The synthesis of chiral amino diol tridentate ligands and their enantioselective induction during the addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2013.11.007

A series of C₂-symmetric chiral amino diol tridentate ligands 3a-g were prepared from achiral bulky organolithiums, achiral bulky primary amines, and optically active epichlorohydrin (ECH). The prepared C ₂-symmetric chiral amino diol tridentate ligands were capable of inducing enantioselectivity in the model reaction of aromatic and aliphatic aldehydes with diethylzinc with an ee of up to 96%. The enantioselectivity can be modulated by adjusting the steric hindrance of the achiral reagents employed in the synthesis of the chiral ligand. The configuration of the addition product depended on the configuration of the amino diol ligands, which can be simply controlled as desired by using the ECH with the desired configuration during the preparation of the ligand.

Full text of DOI:10.1016/j.tetasy.2013.11.007

Tetrahedron: Asymmetry 25 (2014) 289–297
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The synthesis of chiral amino diol tridentate ligands and their
enantioselective induction during the addition of diethylzinc
to aldehydes
⇑
⇑
An-lin Zhang, Li-wen Yang , Nian-fa Yang , Yan-ling Liu
Key Laboratory of Environmentally Friendly Chemistry and Applications of Ministry of Education, College of Chemistry, Xiangtan University, Hunan 411105, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 August 2013
Accepted 5 November 2013
A series of C2-symmetric chiral amino diol tridentate ligands 3a–g were prepared from achiral bulky
organolithiums, achiral bulky primary amines, and optically active epichlorohydrin (ECH). The prepared
C2-symmetric chiral amino diol tridentate ligands were capable of inducing enantioselectivity in the
model reaction of aromatic and aliphatic aldehydes with diethylzinc with an ee of up to 96%. The enanti-
oselectivity can be modulated by adjusting the steric hindrance of the achiral reagents employed in the
synthesis of the chiral ligand. The configuration of the addition product depended on the configuration of
the amino diol ligands, which can be simply controlled as desired by using the ECH with the desired con-
figuration during the preparation of the ligand.
Ó 2014 Published by Elsevier Ltd.
1. Introduction
of azides to meso epoxides.27 The problem for preparing chiral
amino diol when applying the reaction of an amine with optically
Chiral amino alcohols possess the ability to induce enantiose-
lective reactions and have been used as chiral ligands in many
asymmetric reactions, such as asymmetric additions of diethylzinc
to aldehydes,1–6 asymmetric Michael addition reactions,7–9 asym-
metric Diels–Alder reactions,10,11 and asymmetric hydrogenations
of aromatic ketones.12–15 There are two common methods for pre-
paring a chiral amino alcohol: one is to reduce a natural amino
acid,16–19 while the other is to resolve a racemic amino alco-
hol.20–22 With the method that reduces a natural amino acid, the
structure of the obtained amino alcohol is restricted by the struc-
ture of the amino acid used. With the method that resolves a race-
mic amino alcohol, an expensive chiral reagent must be employed.
In order to diversify the structure of chiral amino alcohols, the
reaction of an amine with an optically active epoxide has been
used in recent years. Manickam and Sundararajan applied the reac-
tion of optically active styrene oxide with benzylamine to obtain a
chiral, C2-symmetric amino diol tridentate ligand23 and found that
the obtained amino diol possessed the ability to enantioselectively
induce Michael addition reactions24 and Diels–Alder reactions.25
Grassi et al. prepared (+)-(S,S,S)-triisopropanolamine with 94% ee
via the reaction of (S)-(+)-1-amino-2-propanol with ammonia26
while Nugent employed (+)-(S,S,S)-triispropanolamine as a ligand
to prepare a chiral Lewis acid to catalyze enantioselective additions
active epoxide is the source of the chiral epoxide. There are two
methods for preparing optically active epoxides: one is by kinetic
resolution of a racemic epoxide28 while the other is by asymmetric
epoxidation of an olefin.29–33 There is no universal kinetic resolving
method and no universal resolving conditions for the resolution of
epoxides with various structures. Therefore, the availability of
optically active epoxides is limited.
Recently, a method for the kinetic resolution of racemic epichlo-
rohydrin (ECH) has been established. Due to the ease of recovering
and recycling the hydrolyzing product, ECH is not lost during the
kinetic resolution process. So far, the kinetic resolution of ECH
has been industrialized and both (R)-ECH and (S)-ECH have be-
come very inexpensive (ca. US$ 9 per kilogram).34 Based on the
inexpensive optically active ECH, C2-symmetric chiral amino diol
tridentate ligands were synthesized using optically active ECH as
the chiral source and their enantioselective inductivity in the addi-
tion of diethylzinc to aldehydes was assessed.
2. Results and discussion
2.1. The design strategy for the synthesis of chiral amino diol
tridentate ligands
The reaction of an organometallic reagent R–M with optically
active ECH should create an optically active, substituted propylene
epoxide 2 (Scheme 1). The reaction of 2 with a primary amine
should create chiral amino diol tridentate ligand 3. The designed
synthetic route to the amino diols is shown in Scheme 1.
⇑
Corresponding authors. Tel.: +86 0731 5829383.
E-mail addresses: yangliwen_0519@163.com (L. Yang), nfyang@xtu.edu.cn
(N. Yang).
0957-4166/$ - see front matter Ó 2014 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetasy.2013.11.007

290
A. Zhang et al. / Tetrahedron: Asymmetry 25 (2014) 289–297
R1
N
OH-
MO
O
R1 NH2
O
+
R
M
R
R
Cl
-MCl
R
Cl
R
OH OH
3
1
2
Scheme 1. Route for synthesizing chiral amino diol tridentate ligands.
By selecting various R and R1 groups, the steric hindrance of the
by n-BuLi to afford solutions of organolithium A and organolithium
B, respectively.
chiral amino diol ligand 3 could be adjusted and the enantioselec-
tive influence of 3 improved. We assumed that an increase in the
bulk of R would be favorable not only to the enhancement of the
enantioselectivity of the ligand, but also to the reinforcement of
the attack at the CH2 group of the epoxide ring and to the suppres-
sion of attack at the CH of the epoxide ring. Therefore, the bulky
organolithium reagents 9-ethyl-9-lithiumfluorene A, triphenyl-
methyl-lithium B, and 5-pentyl-5-lithiumdibenzo[a,e] suberane
(C) (Fig. 1) were selected as nucleophilic reagents to react with
The preparation of organolithium reagent C is described in
Scheme 3. 5-Methene dibenzosuberane was reacted with
n-butyllithium in tetrahydrofuran (THF) to afford a solution of C.
A solution of optically active ECH was added dropwise to a solu-
tion of the organolithium reagent at ꢀ70 °C with stirring. After the
addition, the reaction mixture was stirred at ꢀ70 °C for 1 h and
then stirred at room temperature for 2 h to create the optically
active propene oxide 2. The yield obtained for 2a, 2b, and 2c was
R1
Ph
N
Ph
C
Li
Ph
O
R
R
R
Li
C2H5
Li
OH
3a-c
n-C5H11
HO
A
B
C
2a-c
Ph
C
Ph
R1
=
b: R =
a: R =
c: R =
CH2 Ph
C2H5
Ph
n-C5H11
Figure 1. The structures of the organolithium reagent, substituted propylene epoxides 2a–c, and chiral amino diol tridentate ligands 3a–c.
optically active ECH to create optically active, substituted propyl-
ene epoxides 2a–c, respectively (Fig. 1). The bulk of the R1 group
n-C4H9Li / n-hexane
should also have an impact on the enantioselectivity of 3.
THF, 0°C(1h), 50°C(1h)
Li
n-C5H11
With benzylamine in hand, amino diols 3a–c (Fig. 1) were syn-
thesized. The impact of the R group on the enantioselectivity of the
amino diol chiral ligand was examined in order to determine
which R group gave the amino diol ligand with the best enantiose-
lectivity. Then with the R group established, other amino diols
were synthesized and the impact of the R1 group on the enantiose-
lectivity of the chiral amino diol ligand was examined.
C
Scheme 3. The preparation of organolithium C.
70.3%, 64.8%, and 46.7% respectively. The mechanism of the reac-
tion is shown in Scheme 4.
The nucleophilic reagent Rꢀ attacks the epoxide ring at the less
hindered CH2 to create the ring-opening intermediate 4. After the
temperature is increased to room temperature, the elimination of
LiCl from the intermediate 4 takes place to create epoxide 2. The
configuration of the stereogenic carbon atom is retained because
it is not involved in the reaction process.
2.2. The synthesis of chiral amino diol ligands 3
2.2.1. The synthesis of substituted propene oxides 2
The preparation of organolithium reagent A and organolithium
reagent B is described in Scheme 2. 9-Ethylfluorene and triphenyl-
In order to confirm the mechanism, the reaction of organolith-
ium A with ECH was quenched with water after the addition of
ECH and intermediate 5a (R = 9-ethylfluoren-9-yl) was obtained
in 81.3% yield. When 5a was stirred in aqueous NaOH at room tem-
perature for two hours, epoxide 2a was formed.
The ECH addition temperature was chosen to be ꢀ70 °C in order
to ensure that nucleophilic attack took place entirely at the meth-
ene CH2– of the epoxide ring, rather than at the sterically hindered
methine CH–. The yield of 2 was high (>67%) when the ECH addi-
tion temperature was below ꢀ20 °C. When the addition tempera-
ture rose to 0 °C, the yield of 2 decreased dramatically (22%). The
structures of 2a–c were determined by 1H NMR, 13C NMR, and ele-
mental analysis. Analysis by chiral high performance liquid chro-
matography (HPLC) confirmed that the enantiomeric excess of
2a–c was the same as that of the starting material ECH (98.8%
ee). The configuration of 2 was (S) when (S)-ECH was used as
n-C4H9Li / n-hexane
THF, r.t., 1 h
C2H5
Li
C2H5
Ph
H
A
Ph
C
n-C4H9Li / n-hexane
Ph
C
Ph
Ph
Ph
THF, 0°C, 1 h
Li
B
H
Scheme 2. The preparation of organolithium A and B.
methane were used, respectively as starting materials. The active
hydrogen atom of the starting material molecule was removed

A. Zhang et al. / Tetrahedron: Asymmetry 25 (2014) 289–297
291
LiO
O
- LiCl
r. t.
O
+
R
Li
Cl
R
-70°C
R
Cl
2 (46.7%-70.3%, ee>98%)
A-C
4
H2O
HO
R
Cl
5
Scheme 4. The formation of optically active propene oxide 2.
Table 1
starting material, while the configuration of 2 was (R) when (R)-
The enantioselective inductivity of the amino diols 3a–c for the reaction of
ECH was used.
diethylzinc with benzaldehydea
Bn
N
2.2.2. The reaction of the chiral, substituted propene oxides 2
with benzylamine
R
R
3a-c
Benzylamine reacted with chiral epoxides 2a–c at reflux to cre-
ate chiral amino diols 3a–c. In the reaction, the nucleophilic amine
attacked the epoxide group at the less sterically hindered methene
CH2 and the configuration of the asymmetric carbon was retained.
Compound (S)-3 was obtained when using (S)-2 as a reactant while
(R)-3 was obtained when using (R)-2 as a reactant. The reaction is
described in Scheme 5.
OH
HO
OH
Ph CHO
Et2Zn
+
Ph
Ti(O-i-Pr)4, toluene
Entry
Ligandb
Product
Config.d
Yieldc (%)
eee (%)
1f
2
3
5
6
(S)-3a
(S)-3a
(S)-3b
(S)-3c
(R)-3b
95
77
80
92
83
(S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
(R)-(+)
45
66
68
55
67
(S)-3a: 52.4%, [α]D20 = +106.4
(R)-3b: 49.4%, [α]D20 = +78.8
Bn
N
a
Toluene: 13 mL; PhCHO: 1 mmol; Reaction time: 24 h; Reaction temperature:
0 °C; n(PhCHO)/n(Et2Zn)/n(Ti(O-i-Pr)4)/n(ligand) = 1/3/1.8/0.1.
O
PhCH2NH2
ethanol
R
R
R
b
(S)-3b: 49.4%, [α]D20 = -78.0
(S)-3c: 62.2%, [α]D20 = +66.8
OH OH
The letter in the bracket denotes the configuration of the stereogenic carbon
atom in the ligand.
2a-c
3a-c
c
The isolated yield.
d
The absolute configurations of the products were determined by comparing
their sign of rotation with that reported in the literature.
Scheme 5. The reaction of the chiral epoxide with benzylamine.
e
The ee of the product was measured by chiral HPLC.
f
No Ti(O-i-Pr)4 was added.
The amino diols obtained were C2-symmetric. Their structure
was confirmed by NMR and elemental analysis. Chiral HPLC analy-
sis confirmed that the ee value of 3 was the same as that of the cor-
responding 2. The isolated yields were 49.4–62.2%.
mined by comparing their sign of rotation with that reported in the
literature.
It has been reported that Ti(O-i-Pr)4 is capable of increasing the
enantioselectivity of the reaction.44 Our experiment confirmed that
the enantioselectivity of the reaction was improved by the addition
of Ti(O-i-Pr)4 (entry 2 vs entry 1 in Table 1). Therefore, Ti(O-i-Pr)4
was added when assessing the enantioselectivity of the
C2-symmetric amino diol.
The data listed in Table 1 shows that the chiral amino diol tri-
dentate ligand 3 derived from optically active ECH possessed the
ability to enantioselectively induce the reaction of diethylzinc with
benzaldehyde. From Table 1, we can conclude that: (1) (S)-3b pos-
sesses the highest level of enantioselective induction among the
three ligands; and (2) changing the configuration of the stereog-
neic carbon in the ligand inverts the configuration of the product.
Therefore, (S)-2b was used in subsequent work for seeking an ami-
no diol that possesses a high level of enantioselective induction.
2.3. The enantioselectivity of the chiral, C2-symmetric amino
diol tridentate ligands 3a–c
The enantioselective addition of organozinc reagents to aryl
aldehydes in the presence of a catalytic amount of chiral ligand
has emerged as an attractive method for the synthesis of optically
active secondary alcohols.35 Recently, C2-symmetric aziridino
diols,36 chiral epoxy alcohol ligands derived from (+)-camphor
and (ꢀ)-fenchone,37 C2-symmetric chiral 2,20-bipyridine diol
ligands,38 C2-symmetrical bis-b-amino alcohols,39 chiral pyridine
ligands,40 chiral (3R,5R)-dihydroxypiperidine derivative ligands,41
chiral hydrazone and imine ligands,42 and pinane-type tridentate
aminodiol ligands43 have been synthesized and employed as chiral
ligands for the enantioselective addition of diethylzincs to aryl
aldehydes. However, to the best of our knowledge, there are no
C2-symmetric chiral amino diol tridentate ligands derived from
optically active epoxides bearing a bulky group that have been
studied except for (1R, 5R)-3-aza-3-benzyl-1,5-diphenylpentan-
1,5-diol which is derived from the (R)-styrene oxide.23–25
Since the enantioselective addition of diethylzinc to an alde-
hyde is an attractive reaction for the synthesis of optically active
secondary alcohols and is frequently used as a model reaction to
assess the enantioselectivity of a chiral catalyst, we selected this
addition as a model reaction in order to assess the enantioselectiv-
ity of the C2-symmetric amino diol ligands 3. The enantioselectivity
of 3a–c for the reaction of diethylzinc with benzaldehyde is listed
in Table 1. The absolute configurations of the products were deter-
2.4. Impact of the steric hindrance of R1 on the
enantioselectivity
Since the steric hindrance of the R group in the ligand had a sig-
nificant impact on the enantioselectivity of the chiral amino diol li-
gand, the steric hindrance of the R1 group in the ligand should also
have an important impact on the enantioselectivity of the ligand.
In order to determine which chiral amino diol ligand gave better
enantioselectivity, the chiral amino diol ligands (S)-3d–g were syn-
thesized. The reaction conditions and the yield are shown in
Scheme 6. The enantioselectivity of compounds (S)-3d–g for the
addition of diethylzinc to benzaldehyde was examined.

292
A. Zhang et al. / Tetrahedron: Asymmetry 25 (2014) 289–297
n-Bu
N
N
Ph3C
CPh3
Ph3C
CPh3
(S)-3e (68.50%, [α]D20 = -72.6)
OH
OH
OH
OH
-3d
α
(S)
(72.12%, [
]
D
20 = -70.1)
NH2
O
Ph3C
CHPh2
(S)-2b
t-Bu
N
N
Ph3C
CPh3
Ph3C
CPh3
OH OH
OH
OH
(S)- (69.12%, [α]D20 = -69.4)
3f
(86.26%, [α]D20 =-82.55)
3g
(S)-
Scheme 6. The synthetic routes of chiral amino diol ligands (S)-3d–g.
Table 3
The enantioselectivity data of ligands (S)-3d–g are listed in
The enantioselectivity of (S)-3g for the reaction of diethylzinc with different
Table 2. Chiral amino diol ligands (S)-3f and (S)-3g gave a high
aldehydesa
OH
3g
Ti(O-i-Pr)4, (S)-
R2 CHO
Et2Zn
+
Table 2
R2
toluene
The enantioselectivity of (S)-3d–g toward the reaction of diethylzinc with
a
benzaldehydea
Entry
R2
(S)-3g (mol %)
Product
Yieldb (%)
eec (%)
OH
Ti(O-i-Pr)4, (S)-3d-g
Ph CHO
Et2Zn
+
1
Phenyl
Phenyl
5
10
5
10
5
10
5
10
5
10
5
5
5
5
5
5
5
5
5
5
5
5
72
68
56
50
84
78
68
58
70
62
65
67
91
85
82
91
81
84
89
76
92
90
86
76
94
96
82
86
90
96
81
86
82
88
91
93
90
93
87
93
95
90
91
95e
80f
78f
88f
84f
toluene
Ph
Product
2
3d
2-Hydroxyphenyl
2-Hydroxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
2-Phenylvinyl
2-Phenylvinyl
2-Pyridyl
2-Pyridyl
4-Chlorophenyl
2-Naphthyl
Entry
Ligand
4d
Yieldb (%)
eec (%)
5
1
2
3
4
(S)-3d
(S)-3e
(S)-3f
(S)-3g
76
72
75
72
80
84
90
94
6
7d
8d
9d
10d
11
12
13
14
15
16
17
18
19
20
21d
22d
23d
24d
a
Toluene: 13 mL; PhCHO: 1 mmol; Reaction time: 24 h; Reaction temperature:
0 °C; n(PhCHO)/n(Ti(O-i-Pr)4)/Et2Zn/ligand = 1/1.8/3/0.05.
b
The isolated yield.
The ee of the product was measured by chiral HPLC.
2-Furyl
c
4-Dimethylaminophenyl
2-Methoxyphenyl
3-Methoxyphenyl
1-Naphthyl
4-Methylphenyl
3-Phenylpropyl
2,2,2-Triphenylethyl
Cyclohexyl
level of enantioselective induction even when 5% mol of the chiral
ligand was used. The ee of the addition product was 90% and 94% in
the presence of ligands (S)-3f and (S)-3g, respectively (entries 3
and 4 in Table 2).
n-Amyl
n-Octy
n-Hexyl
To further investigate the enantioselectivity of ligand (S)-3g,
other aldehydes were employed to replace the benzaldehyde sub-
strate. The results are listed in Table 3. The absolute configurations
of the products were determined by comparing their sign of
rotation with that reported in the literature except for product 1-
(triphenylmethyl)-2-butanol (entry 20). In order to determine the
configuration of the product 1-(triphenylmethyl)-2-butanol,
(S)-1-(triphenylmethyl)-2-butanol was synthesized via the reac-
tion of (R)-2b with methyllithium, which is shown in Scheme 7.
The reaction shown in Scheme 7 did not involve the asymmetric
carbon atom and the configuration of the asymmetric carbon was
retained; therefore the reaction of (R)-2b with methyllithium cre-
ated (S)-1-(triphenylmethyl)-2-butanol. The sign of rotation of the
obtained (S)-1-(triphenylmethyl)-2-butanol was minus (ꢀ) and
was the same as that of the product created by the 3g-induced
reaction of 3,3,3-triphenylpropanal with diethylzinc. Thus the con-
figuration of the product created by the 3g-induced reaction of
3,3,3-triphenylpropanal was assigned as (S).
5
5
Toluene: 13 mL; R2CHO: 1 mmol; Reaction time: 24 h; Reaction temperature:
a
0 °C; n(R2CHO)/n(Ti(O-i-Pr)4)/Et2Zn = 1/1.8/3.
b
The isolated yield.
c
The ee values of the product were determined by chiral HPLC. The absolute
configurations of the products were determined by comparing their sign of rotation
with those reported in the literature.
d
Reaction temperature: ꢀ10 °C.
e
The configuration was determined by comparing the sign of the specific rota-
tion with that of (S)-1-(triphenylmethyl)-2-butanol prepared via the reaction of
(S)-4,4,4-triphenyl-1-butene oxide with MeLi.
f
The ee value was measured via its benzoate ester.
O
OH
1) CH3Li, - 70°C
2) aq. HCl
Ph3C
Ph3C
H
H
2b
(S)-1-(triphenylmethyl)-2-butanol
(R)-
For all of the aldehydes tested, ligand (S)-3g showed a satisfying
level of enantioselective induction. The substituent on the ring of
Scheme 7. The synthetic route to (S)-1-(triphenylmethyl)-2-butanol.

A. Zhang et al. / Tetrahedron: Asymmetry 25 (2014) 289–297
293
the aromatic aldehyde had some impact on the level of the enan-
tioselective induction but the impact was not much. It is notewor-
thy that (S)-3g not only gave up to 91% yield and 96% ee value for
the aromatic aldehydes tested, but also gave 76–92% yields and
78–95% ee values for all of the aliphatic aldehydes tested (entries
19–24 in Table 3). An enantiomeric excess of 95% was obtained
for 3,3,3-triphenylpropanal. So far, many excellent chiral ligands
for the enantioselective addition of diethylzinc to aromatic alde-
hydes have been reported with very high yields and ee values,
but most of them are not suitable for aliphatic aldehydes or they
have only a limited substrate scope of aliphatic aldehydes.
proposed a penta coordinated Ti transition state for the enantiose-
lective addition induced by C2-symmetric VERDI disulfonamides.48
On the basis of the above mechanistic considerations, we sug-
gest that the asymmetric addition of diethylzinc to an aldehyde in-
duced by
a chiral amino diol ligand goes through a hexa-
coordinated Ti transition state complex, which contains one chiral
amino diol ligand, one ethyl, and one isopropoxy group.
The 1H NMR of the –CH–O methyne confirmed our hexa-
coordinated Ti transition state suggestion. The –CH–O methyne
resonance of 3g is at d 3.49 ppm (Fig. 2a). The complex (3g)2Ti
can be readily prepared by removal of isopropanol from a 2:1 mix-
Figure 2. The partial 1H NMR spectra of 3g, (3g)2Ti complex, i-PrOH, and titration of 3g by titanium tetraisopropoxide. (a): 3g; (b): (3g)2Ti complex obtained from evaporating
the mixture of 2 mmol of 3g and 1 mmol of titanium tetraisopropoxide in vacuo. (c): i-PrOH; (d): Ti(O-i-Pr)4. (e–h): Titration of 3g by titanium tetraisopropoxide for the ratio
1:1 (e), 1:2 (f), 1:3 (g) and 1:5 (h).
Generally, 5% ligand loading gave a satisfactory level of asym-
metric induction. An increase in the ligand loading could enhance
the level of asymmetric induction, but the magnitude of enhance-
ment was not much. When the ligand loading was raised to
10 mol %, the magnitude of ee enhancement of the product alcohol
was not more than 6%.
ture of 3g and titanium tetraisopropoxide under reduced pressure.
The 1H NMR spectrum of the (3g)2Ti complex is shown in Figure 2b.
The –CH–O methyne resonance of the (3g)2Ti complex remains al-
most unchanged (d 3.47 ppm, Fig. 2b) (possibly due to the N atom
participating in the coordination). The i-PrOH methyne resonance
is at d 4.04 ppm (Fig. 2c) and the –CH–O methyne resonance of
Ti(O-i-Pr)4 is at 4.43 ppm (Fig. 2d). Figure 2f shows the –CH–O
methyne resonance of the mixture derived from the titration of
3g by titanium tetraisopropoxide in a 1:2 ratio. In Figure 2f, V be-
longs to the OH, while W and X belong respectively to the –CH–O
methyne resonance of Ti(O-i-Pr)4 and i-PrOH and Y and Z are the
–CH–O methyne resonance of complexes formed by the coordina-
tion of Ti with other coordinating group such as –NCHO–,
–NCHOH–, i-PrO–. Figure 2e–h shows respectively the –CH–O
methyne resonance of the mixture derived from the titration of
3g by titanium tetraisopropoxide for the 1:1, 1:2, 1:3, and 1:5
ratios. From the numbers of W, Y, and Z, we can calculate the
number (n) of Ti coordinated by other groups.
2.5. Mechanistic considerations
The exact mechanism for the titanium promoted diethylzinc
addition to aldehydes is so far not known for certain and can be dif-
ferent for various types of ligand.45 Balsells et al. concluded that
the active catalytic intermediate could be an ethyl titanium species
derived from the transfer of an ethyl group from zinc to titanium.46
Bauer proposed a hexa-coordinate Ti transition state for the enan-
tioselective addition catalyzed by
the enantioselective additions induced by
D
-glucosamine derivatives.45 For
-hydroxy carboxylic
a
acids, Tomasz Bauer proposed a penta coordinated Ti transition
state with hydrogen bonding between the oxygen of the ligand
and the formyl hydrogen of the coordinated aldehyde.47 Paquette
The 1H NMR spectrum of a CDCl3 solution of 3g and titanium
tetraisopropoxide (1 equiv) showed a set of resonances derived

294
A. Zhang et al. / Tetrahedron: Asymmetry 25 (2014) 289–297
from 3g and free i-PrOH without any signals for Ti(O-i-Pr)4
(Fig. 2e). Mixing the ligand 3g with Ti(O-i-Pr)4 in a 1:2 ratio gives
the 3g-titanate quantitatively and instantaneously, while 1H NMR
analysis indicates that excess tetraisopropyl titanate does not lead
to new species such as doubly titanated complex 3g(Ti)2 (Fig. 2f).
When mixed with an excess of up to 4 equiv of Ti(O-i-Pr)4, the
3g-titanate with only one Ti-containing ring, is still formed
(Fig. 2g and h).
C2H5
CH2CPh3
C2H5
CH2CPh3
O
O
N
N
Ph3CH2C
Ph3CH2C
Ti
Ti
O
O
O
O
O
Si
O
H
H
Ph
Ph
Si-attack
Ia
Ib
Table 4 lists the number of coordination groups in the initiate
feeds and titration mixtures, the number of Ti, and the number
of calculated coordination groups in the titration mixtures.
Table 4 shows that the coordination number (n) of the Ti com-
plex in solution in the presence of 3g is 6. There are six possible
steric isomers for the hexa-coordinate Ti transition state complex,
which are shown in Figure 3.
Steric isomers III, IV, V, and VI can be ignored due to the unfa-
vorable interactions between the benzaldehyde molecule and the
ambient group; hence we focused our attention on steric isomers
I and II. The formyl hydrogen can form hydrogen bonds with the
oxygen atoms of the amino diol in two possible manners which
are depicted in Figure 4.
C2H5
Ph3CH2C
O
C2H5
Ph3CH2C
O
N
N
CH2CPh3
CH2CPh3
Ti
Ti
O
O
O
O
O
O
H
H
Si
Ph
Si-attack
Ph
IIa
IIb
Figure 4. Stereochemical models for the attack of an ethyl group to the carbonyl of
the benzaldehyde.
Isomers Ia and IIa are unstable due to the high steric energy
resulting from the unfavorable interaction between the benzalde-
hyde and the front Ph3CCH2 group. They hardly contribute to the
asymmetric addition reaction. Isomers Ib and IIb have little steric
hindrance and control the enantioselective orientation of the reac-
tion. It is obvious that the ethyl group in Ib and IIb only attacks the
Si face of the carbonyl group to create the (S)-product. However,
when the R1 group in the ligand is not bulky, the situation changes.
For example, in the circumstance of using (S)-3d (R1 is n-butyl) as a
ligand, the content of IIIa and VIa (see Fig. 5) increases and Re-at-
tack increases.
Re-attack
n-Bu
Ph
C
Ph
C
n-Bu
N
i-Pr
O
O
H
H
C2H5
Ph3CH2C
O
N
CH2CPh3
CH2CPh3
Ph3CH2C
Ti
Ti
O
O
O
i-Pr
O
O
C2H5
-attack
Re
VIa
IIIa
Figure 5. The increase of the Re-attack for less bulkiness R1.
Table 4
1H NMR titration of 3g in CDCl3 by titanium tetraisopropoxidea
Run
Ratiob
The number of groups participating in coordination
–CHO– in the titration mixture
nd
–NCH2CHO–
N
Me2CHO-Ti
Ti
W
Y
Z
Uc
1
2
3
4
1:1
1:2
1:3
1:5
2
2
2
2
1
1
1
1
4
8
12
20
1
2
3
5
0
3.13
5.09
14.96
3.48
4.43
6.25
3.27
1.58
1.75
2.36
2.98
1
6.06
6.06
5.98
5.96
1.22
1.727
1.26
a
b
c
Determined by 13H NMR in CDCl3 using TMS as an internal standard.
The initial mole ratio of 3g to Ti(O-i-Pr)4.
The number of Ti coordinated by other coordinating groups, calculated from the formula: (Me2CHO–Ti–W)ꢁ4.
d
Coordination number calculated from the formula: ðY þ ZÞ ꢁ U þ 1 (the number of nitrogen atom.
i-Pr
CHPh
i-Pr
Ph3CH2C
C2H5
CH2CPh3 Ph3CH2C
C2H5
Ph3CH2C
C2H5
O
O
O
N
N
N
CH2CPh3
CH2CPh3
Ti
Ti
Ti
O
O
O
O
O
O
O
O
O
i-Pr
CHPh
CHPh
III
I
II
i-Pr
CHPh
PhHC
PhHC
i-Pr
C2H5
CH2CPh3
O
O
O
O
O
N
N
N
CH2CPh3
CH2CPh3
Ph3CH2C
Ph3CH2C
Ph3CH2C
Ti
Ti
Ti
O
O
O
O
O
O
O
C2H5
C2H5
i-Pr
IV
V
VI
Figure 3. Six steric isomers for the hexa-coordinate Ti complex transition state.

A. Zhang et al. / Tetrahedron: Asymmetry 25 (2014) 289–297
295
4.3. Synthesis of 1-chloro-3-(9-ethylfluoren-9-yl)-2-(S)-propanol
(S)-5a
3. Conclusion
The C2-symmetric chiral amino diol tridentate ligands were syn-
thesized from an achiral bulky organolithium RLi, achiral primary
amine R1NH2 and optically active ECH, which is inexpensive and
commercially available. The chiral amino diol ligands synthesized
were employed to induce the enantioselective addition of diethyl-
zinc to aldehydes. The steric hindrance of R and R1 has a significant
impact on the enantioselectivity of the ligands. The ligand (S)-3g, in
which R was triphenylmethyl and R1 was tert-butyl, gave high
enantioselectivity. Ligand (S)-3g not only gave up to 91% yield with
96% ee for the aromatic aldehydes tested, but also gave 76–92%
yields and 78–95% ee for all of the aliphatic aldehydes tested.
The reaction described in Section 4.2 was quenched with 40 mL
of water after (S)-ECH was reacted with 9-ethyl-9-lithiumfluorene
at ꢀ70 °C for 10 min. Next, 20 mL of diethyl ether was added. The
ether layer was separated and the aqueous layer was extracted
with diethyl ether. The ether solutions were then combined. Next,
the combined ether solution was dried over anhydrous CaCl2 and
concentrated under reduced pressure to afford a solid. The solid
was recrystallized from ethanol to obtain (S)-5a as white crystals.
Yield: 81.3%; mp: 107–108 °C; ½a D20
¼ ꢀ19:0 (c 1, THF); Elem. Anal.
ꢂ
Calcd for C18H19ClO: C, 75.38; H, 6.68. Found: C, 75.44; H, 6.70. 1H
NMR (CDCl3) d (ppm): 7.74 (d, J = 3.3 Hz, 2H, Ar-H), 7.45 (d,
J = 6.6 Hz, 2H, Ar-H), 7.34–7.37 (m, 4H, Ar-H), 3.06–3.11 (m, 2H,
CH2), 2.98–3.02 (m, 1H, CH), 2.37–2.38 (m, 2H, CH2), 0.26–0.35
(m, 3H, CH3); 13C NMR (CDCl3) d (ppm): 148.65, 141.06, 140.04,
140.02, 127.57, 127.52, 127.45, 127.24, 123.35, 123.03, 120.23,
120.09, 68.70, 53.80, 50.22, 44.11, 33.83, 7.83.
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were acquired on Bruck Avance
400 at 400 MHz and 100 MHz, respectively using CDCl3 as the sol-
vent and tetramethylsilane as the internal standard. The enantio-
meric excess was determined by HPLC analysis performed on
Dionex P680 equipped with a UV detector and Chiralcel OD-H
(Diacel) chiral column using mixtures of n-hexane/isopropanol as
the mobile phase in appropriate ratios given in the Experimental;
the detecting wavelength was 254 nm; flow (f) is given in
mL/min; retention times tR [for the (R)-isomer] and tS (for the
(S)-isomer) are given in minutes.
Diethylzinc (1 M in n-hexane) and titanium (IV) isopropoxide
were purchased from Aladdin Company, Shanghai. THF and diethyl
ether were distilled from sodium-benzophenone under argon be-
fore use. Optically active epichlorohydrin (ECH) was purchased
from Yueyang Branch Company, Shenzhen Yawangkangli Technol-
ogy Co., Ltd. 9-Ethylfluorene was prepared according to the litera-
ture.49 Other reagents were commercially available and used
without special treatment.
4.4. Synthesis of (R)- or (S)-4,4,4-triphenyl-1-butene oxide (S)-2b
(S)-4,4,4-Triphenyl-1-butene oxide (S)-2b was prepared with
the method used in the preparation of (S)-3-(9-ethylfluoren-9-yl)
propene oxide (S)-2a except that triphenylmethane was used in-
stead of 9-ethylfluorene and that butyllithium solution was added
at 0 °C instead of at room temperature. (R)-ECH was used for syn-
thesizing (R)-4,4,4-triphenyl-1-butene oxide. Yield: 64.8%; mp:
100–102 °C; ½a 2D0
¼ ꢀ28:0 (c 1, THF) [for the (S)-isomer), +28.4 (c
ꢂ
1, THF) [for the (R)-isomer]; ee: 98.2% (n-hexane/isopropa-
nol = 98/2, f = 1 mL/min, tS = 9.547 min, tR = 10.425 min). Elem.
Anal. Calcd for C22H20O: C, 87.96; H, 6.71. Found: C, 87.86; H,
7.80. 1H NMR (CDCl3) d (ppm): 7.21–7.45 (m, 15H, Ar-H), 3.30
(dd, 1H, J = 3.5 Hz, J = 14.5 Hz, CH2), 2.90–2.93 (m, 1H, CH), 2.49–
2.51 (m, 1H, CH2), 2.42 (dd, 1H, J = 6.8 Hz, J = 14.4 Hz, CH2), 2.14
(m, 1H, CH2); 13C NMR (CDCl3) d (ppm): 146.8, 129.0, 127.9,
126.2, 55.8, 50.2, 48.9, 43.7.
4.2. Synthesis of (S)-3-(9-ethylfluoren-9-yl) propene oxide (S)-2a
4.5. Synthesis of (S)-3-(5-pentyl-dibenzo[a,e]suber-5-yl)propene
oxide (S)-2c
A nitrogen-flushed flask equipped with a stirrer was charged
with 9.7 g (50 mmol) of 9-ethylfluorene and 40 mL of THF. To the
solution of 9-ethylfluorene was added 20 mL of n-butyllithium
solution in n-hexane (2.5 mol/L) at room temperature with stirring.
The mixture was stirred at room temperature for 1 h to afford a red
solution of 9-ethyl-9-lithiumfluorene A. After the temperature of
the mixture was cooled to ꢀ70 °C, 3.5 g of (S)-(+)-ECH was added
dropwise. The reaction mixture was then stirred at ꢀ70 °C for 1 h
after the addition of ECH and then stirred at room temperature
for 2 h. Next, THF in the reaction mixture was removed under re-
duced pressure after which 40 mL of water and 20 mL of diethyl
ether were added. The ether layer was separated and the aqueous
layer was extracted by diethyl ether. The ether solutions were
combined and the combined ether solution was concentrated un-
der reduced pressure. The concentrated residue was recrystallized
from methanol to obtain (S)-3-(9-ethylfluoren-9-yl) propene oxide
Anitrogen-flushedflask equippedwithastirrerwas chargedwith
10.3 g (50 mmol) of 5-methenedibenzo[a,e]suberane and 40 mL of
THF. To the solution of 5-methenedibenzo[a,e]-suberane was added
20 mL of n-butyllithium solution in n-hexane (2.5 mol/L) at 0 °C. The
mixture was then stirred at 0 °C for 1 h and at 50 °C for another 1 h to
afford a solution of 5-pentyl-5-lithiumdibenzo[a,e]suberane C. Next,
3.5 g of (S)-(+)-ECH was added dropwise at ꢀ70 °C. The mixture was
then stirred at ꢀ70 °C for 1 h after the addition of ECH and then stir-
red at room temperature for 2 h. Next, 40 mL of water and 20 mL of
diethyl ether were added after the THF in the reaction mixture was
removed under reduced pressure. The ether layer was separated
and aqueous layer was extracted by diethyl ether. The ether solu-
tions were combined. The combined ether solution was dried over
anhydrous CaCl2 and concentratedunder reducedpressure. Thecon-
centratedpurifiedwas refinedby meansof chromatography onsilica
gel using a mixture of petroleum ether and ethyl acetate (12:1) as
eluate to obtain a sticky, oily (S)-3-(5-pentyl-dibenzo[a,e]suber-5-
(S)-2a as white crystals. Yield: 70.3%; mp: 74–75 °C; ½a D20
¼ þ23:1
ꢂ
(c 0.8, THF). ee: 98.8% (n-hexane/isopropanol = 98/2, f = 1 mL/min,
tS = 11.667 min, tR = 13.275 min). Elem. Anal. Calcd for C18H18O:
C, 86.36; H, 7.25. Found: C, 86.30; H, 7.34. 1H NMR (CDCl3)
d (ppm): 7.73 (d, J = 5.6 Hz, 2H, Ar-H), 7.44 (d, J = 7.2, 1H, Ar-H),
7.29–7.39 (m, 5H, Ar-H), 2.41–2.45 (m, 1H, CH), 2.25–2.28 (m,
2H, CH2), 1.99–2.12 (m, 4H, CH2), 0.33 (t, J = 7.4 Hz, 3H, CH3); 13C
NMR (CDCl3) d (ppm): 149.20, 148.96, 141.12, 140.94, 127.30,
127.26, 127.17, 127.12, 123.29, 123.00, 119.93, 119.90, 54.05,
49.01, 47.21, 42.87, 32.60, 8.02.
yl)propene oxide (S)-2c. Yield: 46.7%; ½a D20
¼ þ82:2 (c 1, THF) ee
ꢂ
98.4% (n-hexane/isopropanol = 98/2, f = 1 mL/min, tS = 8.042 min,
tR = 8.642 min). Elem. Anal. Calcd for C23H28O: C, 86.20; H, 8.81; N,
2.30. Found: C, 86.28; H, 8.74. 1H NMR (CDCl3) d (ppm): 7.66 (d,
J = 8.1 Hz, 1H, Ar-H), 7.55 (d, J = 8.1 Hz, 1H, Ar-H), 7.17–7.31 (m,
2H, Ar-H), 7.03–7.14 (m, 4H, Ar-H), 2.80–3.02 (m, 4H, CH2CH2),
2.79 (d, J = 3.8 Hz, 1H, CH), 2.55–2.57 (m, 1H, CH2), 2.27–2.32 (m,

296
A. Zhang et al. / Tetrahedron: Asymmetry 25 (2014) 289–297
2H, CH2), 2.13–2.27 (m, 1H, CH2), 1.90–1.95 (m, 1H, CH2), 1.75–1.77
(m, 1H, CH2), 0.97–1.08 (m, 4H, CH2), 0.93–0.96 (m, 2H, CH2), 0.69–
0.72 (m, 3H, CH3); 13C NMR (CDCl3) d (ppm): 144.58, 143.67,
143.11, 129.66, 126.29, 125.84, 54.12, 51.27, 49.53, 47.44, 38.33,
32.07, 23.70, 22.25, 13.87.
C, 85.32; H, 7.81; N, 2.02. 1H NMR (CDCl3) d (ppm): 7.36 (d,
J = 7.2 Hz, 10H, Ar-H), 7.28 (d, J = 11.3 Hz, 18H, Ar-H), 7.20 (d,
J = 7.0 Hz, 2H, Ar-H), 3.58 (s, 2H, CH), 3.04 (d, J = 14.7 Hz, 1H,
CH2), 2.57 (d, J = 14.5 Hz, 1H, CH2), 2.20–2.41 (m, 4H, CH2), 1.93
(d, J = 11.9 Hz, 4H, CH2), 1.32 (d, J = 19.5 Hz, 4H, CH2), 0.87 (d,
J = 6.9 Hz, 3H, CH3); 13C NMR (CDCl3) d (ppm): 147.24, 129.27,
128.00, 126.08, 67.31, 55.85, 48.86, 46.17, 32.04, 20.27, 13.91.
4.6. General procedure for the preparation of chiral amino diol
tridentate ligands
4.6.5. Cyclohexyl bis[3-triphenylmethyl-2(S)-hydroxypropyl]
amine (S)-3e
A flask equipped with a stirrer was charged with 4 mmol of
amine, 8 mmol of substituted propylene epoxide, and 10 mL of eth-
anol. The mixture was then stirred at 0 °C for 1 h and refluxed for
10 h. Ethanol was then evaporated under reduced pressure. The res-
idue was purified by chromatography on silica gel using a mixture
of petroleum ether and ethyl acetate as eluate to obtain amino diol.
Yellowish oily liquid; yield: 68.50%; ½a D20
¼ ꢀ72:6 (c 1, THF);
ꢂ
Elem. Anal. Calcd for C50H53NO2: C, 85.80; H, 7.63; N, 2.00. Found
C, 85.55; H, 7.62; N, 1.95. 1H NMR (CDCl3) d (ppm): 7.04–7.44
(m, 15H, Ar-H), 3.52 (s, 2H, CH), 3.06 (d, J = 14.6 Hz, 1H, CH2),
2.53 (d, J = 14.5 Hz, 1H, CH2), 1.93–2.26 (m, 8H, CH2), 1.61 (d,
J = 11.5 Hz, 2H, CH2),1.12 (s, 4H, CH2), 0.99 (d, J = 6.4 Hz, 2H,
CH2), 0.88 (d, J = 10.6 Hz, 2H, CH2); 13C NMR (CDCl3) d (ppm):
147.27, 129.29, 127.99, 126.06, 67.76, 56.02, 51.76, 46.90, 33.95,
33.41, 26.06, 24.99.
4.6.1. Benzyl bis[3-(9-ethylfluoren-9-yl)-2(S)-hydroxypropyl]
amine (S)-3a
Colorless oily liquid; yield: 52.4%; ½a D20
¼ þ106:4 (c 1, THF);
ꢂ
Elem. Anal. Calcd for C43H45NO2: C, 84.79; H, 7.46; N, 2.30. Found:
C, 84.32; H, 7.40; N, 2.24. 1H NMR (CDCl3, 400 MHz) d (ppm): 7.69
(t, J = 7.1 Hz, 5H, Ar-H), 7.27–7.47 (m, 8H, Ar-H), 7.01–7.27 (m, 8H,
Ar-H), 3.00–3.04 (d, J = 7.4 Hz, 2H, OH), 2.83–2.86 (dd, J = 14.2,
6.1 Hz, 2H, CH), 1.98–2.00 (m, 2H, CH2), 1.94–1.96 (m, 4H, CH2),
1.87–1.88 (m, 1H, CH2), 1.53–1.76 (dd, J = 15.0, 7.3 Hz, 1H, CH2),
1.28–1.43 (m, 2H, CH2), 1.24–1.26 (t, J = 7.1 Hz, 2H, CH2), 0.66 (t,
J = 8.8 Hz, 6H, CH3); 13C NMR (CDCl3) d (ppm): 149.71, 149.15,
141.09, 140.94, 128.98, 128.12, 127.29, 127.23, 127.12, 127.08,
126.91, 123.62, 123.07, 119.93, 119.87, 65.40, 60.89, 58.41, 53.95,
44.85, 33.58, 7.96.
4.6.6. Diphenylmethyl bis[3-triphenylmethyl-2(S)-hydroxypropyl]
amine (S)-3f
Colorless oily liquid; Yield: 69.12%; ½a D20
¼ ꢀ69:40 (c 10 mg/mL,
ꢂ
THF); Elem. Anal. Calcd for C57H53NO2: C, 87.43; H, 6.69; N, 1.79.
Found: C, 88.12; H, 6.07; N, 1.72. 1H NMR (CDCl3) d (ppm):
1H NMR (400 MHz, CDCl3) d 6.99–7.34 (m, 40H, Ar-H), 4.54 (s,
1H, CH), 3.58 (s, 2H, OH), 2.76 (dd, J = 14.9, 4.9 Hz, 2H, CH), 2.52–
2.65 (m, 2H, CH2), 2.20–2.34 (m, 4H, CH2), 2.02–2.14 (m, 2H,
CH2); 13C NMR (400 MHz, CDCl3)
d (ppm): 147.17, 129.19,
128.46, 127.99, 127.14, 126.10, 68.22, 66.94, 54.45, 46.26.
4.6.2. Benzyl bis(3-triphenylmethyl-2-hydroxypropyl) amine
(S)-3b
4.6.7. tert-Butyl bis[3-triphenylmethyl-2(S)-hydroxypropyl]
amine (S)-3g
White power; yield: 49.4%; ½a D20
ꢂ
¼ þ78:8 (c 1, THF) (for the
Colorless oily liquid; yield: 86.26%; ½a D20
¼ ꢀ82:55 (c 1, THF);
ꢂ
(R)-isomer), ꢀ78.0 °C (for the (S)-isomer) (c 1, THF); Elem. Anal.
Calcd for C51H49NO2: C, 86.53; H, 6.98; N, 1.98. Found: C, 86.32;
H, 6.67; N, 1.76. 1H NMR (CDCl3) d (ppm): 7.04–7.52 (m, 35H, Ar-
H), 3.61 (dd, J = 13.8, 9.3 Hz, 2H, OH), 3.54–3.58 (m, 2H, CH),
2.69–3.01 (m, 2H, CH2), 2.58–2.63 (dd, J = 14.8, 4.2 Hz, 4H, CH2),
2.31–2.37 (dd, J = 14.7, 5.0 Hz, 2H, CH2), 2.05–2.07 (d, J = 9.4 Hz,
Elem. Anal. Calcd for C48H51NO2: C, 85.55; H, 7.63; N, 2.08. Found:
C, 85.62, H, 7.77; N, 2.10. 1H NMR (CDCl3) d (ppm): 7.35–7.37 (m,
9H, Ar-H), 7.25–7.29 (m, 14H, Ar-H), 7.16–7.20 (t,J = 16.0 Hz, 7H,
Ar-H), 3.48–3.49 (d, J = 4.0 Hz, 2H, CH), 3.05–3.09 (dd, J = 4.0,
3.6 Hz, 1H, CH2), 2.53–2.57 (dd, J = 4.0, 3.6 Hz, 1H, CH2), 2.10–
2.15 (t, J = 20.0 Hz, 4H, CH2), 1.87–1.91 (dd, J = 2.8, 2.2 Hz, 2H,
CH2), 0.93(s, 9H, CH3); 13C NMR (CDCl3) d (ppm): 147.29, 129.29,
127.95, 126.03, 68.34, 56.25, 50.31, 48.93, 46.50, 28.96.
2H, CH2); 13C NMR (CDCl3)
d
(ppm): 147.23, 147.15,
140.15,129.25, 128.86, 128.38, 128.00, 127.98, 126.96, 126.10,
126.05, 67.57, 56.27, 55.52, 53.35, 46.13.
4.7. A typical asymmetric addition reaction of diethylzinc with
aldehydes induced by chiral amino diol tridentate ligands
4.6.3. Benzyl bis[3-(1-pentyldibenzo[a,e]suber-1-yl)-2(S)-hydroxy-
propyl] amine (S)-3c
Colorless oily liquid; Yield: 62.2%; ½a D20
ꢂ
¼ þ66:8 (c 1, CH2Cl2);
A flask flushed with argon was charged with 10 mL of toluene
and chiral amino diol tridentate ligand. To the flask was added
Ti(O-i-Pr)4 under an argon stream. The mixture was then stirred
at room temperature for 1 h. Next, 3 mL of the solution of dieth-
ylzinc in n-hexane was added dropwise and the mixture was
stirred for 1 h. 1 mmol of the aldehyde was added at 0 °C and
the reaction mixture was stirred at 0 °C for several hours after
the addition of aldehyde. The reaction was quenched with
hydrochloric acid (1 mol/L). The organic layer was separated
and the aqueous layer was extracted with diethyl ether. The or-
ganic layer and ether extraction were combined, dried over
anhydrous MgSO4, and concentrated under reduced pressure.
The concentrated residue was purified by chromatography on
silica gel to obtain the product. The ee of the product was deter-
mined by chiral HPLC.
Elem. Anal. Calcd for C53H65NO2: C, 85.09; H, 8.76; N, 1.87. Found:
C, 84.96; H, 8.60; N, 1.82. 1H NMR (CDCl3)
d (ppm): 7.61
(d, J = 8.1 Hz, 2H, Ar-H), 7.30–7.54 (m, 1H, Ar-H), 6.97–7.30 (m,
18H, Ar-H), 3.25 (s, 2H, OH), 3.18 (d, J = 13.3 Hz, 2H, CH), 2.95
(m, 8H, CH2), 2.61–2.66 (m, 2H, CH2), 2.04 (dd, J = 4.0, 10.7 Hz,
2H, CH2), 1.89–1.91 (m, 2H, CH2), 1.82–1.85 (m, 2H, CH2), 1.43
(m, 2H, CH2), 1.26 (m, 4H, CH2), 0.95 (d, J = 7.25 Hz, 8H, CH2),
0.86 (s, 4H, CH2), 0.67–0.70 (t, J = 6.6 Hz, 6H, CH3); 13C NMR (CDCl3)
d (ppm): 144.55, 144.39, 143.91, 143.39, 130.87, 130.19, 129.89,
129.78, 129.70, 129.12, 128.88, 128.16, 126.96, 126.32, 126.25,
125.84, 125.62, 125.52, 66.31, 61.04, 58.62, 54.57, 53.59, 48.32,
38.40, 30.66, 29.71, 23.69, 22.26, 13.89.
4.6.4. n-Butyl bis[3-triphenylmethyl-2(S)-hydroxypropyl] amine
(S)-3d
Chromatographic conditions for measuring the ee value of the
addition products and the retention time of each enantiomer are
listed below.
Colorless oily liquid; yield: 72.12%; ½a D20
¼ ꢀ70:1 (c 1, THF);
ꢂ
Elem. Anal. Calcd for C48H51NO2: C, 85.55; H, 7.63; N, 2.08. Found:

A. Zhang et al. / Tetrahedron: Asymmetry 25 (2014) 289–297
297
1-Phenyl-1-propanol: n-hexane/isopropanol = 98/2, f = 0.8 mL/
Acknowledgement
min, tR = 10.118 min, tS = 11.132 min.
1-Phenyl-1-penten-3-ol: n-hexane/isopropanol = 90/10, f = 0.8
mL/min, tR = 23.373 min, tS = 25.920 min.
We are grateful to the National Natural Science Foundation of
China (No. 21172186) for generous financial support for our
programs.
1-(40-Methoxyphenyl)-1-propanol:
n-hexane/isopropa-
nol = 95.5/4.5, f = 1 mL/min, tR = 14.993 min, tS = 16.118 min.
1-(40-Chlorophenyl)-1-propanol: n-hexane/isopropanol = 99.8/
0.2, f = 1.2 mL/min, tR = 6.470 min, tS = 5.413 min.
References
1-(20-Furyl)-1-propanol:
n-hexane/isopropanol = 98/2,
1. Banerjee, S.; Camodeca, A. J.; Griffin, G. G.; Hamaker, C. G.; Hitchcock, S. R.
Tetrahedron: Asymmetry 2010, 21, 549–557.
2. Lin, R. X.; Chen, C. J. Mol. Catal. A: Chem. 2006, 243, 89–98.
3. Tanyeli, C.; Sünbül, M. Tetrahedron: Asymmetry 2005, 16, 2039–2043.
4. Jaworska, M. K.; Ła˛czkowski, Z.; Wełniak, M.; Welke, M.; Wojtczak, A. Appl.
Catal. A 2009, 357, 150–158.
5. Yang, X. F.; Hirose, T.; Zhang, G. Y. Tetrahedron: Asymmetry 2008, 19, 1670–
1675.
6. Blay, G.; Fernández, I.; Hernández-Olmos, V.; Marco-Aleixandre, A.; Pedro, J. R.
J. Mol. Catal. A: Chem. 2007, 276, 235–243.
7. Wang, J.; Li, H.; Zu, L. S.; Wang, W. Org. Lett. 2006, 8, 1391–1394.
8. Shepherd, N. E.; Tanabe, H.; Xu, Y. J. Am. Chem. Soc. 2010, 132, 3666–3667.
9. Lu, D.; Li, Y.; Gong, Y. J. Org. Chem. 2010, 75, 6900–6907.
10. Ma, Y. H.; Zhang, Y. J.; Jin, S. B. Tetrahedron Lett. 2009, 50, 7388–7391.
11. Takenaka, N.; Huang, Y.; Rawal, V. H. Tetrahedron 2002, 58, 8299–8305.
12. Mao, J. C.; Wan, B. S.; Wu, F.; Lu, S. W. Tetrahedron Lett. 2005, 46, 7341–7344.
13. Ohno, K.; Kataoka, Y.; Mashima, K. Org. Lett. 2004, 6, 4695–4697.
14. Aboulaala, K.; Goux-Henry, C.; Sinou, D.; Safi, M.; Soufiaoui, M. J. Mol. Catal. A:
Chem. 2005, 237, 259–266.
15. Wu, X. F.; Li, X. H.; McConville, M.; Saidi, O.; Xiao, J. L. J. Mol. Catal. A: Chem.
2006, 247, 153–158.
16. Tanyeli, C.; Odabas, S.; Erdem, M. Tetrahedron: Asymmetry 2007, 18, 2349–
2357.
f = 0.6 mL/min, tR = 14.280 min, tS =16.590 min.
1-(20-Pyridyl)-1-propanol:
n-hexane/isopropanol = 97.5/2.5,
f = 0.7 mL/min, tR = 11.463 min, tS = 14.065 min.
1-(20-Hydroxyphenyl)-1-propanol:
n-hexane/isopropa-
nol = 95.5/4.5, f = 1 mL/min, tR = 13.520 min, tS = 11.672 min.
1-(20-Naphthyl)-1-propanol:
n-hexane/isopropanol = 97/3,
f = 0.8 mL/min, tR = 15.575 min, tS = 12.498 min.
1-(40-Dimethylaminophenyl)-1-propanol: n-hexane/isopropa-
nol = 99.8/0.2, f = 0.8 mL/min, tR = 13.288 min, tS = 11.007 min.
1-(Triphenylmethyl)-2-butanol:
n-hexane,
f = 0.8 mL/min,
tR = 14.640 min, tS = 16.638 min.
1-(20-Methoxyphenyl)-1-propanol: n-hexane/isopropanol = 98/
2, f = 1.2 mL/min, tR = 13.795 min, tS = 12.027 min.
1-(30-Methoxyphenyl)-1-propanol: n-hexane/isopropanol = 95/
5, f = 1.2 mL/min, tR = 13.577 min, tS = 11.168 min.
1-(10-Naphthyl)-1-propanol:
n-hexane/isopropanol = 90/10,
f = 1.2 mL/min, tR = 16.715 min, tS = 12.823 min.
1-Phenyl-3-pentanol: n-hexane/isopropanol = 90/10, f = 1 mL/
min, tR = 6.993 min, tS = 7.635 min.
17. Da, C.; Ni, M.; Han, Z.; Yang, F.; Wang, R. J. Mol. Catal. A: Chem. 2006, 245, 1–7.
18. Huang, L. N.; Hui, X. P.; Xu, P. F. J. Mol. Catal. A: Chem. 2006, 258, 216–220.
19. Unaleroglu, C.; Aydin, A. E.; Demir, A. S. Tetrahedron: Asymmetry 2006, 17, 742–
749.
20. Abu zarga, M. H.; Shamma, M. Tetrahedron Lett. 1980, 21, 3739–3742.
21. Schiffers, I.; Rantanen, T.; Schmidt, F.; Bergmans, W.; Zani, L.; Bolm, C. J. Org.
Chem. 2006, 719, 2320–2331.
1-(40-Methylphenyl)-1-propanol: n-hexane/isopropanol = 95/5,
f = 1.2 mL/min, tR = 16.715 min, tS = 12.823 min.
3-Octanol: HPLC (as benzoate): n-hexane, f = 0.8 mL/min,
tS = 18.341 min, tR = 20.134 min.
22. Periasamy, M.; Kumar, N. S.; Kumar, S. S.; Rao, V. D.; Ramanathan, C. R.;
Venkatraman, L. J. Org. Chem. 2001, 66, 3828–3833.
1-Cyclohexyl-1-propanol: HPLC (as benzoate): n-hexane/iso-
propanol = 99/1,
tR = 26.734 min.
3-Nonanol: HPLC (as benzoate): n-hexane/isopropanol = 99/1,
f = 1 mL/min, tS = 12.450 min, tR = 15.234 min.
3-Undecanol: HPLC (as benzoate): n-hexane/isopropanol = 99/
1, f = 0.5 mL/min, tS = 10.605 min, tR = 12.054 min.
f = 0.6 mL/min,
tS = 28.451 min,
23. Manickam, G.; Sundararajan, G. Tetrahedron: Asymmetry 1997, 8, 2271–2278.
24. Manickam, G.; Sundararajan, G. Tetrahedron 1999, 55, 2721–2736.
25. Manickam, G.; Sundararajan, G. Tetrahedron: Asymmetry 1999, 10, 2913–2925.
26. Grassi, M.; Disilvestro, G.; Farina, M. Tetrahedron 1985, 41, 177–181.
27. Nugent, W. A. J. Am. Chem. Soc. 1992, 114, 2768–2769.
28. Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B.
J. Am. Chem. Soc. 1981, 103, 6237–6240.
29. Wong, O. A.; Shi, Y. Chem. Rev. 2008, 108, 3958–3987.
30. Wu, M.; Wang, B.; Wang, S. F.; Xia, C. G.; Sun, W. Org. Lett. 2009, 11, 3622–3625.
31. Wang, B.; Wong, O. A.; Zhao, M. X.; Shi, Y. J. Org. Chem. 2008, 73, 9539–9543.
32. Shi, Y. Acc. Chem. Res. 2004, 37, 488–496.
33. Tian, H. Q.; She, X. G.; Xu, J. X.; Shi, Y. Org. Lett. 2001, 3, 1929–1931.
34. The price of (S)-ECH is RMB ¥50 or US $8.1 per kilogram and the price of
(R)-ECH is RMB ¥60 or US $9.7 per kilogram, purchased from Yueyang Branch
Company, Shenzhen Yawangkangli Technology Co., Ltd.
4.8. Preparation of (S)-1-(triphenylmethyl)-2-butanol
A nitrogen-flushed flask equipped with a stirrer was charged
with 0.6 g (2 mmol) of (S)-4,4,4-triphenyl-1-butene oxide and
10 mL of THF. To the solution of (S)-4,4,4-triphenyl-1-butene oxide
was added 2 mL of methyllithium solution in n-hexane (1.3 mol/L)
at ꢀ70 °C with stirring. The mixture was then stirred at room tem-
perature for 1 h. The reaction was then quenched with 1 mL of
water. Next, 20 mL of diethyl ether was added. The ether layer
was separated and the aqueous layer was extracted with diethyl
ether. The ether solutions were then combined. The combined
ether solution was dried over anhydrous CaCl2, and concentrated
under reduced pressure to afford a liquid. The liquid was purified
by chromatography on silica gel using a mixture of petroleum
ether and ethyl acetate as eluate to obtain (S)-1-(triphenyl-
35. Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757–824.
36. Tanner, D.; Kornø, H. T. Tetrahedron 1998, 54, 14213–14232.
37. Philipova, I.; Dimitrov, V. Tetrahedron: Asymmetry 1999, 10, 1381–1391.
38. Kwong, H. L.; Lee, W. S. Tetrahedron: Asymmetry 1999, 10, 3791–3801.
39. Xu, Q. Y.; Wang, H.; Pan, X. F. Tetrahedron Lett. 2001, 42, 6171–6173.
40. Goanvic, D. L.; Holler, M.; Pale, P. Tetrahedron: Asymmetry 2002, 13, 119–121.
41. Roudeau, R.; Pardo, D. G. Tetrahedron 2006, 62, 2388–2394.
42. Mino, T.; Suzuki, A.; Yamashita, M.; Narita, S.; Shirae, Y.; Sakamoto, M.; Fujita,
T. J. Organomet. Chem. 2006, 691, 4297–4303.
43. Csillag, K.; Németh, L.; Martinek, T. A.; Szakonyi, Z. Tetrahedron: Asymmetry
2012, 23, 144–150.
44. (a) Gou, S. H.; Judeh, Z. M. A. Tetrahedron Lett. 2009, 50, 281–283; (b) Zhou, S.
L.; Chuang, D. W.; Chang, S. J.; Gau, H. M. Tetrahedron: Asymmetry 2009, 20,
1407–1412; (c) Xu, T.; Liang, C.; Cai, Y.; Li, J.; Li, Y. M.; Hui, X. P Tetrahedron:
Asymmetry 2009, 20, 2733–2736; (d) Fang, T.; Du, D. M.; Lu, S. F.; Xu, J. X. Org.
Lett. 2005, 7, 2081–2084; (e) Koyuncu, H.; Dogan, Ö. Org. Lett. 2007, 9, 3477–
3479; (f) You, J. S.; Shao, M. Y.; Gau, H. M. Organometallics 2000, 19, 3368–
3373; (g) Wu, K. H.; Gau, H. M. Organometallics 2003, 22, 5193–5200.
45. Bauer, T.; Smolin
´ ski, S. Appl. Catal. A 2010, 375, 247–251.
46. Balsells, J.; Davis, T.; Carroll, J. P.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124,
10336–10348.
methyl)-2-butanol. Yield: 88.2%, ½a D20
ꢂ
¼ ꢀ33:9 (c 1, THF); 1H NMR
(CDCl3) d (ppm): 7.33–7.35 (d, J = 8.0 Hz, 3H, Ar-H), 7.26–7.30 (t,
J = 2.8 Hz, 9H, Ar-H), 7.18–7.21 (t, J = 6.8 Hz, 7.2 Hz, 3H, Ar-H),
3.57 (s, 2H, CH), 2.93–2.97 (d, J = 14.8 Hz, 1H, CH2), 2.64–2.70
(dd, J = 8.0, 7.2 Hz, 1H, CH2), 1.41–1.49 (m, 2H, CH2), 0.86–0.89 (t,
J = 7.2 Hz, 3H, CH3); 13C NMR (CDCl3) d (ppm): 147.29, 129.53,
128.05, 126.43, 70.24, 66.05, 42.34, 31.03, 14.02.
47. Bauer, T.; Gajewiak, J. Tetrahedron 2004, 60, 9163–9170.
48. Paquette, L. A.; Zhou, R. J. J. Org. Chem. 1999, 64, 7929–7934.
49. Schoen, K. L.; Becker, E. I. Org. Synth. 1963, 4, 623.