Crystal-state studies on p-toluenesulfonates of N-oxyimides - A possible structural basis of serine proteases inhibition

Article abstract of DOI:10.1039/b513741a

A series of p-toluenesulfonates of N-oxyimides has been synthesized and their X-ray structures show a flattened pyramidal geometry of the hydroxyimide ring nitrogen. This structural feature is considered to be responsible for a specific chemical reactivit

Full text of DOI:10.1039/b513741a

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Crystal-state studies on p-toluenesulfonates of N-oxyimides—a possible
structural basis of serine proteases inhibitionw
Piotr Stefanowicz, yukasz Jaremko,* Mariusz Jaremko* and Tadeusz Lis
Received (in Montpellier, France) 27th September 2005, Accepted 29th November 2005
First published as an Advance Article on the web 19th December 2005
DOI: 10.1039/b513741a
A series of p-toluenesulfonates of N-oxyimides has been synthesized and their X-ray structures
show a flattened pyramidal geometry of the hydroxyimide ring nitrogen. This structural feature is
considered to be responsible for a specific chemical reactivity towards nucleophiles and inhibitory
properties against proteases of these compounds.
Introduction
Results and discussion
N-Hydroxyimides form stable and crystalline ester derivatives
with many aryl-, alkylsulfonic, and carboxylic acids.1,2 In
contrast to N-hydroxyimidyl esters of carboxylic acids,
which are widely used in peptide synthesis and biochemistry
as selective acylating reagents,3 N-hydroxyimidyl derivatives
of sulfonic acids react with amines through carbonyl groups
of the succinimidic ring to form ureido derivatives (Fig. 1).
The mechanism of these reactions is closely related to the
Lossen rearrangement.4,5 Many derivatives of these com-
pounds are known as inhibitors of serine proteases, mainly
a-chymotrypsin and human leucocyte elastase.6–10 Enzyme
induced ring opening results in instantaneous Lossen rearran-
gement via the O-sulfonyl derivative releasing the isocyanate.
Reactive isocyanate formed in the active centre reacts with the
histidine’s imidazoyl ring,7 irreversibly deactivating the
enzyme. Surprisingly, there are only few references
concerning the crystal structures of N-hydroxyimide sulfonic
acid esters.1,11
The p-toluenesulfonates of N-oxyimides I–IV (Scheme 1) were
prepared by direct reaction of N-hydroxyimides with p-to-
luenesulfonyl chloride in the presence of triethylamine. Tetra-
hydrofuran was used as a solvent. This procedure is based on
Bauer’s approach,4,12 but our modification gave a higher yield.
Two N-hydroxyimides, N-hydroxysuccinimide and N-hy-
droxyphthalimide, are commercially available while N-hydro-
xyimides used as substrates for compounds II and III were
obtained by direct reaction of corresponding, cyclic anhy-
drides with hydroxylamine in water–dioxane solution (Fig.
2). This reaction was based on the synthesis of N-hydroxy-
imide described by Anderson et al.13
The molecular structures of compounds I–IV with the
atomic numbering schemes are shown in Figs. 3–6, respec-
tively.
The S atoms lie in the same plane as the tosyl aromatic ring
in compounds I, II, and IV. Only in III the sulfur atom is
displaced from the plane of the adjacent aromatic moiety by
0.169(3) A which can result from the steric hindrance. The
configuration of sulfur is a distorted tetrahedron with the
S–O1 and S–O2 bonds shorter than the S–O3 bond that is in
good agreement with the numerous crystallographic data for
The chemical reactivity of arylsulfonic esters of N-hydro-
xyimides towards amines and
a significant biological
importance of this class of compounds are the reasons of X-
ray diffraction experiments on the esters of p-toluenesulfonic
and N-hydroxysuccinimidic derivatives. Non planar nitrogen
geometry in the pentaatomic ring which does not appear in
carboxylic esters of N-hydroxyimides is a structural feature
present in every described arylsulfonic ester of N-hydroxyi-
mides. It can be considered as a reason for the observed
characteristic chemical reactivity and biological properties of
this class of compounds.
We describe here the synthesis, characterization, and results
of the crystallographic analysis of esters of N-hydroxysuccini-
mides and (4-methylphenyl)sulfonyl acid (Scheme 1).
Faculty of Chemistry, University of Wroc!aw, ul. F. Joliot-Curie 14,
50-383 Wroc!aw, Poland. E-mail: jaremko@gmail.com;
Fax: (048)(71)3-282-348; Tel: (048)(71)375-7257
w Electronic supplementary information (ESI) available. CCDC re-
ference numbers 284049–284052. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b513741a
Scheme
1 (I) 1-{[(4-methylphenyl)sulfonyl]oxy}pyrrolidine-2,5-
dione; (II) benzyl (3S)-1-[(methylsulfonyl)oxy]-2,5-dioxopyrrolidin-3-
ylcarbamate; (III) ethyl (3S)-1-{[(4-methylphenyl)sulfonyl]oxy}-2,5-
dioxopyrrolidin-3-ylcarbamate;
nyl]oxy}-1H-isoindole-1,3(2H)-dione.
(IV)
2-{[(4-methylphenyl)sulfo-
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Fig. 5 Molecular geometry and atom-numbering scheme of III.
Displacement ellipsoids are drawn at the 30% probability level.
Fig. 1 Comparison of the reactions of aryl/alkylsulfonic and car-
boxylic acids esters of N-oxysuccinimide with amines. R, R = aryl or
alkyl moiety.
1,3(2H)-dione and 1-[(2-naphthylsulfonyl)oxy]pyrrolidine-
2,5-dione, where nitrogen atoms were also found to be flat-
tened pyramids with deviation from the plane of the surround-
ing atoms equal to 0.150(1) A.1,11 Deviations of the
succinimide nitrogen atom from the C1–O1–C4 plane for the
described compounds equal 0.214(1), 0.180(1), 0.200(2), and
0.243(2) A for I, II, III, and IV, respectively.
Fig. 2 The scheme of synthesis of compounds II–III.
The N1–C4 and N1–C1 bond lengths of I, II, III [average
1.402 A], and IV [average 1.417 A] are longer than typical N–C
peptide bonds [ca. 1.32 A]18 and longer than typical N–C
bonds in the succinimide ring [ca. 1.384 A].2,19
this residue.1,14 The increased angle O2–S–O3 and the result-
ing angle C1–S–O2, smaller than typical tetrahedral values for
sulfonic groups, are attributed to the Thorpe–Ingold effect.15
The O1–N1–C1, O1–N1–C4, and C1–N1–C4 angles (Table
1) are very similar to those observed for (ꢁ)-N-hydroxyimide
of (10-pinene-2-yl) succinimic acid16 and N-hydroxy-1H-iso-
indole-1,3(2H)-dione17 where the nitrogen atom is planar,
and for 2-[(phenylsulfonyl)oxy]-1H-benzo[de]isoquinoline-
This change of bonds length and also displacement of the
nitrogen atom from the plane defined by C1, O1, and C4
atoms can be considered as an evidence that the charge
distribution in molecules of N-oxyimido sulfonates is different
from that of cyclic imides. The shift of the electron pair from
nitrogen to the carbon atom is significantly reduced. Conse-
quently the charge density on carbon is decreased and the
carbonyl group is more susceptible to the nucleophile attack.20
These features of the succinimidic ring can explain the biolo-
gical activity of some similar structures of aryl- and alkyl-
sulfonic esters of succinimides.
Non-planar nitrogen atom exists also in b-lactam antibiotics
and is believed to be responsible for their biochemical proper-
ties. In Woodward’s opinion a pronounced pyramidal char-
acter of the nitrogen atom in the b-lactam ring results in a
decreased charge density on the carbon atom in the carbonyl
group, which is a cause of the increased reactivity of the lactam
Fig. 3 Molecular geometry and atom-numbering scheme of I. Dis-
placement ellipsoids are drawn at the 30% probability level.
Fig. 4 Molecular geometry and atom-numbering scheme of II. Dis-
Fig. 6 Molecular geometry and atom-numbering scheme of IV.
placement ellipsoids are drawn at the 30% probability level.
Displacement ellipsoids are drawn at the 30% probability level.
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Table 1 Selected bond distances (A), bond angles (1), and torsion
angles (1) for compounds I–IV
I
II
III
IV
˚
Distance/A
O1–N1
N1–C1
N1–C4
C1–O4
C4–O5
C2–C3
C1–C2
C4–C3
C2–N2
N2–C5
C5–O7
C5–O6
1.391 (2) 1.397 (2) 1.396 (2) 1.398 (2)
1.406 (2) 1.399 (2) 1.404 (2) 1.414 (3)
1.403 (2) 1.401 (2) 1.399 (2) 1.421 (2)
1.203 (2) 1.202 (2) 1.193 (2) 1.202 (2)
1.200 (2) 1.204 (3) 1.204 (2) 1.199 (2)
1.529 (2) 1.545 (2) 1.534 (3) 1.397 (3)
1.503 (2) 1.533 (2) 1.536 (3) 1.495 (3)
1.505 (2) 1.509 (3) 1.502 (3) 1.484 (3)
Fig. 7 The scheme showing the stacking of adjacent molecules of I
[code of symmetry: ꢁx þ 1, ꢁy þ 1, ꢁz þ 1]. To indicate a molecule
with the x, y, z code of symmetry the S atom has been labelled. Dashed
line is the distance between the midpoints X1A and X1AA of adjacent
aromatic rings which equals 3.717(2) A. The distance between the
planes of parallel rings is 3.58(2) A.
—
—
—
—
1.452 (2) 1.440 (2)
1.355 (2) 1.351 (2)
1.346 (2) 1.339 (2)
1.213 (2) 1.220 (2)
—
—
—
—
Bond
angle/1
peptidomimetics.3 The angle between the succinimide ring and
the benzyl and toluyl groups of II is equal to 33(1)1 and 58(1)1,
respectively.
C1–N1–O1
O1–N1–C4
C1–N1–C4
C1–C2–C3
C4–C3–C2
N1–C1–C2
N1–C4–C3
120.0(1)
118.5(1)
114.4(2)
106.0(1)
106.1(2)
105.8(1)
105.3(2)
118.6(2)
120.4(2)
115.0(2)
104.9(2)
105.9(2)
105.7(2)
105.4(2)
118.9(2)
120.9(2)
115.3(2)
105.2(2)
106.5(2)
105.1(2)
105.4(2)
120.9(2)
117.4(2)
113.5(2)
109.2(2)
109.0(2)
103.4(2)
103.8(2)
A noticeable difference in the C2–C3 bond length between
investigated sulfonic esters of N-hydroxysuccinic acid and
ester of N-hydroxyphthalimide can be explained by the aro-
matic character of the phthalimic six-membered ring. Other
C–C bond lengths differences can be considered as a result of
different packing of molecules in a unit cell. C1–C2–C3 and
C4–C3–C2 angles are significantly larger for compound IV
than for other investigated compounds because of the shorter
C2–C3 bond length. The differences in the bonds and angles
values mentioned above for I, II, and III result in the puckered
and twisted succinic ring. This twist is characterized by a
pseudo twofold axis bisecting the middle of the C4–N1 bond
and C2 atom, and the pentaatomic ring in IV is in the envelope
conformation. The Cremer and Pople parameters26 are listed
in Table 1.
Torsion
angle/1
C61–C11–S–O2
C21–C11–S–O3
C1–N1–O1–S
C4–N1–O1–S
N1–C1–C2–N2
14.2(2)
ꢁ26.4(2)
98.1(2)
4.7(2)
ꢁ39.0(2)
20.1(2)
ꢁ26.5(2)
23.9(2)
ꢁ17.3(2)
103.3(2)
100.9(2)
102.5(2)
ꢁ112.8(1) ꢁ105.3(2) ꢁ105.0(2) ꢁ111.1(2)
—
ꢁ127.4(2) ꢁ127.7(2)
—
Cremer and Pople
parameters26
(N1–C1–C2–C3–C4)
q2
w2
0.140(2) A 0.160(2) A 0.144(2) A 0.098(3) A
182(2)1
163(1)1
154(1)1
154(1)1
Closest description
Twisted
on C4–N1 on C4–N1 on C4–N1 on N1
Twisted
Twisted
Envelope
The analysis of the aromatic rings arrangement showed
classical stacking interactions in the crystals of I (Fig. 7).
The distance between the aromatic rings centers in adjacent
molecules is equal to 3.717(2) A, straight distance between the
rings planes is 3.58(2) A. The angle between the normal and
line linking middle points (X1A and X1AA) of the aromatic
rings involved in stacking and the plane of the aromatic ring
equals 20(1)1 (Fig. 7). Stacking interactions involving aromatic
rings of tosyl groups can be also recognized for compound IV
(Fig. 8) The distance between the middle points of stacked
rings is 3.796(2) A, and the distance between the rings planes is
3.56(2) A. Fitting of structures I and IV confirms a significant
structural agreement between the pentaatomic rings of men-
tioned compounds (Fig. 9a). This noticeable compatibility
is caused by significant similarities of the C1–N1–O1–S and
C4–N1–O1-S torsion angles.
ring toward nucleophiles. In this case biological activity is a
result of irreversible reaction of the b-lactam ring with a serine
residue in the transpeptidase active center.21 Other authors,22
however, claim that the pyramidal atom is not the only source
of biological activity because of the lack of simple correlation
between the pyramidal character of nitrogen and antibacterial
activities of investigated b-lactams.
The N1–O1 bond lengths for sulfonic esters of N-oxyimides
are in the range of 1.384(2)11–1.398(2) A (for IV). These values
are slightly longer than values observed for non-tosylated N-
hydroxyimides, like N-hydroxyphthalimide [1.375(5) A]17 and
N-hydroxysuccinimide [1.377(2) A]19 and noticeably longer
than the N–O bond lengths existing in N-oxyimides anions
[1.360(2) A],23 but similar to those reported for carboxylic
esters of N-oxyimides2 and N-oxyimides carbonates.24 The
torsion angles of the carbamate moiety of II and III (C1–C2–
N2–C5), 53.3(2)1 and 48.9(2)1, respectively, are also similar in
magnitude to those found for succinimide peptides.25 The
plane of the N2–C5–O6 atoms in II and III is approximately
perpendicular (891 and 831) to the succinimide ring, which has
also been found in the structures of hydroxysuccinimide-based
Noticeable differences in the values of the C61–C11–S–O2
and C21–C11–S–O3 torsion angles can explain the lack of
fitting of the tosyl group rings in compounds II and III. Fitting
of the pentaatomic rings and the protected amino moiety for
compounds II and III is almost complete (Fig. 9b).
A short contact between the C1 and O4 atoms of adjacent
carbonyl groups indicates short antiparallel carbonyl interac-
tions in the crystal structure of compound I. The distance
between carbon of one carbonyl group and the oxygen atom of
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Fig. 8 The scheme showing the stacking of adjacent molecules of IV
[code of symmetry: 2 ꢁ x, 2 ꢁ y, ꢁz]. To indicate a molecule with the
x, y, z code of symmetry the S atom has been labelled. Dashed line is
the distance between the midpoints X1A and X1AA of adjacent
aromatic rings which equals 3.796(2) A. The distance between the
planes of parallel rings is 3.56(2) A.
another (symmetry operation: ꢁx, 2 ꢁ y, 1 ꢁ z) is 2.918(3) A.
The carbonyl group involved in the imide bond in compound
II interacts with the oxygen atom of sulfonyl group of the
adjacent molecule. The distance of this weak interaction is
equal to 2.943(2) A (1 þ x,y,z). Three C–Hꢂ ꢂ ꢂO short interac-
tions were recognized for compound I. They are suspected
with other weak interactions to increase structure’s packing
and the stacking interaction mentioned above. Packing of I is
presented in Fig. 10. In compound II, four intermolecular
interactions were recognized, including one typical hydrogen
bond N2–H2Nꢂ ꢂ ꢂO5 and three C–Hꢂ ꢂ ꢂO type short contacts.
In compound III, the C2 carbon atom as an H2 atom donor
creates two short interactions of the C–Hꢂ ꢂ ꢂO type with the O3
(2 ꢁ x, ꢁ1/2 þ y, 3/2 ꢁ z) and O5 atoms (3 ꢁ x, ꢁ1/2 þ y, 3/2
ꢁ z) of surrounding molecules. Compound III is characterized
by one typical N2–H2Nꢂ ꢂ ꢂO5 and four C–Hꢂ ꢂ ꢂO type short
interactions. There are no typical hydrogen bonds in com-
pound IV, in which only three C–Hꢂ ꢂ ꢂO type short contacts
were recognized. All hydrogen bond parameters are shown in
Table 2. The hydrogen bond donor atom in presented com-
pounds II and III is nitrogen of the carbamate bond. Carbonyl
groups in the succinimic ring are hydrogen bond acceptors.
The adjacent molecules of II and III are linked together by
N–Hꢂ ꢂ ꢂO hydrogen and C–Hꢂ ꢂ ꢂO bonding interactions, form-
ing a three-dimensional network. Packings of II, III and IV
within the unit cell are shown in Figs. 11–13, respectively.
Fig. 10 The packing arrangement of I along the b axis.
Presented analysis of molecular packing shows that the
nitrogen atom geometry is not dependent on the molecular
arrangement in the described crystals. The structures of four
compounds presented in this work can be divided into two
types distinguished according to the structural motifs that are
presented in Fig. 9. Previously described 1-[(2-naphthylsulfo-
nyl)oxy]pyrrolidine-2,5-dione was characterized also by the
non planar nitrogen atom.11
Conclusions
Present study has shown the structural features which might
be responsible for specific chemical reactivity towards nucleo-
philes and biological activity of arylsulfonic esters of N-
hydroxyimides. All four structures are characterized by non-
planar nitrogen of the pentaatomic ring and relatively long
C1–N1 and C4–N1 bonds that imply reduction of the amide
resonance in comparison to carboxylic esters of succinimides.
In arylsulfonic esters the nucleophilic attack of amines on
succinimide carbonyls results in Lossen type rearrangements
of these compounds and opening of the succinimidic ring4,5
(Fig. 1). This effect may also play a role in inhibitory proper-
ties shown by p-toluenesulfonates of N-oxyimides in respect to
proteolytic enzymes. According to literature data, interaction
of N-hydroxyimidyl sulfonates with proteolytic enzymes is
initiated by nucleophilic opening of the imide ring. A similar
effect is also observed for b-lactam antibiotics where nitrogen
aplanarity is also considered to play a key role in activity of
those systems.21
Fig. 9 The comparisons of structures: (a). I and IV; (b). II and III;
The common reference points are C1, C2, C3, and C4 atoms.
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Table 2 Hydrogen bond geometry details of I, II, III, and IV
˚
D–H/A
˚
˚
Compound
I
Hꢂ ꢂ ꢂA/A
2.46(2)
2.54(2)
2.44(2)
Dꢂ ꢂ ꢂA/A
D–Hꢂ ꢂ ꢂA/1
125(2)
126(2)
162(2)
Symmetry operations on A
C2–H2Aꢂ ꢂ ꢂO3
C3–H3Aꢂ ꢂ ꢂO5
C31–H31ꢂ ꢂ ꢂO4
0.92(2)
0.95(2)
0.98(2)
3.076(2)
3.191(2)
3.383(2)
x, 3/2 ꢁ y, ꢁ1/2 þ z
1 ꢁ x, 2 ꢁ y, 1 ꢁ z
1 þ x, 3/2 ꢁ y, 1/2 þ z
II
N2–H2Nꢂ ꢂ ꢂO5
C2–H2ꢂ ꢂ ꢂO5
0.77(2)
0.98(2)
0.96(2)
0.98(2)
2.54(2)
2.58(2)
2.63(2)
2.59(2)
3.073(2)
3.116(2)
3.555(2)
3.389(2)
128(2)
115(2)
163(2)
140(2)
1 ꢁ x, 1/2 þ y, 1/2 ꢁ z
1 ꢁ x, 1/2 þ y, 1/2 ꢁ z
1 ꢁ x, 1/2 þ y, 1/2 ꢁ z
x ꢁ 1,y,z
C3–H3Aꢂ ꢂ ꢂO6
C6–H6Aꢂ ꢂ ꢂO4
III
N2–H2Nꢂ ꢂ ꢂO5
C2–H2ꢂ ꢂ ꢂO3
0.79(2)
0.96(2)
0.96(2)
0.93(2)
0.98
2.35(2)
2.52(2)
2.54(2)
2.58(2)
2.48
2.963(2)
3.107(2)
3.133(2)
3.475(2)
3.346(3)
134(2)
118(2)
121(2)
159(2)
165
3 ꢁ x, y ꢁ 1/2, 3/2 ꢁ z
2 ꢁ x, y ꢁ 1/2, 3/2 ꢁ z
3 ꢁ x, y ꢁ 1/2, 3/2 ꢁ z
3 ꢁ x, y ꢁ 1/2, 3/2 ꢁ z
5/2 ꢁ x, 1 ꢁ y, 1/2 þ z
C2–H2ꢂ ꢂ ꢂO5
C3–H3Aꢂ ꢂ ꢂO6
C71–H712ꢂ ꢂ ꢂO6
IV
C16–H16ꢂ ꢂ ꢂO2
C21–H21ꢂ ꢂ ꢂO3
C61–H61ꢂ ꢂ ꢂO4
0.89(2)
0.96(2)
0.98(2)
2.50(3)
2.50(3)
2.43(3)
3.369(2)
3.334(2)
3.392(2)
161(2)
146(2)
167(2)
1/2 þ x, 3/2 ꢁ y, 1/2 þ z
2 ꢁ x, 1 ꢁ y, ꢁz
3/2 ꢁ x, 1/2 þ y, 1/2 ꢁ z
This study shows the structural features of investigated
compounds in the solid state which might help in understand-
ing the chemical reactivity and biological activity of alkyl- and
arylsulfonic esters of N-hydroxyimides and which play a
pivotal role in the design of new potentially active serine
protease ‘‘suicide’’ inhibitors.
taining 10ꢁ4 M NaCl was used as a solvent for ESI-MS
measurements.
Syntheses
1-{[(4-Methylphenyl)sulfonyl]oxy}pyrrolidine-2,5-dione (I).
1-Hydroxypyrrolidine-2,5-dione (10.7 g, 93 mmol) and tosyl
chloride (19.65 g, 100 mmol) were dissolved in tetrahydrofur-
an (100 ml) and then triethylamine (14.70 ml) was added
dropwise for 20 minutes. After 40 minutes the solvent was
removed in vacuo and 100 ml of distilled water with 3 drops of
concentrated hydrochloric acid were added. The product was
filtered off, washed twice with water and crystallized from
ethyl acetate to give I (23.10 g, 92% yield). For crystallo-
graphic studies the product was recrystallized from dichlor-
omethane by slow evaporation. mp = 143–144 1C, ESI-MS
m/z 292 ([MNa]1), 1H NMR (CDCl3, 500 MHz) d 2.44
(s, 3H), 2.76 (s, 4H), 7.35 (d, 2H, J = 8.4 Hz), 7.87 (d, 2H,
J = 8.4 Hz).
Experimental
Investigated compounds were synthesized according to the
procedures described below. Melting points (uncorrected)
were measured with a Boethius PHMK (VEB Analytik,
Dresden, Deutschland) apparatus. The optical rotation was
measured with a Jasco DIP 1000 polarimeter (Tokyo, Japan)
at 546 nm. 1H NMR spectra were recorded on a Bruker
spectrometer at 500 MHz using TMS as the internal standard.
Mass spectra were obtained on a Finnigan TSQ-700 instru-
ment equipped with an electrospray ion source. MeOH con-
Fig. 11 The packing arrangement of II along the a axis.
Fig. 12 The packing arrangement of III along the a axis.
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24
yield), mp = 141–142 1C, [a]D = ꢁ3.78 (c = 2.2, MeOH),
ESI-MS m/z 228 ([MNa]1). Next CEt-L-aspartic acid (CEt =
carboethoxy) (36.30 g, 0.177 mmol) and N,N0-dicyclohexyl-
carbodiimide (36.52 g, 0.177 mmol) were dissolved in 30 ml of
THF and incubated for 12 h at 0 1C. After filtering off the
N,N0-dicyclohexylurea precipitate THF was evaporated under
reduced pressure. The obtained crude anhydride (18.5 g, 99
mmol) was added to the solution of hydroxylamine hydro-
chloride (7.56 g, 108 mmol) in 29.6 ml of dioxane and 27.2 ml
of 4 M NaOH. Reaction was carried out for one hour at 60 1C.
Then water and dioxane were evaporated under reduced
pressure and the residue was heated at 145 1C for 5 minutes
in vacuo. Ethyl (3S)-1-hydroxy-2,5-dioxopyrrolidin-3-ylcarba-
mate was extracted with acetone and the solution was evapo-
rated to dryness (ESI-MS m/z 225 ([MNa]1). Attempts at
crystallization of the product failed. Obtained product (9.8 g,
48.5 mmol) and p-toluenesulfonic chloride (10 g, 52.4 mmol)
were dissolved in 150 ml of tetrahydrofuran and then 7.70 ml
of triethylamine were added for 15 minutes and the solution
was stirred for one hour. Then the solution was evaporated
and the solid residue was washed with water. Finally 10.60 g of
Fig. 13 The packing arrangement of IV along the b axis.
Benzyl (3S)-1-[(4-methylphenyl)sulfonyl]-oxy-2,5-dioxopyr-
rolidin-3-ylcarbamate (II). The synthesis of benzyl (3S)-1-
hydroxy-2,5-dioxopyrrolidin-3-ylcarbamate was carried out
by condensation of Cbz-L-aspartic acid anhydride (Cbz =
carbobenzoxy), obtained according to the standard proce-
dure,27 with hydroxylamine. Cbz-L-aspartic acid anhydride
(5 g, 20 mmol) was added to a solution of hydroxylamine
hydrochloride NH3(OH)Cl (1.54 g, 22 mmol) and NaOH (0.83
g, 21 mmol) dissolved in 12 ml of the water–dioxane mixture
(1 : 1). The solution was stirred for 15 minutes at room
temperature and then for 2 h at 60 1C. Then water and dioxane
were evaporated under reduced pressure and the residue was
heated at 145 1C for 5 minutes in vacuo. The product was
extracted with ethyl acetate. The extracts were evaporated and
benzyl (3S)-1-hydroxy-2,5-dioxopyrrolidin-3-ylcarbamate (2)
was washed with diethyl ether and dried over P2O5 (4 g, 75%
pure and crystalline compound III were obtained via recrys-
24
tallization from ethyl acetate. mp = 137–139 1C, [a]D
=
þ3.89 (c = 1.7 , MeOH), ESI-MS m/z 379 ([MNa]1), 1H
NMR (CDCl3, 500 MHz) d 1.23 (t, 3H, J = 7.06), 2.45 (s, 3H),
2.88 (m, 1H), 3.15 (m, 1H), 4.12 (q, 2H J = 7.03) 4.38 (broad
s, 1H), 5.30, (broad s, 1H), 7.36 (d, 2H, J = 8.05), 7.92 (d, 2H,
J = 8.20 Hz).
2-{[(4-Methylphenyl)sulfonyl]oxy}-1H-isoindole-1,3(2H)-dione
(IV). 2-Hydroxy-1H-isoindole-1,3(2H)-dione (5.00 g, 30.7
mmol) and p-toluenesulfonic chloride (5.84 g, 30.7 mmol) were
dissolved in tetrahydrofuran (100 ml) and then triethylamine (5
ml) was added dropwise for 15 minutes. After 40 minutes the
solvent was removed in vacuo and 30 ml of distilled water with 1
drop of concentrated hydrochloric acid were added. Pure
product IV was filtered off and washed twice with water (8.85
g, 91% yield). The product IV was recrystallized from ethyl
acetate. mp = 155–157 1C, ESI-MS m/z 340 ([MNa]1), 1H
NMR (CDCl3, 500 MHz) d 2.48 (s, 3H), 7.39 (d, 2H, J = 8.2
Hz), 7.78 (m, 2H), 7. 85 (m, 2H) 7.93 (d, 2H, J = 8.3 Hz).
24
yield, mp = 139–142 1C [a]D = ꢁ39.8 (c = 1.4, MeOH),
ESI-MS m/z 287 ([MNa]1). p-Toluenesulfonic chloride (0.87
g, 4.5 mmol) and 2 (1.12 g, 4.2 mmol) were dissolved in
tetrahydrofuran (10 ml) and then triethylamine (0.67 ml)
was added dropwise for 5 minutes. After 60 minutes the
solvent was removed in vacuo and the obtained oil was
dissolved in the mixture of water and ethyl acetate. The
organic phase was dried with anhydrous MgSO4. Product II
crystallized after addition of pentane and was purified by
crystallization from benzene–octane (1 : 1) (1.54 g, 87% of
theoretical yield). Single crystals of II were obtained from
Crystallography
X-ray data were collected using an ‘Xcalibur PX k geometry
diffractometer’ (o and f-scans) with a graphite-monochroma-
tized MoKa radiation. All structures were solved by direct
methods using the SHELXS97 program28 and refined using
SHELXL97.29 The absolute configurations of II and III were
defined from the Flack parameters and are equal to the
stereochemistry of L-aspartic acid.
24
dichloromethane. mp = 128–129 1C, [a]D = þ8.56 (c = 1,
1
MeOH), ESI-MS m/z 441 ([MNa]1), H NMR (CDCl3, 500
MHz) d 2.44 (s, 3H), 2.86 (m, 1H), 3.11 (m, 1H), 4.379 (broad
s, 1H), 5.08 (s, 2H), 5.69, (broad s, 1H), 7.31 (m, 7H), 7.90
(d, 2H, J = 7.7 Hz).
All positions of the H atoms, except hydrogens of methyl
moieties of all compounds, were found from difference Fourier
maps and refined isotropically with Uiso(H) = 1.2Ueq (C) for
aromatic, CH, and CH2 moieties and 1.5Ueq (C) for methyl H
atoms. The hydrogens from methyl groups were positioned
geometrically using AFIX 137 instructions.
All figures were generated using XP30 and Ortep for Win-
dows.31 The details of structure refinements and crystal data
are given in Table 3. The comparison of selected angles and
Ethyl (3S)-1-[(4-methylphenyl)sulfonyl]-oxy-2,5-dioxopyrro-
lidin-3-ylcarbamate (III). L-Aspartic acid (40 g, 300 mmol)
was dissolved in 75 ml of 4 M NaOH and 31.4 ml of ethyl
chloroformate and 90 ml of 4 M NaOH were added alternately
for 30 minutes. After bringing pH to 1 with conc. HCl the
product was extracted with ethyl acetate. The organic phase
was evaporated giving 38 g of CEt-L-aspartic acid (61.7%
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New J. Chem., 2006, 30, 258–265 | 263

View Article Online
Table 3 Experimental data
I
II
III
IV
Crystal data
Empirical formula
Molecular weight/g molꢁ1
Crystal system
Space group
a/A
C11H11NO5S
269.27
Monoclinic
P21/c
9.847(3)
11.791(3)
11.014(3)
110.58(3)
1197.2(6)
4
C19H18N2O7S
418.41
Orthorhombic
P212121
7.900(2)
C14H16N2O7S
356.35
Orthorhombic
P212121
7.764(2)
C15H11NO5S
317.31
Monoclinic
P21/n
14.343(4)
6.654(2)
15.080(4)
108.16(3)
1367.5(7)
4
b/A
c/A
10.140(3)
23.717(4)
10.265(3)
19.787(4)
b/1
V/A3
1899.8(8)
4
1.463
0.217
872
1577.0(7)
4
1.501
0.246
744
Z
Dcalc/g cmꢁ3
1.494
0.283
1.541
0.261
m/mmꢁ1
F(000)
560
0.40 ꢃ 0.30 ꢃ 0.15
656
0.30 ꢃ 0.15 ꢃ 0.10
Crystal size/mm
Crystal form
Crystal colour
0.20 ꢃ 0.20 ꢃ 0.03
0.25 ꢃ 0.20 ꢃ 0.05
Block
Colourless
Plate
Colourless
Plate
Colourless
Needle
Colourless
Data collection
Monochromator
Radiation type
T/K
Graphite
MoKa
120(2)
Graphite
MoKa
100(2)
Graphite
MoKa
100(2)
Graphite
MoKa
100(2)
2ymax /1
Indexes range
60.00
56.78
60.00
60.00
ꢁ12 r h r 13
ꢁ16 r k r 16
ꢁ15 r l r 15
None
17 300
3488
ꢁ10 r h r 10
ꢁ10 r k r 13
ꢁ27 r l r 31
None
12 930
4431
ꢁ10 r h r 10
ꢁ14 r k r 14
ꢁ27 r l r 27
None
29 265
4579
ꢁ19 r h r 20
ꢁ9 r h r 8
ꢁ20 r h r 21
None
23 525
3986
Absorption correction
No. of measured reflections
No. of independent reflections
No. of observed reflections
(I 4 2s(I))
3105
0.0535
3822
0.0375
4096
0.0785
3100
0.0714
Rint
Refinement
Refinement on
Number of parameters
R (Fo 4 2s(Fo))
R (all data)
F2
188
F2
308
F2
250
F2
224
R = 0.0423
R = 0.0469
wR2 = 0.1193
1.059
0.080
0.357
R = 0.0333
R = 0.0431
wR2 = 0.0657
1.023
0.0350
0
R = 0.0422
R = 0.0525
wR2 = 0.0852
1.055
0.040
0
R = 0.0563
R = 0.0795
wR2 = 0.1437
1.157
0.0832
0
GooF = S
Weighting parameter a
Weighting parameter b
w = 1/[s2(Fo2) þ (aP)2 þ bP], where P = (Fo þ 2Fc2)/3
2
(D/s)max
0.005
0.44
ꢁ0.43
0
0
0
Drmax/eAꢁ3
Drmin/eAꢁ3
0.21
ꢁ0.33
0.33
ꢁ0.39
0.62
ꢁ0.44
bond distances of four investigated compounds is listed in
Table 1. The geometry of hydrogen bonds and C–Hꢂ ꢂ ꢂO short
contacts is given in Table 2.
8 W. C. Groutas, H. Huang, J. B. Epp, M. J. Brubaker, C. E. Keller
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This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2006
New J. Chem., 2006, 30, 258–265 | 265