Preparation of prolinamide with adamantane for aldol reaction catalysis in brine and separation using a poly(AN-MA-β-CD) nanofibrous film via host-guest interaction

Article abstract of DOI:10.1039/c8ra04802a

Prolinamides with double-H potential were prepared and employed as organocatalysts in asymmetric aldol reactions. The catalyst with adamantane showed improved catalytic activity, which was further enhanced by using brine as the solvent. A series of aldol

Full text of DOI:10.1039/c8ra04802a

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PAPER
Preparation of prolinamide with adamantane for
aldol reaction catalysis in brine and separation
using a poly(AN-MA-b-CD) nanofibrous film via
host–guest interaction†
Cite this: RSC Adv., 2018, 8, 28376
Rui Wang,a Enjie Xu,a Zhenming Su,b Haifeng Duan,a Jinjin Wang,a Longqi Xue,a
a
a
Yaoxian Li,a Zhonglin Weia and Qingbiao Yang
*
Yingjie Lin,
Prolinamides with double-H potential were prepared and employed as organocatalysts in asymmetric aldol
reactions. The catalyst with adamantane showed improved catalytic activity, which was further enhanced by
using brine as the solvent. A series of aldol reactions in brine at 0 ꢀC provided good yields (up to 98%) with
high diastereoselectivities (>99 : 1) and enantioselectivities (>99%). The prepared catalyst was adsorbed by
a nanofibrous film of poly(AN-MA-b-CD) via host–guest interaction in the reaction system. The catalyst was
separated from the film by applying ultrasound, with a total recovery of 96.2%. The catalyst was reused up to
five times without a significant change in diastereoselectivity and enantioselectivity.
Received 5th June 2018
Accepted 27th July 2018
DOI: 10.1039/c8ra04802a
rsc.li/rsc-advances
solvents to water offers low cost, safety, and environmentally
benign nature.6 Since Breslow reported that the acceleration of
Introduction
Diels–Alder reaction in water, there is a surge of interest in
using water as reaction medium.7
Asymmetric aldol reactions play an important role in carbon–
carbon bond forming reactions. The design and synthesis of
small molecule organocatalysts based on L-proline have been
given considerable attention aer List and co-workers reported
the L-proline-catalyzed direct aldol reaction.1 In the L-proline-
catalyzed reaction, the necessity of using the carboxylic acid
of proline remains unclear. Since Tang and co-workers reported
prolinamide-catalyzed aldol reactions of 4-nitrobenzaldehyde
with acetone,2 effective organocatalysts have been developed
based on proline to afford facile atom economic access to
optically pure compounds.3 In 2010, Moorthy demonstrated the
use of double-H potential catalysts based on L-proline and o-
phenylenediamine to catalyze the aldol reaction of p-nitro-
benzaldehyde with cyclohexanone in DMF in the presence of
TFA with desirable yield (94%), stereoselectivity (>98%), and
diastereoselectivity (97 : 3).4 Yang et al. used benzyl chloride
instead of nitrobenzene sulfonic acid to synthesize prolinamide
catalysts, which resulted in faster reactions with good diaster-
eoselectivity in brine at room temperature.3 Nonetheless, the
asymmetric reactions are usually conducted in organic solvents,
such as DMF, DMSO, PhMe, and MeCN. To promote the use of
environmentally friendly solvents for catalytic reaction, inor-
ganic systems are desired as solvents.5 Switching organic
Recycling catalysts decreases the consumption of auxiliary
substances in obtaining pure catalyst, leading to signicant
economic and environmental benets.8 To realize recyclability
of catalyst, researchers have focused on immobilizing catalysts
on diverse solid supports.9 So far, nanoparticles and polymers
have been used support, from which catalysts can be recovered
and reused aer centrifugation, magnetic decantation or
ltration.10 However, a general and conventional method for
immobilizing different types of organocatalysts considering
stability, reactivity, and recyclability of the obtained heteroge-
neous materials has not been established.11 Moreover, sup-
ported catalysts for heterogeneous catalysis generate poor yield
and stereoselectivity. Compared with supported heterogeneous
catalysts, homogeneous ones provide many advantages in
catalytic reaction. Nevertheless, recycling catalysts has obvious
shortcomings, such as large consumption, difficult separation,
and high cost. Hence, the concept wherein reaction is con-
ducted in homogeneous medium and catalyst is recovered in
heterogeneous system is highly benecial to the development of
environmentally friendly catalytic reactions. The design of self-
assembled aggregates that employ host–guest interactions
choosing geometrically complementary host and guest mole-
cules is an important method of physical adsorption.12 Previ-
ously, we reported that assembly and separation of small
organic molecules were driven by adamantane and b-cyclodex-
trin (b-CD) via host–guest interaction.13 The recovery of orga-
nocatalysts via host–guest interactions could solve a traditional
aCollege of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012,
P. R. China. E-mail: yangqb@jlu.edu.cn
bSecurity Check, Jilin Province, 566B Guigu Street, Changchun 130012, P. R. China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c8ra04802a
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problem regarding heterogeneity of solid-supported catalyst.14
We reported the aldol product of p-nitrobenzaldehyde with
cyclohexanone in toluene at –20 ꢀC was separated by a-CD from
the reaction system in Scheme 1.15 However, a-CD being easy to
dissolve in water is to the disadvantage of the overall recycling
of the product. Therefore, the developing the water insoluble a-
CD or b-CD is of the essence.
Herein, we synthesize adamantine-modied catalysts
separated by supported b-CD via host–guest interaction. O-
phenylenediamine catalysts with double hydrogen potential
based on L-proline or trans-4-hydroxy-L-proline were synthe-
sized to catalyze aldol reactions of ketone and aldehyde
(Fig. 1). Prolinamides with 1-adamantane carboxylic acid
could improve the catalytic activity by replacing benzoic acid.
Improved results were obtained by switching the solvent to an
Fig. 1 Adamantane-modified prolinamide catalysts.
ꢀ
inorganic system. The brine was used as medium at 0 C for
catalyzing the aldol reaction of aldehyde and ketone, resulting
in excellent yields with good stereoselectivity and diaster-
eoselectivity. b-CD-modied polymer (poly(AN-MA-b-CD)) was
synthesized by using co-polymer (poly(AN-MA)) and b-CD, and
then nanobrous lm was prepared by electrospinning. A
owchart of catalyst separation from the lm is described in
Scheme 2. Aer each run, the catalyst could be adsorbed by the
lm via host–guest interaction in the reaction system and
separated by washing with MeOH under ultrasound from the
lm.
Results and discussion
Asymmetric aldol reaction
Initially, we employed chiral prolinamide catalysts 1a–1d to
screen the direct aldol reaction of p-nitrobenzaldehyde with
cyclohexanone at room temperature (Scheme 2). A series of
experiments were then performed under different reaction
conditions (different catalysts, loading, and solvents). The
results are summarized in Table 1. In the beginning of the
experiment (Table 1, entries 1–4), the reactions were catalyzed
by different prolinamides (10 mol%) at room temperature for
36 h in DCM. Interestingly, all catalysts provided the desired
aldol products with good yields. The aldol reactions in the
presence of prolinamides 1a and 1b generated 69% and 77% of
enantioselectivity (Table 1, entries 1 and 2). When used to
catalyze the aldol reaction of 4-nitrobenzaldehyde and cyclo-
hexanone, compounds 1c and 1d afforded good yields with
higher diastereoselectivity and enantioselectivity than 1a and
1b. This result may be due to replacement of benzoic acid with
the large steric hindrance of adamantane. Compared with
compound 1c, the desired product was formed in 91% yield
with 89% stereoselectivity when catalyst 1d was employed
(Table 1, entry 4). Compared to results reported respectively by
Moorthy' and Yang' research groups, the catalyst 1d improves
the catalytic activity. Our group have reported that the
adamantine provided by 4-substitution position based on L-
proline played an important role in diastereoselectivity and
enantioselectivity.15 In addition, catalysts with adamantyl group
were employed in other asymmetrical reactions provided good
diastereoselectivity or enantioselectivity.14,16 Although catalyst
loading was varied from 10 mol% to 30 mol%, no further
improvement in diastereoselectivity and enantioselectivity was
observed (Table 1 entries 4–6). Poor diastereoselectivity was
obtained at low catalyst loading of 5 mol% or 2 mol% (Table 1,
entries 7–8). Considering that the catalyst 1d of 10 mol%
afforded a good conversion with desirable diastereoselectivity
and enantioselectivity, entry 4 was selected as an optimal
reaction. Compound 1d of 10 mol% was employed as catalyst in
nine solvents with different polarities at room temperature for
36 h of reaction under vigorous stirring. The aldol reactions
being conducted in nine solvents investigated showed no
Scheme
1 Adamantane-modified organocatalysts for asymmetric
aldol reactions and recovery of the catalysts.
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Scheme 2 Illustration for recyclability of catalyst.
signicant change in yield (from 90% to 96%) and diaster- the best (Table 1, entry 16). Therefore, brine was employed as
eoselectivity (from 96 : 4 to 99 : 1). However, the stereo- solvent in further study.
selectivity was signicantly inuenced on ranging from 82%
To optimize the reaction conditions, we determined the
(MeOH) to 95% (brine). Among the seven other organic effect of acid additive17 and reaction temperature.18 The most
solvents, high stereoselectivity (91%) was obtained when THF relevant results were detailed in Table 2. As indicated by entries
was used as solvent (Table 1, entry 9). Compared with organic 1–5 in Table 2, 10 mol% organic acid (such as 4-nitrobenzoic
solvents, the inorganic medium was found to be superior in acid, benzoic acid, triuoroacetic acid, acetic acid and meth-
terms of stereoselectivity. For example, brine provided the best anolic acid) was added to the reaction in brine at room
stereoselectivity of the aldol product (95%) to proved itself be temperature for 36 h. When the reactions were carried out in the
presence of an organic acid, the yields were slightly improved,
Table 1 Screening catalysts and solventsa
while diastereoselectivity and stereoselectivity showed no
signicant differences. A high efficiency was obtained when no
additive was added to the reaction mixture (Table 2, entry 6). In
Entry Catalyst Mol% Solvent Yieldb (%) drc (anti/syn) eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1b
1c
10
10
10
10
20
30
5
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
89
96
93
91
93
96
90
85
95
94
96
90
91 : 9
88 : 12
97 : 3
97 : 3
97 : 3
97 : 3
95 : 5
95 : 5
97 : 3
99 : 1
99 : 1
96 : 4
99 : 1
98 : 2
97 : 3
98 : 2
69
77
82
89
89
89
88
88
91
86
87
86
82
86
90
95
Table 2 Screening additive and temperaturea
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
Entry Additive
T (ꢀC) Yieldb (%) drc (anti/syn) eec (%)
1
2
3
4
5
6
7
8
9d
4-NO2PhCOOH rt
98
98
96
95
96
95
95
93
98
97 : 3
96 : 4
96 : 4
95 : 5
95 : 5
98 : 2
98 : 2
98 : 2
98 : 2
94
95
93
94
93
95
95
96
96
2
PhCOOH
CF3OOH
CH3OOH
HCOOH
—
rt
rt
rt
rt
rt
10
0
10
10
10
10
10
10
10
10
HEXd
EtOAc
MeCN
MeOH 92
DMSO 92
—
—
H2O
91
95
—
0
Brinee
a
Reaction conditions: p-nitrobenzaldehyde (0.5 mmol), cyclohexanone
a
Reaction conditions: p-nitrobenzaldehyde (0.5 mmol), cyclohexanone (10 equiv.), catalyst 1d (0.05 mmol, 10 mol%), solvent (1.0 mL), room
(10 equiv.), solvent (1.0 mL), room temperature, 36 hours with temperature, 36 hours with vigorous stirring. Combined yields of
b
b
c
c
vigorous stirring. Combined yields of isolated. Determined by isolated.
Determined by HPLC with
a chiral AD-H column.
HPLC with a chiral AD-H column. n-hexane. e Solubility of 20%.
Vigorous stirring for 48 hours.
d
d
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an effort to improve the catalytic activity, the reaction temper- to provide the corresponding products in excellent yields with
ature further was investigated. By lowering the reaction high diastereoselectivity and enantioselectivity (Table 3, entries
ꢀ
temperature to 10 C, the reaction went smoothly to form the 1–7). Moderate conversions were obtained by benzaldehydes
desired aldol product without signicant change in diaster- with weak electronic-withdrawing and electronic-neutral groups
eoselectivity and stereoselectivity. A further reduced of the (Table 3, entries 8–16). Compared to benzaldehyde, 2-naph-
reaction temperature to 0 ꢀC, a slight increase of stereo- thaldehyde provides poor diastereoselectivity and enantiose-
selectivity was observed. Lengthening reaction time to 48 h lectivity. Aldehydes with electronic-donating were found to have
drove the reaction towards completion (yield 98%). Entry 9 was very low reactivity and generated aldol products in <10% yield
performed under the optimized reaction conditions.
(Table 3, entries 17–19). Ketone with different substituents were
Aer determining the optimal reaction conditions, we then investigated. In contrast to the aldehyde substrates, poor
further explored the substrate scope of aldol reactions; the diastereoselectivity was produced by cyclopentanone (Table 3,
results are summarized in Table 3. In the initial experiment, entry 20). When 2-butanone as reagent led to the formation of
aldol reactions of cyclohexanone with different aldehydes were regioisomers, three pairs of enantiomers were obtained with
investigated at 0 ꢀC. Satisfactorily, reactions gave the desired poor enantioselectivities (Table 3, entry 21). Inuenced by water
products in good yields with high diastereoselectivity and hydrolyzing and steric hinderance, 2-butanone was easily
enantioselectivity. Benzaldehydes substituents with different transformed into stable carbanion. Therefore, the aldol product
electronic characters were studied, including electronic- with one pair of enantiomer was dominant of 3-pentone. The
withdrawing (NO2, CN, CF3, Cl, Br and F), electronic-neutral aldol reaction in the presence of acetone also provided
(H) and electronic-donating (OCH3 and CH3) groups. Aromatic moderate yield with poor enantioselectivity (Table 3, entry 22).
aldehydes with ortho-, meta-, and para-substituents generated Enantioselectivities of large-scale asymmetric aldol reactions
aldol products with similar yields. Aromatic aldehydes with were reduced because a lot of aldehyde did not dissolve in brine
strong electronic-withdrawing group underwent aldol reactions under unevenly stringing.
Table 3 Scope for aldol reaction of ketones with aldehydes employing catalyst 1da
Entry
Aldehyde (2) R1
Ketone (3) R2, R3
Product (4)
Yieldb (%)
drc (anti/syn)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
p-NO2Ph
m-NO2Ph
o-NO2Ph
p-CNPh
m-CNPh
o-CNPh
p-CF3Ph
2,4-Cl2Ph
p-ClPh
m-ClPh
o-ClPh
p-BrPh
o-BrPh
p-FPh
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)2–
H, CH3
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
98
97
97
93
90
91
94
90
57
54
59
50
55
46
49
36
<10
<10
<10
90
88
95
98 : 2
99 : 1
>99 : 1
99 : 1
97 : 3
94 : 6
98 : 2
99 : 1
99 : 1
99 : 1
99 : 1
>99 : 1
99 : 1
98 : 2
99 : 1
88 : 12
96
98
97
97
97
97
97
98
98
98
99
98
97
95
97
89
Ph
2-Naphthyl
Furan
p-OCH3Ph
p-CH3Ph
p-NO2Ph
p-NO2Ph
p-NO2Ph
4s
4t
4u
4v
67 : 33
—
—
64
75
22
H, H
a
Reaction conditions: aldehyde (0.5 mmol), ketone (10 equiv.), catalyst 1d (0.05 mmol, 10 mol%), solvent (1.0 mL), vigorous stirring with
correspond time. b Combined yields of isolated. c Determined by HPLC with chiral AD-H column, chiral OD-H column and chiral AS-H column.
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Fig. 2 FTIR spectra of poly(AN-MA) (a), poly(AN-MA-b-CD) (b) and
catalyst into poly(AN-MA-b-CD) (c).
FTIR analysis
To conrm the composition and graing, polymers were studied
by FTIR spectroscopy (Fig. 2). A FTIR spectrum for poly(AN-MA) is
shown in Fig. 2(a). Fig. 2(a) exhibits peaks at 2940 and 2240 cmꢁ1
,
Fig. 3 SEM images of different mass fraction with poly(AN-MA-b-CD)
in DMF: (a) 36%, (b) 33%, (c) 30%, (d) 25%, (e) 20%, and (f) catalyst bind
to poly(AN-MA-b-CD).
which were attributed to asymmetric C–H stretching from
(–CH2–)n and asymmetric C–N stretching from cyano group. The
characteristic peak of cyano group could be observed in Fig. 2(b)
and (c). The broad peak at 3340 cmꢁ1 was the symmetric –OH
stretching from b-CD molecule in Fig. 2(b), which could prove
that b-CD was graed on the polymer surface. In Fig. 2(c), the
characteristic peaks of benzene framework vibration peaks can
be observed at 1523, 1453, and 1412 cmꢁ1. These bands, however,
are not present in Fig. 2(a) and (b). Thus, the catalyst could
successfully bind into poly(AN-MA-b-CD).
reports, benzene and adamantane can be recovered by CD via
host–guest interaction.12 The reaction of cyclohexanone with
m-nitrobenzaldehyde was selected as a model for assessing the
recyclability of catalyst because m-nitrobenzaldehyde with steric
hindrance did not easily turn into the b-CD cavity and
adamantine-modied catalyst was recovered by brous
membrane via host–guest interaction from the reaction
medium. The recycling process of catalyst is shown in Scheme
2. The adsorption rate of catalyst in mixture of MeOH/H2O
98.5%, and the separation rate from the brous membrane was
97.7%. Therefore, the total recovery rate was 96.2%. The rele-
vant results about recyclability of catalyst are summarized in
Table 4. In the rst three recycles, conversions were above 95%
with excellent diastereoselectivities and enantioselectivities
under the same reaction time. Prolonging the reaction time
could also provide good yields with desirable diaster-
eoselectivities from the third cycle. In the sixth run, the yield
SEM analysis
Typical SEM images of nanobrous lms of poly(AN-MA-b-CD)
are shown in Fig. 3. It could be clearly seen that the membranes
were composed of numerous and randomly oriented nanobers.
When the mass fraction of poly(AN-MA-b-CD) in DMF was <20%,
a brous membrane was not formed. At mass fraction of >36%,
poly(AN-MA-b-CD) did not dissolve in DMF in a short time. The
SEM images showed that this membrane feature was affected by
the mass fraction from 20% to 36% (Fig. 3). Fig. 3(a) and (b)
showed that the nanobrous lm have an average diameter of
exceed 1 mm. With further reduction in the mass fraction, the
diameter of the resulting brous membranes (Fig. 3 (c)–(e)) had
decreased. In particular, Fig. 3(c) and (d) respectively show an
average diameter of about 440 nm and 430 nm with smooth
surfaces. At mass fraction of 20%, the average diameter of the
lm was approximately 160 nm with smooth surface (Fig. 3(e)). In
general, 20% poly(AN-MA-b-CD) formed plentiful brous
membranes. Compared with Fig. 3(e), the result in Fig. 3(f)
showed coarser surfaces and larger diameter.
Table 4 Recycling experimentsa
Entry
Time (h)
Yieldb (%)
drc (syn/anti)
eec (%)
1
2
3
4
5
6
48
48
48
60
60
72
97
98
95
95
90
92
99 : 1
>99 : 1
98 : 2
99 : 1
98 : 2
94 : 6
98
99
97
97
96
92
a
Reaction conditions: m-nitrobenzaldehyde (0.5 mmol), cyclohexanone
Recyclability of catalyst
(10 equiv.), catalyst 1d (0.05 mmol, 10 mol%) only being added at rst
b
run, solvent (1.0 mL),
0
ꢀC.
Combined yields of isolated.
c
In the next moment, we further evaluated the recyclability of the
catalyst in the direct aldol reactions. According to related
Determined by HPLC with a chiral AD-H column.
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was 92% with ee value of 92%. As shown in Table 4, the catalyst a solution of acid (10.0 mmol, 1.0 equiv.), DMAP (0.98 g,
can also be reused for up to ve times without showing signif- 8.0 mmol, 0.8 equiv.), and EDCI (2.30 g, 12.0 mmol, 1.2 equiv.)
icant change in diastereoselectivity and enantioselectivity.
in CH2Cl2 (20 mL) was added into solvent aer 5 min with
vigorous stirring. The resulting reaction mixture was stirred at
room temperature for overnight. The solvent was evaporated.
The aqueous layer was extracted with ethyl acetate. The
combined organic layer was dried (MgSO4) and then evaporated
under reduced pressure to the crude products which was
further puried via silica gel column chromatography
(EtOAc : PE ¼ 1 : 5) to afford compound.
Conclusions
In summary, organocatalysts based on L-proline or trans-4-hydroxy-
L-proline with double-H potential were synthesized. Catalyst 1d
(10 mol%) demonstrated very efficient performance for catalyzing
direct aldol reactions. The use of brine as solvent afforded aldol
products in excellent yields (up to 98% yield) with high diaster-
eoselectivity (>99 : 1) and enantioselectivity (>99%). A nanobrous
lm of 20% poly(AN-MA-b-CD) was formed by electrospinning and
characterized by FTIR and SEM analyses. Aer each run, the
catalyst adsorbed on the lm via host–guest interaction in the
reaction system and then separated from the lm using ultra-
sound. The total recovery rate of the catalyst was 96.2%, and the
catalyst could be reused for up to ve times without exhibiting
signicant change in diastereoselectivity and enantioselectivity.
Boc-L-hydroxyproline or Boc-L-proline (6.0 mmol, 1.2 equiv.)
ꢀ
was dissolved in dry CH2Cl2 (20 mL) and cooled to 0 C. And
DMAP (0.49 g, 4.0 mmol, 0.8 equiv.) and EDCI (1.15 g, 6.0 mmol,
1.2 equiv.) were added. A solution of phenylamine 1 (1.06 g, 5.0
mmol) in dry CH2Cl2 (20 mL) was then added dropwise aer
15 min with vigorous stirring. The resulting reaction mixture
was stirred at room temperature and monitored by TLC. Aer
completion of the reaction, the mixture was partitioned
between EtOAc and water. The organic layer was washed with
saturated brine. The combined organic layer was dried (MgSO4)
and then evaporated under reduced pressure to crude product.
The crude product was then dissolved in CH2Cl2 (20 mL) and
cooled to 0 ꢀC. Triuoroacetic acid (10.0 equiv.) was added
dropwise to mixture solution and further stirred at room
temperature for another 4 h. Aer the reaction was completed,
mixture was quenched with saturated NaHCO3 aqua. The
aqueous layer was extracted with ethyl acetate, and the organic
layer was successively washed with water and another portion of
saturated brine, dried (MgSO4) and evaporated under reduced
pressure. The oily residue was puried by silica gel chroma-
tography (ethyl acetate/methanol (3% Et3N) ¼ 10 : 1) to give
compound.
Experimental
General procedure
All chemicals were used as received unless otherwise noted. All
reagents were purchased from J&K or Sigma-Aldrich Chemical
Co. and were used without any further purication. Solvents
were dried according to standard procedures. Reactions were
monitored by thin-layer chromatography (TLC) carried out on
silica gel 60F254 plates. Flash column chromatography was
performed using silica gel (200–300 mesh, Qingdao Haiyang
Chemical Co.). 1H and 13C NMR spectra were taken on a Bruker
AV-400 MHz spectrometer. All chemical shis (d) were given
in ppm. Chemical shis (d ppm) are relative to the resonance of
the deuterated solvent as the internal standard (CDCl3,
d 7.26 ppm for proton NMR, d 77.36 ppm for carbon NMR;
DMSO-d6, d 2.54 ppm for proton NMR, d 40.45 ppm for carbon
NMR). Data are presented as follows: chemical shi, integra-
tion, multiplicity (br ¼ broad, s ¼ singlet, d ¼ doublet, t ¼
triplet, q ¼ quartet, m ¼ multiplet) and coupling constant in
hertz (Hz). Mass spectra were recorded on the Bruker Agilent
1290 MicrOTOF Q II. Melting points were measured on
a melting point apparatus and were uncorrected. The ee values
determination was carried out using chiral HPLC (Waters) with
Chiracel AD-H column, Chiracel OD-H column and Chiracel AS-
H column. Optical rotations were measured on a Shanghai Shen
Guang SGW-2 Polarimeter at l ¼ 589 nm. Optical rotations are
reported as follows: [a]2D5 (c ¼ g/100 mL, solvent). IR spectra were
recorded on a Bruker Vector-22 spectrometer. UV-Vis spectra
were recorded on a Hitachi U-3010 UV-Vis spectrophotometer.
High voltage power (0–50 kV) DW-P503-1AC (Tianjin, China),
and scanning electron microscope (SEM) were also used.
(S)-N-(2-Benzamidophenyl)-4-hydroxyprolinamide
(1a).
White solid (1.12 g, yield 69%). Mp ¼ 164–165 ꢀC, [a]D25 ¼ +11.6
(c ¼ 0.5, CH3OH). 1H NMR (400 MHz, DMSO) d ¼ 10.22 (d, J ¼
15.4 Hz, 1H), 8.05 (dd, J ¼ 12.8, 7.9 Hz, 2H), 7.65 (t, J ¼ 7.2 Hz,
1H), 7.59 (t, J ¼ 7.4 Hz, 1H), 7.40 (d, J ¼ 7.8 Hz, 1H), 7.32 (t, J ¼
7.7 Hz, 1H), 7.19 (t, J ¼ 7.6 Hz, 1H), 4.70 (d, J ¼ 2.6 Hz, 1H), 4.15
(s, 1H), 3.91 (t, J ¼ 8.2 Hz, 1H), 3.40 (s, 1H), 2.64 (dt, J ¼ 11.5,
7.4 Hz, 1H), 2.10–2.00 (m, 1H), 1.83–1.73 (m, 1H) ppm. 13C NMR
(101 MHz, DMSO) d ¼ 174.34, 166.77, 134.99, 134.46, 132.72,
129.41, 129.20, 128.59, 128.15, 127.59, 124.83, 122.56, 72.33,
60.90, 55.65, 40.54 ppm. HRMS (ESI): calcd for C18H20N3O3+ [M
+ H]+ 326.1499; found 326.1500.
(S)-N-(2-Benzamidophenyl)prolinamide (1b). White solid
(0.93 g, yield 60%). Mp ¼ 159–160 ꢀC, [a]D25 ¼ ꢁ6.0 (c ¼ 0.5,
CH3OH). 1H NMR (400 MHz, DMSO): d ¼ 10.24 (d, J ¼ 13.2 Hz,
1H), 8.07 (dd, J ¼ 16.6, 7.8 Hz, 2H), 7.62 (dt, J ¼ 14.7, 7.1 Hz, 2H),
7.43–7.28 (m, 1H), 7.19 (t, J ¼ 7.5 Hz, 1H), 3.73 (dd, J ¼ 9.1,
4.6 Hz, 1H), 3.20 (s, 1H), 2.78 (dd, J ¼ 11.7, 4.7 Hz, 1H), 2.65–
2.56 (m, 1H), 2.09–1.96 (m, 1H), 1.80 (dd, J ¼ 12.0, 5.6 Hz, 1H),
1.57 (dt, J ¼ 13.3, 6.6 Hz, 1H) ppm. 13C NMR (101 MHz, DMSO):
d ¼ 174.50, 166.73 (s), 134.93, 134.62, 132.73, 129.42, 129.14,
128.56, 128.18, 127.63, 61.58, 47.45, 31.41, 26.75 ppm. HRMS
(ESI): calcd for C18H20N3O2+ [M + H]+ 310.1550; found 310.1550.
(S)-N-(2-(Adamantane-1-carboxamidophenyl))-4-
Synthesis of catalysts: the catalysts were prepared according to
previous works3,4
To a ask containing o-phenylenediamine (1.08 g, 10.0 mmol,
1.0 equiv.) dissolved in dry CH2Cl2 (30 mL) at 0 ꢀC, and hydroxyprolinam-ide (1c). White solid (1.36 g, yield 71%). Mp ¼
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209–210 ꢀC, [a]D25 ¼ ꢁ11.2 (c ¼ 0.5, CH3OH). 1H NMR (400 MHz,
DMSO): d ¼ 10.02 (s, 1H), 9.11 (s, 1H), 8.01 (d, J ¼ 8.2 Hz, 1H),
7.24 (dd, J ¼ 12.1, 4.5 Hz, 3H), 7.15–7.09 (m, 1H), 4.81 (s, 1H),
4.25 (s, 1H), 3.95 (t, J ¼ 8.3 Hz, 1H), 3.04 (q, J ¼ 7.2 Hz, 2H), 2.91–
2.81 (m, 3H), 2.08 (d, J ¼ 9.7 Hz, 4H), 2.02–1.92 (m, 8H), 1.80–
1.72 (m, 8H), 1.18 (t, J ¼ 7.3 Hz, 3H). 13C NMR (101 MHz,
DMSO): d ¼ 177.40, 174.08, 134.18, 129.54, 128.15, 127.07,
124.67, 122.26, 72.25, 60.88, 55.87, 46.61, 41.46, 39.57, 37.06,
General procedure for asymmetric aldol reaction
The following procedure for the reaction of cyclohexanone with
p-nitrobenzaldehyde in brine using catalyst 1d was representa-
tive. To a mixture of catalyst 1d (18.4 mg, 0.05 mmol) and p-
nitrobenzaldehyde (75 mg, 0.5 mmol) in brine (1 mL) was added
under air in a closed system. The reaction mixture was stirred at
0 ꢀC for 15 min, and then cyclohexanone (10 equiv.) was added.
Aer the reaction mixtures were stirred for 48 h, the mixtures
were quenched with 2 M ammonium chloride solution and
extracted with ethyl acetate. The organic layer was dried over
Na2SO4, ltered, and concentrated to give pure aldol product
aer ash column chromatography (silica gel, petroleum ether/
ethyl acetate ¼ 3/1). The product was a light yellow or white
solid. The absolute conguration of aldol products was
extrapolated by comparison of the HPLC-data with known
literatures.15,21
+
28.64 ppm. HRMS (ESI): calcd for C22H30N3O3 [M + H]+
384.2282; found 384.2282.
(S)-N-(2-(Adamantane-1-carboxamidophenyl))prolinamide
(1d). White solid (1.23 g, yield 67%). Mp ¼ 213–214 ꢀC, [a]D25
¼
ꢁ24.4 (c ¼ 0.5, CH3OH). 1H NMR (400 MHz, DMSO): d ¼ 10.08
(s, 1H), 9.01 (s, 1H), 7.82 (d, J ¼ 7.9 Hz, 1H), 7.36–7.32 (m, 1H),
7.27–7.22 (m, 1H), 7.18 (dd, J ¼ 10.8, 4.4 Hz, 1H), 4.05 (dd, J ¼
8.7, 6.0 Hz, 1H), 3.17–2.97 (m, 3H), 2.22 (dt, J ¼ 15.8, 8.0 Hz, 1H),
2.06 (s, 3H), 1.96 (d, J ¼ 7.1 Hz, 6H), 1.84–1.68 (m, 10H), 1.21 (t, J
¼ 7.3 Hz, 1H) ppm. 13C NMR (101 MHz, DMSO): d ¼ 177.19,
171.96, 132.98, 130.61, 127.78, 126.74, 125.49, 123.75, 61.15,
47.35, 41.52, 39.53, 37.02, 31.04, 28.61, 25.95 ppm. HRMS (ESI):
calcd for C22H30N3O2+ [M + H]+ 368.2333; found 368.2333.
(2S,10R)-2-(Hydroxy-(4-nitrophenyl)methyl)cyclohexan-1-one
(4a). Reaction time: 48 h; yield: 98%; light yellow solid. Enan-
tiomeric excess: 96%, determined by HPLC with a Chiral-pack
AD-H column (90 : 10 hexane : 2-propanol), 1 mL minꢁ1
;
254 nm, 25 ꢀC; tR (major) ¼ 31.2 min, tR (minor) ¼ 23.7 min. 1H
NMR (400 MHz, DMSO): d ¼ 8.20 (t, J ¼ 7.6 Hz, 2H), 7.63 (t, J ¼
8.9 Hz, 2H), 5.54 (d, J ¼ 27.0 Hz, 1H), 5.12 (d, J ¼ 7.0 Hz, 1H),
2.71 (ddd, J ¼ 20.8, 10.9, 5.5 Hz, 1H), 2.37 (s, 2H), 1.58 (s, 5H),
1.20 (td, J ¼ 19.3, 9.1 Hz, 1H) ppm. 13C NMR (101 MHz, DMSO):
d ¼ 211.39, 153.81, 147.23, 128.81, 128.10, 123.72, 69.31, 57.15,
42.25, 30.20, 28.12, 24.31 ppm.
The preparation of poly(AN-MA-b-CD)
The poly(AN-MA-b-CD) was prepared according to previous
works in our group.19 AN (30 g, 0.57 mol) and MA (7.21 g, 0.1
mol) were dissolved in dry DMF (149 g) at 0 ꢀC for vigorous
string 15 min. And then PVP (0.037 g) and AIBN (0.372 g) was
added into solvent. The resulting reaction mixture was stirred at
70 ꢀC for overnight. Aer reaction, a large of distilled water was
added and precipitate was observed. The solid was washed with
distilled water another three times and dried at vacuum oven
for overnight to give the poly(AN-MA) 18.23 g (yield: 49%).
The polymer (5 g) dissolved in dry DMF (80 mL) at 0 ꢀC, and
then DMAP (19.17 g, 0.1 mol) and EDCI (1.22 g, 0.01 mol) was
added into solvent aer vigorous stirring with 5 min. b-CD in
dry DMF (500 mL) was added dropwise under 0 ꢀC. The
resulting reaction mixture was stirred at room temperature for
overnight. The solvent was evaporated aer complete reaction.
A large of distilled water was added and solid was precipitated.
The solid was washed with distilled water another three times
and dried at vacuum oven for overnight to give poly(AN-MA-b-
CD) 11.03 g.
(2S,10R)-2-(Hydroxy-(3-nitrophenyl)methyl)cyclohexan-1-one
(4b). Reaction time: 48 h; yield: 97%; light yellow solid. Enan-
tiomeric excess: 98%, determined by HPLC with a Chiralpack
AD-H column (95 : 5 hexane : 2-propanol), 1 mL minꢁ1; 254 nm,
1
ꢀ
25 C; tR (major) ¼ 34.8 min, tR (minor) ¼ 44.5 min. H NMR
(400 MHz, DMSO): d ¼ 8.17 (s, 1H), 8.08 (d, J ¼ 8.3 Hz, 1H), 7.76
(d, J ¼ 7.1 Hz, 1H), 7.58 (t, J ¼ 7.9 Hz, 1H), 5.52 (d, J ¼ 4.4 Hz,
1H), 5.13–5.03 (m, 1H), 2.70 (d, J ¼ 4.7 Hz, 1H), 2.30 (s, 2H), 1.78
(d, J ¼ 25.2 Hz, 2H), 1.55 (s, 3H), 1.15 (d, J ¼ 11.8 Hz, 1H) ppm.
13C NMR (101 MHz, DMSO): d ¼ 211.75, 148.51, 146.96, 134.61,
130.25, 122.83, 122.35, 71.20, 58.14, 42.21, 30.31, 28.30,
24.15 ppm.
(2S,10R)-2-(Hydroxy-(2-nitrophenyl)methyl)cyclohexan-1-one
(4c). Reaction time: 48 h; yield: 97%; light yellow solid. Enan-
tiomeric excess: 97%, determined by HPLC with a Chiralpack
AD-H column (95 : 5 hexane : 2-propanol), 1 mL minꢁ1; 254 nm,
1
ꢀ
25 C; tR (major) ¼ 16.8 min, tR (minor) ¼ 19.1 min. H NMR
(400 MHz, DMSO): d ¼ 7.81 (d, J ¼ 8.1 Hz, 1H), 7.69 (d, J ¼
4.2 Hz, 2H), 7.50 (dt, J ¼ 8.3, 4.3 Hz, 1H), 5.76 (s, 1H), 5.60 (d, J ¼
4.5 Hz, 1H), 2.89–2.69 (m, 1H), 2.46–2.35 (m, 1H), 2.28 (dd, J ¼
12.8, 4.4 Hz, 1H), 1.90 (s, 1H), 1.75–1.66 (m, 1H), 1.63–1.49 (m,
2H), 1.44 (d, J ¼ 13.2 Hz, 1H), 1.37–1.21 (m, 1H) ppm. 13C NMR
(101 MHz, DMSO): d ¼ 211.13, 149.60, 138.36, 133.34, 130.33,
129.04, 124.09, 67.28, 57.85, 42.59, 31.28, 28.57, 24.68 ppm.
(2S,10R)-2-(Hydroxy-(4-cyanophenyl)methyl)cyclohexan-1-
The preparation of brous lm
The poly(AN-MA-b-CD) dissolved in DMF was changed into
brous membrane by electrospinning, and the preparation
owchart of brous membrane was shown in Scheme 2.20 The
electrospinning solution was moved into the 5.0 mL injector
with a stainless-steel needle of inner diameter about 1 mm, and
the distance from the needle to the receiving plate was adjusted
to 15–18 cm. Fibrous membrane was collected on aluminium
foil with a liquid ow rate of 1.0 mL hꢁ1 and a voltage of 15.4 kV.
Aer 4 h of continuous electrospinning, aluminium foil was
one (4d). Reaction time: 48 h; yield: 93%; white solid. Enan-
tiomeric excess: 97%, determined by HPLC with a Chiralpack
OD-H column (95 : 5 hexane : 2-propanol),
1 ;
mL minꢁ1
220 nm, 25 ꢀC; tR (major) ¼ 25.7 min, tR (minor) ¼ 37.3 min. 1H
ꢀ
placed into the oven at 40 C for 6 h.
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NMR (400 MHz, DMSO): d ¼ 7.78 (d, J ¼ 8.0 Hz, 2H), 7.53 (d, J ¼ H column (95 : 5 hexane : 2-propanol), 1 mL minꢁ1; 220 nm,
1
ꢀ
8.0 Hz, 2H), 5.46 (s, 1H), 5.03 (d, J ¼ 7.2 Hz, 1H), 2.67 (dd, J ¼ 25 C; tR (major) ¼ 12.0 min, tR (minor) ¼ 16.3 min. H NMR
13.2, 8.9 Hz, 1H), 2.34 (t, J ¼ 6.2 Hz, 2H), 1.92–1.69 (m, 2H), (400 MHz, DMSO): d ¼ 7.41–7.31 (m, 4H), 5.29 (d, J ¼ 4.4 Hz,
1.68–1.45 (m, 3H), 1.15 (dd, J ¼ 20.6, 10.6 Hz, 1H) ppm. 13C 1H), 4.96 (dd, J ¼ 7.7, 4.4 Hz, 1H), 2.61 (td, J ¼ 8.9, 5.3 Hz, 1H),
NMR (101 MHz, DMSO): d ¼ 211.70, 150.31, 132.75, 128.79, 2.41–2.28 (m, 2H), 1.89–1.70 (m, 2H), 1.64 (ddd, J ¼ 12.4, 5.8,
119.86, 110.61, 71.62, 58.18, 42.13, 30.44, 28.37, 24.05 ppm.
3.4 Hz, 1H), 1.57–1.45 (m, 2H), 1.21–1.08 (m, 1H) ppm. 13C NMR
(101 MHz, DMSO): d ¼ 212.13, 143.47, 132.40, 129.67, 128.76,
(2S,10R)-2-(Hydroxy-(3-cyanophenyl)methyl)cyclohexan-1-
one (4e). Reaction time: 48 h; yield: 90%; white solid. Enantio- 71.58, 58.49, 41.99, 30.49, 28.50, 23.86 ppm.
meric excess: 97%, determined by HPLC with a Chiralpack OD-
(2S,10R)-2-(Hydroxy-(3-chlorophenyl)methyl)cyclohexan-1-
H column (95 : 5 hexane : 2-propanol), 1 mL minꢁ1; 220 nm, one (4j). Reaction time: 48 h; yield: 54%; white solid. Enantio-
1
ꢀ
25 C; tR (major) ¼ 24.8 min, tR (minor) ¼ 29.3 min. H NMR meric excess: 98%, determined by HPLC with a Chiralpack AD-
(400 MHz, DMSO): d ¼ 7.76 (s, 1H), 7.70 (dd, J ¼ 12.9, 7.8 Hz, H column (95 : 5 hexane : 2-propanol), 1 mL minꢁ1; 220 nm,
1
ꢀ
2H), 7.54 (t, J ¼ 7.7 Hz, 1H), 5.43 (s, 1H), 5.00 (d, J ¼ 7.2 Hz, 1H), 25 C; tR (major) ¼ 17.1 min, tR (minor) ¼ 15.1 min. H NMR
2.70 (t, J ¼ 10.9 Hz, 1H), 2.33 (d, J ¼ 5.8 Hz, 2H), 1.93–1.69 (m, (400 MHz, DMSO): d ¼ 7.37–7.23 (m, 4H), 5.31 (d, J ¼ 4.5 Hz,
2H), 1.69–1.43 (m, 3H), 1.22–1.08 (m, 1H) ppm. 13C NMR (101 1H), 4.92 (dd, J ¼ 7.6, 4.5 Hz, 1H), 2.69–2.55 (m, 1H), 2.37–2.27
MHz, DMSO): d ¼ 211.40, 145.74, 132.32, 131.27, 130.94, 129.61, (m, 2H), 1.85–1.68 (m, 2H), 1.66–1.56 (m, 1H), 1.55–1.42 (m,
119.44, 111.30, 70.93, 57.63, 41.72, 30.03, 27.95, 23.62 ppm.
2H), 1.20–1.07 (m, 1H) ppm. 13C NMR (101 MHz, DMSO): d ¼
(2S,10R)-2-(Hydroxy-(2-cyanophenyl)methyl)cyclohexan-1-
211.80, 146.95, 133.41, 130.47, 127.65, 127.39, 126.34, 71.45,
one (4f). Reaction time: 48 h; yield: 91%; white solid. Enantio- 58.14, 41.86, 30.36, 28.29, 23.74 ppm.
meric excess: 97%, determined by HPLC with a Chiralpack OD-
(2S
10R)-2-(Hydroxy-(2-chlorophenyl)methyl)cyclohexan-1-
H column (95 : 5 hexane : 2-propanol), 1 mL minꢁ1; 220 nm, one (4k). Reaction time: 48 h; yield: 59%; white solid. Enan-
1
ꢀ
25 C; tR (major) ¼ 16.3 min, tR (minor) ¼ 18.6 min. H NMR tiomeric excess: 99%, determined by HPLC with a Chiralpack
(400 MHz, DMSO): d ¼ 7.78 (d, J ¼ 7.7 Hz, 1H), 7.72 (t, J ¼ 7.6 Hz, OD-H column (95 : 5 hexane : 2-propanol),
1
mL minꢁ1
;
1
ꢀ
1H), 7.63 (d, J ¼ 7.9 Hz, 1H), 7.47 (t, J ¼ 7.5 Hz, 1H), 5.67 (d, J ¼ 220 nm, 25 C; tR (major) ¼ 9.7 min, tR (minor) ¼ 6.0 min. H
4.1 Hz, 1H), 5.17 (dd, J ¼ 8.8, 4.0 Hz, 1H), 2.76 (td, J ¼ 9.5, NMR (400 MHz, DMSO): d ¼ 7.54 (d, J ¼ 7.6 Hz, 1H), 7.37 (t, J ¼
5.4 Hz, 1H), 2.38 (ddd, J ¼ 17.6, 11.4, 6.3 Hz, 2H), 1.96–1.81 (m, 8.7 Hz, 2H), 7.27 (t, J ¼ 7.6 Hz, 1H), 5.38 (d, J ¼ 3.8 Hz, 1H), 5.32
1H), 1.69 (ddd, J ¼ 19.2, 18.5, 13.2 Hz, 2H), 1.56 (dd, J ¼ 16.1, (d, J ¼ 8.7 Hz, 1H), 2.75–2.60 (m, 1H), 2.37 (t, J ¼ 6.5 Hz, 2H),
6.6 Hz, 1H), 1.40–1.30 (m, 1H), 1.23 (dd, J ¼ 19.8, 10.0 Hz, 1.85 (dd, J ¼ 11.2, 5.7 Hz, 1H), 1.71 (dt, J ¼ 12.3, 9.9 Hz, 2H), 1.53
1H) ppm. 13C NMR (101 MHz, DMSO): d ¼ 211.41, 148.19, (dd, J ¼ 9.0, 3.6 Hz, 1H), 1.45–1.27 (m, 2H) ppm. 13C NMR (101
134.31, 133.40, 129.08, 129.03, 118.77, 111.23, 70.52, 58.02, MHz, DMSO): d ¼ 211.62, 142.03, 132.44, 129.69, 129.43, 129.41,
42.48, 31.27, 28.93, 24.42 ppm.
128.14, 68.42, 58.31, 42.30, 30.93, 28.73, 24.30 ppm.
(2S,10R)-2-(Hydroxy-(4-triuoromethylphenyl)methyl)cycloh-
(2S,10R)-2-(Hydroxy-(4-bromophenyl)methyl)cyclohexan-1-
exan-1-one (4g). Reaction time: 48 h; yield: 94%; white solid. one (4l). Reaction time: 48 h; yield: 50%; white solid. Enantio-
Enantiomeric excess: 97%, determined by HPLC with a Chir- meric excess: 99%, determined by HPLC with a Chiralpack AD-
alpack AD-H column (90 : 10 hexane : 2-propanol), 1 mL minꢁ1
;
H column (90 : 10 hexane : 2-propanol), 1 mL minꢁ1; 220 nm,
1
1
220 nm, 25 ꢀC; tR (major) ¼ 12.8 min, tR (minor) ¼ 10.4 min. H 25 C; tR (major) ¼ 16.7 min, tR (minor) ¼ 14.4 min. H NMR
NMR (400 MHz, DMSO): d ¼ 7.68 (d, J ¼ 8.1 Hz, 2H), 7.56 (d, J ¼ (400 MHz, DMSO): d ¼ 7.47 (d, J ¼ 7.8 Hz, 2H), 7.26 (d, J ¼
8.1 Hz, 2H), 5.42 (d, J ¼ 4.5 Hz, 1H), 5.05 (dd, J ¼ 7.2, 4.6 Hz, 7.7 Hz, 2H), 5.24 (s, 1H), 4.90 (d, J ¼ 7.7 Hz, 1H), 3.35 (s, 1H),
1H), 2.72–2.64 (m, 1H), 2.36 (t, J ¼ 6.5 Hz, 2H), 1.91–1.70 (m, 2.39–2.22 (m, 2H), 1.74 (dd, J ¼ 31.9, 5.4 Hz, 2H), 1.61 (s, 1H),
ꢀ
2H), 1.70–1.47 (m, 3H), 1.16 (ddd, J ¼ 13.2, 10.4, 6.9 Hz, 1.48 (d, J ¼ 9.3 Hz, 2H), 1.12 (dd, J ¼ 12.1, 6.9 Hz, 1H) ppm. 13
C
1H) ppm. 13C NMR (101 MHz, DMSO): d ¼ 211.67, 149.11, NMR (101 MHz, DMSO): d ¼ 211.90, 143.70, 131.47, 129.85,
128.49, 128.39, 125.45, 71.44, 58.12, 41.89, 30.28, 28.22, 120.73, 71.42, 58.24, 41.79, 30.28, 28.28, 23.67 ppm.
23.80 ppm.
(2S,10R)-2-(Hydroxy-(2,4-dichlorophenyl)methyl)cyclohexan-
(2S,10R)-2-(Hydroxy-(2-bromophenyl)methyl)cyclohexan-1-
one (4m). Reaction time: 48 h; yield: 55%; white solid. Enan-
1-one (4h). Reaction time: 48 h; yield: 90%; white solid. Enan- tiomeric excess: 97%, determined by HPLC with a Chiralpack
tiomeric excess: 98%, determined by HPLC with a Chiralpack AD-H column (90 : 10 hexane : 2-propanol), 1 mL minꢁ1
;
OD-H column (95 : 5 hexane : 2-propanol),
1
mL minꢁ1
;
220 nm, 25 ꢀC; tR (major) ¼ 11.0 min, tR (minor) ¼ 12.8 min. 1H
220 nm, 25 ꢀC; tR (major) ¼ 9.5 min, tR (minor) ¼ 11.7 min. 1H NMR (400 MHz, DMSO): d ¼ 7.53 (ddd, J ¼ 11.6, 7.9, 1.3 Hz, 2H),
NMR (400 MHz, DMSO): d ¼ 7.54 (d, J ¼ 8.4 Hz, 2H), 7.44 (dd, J 7.40 (dd, J ¼ 11.0, 3.9 Hz, 1H), 7.19 (td, J ¼ 8.0, 1.7 Hz, 1H), 5.41
¼ 8.5, 1.4 Hz, 1H), 5.48 (d, J ¼ 4.6 Hz, 1H), 5.25 (dd, J ¼ 8.4, (s, 1H), 5.27 (d, J ¼ 8.7 Hz, 1H), 2.68 (dd, J ¼ 15.7, 8.1 Hz, 1H),
4.6 Hz, 1H), 2.71–2.61 (m, 1H), 2.42–2.30 (m, 2H), 1.92–1.32 (m, 2.37 (dd, J ¼ 10.6, 5.4 Hz, 2H), 1.86 (dd, J ¼ 11.5, 5.3 Hz, 1H),
6H) ppm. 13C NMR (101 MHz, DMSO): d ¼ 211.07, 132.91, 1.80–1.61 (m, 2H), 1.60–1.45 (m, 1H), 1.41–1.30 (m, 2H) ppm.
132.65, 130.93, 128.52, 128.09, 67.89, 57.67, 42.13, 30.70, 28.37, 13C NMR (101 MHz, DMSO): d ¼ 211.74, 143.84, 132.88, 130.14,
24.11 ppm.
(2S,10R)-2-(Hydroxy-(4-chlorophenyl)methyl)cyclohexan-1-
one (4i). Reaction time: 48 h; yield: 57%; white solid. Enantio-
129.98, 128.88, 123.37, 71.07, 58.58, 42.61, 31.29, 28.93,
24.65 ppm.
(2S,10R)-2-(Hydroxy-(4-uorophenyl)methyl)cyclohexan-1-
meric excess: 98%, determined by HPLC with a Chiralpack OD- one (4n). Reaction time: 48 h; yield: 46%; white solid.
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Enantiomeric excess: 95%, determined by HPLC with a Chir- column (70 : 30 hexane : 2-propanol), 1 mL minꢁ1; 254 nm,
1
alpack OD-H column (95 : 5 hexane : 2-propanol), 1 mL minꢁ1
;
25 C; tR (major) ¼ 12.8 min, tR (minor) ¼ 15.5 min. H NMR
ꢀ
220 nm, 25 ꢀC; tR (major) ¼ 13.7 min, tR (minor) ¼ 12.6 min. 1H (400 MHz, DMSO): d ¼ 8.22 (t, J ¼ 14.5 Hz, 2H), 7.65 (d, J ¼
NMR (400 MHz, DMSO) d ¼ 7.39 (ddd, J ¼ 11.4, 8.5, 5.8 Hz, 1H), 8.2 Hz, 2H), 5.72 (d, J ¼ 4.7 Hz, 1H), 5.16 (dd, J ¼ 11.6, 5.9 Hz,
7.20–7.10 (m, 1H), 5.24 (d, J ¼ 19.1 Hz, 1H), 5.06 (dd, J ¼ 54.9, 1H), 2.76 (d, J ¼ 6.5 Hz, 2H), 2.15 (s, 3H) ppm. 13C NMR (101
6.3 Hz, 1H), 2.61 (ddd, J ¼ 15.6, 9.5, 5.2 Hz, 1H), 2.47–2.26 (m, MHz, DMSO): d ¼ 206.77, 153.70, 146.98, 127.49, 123.83, 68.57,
1H), 1.96–1.49 (m, 3H) ppm. 13C NMR (101 MHz, DMSO) d ¼ 52.84, 30.87 ppm.
212.33, 163.39, 140.65, 129.71, 129.63, 115.63, 115.23, 71.68,
57.85, 41.93, 30.56, 28.57, 24.37, 23.76 ppm.
Conflicts of interest
(2S,10R)-2-(Hydroxy(phenyl)methyl)cyclohexan-1-one
(4o).
Reaction time: 48 h; yield: 49%; white solid. Enantiomeric There are no conicts to declare.
excess: 97%, determined by HPLC with a Chiralpack OD-H
column (95 : 5 hexane : 2-propanol), 1 mL minꢁ1; 220 nm,
25 C; tR (major) ¼ 11.4 min, tR (minor) ¼ 14.7 min. H NMR
Acknowledgements
1
ꢀ
(400 MHz, DMSO): d ¼ 7.35–7.22 (m, 5H), 5.19 (d, J ¼ 4.3 Hz, This study was funded by the National Natural Science Foun-
1H), 4.93 (dd, J ¼ 8.3, 4.3 Hz, 1H), 2.60 (td, J ¼ 8.4, 5.4 Hz, 1H), dation of China (No. 21174052) and the Natural Science Foun-
2.45–2.23 (m, 2H), 1.83–1.64 (m, 3H), 1.56–1.43 (m, 2H), 1.18 dation of Jilin Province of China (No. 20160101311JC and
(ddd, J ¼ 12.5, 8.8, 4.0 Hz, 1H) ppm. 13C NMR (101 MHz, 20170101105JC).
DMSO): d ¼ 212.49, 144.45, 128.86, 128.03, 127.82, 72.50, 58.73,
41.87, 30.70, 28.66, 23.68 ppm.
References
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Reaction time: 48 h; yield: 36%; white solid. Enantiomeric
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column (90 : 10 hexane : 2-propanol), 1 mL minꢁ1; 220 nm,
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25 C; tR (major) ¼ 14.7 min, tR (minor) ¼ 17.0 min. H NMR
(400 MHz, DMSO): d ¼ 7.92–7.86 (m, 1H), 7.83 (s, 1H), 7.55–7.46
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254 nm, 25 ꢀC; tR (major) ¼ 11.2 min, tR (minor) ¼ 23.2 min. 1H
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25 C; tR (major) ¼ 10.4 min, tR (minor) ¼ 11.0 min. H NMR
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