ω-methylsulfanylalkyl glucosinolates: A general synthetic pathway

Article abstract of DOI:10.3390/molecules23040786

A general pathway was devised to synthesize ω-methylsulfanylalkyl glucosinolates, which represent an important class of structurally homogeneous plant secondary metabolites. The required thiofunctionalized hydroximoyl chlorides were obtained from the corresponding α,ω-nitroalkyl methylsulfide precursors, involving as the key-step, a nitronate chlorination strategy. A coupling reaction with 1-thio-beta-D-glucopyranose, followed by O-sulfation of the intermediate thiohydroximate and final deprotection of the sugar moiety afforded the target compounds.

Full text of DOI:10.3390/molecules23040786

molecules
Article
ω-Methylsulfanylalkyl Glucosinolates: A General
Synthetic Pathway
Manolis Mavratzotis 1, Stéphanie Cassel 1,2, Sabine Montaut 3 and Patrick Rollin 1,
*
ID
1
Institut de Chimie Organique et Analytique (ICOA), Université d’Orléans et CNRS, UMR 7311, BP 6759,
F-45067 Orléans CEDEX 2, France; mavratzotis.manolis@gr.sika.com (M.M.); cassel@chimie.ups-tlse.fr (S.C.)
Laboratoire IMRCP, UMR CNRS 5623, Université P. Sabatier Toulouse III, 118 route de Narbonne,
31062 Toulouse CEDEX 9, France
Department of Chemistry and Biochemistry, Biomolecular Sciences Programme, Laurentian University,
Sudbury, ON P3E 2C6, Canada; smontaut@laurentian.ca
2
3
*
Correspondence: patrick.rollin@univ-orleans.fr; Tel.: +33-238-417-370
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 9 March 2018; Accepted: 21 March 2018; Published: 28 March 2018
Abstract: A general pathway was devised to synthesize
ω-methylsulfanylalkyl glucosinolates,
which represent an important class of structurally homogeneous plant secondary metabolites.
The required thiofunctionalized hydroximoyl chlorides were obtained from the corresponding
α,ω-nitroalkyl methylsulfide precursors, involving as the key-step, a nitronate chlorination strategy.
A coupling reaction with 1-thio-beta-D-glucopyranose, followed by O-sulfation of the intermediate
thiohydroximate and final deprotection of the sugar moiety afforded the target compounds.
Keywords: glucosinolate; thiohydroximate; thiofunctionalized; nitronate
1. Introduction
Glucosinolates (GLs) 1 stand as molecular tags of the plant order Brassicales [1,2]. Those strikingly
bio-relevant thiosaccharidic secondary metabolites are found without exception in all 17 families
of this order. All of the known GLs (ca. 130 molecules to date) display a remarkable structural
homogeneity based on a hydrophilic beta-D-glucopyrano unit, which bears a O-sulfated anomeric
(Z)-thiohydroximate function connected to a rather hydrophobic side chain R. Depending on plant
species, the constitution of R is the sole structural variant, in which diversified aliphatic, arylaliphatic,
or indolic arrangements can be found. Associated in plants with an atypical glycohydrolase, myrosinase
(E.C. 3.2.1.147), GLs can undergo hydrolytic cleavage of the anomeric C–S bond. After D-glucose
release, the detached aglycon undergoes a Lossen-type rearrangement to produce biologically active
isothiocyanates (Figure 1) [1–3]. GLs can thus be regarded as isothiocyanate bio-precursors.
Figure 1. Glucosinolates (GLs) and their enzymatic degradation.
It is remarkable that more than one-third of the actually registered GL structures display
an additional thio-function—namely sulfide (
aglycon chain, as represented in Figure 2 [4,5].
2), sulfoxide (3) or sulfone (4)—in ω-position of their
Molecules 2018, 23, 786; doi:10.3390/molecules23040786
www.mdpi.com/journal/molecules

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Figure 2. Glucosinolates bearing an ω-thiofunctionalized side chain [4,5].
Mainly found in the Brassicaceae and Capparaceae families, such thiofunctionalized GLs have been
investigated over the last decade for their redox properties in various in vitro free radical-scavenging
assays, with a view to assessing their antioxidant potential [6–8].
Notwithstanding the large number of known GL-containing plant species, accessing these compounds
from appropriate vegetable sources via extractive processes is generally not straightforward [
“Specialist” plants, which can be considered for convenient isolation of one specific GL in reasonable
amount, are in very limited number [11 13]. This is particularly the case for thiofunctionalized GLs,
for which the synthetic approach should be privileged to make available attractive substrates for biological
studies [14 15]. Nevertheless, since our pioneering work [16], only a small number of syntheses have
9,10].
–
,
focused on GLs bearing an external thio-function in the aglycon part. Starting from a sulfoxide-oxime
precursor, isotopically labelled 4-methylsulfinylbutyl GL (glucoraphanin) was synthesized by Botting et al.
for analysis and metabolic studies [17,
18]. 4-Methylsulfanylbut-3-enyl GL (glucoraphasatin) and 13C-labelled
4-methylsulfanylbutyl GL (glucoerucin) were also synthesized [19,20].
For most synthetic methods that have been developed for GLs over the years, the key step was
the stereospecific formation of a thiohydroximate function, usually resulting from the 1,3-addition
of a glucosyl mercaptan onto a transient nitrile oxide [15]. As they are generally unstable molecular
species, nitrile oxides have to be generated in situ through base-induced conversion of hydroximoyl
chlorides, (Figure 3), which in turn currently result from electrophilic chlorination of aldoximes [21].
Figure 3. Methods to generate nitrile oxides [15].
In this particular case, however, the presence on the carbon chain of a methylsulfanyl moiety
a priori precludes the use of reagents like chlorine or N-chlorosuccinimide which are prone to oxidize
a sulfide function [22].
Therefore the alternative nitronate chlorination methodology (Scheme 1) was selected to access the
nitrile oxide precursors [15]. In this paper, we report a general synthetic pathway to
ω-methylsulfanylalkyl
GLs 2 starting from readily prepared ω-nitroalkyl methyl sulfides 5.

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Scheme 1. Nitronate method vs. oxime method to access hydroximoyl chlorides [20].
2. Results and Discussion
The preparation of a range of linear
ω-nitroalkyl methyl sulfides
5
of variable length (n = 3–12)
from commercially available ω-bromochloroalkanes 6 was expected to be straightforward. However,
in the case of small sized polymethylene chain (n = 3–6), undesirable side-reactions took place. Hence,
distinct strategies had to be devised to provide the ω-nitroalkyl methyl sulfide precursors 5.
Method A (Scheme 2) is suggested for dihaloalkanes 6a (n = 3) or 6d (n = 6). In the cases of 6b
and 6c (n = 4 and 5), the reaction sequence was almost disrupted because of the formation of cyclic
sulfonium salts 9 and 10 [23,24].
Scheme 2. Access to small-sized ω-nitroalkyl methyl sulfides 5a–d.
Compounds
7 and 8 have a tendency to undergo cyclization during their formation, on standing
or/and during their purification by distillation. Sulfonium salts formation rate is carbon chain
length-, temperature-, and halogen type-dependent. Thus, rapid cyclization occurred in the case of
ω
-methylsulfanyl-iodobutane 8b and -pentane 8c. Slightly slower, but still significant, cyclization
took place with the corresponding chloro-analogues, -methylsulfanyl-chlorobutane 7b and -pentane
7c while in the case of 6-methylsulfanyl-1-chlorohexane 7d, the cyclization was minimized (Table 1).
Halogen-exchange reaction of compounds with iodide ion was very slow, even at an elevated
ω
7
temperature, thus explaining the result reported in Table 1 for n = 4 or 5. In cases where n = 3 or 6,
chloro- and iodo-compounds were more stable—enough at least for completing the method A reaction
sequence and afford the desired α,ω-nitro-sulfides 5.

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α
,
ω-Bis-methylsulfanylalkanes can be simultaneously formed [25] during the preparation of
compounds . Their occurrence can be minimized by controlling the temperature, the reaction time,
7
and the molar ratio of CH3SNa. Nevertheless, even if they are not separated from the reactive
intermediates, the presence of such side-products is not likely to disturb the subsequent reaction steps.
Table 1. Preparation of small-sized intermediates.
◦
◦
◦
cpd n
Chain Size n
cpd n
Yield (%)
cpd n
Yield (%)
Yield (%)
3
4
5
6
7a
7b
7c
47
72
86
94
8a [26]
8b
8c
68
–
–
5a
5b
5c
60
–
–
7d
8d
56
5d
74
According to method B (Scheme 2), reaction of NaNO2 with
-chloro-nitroalkanes 11 together with the isomeric nitrites 12
be time-controlled for each dihaloalkane in order to optimize the nitro-compound to nitrite ratio
ω-bromo-chloroalkanes
6 afforded
the
ω
[27,28]. The reaction needed to
6
(Table 2), and at the same time to prevent destruction of the nitro-derivatives 11 due to the simultaneous
presence of the nitrite ion and an alkyl nitrite [29].
In the case of 6a (n = 3), notably, the formation in ca. 40% yield of the known 3-nitro-2-isoxazoline
13a occurred, because of the interaction of the nitro-derivative 11a with the nitrite 12a
a prolonged reaction of 1,3-bromochloropropane with NaNO2 in the presence of 1-propyl nitrite
has been patented [31] as a preparative method for 13a 32]. In contrast in the case of 5b (n = 4),
[30]. In fact,
[
no side-formation of the corresponding oxazine 13b was observed.
Table 2. Preparation of small-sized chloro-nitro derivatives 11a–d.
◦
Chain Size n
cpd n
Reaction Time (h)
Nitro/Nitrite Ratio (%)
Isolated Yield (%)
3
4
5
6
11a
11b
11c
11d
2.5
4.0
4.5
4.5
46/–
70/15
74/20
76/21
39–42
57–60
64–69
73–78
The
characterized by GC-MS and NMR analysis. Subsequent conversion of 11a
-methylsulfanyl-nitroalkanes 5a was carried out by reaction with freshly prepared sodium
ω-chloro-nitroalkanes 11a
–
d
were isolated by flash chromatography and were
–
d
into the expected
ω
–d
methanethiolate, obtained by passing CH3SH gas in a 1 M methanolic solution of sodium methoxide.
Indeed, commercial powdered CH3SNa inevitably gave poor conversion yields and produced
a number of unexpected side products (acids, esters, lactones, thiosulfonates...), e.g., a high yield of
γ-butyrolactone in the case of 11b (n = 4).
After their formation,
ω-methylsulfanyl-nitroalkanes 5 had to be recovered from the basic reaction
medium by the addition of a protic acid. However the regeneration of aliphatic nitro-compounds from
their salts is not a routine matter [33]. Depending on the experimental conditions, acidic treatment
of primary nitronates often results in the production of aldehydes and/or hydroxamic acids via Nef
and Meyer reactions [34]. Optimization of nitroalkane recovery is dependent on resorting to mild
acidification protocols, such as hydroxylamine hydrochloride in 10% aqueous acetic acid at low
temperature. Applying such conditions in the knotty case of 11b (n = 4) allowed to satisfactorily
recover (1-methylsulfanyl)-4-nitrobutane 5b, without the formation of γ-butyrolactone.
Access to longer chain
(Method C, Scheme 3). Commercially available
-methylsulfanyl bromoalkanes 15e (#60% yield), together with minor amounts of the corresponding
-bis-methylsulfanylalkanes [25]. Finally, compounds 15e were converted, as described above, into the
desired ω-methylsulfanyl nitroalkanes 5e-g in 65–70% yields.
ω-methylsulfanyl-nitroalkanes 5e-g (n = 8, 10, 12) was more straightforward
α,ω-dibromoalkanes 14 were reacted with CH3SNa to afford
ω
-g
α,ω
-g

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Scheme 3. Access to longer chain ω-methylsulfanyl nitroalkanes 5e–g.
Following a procedure previously established by Kjaer [35 36], all of the nitro-compounds
,
5
were
converted into their moisture-sensitive sodium salts, which were isolated by brief filtration under dry
atmosphere, then reacted in chloroform with SOCl2 (in our hands, the oxalyl chloride variant [37] did
not bring substantial improvement) at low temperature (
60 ◦C) to afford the hydroximoyl chlorides
−
16. Those were subsequently used without further purification in the next steps of the synthesis
(Scheme 4).
Scheme 4. Coupling reaction to deliver tetra-O-acetylated
followed by O-sulfation and deprotection to yield GLs 2.
ω-methylthioalkyl (Z)-thiohydroximates 18,
The intermediate nitrile oxides 17 were generated in situ by base-catalyzed (NEt3) 1,3-elimination
on hydroximoyl chlorides 16 to react [15 38] with 2,3,4,6-tetra-O-acetyl-1-thio- -D-glucopyranose [39
to afford the corresponding ω-methylthioalkyl (Z)-thiohydroximates 18.
Final conversion of the thiohydroximates 18a into the target GLs 2a–g was performed according
,
β
]
–
g
to a previously described protocol [15]. O-Sulfation of the hydroximino moiety using sulfur trioxide
pyridine complex, followed by quenching with aqueous potassium hydrogenocarbonate afforded
the per-O-acetylated GLs 19a–g, the carbohydrate part of which was readily deprotected under basic
conditions to afford the corresponding GLs.
3. Experimental Section
3.1. General Information
α,ω-Bromochloroalkanes 6a–d Br-(CH2)n-Cl (n = 3–6) and α,ω-dibromoalkanes 14 Br-(CH2)n-Br
(n = 8, 10, 12) were obtained from commercial sources (Sigma-Aldrich, Saint-Quentin-Fallavier, France)
and were used without further purification. Anhydrous reactions were performed under argon
atmosphere in pre-dried flasks, using distilled anhydrous solvents. Unless otherwise stated, all of the
chemicals obtained from Sigma-Aldrich were used without further purification. TLC on precoated
aluminum-back plates (Merck Kieselgel 60F254, E. Merck, Darmstadt, Germany) were generally
visualized by UV light (254 nm) and by charring after exposure to a 5% H2SO4 solution in ethanol.
Flash column chromatography was carried out using silica gel (E. Merck, 36–63 mesh, unless otherwise
◦
indicated). Melting points ( C) were obtained using a Büchi 510 apparatus (Büchi Sarl, Rungis, France)
and are uncorrected. Optical rotations were measured at 20 ◦C with a Perkin Elmer 341 polarimeter

Molecules 2018, 23, 786
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1
(Perkin Elmer France, Villebon s/Yvette, France) with a path length of 1 dm. H and 13C-NMR spectra
were recorded on 250 MHz Bruker Avance DPX250 or 400 MHz Bruker Avance2 spectrometers (Bruker
France, Wissembourg, France). Chemical shifts are expressed in parts per million (ppm) downfield
from TMS internal standard and coupling constants are given in Hz. NMR peak assignments were
established using NOESY, COSY, HSQC, and HMBC methods for all the reported compounds.
GC monitoring was carried out using a Varian 3700 gas chromatograph (Agilent Technologies,
Les Ulis, France) equipped with a split/splitess injector at 240 ◦C, a DB-5 (Agilent) capillary column
(30 m
×
0.25 mm, 0.25
µ
m film thickness—carrier gas nitrogen 1 mL
min−1) and a flame ionization
·
◦
detector at 280 C. Depending on the solute analyzed, two temperature programs were used: (1) initial
temperature 100 ◦C, held for 2 min, and then ramped to 220 ◦C with a 10 ◦C min−1 rate maintained
·
for 10 min. (2) initial temperature 100 ◦C, held for 2 min, then ramped to 250 ◦C with a 15 ◦C
rate maintained for 15 min.
·
min−1
GC-MS analyses were performed using a HP-5890 (Agilent) chromatograph hyphenated to
a HP-5970 mass spectrometer (Agilent quadrupole). Spectra were obtained in EI mode at 70 eV.
The gas chromatograph was equipped with a HP-1 capillary column (Agilent, 100% dimethylsiloxane,
30 m
sample was injected with a 1/100 split ratio under a constant helium flow (1 mL
temperature was initially held at 60 ◦C for 3 min, and then ramped with a 3 ◦C min−1 rate to 80 ◦C.
min−1 rate to 150 ◦C. A 5 ◦C min−1
×
0. 25 mm, 0.33
µ
m film thickness). The injector temperature was held at 200 ◦C and a 1
min−1). The oven
µL
·
·
This temperature was held for 1 min, then ramped with a 3 ◦C
·
·
rate was used to bring the oven temperature to 200 ◦C. The final temperature of 230 ◦C was reached
with a 10 ◦C·min−1 rate and maintained for 20 min.
Mass spectra (ion spray; IS) were recorded on a Perkin–Elmer Sciex API-300 spectrometer (Sciex
Sarl, Les Ulis, France).
High resolution mass spectra (HRMS) were recorded with a MicrOTOF-QII spectrometer (Bruker
France S.A.S., Champs-sur-Marne, France) in the electrospray ionisation (ESI) mode.
3.2. Synthesis
3.2.1. General Procedure for the Synthesis of Small-Sized Chloroalkyl Methyl Sulfides 7a–d
A 2.6 M methanolic solution of MeSNa (23 mL, 1.2 equiv.) was added dropwise to a stirred
solution of
ω-bromochloroalkane 6 (50 mmol) in dry methanol (80 mL) at room temperature (r.t.).
Stirring was continued until complete consumption of the dihalide (2–3 h, GC monitoring). The mixture
was concentrated in vacuo and the resulting white slurry was taken in cold water and extracted with
dichloromethane. After drying the organic phase over MgSO4, filtration and concentration in vacuo,
the oily residue was purified by flash chromatography using silica gel (230–400 mesh) with hexane as
eluent to afford 7a–d as light yellow oils.
ω-Chloro-1-methylsulfanylpropane 7a [24,40], -butane 7b [24], -pentane 7c [24].
6-Chloro-1-methylsulfanylhexane [98429-85-7] 7d [41,42].
3.2.2. General Procedure for the Synthesis of Long-Sized Bromoalkyl Methylsulfides 15e–g
Similarly, the
α,ω-dibromoalkane 14 (50 mmol) dissolved in a stirred methanol (200 mL)-
dichloromethane (50 mL) mixture was treated dropwise (over 30 min) by a 2.6 M methanolic solution
of MeSNa (20 mL, 1.04 equiv.), while cooling at r.t. After complete consumption of the dihalide (1–2 h,
TLC monitoring), the mixture was concentrated in vacuo and the resulting white slurry was taken in
cold water and extracted with dichloromethane. After drying the organic phase over MgSO4, filtration
and concentration in vacuo, the oily residue was purified by flash chromatography using silica gel
(230–400 mesh) with hexane as eluent to afford 15e–g [25].
1
8-Bromo-1-methylsulfanyloctane [64053-04-9] 15e
(CDCl3)
[
43]. Light yellow viscous oil (57% yield). H-NMR
δ
1.25–1.44 (m, 8H, CH2), 1.57 (qt, 2H, H-2), 1.84 (qt, 2H, H-7), 2.08 (s, 3H, MeS), 2.48 (t, 2H,

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Jvic = 7.3, H-1), 3.39 (t, 2H, Jvic = 6.8, H-8). 13C-NMR δ 15.3 (MeS), 27.9, 28.5, 28.9 (C-2-C-6), 32.6 (C-7),
33.8 (C-8), 34.1 (C-1). ESI-MS m/z 240.2 [M + H]+.
1
10-Bromo-1-methylsulfanyldecane 15f. Light yellow solid (55% yield). H-NMR (CDCl3)
δ
1.22–1.47 (m,
12H, CH2), 1.58 (qt, 2H, H-2), 1.85 (qt, 2H, H-9), 2.08 (s, 3H, MeS), 2.47 (t, 2H, Jvic = 7.3, H-1), 3.39 (t,
2H, Jvic = 6.8, H-10). 13C-NMR
(C-1). ESI-MS m/z 268.3 [M + H]+.
δ
15.3 (MeS), 28.0, 28.6, 29.0, 29.2 (C-2-C-8), 32.7 (C-9), 33.8 (C-10), 34.1
1
12-Bromo-1-methylsulfanyldodecane 15g. Light yellow solid (59% yield). H-NMR (CDCl3)
δ
1.19–1.48
(m, 16H, CH2), 1.58 (qt, 2H, H-2), 1.84 (qt, 2H, H-11), 2.08 (s, 3H, MeS), 2.48 (t, 2H, Jvic = 7.3, H-1), 3.39
(t, 2H, Jvic = 6.8, H-12). 13C-NMR
δ
15.4 (MeS), 28.0, 28.6, 28.7, 29.0, 29.1, 29.3, 29.4 (C-2-C-10), 32.7
(C-11), 33.9 (C-12), 34.2 (C-1). ESI MS m/z 296.3 [M + H]+.
3.2.3. Procedures for the Synthesis of Nitroalkyl Methylsulfides 5
Method A. Synthesis of 5a (n = 3) and 5d (n = 6)
The chloroalkyl methyl sulfide
7 (42 mmol) was refluxed in dry acetone with dry NaI (13.5 g,
90 mmol) for 2–3 days until the complete conversion of the starting material (GC monitoring). After
concentration in vacuo, the resulting slurry was taken in a 0.6 M aqueous sodium thiosulfate solution,
and extracted with CH2Cl2. The combined organic phases were dried over MgSO4, filtered and
concentrated in vacuo to afford compound
next step.
8 as fragrant pale orange oil, which was used as such in the
To a solution of dry sodium nitrite (2.0 g, 29 mmol) in DMSO (80 mL), a solution of
8
(24 mmol)
◦
in DMSO (15 mL) was added dropwise, while keeping the temperature at 20–25 C. After 2–3 h,
the reaction was quenched by adding ice-water (300 mL) and repeatedly extracted with diethyl ether.
The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The residue
was purified by silica gel column chromatography (petroleum ether–Et2O 4:1) to afford 5a and 5d as
colourless oils.
1
(1-Methylsulfanyl)-3-nitropropane [182258-93-1] 5a. Colourless oil (2.27 g, 40% overall yield). H-NMR
(CDCl3) δ 2.09 (s, 3H, MeS), 2.27 (qt, 2H, H-2), 2.58 (t, 2H, Jvic = 6.8, H-1), 4.51 (t, 2H, Jvic = 6.8, H-3).
13C-NMR δ 15.1 (MeS), 26.1 (C-2), 30.4 (C-1), 73.7 (C-3). MS IS m/z 136.2 [M + H]+.
(1-Methylsulfanyl)-6-nitrohexane 5d. Colourless oil (3.13 g, 42% overall yield). 1H-NMR (CDCl3)
δ
1.32–1.48 (m, 4H, H-3, H-4), 1.54–1.63 (m, 2H, H-2), 1.94–2.04, m, 2H, H-5), 2.06 (s, 3H, MeS), 2.46 (t,
2H, Jvic = 7.3, H-1), 4.36 (t, 2H, Jvic = 7.3, H-6). 13C-NMR
15.2 (MeS), 25.6 (C-4), 27.0 (C-5), 27.7 (C-3),
28.4 (C-2), 33.8 (C-1), 75.5 (C-6). MS IS m/z 178.3 [M + H]+.
δ
Method B. Synthesis of 5a–d (n = 3–6) from ω-bromochloroalkanes 6a–d
To a solution of dry sodium nitrite (1.24 g, 18 mmol) in DMSO (100 mL), a solution of
ω
-bromochloroalkane ◦
6 (15 mmol) in DMSO (20 mL) was added dropwise while keeping the
temperature at 20–25 C. After 2–5 h, the reaction was quenched by adding ice-water (400 mL)
and was repeatedly extracted with diethyl ether. The combined organic phases were dried over
MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography
(petroleum ether–Et2O 5:1) to afford ω-chloronitroalkanes 11 as colourless oils.
1-Chloro-3-nitropropane [16694-52-3] 11a. Colourless oil (0.8 g, 42% yield) 1H-NMR (CDCl3)
δ
2.45 (qt,
2H, H-2), 3.65 (t, 2H, Jvic = 6.3, H-1), 4.58 (t, 2H, Jvic = 6.3, H-3). 13C-NMR
δ 29.6 (C-2), 40.7 (C-1),
72.1 (C-3) [44].
1-Chloro-4-nitrobutane [41168-66-5] 11b. Colourless oil (1.2 g, 60% yield) 1H-NMR (CDCl3) δ 1.83–1.92
(m, 2H, H-2), 2.13–2.23 (m, 2H, H-3), 3.58 (t, 2H, Jvic = 6.1, H-1), 4.43 (t, 2H, Jvic = 6.8, H-4). 13C-NMR
δ
24.4 (C-2), 28.8 (C-3), 43.5 (C-1), 74.6 (C-4) [45].

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1-Chloro-5-nitropentane [1173694-33-1] 11c. Colourless oil (1.5 g, 66% yield) 1H-NMR (CDCl3)
δ
1.51–1.60
(m, 2H, H-3), 1.77–1.87 (m, 2H, H-2), 1.98–2.08 (m, 2H, H-4), 3.54 (t, 2H, Jvic = 6.3, H-1), 4.39 (t, 2H,
Jvic = 7.0, H-5). 13C-NMR δ 23.4 (C-3), 26.4 (C-4), 31.5 (C-2), 44.2 (C-1), 75.3 (C-5).
1-Chloro-6-nitrohexane [898543-32-3] 11d. Colourless oil (1.9 g, 76% yield) 1H-NMR (CDCl3)
δ 1.38–1.55
(m, 4H, H-3, H-4), 1.73–1.83 (m, 2H, H-2), 1.97–2.07 (m, 2H, H-5), 3.53 (t, 2H, Jvic = 6.6, H-1), 4.38 (t, 2H,
Jvic = 7.0, H-6). 13C-NMR δ 25.4 (C-4), 25.9 (C-3), 27.0 (C-5), 31.9 (C-2), 44.6 (C-1), 75.4 (C-6) [46].
A solution of chloronitro derivative 11 (25 mmol) in dry methanol (50 mL) was reacted with a 2.6
M methanolic solution of MeSNa (20 mL, 2.08 equiv.) under the conditions that are reported in Table 3.
After concentration in vacuo, the resulting slurry was poured into ice water (200 mL) under vigorous
◦
stirring and treated dropwise at 0 C by a cooled solution of hydroxylamine hydrochloride (4.0 g,
57 mmol) in 20% aqueous acetic acid (17 mL) [28]. The two-phase system obtained was extracted
three times with CH2Cl2, and the combined organic phases were dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by column chromatography (petroleum ether–Et2O
4:1) to afford 5a–d as colourless oils (5a and 5d were described above).
1
(1-Methylsulfanyl)-4-nitrobutane [182258-94-2] 5b. Colourless oil (1.6 g, 43% yield). H-NMR (CDCl3)
δ
1.63–1.73 (m, 2H, H-2), 2.03–2.16 (m, 5H, MeS, H-3), 2.52 (t, 2H, Jvic = 7.0, H-1), 4.40 (t, 2H, Jvic = 7.0,
H-4). 13C-NMR δ 15.1 (MeS), 25.2 (C-2), 25.9 (C-3), 33.0 (C-1), 75.0 (C-4). MS IS m/z 150.2 [M + H]+.
1
(1-Methylsulfanyl)-5-nitropentane [182258-95-3] 5c. Colourless oil (3.5 g, 86% yield). H-NMR (CDCl3) d
1.42–1.52 (m, 2H, H-3), 1.58–1.68 (m, 2H, H-2), 1.96–2.06 (m, 2H, H-4), 2.07 (s, 3H, MeS), 2.48 (t, 2H,
Jvic = 7.1, H-1), 4.37 (t, 2H, Jvic = 7.1, H-5). 13C-NMR
33.5 (C-1), 75.3 (C-5). MS IS m/z 164.2 [M + H]+.
δ 15.2 (MeS), 25.0 (C-3), 26.7 (C-4), 28.00 (C-2),
Table 3. Alternative preparation (method B) of small-sized precursors 5.
◦
◦
Chain Size n
cpd n
T ( C)
Reaction Time (h)
Yield (%)
3
4
5
6
5a
5b
5c
25
40
1
3
25
40
87
93
reflux
reflux
reflux
5d
4
Method C. Synthesis of Long-Sized Nitroalkyl Methylsulfides 5e–g (n = 8, 10, 12)
To a solution of dry sodium nitrite (2.0 g, 29 mmol) in DMSO (80 mL), a solution◦of 15 (24 mmol)
in DMSO (15 mL) was added dropwise, while keeping the temperature at 20–25 C. After 2–3 h,
the reaction was quenched by adding ice-water (300 mL) and repeatedly extracted with diethyl ether.
The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The residue
was purified by column chromatography (petroleum ether-Et2O 19:1) to afford 5e
–
g
as colourless oils.
1
(1-Methylsulfanyl)-8-nitrooctane 5e. Colourless oil (3.2 g, 65% yield). H-NMR (CDCl3)
δ
1.23–1.42 (m,
8H, H-3-6), 1.57 (qt, 2H, H-2), 1.98 (qt, 2H, H-7), 2.07 (s, 3H, MeS), 2.46 (t, 2H, Jvic = 7.3, H-1), 4.36 (t,
2H, Jvic = 7.3, H-8). 13C-NMR
15.3 (MeS), 25.9 (C-4), 27.1 (C-7), 28.3, 28.5, 28.6, (C-3, C-5, C-6), 28.8
(C-2), 34.0 (C-1), 75.6 (C-8). MS IS m/z 206.3 [M + H]+.
δ
1
(1-Methylsulfanyl)-10-nitrodecane 5f. Colourless oil (3.8 g, 68% yield). H-NMR (CDCl3)
12H, H-3-8), 1.57 (qt, 2H, H-2), 1.99 (qt, 2H, H-9), 2.07 (s, 3H, MeS), 2.47 (t, 2H, Jvic = 7.3, H-1), 4.36
(t, 2H, Jvic = 7.3, H-10). 13C-NMR
15.3 (MeS), 26.0, 27.2, 28.5, 28.6, 28.9, 29.0 (C-3-9), 29.1 (C-2), 34.1
(C-1), 75.6 (C-10). MS IS m/z 234.4 [M + H]+.
δ 1.21–1.41 (m,
δ
1
(1-Methylsulfanyl)-12-nitrododecane 5g. Colourless oil (4.2 g, 67% yield). H-NMR (CDCl3)
(m, 16H, H-3-10), 1.58 (qt, 2H, H-2), 2.0 (qt, 2H, H-11), 2.09 (s, 3H, MeS), 2.48 (t, 2H, Jvic = 7.3, H-1), 4.37
(t, 2H, Jvic = 7.3, H-12). 13C-NMR
15.3 (MeS), 26.0, 27.2, 28.6, 28.9, 29.2 (C-3-11), 29.3 (C-2), 34.1 (C-1),
75.6 (C-12). MS IS m/z 262.4 [M + H]+.
δ 1.21–1.42
δ

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3.2.4. General Procedure for the Nitronate Chlorination and Coupling with the Thioglucose Unit
Nitronate formation. To a stirred freshly prepared solution of sodium (0.3 g) in 2-butanol (17 mL),
under argon atmosphere, a solution of nitro derivative 5 (13 mmol) in anhydrous ether (20 mL) is added
dropwise under exclusion of moisture. The slow addition of anhydrous ether (200 mL) while stirring
caused precipitation of the nitronate as a white solid. After 10 min more stirring, the suspension was
rapidly filtered off on sintered glass, and, after rinsing with anhydrous ether (20–30 mL), the nitronate
cake was dried in vacuo for 30 min (preparation of nitronates can be more confortably realized in
a glovebox).
Conversion of nitronate into hydroximoyl chloride. The powdered nitronate obtained was suspended
in dry chloroform (40 mL), the stirred mixture was cooled at
−
60 ◦C, and a chloroform solution of
freshly distilled thionyl chloride (1 mL in 5 mL) was added dropwise. After 20 min more stirring at
◦
−
60 C, the reaction was quenched by pouring the mixture into ice water; the chloroform solution was
separated and the aqueous phase was extracted twice with chloroform. The combined organic phases
were dried over MgSO4, filtered and concentrated in vacuo to afford the raw hydroximoyl chloride as
a greenish oil.
Coupling with the thioglucose unit. This oily residue was immediately dissolved in 70 mL of
a dry dichloromethane–diethyl ether mixture (2:1 v/v), 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranose
(3.64 g, 10 mmol) was added, then dry argon was bubbled for 15 min in the solution cooled to
−10 ◦C. A solution of triethylamine (4.2 mL, 30 mmol) in dichloromethane (10 mL) was added in one
portion and the mixture was stirred during 45 min more. After washing with ice-cold 1N sulfuric
acid, the organic phase was separated and the aqueous phase extracted twice with dichloromethane.
The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The syrupy
residue was purified by column chromatography (petroleum ether–EtOAc 3:2) to afford the glycosyl
thiohydroximates 18 as amorphous solids.
S-(2,3,4,6-Tetra-O-acetyl-
amorphous powder (32% yield), [
β
-D-glucopyranosyl) (Z)-(30-methylsulfanyl)propanethiohydroximate 18a. White
1
α
]
−
20 (c = 1.0, CHCl3). H-NMR (CDCl3)
δ
2.00, 2.03, 2.05, 2.10,
D
0
0
(4s, 12H, CH3CO), 2.14 (s, 3H, MeS), 2.78–2.81 (m, 4H, H-2 , H-3 ), 3.78 (dt, 1H, J4–5 = 10.0, H-5), 4.17 (d,
2H, J5–6a = J5–6b = 3.9, H-6a, H-6b), 5.05–5.12 (m, 3H, H-1, H-2, H-4), 5.24–5.30 (m, 1H, H-3), 8.04 (brs,
NOH). 13C-NMR 15.5 (MeS), 20.3, 20.4, 20.6 (CH3CO), 31.1 (C-20), 32.7 (C-10), 62.0 (C-6), 67.9 (C-4),
δ
70.0 (C-2), 73.6 (C-3), 75.9 (C-5), 79.9 (C-1), 150.8 (C=N), 169.4, 169.5, 170.3, 170.8 (C=O). HR-ESI-MS:
C18H27NO10S2: calcd. 481.1076; found 481.1061.
S-(2,3,4,6-Tetra-O-acetyl-
amorphous powder (34% yield), [
β
-D-glucopyranosyl) (Z)-(40-methylsulfanyl)butanethiohydroximate 18b. White
1
0
α
]
D
−
16 (c = 1.0, CHCl3). H-NMR (CDCl3) δ 1.90–1.95 (m, 2H, H-3 ),
1.99, 2.01, 2.03, 2.06 (4s, 12H, CH3CO), 2.10 (s, 3H, MeS), 2.52–2.67 (m, 4H, H-20, H-40), 3.82 (ddd, 1H,
J4–5 = 9.9, H-5), 4.13 (dd, 1H, J5–6b = 2.4, Jgem = 11.8, H-6b), 4.20 (dd, 1H, J5–6a = 5.0, H-6a), 5.00–5.12
(m, 3H, H-1, H-2, H-4), 5.24 (t, 1H, J3–4 = 9.0, H-3), 8.80 (brs, NOH). 13C-NMR
δ 15.4 (MeS), 20.4, 20.5,
20.6 (CH3CO), 26.1 (C-30), 30.9 (C-40), 33.4 (C-20), 62.0 (C-6), 67.9 (C-4), 70.1 (C-2), 73.8 (C-3), 75.8 (C-5),
79.8 (C-1), 151.7 (C=N), 169.3, 169.5, 170.4, 170.8 (C=O). HR-ESI-MS: C19H29NO10S2: calcd. 495.1233;
found 495.1230.
S-(2,3,4,6-Tetra-O-acetyl-β
-D-glucopyranosyl) (Z)-(50-methylsulfanyl)pentanethiohydroximate 18c. White
1
0
amorphous powder (40% yield), [
α
]
D
−
17 (c = 1.0, CHCl3). H-NMR (CDCl3) δ 1.60–1.85 (m, 4H, H-3 ,
0
0
0
H-4 ), 2.02, 2.05, 2.07, 2.09 (4s, 12H, CH3CO), 2.11 (s, 3H, MeS), 2.45–2.55 (m, 4H, H-2 , H-5 ), 3.79 (ddd,
1H, J4–5 = 9.7, H-5), 4.14 (dd, 1H, J5–6b = 2.5, Jgem = 12.6, H-6b), 4.22 (dd, 1H, J5–6a = 5.4, H-6a), 5.05–5.15
(m, 3H, H-1, H-2, H-4), 5.25 (dd, 1H, J3–4 = 9.3, H-3), 8.20 (brs, NOH). 13C-NMR
δ 15.3 (MeS), 20.4, 20.5
(CH3CO), 25.8 (C-40), 28.0 (C-30), 31.9 (C-50), 33.5 (C-20), 62.1 (C-6), 68.0 (C-4), 70.1 (C-2), 73.7 (C-3),
75.8 (C-5), 79.8 (C-1), 152.0 (C=N), 169.3, 169.5, 170.3, 170.8 (C=O). HR-ESI-MS: C20H31NO10S2: calcd.
509.1389; found 509.1378.

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S-(2,3,4,6-Tetra-O-acetyl-
amorphous powder (48% yield), [
β
-D-glucopyranosyl) (Z)-(60-methylsulfanyl)hexanethiohydroximate 18d. White
α
]
−
11 (c = 1.0, CHCl3). 1H-NMR (CDCl3)
δ 1.40–1.51 (m, 2H,
D
H-40), 1.58–1.72 (m, 4H, H-30, H-50), 2.01, 2.02, 2.04, 2.08 (4s, 12H, CH3CO), 2.10 (s, 3H, MeS), 2.50 (t,
4H, Jvic = 7.1, H-20, H-60), 3.75 (ddd, 1H, J4–5 = 10.1, H-5), 4.11 (dd, 1H, J5–6b = 2.4, Jgem = 12.3, H-6b),
4.20 (dd, 1H, J5–6a = 5.6, H-6a), 5.04–5.12 (m, 3H, H-1, H-2, H-4), 5.27 (dd, 1H, J3–4 = 9.3, H-3), 8.20 (brs,
NOH). 13C-NMR
δ
15.3 (MeS), 20.4, 20.5 (CH3CO), 26.4 (C-40), 28.0 (C-50), 28.5 (C-30), 32.3 (C-60), 33.8
0
(C-2 ), 62.1 (C-6), 68.0 (C-4), 70.0 (C-2), 73.7 (C-3), 75.9 (C-5), 79.8 (C-1), 152.1 (C=N), 169.3, 169.5, 170.5,
170.7 (C=O). HR-ESI-MS: C21H33NO10S2: calcd. 523.1546; found 523.1541.
S-(2,3,4,6-Tetra-O-acetyl-
amorphous powder (47% yield), [
H-50, H-60), 1.47–1.64 (m, 4H, H-30, H-70), 1.99, 2.01, 2.02, 2.05 (4s, 12H, CH3CO), 2.07 (s, 3H, MeS),
β
-D-glucopyranosyl) (Z)-(80-methylsulfanyl)octanethiohydroximate 18e. White
1
0
α
]
D
−
11 (c = 1.0, CHCl3). H-NMR (CDCl3) δ 1.32–1.40 (m, 6H, H-4 ,
0
0
2.41–2.46 (m, 4H, H-2 , H-8 ), 3.73 (ddd, 1H, J4–5 = 10.0, H-5), 4.09 (dd, 1H, J5–6b = 2.1, Jgem = 12.3, H-6b),
4.18 (dd, 1H, J5–6a = 5.4, H-6a), 5.02–5.10 (m, 3H, H-1, H-2, H-4), 5.25 (dd, 1H, J3–4 = 9.4, H-3), 8.83 (brs,
NOH). 13C-NMR
δ
15.3 (MeS), 20.4, 20.5 (CH3CO), 26.8, 28.5, 28.7 (C-40, C-50, C-60), 28.8 (C-70), 28.9
(C-30), 32.3 (C-80), 34.5 (C-20), 62.1 (C-6), 68.0 (C-4), 70.0 (C-2), 73.7 (C-3), 75.9 (C-5), 79.8 (C-1), 152.2
(C=N), 169.3, 169.5, 170.4, 170.7 (C=O). HR-ESI-MS: C23H37NO10S2: calcd. 551.1859; found 551.1851.
S-(2,3,4,6-Tetra-O-acetyl-
amorphous powder (51% yield), [
β
-D-glucopyranosyl) (Z)-(100-methylsulfanyl)decanethiohydroximate 18f. White
1
α
]
D
−
12 (c = 1.0, CHCl3). H-NMR (CDCl3)
δ
1.28–1.34 (m, 10H,
H-40 to H-80), 1.51–1.063 (m,04H, H-30, H-90), 1.98, 2.01, 2.02, 2.04 (4s, 12H, CH3CO), 2.06 (s, 3H, MeS),
2.38–2.47 (m, 4H, H-2 , H-10 ),3.71 (ddd, 1H, J4–5 = 10.0, H-5), 4.08 (dd, 1H, J5–6b = 2.4, Jgem = 12.1, H-6b),
4.19 (dd, 1H, J5–6a = 5.2, H-6a), 5.00–5.09 (m, 3H, H-1, H-2, H-4), 5.22 (dd, 1H, J3–4 = 9.2, H-3), 8.86 (brs,
0 0 0 0
δ 15.3 (MeS), 20.4, 20.5 (CH3CO), 26.9, 28.6, 28.9, (C-4 to C-8 ), 29.0 (C-9 ), 29.2 (C-3 ),
NOH). 13C-NMR
32.4 (C-100), 34.1 (C-20), 62.1 (C-6), 68.0 (C-4), 70.0 (C-2), 73.7 (C-3), 75.9 (C-5), 79.8 (C-1), 152.3 (C=N),
169.3, 169.5, 170.4, 170.7 (C=O). HR-ESI-MS: C25H41NO10S2: calcd. 579.2172; found 579.2163.
S-(2,3,4,6-Tetra-O-acetyl-
amorphous powder (56% yield), [
β
-D-glucopyranosyl) (Z)-(120-methylsulfanyl)dodecanethiohydroximate 18g. White
1
α
]
D
−
12 (c = 1.0, CHCl3). H-NMR (CDCl3)
δ
1.31–1.38 (m, 14H,
H-40 to H-100), 1.53–10.66 (m, 4H, H-30, H-110), 1.98, 2.01, 2.02, 2.05 (4s, 12H, CH3CO), 2.07 (s, 3H, MeS),
0
2.40–2.45 (m, 4H, H-2 , H-12 ), 3.72 (ddd, 1H, J4–5 = 9.8, H-5), 4.09 (dd, 1H, J5–6b = 2.5, Jgem = 12.5, H-6b),
4.19 (dd, 1H, J5–6a = 5.5, H-6a), 5.01–5.12 (m, 3H, H-1, H-2, H-4), 5.24 (dd, 1H, J3–4 = 9.5, H-3), 8.88 (brs,
NOH). 13C-NMR
δ
15.3 (MeS), 20.4, 20.5 (CH3CO), 26.7, 28.9, 29.0 (C-40 to C-100), 29.1 (C-110), 29.2
(C-30), 32.4 (C-120), 34.3 (C-20), 62.1 (C-6), 67.9 (C-4), 70.0 (C-2), 73.6 (C-3), 75.8 (C-5), 79.8 (C-1), 152.3
(C=N), 169.2, 169.5, 170.3, 170.6 (C=O). HR-ESI-MS: C27H45NO10S2: calcd. 607.2485; found 607.2478.
3.2.5. General Procedure for NO-Sulfation of the Glucosyl Thiohydroximates 18
Sulfur trioxide pyridine complex (400 mg, 5 eq.) was added to a solution of compound 18
(0.5 mmol) in dimethylformamide (7 mL). After 24 h stirring at rt, the reaction mixture was treated
with a 0.2 M aqueous solution of KHCO3 (12 mL) then the solvents were evaporated in vacuo.
Chromatographic purification (CH2Cl2/MeOH 17:3) provided compounds 19.
Per-O-acetylated 2-methylsulfanylethyl glucosinolate 19a. White amorphous powder (61% yield),
[α]D −20 (c = 0.9, MeOH). 1H-NMR (DMSO-d6)
δ 1.96, 1.99, 2.01, 2.03 (4s, 12H, CH3CO), 2.23 (s,
3H, MeS), 2.46–2.53 (m, 4H, H-1 , H-2 ), 4.03–4.15 (m, 3H, H-5, H-6a, H-6b), 4.88 (t, 1H, J2–3 = 9.4, H-2),
0
0
4.94 (t, 1H, J4–5 = 8.6, H-4), 5.39 (dd, 1H, J3–4 = 9.6, H-3), 5.56 (d, 1H, J1–2 = 10.1, H-1). 13C-NMR
δ
14.6 (MeS), 20.2, 20.3, 20.5 (CH3CO), 26.5 (C-20), 32.9 (C-10), 62.2 (C-6), 68.1 (C-4), 69.8 (C-2), 72.9 (C-3),
74.0 (C-5), 78.3 (C-1), 153.2 (C=N), 169.4, 169.7, 170.0, 170.3 (C=O). HR-ESI-MS: C18H26NO13S3: calcd.
560.0566; found 560.0571.
Per-O-acetylated 3-methylsulfanylpropyl glucosinolate 19b. White amorphous powder (68% yield), [
22 (c = 1.1, MeOH). 1H-NMR (DMSO-d6) 1.79–1.90 (m, 2H, H-20), 1.94, 1.97, 1.99, 2.00 (4s, 12H,
CH3CO), 2.05 (s, 3H, MeS), 2.53 (t, 2H, Jvic = 7.3, H-30), 2.63 (t, 2H, Jvic = 7.3, H-10), 4.00–4.18 (m, 3H,
α]
D
−
δ

Molecules 2018, 23, 786
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H-5, H-6a, H-6b), 4.86 (t, 1H, J2–3 = 9.0, H-2), 4.89 (t, 1H, J4–5 = 8.8, H-4), 5.43 (dd, 1H, J3–4 = 9.3, H-3),
5.50 (d, 1H, J1–2 = 10.2, H-1). 13C-NMR
δ
14.7 (MeS), 20.2, 20.3, 20.5 (CH3CO), 26.4 (C-30), 30.3, 32.5
(C-10, C-20), 62.1 (C-6), 68.0 (C-4), 69.6 (C-2), 72.8 (C-3), 74.4 (C-5), 78.2 (C-1), 153.5 (C=N), 169.4, 169.6,
169.9, 170.3 (C=O). HR-ESI-MS: C19H28NO13S3: calcd. 574.0723; found 574.0730.
Per-O-acetylated 4-methylsulfanylbutyl glucosinolate 19c. White amorphous powder (86% yield), [α]D −18
(c = 1.0, MeOH). 1H-NMR (DMSO-d6)
δ
1.52–1.68 (m, 4H, H-20, H-30), 1.94, 1.97, 1.99, 2.00 (4s, 12H,
CH3CO), 2.02 (s, 3H, MeS), 2.48–2.59 (m, 4H, H-10, H-40), 4.00–4.15 (m, 3H, H-5, H-6a, H-6b), 4.86 (t,
1H, J2–3 = 9.5, H-2), 4.91 (t, 1H, J4–5 = 8.5, H-4), 5.43 (dd, 1H, J3–4 = 9.5, H-3), 5.50 (d, 1H, J1–2 = 10.2,
H-1). 13C-NMR
δ
14.5 (MeS), 20.2, 20.3, 20.5 (CH3CO), 25.7 (C-40), 27.9, 31.0, 32.8 (C-10, C-20, C-30),
62.2 (C-6), 68.1 (C-4), 69.6 (C-2), 72.8 (C-3), 74.4 (C-5), 78.2 (C-1), 154.0 (C=N), 169.4, 169.6, 169.9, 170.3
(C=O). HR-ESI-MS: C20H30NO13S3: calcd. 588.0879; found 588.0887.
Per-O-acetylated 5-methylsulfanylpentyl glucosinolate 19d
. White amorphous powder (84% yield),
1
[α]D −15 (c = 1.1, MeOH). H-NMR (DMSO-d6)
δ
1.38–1.68 (m, 6H, H-20, H-30, H-40), 1.94, 1.98,
1.99, 2.00 (4s, 12H, CH3CO), 2.02 (s, 3H, MeS), 2.43–2.57 (m, 4H, H-10, H-50), 3.98–4.15 (m, 3H, H-5,
H-6a, H-6b), 4.86 (t, 1H, J2–3 = 9.8, H-2), 4.91 (t, 1H, J4–5 = 8.8, H-4), 5.45 (dd, 1H, J3–4 = 9.7, H-3), 5.51 (d,
1H, J1–2 = 10.2, H-1). 13C-NMR 15.6 (MeS), 20.2, 20.4, 20.5 (CH3CO), 26.4 (C-50), 27.8, 28.2, 31.4, 33.2
δ
0
0
(C-1 to C-4 ), 62.2 (C-6), 68.2 (C-4), 69.6 (C-2), 72.8 (C-3), 74.4 (C-5), 78.2 (C-1), 154.1 (C=N), 169.4, 169.6,
169.9, 170.3 (C=O). HR-ESI-MS: C21H32NO13S3: calcd. 602.1036; found 602.1041.
Per-O-acetylated 7-methylsulfanylheptyl glucosinolate 19e. White amorphous po0wder (83% yield),
0 0
δ 1.24–1.39 (m, 6H, H-3 , H-4 , H-5 ), 1.44–1.65 (m, 4H,
[α]D −17 (c = 1.0, MeOH). 1H-NMR (DMSO-d6)
H-20, H-60), 1.94, 1.97, 1.99, 2.01 (4s, 12H, CH3CO), 2.01 (s, 3H, MeS), 2.40–2.54 (m, 4H, H-10, H-70),
3.98–4.15 (m, 3H, H-5, H-6a, H-6b), 4.85 (t, 1H, J2–3 = 9.2, H-2), 4.91 (t, 1H, J4–5 = 8.8, H-4), 5.46 (dd,
1H, J3–4 = 9.4, H-3), 5.49 (d, 1H, J1–2 = 10.3, H-1). 13C-NMR
δ 14.7 (MeS), 20.2, 20.3, 20.4 (CH3CO), 26.8
(C-70), 28.2, 28.3, 28.6, 31.4, 33.2 (C-10 to C-60), 62.2 (C-6), 68.2 (C-4), 69.6 (C-2), 72.8 (C-3), 74.4 (C-5),
78.2 (C-1), 154.1 (C=N), 169.4, 169.6, 169.9, 170.2 (C=O). HR-ESI-MS: C23H36NO13S3: calcd. 630.1049;
found 630.1060.
Per-O-acetylated 9-methylsulfanylnonyl glucosinolate 19f. White amorphous powder (85% yield), [α]D −16
(c = 1.0, MeOH). 1H-NMR (DMSO-d6)
δ
1.21–1.40 (m, 10H, H-30 to H-70), 1.44–1.59 (m, 4H, H-20, H-80),
1.95, 1.97, 1.98, 2.00 (4s, 12H, CH3CO), 2.01 (s, 3H, MeS), 2.40–2.54 (m, 4H, H-10, H-90), 3.98–4.14 (m,
3H, H-5, H-6a, H-6b), 4.84 (t, 1H, J2–3 = 9.7, H-2), 4.90 (t, 1H, J4–5 = 8.5, H-4), 5.46 (dd, 1H, J3–4 = 9.7,
H-3), 5.50 (d, 1H, J1–2 = 10.0, H-1). 13C-NMR 15.1 (MeS), 20.2, 20.3, 20.4 (CH3CO), 26.9 (C-90), 28.2,
δ
28.4, 28.5, 28.8, 29.1, 31.6, 34.3 (C-10 to C-80), 62.2 (C-6), 68.4 (C-4), 70.0 (C-2), 73.1 (C-3), 74.7 (C-5),
78.7 (C-1), 154.5 (C=N), 169.3, 169.5, 170.0, 170.3 (C=O). HR-ESI-MS: C25H40NO13S3: calcd. 658.1662;
found 658.1665.
Per-O-acetylated 11-methylsulfanylundecyl glucosinolate 19g. White amorphous powder (84% yield),
[
α
]
−
16 (c = 1.0, MeOH). 1H-NMR (DMSO-d6) 1.24–1.40 (m, 14H, H-30 to H-90), 1.42–1.63 (m, 4H,
δ
D
H-20, H-100), 1.96, 1.98, 2.00, 2.02 (4s, 12H, CH3CO), 2.01 (s, 3H, MeS), 2.47–2.56 (m, 4H, H-10, H-110),
3.93–4.13 (m, 3H, H-5, H-6a, H-6b), 4.86 (t, 1H, J2–3 = 9.6, H-2), 4.93 (t, 1H, J4–5 = 8.8, H-4), 5.47 (dd, 1H,
J3–4 = 9.5, H-3), 5.51 (d, 1H, J1–2 = 10.0, H-1). 13C-NMR
δ 14.71 (MeS), 20.2, 20.3, 20.4 (CH3CO), 26.5
(C-110), 28.8, 29.0, 29.3, 29.5, 29.9, 31.5, 32.4, 34.8 (C-10 to C-100), 62.1 (C-6), 68.4 (C-4), 69.8 (C-2), 73.2
(C-3), 75.1 (C-5), 78.3 (C-1), 154.5 (C=N), 169.4, 169.6, 170.0, 170.3 (C=O). HR-ESI-MS: C27H44NO13S3:
calcd. 686.1975; found 686.1987.
3.2.6. General Procedure for Deprotection of the Glucopyranosyl Moiety
To a suspension of peracetylated glucosinolate 19 (0.1 mmol) in dry methanol (5 mL) under argon,
a freshly prepared 1 M solution of potassium methoxide was added dropwise until the pH reached
9. After 4 h standing at rt, the reaction mixture was neutralized by the addition of Dowex H+ resin.

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After filtration and evaporation in vacuo, the resulting crude was purified by C-18 silica gel column
chromatography (eluent: water) and freeze-drying to provide glucosinolates 2.
2-Methylsulfanylethyl glucosinolate [27303-30-6] 2a. White amorphous powder (80% yield), [
(c = 0.95, H2O). 1H-NMR (D2O) 2.19 (s, 3H, MeS), 2.92–2.98 (m, 2H, H-20), 3.04–3.10 (m, 2H, H-10),
3.44–3.53 (m, 2H, H-2, H-4), 3.58–3.69 (m, 2H, H-3, H-5), 3.76 (dd, 1H, J5–6b = 5.8, Jgem = 13.0, H-6b),
α
]
D
−
27
δ
3.95 (dd, 1H, J5–6a = 2.6, H-6a), 5.09 (d, 1H, J1–2 = 10.1, H-1). 13C-NMR 15.3 (MeS), 30.5 (C-20), 33.0
δ
(C-10), 61.5 (C-6), 70.2 (C-4), 73.5 (C-2), 78.3 (C-3), 81.5 (C-5), 83.1 (C-1), 164.9 (C=N). HR-ESI-MS:
C10H18NO9S3: calcd. 392.0144; found 392.0133.
3-Methylsulfanylpropyl glucosinolate [26888-03-9] 2b
.
Glucoibervirin. White amorphous powder
2.05 (qt, 2H, H-20), 2.16 (s, 3H, MeS), 2.67 (t,
(84% yield), [ δ
α
]
−
21 (c = 1.05, H2O). 1H-NMR (D2O)
D
2H, Jvic = 7.5, H-30), 2.63 (t, 2H, Jvic = 7.5, H-10), 3.46–3.52 (m, 2H, H-2, H-4), 3.55–3.66 (m, 2H, H-3,
H-5), 3.73 (dd, 1H, J5–6b = 5.8, Jgem = 13.2, H-6b), 3.93 (dd, 1H, J5–6a = 2.7, H-6a), 5.09 (d, 1H, J1–2 = 10.1,
H-1). 13C-NMR 15.3 (MeS), 26.7 (C-20), 30.9 (C-30), 34.1 (C-10), 61.4 (C-6), 70.7 (C-4), 73.2 (C-2), 78.2
δ
(C-3), 82.5 (C-5), 83.8 (C-1), 165.1 (C=N). HR-ESI-MS: C11H20NO9S3: calcd. 406.0300; found 406.0291.
4-Methylsulfanylbutyl glucosinolate [21973-56-8] 2c
.
Glucoerucin. White amorphous powder (90% yield),
1
[
α
]
−
20 (c = 1.00, H2O). H-NMR (D2O)
δ
1.67–1.89 (m, 4H, CH2), 2.12 (s, 3H, MeS), 2.61 (t, 2H,
D
Jvic = 7.5, H-40), 2.76 (t, 2H, Jvic = 7.5, H-10), 3.42–3.51 (m, 2H, H-2, H-4), 3.57–3.63 (m, 2H, H-3, H-5),
3.72 (dd, 1H, J5–6b = 5.8, Jgem = 13.1, H-6b), 3.91 (dd, 1H, J5–6a = 2.7, H-6a), 5.06 (d, 1H, J1–2 = 10.1,
H-1). 13C-NMR 15.2 (MeS), 25.7 (C-20), 28.2 (C-30), 31.6 (C-40), 33.0 (C-10), 62.2 (C-6), 71.2 (C-4), 73.5
δ
(C-2), 78.7 (C-3), 81.8 (C-5), 83.0 (C-1), 165.4 (C=N) [47]. HR-ESI-MS: C12H22NO9S3: calcd. 420.0457;
found 420.0453.
5-Methylsulfanylpentyl glucosinolate [29611-01-6] 2d
.
Glucoberteroin. White amorphous powder (90%
yield), [
α
]
−
21 (c = 0.95, H2O). 1H-NMR (D2O)
δ
1.44 (qt, 2H, Jvic = 7.4, H-30), 1.61 (qt, 2H, Jvic = 7.3,
D
H-40) 1.70 (qt, 2H, Jvic = 7.3, H-20), 2.06 (s, 3H, MeS), 2.53 (t, 2H, Jvic = 7.3, H-50), 2.68 (t, 2H, Jvic = 7.3,
H-10), 3.38–3.45 (m, 2H, H-2, H-4), 3.50–3.56 (m, 2H, H-3, H-5), 3.68 (dd, 1H, J5–6b = 5.8, Jgem = 13.1,
H-6b), 3.85 (dd, 1H,0J5–6a = 2.6, 0H-6a), 5.000(d, 1H, J1–2 = 10.0, H-1). 13C-NMR δ 15.1 (MeS), 27.5 (C-30),
0
28.5 (C-2 ), 29.0 (C-4 ), 33.0 (C-5 ), 34.2 (C-1 ), 61.8 (C-6), 70.3 (C-4), 73.3 (C-2), 78.4 (C-3), 81.4 (C-5), 83.0
(C-1), 164.5 (C=N) [48].HR-ESI-MS: C13H24NO9S3: calcd. 434.0613; found 434.0610.
7-Methylsulfanylheptyl glucosinolate [80667-67-0] 2e. White amorphous powder (90% yield), [
(c = 1.00, H2O). 1H-NMR (D2O)
1.24–1.39 (m, 6H, CH2), 1.44–1.65 (m, 4H, CH2), 2.01 (s, 3H, MeS),
2.38–2.54 (m, 4H, CH2), 3.45–3.52 (m, 2H, H-2, H-4), 3.55–3.63 (m, 2H, H-3, H-5), 3.68 (dd, 1H, 5–6b = 5.7
15.1(MeS),
α
]
D
−
22
δ
J
,
J
gem = 12.8, H-6b), 3.89 (dd, 1H, J5–6a = 2.6, H-6a), 5.06 (d, 1H, J1–2 = 10.0, H-1). 13C-NMR
δ
27.8, 28.7, 28.9 (C-30-C-50), 29.0 (C-20), 29.2 (C-60), 33.0 (C-10), 34.3 (C-70), 61.6 (C-6), 70.1 (C-4), 73.0
(C-2), 78.2 (C-3), 81.2 (C-5), 82.9 (C-1), 165.4 (C=N). HR-ESI--MS: C15H28NO9S3: calcd. 462.0926; found
462.0932 [48]. HR-ESI-MS: C15H28NO9S3: calcd. 462.0926; found 462.0919.
9-Methylsulfanylnonyl glucosinolate [81149-01-1] 2f. White amorphous powder (93% yield), [
(c = 0.84, H2O). 1H-NMR (D2O)
1.21–1.40 (m, 10H, CH2), 1.44–1.59 (m, 4H, CH2), 2.00 (s, 3H, MeS),
2.43–2.58 (m, 4H, (CH2), 3.40–3.51 (m, 2H, H-2, H-4), 3.57–3.62 (m, 2H, H-3, H-5), 3.71 (dd, 1H,
α
]
−
19
D
δ
J
5–6b = 5.7, Jgem = 13.0, H-6b), 3.91 (dd, 1H, J5–6a = 2.7, H-6a), 5.06 (d, 1H, J1–2 = 10.1, H-1). 13C-NMR
δ
15.4 (MeS), 26.9, 28.2, 28.4, 28.6 (C-30-C-70), 28.9 (C-20), 29.2 (C-80), 31.9 (C-10), 34.6 (C-90), 61.4 (C-6),
70.5 (C-4), 73.4 (C-2), 78.3 (C-3), 82.2 (C-5), 83.5 (C-1), 164.8 (C=N). HR-ESI-MS: C17H32NO9S3: calcd.
490.1239; found 490.1231.
11-Methylsulfanylundecyl glucosinolate 2g. Colourless gum (91% yield), [
1H-NMR
(D2O) 1.26–1.44 (m, 10H, CH2), 1.42–1.63 (m, 4H, (CH2), 2.02 (s, 3H, MeS), 2.44–2.56 (m, 4H,
(CH2), 3.39–3.50 (m, 2H, H-2, H-4), 3.54–3.61 (m, 2H, H-3, H-5), 3.74 (dd, 1H, J5–6b = 5.8, gem = 13.0
H-6b), 3.93 (dd, 1H, J5–6a = 2.6„ H-6a), 5.06 (d, 1H, , J1–2 = 10.1, H-1). 13C-NMR
15.2 (MeS), 26.5, 28.9,
α
]
−
21 (c = 0.92, H2O).
D
δ
J
,
δ

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0
0
0
0
0
0
29.0, 29.5 (C3 -C-9 ), 29.7 (C-2 ), 30.0 (C-10 ), 32.2 (C-1 ), 34.8 (C-11 ), 61.6 (C-6), 70.2 (C-4), 73.1 (C-2), 78.7
(C-3), 81.3 (C-5), 83.0 (C-1), 165.4 (C=N). HR-ESI-MS: C19H36NO9S3: calcd. 518.1552; found 518.1547.
4. Conclusions
We have developed a general pathway for the synthesis of biologically critical
GLs involving tailor-made -methylsulfanyl nitroalkanes precursors. Synthetic conditions to access those
key-intermediates were adjusted according to the length of the alkyl chain that is required. Extension of this
ω-methylsulfanylalkyl
ω
work to the synthesis of
research group.
ω-methylsulfinyl and ω-methylsulfonyl GLs is under current development in our
Acknowledgments: The authors are grateful to Vassilis Dourtoglou (Vioryl S.A., Afidnes, Greece) and the
Greek-French Platon PHC. We also wish to thank Agnès Chartier for GC expertise. The multiform support of
Gérald Guillaumet (University of Orléans) is sincerely acknowledged.
Author Contributions: P.R. designed the synthetic route and M.M. performed the experimental work, P.R. wrote
the manuscript, which was revised by S.C. and S.M.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
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2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).