Synthesis of three putative kairomones of the beech leaf-mining weevil Orchestes fagi (L.)

Article abstract of DOI:10.1080/00397911.2016.1185126

The beech leaf-mining weevil, Orchestes fagi (L.), also known as the beech flea weevil, is a common and widespread pest of beech, Fagus sylvatica L., in its native Europe. It now appears to be well established in Nova Scotia, Canada. We report a novel synthesis of 9-geranyl-p-cymene and syntheses of 9-geranyl-α-terpinene and 1,1-dimethyl-3-methylene-2-vinylcyclohexane, making partial use of known methods. All three of these compounds are found in beech leaf volatiles and/or wood and are putative kairomones of the beech leaf-mining weevil.

Full text of DOI:10.1080/00397911.2016.1185126

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis of Three Putative Kairomones of the
Beech Leaf-Mining Weevil Orchestes fagi (L.)
P. D. Mayo, P. J. Silk, S. D. Abeysekera & D. I. MaGee
To cite this article: P. D. Mayo, P. J. Silk, S. D. Abeysekera & D. I. MaGee (2016): Synthesis of
Three Putative Kairomones of the Beech Leaf-Mining Weevil Orchestes fagi (L.), Synthetic
Communications, DOI: 10.1080/00397911.2016.1185126
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1185126
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Date: 13 June 2016, At: 04:38

SYNTHESIS OF THREE PUTATIVE KAIROMONES OF THE BEECH LEAF-
MINING WEEVIL Orchestes fagi (L.)
P. D. Mayo1, P. J. Silk1, S. D. Abeysekera1, D. I. MaGee2
1Natural Resources Canada, Canadian Forest Service - Atlantic Forestry Centre,
Fredericton, New Brunswick, Canada
2Department of Chemistry, University of New Brunswick, Fredericton, New Brunswick,
Canada
Abstract
The beech leaf-mining weevil, Orchestes fagi (L.), also known as the beech flea weevil,
is a common and widespread pest of beech, Fagus sylvatica L., in its native Europe. It
now appears to be well established in Nova Scotia, Canada. We report a novel synthesis
of 9-geranyl-p-cymene, and syntheses of 9-geranyl-α-terpinene and 1,1-dimethyl-3-
methylene-2-vinylcyclohexane making partial use of known methods. All three of these
compounds are found in beech leaf volatiles and / or wood, and are putative kairomones
of the beech leaf-mining weevil.
KEYWORDS: Beech leaf-mining weevil, 9-geranyl-p-cymene, 9-geranyl-α-terpinene,
1,1-dimethyl-3-methylene-2-vinylcyclohexane, kairomones.
INTRODUCTION
1

The beech leaf-mining weevil, Orchestes fagi (L.) (Curculionidae: Curculioninae:
Rhamphini), also known as the beech flea weevil, is a common and widespread pest of
beech, Fagus sylvatica L. (Fagaceae), in its native Europe. It now appears to be well
established in Nova Scotia, Canada.[1] Adult insects and mating pairs appear to be
attracted to beech buds just prior to bud burst. Examination of volatiles from eclosing
beech buds has identified two possibly attractive diterpene compounds, 9-geranyl-p-
cymene 1 and 9-geranyl-α-terpinene 2a, (see Scheme 1). A third compound, 1,1-
dimethyl-3-methylene-2-vinylcyclohexane 3, is an additional putative kairomone of the
same insect, found in both beech leaf volatiles and wood, bearing a structural
resemblance to published cyclohexylidene curculionid pheromones;[2] to the best of our
knowledge, there is no precedence for its synthesis in the literature. There is a report,
however, of 3 being a constituent of the volatiles of the plant Melinis minutiflora.[3]
There are only sparse literature examples detailing the synthesis of E-2,6-dimethyl-10-(p-
tolyl)-2,6-undecadiene (9-geranyl-p-cymene, geracymene) 1[4, 5] and E-2,6-dimethyl-10-
(4’-methyl-1’,3’-cyclohexadienyl)-2,6-undecadiene (9-geranyl-α-terpinene,
geraterpinene) 2a,[6] even though they are apparently relatively simple diterpenes.
Compounds 1 and 2a have been detected in the oils of various plants; compound 1 in
Sideritis trojana,[7] Sideritis cilicica,[8] Anthemis dispacea,[9] Anthemis rosea ssp.
carnea,[10] Calamina pamphylica ssps. pamphylica, davisii and alanyense,[11] Artemisia
absinthium from Tajikistan,[12] and Cydonia oblonga Miller.[13] Both compounds 1 and 2a
have been found together in the same plant; for instance in Artemisa absinthium L.,[14]
Sideritis dichotoma[15] and Helichrysum species.[16]
2

DISCUSSION
Retrosynthetically, 1 would seem the simpler of the two diterpenes to synthesize because
the p-tolyl moiety could be readily obtained from the Grignard reagent p-tolylmagnesium
bromide 4, and the 13-C chain could also be easily obtained from geranylacetone 5 or
fuscumol[17] 6 (see Scheme 2).
Examination of compound 2a suggested that it would be more challenging to synthesize
as a reagent that could deliver a 4-methyl-1,3-cyclohexadien-1-yl group is not readily
known. Consequently, the cyclohexadiene ring of 2a would need to be synthesized de
novo.
With this in mind, efforts were focused first on synthesis of 1 with two methods being
targeted. The first involved a very simple cuprate coupling of commercially available p-
tolylmagnesium bromide 4 with E-10-iodo-2,6-dimethyl-2,6-undecadiene 7, itself
available by a straightforward iodination of commercially available racemic fuscumol[17]
6 (E-2-hydroxy-6,10-dimethyl-5,9-undecadiene, see Scheme 3). The cuprate coupling
proceeded with only 3 % yield, after separation from the byproduct bis(p-tolyl), which
was accomplished with a silver nitrate / silica gel cartridge. Given that unactivated
secondary alkyl iodides are only borderline substrates for alkylation reactions, the low
yield of this cuprate coupling was not surprising.
The second method, closely related to the syntheses published by Pietsch et al.[4] and
Sabharwal et al.[5], involved treating geranylacetone 5 (E-6,10-dimethyl-5,9-undecadien-
3

2-one) with p-toylmagnesium bromide 4 to give E-6,10-dimethyl-2-hydroxy-2-(p-tolyl)-
5,9-undecadiene 8 (quantitative yield), which could then be deoxygenated to give 1 (see
Scheme 4).
Several deoxygenation methods were attempted before a satisfactory one was found. Two
direct deoxygenations of 8 were attempted; these were catalytic hydrogenolysis with
Lindlar’s Pd[18] and catalytic hydrogenolysis with P2 nickel,[19] both of which resulted in
no reaction. The well-known Barton and McCombie deoxygenation[20] failed to produce
any 9-geranyl-p-cymene 1 because the intermediate xanthate esters 9 or 10 could not be
generated from 8 by either of the two methods shown in Scheme 5.
Despite these failures, it was found that protection of 8 with ethyl vinyl ether (EVE),
which proceeded in 78 % yield, then treatment of 11 with lithium naphthalenide[21]
cleanly gave 1 in 75 % yield (see Scheme 6). This is similar to the syntheses of 1 reported
by Pietsch et al. in 2003[4] and Sabharwal et al. in 1990,[5] however, their methods
involved a one-pot Grignard reaction and dissolving metal reduction in liquid ammonia to
generate 1.
Success in the synthesis of 2a was obtained by modifying the first three steps of the
synthesis previously reported by Vig.[6] Our work is shown in Schemes 7 and 8. Geranyl
acetone 5 was treated with the commercially available Grignard reagent, 4-
methoxyphenylmagnesium bromide 12 to give 13 in 69 % yield.
4

Subsequent ethyl vinyl ether protection of 13 was carried out to give 14 in 95 % yield,
followed by deoxygenation under Birch conditions to give 15 in 79 % yield. Further
Birch reduction of 15 gave 16, which was then converted to 2a using a slight
modification of the method reported by Vig,[6] namely the use of p-toluenesulfonic acid
in refluxing wet THF. This provided a much higher yield for the hydrolysis of the methyl
enol ether in 16. The spectral data of the intermediates 19 and 20 in this process closely
correlated with those reported by Vig,[6] however, as well as 2a, GC/MS, 1H- and 13C-
NMR revealed the presence of isomers 2b and a trace amount of 2c (structures tentatively
assigned) in the product mixture.
A lithium naphthalenide deoxygenation of 14 was also attempted, as this method
conveniently did not require liquid ammonia. However, the drawback of this method was
the formation of a significant amount of 17 (~50 % of the product, see Scheme 7). This
presumably occurred by the anion initially formed from 14 abstracting a methyl group
from the methoxy functionality of another molecule of 14. Anisole 17 could then undergo
Birch reduction to give 18, which would react in the same way as 16 throughout the
remaining steps of the synthesis. However, it was found that the use of Birch conditions
on 14 cleanly gave 15 as previously mentioned, so this problem was accordingly
circumvented.
Two routes to diene 3 achieved success (see Schemes 9, 10 and 11). The first route,
considerably shorter than the other, involved deconjugation of commercially available β-
cyclocitral 21 using strong base (NaHMDS). Although complete deconjugation was not
5

realized, separation of conjugated from unconjugated compounds by silica gel
chromatography could be realized. Unfortunately, an inseparable mixture of
deconjugated isomers 22 (γ-cyclocitral) and 23 (α-cyclocitral) were obtained. Regardless,
Wittig reaction of the inseparable mixture of deconjugated isomers 22 (γ-cyclocitral) and
23 (α-cyclocitral) gave a mixture of 3 and 24, which were partially separable by silica gel
chromatography (see Scheme 9). Consequently a 4:1 mixture of 3 and 24 was readily
obtained by this method and used for trapping studies of O. fagi. Subsequently, it was
found that α-cyclocitral 23 could be prepared exclusively from β-cyclocitral 21 by
equilibration with potassium hexamethyldisilylamide (KHMDS). Following removal of
unconverted 21 by silica gel column chromatography, diene 24 could then be made very
easily in 100 % purity by Wittig homologation of 23 (see Scheme 10). The above brings
to mind the fact that if γ-cyclocitral 22, although not commercially available, could be
obtained in complete isomeric purity, 3 could easily be obtained by Wittig homologation
of 22.
To complete the series of isomers of 3, the conjugated diene 25 was obtained by a
straightforward Wittig homologation of 21 (see Scheme 10), albeit with ~1% of 3 and
~1% of 24 present (as determined by GC/MS) as an inseparable mixture; this is not
surprising in light of the fact that under basic conditions 21 isomerizes to 22 and / or 23.
The intended target, however, remained molecule 3; it was realized by the use of a
previously reported method that gave an intermediate ester (compound 29, Scheme 11)
that could easily be converted to 3. Fehr and Galindo[22, 23] report that methyl γ-
6

cyclogeranate 29 can be obtained with complete regioselectivity by deprotonation of
methyl β-cyclogeranate 27 with butyllithium, trapping with TMSCl
(chlorotrimethylsilane) to give 28 and subsequent protonation (see Scheme 11). Also
noteworthy is the synthesis of 29 as separate enantiomers by the same authors.[22] Acid 26
can be prepared readily by air oxidation of β-cyclocitral 21. Methylation of 26 gives 27,
according to the method of Fehr and Galindo.[22] Reduction of 29 with lithium aluminum
hydride, then PCC oxidation of 30 and Wittig homologation of 22 (γ-cyclocitral) was
found to yield 3 in 100 % purity.
Consequently, the synthetic targets 1 (three steps, 59 % overall yield), 2a (seven steps,
8.3 % overall yield) and 3 (seven steps, 1.3 % overall yield) were obtained in a
straightforward manner and used in field-trapping studies with Orchestes fagi, the
complete results of which are still pending.
EXPERIMENTAL
Diterpene 1: In a flame-dried round-bottom flask with a glass-coated stir bar was put
naphthalene (1.99 g, 15.5 mmol), THF (20 mL) and lithium (130 mg, 18.7 mmol). The
lithium was broken into pieces with a clean, dry metal scoop after addition. After 30 min
of stirring at RT, the characteristic dark-green color of lithium naphthalenide appeared,
and the reaction was allowed to stir at RT for a further 3.5 h. Another flame-dried round-
bottom flask equipped with a glass-coated stir bar was charged with acetal 11 (265 mg,
0.740 mmol), THF (10 mL) and stirred at RT. The lithium naphthalenide solution was
added to acetal 11 via syringe, and the reaction was stirred for 19 h at RT. Water (30 mL)
7

was added, the layers were separated, and the aqueous layer was extracted with hexanes
(2 × 20 mL). The combined organic layers were washed with brine (30 mL) and dried
(MgSO4). Column chromatography on silica gel (hexanes->20% EtOAc:hexanes as
eluent) and removal of solvent in vacuo yielded 1 as a colorless, transparent liquid (150
mg, 0.56 mmol, 75 %). 1H NMR for 1 matched closely with that reported by Pietsch.[4]
13C NMR was identical to that reported by Pietsch,[4] and the IR spectrum determined in
our laboratory was identical with that reported by Sabharwal.[5] For bp and elemental
analysis data, see Sabharwal.[5] For 1H and 13C NMR, as well as IR and LRMS, see
supporting information.
Diterpene 2a: In a flame-dried round-bottom flask was put alcohol 20 (12 mg, 0.041
mmol) and pyridine (anhydrous, 5 mL). The reaction mixture was cooled to 0 °C, and
POCl3 (0.10 mL, 1.1 mmol) was added. After stirring for 23 h at 0 °C, water (20 mL) was
added, and the reaction mixture was extracted with Et2O (4 × 15 mL). The combined
extractions were washed with brine (30 mL) and dried (MgSO4). Column
chromatography on silica gel (hexanes as eluent) yielded 2a (inseparable from 2b and 2c)
in a ratio of approximately 0.36 : 0.60 : 0.04 as determined by GC/MS. For 1H and 13C
NMR, and IR spectral data of 2a / 2b / 2c, as well as LRMS data of 2a, see supporting
information. For literature IR and 1H NMR spectral data, and elemental analysis data of
2a, see Vig.[6]
Diene 3: A flame-dried round-bottom flask was charged with
methyltriphenylphosphonium bromide (1.90 g, 5.33 mmol), THF (30 mL) and cooled to 0
8

°C. NaHMDS (5.3 mL, 1.0 M in THF, 5.3 mmol) was added dropwise over 3 min, and
the reaction was stirred for 30 min at 0 °C, then 1 h at RT. The solution was then cooled
to -78 °C, and aldehyde 22 (54 mg, 0.36 mmol) in THF (2 mL) was added via syringe
with rinsing with THF (2 × 2 mL). The reaction mixture was allowed to warm to RT
overnight, water (20 mL) was added, and the solution was extracted with Et2O (3 × 30
mL). The combined organic layers were washed with brine (50 mL) and dried (MgSO4).
Removal of the solvent in vacuo, then filtration through a plug of silica using Et2O as
eluent removed excess methyltriphenylphosphonium bromide and triphenylphosphine
oxide. Silica gel column chromatography (pentane as eluent) and removal of solvent at 60
mbar and 5 °C yielded diene 3 (32 mg, 0.21 mmol, 60 %) as a colorless, transparent
liquid. Rf (hexanes) = 0.84. 1H NMR (CDCl3, 400 MHz): δ 5.93 (dt, 1H, J = 16.9, 10.3
Hz), 5.08 (dd, 1H, J = 10.3, 2.3 Hz), 5.03 (dd, 1H, J = 17.0, 2.2 Hz), 4.74 (br. s, 1H), 4.58
(br. s, 1H), 2.42 (d, 1H, J = 9.6 Hz), 2.27 (m, 1H), 2.04 (m, 1H), 1.43-1.62 (m, 3H), 1.34
(m, 1H), 0.90 (s, 3H), 0.81 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 150.2, 137.7, 116.4,
108.3, 59.0, 39.1, 34.9, 34.6, 29.4, 23.4, 23.2. IR (neat, cm-1): 3073 (w), 2927 (s), 2866
(m), 2863 (m), 1644 (w), 1458 (w), 1436 (w), 1385 (w), 1364 (w), 1005 (w). LRMS (EI,
70 eV) m/z (main peaks): 53, 55, 57, 65, 67, 69 (base peak), 77, 79, 81, 91, 93, 94, 107,
121, 135, 150 (M+). HRMS: [C11H18Ag]+; Calc. 257.0454, Found 257.0446. Mass
measurement error: -3.29 ppm.
SUPPORTING INFORMATION
Full experimental detail, and 1H and 13C NMR spectra. This material can be found via the
“Supplementary Content” section of this article’s webpage.
9

ACKNOWLEDGMENTS
We would like to thank Matt Brophy for technical assistance and Natural
Resources Canada for funding this research. This research was partially supported by an
Atlantic Canada Opportunities Agency, Atlantic Innovation Fund (No. 197853). All
experiments reported here comply with the laws of Canada.
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12

Scheme 1. 9-Geranyl-p-cymene 1; 9-geranyl-α-terpinene 2a and 1,1-dimethyl-3-
methylene-2-vinylcyclohexane 3.
13

Scheme 2. Retrosynthesis of 9-geranyl-p-cymene 1.
14

Scheme 3. (a) I2, PPh3, imidazole, 1:3 CH3CN:Et2O, RT, 98 %. (b) Li2CuCl4, p-
tolylmagnesium bromide, THF, -78 °C – RT, 3 % after purification.
15

Scheme 4. (a) Et2O, RT, quantitative. (b) Deoxygenation.
16

Scheme 5. (a) (i) NaH, THF, HMPA, RT. (ii) CS2, RT – reflux. (iii) MeI, reflux. (b) 1,1’-
Thiocarbonyldiimidazole, CH2Cl2, RT.
17

Scheme 6. (a) Ethyl vinyl ether, PPTS, CH2Cl2, RT, 78 %. (b) Li / naphthalene, THF, RT,
75 %.
18

Scheme 7. (a) THF, 0 °C – RT, 69 %. (b) Ethyl vinyl ether, PPTS, CH2Cl2, RT, 95 %. (c)
Li, naphthalene, THF, RT, 58 %, or Li, NH3, EtOH, Et2O, -78 °C – RT, 79 %. (d) Li,
NH3, EtOH, Et2O, -78 °C – RT, yield not determined. (e) See Scheme 8.
19

Scheme 8. (a) 0.1 M aqueous TsOH, THF, reflux. (b) MeMgI, Et2O, RT – reflux, 23 %
over 3 steps. (c) POCl3, pyridine, 0 °C – RT, 70 %.
20

Scheme 9. (a) NaHMDS, THF, 0 °C, 18 % yield of aldehydes 22 and 23 after removal of
recovered 21 by silica gel column chromatography. (b) CH3PPh3Br, NaHMDS, THF, -78
°C – RT, 8 % yield of a 4:1 mixture of 3 and 24 after purification. 3 and 24 are partially
separable by silica gel column chromatography.
21

Scheme 10. KHMDS, THF, 0 °C, 17 % of 23 after removal of recovered 21 by silica gel
column chromatography. (b) CH3PPh3Br, NaHMDS, THF, -78 °C – RT, 57 %. (c)
CH3PPh3Br, NaHMDS, THF, -78 °C – RT, 41 %.
22

Scheme 11. (a) Air, CH2Cl2, RT, 54 %. (b) CH3I, K2CO3, acetone, reflux, 63 %. (c) (i)
nBuLi, THF, -10 °C – RT. (ii) TMSCl, -30 °C – RT, 28 not isolated. (d) HCl, H2O, RT,
34 % over 2 steps. (e) LiAlH4, THF 0 °C – RT, 39 %. (f) PCC, CH2Cl2, RT, 47 %. (g)
CH3PPh3Br, NaHMDS, THF, -78 °C – RT, 60 %.
23