Synthesis of novel chiral bidentatephosphite ligands derived from the pyranoside backbone of monosaccharides and their application in the Cu-catalyzed conjugate addition of dialkylzinc to enones

Article abstract of DOI:10.1016/j.tetasy.2011.11.003

A series of novel bidentatephosphite ligands, derived from methyl 3,6-anhydro-α-d-glucopyranoside and chlorophosphoric acid diaryl ester, were easily synthesized. These ligands were successfully employed in the Cu-catalyzed asymmetric conjugate 1,4-additi

Full text of DOI:10.1016/j.tetasy.2011.11.003

Tetrahedron: Asymmetry 22 (2011) 1885–1890
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Tetrahedron: Asymmetry
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Synthesis of novel chiral bidentatephosphite ligands derived from the
pyranoside backbone of monosaccharides and their application in the
Cu-catalyzed conjugate addition of dialkylzinc to enones
Qing-Lu Zhao a,b, Lai-Lai Wang a,
⇑
a State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China
b Research Institute of Qilu Branch Co., Sinopec, Zibo 255400, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel bidentatephosphite ligands, derived from methyl 3,6-anhydro-a-D-glucopyranoside and
Received 28 September 2011
Revised 2 November 2011
Accepted 4 November 2011
chlorophosphoric acid diaryl ester, were easily synthesized. These ligands were successfully employed in
the Cu-catalyzed asymmetric conjugate 1,4-addition of the organozinc reagents diethylzinc and/or
dimethylzinc to enones. The stereochemically matched combination of glucopyranoside and (R)-H8-
binaphthyl in ligand 2,4-bis{[(R)-1,10-H8-binaphthyl-2,20-diyl] phosphite}-methyl 3,6-anhydro-
a-D-
glucopyranoside was essential to afford 85% ee for 3-ethylcyclohexanone with an (S)-configuration in
THF, using Cu(OTf)2 as a catalytic precursor. When the reaction was carried out at lower temperatures,
changing from ꢀ10 to ꢀ80 °C, a marginal influence of the temperature on the enantioselectivity of the
reaction was observed. The presence of the methyl substituent at the 1-position of the glucopyranoside
skeleton had a negative effect on the enantioselectivity in the 1,4-addition of ZnEt2 to acyclic enones.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
have led to the development of some highly efficient chiral ligands
used in transition metal catalytic reactions. It is noteworthy that
The development of highly efficient chiral ligands for homoge-
neous transition metal catalyzed 1,4-conjugate addition, which is
one of the most powerful tools for the synthesis of many biologi-
cally active compounds, has been received much attention both
from academia and industry. Over the past decades, much effort
has been focused on the development of Cu-catalyzed enantiose-
ligand tuning has allowed the rapid development of efficient cata-
lytic systems.1a,6c–e,7,9
In our group, we have reported that bidentatephosphite ligands
1a–1d (Fig. 1), which were derived from a phenyl 3,6-anhydro-b-D-
glucopyranoside backbone, were synthesized and employed suc-
cessfully in Cu-catalyzed asymmetric 1,4-additions of dialkylzinc
reagents to enones with up to 93% ee.10 The stereochemically
lective 1,4-conjugate additions of organozincs to
a,b-unsaturated
carbonyl compounds.1 Several successful chiral ligands, such as
P,N-ligands,2 phosphoramidites,3 phosphites,4 and aryl diphosph-
ites5 have been synthesized and employed in Cu-catalyzed asym-
metric conjugate addition reactions, and good results have been
obtained. Using carbohydrates (and derivatives) as starting materi-
als for the synthesis of chiral ligands6 has several advantages: (1)
the raw materials are of high enantiomeric purity and are readily
available; and (2) the multifunctional properties make it possible
to design various structures through a series of modifications. In
particular, phosphites, which are derived from carbohydrates, ow-
ing to their efficiency, facile preparation, and lower sensitivity to
air and moisture, have emerged as efficient ligands for Cu-cata-
lyzed asymmetric conjugate 1,4-addition.1a,6c–e,7 In recent decades,
combinatorial and high-throughput synthetic strategies have been
applied to the design and synthesis of new chiral catalysts,8 and
matched combination of the phenyl 3,6-anhydro-b-D-glucopyrano-
side backbone and chlorophosphoric acid diaryl ester in ligands 1a
and 1c was essential in inducing high enantioselectivity for prod-
ucts with an (R)-configuration. However, the reaction did have a
major problem, in that the use of ligands 1b and 1d with the same
glucopyranoside backbone as ligands 1a and 1c, and (S)-binaphthol
and/or (S)-H8-binaphthol moieties, gave low enantioselectivities
for products with an (S)-configuration, which is the desired active
pharmaceutical ingredient of erogorgiaene11a and ibuprofen.11b In
an effort to overcome this problem and enhance the enantioselec-
tivity for products with an (S)-configuration, we considered tuning
ligands 1a–1d to develop novel chiral ligands bearing a D-glucopy-
ranoside scaffold. For ligands 1a–1d based on glucopyranoside
derivatives, it is interesting to note that the 31P NMR spectra of li-
gands 1b and 1d showed two singlets (one for each phosphorus
moiety), while two doublets for ligands 1a and 1c were presented.
There were different JPP values in ligands 1a (JPP = 5.5 Hz) and 1c
(JPP = 6.1 Hz).10 In view of the 31P NMR spectral analysis of ligands
⇑
Corresponding author. Tel.: +86 (0) 931 4968161; fax: +86 (0) 931 4968129.
E-mail address: wll@licp.cas.cn (L.-L. Wang).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.11.003

1886
Q.-L. Zhao, L.-L. Wang / Tetrahedron: Asymmetry 22 (2011) 1885–1890
OPh
O
O
O
O
OMe
O
O
O
O
O
O
O
O
P
P
P
P
O
O
*
*
*
O
O
*
1a-1d
2a-2d
O
a: (R)ax
b: (S)ax
c: (R)ax
d: (S)ax
O
O
O
=
or
*
O
O
1a: δ 109.6 (d, 1P, JPP = 5.5Hz), 146.0 (d, 1P, JPP = 5.5Hz) ppm.
1b: δ 110.0 (s, 1P), 146.8 (s, 1P) ppm.
1c: δ 139.4 (d, 1P, JPP = 6.1Hz), 130.6 (d, 1P, JPP = 6.1Hz) ppm.
1d: δ 136.8 (s, 1P), 136.3 (s, 1P) ppm.
2a: δ 148.9 (s, 1P), 146.1 (s, 1P) ppm.
2b: δ 146.6 (s, 1P), 143.5 (s, 1P) ppm.
2c: δ 141.7 (s, 1P), 140.5 (s, 1P) ppm.
2d: δ 139.9 (s, 1P), 138.3 (s, 1P) ppm.
Figure 1. Chiral bidentatephosphite ligands derived from glucopyranoside.
1a–1d, and, the large difference in reactivity and enantioselectivi-
ty, which was induced by ligands 1a–1d, we decided to vary the
substituents at the 1-position of the glucopyranoside skeleton in
the hope of further improving the performance of the chiral cata-
lyst. Herein we report the synthesis of novel bidentatephosphite
ligands 2a–2d (Fig. 1 and Scheme 1) based on methyl 3,6-anhy-
commercially available, enantiopure 2,20-dihydroxy-1,10-binaph-
thol or 2,20-dihydroxy-5,50,6,60,7,70,8,80-octahydro-1,10-binaphthol.
Compounds 310 and 4a–4d12 were prepared conveniently accord-
ing to the literature procedures. All of the ligands were stable
during the purification of neutral silica gel under a nitrogen atmo-
sphere with reasonable yields, while the 1H NMR, 13C NMR, and
HRMS were consistent with the expectation for them. The 31P
NMR spectra of ligands 2a–2d showed two singlets (one for each
phosphorus moiety, Fig. 1).
dro-a-D-glucopyranoside, and their application in the Cu-catalyzed
asymmetric 1,4-additions of dialkylzincs to enones.
2. Results and discussion
2.2. Asymmetric 1,4-conjugate addition of ZnR2 to enones
2.1. Synthesis of phosphite ligands 2a–2d
In the first set of experiments, ligands 2a–2d were screened sep-
arately in the asymmetric 1,4-addition of ZnEt2 to cyclohexenone 5a
using Cu(OTf)2 as the catalytic precursor in THF (Table 1, entries 1–
4). Ligand 2a gave a 68% yield and 55% ee (S) (Table 1, entry 1). In con-
trast, the use of ligand 2b, based on the same glucopyranoside as li-
gand 2a, but with an opposite configuration of the binaphthyl
As shown in Scheme 1, bidentatephosphite ligands 2a–2d were
synthesized stereospecifically in one step from methyl 3,6-anhy-
dro-a-D
-glucopyranoside 3, and 2,20-dihydroxy-1,10-binaphthyl
phosphochloridites 4a–4b or 2,20-dihydroxy-5,50,6,60,7,70,8,80-octa-
hydro-1,10-binaphthyl phosphochloridites 4c–4d, by starting from
O
O
O
O
DMAP, NEt3
CH2Cl2
OMe
O
+
P
Cl
OMe
*
O
O
O
O
O
OH
OH
P
P
O
O
*
*
2a-2d
3
4a-4d
O
O
a: (R)ax
O
c: (R)ax
O
O
=
or
ax
ax
*
b:
d:
(S)
(S)
O
Scheme 1. The synthesis of chiral bidentatephosphite ligands 2a–2d derived from methyl 3,6-anhydro-a-D-glucopyranoside.

Q.-L. Zhao, L.-L. Wang / Tetrahedron: Asymmetry 22 (2011) 1885–1890
1887
Table 1
Cu-catalyzd asymmetric conjugate 1,4-addition of ZnEt2 to 2-cyclohexenone 5aa
O
O
Cu(OTf)2 or (CuOTf)·C6H6
Et2Zn
+
2a-2d,
ligand
THF, 0°C, 4 h
*
Et
5a
6a
b
c
Entry
Cu salts
Ligand
L./Cu
Conv.b (%)
Yield (%)
% ee (Conf.)
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
(CuOTf)2ꢂC6H6
(CuOTf)2ꢂC6H6
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
2a
2b
2c
2d
2a
2c
2c
2c
2c
2
2
2
2
2
2
0.5
1
1.1
91
36
>99
73
94
>99
84
68
27
92
52
74
96
56
90
90
55 (S)
23 (R)
80 (S)
22 (R)
42 (S)
60 (S)
77 (S)
81 (S)
80 (S)
99
99
a
Reaction conditions: Cu(OTf)2 (0.005 mmol) or (CuOTf)2ꢂC6H6 (0.0025 mmol), ligand (0.025–0.015 mmol), ZnEt2 (1.0 M in hexane, 0.6 mmol), 5a (0.25 mmol), THF (4 mL),
0 °C, 4 h.
b
The data on conversions and yields were determined by GC using dodecane as an internal standard with an SE-30 column (30 m ꢁ 0.32 mm ID).
c
The enantiomeric excess of 6a was determined by GC equipped with a Chiraldex A–TA column (50 m ꢁ 0.25 mm ID). The absolute configuration of 6a was determined by
comparison with an authentic sample.
Table 2
Cu-catalyzed asymmetric 1,4-addition of dialkylzinc to cyclic enonesa
O
O
Cu(OTf)2, Ligand 2c
+
ZnR2
*
Solvent
R
n
n
6a
n=1, R=Et
5a n=1
5b
5c n=2
6b n=0, R=Et
6c n=2, R=Et
6d
n=0
n=1, R=Me
b
b
b
Entry
Sub.
Solvent
T (°C)
Time (h)
Conv. (%)
Yield (%)
% ee (Conf.)
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5c
5a
CH2Cl2
Toluene
Et2O
THF
THF
THF
THF
THF
THF
THF
0
0
0
4
4
4
4
4
4
6
8
12
12
12
12
12
12
24
>99
>99
>99
98
97
85
92
96
98
95
90
14
>99
89
62
62
86
73
93
93
79
92
89
91
78
63
3
19 (S)
26 (R)
14 (R)
73 (S)
80 (S)
84 (S)
85 (S)
85 (S)
84 (S)
81 (S)
82 (S)
81 (S)
61 (S)
65 (S)
47 (R)
20
ꢀ10
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ30
ꢀ40
ꢀ80
ꢀ20
ꢀ20
ꢀ20
9
10
11
12
13
14c
15c,d
THF
THF
THF
THF
32
67
25
THF
a
b
c
Reaction conditions: Cu(OTf)2 (0.005 mmol), ligand 2c (0.0055 mmol), ZnEt2 (1.0 M in hexane, 0.6 mmol), cyclic enones (0.25 mmol), solvent (4 mL).
The data on conversions, yields, enantiomeric excesses, and the absolute configuration of products 6b–6d were determined using the same conditions as noted in Table 1.
The enantiomeric excess was determined by GC equipped with a CP-Chirasil-Dex CB column (25 m ꢁ 0.25 mm ID).
ZnMe2 (1.1 M in toluene, 0.6 mmol).
d
moieties, afforded a much lower yield of 27% and an enantioselectiv-
ity of 23% (R) (Table 1, entry 2). Using ligand 2c, containing the same
glucopyranoside skeleton as ligand 2a and axially chiral
(R)-H8-binaphthyl moieties, the yield and enantioselectivity were
enhanced to 92% and 80% ee (S), respectively (Table 1, entry 3). How-
ever, ligand 2d bearing the same glucopyranoside skeleton as ligand

1888
Q.-L. Zhao, L.-L. Wang / Tetrahedron: Asymmetry 22 (2011) 1885–1890
Cu(OTf)2, ligand 2c
O
O
ZnEt2
+
*
THF, -20 oC, 24 h
R'
R''
R'
R''
7a-7c
8a-8c
8a
8b
: R' = Ph, R'' = Ph, 35% yield, 13% ee (S)
: R' = 4-ClC6H4, R'' = Ph, 31% yield, 13% ee (S)
8c: R' = 4-MeOC6H4, R'' = Ph, 33% yield, 11% ee (R)
Scheme 2. Cu-catalyzed asymmetric 1,4-addition of ZnEt2 to acyclic enones 7a–7c.
2a and (S)-H8-binaphthyl moieties, gave a 52% yield and 22% ee (R)
(Table 1, entry 4). The results clearly indicated that the matched
combination of methyl 3,6-anhydro-a-D-glucopyranoside and (R)-
ligands 1c–1d (Fig. 1).10a In the presence of ligand 2c, the asym-
metric 1,4-addition of ZnEt2 to acyclic enones was evaluated.
However, poor enantioselectivities were observed; 13% ee (S) for
1,3-diphenyl-1-pentanone 8a, 13% ee (S) for 3-(4-chlorophenyl)-
1-phenylpentanone 8b, and 11% ee (R) for 3-(4-methoxyphenyl)-
1-phenylpentanone 8c (Scheme 2).
This indicated that ligand 2c was inferior for the reaction of
ZnEt2 to acyclic enones 7a–7c. These results suggested that the
presence of the methyl substituent at the 1-position of the gluco-
pyranoside skeleton had a negative effect on the enantioselectivity
of the 1,4-addition of ZnEt2 to acyclic enones 7a–7c.
H8-binaphthyl moieties of ligand 2c was more favorable with re-
spect to inducing higher enantioselectivity than ligands 2a, 2b,
and 2d (Table 1, entries 1 vs 2, and entries 3 vs 4). The reason, why
the stereocontrol capability of ligand 2c was higher than ligand 2a
(Table 1, entries 1 and 3), in our opinion, may be attributed to the
wider bite angle of H8-binaphthol.13 The enantioselectivities for
product 6a with an (S)-configuration can be greatly improved upon
by the use of ligand 2c in the place of ligands 1a–1d.10
Next, the influence of the copper precursor as well as the ratio
of the molar ligand to copper salts on the catalytic activity and
enantioselectivity were examined (Table 1, entries 5–9). The cata-
lysts formed in situ by (CuOTf)2ꢂC6H6, in the place of Cu(OTf)2, and
ligands 2a and 2c respectively, gave lower enantioslectivity 42% (S)
and 60% (S) (Table 1, entries 5 and 6). Thus, Cu(OTf)2, owing to its
lower sensitivity to air and moisture than (CuOTf)2ꢂC6H6, was se-
lected as a catalytic precursor in the next cases. An enhancement
in enantioselectivity was observed when the ratio of the molar li-
gand to Cu(OTf)2 ranged from 0.5/1 to 1/1 (Table 1, entries 7 and 8).
A further increase of the ratio afforded no obvious change in the
catalytic activity and enantioselectivity (Table 1, entries 3 and 9).
Using the catalyst prepared in situ from Cu(OTf)2 and ligand
2c, the enantioselective 1,4-addition of ZnEt2 to substrate 5a with
a variety of solvents and various temperatures was investigated.
The type of solvent had a decisive influence on the performance
of the catalysts. The reaction in CH2Cl2 afforded low enantioselec-
tivity [19% (S)] (Table 2, entry 1). When using toluene and Et2O as
the solvents, ligand 2c gave 26% (R) ee and 14% (R) ee, respec-
tively (Table 2, entries 2 and 3). However, in comparison with
CH2Cl2, the opposite configuration of product 6a was found. We
identified THF as the most appropriate solvent (Table 1, entry 9
vs Table 2, entries 1–3). When the reaction was carried out at
lower temperatures, changing from ꢀ10 to ꢀ80 °C, a marginal
influence of the temperature on the enantioselectivity of the reac-
tion was observed (Table 2, entries 5–12). In comparison, at
ꢀ20 °C, the highest enantioselectivity was achieved with up to
85% ee (S) (Table 2, entries 6–9). Under the optimum reaction
conditions, we then assessed the 1,4-addition of ZnEt2 to 2-cyclo-
pentenone 5b and 2-cycloheptenone 5c in the presence of ligand
2c/Cu(OTf)2. 3-Ethylcyclopentanone 6b was obtained in 61% ee
(S), while 3-ethylcycloheptanone 6c was obtained in 65% ee (S)
(Table 2, entries 13 and 14). These results indicated a significant
dependence of the enantioselectivity on the ring size of the cyclic
enones. The 1,4-addition reaction of ZnMe2 to substrate 5a gave
low enantioselectivity [47% ee (R), Table 2, entry 15]. These re-
sults indicated a significant dependence of the enantioselectivity
on the type of organozinc reagents employed in the reaction.
In our previous work, it had been found that acyclic enones gave
lower enantioselectivities in the presence of bidentatephosphite
3. Conclusion
In conclusion, we have described a new series of chiral bide-
ntatephosphite ligands 2a–2d, which have binaphthol or H8-
binaphthol moieties and a glucopyranoside backbone. The ligands
were applied successfully to the Cu-catalyzed asymmetric 1,4-
addition of dialkylzincs to enones with good enantioselectivity.
The stereogenic centers of the glucopyranoside skeleton and the
axially chiral diaryl moieties of ligands 2a–2d had a cooperative ef-
fect on the reactivity and enantioselectivity. The combination of
carbohydrates and artificial chiral moieties provides an easily
accessible tool-box for the fine tuning of efficient ligands. Research
concerning other substrates and the use of these ligands in other
transition metal-catalyzed reactions is currently underway.
4. Experimental
4.1. General
Optical rotations were measured on a Perkin-Elmer 241 MC
polarimeter at 20 °C. Melting points were determined using an X-
4 melting point apparatus and were uncorrected. HRMS were re-
corded on a Bulker micrOTOF-QII mass instrument. NMR spectra
were recorded on Bulker spectrometers. 31P NMR spectra were re-
ported in parts per million with 85% H3PO4 as an external refer-
ence. 1H NMR and 13C NMR spectra were reported in parts per
million with TMS (d = 0.00 ppm) as an internal standard. Proton
chemical shifts (d) and coupling constants (J) are reported in
ppm and Hz, respectively. Spin multiplicities are given as s (sin-
glet), d (doublet), t (triplet), and m (multiplet).
All non-aqueous reactions and manipulations were performed
under an N2 atmosphere with standard Schlenk techniques. All
reactions were monitored by thin layer chromatography (TLC, sil-
ica gel GF254 plates). Column chromatography separations were
conducted on silica gel (200–300 mesh). THF, Et2O, NEt3, and tolu-
ene were distilled with Na using benzophenone as an indicator,
and CH2Cl2 was dried over CaH2 before. H8-binaphthol was pre-
pared by using a literature procedure.12a All other chemicals were
obtained commercially and used without further purification.

Q.-L. Zhao, L.-L. Wang / Tetrahedron: Asymmetry 22 (2011) 1885–1890
1889
4.2. Synthesis of ligands 2a–2d
4.59–4.64 (m, 2H), 4.41–4.48 (m, 2H), 4.89–4.94 (m, 1H), 3.62
(dd, J = 9.6, 4.8 Hz, 1H), 3.35 (s, 3H), 2.77–2.83 (m, 8H), 2.57–2.64
(m, 4H), 2.09–2.16 (m, 4H), 1.72–1.76 (m, 12H), 1.45–1.53 (m,
4H). 13C NMR (75 MHz, DMSO-d6) d 145.5, 145.2, 137.8, 137.0,
134.6, 133.6, 129.4, 129.1, 128.5, 128.4, 127.2, 118.7, 118.5,
103.9, 84.9, 77.7, 77.5, 72.1, 70.4, 55.1, 28.3, 27.2, 27.1, 22.0,
4.2.1. 2,4-Bis{[(R)-1,10-binaphthyl-2,20-diyl]phosphite}-methyl
3,6-anhydro-a-D-glucopyranoside 2a
A solution of (R)-H8-binaphthol (2.0 g) in 10 mL of PCl3 and
30 mL of toluene was stirred for 24 h at 110 °C under a nitrogen
atmosphere in a 100 mL Schlenk flask equipped with a condenser.
After removal of the excess PCl3 and toluene, the residue was dis-
solved in toluene (20 mL) and then transferred to another Schlenk
flask, and toluene was removed in vacuo to obtain (R)-1,10-binaph-
thyl-2,20-diyl-chlorophosphite 4a as a white powder, which was
used directly in the following reaction without further purification.
To a stirred solution of compound 3 (0.6 mmol, 106 mg), 4a
(2.4 mmol, 842 mg), and DMAP (0.12 mmol, 14.6 mg) in CH2Cl2
(15 mL), was slowly added anhydrous NEt3 (0.34 mL) at ꢀ15 °C un-
der nitrogen for 0.5 h. The reaction mixture was then stirred at rt
for 1 h. Next, CH2Cl2 was distilled off in vacuo, and then toluene
(20 mL) was added. The solid was removed by filtration through
a pad of silica gel, and the solvent was distilled in vacuo. The res-
idue was purified by flash chromatography (toluene, Rf = 0.49), to
give ligand 2a as a white foamy solid (284 mg, 59% yield), mp
21.9, 21.8 ppm. HRMS (ESI) calcd for
821.3003, found: 821.2995.
C
47H51O9P2 (M+H)+
4.2.4. 2,4-Bis{[(S)-1,10-H8-binaphthyl-2,20-diyl]phosphite}-
methyl 3,6-anhydro- -glucopyranoside 2d
a-D
(S)-1,10-H8-Binaphthyl-2,20-diyl-chlorophosphite 4d was syn-
thesized by the same procedure as that for 4a, and was used di-
rectly without further purification. Treatment of compound 3
(0.6 mmol, 106 mg), 4d (1.32 mmol, 474 mg) and DMAP
(0.12 mmol, 14.6 mg) as described for ligand 2a afforded ligand
2d, which was purified by flash chromatography (toluene,
Rf = 0.30) to produce a white foamy solid (154 mg, 31% yield), mp
106–108 °C; ½a 2D0
ꢃ
¼ þ309 (c 0.2, CH2Cl2); 31P NMR (162 MHz,
DMSO-d6): d 139.9 (s, 1P), 138.3 (s, 1P) ppm. 1H NMR (400 MHz,
DMSO-d6): d 7.03–7.27(m, 6H), 6.98 (d, J = 8.0 Hz, 1H), 6.91 (d,
J = 8.0 Hz, 1H), 5.09 (d, J = 4.0 Hz, 1H), 4.55 (t, J = 5.6 Hz, 1H),
4.45–4.50 (m, 2H), 4.37–4.41 (m, 1H), 3.80–3.85 (m, 1H), 3.54
(dd, J = 8.8, 6.4 Hz, 1H), 3.40 (s, 3H), 2.77–2.83 (m, 8H), 2.59–2.63
(m, 4H), 2.11–2.15 (m, 4H), 1.72 (m, 12H), 1.47–1.49 (m, 4H)
ppm. 13C NMR (100 MHz, DMSO-d6): d 145.6, 145.4, 137.9, 136.9,
134.7, 133.6, 129.5, 129.1, 128.6, 127.1, 119.1, 118.8, 103.9, 84.9,
78.4, 77.3, 72.7, 69.7, 55.0, 28.4, 27.2, 22.1, 22.0, 21.9, 21.8 ppm.
HRMS (ESI) calcd for C47H50NaO9P2 (M+Na)+ 843.2822, found:
847.2790.
123–124 °C; ½a 2D0
ꢃ
¼ ꢀ321 (c 0.2, CH2Cl2); 31P NMR (162 MHz,
DMSO-d6): d 148.9 (s, 1P), 146.1 (s, 1P) ppm. 1HNMR (400 MHz,
DMSO-d6): d 8.04–8.20 (m, 8H), 7.65 (d, J = 8.8 Hz, 1H), 7.61 (d,
J = 8.8 Hz, 1H), 7.45–7.56 (m, 6H), 7.35–7.36 (m, 4H), 7.15–7.27
(m, 4H), 5.12 (d, J = 4.0 Hz, 1H), 4.70–4.78 (m, 2H), 4.59–4.63 (m,
1H), 4.53 (dd, J = 6.0, 4.0 Hz, 1H), 3.94 (dd, J = 9.6, 4.8 Hz, 1H),
3.71 (dd, J = 9.6, 4.8 Hz, 1H), 3.40 (s, 3H) ppm. 13C NMR (75 MHz,
DMSO-d6): d 147.3, 146.7, 131.9, 131.7, 131.2, 130.8, 130.7,
130.3, 128.6, 128.5, 126.7, 126.6, 125.9, 125.8, 125.4, 125.1,
123.3, 121.9, 121.7, 121.6, 104.1, 84.9, 77.9, 77.7, 72.7, 70.9,
55.3 ppm. HRMS (ESI) calcd for C47H34NaO9P2 (M+Na)+ 827.1570,
found: 827.1577.
4.3. Typical procedure for the asymmetric conjugate addition of
dialkylzinc to enones
4.2.2. 2,4-Bis{[(S)-1,10-binaphthyl-2,20-diyl] phosphite}-methyl
3,6-anhydro-a-D-glucopyranoside 2b
A solution of Cu(OTf)2 (0.005 mmol, 1.8 mg) and ligand 2c
(0.0055 mmol, 4.5 mg) in THF (4 mL) was stirred for 1 h at rt under
nitrogen. After the solution was cooled down to 0 °C, 2-cyclohexe-
none (0.25 mmol, 0.024 mL) was added, and the solution was stir-
red for 10 min at 0 °C. Then ZnEt2 (0.6 mmol, 0.6 mL of 1.0 M
solution in hexane) was added dropwise using a syringe within
2 min. After 4 h., the reaction was quenched by H2O (2 mL) and
2 M HCl (2 mL), and extracted with ethyl acetate (5 mL ꢁ 3). The
combined extracts were washed using a saturated NaHCO3 solu-
tion, brine, and then dried over anhydrous Na2SO4, filtered, and
concentrated to afford the crude product. The conversion and the
yield were determined by GC equipped with a SE-30 column
(30 m ꢁ 0.32 mm ID) using dodecane as an internal standard. The
enantiomeric excess was determined by GC with a Chiraldex A-
TA column (50 m ꢁ 0.25 mm ID) or a CP-Chirasil-Dex CB column
(25 m ꢁ 0.25 mm ID). The absolute configuration was determined
by comparison with authentic samples.
The 1,4-addition of ZnEt2 to acyclic enone substrates was the
same as for the cyclic substrate enones. However, the 1,4-adducts
were separated by column chromatography on silica gel (200–
300 mesh) and eluted with Petroleum ether/EtOAc (40/1–20/1),
and the enantiomeric excess was determined by HPLC (Daicel Chi-
ralcel AD-H 25 cm ꢁ 4.6 mm ID). The analytical conditions for the
1,4-adducts are as follows.
(S)-1,10-Binaphthyl-2,20-diyl-chlorophosphite 4b was synthe-
sized by the same procedure as that for 4a, and was used directly
without further purification. Treatment of compound 3 (0.6 mmol,
106 mg), 4b (1.44 mmol, 505 mg) and DMAP (0.12 mmol, 14.6 mg)
as described for ligand 2a afforded ligand 2b, which was purified
by flash chromatography (toluene, Rf = 0.27) to produce a white foa-
my solid (167 mg, 35% yield), mp 95–96 °C; ½a D20
¼ þ502 (c 0.2,
ꢃ
CH2Cl2); 31P NMR (162 MHz, DMSO-d6): d 146.6 (s, 1P), 143.5 (s,
1P) ppm. 1HNMR (400 MHz, DMSO-d6): d 8.06–8.19 (m, 8H), 7.59–
7.66(m, 3H), 7.48–7.54 (m, 5H), 7.32–7.38 (m, 4H), 7.14–7.27 (m,
4H), 5.12 (d, J = 3.6 Hz, 1H), 4.51–4.62 (m, 4H), 3.86 (dd, J = 9.2,
5.2 Hz, 1H), 3.59 (dd, J = 9.2, 6.4 Hz, 1H), 3.48 (s, 3H) ppm. 13C
NMR (100 MHz, DMSO-d6): d 147.4, 146.7, 131.9, 131.6, 131.1,
130.9, 130.8, 130.7, 130.1, 130.0, 128.6, 128.5, 126.7, 126.6, 126.5,
125.9, 125.8, 125.7, 125.3, 125.1, 125.0, 123.3, 122.0, 121.7, 121.6,
103.9, 84.9, 78.6, 77.3, 72.9, 69.6, 55.1 ppm. HRMS (ESI) calcd for
C
47H34NaO9P2 (M+Na)+ 827.1570, found: 827.1544.
4.2.3. 2,4-Bis{[(R)-1,10-H8-binaphthyl-2,20-diyl] phosphite}-
methyl 3,6-anhydro- -glucopyranoside 2c
a
-D
(R)-1,10-H8-Binaphthyl-2,20-diyl-chlorophosphite 4c was syn-
thesized by the same procedure as that of 4a, and was used directly
without further purification. Treatment of compound 3 (0.6 mmol,
106 mg), 4c (1.32 mmol, 474 mg) and DMAP (0.12 mmol, 14.6 mg)
as described for ligand 2a afforded ligand 2c, which was purified by
flash chromatography (toluene, Rf = 0.39) to produce a white foa-
4.3.1. 3-Ethylcyclohexanone 6a
Chiral GC, Chiraldex A–TA column (50 m ꢁ 0.25 mm ID), T:
120 °C, Rt1 = 11.55 min (R), Rt2 = 11.93 min (S).
my solid (210 mg, 43% yield), mp 91–92 °C; ½a D20
¼ ꢀ126 (c 0.2,
ꢃ
CH2Cl2); 31P NMR (121 MHz, DMSO-d6): d 141.7 (s, 1P), 140.5 (s,
1P). 1H NMR (300 MHz, DMSO-d6) d 7.02–7.28 (m, 6H), 6.92 (d,
J = 8.4 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 5.01 (d, J = 3.6 Hz, 1H),
4.3.2. 3-Ethylcyclopentanone 6b
Chiral GC, Chiraldex A–TA column (50 m ꢁ 0.25 mm ID), T:
110 °C, Rt1 = 14.39 min (R), Rt2 = 13.73 min (S).

1890
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2879.
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Rt1 = 13.68 min (R), Rt2 = 13.20 min (S).
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Chiral GC, CP-Chirasil-Dex CB (25 m ꢁ 0.25 mm ID), T: 70 °C,
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4.3.5. 1,3-Diphenyl-1-pentanone 8a
Chiral-HPLC, Daicel Chiralcel AD-H (25 cm ꢁ 4.6 mm ID), hex-
ane/i-PrOH = 95/5, flow rate = 0.5 mL/min at 25 °C, detected at
254 nm. Rt1 = 15.41 min (R), Rt2 = 13.19 min (S).
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4.3.7. 3-(4-Methoxyphenyl)-1-phenylpentanone 8c
Chiral-HPLC, Daicel Chiralcel AD-H (25 cm ꢁ 4.6 mm ID), hex-
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Acknowledgements
This work was supported by the National Natural Science Foun-
dation of China (NSFC 20343005, 20473107, 20673130, 20773147,
21073211, and 21174155).
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