Total synthesis of Cytosporone B

Article abstract of DOI:10.1002/cjoc.201090163

The total synthesis of Cytosporone B, a naturally occurring agonist for Nur77, has been accomplished. The key steps are the sequential Grignard reaction and Lemieux-van Rudloff oxidation followed by a deprotection of the methyl aromatic ether to phenol an

Full text of DOI:10.1002/cjoc.201090163

NOTE
Total Synthesis of Cytosporone B
Huang, He(黄河)
Ding, Xiao(丁晓)
Zhang, Lei(张磊)
Shen, Xu(沈旭)
Zhang, Xiaodong(张小栋)
Jiang, Hualiang(蒋华良)
Ji, Xun(姬勋)
Liu, Hong*(柳红)
Drug Discovery and Design Centre, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Shanghai Institutes for Biological Sciences, and Graduate School, Chinese Academy of Sciences, 555 Zuchongzhi
Road, Shanghai 201203, China
The total synthesis of Cytosporone B, a naturally occurring agonist for Nur77, has been accomplished. The key
steps are the sequential Grignard reaction and Lemieux-van Rudloff oxidation followed by a deprotection of the
methyl aromatic ether to phenol and subsequent Friedel-Crafts acylation.
Keywords Cytosporone B, total synthesis, agonist, antitumor agents
Introduction
one of the orphan receptors which act as transcription
factors to regulate the expression of target genes by tar-
geting their response elements.9-12 However, a physio-
logical ligand for Nur77 has not been identified. Re-
markably, Cytosporone B is a naturally occurring ago-
nist for Nur77.4 It has a strong affinity for Nur77 and
stimulates the transactivational activity of Nur77.
Moreover, it increases Nur77-mediated induction of
apoptosis, increases growth inhibition of xenograft tu-
mors in nude mice, and enhances gluconeogenesis in
mouse liver. Importantly, Cytosporone B does not exert
any of these effects on Nur77-null mice or cells. These
results reveal that Cytosporone B may be useful in the
development of new therapeutic drugs to treat cancer
and hypoglycemia.4 The novel structures of Cyto-
sporone B combining with remarkable biological activ-
ity and lack of availability from natural sources have
attracted interest from chemists for its total synthesis. In
the following we report on the total synthesis of this
compound.
Cytosporone B, isolated from Cytospora sp. CR200
and Dothiorella sp. HTF3, belongs to a family including
Cytosporones A, B, C, D and E (Scheme 1).1 Some of
them display antibacterial activity.1-3 Particularly, a re-
cent excellent report by Wu et al.4 has revealed that
Cytosporone B acted as an agonist for Nur77. Nuclear
receptors play important roles in numerous biological
processes such as cell proliferation, differentiation,
apoptosis, metabolism and development.5-8 Nur77 is
Scheme 1 Structures of Cytosporones A—
E
Results and discussion
The key to the synthesis of the Cytosporone B was
the construction of the 2-phenylacetic acid skeleton.
Many methods have been reported, such as the
self-condensation of dimethyl 1,3-acetonedicarboxy-
late,13,14 decarboxylation of 2-phenylmalonic acids,15-18
and oxidation of allylbenzene.19-21 Progress in the total
synthesis of Cytosporone B has been made recently.
Zhang et al.22 constructed the 2-phenylacetic acid
skeleton via hydrolysis using 2-phenylacetonitrile,
which was prepared from benzyl methanesulfonate and
sodium cyanide. Such synthetic route has been shown to
be effective in generating the 2-(dihydroxyphenyl)acetic
acids. However, this process needs a long synthetic
*
E-mail: hliu@mail.shcnc.ac.cn; Tel.: 0086-021-50807042; Fax: 0086-021-50807088
Received September 9, 2009; revised November 2, 2009; accepted March 1, 2010.
Project supported by the National Natural Science Foundation of China (Nos. 20721003 and 20872153).
Chin. J. Chem. 2010, 28, 1041— 1043
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Huang et al.
NOTE
route and hypertoxic reagent. A general method for the
oxidation of olefins is using KMnO4 together with
NaIO4 as the oxidants. The reaction conditions are mild
and the protocol is convenient. Therefore, we chose the
oxidation of allylbenzene to prepare the 2-phenylacetic
acid skeleton.
The retrosynthetic analysis is as follows (Scheme 2).
Cytosporone B would be synthesized by deprotection of
ethyl 2-(3,5-dimethoxy-2-octanoylphenyl)acetate gen-
erated via a Friedel-Crafts acylation. The key interme-
diate 4 would be obtained by an Grignard reaction of
1-bromo-3,5-dimethoxybenzene (1) with 3-bromoprop-
1-ene, followed by sequential oxidation and esterifica-
tion of the olefin 2.
The synthetic routine is shown in Scheme 3. The
first step in the synthesis of 1-allyl-3,5-dimethoxyben-
zene (2) was the Grignard reaction of 1-bromo-3,5-
dimethoxybenzene. In order to construct the
2-phenylacetic acid moiety, an oxidation reaction of the
compound 2 was envisaged. The attempted oxidation by
means of RuCl3/NaIO4 was unsuccessful.20 Finally, a
Lemieux-van Rudloff oxidation19 (substoichiometric
amounts of KMnO4 together with an excess of NaIO4)
allowed the isolation of acid 3 in moderate yield (51%,
two steps).
With the key intermediate 4 now available by the
oxidation and esterification, the sequential Friedel-
Crafts acylation and deprotection were performed sub-
sequently. The Friedel-Crafts reaction proceeded
smoothly enough, with 86% yield of the purified prod-
uct. However, the subsequent phenolic deprotection was
problematic. Initially, an attempt to deprotect ethyl
2-(3,5-dimethoxy-2-octanoylphenyl)acetate (5) using
BBr3 failed. Next, the ether was deprotected to the phe-
nol by refluxing with HBr/AcOH.23 Unfortunately, the
reaction conditions chosen did not yield the product.
Another attempt was then made with AlCl3. Despite an
earlier report24 of a similar reaction, the reagent could
not give the deprotected product yet. The reaction pro-
ceeded difficultly and hence was abandoned.
Scheme 2 Retrosynthetic analysis of Cytosporone B
A benzyl ether protecting group for the phenol was
used next, simply because the benzyl group could be
deprotected in mild reaction conditions. The ether in 4
was deprotected first to phenol 6 using BBr3, followed
Scheme 3
Reagents and conditions: (a) Mg, I2, THF, 3-bromoprop-1-ene, r.t., 3 h; (b) KMnO4, NaIO4, K2CO3, t-BuOH/H2O, r.t., 4 h; (c) DCC, EtOH, r.t.,
3 h; (d) AlCl3, 1,2-dichloroethane, octanoyl chloride, 0 ℃ to r.t., 8 h; (e) BBr3, CH2Cl2, 0 ℃ to r.t., 10 h; or 57% HBr/AcOH, reflux, 8 h; or
DCM, AlCl3 (6.00 equiv.), 0 ℃ to r.t., 12 h; (f) BBr3, CH2Cl2, 0 ℃ to r.t., 10 h; (g) BnBr, K2CO3, DMF, 60 ℃, 5 h; (h) AlCl3, 1,2-dichloroethane,
octanoyl chloride, 0 ℃ to r.t., 8 h; (i) H2, 10% Pd/C, 4 h
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1041— 1043

Total Synthesis of Cytosporone B
by etherification with benzyl bromide to yield the in-
termediate 7 (56% yield, two steps). The hydroxyl pro-
tection step was followed by an attempt to acylation of
this protected phenol with octanoyl chloride catalyzed
by AlCl3 (83% yield). Finally, the debenzylation of
ethyl 2-(3,5-bis(benzyloxy)-2-octanoylphenyl)acetate (8)
under H2 proceeded very smoothly (95% yield) and very
pure Cytosporone B was obtained.25 Characterization
data were in complete agreement with the existing lit-
erature.1
9
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Conclusion
In summary, the total synthesis of Cytosporone B
has been achieved from 1-bromo-3,5-dimethoxybenzene.
It is possible to extend the present protocol developed
for the synthesis of other natural products with the
2-phenylacetic acid skeleton. The synthesis is amenable
to large scale, and a similar strategy will allow the syn-
thesis of analogs of Cytosporones for further struc-
ture-activity relationship study.
References and note
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25 Analytical data for Cytosporone B: yellow oil; H NMR
(CDCl3, 300 MHz) δ: 6.35 (d, J＝2.1 Hz, 1H), 6.32 (d, J＝
2.1 Hz, 1H), 4.08 (q, J＝7.2 Hz, 2H), 3.57 (s, 2H), 2.78 (t,
J＝7.2 Hz, 2H), 1.64—1.55 (m, 2H), 1.28—1.21 (m, 8H),
1.20 (t, J＝7.2 Hz, 3H), 0.83 (t, J＝7.2 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ: 206.7, 171.3, 164.3, 160.4, 136.6,
116.4, 112.6, 103.1, 61.5, 43.3, 47.1, 31.6, 29.1, 29.0, 24.9,
22.5, 14.1, 14.0; MS (ESI) m/z: 323.1 [M＋H]＋; HRMS
(ESI) calcd for C18H27O5 [M ＋ H] ＋ 323.1858, found
323.1860.
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Chin. J. Chem. 2010, 28, 1041— 1043
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