Development of new chiral P,N ligands and their applications in enantioselective 1,4-conjugate additions of diethylzinc to chalcones

Article abstract of DOI:10.1016/j.tetasy.2003.09.001

Examples of a new type of chiral phosphine-pyridine ligand have been synthesized from (R)-2-amino-2′-hydroxy-6,6′-dimethyl-1,1′- biphenyl and (R)-2-amino-2′-hydroxy-4,4′,6,6′-tetramethyl-1, 1′-biphenyl in six steps and successfully employed in Cu(I)-catal

Full text of DOI:10.1016/j.tetasy.2003.09.001

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3211–3217
Development of new chiral P,N ligands and their applications
in enantioselective 1,4-conjugate additions of diethylzinc
to chalcones
Yuxue Liang, Shuang Gao, Huihui Wan, Yuanchun Hu, Huilin Chen, Zhuo Zheng and
Xinquan Hu*
Dalian Institute of Chemical Physics, the Chinese Academy of Sciences, Dalian 116023, PR China
Received 24 June 2003; accepted 26 August 2003
Abstract—Examples of a new type of chiral phosphine-pyridine ligand have been synthesized from (R)-2-amino-2%-hydroxy-6,6%-
dimethyl-1,1%-biphenyl and (R)-2-amino-2%-hydroxy-4,4%,6,6%-tetramethyl-1,1%-biphenyl in six steps and successfully employed in
Cu(I)-catalysed conjugate additions of diethylzinc to chalcones. Up to 96.1% ee and high activities were achieved.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Zhang’s phosphine−pyridine ligand I (Fig. 1)3f showed
excellent enantioselectivities in the 1,4-conjugate addi-
tions of diethylzinc to enones. Although many efficient
chiral copper catalytic systems have been developed for
the 1,4-conjugate additions of diorganozinc to various
types of enones,4–9 only a few copper complexes coordi-
nated with chiral P,N ligands have proven to be
efficient when chalcone was used as the enone sub-
strate.2a,3f,9c On the basis of our latest report10 on the
The development of new chiral ligands plays an impor-
tant role for catalytic asymmetric reactions.1 Over the
past decade, chiral ligands derived from 2-amino-2%-
hydroxy-1,1%-binaphthyl (NOBIN2), especially, those
from
2-amino-2%-diphenylphosphino-1,1%-binaphthyl
(MAP3), have exhibited good asymmetric induction.
Among those chiral ligands derived from MAP,
Figure 1.
* Corresponding author. Tel.: 0086+411-4379233; fax: 0086+411-4684746; e-mail: xinquan@ms.dicp.ac.cn
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.09.001

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Y. Liang et al. / Tetrahedron: Asymmetry 14 (2003) 3211–3217
Cu(I)-catalysed 1,4-conjugate addition with phosphite−
pyridine ligands III (Fig. 1) derived from the electron-
rich chiral biphenyl backbone,11 where the electronic
property of the ligands played a very important role in
obtaining high ee, compared to the phosphite−pyridine
ligands II (Fig. 1) from the NOBIN backbone, we are
interested in synthesizing MAP-type ligands 7 (Scheme
1) from the new chiral biphenyl backbone 1 to compare
to Zhang’s phosphine−pyridine ligands I (Fig. 1) in the
applications of Cu(I)-catalysed 1,4-conjugate additions
of diethylzinc to chalcones.
of 3a with Ph2P(O)H to form the phosphine oxide 4a
under Pd-catalysis proceeded smoothly in DMSO at
120°C in 86% yield. Aminophosphine 6a could then be
obtained by direct reduction of 4a with trichlorosilane,
but was usually accompanied by the N-ethyl by-
product,3g which could be avoided by the deacetylation
of 4a, followed by reduction with trichlorosilane.3e The
deacetylation of 4a with HCl under similar conditions
did not work well, but we found it was a convenient
process to perform this deacetylation when 4a was
refluxed in KOH–ethanol solution for 12 h, giving the
aminophosphine oxide 5a which was obtained as a
white solid in 91% yield. Reduction of 5a with
trichlorosilane then produced aminophosphine 6a in
72% yield. The amidation of 6a with 6-methyl-2-picol-
inic acid in the presence of 4-(4,6-dimethoxy-1,3,5-tri-
2. Results and discussions
Phosphine–pyridine ligand 7a was synthesized from the
chiral biphenyl backbone 1a in six steps (Scheme 1).
Acetylation of 1a with excess acetyl chloride gave the
N,O-diacetate, followed by selective hydrolysis of the
OAc group with 1% aqueous NaOH to afford the
hydroxy amide 2a in 96% yield. Treatment of 2a with
trifluoromethanesulfonic anhydride (Tf2O) at 0°C
afforded the triflate 3a in 96% yield. Phosphinoylation
azin-2-yl)-4-methylmorpholinium
chloride
(DMT-
MM)12 proceeded smoothly to afford the phosphine−
pyridine ligand 7a in 82% yield. Using the same proce-
dure, the phosphine−pyridine ligand 7b was also
prepared from the chiral biphenyl backbone 1b, with
the yields of every step listed in Scheme 1.
Scheme 1. Reagents and conditions: (a) i. CH3COCl, Et3N, CH2Cl2, 0°C; ii. NaOH, MeOH/H2O; (b) Tf2O, pyridine, CH2Cl2, 0°C;
(c) Ph2P(O)H, Pd(OAc)2, dppb, EtN(i-Pr)2, DMSO, 120°C; (d) KOH, EtOH/H2O, reflux; (e) Cl3SiH, xylene, reflux; (f)
6-methylpicolinic acid, DMTMM, THF, rt.

Y. Liang et al. / Tetrahedron: Asymmetry 14 (2003) 3211–3217
3213
As racemization can occur relatively easily for
biphenyl backbones under some of the critical reaction
conditions,13 e.g. at high temperatures and strong
base, it was worth studying the enantiomeric purities
of compounds 4a, 5a and 6a during the synthesis. We
prepared these racemic compounds from racemic 1a
using the same procedure as described previously. It
was found that chiral HPLC analysis with Daicel Chi-
ralcel OD-H and Chiralpak AD columns could sepa-
rate the enantiomers of these racemic biphenyl
compounds. HPLC results showed no racemization
during the preparation of homochiral compounds 4a,
5a and 6a (>99.5% ee).
Under the optimal reaction conditions for enantiose-
lective 1,4-conjugate additions, various chalcones were
successfully converted into the corresponding chiral
ketones using ligands 7a and 7b (Table 2). As can be
seen in Table 2, ligand 7a provides all chalcones into
chiral ketone products in 90–95% ee, although ligand
7b provides the best ee (96.1%). 4-Methoxychalcone
proved to be the best substrate to give high enantiose-
lectivity with either 7a or 7b as the ligand for the
1,4-conjugate addition (entries 4).
From Table 2, our new chiral P,N ligands 7 showed
high catalytic activity with good to excellent ee’s for
various para-substituted chalcones compared with
Zhang’s P,N ligands based on NOBIN, which pro-
vided the best ees in the 1,4-conjugate addition of
Et2Zn to chalcones to date but with relatively lower
catalytic activity.3f A possible reason was that the elec-
tron-rich phosphine, which was donated by the methyl
substituted phenyl ring in the backbone, could result
in a highly active Cu(I) catalytic species in the 1,4-con-
jugate addition.
We chose chalcone as the substrate and the phos-
phine−pyridine ligand 7a as the ligand to optimize the
reaction conditions for the Cu-catalysed asymmetric
1,4-conjugate additions (Table 1). [Cu(CH3CN)4]BF4
was selected as the copper precursor.2a,3f,14 The conju-
gate addition of Et2Zn to chalcone was conducted in
the presence of 1 mol% of [Cu(CH3CN)4]BF4 and 2.5
mol% of ligand 7a. The catalyst was prepared via
treatment of ligand 7a with [Cu(CH3CN)4]BF4 in tolu-
ene (25°C) and removal of the coordinated acetonitrile
via stripping the solvent in vacuo.3f Enantioselective
1,4-conjugate addition of Et2Zn to chalcone gave bet-
ter yields and enantioselectivity in toluene than in
dichloroethane, mixed solvents also achieved good
yields and enantioselectivity (entries 1–4). Interestingly,
on increasing the proportion of dichloroethane, the
isolated yield of the addition product had a decreasing
trend. The influence of temperature on the reaction
was also examined (entries 4−8) with the optimal reac-
tion temperature for obtaining high enantioselectivity
being −10°C (entry 4). The reaction time from 3–12 h
had only a marginal effect on the enantioselectivity
and yield (entries 4, 9–11).
3. Conclusion
In conclusion, we have successfully synthesized a new
type of chiral phosphine−pyridine ligand 7 from (R)-2-
amino-2%-hydroxy-6,6%-dimethyl-1,1%-biphenyl 1a and
(R)-2-amino-2%-hydroxy-4,4%,6,6%-tetra -methyl-1,1%-bi-
phenyl 1b in six steps and employed them in Cu-
catalysed 1,4-conjugate additions of Et2Zn to chal-
cones. Excellent enantioselectivities (up to 96.1% ee)
have been obtained. Future studies will focus on the
development of new chiral P,N ligands derived from
MAP-type compound 6 and their applications in other
catalytic asymmetric reactions.
Table 1. Cu-catalyzed enantioselective 1,4-conjugate addition of Et2Zn to chalconea
Entry
Solvent
T (°C)
Time (h)
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
Toluene/Cl(CH2)2Cl (2/1)
Toluene/Cl(CH2)2Cl (1/1)
Cl(CH2)2Cl
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
−10
−10
−10
−10
10
12
12
12
12
12
12
12
12
9
75.2
62.4
30.1
80.4
71.8
78.2
57.9
32.3
80.3
81.0
76.4
93.4
93.6
90.3
93.1
89.0
91.0
89.6
86.8
91.9
91.6
92.6
0
−20
−30
−10
−10
−10
9
10
11
6
3
Toluene
a The reaction was carried out in 3 ml of solvent, chalcone (0.5 mmol)/[Cu(CH3CN)4]BF4/ligand 7a=1/0.01/0.025.
b Isolated yield.
c The ee values were determined by HPLC with a Daicel Chiralpak-AD column.

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Y. Liang et al. / Tetrahedron: Asymmetry 14 (2003) 3211–3217
Table 2. Cu-catalyzed enantioselective 1,4-conjugate addition of Et2Zn to chalconesa
Entry
R1
R2
7a
7b
(Config.)d
Yieldb (%)
E.e.c (%)
Yieldb (%)
Eec (%)
1
2
3
4
5
6
7
Ph
Ph
Ph
78.7
83.5
74.8
75.8
38.2
79.2
83.5
92.1
94.1
93.6
95.3
93.1
90.1
94.1
84.0
81.6
71.2
81.2
46.7
69.8
76.2
91.4
93.1
92.5
96.1
94.9
88.8
86.8
R
e
4-Me-C6H4
Ph
4-MeO-C6H4
Ph
4-Cl-C6H4
Ph
–
–
e
4-Me-C6H4
Ph
4-MeO-C6H4
Ph
R
e
+
–
+
e
e
4-Cl-C6H4
a The reaction was carried out at −10°C for 3 h in 3 ml of toluene, substrate (0.5 mmol)/[Cu(CH3CN)4]BF4/ligand 7=1/0.01/0.025.
b Isolated yield.
c The ee values were determined by HPLC with a Daicel Chiralpak-AD column.
d The absolute configuration was assigned by the comparison of the specific rotation with the reported data.
e Sign of the specific rotation of the addition product.
4. Experimental
4.1. General methods
eluent to give 2.3 g of 2a (96%) as a white solid: mp
150–152°C; [h]D23=−7.9 (c 0.5, THF); 1H NMR
(DMSO-d6) l 1.82 (s, 6H), 1.90 (s, 3H), 6.77–6.82 (m,
2H), 7.06–7.13 (m, 2H), 7.20 (t, J=7.6 Hz, 1H), 7.65
(d, J=7.0 Hz, 1H), 7.99 (s, 1H), 9.10 (s, 1H); 13C NMR
l 19.33, 19.70, 23.63, 113.20, 120.78, 121.11, 123.07,
125.72, 126.81, 128.45, 130.24, 136.05, 136.81, 137.46,
154.72, 168.20; HRMS (m/z): M+ calcd for C16H17NO2
255.1259; found, 255.1261.
Melting points were measured on a Yazawa micro
melting point apparatus (uncorrected). Optical rota-
tions were measured on a JASCO 1200 polarimeter. H
1
and 13C NMR spectra were recorded on a Bruker DRX
400 system with TMS as an internal reference. 31P
NMR spectra were recorded with 85% phosphoric acid
as the external standard. High resolution mass spectra
were recorded on Mat 95 (EI: 70 eV) for 2a–6a and on
ABMS 5303 (ESI) for 7a, 2b–7b. Enantiomeric excesses
(ee) were determined by HPLC analysis (Agilent 1100
series). All experiments were carried out under an argon
atmosphere. All solvents were dried with standard pro-
cedures before use.
4.3. (R)-(−)-2-(Acetamido)-2%-hydroxy-4,4%,6,6%-tetra-
methyl-1,1%-biphenyl 2b
Following the same method for the synthesis of 2a, 2b
(2.5 g) was obtained from 1b (2.4 g, 10 mmol) in 93%
yield as a white solid: mp 159–161°C; [h]2D3=−7.6 (c 0.5,
1
THF); H NMR (CDCl3) l 1.89 (s, 3H), 1.93 (s, 3H),
1.95 (s, 3H), 2.33 (s, 3H), 2.37 (s, 3H), 5.58 (br, 1H),
6.71 (s, 1H), 6.73 (s, 1H), 6.83 (s, 1H), 6.93 (s, 1H), 8.03
(s, 1H). 13C NMR l 19.38, 19.71, 21.34, 21.55, 21.62,
113.92, 118.38, 119.39, 120.94, 123.49, 127.28, 136.38,
137.73, 138.06, 139.21, 139.81, 153.13, 168.80; HRMS
(m/z): (M+1)+ calcd for C18H22NO2 284.1655; found,
284.1645.
4.2. (R)-(−)-2-(Acetamido)-2%-hydroxy-6,6%-dimethyl-
1,1%-biphenyl 2a
Acetyl chloride (2.2 g, 28.0 mmol) was slowly added to
a solution of 1a (2.0 g, 9.4 mmol) in 80 ml of dry
dichloromethane and 5 ml of pyridine at 0°C, with the
resulting mixture then stirred at room temperature for 2
h. The solvent was evaporated and the residue purified
by silica gel column with dichloromethane to give 2-
(acetamido)-2%-acetate-6,6%-dimethyl-1,1%-biphenyl (di-
4.4. (R)-(−)-2-(Acetamido)-2%-(trifluoromethylsulfonyl-
oxy)-6,6%-dimethyl-1,1%-biphenyl 3a
1
acetate): H NMR (CDCl3) l 1.87 (s, 3H), 1.91 (s, 3H),
Tf2O (2.7 g, 8.4 mmol) was slowly added to a solution
of 2a (2.0 g, 7.8 mmol) and 2 ml of pyridine in 35 ml of
dichloromethane at 0°C, and the mixture was stirred
for 3 h. The mixture was then diluted with 30 ml of
dichloromethane and washed with 5% HCl (2×20 ml),
20 ml of saturated NaHCO3 and 20 ml of water. The
organic phase was dried over anhydrous Na2SO4, con-
centrated under reduced pressure, and purified by silica
gel column with 5:1 petroleum ether−ethyl acetate as
eluent to give 2.9 g of 3a (96%) as a white solid: mp
1.94 (s, 3H), 1.95 (s, 3H), 6.98–7.00 (m, 2H), 7.05 (d,
J=7.2 Hz, 1H), 7.23–7.29 (m, 2H), 7.35 (t, J=8.0 Hz,
1H), 7.90 (d, J=7.2 Hz, 1H). The diacetate was dis-
solved in 100 ml of methanol, after which 15 ml of 1%
aqueous NaOH was added. The mixture was stirred at
room temperature for 2 h. The solvent was then evapo-
rated under reduced pressure and the residue extracted
with dichloromethane (3×30 ml). The combined
extracts were dried over anhydrous Na2SO4 and con-
centrated under reduced pressure, purified by silica gel
column with a 1:1 petroleum ether−ethyl acetate as
1
62–64°C; [h]2D3=−36.3 (c 0.5, THF); H NMR (DMSO-
d6) l 1.76 (s, 3H), 1.92 (s, 3H), 2.03 (s, 3H), 7.16 (d,

Y. Liang et al. / Tetrahedron: Asymmetry 14 (2003) 3211–3217
3215
J=7.0 Hz, 1H), 7.29–7.31 (m, 2H), 7.46–7.49 (m, 3H),
8.55 (s, 1H); 13C NMR l 19.29, 19.40, 23.06, 116.12,
118.31, 119.31, 123.03, 126.67, 127.81, 128.46, 129.57,
130.26, 136.35, 136.82, 140.98, 146.86, 168.16; HRMS
(m/z): M+ calcd for C17H16F3NO4S 387.0753; found,
387.0752.
1H); 13C NMR l 19.31, 19.66, 20.54, 20.75, 23.42,
124.65, 127.31, 127.73, 127.85, 128.48, 128.59, 130.16,
130.25, 130.51, 130.76, 130.87, 131.07, 131.33, 131.63,
131.71, 131.86, 132.11, 132.34, 134.95, 135.97, 136.37,
136.49, 136.74, 138.31, 138.39, 138.50, 138.60, 167.56;
31P NMR l 28.99; HRMS (m/z): (M+1)+ calcd for
C30H31NO2P 468.2108; found, 468.2087.
4.5. (R)-(−)-2-(Acetamido)-2%-(trifluoromethylsulfonyl-
oxy)-4,4%,6,6%-tetramethyl-1,1%-biphenyl 3b
4.8. (R)-(−)-2-Amino-2%-(diphenylphosphinyl)-6,6%-
dimethyl-1,1%-biphenyl 5a
Following the same method for the synthesis of 3a, 3b
(3.3 g) was obtained from 2b (2.3 g, 8.5 mmol) in 93%
yield as a yellow oil: [h]2D3=−38.4 (c 0.5, THF); 1H
NMR (CDCl3) l 1.90 (s, 3H), 1.94 (s, 3H), 1.99 (s, 3H),
2.37 (s, 3H), 2.43 (s, 3H), 6.78 (s, 1H), 6.94 (s, 1H), 7.04
(s, 1H), 7.20 (s, 1H), 7.28 (s, 1H), 7.77 (s, 1H); 13C
NMR l 19.45, 19.66, 21.03, 21.34, 24.19, 116.58,
119.58, 119.76, 121.16, 122.04, 127.24, 131.32, 135.49,
136.64, 138.98, 140.29, 140.70, 147.27, 168.30; HRMS
(m/z): (M+1)+ calcd for C19H21F3NO4S 416.1151;
found, 416.1138.
To a solution of 4a (2.6 g, 5.9 mmol) in 50 ml of
ethanol was added 50 ml of 50% aqueous KOH, the
reaction mixture was stirred under reflux for 12 h. After
cooling to room temperature, most of the ethanol was
removed under reduced pressure. 40 ml of water was
then added to the residue. The crude product was
extracted with dichloromethane (3×30 ml). The com-
bined extracts were washed with water (2×30 ml), then
dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel
column with 1:1 petroleum ether−ethyl acetate as eluent
to give 2.2 g of 5a (91%) as a white solid: mp 216–
218°C; [h]2D3=−87.9 (c 0.5, THF); 1H NMR (DMSO-d6)
l 1.54 (s, 3H), 1.84 (s, 3H), 3.92 (s, 2H), 6.18-6.22 (m,
2H), 6.69 (t, J=7.6 Hz, 1H), 7.18–7.24 (m, 1H), 7.32–
4.6. (R)-(−)-2-(Acetamido)-2%-(diphenylphosphinyl)-6,6%-
dimethyl-1,1%-biphenyl 4a
To a mixture of 3a (1.0 g, 2.6 mmol), diphenylphos-
phine oxide (1.0 g, 4.9 mmol), palladium(II) acetate
(112 mg, 0.5 mmol), and 1,4-bis(diphenylphos-
phino)butane (dppb, 213 mg, 0.5 mmol) was added 50
ml of DMSO and 1.5 ml of diisopropylethylamine with
the resulting mixture stirred at 120°C for 4 h. After
cooling to room temperature, the reaction mixture was
poured into 300 ml of 5% HCl with the product
extracted with dichloromethane (3×50 ml). The com-
bined extracts were washed with 1% HCl and water,
dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel
column with 1:1 petroleum ether–ethyl acetate as eluent
to give 1.0 g of 4a (86%) as a white solid: mp 166–
7.36 (m, 3H), 7.40–7.52 (m, 4H), 7.55–7.66 (m, 5H); 13
C
NMR l 19.07, 20.07, 112.47, 117.98, 123.64, 127.00,
127.13, 127.82, 127.93, 128.03, 128.15, 131.00, 131.17,
131.28, 131.36, 132.19, 132.34, 132.79, 133.21, 133.35,
133.80, 133.98, 136.03, 138.67, 138.77, 142.04, 142.12,
145.22; 31P NMR l 26.96; HRMS (m/z): M+ calcd for
C26H24NOP 397.1596; found, 397.1585; >99.5% ee.
HPLC analysis condition for racemic 5a: Chiralpak
AD, 80/20 hexanes/i-PrOH, 0.7 ml/min, 25°C, retention
time: tR=9.84 min; tS=11.98 min.
4.9. (R)-(−)-2-Amino-2%-(diphenylphosphinyl)-4,4%,6,6%-
tetramethyl-1,1%-biphenyl 5b
1
168°C; [h]2D3=−130.4 (c 0.5, THF); H NMR (DMSO-
d6) l 1.41 (s, 3H), 1.73 (s, 3H), 1.76 (s, 3H), 6.56 (d,
J=7.6 Hz, 1H), 7.04 (t, J=7.6 Hz, 1H), 7.16–7.30 (m,
4H), 7.39–7.48 (m, 4H), 7.55–7.62 (m, 4H), 7.86–7.90
(m, 2H), 9.03 (s, 1H); 13C NMR l 19.34, 19.67, 23.36,
124.32, 126.57, 127.56, 127.70, 127.80, 127.99, 128.11,
128.61, 128.72, 130.29, 130.38, 130.58, 130.99, 131.09,
131.31, 131.68, 131.77, 132.00, 133.59, 134.36, 136.05,
136.57, 138.47, 138.57, 141.10, 141.18, 167.71; 31P
Following the same method for the synthesis of 5a, 5b
(0.9 g) was obtained from 4b (1.1 g, 2.4 mmol) in 90%
yield as a white solid: mp 60–64°C; [h]2D3=−78.7 (c 0.5,
1
THF); H NMR (DMSO-d6) l 1.52 (s, 3H), 1.81 (s,
3H), 2.00 (s, 3H), 2.23 (s, 3H), 3.82 (s, 2H), 5.92 (s,
1H), 5.99 (s, 1H), 7.04 (d, J=13.8 Hz, 1H), 7.30–7.66
(m, 11H); 13C NMR l 19.10, 20.05, 20.81, 113.08,
119.04, 120.87, 127.57, 127.68, 127.93, 128.05, 130.65,
130.80, 130.89, 131.06, 131.26, 131.34, 131.71, 131.83,
132.24, 132.59, 133.11, 133.26, 134.69, 135.88, 136.36,
138.68, 138.79, 139.10, 145.11; 31P NMR l 27.15;
HRMS (m/z): (M+1)+ calcd for C28H29NOP 426.1956;
found, 426.1981.
NMR
l
29.13; HRMS (m/z): M+ calcd for
C28H26NO2P 439.1701; found, 439.1706; >99.5% ee.
HPLC analysis condition for racemic 4a: Chiralcel OD-
H, 90/10 hexanes/i-PrOH, 0.7 ml/min, 25°C, retention
time: tS=12.76 min; tR=16.40 min.
4.7. (R)-(−)-2-(Acetamido)-2%-(diphenylphosphinyl)-
4,4%,6,6%-tetramethyl-1,1%-biphenyl 4b
4.10. (R)-(−)-2-Amino-2%-(diphenylphosphino)-6,6%-
dimethyl-1,1%-biphenyl 6a
Following the same method for the synthesis of 4a, 4b
(1.0 g) was obtained from 3b (1.1 g, 2.7 mmol) in 81%
yield as a white solid: mp 180–182°C; [h]2D3=−94.3 (c
0.5, THF); 1H NMR (DMSO-d6) l 1.38 (s, 3H), 1.74 (s,
3H), 1.75 (s, 3H), 2.17 (s, 3H), 2.24 (s, 3H), 6.35 (s,
1H), 6.97–7.03 (m, 2H), 7.29–7.87 (m, 11H), 8.98 (s,
Trichlorosilane (3.0 g, 22.2 mmol) was added to a
mixture of 5a (870 mg, 2.2 mmol) and 4 ml of triethyl-
amine in 40 ml of xylene at 0°C, with the resulting
mixture heated to 120°C and stirred for 5 h. After
cooling to room temperature, the mixture was diluted
with dichloromethane and quenched with saturated

3216
Y. Liang et al. / Tetrahedron: Asymmetry 14 (2003) 3211–3217
NaHCO3. The resulting suspension was filtered through
Celite and the solid washed with dichloromethane. The
combined organic filtrates were dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The
residue was purified by silica gel column with 5:1
petroleum ether−ethyl acetate as eluent to give 600 mg
of 6a (72%) as a white solid: mp 122–124°C; [h]2D3=−
128.29, 128.59, 128.77, 129.00, 129.07, 131.45, 131.98,
132.81, 133.01, 133.26, 133.46, 135.27, 136.11, 136.23,
136.34, 137.09, 137.14, 138.01, 138.12, 138.27, 140.90,
141.22, 148.18, 156.51, 160.46; 31P NMR l −12.51;
HRMS (m/z): (M+1)+ calcd for C33H30N2OP 501.2075;
found, 501.2090.
1
83.9 (c 0.5, THF); H NMR (DMSO-d6) l 1.45 (s, 3H),
1.90 (s, 3H), 6.41 (d, J=7.2 Hz, 1H), 6.54 (d, J=8.0
Hz, 1H), 6.92–6.96 (m, 2H), 7.10–7.14 (m, 4H), 7.28–
7.38 (m, 8H); 13C NMR l 19.35, 19.57, 112.22, 117.92,
124.43, 124.50, 127.64, 127.82, 128.10, 128.39, 128.62,
131.17, 131.96, 132.58, 132.78, 133.44, 133.64, 135.76,
136.78, 136.92, 137.09, 137.14, 137.49, 137.58, 138.16,
138.30, 143.36, 143.69, 144.67; 31P NMR l −12.97;
HRMS (m/z): M+ calcd for C26H24NP 381.1647; found,
381.1629; >99.5% ee. HPLC analysis condition for
racemic 6a: Chiralpak AD, 80/20 hexanes/i-PrOH, 0.7
ml/min, 25°C, retention time: tR=5.20 min; tS=6.40
min.
4.13. (R)-(−)-2-(6-Methyl-2-pyridinylcarboxamido)-2%-
(diphenylphosphino)-4,4%,6,6%-tetramethyl-1,1%-biphenyl
7b
Following the same method for the synthesis of 7a, 7b
(326 mg) was obtained from 6b (330 mg, 0.73 mmol) in
84% yield as a white solid: mp 158–160°C; [h]2D3=−
1
180.9 (c 0.5, THF); H NMR (DMSO-d6) l 1.73 (s,
3H), 1.84 (s, 3H), 2.16 (s, 3H), 2.27 (s, 3H), 2.35 (s,
3H), 6.82–6.92 (m, 6H), 7.03–7.12 (m, 3H), 7.32–7.37
(m, 4H), 7.45 (d, J=7.6 Hz, 1H), 7.80–7.82 (m, 1H),
7.90 (t, J=7.6 Hz, 1H), 8.21 (s, 1H), 9.74 (s, 1H); 13C
NMR l 19.39, 19.68, 20.87, 21.32, 23.06, 116.13,
118.54, 125.67, 126.24, 127.76, 128.20, 128.60, 128.74,
132.36, 132.51, 132.67, 132.87, 133.24, 133.44, 135.32,
136.13, 136.47, 136.58, 137.13, 137.54, 137.88, 137.99,
138.20, 138.36, 138.52, 148.24, 156.46, 160.33; 31P
NMR l –12.65; HRMS (m/z): (M+1)+ calcd for
C35H34N2OP 529.2427; found, 529.2403.
4.11. (R)-(−)-2-Amino-2%-(diphenylphosphino)-4,4%,6,6%-
tetramethyl-1,1%-biphenyl 6b
Following the same method for the synthesis of 6a, 6b
(534 mg) was obtained from 5b (770 mg, 1.8 mmol) in
72% yield as a white solid: mp 58–62°C; [h]2D3=−78.4 (c
0.5, THF); 1H NMR (DMSO-d6) l 1.43 (s, 3H), 1.86 (s,
3H), 2.15 (s, 3H), 2.16 (s, 3H), 3.92 (s, 2H), 6.23 (s,
1H), 6.36 (s, 1H), 6.78 (s, 1H), 7.12–7.17 (m, 5H),
7.29–7.32 (m, 6H); 13C NMR l 19.37, 19.59, 20.83,
21.04, 112.81, 119.03, 121.84, 121.91, 128.01, 128.33,
132.13, 132.35, 132.57, 132.77, 133.35, 133.55, 135.74,
136.31, 137.12, 137.20, 137.41, 137.51, 138.42, 138.57,
140.70, 141.04, 144.71; 31P NMR l –13.22; HRMS
(m/z): (M+1)+ calcd for C28H29NP 410.2027; found,
410.2032.
4.14. General procedure for asymmetric 1,4-conjugate
additions
Preparation of catalyst. 7a (50.2 mg, 0.10 mmol),
[Cu(CH3CN)4]BF4 (12.6 mg, 0.04 mmol), and 8 ml of
toluene were added to a 25 ml flame-dried Schlenk tube
under an argon atmosphere. After 30 min of stirring at
room temperature, the solvent was stripped off in vacuo
8 ml of CH2Cl2 was then added to the flask and the
catalyst solution used for four separated conjugate
addition reactions. Asymmetric 1,4-conjugate addition.
The chalcone substrate (1 mmol) and 1 ml of the above
prepared catalyst solution were added to a flame-dried
Schlenk tube under an argon atmosphere. After the
solvent had been stripped off, 3 ml of toluene was
added. The slurry was stirred at room temperature for
10 min and then cooled to the desired temperature.
After the slurry had been stirred for 15 min, 0.7 ml of
Et2Zn (1.1 M in toluene, 1.5 equiv.) was added slowly.
The resulting mixture was stirred at that temperature
for 3 h. 4 ml of 5% hydrochloric acid was added to
quench the reaction. The mixture was then allowed to
warm to room temperature after which 15 ml of diethyl
ether was added. The organic layer was washed with 5
ml of saturated NaHCO3 and 5 ml of brine and then
dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and the residue
purified by silica gel column and eluted with EtOAc/
hexanes (1/40–1/20) to afford the addition product. The
enantiomeric excesses (ees) were determined by HPLC
with a Chiral Daicel Chiralpak AD column. The
detailed analytical conditions are given in the Support-
ing Information of reference 2a.
4.12. (R)-(−)-2-(6-Methyl-2-pyridinylcarboxamido)-2%-
(diphenylphosphino)-6,6%-dimethyl-1,1%-biphenyl 7a
A mixture of 6-methylpicolinic acid (345 mg, 2.5 mmol)
and 6a (800 mg, 2.1 mmol) in 10 ml of THF was stirred
at room temperature for 10 min. DMTMM (700 mg,
2.5 mmol) was added to the mixture and stirred at
room temperature. After the reaction was complete
(detected by TLC), 10 ml of water was added into the
reaction mixture. After separating the layers, the
aqueous layer was extracted with diethyl ether (3×20
ml), the combined organic layers successively washed
with saturated NaHCO3, brine, 5% HCl and brine, then
dried over anhydrous Na2SO4. The solvent was concen-
trated under reduced pressure. The residue was purified
by silica gel column with 10:1 petroleum ether−ethyl
acetate as eluent to give 861 mg of 7a (82%) as a white
1
solid: mp 104–106°C; [h]2D3=−176.6 (c 0.5, THF); H
NMR (DMSO-d6) l 1.76 (s, 3H), 1.89 (s, 3H), 2.18 (s,
3H), 6.85–6.91 (m, 4H), 7.03–7.11 (m, 5H), 7.33–7.37
(m, 4H), 7.44–7.51 (m, 3H), 7.82–7.90 (m, 2H), 8.36 (d,
J=8.0 Hz, 1H), 9.73 (s, 1H); 13C NMR l 19.35, 19.70,
23.37, 115.66, 118.58, 124.94, 126.21, 127.79, 127.85,

Y. Liang et al. / Tetrahedron: Asymmetry 14 (2003) 3211–3217
3217
Acknowledgements
Swingle, H. M. Chem. Rev. 1992, 92, 771 and references
cited therein.
This work was supported by the National Natural
Science Foundation of China (29933050) and the
Young Faculty Research Fund of DICP.
5. For phosphorus-amidites ligands, see: (a) Zhou, H.;
Wang, W.-H.; Fu, Y.; Xie, J.-H.; Shi, W.-J.; Wang,
L.-X.; Zhou, Q.-L. J. Org. Chem. 2003, 68, 1582; (b)
Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J.
Am. Chem. Soc. 2002, 124, 5262; (c) Martorell, A.;
Naasz, R.; Feringa, B. L.; Rringle, P. G. Tetrahedron:
Asymmetry 2001, 12, 2497; (d) Naasz, R.; Arnold, L. A.;
Pineschi, M.; Keller, E.; Feringa, B. L. J. Am. Chem. Soc.
1999, 121, 1104; (e) Feringa, B. L.; Pineschi, M.; Arnold,
L. A.; Imbos, R.; de Vries, A. H. M. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2620; (f) de Vries, A. H. M.; Mettsma,
A.; Feringa, B. L. Angew. Chem., Int. Ed. Engl. 1996, 35,
2374.
References
1. (a) Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed.;
VCH: Weinheim, Germany, 1999; (b) Comprehensive
Asymmetric Catalysis I–III. Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: Berlin, Germany, 1999;
(c) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994.
6. For monophosphite ligands, see: (a) Alexakis, A.; Vastra,
J.; Burton, J.; Benhaim, C.; Mangency, P. Tetrahedron
Lett. 1997, 39, 7869. (b) Alexakis, A.; Vastra, J.; Burton,
J.; Mangency, P. Tetrahedron: Asymmetry 1997, 8, 3193.
7. For diphosphine ligands, see: Yamanoi, Y.; Imamoto, T.
J. Org. Chem. 1999, 64, 2988.
8. For diphosphite ligands, see: (a) Reetz, M. T.; Gosberg,
A.; Moulin, D. Tetrahedron Lett. 2002, 43, 1189; (b)
Liang, L.; Au-Yeung, T. T.-L.; Chan, A. S. C. Org. Lett.
2002, 4, 3799; (c) Yan, M.; Zhou, Z.-Y.; Chan, A. S. C.
Chem. Commun. 2000, 115; (d) Yan, M.; Chan, A. S. C.
Tetrahedron Lett. 1999, 40, 6645; (e) Yan, M.; Yang,
L.-W.; Wong, K.-Y.; Chan, A. S. C. Chem. Commun.
1999, 11.
9. For P, N ligands, see: (a) Hird, A. W.; Hoveyda, A. H.
Angew. Chem.; Int. Ed. Engl. 2003, 42, 1276; (b) Degrado,
S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc.
2002, 124, 13362; (c) Shintani, R.; Fu, G. C. Org. Lett.
2002, 4, 3699; (d) Mizutani, H.; Degrado, S. J.; Hoveyda,
A. H. J. Am. Chem. Soc. 2002, 124, 779; (e) Alexakis, A.;
Rosset, S.; Allamand, J.; March, S.; Guillen, F.; Ben-
haim, C. Synlett 2001, 1375; (f) Degrado, S. J.; Mizutani,
H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755; (g)
Escher, I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879; (h)
Knobel, A. K. H.; Escher, I. H.; Pfaltz, A. Synlett 1997,
1429; (i) Strangeland, E. L.; Sammakia, T. Tetrahedron
1997, 53, 16503.
2. (a) Hu, Y.; Liang, X.; Wang, J.; Zheng, Z.; Hu, X. J.
Org. Chem. 2003, 68, 4542; (b) Yuan, Y.; Li, X.; Sun, J.;
Ding, K. J. Am. Chem. Soc. 2002, 124, 14866; (c) Yuan,
Y.; Long, J.; Sun, J.; Ding, K. Chem. Eur. J. 2002, 8,
5033; (d) Hamada, T.; Buchwald, S. L. Org. Lett. 2002, 4,
999; (e) Chieffi, A.; Kamikawa, K.; Ahman, J.; Fox, J.
M.; Buchwald, S. L. Org. Lett. 2001, 3, 1897; (f) Belokon,
Y. N.; Kochetkov, K. A.; Churkina, T. D.; Ikonnikov,
N. S.; Larionov, O. V.; Harutyunyan, S. R.; Vyskocil, S.;
North, M.; Kagan, H. B. Angew. Chem., Int. Ed. Engl.
2001, 40, 1948; (g) Lloyd-Jones, G. C.; Stephen, S. C.;
Murray, M.; Butts, C. P.; Vyskocil, S.; Kovovsky, P.
Chem. Eur. J. 2000, 6, 4348; (h) Yin, J.; Buchwald, S. L.
J. Am. Chem. Soc. 2000, 122, 12051; (i) Kocovsky, P.;
Vyskocil, S.; Cisarova, I.; Sejbal, J.; Tislerova, I.;
Smrcina, M.; Lloyd-Jones, G. C.; Stephen, S. C.; Butts,
C. P.; Murray, M.; Langer, V. J. Am. Chem. Soc. 1999,
121, 7714; (j) Vsykocil, S.; Jaracz, S.; Smrcina, M.;
Sticha, M.; Hanus, V.; Polasek, M.; Kocovsky, P. J. Org.
Chem. 1998, 63, 7727; (k) Singer, R. A.; Carreira, E. M.
J. Am. Chem. Soc. 1995, 117, 12360; (l) Carreira, E. M.;
Lee, W.; Singer, R. A. J. Am. Chem. Soc. 1995, 117,
3649; (m) Carreira, E. M.; Singer, R. A.; Lee, W. J. Am.
Chem. Soc. 1994, 116, 8837.
3. (a) Wang, Y.; Li, X.; Ding, K. Tetrahedron Lett. 2002,
43, 159; (b) Wang, Y.; Guo, H.; Ding, K. Tetrahedron:
Asymmetry 2000, 11, 4153; (c) Ding, K.; Wang, Y.; Yun,
H.; Liu, J.; Wu, Y.; Terada, M.; Okubo, Y.; Mikami, K.
Chem. Eur. J. 1999, 5, 1734; (d) Hu, X.; Chen, H.;
Zhang, X. ACTA CHIMICA SINICA 2000, 58, 1163; (e)
Hu, X.; Chen, H.; Zhang, X. ACTA CHIMICA SINICA
2000, 58, 1156; (f) Hu, X.; Chen, H.; Zhang, X. Angew.
Chem., Int. Ed. Engl. 1999, 38, 3518; (g) Vsykocil, S.;
Jaracz, S.; Smrcina, M.; Sticha, M.; Hanus, V.; Polasek,
M.; Kocovsky, P. J. Org. Chem. 1998, 63, 7738.
10. Wan, H.; Hu, Y.; Liang, Y.; Gao, S.; Wang, J.; Zheng,
Z.; Hu, X. J. Org. Chem., in press.
11. Liang, Y.; Gao, S.; Wan, H.; Wang, J.; Chen, H.; Zheng,
Z.; Hu, X. Tetrahedron: Asymmetry 2003, 14, 1267.
12. Kunishima, M.; Kawachi, C.; Iwasaki, F.; Terao, K.;
Tani, S. Tetrahedron Lett. 1999, 40, 5327.
13. Schmid, R.; Cereghetti, M.; Heiser, B.; Schonholzer, P.;
Hansen, H. J. Helv. Chim. Acta 1988, 71, 897.
14. (a) Fraser, P. K.; Woodward, S. Chem. Eur. J. 2003, 9,
776; (b) Bennett, S. M. W.; Brown, S. M.; Cunninghan,
A.; Dennis, M. R.; Muxworthy, J. P.; Woodward, S.
Tetrahedron 2000, 56, 2847; (c) Bennett, S. M. W.;
Brown, S. M.; Muxworthy, J. P.; Woodward, S. Tetra-
hedron Lett. 1999, 40, 1767.
4. For reviews, see: (a) Alexakis, A.; Benhaim, C. Eur. J.
Org. Chem. 2002, 3221; (b) Krause, N.; Roder. A. H.
Synthesis 2001, 171; (c) Feringa, B. L. Acc. Chem. Res.
2000, 33, 346; (d) Krause, N. Angew. Chem., Int. Ed.
Engl. 1998, 37, 283; (e) Krause, N.; Gerold, A. Angew.
Chem., Int. Ed. Engl. 1997, 36, 186; (f) Rossiter, B. E.;