Improving resins for solid phase synthesis: Incorporation of 1-[2-(2-methoxyethoxy)ethoxy]-4-vinyl-benzene

Article abstract of DOI:10.1016/S0040-4020(03)01100-1

The preparation, characterisation and application of a series of non-grafted polystyrene (PS) resins containing a styrenic methoxypoly(ethylene glycol) (MPEG) derivative is presented. These novel PS-MPEG resins were designed to balance swelling and solvation with improved handling. The monomer, 1-[2-(2-methoxyethoxy)ethoxy]-4-vinyl-benzene, contained an inert phenyl ether linkage designed to provide broad chemical compatibility and stability, yet imparting all the favourable properties of the PEG group into the new resin, whilst maintaining a high loading capacity. The synthetic performance of the new resins compared very favourably to those of TentaGel, ArgoGel and aminomethyl PS.

Full text of DOI:10.1016/S0040-4020(03)01100-1

Tetrahedron 59 (2003) 7163–7169
Improving resins for solid phase synthesis: incorporation
of 1-[2-(2-methoxyethoxy)ethoxy]-4-vinyl-benzene
Sonia M. Alesso,a Zhanru Yu,a David Pears,b Paul A. Worthington,c Richard W. A. Luked
and Mark Bradleya
,
*
aDepartment of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
bAvecia, P.O. Box 42, Hexagon House, Blackley, Manchester M9 8ZS, UK
cSyngenta, Jealott’s Hill Research Station, Bracknell, Berkshire RG42 6EY, UK
dAstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
Received 29 July 2002; revised 23 June 2003; accepted 10 July 2003
Abstract—The preparation, characterisation and application of a series of non-grafted polystyrene (PS) resins containing a styrenic
methoxypoly(ethylene glycol) (MPEG) derivative is presented. These novel PS-MPEG resins were designed to balance swelling and
solvation with improved handling. The monomer, 1-[2-(2-methoxyethoxy)ethoxy]-4-vinyl-benzene, contained an inert phenyl ether linkage
designed to provide broad chemical compatibility and stability, yet imparting all the favourable properties of the PEG group into the new
resin, whilst maintaining a high loading capacity. The synthetic performance of the new resins compared very favourably to those of
TentaGele, ArgoGele and aminomethyl PS.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
of this resin type is the inherently low resin substitution due
to the mass of the PEG attached to the beads reducing the
substitution of the initial resin loading significantly, while
the degree of swelling is also often too large to be useful for
solid phase organic synthesis. There are also potential
problems with the long PEG chain complexing Lewis acids
as well as problems of PEG leakage following cleavage and
the not inconsiderable cost of the grafted PS-PEG supports.
An alternative approach to post polymerisation grafting is
inclusion of vinyl-functionalised PEG or tetrahydrofuran10
monomers in the copolymer formulation. One important
class are the gel-type polystyrenes which have been lightly
cross-linked by PEG derivatives (Fig. 1) introduced by
Itsuno,11 Pillai,12 Meldal13,14 and Kurth,15 amongst others
allowing tailoring of resin swelling. The advantage of
co-polymerisation of PEG derivatives in suspension
polymerisation is that it should afford highly predictable
Since Merrifield’s pioneering work1 on peptide synthesis,
considerable efforts have been directed towards the
development of new supports for solid phase synthesis
with differing compositions and properties, ranging from
novel beads to new methods of bead encapsulation and
handling.2–4
Polystyrene (PS)-based resins are currently the most widely
used supports in solid phase synthesis.5,6 However, such
resins suffer from an incompatibility with polar solvents
which induces restricted swelling and as a consequence
permits only limited accessibility of reagents into the
beads.7 One method of manipulating the hydrophobic nature
of PS is to graft a hydrophilic poly(ethylene glycol) (PEG)
moiety onto the polymer backbone, and hence generate a
highly solvatable environment.8 TentaGele is a well-
known example of this type of material, in which a PS
resin has been derivatised with ethylene oxide to give a long
PEG chain grafted to the PS resin, such that approximately
75% of the resin by mass is PEG.9 The resin’s compatibility
with polar solvents and the high quality H and 13C NMR
1
spectra that can be obtained on these bead types are
important advantages. However, one significant drawback
Keywords: styrenic methoxypoly(ethylene glycol) (MPEG); monomer;
resins; solid supports; solid phase synthesis.
*
Corresponding author. Tel.: þ44-2380593598; fax: þ44-2380596766;
e-mail: mb14@soton.ac.uk
Figure 1. Several PEG derivative cross-linkers.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01100-1

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S. M. Alesso et al. / Tetrahedron 59 (2003) 7163–7169
and reproducible loadings as long as issues such as relative
reaction coefficients and water partitioning are taken into
account. The physical properties of the resulting resin
network are influenced by the nature of the cross-link
junction, the PEG length and the percentage of the
incorporated monomer.16,17 These resins swell, for
example, dramatically in non polar solvents since they are
still predominantly hydrophobic in nature, although the
cross-linker is highly polar. A major problem faced with
many supports is their excessive swelling which compli-
cates resin handling and synthesis due to the large volumes
of solvent needed for washing and the large volumes of
reagents needed to promote efficient synthesis. Another
drawback with these resins is that they often contain
chemically labile benzylic ether linkages.
Figure 2. PS-MPEG Resin beads (125–250 mm) with 7% monomer (1) and
2% DVB in DMF.
2.2. Preparation of the PS-MPEG resin beads
The resins were obtained by suspension copolymerisa-
tion19–21 using a multi-parallel polymerisation reactor
designed in our laboratories,22 and gave good quality
beaded materials as shown in Figure 2. Various mole
fractions (from 5 to 43%) of the monomer (1) were
incorporated into the resin beads along with styrene, 4-vinyl
benzylchloride (to give a loading of 1 mmol/g) and
divinylbenzene (tech. grade, 80%) (from 2 to 8%), and a
selection of the resins made is given in Table 1.
Here we now report on the preparation, characterisation
and application of a series of new, non-grafted PS-
MPEG resins, containing the styrene MPEG derivative
(1) (Scheme 1) in which solvent compatibility and
improved reaction kinetics were engineered into the
supports without the need for excessive solvent swelling
character.
2.3. Resin properties
Swelling studies and reactions on the resins were performed
and compared with three commonly used supports of the
same bead size (125–250 mm): 2% cross-linked amino-
methyl polystyrene (made in-house, 1 mmol/g), TentaGele
(0.25 mmol/g) and ArgoGele (0.35 mmol/g) resins. The
swelling profiles of the resins are given in Table 2. Resin
swelling was found to be broadly dependent on the
percentage of the PEG monomer (1) incorporated with a
7% level of incorporation observed to impart comparable
swelling to TentaGele resin. The chemical and physical
stability of these PS-MPEG copolymers was observed to be
very good. Thus when the resins were treated for 12 h at
room temperature with a variety of acids (TFA, 6M HCl),
bases (piperidine, 2M NaOH), the beads were stable
(chemically and physically) with no PEG fragments being
observed by MS. The resins were robust toward mechanical
shaking and gentle magnetic stirring over a 24-hour period.
Scheme 1. (i) TsCl (1.5 equiv.), NEt3 (1.5 equiv.), DMAP (cat.), DCM, 08C
to ambient temperature, 24 h; (ii) Amberlite IRA 96 (Scavenging)
(3 equiv.), ambient temperature, overnight; (iii) p-hydroxy-acetophenone
(1.2 equiv.), K2CO3 (1.2 equiv.), CH3CN, reflux, 24 h; (iv) NaBH4
(1 equiv.), THF/EtOH 1:1, ambient temperature, 3 h; (v) Pyridinium
tosylate (cat.), toluene, reflux, overnight.
2.4. Resin based synthesis
The novel PS-MPEG resins were used as solid supports for a
range of chemistries including, peptide synthesis, Suzuki23
coupling, Mitsunobu24 condensations and reduction in
methanol as shown in Scheme 2. Thus the chloromethyl
resins were converted into the corresponding aminomethyl-
ated materials25 to give loadings26 ranging from 0.63 to
2. Results and discussion
2.1. Preparation of the monomer (1)
Monomer (1), 1-[2-(2-methoxyethoxy)ethoxy]-4-vinyl-
benzene, was prepared on a large-scale (up to 500 g), as
shown in Scheme 1, following a procedure for the prepar-
ation of a,v-bis(p-vinylphenyl)oligo(oxyethylenes)
described by Inokuma.18 Monomer (1) was obtained by
the sequence of tosylation of diethylene glycol monomethyl
ether, Williamson ether formation, reduction and dehy-
dration in an overall yield of 71%. A scavenging resin was
used for the purification on a large scale. This monomer
contained a stable phenyl ether linkage designed to provide
broad chemical compatibility.
Table 1. Preparation of the resin beads
Entry DVB (%) Monomer (1) (%) Loading (mmol/g) Yield (%)
1
2
3
4
5
6
8
3
2
2
2
2
12
5
7
14
24
43
–
60
90
64
60
78
71
1.0
1.0
1.0
0.90
0.96

S. M. Alesso et al. / Tetrahedron 59 (2003) 7163–7169
7165
Scheme 2. (i) Potassium phthalamide (5 equiv.), DMF 1208C, 18 h; (ii) hydrazine (10 equiv.), EtOH reflux, 5 h; (iii) Fmoc-Rink-linker (1.5 equiv.), HOBt
(1.5 equiv.), DIC (1.5 equiv.), DCM, 4 h; (iv) 20% piperidine/DMF, (2£20 min); (v) Fmoc-AA-OH (2 equiv.), DIC (2 equiv.), HOBt (3 equiv.), DCM, 3 h; (vi)
TFA/H2O (95:5) (1 or 2 h); (vii) Fmoc-Gly-OH (5 equiv.), HOBt (5 equiv.), DCM, 3 h; (viii) 4-iodobenzoic acid (5 equiv.), DIC (5 equiv.), HOBt (5 equiv.),
DCM, 5 h; (ix) phenylboronic acid (2 equiv.), Cs2CO3 (2 equiv.), Pd(PPh3)4 (0.1 equiv.), DMF, 908C, 24 h; (x) Ac-Tyr-OH (5 equiv.), DIC (5 equiv.), HOBt
(5 equiv.), DCM, 3 h; (xi) PhCH2OH (10 equiv.), PPh3 (5 equiv.), DEAD (5 equiv.), THF, 12 h; (xii) 4-acetylbenzoic acid (5 equiv.), DIC (5 equiv.), HOBt
(5 equiv.), DCM, overnight; (xiii) NaBH4 (5 equiv.), MeOH, overnight; (xiv) TFA/DCM (50/50), (2£30 min). DIC¼diisopropylcarbodiimmide, HOBt¼1-
hydroxybenzotriazole.
0.77 mmol/g. These resins were then loaded with the Fmoc-
Rink linker27 and in parallel used to prepare a model
tripeptide, a biaryl compound, an arylether, and an alchol
via ketone reduction. The results of these investigations are
shown in Tables 3 and 4.
resin containing 7% of the monomer (1) gave the best results
in terms of the overall yields and purities of the final
products 2-4 amongst the various resins tested including
those containing higher levels of the PEG derivative. This
resin was comparable, if not better, than TentaGele and
AM-PS resins.
During the synthesis of peptide (2) the biaryl derivative (3)
and the arylether derivative (4) (Table 3), the PS-MPEG
The reduction of a ketone in methanol, a much more polar
Table 2. Resin swelling (mL/g) of various non-grafted resins compared to TentaGele and ArgoGele (^0.2 mL/g)
Mon. (1) (%)
Dry vol.
DCM
Dioxane
THF
DMF
DME
Toluene
MeOH
2-PrOH
H2O
0
7
14
24
43
1.8
2.0
2.0
2.0
2.0
2.0
2.0
5.4
8.2
7.6
8.0
8.2
5.5
8.6
4.8
7.0
6.8
6.8
8.2
3.9
6.4
6.0
8.4
7.2
6.8
8.2
3.9
6.4
4.6
5.8
5.8
6.6
8.0
4.0
7.0
4.6
5.8
5.8
6.6
8.6
4.0
6.0
5.2
6.6
7.0
7.6
9.4
5.2
6.2
2.4
2.8
2.8
2.8
3.0
3.0
4.9
2.2
2.6
2.6
2.8
2.8
3.0
4.9
2.0
2.4
2.6
2.4
2.8
3.0
4.0
TentaGele
ArgoGele
Table 3. Comparison of PS-MPEG resins for the synthesis of peptide (2), biaryl derivative (3) and arylether derivative (4)
Resina
Loadingb (mmol/g)
Peptide (2)
Biaryl derivative (3)
Yieldc (%) Puritye (%)
Arylether derivative (4)
Yieldc (%) Puritye (%)
Yieldc (%)
Purityd (%)
7f
0.77
0.63
0.70
0.67
0.25
1.13
1.0
80
50
65
58
43
72
56
94
94
85
89
83
95
95
97
80
74
84
94
71
99
95
63
84
84
97
88
67
70
80
77
77
14f
24f
43f
TentaGele
AM-PS (1%)
AM-PS (2%)
65
43
68
51
a
Beads size 125–75 mm.
Loading of the amino resin.
Yield relative to the loading of amino resin.
Determined by HPLC, l¼220 nm.
Determined by HPLC, l¼254 nm.
Percentage of monomer (1).
b
c
d
e
f

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S. M. Alesso et al. / Tetrahedron 59 (2003) 7163–7169
Table 4. Comparison of PS-MPEG resins for the synthesis of alcohol (5)
to acetonitrile containing 0.042% trifluoroacetic acid was
run over 20 min followed by 5 min at acetonitrile.
Resina
Loadingb (mmol/g) Overall yieldc (%) Molar ratiod
Aluminium backed silica plates (0.25 mm layer of silica gel
60 with the florescent indicator Alugram SIL G/UV254
7e
0.77
0.63
0.70
0.50
0.25
95
84
82
62
83
90
92
90:10
97:3
14e
)
24e
ArgoGele
TentaGele
AM-PS (1%) 1.11
AM-PS (2%) 1.0
100:0
100:0
100:0
80:20
79:21
were used for thin layer chromatography (TLC). UV
(254 nm) was used to visualize compounds unless stated
otherwise. Resin beads were sieved using a Retsch AS 200
control Sieve Shaker. All amino acids used were the natural
L configuration. All chemicals and solvents were used from
purchase unless otherwise stated.
a
Beads size 125–75 mm.
Loading of amino resin.
Yield relative to the loading of the amino resin.
Between the product (5) and the ketone and calculated by H NMR.
Percentage of monomer (1).
b
c
d
e
1
3.1.1. Synthesis of 2-(2-methoxyethoxy)ethyl 4-methyl-1-
benzenesulfonate.28 To a solution of diethylene glycol
monomethyl ether (5 mL, 42 mmol, 1 equiv.) and dry
triethylamine (8.48 g, 84 mmol, 2 equiv.) in anhydrous
THF (50 mL), p-toluene sulfonyl chloride (12 g, 63 mmol,
1.5 equiv.) was slowly added over a 20-minute period at
08C. The mixture was allowed to warm to room tempera-
ture, stirred for 24 h and monitored by TLC. The white solid
(Et3N·HCl) present in the mixture was removed by filtration
and the solvent removed in vacuo to give a yellow oil. The
product was purified by column chromatography on silica
gel using Pet/EtOAc (7:3) as the eluent to give 9.7 of the
title product as a yellow oil. Yield 84%.
solvent, was examined to compare this reaction with
ArgoGele and TentaGele. As shown in Table 4, all the
resins containing the new monomer (1) gave better results
than standard PS resins, and ArgoGele in terms of isolated
yields although only the resin containing higher percentages
(24%) of (1) allowed full reduction of the ketone into the
corresponding alcohol (5).
In conclusion, a series of novel non-grafted chloromethyl-
ated PS-MPEG resins were prepared by copolymerisation.
Relative to traditional PEG-grafted resins, the MPEG-based
resins had a much higher loading capacity while maintain-
ing broad solvent compatibility. The co-polymers were
stable to strongly acidic/basic conditions and a range of
physical manipulations. The resin containing 7% of the new
monomer (1) proved to be highly suitable for peptide
synthesis, Suzuki and Mitsunobu couplings, having
improved performance over TentaGele and Merrifield
resins. For reaction in methanol, the resins containing the
new monomer (1) gave better results than standard PS resins
while all MPEG-based resins were better than ArgoGele in
terms of the isolated yield. These resins thus provide an
alternative to conventional PEG grafted supports.
Alternative purification. Polyamine resin Amberlite IRA-96
(3 equiv.) was washed thoroughly with DCM (50 mL),
MeOH (30 mL), Et2O (30 mL) and dried in vacuo. The resin
was swollen with THF. Crude 2-(2-methoxyethoxy)ethyl
4-methyl-1-benzensulfonate (1) (1 equiv.) was dissolved in
THF and added to the resin slurry. The mixture was then
shaken overnight. The resin was washed with THF and the
solvent was evaporated in vacuo to give compound (1).
HPLC purity: 93% and yield: 95%
Rf¼0.35 (Pet/EtOAc 7:3); IR: n¼2878, 1598, 1451, 1353,
1108 cm21
;
1H NMR (300 MHz, CDCl3): d¼7.80
(d, J¼8 Hz, 2H, ArH), 7.34 (d, J¼8 Hz, 2H, ArH), 4.18
(m, 2H, CH2OSO2), 3.70 (m, 2H, CH2O), 3.58 (m, 2H,
CH2O), 3.49 (m, 2H, CH2O), 3.36 (s, 3H, OCH3), 2.45
(s, 3H, ArCH3); 13C NMR (75 MHz, CDCl3): d¼144.9 (0),
133.1 (0), 130.0 (1), 128.0 (1), 71.9 (2), 70.8 (2), 69.4 (2),
68.8 (2), 59.2 (3); 21.8 (3); MS (APþ): m/z (%): 275.1 (100)
[MþH]þ, 297.0 (20) [MþNa]þ; RP HPLC (l¼254 nm)
14.6 min.
3. Experimental
3.1. General
NMR spectra were recorded using a Bruker AC300
1
spectrometer operating at 300 MHz for H and 75 MHz
for 13C, or a Bruker DPX400 spectrometer operating at
400 MHz for 1H and 100 MHz for 13C (d scale in parts per
million). ESI mass spectra were recorded using a VG
Platform Quadrupole Electrospray Ionisation mass spec-
trometer, measuring mono-isotopic masses. Infra-red spec-
tra were recorded on a BIORAD Golden Gate FTS 135. All
samples were run as either neat solids or oils. In the case of
resin linked compounds, the resins beads were washed with
dichloromethane, diethyl ether and then dried in vacuo.
Melting points were determined using a Gallenkamp
melting point apparatus and are uncorrected. UV–Vis
spectra were recorded using an 8452A Diode Array
Spectrophotometer. Analytical HPLC was accomplished
using a Hewlett–Packard HP1100 Chemstation, using a
Phenomenex C18 prodigy 5 mm (150 mm£3 mm) column.
A gradient from water containing 0.1% trifluoroacetic acid
3.1.2. Synthesis of 1-{4-[2-(2-methoxyethoxy)ethoxy]-
phenyl}-ethan-1-one. 2-(2-Methoxyethoxy)ethyl 4-methyl-
1-benzenesulfonate (1.01 g) (1.01 g, 3.64 mmol, 1 equiv.)
and potassium iodide (20 mg) were dissolved in acetonitrile
(15 mL), and stirred for 5 min. A mixture of p-hydroxy-
acetophenone (0.74 g, 5.50 mmol, 1.5 equiv.) and potas-
sium carbonate (0.75 g, 5.50 mmol, 1.5 equiv.) dissolved in
acetonitrile (10 mL), was added. The reaction mixture was
refluxed for 24 h. The white solid in the mixture was
removed by filtration and the solvent was removed in vacuo.
The crude product was dissolved in EtOAc (10 mL) and
washed with sodium hydroxide (20 mL, 1 mM). The
organic layer was dried over sodium sulphate and the
solvent removed in vacuo to give 0.76 g of the title
compound as a yellow oil that needed no further
purification. Yield 89%.

S. M. Alesso et al. / Tetrahedron 59 (2003) 7163–7169
7167
Rf¼0.25 (Pet/EtOAc 7:3); IR: n¼2876, 1674, 1599,
J¼8 Hz, ArH), 6.87 (d, 2H, J¼8 Hz, ArH), 6.65 (dd, 1H,
Jtrans¼18 Hz, Jcis¼11 Hz, CHCH2), 5.60 (d, 1H, Jtrans¼18
Hz, CHH), 5.12 (d, 1H, Jcis¼11 Hz, CHCH), 4.14 (m, 2H,
CH2OAr), 3.86 (m, 2H, OCH2), 3.72 (m, 2H, OCH2), 3.58
(m, 2H, OCH2), 3.39 (s, 3H, OCH3); 13C NMR (75 MHz,
CDCl3): d¼158.6 (0), 136.4 (0), 130.7 (1), 127.5 (1), 114.7
(1), 111.7 (2), 72.0 (2), 71.0 (2), 70.0 (2), 67.5 (2), 59.2 (3);
MS (ESþ): m/z (%): 240.2 (100) [MþNH4]þ, 245.1 (18)
[MþNa]þ, 261.1 (8) [MþK]þ, 286.2 (50) [MþNaþCH3-
CN]þ); HRMS calcd for C13H18O3: 222.1256, found:
222.1253; RP HPLC (l¼254 nm): 10.8 min.
1
1358 cm21; H NMR (300 MHz, CDCl3): d¼7.92 (d, 2H,
J¼9 Hz, ArH), 6.94 (d, 2H, J¼9 Hz, ArH), 4.20 (m, 2H,
CH2OAr), 3.88 (m, 2H, CH2O), 3.72 (m, 2H, CH2O), 3.59
(m, 2H, CH2O), 3.39 (s, 3H, OCH3), 2.55 (s, 3H, COCH3);
13C NMR (75 MHz, CDCl3): d¼197.0 (0); 162.8 (0); 130.7
(0); 130.5 (1); 114.4 (1); 72.0 (2), 71.0 (2), 70.0 (2), 68.0 (2),
59.2 (3); 26.5 (3); MS (ESþ): m/z (%): 239.2 (100)
[MþH]þ, 256.2 (25), [MþNH4]þ, 261.2 (5), [MþNa]þ;
HRMS calcd for C13H18O4: 238.1205, found: 238.1204; RP
HPLC (ELSD): 8.6 min.
3.1.3. Synthesis of 1-{4-[2-(2-methoxyethoxy)ethoxy]-
phenyl}-ethan-1-ol. 1-{4-[2-(2-Methoxyethoxy)ethoxy]-
phenyl}-ethan-1-one (1.0 g, 4.20 mmol, 1 equiv.) was
dissolved in ethanol (10 mL) and stirred at 08C. Sodium
borohydride (0.16 g, 4.23 mmol, 1 equiv.) was slowly added
in portions. The mixture was stirred for 3 h and excess
sodium borohydride quenched with 2 M HCl in ethanol. The
solvent was removed by distillation, water (30 mL) was
added and the compound was extracted with DCM
(100 mL). The organic layer was dried with sodium sulphate
and the solvent removed in vacuo to give 0.95 g of the title
compound as yellow oil. Yield 95%.
3.2. Suspension polymerisation22
Pre-mixedorganic phases (Table 5) were added to the aqueous
phase (1.0 g of PVA (polyvinyl alcohol, 87–89% hydro-
lyzed—Mr 85–146 kDa), 5 g of Na2SO4, 200 mL H2O) while
stirring in 500 mL cylindrical reaction vessels, equipped with
mechanical stirring connected to a central stirring motor, and
purged with N2. The suspensions were allowed to equilibrate
for 30 min, and the temperature raised to 658C for 16 h. The
crude polymers were collected in six polypropylene
filtration bags and washed with water, water/THF (1:1),
THF, THF/MeOH (1:1), and MeOH. The beads were dried in
vacuo and sieved to afford resins in five size ranges (.355,
355–250, 250–125, 125–75, 75–45 mm).
Rf¼0.2 (Pet/EtOAc 7:3); IR: n¼3422, 2877 cm21; 1H NMR
(300 MHz, CDCl3): d¼7.22 (d, 2H, J¼9 Hz, ArH), 6.88
(d, 2H, J¼9 Hz, ArH), 4.35 (q, 1H, J¼7 Hz, CHCH3), 4.14
(m, 2H, CH2OAr), 3.85 (m, 2H, CH2O), 3.72 (m, 2H,
CH2O), 3.58 (m, 2H, CH2O), 3.39 (s, 3H, OCH3), 1.40
(d, 3H, J¼7 Hz, CHCH3); 13C NMR (75 MHz, CDCl3):
d¼158.2 (0), 136.5 (0), 127.8 (1), 114.6 (1), 72.0 (1), 71.0
(2), 70.0 (2), 67.0 (2), 64.0 (2), 59.2 (3); 24.3 (3); MS (ESþ):
m/z (%): 258.3 (30) [MþNH4]þ, 263.2 (100) [MþNa]þ,
279.2 (10) [MþK]þ; HRMS calcd for C13H20O4: 240.1362,
found: 240.1365; RP HPLC (ELSD): 7.7 min.
3.2.1. Solid phase synthesis of tripeptide Ala-Val-Phe-
NH2 (2). The Fmoc-Rink linker, p-[(R,S)-a-[1-(9H-fluoren-
9-yl)-methoxyformamido]-2,4-dimethoxybenzyl]-phenoxy-
acetic acid (1.5 equiv.), was coupled onto the aminomethyl
resins (75–125 mm) with DIC/HOBt (1.5 equiv.) in DCM
and then Fmoc deprotected with 20% piperidine in DMF
(2£20 min). H-Rink amide-PS resin (200 mg) was swollen
in a minimum amount of DCM/DMF (10:1) for 30 min. The
Fmoc-amino acid (2 equiv.) and HOBt (2 equiv.) were
dissolved in DCM/DMF (10:1) for 10 min. DIC (3 equiv.)
was added and the mixture stirred for 10 min before addition
to the resin. The resins were agitated for 3 h to effect
coupling. The resins were washed with DMF (£3), DCM
(£3), MeOH (£3) and Et2O (£2) and dried under vacuum
for 30 min. Fmoc removal was performed using 20%
piperidine in DMF with two sequential treatments of
20 min. The resins were filtered and washed with DMF
(£3), DCM (£3), MeOH (£3) and Et2O (£2) and dried
under vacuum. Peptides were cleaved from the resin by
treating the resin with TFA/DCM (95:5) (2 mL) for 2 h. The
resins were removed by filtration, the filtrates concentrated
to ca. 1 mL and added to cold Et2O (25 mL). The resulting
precipitates were collected by centrifugation and washed
with Et2O (25 mL£2).
3.1.4. Synthesis of 1-[2-(2-methoxyethoxy)ethoxy]-4
vinyl benzene. A solution of 1-{4-[2-(2-methoxyethoxy)-
ethoxy]phenyl}-ethan-1-ol (140 mg, 0.57 mmol) and pyri-
dinium tosylate (14 mg, 0.056 mmol) in toluene (30 mL)
was refluxed overnight using a Dean–Stark trap. The cooled
solution was washed with water (30 mL) and a saturated
solution of sodium chloride (30 mL). The toluene layer was
dried with sodium sulfate and the solvent removed in vacuo.
The product was purified by column chromatography on
alumina eluting with Pet/EtOAc (7:3) to give 0.12 g of the
title product as a pale yellow oil. Yield 95%.
Rf¼0.48 (Pet/EtOAc 7:3) on alumina; IR: n¼2876, 1606,
1
1509 cm21; H NMR: (300 MHz, CDCl3): d¼7.33 (d, 2H,
Table 5. Composition of the organic phase for suspension polymerization
Entry
Resin cross-linking (%)
Styrene (g)
DVB (g)
Monomer (1) (g)
Vinyl benzyl chloride (g)
Toluenea (mL)
1
2
3
4
5
6
8
3
2
2
2
2
27.5
34.4
13.8
10.9
6.6
3.6
1.6
0.45
0.45
0.3
8.8
4.0
2.6
4.94
5.78
8.74
0
6.1
3.75
3.75
2.29
2.29
25
20
11
11
8
3.7
0.27
7
a
Initiator AIBN (1.0%, w/w) was added to the organic phase.

7168
S. M. Alesso et al. / Tetrahedron 59 (2003) 7163–7169
Rf¼0.50 (DCM/MeOH 9:1). Mp: 215–2168C; IR:
n¼3375–3299, 1671, NMR
1632 cm21 1H
(400 MHz, (CD3)2SO): d¼8.06 (d, 1H, J¼8 Hz, CONH),
7.48 (m, 5H, ArH), 7.25 (d, 2H, J¼8 Hz, ArH), 7.09 (br s,
2H, CONH2), 7.01 (d, 2H, J¼8 Hz, ArH), 5.16 (s, 2H,
OCH2Ph), 4.34 (m, 1H, CONHCH), 3.02 (dd, 1H, J¼5 and
14 Hz, CHaHbPh), 2.78 (dd, 1H, J¼9 and 14 Hz, CHaHb-
Ph), 1.85 (s, 3H, COCH3); 13C NMR (100 MHz, (CD3)2SO):
d¼173.8 (0), 169.4 (0), 157.3 (0), 137.7 (0), 130.7 (0), 130.5
(1), 128.8 (1), 114.8 (1), 69.6 (2), 54.5 (1), 37.3 (2), 23.0 (3);
MS (ESþ): m/z (%): 313.2 (70) [MþH]þ, 335.0 (10)
[MþNa]þ, 625.3 (10) [2MþH]þ, 647.3 (10) [2MþNa]þ;
HRMS ([MþH]þ) calcd for C18H21N2O3: 313.1553, found:
313.1547; RP HPLC (l¼254 nm): 8.6 min.
;
(400 MHz,(CD3)2SO): d¼8.34 (d, J¼9 Hz, 1H, NH), 8.10
(d, J¼8 Hz, 1H, NH), 7.43 (br, 2H, CONH2), 7.23 (m, 5H,
ArH), 7.10 (br, 2H, CH3CHNH2), 4.54 (ddd, 1H, J1¼5, 9
and 9 Hz, J3¼9 Hz, CHCH2Ph), 4.23 (m, 1H,
CHCH(CH3)2), 3.94 (q, 1H, J¼7 Hz, CHCH3), 3.04 (dd,
1H, J¼5 and 14 Hz, CHCHaHbPh), 2.85 (dd, 1H, J¼9 and
14 Hz, CHCHaHbPh), 1.99 (m, 1H, CHCH(CH3)2), 1.30 (d,
3H, J¼7 Hz, CH3CHNH2), 0.87 (d, 6H, J¼7 Hz,
CH(CH3)2); 13C NMR (100 MHz, (CD3)2SO): d¼173.1
(0), 170.5 (0), 170.0 (0), 138.2 (0), 129.5 (1), 128.4 (1),
126.6 (1), 58.3 (1), 53.9 (1), 48.5 (1), 38.2 (2), 31.1 (1), 19.6
(3), 18.5 (3), 17.9 (3); MS (ESþ): m/z (%): 335.3 (100)
[MþH]þ, 669.5 (5) [2MþH]þ; HRMS ([MþNa]þ) calcd
for C17H26N4O3Na: 357.1897, found: 357.1890; RP HPLC
(l¼220 nm): 6.5 min.
3.2.4. Solid phase synthesis of N-(carbamoylmethyl)-4-
(1-hydroxyethyl)-benzamide (5). Fmoc-Glycine (5 equiv.)
was coupled onto the H-Rink amide resins (400 mg)
prepared as above. After deprotection of the Fmoc group,
the resins was swollen in DCM and coupled with
4-acetylbenzoic acid (5 equiv.) according to the method
described above. The resultant resins were suspended in
MeOH (4 mL) and NaBH4 (5 equiv.) was added. The
resulting suspensions were shaken overnight at room
temperature. Resins were filtered and washed with MeOH
(3£10 mL), DMF (3£10 mL), DCM (3£10 mL) and dried
in vacuo. The final compound (5) was cleaved from the
resins with TFA/DCM (1:1, v/v) (5 mL) shaking the
suspension for 30 min. The resin was removed by filtration,
and the TFA evaporated in vacuo, and the materials
analysed by HPLC and ES-MS.
3.2.2. Solid phase synthesis of N-(carbamoylmethyl)
biphenyl-4-carboxamide (3). Fmoc-Glycine (5 equiv.)
was coupled onto the H-Rink amide resins (300 mg) prepared
as above. The loadings of the resins were calculated by a
quantitative Fmoc test. After deprotection of the Fmoc group,
the resins was swollen in DCM and coupled with 4-iodo-
benzoic acid (5 equiv.) according to the method described
above. The resultant resins were suspended in DMF and
Cs2CO3 (2 equiv.), Pd(PPh3)4 (0.1 equiv.) and phenyl boronic
acid (1.5 equiv.) were added under N2. The resulting
suspensions were heated at 1008C for 24 h. Resins were
filtered and washed with DMF (3£10 mL), DCM (3£10 mL),
MeOH, Et2O and dried in vacuo. The final compound (3) was
cleaved from the resins with TFA/H2O (95:5) (3 mL) shaking
the suspension for 1 h. The resin was removed by filtration,
and the TFA evaporated in vacuo. The crude materials were
analysed by HPLC and ES-MS.
Mp: 153–1558C; IR: n¼3312, 3213, 2974, 1672, 1642,
1542, 1503, 1301, 1091 cm21 1H NMR: (400 MHz,
;
(CD3)2SO): d¼8.61 (t, 1H, J¼6 Hz, CONH), 7.87 (d, 2H,
J¼8.5 Hz, ArH), 7.46 (d, 2H, J¼8.5 Hz, ArH), 7.38 (s, 1H,
CONH), 7.01 (s, 1H, CONH), 4.81 (q, 1H, J¼6.5 Hz, OCH),
3.84 (d, 2H, J¼6 Hz, COCH2), 1.37 (d, 3H, J¼6.5 Hz,
CH3); 13C NMR (100 MHz, (CD3)2SO): d¼172.0 (0), 167.2
(0), 151.7 (0), 133.4 (0), 128.1 (1), 126.0 (1), 68.7 (1), 43.4
(2), 26.8 (3); MS (ESþ): m/z (%): 223.1 (13) [MþH]þ,
245.0 (100) [MþNa]þ, 246.0 (11) [MþNaþH]þ, 467.2 (22)
[2MþNa]þ; HRMS ([MþNa]þ) calcd for C11H14N2O3Na:
245.0896, found: 245.0896.
1
Mp: 210–2128C; IR: n¼3382, 3330, 1660, 1633 cm21; H
NMR: (400 MHz, (CD3)2SO): d¼8.81 (t, 1H, J¼6 Hz,
CONH), 8.09 (d, 2H, J¼8 Hz, ArH), 7.89 (d, 2H,
J¼8 Hz, ArH), 7.85 (d, 2H, J¼7 Hz, ArH), 7.61 (t, 2H,
J¼7 Hz, ArH), 7.52 (t, 1H, J¼7 Hz, ArH), 3.96 (d, 2H,
J¼6 Hz, COCH2); 13C NMR (100 MHz, (CD3)2SO):
d¼169.8 (0), 164.8 (0), 141.5 (0), 137.9 (0), 131.7 (0),
127.8 (1), 126.8 (1), 125.6 (1), 125.2 (1), 41.2 (2); MS
(ESþ): m/z (%): 255.0 (30) [MþH]þ, 318.0 (100) [Mþ
NaþMeCN]þ, 531.1 (80) [2MþNa]þ, 785.0 (20)
[3MþNa]þ; HRMS ([MþNa]þ) calcd for C15H14N2O2Na:
277.0950, found: 277.0947; RP HPLC (l¼254 nm):
8.1 min.
Acknowledgements
We thank AstraZeneca PLC and Avecia Ltd for a
studentship (S. A.) and a SRF research fellowship (Z. Y.),
and Dr Andy Shooter for helpful advice.
3.2.3. Solid phase synthesis of 2-(acetylamino)-3-[4-
(benzyloxy)phenyl]propanamide (4). N-Acetyltyrosine
(5 equiv.) was coupled onto the resin Rink linker
(300 mg) as above. A solution of PPh3 (5 equiv.) and
benzyl alcohol (10 equiv.) in dry THF (3 mL) was added to
the dried resin and DEAD (5 equiv.) was added in four
portions over 5 min. The resins were shaken overnight,
washed with THF, DCM and Et2O and dried in vacuo.
Compound (4) was cleaved from the resins with TFA/H2O
(95:5) (3 mL) and shaking the suspension for 1 h. The crude
materials were analysed by HPLC and ES-MS.
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