Novel atropisomeric bisphosphine ligands with a bridge across the 5,5′-position of the biphenyl for asymmetric catalysis

Article abstract of DOI:10.1016/j.tetasy.2008.01.023

A new type of atropisomeric bisphosphine ligand 2 with a bridge across the 5,5′-position of the biphenyl has been developed. The axial chirality of this type of ligands can be retained by macrocyclic ring strain produced from 5,5′-linkage of the biphenyl

Full text of DOI:10.1016/j.tetasy.2008.01.023

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 482–488
Novel atropisomeric bisphosphine ligands with a bridge across the
5,50-position of the biphenyl for asymmetric catalysis
Hao Wei, Yong Jian Zhang, Feijun Wang and Wanbin Zhang*
School of Chemistry and Chemical Technology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
Received 11 December 2007; accepted 16 January 2008
Abstract—A new type of atropisomeric bisphosphine ligand 2 with a bridge across the 5,50-position of the biphenyl has been developed.
The axial chirality of this type of ligands can be retained by macrocyclic ring strain produced from 5,50-linkage of the biphenyl
even without 6,60-substituents on the biphenyls. Ligand (R)-2a showed good catalytic activity and enantioselectivity for Rh(I)-catalyzed
asymmetric hydrogenation of (Z)-a-acetamidocinnamic acid 11.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
H
H
L
L
L
L
H
H
The design and synthesis of chiral phosphine ligands has
played a significant role in the development of transition-
metal catalyzed asymmetric reactions, and have attracted
a great deal of attention from both academia and industry.1
Since Noyori et al. developed the axially chiral bisphos-
phine ligand BINAP in the early 1980s,2 many bisphos-
phine ligands supported by an atropisomeric scaffold
have been developed and applied successfully in various
asymmetric catalytic reactions.3 It was found that modula-
tion of the steric and electronic properties of the atropiso-
meric scaffold of the ligand could remarkably influence
their efficiency in asymmetric catalytic reactions. Recently,
the steric design of the biaryl core has been extensively ex-
plored with ligands such as BIPHEMP,4 MeO-BIPHEP,4
TunePhos,5 SEGPHOS,6 SYNPHOS,7 and DIFLUOR-
PHOS.8 It was demonstrated that the ligands display a nar-
row dihedral angle of biaryl backbone and showed better
enantioselectivities in the Ru(II)-catalyzed asymmetric
hydrogenation of b-keto esters. Recently, we have devel-
oped a novel atropisomeric framework 1 (Fig. 1),9 in which
the biphenyl has only two coordinating groups next to the
axis, and the axial chirality of the ligands can be retained
by steric hindrance of two bulky coordinating groups and
macrocyclic ring strain produced from the 5,50-linkage of
the biphenyls even without 6,60-substituents. The modula-
tion of the length of the backbone carbon chain could con-
(CH2)
(CH2)
n
n
O
O
1 (aR)
1 (aS)
L = Coordination Group
Figure 1. Atropisomeric ligands with a bridge across the 5,50-positions of
the biphenyl.
trol the conformational flexibility of the metal chelate rings
formed with atropisomeric ligands to provide a more suit-
able chiral environment for asymmetric catalysis. When the
coordinating groups are chiral oxazolines, they display sta-
ble axial chirality, and their palladium complexes as cata-
lysts show high catalytic activity and enantioselectivity in
the asymmetric Wacker-type cyclization of allylphenols.9
In contrast with atropisomeric BINAP-type ligands, their
simple analog NAPHOS (Fig. 2), which forms a nine-mem-
bered ring with metals, is not so effective for asymmetric
hydrogenation.10 It is generally believed that the low
enantioselectivities with NAPHOS-type atropisomeric
phosphines are largely due to the formation of conforma-
tionally flexible nine-membered metal-chelate rings. Thus,
a transfer of the backbone chirality through an additional
methylene group before the phenyl group on the phosphine
may not be efficient. Significantly, high enantioselectivities
were achieved for the Rh(I)-catalyzed asymmetric
*
Corresponding author. Tel./fax: +86 21 5474 3265; e-mail: wanbin@
sjtu.edu.cn
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.01.023

H. Wei et al. / Tetrahedron: Asymmetry 19 (2008) 482–488
483
1,10-biphenyls 2, the evaluation of their stability of axial
configurations, and their application in Rh(I)-catalyzed
asymmetric hydrogenation of a model functional olefin.
O
Ph
Ph
PPh2
PPh2
PPh2
PPh2
PPh2
PPh2
H
H
(CH2)
n
O
2. Results and discussion
NAPHOS
2
Ph-o-NAPHOS
Figure 2. NAPHOS-type ligands forming nine-membered metal chelate
rings.
The enantiomerically pure bisphosphine ligands 2 were
readily prepared from 2-bromo-4-methoxyacetophenone
3
12 as illustrated in Scheme 1. Bromoform reaction of start-
ing material 3 followed by esterification afforded carboxylic
ester 4 in 86% yield.13 Ullman coupling of methyl 2-bromo-
4-methoxybenzoate 4 with activated copper powder fur-
nished the biphenyl skeleton 5 in 61% yield. Demethylation
of 5 with aluminum chloride and 1-dodecanethiol afforded
a mixture of the corresponding diphenol diester 6, diphenol
monoacid, and diphenol diacid. This mixture was further
converted to diphenol diester 6 by esterification with SOCl2
in methanol with 81% yield from 5. Cyclization of 6 with
1,8-dibromooctane and 1,10-dibromodecane led to key
intermediates 7a and 7b in 41% and 39% yields, respec-
tively. Straightforward reduction of 7a to the hydroxy-
methyl-biphenyl 8a with LiAlH4 and subsequent reaction
of 8a with thionyl chloride led to chloromethylbiphenyl
9a in 76% yield from 7a. Nucleophilic attack of compound
9a with lithium diphenylphosphine oxide produced the
hydrogenation of functional olefins using modified NA-
PHOS (Ph-o-NAPHOS) in which two phenyl groups were
introduced at the 3,30-positions of NAPHOS to improve
the conformational rigidity of the nine-membered metal
chelate ring.11 Based on this knowledge, if the phosphino-
methyl groups were introduced at the 2,2-positions on
our atropisomeric framework 1, the conformational
flexibility of nine-membered metal chelate rings could be
controlled by a macrocyclic ring strain of the 5,50-linkage
of the biphenyls to lead to an improvement of enantioselec-
tivities for Rh(I)-catalyzed asymmetric hydrogenation of
functional olefins. Thus, we report herein the synthesis of
a new type of atropisomeric bisphosphine ligand with a
bridge across the 5,50-positions of that biphenyl, 2,20-
bis(diphenylphosphinomethyl)-5,50-(polymethylenedioxy)-
MeO
HO
O
COOMe
Br
Br
COOMe
COOMe
COOMe
COOMe
a
b
c
OMe
4
OMe
3
MeO
HO
5
6
O
O
O
OH
OH
Cl
Cl
COOMe
COOMe
e
d
f
(CH2)n
(CH2)n
(CH2)n
O
O
O
7a-b
8a-b
9a-b
O
O
H
O
O
PPh2
O
PPh2
O
PPh2
g
h
H
H
(CH2)n
(CH2)n
(CH2)n
H
PPh2
O
PPh2
O
PPh2
O
O
O
O
10a-b
(R)-10a-b
(S)-10a-b
i
O
O
PPh2
PPh2
PPh2
PPh2
H
H
H
H
(CH2)n
(CH2)n
O
O
(R)-2a, n = 8
(S)-2a, n = 8
(R)-2b, n = 10
(S)-2b, n = 10
Scheme 1. Reagents and conditions: (a) (i) Br2, NaOH; (ii) SOCl2, MeOH, 86%; (b) Cu, 61%; (c) (i) AlCl3, 1-dodecanethiol, CH2Cl2; (ii) SOCl2, MeOH,
81%; (d) Br(CH2)nBr, K2CO3, DMF; for 7a, 41%; for 7b, 39%; (e) LiAlH4, THF; for 8a, 98%; for 8b, 99%; (f) SOCl2, CH2Cl2; for 9a, 78%; for 9b, 76%; (g)
n-BuLi, HP(O)Ph2, THF; for 10a, 93%; for 10b, 91%; (h) chiral preparative HPLC, a Daicel Chiralcel OD-H column, for 10a, 88%; for 10b, 86%; (i)
HSiCl3, Et3N, toluene; for 2a, 61%; for 2b, 59%.

484
H. Wei et al. / Tetrahedron: Asymmetry 19 (2008) 482–488
desired 2,20-bis(diphenylphosphinomethyl)-5,50-(octamethyl-
enedioxy)-1,10-biphenyl dioxide 10a in 93% yield. The res-
olution of racemic 10a by chiral preparative HPLC using
a Daicel Chiralcel OD-H column obtained enantiomeri-
cally pure (>99% ee) (+)-10a and (ꢀ)-10a, respectively, in
88% yield. Reduction of the resolved bisphosphine oxide
10a with trichlorosilane in toluene at 90 °C produced enan-
tiomerically pure bisphosphine ligand 2a without racemiza-
tion during the reduction process, which was in accordance
with the enantiomeric purities determined by HPLC. In the
same way, the enantiomerically pure bisphosphine ligand
2b was prepared from dimethyl 5,50-decamethylenedioxy-
biphenyl-2,20-dicarboxylate 7b in 35% overall yield. The
sense of the axial chirality of 10a was determined by the
major Cotton effects (CE) in the CD spectra. The CD curve
of (ꢀ)-10a displayed a positive CE at 310.6 nm. This signed
feature is the characteristic of (R)-configuration at the
chiral axis, which was in contrast with the spectra in the
literature of axially chiral biphenyl compounds.14
To evaluate the effectiveness of our atropisomeric bispho-
phine ligands 2 in Rh(I)-catalyzed asymmetric hydrogena-
tion, typically, (Z)-a-acetamidocinnamic acid 11a was used
as a model substrate for the hydrogenation. The hydro-
genation reaction was catalyzed by 1 mol % of the Rh(I)-
(R)-2a complex generated in situ by mixing Rh(COD)2BF4
with bisphosphine (R)-2a in methanol at room tempera-
ture. It was found that the catalytic efficiency largely
depended on the hydrogen pressure. As shown in Table
1, the hydrogenation reaction showed higher catalytic
activity with the hydrogen pressure being increased (entries
1–5). The enantioselectivity was also enhanced with the
hydrogen pressure being increased from 1 to 10 atm (from
51% to 84% ee, entries 1–3). However, by further increasing
the hydrogen pressure, the enantioselectivity decreased
remarkably (entries 4 and 5). With (R)-2b as a ligand,
which has a decamethylenedioxy bridge, the enantioselec-
tivity decreased to 81% ee under 10 atm of hydrogen pres-
sure (entry 6). The reaction medium also affects the
catalytic activity and the enantioselectivity of the product
(entries 7–12). The highest enantioselectivity (86% ee) was
obtained in acetone under 10 atm of hydrogen pressure
(entry 12). It is noteworthy that the enantioselectivity ob-
tained with our atropisomeric ligands 2 is much higher
than that obtained with NAPHOS ligand (54% ee).10a
To evaluate the stability of the axial configuration of bis-
phosphine ligands 2, two enantiomerically pure ligands
(S)-2a and (S)-2b were dissolved, respectively, in toluene,
and stirred at 90 °C for 18 h. As a result, no racemization
had occurred by the determination by HPLC. However,
when the temperature was increased to 100 °C, the ligands
underwent racemization in toluene. As illustrated in Figure
3, the axial configuration of ligand 2a with octamethylene-
dioxy bridge is more stable than that of ligand 2b. The
enantiomeric purity of (S)-2a dropped to 64% ee, whereas
the ee value of (S)-2b dropped to 43% after 32 h at
100 °C. When the temperature was increased to 110 °C,
ligands (S)-2a and (S)-2b were completely converted to a
racemic mixture after 24 h. Nevertheless, these results
clearly showed that the atropisomeric bisphosphine ligands
2 could be applied in general transition-metal catalyzed
asymmetric reactions due to their stable axial chirality at
90 °C. In addition, the axial configuration could be further
stabilized through the chelation of the ligand with a metal
to form a metal chelate ring in catalytic reactions.
Table 1. Rh(I)-catalyzed asymmetric hydrogenation of (Z)-a-acetamido-
cinnamic acid using atropisomeric bisphosphines 2 as a liganda
H2
COOH
COOH
2
R)-
Rh(COD)2BF4/(
NHAc
11a
NHAc
12a
rt, 24 h
Entry Ligand H2 pressure (atm) Solvent Conv.b (%) eec (%)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2b
2a
2a
2a
2a
2a
2a
1
5
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
THF
CH2Cl2
Toluene
EtOH
63
78
80
100
100
85
86
65
40
75
51
71
84
45
41
81
78
51
66
83
81
86
10
20
40
10
10
10
10
10
10
10
9
10
11
12
i-PrOH
Acetone
75
78
100
2a-100 ºC
2b-100 ºC
a All reactions were carried out at room temperature for 24 h. The catalyst
was prepared in situ from Rh(COD)2BF4 and ligand (substrate:Rh:
ligand = 100:1:1.1).
2a-110 ºC
2b-110 ºC
80
b Determined by 1H NMR analysis.
60
c The enantiomeric excesses were determined by chiral HPLC using a
Daicel Chiralcel OD-H column. The (S)-absolute configurations were
assigned by comparison of specific rotations with the known reported
data.15
40
20
0
The scope of the asymmetric hydrogenation reaction with
different substrates is shown in Table 2. A series of (Z)-a-
acetamido-b-arylacrylic acids 11 were hydrogenated with
Rh(I)-(R)-2a complex as a catalyst in acetone under
10 atm of hydrogen pressure. All the reactions were not
completely accomplished under these reaction conditions.
Only a small electronic effect of the aryl ring was observed
on the enantioselectivity (82–86% ee).
0
5
10
15
20
25
30
35
40
Time (h)
Figure 3. Rate of racemization for atropisomeric bisphosphines 2 in
toluene at 100 °C and 110 °C (determined by HPLC using a Daicel
Chiralcel AD-H column).

H. Wei et al. / Tetrahedron: Asymmetry 19 (2008) 482–488
485
Table 2. Rh(I)-catalyzed asymmetric hydrogenation of (Z)-a-acetamido-
b-arylacrylic acids using atropisomeric bisphosphine (R)-2a as a liganda
4.2. Methyl 2-bromo-4-methoxybenzoate 4
Sodium hypobromite solution was freshly prepared by
adding bromine (46.0 mL, 0.90 mol) to 20% sodium
hydroxide solution (585 mL) at 0–10 °C. To a rapidly stir-
red sodium hypobromite solution at room temperature,
2-bromo-4-methoxyacetophenone 3 (58.0 g, 0.25 mol) was
added over a 25-min period. Stirring was continued at
35–38 °C for 24 h. Unreacted sodium hypobromite was
destroyed by sodium bisulfite solution, and extracted with
ether to remove the unreacted ketone. The aqueous layer
was acidified with concentrated hydrochloric acid to give
a white precipitate, which was filtered to obtain a white
Entry
Substrate
Ar
Conv.b (%)
eec (%)
1
2
3
4
5
6
11a
11b
11c
11d
11e
11f
Ph
78
57
61
45
71
75
86
82
85
85
86
86
p-Me-Ph
p-F-Ph
p-Cl-Ph
o-Cl-Ph
p-Br-Ph
1
a All reactions were carried out at room temperature under 10 atm of H2
for 24 h. The catalyst was prepared in situ from Rh(COD)2BF4 and
ligand (substrate:Rh:ligand = 100:1:1.1).
solid (53.5 g, 92%). Mp 197–198 °C; H NMR (400 MHz,
CDCl3): d 8.04 (d, J = 8.8 Hz, 1H, ArH), 7.23 (d,
J = 2.4 Hz, 1H, ArH), 6.90 (dd, J = 2.8, 8.8 Hz, 1H,
ArH), 3.87 (s, 3H, OCH3). Thionyl chloride (105 mL,
1.44 mol) was added dropwise to the solution of 2-bro-
mo-4-methoxybenzoic acid (99.2 g, 0.4 mol) in methanol
(150 mL) at 0 °C. The mixture was stirred at reflux temper-
ature for 14 h. Excess SOCl2 and methanol was removed by
distillation. The residue was dissolved in ethyl acetate,
washed with water and 5% sodium hydroxide solution
(70 mL), dried over MgSO4, filtered, and concentrated in
b Determined by 1H NMR analysis.
c The enantiomeric excesses were determined by chiral HPLC using a
Daicel Chiralcel OD-H column. The (S)-absolute configurations were
assigned by comparison of specific rotations with the known reported
data.15
3. Conclusion
1
vacuo to give product 4 (100.1 g, 95%). Mp 25–26 °C; H
NMR (400 MHz, CDCl3): d 7.86 (d, J = 8.8 Hz, 1H,
ArH), 7.19 (d, J = 2.4 Hz, 1H, ArH), 6.86 (dd, J = 2.4,
8.8 Hz, 1H, ArH), 3.89 (s, 3H, OCH3), 3.84 (s, 3H,
OCH3); 13C NMR (100 MHz, CDCl3): d 165.55, 162.13,
133.09, 123.36, 123.01, 119.71, 112.74, 55.53, 51.95.
In conclusion, we have developed a new type of atropiso-
meric bisphosphine ligand 2 with a bridge across the 5,50-
position of the biphenyl. It was demonstrated that the axial
chirality of this type of ligands can be retained by macro-
cyclic ring strain produced from the 5,50-linkage of the
biphenyl. For the Rh(I)-catalyzed asymmetric hydrogena-
tion of (Z)-a-acetamido-b-arylacrylic acids 11, ligand
(R)-2a showed good catalytic activity and enantioselec-
tivity. Further studies will focus on the development and
application of this class of atropisomeric ligands.
4.3. 5,50-Dimethoxy-diphenic acid dimethyl ester (5)
A mixture of compound 4 (61.3 g, 0.3 mol) and activated
copper powder (55.9 g, 0.9 mol) was stirred at 160–180 °C
for 24 h. The residue was cooled, and CH2Cl2 (200 mL)
was added. It was then filtered and washed with CH2Cl2
(40 mL ꢁ 5), and the filtrate was concentrated. The ob-
tained residue was recrystallized with ethyl acetate and
petroleum ether to give white solid 5 (25.2 g, 61%). mp
166–167 °C; 1H NMR (400 MHz, CDCl3): d 8.01 (d,
J = 8.8 Hz, 2H, ArH), 6.91 (dd, J = 2.8, 9.2 Hz, 2H,
ArH), 6.69 (d, J = 3.2 Hz, 2H, ArH), 3.84 (s, 6H, OCH3),
3.61 (s, 6H, OCH3); 13C NMR (100 MHz, CDCl3): d
166.74, 161.97, 146.04, 132.17, 121.57, 115.54, 112.36,
55.51, 51.68. Anal. Calcd for C18H18O6: C, 65.45; H,
5.49. Found: C, 65.21; H, 5.90.
4. Experimental
4.1. General experimental conditions
All air- and moisture-sensitive manipulations were carried
out with standard Schlenk techniques under nitrogen.
The reaction solvents were distilled prior to use (toluene
and dichloromethane were distilled from CaH2, THF was
distilled from Na). The commercially available reagents
were used without further purification. Column chromato-
graphy was run on silica gel (100–200 mesh). Melting
4.4. Dimethyl 5,50-dihydroxybiphenyl-2,20-dicarboxylate 6
1
points were uncorrected. H NMR spectra and 13C NMR
A solution of biphenyl diester 5 (10.0 g, 30.0 mmol) in
CH2Cl2 (20 mL) was added dropwise to a mixture prepared
from 1-dodecanethiol (40.5 g, 0.2 mol) and aluminum tri-
chloride (13.4 g, 0.1 mol) in CH2Cl2 (50 mL) at room tem-
perature. The mixture was stirred overnight at room
temperature, and then poured into ice-water, extracted
with CH2Cl2. The organic layer was washed with water,
and then basified by the addition of a solution of sodium
hydroxide (3.0 M, 40 mL). The aqueous layer was washed
with CH2Cl2, acidified with concentrated hydrochloric
acid, and then extracted with ethyl acetate. The organic
layer was dried over MgSO4, and concentrated in vacuo
spectra were recorded on a Varian MERCURY plus-400
spectrometer. The ee values were determined by HPLC
using a Daicel Chiralcel OD-H column or a Daicel Chir-
alpak AD-H column. Optical rotations (concentration c gi-
ven as g/100 mL) and CD spectrum were measured at the
Shanghai Institute of Organic Chemistry, Chinese Acad-
emy of Science. Elemental analysis was performed at the
Instrumental Analysis Center of Shanghai Jiao Tong Uni-
versity. HRMS was performed on a Micromass LCTTM at
the Analysis and Research Center of East China University
of Science and Technology.

486
H. Wei et al. / Tetrahedron: Asymmetry 19 (2008) 482–488
to gain demethylated compounds. Thionyl chloride
(22 mL, 0.3 mol) was added dropwise at 0 °C to a solution
of demethylated compounds in methanol (50 mL) and the
mixture was refluxed for 14 h. Excess SOCl2 and methanol
was removed by distillation. The residue was dissolved in
ethyl acetate, then washed with water, dried over MgSO4,
then concentrated in vacuo, recrystallized with ethyl ace-
tate and petroleum ether to give 6 (7.4 g, 81%) as a white
for 1 h. The reaction mixture was stirred at room tempera-
ture for 12 h. The reaction mixture was quenched with sat-
urated aqueous Na2SO4 at 0 °C until the gray color of
unreacted lithium aluminum hydride became white. The
resulting residue was acidified with 1 M HCl, extracted
with EtOAc, washed with water and brine, dried over
MgSO4, and concentrated in vacuo to give product 8a as
a white solid (3.1 g, 98%). Mp 187–189 °C; 1H NMR
(400 MHz, CDCl3): d 7.37 (d, J = 8.4 Hz, 2H, ArH), 6.92
(dd, J = 8.4, 2.8 Hz, 2H, ArH), 6.70 (d, J = 2.8 Hz, 2H,
ArH), 4.21–4.36 (m, 6H, OCH2 and CH2OH), 4.05 (m,
2H, OCH2), 3.42 (br s, 2H, OH), 1.89 (m, 2H, CH2), 1.52
(m, 2H, CH2), 1.45–1.16 (m, 8H, CH2); 13C NMR
(100 MHz, CDCl3): d 158.00, 141.75, 131.62, 130.84,
118.61, 113.83, 65.87, 62.14, 28.93, 28.45, 24.92. Anal.
Calcd for C22H28O4: C, 74.13; H, 7.92. Found: C, 72.15;
H, 8.07.
1
solid. Mp 224–225 °C. H NMR (400 MHz, acetone-d6):
d 9.02 (s, 2H, OH), 7.87 (d, J = 8.4 Hz, 2H, ArH), 6.88
(dd, J = 2.0, 8.4 Hz, 2H, ArH), 6.64 (d, J = 3.2 Hz, 2H,
ArH), 3.52 (s, 6H, OCH3); 13C NMR (100 MHz, acetone-
d6): d 167.09, 160.89, 147.03, 132.85, 121.80, 117.78,
114.50, 51.41. Anal. Calcd for C16H14O6: C, 63.57; H,
4.67. Found: C, 63.23; H, 4.87.
4.5. Dimethyl 5,50-(octamethylenedioxy)-biphenyl-2,20-
dicarboxylate 7a
4.8. 2,20-Bis(hydroxymethyl)-5,50-(decamethylenedioxy)-
1,10-biphenyl 8b
To a suspension of anhydrous potassium carbonate (7.76 g,
56.2 mmol) in DMF (50 mL) was added dropwise a solu-
tion of compound 6 (5.7 g, 18.7 mmol) and 1,8-dibromo-
octane (5.1 g, 18.7 mmol) in DMF (20 mL) at 80 °C for
5 h. The mixture was stirred further at 80 °C for 24 h.
The reaction mixture was filtered, and the filtrate was
concentrated in vacuo. The resulting residue was dissolved
in CH2Cl2 (50 mL), washed with water and brine, dried
over MgSO4, concentrated in vacuo, then purified by
chromatography on silica gel to give product 7a as white
crystals (3.2 g, 41%). Mp 124–125 °C; 1H NMR
(400 MHz, CDCl3): d 7.94 (d, J = 8.8 Hz, 2H, ArH), 6.90
(dd, J = 2.4, 8.8 Hz, 2H, ArH), 6.76 (d, J = 2.4 Hz, 2H,
ArH), 4.38 (ddd, J = 6.8, 6.8, 12.0 Hz, 2H, OCH), 4.10
(ddd, J = 4.8, 7.2, 12.8 Hz, 2H, OCH), 3.62 (s, 6H,
OCH3), 1.97–1.92 (m, 2H, CH), 1.62–1.53 (m, 2H, CH),
1.47–1.25 (m, 8H, CH); 13C NMR (100 MHz, CDCl3): d
166.96, 161.45, 146.00, 132.00, 121.57, 116.66, 113.49,
65.97, 51.70, 28.69, 28.39, 24.73. Anal. Calcd for
C24H28O6: C, 69.88; H, 6.84. Found: C, 69.83; H, 6.28.
Product 8b was obtained as a white solid in 99% yield
following the procedure for the synthesis of 8a. Mp 164–
165 °C; 1H NMR (400 MHz, CDCl3):
d 7.36 (d,
J = 8.8 Hz, 2H, ArH), 6.91 (dd, J = 8.8, 2.4 Hz, 2H,
ArH), 6.67 (d, J = 2.4 Hz, 2H, ArH), 4.20–4.29 (m, 6H,
OCH2 and CH2OH), 4.06 (m, 2H, OCH2), 3.42 (s, 2H,
OH), 1.82 (m, 2H, CH2), 1.56 (m, 2H, CH2), 1.36–1.20
(m, 12H, CH2); 13C NMR (100 MHz, CDCl3): d 157.91,
141.82, 131.54, 131.20, 117.10, 115.19, 68.15, 62.07,
28.85, 28.65, 27.77, 24.95. Anal. Calcd for C24H32O4: C,
74.97; H, 8.39. Found: C, 73.85; H, 8.42.
4.9. 2,20-Bis(chloromethyl)-5,50-(octamethylenedioxy)-1,10-
biphenyl 9a
Thionyl chloride (3.2 mL) was added to a solution of 2,20-
bis(hydroxymethyl)-5,50-(octamethylenedioxy)-1,10-biphenyl
8a (3.1 g, 8.7 mmol) in dichloromethane (50 mL) under ice-
cooling, and then the resulting mixture was stirred at rt for
12 h. The excess SOCl2 was destroyed slowly by the drop-
wise addition of ice-water. The organic layer was washed
with water and dried over MgSO4, and concentrated in
vacuo. Finally, the residue obtained was purified by column
chromatography (eluent: ethyl acetate and petroleum ether)
4.6. Dimethyl 5,50-(decamethylenedioxy)-biphenyl-2,20-
dicarboxylate 7b
Compound 7b was obtained as a white crystal in 39% yield
following the procedure for the synthesis of 7a. Mp 104–
105 °C; 1H NMR (400 MHz, CDCl3):
d
7.97 (d,
to give white solid 9a (2.7 g, 78%). Mp 114–115 °C; H
1
J = 9.2 Hz, 2H, ArH), 6.89 (dd, J = 3.2, 8.8 Hz, 2H,
ArH), 6.71 (d, J = 2.0 Hz, 2H, ArH), 4.24 (ddd, J = 6.0,
8.0, 11.2 Hz, 2H, OCH), 4.09 (ddd, J = 6.4, 7.2, 13.6 Hz,
2H, OCH), 3.61 (s, 6H, OCH3), 1.87–1.80 (m, 2H, CH),
1.70–1.63 (m, 2H, CH), 1.42–1.25 (m, 12H, CH); 13C
NMR (100 MHz, CDCl3): d 166.88, 161.25, 146.06,
132.00, 121.53, 115.61, 114.84, 68.07, 51.64, 28.58, 28.51,
27.66, 25.13. Anal. Calcd for C26H32O6: C, 70.89; H,
7.32. Found: C, 70.85; H, 7.22.
NMR (400 MHz, CDCl3): d 7.44 (d, J = 8.4 Hz, 2H,
ArH), 6.96 (dd, J = 8.4, 2.8 Hz, 2H, ArH), 6.74 (d,
J = 2.8 Hz, 2H, ArH), 4.46 (d, J = 11.6 Hz, 2H, CH2Cl),
4.41 (d, J = 11.6 Hz, 2H, CH2Cl), 4.36–4.29 (m, 2H,
OCH2), 4.10–4.04 (m, 2H, OCH2), 1.92 (m, 2H, CH2),
1.59 (m, 2H, CH2), 1.46–1.16 (m, 8H, CH2); 13C NMR
(100 MHz, CDCl3): d 158.74, 141.15, 131.85, 127.17,
118.71, 114.05, 65.97, 44.33, 28.97, 28.66, 24.94. Anal. Calcd
for C22H26O2: C, 67.18; H, 6.66. Found: C, 65.98; H, 6.75.
4.7. 2,20-Bis(hydroxymethyl)-5,50-(octamethylenedioxy)-1,10-
biphenyl 8a
4.10. 2,20-Bis(chloromethyl)-5,50-(decamethylenedioxy)-1,10-
biphenyl 9b
To a suspension of lithium aluminum hydride (1.7 g,
44.8 mmol) in THF (30 mL) was added dropwise a solution
of diester 7a (3.7 g, 9.0 mmol) in dry THF (20 mL) at 0 °C
Product 9b was obtained as a white solid in 76% yield
following the procedure for the synthesis of 9a. Mp 76–
78 °C; 1H NMR (400 MHz, CDCl3):
d
7.43 (d,

H. Wei et al. / Tetrahedron: Asymmetry 19 (2008) 482–488
487
J = 8.4 Hz, 2H, ArH), 6.96 (dd, J = 2.8, 8.4 Hz, 2H, ArH),
6.74 (d, J = 2.8 Hz, 2H, ArH), 4.38 (d, J = 11.2 Hz, 2H,
CH2Cl), 4.34 (d, J = 11.2 Hz, 2H, CH2Cl), 4.25–4.19 (m,
2H, OCH2), 4.13–4.06 (m, 2H, OCH2), 1.88–1.78 (m, 2H,
CH2), 1.62–1.41 (m, 2H, CH2), 1.37–1.1 (m, 12H, CH2);
13C NMR (100 MHz, CDCl3): d 158.52, 141.20, 131.79,
127.54, 117.76, 115.37, 68.10, 44.53, 28.86, 28.60, 27.88,
24.97. Anal. Calcd for C24H30O2: C, 68.40; H, 7.18. Found:
C, 67.96; H, 7.22.
7.40–7.36 (m, 6H, ArH), 7.25–7.16 (m, 8H, ArH), 6.82
(dd, J = 8.4 Hz, 2.4 Hz, 2H, ArH), 5.76 (d, J = 2.8 Hz,
2H, ArH), 3.86 (m, 4H, OCH2), 3.47–3.35 (m, 4H, PhCH2),
1.66 (m, 2H, CH2), 1.52 (m, 2H, CH2), 1.29–1.14 (m, 12H,
CH2); 13C NMR (100 MHz, CDCl3): d 157.53, 141.89,
141.66, 133.57, 132.59, 131.97, 131.83, 131.65, 131.42,
131.33, 131.20, 131.11, 128.84, 128.73, 128.39, 128.28,
120.91, 120.84, 116.64, 116.42, 68.09, 33.88, 33.22, 28.70,
28.62, 27.47, 25.17; 31P NMR (161 MHz, CDCl3) d 31.21.
Anal. Calcd for C48H50O4P2: C, 76.58; H, 6.69. Found:
C, 75.85; H, 6.58. HRMS (Micromass LCT) calcd for
C48H51O4P2: 753.3286; found: 753.3263.
4.11. 2,20-Bis(diphenylphosphinomethyl)-5,50-(octamethylene-
dioxy)-1,10-biphenyl dioxide 10a
n-BuLi (5.1 mL, 9.5 mmol, 1.86 M in hexane) was added
dropwise to a solution of diphenylphosphine oxide (1.9 g,
9.5 mmol) in dry THF at ꢀ78 °C after which the resulting
mixture was stirred for 1 h. To this mixture, a solution
of 2,20-bis(chloromethyl)-5,50-(octamethylenedioxy)-1,10-
biphenyl 9a (1.5 g, 3.8 mmol) in THF was added dropwise
over 20 min. The solution was allowed to stir overnight at
room temperature. The reaction mixture was quenched by
saturated aqueous NH4Cl, and THF was concentrated in
vacuo, and the aqueous layer extracted twice with EtOAc.
The combined organic solution was washed twice with
water and dried over MgSO4. The organic solvent was
evaporated, and the resulting residue was recrystallized
from EtOAc to give white solid 10a (2.6 g, 93%). Mp
245–246 °C; 1H NMR (400 MHz, CDCl3): d 7.61 (dd,
J = 8.4 Hz, 1.6 Hz, 2H, ArH), 7.55–7.47 (m, 6H, ArH),
7.43–7.36 (m, 6H, ArH), 7.23–7.18 (m, 4H, ArH), 7.16–
7.11 (m, 4H, ArH), 6.85 (dd, J = 8.4 Hz, 2.8 Hz, 2H,
ArH), 5.54 (d, J = 2.8 Hz, 2H, ArH), 3.86 (m, 4H), 3.55–
3.47 (m, 4H, PhCH2), 1.64 (m, 2H, CH2), 1.49 (m, 2H,
CH2), 1.15–1.28 (m, 8H, CH2); 13C NMR (100 MHz,
CDCl3): d 157.42, 157.39, 141.72, 141.65, 133.42, 132.59,
132.45, 132.06, 132.01, 131.97, 131.61, 131.52, 131.49,
131.43, 131.20, 131.12, 128.83, 128.72, 128.22, 128.11,
120.51, 117.91, 117.89, 114.15, 66.66, 34.07, 33.41, 28.58,
27.56, 24.57; 31P NMR (161 MHz, CDCl3) d 30.80. Anal.
Calcd for C46H46O4P2: C, 76.23; H, 6.40. Found: C,
75.69; H, 6.30. HRMS (Micromass LCT) calcd for
C46H47O4P2: 725.2986; found: 725.2950.
4.15. (R)-(ꢀ)-2,20-Bis(diphenylphosphinomethyl)-5,50-
(decamethylenedioxy)-1,10-biphenyl dioxide (R)-(ꢀ)-10b
25
½aꢂD ¼ ꢀ37:5 (c 1.1, CHCl3); mp 86–90 °C; all other
analytical data were identical to those of 10b.
4.16. (S)-(+)-2,20-Bis(diphenylphosphinomethyl)-5,50-
(decamethylenedioxy)-1,10-biphenyl dioxide (S)-(+)-10b
25
½aꢂD ¼ þ36:8 (c 1.1, CHCl3); mp 86–90 °C; all other
analytical data were identical to those of 10b.
4.17. (R)-(ꢀ)-2,20-Bis(diphenylphosphinomethyl)-5,50-
(octamethylenedioxy)-1,10-biphenyl (R)-(ꢀ)-2a
Trichlorosilane (5.6 mL, 56 mmol) was added to a solution
of 2,20-bis(diphenylphosphinomethyl)-5,50-(octamethylene-
dioxy)-1,10-biphenyl dioxide 10a (2.0 g, 2.8 mmol) and
triethylamine (8.0 mL, 56 mmol) in toluene (50 mL) at
0 °C. The reaction mixture was stirred at 90 °C for 12 h.
After cooling to room temperature, degassed aqueous so-
dium hydroxide (10 M) was added to quench the reaction
until the organic and aqueous layers became clear, and
was extracted twice with degassed EtOAc. The combined
organic layer was washed with 2 M hydrochloric acid, sat-
urated aqueous sodium hydrogen carbonate, and brine,
and then dried over anhydrous sodium sulfate. Removal
of the solvent and flash column chromatography on silica
gel (eluent: ethyl acetate and petroleum ether) gave 2a as
25
a white solid (1.2 g, 61%). Mp 134–138 °C; ½aꢂD ¼ ꢀ28:6
1
4.12. (R)-(ꢀ)-2,20-Bis(diphenylphosphinomethyl)-5,50-
(c 1, CHCl3); H NMR (400 MHz, CDCl3): d 7.39–7.27
(octamethylenedioxy)-1,10-biphenyl dioxide (R)-(ꢀ)-10a
(m, 14H, ArH), 7.22–7.16 (m, 8H, ArH), 6.78 (dd,
J = 8.8 Hz, 2.8 Hz, 2H, ArH), 6.11 (d, J = 2.8 Hz, 2H,
ArH), 4.15–4.05 (m, 2H, OCH2), 4.00–3.90 (m, 2H,
OCH2), 3.40–3.20 (m, 4H), 1.84 (m, 2H, CH2), 1.56 (m,
2H, CH2), 1.48–1.29 (m, 8H, CH2); 13C NMR (100 MHz,
CDCl3): d 156.04, 134.00, 133.36, 133.18, 133.01, 132.83,
132.07, 130.99, 130.79, 130.03, 129.17, 129.03, 128.93,
128.83, 128.76, 128.71, 128.58, 128.27, 128.10, 128.04,
117.23, 65.80, 32.07, 30.51, 28.67, 27.96, 24.85; 31P NMR
(161 MHz, CDCl3) d ꢀ8.27; HRMS (Micromass LCT)
calcd for C46H46O2P2Na: 715.2871; found: 715.2876.
25
½aꢂD ¼ ꢀ34:1 (c 1, CHCl3); mp 113–117 °C; all other
analytical data were identical to those of 10a.
4.13. (S)-(+)-2,20-Bis(diphenylphosphinomethyl)-5,50-
(octamethylenedioxy)-1,10-biphenyl dioxide (S)-(+)-10a
25
½aꢂD ¼ þ33:8 (c 1, CHCl3); mp 113–117 °C; all other
analytical data were identical to those of 10a.
4.14. 2,20-Bis(diphenylphosphinomethyl)-5,50-(decamethylene-
dioxy)-1,10-biphenyl dioxide 10b
4.18. (R)-(ꢀ)-2,20-Bis(diphenylphosphinomethyl)-5,50-
(decamethylenedioxy)-1,10-biphenyl (R)-(ꢀ)-2b
Compound 10b was obtained as a white solid in 91% yield
following the procedure for the synthesis of 10a. Mp 219–
Compound 2b was obtained as a white solid in 56% yield
following the procedure for the synthesis of 2a. Mp 112–
222 °C; 1H NMR (400 MHz, CDCl3):
d
7.60 (dd,
25
1
J = 8.8 Hz, 2.4 Hz, 2H, ArH), 7.55–7.52 (m, 6H, ArH),
116 °C; ½aꢂD ¼ ꢀ31:5 (c 1, CHCl3); H NMR (400 MHz,

488
H. Wei et al. / Tetrahedron: Asymmetry 19 (2008) 482–488
Springer: Berlin, 1999; (c) Zhang, X. Chem. Rev. 2003, 103,
3029.
CDCl3): d 7.49–7.16 (m, 14H, ArH), 7.06–7.04 (m, 8H,
ArH), 6.71 (dd, J = 8.8 Hz,1.6 Hz, 2H, ArH), 6.33 (d,
J = 1.6 Hz, 2H, ArH), 4.11–4.03 (m, 2H, OCH2), 4.00–
3.92 (m, 2H, OCH2), 3.21 (s, 4H, PhCH2), 1.76 (m, 2H,
CH2), 1.63 (m, 2H, CH2), 1.48–1.26 (m, 12H, CH2); 13C
NMR (100 MHz, CDCl3): d 156.54, 144.00, 140.23,
134.20, 134.03, 133.30, 133.10, 132.94, 128.75, 128.73,
128.70, 128.61, 128.49, 128.43, 128.26, 128.20, 116.29,
68.10, 29.86, 29.82, 28.68, 28.64, 27.84, 25.09; 31P NMR
(161 MHz, CDCl3) d ꢀ9.38; HRMS (Micromass LCT)
calcd for C48H50O2P2Na: 743.3188; found: 743.3184.
2. (a) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito,
T.; Souchi, T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932;
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57, 3809; (b) Che, C.-M.; Huang, J.-S. Coord. Chem. Rev.
2003, 242, 97; (c) Au-Yeung, T. T.-L.; Chan, S.-S.; Chan, A.
S. C. Adv. Synth. Catal. 2003, 345, 537; (d) Shimizu, H.;
Nagasaki, I.; Saito, T. Tetrahedron 2005, 61, 5405.
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4.19. General procedure for Rh(I)-catalyzed asymmetric
hydrogenation of (Z)-a-acetamidocinnamic acid 11a
M.; Crameri, Y.; Foricher, J.; Lalonde, M.; Muller, R. K.;
¨
Scalone, M.; Schoettel, G.; Zutter, U. Pure Appl. Chem. 1996,
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[Rh(COD)2]BF4 (0.01 mmol) and (R)-2a (0.011 mmol)
were dissolved in degassed MeOH (2 mL) and stirred for
20 min to form a solution of [Rh(COD)(R)-2a]BF4 catalyst
for the asymmetric hydrogenation. Then a solution of sub-
strate 11a (1 mmol) in MeOH (2 mL) was added to a cata-
lyst solution prepared above. The hydrogenation was
performed in a stainless steel autoclave at room tempera-
ture under 10 atm of hydrogen for 24 h. The resulting solu-
tion was passed through a short silica gel column to remove
the catalyst. The ee value and conversion of the product
were measured by chiral HPLC and 1H NMR spectroscopy
without any further purification. The products were con-
verted to the corresponding methyl ester for the determina-
tion of their ee value using chiral HPLC (a Daicel Chiralcel
OD-H column, flow rate = 0.5 mL/min, hexane/2-propa-
nol (75:25), UV detector, 254 nm).
5. Zhang, Z.; Qian, H.; Longmire, J.; Zhang, X. J. Org. Chem.
2000, 65, 6223.
6. Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.;
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264.
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Ratovelomanana-Vidal, V.; Geneˆt, J. P.; Champion, N.;
Dellis, P. Eur. J. Org. Chem. 2003, 1931.
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320–325.
9. Wang, F.; Zhang, Y. J.; Wei, H.; Zhang, J.; Zhang, W.
Tetrahedron Lett. 2007, 48, 4083.
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Acknowledgments
11. Zhou, Y.-G.; Zhang, X. Chem. Commun. 2002, 1124.
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This work was supported by the National Natural Science
Foundation of China (Grant Nos. 20572070, 20502015)
and the Ministry of Education of China (EYTP and
SRFDP).
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