General synthesis of n-membered cyclic sulfamides

Article abstract of DOI:10.1016/S0040-4020(03)00982-7

A general method for the synthesis of n-membered cyclic sulfamides (cyclosulfamides) is described. An application to the synthesis of constrained peptidal cyclic sulfamide is illustrated.

Full text of DOI:10.1016/S0040-4020(03)00982-7

Tetrahedron 59 (2003) 6051–6056
General synthesis of n-membered cyclic sulfamides
Zine Regaınia,a,b Jean-Yves Winum,a Fatma-Zohra Smaine,a,b Loic Toupet,c Nour-Eddine Aoufb
´
¨
and Jean-Louis Monteroa
,
*
a
´ ´
Laboratoire de Chimie Biomoleculaire, UMR 5032, Universite Montpellier II, ENSCM, 8 Rue de l’Ecole Normale, 34296 Montpellier
Cedex – France
b
´
Laboratoire de Chimie Bioorganique, Universite d’Annaba, BP 12 Annaba – Algeria
´
c
` ´ ´ ´ ´
Groupe Matiere Condensee et Materiaux, UMR 6626, Universite de Rennes I, Campus de Beaulieu, Avenue du General Leclerc, 35042
Rennes Cedex – France
Received 31 March 2003; revised 26 May 2003; accepted 20 June 2003
Abstract—A general method for the synthesis of n-membered cyclic sulfamides (cyclosulfamides) is described. An application to the
synthesis of constrained peptidal cyclic sulfamide is illustrated.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Cyclic sulfamides are attractive molecules with potential
application in medicinal chemistry. They have been shown
to display promising value as cyclic scaffolds for peptido-
mimetics in the design of protease inhibitors such as HIV
protease,1 serine protease2 and metalloprotease.3
As outlined in Scheme 1, the different heterocycles were
prepared in a two-step reaction sequence starting from
N-benzyl-N0-tert-butoxycarbonylsulfamide 1. This requisite
substrate was prepared by sulfamoylation of benzylamine as
previously described.10 Regiospecific N-alkylation of 1 was
carried out in heterogeneous system using potassium
carbonate in acetone to afford compounds 2 in moderate
to good yields for n.3. In the case of n¼2 or 3, cyclized
products were directly obtained under these experimental
conditions. Alternatively, a synthetic approach using
Mitsunobu reaction could be applied starting from bro-
moalcohol.9b Compounds 2a–k are obtained in good yields.
The reported strategies for the synthesis of cyclosulfamides
are based either on the incorporation of the sulfamoyl
moiety reacting sulfuryl chloride4 or sulfonyl urea (H2-
NSO2NH2)1d,5 on vicinal diamines, or by intramolecular
cyclization of linear sulfamides using reductive cross-
coupling reaction6 or ring-closing metathesis synthesis.7
Others processes leading to fused ring cyclic sulfamides
have been also described.8
In the next stage of the synthesis, compounds 2 were
subjected to cyclization in diluted basic medium under
solvent reflux to afford cyclosulfamides 3. This approach in
two steps permits us to obtain final cyclosulfamides in
satisfactory yield. Synthesis in one step has also been
envisioned, but in this case cyclosulfamides were obtained
in bad yields after fastidious purifications.
In our previous studies,9 we described a convenient access
to a series of five-membered cyclic sulfamides N,N0-
disubstituted by orthogonal protections A (Fig. 1), starting
from aminoacids and chlorosulfonylisocyanate. These
heterocycles could be useful as a starting point for the
construction of an array of peptidomimetic scaffolds.
Following our synthetic effort to design new cyclic
sulfamides, we decided to explore the possibility for ring
extension. So we wish to report herein a general method
allowing the preparation of cyclic sulfamides with different
sizes (B Fig. 1).
Identification of all isolated products 2 and 3 was
accomplished with the aid of 1H and 13C NMR spectroscopies
Keywords: cyclic sulfamides; cyclisation; sulfamides; peptidomimetic
scaffold.
*
Corresponding author. Tel./fax: þ33-4-671-443-43;
e-mail: montero@univ-montp2.fr
Figure 1.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00982-7

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Z. Regaınia et al. / Tetrahedron 59 (2003) 6051–6056
6052
Scheme 2. Example of preparation of constrained dipeptidal cyclic
sulfamide. Reagents and conditions: (a) TFA, CH2Cl2; (b) tert-butylbro-
moacetate, DBU; (c) ammonium formate, Pd/C, EtOH; (d) Boc-Val-OH,
BOP, DMF.
Scheme 1. General synthesis of n-membered cyclosulfamides. Reagents
and conditions: (a) dibromoalkane 1 equiv., K2CO3 3 equiv., acetone for
n.3 or bromoalcohol 1 equiv., PPh3 1.1 equiv., DIAD 1.1 equiv., THF; (b)
NaOH 1.5 equiv. DMSO.
N-alkylation. We also demonstrate the useful application of
these cyclic sulfamides in the preparation of pseudo
peptides. This flexible strategy is amenable to a number of
variations (cycle size, nature of amino acid, length of
peptide) and further work are currently being pursued to
incorporate these cyclic sulfamides scaffold into peptidic
sequences of biological interest.
and mass spectrometry. Structural proof was obtained by
X-ray analysis of compound 3b.11 (Fig. 2)
4. Experimental
4.1. General
All commercial chemicals and solvents were used as
received. Melting points were determined in open capillary
tubes on a Buchi apparatus and are uncorrected. 1H and 13
C
Figure 2. X-Ray crystal structure of compound 3b.
spectra were respectively recorded in a 250 MHz and
400 MHz Bruker spectrometers. Chemicals shifts are
reported in d units (ppm). All coupling constants J are
reported in Hertz. Multiplicity is indicated as s (singlet), d
(doublet), t (triplet), q (quadruplet), m (multiplet) and
combination of these signals. Electron Ionization mass
spectra (30 eV) were recorded in positive or negative mode
on a Water MicroMass ZQ. High-resolution mass spectra
were measured on a Jeol SX102 mass spectrometer and
recorded in FAB positive mode. All reactions were
monitored by TLC on silica Merck 60 F254 precoated
aluminium plates and were developed by spraying with
ninhydrin solution. Columns chromatographies were per-
formed on Merck silica gel (230–400 mesh).
A sequential deprotection protocol was next used for the
introduction of conformation constraint in various peptide
chains. As proof of this concept we choose to prepare a
constrained dipeptidal cyclic sulfamide (Scheme 2) where
amino acid where sequentially coupled on each side of
sulfamide function. Selective cleavage of the tert-butox-
ycarbonyl protection under TFA conditions and the
coupling with tert-butyl bromoacetate in the presence of
DBU gave compound 4 in good yield. Attempts to
incorporate the amino acid moiety employing Mitsunobu
reaction (PPh3/DIAD or P(Bu3)/ADDP) with an a-hydro-
xyester did not permit the isolation of the expected
compound. Alternatively, debenzylation using Pd(0)-cata-
lyzed hydrogenolysis in ethanol, followed by peptidic
coupling with N-Boc protected valine afforded the pseudo-
peptide 5 in good yield (Scheme 2).
4.2. General procedure for the synthesis of N0-benzyl-N0-
bromoalkyl-N0-tert-butoxycarbonylsulfamide
Method A: using heterogeneous system K2CO3/Acetone
(n.3). A mixture of 1 equiv. of N-benzyl-N0-tert-butox-
ycarbonyl sulfamide and 1 equiv. of dibromoalkane was
stirred at 608C with 3 equiv. of K2CO3 in acetone during
24 h. After filtration, and concentration, the residue was
purified by chromatography on silica gel.
3. Conclusion
In summary, we 0 have shown that facile formation of
n-membered N,N -protected cyclic sulfamides can be
carried out in two steps by an inter- and intramolecular

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6053
Method B. Using Mitsunobu conditions. 1 equiv. of N-
benzyl-N0-tert-butoxycarbonyl sulfamide and 1 equiv. of
bromoalcohol were dissolved in the minimum of THF.
1.1 equiv. of PPh3 and 1.1 equiv. of DIAD were succes-
sively added. The mixture was stirred 3 h at room
temperature, and then concentrated under reduced pressure.
The residue was purified by chromatography on silica gel.
84.2, 48.5, 48.1, 34.2, 33.0, 30.0, 28.7, 28.4, 26.7; MS
(ESIþ, 30 eV): 486 [MþNa]þ; HRMS calcd for C19H31-
BrN2O4SþHþ: m/z [MþH]þ 463.1266, found 463.1262.
4.2.7. N-Benzyl-N0-bromooctyl-N0-tert-butoxycarbonyl
1
sulfamide 2g. Yield: 58%; mp: oil; H NMR (CDCl3) d:
7.2 (m, 5H, Ar-H), 5.5 (t, 1H, NH), 4.1 (d, 2H, J¼5.3 Hz,
CH2Ar), 3.5 (t, 2H, J¼7.4 Hz, CH2Br), 3.35 (t, 2H,
4.2.1. N-Benzyl-N0-bromoethyl-N0-tert-butoxycarbonyl
sulfamide 2a. Yield: 65%; mp: 97–988C; 1H NMR
(CDCl3) d: 7.35 (m, 5H, Ar-H), 5.6 (t, 1H, J¼6.5 Hz,
NH), 4.2 (d, 2H, J¼6.1 Hz, CH2Ar), 3.95 (t, 2H, J¼7 Hz,
J¼6.7 Hz, CH2N), 1.4 (s, 9H, Bu), 1.2–1.8 (m, 12H,
t
6CH2); 13C NMR (CDCl3) d: 152.3, 135.8, 129.1, 128.5,
84.3, 48.5, 48.1, 34.3, 33.1, 30.0, 28.8, 28.5, 28.4, 26.6; MS
(ESIþ, 30 eV): 500 [MþNa]þ; HRMS calcd for C20H33-
BrN2O4SþHþ: m/z [MþH]þ 477.1423, found 477.1420.
CH2Br), 3.45 (t, 2H, J¼7.2 Hz, CH2N), 1.5 (s, 9H, tBu); 13
C
NMR (CDCl3) d: 151.7, 135.7, 129.3, 128.7, 85.2, 48.6,
48.3, 29.4, 28.4; MS (ESIþ, 30 eV): 416 [MþNa]þ; HRMS
calcd for C14H21BrN2O4SþHþ: m/z [MþH]þ 393.0484,
found 393.0481.
4.2.8. N-Benzyl-N0-bromononyl-N0-tert-butoxycarbonyl
sulfamide 2h. Yield: 47%; mp: 57–588C; 1H NMR
(CDCl3) d: 7.35 (m, 5H, Ar-H), 5.6 (t, 1H, NH), 4.15 (d,
2H, J¼6.2 Hz, CH2Ar), 3.6 (t, 2H, J¼7.2 Hz, CH2Br), 3.4
(t, 2H, J¼6.9 Hz, CH2N), 1.5 (s, 9H, tBu), 1.3–1.8 (m, 14H,
7CH2); 13C NMR (CDCl3) d: 152.3, 136.0, 129.2, 128.5,
84.1, 48.5, 48.2, 34.3, 33.1, 30.1, 29.6, 29.4, 29.0, 28.4,
26.9; MS (ESIþ, 30 eV): 514 [MþNa]þ; HRMS calcd for
C21H35BrN2O4SþHþ: m/z [MþH]þ 491.1579, found
491.1579.
4.2.2. N-Benzyl-N0-bromopropyl-N0-tert-butoxycarbonyl
sulfamide 2b. Yield: 69%; mp: 106–1078C; 1H NMR
(CDCl3) d: 7.35 (s, 5H, Ar-H), 4.38 (s, 2H, CH2Ar), 3.98 (t,
2H, J¼5.7 Hz, CH2Br), 3.42 (t, 2H, J¼5.9 Hz, CH2N), 1.8
(m, 2H, CH2), 1.55 (s, 9H, tBu); 13C NMR (CDCl3) d: 152.1,
135.8, 129.2, 128.5, 84.8, 48.5, 46.8, 33.1, 30.2, 28.4; MS
(ESIþ, 30 eV): 430 [MþNa]þ; HRMS calcd for C15H23-
BrN2O4SþHþ: m/z [MþH]þ 407.0640, found 407.0640.
4.2.3. N-Benzyl-N0-bromobutyl-N0-tert-butoxycarbonyl
sulfamide 2c. Yield: 65%; mp: 98–998C; 1H NMR
(CDCl3) d: 7.35 (m, 5H, Ar-H), 5.6 (t, 1H, J¼6.8 Hz,
NH), 4.15 (d, 2H, J¼6.1 Hz, CH2Ar), 3.6 (t, 2H, J¼7 Hz,
CH2Br), 3.4 (t, 2H, J¼6.3 Hz, CH2N), 1.85 (m, 4H, CH2),
1.5 (s, 9H, tBu); 13C NMR (CDCl3) d: 151.9, 135.5, 128.9,
128.2, 84.3, 48.3, 46.9, 33.1, 29.8, 28.4, 28.1; MS (ESIþ,
30 eV): 444 [MþNa]þ; HRMS calcd for C16H25BrN2O4-
SþHþ: m/z [MþH]þ 421.0797, found 421.0795.
4.2.9. N-Benzyl-N0-bromodecyl-N0-tert-butoxycarbonyl
sulfamide 2i. Yield: 43%; mp: 38–408C; 1H NMR
(CDCl3) d: 7.2 (m, 5H, Ar-H), 5.5 (t, 1H, J¼6.2 Hz, NH),
4.1 (d, 2H, J¼6.2 Hz, CH2Ar), 3.5 (t, 2H, J¼7.4 Hz,
CH2Br), 3.36 (t, 2H, J¼6.8 Hz, CH2N), 1.8 (m, 2H, CH2),
1.5 (m, 2H, CH2), 1.4 (s, 9H, tBu), 1.2 (m, 12H, 6CH2); 13
C
NMR (CDCl3) d: 152.3, 135.8, 129.3, 128.8, 84.3, 48.6,
48.1, 34.4, 33.2, 30.3, 29.8, 29.5, 29.3, 29.1, 28.5, 28.4,
26.9; MS (ESIþ, 30 eV): 528 [MþNa]þ; HRMS calcd for
C22H37BrN2O4SþHþ: m/z [MþH]þ 505.1736, found
505.1730.
4.2.4. N-Benzyl-N0-bromopentyl-N0-tert-butoxycarbonyl
sulfamide 2d. Yield: 63%; mp: 65–688C; 1H NMR
(CDCl3) d: 7.29 (m, 5H, Ar-H), 5.56 (t, 1H, NH), 4.11 (d,
2H, J¼6.3 Hz, CH2Ar), 3.55 (t, 2H, J¼7.3 Hz, CH2Br), 3.37
(t, 2H, J¼6.6 Hz, CH2N), 1.46 (s, 9H, tBu), 1.4–1.9 (m, 6H,
3CH2); 13C NMR (CDCl3) d: 152.2, 135.9, 129.2, 128.6,
84.4, 48.5, 47.8, 33.8, 32.5, 29.3, 28.4, 25.5; MS (ESIþ,
30 eV): 458 [MþNa]þ; HRMS calcd for C17H27BrN2O4-
SþHþ: m/z [MþH]þ 435.0953, found 435.0950.
4.2.10. N-Benzyl-N0-bromoundecyl-N0-tert-butoxycarbo
1
nyl sulfamide 2j. Yield: 46%; mp: 31–338C; H NMR
(CDCl3) d: 7.3 (m, 5H, Ar-H), 5.55 (t, 1H, NH), 4.1 (d, 2H,
J¼6.3 Hz, CH2Ar), 3.6–3.3 (m, 4H, CH2Br and CH2N), 1.9
(m, 2H, CH2), 1.5 (s, 9H, tBu), 1.1–1.5 (m, 16H, 8CH2); 13
C
NMR (CDCl3) d: 152.2, 135.9, 129.1, 128.7, 84.2, 48.5,
48.2, 34.5, 33.2, 30.3, 29.8, 29.5, 29.3, 29.1, 28.6, 28.4,
26.8; MS (ESIþ, 30 eV): 542 [MþNa]þ; HRMS calcd for
C23H39BrN2O4SþHþ: m/z [MþH]þ 518.1813, found
518.1810.
4.2.5. N-Benzyl-N0-bromohexyl-N0-tert-butoxycarbonyl
sulfamide 2e. Yield: 58%; mp: 43–458C; 1H NMR
(CDCl3) d: 7.30 (m, 5H, Ar-H), 5.56 (t, 1H, NH), 4.10 (d,
2H, J¼6.2 Hz, CH2Ar), 3.52 (t, 2H, J¼7.0 Hz, CH2Br), 3.32
(t, 2H, J¼7.4 Hz, CH2N), 1.42 (s, 9H, tBu), 1.2–1.8 (m, 8H,
4CH2); 13C NMR (CDCl3) d: 152.2, 135.9, 129.2, 128.6,
84.3, 48.5, 48.0, 34.0, 32.9, 29.9, 28.4, 28.1, 26.1; MS
(ESIþ, 30 eV): 472 [MþNa]þ; HRMS calcd for C18H29-
BrN2O4SþHþ: m/z [MþH]þ 449.1010, found 449.1012.
4.2.11. N-Benzyl-N0-bromododecyl-N0-tert-butoxycarbo
nyl sulfamide 2k. Yield: 45%; mp: 45–478C; H NMR
1
(CDCl3) d: 7.4 (m, 5H, Ar-H), 5.6 (t, 1H, J¼7 Hz, NH), 4.15
(d, 2H, J¼6.2 Hz, CH2Ar), 3.6 (t, 2H, J¼7.6 Hz, CH2Br),
3.4 (t, 2H, J¼6.8 Hz, CH2N), 1.9 (m, 2H, CH2), 1.5 (s, 9H,
tBu), 1.2–1.8 (m, 18H, 9CH2); 13C NMR (CDCl3) d: 152.3,
136.0, 129.2, 128.6, 84.1, 48.5, 48.2, 34.4, 33.2, 30.2, 29.8,
29.5, 29.1, 28.5, 28.4, 26.9; MS (ESIþ, 30 eV): 556
[MþNa]þ; HRMS calcd for C24H41BrN2O4SþHþ: m/z
[MþH]þ 533.2049, found 532.2046.
4.2.6. N-Benzyl-N0-bromoheptyl-N0-tert-butoxycarbonyl
sulfamide 2f. Yield: 40%; mp: 52–548C; 1H NMR (CDCl3)
d: 7.4 (m, 5H, Ar-H), 5.6 (t, 1H, NH), 4.1 (d, 2H, J¼6.2 Hz,
CH2Ar), 3.6 (t, 2H, J¼7.3 Hz, CH2Br), 3.4 (t, 2H,
4.3. General procedure for cyclization of compounds 2
t
J¼6.7 Hz, CH2N), 1.5 (s, 9H, Bu), 1.2–1.8 (m, 10H,
A diluted solution of 1 equiv. of pure compound 2,
0.1 equiv. of tetrabutylammonium iodide and 5 equiv. of
5CH2); 13C NMR (CDCl3) d: 152.3, 135.9, 129.2, 128.6,

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6054
K2CO3 in acetone was warmed 18 h. The reaction was then
filtered and the filtrate concentrated under reduced pressure.
The residue was chromatographed on a silica gel column.
1H NMR (CDCl3) d: 7.3 (m, 5H, Ar-H), 4.7 (s, 2H, CH2Ar),
3.84 (t, 2H, J¼6.9 Hz, CH2NBoc), 3.42 (t, 2H, J¼6.1 Hz,
CH2NBn), 1.8 (m, 2H, CH2), 1.60 (s, 9H, tBu), 1.4–1.20 (m,
8H, 4CH2); 13C NMR (CDCl3) d: 152.3, 135.4, 129.1,
128.2, 84.2, 52.5, 48.1, 34.4, 33.4, 30.1, 28.8, 28.5, 28.4,
26.2; MS (ESIþ, 30 eV): 419 [MþNa]þ; HRMS calcd for
C20H32N2O4SþHþ: m/z [MþH]þ 397.2161, found
397.2160.
4.3.1. 2-Benzyl-5-tert-butoxycarbonyl-1,2,5-thiadiazoli-
1
dine-1,1-dioxide 3a. Yield: 80%; mp: 83–848C; H NMR
(CDCl3) d: 7.3 (m, 5H, Ar-H), 4.20 (s, 2H, CH2Ar), 3.7 (t,
2H, J¼6.4 Hz, CH2), 3.19 (t, 2H, J¼6.5 Hz, CH2), 1.5 (s,
t
9H, Bu); 13C NMR (CDCl3) d: 149.8, 134.5, 129.2, 128.8,
85.0, 50.9, 43.3, 42.9, 28.4; MS (ESIþ, 30 eV): 335
[MþNa]þ; HRMS calcd for C14H20N2O4SþHþ: m/z
[MþH]þ 313.1222, found 313.1222.
4.3.8. 2-Benzyl-12-tert-butoxycarbonyl-1,2,12-thiadiazo
1
dodecine-1,1-dioxide 3h. Yield: 62%; mp: 99–1028C; H
NMR (CDCl3) d: 7.4 (m, 5H, Ar-H), 4.7 (s, 2H, CH2Ar),
3.85 (t, 2H, J¼7.9 Hz, CH2NBoc), 3.2 (t, 2H, J¼8 Hz,
t
4.3.2. 2-Benzyl-6-tert-butoxycarbonyl-1,2,6-thiadiazine-
1
CH2NBn), 1.6 (m, 4H, 2CH2), 1.4 (s, 9H, Bu), 0.95 (m,
1,1-dioxide 3b. Yield: 85%; mp: 107–1088C; H NMR
(CDCl3) d: 7.3 (m, 5H, Ar-H), 4.32 (s, 2H, CH2Ar), 3.92 (t,
2H, J¼5.8 Hz, CH2NBoc), 3.4 (t, 2H, J¼5.8 Hz, CH2), 1.5
10H, 5CH2); 13C NMR (CDCl3) d: 153.3, 136.2, 129.2,
128.2, 84.6, 51.5, 48.2, 34.2, 33.3, 30.3, 29.4, 29.0, 28.4,
27.1; MS (ESIþ, 30 eV): 433 [MþNa]þ; HRMS calcd for
C21H34N2O4SþHþ: m/z [MþH]þ 411.2318, found
411.2312.
t
(s, 9H, Bu); 13C NMR (CDCl3) d: 152.2, 135.6, 129.2,
128.9, 84.3, 52.4, 47.5, 28.4, 19.9; MS (ESIþ, 30 eV): 349
[MþNa]þ; HRMS calcd for C15H22N2O4SþHþ: m/z
[MþH]þ 327.1379, found 327.1379.
4.3.9. 2-Benzyl-13-tert-butoxycarbonyl-1,2,13-thiadiazo
1
tridecine-1,1-dioxide 3i. Yield: 60%; mp: 72–758C; H
NMR (CDCl3) d: 7.2 (m, 5H, Ar-H), 4.4 (s, 2H, CH2Ar), 3.5
4.3.3. 2-Benzyl-7-tert-butoxycarbonyl-1,2,7-thiadiaze-
1
pine-1,1-dioxide 3c. Yield: 75%; mp: 90–918C; H NMR
(CDCl3) d: 7.3 (s, 5H, Ar-H), 4.5 (s, 2H, CH2Ar), 3.7 (m, 2H,
(t, 2H, J¼7.4 Hz, CH2NBoc), 3.1 (t, 2H, J¼7.9 Hz,
t
CH2NBn), 1.8 (m, 4H, 2CH2), 1.4 (s, 9H, Bu), 1.20 (m,
CH2NBoc), 3.25 (m, 2H, CH2NBn), 1.8–1.7 (m, 4H, 2CH2),
t
12H, 6CH2); 13C NMR (CDCl3) d: 152.1, 137.1, 128.9,
128.4, 83.5, 53.0, 49.5, 48.5, 34.3, 33.2, 29.7, 28.6, 28.4,
27.0, 26.9; MS (ESIþ, 30 eV): 447 [MþNa]þ; HRMS calcd
for C22H36N2O4SþHþ: m/z [MþH]þ 425.2474, found
425.2469.
1.5 (s, 9H, Bu); 13C NMR (CDCl3) d: 153.2, 136.3, 129.2,
128.4, 84.1, 52.1, 46.0, 28.7, 28.4, 24.2; MS (ESIþ, 30 eV):
363 [MþNa]þ; HRMS calcd for C16H24N2O4SþHþ: m/z
[MþH]þ 341.1535, found 341.1532.
4.3.4. 2-Benzyl-8-tert-butoxycarbonyl-1,2,8-thiadiazo-
1
4.3.10. 2-Benzyl-14-tert-butoxycarbonyl-1,2,14-thiadiazo
1
cine-1,1-dioxide 3d. Yield: 58%; mp: 92–958C; H NMR
(CDCl3) d: 7.3 (m, 5H, Ar-H), 4.4 (s, 2H, CH2Ar), 3.4 (t,
2H, J¼6.8 Hz, CH2NBoc), 3.05 (t, 2H, J¼5.1 Hz,
tetradecine-1,1-dioxide 3j. Yield: 40%; mp: 81–848C; H
NMR (CDCl3) d: 7.4 (m, 5H, Ar-H), 4.7 (s, 2H, CH2Ar), 3.8
(t, 2H, J¼6.2 Hz, CH2NBoc), 3.4 (t, 2H, J¼6.7 Hz,
t
t
CH2NBn), 1.65–1.5 (m, 6H, 3CH2), 1.5 (s, 9H, Bu); 13C
CH2NBn), 1.8–1 (m, 18H, 9CH2), 1.5 (s, 9H, Bu); 13C
NMR (CDCl3) d: 153.3, 134.9, 129.2, 128.6, 84.3, 52.4,
46.8, 32.8, 32.2, 29.3, 28.4; MS (ESIþ, 30 eV): 377
[MþNa]þ; HRMS calcd for C17H26N2O4SþHþ: m/z
[MþH]þ 355.1692, found 355.1688.
NMR (CDCl3) d: 154.2, 136.2, 129.1, 128.8, 84.2, 52.3,
48.5, 34.6, 33.7, 30.2, 29.7, 29.5, 29.3, 29.1, 28.7, 28.4,
26.9; MS (ESIþ, 30 eV): 461 [MþNa]þ; HRMS calcd for
C23H38N2O4SþHþ: m/z [MþH]þ 439.2631, found
439.2625.
4.3.5. 2-Benzyl-9-tert-butoxycarbonyl-1,2,9-thiadiazo-
nine-1,1-dioxide 3e. Yield: 60%; mp: 123–1268C; 1H
NMR (CDCl3) d: 7.2 (m, 5H, Ar-H), 4.8 (s, 2H, CH2Ar), 3.8
(t, 2H, J¼5.5 Hz, CH2NBoc), 3.2 (t, 2H, J¼5.9 Hz,
13C NMR (CDCl3) d: 151.6, 133.9, 129.2, 128.4, 83.3, 51.5,
48.0, 34.0, 32.9, 29.9, 28.4, 28.1; MS (ESIþ, 30 eV): 391
[MþNa]þ; HRMS calcd for C18H28N2O4SþHþ: m/z
[MþH]þ 369.1848, found 369.1842.
4.3.11. 2-Benzyl-15-tert-butoxycarbonyl-1,2,15-thiadiazo
pentadecine-1,1-dioxide 3k. Yield: 40%; mp: 95–988C; 1H
NMR (CDCl3) d: 7.3 (m, 5H, Ar-H), 4.5 (s, 2H, CH2Ar),
3.68 (t, 2H, J¼7.4 Hz, CH2NBoc), 3.2 (t, 2H, J¼7.5 Hz,
CH2NBn), 1.8 (m, 4H, 2CH2), 1.7–1.4 (m, 10H, 5CH2), 1.3
(s, 9H, tBu), 0.9 (m, 6H, 3CH2); 13C NMR (CDCl3) d: 153.3,
136.2, 129.2, 128.1, 84.8, 52.5, 48.1, 34.2, 33.3, 30.2, 29.8,
29.5, 29.1, 28.5, 28.4, 27.0; MS (ESIþ, 30 eV): 475
[MþNa]þ; HRMS calcd for C24H40N2O4SþHþ: m/z
[MþH]þ 453.2787, found 453.2781.
t
CH2NBn), 1.65–1.45 (m, 8H, 4CH2), 1.40 (s, 9H, Bu);
4.3.6. 2-Benzyl-10-tert-butoxycarbonyl-1,2,10-thiadiaze
cine-1,1-dioxide 3f. Yield: 60%; mp: 131–1358C; 1H
NMR (CDCl3) d: 7.3 (m, 5H, Ar-H), 4.7 (s, 2H, CH2Ar),
3.85 (t, 2H, J¼5.5 Hz, CH2NBoc), 3.25 (t, 2H, J¼5.9 Hz,
4.4. Preparation of compound 4
t
CH2NBn), 1.65–1.40 (m, 8H, 4CH2), 1.5 (s, 9H, Bu); 13C
Compound 3a was dissolved in a 20% solution of TFA in
CH2Cl2 and stirred at room temperature until TLC analysis
indicated the disappearance of the starting material. The
solution was then concentrated under vacuum, and the
residue purified by column chromatography with silica gel
(eluent: CH2Cl2) to give the expected deprotected com-
NMR (CDCl3) d: 154.3, 136.5, 129.2, 128.6, 84.5, 51.5,
48.1, 34.3, 33.2, 30.4, 28.8, 28.4; MS (ESIþ, 30 eV): 405
[MþNa]þ; HRMS calcd for C19H30N2O4SþHþ: m/z
[MþH]þ 383.2005, found 383.2001.
1
4.3.7. 2-Benzyl-11-tert-butoxycarbonyl-1,2,11-thiadiazo
undecine-1,1-dioxide 3g. Yield: 30%; mp: 125–1288C;
pound in 90% yield. (mp: 37–398C; H NMR (CDCl3) d:
7.4 (m, 5H, Ar-H), 4.6 (t, 1H, NH), 4.2 (s, 2H, CH2Ar), 3.5

´
¨
Z. Regaınia et al. / Tetrahedron 59 (2003) 6051–6056
6055
(q, 2H, J¼6.4, 13 Hz, CH2NH), 3.3 (t, 2H, J¼6.7 Hz,
CH2NBn); MS (ESIþ, 30 eV): 235 [MþNa]þ). This
compound was then treated at room temperature with a
solution of DBU (1.5 equiv.) in anhydrous THF. After 15
minutes, tert-butyl bromoacetate (1 equiv.) was added and
the reaction mixture was stirred 4 h at room temperature,
then concentrated under vacuum and purified by chroma-
tography on silica gel. Compound 4 was obtained as a white
SIR-97 (Altomare, A.; Burla, M. C.; Camalli, M.;
Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Moliterni,
A. G. G.; Polidori, G.; Spagna. R. J. Appl. Crystallogr.
1998, 31, 74.) which reveals the non hydrogen atoms of the
compound. After anisotropic refinement a Fourier Differ-
ence reveals many hydrogene atoms. The whole structure
was refined with SHELXL97 (Sheldrick, G. M. (1997).
SHELX97. Program for the Refinement of Crystal Struc-
1
¨
powder in 76% yield; mp: 55–588C; H NMR (CDCl3) d:
tures, Univ. of Gottingen, Germany.) by the full-matrix
7.4 (m, 5H, Ar-H), 4.2 (s, 2H, CH2Ar), 3.8 (s, 2H,
NCH2CO), 3.55 (t, 2H, J¼6.3 Hz, CH2NBn), 3.25 (t, 2H,
J¼6.7 Hz, CH2N), 1.5 (s, 9H, tBu); MS (ESIþ, 30 eV): 349
[MþNa]þ.
least-square techniques (use of F square magnitude; x, y, z,
bij for S, O, N and C atoms, x, y, z in riding mode for H
atoms; 200 variables and 2978 observations; calc
w¼1/[s 2(Fo 2)þ(0.061P)2þ0.19P] where P¼(Fo 2þ
2Fc 2)/3 with the resulting R¼0.035, Rw¼0.096 and
Sw¼1.001 (residual Dr#0.22 eA23). (International Tables
˚
4.5. Preparation of compound 5
for X-ray Crystallography (1992). Vol. C. Ed. A. J. C.
(Kluwer Academic Publishers, Dordrecht)). Ortep views
realized with PLATON98 (Spek, A. L. (1998) PLATON. A
multipurpose crystallographic tool, Utrecht University,
Utrecht, The Netherlands).
To a solution of compound 4 in ethanol was added
ammonium formate (5 equiv.) and Pd/C. The mixture was
refluxed until total disappearance of the starting material
(TLC monitoring). The reaction mixture was then filtered
through celite, and the filtrate concentrated. The residue was
purified by chromatography on silica gel to give the
N-debenzylated intermediate in 85% yield. (mp: 108–
Acknowledgements
1
1118C; H NMR (CDCl3) d: 4.5 (t, 1H, NH), 4.8 (s, 2H,
NCH2CO), 3.6 (m, 4H, CH2N and CH2NH), 1.5 (s, 9H, tBu);
MS (ESIþ, 30 eV): 259 [MþNa]þ). To a solution of the
above compound in DMA (N,N-dimethyl acetamide) was
added N-Boc Valine (1 equiv.), BOP (1.5 equiv.) and DIEA
(1.5 equiv.). The mixture was stirred at room temperature
overnight then poured in water and extracted twice with
ethyl acetate. The combined extracts were washed twice
with NaHCO3, followed by brine, dried and concentrated.
The residue was purified by chromatography to give 5 as a
`
Financial support of this work by the Ministere Franc¸ais des
Affaires Etrangeres (projet CMEP Franco-Algerien, 99
MEN 433) is gratefully acknowledged.
`
´
References
´
1. (a) Schaal, W.; Karlsson, A.; Ahlsen, G.; Lindberg, J.;
Andersson, H. O.; Danielson, U. H.; Classon, B.; Unge, T.;
1
white powder in 60% yield; mp: 118–1238C; H NMR
(CDCl3) d: 5.6 (d, 2H, J¼8.4 Hz, NH), 4.7 (m, 1H, C£H),
4.1 (2m, 2H, CH2NCO), 3.8 (s, 2H, NCH2CO), 3.65 (t, 2H,
J¼6.8 Hz, CH2N), 2.2 (m, 1H, –CH–), 1.45 and 1.5 (2 s,
J¼10.2 Hz, CH3); 13C NMR (CDCl3) d: 172.9, 169.1,
157.9, 82.5, 60.4, 56.1, 51.1, 46.6, 45.7, 33.8, 32.4, 31.0,
30.7, 22.4, 19.2; MS (ESIþ, 30 eV): 458 [MþNa]þ; HRMS
calcd for C17H33N3O6SþHþ: m/z [MþH]þ 408.2168, found
408.2162.
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¨ ¨
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4.6. X-Ray structural analysis of 3b
˚
C15H22N2O4S, Mw¼326.41, triclinic, P21, a¼6.259(2) A,
˚
˚
b¼9.422(2) A, c¼14.375(9) A, a¼82.68(1), b¼82.82(2),
g¼81.28(2), V¼826.3(3) A23, Z¼2, Dx¼1.312 Mg m23
,
˚
l(Mo Ka)¼0.71073 A, m¼2.15 cm21
,
F(000)¼348,
˚
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K-11,11; L-18,18) gives 2978 unique reflections from which
2255 with I.2.0s(I). After Lorenz and polarization
corrections (Spek, A. L. (1997) HELENA. Program for
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¨
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