Highly enantioselective 1,4-conjugate addition of diethylzinc to acyclic enones with chiral phosphite-pyridine ligands derived from H8-NOBIN

Article abstract of DOI:10.1016/j.tetasy.2003.09.020

A series of new phosphite-pyridine ligands, based on the H ₈-binaphthyl backbone, were synthesized and employed in the copper-catalyzed enantioselective 1,4-conjugate addition of diethylzinc to acyclic enones. Ligands derived from (S)-H₈

Full text of DOI:10.1016/j.tetasy.2003.09.020

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3907–3915
Highly enantioselective 1,4-conjugate addition of diethylzinc to
acyclic enones with chiral phosphite–pyridine ligands derived
from H8-NOBIN
Yuanchun Hu, Xinmiao Liang, Junwei Wang, Zhuo Zheng and Xinquan Hu*
Dalian Institute of Chemical Physics, the Chinese Academy of Sciences, Dalian 116023, PR China
Received 29 August 2003; accepted 8 September 2003
Abstract—A series of new phosphite–pyridine ligands, based on the H8-binaphthyl backbone, were synthesized and employed in
the copper-catalyzed enantioselective 1,4-conjugate addition of diethylzinc to acyclic enones. Ligands derived from (S)-H8-NOBIN
provided better results than their parent ligands in the reaction. Ligand L1 provided excellent ees for trans-4-aryl-3-buten-2-ones
(up to 97.8% ee) as substrates. Ligand L2 was very efficient for various para-chalcones, and up to 97.2% ee was achieved.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
ligands have played very important roles in the success-
ful applications of 1,4-conjugate addition of Et2Zn to
cyclic enones, where a few of them obtained good
results for acyclic enones.8d,f–j However, very few lig-
ands can provide high enantioselectivities for both chal-
cones and trans-4-aryl-3-buten-2-ones.8i
The enantioselective 1,4-conjugate addition of
organometallic reagents to enones is an attractive
method for carbonꢀcarbon bond formation.1 Although
highly stereoselective 1,4-conjugate additions have been
reported with the use of some chiral auxiliaries and
stoichiometric reagents, the development of a stereose-
lective catalytic version of this transformation has
recently gained much attention. The Cu-catalyzed enan-
tioselective 1,4-conjugate addition of organozinc
reagents to enones using chiral trivalent phosphorus
ligands, originally introduced by Alexakis,2 has there-
fore been investigated extensively.3 A number of chiral
phosphorus ligands, such as phosphoramidites,4 phos-
phites,5 aryl diphosphites,6 MiniPHOS7 and other chiral
P,N ligands,8 have been reported and successfully
applied in the reaction. In recent years, phosphorus
Recently, we synthesized chiral phosphite–pyridine lig-
ands of type 1, derived from (S)-2-amino-2%-hydroxy-
1,1%-binaphthyl (NOBIN) and (S)-2,2%-dihydroxy-
1,1%-binaphthyl (BINOL), and obtained high enantiose-
lectivities in the Cu(I)-catalyzed 1,4-conjugate additions
of Et2Zn to acyclic enones.9 However, ligand 1 did not
provide satisfactory enantioselectivities for 4%-methoxy-
chalcone and 4%-methylchalcone. The substrate limita-
tion has very recently been overcome by using relatively
electron-rich phosphite–pyridine ligands 2 (Fig. 1).10
The results from ligands 1 and ligands 2 showed that
the electronic properties of the ligands played very
important role in the Cu-catalyzed 1,4-conjugate addi-
tion. This prompted us to modify the electronic prop-
erty of ligands 1. Partial hydrogenation of binaphthyl
rings was one of the most convenient and effective
methods. In fact, some chiral catalysts based on
5,5%,6,6%,7,7%,8,8%-octahydro-1,1%-binaphthyl
(H8-1,1%-
binaphthyl) have exhibited higher catalytic ability than
their parent ligands from 1,1%-binaphthyl in some asym-
metric reactions.6a,b,11–13
Figure 1.
We herein report the synthesis of a series of new
phosphite–pyridine ligands L1–6 derived from 2-amino-
2%-hydroxy-5,5%,6,6%,7,7%,8,8%-octahydro-1,1%-binaphthyl
* 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.2003.09.020

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Y. Hu et al. / Tetrahedron: Asymmetry 14 (2003) 3907–3915
Scheme 1. Synthesis of phosphite–pyridine ligands L1–6.
(H8-NOBIN) and/or 2,2%-dihydroxy-5,5%,6,6%,7,7%,8,8%-
octahydro-1,1%-binaphthyl (H8-BINOL). We envisioned
that new ligands would be efficient for the 1,4-conju-
gate addition of Et2Zn to acyclic enones due to the
relatively electron-rich H8-binaphthyl moieties.
while the amides (S)-3c and (S)-3d had been described
in previous report.9 The phosphite–pyridine ligands
(S,S)-L1 and (S,S)-L2 were subsequently obtained in
high yields by refluxing the amide 3a or 3b and (S)-
MonoPhos in toluene. Ligands L3–6 were prepared
with the similar method, but (S)-H8-MonoPhos was
prepared from (S)-H8-BINOL and hexamethylphos-
phorous triamide (HMPT) and directly used.
2. Results and discussion
2.1. Synthesis of phosphite–pyridine ligands L1–6
2.2. Enantioselective 1,4-conjugate addition of Et2Zn to
enones
In our previous study of the application of ligands 1 in
Cu(I)-catalyzed enantioselective 1,4-addition of Et2Zn
to various enones, we found (S)-NOBIN and (S)-
Chalcone was chosen as the substrate to optimize the
reaction temperature for the asymmetric 1,4-conjugate
addition (Table 1). [Cu(CH3CN)4]BF4 was selected as
the metal precursor because of its high performance in
the addition reaction.9,10,15 The 1,4-conjugate additions
of Et2Zn to chalcone were conducted in the presence of
1 mol% of [Cu(CH3CN)4]BF4 and 2.5 mol% of L2. As
shown in Table 1, the reaction temperature between
−30 to 0°C had slight effect on the enantioselectivity of
the addition products, and the best ee (93.8%) was
achieved when the reaction temperature was −20°C
(entry 3).
BINOL
moieties
were
matched
for
high
enantioselectivity9 and a 6-methyl group of the pyridine
moiety of the ligand was helpful for obtaining high
enantioselectivities for chalcones but deleterious for
trans-4-aryl-3-buten-2-ones.9,10 Herein, we therefore
focus on the syntheses and applications of new P,N
ligands from (S)-H8-NOBIN and/or (S)-H8-BINOL
with or without a 6-methyl group of the pyridine ring.
As shown in Scheme 1, ligands L1–6 can be conve-
niently synthesized in two steps from (S)-NOBIN or
(S)-H8-NOBIN and (S)-MonoPhos or (S)-H8-
MonoPhos.9 Amidation of (S)-H8-NOBIN with 2-
picolinic acids in the presence of 4-(4,6-dimethoxy-
The ligands L1–6 were thus used in Cu(I)-catalyzed
1,4-conjugate additions of Et2Zn to three types of
enones: para-substituted chalcones, trans-aryl-3-buten-
2-ones, and cyclic enones. In a typical procedure, 1
mol% of Cu(CH3CN)4BF4 and 2.5 mol% of chiral
1,3,5-triazin-2-yl)-4-methylmorpholinium
chloride
(DMTMM)14 as the condensation reagent proceeded
smoothly to provide amides 3a and 3b in high yields,

Y. Hu et al. / Tetrahedron: Asymmetry 14 (2003) 3907–3915
3909
Table 1. Cu-catalyzed enantioselective 1,4-conjugate addition of Et2Zn to chalconea
Entry
T [°C]
Yield (%)b
Ee (%)c
Config.d
1
2
3
4
0
−10
−20
−30
67.4
67.4
71.5
77.6
91.0
92.6
93.8
91.8
S
S
S
S
a The reaction was carried out for 12 h in 1.5 ml toluene, chalcone (0.5 mmol)/[Cu(CH3CN)4]BF4/ligand L2=1/0.01/0.025, Et2Zn:substrate=1.5:1.
b Isolated yield.
c The ee values were determined by HPLC with a ChiralPak-AD column.
d The absolute configuration was assigned by comparison of the specific rotation with reported data.
ligand were applied in the addition reactions of Et2Zn
to enones, with a ratio of 1.5:1 of Et2Zn to enone
substrate. The reactions were carried out in toluene at
–20°C for 12 h.
of Et2Zn to 2-cyclohexen-1-one and 2-cyclohepten-1-
one (Table 4). However, all ligands were not as efficient
as in the reaction to acyclic enones.
The results of ligands L1–6 in the 1,4-conjugate addi-
tions of Et2Zn to various para-substituted chalcones
(Table 2) showed the structure with partial hydrogena-
tion in (S)-NOBIN unit was efficient. Ligand L1 gave
high enantioselectivities and the more sterically hin-
dered ligand L2 was better, which was consistent with
previous report.9,10 Compared with its parent ligand 1b,
ligand L2 gave different results. When 4%-methoxy-chal-
cone was used as substrate, the ee of addition product
was significantly improved from 73.6 to 92.2% although
it provided a relatively lower ee (85.6 versus 95.3%) for
4%-chloro-chalcone. Ligand L3 based on (S)-H8-BINOL
unit also provided good enantioselectivities for some
chalcone substrates, but ligand L4 gave only moderate
enantioselectivities for all para-substituted chalcones.
However, ligands L5–6, with both (S)-H8-BINOL and
(S)-H8-NOBIN moieties, only showed poor to moder-
ate activities and enantioselectivities. The results with
ligand L6 was similar to those from L4, while L5 was
nearly ineffective in the 1,4-conjugate additions.
3. Conclusion
We have synthesized six new phosphite–pyridine lig-
ands in two steps based on relative electron-rich H8-
binaphthyl backbone, and employed in the
Cu(I)-catalyzed enantioselective 1,4-conjugate additions
of diethylzinc to acyclic enones. The results showed the
partial reduction in NOBIN backbone was helpful for
obtaining high ee in the 1,4-conjugate addition reac-
tions. Ligand L2 was very efficient for various para-
substitute chalcones (up to 97.2% ee), while L1 showed
high enantioselectivities for trans-4-aryl-3-buten-2-one
as substrates (up to 97.8% ee). This is the best result for
the enantioselective 1,4-conjugate additions of Et2Zn to
trans-4-aryl-3-buten-2-ones to date.
4. Experimental
4.1. General
Under the same reaction conditions, ligands L1–6 were
also employed in Cu(I)-catalyzed 1,4-conjugate addi-
tions of Et2Zn to some trans-4-aryl-3-buten-2-ones
(Table 3). As illustrated in Table 3, ligand L1 showed
good catalytic activity and enantioselectivity. When
trans-(4-chloro-phenyl)-3-buten-2-one was used as sub-
strate, up to 97.8% ee was achieved. To the best of our
knowledge, this is the best result for the enantioselective
1,4-conjugate addition of Et2Zn to trans-4-aryl-3-
buten-2-one to date. The results from more sterically
hindered ligand L2 were accordance with the previous
reports, only afforded moderate ees in low chemical
yields.9,10 Ligands L3–6 with an (S)-H8-BINOL moiety
were much less efficient in the 1,4-conjugate addition of
Et2Zn to trans-4-aryl-3-buten-2-ones.
Melting points were measured on a Yazawa micro
melting point apparatus (uncorrected). Optical rota-
1
tions were measured on a JASCO 1200 polarimeter. H
and 13C NMR spectra were recorded on a BRUKER
DRX 400 system with TMS as an internal standard. 31
P
NMR spectra were recorded with 85% phosphoric acid
as the external standard. The ee values were determined
by HPLC with a Daicel ChiralPak-AD column or by
GC with a Supelco g-DEX 225 column. High resolu-
tion mass spectra (HRMS) were recorded on ABMS
5303 (ESI). All experiments were carried out under an
argon atmosphere using standard Schlenk techniques.
All solvents were dried before use according to stan-
dard procedures and stored under argon. (S)-BINOL
was purchased from Nanjing University, NOBIN,16
(S)-H8-NOBIN17 and (S)-H8-BINOL18 were prepared
according to literature procedure. (S)-MonoPhos19 was
synthesized and isolated according to literature proce-
To expand the substrate scope of the 1,4-conjugate
addition, we also applied these ligands in the reactions

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Y. Hu et al. / Tetrahedron: Asymmetry 14 (2003) 3907–3915
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Y. Hu et al. / Tetrahedron: Asymmetry 14 (2003) 3907–3915
Table 4. Cu-catalyzed enantioselective 1,4-conjugate addition of Et2Zn to cyclic enonesa
Entry
Ligand
n=1
n=2
Conv. (%)b
Ee (%)c
Conv. (%)b
Ee (%)c
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
76.0
53.3
38.3
60.0
77.8
67.3
22.2
29.3
30.7
65.3
23.8
14.2
44.0
50.2
56.0
22.0
47.5
33.5
8.3
13.9
23.7
49.3
19.4
18.6
a The reaction was carried out at −20°C for 12 h in 1.5 ml of toluene, substrate (0.5 mmol)/[Cu(CH3CN)4BF4/L=1/0.01/0.025, Et2Zn:substrate=
1.5:1.
b Isolated yield.
c The ee value was determined by GC with a Chiral capillary gamma-225 column.
dure. (S)-H8-MonoPhos was prepared according to the
same method as for the synthesis of (S)-MonoPhos and
directly used for the synthesis of ligands.
3b. Following the same method for the synthesis of 3a,
amide 3b (0.961 g, 95%) was prepared from 6-methyl-
picolinic acid (0.411 g, 3.0 mmol) and (S)-H8-NOBIN
(0.714 g, 2.4 mmol) as a white solid: mp 227–229°C;
[h]2D2=–119.1 (c 0.5, CHCl3); 1H NMR (CH2Cl2) l
1.61–1.77 (m, 8H), 2.16–2.35 (m, 7H), 2.78–2.80 (m,
4H), 4.90 (s, 1H), 6.83 (d, J=8.4 Hz, 1H), 7.12 (d,
J=8.4 Hz, 1H), 7.18 (d, J=8.0 Hz, 2H), 7.65 (t, J=7.6
Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 8.45 (d, J=8.4 Hz,
1H), 10.03 (s, 1H); 13C NMR (CH2Cl2) l 23.46, 23.69,
24.09, 27.75, 29.93, 30.09, 113.58, 117.35, 119.15,
121.69, 124.19, 126.24, 130.57, 131.10, 134.32, 134.91,
137.07, 137.30, 138.08, 149.68, 151.45, 157.60, 162.25;
HRMS (m/z): (M++1) calcd for C27H29N2O2 413.2224;
found, 413.2210.
4.2. Synthesis of phosphite–pyridine ligands
4.2.1. Synthesis of amides
4.2.1.1.
(S)-(–)-2-(2-Pyridinylcarboxamido)-2%-
hydroxy-5,5%,6,6%,7,7%,8,8%-octahydro-1,1%-binaphthyl 3a.
A mixture of picolinic acid (1.230 g, 10.0 mmol) and
(S)-H8-NOBIN (0.877 g, 3.0 mmol) in 25 ml of THF
was stirred at room temperature for 10 min. Condensa-
tion agent DMTMM (0.910 g, 3.3 mmol) was added to
the mixture and stirred at room temperature. After the
reaction was complete (detected by TLC), 20 ml of
water was added into the reaction mixture. The two
layers were seperated, and the aqueous layer was
extracted with diethyl ether (3×20 ml). The combined
organic layers were subsequentially washed with 5 ml of
saturated NaHCO3, brine, 5% HCl and brine, then
dried over anhydrous Na2SO4. The solvent was concen-
trated under reduced pressure. The residue was chro-
matographed on a silica gel column (eluted with
CH2Cl2) to afford 1.154 g (96%) of amide 3a as a white
4.2.2. Synthesis of the ligands
4.2.2.1. (S,S)-(+)-L1. Amide 3a (438.0 mg, 1.1
mmol), (S)-MonoPhos (514.0 mg, 1.4 mmol) and 10 ml
of xylene were added to 50 ml air-free Schlenk flask
with a reflux condenser under an argon atmosphere.
The mixture was heated to reflux. After the reaction
was complete (detected by TLC), the reation solution
was cooled to room temperature and purified by flash
chromatograghy on a silica gel column (eluted with
hexanes/CH2Cl2 (1/1)) to afford 744.0 mg (95%) of
(S,S)-L1 as a white foamy solid: mp 252–255°C; [h]2D2=
1
solid: mp 187–189°C; [h]2D1=–113.9 (c 0.5, CHCl3); H
NMR (CD2Cl2) l 1.57–1.78 (m, 8H), 2.12–2.26 (m,
3H), 2.34–2.41 (m, 1H), 2.76–2.82 (m, 4H), 5.06–5.10
(m, 1H), 6.82 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz,
1H), 7.17 (d, J=8.4 Hz, 1H), 7.31–7.34 (m, 1H), 7.76–
7.80 (m, 1H), 8.10 (d, J=7.6 Hz, 1H), 8.25 (d, J=4.4
Hz, 1H), 8.37 (d, J=8.4 Hz, 1H), 9.79 (s, 1H); 13C
NMR (CD2Cl2) l 23.61, 23.85, 27.92, 30.08, 30.29,
113.83, 118.26, 121.94, 122.53, 125.29, 126.85, 130.64,
130.89, 131.10, 134.86, 137.04, 137.54, 138.17, 148.60,
150.71, 151.58, 162.56; HRMS (m/z): (M++1) calcd for
C26H27N2O2 399.2067; found 399.2074.
1
+177.3 (c 0.5, THF); H NMR (CD2Cl2) l 1.64–1.78
(m, 8H), 2.16–2.46 (m, 4H), 2.84–2.86 (m, 4H), 6.78 (d,
J=8.4 Hz, 1H), 7.14–7.31 (m, 8H), 7.36–7.43 (m, 3H),
7.71–7.74 (m, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.86–7.96
(m, 3H), 8.10 (d, J=7.6 Hz, 1H), 8.18 (d, J=4.4 Hz,
1H), 8.47 (d, J=8.4 Hz, 1H), 9.69 (s, 1H); 13C NMR
(CD2Cl2) l 23.55, 23.66, 23.83, 28.05, 28.67, 30.33,
30.38, 117.99, 119.28, 119.36, 122.38, 122.68, 123.28,
124.92, 125.60, 125.84, 126.63, 126.75, 126.88, 126.99,
127.28, 127.45, 128.40, 129.07, 130.04, 130.40, 130.94,
131.02, 131.93, 132.30, 132.98, 133.40, 134.33, 134.72,
135.70, 136.87, 138.01, 138.69, 147.86, 148.29, 148.47,
150.86, 162.21; 31P NMR l +145.77; HRMS (m/z):
4.2.1.2. (S)-(–)-2-(6-Methyl-2-pyridinylcarboxamido)-
2%-hydroxy-5,5%,6,6%,7,7%,8,8%-octahydro-1,1%-binaphthyl

Y. Hu et al. / Tetrahedron: Asymmetry 14 (2003) 3907–3915
3913
(M++1) calcd for C46H38N2O4P 713.2564; found,
(s, 3H), 2.02–2.11 (m, 2H), 2.49–2.74 (m, 6H), 6.06 (d,
J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.83 (d, J=8.0
Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 7.06 (d, J=7.6 Hz,
1H), 7.18–7.30 (m, 4H), 7.39–7.46 (m, 2H), 7.57–7.61
(m, 2H), 7.87 (d, J=7.6 Hz, 1H), 7.96–8.02 (m, 2H),
8.12–8.18 (m, 2H), 9.09 (d, J=9.2 Hz, 1H), 10.16 (s,
1H); 13C NMR (CD2Cl2) l 22.88, 23.06, 23.87, 28.12,
29.52, 119.13, 119.22, 119.76, 120.28, 122.17, 122.24,
122.85, 125.30, 125.96, 126.04, 126.25, 127.19, 127.93,
128.66, 128.83, 129.53, 129.78, 130.04, 131.32, 132.00,
133.84, 134.17, 134.70, 135.66, 136.18, 137.83, 137.99,
138.98, 145.70, 146.06, 149.09, 149.32, 157.36, 162.15;
31P NMR l +136.87; HRMS (m/z): (M++1) calcd for
C47H40N2O4P 727.2720; found, 727.2703.
713.2590.
4.2.2.2. (S,S)-(+)-L2. Following the similar method
for the synthesis of L1, Ligand L2 (704.3 mg, 97%) was
prepared from amide 3b (411.0 mg, 1.0 mmol) and
(S)-MonoPhos (467.1 mg, 1.3 mmol) as a white foamy
1
solid: mp 211–212°C; [h]2D2=+173.5 (c 0.5, THF); H
NMR (CD2Cl2) l 1.63–1.75 (m, 8H), 2.18–2.45 (m,
7H), 2.85 (br. m, 4H), 6.70 (d, J=8.8 Hz, 1H), 7.10–
7.30 (m, 8H), 7.33–7.41 (m, 3H), 7.61 (t, J=7.6 Hz,
1H), 7.76 (d, J=8.8 Hz, 1H), 7.84–7.95 (m, 4H), 8.54
(d, J=8.4 Hz, 1H), 9.90 (s, 1H); 13C NMR (CD2Cl2) l
23.36, 23.48, 23.63, 24.06, 27.85, 28.50, 30.16, 117.02,
118.99, 119.14, 119.22, 122.20, 122.51, 123.05, 124.67,
125.38, 125.62, 126.02, 126.14, 126.53, 126.78, 127.05,
127.25, 128.24, 128.87, 129.89, 130.17, 130.82, 131.73,
132.10, 132.75, 133.20, 133.80, 134.71, 135.39, 136.57,
137.94, 138.66, 147.69, 148.07, 149.81, 157.37, 161.94;
31P NMR l +145.81; HRMS (m/z): (M++1) calcd for
C47H40N2O4P 727.2720; found, 727.2765.
4.2.2.5. (S,S)-(+)-L5. Following the same method for
the synthesis of L3, ligand L5 (510.0 mg, 64%) was
prepared from amide (S)-3a (437.9 mg, 1.1 mmol) and
1.4 mmol of (S)-H8-MonoPhos as a white foamy solid:
mp 170–712°C; [h]D22=+45.9 (c 0.5, THF); 1H NMR
(CD2Cl2) l 1.49–1.74 (m, 16H), 2.14–2.18 (m, 6H),
2.73–2.85 (m, 10H), 6.21 (d, J=8.4 Hz, 1H), 6.85–6.90
(m, 2H), 7.06 (t, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz,
1H), 7.26–7.30 (m, 2H), 7.77 (t, J=7.6 Hz, 1H), 8.11
(d, J=8.0 Hz, 1H), 8.21 (d, J=4.8 Hz, 1H), 8.44 (d,
J=8.4 Hz, 1H), 9.65 (s, 1H); 13C NMR (CD2Cl2) l
23.16, 23.33, 23.56, 23.68, 23.85, 28.02, 28.41, 28.65,
29.79, 30.31, 30.38, 117.87, 119.30, 119.39, 119.54,
119.67, 122.38, 126.66, 126.94, 128.32, 129.79, 129.95,
129.99, 130.84, 134.24, 134.60, 134.84, 135.45, 135.79,
136.75, 138.05, 138.57, 139.16, 146.18, 146.59, 147.91,
148.00, 148.51, 150.96, 162.16; 31P NMR l +137.49;
HRMS (m/z): (M++1) calcd for C46H46N2O4P 721.3190;
found, 721.3175.
4.2.2.3. (S,S)-(+)-L3. (S)-H8-BINOL (353.2 mg, 1.2
mmol), hexamethylphosphorustriamide (244.5 mg, 1.5
mmol), 2.5 mg of NH4Cl and 5 ml of benzene were
added to a 25 ml air-free Schlenk flask equipped with a
reflux condenser under an argon atmosphere. The mix-
ture was refluxed for 12 h, then the reaction mixture
was filtered. The filtrate was concentrated under
reduced pressure. The residue in 15 ml toluene and
(S)-3c (346.4 mg, 0.89 mmol) were added to a new
dried 50 ml Schlenk flask under an argon atmosphere.
The mixture was heated to reflux. After the reaction
was complete (detected by TLC), the reation solution
was cooled. White precipitation occurred. The resulting
solid was collected by filtration under argon and
washed with toluene (2×2 ml) to afford 477.0 mg of
(S,S)-L3 as a white solid. The filtrate was purified by
flash chromatograghy on a silica gel column (eluted
with CH2Cl2) to afford another 110.0 mg of (S,S)-L3,
the yield was 92%: mp 282–285°C; [h]2D2=+60.3 (c 0.5,
4.2.2.6. (S,S)-(+)-L6. Following the same method for
the synthesis of L3, ligand L6 (589.3 mg, 80%) was
prepared from amide (S)-3b (412.0 mg, 1.0 mmol) and
1.4 mmol of (S)-H8-MonoPhos as a white foamy solid:
mp 264–267°C; [h]D22=+37.7 (c 0.5, THF); 1H NMR
(CD2Cl2) l 1.46–1.73 (m, 16H), 2.11–2.42 (m, 9H),
2.53–2.84 (m, 10H), 6.13 (d, J=8.0 Hz, 1H), 6.85 (t,
J=8.4 Hz, 2H), 7.05 (t, J=8.4 Hz, 2H), 7.14 (d, J=7.6
Hz, 1H), 7.21–7.26 (m, 2H), 7.64 (t, J=7.6 Hz, 1H),
7.88 (d, J=7.6 Hz, 1H), 8.49 (d, J=8.4 Hz, 1H), 9.88
(s, 1H); 13C NMR (CD2Cl2) l 22.94, 23.11, 23.37,
23.50, 23.65, 24.08, 27.81, 28.20, 28.49, 29.57, 30.15,
116.91, 118.98, 119.15, 119.30, 119.51, 126.02, 126.21,
128.08, 128.19, 129.57, 129.77, 130.75, 133.69, 134.58,
134.65, 135.14, 135.58, 136.42, 137.80, 137.96, 138.55,
138.97, 145.95, 146.40, 147.96, 149.90, 157.38, 161.88;
31P NMR l +137.53; HRMS (m/z): (M++1) calcd for
C47H48N2O4P 735.3346; found, 735.3307.
1
THF); H NMR (CD2Cl2) l 1.41–1.45 (m, 2H), 1.69–
1.70 (m, 6H), 2.05–2.12 (m, 2H), 2.52–2.80 (m, 6H),
6.17 (d, J=8.0 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.86
(d, J=8.4 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 7.15–7.29
(m, 5H), 7.40–7.46 (m, 2H), 7.61 (d, J=8.8 Hz, 1H),
7.72 (t, J=7.6 Hz, 1H), 7.97–8.02 (m, 3H), 8.11–8.20
(m, 3H), 9.03 (d, J=8.8 Hz, 1H), 9.96 (s, 1H); 13C
NMR (CD2Cl2) l 23.07, 23.26, 28.33, 29.74, 119.33,
119.47, 120.66, 121.22, 122.30, 122.37, 122.48, 123.00,
125.66, 126.16, 126.35, 126.83, 127.39, 128.08, 128.85,
129.04, 129.77, 130.01, 130.17, 131.57, 132.09, 134.03,
134.30, 134.91, 135.87, 136.18, 138.06, 139.18, 145.92,
146.25, 148.45, 149.21, 150.36, 162.47; 31P NMR l
+136.87; HRMS (m/z): (M++1) calcd for C46H38N2O4P
713.2564; found, 713.2544.
4.3. General procedure for asymmetric 1,4-conjugate
addition
4.2.2.4. (S,S)-(+)-L4. Following the same method for
the synthesis of L3, ligand L4 (694.7 mg, 80%) was
prepared from amide (S)-3d (485.0 mg, 1.2 mmol) and
1.4 mmol of (S)-H8-MonoPhos as a white foamy solid:
mp 243–245°C; [h]D22=+57.1 (c 0.5, THF); 1H NMR
(CD2Cl2) l 1.40–1.43 (m, 2H), 1.66–1.69 (m, 6H), 1.96
4.3.1. Preparation of the catalyst. L1 (71.2 mg, 0.10
mmol), 12.6 mg of [Cu(CH3CN)4]BF4 (0.04 mmol) and
10 ml of toluene were added to a 50 ml air-free Schlenk
flask under an argon atmosphere. After stirring 30 min
at room temperature, the solvent was stripped off in
vacuo, 8 ml of CH2Cl2 was added to the flask and the

3914
Y. Hu et al. / Tetrahedron: Asymmetry 14 (2003) 3907–3915
catalyst solution was used for eight separate conjugate
addition reactions.
6. (a) Liang, L.; Au-Yeung, T. T.-L.; Chan, A. S. C. Org.
Lett. 2002, 4, 3799; (b) Liang, L.; Chan, A. S. C. Tetra-
hedron: Asymmetry 2002, 13, 1393; (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.
4.3.2. Asymmetric 1,4-conjugate addition. Substrate (0.5
mmol) and 1.0 ml of the above prepared catalyst solu-
tion were added to a flame-dried Schlenk tube under an
argon atmosphere. After stripping off the solvent, 1.5
ml of toluene was added. The slurry was stirred at
room temperture for 10 min and then cooled to –20°C.
After the slurry was stired for 15 min, 0.7 ml of Et2Zn
(1.1 M in toluene, 1.5 mol equiv.) was added slowly.
The resulting mixture was stired at –20°C for 12 h. 2 ml
of 5% HCl was added to quench the reaction. The
mixture was allowed to warm to room temperature,
and then 15 ml of diethyl ether was added. The orgnic
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, the
residue was purified by column chromatagraphy on
silica gel and eluted with EtOAc/hexanes (1/40–1/20) to
afford the addition product. The ees of the addition
products were determined by chiral HPLC or capillary
GC, which were detailed described in the supporting
information of Refs. 9 and 10.
7. Yamanoi, Y.; Imamoto, T. J. Org. Chem. 1999, 64, 2988.
8. (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) Hird, A. W.; Hoveyda, A. H. Angew. Chem., Int. Ed.
Engl. 2003, 42, 1276; (c) Degrado, S. J.; Mizutani, H.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 13362; (d)
Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am.
Chem. Soc. 2002, 124, 779; (e) Degrado, S. J.; Mizutani,
H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755; (f)
Shintani, R.; Fu, G. C. Org. Lett. 2002, 4, 3699; (g)
Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J.
Am. Chem. Soc. 2002, 124, 5262; (h) Alexakis, A.; Rosset,
S.; Allamand, J.; March, S.; Guillen, F.; Benhaim, C.
Synlett 2001, 1375; (i) Hu, X.; Chen, H.; Zhang, X.
Angew. Chem., Int. Ed. Engl. 1999, 38, 3518; (j) Escher, I.
H.; Pfaltz, A. Tetrahedron 2000, 56, 2879; (k) Knobel, A.
K. H.; Escher, I. H.; Pfaltz, A. Synlett 1997, 1429.
9. Hu, Y.; Liang, X.; Wang, J.; Zheng, Z.; Hu, X. J. Org.
Chem. 2003, 68, 4542.
10. Wan, H.; Hu, Y.; Liang, Y.; Gao, S.; Wang, J.; Zheng,
Acknowledgements
Z.; Hu, X. J. Org. Chem. 2003, 68, 8277.
11. For early reports on the ligands with H8-1,1%-binaphthyl,
see: (a) Zhang, F.-Y.; Kwok, W. H.; Chan, A. S. C.
Tetrahedron: Asymmetry 2001, 12, 2337; (b) Zhang, F.-
Y.; Pai, C.-C.; Chan, A. S. C. J. Am. Chem. Soc. 1998,
120, 5808; (c) Zhang, F.-Y.; Chan, A. S. C. Tetrahedron:
Asymmetry 1998, 9, 1179; (d) Liu, G.-B.; Tsukinoki, T.;
Kanda, T.; Mitoma, Y.; Tashiro, M. Tetrahedron Lett.
1998, 39, 5991; (e) Chan, A. S. C; Zhang, F.-Y.; Yip,
C.-W. J. Am. Chem. Soc. 1997, 119, 4080; (f) Zhang,
F.-Y.; Chan, A. S. C. Tetrahedron: Asymmetry 1997, 8,
3651; (g) Uemura, T.; Zhang, X.; Matsumura, K.; Sayo,
N.; Kumobayashi, H.; Ohta, T.; Nozaki, K.; Takaya, H.
J. Org. Chem. 1996, 61, 5510; (h) Zhang, X.; Taketomi,
T.; Yoshizumi, T.; Kumobayashi, H.; Akutagawa, S.;
Mashima, K.; Takaya, H. J. Am. Chem. Soc. 1993, 115,
3318.
12. For recent reports on the ligands derived from H8-
BINOL, see: (a) Guo, R.; Au-Yeung, T. T.-L.; Wu, J.;
Choi, M. C. K.; Chan, A. S. C. Tetrahedron: Asymmetry
2002, 13, 2519; (b) Zeng, Q.; Liu, H.; Mi, A.; Jiang, Y.;
Li, X.; Choi, M. C. K.; Chan, A. S. C. Tetrahedron 2002,
58, 8799; (c) Wang, B.; Feng, X.; Huang, Y.; Liu, H.;
Cui, X.; Jiang, Y. J. Org. Chem. 2002, 67, 2175; (d) Lu,
G.; Li, X.; Chan, W. L.; Chan, A. S. C. Chem. Commun.
2002, 172; (e) Long, J.; Hu, J.; Shen, X.; Ji, B.; Ding, K.
J. Am. Chem. Soc. 2002, 124, 10; (f) Zeng, Q.; Liu, H.;
Cui, X.; Mi, A.; Jiang, Y.; Li, X.; Choi, M. C. K.; Chan,
A. S. C. Tetrahedron: Asymmetry 2002, 13, 115 and
references cited therein.
This work was supported by the National Science
Foundation of China (29933050) and the Young Fac-
ulty Research Fund of DICP.
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