Synthesis of novel carbohydrate-based chiral P, N ligands and their applications in Cu-catalyzed enantioselective 1, 4-conjugate additions

Article abstract of DOI:10.1016/j.catcom.2011.09.021

A new type of phosphate-pyridine (P, N) ligand derived from d-glucosamine and BINOL was synthesized and successfully applied in Cu-catalyzed enantioselective conjugate addition of diethylzinc to chalcones for the first time, high yields and enantioselectivities were obtained when the ligand 10a which contains (S)-BINOL was used. The results also showed that the configuration of BINOL at the ligand backbone had remarkable effects on the activities and enantioselectivities.

Full text of DOI:10.1016/j.catcom.2011.09.021

Catalysis Communications 16 (2011) 155–158
Contents lists available at SciVerse ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short Communication
Synthesis of novel carbohydrate-based chiral P, N ligands and their applications in
Cu-catalyzed enantioselective 1, 4-conjugate additions
Haijun Xia a, Hua Yan b, Chao Shen a, Fangyi Shen a, Pengfei Zhang a,
⁎
a
College of Material Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, China
b
School of Pharmaceutical and Chemical Engineering, Taizhou University, Linhai 317000, Zhejiang Province, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 August 2011
Received in revised form 16 September 2011
Accepted 16 September 2011
Available online 23 September 2011
A new type of phosphate-pyridine (P, N) ligand derived from D-glucosamine and BINOL was synthesized and
successfully applied in Cu-catalyzed enantioselective conjugate addition of diethylzinc to chalcones for the
first time, high yields and enantioselectivities were obtained when the ligand 10a which contains (S)-BINOL
was used. The results also showed that the configuration of BINOL at the ligand backbone had remarkable effects
on the activities and enantioselectivities.
© 2011 Elsevier B.V. All rights reserved.
Keywords:
D-glucosamine
BINOL
Phosphate-pyridine (P N)
Ligand
1. Introduction
co-workers showed that a series of phosphinoamide–phosphinoester
ligands which derived from amino-sugar were highly effective for
Asymmetric conjugate additions of carbon nucleophiles to acceptor-
activated double bonds represent an attractive tool for the stereoselec-
tive formation of C―C bonds [1–4]. In this regard, copper-mediated
conjugate additions of diorganozinc reagents to α, β-unsaturated
ketones have attracted particular synthetic interest and have dom-
inated the field since their discovery in the 1990s [5–9]. And lots of
chiral heterobidentate ligands which when equipped with a weak
or a strong heteroatom pair such as P/N, P/O, P/P, or N/N also have
been successfully prepared and applied in asymmetric reaction [10].
Such ligands also have been proven to be effective for obtaining high
enantioselectivities through electronic and steric differentiations. In
these ligands, the P,N ligands have been widely used for catalytic appli-
cation and a great advance has been made in the past decades in
achieving high enantioselectivities [11–13]. So more and more struc-
ture based on the biphenyl systems [14,15], binaphthyl-type ligands
[16–19], Trost modular [20–22] and paracyclophanes [23,24] novel
ligands were synthesized and applied. However, to the best of our
knowledge, there are only a few reports on the study of chiral P,N ligands
derivative from carbohydrates for asymmetric catalysis [25,26].
achieving high enantioselectivities in asymmetric copper 1,4-addition
reactions [28]. Recently, our group has described the synthesis of
carbohydrate-based iminophosphinite ligands and their successful
applications in Pd-catalyzed asymmetric allylic alkylations [29] (Fig. 1).
On the basis of our experience at studying carbohydrate and
inspired by these successful carbohydrate-based ligands designed, we
have designed and developed a new type of phosphate-pyridine (P,N)
ligands 10a and 10b by tethering a pyridine amido component and a
phosphate component to a N-acetylglucosamine. The new type of
carbohydrate-based ligand was successfully employed in Cu-catalyzed
conjugate addition of diethylzinc to chalcones and achieved moderate
enantioselectivities. In addition, the novel ligands with carbohydrate
chirality provide a more effective asymmetric environment for the
enantioselective discrimination on a prochiral substrate, electronic
and steric properties, so it could be finely tuned and future research is
being carried out.
2. Experimental
As we all know, carbohydrates have been widely used as cheap
original material or chiral auxiliaries in organic synthesis. In recent
years, some carbohydrate-based P,N ligands have been reported, for
instance, Kunz et al. reported some carbohydrate-based ligands for
the Pd-catalyzed asymmetric allylic substitution [27]. Woodward and
2.1. General
All syntheses were performed using standard Schlenk techniques
under a nitrogen atmosphere. All solvents were dried before using
accord to standard procedures and stored under nitrogen. Column
chromatography was performed on silica gel grade 60 (230–400
mesh). Analytical TLC: Silica Gel 60, F254 plates from Merck, which
were visualized by UV and phosphomolybdic acid staining. Optical
rotation values were measured on a PerkinElmer P241 polarimeter.
⁎
Corresponding author. Tel./fax: +86 571 28862867.
E-mail address: chxyzpf@hotmail.com (P. Zhang).
1566-7367/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2011.09.021

156
H. Xia et al. / Catalysis Communications 16 (2011) 155–158
Fig. 1. Development of carbohydrate-based ligands in asymmetric catalytic reactions.
Enantiomeric excesses (% ee) were determined by HPLC (Agilent
1100 series) analysis using Chiralpak AD-H column and GC equipped
with a Chiraldex A-TA column (50 m×0.25 mm I.D.). The 1H, 13C,
and 31P NMR spectra were recorded on a Bruker Avance DRX-400
spectrometer; chemical shifts (d) are given in ppm and are refer-
enced to residual solvent peaks (1H NMR and 13C NMR) or to an
85% H3PO4 in D2O externally (31P NMR). Elemental analyses were
performed on Carlo-Erba 1106. Compounds 2-aminoglucose 6 and
Feringa's phosphorus-amidite (8, 9) were prepared by previously
described methods [30,31].
aminoglucose 6 with 1.0 equiv of 2-picolinic acid in the presence of
1.0 equiv 1,1′-carbonyldiimidazole (CDI) as the condensation reagent
proceeded smoothly to afford the amide 7 through column chromatog-
raphy in 85% yield. The (S)-Feringa's phosphorus-amidite ligand 8 was
obtained in 90% yield and the (R)-Feringa's phosphorus-amidite ligand
9 was obtained in 92% yield refer to the literature. Then the optically
pure phosphite-pyridine ligands 10a and 10b were respectively
provided though refluxing the mixture of the amide 7 with 8 or 9 in
toluene under nitrogen atmosphere in 78% and 52% yield respectively.
The obtained ligands 10a and 10b are quite stable in the solid state
and their 31P NMR, 1H NMR, and 13C NMR spectral data are in good
agreement with the suggested structures.
2.2. General procedure for asymmetric 1, 4-conjugate
addition: preparation of catalyst
3.2. Cu-catalyzed enantioselective 1,4-conjugate additions
Ligand 10a or 10b (77.6 mg, 0.1 mmol), copper salt (0.1 mmol),
and 10 mL of toluene were added to a 50 mL air-free Schlenk flask
under a nitrogen atmosphere. After 30 min of stirring at room temper-
ature, the solvent was stripped off in vacuo, 6 mL of CH2Cl2 was added
to the flask, and the catalyst solution was used for the 1,4-conjugate
addition reactions.
We initially tested the addition of Et2Zn to chalcone in the pres-
ence of several copper salts and ligands 10a and 10b in toluene at
room temperature. All the results are summarized in Table 1. Variety
of copper (I) and (II) salts (i.e., CuBr, CuCl, CuF2, Cu(OTf)2, Cu
(OAc)2·2H2O, [Cu(CH3CN)4]BF4 and Cu(CF3SO3)2·C6H6) were
screened in this study. The first promising results were achieved
with Cu(OAc)2·2H2O, which gave 82% yield and 70% ee in the addi-
tion of Et2Zn to the model substrate chalcone at room temperature
(entry 5, Table 1).
2.3. General procedure for asymmetric 1,4-conjugate addition
Chalcone substrate (0.5 mmol) and 3.0 mL of the above prepared
catalyst solution were added to a flame-dried Schlenk tube under a
nitrogen atmosphere. After the solvent has been stripped off, 4 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
has been stirred for 15 min, 0.75 mL of Et2Zn (1.0 M in toluene, 1.5 mol
equiv) was added slowly. The resulting mixture was stirred at that
temperature for 12 h and 4 mL of 5% hydrochloric acid 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 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 was purified by column
chromatography on silica gel and eluted with EtOAc/petroleum
ether (1/40-1/20) to afford the addition product. The ee values of
the addition products were determined by chiral HPLC (Chiralcel
AD-H column, hexane/2-propanol=99:1, 1.0 mL/min). The configura-
tion of 1,4-conjugate addition product from these reactions was proven
to be (S) by comparing the specific rotation with the literature values
[32,33].
Some other copper salts such as Cu(OTf)2 and [Cu(CH3CN)4]BF4
showed almost the same results about 60% ee(entries 4 and 6,
Table 1). The copper (II) salts gave good ee than copper (I) salts in
generally (entries 4–7 vs 1–3, Table 1). On the basis of these results,
we employed Cu(OAc)2·2H2O in the following studies, and some
other choices may also be effective. Then different temperatures
from −10 °C to −40 °C were also screened (entries 8–10, Table 1).
Lowering the reaction temperature to −10 °C improves the enantios-
electivity of the conjugate addition (entry 5 versus entry 8), without
altering the reaction rate. A decrease in the reaction temperature
from −10 °C to −40 °C did not give a favorable ee except the drop
of yields (entries 9 and 10, Table 1). Replacing ligand 10a with its di-
astereomer 10b led to the addition products in poor yields and with
low enantioselectivities (entry 8 versus entry 12), the results indicated
that yields and enantioselectivities are affected by the configuration at
the biaryl phosphite moieties. Both ligands afforded the same configu-
ration in the end product, namely the (S)-enantiomer [34].
We next studied with the best ligand 10a, the effect of several
reaction parameters, such as solvent (i.e., THF, Et2O, CH2Cl2, and
ClCH2CH2Cl) copper-to-ligand ratio and Et2Zn-to-substrate ratio. The
results summarized in Table 2 showed that pure PhMe is advantageous
over THF, Et2O, CH2Cl2, ClCH2CH2Cl and mixed solvents for achieving
high enantioselectivity(entries 1–6, Table 2). No improvement in
enantioselectivity was observed with a ratio of Cu(OAc)2·2H2O/L
10a ranging from 1/1 to 1/1.5 and 1/2 (entries 6–8, Table 2) and 1.5
equiv diethylzinc is better than 1.0 equiv for getting high ee (entry
6 versus entry 9, Table 2).
3. Results and discussion
3.1. Synthesis of carbohydrate-based phosphate-pyridine (P,N) ligands
The synthesis of chiral ligands 10a and 10b were initiated from
inexpensive N-acetylglucosamine using a standard procedure. As
shown in Scheme 1, C-1 is selectively benzylated at the α-position,
then positions C-4 and C-6 are protected with a benzylidene ring
and the protection at C-2 can be removed easily. Amidation of 2-
With the optimized reaction conditions in hand ( PhMe as solvent,
Cu(OAc)2·2H2O as copper salt, Cu(OAc)2·2H2O/ligand=1:1,

H. Xia et al. / Catalysis Communications 16 (2011) 155–158
157
Scheme 1. Synthesis of ligands 10a and 10b derived from N-acetylglucosamine. Reagents and conditions: (i) BnOH, H+; (ii) PhCHO, ZnCl2; (iii) KOH, EtOH; (iv) 2-picolinic acid, CDI,
CH2Cl2; (v) PhMe, reflux.
Et2Zn/chalcone=1.5:1, and completing the reaction at −10 °C), we
used ligand 10a for Cu-catalyzed enantioselective conjugate addition
of diethylzinc to various substituted chalcones (Table 3). The reac-
tions were carried out at −10 °C in pure toluene with 1.5 equiv of
diethylzinc as the nucleophilic reagent. From the results we found
that there was no electronic effect for 4-substituted chalcones, the
reason is that all of the 4-substituted chalcones gave almost enantios-
electivities (entries 2–5, Table 3). Trans-4-phenyl-3-buten-2-one was
also used as the substrate for the conjugate additions (entry 6,
Table 3), but the reaction is not working. Next, the 1,4-additions of
ZnEt2 to 2-cyclohexenone were examined. However, poor enantios-
electivities were observed (entries 1 and 2, Table 4).
Table 1
Optimizations of copper saltsa.
Entry
Ligand
Cu salts
T
(°C)
t
Yieldb
(%)
eec (%)
Table 2
(config.)d
Optimizations of the solvent, Cu salts/ L10a and Et2Zn/chalcone ratio of the reactiona.
(h)
1
2
3
4
5
6
7
8
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10b
10b
CuBr
CuCl
CuF2
Cu(OTf)2
Cu(OAc)2·2H2O
[Cu(CH3CN)4]BF4
Cu(CF3SO3)2·C6H6
Cu(OAc)2·2H2O
Cu(OAc)2·2H2O
Cu(OAc)2·2H2O
Cu(OTf)2
rt
rt
rt
rt
rt
rt
rt
−10
−25
−40
−10
−10
12
12
24
12
12
24
12
12
48
48
24
12
82
90
30
83
82
43
73
81
56
16
68
77
41 (S)
40 (S)
42 (S)
63 (S)
70 (S)
60 (S)
55 (S)
78 (S)
76 (S)
79 (S)
31 (S)
43 (S)
Entry
Solvent
Cu salts
L10a
Et2Zn/
chalcone
Yieldb
(%)
eec (%)
(config.)d
1
2
3
4
5
6
7
8
9
THF
Et2O
CH2Cl2
toluene/CH2Cl2 (1/1)
ClCH2CH2Cl
toluene
toluene
toluene
1/1
1/1
1/1
1/1
1/1
1/1
1/1.5
½
1.5/1
1.5/1
1.5/1
1.5/1
1.5/1
1.5/1
1.5/1
1.5/1
1/1
87
49
67
70
44
81
86
59
77
34 (S)
28 (S)
33 (S)
53 (S)
17 (S)
78 (S)
70 (S)
71 (S)
46 (S)
9
10
11
12
Cu(OAc)2·2H2O
toluene
1/1
a
a
Reaction was carried out under nitrogen in 3 ml of toluene, 0.5 mmol of chalcone,
Reaction was carried out under nitrogen for 12 h in 3 ml of solvent, 0.5 mmol of
0.75 mmol of Et2Zn, 0.05 mmol of Cu(OAc)2·2H2O, 0.05 mmol of Ligand 10a-b.
chalcone, 0.05 mmol of Cu(OAc)2·2H2O, 0.05 mmol of Ligand 10a.
b
b
Isolated yield.
Isolated yield.
c
c
Determined by chiral HPLC using a Chiralpak AD-H column (eluent: hexane/2-
Determined by chiral HPLC using a Chiralpak AD-H column (eluent: hexane/2-
propanol=99:1, 1.0 ml/min).
propanol=99:1, 1.0 ml/min).
d
d
The absolute configuration was determined by comparison of the specific rotation
The absolute configuration was determined by comparison of the specific rotation
with that of the literature [33,34].
with that of the literature [33,34].

158
H. Xia et al. / Catalysis Communications 16 (2011) 155–158
Table 3
Province (2010R50017) and the Science and Technology Plan of Zhejiang
Province (2011C24004).
Enantioselective 1,4-conjugate addition of Et2Zn to acyclic enonesa.
Entry
Ligand
R1
R2
Yieldb (%)
eec (%) (config.)d
1
2
3
4
5
6
7
10a
10a
10a
10a
10a
10a
10a
Ph
Ph
Ph
Ph
Ph
81
52
60
43
30
Trace
27
78 (S)
74 (S)
73 (S)
73 (S)
46 (S)
N.D.e
Appendix A. Supplementary data
4-Cl-C6H4
4-Me-C6H4
4-MeO-C6H4
4-O2N-C6H4
Ph
Supplementary data to this article can be found online at doi:10.
1016/j.catcom.2011.09.021.
Ph
Me
4-Me-C6H4
Ph
48 (S)
a
References
Reaction was carried out under nitrogen at −10 °C for 12 h in 3 ml of toluene,
0.5 mmol of substrate, 0.75 mmol of Et2Zn, 0.05 mmol of Cu(OAc)2·2H2O, 0.05 mmol
of Ligand 10a.
[1] S.-M. Guo, Y.-J. Xie, X.-Q. Hu, C.-G. Xia, H.-M. Huang, Angewandte Chemie Inter-
national Edition 49 (2010) 2728.
[2] S. Woodward, M. Diéguez, O. Pàmies, Coordination Chemistry Reviews 254
(2010) 2007.
[3] H.-C. Guo, J.-A. Ma, Angewandte Chemie International Edition 118 (2006) 362.
[4] B.L. Feringa, Accounts of Chemical Research 33 (2000) 346.
[5] H.-Y. Cheung, W.-Y. Yu, T.T.-L. Au-Yeung, Z.-Y. Zhou, A.S.C. Chan, Advanced Syn-
thesis and Catalysis 351 (2009) 1412.
b
Isolated yield.
c
Determined by chiral HPLC using a Chiralpak AD-H column (eluent: hexane/2-
propanol=99:1, 1.0 ml/min).
d
The absolute configuration was determined by comparison of the specific rotation
with that of the literature [33,34].
e
N.D. means not determined.
[6] R. Kramer, R. Brűckner, Angewandte Chemie International Edition 46 (2007)
6537.
[7] R. Noyori, Angewandte Chemie International Edition 41 (2002) 2008.
[8] A. Alexakis, J. Frutos, P. Mangeney, Tetrahedron-Asymmetry 4 (1993) 2427.
[9] A. Alexakis, S. Mutti, J.F. Normant, Journal of the American Chemical Society 113
(1991) 6332.
[10] T. Ikariya, A.J. Blacker, Accounts of Chemical Research 40 (2007) 1300.
[11] C.K. Seubert, Y. Sun, W.R. Thiel, Dalton Transactions (2009) 4971.
[12] A. Mikhailine, A.J. Lough, R.H. Morris, Journal of the American Chemical Society
131 (2009) 1394.
[13] K. Glegola, S.A. Johannesen, L. Thim, C. Goux-Henry, T. Skrydstrup, E. Framery,
Tetrahedron Letters 49 (2008) 6635.
[14] H.-S. Lai, Z.-Y. Huang, Q. Wu, Y. Qin, The Journal of Organic Chemistry 74 (2008)
283.
[15] L.B. Schenkel, J.A. Ellman, Organic Letters 5 (2003) 545.
[16] J. Feng, D.S. Bohle, C. Li, Tetrahedron-Asymmetry 18 (2007) 1043.
[17] R. Stranne, J.L. Vasse, C. Moberg, Organic Letters 3 (2001) 2525.
[18] X.-Q. Hu, H.-L. Chen, X.-M. Zhang, Angewandte Chemie International Edition 38
(1999) 3518.
Table 4
Enantioselective 1,4-conjugate addition of Et2Zn to 2-cyclohexenonea.
Entry
Ligand
Yieldb (%)
ee (%)c
Configd
1
2
10a
10b
51
47
22
17
(S)
(S)
a
Reaction was carried out under nitrogen at −10 °C for 12 h in 3 ml of toluene,
0.5 mmol of substrate, 0.75 mmol of Et2Zn, 0.05 mmol of Cu(OAc)2·2H2O, 0.05 mmol
of Ligand 10a-b.
b
Isolated yield.
c
Determined by GC equipped with a Chiraldex A-TA column (50 m×0.25 mm I.D.).
The absolute configuration was determined by comparison with an authentic
d
sample.
[19] Y. Imai, W. Zhang, T. Kida, Y. Nakatsuji, I. Ikeda, Tetrahedron Letters 39 (1998)
4343.
4. Conclusion
[20] C.P. Butts, E. Filali, G.C. Lloyd-Jones, P. Norrby, D.A. Sale, Y. Schramm, Journal of
the American Chemical Society 131 (2009) 9945.
[21] B.M. Trost, G.M. Schroeder, Chemical European Journal 11 (2005) 174.
[22] B.M. Trost, D.L. Van Vranken, Angewandte Chemie International Edition 31
(1992) 228.
[23] B. Jiang, Y. Lei, X. Zhao, The Journal of Organic Chemistry 73 (2008) 7833.
[24] N.V. Vorontsova, V.I. Rozenberg, E.V. Sergeeva, E.V. Vorontsov, Z.A. Starikova, K.A.
Lyssenko, H. Hopf, Chemical European Journal 14 (2008) 4600.
[25] B.M. Trost, M.L. Crawley, Chemical Reviews 103 (2003) 2921.
[26] V. Benessere, R.D. Litto, A.D. Roma, F. Ruffo, Coordination Chemistry Reviews 254
(2010) 390.
In summary, we have described a new type of carbohydrate-based
phosphate-pyridine ligands 10a and 10b which have been successfully
applied in Cu-catalyzed conjugate addition of Et2Zn to chalcones. The
advantage of these phosphate-pyridine ligands is that they can be easily
prepared in a few steps from commercial N-acetylglucosamine, an
inexpensive natural chiral feedstock, and electronic and steric prop-
erties could be finely tuned. Our investigations will be focused on the
applications of these new P, N ligands 10a and 10b in other asymmet-
ric catalytic reactions, as well as studying the mechanism. Further
screening of these new chiral ligands with respect to other enones
currently in progress and will be reported in due course.
[27] B. Gläser, H. Kunz, Synlett (1998) 53.
[28] A. De Roma, F. Ruffo, S. Woodward, Chemical Communications (2008) 5384.
[29] C. Shen, H.-J. Xia, H. Zheng, P.-F. Zhang, X.-Z. Chen, Tetrahedron-Asymmetry 21
(2010) 1936.
[30] R. Hulst, N.K. De Vries, B.L. Feringa, Tetrahedron-Asymmetry 5 (1994) 699.
[31] V. Benessere, R. Del Litto, F. Ruffo, C. Moberg, European Journal of Organic Chem-
istry (2009) 1352.
[32] Y.-C. Hu, X.-M. Liang, X.-Q. Hu, The Journal of Organic Chemistry 68 (2003) 4542.
[33] A. Hajra, N. Yoshikai, E. Nakamura, Organic Letters 8 (2006) 4153.
[34] V. Benessere, A. De Roma, F. Ruffo, ChemSusChem 1 (2008) 425.
Acknowledgments
This work was supported by the National Natural Science Foundation
of China (No. 21076052), Key Sci-tech Innovation Team of Zhejiang