Synthesis and preliminary studies on a novel class of soluble amino alcohol reagents based on methacrylate copolymers

Article abstract of DOI:10.1016/S0040-4020(03)00975-X

A class of soluble polymers containing chiral β-amino alcohol ligands, based on methacryate copolymers, are described. The use of copolymers permits the selective introduction of material to control the solubility and a functional group in a controllable ratio and polymer length. The application of the supported polymers to diethylzinc additions is described.

Full text of DOI:10.1016/S0040-4020(03)00975-X

Tetrahedron 59 (2003) 5823–5830
Synthesis and preliminary studies on a novel class of soluble amino
alcohol reagents based on methacrylate copolymers
Christopher W. Edwards,a David M. Haddleton,a David Morsley,a Mark R. Shiptonb
and Martin Willsa
,
*
aDepartment of Chemistry, University of Warwick, Gibbit Hill Road, Coventry CV4 7AL, UK
bGlaxoSmithKline Pharmaceuticals PLC, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK
Received 11 April 2003; revised 27 May 2003; accepted 19 June 2003
Abstract—A class of soluble polymers containing chiral b-amino alcohol ligands, based on methacryate copolymers, are described. The use
of copolymers permits the selective introduction of material to control the solubility and a functional group in a controllable ratio and
polymer length. The application of the supported polymers to diethylzinc additions is described.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
from the bulk reaction by a process such as precipitation, or by
filtration through a nanofiltration membrane.5 In principle this
alsoprovidesa meansbywhich thecatalysts mayberecovered
and reused. The attachment of a chiral ligand to a long
polyethylene glycol chain, for example, provides a means for
the separation of the catalyst from the reaction through
precipitation upon addition of ether.5a–d In other approaches,
functionalised dendrimers have been prepared in which
several ligand or catalyst molecules are attached to a single
high molecular-weight molecule.5e,f A nanofiltration mem-
brane may then be used to separate the products from the
catalyst at the end of the reaction. In this paper we describe the
synthesis and preliminary studies on a new class of polymer-
supported ligands for asymmetric catalysis, which also have
the potential for use in a membrane reactor.
Whilst homogeneous asymmetric catalysts benefit from a
well-defined catalyst structure which can, to some extent, be
predictably modified, they are often difficult to remove from
reaction mixtures after use.1 In cases where the catalyst
contains a toxic metal, this presents a particular challenge to
product purification. Heterogeneous asymmetric catalysts
offer complimentary benefits and drawbacks, i.e. the
catalyst is readily separable from the reagents and products,
however, the selective modification of the catalyst is highly
challenging.2 The benefits of both methods may, in
principle, be combined in an asymmetric homogeneous
catalyst which has been converted to heterogeneous
variant.3 Such a combination may be achieved, for example,
through the coupling of a catalyst or ligand to a solid support
such as polymer (typically polystyrene) beads or silica.
Although significant success has been achieved for a
number of reactions, including diethylzinc additions to
enones and asymmetric ketone reduction, a number of
drawbacks and challenges remain to be addressed.4 Most
notable of these are the access of reagents to the active site,
which is often limited by the permeability of the supports, as
well as the mechanical stability of the materials used. As a
result, reagents of this type are frequently of lower reactivity
than the free ligands or catalysts.
2. Results and discussion
In a project directed at the synthesis of a general class of
polymer support for use in asymmetric catalysis, we reasoned
that copolymers of methacrylates would represent an ideal
class of material for this application (Figure 1). By combining
two monomers in a known ratio in the presence of a chain
transfer agent, both the polymer weight and the ratio of
monomers can be controlled.6 A judicious choice of mono-
mers would permit the control of solubility whilst also
incorporating a positionfor attachment of a ligand or catalyst.7
An alternative approach to the ‘heterogenisation’ of homo-
geneous reagents istoconvert themto a highmolecularweight
form which is fully soluble and homogeneous, yet separable
For our initial studies into the synthesis of a functionalised
polymer, we investigated supported reagents for the
catalysis of diethylzinc additions to aldehydes, a valuable
asymmetric C–C bond-forming process which can be
catalysed by an enantiomerically pure b-amino alcohol,
Keywords: soluble polymers; asymmetric; catalyst; ligand; dialkylzinc.
*
Corresponding author. Tel.: þ44-24-7652-3260; fax: þ44-24-7652-4112;
e-mail: m.wills@warwick.ac.uk
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00975-X

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C. W. Edwards et al. / Tetrahedron 59 (2003) 5823–5830
with tosyl chloride and triethylamine, for example, resulted
in formation of the tosylated derivative 2, which could be
clearly characterised from the NMR spectrum (Figure 2).
The migration of the methylene peak adjacent to the
hydroxyl group to lower field following introduction of the
electron-withdrawing function serves to indicate that the
reaction has gone to completion. In the next step the reaction
of 2 with an excess of the sodium salt of p-bromophenol
resulted in clean substitution to give product 3. At each
stage the product was isolated by extractions in a sequence
typical for any organic compound, without the requirement
for specialised polymer isolation techniques.
Figure 1. Copolymers of methacrylates.
The attachment of a chiral ligand to polymer 3 was our next
objective. In order to achieve this we envisaged the use of a
palladium-mediated coupling process with the p-bromo-
benzyl derivative 4 of (2)-norephedrine 5, which was
prepared by the two-step route shown in Scheme 2.
such as a tertiary amine derivative of ephedrine.8,9 As a
polymer support, we examined the use of a copolymer of
methyl methacryate (MMA) and 2-hydroxyethyl methacry-
late (HEMA) (1). An established method was employed to
prepare quantities of a 7:3 copolymer of MMA/HEMA
using a cobalt-based chain transfer reagent (CoBF; ([bis[m-
[(2,3-butanedione dioximato)(2-)-O:O0]] tetraflurodibor-
ato(2-)-N,N0,N00,N000) to control the overall molecular weight
of the product.6
Our rationale for the choice of linker was to introduce a
separation between the ligand and the polymeric backbone,
thus permitting the former to act unhindered by the latter.
Following some experimentation (see below) we were able
to achieve the coupling process to give 6 in a yield of 54%.10
Removal of the TBS group from 6 was then completed in
80% yield, providing the required functionalised polymer 7
for use in catalytic reactions (Scheme 2).
Through the use of an appropriate amount of CoBF, it was
possible to form polymers with a molecular weight average of
ca. 5000 Da in large quantities (.100 g) in a reproducible
manner (Scheme 1). As well as using GPC to determine the
average molecular weight, the ready solubility of the polymer
in a variety oforganic solvents permitted a further directcheck
on its mass to be determined at each stage of the synthesis.
As was the case for previous intermediates, the compound
could be analysed by proton NMR spectroscopy and the
structureconfirmed(Figure 3 illustrates the 1H NMRspectrum
of 6). The attachment of the ephedrine to the polymer in 6 was
supported by the ratio of peaks in the 1H NMR (i.e. relative of
hydroxyethyl to ephedrine). In addition the spectrum of
polymer 6 exhibited a sharp contrast to a spectrum of a 1:1
mixture of 3 with 4. In the latter spectrum (Figure 4), the
ephedrine peaks are clearly quite sharp and well defined,
unlike the polymer-bound material in which the peaks are
broad, as would be predicted.
1
Figure 1 illustrates the H NMR spectrum of a sample of
polymer 1. The peaks for the methylene groups in the HEMA
unit are clearly visible, as are those for the methyl ester groups
in the MMA, thus permitting a direct measurement of the ratio
of monomers in the polymer to be determined. In addition,
since the terminal alkene group is clearly visible and
integratable on the 1H NMR spectrum, this provides a ‘double
check’ on the overall molecular weight average.
The capacity of the polymer for analysis by 1H NMR
spectroscopy also permits its subsequent functionalisation
to be followed closely the same technique. The reaction of 1
Our coupling step was developed through experimentation
directed at the synthesis of compounds 8 and 9 via
palladium-coupling with 4. These were formed in 38 and
40% yield respectively.
With polymer 7 in hand, we wished to examine its behaviour
towards the control of asymmetric reactions. The reaction
which we selected for this investigation was the addition of
diethylzinc to benzaldehyde, a reaction which is known to be
catalysed by b-amino alcohols, including derivatives of
ephedrine (Scheme 3). Although other polymer-supported
reagents have been reported for this application, including
those of ephedrine, these have focussed on the preparation and
use of alternative supported reagents.9
Scheme 1. Reagents and conditions: (i) cat. AIBN, sodium bis (2-
ethylhexyl)sulfosuccinate, 0.06 mol% CoBF, 4 h, rt.

C. W. Edwards et al. / Tetrahedron 59 (2003) 5823–5830
5825
Figure 2. 1H NMR spectra of polymers.
In our studies, we chose to investigate the non-polymer
supported reagents ephedrine 5, and the desilylated
derivative 10 of intermediate 4 to provide a baseline
comparison with the supported ligand (Table 1). The initial
studies proceeded as expected, with the tertiary amine 10
giving superior results over the secondary amine 5. The
ready solubility of 7 permitted the mol% loading with this
material to be calculated relatively easily (details are given
in Section 3).
As expected, the reaction of diethylzinc with benzaldehyde
clearly requires an amino alcohol additive for the reaction to
take place. Appropriate control reactions were carried out to
provide a baseline; significantly the N-benzylated ephedrine
derivative 10 (prepared by desilylation of 4 in 70% yield)
gave a product in high e.e. and yield after an overnight
reaction, the enantioselectivity being comparable to that
achieved with analogous reagents. Also, as predicted, the
(1R,2S) enantiomer of ephedrine, which was used through-
out, gave products of R configuration.9 Ephedrine (5) itself
was also effective but gave products with slightly lower
enantioselectivity.
Figure 3. 1H NMR of 7.
Scheme 2. Reagents and conditions: (i) TsCl, Et3N, DCM, DMAP, 2 days.
(ii) 4-bromophenol, NaH, THF, reflux, o/n. (iii) TBSCl, Imidazole, DMF,
reflux, 2 days 91%. (iv) pBrC6H4CH2Br, Et3N, THF, 2 days, 40%. (v) 4,
Pd(dppf)Cl2·DCM, THF, KOAc, bis (pinacolato)diboron, 808C, 2 h; then 3,
Na2CO3, Pd(dppf)Cl2, THF, 808C, o/n. (vi) TBAF, THF, 4 h, rt.
Scheme 3. Reagents and conditions: (i) Et2Zn, hexane/toluene, ligand 4, 5
or 7, see Table 1.

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C. W. Edwards et al. / Tetrahedron 59 (2003) 5823–5830
Table 1. Asymmetric catalysis of diethylzinc addition to benzaldehyde
The white cloudy reaction mixture was then heated at reflux
for 2 days. The resulting yellow coloured reaction mixture
was allowed to cool before diluting with diethyl ether
(100 mL) and washed with water (200 mL). The water layer
was extracted using diethyl ether (100 mL) and the
combined organic extracts were dried using magnesium
sulfate, filtered and concentrated in vacuo to give the crude
product as a yellow oil. The crude product was purified
using column chromatography (EtOAc/hexane gradient) to
give the pure product as a pale yellow oil (13.85 g, 91%
yield). The following experimental data was in accordance
with published data;12 dH (250 MHz, CDCl3) 7.52–7.44
(5H, m, Ar), 4.81 (1H, d, J¼4.9 Hz, CH), 2.91–2.84 (1H, m,
CH), 2.58 (3H, s, CH3), 1.22 (3H, d, J¼6.4 Hz, CH3), 1.10
(9H, s, CH3), 0.12 (6H, d, J¼6.5 Hz, CH3); dC (300 MHz,
CDCl3) 142.9 (ipso C), 128.0 (Ar), 127.2 (Ar), 126.8 (Ar),
77.4 (CH7 or CH), 61.6 (CH), 34.0 (CH3), 25.8 (CH3), 18.2
(C), 14.6 (CH3), 24.6 (CH3); m/z (CI) 280 (MHþ), 222
(MHþ2C(CH3)3), 91, 58; [a]2D2¼229 (c¼1, methanol), lit.
[a]2D2¼231 (c¼1, chloroform).12
Solvent
Ligand Mol (%) Yield (%) e.e. (%)
ligand
Notes
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Toluene
None
5
5
–
6
6
6
6
6
10
2
3
6
0
0
08C o/n
rt, o/n
rt, o/n
rt, o/n
08C, 4 h
rt, o/n
rt, o/n (þDCM)
rt, 30 h
rt, 30 h
rt, 30 h
76
91
74
72
95
94
20
36
85
23 (R)
69 (R)
67 (R)
80 (R)
82 (R)
81 (R)
nd
5
10
10
10
7
7
7
nd
70 (R)
3.1.2. (1R,2S)-2-(Bromobenzylmethylamino)-1-phenyl-
[(t-butyl-dimethylsilyl)oxy]-propane 4. (1R,2S)-(2)-2-
(Methyl-amino)-1-phenyl-[(t-butyldimethylsilyl)oxy]-pro-
pane, (12.40 g, 44.44 mmol) was dissolved in THF (50 mL).
Triethylamine (8.98 g, 12.37 mL, 88.88 mmol) was added
to the solution and stirred for 30 min. Bromobenzyl bromide
(13.33 g, 53.33 mmol) was added to the reaction mixture
and heated at reflux for 2 days. The resulting thick white
reaction mixture was allowed to cool before diluting with
EtOAc (200 mL). The reaction solution was then washed
with water (150 mL) and the water extracted with EtOAc
(100 mL). The combined organic extracts were dried using
magnesium sulfate, filtered and concentrated in vacuo to
give the crude product as a yellow oil. The crude product
was purified using column chromatography (EtOAc/hexane
gradient) to give the product 4 as a pale yellow oil (7.28 g,
40% yield). dH (250 MHz, CDCl3) 7.28–7.19 (7H, m, Ar),
6.73 (2H, d, J¼8.3 Hz, Ar), 4.54 (1H, d, J¼7.4 Hz, CH),
3.47 (1H, d, J¼13.9 Hz, CH2), 3.36 (1H, d, J¼13.9 Hz,
CH2), 2.82–2.72 (1H, m, CH), 2.18 (3H, s, CH3), 1.09 (3H,
d, J¼6.8 Hz, CH3), 0.83 (9H, s, CH3), 20.16 (6H, d,
J¼7.1 Hz, CH3); dC (300 MHz, CDCl3) 144.8 (ipso C),
139.3 (ipso C), 130.9 (Ar), 123.0 (Ar), 127.6 (Ar), 127.0
(Ar), 126.8 (Ar), 120.0 (ipso C), 77.4 (CH), 64.6 (CH), 58.3
(CH2), 37.2 (CH2), 25.8 (CH3), 18.1 (C), 9.1 (CH3), 24.4
(CH3), 25.0 (CH3); mmax (liquid film)/cm21 3088–2790
(CH stretch), 1947–1800, 1591, 1480–1450 (asymmetric
CH bend), 1361 (symmetric CH bend), 1257, 1069, 1011;
m/z (CI) 450 (MHþBr81), 448 (MHþBr79), 370 (MHþ2Br),
318 (MHþBr812OTBS), 316 (MHþBr792OTBS), 280
(MHþ2C7H6Br), 228 (C10H13Br81N), 226 (C10H13Br79N),
108, 83, 58; HRMS found [MþH]þ 448.1671, requires
448.1671; [a]2D2¼þ2 (c¼1, methanol).
1
Figure 4. H NMR of 4/polymer.
Use of the polymer was hindered by solubility problems
when used in hexane. Although alcohol product was
formed, the yield was low and the product essentially
racemic, suggesting that the ligand is unable to interact
effectively with the zinc reagent. The problem was less
acute in toluene solvent, where an 85% yield of product was
obtained in 30 h. The e.e. was low, however, at 70%. There
is clearly still room for catalyst improvement, however, the
later result does serve to underline the potential of this class
of supported reagent in asymmetric catalysis.
In conclusion, in this paper we have described the successful
synthesis of a novel type of supported ligand based on
poly(methylmethacrylate) copolymers which may, in prin-
ciple, be tuned for particular applications. Although the
actual supported catalyst prepared in this paper is not
optimal for the subject application, the results demonstrate
the principle of the approach and in particular the ease of
solubility and analysis of the products. Work is currently in
progress towards the development of these reagents to
specific applications.
3. Experimental
3.1. General
3.1.3. (1R,2S)-2-(Bromobenzylmethylamino)-1-phenyl-
1-propanol 10. TBAF (0.85 g, 2.68 mmol) was added to a
solution consisting of (1R,2S)-2-(bromobenzylmethyl-
General experimental conditions have been described in a
previous publication.11
amino)-1-phenyl-[(t-butyldimethylsilyl)oxy]-propane,
4,
3.1.1. (1R,2S)-(2)-2-(Methylamino)-1-phenyl-[(t-butyl-
dimethyl-silyl)oxy]-propane. t-Butyldimethylsilyl chlor-
ide (9.85 g, 65.36 mmol) and imidazole (9.27 g,
136.17 mmol) were added to a solution of (1R,2S)-(2)-
ephedrine (9.0 g, 54.47 mmol) dissolved in DMF (40 mL).
(0.60 g, 1.34 mmol) dissolved in THF (20 mL). The
reaction mixture was allowed to stir at room temperature
overnight. The yellow reaction mixture was diluted with
EtOAc (150 mL) and washed with water (200 mL). The

C. W. Edwards et al. / Tetrahedron 59 (2003) 5823–5830
5827
water layer was extracted using EtOAc (100 mL) and the
combined organic extracts were dried using magnesium
sulfate, filtered and concentrated in vacuo to give the crude
product as a yellow oil. The crude product was purified by
column chromatography (EtOAc/hexane gradient) to give
the pure product 10 as a white solid (0.31 g, 70% yield), mp
55–568C; dH (250 MHz, CDCl3) 7.41–7.24 (7H, m, Ar),
7.06 (2H, d, J¼8.5 Hz, Ar), 4.84 (1H, d, J¼5.2 Hz, CH),
3.54 (2H, s, CH2), 2.96–2.86 (1H, m, CH), 2.17 (3H, s,
CH3), 0.99 (3H, d, J¼6.7 Hz, CH3); dC (300 MHz, CDCl3)
142.6 (ipso C), 138.6 (ipso C), 131.3 (Ar), 130.2 (Ar), 128.1
(Ar), 127.1 (Ar), 126.2 (Ar), 120.6 (ipso C), 74.0 (CH), 63.5
(CH), 58.4 (CH2), 38.5 (CH3), 9.8 (CH3); mmax (nujol)/cm21
3178 (OH stretch), 2000–1700, 1248, 1120, 1068; m/z (CI)
336 (MHþBr81), 334 (MHþBr79), 318 (MHþBr812H2O),
316 (MHþBr792H2O), 256 (MHþ2Br), 228 (MHþBr812
C7H8O), 226 (MHþBr792C7H8O), 202, 200, 178, 148, 122,
108 (C7H8O); HRMS found [MþH]þ 333.0745, requires
333.0728; [a]2D2¼235 (c¼0.6, methanol).
d, J¼13.9 Hz, CH2), 2.86–2.77 (1H, m, CH), 2.14 (3H, s,
CH3), 1.09 (3H, d, J¼6.6 Hz, CH3), 0.82 (9H, s, CH3),
20.17 (6H, d, CH3); dC (300 MHz, CDCl3) 158.9 (ipso C),
144.9 (ipso C), 138.9 (ipso C), 138.7 (ipso C), 133.7 (ipso
C), 128.7 (Ar), 128.0 (Ar), 127.5 (Ar), 127.0 (Ar), 126.7
(Ar), 126.2 (Ar), 114.1 (Ar), 77.3 (CH), 64.6 (CH), 58.5
(CH120), 55.3 (OMe), 37.4 (CH3), 25.8 (CH3), 18.1 (C), 9.0
(CH3), 24.4 (CH3); mmax (liquid film)/cm21 3028–2855
(CH stretch), 2054–1700, 1610, 1490–1463 (asymmetric
CH bend), 1377 (symmetric CH bend), 1248, 1180, 1062;
m/z (CI) 476 (MHþ), 280, 254, 197; HRMS found [MþH]þ
476.2973, requires 476.2984; [a]2D2¼þ9 (c¼0.4, chloro-
form).
3.1.5. (1R,2S)-2-(40-Phenylbenzylmethylamino)-1-phe-
nyl-[(t-butyldimethyl silyl)oxy]-propane 9. (1R,2S)-2-
(Bromobenzylmethylamino)-1-phenyl-[(t-butyldimethyl-
silyl)oxy]-propane, 4, (0.88 g, 1.79 mmol), phenylboronic
acid (0.54 g, 4.46 mmol), tetrabutylammonium bromide
(0.60 g, 1.79 mmol) and palladium diacetate (0.02 g,
0.09 mmol) were added to a solution of potassium carbonate
(0.62 g, 4.46 mmol) dissolved in water (20 mL). The
resulting reaction mixture was then heated at reflux for
2 h. The resulting black reaction mixture was allowed to
cool before extracting with EtOAc (250 mL). The organic
layer was dried using magnesium sulfate, filtered and
concentrated in vacuo to give the crude product as a yellow
oil. The crude product was purified by Kugelrohr distillation
(0.5 torr, ,2008C) to give the product 9 as a clear oil,
(0.35 g, 40% yield); dH (250 MHz, CDCl3) 7.51 (2H, d,
J¼7.0 Hz, Ar), 7.36–7.33 (4H, m, Ar), 7.28–7.19 (6H, m,
Ar), 6.97–6.94 (2H, d, J¼8.3 Hz, Ar), 4.58 (1H, d,
J¼7.2 Hz, CH), 3.57 (1H, d, J¼13.8 Hz, CH2), 3.46 (1H,
d, J¼14.3 Hz, CH2), 2.86–2.77 (1H, m, CH), 2.15 (3H, s,
CH3), 1.10 (3H, d, J¼6.6 Hz, CH3), 0.82 (9H, s, CH3),
20.15 (6H, d, J¼7.2 Hz, CH3); dC (300 MHz, CDCl3) 144.9
(ipso C), 141.1 (ipso C), 139.4 (ipso C), 139.3 (ipso C),
128.7 (Ar), 128.6 (Ar), 127.5 (Ar), 127.0 (Ar), 126.7 (Ar),
126.6 (Ar), 77.3 (CH7 or CH8), 64.6 (CH), 58.5 (CH2), 37.4
(CH3), 25.8 (CH3), 18.1 (C), 9.0 (CH3), 24.4 (CH3); mmax
(liquid film)/cm21 3060–2856 (CH stretch), 2000–1670,
1600, 1488–1452 (asymmetric CH bend), 1361 (symmetric
bend), 1257, 1061; m/z (CI) 446 (MHþ), 314 (MHþ2
OTBS), 280, 224, 198, 167; HRMS found [MþH]þ
446.2886, requires 446.2880; [a]2D2¼þ14 (c¼0.2, chloro-
form).
3.1.4. (1R,2S)-2-(40-Anisylbenzylmethylamino)-1-phe-
nyl-[(t-butyldimethylsilyl)oxy]-propane 8. Method 1.
(1R,2S)-2-(Bromobenzylmethylamino)-1-phenyl-[(t-butyl-
dimethyl-silyl)oxy]-propane, 4, (0.14 g, 0.33 mmol), meth-
oxybenzeneboronic
acid
(0.13 g,
0.83 mmol),
tetrabutylammonium bromide (0.11 g, 0.33 mmol) and
palladium diacetate (0.004 g, 0.02 mmol) were added to a
solution of potassium carbonate (0.11 g, 0.83 mmol)
dissolved in water (5 mL). The reaction mixture was heated
at reflux for 90 min.13 The resulting black reaction mixture
was allowed to cool before extracting with EtOAc
(250 mL). The organic layer was dried using magnesium
sulfate, filtered and concentrated in vacuo to give the crude
product as a yellow oil. The crude product was purified by
column chromatography (EtOAc/hexane gradient) to give
the pure product 8 as a pale yellow oil, (0.06 g, 38% yield).
Experimental data can be found at the end of Method 2.
Method 2. (1R,2S)-2-(Bromobenzylmethylamino)-1-phe-
nyl-[(t-butyldimethylsilyl)oxy]-propane, 4, (0.10 g,
0.24 mmol) was dissolved in DMF (5 mL). To the stirred
solution of ephedrine derivative was added dichloro[1,1-bis-
diphenylphosphinoferrocene]-palladium(II)·DCM (0.005 g,
0.007 mmol), bis(pinacolato)diboron (0.07 g, 0.27 mmol)
and potassium acetate (0.07 g, 0.73 mmol).14 The orange
reaction mixture was heated at 808C for 2 h. The resulting
black reaction mixture was allowed to cool before the
addition of bromoanisole (0.09 g, 0.06 mL, 0.48 mmol),
dichloro[1,1-bisdiphenylphosphino-ferrocene]palladiu-
m(II)·DCM (0.005 g, 0.007 mmol) and sodium carbonate
(2 M, 5 mL, 0.66 g). The reaction mixture was then reheated
at 808C overnight.14 The black reaction mixture was
allowed to cool before extracting the product with diethyl
ether (150 mL). The organic layer was then washed with
water (100 mL) and a brine solution (100 mL). The organic
layer was then dried using magnesium sulfate, filtered and
concentrated in vacuo to give the crude product as a yellow
oil. This was purified by column chromatography (EtOAc/
hexane gradient) to give the pure product 8 as a pale yellow
oil, (0.06 g, 48% yield); dH (250 MHz, CDCl3) 7.44 (2H, d,
J¼8.7 Hz, Ar), 7.30 (2H, d, J¼8.1 Hz, Ar), 7.24–7.16 (5H,
m, Ar), 6.95–6.89 (4H, m, Ar), 4.58 (1H, d, J¼7.0 Hz, CH),
3.78 (3H, s, CH3), 3.55 (1H, d, J¼13.8 Hz, CH2), 3.45 (1H,
3.1.6. HEMA/MMA soluble copolymer 1.6 Sodium bis(2-
ethylhexyl) sulphosuccinate (2.0 g) was added to a 1 L
flange flask glass reactor under a nitrogen atmosphere.
Water (450 mL) was added to the reactor, heated to 808C
and stirred using a turbine impeller at 150 rpm. 4,40-Azo-
bis(4-cyanovaleric acid) (2.0 g) was added to the reaction
mixture immediately prior to the monomer/catalyst feed. A
solution of catalytic chain transfer agent (CoBF) (0.024 g,
6.2£1025 mol) in MMA (114 mL, 1.07 mol)) and HEMA
(65 mL, 0.46 Mol) was fed from a Schlenk tube via a FMI
pump set at a rate of 3.33 mL min21. The polymerisation
was left for 4 h at which time 100% conversion was reached.
The solvent was removed from the polymer using an oven
set at 1508C to give the polymer 1 as a yellow solid which
when ground appeared as a white powder (70.0 g, 42%). dH
(250 MHz, CDCl3) 6.18 (m, CH), 5.55 (m, CH), 4.12 (bs,

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C. W. Edwards et al. / Tetrahedron 59 (2003) 5823–5830
CH2), 3.85 (bs, CH2), 3.61 (bs, CH30 ), 2.01 (bs, CH2), 0.99
(bs, CH3); dC (300 MHz, CDCl3) 178.0 (CvO), 176.8
(CvO), 66.7 (CH2), 60.2 (CH2), 54.2 (C), 51.7 (CH3), 44.7
(CH2), 44.4 (CH2), 18.4 (CH3), 16.5 (CH3); mmax (nujol)/
cm21 3434 (OH stretch), 1727 (CvO stretch), 1277, 1152,
1075; m/z (GPC) Mn¼2940, PDi¼1.78; Tg¼598C (inflection
point), 498C (onset), heated from 0 to 1608C at 208C/min.
3.1.9. Suzuki coupling between bromophenyl derivatised
HEMA/MMA 3 and bromoanisole to give 40-methoxy-
biphenyl functionalised HEMA/MMA copolymer. This
was carried out in order test the coupling process.
Bromophenyl functionalised HEMA/MMA copolymer, 3,
(0.40 g, 0.1 mmol), palladium diacetate (0.015 g,
0.039 mmol), tetrabutylammonium bromide (0.25 g,
0.79 mmol) and methoxybenzeneboronic acid (0.30 g,
1.97 mmol) were added to a solution of potassium carbonate
(0.27 g, 1.97 mmol) dissolved in water (10 mL). The
reaction mixture was heated at 1008C for 90 min.13 The
black reaction mixture was allowed to cool before
extraction with EtOAc (200 mL). The organic layer was
dried using magnesium sulfate, filtered and concentrated in
vacuo to give the crude product as a black solid. This was
purified by the addition of methanol (2£100 mL) in which
the product was stirred vigorously. The methanol was
carefully removed to leave the pure product as a black solid
(0.24 g, 57% yield); dH (250 MHz, CDCl3) 7.47 (bs, Ar),
6.96 (bs, Ar), 6.19 (bs, CH2), 5.47 (bs, CH2), 4.31 (bs, CH2),
4.19 (bs, CH2), 3.84 (bs, CH3), 3.59 (bs, CH3), 1.89–1.81
(bs, CH2), 0.84 (bs, CH3); dC (300 MHz, CDCl3) 177.8
(CvO), 176.9 (CvO), 158.7 (ipso C), 157.4 (ipso C), 133.8
(ipso C), 133.2 (ipso C), 132.3, 127.7, 116.4, 114.8, 114.2,
65.4 (CH2), 63.4 (CH2), 55.3 (MeO), 54.4 (C), 51.8 (MeO),
44.8 (CH2), 44.5 (CH2), 18.7 (CH3), 16.4 (CH3); mmax (solid
state)/cm21 2948 (CH stretch), 1723 (CvO stretch), 1606,
1541, 1456, 1240, 1144, 822; m/z (GPC) refractive index
detector Mn¼7016, PDi¼1.64; UV detector Mn¼5476,
PDi¼1.72; Tg¼698C (inflection point), 618C (onset), heated
from 0 to 1608C at 208C/min.
3.1.7. Tosylated HEMA/MMA soluble copolymer 2.
Triethylamine (4.85 g, 6.68 mL, 48 mmol) was added to
HEMA/MMA copolymer, 1, (10.0 g, 3.4 mmol) which was
dissolved in DCM (70 mL). Tosyl chloride (9.17 g,
48 mmol) and DMAP (0.50 g, catalytic) were added to the
reaction mixture and the reaction was allowed to stir for 2
days. The orange/red solution was concentrated in vacuo to
give a yellow solid. The yellow solid was transferred to a
sinter funnel and washed with diethyl ether (200 mL) and
hexane (100 mL). The pale yellow solid was redissolved in
DCM (100 mL) and washed with water (300 mL), dried
using magnesium sulfate and concentrated in vacuo to give
a pale yellow solid. This was ground using a pestle/mortar
and transferred to a sinter funnel and washed further with
diethyl ether (200 mL), methanol (200 mL), hexane
(100 mL) to give the product 2 as a white powder
(10.60 g, 78% yield); dH (250 MHz, CDCl3) 7.81 (bs, Ar),
7.39 (br d, J¼14.0 Hz, Ar), 6.21 (bs, CH2), 5.47 (bs, CH2),
4.22 (bs, CH2), 4.15 (bs, CH2), 3.60 (bs, CH3), 2.47 (bs,
CH3), 1.86 (bs, CH2), 0.99 (bs, CH3); dC (300 MHz, CDCl3)
177.8 (CvO), 176.9 (CvO), 145.1 (ipso C), 132.8 (ipso C),
130.0 (Ar), 127.9 (Ar), 62.2 (CH2), 62.0 (CH2), 54.2 (C),
51.8 (CH3), 44.9 (CH2), 44.5 (CH2), 21.7 (CH3), 18.7 (CH3),
16.7 (CH3); mmax (nujol)/cm21 1730 (CvO), 1598, 1275,
1244, 1177, 1150, 923, 815, 748; m/z (GPC) Mn¼4116,
PDi¼1.56; Tg¼518C (inflection point), 408C (onset), heated
from 0 to 1608C at 208C/min.
3.1.10. Suzuki coupling between bromophenyl deriva-
tised HEMA/MMA 3 and (1R,2S)-2-(bromobenzyl-
methyl-amino)-1-phenyl-[(t-butyldimethylsilyl)oxy]-
propane. (1R,2S)-2-(bromobenzylmethylamino)-1-phenyl-
[(t-butyldimethylsilyl)oxy]-propane, 4, (0.20 g, 0.45 mmol)
and dichloro[1,1-bisdiphenylphosphino ferrocene]-palla-
dium(II)·DCM (0.01 g, 0.013 mmol) were dissolved in
THF (10 mL). Potassium acetate (0.13 g, 1.34 mmol) and
bis(pinacolato)diboron (0.12 g, 0.49 mmol) were added to the
reaction mixture which was heated at 808C for 2 h. The black
coloured reaction mixture was allowed to cool before the
addition of bromo derivatised HEMA/MMA copolymer, 3,
(0.30 g, 0.08 mmol), sodium carbonate solution (2 M, 0.53 g,
2.5 mL, 2.24 mmol) and dichloro[1,1-bisdiphenylphosphino-
ferrocene]-palladium(II)·DCM (0.01 g, 0.013 mmol). The
reaction mixture was then heated at 808C overnight.14 The
black reaction mixture was allowed to cool before being
concentratedinvacuo togivethecrudeproduct asa black/grey
solid. This was redissolved in EtOAc (200 mL) and washed
with water (100 mL). The organic layer was dried using
magnesium sulfate, filtered and concentrated in vacuo to give
the crude product as a black oil. Methanol (2£50 mL) was
added to the crude product and stirred vigorously. The
methanol extract was then carefully removed to leave the
purified product 6 as a black solid (0.24 g, 54% yield); dH
(250 MHz, CDCl3) 7.48–6.98 (bs, Ar), 6.16 (bs, CH2), 4.64
(bs, CH), 4.32 (bs, CH2), 4.20 (bs, CH2), 3.58 (bs, OMe), 2.87
(bs, CH), 2.17 (bs, CH3), 1.86 (bs, CH2), 1.13 (bs, CH3), 1.03
(bs, CH3), 0.87 (bs, CH3), 20.13 (bs, d, CH3); dC (300 MHz,
CDCl3) 177.7 (CvO), 176.9 (CvO), 157.8 (ipso C), 157.7
(ipso C), 144.9 (ipso C), 138.8 (ipso C), 134.0 (ipso C), 128.7,
3.1.8. Synthesis of bromophenyl derivatised
HEMA/MMA soluble copolymer 3. Sodium hydride
(0.45 g, 18.79 mmol) was added to THF (30 mL) and
allowed to stir for 20 min before the addition of bromo-
phenol (1.63 g, 9.39 mmol). Tosylated HEMA/MMA copo-
lymer, 2, (1.60 g, 0.40 mmol) was added to the reaction
mixture and the reaction allowed to reflux for 48 h. The
reaction mixture was allowed to cool before filtering
through a sinter funnel and the filtrate concentrated in
vacuo to give a pale brown solid. The pale brown solid was
redissolved in EtOAc (100 mL) and washed with water
(100 mL). The organic layer was dried using magnesium
sulfate and concentrated in vacuo to give the crude product
as a brown solid. This was triturated using diethyl ether
(60 mL) to give the product 3 as a pale brown solid (0.95 g,
60% yield); dH (250 MHz, CDCl3) 7.34 (bs, Ar), 6.82 (bs,
Ar), 4.29 (bs, CH2), 4.12 (bs, CH2), 3.59 (bs, CH3), 1.90–
1.82 (bs, CH2), 1.18 (bs, CH3), 1.03 (bs, CH3); dC
(300 MHz, CDCl3) 177.7 (CvO), 176.4 (CvO), 157.4
(ipso C), 132.2 (Ar), 117.2, 116.3, 113.2 (ipso C), 65.5
(CH2), 63.1 (CH2), 54.3 (C), 51.7 (CH3), 44.8 (CH2), 44.4
(CH2), 18.6 (CH3), 16.3 (CH3); mmax (nujol)/cm21 2400–
1800, 1729 (CvO stretch), 1591, 1489, 1273, 1245, 1150,
1066, 824; m/z (GPC) refractive index detector Mn¼5192,
PDi¼1.36; UV detector Mn¼4205, PDi¼1.48; Tg¼768C
(inflection point), 638C (onset), heated from 0 to 1608C at
208C/min.

C. W. Edwards et al. / Tetrahedron 59 (2003) 5823–5830
5829
128.0, 127.5, 126.9, 126.7, 126.2, 114.8, 65.3 (CH2), 64.7
(CH), 63.4 (CH2), 58.5 (CH2), 54.4 (C), 51.8 (MeO), 44.7
(CH2), 37.4 (CH3), 25.8 (CH3), 18.6 (CH3), 18.1 (C), 16.4
(CH3), 9.1 (CH3), 24.7 (CH3); mmax (solid state)/cm21 2949
(CH stretch), 1729 (CvO stretch), 1608, 1497, 1456, 1242,
1145, 1060, 832; Tg¼1078C (inflection point), 998C (onset),
heated from 0 to 1608C at 208C/min; m/z (GPC) sample
insoluble in solvent system.
CDCl3) 145.0 (ipso C6), 128.8 (CH), 127.9 (CH), 126.4
(CH), 76.4 (CH), 32.3 (CH2), 10.6 (CH3); m/z (EI) 136
(Mþ), 107 (Mþ2C2H5), 91, 77, 59; [a]2D2¼þ47 (c¼0.7,
chloroform) which corresponds to an e.e. of 82%, lit.
[a]2D2¼245 (S-isomer, c¼5, chloroform).9a HPLC con-
ditions, eluent: 5% EtOH/hexaneþ0.1%Et2NH; wave-
length, 254 nm; flow rate, 0.5 mL min21; retention times,
tR for major peak¼13.14, tR for minor peak¼14.89. A
racemic sample of product supplied by Aldrich was used as
a reference.
3.1.11. Removal of the TBS group from the
HEMA/MMA supported chiral ephedrine derivative.
HEMA/MMA supported TBS protected chiral ephedrine 6,
(0.10 g, 0.02 mmol) was dissolved in THF (6 mL) before
the addition of tetrabutylammonium fluoride (0.35 g,
1.10 mmol). The reaction mixture was allowed to stir for
4 h at room temperature. The black reaction mixture was
concentrated in vacuo to give the crude product as a black
solid. The crude product was redissolved in EtOAc
(150 mL) and washed with water (100 mL). The organic
layer was dried using magnesium sulfate, filtered and
concentrated in vacuo to give the crude product as a black
solid. Methanol (2£50 mL) was added to the crude product
and vigorously stirred. The methanol extract was then
carefully removed from the sample to leave the pure product
7 as a black solid (0.07 g, 80% yield); dH (250 MHz, CDCl3)
7.48–6.96 (bs, Ar), 4.90 (bs, CH), 4.31 (bs, CH72), 4.20 (bs,
CH2), 3.58 (bs, MeO), 2.95 (bs, CH), 2.22 (bs, CH3), 1.85
(bs, CH2), 1.00–0.84 (bs, CH3); dC (300 MHz, CDCl3)
177.7 (CvO), 176.9 (CvO), 158.8 (ipso C), 157.4 (ipso C),
144.9 (ipso C), 138.8 (ipso C), 134.1 (ipso C), 128.7, 128.0,
127.6, 127.0, 126.7, 126.2, 114.8, 64.7 (CH2), 63.2 (bs, CH),
63.0 (bs, CH2), 58.5 (bs, CH2), 54.3 (bs, C), 51.8 (bs, MeO),
44.5 (bs, CH2), 37.8 (bs, CH3), 18.1 (bs, CH3), 16.5 (bs,
CH3), 9.1 (bs, CH3); mmax (solid state)/cm21 3568 (OH
stretch), 2948 (CH stretch), 1725 (CvO stretch), 1607,
1496, 1454, 1240, 1144, 1061, 821; m/z (GPC) refractive
index detector Mn¼6753, PDi¼1.69; UV detector
Mn¼5155, PDi¼1.79; Tg¼1178C (inflection point), 1128C
(onset), heated from 0 to 1608C at 208C/min.
Acknowledgements
We thank the EPSRC and GlaxoSmithKline for CASE
funding of this project (to C. W. E.) and Professor D. Games
and Dr B. Stein of the EPSRC National Mass Spectroscopic
service (Swansea) for HRMS analysis of certain com-
pounds. We wish to acknowledge the use of the EPSRC’s
Chemical Database Service at Daresbury.15
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