Total Synthesis of Eleuthoside A; Application of Rh-Catalyzed Intramolecular Cyclization of Diazonaphthoquinone

Article abstract of DOI:10.1055/s-0036-1589118

The first total synthesis of (±)-eleutherol and eleuthoside A, the natural cytotoxic substances extracted from medicinal Indonesian plant, is described. First, the synthesis of (±)-eleutherol has been accomplished in nine steps starting from bromo methoxy aldehyde with the aid of diazo-transfer chemistry approach. Second, a metal-catalyzed intramolecular cyclization reaction of the corresponding diazonaphthoquinone led to the desired eleuotherol, which served as a precursor to eleuthoside A. Then, several glycosidation routes, using different glucosyl donors, were experimented to reach effective O-glycosidation of eleutherol. The only successful strategy involved Koenigs-Knorr glycosidation using peracetyl glycosyl bromide in the presence of Ag ₂ O and quinoline. This strategy furnished our desired acetylated glycoside of β-configuration, regioselectively. Finally, deacetylation and successive separation of diastereomers were conducted to give eleuthoside A.

Full text of DOI:10.1055/s-0036-1589118

SYNLETT
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2
0
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Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
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A
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Synlett
D. I. A. Othman et al.
Letter
Total Synthesis of Eleuthoside A; Application of Rh-Catalyzed
Intramolecular Cyclization of Diazonaphthoquinone
Dina I. A. Othmana,b
Kota Otsukaa
Shuhei Takahashia
Khalid B. Selimb
Magda A. El-Sayedb
Atif S. Tantawyb
Key steps: Diazo transfer reaction
Rh-catalyzed C–H insertion cyclization
HO
HO
HO
Glycosidation
O
O
N3 Cl–
OMe OH
OMe
O
OMe OH
HO OMe
+
MeN
OEt
NMe
N2
O
Rh cat.
O
O
OEt
ADMC
Tatsuo Okauchia
Mitsuru Kitamura*a
O
O
O
Eleutherol
Eleuthoside A
a
Department of Applied Chemistry, Kyushu Institute
of Technology, 1-1 Sensuicho, Tobata, Kitakyushu,
804-8550, Japan
kita@che.kyutech.ac.jp
Department of Pharmaceutical Organic Chemistry,
b
Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
Received: 27.08.2017
Accepted after revision: 20.09.2017
Published online: 03.11.2017
anticancer agent. In more detailed accounts in 2013, Young
Ho et al. revealed further information about the anti-
inflammatory properties of the same plant.3
DOI: 10.1055/s-0036-1589118; Art ID: st-2017-u0649-l
In this paper, we made use of the efficient and short di-
rected synthetic method of diazonaphthoquinone from
naphthol by adopting our approach of diazo-transfer chem-
istry using 2-azido-1,3-dimethylimidazolinium chloride
Abstract The first total synthesis of (±)-eleutherol and eleuthoside A,
the natural cytotoxic substances extracted from medicinal Indonesian
plant, is described. First, the synthesis of (±)-eleutherol has been
accomplished in nine steps starting from bromo methoxy aldehyde
with the aid of diazo-transfer chemistry approach. Second, a metal-
catalyzed intramolecular cyclization reaction of the corresponding
diazonaphthoquinone led to the desired eleuotherol, which served as a
precursor to eleuthoside A. Then, several glycosidation routes, using
different glucosyl donors, were experimented to reach effective O-gly-
cosidation of eleutherol. The only successful strategy involved Koenigs–
Knorr glycosidation using peracetyl glycosyl bromide in the presence of
4
(ADMC). Recently, this method is more likely to find wide-
spread uses in the field of total synthesis of natural com-
5,6
pounds with the aid of metal-catalyzed reactions. To our
knowledge, this developed diazo-transfer methodology has
never been used so far to synthesize eleuthoside A (1).
Moreover, the interesting biological activities of this sub-
stance 1 have inspired us toward these attempts (adopting
this methodology). Hence, the first total synthesis of the cy-
totoxic natural eleuthoside A (1) was investigated via met-
al-catalyzed intramolecular C–H insertion cyclization reac-
tion of the appropriate diazonaphthoquinone, followed by
selective β-glycosidation and resolution of the final prod-
uct. This developed strategy takes the advantage of both di-
azo-transfer reaction and metal-catalyzed reaction. In this
investigation, we wish to describe the full details of our to-
tal synthesis of eleuthoside A (1) and eleutherol (2, Figure 1).
Ag O and quinoline. This strategy furnished our desired acetylated gly-
2
coside of β-configuration, regioselectively. Finally, deacetylation and
successive separation of diastereomers were conducted to give eleu-
thoside A.
Key words diazonapthoquinone, rhodium, eleutherol, eleuthoside A,
glycosidation, intramolecular cyclization, 1 Introduction, 2 Results and
Discussion, 2.1 Synthetic Strategy, 2.2 Synthesis of Aglycone, Eleuther-
ol, 2.3 Glycosidation and Synthesis of Eleuthoside A, 3 Conclusions
1
Introduction
HO
In 1997, Hirotaka Shibuya and co-workers disclosed the
isolation and structure of three new aromatic glycosides
named eleuthosides A (1), B, and C. They have been found
in the bulbs of Eleutherine palmifolia (Iridaceae). This plant
is an Indonesian medicinal one that is used traditionally as
O
HO
HO
O
1,2
HO OMe
OMe OH
Me
O
Me
O
1
O
2
O
Figure 1 Structures of eleuthoside A (1) and eleutherol (2)
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Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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Synlett
D. I. A. Othman et al.
Letter
2
Results and Discussion
ment with H /Pd(C) and NaOEt, respectively, to afford the
2
corresponding naphthol 9 (90% yield over two steps). Then,
naphthol 9 was anticipated to form eleutherol (2) via met-
al-catalyzed intramolecular cyclization of diazonaphtho-
quinone 11. Compound 11 was prepared by the efficient
one-step diazo-transfer reaction of naphthol 9 using ADMC
2.1 Synthetic Strategy
As obviously shown in Figure 1, the structure of eleu-
thoside A (1) is composed mainly of two domains: eleuth-
erol (2) and glucosyl residue which are bonded together
through β-glycosidic linkage. The retrosynthetic analysis
4
(10). It was observed that, using 3.2 equivalents of ADMC
2
and 3.8 equivalents of Et N, efficiently afforded the di-
3
for eleuthoside A (1) is outlined in Scheme 1 which starts
with the fragmentation of the target into two moieties, a
sugar (glucose) and aglycone part, eleutherol (2). The lac-
tone part in compound 2 could be constructed by C–H in-
sertion reaction of metal carbene II formed from dia-
azonaphthoquinone 11 in 85% yield.
t
O Bu
O
Br
O
P
,
NaH (1.1equiv)
t
O
O Bu
COOEt
(EtO)2
THF, 0 °C–r.t.
overnight
OEt
(
EtO)2P
7
zonaphthoquinone III, which in turn would be synthesized
3
O
O
4
90%
from naphthol IV by diazo-transfer reaction with ADMC as
mentioned previously (Scheme 1). An interesting feature is
that the ethyl ester employed during the construction of
naphthol IV is incorporated into our final product. During
our work on the synthetic plan, two problems have
emerged. At first, undesired intermolecular OH or benzyl
insertion side products were observed with our desired
compound 2 during C–H insertion cyclization reaction. Al-
so, some difficulty was experienced when trying to attach
the sugar ring in the glycosidation step, as will be explained
later.
OMe
O
5, NaH (1.1 equiv)
t
TFA:H O (7:1)
2
O Bu
OEt
THF
r.t., 1 h
0
°C–r.t., 1 h
6
Br
O
OMe
O
OMe OAc
NaOAc (2 equiv)
Ac2O
OH
OEt
OEt
1
40 °C, 5 h
Br
7
O
Br
8
O
3
0% (3 steps)
OMe OH
1) H , Pd/C (0.1 equiv)
2
10 (3.2 equiv)
Et3N (2.4 equiv)
EtOH, r.t., 48 h
HO
HO
RO
RO
RO
OEt
MeCN, THF
–20 °C, 3 h
85%
O
O
2) NaOEt (3 equiv)
O
9
0
°C–r.t., 24 h
HO
O
O
HO OMe
ROOMe
90% (2 steps)
Me
O
Me
O
N–
+
OMe
O
OMe
N
N
N2
O
I
+
Cl–
eleuthoside A (1)
O
O
MeN
NMe
OEt
CHO
RO
RO
RO
OMe OH
Me
C–H
insertion
OMe
O
H
11
Br
5
ADMC 10
O
X
M
Me
O
Scheme 2 Synthesis of ethyl 3-diazo-3, 4-dihydro-4-oxo-5-methoxy-2-
naphthalenecarboxylate (11)
OR
O
O
eleutherol (2)
II (M: Metal)
OMe OH
O
OMe
O
Finally, the resultant diazonapthoquinone 11 was sub-
jected to intramolecular cyclization reaction to get the de-
sired eleutherol (2, Table 1). When 11 was exposed to cata-
lytic amount of rhodium(II) octanoate, dimer (Rh (oct) ) in
refluxing benzene, the desired compound 2 was not
formed, whereas naphthalene diol 12 was mainly formed.
H
diazo
transfer
N2
Me
Me
O
O
III
2
4
O
IV
O
Scheme 1 Retrosynthetic analysis of eleuthoside A (1)
9
This might result from the O–H insertion reaction of di-
2
.2 Synthesis of Aglycone, Eleutherol
azonapthoquinone 11 with the contaminated water
(Table 1, entry 1). As a result, the reaction was repeated in
As shown in Scheme 2, we began our investigation by
the presence of MS 4 Å (pellets; Table 1, entry 2). In this
case, eleutherol (2) was difficultly isolated in 20% yield
along with diol 12 (45% yield). To a great extent, this prob-
lem could be overcome by using 3 mol% Rh (oct) in the
the preparation of phosphonate 4 from the commercially
8
available phosphonoacetate 3. Then, we followed the mod-
ified Wittig–Horner reaction of aldehyde 5 smoothly to af-
ford tert-butyl diester 6. The latter compound was selec-
tively hydrolyzed under acidic conditions to give unsaturat-
2
4
presence of pre-activated powdered-type MS 4Å under
completely anhydrous conditions to give compound 2 as a
8b
10
ed acid 7. The treatment of 7 with acetic anhydride in the
presence of NaOAc led to naphthalene 8. Both bromo and
acetyl groups were removed from compound 8 by treat-
sole product in 63% yield (Table 1, entry 3). Moreover,
Rh (oct) -catalyzed reaction of 11 proceeded more rapidly
2
4
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Synlett
D. I. A. Othman et al.
Letter
in refluxing toluene, but the yield of 2 was decreased and
the benzyl insertion derivative 13 was observed as byprod-
uct (Table 1, entry 4).
2.3 Glycosidation and Synthesis of Eleuthoside A
There are several well-known glycosyl donors for aro-
matic compounds, such as acetates, halides, and trichloro-
acetimidates.1
2,13
As shown in Figure 2, a number of differ-
Table 1 Toward the Total Synthesis of Eleutherol (2): Studies for the
Rh-Catalyzed Intramolecular Cyclization of Diazonaphthoquinone 11
14
ent donors, flurobenzylated glucose 16, trichloroacetimi-
15
date-acetylated glucose 17,
and peracetyl glucosyl
OMe
O
OMe OH
15,16
Me
O
bromide 18
have been synthesized, according to previ-
N2
Rh2(oct)4 cat.
ously reported literatures, in order to be used for several
glycosidation routes as will be illustrated.
OEt
additive
benzene
11
2
O
O
BnO
BnO
AcO
AcO
AcO
AcO
O
O
CCl3
NH
O
OMe OH
OMe OH
F
O
Br
BnO
AcO
AcO
OH
OEt
O
OBn
OAc
OAc
Ph
16
17
18
OEt
Figure 2 Glucosyl donors
1
2
13
O
The glycosidation step was so challenging. With the key
eleutherol (2) and glucosyl donor fragments in hand, sever-
al trials have been made to join them into our final desired
glycoside 1 (Scheme 4). Thus, a number of benzylated or
acetylated glucosyl donors were treated with acceptor 2
under several glycosidation conditions (using different pro-
moter systems). Throughout our attempts of O-glycosida-
tion, we started with Mukaiyama–Suzuki conditions using
Entry Rh cat. (mol%) Additive
Temp (°C) Time (min) Product (%)
1
2
3
1.5
1.5
3
–
90
90
30
45
15
10
12 84
MS 4Åa
MS 4Åb
MS 4Åb
2 20, 12 45
2 63
90
4c
3
110
2 51, 13 12
a
Pellets MS 4Å was used.
Powdered MS 4Å was used.
Reaction was carried out in toluene.
b
c
2
,3,4,6-tetra-O-benzyl-D-glucopyranosyl fluoride (16) and
the most powerful promotor system Cp HfCl ·AgClO
4
2
2
17
It is also worth noting that we tried to obtain eleutherol
2) as enantiomerically pure form through the optical reso-
lution. (–)-(1S)-Camphanoyl chloride (14) has been proved
to be an efficient and powerful chiral derivatization reagent
for stereoisomeric separation used for stereoisomers con-
taining hydroxy functional groups. As a result, its utilities
for chiral derivatization of 2 was taken into consideration,
hoping to separate the enantiomeric pure compound prior
to the glycosidation step, as shown in Scheme 3. However,
no separation was detected for these diastereomers 15.
Therefore, we decided to go forward using the racemic mix-
ture form 2.
(method A). However, no glycosidation was observed.
Thus, we increased the time of the reaction but many unde-
sired side products were obtained.
(
RO
O
RO
RO
11
O
OMe
Method A:
6, Cp2HfCl2, AgClO4a
RO
Me
O
1
2
Method B:
7, BF3•OEt2b
1
O
19: R = Bn, 0%
20: R = Ac, 0%
Scheme 4 Attempted O-glycosidation reaction toward the total syn-
thesis of eleuthoside A (1); comparative studies for the attachment of
OMe OH
Me
O
R*Cl 14 (4.5 equiv)
DMAP (0.6 equiv)
the floride and imidate sugar donors. a Method A: 16 (0.5 equiv),
Cp HfCl (0.5 equiv), AgClO (1 equiv), MS 4Å, CH Cl , –70 °C to r.t.,
2
2
4
2
2
b
pyridine, r.t.
1 or 24 h. Method B: 17 (2 equiv), BF ·Et O (0.2 equiv), MS 4Å, CH Cl ,
3
2
2
2
48 h
–10 °C to r.t., 24 h.
2
O
R*
OMe
O
Me
O
Then, hoping for further improvement, less bulky gluco-
syl donor and another different promotor system have been
examined. BF ·OEt -catalyzed Schmidt glycosidation reac-
O
+
2: 35%
R* =
O
O
3
2
O
15: 20%
tion which has used the acetyl-protected trichloroacetimi-
15b,18
date derivative 17 as a glucosyl donor was adopted.
Scheme 3 Unsuccessful optical resolution protocol of eleutherol (2)
This reaction was reported as the most common efficient
method for the synthesis of such sensitive or complicated
targets (method B). Unfortunately, this attempt gave back
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D. I. A. Othman et al.
Letter
the starting material 2. These observed results suggested
that the hydroxyl group in compound 2 was less suitable for
such glycosidation conditions.
the hydroxyl signal of eleutherol (2) and the appearance of
four acetoxymethyl groups.
At this point, our strategy had converged on this late-
stage intermediate 20 as nonseparable diastereomers. To-
ward the completion of the total synthesis of eleuthoside A
(1), careful deprotection of the four acetyl groups in the
glucose unit was implemented smoothly using K CO in
Due to the lack of success in O-glycosidation under both
Mukaiyama–Suzuki’s and Schmidt’s methodology, bro-
mides were taken into our consideration as one of the most
frequently glycosyl donors described in similar prior
2
3
13
21
work. Therefore, direct O-glycosidation of 2 was per-
formed with peracetyl glycosyl bromide 18 under Koen-
nigs–Knorr conditions in a biphasic media (CH Cl /H O) us-
methanol. A mixture of eleuthoside A (1) and its α-epimer
2
2
were obtained as white solid in 56% yield (Scheme 6). All
spectroscopic and analytical data of the synthesized mate-
rial were in a close agreement with those reported for the
naturally occurring compound published earlier by Shibuya
2
2
2
ing tetrabutylammonium bromide (TBAB) as phase-trans-
19
fer catalyst and NaOH as a base (Scheme 5). Again, this
stage was troublesome owing to the aquatic basic condi-
tions, which caused deacetylation of the sugar moiety and
the product couldn’t be confirmed clearly. At this juncture,
we decided to avoid this aquatic environment by using
quinoline and silver oxide as insoluble halophile promotor.20
2
et al. It is also worth noting to mention that purification of
this sensitive glycoside 1 could be simply achieved by PTLC
silica gel chromatography. Running the plate twice using
(CHCl /MeOH, 6:1) was useful to separate the single isomer
3
in 20%, which was found to be identical to the natural gly-
coside. Also, 28% and 8% mixed isomers were obtained with
a ratio of natural isomer to unnatural isomer 3:1 and 1:1,
respectively, as illustrated in Scheme 6.
HO
O
HO
HO
O
OMe
HO
Me
*
1
8 (1.2 equiv)
TBAB (1.3 equiv)
AcO
AcO
AcO
HO
HO
HO
O
O
O
NaOH (5%)
CH2Cl2
O
O
AcO OMe
HO OMe
1: 14 %
O
Me
O
Me
35 °C, 20 h
2 3
K CO
OMe OH
+
Me
O
(2.5 equiv) PTLC
3
2: 21% (rec.)
O
MeOH
r.t., 1 h
SiO2
AcO
β
20
O
O
O
AcO
AcO
1: 20%
O
O
+
2
OMe
Mixed isomer 36%
8%: 1/3-epi-1 = 3:1
% : 1/3-epi-1 = 1:1
AcO
Me
*
2
18 (2 equiv)
8
O
Ag2O (1.1 equiv)
quinoline
Scheme 6 The final step toward total synthesis of eleuthoide A (1)
O
r.t., 24 h
β-20:64%
α-20: trace
+
For further enhancement of the yield, we expected that
epimerization23 may play a role in converting one isomer
into another. As a result, epimerization was attempted un-
der several conditions as illustrated in Scheme 7. However,
we were not able to obtain one dominant isomer from the
mixture of 1 and 3-epi-1 either under basic epimerization
conditions using DBU, t-BuOK or KOH or under acidic epi-
Scheme 5 Acetylated bromide donor for successful O-glycosidation of
eleutherol (2)
As depicted in Scheme 5, we were excited to find that
the coupling of peracetyl glycosyl bromide 18 and precur-
sor 2 was successfully implemented affording our desired
product 20.
23
merization using BF ·OEt .
3
2
1
Judged by the H NMR spectrum, 20 was exhibited as di-
HO
HO
HO
HO
HO
HO
astereisomeric mixture (1:1) in 64% yield due to the pres-
ence of stereocenter in the lactone ring. In addition, the
configuration at the anomeric position was clarified as β-
anomer as a major one along with traces of α-anomer,
which was easily removed by chromatography. The exclu-
sive formation of the major β-glycoside 20 was confirmed
by the coupling constant of the anomeric proton (J = 7.8
Hz), while in case of α-anomer, the coupling constant (J)
was 3.0 Hz. Furthermore, the spectrum of peracetate of
eleuthoside A 20 was characterized by the disappearance of
O
O
O
O
base
or
acid
HO OMe
HO OMe
Me
Me
3
a
3
O
O
mixture of
1 and 3-epi-1
O
O
1
Scheme 7 Unsuccessful epimerization attempts of eleuthoside A (1).
a
Examined conditions: DBU, THF, r.t.; t-BuOK, THF, r.t.; KOH, MeOH, r.t.;
BF ·OEt , acetone, MS 4Å.
3
2
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Synlett
D. I. A. Othman et al.
Letter
Despite these unfruitful epimerization trials, the proto-
col previously shown in Scheme 6 allowed us to successful-
ly achieve our goal, and obtain eleuthoside A (1) in 20% sin-
gle isomer.
(2) Shibuya, H.; Fukushima, T.; Ohashi, K.; Nakamura, A.; Riswan,
S.; Kitagawa, I. Chem. Pharm. Bull. 1997, 45, 1130.
(
3) Minh, Ha. L.; Huyen, D. T. T.; Kiem, P. V.; Minh, C. V.; Van N, T.
H.; Nhiem, N. X.; Tai, B. H.; Long, P. Q.; Anh, B. K.; Hyun, K. S.;
Hye-Jin, H.; Sohyun, K.; Young-Sang, K.; Young, Ho. K. Bull.
Korean Chem. Soc. 2013, 34, 633.
(
4) (a) Kitamura, M.; Sakata, R.; Tashiro, N.; Ikegami, A.; Okauchi, T.
Bull. Chem. Soc. Jpn. 2015, 88, 824. (b) Kitamura, M.; Tashiro, N.;
Sakata, R.; Okauchi, T. Synlett 2010, 2503.
3
Conclusions
(
5) For a review, see: Othman, D.; Kitamura, M. Heterocycles 2016,
The first total synthesis of the natural eleutherol (2) and
9
2, 1761.
6) (a) Kitamura, M.; Takahashi, S.; Okauchi, T. J. Org. Chem. 2015,
0, 8406. (b) Kitamura, M.; Kubo, K.; Yoshinaga, S.; Matsuzaki,
eleuthoside A (1) has been accomplished, involving simple
and readily accessible starting materials such as glucose
and bromomethoxy aldehyde. Depending on our modest
observations, the main challenge was that finding proper
reaction conditions for both intramolecular cyclization re-
action and glycosidation reaction. In brief, the presence of 3
mol% of Rh catalyst, pre-activated powdered molecular
sieve, and anhydrous benzene were essential to avoid OH-
or benzyl-insertion reactions. Furthermore, the best condi-
tions found for smooth O-glycosidation involved the treat-
ment of eleutherol (2) with two equivalents of acetobromo-
(
8
H.; Ezaki, K.; Matsuura, T.; Matsuura, D.; Fukuzumi, N.; Araki,
K.; Narasaki, M. Tetrahedron Lett. 2014, 55, 1653.
(7) For reviews, see: (a) Zhang, Z.; Wang, J. Tetrahedron 2008, 64,
6577. (b) Doyle, M. P.; Ye, T.; McKervey, M. A. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; John
Wiley and Sons: New York, 1998. (c) Ye, T.; McKervey, M. A.
Chem. Rev. 1994, 94, 1091. (d) Padwa, A.; Austin, D. J. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1797. (e) Doyle, M. P. Chem. Rev.
1986, 86, 919.
(8) (a) Owton, W. M.; Gallagher, P. T.; Juan-Montesinos, A. Synth.
Commun. 1993, 23, 2119. (b) Snyder, S. A.; Sherwood, T. C.; Ross,
A. G. Angew. Chem. Int. Ed. 2010, 49, 5146.
glucose in quinoline in the presence of Ag O at room tem-
2
perature. Finally, subsequent deacetylation was done to
furnish 20% eleuthoside A (1) in β-configuration. The spec-
tral data of both eleutherol (2) and eleuthoside A (1)
matched strongly with those previously reported for the
(9) Related reactions, see: Kitamura, M.; Otsuka, K.; Takahashi, S.;
Okauchi, T. Tetrahedron Lett. 2017, 58, 3508.
(
10) Experimental Procedure and Physical Data of Eleutherol (2)
To a solution of diazonaphthoquione 11 (100 mg, 0.37 mmol) in
benzene (4 mL) in the presence of 0.2 g preactivated powdered
MS 4Å, Rh (oct) (8.6 mg, 0.011 mmol) was added at 90 °C as
2
natural one. This reported chemistry allows not only ac-
cess to the rare naturally occurring substances but also to
attractive designed analogues as a new class of potential
anticancer agents for future investigation.
2
4
the bath temperature. The mixture was stirred for 15 min at the
same temperature. After cooling, the mixture was filtered
through Celite pad and concentrated in vacuo to afford the
crude compound, which was purified by PTLC (silica gel, R =
f
0
.7; toluene/acetone, 9:1) to give 2 (60 mg, 63%) as a yellow
Funding Information
1
solid; mp 190 °C. H NMR (500 MHz, CDCl ): δ = 9.65 (s, 1 H),
3
This work was supported by JSPS KAKENHI Grant Number 26410054.
S
JPKSA-
7.90 (s, 1 H), 7.60 (d, 1 H, J = 8.0 Hz), 7.43 (dd, 1 H, J = 7.7, 8.0
Hz), 6.93 (d, 1 H, J = 7.7 Hz), 5.75 (q, 1 H, J = 6.6 Hz), 4.19 (s, 3 H),
K
E
N
HI
2(
6
4
1
0
0
5
4)
13
1
.75 (d, 3 H, J = 6.6 Hz). C NMR (125 MHz, CDCl ): δ = 170.6,
3
156.5, 149.1, 137.2, 127.9, 126.5, 125.9, 123.6, 117.5, 116.5,
Acknowledgment
106.2, 77.4, 56.3, 19.1. IR (ATR): 3358, 2920, 1753, 1595, 1458
–1
+
+
cm . HRMS (FAB ): m/z [M + H] calcd for C14H13O : 245.0736;
4
The authors would like to thank the Cultural Affairs and Mission Sec-
tor (Ministry of higher education)-Egypt.
found: 245.0817.
(
11) (a) Licea-Perez, H.; Wang, S.; Rodgers, C.; Bowen, C. L.; Fang, K.;
Szapacs, M.; Evans, C. A. Bioanalysis 2015, 7, 3005. (b) Kitamura,
M.; Ohmori, K.; Kawase, T.; Suzuki, K. Angew. Chem. Int. Ed.
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2, 455. (b) Schmidt, R. R.; Castro-Palomino, J. C.; Retz, O. Pure
(
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589118.
1
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
Appl. Chem. 1999, 71, 729. (c) Jensen, K. J. J. Chem. Soc., Perkin
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(
13) Jacobson, M.; Malmberg, J.; Ellervik, U. Carbohydr. Res. 2006,
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3
41, 1266.
14) (a) Brenstrum, T. J.; Brimble, M. A. Arkivoc 2001, (vii), 37.
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56.
(
(1) There have been reported two kinds of eleuthoside A. One is
(
5
isolated by Kashman Y. et al. and the other is (3R)-4-(β-d-gluco-
pyranosyloxy)-5-methoxy-3-methyl-naphtho[2,3-c]furan-
2
(15) (a) Mancini, R. S.; McClary, C. A.; Anthonipillai, S.; Taylor, M. S. J.
Org. Chem. 2015, 80, 8501. (b) Aitken, H. R. M.; Johannes, M.;
Loomes, K. M.; Brimble, M. A. Tetrahedron Lett. 2013, 54, 6916.
1(3H)-one, isolated by Shibuya H. et al. In this paper, synthetic
study of latter eleuthoside A and related compounds are
described. For the isolation of eleuthoside A, see: Ketzinel, S.;
Rudi, A.; Schleyer, M.; Benayahu, Y.; Kashman, Y. J. Nat. Prod.
(16) (a) Yong-lin, J.; Bin, L.; Bai-chun, B. Huaxue Yu Nianhe 2007, 29,
189. (b) Shuhan, Z.; Kejun, S. CN 1803818 A, 2006.
1996, 59, 873.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
Synlett
D. I. A. Othman et al.
Letter
(
17) (a) Matsumoto, T.; Katsuki, M.; Jona, H.; Suzuki, K. J. Am. Chem.
(1 h). Then, the reaction mixture was concentrated under
reduced pressure and purified by PTLC eluting with
Soc. 1991, 113, 6982. (b) Mukaiyama, T.; Murai, Y.; Shoda, S.
Chem. Lett. 1981, 10, 431. (c) Oyama, K.; Kondo, T. J. Org. Chem.
(CHCl /MeOH, 6:1) to afford (1.5 mg, 20%) eleuthoside A (1) as a
3
2
004, 69, 5240. (d) Matsumoto, T.; Katsuki, M.; Suzuki, K. Chem.
single isomer along with 28% mixed isomer with the ratio 1/3-
epi-1 (3:1) and 8% mixed isomer with the ratio 1:1. The spectral
data of the white crystals of the natural isomer will be detailed
below
Lett. 1989, 18, 437.
(
18) (a) Zhao, Y.; Lu, Y.; Ma, J.; Zhu, L. Chem. Biol. Drug Des. 2015, 86,
691. (b) Tietze, L. F.; Gericke, K. M.; Güntner, C. Eur. J. Org. Chem.
2
006, 4910. (c) Kumazawa, T.; Ohki, K.; Ishida, M.; Sato, S.;
Mp 210 °C. R = 0.42 (CHCl /MeOH, 6:1), [α] –58.6 (c 0.0015, in
f
3
D
1
Onodera, J.-I.; Matsuba, S. Bull. Chem. Soc. Jpn. 1995, 68, 1379.
d) Toshima, K. Carbohydr. Res. 2000, 327, 15. (e) Yamaguchi, M.;
Horiguchi, A.; Fukuda, A.; Minami, T. J. Chem. Soc., Perkin Trans.
1990, 1079. (f) Oyama, K.; Kondo, T. Synlett 1999, 1627.
g) Wozney, Y. V.; Kalicheva, I. S.; Galoyan, A. A. Bioorg. Khim.
982, 8, 1388. (h) Giam, C. S.; Goldschmid, H. R.; Perlin, A. S.
MeOH at 25 °C). H NMR (500 MHz, CD OD): δ = 8.22 (s, 1 H, H-
3
(
9), 7.68 (d, 1 H, J = 8.0 Hz, H-8), 7.54 (dd, 1 H, J = 7.9, 8.0 Hz, H-
7), 7.15 (d, 1 H J = 7.9 Hz, H-6), 6.07 (q, 1 H, J = 6.6 Hz, H-3), 5.01
1
(
1
(d, 1 H, J = 7.6 Hz, H-1′), 4.02 (s, 3 H, OCH ), 3.72 (dd, 1 H, J = 2.1,
3
11.6 Hz, H-6B′), 3.61 (dd, 2 H, H-2′, H-6A′), 3.49 (dd, 1 H, J = 9.2,
9.5 Hz, H-3′), 3.42 (dd, 1 H, J = 9.4, 9.5 Hz, H-4′), 3.12 (ddd, 1 H, J
= 2.1, 5.8, 9.4 Hz, H-5′), 1.74 (d, 3 H, J = 6.6 Hz, 3-CH3). 1 H NMR
Can. J. Chem. 1961, 39, 2025.
(19) Chen, C.-Y.; Sun, J.-G.; Liu, F.-Y.; Fung, K.-P.; Wu, P.; Huang, Z.-Z.
Tetrahedron 2012, 68, 2598.
(500 MHz, CDCl ): δ = 8.27 (s, 1 H, H-9), 7.68 (d, 1 H, J = 8.0 Hz,
H-8), 7.53 (dd, 1 H, J = 7.9, 8.0 Hz, H-7), 7.10 (d, H J = 7.9 Hz, H-
3
(20) (a) Frackowiak, A.; Skibinski, P.; Gawel, W.; Zaczynska, E.;
Czarny, A.; Gancarz, R. Eur. J. Med. Chem. 2010, 45, 1001.
6), 5.91 (q, 1 H, J = 6.6 Hz, H-3), 4.95 (d, 1 H, J = 7.6 Hz, H-1′),
4.02 (s, 3 H, OCH ), 3.82 (s, 2 H, br OH), 3.78–3.72 (m, 2 H, J =
3
(
b) Belyanin, M. L.; Stepanova, E. V.; Ogorodnikov, V. D. Carbo-
7.4, 9.5 Hz, H-6B′, H-6A′), 3.68 (d, 2 H, H-2, H-4′, J = 8.8, 9.5 Hz),
3.49 (dd, 1 H, J = 9.2, 9.5 Hz, H-3′), 3.12 (ddd, 1 H, J = 4.5, 8.8, 9.0
Hz, H-5′), 2.84 (s, 1 H, br-OH), 2.73 (s, 1 H, br-OH), 1.73 (d, 3 H, J
hydr. Res. 2012, 363, 66.
(
21) Zhao, Y.; Ni, C.; Zhang, Y.; Zhu, L. Arch. Pharm. Chem. Life Sci.
13
2
012, 345, 622.
22) Experimental Procedure and Physical Data of Eleuthoside A
1)
= 6.5 Hz, 3-CH3). C NMR (125 MHz, CD3OD): δ = 170.9, 156.0,
146.4, 139.3, 138.0, 127.06, 124.5, 122.6, 122.6, 122.3, 108.3,
104.7, 79.5, 76.9, 76.4, 74.6, 70.1, 61.0, 54.7, 17.9. IR (ATR): 3404
(
(
–1
+
The solid of peracetyl glycoside 20 (8.0 mg, 0.1 mmol) was dis-
(OH), 2971, 1750 (C=O), 1586, 1033 cm . HRMS (ESI ): m/z =
solved in MeOH (2 mL), and then, K CO (4.8 mg, 0.25 mmol)
429 [M + Na+]; calcd for C20H22NaO9: 429.1162; found:
2
3
was added. The reaction mixture was stirred at room tempera-
ture until TLC showed complete conversion of starting material
429.1154.
(23) Cheng, K.; Liang, G.; Hu, C. Molecules 2008, 13, 938.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F