Concise synthesis of the tetracyclic framework of azadiradione: Tandem radical cyclization route

Article abstract of DOI:10.1246/cl.2013.220

Azadiradione, a limonoid isolated from the neem plant, possesses a unique stereostructure distinct from that of the steroids. We describe a concise synthesis of the tetracyclic framework of azadiradione by a tandem radical cyclization process.

Full text of DOI:10.1246/cl.2013.220

doi:10.1246/cl.2013.220
220
Published on the web February 16, 2013
Concise Synthesis of the Tetracyclic Framework of Azadiradione:
Tandem Radical Cyclization Route
Shuji Yamashita,*1 Akito Naruko,1 Takahiro Yamada,1 Yujiro Hayashi,1 and Masahiro Hirama1,2
1Department of Chemistry, Graduate School of Science, Tohoku University, Sendai, Miyagi 980-8578
2Research and Analytical Center for Giant Molecules, Graduate School of Science,
Tohoku University, Sendai, Miyagi 980-8578
(Received November 27, 2012; CL-121180; E-mail: s-yamashita@m.tohoku.ac.jp)
Azadiradione, a limonoid isolated from the neem plant,
(Scheme 2).15 Simultaneous removal of the ethyl ester and
chlorine of 8 was accomplished by the Krapcho reaction to give
enone 9 in 61% yield.13,14 Finally, chemo- and regioselective
dimethylation at the C4 position of 9 furnished the azadiradione
framework 10 in 41% yield.
possesses a unique stereostructure distinct from that of the steroids.
We describe a concise synthesis of the tetracyclic framework of
azadiradione by a tandem radical cyclization process.
In summary, we have developed a concise radical route to
the framework of 1, in which the four carbon-carbon bonds and
seven stereocenters featuring the C13,14-cis configuration were
Limonoids, highly oxygenated triterpenes, are abundant
secondary metabolites of citrus fruit, and more than 300
congeners have been isolated.1 While the prototypical limonoid
framework is characterized by a 4,4,8-trimethyl-17-furylandros-
tane, this family encompasses a diverse array of structural
architectures as a result of oxidation and skeletal rearrange-
ments, and features a unique C13¡-methyl group. Limonoids
exhibit a wide spectrum of biological properties such as
antifeedent and growth regulating activities on insects, as well
as antibacterial, antifungal, anticancer, antiviral, and a number of
pharmacological activities in humans.2 Owing to their signifi-
cant biological activities and complex architectures, the limo-
noids have attracted keen interest from synthetic chemists. Only
two groups have succeeded in the total synthesis of limonoids to
date,3,4 though many synthetic efforts have been conducted.5 We
describe here a concise synthesis of the framework of azadir-
adione (1) (Chart 1),6 a representative member of the limonoids,
through a tandem radical cyclization reaction.
Our synthesis commenced with farnesol (2), which was
converted to allylic alcohol 3 (Scheme 1).15 Subsequent chlori-
nation of 3, addition of ethyl 2-chloroacetoacetate dianion,7 and
removal of the TMS group furnished acyclic ¢-ketoester 4.
Manganese-mediated tandem radical cyclization of 4 according
to Snider’s method8 gave rise to the tetracyclic framework 5
along with its C13-epimer 6 (23% combined yield, 5:6 = 2:1).
The structures of 5 and 6 were unambiguously confirmed by
X-ray crystallographic analyses of 5 and 7, the latter of which
was derived from dechlorination of 6, respectively9 (Figures 1
and 2).15 Note that 5 possesses the cis-fused CD-ring, which is a
characteristic of limonoids, while a well-established cation-³
cyclization gave only the trans-fused isomer.10-12
1. PCl3, DMF, THF
2. m-CPBA, K2CO3
TMS
CH2Cl2, -40 to 0 °C
3. LiCH2C≡CTMS
THF, -40 to 0 °C
OH
4. Al(Oi-Pr)3, toluene
reflux
49% (4 steps)
HO
farnesol (2)
3
1. SOCl2, pentane, 0 °C
2. Ethyl 2-chloroacetoacetate
NaH, n-BuLi
DMPU, THF, 0 °C
3. TBAF, THF
35%
(3 steps)
13
14
C
D
A
H
H
B
O
O
Cl
H
Mn(OAc)3·2H2O
AcOH
5
O
OEt
+
O
23% (dr = 2:1)
Cl
13
O
OEt
4
H
H
X
H
6: X = α-Cl
7: X = β-H
Zn, AcOH
85%
O
OEt
Scheme 1. Tandem radical cyclization.
Oxidative cleavage of the exo methylene of 5 with a
catalytic amount of RuCl3 in the presence of NaIO4 afforded 8
O
17
13
O
1
8
H
4
O
OAc
H
Chart 1.
Figure 1. ORTEP drawing of 5.
Chem. Lett. 2013, 42, 220-221
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

221
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Crystallographic data of compounds 5 and 7 have been
deposited with Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-911770 and CCDC-
911771, respectively. Copies of the data can be obtained free
of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge, CB2 1EZ, U.K.; fax: +44 1223
336033; or deposit@ccdc.cam.ac.uk).
Figure 2. ORTEP drawing of 7.
cat. RuCl3
O
NaIO4, CCl4
CH3CN, H2O
0 °C
LiCl, H2O
DMSO, 180 °C
5
5
6
H
H
37%
61%
O
Cl
H
O
OEt
8
7
8
O
O
MeI, t-BuOK
t-BuOH, 40 °C
9
H
H
H
H
4
41%
O
O
4
azadiradione framework (10)
9
Scheme 2. Synthesis of azadiradione framework.
constructed in one step (4 ¼ 5). The application of this radical
strategy to the total syntheses of 1 and other limonoids is being
actively investigated in our laboratory.
10 For selected reviews on cation-³ cyclization, see: a) W. S.
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references therein.
11 For selected examples of a one-step construction of the
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This work was supported financially by a Grant-in-Aid for
Scientific Research (B) and (C) from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT), Japan, and
the Suntory Foundation for Life Sciences. We are grateful to Dr.
S. Ishida at the Graduate School of Science, Tohoku University
for his assistance with X-ray crystallographic analysis and
helpful discussions.
References and Notes
1
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2
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3
4
Total synthesis of azadiradione (1) by Corey and co-workers,
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14 The C4-chlorine is crucial not only for transforming 8 into 9
in one step, but also for preventing overreactions in radical
cyclization (4 ¼ 5). See: B. B. Snider, J. J. Patricia, S. A.
Kates, J. Org. Chem. 1988, 53, 2137.
15 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.
html.
Total synthesis of azadiractin by Ley and co-workers, see: a)
Chem. Lett. 2013, 42, 220-221
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/