First total synthesis of 4-methylthio-3-butenyl glucosinolate

Article abstract of DOI:10.1271/bbb.80862

The first total synthesis of 4-methylthio-3-butenyl glucosinolate (MTBG), a natural bioactive compound and a precursor of radish phototropism-regulating substances, was achieved from commercially available 1,4-butanediol. The glucosinolate framework was prepared by coupling of an oximyl chloride derivative and tetraacetyl thioglucose. A methylthio group was introduced to the framework by a Wittig reaction between triphenylphosphonium thiomethylmethylide and an aldehyde intermediate of glucosinolate. The synthetic route should facilitate preparation of various derivatives needed for probe synthesis based on MTBG.

Full text of DOI:10.1271/bbb.80862

Biosci. Biotechnol. Biochem., 73 (3), 785–787, 2009
Communication
First Total Synthesis of 4-Methylthio-3-butenyl Glucosinolate
1;2
1
1;y
Sayumi YAMAZOE, Koji HASEGAWA, and Hideyuki SHIGEMORI
1
Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8572, Japan
Institute for Chemical Research and Institute for Integrated Cell-Material Sciences, Kyoto University,
Uji, Kyoto 611-0011, Japan
2
Received December 5, 2008; Accepted January 15, 2009; Online Publication, March 7, 2009
[doi:10.1271/bbb.80862]
The first total synthesis of 4-methylthio-3-butenyl
Blue light
glucosinolate (MTBG), a natural bioactive compound
and a precursor of radish phototropism-regulating
substances, was achieved from commercially available
Myrosinase
OH
OSO3−
1
,4-butanediol. The glucosinolate framework was pre-
O
MeS
HO
HO
N
pared by coupling of an oximyl chloride derivative and
tetraacetyl thioglucose. A methylthio group was intro-
duced to the framework by a Wittig reaction between
triphenylphosphonium thiomethylmethylide and an al-
dehyde intermediate of glucosinolate. The synthetic
route should facilitate preparation of various deriva-
tives needed for probe synthesis based on MTBG.
S
N C S
HO
SMe
MTBG(1)
MTBI
a Radish Phototropism-Regulating
Fig. 1. Formation of MTBI,
Substance, from MTBG (1).
side chain keeping the fundamental framework of
MTBG (1) and MTBI. The glucosinolate framework
for MTBG (1) was prepared with the most convenient
synthetic route to glucosinolates, which involves the
coupling of an oximyl chloride derivative and a
Key words: 4-methylthio-3-butenyl glucosinolate; pho-
totropism; radish; synthesis; natural product
4
-Methylthio-3-butenylisothiocyanate (MTBI) was
5
)
isolated and identified from light-grown radish seedlings
as candidates for growth inhibitors involved in the
phototropism of radish (Raphanus sativus) hypoco-
tyls.1 More recently, MTBI and its bioprecursor, 4-
methylthio-3-butenyl glucosinolate (MTBG, 1), have
been found to possess unique antioxidant and cytotoxic
commercially available tetraacetyl thioglucose. Syn-
thesis of the desired aldehyde (2) commenced from 1,4-
butanediol (3) (Scheme 1). Compound 3 was monosily-
lated to known 4-[(t-butyldimethylsilyl)oxyl]-butan-1-ol
,2)
6
)
7)
(4), followed by an oxidation reaction using PCC to
afford the silyl ether of 4-hydroxybutanal 5. Aldehyde 5
was treated with hydroxylamine hydrochloride in the
presence of sodium carbonate at room temperature for
1 h to yield a mixture of syn- and anti-oximes 6 (89%),
which was treated in turn with N-chlorosuccinimide
(NCS) at room temperature overnight to give the
corresponding oximyl chloride 7 with a yield of 85%.
The coupling between 7 and tetraacetylthioglucose was
carried out in dry THF in the presence of TEA at room
temperature for 3.5 h to give 8. The thiohydroximate 8
was found to be unstable and hence was used without
purification in the next reaction. Compound 8 was
3
)
activities, boosting intense research interest in them.
Kosemura et al. (1993) suggested that MTBI is
released from MTBG via myrosinase (thioglucosidase)
action (Fig. 1).4 However, no work has been done on
receptors or direct binding molecules of these substances
so far, while the identification of interacting targets is
essential to figure out the mechanism underlying several
bioactivities including plant-growth inhibition and se-
lective cytotoxicity. Labeling of MTBI and MTBG (1)
such as biotinylation or fluorescence-probing is presum-
ably a powerful means to identify its receptors. The
problem with the probe synthesis based on MTBI and
MTBG (1) is the difficulty in directly labeling them with
important sites retaining their bioactivities. Hence, we
carried out the synthetic study of MTBG (1) to obtain
intermediates which can be converted to various
derivatives needed to design probes of both MTBG (1)
and MTBI. Since the total synthesis of MTBG (1) have
not reported yet, in this communication we report the
first total synthesis of MTBG (1).
)
acetylated in dry pyridine with Ac O at room temper-
2
ature overnight to obtain pentaacetate 9, which was then
desilylated without purification to give 10 with an
overall yield of 55% from 7. The terminal hydroxyl of
10 was oxidized with Dess-Martin periodinane at room
temperature for 3.5 h to give the aldehyde 2 in 84%
yield.
Following introduction of a methylthio group, we
utilized a Wittig reaction between triphenylphospho-
nium thiomethylmethylide and the prepared aldehyde 2
(Scheme $$). This type of reaction is not generally
stereospecific, and Wittig thiomethylenation of 2 af-
forded a 100:77 mixture of the E and Z vinyl sulfides 11
As the synthetic route of MTBG (1), we envisaged the
introduction of a thioalkyl side chain into a glucosino-
late framework, since the use of alkylation reagents with
different structures enables us to obtain new derivatives
bearing various lengths and structures of the thioalkyl
8
)
(72%). At this point, the products included anti/syn
y
To whom correspondence should be addressed. Tel/Fax: +81-29-853-4603; E-mail: hshige@agbi.tsukuba.ac.jp

786
S. YAMAZOE et al.
PCC,
TBDMSCl,
NaH
AcONa
OTBS
OH
OTBS
HO
HO
O
THF
0%
CH2Cl2
60%
5
3
4
8
H NOH·HCl,
2,3,4,6-tetra-O-acetyl-1-thio-β-D-
2
NCS
Cl
glucopyranose, TEA
Na CO3
2
HO
OTBS
HO
N
OTBS
N
S
CH Cl
THF
2
2
H2O
6
85%
7
89%
OAc
OH
N
OAc
O
OAc
N
Ac O
TBAF
THF
5%
(orverall yield from 6)
O
2
AcO
AcO
AcO
AcO
S
pyridine
AcO
AcO
5
OTBS
OTBS
9
8
OAc
O
OAc
N
Dess-Martin
periodinane
OAc
O
OAc
Ac
AcO
AcO
AcO
N
S
S
O
AcO
CH2Cl2
AcO
84%
OH
2
H
1
0
Scheme 1. Synthesis of 2.
OAc
O
OAc
OAc
O
OH
N
+
−
ClSO3H
pyridine
Ph3P CH SCH3
N2H4 ·AcOH
AcO
AcO
N
2
S
AcO
AcO
S
THF
AcO
DMF
CH Cl
AcO
2
2
SMe
9
5%
SMe 83%
72%
1
1
12
OAc
O
OSO −K+
OH
OSO3−K+
3
KOMe
O
AcO
AcO
N
HO
HO
N
S
S
MeOH
98%
AcO
HO
SMe
SMe
1
13
oxmic and E/Z vinyl isomers, which were separated by
C18 reversed-phase HPLC to yield four isomeric pure
sulfides. Among them, one isomer 11a (21%) showed
retention time were identical with those of the natural
9);
*
compound.
In summary, the first total synthesis of MTBG (1) was
accomplished starting from 1,4-butanediol (3). The
disclosed synthetic route in this study may be amenable
to the synthesis of new analogs of MTBG (1), which are
required for preparing probes of putative bioactive
substances relating to phototropism and also may be
useful to clarify the structural requirements for its
various bioactivities.
1
oximic and vinyl proton signals in the H NMR
spectrum, in agreement with the values given in those
of the desulfated and acetylated derivatives of natural
MTBG. While the E-configuration of the vinyl sulfide in
1
1a was proved by the coupling constant (J ¼ 15:1 Hz)
of the vinyl protons, it was not possible to determine the
streochemistry of the oxime moiety. Selective deacety-
lation of the acetoxime group by treatment of 11a with
hydrazine acetate in DMF at room temperature for
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24
(
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8
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