N,N′-substituted 1,2,5 thiadiazolidine 1,1-dioxides: Synthesis, selected chemical and spectral proprieties and antimicrobial evaluation

Article abstract of DOI:10.3390/10111387

The sulfamide functional group is increasingly relevant in both medicinal and bioorganic chemistry. We report here practical access to a series of N2,N5-substituted five-membered cyclosulfamides. The five-membered heterocyclic motif was prepared starting from proteogenic amino acids and chlorosulfonyl isocyanate via the Mitsunobu reaction. Selected chemical and spectral proprieties and the antimicrobial evaluation of these compounds are detailed.

Full text of DOI:10.3390/10111387

Molecules 2005, 10, 1387-1398
molecules
ISSN 1420-3049
http://www.mdpi.org
N,N’-Substituted 1,2,5 Thiadiazolidine 1,1-Dioxides: Synthesis,
Selected Chemical and Spectral Proprieties and Antimicrobial
Evaluation†
Amel Bendjeddou, Ryad Djeribi, Zine Regainia and Nour-Eddine Aouf *
Laboratoire de Chimie Organique Appliquée. Groupe de Chimie Bioorganique, Faculté des Sciences.
Département de Chimie. Université d’Annaba. BP 12, Algeria. Fax (+213) 38 87 27 89
†
Dedicated to the memory of Professor Arrar Mostefa (1961-2004)
*Author to whom correspondence should be addressed; E-mail: noureddineaouf@yahoo.fr
Received: 28 June 2005; in revised form: 5 September 2005 / Accepted: 10 September 2005 /
Published: 30 November 2005
Abstract: The sulfamide functional group is increasingly relevant in both medicinal and bioorganic
chemistry. We report here practical access to a series of N2,N5-substituted five-membered
cyclosulfamides. The five-membered heterocyclic motif was prepared starting from proteogenic
amino acids and chlorosulfonyl isocyanate via the Mitsunobu reaction. Selected chemical and
spectral proprieties and the antimicrobial evaluation of these compounds are detailed
.
Keywords: Amino acids, cyclic sulfamides, cyclization, Mitsunobu reaction,
propionylation, constrained peptides.
Introduction
The synthesis and reactivity of heterocyclic compounds containing sulfonyl moieties have attracted
much interest in recent years because of the interesting chemical and biological proprieties associated
with their structural similarities with biomolecules containing carbonyl groups. Cyclosulfamides have
enjoyed popularity in the field of medicinal chemistry as nonhydrolysable components in
peptidomimetics [1-2], agonists of the 5-HTID receptor (regulating serotonin levels) [3], HIV and
serine protease inhibitors [4-7], and constrained di-and tripeptides [8]. The reported strategies for the
synthesis of cyclosulfamides are based either on the incorporation of the sulfamoyl moiety by reacting

Molecules 2005, 10
1388
sulfuryl chloride [9] or sulfonyl urea [10] with vicinal diamines, or ring-closing metathesis syntheses
[11]. Recently, Johnson and co-workers reported the synthesis of N-Arylcyclosulfamides starting from
sulfuryl chloride and chloroethyl-amine [12]. In previous publications [13-15], we have described a
convenient access to a series of five and n-membered cyclic sulfamides B and N,N’-disubstituted
orthogonally protected ones A (Figure 1), starting from natural amino acids, chloroethylamine and
chlorosulfonylisocynanate (CSI) followed by 5-exo-tet closure with base. These heterocycles could be
useful starting points for the construction of an array of peptidomimetic scaffolds and constrained di
and-tripeptides. CSI has been found to be versatile reagent of great interest in synthetic heterocyclic
chemistry [16]. In this case, CSI contains the required sulfonyl group and one of the nitrogens of the
1,2,5-thiadiazolidine1,1-dioxides.
Figure 1. Cyclosulfamide stuctures
R
CH3
(CH2)n
R
R
O
N
O
N
O
N
N
O
N
O
N
O
CO2Et
MeO2C
Boc
Bn
Boc
N
O
N
MeO2C
Bn
S
S
S
S
O
O
R= H, Me, iBu, Bn
n= 2- 12.
R AA =Ala, Val, Leu, Asp, Glu
R'= Me, Et
A
B
C
D
In continuation of our efforts to design and synthesize new cyclic sulfamides, we have extended
our studies to a series of new heterocyclic constrained peptides containing sulfamide groups C and D
(Figure 1). The derivatization of amino acids allowed the introduction N-C* moieties with a well-
defined configuration. Herein, we describe the synthesis and the preliminary results of the biological
evaluation of a series of these new heterocycles containing sulfamido groups.
Results and Discussion
As outlined in Scheme 1, the different heterocyles 1b-5b were prepared in a two-step reaction
sequence starting from (tert-butyloxycarbonylsulfonyl) L-amino acid methyl esters 1-5. These
compounds were synthesized by sulfamoylation of aminoester derivatives (Ala, Val, Leu, Asp, Glu) as
previously described [17-19].
Scheme 1. General synthesis of N2, N5 cyclosulfamides
Cl
H
N
R'
H
N
H
N
CO2 Me
Boc
CO2 Me
b
Boc
N
S
N
Boc
RO
N
S
a
2 C
S
R
O
O
O
R
O
O
O
1-5
1a-5a
1b-5b
Reagents and conditions: (a) Chloroethanol (1 equiv.), PPh3 (1 equiv.), DEAD (1 equiv.),
THF; (b) K2CO3 (1.5 equiv.), DMSO.

Molecules 2005, 10
1389
In these Boc-sulfamides 1-5, the Boc (t-butyloxycarbonyl) group increases the acidity of the
adjacent NH group and allows an expedient regiospecific alkylation under Mitsunobu conditions [20-
21] using chloroethanol, which provides the N-substituted Boc–sulfamides 1a-5a in good yields. The
cyclization reaction of these N,N’-sulfamides 1a-5a under basic conditions in DMSO gives N2,N5-
substituted cyclosulfamides 1b-5b in satisfactory yields.
Selective cleavage of the t-butyloxycarbonyl protective group with trifluoroacetic acid gives
compounds 1c-5c in good yield (Scheme 2). N2,N5-Cyclosulfamides 1d-5d were readily prepared in
quantitative yield from the cyclosulfamides 1c-5c by treatment with propionyl chloride in the presence
of triethylamine. These compounds can be used in asymmetric aldol reactions. Also, attempts to
incorporate the amino acid moiety employing the Mitsunobu reaction using an α-hydroxy ester (L-(-)-
ethyl lactate) allowed us to obtain two constrained dipeptidal cyclic sulfamides 1e-2e in moderate
yields with inversion of the configuration.
Scheme 2. Preparation of constained dipeptide cyclic sulfamides
N
O
MeO2C
N
S
b
O
N
O
MeO2C
N-H
O
O
R
a
N
O
MeO2C
S
N-Boc
O
1d-5d
S
R
R
CO2Et
N
MeO2C
N
c
1c-5c
S
1b-5 b
O
O
R
R
1e-2e
Reagents and conditions: (a) TFA, CH2Cl2; (b) propionyl chloride (1 equiv.), TEA
(1 equiv.), CH2Cl2; (c) (L)-(-) ethyl lactate (1 equiv.), PPh3 (1 equiv.), DEAD (1
equiv.), THF.
The structures of all compounds were unambiguously confirmed by the usual spectroscopic
methods: 1H- and 13 C-NMR spectroscopy, mass spectrometry and IR spectra.
Biological Activity
The bacterial strains used in this study were Staphylococcus aureus and Escherichia coli species.
They were isolated from an aquatic medium, followed by successive isolations carried out periodically
in specific media in order to obtain strains as pure as possible. The solid media of MacConkey and
Chapman have been used for Escherichia coli and Staphylococcus aureus, respectively. Microscopic
study, after Gram coloration, was carried out after incubation at 37°C for 24 hours. The biochemical
characteristics of each strain have been determined using a classic biochemical gallery. Finally, the
pathogenic power of Staphylococcus aureus has been confirmed by showing that the coagulase of this
strain was hemolytic, in vitro, towards rabbit or human plasma.

Molecules 2005, 10
1390
In vitro evaluation of the bacterial sensitivity of the strains to cyclosulfamides 4a and 4d:
To draw the antibiogram, the dilution in a liquid medium method was chosen. It is based on putting
innoculums of each studied strain in contact with increasing concentrations of the cyclosulfamides 4b
and 4d. In a glucose medium, each bacterial inoculum (100 µL per suspension) was distributed in a
series of tubes (macro-dilution method) containing increasing sulfamide concentrations [22]. The
bacterial innoculum corresponding to the two studied strains, was previously prepared from a colony
that was collected from a solid medium and then put in suspension in a glucose medium for 18 hours at
37°C. After the incubation of the whole tubes at 37°C for 24 hours, the MIC (minimal inhibited
concentration) of each of the two cyclosulfamides with respect to each strain (Escherichia coli and/or
Staphylococcus aureus) was measured as indicated by the tube that contained the lower concentration
of the product and where no apparent bacterial growth is noticed. The results of the in vitro evaluation
of the sensitivity of the bacteria Escherichia coli and Staphylococcus aureus towards cyclosulfamides
4b and 4d are presented in Tables 1 and 2, respectively.
Table 1. Strain sensitivity towards cyclosulfamide 4b
µg/mL
2
+
+
3
+
+
5
+
+
8
MIC
+
10
-
15
-
20
-
30
-
40
-
50
-
80 100
strain
E. coli
-
-
S. aureus
+
+
+
+
+
+
+
+
Table 2. Strain sensitivity towards cyclosulfamide 4d
µg/mL
2
+
+
3
MIC
+
5
-
8
-
10
-
15
-
20
-
30
-
40
-
50
-
80 100
strain
E. coli
-
-
S. aureus
+
+
+
+
+
+
+
+
+
+
No inhibitory effect on the growth of the Staphylococcus aureus strain was observed in the
presence of cyclosulfamide 4b. The cyclosulfamide 4d, also tested in this study, similarly showed no
significant antimicrobial activity towards S. aureus. It is therefore clear that this species is resistant to
these particular compounds. In contrast, however, a significant bacteriostatic effect has been observed
towards Escherichia coli, with no growth being observed in tubes containing sulfamide concentrations

Molecules 2005, 10
1391
of 4b equal or greater than 8 µg/mL, while cyclosulfamide 4d also showed a marked antimicrobial
activity with regards to Escherichia coli and a MIC of 3µg/mL was obtained for this molecule.
Conclusions
We have established a new synthetic strategy to prepare peptidic structures constrained with a
cyclosulfamide moiety. The N2,N5-unsymmetric cylic sulfamides can be prepared in three steps
(alkylation, cyclization, deprotection). We have also demonstrated the useful application of these cyclic
sulfamides in the preparation of pseudopeptides. The preliminary results of antimicrobial activity are
encouraging. Further biological evaluation of the resulting compounds and their incorporation into
biomolecule analogues are currently in progress.
Acknowledgements
This work was partially supported by the National Agency for Research in Health (ANDRS, Project
N°05/05/00039), CNEPRU Project E2301/02/04 and Applied Organic Chemistry Laboratory (F.N.R.
2000) National Research Fund (Algerian Research Ministry, MERS). Fruitful discussions with Ms.
Hadjira Mesbahi (Faculty of Sciences) are greatly appreciated.
Experimental
General
All commercial chemicals and solvents were used as received. Melting points were determined in
open tubes on a Büchi apparatus and are uncorrected. IR spectra were recorded on a Perkin-Elmer
spectrophotometer. Microanalyses were performed in the Microanalysis Laboratory of ENSCM
1
13
(Montpellier). H and C- Nuclear Magnetic Resonance spectra were determined on a Brüker AC 250
spectrometer. Chemical shifts are recorded in ppm (δ) and coupling constants in Hertz, relative to
tetrametylsilane used as internal standard. Multiplicity is indicated as s (singlet), d (doublet), q
(quadruplet), m (multiplet) and combinations of these signals. Fast-atom bombardment mass spectra
(FAB) were recorded in positive or negative mode with glycerol (G), thioglycerol (GT), or 3-nitrobenzyl
alcohol (NOBA) as matrix. Optical rotations for solutions in CHCl3 were measured with a POLAX
model 2L digital polarimeter. All reactions were monitored by Thin Layer Chromatography (TLC) on
silica gel Merck 60 F254 precoated aluminium plates, developed by spraying with ninhydrin solution.
Column chromatography was performed using silica gel 60 (230-400 mesh).
General synthetic procedure for carbamoylation–sulfamoylation:
A solution of N-chlorosulfonyl tert-butylcarbamate (0.05 mol) was prepared by addition of tert-
butanol (4.8 mL in 50 mL of dried dichloromethane) into a solution of CSI (7.1 g in the same solvent).
The resulting solution of Boc-sulfamoyl chloride (25 mL) and triethylamine (17.40 g, 17.1 mL, 85
mmol) in dichloromethane (100 mL) was added into a suspension of amino ester (0.05 mol) in the same
solvent (120 mL) at 0°C. The reaction was complete in 45 minutes. The reaction mixture was then

Molecules 2005, 10
1392
diluted with dichloromethane (100 mL) and washed with two portions of 0.1 N HCl solution. The
organic layer was dried (Na2SO4) and concentrated in vacuo to give the crude product, which was
purified by column chromatography eluting with dichloromethane to give compounds 1-5 in 75-80%
yield. The synthesis by this general method of compounds 1-4 from CSI, tert-butyl alcohol and the
methyl esters of the amino acids L-alanine, L-valine, L-leucine and L-aspartic acid was previously
described [18-19].
(S)-Dimethyl [N-(N- tertiobutyloxycarbonyl)-sulfamoyl] glutamate (5). Yield=76%; TLC: Rf=0.34
(CHCl2-MeOH 9:1); m.p=105-106°C; [α]D =+17 (c=1; MeOH). IR (KBr) ν cm-1: 1744, 1706 (C=O),
1380 and 1160 (SO2), 3305 and 3353 (NH). 1H-NMR (CDCl3) δ ppm: 7.72 (s, 1H), 5.55 (d, J=8.4 Hz,
1H), 4.42 (m, 1H), 3.72-3.80 (2s, 6H), 3.00 (ddd, J=16.5, 6.4, 6.4 Hz, 2H), 3.20 (ddd, J=16.5, 6.4, 6.4
13
Hz, 2H), 2,20 (m, 2H), 1.50 (s, 9H); C-NMR (CDCl3 δ ppm: 173, 171, 151, 85, 56, 53, 52, 48, 41,
29, 28, 27; M.S: (NOBA, FAB< 0): 353 [M-H] -, 253, 707. M=354; Anal. Calcd. for C12H22 N2O8S: C,
40.67; H, 6.21; N, 7.90; S, 9.03; found C,40.73; H, 6.24; N, 7.94; S, 8.92.
General procedure for the synthesis of N-Boc, N’-(2-chlroalkyl) sulfamides 1a-5a
A solution of N-tert-butyloxycarbonylsulfamoylamino esters 1-5 (30 mmol), triphenyl-phosphine
(7.6 g) and chloroethanol (2.4g; 2 mL) in THF (25 mL) was added dropwise (20 min, 5°C) to a solution
of equimolar quantities of diethyl (diisopropyl) azodicarboxylate (30 mmol; 5.22 g or 6.06 g) in the
same solvent (25 mL). The reaction medium was stirred under an atmosphere of dry nitrogen for about
45 min. TLC revealed that the substituted compound formed is less polar than its precursor (UV,
ninhydrin). Oxydoreduction compounds were removed by filtration after precipitation into diethyl
ether. The filtrate was concentrated and the crude residue was purified by column chromatography
eluting with dichloromethane. Substituted compounds 1a-5a were recovered in 65-75% yield.
(S) Methyl [N,N’-tert-butyloxycarbonyl, N’-chloroethyl)sulfamoyl] alaninate (1a). Yield=65%; TLC:
Rf=0.52 (CHCl3); m.p.=88-90 °C; [α]D = -17 (c=1, MeOH); IR (KBr) ν cm-1: 1744, 1706 (C=O), 1380
and 1160 (SO2), 3305 (NH); 1H-NMR (CDCl3) δ ppm: 5.55 (d, J=8.42 Hz, 1H), 4.42 (m, 1H), 3,70 (s,
13
3H), 3,65 (t, J=6.8 Hz, 2H), 3.95 (t, J=6.8 Hz, 2H), 1.50 (s, 9H ), 1.30 (d, J=7.2 Hz, 3H). C-NMR
(CDCl3 δ ppm: 170, 150, 84, 54, 52 49, 29, 27, 25; M.S: (NOBA, FAB<0): 343 [M-H]-, 243, 687.
M=344-346; Anal. Calcd. for C11H21N2O6SCl: C, 38.31; H, 6.09; N, 8.12; S, 9. 28; found: C, 38.33; H,
6.09; N, 8.09; S, 9.22.
(S) Methyl [N-( N’-tert-butyloxycarbonyl, N’-chloroethyl)sulfamoyl] valinate (2a). Yield=68%; TLC:
Rf=0.65 (CHCl3); m.p.=60-62 °C; [α]D=-9 (c=1; MeOH) ; IR (KBr) ν cm-1: 1730, 1700 (C=O), 1390
and 1160 (SO2), 3310 (NH); 1H-NMR (CDCl3) δ ppm: 5.80 (d, J=8.42 Hz, 1H), 3.95 (t, J=6,8 Hz, 2H),
3.87 (m, 1H), 3.68 (s, 3H), 3.65 (t, J=6.8 Hz, 2H), 2.10 (m, 1H ), 1.52 (s, 9H), 0.98 (2d, J=6,9 Hz, 6H,
2CH3); 13C-NMR (CDCl3) δ ppm: 172, 152, 85,55, 52, 48, 41, 28, 27, 22; M.S: (NOBA, FAB>0): 373
[M+H] +, 273, 747. M=372-274; Anal. Calcd. for C13H25 N2O6SCl: C, 41.88; H, 6.71; N, 7.51; S, 8.59;
found: C, 41.93; H, 6.74; N, 7.46; S, 8.51.

Molecules 2005, 10
1393
(S) Methyl [N-(N’-tert-butyloxycarbonyl, N’-chloroethyl)-sulfamoyl] leucinate (3a). Yield=75%; TLC:
Rf =0.60 (CHCl3); m.p.=67-69°C; [α]D=-23 (c=1; MeOH); IR (KBr) ν cm-1: 1740, 1712 (C=O), 1390
and 1160 (SO2), 3267 (NH); 1H-NMR (CDCl3) δ ppm: 5.80 (d, J=8.8 Hz, 1H), 3,95 (t, J=6,8 Hz, 2H),
3.87 (q, J=6.8 Hz, 1H), 3.68 (s, 3H), 3,65 (t, J=6.8 Hz, 2H), 1,87 (m, 2H), 1.55 (s, 9H), 1.48 (m, 1H),
13
0.98-0.88 (2d, J=3.9 Hz, 6H); C-NMR (CDCl3) δ ppm: 172, 152, 85, 56, 53, 48, 43, 41, 28, 25, 24,
22; M.S: (NOBA, FAB>0): 387 [M+H] +, 287, 773. M=386-388; Anal. Calcd. for C14H27N2O6SCl: C,
43.46; H, 6.98; N, 7.24; S, 8.28; found: C, 43.49; H, 6.94; N, 7.20; S, 8.21.
(S) Methyl [N-(N’-tert-butyloxycarbonyl, N’-chloroethyl)-sulfamoyl] aspartate (4a). Yield=70%; TLC:
Rf =0.67 (CHCl3); oil; [α]D=-33 (c=1; MeOH) ; IR (KBr) ν cm-1: 1755, 1715 (C=O) 1370 and 1130
1
(SO2), 3269 (NH); H-NMR (CDCl3) δ ppm: 5.85 (d, J=8.4 Hz, 1H), 4.30 (q, J=8.4 Hz, 1H), 3.90 (t,
J=6.7 Hz, 2H), 3.70-3.80 (2s, 6H), 3.68 (t, J=6.7Hz, 2H), 3.50 (2dd, J= 4.1, 8.4 Hz, 2H), 1.50 (s, 9H);
13C-NMR (CDCl3 δ ppm: 171, 170, 150, 85, 55, 51, 52, 49, 42, 28, 27; M.S: (NOBA, FAB>0): 407
[M+H] +, 307, 805. M=406-404; Anal. Calcd. for C13H23 N2O8SCl: C,38.75; H, 5.71; N, 6.95; S, 7.95;
found: C, 38. 73; H, 5.74; N, 6.94; S, 7.92.
(S) Methyl [N-(N’-tert-butyloxycarbonyl, N’-chloroethyl)-sulfamoyl] glutamate (5a). Yield=72%;
TLC: Rf =0.65 (CHCl3); oil; [α]D =-21 (c=1; MeOH) ; IR (KBr) ν cm-1: 1746, 1715 (C=O) 1395 and
1156 (SO2), 3310 (NH); 1H-NMR (CDCl3) δ ppm: 6.10 (d, J=8.5 Hz, 1H), 4.30 (m, 1H), 3.90 (t, J=6.7
Hz, 2H), 3.68 (t, J=6.9 Hz 2H), 3.60-3.65 (2s, 6H), 2.48 (m, 2H), 2.10 (m, 2H),1.50 (s, 9H); 13C-NMR
(CDCl3 δ ppm: 173, 171, 151, 85, 56, 53, 52, 48, 41, 29, 28, 27; M.S: (NOBA, FAB>0): 417 [M+H] +,
317, 833. M=416-418; Anal. Calcd. for C14H25 N2O8SCl: C, 40.33; H, 6.02; N, 6.72; S, 7.68; found: C,
40.42; H, 6.04; N,6.75; S, 7.62.
General procedure for preparation of N-Boc-N-substituted)-1,2,5-thiadiazolidine 1,1-dioxides 1b-5b.
Cyclization with K2CO3 in DMSO
The 2-chloroalkyl compounds (10 mmol) were dissolved in dimethysulfoxide (DMSO) and
anhydrous K2CO3 (1.5 equiv.) was added in one portion. The resulting mixture was stirred at room
temperature for 8 h, diluted with dichloromethane (200 mL) and acidified with 5% HCl. The organic
layer was washed with water, dried (Na2SO4) and concentrated under reduced pressure. The residue
was purified by chromatography on silica gel. Recristallization of the crude product from CH2Cl2-
petroleum ether (1:5) afforded the pure expected cyclosulfamides 1b-5b in 82-92% yields.
(N2-(2’S)-Propionic acid methyl ester, N5-tert-butyloxycarbonyl)-1,2,5-thiadiazolidine 1,1-dioxide (1b).
Yield=86%; TLC: Rf =0.58 (CHCl3); Mp=132-134°C; [α]D=-34. (c=1; MeOH); IR (KBr) ν cm-1: 1750
1
1712, 1378 and 1167 (SO2); H-NMR (CDCl3) δ ppm: 4.15 (q, J=7.8 Hz, 1H), 3.80 (t, J=6.4 Hz 2H),
3.70 (s, 3H), 3.65 (t, J=6.4 Hz, 2H), 1.50 (d, J=7.8 Hz, 1H), 1.52 (s, 9H); 13C-NMR (CDCl3 δ ppm: 172,
150, 84, 56, 52, 43, 39, 28, 27; M.S: (NOBA, FAB< 0): 307 [M-H]-, 207; M=308; Anal. Calcd. for
C11H20N2O6S: C, 42.85; H, 6.49; N, 9.09; S, 10.39; found: C, 42.83; H, 6.44; N, 9.04; S, 10,32.

Molecules 2005, 10
1394
(N2-(2’S)-3’-methylbutyric acid methyl ester, N5-tert-butyloxycarbonyl)-1,2,5-thiadiazolidine-1,1-
dioxide (2b). Yield=90%; TLC: Rf =0.60 (CHCl3); m.p.=154-155°C; [α]D=-38 (c=1; MeOH); IR (KBr)
1
ν cm-1: 1745, 1718 (C=O), 1390 and 1160 (SO2); H-NMR (CDCl3) δ ppm: 4.15 (d, J=7.2 Hz, 1H),
3,95 (t, J=6.4 Hz, 2H), 3.80 (t, J=6.4 Hz, 2H), 3.70 (s, 3H), 2.20 (m, 1H), 1.57 (s, 9H),1.30 (d, J= 7.2
Hz, 3H), 0,98 (2d, J=6.9 Hz, 6H); 13C-NMR (CDCl3 δ ppm: 172, 149, 84, 56, 53, 43, 39, 28, 26, 23, 22;
M.S: (NOBA, FAB>0): 337 [M+H] +, 237; M=336; Anal. Calcd. for C13H24 N2O6S: C, 46.43; H, 7.14;
N, 8.33; S, 9.52; found: C, 46.48; H, 7.17; N, 8.34; S, 9.44.
(N2-(2’S)-4’-Methylpentanoic acid methyl ester, N5-tert-butyloxycarbonyl)-1,2,5-thiadiazolidine-1,1-
dioxide (3b). Yield= 87%; TLC: Rf =0.58 (CHCl3); m.p.=138-139 °C; [α]D =-53 (c=1; MeOH) ; IR
1
(KBr) ν cm-1: 1747, 1728 (C=O), 1360 and 1120 (SO2) ; H-NMR (CDCl3) δ ppm: 4.30 (t, J=8.4 Hz),
3.95 (t, J=6.4 Hz, 2H), 3.72 (s, 3H), 3.55 (t, J=6.4 Hz, 2H), 1.55-1.65 (m, 3H), 1.51 (s, 9H), 0.95-1.00
(2d, J=6.9 Hz, 6H) ;13C-NMR (CDCl3 δ ppm: 171, 149, 86, 54, 53, 43, 39, 37, 28, 25, 23, 21 ; M.S:
(NOBA, FAB>0): 351 [M+H] +, 251 ; M=350; Anal. Calcd. for C14H26 N2O6S: C, 48.00; H, 7.43; N,
8.00; S, 9. 14; found: C, 48.07; H, 7.48; N, 7.94; S, 9.07.
(N2-(2’S)-Bis(1’,3’-methoxycarbonyl)ethyl),N5-tert-butyloxycarbonyl)-1,2,5-thiadiazolidine-1,1-dioxide
(4b). Yield=82%; Rf =0.61(CHCl3); oil; [α]D =+38 (c=1; MeOH); IR (KBr) ν cm-1: 1754, 1751, 1710
(C=O) 1390 and 1150 (SO2); 1H-NMR (CDCl3) δ ppm: 4.30 (m, 1H), 3.70-3.80 (2s, 6H), 3.95 (t, J=6.4
13
Hz, 2H, 3.55 (t, J=6.4 Hz, 2H), 3.50 (ddd, J=17.2, 7.1, 4.5 Hz, 2H), 1,50 (s, 9H); C-NMR (CDCl3 δ
ppm: 177, 171, 150, 85, 57 53, 52, 43, 39, 28, 25; M.S: (NOBA, FAB>0): 367 [M+H] +, 267; M=366;
Anal. Calcd. for C13H22 N2O8S: C, 42.62; H, 6.01; N, 7.65; S, 8.74; found : C, 42.63; H, 6.04; N, 7.69;
S, 8.69.
(N2-(2’S’)-Bis(1’,4’-methoxycarbonyl)propyl,N5-tert-butyloxycarbonyl)-1,2,5-thiadiazolidine-1,1-
dioxide (5b). Yield=92%; TLC: Rf =0.58 (CHCl3); oil; [α]D =+38 (c=1; MeOH); IR (KBr) ν cm-1: 1748,
1
1745, 1720 (C=O), 1360 and 1120 (SO2) ; H-NMR (CDCl3) δ ppm: 4.30 (m, 1H), 3.95 (t, 2H, J=6,4
13
Hz), 3.68 (t, J=6,4 Hz, 2H), 3.72-3.65 (2s, 6H), 2.48 (m, 2H), 2.10 (m, 2H),1.50 (s, 9H) ; C-NMR
(CDCl3 δ ppm: 173, 170, 150, 85, 56, 53, 52, 43, 41, 30, 28, 27 ; M.S: (NOBA, FAB>0): 381 [M+H] +,
281; M=380; Anal. Calcd. for C14H24 N2O8S : C, 44.21; H, 6.31; N, 7.37; S, 8.42; found C, 44.30; H,
6.34; N, 7.34; S, 8.36.
Deprotection
A solution of trifluoroacetic acid (50% in dried dichloromethane; 3 equiv) was added dropwise into
a strirred solution of N,N’-substituted cyclosufamides 1b-5b (20 mmol) in dried dichloromethane (15
mL) at 0°C. The reaction medium was stirred during two hours, concentrated under reduced pressure
and coevaporated with diethyl ether. The residue was purified by flash chromatography. Elution with
CH2Cl2-MeOH (95:5) gave deprotected cyclic sulfamides 1c-5c in 85%-90% yield.
N2-(2’S)-(Propionic acid methyl ester) 1,2,5-thiadiazolidine 1,1-dioxide (1c). Yield=90%; TLC: Rf
=0.45 (CHCl3); m.p.=124-125 °C; [α]D=-34. (c=1; MeOH) ; IR (KBr) ν cm-1: 1751 (C=O) 1375 and
1160 (SO2), 3345 (NH); 1H-NMR (CDCl3) δ ppm: 6.24 (t, J=6.7 Hz, 1H), 4.15 (q, 1H, J=7,8 Hz, 1H),

Molecules 2005, 10
1395
13
3,80 (t, J=6.7Hz, 2H), 3.70 (s, 3H), 3.65 (m, 2H), 1.50 (d, J=7.8 Hz, 3H); C-NMR (CDCl3 δ ppm:
172, 56, 52, 41, 39, 28; M.S: (NOBA, FAB< 0): 207 [M-H] -, 415; M=208; Anal. Calcd. for C6H12
N2O4S: C, 34.61; H, 5.77; N, 13.46; S, 15.38; found C, 34.63; H, 5.84; N, 13.44; S, 15.32.
N2-(2’S)-(3-methylbutyric acid methyl ester) 1,2,5-thiadiazolidine 1,1-dioxide (2c). Yield=85%; TLC:
Rf =0.55 (CHCl3); m.p.=134-135°C; [α]D =-44 (c=1; MeOH); IR (KBr) ν cm-1: 1745 (C=O), 1390 and
1160 (SO2), 3340 (NH); 1H-NMR (CDCl3) δ ppm: 6.30 (tJ=6.8Hz, 1H), 4.15 (d, J=7.2 Hz, 1H), 3.90 (t,
J= 6,7 Hz, 2H), 3.70 (s, 3H), 3.60 (m, 2H), 1.30 (m, 1H), 0,98 (2d, J=6.9 Hz, 6H); 13C-NMR (CDCl3 δ
ppm: 171, 56, 53, 41, 39, 26, 23, 22; M.S: (NOBA, FAB>0): 237 [M+H] +, 473; M=236; Anal. Calcd.
for C8H16 N2O4S: C, 40.67; H, 6.78; N, 11.86; S, 13.60; found: C, 40.73; H, 6.84; N, 11.94; S,13.52
N2-(2’S)-4’-methylpentanoic acid methyl ester) 1,2,5-thiadiazolidine 1,1-dioxide (3c). Yield= 90%;
TLC: Rf =0.53 (CHCl3); m.p.=128-130 °C; [α]D=+76 (c=1; MeOH); IR (KBr) ν cm-1: 1747, 1360 and
1120 (SO2), 3320 (NH); 1H-NMR (CDCl3) δ ppm: 6.30 (tJ=6.8Hz,1H), 4.30 (m, 1H), 3.85 (t, J=6.4 Hz,
2H), 3.72 (s, 3H), 3.55 (m, 2H), 1.55-1.65 (m, 3H), 0,98 (2d, J=6.9 Hz, 6H);13C-NMR (CDCl3 δ ppm:
177, 57, 53, 41, 39, 28, 25, 22, 21; M.S: (NOBA, FAB>0): 251 [M+H] +, 501. M=250; Anal. Calcd. for
C9H18N2O4S: C, 43.20; H,7.20; N, 11.20; S, 12.80; found: C, 43.23; H, 7.24; N, 11.17; S, 12.72.
N2-(2’S’)-bis(1’,3’-methoxycarbonyl)ethyl] 1,2,5-thiadiazolidine 1,1-dioxide (4c). Yield=88%; Rf
=0.56 (CHCl3); oil; [α]D =-56 (c=1; MeOH); IR (KBr) ν cm-1: 1750-1755 (2C=O) 1390 and 1150
1
(SO2), 3325 (NH); H-NMR (CDCl3) δ ppm: 6.80 (tJ=6.7Hz,1H), 4.25 (2d, J=7.1, 4.6 Hz, 1H), 3.70-
13
3.80 (2s, 6H), 3.70 (t, J=6.7 Hz, 2H), 3.55 (m, 2H), 3.50 (ddd, J= J=17.2, 7.1, 4.5 Hz, 2H) ; C-NMR
(CDCl3 δ ppm: 177, 175, 57, 53, 52, 41, 39, 28; M.S: (NOBA, FAB>0): M=267 [M+H]+, 533; M=266;
Anal. Calcd. for C8H14O6N2S: C, 36.09; H, 5.26; N, 10.52; S, 12.03; found: C, 36.13; H 5.24; N, 10.54;
S, 12.00.
N2-(2’S’)-bis(1’,4’-methoxycarbonyl)propyl] 1,2,5-thiadiazolidine 1,1-dioxide (5c). Yield=89%; TLC:
Rf =0.54 (CHCl3); oil; [α]D= +67 ( c=1; MeOH) ; IR (KBr) ν cm-1: 1745-1738 (2C=O) 1360 and 1120
1
(SO2), 3145 (NH) ; H-NMR (CDCl3) δ ppm: 6.60 (tJ=6.8Hz,1H), 4,30 (m, 1H), 3,70 (t, J=6.4 Hz,
2H), 3.65 (m, 2H), 3.72-3.65 (2s, 6H), 2.50 (m, 2H), 2.10 (m, 2H) ; 13C-NMR (CDCl3 δ ppm: 172, 170,
+
56, 53, 52, 42, 40, 30, 28 ; M.S: (NOBA, FAB>0): 281[M+H] , 561. M=280; Anal. Calcd. for
C9H16N2O6S: C, 38.57; H, 5.71; N, 10.00; S, 11.43; found: C,38.63; H, 5.74; N, 10.04; S, 11.36.
Propionylation
To a stirring solution of N-substituted cyclosulfamide 1c-5c (20 mmol), in dichloromethane (50
mL) was added triethylamine (1.1 equiv., 22 mmol, 2.22 g, 1.60 mL), and catalytic quantities of
dimetylaminopyridine (DMAP). Propionyl chloride (1.5 equiv., 30 mmol, 2.41 g, 2.57 mL) diluted in
the same solvent (15 mL) was added slowly to the resulting solution. When the addition was
completed, the reaction mixture was stirred under an atmosphere of dry nitrogen. TLC reveals the
formation of a substituted compound less polar than its precursor. The reaction mixture was
concentrated in vacuo. The residue diluted with dichoromethane (50 mL), acidified with 0.1 N HCl
solution and washed with water. The organic layer was dried with (Na2SO4) and concentrated under

Molecules 2005, 10
1396
reduced pressure to give the crude product. The residue was purified on silica gel by column
chromatography eluting with dichloromethane to give the N2, N5 substituted cyclosulfamides 1d-5d in
75-90 % yields.
[N2-(2’S’)-(propionic acid methyl ester), N5-propionyl] 1,2,5-thiadiazolidine 1,1-dioxide (1d). Yield=-
90%; TLC: Rf=0.59 (CHCl3); m.p.=88-89°C; [α]D=-17 (c=1; MeOH); IR (KBr) ν cm-1: 1750-1715
(C=O), 1375 and 1160 (SO2) ; 1H-NMR (CDCl3) δ ppm: 4.15 (q, J=7.8 Hz, 1H), 3.80 (t, J=6.2 Hz, 2H),
3.70 (s, 3H), 3.65 (t, J=6.7 Hz, 2H), 2.85 (q, J=7.4 Hz, 2H), 1.50 (d, 3H, J=7.8 Hz), 1.15 (t, 3H, J=7.4
13
Hz, 3H); C-NMR (CDCl3) δ ppm: 172, 170, 56, 53, 41, 39, 29, 28, 12; M.S: (NOBA, FAB>0): 265
[M+H] +, 208; M=264; Anal. Calcd. for C9H16O5N2S: C, 40.91; H, 6.06;N, 10.60; S, 12.12; found: C,
40.98; H, 6.17; N, 10.65; S, 12.05.
[N2-(2’S)-(3’-methylbutyric acid methyl ester), N5-propionyl] 1,2,5-thiadiazolidine 1,1-dioxide (2d).
Yield=88%; TLC: Rf =0,62 (CHCl3); m.p.=94-95°C; [α]D =-14 (c=1; MeOH). IR (KBr) ν cm-1: 1748-
1
1712 (C=O), 1389-1163 (SO2); H-NMR (CDCl3) δ ppm: 4.15 (d, J=7.2 Hz, 1H), 3.95 (t, J=6.7 Hz,
2H), 3.8 (t, J=6,7 Hz, 2H), 3.70 (s, 3H), 2.85 (q, 2H, J=7.4 Hz, 2H), 1.30 (m, 1H), 1.16 (t, J=7,4 Hz,
13
3H), 0.98 (2d, J=6.9 Hz, 6H); C-NMR (CDCl3 δ ppm: 172, 170, 56, 53, 43, 39, 26, 28, 23, 22, 13;
M.S: (NOBA, FAB>0): M=373 [M+H] +, 174 ,745; M=372; Anal. Calcd. for C11H20 N2O5S; C, 45.20;
H, 6.85; N, 9.59; S, 10.96; found: C, 45.23; H, 6.19; N, 9.54; S, 10.89.
[N2-(2’S)-4’-methylpentanoic acid methyl ester), N5-propionyl] 1,2,5-thiadiazolidine 1,1-dioxide (3d).
Yield=85%; TLC: Rf =0.65 (CHCl3); m.p.=106-108°C; [α]D=+54 (c=1; MeOH); IR (KBr) ν cm-1:
1
1747-1718 (C=O), 1362 and 1125 (SO2); H-NMR (CDCl3) δ ppm: 4.10 (m, 1H), 3.92 (t, J= 6.7 Hz,
2H), 3.75 (t, J=6.7 Hz, 2H), 3.72 (s, 3H), 2.85 (q, J=7,4 Hz, 2H), 1,55-1,65 (m, 12H), 1.15 (t, J=7.4 Hz,
13
3H), 0.98-1.00 (2d, J=6.9 Hz, 6H); C-NMR (CDCl3 δ ppm: 175 ,170, 57, 53, 41,39, 28, 29, 25, 23,
21, 12; M.S: (NOBA, FAB>0): 307 [M+H] +, 250; M=306; Anal. Calcd. for C12H22N2O5S: C, 47.06; H,
7.19; N, 9.15; S, 10.46; found: C, 47.12; H, 7.25; N, 9.08; S, 10.42.
[N2-(2’S’)-bis(1’,3’-methoxycarbonylethyl), N5-propionyl] 1,2,5-thiadiazolidine 1,1-dioxide (4d).
Yield=80%, TLC: Rf =0.67 (CHCl3); oil; [α]D =-87 (c=1; MeOH); IR (KBr) ν cm-1: 1749, 1753 and
1715 (C=O) 1380 and 1150 (SO2); 1H-NMR (CDCl3) δ ppm: 4.30 ( 2d, J=7.3, 4.6 Hz, 1H), 3.70-3.80
(2s, 6H), 3.85 (t, J=6.8 Hz, 2H), 3.60 (t, J=6.8 Hz, 2H), 3.50 (ddd, J=J=17.2, 7.3, 4.6 Hz, 2H), 2.85 (q,
J=7,4 Hz, 2H), 1.18 (t, J=7,4 Hz, 3H) ; 13C-NMR (CDCl3 δ ppm: 173, 172, 165, 57, 53, 52, 43, 40, 29,
+
25, 12; M.S: (NOBA, FAB>0): M=323 [M+H] , 266. M=322; Anal. Calcd. for C11H18N2O7S: C,
40.99; H, 5.54; N, 8.69; S, 9.34; found: C, 41.03; H, 5.64; N, 8.80; S, 9.30.
[ N2-(2’S’)-bis(1’,4’-methoxycarbonylpropyl), N5-propionyl] 1,2,5-thiadiazolidine 1,1-dioxide (5d).
Yield=75%, TLC: Rf =0.51 (CHCl3); oil; [α]D=+43 (c=1; MeOH); IR (KBr) ν cm-1: 1745, 1738 and
1713 (C=O), 1360 and 1120 (SO2); 1H-NMR (CDCl3) δ ppm: 4.30 (m, 1H), 3.85 (t, J=6.4Hz, 2H), 3.65
(t, J=6.4 Hz, 2H), 3.72-3.65 (2s, 6H), 2.48 (m, 2H), 2.10 (m, 2H), 2.85 (q, J=7,4 Hz, 2H), 1.14 (t, J=7.4
13
Hz, 3H); C-NMR (CDCl3) δ ppm: 173, 171, 165, 56, 53, 52, 42, 41, 30, 29, 25, 12; Anal. Calcd. for
C12H20O7N2S: C, 42.86; H, 5.95; N, 8.33; S, 9.52; found: C, 42.92; H, 9.87; N, 8.28; S, 9.43.

Molecules 2005, 10
1397
Alkylation via the Mitsunobu Reaction
To a stirring solution of N-substituted cyclosulfamide 1d-2d (3.23 mmol) in THF (2 mL) was
slowly added DEAD (3.23 mmol, 0.5 mL) via dropwise addition. A solution consisting of (L)-(-)- ethyl
lactate (3.23 mmol, 0.37 mL) and PPh3 (3.23 mmol, 847 mg) in THF (3mL), was slowly transferred via
cannula into the cyclosulfamide solution. The reaction medium was stirred under an atmosphere of dry
nitrogen for about 45 min. TLC reveals (UV, ninhydrin) the formation of a substituted compound less
polar than its precursor. Oxydoreduction compounds were removed by filtration after precipitation into
diethylether. The filtrate was concentrated and the crude residue was purified by colunm
chromatography eluting with dichloromethane. N,N’-Substituted cyclosufamides 1e-2e were recovered
in 65-75% yield.
[N2-(2S)-(Methoxycarbonylethyl), N5-(2’R)-(propionic acid ethyl ester)]-1,2,5-thiadiazolidine 1,1-
dioxide (1e). Yield=65%; TLC: Rf=0.64 (CHCl3); m.p.=88-89°C; [α]D=-65 (c=1; MeOH); IR (KBr) ν
cm-1: 1750-1731 (C=O), 1360 and 1152 (SO2); 1H-NMR (CDCl3) δ ppm: 4.76 (q, J=7.3, 1H), 4.65 (q,
J=7.2, 1H), 4.15 (q, J=7.2 Hz, 1H), 3.80 (t, J=6.7 Hz, 2H), 3.70 (s, 3H), 3.65 (t, J=6.7 Hz, 2H),1.44 (d,
J=7.2, 3H), 1.39 (d, J=7.1 Hz, 3H), 1.28 (t, J=7.2, 3H); 13C-NMR (CDCl3 δ ppm: 172, 170, 56, 55, 53,
+
50, 41, 39, 29, 28, 12; M.S: (NOBA, FAB>0): M=309 [M+H] . M=308; Anal. Calcd. for C11H20
N2O6N2S C, 42.86, H, 6.49, N, 9.09. S,10.03. Found: C, 40.86, H,6.13, N,9.47. S, 10.03.
[N2-(2S)-(3-Methylmethoxycarbonylpropyl), N5-(2’R)-propionic acid ethyl ester)] 1,2,5-thiadiazol-
idine-1,1-dioxide (2e). Yield =75%; TLC: Rf =0.61 (CHCl3); m.p.=80-81°C; [α]D =-12.0 (c=0,5,
1
CHCl3); IR (KBr) ν cm-1: 1745, 1729, 1346, 1145; H-NMR (CDCl3) δ ppm: 4.70 (q, J=7.3 Hz, 1H),
4.20 (q, J=7.1Hz, 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); 13C-NMR
(CDCl3 δ ppm: 172, 169, 56, 55, 53, 52, 50, 41, 39, 28, 22, 21, 14; M.S: (NOBA, FAB>0): 337
[M+H]+. M=336; Anal. Calcd. for C13H24N2O6S: C, 46.43; H, 7.14; N, 8.33; C, 9.52. Found: C, 46.49;
H, 7.18; N, 8.34; S, 9.43.
References
1.
2.
3.
Groutas, W. C.; Kuang, R.; Venkataraman, R.; Epp, J.B.; Ruan, S.; Prakash, O.
Biochemistry 1997, 36, 4739-4750.
Groutas, W. C.; Kuang, R.; Ruan, S.; Epp, J. B.; Venkataraman, R.; Truong, T. M. Bioorg. Med.
Chem. 1998, 8, 661-671.
Castro, J. L.; Baker, L.; Guiblin, A. R.; Hobbs, S. C.; Jenkins, M. R.; Russel, M. G. N.; Beer, M.
S.; Stanton, J. A.; Scholey, K.; Hargreaves, R. J. J. Med. Chem. 1994, 37, 3023-3032.
4. Bäkbro, K.; Löwgren, S.; Österlund, K.; J. Atepo, J.; Unge, T.; Hultén, J.; Bonham, N. M.; Schaal,
W.; Karlén, A. Hallberg, A. J. J. Med. Chem. 1997, 40, 898-902.
5.
6.
Hultén, J.; Bonham, N. M.; Nillroth, U.; Hansson, T.; Zucccarello, G.; Bouzide, A.; Aqvist, J.;
Classon, B.; Danielson, U. H.; Karlèn, A. J. Med. Chem. 1997, 40, 885-897.
Schaal, W.; Kalsson, A.; Ahlsén, G.; Andersson, H. O.; Danielson, U. H.; Classon, B.; Unge, T.;
Samuelsson, B.; Hultén, A.; Hallberg, A. J.; Karlén, A. J. Med. Chem. 2001, 44, 155-164.

Molecules 2005, 10
1398
7.
(a) Lai, Z.; Gan, X.; Wei, L.; Alliston, K. R.;Yu,H.; Li, Y.H.; W. C. Groutas, W. C. Arch.
Biochem. Biophys. 2004, 429, 191-197; (b) Groutas, W. C.; Epp, J. B.; Kuang, R.; Ruan, S.;
Chong, S.L.; Venkataraman, R.; Tu, J.; He, S.; Fu,Q.; Y.H. Li.; Truong, T. M.; Vu. N. Arch.
Biochem. Biophys. 2001, 385, 162 -169.
8.
9.
Boudjabi, S.; Dewynter, G.; Voyer, N.; Toupet, L.; Montero, J.L Eur. J. Org. Chem. 1999, 2275-
2283.
M. Knollmuller, M. Monatsh. Chem. 1970, 101, 1443-1448.
10. Ahn, K. H.; Yoo, D. J.; Kim, J. S.; Tetrahedron Lett. 1992, 33, 6661-6664.
11. Dougherty, J. M.; Probst, D. A.; Robinson, R. E.; Moore, D. J.; Klien, T. A.; Snelgrove, K. A.;
Hanson, P. R.Tetrahedron 2000, 56, 9782- 9790 ; (b) Jun, J. H.; Dougherty, J. M.; Probst, D. A.;
Jiménez, M. S.; Hanson, P. R. Tetrahedron 2003, 59, 8901-8912.
12. Johnson, P. D.; Jewell, S. A.; Romero, D.L. Tetrahedron Lett. 2003, 44, 5483-5485.
13. Regainia, Z.; Abdaoui, M.; Aouf, N.; Dewynter, G.; Montero, J. L. Tetrahedron 2000, 56, 381-
387.
14. Regainia, Z.; Winum, J.Y.; Smain, F.T.; Toupet, L.; Aouf, N.; Montero, J. L. Tetrahedron 2003,
59, 6051-6056.
15. Berredjem, M.; Djebbar, H.; Regainia, Z.; Aouf, N.; G. Dewynter, G.; J.-Y. Winum, J. Y.;
Montero, J. L. Phosphorus, Sulfur Silicon 2003, 178, 693-705.
16. Dhar, N.D.; Murthy, K. S. Synthesis 1986, 437-449
17. Dewynter, G.; Aouf, N.; Regainia, Z.; Montero, J.L. Tetrahedron 1996, 52, 993-1004.
18. Dewynter, G.; Aouf, N.; Criton, M.; Montero, J. L. Tetrahedron 1993, 49, 65-76.
19. Aouf, N.; Dewynter, G.; Montero, J. L. Tetrahedron Lett. 1991, 32, 6545-6546.
20. Mitsunobu. O. Synthesis 1981, 1-29.
21. Hughes, D. L. Org. React. 1992, 42, 335-380.
22. Laverdière, M.; Sabath, L.D. J. Med. 1977, 44, 73-88.
Sample availability: Available from the authors.
© 2005 by MDPI (http:www.mdpi.org). Reproduction is permitted for noncommercial purposes.