Enantioselective synthesis of a mealybug pheromone with an irregular monoterpenoid skeleton

Article abstract of DOI:10.1021/jo801147c

(Chemical Equation Presented) The first enantioselective synthesis of a mealybug sex pheromone with an unprecedented monoterpenoid skeleton has been accomplished by using a highly diastereoselective conjugate addition of an organocopper reagent to a γ-alkyl-α,β-unsaturated ester intermediate as the key step.

Full text of DOI:10.1021/jo801147c

isoprene units as shown in Figure 1 and its potential use in insect
pest management prompted our efforts for its synthesis.5 In this
paper, we describe the first enantioselective synthesis of 1.
Enantioselective Synthesis of a Mealybug
Pheromone with an Irregular Monoterpenoid
Skeleton
Kosuke Hashimoto, Akira Morita, and Shigefumi Kuwahara*
Laboratory of Applied Bioorganic Chemistry, Graduate
School of Agricultural Science, Tohoku UniVersity,
Tsutsumidori-Amamiyamachi, Aoba-ku,
Sendai 981-8555, Japan
FIGURE 1. Sex pheromone of the obscure mealybug (1) with an
unprecedented monoterpenoid skeleton.
skuwahar@biochem.tohoku.ac.jp
Our retrosynthetic analysis of 1 is shown in Scheme 1. The
cyclic monoterpene 1 would be obtainable by intramolecular
alkylation of 2 followed by reduction of the ester functionality
and subsequent acetylation of the resulting alcohol intermediate.
To install the methyl substituent ꢀ to the ester group of 2, we
planned to utilize a distereoselective conjugate addition of a
methyl anion species to γ-substituted R,ꢀ-unsaturated ester 3,
which in turn could be derived from chiral oxazolidinone
derivative 4 via the Evans asymmetric alkylation and subsequent
chain elongation by the Wittig reaction. The N-acyl oxazolidi-
none 4 should be readily prepared from 5 by the orthoester
Claisen rearrangement with use of triethyl orthoacetate, followed
by installation of the (S)-phenylalaninol-derived auxiliary (XN).
ReceiVed May 26, 2008
The first enantioselective synthesis of a mealybug sex
pheromone with an unprecedented monoterpenoid skeleton
has been accomplished by using a highly diastereoselective
conjugate addition of an organocopper reagent to a γ-alkyl-
R,ꢀ-unsaturated ester intermediate as the key step.
SCHEME 1. Retrosynthetic Analysis of 1
The obscure mealybug, Pseudococcus Viburni, is an important
agricultural pest of worldwide distribution that damages a broad
range of economically important plants such as grapes, glass-
house crops, tee trees, and ornamental plants.1 The flightless
adult females release a potent sex pheromone to attract the short-
lived, nonfeeding, winged adult males for reproduction. The
sex pheromone was recently isolated by Millar and co-workers,
and the structure was deduced, mainly from its mass and NMR
spectra, to have a highly irregular monoterpenoid skeleton (1).2
The relative stereochemistry of 1 was confirmed by a nonste-
reoselective synthesis of a mixture of its four possible diaster-
eomers, followed by isolation of the natural diastereomer by
preparative GC and NOE analysis of the isolated diastereomer.2
They also achieved a diastereoselective synthesis of 1 as the
racemate,3 which, through enzymatic resolution of the synthetic
racemate coupled with vibrational circular dichroism analysis
of the isolated natural enantiomer, enabled them to determine
the absolute configuration of the pheromone as depicted in
Figure 1.4 The highly irregular monoterpenoid structure of 1
bearing the unprecedented 2′-2 and 3′-4 linkages between two
Known carboxylic acid 6, prepared from 5 by the orthoester
Claisen rearrangement and subsequent alkaline hydrolysis,6 was
converted into chiral oxazolidinone derivative 4 in a single
operation by treatment of 6 with pivaloyl chloride and Et3N in
THF followed by exposure of the resulting mixed anhydride to
(S)-4-benzyl-3-lithio-2-oxazolidinone (Scheme 2).7 The asym-
metric methylation at the considerably congested R-position of
4 proceeded uneventfully to give a 74% isolated yield of 7a as
a single stereoisomer, as judged by 1H and 13C NMR analyses.8
The methylation product 7a was reduced with NaBH4 to furnish
alcohol 7b, which was then subjected to the Swern oxidation
(5) For examples of irregular non-head-to-tail monoterpenoids, see: (a)
Croteau, R. Chem. ReV. 1987, 87, 929–954. (b) Poulter, C. D. Acc. Chem. Res.
1990, 23, 70–77. (c) Rivera, S. B.; Swedlund, B. D.; King, G. J.; Bell, R. N.;
Hussey, C. E., Jr.; Shattuck-Eidens, D. M.; Wrobel, W. M.; Peiser, G. D.; Poulter,
C. D. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 4373–4378. (d) Figade`re, B. A.;
McElfresh, J. S.; Borchardt, D.; Daane, K. M.; Bentley, W.; Millar, J. G.
Tetrahedron Lett. 2007, 48, 8434–8437.
(1) (a) Blumberg, G.; Van Driesche, R. G. Biol. Control 2001, 22, 191–199.
(b) Laflin, H. M.; Gullan, P. J.; Parrella, M. P. Proc. Entomol. Soc. Wash. 2004,
106, 475–477. (c) Culik, M. P.; Gullan, P. J. Zootaxa 2005, 964, 1–8. (d)
Abbasipour, H.; Taghavi, A.; Askarianzadeh, A. Entomol. Res. 2007, 37, A120.
(2) Millar, J. G.; Midland, S. L.; McElfresh, J. S.; Daane, K. M. J. Chem.
Ecol. 2005, 31, 2999–3005.
(6) Kleschick, W. A. J. Org. Chem. 1986, 51, 5429–5433.
(3) Millar, J. G.; Midland, S. L. Tetrahedron Lett. 2007, 48, 6377–6379.
(4) Figade`re, B.; Devlin, F. J.; Millar, J. G.; Stephens, P. J. Chem. Commun.
2008, 1106–1108.
(7) Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108, 6757–6761.
(8) Dehnhardt, C.; McDonald, M.; Lee, S.; Floss, H. G.; Mulzer, J. J. Am.
Chem. Soc. 1999, 121, 10848–10849.
10.1021/jo801147c CCC: $40.75
Published on Web 08/05/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6913–6915 6913

SCHEME 2
SCHEME 3
reomer 9 would be rationalized by postulating a Felkin-Anh-
type transition state model 10.10
Having secured the olefinic ester 9 in stereochemically
homogeneous form, we moved on to the final stage of the
synthesis (Scheme 3). Compound 9 was subjected to ozonolysis
followed by reductive workup with NaBH4 to afford alcohol
11a, which was then transformed into the corresponding triflate
11b. Intramolecular alkylation of 11b to cyclic ester 12
proceeded smoothly despite our concern that the steric conges-
tion around the electrophilic site of 11b might interfere with
the cyclization.14 Fortunately, the cyclization product was
obtained as a single stereoisomer, probably due to much greater
thermodynamic stability of 12 as compared to the corresponding
epimeric ester. When this cyclization was conducted with the
corresponding mesylate (11, X ) OMs) or iodide (11, X ) I)
as the cyclization precursor, only the formation of complex
mixtures was observed. Finally, reduction of the ester 12 with
DIBAL and acetylation of the resulting alcohol 13a gave the
target molecule 1. The enantiomeric excess of 13a was estimated
conditions to afford an aldehyde intermediate. The resulting
aldehyde was, however, so volatile that the isolated yield of
the product was very poor. This problem was readily circum-
vented by conducting the two-step conversion of 7b into 8
(Swern oxidation followed by Wittig olefination) in one pot
without isolating the aldehyde intermediate.9 The E-olefinic ester
8 was thus obtained in a satisfactory yield of 83% in geo-
metrically pure form after chromatographic purification. For the
diasteroselective introduction of a methyl group at the ꢀ-position
of the enoate 8 to form 9 bearing erythro vicinal methyl groups,
we examined the conjugate addition of organocopper reagents.
In general, the conjugate addition of organocopper reagents to
R,ꢀ-unsaturated esters is known to be sluggish as compared to
the addition to R,ꢀ-unsaturated ketones, resulting in the recovery
of starting enoates or the formation of desired products in low
yields.10 However, it has also been reported that some Lewis
acidic additives such as BF3 ·OEt2 and TMSCl can activate the
conjugate reaction,10,11 and moreover, when the Lewis acid-
promoted reactions are applied to (E)-γ-alkyl-R,ꢀ-unsaturated
esters like 8, the corresponding ꢀ,γ-erythro conjugate adducts
like 9 predominate.10,12 According to these precedents, we first
attempted the following three reaction conditions for the
conversion of 8 into 9: (1) Me2CuLi·LiI/BF3 ·OEt2 in ether,
(2) Me2CuLi·LiBr·Me2S/TMSCl in THF, and (3) Me2CuLi·
LiBr·Me2S/TMSCl in THF/HMPA. Contrary to our expectation,
none of these conditions were successful, resulting only in the
recovery of the starting ester 8. Faced with these disappointing
outcomes, we next tried Yamamoto’s method using Me2CuLi/
TMSCl in CH2Cl2, which was reported as the most powerful
reagent system for the methylation of sterically congested R,ꢀ-
enoates.13 This method, which had never been applied to R,ꢀ-
unsaturated esters bearing an asymmetric center at the γ-posi-
tion, brought about dramatic success, furnishing the desired
conjugate adduct 9 in 81% yield with complete diastereoselec-
1
to be ca. 98% by analyzing the H NMR spectra of the (R)-
and (S)-MTPA esters (13b) derived from 13a.15 The H and
1
13C NMR spectra of the synthetic product 1 were identical with
those of the natural pheromone, and the specific rotation of 1
{[R]27D +15.1 (c 1.50, CDCl3)} was equal in sign to that of an
authentic sample of the natural pheromone {[R]D +9.1 (c 0.4,
CDCl3)},4 although the magnitude of the specific rotation of
the synthetic sample 1 was considerably larger than the reported
value for the authentic sample.
In conclusion, the first enantioselective synthesis of the sex
pheromone of the obscure mealybug (1) was accomplished in
10 steps with an overall yield of 13% from known carboxylic
acid 6, using the Evans asymmetric alkylation of chiral
oxazolidinone derivative 4, the highly diastereoselective con-
jugate addition of lithium dimethylcuprate to γ-methyl-R,ꢀ-
unsaturated ester 8, and the intramolecular cyclization of triflate
11b as the key steps.
Experimental Section
1
tivity; no diastereomer was detected by the H and 13C NMR
(S)-4-Benzyl-3-(2,3,3-trimethyl-4-pentenoyl)-2-oxazolidinone (7a).
To a stirred solution of NaHMDS (1.07 M in THF, 45.8 mL, 49.0
mmol) in THF (220 mL) was added dropwise a solution of 4 (11.8
g, 41.0 mmol) in THF (100 mL) at -78 °C. After 1 h, MeI (5.1
mL, 82.0 mmol) was added, and the resulting mixture was gradually
analyses of the product. The selective formation of the diaste-
(9) Ireland, R. E.; Norbeck, D. W. J. Org. Chem. 1985, 50, 2198–2200.
(10) (a) Yamamoto, K.; Ogura, H.; Jukuta, J.; Inoue, H.; Hamada, K.;
Sugiyama, Y.; Yamada, S. J. Org. Chem. 1998, 63, 4449–4458. (b) Chounan,
Y.; Ono, Y.; Nishii, S.; Kitahara, H.; Ito, S.; Yamamoto, Y. Tetrahedron 2000,
56, 2821–2831.
(11) Yamamoto, Y.; Yamamoto, S.; Yatagai, H.; Ishihara, Y.; Maruyama,
K. J. Org. Chem. 1982, 47, 119–126, and references cited therein.
(12) Yamamoto, Y.; Nishii, S.; Ibuka, T. J. Chem. Soc., Chem. Commun.
1987, 1572–1573.
(14) For a similar cyclization, see: Liu, D.; Hong, S.; Corey, E. J. J. Am.
Chem. Soc. 2006, 128, 8160–8161.
(15) The 1H NMR signals for the two protons on the oxygen-bearing
methylene carbon of the (R)-MTPA ester [δ 4.26 (1H, dd, J ) 10.5, 6.8 Hz),
4.29 (1H, dd, J ) 10.5, 5.9 Hz)] were clearly distinguishable from those of the
(S)-MTPA ester [δ 4.19 (1H, dd, J ) 10.5, 7.1 Hz), 4.34 (1H, dd, J ) 10.5, 5.6
Hz)].
(13) Asao, N.; Lee, S.; Yamamoto, Y. Tetrahedron Lett. 2003, 44, 4265–
4266.
6914 J. Org. Chem. Vol. 73, No. 17, 2008

warmed to 0 °C. The mixture was poured into aq NH4Cl, acidified
to pH 2.0 with 1 M aq sulfuric acid, and extracted with EtOAc.
The extract was successively washed with saturated aq NaHCO3,
saturated aq Na2S2O3, and brine, dried (MgSO4), and concentrated
in vacuo. The residue was purified by silica gel chromatography
(hexane/EtOAc ) 10:1) to give 9.09 g (74%) of 7a as a white
solid, which was recrystallized from hexane/EtOAc to afford white
needles; mp 77.8-78.0 °C; [R]24D +86.3 (c 1.30, CHCl3); IR νmax
3087 (w), 3028 (w), 1761 (s), 1696 (s), 1207 (m); 1H NMR δ 1.10
(3H, s), 1.11 (3H, s), 1.17 (3H, d, J ) 7.0 Hz), 2.75 (1H, dd, J )
13.7, 9.8 Hz), 3.26 (1H, dd, J ) 13.7, 3.0 Hz), 4.00 (1H, q, J )
7.0 Hz), 4.11-4.16 (2H, m), 4.61-4.67 (1H, m), 4.98 (1H, d, J )
17.3 Hz), 4.99 (1H, d, J ) 11.0 Hz), 5.95 (1H, dd, J ) 17.3, 11.0
Hz), 7.22 (2H, d, J ) 7.3 Hz), 7.27 (1H, t, J ) 7.3 Hz), 7.33 (2H,
t, J ) 7.3 Hz); 13C NMR δ 12.9, 23.5, 24.6, 37.8, 39.5, 44.1, 55.5,
65.7, 111.9, 127.3, 128.9 (2C), 129.4 (2C), 135.3, 145.9, 153.4,
175.9; HRMS (FAB) m/z calcd for C18H24NO3 ([M + H]+)
302.1756, found 302.1754.
O3 by a stream of O2, NaBH4 (58.6 mg, 1.55 mmol) was added at
-78 °C, and the resulting mixture was gradually warmed to room
temperature and stirred for 2 h. The mixture was quenched with
saturated aq NH4Cl and extracted with ether. The extract was dried
(Na2SO4) and concentrated in vacuo. The residue was purified by
silica gel chromatography (hexane/EtOAc ) 10:1) to give 84.2 mg
(80%) of 11a as a colorless oil; [R]22 +4.7 (c 1.00, CHCl3); IR
D
1
ν
max 3457 (m), 1737 (s), 1279 (m), 1172 (m), 1040 (m); H NMR
δ 0.80 (3H, d, J ) 7.5 Hz), 0.86 (3H, s), 0.94 (3H, s), 0.96 (3H,
d, J ) 7.0 Hz), 1.27-1.36 (1H, br s, OH), 1.47 (1H, dq, J ) 1.0,
7.5 Hz), 1.97 (1 H, dd, J ) 15.0, 11.5 Hz), 2.28-2.37 (1H, m),
2.45 (1H, dd, J ) 15.0, 1.5 Hz), 3.39 (1H, d, J ) 10.7 Hz), 3.43
(1H, d, J ) 10.7 Hz), 3.67 (3H, s); 13C NMR δ 8.8, 21.6, 22.1,
22.3, 29.3, 37.5, 38.4, 42.5, 51.4, 70.7, 174.5; HRMS (FAB) m/z
calcd for C11H23O3 ([M + H]+) 203.1647, found 203.1650.
Methyl (1S,2S,3R)-2,3,4,4-Tetramethylcyclopentanecarboxylate
(12). To a stirred solution of 11a (0.338 g, 1.67 mmol) in CH2Cl2
(17 mL) was added 2,6-lutidine (0.21 mL, 1.84 mmol) at -50 °C.
After 15 min, Tf2O (0.31 mL, 1.84 mmol) was added, and the
resulting mixture was gradually warmed to 0 °C. The reaction
mixture was washed quickly with 0.1 M aq HCl, dried (MgSO4),
and concentrated in vacuo to give crude 11b, which was then taken
up in THF (17 mL). To the solution was added dropwise a solution
of NaHMDS (1.07 M in THF, 1.87 mL, 2.00 mmol) at -78 °C.
The reaction mixture was gradually warmed to 0 °C and then poured
into saturated aq NH4Cl. The mixture was extracted with ether,
and the extract was successively washed with water and brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified by
silica gel chromatography (pentane/ether ) 200:1) to give 0.221 g
Methyl (R)-4,5,5-Trimethyl-2,6-heptadienoate (8). To a stirred
solution of (COCl)2 (0.510 mL, 5.98 mmol) in CH2Cl2 (13.6 mL)
was added a solution of DMSO (0.85 mL, 12 mmol) in CH2Cl2
(21 mL) at -78 °C. After 15 min, a solution of 7b (0.697 g, 5.43
mmol) in CH2Cl2 (10 mL) was added, and the resulting mixture
was stirred for 1 h at -78 °C. To the mixture was added dropwise
Et3N (3.8 mL, 27 mmol), and the mixture was gradually warmed
to -20 °C then stirred overnight. Ph3PdCHCO2Me (9.1 g, 27.2
mmol) was then added, and the reaction mixture was gradually
warmed to room temperature, then refluxed overnight. The mixture
was washed with 0.1 M HCl (2×), saturated aq NaHCO3, water,
and brine, dried (MgSO4), and concentrated in vacuo. The residue
was purified by silica gel chromatography (hexane/EtOAc ) 50:1)
to give 0.831 g (84%) of 8 as a colorless oil; [R]22D +30.5 (c 1.10,
(72%) of 12 as a colorless oil; [R]21 +32.6 (c 1.30, CHCl3); IR
D
1
ν
max 1736 (s), 1260 (m), 1193 (m), 1171 (m), 1023 (m); H NMR
δ 0.78 (3H, d, J ) 7.8 Hz), 0.86 (3H, s), 0.99 (3H, d, J ) 6.8 Hz),
1.02 (3H, s), 1.64-1.69 (1H, m), 1.69-1.79 (2 H, m), 2.43-2.52
(2H, m), 3.68 (3H, s); 13C NMR δ 10.2, 17.0, 23.7, 29.4, 40.2,
41.8, 43.9, 46.2, 50.0, 51.5, 177.3; HRMS (EI) m/z calcd for
C11H20O2 (M+) 184.1463, found 184.1460.
1
CHCl3); IR νmax 1728 (vs), 1654 (m), 1270 (s); H NMR δ 0.98
(3H, d, J ) 4.9 Hz), 0.99 (6H, s), 2.14-2.21 (1H, m), 3.73 (3H,
s), 4.96 (1H, dd, J ) 17.5, 1.5 Hz), 5.01 (1H, dd, J ) 11.0, 1.5
Hz), 5.77 (1 H, dd, J ) 17.5, 11.0 Hz), 5.79 (1H, dd, J ) 15.5, 1.0
Hz), 6.93 (1H, dd, J ) 15.5, 9.3 Hz); 13C NMR δ 14.6, 23.6, 25.2,
39.2, 46.1, 51.3, 112.1, 120.8, 146.0, 152.1, 167.0; HRMS (FAB)
m/z calcd for C11H19O2 ([M + H]+) 183.1385, found 183.1390.
Methyl (3R,4R)-3,4,5,5-Tetramethyl-6-heptenoate (9). To a stirred
suspension of CuI (13.5 g, 71.0 mmol) in ether (70 mL) was added
MeLi (1.09 M in ether, 129 mL, 141 mmol) at 0 °C, and the
resulting mixture was stirred for 1 h. The solvent was removed
under reduced pressure at 0 °C, and CH2Cl2 (50 mL) was added to
the residue. The mixture was stirred for 10 min at 0 °C, and then
the solvent was removed again under reduced pressure at 0 °C. To
the residue was added precooled CH2Cl2 (180 mL), and the mixture
was cooled to -78 °C. To the mixture were successively added
TMSCl (9.0 mL, 71.0 mmol) and a solution of 8 (1.29 g, 7.10
mmol) in CH2Cl2 (14 mL). The mixture was gradually warmed to
0 °C, then stirred for 5 days. The mixture was quenched with a
mixture of saturated aq NH4Cl and 28% aq NH3 (1:1) and extracted
with ether. The extract was washed with water and brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
silica gel chromatography (hexane/EtOAc ) 20:1) to give 1.13 g
(81%) of 9 as a colorless oil; [R]23D -5.5 (c 1.20, CHCl3); IR νmax
[(1S,2S,3R)-2,3,4,4-Tetramethylcyclopentyl]methyl Acetate (1).
To a stirred solution of 13a (31.3 mg, 0.200 mmol) in pyridine
(0.4 mL) was added dropwise Ac2O (0.030 mL, 0.317 mmol) at 0
°C. The mixture was gradually warmed to room temperature and
stirred overnight. The mixture was poured into saturated aq NH4Cl
and extracted with pentane. The organic layer was successively
washed with 0.5 M HCl (2×), water, and brine, dried (MgSO4),
and concentrated in vacuo. The residue was purified by silica gel
chromatography (pentane/ether ) 100:1) to give 33.9 mg (85%)
of 1 as a colorless oil; [R]27D +15.1 (c 1.50, CDCl3); IR νmax 1743
1
(vs), 1242 (s), 1043 (m); H NMR δ 0.78 (3H, d, J ) 7.3 Hz),
0.85 (3H, s), 0.95 (3H, d, J ) 6.8 Hz), 0.97 (3H, s), 1.15 (1H, dd,
J ) 12.7, 9.3 Hz), 1.65 (1H, qui, J ) 7.3 Hz), 1.67 (1H, dd, J )
12.7, 7.3 Hz), 1.87-1.96 (2H, m), 2.05 (3H, s), 3.99 (1H, dd, J )
10.7, 6.3 Hz), 4.06 (1H, dd, J ) 10.7, 5.4 Hz); 13C NMR δ 10.2,
17.1, 21.0, 23.8, 29.7, 39.1, 41.2, 44.4, 44.5, 46.2, 68.7, 171.4;
HRMS (EI) m/z calcd for C12H22O2 (M+) 198.1620, found 198.1629.
Acknowledgment. We are grateful to Prof. Millar (University
of California, Riverside) for providing the NMR spectra of the
mealybug pheromone. This work was financially supported, in
part, by a Grant-in-Aid for Scientific Research (B) from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan (No. 19380065).
1
3083 (w), 1740 (s), 1278 (m), 1171 (m); H NMR δ 0.78 (3H, d,
J ) 7.0 Hz), 0.92 (3H, d, J ) 7.0 Hz), 0.99 (3H, s), 1.03 (3H, s),
1.30 (1H, dq, J ) 1.5, 7.0 Hz), 1.88 (1 H, dd, J ) 11.5, 15.3 Hz),
2.29-2.37 (1H, m), 2.45 (1H, dd, J ) 15.3, 2.5 Hz), 3.66 (3H, s),
4.95 (1H, dd, J ) 17.5, 1.5 Hz), 4.96 (1H, dd, J ) 11.0, 1.5 Hz),
5.83 (1H, dd, J ) 17.5, 11.0 Hz); 13C NMR δ 9.0, 21.5, 25.1, 25.6,
29.7, 37.1, 40.1, 47.1, 51.3, 111.2, 147.1, 174.4; HRMS (EI) m/z
calcd for C12H22O2 (M+) 198.1620, found 198.1619.
Supporting Information Available: Experimental proce-
dures and NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Methyl (3R,4R)-6-Hydroxy-3,4,5,5-tetramethylhexanoate (11a).
Olefin 9 (102 mg, 0.516 mmol) in MeOH/CH2Cl2 (5:1, 5.2 mL)
was treated with ozone at -78 °C for 1 h. After removal of excess
JO801147C
J. Org. Chem. Vol. 73, No. 17, 2008 6915