QSAR analysis of the catalytic asymmetric ethylation of ketone using physical steric parameters of chiral ligand substituents

Article abstract of DOI:10.1016/j.tet.2013.12.054

We have demonstrated that a validated QSAR (quantitative structure-activity relationship) model can be constructed between sterimol steric parameters of the N-substituents of chiral 1,2-amino-phosphoramide ligands and the enantiomeric ratios of alcohol products produced in the asymmetric additions of diethylzinc to acetophenone, which is powerful for predicting the steric effects of ligand substituents on enantioselectivities and instructive for ligand optimization.

Full text of DOI:10.1016/j.tet.2013.12.054

Tetrahedron 70 (2014) 1289e1297
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
QSAR analysis of the catalytic asymmetric ethylation of ketone using
physical steric parameters of chiral ligand substituents
*
Huayin Huang, Hua Zong, Bin Shen, Huifeng Yue, Guangling Bian, Ling Song
The State Key Lab of Structural Chemistry, The Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian Institute of Research on the
Structure of Matter, Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou, Fujian 350002, China
a r t i c l e i n f o
a b s t r a c t
Article history:
We have demonstrated that a validated QSAR (quantitative structureeactivity relationship) model can be
constructed between sterimol steric parameters of the N-substituents of chiral 1,2-amino-phosphor-
amide ligands and the enantiomeric ratios of alcohol products produced in the asymmetric additions of
diethylzinc to acetophenone, which is powerful for predicting the steric effects of ligand substituents on
enantioselectivities and instructive for ligand optimization.
Received 21 September 2013
Received in revised form 10 December 2013
Accepted 20 December 2013
Available online 31 December 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Sterimol parameters
Asymmetric catalysis
Ketones
Molar refraction
1. Introduction
our group has also shown that excellent QSARs between ligand
substituent sizes and enantiomeric ratios of products can be con-
Exploring the relationship between structures and catalytic
properties of chiral ligands is instructive for the reasonable pre-
diction and modification of ligand structure. However, for a long
time, optimizing chiral ligands in asymmetric reactions has been
mainly based on qualitative correlation between the steric and
electronic effects of ligands and enantioselectivities, which is not
practically useful for instructing ligand modification due to the lack
of accurate information. In this decade, investigating quantitative
correlation between the structures of chiral ligands and the enan-
tioselectivities of asymmetric reactions by using computer
methods based on transition state models has achieved significant
progress.1e15 Recently, Sigman and his co-workers have also shown
that QSARs (quantitative structureeactivity relationships) between
structures and enantioselectivities can be established by using
varied physical reference parameters, such as sterimol parameters,
Hammett electronic parameters, pKa values, and Charton values,
etc.16e27
structed by appropriately combining the sets of substituents and
steric reference parameters.33 As one of the most common used
strategies to generate a quaternary stereogenic carbon center, the
asymmetric addition of organozinc reagents to ketones is a hot
topic.34e37 However, in sharp contrast with aldehydes, simple ke-
tones such as acetophenone have much more steric and electronic
constraints. On the other hand, dialkylzinc reagents have lower
reactivities compared with diphenylzinc and dialkynylzinc re-
agents. Moreover, many side reactions can be caused by the basicity
of dialkyzinc reagents. Therefore, as far as we known, only a few
excellent chiral ligands have been reported for the catalytic
asymmetric addition of dialkylzinc reagent to simple ketone.38e54
In 2007, Ishihara and co-workers reported their pioneering work
on the efficient catalytic enantioselective additions of diorganozinc
reagents to ketones using L-valine-derived phosphoramide ligand
with up to 98% ee.49 However, no QSAR studies based on systematic
modification of chiral ligand structures have been reported for this
reaction system.
Several computer assisted studies on the quantitative correla-
tions of chiral ligand structures with enantioselectivities of the
asymmetric addition reactions of organozinc reagents to aldehydes
have been reported using the enantioselective ethylation of ben-
zylaldehyde as a model reaction.6,7,9,28e32 With this model reaction,
Herein, we report our investigation on the quantitative corre-
lations of the substituent sizes of chiral ligands and the enantio-
meric ratios of alcohol products in the asymmetric addition
reactions of diethylzinc to ketones with the uses of steric param-
eters. Our results show that an excellent QSAR model between
sterimol steric parameters of ligand substituents and enantiose-
lectivities can be constructed, which is powerfully useful for
* Corresponding author. Tel.: þ86 591 83720913; fax: þ86 591 83722697; e-mail
address: songling@fjirsm.ac.cn (L. Song).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.12.054

1290
H. Huang et al. / Tetrahedron 70 (2014) 1289e1297
predicting the steric effects of chiral ligand substituents on enan-
tioselectivities of the asymmetric reactions.
O
PPh2
HN
Ph
2. Results and discussion
Ph
H3C
CH3
N
C
Investigation on the catalytic properties of several N-substituted
ligands (1e3 and 4a in Table 1, entries 1e4) derived from (1R,2R)-
cyclohexanediamine, cinchona alkaloids, and (1R,2R)-diphenyle-
thylenediamine showed that chiral phosphoramide ligand 4a de-
rived from chiral (1R,2R)-diphenylethylenediamine was most
active for the asymmetric addition reaction of diethylzinc to ace-
tophenone with 52% of yield and 81% of ee value (Table 1, entry 4). It
was noteworthy that chiral ligand 1, which was highly efficient for
the asymmetric addition of diethylzinc to benzylaldehyde,33 was
very poor for this addition reaction and only 3% of yield and 58% of
ee value of the tertiary alcohol product were obtained (Table 1,
entry 1). Therefore, chiral ligand 1 was not suitable for QSAR study.
For cinchona alkaloids based chiral ligand 2 and 3, which showed
good to excellent activities in the ethylation of a variety of alde-
hydes,55 were also less active for acetophenone as the substrate. In
addition, the N-alkyl groups on the skeletons of chiral ligand 2 and
3 could not be modified systematically. Therefore, we chose
(1R,2R)-diphenylethylenediamine as the chiral pool to synthesize
a series of chiral ligands 4ae4g (Table 1, entries 4e10) with varied
N-substituents as the training set for the development of a QSAR
model. Each chiral ligand was used three times and the ee values
were averaged.
C
H2
H2
4g
Fig. 1. Sterimol parameters using ethyl group of chiral ligand 4g as an example.
investigate the quantitative correlation of ligand N-substituent
sizes and enantioselectivities in the asymmetric additions of
diethylzinc to acetophenone. The sterimol parameters used in our
investigation are listed in Table 2.
Table 2
Sterimol parametersa (B1, B5, L) of R groups
Entry
R group
B1
B5
L
1
2
3
4
5
6
7
8
9
H
Me
Et
Bu
CH2i-Pr
CH2Bu
i-Pr
s-Bu
c-C6H11
1
1
2.06
2.87
4.11
6.17
4.92
6.97
4.11
4.92
6.17
1.52
1.52
1.52
1.52
1.52
1.90
1.90
1.91
2.04
3.17
4.54
4.45
4.94
3.17
3.49
3.49
a
See Refs. 56e58.
Table 1
Evaluation of chiral phosphoramide ligands in the enantioselective ethylation re-
actions of acetophenone with diethylzinc
We evaluated two sets of three-dimensional sterimol parame-
ters simultaneously. The base model included all sterimol sub-pa-
rameters of N-substituents (R1, R2) of chiral phosphoramide 4 and
cross-terms relating each R1-sterimol subparameter to the R2-
sterimol subparameter. A backward stepwise regression analysis
was performed on the system by removing terms and optimizing
the model based on f-tests of statistical significance for the model
and p-tests for the individual coefficients, to generate the correla-
tion represented by Eq. 1, in which X and Y represent the respective
R1 and R2 substituents.
OH
O
Ligand (10 mol%)
CH3
+
Et2Zn
toluene, r.t., 24 h
H
4a: R1 = H, R2 = i-Pr
4b: R1 = H, R2 = c-Hex
4c: R1 = H, R2 = Bu
4d: R1 = H, R2 = CH2i-Pr
4e: R1 = H, R2 = H
O
O
H
N
Ph2P
N
PPh2
HN
H
O
R
Ph
Ph
Ph2P NH HN i-Pr
4f: R1 = Me, R2 = Me
4g: R1 = Et, R2 = Et
N
R1
R2
N
DDGz ¼ 2:260 ꢀ 0:837 ꢁ XL þ 0:162 ꢁ XB ꢁ YB þ 0:059 ꢁ XB
4
1
2: R = H; 3: R = OMe
1
1
5
Yielda (%)
Averaged eeb (%)
ꢁ YB þ 0:067 ꢁ XB ꢁ YL
Entry
Ligand
5
5
1
2
3
4
5
6
7
8
9
1
2
3
4a
4b
4c
4d
4e
4f
4g
3
19
33
52
41
55
50
15
25
19
58.1
60.2
62.2
80.5
84.2
84.8
81.7
63.8
62.6
50.7
(1)
Analysis of the sterimol-based model shows that DDGz is related
to both substituents (see Supplementary data for details). The rel-
atively large negative coefficient value relating the XL term in-
dicates that a R1 substituent with increased length along the
primary bond will lead to a decrease in the level of enantiose-
lectivity dramatically. In contrast, the XB and XB terms of a R1
1
5
substituent and all sub-parameters of a R2 substituent make posi-
tive contributions to DDGz. Fig. 2 shows that a plot of the predicted
DDGz values from Eq. 1 and experimentally determined DDGz values
is linear with slope¼0.999 and R2¼0.999.
10
a
Isolated yields.
Determined by chiral GC analysis.
b
To examine the predictive power of the model Eq. 1, additional
four ligands 4he4k with varied N-substituents were synthesized as
test set. By using these four chiral ligands in the model reaction of
asymmetric addition of diethylzinc to acetopheneone, 12 experi-
mental enantioselectivities were obtained. The predicted and ob-
served values for these four ligands are listed in Table 3 and
depicted in Fig. 3 as a linear plot with slope¼0.879 and R2¼0.960.
Since a linear model with the slope in the range of 0.6e1.4 for test
set is considered predictive,26 the slope of 0.879 indicates that Eq. 1
is a validated QSAR model and highly predictive.
Sterimol parameters (L, B1, B5), which were proposed by
Verloop,56e58 are dimensions of a substituent. L is defined as the
length of the substituent measured along the axis of the primary
bond that joins the substituent to the parent molecule. B1 and B5
are the minimum and maximum distances from the axis of the
primary bond (Fig. 1).
Since sterimol reference parameters had shown their advan-
tages on constructing QSAR in the enantioselective ethylation of
benzylaldehyde in our previous study,33 they were chosen firstly to

H. Huang et al. / Tetrahedron 70 (2014) 1289e1297
1291
Since a better model could be constructed with more experi-
mental data points, we combined the ligands of training and test
sets to investigate the quantitative correlation between sterimol
parameters and enantioselectivities. Using the same analysis
methodology as above, we obtained Eq. 2, in which X and Y rep-
resent the respective R1 and R2 substituents.
DDGz ¼ 2:727 ꢀ 1:067 ꢁ XL þ 0:184 ꢁ XB ꢁ YB þ 0:060 ꢁ XB
5
1
5
ꢁ YB þ 0:064 ꢁ XB ꢁ YL
5
5
(2)
Analysis of Eqs. 1 and 2 shows that they are different but similar.
In Eq. 2, XL of a R1 group makes large negative contribution to DDGz,
and all sub-parameters of a R2 group make positive contributions to
DDGz, which are similar as in Eq. 1 constructed with training set
only. Fig. 4 shows that a plot of the predicted DDGz values from Eq. 2
and experimentally determined DDGz values is linear with
slope¼0.994 and R2¼0.995. The results indicate that XL, X , YB , YB
B5
1
5
and YL are the key steric factors in our investigated system and
a high enantioselectivity is favored by a chiral ligand, which has
a R1 group with short length along the primary bond and a large R2
group.
Fig. 2. Plot of averaged experimental DDGz values versus predicted DDGz values from
Eq. 1 for ligands 4ae4g using acetophenone as the substrate.
Table 3
Experimental and predicted ee values of the asymmetric additions of Et2Zn to
acetophenone catalyzed by chiral phosphoramides 4he4k
O
4h: R1 = H, R2 = Et
4i: R1 = H, R2 = CH2Bu
4j: R1 = H, R2 = s-Bu
4k: R1 = Me, R2 = Et
PPh2
HN
Ph
Ph
N
R1
R2
Entry Ligand Yielda (%) Averaged
Averaged
Averaged
experimental experimental predicted DDGzd
eeb (%)
DDGzc
1
2
3
4
4h
4i
4j
51
58
56
41
79.6
86.8
83.6
74.9
1.288
1.570
1.429
1.150
1.244
1.540
1.379
1.175
4k
a
b
c
Isolated yields.
Determined by using chiral GC analysis.
Estimated at 298 K (25 ꢂC), DDGz¼ꢀRT ln(S/R), R¼0.001986 kcal Kꢀ1 molꢀ1
.
d
Predicted DDGz was calculated by Eq. 1.
Fig. 4. Plot of averaged experimental DDGz values versus predicted DDGz values from
Eq. 2 for ligand 4ae4k using acetophenone as the substrate.
In order to investigate the effect of changing substrate on the
construction of QSAR model, we also run the asymmetric addition
reactions of diethylzinc with 3,5-bis(trifluoromethyl)-acetophe-
none catalyzed by these 11 chiral ligands. Compared with aceto-
phenone, 3,5-bis(trifluoromethyl)-acetophenone gave higher
yields and ee values as shown in Table 4. With sterimol values, Eq. 3
was given as follow in which X and Y represent the respective R1
and R2 substituents.
DDGz ¼ 3:225 ꢀ 1:366 ꢁ XL þ 0:184 ꢁ XB ꢁ YB þ 0:331 ꢁ XL
1
5
ꢁ YB þ 0:033 ꢁ XL ꢁ YL
1
(3)
In Eq. 3, similar as in Eq. 2, XL of a R1 group still has large neg-
ative coefficient value, and all sub-parameters of a R2 group still
make positive contributions to DDGz. Fig. 5 presents an excellent
linear relationship with R2¼0.997 between the predicted DDGz
values from Eq. 3 and experimentally determined DDGz values
shown in Table 4. These results indicate that similar QSAR models
could be established with different ketones despite the differences
of catalytic properties of these chiral ligands for the substrates.
Fig. 3. Plot of averaged experimental DDGz values versus predicted DDGz values from
Eq. 1 for ligand 4he4k using acetophenone as the substrate.

1292
H. Huang et al. / Tetrahedron 70 (2014) 1289e1297
Table 4
acetophenone as the substrates, respectively, in which X and Y
represent the respective R1 and R2 substituents.
Evaluation of chiral phosphoramides in the enantioselective ethylation of 3,5-
bis(trifluoromethyl)-acetophenone with diethylzinc
DDGz ¼ 1:034 ꢀ 0:503 ꢁ XMR þ 0:221 ꢁ YMR
DDGz ¼ 1:776 ꢀ 0:956 ꢁ XMR þ 0:485 ꢁ YMR
(4)
(5)
OH
O
Ligand 4 (10 mol%)
F3C
F3C
CH3
+
Et2Zn
toluene, r.t., 24 h
CF3
CF3
Eqs. 4 and 5 are similar with different coefficient values. Both
equations have negative coefficients of XMR and positive co-
efficients of YMR, indicating that decreasing R1 size and increasing
R2 size lead to higher enantioselectivity. The plots of the predicted
via experimentally determined DDGz values with R2¼0.900 for
acetophenone and R2¼0.901 for 3,5-bis(trifluoromethyl)-aceto-
phenone as shown in Fig. 6 demonstrate that MR parameters can
also be used to construct QSAR, but are less accurate as sterimol
parameters do. The advantages of sterimol over MR parameters
may be that sterimol parameters are three-dimensional parameters
of substituents and MR parameters are only one-dimensional pa-
rameters. However, poor quantitative relationships were observed
for N-mono substituted ligands or all of the N-substituted ligands
between substituent sizes and enantioselectivities in the asym-
metric additions of diethylzinc to both ketones with the use of
Charton values61e65 as the steric parameters (for details please see
Supplementary data), which give excellent linear relationship in
the asymmetric addition of diethylzinc to benzylaldehyde for
Entry
Ligand
Yielda (%)
Averaged eeb (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
56
86
84
58
10
84
12
57
86
83
45
97.4
98.0
97.8
97.5
83.0
86.9
74.4
96.3
98.4
97.9
93.2
9
10
11
4j
4k
a
Isolated yields.
Determined by chiral GC analysis.
b
Fig. 5. Plot of averaged experimental DDGz values versus predicted DDGz values from
Eq. 3 for ligand 4ae4k using 3,5-bis(trifluoromethyl)-acetophenone as the substrate.
Next, we also examined the quantitative correlations between
other kinds of steric parameters and enantioselectivities in this
reaction system. Molar refraction (MR) is a particularly useful
physical parameter in chemistry, pharmaceutical science, and bi-
ological chemistry because it is closely related to the bulkiness and
polarizability of a molecule. It is usually defined by LorenzeLorentz
equation: MR¼((n2ꢀ1)*M)/((n2þ2)*
r
), where n is the relative index,
M is the molecular weight, and
r
is the density.59 They have been
widely used as steric parameters in QSAR analysis of drug de-
sign,57,60 but have not been applied in QSAR analysis of asymmetric
reactions. With MR parameters (Table 5), Eqs. 4 and 5 were ob-
tained using acetophenone and 3,5-bis(trifluoromethyl)-
Table 5
MR parametersa of R groups
Entry
Substituent
MR
Entry
Substituent
MR
1
2
3
4
5
H
Me
Et
i-Pr
Bu
0.10
0.56
1.03
1.50
1.96
6
7
8
9
10
CH2i-Pr
s-Bu
CH2Bu
c-C6H11
d
1.96
1.96
2.42
2.67
d
Fig. 6. Plots of averaged experimental DDGz values versus predicted DDGz values for
ligands 4ae4k with MR as the steric parameters using (a) acetophenone and (b) 3,5-
bis(trifluoromethyl)-acetophenone as the substrates, respectively.
a
See Refs. 57,58.

H. Huang et al. / Tetrahedron 70 (2014) 1289e1297
1293
N-mono substituted ligands.33 These results indicate the limita-
tions of applying Charton parameters for sterically large groups in
quantitative correlation analysis.23,24
of physical reference parameters and the power of an excellent
QSAR model for instructing ligand optimization.
In order to present how the R1 and R2 groups of the catalysts
interact with the substrates, a working model is given in Fig. 7 on
the basis of Ishihara’s conjugate Lewis acideLewis base double
activated transition state mode.49 This model clearly shows that
a Re-face attack, which leads to (R)-product should be favored
without steric repulsion between the R1 and R2 groups of the chiral
catalytic zinc complex and the benzyl group of acetophenone. In
addition, for the Re-face attack, a catalyst with a small R1 and a big
R2 would give higher enantioselectivity because of the less steric
hindrance with the methyl group of acetophenone. Therefore,
4. Experimental section
4.1. General methods
Unless stated otherwise, all experiments were carried out in
dried glassware with magnetic stirring under an atmosphere of dry
nitrogen. 1H NMR (400 MHz), 13C NMR (100 MHz), and 31P NMR
(162 MHz) spectra were recorded in CDCl3 solutions using
a 400 MHz spectrometer. Chemical shifts were reported in parts per
million (ppm, d) relative to CDCl3 (d (d
7.26 for 1H NMR), or CDCl3
77.0 for 13C NMR). Multiplicities are indicated as s (singlet),
d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad).
Commercial reagents were used as received unless otherwise in-
dicated. All solvents were purified and dried prior to use according
to standard methods. Optical rotations were measured on a polar-
T
imeter and reported as follows: [
a
]
(c g/100 mL, solvent). GC
D
analysis was performed on a gas chromatograph with a FID de-
tector on fused silica chiral capillary column (Chirasil Dex CB col-
umn, 25 m lengthꢁ0.32 mm IDꢁ0.25 mm film thickness). High-
resolution mass spectra (HRMS) were obtained by the ESI ioniza-
tion sources. Chiral ligands 1 were prepared according to litera-
ture,33 2 and 3 were prepared according to literature.55
4.2. Representative procedure for preparing chiral ligands 4a,
4b, 4e, 4j
Fig. 7. The proposed working model.
O
NH2
PPh2
Ph
HN
Ph
O
O
O
1. p-TsOH·H2O,
NH2
Ph
N
N
Ph PCl,
2
toluene, reflux, 2 h
O
Et3N
Ph
Ph
Ph
+
O
DCM,
0 oC ~ r.t., 4 h
2. sat. K2CO3, DCM
r.t., 10 h
O
O
NH2
O
7
5
6
O
O
PPh2
HN
PPh2
HN
Ph
N2H4·H2O, EtOH
reflux, 2 h
N-alkylation
7
Ph
Ph
NH2
4e
Ph
HN
R (H)
4a, 4b, 4j
among these 11 chiral ligands, 4i is the most efficient catalyst in the
asymmetric ethylation reaction and gives the highest enantiose-
lectivity of the tertiary alcohol product.
4.2.1. 2-[(1R,2R)-2-Amino-1,2-diphenylethyl]-2,3-dihydro-1H-iso-
indole-1,3-dione (6). A solution of p-TsOH$H2O (5.70 g, 30 mmol) in
toluene (30 mL) was dehydrated by azeotropic distillation (oil bath
120 ꢂC). After being cooled to room temperature, (1R,2R)-1,2-
diphenylethane-1,2-diamine (6.36 g, 30 mmol) was added to the
solution, followed by phthalic anhydride (4.44 g, 30 mmol). The
mixture was stirred at reflux for 12 h, then cooled to room tem-
perature. The solid crude product was collected by filtration,
washed with tolueneehexane and air-dried. The solid crude prod-
uct was then added to a solution of saturated K2CO3 solution
(150 mL) and CH2Cl2 (150 mL), and stirred overnight. After that, the
organic solution was separated and extracted with CH2Cl2 (150 mL)
to give combined organic layers, which were washed with brine,
dried over MgSO4, and concentrated in vacuo to give 7.39 g (72%) of 6
3. Conclusion
In summary, we have explored quantitative correlations be-
tween the N-substituent sizes of chiral phosphoramide ligands and
enantioselectivities in the asymmetric addition reactions of dieth-
ylzinc to ketones using different steric parameters. Our results
show that both sterimol and MR parameters can be used to con-
struct QSAR models in this system. With different substrates, the
catalytic properties of chiral ligands are different, but similar QASR
models can be established. Using sterimol parameters, the de-
veloped QSAR model is highly predictive for ee values of tertiary
alcohol products catalyzed by new synthesized chiral ligands. In
addition, Charton values are not suitable for this system. Our
studies on the effects of different steric parameters on QSAR con-
struction demonstrate the importance of choosing appropriate sets
as a white solid. Compound 6 was directly used in the following step
24.7
without further purification. Mp 133e134 ꢂC; [
a]
79.8 (c 1.00,
D
CH2Cl2); Rf¼0.35 (petroleum ether/EtOAc¼1:1). 1H NMR (400 MHz,
CDCl3):
d
1.67e1.70 (br, 2H), 5.40 (dd, J¼11.0, 36.0 Hz, 2H), 7.13e7.31
(m, 8H), 7.39e7.45 (m, 2H), 7.70e7.76 (m, 2H), 7.83e7.91 (m, 2H).13
C

1294
H. Huang et al. / Tetrahedron 70 (2014) 1289e1297
NMR (100 MHz, CDCl3):
d
56.0, 62.9, 123.3, 127.3, 127.4, 127.7, 128.3,
1.00, CH2Cl2); Rf¼0.30 (MeOH/CH2Cl2¼1:30). 1H NMR (400 MHz,
128.5, 129.1, 131.9, 134.0, 137.9, 143.0, 168.9. HRMS (ESI): (m/z) calcd
CDCl3):
d
0.89 (d, J¼6.1 Hz, 3H), 0.97 (d, J¼6.4 Hz, 3H), 2.51e2.65 (m,
for C22H18N2O2 [MþH]þ: 343.1447, found: 343.1444.
1H), 4.00 (d, J¼6.1 Hz, 1H), 4.29e4.37 (m, 1H), 4.45e4.65 (br, 1H),
7.05e7.16 (m, 5H), 7.17e7.22 (m, 2H), 7.23e7.33 (m, 7H), 7.34e7.44
(m, 2H), 7.51e7.61 (m, 2H), 7.65e7.75 (m, 2H). 13C NMR (100 MHz,
4.2.2. 2-[(1R,2R)-2-[(Diphenylphosphoroso)amino]-1,2-
diphenylethyl]-2,3-dihydro-1H-isoindole-1,3-dione (7). To a solution
of 6 (6.84 g, 20 mmol) in dry CH2Cl2 (60 mL), Et3N (6.06 g, 60 mmol)
was added at room temperature. After being stirred for 10 min,d-
iphenylphosphinic chloride (9.46 g, 40 mmol) in dry CH2Cl2 (30 mL)
was added dropwise to the solution at 0 ꢂC. The mixture was stirred
for 4 h at room temperature, cooled in ice bath, and diluted with
water (20 mL). Extraction with CH2Cl2 gave combined organic layers,
which were washed with brine, dried over MgSO4, and concentrated
in vacuo to give a residue. This residue was subjected to silica gel
column chromatography (EtOAc/hexane¼1:2) to afford 7.37 g (68%)
CDCl3):
d
21.6, 24.1, 45.3, 60.9, 66.0 (d, J¼6.8 Hz), 126.9, 127.1, 127.3,
127.7, 127.9, 128.0, 128.04, 128.1, 128.3, 131.24, 131.28, 131.36, 131.4,
131.7, 131.8, 132.1, 132.2, 133.1, 133.14, 140.67, 140.69, 140.8. 31P NMR
(162 MHz, CDCl3):
d 22.4. HRMS (ESI): (m/z) calcd for C29H31N2OP
[MþH]þ: 455.2244, found: 455.2244.
4.2.5. [(1R,2R)-2-[(Cyclohexylamino)-1,2-diphenyl] (diphenylphos-
phoroso)amine (4b). Cyclohexanone (108 mg, 1.1 mmol) was added
to a stirred solution of 4e (412 mg, 1.0 mmol) in dried methanol (10
mL) with molecular sieves (2 g), followed by three drops of glacial
acetic acid. After being stirred for 2 h, sodium cyanoborohydride
(158 mg, 2.5 mmol) was added to the solution, and the resulting
mixture was stirred overnight at room temperature. The molecular
sieves were filtered through filter paper and the solution was
concentrated in vacuo to remove the methanol. The residue was
dissolved in CH2Cl2 (60 mL) and washed with saturated K2CO3 so-
lution (50 mL). Then the organic layer was dried over anhydrous
MgSO4 and concentrated in vacuo to give a residue that was sub-
of 7 as a white solid. Mp 103e104 ꢂC; [
a]
D
27.7 ꢀ76.4 (c 1.00, CH2Cl2);
Rf¼0.45 (petroleum ether/EtOAc¼1:1). 1H NMR (400 MHz, CDCl3):
d
4.47 (t, J¼10.1 Hz,1H), 5.40 (q, J¼20.3 Hz,1H), 5.79 (d, J¼9.2 Hz,1H),
7.05e7.25 (m, 10H), 7.28e7.49 (m, 8H), 7.57e7.71 (m, 4H), 7.73e7.80
(m, 2H). 13C NMR (100 MHz, CDCl3):
d
56.6, 61.3, 123.2, 126.9, 127.2,
127.7, 128.00, 128.04, 128.1, 128.2, 128.3, 129.1, 131.40, 131.43, 131.56,
131.6, 131.7, 131.8, 132.2, 132.3, 132.7, 133.1, 133.8, 136.5, 140.6, 168.8.
31P NMR (162 MHz, CDCl3):
d 22.5. HRMS (ESI): (m/z) calcd for
C
34H27N2O3P [MþH]þ: 543.1833, found: 543.1832.
jected to silica gel column chromatography (EtOAc/hexane¼1:1) to
26.9
afford 351 mg (71%) of 4b as a white solid. Mp 204e205 ꢂC; [
a]
D
4.2.3. [(1R,2R)-2-Amino-1,2-diphenylethyl](diphenylphosphoroso)
amine (4e). A solution of 7 (7.37 g, 13.6 mmol) in ethanol (50 mL)
containing hydrazine monohydrate (13.6 mL) was stirred at reflux
for 1 h. The mixture was then cooled to room temperature and
diluted with diethyl ether, forming a precipitate that was removed
by filtration. The filtrate was dried over MgSO4 and concentrated in
vacuo to afford 5.32 g (95%) 4e as a white solid, which was used in
57.2 (c 1.00, CH2Cl2); Rf¼0.20 (EtOAc/hexane¼1:2). 1H NMR
(400 MHz, CDCl3):
d 0.76e0.88 (m, 1H), 0.97e1.17 (m, 4H),
1.40e1.70 (m, 5H), 1.74e1.82 (m, 1H), 2.18e2.30 (m, 1H), 4.06 (d,
J¼6.0 Hz, 1H), 4.30 (m, 1H), 4.54 (t, J¼6.7 Hz, 1H), 7.07e7.19 (m, 5H),
7.19e7.25 (m, 2H), 7.26e7.34 (m, 7H), 7.35e7.45 (m, 2H), 7.45e7.55
(m, 2H), 7.63e7.75 (m, 2H). 13C NMR (100 MHz, CDCl3):
d 24.3, 24.9,
26.0, 32.2, 34.6, 52.8, 61.1, 65.4 (d, J¼7.1 Hz), 127.0, 127.2, 127.3,
127.9, 128.0, 128.10, 128.12, 128.14, 128.3, 128.4, 131.4 (d, J¼2.8 Hz),
131.5 (d, J¼2.6 Hz),131.8,131.9,132.0,132.1,132.2,132.3,133.1,133.4,
the following step without further purification. Mp 217e218 ꢂC;
26.8
[
a]
ꢀ78.0 (c 1.00, CH2Cl2); Rf¼0.30 (MeOH/CH2Cl2¼1:20). 1H
D
NMR (400 MHz, CDCl3):
d
1.67 (br, 2H), 4.21e4.30 (m, 1H),
140.9, 141.2. 31P NMR (162 MHz, CDCl3):
d 22.1. HRMS (ESI): (m/z)
4.30e4.35 (m, 1H), 4.45 (t, J¼9.2 Hz, 1H), 7.15e7.27 (m, 7H),
calcd for C32H35N2OP [MþH]þ: 495.2564, found: 495.2560.
7.27e7.39 (m, 10H), 7.39e7.45 (m, 1H), 7.65e7.76 (m, 2H). 13C NMR
(100 MHz, CDCl3):
d
61.3, 61.4, 126.9, 127.1, 127.2, 127.5, 128.09,
4.2.6. (Butan-2-yl)[(1R,2R)-2-[(diphenylphosphoroso)amino]-1,2-
diphenyethyl]amine (4j). The title compound was prepared follow-
ing the general procedure described for 4a on the same scale and was
128.10, 128.18, 128.21, 128.23, 131.31, 131.33, 131.48, 131.5, 132.0,
132.10, 132.12, 132.2, 132.4, 132.6, 133.6, 141.50, 141.52, 142.4. 31P
NMR (162 MHz, CDCl3):
C
d
21.3. HRMS (ESI): (m/z) calcd for
obtained as a white solid with the yield of 314 mg (67%). Mp
26.0
26H25N2OP [MþH]þ: 413.1775, found: 413.1774.
203e204 ꢂC;
[
a
]
ꢀ51.9 (c 1.00, CH2Cl2); Rf¼0.25 (EtOAc/
D
hexane¼1:1). 1H NMR (400 MHz, CDCl3):
d
0.52 (t, J¼7.5 Hz, 1H),
4. 2. 4. [(1R, 2R)-2-[(Diphenylphosphoroso)amino]-1, 2-
diphenylethyl](propan-2-yl)amine (4a). To the solution of 4e (412
mg, 1.0 mmol) in CH3CN (5 mL), K2CO3 (414 mg, 3.0 mmol) and iso-
propyl iodide (540 mg, 3.0 mmol) were added at room temperature.
The resulting mixture was stirred at reflux overnight, cooled to
room temperature, and concentrated in vacuo to give an oily resi-
due. The residue was diluted with CH2Cl2 (20 mL) and water
(20 mL). Then, the organic layer was separated and the aqueous
layer (pH w10) was extracted with CH2Cl2 (3ꢁ15 mL). The com-
bined organic layers were washed with brine, dried over MgSO4,
and concentrated in vacuo, to give a residue that was subjected to
silica gel column chromatography (MeOH/CH2Cl2¼1:40) to afford
0.65e0.87 (m, 5H), 1.00e1.38 (m, 3H), 2.20e2.41 (m, 1H), 3.80e4.00
(m, 1H), 4.15e4.30 (m, 1H), 4.49 (br, 1H), 6.87e7.50 (m, 18H),
7.55e7.65 (m, 2H). 13C NMR (100 MHz, CDCl3):
d 7.7, 9.4, 17.9, 19.7,
26.3, 28.6, 29.8, 49.7, 49.8, 60.1, 64.7 (d, J¼7.0 Hz), 65.2 (d, J¼7.3 Hz),
126.0, 126.2, 126.3, 126.4, 126.8, 126.9, 127.0, 127.02, 127.07, 127.1,
127.2, 127.3, 130.3, 130.35, 130.4, 130.43, 130.7, 130.77, 130.83, 130.87,
130.9, 131.07, 131.15, 131.18, 131.24, 131.3, 132.0, 132.1, 132.3, 132.4,
139.7, 139.82,139.84,140.2. 31P NMR (162 MHz, CDCl3):
d 22.2. HRMS
(ESI): (m/z) calcd for
469.2403.
C
30H33N2OP [MþH]þ: 469.2402, found:
4.3. Representative procedure for preparing chiral ligands 4c,
4d, 4f, 4g, 4h, 4i, 4k
254 mg (56%) of 4a as a white solid. Mp 206e207 ꢂC; [
a]
20.5 ꢀ18.4 (c
D
NH2
R
R (H)
N
O
Ph
Ph
N H ·H O, EtOH
1.
2
4
2
Ph
PPh2
Ph
O
K CO
R-I,
HN
Ph
2
3
reflux, 2 h
N
O
O
N
Ph
O
CH3CN, reflux
Ph POCl,
2.
Et3N,
2
DCM, 0 oC ~ r.t., 4 h
N
R
R (H)
4c ,4d, 4f, 4g, 4h, 4i, 4k
8
6

H. Huang et al. / Tetrahedron 70 (2014) 1289e1297
1295
4.3.1. 2-[(1R,2R)-2-(Butylamino)-1,2-diphenylethyl]-2,3-dihydro-1H-
isoindole-1,3-dione (8c). To the solution of 6 (342 mg, 1.0 mmol) in
CH3CN (5 mL) at room temperature, K2CO3 (276 mg, 2.0 mmol) and
1-butyl iodide (368 mg, 2 mmol) were added. The resulting mixture
was stirred at reflux overnight, cooled to room temperature, and
concentrated in vacuo to give an oily residue. The residue was di-
luted with CH2Cl2 (20 mL) and water (20 mL). The organic layer was
separated and the aqueous layer (pH w10) was extracted with
CH2Cl2 (3ꢁ15 mL). The combined organic layers were washed with
brine, dried over MgSO4, and concentrated in vacuo, to give a resi-
due that was subjected to silica gel column chromatography
1.97e2.15 (m, 2H), 2.50e2.86 (m, 2H), 5.32 (d, J¼12.1 Hz, 1H), 6.01
(d, J¼12.1 Hz, 1H), 7.03e7.26 (m, 8H), 7.51e7.59 (m, 2H), 7.65e7.74
(m, 2H), 7.76e7.91 (m, 2H). 13C NMR (100 MHz, CDCl3):
d 14.1, 43.6,
55.1, 61.8, 122.9, 123.1, 127.1, 127.6, 127.8, 128.2, 129.3, 129.9, 131.7,
132.5, 133.7, 133.8, 135.3, 137.2, 168.3, 168.7. HRMS (ESI): (m/z) calcd
for C26H26N2O2 [MþH]þ: 399.2068, found: 399.2067.
4.3.5. 2-[(1R,2R)-2-(Ethylamino)-1,2-diphenylethyl]-2,3-dihydro-
1H-isoindole-1,3-dione (8h). To the solution of 6 (342 mg,1.0 mmol)
in CH3CN (5 mL) at room temperature, K2CO3 (276 mg, 2.0 mmol)
and ethyl iodide (312 mg, 2 mmol) were added. The resulting
mixture was stirred at reflux overnight, cooled to room tempera-
ture, and concentrated in vacuo to give an oily residue. The residue
was diluted with CH2Cl2 (20 mL) and water (20 mL). The organic
layer was separated and the aqueous layer (pHw10) was extracted
with CH2Cl2 (3ꢁ15 mL). The combined organic layers were washed
with brine, dried over MgSO4, and concentrated in vacuo, to give
a residue that was subjected to silica gel column chromatography
(EtOAc/hexane¼1:40) to afford 259 mg (65%) of 8c as a white solid.
26.1
Mp 131e133 ꢂC; [
a]
69.5 (c 1.00, CH2Cl2); Rf¼0.25 (EtOAc/
D
hexane¼1:10). 1H NMR (400 MHz, CDCl3):
d
0.75 (t, J¼7.3 Hz, 3H),
1.07e1.21 (m, 2H), 1.22e1.36 (m, 2H), 2.31e2.53 (m, 2H), 5.07 (d,
J¼11.0 Hz, 1H), 5.48 (d, J¼11.0 Hz, 1H), 7.08e7.32 (m, 8H), 7.41e7.51
(m, 2H), 7.63e7.76 (m, 2H), 7.82e7.91 (m, 2H). 13C NMR (100 MHz,
CDCl3):
d 13.8, 21.2, 32.2, 46.6, 61.2, 62.0, 123.2, 127.2, 127.6, 128.0,
128.2, 128.3, 129.4, 132.1, 133.8, 137.8, 168.8. HRMS (ESI): (m/z) calcd
(EtOAc/hexane¼1:20) to afford 274 mg (74%) of 8h as a white solid.
27.8
for C26H26N2O2 [MþH]þ: 399.2067, found: 399.2067.
Mp 102e103 ꢂC; [
a]
31.4 (c 1.00, CH2Cl2); Rf¼0.30 (EtOAc/
D
hexane¼1:10). 1H NMR (400 MHz, CDCl3):
d
0.91 (t, J¼7.1 Hz, 3H),
4.3.2. 2-[(1R,2R)-2-[(2-Methylpropyl)amino]-1,2-diphenylethyl]-2,3-
dihydro-1H-isoindole-1,3-dione (8d). The title compound was pre-
pared following the general procedure described for 8c on the same
1.45 (br, 1H), 2.36e2.52 (m, 2H), 5.06 (d, J¼11.3 Hz, 1H), 5.42 (d,
J¼11.3 Hz, 1H), 7.04e7.28 (m, 8H), 7.32e7.46 (m, 2H), 7.65e7.74 (m,
2H), 7.80e7.89 (m, 2H). 13C NMR (100 MHz, CDCl3):
d 15.3, 41.2, 61.2,
scale and was obtained as a white solid with the yield of 239 mg
61.7, 123.2, 127.2, 127.5. 127.9, 128.1, 128.2, 129.3, 132.0, 133.8, 137.8,
141.1, 168.8. HRMS (ESI): (m/z) calcd for C24H22N2O2 [MþH]þ:
371.1752, found: 371.1754.
25.9
(60%). Mp 116e117 ꢂC; [
a
]
8.9 (c 1.00, CH2Cl2); Rf¼0.25 (EtOAc/
D
hexane¼1:8). 1H NMR (400 MHz, CDCl3):
d
0.68 (d, J¼6.7 Hz, 3H),
0.71 (d, J¼6.7 Hz, 3H), 1.30e1.60 (m, 2H), 2.13e2.35 (m, 2H), 5.01 (d,
J¼11.5 Hz, 1H), 5.48 (d, J¼11.5 Hz, 1H), 7.06e7.32 (m, 8H), 7.43e7.51
(m, 2H), 7.64e7.74 (m, 2H), 7.83e7.89 (m, 2H). 13C NMR (100 MHz,
4.3.6. 2-[(1R,2R)-2-(Pentylamino)-1,2-diphenylethyl]-2,3-dihydro-
1H-isoindole-1,3-dione (8i). The title compound was prepared fol-
lowing the general procedure described for 8g on the same scale
CDCl3): d 20.5, 28.5, 55.2, 61.2, 62.3, 123.2, 127.2, 127.6, 127.9, 128.2,
128.3, 129.4, 132.1, 133.9, 137.7, 141.3, 168.9. HRMS (ESI): (m/z) calcd
and was obtained as a white solid with the yield of 280 mg (68%).
25.9
for C26H26N2O2 [MþH]þ: 399.2065, found: 399.2070.
Mp 104e105 ꢂC; [
a
]
17.3 (c 1.00, CH2Cl2); Rf¼0.25 (EtOAc/
D
hexane¼1:10). 1H NMR (400 MHz, CDCl3):
d
0.72 (d, J¼7.2 Hz, 3H),
4.3.3. 2-[(1R,2R)-2-(Dimethylamino)-1,2-diphenylethyl]-2,3-
1.03e1.21 (m, 4H), 1.24e1.49 (m, 3H), 2.32e2.54 (m, 2H), 5.05 (d,
J¼11.3 Hz, 1H), 5.48 (d, J¼11.3 Hz, 1H), 7.08e7.31 (m, 8H), 7.42e7.50
(m, 2H), 7.67e7.75 (m, 2H), 7.81e7.92 (m, 2H). 13C NMR (100 MHz,
dihydro-1H-isoindole-1,3-dione (8f). A mixture of
6 (342 mg,
1.0 mmol), 80% formic acid (1.0 mL), and 36% formaldehyde solu-
tion (0.6 mL, 6.0 mmol) was stirred at reflux (oil bath 85 ꢂC) for 8 h.
Then, the solvent was removed in vacuo, followed by the addition
of saturated Na2CO3 solution (10 mL) and extraction with CH2Cl2
(3ꢁ10 mL). The combined organic layers were washed with brine,
dried over MgSO4, and concentrated in vacuo to give a residue that
was subjected to silica gel column chromatography (EtOAc/
CDCl3):
d 14.0, 22.4, 29.3, 29.7, 61.1, 62.0, 123.2, 127.2, 127.6, 127.9,
128.2, 128.3, 129.4, 132.1, 133.8, 137.2, 168.8. HRMS (ESI): (m/z) calcd
for C27H28N2O2 [MþH]þ: 413.2220, found: 413.2223.
4.3.7. 2-[(1R,2R)-2-[Ethyl(methyl)amino]-1,2-diphenylethyl]-2,3-
dihydro-1H-isoindole-1,3-dione (8k). A mixture of 8h (370 mg,
1.0 mmol), 80% formic acid (1.0 mL), and 36% formaldehyde solu-
tion (0.3 mL, 5.0 mmol) was stirred at reflux (oil bath 85 ꢂC) for 8 h.
The solvents were removed in vacuo, followed by the addition of
saturated Na2CO3 solution (10 mL) and extraction with CH2Cl2
(10 mLꢁ3). The combined organic layers were washed with brine,
dried over MgSO4, and concentrated in vacuo to give a residue that
was subjected to silica gel column chromatography (EtOAc/
hexane¼1:30) to afford 311 mg (84%) of 8f as a white solid. Mp
26.8
211e212 ꢂC;
[
a]
ꢀ88.6 (c 1.00, CH2Cl2); Rf¼0.25 (EtOAc/
D
hexane¼1:15). 1H NMR (400 MHz, CDCl3):
d 2.10 (s, 6H), 5.22 (d,
J¼12.4 Hz,1H), 5.98 (d, J¼12.3 Hz,1H), 7.03e7.26 (m, 8H), 7.50e7.56
(m, 2H), 7.65e7.71 (m, 2H), 7.79e7.88 (m, 2H). 13C NMR (100 MHz,
CDCl3):
d 40.8, 54.9, 66.0, 123.1, 123.5, 127.2, 127.6, 127.7, 128.2,
128.5, 129.2, 129.6, 132.7, 133.7, 133.9, 137.5, 168.6. HRMS (ESI): (m/
z) calcd for C24H22N2O2 [MþH]þ: 371.1758, found: 371.1757.
hexane¼1:30) to afford 322.5 mg (84%) of 8k as a white solid. Mp
26.8
157e158 ꢂC; [
a]
ꢀ134.8 (c 1.00, CH2Cl2); Rf¼0.25 (EtOAc/
D
4.3.4. 2-[(1R,2R)-2-(Diethylamino)-1,2-diphenylethyl]-2,3-dihydro-
1H-isoindole-1,3-dione (8g). To the solution of 6 (342 mg, 1.0 mmol)
in CH3CN (5 mL) at room temperature, K2CO3 (276 mg, 2.0 mmol)
and ethyl iodide (624 mg, 4 mmol) were added. The resulting
mixture was stirred at reflux overnight, cooled to room tempera-
ture, and concentrated in vacuo to give an oily residue. The residue
was diluted with CH2Cl2 (20 mL) and water (20 mL). The organic
layer was separated and the aqueous layer (pH w10) was extracted
with CH2Cl2 (3ꢁ15 mL). The combined organic layers were washed
with brine, dried over MgSO4, and concentrated in vacuo, to give
a residue that was subjected to silica gel column chromatography
hexane¼1:15). 1H NMR (400 MHz, CDCl3):
d
0.85 (t, J¼7.0 Hz, 3H),
2.1 (s, 3H), 2.13e2.23 (m, 1H), 2.38e2.49 (m, 1H), 5.27 (d, J¼12.3 Hz,
1H), 6.02 (d, J¼12.2 Hz, 1H), 7.04e7.11 (m, 1H), 7.12e7.18 (m, 3H),
7.19e7.25 (m, 4H), 7.50e7.59 (m, 2H), 7.64e7.71 (m, 2H), 7.77e7.91
(m, 2H). 13C NMR (100 MHz, CDCl3):
d 13.6, 29.6, 36.8, 47.5, 54.9,
65.3, 122.9, 127.0, 127.2, 127.5, 127.7, 128.1, 129.3, 129.6, 131.6, 132.4,
133.6, 133.7, 137.3, 168.5. HRMS (ESI): (m/z) calcd for C25H24N2O2
[MþH]þ: 385.1913, found: 385.1914.
4.3.8. Butyl[(1R,2R)-2-[(diphenylphosphoroso)amino]-1,2-
diphenyethyl]amine (4c). A solution of 8c (796 mg, 2.0 mmol) in
ethanol (5 mL) containing hydrazine monohydrate (2.0 mL) was
stirred at reflux for 1 h. The mixture was then cooled to room
temperature and diluted with diethyl ether, forming a precipitate
(EtOAc/hexane¼1:40) to afford 295 mg (74%) of 8g as a white solid.
27.8
Mp 152e153 ꢂC; [
a]
ꢀ212.5 (c 1.00, CH2Cl2); Rf¼0.30 (EtOAc/
D
hexane¼1:20). 1H NMR (400 MHz, CDCl3):
d
0.88 (t, J¼7.2 Hz, 6H),

1296
H. Huang et al. / Tetrahedron 70 (2014) 1289e1297
that was removed by filtration. The filtrate was dried over MgSO4
and concentrated in vacuo to give 480 mg of colorless oil, which
was used in the following step without further purification. To
a solution of this oil in dry CH2Cl2 (4 mL), Et3N (606 mg, 6 mmol)
was added at room temperature. After being stirred for 10 min,
diphenylphosphinic chloride (710 mg, 3 mmol) in dry CH2Cl2 (10
mL) was added dropwise to the solution at 0 ꢂC. The mixture was
stirred for 4 h at room temperature, cooled in ice bath, and diluted
with water (20 mL). Extraction with CH2Cl2 gave combined organic
layers that were washed with brine, dried over MgSO4 and con-
centrated in vacuo to give a residue. This residue was subjected to
silica gel column chromatography (EtOAc/hexane¼1:2) to afford
31P NMR (162 MHz, CDCl3):
d 23.1. HRMS (ESI): (m/z) calcd for
C
30H33N2OP [MþH]þ: 469.2407, found: 469.2403.
4.3.12. [(1R,2R)-2-[(Diphenylphosphoroso)amino]-1,2-
diphenyethyl](ethyl)amine (4h). The title compound was prepared
following the general procedure described for 4c on the same scale
and was obtained as a white solid with the yield of 598 mg (68%).
22.1
Mp 202e203 ꢂC; [
a
]
D
ꢀ58.9 (c 1.00, CH2Cl2); Rf¼0.20 (EtOAc/
hexane¼1:1). 1H NMR (400 MHz, CDCl3):
d
0.99 (t, J¼6.9 Hz, 3H),
1.45e1.80 (br, 1H), 2.26e2.41 (m, 1H), 2.46e2.57 (m, 1H), 3.91e4.00
(m, 1H), 4.27e4.42 (m, 2H), 7.10e7.26 (m, 7H), 7.26e7.36 (m, 7H),
7.38e7.52 (m, 4H), 7.66e7.76 (m, 2H). 13C NMR (100 MHz, CDCl3):
721 mg (77%) of 4c as a white solid. Mp 201e202 ꢂC; [
a
]
21.6 ꢀ42.1 (c
d
15.2, 41.6, 60.9, 68.7 (d, J¼6.5 Hz), 127.1, 127.28, 127.33, 128.01,
D
1.00, CH2Cl2); Rf¼0.20 (EtOAc/hexane¼1:1). 1H NMR (400 MHz,
128.04, 128.12, 128.17, 128.24, 128.4, 131.5 (d, J¼2.5 Hz), 131.8, 132.0,
CDCl3):
d
0.81 (t, J¼7.3 Hz, 3H), 1.13e1.39 (m, 5H), 2.22e2.34 (m,
132.1, 132.2, 132.4, 133.0, 133.3, 140.6, 140.9. 31P NMR (162 MHz,
1H), 2.40e2.52 (m, 1H), 3.91 (d, J¼5.7 Hz, 1H), 4.29e4.37 (m, 1H),
4.37e4.44 (m, 1H), 7.11e7.21 (m, 5H), 7.22e7.25 (m, 2H), 7.26e7.35
(m, 7H), 7.37e7.53 (m, 4H), 7.67e7.76 (m, 2H). 13C NMR (100 MHz,
CDCl3):
441.2095, found: 441.2090.
d
22.1. HRMS (ESI): (m/z) calcd for C28H29N2OP [MþH]þ:
CDCl3):
d
13.8, 20.2, 30.0, 47.0, 61.0, 68.8 (d, J¼6.7 Hz), 127.0, 127.2,
4.3.13. [(1R,2R)-2-[(Diphenylphosphoroso)amino]-1,2-
diphenyethyl](pentyl)amine (4i). The title compound was prepared
following the general procedure described for 4c on the same scale
127.3, 128.0, 128.1, 128.2, 128.3, 131.4, 131.7, 131.9, 132.0, 132.1, 132.3,
133.0, 133.4, 140.6, 140.9. 31P NMR (162 MHz, CDCl3):
d 21.9. HRMS
(ESI): (m/z) calcd for C30H33N2OP [MþH]þ: 469.2403, found:
and was obtained as a white solid with the yield of 704 mg (73%).
20.9
469.2403.
Mp 176e177 ꢂC; [
a]
ꢀ74.8 (c 1.00, CH2Cl2); Rf¼0.25 (EtOAc/
D
hexane¼1:1). 1H NMR (400 MHz, CDCl3):
d
0.82 (t, J¼7.2 Hz, 3H),
4. 3. 9. [(1R, 2R)-2-[(Diphenylphosphoroso)amino]-1, 2-
diphenyethyl](2-methylpropyl)amine (4d). The title compound was
prepared following the general procedure described for 4c on the
1.07e1.25 (m, 4H), 1.31e1.41 (m, 2H), 1.51e1.77 (br, 1H), 2.22e2.35
(m, 1H), 2.38e2.53 (m, 1H), 3.91 (d, J¼5.4 Hz, 1H), 4.29e4.37 (m,
1H), 4.37e4.48 (m, 1H), 7.09e7.36 (m, 14H), 7.38e7.52 (m, 4H),
same scale and was obtained as a white solid with the yield of
7.64e7.76 (m, 2H). 13C NMR (100 MHz, CDCl3):
d 14.0, 22.5, 29.3,
23.3
749 mg (80%). Mp 214e215 ꢂC; [
a
]
ꢀ58.8 (c 1.00, CH2Cl2);
29.5, 47.2, 61.0, 68.8 (d, J¼6.7 Hz), 127.1, 127.30, 127.34, 128.01,
128.03, 128.14, 128.16, 128.22, 128.4, 131.5, 131.7, 131.9, 132.0, 132.1,
132.25,132.35,133.0,133.4,140.6,140.9. 31P NMR (162 MHz, CDCl3):
D
Rf¼0.20 (EtOAc/hexane¼1:1). 1H NMR (400 MHz, CDCl3):
d 0.78 (d,
J¼6.7 Hz, 6H), 1.51e1.70 (m, 2H), 2.08e2.17 (m, 1H), 2.21e2.30 (m,
1H), 3.88 (d, J¼5.8 Hz, 1H), 4.27e4.51 (m, 2H), 7.12e7.26 (m, 7H),
7.27e7.36 (m, 7H), 7.38e7.51 (m, 4H), 7.65e7.76 (m, 2H). 13C NMR
d
22.0. HRMS (ESI): (m/z) calcd for C31H35N2OP [MþH]þ: 483.2552,
found: 483.2557.
(100 MHz, CDCl3):
d
20.4, 20.6, 28.3, 55.3, 61.1, 68.9 (d, J¼7.0 Hz),
127.1, 127.26, 127.3, 128.0, 128.1, 128.2, 128.3, 131.4, 131.9, 132.0,
4.3.14. (Diphenylphosphoroso)[(1R,2R)-2-[ethyl(methyl)amino]-1,2-
diphenyl]amine (4k). The title compound was prepared following
the general procedure described for 4c on the same scale and was
132.2, 132.3, 140.7, 140.9. 31P NMR (162 MHz, CDCl3):
d 21.9. HRMS
(ESI): (m/z) calcd for C30H33N2OP [MþH]þ: 469.2397, found:
469.2400.
obtained as a white solid with the yield of 699 mg (77%). Mp
22.5
177e178 ꢂC;
[
a]
46.4 (c 1.00, CH2Cl2); Rf¼0.25 (EtOAc/
D
4.3.10. [(1R,2R)-2-(Dimethylamino)-1,2-diphenylethyl](diphenylphos
phoroso)amine (4f). The title compound was prepared following the
general procedure described for 4c on the same scale and was ob-
hexane¼1:1). 1H NMR (400 MHz, CDCl3):
d
1.09 (t, J¼7.1 Hz, 3H),
2.24 (s, 3H), 2.25e2.35 (m, 1H), 2.49e2.61 (m, 1H), 3.82 (d,
J¼10.8 Hz, 1H), 4.87 (t, J¼10.9 Hz, 1H), 5.52 (s, 1H), 6.78e6.86 (m,
3H), 6.91e6.98 (m, 2H), 7.00e7.09 (m, 4H), 7.10e7.22 (m, 4H),
7.39e7.60 (m, 5H), 7.82e7.93 (m, 2H). 13C NMR (100 MHz, CDCl3):
tained as a white solid with the yield of 660 mg (75%). Mp
27.1
197e198 ꢂC;
[a]
82.9 (c 1.00, CH2Cl2); Rf¼0.20 (EtOAc/
D
hexane¼1:1). 1H NMR (400 MHz, CDCl3):
d
2.24 (s, 6H), 3.72 (d,
d 13.6, 36.1, 47.3, 54.5, 73.6, 73.7, 126.6, 127.3, 127.4, 127.5, 127.6,
J¼10.7 Hz, 1H), 4.83 (t, J¼11.0 Hz,1H), 5.37 (s,1H), 6.78e6.87 (m, 3H),
128.3, 128.5, 128.6, 129.8, 130.7, 130.73, 131.2, 131.3, 131.36, 131.44,
6.90e6.98 (m, 2H), 6.99e7.09 (m, 4H), 7.11e7.23 (m, 4H), 7.40e7.60
131.5, 132.4, 132.5, 132.7, 133.3, 133.6, 134.9, 140.8. 31P NMR
(m, 5H), 7.82e7.97 (m, 2H). 13C NMR (100 MHz, CDCl3):
d
40.5, 54.7
(162 MHz, CDCl3): d 23.7. HRMS (ESI): (m/z) calcd for C29H31N2OP
(d, J¼2.0 Hz), 74.5, 74.6, 126.5, 127.31, 127.37, 127.4, 127.5, 127.52,
128.3, 128.5, 128.6, 129.9, 130.7, 130.72, 131.2, 131.3, 131.4, 131.47,
131.5, 132.36, 132.42, 132.46, 132.5, 133.5, 134.8, 140.8. 31P NMR
[MþH]þ: 455.2245, found: 455.2244.
4.4. General procedure for the enantioselective additions of
diethylzinc to ketones
(162 MHz, CDCl3):
d 23.8. HRMS (ESI): (m/z) calcd for C28H29N2OP
[MþH]þ: 441.2090, found: 441.2090.
A well-dried Pyrex Schlenk tube was charged with chiral ligand
4 (0.10 mmol). Then, diethylzinc (2.0 mL of 1.5 M solution in tolu-
ene, 3.0 mmol) was slowly added at 0 ꢂC under nitrogen atmo-
sphere and the mixture was stirred for 30 min, followed by the
addition of acetophenone (1.0 mmol) dropwise. The resulting
mixture was stirred for 24 h at room temperature, cooled in ice
bath, and quenched with aqueous HCl (10%, 10 mL). Extraction with
EtOAc (10 mLꢁ3) gave combined organic layers, which were
washed with brine (10 mL), dried over MgSO4, and concentrated in
vacuo to give a residue. This residue was subjected to silica gel
column chromatography (EtOAc/hexane¼1:10) to afford the de-
sired tertiary alcohol product. The enantiomeric purity was de-
termined by GC on chiral column.
4.3.11. [(1R,2R)-2-(Diethylamino)-1,2-diphenylethyl](diphenylphos
phoroso)amine (4g). The title compound was prepared following
the general procedure described for 4c on the same scale and was
obtained as a white solid with the yield of 749 mg (80%). Mp
23.0
167e168 ꢂC;
[
a]
43.7 (c 1.00, CH2Cl2); Rf¼0.20 (EtOAc/
D
hexane¼1:1). 1H NMR (400 MHz, CDCl3):
d
1.09 (t, J¼7.1 Hz, 6H),
2.06e2.24 (m, 2H), 2.77e2.94 (m, 2H), 3.93 (d, J¼10.7 Hz, 1H), 4.88
(t, J¼10.6 Hz, 1H), 5.62 (s, 1H), 6.78e6.88 (m, 3H), 6.91e6.99 (m,
2H), 7.00e7.20 (m, 8H), 7.37e7.62 (m, 5H), 7.82e7.95 (m, 2H). 13
C
NMR (100 MHz, CDCl3):
d 14.0, 42.7, 54.5, 69.7, 69.8, 126.6, 127.2,
127.4, 127.5, 127.6, 128.1, 128.3, 128.4, 128.6, 129.8,130.6, 130.7, 131.1,
131.2, 131.3,131.4,131.7,132.2,132.4,133.0,133.6, 134.6,134.9,140.9.

H. Huang et al. / Tetrahedron 70 (2014) 1289e1297
1297
28.3
4.4.1. 2-Phenylbutan-2-ol.40 Colorless oil, [
a
]
þ16.5 (c 1.0, ace-
15. Denmark, S. E.; Gould, N. D.; Wolf, L. M. J. Org. Chem. 2011, 76, 4337e4357.
D
16. Jensen, K. H.; Sigman, M. S. Angew. Chem., Int. Ed. 2007, 46, 4748e4750.
17. Miller, J. J.; Sigman, M. S. Angew. Chem., Int. Ed. 2008, 47, 771e774.
18. Sigman, M. S.; Miller, J. J. J. Org. Chem. 2009, 74, 7633e7643.
19. Jensen, K. H.; Sigman, M. S. J. Org. Chem. 2010, 75, 7194e7201.
20. Jensen, K. H.; Webb, J. D.; Sigman, M. S. J. Am. Chem. Soc. 2010, 132,
17471e17482.
21. Harper, K. C.; Sigman, M. S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 2179e2183.
22. Harper, K. C.; Sigman, M. S. Science 2011, 333, 1875e1878.
23. Gustafson, J. L.; Sigman, M. S.; Miller, S. J. Org. Lett. 2010, 12, 2794e2797.
24. Harper, K. C.; Bess, E. N.; Sigman, M. S. Nat. Chem. 2012, 4, 366e374.
25. Harper, K. C.; Sigman, M. S. J. Org. Chem. 2013, 78, 2813e2818.
26. Harper, K. C.; Vilardi, S. C.; Sigman, M. S. J. Am. Chem. Soc. 2013, 135,
2482e2485.
tone) for 87% ee (R) [lit.40
[
a
]
D
20.0 ꢀ16.7 (c 0.72, acetone) for 96% ee
(S)]; Rf¼0.30 (EtOAc/hexane¼1:8). 1H NMR (400 MHz, CDCl3)
d 0.83
(t, J¼7.4 Hz, 3H), 1.58 (s, 3H), 1.77 (s, 1H), 1.87 (m, 2H), 7.24e7.47 (m,
5H); 13C NMR (100 MHz, CDCl3)
d 8.3, 29.6, 36.7, 74.9, 124.9, 126.5,
128.1, 147.8. The ee value was determined by Chiral GC Chirasil Dex
CB [column temperature: 130 ꢂC, tR¼9.9 min (minor, S),
tR¼10.3 min (major, R)].
4.4.2. 2-[3,5-Bis(trifluoromethyl)]butan-2-ol.66 Colorless oil, [
a]
29.0
D
þ9.9 (c 1.80, CHCl3) for 98.4% ee (R) [lit.66
[
a]
20.0 ꢀ1.1 (c 1.0, CHCl3)
D
27. Miller, S. J. Nat. Chem. 2012, 4, 344e345.
for 22% ee (S)]; Rf¼0.30 (EtOAc/hexane¼1:10). 1H NMR (400 MHz,
28. Rudolph, J.; Bolm, C.; Norrby, P. O. J. Am. Chem. Soc. 2005, 127, 1548e1552.
29. Sciabola, S.; Alex, A.; Higginson, P. D.; Mitchelll, J. C.; Snowden, M. J.; Morao, I. J.
Org. Chem. 2005, 70, 9025e9027.
30. Zhu, H. J.; Jiang, J. X.; Saebo, S.; Pittman, C. U. J. Org. Chem. 2005, 70, 261e267.
31. Huang, J.; Ianni, J. C.; Antoline, J. E.; Hsung, R. P.; Kozlowski, M. C. Org. Lett. 2006,
8, 1565e1568.
32. Kozlowski, M. C.; Ianni, J. C. J. Mol. Catal. A: Chem. 2010, 324, 141e145.
33. Huang, H. Y.; Zong, H.; Bian, G. L.; Song, L. J. Org. Chem. 2012, 77, 10427e10434.
34. Fuji, K. Chem. Rev. 1993, 93, 2037e2066.
CDCl3):
d
0.82 (t, J¼7.5 Hz, 3H), 1.59 (s, 3H), 1.80e1.93 (m, 2H),
1.94e1.99 (m, 1H), 7.76 (s, 1H), 7.90 (s, 2H). 13C NMR (100 MHz,
CDCl3):
d 7.9, 29.7, 36.7, 74.7, 120.6 (m), 122.2, 124.9, 125.4 (d,
J¼3.2 Hz), 131.3, 131.6, 150.5. 19F NMR (376 MHz, CDCl3):
d
ꢀ62.9.
The ee value was determined by Chiral GC Chirasil Dex CB [column
temperature: 110 ꢂC, tR¼12.4 min (minor, S), tR¼13.6 min
(major, R)].
35. Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388e401.
36. Pu, L. Tetrahedron 2003, 59, 9873e9886.
37. Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2004, 43, 284e287.
38. Ramon, D. J.; Yus, M. Tetrahedron Lett. 1998, 39, 1239e1242.
39. Ramon, D. J.; Yus, M. Tetrahedron 1998, 54, 5651e5666.
40. Garcia, C.; LaRochelle, L. K.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124,
10970e10971.
41. Yus, M.; Ramon, D. J.; Prieto, O. Tetrahedron: Asymmetry 2002, 13, 2291e2293.
42. Yus, M.; Ramon, D. J.; Prieto, O. Eur. J. Org. Chem. 2003, 2745e2748.
43. Yus, M.; Ramon, D. J.; Prieto, O. Tetrahedron: Asymmetry 2003, 14, 1103e1114.
44. de Parrodi, C. A.; Walsh, P. J. Synlett 2004, 2417e2420.
45. Forrat, V. J.; Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry 2005, 16,
3341e3344.
Acknowledgements
The authors would like to thank State Key Lab of Structural
Chemistry, Fujian Institute of Research on the Structure of Matter,
Chinese Academy of Sciences for financial support.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.12.054.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
46. Jeon, S. J.; Li, H. M.; Garcia, C.; LaRochelle, L. K.; Walsh, P. J. J. Org. Chem. 2005,
70, 448e455.
47. Jeon, S. J.; Li, H. M.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 16416e16425.
48. Cozzi, P. G. Angew. Chem., Int. Ed. 2006, 45, 2951e2954.
49. Hatano, M.; Miyamoto, T.; Ishihara, K. Org. Lett. 2007, 9, 4535e4538.
50. Fernandez-lbanez, M. A.; Macia, B.; Minnaard, A. J.; Feringa, B. L. Chem. Com-
mun. 2008, 2571e2573.
51. Forrat, V. J.; Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry 2008, 19, 537e541.
52. Hanato, M.; Ishihara, K. Chem. Rec. 2008, 8, 143e155.
53. Hatano, M.; Mizuno, T.; Ishihara, K. Tetrahedron 2011, 67, 4417e4424.
54. Hatano, M.; Gouzu, R.; Mizuno, T.; Abe, H.; Yamada, T.; Ishihara, K. Catal. Sci.
Technol. 2011, 1, 1149e1158.
55. Shen, B.; Huang, H. Y.; Bian, G. L.; Zong, H.; Song, L. Chirality 2013, 25, 561e566.
56. Verloop, A.; Tipker, J. In QSAR in Drug Design and Toxicology; Hadzi, D., Borka, J.
B., Eds.; Elsevier: Amsterdam, 1987; pp 97e100.
57. Hansch, C.; Leo, A. Exploring QSAR: Fundamentals and Applications in Chemistry
and Biology; American Chemical Society: Washington, DC, 1995.
58. Hansch, C.; Leo, A.; Hoekma, D. Exploring QSAR: Hydrophobic, Electronic, and
Steric Constants; American Chemical Society: Washington, DC, 1995.
59. Consonni, V.; Todeschini, R. Handbook of Molecular Descriptors; Wiley-VCH:
Weinheim, Germany/New York, NY, 2000; pp 297e298.
60. Kubinyi, H. QSAR: Hansch Analysis and Related Approaches; Wiley-VCH: Wein-
heim, Germany/New York, NY, 1993; pp 40e43.
61. Charton, M. J. Am. Chem. Soc. 1975, 97, 1552e1556.
62. Charton, M. J. Org. Chem. 1976, 41, 2217e2220.
63. Taft, R. W. J. Am. Chem. Soc. 1952, 74, 2729e2732.
64. Taft, R. W. J. Am. Chem. Soc. 1953, 75, 4538e4539.
65. Charton, M. J. Org. Chem. 1977, 42, 3535e3538.
66. Madduri, A. V. R.; Harutyunyan, S. R.; Minnaard, A. J. Angew. Chem., Int. Ed. 2012,
51, 3164e3167.
References and notes
1. Oslob, J. D.; Akermark, B.; Helquist, P.; Norrby, P. O. Organometallics 1997, 16,
3015e3021.
2. Lipkowitz, K. B.; D’Hue, C. A.; Sakamoto, T.; Stack, J. N. J. Am. Chem. Soc. 2002,
124, 14255e14267.
3. Lipkowitz, K. B.; Kozlowski, M. C. Synlett 2003, 1547e1565.
4. Kozlowski, M. C.; Panda, M. J. Org. Chem. 2003, 68, 2061e2076.
5. Alvarez, S.; Schefzick, S.; Lipkowitz, K.; Avnir, D. Chem.dEur. J. 2003, 9,
5832e5837.
6. Kozlowski, M. C.; Dixon, S. L.; Panda, M.; Lauri, G. J. Am. Chem. Soc. 2003, 125,
6614e6615.
7. Ianni, J. C.; Annamalai, V.; Phuan, P. W.; Panda, M.; Kozlowski, M. C. Angew.
Chem., Int. Ed. 2006, 45, 5502e5505.
8. Chen, J.; Wen, J. W.; Li, M. Z.; Tianpa, Y. P. J. Mol. Catal. A: Chem. 2006, 258,
191e197.
9. Urbano-Cuadrado, M.; Carbo, J. J.; Maldonado, A. G.; Bo, C. J. Chem. Inf. Model.
2007, 47, 2228e2234.
10. Houk, K. N.; Cheong, P. H. Y. Nature 2008, 455, 309e313.
11. Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2009, 131, 15358e15374.
12. Donoghue, P. J.; Helquist, P.; Norrby, P. O.; Wiest, O. J. Am. Chem. Soc. 2009, 131,
410e411.
13. Maldonado, A. G.; Rothenberg, G. Chem. Soc. Rev. 2010, 39, 1891e1902.
14. Denmark, S. E.; Gould, N. D.; Wolf, L. M. J. Org. Chem. 2011, 76, 4260e4336.