Synthesis of 9-geranylterpinolene as a mixture of isomers, and synthesis of α- and β-springene, possible kairomones of the beech leaf-mining weevil, Orchestes fagi (L.)

Article abstract of DOI:10.1080/00397911.2018.1463544

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 have previously reported the synthesis of 9-geranyl-p-cymene and 9-geranyl-α-terpinene, as they are both found in eclosing beech buds, and have researched the synthesis of other diterpenes that are isomers of 9-geranyl-α-terpinene. We now wish to report a synthesis of the diterpene 9-geranylterpinolene as a mixture of isomers, as a novel diterpene, and as a possible kairomone of O. fagi. Also, all trans-α-springene, its 3Z-isomer, and β-springene were synthesized as a mixture, as well as pure β-springene, utilizing known methods.

Full text of DOI:10.1080/00397911.2018.1463544

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis of 9-geranylterpinolene as a mixture
of isomers, and synthesis of α- and β-springene,
possible 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 (2018): Synthesis
of 9-geranylterpinolene as a mixture of isomers, and synthesis of α- and β-springene, possible
kairomones of the beech leaf-mining weevil, Orchestes fagi (L.), Synthetic Communications, DOI:
10.1080/00397911.2018.1463544
To link to this article: https://doi.org/10.1080/00397911.2018.1463544
Published online: 11 Jun 2018.
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SYNTHETIC COMMUNICATIONS
https://doi.org/10.1080/00397911.2018.1463544
Synthesis of 9-geranylterpinolene as a mixture of isomers,
and synthesis of a- and b-springene, possible kairomones
of the beech leaf-mining weevil, Orchestes fagi (L.)
a
a
a
b
P. D. Mayo
, P. J. Silk , S. D. Abeysekera , and D. I. MaGee
a
Natural Resources Canada, Canadian Forest Service – Atlantic Forestry Centre, Fredericton, New
b
Brunswick, Canada; Department of Chemistry, University of New Brunswick, Fredericton, New
Brunswick, Canada
ABSTRACT
ARTICLE HISTORY
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 have previously reported the synthesis
of 9-geranyl-p-cymene and 9-geranyl-a-terpinene, as they are both
found in eclosing beech buds, and have researched the synthesis of
other diterpenes that are isomers of 9-geranyl-a-terpinene. We now
wish to report a synthesis of the diterpene 9-geranylterpinolene as a
mixture of isomers, as a novel diterpene, and as a possible kairomone
of O. fagi. Also, all trans-a-springene, its 3Z-isomer, and b-springene
were synthesized as a mixture, as well as pure b-springene, utilizing
known methods.
Received 24 January 2018
KEYWORDS
Beech leaf-mining weevil;
9
-geranylterpinolene;
kairomones; a-spring-
ene; b-springene
GRAPHICAL ABSTRACT
9-geranyl-4E-terpinolene
(
3E
)- and (3
Z
)-α-springene
β-springene
Introduction
The beech leaf-mining weevil (Orchestes fagi (L.)) (Curculionidae: Curculioninae:
Rhamphini), also known as the beech flea weevil or the beech weevil, is a common and
widespread pest of beech, Fagus sylvatica L. (Fagaceae), in its native Europe. It now
CONTACT Peter Mayo
Forestry Centre, Fredericton, New Brunswick, Canada.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
peter.mayo@canada.ca
Natural Resources Canada, Canadian Forest Service – Atlantic
1
13
Supplemental data ( H and C NMR spectra for the mixture of 5a–b and 6; 6 alone; the mixture of 7a–g); 13a; and
6, as well as LRMS for compounds 7a–g, can be accessed on the publisher’s website.
1
ß 2018 Crown Copyright

2
P. D. MAYO ET AL.
2
1
3
4
Scheme 1. 9-Geranyl-a-terpinene 1, 9-geranyl-c-terpinene 2, 9-geranyl-b-terpinene 3 and 9-geranyl-p-
cymene 4.
[
1]
appears to be well established in Nova Scotia, Canada. Interest in the semiochemistry
of this insect has prompted us to synthesize a suite of potential kairomones, one of
which is 9-geranyl-a-terpinene 1 (IUPAC name: E-2,6-dimethyl-10-(4-methyl-1,3-cyclo-
hexadienyl)-2,6-undecadiene) and its two isomers, 9-geranyl-c-terpinene 2 (IUPAC
name: E-2,6-dimethyl-10-(4-methyl-1,4-cyclohexadienyl)-2,6-undecadiene) and 9-ger-
anyl-b-terpinene 3 (IUPAC name: E-2,6-dimethyl-10-(4-methylene-1-cyclohexenyl)-2,6-
[
2]
undecadiene) as an inseparable mixture (see Scheme 1). Also, 9-geranyl-p-cymene 4
[
2]
(
IUPAC name: E-2,6-dimethyl-10-p-tolyl-2,6-undecadiene) was synthesized, and found
[3]
to have kairomonal activity toward the beech weevil. The activity of compounds 1–4
see Scheme 1) in both laboratory bioassays and field trapping tests with live O. fagi is
reported elsewhere by our group ; generally, although compound 4 was behaviorally
active toward the beech weevil, compound 1, or at least the mixture of 1–3, was not.
Also, it was noted that over time and exposure to atmospheric oxygen, all of compounds
(
[
3]
1–3 are converted to 9-geranyl-p-cymene 4 (see experimental for our studies into this).
Compounds 1 as well as 4 were found in the volatiles from eclosing beech buds by
[
3]
GC/MS, , which initially prompted our interest in the synthesis of these compounds.
As small amounts of other diterpenes (isomeric with 1–3, having molecular ions of
m/z ¼ 272) were also detected by GC/MS of beech bud volatiles, we decided to further
this study by synthesizing compounds 5a, 5b, 6, and 7a (see Scheme 2). To this end, all-
trans-a-springene (E,E,E-3,7,11,15-tetramethyl-1,3,6,10,14-hexadecapentaene) 5a, its
3Z-isomer 5b, and its double-bond positional isomer, all-trans-b-springene (E,E-7,11,15-
trimethyl-3-methylene-1,6,10,14-hexadecatetraene) 6 were synthesized as an inseparable
mixture. Pure b-springene 6, and 9-geranyl-4E-terpinolene 7a (2,6-dimethyl-10-(4-
methyl-3-cyclohexene-1-ylid-4E-ene)-2,6E-undecadiene) as a mixture of isomers were
also synthesized. b-Springene 6, along with a closely related homoditerpene, has
previously been found in the Dufour gland of the ectoparasitoid Habrobracon hebetor
[
4]
(
Say) (Hymenoptera: Braconidae), as well as in the dorsal cutaneous secretions of the
[5]
springbok, Antidorcas marsupialas, the paracloacal gland secretions of the smooth-
fronted Caiman (Paleosuchus trigonatus), and in the essential oils of the leaves of the
[
6]
[7]
herb Heracleum persicum Desf. ex Fischer. The essential oil secreted by the hairs of
outer and inner involucral bracts of Sigesbeckia jorullensis Kunth (Asteraceae) was also
[
8]
found to contain b-springene 6. a-Springene 5a has been found in the Dufour gland

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SYNTHETIC COMMUNICATIONS
3
5a
5b
6
7a
Scheme 2. E,E,E-a-springene 5a, 3Z,6E,10E-a-springene 5b, b-springene 6, 9-geranyl-4E-terpinolene 7a.
[
9]
of the ant Nothomyrmecia macrops, as well as in the leaves of the herb Ligularia
[
10]
fischeri var. spiciformis
3Z,6E,10E)-a-springene 5b.
b-springene 6, were found to be formed enzymatically from geranylgeranyldiphosphate
and in the essential oil of Teucrium marum L., along with
[
11]
(
Both isomers of a-springene (5a and 5b), as well as
(
GGDP) in the presence of diterpene cyclases encoded by genes from Streptomyces gri-
[12]
seolosporeus MF730-N6.
the dorsal gland of both sexes of the collared peccary (Tayassu tajacu).
All three isomers, 5a, 5b, and 6, were found in secretions of
[
13]
Discussion
Initial attempts to synthesize 5a were hampered by its apparent lack of stability, in that
pure product could not be isolated by any workup procedure when a standard POCl3
facilitated dehydration was attempted. So a new synthesis of 5 (as a 1:1 mixture of
3E:3Z isomers, 5a and 5b, with 6 as 10% of the product, see Scheme 2), as well as a
study of the stabilities of 1–3 and 5/6 with respect to atmospheric oxygen was under-
taken. The synthesis of 5/6 reported here (see Scheme 3) from commercially available
geranylgeraniol 8 was adapted from a synthesis of b-ocimene (3,7-dimethyl-1,3,6-octa-
[
14]
triene) as a cis- and trans-mixture reported by Majetich et al.
A similar synthesis of a
mixture of 5a, 5b, and 6 involving palladium catalyzed elimination of acetic acid from
E,E-3-acetoxy-3,7,11,15-tetramethyl-1,6,10,14-hexadecatetraene 9 (see Scheme 4) was
[
15]
reported by Burger et al.,
who were able to isolate 5a and 6 by preparative gas chro-
matography (GC). Interestingly, Burger et al. noted that both 5a and 5b are readily
[
15]
autoxidized.
It was observed in our laboratory that a small sample of ꢀ10 mg of a
mixture of 5a, 5b, and 6 completely decomposed into a resinous solid after exposure to
air for 4 d (see Experimental). Our initial efforts to synthesize 5 by direct dehydration
of geranylgeraniol 8 (see Scheme 5) using POCl in pyridine resulted in no product
3
5a/b or 6 being isolated, either using a standard aqueous workup to isolate the product,
or direct column chromatography of the crude reaction mixture on silica or alumina.
Thin-layer chromatography (TLC) and GC/MS seemed to indicate that the product mix-
ture 5a/5b/6 was in fact present in the crude reaction mixture before work-up. Also, a
[16]
concise synthesis of pure b-springene 6
was discovered in the literature and imple-
mented (see Scheme 6). Another, somewhat more lengthy, synthesis of b-springene 6

4
P. D. MAYO ET AL.
a
5
a + 5b + 6
OH
8
ꢁ
Scheme 3. (a) DCC, CuCl, THF, RT then 90 C, 5a:5b:6 in 0.45:0.45:0.1 ratio, 87% overall yield.
a
5a + 5b + 6
OAc
9
Scheme 4. (a) Pd(OAc) , 5a:5b:6 in a 0.17:0.05:0.78 ratio, 70% overall yield.
2
a
5a / 5b / 6
OH
8
ꢁ
Scheme 5. (a) POCl , Pyridine, 0 C – rt, no 5a, 5b or 6 formed.
3
a
OH
OTHP
8
10
b
6
t
Scheme 6. (a) DHP, PPTS, CH Cl , 95%. (b) KO Bu, 18-crown-6, THF, reflux, 53%.
2
2
[17]
has been reported.
As well as the springenes, the synthesis of 9-geranyl-4E-terpino-
lene 7a was attempted (see Scheme 7), as it is also an isomer of 1, 2, 3, and 5a/b and 6.
To this end, a Diels-Alder reaction between methyl vinyl ketone (MVK, 11) and iso-
prene 12 gave an inseparable mixture of ketones 13a and 13b. The use of SnCl ;5H O
4
2
as a Lewis acid catalyst in the Diels-Alder reaction gave ketone 13a in 92% regioselectiv-
ity. Alkylation of the methyl group of 13a was accomplished by using lithium
diisopropylamide (LDA) to generate the kinetic enolate of 13a, then trapping it
with geranyl bromide 14. Ketone 15, however, is unstable toward silica gel chromatog-
raphy, and thus the crude product 15 was treated with methylmagnesium iodide to
give the tertiary alcohol 16. Column chromatography of 16 and finally POCl3
dehydration gave 7a along with six other detectable isomers, six being identifiable
(
see Scheme 7, 7a–f) and the seventh (7g, not shown) not identifiable, as an inseparable
1
13
mixture. For the characterization by GC/MS, H and C NMR of these seven com-
pounds, as well as their proportion of the overall mixture, see Experimental and
Supporting Information.

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SYNTHETIC COMMUNICATIONS
5
O
O
O
a
b
+
+
O
11
12
13b
1
3a
15
Br
c
14
OH
d
16
+
+
7a
7b
+
+
7
c
7d
7e
+
7g
+
7
f
ꢁ
Scheme 7. (a) SnCl ꢂ5H O, benzene, rt, 10%; 13a:13b ¼ 0.92:0.08. (b) (i) LDA, THF, ꢃ78 C; (ii) 14,
4
2
ꢁ
ꢁ
ꢃ78 C – rt, yield not determined. (c) MeMgI, Et O, reflux, 18% over 2 steps. (d) POCl , pyridine, 0 C
2
3
–
1
rt, 7a (2,6-dimethyl-10-(4-methyl-3-cyclohexene-1-ylid-4E-ene)-2,6E-undecadiene): 7b (2,6-dimethyl-
0-(4-methyl-3-cyclohexene-1-ylid-4Z-ene)-2,6E-undecadiene): 7c (E,Z-2,6-dimethyl-10-(4-methyl-3-cyclo-
hexenyl)-2,6,9-undecatriene): 7d (E,E-2,6-dimethyl-10-(4-methyl-3-cyclohexenyl)-2,6,9-undecatriene):
e (E-6,10-dimethyl-2-(4-methyl-3-cyclohexenyl)-1,5,9-undecatriene): 7f (E-6,10-dimethyl-2-(3-methyl-3-
cyclohexenyl)-1,5,9-undecatriene): 7g (structure not determined) in a 0.12: 0.12: 0.04: 0.41: 0.23: 0.02:
7
0.06 ratio, 91% overall yield.
The fact that compound 7 is obtained as a mixture of seven apparent isomers makes
it difficult to determine which of the seven compounds in the mixture would be behav-
iorally active towards O. fagi, if in fact the mixture is proven to be behaviorally active,
either in laboratory bioassays or field studies. Likewise the a-springene is obtained as a
mixture of 3 isomers as well; the b-springene, however, is produced in pure form.
If it is proven that either of these mixtures is attractive to O. fagi, and a possible lure/
trap could be derived and potentially used as a detection tool, is it then important
(
from a practical viewpoint) which of the constituents in the mixture is attractive? The

6
P. D. MAYO ET AL.
a-springene mixture (1 step synthesis) and b-springene (2 step synthesis) are fairly easy
to make in relatively small quantities (ꢀ100 mg); a field test of either of these two
compounds is feasible and, should it prove successful, could provide a lead into these
compounds’ use as a monitoring tool for O. fagi.
Experimental
Studies on the stabilities of diterpenes toward atmospheric oxygen
[
2]
A mixture of 1, 2, and 3 (1.8 mg, synthesis described elsewhere ) was placed in an
amber glass vial equipped with a septum with a hollow needle through it to allow
atmospheric oxygen into the vial. GC/MS was used to monitor the oxidation of 1/2/3
into 4 on a weekly basis; it was found that, after 22 weeks, the residue in the vial was
approximately 90% 4, and 10% 2. After 30 weeks, neither 1, 2, or 3 were detectable.
Interestingly, no other compounds, either hydrocarbons or oxygenated hydrocarbons,
were apparent.
A mixture of 5a/5b/6 (10.0 mg) was placed in an amber glass vial equipped with a
septum with a hollow needle through it to allow atmospheric oxygen into the vial. GC/
MS was used to monitor the oxidation of 5a/5b/6 on a daily basis. It was found that
after 4 d, the residue in the vial contained no 5a, 5b, or 6. A resinous material of inde-
terminable composition was left in its place.
Syntheses
All nonaqueous reactions were conducted in flame-dried glassware under an argon
atmosphere. Air-sensitive reagents were transferred via syringe through rubber septa.
Reagents were purchased from commercial suppliers and directly used without further
purification. Analytical thin-layer chromatography (TLC) was performed using
Whatman TLC plates, precoated with 0.25 mm of UV254 silica gel on aluminum backing.
Visualization was done by dipping the TLC plate in potassium permanganate solution,
followed by baking on a hot plate. Flash column chromatography was performed using
V
R
a glass column filled with 230 to 400-mesh SiliaFlash without further purification. All
compounds purified by SiO chromatography were greater than 95% purity as deter-
2
mined by GC/MS and/or NMR. Synthetic compounds were characterized by GC/MS on
an Agilent 6890 GC and an Agilent 5973 mass selective detector in the electron impact
(
unit resolution, EI, 70 eV) mode. For the analyses of compound 13a/b, we employed a
ꢁ
ꢁ
temperature program of 50 C for 2 min, then an increase in temperature of 6 C/min
until the oven temperature reached 220 C, which was then maintained for 35 min. For
the analyses of all other compounds, we employed a temperature program of 70 C for
2
2
ꢁ
ꢁ
ꢁ
min, then an increase in temperature of 10 C/min until the oven temperature reached
ꢁ
20 C, which was then maintained for 25 min. A Zebron ZB-5MS Inferno capillary GC
column (Phenomenex, Torrance, CA; 30 m, 0.25 mm id, 0.25 lm film) was used for all
1
13
analyses. NMR spectroscopy, ( H and C) was carried out on a Varian Unity 400 MHz
spectrometer in CDCl or C6D6 as specified, with tetramethylsilane (TMS) as internal
3
standard, with chemical shifts reported in parts per million (ppm) (d). IR spectra were
recorded on a Varian 640-IR FT-IR spectrometer. High-resolution mass spectra (HRMS)

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SYNTHETIC COMMUNICATIONS
7
were obtained at Dalchem Mass Spectrometry Laboratory in Halifax, NS, Canada. For
1
13
H and C NMR spectra of the mixture of 5a–b and 6; 6 alone; the mixture of 7a–g;
3a; and 16; as well as LRMSs of 7a, 7b, 7c, 7d, 7e, 7f and 7g, please see
1
Supplementary material.
[
14]
Synthesis of 5 was adapted from that reported by Majetich et al.
A round-bottom
flask was charged with geranylgeraniol 8 (54.7 mg, 0.189 mmol), tetrahydrofuran (THF)
(
0
20 mL), dicyclohexylcarbodiimide (DCC, 68.5 mg, 0.332 mmol), CuCl (34.9 mg,
.353 mmol), and the mixture was stirred for 24 h at 21 C. After rotary evaporation to
ꢁ
near dryness, the reaction mixture was transferred to a reaction tube, THF (2 mL) was
ꢁ
added, the reaction tube was purged with Ar , sealed, and heated to 90 C for 3 d.
(g)
Removal of the solvent by rotary evaporation and column chromatography of the crude
product (SiO , hexanes as eluent) yielded an inseparable mixture of 5a/5b/6
2
(
0.45:0.45:0.1, 44.8 mg, 0.165 mmol, 87%) as a colorless, transparent liquid. Spectral data
1
for 5a/5b are as follows: H NMR (C D , 400 MHz): d 6.87 (ddd, 0.5H, J ¼ 17.3, 10.9,
6
6
0
2
(
.9 Hz), 6.45 (dd, 0.5H, J ¼ 17.3, 10.6 Hz), 5.51 (t, 0.5H, J ¼ 6.8 Hz), 4.89–5.43 (m, 5.5H),
.88 (t, 1.0H, J ¼ 7.2 Hz), 2.82 (t, 1.0H, J ¼ 7.1 Hz), 2.03–2.18 (m, 8H), 1.54–1.79
1
3
m, 15H). C NMR (C D , 100 MHz): d 142.00, 135.70, 135.58, 135.12, 135.08, 134.12,
6 6
1
1
34.07, 132.29, 132.04, 131.12, 131.11, 130.02, 124.96, 124.95, 124.69, 124.67, 123.06,
22.71, 113.60, 110.70, 40.20 (two signals), 40.08, 40.07, 27.61, 27.23 (two signals), 27.00
(
two signals), 26.79, 25.86 (two signals), 19.94 (two signals), 17.75 (two signals), 16.14,
1
6.13, 16.12 (two signals).
1
H NMR (CDCl , 400 MHz): d 6.81 (ddd, 0.5H, J ¼ 17.3, 10.9, 0.9 Hz), 6.36 (dd, 0.5H,
3
J ¼ 17.2, 10.7 Hz), 5.46 (t, 0.5H, J ¼ 7.3 Hz); 5.35 (t, 0.5H, J ¼ 7.4 Hz), 5.20 (d, 0.5H,
J ¼ 18.2 Hz), 5.06–5.17 (m, 4H), 4.93 (d, 0.5H, J ¼ 10.7 Hz), 2.82–2.89 (m, 2H), 1.95–2.11
13
(
m, 8H), 1.81 (d, 1.5H, J ¼ 1.2 Hz), 1.76 (d, 1.5H, J ¼ 0.9 Hz), 1.59–1.68 (m, 12H).).
C
NMR (CDCl , 100 MHz): d 141.6, 135.8, 135.7, 135.1, 135.0, 133.72, 133.69, 131.93,
3
1
1
2
31.87, 131.31, 131.27, 129.7, 124.4 (two signals), 124.13, 124.12, 122.4, 122.1, 113.5,
10.5, 39.73 (two signals), 39.66 (two signals), 27.2, 26.8 (two signals), 26.6 (two signals),
6.4, 25.7 (two signals), 19.7 (two signals), 17.7 (two signals), 16.13, 16.11, 16.0 (two sig-
ꢃ1
nals). IR (neat, cm ): 3089 (w), 2966 (s), 2922 (s), 2854 (s), 2728 (w), 1669 (w), 1640
(
w), 1439 (s), 1377 (s), 1150 (w), 1099 (m). LRMS: The two principle components in the
mixture, 5a and 5b, co-eluted in the GC and thus a LRMS cannot be assigned to either
þ
5
a or 5b. HRMS: [C H ] calc. 273.257841; found 273.2570. Mass measurement
2
0
33
error: ꢃ3.08 ppm.
b-Springene 6 (as ꢀ10% in the mixture of 5a:5b:6, not all proton signals of 6 were
1
visible in the spectra): H NMR (CDCl , 400 MHz): visible peaks d 6.38 (dd, 1H,
3
13
J ¼ 17.4, 10.9 Hz), 5.24 (d, 1H, J ¼ 17.6 Hz), 5.01 (s, 1H), 4.99 (s, 1H). C NMR (CDCl3,
1
3
00 MHz): d 146.2, 139.0, 135.4, 135.0, 131.1, 124.4, 124.2, 124.0, 115.7, 113.0, 39.74,
1
13
9.71, 31.4, 26.8, 26.64, 26.62, 25.7, 17.7, 16.05, 16.02. H NMR (visible peaks) and
NMR match Baeckstr o€ m and Li.
Synthesis of 6 in pure form: As described by Otera et al.
match those reported by Baeckstr o€ m and Li.
C
[
18]
[
16] 1
13
H and C NMR spectra
[
18]
1
IR and H NMR match those reported
[
17]
[17]
by Vig et al.
Vig et al. also report elemental analysis.
Ketone 13a: The synthesis of 13 as a mixture of positional isomers 13a and 13b with-
[
19]
out a Lewis acid catalyst was reported by Lutz and Bailey.
Preliminary studies on this
synthetic route involved first attempting synthesis of 13 without a Lewis acid catalyst,

8
P. D. MAYO ET AL.
[
19]
20]
and our results mirrored those reported (13a:13b in a 0.71 to 0.29 ratio).
Subsequently, the same Diels–Alder reaction with the Lewis acid catalyst SnCl ;5H O
[
4
2
gave 13a:13b in a 0.92:0.08 ratio. This was also similar to that reported (0.93 to 0.07
[
19]
13a:13b).
To this end, a round-bottomed flask was charged with isoprene (3.10 mL,
3
1.0 mmol), methyl vinyl ketone (2.54 mL, 31.3 mmol), benzene (30 mL), tin (IV) tetra-
ꢁ
chloride pentahydrate (2.10 g, 5.99 mmol), and the reaction was stirred at 21 C for 1 h.
Water (30 mL) was added, the layers were separated, the aqueous layer was extracted
with diethyl ether (3 ꢄ 20 mL), and the combined organic layers were washed with water
(
(
(
30 mL), brine (30 mL) and dried (MgSO ). Column chromatography on silica gel
30% diethyl ether/hexanes as eluent) yielded 13a as a colorless, transparent liquid
440 mg, 3.19 mmol, 10%). Spectral data for 13a are as follows: H NMR (CDCl ,
4
1
3
4
00 MHz): d 5.39 (m, 1H), 2.53 (m, 1H), 2.17 (s, 3H), 1.93–2.16 (m, 4H), 1.54–1.65
1
3
(
m, 5H). C NMR (CDCl , 100 MHz): d 211.8, 133.8, 119.2, 47.2, 29.4, 27.9, 27.0, 24.9,
3
ꢃ1
2
3.3. IR (neat): cm 3010 (w), 2963 (w), 2916 (m), 2857 (w), 2835 (w), 1707 (s), 1439
(
1
(
m), 1376 (m), 1352 (m), 1299 (w), 1282 (w), 1250 (w), 1224 (w), 1166 (m), 1114 (w),
054 (w). LRMS (EI, 70 eV) m/z (main peaks): 55, 67, 79, 91, 93, 95, 105, 123, 138
M , base peak). HRMS: [C H O] calc. 139.111801; found 139.1122. Mass measure-
9 15
þ
þ
ment error: 2.87 ppm.
Ketone 15: A flame-dried round-bottomed flask was charged with ketone 13a
ꢁ
(
(
330 mg, 2.39 mmol), THF (30 mL), and cooled to ꢃ78 C. Lithium diisopropylamide
LDA, 1.0 M in THF, 3.10 mL, 3.10 mmol) was added dropwise over 5 min, and the
ꢁ
reaction was stirred at ꢃ78 C for 1 h. Geranyl bromide 14 (0.60 mL, 3.0 mmol) was
ꢁ
added, and the reaction was stirred for 1 h at ꢃ78 C, then warmed to RT and stirred a
further 16 h. Water (70 mL) was added, the layers were separated, and the aqueous layer
was extracted with diethyl ether (3 ꢄ 50 mL). The combined organic layers were washed
with brine (75 mL) and dried (MgSO ). Ketone 15 was unstable toward silica gel chro-
4
matography, so the crude product 15 was used in the following step without further
purification.
Alcohol 16: A flame-dried round-bottomed flask was charged with methylmagnesium
iodide (3 M solution in diethyl ether, 5.0 mL, 15.0 mmol), diethyl ether (40 mL), then
ketone 15 (as a crude mixture from the previous step, exact mass not determined) in THF
ꢁ
(
6 mL) was added, and the reaction was stirred at 21 C for 2 h, then heated to reflux for
3
0 min. Upon cooling, saturated NH Cl
(45 mL) was added, the layers were separated,
4
(aq)
and the aqueous layer was extracted with diethyl ether (20 mL ꢄ3). The combined organic
layers were washed with brine (50 mL) and dried (MgSO ). Column chromatography
4
(automated chromatography on silica gel with 0–20% EtOAc:hexanes solvent gradient)
yielded alcohol 16 (121.9 mg, 0.420 mmol, 18% over two steps) as a colorless, transparent
1
liquid. Spectral data for 16 (as a mixture of two diastereomers) are as follows: H NMR
(
CDCl , 400 MHz): d 5.37–5.41 (m, 1H), 5.07–5.16 (m, 2H), 1.49–2.10 (m, 28H), 1.14
3
13
(s, 1.50H), 1.11 (s, 1.50H). C NMR (CDCl , 100 MHz): d 135.32, 135.31, 134.1, 133.8,
3
1
4
2
31.4 (two signals), 124.4 (two signals), 124.3 (two signals), 120.8, 120.5, 74.33, 74.32, 43.3,
3.0, 40.1, 39.7 (two signals), 39.3, 31.1, 31.0, 26.9, 26.66, 26.65, 26.1, 25.7 (two signals),
3.99, 23.96, 23.34, 23.31, 23.28, 23.2, 22.2, 22.0, 17.7 (two signals), 16.0 (two signals). IR
ꢃ1
(neat): cm 3413 (br., m), 2964 (s), 2921 (s), 2854 (s), 2727 (w), 1700 (w), 1672 (w), 1439
(s), 1375 (s), 1292 (w), 1249 (w), 1222 (w), 1154 (m), 1104 (s), 1068 (m), 1017 (m). LRMS
(EI, 70 eV) m/z (main peaks): 55, 69 (base peak), 81, 93, 107, 119, 134, 147, 159, 161, 177,

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R
SYNTHETIC COMMUNICATIONS
9
7
d
7
e
7
a or 7b
7
g
7a or 7b
7
c
7
f
1
8.4
18.6
18.8
19
19.2
19.4
Retention time (minutes)
Scheme 8. Total Ion Chromatogram (TIC) of the mixture of 7a–g. For mass spectra of peaks 7a–g,
see Supporting Information, and Experimental for mass spectral data in text form.
pm.2992.1h.fid
pm-2992
1
1
c:
5
.5
5.0
4.5
4.0
3.5
3.0
2.5
[ppm]
1
Scheme 9. Expansion of the region between 2.2 and 5.5 ppm in the H NMR spectrum of the mixture
of 7a–g. The multiplet at ꢀ5.4 ppm is the olefinic protons on the cyclohexene ring of 7a–g, the multi-
plet at ꢀ5.1 ppm is the olefinic protons of the geranyl side chain of 7a–g, the multiplet at ꢀ4.75 ppm
is the exo-methylene protons of 7e, and the two small multiplets at ꢀ4.68 ppm are the exo-methy-
lene protons of 7f. The multiplet at ꢀ2.7 ppm is the doubly allylic methylene protons of 7a, 7b, 7c
and 7d. The quartet at ꢀ2.3 ppm is the protons from one of the allylic methylene groups on the
cyclohexene ring of 7a and 7b.
þ
þ
1
87, 203, 229, 257, 272, 290 (M ). HRMS: [C H NaO] calc. 313.250341; found
20 34
313.2505. Mass measurement error: 0.51 ppm.
9
-Geranyl-4E-terpinolene 7a: A flame-dried round-bottomed flask was charged with
ꢁ
alcohol 16 (27.8 mg, 0.0959 mmol) and pyridine (5 mL) and cooled to 0 C. POCl
0.12 mL, 1.29 mmol) was added, and the reaction was stirred at 0 C for 2 h, then at
3
ꢁ
(

1
0
P. D. MAYO ET AL.
ꢁ
1 C for 48 h. After quenching with water (20 mL), the crude reaction mixture was
2
extracted with diethyl ether (4 x 15 mL), washed with water (20 mL) and brine (20 mL)
and dried (MgSO ). Silica gel column chromatography (hexanes as eluent) yielded 7
4
(
23.7 mg, 0.0871 mmol, 91%) as a colorless, transparent liquid. 7 was obtained as an
inseparable mixture of seven detectable isomers, four of which are two cis/trans pairs
see Scheme 7 for all of the isomers of 7 that were obtained). The ratio of
a:7b:7c:7d:7e:7f:7g (7g being an isomer of 7 having unknown structure) was deter-
(
7
mined to be: 0.12:0.12:0.04:0.41:0.23:0.02:0.06 by integrating the peaks in the total ion
chromatogram of 7 (see Scheme 8 and Supporting Information). This ratio was
1
supported by integration of the peaks in the H NMR spectrum where possible of the
mixture of the isomers of 7 (see Scheme 9). However, the isomer 7g was not detected in
1
the H NMR spectrum and thus could potentially be a GC injector port or column arti-
fact. As it is indicated to be only ꢀ6% of the total product mixture by GC/MS, it could
1
easily be present yet impossible to detect, let alone characterize correctly, by either H
1
3
or C NMR. For this reason, no structure was assigned to 7g. The presence of a very
prominent base peak at m/z ¼ 203 in the mass spectrum of 7g (272 amu–69 amu, loss of
an isoprenyl group) indicates perhaps a cyclic structure, with an isoprenyl side chain.
For low-resolution mass spectra (LRMS) of 7a–g, see Supporting Information. Also, for
these data in text form, see spectral data below. Similarities in the LRMS of cis/trans iso-
mers were used to help with the spectral assignments. Spectral data for the mixture of
1
7
4
0
1
1
2
6
1
a:7b:7c:7d:7e:7f:7g (0.12:0.12:0.04:0.41:0.23:0.02:0.06) are as follows: H NMR (CDCl ,
3
00 MHz): d 5.34–5.45 (m, 1H), 5.08–5.16 (m, 2.45H), 4.76 (br. s, 0.23H), 4.75 (dd,
.23H, J ¼ 2.6, 1.3 Hz), 4.68 (m, 0.04H), 2.63–2.75 (m, 1.50H), 2.29–2.34 (m, 0.48H),
1
3
.42–2.28 (m, 26.07H). C NMR of major isomer 7d (CDCl , 100 MHz): d 139.3, 134.9,
3
33.7, 131.3, 124.4, 123.4, 121.8, 120.9, 42.8, 39.7, 30.80, 30.76, 28.0, 26.8, 26.7, 25.7,
2.7, 17.7, 16.1, 14.1. LRMS of major isomer 7d (EI, 70 eV) m/z (main peaks): 55, 67,
9, 77, 79, 81, 91, 93, 95, 105, 107, 109, 119, 121, 123 (base peak), 133, 135, 147, 161,
þ
13
77, 187, 189, 203, 204, 215, 229, 257, 272 (M ). C NMR of 7e (CDCl , 100 MHz,
3
assignable peaks): d 154.3, 135.1, 133.7, 131.3, 124.4, 124.2, 120.8, 107.1, 39.8, 39.7, 30.8,
6.74, 26.71, 25.7, 23.5, 17.7, 16.1. LRMS of 7e (EI, 70 eV) m/z (main peaks): 55, 69
base peak), 79, 81, 91, 93, 95, 105, 107, 109, 119, 121, 133, 134, 147, 159, 161, 175, 187,
2
(
2
þ
13
04, 216, 229, 244, 257, 272 (M ). C NMR of 7a/7b (CDCl , 100 MHz, assignable
3
peaks): d 135.0, 134.8, 134.20, 134.16, 131.32, 131.26, 128.4, 128.3, 125.9, 125.7, 120.8,
1
20.7, 39.7 (two signals), 29.4 (two signals), 26.7 (two signals), 25.7 (two signals), 17.7
ꢃ1
(
two signals), 16.1 (two signals). IR (neat, cm ): 2957 (s). 2921 (s), 2871 (m), 2854 (s),
1673 (w), 1641 (w), 1449 (m), 1377 (m), 1148 (w), 1108 (w), 1050 (w), 1019 (w). LRMS
of 7a or 7b (peak at 18.9 min. retention time) (EI, 70 eV) m/z (main peaks): 55, 69, 77,
7
1
9, 81, 91, 93, 105, 107, 119 (base peak), 121, 132, 134, 135, 145, 147, 159, 161, 175,
87, 197, 204, 216, 229, 257, 272 (M ). LRMS of 7a or 7b (peak at 19.1 min. retention
þ
time) (EI, 70 eV) m/z (main peaks): 55, 69, 77, 79, 81, 91, 93, 105, 107 (base peak), 119,
þ
1
32, 134, 135, 145, 159, 187, 197, 257, 272 (M ). LRMS of 7g (EI, 70 eV) m/z (main
peaks): 55, 67, 69, 77, 79, 81, 91, 93, 95, 105, 107, 109, 119, 121, 123, 133, 147, 161, 175,
1
8
1
6
87, 203 (base peak), 229. LRMS of 7c (EI, 70 eV) m/z (main peaks): 55, 67, 69, 77, 79,
1, 91, 93 (base peak), 95, 105, 107, 109, 115, 119, 121, 123, 132, 133, 134, 135, 147,
þ
59, 161, 177, 187, 203, 229, 272 (M ). LRMS of 7f (EI, 70 eV) m/z (main peaks): 55,
7, 69 (base peak), 79, 81, 91, 93, 95, 105, 107, 109, 119, 121, 132, 133, 134, 135, 147,

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SYNTHETIC COMMUNICATIONS
11
þ
þ
1
59, 161, 187, 272 (M ). HRMS (for the mixture of all seven isomers of 7): [C H ]
20 33
calc. 273.257841; found 273.2569. Mass measurement error: ꢃ3.44 ppm.
Acknowledgments
We thank Natural Resources Canada for funding this research. This research was partially sup-
ported by the Atlantic Canada Opportunities Agency, Atlantic Innovation Fund (No. 208171). All
experiments reported here comply with the laws of Canada.
Disclosure statement
No potential conflict of interest was reported by the authors.
ORCID
P. D. Mayo
D. I. MaGee
http://orcid.org/0000-0002-8668-7469
http://orcid.org/0000-0002-2598-2675
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