Synthesis and properties of novel helical 3-vinylpyridine polymers containing proline moieties for asymmetric aldol reaction

Article abstract of DOI:10.1039/c5ra07207g

Novel optically active polymers containing pendant proline moieties, poly{(-)-l- and (+)-d-proline-[5-(4'-tert-butylphenyl)-3-vinylpyridin-2-yl]amide}, were prepared through radical polymerization of (-)-l- and (+)-d-N-Boc-proline-[5-(4'-tert-butylphenyl)-3-vinylpyridin-2-yl]amide, followed by de-protection of the Boc group. Polarimetry and circular dichroism spectroscopy studies indicated that these polymers took chiral secondary structures. They were employed to catalyze the homogeneous asymmetric aldol reaction of 4-nitrobenzaldehyde with cyclohexanone. The polymeric catalysts showed obviously enhanced reaction rate but slightly reduced enantio-selectivity compared with (-)-l- and (+)-d-proline-[5-(4'-tert-butylphenyl)-3-vinylpyridin-2-yl]amide, the low molar mass counterparts. The lowered enantio-selectivity of the polymeric catalyst might be attributed to the antagonistic action of the configurational chirality of the side-group and the conformational chirality of the polymer backbone on the stereochemistry of aldol reaction.

Full text of DOI:10.1039/c5ra07207g

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DOI: 10.1039/C5RA07207G
Synthesis and Property of Novel Helical 3-Vinylpyridine
Polymers Containing Proline Moieties for Asymmetric Aldol
Reaction
Novel helical vinyl polymers bearing L/D-proline amide moieties were prepared to catalyze
asymmetric aldol reactions, which afforded faster reaction rate but slightly poorer
enantio-selectivity than the low molar mass counterparts.

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DOI: 10.1039/C5RA07207G
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ARTICLE TYPE
Synthesis and Property of Novel Helical 3-Vinylpyridine Polymers
Containing Proline Moieties for Asymmetric Aldol Reaction
Heng Wang, Na Li, Zijia Yan, Jie Zhang, and Xinhua Wan*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Novel optically active polymers containing pendant proline moieties, poly{(−)-L- and (+)-D-proline-[5-
(4’-tert-phenyl)-3-vinyl-pyridin-2-yl]amide}, were prepared through radical polymerization of (−)-L- and
(+)-D-N-Boc-proline-[5-(4’-tert-phenyl)-3-vinyl- pyridin-2-yl]amide, followed by de-protection of Boc
group. Polarimetry and circular dichroism spectroscopy studies indicated that these polymers took chiral
10 secondary structures. They were employed to catalyze the homogeneous asymmetric aldol reaction of 4-
nitrobenzaldehyde with cyclohexanone in bulk. The polymeric catalysts showed obviously enhanced
reaction rate but slightly shrunken enantio-selectivity compared with (−)-L- and (+)-D-proline-[5-(4’-tert-
phenyl)-3-vinyl-pyridin-2-yl]amide, the low molar mass counterparts. The lowered enantio-selectivity of
polymeric catalyst might be attributed to the antagonistic action of configurational chirality of side-group
15 and conformational chirality of polymer backbone on the stereochemistry of aldol reaction.
Recently, the effect of the micro-environment given by polymer
Introduction
matrix on the reactivity and stereo-selectivity of the catalyst
Asymmetric catalysis has drawn increasing attentions for its
outstanding ability to produce enantiomerically rich or even pure
compounds.1, 2 As a result, it is considered as the heart part of
20 contemporary organic chemistry and has found remarkable
practical and potential applications in medicine, pesticide and
perfume industry.3 Asymmetric aldol catalysis is one of the most
powerful and widely applied C−C bond forming transformation
to afford β-hydroxyketones with one or two new stereocenters by
25 combining two molecules of carbonyl compounds.4 Among many
aldolases, proline and its derivatives are the simplest but most
effective, successful and commonly employed class of catalysts,
that catalyze a great number of aldol reactions with excellent
yield and high enantio-selectivity.5-8 Apart from aldolization,
30 proline and its derivatives via enamine catalysis are widely
utilized in asymmetric Mannich reactions,9-11 Michael
50 attracts more and more attention. Some well-defined polymer
aggregates, which could be switched by solvent,31 pH,34 and
36
temperature,35,
were prepared to promote aldol reaction
performance. Dendrimers instead of linear or cross-linked
polymers were also used as the matrix to immobilize aldolases.38,
39
55
Especially, some helical polymers with one-prevailing
handedness are found to significantly enhance the enantio-
selectivity by the resemblance to enzymes.40-43 Sanda and co-
workers
bonded
trans-4-hydroxy-L-proline
to
poly(phenylacetylene)s via ester bonds and found the resultant
60 polymers yielded the aldol reaction adducts with opposite
configurations to their lower molar mass counterparts.44 Deng et
al introduced L-proline to polyacetylenes through amide groups
and achieved good enantio-selectivity.45
Our group developed a novel type helical vinyl polymers
65 containing laterally attached biphenyl or p-terphenyl groups
terminated by chiral alkyloxy or alkyloxycarbonyl groups, whose
helical conformations are driven and stabilized by the steric
repulsive interaction of bulky side chains.46-53 These polymers
display interesting “chiral memory effect”,46 “odd-even effect”,48-
70 50 and remarkable chemical and physical stability. They can even
be conveniently prepared via free radical polymerization. These
characteristics enable them to act as chiral scaffolds to
asymmetrically position function groups in space around polymer
backbone and find wide potential applications such as
75 asymmetric catalysis and chiral recognition.
reactions,12-14 D–A reactions,15-17 and α-aminations.18,
19
Moreover, their nitrogen dioxides are used as organocatalysts or
the chiral ligands of organometallic catalyst in various
35 asymmetric transformations,20 including α-chlorinations,21
cycloadditions,22 Roskamp-Feng reactions,23 Friedel-Crafts
reactions,24 homologations of carbonyl compounds,25 Ene26 and
Aza-Ene reactions.27
In order to facilitate the recyclability and reduce the cost, great
40 efforts have been made to tether proline-based small molecule
catalysts onto polymer matrix.28 The most commonly used
polymeric matrix includes commercially available polymers, such
as polystyrene,29-31 polyethylene glycol,32 and polymethyl
methacrylate.33-37 In most cases, proline moieties are introduced
45 to the polymer backbone through long and flexible spacers. Such
a macromolecular design has the advantage to avoid or reduce the
adverse influence of polymer backbone on catalytic property.
The present work aimed to devise a novel kind of polymer
catalyst consisting of proline as a “privileged framework” and
conformational specific helical polymer as a linker to build a
macro “chiral environment”. To this end, a pair of optically active
This journal is © The Royal Society of Chemistry [year]
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helical polymers, poly{(−)-L- and (+)-D-proline-[5-(4’-tert-
phenyl)-3-vinyl-pyridin-2-yl]amide} were synthesized and
a JASCO Model P-1030 digital polarimeter using a water-
jacketed 50 mm cell at 25 ºC. For Boc-protected monomers and
characterized by polarimetry and circular dichroism (CD) 60 polymers, measurements were run in THF whereas those de-
spectroscopy. They were applied as catalysts of asymmetric
aldolization of cyclohexanone with 4-nitrobenzaldehyde. Various
amount of water and organic acids were added to optimize
reaction condition. Compared with their low molar mass
counterparts, polymeric catalysts showed obviously faster
reaction rate but slightly lower enantio-selectivity, implying an
protected in methanol due to the distinct solubility. UV-Vis
absorption spectra were determined on a Varian Cary 1E UV-Vis
spectrometer. CD spectra were recorded on a JASCO J-810 with
a 10 mm quartz cell at 25 ºC. The temperature was mediated with
5
65
a Julabo F25-Me controller. The enantiomer excess was
estimated on a high performance liquid chromatography (HPLC)
equipped with a JASCO PU-2089 pump, a AS-2055 automatic
sampler, a UV-2070 UV-Vis spectrometer, a CD-2095 circular
dichroism spectrometer, and a Daicel CHIRALPAK AD-H
10 antagonistic effect on aldol reaction stereochemistry of
configurational and conformational chirality originated from side-
groups and polymer backbone, respectively.
70 column. The eluents used were the mixtures of isopropanol and
hexane with the compositions of 10/90 (v/v) at a rate of 1.0
mL/min.
Experimental Section
Materials.
Monomer Synthesis.
15 2-Amino-3-methyl-5-bromopyridine (97%, Alfa Aesar), phthalic
anhydride (AR, Beijing Chemical Co.), tetrachloromethane (CCl4,
AR, Beijing Chemical Co.), N-bromosuccinimide (NBS, 99%,
Aldrich), triphenylphosphine (PPh3, 99%, Acros), hydrazine
hydrate (85%, Sinopharm Chemical reagent Co.), aqueous
20 formaldehyde solution (40%, AR, Beijing Chemical Co.), 4-tert-
butylphenylboronic acid (98%, J&K Scientific Ltd.),
2-(3-Methyl-5-bromopyridin-2-yl)-isoindole-1,3-dione (I).
75
2-Amino-3-methyl-5-bromopyridine (93.5 g. 0.50 mol) and
phthalic anhydride (74.0 g, 0.50 mol) were mixed and then heated
at 190 °C for 5 h. After cooled to room temperature, the mixture
was dissolved in CH2Cl2 (600 mL). The solution was washed
with water (2 × 200 mL) and saturated brine (200 mL), dried over
80 MgSO4, filtrated, treated with activated carbon, and then
concentrated under vacuum. The solid residue was triturated with
ether. Solid products were collected by filtration and dried under
vacuum to give 139.5 g of product as white powders. Yield: 88%.
1H-NMR (300 MHz, CDCl3, δ ppm): 8.56 (d, 1H, 6-H pyridinyl
85 group), 7.93-7.99 (m, 2H, 3, 4-H phenyl group), 7.87 (d, 1H, 4-H
pyridinyl group), 7.77-7.82 (m, 2H, 2, 5-H phenyl group), 2.28 (s,
3H, -CH3).
tetrakis(triphenylphosphine)palladium(0)
(Pd(PPh3)3,
99%,
Acros), dicyclohexylcarbodiimide (DCC, Beijing Ouhe
Technology Co.), N-Boc-L-proline (99%, J&K Scientific Ltd.),
25 and N-Boc-D-proline (99%, J&K Scientific Ltd.) were used as
purchased. Azobisisobutyronitrile (AIBN, AR, Wuhan Chemical
Co.) was recrystallized from ethanol and dried under vacuum at
room temperature. Tetrahydrofuran (THF, AR, Beijing Chemical
Co.), anisole (AR, Beijing Chemical Co.), and hexane (AR,
30 Beijing Chemical Co.) were refluxed with sodium and distilled
out just before use. Benzene (AR, Beijing Chemical Co.) and
toluene (AR, Beijing Chemical Co.) were washed with oil of
vitriol three times, water three times, saturated brine once, dried
with magnesium sulfate, and then refluxed over sodium and
35 distilled out before use.
2-(3-Vinyl-5-bromopyridin-2-yl)-isoindole-1,3-dione (II).
A mixture of 2-(3-methyl-5-bromopyridin-2-yl)-isoindole-1,3-
90 dione (23.8 g, 0.10 mol), NBS (19.6 g, 0.11 mol) in CCl4 (270
mL) was refluxed upon sun lamp (250 W each) exposure. The
bromination reaction was initiated by AIBN in 50 mg portions,
and 200 mg of AIBN was added in total over 3 hours. Opon
cooled to room temperature, the solids suspended on the surface
95 of the reaction mixture were filtered off. The solvent was
removed under vacuum. The residue was dissolved in CH2Cl2
(300 mL) and washed with warm water (3 × 200 mL), saturated
brine (200 mL), dried with anhydrous Na2SO4, filtrate and then
concentrated in vacuum. The residue was mixed with PPh3 (26.2
100 g, 0.10 mol) and acetone (250 mL). The mixture was refluxed for
4 hours, and a great amount of precipitates were formed. The
solids were collected by filtration and washed with chilly acetone
to afford {[5-bromo-2-(1,3-dioxoisoindolin-2-yl)-pyridin-3-yl]-
methyl}-triphenylphosphonium bromide as white powders. The
105 phosphonium bromide was dissolved 200 mL of CH2Cl2, and 250
mL aqueous formaldehyde (40%, 250 mL) was then added. The
mixture was cool to 0 ℃. With a rapid stirring, 2 mol/L K2CO3
aqueous solution (90 mL) was dropped slowly over 1 hour. The
mixture was stirred for another 2 hours at room temperature.
110 When the reaction was completed, organic layer was separated.
The aqueous layer was extracted with 2 × 200 mL portions of
CH2Cl2. The organic layers were combined and dried over
anhydrous Na2SO4. The solvent was taken away under reduced
pressure and the residue was purified by silica gel column
115 (CH2Cl2 as eluent) to give 14.80 g of product as white powders.
Measurements.
1H-NMR (400 MHz) and 13C-NMR (100 MHz) spectra were
1
recorded on a Bruker ARX400 spectrometer, and H-NMR (300
MHz) spectra were recorded on
a Varian Mercury Plus
40 spectrometer at room temperature in CDCl3 with
tetramethylsilane (TMS) as an internal standard. High resolution
mass spectra (HRMS) were collected on a Burker Apex IV FTMS
mass spectrometer. The melting points were collected on a SGW
X-4 melting point apparatus equipped with a microscope. The
45 weight- and number-average molecular weights (Mw and Mn,
respectively) were estimated by a gel permeation chromatography
(GPC) apparatus equipped with a Waters 2410 refractive-index
detector and a Water 515 pump. Three Waters Styragel columns
with a 10 ꢀm bead size were connected in series. Their effective
50 molecular weight ranges were 100–10,000 Dalton for Styragel
HT2, 500–30,000 Dalton for Styragel HT3, and 5000–600,000
Dalton for Styragel HT4, separately. The pore sizes were 50, 100,
and 1000 nm for Styragel HT2, HT3, and HT4, respectively. THF
was employed as the eluent at a flow rate of 1.0 mL min-1. The
55 temperature of column chamber was mediated at 35 ºC. All GPC
curves were calibrated against a series of monodispersed
polystyrene standards. Specific optical rotations were obtained on
2
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The total yield of the three steps is 45%.
overnight. After the reaction was stopped, the mixture was
1H-NMR (300 MHz, CDCl3, δ ppm): 5.48 (d, 1H, =CH2), 5.85 (d, 60 filtered. The filtrate was concentrated under vacuum. The residue
1H, =CH2), 6.54 (dd, 1H, -CH=), 7.81-7.85 (m, 2H, phenyl rings),
7.96-7.99 (m, 2H, phenyl rings), 8.17 (dd, 1H, 4-H pyridinyl
group), 8.61 (dd, 1H, 6-H pyridinyl group).
was purified by silica gel column (CH2Cl2/acetone: 10/1 (v/v) as
eluent) twice to afford 2.38 g of product as foamy solids. Yield:
53%.
1H-NMR (400 MHz, CDCl3, δ ppm): 1.37 (s, 9H, -Ph-C(CH3)3),
5
3-Vinyl-2-amino-5-bromopyridine (III).
A hot solution of 2-(3-vinyl-5-bromopyridin-2-yl)-isoindole- 65 1.52 (s, 9H, -O-C(CH3)3), 1.80-2.70 (m, 4H, -CH2-CH2-CH2N-),
1,3-dione (16.45 g, 0.05 mol) in 600 mL ethanol was added into
hydrazine hydrate (80%, 1.8 mL). The mixture was stirred at
5.30-5.70 (m, br, 2H, -CH-CH2-N-), 5.35-5.65 (m, br, 1H, -CO-
CH-CH2-), 3.34-3.62 (br, 2H, -CH2N-), 4.33-4.62(br, 1H, -
COCH-), 5.39-5.50 (d, 1H, =CH2), 5.73-5.90 (d, 1H, =CH2),
6.65-6.95 (br, 1H, =CH-), 7.48-7.55 (m, 4H, H phenyl ring), 8.02
10 room temperature over night and white solids formed gradually.
The precipitates were filtered off and the filtrate was concentrated
under vacuum. The semisolid residue was extracted with CH2Cl2 70 (s, 1H, 4-H pyridinyl ring), 8.18 (s, 0.3 H, -CONH-), 8.59 (s, 1H,
(3 × 150 mL). The CH2Cl2 solution was extracted by 5% HCl
aqueous solution (3 × 75 mL). The collected water phase was
15 neutralized by 2 mol/L NaOH aqueous solution, and extracted by
CH2Cl2 (3 × 150 mL). The combined organic layers were washed
6-H pyridinyl ring), 9.36 (s, 0.7H, -CONH-). 13C-NMR (100
MHz, CDCl3, δ ppm): 170.3, 156.3, 151.2, 146.8, 146.1, 134.5,
134.2, 133.1, 131.6, 126.7, 126.4, 126.0, 117.6, 80.9, 61.7, 60.6,
47.4, 34.6, 31.3, 28.4, 24.7. HRMS (m/z): 450.2756 (MH+),
with saturated brine (3 × 200 mL), dried over anhydrous Na2SO4. 75 C27H36N3O3 required 450.2757. Optical rotation: [α]36525 = −399°
The evaporation of solvent under vacuum gave 9.15 g of light
yellow oil (92% yield), which was directly used for the next
20 reaction without further purification.
1H-NMR (400 MHz, CDCl3, δ ppm): 4.33~5.05 (br, 2H, -NH2),
(c 0.1 g/dL, THF). Melting point: 83-89 °C.
(+)-D-N-Boc-proline-[5-(4’-tert-phenyl)-3-vinyl-pyridin-2-
yl]amide (R-BPhVPyA).
1H-NMR (400 MHz, CDCl3, δ ppm): 1.37 (s, 9H, -Ph-C(CH3)3),
5.43 (d, 1H, -CH=CH2), 5.67 (d, 1H, -CH=CH2), 6.56 (dd, 1H, - 80 1.52 (s, 9H, -O-C(CH3)3), 1.80-2.70 (m, 4H, -CH2-CH2-CH2N-),
CH=CH2), 7.59 (dd, 1H, 4-H pyridinyl ring), 8.04 (dd, 1H, 6-H
pyridinyl ring). 13C-NMR (100 MHz, CDCl3, δ ppm): 108.86,
25 118.54, 120.18, 130.63, 137.00, 147.76, 154.35. HRMS (m/z):
198.9864 (MH+), 200.9843 (MH+), C7H8N2Br required 198.9865,
200.9850.
5.30-5.70 (m, br, 2H, -CH-CH2-N-), 5.35-5.65 (m, br, 1H, -CO-
CH-CH2-), 3.34-3.62 (br, 2H, -CH2N-), 4.33-4.62(br, 1H, -
COCH-), 5.40-5.50 (d, 1H, =CH2), 5.74-5.91 (d, 1H, =CH2),
6.66-6.96 (br, 1H, =CH-), 7.48-7.55 (m, 4H, H phenyl ring), 8.02
85 (s, 1H, 4-H pyridinyl ring), 8.18 (s, 0.3 H, -CONH-), 8.59 (s, 1H,
6-H pyridinyl ring), 9.36 (s, 0.7H, -CONH-). 13C-NMR (100
MHz, CDCl3, δ ppm): 170.3, 156.3, 151.2, 146.8, 146.1, 134.5,
134.2, 133.1, 131.6, 126.7, 126.4, 126.0, 117.6, 80.9, 61.7, 60.6,
3-Vinyl-5-(4’-tert-phenyl)-2-amino-pyridine (IV).
To a degassed mixture of 3-vinyl-2-amino-5-bromopyridine
30 (2.78 g, 13.9 mmol), 4-tert-butylphenylboronic acid (3.60 g, 20.2
mmol), 2,6-di-tert-butyl-4-methylphenol (25 mg, 0.1 mmol), LiCl
47.4, 34.6, 31.3, 28.4, 24.7. HRMS (m/z): 450.2752 (MH+),
25
(1.85 g, 43.6 mol), and Pd(PPh3)4 (0.73 g, 0.07 mmol), were 90 C27H36N3O3 required 450.2757. Optical rotation: [α]365 = +430°
added into benzene (60 mL), ethanol (60 mL) and aqueous
Na2CO3 solution (1 mol/L, 30 mL) under a continuous stream of
35 nitrogen. The mixture was vigorously stirred and refluxed for 4
hours. Afterwards, the organic layer was separated, and the
(c 0.1 g/dL, THF). Melting point: 78-82 °C.
(−)-L-proline-[5-(4’-tert-phenyl)-3-vinyl-pyridin-2-yl]amide (S-
PhVPyA).
To a mixture of S-BPhVPyA (0.45 g, 1.0 mmol) and CH2Cl2
aqueous layer was extracted by CH2Cl2 (3 × 30 mL). The 95 (2 mL) was added TFA (2 mL) dropwise at 0 °C. The solution
separated organic layers were combined and washed with water
(3 × 50 mL), saturated brine (50 mL), and dried over anhydrous
40 Na2SO4. After evaporation of solvent under reduced pressure, the
residue was purified by silica gel column (CH2Cl2/acetone: 3/1
was vigorously stirred for 3 hours at room temperature.
Afterwards, the solvent was taken away under reduced pressure
and the residue was dissolved in another 10 mL of CH2Cl2. The
obtained solution was washed by 1 mol/L NaOH aqueous
(v/v) as eluent) to give 2.88 g of product as yellow solids. Yield: 100 solution (3 × 5 mL), saturated brine (2 × 5 mL), and dried over
82%.
anhydrous Na2SO4. The solution was concentrated under vacuum
and the residue was purified by silica gel column
(CH2Cl2/methanol: 20/1 (v/v) as eluent) to give 0.30 g of product
as colorless oil. Yield: 86%.
1H-NMR (400 MHz, CDCl3, δ ppm): 1.36 (s, 9H, -C(CH3)3)，
45 4.36-4.98 (s, 2H, -NH2), 5.43 (d, 1H, -CH=CH2), 5.75 (d, 1H, -
CH=CH2), 6.70 (dd, 1H, -CH=CH2), 7.53 (dd, 4H, phenyl ring),
7.72 (d, 1H, 4-H pyridinyl ring), 8.25 (d, 1H, 6-H pyridinyl ring). 105 1H-NMR (400 MHz, CDCl3, δ ppm): 1.36 (s, 9H, -C(CH3)3), 1.83
13C-NMR (100 MHz, CDCl3, δ ppm): 31.32, 34.50, 117.55,
118.33, 125.84, 126.03, 128.07, 128.41, 131.72, 132.03, 133.71,
50 135.23, 145.35, 150.07, 154.66. HRMS (m/z): 258.1707 (MH+),
C17H21N2 required 258.1705. Melting point: 118-120 °C.
(−)-L-N-Boc-proline-[5-(4’-tert-phenyl)-3-vinyl-pyridin-2-
yl]amide (S-BPhVPyA).
(m, 2H, -CH2-CH2N-), 2.10-2.25 (m, 2H, -CH-CH2-), 2.30-2.90
(br, 1H, -NH), 2.95 (m, 2H, -CH2N-), 3.75 (dd, 1H, -COCH-),
5.22 (d, 1H, =CH2), 5.63(d, 1H, =CH2), 6.64(dd, 1H, =CH-),
7.38(m, 4H, H phenyl ring), 8.12(dd, 1H, 6-H pyridinyl ring),
110 8.58 (dd, 1H, 4-H pyridinyl ring), 8.5-11.0 (br, 1H, -CONH-).
13C-NMR (100 MHz, CDCl3, δ ppm): 25.84, 30.40, 31.38, 34.25,
46.91, 60.62, 116.86, 120.74, 125.33, 126.39, 127.81, 131.19,
133.35, 134.51, 147.40, 147.44, 156.35, 173.39. MS (m/z):
350.22344 (MH+), C22H28N3O required 350.2332. Optical
A mixture of 3-vinyl-5-(4’-tert-phenyl)-2-amino-pyridine (2.58
55 g, 0.010 mol), L-N-Boc-proline (2.34 g, 0.011 mol) and
anhydrous CH2Cl2 was cooled to 0 °C. DCC (4.12 g, 0.020 mol)
was added into the mixture and the obtained solution was stirred 115 rotation: [α]36525 = −122° (c 0.1 g/dL, methanol).
vigorously first at 0 °C for 2 hours and then at room temperature
(+)-D-proline-[5-(4’-tert-phenyl)-3-vinyl-pyridin-2-yl]amide (R-
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PhVPyA).
1H-NMR (400 MHz, CDCl3, δ ppm): 1.37 (s, 9H, -C(CH3)3), 1.81
(m, 2H, -CH2-CH2N-), 2.10-2.28 (m, 2H, -CH-CH2-), 1.90-2.60
1 mol/L NaOH aqueous solution. The solids were collected by
filtration and dried under vacuum at 50 °C for 48 hours, which
gave 0.11 g of poly{(−)-L-proline-[5-(4’-tert-phenyl)-3-vinyl-
(br, 1H, -NH), 2.97 (m, 2H, -CH2N-), 3.75 (m, 1H, -COCH-), 40 pyridin-2-yl]amide} (P(S)-PhVPyA) as white solids. Yield: 91%.
5
5.22 (d, 1H, =CH2), 5.63 (d, 1H, =CH2), 6.68 (dd, 1H, =CH-),
7.40 (m, 4H, H phenyl ring), 8.10 (dd, 1H, 6-H pyridinyl ring),
8.60 (dd, 1H, 4-H pyridinyl ring), 9.0-11.0 (br, 1H, -CONH-).
13C-NMR (100 MHz, CDCl3, δ ppm): 25.84, 30.42, 31.32, 34.33,
1H-NMR (400 MHz, CD3OD,
δ (ppm)): 0.0-2.5 (broad peaks, -
COCHCH2CH2CH2N-, -CH-CH2-, C(CH3)3), 2.5-4.8 (broad
peaks, -COCHCH2CH2CH2N-), 6.0-8.8 (broad peaks, H pyridine
ring, H phenyl ring). Optical rotation: [α]36525 = +136° (c 0.1 g/dL,
47.03, 60.65, 116.88, 120.74, 125.33, 126.39, 127.81, 131.22, 45 methanol).
10 133.38, 134.49, 147.40, 147.44, 156.35, 173.42. Optical rotation:
[α]36525 = +127° (c 0.1 g/dL, methanol).
Radical polymerization.
Procedure of aldol catalysis by polymeric catalysts
Take P(S)-PhVPyA as an example. P(S)-PhVPyA (17.5 mg,
0.05 mmol) was dissolved in 2 mL of cyclohexanone. To the
solution were added water (90 mg, 5 mmol), 4-nitrobenzoic acid
Take S-BPhVPyA as an example. S-BPhVPyA (0.200 g, 0.44
mmol), AIBN (0.7 mg, 0.004 mmol), and benzene (1.0 mL) were 50 (16.7 mg, 0.10 mmol), and 4-nitrobenzaldehyde (38.0 mg, 0.25
15 added into a reaction tube. After three freeze-pump-thaw cycles,
the tube was sealed under vacuum and put into an oil bath
thermostated at 60 °C for 24 hours. After being cooled to room
temperature, the tube was opened and the solution was diluted
mmol) consequently. The mixture was stirred vigorously at a
water bath thermostated at 25 °C until the full conversion of 4-
nitrobenzaldehyde monitored by TLC. The mixture was poured
into 25 mL of acetate ester and filtered. The precipitate was
with 10 mL of THF. The solution was dropped into hexane (200 55 collected, washed by fresh ethyl acetate three times and dried
20 mL). The precipitates were collected by filtration and washed by
fresh hexane. After drying under vacuum at 50 °C for 48 hours,
0.17 g of poly{(−)-L-N-Boc-proline-[5-(4’-tert-phenyl)-3-vinyl-
pyridin-2-yl]amide} (P(S)-BPhVPyA) as white solids was
obtained. Yield: 81%.
25 1H-NMR (400 MHz, CDCl3, δ ppm): 0.2-2.8 (broad peaks, -
COCHCH2CH2CH2N-, -CH-CH2-, Ph-C(CH3)3, -COC(CH3)3),
2.8-5.2 (broad peaks, -COCHCH2CH2CH2N-), 5.5-9.0 (broad
peaks, H pyridine ring and phenyl rings). Mn= 3.2 ×105 Da, PDI
= 1.76. Optical rotation: [α]36525 = −264° (c 0.1 g/dL , THF).
30 De-protection of Boc group
under vacuum at 50 °C for 48 hours. The filtrate was
concentrated under reduced pressure and the residue was purified
by silica gel column (estate ester/petroleum: 1/3 (v/v) as eluent)
to give 60 mg of product as white solids. Yield: 97%, dr
60 (endo/exo): 2.8/1, ee%: 62%.
1H-NMR (300 MHz, CDCl3, δ ppm): 1.00-1.65 (m, 4H, -
COCH2CH2CH2CH2CH-),
1.65-2.20
(m,
2H,
-
COCH2CH2CH2CH2CH-),
2.20-2.65
(m,
3H,
-
COCH2CH2CH2CH2CH-), 3.20 (s, br, 1H, -OH of syn product),
65 4.09 (s, br, 1H, -OH of anti product), 4.90 (d, 1H, -CH(OH)- of
anti product), 5.50 (d, 1H, -CH(OH)- of syn product), 7.50 (dd,
2H, 2, 6 H in the phenyl group), 8.21 (dd, 2H, 3, 5 H in the
phenyl group). Chiral HPLC analysis (Daicel CHIRALPAK AD-
H, isopropanol/hexane = 10/90, 1.0 mL/min, 25°C, UV detector
Take P(S)-BPhVPyA as an example. P(S)-BPhVPyA (0.15 g,
0.33 mmol) was dissolved in 5 mL of chloroform. To this
solution cooled to 0 °C was added dropwise 3 mL of TFA.
Afterwards, the mixture was stirred at room temperature for 6 70 240 nm, CD detector 240 nm). tR1(syn) = 11.4 min，tR2(syn) =
35 hours, and was concentrated under reduced pressure. The residue
was dissolved in 10 mL of methanol and dropped into 200 mL of
12.3 min，tR1(anti) = 13.4 min，tR2(anti) = 17.1 min.
Scheme 1 Syntheses of the monomers S-BPhVPyA, R-BPhVPyA, S-PhVPyA, R-PhVPyA and their corresponding polymers P(S)-BPhVPyA, P(R)-
BPhVPyA, P(S)-PhVPyA, P(R)-PhVPyA.
75
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Table 1 Summary of radical polymerization results of S-BPhVPyA and
R-BPhVPyA and chiroptical properties of P(S)-PhVPyA and P(R)-
PhVPyAa
Results and Discussion
Synthesis
The synthetic routes of S-BPhVPyA and R-BPhVPyA were
illuminated in Scheme 1. Phthalic anhydride was used to protect
the amine group of the starting reagent, 2-amino-5-bromopyridine.
Bromination of the phthalic anhydride protected compound with
NBS, followed by the reaction with triphenylphosphine, yielded
[5-bromo-2-(1,3-dioxoisoindolin-2-yl)-pyridin-3-yl]-ethyl-
triphenylphosphonium bromide. The Wittig reaction of
b
25d
Yield Mn
[α]365
(°)
b
Entry Polymer
Sol.
Anisole 89
THF 82
Mw/Mn Polymerc
(%) (×104)
5
P(S)-
1
P(S)-
1.2
28
26
23
15
32
28
+86
+113
+122
+132
+136
-130
BPhVPyA
PhVPyA
P(S)-
1.3
P(S)-
2
BPhVPyA
PhVPyA
P(S)-
1.4
P(S)-
3
Toluene 90
Heptane 93
Benzene 89
Benzene 90
BPhVPyA
PhVPyA
P(S)-
1.8
P(S)-
4
10 phosphonium bromide with formaldehyde in aqueous solution
under alkaline condition produced 2-(3-vinyl-5-bromopyridin-2-
yl)-isoindole-1,3-dione (II). It was treated with hydrazine hydrate
to produce 3-vinyl-2-amino-5-bromopyridine (III). The Suzuki
coupling reaction of vinylpyridine bromide with 4-tert-
15 butylbenzeneboronic acid catalyzed by Pd(PPh3)4 produced the
key intermediate, 3-vinyl-5-(4’-tert-phenyl)-2-aminopyridine
(IV), which was condensed with L- or D-N-Boc-proline using
DCC as the activator to yield the target monomers, (−)-L-N-Boc-
BPhVPyA
PhVPyA
P(S)-
1.2
P(S)-
5
BPhVPyA
P(R)-
6
PhVPyA
P(R)-
1.2
BPhVPyA
PhVPyA
a.
50
Polymerization conditions: monomer concentration [M], 0.2 g/mL;
b.
initiatior, AIBN; [M]/[I] =100:1; temperature 60 °C. Number-average
molecular weight (Mn), weight-average molecular weight (Mw) and
c.
polydispersity (Mw/Mn) were determined by GPC. P(S)-PhVPyA and
P(R)-PhVPyA were prepared from their corresponding polymeric
proline-[5-(4’-tert-phenyl)-3-vinyl-pyridin-2-yl]amide
(S-
d.
55 precursors via de-protection of Boc group by TFA. Specific optical
rotations of de-protected polymers measured in methanol solution (c = 0.1
g/dL).
20 BPhVPyA) and (+)-L-N-Boc-proline-[5-(4’-tert-phenyl)-3-vinyl-
pyridin-2-yl]amide (R-BPhVPyA), respectively. S-PhVPyA and
R-PhVPyA, employed as the low molar mass model compounds,
were obtained from S-BPhVPyA and R-BPhVPyA via de-
protection of Boc groups.
Fig. 1 displays the 1H-NMR spectra of S-BPhVPyA and P(S)-
BPhVPyA. The peaks at 5.39–5.50, 5.73–5.90 and 6.65–6.95
60 ppm were attributed to the proton resonances of vinyl group (Fig.
1a). They vanished after polymerization, accompanied by the
appearance of broad peaks in the region of 0–1.50 ppm (Fig. 1b),
implying the formation of polymer backbone. In addition, the
proton resonance peaks became obviously dispersed after the
65 polymerization, owing to the limited mobility of protons in the
polymer chain.
25
Probably owing to the electron deficiency of II, the
bromination of methyl group by NBS could not take place just
through heating, one commonly used method. To efficiently
induce the reaction, sunshine or sun lamp was applied. In addition,
it is necessary to run Suzuki coupling reaction after
30 hydrazinolysis because the intermediate II may complex with
pd(0) and poison the catalyst. The chemical structures of all the
key intermediates, model compounds, and monomers were
confirmed by 1H/13C-NMR, and HRMS.
Catalytically active polymers, P(S)-PhVPyA and P(R)-
PhVPyA were derived from P(S)-BPhVPyA and P(R)-
BPhVPyA through the decomposition of Boc group under acidic
70 condition. They had poor solubilities in less polar solvents
(chloroform, THF, anisole, etc), but good solubilities in polar
solvents (methanol, ethanol, DMF, DMSO, etc).
Polymerization
35 Free radical polymerizations of S-BPhVPyA and R-BPhVPyA
were carried out at 60 °C with AIBN as the initiator. For S-
BPhVPyA, various solvents were utilized to investigate their
effects on the chiroptical property of the resultant polymers. The
results are summarized in Table 1 (Entries 1~5). Under all
40 conditions, the obtained polymers had high molar masses (Mn =
15~32 × 104 Da), moderate polydispersities (PDI = 1.2~1.8), and
good solubilities in various solvents (chloroform, THF, anisole,
methanol, etc). The polymer prepared in benzene had the highest
molar mass and lowest polydispersity. Therefore, benzene was
45 selected as the radical polymerization solvent of R-BPhVPyA
(Entry 6, Table 1).
Fig. 2 shows the FT-IR spectra of P(S)-PhVPyA and P(S)-
BPhVPyA. The vibration of C=O stretching, symmetric in-plane
75
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Chiroptical properties.
The specific optical rotation [α]36525 of S-PhVPyA is −122° (c: 1
mg/mL, methanol). The corresponding polymer, P(S)-PhVPyA,
15 shows an [α]36525 value of +132°. This distinct variation indicated
that the optical activity of P(S)-PhVPyA did not solely arise from
the configurational chirality of the side group, but a higher chiral
structure, most likely helical conformation of the main chain was
formed. Changing the configuration of stereocenter from S to R,
20 as in R-PhVPyA and P(R)-PhVPyA, led to an inversion of the
sign of specific optical rotations for both monomer and polymer,
suggesting that the stereocenter in the side group played a
dominant role in the induction of a prevailing twist sense. It
25
should be noted that P(S)-BPhVPyA displayed an [α]365 value
25 of -264°. The optical rotation sign alternation before and after de-
protection might be attributed to the change in the orientation of
proline pendants. Boc groups are bulky and have strong steric
conflicts with polymer backbone. As a result, the carboxyamide
groups tend to be away from polymer backbone. Whereas, the
30 amine groups of proline moieties in P(S)-PhVPyA are smaller
and may orient in a different way, which caused conformational
variation of side-groups. Another possible explanation is the
difference of solvents in which optical rotations were measured,
THF for of P(S)-BPhVPyA and methanol for P(S)-PhVPyA.
35
Circular dichroism (CD) spectrometry was applied to further
characterize the secondary structures of polymers. Fig. 3 shows
the CD and UV-Vis spectra of S-PhVPyA, P(S)-PhVPyA and
P(R)-PhVPyA. The UV-Vis spectrum of monomer S-PhVPyA
presents four obvious absorption bands centered at 213 nm, 240
40 nm, 266 nm, 310 nm, which may be assigned as the electronic
transitions of side carbonyl, vinyl, phenylpyridinyl and
phenylpyridinyl amide groups, respectively.54,
55
The CD
spectrum of S-PhVPyA only shows very week negative Cotton
effects around 210 nm. The corresponding polymer, P(S)-
45 PhVPyA exhibits three obvious absorption bands in the UV-Vis
spectrum centered at 210 nm, 265 nm and 285 nm, separately.
The CD spectrum of P(S)-PhVPyA presents one intensive and
two weak negative peaks at 220 nm, 250 nm and 315 nm, and an
intensive positive peak at 285 nm, suggesting the side groups
Fig. 1 1H-NMR spectra of S-BPhVPyA (a) and P(S)-BPhVPyA (b) in
CDCl3 solution with TMS as an internal standard.
50 were arranged in a skewed way. By analogous to the previously
reported polymers,46,
1450
51
2966
1674
the formation of chiral secondary
structure was proposed for P(S)-PhVPyA. The CD curve of P(S)-
PhVPyA had mirror symmetry with that of P(R)-PhVPy,
indicating again that the prevailing twist sense of polymer
55 backbone was determined by the configuration of stereocenter.
P(S)-PhVPyA
1395
1366
1269
2966
1701
P(S)-BPhVPyA
4000
3000
1800 1600 1400 1200 1000 800 600 400
Wavenumber (cm-1)
5
Fig. 2 FT-IR spectra of P(S)-BPhVPyA and P(S)-PhVPyA
H−C−H bending, and out-of-plane H−C−H bending of Boc group
are observed at 1701, 1395 and 1366, and 1269 cm-1, respectively.
They are absent in the spectrum of P(S)-PhVPyA, suggesting the
10 complete removal of Boc groups.
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20 methyl]cyclohexanone, defined as MSR, MRS, MSS, and MRR
,
9.0x104
1.6x104
S-PhVPyA
P(S)-PhVPyA
P(R)-PhVPyA
respectively, could be obtained according to the configuration of
newly formed stereocenters. Among these isomers, MSR and MRS
are a pair of enantiomers with anti-configuration, while MSS and
MRR are the syn-configuration enantiomers. The diastereomer
25 ratio of aldol transformation was defined as dr = anti/syn, and the
enantiomer excess of the anti-configuration products was defined
as ee% (anti) = (MSR−MRS)/( MSR+MRS)×100% (MSR as the major
product) or ee% (anti) = (MRS−MSR)/( MSR+MRS)×100% (MRS as
the major product).
8.0x103
0.0
6.0x104
-8.0x103
-1.6x104
-2.4x104
-3.2x104
30
Table 2 summaries the results of catalytic reactions in
cyclohexanone bulk solution with water and 4-nitrobenzoic acid
as the additives. It was evident that the polymeric aldolases
promoted the reaction between 4-nitrobenzaldehyde and
cyclohexanone to proceed much faster than low molar mass ones.
3.0x104
35 For example, it took only 10 h for 4-nitrobenzaldehyde to be fully
converted in the presence of P(S)-PhVPyA (Entry 3, Table 2).
Whereas, 24 h was needed when S-PhVPyA was employed
(Entry 2, Table 2). All the reactions yielded cis-isomers as the
major products with dr around 3.0 (Entry 2~5). Besides the
40 reaction activity and diastereo-selectivity, the next and most
important parameter of asymmetric catalysis is its enantio-
selectivity. When S-PhVPyA acted as the catalyst, the reaction
afforded MSR as the major isomer with the enantio-selectivity as
0.0
200
220
240
260
280
300
320
340
Wavelength (nm)
Fig. 3 CD and UV-Vis spectra of S-PhVPyA, P(S)-PhVPyA and P(R)-
PhVPyA in THF at 25 °C with a concentration of 5×10-5 mol/L
5
high as 87% ee, which was comparable to the catalytic results of
45 most reported L-proline derivative organocatalysts.6,
7
The polymers resulted from the polymerization of S-
BPhVPyA in polar solvent such as anisole and THF displayed
lower optical rotations than those obtained from apolar solvents.
It might be rationalized by the lack of hydrogen bonding between
The
transformation catalyzed by P(S)-PhVPyA also mainly yielded
MSR but with slightly lower enantio-selectivity, i.e. 62% ee.
Changing the configuration of catalyst led to the configuration
inversion of product, indicating that the chirality of side groups
50 dominated the stereoselection of the aldol reaction. Furthermore,
it seemed that the configurational chirality of side groups and the
conformational chirality of polymer main chain exerted
competitive influence.
10 amide groups during polymerization in polar sovent. 51
Asymmetric aldol catalysis
Table 2 Results of asymmetric aldol reactions between cyclohexanone
55 and 4-nitrobenzaldehyde catalyzed by P(S)-PhVPyA, P(R)-PhVPyA and
their low molecular mass counterpartsa
Time
Entry
Cat.
Yield (%)b ee% (anti)c dr (anti/syn)d
(h)
24
24
10
24
e
e
1
2
3
4
5
None
NULL
93
–
–
S-PhVPyA
P(S)-PhVPyA
R-PhVPyA
87 (MSR
62 (MSR
86 (MRS
62 (MRS
)
)
)
)
3.0/1
3.4/1
3.0/1
3.2/1
Scheme 2. Asymmetric aldol catalysis of cyclohexanone with p-
nitrobenzaldehyde.
>95
91
P(R)-PhVPyA 10
>95
15
The helical polymers, P(S)-PhVPyA and P(R)-PhVPyA, and
their corresponding low molar mass counterparts, S-PhVPyA and
R-PhVPyA, were separately applied in the asymmetric aldol
reaction of cyclohexanone with 4-nitrobenzaldehyde (Scheme 2).
a.
Reaction temperature: 25 °C; 4-nitrobenzaldehyde: 0.25 mmol;
cyclohexanone: 2 mL; catalyst: 0.05 mmol; 4-nitrobenzoic acid: 0.10
mmol; H2O: 5.0 mmol. The time for full conversion was monitored by
60 TLC. b. Isolated product after column separation. c. Determined by HPLC
using a Daicel CHIRALPAK AD-H column. d. Determined by 1H-NMR. e.
Not determined.
Four
stereoisomers
of
2-[hydroxyl-(4-nitrophenyl)-
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ARTICLE TYPE
Table 3 Results of asymmetric aldol catalysis between cyclohexanone and 4-nitrobenzaldehyde by P(S)-PhVPyA and S-PhVPyA in the presence of
various additivea
Entry
Cat.
Additive
−
−
H2O (20 eq.)
H2O (20 eq.)
Time
72
72
72
24
72
24
24
10
24
10
10
Conv.(%)b
trace
73
trace
92
ee% (anti)c
dr (anti/syn)b
−
1
2
3
4
5
6
7
8
9
S-PhVPyA
P(S)-PhVPyA
S-PhVPyA
P(S)-PhVPyA
S-PhVPyA
P(S)-PhVPyA
S-PhVPyA
P(S)-PhVPyA
S-PhVPyA
−
28
−
1.9/1
−
20
28
32
79
50
87
62
50
2.2/1
2.1/1
2.1/1
2.3/1
2.9/1
3.0/1
3.4/1
2.0/1
p-NO2PhCOOH (0.2 eq.)
p-NO2PhCOOH (0.2 eq.)
p-NO2PhCOOH (0.2 eq.) H2O (20 eq.)
p-NO2PhCOOH (0.2 eq.) H2O (20 eq.)
p-NO2PhCOOH (0.4 eq.) H2O (20 eq.)
p-NO2PhCOOH (0.4 eq.) H2O (20 eq.)
p-NO2PhCOOH (1 eq.) H2O (20 eq.)
TFA (0.4 eq.)
48
>95
80
94
93
>95
>95
10
11
P(S)-PhVPyA
P(S)-PhVPyA
12
P(S)-PhVPyA
10
91
26
1.7/1
H2O (20 eq.)
PhCOOH (0.4 eq.)
H2O (20 eq.)
13
14
P(S)-PhVPyA
P(S)-PhVPyA
P(S)-PhVPyA
24
24
24
89
88
78
24
19
39
1.8
p-CH3OPhCOOH (0.4 eq.) H2O (20 eq.)
TFA (0.4 eq.)
H2O (20 eq.)
p-NO2PhCOOH (0.4 eq.) H2O (20 eq.)
p-NO2PhCOOH (0.4 eq.) H2O (20 eq.)
1.7/1
3.0/1
15d
16e
17f
P(S)-PhVPyA
P(S)-PhVPyA
24
24
80
38
37
34
2.5/1
1.5/1
a. All experiments were carried out under 25°C water bath, 4-nitrobenzaldehyde (0.25 mmol), cyclohexanone (2 mL), catalyst (0.05 mmol); the time for
full conversion in all cases monitored by TLC. b. Determined by 1H-NMR. c. Determined by HPLC using a Daicel CHIRALPAK AD-H. d. 2 mL of
chloroform was used as solvent. e. 2 mL of DMSO was used as solvent. f. 2 mL of methanol was used as solvent.
5
Water and Brønsted acid are known to enhance the catalytic 35 catalyzed by P(S)-PhVPyA. In nonpolar chloroform, the
performance of proline amide based aldolases.56-58 In order to
polymeric catalyst was not soluble and afforded the products in
relative low yield and poor stereo-selectivity (Entry 15, Table 3).
The reactions in DMSO and methanol did not proceed well, too
(Entries 16 and 17, Table 3) and many substrate were
optimize the catalytic condition, the aforementioned reaction was
10 carried out in the presence of various additives. The results are
summarized in Table 3. Without any additive, S-PhVPyA yielded
only trace products over 72 h (Entry 1, Table 3). By contrast, the 40 transformed to unidentified by-products.
reaction catalyzed by P(S)-PhVPyA presented a moderate yield
(73%) under otherwise identical condition, although ee% and dr
15 were low (Entry 2, Table 3). When 20 eq. of water was added, the
reaction rate catalyzed by P(S)-PhVPyA was dramatically
increased with similar ee% and dr (Entry 4, Table 3)); however,
S-PhVPyA still did not efficiently catalyze the reaction (Entry 3,
Table 3). p-Nitrobenzoic acid could also promote the reaction
20 together with P(S)-PhVPyA (Entry 6, Table 3). But unlike water,
it was also efficient to promote S-PhVPyA to catalyze reaction
and showed a yield of 48% with 28% ee and 2.1 dr. The addition
of both water and p-nitrobenzoic acid together could further
enhance the reaction rate and improve stereoselectivity. The
25 addition of 20 eq. water and 0.4 eq. of 4-nitrobenzoic acid
together resulted in the best results in terms of chemical yield and
stereoselectivity (Entries 7 and 8, Table 3). When the amount of
water added was fixed, more or less 4-nitrobenzoic acid led poor
ee% and dr values. Other organic acid such as TFA, 4-
30 methoxylbenzoic acid, and benzoic acid were applied as additives
instead of 4-nitrobenzoic acid (Entry 11~14). Unfortunately, all
the reactions gave undesired results.
Proposed Catalytic Mechanism.
The proposed catalytic cycle of the aldol reaction is presented in
59-61
The carbonyl groups of both substrates are
Scheme 3.5,
protonated and activated by the additive (i.e., 4-nitro-benzoic
45 acid). The activated cyclohexanone is attacked by the amino
group of P(S)-PhVPyA to afford the intermediate 1, which sets
off one H2O molecule and rearranges from iminium (2) to
enamine (3). The intermediate 3 attacks the carbonyl group of 4-
nitrobenzaldehyde through the transition state
4 to yield
50 intermediate 5. The iminium 5 is hydrolyzed and releases a
molecule of product to recycle the catalyst.
55
In order to shed light on the effect of solvent, chloroform,
DMSO, and methanol were used as the solvents of reactions
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BPhVPyA and R-BPhVPyA and subsequent de-protection of
Boc groups. They efficiently catalyzed asymmetric aldol
40 reactions of cyclohexanone and 4-nitrobenzaldehyde using water
and 4-nitrobenzoic acid as additives. Compared to low molar
mass counterparts, the polymeric catalysts afforded faster
reaction rate but slightly poorer enantio-selectivity. The shrunken
enantio-selectivity of polymeric catalyst suggested that the side-
45 group and polymer backbone did not act synergically on the
stereochemistry of aldol catalysis. This mismatch should be
avoided in the design of helical polymeric catalysts to mimic
enzymes.
Acknowledgements
50 The financial supports of the National Natural Science Foundation of
China (No. 21274003) and the Research Fund for Doctoral Program of
Higher Education of MOE (No. 20110001110084) are greatly appreciated.
Notes and references
* Beijing National Laboratory for Molecular Sciences, Key Laboratory of
55 Polymer Chemistry and Physics of MOE, Center for Soft Matter Science
and Engineering, College of Chemistry and Molecular Engineering,
Peking University
Scheme 3 Proposed catalytic cycle of cyclohexanone with 4-nitro-
benzaldehyde catalyzed by P(S)-PhVPyA
Chengfu Road 202, Haidian District, Beijing 100871, China. Fax: 86 10
6275 1708; Tel: 86 10 6275 4187; E-mail: xhwan@pku.edu.cn
60 † Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
Based on this mechanism, the diastereo-selectivity and enantio-
selectivity of the reaction is determined by the position and
direction where the enamine 3 attacks the aldehyde. With the help
of the intermolecular hydrogen bond, the aldehyde substrate tends
to be arranged the same side with the amide bond of the catalyst.
As a result, the enamine faces the aldehyde with its Si face. In
5
1. K. Mikami and M. Lautens, New Frontiers in Asymmetric Catalysis,
John Wiley & Sons, Inc., Hoboken, NJ, 2007.
65 2. I. Ojima, Catalytic Asymmetric Synthesis, Wiley, New York, 2009.
3. R. Noyori, Angew. Chem. Int. Ed. , 2002, 41, 2008-2022.
4. R. Mahrwald and D. A. Evans, Modern aldol reactions, Wiley-VCH
Weinheim, 2004.
10 addition, when nucleophilic addition reaction happens, the
enamine and aldehyde are arranged in a six-membered ring
transition state, in which 4-nitro-phenyl, the larger group of the
aldehyde, has a higher opportunity to settle at the equatorial bond
than at the axial bond. The favored equatorial arrangement of 4-
15 nitro-phenyl group affords the MSR isomer, while the not favored
axial form affords the MRR one. MSS and MRS isomers are obtained
when the aldehyde steps forward 3 on the opposite side of the
amide bond (Re face of the enamine bond). As a result, the
catalytic aldol reaction afford anti adduct with enantio-selectivity.
5. B. List, R. A. Lerner and C. F. Barbas, J. Am. Chem. Soc., 2000, 122,
70
2395-2396.
6. B. M. Trost and C. S. Brindle, Chem. Soc. Rev., 2010, 39, 1600-1632.
7. B. List, Tetrahedron, 2002, 58, 5573-5590.
8. W. Notz, F. Tanaka and C. F. Barbas, Acc. Chem. Res. , 2004, 37,
580-591.
75 9. B. List, J. Am. Chem. Soc., 2000, 122, 9336-9337.
10. B. List, P. Pojarliev, W. T. Biller and H. J. Martin, J. Am. Chem.
Soc., 2002, 124, 827-833.
20
During the catalytic cycle, the acid additive, i.e. 4-nitro-
benzoic acid, plays the key roles of activating the carbonyl
groups of the both substrates. Furthermore, the additional protons
benefit for the formation of the six-membered ring transition state
4 through the hydrogen bond, which dramatically enhance the
11. Y. Hayashi, W. Tsuboi, I. Ashimine, T. Urushima, M. Shoji and K.
Sakai, Angew. Chem. Int. Ed. , 2003, 42, 3677-3680.
80 12. J. M. Betancort and C. F. Barbas, Org. Lett., 2001, 3, 3737-3740.
13. B. List, P. Pojarliev and H. J. Martin, Org. Lett., 2001, 3, 2423-2425.
14. I. K. Mangion and D. W. C. MacMillan, J. Am. Chem. Soc., 2005,
127, 3696-3697.
25 influence from the chiral proline moiety and increase the enantio-
selectivity. On the other hand, the added water helps to accelerate
the aldol reaction possibly because of the hydrogen bond bridge
between the catalyst molecule with the substrate molecules.
Without the additives, P(S)-PhVPyA prohibit the enhancement
30 in catalytic activity (Table 3, Entry 1, 2), probably because the
amide protons of the neighbor side groups in the polymeric
catalysts help to form additional hydrogen bonds with the
substrate.45
15. D. B. Ramachary, N. S. Chowdari and C. F. Barbas Iii, Tetrahedron
85
Lett., 2002, 43, 6743-6746.
16. R. Thayumanavan, B. Dhevalapally, K. Sakthivel, F. Tanaka and C.
F. Barbas Iii, Tetrahedron Lett., 2002, 43, 3817-3820.
17. G. Sabitha, N. Fatima, E. V. Reddy and J. S. Yadav, Adv. Synth.
Catal., 2005, 347, 1353-1355.
90 18. A. Bøgevig, K. Juhl, N. Kumaragurubaran, W. Zhuang and K. A.
Jørgensen, Angew. Chem. Int. Ed. , 2002, 41, 1790-1793.
19. B. List, J. Am. Chem. Soc., 2002, 124, 5656-5657.
20. X. Liu, L. Lin and X. Feng, Acc. Chem. Res. , 2011, 44, 574-587.
21. Y. Cai, W. Wang, K. Shen, J. Wang, X. Hu, L. Lin, X. Liu and X.
95
Feng, Chem. Commun. , 2010, 46, 1250-1252.
Conclusions
22. M. Xie, X. Chen, Y. Zhu, B. Gao, L. Lin, X. Liu and X. Feng,
Angew. Chem. Int. Ed. , 2010, 49, 3799-3802.
35 In this work, a pair of L- and D-proline amide containing
optically active helical polymers, P(S)-PhVPyA and P(R)-
PhVPyA, were synthesized via radical polymerizations of S-
23. W. Li, J. Wang, X. Hu, K. Shen, W. Wang, Y. Chu, L. Lin, X. Liu
and X. Feng, J. Am. Chem. Soc., 2010, 132, 8532-8533.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 9

Page 11 of 11
RSC Advances
View Article Online
DOI: 10.1039/C5RA07207G
24. W. Chen, Y. Cai, X. Fu, X. Liu, L. Lin and X. Feng, Org. Lett., 2011,
13, 4910-4913.
25. W. Li, X. Liu, F. Tan, X. Hao, J. Zheng, L. Lin and X. Feng, Angew.
Chem. , 2013, 125, 11083-11086.
5
26. K. Zheng, J. Shi, X. Liu and X. Feng, J. Am. Chem. Soc., 2008, 130,
15770-15771.
27. K. Zheng, X. Liu, J. Zhao, Y. Yang, L. Lin and X. Feng, Chem.
Commun. , 2010, 46, 3771-3773.
28. S. Itsuno, Polymeric Chiral Catalyst Design and Chiral Polymer
Synthesis, John Wiley & Sons, Inc., Hoboken, NJ, 2011.
29. E. Alza, X. C. Cambeiro, C. Jimeno and M. A. Pericàs, Org. Lett.,
2007, 9, 3717-3720.
10
30. A. C. Evans, A. Lu, C. Ondeck, D. A. Longbottom and R. K.
O’Reilly, Macromolecules, 2010, 43, 6374-6380.
15 31. A. Lu, T. P. Smart, T. H. Epps, D. A. Longbottom and R. K.
O’Reilly, Macromolecules, 2011, 44, 7233-7241.
32. M. Benaglia, M. Cinquini, F. Cozzi, A. Puglisi and G. Celentano,
Adv. Synth. Catal., 2002, 344, 533-542.
33. E. G. Doyagüez, G. Corrales, L. Garrido, J. Rodríguez-Hernández, A.
20
Gallardo and A. Fernández-Mayoralas, Macromolecules, 2011, 44,
6268-6276.
34. E. G. Doyagüez, J. Rodríguez-Hernández, G. Corrales, A. Fernández-
Mayoralas and A. Gallardo, Macromolecules, 2012, 45, 7676-7683.
35. H. A. Zayas, A. Lu, D. Valade, F. Amir, Z. Jia, R. K. O’Reilly and
M. J. Monteiro, ACS Macro Letters, 2013, 2, 327-331.
36. A. Lu, D. Moatsou, I. Hands-Portman, D. A. Longbottom and R. K.
O’Reilly, ACS Macro Letters, 2014, 3, 1235-1239.
25
37. Y. Liu, Q. Tong, L. Ge, Y. Zhang, L. Hua and Y. Fan, RSC
Advances, 2014, 4, 50412-50416.
30 38. T. Kehat and M. Portnoy, Chem. Commun. , 2007, 2823-2825.
39. Y. Chi, S. T. Scroggins, E. Boz and J. M. J. Fréchet, J. Am. Chem.
Soc., 2008, 130, 17287-17289.
40. M. Reggelin, S. Doerr, M. Klussmann, M. Schultz and M. Holbach,
Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 5461-5466.
35 41. T. Yamamoto and M. Suginome, Angew. Chem. Int. Ed. , 2009, 48,
539-542.
42. A. J. Boersma, R. P. Megens, B. L. Feringa and G. Roelfes, Chem.
Soc. Rev., 2010, 39, 2083-2092.
43. Z. L. Tang, H. Iida, H. Y. Hu and E. Yashima, ACS Macro Letters,
40
2012, 1, 261-265.
44. A. Ikeda, K. Terada, M. Shiotsuki and F. Sanda, J. Polym. Sci., Part
A: Polym. Chem., 2011, 49, 3783-3796.
45. D. Zhang, C. Ren, W. Yang and J. Deng, Macromolecular Rapid
Communications, 2012, 33, 652-657.
45 46. Z. Yu, X. Wan, H. Zhang, X. Chen and Q. Zhou, Chem. Commun. ,
2003, 974-975.
47. J. Cui, A. Liu, J. Zhi, Z. Zhu, Y. Guan, X. Wan and Q. Zhou,
Macromolecules, 2008, 41, 5245-5254.
48. J. Zhi, Z. Zhu, A. Liu, J. Cui, X. Wan and Q. Zhou, Macromolecules,
50
2008, 41, 1594-1597.
49. J. Cui, X. Lu, A. Liu, X. Wan and Q. Zhou, Macromolecules, 2009,
42, 7678-7688.
50. A. Liu, Z. Zhao, R. Wang, J. Zhang and X. Wan, J. Polym. Sci., Part
A: Polym. Chem., 2013, 51, 3674-3687.
55 51. Z. Zhu, J. Cui, J. Zhang and X. Wan, Polymer Chemistry, 2012, 3,
668-678.
52. R. Wang, X. Li, J. Bai, J. Zhang, A. Liu and X. Wan,
Macromolecules, 2014, 47, 1553-1562.
53. Z. Zhao, J. Bai, J. Zhang, A. Liu and X. Wan, Sci. China Chem.,
60
2014, 57, 982-994.
54. P. Krumholz, J. Am. Chem. Soc., 1951, 73, 3487-3492.
55. C. Helgen and C. G. Bochet, Heterocycles, 2006, 67, 797-805.
56. J.-R. Chen, X.-L. An, X.-Y. Zhu, X.-F. Wang and W.-J. Xiao, J. Org.
Chem., 2008, 73, 6006-6009.
65 57. Z.-H. Tzeng, H.-Y. Chen, R. J. Reddy, C.-T. Huang and K. Chen,
Tetrahedron, 2009, 65, 2879-2888.
58. A. J. Pearson and S. Panda, Tetrahedron, 2011, 67, 3969-3975.
59. M. Arnó and L. R. Domingo, Theor Chem Acc, 2002, 108, 232-239.
60. C. Marquez and J. O. Metzger, Chem. Commun. , 2006, 1539-1541.
70 61. S. Bahmanyar, K. N. Houk, H. J. Martin and B. List, J. Am. Chem.
Soc., 2003, 125, 2475-2479.
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