand and phenylboronic
acid as the phenyl resource. Representative results are given in
Table 5 [10,17].
Similar to enantioselective addition of diethylzinc to aldehydes,
less polar solvents such as xylene, benzene, or n-hexane gave the
most promising results (Table 5, entries 1e3), and a mixture of
xylene and benzene (the ratio of xylene-to-benzene ¼ 3:1) gave the
afforded the corresponding propargylic alcohol in good yield with
ꢁ
55% ee at ꢀ10 C (Table 7, entry 5).
Further optimization of the reaction conditions suggested that a
mixture of xylene and benzene was the preferred media for the
reactions. The reaction gave highest ee when the reaction was
carried out in a mixture of xylene and benzene (the ratio of xylene-
ꢁ
to-benzene ¼ 3:1) for 24 h at ꢀ20 C with 10 mol% of chiral ligand
representative results 3e (Table 8) [10].
5

E. Gao, Q. Li, L. Duan et al.
Tetrahedron xxx (xxxx) xxx
Table 9
a
Enantioselective addition of alkynylzinc to aldehydes catalyzed by Zn-3e .
3e
5
entry
Aldehydes
product
yield (%)b
ee (%)c
configd
1
2
3
4
5
6
7
8
9
Benzaldehyde
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
75
62
55
56
54
65
54
67
63
55
59
67
64
66
80
60
81
78
76
84
76
75
73
74
71
70
72
76
73
71
75
51
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
4-methylbenzaldehyde
3-methylbenzaldehyde
2-methylbenzaldehyde
4-methoxybenzaldehyde
2-methoxybenzaldehyde
3,4-dimethylbenzaldehyde
4-isopropylbenzaldehyde
4-trifluoromethylbenzaldehyde
1-naphthaldehyde
10
11
12
13
14
15
16
2-naphthaldehyde
4-fluorobenzaldehyde
4-chlorobenzaldehyde
4-bromobenzaldehyde
2-bromobenzaldehyde
2-furanphenaldehyde
a
b
c
The mole ratio of phenylacetylene: Et
Isolated yields.
Determined by HPLC using a Chiralcel OD-H column. In all cases, the product chromatograms were compared against a known racemic mixture.
Absolute configuration assigned by the direction of optical rotations and elution order from a Chiralcel OD-H column according to the literature [22].
2
Zn: benzaldehyde was 2:2:1. All reactions were performed with benzaldehyde (125 mmol), ligand (10 mol%), in solvent for 24 h.
d
Fig. 4. Plausible transition state for the enantioselective addition of diethylzinc to
aldehydes using 1b as chiral ligand.
On the basis of the literature reports and the preliminary
computation model, a tentative transition state was proposed to
account for the enantioselective formation of the products (Fig. 4).
Taking chiral ligand 1b as an example, the orientation of the
benzaldehyde and the diethylzinc was governed by the chiral
ligand, and approaching of the ethyl group from Re-face was
favored, leading to (R)-1-phenyl propan-1-ol as the predominant
product.
Different aldehydes were also tested to examine the scope of the
reactions. The results are shown in Table 9. In general, the reaction
gave satisfactory yields and good enantiomeric excesses for most
aromatic aldehydes (Table 9, entries 1e16). Substrate 2-
methylbenzaldehyde bearing an ortho-substituent gave higher ee
(
84% ee, Table 9, entry 4) than aldehydes bearing meta- or para-
substituents did, possibly due to better steric feature of the ortho
substituent in the substrate. Even with the bulky aldehydes such as
1
- or 2-naphthalenealdehyde, the reactivity and enantioselectivity
were still maintained (70% ee and 72% ee, Table 9 entries 10 and 11).
Enantioselective addition of Et Zn to aldehydes using 1,2-amino
2
alcohols as chiral ligands was extensively studied by Noyori et al.,
and a 5/4/4 tricyclic transition state would well explain the process
of chirality transfer [11,23]. In the current reaction system, pre-
liminary DFT calculation suggested that a mononuclear species Zn-
1
b was favored over the dinuclear one when 1b was used as chiral
ligand, and the formation of Zn-1b dimer was less likely due to the
steric hindrance.
Fig. 5. A plausible transition-state for 3e-involved enantioselective arylation and
alkynylation reactions.
6

E. Gao, Q. Li, L. Duan et al.
Tetrahedron xxx (xxxx) xxx
For enantioselective aryl transfer reactions and alkynylation
2.46e2.37 (m, 2H), 1.97e1.92 (m, 2H), 1.88e1.83 (m, 4H), 1.74e1.66
(m, 4H), 1.59e1.53 (m, 2H), 1.32 (s, 6H), 1.29 (s, 6H). C NMR
13
reactions in which 3e was involved, dinuclear species R
2
Zn
2
-3e
were favored (R ¼ Ph or PhC≡C-) [10]. A plausible transition state
for 3e-involved enantioselective arylation and alkynylation of al-
dehydes from the Si-face could be proposed based on the pre-
liminary computer model of the catalyst (Fig. 5).
(101 MHz, Chloroform-d)
d
82.2, 72.9, 67.2, 54.6, 34.4, 26.6, 25.7,
ꢀ1
23.5, 23.2, 15.2. IR (KBr):
HRMS (ESI, M þ H ) calcd. for C19
y
¼ 3465, 2982, 1674, 1549, 725, 695 cm
.
þ
39 2 4
H N O , 359.2910; found
359.2910.
Compound 1g was prepared according to the general procedure
and was isolated as brown solid (67% yield) after flash chroma-
3
. Conclusions
ꢁ
20
tography (MeOH/DCM 2% v/v). mp: 162e165 C; [
a
]
D
¼ þ28.0
1
In summary, isosteric approach, which is a general strategy in
(c ¼ 0.1, CHCl
3
); H NMR (400 MHz, Chloroform-d):
d
4.16e4.09 (m,
drug design, can also be extended to the design of chiral ligands.
The structure diversity of the chiral ligands can be expanded in this
manner. Better understanding of the coordination conditions of the
central metals will help to understand the process of chirality
transfer, and to further improve the stereoselectivity of the re-
actions. Under optimized conditions, enantioselective addition of
diethylzinc to aldehydes using isosterically design 1b as the chiral
ligand provided the desired (R)-alcohols in excellent yields and
enantioselectivity (up to 99% ee). Similarly, using 3e as chiral ligand,
phenyl transfer reactions and alkynylation reactions also provided
the desired products in up to 99% ee and 84% ee, respectively. Fine-
tuning the structure of the chiral ligands are in good progress, and
the results will be reported in due time. Thus, the isotereic
approach would be a useful strategy to expand the structure di-
versity of the chiral ligands.
2H), 3.45e3.34 (m, 4H), 2.84e2.77 (m, 4H), 2.53e2.49 (m, 2H),
2.36e2.26 (m, 4H), 1.90e1.79 (m, 4H), 1.61e1.56 (m, 2H), 1.41e1.23
(m, 2H), 1.12e1.08 (m, 2H), 0.73e0.71 (m, 4H), 0.32e0.28 (m, 2H).
13
C NMR (101 MHz, Chloroform-d)
20.1, 17.8, 16.8, 9.8. IR (KBr):
d 75.6, 66.4, 63.9, 56.2, 24.1, 22.8,
y
¼ 3427, 2939, 1649, 1507, 717,
ꢀ1
þ
641 cm . HRMS (ESI, M þ H ) calcd. for C19
35 2
H N O4, 355.2597;
found 355.2599.
4.3. General procedure for the enantioselective addition of
diethylzinc to aldehydes using 1b as chiral ligand
To a solution of 1b (8.25 mg, 25
mmol, 10 mol %) in dry xylene
(1 mL) was added Et
at 0 C via a syringe under argon atmosphere, and the reaction
mixture was stirred for 20 min. A solution of benzaldehyde
2
Zn (0.5 mL, 1 M in toluene, 2 equiv) dropwise
ꢁ
(26.5 mg, 0.25 mmol) in dry benzene (0.5 mL) was added dropwise
4
. Experimental section
to the mixture via a syringe, and the mixture was stirred for
ꢁ
24 h at ꢀ20 C. The reaction was quenched by addition of 1 M HCl
4.1. General
(2 mL), water (10 mL) was added to the mixture, and the aqueous
layer was extracted with EtOAc (10 mL ꢂ 3). The extract was dried
All 1HNMR and 13CNMR (with complete proton decoupling)
2 4
over anhydrous Na SO and concentrated under reduced pressure,
spectra were recorded on a 400 MHz spectrometer. Chemical shifts
and the residue was purified by column chromatography (EtOAc/
petroleum ether 5% v/v) to afford the corresponding secondary
alcohol (2). The ee values of the secondary alcohols were deter-
mined by chiral HPLC analysis analysis [13a,14].
1
of H NMR were given in ppm relative to tetramethylsilane (
d
¼ 0.0)
as an internal standard, and those of C NMR are given relative to
the residual solvent peak ( solution. The coupling
13
d
¼ 77.2) in CDCl
3
constants J are given in hertz (Hz). Mass spectra were recorded
using electrospray ionization mass spectrometry (ESI MS). IR
4.3.1. 1-Phenylpropan-1-ol (2a)
ꢀ
1
spectra are reported in reciprocal centimeters (cm ). Enantiomeric
excesses (ee) were determined by HPLC analysis using the corre-
sponding commercial chiralpak column as stated in the experi-
86% yield, 99% ee (R) (conducted with 1b). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OD-H, 3% IPA in
hexane, 1.0 mL/min, 215 nm UV detector). Retention times:
ꢁ
mental procedures at 35 C. Optical rotations are measured on a
t
[
d
r
a
¼ 10.1 min for (R)-isomer and t
r
¼ 12.0 min for (S)-isomer.
¼ þ40.5 (c ¼ 0.52, DCE). HNMR (400 MHz, Chloroform-d):
7.33e7.08 (m, 5H), 4.57 (t, J ¼ 6.7 Hz, 1H), 2.03 (br s, 1H),
T
20
1
commercial polarimeter and are reported as follows: [
00 mL, solvent). Melting points are reported uncorrected.
a]
D
(c ¼ g/
]
D
1
13
All commercially available substrates were used as received
1.89e1.55 (m, 2H), 0.91 (t, J ¼ 7.4 Hz 3 H). C NMR (101 MHz,
Chloroform-d) 144.6, 128.4, 127.5, 126.0, 76.0, 31.9, 10.2 [13b].
unless noted. Dry n-hexane, xylene, toluene, were prepared by
distillation from sodium grains and stored over sodium wire under
argon atmosphere. Dry dichloromethane (DCM) and 1,2-
d
4.3.2. 1-(4-Methylphenyl)propan-1-ol (2b)
dichloroethane (DCE) were prepared by distillation from CaH
2
75% yield, 94% ee (R) (conducted with 1b). The ee value was
determined by chiral HPLC analysis (CHIRALCEL AD-H, 5% IPA in
hexane, 1.0 mL/min, 215 nm UV detector). Retention times:
and stored over 4 Å MS under argon atmosphere. Dry tetrahydro-
furan (THF) and dioxane were freshly distilled from sodium and
benzophenone as a moisture indicator under argon atmosphere
before use. All liquid aldehydes were freshly distilled under
reduced pressure, and aldehydes were purified by silica gel column
chromatography before use.
t
[
d
r
a
¼ 7.9 min for (R)-isomer and t
r
¼ 8.9 min for (S)-isomer.
¼ þ26.8 (c ¼ 0.52, DCE) H NMR (400 MHz, Chloroform-d)
7.20 (d, J ¼ 7.8 Hz, 2H), 7.14 (d, J ¼ 7.8 Hz, 2H), 4.55 (t,
1
5
1
]
D
J ¼ 6.6 Hz, 1H), 2.34 (s, 3H), 1.89e1.75 (m, 2H), 1.72 (br s, 1H), 0.90 (t,
13
J ¼ 7.4 Hz, 3H). C NMR (101 MHz, Chloroform-d)
d 141.6, 137.2,
4.2. General procedure for the preparation of chiral ligands 1a-1g
129.1, 125.9, 75.9, 31.8, 21.1, 10.2 [14].
Compounds 1a-1e were prepared following known procedures
4.3.3. 1-(3-Methylphenyl)propan-1-ol (2c)
and all the data were consistent with previously reported ones [8].
Compounds 1f and 1g were also prepared via similar protocol [8].
Compound 1f was prepared according to the general procedure
and was isolated as off-white solid (45% yield) after flash chroma-
79% yield, 96% ee (R) (conducted with 1b). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OD-H, 2% IPA in
hexane, 1.0 mL/min, 220 nm UV detector). Retention times:
t
[
d
r
a
¼ 11.0 min for (R)-isomer and t
r
¼ 14.9 min for (S)-isomer.
ꢁ
20
20
1
tography (MeOH/DCM 2% v/v). mp: 173e175 C; [
a
d
]
D
¼ þ25.0
]
D
¼ þ40.5 (c ¼ 0.50, DCE); H NMR (400 MHz, Chloroform-d)
1
(
c ¼ 0.1, CHCl
3
); H NMR (400 MHz, Chloroform-d):
11.17 (s, br.
7.45 (d, J ¼ 7.6 Hz, 1H), 7.27e7.09 (m, 3H), 4.86 (t, J ¼ 6.4 Hz,
2
H), 3.71e3.56 (m, 6H), 3.35e3.31 (m, 2H), 3.11e3.03 (m, 2H),
1H), 2.33 (s, 3H), 1.81 (br s, 1H), 1.74e1.62 (m, 2H), 0.97 (t, J ¼ 7.4 Hz,
7

E. Gao, Q. Li, L. Duan et al.
Tetrahedron xxx (xxxx) xxx
3
H). 13C NMR (101 MHz, Chloroform-d)
d
142.7, 134.6, 130.3, 127.1,
d
8.13e8.10 (m, 1H), 7.88e7.86 (m, 1H), 7.79e7.76 (m, 1H),
1
26.2, 125.2, 72.1, 30.9, 19.1, 10.4 [24].
7.64e7.62 (m, 1H), 7.53e7.45 (m, 3H), 5.40 (dd, J ¼ 7.6, 5.0 Hz, 1H),
13
1
.97 (m, 2H), 1.96 (br s, 1H), 1.03 (t, J ¼ 7.4 Hz, 3H). C NMR
4.3.4. 1-(2-Methylphenyl)propan-1-ol (2d)
(101 MHz, Chloroform-d) 140.2, 133.8, 130.5, 128.9, 127.9, 125.9,
d
8
0% yield, 92% ee (R) (conducted with 1b). The ee value was
125.5, 125.4, 123.2, 122.9, 72.6, 31.1, 10.6 [13b].
determined by chiral HPLC analysis (CHIRALCEL AD-H, 1% IPA in
hexane, 1.0 mL/min, 215 nm UV detector). Retention times:
4.3.10. 1-(Naphthalen-2-yl)propan-1-ol (2j)
t
[
d
r
a
¼ 15.8 min for (R)-isomer and t
r
¼ 19.0 min for (S)-isomer.
74% yield, 95% ee (R) (conducted with 1b). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OD-H, 2% IPA in
hexane, 0.5 mL/min, 215 nm UV detector). Retention times:
1
5
1
]
D
¼ þ43.0 (c ¼ 0.52, DCE); H NMR (400 MHz, Chloroform-d)
7.46 (d, J ¼ 7.8 Hz, 1H), 7.26e7.06 (m, 3H), 4.85 (t, J ¼ 6.8 Hz,
1
3
1
H), 2.33 (s, 3H), 1.82 (br s, 1H), 1.79e1.70 (m, 2H), 0.97 (t, J ¼ 7.4 Hz,
t
[
d
r
a
¼ 63.5 min for (S)-isomer and t
r
¼ 72.9 min for (R)-isomer.
13
20
1
H). C NMR (101 MHz, Chloroform-d)
d
142.8, 134.6, 130.3, 127.1,
]
D
¼ þ27.6 (c ¼ 0.50, DCE); H NMR (400 MHz, Chloroform-d)
26.2, 125.2, 72.0, 30.9, 19.1, 10.4 [14].
7.84e7.77 (m, 4H), 7.48e7.46 (m, 3H), 4.76 (t, J ¼ 6.6 Hz, 1H),
13
2
.01 (br s, 1H), 1.92e1.82 (m, 2H), 0.94 (t, J ¼ 7.4 Hz, 3H). C NMR
4
.3.5. 1-(4-Methoxyphenyl)propan-1-ol (2e)
(101 MHz, Chloroform-d)
d
141.9, 133.3, 133.0, 128.2, 127.9, 127.7,
6
5% yield, 99% ee (R) (conducted with 1b). The ee value was
126.1, 125.8, 124.7, 124.1, 76.1, 31.8, 10.2 [24].
determined by chiral HPLC analysis (CHIRALCEL OD-H, 1% IPA in
hexane, 1.0 mL/min, 215 nm UV detector). Retention times:
4.3.11. 4-(1-Hydroxypropyl)benzonitrile (2k)
t
[
d
r
a
¼ 37.6 min for (R)-isomer and t
r
¼ 44.4 min for (S)-isomer.
¼ þ30.6 (c ¼ 0.52, DCE). H NMR (400 MHz, Chloroform-d)
7.26 (d, J ¼ 8.6 Hz, 2H), 6.88 (d, J ¼ 8.6 Hz, 2H), 4.53 (t,
J ¼ 6.7 Hz,1H), 3.80 (s, 3H), 1.86e1.77 (m, 2H),1.73 (br s, 1H), 0.89 (t,
81% yield, 90% ee (R) (conducted with 1b). The ee value was
determined by chiral HPLC analysis (CHIRALCEL IA, 5% IPA in hex-
ane, 0.4 mL/min, 220 nm UV detector). Retention times:
2
0
1
]
D
t
[
d
r
a
¼ 41.6 min for (R)-isomer and t
r
¼ 46.8 min for (S)-isomer.
¼ þ36.6 (c ¼ 0.50, DCE); H NMR (400 MHz, Chloroform-d)
7.63 (d, J ¼ 8.2 Hz, 2H), 7.46 (d, J ¼ 8.2 Hz, 2H), 4.69 (t,
13
20
1
J ¼ 7.4 Hz, 3H). C NMR (101 MHz, Chloroform-d)
27.2, 113.8, 75.7, 55.3, 31.8, 10.2 [13b].
d
159.0, 136.7,
]
D
1
J ¼ 6.4 Hz, 1H), 2.17 (br s, 1H), 1.83e1.65 (m, 2H), 0.93 (t, J ¼ 7.4 Hz,
13
4
.3.6. 1-(3-Methoxyphenyl)propan-1-ol (2f)
3H). C NMR (101 MHz, Chloroform-d)
111.0, 75.0, 32.1, 9.8 [27].
d 149.9, 132.2, 126.6, 118.9,
6
0% yield, 91% ee (R) (conducted with 1b). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OD-H, 2% IPA in
hexane, 0.5 mL/min, 220 nm UV detector). Retention times:
4.3.12. 1-(3-Fluorophenyl)propan-1-ol (2l)
tr ¼ 51.2 min for (R)-isomer and t
r
¼ 63.1 min for (S)-isomer.
¼ þ29.8 (c ¼ 0.51, DCE); H NMR (400 MHz, Chloroform-d)
7.27e7.23 (m, 1H), 6.92e6.83 (m, 2H), 6.83e6.80 (m, 1H), 4.56
t, J ¼ 6.6 Hz, 1H), 3.81 (s, 3H), 1.98 (br s, 1H), 1.81e1.74 (m, 2H), 0.92
83% yield, 94% ee (R) (conducted with 1b). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OB-H, 1% IPA in
hexane, 0.5 mL/min, 220 nm UV detector). Retention times:
2
0
1
[a]
D
d
(
(
1
t
r
¼ 13.9 min for (S)-isomer and t
r
¼ 16.4 min for (R)-isomer.
¼ þ30.1 (c ¼ 0.51, DCE); H NMR (400 MHz, Chloroform-d)
7.32e7.26 (m, 1H), 7.11e7.05 (m, 2H), 6.98e6.93 (m, 1H), 4.61
13
20
1
t, J ¼ 7.4 Hz, 3H). C NMR (101 MHz, Chloroform-d)
29.4, 118.3, 112.9, 111.4, 75.9, 55.2, 31.8, 10.2 [25].
d
159.7, 146.4,
[
a
]
D
d
(
td, J ¼ 6.6, 2.9 Hz, 1H), 1.94 (br s, 1H), 1.84e1.69 (m, 2H), 0.92 (t,
19
13
4.3.7. 1-(3,4-Dimethylphenyl)propan-1-ol (2g)
J ¼ 7.4 Hz, 3H). F NMR (376 MHz, CDCl
3
)
d
ꢀ113.1. C NMR
5
9% yield, 92% ee (R) (conducted with 1b). The ee value was
(101 MHz, Chloroform-d)
d
163.0 (d, J ¼ 245.7 Hz), 147.3 (d,
determined by chiral HPLC analysis (CHIRALCEL AD-H, 5% IPA in
hexane, 0.5 mL/min, 220 nm UV detector). Retention times:
J ¼ 6.7 Hz), 129.9 (d, J ¼ 8.1 Hz), 121.5 (d, J ¼ 2.9 Hz), 114.3 (d,
J ¼ 21.1 Hz), 112.8 (d, J ¼ 21.6 Hz), 75.3, 31.9, 9.9 [26].
t
[
d
r
a
¼ 18.8 min for (R)-isomer and t
r
¼ 21.3 min for (S)-isomer.
2
0
1
]
D
¼ þ18.0 (c ¼ 0.50, DCE); H NMR (400 MHz, Chloroform-d)
4.3.13. 1-(3-Chlorophenyl)propan-1-ol (2m)
7.25e7.04 (m, 3H), 4.52 (t, J ¼ 6.6 Hz, 1H), 2.26 (s, 3H), 2.25 (s,
90% yield, 95% ee (R) (conducted with 1b). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OB-H, 1% IPA in
hexane, 0.5 mL/min, 220 nm UV detector). Retention times:
1
3
3
H), 1.85 (br s, 1H), 1.83e1.71 (m, 2H), 0.91 (t, J ¼ 7.4 Hz, 3H).
C
NMR (101 MHz, Chloroform-d)
d
142.1, 136.6, 135.8, 129.6, 127.3,
1
23.4, 76.0, 31.8, 19.9, 19.5, 10.3 [26].
t
[
d
r
a
¼ 14.4 min for (S)-isomer and t
r
¼ 17.4 min for (R)-isomer.
2
0
1
]
D
¼ þ25.6 (c ¼ 0.50, DCE); H NMR (400 MHz, Chloroform-d)
4.3.8. (E)-1-Phenylpent-1-en-3-ol (2h)
7.35 (s, 1H), 7.29e7.19 (m, 3H), 4.58 (td, J ¼ 6.5, 3.0 Hz, 1H), 1.92
13
8
5% yield, 88% ee (R) (conducted with 1b). The ee value was
(br s, 1H), 1.83e1.60 (m, 2H), 0.92 (t, J ¼ 7.4 Hz, 3H). C NMR
determined by chiral HPLC analysis (CHIRALCEL AS-H, 1% IPA in
hexane, 0.5 mL/min, 220 nm UV detector). Retention times:
(101 MHz, Chloroform-d)
75.3, 31.9, 10.0 [14].
d 146.7, 134.3, 129.7, 127.6, 126.2, 124.1,
t
[
d
r
a
¼ 23.2 min for (R)-isomer and t
r
¼ 27.5 min for (S)-isomer.
¼ þ7.0 (c ¼ 0.50, DCE); H NMR (400 MHz, Chloroform-d)
7.40e7.37 (m, 2H), 7.33e7.30 (m, 2H), 7.25e7.22 (m, 1H), 6.57
dd, J ¼ 15.9, 1.1 Hz, 1H), 6.22 (dd, J ¼ 15.9, 6.8 Hz, 1H), 4.24e4.19
2
0
1
]
D
4.3.14. 1-(2-Chlorophenyl)propan-1-ol (2n)
85% yield, 96% ee (R) (conducted with 1b). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OB-H, 1% IPA in
hexane, 0.5 mL/min, 220 nm UV detector). Retention times:
(
(
13
m,1H), 1.85 (br s,1H), 1.72e1.60 (m, 2H), 0.97 (t, J ¼ 7.5 Hz, 3H).
C
NMR (101 MHz, Chloroform-d)
d
136.7, 132.3, 130.5, 128.6, 127.6,
t
[
d
r
a
¼ 11.7 min for (S)-isomer and t
r
¼ 14.0 min for (R)-isomer.
¼ ꢀ41.7 (c ¼ 0.51, DCE); H NMR (400 MHz, Chloroform-d)
7.56e7.54 (m, 1H), 7.34e7.25 (m, 2H), 7.22e7.17 (m, 1H), 5.06
2
0
1
126.5, 74.4, 30.2, 9.8 [24].
]
D
4
.3.9. 1-(Naphthalen-1-yl)propan-1-ol (2i)
(dd, J ¼ 8.0, 4.1 Hz, 1H), 2.01 (br s, 1H), 1.85e1.75 (m, 2H), 0.99 (t,
13
6
0% yield, 83% ee (R) (conducted with 1b). The ee value was
J ¼ 7.4 Hz, 3H). C NMR (101 MHz, Chloroform-d)
d 142.0, 132.0,
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
hexane, 1.0 mL/min, 254 nm UV detector). Retention times:
129.4, 128.4, 127.1, 127.0, 72.0, 30.5, 10.1 [14].
t
[
r
a
¼ 7.7 min for (S)-isomer and t
r
¼ 13.4 min for (R)-isomer.
4.3.15. 1-(4-Bromophenyl)propan-1-ol (2o)
2
0
1
]
D
¼ þ44.3 (c ¼ 0.50, DCE); H NMR (400 MHz, Chloroform-d)
86% yield, 97% ee (R) (conducted with 1b). The ee value was
8

E. Gao, Q. Li, L. Duan et al.
Tetrahedron xxx (xxxx) xxx
1
determined by chiral HPLC analysis (CHIRALCEL OB-H, 1% IPA in
hexane, 0.5 mL/min, 220 nm UV detector). Retention times:
(c ¼ 1.0, DCE); H NMR (400 MHz, Chloroform-d)
d 7.58e7.44 (m,
7H), 7.28e7.18 (m, 10H), 7.18e7.07 (m, 3H), 4.69 (s, 2H),3.64 (dd,
t
[
d
r
a
¼ 16.0 min for (S)-isomer and t
r
¼ 18.5 min for (R)-isomer.
¼ þ16.5 (c ¼ 0.51, DCE); H NMR (400 MHz, Chloroform-d)
7.47 (d, J ¼ 8.4 Hz, 2H), 7.22 (d, J ¼ 8.4 Hz, 2H), 4.57 (t,
J ¼ 9.0, 3.5 Hz, 2H), 3.04e2.95 (m, 2H), 2.25e2.15 (m, 2H), 1.88e1.76
2
0
1
13
]
D
(m, 2H), 1.69e1.53 (m, 8H), 1.51e1.41 (m, 2H), 1.12e1.03 (m, 2H).
C
NMR (101 MHz, Chloroform-d)
d 148.1, 146.5, 128.0, 127.9, 126.2,
J ¼ 6.6 Hz, 1H), 1.92 (br s, 1H), 1.83e1.64 (m, 2H), 0.90 (t, J ¼ 7.4 Hz,
126.1, 125.7, 125.5, 77.7, 71.3, 55.3, 54.0, 29.5, 28.0, 24.4. IR (KBr):
13
ꢀ1
þ
3
7
H). C NMR (101 MHz, Chloroform-d)
5.3, 31.9, 10.0 [25].
d
143.5, 131.5, 127.7, 121.2,
y
¼ 3339, 2943, 36, 1492, 746, 637 cm . HRMS (ESI, M þ H ) calcd.
for C37 547.3325 found 547.3325.
43 2 2
H N O
Compound 3f was prepared according to the general procedure
and was isolated as brown oil (75% yield) after flash chromatog-
4
.3.16. 1-(2-Bromophenyl)propan-1-ol (2p)
2
0
1
8
4% yield, 94% ee (R) (conducted with 1b). The ee value was
raphy (MeOH/DCM 2.5% v/v). [
(400 MHz, Chloroform-d):
a
]
D
¼ ꢀ49.8 (c ¼ 1.0, DCE); H NMR
determined by chiral HPLC analysis (CHIRALCEL OB-H, 1% IPA in
hexane, 0.5 mL/min, 220 nm UV detector). Retention times:
d
4.52 (s, 2H), 4.10 (dd, J ¼ 12.3, 3.4 Hz,
2H), 3.33 (dd, J ¼ 12.3,1.9 Hz, 2H), 3.07e3.02 (m, 4H), 2.05e2.02 (m,
1
3
t
r
¼ 12.0 min for (S)-isomer and t
r
¼ 14.1 min for (R)-isomer.
3H), 1.96e1.90 (m, 4H), 1.87e1.56 (m, 11H), 1.31e1.26 (m, 2H).
C
2
0
1
[
a
]
D
¼ þ44.1 (c ¼ 0.50, DCE); H NMR (400 MHz, Chloroform-d)
NMR (101 MHz, Chloroform-d) 64.0, 63.5, 62.6, 52.6, 49.3, 28.7,
d
ꢀ
1
d
7.55e7.50 (m, 2H), 7.35e7.33 (m,1H), 7.14e7.10 (m, 1H), 5.01 (dd,
24.8, 24.3, 22.7. IR (KBr):
y
¼ 3354, 2932, 1738, 1445, 737, 624 cm
.
þ
J ¼ 7.9, 4.6 Hz, 1H), 2.09 (s, 1 H), 1.87e1.83 (m, 1H), 1.74e1.67 (m,
HRMS (ESI, M þ H ) calcd. for C15
31 2 2
H N O , 271.2386, found
13
1
d
H), 1.00 (t, J ¼ 7.4 Hz, 3H). C NMR (101 MHz, Chloroform-d)
271.2385.
143.5, 132.6, 128.7, 127.7, 127.4, 122.1, 74.2, 30.6, 10.1 [25].
Compound 3g was prepared according to the general procedure
and was isolated as brown oil (72% yield) after flash chromatog-
2
0
1
4
.4. General procedure for the preparation of compounds 3a and 3h
raphy (MeOH/DCM 2.5% v/v). [
a
]
D
¼ 83.8 (c ¼ 1.0, DCE); H NMR
(400 MHz, Chloroform-d):
d
4.21 (t, J ¼ 6.1 Hz,1H), 4.15 (t, J ¼ 6.1 Hz,
The method for preparation of 3a and 3h. can be found in our
1H), 3.47 (t, J ¼ 6.5 Hz, 1H), 3.15 (d, J ¼ 12.4 Hz, 2H), 2.66e2.59 (m,
2H), 2.38e2.35 (m, 2H), 2.22e2.15 (m, 1H), 2.07e2.06 (m, 3H),
1.88e1.85 (m, 2H), 1.69 (d, J ¼ 13.1 Hz, 2H), 1.60 (d, J ¼ 11.2 Hz, 2H),
previously report [8].
Compound 3a was prepared according to the general procedure
and was isolated as brown oil (54% yield) after flash chromatog-
13
1.41e1.31 (m, 5H), 1.19 (s, 6H), 1.12 (s, 6H). C NMR (101 MHz,
2
0
1
raphy (MeOH/DCM 2.5% v/v). [
400 MHz, Chloroform-d):
a
]
D
¼ ꢀ27.6 (c ¼ 1.0, DCE); H NMR
Chloroform-d) d 71.8, 68.3, 50.9, 47.6, 30.0, 26.4, 21.4, 20.8, 18.6. IR
ꢀ
1
(
3
2
d
3.65e3.61 (m, 2H), 3.47e3.42 (m, 2H),
(KBr):
M þ H ) calcd. for C19
y
¼ 3368, 2934, 1734, 1466, 779, 699 cm . HRMS (ESI,
þ
.15e3.12 (m, 2H), 3.03e2.96 (m, 2H), 2.64e2.61 (m, 2H),
.43e2.37 (m, 2H), 2.22 (q, J ¼ 8.7 Hz, 2H), 1.87e1.80 (m, 2H),
39 2 2
H N O , 327.3012, found 327.3012.
Compound 3h was prepared according to the general procedure
and was isolated as off-white solid (87% yield) after flash chroma-
13
1
.77e1.66 (m, 6H), 1.62e1.45 (m, 2H). C NMR (101 MHz,
Chloroform-d) 65.9, 64.9, 55.4, 54.6, 27.2, 27.0, 23.8. IR (KBr):
¼ 3386, 2951, 1740, 1457, 750, 606 cm . HRMS (ESI, M þ H )
calcd. for C13 , 243.2073 found 243.2075.
ꢁ
20
d
tography (MeOH/DCM 2.5% v/v). mp: 100e103 C; [
a
]
D
¼ ꢀ12.9
ꢀ
1
þ
1
y
(c ¼ 1.0, DCE); H NMR (400 MHz, Chloroform-d):
d 5.12 (s, 2H),
H N
27 2
O
2
3.67e3.59 (m, 2H), 3.11e3.06 (m, 2H), 1.89e1.86 (m, 2H), 1.82e1.77
(m, 8H), 1.70e1.56 (m, 6H), 1.26e1.17 (m, 4H), 0.90e0.84 (m, 2H),
Compound 3b was prepared according to the general procedure
and was isolated as brown oil (93% yield) after flash chromatog-
13
0.79e0.74 (m, 2H), 0.53e0.49 (m, 2H), 0.27e0.22 (m, 2H). C NMR
2
0
1
raphy (MeOH/DCM 2.5% v/v). [
400 MHz, Chloroform-d):
a
]
D
¼ ꢀ42.0 (c ¼ 0.1, DCE); H NMR
(101 MHz, Chloroform-d)
d
70.2, 55.5, 52.7, 49.5, 28.1, 24.7, 24.6,
ꢀ1
(
d
3.13e2.99 (m, 2H), 2.94e2.80 (m, 2H),
22.0, 19.2, 9.1. IR (KBr):
HRMS (ESI, M þ H ) calcd. for C19
y
¼ 3469, 2932, 1642, 1507, 702, 629 cm
.
þ
2
6
5
.64e2.48 (m, 4H), 2.45e2.35 (m, 2H), 1.86e1.59 (m, 12H), 1.16 (s,
H), 1.11 (s, 6H). 13C NMR (101 MHz, Chloroform-d)
74.1, 72.5, 57.8,
5.2, 28.8, 28.4, 27.3, 25.2, 25.1. IR (KBr):
¼ 3397, 2968, 1668, 1463,
46, 589 cm . HRMS (ESI, M þ H ) calcd. for C17 299.2699,
found 299.2698.
35 2 2
H N O 323.2699, found
d
323.2701.
y
ꢀ
1
þ
7
H
35
N
2
O
2
4.5. General procedure for the enantioselective arylation of
arylaldehydes using 3e as chiral ligand
Compound 3c was prepared according to the general procedure
and was isolated as brown oil (90% yield) after flash chromatog-
A dried Schlenk tube containing xylene (1.0 mL), aryl boronic
2
0
1
raphy (MeOH/DCM 2.5% v/v). [
400 MHz, Chloroform-d):
a
]
D
¼ ꢀ96.4 (c ¼ 1.0, DCE); H NMR
acid (15.2 mg, 125
toluene, 375
m
mol), and diethylzinc (0.25 mL, 1.5 M solution in
ꢁ
(
d
3.06e2.89 (m, 2H), 2.77e2.56 (m, 6H),
mmol) was heated at 60 C for 12 h. After the mixture
2
.53e2.40 (m, 2H), 1.81e1.63 (m, 10H), 1.61e1.40 (m, 7H), 1.40e1.22
was cooled to room temperature, a solution of chiral ligand 3e
13
(
m, 3H), 0.85 (m, 12H). C NMR (101 Hz, Chloroform-d)
d
75.6, 70.6,
(7 mg, 12.5
m
mol, 10 mol %) in benzene (0.5 mL) was added, the
ꢁ
57.5, 54.9, 29.1, 26.8, 26.1, 25.2, 8.0, 7.7. IR (KBr):
y
¼ 3454, 2965,
mixture was cooled to ꢀ20 C, and
a
solution of 4-
ꢀ1
þ
1
C
677, 1460, 767, 620 cm . HRMS (ESI, M þ H ) calcd. for
chlorobenzaldehyde (17.5 mg, 125
m
mol) in xylene (0.5 mL) was
ꢁ
21
H
43
N
2
O
2
, 355.3325, found 355.3324.
added under argon atmosphere. After reacting for 24 h at ꢀ20 C,
the reaction was quenched by the addition of 1 N HCl (2e3 mL). The
mixture was extracted with ethyl acetate (10 mL ꢂ 3). The com-
bined organic layers were washed with brine, dried over anhydrous
Compound 3d was prepared according to the general procedure
and was isolated as brown oil (85% yield) after flash chromatog-
2
0
1
raphy (MeOH/DCM 2.5% v/v). [
400 MHz, Chloroform-d):
a
]
D
¼ ꢀ66.4 (c ¼ 1.0, DCE); H NMR
(
d
3.56 (t, J ¼ 6.2 Hz, 1H), 3.47 (t,
2 4
Na SO and evaporated under reduced pressure, and the residue
J ¼ 7.0 Hz,1H), 3.02e2.85 (m, 5H), 2.68e2.56 (m,1H), 2.53e2.40 (m,
was purified by column chromatography (EtOAc/petroleum ether
5% v/v) to give compound (4). The ee was determined by HPLC
analysis using a chiral column.
3
H), 2.38e2.32 (m, 1H), 2.12e1.87 (m, 5H), 1.80e1.62 (m, 8H),
13
1.15e0.82 (m, 24H). C NMR (101 MHz, Chloroform-d)
d
78.8, 76.5,
6
y
9.9, 68.3, 34.3, 32.4, 27.7, 22.6, 20.2, 18.2, 18.0, 16.8. IR (KBr):
ꢀ
1
þ
¼ 3365, 2963, 1734, 1468, 736, 624 cm . HRMS (ESI, M þ H )
, 411.3951 found 411.3953.
4.5.1. (4-Methylphenyl) (phenyl)methanol (4a)
calcd. for C25
H
51
N
2
O
2
79% yield, 98% ee (S) (conducted with 3e). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OD-H, 2% IPA in
hexane, 1.0 mL/min, 220 nm UV detector). Retention times:
Compound 3e was prepared according to the general procedure
and was isolated as off-white solid (89% yield) after flash chroma-
ꢁ
20
tography (MeOH/DCM 2.5% v/v). mp: 143e147 C; [
a
]
D
¼ ꢀ17.5
t
r
¼ 26.7 min for (S)-isomer and t ¼ 31.3 min for (R)-isomer.
r
9

E. Gao, Q. Li, L. Duan et al.
Tetrahedron xxx (xxxx) xxx
1
5
¼ ꢀ7.7 (c ¼ 0.4, DCE); 1HNMR (400 MHz, Chloroform-d):
20
¼ þ3.1 (c ¼ 0.45, DCE); 1H NMR (400 MHz, Chloroform-d)
[
a
]
D
[a]
D
d
1
d
7.37e7.30 (m, 4H), 7.26e7.24 (m, 3H), 7.16e7.12 (m, 2H), 5.79 (s,
H), 2.32 (s, 3H), 2.25 (s, 1H). C NMR (101 MHz, Chloroform-d)
144.0, 141.0, 137.3, 129.2, 128.5, 127.5, 126.5, 126.4, 76.1, 21.1 [16].
d 7.38e7.36 (m, 2H), 7.34e7.32 (m, 2H), 7.26e7.24 (m, 1H),
7.14e7.08 (m, 3H), 5.77 (s, 1H), 2.24 (s, 1H) 2.23 (s, 6 H). C NMR
(101 MHz, Chloroform-d) 144.0, 141.4, 136.8, 136.0, 129.8, 128.5,
13
13
d
127.8, 127.4, 126.4, 124.0, 76.2, 19.9, 19.5 [30].
4.5.2. (3-Methylphenyl) (phenyl)methanol (4b)
7
6% yield, 97% ee (S) (conducted with 3e). The ee value was
4
.5.8. (E)-1,3-Diphenylprop-2-en-1-ol (4h)
determined by chiral HPLC analysis (CHIRALCEL OB-H, 10% IPA in
hexane, 1.0 mL/min, 220 nm UV detector). Retention times:
70% yield, 86% ee (S) (conducted with 3e). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
hexane, 1.0 mL/min, 220 nm UV detector). Retention times:
t
[
d
1
d
r
a
¼ 13.9 min for (R)-isomer and t
r
¼ 25.1 min for (S)-isomer;
2
0
1
]
D
¼ ꢀ1.5 (c ¼ 0.45, DCE); H NMR (400 MHz, Chloroform-d)
t
r
¼ 13.0 min for (R)-isomer and t ¼ 16.8 min for (S)-isomer;
r
7.38e7.31 (m, 4H), 7.27e7.15 (m, 4H), 7.08e7.06 (m, 1H), 5.79 (s,
H),2.33 (s, 3H), 2.31 (s, 1H). C NMR (101 MHz, Chloroform-d)
143.9, 143.8, 138.2, 128.5, 128.4, 128.3, 127.5, 127.2, 126.5, 123.6,
15
1
[
a
]
D
¼ ꢀ29.0 (c ¼ 0.45, DCE); H NMR (400 MHz, Chloroform-d)
13
d
7.45e7.42 (m, 2H), 7.40e7.35 (m, 4H), 7.32e7.30 (m, 3H),
.25e7.23 (m, 1H), 6.69 (dd, J ¼ 15.8, 1.1 Hz, 1H), 6.38 (dd, J ¼ 15.9,
7
6
7
6.3, 21.5 [13a].
13
.5 Hz, 1H), 5.38 (d, J ¼ 6.5 Hz, 1H), 2.10 (s, 1H). C NMR (101 MHz,
Chloroform-d)
d 142.8, 136.5, 131.5, 130.6, 128.7, 128.6, 127.8, 127.7,
4
.5.3. (2-Methylphenyl) (phenyl)methanol (4c)
126.6, 126.4, 75.2 [26].
8
0% yield, 97% ee (S) (conducted with 3e). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OJ-H, 10% IPA in
hexane, 0.4 mL/min, 210 nm UV detector). Retention times:
4
.5.9. (4-Isopropylphenyl) (phenyl)methanol (4i)
60% yield, 98% ee (S) (conducted with 3e). The ee value was
t
[
d
r
¼ 29.2 min for (R)-isomer and t
r
¼ 31.1 min for (S)-isomer;
¼ þ7.0 (c ¼ 0.46, DCE); H NMR (400 MHz, Chloroform-d)
7.54e7.49 (m, 1H), 7.34e7.29 (m, 4H), 7.28e7.17 (m, 3H),
2
0
1
determined by chiral HPLC analysis (CHIRALCEL OD-H, 5% IPA in
hexane, 1.0 mL/min, 220 nm UV detector). Retention times:
a
]
D
.15e7.10 (m, 1H), 5.98 (s, 1H), 2.23 (s, 3H), 2.22 (s, 1H). 1 C NMR
3
tr ¼ 24.7 min for (S)-isomer and t ¼ 28.0 min for (R)-isomer;
r
7
2
0
1
[
a
]
D
¼ ꢀ56.0 (c ¼ 0.46, DCE). H NMR (400 MHz, Chloroform-d)
(
101 MHz, Chloroform-d) d 142.9, 141.4, 135.4, 130.6, 128.5, 127.6,
d
7.40e7.37 (m, 2H), 7.35e7.29 (m, 3H), 7.27e7.25 (m, 2H),
.20e7.18 (m, 2H), 5.80 (s, 1H), 2.90e2.84 (m, 1H), 2.26 (s, 1 H), 1.23
127.5, 127.1, 126.3, 126.2, 73.4, 19.4 [28].
7
13
(s, 3H), 1.22 (s, 3H). C NMR (101 MHz, Chloroform-d)
d 148.3,
4.5.4. (4-Methoxyphenyl) (phenyl)methanol (4d)
143.9, 141.3, 128.5, 127.5, 126.6, 126.5, 76.2, 33.8, 24.0 [31].
6
5% yield, 98% ee (S) (conducted with 3e). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OD-H, 3% IPA in
hexane, 1.0 mL/min, 215 nm UV detector). Retention times:
0
4
.5.10. [1,1 -Biphenyl]-4-yl(phenyl)methanol (4j)
8
t
[
d
r
a
¼ 99.6 min for (R)-isomer and t
r
¼ 108.6 min for (S)-isomer;
5% yield, 98% ee (S) (conducted with 3e). The ee value was
determined by chiral HPLC analysis (CHIRALCEL AD-H, 2% IPA in
hexane, 1.0 mL/min, 220 nm UV detector). Retention times:
¼ 50.8 min for (S)-isomer and t ¼ 59.0 min for (R)-isomer;
¼ þ6.7 (c ¼ 0.45, DCE); H NMR (400 MHz, Chloroform-d)
7.57e7.55 (m, 4H), 7.45e7.41 (m, 6H), 7.37e7.33 (m, 3H),
.30e7.28 (m, 1H), 5.88 (s, 1H), 2.31 (s, 1H). C NMR (101 MHz,
Chloroform-d)
27.1, 127.0, 126.6, 126.5, 76 [32].1.
2
0
1
]
D
¼ ꢀ16.1 (c ¼ 0.50, DCE); H NMR (400 MHz, Chloroform-d)
7.37e7.30 (m, 4H), 7.28e7.24 (m, 3H), 6.85 (d, J ¼ 8.7 Hz, 2H),
13
5
.78 (s, 1H), 3.77 (s, 3H), 2.27 (s, 1H). C NMR (101 MHz,
159.0, 144.0, 136.2, 128.4, 127.9, 127.4, 126.4, 113.9,
t
r
r
Chloroform-d)
d
20
1
[
a
]
D
7
5.8, 55.3 [16].
d
13
7
4.5.5. (3-Methoxyphenyl) (phenyl)methanol (4e)
d 143.8, 142.8, 140.8, 140.5, 128.8, 128.6, 127.7, 127.3,
7
5% yield, 95% ee (S) (conducted with 3e). The ee value was
1
determined by chiral HPLC analysis (CHIRALCEL IB, 5% IPA in hex-
ane, 0.8 mL/min, 220 nm UV detector). Retention times:
4
.5.11. Phenyl(4-(trifluoromethyl)phenyl)methanol (4k)
81% yield, 96% ee (S) (conducted with 3e). The ee value was
determined by chiral HPLC analysis (CHIRALCEL AD-H, 10% IPA in
hexane, 1.0 mL/min, 220 nm UV detector). Retention times:
t
[
d
r
a
¼ 17.8 min for (S)-isomer and t
r
¼ 23.4 min for (R)-isomer;
¼ þ14.3 (c ¼ 0.50, DCE); H NMR (400 MHz, Chloroform-d)
7.39e7.31 (m, 4H), 7.25e7.24 (m, 2H), 6.96e6.93 (m, 2H),
2
0
1
]
D
13
6
(
.81e6.79 (m, 1H), 5.80 (s, 1H), 3.78 (s, 3H), 2.29 (s, 1H). C NMR
159.7, 145.5, 143.7, 129.5, 128.5, 127.6,
t
r
¼ 6.2 min for (R)-isomer and t
r
¼ 7.2 min for (S)-isomer;
101 MHz, Chloroform-d)
d
2
0
1
[
a
]
D
¼ ꢀ17.6 (c ¼ 0.50, DCE); H NMR (400 MHz, Chloroform-d)
126.5, 118.9, 113.0, 112.1, 76.2, 55.2 [29].
d
7.58 (d, J ¼ 8.2 Hz, 2H), 7.50 (d, J ¼ 8.1 Hz, 2H), 7.36e7.32 (m,
19
4
H), 7.32e7.27 (m, 1H), 5.87 (s, 1H), 2.42 (d, J ¼ 3.3 Hz, 1H)$
F
4.5.6. (2-Methoxyphenyl) (phenyl)methanol (4f)
13
NMR(376 MHz, CDCl
3
)
d
ꢀ62.4. C NMR (101 MHz, Chloroform-d)
8
5% yield, 99% ee (S) (conducted with 3e). The ee value was
d
147.5, 143.1, 129.8 (q, J ¼ 33.2 Hz), 128.8, 128.1, 126.7, 126.6,
determined by chiral HPLC analysis (CHIRALCEL OD-H, 2% IPA in
hexane, 1.0 mL/min, 220 nm UV detector). Retention times:
1
25.4 (q, J ¼ 3.9 Hz), 122.8 (q, J ¼ 271 Hz), 75.8 [33].
t
[
d
r
a
¼ 34.1 min for (S)-isomer and t
r
¼ 47.4 min for (R)-isomer;
¼ ꢀ30.6 (c ¼ 0.52, DCE); H NMR (400 MHz, Chloroform-d)
7.40e7.38 (m, 2H), 7.34e7.30 (m, 2H), 7.25e7.21 (m, 3H),
2
0
1
]
D
4.5.12. Naphthalen-1-yl(phenyl)methanol (4l)
50% yield, 95% ee (S) (conducted with 3e). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
hexane, 1.0 mL/min, 220 nm UV detector). Retention times:
13
6
(
.96e6.88 (m, 2H), 6.05 (s, 1H), 3.81 (s, 3H), 3.07 (s, 1H). C NMR
156.7, 143.2, 131.9, 128.8, 128.2, 127.9,
101 MHz, Chloroform-d)
d
1
27.2, 126.6, 120.8, 110.7, 72.3, 55.4 [16].
t
[
d
r
a
¼ 13.1 min for (S)-isomer and t
r
¼ 28.6 min for (R)-isomer;
2
0
1
]
D
¼ ꢀ40.0 (c ¼ 0.50, DCE); H NMR (400 MHz, Chloroform-d)
4.5.7. (3,4-Dimethylphenyl) (phenyl)methanol (4g)
8.03e8.01 (m, 1H), 7.86e7.84 (m, 1H), 7.81 (d, J ¼ 8.2 Hz, 1H),
8
7% yield, 94% ee (S) (conducted with 3e). The ee value was
7.62 (d, J ¼ 7.1 Hz, 1H), 7.49e7.47 (m, 1H), 7.46e7.42 (m, 4H),
1
3
determined by chiral HPLC analysis (CHIRALCEL OD-H, 2% IPA in
hexane, 1.0 mL/min, 220 nm UV detector). Retention times:
7.33e7.30 (m, 2H), 7.28e7.242 (m, 1H), 6.52 (s, 1H), 2.43 (s, 1H).
NMR (101 MHz, Chloroform-d) 143.1, 138.8, 133.9, 130.7, 128.8,
128.6, 128.5, 127.7, 127.1, 126.2, 125.6, 125.4, 124.6, 124.0, 73.7 [33].
C
d
t
r
¼ 13.7 min for (S)-isomer and t ¼ 18.2 min for (R)-isomer;
r
10

E. Gao, Q. Li, L. Duan et al.
Tetrahedron xxx (xxxx) xxx
4.5.13. Naphthalen-2-yl(phenyl)methanol (4m)
4.6. General procedure for the asymmetric alkynylation of
5
5% yield, 93% ee (S) (conducted with 3e). The ee value was
arylaldehydes using 3e as chiral ligand
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
hexane, 1.0 mL/min, 220 nm UV detector). Retention times:
Diethylzinc (0.17 mL, 1.5 mol/l in toluene, 250 mmol) and phe-
t
[
d
r
a
¼ 14.0 min for (S)-isomer and t
r
¼ 17.1 min for (R)-isomer;
nylacetylene (26 mg, 250 mmol) were added to a dried Schlenk tube
containing xylene (1.5 mL) under argon atmosphere. Chiral ligand
2
0
1
]
D
¼ ꢀ6.0 (c ¼ 0.50, DCE); H NMR (400 MHz, Chloroform-d)
7.89e7.88 (m, 1H), 7.84e7.77 (m, 3H), 7.47e7.46 (m, 2H),
.43e7.41 (m, 3H), 7.34e7.32 (m, 2H), 7.28e7.24 (m, 1H), 5.99 (s,
3e (7 mg, 10 mol%) was added and the resulting mixture was stirred
ꢁ
ꢁ
7
1
1
1
at 0 C for 2 h. After the mixture was cooled to ꢀ20 C, and a so-
H), 2.38 (s, 1H). 13C NMR (101 MHz, Chloroform-d)
d
143.6, 141.1,
33.3, 132.9, 128.6, 128.4, 128.1, 127.7, 126.7, 126.2, 126.0, 125.0,
24.8, 76.4 [16].
lution of aldehyde (13.3 mg, 125 mol) in benzene (0.5 mL) was
m
subsequently added under argon atmosphere. The reaction mixture
ꢁ
was stirred for 24 h at ꢀ20 C. The reaction was quenched by the
addition of 1 N HCl (2e3 mL). The mixture was extracted with ethyl
acetate (3 ꢂ 10 mL). The combined organic layers were washed
4
.5.14. (4-Chlorophenyl) (phenyl)methanol (4n)
8
9% yield, 95% ee (S) (conducted with 3e). The ee value was
2 4
with brine, dried over anhydrous Na SO and evaporated under
determined by chiral HPLC analysis (CHIRALCEL AD-H, 5% IPA in
hexane, 1.0 mL/min, 220 nm UV detector). Retention times:
reduced pressure, and the residue was purified by column chro-
matography (EtOAc/petroleum ether 5% v/v) to give compound (5).
The ee was determined by HPLC analyses using a chiral column.
t
[
d
r
a
¼ 13.2 min for (R)-isomer and t
r
¼ 14.5 min for (S)-isomer.
2
0
1
]
D
¼ þ18.6 (c ¼ 0.50, DCE); H NMR (400 MHz, Chloroform-d)
7.37e7.34 (m, 2H), 7.33e7.31 (m, 2H), 7.30e7.24 (m, 5H), 5.79 (s,
4.6.1. 1,3-Diphenylprop-2-yn-1-ol (5a)
1
H), 2.33 (s, 1H). 13C NMR (101 MHz, Chloroform-d)
d
143.4, 142.2,
75% yield, 81% ee (R) (conducted with 3e). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
hexane, 1.0 mL/min, 220 nm UV detector). Retention times:
128.7, 128.6, 128.5, 127.9, 127.6, 126.5, 75.6 [29].
4
.5.15. (4-Bromophenyl) (phenyl)methanol (4o)
t
[
d
r
¼ 11.8 min for (R)-isomer and t
r
¼ 21.5 min for (S)-isomer;
); HNMR (400 MHz, Chloroform-d):
7.63e7.61 (m, 2H), 7.49e7.46 (m, 2H), 7.42e7.39 (m, 2H),
2
0
1
9
2% yield, 97% ee (S) (conducted with 3e). The ee value was
a
]
D
¼ þ6.5 (c ¼ 0.50, CHCl
3
determined by chiral HPLC analysis (CHIRALCEL AD-H, 5% IPA in
hexane, 1.0 mL/min, 220 nm UV detector). Retention times:
13
7.37e7.31 (m, 4H),5.69 (d, J ¼ 5.9 Hz,1H), 2.40 (d, J ¼ 6.2 Hz, 1H).
C
t
[
d
r
¼ 14.0 min for (R)-isomer and t
r
¼ 15.6 min for (S)-isomer;
¼ þ18.7 (c ¼ 0.50, DCE); H NMR (400 MHz, Chloroform-d)
7.46e7.44 (m, 2H), 7.34e7.33 (m, 4H), 7.29e7.24 (m, 3H), 5.78
s, 1H), 2.33 (s, 1H). 13C NMR (101 MHz, Chloroform-d)
143.3,
NMR (101 MHz, Chloroform-d) d 140.6, 131.8, 128.7, 128.6, 128.5,
2
0
1
a
]
D
128.3, 126.8, 122.4, 88.7, 86.7, 65.1 [22b].
(
d
4.6.2. 3-Phenyl-1-(p-tolyl)prop-2-yn-1-ol (5b)
1
42.7, 131.6, 128.7, 128.2, 127.9, 126.5, 121.4, 75.7 [34].
62% yield, 78% ee (R) (conducted with 3e). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
hexane, 1.0 mL/min, 220 nm UV detector). Retention times:
4.5.16. (2-Bromophenyl) (phenyl)methanol (4p)
8
8% yield, 96% ee (S) (conducted with 3e). The ee value was
t
[
d
r
a
¼ 9.1 min for (R)-isomer and t
r
¼ 18.5 min for (S)-isomer;
2
0
1
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
hexane, 1.0 mL/min, 210 nm UV detector). Retention times:
]
D
¼ þ3.0 (c ¼ 0.50, CHCl
3
). HNMR (400 MHz, Chloroform-d):
7.50e7.45 (m, 4H), 7.31e7.29 (m, 3H), 7.21e7.19 (d, J ¼ 7.9 Hz,
13
t
[
d
r
a
¼ 8.1 min for (R)-isomer and t
r
¼ 9.9 min for (S)-isomer;
¼ ꢀ50.5 (c ¼ 0.50, DCE); H NMR (400 MHz, Chloroform-d)
7.60e7.53 (m, 2H), 7.41e7.39 (m, 2H), 7.36e7.31 (m, 3H),
2H), 5.64 (d, J ¼ 5.8 Hz, 1H), 2.41 (d, J ¼ 6.0 Hz, 1H), 2.36 (s, 3H).
C
2
0
1
]
D
NMR (101 MHz, Chloroform-d) d 138.3, 137.8, 131.8, 129.4, 128.6,
128.3, 126.7, 122.5, 89.9, 86.5, 65.0, 21.2 [22b].
13
7
.30e7.27 (m, 1H), 7.17e7.10 (m, 1H), 6.20 (s, 1H), 2.41 (s, 1H).
C
NMR (101 MHz, Chloroform-d)
d
142.5, 142.1, 132.9, 129.1, 128.5,
4.6.3. 3-Phenyl-1-(m-tolyl)prop-2-yn-1-ol (5c)
1
27.8, 127.7, 127.6, 127.0, 122.8, 74.8 [33].
55% yield, 76% ee (R) (conducted with 3e). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
hexane, 1.0 mL/min, 254 nm UV detector). Retention times:
4.5.17. Furan-2-yl(phenyl)methanol (4q)
4
5% yield, 96% ee (R) (conducted with 3e). The ee value was
t
[
d
r
a
¼ 10.8 min for (R)-isomer and t
r
¼ 27.4 min for (S)-isomer;
); HNMR(400 MHz, Chloroform-d):
7.49e7.46 (m, 2H), 7.42e7.40 (m, 2H), 7.34e7.27 (m, 4H),
2
0
1
determined by chiral HPLC analysis (CHIRALCEL OD-H, 3% IPA in
hexane, 0.25 mL/min, 220 nm UV detector). Retention times:
]
D
¼ þ2.9 (c ¼ 0.51, CHCl
3
13
t
[
d
r
a
¼ 68.1 min for (R)-isomer and t
r
¼ 81.0 min for (S)-isomer;
¼ þ5.6 (c ¼ 0.50, DCE); H NMR (400 MHz, Chloroform-d)
7.45e7.43 (m, 2H), 7.38e7.34 (m, 2H), 7.32e7.30 (m, 1H), 7.25
7.17e7.15 (m, 1H), 5.65 (s, 1H), 2.39 (s, 3H), 2.36 (s, 1H). C NMR
(101 MHz, Chloroform-d) 140.6, 138.5, 131.8, 129.2, 128.6, 128.5,
128.3, 127.4, 123.8, 122.5, 88.8, 86.6, 65.2, 21.5 [22b].
2
0
1
]
D
d
(
dd, J ¼ 5.1, 1.4 Hz, 1H), 6.93 (dd, J ¼ 5.0, 3.5 Hz, 1H), 6.87 (d,
13
J ¼ 3.3 Hz,1H), 6.04 (d, J ¼ 3.6 Hz,1H), 2.51 (d, J ¼ 3.6 Hz, 1H).
C
4.6.4. 3-Phenyl-1-(o-tolyl)prop-2-yn-1-ol (5d)
NMR (101 MHz, Chloroform-d)
d
148.1, 143.1, 128.6, 128.0, 126.7,
56% yield, 84% ee (R) (conducted with 3e). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
hexane, 1.0 mL/min, 254 nm UV detector). Retention times:
126.3, 125.4, 124.9, 72.4 [29].
4
.5.18. Phenyl(thiophen-2-yl)methanol (4r)
t
[
r
¼ 9.4 min for (R)-isomer and t
r
¼ 19.8 min for (S)-isomer;
2
0
1
5
5% yield, 99% ee (R) (conducted with 3e). The ee value was
a
]
D
¼ ꢀ12.0 (c ¼ 0.52, CHCl
3
); HNMR(400 MHz, Chloroform-d):
determined by chiral HPLC analysis (CHIRALCEL OD-H, 5% IPA in
hexane, 1.0 mL/min, 220 nm UV detector). Retention times:
d 7.73e7.71 (m, 1H), 7.47e7.44 (m, 2H), 7.32e7.26 (m, 6H), 5.83 (s,
13
1H), 2.49 (s, 3H), 2.30 (s, 1H). C NMR (101 MHz, Chloroform-d)
138.4, 136.0, 131.7, 130.8, 128.6, 128.5, 128.3, 126.6, 126.3, 122.5,
t
r
¼ 13.9 min for (S)-isomer and t
r
¼ 17.2 min for (R)-isomer;
¼ ꢀ18.5 (c ¼ 0.50, DCE); H NMR (400 MHz, Chloroform-d)
7.45e7.43 (m, 2H), 7.38e7.29 (m, 3H), 7.27e7.22 (m, 1H), 6.93
d
2
0
1
[
a
]
D
88.5, 86.5, 63.0, 19.0 [22b].
d
(
2
1
dd, J ¼ 5.1, 3.5 Hz, 1H), 6.89e6.85 (m, 1H), 6.05 (d, J ¼ 3.7 Hz, 1H),
4.6.5. 1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-ol (5e)
54% yield, 76% ee (R) (conducted with 3e). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
13
.47 (d, J ¼ 4.0 Hz, 1H). C NMR (101 MHz, Chloroform-d)
d
148.1,
43.1, 128.6, 128.0, 126.7, 126.3, 125.5, 124.9, 72.5 [18a].
11

E. Gao, Q. Li, L. Duan et al.
Tetrahedron xxx (xxxx) xxx
hexane, 1.0 mL/min, 254 nm UV detector). Retention times:
4.6.11. 1-(Naphthalen-2-yl)-3-phenylprop-2-yn-1-ol (5k)
t
[
d
r
a
¼ 13.4 min for (R)-isomer and t
r
¼ 30.2 min for (S)-isomer;
59% yield, 72% ee (R) (conducted with 3e). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OD-H, 20% IPA in
hexane, 1.0 mL/min, 254 nm UV detector). Retention times:
2
0
1
]
D
¼ 22.1 (c ¼ 0.52, CHCl
3
); HNMR(400 MHz, Chloroform-d):
7.55e7.53 (m, 2H), 7.48e7.46 (m, 2H), 7.33e7.28 (m, 3H),
.98e6.87 (m, 2H), 5.64 (d, J ¼ 5.5 Hz, 1H), 3.82 (s, 3H), 2.33 (s, 1H).
6
t
[
d
r
a
¼ 8.9 min for (R)-isomer and t
r
¼ 27.3 min for (S)-isomer.
); HNMR(400 MHz, Chloroform-d):
8.05e8.03 (m, 1H), 7.90e7.84 (m, 3H), 7.74e7.71 (m, 1H),
1
3
20
1
C NMR (101 MHz, Chloroform-d)
d
159.7, 133.0, 131.8, 128.6, 128.3,
]
D
¼ ꢀ20.9 (c ¼ 0.52, CHCl
3
1
28.2, 122.5, 114.0, 88.9, 86.5, 64.7, 55.4 [22b].
13
7.51e7.48 (m, 4H), 7.34e7.32 (m, 3H), 5.86 (s, 1H), 2.46 (s, 1H).
C
NMR (101 MHz, Chloroform-d)
d 138.0, 133.3, 133.2, 131.8, 128.7,
4
.6.6. 1-(2-Methoxyphenyl)-3-phenylprop-2-yn-1-ol (5f)
128.6, 128.4, 128.3, 127.7, 126.4, 125.5, 124.7, 122.4, 88.7, 86.9, 65.3
6
5% yield, 75% ee (R) (conducted with 3e). The ee value was
[
22b].
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
hexane, 1.0 mL/min, 254 nm UV detector). Retention times:
4.6.12. 1-(4-Fluorophenyl)-3-phenylprop-2-yn-1-ol (5l)
t
r
¼ 13.9 min for (R)-isomer and t
r
¼ 17.7 min for (S)-isomer;
); HNMR(400 MHz, Chloroform-d):
7.65 (m, 1H), 7.52e7.44 (m, 2H), 7.36e7.28 (m, 4H), 7.06e6.96
2
0
1
67% yield, 76% ee (R) (conducted with 3e). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
hexane, 1.0 mL/min, 254 nm UV detector). Retention times:
[
a
]
D
¼ ꢀ6.0 (c ¼ 0.52, CHCl
3
d
13
(
(
m, 1H), 6.94 (m, 1H), 5.93 (s, 1H), 3.92 (s, 3H), 3.11 (s, 1H). C NMR
101 MHz, Chloroform-d) 156.9, 131.8, 129.8, 128.8, 128.4, 128.3,
t
[
d
r
a
¼ 8.8 min for (R)-isomer and t
r
¼ 26.8 min for (S)-isomer.
). HNMR (400 MHz, Chloroform-d):
7.53e7.51 (m, 2H), 7.42e7.39 (m, 2H), 7.28e7.27 (m,
d
2
0
1
]
D
¼ þ5.3 (c ¼ 0.52, CHCl
3
128.1, 122.8, 120.9, 88.3, 86.1, 61.7, 55.6 [22b].
19
3
CDCl
H),7.08e6.90 (m, 2H), 5.60 (s, 1H), 2.46 (s, 1H). F NMR (376 MHz,
4
.6.7. 1-(3,4-Dimethylphenyl)-3-phenylprop-2-yn-1-ol (5g)
13
3
)
d
ꢀ113.7. C NMR (101 MHz, Chloroform-d)
d 162.7(d,
5
4% yield, 73% ee (R) (conducted with 3e). The ee value was
J ¼ 246.8 Hz), 136.5(d, J ¼ 3.0 Hz), 131.8, 128.8, 128.6(d, J ¼ 8.5 Hz),
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
hexane, 1.0 mL/min, 254 nm UV detector). Retention times:
128.4, 122.2, 115.5(d, J ¼ 21.4 Hz), 88.5, 86.9, 64.4 [22b].
t
[
d
r
a
¼ 10.3 min for (R)-isomer and t
r
¼ 25.7 min for (S)-isomer;
2
0
1
4.6.13. 1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-ol (5m)
4% yield, 73% ee (R) (conducted with 3e). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
hexane, 1.0 mL/min, 254 nm UV detector). Retention times:
]
D
¼ 5.0 (c ¼ 0.52, CHCl
3
). HNMR (400 MHz, Chloroform-d):
6
7.48e7.46 (m, 2H), 7.38e7.29 (m, 5H), 7.16 (d, J ¼ 7.7 Hz,
H),5.63 (s, 1H), 2.32 (s, 1H) 2.29 (s, 3H), 2.27 (s, 3H). 13C NMR
1
(
1
101 MHz, Chloroform-d) d 138.2, 137.0, 131.8, 129.9, 128.5, 128.3,
28.0, 124.2, 122.6, 89.0, 86.4, 65.0, 19.9, 19.6 [22b].
t
[
d
r
a
¼ 9.3 min for (R)-isomer and t
r
¼ 30.4 min for (S)-isomer;
2
0
1
]
D
¼ þ5.6 (c ¼ 0.50, CHCl
3
); HNMR (400 MHz, Chloroform-d):
7.55e7.52 (m, 2H), 7.48e7.44 (m, 2H), 7.38e7.29 (m, 5H), 5.66
4
.6.8. 1-(4-Isopropylphenyl)-3-phenylprop-2-yn-1-ol (5h)
13
(
d, J ¼ 5.8 Hz, 1H), 2.47 (d, J ¼ 6.0 Hz,1H). C NMR (101 MHz,
Chloroform-d) 139.1, 134.2, 133.1, 131.8, 128.8, 128.4, 128.1, 122.1,
8.2, 87.0, 64.4 [22b].
6
7% yield, 74% ee (R) (conducted with 3e). The ee value was
d
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
hexane, 1.0 mL/min, 254 nm UV detector). Retention times:
8
t
[
d
r
a
¼ 7.6 min for (R)-isomer and t
r
¼ 23.0 min for (S)-isomer;
). HNMR (400 MHz, Chloroform-d):
7.55e7.53 (m, 2H), 7.49e7.46 (m, 2H), 7.32e7.27 (m, 5H), 5.66
4
.6.14. (4-Bromophenyl)-3-phenylprop-2-yn-1-ol (5n)
2
0
1
]
D
¼ 3.0 (c ¼ 0.50, CHCl
3
6
6% yield, 71% ee (R) (conducted with 3e). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
hexane, 1.0 mL/min, 254 nm UV detector). Retention times:
13
(
s, 1H), 2.96e2.89 (m, 1H), 2.32 (s, 1H), 1.26 (s, 3H), 1.25 (s, 3H).
d 149.3, 138.1, 131.8, 131.7, 128.6,
28.3, 126.8, 122.5, 88.9, 86.5, 65.0, 33.9, 24.0 [22b].
C
NMR (101 MHz, Chloroform-d)
1
t
r
¼ 9.9 min for (R)-isomer and t
r
¼ 33.5 min for (S)-isomer;
20
1
[
a
]
D
¼ þ7.8 (c ¼ 0.52, CHCl
3
); HNMR (400 MHz, Chloroform-d):
d
13
7.54e7.46 (m, 6H), 7.34e7.33 (m, 3H), 5.65 (s, 1H), 2.43 (s, 1H).
4
.6.9. 3-Phenyl-1-(4-(trifluoromethyl)phenyl)prop-2-yn-1-ol (5i)
C NMR (101 MHz, Chloroform-d)
d 139.6, 133.1, 131.9, 128.8,
6
3% yield, 71% ee (R) (conducted with 3e). The ee value was
128.4128.3, 122.4, 122.1, 88.1, 87.0, 64.5 [22b].
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
hexane, 1.0 mL/min, 254 nm UV detector). Retention times:
t
[
d
4.6.15. (2-Bromophenyl)-3-phenylprop-2-yn-1-ol (5o)
r
¼ 8.3 min for (R)-isomer and t
r
¼ 40.8 min for (S)-isomer;
80% yield, 75% ee (R) (conducted with 3e). The ee value was
2
0
1
a
]
D
¼ þ7.8 (c ¼ 0.52, CHCl
3
); HNMR(400 MHz, Chloroform-d):
determined by chiral HPLC analysis (CHIRALCEL OD-H, 5% IPA in
hexane, 1.0 mL/min, 254 nm UV detector). Retention times:
7.74 (d, J ¼ 8.2 Hz, 2H), 7.66 (d, J ¼ 8.2 Hz, 2H), 7.48e7.46 (m,
19
2
CDCl
1
H), 7.35e7.33 (m, 3H), 5.75 (s, 1H), 2.49 (s, 1H). F NMR (376 MHz,
t
r
¼ 21.0 min for (R)-isomer and t
r
¼ 24.9 min for (S)-isomer;
1
3
)
d
ꢀ62.5. C NMR (101 MHz, Chloroform-d)
d
144.3, 131.8,
20
1
3
[
a
]
¼ ꢀ45.0 (c ¼ 0.45, CHCl
); HNMR(400 MHz, Chloroform-d):
D
3
30.7, 130.4, 128.9, 128.4, 127.0, 125.6 (q, J ¼ 3.8 Hz), 122.7 (q,
d
7.86e7.83 (m,1H), 7.60e7.58 (m,1H), 7.49e7.46 (m, 2H), 7.41e7.36
J ¼ 272 Hz), 87.9, 87.3, 64.4 [22b].
(
1
d
m, 1H),7.34e7.30 (m, 3H), 7.23e7.21 (m, 1H), 6.02 (d, J ¼ 5.4 Hz,
13
H), 2.63 (d, J ¼ 5.5 Hz, 1H). C NMR (101 MHz, Chloroform-d)
4
.6.10. 1-(Naphthalen-1-yl)-3-phenylprop-2-yn-1-ol (5j)
139.5, 133.1, 131.8, 130.0, 128.7, 128.3, 127.9, 122.8, 122.3, 87.6,
5
5% yield, 70% ee (R) (conducted with 3e). The ee value was
86.8, 64.7 [22b].
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
hexane, 1.0 mL/min, 254 nm UV detector). Retention times:
4.6.16. 1-(Furan-2-yl)-3-phenylprop-2-yn-1-ol (5p)
t
[
d
r
a
¼ 15.4min for (R)-isomer and t
r
¼ 33.5 min for (S)-isomer;
); HNMR(400 MHz, Chloroform-d):
8.38e8.36 (m, 1H), 7.93e7.85 (m, 3H), 7.60e7.54 (m, 1H),
60% yield, 51% ee (R) (conducted with 3e). The ee value was
determined by chiral HPLC analysis (CHIRALCEL OD-H, 10% IPA in
hexane, 1.0 mL/min, 254 nm UV detector). Retention times:
2
0
1
]
D
¼ ꢀ26.8 (c ¼ 0.52, CHCl
3
13
7
.52e7.44 (m, 4H), 7.32e7.30 (m, 3H), 6.35 (s, 1H), 2.49 (s, 1H).
C
t
[
r
a
¼ 10.1 min for (R)-isomer and t
r
¼ 18.6 min for (S)-isomer;
2
0
1
NMR (101 MHz, Chloroform-d)
1
d
135.7, 134.1, 131.8, 130.6, 129.5,
]
D
¼ þ26.0 (c ¼ 0.52, CHCl
3
); HNMR (400 MHz, Chloroform-d):
28.8, 128.6, 128.3, 126.5, 125.9, 125.3, 124.8, 124.0, 122.5, 88.5, 87.4,
d
7.50e7.48 (m, 2H), 7.45e7.43 (m, 1H), 7.36e7.32 (m, 3H), 6.53 (d,
6
3.4 [22b].
J ¼ 3.3 Hz, 1H), 6.39e6.38 (m, 1H), 5.70 (d, J ¼ 6.9 Hz, 1H), 2.40 (d,
12

E. Gao, Q. Li, L. Duan et al.
Tetrahedron xxx (xxxx) xxx
J ¼ 7.0 Hz, 1H). 13C NMR (101 MHz, Chloroform-d)
d 152.9, 143.1,
Chem. Res. 41 (2008) 655;
c) Z. Lu, S. Ma, Angew. Chem. Int. Ed. 47 (2008) 258.
7] (a) I. Ojima, Pure Appl. Chem. 56 (1984) 99;
b) B.M. Trost, H. Ito, J. Am. Chem. Soc. 122 (2000) 12003;
(c) J. Kofoed, M. Machuqueiro, J.-L. Reymond, T. Darbre, Chem. Commun.
2004) 1540.
(
1
31.8, 128.8, 128.3, 122.1, 110.5, 107.9, 86.1, 85.8, 58.7 [22b].
[
(
Declaration of competing interest
(
[
[
8] E. Gao, M. Li, L. Duan, L. Li, Y.-M. Li, Tetrahedron 75 (2019) 130492.
9] (a) K. Zheng, B. Qin, X. Liu, X. Feng, J. Org. Chem. 72 (2007) 8478;
(b) H. Zhou, D. Peng, B. Qin, Z. Hou, X. Liu, X. Feng, J. Org. Chem. 72 (2007)
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
1
(
9
0302;
c) B. Qin, X. Xiao, X. Liu, J. Huang, Y. Wen, X. Feng, J. Org. Chem. 72 (2007)
323;
(d) X.H. Liu, L.L. Lin, X.M. Feng, Acc. Chem. Res. 44 (2011) 574;
Acknowledgments
(
(
(
e) H. Mei, X. Xiao, X. Zhao, B. Fang, X. Liu, L. Lin, X. Feng, J. Org. Chem. 80
2015) 2272;
f) C. Tan, X. Liu, L. Wang, J. Wang, X. Feng, Org. Lett. 10 (2008) 5305;
We acknowledge financial support from the National Natural
Science Foundation of China (NSFC 21672106, and 21272121). Y.M.L.
acknowledges the support from Key Laboratory of Synthetic
Chemistry of Natural Substances, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences. En Gao acknowledges the
support from Ph.D. Students Innovative Research Program from
Nankai University.
(g) F. Wang, X. Liu, Y. Zhang, L. Lin, X. Feng, Chem. Commun. (2009) 7297;
(h) B. Fang, X. Liu, J. Zhao, Y. Tang, L. Lin, X. Feng, J. Org. Chem. 80 (2015) 3332;
(i) Q. Chen, Y. Tang, T. Huang, X. Liu, L. Lin, X. Feng, Angew. Chem. Int. Ed. 55
(2016) 5286;
(j) X. Liu, H. Zheng, Y. Xia, L. Lin, X. Feng, Acc. Chem. Res. 50 (2017) 2621;
(k) X. Liu, S. Dong, L. Lin, X. Feng, Chin. J. Chem. 36 (2018) 791.
[
[
[
10] Please refer to the Supporting Information for details.
11] M. Kitamura, S. Okada, S. Suga, R. Noyori, J. Am. Chem. Soc. 111 (1989) 4028.
12] (a) M. Kitamura, S. Suga, K. Kawai, R. Noyori, J. Am. Chem. Soc. 108 (1986)
6071;
Appendix. ASupplementary data
(
(
b) K. Soai, A. Ookawa, T. Kaba, K. Ogawa, J. Am. Chem. Soc. 109 (1987) 7111;
c) R. Noyori, S. Suga, K. Kawai, S. Okada, M. Kitamura, N. Oguni, M. Hayashi,
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131648.
T. Kaneko, Y. Matsuda, J. Organomet. Chem. 382 (1990) 19;
(d) K. Soai, S. Niwa, Chem. Rev. 92 (1992) 833;
(e) M. Yus, D.J. Ramon, Pure Appl. Chem. 77 (2005) 2111.
[
13] (a) A. Bisai, P.K. Singh, V.K. Singh, Tetrahedron 63 (2007) 598;
References
(
(
b) C. Nottingham, R. Benson, H. Müller-Bunz, P.J. Guiry, J. Org. Chem. 80
2015) 10163;
[1] (a) M.K. O’Brien, B. Vanasse, Curr. Opin. Drug Discov. Dev 3 (2000) 793;
(c) F. Prause, S. Wagner, M. Breuning, Tetrahedron 75 (2019) 94.
(
(
(
(
b) R. Noyori, Angew. Chem. Int. Ed. 41 (2002) 2008;
[14] T. Hirose, K. Sugawara, K. Kodama, J. Org. Chem. 76 (2011) 5413.
[15] C. Bolm, J. Rudolph, J. Am. Chem. Soc. 124 (2002) 14850.
[16] M.-C. Wang, Q.-J. Zhang, W.-X. Zhao, X.-D. Wang, X. Ding, T.-T. Jing, M.-
P. Song, J. Org. Chem. 73 (2008) 168.
[17] Please Refer to the Supporting Information for a Full List of Gaussian 09 D01
Authors.
c) T. Iida, T. Mase, Curr. Opin. Drug Discov. Dev 5 (2002) 834;
d) J.M. Hawkins, T.J.N. Watson, Angew. Chem. Int. Ed. 43 (2004) 3224;
e) V. Farina, J.T. Reeves, C.H. Senanayake, J.J. Song, Chem. Rev. 106 (2006)
2
734;
f) C. Grondal, M. Jeanty, D. Enders, Nat. Chem. 2 (2010) 167.
2] (a) D.J. Berrisford, C. Bolm, K.B. Sharpless, Angew. Chem. Int. Ed. 34 (1995)
059;
(
[
[18] (a) A.M. DeBerardinis, M. Turlington, J. Ko, L. Sole, L. Pu, J. Org. Chem. 75
(2010) 2836;
1
(
(
(
b) P.I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 40 (2001) 3726;
c) C. Gennari, U. Piarulli Chem. Rev. 103 (2003) 3071;
d) L.-X. Dai, T. Tu, S.-L. You, W.-P. Deng, X.-L. Hou, Acc. Chem. Res. 36 (2003)
(b) A. Uenishi, Y. Nakagawa, H. Osumi, T. Harada, Chem. Eur J. 19 (2013) 4896.
[19] X. Wu, X. Liu, G. Zhao, Tetrahedron: Asymmetry 16 (2005) 2299.
[20] For recent examples, see: (a) Q. Chen, Y. Tang, T. Huang, X. Liu, L. Lin, X. Feng,
Angew. Chem. Int. Ed. 55 (2016) 5286;
6
59;
(
(
(
(
(
(
(
(
(
e) M. Di eꢀ guez, O. P aꢁ mies, C. Claver, Chem. Rev. 104 (2004) 3189;
f) G. Desimoni, G. Faita, K.A. Jørgensen, Chem. Rev. 106 (2006) 3561;
g) D. Enders, O. Niemeier, A. Henseler, Chem. Rev. 107 (2007) 5606;
h) M.J. Gaunt, C.C.C. Johansson, Chem. Rev. 107 (2007) 5596;
i) T. Hashimoto, K. Maruoka, Chem. Rev. 107 (2007) 5656;
j) P. Melchiorre, M. Marigo, A. Carlone, G. Bartoli, Angew. Chem. Int. Ed. 47
2008) 6138;
(b) Y. Tang, J. Xu, J. Yang, L. Lin, X. Feng, X. Liu, Inside Chem. 4 (2018) 1658.
[21] (a) O.Y. Okhlobystin, L.I. Zakharkin, J. Organomet. Chem. 3 (1965) 257;
(b) D. Moore, L. Pu, Org. Lett. 4 (2002) 1855;
(c) G. Lu, X. Li, W.L. Chan, A.S.C. Chan, Chem. Commun. (2002) 172.
[22] (a) H. Koyuncu, O. Dogan, Org. Lett. 9 (2007) 3477;
(b) G. Blay, L. Cardona, I. Fern ꢀa ndez, A. Marco-Aleixandre, M.C. Mu n~ oz,
J.R. Pedro, Org. Biomol. Chem. 7 (2009) 4301.
k) M. Shibasaki, M. Kanai, S. Matsunaga, N. Kumagai, Acc. Chem. Res. 42
2009) 1117.
[23] M. Yamakawa, R. Noyori, J. Am. Chem. Soc. 117 (1995) 6327.
[24] J. Zhang, S. Li, X. Zheng, H. Li, P. Jiao, Tetrahedron Lett. 60 (2019) 1913.
[25] P. Zhang, J. Yu, F. Peng, X. Wu, J. Jie, C. Liu, H. Tian, H. Yang, H. Fu Chem, Eur. J.
22 (2016) 17477.
[26] B. Zhou, Z. Li, C. Yang, L. Li, L. Fan, H. Huang, J. Li Arkivoc (2018) 1.
[27] C. Sappino, A. Mari, A. Mantineo, M. Moliterno, M. Palagri, C. Tatangelo,
L. Suber, P. Bovicelli, A. Ricelli, G. Righi, Org. Biomol. Chem. 16 (2018) 1860.
[28] F. Ling, S. Nian, J. Chen, W. Luo, Z. Wang, Y. Lv, W. Zhong, J. Org. Chem. 83
(2018) 10749.
[29] Y.-X. Yang, Y. Liu, L. Zhang, Y.-E. Jia, P. Wang, F.-F. Zhuo, X.-T. An, C.-S. Da,
J. Org. Chem. 79 (2014) 10696.
[30] H. Li, D. Zhu, L. Hua, E.R. Biehl, Adv. Synth. Catal. 351 (2009) 583.
[31] S. Morikawa, K. Michigami, H. Amii, Org. Lett. 12 (2010) 2520.
[32] Y. Muramatsu, S. Kanehira, M. Tanigawa, Y. Miyawaki, T. Harada, Bull. Chem.
Soc. Jpn. 83 (2010) 19.
[
3] (a) R. Noyori, H. Takaya, Acc. Chem. Res. 23 (1990) 345;
b) P. Ko ꢂc ovský, S. Vyskocil, M. Smrcina, Chem. Rev. 103 (2003) 3213;
ꢂ
ꢂ
ꢂ
(
(
(
c) Y. Chen, S. Yekta, A.K. Yudin, Chem. Rev. 103 (2003) 3155;
d) M. Berthod, G. Mignani, G. Woodward, M. Lemaire, Chem. Rev. 105 (2005)
1801;
(
(
(
e) J.M. Brunel, Chem. Rev. 105 (2005) 857;
f) M. Shibasaki, S. Matsunaga, Chem. Soc. Rev. 35 (2006) 269;
g) D. Parmar, E. Sugiono, S. Raja, M. Rueping, Chem. Rev. 114 (2014) 9047.
[
[
[
4] (a) E.R. Jarvo, S.J. Miller, Tetrahedron 58 (2002) 2481;
(
(
(
b) A. Bassan, W. Zou, E. Reyes, F. Himo, A. C oꢀ rdova Angew. Chem. Int. Ed. 44
2005) 7028;
c) T. Wang, X. Han, F. Zhong, W. Yao, Y. Lu, Acc. Chem. Res. 49 (2016) 1369.
5] (a) H. Gr o€ ger, J. Wilken Angew. Chem. Int. Ed. 40 (2001) 529;
(
(
(
b) A. Lattanzi, Chem. Commun. (2009) 1452;
c) X. Liu, L. Lin, X. Feng, Org. Chem. Front. 1 (2014) 298;
d) J. Liu, L. Wang, Synthesis 49 (2017) 960.
[33] Z. Lu, H. Zhang, Z. Yang, N. Ding, L. Meng, J. Wang, ACS Catal. 9 (2019) 1457.
[34] M.R. Harris, L.E. Hanna, M.A. Greene, C.E. Moore, E.R. Jarvo, J. Am. Chem. Soc.
135 (2013) 3303.
6] (a) S. Kobayashi, K. Manabe, Acc. Chem. Res. 35 (2002) 209;
b) D.H. Paull, C.J. Abraham, M.T. Scerba, E. Alden-Danforth, T. Lectka, Acc.
(
13