The S2 oxygen atoms are essential for the pronounced fungitoxicity of the sulfur-rich natural product, dysoxysulfone

Article abstract of DOI:10.1071/CH03253

Synthesis and antifungal testing of 2,4,5,7,9-pentathiadecane 9,9-dioxide has established that the absence of oxygen atoms on S2 significantly attenuates fungitoxicity in accord with our earlier proposal. Attempts to convert that compound into dysoxysulfone led to the discovery of a novel oxidative conversion of unsymmetrical γ-sulfonyl disulfides into the corresponding symmetrical γ-sulfonyl disulfides. CSIRO 2005.

Full text of DOI:10.1071/CH03253

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2005, 58, 218–223
www.publish.csiro.au/journals/ajc
The S Oxygen Atoms Are Essential for the Pronounced Fungitoxicity
2
of the Sulfur-Rich Natural Product, Dysoxysulfone
A
A
A
A,C
Sharon A. Bewick, Stephen Duffy, Stephen P. Fletcher, Richard F. Langler,
A
A
B,D
Heather G. Morrison, Erin M. O’Brien, Charles Ross,
and Vanessa C. StephensonA
A
Department of Chemistry, Mount Allison University, Sackville, New Brunswick E4L 1G8, Canada.
Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
Corresponding author (organic chemistry). Email: rlangler@mta.ca
B
C
D
Corresponding author (crystallography). Email: charles.ross@stjude.org
Synthesis and antifungal testing of 2,4,5,7,9-pentathiadecane 9,9-dioxide has established that the absence of oxygen
atoms on S2 significantly attenuates fungitoxicity in accord with our earlier proposal. Attempts to convert that
compound into dysoxysulfone led to the discovery of a novel oxidative conversion of unsymmetrical γ-sulfonyl
disulfides into the corresponding symmetrical γ-sulfonyl disulfides.
Manuscript received: 22 April 2003.
Final version: 16 June 2004.
Introduction
Some time ago, dysoxysulfone (1, Scheme 1) was isolated
More recently, we have undertaken the synthesis of 2 with
two goals in mind: (a) to establish that, in the absence of
oxygen atoms at S2, the dysoxysulfone framework would
havesharplydiminishedantifungalactivityinaccordwithour
earlier conclusions and (b) to examine selected oxidation
reactions of 2.
[1]
[2]
from Fijian mahogany plants. Subsequently, Block et al.
synthesized 1 and demonstrated that it has, among others,
antifungal and anticancer properties.Thereafter, we disclosed
structure–activity results supporting the conclusion that
[
3]
[3–5]
α-sulfone disulfides are effective fungitoxins.
Further-
Results and Discussion
more, we have shown that our α-sulfone disulfides exhibit
significant antileukemic behaviour and that they are toxic to
Our synthesis of 2 began with the α-chlorosulfone 3
[6]
[7]
Scheme 2). Earlier, a successful synthesis of 3 followed
non-transformed (i.e. normal) human cells.
(
by a significant improvement in the regiochemistry of the
step that introduces the first oxygen atom were reported.
CH SO CH SCH S-SCH SO CH
3
2
2
2
2
2
3
[8]
10
9
8
7 6
5
4 3
2
1
The first step in the conversion of 3 into 2 introduces S5.
Deacylation of 4 proved to be problematic because the
resultant mercaptide anion extrudes/adds thioformaldehyde,
leading to a mixture of alternating carbon/sulfur frame-
works of different lengths. Related behaviour is known in
1
CH SO CH SCH SSCH SCH
3
3
2
2
2
2
2
Scheme 1.
the chemistry of α-mercaptosulfones and α-mercaptosulfide
Pyridine
[2,9]
anions.
The mercaptide anion formed by deacylation
CH SO CH SCH Cl ꢀ HSAc
CH SO CH SCH SAc
3 2 2 2
3
2
2
2
ꢁ
of 4 was successfully trapped when the solvent was
changed to dimethyl disulfide/dimethyl sulfoxide (DMSO;
see Scheme 3).
3
4
Scheme 2.
Compound 5 was smoothly converted to 2 by dispropor-
tionation in the appropriate solvent (see Scheme 4).
Biological testing of 5 and 2 showed substantially dimin-
ished antifungal activity relative to that of typical α-sulfone
DMSO
CH S)
CH SO CH SCH SAc ꢀ CH ONa
CH SO CH SCH SSCH
3 2 2 2 3
3
2
2
2
3
(
3
2
4
5
Scheme 3.
CH SNa
3
CH SO CH SCH SSCH
CH SO CH SCH SSCH SCH ꢀ (CH SO CH SCH S)
3 2 2 2 2 3 3 2 2 2 2
3
2
2
2
3
(
CH SCH S)
3 2 2
5
2
6
Scheme 4.
CSIRO 2005
©
10.1071/CH03253
0004-9425/05/030218

The S2 Oxygen Atoms and Fungitoxicity of Dysoxysulfone
219
Table 1. Disulfides as antifungal agents
Each compound was introduced (in acetone) onto a small paper disk, which was placed in a
culture medium. The diameter of the clear zone (the area where the fungus, Aspergillus niger
and Aspergillus flavus did not grow) around each disk indicated antifungal activity.
Sulfur compound tested
Dose [µg per disk]
Diameter of clear zone [mm]A
A. niger
A. flavus
CH3SO2CH2SCH2SSCH3 5
25
25
25
25
100
1.4
1.9
4.8
13.8
0
1.5
2.7
3.3
11.7
0
CH3SO2CH2SCH2SSCH2SCH3 2
[
3]
CH3SO2CH2SSCH2CH3
CH3SO2CH2SS(CH2)4CH3
[
5]
CH3SO2(CH2)3SSCH2SCH3 11
A
For each test, four replicates were done.
H O
CHCl3
2
2
CH SCH SCH SSCH SCH
CH S(O)CH SCH SSCH S(O)CH
3
CH3SO2CH2SCH2SSCH2SCH3 ꢀ m-CPBA
(CH3SO2CH2SCH2S)2
3
2
2
2
3
3
2
2
2
HOAc
7
8
2
6
50%
KMnO , Zn(OAc)
4
2
KMnO , FeCl
MgSO , acetone
4
Scheme 7.
4
3
MgSO , acetone
4
CH SNa
3
CH SO CH CH CH SSCH
CH SO CH CH CH SSCH SCH
CH SO CH SCH SSCH SO CH
3
3
2
2
2
2
3
3
2
2
2
2
2
3
3
2
2
2
2
2
(
CH SCH S)
3 2 2
1
10
11
Scheme 5. Block’s syntheses of dysoxysulfone 1.
Scheme 8.
CH SO CH SCH SSCH S(O)CH
3
3
2
2
2
2
9
CH SO
S
S
R
S
3
2
ꢂ
Scheme 6.
C
2
C
H
Nu
SR ꢀ 2CH S ꢀ CH SO
2 3 2
H
2
ꢂ
2
, 5
Nu
disulfides (see Table 1). Note that simple α-sulfide disulfides
show little or no antifungal activity at 100 µg per disk (see
results for 2,3,5-trithiahexane and 2,4,5,7-tetrathiaoctane in
ref. [3]). Hence, results reported in Table 1 support the con-
clusion that dysoxysulfone 1, itself, is an effective antifungal
Scheme 9.
m-CPBA
CH SO CH CH CH SSCH SCH
(CH SO CH CH CH S)
3 2 2 2 2 2
3
2
2
2
2
2
3
[2]
agent because it is an α-sulfone disulfide.
CHCl3
1
1
12 58%
[2]
Given that Block’s syntheses proceed by oxidation of
the pre-assembled skeleton of 1 (see Scheme 5), it seemed
that our synthesis of 2 should constitute a formal synthesis of
dysoxysulfone 1.When we attempted to oxidize 2 with hydro-
genperoxide, wewereunabletoisolatesignificantamountsof
the target sulfoxide (9, Scheme 6). Attempts to convert 2 into
Scheme 10.
CH CH CH SNa
3
2
2
(
CH SO CH CH CH S)
3 2 2 2 2 2
(
CH CH CH S)
3
2
2
2
12
[2]
1
with permanganate in the presence of Block’s Lewis acids
CH SO CH CH CH SSCH CH CH
wereunsuccessful. SinceBlocketal. assumedthattheirinitial
difficulties arose from reactions with base, generated dur-
ing the oxidation reactions, we initiated exploratory work on
the oxidation of 2 with meta-chloroperoxybenzoic acid (m-
CPBA)/chloroform. It came as something of a surprise to
find that the principal organic product from the oxidation of
3
2
2
2
2
2
2
3
13
Scheme 11.
m-CPBA
CH SO CH CH CH SSCH CH CH
(CH SO CH CH CH S)
3 2 2 2 2
[2]
3
2
2
2
2
2
2
3
2
2
was the symmetrical disulfide 6 (see Scheme 7). It was,
CHCl3
1
3
12 17%
in fact, the presence of 6 in product mixtures obtained from
[
2]
KMnO4/MgSO4 oxidations of 7 that led Block et al. to
postulate a base-induced elimination reaction which would
partially degrade 1 to furnish 7. Our conditions would not
permit application of their rationale to the Scheme 7 reaction.
In order to gain more insight into the reaction shown
in Scheme 7, we have replaced S7 in compound 2 with a
methylene group. Our synthesis is outlined in Scheme 8.
Scheme 12.
CHCl3
PhCH SSCH ꢀ m-CPBA
CH SSCH ꢀ PhCH SSCH Ph
2
3
3
3
2
2
0
%
0.1%
Scheme 13.

2
20
S. A. Bewick et al.
CH SO CH CH CH SSCH
CH3
H2
C
3
2
2
2
2
2
ꢀ
CH3
S
11
S
S
S
O
C
O
ꢂ
O
O
CH2
CH2
H
O
H
ꢂ O
S 2
ꢀ
H C
C
H
3
2
Cl
S
CH CH CH SO CH
2 2 2 2 3
ꢂ
CH3
Nu
CH3SCH2
S
S
CH2
S
S
O
CH2
CH2
ꢂ
O
S 2
ꢀ
CH SO (CH )
2 3
S
ꢀ
3
2
S
(CH ) SO CH
H C
C
H
2
3
2
3
3
2
ꢂ
ꢂ
2
ꢂ
Nu ꢃ m-Cl(C H )CO or CH SO
6
4
3
(
CH SO CH CH CH S)
3
2
2
2
2
2
12
Scheme 14.
m-CPBA
CH SO CH CH CH SSCH SCH
CH SO CH CH CH SSCH S(O)CH
3
2
2
2
2
2
3
3
2
2
2
2
2
3
11
ꢂ
O
E1
CH SO CH CH CH SOH ꢀ S
CH
S(O)CH3
CH SO CH CH CH SSCH S(O)CH
3 2 2 2 2 2 3
3
2
2
2
2
ꢀ
(
CH SO CH CH S)
3 2 2 2 2
12
Scheme 15. Alternative to the Scheme 14 proposal.
ꢀ
yield (see Scheme 10). In addition to full spectroscopic char-
acterization, the structure of 12 was established by X-ray
crystallography (see Fig. 1 and Table 2).
CH SO CH CH CH SS(OH)CH CH CH
3
3
2
2
2
2
2
2
14
Scheme 16.
Next we prepared compound 13 in which both S7 and
S2 (compare 2) have been replaced by methylenes (see
Scheme 11). Peroxidation of 13 furnished a modest amount
of symmetrical disulfide 12 (see Scheme 12).
Finally, peroxidation of a simple unsymmetrical disul-
fide furnished essentially no symmetrical disulfides (see
Scheme 13).
The results disclosed in Schemes 7, 10, 12, and 13 sug-
gest (a) that the, initially unexpected, efficient conversion of
dysoxysulfone relatives into symmetrical disulfides, requires
sulfenyl sulfur at S2 and sulfonyl sulfur at S9 and (b) that
no step in the mechanism for these reactions involves strong
Note that 11 has no fungitoxicity at 100 µg per disk (see
Table 1), in accord with the earlier assertion that simple
α-sulfide disulfides show little or no fungitoxicity. The dif-
ference in fungitoxicities for 2, 5, and 11 may be ascribed to
mild activation of the disulfide linkage by the remote sul-
fonyl group in 2 and 5 which is not available to 11 (see
Scheme 9). The reaction shown in Scheme 9 conforms to
[
3]
our earlier suggestion, which rationalizes fungitoxicity for
simple α-sulfone disulfides. Oxidation of 11 with m-CPBA
furnished the symmetrical disulfone disulfide 12 in good

The S2 Oxygen Atoms and Fungitoxicity of Dysoxysulfone
221
S2
otherwise specified, all NMR spectra were obtained for the com-
pounds in deuterated chloroform solutions using tetramethyl silane as
an internal standard. Routine mass spectra (MS) were obtained on a
Hewlett–Packard 5988A gas-liquid chromatography mass spectrometer
(GLC/MS) system. Operating conditions for the GLC/MS were as fol-
lows: column packing Supelco SPB-1; column dimensions 0.2 mm ×
O4
S4
O2
C3
S1
C4
C8
C1
C6
C5
C2
S3
C7
−
1
O3
12 m; carrier gas He (flow 1 mL min ) with a split ratio of 100:1; sol-
O1
◦
vent delay 1.5 min; temperature program heated from 50 to 225 C at
+
◦
−1
◦
15 C min ; ion source temperature 225 C. Melting point analyses
Fig. 1. A perspective drawing of compound 12.
were determined on a Gallenkamp MFB-595 capillary melting point
apparatus and are uncorrected.
Table 2. Non-hydrogen atom bond lengths [Å]A for compound 12
Yield Determinations for Reactions with m-CPBA
Bond
Distance
Bond
Distance
Samples were weighed analytically and diluted to the low ppm range
before analysis. Samples (1 µL) were analyzed using a Varian CP-3800
gas chromatograph (GC) equipped with a CP-8410 autoinjector, con-
nected to a Saturn 2000 mass selective detector. The GC oven contained
a Varian 30 m × 0.25 mm i.d. × 0.25 µm film thickness CP-Sil 8 CB
low bleed/MS column. The GC temperature program was as follows,
C(1)–S(1)
S(1)–O(1)
S(1)–O(2)
S(1)–C(2)
C(2)–C(3)
C(3)–C(4)
C(4)–S(2)
S(2)–S(3)
1.78(2)
1.423(18)
1.444(17)
1.77(2)
1.53(2)
1.50(2)
1.82(2)
2.04(2)
C(8)–S(4)
S(4)–O(4)
S(4)–O(3)
S(4)–C(7)
C(7)–C(6)
C(6)–C(5)
C(5)–S(3)
1.77(2)
1.438(18)
1.440(16)
1.78(2)
1.53(2)
1.52(2)
1.82(2)
◦
◦
injection temperature 250 C, initial temperature 50 C, hold for 2 min,
◦
◦
−1
◦
ramp to 220 C at +20 C min and hold for 2 min, ramp to 260 C at
◦ −1
5 C min and hold for 21.5 min for a total analysis time of 42 min.
+
Helium gas was used as the carrier and the column flow rate was held
constant at 1.0 mL min . On occasion, the GC run was terminated
A
Corresponding bond lengths were constrained to be equal in left and
right halves of the molecule.
−1
before the final time was reached provided that the analyte had eluted
from the column. The mass selective detector was operated in both the
electron impact (EI) and the chemical (CH4) ionization (CI) modes.
The mass range selected was typically 50 to 500 amu. A minimum of
three microscans were averaged to produce each scan, resulting in a data
accumulation rate of 0.5 s per scan for EI and 0.62 s per scan for CI. The
emission current was set at 30 µA. Percent yields were calculated based
on response factors for each of the identified compounds, by comparing
the integrated peak areas of standards to the peak areas obtained from
reaction products through the use of the Saturn GC/MS workstation
software.
base. A mechanism, consistent with the foregoing results is
presented in Scheme 14. There have been some reports
suggesting that sulfonyl oxygen can coordinate electrophilic
sites in accord with the heart of the mechanism shown in
Scheme 14.
[
10–12]
A referee has suggested an alternative mechanism for the
results disclosed in Schemes 7, 10, 12, and 13. In that pro-
posal, oxidation would furnish a sulfoxide thiosulfinate with
the regiochemistry shown in Scheme 15. Both Scheme 14
and Scheme 15 can account for the results in Schemes 7, 10,
and 13. However, Scheme 12 shows significant symmetri-
cal disulfide formation (17%) for a substrate which lacks the
α-sulfide disulfide functionality. Absent the α-sulfide link-
age, the Scheme 15 mechanism doesn’t apply to Scheme 12.
The expected regiochemistry for oxidation of 13 would pro-
duce the cationic intermediate 14 (Scheme 16) which could
be cleaved by the neighbouring sulfonyl group in a manner
analogous to that pictured in Scheme 14.
Biological Testing
[
3]
Details have been provided earlier.
Preparation of 2,4-Dithiapentane 2,2-Dioxide-5-thiolacetate 4
[
7]
The chlorosulfide sulfone 3 (0.30 g, 1.72 mmol) and thioacetic S-acid
(
0.127 g) were added to dry pyridine (3 mL). The reaction mixture was
◦
immersed in a constant temperature bath (82 C) for 1.5 h.
Chloroform (100 mL) was added and the resultant mixture washed
with 5% hydrochloric acid (100 mL). The organic layer was then
extracted with 2.5% w/v sodium hydroxide solution (100 mL), dried
(
MgSO4), filtered, and the solvent evaporated.
Crude 4 was recrystallized from methanol affording sulfone sulfide
thiolacetate 4 (0.135 g, 0.63 mmol, 37%).An analytical sample was pre-
pared by sublimation (60 C, 1.7 Torr). After 18 h, the cold finger was
◦
Conclusions
cleaned and the sublimation resumed for 3.5 h. Crystalline, sublimed
1
. Synthesis and biological testing of dideoxydysoxysulfone
shows it to be a weak antifungal agent. Compound 2
◦
thiolacetate (mp 77.8–80.5 C) was obtained (Found: C 27.8, H 4.5.
−
1
2
C H O S requires C 28.0, H 4.7%). νmax/cm 1700, 1320, 1140. δH
5
10
3 3
is an order of magnitude less fungitoxic than the pentyl
disulfide (Table 1) which is an α-sulfone disulfide that has
the same skeletal length as 2.
. Peroxidations (m-CPBA) of 2 and 11 led to unexpectedly
high yields of symmetrical disulfone disulfides. The pro-
posed mechanism (Scheme 14) involves participation of
S2 and a sulfonyl oxygen on S9.
(60 MHz; CDCl3; Me4Si) 2.36 (3H, s, CH3CO), 3.03 (3H, s, CH3SO2),
3
3
.93 (2H, s, CH2), 4.30 (2H, s, CH2). δC (68 MHz; CDCl3; Me4Si)
0.55, 31.87, 38.26, 53.08, 193.78. m/z (GLC/MS, Rt 26.2 min) 135
+
•
(
54%, M – CH3SO2), 89 (36), 43 (100).
2
Preparation of 2,4,6,7-Tetrathiaoctane 2,2-Dioxide 5
Sodium metal (34 mg, 1.47 mmol) was dissolved in methanol (10 mL)
and the solvent evaporated. The residue was dried in vacuo. DMSO
(
3 mL) was added and the resultant mixture stirred vigorously (mechan-
ical stirrer) for 5 h. During this period, the reaction mixture was open
to the atmosphere. Thereafter, 4 (0.30 g, 1.37 mmol) was dissolved in
DMSO (1 mL) and the resultant solution added to the reaction mixture.
Dimethyl disulfide (6 mL) was added, the flask stoppered and the reac-
tion gently stirred at ambient temperature for 50 h.The reaction mixture,
initially yellow, turned orange by the time the reaction was completed.
Experimental
IR spectra were recorded on a Perkin–Elmer 710B grating spectropho-
1
tometer. H NMR spectra (60 MHz) were obtained on aVarian EM360L
1
13
instrument. H NMR (270 MHz) and C NMR spectra were obtained
on a JEOL JNM-GSX 270 Fourier-transform NMR system. Unless

2
22
S. A. Bewick et al.
[3]
the atmosphere. Dimethyl disulfide (10 mL) and CH3SO2(CH2)3SAc
2
.5% Hydrochloric acid (100 mL) was added and the resultant mix-
ture extracted with diethyl ether (3 × 100 mL portions). The organic
layer was concentrated, 2.5% hydrochloric acid (100 mL) added and the
resultant mixture extracted with diethyl ether (3 × 100 mL aliquots).The
combined organic layers were dried (MgSO4), filtered, and the solvent
evaporated.
(1.0 g, 5.1 mmol) were added and the reaction mixture stirred at ambient
temperature for 2 d.
2.5% Hydrochloric acid (100 mL) was added and the resultant mix-
ture extracted with diethyl ether (3 × 100 mL aliquots). The combined
organic layers were evaporated. 2.5% Hydrochloric acid (100 mL) was
added to the residue and the resultant mixture extracted with diethyl
ether (3 × 100 mL aliquots). The combined organic layers were dried
(MgSO4), filtered, and concentrated. The residue was recrystallized
from methanol (4 mL) affording the disulfone disulfide 12 (0.488 g,
1.24 mmol, 50%). After a second recrystallization, 12 had mp 107.1–
Crude product was chromatographed on silica gel (30 g) employing
chloroform for elution (30 mL fractions). Fraction 5 was concentrated
affording the sulfone sulfide disulfide 5 (0.17 g, 8.0 mmol, 58%) as an
−1
oil. νmax/cm (liquid film) 1300, 1140. δH (270 MHz; CDCl3; Me4Si)
.51 (3H, s, CH3SS), 3.07 (3H, s, CH3SO2), 4.05 (2H, s, CH2), 4.19
2H, s, CH2). δC (68 MHz; CDCl3; Me4Si) 23.26, 38.45, 41.22, 51.49.
2
◦
−
1
(
108.3 C. The X-ray crystal structure is determined below. νmax/cm
+
•
m/z (GLC/MS, Rt 9.8 min) 218 (19%, M ), 139 (100), 93 (73).
(KBr) 1317, 1216, 1141. δH (270 MHz; CDCl3; Me4Si) 2.30 (4H, quin-
tet, CH2), 2.85 (4H, t, CH2), 2.96 (6H, s, CH3SO2), 3.18 (4H, t, CH2).
δC (68 MHz; CDCl3; Me4Si) 21.63, 36.42, 41.05, 52.81. m/z (GLC/MS)
Preparation of 2,4,6,7,9-Pentathiadecane 2,2-Dioxide 2
+
•
3
06 (17%, M ), 121 (100).
Sodium metal (0.016 g) was dissolved in methanol (5 mL). Methanethiol
(
20 mL) was slowly bubbled through the solution.The solvent was evap-
Preparation of 2,6,7-Trithiadecane 2,2-Dioxide 13
orated and the residual sodium methanethiolate dried in vacuo. DMSO
(
10 mL) was added and the resultant solution stirred for 0.5 h.
Sodium metal (20 mg) was dissolved in methanol (10 mL) and
1-propanethiol (73 mg) added. The solvent was evaporated and the
residue dried in vacuuo for 1 h. DMSO (1 mL) and di-n-propyl disulfide
(5 mL) were added. The reaction mixture was stirred at ambient temper-
ature for 1 h. The disulfone disulfide 12 (0.265 g, 0.86 mmol) was added
and the reaction mixture stirred at ambient temperature for 7 d.
2.5% Hydrochloric acid (100 mL) was added, the resultant mix-
ture extracted with diethyl ether (2 × 100 mL aliquots) and the solvent
evaporated. 2.5% Hydrochloric acid (100 mL) was added and the resul-
tant mixture extracted with diethyl ether (2 × 100 mL portions). The
combined organic layers were dried (MgSO4), filtered, and the solvent
evaporated.
A portion (0.3 mL) of the sodium thiolate solution was added to a
[
13]
(3 mL) and the
solution of 5 (0.50 g, 2.29 mmol) in (CH3SCH2S)2
reaction stirred at ambient temperature for 7 d.
The entire reaction mixture was poured onto a chromatography col-
umn (50 g silica gel in light petroleum). The column was eluted with
light petroleum (10 × 50 mL fractions). Thereafter, chloroform (50 mL
fractions) were collected. Fractions 5–14 were combined affording
unchanged (CH3SCH2S)2 (3 g). Fractions 15–17 were combined and
concentrated, furnishing dideoxydysoxysulfone 2 (0.531 g, 2.01 mmol,
8
7%).The bulk of minor contaminants were trapped on the cold finger of
◦
a sublimator (bath, 60 C, 1.3 Torr; 192 h). Recrystallization from chlo-
roform furnished 2 (mp 68–70 C) (Found: C 22.9, H 4.3. C5H12O2S5
requires C 22.7, H 4.6%). νmax/cm (KBr) 1300, 1100. δH (270 MHz;
CDCl3; Me4Si) 2.53 (3H, s, CH3SS), 3.06 (3H, s, CH3SO2), 3.94 (2H,
s, CH2), 4.08 (2H, s, CH2), 4.27 (2H, s, CH2). δC (68 MHz; CDCl3;
Me4Si) 15.21, 38.55, 42.04, 44.94, 51.44. m/z (GLC/MS, Rt 12.5 min)
◦
The crude product was chromatographed on silica gel (35 g) employ-
ing chloroform for elution (25 mL fractions). Fractions 9–12 were
combined and concentrated affording 13 as a reddish oil (78 mg,
0.34 mmol, 20%). Bulb-to-bulb distillation (0.25 Torr) furnished 13 as
a pale yellow oil (43 mg). δH (270 MHz; CDCl3; Me4Si) 1.00 (3H, t,
CH3C), 1.70 (2H, sextet, CH2), 2.30 (2H, quintet, CH2), 2.68 (2H, t,
CH2), 2.81 (2H, t, CH2), 2.94 (3H, s, CH3SO2), 3.17 (2H, t, CH2).
δC (68 MHz; CDCl3; Me4Si) 13.12, 21.65, 22.52, 36.43, 40.87, 40.93,
−
1
+
•
2
64 (5%, M ), 93 (11), 61 (100).
Fractions 18–20 were combined and concentrated affording the
[
2]
bissulfide disulfide disulfone 6 (0.021 g, 0.061 mmol, 5%). After
recrystallization from methanol, 6 had mp 125.3–125.6 C. νmax/cm
◦
−1
+•
52.96. m/z (GLC/MS) 228 (18%, M ), 121 (100), 105 (42).
(
KBr) 1228, 1126. δH (270 MHz; CDCl3; Me4Si) 3.04 (6H, s, CH3SO2),
4
4
.05(4H, s, CH2), 4.26(4H, s, CH2). δC (68 MHz;CDCl3;Me4Si)38.64,
1.74, 51.37.
Preparation of Benzyl Methyl Disulfide
Sodium metal (20 mg) was dissolved in methanol (1 mL). Benzyl thiol
(
0.1 mL) was added, the solvent evaporated and the residue dried in vac-
Preparation of 2,6,7,9-Tetrathiadecane 2,2-Dioxide 11
uuo for 45 min. DMSO (6 mL), dibenzyl disulfide (2.01 g, 8.17 mmol),
and dimethyl disulfide (12 mL) were added and the reaction mixture
stirred at ambient temperature for 48 h.
2.5% Hydrochloric acid (70 mL) was added and the resultant mix-
ture extracted with diethyl ether (3 × 50 mL portions). The combined
organic layers were concentrated. 2.5% Hydrochloric acid (70 mL) was
added and the resultant mixture washed with diethyl ether (3 × 50 mL
aliquots). The combined organic layers were dried (MgSO4), filtered,
and the solvent evaporated.The residue was rectified at reduced pressure
affording benzyl methyl disulfide (2.29 g, 13.5 mmol, 83%, bp 105–
A sodium methanthiolate/DMSO solution was prepared as described
for the preparation of 2. A portion of the sodium methanethiolate solu-
[
3]
tion (0.4 mL) was added to a solution of the sulfone disulfide 10
[
13]
(3 mL) and the reaction stirred
(
0.50 g, 2.50 mmol) in (CH3SCH2S)2
at ambient temperature for 21 d.
The entire reaction mixture was poured onto a chromatography
column (50 g silica gel in light petroleum). The column was eluted
with light petroleum (15 × 50 mL fractions), followed by chloroform
(
(
50 mL fractions). The light petroleum fractions furnished unchanged
CH3SCH2S)2. Fractions 22–27 were combined and concentrated
◦
110 C/2.5 Torr). δH (270 MHz; CDCl3; Me4Si) 2.09 (3H, s, CH3SS),
3.89 (2H, CH2), 7.32 (5H, m, Ph). m/z (GLC/MS) 170 (19%, M ),
91 (100).
+
•
affording the sulfone sulfide disulfide 11 (0.62 g, 2.50 mmol, 100%).
◦
Recrystallization frommethanolgave 11 (mp 56–58 C). (Found:C29.5,
−
1
H 6.0. C6H14O2S4 requires C 29.2, H 5.7%). νmax/cm (KBr) 1317,
214, 1141. δH (270 MHz; CDCl3; Me4Si) 2.23 (3H, s, CH3S), 2.30
2H, quintet, CH2), 2.93 (2H, t, CH2), 2.95 (3H, s, CH3SO2), 3.18 (2H,
t, CH2), 3.84 (2H, s, CH2). δC (68 MHz; CDCl3; Me4Si) 15.30, 21.72,
1
(
Reaction of Unsymmetrical Disulfides with m-CPBA
Unsymmetrical disulfides 2, 11, 13, and benzyl methyl disulfide were
separately treated with m-CPBA as outlined below for 11.
+
•
3
6.80, 40.90, 44.84, 52.81. m/z (GLC/MS, Rt 12.0 min) 246 (5%, M ),
5
0% m-CPBA (0.255 g) was covered with THF (8 mL) and water
7
9 (5), 61 (100).
(
2 mL) and the reaction mixture stirred briefly.The sulfone sulfide disul-
fide 11 (99 mg, 0.4 mmol) was added and the reaction mixture stirred at
ambient temperature for 7 d.
Preparation of 2,6,7,11-Tetrathiadodecane 2,2,11,11-Tetroxide 12
Sodium metal (0.12 g) was dissolved in methanol (10 mL), the sol-
vent evaporated and the residue dried in vacuuo. DMSO (3.5 mL) was
added and the resultant mixture stirred vigorously with a mechani-
cal stirrer for 5 h. During this time, the reaction mixture was open to
TheTHF was evaporated and chloroform (200 mL) added.The resul-
tant mixture was extracted with 2.5% w/v sodium hydroxide (2 × 50 mL
aliquots). The combined aqueous layers were back-extracted with chlo-
roform (50 mL). The combined organic layers were dried (MgSO4),

The S2 Oxygen Atoms and Fungitoxicity of Dysoxysulfone
223
filtered, and concentrated, affording crude product (62 mg). Both 1H
density was 0.86 e Å .This and several other peaks in the residual map
appear to correspond to the S atoms in an alternative orientation of the
molecule in the unit cell.
−3
1
3
and C NMR showed that dominant peaks matched appropriate che-
mical shifts for the disulfone disulfide 12. GLC/MS established that the
crude contained 12 (0.036 g, 58%). Recrystallization furnished 12 with
◦
mp 107.0–108.2 C.
Acknowledgments
Oxidation of the unsymmetrical disulfides gave symmetrical disul-
fides (% yield): 2 furnished 6 (50%); 11 furnished 12 (58%); 13 fur-
nished 12 (17%); benzyl methyl disulfide furnished dimethyl disulfide
The authors acknowledge technical assistance from
13
1
M. Marchand and D. Ryan. The C and 270 MHz H NMR
spectra were obtained by D. Durant, and the mass spectra by
R. Smith.
(
0%) and dibenzyl disulfide (0.1%).
Crystallography
A small single crystal was selected and mounted on a Bruker Proteum-R
single-crystal diffractometer (SMART 6000 CCD area detector on a
MacScience rotating-anode generator). Data were collected at 25 C
References
◦
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using CuKα radiation generated 50 kV, 90 mA, and monochromated
by Osmic ‘blue’ optics. Data were collected using the Proteum pro-
gram suite; images were processed using SAINT and scaled and
absorption-corrected using SADABS.
The data consisted of four sets of 600 images, the crystal being
reoriented between sets to maximize coverage of reciprocal space. Each
◦
◦
image is a 0.3 ω-scan. Sets 1 and 2 (detector setting 90 2θ) were
◦
collected for 20 s per image, set 3 (35 2θ) for 15 s per image, and set 4
0 2θ) for 10 s.
◦
(
Examination of the diffraction pattern revealed that the lattice was
monoclinic, with systematic absences consistent with the space group
P21 or P21/m. Refinement of the unit cell resulted in the parameters:
◦
a 4.85(8), b 29.97(45), c 5.38(7) Å; β 112.7(5) . The relatively large
uncertainty in the cell parameters is ascribed to the poor crystallinity
of the sample. The reflections were integrated from the scaled set of
images, resulting in a dataset consisting of 1685 reflections in the range
−
3 < h < 4, −23 < k < 29, −5 < l < 5, corresponding to a resolution
limit of ∼1 Å. Rint = 0.031 for the 1067 unique reflections.
Examination of intensity statistics strongly suggested that P21 was
the proper choice of space group and the structure was solved in that
space group using SHELXS. Due to the relatively small number of data,
the structural refinement (using SHELXL) was highly restrained. All
hydrogen atoms were forced to adopt ideal geometry and correspond-
ing bond lengths and bond angles in the two halves of the molecule were
restrained to the same value. The crystal was found to be twinned and
the twin proportion was refined to 0.27(9). The final refinement statis-
tics were: wR2 0.19, R1 0.071, S 1.11. The maximum residual electron
[12] H. O. Fong,W. R. Hardstaff, D. G. Kay, R. F. Langler, R. G. Morse,
D. N. Sandoval, Can. J. Chem. 1979, 57, 1206.
[13] P. Dubs, R. Stuessi, Helv. Chim. Acta 1978, 61, 2351.
doi:10.1002/HLCA.19780610708