Improved Synthesis of Glucosinolates

Article abstract of DOI:10.1055/s-0036-1591895

Herein we describe an improved synthesis of glucosinolates, in which the quantity and cost of materials have been reduced by approximately an order of magnitude compared to typical literature procedures. This allowed us to produce multiple glucosinolates in 10-25 gram batches using vessel sizes no larger than 0.5 litres.

Full text of DOI:10.1055/s-0036-1591895

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–K
paper
A
en
Y. W. Lim et al.
Paper
Synthesis
Improved Synthesis of Glucosinolates
Yi Wee Lim
KO3SO
N
O
OH
OH
Michelle Jui Hsien Ong
HO
O
O
S
R
Russell J. Hewitt*
0
0
0
0
0-
0
0
3
3-
4
9
3
0-
3
5
6
+
HO
HO
HO
H
R
OH
OH
Division of Organic Chemistry, Institute of Chemical and
Engineering Sciences, Agency for Science, Technology and
Research (A*STAR), 8 Biomedical Grove, #07-01 Neuros
Building, Biopolis 138665, Singapore
Up to 40% yield from D-glucose
Average PMI <100
Scale up to 25 grams
OH
russell_hewitt@ices.a-star.edu.sg
Received: 27.10.2017
Accepted: 15.12.2017
Published online: 24.01.2018
DOI: 10.1055/s-0036-1591895; Art ID: ss-2017-t0694-op
Derived from amino acids,6 glucosinolates undergo
degradation to produce a variety of compounds including
isothiocyanates and nitriles. This conversion occurs in the
presence of the myrosinase enzyme, contained in a sepa-
rate compartment within plants. In addition, degradation
can be promoted by gut microflora and various other
stimuli such as acid/alkali, or high temperatures when
cooking such vegetables.5,7 Isothiocyanates in particular are
known for their wide-ranging bioactivities which may be
exploited in a multitude of medicinal and antimicrobial ap-
plications, including protection against carcinogenesis.7,8
However, the poor availability of pure glucosinolates
remains a barrier for further studies, with most chemical
suppliers providing pack sizes of 100 mg or less. Sinigrin (1,
R = allyl), the most common glucosinolate, is the least ex-
pensive and most readily available, with pack sizes of up to
1 g. The typical route for the synthesis of glucosinolates
Abstract Herein we describe an improved synthesis of glucosinolates,
in which the quantity and cost of materials have been reduced by ap-
proximately an order of magnitude compared to typical literature pro-
cedures. This allowed us to produce multiple glucosinolates in 10–25
gram batches using vessel sizes no larger than 0.5 litres.
Key words carbohydrates, glucosinolates, green chemistry, isothio-
cyanates, scale-up
Glucosinolates1–5 are found extensively in plants of the
family Brassicaceae (formerly Cruciferae), among selected
others. Within this family, Brassica oleracea is undoubtedly
one of the most important plants in human nutrition, with
its cultivars now comprising a large number of green vege-
tables. Glucosinolates 1 share the common structure as de-
tailed in Scheme 1, with variation only in the side chain.
The number of glucosinolates known is now approximately
200, with several of the most common side chains exempli-
fied in Scheme 1.
O
OH
OH
O
SH
HO
AcO
AcO
HO
OAc
OH
OAc
2
KO3SO
N
HO
Cl
N
O
N
R
myrosinase
O
S
R
R
NCS
+
3
R
CN
HO
HO
R
O
4
OH
HO
KO3SO
OH
N
N
1
O
S
R
S
R
R = allyl
PhCH2
(sinigrin)
(glucotropaeolin)
PhCH2CH2 (gluconasturtiin)
MeS(CH2)4 (glucoerucin)
MeSO(CH2)4 (glucoraphanin)
AcO
AcO
HO
OAc
HO
OH
OAc
OH
1
Scheme 1 Glucosinolates as isothiocyanate and nitrile precursors
Scheme 2 Typical synthesis of glucosinolates
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

B
Y. W. Lim et al.
Paper
Synthesis
(Scheme 2) was first established by Benn9 in 1963, and sub-
sequently many others have followed this synthesis to ob-
tain a variety of glucosinolates.10–16
they too would undergo degradation to provide the antimi-
crobial isothiocyanates in a similar manner to the natural
glucosinolates.
This route involves coupling of thiosugar 2 with nitrile
oxides 3, usually generated in situ via base treatment of
N-hydroxyimidoyl chlorides 4, which in turn are typically
accessed by chlorination of either an aldoxime, or a nitro-
nate (azinate) salt.10,11 The aldoxime pathway is the most
straightforward; however, in the case of sinigrin and others,
the nitronate pathway may be necessary to achieve chlori-
nation.10–12 While most synthetic procedures report the
preparation of glucosinolates in milligram to gram quanti-
We initially prepared two exemplary glucosinolates,
gluconasturtiin (2-phenylethylglucosinolate) and n-heptyl-
glucosinolate, with procedures closely following those typi-
cal in literature syntheses.13,15 This also allowed us to gain
insight into where costs and materials use could be re-
duced. The experimental for this synthesis is given in the
Supporting Information, and all modifications to this meth-
odology are discussed below.
Embarking on our improved synthesis, we formed
oximes 5 via reaction of the corresponding aldehydes with
hydroxylamine hydrochloride (Scheme 3). Sodium hydrox-
ide was used to incompletely neutralise the hydroxylamine
salt, as complete neutralisation leads to side reactions in
the case of aliphatic aldehydes, presumably via aldol
condensations under the alkaline conditions.
ties,
a notable exception is that of Abramski and
Chmielewski’s preparation of sinigrin in a quantity in the
tens of grams.11 We sought to further improve the synthesis
of glucosinolates, with a focus on the more common aldox-
ime-based pathway. In addition to preparing multigram
quantities of synthetic glucosinolates on the laboratory
scale, we incorporated green chemistry principles to ensure
the cost and quantity of materials were minimised, and the
majority of hazardous materials were either removed or re-
placed. We therefore approached this synthesis with a com-
plete analysis of the entire process, to ensure it could be
made as safe and efficient as possible. To ensure our synthe-
sis was robust, reliable and applicable to a wide range of
glucosinolates, we elected to continue to use the typical
synthesis outlined in Scheme 2, despite the number of steps
involved. Whilst elimination of protecting groups offers
greater simplicity, we chose not to, as this would likely
complicate isolation and purification of intermediates, for
comparatively little overall benefit in cost or materials use.
Fortunately, we realised certain intermediates did not re-
quire isolation or purification, which led to a dramatic
reduction in materials use and process steps.
We elected to commence our synthesis from D-glucose,
due to its low cost compared to more advanced, commer-
cially available intermediates such as thiosugar 2. This also
ensured we kept to the recommendation of avoiding expen-
sive or rare starting materials, as suggested by Sheldon and
co-workers.17 The common core structure of glucosinolates
allows access to a large number of analogues, simply by
changing the N-hydroxyimidoyl chloride 4 in the synthesis
depicted in Scheme 2. In our case, we chose to employ read-
ily available aldehydes to demonstrate the utility of our im-
proved synthesis. Of the common natural glucosinolates,
glucotropaeolin (1, R = CH2Ph) and gluconasturtiin (1,
R = CH2CH2Ph) may be prepared from 2-phenylacetalde-
hyde and 3-phenylpropionaldehyde, respectively, both of
which are naturally occurring and commercially available
fragrance compounds. In addition to these, we sought access
to three glucosinolates with n-alkyl side chains, derived
from butyraldehyde, hexanal and octanal. It is noteworthy
that such alkylglucosinolates are also observed in nature,
albeit in low concentrations compared to the more well-
known glucosinolates (Scheme 1),2 yet it is expected that
a
b
c
d
e
HO
R = PhCH2
O
(a)
N
R = PhCH2CH2
R = n-propyl
R = n-pentyl
R = n-heptyl
H
R
H
R
5a–e
Scheme 3 Preparation of oximes 5. Reagents and conditions: (a)
NH2OH·HCl, NaOH, MeOH, H2O (5a,b), r.t. to 40 °C, 2 h, 83–98%.
The reaction is normally buffered at a lower pH, in
which sodium acetate is often used as a base; however, the
change to sodium hydroxide eliminated the need for labori-
ous quenching of the acetic acid formed after neutralisation
of the hydroxylamine hydrochloride. Running the reaction
in aqueous methanol allowed for concentration of the
solution and subsequent precipitation of the product, for
the 2-phenylacetaldehyde and 3-phenylpropionaldehyde
oximes. In contrast, the aliphatic oximes failed to crystallise,
as their melting points are low. Thus, for these substrates,
the reaction was performed in methanol only, which was
then thoroughly evaporated to provide a slurry of primarily
oxime and inorganic materials. This slurry was diluted with
ethyl acetate and filtered to remove the inorganic salts,
which was followed by concentration of the filtrate to pro-
vide the neat oxime. All oximes were obtained in high yield
(83–98%) and in good purity, provided the aldehydes were
distilled before use.
Typically, thiosugar 2 is obtained from D-glucose (6) via
acetobromoglucose (7, Scheme 4), which in turn is formed
in a one-pot procedure via acid-catalysed acetylation and
subsequent addition of excess hydrogen bromide (typically
as a solution in acetic acid). Literature precedence18,19
shows that hydrogen bromide can function as the acid cata-
lyst, circumventing the need for typical catalysts such as
perchloric acid (explosive) and sulfuric acid (acetylation
difficult to control). While hydrogen bromide is not as
effective a catalyst for acetylation, this ensures the exo-
thermic reaction may be easily controlled with occasional
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Y. W. Lim et al.
Paper
Synthesis
submersion in an ice bath. We found we could reduce the
typical amount of both acetic anhydride and hydrogen bro-
mide, which also allowed us to add the entire portion of
hydrogen bromide at the beginning of the reaction, to act as
both acylation catalyst and the brominating agent. Upon
complete dissolution of the sugar (<30 min), the reaction
was held for several hours to ensure high conversion into
the bromosugar 7.
aqueous phase as it forms. To prevent the conversion of
thiosugar 2 into the disulfide (i.e., dimerisation),20 we used
degassed solutions and maintained a stream of argon
throughout the reaction. The thiol was isolated in very good
purity and near quantitative yield from 8; thus, it was de-
termined the isolation of 2 was not necessary in the scale-
up synthesis of glucosinolates. Upon full optimisation of all
steps, the thiol was liberated and immediately used as a
solution in ethyl acetate to form the thiohydroximates 9
without purification (Scheme 5).
O
OH
OH
O
Br
HO
HO
AcO
AcO
(a)
As N-hydroxyimidoyl chlorides are known to be unsta-
ble,12,21 we telescoped the formation of the N-hydroxyimi-
doyl chloride and the subsequent coupling with the thio-
sugar (see Scheme 5). We were inspired by an earlier syn-
thesis of isoxazoles,22 which also utilises nitrile oxide
precursors, adapting this protocol for thiohydroximates.
The use of ethyl acetate as solvent allowed us to eliminate
N,N-dimethylformamide from our synthesis, which is typi-
cally the solvent of choice for this step.13,15 We observed
that this chlorination step gave an intense blue colour, pre-
sumably due to elemental chlorine, generated upon reac-
tion of the hydrochloric acid catalyst with the N-chloro-
succinimide.22 We were able to add the oximes neat, in a
single portion to the reaction mixture, which in our hands
led to a moderate exotherm at scale (0.1 mol); the internal
temperature within the round-bottomed flask typically
rose to ca. 50 °C. Upon addition of thiosugar 2, we observed
unreacted N-chlorosuccinimide could oxidise thiosugar 2 to
its disulfide. We thus employed a ca. 5 mol% excess of ox-
ime for the chlorination step, to ensure full consumption of
the N-chlorosuccinimide. This also allowed us to monitor
the chlorination, which was complete upon loss of the blue
colour, indicating the N-chlorosuccinimide was fully con-
sumed. Once the chlorination step was fully optimised, we
moved on to telescoping this step with the subsequent
base-mediated generation of the nitrile oxide, and sub-
sequent coupling with thiosugar 2. Indeed, precursors 5
and 8 could be simultaneously converted into the thiosugar
and the N-hydroxyimidoyl chloride, respectively, then the
two mixtures combined as solutions of ethyl acetate. Sub-
sequent treatment with a solution of aqueous potassium
carbonate allowed conversion of the N-hydroxyimidoyl
chloride into the required nitrile oxide (not shown in
Scheme 5).
OAc
OH
OAc
(b)
6
7
HN
NH2·HBr
O
SH
AcO
AcO
O
S
(c)
AcO
AcO
OAc
OAc
OAc
OAc
2
8
Scheme 4 Synthesis of thiosugar 2. Reagents and conditions: (a) Ac2O,
33% (w/w) HBr in AcOH, r.t. to 55 °C, 3 h; (b) thiourea, 80 °C, 1 h, 68%
from 6; (c) Na2SO3, H2O, EtOAc, 40 °C, 1 h, 99%.
Acetobromoglucose (7) is usually isolated by dissolution
with dichloromethane, followed by washing with copious
amounts of water and sodium bicarbonate solution to re-
move the large quantity of hydrobromic and acetic acids,
then recrystallisation from diethyl ether. To create a suit-
ably safe and scalable synthesis, we sought to eliminate
both of these hazardous organic solvents, and the laborious
workup. We reasoned that isolation of acetobromoglucose
was not strictly necessary, as the reaction of alkyl halides
with thiourea can be performed in a variety of solvents. For
acetobromoglucose, it is important to avoid the use of
alcohols as solvent, which can lead to deacetylation of the
sugar.
Therefore, the solution of acetobromoglucose (7) was
treated with sodium acetate to neutralise the excess hydro-
gen bromide,19 then the precipitated sodium bromide was
removed by filtration, followed by washing the precipitate
with a small quantity of ethyl acetate. This crude filtrate
solution, comprised primarily of acetobromoglucose in ace-
tic acid, was directly reacted with thiourea. This simplified
protocol provided the glucosylisothiouronium salt 8, which
precipitated from the reaction mixture, and was simply fil-
tered and washed with ethyl acetate. The product was iso-
lated in 68% yield from D-glucose in three chemical steps,
and was deemed to be adequately pure. This protocol was
routinely performed using 50-gram batches of D-glucose.
Hydrolysis of glucosyl salt 8 to liberate the thiol func-
tionality (thiosugar 2) was conducted in aqueous sodium
sulfite (less odorous than sodium metabisulfite) and ethyl
acetate, which serves to extract the thiosugar from the
Thiosugar 2 was added to the N-hydroxyimidoyl chlo-
ride before the base, to minimise the dimerisation of nitrile
oxide to furoxans.21,23 This efficient click-like reaction gave
us the thiohydroximate products 9 in yields of 70–86% from
glucosyl salt 8, without any isolation of the thiosugar or
N-hydroxyimidoyl chloride intermediates. Upon completion
of the reaction and brief workup, the organic phase was
concentrated, then the product recrystallised from aqueous
methanol to remove the majority of the impurities, primar-
ily furoxans and succinimide. For 2-phenethyl thiohydroxi-
mate 9b, the product precipitated from solution during the
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Y. W. Lim et al.
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Synthesis
HN
NH2·HBr
O
SH
AcO
AcO
O
S
(a)
AcO
AcO
OAc
OAc
(b)
OAc
(c)
OAc
2
8
HO
H
HO
Cl
N
N
R
R
KO3SO
KO3SO
HO
N
N
N
5a–e
4a–e
(d)
(e)
O
S
R
O
S
R
O
S
R
AcO
AcO
HO
HO
AcO
AcO
a
b
c
d
e
R = PhCH2
R = PhCH2CH2
R = n-propyl
R = n-pentyl
R = n-heptyl
OAc
OH
OAc
OAc
OH
OAc
9a–e
10a–e
1a–e
Scheme 5 Synthesis of glucosinolates. Reagents and conditions: (a) Na2SO3, H2O, EtOAc, r.t., 1–1.5 h; (b) N-chlorosuccinimide, cat. py (5a), cat. concd
HCl (5b–d), EtOAc, r.t. to 50 °C, 1–4 h; (c) K2CO3, H2O, r.t., 1 h, 70–86% from 8; (d) i) py·SO3, cat. py, MeCN, reflux, 1–2.5 h, ii) K2CO3, H2O, EtOAc, 60 °C,
10 min, 51–75% from 9; (e) cat. KOH, MeOH, r.t., 2–2.5 h, 95% to quantitative.
coupling reaction; after the workup, the precipitate was
isolated, and a second crop was obtained after partial con-
centration of the filtrate. This provided 9b in comparable
purity to the other thiohydroximates, obviating the need
for recrystallisation.
The initial attempt at forming benzyl thiohydroximate
9a was unsuccessful at scale, providing a complex mixture
of which ca. 50% of the material was the desired product.
Investigation revealed the chlorination of benzyl oxime was
generating a number of products, as determined by TLC and
NMR analysis, presumably due to the lability of the benzylic
position. This was solved by conducting the chlorination
with catalytic pyridine, which required a higher tempera-
ture and extended reaction time. Subsequent coupling pro-
ceeded well, with the yield comparable to the other ana-
logues, despite the smaller scale used (1 g).
The sulfation of thiohydroximates 9 was also improved,
although it remains a challenging step, as previously not-
ed.13 While typical procedures exploit a large excess (ca.
2.5–5 equiv) of pyridine–sulfur trioxide complex,13–16 we
realised this was likely to provide full conversion and/or to
allow for partially hydrolysed batches of the complex to be
used. Reduction of the amount of complex used was a key
focus for this step, primarily due to the high cost of this re-
agent. Dichloromethane is the solvent of choice when this
reagent is used in glucosinolate synthesis; however, we
found any aprotic solvent promoted sulfation of the thio-
hydroximates 9. Slow conversion was observed in acetone
and ethyl acetate, which was attributed to poor solubility of
pyridine–sulfur trioxide complex in these solvents. Acetoni-
trile, however, offered an excellent alternative due to its ad-
equate solubilisation of the complex, plus the higher reflux
temperature ensured complete reaction occurred within a
few hours. Careful monitoring of the reaction was required,
as under extended reaction times the material underwent
degradation, as evidenced by the presence of the previously
observed thiosugar disulfide in the reaction mixture. With
anhydrous acetonitrile, we found just 1.5 equivalents of the
complex was sufficient, even when using a batch that was
several years old.
Subsequent treatment with potassium carbonate and
isolation converted the intermediate pyridinium salts into
the potassium salts 10. This base was chosen in place of the
more expensive and less common potassium bicarbonate; a
slight excess of base and rapid stirring were used to avoid
hydrolysis of the acetate groups. The high polarity of the
sulfated products 10 led us to attempt recrystallisation
from methanol; unfortunately, this also led to partial desul-
fation of the material, as observed previously.13 We noted
the products were sparingly soluble in both water and ethyl
acetate; thus, recrystallisation from a mixture of these sol-
vents was sufficient to remove all impurities, such as water-
soluble reagent byproducts and any residual starting
material. This atypical crystallisation using a mixture of
immiscible solvents became a single phase with full dis-
solution of the product only when approaching the boiling
point of ethyl acetate.
Deprotection of acetylated glucosinolates is usually per-
formed using either ammonia or potassium methoxide in
methanol, to provide the glucosinolates as the natural
potassium salts. We elected to use potassium hydroxide in
methanol, which would introduce a small quantity of water
in the reaction. Nevertheless, this was not deemed to be a
problem due to the small amount of base required (0.05
equiv, or 0.0125 equiv per acetate group). The deprotection
proceeded swiftly, with full conversion achieved within 2
hours for all substrates. In the preliminary synthesis, the re-
action mixtures were neutralised with sulfonic acid func-
tionalised Amberlite®, yet this appeared to cause colouring
of the material. For the scale-up batches, neutralisation was
achieved with carboxylic acid functionalised Amberlite®,
followed by treatment with charcoal for further decolouri-
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E
Y. W. Lim et al.
Paper
Synthesis
sation. Concentration and drying under reduced pressure
provided the glucosinolates in quantities of up to 25 grams
per batch.
The completed synthesis gave us overall yields of 25–
40% from D-glucose (seven chemical steps). The improved
protocol involves only five isolation steps, of which only ad-
vanced intermediates 9 and 10 required purification.
A summary of the synthetic route is given in Table 1,
with PMI (process mass intensity) given. Calculations used
procedures given in the experimental section and the Sup-
porting Information. While the yields were comparable
with the preliminary routes, the clear advantage in this
synthesis is shown by the dramatic reduction in PMI. For
the syntheses of 1b and 1e, the improvement is by approxi-
mately an order of magnitude (reduction in PMI 94% (1b)
and 96% (1e)).
Figure 1 Solvent distribution in the synthesis of gluconasturtiin (1b)
In summary, we have demonstrated a complete trans-
formation of the standard aldoxime pathway for the syn-
thesis of glucosinolates. The synthetic procedures have
been dramatically simplified and demonstrated to be suc-
cessful on a multigram scale. This allows for the synthesis of
significant quantities of glucosinolates using a fraction of
the materials of a typical synthesis. We anticipate this work
will enable further progress in glucosinolate research.
Table 1 Comparison between Preliminary and Scale-Up Routes of 1
Glucosinolate Route
PMI (g/g)
Overall yield from 6
1H and 13C NMR spectra were recorded on a Bruker NMR spectrome-
ter operating at 400 MHz for 1H and 100 MHz for 13C acquisitions.
Chemical shifts (δ) are reported in parts per million (ppm) from TMS
(0.00 ppm). NMR spectra were referenced to the residual solvent
peaks (CDCl3: 7.26 ppm for 1H, 77.16 ppm for 13C; DMSO-d6: 2.50 ppm
for 1H, 39.52 ppm for 13C; D2O: not referenced). IR spectra were re-
corded neat on a PerkinElmer Spectrum 100 FT-IR spectrophoto-
meter. High-resolution mass spectra were obtained on an Agilent
LC-TOF instrument using an electrospray ionisation (ESI) source in
either positive mode or negative mode, as indicated by the reported
ion. Elemental analyses were performed on a Eurovector EuroEA3000
CHNS Elemental Analyzer. Unless otherwise stated, products were
synthesised using the general procedures outlined below and were
used without further purification in all cases. Anhydrous MeCN was
obtained by passing commercially available, pre-dried, oxygen-free
solvent through activated columns. Aldehydes were distilled immedi-
ately before reactions. All other reagents and solvents were of analyt-
ical quality and used as received.
1a
1b
1b
1c
1d
1e
1e
scale-up
160
62
34%
40%
43%
25%
32%
40%
29%
scale-up
preliminary
scale-up
1000
91
scale-up
72
scale-up
56
preliminary
1500
The reduction in PMI was principally achieved by elimi-
nating all chromatographic purification, and running all op-
erations at high solvent concentration, in addition to the
process improvements mentioned earlier. This also allows
such scale-up procedures to be done in standard research
lab glassware, in which vessel sizes of up to 0.5 litre were
employed, even on a 50 gram reaction scale. This significant
reduction in PMI also allows an approximately 10-fold
reduction in the cost of materials, as determined based on
the current (2017) costing for the procedures described.
Furthermore, the solvent contributions have changed
dramatically, both in identity and quantity (ca. 20-fold re-
duction). As an example, the charts in Figure 1 compare the
preliminary and improved synthesis of 1b. The solvent use
was critically evaluated throughout the synthesis, and we
successfully eliminated hazardous solvents such as di-
chloromethane, diethyl ether, N,N-dimethylformamide and
hexanes. The solvent inventory used for scale-up is both
simple and safe, eliminating all solvents which are regarded
as in need of replacement in pharmaceutical manufactur-
ing.24,25
All scale-up procedures are given below; preliminary experimental
procedures, all of which closely follow prior literature, are given in the
Supporting Information, with characterisation data for compounds
that are not listed in the experimental section. Copies of NMR spectra
for all isolated materials from scale-up procedures (i.e., compounds 1,
5, 8–10) are given in the Supporting Information.
Aromatic Oximes 5a and 5b; General Procedure
A solution of NaOH (ca. 0.275 mol) in H2O (100 mL) was diluted with
MeOH (250 mL), then treated successively with hydroxylamine hydro-
chloride (ca. 0.300 mol) and aldehyde (ca. 0.250 mol). Upon addition
of the aldehyde, a minor exotherm was observed, with the internal
temperature rising to ca. 40 °C. The reaction mixture was stirred at r.t.
for 2 h. The mixture was concentrated to remove the MeOH, then
filtered. The precipitate was washed with H2O (2 × 25 mL) and dried
under vacuum to provide the oxime as a white crystalline solid.
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Y. W. Lim et al.
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Synthesis
2-Phenylacetaldehyde Oxime (5a)
13C NMR (100 MHz, CDCl3): δ = 153.1 (Z), 152.4 (E), 31.5 (E), 27.0 (Z),
20.1 (E), 19.6 (Z), 14.0 (Z), 13.7 (E).
HRMS-TOF: m/z [M + H]+ calcd for C4H10NO+: 88.0757; found:
NaOH (10.96 g, 0.274 mol) was treated with hydroxylamine hydro-
chloride (20.85 g, 0.300 mol) and 2-phenylacetaldehyde (30.06 g,
0.250 mol). Oxime 5a was obtained as a white crystalline solid (33.19
g, 98%). The NMR data were in excellent agreement with those previ-
ously obtained.26,27
88.0760.
Hexanal Oxime (5d)
Mp 82–84 °C (Lit.28 83–86 °C).
NaOH (10.99 g, 0.275 mol) was treated with hydroxylamine hydro-
chloride (20.90 g, 0.301 mol) and hexanal (25.13 g, 0.251 mol). Oxime
5d was obtained as a white crystalline solid (27.24 g, 94%). The NMR
data were in excellent agreement with those previously obtained.29
IR: 3209, 3087, 3029, 2870, 1662, 1497, 1454, 1438, 1328, 1056, 927,
749, 696 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.85 (br s, 1 H (E or Z)), 7.54 (t, J = 6.3
Hz, 1 H (E)), 7.41 (br s, 1 H (E or Z)), 7.35–7.31 (m, 2 H), 7.28–7.21 (m,
3 H), 6.90 (t, J = 5.3 Hz, 1 H (Z)), 3.74 (d, J = 5.2 Hz, 2 H (Z)), 3.54 (d,
J = 6.3 Hz, 2 H (E)).
13C NMR (100 MHz, CDCl3): δ = 151.1 (Z), 150.9 (E), 136.6, 136.2,
129.0, 128.94, 128.90, 127.1, 126.9, 36.0 (E), 31.8 (Z).
Mp 44–47 °C (Lit.30 51 °C).
IR: 3250, 2958, 2929, 2861, 1466, 1324, 1049, 931, 722 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.16 (br s, 1 H (E or Z)), 7.78 (br s, 1 H
(E or Z)), 7.42 (t, J = 6.1 Hz, 1 H (E)), 6.72 (t, J = 5.5 Hz, 1 H (Z)), 2.37 (td,
J = 7.6, 5.5 Hz, 2 H (Z)), 2.19 (td, J = 7.5, 6.2 Hz, 2 H (E)), 1.48 (quin,
J = 7.2 Hz, 2 H), 1.37–1.28 (m, 4 H), 0.91–0.87 (m, 3 H).
HRMS-TOF: m/z [M + H]+ calcd for C8H10NO+: 136.0757; found:
13C NMR (100 MHz, CDCl3): δ = 153.3 (Z), 152.6 (E), 31.7, 31.4, 29.6,
136.0758.
26.4, 25.9, 25.0, 22.50, 22.49, 14.06, 14.05.
3-Phenylpropionaldehyde Oxime (5b)
HRMS-TOF: m/z [M + H]+ calcd for C6H14NO+: 116.1070; found:
NaOH (11.06 g, 0.277 mol) was treated with hydroxylamine hydro-
chloride (20.83 g, 0.300 mol) and 3-phenylpropionaldehyde (33.58 g,
0.250 mol). Oxime 5b was obtained as a white crystalline solid (36.2
g, 97%). The NMR data were in excellent agreement with those previ-
ously obtained.29
116.1073.
Octanal Oxime (5e)
NaOH (11.08 g, 0.277 mol) was treated with hydroxylamine hydro-
chloride (20.86 g, 0.300 mol) and octanal (32.13 g, 0.251 mol). Oxime
5e was obtained as a white crystalline solid (35.17 g, 98%). The NMR
data were in excellent agreement with those previously obtained.31
Mp 83–84 °C (Lit.28 92–94 °C).
IR: 3189, 3062, 3028, 2860, 1662, 1500, 1456, 1431, 1311, 1078, 938,
920, 912, 850, 758, 724, 700 cm–1
.
Mp 49–51 °C (Lit.30 60 °C).
1H NMR (400 MHz, CDCl3): δ = 8.38 (br s, 1 H (E or Z)), 7.91 (br s, 1 H
(E or Z)), 7.47 (t, J = 5.9 Hz, 1 H (E)), 7.33–7.29 (m, 2 H), 7.23–7.19 (m,
3 H), 6.76 (t, J = 5.3 Hz, 1 H (Z)), 2.85–2.81 (m, 2 H), 2.75–2.69 (m, 2 H
(Z)), 2.53 (td, J = 7.8, 6.0 Hz, 2 H (E)).
13C NMR (100 MHz, CDCl3): δ = 152.0 (Z), 151.6 (E), 140.8, 140.6,
128.7, 128.5, 128.4, 126.4, 32.9 (E), 32.1 (Z), 31.4 (E), 26.5 (Z).
IR: 3209, 2957, 2925, 2855, 1466, 1323, 921, 865, 825, 721 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.89 (br s, 1 H (E or Z)), 7.52 (br s, 1 H
(E or Z)), 7.42 (t, J = 6.1 Hz, 1 H (E)), 6.71 (t, J = 5.5 Hz, 1 H (Z)), 2.37 (td,
J = 7.6, 5.5 Hz, 2 H (Z)), 2.19 (td, J = 7.5, 6.2 Hz, 2 H (E)), 1.48 (quin,
J = 7.3 Hz, 2 H), 1.36–1.22 (m, 8 H), 0.90–0.86 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 153.4 (Z), 152.7 (E), 31.86, 31.85, 29.6,
29.5, 29.2, 29.13, 29.11, 26.7, 26.2, 25.1, 22.6, 14.2.
HRMS-TOF: m/z [M + H]+ calcd for C9H12NO+: 150.0913; found:
150.0915.
HRMS-TOF: m/z [M + H]+ calcd for C8H18NO+: 144.1383; found:
144.1384.
Alkyl Oximes 5c–e; General Procedure
A solution of NaOH (ca. 0.275 mol) in MeOH (80 mL) was treated with
a solution of hydroxylamine hydrochloride (ca. 0.300 mol) in MeOH
(170 mL), then treated with freshly distilled aldehyde (ca. 0.250 mol).
Upon addition of the aldehyde, a minor exotherm was observed, with
the internal temperature rising to ca. 40 °C. The reaction mixture was
stirred at r.t. for 2 h. The mixture was concentrated to remove the
MeOH, filtered, then the precipitated salt was washed with EtOAc
(100 mL). The filtrate was concentrated to provide the oxime as a
clear colourless liquid or a white crystalline solid.
S-(2,3,4,6-Tetra-O-acetyl-1-β-D-glucopyranosyl)isothiouronium
Bromide (8)
A magnetically stirred solution of D-glucose (6; 50.04 g, 0.278 mol) in
Ac2O (140 mL, 1.48 mol) was treated with a solution of 33% (w/w)
HBr in AcOH (80 mL, 0.444 mol), and allowed to react, using an ice
bath to maintain a temperature of 45–55 °C. After complete con-
sumption of the D-glucose, the mixture was stirred at 35 °C for 3 h.
Then, the mixture was neutralised with NaOAc (13.64 g, 0.166 mol),
and filtered to remove the precipitated NaBr, which was washed with
a small quantity of EtOAc (20 mL). The filtrate was treated with
thiourea (21.12 g, 0.277 mol), then placed on a heating mantle pre-
heated to 80 °C. Upon dissolution of the thiourea, the solution was
seeded with a small quantity of product 8 (1.02 g, 2.1 mmol), and al-
lowed to react further (1 h total heating time). The mixture was
cooled in a fridge overnight, filtered, washed with EtOAc (80 mL),
then dried under reduced pressure to provide compound 8 (93.35 g,
68% excluding seed material). The NMR data were in excellent agree-
ment with those previously obtained.32
Butyraldehyde Oxime (5c)
NaOH (11.10 g, 0.278 mol) was treated with hydroxylamine hydro-
chloride (20.88 g, 0.300 mol) and butyraldehyde (18.16 g, 0.252 mol).
Oxime 5c was obtained as a clear colourless liquid with ca. 4.9% (w/w)
EtOAc (19.15 g, 83%). The NMR data were in excellent agreement with
those previously obtained.27
IR: 3259, 3107, 2964, 2936, 2876, 1461, 933, 885 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.09 (br s, 1 H (E or Z)), 8.70 (br s, 1 H
(E or Z)), 7.42 (t, J = 6.2 Hz, 1 H (E)), 6.72 (t, J = 5.4 Hz, 1 H (Z)), 2.36 (td,
J = 7.5, 5.4 Hz, 2 H (Z)), 2.18 (td, J = 7.3, 6.2 Hz, 2 H (E)), 1.52 (sext,
J = 7.5 Hz, 2 H), 0.98–0.93 (m, 3 H).
Mp 192–193 °C (Lit.32 203–204 °C).
IR: 3268, 3055, 1753, 1655, 1371, 1252, 1221, 1055, 1036 cm–1
.
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G
Y. W. Lim et al.
Paper
Synthesis
1H NMR (400 MHz, DMSO-d6): δ = 9.12 (br s, 4 H), 5.67 (d, J = 9.9 Hz, 1
H), 5.32 (t, J = 9.4 Hz, 1 H), 5.14–5.09 (m, 2 H), 4.23–4.16 (m, 2 H),
4.11–4.07 (m, 1 H), 2.06 (s, 3 H), 2.03 (s, 3 H), 2.00 (s, 3 H), 1.98 (s, 3
H).
13C NMR (100 MHz, DMSO-d6): δ = 169.9, 169.4, 169.23, 169.16,
166.2, 79.8, 75.3, 72.4, 68.7, 67.4, 61.6, 20.5, 20.3, 20.23, 20.16.
HRMS-TOF: m/z [M – Br]+ calcd for C15H23N2O9S+: 407.1119; found:
407.1111; m/z [M + Na]+ calcd for C15H2379BrN2O9SNa+: 509.0200;
found: 509.0186.
2.4 mmol), then the organic phase was concentrated. The crude prod-
uct was recrystallised from MeOH (2 mL) and H2O (1 mL), with the
precipitate washed with additional H2O (1 mL), and dried under
vacuum to provide compound 9a as a white solid with ca. 2.1% (w/w)
succinimide (1.07 g, 70%). A second recrystallisation from MeOH and
H2O provided the product with no observable succinimide impurity.
Mp 163–164 °C (Lit.15 163–164 °C); Rf = 0.50 (hexanes–EtOAc, 1:1).
IR: 3366, 1750, 1741, 1729, 1381, 1229, 1054, 976, 916, 707 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 11.45 (s, 1 H), 7.35–7.28 (m, 4 H),
7.23 (t, J = 6.9 Hz, 1 H), 5.37 (d, J = 10.1 Hz, 1 H), 5.31 (t, J = 9.4 Hz, 1
H), 4.92 (t, J = 9.7 Hz, 1 H), 4.85 (t, J = 9.7 Hz, 1 H), 4.07 (dd, J = 12.1, 5.6
Hz, 1 H), 3.99 (ddd, J = 9.8, 5.7, 1.8 Hz, 1 H), 3.90 (s, 2 H), 3.85 (dd,
J = 12.0, 1.7 Hz, 1 H), 1.98 (s, 3 H), 1.97 (s, 3 H), 1.96 (s, 3 H), 1.94 (s, 3 H).
Anal. Calcd for C15H23N2O9SBr: C, 36.97; H, 4.76; N, 5.75; S, 6.58.
Found: C, 36.70; H, 4.67; N, 5.62; S, 6.71.
Thiohydroximates 9; General Procedure
13C NMR (100 MHz, DMSO-d6): δ = 169.8, 169.4, 169.2, 168.9, 148.6,
136.6, 128.7, 128.3, 126.5, 78.2, 74.3, 72.8, 69.7, 67.8, 61.8, 37.2, 20.4,
20.29, 20.25, 20.2.
HRMS-TOF: m/z [M + H]+ calcd for C22H28NO10S+: 498.1428; found:
498.1443.
Unless otherwise stated, a mixture of sodium sulfite (ca. 0.100 mol)
in H2O (50 mL) and EtOAc (50 mL) was degassed under argon for ca.
10 min, then added to S-(2,3,4,6-tetra-O-acetyl-1-β-D-glucopyrano-
syl)isothiouronium bromide (8; ca. 0.100 mol). The biphasic solution
was stirred rapidly at r.t., with a stream of argon passing through it,
until the precipitate had fully dissolved, then stirred for at least an ad-
ditional 15 min (total 1–1.5 h). The organic phase was removed to
S-(2,3,4,6-Tetra-O-acetyl-1-β-D-glucopyranosyl)-3-phenylpropane-
thiohydroximate (9b)
provide 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranose (2) as
a
solution in EtOAc, which was used immediately.
Glucosylisothiouronium salt 8 (48.86 g, 0.100 mol) was treated with
sodium sulfite (12.61 g, 0.100 mol) to provide thiosugar 2.
Separately, a solution of oxime (ca. 0.105 mol) in EtOAc (100 mL) was
treated successively with concd HCl (0.40 mL, 4.7 mmol) and N-chloro-
succinimide (NCS, ca. 0.100 mol) and stirred for 1 h at r.t., upon which
the blue colour disappeared (an exotherm was observed, with the
internal temperature rising to ca. 50 °C), to provide a solution of N-
hydroxyimidoyl chloride.
Oxime 5b (15.66 g, 0.105 mol) was treated with NCS (13.38 g, 0.100
mol) to form N-hydroxy-3-phenylpropanimidoyl chloride and subse-
quently treated with thiosugar 2 and K2CO3 (16.63 g, 0.120 mol), with
additional EtOAc (50 mL) to promote stirring. After the reaction, the
organic phase was acidified with 2.4 M HCl (3.0 mL, 7.2 mmol). The
precipitate was washed with EtOAc (50 mL) and H2O (50 mL), then
dried under vacuum to provide compound 9b as a white solid with ca.
2.3% (w/w) succinimide (37.94 g, 72%). The filtrate was concentrated
to ca. 50 g to precipitate additional product; this was filtered and
washed successively with MeOH (5 mL) and H2O (5 mL), and dried un-
der vacuum to provide a second crop as an off-white solid with ca.
4.8% (w/w) succinimide (3.73 g, 7%). A portion of the first crop was
recrystallised from MeOH and H2O to provide an analytical sample.
The N-hydroxyimidoyl chloride mixture was treated successively
with the 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranose solution,
and a solution of K2CO3 (ca. 0.12 mol) in H2O (40 mL), then the mix-
ture was stirred for 1 h at r.t. The mixture was separated, the organic
phase was washed with a small quantity of 2.4 M HCl to fully acidify
the product, then the organic phase was concentrated. The crude
product was recrystallised from MeOH and H2O (2:1 (v/v)). The pre-
cipitate was collected by filtration, washed with H2O, then dried un-
der vacuum to provide the thiohydroximate 9 as a white or off-white
solid. The solid was contaminated with succinimide, with the amount
quoted as determined by 1H NMR analysis; the values are in good
agreement with those determined by elemental analysis (actual
sulfur content vs calculated). A small quantity of product was recrys-
tallised from MeOH and H2O to provide an analytical sample.
Mp 200–201 °C (Lit.15 198–199 °C); Rf = 0.55 (hexanes–EtOAc, 1:1).
IR: 3311, 1746, 1713, 1379, 1248, 1225, 1041, 952, 695, 617 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 11.27 (s, 1 H), 7.31–7.26 (m, 4 H),
7.20 (sext, J = 4.2 Hz, 1 H), 5.60 (d, J = 10.1 Hz, 1 H), 5.47 (t, J = 9.4 Hz,
1 H), 4.93 (d, J = 10.0 Hz, 1 H), 4.88 (d, J = 10.1 Hz, 1 H), 4.16–4.12 (m,
1 H), 4.07–3.98 (m, 2 H), 2.95–2.77 (m, 4 H), 2.02 (s, 3 H), 1.99 (s, 3 H),
1.96 (s, 3 H), 1.78 (s, 3 H).
S-(2,3,4,6-Tetra-O-acetyl-1-β-D-glucopyranosyl)-2-phenylethan-
ethiohydroximate (9a)
13C NMR (100 MHz, DMSO-d6): δ = 169.8, 169.5, 169.3, 169.0, 149.0,
140.9, 128.3, 128.2, 125.9, 77.9, 74.3, 72.7, 69.7, 68.2, 62.2, 32.6, 32.3,
20.33, 20.31, 20.2, 20.1.
HRMS-TOF: m/z [M + H]+ calcd for C23H30NO10S+: 512.1585; found:
512.1583.
A mixture of sodium sulfite (408 mg, 3.24 mmol) in H2O (5 mL) and
EtOAc (5 mL) was degassed under argon for ca. 10 min, then added to
glucosylisothiouronium salt 8 (1.46 g, 3.00 mmol). The biphasic solu-
tion was stirred rapidly at r.t., with a stream of argon passing through
it, until the precipitate had fully dissolved, then stirred for an addi-
tional 15 min (total 1.5 h). The organic phase was removed to provide
thiosugar 2 as a solution in EtOAc, which was used immediately.
S-(2,3,4,6-Tetra-O-acetyl-1-β-D-glucopyranosyl)butanethio-
hydroximate (9c)
Separately, a solution of oxime 5a (420 mg, 3.11 mmol) in EtOAc (3
mL) was treated successively with pyridine (10 μL, 0.1 mmol) and NCS
(398 mg, 2.98 mmol), and stirred for 4 h at 50 °C, to provide a solution
of N-hydroxy-2-phenylacetimidoyl chloride (4a). The imidoyl chlo-
ride 4a mixture was treated successively with the thiosugar 2 solu-
tion, and a solution of K2CO3 (496 mg, 3.59 mmol) in H2O (2 mL), then
the mixture was stirred for 1 h. The mixture was separated, the
organic phase was washed with a small quantity of 2.4 M HCl (1 mL,
Glucosylisothiouronium salt 8 (48.75 g, 0.100 mol) was treated with
sodium sulfite (12.62 g, 0.100 mol) to provide thiosugar 2.
Oxime 5c (9.74 g, 0.105 mol, with ca. 6% (w/w) EtOAc) was treated
with NCS (13.33 g, 99.8 mmol) to form N-hydroxybutanimidoyl chlo-
ride and subsequently treated with thiosugar 2 and K2CO3 (16.58 g,
0.120 mol). After the reaction, the organic phase was acidified with
2.4 M HCl (2.5 mL, 6.0 mmol). The crude product was subsequently
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

H
Y. W. Lim et al.
Paper
Synthesis
recrystallised from MeOH (30 mL) and H2O (15 mL), with the precipi-
tate washed with additional H2O (15 mL). This provided product 9c as
an off-white solid with ca. 6.8% (w/w) succinimide (35.39 g, 73%). A
portion was recrystallised from MeOH and H2O to provide an analyti-
cal sample.
1H NMR (400 MHz, DMSO-d6): δ = 11.17 (s, 1 H), 5.47–5.42 (m, 2 H),
4.92 (t, J = 9.6 Hz, 1 H), 4.86 (t, J = 9.7 Hz, 1 H), 4.15–4.01 (m, 3 H),
2.56–2.43 (m, 2 H), 2.003 (s, 6 H), 1.996 (s, 3 H), 1.95 (s, 3 H), 1.63–
1.52 (m, 2 H), 1.36–1.19 (m, 8 H), 0.87 (t, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 169.8, 169.5, 169.2, 169.0, 149.6,
78.0, 74.2, 72.8, 69.8, 68.1, 62.1, 31.2, 31.1, 28.5, 28.4, 26.6, 22.0, 20.4,
20.3, 20.2, 13.9.
Mp 150–152 °C; Rf = 0.45 (hexanes–EtOAc, 1:1).
IR: 3322, 2959, 2938, 2876, 1749, 1709, 1378, 1246, 1228, 1040 cm–1
.
HRMS-TOF: m/z [M + H]+ calcd for C22H36NO10S+: 506.2054; found:
506.2033.
1H NMR (400 MHz, DMSO-d6): δ = 11.18 (s, 1 H), 5.47–5.42 (m, 2 H),
4.92 (t, J = 9.6 Hz, 1 H), 4.86 (t, J = 9.7 Hz, 1 H), 4.16–4.01 (m, 3 H),
2.52–2.46 (m, 2 H), 2.01 (s, 3 H), 2.004 (s, 3 H), 1.997 (s, 3 H), 1.95 (s, 3
H), 1.67–1.54 (m, 2 H), 0.93 (t, J = 7.3 Hz, 3 H).
2′,3′,4′,6′-Tetra-O-acetylglucotropaeolin Monohydrate (10a)
13C NMR (100 MHz, DMSO-d6): δ = 169.9, 169.5, 169.2, 169.0, 149.4,
78.0, 74.3, 72.8, 69.8, 68.2, 62.1, 33.1, 20.4, 20.3, 20.2, 20.1, 13.5.
HRMS-TOF: m/z [M + H]+ calcd for C18H28NO10S+: 450.1428; found:
450.1418.
Thiohydroximate 9a prepared as above (698 mg, 1.40 mmol) was
treated successively with MeCN (0.5 mL), pyridine (60 μL, 0.7 mmol)
and pyridine–sulfur trioxide complex (332 mg, 2.09 mmol), and the
mixture refluxed for 1 h. The solution was cooled to ca. 60 °C, treated
with EtOAc (1 mL), then a solution of K2CO3 (244 mg, 1.76 mmol) in
H2O (1 mL) was added with rapid stirring. Once effervescence had
ceased (ca. 10 min), a thick precipitate was formed. The mixture was
slurried in EtOAc (2 mL) and H2O (2 mL), filtered and dried under
vacuum. The residue was suspended in refluxing H2O (5 mL) and EtO-
Ac (5 mL), cooled, filtered and washed sequentially with H2O (5 mL)
and EtOAc (5 mL); then, this process was repeated again with the
same quantities. The precipitate was dried under vacuum to afford
compound 10a as a white solid (667 mg, 75%).
S-(2,3,4,6-Tetra-O-acetyl-1-β-D-glucopyranosyl)-2-hexanethio-
hydroximate (9d)
Glucosylisothiouronium salt 8 (48.74 g, 0.100 mol) was treated with
sodium sulfite (12.63 g, 0.100 mol) to provide thiosugar 2.
Oxime 5d (12.10 g, 0.105 mol) was treated with NCS (13.36 g, 0.100
mol) to form N-hydroxyhexanimidoyl chloride and subsequently
treated with thiosugar 2 and K2CO3 (16.56 g, 0.120 mol). After the re-
action, the organic phase was acidified with 2.4 M HCl (2.5 mL, 6.0
mmol). The crude product was subsequently recrystallised from
MeOH (40 mL) and H2O (20 mL), with the precipitate washed with ad-
ditional H2O (20 mL). This provided product 9d as a white solid with
ca. 0.8% (w/w) succinimide (35.79 g, 74%). A portion was recrystal-
lised from MeOH and H2O to provide an analytical sample.
Mp 155–157 °C (Lit.15 196–198 °C); Rf = 0.35 (EtOAc–MeOH, 9:1).
IR: 1750, 1729, 1369, 1283, 1248, 1223, 1057, 1032, 905, 817, 793,
729, 642, 601 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 7.41–7.33 (m, 4 H), 7.30–7.25 (m, 1
H), 5.30–5.25 (m, 2 H), 4.91 (td, J = 9.7, 1.6 Hz, 1 H), 4.82 (td, J = 9.7,
1.7 Hz, 1 H), 4.05–3.88 (m, 4 H), 3.75 (d, J = 12.2 Hz, 1 H), 1.99 (s, 3 H),
1.97 (s, 3 H), 1.94 (s, 3 H), 1.93 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 169.8, 169.4, 169.1, 168.9, 152.2,
136.0, 128.4, 128.2, 126.7, 78.4, 74.2, 72.7, 69.5, 67.6, 61.5, 37.0, 20.4,
20.3, 20.21, 20.15.
HRMS-TOF: m/z [M – K]– calcd for C22H26NO13S2–: 576.0851; found:
576.0834; m/z [M + H]+ calcd for C22H27NO13S2K+: 616.0555; found:
616.0574.
Mp 137–138 °C; Rf = 0.55 (hexanes–EtOAc, 1:1).
IR: 3319, 2958, 2938, 2876, 1750, 1709, 1378, 1246, 1228, 1040 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 11.17 (s, 1 H), 5.47–5.42 (m, 2 H),
4.92 (t, J = 9.5 Hz, 1 H), 4.86 (t, J = 9.7 Hz, 1 H), 4.15–4.01 (m, 3 H),
2.56–2.43 (m, 2 H), 2.002 (s, 6 H), 1.995 (s, 3 H), 1.95 (s, 3 H), 1.63–
1.52 (m, 2 H), 1.35–1.28 (m, 4 H), 0.88 (t, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 169.8, 169.5, 169.2, 169.0, 149.6,
78.0, 74.2, 72.8, 69.8, 68.1, 62.1, 31.1, 30.8, 26.2, 21.8, 20.4, 20.3, 20.2,
13.9.
Anal. Calcd for C22H26NO13S2K·H2O: C, 41.70; H, 4.45; N, 2.21; S, 10.12.
Found: C, 41.75; H, 4.25; N, 2.23; S, 10.18.
HRMS-TOF: m/z [M + H]+ calcd for C20H32NO10S+: 478.1741; found:
478.1736.
2′,3′,4′,6′-Tetra-O-acetylgluconasturtiin Monohydrate (10b)
Thiohydroximate 9b prepared as above (36.51 g, 69.7 mmol, contami-
nated with succinimide) was treated successively with MeCN (35 mL),
pyridine (2.8 mL, 35 mmol) and pyridine–sulfur trioxide complex
(16.63 g, 104 mmol), and the mixture refluxed for 1 h. The solution
was cooled to ca. 60 °C, treated with EtOAc (35 mL), then a solution of
K2CO3 (11.61 g, 84 mmol) in H2O (35 mL) was added with rapid stir-
ring. Once effervescence had ceased (ca. 10 min), the solution was
diluted with H2O (35 mL), separated, and the organic phase was con-
centrated. The residue was suspended in refluxing H2O (100 mL) and
EtOAc (100 mL), cooled, filtered and washed sequentially with H2O
(50 mL) and EtOAc (50 mL); then, this process was repeated again
with quantities reduced by 50%. The precipitate was dried under
vacuum to afford compound 10b as an off-white solid (33.46 g, 74%).
S-(2,3,4,6-Tetra-O-acetyl-1-β-D-glucopyranosyl)-2-octanethio-
hydroximate (9e)
Glucosylisothiouronium salt 8 (48.75 g, 0.100 mol) was treated with
sodium sulfite (12.62 g, 0.100 mol) to provide thiosugar 2.
Oxime 5e (15.04 g, 0.105 mol) was treated with NCS (13.34 g, 99.9
mmol) to form N-hydroxyoctanimidoyl chloride and subsequently
treated with thiosugar 2 and K2CO3 (16.52 g, 0.120 mol). After the re-
action, the organic phase was acidified with 2.4 M HCl (3.0 mL, 7.2
mmol). The crude product was subsequently recrystallised from
MeOH (50 mL) and H2O (25 mL), with the precipitate washed with ad-
ditional H2O (25 mL). This provided product 9e as an off-white solid
with ca. 3.2% (w/w) succinimide (44.70 g, 86%). A portion was recrys-
tallised from MeOH and H2O to provide an analytical sample.
Mp 152–154 °C (Lit.15 199–201 °C); Rf = 0.40 (EtOAc–MeOH, 9:1).
Mp 129–130 °C (Lit.33 127 °C); Rf = 0.60 (hexanes–EtOAc, 1:1).
IR: 1749, 1371, 1275, 1247, 1222, 1056, 1031 cm–1
.
IR: 3319, 2928, 2857, 1749, 1712, 1377, 1246, 1230, 1042 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

I
Y. W. Lim et al.
Paper
Synthesis
1H NMR (400 MHz, DMSO-d6): δ = 7.36–7.28 (m, 4 H), 7.21 (t, J = 7.1
Hz, 1 H), 5.65 (d, J = 10.0 Hz, 1 H), 5.49 (t, J = 9.3 Hz, 1 H), 4.92 (t,
J = 9.7 Hz, 1 H), 4.90 (t, J = 9.6 Hz, 1 H), 4.16–4.11 (m, 1 H), 4.05–3.98
(m, 2 H), 2.97–2.79 (m, 4 H), 2.03 (s, 3 H), 2.00 (s, 3 H), 1.96 (s, 3 H),
1.74 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 169.8, 169.5, 169.2, 169.0, 153.0,
140.7, 128.4, 128.2, 126.0, 77.9, 74.4, 72.7, 69.5, 68.1, 62.2, 32.9, 32.4,
20.33, 20.31, 20.2, 20.0.
Mp 156–158 °C; Rf = 0.35 (EtOAc–MeOH, 9:1).
IR: 3506, 2953, 1749, 1728, 1441, 1369, 1276, 1252, 1225, 1052, 899,
795, 644, 622 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 5.52–5.44 (m, 2 H), 4.93 (t, J = 9.6
Hz, 1 H), 4.88 (t, J = 9.7 Hz, 1 H), 4.17–4.01 (m, 3 H), 2.61–2.47 (m, 2
H), 2.02 (s, 3 H), 2.01 (s, 3 H), 2.00 (s, 3 H), 1.96 (s, 3 H), 1.68–1.51 (m,
2 H), 1.40–1.28 (m, 4 H), 0.89 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 169.8, 169.5, 169.2, 169.0, 153.6,
78.1, 74.3, 72.7, 69.6, 68.1, 62.1, 31.4, 30.8, 26.5, 21.8, 20.4, 20.3, 20.2,
13.9.
HRMS-TOF: m/z [M – K]– calcd for C20H30NO13S2–: 556.1164; found:
556.1152; m/z [M + H]+ calcd for C20H31NO13S2K+: 596.0868; found:
596.0873.
.
HRMS-TOF: m/z [M – K]– calcd for C23H28NO13S2–: 590.1008; found:
590.1002; m/z [M + H]+ calcd for C23H29NO13S2K+: 630.0712; found:
630.0703.
Anal. Calcd for C23H28NO13S2K·H2O: C, 42.65; H, 4.67; N, 2.16; S, 9.90.
Found: C, 42.50; H, 4.66; N, 2.12; S, 10.01.
Anal. Calcd for C20H30NO13S2K·0.5 H2O: C, 39.73; H, 5.17; N, 2.32; S,
10.60. Found: C, 39.63; H, 5.13; N, 2.28; S, 10.49.
2′,3′,4′,6′-Tetra-O-acetyl-n-propylglucosinolate Hemihydrate (10c)
Thiohydroximate 9c prepared as above (34.29 g, 71.1 mmol, contami-
nated with succinimide) was treated successively with MeCN (18 mL),
pyridine (2.9 mL, 36 mmol) and pyridine–sulfur trioxide complex
(16.97 g, 107 mmol), and the mixture refluxed for 2.5 h. The solution
was cooled to ca. 60 °C, treated with EtOAc (36 mL), then a solution of
K2CO3 (12.30 g, 89.0 mmol) in H2O (36 mL) was added with rapid stir-
ring. Once effervescence had ceased (ca. 10 min), the mixture was
diluted further with H2O (36 mL), separated, then the organic phase
was diluted further with EtOAc (36 mL) and H2O (36 mL), separated,
then finally washed with brine (36 mL). The residue was concentrated
to dryness, slurried from hot EtOAc (100 mL), cooled, filtered and
washed with EtOAc (50 mL); then, this process was repeated again
with the same quantities. The precipitate was dried under vacuum to
afford compound 10c as a white solid (20.87 g, 51%).
2′,3′,4′,6′-Tetra-O-acetyl-n-heptylglucosinolate Hemihydrate (10e)
Thiohydroximate 9e prepared as above (42.55 g, 81.5 mmol, contami-
nated with succinimide) was treated successively with MeCN (21 mL),
pyridine (3.3 mL, 41 mmol) and pyridine–sulfur trioxide complex
(19.57 g, 123 mmol), and the mixture refluxed for 1.5 h. The solution
was cooled to ca. 60 °C, treated with EtOAc (41 mL), then a solution of
K2CO3 (14.11 g, 102 mmol) in H2O (41 mL) was added with rapid stir-
ring. Once effervescence had ceased (ca. 10 min), a thick precipitate
was formed. The mixture was slurried in H2O (41 mL), filtered and
dried under vacuum. The residue was suspended in refluxing H2O
(100 mL) and EtOAc (100 mL), cooled, filtered and washed sequential-
ly with H2O (50 mL) and EtOAc (50 mL); then, this process was repeat-
ed again with quantities reduced by 50%. The precipitate was dried
under vacuum to afford compound 10e as an off-white solid (35.33 g,
68.5%).
Mp 153–156 °C; Rf = 0.30 (EtOAc–MeOH, 9:1).
IR: 3505, 2963, 1743, 1435, 1369, 1224, 1059, 910, 808, 620 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 5.50 (d, J = 10.1 Hz, 1 H), 5.46 (t, J =
9.4 Hz, 1 H), 4.93 (t, J = 9.9 Hz, 1 H), 4.88 (t, J = 9.8 Hz, 1 H), 4.15 (ddd,
J = 9.9, 5.7, 2.7 Hz, 1 H), 4.10–4.02 (m, 2 H), 2.57–2.48 (m, 2 H), 2.02 (s,
3 H), 2.01 (s, 3 H), 2.00 (s, 3 H), 1.96 (s, 3 H), 1.68–1.55 (m, 2 H), 0.96
(t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 169.9, 169.5, 169.2, 169.0, 153.5,
78.1, 74.3, 72.7, 69.6, 68.1, 62.1, 33.2, 20.4, 20.31, 20.27, 20.2, 13.5.
HRMS-TOF: m/z [M – K]– calcd for C18H26NO13S2–: 528.0851; found:
528.0838; m/z [M + H]+ calcd for C18H27NO13S2K+: 568.0555; found:
568.0571.
Mp 151–153 °C (Lit.33 107–109 °C); Rf = 0.40 (EtOAc–MeOH, 9:1).
IR: 3508, 2934, 1749, 1372, 1276, 1249, 1225, 1088, 1050, 914, 791
cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 5.51–5.44 (m, 2 H), 4.93 (t, J = 9.6
Hz, 1 H), 4.87 (t, J = 9.7 Hz, 1 H), 4.16–4.01 (m, 3 H), 2.61–2.47 (m, 2
H), 2.02 (s, 3 H), 2.01 (s, 3 H), 2.00 (s, 3 H), 1.96 (s, 3 H), 1.65–1.50 (m,
2 H), 1.38–1.22 (m, 8 H), 0.87 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 169.8, 169.5, 169.2, 169.0, 153.6,
78.1, 74.3, 72.7, 69.6, 68.1, 62.1, 31.4, 31.2, 28.6, 28.4, 26.8, 22.0, 20.4,
20.3, 20.2, 13.9.
Anal. Calcd for C18H26NO13S2K·0.5 H2O: C, 37.49; H, 4.72; N, 2.43; S,
11.12. Found: C, 37.58; H, 4.59; N, 2.41; S, 11.12.
HRMS-TOF: m/z [M – K]– calcd for C22H34NO13S2–: 584.1477; found:
584.1474; m/z [M + H]+ calcd for C22H35NO13S2K+: 624.1181; found:
624.1172.
2′,3′,4′,6′-Tetra-O-acetyl-n-pentylglucosinolate Hemihydrate (10d)
Anal. Calcd for C22H34NO13S2K·0.5 H2O: C, 41.76; H, 5.58; N, 2.21; S,
10.13. Found: C, 41.67; H, 5.57; N, 2.23; S, 9.88.
Thiohydroximate 9d prepared as above (34.66 g, 72.0 mmol, contami-
nated with succinimide) was treated successively with MeCN (18 mL),
pyridine (2.9 mL, 36 mmol) and pyridine–sulfur trioxide complex
(17.19 g, 108 mmol), and the mixture refluxed for 2.5 h. The solution
was cooled to ca. 60 °C, treated with EtOAc (36 mL), then a solution of
K2CO3 (12.38 g, 89.6 mmol) in H2O (36 mL) was added with rapid stir-
ring. Once effervescence had ceased (ca. 10 min), a thick precipitate
was formed. The mixture was slurried in H2O (36 mL), filtered and
dried under vacuum. The residue was suspended in refluxing H2O
(100 mL) and EtOAc (100 mL), cooled, filtered and washed sequential-
ly with H2O (50 mL) and EtOAc (50 mL); then, this process was repeat-
ed again with quantities reduced by 50%. The precipitate was dried
under vacuum to afford compound 10d as a white solid (27.38 g,
63%).
Glucotropaeolin (1a)
A solution of tetra-O-acetylglucotropeolin monohydrate (10a; 499
mg, 0.79 mmol) in MeOH (1.6 mL) was treated with a solution of
methanolic KOH (2 M; 20 μL, 0.04 mmol). After being stirred for 2 h,
the solution was neutralised using Amberlite® IRC76 hydrogen form
(40 mg), then decolourised by treatment with charcoal (5 mg). The
mixture was filtered, washed with MeOH (2 × 1 mL) and the filtrate
concentrated to afford compound 1a as an off-white hygroscopic solid
(336 mg, 95%). The NMR data were in excellent agreement with those
previously obtained.15
Rf = 0.40 (EtOAc–MeOH, 3:1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

J
Y. W. Lim et al.
Paper
Synthesis
IR: 3415, 1571, 1454, 1244, 1058, 948, 875, 796, 703, 648, 605 cm–1
.
n-Pentylglucosinolate (1d)
1H NMR (400 MHz, D2O): δ = 7.48–7.37 (m, 5 H), 4.75–4.65 (m, 1 H),
4.15 (s, 2 H), 3.70–3.61 (m, 2 H), 3.43–3.23 (m, 4 H).
13C NMR (100 MHz, D2O): δ = 162.7, 135.2, 129.2, 128.1, 127.6, 81.4,
79.9, 77.0, 71.8, 68.9, 60.4, 38.3.
HRMS-TOF: m/z [M – K]– calcd for C14H18NO9S2–: 408.0429; found:
408.0422; m/z [M + K]+ calcd for C14H18NO9S2K2+: 485.9692; found:
485.9697.
A solution of tetra-O-acetyl-n-pentylglucosinolate hemihydrate (10d;
16.65 g, 27.5 mmol) in MeOH (56 mL) was treated with a solution of
methanolic KOH (2 M; 0.7 mL, 1.4 mmol). After being stirred for 2 h,
the solution was neutralised using Amberlite® IRC76 hydrogen form
(1.5 g), then decolourised by treatment with charcoal (0.1 g). The mix-
ture was filtered, washed with MeOH (2 × 10 mL) and the filtrate con-
centrated to afford compound 1d as an off-white hygroscopic solid
(11.73 g, quantitative).
Anal. Calcd for C14H18NO9S2K·0.5 H2O: C, 36.83; H, 4.20; N, 3.07; S,
14.05. Found: C, 36.92; H, 4.20; N, 2.94; S, 14.04.
Rf = 0.35 (EtOAc–MeOH, 3:1).
IR: 3419, 2931, 1575, 1423, 1243, 1057, 878, 798, 643, 638 cm–1
.
1H NMR (400 MHz, D2O): δ = 5.01 (d, J = 9.8 Hz, 1 H), 3.89 (dd, J = 12.6,
1.9 Hz, 1 H), 3.72 (dd, J = 12.6, 5.6 Hz, 1 H), 3.58–3.53 (m, 2 H), 3.49–
3.43 (m, 2 H), 2.70 (t, J = 7.6 Hz, 2 H), 1.71 (quin, J = 7.2 Hz, 2 H), 1.43–
1.29 (m, 4 H), 0.89 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, D2O): δ = 165.0, 81.9, 80.2, 77.1, 72.0, 69.2, 60.7,
32.2, 30.5, 26.7, 21.7, 13.3.
HRMS-TOF: m/z [M – K]– calcd for C12H22NO9S2–: 388.0741; found:
388.0733; m/z [M + K]+ calcd for C12H22NO9S2K2+: 466.0005; found:
466.0017.
Gluconasturtiin (1b)
A solution of tetra-O-acetylgluconasturtiin monohydrate (10b; 16.39
g, 25.3 mmol) in MeOH (78 mL) was treated with a solution of metha-
nolic KOH (2 M; 0.65 mL, 1.3 mmol). After being stirred for 2.5 h, the
solution was neutralised using Amberlite® IRC76 hydrogen form (1.5
g), then decolourised by treatment with charcoal (50 mg). The mix-
ture was filtered, washed with MeOH (2 × 10 mL) and the filtrate con-
centrated to afford compound 1b as an off-white hygroscopic solid
(11.76 g, quantitative). The NMR data were in excellent agreement
with those previously obtained.15
Anal. Calcd for C12H22NO9S2K: C, 33.71; H, 5.19; N, 3.28; S, 15.00.
Found: C, 33.38; H, 5.31; N, 3.17; S, 14.70.
Rf = 0.40 (EtOAc–MeOH, 3:1).
IR: 3421, 2926, 1576, 1497, 1454, 1243, 1058, 879, 792, 701, 631 cm–1
.
n-Heptylglucosinolate (1e)
1H NMR (400 MHz, D2O): δ = 7.31–7.24 (m, 4 H), 7.20 (tt, J = 6.9, 2.0
Hz, 1 H), 4.79 (d, J = 9.5 Hz, 1 H), 3.74 (dd, J = 12.6, 1.7 Hz, 1 H), 3.57
(dd, J = 12.6, 5.2 Hz, 1 H), 3.42–3.31 (m, 4 H), 3.02–2.85 (m, 4 H).
13C NMR (100 MHz, D2O): δ = 163.3, 140.5, 128.72, 128.69, 126.6,
81.6, 80.1, 77.0, 71.8, 69.1, 60.5, 33.9, 32.5.
HRMS-TOF: m/z [M – K]– calcd for C15H20NO9S2–: 422.0585; found:
422.0587; m/z [M + H]+ calcd for C15H21NO9S2K+: 462.0289; found:
462.0293.
A solution of tetra-O-acetyl-n-heptylglucosinolate hemihydrate (10e;
35.06 g, 55.4 mmol) in MeOH (112 mL) was treated with a solution of
methanolic KOH (2 M; 1.4 mL, 2.8 mmol). After being stirred for 2 h,
the solution was neutralised using Amberlite® IRC76 hydrogen form
(3.0 g), then decolourised by treatment with charcoal (0.1 g). The mix-
ture was filtered, washed with MeOH (2 × 10 mL) and the filtrate con-
centrated to afford compound 1e as an off-white hygroscopic solid
(25.20 g, quantitative).
Anal. Calcd for C15H20NO9S2K·0.5 H2O: C, 38.29; H, 4.50; N, 2.98; S,
13.63. Found: C, 38.38; H, 4.45; N, 2.85; S, 13.89.
Rf = 0.40 (EtOAc–MeOH, 3:1).
IR: 3419, 2927, 2857, 1574, 1457, 1243, 1057, 877, 796, 643, 628 cm–1
.
1H NMR (400 MHz, D2O): δ = 5.00 (d, J = 9.8 Hz, 1 H), 3.89 (dd, J = 12.6,
2.0 Hz, 1 H), 3.72 (dd, J = 12.6, 5.5 Hz, 1 H), 3.58–3.52 (m, 2 H), 3.50–
3.43 (m, 2 H), 2.70 (t, J = 7.6 Hz, 2 H), 1.71 (quin, J = 7.3 Hz, 2 H), 1.41–
1.24 (m, 8 H), 0.87 (t, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, D2O): δ = 165.0, 81.9, 80.2, 77.1, 72.0, 69.1, 60.7,
32.2, 31.0, 28.15, 28.06, 27.0, 22.0, 13.4.
HRMS-TOF: m/z [M – K]– calcd for C14H26NO9S2–: 416.1054; found:
416.1064; m/z [M + H]+ calcd for C14H27NO9S2K+: 456.0759; found:
456.0764.
n-Propylglucosinolate (1c)
A solution of tetra-O-acetyl-n-propylglucosinolate hemihydrate (10c;
20.51 g, 35.6 mmol) in MeOH (72 mL) was treated with a solution of
methanolic KOH (2 M; 0.9 mL, 1.8 mmol). After being stirred for 2 h,
the solution was neutralised using Amberlite® IRC76 hydrogen form
(1.5 g), then decolourised by treatment with charcoal (0.2 g). The mix-
ture was filtered, washed with MeOH (2 × 10 mL) and the filtrate con-
centrated to afford compound 1c as an off-white hygroscopic solid
(14.18 g, quantitative).
Rf = 0.30 (EtOAc–MeOH, 3:1).
IR: 3399, 2934, 1632, 1574, 1423, 1242, 1058, 908, 883, 801, 630 cm–1
Anal. Calcd for C14H26NO9S2K: C, 36.91; H, 5.75; N, 3.07; S, 14.07.
Found: C, 36.68; H, 5.78; N, 2.95; S, 14.21.
.
1H NMR (400 MHz, D2O): δ = 5.02 (d, J = 9.8 Hz, 1 H), 3.90 (dd, J = 12.6,
1.9 Hz, 1 H), 3.72 (dd, J = 12.6, 5.6 Hz, 1 H), 3.59–3.55 (m, 2 H), 3.49–
3.43 (m, 2 H), 2.68 (t, J = 7.5 Hz, 2 H), 1.73 (sext, J = 7.4 Hz, 2 H), 0.98
(t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, D2O): δ = 164.7, 81.8, 80.1, 77.1, 72.0, 69.2, 60.7,
34.1, 20.5, 12.7.
Funding Information
This work was supported by the Institute of Chemical and Engineer-
ing Sciences, Agency for Science, Technology and Research (A*STAR),
Singapore (ICES/14-3E5A02 and ICES/15-1E5A06).
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HRMS-TOF: m/z [M – K]– calcd for C10H18NO9S2–: 360.0428; found:
360.0422; m/z [M + H]+ calcd for C10H19NO9S2K+: 400.0133; found:
400.0136.
Supporting Information
Anal. Calcd for C10H18NO9S2K·H2O: C, 28.77; H, 4.83; N, 3.36; S, 15.36.
Found: C, 28.69; H, 4.77; N, 3.29; S, 15.08.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591895.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

K
Y. W. Lim et al.
Paper
Synthesis
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