A General Route to the Synthesis of N-Protected 1-Substituted and 1,2-Disubstituted Taurines

Article abstract of DOI:10.1055/s-2003-44382

N-Benzyloxycarbonyl protected α-substituted and αβ- disubstituted taurines were synthesized from olefins and epoxides via N-benzyloxycarbonylamino alcohol thioacetates as key intermediates. They are important sulfur analogues of naturally occurring amino acids and building blocks for the synthesis of α-substituted and α,β- disubstituted β-sulfonopeptides.

Full text of DOI:10.1055/s-2003-44382

276
PAPER
A General Route to the Synthesis of N-Protected 1-Substituted and
1,2-Disubstituted Taurines
Synthesis
i
of
N
-Pr
a
otected 1-S
x
ubstituted an
i
d
1,2-Disubs
X
tituted Taurines u,* Shu Xu
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology,
College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. China
Fax +86(10)62751708; E-mail: jxxu@chem.pku.edu.cn
Received 8 October 2003; revised 6 November 2003
tant to develop an effective and general method for the
Abstract: N-Benzyloxycarbonyl protected -substituted and , -
preparation of 1-substituted and 1,2-disubstituted tau-
rines. Herein we describe a general route to 1-substituted
and 1,2-disubstituted taurines from olefins and epoxides.
disubstituted taurines were synthesized from olefins and epoxides
via N-benzyloxycarbonylamino alcohol thioacetates as key inter-
mediates. They are important sulfur analogues of naturally occur-
ring amino acids and building blocks for the synthesis of
substituted and , -disubstituted -sulfonopeptides.
-
SO3H
SO3H
H2N
H2N
Key words: amino acid, aminoalkanesulfonic acid, epoxide, olefin,
synthesis
R
taurine
R
1-substituted taurine
R1
SO3H
SO3H
H2N
There is a growing interest in the structural modification
of natural peptides to overcome the limitations associated
with their development as therapeutically useful agents,
and to gain information on the nature and mechanism of
the peptide-receptor interactions.1–3 The phosphonami-
date, phosphonate and sulfonamide-linked peptides are
very important modified peptides and are recognized to be
able to mimic transition-state analogues of hydrolysis of
ester and amide bonds because of their tetrahedrally struc-
tural properties. During the last decade aminoalkylphos-
phonic acid and aminoalkanesulfonic acid derivatives,
and phosphonopeptides and sulfonopeptides have been
used as enzyme inhibitors and haptens in the development
of catalytic antibodies.4–7 Sulfonopeptides are more stable
under both mildly acidic and basic conditions compared to
phosphonopeptides and will be used more widely. -Ami-
noalkanesulfonic acids are very important sulfur ana-
logues of naturally occurring amino acids for the synthesis
of sulfonopeptides because -aminoalkanesulfonic acids
and their derivatives are unstable.8 There are three types
of structural analogues of naturally occurring amino acids
for -aminoalkanesulfonic acids, which include 1-substi-
tuted taurines, 2-substituted taurines, and 1,2-disubstitut-
ed taurines (Figure 1). 2-Substituted taurines have been
synthesized effectively from -amino primary alcohols,9–
18 which were easily obtained by reduction of natural ami-
no acids, from -amino secondary alcohols19,20 via sulfite
displacement of their methanesulfonates,9–12 peroxy acid
oxidation of their thioacetates,13–17,21 and sulfite ring-
opening of aziridines.18 But little attention has been paid
to the synthesis of 1-substituted and 1,2-disubstituted
taurines15,21,22 and their sulfonopeptides.21,23,24 To synthe-
size structurally diverse sulfonopeptides, it is very impor-
H2N
R2
2-substituted taurine
1,2-disubstituted taurine
Figure 1
Taurine and substituted taurines
As part of a program to synthesize structurally diverse sul-
fur analogues of naturally occurring amino acids, we
sought to prepare 1-substituted and 1,2-disubstituted tau-
rines. 1,2-Amino secondary alcohols are important key in-
termediates for synthesizing 1-substituted taurines. They
could be prepared from available terminal olefins or 1,2-
epoxyalkanes. Although alkenes could be converted to
1,2-N-protected amino alcohols directly via Sharpless
aminohydroxylation, terminal alkenes generally yield a
mixture of 1,2-N-protected amino primary/secondary al-
cohols in most cases.25 Recently there was a report on the
preparation of useful levels of 1,2-N-protected amino sec-
ondary alcohols in high regioselectivity, however, the alk-
enes used were limited to styrenes.26 Thus, we planned to
prepare 1,2-amino secondary alcohols via ammonia ring
opening of epoxides, which could be synthesized from
terminal alkenes. Firstly, terminal olefin styrene (1a) was
converted to styrene oxide (3a) using Oxone and 1,3-
dichloroacetone in 63% yield.27 The yield is not satisfac-
tory and a large quantity of Oxone was necessary. Finally,
terminal olefins styrene (1a) and hex-1-ene (1b) were
converted conveniently to corresponding bromohydrins
2a,b with NBS in water,28 which were treated with ammo-
nia to yield aminohydrins 4a,b directly via epoxide inter-
mediates 3a,b, followed by reaction with benzyl
chloroformate to afford benzyl N-(2-hydroxyalkyl)car-
bamates 5a,b. The 1,2-epoxyalkanes 3c–e were treated
with ammonia, followed by reaction with benzyl chloro-
SYNTHESIS 2004, No. 2, pp 0276–0282
x
x
.
x
x
.2
0
0
3
Advanced online publication: 15.12.2003
DOI: 10.1055/s-2003-44382; Art ID: F09303SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of N-Protected 1-Substituted and 1,2-Disubstituted Taurines
277
formate to afford carbamates 5c–e. In the case of epoxide fides or their thioacetates.13–17 The hydroxy carbamates
3d, the chloro group was also converted to (benzyloxycar- 5a–e were esterified with thiolacetic acid, DEAD (diethyl
bonyl)amino group at the same time.
azodicarboxylate), and triphenylphosphine under Mit-
sunobu conditions to give (benzyloxycarbonyl)ami-
noalkyl thioacetates 7a–e.13–15 Although vicinal N-
acylamino alcohols afford oxazoline or oxazole deriva-
tives usually as main byproducts or desired products un-
der the Mitsunobu conditions,29–32 no oxazoline derivative
was found in the present reaction mixture due to the diffi-
cult enolization of the carbamates and the existence of a
strong nucleophilic thioacetate anion in the reaction medi-
um. The preparation of thioacetates 7c was also attempted
from the reaction of methanesulfonate 6c and potassium
thioacetate in DMF at room temperature and heating con-
ditions. However, no desired product was obtained al-
though 2-(benzyloxycarbonyl)aminoalkan-1-ol methane-
sulfonate can undergo a substitution reaction smoothly
with potassium or cesium thioacetate.10,15–17 The differ-
ence was presumed to be due to the more steric hindrance
of a secondary alcohol methansulfonate. The thioacetates
7a–e were oxidized with performic acid, generated in situ
by mixing formic acid and hydrogen peroxide, to produce
desired N-protected 1-substituted taurines 8a–e after mix-
ing the crude product with silica gel, evaporation at room
temperature, and silica gel chromatographic separation. If
direct removal of solvent and excess performic acid by
evaporation under reduced pressure at above 50 °C was
carried out, free 1-substituted taurines 9a,c were obtained
directly (Scheme 1).
When we investigated the mechanism of transformation
of -amino alcohol methanesulfonate hydrochlorides into
sodium -amino alkanesulfonates with sodium sulfite, we
found that -amino alcohol methanesulfonates favor the
formation of aziridines via intramolecular amino substitu-
tion by participation of a neighboring group and then un-
dergo a ring-opening reaction through sulfite attack at the
less steric carbon atom in the aziridine ring.18 We pre-
sumed first that the nucleophilicity of the amino group of
-amino alcohol methanesulfonates could be reduced if it
is protected with a carbamate group and 1-substituted tau-
rines could be prepared from N-protected -amino sec-
ondary alcohol methanesulfonates. Thus, 1-(benzyloxy-
carbonyl)aminopropan-2-ol methanesulfonate (6c) was
prepared first from carbamate 5c via methanesulfonation
with methanesulfonyl chloride. Although 2-(benzyloxy-
carbonyl)aminopropan-1-ol methanesulfonate reacted
with sodium bisulfite or sodium sulfite smoothly to yield
2-(benzyloxycarbonyl)aminopropane-1-sulfonic acid in
good yield,9–12 methanesulfonate 6c did not react with so-
dium bisulfite or sodium sulfite under a variety of reaction
conditions, which included sodium bisulfite or sodium
sulfite in a mixture of ethanol and water, in DMF or DM-
SO, or in a biphase mixture of dichloromethane and water
with the phase-transfer catalyst TEBA, etc. (Scheme 1).
This indicates that the nucleophilicity of bisulfite and
sulfite is not strong enough to attack the secondary alco- In a similar manner, two cyclic aminoalkanesulfonic acids
hol methanesulfonate possibly because there is more ster- 8f,g, a type of 1,2-disubstituted taurines, were also pre-
ic hindrance here than
methanesulfonate.
a
primary alcohol pared from cyclopentene (1f) and cyclohexene (1g), re-
spectively. Bromohydrination of 1f,g gave trans-2-
bromocycloalkanols trans-2f,g. During treatment with
ammonia trans-2-bromocycloalkanols trans-2f,g were
converted first to meso-1,2-epoxycycloalkanes 3f,g as in-
An alternative method to prepare aminoalkanesulfonic ac-
ids is the oxidation of aminoalkyl mercaptans, their disul-
Oxone, (ClCH2)2C=O
OH
.
.
OH
NBS
H2O
NH3 H2O
PhCH2OCOCl
NaOH, CH2Cl2
NH3 H2O
O
NH2
R
Br
R
R
R
1a,b
4a-e
3a-e
2a,b
a: R=Ph, b: R=Bu
a: R=Ph, b: R=Bu, c; R=Me, a: R=Ph, b: R=Bu, c; R=Me,
d: R=ClCH2, e: R=PhOCH2 d: R=H2NCH2, e: R=PhOCH2
O
O
O
H2O2, HCO2H
R
AcSH
R
Ph
O
N
R
Ph
O
N
Ph
O
N
H
H
S
H
DEAD, Ph3P
SO3H
OH
8a-e
O
5a-e
7a-e
a: R=Ph, b: R=Bu, c; R=Me,
d: R=ZNHCH2, e: R=PhOCH2
KSAc
H2O2, HCO2H
R
MsCl
Et3N
+H3N
-
SO3
O
NaHSO3
or Na2SO3
9a,c
No reaction
Ph
O
N
H
OMs
6c
Scheme 1 Synthesis of 1-substituted taurines
Synthesis 2004, No. 2, 276–282 © Thieme Stuttgart · New York

278
J. Xu, S. Xu
PAPER
HO
Br
n
O
HO
NH2
n
.
.
NBS
H2O
NH3 H2O
PhCH2OCOCl
NaOH, CH2Cl2
NH3 H2O
n
n
1
trans-(+)-2f,g
3f,g
trans-(+)-4f,g
f: n=1, g: n=2
O
O
n
n
O
H2O2, HCO2H
n
AcSH
Ph
O
N
Ph
O
N
Ph
O
N
H
H
S
H
DEAD, Ph3P
SO3H
OH
trans-(+)-5f,g
cis-(+)-8f,g
O
cis-(+)-7f,g
Scheme 2 Synthesis of 1,2-disubstituted taurines
1-Bromohexan-2-ol (2b)
termediates, which further underwent a ring-opening re-
action followed by N-protection with benzyl
chloroformate to give trans-2-(benzyloxycarbonyl)ami-
nocycloalkanols trans-5f,g. The alcohols trans-5f,g were
converted to the corresponding thioacetates cis-7f,g by
Mitsunobu reaction,13–15 in which Walden conversion oc-
curred completely. The thioacetates cis-7f,g were subse-
quenetly oxidized with performic acid to afford cis-2-
(benzyloxycarbonyl)aminocycloalkanesulfonic acids cis-
8f,g in good yields (Scheme 2). The cyclic aminoalkane-
sulfonic acids could be considered as a type of sulfur mi-
metics of proline.
Colorless liquid; yield: 82%; bp 100–104 °C/6 mmHg (Lit.33 color-
less liquid).
trans-2-Bromocyclopentanol (2f)
Colorless liquid; yield: 64%; bp 105–130 °C/25 mmHg (Lit.34 col-
orless liquid).
trans-2-Bromocyclohexanol (2g)
Colorless liquid; yield: 54%; bp 70–76 °C/6 mmHg (Lit.28 bp 73–75
°C/5 mmHg).
Vicinal Benzyloxycarbonylamino Alcohols 5; General Proce-
dure
To 26–28% aq ammonia (or a mixture with some EtOH for water-
insoluble bromohydrin, 500 mL) was added rapidly a solution of
bromohydrin 2 or epoxide 3 (25 mmol) in EtOH (15 mL) under stir-
ring at r.t. After stirring for 12–24 h, the resulting mixture was con-
centrated (for bromohydrins, the resulting mixtures were
neutralized with aq 1 N NaOH to convert NH4Br into NaBr and
NH3, so that NH3 could be removed during concentration) to afford
a residue (about 10–20 mL) under reduced pressure below 80 °C
(below 40 °C for 1-aminopropan-2-ol).35 The residue was added to
a mixture of aq 1 N NaOH (25 mL) and CH2Cl2 (25 mL). To the so-
lution was added dropwise a 50% (wt) solution of benzyl chlorofor-
mate in toluene (8.53 g, 25 mmol) under vigorous stirring over 10
min at –5 to 5 °C in an ice-salt bath. The resulting solution was al-
lowed to warm to r.t., and stirred overnight. After separation, the
aqueous phase was extracted with CH2Cl2 (15 mL) and the com-
bined organic layers were washed with H2O (2 × 10 mL), brine (10
mL), and dried (MgSO4). After removal of solvent, a colorless crys-
talline or an oily product was obtained, which could be purified by
crystallization from petroleum ether–EtOAc. For the preparation of
dicarbamate 5d, 50 mmol of NaOH and benzyl chloroformate were
used.36
In summary, 1-substituted and 1,2-disubstituted (cyclic)
taurines were prepared from olefins and epoxides by em-
ploying N-protected 2-aminoalkan-1-ol thioacetates as
key intermediates. They are important sulfur analogues of
naturally occurring amino acids and building blocks for
synthesis of -substituted and , -disubstituted -sul-
fonopeptides and other substituted 2-aminoethanesulfonic
acid containing compounds.
Melting points were measured on a Yanaco MP-500 melting point
1
apparatus and are uncorrected. H and 13C NMR spectra were re-
corded on a Varian Mercury 200 (200 MHz) or Mercury Plus 300
(300 MHz) spectrometer in CDCl3 with TMS as an internal standard
or in DMSO-d6. Mass spectra were obtained on a VG-ZAB-HS
mass spectrometer or a Bruker ESQUIRE-LCTM ESI ion trap spec-
trometer. CHN analyses were recorded on an Elementar Vario EL
analyzer. The analytical data of all known compounds are identical
to those reported earlier in the literature.25–27
THF was refluxed over sodium and distilled prior to use. Et3N was
refluxed over NaOH and distilled prior to use.The petroleum ether
used had a bp range 60–90 °C.
Benzyl N-(2-Hydroxy-2-phenylethyl)carbamate (5a)
Colorless crystals; yield: 62%; mp 120–121 °C (Lit.25 mp 114–115
°C).
Vicinal Bromohydrins 2; General Procedure
Alkene 1 (10 mmol) and NBS (1.78 g, 10 mmol) were added to H2O
(4 mL). The resulting suspension was stirred for 1 to 48 h depending
on alkene (monitoring by TLC). After the reaction was over, the
mixture was separated and the aqueous phase was extracted with
Et2O (2 × 15 mL). The combined organic layers were washed with
aq 10% NaHSO3 (2 × 15 mL) to remove excess NBS and Br2 (Cau-
tion! it is advisable to use a big separatory funnel due to Br2 vapors)
and dried (Na2SO4). After concentration, the residue was distilled to
afford the bromohydrin as a colorless oil.
Benzyl N-(2-Hydroxyhexyl)carbamate (5b)
Colorless needles; yield: 84%; mp 60.5–61 °C; Rf 0.40 (petroleum
ether–EtOAc, 2:1, silica gel plate).
IR (KBr): 3400 and 3346 (NH, OH), 1701 cm–1 (C=O).
1H NMR (200 MHz, CDCl3): = 7.35 (s, 5 H, C6H5), 5.26 (br s, 1
H, NH), 5.10 (s, 2 H, OCH2), 3.68 (m, 1 H, CH), 3.38 (ddd, J = 3.0,
6.4, 13.8 Hz, 1 H, NCHH), 3.05 (ddd, J = 5.2, 7.8, 13.8 Hz, 1 H,
NCHH), 2.31 (s, 1 H, OH), 1.41–1.33 (m, 6 H, 3 × CH2), 0.90 (t,
J = 6.2 Hz, 3 H, CH3).
13C NMR (50 MHz, CDCl3): = 156.93, 136.22, 128.23, 127.84,
127.79, 70.77, 66.51, 46.74, 34.07, 27.42, 22.40, 13.78.
2-Bromo-1-phenylethanol (2a)
Colorless liquid; yield: 72%; bp 140–160 °C/6 mmHg (Lit.28 bp
120–123 °C/5 mmHg).
Synthesis 2004, No. 2, 276–282 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Protected 1-Substituted and 1,2-Disubstituted Taurines
279
MS (EI): m/z (%) = 251 (M+, 1.6), 165 (M+ – BuCHO, 18), 150
1-Substituted 2-(Benzyloxycarbonyl)aminoethyl Thioacetates
and 1-Substituted 2-(Benzyloxycarbonyl)aminocycloalkyl
Thioacetates 7; General procedure
(M+ – PhCH2O2CNH, 2.7), 108 (PhCH2OH+, 17), 91 (PhCH2 ,
+
100).
Diethyl azodicarboxylate (1.74 g, 10 mmol) in anhyd THF (6 mL)
was added to an efficiently stirred solution of Ph3P (2.62 g, 10
mmol) in anhyd THF (12 mL) at –10 °C. The mixture was stirred at
for 0.5 h at –10 °C. A white precipitate appeared. The Cbz-amino
alcohol 5 (5 mmol) and thiolacetic acid (0.76 g, 10 mmol) in THF
(12 mL) were added dropwise over 30 min and the mixture was
stirred for 1 h at –10 °C and for 20 h at r.t.. The resulting mixture
was concentrated in reduced pressure. The triphenylphosphine ox-
ide crystallized out upon addition of EtOAc–petroleum ether. The
combined filtrates were concentrated in vacuo and subjected to sil-
ica gel column chromatographic separation with a mixture of petro-
leum ether and Et2O (8:1) as an eluent to give the thioacetate 7.
Anal. Calcd for C14H21NO3 (251.32): C, 66.91; H, 8.42; N, 5.57.
Found: C, 66.69; H, 8.69; N, 5.65.
Benzyl N-(2-Hydroxypropyl)carbamate (5c)
Colorless oil; yield: 77% (based on 1- aminopropan-2-ol) (Lit.37 mp
31–32 °C).
Dibenzyl N,N -1,3-(2-Hydroxypropylene)dicarbamate (5d)
Colorless crystals; yield: 73%; mp 127.5–128.5 °C (Lit.38 mp 122–
123 °C).
Benzyl N-(2-Hydroxy-3-phenoxypropyl)carbamate (5e)
Colorless crystals; yield: 86%; mp 77.5–78 °C; Rf 0.20 (petroleum
ether–EtOAc, 2:1, silica gel plate).
IR (KBr): 3356 (NH, OH), 1703 cm–1 (C=O).
2-(Benzyloxycarbonyl)amino-1-phenylethyl Thioacetate (7a)
Colorless crystals, yield: 63%; mp 75–76 °C; Rf 0.30 (petroleum
ether–Et2O, 3:1, silica gel plate).
1H NMR (300 MHz, CDCl3): = 7.29–6.82 (m, 10 H, 2 × C6H5),
5.53 (t, J = 6.6 Hz, 1 H, NH), 5.06 (s, 2 H, OCH2), 4.04 (m, 1 H,
CH), 3.89 (m, 2 H, OCH2), 3.46 (ddd, J = 3.9, 6.6, 14.1 Hz, 1 H,
NCHH), 3.29 (ddd, J = 5.7, 6.6, 14.1 Hz, 1 H, NCHH), 3.23 (s, 1 H,
OH).
13C NMR (75.5 MHz, CDCl3): = 158.20, 157.17, 136.19, 129.39,
128.38, 128.03, 127.94, 121.09, 114.39, 69.37, 69.29, 66.81, 43.69.
IR (KBr): 3342 (NH), 1718 (C=O), 1696 cm–1 (C=O).
1H NMR (300 MHz, CDCl3): = 7.32–7.29 (m, 10 H, 2 × C6H5),
5.08 (s, 2 H, OCH2), 4.96 (s, 1 H, NH), 4.72 (t, J = 7.5 Hz, 1 H, CH),
3.68 (dd, J = 6.9, 7.5 Hz, 2 H, NCH2), 2.30 (s, 3 H, CH3).
13C NMR (75.5 MHz, CDCl3): = 194.27, 156.09, 138.46, 136.38,
128.77, 128.64, 128.38, 127.98, 127.84, 127.79, 66.69, 47.81,
45.55, 30.34.
MS (EI): m/z (%) = 301 (M+, 0.87), 208 (M+ – PhO, 9.0), 192
MS (EI): m/z (%): 329 (M+, 1.2), 286 (M+ – Ac, 15), 254 (M+ – AcS,
(M+ – H2O – PhCH2, 23), 108 (PhCH2OH+, 7.7), 107 (PhCH2O+,
2.4), 253 (M+ – AcSH, 8.6), 238 (M+ – PhCH2, 20), 108
+
9.8), 91 (PhCH2 , 100).
+
(PhCH2OH+, 5.9), 91 (PhCH2 , 100).
Anal. Calcd for C17H19NO4 (301.34): C, 67.76; H, 6.36; N, 4.65.
Found: C, 67.59; H, 6.49; N, 4.75.
Anal. Calcd for C18H19NO3S (329.41): C, 65.63; H, 5.81; N, 4.25.
Found: C, 65.51; H, 5.69; N, 4.05.
trans-Benzyl N-(2-Hydroxycyclopentyl)carbamate (5f)
Colorless crystals; yield: 60%; mp 61.5–62 °C (Lit.39 mp 57–
59 °C).
1-(Benzyloxycarbonyl)aminomethylpentyl Thioacetate (7b)
Yellowish oil; yield: 37%; Rf 0.25 (petroleum ether–Et2O, 5:1, sili-
ca gel plate).
trans-Benzyl N-(2-Hydroxycyclohexyl)carbamate (5g)
Colorless needles; yield: 78%; mp 109.5–110 °C (Lit.40 mp 115–
116 °C).
IR (KBr): 3344 (NH), 1718 (C=O), 1695 cm–1 (C=O)
1H NMR (300 MHz, CDCl3): = 7.33–7.31 (m, 5 H, C6H5), 5.13 (br
s, 1 H, NH), 5.09 (s, 2 H, OCH2), 3.58 (dddd, J = 5.1, 5.1, 7.2, 7.2
Hz, 1 H, CH), 3.46 (ddd, J = 5.1, 5.1, 14.1 Hz, 1 H, NCHH), 3.31
(ddd, J = 7.2, 7.2, 14.1 Hz, 1 H, NCHH), 2.29 (s, 3 H, COCH3),
1.65–1.44 (m, 2 H,CH2), 1.41–1.26 (m, 4 H, 2 × CH2), 0.88 (t,
J = 6.6 Hz, 3 H, CH3).
13C NMR (75.5 MHz, CDCl3): = 195.77, 156.35, 136.42, 128.35,
127.96, 127.87, 66.58, 44.99, 44.88, 31.29, 30.63, 28.86, 22.26,
13.77.
1-(Benzyloxycarbonyl)aminopropan-2-ol Methanesulfonate
(6c)
To an ice-cooled solution of 5c (0.65 g, 3.1 mmol) and Et3N (0.35
g, 3.4 mmol) in CH2Cl2 (10 mL) was added a solution of MsCl (0.39
g, 3.4 mmol) in CH2Cl2 (10 mL) dropwise over 0.5 h. The mixture
was evaporated in vacuo, and the residue was treated with EtOAc
and H2O. The separated organic layer was washed with 5% aq
NaHCO3 and brine, and dried (Na2SO4). The solvent was removed
in vacuo to give a colorless oil; yield: 98%.
MS (EI): m/z (%) = 309 (M+, 0.81), 266 (M+ – Ac, 0.78), 233 (M+ –
+
AcSH, 10), 108 (PhCH2OH+, 8.0), 91 (PhCH2 , 100).
IR (KBr): 3389 (NH), 2939 (C–H), 1718 (C=O), 1252 (SO2), 1176
cm–1 (SO2).
Anal. Calcd for C16H23NO3S (309.42): C, 62.11; H, 7.49; N, 4.53.
Found: C, 61.89; H, 7.39; N, 4.45.
1H NMR (300 MHz, CDCl3): = 7.34 (s, 5 H, C6H5), 5.38 (br s, 1
H, NH), 5.10 (s, 2 H, OCH2), 4.84 (ddq, J = 3.3, 6.3, 6.6 Hz, 1 H,
CH), 3.47 (ddd, J = 3.3, 6.2, 15.0 Hz, 1 H, NCHH), 3.27 (ddd,
J = 6.3, 7.2, 15.0 Hz, 1 H, NCHH), 2.92 (s, 3 H, CH3SO3), 1.38 (d,
J = 6.6 Hz, 3 H, CH3).
2-(Benzyloxycarbonyl)amino-1-methylethyl Thioacetate (7c)
Yellowish oil; yield: 51%; Rf 0.25 (petroleum ether–Et2O, 1:1, sili-
ca gel plate).
IR (KBr): 3344 (NH), 1721 (C=O), 1692 cm–1 (C=O).
13C NMR (75.5 MHz, CDCl3): = 156.42, 136.19, 128.44, 128.12,
128.05, 78.19, 66.83, 45.83, 38.06, 18.44.
ESI-MS: m/z (%) = 287 (MH+, 10), 310 (MNa+, 100).
1H NMR (300 MHz, CDCl3): = 7.40–7.27 (m, 5 H, C6H5), 5.10 (s,
2 H, OCH2), 5.02 (br s, 1 H, NH), 3.66 (ddq, J = 6.3, 6.9, 6.9 Hz, 1
H, CH), 3.43 (ddd, J = 5.7, 6.3, 13.9 Hz, 1 H, NCHH), 3.31 (ddd,
J = 6.9, 6.9, 13.9 Hz, 1 H, NCHH), 2.30 (s, 3 H, COCH3), 1.30 (d,
J = 6.9 Hz, 3 H, CH3).
13C NMR (75.5 MHz, CDCl3): = 195.69, 156.41, 136.35, 128.45,
128.07, 127.98, 66.73, 46.08, 39.72, 30.68, 18.06.
Anal. Calcd for C12H17NO5S (287.33): C, 50.16; H, 5.96; N, 4.87.
Found: C, 50.30; H, 5.79; N, 5.03.
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280
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PAPER
MS (EI): m/z (%) = 267 (M+, 1.1), 224 (M+ – Ac, 1.2), 191 (M+ –
Anal. Calcd for C16H21NO3S (307.41): C, 62.51; H, 6.89; N, 4.56.
Found: C, 62.51; H, 6.69; N, 4.65.
AcSH, 9.3), 108 (PhCH2OH+, 13.7), 107 (PhCH2O+, 8.2), 91
+
(PhCH2 , 100).
1-Substituted 2-(Benzyloxycarbonyl)aminoethanesulfonic
Acids and 2-(Benzyloxycarbonyl)aminocycloalkanesulfonic
Acids 8; General Procedure
Anal. Calcd for C13H17NO3S (267.35): C, 58.40; H, 6.41; N, 5.24.
Found: C, 58.61; H, 6.29; N, 5.09.
To a performic acid solution, prepared by mixing and stirring 30%
H2O2 (1.2 mL) and 88% HCO2H (12 mL) at r.t. for 1 h and cooled
in an ice bath, was added the appropriate thioacetate derivative 7 (2
mmol) in 88% HCO2H (2.7 mL) dropwise, keeping the temperature
at 0 °C. After stirring the mixture for an additional 2 h at 0 °C and
for 20 h at r.t., the resulting mixture was mixed with silica gel and
evaporated to dryness at r.t. The residue was separated on a silica
gel column with a mixture of CHCl3 and MeOH (20:1 to 10:1) and
MeOH as eluents to give pure 8.
2-(Benzyloxycarbonyl)amino-1-(benzyloxycarbonyl)aminome-
thylethyl Thioacetate (7d)
Yellowish solid; directly used for oxidation without further purifi-
cation.
2-[(Benzyloxycarbonyl)amino]-1-phenoxymethylethyl Thioace-
tate (7e)
Colorless crystals; yield: 55%; mp 101.5–102.5 °C; Rf 0.20 (petrol-
eum ether–EtOAc, 9:1, silica gel plate).
IR (KBr): 3355 (NH), 1695 (C=O), 1693 cm–1 (C=O).
2-(Benzyloxycarbonyl)amino-1-phenylethanesulfonic Acid (8a)
Colorless crystals; yield: 91%; mp 192–194 °C; Rf 0.40 (CHCl3–
MeOH, 4:1, silica gel plate).
1H NMR (300 MHz, CDCl3): = 7.29–6.84 (m, 10 H, 2 × C6H5),
5.39 (dd, J = 5.7, 6.3, 1 H, NH), 5.09 (s, 2 H, OCH2), 4.12 (dd,
J = 5.1, 6.4 Hz, 1 H, PhOCHH), 4.01 (m, 1 H, H in PhOCHH), 3.99
(m, 1 H, CH), 3.63 (ddd, J = 5.7, 5.7, 14.1 Hz, 1 H, NCHH), 3.50
(ddd, J = 6.3, 6.3, 14.1 Hz, 1 H, NCHH), 2.67 (s, 3 H, COCH3).
13C NMR (75.5 MHz, CDCl3): = 194.64, 157.96, 156.24, 136.25,
129.28, 128.23, 127.84, 127.73, 121.08, 114.36, 67.87, 66.51,
43.47, 41.95, 30.41.
IR (KBr): 3413 (br, NH and SOH), 1698 (C=O), 1222 (SO2), 1172
cm–1 (SO2).
1H NMR (200 MHz, DMSO-d6): = 7.36–7.22 (m, 10 H, ArH),
6.99 (s, 1 H, NH), 4.92 (s, 2 H, OCH2), 3.78 (dd, J = 8.6, 14.6 Hz,
1 H, CH), 3.64 (m, 2 H, NCH2).
13C NMR (50 MHz, DMSO-d6):
= 155.79, 137.48, 137.22,
MS (EI): m/z = 359 (M+, 0.35), 284 (M+ – AcS, 15), 266 (M+ – PhO,
129.48, 128.33, 127.66, 127.45, 127.40, 126.47, 65.05, 64.42,
42.55.
+
5.2), 224 (M+ – PhCH2O2C, 14), 91 (PhCH2 , 100).
MS (ESI, negative ion): m/z = 334 (M – H)–.
Anal. Calcd for C19H21NO4S (359.44): C, 63.49; H, 5.89; N, 3.90.
Found: C, 63.51; H, 5.69; N, 4.05.
Anal. Calcd for C16H17NO5S (335.38): C, 57.30; H, 5.11; N, 4.18.
Found: C, 57.52; H, 5.29; N, 4.06.
cis-2-[(Benzyloxycarbonyl)amino]cyclopentyl Thioacetate (7f)
Colorless crystals; yield: 65%; mp 66–66.5 °C; Rf 0.20 (petroleum
ether–Et2O, 8:1, silica gel plate).
IR (KBr): 3342 (NH), 1711 (C=O), 1695 cm–1 (C=O).
2-(Benzyloxycarbonyl)amino-1-butylethanesulfonic Acid (8b)
Colorless crystals; yield: 83%; mp >360 °C; Rf 0.60 (CHCl3–
MeOH, 4:1, silica gel plate).
1H NMR (300 MHz, CDCl3): = 7.36 (s, 5 H, C6H5), 5.09 (s, 2 H,
OCH2), 4.86 (br s, 1 H, NH), 4.25 (m, 1 H, SCH), 3.97 (m, 1 H,
NCH), 2.29 (s, 3 H, CH3), 2.21–1.98 (m, 2 H, CH2), 1.81–1.58 (m,
3 H, CH2), 1.56–1.41 (m, 1 H, CHH).
13C NMR (50 MHz, CDCl3): = 177.05, 155.78, 136.48, 128.45,
128.09, 128.04, 66.73, 54.31, 47.20, 31.06, 30.71, 30.53, 20.99.
IR (KBr): 3382 and 3291 (br, NH and SOH), 1692 (C=O), 1230
(SO2), 1168 cm–1 (SO2).
1H NMR (200 MHz, DMSO-d6): = 7.32 (s, 5 H, C6H5), 6.85 (br s,
1 H, NH), 5.00 (s, 2 H, OCH2), 3.29 (t, J = 5.4 Hz, 2 H, NCH2), 2.42
(tt, J = 5.4, 7.6 Hz, 1 H, CH), 1.31–1.20 (m, 6 H, 3 × CH2), 0.82 (t,
J = 6.6 Hz, 3 H, CH3).
MS (EI): m/z = 293 (M+, 0.49), 217 (M+ – AcS, 13), 108
13C NMR (50 MHz, DMSO-d6):
= 155.90, 137.27, 128.38,
+
(PhCH2OH+, 5.3), 91 (PhCH2 , 100).
127.81, 127.67, 65.30, 58.23, 40.92, 29.00, 27.39, 22.33, 13.87.
MS (ESI, negative ion): m/z = 314 (M – H)–.
Anal. Calcd for C15H19NO3S (293.38): C, 61.41; H, 6.53; N, 4.77.
Found: C, 61.31; H, 6.39; N, 4.95.
Anal. Calcd for C14H21NO5S (315.39): C, 53.32; H, 6.71; N, 4.44.
Found: C, 53.51; H, 6.89; N, 4.70.
cis-2-[(Benzyloxycarbonyl)amino]cyclohexyl Thioacetate (7g)
Colorless needles; yield: 38%; mp 105.5–106 °C; Rf 0.40 (petrol-
eum ether–Et2O, 5:1, silica gel plate).
IR (KBr): 3335 (NH), 1716 (C=O), 1697 cm–1 (C=O).
2-(Benzyloxycarbonyl)amino-1-methylethanesulfonic Acid (8c)
Colorless crystals; yield: 90%; mp >360 °C; Rf 0.50 (CHCl3–
MeOH, 4:1, silica gel plate).
1H NMR (300 MHz, CDCl3): = 7.34–7.27 (m, 5 H, C6H5), 5.08 (s,
2 H, OCH2), 4.98 (d, J = 7.8 Hz, 1 H, NH), 4.07 (dt, J = 4.0, 4.0 Hz,
1 H, SCH), 3.91 (m, 1 H, NCH), 2.31 (s, 3 H, COCH3), 1.83–1.71
(m, 3 H, CH2), 1.71–1.61 (m, 1 H, CHH), 1.61–1.49 (m, 1 H, CHH),
1.49–1.26 (m, 3 H, CH2).
13C NMR (75.5 MHz, CDCl3): = 194.26, 155.40, 136.38, 128.36,
128.05, 127.96, 66.58, 51.09, 46.51, 30.95, 30.82, 30.20, 23.59,
22.30.
IR (KBr): 3362 (br, NH and SOH), 1701 (C=O), 1215 (SO2), 1170
cm–1 (SO2).
1H NMR (300 MHz, DMSO-d6): = 7.33 (s, 5 H, C6H5), 7.04 (s, 1
H, NH), 4.99 (s, 2 H, OCH2), 3.40–3.28 (m, 1 H, NCHH), 3.08 (ddd,
J = 7.5, 7.5, 12.9 Hz, 1 H, NCHH), 2.57 (m, 1 H, CH), 1.06 (d,
J = 6.9 Hz, 3 H, CH3).
13C NMR (75.5 MHz, DMSO-d6): = 156.11, 137.30, 128.47,
127.88, 127.80, 65.33, 53.66, 42.77, 13.80.
MS (ESI, negative ion): m/z = 272 (M – H)–.
MS (EI): m/z = 307 (M+, 0.85), 264 (M+ – Ac, 0.90), 231 (M+ – Ac-
SH, 10), 216 (M+ – PhCH2, 19.8), 108 (PhCH2OH+, 6.1), 91
+
(PhCH2 , 100).
Anal. Calcd for C11H15NO5S (273.31): C, 48.34; H, 5.53; N, 5.12.
Found: C, 48.50; H, 5.79; N, 5.00.
Synthesis 2004, No. 2, 276–282 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Protected 1-Substituted and 1,2-Disubstituted Taurines
281
2-(Benzyloxycarbonyl)amino-1-(benzyloxycarbonyl)aminome-
thylethanesulfonic Acid (8d)
Colorless crystals; yield: 41% {based on 1,3-di[(benzyloxycarbon-
yl)amino]propan-2-ol}; mp 255–256 °C; Rf 0.40 (CHCl3–
MeOH, 4:1, silica gel plate).
MS (ESI, negative ion): m/z = 312 (M – H)–.
Anal. Calcd for C14H21NO5S (313.37): C, 53.66; H, 6.11; N, 4.47.
Found: C, 53.42; H, 6.00; N, 4.18.
1-Substituted 2-Aminoethanesulfonic Acids 9; General Proce-
dure
IR (KBr): 3376 and 3260 (br, NH and SOH), 1699 (C=O), 1240
(SO2), 1176 cm–1 (SO2).
1H NMR (300 MHz, DMSO-d6): = 7.33 (s, 10 H, 2 × C6H5), 6.96
(br s, 2 H, 2 × NH), 5.00 (s, 4 H, 2 × OCH2), 3.25 (m, 4 H,
2 × NCH2), 2.59 (quintet, J = 6.0 Hz, 1 H, CH).
13C NMR (75.5 MHz, DMSO-d6): = 155.93, 137.17, 128.46,
127.87, 127.78, 65.44, 58.04, 37.67.
To a performic acid solution, prepared by mixing and stirring 30%
H2O2 (1.2 mL) and 88% HCO2H (12 mL) for 1 h at r.t. and cooled
in an ice bath, was added the corresponding thioacetate derivative 7
(2 mmol) in 88% HCO2H (2.7 mL) dropwise. The resulting mixture
was refluxed and stirred overnight. After removal of solvent, the
residue was crystallized from MeOH to give pure 9.
MS (ESI, negative ion): m/z = 421 (M – H)–.
2-Amino-1-phenylethanesulfonic Acid (9a)
Colorless crystals; yield: 90%; mp 281–282 °C (Lit.22 mp 283–
286 °C).
Anal. Calcd for C19H22N2O7S (422.45): C, 54.02; H, 5.25; N, 6.63.
Found: C, 53.96; H, 5.03; N, 6.69.
2-Amino-1-methylethanesulfonic Acid (9c)
2-(Benzyloxycarbonyl)amino-1-phenoxymethylethanesulfonic
Acid 8e
Colorless crystals; yield: 83%; mp >360 °C (Lit.22 mp 379 °C).
Colorless crystals; yield: 91%; mp 251–253 °C; Rf 0.30 (CHCl3–
MeOH, 4:1, silica gel plate).
Acknowledgment
IR (KBr): 3441 (br, NH and SOH), 1700 (C=O), 1239 (SO2), 1200
cm–1 (SO2).
1H NMR (200 MHz, DMSO-d6): = 7.29–6.87 (m, 10 H, ArH),
6.25 (br s, 1 H, NH), 4.99 (s, 2 H, OCH2), 4.38 (d, J = 8.4 Hz, 1 H,
PhOCHH), 4.00 (dd, J = 8.4, 9.2 Hz, 1 H, PhOCHH), 3.52 (m, 2 H,
NCH2), 3.05 (m, 1 H, CH).
The project was supported partly by National Natural Science Foun-
dation of China (No. 20272002), Ministry of Education of P. R.
China (SRF for ROCS and EYTP), and Peking University (Presi-
dent grant).
References
13C NMR (50 MHz, DMSO-d6):
= 158.52, 156.00, 137.25,
129.67, 128.50, 127.91, 127.78, 120.85, 114.75, 66.25, 65.55,
57.95, 39.92.
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MS (ESI, negative ion): m/z = 364 (M – H)–.
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Anal. Calcd for C17H19NO6S (365.40): C, 55.88; H, 5.24; N, 3.83.
Found: C, 56.01; H, 5.01; N, 3.97.
cis-2-(Benzyloxycarbonyl)aminocyclopentanesulfonic Acid (8f)
Colorless crystals; yield: 91%; mp 173–176 °C; Rf 0.60 (CHCl3–
MeOH, 6:1, silica gel plate).
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IR (KBr): 3413 (br, NH and SOH), 1694 (C=O), 1212 (SO2), 1181
cm–1 (SO2).
1H NMR (300 MHz, DMSO-d6): = 7.41 (s, br, 1 H, NH), 7.33 (s,
5 H, ArH), 4.97 (s, 2 H, CH2O), 3.78 (m, 1 H, CHN), 2.93 (m, 1 H,
CHS), 1.92–1.74 (m, 3 H, CH2), 1.67 (m, 2 H, CH2), 1.49 (m, 1 H,
H in CHH).
13C NMR (75.5 MHz, DMSO-d6): = 157.45, 137.10, 128.40,
128.31, 127.87, 65.22, 59.53, 53.49, 31.50, 26.12, 21.04.
MS (ESI, negative ion): m/z = 298 (M – H)–.
Anal. Calcd for C13H17NO5S (299.34): C, 52.16; H, 5.72; N, 4.68.
Found: C, 51.97; H, 5.99; N, 4.82.
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cis-2-(Benzyloxycarbonyl)aminocyclohexanesulfonic Acid (8g)
Colorless crystals; yield: 91%; mp 181–182 °C; Rf 0.60 (CHCl3–
MeOH, 4:1, silica gel plate).
IR (KBr): 3426 (br, NH and SOH), 1693 (C=O), 1202 (SO2), 1175
cm–1 (SO2).
1H NMR (300 MHz, DMSO-d6): = 7.42–7.20 (m, 5 H, ArH), 6.92
(br s, 1 H, NH), 5.01 (d, J = 12.6 Hz, 1 H, H in CH2O), 4.94 (d,
J = 12.6 Hz, 1 H, H in CH2O), 3.83 (m, 1 H, CHN), 2.56 (m, 1 H,
CHS), 2.18 (m, 1 H, CHH), 1.83–1.60 (m, 3 H, CH2), 1.50–1.16 (m,
4 H, 2 × CH2).
13C NMR (75.5 MHz, DMSO-d6): = 155.64, 137.18, 128.45,
128.39, 127.84, 65.20, 58.05, 48.35, 39.78, 28.59, 23.62, 20.51.
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282
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PAPER
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Synthesis 2004, No. 2, 276–282 © Thieme Stuttgart · New York