Chiral synthesis of maconelliol: A novel cyclobutanoid terpene alcohol from pink hibiscus mealybug, Maconellicoccus hirsutus

Article abstract of DOI:10.1016/j.tetlet.2004.10.131

The chiral synthesis of maconelliol, [2,2-dimethyl-3-(1-methylethylidene) cyclobutyl] methanol, the alcohol moiety of the major sex pheromone component isolated from the pink hibiscus mealybug, Maconellicoccus hirsutus, is described. The compound was synthesized in six steps from alpha-pinene and the key step is dehydration of 5 to 7 through the intermediate 6. The absolute configuration of the naturally occurring maconelliol was determined as R.

Full text of DOI:10.1016/j.tetlet.2004.10.131

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9401–9403
Chiral synthesis of maconelliol: a novel cyclobutanoid
terpene alcohol from pink hibiscus mealybug,
Maconellicoccus hirsutus
*
Aijun Zhang, Junying Nie and Ashot Khrimian
USDA-ARS Chemicals Affecting Insect Behavior Laboratory, Beltsville Agriculture Research Center-West,
Beltsville, MD 20705, USA
Received 14 September 2004; revised 13 October 2004; accepted 20 October 2004
Available online 6 November 2004
Abstract—The chiral synthesis of maconelliol, [2,2-dimethyl-3-(1-methylethylidene)cyclobutyl] methanol, the alcohol moiety of the
major sex pheromone component isolated from the pink hibiscus mealybug, Maconellicoccus hirsutus, is described. The compound
was synthesized in six steps from alpha-pinene and the key step is dehydration of 5 to 7 through the intermediate 6. The absolute
configuration of the naturally occurring maconelliol was determined as R.
ꢀ
2004 Elsevier Ltd. All rights reserved.
Recently, we identified maconelliyl 2-methylbutanoate
, [(R)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]-
O
1
methyl (S)-2-methylbutanoate, as a major sex phero-
mone component of pink hibiscus mealybug, Maco-
nellicoccus hirsutus. This novel cyclobutanoid monoter-
pene derivative and lavandulyl 2-methylbutanoate, (R)-
O
HO
H
H
H
1
2
-isopropenyl-5-methylhex-4-enyl (S)-2-methylbutano-
1
2
ate, together constitute a blend, which proved to be a
potent male attractant at a concentration as low as
0
Figure 1. Structure of maconelliol 2 and major sex pheromone
component 1.
.1lg per trap in field bioassays conducted in Florida,
2
USA. The terpene alcohol moiety of 1, maconelliol 2,
contains a methylethylidene group that separates 2 from
all cyclobutane derivatives previously discovered as sem-
iochemicals, and underlines its novelty (Fig. 1). We
undertook synthesis of 2 in order to confirm the maco-
nelliolÕs structure, unambiguously determine the abso-
lute configuration of pheromone component 1, and
provide material for field bioassays. Herein we report
the conveniently chiral synthesis of maconelliol 2 in six
steps from a-pinene.
5
resultant verbenone. Treatment of 4 (91% ee) with three
equivalent of CH MgCl in THF gave the tertiary hydr-
3
oxy acid 5 as white crystals (67% yield, 80% ee). Partial
loss of chirality is due to double epimerization during
nucleophilic addition.
6
To prevent possible decarboxylation during the dehy-
dration, 5 was converted into the methyl ester using
thionyl chloride in absolute methanol. After examina-
tion of four dehydration reagents reacting with both
7
Our approach began with the preparation of the known
(
ee) by allylic oxidation
+)-(cis)-pinononic acid 4 from (1R)-(+)-a-pinene (91%
3,4
methyl ester and free acid 5, phosphorus oxychloride
8
and oxidative cleavage of
in pyridine was found to be the most appropriate.
The reaction of 5 with POCl in pyridine at room tem-
3
9
perature for 24 h yielded lactone 6 (75%) exclusively,
and no dehydrated isomer could be detected. The enan-
Keywords: Maconellicoccus hirsutus; Cyclobutanoid terpene alcohol;
Maconelliol; Sex pheromone; Chiral synthesis.
*
Corresponding author. Tel.: +1 301 504 5223; fax: +1 301 504
580; e-mail: zhanga@ba.ars.usda.gov
tiomeric purity of resulting 6 was determined by chiral
1
GC analysis to be 80% ee (Scheme 1).
0
6
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.131

9402
A. Zhang et al. / Tetrahedron Letters 45 (2004) 9401–9403
O
H
a
1R)-(+)-alpha-Pinene
O
b
O
c
H
O
O
H
(
3
4
O
H
O
O
H
d
e
O
O
H
H
O
H
H
5
6
7
H
R
f
O
H
2
Scheme 1. Preparation of the optically active maconelliol 2. Reagents and conditions: (a) O
RuCl /CCl /acetone/H O (2:2:3), rt, 24h; (c) CH MgCl/THF, reflux, 2h; (d) POCl
rt, overnight.
2
/Co(4-MeC
5
H
4
N) Br
2
2
, rt, 7d, steam dist.; (b) NaIO
4
/
3
4
2
3
3
/pyridine, rt, 24h; (e) p-TsOH/C
6
H
6
, reflux, 2d; (f) LiAlH /ether,
4
1
1
The lactone 6 was then easily converted to 7 (78%) by
2
imply recommendation or endorsement by the US
Department of Agriculture.
1
p-toluenesulfonic acid in benzene without isomeriza-
tion of the double bond. The resultant acid 7 was
1
3,14
reduced with LiAlH in ether
4
(
to furnish the (R)-
1
5
24
D
ꢀ)-maconelliol 2 {88%, 78% ee, ½aŠ ꢀ 31 (c 0.1,
References and notes
MeOH)}. Similarly, (1S)-(ꢀ)-a-pinene (85% ee) was also
24
converted into (S)-(+)-maconelliol 2 {70% ee, ½aŠ þ 23
D
c 0.1, MeOH)}. All spectral and chiral GC data of syn-
1
. Zhang, A.; Amalin, D.; Shirali, S.; Serrano, M. S.;
Franqui, R. A.; Oliver, J. E.; Klun, J. A.; Aldrich, J. R.;
Meyerdirk, D. E.; Lapointe, S. L. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 9601–9606.
(
thetic (R)-(ꢀ)-maconelliol 2 are in good accord with
1
those of the naturally occurring product.
2
3
. Zhang, A.; Amalin, D. Environ. Entomol., in press.
. Lajunen, M.; Koskinen, A. M. P. Tetrahedron Lett. 1994,
35, 4461–4464.
In conclusion, the first chiral synthesis of (ꢀ)- and (+)-
maconelliol 2 was accomplished starting from a-pinene.
The key step was dehydration of 5 to 7. It was success-
fully achieved through lactonization. All other attempts
to dehydrate 5 or its methyl ester resulted in undesired
isopropenyl isomer, which could not be efficiently sepa-
rated from 7 by column chromatography. The absolute
configuration of the naturally occurring maconelliol 2
was determined to be R. Therefore, the major sex phero-
mone component 1 from M. hirsutus has been assigned
4. King, H. C. A.; Koros, E.; Nelson, S. M. J. Chem. Soc.
1963, 5449–5457.
5
. Moglioni, A. G.; Carcia-Exposito, E.; Aguado, G. P.;
Parella, T.; Branchadell, V.; Moltrasio, G. Y.; Ortuno, R.
M. J. Org. Chem. 2000, 65, 3934–3940.
6
. Conversion of ketoacid 4 to hydroxyacid 5 without
epimerization at both stereogenic centers was essential.
We tried different conditions with purified (1R,3S) keto-
acid 4 by crystallization (>96% ee) as precursor. Reaction
of methylmagnesium chloride with (1R,3S) 4 formed an
insoluble in THF intermediate bromomagnesium salt, the
further reaction of which at the carbonyl group required
either heating or sonication at rt. As a result, partial
epimerization occurred at both centers. Methyllithium, on
the other hand, gave with (1R,3S) 4 a THF-soluble
carboxylate that reacted with an additional 1.2equiv of
MeLi at ꢀ20ꢁC, but still ꢁ15% double epimerization took
place. A solution has been found by reacting (1R,3S) 4
with 1.0equiv MeLi at ꢀ20ꢁC, followed by the addition of
1
as (R)-maconelliyl (S)-2-methylbutanoate after esterifi-
cation of (R)-(ꢀ)-maconelliol 2 with (S)-(+)- and (R)-
1
6
(
ꢀ)-2-methylbutyric acids individually.
Acknowledgements
We thank Dr. James Oliver of the Chemicals Affecting
Insect Behavior Laboratory for assistance with synthe-
ses, and Dr. Walter Schmidt and Ms. Ute Klingebiel,
NMR Facility for help in NMR spectroscopy. Mention
of trade names or commercial products is solely for the
purpose of providing specific information and does not
1
.6equiv of MeMgCl, from which (1R,3S) 5 was isolated
in 89% yield and 96% ee with virtually no change of
chirality. This methodology will be used to scale up (R)-
(ꢀ)-maconelliol 2 synthesis in the future.

A. Zhang et al. / Tetrahedron Letters 45 (2004) 9401–9403
9403
7
. Zhang, A.; Robbins, P. S.; Leal, W. S.; Linn, C. E., Jr.;
Villani, M. G.; Roelofs, W. L. J. Chem. Ecol. 1997, 23,
(75MHz, C
(@C), 47.47 (C
6
D
6
): d 179.78 (C@O), 135.57 (C
3
), 123.27
2
), 45.09 (C ), 28.15 (C –CH3-trans), 25.94
1
2
2
31–245.
(C ), 22.09 (C –CH ), 19.51 (@C–CH ), 18.52 (@C–
4
2
3-cis
3
+
8. Tomas, A. F.; Vial, C.; Ozainne, M.; Ohloff, G. Helv.
Chim. Acta 1973, 56, 238–239.
9. Properties of synthetic 6: colorless oil; optical purity:
3
CH ); EI-MS m/z (%): 168 [M] (38), 153 (38), 135 (8), 125
(21), 123 (27), 107 (59), 93 (29), 81 (100), 67 (30), 53 (16),
41 (25); HREIMS: obsd. 168.1152, calcd. for C10
168.1150.
16 2
H O
1
8
0% ee; H NMR (300MHz, CDCl ): d 1.14 (3H, s, C –
3
6
CH3-ax), 1.37 (3H, s, C
4
–CH
3
), 1.38 (3H, s, C
4
–CH
3
), 1.49
12. Screttas, C. G.; Smonou, I. C. J. Org. Chem. 1988, 53,
893–894.
(
6
3H, s, C –CH3-eq), 1.81 (1H, d, J = 10.59Hz, H7-ax), 2.10
(
1H, dd, J = 6.05, 5.67Hz, H ), 2.48 (1H, ddd, J = 10.59,
5
13. Nie, J.; Shi, D.; Daly, J. W.; Daly; Kirk, K. L. Med. Chem.
Res. 1996, 318–331.
5
.67, 5.30Hz, H7-eq), 2.63 (1H, dd, J = 6.05, 5.30Hz, H
1
);
),
1
3
C NMR (75MHz, CDCl
0.34 (C ), 50.01 (C ), 40.91 (C
3
): d 175.04 (C
2
), 82.44 (C
), 29.11 (CH ), 26.11
3
4
14. Moffett, R. B. Org. Synth. Coll. 1963, IV, 834–835.
15. Properties of synthetic 2: colorless oil; optical purity: 78%
5
1
5
6
2
D
4
1
(
CH ), 25.81 (CH ), 25.27 (C ), 25.25 (CH ); EI-MS m/z
3
ee; ½aŠ ꢀ31 (c 0.1, MeOH); H NMR (300MHz, CDCl ):
3
7
3
3
(
6
(
%): 153 (26), 125 (20), 110 (40), 109 (55), 95 (100), 83 (27),
9 (72), 68 (78), 67 (60), 55 (42), 43 (35), 41 (38); HREIMS
d 1.15 (3H, s, C
2
–CH3-cis), 1.25 (3H, s, C
2
–CH3-trans), 1.38
(1H, br, OH), 1.44 (3H, br s, @C–CH
@C–CH ), 2.08 (2H, m, H and H ), 2.58 (1H, bm, H
3.62 (1H, dd, J = 17.00, 11.40Hz, O–CH), 3.75 (1H, dd,
3
), 1.57 (3H, br s,
+
M ꢀCH
3
): obsd. 153.0911, calcd. for C
H
9 13
O
2
153.0916.
3
1
4
4
),
1
1
0. Chiral GC analysis was carried on a Hewlett Packard 6890
GC equipped with a 30m · 0.25mm ID, 0.25lm film-
thickness b-DEX 120capillary column (Supeco, Inc.,
Bellefonte, PA) in the split mode (100:1) with hydrogen as
carrier (55cm/s, either 90or 1 00 ꢁC isothermal).
1
3
J = 17.00, 11.30Hz, O–CH); C NMR (75MHz, CDCl
d 137.42 (C ), 122.43 (C@), 64.36 (C–OH), 44.11 (C
3
):
),
3
2
42.74 (C ), 28.69 (C –CH ), 27.71 (C ), 20.91 (C –CH ),
3
1
2
3
4
2
19.53 (@C–CH ), 18.48 (@C–CH ); EI-MS m/z (%): 154
3
3
1. Properties of synthetic 7: colorless oil; optical purity:
(17), 139 (18), 136 (13), 121 (59), 111 (14), 105 (12), 95
(34), 93 (28), 91 (15), 81 (100), 67 (23), 55 (14), 41 (20);
HREIMS: obsd. 154.1362, calcd. for C H O 154.1358.
1
0% ee; H NMR (300MHz, CDCl
8
3
): d 1.19 (3H, s, C
2
–
CH ), 1.37 (3H, s, C –CH ), 1.48 (3H, br s, @C–CH ),
1
m, H and H4-trans), 10.50 (1H, s, COOH); C NMR
3
2
3
3
10 18
.58 (3H, br s, @C–CH
3
), 2.55 (1H, m, H4-cis), 2.81 (2H,
16. Shirali, S.; Zhang, A. Synth. Commun. 2004, 34, 3435–
3441.
1
3
1