Application of bidentate oxazoline-carbene ligands with planar and central chirality in asymmetric β-Boration of α,β-unsaturated esters

Article abstract of DOI:10.1021/jo5021135

A series of new oxazoline-substituted imidazolium salts based on [2.2]paracyclophane were synthesized and characterized. The new bidentate oxazoline-carbene precursor with planar and central chirality had significant advantage than the bicyclic 1,2,4-triazolium salt derived from [2.2]paracyclophane as a monodentate carbene ligand in Cu(I)-catalyzed asymmetric β-boration of α,β-unsaturated esters, giving the desired products in high enantioselectivities and yields.

Full text of DOI:10.1021/jo5021135

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Note
The application of bidentate oxazoline-carbene ligands with planar and
central chirality in asymmetric beta-boration of alpha,beta-unsaturated esters
Zonghong Niu, Jianqiang Chen, Zhen Chen, Manyuan Ma, Chun Song, and Yudao Ma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5021135 • Publication Date (Web): 05 Dec 2014
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The application of bidentate oxazolineꢀcarbene ligands with planar
and central chirality in asymmetric βꢀboration of α,βꢀunsaturated
esters
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Zonghong Niu#, Jianqiang Chen#, Zhen Chen, Manyuan Ma, Chun Song*, and Yudao
Ma*
Department of Chemistry, Shandong University, Shanda South Road No. 27,
Jinan 250100, P. R. China
[#] These authors contributed equally to this work.
[*] ydma@sdu.edu.cn; chunsong@sdu.edu.cn
Table of Contents Graphic
ABSTRACT:
A series of new oxazoline substituted imidazolium salts based on
[2.2]paracyclophane was synthesized and characterized. The new bidentate
oxazolineꢀcarbene precursor with planar and central chirality had significant
advantage than the bicyclic 1,2,4ꢀtriazolium salt derived from [2.2]paracyclophane as
a monodentate carbene ligand in Cu(I)ꢀcatalyzed asymmetric βꢀboration of
α,βꢀunsaturated esters, giving the desired products in high enantioselectivities and
yields.
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The asymmetric conjugate addition of diboron reagents to α,βꢀunsaturated
compounds has been studied for a long time because the C−B bond can be converted
into a wide variety of functional groups without loss of enantiopurity. 1 In recent years,
many publications have focused on this transformation. 2 In 2008, the first attempt to
catalyze the asymmetric βꢀboration of α,βꢀunsaturated esters was made by Yun et al. 3
Then copperꢀcatalyzed asymmetric conjugate additions of diboron reagents to α,βꢀ
and α,β,γ,δꢀunsaturated esters using different chiral bidentate phosphines as ligands
have been developed. 4 In 2009, Fernández and coꢀworkers firstly applied the
monodentate NHCꢀcopper complex to enantioselective boration of α,βꢀunsaturated
esters. 5 Since then, catalysis mediated by NHC metal complexes has emerged as a
powerful tool for this asymmetric transformation 6 because these catalysts have
significant advantages over their phosphine counterparts. 7 Of course, the asymmetric
conjugate addition of diboron reagents to α,βꢀunsaturated esters was also studied by
Kobayashi and Nishiyama using chiral bidentate Nꢀcontaining ligands. 8 On the other
hand, Hoveyda first disclosed the metalꢀfree catalytic βꢀboration of α,βꢀunsaturated
esters and ketones.9a The NHCꢀcatalyzed enantioselective boron conjugate additions
were shown to be mechanistically unique, allowing them to be complementary to the
more extensively examined copperꢀcatalyzed variants.9 Despite the fact that many
exciting results have been achieved, the design of novel chiral ligands to enhance the
enantioselectivity is still a challenge.
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Planar chiral [2.2]paracyclophaneꢀbased ligands play an important role in
asymmetric catalysis.10 In 2003, the synthesis and application of chiral
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pseudoꢀorthoꢀdisubstituted [2.2]paracyclophanyl bidentate oxazolineꢀcarbene ligands
were firstly reported by Bolm et al.10a Since then, our group identified both
diastereoisomers of pseudoꢀgeminal and pseudoꢀortho oxazoline substituted
[2.2]paracyclophanyl imidazo[1,5ꢀa]pyridinium triflates and successfully applied
them to copper(I)ꢀcatalyzed enantioselective boration of α,βꢀunsaturated ketones. 10n
Very recently, our group had synthesized and characterized a series of monodentate
bicyclic triazolium ligands based on [2.2]paracyclophane which induced exceptional
enantioselectivities in copper(I)ꢀmediated βꢀboration of α,βꢀunsaturated
Nꢀacyloxazolidinones and α,βꢀunsaturated acyclic enones. 11 However, the above
monodentate carbeneꢀcopper complexes induced βꢀboration of α,βꢀunsaturated esters
in only low to moderate enantioselectivity. We therefore report a series of new
pseudoꢀortho oxazoline substituted [2.2]paracyclophanyl imidazo[1,5ꢀa]pyridinium
salts and their applications in copper(I)ꢀcatalyzed asymmetric βꢀboration of
α,βꢀunsaturated esters.
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Table 1. Screening of the reaction conditionsa
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entry ligand
solvent T (oC)
base
yield(%)b ee(%)c
1d
2
(S,SP)ꢀ4 THF
0
0
0
0
0
Cs2CO3 (5 mol %)
Cs2CO3 (5 mol %)
Cs2CO3 (5 mol %)
Cs2CO3 (5 mol %)
Cs2CO3 (5 mol %)
Cs2CO3 (5 mol %)
Cs2CO3 (5 mol %)
Cs2CO3 (5 mol %)
Cs2CO3 (5 mol %)
Cs2CO3 (5 mol %)
Cs2CO3 (5 mol %)
Cs2CO3 (5 mol %)
Cs2CO3 (5 mol %)
Cs2CO3 (2.5 mol %)
Cs2CO3 (7.5 mol %)
Cs2CO3 (20 mol %)
CsF (5 mol %)
80
86
88
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87
85
87
85
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42
80
84
86
84
88
90
21 (S)
85 (S)
95 (S)
58 (R)
93 (S)
93 (S)
80 (S)
95 (S)
91 (S)
96 (S)
94 (S)
91 (S)
95 (S)
40 (S)
74 (S)
66 (S)
80 (S)
10 (S)
71 (R)
(S,SP)ꢀ5 THF
(S,SP)ꢀ6 THF
(S,RP)ꢀ6 THF
(S,SP)ꢀ6 THF
3
4
5e
6
(S,SP)ꢀ6 dioxane 0
7
8
9
(S,SP)ꢀ6 CH2Cl2
(S,SP)ꢀ6 Et2O
(S,SP)ꢀ6 PhCH3
(S,SP)ꢀ6 DME
(S,SP)ꢀ6 DME
(S,SP)ꢀ6 DME
(S,SP)ꢀ6 DME
(S,SP)ꢀ6 DME
(S,SP)ꢀ6 DME
(S,SP)ꢀ6 DME
(S,SP)ꢀ6 DME
(S,SP)ꢀ7 DME
(R,RP)ꢀ8 DME
0
0
0
0
25
40
ꢀ10
0
0
0
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18
19
0
0
0
Cs2CO3 (5 mol %)
Cs2CO3 (5 mol %)
aThe reaction was carried out with ligand (5.0 mol %), Cu2O (2.5 mol %), B2Pin2
b
(0.21 mmol), 1a (0.19 mmol) and MeOH (0.38 mmol) in solvent (1.0 mL). Yield of
isolated product after oxidated by NaBO3.4H2O. cDetermined by HPLC analysis using
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d
a chiral stationary phase (Chiralpak IA column). The carbeneꢀCu(I) was prepared by
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reaction of Cu2O (2.5 mol %), (S,Sp)ꢀ4 (5.0 mol %)and KI (5.0 mol %) in THF at 60
oC for 12 h. eUsing the carbeneꢀCuCl2 as a catalyst.
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According to our previously reported procedure for the asymmetric boration of
α,βꢀunsaturated ketones, 10n ethyl cinnamate 1a was selected as the model substrate.
With 5.0 mol % of (S,SP)ꢀ4, 2.5 mol % of Cu2O, 5.0 mol % of KI, 5.0 mol % of
Cs2CO3, 1.1 equiv of B2Pin2, 1.0 equiv of 1a, and 2.0 equiv of MeOH in 1.0 mL THF,
the boration reaction proceeded smoothly at 0 oC to provide, after the usual sodium
perborate workup, the hydroxyl compound 3a with high yield (80%) but low
enantioselectivity (21% ee) (Table1, entry1). It is worth to note that the reaction of
imidazo[1,5ꢀa]pyridinium triflate (S,SP)ꢀ4 and Cu2O failed to give any carbeneꢀCu
complexes. However, in the presence of KI, a mixture of carbene copper complexes
generated in situ by reaction of (S,SP)ꢀ4 and Cu2O was not a good catalyst (Table 1,
entry 1). Based on our previous research, 11 imidazo[1,5ꢀa]pyridinium chloride
(S,SP)ꢀ5 prepared by anion exchange of the (S,SP)ꢀ4 with an ion exchange resin 12 may
be a suitable carbene precursor. To our delight, the reaction afforded improved
enantioselectivity (85% ee) by using (S,SP)ꢀ5 as a ligand (Table 1, entry 2). Inspired
by this result, we turned our attention to the preparation of new
imidazo[1,5ꢀa]pyridinium chlorides and investigation of new catalyst systems for the
asymmetric boration reaction. We were interested to see whether the
enantioselectivity could be enhanced by introducing a methyl group to the αꢀposition
of pyridinium. Hence imidazo[1,5ꢀa]pyridinium chlorides (S,SP)ꢀ6 and (S,RP)ꢀ6 were
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synthesized and examined in conjugate boration of ethyl cinnamate. Fortunately, the
desired product 3a was obtained in 88% yield and 95% ee with ligand (S,SP)ꢀ6 (Table
1, entry 3). However, its diastereomer (S,RP)ꢀ6 gave the corresponding product in 80%
yield but in only 58% ee (Table 1, entry 4). The absolute configuration of the major
enantiomer obtained with (S,SP)ꢀ6 was opposite to that obtained with (S,RP)ꢀ6 by
comparing the sign of optical rotation of product 3a, which revealed that the absolute
configuration of product 3a was determined by the planar chirality of the imidazolium
salts. Moreover, the best result among them was obtained by using ligand (S,SP)ꢀ6, in
which the planar chirality and central chirality have the cooperative effect.
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In order to optimize conditions with (S,SP)ꢀ6 as carbene precursor, a number of
parameters were varied by using ethyl cinnamate 1a as substrate. CarbeneꢀCu (II)
displayed lower catalytic activity in this reaction in terms of either yield or
enantioselectivity (Table 1, entry 5). Among the solvents screened (Table 1, entries
6ꢀ10), ethylene glycol dimethyl ether gave the best enantioselectivity (96% ee) and a
good yield (87%), so it was chosen as the optimal solvent (Table 1, entry 10). The
impact of temperature on the boration reaction was investigated next. The
enantioselectivity could be increased by decreasing reaction temperature from 40 to 0
oC (Table 1, entries 10ꢀ12). However, there was no improvement in the enantiomeric
excess of 3a by a further decrease in temperature from 0 to ꢀ10 oC (Table 1, entry 13).
These results suggested that the convenience of 0 oC made it the preferred
temperature for the asymmetric reaction. The effect of the bases was also evaluated
(Table 1, entries 14ꢀ17). The reduction of the amount of Cs2CO3 from 5 to 2.5 mol %
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caused a significant decrease in the reaction rate and enantioselectivity (Table 1, entry
14), while increasing the amounts of Cs2CO3 resulted in low enantioselectivities
(Table 1, entries 15ꢀ16). The enantioselectivity was not improved by using CsF
instead of Cs2CO3 (Table 1, entries 17). As catalytic activity reached an acceptable
level, we extensively screened triazolium ligands (S,SP)ꢀ7 and (R,RP)ꢀ8 which induced
exceptional enantioselectivities in the copper(I)ꢀmediated βꢀboration of
α,βꢀunsaturated Nꢀacyloxazolidinones and α,βꢀunsaturated acyclic enones. 10 However,
the enantioselectivities dropped severely under the optimized conditions (Table 1,
entries 18, 19). The screening indicated that imidazo[1,5ꢀa]pyridinium chloride
(S,SP)ꢀ6 was still the optimal ligand in terms of enantioselectivity and catalytic
activity.
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Table 2. Investigating the substrate scope of the reactiona
entry
R1
R2
yield b(%)
eec (%)
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2
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7
Ph
Et
Me
87 (3a)
84 (3b)
87 (3c)
82 (3d)
86(3e)
95 (3f)
86 (3g)
96 (S)
95 (S)
96 (S)
96 (S)
95 (S)
95 (S)
94 (S)
Ph
Ph
Ph
tꢀBu
iꢀBu
Bn
Ph
Ph
CHPh2
Et
2ꢀMeC6H4
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3ꢀMeC6H4
4ꢀMeC6H4
2ꢀClC6H4
3ꢀClC6H4
4ꢀClC6H4
2ꢀMeOC6H4
3ꢀMeOC6H4
2ꢀCF3C6H4
3ꢀCF3C6H4
4ꢀCF3C6H4
1ꢀNaphthyl
2ꢀNaphthyl
2ꢀFuryl
Et
Et
95 (3h)
85 (3i)
92 (3j)
90 (3k)
87 (3l)
89 (3m)
86 (3n)
66 (3o)
68 (3p)
76 (3q)
85 (3r)
83 (3s)
80 (3t)
91 (3u)
90 (3v)
96 (S)
88 (S)
96 (S)
90 (S)
97 (S)
97 (S)
95 (S)
96 (S)
78 (S)
97 (S)
90 (S)
96 (S)
77 (S)
70 (R)
92 (S)
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22d
Et
Et
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Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
CHPh2
Et
Cyclohexyl
aThe reaction was carried out with (S,SP)ꢀ6 (5.0 mol %), Cu2O (2.5 mol %),
Cs2CO3 (5.0 mol %), B2Pin2 (0.21 mmol), Substrate (0.19 mmol) and MeOH (0.38
mmol) in DME (1.0 mL) at 0 oC. Yield of isolated product after oxidated by
b
c
NaBO3.4H2O. Determined by HPLC analysis using a chiral stationary phase
d
(Chiralpak IB or IA column). The ee value was determined as benzoylated
compound.
Having established an optimal protocol, we then investigated the reaction with a
variety of α,βꢀunsaturated esters. As shown in Table 2, the enantiomeric excess for the
methyl cinnamate was similar to that obtained in the ethyl cinnamate case (Table 2,
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entries 1ꢀ2). A further increase in the size of the ester moiety of the substrate to iꢀbutyl
as well as tꢀbutyl could not alter the enantioselectivity by any appreciable amount
(Table 2, entries 3ꢀ4). We also observed that the benzyl ester (95% ee) and the more
bulky diphenyl methyl ester derivatives of cinnamic acid (95% ee) provided
asymmetric inductions very similar to that found for 1a (96% ee), although diphenyl
methyl cinnamate showed an increase in yield to 95% (Table 2, entries 5ꢀ6). These
results disclosed that the structures of different ester moieties do not significantly
influence the enantioselectivity of the reaction. Then, we continued to evaluate
various βꢀaryl substituted unsaturated ethyl esters in order to investigate the
substituent effect. It is worthy to note that the electronic properties of the ethyl
cinnamate derivatives have an important effect on both reactivity and
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enantioselectivity. When ethyl cinnamate derivatives having an electronꢀdonating
group in the phenyl ring were subjected to the boration reaction, high yields (85ꢀ95%)
and enantioselectivities (94ꢀ97% ee) were observed except for the case of ethyl
βꢀ(4ꢀmethylphenyl)acrylate, in which the enantioselectivity was only 88% ee. The
substrates bearing an electronꢀwithdrawing group such as Cl and CF3 at the 2 or
4ꢀposition in the aromatic ring provided the products with excellent enantioselectivity
(96ꢀ97% ee), while, 3ꢀposition substitution at the phenyl ring lowered the ee value
(Table 2, entries 11 and 16). On the other hand, when a trifluoromethyl group was
introduced to the phenyl ring of ethyl cinnamate, lower yields were obtained (Table 2,
entries 15ꢀ17). Moreover, 1ꢀ and 2ꢀnaphthyl substituted α,βꢀunsaturated esters were
also tolerated and gave the corresponding products in good yields (83ꢀ85%) and
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enantioselectivities (90ꢀ96% ee). However, the heteroaromatic furanꢀsubstituted
substrate afforded the desired product with a lower enantioselectivity (77% ee). The
scope was also extended to βꢀalkyl substituted unsaturated ester. The diphenylmethyl
methylacrylate gave satisfactory conversion within the reaction time but yielded the
product with poor enantioselectivity (70% ee). When ethyl βꢀ(cyclohexyl)acrylate was
used as a substrate for the reaction, the high yield and enantioselectivity were
obtained again (Table 2, entry 22).
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Based on the absolute configuration of the products, a postulated model of
transition states is shown in Figure 1. The observed sense of chiral induction is in
compliance with a proposed transition state model where the steric bulkiness of the
tertꢀbutyl group and the methyl group may give rise to an enantiofacial preference for
the accessible Si face and as a result, lead to the major (S)ꢀproduct (Figure 1, Favored).
In contrast to reactions with the less sterically demanding Siꢀface attack, the activated
C=C bond is approached by the boryl group at its Reꢀface to cause steric repulsion
between the substituents on the oxazolineꢀcarbene skeleton and the cinnamate
substrate, leading to the minor (R)ꢀproduct (Figure 1, Disfavored). Such a transition
state model can provide a clear explanation of the high enantioselectivities observed
for the asymmeric boration of α,βꢀunsaturated esters.
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Figure 1. Postulated model of transition states for the asymmetric boration
In conclusion, we have developed a series of chiral bidentate oxazolineꢀcarbene
precursors based on [2.2]paracyclophane and demonstrated their utilization in
copperꢀcatalyzed enantioselective βꢀboration of α,βꢀunsaturated eaters. The new
imidazo[1,5ꢀa]pyridinium chloride is more efficient than the bicyclic triazolium salts
derived from [2.2]paracyclophane with regard to both reactivity and enantioselectivity
and affords the desired products with high yields and excellent enantiomeric excesses
regardless of the structures of different ester moieties.
Experimental Section
imidazo[1,5ꢀa]pyridinium triflate (S,SP)ꢀ4 was synthesized following a reported
procedure. 10n
General procedure for the synthesis of imidazo[1,5ꢀa]pyridinium chloride.
A solution of 4ꢀaminoꢀ12ꢀoxazolinyl[2.2]paracyclophane10n (0.14 mmol) and
6ꢀmethylꢀ2ꢀpyridine aldehyde (0.14 mmol) in toluene (2.0 mL) was stirred and
refluxed overnight. The reaction mixture was concentrated in vacuum to give the
corresponding imine as yellow oil, which was not stable enough for further
purification and used to next step directly. To a suspension of AgOTf (62.5 mg, 0.24
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mmol) in THF (1.0 mL) was added chloromethyl pivalate (0.036 mL, 0.24 mmol) and
the resulting suspension was sealed and stirred for 30 min in the dark. Then the above
imine in DCM (1.0 mL) was added and the mixture was stirred in a sealed tube in the
dark at 40 oC for 12 h. After the reaction mixture was cooled to room temperature,
EtOH (1.0 mL) was added and filtered. The filtrate was concentrated in vacuum and
subjected to column chromatography on silica gel (DCM/MeOH = 30:1) to afford the
desired imidazo[1,5ꢀa]pyridinium triflate as a white solid. The corresponding
imidazo[1,5ꢀa]pyridinium chloride was obtained easily by anion exchange of its
triflate analogue with an ionꢀexchange resin (chloride form) according the same
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method as described by McQuade.12
imidazolium salt (S,SP)ꢀ5. White solid: 32.8 mg, 48.2% yield, mp171–173 oC, [α]D
+180 ( c 0.14 CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 11.47 (s, 1H), 9.64 (d, J =
5.7Hz, 1H), 9.53 (s, 1H), 7.79 (d, J = 9.3 Hz, 1H), 7.23 (d, J = 2.7Hz, 1H), 7.09 –
7.05 (m, 1H), 6.91 – 6.77 (m, 6H), 4.40 – 4.33 (m, 1H), 4.00 (dd, J = 11.7, 3.0 Hz,
1H), 3.91 – 3.80 (m, 2H), 3.65 – 3.58 (m, 1H), 3.29 – 3.13 (m, 1H), 3.10 – 2.94 (m,
4H), 2.41 – 2.28 (m, 1H), 1.00 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 170.3, 142.1,
140.2, 137.8, 136.8, 136.4, 136.0, 135.1, 134.9, 133.7, 133.0, 130.2, 128.9, 127.6,
=
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126.7, 125.9, 125.1, 118.1, 117.5, 112.6, 59.4, 45.3, 35.3, 34.4, 33.6, 33.2, 26.8, 25.9.
HRMS (ESIꢀTOF) m/z: [MꢀCl]+ calcd for C30H32N3O 450.2545; found 450.2573.
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imidazolium salt (S,SP)ꢀ6. White solid: 46.5 mg, 66.4% yield, mp 167–169 oC, [α]D
= +300 (c 0.17 CH2Cl2);1H NMR (300 MHz, CDCl3) δ 11.26 (s, 1H), 9.66 (s, 1H),
7.61 (d, J = 9.2 Hz, 1H), 7.20 (d, J = 6.0 Hz, 1H), 7.17 (d, J = 6.9Hz, 1H), 6.95 (d, J =
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0.9Hz, 1H), 6.89 (s, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.79 – 6.74 (m, 3H), 4.60 – 4.41 (m,
1H), 4.38 – 4.27 (m, 2H), 4.08 – 4.00 (m, 1H), 3.74 – 3.67 (m, 1H), 3.28 – 3.18 (m,
1H), 3.16 – 3.01 (m, 5H), 2.95 – 2.73 (m, 2H), 2.42 – 2.26 (m, 1H), 1.06 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ 165.2, 142.0, 140.7, 139.6, 137.8, 137.7, 136.2, 135.1,
133.8, 130.9, 130.5, 128.3, 126.8, 126.2, 125.3, 116.5, 115.8, 115.7, 114.3, 114.2, 75.3,
69.3, 35.8, 34.5, 34.1, 33.7, 33.6, 26.0, 19.9. HRMS (ESIꢀTOF) m/z: [MꢀCl]+ calcd
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for C31H34N3O 464.2702; found 464.2704.
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imidazolium salt (S,RP)ꢀ6. White solid: 20.4 mg, 29.1% yield, mp153–155 oC, [α]D
+170 (c 0.17 CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 11.37 (d, J = 9.0 Hz, 1H), 9.77
(s, 1H), 7.71 (d, J = 9.3 Hz, 1H), 7.23 (dd, J = 9.3, 6.9 Hz, 1H), 7.11 (s, 1H), 6.93 (d,
J = 6.6 Hz, 1H), 6.91 (d, J = 5.1 Hz, 1H), 6.81 – 6.76 (m, 4H), 4.56 – 4.50 (m, 1H),
=
4.31 – 4.19 (m, 2H), 3.88 (dd, J = 13.2, 9.6 Hz, 1H), 3.82 – 3.74 (m, 1H), 3.27 – 3.16
(m, 1H), 3.16 – 3.03 (m, 5H), 2.98 – 2.88 (m, 1H), 2.82 – 2.71 (m, 1H), 2.30 – 2.24
(m, 1H), 1.15 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 165.7, 141.9, 140.1, 139.7, 137.9,
136.1, 135.2, 135.1, 134.5, 134.2, 133.7, 131.1, 130.0, 128.3, 126.2, 125.9, 125.6,
117.0, 115.9, 114.2, 69.0, 35.1, 34.0, 33.8, 33.7, 33.5, 26.6, 19.6. HRMS (ESIꢀTOF)
m/z: [MꢀCl]+ calcd for C31H34N3O 464.2702; found 464.2704.
General procedure for the copperꢀcatalyzed βꢀboration of α,βꢀunsaturated esters.
imidazolium salt (S,SP)ꢀ6 (4.74 mg, 9.5 × 10ꢀ3 mmol), Cu2O (0.68 mg, 4.75 × 10ꢀ3
mmol) were added to 1.0 mL anhydrous THF in an oven dried Schlenk flask under an
o
argon atmosphere. The mixture was stirred at 60 C overnight to give a yellow
solution of the Cuꢀcomplex. Then the solvent was evaporated under argon at 80 oC
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and 1.0 mL anhydrous DME was added at room temperature. Cs2CO3 (3.1 mg, 9.5 ×
10ꢀ3 mmol) and bis(pinacolato)diboron (53.1 mg, 0.209 mmol) were added
consecutively. The mixture was stirred at room temperature for 10 minutes and cooled
to 0 oC. Then α,βꢀunsaturated esters (0.19 mmol) and MeOH (15.2 ꢁL, 0.38 mmol)
were added simultaneously to the stirred mixture. After being stirred for 4h at 0 oC,
the solvent was removed under the reduced pressure and the crude product was
subjected to the oxidation with sodium peroxoborate (146 mg, 5.0 equiv) in THF (1.0
mL) and H2O (1.0 mL) at room temperature for 1.5 h. The reaction mixture was
concentrated in vacuum and the residue was purified by column chromatography on
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silica gel (hexanes/ethyl acetate = 30:1 – 10:1), giving the corresponding alcohol 3.
(S)ꢀEthyl 3ꢀhydroxyꢀ3ꢀphenylpropanoate 3a. Colorless oil: 32.1 mg, 87% yield,
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96% ee, [α]D = ꢀ49.2 (c 0.1, CHCl3); The enantiomeric excess was determined by
HPLC with a Chiralpak IA column, nꢀhexane/iꢀPrOH (75:1, 220nm, 1.0 mL/min),
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retention time: 33.7 min (minor), 35.5 min (major); H NMR (300 MHz, CDCl3) δ
7.46 – 7.27 (m, 5H), 5.13 (dd, J = 8.3, 4.5 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.27 (s,
1H), 2.87 – 2.61 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). Other spectra and properties data
matched those reported in the literature.8c
(S)ꢀMethyl 3ꢀhydroxyꢀ3ꢀphenylpropanoate 3b. Colorless oil: 28.8 mg, 84% yield,
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95% ee, [α]D = ꢀ55.2 (c 0.15, CHCl3); The enantiomeric excess was determined by
HPLC with a Chiralpak IA column, nꢀhexane/iꢀPrOH (75: 1, 220nm, 1.0 mL/min),
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retention time: 41.1 min (minor), 44.0 min (major); H NMR (300 MHz, CDCl3) δ
7.43 – 7.22 (m, 5H), 5.14 (dd, J = 8.4, 4.4 Hz, 1H), 3.73 (s, 3H), 3.17 (s, 1H), 2.87 –
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2.62 (m, 2H). Other spectra and properties data matched those reported in the
literature.8c
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(S)ꢀtertꢀButyl 3ꢀhydroxyꢀ3ꢀphenylpropanoate 3c. Colorless oil: 36.7 mg, 87% yield,
96% ee, [α]D25 = ꢀ41.6 (c 0.15, CHCl3); The enantiomeric excess was determined by
HPLC with a Chiralpak IA column, nꢀhexane/iꢀPrOH (75: 1, 220nm, 1.0 mL/min),
retention time: 22.9 min (minor), 25.0 min (major); 1H NMR (300 MHz, CDCl3) δ
7.42 – 7.26 (m, 5H), 5.09 (dd, J = 7.8, 4.9 Hz, 1H), 3.37 (s, 1H), 2.75 – 2.58 (m, 2H),
1.45 (s, 9H). Other spectra and properties data matched those reported in the
literature.8c
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(S)ꢀisoꢀButyl 3ꢀhydroxyꢀ3ꢀphenylpropanoate 3d. Colorless oil: 34.6 mg, 82% yield,
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96% ee, [α]D
= ꢀ40.5 (c 0.1, CHCl3); The enantiomeric excess was determined by
HPLC with a Chiralpak IA column, nꢀhexane/iꢀPrOH (200: 1, 220nm, 1.0 mL/min),
retention time: 74.0 min (minor), 77.8 min (major); 1H NMR (300 MHz, CDCl3) δ
7.43 – 7.26 (m, 5H), 5.14 (dd, J = 8.2, 4.6 Hz, 1H), 3.91 (d, J = 6.7 Hz, 2H), 2.97 (s,
1H), 2.84 – 2.67 (m, 2H), 1.93 (dp, J = 13.4, 6.7 Hz, 1H), 0.92 (d, J = 6.7 Hz, 6H).
Other spectra and properties data matched those reported in the literature.6b
(S)ꢀBenzyl 3ꢀhydroxyꢀ3ꢀphenylpropanoate 3e. Colorless oil: 41.9 mg, 86% yield,
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95% ee, [α]D
= ꢀ25.1 (c 0.12, CHCl3); The enantiomeric excess was determined by
HPLC with a Chiralpak IA column, nꢀhexane/iꢀPrOH (50: 1, 220nm, 1.0 mL/min),
retention time: 40.8 min (minor), 47.6 min (major); 1H NMR (300 MHz, CDCl3) δ
7.45 – 7.17 (m, 10H), 5.56 (dd, J = 8.8, 4.8 Hz, 1H), 5.19 – 5.09 (m, 2H), 3.17 (s, 1H),
3.00 – 2.61 (m, 2H). Other spectra and properties data matched those reported in the
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(S)ꢀDiphenyl methyl 3ꢀhydroxyꢀ3ꢀphenylpropanoate 3f. white solid: 60.0 mg, 95%
yield, 95% ee, [α]D25 = ꢀ35.1 (c 0.15, CHCl3); mp 63–65 oC The enantiomeric excess
was determined by HPLC with a Chiralpak IA column, nꢀhexane/iꢀPrOH (75: 1,
220nm, 1.0 mL/min), retention time: 71.4 min (major), 78.0 min (minor); 1H NMR
(300 MHz, CDCl3) δ 7.40 – 7.25 (m, 15H), 6.92 (s, 1H), 5.16 (dd, J = 8.4, 4.2 Hz,
1H), 3.11 (s, 1H), 2.95 – 2.80 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 171.4, 142.4,
139.8, 139.7, 128.6, 128.5, 128.1, 128.0, 127.8, 127.1, 127.0, 125.7, 70.3, 43.6;
HRMS (ESIꢀTOF) m/z: [M+Na]+calcd for C22H20NaO3 355.1310; found 355.1319.
(S)ꢀEthyl 3ꢀhydroxyꢀ3ꢀ(2ꢀmethylphenyl)propanoate 3g. Colorless oil: 34.0 mg,
86% yield, 94% ee, [α]D25 = ꢀ61.8 (c 0.1, CHCl3); The enantiomeric excess was
determined by HPLC with a Chiralpak IB column, nꢀhexane/iꢀPrOH (30: 1, 220nm,
0.5 mL/min), retention time: 19.1 min (major), 23.0 min (minor); 1H NMR (300 MHz,
CDCl3) δ 7.55 – 7.44 (m, 1H), 7.27 – 7.10 (m, 3H), 5.34 (dd, J = 8.5, 4.2 Hz, 1H),
4.19 (q, J = 7.2 Hz, 2H), 3.11 (s, 1H), 2.76 – 2.57 (m, 2H), 2.34 (s, 3H), 1.27 (t, J =
7.1 Hz, 3H). Other spectra and properties data matched those reported in the
literature.8c
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(S)ꢀEthyl 3ꢀhydroxyꢀ3ꢀ(3ꢀmethylphenyl)propanoate 3h. Colorless oil: 37.6 mg,
95% yield, 96% ee, [α]D25 = ꢀ48.3 (c 0.1, CHCl3); The enantiomeric excess was
determined by HPLC with a Chiralpak IB column, nꢀhexane/iꢀPrOH (30: 1, 220nm,
0.5 mL/min), retention time: 22.4 min (major), 25.2 min (minor); 1H NMR (300 MHz,
CDCl3) δ 7.30 – 7.05 (m, 4H), 5.10 (dd, J = 8.5, 4.3 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H),
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3.23 (s, 1H), 2.84 – 2.62 (m, 2H), 2.35 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H). Other spectra
and properties data matched those reported in the literature.8c
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(S)ꢀEthyl 3ꢀhydroxyꢀ3ꢀ(4ꢀmethylphenyl)propanoate 3i. Colorless oil: 33.6 mg,
85% yield, 88% ee, [α]D25 = ꢀ41.5 (c 0.12, CHCl3); The enantiomeric excess was
determined by HPLC with a Chiralpak IA column, nꢀhexane/iꢀPrOH (30: 1, 220nm,
1.0 mL/min), retention time: 35.4 min (major),40.2 min (minor); 1H NMR (300 MHz,
CDCl3) δ 7.26 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 5.09 (dd, J = 8.7, 4.1 Hz,
1H), 4.17 (q, J = 7.1 Hz, 2H), 3.18 (s, 1H), 2.84 – 2.58 (m, 2H), 2.34 (s, 3H), 1.26 (t,
J = 7.1 Hz, 3H). Other spectra and properties data matched those reported in the
literature.8c
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(S)ꢀEthyl 3ꢀhydroxyꢀ3ꢀ(2ꢀchlorophenyl)propanoate 3j. Colorless oil: 40.0 mg, 92%
yield, 96% ee, [α]D25 = ꢀ74.8 (c 0.1, CHCl3); The enantiomeric excess was determined
by HPLC with a Chiralpak IB column, nꢀhexane/iꢀPrOH (30: 1, 220nm, 0.5 mL/min),
retention time: 17.6 min (major), 27.2 min (minor); 1H NMR (300 MHz, CDCl3) δ
7.65–7.62 (m, 1H), 7.35 – 7.19 (m, 3H), 5.49 (dd, J = 9.6, 2.6 Hz, 1H), 4.20 (q, J =
7.1 Hz, 2H), 3.24 (s, 1H), 2.86 (dd, J = 16.6, 2.7 Hz, 1H), 2.69 – 2.51 (m, 1H), 1.28 (t,
J = 7.1 Hz, 3H). Other spectra and properties data matched those reported in the
literature.13a
(S)ꢀEthyl 3ꢀhydroxyꢀ3ꢀ(3ꢀchlorophenyl)propanoate 3k. Colorless oil: 39.1 mg,
90% yield, 90% ee, [α]D25 = ꢀ35.5 (c 0.1, CHCl3); The enantiomeric excess was
determined by HPLC with a Chiralpak IB column, nꢀhexane/iꢀPrOH (30: 1, 220nm,
0.5 mL/min), retention time: 21.8 min (major), 30.0 min (minor); 1H NMR (300 MHz,
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CDCl3) δ 7.40 (s, 1H), 7.33 – 7.21 (m, 3H), 5.11 (t, J = 6.3 Hz, 1H), 4.19 (q, J = 7.1
Hz, 2H), 3.39 (s, 1H), 2.71 (d, J = 6.4 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). Other spectra
and properties data matched those reported in the literature.13b
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(S)ꢀEthyl 3ꢀhydroxyꢀ3ꢀ(4ꢀchlorophenyl)propanoate 3l. Colorless oil: 37.8 mg, 87%
yield, 97% ee, [α]D25 = ꢀ39.5 (c 0.11, CHCl3); The enantiomeric excess was
determined by HPLC with a Chiralpak IA column, nꢀhexane/iꢀPrOH (75: 1, 220nm,
1.0 mL/min), retention time: 73.1 min (minor), 76.6 min (major); 1H NMR (300 MHz,
CDCl3) δ 7.36 – 7.28 (m, 4H), 5.10 (dd, J = 7.4, 5.4 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H),
3.35 (s, 1H), 2.72 – 2.67 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H). Other spectra and
properties data matched those reported in the literature.8c
(S)ꢀEthyl 3ꢀhydroxyꢀ3ꢀ(2ꢀmethoxyphenyl)propanoate 3m. Colorless oil: 37.9 mg,
89% yield, 88% ee, [α]D25 = ꢀ51.2 (c 0.1, CHCl3); The enantiomeric excess was
determined by HPLC with a Chiralpak IB column, nꢀhexane/iꢀPrOH (75: 1, 220nm,
0.5 mL/min), retention time: 61.2 min (major), 66.0 min (minor); 1H NMR (300 MHz,
CDCl3) δ 7.44 – 4.41 (m, 1H), 7.29 – 7.23 (m, 1H), 7.00 – 6.98 (m, 1H), 6.95 – 6.86
(m, 1H), 5.36 (dd, J = 9.0, 3.7 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 2.86 –
2.66 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). Other spectra and properties data matched
those reported in the literature.13a
(S)ꢀEthyl 3ꢀhydroxyꢀ3ꢀ(3ꢀmethoxyphenyl)propanoate 3n. Colorless oil: 36.6 mg,
86% yield, 95% ee, [α]D25 = ꢀ33.4 (c 0.2, CHCl3); The enantiomeric excess was
determined by HPLC with a Chiralpak IB column, nꢀhexane/iꢀPrOH (30: 1, 220nm,
0.5 mL/min), retention time: 31.7 min (major), 35.2 min (minor); 1H NMR (300 MHz,
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CDCl3) δ 7.29 – 7.23 (m, 1H), 6.95 – 6.92 (m, 2H), 6.84 – 6.80 (m, 1H), 5.11 (dd, J =
8.1, 4.7 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 3.29 (s, 1H), 2.81 – 2.63 (m,
2H), 1.27 (t, J = 7.1 Hz, 3H). Other spectra and properties data matched those
reported in the literature.13a
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(S)ꢀEthyl 3ꢀhydroxyꢀ3ꢀ(2ꢀtrifluoromethylphenyl)propanoate 3o. Colorless oil:
33.0 mg, 66% yield, 96% ee, [α]D25 = ꢀ42.0 (c 0.2, CHCl3); The enantiomeric excess
was determined by HPLC with a Chiralpak IB column, nꢀhexane/iꢀPrOH (15: 1,
254nm, 0.5 mL/min), retention time: 11.2 min (major), 27.4 min (minor); 1H NMR
(300 MHz, CDCl3) δ 7.85 – 7.82 (m, 1H), 7.65 – 7.57 (m, 2H), 7.42 – 7.37 (m, 1H),
5.55 (d, J = 8.5 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.50 (d, J = 2.4 Hz, 1H), 2.78 –
2.55 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H). Other spectra and properties data matched
those reported in the literature.13c
(S)ꢀEthyl 3ꢀhydroxyꢀ3ꢀ(3ꢀtrifluoromethylphenyl)propanoate 3p. Colorless oil:
33.9 mg, 68% yield, 78% ee, [α]D25 = ꢀ27.5 (c 0.12, CHCl3); The enantiomeric excess
was determined by HPLC with a Chiralpak IB column, nꢀhexane/iꢀPrOH (30: 1,
220nm, 0.5 mL/min), retention time: 18.5 min (major), 28.6 min (minor); 1H NMR
(300 MHz, CDCl3) δ 7.66 (s, 1H), 7.59 – 7.45 (m, 3H), 5.19 (td, J = 6.3, 3.6 Hz, 1H),
4.20 (q, J = 7.1 Hz, 2H), 3.49 (d, J = 3.5 Hz, 1H), 2.74 (d, J = 6.4 Hz, 2H), 1.27 (t, J =
7.1 Hz, 3H). Other spectra and properties data matched those reported in the
literature.13d
(S)ꢀEthyl 3ꢀhydroxyꢀ3ꢀ(4ꢀtrifluoromethylphenyl)propanoate 3q. Colorless oil:
38.0 mg, 76% yield, 95% ee, [α]D25 = ꢀ39.5 (c 0.1, CHCl3); The enantiomeric excess
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was determined by HPLC with a Chiralpak IA column, nꢀhexane/iꢀPrOH (50: 1,
220nm, 1.0 mL/min), retention time: 24.6 min (major), 27.5 min (minor); 1H NMR
(300 MHz, CDCl3) δ 7.61 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 5.20 – 5.17 (m,
1H), 4.19 (q, J = 7.1 Hz, 2H), 3.54 (d, J = 3.0 Hz, 1H), 2.72 (d, J = 6.3 Hz, 2H), 1.27
(t, J = 7.1 Hz, 3H). Other spectra and properties data matched those reported in the
literature.8c
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(S)ꢀEthyl 3ꢀhydroxyꢀ3ꢀ(naphthalenꢀ1ꢀyl)propanoate 3r. Colorless oil: 39.4 mg,
85% yield, 90% ee, [α]D25 = ꢀ65.2 (c 0.1, CHCl3); The enantiomeric excess was
determined by HPLC with a Chiralpak IB column, nꢀhexane/iꢀPrOH (30: 1, 254nm,
0.5 mL/min), retention time: 39.6 min (major), 46.8 min (minor); 1H NMR (300 MHz,
CDCl3) δ 8.05 (d, J = 8.0 Hz, 1H), 7.89 – 7.83 (m, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.70
(d, J = 7.1 Hz, 1H), 7.58 – 7.43 (m, 3H), 5.92 (dd, J = 9.1, 3.4 Hz, 1H), 4.22 (q, J =
7.1 Hz, 2H), 3.34 (s, 1H), 2.97 – 2.78 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H). Other spectra
and properties data matched those reported in the literature.8c
(S)ꢀEthyl 3ꢀhydroxyꢀ3ꢀ(naphthalenꢀ2ꢀyl)propanoate 3s. Colorless oil: 38.5 mg,
83% yield, 96% ee, [α]D25 = ꢀ27.5 (c 0.12, CHCl3); The enantiomeric excess was
determined by HPLC with a Chiralpak IB column, nꢀhexane/iꢀPrOH (30: 1, 220nm,
0.5 mL/min), retention time: 81.5 min (major), 84.5 min (minor); 1H NMR (300 MHz,
CDCl3) δ 7.88 – 7.78 (m, 4H), 7.52 – 7.42 (m, 3H), 5.30 (dd, J = 7.8, 4.9 Hz, 1H),
4.19 (q, J = 7.1 Hz, 2H), 3.40 (s, 1H), 2.94 – 2.71 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H).
Other spectra and properties data matched those reported in the literature.8c
(S)ꢀEthyl 3ꢀhydroxyꢀ3ꢀ(furanꢀ2ꢀyl)propanoate 3t. Colorless oil: 28.0 mg, 80% yield,
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77% ee, [α]D25 = ꢀ17.5 (c 0.1, CHCl3
)
; The enantiomeric excess was determined by
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HPLC with a Chiralpak IA column, nꢀhexane/iꢀPrOH (50: 1, 220nm, 1.0 mL/min),
retention time: 32.6 min (minor), 35.5 min (major); 1H NMR (300 MHz, CDCl3) δ
7.38 (dd, J = 1.8, 0.8 Hz, 1H), 6.34 – 6.32 (m, 1H), 6.29 – 6.27 (m, 1H), 5.14 (dd, J =
8.1, 4.4 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.27 (s, 1H), 2.95 – 2.79 (m, 2H), 1.27 (t, J
= 7.1 Hz, 3H). Other spectra and properties data matched those reported in the
literature.13b
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(R)ꢀDiphenyl methyl 3ꢀhydroxyꢀ3ꢀmethylpropanoate 3u. Colorless oil: 36.0 mg,
91% yield, 70% ee, [α]D25 = ꢀ23.5 (c 0.2, CHCl3); The enantiomeric excess was
determined by HPLC with a Chiralpak IB column, nꢀhexane/iꢀPrOH (30: 1, 220nm,
0.5 mL/min), retention time: 33.9 min (major), 36.0 min (minor); 1H NMR (300 MHz,
CDCl3) δ 7.37 – 7.25 (m, 10H), 6.91 (s, 1H), 4.33 – 4.17 (m, 1H), 2.87 (s, 1H), 2.66 –
2.50 (m, 2H), 1.22 (d, J = 6.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 171.9, 139.9,
139.8, 128.6, 128.5, 128.1, 128.0, 127.1, 127.0, 64.3, 43.1, 22.4; HRMS (ESIꢀTOF)
m/z: [M+Na]+ calcd for C17H18NaO3 293.1154; found 293.1142.
(S)ꢀEthyl 3ꢀhydroxyꢀ3ꢀcyclohexylpropanoate 3v. Colorless oil: 34.2 mg, 90% yield,
92% ee, The enantiomeric excess value was determined as benzoylated compound by
HPLC with a Chiralpak IA column, nꢀhexane/iꢀPrOH (75: 1, 220nm, 1.0 mL/min),
retention time: 10.5 min (minor), 16.9 min (major); [α]D25 = ꢀ56.0 (c 0.2, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 4.17 (q, J = 7.1 Hz, 2H), 3.81 – 3.75 (m, 1H), 2.90 (s, 1H),
2.51 (dd, J = 16.2, 3.0 Hz, 1H), 2.41 (dd, J = 16.2, 9.3 Hz, 1H), 1.89 – 1.65 (m, 5H),
1.44 – 0.95 (m, 9H). Other spectra and properties data matched those reported in the
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The synthesis of (S)ꢀEthyl 3ꢀbenzoyloxyꢀ3ꢀcyclohexylpropanoate 3v’.
To the oxidized product (0.17 mmol) in dichloromethane (1.0 mL) was added pyridine
(67.2 mg, 0.85 mmol) and benzoyl chloride (47.8 mg, 0.34 mmol). After the reaction
mixture was stirred for 1 h at 0 oC, the resulting mixture was quenched with 1.0 mL
water. The obtained organic layer was dried over anhydrous Na2SO4. After removal of
the solvent, the residue was purified by preparative TLC (nꢀhexane/AcOEt = 75/1) to
afford benzoylated product as a colorless oil: 33.0 mg, 64% yield, [α]D25 = ꢀ85.9 (c
0.16, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.08 – 7.99 (m, 2H), 7.58 – 7.53 (m, 1H),
7.46 – 7.41 (m, 2H), 5.45 – 5.31 (m, 1H), 4.15 – 4.02 (m, 2H), 2.71 – 2.68 (m, 2H),
1.85 – 1.67 (m, 5H), 1.44 – 1.08 (m, 9H). 13C NMR (75 MHz, CDCl3) δ 171.1, 166.1,
133.1, 130.6, 129.9, 128.6, 74.9, 60.9, 41.7, 37.3, 29.0, 28.3, 26.5, 26.3, 26.2, 14.3.
HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C18H25O4 305.1753; found 305.1753.
Acknowledgment. Financial support from the National Natural Science Foundation
of China (Grant No. 21372144) and Shandong Provincial Natural Science Foundation
(ZR2011BM013) is gratefully acknowledged.
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Supporting Information Available: Full compound characterization and detailed
spectral data for products, this material is available free of charge via the Internet at
http://pubs.acs.org.
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