Enantioselectivity switch controlled by N,N′-di- or N,N,N′,N′-tetra-substituted chiral thiophosphorodiamide ligands, structural relatives of thioureas, in catalytic additions of diethylzinc to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2013.12.014

We have developed a series of new chiral thiophosphorodiamide ligands derived from (1R,2R)-(+)-1,2-diphenylethylenediamine, which are the structural relatives of thioureas. An investigation into their catalytic properties in asymmetric additions of diethylzinc to aldehydes has shown that N,N,N′,N′-tetra-substituted chiral thiophosphorodiamides can give (R)-secondary alcohols with up to 98% yield and 98% ee, while N,N′-di-substituted chiral thiophosphorodiamides give (S)-secondary alcohols with up to 99% yield and 97% ee values. The enantioselectivity switch is highly efficient with a broad substrate scope. We have also proposed hypothetical reaction pathways, which result in an enantioselectivity switch.

Full text of DOI:10.1016/j.tetasy.2013.12.014

Tetrahedron: Asymmetry 25 (2014) 170–180
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselectivity switch controlled by N,N0-di- or N,N,N0,N0-
tetra-substituted chiral thiophosphorodiamide ligands, structural
relatives of thioureas, in catalytic additions of diethylzinc to
aldehydes
⇑
Huifeng Yue, Huayin Huang, Guangling Bian, Hua Zong, Fangling Li, 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, 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:
Received 22 October 2013
Accepted 6 December 2013
We have developed a series of new chiral thiophosphorodiamide ligands derived from (1R,2R)-(+)-1,2-
diphenylethylenediamine, which are the structural relatives of thioureas. An investigation into their cat-
alytic properties in asymmetric additions of diethylzinc to aldehydes has shown that N,N,N0,N0-tetra-
substituted chiral thiophosphorodiamides can give (R)-secondary alcohols with up to 98% yield and
98% ee, while N,N0-di-substituted chiral thiophosphorodiamides give (S)-secondary alcohols with up to
99% yield and 97% ee values. The enantioselectivity switch is highly efficient with a broad substrate
scope. We have also proposed hypothetical reaction pathways, which result in an enantioselectivity
switch.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
which the positions of the amine and sulfonamide groups are
exchanged. Under optimized conditions, these two ligands
In metal promoted asymmetric catalysis, one of the most
important fields is the development of excellent chiral ligands.1–3
As a model reaction, the asymmetric addition of diethylzinc to
aldehyde is widely used for testing the catalytic properties of var-
ious new chiral ligands and a variety of effective chiral ligands have
been reported so far.4–15 In general, only one enantiomer of the
secondary alcohol product can be obtained from a series of struc-
turally related chiral ligands with identical chirality. However,
recent reports have demonstrated that both enantiomers of a prod-
uct can be obtained by structural modification of a chiral ligand in
the reaction (Scheme 1).16–22
The high efficiency of an enantioselectivity switch can be
achieved by exchanging the positions of functional groups attached
on different stereogenic centers. Krzeminski et al. showed that reg-
ioisomeric amino alcohols I-A and I-B, derived from one enantio-
mer of nopinone, provided antipodal enantiofacial selectivity in
dialkylzinc addition reactions with various aldehydes. Up to 99%
ee of the secondary alcohol products with opposite configurations
were obtained.16 Hirose et al. reported the switching of enantiose-
lectivity in catalytic additions of diethylzinc to aldehydes by regio-
isomeric chiral 1,3-amino sulfonamide ligands II-A and II-B, in
provided (S)- and (R)-enantiomeric secondary alcohols with good
to excellent enantioselectivities, respectively.17 An efficient enanti-
oselectivity switch was also reported by Wang et al. who changed
the position of the functional groups of III-A and III-B.18 In addi-
tion, Burguete et al. reported on effective chirality switching in
the addition of diethylzinc to aldehydes by using simple alpha-
amino amides derived from natural amino acids. Moderate to good
enantioselectivities were obtained by straightforward adjustment
of the stoichiometry of the Ni complexes (1:1 and 1:2 complexes
IV-A and IV-B).19
The effect of the substituent size on the enantioselectivity
switch has also been investigated in the asymmetric addition reac-
tions of diethylzinc to benzaldehyde. Alvarez-Ibarra et al. showed
that attaching a bulky diphenyl group V-B on the neighboring
carbon of the hydroxyl group of ligand V-A inverted the enantiose-
lectivity of the asymmetric addition reaction from 76% ee with an
(R)-configuration to 79% with an (S)-configuration.20 Szakonyi et al.
reported that the enantioselectivity in asymmetric addition reac-
tions could be switched by changing the size of one substituent
of a chiral ligand derived from pinane-based 1,3-diamines VI-A
and VI-B, but the best enantioselectivity was only 65% for the
(R)-alcohol and 83% for the (S)-alcohol.21 However, Soai et al.
reported that highly enantioselective switching could be achieved
by changing the size of two substituents at two key positions of a
chiral ligand VII-A and VII-B.22
⇑
Corresponding author. Tel.: +86 591 83720913; fax: +86 591 83722697.
E-mail address: songling@fjirsm.ac.cn (L. Song).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.12.014

H. Yue et al. / Tetrahedron: Asymmetry 25 (2014) 170–180
171
O
N
O
Ph
Ph
H
O
Ph
Ph
H
N
H
H
N
O
OH
NHTs
NMe2
NHTs
N
H
H
H
H
HO
N
H
Me
H
Ph
Ph
Me
I-A
II-B
III-B
II-A
III-A
I-B
O
N
O
N
H2N
H2N
tBu
tBu
H2N
tBu
Ni
Ni
N
O
MeO
H2O
1: 2 complex
1: 1 complex
IV-A
IV-B
Ph
NHTs
N
H
NHTs
N
Ph
Ph
N
N
H
Me
Ph
N
N
OH
HO
OH
HO
Ph
Me
O
O
Ph Ph
VI-A
VII-B
VI-B
V-B
V-A
VII-A
Scheme 1. Reported ligands, derived from the same chirality, which can switch the enantioselectivity in asymmetric additions of organozinc reagents to aldehydes.
Ishihara et al. reported that a series of N,N-di-substituted chiral
phosphoramide ligands derived from -valine showed high enanti-
cal Eschweiler–Clarke reaction in 85% yield while 4–6 were by
reaction of compound 2 with three different iodoalkanes and anhy-
drous potassium carbonate at reflux in 75–98% yields. The asym-
metric N,N-di-substituted compounds 10–12 were obtained
according to the same procedure for 3 in 85–90% yields from
compounds 7–9, which were synthesized according to the same
procedure for 4–6 in 75–83% yields. The N-mono-substituted com-
pounds 13–15 were obtained via reaction of compound 2 with
three types of acylating reagents (CH3COCl, Boc2O, CbzCl) under
mild conditions in 70–99% yields. Deprotecting compounds 3–6
and 10–15 by treatment with hydrazine hydrate at reflux for two
hours gave 16–25 in 85–95% yields. Further treatment with phe-
nylthiophosphonic dichloride and triethylamine in acetonitrile
produced N,N,N0,N0-tetra-substituted and N,N0-di-substituted chiral
thiophosphorodiamide ligands 26–35 in 60–85% yields.
In order to examine the catalytic properties of the above syn-
thesized chiral ligands, the asymmetric addition of diethylzinc to
benzaldehyde was carried out in the presence of catalytic amounts
of ligands 26–35. As shown in Table 1, the structures of the ligands
dramatically varied the enantioselectivities of the asymmetric
addition reactions. All of the N,N,N0,N0-tetra-substituted ligands
26–32 gave secondary alcohol products with an (R)-configuration,
while all of the N,N0-di-substituted ligands 33–35 gave the corre-
sponding products with an (S)-configuration. For N,N,N0,N0-
tetra-substituted ligands 26–32, the ee values of the (R)-alcohol
products varied from 4% to 93% (entries 1–7). Compared with the
symmetric N,N,N0,N0-tetra-substituted ligands 26–29, the asym-
metric N,N,N0,N0-tetra-substituted ligands 30–32 significantly in-
creased the enantioselectivities of the asymmetric reactions and
the highest ee value of (R)-37a was obtained with ligand 31 con-
taining an N-Me(iPr) group. For the N,N0-di-substituted ligands
33–35, the ee values of the (S)-alcohol products were controlled
by the substituent sizes (entries 8–10). Ligand 33 containing a
small acetyl group showed poor enantioselectivity for the reaction
and with only an 19% ee value for (S)-37a being obtained. However,
ligand 35 containing a very bulky Cbz group gave 92% ee for
(S)-37a. Moreover, for ligand 35, reducing the reaction time to
1 h favored the addition reaction to give an increased ee value of
95% for (S)-37a without decreasing the yield of the product.
L
oselectivities in asymmetric additions of organozinc reagents to
aldehydes and ketones.23–26 In order to develop better chiral cata-
lysts in the family of chiral phoshphoramide ligands, our group has
recently explored the asymmetric addition of diethylzinc to
aldehydes catalyzed by a variety of N-mono-substituted and
N,N-di-substituted chiral phosphoramide ligands derived from
(1R,2R)-cyclohexane-1,2-diamine and cinchona alkaloids.27–29
Structural modification of these ligands from a uniform chirality
affords only one enantiomer of a secondary alcohol as the major
product. We have found that the enantioselectivity of the reaction
can be switched efficiently by using N,N,N0,N0-tetra-substituted and
N,N0-di-substituted chiral thiophosphorodiamide ligands derived
from (1R,2R)-(+)-1,2-diphenylethylenediamine. Chiral thiophosp-
horodiamide ligands have been used as structural relatives of thio-
ureas in organocatalysis,30 but there is no report of using these
types of chiral ligands in metal catalyzed reactions. Herein we
report an efficient enantioselectivity switch controlled by the
N-substituents of the chiral thiophosphorodiamide ligands in
asymmetric additions of diethylzinc to aldehydes. The N,N,N0,
N0-tetra-substituted chiral thiophosphorodiamides gave (R)-sec-
ondary alcohols with up to 98% yield and 98% ee, while the
N,N0-di-substituted chiral thiophosphorodiamides gave (S)-second-
ary alcohols with up to 99% yield and 97% ee value.
2. Results and discussion
As shown in Scheme 2, a series of N,N,N0,N0-tetra-substituted
and N,N0-di-substituted chiral thiophosphorodiamide ligands
26–35 were derived from commercially available chiral (1R,2R)-
(+)-1,2-diphenylethylenediamine 1. Chiral 1,2-diamine 1 reacted
with phthalic anhydride in the presence of p-toluenesulfonic acid
at reflux to afford compound 2 in 72% yield, followed by various
N-substituent modifications to give seven symmetric and asym-
metric N,N,N0,N0-tetra-substituted and three N,N0-di-substituted
chrial thiophosphorodiamide ligands. For the symmetric N,N-
di-substituted compounds 3–6, ligand 3 was obtained via a classi-

172
H. Yue et al. / Tetrahedron: Asymmetry 25 (2014) 170–180
Ph
Ph
NH2
N
Ph
Ph
NH2
NH2
a, b
O
72%
O
1
2
O
O
Me
N
Ph
Ph
N
N
H
O
Ph
Me
O
e
c
99%
Ph
N
85%
O
13
3
R1
Boc
N
Ph
Ph
H
O
Ph
Ph
N
R2
O
4: R1 = R2 = Et (75%)
d
f
1
: R R2 = (CH2)4 (98%)
5
2
6: R1R2 = (CH2)5 (89%)
N
N
95%
O
O
14
Cbz
H
Me
Ph
Ph
N
N
H
R3
O
Ph
N
R3
O
Ph
Ph
N
d
c
g
O
Ph
N
N
70%
O
O
O
10:R3 = Et (85%)
:R3 = Et (83%)
8:R3 = iPr (82%)
15
7
3
:R = iPr (90%)
11
12:R3 = CH2Bu (88%)
:R3 = CH2Bu (75%)
9
16 and 26: R4 = R5 = Me
and : R4 = R5 = Et
R4
17
27
S
Ph
18 and 28: R4R5 = (CH2)4
Ph
N
R5
Ph
Ph
P
4
and : R R5 = (CH2)5
h
19
29
i
3-6,
N
20 and 30: R4 = Me, R5 = Et
21 31
N
10-15
H
H
and : R4 = Me, R5 = iPr
22 and 32: R4 = Me, R5 = CH2Bu
23 33
85-95%
Ph
Ph
60-85%
Ph
NH2
R5
N
R4
N
R4
R5
and : R4 = H, R5 = acetyl
24 and 34: R4 = H, R5 = Boc
25 35
and : R4 = H, R5 = Cbz
16-25
26-35
Scheme 2. Synthesis of chiral thiophosphorodiamide ligands 26–35. Reagents and conditions: (a) phthalic anhydride, p-TsOHꢁH2O, toluene, reflux; (b) K2CO3, CH2Cl2, rt;
i
(c) 37% HCOH aq, 80% HCOOH, reflux; (d) iodoalkane (EtI for 4 and 7, 1,4-diiodobutane for 5, 1,5-diiodopentane for 6, PrI for 8, iodopentane for 9), K2CO3, CH3CN, reflux;
(e) acetyl chloride, Et3N, CH2Cl2, 0 °C – rt; (f) Boc2O, C2H5OH, rt; (g) CbzCl, Et3N, CH2Cl2, 0 °C – rt; (h) N2H4ꢁH2O, EtOH, reflux; (i) phenylthiophosphonic dichloride, Et3N,
CH3CN, 0 °C – rt.
Next, we optimized the reaction conditions for the asymmetric
addition of diethylzinc to benzaldehyde catalyzed by ligands 31
and 35, respectively, as shown in Tables 2 and 3. We first studied
the solvent effect under identical conditions and found that both
toluene and hexane were suitable solvents for the reaction, with
hexane being slightly better for both ligands (Table 2, entries 1
and 2 and Table 3, entries 1 and 2). Decreasing the temperature
favored the asymmetric reaction catalyzed by ligand 31 with a
higher enantioselectivity while the optimized temperature was
ꢀ15 °C–rt (Table 2, entries 2–4). For ligand 35, changing the tem-
perature from 0 °C–rt to ꢀ15 °C–rt had almost no effect on the ee
value or yield of the alcohol product, although increasing the tem-
perature to rt decreased both values (Table 3, entries 2–4). There-
fore, 0 °C–rt was chosen as the optimized temperature for ligand
35. In addition, the amount of Et2Zn could be reduced to 1.5 equiv
without decreasing the enantioselectivities (Tables 2 and 3, entries
4–8). Lower ee values of the corresponding products were obtained
when using lower loading of ligands (Tables 2 and 3, entries 7, 9,
and 10).
effect of the substrate was studied using OMe-, H-, Cl-, and
CF3-4-substituted benzaldehydes. As shown in entries 1–4 of
Table 4, for the 31 and 35 catalyzed asymmetric reactions, both
electron-donating and -withdrawing group 4-substitutions of the
benzaldehyde decreased the ee values of the corresponding alcohol
products. The substituent steric effect of the substrate was also
examined. Ligand 31, compared with 95% yield and 98% ee value
of (R)-37a obtained from benzylaldehyde, compound (R)-37f was
obtained in only 87% yield and with a slightly lower ee value of
96% from 2-methyl substituted benzylaldehyde. As for ligand 35,
compared with 92% yield and 97% ee of (S)-37a obtained from ben-
zylaldehyde, the 2-methyl substituted benzylaldehyde gave a dra-
matically lower yield and ee value of (S)-37f (65% yield and 82% ee
value) as shown in entries 1 and 6. Similar results were observed
for 1-naphthaldehyde and 2-naphthaldehyde (entries 7 and 8).
The results indicated that the steric hindrance had a dramatic ef-
fect on the activity, but had a small influence on the enantioselec-
tivity for ligand 31 catalyzed reactions. However, for the ligand 35
catalyzed reactions, both the yields and ee values of the alcohol
products were significantly affected by the steric effects of the sub-
strates. In addition to substituted benzylaldehydes, ligands 31 and
35 also worked very well for other types of aromatic aldehydes. For
With the optimized condition in hand, we next investigated the
scope and limitations of the substrates using ligands 31 and 35 and
the results are summarized in Table 4. The substituent electronic

H. Yue et al. / Tetrahedron: Asymmetry 25 (2014) 170–180
173
Table 1
Asymmetric additions of diethylzinc to benzaldehyde catalyzed by ligands 26–35a
S
Ph
Ph
Ph
P
OH
*
O
26-35
(0.1 equiv)
N
H
N
H
+
Et2Zn
Ph
Ph
Ph
Ph
H
toluene, 0oC~rt, 6 h
R5
N
N
R4
R5
(3 equiv)
R4
36a
37a
26-35
Entry
Ligand
R4
R5
Yieldb (%)
eec
Configd
1
2
3
4
5
6
7
8
26
27
28
29
30
31
32
33
34
35
35
Me
Et
–C4H8–
–C5H10
Me
Me
Me
H
Me
Et
84
53
47
39
98
98
93
73
98
88
89
76
31
65
4
86
93
87
19
80
92
95
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(S)
(S)
–
Et
iPr
CH2Bu
Acetyl
Boc
Cbz
Cbz
9
H
H
H
10
11e
a
b
c
All reactions were conducted with PhCHO (0.5 mmol) and Et2Zn (1.5 M in toluene, 1.0 mL) in the presence of 10 mol % of chiral ligands.
Isolated yield.
Determined by chiral GC analysis.
d
e
The configuration was determined by comparing GC analysis tR and the specific rotation with the literature data.29
Reaction time is 1 h.
Table 2
Optimization of reaction conditions for the asymmetric addition of diethylzinc to benzaldehyde catalyzed by 31a
O
OH
31
(Y equiv)
Et2Zn
+
Ph
H
Ph
(R)-
solvent, temp., 6 h
(X equiv)
36a
37a
Entry
Solvent
Temp
Et2Zn (X equiv)
31 (Y equiv)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
Toluene
0 °C – rt
0 °C – rt
3.0
3.0
3.0
3.0
2.5
2.0
1.5
1.2
1.5
1.5
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.05
0.03
98
98
98
98
98
96
95
88
70
70
93
94
87
98
98
98
98
96
93
72
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
rt
ꢀ15 °C – rt
ꢀ15 °C – rt
ꢀ15 °C – rt
ꢀ15 °C – rt
ꢀ15 °C – rt
ꢀ15 °C – rt
ꢀ15 °C – rt
a
b
c
All reactions were conducted with PhCHO (0.5 mmol), Et2Zn (1.0 M in n-hexane, X equiv), and toluene or n-hexane as a solvent in the presence of 31 (Y equiv) for 6 h.
Isolated yield.
Determined by chiral GC analysis.
example, 2-thienylaldehyde gave 91% yield/95% ee of (R)-37i with
ligand 31 and 98% yield/96% ee of (S)-37i with ligand 35 (entry 9).
In addition, aliphatic aldehydes also gave the corresponding alco-
hol products in moderate to good yields and good to excellent ee
values with the use of ligands 31 and 35 (entries 10 and 11). A
72% yield/90% ee of (R)-37l with ligand 31 and 95% yield/94% ee
of (S)-37l with ligand 35 were also obtained from the alpha,beta-
unsaturated aldehyde shown in entry 12. The additions of Me2Zn
to aromatic aldehydes were also studied (entries 13 and 14). Good
yields and high ee values were obtained for ligand 35 catalyzed
reactions, while only low yields and moderate ee values were ob-
tained for ligand 31 catalyzed reactions.
Ligand 35 first reacts with two equivalents of Et2Zn to form a
chiral 35–bimetallic Zn complex and releases four equivalents of
ethane. This chiral complex serves as a trifunctional catalyst, con-
taining two N,N-chelated Zn metal centers as two Lewis acids to
doubly activate the benzaldehyde and one P@S moiety as a conju-
gate Lewis base to activate Et2Zn through conjugation among the
Zn–N–P@S bonds. Further reaction of the chiral complex with Et2-
Zn and PhCHO forms a 35–Zn catalyst–reagent complex. Double
zinc activation increases the electrophilicity of PhCHO for higher
reactivity and makes the conformation of the transition state
more rigid for better enantioselectivity. This complex is a 5/6/5
tricyclic system and prefers a transoid conformation, which has
two possible geometries of 35–Zn catalyst–reagent complexes I
and II. Compared with the 35–Zn catalyst–reagent complex II,
35–Zn catalyst–reagent complex I in which the Et2Zn attached
to the P@S is situated on the Si-face of PhCHO is favored because
the Ph-group of the PhCHO prefers to be at the opposite position
of the bulky Cbz group of 35 and thus gives an (S)-alcohol
product.
Based on our experimental findings, several tricyclic geometries
involved in the asymmetric additions of diethylzinc with alde-
hydes17,20,31–34 and Ishihara’s conjugate Lewis acid–Lewis base
activated transition state mode for chiral phosphoramide derived
from L
-valine,27 we have proposed hypothetical reaction pathways
for the ligand 31 and 35 catalyzed asymmetric reactions of dieth-
ylzinc with (Scheme 3).

174
H. Yue et al. / Tetrahedron: Asymmetry 25 (2014) 170–180
Table 3
Optimization of the reaction conditions for the asymmetric addition of diethylzinc to benzaldehyde catalyzed by 35a
OH
O
35 (Y equiv)
Et2Zn
+
Ph
(S)-37a
solvent, temp., 1 h
Ph
H
(X equiv)
36a
Entry
Solvent
Temp
Et2Zn (X equiv)
35 (Y equiv)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
Toluene
0 °C – rt
0 °C – rt
rt
ꢀ15 °C – rt
0 °C – rt
0 °C – rt
0 °C – rt
0 °C – rt
0 °C – rt
0 °C – rt
3.0
3.0
3.0
3.0
2.5
2.0
1.5
1.2
1.5
1.5
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.05
0.03
89
92
85
92
92
92
92
24
83
61
95
95
88
96
97
96
97
85
92
86
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
a
b
c
All reactions were conducted with PhCHO (0.5 mmol), Et2Zn (1.0 M in n-hexane, X equiv), and toluene or n-hexane as a solvent in the presence of 35 (Y equiv) for 1 h.
Isolated yield.
Determined by chiral GC analysis.
Table 4
Enantioselective additions of dialkylzinc to aldehydes catalyzed by ligands 31 and 35a
R72Zn (1.5 equiv)
35 (0.1 equiv)
R72Zn (1.5 equiv)
31 (0.1 equiv)
OH
O
OH
R6
R7
n-hexane, -15oC - r.t., 6 h
R6
(R)-
R7
37
R6
H
n-hexane, 0oC - r.t., 1 h
(S)-37
36
Entry
R6
=
R7
=
Product
Conducted with 31
Conducted with 35
Yieldb (%) eec,d (%)
Yieldb (%)
eec,d (%)
1
2
3
4
5
6
7
8
Ph
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
37a
37b
37c
37d
37e
37f
37g
37h
37i
37j
37k
37l
37m
37n
95
98
97
93
94
87
91
75
91
49
75
72
45
5
98 (R)
90 (R)
93 (R)
90 (R)
92 (R)
96 (R)
90 (R)
88 (R)
95 (R)
84 (R)
78 (R)
90 (R)
72 (R)
68 (R)
92
97
98
97
90
65
99
89
98
50
80
95e
91
73
97 (S)
87 (S)
94 (S)
95 (S)
88 (S)
82 (S)
95 (S)
83 (S)
96 (S)
85 (S)
90 (S)
94 (S)
96 (S)
90 (S)
4-CF3-C6H4
4-Cl-C6H4
4-CH3O-C6H4
2-CH3O-C6H4
2-CH3-C6H4
2-Naphthyl
1-Naphthyl
2-Thienyl
Cyclohexyl
n-C8H17
(E)-C6H5CH@CMe
4-CF3-C6H4
4-CH3O-C6H4
9
10
11
12
13f
14f
Me
Me
a
All reactions were conducted with RCHO (0.5 mmol), Et2Zn (1.0 M in n-hexane, 0.75 mL), and n-hexane (0.75 mL) in the presence of 31 (0.1 equiv, 34 mg) for 6 h or in the
presence of 35 (0.1 equiv, 42 mg) for 1 h.
b
Isolated yield.
c
Determined by chiral GC analysis.
d
The configuration was determined by comparing GC analysis tR and the specific rotation with the literature data.11,29
e
Reaction time is 6 h.
Reaction time is 24 h.
f
Since ligand 31 is an N,N,N0,N0-tetra-substituted compound, only
3. Conclusions
two equivalents of ethane are released when 31 reacts with Et2Zn
to form a 31–bimetallic Zn complex as the trifunctional catalyst in
which each Zn still contains one Et group. This catalyst then forms
a 31–Zn catalyst–reagent complex with Et2Zn and PhCHO. This
complex is also a 5/6/5 tricyclic system and prefers a transoid con-
formation, which has two possible geometries of 31–Zn catalyst–
reagent complexes I and II. Compared with 31–Zn catalyst–reagent
complex II, 31–Zn catalyst–reagent complex I in which the Et2Zn
attached to the P@S is situated on the Re-face of the PhCHO is fa-
vored because the Ph-group on the PhCHO prefers to be at the
opposite position of the Et group on the neighboring Zn for less ste-
ric repulsion and thus gives an (R)-alcohol product.
In conclusion, we have developed a series of new chiral thio-
phosphorodiamide ligands and investigated their catalytic proper-
ties in asymmetric addition reactions of diethylzinc to aldehydes.
Our results show that all of the N,N,N0,N0-tetra-substituted chiral
thiophosphorodiamides give alcohol products with an (R)-configu-
ration while all of the N,N0-di-substituted chiral thiophosphorodia-
mides give the corresponding alcohols with an (S)-configuration in
the asymmetric addition reactions. The enantioselectivity switch is
highly efficient and has a broad substrate scope. Up to 98% yield
and 98% ee value of the (R)-secondary alcohol can be obtained with
ligand 31, while up to 99% yield and 97% ee value of the (S)-second-

H. Yue et al. / Tetrahedron: Asymmetry 25 (2014) 170–180
175
ZnEt2
Ph
S
S
P
S
P
Ph
Ph
P
Ph
Ph
Ph
Ph
Ph
Ph
N
Ph
Ph
HN
N
NH
Ph
Ph
Ph
Ph
N
N
Et2Zn
2Et2Zn
Zn
Zn
N
Zn
Zn
PhCHO
-4Ethane
N
NH
Cbz
HN
Cbz
N
N
O
Cbz
Cbz
Cbz
Cbz
Ph
H
35
35-bimetallic Zn complex
35-Zn catalyst-reagent complex
5/6/5 transoid tricyclic system
Ph
H
Ph
H
Cbz
Cbz
Et
Et
Zn
Zn
Ph
Ph
Zn
Zn
Et
Et
Cbz
N
N
N
N
O
O
S
P
N
Zn
Ph
+
Zn
Ph
S
Cbz
Ph
Ph
P
N
N
N
Ph
Ph
Ph
Ph
Re attack: less favored
Si attack: favored
35-Zn catalyst-reagent complex I
35-Zn catalyst-reagent complex II
ZnEt2
Ph
(S)-alcohol
S
S
S
P
Ph
Ph
P
P
Ph
Ph
2Et2Zn
Ph
Ph
N
Ph
Ph
HN
N
N
Ph
Ph
NH
Ph
Ph
N
N
N
Et
Et
Et
Et
Zn
Zn
Zn
Zn
Et2Zn
-2Ethane
Ph
PhCHO
Ph
N
N
N
N
O
iPr
iPr
Me iPr
iPr
Me iPr
Me
Me
Me iPr
H
Me
Ph
31
31-bimetallic Zn complex
31-Zn catalyst-reagent complex
5/6/5 transoid tricyclic system
More steric
Less steric
H
H
Me
Ph
Ph
Me
Ph
iPr
Et
Ph
Et
Zn
iPr
Et
Et
N
N
Et
N
N
O
P
Et
O
P
Zn
Zn
+
Zn
Zn
iPr
S
Zn
S
iPr
Ph
Ph
N
Et
Ph
N
Me
N
Et
Ph
N
Me
Ph
Ph
Ph
Ph
Si attack: less favored
31-Zn catalyst-reagent complex I
Re attack: favored
31-Zn catalyst-reagent complex II
(R)-alcohol
Scheme 3. The proposed reaction pathways catalyzed by ligand 31 and 35.
ary alcohol can be obtained with ligand 35. Moreover, ligand 35
also works well in the addition reactions of Me2Zn to aromatic
aldehydes. Furthermore, we have proposed a possible reaction
pathway catalyzed by ligands 31 and 35.
cated. All solvents were purified and dried prior to use according to
standard methods. Unless otherwise noted, all experiments were
carried out in dried glassware with magnetic stirring under an
atmosphere of dry nitrogen.
4.2. (1R,2R)-N-Phthaloyl-1,2-diphenylethylenediamine 2
4. Experimental
4.1. General
A solution of p-TsOHꢁH2O (5.70 g, 30 mmol) in toluene (30 mL)
was dehydrated by azeotropic distillation. After cooling to room
temperature, to the solution was added (1R,2R)-(+)-1,2-diphenyle-
thylenediamine (6.37 g, 30 mmol) followed by phthalic anhydride
(4.45 g, 30 mmol). The mixture was heated with stirring until a
homogeneous solution was obtained and a white solid began to
crystallize. The white solid was collected by filtration, washed with
toluene–hexane and air-dried. Next, a solution of the white solid in
dichloromethane (150 mL) was stirred overnight with saturated
aqueous K2CO3 solution (150 mL). The organic solution was sepa-
rated, dried over MgSO4, and the solvent was removed to give 2
(7.40 g, 21.6 mmol, 72% yield) as a white solid. Mp: 133–134 °C.
1H NMR (400 MHz), 13C NMR (100 MHz) spectra were recorded
in solvents indicated using a Bruker Avance 400 MHz spectrometer
(Switzerland). Chemical shifts were reported in parts per million
(ppm, d) relative to CDCl3 (d 7.26 for 1H NMR), or CDCl3 (d 77.0
for 13C NMR). Optical rotations were measured on SGW-1 auto-
matic polarimeter and reported as follows: ½a DT
ꢂ
(c g/100 mL, sol-
vent). GC analysis was performed on a gas chromatograph with a
FID detector on fused silica chiral capillary column (Chirasil Dex
CB column, 25 m Length ꢃ 0.32 mm ID ꢃ 0.25 mm film thickness).
Commercial reagents were used as received unless otherwise indi-

176
H. Yue et al. / Tetrahedron: Asymmetry 25 (2014) 170–180
½
a 3D1
ꢂ
¼ þ80:5 (c 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 1.67 (br
NMR (400 MHz, CDCl3): d 0.91 (t, J = 7.1 Hz, 3H), 1.26 (s, 1H)
2.34–2.57 (m, 2H), 5.06 (d, J = 11.3 Hz, 1H), 5.43 (d, J = 11.2 Hz,
1H), 7.03–7.25 (m, 8H), 7.36–7.46 (m, 2H), 7.64–7.75 (m, 2H),
7.77–7.98 (m, 2H); 13C NMR (100 MHz, CDCl3): d 15.4, 41.2, 61.3,
61.8, 123.2, 127.2, 127.6, 128.0, 128.2, 128.3, 129.3, 132.1, 133.9,
137.8, 141.1, 168.8. HRMS (ESI): (m/z) calcd for C24H22N2O2
[M+H]+: 371.1752, found: 371.1754.
s, 2H), 5.32 (d, J = 11.0 Hz, 1H), 5.42 (d, J = 11.0 Hz, 1H), 7.07–7.29
(m, 8H), 7.35–7.43 (m, 2H), 7.63–7.75 (m, 2H), 7.78–7.90 (m,
2H); 13C NMR (100 MHz, CDCl3): d 56.0, 63.0, 123.3, 127.3, 127.4,
127.7, 128.3, 128.5, 129.1, 132.0, 134.0, 137.9, 143.0, 168.9. HRMS
(ESI): (m/z) calcd for
343.1444.
C
22H18N2O2 [M+H]+: 343.1447, found:
4.3. General procedure for the synthesis of diamines 4–9
4.3.5. (1R,2R)-N-Isopropyl-N0-phthaloyl-1,2-diphenylethylenedi-
amine 8
To a solution of 2 (3.42 g, 10 mmol) in CH3CN (25 mL) at room
temperature were added K2CO3 (2.76 g, 20 mmol) and ethyl iodide
(7.80 g, 50 mmol). The resulting mixture was stirred at reflux over-
night, cooled to room temperature and concentrated in vacuo. The
residue was diluted with CH2Cl2 (50 mL) and water (50 mL). The
organic layer was separated, and the aqueous layer was extracted
with CH2Cl2 (3 ꢃ 20 mL). The combined organic layers were
washed with brine and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure, and the residue was purified
by silica gel column chromatography (EtOAc/hexane = 1:40) to af-
ford the diamine 4 (2.99 g, 7.5 mmol, 75% yield) as a white solid.
The title compound (3.15 g, 8.2 mmol, 82% yield) was obtained
as a white solid according to the general procedure using 2 (3.42 g,
10 mmol), K2CO3 (2.76 g, 20 mmol), and isopropyliodide (8.50 g,
50 mmol) at reflux overnight. Mp: 126–127 °C. ½a D31
¼ þ16:5 (c
ꢂ
1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 0.80 (d, J = 6.3 Hz,
3H), 0.92 (d, J = 6.1 Hz, 3H), 2.37–2.70 (m, 1H), 5.12 (d,
J = 11.2 Hz, 1H), 5.36 (d, J = 11.3 Hz, 1H), 7.03–7.25 (m, 8H), 7.36–
7.46 (m, 2H), 7.65–7.74 (m, 2H), 7.79–7.89 (m, 2H); 13C NMR
(100 MHz, CDCl3): d 22.0, 24.5, 45.4, 59.5, 61.5, 123.2, 127.1,
127.6, 127.8, 128.1, 128.2, 129.5, 132.1, 133.8, 137.8, 141.6,
168.8. HRMS (ESI): (m/z) calcd for C25H24N2O2 [M+H]+: 385.1913,
found: 385.1914.
4.3.1. (1R,2R)-N,N-Diethyl-N0-phthaloyl-1,2-diphenylethylenedi-
amine 4
4.3.6. (1R,2R)-N-Pentyl-N0-phthaloyl-1,2-diphenyl ethylenedi-
amine 9
The title compound (3.09 g, 7.5 mmol, 75% yield) was obtained
as a white solid according to the general procedure using 2 (3.42 g,
10 mmol), K2CO3 (2.76 g, 20 mmol), and iodopentane (5.94 g,
Mp: 152–153 °C. ½a D31
ꢂ
¼ ꢀ213:0 (c 1.00, CH2Cl2). 1H NMR
(400 MHz, CDCl3): d 0.87 (t, J = 7.1 Hz, 6H), 1.91–2.18 (m, 2H),
2.53–2.78 (m, 2H), 5.32 (d, J = 12.1 Hz, 1H), 6.00 (d, J = 12.2 Hz,
1H), 7.04–7.25 (m, 8H), 7.48–7.60 (m, 2H), 7.64–7.72 (m, 2H),
7.77–7.93 (m, 2H); 13C NMR (100 MHz, CDCl3): d 14.1, 43.6, 55.1,
61.8, 123.0, 127.1, 127.6, 127.8, 128.2, 129.3, 129.9, 133.7, 135.3,
137.2, 168.3, 168.7. HRMS (ESI): (m/z) calcd for C26H26N2O2
[M+H]+: 399.2068, found: 399.2067.
30 mmol). Mp: 104–105 °C. ½a D31
ꢂ
¼ þ19:0 (c 1.00, CH2Cl2). 1H
NMR (400 MHz, CDCl3): d 0.70 (t, J = 7.2 Hz, 3H), d 0.94–1.39 (m,
7H), 2.26–2.58 (m, 2H), 5.03 (d, J = 11.2 Hz, 1H), 5.45 (d,
J = 11.2 Hz, 1H), 7.06–7.25 (m, 8H), 7.36–7.49 (m, 2H), 7.65–7.74
(m, 2H), 7.78–7.90 (m, 2H); 13C NMR (100 MHz, CDCl3): d 14.0,
23.4, 29.3, 46.9, 61.1, 62.0, 123.2, 127.2, 127.6, 127.9, 128.3,
129.4, 132.1, 133.8, 137.7, 168.8. HRMS (ESI): (m/z) calcd for
4.3.2. 2-[(1R,2R)-1,2-Diphenyl-2-(pyrrolidin-1-yl)ethyl]-2,3-
dihydro-1H-isoindole-1,3-dione 5
The title compound (3.89 g, 9.8 mmol, 98% yield) was obtained
as a white solid according to the general procedure using 2 (3.42 g,
10 mmol), K2CO3 (2.76 g, 20 mmol), and 1,4-diodobutane (6.20 g,
C
27H28N2O2 [M+H]+: 413.2220, found: 413.2223.
4.4. General procedure for the synthesis of diamines 3 and 10–
12
20 mmol). Mp: 204–205 °C. ½a D31
ꢂ
¼ ꢀ111:1 (c 1.00, CH2Cl2). 1H
NMR (400 MHz, CDCl3): d 1.30–1.57 (m, 4H), 2.28–2.65 (m, 4H),
5.48 (d, J = 12.2 Hz, 1H), 6.03 (d, J = 12.2 Hz, 1H), 7.03–7.32 (m,
8H), 7.50–7.61 (m, 2H), 7.65–7.74 (m, 2H), 7.79–7.92 (m, 2H);
13C NMR (100 MHz, CDCl3): d 22.9, 47.6, 56.1, 62.0, 123.1, 127.2,
127.6, 127.8, 129.6, 129.8, 133.7, 137.7, 168.7. HRMS (ESI): (m/z)
calcd for C26H24N2O2 [M+H]+: 397.1905, found: 397.1911.
A solution of 2 (3.42 g, 10 mmol), 37% HCHO aq (7.5 mL,
100 mmol), and 80% HCOOH (6.0 mL, 100 mmol) was stirred at
reflux for five hours. The reaction mixture was then cooled and sat-
urated Na2CO3 aq (20 mL) was added dropwise at 0 °C. The result-
ing mixture was diluted with CH2Cl2 (30 mL) and water (20 mL).
The organic layer was separated, and the aqueous layer was ex-
tracted with CH2Cl2 (3 ꢃ 20 mL). The combined organic layers were
washed with brine, and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure, and the residue was purified
by silica gel column chromatography (EtOAc/hexane = 1:30) to
afford the diamine 3 (3.15 g, 8.5 mmol, 85% yield) as a white solid.
4.3.3. 2-[(1R,2R)-1,2-Diphenyl-2-(piperidin-1-yl)ethyl]-2,3-dihyd-
ro-1H-isoindole-1,3-dione 6
The title compound (3.65 g, 8.9 mmol, 89% yield) was obtained
as a white solid according to the general procedure using 2 (3.42 g,
10 mmol), K2CO3 (2.76 g, 20 mmol), and 1,5-diiodopentane (6.48 g,
20 mmol). Mp: 197–198 °C. ½a D31
ꢂ
¼ ꢀ110:9 (c 1.00, CH2Cl2). 1H
NMR (400 MHz, CDCl3): d 1.02–1.37 (m, 6H), 1.89–2.65 (m, 4H),
5.07 (d, J = 12.2 Hz, 1H), 6.02 (d, J = 12.2 Hz, 1H), 7.02–7.35 (m,
8H), 7.47–7.62 (m, 2H), 7.64–7.78 (m, 2H), 7.79–7.95 (m, 2H);
13C NMR (100 MHz, CDCl3): d 24.5, 26.9, 54.8, 67.5, 122.9, 123.1,
127.3, 127.6, 127.8, 128.3, 129.2, 129.7, 134.1, 137.5, 168.8. HRMS
4.4.1. (1R,2R)-N,N-Dimethyl-N0-phthaloyl-1,2-diphenylethylene-
diamine 3
Mp: 211–212 °C.
½
a 3D1
ꢂ
¼ ꢀ89:5 (c 1.00, CH2Cl2). 1H NMR
(400 MHz, CDCl3): d 2.10 (s, 6H), 5.22 (d, J = 12.3 Hz, 1H), 5.98 (d,
J = 12.4 Hz, 1H), 7.04–7.25 (m, 8H), 7.48–7.56 (m, 2H), 7.64–7.72
(m, 2H), 7.77–7.89 (m, 2H); 13C NMR (100 MHz, CDCl3): d 40.8,
54.9, 66.0, 123.2, 127.2, 127.6, 127.7, 128.3, 129.6, 132.8, 133.7,
137.5, 168.6. HRMS (ESI): (m/z) calcd for C24H22N2O2 [M+H]+:
371.1758, found: 371.1757.
(ESI): (m/z) calcd for
C
27H26N2O2 [M+H]+: 411.2061, found:
411.2067.
4.3.4. (1R,2R)-N-Ethyl-N0-phthaloyl-1,2-diphenylethylenediamine
7
The title compound (3.07 g, 8.3 mmol, 83% yield) was obtained
as a white solid according to the general procedure using 2 (3.42 g,
10 mmol), K2CO3 (2.76 g, 20 mmol), and ethyl iodide (2.34 g,
4.4.2. (1R,2R)-N-Ethyl-N-methyl-N0-phthaloyl-1,2-diphenyleth-
ylenediamine 10
The title compound (1.96 g, 5.1 mmol, 85% yield) was obtained
as a yellow solid according to the general procedure using 7
15 mmol). Mp: 102–103 °C. ½a D31
ꢂ
¼ þ32:2 (c 1.00, CH2Cl2). 1H

H. Yue et al. / Tetrahedron: Asymmetry 25 (2014) 170–180
177
(2.31 g, 6 mmol), 37% HCHO aq (2.3 mL, 30 mmol), and 80% HCOOH
idue was purified by silica gel column chromatography (EtOAc/
(3.5 mL, 60 mmol). Mp: 157–158 °C. ½a D31
ꢂ
¼ ꢀ135:5 (c 1.00, CH2-
hexane = 1:8) to afford diamine 14 (4.20 g, 9.5 mmol, 95% yield)
Cl2). 1H NMR (400 MHz, CDCl3): d 0.85 (t, J = 7.1 Hz, 3H), 2.08 (s,
3H), 2.12–2.25 (m, 1H), 2.35–2.52 (m, 1H), 5.27 (d, J = 12.2 Hz,
1H), 6.01 (d, J = 12.2 Hz, 1H), 7.03–7.25 (m, 8H), 7.47–7.59 (m,
2H), 7.64–7.73 (m, 2H), 7.74–7.95 (m, 2H); 13C NMR (100 MHz,
CDCl3): d 13.8, 36.9, 47.6, 55.0, 65.4, 123.1, 127.2, 127.6, 127.8,
128.3, 129.4, 129.7, 133.9, 137.5, 168.6. HRMS (ESI): (m/z) calcd
for C25H24N2O2 [M+H]+: 385.1913, found: 385.1914
as a white solid. Mp: 162–163 °C. ½a D31
¼ ꢀ29:2 (c 1.00, CH2Cl2).
ꢂ
1H NMR (400 MHz, CDCl3): d 1.27 (s, 9H), 5.95 (s, 2H), 6.20 (br s,
1H), 7.09–7.17 (m, 1H), 7.18–7.39 (m, 7H), 7.46 (d, J = 7.2 Hz,
2H), 7.64–7.74 (m, 2H), 7.75–7.82 (m, 2H); 13C NMR (100 MHz,
CDCl3): d 28.2, 55.5, 59.1, 79.3, 123.4, 126.7, 127.4, 127.8, 128.3,
128.4, 128.5, 131.5, 134.1, 155.3, 168.6. HRMS (ESI): (m/z) calcd
for C27H26N2O4 [M+Na]+: 465.1784, found: 465.1785.
4.4.3. (1R,2R)-N-Isopropyl-N-methyl-N0-phthaloyl-1,2-diphenyl-
ethylenediamine 11
4.7. (1R,2R)-N-Cbz-N0-Phthaloyl-1,2-diphenylethylenediamine 15
The title compound (2.15 g, 5.4 mmol, 90% yield) was obtained
as a yellow solid according to the general procedure using 8
(2.31 g, 6 mmol), 37% HCHO aq (2.3 mL, 30 mmol), and 80% HCOOH
To a solution of 2 (3.42 g, 10 mmol) and Et3N (2.8 mL, 20 mmol)
in dry CH2Cl2 (30 mL) was added benzyl chloroformate (2.2 mL,
15 mmol) dropwise over a period of 30 min at 0 °C. The reaction
mixture was then stirred at room temperature for 10 h. The reac-
tion mixture was diluted with water and extracted with CH2Cl2.
The combined organic layers were washed with brine and dried
over anhydrous Na2SO4. The solvent was evaporated and the resi-
due was purified by silica gel column chromatography (EtOAc/hex-
ane = 1:8) to afford diamine 15 (3.34 g, 7.0 mmol, 70% yield) as a
(3.5 mL, 60 mmol). Mp: 146–147 °C.
½
a 3D1
ꢂ
¼ ꢀ104:7 (c 1.00,
CH2Cl2). 1H NMR (400 MHz, CDCl3): d 0.51–0.82 (m, 6H), 2.14 (s,
3H), 2.94–3.17 (m, 1H), 5.35 (d, J = 12.1 Hz, 1H), 5.98 (d,
J = 12.0 Hz, 1H), 7.03–7.31 (m, 8H), 7.49–7.57 (m, 2H), 7.61–7.72
(m, 2H), 7.76–7.91 (m, 2H); 13C NMR (100 MHz, CDCl3): d 19.7,
21.0, 30.2, 52.5, 55.6, 65.9, 123.0, 127.1, 127.6, 127.9, 128.2,
129.8, 133.7, 136.8, 137.6, 168.7. HRMS (ESI): (m/z) calcd for
white solid. Mp: 79–80 °C. ½a D31
ꢂ
¼ þ23:8 (c 1.00, CH2Cl2). 1H NMR
C
26H26N2O2 [M+H]+: 399.2067, found: 399.2067.
(400 MHz, CDCl3): d 4.89–5.18 (m, 2H), 5.87–6.14 (m, 2H), 6.14
(br s, 1H), 7.06–7.51 (m, 15H), 7.64–7.74 (m, 2H), 7.75–7.82 (m,
2H); 13C NMR (100 MHz, CDCl3): d 28.2, 55.5, 59.1, 123.4, 126.7,
127.4, 127.8, 128.3, 128.5, 131.5, 134.1, 136.2, 139.4, 155.3,
4.4.4. (1R,2R)-N-Pentyl-N-methyl-N0-phthaloyl-1,2-diphenylet-
hylenediamine 12
The title compound (2.25 g, 5.3 mmol, 88% yield) was obtained
as a white solid according to the general procedure using 9 (2.48 g,
6 mmol), 37% HCHO aq (2.3 mL, 30 mmol), and 85% HCOOH
168.6. HRMS (ESI): (m/z) calcd for
C
30H24N2O4 [M+Na]+:
499.1624, found: 499.1628.
(3.5 mL, 60 mmol). Mp: 129–130 °C.
½
a 3D1
ꢂ
¼ þ107:1 (c 1.00,
4.8. General procedure for the synthesis of diamines 16–25
CH2Cl2). 1H NMR (400 MHz, CDCl3): d 0.63 (t, J = 7.3 Hz, 3H), d
0.91–1.36 (m, 6H), 2.07 (s, 3H), 2.19–2.41 (m, 2H), 5.27 (d,
J = 12.3 Hz, 1H), 6.04 (d, J = 12.3 Hz, 1H), 7.03–7.32 (m, 8H), 7.50–
7.61 (m, 2H), 7.65–7.74 (m, 2H), 7.78–7.94 (m, 2H); 13C NMR
(100 MHz, CDCl3): d 14.0, 22.6, 27.6, 29.4, 36.6, 53.8, 54.9, 66.3,
123.1, 127.2, 127.6, 127.7, 128.3, 129.4, 129.7, 133.6, 133.9,
137.5, 168.6, 168.8. HRMS (ESI): (m/z) calcd for C28H30N2O2
[M+H]+: 427.2375, found: 427.2380.
A solution of 3 (1.76 g, 5 mmol) in ethanol (10 mL) containing
hydrazine monohydrate (2.5 mL, 50 mmol) was stirred at reflux
for 2 h. The mixture was then cooled to room temperature and di-
luted with diethyl ether, to give a precipitate which was removed
by filtration. The filtrate was dried over MgSO4 and concentrated in
vacuo to afford diamine 16 (1.11 g, 4.6 mmol, 92% yield) as a color-
less oil, which was used in the following step without further
purification.
Compounds 17–22 were obtained as colorless oils from 4–6 and
10–12 according to the general procedure on the same scale with
yields ranging from 90% to 95%, and then used in the following step
without further purification.
4.5. (1R,2R)-N-Acetyl-N0-phthaloyl-1,2-diphenylethylenediamine
13
To a solution of 2 (3.42 g, 10 mmol) and triethylamine (1.7 mL,
12 mmol) in dichloromethane (20 mL), acetyl chloride (0.8 mL,
11 mmol) was slowly added over a 10 min period at 0 °C. The
resulting solution was then stirred for 10 min at 0 °C and stirred
for 30 min at room temperature. Next, the reaction mixture was
poured into ice-cold water (20 mL). The organic layer was then
separated and the aqueous layer was extracted with CH2Cl2
(3 ꢃ 20 mL). The combined organic layers were washed with brine,
and dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure to afford diamine 13 (3.82 g, 9.9 mmol, 99%
Compounds 23–25 were obtained as white solids from 13–15
according to the general procedure on the same scale with yields
ranging from 85% to 92%, and then used in the following step with-
out further purification.
4.9. General procedure for the synthesis of thiophosphorodi-
amide 26–35
yield) as a white solid. Mp: 209–210 °C. ½a D31
¼ þ9:9 (c 1.00, CH2-
ꢂ
To solution of 16 (961 mg, 4 mmol) and triethylamine (0.6 mL,
4 mmol) in dry acetonitrile (10 mL) was added dropwise a solution
of phenylphosphonothioyl dichloride (0.42 g, 2 mmol) in dry ace-
tonitrile (2 mL) at 0 °C. The resulting mixture was then allowed
to warm to room temperature and stirred for four hours. Next,
the solvent was evaporated and the residue was diluted with CH2-
Cl2 (20 mL) and water (20 mL). The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (3 ꢃ 10 mL).
The combined organic layers were washed with saturated NaHCO3,
and dried over anhydrous Na2SO4. After removal of the solvent, the
crude product was purified by silica gel column chromatography
(CH3OH/CH2Cl2 = 1:200) to afford thiophosphorodiamide 26
(743 mg, 1.20 mmol, 60% yield) as a white solid.
Cl2). 1H NMR (400 MHz, CDCl3): d 1.94 (s, 3H), 6.06 (d, J = 6.9 Hz,
1H), 6.25 (t, J = 8.4 Hz, 1H), 7.05–7.47 (m, 10H), 7.63–7.86 (m,
5H); 13C NMR (100 MHz, CDCl3): d 23.2, 54.3, 58.6, 123.5, 126.4,
127.5, 127.9, 128.5, 128.6, 131.2, 134.4, 136.0, 138.9, 168.8,
169.7. HRMS (ESI): (m/z) calcd for C24H20N2O3 [M+H]+: 385.1540,
found: 385.1546.
4.6. (1R,2R)-N-Boc-N0-phthaloyl-1,2-diphenylethylenediamine 14
A mixture of 2 (3.42 g, 10 mmol) and Boc2O (3.5 mL, 15 mmol)
in C2H5OH (30 mL) was stirred at room temperature for 30 min.
The solvent was then removed under reduced pressure and the res-

178
H. Yue et al. / Tetrahedron: Asymmetry 25 (2014) 170–180
4.9.1. [(1R,2R)-2-(Dimethylamino)-1,2-diphenylethyl]({[(1R,2R)-
2-(dimethylamino)-1,2-diphenylethyl]amino}(phenyl)thiophos-
phoryl)amine 26
4.9.5. [(1R,2R)-2-[Ethyl(methyl)amino]-1,2-diphenylethyl]({[(1R,-
2R)-2-[ethyl(methyl)amino]-1,2-diphenylethyl]amino}(phenyl)-
thiophosphoryl)amine 30
Mp: 208–209 °C. ½a D31
ꢂ
¼ þ141:0 (c 1.00, CH2Cl2). 1H NMR
The title compound (840 mg, 1.30 mmol, 65% yield) was ob-
tained as a white solid from 20 according to the general procedure
(400 MHz, CDCl3): d 1.63 (s, 6H), 2.04 (s, 6H), 3.44 (d, J = 10.1 Hz,
2H), 4.29 (s, 1H), 4.58 (t, J = 12.0 Hz, 1H), 4.80 (d, J = 4.6 Hz, 1H),
5.11–5.25 (m, 1H), 6.64 (d, J = 3.7 Hz, 3H), 6.86 (d, J = 7.1 Hz, 4H),
6.97–7.25 (m, 14H), 7.29–7.40 (m, 2 H), 7.70–7.84 (m, 2H); 13C
NMR (100 MHz, CDCl3): d 39.6, 40.3, 55.6, 56.4, 73.2, 73.4, 126.2,
126.9, 127.0, 127.2, 127.3, 127.5, 127.6, 128.0, 128.5, 129.4,
129.9, 130.3, 130.5, 131.2, 131.3, 132.7, 135.2, 136.4, 139.3,
142.7. 31P NMR (162 MHz, CDCl3): d 75.2. HRMS (ESI): (m/z) calcd
for C38H43N4PS [M+H]+: 619.3005, found: 619.3019.
on the same scale. Mp: 184–185 °C. ½a D31
¼ þ140:2 (c 1.00, CH2Cl2).
ꢂ
1H NMR (400 MHz, CDCl3): d 0.68 (t, J = 7.0 Hz, 3H), 0.89 (t,
J = 7.0 Hz, 3H), 1.49–1.62 (m, 5H), 1.86–2.07 (m, 5H), 3.53 (d,
J = 10.7 Hz, 1H), 3.65 (d, J = 10.8 Hz, 1H), 4.39 (br s, 1H), 4.52–
4.68 (m, 1H), 4.98 (br s, 1H), 5.15–5.32 (m, 1H), 6.58–6.94 (m,
7H), 6.96–7.25 (m, 14H), 7.31–7.37 (m, 2H), 7.68–7.81 (m, 2H);
13C NMR (100 MHz, CDCl3): d 13.2, 35.2, 36.5, 46.2, 47.6, 55.7,
56.2, 69.8, 74.9, 126,2, 126.8, 126.9, 127.0, 127.1, 127.3, 127.6,
128.0, 128.4, 129.4, 129.9 130.3, 130.4, 131.0, 131.1, 133.4, 133.7,
135.3, 136.6, 139.6, 143.2. 31P NMR (162 MHz, CDCl3): d 74.5.
HRMS (ESI): (m/z) calcd for C40H47N4PS [M+H]+: 647.3358, found:
647.3332.
4.9.2. [(1R,2R)-2-(Diethylamino)-1,2-diphenylethyl]({[(1R,2R)-2-
(diethylamino)-1,2-diphenylethyl]amino}(phenyl)thiophospho-
ryl)amine 27
The title compound (1.15 g, 1.70 mmol, 85% yield) was obtained
as a white solid from 17 according to the general procedure on the
4.9.6. [(1R,2R)-2-[Methyl(propan-2-yl)amino]-1,2-diphenylet-
hyl]({[(1R,2R)-2-[methyl(propan-2-yl)amino]-1,2-diphenylet-
hyl]amino}(phenyl)thiophosphoryl)amine 31
same scale. Mp: 195–196 °C. ½a D31
ꢂ
¼ þ69:7 (c 1.00, CH2Cl2). 1H NMR
(400 MHz, CDCl3): d 0.68 (t, J = 6.9 Hz, 6H), 0.77 (t, J = 6.9 Hz, 6H),
1.80–2.18 (m, 4H), 2.38–2.79 (m, 4H), 3.65 (d, J = 10.4 Hz, 1H),
3.80 (d, J = 10.7 Hz, 1H), 4.55 (s, 1H), 4.58–4.73 (m, 1H), 5.09–
5.32 (m, 2H), 6.58–6.73 (m, 3H), 6.82–6.90 (m, 2H), 6.91–6.97
(m, 2H), 6.99–7.30 (m, 14H), 7.31–7.41 (m, 2H), 7.74–7.91 (m,
2H); 13C NMR (100 MHz, CDCl3): d 13.3, 13.6, 42.3, 42.6, 55.8,
56.0, 68.3, 71.1, 126.2, 126.8, 127.0, 127.1, 127.3, 127.7, 128.0,
128.4, 129.3, 129.8, 130.2, 130.4, 131.3, 131.4, 134.7, 134.9,
135.1, 135.9, 140.2, 143.6. 31P NMR (162 MHz, CDCl3): d 74.1.
HRMS (ESI): (m/z) calcd for C42H51N4PS [M+H]+: 675.3673, found:
675.3645.
The title compound (836 mg, 1.24 mmol, 62% yield) was ob-
tained as a white solid from 21 according to the general procedure
on the same scale. Mp: 204–205 °C. ½a D31
¼ þ140:2 (c 1.00, CH2Cl2).
ꢂ
1H NMR (400 MHz, CDCl3): d 0.59 (d, J = 6.48 Hz, 3H), 0.64–0.81 (m,
9H), 1.73 (s, 3H), 2.01 (m, 3H), 2.51–2.67 (m, 1H), 2.75–2.89 (m,
1H), 3.68 (d, J = 10.3 Hz, 1H), 3.75 (d, J = 10.5 Hz, 1H), 4.34 (br s,
1H), 4.46–4.59 (m, 1H), 5.01 (br s, 1H), 5.03–5.18 (m, 1H), 6.55–
6.94 (m, 7H), 6.96–7.25 (m, 14H), 7.27–7.34 (m, 2H), 7.68–7.81
(m, 2H); 13C NMR (100 MHz, CDCl3): d 19.2, 20.2, 21.1, 29.4, 30.9,
52.8, 53.1, 56.2, 57.0, 69.6, 74.0, 126.0, 126.7, 126.8, 127.0, 127.1,
127.4, 127.7, 128.0, 128.4, 129.4, 129.8, 130.0, 130.3, 130.7,
130.8, 136.3, 137.0, 139.8, 143.3. 31P NMR (162 MHz, CDCl3): d
74.0. HRMS (ESI): (m/z) calcd for C42H51N4PS [M+H]+: 675.3623,
found: 675.3645.
4.9.3. [(1R,2R)-1,2-Diphenyl-2-(pyrrolidin-1-yl)ethyl]({[(1R,2R)-
1,2-diphenyl-2-(pyrrolidin-1-yl)ethyl]amino}(phenyl)thiophos-
phoryl)amine 28
The title compound (886 mg, 1.32 mmol, 66% yield) was ob-
tained as a white solid from 18 according to the general procedure
4.9.7. [(1R,2R)-2-[Methyl(pentyl)amino]-1,2-diphenylethyl]({[(1R,
2R)-2-[methyl(pentyl)amino]-1,2-diphenylethyl]amino}(phenyl)-
thiophosphoryl)amine 32
on the same scale. Mp: 183–184 °C. ½a D31
¼ þ67:1 (c 1.00, CH2Cl2).
ꢂ
1H NMR (400 MHz, CDCl3): d 1.21–1.53 (m, 8H), 2.24–2.51 (m, 8H),
3.58 (d, J = 8.3 Hz, 1H), 3.72 (d, J = 9.0 Hz, 1H), 3.89 (d, J = 3.9 Hz,
1H), 4.64 (br s, 1H), 4.69–4.84 (m, 1H), 5.10–5.28 (m, 1H),
6.52–6.87 (m, 7H), 6.97–7.35 (m, 16H), 7.64–7.81 (m, 2H); 13C
NMR (100 MHz, CDCl3): d 22.7, 22.9, 48.4, 49.2, 56.6, 57.1, 72.0,
126.3, 126.8, 126.9, 127.0, 127.2, 127.3, 127.4, 127.6, 127.9,
128.2, 128.9, 130.0, 130.3, 130.6, 130.9, 131.0 134.4, 135.0, 135.5,
136.7, 139.8, 143.1. 31P NMR (162 MHz, CDCl3): d 72.5. HRMS
The title compound (1.17 g, 1.60 mmol, 80% yield) was obtained
as a white solid from 22 according to the general procedure on the
same scale. Mp: 114–115 °C. ½a D31
ꢂ
¼ þ104:6 (c 1.00, CH2Cl2). 1H
NMR (400 MHz, CDCl3):
d 0.75 (t, J = 7.3 Hz, 3H), 0.99 (t,
J = 7.2 Hz, 6H), 1.04–1.14 (m, 3H), 1.19–1.33 (m, 7H), 1.35–1.45
(m, 3H), 1.52 (s, 3H), 1.95 (s, 3H), 3.52 (d, J = 10.8 Hz, 1H), 3.63
(d, J = 11.0 Hz, 1H), 4.41 (br s, 1H), 4.60 (t, J = 11.6 Hz, 1H), 5.00
(br s, 1H), 5.16–5.29 (m, 1H), 6.64 (s, 3H), 6.77–6.94 (m, 4H),
6.96–7.24 (m, 14H), 7.28–7.42 (m, 2H), 7.72–7.85 (m, 2H); 13C
NMR (100 MHz, CDCl3): d 13.9, 14.3, 22.5, 22.8, 27.3, 27.5, 29.0,
29.8, 35.4, 54.3, 55.7, 56.3, 70.1, 75.0, 126.1, 126.7, 126.8, 127.0,
127.1, 127.3, 127.5, 128.0, 128.5, 129.4, 129.9, 130.2, 130.4,
130.9, 131.0, 133.4, 133.6, 139.6, 143.2. 31P NMR (162 MHz, CDCl3):
d 74.3. HRMS (ESI): (m/z) calcd for C46H59N4PS [M+H]+: 731.4273,
found: 731.4271.
(ESI): (m/z) calcd for
C
42H47N4PS [M+H]+: 671.3359, found:
671.3345.
4.9.4. [(1R,2R)-1,2-Diphenyl-2-(piperidin-1-yl)ethyl]({[(1R,2R)-1,
2-diphenyl-2-(piperidin-1-yl)ethyl]amino}(phenyl)thiophos-
phoryl)amine 29
The title compound (1.01 g, 1.44 mmol, 72% yield) was obtained
as a white solid from 19 according to the general procedure on the
same scale. Mp: 230–231 °C. ½a D31
ꢂ
¼ þ118:4 (c 1.00, CH2Cl2). 1H
NMR (400 MHz, CDCl3): d 0.59–1.25 (m, 12H), 1.79–2.55 (m, 8H),
3.42 (d, J = 10.5 Hz, 1H), 3.57 (d, J = 10.8 Hz, 1H), 4.51–4.73 (m,
2H), 5.13–5.28 (m, 2H), 6.58–6.72 (m, 3H), 6.79–6.95 (m, 4H),
6.97–7.24 (m, 14H), 7.30–7.39 (m, 2H), 7.66–7.81 (m, 2H); 13C
NMR (100 MHz, CDCl3): d 24.1, 25.5, 25.9, 29.7, 55.6, 55.9, 75.0,
126.2, 126.6, 126.9, 127.0, 127.2, 127.3, 127.5, 127.9, 128.3,
129.2, 129.8, 130.1, 130.4, 131.1, 131.2, 133.7, 133.9, 135.0,
136.2, 140.0, 143.8. 31P NMR (162 MHz, CDCl3): d 74.6. HRMS
4.9.8. N-[(1R,2R)-2-[({[(1R,2R)-2-Acetamido-1,2-diphenylethyl]-
amino}(phenyl)thiophosphoryl)amino]-1,2-diphenylethyl]acet-
amide 33
The title compound (828 mg, 1.28 mmol, 64% yield) was ob-
tained as a white solid from 23 according to the general procedure
on the same scale. Mp: 136–137 °C. ½a D31
¼ þ65:0 (c 1.00, CH2Cl2).
ꢂ
1H NMR (400 MHz, CDCl3): d 1.49 (s, 3H), 2.00 (s, 3H), 3.14–3.28
(m, 1H), 4.25–4.42 (m, 1H), 4.67–4.81 (m, 1H), 4.83–4.97 (m,
1H), 5.02–5.24 (m, 2H), 6.53 (d, J = 7.3 Hz, 2H), 6.83–7.08 (m,
11H), 7.09–7.25 (m, 8H), 7.31–7.37 (m, 1H), 7.46–7.53 (m, 1H)
(ESI): (m/z) calcd for
C
44H51N4PS [M+H]+: 699.3664, found:
699.3645.

H. Yue et al. / Tetrahedron: Asymmetry 25 (2014) 170–180
179
7.57–7.79 (m, 4H); 13C NMR (100 MHz, CDCl3): d 22.3, 23.5, 59.4,
59.9, 60.2, 60.4, 127.2, 127.4, 127.5. 127,7, 128.0, 128.2, 128.5,
131.3, 131.4, 131.8, 133.7, 134.9, 139.3, 139.7, 140.2, 141.1,
169.6, 170.3. 31P NMR (162 MHz, CDCl3): d 70.7. HRMS (ESI): (m/
z) calcd for C38H39O2N4PS [M+Na]+: 669.2423, found: 669.2424.
The ee value and absolute configuration were determined by
comparing Chiral GC Chirasil Dex CB analysis tR and the specific
rotation with the literature data.11,29
4.10.3. 1-Phenylpropan-1-ol 37a
95% yield, 98% ee (R) (conducted with 31) and 92% yield, 97% ee
4.9.9. tert-Butyl N-[(1R,2R)-2-[({[(1R,2R)-2-{[(tert-butoxy)car-
bonyl]amino}-1,2-diphenylethyl]amino}(phenyl)thiophospho-
ryl)amino]-1,2-diphenylethyl]carbamate 34
(S) (conduct with 35). ½a D31
¼ þ36:5 (c 1.20, CHCl3) for 98% ee (R).
ꢂ
The ee value was determined by Chiral GC Chirasil Dex CB [Column
temperature: 130 °C, tR = 7.5 min for (R)-isomer and tR = 7.9 min
for (S)-isomer]. 1H NMR (400 MHz, CDCl3): d 0.95 (t, J = 7.4 Hz,
3H), 1.70–1.90 (m, 2H), 1.97 (br s, 1H), 4.61 (t, J = 6.6 Hz, 1H),
7.26–7.40 (m, 5H); 13C NMR (100 MHz, CDCl3): d 10.2, 31.9, 75.8,
126.1, 127.4, 128.4, 144.8.
The title compound (946 mg, 1.24 mmol, 62% yield) was ob-
tained as a white solid from 24 according to the general procedure
on the same scale. Mp: 93–95 °C. ½a D31
ꢂ
¼ þ30:8 (c 1.00, CH2Cl2). 1H
NMR (400 MHz, CDCl3): d 1.26–1.54 (m, 18H), 2.99 (s, 1H), 3.75 (s,
1H), 4.37–4.67 (m, 2H), 4.83 (s, 1H), 4.98 (d, J = 11.8 Hz, 1H), 5.93
(d, J = 7.6 Hz, 1H), 6.14 (s, 1H), 6.62 (s, 2H), 6.74–6.88 (m, 2H),
6.92–7.26 (m, 17H), 7.31–7.44 (m, 2H), 7.60–7.71 (m, 2H); 13C
NMR (100 MHz, CDCl3): d 28.3, 28.5, 29.7, 60.0, 60.6, 61.4, 65.5,
79.5, 79.9, 127.1, 127.2, 127.5, 127.7, 127.9, 128.0, 128.4, 130.9,
131.0, 131.5, 139.3, 139.7, 155.5. 31P NMR (162 MHz, CDCl3): d
4.10.4. 1-(4-Trifluoromethylphenyl)-1-propanol 37b
98% yield, 90% ee (R) (conducted with 31) and 97% yield, 87% ee
(S) (conduct with 35). ½a D31
¼ þ42:6 (c 1.50, CHCl3) for 90% ee (R).
ꢂ
The ee value was determined by Chiral GC Chirasil Dex CB [Column
temperature: 150 °C, tR = 4.8 min for (R)-isomer and tR = 5.1 min
for (S)-isomer]. 1H NMR (400 MHz, CDCl3) d 0.93 (t, J = 7.4 Hz,
3H), 1.64–1.94 (m, 2H), 2.33 (br s, 1H), 4.67 (t, J = 6.2 Hz, 1H),
7.45 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 9.9, 32.0, 75.3, 122.8, 125.3, 126.2, 129.4,
129.8, 148.5.
68.4. HRMS (ESI): (m/z) calcd for
C
44H51O4N4PS [M+Na]+:
785.3285, found: 785.3261.
4.9.10. Benzyl N-[(1R,2R)-2-[({[(1R,2R)-2-{[(benzyloxy)carbonyl]-
amino}-1,2-diphenyl ethyl]amino}(phenyl)thiophosphoryl)ami-
no]-1,2-diphenylethyl]carbamate 35
The title compound (1.12 g, 1.34 mmol, 67% yield) was obtained
as a white solid from 25 according to the general procedure on the
4.10.5. 1-(4-Chlorophenyl)-1-propanol 37c
97% yield, 93% ee (R) (conducted with 31) and 98% yield, 94% ee
same scale. Mp: 108–109 °C. ½a D31
ꢂ
¼ þ28:8 (c 1.00, CH2Cl2). 1H NMR
(S) (conduct with 35). ½a D31
¼ þ32:5 (c 1.20, CHCl3) for 93% ee (R).
ꢂ
(400 MHz, CDCl3): 3.03 (s, 1H), 3.95 (s, 1H), 4.49 (s, 1H), 4.64 (s,
1H), 4.79 (s, 2H), 4.85–5.31 (m, 4H), 6.61 (d, J = 7.0 Hz, 4H), 6.85
(d, J = 6.4 Hz, 2H), 6.91–7.22 (m, 19H), 7.23–7.42 (m, 10H), 7.49–
7.71 (m, 2H); 13C NMR (100 MHz, CDCl3): d 60.1, 60.3, 61.7, 66.7,
127.3, 127.4, 127.5, 127.7, 127.8, 127.9, 128.0, 128.1, 128.4,
128.5, 131.0, 131.7, 136.4, 136.7, 139.5, 141.0. 156.0, 156.7. 31P
NMR (162 MHz, CDCl3): d 69.8. HRMS (ESI): (m/z) calcd for C50H47-
O4N4PS [M+Na]+: 853.2960, found: 853.2948.
The ee value was determined by Chiral GC Chirasil Dex CB [Column
temperature: 150 °C, tR = 8.9 min for (R)-isomer and tR = 9.7 min
for (S)-isomer]. 1H NMR (400 MHz, CDCl3) d 0.90 (t, J = 7.5 Hz,
3H), 1.58–1.89 (m, 2H), 2.38 (br s, 1H), 4.55 (t, J = 6.8 Hz, 1H),
7.12–7.43 (m, 4H); 13C NMR (100 MHz, CDCl3) d 10.0, 31.9, 75.2,
127.4, 128.5, 133.0, 143.0.
4.10.6. 1-(4-Methoxyphenyl)-1-propanol 37d
93% yield, 90% ee (R) (conducted with 31) and 97% yield, 95% ee
4.10. General procedure for the enantioselective addition of
diethylzinc to aldehydes using 31 or 35 as the chiral ligand
(S) (conduct with 35). ½a D31
¼ þ28:6 (c 1.20, CHCl3) for 90% ee (R).
ꢂ
The ee value was determined by Chiral GC Chirasil Dex CB [Column
temperature: 150 °C, tR = 8.7 min for (R)-isomer and tR = 9.1 min
for (S)-isomer]. 1H NMR (400 MHz, CDCl3) d 0.87 (t, J = 7.4 Hz,
3H), 1.52–1.93 (m, 2H), 2.50 (br s, 1H), 3.80 (s, 3H), 4.50 (s, 1H),
6.85 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 7.8 Hz, 2H);13C NMR (100 MHz,
CDCl3) d 10.2, 31.8, 55.2, 75.5, 113.7, 127.2, 136.9, 158.9.
4.10.1. Using 31 as the chiral ligand
To a solution of 31 (33.7 mg, 0.05 mmol) in hexane (0.75 mL),
diethylzinc (0.75 mL of 1.0 M solution in hexane, 0.75 mmol) was
slowly added at ꢀ15 °C under a nitrogen atmosphere and stirred
for 30 min. Next, the aldehyde (0.5 mmol) was added dropwise.
The mixture was stirred for 2 h at ꢀ15 °C and then stirred for 4 h
at room temperature. The solution was then quenched with satu-
rated aqueous HCl (10%, 10 mL). Extraction with EtOAc gave com-
bined organic layers that were washed with brine, dried over
Na2SO4, and concentrated in vacuo to give a residue, which was
subjected to silica gel column chromatography, to afford the corre-
sponding secondary alcohol (R)-37.
4.10.7. 1-(2-Methoxyphenyl)-1-propanol 37e
94% yield, 92% ee (R) (conducted with 31) and 90% yield, 88% ee
(S) (conduct with 35). ½a D31
¼ þ20:4 (c 1.35, CHCl3) for 92% ee (R).
ꢂ
The ee value was determined by Chiral GC Chirasil Dex CB [Column
temperature: 150 °C, tR = 6.8 min for (S)-isomer, and tR = 7.6 min
for (R)-isomer]. 1H NMR (400 MHz, CDCl3) d 0.98 (t, J = 7.4 Hz,
3H), 1.72–1.99 (m, 2H), 2.82 (d, J = 6.1 Hz, 1H), 3.86 (s, 3H), 4.70–
4.93 (m, 1H), 6.77–6.08 (m, 2H), 7.18–7.45 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 10.3, 30.1, 55.1, 71.9, 110.4, 120.5, 128.0,
132.4, 156.4.
4.10.2. Using 35 as the chiral ligand
To a solution of 35 (41.5 mg, 0.05 mmol) in hexane (0.75 mL),
diethylzinc (0.75 mL of 1.0 M solution in hexane, 0.75 mmol) was
slowly added at 0 °C under a nitrogen atmosphere and stirred for
30 min. Next, the aldehyde (0.5 mmol) was added dropwise. The
mixture was stirred for 10 min at 0 °C and then stirred for
50 min at room temperature. The solution was then quenched with
saturated aqueous HCl (10%, 10 mL). Extraction with EtOAc gave
combined organic layers that were washed with brine, dried over
Na2SO4, and concentrated in vacuo to give a residue which was
subjected to silica gel column chromatography, to afford the corre-
sponding secondary alcohol (S)-37.
4.10.8. 1-(2-Methylphenyl)-1-propanol 37f
87% yield, 96% ee (R) (conducted with 31) and 65% yield, 82% ee
(S) (conduct with 35). ½a D31
¼ þ52:3 (c 1.10, CHCl3) for 96% ee (R).
ꢂ
The ee value was determined by Chiral GC Chirasil Dex CB [Column
temperature: 150 °C, tR = 5.2 min for (R)-isomer, and tR = 5.5 min
for (S)-isomer]. 1H NMR (400 MHz, CDCl3) d 0.98 (t, J = 7.4 Hz,
3H), 1.65–1.85 (m, 2H), 2.17 (br s, 1H), 2.34 (s, 3H), 4.84 (t,
J = 6.3 Hz, 1H), 7.05–7.60 (m, 4H); 13C NMR (100 MHz, CDCl3) d
10.4, 19.1, 30.9, 72.0, 125.3, 126.2, 127.1, 130.3, 134.6, 142.8.

180
H. Yue et al. / Tetrahedron: Asymmetry 25 (2014) 170–180
4.10.9. 1-(Naphthalen-2-yl)-1-propanol 37g
The ee value was determined by Chiral GC Chirasil Dex CB [Column
temperature: 145 °C, tR = 4.0 min for (R)-isomer, and tR = 4.3 min
for (S)-isomer]. 1H NMR (400 MHz, CDCl3): d 1.44 (d, J = 6.6 Hz,
3H), 3.86 (br s, 1H), 4.76–4.97 (m, 1H), 7.33–7.68 (m, 4H); 13C
NMR (100 MHz, CDCl3): d 25.0, 69.5, 125.3, 125.6, 149.8.
91% yield, 90% ee (R) (conducted with 31) and 99% yield, 95%
ee(S) (conduct with 35). ½a D31
¼ þ33:1 (c 1.40, CHCl3) for 90% ee
ꢂ
(R). The ee value was determined by Chiral GC Chirasil Dex CB [Col-
umn temperature: 170 °C, tR = 13.4 min for (R)-isomer, and
tR = 13.8 min for (S)-isomer]. 1H NMR (400 MHz, CDCl3) d 0.95 (t,
J = 7.4 Hz, 3H), 1.69–2.01 (m, 2H), 2.61 (br s, 1H), 4.71 (t,
J = 6.2 Hz, 1H), 7.39–7.64 (m, 3H), 7.68–7.96 (m, 4H); 13C NMR
(100 MHz, CDCl3) d 10.2, 31.8, 76.1, 124.3, 124.8, 125.8, 126.1,
127.7, 128.0, 128.2, 133.0, 133.3, 142.0.
4.10.16. 1-(4-Methoxyphenyl)ethan-1-ol 37n
5% yield, 68% ee (R) (conducted with 31) and 73% yield, 90% ee
(S) (conduct with 35). ½a D20
¼ ꢀ25:5 (c 1.10, CH3OH) for 90% ee (S).
ꢂ
The ee value was determined by Chiral GC Chirasil Dex CB [Column
temperature: 125 °C, tR = 17.2 min for (R)-isomer, and tR = 18.6 min
for (S)-isomer]. 1H NMR (400 MHz, CDCl3): d 1.43 (d, J = 6.3 Hz, 3H),
3.24 (br s, 1H), 3.77 (s, 3H), 4.67–4.90 (m, 1H), 6.85 (d, J = 8.6 Hz,
2H), 7.25 (d, J = 8.6 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 25.0,
55.2, 69.6, 113.8, 126.7, 138.3, 158.8.
4.10.10. 1-(1-Naphthyl)-1-propanol 37h
75% yield, 88% ee (R) (conducted with 31) and 89% yield, 83% ee
(S) (conduct with 35). ½a D31
¼ þ50:6 (c 1.25, CHCl3) for 88% ee (R).
ꢂ
The ee value was determined by Chiral GC Chirasil Dex CB [Column
temperature: 170 °C, tR = 13.7 min for (S)-isomer, and tR = 14.5 min
for (R)-isomer]. 1H NMR (400 MHz, CDCl3) d 1.03 (t, J = 7.4 Hz, 3H),
1.76–2.18 (m, 2H), 2.94 (br s, 1H), 5.32 (t, J = 6.2 Hz, 1H), 7.35–7.68
(m, 4H), 7.70–8.24 (m, 3H); 13C NMR (100 MHz, CDCl3) d 10.6, 31.2,
72.4, 123.1, 123.4, 125.5, 126.0, 127.9, 129.0, 130.6, 133.8, 140.4.
Acknowledgements
We would like to thank State Key Lab of Structural Chemistry,
Fujian Institute of Research on the Structure of Matter, Chinese
Academy of Sciences.
4.10.11. 1-(Thiophen-2-yl)propan-1-ol 37i
91% yield, 95% ee (R) (conducted with 31) and 98% yield, 96% ee
References
(S) (conduct with 35). ½a D31
¼ þ24:8 (c 2.00, CHCl3) for 95% ee (R).
ꢂ
1. Privileged Chiral Ligands and Catalysts; Zhou, Qi-Lin, Ed.; Wiley-VCH: Weinheim,
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The ee value was determined by Chiral GC Chirasil Dex CB [Column
temperature: 130 °C, tR = 8.0 min for (R)-isomer, and tR = 8.5 min
for (S)-isomer]. 1H NMR (400 MHz, CDCl3) d 0.94 (t, J = 7.5 Hz,
3H), 1.70–1.98 (m, 2H), 3.14 (br s, 1H), 4.76 (t, J = 6.2 Hz, 1H),
6.56–7.47 (m, 3H); 13C NMR (100 MHz, CDCl3) d 10.2, 32.2, 71.6,
123.8, 124.3, 126.5, 148.8.
7. Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833–856.
4.10.12. 1-Cyclohexylpropan-1-ol 37j
8. Sahin, E.; Kilic, H. Tetrahedron: Asymmetry 2011, 22, 277–282.
9. Szakonyi, Z.; Csillag, K.; Fulop, F. Tetrahedron: Asymmetry 2011, 22, 1021–1027.
10. Cheng, Y. N.; Wu, H. L.; Wu, P. Y.; Shen, Y. Y.; Uang, B. J. Chem. Asian J. 2012, 7,
2921–2924.
11. Bian, G. L.; Huang, H. Y.; Zong, H.; Song, L. Chirality 2012, 24, 825–832.
12. Rachwalski, M.; Jarzynski, S.; Jasinski, M.; Lesniak, S. Tetrahedron: Asymmetry
2013, 24, 689–693.
13. Rachwalski, M.; Jarzynski, S.; Legniak, S. Tetrahedron: Asymmetry 2013, 24,
421–425.
14. Prasad, K. R.; Revu, O. Tetrahedron 2013, 69, 8422–8428.
15. Escorihuela, J.; Gonzalez, L.; Altava, B.; Burguete, M. I.; Luis, S. V. Appl. Catal. A:
Gen. 2013, 462, 23–30.
49% yield, 84% ee (R) (conducted with 31) and 50% yield, 85% ee
(S) (conduct with 35). ½a D31
¼ þ3:4 (c 0.50, CHCl3) for 84% ee (R).
ꢂ
The ee value was determined by Chiral GC Chirasil Dex CB [Column
temperature: 105 °C, tR = 17.1 min for (S)-isomer, and tR = 17.6 min
for (R)-isomer]. 1H NMR (400 MHz, CDCl3) d 0.88 (t, J = 7.4 Hz, 3H),
0.91–1.40 (m, 7H), 1.45–1.81 (m, 6H), 2.00 (br s, 1H), 3.15–3.24 (m,
1H); 13C NMR (100 MHz, CDCl3) d 10.2, 26.2, 26.4, 26.5, 26.7, 27.8,
29.3, 43.1, 76.8.
16. Binder, C. M.; Bautista, A.; Zaidlewicz, M.; Krzeminski, M. P.; Oliver, A.;
Singaram, B. J. Org. Chem. 2009, 74, 2337–2343.
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Asymmetry 2011, 22, 761–768.
19. Burguete, M. I.; Collado, M.; Escorihuela, J.; Luis, S. V. Angew. Chem., Int. Ed.
2007, 46, 9002–9005.
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2010, 21, 2334–2345.
21. Csillag, K.; Szakonyi, Z.; Fulop, F. Tetrahedron: Asymmetry 2013, 24, 553–561.
22. Soai, K.; Ookawa, A.; Ogawa, K.; Kaba, T. J. Chem. Soc., Chem. Commun. 1987,
467–468.
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Technol. 2011, 1, 1149–1158.
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2725.
4.10.13. Undecan-3-ol 37k
75% yield, 78% ee (R) (conducted with 31) and 80% yield, 90% ee
(S) (conduct with 35). ½a D20
¼ ꢀ5:2 (c 8.00, EtOH) for 78% ee (R). The
ꢂ
ee value was determined by Chiral GC Chirasil Dex CB [Column
temperature: 115 °C, tR = 15.1 min for (R)-isomer, and tR = 15.5 min
for (S)-isomer]. 1H NMR (400 MHz, CDCl3) d 0.74–1.06 (m, 6H),
1.26–1.51 (m, 15H), 1.59 (s, 2H), 3.55 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 9.9, 14.1, 22.7, 25.7, 29.3, 29.6, 29.7, 30.1,
31.9, 37.0, 73.4.
4.10.14. (E)-2-Methyl-1-phenylpent-1-en-3-ol 37l
72% yield, 90% ee (R) (conducted with 31) and 95% yield, 94% ee
(S) (conduct with 35). ½a D20
¼ ꢀ32:5 (c 1.20, CHCl3) for 90% ee (R).
ꢂ
The ee value was determined by Chiral GC Chirasil Dex CB [Column
temperature: 135 °C, tR = 20.1 min for (R)-isomer, and tR = 20.8 min
for (S)-isomer]. 1H NMR (400 MHz, CDCl3) d 0.97 (t, J = 7.4 Hz, 3H),
1.17–1.38 (m, 1H), 1.65–1.76 (m, 2H), 1.88 (s, 3H), 4.13 (s, 1H), 6.52
(s, 1H), 7.17–7.43 (m, 5H); 13C NMR (100 MHz, CDCl3) d 9.7, 14.2,
21.0, 30.2, 60.4, 74.4, 126.5, 127.6, 128.6, 130.4, 132.3, 136.8.
30. Wu, R. H.; Chang, X. F.; Lu, A. D.; Wang, Y. M.; Wu, G. P.; Song, H. B.; Zhou, Z. H.;
Tang, C. C. Chem. Commun. 2011, 5034–5036.
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32. Yamakawa, M.; Noyori, R. Organometallics 1999, 18, 128–133.
33. Paleo, M. R.; Cabeza, I.; Sardina, F. J. J. Org. Chem. 2000, 65, 2108–2113.
34. Vazquez, J.; Pericas, M. A.; Maseras, F.; Lledos, A. J. Org. Chem. 2000, 65, 7303–
7309.
4.10.15. 1-[4-(Trifluoromethyl)phenyl]ethan-1-ol 37m
45% yield, 72% ee (R) (conducted with 31) and 91% yield, 96% ee
(S) (conduct with 35). ½a D20
¼ ꢀ34:2 (c 1.50, CHCl3) for 96% ee (S).
ꢂ