Stereoselective synthesis of 4α-Alkyloxy-2-α/β- bromopodophyllotoxin derivatives as insecticidal agents

Article abstract of DOI:10.1002/chem.201100855

Interesting insecticides: 4α-Alkyloxy-2α/β- bromopodophyllotoxin derivatives were readily prepared with excellent stereoselectivity due to intramolecular steric effects (see scheme). The ratio of two stereoisomers, 2α/β-bromo-4-O- tetrahydropyranylpodophyllotoxin, could be well controlled by the reaction temperature. Copyright

Full text of DOI:10.1002/chem.201100855

COMMUNICATION
DOI: 10.1002/chem.201100855
Stereoselective Synthesis of 4a-Alkyloxy-2-a/b-Bromopodophyllotoxin
Derivatives as Insecticidal Agents
Hui Xu,* Qingtian Wang, and Yong Guo[a]
Podophyllotoxin (1), a natu-
rally occurring aryltetralin
lignan, is extracted as the main
component from the roots and
rhizomes of Podophyllum spe-
cies such as P. hexandrum and
P. peltatum. Since two semisyn-
thetic derivatives of 1, etopo-
side (VP-16, 2) and teniposide
(VM-26, 3), have been used as
DNA topoisomerase II inhibi-
tors in chemotherapy for vari-
ous types of cancer, more at-
tention has recently been paid
to extensive structural modifi-
cations on 1 to develop new
antitumor drugs.[1] In addition,
compound 1 has also exhibited
interesting insecticidal activi-
ty.[2]
Scheme 1. The synthetic approach for target compounds I.
More recently, we have sem-
isynthesized a series of 4a-acy-
loxy (4)[3]/4a-alkyloxy-2-chloropodophyllotoxins (5),[4] and
found that some compounds displayed more pronounced in-
secticidal activity than toosendanin, a commercial insecticide
derived from Melia azedarach. Consequently, these encour-
aging results promoted us to further design and prepare 4-
alkyloxy-2-bromopodophyllotoxins (I) as insecticidal agents
and to investigate if their insecticidal activity could be im-
proved when the chlorine atom at the C2 position of 5 was
substituted for a bromine atom.
tion of 6 with Br2 in the presence of lithium diisopropyla-
mide (LDA),[6] to our delight, herein we found that the rela-
tive ratio of two stereoisomers, 2b-bromo-4-O-tetrahydro-
The synthetic route for the preparation of I is proposed in
Scheme 1. First, as described in our previous paper, the 4-
OH group of 1 was smoothly protected by a tetrahydropyr-
anyl (THP) group in the presence of phosphorus oxychlor-
ide (POCl3) and dihydropyran (DHP) at room temperature
to afford 4-O-tetrahydropyranylpodophyllotoxin (6) in 92%
yield.[4,5] Although Durst and co-workers reported the reac-
[a] Prof. Dr. H. Xu, Q. Wang, Dr. Y. Guo
Laboratory of Pharmaceutical Design & Synthesis
College of Sciences, Northwest A & F University
Yangling 712100 (P.R. China)
Fax : (+86)29-87091952
E-mail: orgxuhui@nwsuaf.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100855.
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Table 1. Investigation of 6 reacting with Br2 in the presence of LDA.
Entry
T [8C]
t [h]
Yield [%][a]
Ratio of 8/9
8
9
1
2
3
4
5
6
37
33
30
27
25
21
13
14
14.5
15
15.5
16
4.6
5.6
8.2
9.5
15.7
20.3
25.4
18.4
22.8
20.3
14.8
12.4
1:5.5
1:3.3
1:2.8
1:2.1
1:0.94
1:0.61
[a] Yield of isolated product.
pyranylpodophyllotoxin (8) and 2a-bromo-4-O-tetrahydro-
pyranylpicropodophyllotoxin (9), could be well controlled
by the reaction temperature. The results are described in
Table 1. Following treatment of 6 with LDA at À788C in
dry THF via the intermediate 7, and subsequent substitution
reaction with Br2, the solution was allowed to warm slowly
from À788C to a certain temperature over a number of
hours. For example, when the solution was warmed slowly
from À78 to 378C for 13 h, the molar ratio of 8 and 9 was 1/
5.5; whereas when the solution was warmed slowly from
À78 to 218C for 16 h, the molar ratio of 8 and 9 was 1/0.61.
To obtain the configurations of the lactones of 8 and 9,
the single-crystal structures of 2b-bromopodophyllotoxin
(10), a hydrolysis product of 8, and 4a-n-butanoyloxy-2a-
bromopicropodophyllotoxin (12), a esterification product of
2a-bromopicropodophyllotoxin (11, a hydrolysis product of
9) reacting with n-butyric acid in the presence of N,N’-diiso-
propylcarbodiimide (DIC), were determined by X-ray crys-
tallography[7] (Figure 1). In these structures, the C2 bromine
atoms of 10 and 12 adopted the b- and a configuration, re-
spectively. That is, the configurations of the lactones of 8
and 9 were trans and cis, respectively.
Figure 1. X-ray crystal structures of 10 (top) and 12 (bottom).
The reaction of 10 or 11 with alcohols in the presence of
BF3·Et2O was then investigated as shown in Scheme 2. As
anticipated, and as in our previous report for 2b-chloropo-
dophyllotoxin,[4] when 10 was allowed to react with n-buta-
nol in the presence of BF3·Et2O, only 4a-n-butoxy-2b-bro-
mopodophyllotoxin (13) was obtained in a 54% yield due to
steric effects of the C2b bromine atom, and the assignment
of configuration of C4 position of 13 was based on the J-
n-butoxy groups of 12 and 14 f clearly all adopted the a con-
figuration according to X-ray crystallography (Figure 1 and
Figure 2), and the J
ACHTUNGTRENNUNG
and 14 f were 2.5 and 2.0 Hz, respectively. The JACHTUNGTRENNUNG
values of H4 of 14a–j were 2.0 Hz (see the Supporting Infor-
mation), therefore, at this stage we proposed that the config-
urations of the 4-alkyloxy groups of 14a–j were a. That is,
in contrast to the podophyllotoxin derivatives,[8] the C4-sub-
ACHTUNGTRENNUNG
(H3,H4) coupling constant[8] and X-ray crystallography[7]
(Figure 2). Interestingly, when compound 11 was allowed to
react with different alcohols in the presence of BF3·Et2O for
100–150 min, only 4a-alkyloxy-2a- bromopicropodophyllo-
toxins (14a–j) were produced in 53–86% yields with excel-
lent stereoselectivity. The configurations of C4 position of
14a–j were assigned as follows: The 4-n-butanoyloxy and 4-
stituted picropodophyllotoxin derivatives have a JACHTUNGTRENNUNG(H3,H4)
of approximately 2.0 Hz, which indicates that H3 and H4
are in a trans relationship, and the substituent on the C4 po-
sition of picropodophyllotoxin is in the a configuration.
Based upon the X-ray crystallography of 14 f,[7] the lactone
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Stereoselective Synthesis of 4a-AlkylACTHNUTRGNEUoGN xy-2-a/b-Bromopodophyllotoxin Derivatives
COMMUNICATION
Scheme 2. Investigation of 10 or 11 reacting with alcohols in the presence
of BF3·Et2O.
adopted the endo configuration, and if the alkyloxy group
on the C4 position adopted the b configuration, big steric ef-
fects might be observed between the lactone and the alky-
loxy group. Consequently, the alkyloxy groups on the C4 po-
sition of 14a–j adopting the a configuration was therefore
reasonable.
On the other hand, it was noteworthy to investigate if the
reaction of 4a-alkyloxy-2a-bromopicropodophyllotoxins
(14a–j) completely depended on the reaction time
(Scheme 2). The reaction time for the synthesis of 14a, 14b,
14d, 14 f, and 14h was investigated as examples. When the
reaction time was prolonged to 310–430 min, they were all
converted to the same byproduct 15 in 46–68% yields with
the more rigid structure through an intramolecular Friedel–
Crafts (FC) alkylation reaction, and its configuration was
confirmed by X-ray crystallography (Figure 3).[7] However,
for the reaction of 4a-n-butoxy-2b-bromopodophyllotoxin
(13), even if the reaction time was prolonged to 44 h at
room temperature or 17.5 h
Figure 2. X-ray crystal structures of 13 (top) and 14 f (bottom).
under reflux, the proposed by-
product 16 was not detected by
thin-layer chromatography. Si-
multaneously, compound 13 in
the presence of one equivalent
of aq. HCl (0.12m) in THF at
room temperature for 19 h or
under reflux for 12 h was also
investigated, and no new com-
pound was observed at all
except 13.
Finally, the insecticidal activ-
ity of 8–13, 14a–j, and 15 was
evaluated against the pre-
third-instar larvae of Mythimna
separata Walker in vivo by
Figure 3. X-ray crystal structure of 15.
Chem. Eur. J. 2011, 17, 8299 – 8303
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H. Xu et al.
using the leaf-dipping method at the concentration of
1 mgmLÀ1.[9] Toosendanin was used as the positive control
and the leaves that were treated with acetone alone were
used as a blank control group. The corrected mortality rates
of M. separata caused by 8–13, 14a–j, and 15 with the ad-
vance of time were shown in Table 2. The corresponding
mortality rates after 35 days were far higher than those after
corresponding compounds 9, 11, and 14 f (for the C2a bro-
mine series) were only 44.4, 44.4, and 40.7%, respectively.
In conclusion, we found some interesting results that can
be summarized as follows: 1) When 4-O-tetrahydropyranyl-
podophyllotoxin was allowed to react with Br2 in the pres-
ence of LDA, the ratio of two stereoisomers 8 and 9 could
be well controlled by the reaction temperature. 2) Due to
the intramolecular steric effects, 4a-alkyloxy-2a/b-bromopo-
dophyllotoxin derivatives were readily prepared with excel-
lent stereoselectivity by the treatment of 2a-bromopicropo-
dophyllotoxin or 2b-bromopodophyllotoxin with alcohols in
the presence of BF3·Et2O. 3) With respect to C4-substituted
Table 2. Insecticidal activity of 2a/b-bromopodophyllotoxin derivatives
8–13, 14a–j, and 15 against M. separata at 1 mgmLÀ1
.
Compounds
Corrected mortality rate [%]
20 days
10 days
35 days
picropodophyllotoxin derivatives, a JACTHNUTRGNE(NUG H3,H4) of approxi-
toosendanin
1
8
9
10
11
12
13
14a
14b
14c
14d
14e
14 f
14g
14h
14i
14j
15
24.1 (Æ12.5)
10.4 (Æ12.5)
13.8 (Æ4.7)
10.4 (Æ9.4)
17.2 (Æ8.2)
10.4 (Æ12.5)
13.34 (Æ4.7)
10.4 (Æ4.7)
10.4 (Æ9.4)
3.5 (Æ4.7)
32.1 (Æ12.5)
21.4 (Æ12.5)
28.6 (Æ12.5)
14.3 (Æ16.3)
25.0 (Æ14.1)
14.3 (Æ14.1)
20.7 (Æ4.7)
21.4 (Æ9.4)
21.4 (Æ17.0)
17.9 (Æ12.5)
39.3 (Æ12.5)
25.0 (Æ8.2)
28.6 (Æ12.5)
14.3 (Æ8.2)
10.7 (Æ9.4)
10.7 (Æ9.4)
10.7 (Æ4.7)
25.0 (Æ8.2)
25.0 (Æ8.2)
48.2 (Æ9.4)
44.4 (Æ14.1)
55.6 (Æ14.1)
44.4 (Æ0.0)
48.2 (Æ14.1)
44.4 (Æ16.3)
41.7 (Æ4.7)
51.9 (Æ9.4)
55.6 (Æ8.2)
48.2 (Æ4.7)
63.0 (Æ4.7)
59.3 (Æ12.5)
59.3 (Æ12.5)
40.7 (Æ9.4)
37.0 (Æ12.5)
48.2 (Æ4.7)
40.7 (Æ4.7)
37.0 (Æ12.5)
59.3 (Æ4.7)
mately 2.0 Hz indicates that H3 and H4 have a trans rela-
tionship, and the substituent on the C4 position of picropo-
dophyllotoxin is in the a configuration, which might be used
as the supplement to Leeꢁs rule.[8] 4) 4a-Alkyloxy-2a-bromo-
picropodophyllotoxins were all unexpectedly converted into
15 by an intramolecular FC alkylation reaction when the re-
action time was prolonged (to a certain degree). 5) Of par-
ticular note, some derivatives displayed more potent and
promising insecticidal activity than toosendanin.
17.2 (Æ14.1)
13.8 (Æ17.0)
13.8 (Æ12.5)
3.5 (Æ9.4)
6.95 (Æ8.2)
10.4 (Æ9.4)
10.4 (Æ12.5)
10.4 (Æ12.5)
17.9 (Æ9.4)
Acknowledgements
The present research was partly supported by National Natural Science
Foundation of China (No.31071737), the Program for New Century Ex-
cellent University Talents, State Education Ministry of China (NCET-06-
0868), the Fok Ying Tong Education Foundation for Young Talents
(No.121032), and the Special Funds of Central Colleges Basic Scientific
Research Operating Expenses (QN2009045).
10 and 20 days, therefore these compounds, in a time-depen-
dent manner (different from those conventional neurotoxic
insecticides, such as organophosphates, carbamates, and pyr-
ethroids) exhibited delayed insecticidal activity.[3,4] For ex-
ample, the corrected mortality rate of 14a against M. sepa-
rata after 10 days was only 10.4%, but after 20 days the cor-
responding mortality rate was increased to 21.4%; however,
after 35 days the corresponding mortality rate was rapidly
increased to 55.6%, which was more than five times of the
mortality rate after 10 days. Compared with toosendanin
and the parent compound 1, compounds 8, 13, 14a, 14c–e,
and 15 exhibited more promising and pronounced insectici-
dal activity. Meanwhile, some interesting results with respect
to structure–activity relationships were concluded. In gener-
al, the proper length of straight-chain or branched-chain al-
kyloxy at the C4 position of 2a-bromopicropodophyllotoxins
was very important for the insecticidal activity. For example,
the final mortality rates of 14a (methoxy) and 14d (n-propy-
loxy) were 55.6 and 59.3%, respectively, whereas the final
mortality rates of 14b (ethoxy), 14 f (n-butoxy), and 14h (n-
octyloxy) were only 48.2, 40.7, and 48.2%, respectively. No-
tably, this indicates that a b configuration of the C2 bromine
atom of 2-bromopodophyllotoxins is usually necessary for
the insecticidal activity. The final mortality rates of 8, 10,
and 13 (for the C2b bromine series) were 55.6, 48.2, and
51.9%, respectively, whereas the final mortality rates of the
Keywords: alkylation
chemistry · stereoselectivity · structure–activity relationships
· insecticidal activity · medicinal
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Chem. Eur. J. 2011, 17, 8299 – 8303

Stereoselective Synthesis of 4a-AlkylACTHNUTRGNEUoGN xy-2-a/b-Bromopodophyllotoxin Derivatives
COMMUNICATION
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Received: March 20, 2011
Published online: June 10, 2011
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8303