Binaphthyl-based chiral ligands: Design, synthesis and evaluation of their performance in enantioselective addition of diethylzinc to aromatic aldehydes

Article abstract of DOI:10.1039/d0ob02127j

The design strategy and the performance of binaphthyl-based chiral ligands were evaluated with computation and enantioselective addition of diethylzinc to aromatic aldehydes. Under optimized conditions, enantioselective addition of diethylzinc to aromatic aldehydes provided the desired optically active secondary alcohols in high isolated yields (up to 91%) and excellent enantiomeric excesses (up to 98% ee).

Full text of DOI:10.1039/d0ob02127j

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Binaphthyl-based chiral ligands: design, synthesis
and evaluation of their performance in
enantioselective addition of diethylzinc to
aromatic aldehydes†
Cite this: DOI: 10.1039/d0ob02127j
a,b
Chao Yao,a Piao Wu,a Yue Huang,a Yaoqi Chen,a Lin Lia and Yue-Ming Li
*
Received 21st October 2020,
Accepted 17th November 2020
The design strategy and the performance of binaphthyl-based chiral ligands were evaluated with compu-
tation and enantioselective addition of diethylzinc to aromatic aldehydes. Under optimized conditions,
enantioselective addition of diethylzinc to aromatic aldehydes provided the desired optically active sec-
ondary alcohols in high isolated yields (up to 91%) and excellent enantiomeric excesses (up to 98% ee).
DOI: 10.1039/d0ob02127j
rsc.li/obc
of the carboxyl group was easy to carry out, and successful
transformations would provide diversified functional groups
1. Introduction
Chiral ligand design has been the focal point of asymmetric such as different alcohols, amides or oxazolines. Integration of
synthesis. To this end, significant efforts have been made such functional groups in a single chiral molecule has been
towards the design of new chiral ligands for asymmetric reac- proved to be effective, and chiral ligand 1 has been success-
tions.1 Among the variety of chiral ligands developed, fully used in a variety of asymmetric catalytic reactions.8
binaphthyl-based chiral ligands have played important roles in
a variety of asymmetric catalytic reactions. For examples,
BINOL,2 BINAM,3 BINAP,4 NOBIN,5 binaphthyl dicarboxylic
acid6 and other binaphthyl-related structures have all been
explored in both academia and industry1b (Fig. 1). Among these
structures, BINOL can be regarded as a general starting material
from which different chiral ligands/organocatalysts could be
prepared.2g,7 We are interested in expanding the structure diver-
On the basis of literature results and our understanding on
sity of binaphthyl-based compounds, and in developing new
the design of chiral ligands, compounds 2 bearing both
chiral ligands based on binaphthyl structures. Herein we wish
hydroxyl and oxazoline groups were first proposed.
to report our preliminary progress on design and evaluation of
catalytic activity of several binaphthyl-based chiral ligands.
2. Results and discussion
The work was initiated from the structure modification of 1,1′-
binaphthyl 2,2′-dicarboxylic acid. This compound was chosen
as the starting material due to the fact that the derivatization
The synthesis of chiral ligands 2 started from racemic 1,1′-
binaphthyl-2,2′-dicarboxylic acid 3. A number of monooxazo-
lines bearing binaphthyl backbone were prepared through a
four-step reaction sequence (Scheme 1). Racemic 1,1′-biphenyl-
2,2′-dicarboxylic acid was easily transformed into its monoe-
ster 4, which could then react with different amino alcohols to
generate amides 5. At this stage, we were happy to find that,
when (R)-2-amino-2-phenylethanol (D-phenylglycinol) was
used, the diastereomers 5a and 5b were easy to separate, thus
aState 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. E-mail: ymli@nankai.edu.cn
bCAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, People’s Republic of China
†Electronic supplementary information (ESI) available. CCDC 2039075, 2039077
and 2039078. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/d0ob02127j
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Fig. 1 Examples of successful binaphthyl-based chiral compounds.
Scheme 1 Synthesis of binaphthyl-based monooxazolines. Conditions: (I) K2CO3, BnBr, DMF, 60%; (II) (R)-phenylglycinol or (R)-tert-leucinol, EDCI,
HOBT, Et3N; DCM; 80–90%; (III) TsCl; DMAP; Et3N; DCM; 90–95%; (IV) R2MgBr, THF, 0 °C, 85–90%.
enabling a feasible resolution of 1,1′-biphenyl-2,2′-dicarboxylic
In this regard, chiral ligands 2a–2e were subjected to
acid in an easy-to-carry out manner. This may be due to the enantioselective addition of diethylzinc to benzaldehyde. The
steric hindrance of the bulky functional groups in compounds results are summarized in Table 1. All experiments were
5, which rendered the diasteromers A and B different enough carried out in 0.5 mmol scale. Benzaldehyde (0.5 mmol) was
to allow an easy column chromatography separation. The added to a mixture of 10 mol% of chiral ligand and 2 equiv. of
stereochemistry of compound 5 was also confirmed with X-ray
diffraction experiment on (Ra,R)-5a.
In this regard, the diasteromers of both ligands can be pre-
pared in large quantities from easily available racemic starting
Table 1 Enantioselective addition of diethylzinc to benzaldehyde pro-
moted by chiral ligands 2a–2ea
materials. Subsequently, compounds 5 were converted to oxa-
zoline 6, and reaction of 6 with the corresponding Grignard
reagents furnished the preparation of chiral ligands 2a–2e.
Next, the performance of compounds 2a–2e were evaluated
in enantioselective addition of diethylzinc to aldehydes. Since
Entry
Ligand
Yieldb (%)
eec (%)
Config.d
the pioneer work by Oguni and Omi in 1984,9 huge amount of
works concerning the enantioselective addition of dialkylzincs
to aldehydes have been published, and a plethora of chiral
ligands such as amino alcohols (N,O-ligands), diols (O,O-
ligands), diamines (N,N-ligands) were developed.2g,10 Such
reactions can be carried out under mild conditions, giving the
desired alcohols in good yields and high ee’s. The well docu-
mented feature of the reaction made it an ideal model for the
evaluation of the designing strategy as well as the performance
of the newly designed chiral ligands.
1
2
3
4
5
2a
2b
2c
2d
2e
89
77
61
53
50
46
40
28
25
30
R
R
R
S
R
a Reaction conditions: Benzaldehyde (0.5 mmol) was added to a solu-
tion of the ligand (0.05 mmol) and Et2Zn (1.0 mmol, 1 mL of 1 M
toluene solution) in toluene (2.0 mL). Reaction time: 24 h. b Isolated
yields. c The ee values were determined by HPLC (chiralcel OD-H
column). d Absolute configuration was assigned by comparing the
specific rotation with reported sign and value of the product.8f
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Et2Zn (1 M in toluene), and the desired product was isolated
after 24 h. Preliminary results showed that ligands 2a and 2d
provided products in opposite but different enantiomeric
excesses, suggesting that binaphyl group was responsible for
the enantioselection, and the axial and the central chirality
should match with each other to get
stereoselectivity.
a meaningful
The results in Table 1 suggested that chiral ligands 2a–2e
were not so efficient in inducing enantioselective addition of
diethylzinc to benzaldehyde. We reasoned that the low
enantioselectivity should be due to the insufficient chirality
induction feature of these chiral catalysts. To find new struc-
tures which may be more suitable for the asymmetric induc-
tion, a new type of chiral ligands 8a–8e were proposed. We
envisioned that replacing the tertiary alcohol with amide
would give more diversified structures from which more poten-
tial chiral ligands could be expected (Scheme 2). Further, such
ligands could be conveniently prepared from intermediate (Ra,
S)-6 through saponification and subsequent amide formation.
Due to the availability of the chiral aminoalcohols, (S)-phenyl-
glycinol was used instead of (R)-phenylglycinol in further
study. The stereochemistry of the ligands were also established
based on single crystal X-ray diffraction experiments on 8c and
8e (Fig. 2).
Fig. 2 ORTEP Drawings of compounds 8c and 8e at 30% displacement
ellipsoid probability (the hydrogen atoms were omitted for clarity).
Table 2 Enantioselective addition of diethylzinc to benzaldehyde pro-
moted by 8a–8ea
Again, the performance of compounds 8a–8e were evaluated
in enantioselective addition of diethylzinc to benzaldehyde. All
experiments were carried out by adding 0.5 mmol of benz-
aldehyde to a mixture of 10 mol% of chiral ligand and 2 equiv.
of Et2Zn. The results are listed in Table 2.
The results in Table 2 suggested that, after preliminary
optimization of the reaction conditions, compound 8a gave
product with highest ee. Addition of DiMPEG 2000 showed
little effect on the stereo outcome of the reaction (entry 13).11
The results from 8a and 8e also indicated the binaphyl moiety 8e,g
was responsible for the enantioselection, and the axial and
Entry
Ligand
Yieldb (%)
eec (%)
Config.d
1
2
3
4
8a
8b
8c
8d
8e
8a
8a
8a
8a
8a
8a
8a
8a
7
87
88
26
73
76
85
73
89
75
50
80
86
88
78
68
29
24
23
45
80
60
82
73
23
67
82
83
0
R
R
R
R
S
R
R
R
R
R
R
R
R
—
5
6e
7f
9e,h
10e,i
11e, j
central chirality should match with each other. However, none
of the ee’s in Tables 1 and 2 exceeded 90%, suggesting that 12g
13g,k
14
the chiral transfer mediated by these chiral ligands was not so
efficient. To get structural insights into the chiral induction,
DFT calculation was carried out at M06-2X/SDD level.12 To vali-
date the method, results from DFT calculation and X-ray diffr-
action for 8c were first compared (Fig. 3), and representative
a Reaction conditions: Benzaldehyde (0.5 mmol) was added to a solu-
tion of the ligand (0.05 mmol) and Et2Zn (1.0 mmol, 1 mL of 1 M
toluene solution) in toluene (2.0 mL). Reaction time: 24 h. b Isolated
yields. c The ee values were determined by HPLC (chiralcel OD-H
column). d Absolute configuration assigned by comparison to the lit-
erature.8f e 5 mol% 8a was used. f 2 mol% 8a was used. g Reaction temp-
erature = 0 °C. h Reaction temperature = −10 °C. i Solvent = n-hexane.
j Solvent = DCM. k In the presence of DiMPEG 2000 (10 mol%).
Scheme 2 Synthesis of chiral ligands 8a–8e. Conditions: (I) K2CO3,
MeOH, 92%; (II) RNH2, EDCI, HOBT, Et3N; DCM; 50–95%.
Fig. 3 Computer model of 8c at M06-2X/SDD level.
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Table 3 Comparison of calculated and X-ray diffraction results of 8c
Parameters
Calculated
Found
Dihedral angle
C(2)–C(1)–C(11)–C(12)
C(11)–C(12)–C(30)–O(2)
C(11)–C(12)–C(30)–N(2)
Hydrogen bond
N⋯H
−101.33239
−119.97215
63.21263
−101.22942
−119.39080
65.73975
2.06454
2.08207
Bond angle
O(1)–C(21)–N(1)
116.03199
118.31333
The preparation of chiral ligands 9 started from commercially
available (R)-BINOL (Scheme 3). Monoprotection of hydroxyl
group was realized using CH3I as the methylation agent in the
presence of an appropriate base, and the desired mono-meth-
oxylated compound 10 could be obtained in high yield.
Triflation of the remaining hydroxyl group in 10 furnished
compound 11, and Ni(II)-catalyzed methylation of 11 gave
compound 12 which could be converted 13 via free radical bro-
mination. Using AIBN as the free radical initiator and NBS as
the bromine source, bromination of 12 proceeded readily,
yielding the desired 13 in satisfactory yield. Nucleophilic sub-
stitution of 13 with different amino alcohols gave compounds
14 which could be converted to the desired chiral ligands 9 via
Fig. 4 Computer model of 8a-Zn at M06-2X/SDD level.
data in Table 3 suggested that the calculated structure was very BBr3-promoted demethylation. For the purpose of comparison,
close to X-ray diffraction structure in respect to the torsion of N-oxide 9g was also prepared via oxidation of 9a with m-CPBA.
the binaphyl structure, the torsion of the amide bond, the
Next, ligand 9a–9g were evaluated in enantioselective
structure of the oxazoline as well as the hydrogen bond addition of diethylzinc to benzaldehyde. The results are shown
between the amide hydrogen and the nitrogen atom in the oxa- in Table 4. Compound 9a gave the best result, and the product
zoline (Table 3).
could be obtained in 81% yield and 80% ee (Table 4, entry 1).
After the establishment of the computation method, active Increasing or decreasing the bulkiness of the substituents on
species formed in the reaction between chiral ligand 8a and di- the hydroxylmethyl group resulted in the decrease of the
ethylzinc was proposed and optimized (Fig. 4), and the struc- enantioselectivity of the reaction (Table 4, entries 3, 5 and 7).
ture was examined to get structural insights.
Lower ee also observed when the five-membered ring was
Preliminary computer model suggested that the central replaced with six-membered ring (Table 4, entries 1 vs. 8),
metal Zn in active species 8a-Zn possessed a three-coordi- possibly due to the different conformation of the two ring
nation distorted seesaw structure, the phenyl group of the oxa- systems. It was noteworthy that ligand (Ra,R)-9f afforded the
zoline chiral elements was far away from the reaction center, opposite enantiomer with lower ee, suggesting that the enan-
thus diminishing the effect of oxazoline moiety on the stereo- tioselection came from the prolinol moiety, and the axial chir-
selectivity of the reaction. Carefully examining the model ality and the central chirality of the amino alcohol should
suggested that the chirality transfer was not effective in the match with each other (Table 4, entries 1 vs. 10). Lower ee’s
current catalyst system.
were observed in reactions using N-oxide ligand 9g or
The preliminary computer model suggested that the O-methyl ligand 14a–14c or 14e as chiral ligands, suggesting
binaphthyl moiety should bear appropriate dihedral angle to that both the tertiary amine and the phenolic hydroxyl group
get sufficient chirality transfer during the reaction. In this were necessary for the asymmetric reactions (Table 4, entries 1
regard, another type of chiral ligands 9 which combined the vs. 2, 3 vs. 4, 5 vs. 6 and 8 vs. 9).
potential of both binaphthyl group and proline were pro-
Next, the reaction conditions were further optimized using
posed. Such structures were proposed based on the results 9a as chiral ligand. The results are summarized in Table 5. As
that proline and related structures were important starting shown in Table 5, less polar solvents such as benzene,
materials for the preparation of different chiral ligands/cata- n-hexane, cyclohexane or toluene were suitable for the reac-
lysts,13 and based on our experience in the design of proli- tion, and best result was observed when the reaction was
nol-containing new chiral ligands for asymmetric organic carried out in toluene (81% yield, 86% ee). Reaction carried
reactions.14 In our previous study, we found that the chemi- out in n-hexane or dichloroethane afforded product with good
cal space of a chiral ligand can be effectively expanded using ee’s but relatively low yield, possibly due to the poor solubility
isosteric approach. Encouraged by these preliminary of chiral ligand in these solvents. Almost no reaction was
results,15 we decided to prepare new chiral ligands incorpor- observed when the reactions were carried out in tetrahydro-
ating the advantages of both binaphthyl skeleton and amino furan or 1,4-dioxane, possibly due to the coordination nature
alcohols.
of the solvents. When the catalyst was exposed to such sol-
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Scheme 3 Synthesis of chiral ligands 9a–9g: (I) CH3I, K2CO3, acetone, 92%; (II) Tf2O, pyridine, DCM, 99%; (III) (NiCl2)dppp, CH3MgBr, THF, 96%; (IV)
NBS, AIBN, DCE, 81%; (V) amino alcohols, K2CO3, NaI, CH3CN, 65–88%; (VI) BBr3, DCM, 74–93%; (VII) m-CPBA, DCM, 80%.
vents, all the coordination site of the central metal would be
occupied due to solvent coordination, and the catalyst would
be deactivated as a result. Therefore, toluene was finally
chosen as the reaction medium for further optimization of the
reaction condition.
Table 4 Enantioselective addition of diethylzinc to benzaldehyde using
9a–9g as the chiral ligandsa
When 10 mol% of DiMPEG 2000 was used as additive,11 the
performance of the chiral ligand was significantly enhanced,
and the product could be obtained in 89% isolated yield with
92% ee. Temperature also played a role in the reaction, and
product with 96% ee could be obtained when the reaction was
carried out at 0 °C (Table 5, entry 13). Further lowering the
reaction temperature led to a drop in both yield and enantio-
selectivity (Table 5, entry 16). Catalyst loading was proved to be
crucial as well, and 5 mol% of 9a was sufficient to obtain high
enantioselectivity with a gratifying yield. Further reducing the
amount of 9a to 2 mol% led to a drop of enantioselectivity
(Table 5, entries 14 and 15). Finally, the optimum conditions
were fixed as follows: benzaldehyde (0.5 mmol) was added to a
solution of the ligand 9a (0.025 mmol), DiMPEG 2000
(0.05 mmol), and Et2Zn (1.0 mmol, 1 mL of 1 M toluene solu-
tion) in toluene (2.0 mL). The reaction was carried out at 0 °C
for 24 h.
Entry
Ligand
Yieldb (%)
eec (%)
Config.d
1
2
3
4
5
6
7
8
9a
14a
9b
14b
9c
14c
9d
9e
81
54
46
18
87
52
64
71
43
62
70
80
61
22
12
41
30
30
69
41
67
65
R
R
R
R
R
R
R
R
R
S
9
10
11
14e
9f
9g
R
a Reaction conditions: Benzaldehyde (0.5 mmol) was added to a solu-
tion of the ligand (0.05 mmol) and Et2Zn (1.0 mmol, 1 mL of 1 M
toluene solution) in toluene (2.0 mL). Reaction time: 24 h. b Isolated
yields. c The ee values were determined by HPLC (Chiralcel OD-H
column). d Absolute configuration was assigned by comparison to
reported value and sign of specific rotation of the product.8f.
With the optimum reaction conditions in hand, different
aldehydes were subjected to the same reaction to further study
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Table 5 Optimization of the reaction conditions for 9a-promoted
enantioselective addition of diethylzinc to benzaldehydea
9a
(mol%)
Temp.
(°C)
Yieldb
(%)
eec
(%)
Entry
Solvent
Fig. 5 Possible species in the reaction mixture.
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
10
10
10
10
10
5
Toluene
Chlorobenzene
Benzene
Xylene
CHCl3
DCM
25
25
25
25
25
25
25
25
25
25
25
25
0
81
61
58
62
68
66
47
Trace
Trace
66
71
89
89
86
81
66
86
71
75
59
61
79
81
—
—
81
86
92
96
96
88
84
deduced based on the absolute configuration of the products
which could be assigned by comparison of the specific
rotations with literature results. The substituents on the aro-
matic rings showed some impact on the reaction, and sub-
strates bearing halogen atoms generally gave higher isolated
yields as compared with those bearing electron-donating sub-
stituents (Table 6, entries 2–8 and entries 9–13).
Naphthaldehydes also gave desired results in satisfactory
yields irrespective of the large steric hindrance of the sub-
strates (Table 6, entries 15 and 16). Cinnamaldehyde also gave
product with good yield and satisfactory ee.
To get structural insights into the reaction, DFT calculation
was carried out to study the possible species in the
reaction. When chiral ligand 9a was exposed to excess amount
of diethylzinc, two different species, namely, mono-zinc form
9a-Zn or di-zinc form 9a-Zn2 might be formed. A computation
at M06-2X/SDD level suggested that the di-zinc form 9a-Zn2
was more favored comparing with monozinc moiety 9a-Zn
(Fig. 5).
DCE
THF
9
Dioxane
Cyclohexane
Hexane
Toluene
Toluene
Toluene
Toluene
Toluene
10
11
12d
13d
14d
15
16
0
0
−10
2
10
a Reaction conditions: Benzaldehyde (0.5 mmol) was added to a solu-
tion of the ligand 9a (0.05 mmol) and Et2Zn (1.0 mmol, 1 mL of 1 M
toluene solution) in toluene (2.0 mL). Reaction time: 24 h. b Isolated
yields. c The ee values were determined by HPLC using chiral column
Chiralcel OD-H. d In the presence of DiMPEG 2000 (10 mol%).
the scope of the reaction. The results are summarized in
Table 6. Ligand 9a exhibited excellent catalytic activity for
different aromatic aldehydes. Re-face addition could be
Table 6 Enantioselective addition of diethylzinc to different aldehydesa
Entry
Aldehydes
Product
Yieldb (%)
eec (%)
Config.d
1
2
3
4
5
6
7
8
Benzaldehyde
15a
15b
15c
15d
15e
15f
15g
15h
15i
15j
15k
15l
15m
15n
15o
15p
15q
86
81
79
79
78
84
88
83
86
88
91
89
86
88
86
89
88
96
96
91
94
87
88
96
95
95
97
95
98
96
94
90
95
83
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
2-Methylbenzaldehyde
3-Methylbenzaldehyde
4-Methylbenzaldehyde
3,4-Dimethylbenzaldehyde
2-Methoxybenzaldehyde
3-Methoxybenzaldehyde
4-Methoxybenzaldehyde
3-Fluorobenzaldehyde
2-Chlorobenzaldehyde
3-Chlorobenzaldehyde
2-Bromobenzaldehyde
4-Bromobenzaldehyde
4-Formylbenzonitrile
1-Naphthaldehyde
9
10
11
12
13
14
15
16
17
2-Naphthaldehyde
Cinnamaldehyde
a Reaction conditions: Aldehyde (0.5 mmol) was added to a solution of the ligand 9a (0.025 mmol), DiMPEG 2000 (0.05 mmol) and Et2Zn
(1.0 mmol, 1 mL of 1 M toluene solution) in toluene (2.0 mL) at 0 °C for 24 h. b Isolated yields. c The ee values were determined by HPLC using
chiral columns: Chiralcel OD-H or OB-H or Chiralpak AD-H, respectively. In all cases, the product chromatograms were compared against a
known racemic mixture. d Absolute configuration assigned by comparison to the literature.8f,10m,15h,16
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Fig. 6 Plausible transition state in enantioselective addition of diethyl zinc to aldehydes using 9a as chiral ligand.
Based on the literature reports17 and the preliminary com- thermometer. Infrared spectra were reported in wave number.
putation result, possible reaction intermediate was depicted as HRMS spectra were obtained on a Varian FTICR-MS 7.0T mass
shown in Fig. 6. After reaction of 9a with excess amount of di- spectrometer. HPLC analyses were carried out using Chiralcel
ethylzinc, a dimetal 9a-Zn2 species was formed as the predomi- OD-H, AD-H or OB-H.
nant form of the catalyst. In this model, one of the zinc pos-
sessed a distorted tetrahedral four-coordination structure, and
the other zinc atom possessed a planar three-coordination
structure. Orientation of the aldehyde from a less hindered
direction, with Re-face of the carbonyl group more feasible for
nucleophilic attack.
4.2. Preparation of chiral ligands
4.2.1. 2′-((Benzyloxy)carbonyl)-[1,1′-binaphthalene]-2-carboxylic
acid (4). To a solution of (1,1′-binaphthalene)-2,2′-dicarboxylic
acid (20.00 g, 58 mmol) in 200 mL of DMF was added anhy-
drous potassium carbonate (3.60 g, 26 mmol) in batches at
room temperature. The reaction mixture was stirred for 1 h.
Benzyl bromide (7.0 mL, 58 mmol) was added slowly to the
reaction mixture and the reaction was continued for another
15 h at room temperature. After completion of the reaction,
the solvent was removed in vacuo, and the residue was dis-
solved in 6 M HCl (aq) (50 mL). The aqueous solution was
extracted with DCM (100 mL × 3), and the organic layer was
dried over anhydrous MgSO4. The organic layer was concen-
trated in vacuo, and the residue was purified by silica gel
column chromatography (petroleum ether : ethyl acetate =
5 : 1) to yield 4 (13.20 g, 60% yield) as a white solid, m.p. =
3. Conclusions
In summary, different types of chiral ligands containing both
axial and central chirality were designed, synthesized and eval-
uated using enantioselective addition of diethylzinc to aro-
matic aldehydes as models. The results showed that the chiral
elements should be close to the central metal, and the axial
chirality and the central chirality should match with each
other. All chiral ligands can be used in enantioselective
addition of diethylzinc to aromatic aldehydes, and chiral
ligand 9a derived from BINOL and L-proline exhibited the best
performance among the chiral ligands prepared. Using com-
pound 9a as chiral ligand, the desired chiral alcohols could be
obtained in excellent yields with up to 98% ee at low catalyst
loadings. Further, efficient chemical resolution was realized
when 1,1′-naphthyl-2,2′-dicarboxylic acid was converted to suit-
able diastereomers. This would allow the derivatization of 1,1′-
naphthyl-2,2′-dicarboxylic acid in an easy-to-carry out manner.
Further optimization of these chiral ligands was in good pro-
gress, and the results will be reported in due time.
1
170–171 °C. H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.7 Hz,
1H), 8.03–7.78 (m, 5H), 7.50–7.46 (m, 2H), 7.22–7.04 (m, 5H),
7.01–6.95 (m, 2H), 6.87–6.70 (m, 2H), 4.96–4.76 (m, 2H). 13C
NMR (101 MHz, CDCl3) δ 170.7, 166.9, 140.5, 139.4, 134.9,
134.9, 134.7, 132.6, 128.0, 127.8, 127.8, 127.7, 127.7, 127.6,
127.5, 127.1, 127.0, 127.0, 126.5, 126.2, 125.8, 125.8, 66.6.
4.2.2. Benzyl-2′-(((R)-2-hydroxy-1-phenylethyl)carbamoyl)-
[1,1′-binaphthalene]-2-carboxylate (5a,5b). To a solution of 4
(6.00 g, 14 mmol), Et3N (20 mL, 0.14 mol) and Hobt (3.80 g,
28 mmol) in dry DCM (100 mL) was added dropwise a solution
of EDCI (5.90 g, 31 mmol) in dry DCM (20 mL) with stirring at
0 °C. The reaction mixture was stirred at 0 °C for 2 h and
D-phenylglycinol (2.10 g, 15 mmol) was added. The suspen-
sion was allowed to warm to room temperature and stirred
overnight. TLC analysis (petroleum ether : ethyl acetate = 1 : 1)
4. Experimental section
4.1. General experimental information
Unless otherwise indicated, commercial reagents were used as indicated that the reaction was completed and the reaction
1
received without further purification. H and 13C NMR spectra was quenched by addition of 1 M HCl (aq) (40 mL). The
were recorded in CDCl3 on a 400 MHz spectrometer at 298 K, organic layer was washed twice with 1 M HCl (aq). The com-
using tetramethylsilane (TMS) as an internal standard. bined organic layers were washed with saturated aqueous NaCl
Column chromatography separations were performed employ- (100 mL), dried over MgSO4 and concentrated under reduced
ing 200–300 mesh silica gel. Melting points were measured on pressure. The crude product was purified by silica gel chrom-
a digital melting point apparatus without correction of the atography (petroleum ether : ethyl acetate = 3 : 1) to give
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product 5a (3.00 g, 40% yield) as white solid and 5b (3.00 g, sphere. The reaction mixture was allowed to warm to room
40% yield) as colorless oil. For 5a: m.p. = 143–144 °C. 1H NMR temperature and was stirred overnight. The reaction was moni-
(400 MHz, CDCl3) δ 8.13–7.85 (m, 5H), 7.75 (d, J = 8.2 Hz, 1H), tored with TLC (petroleum ether : ethyl acetate = 10 : 1). After
7.58–7.47 (m, 2H), 7.39–7.03 (m, 10H), 6.91–6.72 (m, 4H), completion of the reaction, the reaction mixture was poured
4.97–4.78 (m, 2H), 4.76–4.71 (m, 1H), 3.07–3.02 (m, 1H), into ice water, and was extracted with EtOAc (30 mL × 2). The
2.93–2.88 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 169.6, 168.9, organic layer was combined and was washed with saturated
138.5, 137.4, 135.0, 134.7, 134.7, 134.1, 133.0, 132.6, 132.1, aqueous NaCl (80 mL), dried over MgSO4 and concentrated in
129.5, 129.0, 128.9, 128.7, 128.6, 128.5, 128.4, 128.3, 128.1, vacuo. The crude product was purified by silica gel chromato-
127.9, 127.7, 127.4, 127.2, 127.0, 126.7, 126.2, 124.9, 124.9, graphy (petroleum ether : ethyl acetate = 8 : 1) to give product
124.7, 67.7, 66.4, 55.9.
2a (610 mg, 88% yield) as white solid. [α]2D0 = 15.0 (c = 1.0,
Crystal data for 5a: C37H29NO4, M = 551.61, a = 10.77140(10) CHCl3); m.p. = 208–210 °C. 1H NMR (400 MHz, CDCl3) δ
Å, b = 11.31850(10) Å, c = 13.33430(10) Å, α = 66.4290(10)°, β = 7.98–7.70 (m, 4H), 7.47 (d, J = 8.8 Hz, 1H), 7.33–7.20 (m, 2H),
80.6470(10)°, γ = 75.0790(10)°, V = 1436.53(2) Å3, T = 100.00(13) 7.13–6.88 (m, 4H), 6.79 (t, J = 7.7 Hz, 2H), 6.71–6.60 (m, 1H),
K, space group P1, Z = 2, μ(CuKα) = 0.659 mm−1, 54 918 reflec- 6.05–5.89 (m, 2H), 5.12–4.96 (m, 1H), 4.45–4.40 (m, 1H),
tions measured, 11 105 independent reflections (Rint = 0.0267). 3.69–3.65 (m, 1H), 1.42 (s, 3H), 1.16 (s, 3H). 13C NMR
The final R1 values were 0.0261 (I > 2σ(I)). The final wR(F2) (101 MHz, CDCl3) δ 166.7, 146.4, 141.8, 141.2, 134.5, 133.6,
values were 0.0655 (I > 2σ(I)). The final R1 values were 0.0266 133.1, 132.2, 131.2, 128.3, 128.2, 128.1, 127.9, 127.4, 127.1,
(all data). The final wR(F2) values were 0.0658 (all data). The 127.0, 126.3, 125.9, 125.9, 125.4, 125.4, 124.6, 75.0, 73.6, 69.4,
goodness of fit on F2 was 1.059. Flack parameter = −0.01(3). 32.8, 30.9. IR (KBr): ν = 3250, 2970, 1644, 1447 cm−1. HRMS
CCDC 2039075.†
(ESI, M + H+) calcd for C32H28NO2 458.2120, found 458.2118.
4.2.5. (Ra,R)-3-(2′-(4-Phenyl-4,5-dihydrooxazol-2-yl)-[1,1′-
For 5b: colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.04–7.81
(m, 5H), 7.75 (d, J = 8.6 Hz, 1H), 7.54–7.44 (m, 2H), 7.35–7.13 binaphthalen]-2-yl)pentan-3-ol (2b). Compound 2b was pre-
(m, 6H), 7.13–6.85 (m, 6H), 6.43–6.25 (m, 2H), 4.89 (q, J = 12.1 pared according to the general procedure of 2a and was iso-
Hz, 2H), 4.67–4.55 (m, 1H), 3.59–3.41 (m, 1H), 2.56–2.53 (m, lated as white solid (610 mg, 85% yield) after flash chromato-
1H). 13C NMR (101 MHz, CDCl3) δ 169.9, 168.6, 138.1, 137.2, graphy (petroleum ether : ethyl acetate
= 4 : 1), m.p. =
135.1, 134.9, 134.3, 134.2, 133.2, 132.6, 132.1, 129.3, 128.8, 79–80 °C; [α]2D0 = +7.0 (c = 1.0, CHCl3). 1H NMR (400 MHz,
128.8, 128.6, 128.4, 128.4, 128.3, 128.0, 127.8, 127.4, 127.3, CDCl3) δ 7.89 (dd, J = 8.5, 0.7 Hz, 1H), 7.83–7.74 (m, 4H),
127.1, 127.0, 126.3, 126.2, 125.2, 124.9, 67.5, 66.6, 56.5.
7.38–7.23 (m, 3H), 7.13–7.03 (m, 1H), 7.01–6.97 (m, 1H), 6.92
4.2.3. Benzyl-2′-((S)-4-phenyl-4,5-dihydrooxazol-2-yl)-[1,1′- (dd, J = 8.7, 1.3 Hz, 2H), 6.81–6.71 (m, 2H), 6.65 (dd, J = 8.7,
binaphthalene]-2-carboxylate (6). To a solution of 5 (3.00 g, 1.0 Hz, 1H), 6.23 (s, 1H), 5.99–5.87 (m, 2H), 5.04 (dd, J = 10.3,
5.44 mmol), Et3N (8.0 mL, 54 mmol) and DMAP (0.06 g, 7.1 Hz, 1H), 4.47 (dd, J = 10.4, 8.4 Hz, 1H), 3.73 (dd, J = 8.4, 7.1
0.54 mmol) in dry DCM (80 mL) was added dropwise a solu- Hz, 1H), 2.08–1.99 (m, 1H), 1.61–1.52 (m, 1H), 1.44–1.29 (m,
tion of TsCl (2.07 g, 10.88 mmol) in dry DCM (20 mL) with stir- 2H), 0.61 (t, J = 7.6 Hz, 3H), 0.49 (t, J = 7.3 Hz, 3H). 13C NMR
ring at 0 °C. The reaction mixture was allowed to warm to (101 MHz, CDCl3) δ 166.8, 143.6, 141.9, 141.2, 134.6, 134.2,
room temperature and stirred overnight. TLC analysis (pet- 133.6, 133.2, 132.2, 128.3, 128.2, 128.1, 127.4, 127.3, 127.1,
roleum ether : ethyl acetate = 4 : 1) indicated that the reaction 126.9, 126.9, 126.9, 126.8, 126.2, 125.9, 125.8, 125.5, 124.9,
was complete and the reaction was quenched by addition of 124.6, 78.4, 75.2, 69.4, 33.5, 32.5, 9.0, 7.7. IR (KBr): ν = 3310,
1 M HCl aq (40 mL), and then organic layer was washed 2950, 1649, 1412 cm−1. HRMS (ESI, M + H+) calcd for
with 1 M HCl (aq) (twice), the combined organic layers were C34H32NO2 486.2433, found 486.2430.
washed with saturated NaCl solution (80 mL), dried over
4.2.6. (Ra,R)-Diphenyl-(2′-(4-phenyl-4,5-dihydrooxazol-2-yl)-
MgSO4 and concentrated under reduced pressure. The crude [1,1′-binaphthalen]-2-yl)methanol (2c). Compound 2c was pre-
product was purified by silica gel chromatography (eluted pared according to the general procedure of 2a and was iso-
with petroleum ether : ethyl acetate = 3 : 1) to give product 6 lated as white solid (780 mg, 90% yield) after flash chromato-
1
(2.60 g, 90% yield) as white solid, m.p. = 163–164 °C. H NMR graphy (petroleum ether : ethyl acetate
= 8 : 1), m.p. =
1
(400 MHz, CDCl3) δ 8.18–8.09 (m, 1H), 8.01 (d, J = 1.3 Hz, 1H), 198–200 °C; [α]2D0 = +1.9 (c = 1.0, CHCl3). H NMR (400 MHz,
7.93–7.77 (m, 4H), 7.50–7.36 (m, 2H), 7.21–7.01 (m, 10H), CDCl3) δ 7.91 (d, J = 2.8 Hz, 2H), 7.86–7.69 (m, 3H), 7.40–7.28
6.82–6.72 (m, 2H), 6.68–6.56 (m, 2H), 5.05–4.76 (m, 4H), (m, 2H), 7.27–7.19 (m, 4H), 7.16–7.07 (m, 6H), 7.06–6.99 (m,
4.19–4.06 (m, 1H), 3.68–3.57 (m, 1H). 13C NMR (101 MHz, 4H), 6.93–6.74 (m, 4H), 6.58–6.54 (m, 1H), 6.24 (dd, J = 8.6, 4.0
CDCl3) δ 167.1, 165.0, 142.5, 139.9, 138.4, 135.5, 135.1, 134.3, Hz, 1H), 4.97 (t, J = 9.9 Hz, 1H), 4.51 (dd, J = 10.1, 8.4 Hz, 1H),
133.1, 128.4, 128.4, 128.3, 128.1, 128.1, 127.9, 127.9, 127.8, 4.10–3.95 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 167.5, 150.7,
127.7, 127.6, 127.1, 126.8, 126.7, 126.4, 126.3, 126.2, 124.7, 144.8, 143.7, 141.5, 140.6, 134.5, 134.4, 134.0, 132.5, 132.3,
74.5, 69.8, 66.6.
129.2, 129.1, 128.6, 128.3, 128.0, 128.0, 127.9, 127.8, 127.7,
4.2.4. (Ra,R)-2-(2′-(4-Phenyl-4,5-dihydrooxazol-2-yl)-[1,1′-binaph- 127.5, 127.3, 127.1, 127.1, 126.9, 126.7, 126.5, 126.3, 126.1,
thalen]-2-yl)propan-2-ol (2a). To a solution of 6 (800 mg, 125.8, 124.9, 124.7, 83.0, 75.5, 70.3. IR (KBr): ν = 3165, 2969,
1.5 mmol) in dry THF (30 mL), was added dropwise 1 M 1647, 1380 cm−1
.
HRMS-ESI (m/z): [M + H]+ calcd for
CH3MgBr (6.0 mL, 6 mmol) in THF at 0 °C under argon atmo- C42H32NO2, 582.2433, found 582.2430.
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4.2.7. (Sa,R)-2-((S)-2′-(4-Phenyl-4,5-dihydrooxazol-2-yl)-[1,1′-
for 2 h and then cyclohexylamine (196 mg, 1.98 mmol) was
binaphthalen]-2-yl)propan-2-ol (2d). Compound 2d was pre- added. The suspension was allowed to warm to room tempera-
pared according to the general procedure of 2a and was iso- ture and stirred overnight. The reaction was monitored with
lated as white solid (500 mg, 85% yield) after flash chromato- TLC (petroleum ether : ethyl acetate = 1 : 1) and was quenched
graphy (petroleum ether : ethyl acetate
=
3 : 1), m.p.
=
by addition of 1 M aqueous HCl (40 mL). The organic layer
83–86 °C; [α]2D0 = +1.6 (c = 1.0, CHCl3). 1H NMR (400 MHz, was washed twice with 1 M HCl, and saturated aqueous NaCl
CDCl3) δ 8.06–7.80 (m, 5H), 7.64 (d, J = 8.9 Hz, 1H), 7.48–7.36 (100 mL), dried over MgSO4 and concentrated in vacuo. The
(m, 2H), 7.27–7.10 (m, 6H), 6.89–6.71 (m, 3H), 4.99–4.95 (m, crude product was purified by silica gel chromatography (pet-
1H), 4.42–4.38 (m, 1H), 3.74 (t, J = 8.5 Hz, 1H), 1.60 (s, 3H), roleum ether : ethyl acetate = 3 : 1) to give product 8a (849 mg,
1.32 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 166.4, 145.6, 141.7, 90% yield), m.p. = 259–261 °C; [α]D20 = +22.3 (c = 1.0, CHCl3).
140.9, 134.4, 133.6, 133.1, 132.0, 130.8, 128.6, 128.1, 128.0, 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 8.5 Hz, 1H), 8.06–7.86
127.9, 127.5, 127.4, 127.3, 127.1, 126.4, 126.3, 126.3, 125.4, (m, 5H), 7.75 (dd, J = 8.5, 1.7 Hz, 1H), 7.55–7.45 (m, 2H), 7.34
125.3, 125.2, 124.8, 74.9, 74.3, 69.7, 32.9, 31.2. IR (KBr): ν = (q, J = 1.9 Hz, 2H), 7.09 (dd, J = 32.4, 8.0 Hz, 2H), 6.91 (t, J = 7.5
3165, 2921, 1647, 1380 cm−1. HRMS (ESI, M + H+) calcd for Hz, 2H), 6.01 (d, J = 7.5 Hz, 2H), 5.16 (t, J = 9.3 Hz, 1H), 4.65 (t,
C32H28NO2 458.2120, found 458.2118.
J = 9.4 Hz, 1H), 3.78 (td, J = 8.2, 1.7 Hz, 1H), 3.55–3.40 (m, 1H),
4.2.8. (Ra,R)-2-(2′-(4-(tert-Butyl)-4,5-dihydrooxazol-2-yl)-[1,1′- 1.71–1.63 (m, 1H), 1.50 (d, J = 13.5 Hz, 1H), 1.43–1.35 (m, 1H),
binaphthalen]-2-yl)propan-2-ol (2e). Compound 2e was pre- 1.25–1.12 (m, 2H), 1.0–0.86 (m, 3H), 0.73 (d, J = 13.0 Hz, 1H),
pared according to the general procedure of 2a and was iso- 0.28–0.15 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 168.8, 166.3,
lated as white solid (440 mg, 86% yield) after flash chromato- 141.7, 137.2, 137.0, 134.6, 134.0, 132.8, 132.3, 132.2, 128.5,
graphy (petroleum ether : ethyl acetate
=
1 : 1), m.p.
=
128.4, 128.3, 128.1, 127.9, 127.8, 127.6, 127.5, 127.1, 126.9,
1
173–175 °C; [α]2D0 = +37.8 (c = 1.0, CHCl3). H NMR (400 MHz, 126.6, 125.9, 125.8, 125.7, 125.0, 124.1, 75.1, 69.6, 47.5, 32.4,
CDCl3) δ 7.82–7.66 (m, 4H), 7.64–7.55 (m, 2H), 7.29–7.25 (m, 32.0, 25.5, 24.6, 24.4. IR (KBr): ν = 3354, 2932, 1649, 1445, 737,
1H), 7.16–7.08 (m, 1H), 7.04–7.00 (m, 1H), 6.90–6.86 (m, 2H), 624 cm−1. IR (KBr): ν = 3431, 3057, 2926, 1649 cm−1
.
6.49–6.47 (dt, 1H), 5.96 (s, 1H), 3.99 (dd, J = 10.0, 8.5 Hz, 2H), HRMS-ESI (m/z): [M + H]+ calcd for C36H33N2O2, 525.2542,
3.82–3.60 (m, 3H), 1.60 (s, 3H), 1.01 (s, 3H), 0.00 (s, 9H). 13C found 525.2538.
NMR (101 MHz, CDCl3) δ 164.6, 145.5, 140.7, 134.3, 133.3,
4.2.11. (Ra,S)-2′-(4-Phenyl-4,5-dihydrooxazol-2-yl)-N-((R)-1-
133.0, 132.1, 128.2, 127.8, 127.7, 127.3, 127.1, 126.8, 126.0, phenylethyl)-[1,1′-binaphthalene]-2-carboxamide (8b). Compound
125.9, 125.6, 125.0, 124.9, 124.8, 124.6, 75.90, 73.0, 68.4, 33.2, 8b was prepared according to the general procedure of 8a and
33.0, 30.6, 24.7. IR (KBr): ν = 3162, 2937, 1648, 1333 cm−1
.
was isolated as white solid (790 mg, 80% yield) after flash
HRMS (ESI, M + H+) calcd for C30H32NO2 438.2433, found chromatography (petroleum ether : ethyl acetate = 4 : 1), m.p. =
1
438.2430.
231–233 °C; [α]2D0 = +8.9 (c = 1.0, CHCl3). H NMR (400 MHz,
4.2.9. 2′-((S)-4-Phenyl-4,5-dihydrooxazol-2-yl)-[1,1′-binaphthal- CDCl3) δ 9.32 (d, J = 8.5 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H),
ene]-2-carboxylic acid (7). A mixture of 6 (6.00 g, 11.24 mmol) 8.01–7.88 (m, 4H), 7.72 (d, J = 8.5 Hz, 1H), 7.57–7.45 (m, 2H),
and NaOH (1.26 g, 22.48 mmol) in MeOH (80 mL) was refluxed 7.40–7.35 (m, 2H), 7.32–7.25 (m, 1H), 7.21–7.12 (m, 3H),
for 16 h. The reaction mixture was concentrated in vacuo to 7.10–7.03 (m, 3H), 6.89 (t, J = 7.7 Hz, 2H), 6.11–5.96 (m, 2H),
remove MeOH. The residue was partitioned between ethyl 5.23–4.48 (m, 3H), 3.79 (t, J = 8.2 Hz, 1H), 0.53 (d, J = 6.8 Hz,
acetate (100 mL) and 1 N aq. HCl (50 mL). The separated 3H). 13C NMR (101 MHz, CDCl3) δ 168.8, 166.3, 143.4, 141.6,
organic layer was washed with water, dried over MgSO4 and 137.1, 137.0, 134.7, 134.2, 133.0, 132.5, 132.3, 128.7, 128.5,
evaporated to dryness. The residue was purified by silica gel 128.4, 128.4, 128.2, 128.0, 127.9, 127.7, 127.7, 127.2, 127.1,
column chromatography (petroleum ether : ethyl acetate = 126.9, 126.8, 126.2, 126.0, 125.9, 125.8, 125.0, 124.1, 75.2, 69.6,
1 : 1) to afford compound 7 (4.60 g, 92% yield), m.p. = 48.6, 21.9. IR (KBr): ν = 3445, 2921, 1641, 648 cm−1. HRMS-ESI
1
148–149 °C, H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.6 Hz, (m/z): [M + H]+ calcd for C38H31N2O2, 547.2386, found
1H), 8.04–7.90 (m, 3H), 7.86 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.4 547.2385.
Hz, 1H), 7.57–7.47 (m, 2H), 7.37–7.20 (m, 3H), 7.14 (d, J = 8.6
4.2.12. (Ra,S)-N-Phenyl-2′-(4-phenyl-4,5-dihydrooxazol-2-yl)-
Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.86 (t, J = 8.0 Hz, 3H), 6.00 (d, [1,1′-binaphthalene]-2-carboxamide (8c). Compound 8c was
J = 7.5 Hz, 2H), 5.21 (m, 1H), 4.77 (m, 1H), 4.03 (t, J = 7.9 Hz, prepared according to the general procedure of 8a and was iso-
1H). 13C NMR (101 MHz, CDCl3) δ 171.4, 168.5, 140.5, 136.48, lated as white solid (350 mg, 50% yield) after flash chromato-
135.4, 134.9, 134.1, 133.3, 132.4, 131.8, 129.4, 129.0, 128.6, graphy (petroleum ether : ethyl acetate
=
3 : 1), m.p.
128.6, 128.3, 128.2, 128.2, 128.0, 127.6, 127.6, 127.4, 127.2, 175–177 °C; [α]2D0 = +48.6 (c = 1.0, CHCl3). H NMR (400 MHz,
126.2, 125.6, 124.3, 124.3, 123.8, 76.4, 68.1. CDCl3 δ 10.45 (s, 1H), 8.25–6.65 (m, 23H), 5.09–3.68 (m, 3H).
=
1
4.2.10. (Ra,S)-N-Cyclohexyl-2′-(4-phenyl-4,5-dihydrooxazol- 13C NMR (101 MHz, CDCl3) δ 168.0, 165.9, 141.0, 138.2, 136.4,
2-yl)-[1,1′-binaphthalene]-2-carboxamide (8a). To a solution 136.0, 134.4, 133.8, 132.5, 132.0, 131.8, 128.8, 128.6, 128.5,
of 7 (800 mg, 1.80 mmol), Et3N (2.6 mL, 18 mmol) and Hobt 128.2, 128.0, 127.8, 127.6, 127.4, 127.0, 126.8, 126.6, 126.6,
(565 mg, 3.73 mmol) in dry DCM (30 mL) was added dropwise 125.9, 125.6, 124.7, 123.9, 123.3, 119.7, 74.7, 69.8. IR (KBr): ν =
a solution of EDCI (760 mg, 3.96 mmol) in dry DCM (10 mL) 3429, 2966, 1652, 698 cm−1. HRMS-ESI (m/z): [M + H]+ calcd
with stirring at 0 °C. The reaction mixture was stirred at 0 °C for C36H27N2O2, 519.2073, found 519.2070.
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Crystal data for 8c: C36H26N2O2, M = 518.59, a = 12.96320 was monitored with TLC. After the completion of the reaction,
(10) Å, b = 12.96320(10) Å, c = 16.2424(2) Å, α = 90°, β = 90°, γ = the residue was washed with DCM (100 mL × 3). The combined
120°, V = 2363.77(5) Å3, T = 294 K, space group P31, Z = 3, organic layer was washed with saturated aqueous NaCl
μ(CuKα) = 0.534 mm−1, 21 690 reflections measured, 6231 (100 mL), dried over MgSO4 and concentrated in vacuo. The
independent reflections (Rint = 0.0170). The final R1 values crude product was purified by silica gel chromatography (pet-
were 0.0329 (I > 2σ(I)). The final wR(F2) values were 0.0963 (I > roleum ether : ethyl acetate = 10 : 1) to give product 10 as color-
1
2σ(I)). The final R1 values were 0.0347 (all data). The final less oil (11.00 g, 92% yield). H NMR (400 MHz, CDCl3) δ 7.99
wR(F2) values were 0.0987 (all data). The goodness of fit on F2 (d, J = 9.1 Hz, 1H), 7.91–7.79 (m, 3H), 7.42 (d, J = 9.1 Hz, 1H),
was 1.100. Flack parameter = 0.11(8). CCDC 2039078.†
7.37–7.31 (m, 2H), 7.31–7.22 (m, 2H), 7.21–7.15 (m, 2H), 7.03
4.2.13. (Ra,S)-N-Isobutyl-2′-(4-phenyl-4,5-dihydrooxazol-2- (d, J = 8.4 Hz, 1H), 4.94 (s, 1H), 3.74 (s, 3H). 13C NMR
yl)-[1,1′-binaphthalene]-2-carboxamide (8d). Compound 8d (101 MHz, CDCl3) δ 156.1, 151.4, 134.2, 133.9, 131.1, 129.9,
was prepared according to the general procedure of 8a and was 129.5, 129.3, 128.3, 127.4, 126.5, 125.0, 124.9, 124.3, 123.3,
isolated as colorless oil (790 mg, 88% yield) after flash chrom- 117.6, 115.5, 115.1, 113.9, 56.8.
atography (petroleum ether : ethyl acetate = 2 : 1); [α]2D0 = +33.1
(c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.82–8.79 (m, methanesulfonate (11). To
4.2.16. (R)-2′-Methoxy-[1,1′-binaphthalen]-2-yl trifluoro-
solution of 10 (10.00 g,
a
1H), 8.19–7.66 (m, 6H), 7.59–7.18 (m, 5H), 7.14–6.82 (m, 4H), 33 mmol) in CH2Cl2 (200 mL) were added pyridine (5.3 mL,
6.15–5.91 (m, 2H), 5.17–5.13 (m, 1H), 4.67–4.62 (m, 1H), 3.77 66 mmol,) and subsequently trifluoromethanesulfonic anhy-
(t, J = 8.3 Hz, 1H), 2.97–2.90 (m, 1H), 2.70–2.64 (m, 1H), dride dropwise (11.20 g, 39.6 mmol) at 0 °C. After the com-
1.29–1.09 (m, 1H), 0.47–0.38 (m, 6H). 13C NMR (101 MHz, pletion of the addition, the cooling bath was removed, the
CDCl3) δ 170.1, 166.3, 141.7, 137.2, 137.0, 134.7, 134.1, 132.9, mixture was allowed to warm to room temperature, and was
132.3, 132.1, 128.7, 128.5, 128.4, 128.2, 127.9, 127.9, 127.6, stirred for 16 h. After the completion of the reaction, the
127.6, 127.2, 127.0, 126.7, 126.0, 126.0, 125.8, 125.2, 124.2, mixture was washed with hydrochloric acid (1 M, 80 mL), satu-
75.2, 69.8, 53.5, 47.0, 28.4, 20.0. HRMS-ESI (m/z): [M + H]+ rated aqueous NaHCO3 (80 mL), and saturated aqueous NaCl
calcd for C34H31N2O2, 499.2386, found 499.2385.
(80 mL). The organic phase was dried over MgSO4, and concen-
4.2.14. (Sa,S)-N-Cyclohexyl-2′-(4-phenyl-4,5-dihydrooxazol-2- trated in vacuo. The product was purified by flash column
yl)-[1,1′-binaphthalene]-2-carboxamide (8e). Compound 8e was chromatography (petroleum ether : ethyl acetate = 10 : 1) to
prepared according to the general procedure of 8a and was iso- afford 11 (14.00 g, 99% yield) as a white solid, m.p. =
lated as white solid (630 mg, 89% yield) after flash chromato- 100–102 °C. 1H NMR (400 MHz, CDCl3) δ 8.16–7.98 (m, 2H),
graphy (petroleum ether : ethyl acetate
=
2 : 1), m.p.
=
7.95 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.60–7.47 (m,
93–95 °C; [α]2D0 = +2.3 (c = 1.0, CHCl3). 1H NMR (400 MHz, 2H), 7.44 (d, J = 9.1 Hz, 1H), 7.40–7.27 (m, 3H), 7.28–7.18 (m,
CDCl3) δ 8.06–7.78 (m, 7H), 7.53–7.46 (m, 2H), 7.35–7.31 (m, 1H), 7.00 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H). 13C NMR (101 MHz,
2H), 7.25–7.13 (m, 4H), 6.94–6.88 (m, 2H), 4.82 (dd, J = 10.1, CDCl3) δ 155.3, 145.8, 133.8, 133.7, 132.7, 131.2, 130.3, 128.9,
8.5 Hz, 1H), 4.38 (dd, J = 10.1, 8.5 Hz, 1H), 3.91 (t, J = 8.5 Hz, 128.4, 128.2, 127.5, 127.4, 127.0, 127.0, 124.9, 123.8, 120.0,
1H), 3.49–3.39 (m, 1H), 1.56–1.45 (m, 1H), 1.41–1.31 (m, 2H), 119.7, 116.8, 115.2, 113.0, 56.3.
1.23–1.14 (m, 1H), 1.07 (ddd, J = 11.6, 3.6, 1.8 Hz, 1H),
4.2.17. (R)-2-Methoxy-2′-methyl-1,1′-binaphthalene (12). All
0.97–0.79 (m, 3H), 0.66–0.50 (m, 2H), 0.21–0.07 (m, 1H). 13C flasks used in the reaction were heated under vacuum for
NMR (101 MHz, CDCl3) δ 169.0, 166.0, 141.8, 137.2, 136.9, 30 minutes and purged with argon for 10 minutes. 1,3-Bis
135.0, 134.3, 133.1, 132.7, 132.4, 129.0, 129.0, 128.9, 128.6, (diphenylphosphino)propane nickel(II) chloride (850 mg,
128.2, 128.2, 128.1, 127.9, 127.8, 127.2, 127.1, 126.9, 126.7, 1.7 mmol) was placed in a 500 mL three-necked round bottom
126.5, 125.4, 124.9, 75.2, 70.5, 47.9, 32.7, 32.4, 25.7, 25.1, 24.9. flask and a solution of triflate 11 (7.00 g, 16.5 mmol) in THF
IR (KBr): ν = 3429, 2966, 1652, 698 cm−1. HRMS-ESI (m/z): [M + (60 mL) was added. The mixture was cooled to 0 °C, and
H]+ calcd for C36H33N2O2, 525.2542, found 525.2539.
CH3MgBr (3.0 M in THF, 20 mL, 75 mmol) was added drop-
Crystal data for 8e: C36H32N2O2, M = 524.63, a = 9.3208(3) Å, wise. The reaction suspension was allowed to warm to room
b = 15.9714(5) Å, c = 19.0521(6) Å, α = 90°, β = 90°, γ = 90°, V = temperature during 2 h and refluxed for 12 h. After the com-
2836.21(16) Å3, T = 133.15 K, space group P212121, Z = 4, pletion of the reaction, the reaction mixture was poured into
μ(MoKα) = 0.076 mm−1, 38 259 reflections measured, 7943 ice water, the aqueous phase was extracted with ethyl acetate
independent reflections (Rint = 0.0416). The final R1 values (100 mL × 3). The combined organic layer was washed with
were 0.0426 (I > 2σ(I)). The final wR(F2) values were 0.0930 (I > water (100 mL), and saturated aqueous NaCl (100 mL), dried
2σ(I)). The final R1 values were 0.0537 (all data). The final over MgSO4, and concentrated in vacuo. The crude product was
wR(F2) values were 0.0993 (all data). The goodness of fit on F2 purified by flash column chromatography on silica gel (pet-
was 1.042. Flack parameter = 0.1(5). CCDC 2039077.†
roleum ether) to provide 12 (4.70 g, 96% yield) as a white solid,
1
4.2.15. (R)-2′-Methoxy-[1,1′-binaphthalen]-2-ol (10). To a m.p. = 66–68 °C, H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 9.0
solution of (R)-BINOL (10.20 g, 40 mmol) and potassium car- Hz, 1H), 7.90–7.80 (m, 3H), 7.48 (d, J = 8.4 Hz, 1H), 7.41 (d, J =
bonate (7.24 g, 52 mmol) in DMF (150 mL) was added drop- 9.1 Hz, 1H), 7.37–7.26 (m, 2H), 7.20–7.11 (m, 3H), 6.99 (d, J =
wise CH3I (2.7 mL, 44 mmol) at room temperature, and the 8.4 Hz, 1H), 3.70 (s, 3H), 2.08 (s, 3H). 13C NMR (101 MHz,
resulting mixture was stirred at 50 °C for 16 h. The reaction CDCl3) δ 154.6, 135.1, 133.8, 133.3, 132.5, 132.3, 129.5, 129.3,
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128.8, 128.1, 128.0, 127.6, 126.7, 126.0, 125.2, 124.8, 123.7, 132.3, 131.6, 129.7, 128.5, 128.1, 127.9, 127.3, 126.5, 125.9,
122.1, 114.0, 56.7, 20.4. 125.4, 125.1, 124.2, 123.4, 119.9, 113.6, 75.5, 69.3, 59.4, 55.8,
4.2.18. (R)-2-(Bromomethyl)-2′-methoxy-1,1′-binaphthalene 54.3, 28.3, 26.6, 26.5, 23.9, 7.8, 7.7.
(13). To a solution of 12 (2.93 g, 10 mmol) and AIBN (165 mg,
4.2.21. (Ra,S)-2-(1-((2′-Methoxy-[1,1′-binaphthalen]-2-yl)methyl)
1 mmol) in DCE (50 mL) was added NBS (1.87 g, 10.5 mmol) pyrrolidin-2-yl)diphenylmethanol (14c). Compound 14c was pre-
in portions in a period of 1 h at room temperature, and the pared according to the procedure of 14a and was isolated as
resulting mixture was refluxed for 6 h. The reaction mixture white solid (1.90 g, 80% yield) after flash chromatography (pet-
was cooled to room temperature and was concentrated in roleum ether : ethyl acetate = 2 : 1), m.p. = 111–112 °C; 1H NMR
vacuo. The residue was washed with DCM (50 × 3 mL), the (400 MHz, CDCl3) δ 8.02 (d, J = 9.1 Hz, 1H), 7.95–7.80 (m, 3H),
combined organic layer was washed with saturated aqueous 7.63 (d, J = 8.5 Hz, 1H), 7.54–7.30 (m, 7H), 7.29–7.14 (m, 3H),
NaCl (50 mL), dried over MgSO4 and concentrated in vacuo. 7.15–7.06 (m, 4H), 7.02 (t, J = 7.5 Hz, 2H), 6.62 (d, J = 8.5 Hz,
The crude product was purified by silica gel chromatography 1H), 3.67 (s, 3H), 3.11–2.71 (m, 3H), 2.29–2.08 (m, 1H),
(petroleum ether) to give product 13 as a white solid (3.20 g, 1.80–1.71 (m, 1H), 1.67–1.42 (m, 4H). 13C NMR (101 MHz,
1
81% yield), m.p. = 86–88 °C, H NMR (400 MHz, CDCl3) δ 7.90 CDCl3) δ 153.8, 147.8, 146.7, 136.5, 134.3, 133.0, 132.7, 132.2,
(d, J = 9.1 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.77 (dd, J = 8.1, 3.3 129.6, 128.9, 128.1, 128.0, 127.9, 127.7, 126.8, 126.7, 126.3,
Hz, 2H), 7.62 (d, J = 8.5 Hz, 1H), 7.35–7.31 (m, 2H), 7.21 (t, J = 126.2, 126.0, 125.6, 125.4, 125.1, 123.7, 120.9, 113.3, 77.9, 70.9,
7.4 Hz, 1H), 7.10 (ddd, J = 23.8, 11.9, 8.4 Hz, 3H), 6.88 (d, J = 58.4, 56.1, 55.5, 29.7, 24.3.
8.5 Hz, 1H), 4.21 (dd, J = 27.0, 10.0 Hz, 2H), 3.65 (s, 3H). 13C
4.2.22. (Ra,S)-2-(1-((2′-Methoxy-[1,1′-binaphthalen]-2-yl)methyl)
NMR (101 MHz, CDCl3) δ 154.9, 134.1, 134.0, 133.9, 133.4, pyrrolidin-2-yl)methanol (14d). Compound 14d was prepared
133.1, 130.3, 129.0, 128.7, 128.2, 128.1, 127.8, 126.8, 126.7, according to the procedure of 14a and was isolated as white
126.6, 126.4, 125.3, 123.9, 119.6, 113.5, 56.4, 32.9.
4.2.19. (Ra,S)-2-(1-((2′-Methoxy-[1,1′-binaphthalen]-2-yl)
solid (2.20 g, 88% yield) after flash chromatography (pet-
roleum ether : ethyl acetate = 1 : 1), m.p. = 86–88 °C; H NMR
1
methyl)pyrrolidin-2-yl)propan-2-ol (14a). (S)-2-(Pyrrolidin-2-yl) (400 MHz, CDCl3) δ 8.02 (d, J = 9.0 Hz, 1H), 7.99–7.84 (m, 3H),
propan-2-ol (4.50 g, 12 mmol), potassium carbonate (2.70 g, 7.77 (d, J = 8.3 Hz, 1H), 7.55–7.37 (m, 2H), 7.32 (t, J = 7.3 Hz,
20 mmol) and NaI (150 mg, 1 mmol) were added into a solu- 1H), 7.20 (dd, J = 15.7, 7.8 Hz, 2H), 7.11 (d, J = 8.4 Hz, 1H),
tion of 13 (3.80 g, 10 mol) in acetonitrile (80 mL). The result- 6.94 (d, J = 8.5 Hz, 1H), 3.78 (d, J = 13.2 Hz, 1H), 3.75 (s, 3H), δ
ing mixture was stirred at room temperature for 16 h. The 3.33–3.06 (m, 3H)., 2.97–2.67 (m, 1H), 2.55–2.31 (m, 1H), 2.16
mixture was washed with ethyl acetate (50 mL × 3). The (d, J = 7.4 Hz, 1H), 1.77–1.56 (m, 2H), 1.56–1.38 (m, 2H). 13C
organic layer was washed with saturated aqueous NaCl NMR (101 MHz, CDCl3) δ 154.1, 134.3, 133.4, 133.2, 133.1,
(50 mL), dried over MgSO4 and concentrated in vacuo. The 129.9, 129.1, 128.1, 128.0, 127.7, 126.7, 126.3, 126.1, 125.6,
crude product was purified by silica gel chromatography (pet- 125.2, 123.9, 121.1, 113.3, 65.3, 61.7, 57.0, 56.4, 54.6, 27.4,
roleum ether : ethyl acetate = 1 : 1) to give product 14a (3.70 g, 23.8.
87% yield) as a white solid, m.p. = 95–96 °C, 1H NMR
4.2.23. (Ra,S)-2-(1-((2′-Methoxy-[1,1′-binaphthalen]-2-yl)methyl)
(400 MHz, CDCl3) δ 8.03 (d, J = 9.0 Hz, 1H), 7.97 (d, J = 8.5 Hz, piperidin-2-yl)propan-2-ol (14e). Compound 14e was prepared
1H), 7.94–7.87 (m, 3H), 7.47 (d, J = 9.1 Hz, 1H), 7.42 (t, J = 7.4 according to the procedure of 14a and was isolated as white
Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.20 (q, J = 7.6 Hz, 2H), 7.11 solid (1.40 g, 65% yield) after flash chromatography (pet-
1
(d, J = 8.5 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 3.86 (d, J = 13.5 Hz, roleum ether : ethyl acetate = 1 : 1), m.p. = 90–91 °C, H NMR
1H), 3.76 (s, 3H), 3.40 (d, J = 13.5 Hz, 1H), 2.81–2.70 (m, 1H), (400 MHz, CDCl3) δ 8.07–8.00 (m, 1H), 7.97 (d, J = 8.6 Hz, 1H),
2.54–2.37 (m, 2H), 1.69 (dt, J = 19.5, 7.4 Hz, 1H), 1.62–1.43 (m, 7.94–7.87 (m, 3H), 7.48–7.39 (m, 2H), 7.33 (ddd, J = 8.1, 6.7,
3H), 0.96 (s, 3H), 0.83 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 1.2 Hz, 1H), 7.21 (dtd, J = 8.2, 6.6, 1.3 Hz, 2H), 7.14 (dd, J = 8.5,
154.3, 137.6, 135.0, 133.7, 133.4, 133.3, 130.2, 129.5, 128.5, 1.2 Hz, 1H), 7.01 (dd, J = 8.5, 1.0 Hz, 1H), 3.91 (s, 1H),
128.2, 127.9, 127.0, 126.6, 126.4, 125.9, 125.8, 124.2, 121.8, 3.78–3.71 (m, 1H), 3.63 (d, J = 13.7 Hz, 1H), 2.80–2.73 (m, 1H),
113.9, 73.7, 73.0, 61.7, 56.7, 55.4, 28.7, 28.3, 25.5, 25.1.
2.59–2.53 (m, 1H), 2.34 (t, J = 5.8 Hz, 1H), 1.60–1.50 (m, 1H),
4.2.20. (Ra,S)-3-(1-((2′-Methoxy-[1,1′-binaphthalen]-2-yl)methyl) 1.43–1.16 (m, 5H), 1.12 (s, 3H), 1.07 (s, 3H). 13C NMR
pyrrolidin-2-yl)pentan-3-ol (14b). Compound 14b was prepared (101 MHz, CDCl3) δ 154.4, 136.9, 134.3, 133.1, 133.0, 132.9,
according to the procedure of 14a and was isolated as yellow 129.8, 129.0, 128.1, 128.0, 127.1, 126.7, 126.3, 126.0, 125.4,
solid (2.40 g, 84% yield) after flash chromatography (pet- 125.4, 123.7, 121.0, 113.1, 72.2, 67.4, 56.8, 56.2, 46.0, 29.2,
roleum ether : ethyl acetate = 1 : 1), m.p. = 107–108 °C; 1H NMR 26.7, 20.7, 20.3, 18.7.
(400 MHz, DMSO-d6) δ 8.10 (d, J = 9.1 Hz, 1H), 8.06–7.90 (m,
4.2.24. (Ra,R)-2-(1-((2′-Methoxy-[1,1′-binaphthalen]-2-yl)methyl)
4H), 7.63 (d, J = 9.1 Hz, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.30 (t, J = pyrrolidin-2-yl)propan-2-ol (14f). Compound 14f was prepared
7.5 Hz, 1H), 7.19 (dd, J = 15.3, 7.8 Hz, 2H), 6.91 (d, J = 8.5 Hz, according to the procedure of 14a and was isolated as white
1H), 6.75 (d, J = 8.5 Hz, 1H), 3.79 (d, J = 13.8 Hz, 1H), 3.72 (s, solid (1.90 g, 75% yield) after flash chromatography (pet-
3H), 3.18 (s, 1H), 3.07 (t, J = 12.4 Hz, 1H), 2.75–2.62 (m, 1H), roleum ether : ethyl acetate = 1 : 1), m.p. = 104–105 °C; 1H NMR
2.39 (t, J = 7.3 Hz, 1H), 2.25–2.10 (m, 1H), 1.64–1.49 (m, 2H), (400 MHz, CDCl3) δ 8.01–7.91 (m, 3H), 7.87 (t, J = 7.3 Hz, 2H),
1.48–1.32 (m, 3H), 1.31–1.12 (m, 3H), 0.68 (q, J = 7.2 Hz, 6H). 7.44–7.34 (m, 2H), 7.32–7.26 (m, 1H), 7.17 (dd, J = 8.3, 6.9 Hz,
13C NMR (101 MHz, DMSO-d6) δ 153.5, 137.6, 133.7, 132.5, 2H), 7.08 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 3.95 (d, J =
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14.5 Hz, 1H), 3.69 (d, J = 6.0 Hz, 3H), 3.32 (d, J = 14.5 Hz, 1H), (dd, J = 9.1, 4.2 Hz, 1H), 3.08–2.77 (m, 3H), 2.18–2.02 (m, 1H),
2.88 (dt, J = 10.7, 5.5 Hz, 1H), 2.57 (s, 1H), 2.49–2.37 (m, 1H), 1.88–1.38 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 150.2, 147.6,
2.10 (dt, J = 10.0, 7.1 Hz, 1H), 1.65–1.49 (m, 3H), 1.35 (dd, J = 146.4, 138.9, 134.0, 133.1, 132.6, 130.2, 130.0, 129.1, 129.0,
11.9, 5.7 Hz, 1H), 1.05 (d, J = 10.3 Hz, 6H). 13C NMR (101 MHz, 129.0, 128.4, 128.3, 128.2, 128.2, 128.1, 128.0, 128.0, 127.0,
CDCl3) δ 155.2, 137.3, 133.5, 133.1, 132.8, 132.0, 129.7, 129.1, 127.0, 126.6, 126.4, 126.3, 126.2, 125.6, 125.6, 125.5, 125.4,
128.0, 127.8, 126.6, 126.2, 126.0, 125.3, 125.2, 123.7, 121.0, 124.5, 123.6, 117.5, 116.8, 78.1, 71.0, 58.3, 55.7, 29.4, 24.3. IR
113.4, 72.9, 72.7, 60.8, 56.4, 55.6, 28.5, 27.7, 25.3, 25.1.
4.2.25. (Ra,S)-2′-((2-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl) H]+ calcd for C38H34NO2, 536.2590, found 536.2588.
methyl)-[1,1′-binaphthalen]-2-ol (9a). To a solution of 14a 4.2.28. (Ra,S)-2′-((2-(Hydroxymethyl)pyrrolidin-1-yl)methyl)-
(KBr): ν = 3649, 2965, 1618, 661 cm−1. HRMS-ESI (m/z): [M +
(425 mg, 1 mmol) in 30 mL DCM was added BBr3 (5 mL, [1,1′-binaphthalen]-2-ol (9d). Compound 9d was prepared
5 mmol, 1 M in DCM) over a period of 1 h at 0 °C under argon. according to the procedure of 9a and was isolated as white
The reaction was monitored with TLC (petroleum ether : ethyl solid (1.40 g, 93% yield) after flash chromatography (pet-
acetate = 1 : 1). After the completion of the reaction, the roleum ether : ethyl acetate = 6 : 1), m.p. = 98–99 °C; [α]D20
=
1
mixture was poured into ice water, extracted with DCM (20 mL +6.8 (c = 1.0, DMSO); H NMR (400 MHz, DMSO-d6) δ 9.63 (s,
× 3). The combined organic layer was washed with saturated 1H), 8.04–7.75 (m, 5H), 7.42 (t, J = 7.2 Hz, 1H), 7.35 (d, J = 8.8
aqueous NaCl (50 mL), dried over MgSO4 and concentrated in Hz, 1H), 7.22 (dd, J = 20.1, 4.2 Hz, 2H), 7.15 (t, J = 7.4 Hz, 1H),
vacuo. The crude product was purified by silica gel chromato- 7.00 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H), 4.17 (s, 1H),
graphy (ethyl acetate) to give product 9a (310 mg, 76% yield) as 3.79 (d, J = 13.2 Hz, 1H), 3.11 (dd, J = 25.4, 11.5 Hz, 2H),
a white solid, m.p. = 91–92 °C; [α]2D0 = +18.9 (c = 1.0, CHCl3); 1H 3.00–2.87 (m, 1H), 2.87–2.69 (m, 1H), 2.33–2.17 (m, 1H), 2.00
NMR (400 MHz, CDCl3) δ 8.01–7.86 (m, 5H), 7.52–7.45 (m, 2H), (d, J = 6.9 Hz, 1H), 1.67 (dd, J = 17.1, 8.2 Hz, 1H), 1.54–1.37 (m,
7.36–7.15 (m, 4H), 6.88 (d, J = 8.4 Hz, 1H), 3.93 (d, J = 13.4 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 152.2, 134.3, 132.6,
1H), 3.61 (d, J = 13.4 Hz, 1H), 2.92 (dt, J = 10.5, 6.7 Hz, 1H), 132.5, 132.4, 129.1, 128.0, 127.9, 127.9, 127.4, 127.1, 126.2,
2.73 (t, J = 6.9 Hz, 1H), 2.61–2.38 (m, 1H), 1.70–1.57 (m, 3H), 125.8, 125.2, 124.0, 122.5, 118.6, 117.2, 65.2, 63.9, 56.8, 54.3,
1.55–1.42 (m, 1H), 0.96 (s, 3H), 0.91 (s, 3H). 13C NMR 28.0, 22.6. IR (KBr): ν = 3578, 3053, 2956, 1733, 818 cm−1
.
(101 MHz, CDCl3) δ 152.2, 135.5, 134.2, 133.4, 133.2, 132.8, HRMS-ESI (m/z): [M + H]+ calcd for C26H26NO2, 384.1964,
130.1, 128.8, 128.7, 128.2, 128.1, 127.8, 126.7, 126.6, 126.5, found 384.1961.
126.3, 124.7, 123.2, 119.0, 117.6, 73.8, 72.0, 61.3, 55.9, 28.1,
27.2, 25.2, 24.6. IR (KBr): ν = 3697, 2967, 1434, 816 cm−1
4.2.29. (Ra,S)-2′-((2-(2-Hydroxypropan-2-yl)piperidin-1-yl)
methyl)-[1,1′-binaphthalen]-2-ol (9e). Compound 9e was pre-
.
HRMS-ESI (m/z): [M + H]+ calcd for C28H30NO2, 412.2277, pared according to the procedure of 9a and was isolated as
found 412.2275.
white solid (300 mg, 83% yield) after flash chromatography
4.2.26. (Ra,S)-2′-((2-(3-Hydroxypentan-3-yl)pyrrolidin-1-yl) (petroleum ether : ethyl acetate = 1 : 1), m.p. = 96–97 °C; [α]D20
=
1
methyl)-[1,1′-binaphthalen]-2-ol (9b). Compound 9b was pre- +33.1 (c = 1.0, CDCl3). H NMR (400 MHz, CDCl3) δ 7.89–7.80
pared according to the procedure of 9a and was isolated as (m, 5H), 7.67 (d, J = 8.8 Hz, 1H), 7.47 (ddd, J = 8.0, 4.8, 3.0 Hz,
yellow solid (600 mg, 74% yield) after flash chromatography 1H), 7.35–7.24 (m, 2H), 7.24–7.17 (m, 2H), 7.16–7.09 (m, 1H),
(petroleum ether : ethyl acetate = 1 : 1), m.p. = 88–89 °C; [α]D20
=
6.76 (d, J = 8.5 Hz, 1H), 4.43 (d, J = 12.8 Hz, 1H), 4.08 (d, J =
1
+47.2 (c = 1.0, DMSO); H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 12.9 Hz, 1H), 3.48–3.27 (m, 1H), 3.02 (dt, J = 14.4, 4.4 Hz,
1H), 8.07–7.79 (m, 5H), 7.41 (t, J = 7.4 Hz, 1H), 7.35 (d, J = 8.8 1H), 2.85 (t, J = 12.3 Hz, 1H), 1.54–1.37 (m, 3H), 1.17 (s, 3H),
Hz, 1H), 7.23 (dd, J = 10.9, 7.1 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 1.09 (d, J = 11.6 Hz, 1H), 1.00 (s, 3H), 0.94–0.77 (m, 2H). 13C
6.99 (d, J = 8.5 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 3.82 (d, J = 13.8 NMR (101 MHz, CDCl3) δ 152.6, 135.7, 133.8, 133.8, 133.2,
Hz, 1H), 3.17 (d, J = 13.4 Hz, 1H), 2.80–2.62 (m, 1H), 2.47–2.35 130.4, 129.2, 128.8, 128.4, 128.2, 127.2, 127.1, 126.9, 126.7,
(m, 1H), 2.33–2.15 (m, 1H), 1.66–1.51 (m, 2H), 1.50–1.33 (m, 124.3, 123.3, 119.2, 116.3, 70.9, 69.2, 60.4, 49.4, 30.7, 25.4,
3H), 1.33–1.11 (m, 3H), 0.68 (q, J = 7.1 Hz, 6H). 13C NMR 20.9, 17.8, 14.2. IR (KBr): ν = 3689, 2975, 1608, 691 cm−1
.
(101 MHz, DMSO-d6) δ 152.0, 134.3, 132.6, 132.5, 129.2, 128.1, HRMS-ESI (m/z): [M + H]+ calcd for C29H32NO2, 426.2433,
127.9, 127.9, 127.3, 127.2, 126.2, 125.7, 125.1, 123.9, 122.5, found 426.2431.
118.3, 116.9, 75.5, 69.5, 59.5, 54.5, 28.3, 26.5, 24.0, 21.3, 7.8. IR
(KBr): ν = 3649, 2968, 1621, 1346 cm−1. HRMS-ESI (m/z): [M + methyl)-[1,1′-binaphthalen]-2-ol (9f). Compound 9f was pre-
H]+ calcd for C30H34NO2, 440.2590, found 440.2588.
pared according to the procedure of 9a and was isolated as
4.2.30. (Ra,R)-2′-((2-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)
4.2.27. (Ra,S)-2′-((2-(Hydroxydiphenylmethyl)pyrrolidin-1- white solid (450 mg, 83% yield) after flash chromatography
yl)methyl)-[1,1′-binaphthalen]-2-ol (9c). Compound 9c was (petroleum ether : ethyl acetate = 1 : 8), m.p. = 106–107 °C. IR
prepared according to the procedure of 9a and was isolated as (KBr): ν = 3691, 2987, 1418, 868 cm−1. HRMS-ESI (m/z): [M +
yellow solid (900 mg, 78% yield) after flash chromatography H]+ calcd for C28H30NO2, 412.2277, found 412.2278. 1H NMR
(petroleum ether : ethyl acetate = 1 : 1), m.p. = 108–110 °C; [α]2D0 (400 MHz, CDCl3) δ 7.87–7.65 (m, 5H), 7.51 (d, J = 8.9 Hz, 1H),
= +63.1 (c = 1.0, CDCl3). 1H NMR (400 MHz, CDCl3) δ 7.98–7.78 7.38 (t, J = 7.7 Hz, 1H), 7.26–7.00 (m, 4H), 6.68 (d, J = 8.5 Hz,
(m, 4H).7.69 (d, J = 8.6 Hz, 1H), 7.43 (dt, J = 17.1, 8.5 Hz, 5H), 1H), 4.04 (d, J = 12.8 Hz, 1H), 3.81 (d, J = 12.9 Hz, 1H), 2.98 (d,
7.34–7.26 (m, 2H), 7.25–7.15 (m, 3H), 7.15–7.02 (m, 5H), J = 28.6 Hz, 1H), 2.95–2.73 (m, 2H), 1.82–1.55 (m, 3H),
7.02–6.93 (m, 1H), 6.51 (d, J = 8.5 Hz, 1H), 4.64 (s, 1H), 3.65 1.46–1.31 (m, 1H), 0.89 (s, 3H), 0.81 (s, 3H). 13C NMR
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(101 MHz, CDCl3) 153.0, 135.3, 134.2, 133.9, 133.3,
130.5, 128.9, 128.7, 128.4, 128.2, 127.2, 127.0, 127.0, 126.9,
124.5, 123.5, 120.0, 117.2, 75.9, 71.2, 60.2, 55.0, 28.0, 27.2,
25.9, 23.8.
Paper
δ
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Acknowledgements
We acknowledge the financial support from the National
Natural Science Foundation of China (NSFC 21672106 and
NSFC 21272121).
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