Cyclosulfamides as constraint dipeptides: The synthesis and structure of chiral substituted 1,2,5-thiadiazolidine 1,1-dioxides: Evaluation of the toxicity

Article abstract of DOI:10.1080/10426500500327014

A general synthesis for the preparation of chiral N-N′ substituted 1,2,5-thiadiazolidine 1,1-dioxides has been developed beginning with proteogenic amino acid, sulfuryl chloride, and dibromoethane. The selected chemistry and spectral properties of these c

Full text of DOI:10.1080/10426500500327014

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Cyclosulfamides as Constraint
Dipeptides: The Synthesis and
Structure of Chiral Substituted
1,2,5-Thiadiazolidine 1,1-
Dioxides: Evaluation of the
Toxicity
Amel Bendjeddou a , Houria Djebbar a , Malika
Berredjem a , Z'Hour Hattab a , Zine Regainia a &
Nour-Eddine Aouf a
a Laboratoire de Chimie Organique Appliquée,
Groupe de Chimie Bioorganique, Faculté des
Sciences, Département de Chimie , Université
d'Annaba , Algérie
Published online: 01 Feb 2007.
To cite this article: Amel Bendjeddou , Houria Djebbar , Malika Berredjem , Z'Hour
Hattab , Zine Regainia & Nour-Eddine Aouf (2006) Cyclosulfamides as Constraint
Dipeptides: The Synthesis and Structure of Chiral Substituted 1,2,5-Thiadiazolidine
1,1-Dioxides: Evaluation of the Toxicity, Phosphorus, Sulfur, and Silicon and the
Related Elements, 181:6, 1351-1362, DOI: 10.1080/10426500500327014
To link to this article: http://dx.doi.org/10.1080/10426500500327014
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Phosphorus, Sulfur, and Silicon, 181:1351–1362, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500327014
Cyclosulfamides as Constraint Dipeptides: The Synthesis
and Structure of Chiral Substituted 1,2,5-Thiadiazolidine
1,1-Dioxides: Evaluation of the Toxicity
Amel Bendjeddou
Houria Djebbar
Malika Berredjem
Z’Hour Hattab
Zine Regainia
Nour-Eddine Aouf
Laboratoire de Chimie Organique Applique´e, Groupe de Chimie
Bioorganique, Faculte´ des Sciences, De´partement de Chimie, Universite´
d’Annaba, Alge´rie
A
general synthesis for the preparation of chiral N-Nꢀ substituted 1,2,5-
thiadiazolidine 1,1-dioxides has been developed beginning with proteogenic amino
acid, sulfuryl chloride, and dibromoethane. The selected chemistry and spectral
properties of these compounds are examined. Overall, routes described are applica-
ble to the synthesis of a variety of constrained dipeptidal sulfamides representing
novel peptidomimetic scaffolds.
Keywords Amino acids; constraints peptides; cyclic sulfamides
A cyclic sulfamide (1,2,5-thiadiazolidine 1,1-dioxides) motif is used as
new type of peptidic constraint to lock two consecutive amide nitrogens
by a sulfonyl bridge. Peptidomimetic analogs have found wide applica-
tion as bioavailable and potent mimetics of naturally occurring biolog-
ically active peptides.1
Major efforts have thus been devoted to the development of agonists
or antagonists of these peptides that could be used as a drug with high
Received June 7, 2005; accepted July 7, 2005.
Dedicated to the loving memories of Dr. Ahmed Benkhamala (1956–2004).
This work is partially supported by the National Agency for the Research in Health
(ANDRS, Project No 05/05/00039), the Applied Organic Chemistry Laboratory (F.N.R
2000), and the National Fund of Research (Algerian Research Ministry, MERS).
Address correspondence to Nour-Eddine Aouf, Laboratoire de Chimie Organique Ap-
plique´e, Chemistry Department, Badji Mokhtar University, PO Box 12, Annaba, Algeria.
E-mail: noureddineaouf@yahoo.fr
1351

1352
A. Bendjeddou et al.
specificity and low toxicity. In the field of medicinal chemistry, a cyclic
sulfamide is one of the most important structural motifs that exist
in many pharmaceutically useful compounds. For example, some sul-
famides, including cyclic ones, are known to be effective HIV2 and serine
protease inhibitors,3 as both agonists and antagonists of serotonin,4 his-
tamine receptors,5 and constrained di- and tripeptides.6 Furthermore,
cyclic sulfamides have also been used as effective chiral auxiliaries
in asymmetric aldol reactions.7 However, most reported methods for
the synthesis of cyclic sulfamides rely on the reaction of amines with
sulfuryl chloride or isocyanate chlorosulfonyl under drastic reaction
conditions.8 Our aim is to develop a new type of constraint that con-
serves the peptidic scaffold while inducting a rigid fold that orients the
side chain of a dipeptide unit into specific spacial relationship. Recently,
we reported the synthesis and the reactivity of new cyclosulfamides.9
We now report the successful extension of this work to the synthesis of
constrained dipeptide incorporation into cyclosulfamides.
To do so, we envisioned the linkage of two consecutive amide nitro-
gens by a dibromoethane reagent to create a cyclosulfamide dipeptide
constraint (Figure 1).
SCHEME 1 ae = a: Ala; b: Val; c: Leu; d: Phe; e: Asp; f: Glu.
Three methods have been used for access to symmetric and unsym-
metric cyclosulfamides. The routes to the symmetric sulfamides 2a–f
center on the coupling of four equivalents of an amino ester with sul-
furyl chloride (SO2Cl2) (Scheme 1). Routes to unsymmetric sulfamide
6 feature the sequential coupling of an alcohol then an aminoester to
FIGURE 1 Predictable constraints induced by the insertion of cyclosulfamide
in a peptidic structure.

Cyclosulfamides as Constraint Dipeptides
1353
chlorosulfonyl isocyanate (OCNSO2Cl), followed by a Mitsunobu reac-
tion (Scheme 2).
SCHEME 2
These two methods have been reviewed.10 In addition, attempts to
directly couple aminoesters (Ala,Val) derivatives with SO2Cl2 were suc-
cessful. By this method, we could obtain simultaneously symmetric and
unsymmetric sulfamides with an acceptable yield (Scheme 3).
SCHEME 3
RESULTS AND DISCUSION
The way to the amino-ester derived C2-symmetric sulfamides 1a–f is
outlined in Scheme 1. The symmetric sulfamides 1a–f were prepared
in 75–85% yields by the treatment of 4 equivalents of α-amino esters
with sulfuryl chloride in pentane or dichloromethane. It was found that
the use of 2 equiv of α-amino ester as base to neutralize the liberated
HCl gave a product superior in purity to that obtained by a prior gener-
ation of a pyridine-sulfuryl chloride adduct followed by the treatment
with aminoesters a–f. The treatment of N,Nꢀ-disubstituted sulfamides
compounds 1a–f in acetone with a large excess of 1,2-dibromoethane
under basic conditions (potassium carbonate K2CO3) and reflux gave
symmetric cyclosulfamides 2a–f in excellent yields (Scheme 1).

1354
A. Bendjeddou et al.
Unsymmetric cyclic sulfamides have been shown to be HIV protease
inhibitors.11
The cyclic unsymmetric sulfamide 6 can be prepared in four steps
starting from a sulfonyl carbamate to differentate its two nucleophilic
N-H sites. In this route, we utilize the pKa difference of the sulfonyl car-
bamate N-H and sulfamide N-H in a selective Mitsunobu/deprotection
sequence first developed by our group12 and later exploited by others.13
Thus, sulfonyl carbamate 3 is utilized in a regioselective Mitsunobu
reaction14 to generate, after deprotection, the unsymmetric sulfamide
5 dipeptidal scaffold in good yield (Scheme 2).
The cyclization was carried out under basic conditions with dibro-
moethane, which produces the unsymmetric N,Nꢀ substituted cyclosul-
famide 6.
In this work, we developed also a new and efficient method in
one step for access to unsymmetric and symmetric sufamides. This
strategy utilizes two amino ester (Valine, Alanine) derivatives, which
were condensed with sulfuryl chloride in triethylamine/pentane or
dichloromethane (1a, 1b, 1g) as outlined in Scheme 3.
The unsymmetric and symmetric sulfamide Alanine and Valine
derivatives (1a, 1b, 1g) can be prepared in one steep starting from
two aminoester chlorhydrates (Ala, Val) simultaneously. In addition, at-
tempts to directly couple amino esters (Ala, Val) with SO2Cl2 in pentane
at 0◦C for 2 h were successful. By this method, we have obtained three
compounds: two symmetric sulfamides (Ala, Val) derivatives 1a, 1b in
a 16% yield and the mixed sulfamide 1g in a 25% yield. TLC reveals
(ninhydrin) unsymmetric sulfamide formation. This latter is more po-
lar than its analogue symmetrical descended from the Valine and is less
polar than that coming from Alanine. This method has the advantage
to lead in a single step to both symmetric and unsymmetric sulfamides.
The crude residue was separated by column chromatography eluted
with dichloromethane. The products were obtained in acceptable yields.
Structures of all compounds were unambiguously confirmed by usual
spectroscopic methods: IR, 1H NMR, and mass spectrometry. The N-Nꢀ-
sulfonyl bis-L-aminoesters 1a–g were characterized by the presence in
IR spectra of bands at 3280 20 cm−1 (NH) and by an intense absorp-
tion at 1730 10 cm−1 for the carbonyl group. NH appeared in the NMR
spectra in the form of a doublet at 5 1 ppm. This signal disappears
in cyclized compounds and shows a signal for ethylene protons at 3.5–
4 ppm. For the resulting compounds containing the five-membered ring
2a–g, IR spectra showed bands at 1730 10 cm−1 (C O) and near 1350
and 1185 cm−1 (SO2).
For the compounds (4–6), the disappearance of the (C O) absorption
and (NH) bands in IR confirm the removal the Boc group and the cy-

Cyclosulfamides as Constraint Dipeptides
1355
clization. Deprotection and cyclization were equally followed in NMR
by the dissapearance of the signal of the ter-butyl and NH protons.
Evaluation of Toxicity of Studied Molecules on the Respiratory
Metabolism of Living Organisms: The protists cilia
The toxicity of synthesized molecules was determined by the respira-
tory kinetics test.15 The microorganism used in the present investiga-
tion was an unicellular biflagellar algae (Tetraselmis suecica) whose
energizing features are identical to that of mammal cells. The used
protists were provided from cultures at an exponential phase of growth
and were kept at 20◦C under continuous light. A polarographic method
was used to estimate to the respiratory activity of protozoan via an elec-
trode Hansatech type. Sulfamides were chosen as molecules under the
following conditions: control cells (in water), control-aceton (in order to
dissolve molecules 1g, 1a, and 1f), cotrimoxazol (marketed Shape, used
like positive control), and 1b and 1e molecules (dissolved in water). All
molecules were tested at a 100 mM concentration. It is the aim of the
present experimental investigation to evaluate the short-term toxicity
of the tested molecules, and kinetics over 15 minutes were recorded.
The results, thus obtained, are summarized in Figure 2.
FIGURE 2 The kinetic of action of molecules on the respiratory activity of
Tetraselmis suecica. (O): Control; (•): control-aceton, ( ): treated with Cotri-
ꢀ
moxazol; (ꢁ): treated with 1b; (ꢀ): treated with 1g; ( ): treated with 1a; (ꢂ):
ꢀ
treated with 1f, and ( ) treated with 1e.
ꢃ

1356
A. Bendjeddou et al.
It is clear that the respiratory activity of control cells, control-aceton-
cells, and cotrimoxazol treated-cells incease with time, reaching 55
nmol/mL after 15 min. The inhibition of 20% is observed after the treat-
ment with the 1e molecule. A more important inhibition is obtained the
after the treatment with the the 1 g molecule. The respiratory activity
is completely stopped in the presence of both 1f and 1a molecules. An
important stimulation of the respiratory activity was observed in the
presence of the 1b molecule, which reaches about 20% in relation to the
control.
In conclusion, it is evident from these results that two of the studied
molecules (1a and 1f) are strongly toxic, whereas the 1b molecule seems
to have small toxic effects. In the same way all other molecules seem to
be rather less toxic. The 1f and 1a molecules could constitute excellent
potentially cytotoxic agents, particilarly in antitumorous therapy.
EXPERIMENTAL SECTION
Melting points were determined in open tubes on an electrothermal
digital apparatus and are uncorrected. FTIR spectra were recorded on
a Perkin-Elmer spectrophotometer. Elemental analysis was determined
on a Perkin-Elmer 240 C elemental analyzer, and the results were in an
acceptable range. Proton Magnetic Resonances were determined with
an AC 250 Bruker spectrometer (Universite´ de Constantine Alge´rie).
Mass spectra (electrospry method) were recorded on a Finnigan MAT
TSQ-700. Optical rotations were measured in a 1-cm cell on a Polax
polarimeter. TLC was performed on silica gel 60 F254 (Merck). Column
chromatography was performed on silica gel 60. All solvents used for
reactions were anhydrous.
General Procedure for the Synthesis of N,Nꢀ-Disubstituted
Sulfamides—Symmetric Derivatives
A solution of sulfuryl chloride (10 mmol, 1.35 g) in pentane (30 mL)
was added dropwise to an ice-cooled, stirred solution of (40 mmol) α-
amino ester in pentane (80 mL) cooled to 0◦C. The reaction mixture
was stirred for 15 min, after which cold water (200 mL) was added, and
the reaction mixture was stirred for additional 15 min. The mixture
was extracted with of CH2Cl2 (200 mL); the organic phase was washed
with 120 mL of 1M HCl, followed with water (120 mL), and dried with
Na2SO4, and the solvent was removed under reduced pressure to give
the crude sulfamide as a colorless, viscous gum. Aquerous fractions
were combined, made basic with 30% (v/v) aqueous NaOH, and ex-
tracted with 2 × 60 mL of CH2Cl2. The combined organic extracts were

Cyclosulfamides as Constraint Dipeptides
1357
washed with 100 mL of water and dried with Na2SO4. The solvent was
removed under reduced pressure to recover the excess of α-amino acid
ester. The crude residue was purified by column chromatography eluted
with dichloromethane, yield (81%) of N,Nꢀ bis sulfonyl aminoesters as
a white powder.
N,Nꢀ-Sulfonyl bis L-Alanine Dimetyl ester 1a, N,Nꢀ-Sulfonyl bis L-
valine dimetyl ester 1b, N,Nꢀ-Sulfonyl bis L-leucine dimetyl ester 1c,
and N,Nꢀ-Sulfonyl bis L-phenylalanine dimetyl ester 1d were prepared
according to the literature procedure, see ref. 10.
N,Nꢀ-Sulfonyl Bis-L-Aspatic Dimetyl Ester 1e
Yield = 78%; Rf = 0.61 in (CH2Cl2); m.p. = 80–82◦C; [α]D = +17 (c =
1, MeOH).
FTIR (KBr, ν cm−1) 3294, 2966, 1735, 1360, 1164. 1H NMR (CDCl3,
δ ppm): 5.90 (d, J = 8.4 Hz, 2H), 4,42 (m, 2H), 3.72–3.80 (2s, 12 H),
3.20–2.80 (ddd, J = 17.2, 4.3, 8.3 Hz, 4H).
MS (ESI): 385 [M + H]+, 407 [M + 23]+, 100%.
M = 384 (C12H20 N2O10S); Calcd %, C, = 37.50; H, = 5.21; N, = 7.29
found C, 37.55; H, 5.23; N, 7.23.
N,Nꢀ-Sulfonyl Bis-L-Glutamic Dimethyl Ester 1f
Yield = 80%; Rf = 0,65 in (CH2Cl2); m.p. = 73–75◦C; [α]D = +45 (c = 1,
MeOH).
FTIR (KBr, ν m−1), 3290, 2976, 1734, 1364, 1160. 1H NMR (CDCl3, δ
ppm): 5.40 (d, J = 8.8 Hz, 2H), 4.42 (m, 2H), 3.69–3.80 (2s, 12H,), 2.50
(m, 4H), 1.80–2.30 (2m, 4H).
MS (ESI + 1): 413 [M + H]+, 435 [M + 23]+, 100%
C14H24N2O10S M, 412 Calcd% C, 40.77; H, 5.82; N, 6.79; found % C,
40.82; H, 5.86; N, 6.71.
N-[[(1S) 1-Methoxycarbonyl-Ethyamino] Sulfonyl]-L-Valine
Methyl Ester 1g
Yield = 25%; Rf = 0.62 (CH2Cl2); m.p. = 67–69◦C; [α]D = −132.3 (c = 1
MeOH).
1
FTIR (KBr, ν cm−1): 3282, 1732, 1338, 1141. H NMR (CDCl3, δ
ppm): 5.10 (m, 2H), 4.15 (m, 1H), 3.90 (dd, J = 4.6, 5.1 Hz, 1H), 3.70
(1s, 6H), 2.10 (m, 1H), 1.40 (d, J = 7.1 Hz, 3H), 0,98 (d, J = 6.8 Hz, 3H),
0,88 (d, J = 6.9 Hz, 3H).
MS (ESI + 1): 413 [M + H]+, 435 [M + 23]+, 100%.
C10H20 N2O6S M = 296 Calcd % C, 40.54; H, 6.76; N, 9.46. Found %
C, 40.59; H, 6.78; N, = 9.44.
(Ter-Butyloxycarbonylsulfonyl) L-valine methyl ester 3 was prepared
using literature procedure; see ref. 8.

1358
A. Bendjeddou et al.
N-Ter-butyloxycarbonyl-Nꢀ[[-1-ethoxycarbonyl-ethylamino]
Sulfonyl]-L-valine Methyl Ester 4
A solution of Boc-sulfamide 3 (1.00 g, 3.23 mmol) (Scheme 4), valine
amino ester derivative, and diethyl azodicarboxylate (508 µL, 3.23
mmol) in THF (10 mL) was added dropwise (15 mn, 5◦C) to a solution of
equimolar quantities of triphenylphosphine (2.52 g) and L-ethyl lactate
(847 mg, 3.23 mmol) in THF (2 mL). The reaction medium was stirred
under atmosphere of dry nitrogen for about 45 min. TLC reveals the for-
mation of a substituted compound (ninhydrine) less polar than its pre-
cuseur. Oxydoreduction compounds (Ph3P O, EtCO2-NH-NH-CO2Et)
were removed by filtration after precipitation into diethylether. The so-
lution was concentrated under reduced pressure to leave a crude oil.
The crude residue was purified by the column chromatography eluted
with dichloromethane. (5:1 hexane/EtOAc), yield 1.07g (81%) of Boc-
protected sulfamide as yellow oil.
SCHEME 4
Yield = 80%; Rf = 0.60 (CH2Cl2); [α]D = + 68.8 (c = 1.00 CHCl3).
1
FTIR (neat, ν m−1): 3297, 1742, 1708, 1695, 1349, 1139. H NMR
(CDCl3, δ ppm): 6.15 (d, J = 7.6 Hz, 1H), 4.89 (q, J = 6.9 Hz, 1H), 4.18
(q, J = 7.1 Hz, 2H); 4.09 (dd, J = 6.9, 4.0 Hz, 1H), 3.77 (s, 3H), 2.15 (m,
1H), 1.57 (d, J = 16.9 Hz, 3H), 1.50 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H), 0.98
(d, J = 6.8 Hz, 3H), 0,88 (d, J = 6.9 Hz, 3H). MS (ESI): 409 [M − H]+,
433 [M + 23]+, 100%.
C16H30N2O8S M = 410 Calcd % C, 46.83; H, 7.32; N, = 6.83. Found
% C, 46.89; H, 7.38; N, 6.85.
N-[[(1R)-1-ethoxycarbonyl-ethylamino]sulfonyl]-L-valine
Methyl Ester 5
A solution of trifluoroacetic acid (3 Eq., 4.17 g, 2.82 mL, 3.66 mmol)
in dichloromethane (v/v) was added dropwise to the Boc-sulfamide 4

Cyclosulfamides as Constraint Dipeptides
1359
(500 mg, 1.22 mmol) dissolved in the same solvent (50 mL). The reac-
tion medium was stirred for 2 h. The reaction mixture was diluted with
CH2Cl2 (15 mL), washed with NaHCO3, and dried (Na2SO4). The or-
ganic layer was concentrated under reduced pressure and coevaporated
with diethyl ether. Residue was recrystallized from dichloromethane;
the deprotected sulfamide 5 was obtained in good yield.
Yield = 90%; Rf = 0,60 (CH2Cl2); m.p. = 80–81◦C; [α]D = −129.2
(c = 0.5 CHCl3).
FTIR (KBr, ν cm−1): 3282, 1732, 1742, 1349, 1139. 1H NMR (CDCl3,
δ ppm): 4.98 (t, J = 10.1, 8.9 Hz, 1H), 4.22 (q, J = 7.1 Hz, 1H), 4.05 (m,
1H); 3.80 (dd, J = 10.2, 4.9 Hz, 1H), 3.70 (s, 3H), 2.08 (m, 1H), 1.37 (d,
J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0,88
(d, J = 6.9 Hz, 3H ).
MS (ESI): 333 [M + 23]+, 100%.
C11 H22 N2O6S M, 310 Calcd % C, 42.58; H, 7.10; N, 9.03; found % C,
42.59; H, 7.18; N, 9.04.
General Procedure for the Cyclization of Symmetric
and Dissymmetric Derivatives
The N, Nꢀ-disubstituted sulfamides compounds (10 mmol) were dis-
solved in dry acetone, and K2CO3 (1.5 equiv., anhydrous) was added
in one fraction. The resulting mixture was stirred at r.t. for 8 h, di-
luted with dichloromethane (200 mL), and acidified with 5% HCl. The
organic layer was washed with water, dried (Na2SO4) and concentrated
in vacuo. The crude product was purified by silica gel chromatography
(eluant H2Cl2) to afford the cyclosulfamides 2a–g derivatives in a 70–
80% yield.
2,2ꢀ-(2S,2Sꢀ)- [2,2ꢀ-Bis-Propionic Acid Dimethyl
Ester]-1,2,5-thiadiazolidine 1,1-Dioxide 2a
Yield = 78%; Rf = 0.64 (CH2Cl2); mp = 68–70◦C; [α]D = − 132.3 (c = 1,
MeOH).
FTIR (KBr, ν cm−1): 1740, 1349, 1137. 1H NMR (CDCl3, δ ppm): 4.12
(q, J = 7.1 Hz, 2H); 3.85 (m, 2H), 3.75. (s, 6H), 3.60 (m, 2H), 1.40 (d, J
= 7.1 Hz, 6H).
MS (ESI): 411 [M + 23]+ 100%.
C10H18 N2O6N2S M, 294 Calcd % C, 40.81; H, 6.12; N, 9.52. Found %
C, 40.86; H, 6.13; N, 9.47.

1360
A. Bendjeddou et al.
2,2ꢀ-(2S, 2Sꢀ)-[3,3ꢀ-Dimethyl Bis-butyric Acid Dimethyl
Ester]-1,2,5-Thiadiazolidine1,1-Dioxide 2b
Yield = 75%; Rf = 0,65 (CH2Cl2); m.p. = 90–92; [α]D = +45.3 (C g/L
concentration = 1, MeOH).
FTIR (KBr, ν cm−1): 1739, 1375, 1180. 1H NMR (CDCl3, δ ppm): 4.05
(d, 3.0 Hz, 2H), 3.90 (m, 2H), 3.80 (s, 6H), 3.60 (m, 2H), 2.10 (m, 2H),
0.95–1.05 (2d, J = 6.6, 6.6 Hz, 12H).
MS (ESI): 373[M + 23]+ 100%.
C14H26 N2O6S M = 350 Calcd % C, 48.00, H, 7.43; N, 8.00. found %
C, 48.05; H, 7.47; N, 7.97.
2,2ꢀ-(2S, 2Sꢀ)-[4,4ꢀ-Dimethyl Bis-Pentanoic Acid Dimethyl
Ester]-1,2,5-Thiadiazolidine 1,1dioxide 2c
Yield = 80%; Rf = 0, 61 (CH2Cl2); m.p. = 115–117◦C; [α]D = − 54.3
(c = 1, MeOH).
FTIR (KBr, ν cm−1): 1740, 1375, 1180. 1H NMR (CDCl3, δ ppm): 4.10
(t, J = 5.2 Hz, 2H); 4.00 (m, 2H), 3.80 (s, 6H), 3.60 (m, 2H), 1.64 (m,
6H), 1.05–0.95 (2d, J = 6.8, 6.8 Hz, 12H).
MS (ESI): 379 [M + H]+, 401 [M + 23]+.
C16H30 N2O6S M = 378 Calcd % C, 50.79; H, 7.93; N, 7.40; found %
C, 50.81; H, 7.96; N, 7.38.
2,2ꢀ-(2S, 2Sꢀ)-[3,3ꢀ-Diphenyl Bis-Propionic Acid Dimethyl
Ester]-1,2,5-Thiadiazolidine 1,1-Dioxide 2d
Yield = 80%; Rf = 0,70 (CH2Cl2); m.p. = 60–62◦C; [α]D = − 89.3 (c = 1,
MeOH).
1
FTIR (KBr, ν cm−1): 1738, 1349, 1170. H NMR (CDCl3, δ ppm):
7.30–7.20 (m, 10H), 4.50 (t, J = 7.5 Hz, 2 H), 3.95 (m, 2H), 3.80 (m, 4H),
3.75 (s, 6H), 3.20–2.90 (ddd, J = 14.2, 7.8, 7.4 Hz, 4H).
MS (ESI): 447 [M + H]+, 469[M + 23]+ 100%.
C22H26 N2O6S M, 446 Calcd % C, 59.19; H, 5.83; N, 6.28. found % C,
59.22; H, 5.89; N, 6.24.
N,Nꢀ-Bis [2,2ꢀ-(2S,2Sꢀ)-bis (1,2-(Metoxycarbonyl)
Ethyl]-1,2,5-Thiadiazolidine 1,1-Dioxide 2e
Yield = 76%; Rf = 0.65 (CH2Cl2); Yellow oil; [α]D = − 25.3 (c = 1, MeOH).
FTIR (film, ν cm−1): 1741, 1356, 1185. 1H NMR (CDCl3, δ ppm): 4.70
(t, J = 7.1 Hz, 2H), 3.75–3.70. (2s, 12H); 3.50–3.65 (m, 4H), 3.15–3.90
(ddd, J = 17.2, 7.1, 4.5 Hz, 4H).

Cyclosulfamides as Constraint Dipeptides
1361
MS (ESI): 411 [M + H]+, 433[M + 23]+ 100%.
C14H22 N2O10S M = 410 Calcd % C, 40.97; H, 5.36; N, 6.83; found %
C, 40.99; H, 5.39; N, 6.80.
N,Nꢀ-Bis[2,2ꢀ-(2S,2Sꢀ)-bis (1,2-(metoxycarbonyl)
Propyl]-1,2,5-Thiadiazolidine1,1-dioxide 2f
Yield = 80%; Rf = 0.65 (CHCl3); Yellow oil; [α]D = − 65.3 (c = 1, MeOH).
FTIR (film, ν cm−1): 1740, 1356, 1185. 1H NMR (CDCl3, δ ppm): 4.35
(2d, J = 5.3, 5.3 Hz, 2H), 3.70–3.80 (2s, 12H), 3.80–3.90 (m, 4Hcycle),
2.50 (m, 4H), 1.90–2.30 (2m, 4H).
MS (ESI + 1): 461 [M + 23]+ 100%.
C16H26 N2O10S M = 438 Calcd % C, 43.83; H, 5.93; N, 6.39; found %
C, 43.89; H, 5.99; N, 6.32.
N2-[(2S)–(3-Methyl methoxycarbonyl-propyl)],
N5-[(2’S)-propionic Acid Methyl Ester]-1,2,5-thiadiazolidine
1,1-dioxide 2g
Yield = 78%; Rf = 0.62 (CH2Cl2); m.p. = 57–58◦ C; [α]D = −129.2 (c =
1, CHCl3).
1
FTIR (KBr, ν cm−1): 1734, 1346, 1145. H NMR (CDCl3, δ ppm) :
4.22 (q, J = 7.1Hz, 1H), 3.90 (d, J = 3.3 Hz, 1H); 3.75–3.70 (2s, 6H),
3.80–3.60 (m, 4H), 2.08 (m, 1H), 1.37 (d, J = 7.1 Hz, 3H), 0,98 (d, J =
6.8 Hz, 3H), 0,88 (d, J = 6.9 Hz,3H).
MS (ESI + 1): 323 [M + H]+, 345 [M + 23]+, 100%.
C12H22 N2O6SM = 322 Calcd% C, 47.72; H, 6.83; N, 8.69; found% C,
47.69; H, 6.88; N, 8.64.
N2-[(2S)–(3-Methyl methoxycarbonyl-propyl)],
N5–[(2’R)-Propionic Acid Ethyl Ester]-1,2,
5-Thiadiazolidine1,1-dioxide 6
Yield = 76%; Rf = 0,60 (CH2Cl2); m.p. =80–81◦C; [α]D = −12.0 (c = 0,5,
CHCl3).
1
FTIR (KBr, ν cm−1): 1745, 1734, 1346, 1145. H NMR ( CDCl3,δ
ppm): 4.70 ( q, J = 7.3 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.90 (d, J =
3.3 Hz, 1H), 3.80–3.60 (m, 4H), 3.70 (s, 3H), 2.12 (m, 1H), 1.39 (d, J =
7.1 Hz, 3H), 1.26 (t, J = 7.3 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.88 (d, J
= 6.9 Hz, 3H).
MS (ESI + 1): 413 [M+H] +, 435 [M+23] +, 100%.
C13H24N2O6S M = 336; Calcd% C, 46.43; H, 7.14; N, 8.33; found% C,
46.49; H, 7.18; N, 8.34.

1362
A. Bendjeddou et al.
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