Synthesis of dendrimer-supported ferrocenylmethyl aziridino alcohol ligands and their application in asymmetric catalysis

Article abstract of DOI:10.1039/c4gc02447h

A series of N-ferrocenylmethyl aziridino alcohol ligands bearing Frchet-type dendrimers were synthesized and applied in the asymmetric addition of diethylzinc to aldehydes affording chiral alcohols in excellent yields (up to 99%) and excellent enantiosele

Full text of DOI:10.1039/c4gc02447h

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Synthesis of dendrimer-supported
ferrocenylmethyl aziridino alcohol ligands and
Cite this: DOI: 10.1039/c4gc02447h
their application in asymmetric catalysis†
Wen-Xian Zhao,*a,b Nian Liu,b,c Gao-Wei Li,a Dong-Li Chen,b An-An Zhang,a
Min-Can Wangb and Lantao Liu*a
Received 16th December 2014,
Accepted 26th February 2015
A series of N-ferrocenylmethyl aziridino alcohol ligands bearing Fréchet-type dendrimers were syn-
thesized and applied in the asymmetric addition of diethylzinc to aldehydes affording chiral alcohols in
excellent yields (up to 99%) and excellent enantioselectivities (ee, up to 98%). The ligands could be
recycled and reused eight times for such a reaction with almost the original high reactivity and selectivity.
DOI: 10.1039/c4gc02447h
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parable to, or even much better than, those of their parental
small molecular catalysts.3 The fine-tunable catalytic pro-
1. Introduction
Development of highly efficient and recyclable chiral catalysts perties of the dendritic chiral catalysts are ascribed to their
which meet the requirements of green and sustainable chem- easily adjustable well-defined structure, size, shape, and solu-
istry is crucial for the application of the asymmetric transform- bility of the dendrimers. In addition, the microenvironment
ations in industry and has been attracting extensive attention of created by the attached dendritic wedges sometimes brings
chemists.1 Although various highly efficient homogeneous positive dendritic effects for the supported catalysts.3a,b Since
chiral catalysts have been developed over the past several the pioneering work of Knapen et al.,4 a number of chiral den-
decades, they often have disadvantages in aspects such as the dritic catalysts with different chelating atoms have been deve-
separation, recycling of expensive chiral catalysts, as well as con- loped and applied in asymmetric transformations,5 which
tamination of the products by the toxic transition metals, which paved a new avenue for a sustainable chemical process.
greatly hamper their industrial application. One of the practical
The catalytic asymmetric addition of organozinc to alde-
strategies to overcome these problems is the immobilization of hydes is one of the most reliable methods to obtain syntheti-
the parent homogeneous chiral catalysts to insoluble supports. cally useful chiral secondary alcohols.6 Chiral catalysts
Most of the conventional heterogeneous catalysts usually exhibit supported on insoluble polymers, inorganic materials and
inferior performance than their homogeneous counterparts due soluble macromolecules have been developed to improve appli-
to the former being of poor accessibility, random anchoring cability of the transformation.1a–d Among these recoverable
and disturbed geometry of active sites in insoluble solids.
catalysts, dendritic TADDOLS,7 BINOLS,8,9 and those derived
Recently, soluble polymer- and dendrimer-supported cata- from Fréchet-type dendrimers in particular,10 have proved to
lysts, with unique features of one-phase catalysis and two- be versatile in the asymmetric addition of organozinc to alde-
phase catalyst separation (via precipitation) after the reaction, hydes. Chiral β-aminoalcohols are undoubtedly the most
have attracted extensive attention.2,3 While the flexible linear efficient ligands for such transformations.6 However, the den-
polymer-supported catalysts often give lower reactivity and dritic Fréchet-type aminoalcohols, which can be prepared by
enantioselectivity than their homogeneous counterparts, most attaching chiral aminoalcohols to Fréchet-type dendrimers,
of the dendritic catalysts often exhibit catalytic properties com- remain less developed.11 Therefore, syntheses of chiral Fréchet
dendrimers supported aminoalcohols and their application in
asymmetric catalysis is highly desirable.
aThe College of Chemistry and Chemical Engineering, Shangqiu Normal University,
When used in asymmetric reactions, the chiral ferrocenyl
298 Wenhua Road, Shangqiu, Henan 476000, P. R. China.
compounds are very excellent ligands and catalysts because of
their rigid structures and outstanding enantioselectivity.12
Chiral aziridino alcohols, a kind of special β-aminoalcohol
possessing a rigid three-member ring moiety, have been
proved to be highly effective catalysts for asymmetric additions
of organozinc species to aldehydes.13 In recent years, a series
E-mail: zhwx2595126@163.com, liult05@iccas.ac.cn; Tel: +86 0370-2595126
bThe College of Chemistry and Molecular Engineering, Zhengzhou University,
Zhengzhou, Henan 450052, P. R. China
cShanghai Modern Hasen (shangqiu) Pharmaceutical Co., Ltd, 12 Yongan Road,
Shangqiu, Henan 476000, P. R. China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4gc02447h
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of chiral ferrocenylaziridino alcohols have been synthesized and followed by the desilylation with TBAF (Scheme 1). With
and successfully applied to highly enantioselective addition of compound 6 in hand, we further synthesized the dendritic
organozinc reagents to aldehydes by us.14 Herein, we would wedges 7 according to the procedure in the literature10 and
like to report the syntheses of novel recyclable chiral dendritic successfully introduced them into compound 6 (Scheme 2).
ligands by coupling the ferrocenylaziridino alcohols with
The syntheses of N-ferrocenyl methyl aziridino alcohol
Fréchet-type dendrimers and their preliminary application in ligands with different dendrimers (8a–c) are summarized in
asymmetric diethylzinc addition to aldehydes with excellent Scheme 2. A mixture of compounds 6 and 7(a–c) was heated at
enantioselectivities (ee).
reflux under vigorous stirring for 2 h with 18-crown-6 as the
phase-transfer catalyst and K2CO3 as the base. The effect of
temperature and solvent on the yield of 8b was studied first. As
shown in Table 1, several solvents were chosen and used to
optimize the reaction conditions. Almost the same yields were
obtained when commercially available THF or anhydrous THF
was used (entries 1 and 2). The reactions could finish within
two hours in most solvents, except in acetone (entry 4) and
2. Results and discussion
2.1 Synthesis of chiral dendritic ligands
Starting from compound 4 as reported by Wang and cowor-
kers,14a compound 6 was synthesized via Grignard reaction
Scheme 1 Synthesis of ferrocenyl β-amino alcohol ligand 6.
Scheme 2 Synthesis of 8a–c.
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Table 1 Yield of 8b in different solventsa,b,c
Table 3 Optimization of reaction conditions for asymmetric addition of
Et2Zn to benzaldehydea
Mol
Yieldb eec
(%)
(%) Confign.d
Entry
Solvent
Reaction time (h)
Yieldd (%)
Entry Ligand (%) Temperature (°C)
1
2
3
4
5
6
7
8
THF
Dry THF
MeCN
Acetone
Dioxane
Dioxane
Toluene
DMF
2
2
2
24
2
24
2
76
73
78
54
42
34
53
53
1
2
3
4
5
6
7
8
8b
8b
8b
8b
8b
8b
8b
8b
8b
8b
6
1
2
3
5
7
10
5
5
5
5
0, 10 h then 20, 38 h 95
41
80
81
89
82
89
88
81
92
81
21
92
63
S
S
S
S
S
S
S
S
S
S
S
S
S
0, 10 h then 20, 38 h 97
0, 10 h then 20, 38 h 96
0, 10 h then 20, 38 h 97
0, 10 h then 20, 38 h 94
0, 10 h then 20, 38 h 96
−20, 48 h
79
56
93
90
49
95
56
2
0, 48 h
a All solvents were used as received without further purification except
in entry 2. b All reactions were carried out at reflux except in entry 6
(75 °C). c The volume of all the solvents was 15 mL. d Isolated yield.
9
20, 48 h
40, 48 h
20, 48 h
20, 48 h
20, 48 h
10
11
12
13
5
5
5
8a
8c
a Reaction was carried out using 0.5 mmol of benzaldehyde in 2 mL of
toluene, PhCHO–Et2Zn
= 1 : 4, Et2Zn (1 M solution in hexane).
b Isolated yield. c Determined by HPLC analysis using DAICEL
CHIRALCEL OD-H. d Absolute configuration was assigned by
comparing the retention time on HPLC with the literature value.15
Table 2 Yields of different chiral ligands in THF and MeCN
Entry
Solventa
Product
Yieldb (%)
1
2
3
4
5
6
THF
MeCN
THF
MeCN
THF
MeCN
8a
8a
8b
8b
8c
8c
64
60
76
78
67
59
ligand concentration was increased from 1 mol% to 2 mol%
(entries 1 and 2, Table 3). It is obvious that the product
yield does not depend on the absolute amount of the ligand as
long as there is some. Furthermore, we examined the tempera-
ture effect on the asymmetric induction in the presence of
5 mol% 8b (Table 3, entries 7–10). As compared with 20 °C,
too low or too high reaction temperature was not conducive to
this reaction.
In order to study the effect of dendritic wedges on the cata-
lytic activity and enantioselectivity, compound 6 was used as
ligand in the reaction of diethylzinc with benzaldehyde. Under
the optimized reaction conditions, it was exciting to find out
that both the yield and ee value were much better by using 8a
and 8b other than ligand 6 when it was linked with dendri-
mers (Table 3, entries 11–13) with 92% ee from the zero-gene-
ration (8a) and the first-generation ligand (8b) (Table 3, entries
12 and 9). However, further increasing the size of dendritic
wedges (8c) dramatically decreases the yield and enantio-
selectivity (Table 3, entry 13). The remarkable dendritic effect
was thought to be due to the interaction between the two
a All solvents were used as received without further purification.
b Isolated yield.
dioxane (entry 6 at 75 °C). Compared to the good yields from
using THF and MeCN (entries 1–3), those solvents with a lower
or higher boiling point could not achieve a satisfactory result
(entries 4–8), indicating that temperature plays an important
role in the reaction.
The yield of 8b was slightly higher (78% vs. 76%, Table 1)
but the yields of 8a and 8c were much lower (60% vs. 64% and
59% vs. 67% respectively, Table 2) when MeCN instead of THF
was used as the solvent. As such, THF was chosen as the most
suitable solvent for the reaction.
2.2 Asymmetric addition of Et2Zn to aldehydes
In order to examine the catalytic behaviour of the chiral den- bulky dendritic wedges. Upon binding of 8 to zinc, chiral cata-
dritic ligands, the reaction of diethylzinc with benzaldehyde lyst 9 with a rigid framework is formed (Scheme 3). According
was investigated next. The optimal ligand for this reaction was to the mathematical expression for the enantioselectivity and
also chosen after optimizing the loading of the ligand and the thermodynamic factors in the conformational equilibrium of
reaction temperature (Table 3).
catalysts by the addition of diethylzinc to benzaldehyde that
As listed in Table 3, although the yield of the product did we have reported previously,14f the bigger steric differentiation
not change much (Table 3, entries 1–6) when the loading of 8b of the diastereoface of the five-membered zinc cycle would
as the chiral ligand was increased from 1 mol% to 10 mol%, bring better enantioselectivity. In the case of the zero-gene-
better enantioselectivity could be obtained with increasing ration ligand (8a) and the first-generation ligand (8b) the steric
amount of ligand, which was most remarkable when the differentiation caused by equatorial and axial R groups is rela-
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Table 5 Reusability of supported ligands for the asymmetric addition
of diethylzinc to benzaldehydea
Run
Ligand
Yieldb
eec
Confign.
Scheme 3 The structure of chiral catalyst 9.
1
2
3
4
5
6
7
8
9
8b
8b
8b
8b
8b
8b
8b
8b
8b
94
87
89
90
89
88
91
93
91
92
93
92
91
91
90
90
87
88
S
S
S
S
S
S
S
S
S
tively larger, so excellent enantioselectivities are obtained. In
the case of 8c, the repulsion effect of the bulky equatorial and
axial R groups makes the flexible equatorial R group point
toward the left side and increases the bulkiness of the left
side. Thus, the enantioselectivity decreases with the decreased
steric differentiation of the diastereoface.
Ligands 8a and 8b were selected for further evaluation on
other substrates. As summarized in Table 4, the dendritic
ligands were effective to all the aromatic aldehydes tested. In
these reactions, all of the aldehyde substrates gave products in
a Reaction was carried out at 20 °C using 0.5 mmol of aldehyde in
2 mL of toluene; PhCHO–Et2Zn = 1 : 4; Et2Zn (1 M solution in hexane);
reaction time: 48 h. b Isolated yield. c Determined by HPLC analysis
using DAICEL CHIRALCEL OD-H.
excellent yields with good to excellent ee values (88–98% ee).
However, o-substituted benzaldehydes underwent addition reac-
tion with slightly lower enantioselectivities when compared to
their m- and p-analogues (entries 7, 8 vs. 9, 10 or 11, 12).
Table 4 Enantioselective diethylzinc addition to aldehydes in the pres-
ence of different chiral ligands 8a and 8ba
2.3 Recycling of a dendritic catalyst
Entry RCHO
Ligand Yieldb (%) eec (%) Confign.d
One major advantage of dendritic ligands is that they may be
easily separated from reaction mixtures through precipitation
due to the solubility change in different solvents. Having
established the efficacy of the dendritic ligands, we then inves-
tigated their recyclability (Table 5). After the completion of the
reaction, ligand 8b could be easily recovered by precipitation
with n-hexane (see the Experimental section). Furthermore, it
was found that the recovered catalyst could be reused up to
nine runs, without any significant loss of reactivity and
enantioselectivity (Table 5, entries 1–9) (Fig. 1).
1
2
3
4
5
6
PhCHO
FcCHO
8a
8b
8a
8b
8a
8b
95
93
98
>99
>99
>99
92
92
93
94
90
91
S
S
S
S
S
S
7
2-CH3OPhCHO 8a
>99
>99
>99
>99
>99
>99
98
>99
>99
>99
86
88
93
92
92
93
94e
98e
91
90
S
S
S
S
S
S
S
S
S
S
8
9
8b
3-CH3OPhCHO 8a
10
11
12
13
14
15
16
8b
4-CH3OPhCHO 8a
8b
4-CH3PhCHO
8a
8b
8a
8b
3. Conclusion
17
18
8a
8b
>99
>99
95
90
S
S
In conclusion, we report here the preparation of three novel
N-ferrocenylmethyl aziridino alcohol ligands bearing dendri-
mers. Good yields (more than 99%) and excellent enantio-
selectivities (up to 98% ee) were achieved by the asymmetric
addition of diethylzinc to aldehydes. For all aromatic alde-
hydes tested, it was found that almost the same level of
enantioselectivity could be obtained for ligands 8a and 8b.
Furthermore, ligand 8b could be quantitatively recovered by
simply adding n-hexane to the reaction mixture after being
reused 8 times, without significant loss of reactivity and
enantioselectivity.
19
20
21
22
2-ClPhCHO
4-ClPhCHO
8a
8b
8a
8b
97
97
>99
>99
92e
93e
98e
92e
S
S
S
S
a Unless otherwise stated, reaction was carried out at 20 °C using
0.5 mmol of aldehyde in 2 mL of toluene; RCHO–Et2Zn = 1 : 4; Et2Zn
(1
M
solution in hexane); reaction time: 48 h. b Isolated yield.
c Determined by HPLC analysis using DAICEL CHIRALCEL OD-H.
d Absolute configuration was assigned by comparing the retention
time on HPLC with the literature value.16 e Determined by HPLC
analysis using DAICEL CHIRALCEL OB-H.
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Fig. 1 The recycling of ligand 8b.
dried over Na2SO4 and after filtration, the solvent was removed
under reduced pressure. The resulting residue was purified by
preparative TLC with petroleum (60–90 °C)–EtOAc (v/v, 6 : 1) as
4. Experimental
4.1. General
Oxygen- and moisture-sensitive reactions were carried out an eluant to give a yellow solid: mp 85–87 °C, yield 70%. [α]D20
=
1
under a nitrogen atmosphere. Solvents were purified and dried −28 (c 0.5, in CHCl3). H NMR (400 MHz, CDCl3) δ 7.24–7.13
by standard methods prior to use unless otherwise stated. All (m, 4H, Ar–H), 6.78–6.70 (m, 4H, Ar–H), 4.12–4.03 (m, 9H,
commercially available reagents were used without further FcH), 3.71 (s, 1H, –OH), 3.51 (d, J = 13.0 Hz, 1H, FcCH′HN),
purification unless otherwise noted. Column chromatography 3.22 (d, J = 13.0 Hz, 1H, FcCH′HN), 2.31 (dd, J = 6.3, 3.5 Hz,
was performed on silica gel (100–200 mesh). Melting points 1H, –N–CH), 1.90 (d, J = 3.5 Hz, 1H, –N–CH′H), 1.48 (d, J = 6.3
were measured on a BEIJING TECH X-5 melting point appar- Hz, 1H, –N–CH′H), 0.99 (s, 9H, –C(CH3)3), 0.96 (s, 9H,
atus and were uncorrected. Infrared spectra were recorded on a –C(CH3)3), 0.20 (d, J = 0.7 Hz, 6H, –CH3), 0.18 (d, J = 3.3 Hz,
Nicolet-NEXUS 670 FT-IR spectrometer. 1H NMR and 13C NMR 6H, –CH3).13C NMR (100 MHz, CDCl3) δ 154.39, 140.73, 137.89,
spectra were recorded on a Bruker DPX-400 (400 MHz) spectro- 127.55, 119.33, 83.88, 73.56, 68.91, 68.47, 68.08, 58.14, 45.77,
meter in CDCl3 with TMS as an internal standard; J values 30.15, 25.66. IR (KBr) 3429, 3084, 2939, 2858, 1607, 1507, 1465,
were given in hertz. Mass spectra were recorded using a Bruker 1404, 1357, 1258, 1171, 1091, 1006, 916, 833, 558, 479. HRMS
esquire-3000 instrument with an electrospray ionization (ESI): calcd for C38H53FeNO3Si2 [M]+ 683.2913, found 683.2944
source (ESI-MS). All of the ESI-MS spectra were recorded using [M + H]+ 684.2947, found 684.2990.
MeOH as the solvent. Optical rotations were measured on a
Perkin-Elmer model 341 Polarimeter at 20 °C in CHCl3. The ee
value was determined by HPLC using a chiral column with
hexane-propan-2-ol (ratio as indicated) as the eluent. The chro-
matographic system was VARIAN PROSTAR, consisting of a
(5 mL) at room temperature in half an hour. The resulting
UV-VIS detector (model 320) and two pumps (model 320). The
column used was a Chiralcel OD-H (250 × 4.6 mm) or Chiralcel
the solution was quenched with pure water. The phases were
OB-H (250 × 4.6 mm) from Daicel Chemical Ind., Ltd (Japan)
4.4. General procedure for the synthesis of compound 6
0.31 g (0.45 mmol) of compound 5 (in 10 mL dry THF) was
dropped into a solution of 1 mL TBAF (1 M in THF) in dry THF
solution was stirred at room temperature for half an hour and
separated and the aqueous phase was extracted with EtOAc
(3 × 10 mL). The combined organic phases were washed with
and operated at ambient temperature.
brine (20 mL), dried over Na2SO4 and after filtration, the
solvent was removed under reduced pressure. The resulting
residue was purified by preparative TLC with CH2Cl2–CH3OH
4.2. General procedure for the synthesis of compound 4
The compound 4 was prepared according to the literature
procedures.14a
(v/v, 20 : 1) as the eluant to give
a yellow solid: mp
1
117–118.3 °C, yield 93%. [α]2D0 = −54 (c 0.724, in CH3OH). H
4.3. General procedure for the synthesis of compound 5
NMR (400 MHz, DMSO) δ 7.12 (dd, J = 25.7, 8.6 Hz, 4H, Ar–H),
A Grignard reagent was prepared from 133 mg (5.5 mmol) 6.62 (dd, J = 8.6, 1.9 Hz, 4H, Ar–H), 5.76 (s, 2H, Ar–OH), 4.38 (s,
magnesium and 1.55 g (4-bromophenoxy)(tert-butyl)dimethyl- 1H, –OH), 4.20–4.00 (m, 9H, FcH), 3.56 (d, J = 13.0 Hz, 1H,
silane (5.4 mmol) in dry THF (15 mL). After adding a small FcCH′HN), 3.00 (d, J = 13.0 Hz, 1H, FcCH′HN), 2.36 (dd, J = 6.1,
crystal of iodine to initiate the reaction, the reaction mixture 3.3 Hz, 1H, –N–CH), 1.52 (d, J = 3.0 Hz, 1H, –N–CH′H), 1.33 (d,
was heated to reflux for 2 h. The solution was cooled to 0 °C J = 6.2 Hz, 1H, –N–CH′H). 13C NMR (100 MHz, DMSO) δ
before adding 0.25 g (0.84 mmol) of compound 4. The reaction 155.88, 138.26, 137.56, 127.93, 127.48, 114.36, 84.92, 74.17,
was quenched with saturated aqueous NH4Cl at 0 °C after com- 69.05, 68.51, 67.69, 58.51, 55.13, 46.38, 29.45. IR (KBr) 3460,
pletion at room temperature. The phases were separated and 2927, 1601, 1509, 1446, 1369, 1236, 1169, 1031, 829, 587, 488.
the aqueous phase was extracted with Et2O (3 × 10 mL). The HRMS (ESI): calcd for C26H25FeNO3 [M + H]+ 456.1217, found
combined organic phases were washed with brine (15 mL), 456.1258 [M + Na]+ 478.1082, found 478.1126.
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4.5. General procedure for the synthesis of chiral ligands
bearing dendrimers
THF was heated at reflux and stirred vigorously for four hours.
The following procedure is the same as that of compound 8a.
The resulting residue was purified by preparative TLC with pet-
4.5.1. Compound 8a. A mixture 0.1 g (0.22 mmol) of com- roleum (60–90 °C)–CH2Cl2–EtOAc (v/v/v, 6 : 4 : 1) as the eluant
pound 6, the corresponding benzyl bromide (53 μL), 0.12 g to give a yellow foam: mp 49–51 °C; yield 67%. [α]2D0 = −5.9
(0.87 mmol) K2CO3 and 0.001 g (0.004 mmol) 18-C-6 in THF (c 0.994, in CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.48–7.27 (m,
was heated at reflux and stirred vigorously for one hour. After 40H, Ar–H), 7.22 (t, J = 4.4 Hz, 4H, Ar–H), 6.86 (t, J = 9.2 Hz,
most of the organic solvent was removed under reduced 4H, Ar–H), 6.72–6.58 (m, 12H, Ar–H), 6.58–6.46 (m, 6H, Ar–H),
pressure, CH2Cl2 (20 mL) and water (20 mL) were added to the 5.05–4.85 (m, 28H, Ar–O–CH2), 4.17–3.94 (m, 9H, FcH), 3.68 (s,
mixture. The phases were separated and the aqueous phase 1H, –OH), 3.46 (d, J = 13.0 Hz, 1H, FcCHH′N), 3.23 (d, J = 12.9
was extracted with CH2Cl2 (3 × 10 mL). The combined organic Hz, 1H, FcCHH′N), 2.30 (dd, J = 6.0, 3.4 Hz, 1H, –N–CH), 1.88
phases were washed with brine (20 mL), dried over Na2SO4 and (d, J = 3.1 Hz, 1H, –N–CH′H), 1.45 (d, J = 6.3 Hz, 1H, –N–CH′H).
after filtration, the solvent was removed under reduced 13C NMR (100 MHz, CDCl3) δ 160.17, 160.08, 160.05, 157.68,
pressure. The resulting residue was purified by preparative 157.53, 140.54, 139.61, 139.56, 139.23, 137.83, 136.78, 128.57,
TLC with petroleum (60–90 °C)–EtOAc (v/v, 4 : 1) as the eluant 127.99, 127.63, 127.54, 114.28, 106.43, 106.41, 101.62, 101.54,
to give a yellow foam: mp 39–41 °C, yield 64%. [α]2D0 = −14 101.48, 83.89, 73.49, 70.11, 70.00, 69.92, 69.01, 68.83, 68.48,
1
(c 1.05, in CHCl3). H NMR (400 MHz, CDCl3) δ 7.46–7.30 (m, 68.16, 68.07, 58.22, 45.65, 30.17. IR (KBr) 3433, 3021, 2869,
10H, Ar–H), 7.30–7.22 (m, 4H, Ar–H), 6.89 (td, J = 9.4, 2.5 Hz, 1598, 1504, 1452, 1375, 1301, 1235, 1154, 1047, 830, 740, 693,
4H, Ar–H), 5.04 (d, J = 8.2 Hz, 4H, Ar–O–CH2), 4.17–3.96 (m, 489. HRMS (ESI): calcd for C124H109FeNO15; [M]+ 1907.7147,
9H, FcH), 3.71 (d, J = 3.6 Hz, 1H, –OH), 3.49 (d, J = 12.9 Hz, 1H, found 1907.6949; [M + H]+ 1908.7180, found 1908.7228.
FcCH′HN), 3.25 (dd, J = 12.9, 1.9 Hz, 1H, FcCH′HN), 2.34 (dd,
4.6 General procedure for the asymmetric diethylzinc
addition to aldehydes
J = 5.9, 3.1 Hz, 1H, –N–CH), 1.90 (d, J = 2.8 Hz, 1H, –N–CH′H),
1.48 (d, J = 6.3 Hz, 1H, –N–CH′H). 13C NMR (100 MHz, CDCl3)
δ 157.71, 157.56, 140.43, 137.69, 137.08, 137.03, 128.56,
128.54, 127.93, 127.59, 127.47, 114.21, 114.17, 83.82, 73.48,
69.93, 69.00, 68.83, 68.46, 68.15, 68.08, 58.20, 45.63, 30.10. IR
(KBr) 3429, 3035, 2921, 1607, 1505, 1456, 1381, 1317, 1236,
1170, 1105, 1024, 820, 737, 694, 635, 486. HRMS (ESI): calcd
for C40H37FeNO3 [M]+ 635.2123, found 635.2088 [M + H]+
636.2156, found 636.2204.
A mixture of 0.025 mmol chiral ligand and 2.0 mmol Et2Zn
(1 M, in hexane) was stirred in 2.0 mL toluene at 0 °C for half
an hour. Then 0.5 mmol freshly distilled aldehyde was added
dropwise via a syringe. After that, the vessel was taken out of
the cooling bath. After stirring for 2 days, the reaction was
quenched with 4 mL of saturated NH4Cl aqueous solution and
was extracted with 10 mL of diethyl ether three times. The
combined organic phase was washed with brine, and was dried
with anhydrous Na2SO4. The solvent was evaporated and the
crude residue was transferred into a centrifugal tube containing
0.5 mL toluene. To the centrifugal tube 10 mL n-hexane was
added. The precipitation (ligand) was separated, collected by
centrifugation and dried for the next run. The mother liquid
was concentrated and purified by thin layer chromatography to
afford the final products (petroleum ether–EtOAc).
4.5.2. Compound 8b. A mixture 0.1 g (0.22 mmol) com-
pound 4, the corresponding 0.17 g (0.44 mmol) of compound
7b, 0.3 g (2.17 mmol) K2CO3 and 0.003 g (0.011 mmol) 18-C-6
in THF was heated at reflux and stirred vigorously for two
hours. The following procedure is the same as that of com-
pound 8a. The resulting residue was purified by preparative
TLC with petroleum (60–90 °C)–CH2Cl2–EtOAc (v/v/v, 6 : 4 : 1)
as the eluant to give a yellow foam: mp 43–45 °C; yield 76%.
[α]2D0 = −15 (c 0.412, in CHCl3). 1H NMR (400 MHz, CDCl3)
δ 7.49–7.20 (m, 24H, Ar–H), 6.87 (dd, J = 10.6, 8.9 Hz, 4H,
Ar–H), 6.69 (dd, J = 10.4, 2.2 Hz, 4H, Ar–H), 6.58 (dt, J = 7.7, 2.2
Hz, 2H, Ar–H), 5.01 (dd, J = 24.6, 7.3 Hz, 12H, Ar–O–CH2),
4.16–3.97 (m, 9H, FcH), 3.71 (s, 1H, –OH), 3.49, 3.27 (d, J =
12.9 Hz, 2H, FcCHH′N), 2.34 (dd, J = 6.2, 3.4 Hz, 1H, –N–CH),
1.91 (d, J = 3.3 Hz, 1H, –N–CH′H), 1.49 (d, J = 6.3 Hz, 1H, –N–
CH′H). 13C NMR (100 MHz, CDCl3) δ 160.14, 157.56, 139.57,
137.77, 136.75, 128.60, 128.03, 127.58, 114.26, 106.34, 101.45,
83.86, 73.47, 70.12, 69.89, 68.93, 68.48, 68.13, 58.24, 45.62,
30.15, 29.70. IR (KBr) 3420, 3033, 2921, 2860, 1598, 1504, 1452,
1376, 1299, 1234, 1154, 1019, 824, 738, 691, 581, 485. HRMS
(ESI): calcd for C68H61FeNO7 [M]+ 1059.3797, found 1059.3811;
[M + H]+ 1060.3831, found 1060.3877; [M + K]+ 1098.3434,
found 1098.3487.
Acknowledgements
We are grateful to the National Natural Sciences Foundation of
China (no. 20972091, 21172139 and 21202095) and the
Program for Science & Technology Innovation Talents in
Universities of Henan Province (14HASTIT016) for financial
support and Dr Xin-He Lai for proofreading of the manuscript.
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