Paracyclophane-derived monodentate phosphoramidite ligands for copper-catalyzed asymmetric conjugate addition of diethylzinc to substituted chalcones

Article abstract of DOI:10.1021/jo502715f

Copper-catalyzed asymmetric conjugate addition of diethylzinc to chalcones could be realized by using [2.2]paracyclophane-derived monodentate phosphoramidite ligands. The excellent yield and enantioselectivity (up to 98% yield and 95% enantiomeric excess) could be realized with low catalyst loading of 1.0 mol % and low ligand loading of 1.2%.

Full text of DOI:10.1021/jo502715f

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Article
[2.2]Paracyclophane-derived Monodentate Phosphoramidite
Ligands for Copper-Catalyzed Asymmetric Conjugate
Addition of Diethylzinc to Substituted Chalcones
Lei Han, Yang Lei, Ping Xing, Xiao-Long Zhao, and Biao Jiang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502715f • Publication Date (Web): 25 Mar 2015
Downloaded from http://pubs.acs.org on March 30, 2015
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[2.2]Paracyclophane-derived Monodentate Phosphoramidite Ligands for Copper-
Catalyzed Asymmetric Conjugate Addition of Diethylzinc to Substituted Chalcones
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Lei Han,† Yang Lei,† Ping Xing,† Xiao-Long Zhao† and Biao Jiang*, †, ‡
E-mail: jiangb@sioc.ac.cn
†CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China
‡Shanghai Advanced Research Institute, Chinese Academy of Sciences, 99 Haike Road, Shanghai, 201210, China
ABSTRACT: The copper-catalyzed asymmetric conjugate addition of diethylzinc to
chalcones could be realized by using [2.2]paracyclophane-derived monodentate
phosphoramidite ligands. The excellent yield and enantioselectivity (up to 98% yield and
95% ee) could be realized with low loadings of catalyst and ligand (catalyst loading is
1.0 mol% and ligand loading is 1.2%) .
INTRODUCTION
The conjugate addition of organometallic reagents to α,β-unsaturated carbonyl
compounds is among the most useful methods for C−C bond formation and has a broad
application in the synthesis of numerous biologically active compounds.1 Many chiral
auxiliaries and stoichiometric reagents have been used in this type of reaction with high
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stereoselectivity.1a, 1e 2 Catalytic enantioselective additions have also been developed,
among which the use of organozinc reagents as donor and copper complexes with
phosphorus ligands as catalysts afforded the most successful results.3 A lot of these
phosphorus ligands are monodentate phosphite and phosphoroamidite type. One of the
pioneering examples were phosphoroamidites derived from BINOL, and some others
derived from TADDOL, biphenol and SPINOL were also effective for this reaction.
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Modifications of this type of ligands on their backbones and exocyclic amines or
alcohols were reported, some of the modified ligands demonstrated excellent
enantioselectivities in the reactions of organozinc reagents with cyclic or acyclic enones.
However, the structures of these phosphoroamidite ligands were limited to axially and
centrally chiral backbones, and until now planar chiral phosphoramidite and phosphite
4
ligands were rarely studied.3j-l, As to the [2.2]paracyclophane backbone,5 chiral
monodentate phosphite ligand derived from 4-hydroxyl[2.2]paracyclophane4b and
bidentate phosphite ligands4a derived from 4,5-dihydroxyl[2.2]paracyclophane were
reported recently. Due to its high rigidity, it is interesting to explore the potential of
[2.2]paracyclophane in the research field of chiral monodentate phosphoroamidite or
phosphite ligands. Herein we describe the preparation of 4,12-disubstituted
[2.2]paracyclophane derived monodentate phosphoroamidite ligands and their
application in the copper-catalyzed asymmetric conjugate addition to acyclic enones.
Results & Discussion
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Our work started from the chiral PHANOL, 6 for it is the simplest 4,12-disubstituted
[2.2]paracyclophane containing two hydroxyl groups. However, PHANOL cannot be
modified to its monophosphoroamidite. The failure might be ascribed to PHANOL’s high
rigidity, and we think that structural rigidity and flexibility of chiral ligands are also an
important issue in asymmetric catalysis involving [2.2]paracyclophane based ligands
(Scheme 1).7
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Scheme 1 Some Skeletons for Phosphoramidite Ligands
Then, our attention turned to compound 1.8 Methylation of (Sp)-2 followed by Suzuki
coupling with o-methoxyphenylboronic acid afforded dimethoxyl compound (Sp)-4,
which could be used to prepare (Sp)-1 after removal of the two methyl groups by reacting
with BBr3. Planar chiral phosphoroamidite ligands 5a-c were easily prepared from (Sp)-1.
Heating the mixture of diol (Sp)-1 and P(NMe2)3 or P(NEt2)3 in toluene for 4 hours gave
(Sp)-5a or (Sp)-5b in about 60% yield. The structure of (Sp)-5b was confirmed by X-ray
analysis. (Sp)-5c was produced by subsequently condensation of (Sp)-1 with PCl3 and i-
Pr2NH.
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Scheme 2 Preparation of Chiral Phosphoroamidite Ligands.
Chalcone (6a) served as substrate to study the behavior of ligand (Sp)-5 in the
asymmetric conjugate addition. The reactions were carried out in the presence of
Cu(OTf)2 and the chiral ligands in toluene. The use of 4 mol% (Sp)-5a and 2 mol% of
Cu(OTf)2 at room temperature afforded the product (7a) of R configuration in 87% yield
and 87% ee (Table 1, Entry 1). Slightly higher yield and ee value could be obtained when
the reaction was carried out at lower temperature (Table 1, Entry 2). Reaction at much
lower temperature (-30 ºC) did not promote yield and enantioselectivity obviously (Table
1, Entry 3). The yield and ee value remained at the same level when reducing the loading
of the catalyst (Table 1, Entry 4). (Sp)-5b and (Sp)-5c were subsequently investigated at
different temperatures and with different loadings. A great improvement of the
enantioselectivity (up to 95% ee) was achieved by employing (Sp)-5b as ligand (Table 1,
Entries 5-8). Temperature lower than 0ºC and catalyst loading higher than 1 mol% were
found unnecessary for obtaining good result (Table 1, Entries 5-7). Using ZnEt2 solution
in toluene instead of ZnEt2 solution in hexane did not affect the result either (Table 1,
Entry 8). (Sp)-5c seemed less efficient than (Sp)-5b since the ee dropped to 87% (Table 1,
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Entries 9-12). It is conspicuous that (Sp)-5b is the most appropriate ligand for the reaction.
(Sp)-5b/Cu(OTf)2 ratio was brought down from 2.0:1 to 1.2:1 and high
enantioselectivities maintained (Table 1, Entries 7 and 13-17). When the ratio came down
to 1.0:1, the enantioselectivity began to slightly decrease. Therefore, the optimal
condition was chosen as 1mol% of Cu(OTf)2, 1.2 mol% of ligand, 0 ºC (Table 1, Entry
16).
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Table 1 Enantioselective Conjugate Addition of ZnEt2 to Chalcone
entry Cu(OTf)2 (mol %) ligand (mol %) T (ºC) t(h) yield (%)a ee (%)b
1
2
2.0
2.0
2.0
1.0
2.0
2.0
1.0
1.0
1.0
2.0
1.0
2.0
2.0
1.0
1.0
1.0
1.0
(Sp)-5a (4.0)
(Sp)-5a (4.0)
(Sp)-5a (4.0)
(Sp)-5a (2.0)
(Sp)-5b (4.0)
(Sp)-5b (4.0)
(Sp)-5b (2.0)
(Sp)-5b (2.0)
(Sp)-5c (2.0)
(Sp)-5c (4.0)
(Sp)-5c (2.0)
(Sp)-5c (4.0)
(Sp)-5b (3.6)
(Sp)-5b (1.6)
(Sp)-5b (1.4)
(Sp)-5b (1.2)
(Sp)-5b (1.0)
r. t.
-20
-30
-20
-20
0
12
1
87
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0
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0
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-20
-20
0
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2
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0
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0
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0
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a
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Isolated yield; Determined by chiral HPLC; . 1.0 M ZnEt2 solution in toluene was
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used.
Behaviors of different copper salts used in the reaction were then explored and the
results are listed in Figure 1a. Cu(I) and Cu(II) salts could result in high
enantioselectivity (Column 1-5, Figure 1a). Volume decrease of corresponding anions
decreases with loss of enantioselectivity (Column 1 vs 3, 2 vs 4, Figure 1a). For single
anions, the smaller the anion is, the lower the ee value is afforded (Column 6-8, Figure
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1a). However, excellent results could be observed when BF4 and PF6 salts were used
respectively (Column 9-10, Figure 1a). A modest negative non-linear effect implied the
existence of a more reactive racemic complex in the catalytic system (Figure 1b).
Figure 1. Asymmetric Catalytic Conjugate Addition with (Sp)-5b using Various
Copper Salts (a) and Non-Linear Effect of Ligand (Sp)-5b (b).
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The scope of 1, 4-addition of ZnEt2 to substituted chalcones catalyzed by Cu(OTf)2/5b
were then explored using the best performing catalytic system and the results were listed
in Table 2. When Ar1 was para- or meta- substituted phenyl group, chalcones bearing
either electronic donating or withdrawing groups have been successfully converted to the
corresponding chiral ketones with high yield and enantioselectivities (Table 2, Entries 1-
6, 90%-97% yield, 93%-95% ee). However, changing Ar1 to o-bromophenyl or o-tolyl
group greatly reduced the selectivities (55% or 71% ee) while the yield remained high
(Table 2, Entries 7 and 12y 7). Reaction at lower temperature (-40 ºC) did not help much
on enhancing enantioselctivity (Table 2, Entry 8). Three substrates with different para-
substituted Ar2 were then tested, and satisfactory results could be observed when the aryl
group was methoxy (Table 2, Entry 9, 90% yield, 94% ee) or bromo substituted (Table 2,
entry 11, 98% yield 95% ee), as to para-chlorophenyl group the yield was still high while
the ee was slightly lower than others (Table 2, Entry 10, 95% yield, 87% ee). Some alkyl
substrates 6m and 6n were also tested, but unfortunately none of these reacted (Table 2,
Entries 13-14), double aromatic groups were needed in our methodology perhaps for the
existence of intermolecular weak interaction.
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带格式的: 字体: 倾斜
带格式的: 字体: 加粗
带格式的: 字体: 加粗
Table 2 Enantioselective Conjugate Addition of ZnEt2 to Substituted Chalcones.
entry Substrate
1
yield (%)a ee (%)b
93 95
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95c
58c
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带格式表格
带格式的: 字体: Times New Roman
域代码已更改
12
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95
71
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带格式的: 字体: Times New Roman
No reaction
No reaction
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a. Isolated yield; b. Determined by chiral HPLC; c. The reaction was carried out at -40 ºC.
CONCLUSION
In summary, monodentate phosphoroamidite type ligands (Sp)-5a/b/c derived from a
flexible 4,12-disubstituted[2.2]paracyclophane were developed. They are highly efficient
in the copper-catalyzed asymmetric conjugate addition of diethylzinc to substituted
chalcones, the results obtained (up to 95% ee) were among the best in this field. To the
best of our knowledge, higher than 95% ee have been usually obtained by using bidentate
P,N-ligands,9 and until now only several methodologies have been reported at low
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temperatures.3b,10 Further studies to explore the scope of these ligands in more
asymmetric catalytic reactions are currently in progress.
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EXPERIMENTAL SECTION
General Remarks: Unless otherwise specified, materials were purchased from
commercial suppliers and used without further purification. All reactions were carried out
under argon atmosphere. Flash chromatography was performed using silica gel H (10-40
μm). Standard reagents and solvents were purified according to known procedures.
Melting points are uncorrected. NMR spectra were recorded using 300 MHz
spectrometer. Chemical shifts (δ) are expressed in ppm relative to CHCl3 at δ =7.26 ppm
1
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for H NMR and to CDCl3 at δ = 77.00 ppm for C NMR. (Rp)-PHANOL,6a (Sp)-2,6d
and (Sp)-37c and were prepared according to the literature.
Procedure for the Preparation of (Sp)-4-Bromo-12-methoxy[2.2]paracyclophane
((Sp)-3): (Sp)-3 was prepared according to the procedure for synthesizing (Rp)-3.7c All the
spectroscopy data was in accordance with that reported. m. p. 167-169 ºC. (lit.7c 181°C).
[]2D4.6 = +10.3 (c = 0.50, chloroform).
Procedure
for
the
Preparation
of
(Sp)-4-methoxy-12-(2-
methoxyphenyl)[2.2]paracyclophane ((Sp)-4): A mixture of (Sp)-3 (1.95 g, 6.1 mmol),
2-methoxyphenylboronic acid (1.12 g, 7.4 mmol), PdCl2(dppf)·CH2Cl2 (50 mg, 61 μmol),
K3PO4 (2.61 g, 12.3 mmol), and 10 mL toluene was heat at 110ºC for 2 h, cooled to room
temperature, filtered. After washing the solid with dichloromethane, the combined filtrate
was concentrated, and purified by chromatography on a silica gel column with 40:1
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petroleum ether/EtOAc to give (Sp)-4 as colourless oil 2.01 g, 95% yield. []2D0.8 = -120.0
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1
(c = 0.30, chloroform). H NMR (300 MHz, CDCl3): δ 7.63 (dd, J = 7.5, 1.5 Hz, 1H),
7.36 (dt, J = 8.2, 1.7 Hz, 1H), 7.16 (t, J = 7.1 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.83 (d,
J = 1.3 Hz, 1H), 6.60-6.56 (m, 2H), 6.44 (dd, J = 7.6, 1.2 Hz, 1H), 6.37 (d, J = 7.6 Hz,
1H), 6.03 (s, 1H), 3.80 (s, 3H), 3.73 (s, 3H), 3.49-3.40 (m, 1H), 3.15-2.94 (m, 4H), 2.91-
2.79 (m, 1H), 2.74-2.58 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 158.1, 156.0, 142.4,
138.8, 135.3, 134.4, 133.2, 132.5, 130.7, 130.6, 129.4, 128.4, 128.2, 125.8, 120.6, 117.2,
110.8, 57.3, 55.3, 34.3, 33.9, 33.6, 31.0. IR (cm-1): 2928, 1596, 1495, 1409, 1254, 1033,
755. MS (EI) m/z 344 [M+] (24.2). HRMS (EI-quadrupole) calcd. for C24H24O2 344.1776,
found 344.1773.
Procedure
for
the
Preparation
of
(Sp)-4-hydroxyl-12-(2-
hydroxylphenyl)[2.2]paracyclophane ((Sp)-1): Cooled a solution of (Sp)-3 (2.0 g, 5.8
mmol) in 20 mL dichloromethane to -78 ºC followed by added 3.4 mL of BBr3 (8.73 g,
34.8 mmol). The mixture was warmed to room temperature and stirred overnight. 20 mL
of water was slowly added at 0 ºC. The mixture was then extracted with dichloromethane
(20 mL×3). The combined organic layer was concentrated and purified by
chromatography on a silica gel column with 10:1 petroleum ether/EtOAc to give (Sp)-1 as
a white solid 1.54 g, 84% yield. m. p. 130-131 ºC. []2D0.8 = -131.8 (c = 0.30, chloroform).
1H NMR (300 MHz, (CD3)2SO): δ 9.15 (s, 1H), 8.72 (s, 1H), 7.61 (dd, J = 7.6, 1.5 Hz,
1H), 7.16 (dt, J = 7.6, 1.6 Hz, 1H), 6.97 (td, J = 7.4, 1.1 Hz, 1H), 6.86 (dd, J = 8.0, 0.9
Hz, 1H), 6.73 (d, J = 1.6 Hz, 1H), 6.51 (d, J = 7.7 Hz, 1H), 6.45-6.40 (m, 1H), 6.34 (dd,
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J = 7.7, 1.6 Hz, 1H), 6.17 (dd, J = 7.7, 1.5 Hz, 1H), 5.70 (d, J = 1.5 Hz, 1H), 3.39-3.32
(m, 1H), 3.06-2.53 (m, 6H), 2.31 (ddd, J = 12.5, 10.3, 4.8 Hz, 1H). 1H NMR (300 MHz,
(CD3)2CO): δ 7.91 (br, 1H), 7.74 (s, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.21 (dt, J = 7.8, 1.6
Hz, 1H), 7.02-6.96 (m, 3H), 6.62 (d, J = 7.7 Hz, 1H), 6.52 (d, J = 7.7 Hz, 1H), 6.40 (d, J
= 7.6 Hz, 1H), 6.31 (dd, J = 7.7, 1.2 Hz, 1H), 5.80 (s, 1H), 3.48 (ddd, J = 12.7, 8.6, 2.6
Hz, 1H), 3.16-3.04 (m, 3H), 3.02-2.91 (m, 1H), 2.81-2.63 (m, 2H), 2.56-2.47 (m, 1H).
13C NMR (75 MHz, (CD3)2SO): δ 154.8, 153.7, 141.4, 138.5, 138.3, 136.0, 134.7, 133.2,
131.9, 131.4, 128.7, 128.6, 128.0, 125.2, 123.6, 119.5, 118.1, 115.2, 34.0, 33.7, 32.9, 31.0.
IR (cm-1): 3483, 3450, 2930, 2580, 1573, 1415, 1261, 1224, 938, 768. MS (ESI) m/z
315.1 [M-H]-. HRMS (MALDI-TOF) calcd. for C22H20O2Na+ 339.1356, found 339.1365.
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(Sp)-5a: A mixture of (Sp)-1 (174 mg, 0.55 mmol), HMPT (99 mg, 0.60 mmol), and 1.5
mL of dry toluene was heated at reflux under argon for 4 h. After cooling to room
temperature, the mixture was concentrated and purified by chromatography on a silica
gel column with 10:1 petroleum ether/EtOAc to give (Sp)-5a as a white solid 133 mg,
62% yield. m. p. 169-171 °C. []2D3.3 = -158.6 (c = 0.17, chloroform). 1H NMR (300 MHz,
CDCl3): δ 7.86 (d, J = 1.5 Hz, 1H), 7.39-7.30 (m, 2H), 7.23-7.14 (m, 2H), 6.75 (d, J =
7.8 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 6.47-6.44 (m, 2H), 6.23 (d, J = 5.8 Hz, 1H), 3.63
(ddd, J = 13.0, 10.5, 4.9 Hz, 1H), 3.36-3.27 (m, 1H), 3.22-3.17 (m, 2H), 3.09-2.72 (m,
10H). 13C NMR (75 MHz, CDCl3): δ 152.8, 152.8, 151.7, 151.6, 141.7, 138.7, 138.5,
137.3, 134.3, 133.8, 132.9, 131.3, 130.0, 128.2, 127.6, 127.0, 123.4, 122.7, 122.6, 117.7,
117.3, 35.3, 35.1, 35.0, 34.8, 32.8, 29.1. 31P NMR (161.92 MHz, CDCl3): δ 139.6. IR
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(cm-1): 2926, 1595, 1566, 1443, 1250, 1213, 977, 876, 764. MS (EI) m/z 353 [M+]
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(100.0). HRMS (EI-quadrupole) calcd. for C24H24NO2P 389.1545, found 389.1548.
(Sp)-5b: was obtained as a white solid 150 mg in 65% yield by employing the same
procedure as for (Sp)-5a using hexaethylphosphorus triamide. m. p. 134-135 ºC. []2D1.6 = -
1
156.3 (c = 0.20, chloroform). H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 1.5 Hz, 1H),
7.30 (dt, J = 7.7, 1.6 Hz, 1H), 7.25 (dd, J = 7.8, 1.7 Hz, 1H), 7.16-7.10 (m, 2H), 6.71 (d,
J = 7.8 Hz, 1H), 6.58 (d, J = 7.7 Hz, 1H), 6.43-6.39 (m, 2H), 6.17 (d, J = 5.5 Hz, 1H),
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3.59-3.39 (m, 5H), 3.29-3.11 (m, 3H), 3.03-2.69 (m, 4H), 1.34 (t, J = 7.1 Hz, 6H). C
NMR (75 MHz, CDCl3): δ 153.1, 153.1, 152.1, 152.0, 141.7, 138.8, 138.6, 137.4, 134.3,
133.8, 132.9, 131.4, 130.2, 128.2, 127.5, 126.9, 123.3, 122.4, 122.4, 117.7, 117.3, 77.4,
77.0, 76.5, 39.3, 39.0, 35.2, 34.9, 32.9, 29.2, 15.2. 31P NMR (161.92 MHz, CDCl3): δ
140.0. IR (cm-1): 2972, 2926, 1494, 1469, 1443, 1411, 1245, 1205, 1179, 1026. MS (EI)
m/z 417 [M+] (69.4). HRMS (EI-quadrupole) calcd. for C26H28NO2P 417.1858, found
417.1852.
(Sp)-5c: To a solution of PCl3 (391 mg, 2.8 mmol)) and NEt3 (1.44 g, 14.2 mmol) in 8
mL dry THF was slowly added a solution of iPr2NH in 8 mL THF via syringe pump in 10
min at 0 ºC, after 2 h stirring at 0 ºC (Sp)-1 was added and the solution was warmed to
room temperature. Having been stirred overnight, the reaction mixture was filtered. The
filtrate was concentrated, and purified by chromatography on a silica gel column with
10:1 petroleum ether/EtOAc to give (Sp)-5c as a white solid 123mg in 50% yield. m. p.
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154-155 ºC. []2D1.9 = -156.1 (c = 0.13, chloroform). H NMR (400 MHz, CDCl3): δ 7.75
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(d, J = 1.5 Hz, 1H), 7.29 (dd, J = 7.4, 1.5 Hz, 1H), 7.22 (dd, J = 7.9, 1.7 Hz, 1H), 7.13-
7.10 (m, 2H), 6.68 (d, J = 7.8 Hz, 1H), 6.55 (d, J = 7.7 Hz, 1H), 6.39-6.37 (m, 2H), 6.14
(d, J = 5.6 Hz, 1H), 4.09-3.98 (m, 2H), 3.53 (ddd, J = 13.1, 10.6, 4.9 Hz, 1H), 3.25-3.06
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(m, 3H), 3.01-2.85 (m, 2H), 2.81-2.66 (m, 2H). C NMR (75 MHz, CDCl3): δ 153.4,
153.3, 152.9, 152.7, 141.8, 141.7, 138.9, 138.6, 137.4, 134.3, 134.2, 133.8, 132.9, 131.5,
130.2, 128.2, 127.5, 127.5, 126.6, 123.1, 122.3, 122.2, 117.6, 117.2, 44.9, 44.7, 35.2,
34.9, 32.9, 29.3, 24.5, 24.4, 24.4, 24.3. 31P NMR (161.92 MHz, CDCl3): δ 140.2. IR (cm-
1): 2969, 2925, 1595, 1565, 1494, 1445, 1247, 1201, 975, 879. MS (EI) m/z 445 [M+]
(85.7). HRMS (EI-quadrupole) calcd. for C28H32NO2P 445.2171, found 445.2169.
General procedure for the copper-catalyzed conjugate addition: A solution of
Cu(OTf)2 (5.5 mg, 15.0 μmol) and ligand 5 (30.0 μmol) in dry toluene (10 mL) was
stirred for 40 min at room temperature under an argon atmosphere. The solution was then
cooled to indicated temperature. To the solution Et2Zn (2.25 mL, 2.25 mmol, 1.0 M
solution in hexane) and substituted chalcone (1.50 mmol) were added subsequently. The
resulting mixture was stirred at the indicated temperature until the reaction was
completed according to TLC, quenched with 20 mL 2 M aqueous HCl and extracted with
dichloromethane (20 mL×3). The combined organic layers were dried over anhydrous
Na2SO4, concentrated under reduced pressure to give a crude product, which was purified
by column chromatography using petroleum ether/EtOAc as eluant to afford the
ethylated product for HPLC analysis.
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7a: Colorless oil 296 mg, 95% yield, 95% ee.[α] D18.7 = -8.4(c = 2.4, ethanol). 1H NMR
(300 MHz, CDCl3): δ 7.93-7.90(m, 2H), 7.54 (t, J = 7.3 Hz, 1H), 7.46-7.41 (m, 2H),
7.32-7.17 (m, 5H), 3.36-3.21 (m, 3H),1.87-1.73 (m, 1H), 1.71-1.58 (m, 1H), 0.82 (t, J =
7.3 Hz, 1H). ChiralPAK® OJ-H chromatography (n-hexane: isopropanol = 99:1), 1.0
mL/min, 214 nm. Retention time: tS = 23.6 min, tR = 31.2 min. The compound was
already known.11a
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7b: White solid 249 mg, 93% yield, 95% ee. m. p. 75-76ºC. [α] D19.8 = +7.6 (c = 0.92,
chloroform). 1H NMR (300 MHz, CDCl3): δ 7.90 (d, J = 7.8 Hz, 2H), 7.53 (t, J = 7.3 Hz,
1H), 7.43 (t, J = 7.6 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 3.77 (s,
3H), 3.28-3.14 (m,3H), 1.83-1.69 (m, 1H), 1.67-1.53 (m, 1H), 0.80 (t, J = 7.3 Hz, 3H).
ChiralPAK® OJ-H chromatography (n-hexane:isopropanol = 99:1), 1.0 mL/min, 214 nm.
Retention time: tminor = 33.3 min, tmajor = 46.8 min. The compound was already known.11b
7c: Colorless oil 263 mg, 90% yield, 95% ee. m. p. 72-74 ºC. [α]D18.3 = +10.5 (c = 1.4,
chloroform). 1H NMR (300 MHz, CDCl3): δ 7.90 (d, J = 7.8 Hz, 2H), 7.56 (t, J = 7.3 Hz,
1H), 7.45 (t, J = 7.7 Hz, 2H), 6.94-6.80 (m, 2H), 3.25-3.16 (m, 3H), 1.83-1.70 (m, 1H),
1.65-1.50 (m, 1H), 0.82 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 199.0, 147.5,
145.7, 138.4, 137.0, 132.8, 128.4, 127.9, 120.6, 108.0, 107.6, 100.7, 45.7, 42.7, 29.3,
12.0. 19F NMR (282 MHz, CDCl3): δ -135.1, -135.2 (m, 2F), -164.15 (tt, J = 20.6, 6.5 Hz,
1F).MS (EI) m/z 292 [M+] (6.5). HRMS (EI-quadrupole) calcd. for C17H15OF3 292.1075,
found 292.1072. IR (cm-1): 2962, 1682, 1533, 1449, 1028, 854, 750. ChiralPAK® OJ-H
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chromatography (n-hexane: isopropanol =99:1), 1.0mL/min, 214nm. Retention time:
tminor = 11.5 min, tmajor = 13.7 min.
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7d: Colorless oil 268 mg, 95% yield, 95% ee. [α]D = -16.9 (c = 0.60, chloroform).
1H NMR (300 MHz, CDCl3): δ 7.94-7.84 (m, 2H), 7.54 (t, J = 7.3 Hz, 1H), 7.43 (t, J =
7.4 Hz, 2H), 6.72-6.65 (m, 3H), 5.91 (s, 2H), 3.29-3.11 (m, 3H), 1.81-1.68 (m, 1H), 1.64-
1.49(m, 1H), 0.80 (t, J = 7.3 Hz, 3H).13C NMR (75 MHz, CDCl3): δ 199.0, 147.5, 145.7,
138.4, 137.0, 132.8, 128.4, 127.9,120.6, 108.0, 107.6, 100.7, 45.7, 42.7, 29.3, 12.0.MS
(EI) m/z 282 [M+] (53.6).HRMS (EI-quadrupole) calcd. for C18H18O3 282.1256, found
282.1246.IR (cm-1): 1683, 1488, 1247, 1041, 940, 895, 805.ChiralPAK® OJ-H
chromatography (n-hexane: isopropanol = 99:1), 1.0 mL/min, 214 nm. Retention time:
tminor = 32.8 min, tmajor = 54.8 min.
7e: Colorless oil 265 mg, 97% yield, 93% ee. [α]D19.4 = -1.1 (c = 0.75, chloroform). 1H
NMR (300 MHz, CDCl3): δ 7.92-7.89 (m, 2H), 7.57-7.52 (m, 1H), 7.46-7.41 (m,
2H),7.24-7.11 (m, 4H), 3.30-3.19 (m, 3H), 1.85-1.72 (m, 1H), 1.69-1.55 (m, 1H), 0.81 (t,
J = 7.3 Hz, 3H). CHIRALPAK® AD-H chromatography (n-hexane:isopropanol = 95:5),
0.4 mL/min, 214 nm. Retention time: tminor = 15.2 min, tmajor = 16.8 min. The compound
was already known.11c
18.5
7f: Yellow solid 267 mg, 95% yield, 93% ee. m. p. 56-58 ºC.[α] D = -18.0 (c = 2.2,
chloroform). 1H NMR (300 MHz, CDCl3): δ 7.91 (d, J = 7.6 Hz, 2H), 7.53 (t, J = 7.3 Hz,
1H), 7.43 (t, J = 7.4 Hz, 2H), 7.10 (d, J = 8.5 Hz, 2H), 6.69 (d, J = 8.5 Hz, 2H), 3.27-
3.09 (m, 3H), 2.91 (s,6H), 1.82-1.68 (m, 1H), 1.68-1.51 (m, 1H), 0.80 (t, J = 7.3 Hz, 3H).
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CHIRALPAK® AD-H chromatography (n-hexane : isopropanol = 95:5), 0.4 mL/min,
214 nm. Retention time: tminor = 9.9 min, tmajor = 13.9 min. The compound was already
known.11d
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7g: Colorless oil 301 mg, 95% yield, 95% ee. [α] D18.3 = +2.8 (c = 2.3, chloroform).1H
NMR (300 MHz, CDCl3): δ 7.96-7.93 (m, 2H), 7.57-7.53 (m, 2H), 7.47-7.41 (m, 2H),
7.30-7.23 (m, 2H), 7.05 (ddd, J = 8.0, 6.3, 2.7 Hz, 1H), 3.90-3.81 (m, 1H), 3.26 (dq, J =
16.5, 7.0 Hz, 2H), 1.88-1.64 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H). CHIRALPAK® AD-H
chromatography (n-hexane : isopropanol = 95:5), 0.8 mL/min, 214 nm. Retention time:
tminor = 8.7 min, tmajor = 12.7 min. The compound was already known.10
7h: Colorless oil 304 mg, 96% yield, 55% ee.[α] D18.4 = +22.1 (c = 1.1, chloroform). 1H
NMR (300 MHz, CDCl3): δ 7.91-7.88 (m, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.46-7.39 (m,
4H), 7.11 (d, J = 8.4 Hz, 2H), 3.29-3.17 (m, 3H), 1.68-1.53 (m, 1H), 1.69-1.61 (m, 1H),
0.80(t, J = 7.3 Hz, 3H). CHIRALPAK® AD-H chromatography, (n-hexane : isopropanol
= 95:5), 0.8 mL/min, 214nm. Retention time: tminor = 8.3 min, tmajor = 10.5 min. When the
reaction was taken at -40 ºC, 95%yield, 58% ee. The compound was already known.11a
7i: Colorless oil 241 mg, 90% yield, 94% ee. [α] D19.9 = +3.0 (c = 0.50, chloroform). 1H
NMR (300 MHz, CDCl3): δ 7.89 (d, J = 8.8 Hz, 1H), 7.31-7.15 (m, 5H), 6.90 (d, J = 8.8
Hz, 1H), 3.85 (s, 3H), 3.27-3.16 (m, 3H), 1.85-1.72 (m, 1H), 1.70-1.55 (m, 1H), 0.79 (t, J
= 7.3 Hz, 3H). CHIRALPAK® AD-H chromatography (n-hexane : isopropanol = 90:10),
0.5 mL/min, 214 nm. Retention time: tminor = 15.3 min, tmajor = 22.1. The compound was
already known.11b
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7j: Colorless oil 259 mg, 95% yield, 87% ee. [α] D19.5 = +2.5 (c = 0.75, chloroform).1H
NMR (300 MHz, CDCl3): δ 7.83 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.6 Hz, 2H), 7.31-7.26
(m, 2H), 7.22-7.16 (m, 3H), 3.31-3.16 (m, 3H), 1.85-1.71 (m, 1H), 1.69-1.57 (m,1H),
0.80 (t, J = 7.3 Hz, 3H). CHIRALPAK® AD-H chromatography (n-hexane : isopropanol
= 90:10), 0.5 mL/min, 214 nm. Retention time: tminor = 7.0 min, tmajor = 8.7 min. The
compound was already known.11b
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7k: White solid 311 mg, 98% yield, 95% ee. m. p. 50-52 ºC. [α] D19.9 = +1.9 (c = 1.34,
chloroform). 1H NMR (300 MHz, CDCl3): δ 7.77-7.74 (m, 2H), 7.58-7.55 (m, 2H), 7.31-
7.26 (m, 2H), 7.22-7.16 (m, 3H), 3.26-3.17 (m, 3H), 1.84-1.71 (m, 1H), 1.69-1.61 (m,
1H), 0.80 (t, J = 7.3Hz, 3H). CHIRALPAK® AD-H chromatography (n-hexane :
isopropanol = 95:5), 0.8 mL/min, 214 nm. Retention time: tminor = 10.4 min, tmajor = 13.4
min. The compound was already known.11b
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7l: White solid 311 mg, 95% yield, 71% ee. m.p. 53-56 ºC. [α]D = -9.3 (c = 1.03,
ethanol). 1H NMR (400 MHz, CDCl3) δ 7.92-7.88 (m, 2H), 7.55-7.50 (m, 1H), 7.45-7.40
(m, 2H), 7.22-7.05 (m, 4H), 3.66-3.55 (m, 1H), 3.30-3.20 (m, 2H), 2.38 (s, 3H), 1.85-
1.57 (m, 2H), 0.80 (t, J = 7.4 Hz, 3H). CHIRALPAK® AD-H chromatography (n-hexane :
isopropanol = 98:2), 1.0 mL/min, 214 nm. Retention time: tminor = 15.4 min, tmajor = 16.5
min. The compound was already known. 11b
ASSOCIATED CONTENT
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Supporting Information
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NMR spectra, chiral HPLC spectra, and crystallographic data (CIF file) for (Sp)-5b. This
material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jiangb@sioc.ac.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the National Basic Research Program of China (973-
2010CB833200 and 973-2010CB833300), the National Natural Science Foundation of
China (21102167), the Science and Technology Commission of Shanghai Municipality
(12DZ1930902), Shanghai Green Chemical Engineering Technology Research Center
and the Knowledge Innovation Program of the Chinese Academy of Sciences.
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