Synthesis of novel functionalized polymers for the diastereoselective protonation of chiral enolates

Article abstract of DOI:10.1002/ejoc.200400429

The polymeric, chelating proton donors 7 and 8 were synthesized by radical polymerization of the monomers 5/6 with different amounts of styrene. Protonation of chiral lithium enolates derived from silyl enol ethers 9 gave cis/trans ratios of up to 94:6 (1

Full text of DOI:10.1002/ejoc.200400429

SHORT COMMUNICATION
Synthesis of Novel Functionalized Polymers for the Diastereoselective
Protonation of Chiral Enolates
Marc Mackenstedt[a] and Norbert Krause*[a]
Keywords: Chelation / Chiral enolates / Diastereoselectivity / Functionalized polymers / Protonations
The polymeric, chelating proton donors 7 and 8 were synthe-
sized by radical polymerization of the monomers 5/6 with dif-
ferent amounts of styrene. Protonation of chiral lithium enol-
ates derived from silyl enol ethers 9 gave cis/trans ratios of
up to 94:6 (10a) and 99:1 (10b), respectively. The polymers
can be recycled and used repeatedly without appreciable
loss of selectivity.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
furthermore, the protonation has to be carried out in a sol-
vent system which enables (at least partial) dissolution of
The stereoselective formation of a CϪH bond by pro- the polymer (use of ethyl acetate or dichloromethane as a
tonation a prochiral or chiral enolate is an attractive cosolvent).[4] Nevertheless, there is still room for improve-
method for the construction of a new stereogenic center in ment, and we now report two new types of polymeric chel-
an organic molecule. For the diastereoselective protonation ating proton donors which provide diastereoselectivities of
of endocyclic keto enolates, chelating proton donors with up to 99% in the protonation of chiral enolates.
a salicylate structure are the reagents of choice since the
formation of a rather rigid chelate complex between the en-
Results and Discussion
olate and the proton source ensures a highly cis-selective,
reagent controlled proton transfer.[1,2] Several applications
in target-oriented synthesis[2,3] emphasize the practicability
of the method. Furthermore, in order to enable the repeated
use of the proton donor and to facilitate its separation from
the product, we have introduced the first polymeric, chelat-
ing protonating agents of type 2 which allowed the pro-
tonation of enolate 1 to be carried out with up to 93% dia-
stereoselectivity (Scheme 1).[4]
The common precursor for both polymer types is 4-vi-
nylbenzyl chloride (4) which was transformed into the sal-
icylate derivative 5 by esterification with sodium salicylate
in the presence of sodium iodide and a phase-transfer cata-
lyst (53% yield).[5] Alternatively, the ether 6 was formed
with 51% yield by treatment of 4 with ethyl 2,5-dihydroxy-
benzoate and potassium carbonate (Scheme 2).[6] The for-
mation of the homopolymers 7a/8a, as well as of statistical
copolymers with 5, 9 or 15 equiv. of styrene, was carried
out by heating the monomer 5 or 6 with the appropriate
amount of styrene in the presence of AIBN (60Ϫ95%
yield).[7,8] The average molecular weight of several of the
polymers was determined by GPC and ranges from 7200 to
25600 g/mol.
The substrates for the diastereoselective protonation, the
lithium enolates of type 1, were formed by treatment of the
thermodynamic silyl enol ethers 9a/b[2,4] with 1 equiv. of
methyllithium in THF solution (Scheme 3). Addition to a
fivefold excess of the polymeric proton donor 7 or 8 in di-
chloromethane and quenching of the lithium salts with
acetic acid as described earlier[1Ϫ3] was followed by gas
chromatographic determination of the diastereomeric ratio
(Table 1).
Scheme 1. Diastereoselective protonation of chiral enolate 1 with
polymeric, chelating proton donors 2
In order to reach stereoselectivities of this magnitude, it
has turned out to be essential that the salicylate units in the
polymer are ‘‘diluted’’ by copolymerization with styrene;
[a]
Organic Chemistry II, University of Dortmund,
In the protonation of the chiral lithium enolate derived
from silyl enol ether 9a, cis/trans ratios around 90:10 were
achieved with all polymeric proton sources examined. In
44221 Dortmund, Germany
Fax: ϩ49 231/755-3884
E-mail: norbert.krause@uni-dortmund.de
Eur. J. Org. Chem. 2004, 4531Ϫ4534
DOI: 10.1002/ejoc.200400429
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M. Mackenstedt, N. Krause
FULL PAPER
Scheme 2. Synthesis of polymeric proton donors 7 and 8
cis-10a:trans-10a ϭ 87:13 observed for the protonation with
5 equiv. of homopolymer 7a could be improved to 94:6 by
using a larger excess (10 equiv.) of the protonating agent.[4]
This value is very close to the ratio of 96:4 found when the
protonation is carried out with ethyl salicylate.[1,2] In the
case of the carvone-derived silyl enol ether 9b, polymers 7
afforded higher selectivities than their counterparts 8, in
particular 7a and 7b which gave excellent cis/trans ratios of
99:1 and 98:2, respectively. In some cases, the diastereosel-
ectivity could again be improved by employing a larger ex-
cess of the proton donor (see Table 1). The recovered poly-
meric proton sources can be used repeatedly without appre-
ciably loss of stereoselectivity; for example, the selectivity
of the protonation of the enolate formed from substrate 9a
with 5 equiv. of copolymer 7c decreased only slightly from
cis-10a:trans-10a ϭ 90:10 (first cycle) to 87:13 in the fifth
cycle.
Scheme 3. Diastereoselective protonation of chiral enolates derived
from silyl enol ethers 9 with polymeric proton donors 7/8
Table 1. Diastereoselectivity of the protonation of chiral enolates
derived from silyl enol ethers 9 with 5 equiv. of polymeric proton
donors 7/8
Proton source
R ϭ H
R ϭ H3CϪCϭCH2
cis-10b/trans-10b[b] [c]
cis-10a/trans-10a[a]
7a
7b
7c
7d
8a
8b
8c
8d
87:13[d]
86:14
90:10
88:12
83:17
92:8
99:1
98:2
88:12[e]
92:8
78:22[f]
85:15
92:8
Conclusion
90:10
89:11
The novel polymeric, chelating proton donors 7 and 8
were synthesized by radical polymerization of the mono-
mers 5/6 with different amounts of styrene. Protonation of
the chiral lithium enolates derived from silyl enol ether 9a
gave cis/trans ratios of up to 94:6, whereas the correspond-
ing carvone-derived silyl enol ether 9b furnished the product
cis-10b with up to 99% diastereoselectivity. In both cases,
the homopolymer 7a afforded the highest selectivities, pro-
ving that a ‘‘dilution’’ of the salicylate units in the polymer
93:7
[a]
cis-10a/trans-10a ϭ 92:8 with 5 equiv. of monomer 5; cis-10a/
[b]
trans-10a ϭ 93:7 with 5 equiv. of monomer 6.
cis-10b/trans-
[c]
10b ϭ 98:2 with 5 equiv. of monomer 5 or 6. cis and trans refer
[d]
to the relative configuration of the two methyl groups of 10b.
cis-10a/trans-10a ϭ 94:6 with 10 equiv. of 7a. [e] cis-10b/trans-10b ϭ
96:4 with 10 equiv. of 7c. [f] cis-10b/trans-10b ϭ 86:14 with 10 equiv.
of 8a.
contrast to the earlier observation made for polymers 2,[4] chain is not necessary with polymeric proton donors of this
the ‘‘concentration’’ of salicylate units hardly affects the type. The polymers can be recycled and used repeatedly
stereoselectivity of the protonation. However, the ratio of without appreciable loss of stereoselectivity.
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Eur. J. Org. Chem. 2004, 4531Ϫ4534

Novel Functionalized Polymers for the Diastereoselective Protonation of Chiral Enolates
FULL PAPER
ing at room temperature, the supernatant liquid was removed, and
the polymer was dried in vacuo. NMR spectroscopy revealed that
the polymers were free of detectable amounts of monomer in-
clusions or solvent.
Experimental Section
General Remarks: The reactions were performed in oven-dried
glassware under Ar. Diethyl ether and THF were distilled from
sodium/benzophenone. Column chromatography was carried out
with MERCK silica gel F 60 (70Ϫ230 mesh). For gel permeation
chromatography, microgel set A22 was used with CHCl3 as the sol-
vent and polystyrene as the standard. GC analyses were carried out
with a Carlo Erba GC 8000 gas chromatograph, equipped with a
OV-1701 capillary column (carrier gas: helium). NMR spectra were
obtained with a BRUKER DRX 400 spectrometer with CDCl3 as
solvent and internal standard (1H NMR: δ ϭ 7.26. 13C NMR: δ ϭ
77.0 ppm). IR spectra were measured with a BRUKER IFS 66
spectrometer. MS and HRMS: FINNIGAN MAT 8200 (EI,
70 eV).
Homopolymer 7a: From 5 (6.50 g, 25.6 mmol) and AIBN (0.30 g,
1.83 mmol); yield: 3.91 g (60%) of 7a as a colorless solid. Average
molecular weight: 7822 g/mol, polydispersity: 3.23.
Copolymer 7b: From
5 (6.00 g, 23.6 mmol), styrene (12.3 g,
118 mmol), and AIBN (0.30 g, 1.83 mmol); yield: 13.2 g (72%) of
7b as a colorless solid.
Copolymer 7c: From
5 (3.03 g, 11.9 mmol), styrene (11.0 g,
106 mmol), and AIBN (0.20 g, 1.22 mmol); yield: 13.3 g (95%) of
7c as a colorless solid. Average molecular weight: 25625 g/mol, po-
lydispersity: 2.05.
4-Vinylbenzyl 2-Hydroxybenzoate (5): A suspension of sodium sal-
icylate (24.0 g, 0.15 mol), 4-vinylbenzyl chloride (3; 15.3 g, 0.10
mol), benzyltriethylammonium chloride (2.28 g, 0.01 mol) and so-
dium iodide (1.50 g, 0.01 mol) in 300 mL of THF was heated to
reflux for 16 h. After cooling to room temperature, 100 mL of brine
was added, and the organic layer was separated. The aqueous layer
was washed twice with ethyl acetate, the combined organic layers
were dried with MgSO4, and the solvent was removed in vacuo.
Crystallization of the crude product from cyclohexane furnished 5
(13.4 g, 53% yield) as slightly yellow crystals (m.p. 54 °C). 1H
NMR: δ ϭ 10.80 (s, 1 H, OH), 7.90 (d, J ϭ 8.0 Hz, 1 H), 7.53Ϫ7.37
(m, 5 H), 7.01 (d, J ϭ 8.3 Hz, 1 H), 6.88 (t, J ϭ 7.9 Hz, 1 H), 6.75
(dd, J ϭ 10.8, 17.6 Hz, 1 H, CHϭCH2), 5.80 (dd, J ϭ 0.8, 17.6 Hz,
1 H, CHϭCH2), 5.40 (s, 2 H, OCH2), 5.35 (dd, J ϭ 0.8, 10.8 Hz,
1 H, CHϭCH2) ppm. 13C NMR: δ ϭ 170.4 (ϫ, CϭO), 162.2 (ϫ,
C-OH), 138.3, 135.1 (2 ϫ), 136.6, 136.2, 130.4, 129.0, 126.9, 119.6,
118.0 (7 ϩ), 115.0 (Ϫ, CHϭCH2), 112.8 (ϫ), 67.1 (Ϫ, OCH2) ppm.
IR: ν˜ ϭ 3129, 1673, 1611, 1514, 1086 cmϪ1. MS: m/z (%) ϭ 254
(5) [Mϩ], 233 (45), 207 (5), 143 (33), 117 (100), 91 (15), 77 (6), 65
(13). HRMS: m/z: calcd. for C16H14O3: 254.0943; found 254.0948.
Copolymer 7d: From
5 (1.03 g, 4.05 mmol), styrene (6.30 g,
60.5 mmol), and AIBN (0.10 g, 0.61 mmol); yield: 5.60 g (76%) of
7d as a colorless solid. Average molecular weight: 24934 g/mol, po-
lydispersity: 1.76.
General Procedure for the Polymerization of 6: A solution of 6, the
appropriate amount of freshly distilled styrene, and AIBN in
100 mL of benzene was degassed by three freeze-pump-thaw cycles
and then heated under argon to 50 °C for 16 h. The mixture was
then cooled to room temperature and poured into 200 mL of pen-
tane. After 2 h standing at room temperature, the polymer was iso-
lated by removal of the supernatant liquid and dried in vacuo.
NMR spectroscopy revealed that the polymers were free of detect-
able amounts of monomer inclusions or solvent.
Homopolymer 8a: From 6 (12.6 g, 42.2 mmol) and AIBN (0.20 g,
1.22 mmol); yield: 8.60 g (68%) of 8a as a colorless solid.
Copolymer 8b: From
6 (2.97 g, 9.96 mmol), styrene (5.28 g,
50.7 mmol), and AIBN (0.23 g, 1.36 mmol); yield: 5.46 g (66%) of
8b as a colorless solid. Average molecular weight: 7288 g/mol, poly-
dispersity: 2.40.
Ethyl 5-(4-Vinylbenzyloxy)-2-hydroxybenzoate (6): A suspension of
ethyl 2,5-hydroxybenzoate (7.90 g, 43.4 mmol), 4-vinylbenzyl chlo-
ride (3; 10.0 g, 65.5 mmol), and K2CO3 (16.0 g, 116 mmol) in
100 mL of acetone was heated to reflux for 22 h. After cooling to
room temperature, the mixture was filtered, and the filtrate was
concentrated in vacuo. Column chromatography of the crude prod-
uct (cyclohexane/ethyl acetate, 20:1) afforded 6 (6.60 g, 51%) as col-
orless crystals (m.p. 78 °C). 1H NMR: δ ϭ 10.46 (s, 1 H, OH),
7.43Ϫ7.36 (m, 5 H), 7.12 (dd, J ϭ 3.0, 9.0 Hz, 1 H), 6.89 (d, J ϭ
9.0 Hz, 1 H), 6.71 (dd, J ϭ 10.8, 17.6 Hz, 1 H, CHϭCH2), 5.75 (d,
J ϭ 17.6 Hz, 1 H, CHϭCH2), 5.25 (d, J ϭ 10.8 Hz, 1 H, CHϭ
CH2), 4.99 (s, 2 H, CH2Ar), 4.38 (q, J ϭ 7.3 Hz, 2 H, CH2CH3),
1.40 (t, J ϭ 7.3 Hz, 3 H, CH2CH3) ppm. 13C NMR: δ ϭ 170.3 (ϫ,
CϭO), 156.7, 151.4, 146.9, 137.8 (4 ϫ), 136.8, 128.2, 126.8, 124.9,
118.9, 114.2 (6 ϩ), 114.6 (Ϫ, CHϭCH2), 112.6 (ϫ), 71.1 (Ϫ,
CH2Ar), 61.9 (Ϫ, CH2CH3), 14.6 (ϩ, CH2CH3) ppm. IR: ν˜ ϭ 3420,
3062, 2977, 2874, 1669, 1610, 1514, 1080 cmϪ1. MS: m/z (%) ϭ 298
(10) [Mϩ], 253 (5), 225 (4), 209 (4), 153 (5), 135 (8), 117 (100), 91
(18), 77 (3), 65 (7). HRMS: m/z: calcd. for C18H18O4: 298.1205;
found 298.1198.
Copolymer 8c: From
6 (3.00 g, 10.1 mmol), styrene (9.40 g,
90.3 mmol), and AIBN (0.20 g, 1.22 mmol); yield: 7.50 g (60%) of
8c as a colorless solid. Average molecular weight: 9387 g/mol, poly-
dispersity: 1.94.
Copolymer 8d: From
301 mmol), and AIBN (0.30 g, 1.83 mmol); yield: 27.7 g (74%) of
8d as a colorless solid.
6 (6.00 g, 20.1 mmol), styrene (31.4 g,
General Procedure for the Protonation of Chiral Enolates: A solu-
tion of 1.0 mmol of the silyl enol ether in 10 mL of THF was
treated at Ϫ50 °C with MeLi (0.63 mL, 1.0 mmol, 1.6  solution
in diethyl ether). The mixture was stirred for 1 h at Ϫ50 °C and
then cooled to Ϫ80 °C. It was added via Teflon tubing in five ali-
quots to precooled solutions (Ϫ80 °C) of five different polymeric
proton donors 7 or 8 (each containing 1.0 mmol of salicylate units)
in 80 mL of CH2Cl2. After 5 min at Ϫ80 °C, the samples were
warmed to room temperature, and each sample was treated with
ca. (50 mg, 0.8 mmol) of acetic acid in a small amount of CH2Cl2.
The sample was then concentrated in vacuo to a volume of ca.
30 mL, and 80 mL of pentane was added. The precipitate was al-
lowed to settle, and the supernatant liquid was removed. After an-
other concentration step, the diastereomeric ratio was determined
by GC. The remaining polymer was dissolved in 20 mL of CH2Cl2,
and the solution was washed with a satd. NaHCO3 solution and
water. After drying with MgSO4, the polymer was isolated by ad-
dition of 80 mL of pentane, removal of the supernatant liquid, and
General Procedure for the Polymerization of 5: A mixture of 5, the
appropriate amount of freshly distilled styrene, and AIBN was de-
gassed by three freeze-pump-thaw cycles and then heated under
argon to 80 °C for 16 h. After cooling to room temperature, the
resulting solid was dissolved in 20 mL of CH2Cl2, and the product
was precipitated by addition of 200 mL of pentane. After 2 h stand-
Eur. J. Org. Chem. 2004, 4531Ϫ4534
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M. Mackenstedt, N. Krause
FULL PAPER
drying in vacuo. The quality of the recovered polymer was checked
by NMR spectroscopy which showed it to be free of detectable
amounts of solvent or water.
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Acknowledgments
[4]
[5]
[6]
[7]
[8]
Generous support of this work by the Deutsche Forschungsgemein-
schaft and the Fonds der Chemischen Industrie is gratefully
acknowledged. We thank Prof. Dr. Rainer Haag (Dortmund Uni-
versity) for the molecular weight determination of polymers 7/8.
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Received June 18, 2004
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