A new and expeditious asymmetric synthesis of (R)- and (S)-2-aminoalkanesulfonic acids from chiral amino alcohols

Article abstract of DOI:10.1016/S0957-4166(02)00312-9

The mechanism for the transformation of β-amino alcohol methanesulfonate hydrochlorides into sodium β-amino alkanesulfonates using sodium sulfite was investigated. The results show that sodium sulfite initially neutralizes the β-amino alcohol methanesulfonate hydrochloride to give a free β-amino alcohol methanesulfonate, which then cyclizes to a 2-alkylaziridine. Attack by the previously formed sodium bisulfite at the less hindered carbon atom of the aziridine ring then yields a β-amino alkanesulfate sodium salt. Based on this mechanistic proposal, a new and rapid asymmetric synthesis of (R)- and (S)-2-aminoalkanesulfonic acids from chiral amino alcohols was developed. Chiral amino alcohols were converted to chiral aziridines through the Wenker method or Mitsunobu reaction and the resulting aziridines were reacted with sodium bisulfite to produce chiral β-amino alkanesulfonic acids.

Full text of DOI:10.1016/S0957-4166(02)00312-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1129–1134
A new and expeditious asymmetric synthesis of (R)- and
(S)-2-aminoalkanesulfonic acids from chiral amino alcohols
Jiaxi Xu
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, PR China
Received 17 December 2001; accepted 3 June 2002
Abstract—The mechanism for the transformation of b-amino alcohol methanesulfonate hydrochlorides into sodium b-amino
alkanesulfonates using sodium sulfite was investigated. The results show that sodium sulfite initially neutralizes the b-amino
alcohol methanesulfonate hydrochloride to give a free b-amino alcohol methanesulfonate, which then cyclizes to a 2-alkylaziridine.
Attack by the previously formed sodium bisulfite at the less hindered carbon atom of the aziridine ring then yields a b-amino
alkanesulfate sodium salt. Based on this mechanistic proposal, a new and rapid asymmetric synthesis of (R)- and (S)-2-aminoalka-
nesulfonic acids from chiral amino alcohols was developed. Chiral amino alcohols were converted to chiral aziridines through the
Wenker method or Mitsunobu reaction and the resulting aziridines were reacted with sodium bisulfite to produce chiral b-amino
alkanesulfonic acids. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
effective routes to prepare chiral amino alkanesulfonic
acids as research materials or building blocks for the
synthesis of sulfonopeptides.
Several 2-aminoalkanesulfonic acids have been found in
many mammalian tissues and are involved in various
important physiological processes.1 However, little
attention has been paid to their syntheses either in
racemic or enantiomerically pure form, which could
allow the study of these physiological processes.1 On
the other hand, there has been increasing 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.2–4 Phosphonamidate-, phosphonate- and
sulfonamide-containing peptides are very important
modified peptides and are recognized to be able to
mimic transition-state analogues for ester and amide
hydrolysis because of their tetrahedral structure.5,6
Recently aminoalkylphosphonic acid and aminoalkane-
sulfonic acid derivatives, and phosphonopeptides and
sulfonopeptides have been widely used as enzyme
inhibitors and heptans in the development of catalytic
antibodies.5,6 Many methods for the synthesis of amino
alkylphosphonic acids have been developed,7,8 but few
methods are available for the synthesis of aminoalkane-
sulfonic acids9–15 and their derivatives.16–23 To carry out
these investigations, it is very important to develop
As part of a program directed towards the synthesis
and study of phosphonopeptides and sulfonopeptides
as enzyme inhibitors, we sought to prepare chiral 2-
aminoalkanesulfonic acids as building blocks. Prepara-
tion of chiral 2-aminoalkanesulfonic acids from chiral
amino alcohols is very useful method. Although both
chiral b-amino primary alcohols and chiral b-amino
secondary alcohols produce chiral 2-aminoalkanesul-
fonic acids,10–13 chiral b-amino primary alcohols pro-
duce chiral 2-aminoalkanesulfonic acids with the same
configuration;10,12,13 however, chiral b-amino secondary
alcohols produce chiral 2-aminoalkanesulfonic acids
with inverted configuration.11 The mechanism of the
reaction is still unclear.11,14 I herein report the study of
the mechanism and a short preparative route to chiral
2-aminoalkanesulfonic acids from chiral b-amino
alcohols.
2. Results and discussion
Chiral 2-aminoalkanesulfonic acids can be prepared
effectively from chiral b-amino alcohols.10–13 However,
inversion of the configuration and rearrangement
occurred when chiral b-amino secondary alcohols were
E-mail: jia xu 99@yahoo.com
–
–
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00312-9

1130
J. Xu / Tetrahedron: Asymmetry 13 (2002) 1129–1134
used in the preparation.11,14 To understand the reaction
and to use the method effectively, the mechanism and
stereochemical outcome of the reaction were examined.
Because the preparation of both (R)- and (S)-2-
aminopropanesulfonic acids (R)-5a and (S)-5a from
(R)- and (S)-2-aminopropanols (R)-1a and (S)-1a or
(S)- and (R)-1-amino-2-propanols (R)-2a and (S)-2a,
respectively, was reported and they were characterized
fully,10,11 these chiral amino alcohols are perfectly
suited for use in model reactions for mechanistic inves-
tigations into the reaction. The amino alcohols (R)-1a
and (S)-1a, and (R)-2a and (S)-2a were converted to
the corresponding amino alcohol methanesulfonate
hydrochlorides (R)-3a and (S)-3a, and (R)-4a and (S)-
4a, respectively, according to literature procedures.10,11
Based on the stereochemistry of the reactions,10,11 it
was rationalized that an aziridine could be a possible
intermediate in the sodium sulfite substitution step. To
verify this, the (R)- and (S)-2-aminopropanol methane-
sulfonate hydrochlorides (R)-3a and (S)-3a were neu-
tralized carefully with the non-nucleophilic sodium
bicarbonate to obtain the corresponding (R)- and (S)-
2-methylaziridines (R)-8a and (S)-8a, respectively,
without configurational inversion. However, the (R)-
bisulfite. The b-amino alcohol methanesulfonates 6 and
7 undergo neighboring-group assisted cyclization to
form the 2-alkylaziridine 8, which is further attacked by
the previously generated sodium bisulfite at the less
hindered carbon atom of the aziridine ring to yield the
b-amino alkanesulfonate sodium salt 5. In the aziridine
formation step, the free amino groups attack sulfonate
groups to form the aziridine rings. For the b-amino
primary alcohol methanesulfonates 6, secondary amines
attack primary alcohol methanesulfonates to form
aziridines 8 with the same configuration as amino alco-
hols 1. However, for b-amino secondary alcohol
methanesulfonates 7, primary amines attack secondary
alcohol methanesulfonates to form aziridines 8 with
inverted configuration due to SN2 substitution. In the
nucleophilic aziridine ring-opening step, sodium
bisulfite always attacks the less hindered atom of the
aziridine ring to yield 2-aminoalkanesulfonic acids 5
without any configurational change. Thus, chiral b-
amino primary alcohols 1 produce chiral 2-aminoalka-
nesulfonic acids 5 having the same configuration.
However, chiral b-amino secondary alcohols 2 produce
chiral 2-aminoalkanesulfonic acids 5 with inverted
configuration (Scheme 1).
and
(S)-1-amino-2-propanol
methanesulfonate
hydrochlorides (R)-4a and (S)-4a give (S)- and (R)-2-
methylaziridines (S)-8a and (R)-8a, respectively, with
inversion at the stereogenic center under the same
reaction conditions. The (R)- and (S)-2-methylaziridi-
nes (R)-8a and (S)-8a were treated with sodium
bisulfite to give (R)- and (S)-2-aminopropanesulfonic
acids (R)-5a and (S)-5a, respectively, in good yields.
The results indicate that aziridines are intermediates in
the reaction of b-amino alcohol methanesulfonate
hydrochlorides and sodium sulfites. The proposed
mechanism is as follows: Sodium sulfite initially neu-
tralizes the b-amino alcohol methanesulfonate hydro-
Based on this mechanism, aziridines should be useful
starting materials for the preparation of 2-aminoalka-
nesulfonic acids. It has been found that preparation of
racemic 2-aminoalkanesulfonic acids was claimed in
patents,24,25 but no report on the asymmetric synthesis
of 2-aminoalkanesulfonic acids from aziridines was
found. There is no available method for the direct
preparation of enantiomerically pure N-unsubstituted
aziridines from olefins, but they can be formed from
chiral b-amino alcohols, which in turn can be readily
prepared from chiral amino acids by reduction.26 Chiral
amino alcohols 1 were converted to chiral aziridines 8
through the Wenker method via their corresponding
hydrogen sulfates.27,28 The chiral amino alcohols were
chloride (3, 4) to give
a free b-amino alcohol
methanesulfonate (6,
7
respectively), and sodium
NH2
OH
OH
NH2
Me
*
Me
*
(R)-1a
(S)-1a
(S)-2a
(R)-2a
1) (Boc)2O
2) MsCl
3) HCl
1) (Boc)2O
2) MsCl
3) HCl
Me
*
(R)-5a
(S)-5a
NH2 .HCl
-
OMs
Na2SO3
SO3
Na2SO3
+H3N
OMs
*
(R)-3a
NH2 .HCl
Me
Me
*
(S)-4a
(R)-4a
(S)-3a
Na2SO3
NaHSO3
NaHCO3
Na2SO3
NaHSO3
NaHCO3
NH2
OMs
NH
OMs
-HSO3
NH2
Me
*
*
Me
*
Me
(R)-6a
(S)-6a
(S)-7a
(R)-7a
(R)-8a
(S)-8a
Scheme 1.

J. Xu / Tetrahedron: Asymmetry 13 (2002) 1129–1134
1131
aziridinemethanols 8f, which were reacted in situ with
sodium bisulfite to yield chiral 2-amino-3-hydroxy-
neutralized with sulfuric acid and the resulting salts
were dehydrated to yield the hydrogen sulfates. Addi-
tion of aqueous potassium hydroxide resulted in the
formation of 2-substituted aziridines 8. In the cycliza-
tion, amino groups attack activated hydroxy groups to
produce the corresponding aziridines without configu-
ration conversion. Chiral amino alcohols 1 were also
converted to chiral aziridines 8 through Mitsunobu
reaction using DEAD (diethyl azodicarboxylate) and
triphenylphosphine as reagents in mild conditions.29
The aziridines 8 were reacted with sodium bisulfite to
produce chiral b-amino alkanesulfonic acids 5 with the
same configurations as the corresponding b-amino pri-
mary alcohols 1 (Scheme 2).
propanesulfonic acids 5f,
D- and L-cysteinolic acids
(Scheme 2). Both carboxy- and hydroxy-functionalized
aziridines can be converted to the corresponding func-
tionalized b-amino alkanesulfonic acids via nucleophilic
substitution with sodium bisulfite.
3. Conclusion
In conclusion, the mechanism for the transformation of
b-amino alcohol methanesulfonate hydrochlorides into
sodium b-amino alkanesulfonates with sodium sulfite
was investigated. The results show that sodium sulfite
neutralizes the b-amino alcohol methanesulfonate
hydrochloride to give sodium bisulfite and the free
b-amino alcohol methanesulfonate, which undergoes a
sequence involving neighboring-group assisted cycliza-
tion to a 2-alkylaziridine. The sodium bisulfite gener-
ated then attacks the aziridine at the less hindered
carbon atom to yield a sodium b-amino alkanesul-
fonate. Based on this mechanism, a new and short
asymmetric synthesis of chiral 2-aminoalkanesulfonic
acids from chiral amino alcohols was developed
through Wenker or Mitsunobu cyclization and nucleo-
philic ring-opening reaction with sodium bisulfite.
To extend the application of this method, four func-
tionalized chiral aziridines were prepared from
-serines. Although - and -serine methyl esters can
L- or
D
L
D
be converted to the corresponding methyl 2-aziridine-
carboxylates directly via Mitsunobu reaction,29 the
yields are not satisfactory due to the volatile nature of
these compounds.30 Additionally, most of the methyl
2-aziridinecarboxylates degraded during work-up.
and -Serines were converted successfully to chiral
methyl 2-aziridinecarboxylates according to the litera-
ture procedure.30
and -Serine methyl ester
L-
D
L
-
D
hydrochlorides were N-tritylated and O-tosylated,
respectively. The resulting products were treated with
triethylamine in refluxing THF to give the correspond-
ing chiral methyl N-trityl 2-aziridinecarboxylates.
Deprotection of the trityl group using excess tri-
fluoroacetic acid and methanol at low temperature fur-
nished the unstable methyl 2-aziridinecarboxylate
trifluoroacete salts 8e·TFA, which were basified and
reacted with sodium bisulfite immediately to produce
sodium 2-amino-2-methoxycarbonylethanesulfonates.
After saponification and purification via ion-exchange
4. Experimental
4.1. General method
Melting points were measured on a Yanaco MP-500
melting point apparatus and are uncorrected. H NMR
1
spectra were recorded on a Varian Mercury 200 (200
MHz) spectrometer in CDCl3 with TMS as an internal
standard or in D2O. Mass spectra were obtained on a
VG-ZAB-HS mass spectrometer. CHN analyses were
recorded on an Elementar Vario EL analyzer. Optical
rotations were measured on a Perkin–Elmer 341LC
polarimeter with a thermally jacketed 10 cm cell (con-
centration c given as g/100 mL). IR spectra were taken
on a Brucker Vector 22 FT-IR spectrophotometer in
KBr pellet. The NMR data of all known compounds
are identical to those earlier reported in the
literature.10,11,27,28,31–33
chromatography,
acids 5e, - and
2-amino-2-carboxyethanesulfonic
-cysteic acids, were obtained in good
D
L
yields. While the methyl 2-aziridinecarboxylate tri-
fluoroacete salts were basified and reduced with lithium
borohydride to give rise to corresponding chiral 2-
NH2
R
1) H2SO4; 2) KOH
or DEAD, Ph3P
NaHSO3
NH
-
OH
SO3
+H3N *
R
*
*
R
(R)-1
(S)-1
(R)-8
(S)-8
(R)-5
(S)-5
(R)- and (S)-Amino alcohols were prepared from the
corresponding chiral amino acids according to known
method26 or were purchased from Aldrich and Acros
Chemical Co., Inc. Dichloromethane was heated under
reflux over calcium hydride and distilled prior to use.
Triethylamine was heated under reflux over sodium
hydroxide and distilled prior to use.
a: R = Me; b: R = CHMe2; c: R = Ph; d: R = PhCH2
1) TrCl, Et3N
NH2HCl
CO2Me
SO3
2) TsCl, Py
NaHSO3
NH
-
OH
+H3N
MeO2C
*
MeO2C
*
*
3) Et3N, THF
4) TFA, MeOH
5) K2CO3
L-SerOMe HCl
D-SerOMe HCl
(S)-8e
(R)-8e
NaOH
O
4.2. General procedure for the synthesis of chiral amino
alcohol methanesulfonate hydrochlorides (R)- and (S)-
3a, and (R)- and (S)-4a
NaBH4
LiCl
HO
HO
-
SO3
+H3N
NaHSO3
NH
-
SO3
+H3N
*
HOH2C
(R)-5e
(S)-5e
(R)- and (S)-amino alcohol methanesulfonate
hydrochlorides 3a and 4a were synthesized from the
corresponding (R)- and (S)-amino alcohols according
to the literature method.11
(R)-5f
(S)-5f
(S)-8f
(R)-8f
Scheme 2.

1132
J. Xu / Tetrahedron: Asymmetry 13 (2002) 1129–1134
4.2.1. (R)-2-Aminopropanol methanesulfonate hydrochlo-
rides (R)-3a. Colorless crystal; mp 135–136°C; [h]2D5=
−10.4 (c, 1.10, DMF). Lit.:10 mp 135–136°C; [h]D25=
−10.3 (c, 1, DMF).
calcd for C5H11N (85.15): C, 70.53; H, 13.02; N, 16.45.
Found: C, 70.31; H, 13.13; N, 16.56%.
4.4.2. (R)-2-Phenylaziridine (R)-8c. Colorless oil; yield:
86%; bp 72–73°C/4 mmHg; [h]2D0=−43.2 (c, 1.07,
EtOH). Lit.:30 bp 73°C/4 mmHg; [h]2D0=−43.4 (c,
1.0062, EtOH).
4.2.2. (S)-2-Aminopropanol methanesulfonate hydrochlo-
rides (S)-3a. Colorless crystal; mp 133–134°C; [h]2D5=
+10.2 (c, 1.08, DMF). Lit.:10 mp 132–133°C; [h]D25=
+10.3 (c, 1, DMF).
4.4.3. (R)-2-Benzylaziridine (R)-8d. Colorless oil; yield:
88%; bp 73–74°C/1 mmHg; [h]2D0=+26.6 (c, 1.07,
EtOH). Lit.:32 bp 73–74°C/1 mmHg; [h]2D4=+26.7 (c,
0.152, EtOH).
4.2.3.
(R)-1-Amino-2-propanol
methanesulfonate
hydrochlorides (R)-4a. Colorless crystal; mp 128–129°C;
[h]2D5=−18.5 (c, 1.02, H2O). Lit.:11 mp. 128–129°C;
[h]2D5=−18.5 (c, 1.0, H2O).
4.4.4. (S)-2-Isopropylaziridine (S)-8b. Colorless oil;
yield: 80%; bp 104–106°C; [h]2D0=−21.7 (c, 1.11, EtOH).
Lit.:27 bp 100–101°C/690 mmHg; [h]2D0=−21.8 (c, 1.5,
EtOH).
4.2.4.
(S)-1-Amino-2-propanol
methanesulfonate
hydrochlorides (S)-4a. Colorless crystal; mp 128–129°C;
[h]D25=+18.4 (c, 1.12, H2O). Lit.:11 mp 128–129°C.
[h]2D5=+18.5 (c, 1.0, H2O).
4.4.5. (S)-2-Phenylaziridine (S)-8c. Colorless oil yield:
85%; bp 72–73°C/4 mmHg; [h]2D0=+43.6 (c, 1.07, H2O).
Lit.:33 [h]2D0=+43.8 (c, 0.26, EtOH).
4.3. Neutralization of chiral amino alcohol methanesul-
fonate hydrochlorides (R)- and (S)-3a, and (R)- and
(S)-4a with sodium bicarbonate, and synthesis of (R)-
and (S)-2-methylaziridines (R)- and (S)-8a
4.4.6. (S)-2-Benzylaziridine (S)-8d. Colorless oil; yield:
87%; bp 73–74°C/1 mmHg; [h]2D0=−26.7 (c, 1.15,
EtOH). Lit.:32 bp 73–74°C/1 mmHg; [h]2D4=−26.6 (c,
0.186, EtOH).
To a solution of amino alcohol methanesulfonate
hydrochlorides 3a or 4a (7.58 g, 40 mmol) in water (20
mL) was added portionwise sodium bicarbonate (5.04
g, 60 mmol) under stirring in an ice bath. The resulting
mixture was stirred for 2 h and then distilled. The
distillate was saturated with potassium hydroxide and
the organic layer separated was dried over potassium
hydroxide and finally with sodium metal to give chiral
2-methylaziridine.28
4.5. General procedure for synthesis of chiral 2-substi-
tuted aziridines 8 (Mitsunobu reaction)
The amino alcohol (20 mmol) was dissolved in toluene
(30 mL) and added to a solution of triphenylphosphine
(5.5 g, 21 mmol) and DEAD (3.65 g, 21 mmol) in
toluene (45 mL). After refluxing overnight, the mixture
was poured into water (75 mL) and diluted with diethyl
ether (75 mL). Drying over MgSO4, filtration, and
concentration gave a residue, which was diluted with
diethyl ether (75 mL) and left in the freezer overnight.
Precipitated triphenylphosphine oxide was filtered off,
and the filtrate was concentrated and subjected to
column chromatography to give aziridine as a colorless
oil. Yield: (R)-8b, 73%; (S)-8b, 71%; (R)-8c, 83%; (S)-
8c, 85%; (R)-8d, 85%; (S)-8d, 86%.
4.3.1. (R)-2-Methylaziridine (R)-8a. Colorless oil; yield:
65%; [h]2D0=+12.4 (c, 1.21, EtOH). Lit.:28 bp 66–67°C;
[h]D=+12.6 (c, 1.43, EtOH).
4.3.2. (S)-2-Methylaziridine (S)-8a. Colorless oil; yield:
63%; [h]2D0=−12.4 (c, 1.13, EtOH). Lit.:28 bp 66–67°C;
[h]D=−12.5 (c, 1.43, EtOH).
4.4. General procedure for synthesis of chiral 2-substi-
tuted aziridines 8 (Wenker method)
A cold mixture of sulfuric acid (98%, 4 g), and water (4
mL) was added to an amino-alcohol (40 mmol) in water
(2.4 mL) at 0–5°C. The mixture was heated to 120°C
and then water was carefully distilled off in vacuo. The
solid sulfate residue was treated with 6.2 M potassium
hydroxide, and steam-distilled. The distillate was satu-
rated with potassium hydroxide pellets and the upper
organic layer, which separated, was fractionally distilled
from potassium hydroxide through a short column to
give a colorless oil aziridine 8.
4.6. General procedure for synthesis of chiral 2-amino-
alkanesulfonic acids 5
Sodium bisulfite (1.25 g, 12 mmol) was added to a
solution of the appropriate 2-substituted aziridine 8 (10
mmol) in water or a mixture of water and ethanol (10
mL) and the mixture was stirred for 24 h. The resulting
solution was passed through columns first of Amberlite
IR-120 (H+ form) then of Dowex 11 (acetate form). The
eluate was evaporated to dryness under reduced pres-
sure and the residue was crystallized from a mixture of
water and ethanol to give 5.
4.4.1. (R)-2-Isopropylaziridine (R)-8b. Colorless oil;
yield: 78%; bp 104–106°C; [h]2D0=+21.7 (c, 1.11, EtOH).
IR (film): w=3220 (NH), 3030 (CH2 in aziridine) cm−1;
1H NMR l=2.91 (1H, br, s, NH), 1.80–0.80 (10H, m,
all aliphatic H); MS (EI) m/z: 84 (M+−H), 70 (M+−
4.6.1. (R)-2-Aminopropanesulfonic acid (R)-5a. Color-
less crystal; yield: 88%; mp >330°C; [h]2D0=−18.5 (c,
1.11, H2O). Lit.:10 mp >330°C; [h]D20=−18.3 (c, 1, H2O).
NH), 56 (M+−NHCH2), 43 (C3H7 , base peak). Anal.
+

J. Xu / Tetrahedron: Asymmetry 13 (2002) 1129–1134
1133
4.6.2. (R)-2-Amino-3-methylbutanesulfonic acid (R)-5b.
Colorless crystal; yield: 90%; mp: 325–326°C; [h]2D0=
−29.6 (c, 0.97, H2O). Lit.:10 mp: 325–326°C; [h]D20=
−29.7 (c, 1, H2O).
4.7.1. (R)-2-Amino-2-carboxyethanesulfonic acid (R)-5.
Colorless crystal; yield: 74%; monohydrate mp 271–
273°C; [h]2D5=+8.3 (c, 7.2, H2O). Lit.:34 mp: 272–274°C;
[h]2D5=+8.5 (c, 7.4, H2O).
4.6.3. (R)-2-Amino-2-phenylethanesulfonic acid (R)-5c.
Colorless crystal; yield: 96%; mp 338–340°C; [h]2D0=
+1.4 (c, 1.07, H2O). Lit.:10 mp >330°C; [h]2D0=+1.3 (c, 1,
H2O).
4.7.2. (S)-2-Amino-2-carboxyethanesulfonic acid (S)-5e.
Colorless crystal; yield: 72%; monohydrate mp 271–
273°C. [h]2D5=−8.4 (c, 7.3, H2O). IR (KBr): w=3300–
2400 (NH3 ), 1221 (SO2), 1176 (SO2) cm−1; H NMR
l=3.38 (1H, dd, J=4, 9 Hz), 3.08 (1H, dd, J=4, 14
Hz), 2.83 (1H, dd, J=9, 14 Hz); MS (FAB) m/z: 170
(MH+). Anal. calcd for C3H7NO5S·H2O (187.17): C,
19.25; H, 4.85; N, 7.48. Found: C, 19.12; H, 5.03; N,
7.19%.
+
1
4.6.4. (R)-2-Amino-3-phenylpropanesulfonic acid (R)-5d.
Colorless crystal; yield: 96%; mp >330°C; [h]2D0=+3.7
(c, 1.10, H2O). Lit.:10 mp >330°C; [h]2D0=+3.6 (c, 1,
H2O).
4.8. General procedure for synthesis of chiral cysteino-
lic acids 5f
4.6.5. (S)-2-Aminopropanesulfonic acid (S)-5a. Colorless
crystal; yield: 87%; mp >330°C; [h]2D0=+18.4 (c, 1.01,
H2O). Lit.:10 mp >330°C; [h]D20=+18.5 (c, 1, H2O).
To a solution of methyl N-trityl 2-aziridinecarboxylate
(3.45 g, 10 mmol) (prepared as described in the
literature30) in dichloromethane (10 mL) and methanol
(12 mL) at −10°C was added trifluoroacetic acid (16
mL) dropwise under nitrogen. After stirring at this
temperature for 10 h, water (40 mL) was added and the
volatiles organic components removed in vacuo to pre-
cipitate of a mixture of triphenylmethanol and methyl
triphenylmethyl ether as a white solid which was
filtered off. To the aqueous filtrate was added solid
potassium carbonate (6.91 g, 50 mmol) and the solution
was stirred for 15 min prior to addition of solid lithium
chloride (2.12 g, 50 mmol) and sodium borohydride
(1.89 g, 50 mmol) portionwise. After the mixture was
stirred overnight, sodium bisulfite (2.08 g, 2 mmol) was
added portionwise under stirring. The resulting solution
was stirred another 24 h and was passed through
columns first of Amberlite IR-120 (H+ form) then of
Dowex 11 (acetate form). The eluate was evaporated to
dryness under reduced pressure and the residue was
crystallized from aqueous ethanol to give 5f.
4.6.6. (S)-2-Amino-3-methylbutanesulfonic acid (S)-5b.
Colorless crystal; yield: 89%; mp 325–326°C; [h]2D0=
+29.6 (c, 0.96, H2O). Lit.:10 mp 325–326°C; [h]D20=+29.8
(c, 1, H2O).
4.6.7. (S)-2-Amino-2-phenylethanesulfonic acid (S)-5c.
Colorless crystal; yield: 95%; mp 338–340°C. [h]2D0+=
−1.4 (c, 1.10, H2O). IR (KBr): w=3300–2400 (NH3 ),
1
1220 (SO2), 1175 (SO2) cm−1; H NMR l=7.46–7.40
(5H, m, ArH), 4.08 (1H, dd, J=6, 10 Hz), 3.43 (1H, dd,
J=6, 13 Hz), 3.23 (1H, dd, J=10, 13 Hz); MS (FAB)
m/z: 202 (MH+). Anal. calcd for C8H11NO3S (201.24):
C, 47.75; H, 5.51; N, 6.96. Found: C, 47.51; H, 5.33; N,
7.06%.
4.6.8. (S)-2-Amino-3-phenylpropanesulfonic acid (S)-5d.
Colorless crystal; yield: 96%; mp >330°C; [h]2D0=−3.6
(c, 0.99, H2O). Lit.:10 mp >330°C; [h]2D0=−3.5 (c, 1,
H2O).
4.7. General procedure for synthesis of chiral cysteic
acids 5e
4.8.1. (R)-2-Amino-3-hydroxypropanesulfonic acid (R)-
5f. Colorless crystal; yield: 78%; mp 279–281°C (dec.);
[h]2D0=+7.6 (c, 1.00, H2O). Lit.:10 mp: 279–281°C (dec.);
[h]2D0=+7.5 (c, 1, H2O).
To a solution of methyl N-trityl 2-aziridinecarboxylate
(3.45 g, 10 mmol) (prepared as described in the
literature30) in dichloromethane (10 mL) and methanol
(12 mL) at −10°C was added trifluoroacetic acid (16
mL) dropwise under nitrogen. After stirring at this
temperature for 10 h, water (40 mL) was added and the
organic volatiles removed in vacuo to precipitate of a
mixture of triphenylmethanol and methyl triphenyl-
methyl ether as a white solid which was filtered off. To
the aqueous filtrate was added solid potassium carbon-
ate (6.91 g, 50 mmol), and the solution stirred for 15
min prior to addition of solid sodium bisulfite (2.08 g,
2 mmol) portionwise. After the mixture was stirred for
24 h, sodium hydroxide (4.0 g, 100 mmol) was added
portionwise under stirring. The resulting solution was
stirred another 8 h and was passed through columns
first of Amberlite IR-120 (H+ form) then of Dowex 11
(acetate form). The eluate was evaporated to dryness
under reduced pressure and the residue was crystallized
from a mixture of water and ethanol to give 5e.
4.8.2. (S)-2-Amino-3-hydroxypropanesulfonic acid (S)-
5f. Colorless crystal; yield: 76%; mp 279–281°C. [h]2D0+=
−7.4 (c, 1.10, H2O). IR (KBr): w=3300–2400 (NH3 ),
1
1222 (SO2), 1177 (SO2) cm−1; H NMR l=3.52 (1H,
dd, J=7, 11 Hz), 3.58 (1H, dd, J=6, 11 Hz), 3.34–3.23
(1H, m), 3.07 (1H, dd, J=4, 14 Hz), 2.82 (1H, dd,
J=9, 14 Hz); MS (FAB) m/z: 156 (MH+). Anal. calcd
for C3H9NO4S (155.17): C, 23.22; H, 5.85; N, 9.03.
Found: C, 23.50; H, 5.79; N, 9.06%.
Acknowledgements
The project was supported by National Natural Science
Foundation of China, Ministry of Education of PR
China, and Peking University.

1134
J. Xu / Tetrahedron: Asymmetry 13 (2002) 1129–1134
17. Moree, W. J.; van Gent, L. C.; van der Marel, G. A.;
References
Liskamp, R. M. J. Tetrahedron 1993, 49, 1133–1150.
18. Luisi, G.; Calcagni, A.; Pinnen, F. Tetrahedron Lett.
1993, 34, 2391–2392.
19. Bischoff, L.; David, C.; Roques, B. P.; Fournie-Zaluski,
M.-C. J. Org. Chem. 1999, 64, 1420–1423.
20. Higashiura, K.; Ienaga, K. J. Org. Chem. 1992, 57,
764–766.
21. Brouwer, A. J.; Monnee, M. C. F.; Liskamp, R. M. J.
Synthesis 2000, 1579–1584.
22. Moree, W. J.; van der Marel, G. A.; Liskamp, R. M. J.
J. Org. Chem. 1995, 60, 5157–5169.
23. Lowik, D. W. P. M.; Liskamp, R. M. J. Eur. J. Org.
Chem. 2000, 1219–1228.
24. Matsura, N.; Myagawa, J.; Goshima, J.; Kitano, M.
JP08268995 1996, 5pp (Chem. Abstr. 1996, 126, 31067).
25. Tsuneki, H.; Kodama, K. JP04352760 1992, 6pp (Chem.
Abstr. 1993, 118, 233480).
1. Huxtable, R. J. Physiol. Rev. 1992, 72, 101–163.
2. Liskamp, R. M. J. Angew. Chem., Int. Ed. Engl. 1994, 33,
633–636.
3. Burgess, K.; Linthicum, D. S.; Shin, H. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 907–909.
4. de Bont, D. B. A.; Dijkstra, G. D. H.; den Hartog, J. A.
J.; Liskamp, R. M. J. Bioorg. Med. Chem. Lett. 1996, 6,
3035–3040 and references cited therein.
5. Pollack, S. J.; Hsiun, P.; Schultz, P. G. J. Am. Chem. Soc.
1989, 111, 5961–5962.
6. Morgan, B. P.; Scholtz, J. M.; Ballinger, M. D.; Zipkin,
I. D.; Bartlett, P. A. J. Am. Chem. Soc. 1991, 113,
297–307.
7. Xu, J. X.; Yu, L. Chin, J. Synth. Chem. (Hecheng
Huaxue) 1999, 7, 153–158.
8. Xu, J. X.; Fu, N. Y. J. Chem. Soc., Perkin. Trans. 1 2001,
1223–1226 and references cited therein.
9. Zheng, T. C.; Richardson, D. E. Tetrahedron Lett. 1995,
36, 837–840.
26. Gassman, P. G.; Fentiman, A. J. Org. Chem. 1967, 32,
2388–2391.
27. El-Abadelah, M. M.; Sabri, S. S.; Jarrar, A. A.; Abu
Zarga, M. H. J. Chem. Soc., Perkin. Trans. 1 1979,
2881–2885.
10. Higashiura, H.; Morino, H.; Matsuura, H.; Toyomaki,
Y.; Ienaga, K. J. Chem. Soc., Perkin. Trans. 1 1989,
1479–1481.
11. Braghiroli, D.; Mussati, E.; Di Bella, M.; Saladini, M.
Tetrahedron: Asymmetry 1996, 7, 831–836.
12. Braghiroli, D.; Di Bella, M. Tetrahedron: Asymmetry
1996, 7, 2145–2150.
28. Yahiro, N. Chem. Lett. 1982, 1479–1480.
29. Lindstrom, U. M.; Somfai, P. Synthesis 1998, 109–117.
30. Baldwin, J. E.; Spivey, A. C.; Schofield, C. J.; Sweeney, J.
B. Tetrahedron 1993, 49, 6309–6330.
31. Nabeya, A.; Shigemoto, T.; Iwakura, Y. J. Org. Chem.
1975, 40, 3536–3539.
32. Coutts, R. T.; Benderly, A.; Mak, A. L. C. J. Fluorine
Chem. 1980, 16, 277–283.
33. Davis, F. A.; Zhou, P.; Liang, C.-H.; Reddy, R. E.
Tetrahedron: Asymmetry 1995, 6, 1511–1514.
34. Lowe, O. G. J. Org. Chem. 1977, 42, 2524–2525.
13. Braghiroli, D.; Avallone, R.; Di Bella, M. Tetrahedron:
Asymmetry 1997, 8, 2209–2213.
14. Braghiroli, D.; Di Bella, M. Tetrahedron Lett. 1996, 37,
7319–7322.
15. van Amijde, J.; Liskamp, R. M. J. Tetrahedron Lett.
2000, 41, 1103–1106.
16. Moree, W. J.; van der Marel, G. A.; Liskamp, R. M. J.
Tetrahedron Lett. 1991, 32, 409–412.