Improved synthesis of the pheromone of the longtailed mealybug

Article abstract of DOI:10.1055/s-0030-1258025

A short and efficient synthesis of the longtailed mealybug pheromone featuring an Ireland-Claisen rearrangement as the key step is described.

Full text of DOI:10.1055/s-0030-1258025

LETTER
2319
Improved Synthesis of the Pheromone of the Longtailed Mealybug
Synthesis of the
P
h
u
eromone of
n
the Longtaile
f
d
Mealy
a
bug n Zou,* Jocelyn G. Millar
Department of Entomology, University of California, Riverside, CA 92521, USA
Fax +1(951)8273086; E-mail: yunfanz@ucr.edu
Received 14 May 2010
OH
OAc
OH
X
Abstract: A short and efficient synthesis of the longtailed mealy-
bug pheromone featuring an Ireland–Claisen rearrangement as the
key step is described.
O
Key words: pheromone, monoterpenoid, allylic cyclopentenol,
Ireland–Claisen rearrangement
1
2
3a X = OEt
3b X = NMe2
3c X = OH
4
Scheme 1
We recently identified the sex pheromone of the long-
tailed mealybug Pseudococcus longispinus as the novel
cause of its potential to provide much shorter and more
easily scalable syntheses.
monoterpenoid derivative 1, with two adjacent quaternary
carbons in a cyclopentene ring.1 The mealybug is a widely
distributed pest of vineyards and glasshouse crops, and it
has recently gained additional importance because of its
role as a vector of leafroll viruses in high value wine
grapes.2,3 In field tests, the pheromone proved to have ex-
traordinary biological activity, with lures loaded with 25
mg of the racemic pheromone remaining highly attractive
to male mealybugs for more than three months. Two syn-
theses of the pheromone have now been reported, but both
have significant drawbacks, particularly in terms of scale-
up syntheses for commercialization of the pheromone. In
our first synthesis of 1, developed primarily to verify the
structure of the pheromone, a key step that used a 2,3-
Wittig rearrangement of an allylic stannane intermediate
proceeded in only 25% yield.1 In a follow-up synthesis,
the core cyclopentane ring structure was constructed by
regiospecific cyclization of an a-diazo-b-ketoester.4 This
synthesis resulted in a higher overall yield and provided
>5 g of the pheromone, but the reaction sequence was still
unacceptably long (12 consecutive steps).
To begin the synthesis, known cyclopentenone 5, pre-
pared in one step on multigram scale from cheap isobutyl
2-butenoate by treatment with hot polyphosphoric acid,8,9
was reduced with LiAlH4 to give the key allylic alcohol
intermediate 4.1 Several sets of reaction conditions were
then tested, beginning with the Johnson–Claisen rear-
rangement by heating alcohol 4 with excess triethyl
orthoacetate in the presence of an acid catalyst. In our ear-
lier, failed attempts with this reaction,4 a carboxylic acid
was used as catalyst and resulted only in production of
1,5,5-trimethylcyclopentadiene from elimination of the
alcohol. Thus, we tried the weaker acid catalyst hydro-
quinone in the hope that elimination would be suppressed
in favor of esterification and rearrangement. In the event,
a complicated mixture was obtained, containing only trace
amounts of the desired rearrangement product 3a along
with unreacted starting material, the previously obtained
elimination product, and several unidentified side prod-
ucts.
We then tried the Eschenmoser–Claisen rearrangement
conditions, expecting that they might give better results
because the reaction is carried out under essentially neu-
tral conditions. Refluxing alcohol 4 with dimethylaceta-
mide dimethyl acetal resulted in a low yield (18%) of the
desired g,d-unsaturated tertiary amide 3b. Whereas this
was readily reduced to alcohol 2 with lithium triethylboro-
hydride, the yield in the rearrangement step was still un-
acceptably low.
Retrosynthetic analyses had indicated that the desired
pheromone 1 might be readily obtainable from reduction
of a g,d-unsaturated carbonyl compound 3, which in turn
might be accessible from a Claisen-type rearrangement of
cyclopentenol 4 (Scheme 1). However, preliminary stud-
ies testing different Claisen rearrangement conditions did
not look promising,4 and so the routes described above
were used to provide material for ongoing field trials.
With material in hand to work with, we then did a more
thorough literature search and determined that there were Finally, we tried the Ireland–Claisen conditions in two
several precedents for allylic cyclopentenols to undergo steps. First, alcohol 4 was esterified with Ac2O,10 DMAP,
Johnson–Claisen,5 Eschenmoser–Claisen,5d,6 or Ireland– and pyridine to give acetate 6.11 Then reaction of 6 with
Claisen rearrangements.5e,7 Encouraged by those results,
we decided to revisit this general route, particularly be-
LDA and tert-butyldimethylsilyl chloride12 in THF fol-
lowed by thermolysis of the resultant silyl ketene acetal
generated the desired tert-butyldimethylsilyl ester, which
was hydrolyzed with aqueous NaOH to give g,d-unsatur-
ated acid 3c in 50% isolated yield. The remaining synthe-
sis required only straightforward reduction of acid 3c with
LiAlH4 and acetylation of alcohol 2 with acetyl chloride
SYNLETT 2010, No. 15, pp 2319–2321
x
x
.x
x
.2
0
1
0
Advanced online publication: 30.08.2010
DOI: 10.1055/s-0030-1258025; Art ID: S02610ST
© Georg Thieme Verlag Stuttgart · New York

2320
Y. Zou, J. G. Millar
LETTER
O
OH
O
PPA
LiAlH4
Et2O
Ac2O, DMAP, py
CH2Cl2
O
5
4
O
O
OTBS
1) reflux
2) NaOH
3) HCl
OH
O
LDA, TBSCl
LiAlH4
Et2O
O
6 (78% for 2 steps)
3c (50%)
OAc
OH
AcCl, py
Et2O
2 (95%)
1 (95%)
Scheme 2
and pyridine, giving acetate 1 in 35% yield from 5 in five
steps (Scheme 2). This relatively short and efficient syn-
thesis of the pheromone will expedite its commercial de-
velopment for detection, monitoring, and control of
longtailed mealybugs and the leafroll viruses that they
vector.
References and Notes
(1) Millar, J. G.; Moreira, J. A.; McElfresh, J. S.; Daane, K. M.;
Freund, A. S. Org. Lett. 2009, 11, 2683.
(2) (a) Golino, D. A.; Sim, S. T.; Gill, R.; Rowhani, A.
California Agric. 2002, 56, 196. (b) Golino, D. A.; Weber,
E.; Sim, S.; Rowhani, A. California Agric. 2008, 62, 156.
(3) Charles, J. G.; Cohen, D.; Walker, J. T. S.; Forgie, S. A.;
Bell, V. A.; Breen, K. C. New Zealand Plant Protec. 2006,
59, 330.
(4) Zou, Y.; Millar, J. G. J. Org. Chem. 2009, 74, 7207.
(5) (a) Imanishi, T.; Matsui, M.; Yamashita, M.; Iwata, C.
Tetrahedron Lett. 1986, 27, 3161. (b) Kobayashi, Y.;
Murugesh, M. G.; Nakano, M.; Takahisa, E.; Usmani, S. B.;
Ainai, T. J. Org. Chem. 2002, 67, 7110. (c) Sumi, S.;
Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Org. Lett.
2003, 5, 1891. (d) Sumi, S.; Matsumoto, K.; Tokuyama, H.;
Fukuyama, T. Tetrahedron 2003, 59, 8571. (e) Yoshikawa,
N.; Tan, L.; Yasuda, N.; Volante, R. P.; Tillyer, R. D.
Tetrahedron Lett. 2004, 45, 7261. (f) Kondo, K.;
Matsumoto, M.; Mori, F. Angew. Chem., Int. Ed. Engl. 1975,
14, 103.
(6) (a) Nakashima, H.; Sato, M.; Taniguchi, T.; Ogasawara, K.
Synlett 1999, 1754. (b) Nakashima, H.; Sato, M.; Taniguchi,
T.; Ogasawara, K. Synthesis 2000, 817. (c) Nonaka, H.;
Wang, Y.; Kobayashi, Y. Tetrahedron Lett. 2007, 48, 1745.
(7) (a) Pearson, A. J.; Chen, Y.; Han, G.; Hsu, S.; Ray, T.
J. Chem. Soc., Perkin Trans. 1 1985, 267. (b) Srikrishna,
A.; Reddy, T. J.; Palani, N.; Balasubramanian, K. K. Synth.
Commun. 2003, 33, 1537. (c) Hu, Q.; Rege, P. D.; Corey,
E. J. J. Am. Chem. Soc. 2004, 126, 5984.
(8) (a) Conia, J. M.; Leriverend, M. L. Bull. Soc. Chim. Fr.
1970, 2981. (b) Gowda, G.; McMurry, T. B. H. J. Chem.
Soc., Perkin Trans. 1 1979, 274. (c) Mori, K.; Sasaki, M.
Tetrahedron 1980, 36, 2197. (d) Schwartz, K. D.; White,
J. D. Org. Synth. 2006, 83, 49.
(1,5,5-Trimethylcyclopent-2-enyl)acetic Acid (3c)
A solution of DIPA (0.51 mL, 3.6 mmol) in anhyd THF (5 mL) un-
der Ar was cooled to 0 °C, n-BuLi (2.1 M in hexane, 1.6 mL, 3.3
mmol) was added, and the solution was stirred at 0 °C for 15 min,
then cooled to –78 °C. A solution of ester 6 (0.50 g, 3.0 mmol) in
anhyd THF (5 mL) was added dropwise, and the mixture was stirred
at –78 °C for 30 min. A solution of tert-butyldimethylsilyl chloride
(0.47 g, 3.15 mmol) in anhyd THF (2 mL) was then slowly added.
After 30 min, the cold bath was removed, the mixture was warmed
and stirred at r.t. for 2 h, and then refluxed for 1 d. The mixture then
was cooled to r.t. and treated with 2 M aq NaOH (6 mL). The mix-
ture was stirred 1 h at r.t., then extracted with hexanes (3×) to re-
move nonacidic side products. The aqueous layer was acidified with
6 M HCl to pH 1.0 and extracted with Et2O (3×). The combined
ether extracts were washed with brine, dried, and concentrated, and
the crude product was purified by Kugelrohr distillation (1.33·10–3
bar, 90 °C) to give 0.25 g (50%) of 3c as a colorless oil. 1H NMR
(400 MHz, CDCl3): d = 5.81 (dt, J = 6.0, 2.0 Hz, 1 H), 5.66 (dt,
J = 6.0, 2.0 Hz, 1 H), 2.38 (d, J = 13.6 Hz, 1 H), 2.24 (d, J = 13.6
Hz, 1 H), 2.19 (dt, J = 16.0, 2.0 Hz, 1 H), 2.12 (dt, J = 16.0, 2.0 Hz,
1 H), 1.03 (s, 3 H), 0.98 (s, 3 H), 0.95 (s, 3 H). 13C NMR (100 MHz,
CDCl3): d = 179.9 (C), 138.6 (CH), 128.3 (CH), 49.9 (C), 46.8
(CH2), 44.3 (C), 40.8 (CH2), 24.6 (CH3), 24.2 (CH3), 19.8 (CH3). IR
(film): 3300–2500 (br), 1707, 1450, 1409, 1295, 1235, 1137, 954,
716 cm–1. MS: m/z (rel. abundance) = 41 (66), 43 (35), 53 (18), 55
(13), 67 (40), 69 (12), 77 (20), 79 (22), 81 (23), 91 (27), 93 (45), 107
(40), 108 (57), 109 (100), 153 (13), 168 (4) [M+]. ESI-HRMS (AP-
CI): m/z calcd for [C10H16O2 + H]+: 169.1223; found: 169.1226.
(9) In ref. 8c and 8d, the a,b-unsaturated ester was reacted with
hot polyphosphoric acid for 10 min and 3 min, respectively,
before the reaction was stopped. However, in our hands,
only starting material was recovered with such short reaction
times. We found the reaction to be complete after ca. 5 h,
which is more consistent with ref. 8a and 8b.
Acknowledgment
We thank the American Vineyard Foundation, the Viticulture
Consortium West, and the Oregon Wine Board for funding in sup-
port of this work.
(10) When AcCl was used instead of Ac2O, the yield was lower
(65%).
Synlett 2010, No. 15, 2319–2321 © Thieme Stuttgart · New York

LETTER
Synthesis of the Pheromone of the Longtailed Mealybug
2321
(11) Data for Acetic Acid 3,4,4-Trimethyl-cyclopent-2-enyl
Ester (6)
67 (21), 77 (22), 91 (24), 93 (100), 108 (15), 109 (36), 111
(24), 126 (17), 153 (2), 168 (7) [M+]. HRMS (CI/CH4 on
GC-MS): m/z calcd for [C10H16O2]+: 168.1150; found:
168.1151.
1H NMR (400 MHz, CDCl3): d = 5.50 (m, 1 H), 5.33 (m, 1
H), 2.13 (dd, J = 14.0, 7.2 Hz, 1 H), 1.99 (s, 3 H), 1.69 (dd,
J = 14.0, 2.8 Hz, 1 H), 1.66 (t, J = 1.6 Hz, 3 H), 1.08 (s, 3 H),
1.01 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 171.3, 155.8,
122.1, 78.4, 46.9, 45.4, 27.9, 27.4, 21.6, 12.4. IR (film):
3055, 2959, 2869, 1734, 1654, 1438, 1373, 1242, 1019, 970
cm–1. MS: m/z (rel. abundance) = 41 (34), 43 (85), 55 (18),
(12) When 1.3 equiv of tert-butyldimethylsilyl chloride was
used, a silicon-containing acidic byproduct was formed,
which was difficult to separate from 3c. With 1.05 equiv, this
byproduct was not observed.
Synlett 2010, No. 15, 2319–2321 © Thieme Stuttgart · New York

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