Bis-β-sulfanylethylester and cyclic disulfide-S-oxides as precursors of bifunctionalized anionic derivatives with two oxidized sulfurs

Article abstract of DOI:10.1016/j.tet.2007.12.023

The cyclic disulfide and the bis-β-sulfanyl ethyl ester derived from dithiol, N,N′-1,2-phenylenebis(3-methyl-3-sulfanylbutanamide) were used as precursors to prepare upon oxidation the cyclic disulfide-S-oxides and the thioether sulfur oxidized species in

Full text of DOI:10.1016/j.tet.2007.12.023

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2198e2206
www.elsevier.com/locate/tet
Bis-b-sulfanylethylester and cyclic disulfide-S-oxides as precursors
of bifunctionalized anionic derivatives with two oxidized sulfurs
*
Rodolphe Alves de Sousa, Isabelle Artaud
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601, Universite´ Paris Descartes,
CNRS 45 rue des Saints Pe`res, 75270 Paris Cedex 06, France
Received 18 October 2007; accepted 10 December 2007
Available online 14 December 2007
Abstract
The cyclic disulfide and the bis-b-sulfanyl ethyl ester derived from dithiol, N,N0-1,2-phenylenebis(3-methyl-3-sulfanylbutanamide) were used
as precursors to prepare upon oxidation the cyclic disulfide-S-oxides and the thioether sulfur oxidized species including thioether/sulfoxide,
bis-sulfoxide, sulfoxide/sulfone, and bis-sulfone. Ring cleavage with KOH/EtOH of the cyclic disulfide-S-monooxide followed by reaction of
the opened intermediate with ethyl acrylate afforded the sulfinate/b-sulfanyl ethyl ester derivative. Selective oxidation with 1 and 2 equiv of
(3S)-3-tert-butyl-3-methyl-2-(phenylsulfonyl)oxaziridine or with 3 equiv of DMD led to the isolation of a series of compounds containing a sul-
fonate and a b-sulfanyl, a b-sulfinyl, and a b-sulfonyl ethyl ester. Retro-Michael reaction applied to the b-sulfonyl/b-sulfinyl and bis-b-sulfonyl
¨
derivatives enabled to produce compounds containing a sulfinate and a b-sulfinyl or a b-sulfonyl ethyl ester as well as the bis-sulfinate dianion.
1
DMD oxidation of the latter afforded the bis-sulfonate dianion. All these anionic species were characterized by H NMR, mass spectrometry,
HRMS or elemental analysis. Sulfenates in such pseudopeptidic structures could not be isolated from the ring cleavage of the cyclic disulfide-S-
dioxide or from a retro-Michael reaction applied to the b-sulfinyl ethyl ester. A cyclization reaction leading to an isothiazolidin-3-one is likely to
¨
occur as observed from the ring cleavage of the cyclic disulfide-S-dioxide. Finally, Ni(II) and Co(III) have been inserted into the disulfinate
dianion leading to the corresponding diamidato/disulfinato complexes S-bonded to Ni(II) or Co(III) centers.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Disulfide-S-oxides; N-Sulfonyloxaziridine; Sulfinate; Sulfonate; Sulfur; Complex
1. Introduction
molecules are concerned, the natural antibiotics, allicin3 and
leinamycin,4 contain a unique disulfide-S-monooxide. In con-
trast, nitrile hydratase (NHase)5 and thiocyanate hydrolase
(SCNase)6 are the only proteins which retain at their active
site three sulfurs in three different oxidation states, thiolate,
sulfenate, and sulfinate. These three sulfur oxidized species
can only coexist since they are stabilized by coordination to
a metal center. In our ongoing research on the synthesis of sul-
fur oxidized species and the study of their reactivity toward
metal cations, our present objective was to find proper condi-
tions to produce small molecules with two sulfurs in two differ-
ent states, one of the sulfurs being oxidized at the level of
sulfinate or sulfonate. The ultimate aim was to prepare mixed
thiolate/sulfinate or sulfonate and mixed sulfinate/sulfenate
and to trap all these species with a metal cation, such as
Ni(II) or Co(III).
Sulfur can occur in many different redox states in proteins or
in low molecular weight compounds used in biology or in medi-
cine. This includes sulfoxides, sulfones and sulfenic, sulfinic
and sulfonic acids, and the lesser known disulfide-S-oxides.1
Usually, proteins or small molecules carry only one type of
sulfur modification at a time. For instance, peroxyredoxins
are involved in the reduction of hydrogen peroxide through
the conversion of their active cysteine to sulfenic acid, and it
is only when the level of H2O2 becomes very high that the
sulfenic acid is over-oxidized to sulfinic acid.2 As far as small
* Corresponding author. Tel.: þ33 1 42862189; fax: þ33 1 42868387.
E-mail address: isabelle.artaud@univ-paris5.fr (I. Artaud).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.023

R. Alves de Sousa, I. Artaud / Tetrahedron 64 (2008) 2198e2206
2199
As starting dithiol, we have selected N,N0-1,2-phenylene-
bis(3-methyl-3-sulfanylbutanamide), 1, which is a 12-atom
tetradentate chelate providing a N2S2 donor set to a metal cat-
ion. Recently, Caupene et al.7 and Sivaramakrishnan et al.8
have described an efficient method to prepare sulfenates using
of a catalytic amount of NaOMe provided the bis-b-sulfanyl
ethyl ester, 2. Oxidation with 1 to 4 equiv of dimethyl dioxi-
rane (DMD) is not selective and provided a mixture of thioether
oxidized species. However, using 1 and 3 equiv of DMD, the
monosulfoxide, 4, and the sulfoxide/sulfone, 6, were isolated,
after purification, in 32% and 46% yield, respectively. Oxida-
tion with an excess of DMD afforded the bis-sulfone, 7, as
a unique product. The bis-sulfoxide, 5, can be prepared by oxi-
dation of 1 either with 2 equiv of DMD or more conveniently,
since the oxidation is selective, with 2 equiv of the N-sulfonyl-
oxaziridine derived from pinacolone, (3S)-3-tert-butyl-3-
methyl-2-(phenylsulfonyl)oxaziridine. This oxaziridine has
been previously described by Perio et al. to selectively oxidize
thiolate to sulfenate at low temperature.11
The cyclic thiosulfinate, 8 (Scheme 1), was prepared, as
recently described,12 in two steps from the corresponding di-
thiol, 1. Oxidation with iodine in the presence of triethylamine
under high dilution conditions afforded the cyclic monodisul-
fide, 3, which was further oxidized to thiosulfinate, 8, with
1 equiv of DMD at ꢀ20 ꢁC. This thiosulfinate was converted
to thiosulfonate, 9, under phase transfer conditions using
OxoneÒ as an oxidant and tricaprylmethylammonium chloride
as a catalyst.13
a retro-Michael reaction initiated by a base from a b-sulfinyl
¨
ester obtained by selective oxidation of the corresponding
b-sulfanyl ester with a N-sulfonyloxaziridine or with dime-
thyldioxirane. We applied this method to a b-sulfonyl ester
to prepare sulfinate. The acyclic bis-thiol was converted to
a bis-b-sulfanyl ethyl ester, which was further oxidized to a se-
ries of mixed species containing thioether, sulfoxide, and sul-
fone. In a second approach, the bis-thiol was oxidized to
a cyclic disulfide, and then to the cyclic disulfide-S-monooxide
(thiosulfinate) and disulfide-S-dioxide (thiosulfonate). Re-
cently, we have studied in detail the cleavage of the cyclic
pseudopeptidic thiosulfinate under basic conditions9 and we
have shown that it selectively promoted, as previously de-
10
scribed by Kice and Liu,
a mixed thiolate/sulfinate species. In this paper, we show
the intermediate formation of
that the cleavage of a b-sulfonyl ester by a retro-Michael reac-
¨
tion or the cleavage of the S(O)eS bond of a thiosulfinate
followed by reaction with ethyl acrylate are two convenient
procedures to access to a series of bis-functionalized com-
pounds containing two sulfur oxidized species with at least
either one sulfinate or one sulfonate.
Compounds 4e7, and 8 and 9 have been characterized by
1H NMR, IR (Table 1) as well as elemental analysis. The sulf-
oxides display in IR a nSO stretching mode at 1022 cmꢀ1 and
the sulfones display two nðSO Þ modes around 1100 and
2
1300 cmꢀ1. When the IR spectra are calibrated relative to
the n(CO) stretching frequency at 1732 cmꢀ1, it appears that
the n(SO) vibration is twice more intense in the bis-sulfoxide,
5, than in the monosulfoxide, 4, whereas the intensities of
2. Results and discussion
2.1. Synthesis of the neutral sulfur oxidized species
the nðSO Þ vibrations are not modified when going from the
Addition of N,N0-1,2-phenylenebis(3-methyl-3-sulfanylbu-
tanamide), 1 (Scheme 1), on ethyl acrylate in the presence
2
sulfoxide/sulfone, 6, to the bis-sulfone, 7. The nSO and nðSO Þ
2
vibrations of the thiosulfinate and of the thiosulfonate are
located at 1070 cmꢀ1, and 1093, 1125, and 1292 cmꢀ1, re-
spectively. In 1H NMR, oxidation of the thioether to sulfoxide
induces a lowfield shift of the amide NH, but this effect is
lower upon oxidation to the sulfone. This result suggests
a strong hydrogen bond between the NH and the SO groups.
The same trend is observed upon oxidation of the cyclic disul-
fide to thiosulfinate and thiosulfonate. However, in both series,
the methyl groups are more deshielded as the thioether is con-
verted to sulfoxide and sulfone, and as the disulfide is oxidized
O
O
O
O
NH HN
NH HN
S
S
S
S
3
COOEt
COOEt
2
O
O
NH HN
SH HS
Table 1
Selected chemical shifts in 1H NMR and selected stretching modes in IR of
neutral sulfur oxidized species as depicted in Scheme 1
O
O
1
N
H
N
H
Compound 1H NMR (d ppm, CDCl3)
IR (ATR, cmꢀ1
)
O
O
NH HN
S(O)x
y(O)S
NH
CH3
SO
SO2
2
4
5
6
7
3
8
9
8.73
1.51
S(O)n
8.75; 8.71 1.47; 1.51
9.28; 9.25 1.69; 1.71
1022
1022
S
COOEt
COOEt
8.90; 8.92 1.56; 1.75; 1.59; 1.76 1022 1105; 1297
x = 0, y = 1 4
x = 1, y = 1 5
x = 2, y = 1 6
x = 2, y = 2 7
n = 1 8
n = 2 9
8.51
8.06
1.82
1.52
1103; 1307
8.02; 8.33 1.49; 1.63
7.69; 8.10 1.71; 1.84
1070
1093; 1125; 1292
Scheme 1. Structures of the neutral sulfur compounds.

2200
R. Alves de Sousa, I. Artaud / Tetrahedron 64 (2008) 2198e2206
to disulfide S-monooxide and disulfide S-dioxide. These
characteristics can help to discriminate between all these
compounds.
O
O
O
O
HN
xOS
NH HN
NH
1 eq Et4NOH
DMF
-
SO2
xOS
SO2
2.2. Synthesis of the anionic derivatives
Et4N+
COOEt
COOEt
COOEt
2.2.1. Synthesis of the bis-sulfinate and of the mixed
oxidized species containing one sulfinate
x = 1, 6
x = 2, 7
x = 1, 11
x = 2, 12
Reaction of the thiosulfinate, 8, with 2 equiv of KOH/
EtOH, followed by the trapping of the opened species with
ethyl acrylate selectively provided the mixed sulfinate/thio-
ether, 10, without any trace of the mixed thioether/sulfone
(Scheme 2). This result shows that (i) the cleavage of the
S(O)eS bond of the thiosulfinate results formally, as previ-
ously described,9,10 from the selective attack of HOꢀ at the
sulfinyl sulfur leading to the formation of a mixed thiolate/sul-
finate and (ii) the sulfinate is not nucleophilic enough to react
with ethyl acrylate. In another study, the mixed thiolate/sulfi-
nate has been trapped with metal cations such as Zn(II),9
Ni(II),9 and Co(III)14 providing the corresponding mixed thio-
late/sulfinate complexes.
Et4NOH 1 eq
DMF
O
O
O
O
NH HN
NH HN
DMD
-
-
SO2
-
-
2OS
SO3
3OS
2 Et4N+
2 Et4N+
13
17
Scheme 3. Synthesis of mixed sulfinates/sulfoxide and sulfone, bis-sulfinate,
and bis-sulfonate via a combination of retro-Michael reactions and DMD
¨
oxidation.
(Scheme 3). In these reactions Et4NOH cannot be replaced by
Et3N. Addition of a second equivalent of Et4NOH to 12 yields
the bis-sulfinate, 13, showing that the two sulfinates masked as
sulfones in 12 can be sequentially deprotected. However, be-
cause the thiolate is not a good leaving group, addition of
1 equiv of Et4NOH to 10 did not allow to revert back to the
mixed thiolate/sulfinate. Some of the sulfinate salts could not
be characterized by elemental analysis, consequently all the
sulfinates 10e13 were converted to the corresponding methyl
sulfones (10-Me to 12-Me and 13-Me2) (Schemes 4 and 5) by
reaction with CH3I and they were thoroughly characterized.
O
O
NH HN
S
S
8
O
1) 2 eq KOH / EtOH, DMF
2) CH2=CHCOOEt
All the methyl sulfones exhibited in IR the typical nðSO Þ
2
O
O
O
O
O
stretching modes around 1110 and 1290 cmꢀ1, and in 1H
NMR a singlet around 3 ppm assigned to the methyl.
NH HN
NH HN
tBu
NSO2Ph
Me
-
-
SO3
K+
S
SO2
K+
S
1 eq
2.2.2. Synthesis of the bis-sulfonate and of the mixed
oxidized species with one sulfonate
10
14
COOEt
O
COOEt
Oxidation of the sulfinate/thioether, 10, with 1 and 2 equiv
of the N-sulfonyloxaziridine promoted the selective formation
of the mixed sulfonate/thioether, 14, and the mixed sulfonate/
sulfoxide, 15, respectively (Scheme 2). DMD is too a strong
oxidant to selectively prepare these intermediates, but with
3 equiv of DMD, 10 was directly converted to the mixed sul-
fonate/sulfone, 16 (Scheme 2). Similarly, the bis-sulfinate, 13,
tBu
3 eq DMD
1 eq
NH
NSO2Ph
Me
O
O
HN
NH
O
O
HN
-
SO3
K+
2OS
-
SO3
K+
OS
COOEt
16
O
O
15
NH HN
xOS
COOEt
Scheme 2. Synthesis of the sulfinate/thioether and of mixed sulfonates/thio-
ether, sulfoxide, and sulfone via a combination of ring-opening of the thiosul-
finate and selective oxidations.
SO2
COOEt
x = 0, 10-Me
x = 1, 11-Me
x = 2, 12-Me
The retro-Michael reaction initiated with 1 equiv of
¨
Et4NOH as a base, produces the selective formations of sulfi-
nate/sulfoxide, 11, from 6, and of sulfinate/sulfone, 12, from 7
Scheme 4. Structures of the sulfones.

R. Alves de Sousa, I. Artaud / Tetrahedron 64 (2008) 2198e2206
2201
was converted to the bis-sulfonate, 17 (Scheme 3), which has
been previously obtained by DMD oxidation of the zinc com-
plex derived from the dithiol, 1, (Et4N)2[Zn(N2S2)].15 The sul-
alkylation of the sulfinate to the formation of 18. Air oxidation
of the sulfenate promotes the formation of the bis-sulfinate
and, after alkylation, the formation of the bis-methylsulfone,
13-Me2. Recently, such isothiazolidin-3-one derivatives have
been prepared as mimics of the inactivation of protein tyro-
sine phosphatase 1B following the oxidation with H2O2 of
its active cysteine to a sulfenic acid.8 This inactivation was
explained by a nucleophilic reaction between the peptide
amide nitrogen and the sulfenic acid providing the formation
of such a cyclic compound that has been identified by X-ray
crystallography.18 This means that the pseudopeptidic struc-
ture of 1 precludes any isolation or trapping of sulfenate spe-
cies, either from compounds containing a b-sulfinyl ethyl
ester, such as 4, 5 or 6 or from the cyclic thiosulfonate 9
(Scheme 1).
1
fonate derivatives 14e17 were characterized by IR, H NMR,
and HRMS. In contrast to sulfinates, as previously reported,16
they did not react with CH3I to yield the expected sulfonyl
methyl ester.
2.3. Reactivity of the cyclic thiosulfonate 9
The cleavage of the S(O2)eS bond of a thiosulfonate with
HOꢀ has been described to occur by selective attack of HOꢀ at
the sulfenyl sulfur resulting in the formation of a sulfinate and
a sulfenate.17 Upon reaction with ethyl acrylate we expected
the direct formation of the mixed sulfinate/sulfoxide, 11, but
we did not get this compound. We tried to trap the opened
intermediates with CH3I. When the reaction was conducted
under air after treatment of 9 with 2 equiv of KOH/EtOH
under argon, we isolated in a 50% yield after purification by
TLC the bis-methyl sulfone 13-Me2 (Scheme 5). When the
opened species was trapped with CH3I under anaerobic condi-
tions, the characteristics of the final product corresponded to
those of the mixed methylsulfone/isothiazolidin-3-one, 18.
The ESIþ mass spectrum exhibits a molecular peak at
m/z¼385.2, [MþHþ]. In 1H NMR, there is only one NH signal
2.4. Metalation of the bis-sulfinate 13
The bis-sulfinate, 13, is a potential tetradentate ligand for
metal cations. After deprotonation of the two amides in
DMF by 2 equiv of Et4NOH at 0 ꢁC, addition of 1 equiv of
NiCl2, leads to the formation of the bis-amidate/bis-sulfinate
complex (Et4N)[Ni(N2(SO2)2)], 13-Ni (Scheme 6), which
1
shows H NMR and IR characteristics similar to those of an
authentic sample previously prepared by another route.12 In-
sertion of Co(III) as the sodium hexanitritocobalt(III) salt in
the presence of t-BuNC in excess to stabilize the six-coordi-
nated species leads, as a major product, to the diamagnetic
six-coordinated complex (Et4N)[Co(N2(SO2)2)(t-BuNC)2],
13-Co (Scheme 6), which was previously selectively prepared
upon DMD oxidation of the dithiolate cobalt complex derived
from the dithiol, 1, (Et4N)[Co(N2S2)].19 The IR spectra of
1
at 8.38 ppm. The methylsulfone is characterized in H NMR
by a methyl resonance at 2.87 ppm in CDCl3, and in IR by
.
the two expected nðSO Þ vibrations at 1102 and 1260 cmꢀ1
2
The formation of these two products can be explained as fol-
lows: after cleavage of the S(O2)eS bond, the sulfenate in this
pseudopeptidic structure would be in equilibrium with the
isothiazolidin-3-one as depicted in Scheme 5, leading after
13-Co and 13-Ni display nðSO Þ vibrations around 1000 and
2
1200 cmꢀ1 typically observed in S-bonded metal sulfinates.
It is worth noting that no metal cations could be inserted
into compounds 10 and 11 containing in addition to the sulfi-
nate a b-sulfanyl ethyl ester and a b-sulfinyl ethyl ester,
O
O
O
O
NH HN
O
NH HN
2OS
S
S
SO2
O
9
13-Me2
2-
2 eq KOH/EtOH
DMF, Ar
CH3I
O
O
O
O
NH HN
N
O
S
O
N
1) 2 eq Et4NOH
2) 1 eq NiCl2
2 Et4N+
O
Ni
-
-
SO2
2OS
S
O
O
O
O
2 Et4N+
NH HN
NH HN
O
Air
2 K+
2 K+
1) 1 eq Na3[Co(NO2)6]
2) tBuNC
13-Ni
13
-
-
-
-
SO2
2OS
SO2
OS
3) 2 eq Et4NOH
13
-
+ KOH - KOH
O
O
L
Co
L
N
O
S
N
O
Et4N+
O
O
O
O
NH
N
NH
N
S
CH3I
CH3CN, Ar
S
S
O
L = C
O
tBu
-
N
SO2
SO2
K+
18
13-Co
Scheme 6. Metalation of the bis-sulfinate with Ni(II) and Co(III).
Scheme 5. Products derived from the ring-opening of the thiosulfonate.

2202
R. Alves de Sousa, I. Artaud / Tetrahedron 64 (2008) 2198e2206
respectively, after addition of 2 equiv of Et4NOH to deproto-
nate the amides. Moreover compounds 10 and 11 are not the
precursors of mixed thiolate/sulfinate and mixed sulfinate/
services at Gif-sur-Yvette CNRS. 1H NMR spectra were
recorded at 300 K on a Bruker ARX-250 spectrometer and
chemical shifts are reported in parts per million downfield
from tetramethylsilane.
sulfenate ligands, respectively. The retro-Michael reaction is
¨
not possible from the b-sulfanyl ethyl ester, 10, since the thio-
late is not a good leaving group and when performed from the
b-sulfinyl ethyl ester, 11, the sulfenate is not stable in such
pseudopeptidic structure, as discussed above.
4.2. Materials
All chemicals were purchased from Acros and Aldrich. The
solvents were reagent grade (SDS) and were dried and distilled
before use following standard procedures. Dried diethyl ether
3. Conclusion
was purchased from Riedel-deHaen. All reactions were
¨
Using a cyclic thiosulfinate and a bis-b-sulfonyl ethyl ester,
and a mixed b-sulfinyl/b-sulfonyl ethyl ester derived from an
acyclic pseudopeptidic dithiol, we thoroughly describe the
synthesis, in high yields, of a series of sulfinate and sulfonate
compounds associated with another sulfur oxidized function.
They are summarized with their formal oxidation states in
Scheme 7. These syntheses use a combination of cleavage of
performed under argon. Products were purified by Flash Mas-
ter chromatography using a BPSUP (AIT) column or by pre-
parative TLC (silica gel F254 MERCK, 1 mm). The
oxaziridine, (3S)-3-tert-butyl-3-methyl-2-(phenylsulfonyl)oxa-
ziridine, was synthesized as previously described.11 Stock so-
lutions of DMD prepared in acetone were titrated by oxidation
of thioanisole into the corresponding sulfoxide as previously
reported.20
the S(O)eS bond or controled retro-Michael reactions and se-
¨
lective oxidations with either N-sulfonyloxaziridine or DMD.
The oxaziridine, described to selectively oxidize thiolate to
sulfenate, appears also to be a mild oxidant, which succes-
sively converts, sulfinate to sulfonate then thioether to sulf-
oxide and sulfoxide to sulfone. DMD as a stronger oxidant
is very convenient to completely oxidize a b-sulfanyl ester
to a b-sulfonyl ester or a disulfinate to a disulfonate. The pres-
ence of a peptide amide, NH, in close proximity of a b-sulfinyl
ethyl ester or of the sulfenyl sulfur of the thiosulfonate pre-
4.2.1. 4,4,7,7-Tetramethyl-1,3,4,7,8,10-hexahydro-5,6,1,10-
benzodithiadiazacyclododecine-2,9-dione 5,5-dioxide 9
To a CH2Cl2 solution (15 mL) of thiosulfinate 812 (50 mg,
0.14 mmol) containing a catalytic amount of tricaprylmethyl-
ammonium chloride (TOMAC),
a
solution of oxoneÒ
(2KHSO5; KHSO4; K2SO4) (112.8 mg, 0.18 mmol) in water
(5 mL) was added dropwise. The solution was stirred for 48 h
at room temperature. After the usual workup, the mixture was
purified by column chromatography over silica gel (5 g) using
vents the isolation of the sulfenate by a retro-Michael reaction
¨
or by opening of the cyclic thiosulfonate with potassium
hydroxide, respectively, probably because a cyclization reac-
tion leads to the formation of a more stable isothiazolidin-
3-one derivative. Finally, among all these anionic derivatives,
the disulfinate is the only one which behaves as a potential
tetradentate ligand for metal cations after deprotonation of
the amides.
1
AcOEt as eluent to give a white solid: 35 mg, yield 67%. H
NMR (250 MHz, CDCl3) d 1.71 (s, 6H), 1.84 (s, 6H), 2.81
(s, 2H), 3.08 (s, 2H), 7.32 (m, 2H), 7.41 (m, 1H), 7.53 (m, 1H),
7.69 (s, 1H), 8.1 (s, 1H). 13C NMR (500 MHz, CDCl3) d 22.9,
31.8, 45.7, 48.4, 58.6, 71.9, 126.1, 127, 127.9, 128.2, 130.7,
132.3, 167, 169.1. IR (ATR, cmꢀ1): 3252, 3238, 1691, 1677,
1093, 1125, 1292. Anal. Calcd for C16H22N2O4S2: C, 51.87;
H, 5.99; N, 7.56. Found: C, 52.29; H, 5.97; N, 7.12.
-
-
-
-
-
SO2
(+2)
SR
(-2)
SO2
(+2)
SO2
(+2)
SO2
(+2)
S(O)R
(0)
SO2
(+2)
S(O2)R
(+2)
4.2.2. Diethyl 3,30-{1,2-phenylenebis[imino(2-methyl-4-
oxobutane-4,2-diyl) thio]}dipropanoate 2
-
-
-
-
-
SO3
(+4)
S(O)R
(0)
SO3
(+4)
S(O2)R
(+2)
SO3
(+4)
SO3
(+4)
SO3
(+4)
SR
(-2)
Ethyl acrylate (63 mL, 0.59 mmol) in 2 mL of EtOH was
added dropwise to an EtOH solution (10 mL) of the dithiol 1
(100 mg, 0.29 mmol, 1 equiv) containing a catalytic amount
of NaOMe in MeOH (1 M, 30 mL, 0.03 mmol, 0.1 equiv). After
stirring the reaction mixture at room temperature for 5 h, and
evaporating the solvents in vacuo the slurry was directly puri-
fied by flash chromatography using CH2Cl2/AcOEt 9:1 as
eluent to give a colorless oil: 150 mg, yield 94%. TLC:
CH2Cl2/AcOEt 9:1, Rf 0.46. 1H NMR (250 MHz, CDCl3)
d 1.26 (t, J¼6.9 Hz, 6H), 1.51 (s, 12H), 2.63 (t, J¼7.3 Hz,
4H), 2.67 (s, 4H), 2.89 (t, J¼7.3 Hz, 4H), 4.14 (q, J¼6.9 Hz,
4H), 7.21 (m, 2H), 7.59 (m, 2H), 8.73 (s, 2H). IR (ATR,
cmꢀ1): 3288, 1732, 1660. Mass (ESIþ/MeOH) m/z 563.3
[MþNaþ]. Anal. Calcd for C26H40N2O6S2: C, 57.75; H, 7.46;
N, 5.18. Found: C, 58.08; H, 7.48; N, 5.11.
Scheme 7. Formal oxidation states of the different sulfinates and sulfonates
synthesized.
4. Experimental
4.1. Physical measurements
IR spectra were obtained with a PerkineElmer Spectrum
One FTIR spectrometer equipped with a MIRacleTM single
reflection horizontal ATR unit (zirconiumeselenium crystal).
ESI-MS mass spectra were performed on a Thermo Finnigan
LCD Advantage spectrometer. HRMS and elemental analyses
were carried out by the mass spectrometry and microanalysis

R. Alves de Sousa, I. Artaud / Tetrahedron 64 (2008) 2198e2206
2203
4.3. General procedure for the oxidation with DMD
J¼6.9 Hz, 2H), 4.32 (q, J¼7.3 Hz, 2H), 7.29 (m, 2H), 7.7 (m,
1H), 7.84 (s, 1H), 8.90 (s, 1H), 8.92 (s, 1H). 13C NMR
(250 MHz, CDCl3) d 14.51, 20.13, 21.66, 22.53, 26.2, 28.45,
41.2, 41.77, 42.37, 44.37, 56.47, 61.84, 62.44, 125.06, 126.19,
126.76, 130.31, 167.91, 168.59, 171.06, 171.75. IR (ATR,
cmꢀ1) 3251, 1733, 1686, 1664, 1297, 1105, 1022. Mass
HRMS (TOF MS ESIþ/MeOH) m/z Calcd for C26H40N2O9NaS2
[6þNaþ]: 611.2073. Found: 611.2059.
A 0.12 M solution of DMD in acetone (1 to 5 equiv) was
added dropwise at ꢀ20 ꢁC to a dry acetone solution (10 mL)
of the bis-thioether (1 equiv). The reaction mixture was allowed
to reach 0 ꢁC, then stirred for 1 h. The yellow slurry obtained
after concentration in vacuo was directly purified by flash
chromatography.
4.3.1. Ethyl 3-[(3-{[2-({3-[(3-ethoxy-3-oxopropyl)sulfinyl]-
3-methylbutanoyl}amino)phenyl]amino}-1,1-dimethyl-3-
oxopropyl)thio]propanoate 4
4.3.4. Diethyl 3,30-{1,2-phenylenebis[imino(2-methyl-4-
oxobutane-4,2-diyl)sulfonyl]}dipropanoate 7
Compound 7 was prepared upon oxidation of 2 (290 mg,
0.536 mmol) with 5 equiv of DMD (22.3 mL, 2.68 mmol).
Precipitation with diethyl ether yielded a white powder:
320 mg, yield 99%. TLC: CH2Cl2/EtOH 98:2, Rf 0.26. 1H
NMR (250 MHz, CDCl3) d 1.49 (t, J¼7.2 Hz, 6H), 1.82
(s, 12H), 3.02 (s, 4H), 3.11 (t, J¼7.5 Hz, 4H), 3.58 (t,
J¼7.5 Hz, 4H), 4.4 (q, J¼7.2 Hz, 4H), 7.37 (m, 2H), 7.81
(m, 2H), 8.51 (s, 2H). 13C NMR (250 MHz, CDCl3) d 14.48,
21.91, 26.13, 41.77, 42.4, 61.86, 62.52, 125.39, 126.6,
130.23, 168.04, 171.12. IR (ATR, cmꢀ1) 3203, 1732, 1641,
1308, 1104. Mass (ESIþ/MeOH) m/z 627.3 [MþNaþ]. Anal.
Calcd for C26H40N2O10S2: C, 51.64; H, 6.67; N, 4.63. Found:
C, 52.26; H, 6.64; N, 4.31.
Compound 4 was obtained as a colorless oil upon oxidation
of 2 (150 mg, 0.27 mmol) with 1 equiv of DMD (2.3 mL,
0.27 mmol). Chromatography: eluent CH2Cl2/MeOH 95:5;
50 mg, yield 32%. TLC: CH2Cl2/EtOH 95:5, Rf 0.5. 1H
NMR (250 MHz, CDCl3) d 1.28 (t, J¼6.9 Hz, 3H), 1.30
(t, J¼6.9 Hz, 3H), 1.47 (s, 3H), 1.51 (s, 9H), 2.61e3.02 (m,
12H), 4.12 (q, J¼6.9 Hz, 2H), 4.21 (q, J¼6.9 Hz, 2H), 7.2
(m, 2H), 7.58 (m, 1H), 7.73 (s, 1H), 8.71 (s, 1H), 8.75 (s,
1H). IR (ATR, cmꢀ1): 3256, 1733, 1687, 1663, 1022. Mass
HRMS (TOF MS ESIþ/MeOH) Calcd for C26H40N2O7NaS2
[4þNaþ]: 579.2175. Found: 579.2169.
4.3.2. Diethyl 3,30-{1,2-phenylenebis[imino(2-methyl-4-
oxobutane-4,2-diyl)sulfinyl]}dipropanoate 5
4.3.5. Bis(N,N,N-triethylethanaminium) 4,40-[1,2-phenylene
di(imino)]bis(2-methyl-4-oxobutane-2-sulfonate) 17
Compound 5 was obtained as a colorless oil upon oxidation
of 2 (290 mg, 0.53 mmol) with 2 equiv of DMD (8.92 mL,
1.07 mmol). Chromatography: eluent CH2Cl2/EtOH 96:4;
280 mg, yield 90%. Another procedure can be used to synthesize
5: (3S)-3-tert-butyl-3-methyl-2-(phenylsulfonyl)oxaziridine
(547 mg, 2.14 mmol) in 10 mL of dry THF was added dropwise
to a THF solution (50 mL) of 2 (580 mg, 1.07 mmol). The reac-
tion mixture was stirred at room temperature for 12 h and was
concentrated in vacuo. Purification by flash chromatography
using CH2Cl2/EtOH 96:4 as eluent gave 5 as a colorless oil:
600 mg, yield 97%. TLC: CH2Cl2/EtOH 96:4, Rf 0.2. 1H
NMR (250 MHz, CDCl3) d 1.52 (t, J¼6.9 Hz, 6H), 1.69 (s,
6H), 1.71 (s, 6H), 2.8e3.24 (m, 12H), 4.43 (q, J¼6.9 Hz, 4H),
7.41 (m, 2H), 7.92 (m, 2H), 9.25 (s, 1H), 9.28 (s, 1H). 13C
NMR (250 MHz, CDCl3) d 14.53, 20.25, 22.20, 28.56, 41.14,
44.05, 56.45, 56.55, 61.62, 124.92, 126.09, 129.97, 168.49,
171.7. IR (ATR, cmꢀ1): 3245, 1732, 1684, 1022. Mass (ESIþ/
MeOH) m/z 573.2 [MþHþ], 595.1 [MþNaþ]. Anal. Calcd for
C26H40N2O8S2: C, 54.52; H, 7.04; N, 4.89. Found: C, 54.56;
H, 7.12; N, 4.83.
Compound 17 was obtained upon oxidation of 13 (20 mg,
0.03 mmol) with 3 equiv of DMD (750 mL, 0.09 mmol). Pre-
cipitation with diethyl ether gave a very hygroscopic yellow
powder: 20.5 mg, yield 99%. Its Physical properties were
similar to those previously described.15
4.3.6. Potassium 4-{[2-({3-[(3-ethoxy-3-oxopropyl)thio]-3-
methylbutanoyl}amino)phenyl]amino}-2-methyl-4-
oxobutane-2-sulfinate 10
A 0.58 M solution of KOH in EtOH (prepared from melted
KOH) (953 mL, 0.553 mmol) was added dropwise at ꢀ40 ꢁC to
the thiosulfinate, 8 (98 mg, 0.276 mmol) dissolved in 4 mL of
DMF. After 1 h at ꢀ40 ꢁC, ethyl acrylate (300 mL, 2.76 mmol)
was added. The reaction mixture was stirred for 2 h and was
allowed to warm to room temperature and was concentrated in
vacuo. Diethyl ether was then added and a pale yellow powder
1
was precipitated and filtered: 126 mg, yield 90%. H NMR
(250 MHz, acetone-d6) d 1.08 (s, 6H), 1.24 (t, J¼6.9 Hz, 3H),
1.50 (s, 6H), 2.59 (s, 2H), 2.63 (t, J¼7.3 Hz, 2H), 2.88 (s, 2H),
3.03 (t, J¼7.3 Hz, 2H), 4.12 (q, J¼6.9 Hz, 2H), 6.94e7 (m,
2H), 7.8e7.82 (m, 1H), 8.16e8.2 (m, 1H), 10.29 (s, 1H), 11.17
(s, 1H). IR (ATR, cmꢀ1) 3248, 1727, 1663, 1031, 969. Mass
(ESIꢀ/MeOH) m/z 471.4 [MꢀKþ]. Anal. Calcd for
C21H31KN2O6S2$0.6 KCl: C, 45.40; H, 5.62; N, 5.04. Found:
C, 45.67; H, 5.69; N, 4.92.
4.3.3. Ethyl 3-[(3-{[2-({3-[(3-ethoxy-3-oxopropyl)sulfinyl]-
3-methylbutanoyl}amino)phenyl]amino}-1,1-dimethyl-3-
oxopropyl)sulfonyl]propanoate 6
Compound 6 was prepared as a colorless oil upon oxidation
of 2 (300 mg, 0.55 mmol) with 3 equiv of DMD (13.75 mL,
1.65 mmol). Chromatography: eluent CH2Cl2/EtOH 98:2;
150 mg, yield 46%. TLC: CH2Cl2/EtOH 98:2, Rf 0.16. 1H
NMR (250 MHz, CDCl3) d 1.40 (t, J¼6.9 Hz, 3H), 1.41
(t, J¼7.3 Hz, 3H), 1.56 (s, 3H), 1.59 (s, 3H), 1.75 (s, 3H), 1.76
(s, 3H), 2.79e3.07 (m, 10H), 3.49 (t, J¼7.7 Hz, 2H), 4.29 (q,
4.4. General procedure for the deprotection with Et4NOH
A 1.4 M solution of Et4NOH in MeOH (1 or 2 equiv)
was added dropwise to a dry CH3CN solution (1 mL) of the

2204
R. Alves de Sousa, I. Artaud / Tetrahedron 64 (2008) 2198e2206
b-sulfanyl ester (1 equiv). The reaction mixture was stirred for
10 min and concentrated in vacuo. After precipitation with
diethyl ether, the yellow powder was filtered and dried under
argon. Because residual salts are difficult to eliminate, the
mass of the isolated sulfinates, 11e13, is higher than the mass
expected for a quantitative yield, and so it is not reported.
ether afforded a pale yellow powder: 30 mg, quantitative yield.
1H NMR (250 MHz, acetone-d6) d 1.23 (t, J¼6.9 Hz, 3H),
1.38 (s, 6H), 1.51 (s, 6H), 2.65 (s, 2H), 2.66 (t, J¼6.9 Hz,
2H), 2.88 (s, 2H), 3.06 (t, J¼6.9 Hz, 2H), 4.12 (q, J¼6.9 Hz,
2H), 7.04 (m, 2H), 7.56 (m, 1H), 8.05 (m, 1H), 9.15 (s, 1H),
9.93 (s, 1H). IR (ATR, cmꢀ1): 3261, 2973.5, 1730, 1663,
1186, 1033. Mass (ESIþ/MeOH) m/z 548.9 [MþNaþ]. Mass
HRMS (TOF MS ESIþ/MeOH)) Calcd for C21H31N2O7NaS2K
[14þNaþ]: 549.1107. Found: 549.1087.
4.4.1. N,N,N-Triethylethanaminium 4-{[2-({3-[(3-ethoxy-3-
oxopropyl)sulfinyl]-3-methylbutanoyl}amino)phenyl]amino}-
2-methyl-4-oxobutane-2-sulfinate 11
Compound 11 was obtained by treatment of 6 (4.6 mg,
0.078 mmol) with 1 equiv of Et4NOH (5.6 mL, 0.078 mmol):
quantitative yield. 1H NMR (250 MHz, CDCl3) d 1.23 (t,
J¼7.3 Hz, 12H), 1.26 (s, 6H), 1.29 (t, J¼6.9 Hz, 3H), 1.6
(s, 6H), 1.94 (s, 2H), 2.24 (s, 2H), 2.87 (m, 4H), 3.17 (q,
J¼7.3 Hz, 8H), 4.21 (q, J¼6.9 Hz, 2H), 7.1 (m, 2H), 7.58
(m, 1H), 8.01 (m, 1H), 9.48 (s, 0.5H), 10.32 (s, 0.5H), 11.23
(s, 0.5H), 12.26 (s, 0.5H). The NH protons appear as a set
of 4 singlets accounting for 0.5H each. This is probably
4.4.5. Potassium 4-{[2-({3-[(3-ethoxy-3-oxopropyl)sulfinyl]-
3-methylbutanoyl}amino)phenyl]amino}-2-methyl-4-
oxobutane-2-sulfonate 15
(3S)-3-tert-Butyl-3-methyl-2(phenylsulfonyl)-1,2-oxaziri-
dine (7.6 mg, 0.03 mmol) was added to a THF solution (2 mL)
of 14 (10.5 mg, 0.02 mmol) placed at ꢀ40 ꢁC. Following the
same procedure as described for 14, compound 15 was isolated
as a yellow powder: 11 mg, quantitative yield. 1H NMR
(250 MHz, acetone-d6) d 1.26 (t, J¼6.9 Hz, 3H), 1.38 (s, 6H),
1.44 (s, 3H), 1.48 (s, 3H), 2.61 (s, 2H), 2.83(m, 4H), 2.86 (s,
2H), 4.16 (q, J¼6.9 Hz, 2H), 7.06 (m, 2H), 7.54 (m, 1H), 8.03
(m, 1H), 8.84 (s, 1H), 10.11 (s, 1H). IR (ATR, cmꢀ1): 3430,
3262, 2979, 1727, 1662, 1184, 1031, 1031. Mass (ESIꢀ/
MeOH) m/z 503 [MꢀKþ]. HRMS (TOF MS ESIꢀ/MeOH)
Calcd for C21H31N2O8S2 [15ꢀKþ]: 503.1522. Found:
503.1542.
because the sulfur of the sulfoxide is chiral. IR (ATR, cmꢀ1
)
3245, 2925, 1731, 1675, 1026, 966. Mass HRMS (TOF MS
ESIꢀ/MeOH) Calcd for C21H31N2O7S2 [11ꢀEt4Nþ]:
487.1573. Found: 487.1572.
4.4.2. N,N,N-Triethylethanaminium 4-{[2-({3-[(3-ethoxy-3-
oxopropyl)sulfonyl]-3-methylbutanoyl}amino)phenyl]amino}-
2-methyl-4-oxobutane-2-sulfinate 12
Compound 12 was obtained by treatment of 7 (14 mg,
0.023 mmol) with 1 equiv of Et4NOH (16.5 mL, 0.023 mmol):
quantitative yield. 1H NMR (CDCl3) d 1.19 (s, 6H), 1.22 (t, J¼
7.3 Hz, 12H), 1.30 (t, J¼6.9 Hz, 3H), 1.66 (s, 6H), 2.67 (d,
J¼13.7 Hz, 2H), 2.91 (t, J¼7.3 Hz, 2H), 3.06 (s, 2H), 3.14 (q,
J¼7.3 Hz, 8H), 3.65 (t, J¼7.3 Hz, 2H), 4.2 (q, J¼6.9 Hz, 2H),
7.07 (m, 2H), 7.65 (m, 1H), 8.08 (m, 1H), 10.51 (s, 1H), 10.69
(s, 1H). IR (cmꢀ1) 3240, 1734, 1677, 1290, 1105, 1026, 966,
919. Mass HRMS (TOF MS ESIꢀ/MeOH) Calcd for
C21H31N3O8S2 [12ꢀEt4Nþ]: 503.1522. Found: 503.1547.
4.4.6. Potassium 4-{[2-({3-[(3-ethoxy-3-oxopropyl)sulfonyl]-
3-methylbutanoyl}amino)phenyl]amino}-2-methyl-4-
oxobutane-2-sulfonate 16
A 0.12 M solution of DMD in acetone (915 mL, 0.11 mmol)
was added dropwise at ꢀ20 ꢁC to a dry acetone solution (3 mL)
of 10 (19 mg, 0.036 mmol). Thereaction mixturewas allowed to
warm to 0 ꢁC and was stirred for 1 h and then concentrated inva-
cuo. Precipitation with Et2O gave a white powder: 12 mg, yield
60%. 1H NMR (250 MHz, acetone-d6) d 1.26 (t, J¼6.9 Hz, 3H),
1.41 (s, 6H), 1.59 (s, 6H), 2.68 (s, 2H), 2.88 (t, J¼6.9 Hz, 2H),
3.02 (s, 2H), 3.67 (t, J¼6.9 Hz, 2H), 4.17 (q, J¼6.9 Hz, 2H),
7.08 (m, 2H), 7.5 (m, 1H), 8.06 (m, 1H), 8.92 (s, 1H), 10.03
(s, 1H). IR (ATR, cmꢀ1) 3445, 3266, 2980, 2938, 1730, 1664,
1293, 1120, 1183, 1031. Mass HRMS (TOF MS ESIꢀ/MeOH)
Calcd for C21H31N2O9S2 [16ꢀKþ]: 519.1471. Found:
519.1446.
4.4.3. Bis(N,N,N-triethylethanaminium) 4,40-[1,2-phenylene
di(imino)]bis(2-methyl-4-oxobutane-2-sulfinate) 13
Compound 13 was obtained by treatment of 7 (20 mg,
0.033 mmol) with 2 equiv of Et4NOH (48 mL, 0.067 mmol):
1
quantitative yield. H NMR (250 MHz, DMSO-d6) d 0.92 (s,
12H), 1.17 (t, J¼7.2 Hz, 24H), 2.32 (s, 4H), 3.22 (q,
J¼7.2 Hz, 16H), 7.02 (m, 2H), 7.6 (m, 2H), 10.6 (s, 2H). IR
(ATR, cmꢀ1) 3363, 3249, 1670, 1173, 1031, 1003, 967, 919.
Mass HRMS (TOF MS ESIꢀ/MeOH) Calcd for
C24H42N3O6S2 [13ꢀEt4Nþ]: 532.2515. Found: 532.2539.
4.5. General procedure for trapping the sulfinates with MeI
MeI (10 or 20 equiv) was added dropwise to a dry CH3CN
solution (3 mL) of the sulfinate prepared by deprotection of
the b-sulfinyl ester (1 equiv). The reaction mixture was stirred
for 2 h and was concentrated in vacuo. Precipitation with Et2O
afforded a powder, which was purified by preparative TLC.
4.4.4. Potassium 4-{[2-({3-[(3-ethoxy-3-oxopropyl)thio]-3-
methylbutanoyl}amino)phenyl]amino}-2-methyl-4-
oxobutane-2-sulfonate 14
(3S)-3-tert-Butyl-3-methyl-2-(phenylsulfonyl)oxaziridine
(10 mg, 0.0391 mmol) was added to a THF solution (2 mL) of
10 (20 mg, 0.039 mmol) placed at ꢀ40 ꢁC. The reaction mix-
ture was stirred for 2 h and was allowed to warm to room tem-
perature and concentrated in vacuo. Precipitation with diethyl
4.5.1. Ethyl 3-({1,1-dimethyl-3-[(2-{[3-methyl-3-(methyl-
sulfonyl)butanoyl]amino}phenyl)amino]-3-oxopropyl}thio)-
propanoate (10-Me)
Compound 10-Me was obtained from 10 (10 mg,
0.0195 mmol) with MeI (12 mL, 0.195 mmol) and isolated as

R. Alves de Sousa, I. Artaud / Tetrahedron 64 (2008) 2198e2206
2205
a yellow powder, which was purified with CH2Cl2/AcOEt 6:4;
8.5 mg, yield 90%. TLC: CH2Cl2/AcOEt 6:4, Rf 0.45. 1H
NMR (250 MHz, acetone-d6) d 1.23 (t, J¼6.9 Hz, 3H), 1.52
(s, 6H), 1.60 (s, 6H), 2.60 (t, J¼6.9 Hz, 2H), 2.79 (s, 2H), 2.83
(s, 2H), 2.95 (t, J¼6.9 Hz, 2H), 3.02 (s, 3H), 4.12 (q,
J¼6.9 Hz, 2H), 7.14e7.18 (m, 2H), 7.67e7.74 (m, 2H), 9.32
(s, 1H), 9.52 (s, 1H). IR (ATR, cmꢀ1) 3235, 1725, 1666, 1290,
1108. Mass (ESIþ/MeOH) m/z 509.3 [MþNaþ], 525.2
[MþKþ]. Anal. Calcd for C22H34N2O6S2: C, 54.30; H, 7.04;
N, 5.76. Found: C, 53.95; H, 6.98; N, 5.71.
was concentrated in vacuo. Precipitation with diethyl ether
afforded a white product, which was filtered and washed with
diethyl ether. 1H NMR (250 MHz, CDCl3) d 1.63 (s, 6H), 1.71
(s, 6H), 2.78 (s, 2H), 2.87 (s, 3H), 2.98 (s, 2H), 7.19e7.29 (m,
2H), 7.41 (d, 2H), 7.87 (d, 2H), 8.38 (s, 1H). IR (ATR, cmꢀ1):
1660, 1289, 1101, 755. Mass (ESIþ/MeOH) m/z 385.2 [100%,
MþHþ], 423 [MþKþ].
4.5.6. (Et4N)[Co(N2(SO2)2)(t-BuNC)2] complex (13-Co)
A DMF solution of Na3[CoIII(NO2)6] (0.041 mmol) pre-
pared in the presence of the minimum amount of water as
previously described14 was added dropwise at ꢀ40 ꢁC to the
bis-sulfinate, 13 (25 mg, 0.041 mmol) dissolved in DMF
(1 mL). A large excess of t-BuNC (200 mL) and 2 equiv of
Et4NOH (59 mL, 0.083 mmol) were then added to the mixture,
which turned orange to brown. The solution was then allowed
to warm to room temperature. After evaporation to dryness in
vacuo, the slurry was dissolved in CH3CN, filtered and precipi-
tated with diethyl ether at 0 ꢁC. The powder was redissolved in
acetone and was slowly poured into diethyl ether to yield
4.5.2. Ethyl 3-({1,1-dimethyl-3-[(2-{[3-methyl-3-(methyl
sulfonyl)butanoyl]amino}phenyl)amino]-3-oxopropyl}-
sulfinyl)propanoate (11-Me)
Compound 11-Me was obtained from 11 (22.9 mg,
0.037 mmol) with MeI (23 mL, 0.37 mmol) and was isolated
as a white oil: 6 mg, yield 33%. TLC: CH2Cl2/MeOH 95:5,
1
Rf 0.22. H NMR (250 MHz, CDCl3) d 1.30 (t, J¼6.9 Hz,
3H), 1.46 (s, 3H), 1.50 (s, 3H), 1.64 (s, 6H), 2.86 (s, 2H),
2.89 (m, 6H), 2.94 (s, 3H), 4.2 (q, J¼6.9 Hz, 2H), 7.2 (m,
2H), 7.68 (m, 2H), 8.55 (s, 1H), 8.72 (s, 1H). IR (ATR,
cmꢀ1): 3252, 2981, 2934, 1731, 1684, 1664, 1291, 1107,
1022. Mass HRMS (TOF MS ESIþ/MeOH) Calcd for
C22H34N2O7NaS2 [11-MeþNaþ]: 525.1705. Found: 525.1728.
1
a brown powder: 20 mg, yield 65%. Its H NMR (250 MHz)
in CD3CN was similar to that of an authentic sample.19 IR
(ATR, cmꢀ1): 3407, 1659, 1221, 1068. Mass (ESIꢀ/MeOH)
m/z 624.9 [55%, MꢀEt4Nþ].
4.5.7. (Et4N)2[Ni(N2(SO2)2)] complex (13-Ni)
4.5.3. Ethyl 3-({1,1-dimethyl-3-[(2-{[3-methyl-3-(methyl
sulfonyl)butanoyl]amino}phenyl)amino]-3-oxopropyl}-
sulfonyl)propanoate (12-Me)
NiCl2$6H2O (20 mg, 0.083 mmol) in 1 mL of DMF was
added at ꢀ40 ꢁC to a DMF solution (2 mL) of the bis-sulfi-
nate, 13 (50 mg, 0.083 mmol). Et4NOH (2 equiv) was then
added and the mixture was allowed to warm to room temper-
ature. After evaporation to dryness in vacuo, the orange slurry
was dissolved in CH3CN and precipitated with diethyl ether.
The solid was washed with acetone and dried to give an orange
Compound 12-Me was prepared upon alkylation of 12
(15 mg, 0.019 mmol) with MeI (15 mL, 0.24 mmol) and was iso-
lated as a white solid: 11 mg, yield 92%. TLC: CH2Cl2/MeOH
95:5, Rf 0.27. 1H NMR (250 MHz, CDCl3) d 1.28 (t,
J¼6.9 Hz, 3H), 1.64 (s, 6H), 1.66 (s, 6H), 2.93 (d, J¼8.2 Hz,
4H), 2.93 (t, J¼7.3 Hz, 2H), 3.02 (s, 3H), 3.39 (t, J¼7.3 Hz,
2H), 4.21 (q, J¼6.9 Hz, 2H), 7.21 (m, 2H), 7.68 (m, 2H), 8.43
(s, 1H), 8.61 (s, 1H). IR (ATR, cmꢀ1): 3328, 1734, 1656,
1665, 1289, 1104, 950. Mass HRMS (TOF MS ESIþ/MeOH)
Calcd for C22H34N2O8NaS2 [12-MeþNaþ]: 541.1654. Found:
541.1667.
1
powder: 41 mg, yield 70%. The H NMR was similar to that
previously described.12 IR (ATR, cmꢀ1): 3371, 1599, 1160,
1054. Mass (ESIþ/MeOH) m/z 848.3 [MþEt4Nþ].
References and notes
1. Jacob, C. Nat. Prod. Rep. 2006, 851e863.
2. Vivancos, A. P.; Castillo, E. A.; Biteau, B.; Nicot, C.; Ayte, J.; Toledano,
M. B.; Hidalgo, E. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 8875.
3. Block, E. Angew. Chem., Int. Ed. Engl. 1992, 31, 1135e1178.
4. Kanda, Y.; Ashizawa, T.; Kakita, S.; Takahashi, Y.; Kono, M.; Yoshida,
M.; Saitoh, Y.; Okabe, M. J. Med. Chem. 1999, 42, 1330e1332.
5. (a) Nagashima, S.; Nakasako, M.; Dohmae, N.; Tsujimura, M.; Takio, K.;
Odaka, M.; Yohda, M.; Kamiya, N.; Endo, I. Nat. Struct. Biol. 1998, 5,
347e351; (b) Fushinobu, S.; Ito, K.; Wakagi, T. Biochem. Biophys. Res.
Commun. 2001, 288, 1169e1174.
4.5.4. N,N0-1,2-Phenylenebis[3-methyl-3-(methylsulfonyl)-
butanamide (13-Me2)
Compound 13-Me2 was prepared from 13 (12.6 mg,
0.019 mmol) with MeI (24 mL, 0.38 mmol) and isolated as
a white solid: 8 mg, yield 98%. TLC: CH2Cl2/MeOH 9:1, Rf
1
0.25. H NMR (250 MHz, CDCl3) d 1.64 (s, 12H), 2.87 (s,
4H), 2.95 (s, 6H), 7.2 (m, 2H), 7.7 (m, 2H), 8.17 (s, 2H). IR
(ATR, cmꢀ1) 3271, 1656, 1284, 1106, 909. Anal. Calcd for
C18H28N2O6S2: C, 49.98; H, 6.52; N, 6.48. Found: C, 49.62;
H, 6.41; N, 6.62.
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4.5.5. N-[2-(5,5-Dimethyl-3-oxoisothiazolidin-2-yl)phenyl]-
3-methyl-3-(methylsulfonyl)butanamide 18
An aqueous solution of KOH (1 M, 170 mL, 0.170 mmol)
was added dropwise at ꢀ30 ꢁC to the thiosulfonate, 9 (30 mg,
0.085 mmol) dissolved in dry DMF (1 mL), then 2 equiv MeI
(11 mL, 0.170 mmol) was quickly added. The reaction mixture
`
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2206
R. Alves de Sousa, I. Artaud / Tetrahedron 64 (2008) 2198e2206
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