Unsymmetrical Organotrisulfide Formation via Low-Temperature Disulfanyl Anion Transfer to an Organothiosulfonate

Article abstract of DOI:10.1021/acs.joc.8b03262

New methodology is presented for the formation of unsymmetrical organotrisulfides in a high yield and purity, relatively free of polysulfide byproducts. The highlight of the method is the low-temperature (-78 °C) deprotection of a disulfanyl acetate with sodium methoxide in THF to form a disulfanyl anion, which reacts rapidly in situ with an organothiosulfonate (S-aryl or S-alkyl) within 30 seconds followed by quenching. The discovery of these new reaction conditions together with the relative greenness of the chemistry overall makes for an efficient protocol, from which a range of organotrisulfides covering aliphatic, aromatic, as well as cysteine and sugar groups can be accessed in a high yield and purity.

Full text of DOI:10.1021/acs.joc.8b03262

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Article
Unsymmetrical Organotrisulfide Formation via Low Temperature
Disulfanyl Anion Transfer to an Organothiosulfonate
Doaa Ali, Roger Hunter, Catherine H. Kaschula, Stephen De Doncker, and Sophie C. M. Rees-Jones
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03262 • Publication Date (Web): 02 Feb 2019
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Unsymmetrical Organotrisulfide Formation via Low Temperature
Disulfanyl Anion Transfer to an Organothiosulfonate
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Doaa Ali,a Roger Hunter,*,a Catherine H. Kaschula,b Stephen De Doncker,a and Sophie C. M.
Rees-Jonesa
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aDepartment of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
bDepartment of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, 7600 South Africa
TOC
NHBoc
STs
1.2 eq
NHBoc
S
(a), (b)
S
EtO2C
1.0 eq
EtO2C
S
+
SSAc
96% yield, 98% purity
(a) THF, -78 °C; (b) NaOMe (1M in MeOH), 1 eq, 30 secs
ABSTRACT: New methodology is presented for formation of unsymmetrical
organotrisulfides in high yield and purity, relatively free of polysulfide by-products. The
highlight of the method is the low temperature (-78 °C) deprotection of a disulfanyl acetate
with sodium methoxide in THF to form a disulfanyl anion, which reacts rapidly in situ with
an organothiosulfonate (S-aryl or S-alkyl) within thirty seconds followed by quenching. The
discovery of these new reaction conditions, together with the relative greenness of the
chemistry overall makes for an efficient protocol, from which a range of organotrisulfides
covering aliphatic, aromatic as well as cysteine and sugar groups can be accessed in high
yield and purity.
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INTRODUCTION
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As with their disulfide1 counterparts, organotrisulfides are well represented in Nature,
appearing as protective agents in a range of natural products2 such as the varacins,3 the
epipolythiodiketopiperazine alkaloids4 and the ene-diyne antibiotics5 such as the
shishijimicins,6 esperamicin7 and calicheamicin,8 as well as protein trisulfides.9 Undoubtedly
the most prevalent natural source of organotrisulfides is to be found in the Alliaceae family10
of which garlic is a key member.11 A much more recent discovery is their application as high-
energy catholytes for rechargeable lithium ion batteries.12 Aliphatic organotrisulfides are
generally quite stable in both aqueous and biological systems, and diallyl trisulfide (DATS)
from garlic has been shown to be involved with glutathione redox-exchange reactions13 that
generate the relatively recently discovered gasotransmitter hydrogen sulfide,14 which itself is
involved in signal transduction in vivo. Importantly, it has been found15 that while
endogenous hydrogen sulfide is cancer-cell protective, exogenously generated hydrogen
sulfide from an external organotrisulfide such as diallyl trisulfide (DATS) exerts the opposite
effect as cytotoxic, and this discovery has created a lot of interest in developing synthetic
organotrisulfides as potential anti-cancer agents (DATS),16 as well as antibacterial agents.17
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Regarding synthesis methodology for producing symmetrical organotrisulfides, most18 of the
methods have focused on carrying out a double substitution on the central organotrisulfide
sulfur, with the latter represented as either a nucleophilic metal sulfide reacting with a
suitable electrophilic partner, eg Bunte salts19 or thiosulfonates,20 or as an electrophilic one of
the type (Lg)2S, where Lg is Cl,21 imidazole22 or phthalimido23 reacting with a suitable
nucleophilic partner as either the thiol or an appropriately activated surrogate such as
(TMS)2S (with a thiosulfinate).24 Base-mediated treatment of a sulfenylthiocarbonate
producing a disulfanyl anion has also been reported for symmetrical organotrisulfide
production.25 However, none of these approaches are suitable for producing unsymmetrical
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organotrisulfides efficiently, since either they produce a fair degree of symmetrical trisulfide
as a by-product that is difficult to remove chromatographically, or they are geared towards
formation of the symmetrical organotrisulfide exclusively. By comparison, effective methods
reported for producing unsymmetrical trisulfides rely on prepreparing a disulfanyl derivative
and reacting accordingly, Scheme 1.
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R1SSPg
promoter
R1SH
RSSSR1
RSLg
RSSLg
promoter
Lg promotor
Lg
Pg promotor
Jiang32: OMe B(C6F5)3
Ts None
Xian27
:
imide Fm DBU
Xu31
:
O
P
S
Witt26a
:
MeO , 0 °C
Ac
Ac
O
This work:
Ts
MeO , -78 °C
Scheme 1. A Summary of Recent Methods for Unsymmetrical Trisulfide Synthesis
Hence, for the nucleophilic variants of this approach, while Witt and coworkers have
demonstrated26a that a hydrodisulfide RSSH26 can be generated from the corresponding
disulfanyl acetate using methoxide ion and reacted in situ cleanly with a sulfenyl derivative
bearing a phosphorodithioate leaving group, Xian has shown27 that 9-fluorenylmethyl
disulfides under base-mediated elimination conditions (DBU) at room temperature can also
act as suitable surrogates for hydrodisulfide production for reaction with sulfenylimides to
afford organotrisulfides. Working things the other way round via a RSSLg species enjoys the
advantage of being able to use a thiol as the nucleophile, in which several leaving groups
have been explored for the electrophilic disulfanyl partner including from the older literature
thiocarbonate,28 phthalimido,29 and chloride.30 In much more recent research though, both
t
tosylate31 (only -butyl was used as the R group of the RSSTs though) and methoxy32 as
leaving groups have been reported, the latter using tris(perfluorophenylborane) as a catalytic
activator in which significant scope in the product range was demonstrated. However,
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sulfenylthiotosylates (RSSTs) have been shown generally to be unstable and extrude S in
polar solvents.33
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Although the synthesis options for producing unsymmetrical organotrisulfides have
significantly improved in recent times, a number of challenges still exist regarding target
scope, product purity and the relative greenness of the method. Notably, the more recent
methods illustrated in Scheme 126a,27,31,32 still either use harsh reagents (Br2, SOCl2)26a,31 to
prepare sulfenyl halide intermediates, are limited in scope,31 involve long exchange
sequences to arrive at the precursor for coupling,27 or involve additional catalysts to promote
coupling.32 Furthermore, none of those methodologies just mentioned have satisfactorily
demonstrated an efficiency for producing aromatic-aromatic trisulfides as the most difficult
class of the group. In this paper we demonstrate a novel, extremely straightforward-to-use
and relatively green-efficient methodology that allows access to all three general classes of
aliphatic-aliphatic, aliphatic-aromatic and aromatic-aromatic products including some
cysteine and sugar trisulfides.
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RESULTS AND DISCUSSION
From the outset, we were intent on developing a disulfanyl transfer agent that met the above
reaction efficiency criteria, in which we eventually opted for a nucleophilic disulfanyl anion
with a thiosulfonate as the electrophilic source, for which, somewhat surprisingly, there were
no literature examples. As an S1 electrophilic source, thiosulfonates have excellent handling
characteristics as well as a facile green access via alkyl halide substitution with commercially
available sodium thiotosylate34 or from a disulfide with iodine and sodium benzenesulfinate,35
both methods avoiding the use of a toxic halogenating agent. The nucleophilic S2 partner was
chosen as an organohydrodisulfide (RSSH), which we appreciated posed a more difficult
challenge regarding its generation.26b Current literature suggests that the role of this
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interesting species is still not fully understood in biological systems, although the general
consensus is that in the form of Cys-SSH it likely provides a storage species or surrogate for
H2S as a gasobiotransmitter.36 For generation of RSSH as a synthesis reagent in solution, a
proven and convenient precursor is undoubtedly the corresponding disulfanyl acetate RSSAc,
which can be deprotected in either acid or base media. However, according to current
literature36 neither medium is ideal; RSSH is relatively stable in acid,36a,37 deprotection is
slow,37 while in basic medium the opposite is true in which S0 extrusion to form the thiolate
occurs,36a, which in the present context would lead to disulfide products. However, the fact
that disulfanyl acetates can be easily accessed from thiosulfonates via reaction with
potassium thioacetate (KSAc) in DCM,38 ultimately persuaded us that investing time and
effort into improving on the troublesome base-promoted deprotection conditions was
warranted. Our quest to achieve this was given a boost by taking note of the somewhat
intriguing findings reported by Witt26a in his sulfenylphosphorodithioate methodology
(Scheme 1), in which he showed good aliphatic-aliphatic unsymmetrical trisulfide outcomes
using 2 equivalents of sodium methoxide in methanol to deprotect his RSSAc in situ at 0 °C
degrees in MeOH as solvent. This set us thinking about fine tuning these conditions for
carrying out a one-pot reaction for our case by also adding the methoxide last, in the
anticipation that the hardness of the methoxide as well as the greater stability of the
disulfanyl anion (as leaving group) over that of the thiolate (from the thiosulfonate) would
result in chemoselective substitution (SNAc) and deprotection of the acetate over that of the
thiosulfonate. A model reaction was carried out between AllylSTs 1a and n-HexSSAc 2b, the
latter chosen in view of its easy access via substitution of the corresponding thiosulfonate (1
equiv) with potassium thioacetate (1.3 equiv) in DCM.38 As representative of an aliphatic
disulfanyl acetate, 2b was perfectly stable towards silica gel chromatography and subsequent
handling. In the event (see Table 2 for a complete numbering set), we were overjoyed to find
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that adding the methoxide as a 1M solution in methanol to a mixture of the two reactants at -
78 °C in THF gave the desired result. Furthermore, interestingly, experiments carried out to
establish both the optimal stoichiometry of reactants as well as the minimum reaction time for
minimising potential exchange reactions leading to polysulfides revealed that a ratio of
thiosulfonate to disulfanyl acetate of 1.2:1 together with a time of only thirty seconds after
methoxide addition (with moderate stirring) with 1 eq. of methoxide achieved full conversion
(TLC; entry 3 in Table 1) to afford the organotrisulfide cleanly, after which the reaction was
quenched with aqueous ammonium chloride. Following chromatography the desired trisulfide
product was obtained in excellent yield and purity (HPLC) in each run. The product
(allylSSSn-hex), as a typical representative of this class of organotrisulfide, was completely
stable towards chromatography and leaving out on the bench for a few days, as well as the
recording of NMR spectra in CDCl3. Each set of conditions gave a single clean and less polar
spot on the TLC plate, with no indication of a by-product, even leaving for a relatively longer
reaction time (entries 2 and 4), as reflected in the yields (Table 1). By comparison, using the
thiosulfonate as limiting reagent with a slight excess of the disulfanyl acetate gave more by-
products, presumably due to subsequent exchange reactions involving the excess nucleophilic
disulfanyl anion. Interestingly, full conversion could be achieved with less than a
stoichiometric amount of methoxide promotor (entries 2 and 4 in Table 1), suggesting that the
sulfinate leaving group from the S-S coupling can also exert a level of acetyl deprotection,
Table 1.
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Table 1: Optimised Conditions for Trisulfide Model Reaction
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(a) THF, -78 °C
AllylSSSn-Hex
n-HexSSAc
AllylSSO2Tol +
(b) NaOMe (1M in MeOH)
1a
2b
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Entry Eq. 1a Eq. 2b Eq. NaOMe Time
Yield %a Purity %b
1
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4
1.5
1.5
1.2
1.2
1
1
1
1
1
30 sec
5 min
30 sec
5 min
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0.7
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0.7
a
After column chromatography. b Measured by HPLC on a C18 column.
With a set of model conditions in hand we next set about applying them to synthesizing the
three different classes of trisulfide mentioned previously as aliphatic-aliphatic, aliphatic-
aromatic and aromatic-aromatic. The results are shown in Table 2 for organotrisulfide
products 3a-m.
Table 2. Synthesis of Unsymmetrical Trisulfides 3a-3m
(a) THF, -78 °C
+
RSSSR1
RSSO2Tol
R1SSAc
(b) NaOMe (1M in MeOH),
1 eq, 30 secs
2
(1.0 eq)
1
(1.2 eq)
Entry
1
R
R1
RSSSR1
Yield Purity
(%)a
(%)b
S
Allyl, 1a
n-Pr, 2a
95
96
S
S
3a
S
2
-(CH2)3OH, 1b
n-Hex, 2b
90
98
HO
S
S
3b
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n-Dodec, 1c
Propargyl,
S
52
96
96
98
S
S
9
2c
3c
NHBoc
NHBoc
S
Allyl, 2d
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S
EtO2C
EtO2C
S
1d
3d
Allyl, 2d
S
S
OBn
OBn
O
S
BnO
5
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89
O
BnO
BnO
BnO
1e OMe
3e
OMe
S
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Bn, 1f
Ph, 1g
n-Hex, 2b
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3f
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S
n-Dodec, 2e
S
9
3g
S
S
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9
p-FC6H4, 1h
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S
p-MeOC6H4, 1i
Allyl, 2d
S
3i
MeO
O
NHBoc
HN
O
10
p-Tolyl, 2f
p-Tolyl, 2f
70
87
EtO2C
O
S
S
1d
S
S
O
3j
S
S
11
12
p-FC6H4, 1h
89
64
60c
78
S
3k
F
S
S
Ph, 1g
p-MeOC6H4,
S
2g
3l
OMe
OMe
S
13
p-FC6H4, 1h
p-MeOC6H4,
81
91
S
2g
3m
F
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b
c
aAfter column chromatography. Measured by HPLC on a C18 column. 92% after
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preparative chromatography.
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The organotrisulfide R groups were varied in terms of lipophilicity, functionality and
substitution on the aromatic ring. The thiosulfonate reactants RSSO2Tol 1 with R as an
aliphatic group could be accessed in a routine fashion using nucleophilic substitution of RBr
with commercially available sodium p-tolylthiosulfonate;34 for aromatic counterparts,
reaction of the corresponding homodisulfide with iodine and sodium p-tolylsulfinate was
used.35 A bonus of the methodology was that the disulfanyl acetates 2 could be accessed from
their corresponding thiosulfonates 1 via reaction with potassium thioacetate in DCM.38
Gratifyingly, the model reaction time of 30 secs held throughout in each case, and products
were stable following column chromatography. All of the trisulfides except 3g (1-dodecyl-3-
phenyltrisulfane) were new compounds and were fully characterised by NMR and IR
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spectroscopy, HPLC (C18 column) and HRMS. H NMR spectroscopy for products
containing an alkyl R group could be used to corroborate trisulfide formation (from disulfide)
by virtue of the downfield shift of the methylene adjacent to S compared to that of the
disulfide (~0.2 ppm to around 2.8 ppm).26a For the aliphatic-aliphatic group (entries 1-6), the
choice of which R group presented as thiotosylate and which as disulfanyl acetate was
arbitrary, and the trisulfide yields were generally excellent and above 85%, except for the
propargylic trisulfide 3c (52%) and the protected mannose trisulfide 3e (66%). Similarly,
their purities, as ascertained by HPLC, were also excellent (above 96%) except for the sugar
case 3e (89%). For the cysteine case (3d), coupling only worked having the amino acid as its
thiotosylate, while the mannose case 3e also had the sugar moiety as a thiotosylate but only
because this was the easier way round to achieve synthetically. This class of organotrisulfide
proved to be very stable even towards leaving on the bench for a few days. Moving to the
aliphatic-aromatic group (entries 7-10), the aromatic partner was always presented as a
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thiotosylate in view of the propensity of aromatic disulfanyl anions to extrude sulfur to form
the corresponding thiolate ion,36a as well as the superior stability (for isolation) of the
thiotosylate over the corresponding aromatic disulfanyl acetate. Yields in this series dropped
down a little to around 60-70%, while purities remained in the 90s except for the cysteine
derivative 3j (87%). Synthesis of 2-(tert-butyltrisulfanyl)pyridine (with 2-pyrido and t-butyl
as the two R groups) was successful and the compound could be chromatographed, but it
proved to be unstable in solution when recording the NMR spectra, presumably due to S-S
exchange reactions promoted through the pyridine lone pair. Generally, though, this class of
organotrisulfide, though less stable than aliphatic-aliphatic variants, proved also to be quite
stable for a day or so on the bench after chromatography. Finally, for the aromatic-aromatic
trisulfide group (entries 11-13), firstly it should be mentioned that these are hardly ever
mentioned in the literature, presumably in view of their propensity to undergo S-S exchange
reactions; testimony to this was that the three cases 3k-3m are all new compounds, in spite of
their relatively simple substitution patterns. Importantly, one of the reactants now had to be
presented as an aromatic disulfanyl acetate, in which once again S-substitution of the
corresponding thiotosylate with potassium thiotosylate in DCM was used, rather than the
older and less green method involving reaction of an aromatic thiol with acetyl sulfenyl
chloride.37 In this case, the appropriate aromatic thiotosylate was accessed using reaction of
the corresponding homodisulfide with iodine and p-tolylsulfinate.35 Importantly, though,
compared to the aliphatic cases (rt required), reactions between the thiotosylate and KSAc
were much quicker in the aromatic series but needed to be carried out at -40 °C in order to
achieve a clean conversion (by TLC). However, unlike the aliphatic cases, the aromatic
disulfanyl acetates (2f and 2g) were unstable on silica gel, and instead were used crude
following the filtration of residual acetate and thiotosylate salts followed by solvent
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evaporation. Importantly, it was pleasing to note that H NMR spectroscopic analysis of the
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crude aromatic disulfanyl acetate products showed a very high product purity, with no
residual acetate or thiotosylate resonances. Once synthesized, these products were used as
soon as possible. Looking at the reaction results from Table 2 (entries 11-13), while yields of
organotrisulfides 3k-3m were on a par with the aliphatic-aromatic group, purities were
generally lower (60-91%), which was attributed to their higher reactivity towards S-S
exchange reactions. These aromatic organotrisulfides (3k-3m) were stable towards work-up
and chromatography. Aromatic rings bearing an electron-withdrawing group (eg entry 13
with p-fluorophenyl to give 3m) needed to be reacted as their thiotosylates and not as
disulfanyl acetates, in which expulsion of sulfur to afford a stabilised aromatic thiolate anion
emerged as a problem. In this regard, all attempts to prepare pyridine-containing
heteroaromatic-aromatic organotrisulfides failed, even using the pyridine moiety as its
thiotosylate, again presumably due to the extremely high reactivity towards S-S exchange
reactions in the reaction medium Aromatic-aromatic organotrisulfides 3k-3m were relatively
labile and needed to be kept in the refrigerator at -20 °C following chromatographic
purification.
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CONCLUSION
In summary, we have developed a new method for producing various classes of
organotrisulfides in high yield and purity involving low temperature sulfenylation of a
disulfanyl anion by an organothiotosylate. Particularly pleasing is that the method holds up to
a fair degree of yield and purity for aromatic-aromatic variants, which have been under-
represented in other studies. The method is extremely straightforward to carry out and uses
inexpensive chemicals. Furthermore, the discovery of low temperature generation and usage
of the disulfanyl anion RSS-, in which R can be varied broadly, opens up the way for
application of this important biosynthon synthetically. Future Chemical Biology studies
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towards studying the mode of action of trisulfides in cancer cells will no doubt benefit from
the results reported herein from the aliphatic-aliphatic and aromatic-aliphatic classes.
.
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EXPERIMENTAL SECTION
Unless otherwise specified, all reagents were purchased from commercial sources and used
without further purification. THF was freshly distilled over sodium wire and benzophenone.
Reactions were carried out in oven-dried glassware with a magnetic stirrer, and performed
under a nitrogen atmosphere unless otherwise stated. The low temperature (-78 °C) of the
trisulfide reactions was achieved with acetone/liquid nitrogen mixtures in a low temperature
1
13
bath. Aqueous solutions were prepared using deionized water. H NMR and C{H} NMR
spectra were recorded on a Bruker 300 MHz (1H, 300 MHz; 13C, 75.5 MHz) or a Bruker 400
13
MHz (1H, 400 MHz; C, 101 MHz) instrument. All spectral data were acquired at 295 K.
Chemical shifts are reported in parts per million (ppm, δ), downfield from tetramethylsilane
(TMS, δ = 0.00 ppm) and are referenced to residual solvent (CDCl3, δ = 7.26 ppm (1H) and
77.16 ppm (13C)). Coupling constants (J) are reported in Hertz (Hz). The multiplicity
abbreviations used are: br broad, s singlet, d doublet, t triplet, q quartet, m multiplet. Infrared
(IR) spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR Spectrometer. High-
resolution mass-spectra were obtained from the University of Stellenbosch Mass
Spectrometry Service and recorded in electrospray positive mode (ES+) or atmospheric solids
analysis probe (ASAP+) with a time-of-flight analyser system on a Waters Synapt G2
machine. Thin layer chromatography was carried out on Merck silica gel 60F254 pre-coated
aluminium foil sheets and were visualised using UV light (254 nm), while non-UV active
compounds were sprayed with a 2.5% solution of p-anisaldehyde in a mixture of sulfuric acid
and ethanol (1:10 v/v), iodine vapour, or ceric ammonium sulfate solution and then heated.
Column chromatography was carried out using silica gel 60 (Merck 7734), eluting with the
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specified solvent system. Optical rotations were measured at 20 °C and are reported as
[α]퐷
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7
8
(c g/ml, solvent). The determination of melting points was carried out using a hot-stage
microscope (HSM) and are uncorrected. HPLC analyses were carried out with a C18 reverse-
phase column.
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General Procedure for Synthesis of Thiotosylates 1a-i.
Aliphatic thiosulfonates 1a,39 1b,40 1c,41 1e and 1f42 were all prepared from the
corresponding alkyl bromide or iodide by substitution with sodium 4-
methylbenzenesulfonothioate in acetonitrile at room temperature according to literature
procedures.34 Aromatic thiosulfonates 1g,43 1h and 1i,44 as well as 1d were all prepared from
the corresponding disulfide and sodium p-tolylsulfinate and iodine, also according to a
literature procedure.35
(R)-Ethyl 2-((tert-butoxycarbonyl)amino)-3-(tosylthio)propanoate, (1d), (86.0 mg, 88%):
mp 52–54 °C;
20 = -2.5 (c = 1.0, CHCl3); IR (νmax/cm−1) 3363, 1735, 1695; 1H NMR (300
[α]퐷
MHz, CDCl3) δ 7.80 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 5.30 (br s, 1H), 4.51 (m,
1H), 4.19 (q, J = 7.2 Hz, 2H), 3.57–3.32 (m, 2H), 2.44 (s, 3H), 1.43 (s, 9H), 1.26 (t, J = 7.2
Hz, 3H); 13C{H} NMR (101 MHz, CDCl3) δ 169.8, 155.1, 145.2, 141.9, 130.1, 127.3, 80.6,
62.3, 53.1, 37.9, 28.4, 21.8, 14.2; HRMS (ESI+) m/z [M + H]+ calcd for C17H26NO6S2
404.1202, found 404.1207.
Prepared from the corresponding tribenzyl-protected -methylmannopyranoside,45 S-
(((2S,3S,4S,5S,6S)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl) methyl) 4-
[α]2퐷0
methylbenzenesulfonothioate (1e), (30.0 mg, 73%):
= +66.3 (c = 1.0, CHCl3); IR
1
(νmax/cm−1) 1138, 698; H NMR (300 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H), 7.41–7.27
(m, 15H), 7.18 (d, J = 8.3 Hz, 2H), 4.94 (d, J = 11.1 Hz, 1H), 4.75–4.50 (m, 6H), 3.85–3.64
13
(m, 4H), 3.49–3.40 (m, 1H), 3.21 (s, 3H), 3.15–3.05 (m, 1H), 2.39 (s, 3H); C{H} NMR
(101 MHz, CDCl3) δ 144.6, 142.1, 138.4, 138.4, 138.3, 129.8, 128.5, 128.5, 128.5, 128.5,
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128.2, 128.0, 127.9, 127.8, 127.8, 127.4, 99.1, 80.2, 77.6, 75.2, 74.8, 73.1, 72.3, 70.5, 55.0,
38.3, 21.7; HRMS (ESI+) m/z [M + H]+ calcd for C35H39O7S2 635.2137, found 635.2130.
General Procedure for Synthesis of Disulfanyl Acetates 2a-g.
Disulfanyl acetates 2a,46 2b38 2c, 2d,46 2e,26a 2f,37 2g,37 were all synthesized by reaction of
the corresponding thiosulfonate (1 equiv) with potassium thioacetate (1.3 equiv) in DCM at rt
for a few hours for aliphatic cases, and -40 °C for aromatic variants, the method modelled on
a recent literature procedure.38 Here, the thiotosylate was always used as the limiting reagent
and checked for total consumption (by TLC). While the aliphatic variants could be column
chromatographed, the aromatic ones needed to be used as crude, in both cases following the
filtration of salts and the evaporation of solvent.
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1-(prop-2-yn-1-ylsulfinothioyl)ethanone (2c), (131.0 mg, 81%): IR (νmax/cm−1) 3287, 1727;
1H NMR (300 MHz, CDCl3) δ 3.48 (d, J = 2.7 Hz, 2H), 2.49 (s, 3H), 2.30 (t, J = 2.7 Hz, 1H);
13C{H} NMR (101 MHz, CDCl3) δ 194.2, 78.4, 73.1, 29.0, 26.8; HRMS (ASAP+) m/z [M +
H]+ calcd for C5H7OS2 146.9938, found 146.9943.
General Procedure for Synthesis of Unsymmetrical Trisulfides 3a-3m.
The thiosulfonate 1 (1.2 eq) and disulfanyl acetate (1.0 eq) were taken up in THF (0.1-0.2 M)
under N2 and cooled to -78 °C for 10 minutes. Sodium methoxide (1 M, 1.0 eq) was added
slowly dropwise via syringe (10-20 sec) and the resultant solution stirred rapidly for 30 sec
following the methoxide addition. The reaction was then quenched with saturated aqueous
ammonium chloride (5 mL), and the product extracted into EtOAc (3 x 10 mL). Following
drying (MgSO4) and evaporation of solvent, the residue was purified via silica column
chromatography using Hexane as eluent for all organotrisulfides (except 3b, 3d, 3e and 3j, in
which case up to 10% EtOAc in Hexane was used), to afford organotrisulfides 3a-3m.
1-Allyl-3-propyltrisulfane, (3a). From 1a (127.8 mg, 0.560 mmol) and 2a (70.0 mg, 0.467
mmol) in THF (3 mL) and sodium methoxide (0.47 mL, 1M, 0.47 mmol) to afford trisulfide
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3a (80.0 mg, 95 %) as an oil. IR (νmax/cm−1) 722, 476; H NMR (300 MHz, CDCl3) δ 5.93–
5
6
5.83 (m, 1H), 5.26–5.18 (m, 2H), 3.51 (d, J = 7.2 Hz, 2H), 2.86 (t, J = 7.2 Hz, 2H), 1.85–1.72
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(m, 2H), 1.02 (t, J = 7.2 Hz, 3H); C{H} NMR (101 MHz, CDCl3) δ 133.0, 119.1, 41.7,
41.2, 22.3, 13.3; HRMS (ASAP+) m/z [M + H]+ calcd for C6H13S3 181.0179, found 181.0186.
3-(Hexyltrisulfanyl)propan-1-ol, (3b). From 1b (119.0 mg, 0.484 mmol and disulfanyl
acetate 2b (77.0 mg, 0.400 mmol) in THF (3 mL) and sodium methoxide (0.4 mL, 1M, 0.40
mmol) to afford trisulfide 3b (86.0 mg, 90%) as a colourless oil. IR (νmax/cm−1) 3325, 788,
475; 1H NMR (300 MHz, CDCl3 δ 3.78 (t, J = 6.2 Hz, 2H), 3.00 (t, J = 7.1 Hz, 2H), 2.88 (t,
J = 7.4 Hz, 2H), 2.07–1.96 (m, 2H), 1.78–1.68 (m, 2H), 1.54 (s, OH, 1H), 1.47–1.28 (m, 6H),
0.89 (t, J = 6.9 Hz, 3H); 13C{H} NMR (101 MHz, CDCl3) δ 61.1, 39.1, 35.4, 31.6, 31.5, 28.9,
28.3, 22.6, 14.1; HRMS (ASAP+) m/z [M]+ calcd for C9H20OS3 240.0676, found 240.0677.
1-Dodecyl-3-(prop-2-yn-1-yl)trisulfane (3c). From thiotosylate 1c (107.0 mg, 0.300 mmol)
and disulfanyl acetate 2c (37.0 mg, 0.253 mmol) in THF (2 mL) and sodium methoxide (0.25
mL, 1M, 0.25 mmol) to afford trisulfide 3c (40.0 mg, 52%) as a colourless oil. IR (νmax/cm−1)
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635, 477; H NMR (300 MHz, CDCl3) δ 3.62 (d, J = 2.7 Hz, 2H), 2.91 (t, J = 7.4 Hz, 2H),
2.33 (d, J = 2.7 Hz, 1H), 1.80–1.68 (m, 2H), 1.45–1.23 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H);
13C{H} NMR (101 MHz, CDCl3) δ 79.1, 72.8, 39.5, 32.1, 29.8, 29.8, 29.7, 29.6, 29.5, 29.3,
29.0, 28.7, 26.8, 22.8, 14.2; HRMS (ASAP+) m/z [M + H]+ calcd for C15H29S3 305.1431,
found 305.1429.
(R)-Ethyl
3-(allyltrisulfanyl)-2-((tert-butoxycarbonyl)amino)propanoate
(3d).
From
thiosulfonate 1d (98.0 mg, 0.243 mmol) and disulfanyl acetate 2d (30.0 mg, 0.203 mmol) in
THF (2 mL) and sodium methoxide (0.20 mL, 1M, 0.20 mmol, 1 eq) to afford trisulfide 3d
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[훼]퐷
(69.0 mg, 96%) as a colourless oil.
= +98.3 (c = 1.0, CHCl3); IR (νmax/cm−1) 635, 477;
1H NMR (300 MHz, CDCl3) δ 5.96–5.80 (m, 1H), 5.38 (br s, 1H), 5.29–5.18 (m, 2H), 4.64
(m, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.50 (d, J = 7.2 Hz, 2H), 3.42–3.25 (m, 2H), 1.45 (s, 9H),
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1.30 (t, J = 7.1 Hz, 3H); 13C{H} NMR (101 MHz, CDCl3) δ 170.6, 155.2, 132.7, 119.5, 80.4,
62.0, 53.2, 41.7, 41.5, 28.5, 14.3; HRMS (ESI+) m/z [M + H]+ calcd for C13H24NO4S3
354.0867, found 354.0869.
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(2S, 3S, 4S, 5S, 6S)-2-((allyltrisulfanyl)methyl)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-
2H-pyran (3e). From thiosulfonate 1e (130.0 mg, 0.205 mmol) and disulfanyl acetate 2d (25
mg, 0.169 mmol) in THF (4 mL) and sodium methoxide (0.17 mL, 1M, 0.17 mmol) to afford
[α]2퐷0
trisulfide 3e (65.0 mg, 66%) as a colourless thick oily liquid.
= +138.9 (c = 1.0,
1
CHCl3); IR (νmax/cm−1) 477; H NMR (300 MHz, CDCl3) δ 7.40–7.27 (m, 15H), 5.94–5.78
(m, 1H), 5.25–5.14 (m, 2H), 4.97 (d, J = 10.8 Hz, 1H), 4.75–4.60 (m, 6H), 3.94–3.75 (m,
4H), 3.49 (d, J = 7.2 Hz, 2H), 3.42 (dd, J =13.4 , 2.1 Hz, 1H), 3.34 (s, 3H), 3.07 (dd, J =
13.4, 9.0 Hz, 1H); 13C{H} NMR (101 MHz, CDCl3) δ 138.6, 138.5, 138.4, 132.8, 128.6,
128.6, 128.5, 128.5, 128.1, 128.0, 127.9, 127.8, 127.8, 119.2, 99.2, 80.4, 77.9, 75.3, 75.0,
73.0, 72.4, 70.7, 55.1, 42.0, 41.7; HRMS (ESI+) m/z [M + H]+ calcd for C31H37O5S3 585.1803,
found 585.1813.
1-Benzyl-3-hexyltrisulfane (3f). From thiosulfonate 1f (86.8 mg, 0.312 mmol) and disulfanyl
acetate 2b (50.0 mg, 0.260 mmol) in THF (2 mL) and sodium methoxide (0.26 mL, 1M, 0.26
1
mmol) to afford trisulfide 3f (60.0 mg, 85%) as a colourless oil. IR (νmax/cm−1) 696, 468; H
NMR (300 MHz, CDCl3) δ 7.38–7.25 (m, 5H), 4.11 (s, 2H), 2.83 (t, J = 7.2 Hz, 2H), 1.80–
1.65 (m, 2H), 1.47–1.25 (m, 6H), 0.91 (t, J = 6.8 Hz, 3H); 13C{H} NMR (101 MHz, CDCl3) δ
136.8, 129.6, 128.8, 127.7, 43.3, 39.2, 31.5, 29.0, 28.3, 22.7, 14.1; HRMS (ASAP+) m/z [M +
H]+ calcd for C13H21S3 273.0805, found 273.0793.
1-Dodecyl-3-phenyltrisulfane (3g). From thiosulfonate 1g (184.0 mg, 0.697 mmol) and
disulfanyl acetate 2e (160.0 mg, 0.579 mmol) in THF (4 mL) and sodium methoxide (0.57
mL, 1M, 0.57 mmol) to afford trisulfide 3g26a (117.0 mg, 59%) as a yellow oil. IR (νmax/cm−1)
1
470; H NMR (300 MHz, CDCl3) δ 7.65–7.58 (m, 2H), 7.39–7.28 (m, 3H), 2.82 (t, J = 7.4
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Hz, 2H), 1.73–1.61 (m, 2H), 1.39–1.22 (s, 18H), 0.89 (t, J = 6.8 Hz, 3H); 13C{H} NMR (101
MHz, CDCl3) δ 137.4, 130.4, 129.2, 128.3, 39.2, 32.1, 29.8, 29.8, 29.7, 29.6, 29.5, 29.3, 29.1,
28.7, 22.8, 14.2.
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1-(4-Fluorophenyl)-3-propyltrisulfane (3h). From thiosulfonate 1h (135.4 mg, 0.480 mmol)
and disulfanyl acetate 2a (60.0 mg, 0.400 mmol) in THF (3 mL) and sodium methoxide (0.40
mL, 1M, 0.40 mmol) to afford trisulfide 3h (57.0 mg, 61%) as a yellow oil. IR (νmax/cm−1)
1
473; H NMR (300 MHz, CDCl3) δ 7.64–7.57 (m, 2H), 7.10–7.02 (m, 2H), 2.81 (t, J = 7.4
Hz, 2H), 1.80–1.65 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C{H} NMR (101 MHz, CDCl3) δ
163.3 (d, JCF = 248.5 Hz), 133.3 (d, JCF = 8.0 Hz), 132.7, 116.4, (d, JCF = 22.1 Hz), 41.4,
22.4, 13.2; HRMS (ASAP+) m/z [M]+ calcd for C9H11FS3 234.0007, found 234.0010.
1-Allyl-3-(4-methoxyphenyl) trisulfane (3i). From thiosulfonate 1i (262.0 mg, 0.891 mmol)
and disulfanyl acetate 2d (110.0 mg, 0.743 mmol) in THF (5 mL) and sodium methoxide
(0.74 mL, 1M, 0.74 mmol) to afford trisulfide 3i (116.0 mg, 64%) as a yellow oil. IR
(νmax/cm−1) 467; 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz,
2H), 5.91–5.72 (m, 1H), 5.19–5.02 (m, 2H), 3.82 (s, 3H), 3.42 (d, J = 7.2 Hz, 2H); 13C{H}
NMR (101 MHz, CDCl3) δ 160.8, 134.2, 132.7, 128.0, 119.2, 114.9, 55.5, 41.8; HRMS
(ASAP+) m/z [M + H]+ calcd for C10H13OS3 245.0129, found 245.0129.
Ethyl N-(tert-butoxycarbonyl)-S-(p-tolyldisulfaneyl)-L-cysteinate (3j). From thiosulfonate 1d
(146.0 mg, 0.362 mmol) and disulfanyl acetate 2f (60.0 mg, 0.303 mmol) in THF (2 mL) and
sodium methoxide (0.30 mL, 1M, 0.30 mmol) to afford trisulfide 3j (86.0 mg, 70%) as a
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[훼]퐷
colourless solid. mp 80-82 °C;
= +115.0 (c = 1.0, CHCl3); IR (νmax/cm−1) 3369, 1735,
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481; H NMR (300 MHz, CDCl3) δ 7.50 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 5.36
(br s, 1H), 4.59 (m, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.42–3.21 (m, 2H), 2.36 (s, 3H), 1.46 (s,
13
9H), 1.29 (t, J = 7.2 Hz, 3H); C{H} NMR (101 MHz, CDCl3) δ 170.6, 155.1, 139.2, 133.0,
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131.5, 130.1, 80.3, 62.0, 53.1, 41.4, 28.5, 21.3, 14.3; HRMS (ESI+) m/z [M + H]+ calcd for
C17H26NO4S3 404.1024, found 404.1018.
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1-(4-Fluorophenyl)-3-(p-tolyl)trisulfane (3k). From thiosulfonate 1h (51.0 mg, 0.181 mmol)
and disulfanyl acetate 2f (30.0 mg, 0.151 mmol) in THF (1 mL) and sodium methoxide (0.15
mL, 1M, 0.15 mmol) to afford trisulfide 3k (38.0 mg, 89%) as a yellow to green oil. IR
(νmax/cm−1) 502; 1H NMR (300 MHz, CDCl3) δ 7.53–7.46 (m, 2H), 7.43–7.39 (m, 2H), 7.12–
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7.07 (m, 2H), 7.00–6.93 (m, 2H), 2.35 (s, 3H); C{H} NMR (101 MHz, CDCl3) δ 163.3 (d,
J = 249.5 Hz), 139.1, 133.4, (d, J = 9.1 Hz), 133.0, 132.0, 131.3, 130.0, 116.3 (d, J = 22.1
Hz), 21.3; HRMS (ASAP+) m/z [M]+ calcd for C13H11FS3 282.0007, found 282.0011.
1-(4-Methoxyphenyl)-3-phenyltrisulfane (3l). From thiosulfonate 1g (148.0 mg, 0.561 mmol)
and disulfanyl acetate 2g (100.0 mg, 0.467 mmol) in THF (3 mL) and sodium methoxide
(0.47 mL, 1M, 0.47 mmol) to afford trisulfide 3l (84.0 mg, 64%) as a green oil. IR
(νmax/cm−1) 469; 1H NMR (300 MHz, CDCl3) δ 7.53–7.45 (m, 4H), 7.32–7.23 (m, 3H), 6.85–
6.78 (m, 2H), 3.81 (s, 3H); 13C{H} NMR (101 MHz, CDCl3) δ 160.8, 136.8, 134.4, 130.0,
129.2, 128.1, 127.4, 114.9, 55.6; HRMS (ASAP+) m/z [M]+ calcd for C13H12OS3 280.0050,
found 280.0053.
1-(4-Fluorophenyl)-3-(4-methoxyphenyl) trisulfane (3m). From thiosulfonate 1h (63.0 mg,
0.223 mmol) and disulfanyl acetate 2g (40.0 mg, 0.187 mmol) in THF (2 mL) and sodium
methoxide (0.18 mL, 1M, 0.18 mmol) to afford trisulfide 3m (45.0 mg, 81%) as a green to
1
yellow oil. IR (νmax/cm−1) 463; H NMR (300 MHz, CDCl3) δ 7.52–7.44 (m, 4H), 7.00–6.93
(m, 2H), 6.83–6.78 (m, 2H), 3.81 (s, 3H); 13C{H} NMR (101 MHz, CDCl3) δ 163.0 (d, J =
165.0 Hz), 160.8, 134.3, 132.9 (d, J = 5.0 Hz), 132.0, 127.1, 116.3 (d, J = 15.1 Hz), 114.9,
55.6; HRMS (ASAP+) m/z [M]+ calcd for C13H11FOS3 297.9956, found 297.9957.
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ASSOCIATED CONTENT
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Supporting Information
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The Supporting Information is available free of charge on the ACS Publication website at
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DOI:
1H and 13NMR spectra and HPLC traces of all compounds (PDF).
AUTHOR INFORMATION
Corresponding Author
*Fax: +27 21 650 5195. E-mail: Roger.Hunter@uct.ac.za
ORCID
Roger Hunter: 0000-0001-8775-083X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank the Third World Academy of Sciences, the South African National
Research Foundation, The Cancer Association of South Africa, and the University of Cape
Town for financial support towards this project.
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