A new strategy for the synthesis of taurine derivatives using the 'safety-catch' principle for the protection of sulfonic acids

Article abstract of DOI:10.1039/b614333d

The safety-catch principle has been applied for the development of a new method for protecting sulfonic acids. 2,2-Dimethylsuccinic acid was reduced to 2,2-dimethylbutane-1,4-diol, which was selectively silylated to give 4-(tert-butyldiphenylsilanyloxy)-2,2-dimethylbutan-1-ol. Reaction of the latter compound with 2-chloroethanesulfonyl chloride in the presence of triethylamine afforded 4-(tert-butyldiphenylsilyloxy)-2,2-dimethylbutyl ethenesulfonate directly. The ethenesulfonate underwent Michael-type addition with secondary amines to give protected derivatives of taurine (2-aminoethanesulfonic acid). Deprotection was achieved on treatment with tetrabutylammonium fluoride, whereby cleavage of the silicon-oxygen bond led to an intermediate alkoxide that immediately cyclised to 2,2-dimethyltetrahydrofuran with liberation of a sulfonate. Pure sulfonic acids were obtained from the crude product by ion exchange chromatography on a strongly basic resin, which was eluted with aqueous acetic acid. The method developed should be generally applicable to the protection of sulfonic acids and is amenable to a multiparallel format. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b614333d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A new strategy for the synthesis of taurine derivatives using the ‘safety-catch’
principle for the protection of sulfonic acids
Sonja Seeberger, Roger J. Griffin, Ian R. Hardcastle and Bernard T. Golding*
Received 2nd October 2006, Accepted 8th November 2006
First published as an Advance Article on the web 24th November 2006
DOI: 10.1039/b614333d
The safety-catch principle has been applied for the development of a new method for protecting
sulfonic acids. 2,2-Dimethylsuccinic acid was reduced to 2,2-dimethylbutane-1,4-diol, which was
selectively silylated to give 4-(tert-butyldiphenylsilanyloxy)-2,2-dimethylbutan-1-ol. Reaction of the
latter compound with 2-chloroethanesulfonyl chloride in the presence of triethylamine afforded
4-(tert-butyldiphenylsilyloxy)-2,2-dimethylbutyl ethenesulfonate directly. The ethenesulfonate
underwent Michael-type addition with secondary amines to give protected derivatives of taurine
(2-aminoethanesulfonic acid). Deprotection was achieved on treatment with tetrabutylammonium
fluoride, whereby cleavage of the silicon–oxygen bond led to an intermediate alkoxide that immediately
cyclised to 2,2-dimethyltetrahydrofuran with liberation of a sulfonate. Pure sulfonic acids were obtained
from the crude product by ion exchange chromatography on a strongly basic resin, which was eluted
with aqueous acetic acid. The method developed should be generally applicable to the protection of
sulfonic acids and is amenable to a multiparallel format.
which can be cleaved to the corresponding sulfonic acid (e.g. 2-
Introduction
morpholin-4-yl-ethanesulfonic acid 4a) rapidly and in high yield
In a research programme aimed at synthesising potential in-
at room temperature using tetrabutylammonium fluoride (TBAF)
hibitors of the histone acetyltransferase enzyme called Tip60
in THF. The resulting sulfonic acids are easily purified by ion
(Tat interacting protein),1 we required a small molecule li-
exchange chromatography. This strategy is an application of
Kenner’s ‘safety-catch’ principle,14,15 whereby a labile intermediate
brary in which all of the members terminated with an N,N-
disubstituted 2-aminoethylsulfonate, i.e. derivatives of taurine
(2-aminoethanesulfonic acid). There is substantial interest in
taurine and its derivatives because of the uncertain, but probable
important role of this abundant amino acid in human and animal
cells.2 The sulfonate moiety can also be used as a surrogate
for carboxylate and phosphate in drug development.3 Sulfonate
groups are key components of antagonists for P2 purinergic
receptors4 and follicle stimulating hormone.5 The wider applica-
tion of sulfonates in medicinal chemistry may have been frustrated
by a lack of satisfactory methods for the masking of this polar,
strongly acidic group. Sulfonic acids have been protected as sul-
fonate esters [isopropyl,5,6 isobutyl,7 neopentyl8 m-nitrophenoxy,4
pentafluorophenyl9 or solid supported benzyl (e.g. Wang resin10)],
as sulfonamides with secondary amines11 and by ‘non-covalent’
masking with a hydrophobic ammonium species.12 The photolabile
2,5-dimethoxyphenacyl group has also been employed for the
protection of sulfonic acids.13 Many of these methods employed
acidic (e.g. tr◦ifluoroacetic acid)8a or basic conditions (e.g. 2 M
NaOH at 70 C)4 in the cleavage step, which may be unsuitable
for some target molecules. We describe a protecting strategy for
sulfonic acids in which the versatile, reactive intermediate 4-(tert-
butyldiphenylsilanyloxy)-2,2-dimethylbutyl ethenesulfonate 1 re-
acts in high yields with different secondary amines (e.g. morpho-
line 2a) to give an adduct (e.g. 2-morpholin-4-yl-ethanesulfonic
acid 4-(tert-butyldiphenylsilanyloxy)-2,2-dimethyl-butyl ester 3a),
is released in situ by removal of a relatively robust protecting group.
Results and discussion
Initially, we planned to introduce the sulfonic acid group in the
last step of a synthetic sequence using sulfite (Na2SO3) to displace
a bromo group. To this end, N-tert-butyloxycarbonylpiperazine
was alkylated with 1,2-dibromoethane and 1,3-dibromopropane
giving 5 and 6, respectively. However, the yields of these molecules,
which were required for further chain extension, were only 5% (5)
and 41% (6), respectively.
We then conceived an alternative strategy based on
a
protected common intermediate ethenesulfonate, 4-(tert-
butyldiphenylsilanyloxy)-2,2-dimethylbutyl ethenesulfonate 1,
which could be reacted with a variety of amines prior to
deprotection. Thus, reaction of the mono-silyl protected alcohol 7
with commercially available 2-chloroethanesulfonyl chloride gave
ethenesulfonate 116 in good yield (Scheme 1). The alcohol 7 was
readily prepared by reduction of 2,2-dimethylsuccinic acid 8 with
lithium aluminium hydride to afford 2,2-dimethylbutane-1,4-diol
9, which was selectively silylated17 with tert-butyldiphenylsilyl
chloride (TBDPS-Cl) at its less hindered hydroxyl group.
Michael-type coupling of ethenesulfonate 1 with secondary
amines R1R2NH 2a–2h occurred smoothly to give adducts 3a–3h,
essentially as previously described.18 Deprotection of the adducts
Northern Institute for Cancer Research, School of Natural Sciences-
Chemistry, Bedson Building, University of Newcastle upon Tyne, Newcastle
upon Tyne, United Kingdom NEI 7RU
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The methods described in this paper should be applicable to
the synthesis of wide range of sulfonic acids. The chemistry is
amenable to scale-up and can be performed in a multiparallel
synthesis format. The methodology described could also be
extended, in principle, to the protection of sulfate mono-esters.22
Scheme 1 Synthesis of 4-(tert-butyldiphenylsilanyloxy)-2,2-dimethylbutyl
ethenesulfonate 1. Reagents and conditions: (i) LiAlH4, ether, reflux, 85%;
(ii) TBDPS-Cl, imidazole, DMF, rt, 79%; (iii) 2-chloroethanesulfonyl
chloride, Et3N, DCM, rt, 93%.
Experimental
General procedures
Chemicals were purchased from the Aldrich Chemical Company.
THF was freshly distilled from sodium–benzophenone. Other
anhydrous solvents were obtained from Aldrich in SureSealTM
bottles. Triethylamine was distilled from calcium hydride.
Thin layer chromatography (TLC) was performed using Merck
silica gel 60F254 pre-coated on aluminium sheets. Medium pressure
(‘medium pressure’) chromatography was carried out using Davisil
silica gel (40–63 lm). For the ion exchange chromatography the
strongly basic anion exchange resin Dowex Monosphere 550 A
(OH) (capacity 1.2 meq cm−3) from Sigma-Aldrich was used.
1H and 13C nuclear magnetic resonance (NMR) spectra were
obtained using a Bruker Spectrospin AC 300 E (1H at 300 MHz
or 13C at 75 MHz) or a JEOL JNM-LA500 spectrometer (1H
at 500 MHz or 13C at 125 MHz). Chemical shifts are reported
in parts per million using residual solvent peaks as internal
standards. Multiplicities are indicated by s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), br s (broad signal) or
combinations thereof. LC-MS spectra were obtained using a
Micromass Platform instrument running in positive or negative
ion electrospray mode. IR spectra were recorded on a Bio-Rad
FTS 3000MX diamond ATR as a neat sample.
with tetrabutylammonium fluoride (TBAF) liberated the desired
sulfonic acids (4a–4h). Cleavage of the Si–O bond releases an
alkoxide that immediately effects an intramolecular displacement
of the sulfonate moiety. Besides providing a neopentyl-like group
already known to be advantageous for protection of sulfonic acids,
the gem-dimethyl group offers two advantages in this strategy.
It ensures regioselective silylation of the intermediate diol 9 and
enhances the rate of cyclisation of the desilylated intermediate
by a ‘Thorpe–Ingold effect’.19 The deprotection reactions were
performed with a small excess (0.1–0.2 equiv.) of TBAF in THF
to afford a mixture containing tetrabutylammonium sulfonates,
TBDPS-F and volatile 2,2-dimethyltetrahydrofuran. Evaporation
removed the dimethyltetrahydrofuran (bp 90 ◦C at 740 mmHg20),
whilst extraction with ethyl acetate removed TBDPS-F. Finally,
purification of the tetrabutylammonium sulfonates by anion
exchange chromatography and elution with aqueous acetic acid
as eluent, afforded highly pure sulfonic acids (Scheme 2). The data
in Table 1 demonstrates the efficiency of the coupling reactions of
1 with secondary amines 2a–2h, as well as the deprotection and
the purification of the sulfonic acids, which were all obtained in
good purity, as determined by 1H NMR and combustion analyses.
Previously, sulfonic acids have been protected with the ‘NeoN-B’
group 108b that was removed by treatment with trifluoroacetic acid,
followed by neutralisation. The liberated amino group effected an
intramolecular cyclisation releasing the sulfonate in an analogous
manner to that described here. However, the synthesis of the
alcohol precursor of NeoN-B is lengthy and only one example
of its use was described without full experimental details. Another
example of this theme is the protection of phenols as carbamates
that are cleaved by intramolecular attack by a hydroxyl function
that is released from a tri-isopropylsilyl ether by TBAF attack.21
Melting points were determined using a Stuart Scientific SMP3
apparatus and are uncorrected.
General procedure A. For the synthesis of the piperazine-
derivatives 5 and 6, tert-butyl piperazine-1-carboxylate, di-
isopropylethylamine and the appropriate dibromoalkane were
heated at reflux with stirring in anhydrous dichloromethane for
at least 2–4 d. After removal of the solvent, the white solid
was extracted with ethyl acetate. Unreacted tert-butyl piperazine-
1-carboxylate was recovered by filtration and the filtrate was
concentrated to give a residue that was purified by medium
pressure chromatography.
Scheme 2 Coupling of secondary amines 2a–2h to ethenesulfonate 1 and deprotection of adducts 3a–3h to sulfonic acids 4a–4h.
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General procedure B. The ethenesulfonate ester 1 was taken up
in dichloromethane and the secondary amine (2–4 equiv., except
morpholine) was added to the mixture. After stirring overnight
at room temperature, the solvent was removed and the residue
was purified by medium pressure chromatography using acetone–
hexane as eluent.
purification. dH (300 MHz, CDCl3) 0.84 (6 H, s, (CH3)2C), 1.5 (2 H,
t, J 5.6, 3-H), 3.27 (2 H, s, 1-H), 3.43 (2 H, s, 2 × OH), 3.64 (2 H, t,
J 5.6, 4-H); dC (75.5 MHz, CDCl3) 25.4 (C(CH3)2), 35.3 (C(CH3)2),
43.2 (CH2CH2OH), 59.4 (CH2OH), 71.9 (C(CH3)3CH2OH).
4-(tert-Butyldiphenylsilanyloxy)-2,2-dimethylbutan-1-ol (7). To
a solution of the diol 9 (7.39 g, 62.5 mmol) in DMF (100 cm3)
was added imidazole (8.05 g, 118.2 mmol, 1.9 equiv.) and tert-
butylchlorodiphenylsilane (16.09 g, 58.5 mmol, 0.94 equiv.). After
stirring at room temperature for 60 h, the reaction was quenched
with saturated aqueous NaHCO3 (50 cm3). The DMF was
removed and the residue was extracted with diethyl ether (5×) and
ethyl acetate (1×). The combined organic extracts were dried over
Na2SO4, filtered and the solvent was removed. The crude product
was purified by medium pressure chromatography (elution with
15% acetone–hexane) to give the title compound (16.4 g, 79%)
as a colourless oil (Found: C, 73.9; H, 9.1. C22H32O2Si requires
C, 74.1; H 9.1%); dH (300 MHz, CDCl3) 0.80 (6 H, s, (CH3)2C),
0.98 (9 H, s, (CH3)3C), 1.47 (2 H, t, J 5.5, 3-H), 3.3 (2 H, s, 1-H),
3.64 (2 H, t, J 5.5, 4-H), 7.3–7.4 (6 H, m, Ph), 7.59–7.63 (4 H, m,
Ph); dC (75.5 MHz, CDCl3) 19.4 (C(CH3)3), 25.1 (C(CH3)3), 27.3
(C(CH3)2), 35.3 (2-C), 42.3 (3-C), 61.5 (4-C), 72.2 (1-C), 128.1,
130.0, 134.0, 136.0.
1,4-Di-(tert-butyldiphenylsilanyloxy)-2,2-dimethyl-butane (2.76 g,
8%) was also obtained. dH (300 MHz, CDCl3) 0.77 (6 H, s,
(CH3)2C), 0.95 (9 H, s, (CH3)3), 0.96 (9 H, s, (CH3)3), 1.56
(2 H, t, J 7.3, 3-H), 3.2 (2 H, s, 1-H), 3.64 (2 H, t, J 7.3, 4-
H), 7.3–7.4 (12 H, m, Ph), 7.5–7.6 (8 H, m, Ph); dC (75.5 MHz,
CDCl3) 19.5 (C(CH3)3), 19.8 (C(CH3)3), 24.8, 27.2, 27.3, 35.4,
41.8 (C(CH3)3CH2), 61.4 (C(CH3)3CH2CH2), 73.1 (CH2O), 127.9,
128.0, 129.9, 134.2, 134.5, 136.0, 136.1.
General procedure C for the cleavage of the sulfonate protecting
group. The sulfonate ester (one of 3a–3h) in THF was added to
TBAF in THF and the mixture was stirred at room temperature
for 2 d. After extraction with ethyl acetate, the organic phase
was washed with water (3×) and the combined aqueous extracts
were concentrated. The residual sulfonic acid (one of 4a–4h)
containing tetrabutylammonium species was purified by ion
exchange chromatography. Dowex Monosphere 550 A (OH) resin
(∼5–7 cm3 wet) was flushed with deionised water. A 12.5% (w/v)
solution of ammonia in deionised water was passed through the
column until the eluent was basic. The resin was rinsed with
deionised water until the eluent was neutral and the sulfonic
acid 4a–4h in deionised water was delivered to the column. After
elution with water to remove Bu4NOH (basic pH), the resin was
eluted with 20% (w/v) aqueous acetic acid (400 cm3; there was
eventually a distinct lightening in colour of the resin). The solvent
◦
was removed and the sulfonic acid 4a–4h was dried at 40–50 C
in vacuo.
tert-Butyl 4-(2-bromoethyl)-piperazine-1-carboxylate (5). Fol-
lowing the general procedure A, the reaction of tert-
butyl piperazine-1-carboxylate (505 mg, 2.71 mmol), 1,2-
dibromoethane (1.0 cm3, 11.6 mmol) and di-isopropylethylamine
(0.50 cm3, 2.88 mmol) in dichloromethane (25 cm3) afforded, after
purification by medium pressure chromatography (elution with
15% petrol–ethyl acetate) compound 5 (42 mg, 5%) as a light
yellow solid. dH (300 MHz, CDCl3) 1.41 (9 H, s, C(CH3)3), 2.41
(4 H, t, J 4.9, Pip3,5), 2.68 (2 H, t, J 6.9, BrCH2CH2N), 3.39 (4 H,
t, J 5.1, Pip2,6), 3.55 (2 H, t, J 6.9, BrCH2CH2N) [not further
characterised].
Ethenesulfonic acid 4-(tert-butyldiphenylsilanyloxy)-2,2-di-
methylbutyl ester (1). To a stirred solution of 4-(tert-butyl-
diphenylsilanyloxy)-2,2-dimethylbutan-1-ol7 (6.55 g, 18.37 mmol)
in dichloromethane (250 cm3) cooled in an ice-bath were added
2-chloroethanesulfonyl chloride (6.8 g, 41.8 mmol) followed by
anhydrous triethylamine (14 cm3, ∼5.2 equiv.). After stirring
overnight at room temperature the brown solution was washed
with 10% (w/v) aqueous Na2CO3 (1×) and water (2×). The
organic layer was dried and the solvent was removed. The residue
was purified by medium pressure chromatography on silica using
10% acetone–hexane as eluent, to give the title compound (7.59 g,
93%) as a viscous, yellow oil (Found: C, 64.4; H, 7.6. C24H34O4SSi
requires C, 64.5; H, 7.67%); dH (300 MHz, CDCl3) 0.86 (6 H, s,
(CH3)2C), 0.99 (9 H, s, (CH3)3C), 1.5 (2 H, t, J 6.6), 3.63 (2 H,
tert-Butyl 4-(3-bromopropyl)-piperazine-1-carboxylate (6).
Following the general procedure A, the reaction of tert-
butyl piperazine-1-carboxylate (519 mg, 2.79 mmol), 1,3-
dibromopropane (1 cm3, 9.85 mmol) and di-isopropylethylamine
(0.50 cm3, 2.88 mmol) in dichloromethane (25 cm3) afforded,
after purification by medium pressure chromatography (elution
with 15% petrol–ethyl acetate) compound 6 (348 mg, 41%) as a
light yellow solid, mp 118–121 ◦C. dH (300 MHz, CDCl3) 1.41
(9 H, s), 1.99 (2 H, t, J 6.8), 2.30–2.40 (4 H, br s), 2.45 (2 H, t,
J 6.9), 3.33–3.45 (6 H, m); dC (125.7 MHz, CDCl3) 28.8, 30.0,
32.0, 43.4, 53.4, 56.8, 80.2, 155.1; HRMS (EI+) C12H23BrN2O2
requires 306.0943; found 306.0944.
=
t, J 6.6), 3.78 (2 H, s, OCH2), 5.97 (1 H, dd, J 0.8, 8.8, C CH),
=
6.24–6.40 (2 H, m, CH CH), 7.29–7.40 (m, 6 H, Ph), 7.57–7.60
(m, 4 H, Ph); dC (75.5 MHz, CDCl3) 19.5, 24.7, 27.4, 34.2, 41.7,
60.9, 79.0, 128.1, 129.5, 130.0, 133.4, 134.3, 136.0.
2,2-Dimethylbutane-1,4-diol (9). A solution of 2,2-dimethyl-
succinic acid 8 (4.77 g, 32.6 mmol) in diethyl ether (75 cm3) was
added dropwise to a 1 M solution of LiAlH4 in diethyl ether
(108 cm3, 0.108 mol). The mixture was heated at reflux for 17 h
and quenched carefully with 4 cm3 water, 4 cm3 15% NaOH and
12 cm3 water. After stirring for 30 min, the slurry was filtered and
the inorganic salts were extracted three times with boiling diethyl
ether. The combined ethereal extracts were dried first with MgSO4
and twice with Na2SO4 and concentrated in vacuo. The resulting
colourless viscous oil 9 (3.27 g, 85%) was used without further
2-Morpholin-4-yl-ethanesulfonic acid 4-(tert-butyldiphenyl-
silanyloxy)-2,2-dimethylbutyl
ester
(3a). Following
the
general procedure B, reaction of ethenesulfonate ester
1
(107 mg, 0.24 mmol) with morpholine (388 mg, 4.4 mmol)
in dichloromethane (50 cm3) afforded, after purification by
medium pressure chromatography (30% acetone–hexane) the title
compound (104 mg, 81%) as a colourless oil (Found: C, 62.9; H,
8.2; N 2.62. C28H43NO5SSi requires C, 63.0; H 8.1; N 2.6%); mmax
(film)/cm−1 1354, 1167, 1109, 956, 820, 738 and 702; dH (300 MHz,
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CDCl3) 0.90 (6 H, s, (CH3)2C), 0.97 (9 H, s, (CH3)3C), 1.55 (2 H,
t, J 6.7), 2.37–2.41 (4 H, m), 2.79 (2 H, dd, J 6.4, 8.7), 3.20 (2 H,
dd, J 6.4, 8.7), 3.60–3.63 (4 H, m), 3.68 (2 H, t, J 6.7), 3.92 (2 H,
s), 7.3–7.39 (6 H, m, Ph), 7.57–7.61 (4 H, m, Ph); dC (75.5 MHz,
CDCl3) 19.5 (C(CH3)3), 24.7 (C(CH3)3), 27.3 (C(CH3)2), 34.2,
41.7 (C(CH3)3CH2), 48.4 (NCH2CH2SO2), 52.7 (NCH2CH2SO2),
53.7 (2 × morpholine-C), 60.9 (C(CH3)3CH2CH2), 67.1, 78.0
(CH2O), 128.0, 130.0, 134.3, 135.9.
2-[4-(2-Hydroxyethyl)-piperidin-1-yl]-ethanesulfonic acid 4-
(tert-butyldiphenylsilanyloxy)-2,2-dimethylbutyl
ester
(3e).
Following the general procedure B, reaction of ethenesulfonate
ester 1 (767 mg, 1.72 mmol) with 4-(2-hydroxyethyl)-piperidine
(579 mg, 4.5 mmol) in dichloromethane (50 cm3) afforded,
after purification by medium pressure chromatography (30%
acetone–hexane), the title compound (836 mg, 84%) as a light
yellow oil (Found: C, 64.0.; H, 8.6; N, 2.3. C31H49NO5SSi requires
C, 64.7; H, 8.6; N, 2.4%); mmax (film)/cm−1 1352, 1165, 1103, 955,
737 and 702; dH (300 MHz, CDCl3) 0.89 (6 H, s, (CH3)2C), 0.97
(9 H, s, (CH3)3C), 1.17–1.65 (9 H, m), 1.98 (2 H, br t), 2.77 (4 H,
m), 3.20 (2 H, m), 3.59–3.68 (4 H, m), 3.89 (2 H, s), 7.32–7.39
(6 H, m, Ph), 7.58–7.60 (4 H, m, Ph); dC (75.46 MHz, CDCl3)
19.5, 24.6, 27.3, 32.7, 34.2, 39.7, 41.7, 48.7, 52.5, 54.0, 60.8, 78.0,
128.0, 130.0, 134.3, 135.9; HRMS (EI+) C31H49NO5SSi requires
575.3101, found 575.3095.
tert-Butyl 4-{2-[4-(tert-butyldiphenylsilanyloxy)-2,2-dimethyl-
butoxysulfonyl]-ethyl}-piperazine-1-carboxylate (3b). Following
the general procedure B, reaction of ethenesulfonate es-
ter
1 (733 mg, 1.64 mmol) with tert-butyl piperazine-1-
carboxylate (600 mg, 3.22 mmol, in 8 cm3 dichloromethane)
in dichloromethane (50 cm3) afforded, after purification by
medium pressure chromatography (15% acetone–hexane), the title
compound (985 mg, 95%) as a light yellow oil (Found: C, 62.8; H,
8.4; N, 4.4. C33H52N2O6SSi requires C, 62.6; H, 8.3; N, 4.4%); mmax
(film)/cm−1 1691, 1358, 1247, 1164, 1107, 1001, 955, 823, 738 and
702; dH (300 MHz, CDCl3) 0.89 (6 H, s, (CH3)2C), 0.97 (9 H, s,
(CH3)3C), 1.39 (9 H, s, (CH3)3C), 1.54 (2 H, t, J 6.7), 2.33 (4 H,
br s), 2.76–2.81 (2 H, m), 3.15–3.20 (2 H, m), 3.35 (4 H, br s), 3.67
(2 H, t, J 6.7), 3.90 (2 H, s), 7.29–7.39 (6 H, m, Ph), 7.57–7.60 (4 H,
m, Ph); dC (75.46 MHz, CDCl3) 19.5, 24.6, 27.3, 28.8, 34.2, 41.7,
44.0, 48.5, 52.3, 53.1, 60.8, 78.0, 80.1 128.0, 130.0, 134.2, 135.9,
155.0.
2-Pyrrolidin-1-yl-ethanesulfonic acid 4-(tert-butyldiphenyl-
silanyloxy)-2,2-dimethylbutyl ester (3f). Following the general
procedure B, reaction of ethenesulfonate ester 1 (738 mg,
1.65 mmol) with pyrrolidine (382.8 mg, 5.4 mmol) in
dichloromethane (50 cm3) afforded, after purification by
medium pressure chromatography (20% acetone–hexane), the
title compound (695 mg, 81%) as a light yellow oil (Found: C,
64.5; H, 8.5; N, 2.6. C28H43NO4SSi requires C, 64.95; H, 8.4;
N, 2.7%); mmax (film)/cm−1 1354, 1165, 1106, 956, 822, 737 and
701; dH (300 MHz, CDCl3) 0.89 (6 H, s, (CH3)2C), 0.97 (9 H, s,
(CH3)3C), 1.52 (2 H, t, J 6.7 Hz), 1.71–1.75 (4 H, br s), 2.48 (4 H,
br s), 2.89 (2 H, dd, J 6.5, 9.0), 3.23 (2 H, dd, J 6.6, 9.0), 3.65
(2 H, t, J 6.7), 3.89 (2 H, s), 7.29–7.39 (6 H, m, Ph), 7.58–7.61
(4 H, m, Ph); dC (75.46 MHz, CDCl3) 19.5, 24.1, 24.6, 27.3, 34.2,
41.7, 50.0, 50.1, 54.1, 60.8, 78.0, 128.0, 130.0, 134.3, 135.9.
2-(4-Acetylpiperazin-1-yl)-ethanesulfonic acid 4-(tert-butyl-
diphenylsilanyloxy)-2,2-dimethylbutyl ester (3c). Following
the general procedure B, reaction of ethenesulfonate ester 1
(738 mg, 1.65 mmol) with N-acetylpiperazine (716 mg, 5.6 mmol)
in dichloromethane (50 cm3) afforded, after purification by
medium pressure chromatography (40% acetone–hexane), the
title compound (806 mg, 85%) as a light yellow oil (Found: C,
62.5; H, 8.2; N 4.4. C30H46N2O5SSi requires C, 62.7; H, 8.1; N,
4.9%); mmax (film)/cm−1 1636, 1427, 1355, 1165, 1105, 996, 953,
822, 739 and 702; dH (300 MHz, CDCl3) 0.90 (6 H, s, (CH3)2C),
0.97 (9 H, s, (CH3)3C), 1.53 (2 H, t, J 6.7), 2.0 (3 H, s, CH3),
2.35–2.40 (4 H, m), 2.80 (2 H, dd, J 6.4, 8.5), 3.18 (2 H, m), 3.37
(2 H, dd, J 6.6, 11.7), 3.52–3.55 (2 H, m), 3.66 (2 H, t, J 6.6),
3.90 (2 H, s), 7.29–7.39 (6 H, m, Ph), 7.57–7.61 (4 H, m, Ph); dC
(75.46 MHz, CDCl3) 19.5, 21.3, 24.6, 27.3, 29.7, 34.2, 41.7, 48.5,
52.1, 60.8, 78.0, 128.0, 130.0, 134.3, 135.9, 169.1.
2-[(2-Dimethylaminoethyl)-methylamino]-ethanesulfonic acid 4-
(tert-butyldiphenylsilanyloxy)-2,2-dimethylbutyl ester (3g). Fol-
lowing the general procedure B, reaction of ethenesulfonate ester
1 (716 mg, 1.60 mmol) with N,N,Nꢀ-trimethylethane-1,2-diamine
(414 mg, 4.1 mmol) in dichloromethane (50 cm3) afforded, after
purification by medium pressure chromatography (40% acetone–
hexane + 5–7% Et3N), the title compound (717 mg, 81%) as a
yellow oil (Found: C, 63.1; H, 8.8; N 4.9. C29H48N2O4SSi requires
C, 63.5; H 8.8; N 5.1%); mmax (film)/cm−1 1352, 1165, 1103, 956,
822, 738 and 701; dH (300 MHz, CDCl3) 0.89 (6 H, s, (CH3)2C),
0.97 (9 H, s, (CH3)3C), 1.52 (2 H, t, J 6.7), 2.21 (9 H, s, NCH3),
2.26–2.50 (7 H, m), 2.85 (2 H, dd, J 6.2, 8.8), 3.18 (2 H, dd, J 6.2,
8.8), 3.65 (2 H, t, J 6.7), 3.89 (2 H, s), 7.29–7.39 (6 H, m, Ph),
7.58–7.61 (4 H, m, Ph); dC (75.46 MHz, CDCl3) 19.5, 24.6, 27.3,
34.2, 41.6, 42.5, 46.0, 48.5, 51.9, 55.7, 57.9, 60.8, 77.9, 128.0, 129.9,
134.3, 135.9.
2-[4-(2-Methoxyethyl)-piperazin-1-yl]-ethanesulfonic acid 4-
(tert-butyldiphenylsilanyloxy)-2,2-dimethylbutyl ester (3d). Fol-
lowing the general procedure B, reaction of ethenesulfonate ester 1
(720 mg, 1.61 mmol) with 1-(2-methoxyethyl)-piperazine (611 mg,
4.2 mmol) in dichloromethane (50 cm3) afforded, after purification
by medium pressure chromatography (30% acetone–hexane), the
title compound (889 mg, 93%) as an oil (Found: C, 62.6.; H,
8.6; N, 4.6. C31H50N2O5SSi requires C, 63.0; H, 8.5; N, 4.7%); mmax
(film)/cm−1 1354, 1165, 1105, 956, 8.22, 738 and 702; dH (300 MHz,
CDCl3) 0.89 (6 H, s, (CH3)2C), 0.97 (9 H, s, (CH3)3C), 1.52 (2 H,
t, J 6.7), 2.47–2.82 (9 H, m), 2.79 (2 H, dd, J 6.4, 8.9), 3.17 (2 H,
dd, J 6.4, 8.9), 3.28 (3 H, s), 3.44 (2 H, m), 3.65 (2 H, t, J 6.7),
3.88 (2 H, s), 7.29–7.39 (6 H, m, Ph), 7.57–7.60 (4 H, m, Ph); dC
(75.46 MHz, CDCl3) 19.5, 24.6, 27.3, 34.2, 41.7, 48.5, 52.2, 53.2,
53.8, 58.1, 59.0, 60.8, 70.9, 78.0, 128.0, 130.0, 134.3, 135.9.
2-[Bis-(2-hydroxyethyl)-amino]-ethanesulfonic acid 4-(tert-
butyldiphenylsilanyloxy)-2,2-dimethylbutyl ester (3h). Following
the general procedure B, reaction of ethenesulfonate ester 1
(738 mg, 1.65 mmol) with diethanolamine (452 mg, 4.3 mmol)
in dichloromethane (50 cm3) afforded, after purification by
medium pressure chromatography (30% acetone–hexane), the
title compound (629 mg, 69%) as an oil (Found: C, 60.2; H,
8.2; N, 2.5. C28H45NO6SSi requires C, 60.9; H, 8.2; N, 2.5%);
mmax (film)/cm−1 1348, 1163, 1103, 951, 822, 738 and 702; dH
(300 MHz, CDCl3) 0.89 (6 H, s, (CH3)2C), 0.97 (9 H, s, (CH3)3C),
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1.52 (2 H, t, J 6.7), 2.59 (4 H, t, J 6), 3.00 (2 H, t, J 6.1), 3.16
(2 H, t, J 6.1), 3.56 (4 H, m), 3.66 (2 H, t, J 6.7), 3.91 (2 H, s),
7.29–7.39 (6 H, m, Ph), 7.57–7.61 (4 H, m, Ph); dC (125 MHz,
CDCl3) 19.0, 24.1, 26.8, 33.7, 40.8, 48.2, 48.5, 56.5, 59.4, 60.3,
77.9, 127.7, 129.8, 133.5, 135.5.
chromatography gave the title compound (91 mg, 81%) as a beige
solid, mp 249–251 ◦C (Found: C, 44.7; H, 8.0; N, 5.9. C9H19NO4S +
0.25 H2O requires C, 44.7; H, 8.1; N, 5.8%); mmax (film)/cm−1 3372,
1451, 1221, 1164, 1038, 962, 941, 916, 816 and 758; dH(300 MHz,
D2O) 1.39–1.46 (4 H, m), 1.89–1.94 (2 H, m), 2.90 (1 H, dt, J 2.4,
J 12.9), 3.19–3.56 (9H, m); dC (125 MHz, D2O) 30.0, 30.5, 37.9,
45.9, 53.0, 54.2, 59.7.
2-Morpholin-4-yl-ethanesulfonic acid (4a). Following the gen-
eral procedure C, reaction of sulfonate ester 3a (248 mg,
0.47 mmol) in THF (10 cm3) with TBAF (1 M in THF,
464 mg, 0.51 mmol) in THF (10 cm3) afforded a mixture of 4a
and tetrabutylammonium species. Purification by ion exchange
chromatography gave the title compound (66–72%) as a white
solid, mp 277–280 ◦C (decomp.) (Found: C, 35.6; H 7.0; N 7.1.
2-Pyrrolidin-1-yl-ethanesulfonic acid (4f). Following the gen-
eral procedure C, reaction of sulfonate ester 3f (244 mg,
0.471 mmol) in THF (10 cm3) with TBAF (1 M in THF,
469 mg, 0.52 mmol) in THF (10 cm3) afforded a mixture of 4f
and tetrabutylammonium species. Purification by ion exchange
chromatography gave the title compound (66 mg, 78%) as a white
solid, mp 216–218 ◦C (Found: C, 38.6; H, 7.1; N, 7.5. C6H13NO3S +
0.5 H2O requires C, 38.3; H, 7.5; N, 7.4%); mmax (film)/cm−1 1455,
1215, 1163, 1032 and 911; dH (300 MHz, D2O) 1.84–2.08 (4 H,
m), 2.98–3.06 (2 H, m), 3.18 (2 H, t, J 7.3), 3.44 (2 H, t, J 7.3),
3.56–3.64 (2 H, m); dC (125 MHz, D2O) 23.54, 47.40, 51.22, 55.47.
1
3
C6H13NO4S + H2O requires C, 35.8; H, 6.9; N, 7.0%); mmax
(film)/cm−1 1458, 1262, 1219, 1169, 1121, 1080, 1032, 978, 870,
822, 793 and 762; dH (300 MHz, D2O) 3.23–3.48 (8 H, m), 3.67–
3.86 (4 H, br s); dC (125 MHz, D2O) 45.45, 52.88, 53.27, 64.62.
4-(2-Sulfoethyl)-piperazine-1-carboxylic acid tert-butyl ester
(4b). Following thegeneralprocedure C, the reaction of sulfonate
ester 3b (261 mg, 0.41 mmol) in THF (10 cm3) with TBAF (1 M in
THF, 413 mg, 0.46 mmol) in THF (10 cm3) afforded a mixture of
4b and tetrabutylammonium species. Purification by ion exchange
chromatography gave the title compound (91 mg, 75%) as a white
solid, mp 228–229 ◦C (Found: C, 43.9; H, 7.5; N, 9.4. C11H22N2O5-
S + 0.5 H2O requires C, 43.6; H, 7.6; N, 9.2%); mmax (film)/cm−1
1693, 1406, 1365, 1227, 1158, 1070, 1036, 1008, 964, 934, 862, 802
and 756; dH (300 MHz, D2O) 1.35 (9 H, s), 3.26–3.51 (12 H, m);
dC (75.48 MHz, D2O) 28.4, 41.4, 45.7, 52.7, 53.2, 83.7, 156.3.
2-[(2-Dimethylaminoethyl)methylamino]-ethanesulfonic
acid
(4g). Following the general procedure C, reaction of sulfonate
ester 3g (255 mg, 0.46 mmol) in THF (10 cm3) with TBAF (1 M in
THF, 462 mg, 0.51 mmol) in THF (10 cm3) afforded a mixture of
4g and tetrabutylammonium species. Purification by ion exchange
chromatography gave the title compound (90 mg, 92%) as a
yellow oil (Found: C, 36.9; H, 8.8; N, 11.8. C7H18N2O3S + H2O
requires C, 36.8; H, 8.8; N, 12.3%); mmax (film)/cm−1 1647, 1467,
1175, 1034 and 731; dH (300 MHz, D2O) 2.31 (3 H, s), 2.80 (6 H,
s), 2.82–2.92 (4 H, m), 3.02–3.07 (2 H, m), 3.22 (2 H, t, J 6.6); dC
(75.48 MHz, D2O) 41.87, 44.06, 48.7, 51.6, 52.8, 55.5.
2-(4-Acetylpiperazin-1-yl)-ethanesulfonic acid (4c). Following
the general procedure C, reaction of sulfonate ester 3c (229 mg,
0.4 mmol) in THF (10 cm3) with TBAF (1 M in THF, 399 mg,
0.44 mmol) in THF (10 cm3) afforded a mixture of 4c and
tetrabutylammonium species. Purification by ion exchange chro-
matography gave the title compound (77 mg, 82%) as a pink
solid, mp 291–293 ◦C (decomp.) (Found: C, 39.6; H, 6.8; N, 11.7.
2-[Bis-(2-hydroxyethyl)-amino]-ethanesulfonic acid (4h). Fol-
lowing the general procedure C, reaction of sulfonate ester 3h
(260 mg, 0.472 mmol) in THF (10 cm3) with TBAF (1 M in THF,
469 mg, 0.52 mmol) in THF (10 cm3) afforded a mixture of 4h
and tetrabutylammonium species. Purification by ion exchange
chromatography give the title compound (91 mg, 90%) as a white
solid, mp 159–160 ◦C (Found: C, 32.9; H, 7.0; N, 6.4. C6H15NO5S +
0.5 H2O requires C, 32.4; H, 7.3; N, 6.3%); mmax (film)/cm−1 3389,
3044, 1327, 1158, 1088, 1032, 961, 891, 862, 758 and 735; dH
(300 MHz, D2O) 3.27 (2 H, t, J 7.0), 3.33–3.37 (4 H, m), 3.62
(2 H, t, J 6.9), 3.81–3.85 (4 H, m); dC (125 MHz, D2O) 45.41,
50.90, 55.95, 56.32.
1
3
C8H16N2O4S + H2O requires C, 39.7; H, 6.9; N, 11.6%); mmax
(film)/cm−1 1629, 1426, 1277, 1216, 1153, 1080, 1049, 997, 962,
838, 804, 764 and 721; dH (300 MHz, D2O) 2.06 (3 H, s, CH3),
3.27–3.48 (6 H, m), 3.50 (2 H, m), 3.79 (2 H, br s); dC (125 MHz,
D2O) 21.0, 39.4, 44.0, 45.7, 52.4, 53.0, 173.5.
2-[4-(2-Methoxyethyl)-piperazin-1-yl]-ethanesulfonic acid (4d).
Following the general procedure C, reaction of sulfonate ester
3d (282.6 mg, 0.478 mmol) in THF (10 cm3) with TBAF (1 M in
THF, 475 mg, 0.53 mmol) in THF (10 cm3) afforded a mixture of
4d and tetrabutylammonium species. Purification by ion exchange
chromatography gave the title compound (110 mg, 91%) as a
pink solid, mp 210–212 ◦C (Found: C, 41.9; H, 7.9; N, 10.8.
Acknowledgements
We thank Cancer Research UK, MRC and OSI Pharmaceuticals
for support of this research.
1
3
C9H20N2O4S + H2O requires C, 41.8; H 8.1; N 10.8%); mmax
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