Stereoselective synthesis of the obscure mealybug pheromone by hydrogenation of a tetrasubstituted alkene precursor

Article abstract of DOI:10.1016/j.tetlet.2011.06.030

An improved diastereoselective synthesis of (1R,2R,3S)-1-acetoxymethyl-2,3, 4,4-tetramethylcyclopentane 1, the sex pheromone of the obscure mealybug, Pseudococcus viburni, is described. The key step was diastereoselective catalytic hydrogenation of the tetrasubstituted double bond in 2,3,4,4-tetramethyl-cyclopent-2-enone 4 to give the thermodynamically less favored cis-2,3,4,4-tetramethyl-cyclopentanone 3a.

Full text of DOI:10.1016/j.tetlet.2011.06.030

Tetrahedron Letters 52 (2011) 4224–4226
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of the obscure mealybug pheromone by hydrogenation
of a tetrasubstituted alkene precursor
⇑
Yunfan Zou , Jocelyn G. Millar
Department of Entomology, University of California, Riverside, CA 92521, USA
a r t i c l e i n f o
a b s t r a c t
⁄
⁄
⁄
Article history:
An improved diastereoselective synthesis of (1R ,2R ,3S )-1-acetoxymethyl-2,3,4,4-tetramethylcyclopen-
tane 1, the sex pheromone of the obscure mealybug, Pseudococcus viburni, is described. The key step was
diastereoselective catalytic hydrogenation of the tetrasubstituted double bond in 2,3,4,4-tetramethyl-
cyclopent-2-enone 4 to give the thermodynamically less favored cis-2,3,4,4-tetramethyl-cyclopentanone
Received 19 April 2011
Revised 4 June 2011
Accepted 7 June 2011
Available online 13 June 2011
3a.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pheromone
Monoterpenoid
Diastereoselective synthesis
Catalytic hydrogenation
⁄
⁄
⁄
We recently identified (1R ,2R ,3S )-1-acetoxymethyl-2,3,4,4-
tetramethylcyclopentane 1 as the female-produced sex pheromone
of the obscure mealybug, Pseudococcus viburni (Homoptera:
insect, an efficient diastereoselective synthesis for production of
the racemate on gram scale was practicable.
In our first, nonstereoselective synthesis of racemic 1, conjugate
2
addition of Me CuLi to 2,4,4-trimethylcyclopent-2-en-1-one 2, fol-
1
Pseudococcidae), a widely distributed pest of ornamental plants,
crop plants, and grape vines. This compound, with its 1-hydroxy-
methyl-2,3,4,4-tetramethylcyclopentane skeleton, represented the
first example of a new structural class of monoterpenoids (Fig. 1).
The relative stereochemistry was determined by nonstereoselec-
tive synthesis of a mixture of all four diastereomers (as pairs of
2
lowed by quenching in the usual fashion produced the undesired,
thermodynamically favored trans-2,3,4,4-tetramethyl-cyclopenta-
none 3b as the major product rather than the desired cis-diastereo-
mer 3a. This problem was partially addressed in a second,
diastereoselective synthesis by quenching the enolate product
from the conjugate addition in the presence of ethyl salicylate as
1
enantiomers). The correct diastereomer was separated by pre-
6
parative GC, conclusively identified from NOE analysis, and unam-
biguously matched with a sample collected from the insects.
Knowing the relative configuration of the molecule, we then devel-
a chelating proton donor, resulting in a reversal of the selectivity
with 3 obtained as a 72:28 mixture of the desired cis-isomer 3a and
undesired trans-isomer 3b (Scheme 1).
3
oped a diastereoselective synthesis of 1 as the racemate, following
Although much improved, this key step that set the relative ste-
reochemistry at carbons 2 and 3 still gave only moderate cis/trans
selectivity, and in practice, was tedious to perform. Diastereomers
3a and 3b were practically inseparable by flash chromatography
and had to be used as a mixture. Separation was only practicable
after the third stereocenter was introduced and still required
which samples of enantiopure 1 were obtained by enzyme-based
kinetic resolution of the synthetic racemate. Comparison of theo-
retically calculated and experimentally determined vibrational cir-
cular dichroism (VCD) spectra of the two enantiomers then
allowed assignment of the absolute configuration of the insect-
produced material as (1S,2S,3R)-1-acetoxymethyl-2,3,4,4-tetram-
4
ethylcyclopentane (+)-1. This assignment was subsequently con-
firmed by independent enantioselective syntheses of both
enantiomers on milligram scale. Fortunately, in field tests the
5
OAc
OAc
racemic compound proved to be as attractive to male mealybugs
as the natural enantiomer, indicating that the unnatural antipode
is not inhibitory. Thus, for the purposes of developing commercial
applications for the pheromone in detection and monitoring of the
(
+)-1
(-)-1
natural enantiomer unnatural enantiomer
⇑
Corresponding author. Tel.: +1 951 827 5821; fax: +1 951 827 3086.
E-mail address: yunfanz@ucr.edu (Y. Zou).
Figure 1. Enantiomers of the obscure mealybug pheromone.
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.030

Y. Zou, J. G. Millar / Tetrahedron Letters 52 (2011) 4224–4226
4225
O
O
O
O
PPA
00 °C
Me CuLi
2
O
+
1
2
, 34%
3a, cis
3b, trans
Reaction conditions
3a : 3b
quench with aq. NH Cl
ethyl salicylate quench, -78 °C
18 : 82
72 : 28
4
Scheme 1. Synthesis of key intermediate 3 by conjugate addition.3
O
O
O
AlCl3
H (1atm)
2
+
Cl
CH Cl
Rh/C, Na CO
2
3
2
2
pentane
4, 55%
3, 81%, cis:trans = 95:5
OH
O
H
.
1
) BH Me S
Zn, CH Br , TiCl
4
3
2
PCC
CH Cl
2
2
THF, CH Cl2
2) NaOH, H O
2 2
2
2
2
5
6, 69% from 3
7, 81%
O
H
OH
OAc
NaOMe, MeOH
LiAlH
4
AcCl, Py
Et O
Et O
2
2
8
9, 97% from 7
1, 80%
⁄
⁄
⁄
Scheme 2. Synthesis of (1R ,2R ,3S )-1-acetoxymethyl-2,3,4,4-tetramethylcyclopentane 1.
careful chromatography. This provided the motivation to develop
an alternate method of establishing the relative stereochemistry
of the vicinal methyl groups in 3a. Because of their cis-stereochem-
istry, we focused our attention on the possibility of stereoselective
catalytic hydrogenation of the tetrasubstituted double bond in
solvent, and particularly, whether the pH was controlled. The situ-
ation was further complicated by reports that even different
batches of the same catalyst produced quite different stereochem-
1
2,14
ical outcomes.
With this history of sensitivity to reaction con-
ditions and variable product ratios, we anticipated that this step
might require considerable experimentation to arrive at a set of
2
,3,4,4-tetramethylcyclopent-2-enone 4 (Scheme 2). Enone 4 ini-
tially was prepared by treatment of 3-methylbut-2-enoic acid
sec-butyl ester with polyphosphoric acid at 100 °C, but the yield
suitable reaction parameters. In the event, the general conditions
7
13,14
developed by Paquette and Barth proved successful.
In their
was only moderate and it was difficult to purify the product by
either distillation or flash chromatography. A route based on acyl-
ation of alkenes generated in situ by hydride transfer from isoalk-
anes proved more satisfactory.8 Both reactions presumably take
place by Nazarov cyclization of the divinylketone intermediate,
but in the latter reaction, the slow delivery of branched alkenes
generated in situ in a steady-state concentration may be responsi-
ble for the increased yield. Thus, reaction of crotonyl chloride and
synthesis of cis-2-ethyl-3-methylcyclopentanone via catalytic
hydrogenation of 2-ethyl-3-methylcyclopent-2-enone, Paquette
and Barth screened different conditions (Pd-C or Rh-C as catalyst,
dichloromethane, ethanol, or petroleum ether as solvent, with or
without base) and their best result, an 18:1 mixture of cis and trans
isomer, was obtained with 5% Rh-C as catalyst, petroleum ether as
2 3
solvent, and with Na CO present to minimize acid-catalyzed epi-
merization of the saturated ketone product. When Helquist and
Kazmierczak applied Paquette’s conditions to 2-isopropyl-3-meth-
ylcyclopent-2-enone, excellent cis selectivity was also achieved. In
our first attempts at hydrogenation of 4 under these conditions, the
reaction was very slow, which we initially thought to be a result of
the added steric hindrance from the 4,4-dimethyl group in our
molecule. As expected, the reaction was more rapid with a higher
catalyst loading, but this was not desirable given the high cost of
the catalyst. With further experimentation, we determined that
the purity of enone 4 was crucial to the rate of hydrogenation.
Thus, hydrogenation of 4 purified by Kugelrohr distillation (ꢀ97%
pure by GC) took several days to complete, whereas under identical
conditions, hydrogenation of 4 purified by flash chromatography
2
3
-methylbutane in the presence of AlCl gave 4 in respectable iso-
9
lated yield (55%).
With a straightforward and readily scalable synthesis of 4 in
hand, we turned our attention to the key hydrogenation step. Be-
cause the general rule is that the rate of hydrogenation of a double
bond decreases as the number and bulk of the substituents in its
vicinity increase, hindered tetrasubstituted alkenes have proven
to be difficult to reduce cleanly.10 A literature search showed that
for
a,b-unsaturated, tetrasubstituted cyclopentenones, the distri-
bution of cis and trans isomers was highly dependent upon the
hydrogenation conditions, a direct result of the sensitivity of the
cis isomer to epimerization.1
1–14
Thus, ratios of the two stereoiso-
1
5,16
mers varied widely depending on the catalyst, the polarity of the
(GC purity >99.5%) was complete in several hours.
Under these

4
226
Y. Zou, J. G. Millar / Tetrahedron Letters 52 (2011) 4224–4226
optimized conditions,17 hydrogenation proceeded in good yield
3 2 2
(4.0 g, 30 mmol) in CH Cl
was added to a stirred suspension of AlCl
°C. After 30 min of stirring, 2-methylbutane (1.8 mL, 15 mmol) in CH
10 mL) was slowly added. The solution was refluxed (with a dry ice-acetone
condenser) for 4 h, and then cooled to room temperature, poured on ice, and
extracted with ether. The combined organic layer was vigorously stirred with
(15 mL) at
0
(
2
Cl
2
(
81%) with good stereoselectivity (95:5 ratio of the desired cis-iso-
18
mer 3a to the undesired trans-isomer 3b).
With this key intermediate in hand, the rest of the synthesis
was straightforward, largely following the steps in our previous
3 2 4
saturated NaHCO for 1 h, washed with brine, dried over Na SO , and
concentrated. The crude product was purified by flash chromatography
3
synthesis. Thus, ketone 3a was cleanly converted into methylene
1
(
hexanes/ether, 5:1) to give 1.14 g (55%) of 4 as a pale yellow oil. The
H
NMR spectrum was in agreement with that reported (Ref. 8). 13
C
NMR
tetramethylcyclopentane 5 by treatment with the Zn–CH
2
Br
2
–TiCl
4
(
(
100 MHz, CDCl
2CH ), 11.9 (CH
3
) d 208.2 (C), 177.1 (C), 134.8 (C), 50.6 (CH
), 8.2 (CH ).
2
), 41.3 (C), 26.9
reagent, with no epimerization at C-2. Hydroboration followed by
oxidation gave alcohol 6 with the wrong configuration at carbon
3
3
3
1
0. Rylander, P. N. Catalytic hydrogenation over platinum metals; Academic Press:
1
. This center was readily inverted by the simple and efficient
New York, 1967. pp 91–92, 98.
1
1
1. Cooke, E.; Paradellis, T. C.; Edward, J. T. Can. J. Chem. 1982, 60, 29–34.
2. Lin, C.-H.; Aristoff, P. A.; Johnson, P. D.; McGrath, J. P.; Timko, J. M.; Robert, A. J.
Org. Chem. 1987, 52, 5594–5601.
13. Barth, W.; Paquette, L. A. J. Org. Chem. 1985, 50, 2438–2443.
4. Kazmierczak, F.; Helquist, P. J. Org. Chem. 1989, 54, 3988–3992.
15. On a 5.0 mmol scale, with 4 purified by Kugelrohr distillation, hydrogenation
took several days to complete (167 h, with 20 wt % catalyst; 73 h, with 30 wt %
catalyst). With 4 purified by flash chromatography to 99.5% purity by GC,
hydrogenation was complete in 3 h with 10 wt % catalyst. When 4 was slightly
less pure, the reaction was much slower (e.g., only about 50% complete
overnight). In such cases, an additional 5 wt % catalyst was added and the
reaction was complete in 2 h.
three-step sequence of oxidation to aldehyde 7, base-catalyzed
epimerization to aldehyde 8, and reduction to alcohol 9 with the
correct relative configuration.19 The synthesis was completed by
acetylation with acetyl chloride and pyridine in ether. Overall, this
1
2
0
improved route provided the obscure mealybug pheromone 1 in
5% yield from ketone 4.
3
Acknowledgment
We thank Trécé, Inc. for financial support of this work.
References and notes
16. The cis to trans ratio did not decrease after long reaction time under our
reaction conditions.
1
7. We also tried different stirring rates, which affect hydrogen availability to the
catalyst, and ran the reaction at lower temperature (0 °C), with no discernable
effects on the cis/trans selectivity.
1
.
.
Millar, J. G.; Midland, S. L.; McElfresh, J. S.; Daane, K. M. J. Chem. Ecol. 2005, 31,
999–3005.
Bentley, W. J.; Zalom, F. G.; Granett, J.; Smith, R. J.; Varela, L. G.; Purcell, A. H.
IPM pest management guidelines grape, insects and mites; University of
California, Univ. Calif., Agric. Nat. Resource 3448: Oakland, CA, 2004.
Millar, J. G.; Midland, S. L. Tetrahedron Lett. 2007, 48, 6377–6379.
18. 2,3,4,4-Tetramethyl cyclopentanone (3). A mixture of 4 (0.69 g, 5.0 mmol), 5%
Rh-C (0.069 g, 10 wt %), and powdered Na CO (1.59 g, 15.0 mmol) in pentane
2
2
3
2
(20 mL) was stirred vigorously under hydrogen until the reaction was
complete (GC), then the mixture was filtered through Celite. The filtrate was
concentrated and purified by vacuum flash chromatography (pentane/ether,
95:5) to give 0.57 g (81%) of 3 (3a:3b = 95:5) as a colorless liquid. 1H NMR
3
4
.
.
Figadère, B.; Devlin, F. J.; Millar, J. G.; Stephens, P. J. Chem. Commun. 2008,
3
(400 MHz, CDCl ) of the desired cis-isomer 3a d 2.60 (dqd, J = 7.6, 7.6, 1.2 Hz,
1
106–1108.
(a) Hashimoto, K.; Morita, A.; Kuwahara, S. J. Org. Chem. 2008, 73, 6913–6915;
b) Hajare, A. K.; Datrange, L. S.; Vyas, S.; Bhuniya, D.; Reddy, D. S. Tetrahedron
1H), 2.12–2.01 (m, 3H), 1.12 (s, 3H), 1.01 (s, 3H), 1.00 (d, J = 7.2 Hz, 3H), 0.83 (d,
J = 7.6 Hz, 3H). The 1H NMR spectrum was in agreement with that reported
(Ref. 3). MS (m/z, rel. abundance): 41 (34), 55 (18), 56 (100), 57 (21), 69 (4), 83
5
.
(
+
Lett. 2010, 51, 5291–5293.
(20), 140 (M , 8).
6.
7.
8.
9.
(a) Krause, N. Angew. Chem. Int. Ed. Engl. 1994, 33, 1764–1765; (b) Krause, N.;
Ebert, S.; Haubrich, A. Liebigs Ann./Recueil 1997, 2409–2418.
(a) Conia, J.-M.; Leriverend, M.-L. Bull. Soc. Chim. Fr. 1970, 2981–2991; (b) Mori,
K.; Sasaki, M. Tetrahedron 1980, 36, 2197–2208.
19. The only minor modification made was that aldehyde 8 was reduced to alcohol
4 4
9 with LiAlH instead of NaBH for workup simplicity.
20. (1R ,2R⁄,3S )-1-Acetoxymethyl-2,3,4.4-tetramethylcyclopentane (1). 1H NMR
⁄
⁄
3
(400 MHz, CDCl ) d 4.06 (dd, J = 10.8, 5.6 Hz, 1H), 3.99 (dd, J = 10.8, 6.8 Hz,
Morel-Fourrier, C.; Dulcère, J.-P.; Santelli, M. J. Am. Chem. Soc. 1991, 113, 8062–
1H), 2.05 (s, 3H), 1.95–1.86 (m, 2H), 1.69–1.62 (m, 2H), 1.15 (dd, J = 12.8,
9.6 Hz, 1H), 0.97 (s, 3H), 0.95 (d, J = 6.8 Hz, 3H). 0.85 (s, 3H), 0.78 (d, J = 7.6 Hz,
3H). The 1H NMR spectrum was in agreement with that reported (Ref. 3).
8
069.
2,3,4,4-Tetramethyl-cyclopent-2-enone (4). This compound was made as
described in Ref. 8. Crotonyl chloride (2.2 mL, 22.5 mmol) in CH Cl (5 mL)
2
2