Simultaneous deprotection and purification based on ionic resin capture: Application to amide formations and Grignard and Mitsunobu reactions

Article abstract of DOI:10.1055/s-2007-983758

Products containing Boc- or Tr-protected amines were caught directly out of reaction mixtures by simultaneous cleavage of the protecting group. By releasing the products with ammonia the corresponding free amines were obtained in high yields and purities.

Full text of DOI:10.1055/s-2007-983758

PAPER
2203
Simultaneous Deprotection and Purification Based on Ionic Resin Capture:
Application to Amide Formations and Grignard and Mitsunobu Reactions
D
eprotection a
e
nd Purifica
t
tion Ba
e
sed on Ion
r
M
Global Discovery Chemistry, Novartis Institutes for BioMedical Research Basel, Lichtstraße 35, 4056 Basel, Switzerland
Fax +41(61)3244236; E-mail: peter.meier@novartis.com
Received 16 April 2007
In this article, a general method of ionic resin based puri-
Abstract: Products containing Boc- or Tr-protected amines were
fication combined with the simultaneous cleavage of an
acid-labile protecting group, as depicted in Scheme 1, is
reported.
caught directly out of reaction mixtures by simultaneous cleavage
of the protecting group. By releasing the products with ammonia the
corresponding free amines were obtained in high yields and puri-
ties. The broadly applicable method of simultaneous deprotection
and purification based on ionic resin capture was applied for Grig-
nard and Mitsunobu reactions as well as amide formations and show
a high potential for multiparallel synthesis.
ionic resin
(Bondesil)
reagents
PG
A
A–B
PG
A
B
B
(amide formation,
Grignard reaction,
Mitsunobu reaction)
Key words: ion exchange, facile purification, Boc deprotection, Tr
deprotection, combinatorial chemistry
purification
and simultaneous
no work-up
cleavage of protecting
group (PG)
A major challenge in parallel synthesis and especially in
the production of combinatorial libraries is the purifica-
tion of numerous intermediates and final compounds.
Many purification and isolation methods lack a generic
nature and can therefore not be used easily in the prepara-
tion of multifold products having very different proper-
ties. In multiparallel extractions, for instance, a certain
number of the reaction mixtures usually show precipi-
tates, do not give sufficient separations of the layers, or
even result in emulsions. Chromatographical methods de-
mand a much higher technical effort and need to be opti-
mized carefully for each series of compounds. One
possible solution is the application of scavengers to re-
move excess reagents or reactants, or to bind temporarily
the product to the solid phase while the excess reagents
and reactants are washed off, and finally to release the pu-
rified product – this is also known as polymer-assisted pu-
rification.1 The general principle was first described by
Siegel et al. and involves the selective binding of a prod-
uct from a reaction solution onto a solid phase, followed
by washing of the solid phase to remove impurities.2 Re-
cently, scavengers were applied in different multistep syn-
theses,3 and several novel scavenger types were
developed4 and are now widely used in multiparallel syn-
thesis.5 We report within this article a powerful and gen-
eral expansion of this procedure to not only amide
formations but also Grignard and Mitsunobu reactions: in-
termediates or final products were bound to the resin and
acid-labile tert-butyloxycarbonyl (Boc) or trityl (Tr) pro-
tecting groups were cleaved simultaneously.
Scheme 1
The formed adduct A–B is fished directly out of the reac-
tion mixture using an acidic scavenger (Bondesil SCX®).7
The protecting group (e.g., Boc, Tr) is cleaved off the
amine under acidic conditions. After washing the resin,
the product A–B is released under basic conditions (e.g.,
ammonia in methanol). The ionic resin based purification
and deprotection is illustrated in three different reaction
types: amide couplings, Mitsunobu reactions, and Grig-
nard reactions.
Grignard Reactions
The corresponding Grignard reagents were added to 1-tri-
tyl-1H-imidazole-4-carbaldehyde (1) in THF (Table 1).
The reaction mixture was quenched after one day with
aqueous ammonium chloride and methanol.
The products were caught by adding Bondesil SCX and
shaking this mixture for three days at room temperature.
This prolonged reaction time was necessary to get a com-
plete trityl deprotection of the imidazoles. To remove ex-
cess reagents and side products, the Bondesil SCX was
washed as described in Table 1. Finally, the product could
by released from the scavenger by treatment with ammo-
nia in methanol. The products with purities of 90% or bet-
ter were isolated in good yields of 77–88%.
Some examples of the cleavage of protecting groups by
scavengers or ion exchangers are described in literature.6
Mitsunobu Reactions
SYNTHESIS 2007, No. 14, pp 2203–2207
Advanced online publication: 03.07.2007
DOI: 10.1055/s-2007-983758; Art ID: Z09707SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
7
The corresponding alcohols 5 were coupled to 4-(1-trityl-
1H-imidazol-4-yl)phenol (4) under classical Mitsunobu
conditions (DIAD, PPh3, Table 2).

2204
P. Meier, S. Müller
PAPER
Table 1 Deprotection and Purification Based on Ionic Resin Cap-
ture: Grignard Reactions
ing for two days, Dowex 2X8-200 was added to remove
HOBt as well as remaining amino acids.
1) R1MgX (2), THF, r.t., 1 d
2) NH4Cl, H2O, MeOH
3) Bondesil SCX, r.t., 3 da
Bondesil SCX and formic acid were added to the reaction
mixture. After shaking for three days at room temperature,
the products were completely bound to the resin and Boc-
deprotected. To remove excess reagents and side prod-
ucts, the Bondesil SCX was washed as described in
Table 3. The products were released from the scavenger
by treatment with ammonia in methanol and obtained with
purities of 85% or more and in good yields of 85–90%.
Tr
H
N
N
4) washingb
5) NH3 in MeOH, r.t., 2 d
N
N
R1
HO
O
1
3
Entry
Grignard reagent 2
Yield (%)
Product 3
1
2
3
4
PhCH2CH2MgBr (2a)
n-PrMgCl (2b)
PhMgBr (2c)
87
77
82
86
3a
3b
3c
3d
Applying this method, several discovery libraries (e.g.,
imidazole derivatives) consisting of overall more than
10000 members were prepared within Novartis.
In summary, we have demonstrated that the method of
ionic resin capture, which allows the preparation of com-
pounds in high yields by catching products out of reaction
mixtures with acidic scavengers, cleaving simultaneously
acid labile protecting groups, and finally releasing prod-
ucts with high purities, is a powerful method for multi-
parallel synthesis. This method has been illustrated with
different examples for Grignard and Mitsunobu reactions
as well as amide formations.
EtMgBr (2d)
a The reaction mixtures were shaken in grooved tubes for better mix-
ing.
b Washing procedure: MeOH; 2 × toluene and MeOH; 3 × H2O; 3 ×
MeOH.
The products were caught by adding Bondesil SCX, for-
mic acid, water and methanol and shaking this mixture for
three days at room temperature. As mentioned for the
Grignard reactions, the prolonged reaction time was nec-
essary to get a complete trityl deprotection of the imida-
zoles. To remove excess reagents and side products, the
Bondesil SCX was washed as described in Table 2. The
products were released from the scavenger by treatment
with ammonia in methanol and isolated with purities of
90% or more and in good yields of 79–84%.
Bondesil SCX (40 mM) was purchased from Varian. The starting
materials were either purchased from various suppliers8 or, in the
case of 4, prepared in analogy to literature.9 1H NMR and 13C NMR
spectra were recorded on a Bruker Biospin 400 spectrometer. The
high-resolution mass spectra were acquired on a Bruker APEXIII
Ion Cyclotron Resonance Fourier Transform Mass Spectrometer
equipped with an electrospray ion source operated in positive ion
mode. Chemical shifts (d) are given in parts per million relative to
the NMR solvent signals (DMSO-d6: 2.5 and 39.51 ppm).
Amide Formations
Grignard reactions; 1-(1H-Imidazol-4-yl)-3-phenylpropan-1-ol
(3a); Typical Procedure
1-Trityl-1H-imidazole-4-carbaldehyde (1; 250 mg, 0.74 mmol)
were dissolved in anhyd THF (25 mL). At 0 °C, 2-phenylethylmag-
The Boc-protected amino acids 7 were activated with
HBTU (Table 3) and the amine 8 was added. After shak-
Table 2 Deprotection and Purification Based on Ionic Resin Capture: Mitsunobu Reactions
H
Tr
1) ROH (5), DIAD, PPh3, THF, r.t., 1 d
2) Bondesil SCX, H2O, MeOH,
HCOOH, r.t., 3 da
N
N
N
N
3) washingb
6
4) NH3 in MeOH, r.t., 2 d
4
R
O
OH
Entry
Alcohol 5
Yield (%)
Product 6
1
2
3
4
5
2-(2-Dimethylaminoethoxy)ethanol (5a)
2-Pyridin-3-ylethanol (5b)
84
79
78
83
83
6a
6b
6c
6d
6e
2-Morpholin-4-ylethanol (5c)
1-(3-Hydroxypropyl)pyrrolidin-2-one (5d)
2-Pyrrolidin-1-yl-ethanol (5e)
a The reaction mixtures were shaken in grooved tubes for better mixing.
b Washing procedure: MeOH; 3 × toluene and MeOH; 3 × H2O, 3 × MeOH.
Synthesis 2007, No. 14, 2203–2207 © Thieme Stuttgart · New York

PAPER
Deprotection and Purification Based on Ionic Resin Capture
2205
Table 3 Deprotection and Purification Based on Ionic Resin Capture: Amide Formations
1) R2R3NH (8), HBTU, DMA, r.t., 2 d
2) Dowex, H2O, r.t., 2 d
Boc
HN
R1
NH2
3) Bondesil SCX, HCOOH, r.t., 5 da
NR2R3
OH
R1
3) washingb
4) NH3 in MeOH, r.t., 2 d
7
O
O
9
Entry
Amino acid 7
Amine 8
Yield (%)
Product 9
1
2
3
4
5
Boc-phenylalanine (7a)
Boc-phenylalanine (7a)
Boc-phenylalanine (7a)
N-Boc-tryptophan (7b)
N-Boc-tryptophan (7b)
Benzylamine (8a)
90
90
89
85
88
9a
9b
9c
9d
9e
1-Methylpiperazine (8b)
1,1-Dimethylethane-1,2-diamine (8c)
1-Methylpiperazine (8b)
1,1-Dimethylethane-1,2-diamine (8c)
a The reaction mixtures were shaken in grooved tubes for better mixing.
b Washing procedure: MeOH; 3 × H2O, 3 × MeOH.
nesium bromide (2a; 1.1 mL, 1.1 mmol, 1 M in THF) was added
dropwise. Then, the mixture was shaken for 1 d at r.t. Sat. aq NH4Cl
(5 mL), H2O (5 mL), MeOH (5 mL), and Bondesil SCX (3.1 g,
loading: 0.79 mmol/g) were added and the mixture was shaken for
3 d at r.t. The Bondesil SCX was filtered off, washed with MeOH
(20 mL), toluene (3 × 20 mL), MeOH (20 mL), H2O (3 × 20 mL),
and MeOH (3 × 20 mL). A solution of NH3 in MeOH (7 M, 25 mL)
was added to the residual Bondesil SCX and the suspension shaken
for 2 d at r.t., filtered, and the solid washed with MeOH (10 mL).
The combined filtrates were evaporated to give the product 3a
(130 mg, 87%).
1H NMR (400 MHz, DMSO-d6): d = 9.01 (s, 1 H), 7.54 (s, 1 H),
7.25–7.31 (m, 2 H), 7.14–7.23 (m, 3 H), 4.62–4.73 (m, 1 H), 2.55–
2.77 (m, 2 H), 1.90–2.08 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 153.8, 141.8, 137.3, 134.5,
128.7, 126.2, 115.6, 63.7, 38.3, 31.3.
13C NMR (100 MHz, DMSO-d6): d = 139.3, 134.7, 116.7, 67.0,
44.8, 30.1.
HRMS (ESI): m/z [M + H]+ calcd for C6H10N2O: 127.0866; found:
127.0865.
Mitsunobu Reactions; (2-{2-[4-(1H-Imidazol-4-yl)phen-
oxy]ethoxy}ethyl)dimethylamine (6a); Typical Procedure
4-(1-Trityl-1H-imidazol-4-yl)phenol (4; 100 mg, 0.25 mmol) was
dissolved in THF (5 mL). 2-(2-Dimethylaminoethoxy)ethanol (5a;
45 mg, 0.34 mmol) and Ph3P (83 mg, 0.32 mmol) were added fol-
lowed by DIAD (0.65 mL, 0.34 mmol) dissolved in THF (1 mL).
The resulting mixture was shaken for 1 d at r.t. Bondesil SCX
(1.04 g, loading: 0.79 mmol/g), H2O (1 mL), MeOH (5 mL) and
HCO2H (1 mL) were added. The suspension was shaken for 3 d.
The Bondesil SCX was filtered off and washed with MeOH
(20 mL), toluene (3 × 20 mL), MeOH (20 mL), H2O (3 × 20 mL),
and MeOH (3 × 20 mL). A solution of NH3 in MeOH (7 M, 15 mL)
was added to the residual Bondesil SCX and the suspension shaken
for 2 d at r.t., filtered and the solid washed with MeOH (10 mL).
The combined filtrates were evaporated to give the product 6a
(58 mg, 84%).
1H NMR (400 MHz, DMSO-d6): d = 9.07 (s, 1 H), 8.02 (d, J = 1.2
Hz, 1 H), 7.75 (d, J = 9.1 Hz, 2 H), 7.09 (d, J = 9.1 Hz, 2 H), 4.18–
4.23 (m, 2 H), 3.75–3.88 (m, 4 H), 3.27–3.34 (m, 2 H), 2.81 (s, 6 H).
13C NMR (100 MHz, DMSO-d6): d = 158.8, 158.0, 157.8, 134.8,
126.8, 115.1, 114.2, 68.7, 66.9, 64.4, 55.9, 42.6.
HRMS (ESI): m/z [M + H]+ calcd for C15H21N3O2: 276.1707; found:
276.1707.
HRMS (ESI): m/z [M + H]+ calcd for C12H14N2O: 203.1179; found:
203.1178.
1-(1H-Imidazol-4-yl)butan-1-ol (3b)
1H NMR (400 MHz, DMSO-d6): d = 8.99 (s, 1 H), 7.50 (s, 1 H),
4.67 (t, J = 6.6 Hz, 1 H), 1.56–1.84 (m, 2 H), 1.10–1.50 (m, 2 H),
0.89 (t, J = 7.5 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 137.7, 134.4, 115.4, 64.0,
38.8, 18.4, 14.0.
HRMS (ESI): m/z [M + H]+ calcd for C7H12N2O: 141.1022; found:
141.1022.
(1H-Imidazol-4-yl)phenylmethanol (3c)
3-{2-[4-(1H-Imidazol-4-yl)phenoxy]ethyl}pyridine (6b)
1H NMR (400 MHz, DMSO-d6): d = 9.15 (d, J = 1.5 Hz, 1 H), 8.88
(d, J = 1.7 Hz, 1 H), 8.71–8.82 (m, 1 H), 8.41 (d, J = 7.8 Hz, 1 H),
8.04 (d, J = 1.5 Hz, 1 H), 7.84–7.93 (m, 1 H), 7.76 (d, J = 8.8 Hz, 2
H), 7.10 (d, J = 9.1 Hz, 2 H), 4.35 (t, J = 6.4 Hz, 2 H), 3.26 (t,
J = 6.5 Hz, 2 H).
1H NMR (400 MHz, DMSO-d6): d = 9.01 (s, 1 H), 7.36–7.48 (m, 5
H), 5.88 (s, 1 H), 5.88 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 142.0, 136.9, 134.5, 128.4,
127.8, 126.3, 115.7, 66.2.
HRMS (ESI): m/z [M + H]+ calcd for C10H10N2O: 175.0866; found:
13C NMR (100 MHz, DMSO-d6): d = 159.0, 144.4, 142.5, 137.8,
175.0864.
135.1, 132.9, 127.3, 126.3, 120.0, 115.6, 115.1, 114.7, 67.4, 32.0.
1-(1H-Imidazol-4-yl)propan-1-ol (3d)
HRMS (ESI): m/z [M + H]+ calcd for C16H15N3O: 266.1288; found:
266.1287.
1H NMR (400 MHz, DMSO-d6): d = 8.19 (s, 1 H), 8.14 (s, 1 H),
7.10 (s, 1 H), 4.50 (t, J = 10.1 Hz, 1 H), 1.59–1.82 (m, 2 H), 0.84 (t,
J = 14.9 Hz, 3 H).
Synthesis 2007, No. 14, 2203–2207 © Thieme Stuttgart · New York

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P. Meier, S. Müller
PAPER
4-{2-[4-(1H-Imidazol-4-yl)phenoxy]ethyl}morpholine (6c)
1H NMR (400 MHz, DMSO-d6): d = 9.13 (s, 1 H), 8.06 (s, 1 H),
7.80 (d, J = 9.1 Hz, 2 H), 7.15 (d, J = 9.1 Hz, 2 H), 4.38–4.48 (m, 2
H), 3.86 (br s, 4 H), 3.55–3.68 (m, 2 H), 3.31–3.45 (m, 4 H).
13C NMR (100 MHz, DMSO-d6): d = 158.4, 135.2, 132.9, 127.2,
119.1, 115.8, 114.9, 63.7, 62.6, 55.3, 52.1.
HRMS (ESI): m/z [M + H]+ calcd for C14H21N3O: 248.1757; found:
148.1757.
2-Amino-N-(2-dimethylaminoethyl)-3-phenylpropionamide
(9c)
1H NMR (400 MHz, DMSO-d6): d = 8.92 (t, J = 5.6 Hz, 1 H), 8.43
(br s, 2 H), 7.22–7.35 (m, 5 H), 4.00 (t, J = 7.1 Hz, 1 H), 3.37–3.48
(m, 2 H), 3.00–3.10 (m, 4 H), 2.77 (s, 6 H).
HRMS (ESI): m/z [M + H]+ calcd for C15H19N3O2: 274.1550; found:
274.1550.
13C NMR (100 MHz, DMSO-d6): d = 168.5, 134.9, 129.4, 128.5,
127.1, 55.1, 53.6, 42.3, 36.7, 33.9.
HRMS: m/z [M + H]+ calcd for C13H21N3O: 236.1757; found:
236.1757.
1-{3-[4-(1H-Imidazol-4-yl)phenoxy]propyl}pyrrolidin-2-one
(6d)
1H NMR (400 MHz, DMSO-d6): d = 9.14 (s, 1 H), 8.03 (s, 1 H),
7.73 (d, J = 9.1 Hz, 2 H), 7.06 (d, J = 9.0 Hz, 2 H), 4.01 (t, J = 6.1
Hz, 2 H), 3.30–3.41 (m, 4 H), 2.20 (t, J = 8.8 Hz, 2 H), 1.84–2.01
(m, 4 H).
2-Amino-3-(1H-indol-3-yl)-1-(4-methylpiperazin-1-yl)propan-
1-one (9d)
1H NMR (400 MHz, DMSO-d6, 120 °C): d = 10.79 (s, 1 H), 7.48 (d,
J = 8.0 Hz, 1 H), 7.40 (d, J = 8.1 Hz, 1 H), 7.24 (s, 1 H), 7.11 (t,
J = 7.5 Hz, 1 H), 7.02 (t, J = 7.4 Hz, 1 H), 4.56 (dd, J = 8.6, 5.9 Hz,
1 H), 4.3–5.8 (br s, 2 H), 3.55 (br s, 2 H), 3.12–3.63 (m, 4 H), 2.51–
2.78 (br s, 2 H), 2.56 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 173.9, 159.2, 134.7, 132.6,
126.9, 120.7, 119.2, 115.1, 114.2, 65.6, 46.4, 30.4, 26.6, 17.5.
HRMS (ESI): m/z [M + H]+ calcd for C16H19N3O2: 286.1550; found:
286.1549.
13C NMR (100 MHz, DMSO-d6, 120 °C): d = 168.0, 136.0, 127.1,
125.2, 121.5, 119.9, 117.6, 115.2, 111.8, 51.7, 49.4, 42.2, 38.5,
27.3.
4-[4-(2-Pyrrolidin-1-ylethoxy)phenyl]-1H-imidazole (6e)
1H NMR (400 MHz, DMSO-d6): d = 9.14 (s, 1 H), 8.06 (s, 1 H),
7.80 (d, J = 8.8 Hz, 2 H), 7.15 (d, J = 8.6 Hz, 2 H), 4.26–4.45 (m, 2
H), 3.55–3.70 (m, 4 H), 3.15–3.22 (m, 2 H), 1.77–2.15 (m, 4 H).
HRMS (ESI): m/z [M + H]+ calcd for C16H22N4O: 287.1866; found:
287.1866.
13C NMR (100 MHz, DMSO-d6): d = 158.4, 134.8, 132.5, 126.9,
120.2, 115.4, 114.5, 63.4, 53.8, 52.7, 22.5.
2-Amino-N-(2-dimethylaminoethyl)-3-(1H-indol-3-yl)pro-
pionamide (9e)
HRMS (ESI): m/z [M + H]+ calcd for C15H19N3O: 258.1601; found:
258.1601.
1H NMR (400 MHz, DMSO-d6): d = 10.44 (s, 1 H), 8.26 (t, J = 5.6
Hz, 1 H), 7.62 (s, 2 H), 6.95 (d, J = 7.8 Hz, 1 H), 6.69 (d, J = 8.1 Hz,
1 H), 6.53 (d, J = 2.2 Hz, 1 H), 6.41 (t, J = 7.0 Hz, 1 H), 6.33 (t,
J = 7.5 Hz, 1 H), 3.27 (br s, 1 H), 2.64–2.86 (m, 2 H), 2.52–2.63 (m,
1 H), 2.22–2.51 (m, 3 H), 2.06 (s, 6 H).
Amide Formations; 2-Amino-N-benzyl-3-phenylpropionamide
(9a); Typical Procedure
Boc-phenylalanine (7a; 250 mg, 0.94 mmol) was dissolved in THF
(25 mL) and DMA (5 mL). HBTU (357 mg, 0.94 mmol) was added
and the suspension shaken for 45 min at r.t. Benzylamine (8a;
82 mL, 0.75 mmol) was added and the resulting mixture was shaken
for 2 d at r.t. H2O (25 mL) and Dowex 2X8-200 (2 g) were added
and the suspension was shaken for 2 d at r.t. The Dowex 2X8-200
was filtered off and washed with MeOH (10 mL) and H2O (20 mL).
Bondesil SCX (3.9 g, loading: 0.79 mmol/g) was added to the com-
bined filtrates and the suspension was shaken for 5 d at r.t. The
Bondesil SCX was filtered off and washed with MeOH (20 mL),
H2O (3 × 20 mL) and MeOH (3 × 20 mL). A solution of NH3 in
MeOH (7 M, 25 mL) was added to the residual Bondesil SCX and
the suspension shaken for 2 d at r.t., filtered and the solid washed
with MeOH (10 mL). The combined filtrates were evaporated to
give the product 9a (215 mg, 83%).
13C NMR (100 MHz, DMSO-d6): d = 169.5, 136.6, 127.4, 125.2,
121.5, 118.7, 115.7, 111.9, 107.3, 55.6, 53.5, 48.9, 42.7, 34.4.
HRMS (ESI): m/z [M + H]+ calcd for C15H22N4O: 275.1866; found:
275.1866.
Acknowledgment
The authors thank the Novartis department for Analytical and Ima-
ging Sciences for HRMS and NMR analyses.
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1H NMR (400 MHz, DMSO-d6): d = 8.84 (s, 1 H), 8.28 (s, 2 H),
7.17. 7.28 (m, 8 H), 7.04 (d, J = 7.3 Hz, 2 H), 4.26–4.36 (m, 1 H),
4.12–4.20 (m, 1 H), 4.00–4.09 (m, 1 H), 3.05 (br s, 2 H).
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128.5, 128.2, 127.3, 127.0, 126.9, 53.6, 42.2, 36.9.
HRMS (ESI): m/z [M + H]+ calcd 255.1492; found: 255.1491.
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(9b)
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7.28 (d, J = 7.6 Hz, 2 H), 4.4–5.4 (br s, 2 H), 4.63 (t, J = 7.2 Hz, 1
H), 3.28–3.64 (m, 4 H), 3.14–3.23 (m, 1 H), 2.96–3.11 (m, 3 H),
2.72–2.90 (m, 2 H), 2.72 (s, 3 H).
(4) Bhattacharyya, S. Curr. Opin. Drug Discovery Dev. 2004, 7,
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(5) (a) Thompson, L. A. Curr. Opin. Chem. Biol. 2000, 4, 324.
(b) Rademann, J. In Highlights in Bioorganic Chemistry.
Polymer Supported Synthetic Methods – Solid-Phase
Synthesis (SPS) and Polymer-Assisted Solution-Phase
(PASP) Synthesis; Wiley-VCH: Weinheim, 2004, 290.
(c) Dolle, R. E. J. Comb. Chem. 2005, 7, 739.
13C NMR (100 MHz, DMSO-d6, 120 °C): d = 159.0, 130.1, 129.0,
127.8, 118.2, 115.3, 52.3, 42.5, 38.9, 37.3.
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(6) (a) Gray, C. J.; Khoujah, A. M. Tetrahedron Lett. 1969, 31,
shaking in multiparallel fashion. The solvent can be removed
therefore faster and more easily than with an organic-
polymer-based ion-exchange resin.
2647. (b) Seto, H.; Mander, L. N. Synth. Commun. 1992, 22,
2832. (c) Liu, Y.-S.; Zhao, C.; Bergbreiter, D. E.; Romo, D.
J. Org. Chem. 1998, 63, 3471. (d) Baxendale, I. R.; Ernst,
M.; Krahnert, W.-R.; Ley, S. V. Synlett 2002, 1641.
(e) Mukade, T.; Dragoli, D. R.; Ellman, J. A. J. Comb.
Chem. 2003, 5, 590.
(8) Grignard reagents were purchased from Rieke Metals Inc.
(NE, USA; 2a) or Fluka Chemie GmbH (CH; 2b, 2c, 2c, 2d)
as solutions in THF. Compound 1 and the alcohols 5b and 5d
were supplied by ABCR GmbH & Co KG (Karlsruhe,
Germany). All other reagents, Dowex 2X8-200 and solvents
were purchased from Fluka Chemie GmbH (Buchs-CH).
(9) Magdolen, P.; Vasella, A. Helv. Chim. Acta 2005, 88, 2454.
(7) Bondesil SCX (purchased from Varian Deutschland GmbH,
Darmstadt, Germany) was used since this silica-based
scavenger has a high density that facilitates the settling after
Synthesis 2007, No. 14, 2203–2207 © Thieme Stuttgart · New York