Oxygen-containing analogues of juvenile hormone III

Article abstract of DOI:10.1016/j.tetlet.2011.01.103

Juvenile hormone III (JH-III) controls several aspects of insect development, and analogues of JH-III are widely used as insect control agents. Recent reports suggest that these compounds may also perturb the normal development of crustaceans, and perhaps

Full text of DOI:10.1016/j.tetlet.2011.01.103

Tetrahedron Letters 52 (2011) 2302–2305
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxygen-containing analogues of juvenile hormone III
⇑
Katherine A. Davies, Kevin G. M. Kou, Jeremy E. Wulff
Department of Chemistry, University of Victoria, Victoria, British Columbia, Canada V8W 3V6
a r t i c l e i n f o
a b s t r a c t
Article history:
Juvenile hormone III (JH-III) controls several aspects of insect development, and analogues of JH-III are
widely used as insect control agents. Recent reports suggest that these compounds may also perturb
the normal development of crustaceans, and perhaps other aquatic species. In an attempt to prepare
more highly degradable (and thus less environmentally persistent) mimics of JH-III, we prepared a series
of analogues incorporating vinyl ether functionality. The stability of these compounds in water or warm,
moist air was evaluated, revealing two distinct decomposition pathways.
Received 8 November 2010
Accepted 25 January 2011
Available online 15 March 2011
Keywords:
Juvenile hormones
Structural analogues
Claisen rearrangement
Iterative synthesis
Vinyl ethers
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Juvenile hormone III (JH-III) is the most important of several
structurally related insect hormones (JH-0 – JH-III, Fig. 1A), and
the only member of the family found outside of Lepidoptera.1
The juvenile hormones regulate insect development,2 reproduc-
tion,3 and caste differentiation.4 During the insect growth cycle,
the concentration of juvenile hormone dictates the progression
from larva to pupa and eventually to adult.5
Many structural analogues of JH-III are known to be agonists of
juvenile hormone activity. Because concentrations of juvenile hor-
mone must be very low for the insect to reach the adult stage, the
presence of these hormone mimics (e.g., methoprene, kinoprene,
epofenonane and fenoxycarb, Fig. 1B) triggers impaired develop-
ment, ultimately resulting in fatal morphological abnormalities.5
As a result, many of these compounds are used as insect control
agents. The most commercially important of these is the S-enantio-
mer of methoprene, which is widely used for the control of mos-
quitoes, flies (in agriculture), fire ants, fleas and other pests.5
Despite its potent activity against many insect species, metho-
prene is nontoxic to both mammals and birds.6 At the same time,
methoprene is known to be acutely toxic to certain species of fish,
shrimp and crabs,7 although it is not known to what extent this
represents a legitimate threat to these species in the natural envi-
ronment. A link between methoprene use and deformities in frogs
has been postulated,8 but this remains controversial.9
A:
B:
H3C
H3C
H3C
H3C
H3C
O
CH3
CH3
O
O
CH3
CH3
O
OCH3
H3C
OCH3
H3C
O
O
JH-0
S-methoprene
H3C
H3C
CH3
CH3
O
O
H3C
CH3
CH3
O
O
OCH3
OCH3
H3C
JH-I
CH3
kinoprene
H3C
H3C
H3C
H3C
CH3
O
H3C
O
epofenonane
JH-II
CH3
O
H3C
CH3
CH3
O
O
O
N
O
CH3
H
H3C
OCH3
O
JH-III
fenoxycarb
D:
C:
H3C
H3C
CH3
O
R1
R2
O
O
H3C
OCH3
H3C
X
O
OR3
methyl farnesoate
1
2
X = CH2
X = O
Figure 1. Structures of the juvenile hormones and related compounds; (A) insect
juvenile hormones; (B) a selection of analogues known to have good activity against
insect populations; (C) methyl farnesoate, a putative crustacean juvenile hormone;
(D) compounds targeted in this work.
Of perhaps greater ecological concern, methoprene has been
shown to have toxic effects on juvenile and adult crustaceans at
very low concentrations, and anecdotal evidence suggests a possi-
ble link between methoprene use and fatal abortive moults in
lobsters.10 This may be due to mimicry by methoprene of methyl
farnesoate (Fig. 1C), which appears to function as a hormone in
crustaceans, and indeed is thought to play similar roles in crusta-
ceans to the juvenile hormones in insects.11
⇑
Corresponding author. Tel.: +1 250 721 7179; fax: +1 250 721 7147.
E-mail address: wulff@uvic.ca (J.E. Wulff).
0040-4039/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.103

K. A. Davies et al. / Tetrahedron Letters 52 (2011) 2302–2305
2303
Methoprene can be degraded both microbially12 and photo-
Table 1
chemically,13 but it is chemically robust. Given recent concerns
about unwanted effects in crustaceans (presumably following
transport of methoprene from treated water supplies into the
ocean), it seems that a more rapidly degradable analogue of the
juvenile hormones might be useful for certain applications.
With this in mind, we targeted a series of vinyl ether-containing
analogues of juvenile hormone III (Fig. 1D, 1 and 2), hypothesizing
that inclusion of the sensitive vinyl ether functions would make
the target compounds prone to decomposition, either by hydroly-
sis or other means.
We first synthesized the bis-vinyl ether analogues 1, through an
iterative conjugate addition14/reduction/conjugate addition se-
quence from epoxy-alcohol 415 and methyl or ethyl alkynoates 5
(Scheme 1). Alkynoates 5a–c were available commercially;16
5d,17 5e18 and 5f19 were prepared following published methods.
The yields for the individual conjugate addition and reduction
steps were generally excellent, and in almost all cases, the target
compounds were isolated as nearly single geometrical isomers (E,
E). In the specific case of conjugate additions to ethyl 4,4,4-tri-
fluoro-2-butynoate (leading to the formation of 6e or 1h), a mix-
ture of geometrical isomers was formed,20 but these could be
separated chromatographically. With the exception of 1c and 1d,
all of the bis-vinyl ethers were sufficiently stable to be purified
by flash chromatography over triethylamine-treated silica gel.
Less-substituted bis-vinyl ethers have been reported previ-
ously,21,22 but molecules of the type described here are unknown
in the literature. It therefore seemed prudent to undertake a care-
ful examination of their stability before planning any biological
assays. In particular, since insect-control experiments are often
conducted either in water (for water-breeding species like mosqui-
toes) or else in warm, humid growth chambers (mimicking a
tropical environment), we sought to characterize the behaviour
of these compounds under similar conditions.
Stabilities of bis-vinyl ether analogues of JH-III
Product
R1
R2
R3
Yield (%)
t1/2
Method Aa
Method Bb
1a
1b
1c
1d
1e
1f
1g
1h
1i
Me
Me
Me
Me
H
Me
H
p-MeOBn
CF3
Me
H
Me
CF3
Me
Et
Me
Me
Me
Et
Me
Me
Me
Et
99
94
<5%
<5%
96
17 h
<5 min
<5 min
3.5 h
f
f
—
—
—
—
f
f
39 h
28 min
73 mine
n. d.g
H
97
>24 hd
>14 d
>14 d
>14 d
60 h
CF3
CF3
Ph
Et
93
58c
98
n. d.g
Me
Et
n. d.g
1j
99
<5 min
a
b
c
d
e
f
Method A: 37 °C, 5% CO2, >90% relative humidity.
Method B: 1:1 CD3OD:D2O, 20 °C.
Isolated along with 42% of the corresponding Z isomer.
Monitoring was complicated by volatility of the substrate.
Decomposition occurred via hydrolysis.
Sufficiently pure compound was not available for testing.
The substrate was insoluble in 1:1 CD3OD:D2O.
g
To compare the stabilities of the synthesized compounds under
humid nonsolution conditions (Table 1, method A), we deposited
acetonic solutions of each substrate, together with 4,40-dibromobi-
phenyl as an internal standard, onto several watch glasses. The sol-
vent was allowed to evaporate over 1 h in a fume hood, after which
the watch glasses were transferred to a cell-culture incubator
(37 °C, 5% CO2, >90% relative humidity23). Samples were periodi-
cally removed, and the composition was evaluated by NMR.
Fig. 2 shows the change in the proton NMR spectrum (normal-
ized to the internal standard) for 1a over time. The substrate
smoothly underwent Claisen rearrangement24 to afford ketone
8a25 (Scheme 2) with a half life of 17 h. Interestingly, continued
monitoring of the reaction revealed that 8a underwent further
decomposition to volatile byproducts, such that the proton NMR
spectrum showed essentially just the internal standard after
1 week of incubation. Simple evaporation of 8a (MW = 270
g/mol) under these conditions was ruled out by the fact that 2a
O
OR3
R1
5
D-tartrate, Ti(OiPr)4
cumene hydroperoxide
H3C
H3C
H3C
O
PMe3 (10 mol%)
OH
H3C
OH
CH2Cl2, 4Å MS
CH2Cl2, 20 o
C
–20 oC to +20 o
C
3
4 (70% ee)
97%
R1
R1
O
H3C
H3C
DIBAL-H
O
O
OR3
Et2O, hexanes
H3C
O
OH
H3C
O
–78 oC to –40 o
C
7
6
7a
6a
R
1 = CH3 97%
R1 = CH3 R3 = Et 98%
7b R1 = H
91%
97%
99%
97%
6b R1 = H
R3 = CH3 94%
R3 = Et 88%
7c
7d
7e
6c
6d
6e
R
R
R
1 = Et
R
R
R
1 = Et
1 = Ph
1 = CF3
1 = Ph
R
R
3 = Et 96%
1 = CF3
3 = Et
39%
+ 54% of the Z isomer
O
OR3
R2
5
R1
R2
O
H3C
H3C
O
PMe3 (10 mol%)
CH2Cl2, 20 oC
O
O
OR3
1
(see Table 1 for yields)
O
O
O
OCH3
OCH3
OCH2CH3
O
H3C
H3C
H
5a
5b
5c
O
O
H3CO
OCH2CH3
OCH3
OCH2CH3
F3C
5e
5d
5f
Ph
Scheme 1. Synthesis of the bis-vinyl ether juvenile hormone mimics.
Figure 2. Decomposition of 1a at 37 °C, 5% CO2, >90% relative humidity.

2304
K. A. Davies et al. / Tetrahedron Letters 52 (2011) 2302–2305
Table 2
H3C
R1
R2
O
H3C
O
Claisen
rearrangement
O
Stabilities of mono-vinyl ether analogues of JH-III
O
O
H3C
O
R1
H3C
O
O
OR3
Product R2
R3
Yield
(%)
t1/2
R2
1
R1 or R2 = alkyl or aryl
8
Method
Aa
Method
Bb
Method
Cc
R3O
R1 = R2 = H
3 he
hydrolysis
elimination
2a
2b
2c
2d
2e
2f
Me
H
Ph
p-MeOBn
CF3
Et
Me 97
Me 99
>14 d
>14 d
8.8 dd
>14 d
14 hd
>14 d
>14 d
>14 d
21 hd
>14 d
<5 mind
>14 d
>14 d
2.7 he
21 he
<5 mind
2.5 he
Et
98
O
H3C
H3C
H3C
Me 96
O
O
+
R1
R2
Et
Et
27
99
OH
H3C
OH
R3O
O
4
4
9
a
b
c
Method A: 37 °C, 5% CO2, >90% relative humidity.
Method B: 1:1 CD3OD:D2O, room temperature.
Method C: 1:1 CD3OD:D2O, pH <1, room temperature.
Decomposition occurred mostly by Claisen rearrangement.
Decomposition occurred mostly by vinyl ether hydrolysis.
Scheme 2. Decomposition pathways for the bis-vinyl ethers. Assignments of the
elimination products are tentative.26
d
e
(MW = 268 g/mol) was not lost in an identical assay. Although the
volatile byproducts could not be conclusively identified in this
experiment, long-term incubation of 1a in D2O led to the tentative
identification of 9a26 (Scheme 2), along with several other species,
suggesting that the final decomposition step involves elimination
of the starting material epoxy-alcohol.
Compounds 1b, 1e and 1j decomposed similarly to 1a, while 1g,
1h and 1i were robust under these incubation conditions. In aque-
ous solution (1:1 CD3OD:D2O, method B), 1a, 1b, 1e and 1j again
decomposed via Claisen rearrangement, but with greatly acceler-
ated rates. Aqueous stabilities for 1g, 1h and 1i could not be eval-
uated, since these compounds were insoluble in water. In fact, the
immiscibility of 1g, 1h and 1i with water may play a role in their
stability under the conditions of method A.
H3C
H3C
neutral
pH
O
CH3
R2
O
O
O
H3C
H3C
O
OR3
R2
R2 = Ph or CF3
H3C
R3O
2
12
O
R2 = alkyl or aryl
pH < 1
H3C
CH3
X
Y
13a
X = OCD3 Y = OD
13b X = OD Y = OCD3
13c X = OD Y = OD
H3C
OH
13
Scheme 4. Decomposition pathways for the mono-vinyl ethers.
Claisen rearrangement was not observed for the less-substi-
tuted analogue 1f under either set of conditions. Instead, this com-
pound underwent hydrolysis in aqueous solution to return
compound 4. The presumed aldehydic co-products from this
hydrolysis reaction were not observed in large amounts, presum-
ably due to further decomposition by aldol processes.
Since the synthesized bis-vinyl ethers proved either unstable or
insoluble in water, we also pursued a series of mono-vinyl ethers
(2) using a phosphine-mediated conjugate addition14 of alkynes 5
to the known alcohol27 11 (Scheme 3). Once again, the yields were
excellent for all synthesized compounds except for the very unsta-
ble trifluoromethyl-substituted analogue 2e.
The mono-vinyl ethers were subjected to the same stability tri-
als (Table 2, method A and method B) as those used for the bis-
vinyl ethers. Under both conditions, 2c decomposed slowly by
Claisen rearrangement, while 2e underwent more rapid decompo-
sition. The other analogues were stable under the assay conditions.
To further evaluate the relative stabilities of the different vinyl
ether groups, we dissolved each compound in a mixture of 50%
CD3OD and 50% acidified (with H2SO4) D2O. Under these forcing
conditions, the epoxide opened rapidly (t1/2 <5 min) to give a mix-
ture of alcohols (13), but the vinyl ether groups hydrolysed with an
analytically convenient range of rates (Table 2, method C). Small
amounts of Claisen-rearranged products were also detected under
these conditions. The decomposition pathways observed for 2 are
summarized in Scheme 4.
In summary, we have prepared and characterized two series of
vinyl ether-containing analogues of juvenile hormone III. As in-
tended, these compounds exhibit a range of stabilities under likely
assay conditions, with half-lives ranging from minutes to weeks.
Depending upon the nature of the substituents and the assay
conditions employed, the synthesized compounds decomposed
by either Claisen rearrangement or vinyl ether hydrolysis. For the
most part, the presence of an electron-rich ‘Western’ olefin (be-
tween C-6 and C-7) and an electron-poor ‘Eastern’ olefin (between
C-2 and C-3) accelerated the rate of the Claisen rearrangement
(e.g., 1a reacts much faster than 2a; 2e reacts much faster than
2a; 1d decomposes during chromatography, while 1a is stable on
silica; 1g is more stable than 1a; etc.). To the best of our knowl-
edge, these trends are not reported elsewhere, and will be a useful
precedent for the synthetic exploitation of bis-vinyl ethers for
other applications.
In cases where the synthesized compounds are not prone to
Claisen rearrangements (e.g., 1f, 2a, 2b, 2d and 2f) or in cases
where the Claisen rearrangement is sufficiently slow (e.g., 2c)
decomposition can occur via vinyl ether hydrolysis. In these cases,
more electron rich vinyl ethers generally hydrolyse faster (e.g.,
2f > 2a > 2b), but a lack of water solubility for more lipophilic
substrates (e.g., 2c and 2d) probably also plays a role in reducing
the rate of hydrolysis for some compounds.
1. AD-mix α, MeSO2NH2
t-BuOH, H2O
H3C
H3C
CH3
H3C
CH3
With knowledge of the relative stabilities of our candidate JH-III
mimics, we are currently planning a series of biological assays to
test their function in insects. Results from this study will be
reported in due course.
O
OAc
2. MsCl, pyridine, CH2Cl2
3. K2CO3, MeOH
( reference 27 )
H3C
OH
10
11
5
R2
O
H3C
CH3
Acknowledgements
O
PMe3 (10 mol%)
CH2Cl2, 20 o
(see Table 2 for yields)
H3C
O
OR3
C
2
We are grateful to the University of Victoria for startup funds,
and to the Canada Foundation for Innovation and the BC Knowl-
edge Development Fund for providing equipment. Additional
Scheme 3. Synthesis of the mono-vinyl ether juvenile hormone mimics.

K. A. Davies et al. / Tetrahedron Letters 52 (2011) 2302–2305
2305
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.103.
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