Short Synthesis of the Antidiabetic Octaketide Ethyl 2-(2,3,4-Trimethoxy-6-octanoylphenyl)acetate

Article abstract of DOI:10.1055/s-0036-1592062

A facile and practical approach for the synthesis of ethyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate, an antidiabetic octaketide analogue of cytosporone B, is described. Unlike known approaches for the synthesis of cytosporones and their analogues, the

Full text of DOI:10.1055/s-0036-1592062

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
en
W. Sun et al.
Letter
Synlett
Short Synthesis of the Antidiabetic Octaketide Ethyl 2-(2,3,4-Tri-
methoxy-6-octanoylphenyl)acetate
Wei Sun
Friedel–Crafts alkylation
Yue Yuan
O
CO2Et
O
Bit Lee
desulfuration
O
O
O
O
CO2Et
SCH3
Hee-Sook Jun
Dongyun Shin
Seung-Yong Seo*
R
+
C7H15
Cl
Cl
O
O
TMPA (1, R = H)
O
College of Pharmacy, Gachon University, 191
Hambakmoe-ro, Yeonsu-gu, Incheon 21960,
Republic of Korea
O
O
O
[65% for 4 steps]
CO2Et
+
C7H15
syseo@gachon.ac.kr
Received: 05.10.2017
Accepted after revision: 24.10.2017
Published online: 28.11.2017
tate (TMPA, 1) was reported by the Wu group to act as an
antagonist of the interaction between NR4A1 and liver ki-
nase B1 (LKB1), as a potential antidiabetic agent.5
DOI: 10.1055/s-0036-1592062; Art ID: st-20017-u0739-l
Abstract A facile and practical approach for the synthesis of ethyl 2-
(2,3,4-trimethoxy-6-octanoylphenyl)acetate, an antidiabetic octa-
ketide analogue of cytosporone B, is described. Unlike known ap-
proaches for the synthesis of cytosporones and their analogues, the key
step of the developed route is a Friedel–Crafts alkylation of 1-(3,4,5-tri-
methoxyphenyl)octan-1-one with ethyl chloro(methylthio)acetate, fol-
lowed by desulfurization.
OH
O
OH
R
O
CO2R
HO
HO
O
Cytosporone A (R = H)
Cytosporone B (R = Et)
Cytosporone C (R = H)
Cytosporone D (R = OH)
OH
H
O
Key words cytosporones, octaketides, TMPA, Friedel–Crafts reaction,
alkylation, medicinal chemistry
HO
HO
O
O
CO2Et
O
O
O
Cytosporone E
TMPA (1)
Cytosporones A–E are octaketide metabolites (Figure 1)
isolated from the broth of the endophytic fungi Cytospora
sp. CR200 and Diaporthe sp. CR146 by the Clardy group.1
Cytosporones A and B are a series of nonisoprenoid pheno-
lic lipids that contain a resorcinol moiety with both octa-
noyl and phenylacetate groups, whereas cytosporones C, D,
Figure 1 The structure of natural and synthetic nonisoprenoid pheno-
lic lipids.
Several synthetic approaches to nonisoprenoid phenolic
lipids such as cytosporones A and B have been reported.6–8
In a general synthesis of cytosporones A and B, ethyl 2-(3,5-
dialkoxyphenyl)acetates were used as starting materials
and were converted into the desired products by Friedel–
Crafts acylation (Scheme 1).6 Similarly, we prepared the
3,4,5-trimethoxy analogue 2 by a Friedel–Crafts acylation
of 3,4,5-trimethoxyphenylacetic acid, followed by esterifi-
cation.9 However, despite its structural similarity to cyto-
sporone B, the synthesis of 1, as reported by Wu and co-
workers, involved seven steps, including the oxidative
cleavage of a 5,6,7-trimethoxyindene intermediate.5 For the
large-scale synthesis of 1, three types of synthetic strate-
gies might be considered. First, an octanoyl moiety might
be introduced directly onto ethyl (2,3,4-trimethoxyphe-
nyl)acetate. Secondly, an acetate moiety might be generated
in the ortho-position of 1-phenyloctan-1-one by appropri-
and
E contain di- or trihydroxy-1,4-dihydro-3H-iso-
chromen-3-one moieties. Cytosporone B was recently re-
ported to bind to the ligand-binding domain of nuclear or-
phan receptor NR4A1 and to stimulate the transactivational
activity of the receptor.2,3 Moreover, cytosporone B enhanc-
es gluconeogenesis in mouse liver, increases the NR4A1-
mediated induction of apoptosis, and retards xenograft tu-
mor growth. These biological effects indicate that cytospo-
rone B might be useful for the development of new thera-
peutic drugs for various cancers or metabolic disorders.
Since the isolation of natural octaketides with unique skele-
tons and biological activities, various octaketide analogues
have been designed and synthesized in attempts to identify
substrates that bind NR4A1 and exhibit antitumor or anti-
diabetic properties.3,4 Notably, the synthetic cytosporone B
analogue, ethyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)ace-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
W. Sun et al.
Letter
Synlett
ate means, such as metal-catalyzed cross-coupling. Thirdly,
both the octanoyl and acetate groups might be generated
simultaneously from an aryne, as previously reported in a
synthesis of cytosporone B via dimethoxybenzyne as an in-
termediate.8 However, we surmised that the acylalkylation
of trimethoxybenzyne might afford isomer 2 instead of 1, as
the introduction of the octanoyl moiety might occur regio-
selectively at the ortho-position of the 3-methoxy group.10
O
O
O
CO2Et
O
CO2Et
O
O
O
O
O
O
a–b
c
5
3
4
O
O
C7H15
+
6
CO2Et
O
O
C7H15
a)
OR'
OH
O
C7H15COX
O
1 (not observed)
and
CO2R
CO2R
O
O
O
R'O
HO
"deprotection"
O
O
CO2H
C7H15
O
O
e-f
Cytosporone A (R = H)
Cytosporone B (R = Et)
OH
d
3,5-dialkoxyphenylacetate
6
b)
O
O
O
O
O
7
O
1. C7H15COCl
AlCl3
O
O
O
O
O
8
O
CO2Et
2. SOCl2
EtOH
CO2H
2
O
C6H13
O
Scheme 2 First attempts to elaborate the octanoyl group at the C6 po-
sition. Reagents and conditions: (a) sulfur, TsOH (cat.), morpholine,
130 °C, 6 h; EtOH, 6 M aq NaOH, 100 °C reflux, 3 h; then H+; (b) SOCl2,
EtOH, overnight; (c) octanoyl chloride, BF3·OEt2, CH2Cl2, r.t., 1 h; reflux
overnight; (d) octanoic anhydride, [Rh(cod)Cl]2, Cs2CO3, mesitylene,
145 °C, 16 h; 6 M NaOH, 100 °C, 1 h; then H+; (e) (1) oxalyl chloride; (2)
TMSCHN2, Et2O, THF; (3) Ag2O, H2O–1,4-dioxane; (f) SOCl2, EtOH.
c)
O
a
O
O
X
path a
+
CO2Et
O
1
b
O
CO2Et
O
path b
O
[M]
CO2Et
O
X
O
O
O
O
O
3
For our second approach, we chose 3,4,5-trimethoxy-
benzaldehyde (9) as a starting material and we treated this
with NBS to give the aryl bromide 10 in 92% yield.14a Addi-
tion of a Grignard reagent followed by PCC oxidation gave
ketone 11.14b We then attempted to introduce an acetate
group at the C2 position of 11 by various transition-metal-
catalyzed cross-coupling reactions.15 However, the cross-
coupling reaction of 11 and diethyl malonate in the pres-
ence of Pd[P(t-Bu)3] or CuBr was unsuccessful. Notably, the
conversion of the bromide into a pinacol boronate and
cross-coupling with ethyl bromoacetate did not give the de-
sired product. The addition of 2-bromozincacetate with a
palladium catalyst was also unsuccessful. Eventually, an al-
lyl group was introduced by using allyl(tributyl)stannane
and Pd(PPh3)4. With product 12 in hand, a four-step synthe-
sis afforded 1 in an improved yield (44% overall, from 9), al-
though an additional step was required compared with the
previous route. The synthesized 1 was identical to that of a
previous report.5
In an attempt to reduce the number of reaction steps,
we turned to our attention to the direct introduction of the
acetate moiety, and we examined several approaches in-
cluding the Willgerodt reaction of acetophenone and a
Friedel–Crafts alkylation with ethyl chloro(methylthio)ac-
etate. As in the synthesis of 11, ketone 13 was prepared
from aldehyde 9 in two steps. However, ketone 14, which
was prepared with AcCl and BF3·OEt2, could not be trans-
O
+
EtO
R
O
(R = C7H15
)
O
(X = H or Br)
Scheme 1 Previous syntheses of cytosporones A and B and a retrosyn-
thetic analysis of TMPA. (a) The approaches of the Liu, Beatriz, and Shen
groups toward cytosporones. (b) Our approach to the 2,3,4-trimethoxy
analogue. (c) Retrosynthetic analysis for TMPA.
We therefore began our study with the preparation of
ethyl (2,3,4-trimethoxyphenyl)acetate (4), which we chose
as a precursor for the Friedel–Crafts acylation. Acetate 4
was synthesized from commercially available 1-(2,3,4-tri-
methoxyphenyl)ethanone (3) by a conventional Willgerodt
reaction.11 However, treatment of 4 with octanoyl chloride
and BF3·OEt2 gave the regioisomer 5, without any TMPA (1).
The synthesis of 1 by conventional Friedel–Crafts acylation
was also unsuccessful. We therefore attempted a Rh-cata-
lyzed ortho-acylation of the aromatic carboxylic acid 6,12
which was treated with octanoic anhydride and
[Rh(cod)Cl]2 to afford keto acid 7. A four-step transforma-
tion of 7, involving an Arndt–Eistert one-carbon homologa-
tion, was carried out,13 but the undesired product 8, con-
taining a heptylidene moiety, was as formed during the
generation of the acid chloride.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
W. Sun et al.
Letter
Synlett
Finally, 16 was readily converted into the desired TMPA (1)
in 94% yield by reductive desulfurization with zinc dust and
acetic acid.
O
O
O
O
O
O
O
Br
O
O
Br
O
a
b–c
C7H15
To optimize the Friedel–Crafts alkylation, the effects of
various reaction conditions and Lewis acids were examined
(Table 1) The reaction using AlCl3 afforded the desired prod-
uct 16 in moderate yield (Table 1, entry 1), whereas
BF3·OEt2, ZnO, or Yb(OTf)3 gave a low yield of the product
(entries 2–4). Although Yb(OTf)3 has been reported to be ef-
ficient in Friedel–Crafts alkylation with 15, the yield of the
reaction with Yb(OTf)3 to give 16 was not satisfactory (en-
try 4).16b In contrast, the use of 1.1 equivalents of SnCl4 with
1.1 equivalents of 15 gave the product in 60% yield (entry
5). Increasing the amount of 15 improved the yield (entries
6 and 7) The use of SnCl4 and 2.0 equivalents of 15 turned
out to be the optimal conditions for the Friedel–Crafts al-
kylation.
CHO
CHO
9
10
11
[M]
CO2Et
d-1, d-2,
d-3, or d-4
O
(see text)
O
e
f–i
1
C7H15
O
12
O
Scheme 3 Attempts at metal-catalyzed cross-coupling via an aryl bro-
mide. Reagents and conditions: (a) NBS, CHCl3, reflux, 3 h; (b) C7H15MgBr,
THF, –40 °C, 2 h; (c) PCC, CH2Cl2, 3 h; (d-1) CH2(CO2Et)2, Pd(dba)2,
P(t-Bu)3·HBF4, K3PO4, 18-crown-6, 160 °C, 8 h; (d-2) CH2(CO2Et)2,
CuBr, NaH, 90 °C, 2 h; 2 M NaOH, THF, then SOCl2, EtOH, overnight;
(d-3) PdCl2(dppf)·CH2Cl2, NaOAc, bis(pinacolato)diboron, 1,4-diox-
ane, 90 °C, 14 h, then BrCH2CO2Et, Pd2(dba)3, BnN+Et3 Cl–, tri(2-tolyl)-
phosphine, KF, THF, 60 °C, overnight; (d-4) BrZnCH2CO2Et, Pd(dba)2,
Xantphos, THF, 65 °C, 8 h; (e) AllSnBu3, Pd(PPh3)4, DMF, 160 °C, 1 h;
(f) OsO4, NMO, MsNH2, acetone, H2O; (g) NaIO4, THF, H2O; (h) NaClO2,
NaH2PO4, 2-methylbut-2-ene, THF, t-BuOH, H2O; (i) SOCl2, EtOH; 44%
(overall yield for 8 steps from 9).
Table 1 Optimization of Friedel–Crafts Alkylation of Ketone 13 with
Ethyl Chloro(methylthio)acetate (15)
SCH3
15
O
O
SCH3
CO2Et
O
O
Cl
CO2Et
O
O
formed into 1 under Willgerodt conditions, despite several
attempts to do so. In a similar manner to the synthesis of 4
shown in Scheme 2, the presence of the neighboring octa-
noyl group might have been the cause of the unsatisfactory
result.
C7H15
C7H15
Lewis acid
solvent, 8 h
O
O
13
16
Entry
Lewis acid (equiv)
15 (equiv)
Solvent
Yielda (%)
A Friedel–Crafts alkylation with ethyl chloro(meth-
ylthio)acetate, followed by reductive desulfurization, has
been developed for the synthesis of arylacetates, which are
considered privileged structures in antiinflammatory
agents such as ibuprofen.16 To our delight, the treatment of
ketone 13 with ethyl chloro(methylthio)acetate (15) in the
presence of SnCl4 as a Lewis acid afforded ethyl (meth-
ylthio)(2,3,4-trimethoxyphenyl)acetate (16) in 91% yield.
1
2
3
4
5
6
7
AlCl3 (2.2)
1.1
1.1
1.1
1.1
1.1
1.5
2.0
CH2Cl2
CH2Cl2
neat
49
1
BF3·OEt2 (0.1)
ZnO (0.5)
16
12
60
70
91
Yb(OTf)3 (0.1)
SnCl4 (1.1)
SnCl4 (1.1)
SnCl4 (1.1)
MeNO2
CH2Cl2
CH2Cl2
CH2Cl2
In conclusion, we have developed a short and practical
synthesis of the antidiabetic cytosporone B analogue ethyl
2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (TMPA; 1)
from readily available 1-(3,4,5-trimethoxyphenyl)octan-1-
one, in which a chloro(methylthio)acetate group was incor-
porated by Friedel–Crafts alkylation.17 Our scalable synthe-
sis involved four steps and gave the product in 65% overall
yield. Further efforts toward the synthesis of TMPA ana-
logues, together with their biological evaluations, are un-
derway and will be reported in due course.
O
O
O
O
O
O
O
a–b
c
9
C7H15
C7H15
O
O
13
14
f
d–e
O
SCH3
O
O
O
O
O
g
CO2Et
C7H15
CO2Et
C7H15
O
O
16
1
Funding Information
Scheme 4 Optimized synthesis of TMPA. Reagents and conditions: (a)
Me(CH2)7MgBr, THF, –40 °C, 2 h; (b) PCC, CH2Cl2, 3 h; (c) AcCl, BF3·OEt2,
CH2Cl2, 4 h; (d) sulfur, TsOH (cat.), morpholine, 130 °C, 6 h; EtOH, 6 M
NaOH, reflux, 2 h, then H+; (e) SOCl2, EtOH, overnight; (f) MeSCH(Cl)CO2Et
(15), SnCl4, CH2Cl2; (g) Zn dust, AcOH, 100 °C, reflux, 4 h; 65% (overall
yield for 4 steps from 9).
This research was supported by the Korea Health Technology R&D
Project through the Korea Health Industry Development Institute,
funded by the Ministry of Health &Welfare (HI14C1135) and the Bio &
Medical Technology Development Program of the NRF funded by the
Korean government, MSIP (NRF-2017M3A9C8027781).
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
W. Sun et al.
Letter
Synlett
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D