Novel tetradentate bisoxazoline ligands from l-serine and β-DDB for asymmetric pinacol coupling reactions of aromatic aldehydes

Article abstract of DOI:10.1016/j.tetasy.2013.05.026

A variety of novel hydroxyl-containing tetradentate bisoxazolines were successfully synthesized from natural l-serine and β-DDB. The applications of these ligands in the asymmetric pinacol coupling of aromatic aldehydes revealed that the absolute configurations of the resulting pinacols were entirely dominated by the axial chirality of the biphenyl component and that the bulky substituent adjacent to the hydroxyl group was favorable for achieving both high diastereoselectivities and enantioselectivities. Among the ligands screened, (S,aR,S)-1c exhibited much better asymmetric induction capacity to furnish the (R,R)-pinacols with diastereoselectivities up to 99/1 and with 63-89% enantiomeric excess. A plausible mechanism of the asymmetric pinacol coupling was also suggested.

Full text of DOI:10.1016/j.tetasy.2013.05.026

Tetrahedron: Asymmetry 24 (2013) 860–865
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Novel tetradentate bisoxazoline ligands from L-serine and b-DDB
for asymmetric pinacol coupling reactions of aromatic aldehydes
⇑
Jiwu Wen , Limin Liu, Xiaochun Zhou, Ronghua Hu, Yaping Xu
School of Chemistry and Chemical Engineering, The Key Laboratory of Coordination Chemistry of Jiangxi Province, Jinggangshan University, Ji’an, Jiangxi 343009, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 April 2013
Accepted 30 May 2013
A variety of novel hydroxyl-containing tetradentate bisoxazolines were successfully synthesized from
natural L-serine and b-DDB. The applications of these ligands in the asymmetric pinacol coupling of aro-
matic aldehydes revealed that the absolute configurations of the resulting pinacols were entirely domi-
nated by the axial chirality of the biphenyl component and that the bulky substituent adjacent to the
hydroxyl group was favorable for achieving both high diastereoselectivities and enantioselectivities.
Among the ligands screened, (S,aR,S)-1c exhibited much better asymmetric induction capacity to furnish
the (R,R)-pinacols with diastereoselectivities up to 99/1 and with 63–89% enantiomeric excess. A plausi-
ble mechanism of the asymmetric pinacol coupling was also suggested.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
addition of diethylzinc11 or diketene12 to aldehydes, palladium cat-
alyzed allylic alkylations,13 and so on.
The reductive coupling of carbonyl compounds such as alde-
hydes or ketones has been proved to be an efficient method for
forming functionalized carbon–carbon bonds.1 A variety of transi-
tion metal complexes with co-reductants have been screened to
control the diastereoselectivity and/or enantioselectivity of the
pinacols.2 So far, very successful results on enantioselective pinacol
coupling have been achieved with low valent titanium complexes
by Riant,3 Joshi,4 and You,5 a chromium (II) complex by Yamamot-
o,6 molybdenum (IV) complexes by Zhu,7 respectively.
Chiral diol ligands prepared by the stereoselective pinacol cou-
pling of formylferrocene with oxazoline motifs have been reported
by Fukuzawa and applied to catalyze asymmetric Diels–Alder reac-
tions.8 This work promoted us to develop a series of biphenyl
bis(oxazoline) ligands from b-DDB to catalyze the asymmetric
pinacol coupling reaction.9 The resulting pinacols were obtained
with excellent diastereoselectivities but with only moderate to
good enantioselectivities. So, it is necessary for us to seek more
efficient chiral ligands for the asymmetric pinacol coupling reac-
Thus, based on the structural skeleton of b-DDB, a series of
novel tetradentate bis-oxazoline ligands from -serine have been
synthesized and applied to catalyze the asymmetric pinacol cou-
pling of aromatic aldehydes. Herein, we would like to report these
results.
L
2. Results and discussion
2.1. Synthesis of hydroxyl-containing tetradentate
bisoxazolines
To synthesize the desired oxazoline ligands, b-DDB was firstly
prepared from gallic acid according to a reported procedure14 with
slight modification. After being hydrolyzed with a 10% KOH solu-
tion of acetone and water, the racemic diacids were obtained as
a white solid with moderate overall yield (51%) (Scheme 1).
Then, diacyl dichlorides, which were prepared from racemic ( )-
diacids by treating with an excess of SOCl2, reacted with L-serine
tion. To the best of our knowledge, L-serine plays an important role
methyl ester hydrochloride and Et3N in CH2Cl2 to give a diastereo-
meric mixture of amide 2. The ring closure reaction of 2 to afford
bisoxazolines (S,aS,S)-3 and (S,aR,S)-3 was accomplished by using
Burgess’ reagent [(methoxycarbonylsulfamoyl) triethylammonium
hydroxide inner salt] in THF under refluxing conditions, and then
separating the mixture with silica gel column chromatography,
successively.15 The resulted (S,aS,S)-3 and (S,aR,S)-3 were contin-
ued to react with either LiAlH4 or Grignard reagents (R0 = Et and
Ph) to afford the desired hydroxyl-containing tetra-dentate bis-
oxazoline ligands 1 (Scheme 2).
in the preparation of chiral ligands with multi-coordinating sites
due to the hydroxyl on the side chain which is considered to be
helpful in asymmetric organic reactions. In fact, a variety of chiral
oxazoline ligands from L-serine have been synthesized and applied
in enantioselective organic reactions such as cyclopropanation,10
⇑
Corresponding author. Tel./fax: +86 796 8100490.
E-mail address: wenjiwu@ustc.edu (J. Wen).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.05.026

J. Wen et al. / Tetrahedron: Asymmetry 24 (2013) 860–865
861
O
O
O
O
HO
HO
H3CO
H3CO
COOCH3
COOCH3
H3CO
H3CO
COOH
COOH
hydrolysis
ref. 14
HO
COOH
O
O
O
O
β-DDB
racemic ( )-diacid
Scheme 1. Synthesis of racemic diacids from b-DDB.
O
O
O
O
HOH2C
(S)
H
N
COOCH3
(S)
COOCH3
Burgess'
H3CO
O
ClH3N
reagent
H3CO
H3CO
COCl
COCl
CH2OH
O
CH2OH
separation
Et3N, CH2Cl2
OCH3
(S)
H3COOC
N
H
O
O
O
O
racemic ( )-diacyldichloride
2
O
O
O
O
N
N
(S)
(S)
H3CO
O
H3CO
COOCH3
COOCH3
O
O
+
O
H3COOC
H3COOC
(S)
OCH3
OCH3
(S)
N
N
O
O
O
O
(S,aS,S)-3
(S,aR,S)-3
O
O
O
O
OH
R
OH
R
N
N
(S)
(S)
H3CO
O
H3CO
(S,aS,S)-3
(S,aR,S)-3
LiAlH4
O
O
R
R
R
R
O
or R'MgX
R
R
HO
(S)
OCH3
OCH3
(S)
N
N
HO
O
O
O
O
(R,aS,R)-1a: R = H
(S,aS,S)-1b: R = Et
(R,aR,R)-1a: R = H
(S,aR,S)-1b: R = Et
(S,aR,S)-1c: R = Ph
(S,aS,S)-1c: R = Ph
Scheme 2. Synthesis of tetradentate hydroxyl-containing bisoxazolines 1.
2.2. Asymmetric pinacol coupling of aromatic aldehydes
catalyzed by Ti-bisoxazoline complexes
with good to excellent diastereoselectivities. However, the
enantioselectivities of the pinacols were varied remarkably
according to the structure of the oxazoline components. Obvi-
ously, the absolute configurations of the pinacol were dominated
by the axial chirality of the ligands (entries 1, 3–5 vs 2, 6–8).
Increasing the size of the substituent adjacent to hydroxyl led
to a substantial increase in both diastereoselectivity and enanti-
oselectivity (see entries 4, 5 compared with 3 and 7, 8 compared
with 6). Furthermore, the match of chiralities between the biphe-
nyl part and the serine showed great importance in controlling
Firstly, the asymmetric pinacol coupling of benzaldehyde was
investigated with 10 mol % catalyst which was prepared in situ
by reacting the ligand with Ti(OiPr)2Cl2, Mg as co-reductant, and
1.5 equiv of TMSCl in dichlomethane at 0 °C under argon atmo-
sphere. The results are listed in Table 1.
As shown in Table 1, hydrobenzoins prepared through the cou-
pling of benzaldehyde were all obtained with high yields and

862
J. Wen et al. / Tetrahedron: Asymmetry 24 (2013) 860–865
Table 1
Screening of the ligands in asymmetric pinacol couplings of benzaldehydea
O
OH
dl
OH
1) Ti-complex 10 mol%
Mg, TMSCl, CH2Cl2, 0 °C
Ph
Ph
+
2
H
Ph
Ph
2) 1 M HCl in THF
OH
OH
meso
Entry
Ligand
Yieldb (%)
dl/mesoc
eed (%) (config.)
1
2
3
4
5
6
7
8
(S,aS,S)-3
73
78
83
85
86
89
90
92
73/27
78/22
76/24
81/19
90/10
82/18
91/9
27 (S,S)
39 (R,R)
21 (S,S)
44 (S,S)
59 (S,S)
34 (R,R)
62 (R,R)
81 (R,R)
(S,aR,S)-3
(R,aS,R)-1a
(S,aS,S)-1b
(S,aS,S)-1c
(R,aR,R)-1a
(S,aR,S)-1b
(S,aR,S)-1c
95/5
a
b
c
Reaction conditions: 2.0 mmol of benzaldehyde, 10 mol % catalyst loading, 2 equiv Mg, 1.5 equiv TMSCl for 24 h.
Isolated yield.
Determined by 1H NMR and HPLC.
Determined by HPLC with a Daicel chiralcel OJ-H column.
d
the stereochemistry of the resulting pinacols (entries 7, 8 com-
pared with 4, 5).
Subsequently, investigations on the asymmetric pinacol cou-
pling of benzaldehyde were pursued with different catalyst load-
ings, several commonly used solvents, and metals at 0 °C. These
results are summarized in Table 2.
As can be seen from Table 2, changing the catalyst loading from
5% to 10% greatly improved the enantioselectivity of the product
(entries 1 and 2). However, further increasing the catalyst loading
to 20% did not enhance the enantioselectivity very much (entry 3).
Several common metals that have been used as co-reductants in
the literature were also screened in the asymmetric pinacol cou-
pling, among which Mg, Zn, and Zn–Cu provided much better results
than Mn (entries 2, 4–6). In comparison, solvents demonstrated
much greater influences on achieving higher stereoselectivities. In-
deed, CH2Cl2 and CH3CN appeared to be the solvents of choice.
The optimal conditions obtained here were very similar to the
reported ones;4 under these conditions, a variety of readily avail-
able aromatic aldehydes have been exploited in the asymmetric
pinacol coupling reaction with 10 mol % catalyst loading, using
Zn as the co-reducing reagent, and CH3CN as the solvent at 0 °C.
The results are listed in Table 3. According to Table 3, all of the aro-
matic aldehydes reacted effectively to provide the corresponding
vicinal diols with excellent yields and good to excellent diastere-
oselectivities and enantioselectivities. Electron-donating groups
(such as methyl or methoxyl) on the benzene ring seemingly
showed a great influence on the diastereoselectivities and enanti-
oselectivities of the pinacols. These results were similar to our
previous work.9
To explain our results, a plausible mechanism for the catalytic
system was suggested as follows (Scheme 3).
First, the hydroxyl-containing tetradentate bisoxazolines
reacted with Ti(OiPr)2Cl2 to furnish the complexes [Ti(bisoxazo-
line)Cl2] which might adopt an octahedral coordination in a b-cis
configuration. The low valent titanium (II) species, which was gen-
erated by reduction with zinc, then combined with the aromatic
aldehydes to form diketel radicals. The (R,R)-diol silyl ethers were
produced through intramolecular dimerization of diketyl radicals
Table 2
Screening the effects of catalyst loading, solvents, and metals in the asymmetric pinacol coupling of benzaldehyde catalyzed by Ti-complexes of (S,aR,S)-1ca
O
OH
OH
1) Ti-complex of (S,aR,S)-1c
metal, TMSCl, solvent, 0 °C
Ph
Ph
+
2
H
Ph
Ph
2) 1 M HCl in THF
OH
OH
meso
dl
Entry
Catalyst (mol %)
Metal
Solvent
Yieldb (%)
dl/mesoc
eed (%)
1
2
3
4
5
6
7
8
9
5
Mg
Mg
Mg
Zn
Zn–Cu
Mn
Zn
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
THF
86
92
95
91
94
81
92
93
76
90/10
95/5
>99/1
96/4
>99/1
82/18
97/3
78/22
86/14
66
81
83
85
79
69
86
37
64
10
20
10
10
10
10
10
10
Zn
Zn
Toluene
a
b
c
Reaction conditions: 2.0 mmol of benzaldehyde, 2 equiv metal, 1.5 equiv TMSCl at 0 °C for 24 h.
Isolated yield.
Determined by 1H NMR and HPLC.
d
Determined by HPLC with a Daicel chiralcel OJ-H column.

J. Wen et al. / Tetrahedron: Asymmetry 24 (2013) 860–865
863
Table 3
Asymmetric pinacol coupling of aromatic aldehydes catalyzed by Ti-complexes of (S,aR,S)-1ca
OH
dl
OH
1) Ti-complex of (S,aR,S)-1c
O
Zn, TMSCl, CH3CN, 0 °C
Ar
Ar
+
2
Ar
Ar
Ar
H
2) 1 M HCl in THF
OH
OH
meso
Entry
ArCHO
Yieldb (%)
dl/mesoc
ee (%)
1
2
3
4
5
6
7
8
Benzaldehyde
4-Tolualdehyde
92
95
93
89
91
83
86
90
97/3
99/1
99/1
89/11
91/9
82/18
90/10
98/2
86d
88d
89e
78f
81f
63f
80e
87e
4-Methoxybenzaldehyde
2-Chlorobenzaldehyde
4-Chlorobenzaldehyde
2,4-Dichlorobenzaldehyde
4-Fluorobenzaldehyde
1-Naphthaldehyde
a
b
c
d
e
f
Reaction conditions: 2.0 mmol of benzaldehyde, 10 mol % catalyst loading, 2 equiv Zn, 1.5 equiv TMSCl at 0 °C for 24 h.
Isolated yield.
Determined by 1H NMR and HPLC.
Determined by HPLC with a Daicel chiralcel OJ-H column.
Determined by HPLC with a chiralcel AD column.
Determined by HPLC with a chiralcel WH column.
ZnCl2
LTi (II)
ArCHO
Zn
H3C
CH3
O
O
O
O
L
Cl
Ti
O
O
O
H
Ti
N
O
Ti(OiPr)2Cl2
O
O
L
Ph
O
O
N
Cl
O
Ti
N
N
L = bisoxazoline
ligand
Ar H H Ar
Ph
H
O
O
Ph
Ph
Ph
O
Ph
OH
OTMS
H+
(R)
(R)
(R)
Ar
Ar
TMSCl
(R)
Ar
Ar
OH
OTMS
Scheme 3. Plausible mechanism for the asymmetric pinacol coupling.
and subsequent cleavage of the titanium-oxygen bonds with
TMSCl, which were then hydrolyzed with an acid solution in THF
to afford the corresponding pinacols with an (R,R)-configuration.
4. Experimental
4.1. General
Melting points were measured by X-4 apparatus and are uncor-
rected. Optical rotations were determined by a WZZ-1 rotation
spectrometer. NMR spectra were measured on a Bruker av300
spectrometer (300 MHz) using CDCl3 as solvent and TMS as an
internal standard. IR spectra were recorded on an Avatar 370
(KBr) spectrometer. Elemental analyses were performed on a
PE2400 II spectrometer. HPLC analyses were carried out by Summit
P680 spectrometer. The diastereomeric excesses were determined
by HPLC or 1H NMR, and enantiomeric excesses were determined
by HPLC with chiralcel columns.
3. Conclusion
In conclusion, a series of hydroxyl-containing tetradentate
bisoxazolines were synthesized from natural L-serine and b-DDB
successfully. The applications of these ligands in the asymmetric
pinacol coupling of aromatic aldehydes revealed that the absolute
configurations of the resulting pinacols were entirely dominated
by the biphenyl component and that the bulky substituent adja-
cent to hydroxyl was favorable for increasing both the diastereose-
lectivity and enantioselectivity; among the ligands screened,
(S,aR,S)-1c exhibited much better asymmetric induction to furnish
the pinacols with up to 99/1 dl/meso-selectivity and 63–89% enan-
tiomeric excess.
All of the reactions were carried out under an argon or nitrogen
atmosphere. Commercial reagents were used without further puri-
fication. THF and toluene were dried and freshly distilled from so-
dium-benzophenone under an atmosphere of dry nitrogen.

864
J. Wen et al. / Tetrahedron: Asymmetry 24 (2013) 860–865
Dichloromethane and acetonitrile were distilled from P2O5 before
use. Liquid aldehydes and trimethylchlorosilane were freshly dis-
4.2.2.1. ((4R,40R)-2,20-((S)-4,40-Dimethoxy-[5,50-bibenzo[d][1,3]
dioxole]-6,6’-diyl)bis(4,5-dihydrooxazole-4,2-diyl))dimethanol
tilled. Solid aldehydes were recrystallized before use. The
L
-serine
(R,aS,R)-1a.
Whitesolid(0.78 g, 78%).Mp97–99 °C. ½a D18
¼ ꢀ54
ꢁ
methyl ester hydrochloride was synthesized from
L
-serine accord-
(c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): d 3.25–3.42 (m, 2H), 3.62–
3.77 (m, 4H), 3.82 (s, 6H), 3.94–4.01 (m, 4H), 6.05 (s, 4H), 7.09 (s, 2H).
13C NMR (300 MHz, CDCl3): d 60.6, 63.8, 67.5, 70.1, 101.5, 107.1,
ing to the reported procedure16 and identified by 1H NMR, 13C
NMR. Burgess reagent was purchased from Chemical Corporation
and used without further purification.
112.2, 130.5, 137.3, 142.8, 149.7, 165.4. Anal. Calcd for C24H24N2O10
:
C, 57.60; H, 4.83; N, 5.60. Found: C, 57.59; H, 4.80; N, 5.61.
4.2. Synthesis of bisoxazoline ligands
4.2.2.2. ((4R,40R)-2,2’-((R)-4,40-Dimethoxy-[5,50-bibenzo[d][1,3]
dioxole]-6,60-diyl)bis(4,5-dihydrooxazole-4,2-diyl))dimethanol
4.2.1. Preparation of (S,aS,S)-3 and (S,aR,S)-3
(R,aR,R)-1a.
Prepared by a similar procedure to that de-
To an oven-dried 100 mL 3-necked flask equipped with a
condenser and magnetic stirring bar were added the racemic
diacids (3.90 g, 10 mmol) and excess SOCl2 (50 mL). The mixture
was heated at reflux for 2 h until the system turned clear. After
the excess SOCl2 was removed, the resulting pale yellow solid
was dissolved in CH2Cl2 (100 mL) and added to a solution of
scribed above; white solid (0.81 g, 81%). Mp 121–123 °C.
½
a 1D8
ꢁ
¼ þ5 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): d 3.23–3.40
(m, 2H), 3.61–3.78 (m, 4H), 3.81 (s, 6H), 3.96–4.04 (m, 4H), 6.06
(s, 4H), 6.99 (s, 2H). 13C NMR (300 MHz, CDCl3): d 60.1, 63.2,
66.9, 69.5, 101.2, 106.4, 111.7, 129.7, 136.8, 142.2, 149.3, 165.1.
Anal. Calcd for C24H24N2O10: C, 57.60; H, 4.83; N, 5.60. Found: C,
57.57; H, 4.79; N, 5.58.
L-serine methyl ester hydrochloride (3.43 g, 22.0 mmol) and Et3N
(6.3 mL, 45.0 mmol) in 100 mL of CH2Cl2 cooled to ꢀ10 °C. The
reaction mixture was stirred overnight, and then washed with
2 M HCl, brine and dried over anhydrous Na2SO4. After removal
of the solvent, a white solid 2 was obtained as a mixture of
diastereoisomers.
To an oven-dried 250 mL round-bottom flask was added a
solution of 2 and Burgess’ reagent [(methoxycarbonylsulfamoyl)
triethylammonium hydroxide inner salt] (8.56 g, 22 mmol) in THF
(150 mL). After refluxing for 4 h, the solvent was evaporated under
reduced pressure and the residue was dissolved in CH2Cl2 (100 mL).
The solution was washed with water (100 mL) and brine (80 mL)
successively, dried over Na2SO4. The residue was purified by silica
gel column chromatography to give (S,aS,S)-3 and (S,aR,S)-3
separately.
4.2.3. Preparation of (S,aS,S)-1b and (S,aR,S)-1b
To a solution of ethyl magnesium bromide prepared by stirring
a mixture of magnesium (0.288 g, 12.0 mmol) and bromoethane
(1 mL, 1.44 g, 13.2 mmol) in THF (12 mL) was added a solution of
(S,aS,S)-3a (1.11 g, 2.0 mmol) in THF (10 mL) at 0 °C. After stirring
at room temperature overnight, the reaction mixture was treated
with saturated NH4Cl solution. The organic layer was separated
by a separatory funnel and the aqueous layer was extracted twice
with CH2Cl2 (10 mL ꢂ 2). The combined organic layers were
washed with brine and dried over anhydrous Na2SO4. After re-
moval of the solvent, the residue was purified by flash column
chromatography (silica gel, petroleum ether/ethyl acetate = 2:1)
to give (S,aS,S)-1a as a white solid.
4.2.1.1. (4S,40S)-Dimethyl 2,20-((S)-4,40-dimethoxy-[5,50-bibe-
nzo[d][1,3]dioxole]-6,60-diyl)bis(4,5-dihydro oxazole-4-carbox-
4.2.3.1.
[1,3]dioxole]-6,60-diyl)bis(4,5-dihydrooxazole-4,2-diyl))bis(pen-
3,30-((4S,40S)-2,20-((S)-4,40-Dimethoxy-[5,50-bibenzo[d]
ylate) (S,aS,S)-3.
Colorless oil (2.28 g, 41%); ½a D18
¼ þ30 (c 1,
ꢁ
tan-3-ol) (S,aS,S)-1b.
White solid (0.71 g, 58%). Mp 127–
CHCl3). 1H NMR (300 MHz, CDCl3): d 3.62 (s, 6H), 3.78 (s, 6H),
4.01–4.11 (m, 4H), 4.23–4.31 (m, 2H), 6.02 (s, 4H), 7.10 (s, 2H).
13C NMR (300 MHz, CDCl3): d 50.8, 59.8, 69.2, 70.1, 101.5, 105.1,
122.2, 125.5, 138.3, 141.8, 148.7, 163.4, 170.3. Anal. Calcd for
128 °C. ½a 1D8
ꢁ
¼ ꢀ37:4 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): d
0.89 (t, 12H, J = 8.01 Hz), 1.58 (q, 8H, J = 8.01 Hz), 3.25–3.31 (m,
2H), 3.69–3.75 (m, 2H), 3.82 (s, 6H), 3.95–4.02 (m, 2H), 6.07 (s,
4H), 7.11 (s, 2H). 13C NMR (300 MHz, CDCl3): d 8.0, 30.7, 60.6,
65.7, 66.4, 78.2, 101.5, 107.1, 112.2, 130.5, 137.3, 149.7, 165.4.
Anal. Calcd for C32H40N2O10: C, 62.73; H, 6.58; N, 4.57. Found: C,
62.71; H, 6.55; N, 4.54.
C26H24N2O12: C, 56.12; H, 4.35; N, 5.03. Found: C, 56.10; H, 4.33;
N, 5.05.
4.2.1.2. (4S,40S)-Dimethyl 2,20-((R)-4,40-dimethoxy-[5,50-bibe-
nzo[d][1,3]dioxole]-6,60-diyl)bis(4,5-dihydro oxazole-4-carbox-
4.2.3.2. 3,30-((4S,40S)-2,20-((R)-4,40-Dimethoxy-[5,50-bibenzo[d]
Colorless oil (2.44 g, 44%); ½a D18
¼ þ51 (c 1.0,
ꢁ
[1,3]dioxole]-6,60-diyl)bis(4,5-dihydrooxazole-4,2-diyl))bis(pen-
ylate) (S,aR,S)-3.
CHCl3). 1H NMR (300 MHz, CDCl3): d 3.66 (s, 6H), 3.82 (s, 6H),
tan-3-ol) (S,aR,S)-1b.
White solid (0.64 g, 52%). Mp 187–
4.04–4.16 (m, 4H), 4.32–4.39 (m, 2H), 6.03 (s, 4H), 7.01 (s, 2H). 13
C
189 °C. ½a 1D8
ꢁ
¼ þ23 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): d
NMR (300 MHz, CDCl3): d 50.6, 60.1, 68.9, 69.9, 101.1, 106.7, 121.8,
130.2, 137.9, 142.1, 149.0, 163.2, 170.4. Anal. Calcd for
0.87 (t, 12H, J = 8.01 Hz), 1.56 (q, 8H, J = 8.01 Hz), 3.22–3.28 (m,
2H), 3.66–3.73 (m, 2H), 3.82 (s, 6H), 3.96–4.01 (m, 2H), 6.04 (s,
4H), 7.01 (s, 2H). 13C NMR (300 MHz, CDCl3): d 7.9, 30.5, 59.9,
65.4, 66.1, 77.9, 101.1, 106.8, 111.7, 130.1, 136.8, 149.5, 165.3.
Anal. Calcd for C32H40N2O10: C, 62.73; H, 6.58; N, 4.57. Found: C,
62.69; H, 6.56; N, 4.55.
C26H24N2O12: C, 56.12; H, 4.35; N, 5.03. Found: C, 56.09; H, 4.33; N,
5.01.
4.2.2. Preparation of (R,aS,R)-1a and (R,aR,R)-1a
A solution of (S,aS,S)-3a (1.11 g, 2.0 mmol) in THF (40 mL) was
added dropwise to a suspension of LiAlH4 (0.23 g, 6.0 mmol) in
THF (25 mL) over 15 min at ꢀ10 °C. The resulting mixture was
continued to stir for 2 h at this temperature, then stirred overnight
at room temperature. After being treated with ethyl acetate, the
solvent was removed by evaporation under reduced pressure.
The residue was dissolved in dichloromethane (75 mL) and the
resulting solution was washed with brine, and dried over anhy-
drous Na2SO4. After removal of dichloromethane, the residue was
further purified by flash chromatography (silica gel, petroleum
ether/ethyl acetate = 2:1) to give (S,aS,S)-1a as a white solid.
4.2.4. Preparation of (S,aS,S)-1c and (S,aR,S)-1c
The experimental procedure was similar to the preparation of
(S,aS,S)-1b and (S,aR,S)-1b except that phenyl magnesium bromide
was used as the Grignard reagent instead of ethyl magnesium
bromide.
4.2.4.1. ((4S,40S)-2,20-((S)-4,40-Dimethoxy-[5,50-bibenzo[d][1,3]
dioxole]-6,60-diyl)bis(4,5-dihydrooxazole-4,2-diyl))bis(diphen-
ylmethanol) (S,aS,S)-1c.
White solid (0.90 g, 56%). Mp 197–
199 °C. ½a 1D8
ꢁ
¼ ꢀ29 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): d

J. Wen et al. / Tetrahedron: Asymmetry 24 (2013) 860–865
865
3.69–3.76 (m, 2H), 3.83 (s, 6H), 3.95–4.08 (m, 4H), 6.06 (s, 4H), 7.08
Acknowledgments
(s, 2H), 7.35–7.50 (m, 20H). 13C NMR (300 MHz, CDCl3): d 60.6,
64.9, 79.6, 85.8, 101.5, 107.1, 112.2, 126.2, 128.2, 129.2, 130.5,
137.3, 142.8, 145.0, 149.7, 165.4. Anal. Calcd for C48H40N2O10: C,
71.63; H, 5.01; N, 3.48. Found: C, 71.59; H, 4.98; N, 3.46.
We are thankful for the financial support from the Department
of Education of Jiangxi Province (GJJ09331) and Jinggangshan
University (JZB11039).
4.2.4.2. ((4S,40S)-2,20-((R)-4,40-Dimethoxy-[5,50-bibenzo[d][1,3]
References
dioxole]-6,60-diyl)bis(4,5-dihydrooxazole-4,2-diyl))bis(diphenyl-
1. Robertson, G. M. In Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon: New York, 1991; Vol. 3, pp 563–611.
methanol) (S,aR,S)-1c.
White solid (1.03 g, 64%). Mp 221–
223 °C. ½a 1D8
ꢁ
¼ þ32 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): d
2. Reviews on pinacol coupling, see: (a) Chatterjee, A.; Joshi, N. N. Tetrahedron
2006, 62, 12137–12158; (b) Wirth, T. Angew. Chem., Int. Ed. 1996, 35, 61–63;
Some recent examples for pinacol coupling, see: (a) Sun, J.; Dai, Z.; Li, C.; Pan,
X.; Zhu, C. J. Organomet. Chem. 2009, 694, 3219–3221; (b) Halterman, R.;
Porterfield, J. P.; Mekala, S. Tetrahedron Lett. 2009, 50, 7172–7174; (c) Aspinall,
H. C.; Greeves, N.; Hin, S. L. F. Tetrahedron Lett. 2010, 51, 1558–1561; (d)
Okamoto, S.; He, J-Q.; Ohno, C.; Ohiwa, Y.; Kawaguchi, Y. Tetrahedron Lett. 2010,
51, 387–390; (e) Rouch, W. D.; Zhang, M.; McCulla, R. D. Tetrahedron Lett. 2012,
53, 4942–4945.
3.67–3.71 (m, 2H), 3.81 (s, 6H), 3.91–4.01 (m, 4H), 6.04 (s, 4H),
6.98 (s, 2H), 7.32–7.47 (m, 20H). 13C NMR (300 MHz, CDCl3): d
58.8, 63.9, 80.1, 86.2, 101.5, 107.2, 112.5, 126.0, 128.4, 129.5,
131.1, 137.8, 143.3, 146.1, 149.9, 165.2. Anal. Calcd for
C48H40N2O10: C, 71.63; H, 5.01; N, 3.48. Found: C, 71.61; H, 4.97;
N, 3.49.
3. Bensari, A.; Renaud, J-L.; Riant, O. Org. Lett. 2001, 3, 3863–3865.
4. Chatterjee, A.; Bennur, T. H.; Joshi, N. N. J. Org. Chem. 2003, 68, 5668–5671.
5. Li, Y-G.; Tian, Q-S.; Zhao, J.; Feng, Y.; Li, M. J.; You, T. P. Tetrahedron: Asymmetry
2004, 15, 1707–1710.
6. Takenaka, N.; Xia, G-Y.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 13198–
13199.
7. Yang, H.; Wang, H.; Zhu, C. J. Org. Chem 2007, 72, 10029–10034.
8. Fukuzawa, S.; Yahara, Y.; Kamiyama, A.; Hara, M.; Kikuchi, S. Org. Lett. 2005, 7,
5809–5812.
9. Wen, J-W.; Tan, Q-T.; You, T. P. J. Mol. Catal. A 2006, 258, 159–164.
10. Zhang, W.; Xie, F.; Matsuo, S.; Imahori, Y.; Kida, T.; Nakatsuji, Y.; Ikeda, I.
Tetrahedron: Asymmetry 2006, 17, 767–777.
11. (a) Braga, A. L.; Rubim, R. M.; Schrekker, H. S.; Wessjohann, L. A.; Bolster, M. W.
G.; Zeni, G.; Sehnema, J. A. Tetrahedron: Asymmetry 2003, 14, 3291–3295; (b)
Fu, B.; Du, D-M.; Wang, J. B. Tetrahedron: Asymmetry 2004, 15, 119–126; (c)
Hua, G-H.; Liu, D-L.; Xie, F.; Zhang, W-B. Tetrahedron Lett. 2007, 48, 385–388.
12. Chu, C.; Morishita, K.; Tanaka, T.; Hayashi, M. Tetrahedron: Asymmetry 2006, 17,
2672–2677.
13. (a) Jones, G.; Richards, C. J. Tetrahedron: Asymmetry 2004, 15, 653–664; (b)
Haddou, H. A.; Hoarau, O.; Cramailÿre, D.; Pezet, F.; Daran, J-C.; Balavoine, G. G.
A. Chem. Eur. J. 2004, 10, 699–707.
14. Chang, J-B.; Chen, R-F.; Guo, R-Y.; Dong, C-H.; Zhao, K. Helv. Chim. Acta 2003, 86,
2239–2246.
15. Imai, Y.; Matsuo, S.; Zhang, W.; Nakatsuji, Y.; Ikeda, I. Synlett 2000, 239–241.
16. Falorni, M.; Collu, C.; Conti, S.; Giacomelli, G. Tetrahedron: Asymmetry 1996, 7,
293–299.
4.3. Typical procedure for asymmetric pinacol coupling
To a solution of Ti(OiPr)2Cl2 (0.2 mmol) in CH3CN (2 mL) was
added a solution of ligand (0.2 mmol) in CH3CN (1 mL) under an ar-
gon atmosphere. After being stirred for 15 min, zinc powder
(3 mmol) was added to the resulting red solution. Stirring for an-
other 30 min led to a dark blue mixture which was then cooled to
0 °C. To this mixture was added aromatic aldehyde (2 mmol), fol-
lowed by the dropwise addition of trimethylchlorosilane (TMSCl).
The reaction mixture was stirred for 24 h and then quenched with
10% sodium bicarbonate solution. After removing the solid by filtra-
tion, the filtrates were extracted with ethyl acetate (15 mL ꢂ 3). The
combined organic solution was evaporated under reduced pressure.
The resulting oil was dissolved in THF solution of 1 M HCl and stir-
red at room temperature until the pinacol product had completely
desilylated. The reaction was diluted with water and extracted with
ethyl acetate (15 mL ꢂ 3). The combined organic layers were dried
over anhydrous Na2SO4, the solvent was removed under reduced
pressure, and the pinacol product was purified by silica gel chroma-
tography or recrystallization.