Synthesis of All Stereoisomers of the Norchrysanthemic Acid Methyl Ester

Article abstract of DOI:10.1081/SCC-120028630

Syntheses of eight stereoisomers of methyl norchrysanthemate, (1R)-trans-(Z)-isomer and (1R)-trans-(E)-isomer from (1R)-trans-chrysanthemic acid, and other six isomers from (+)-3-carene, are described.

Full text of DOI:10.1081/SCC-120028630

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 6, pp. 1001–1010, 2004
Synthesis of All Stereoisomers of the
Norchrysanthemic Acid Methyl Ester
1
2
Kazuya Ujihara,1, Noritada Matsuo, and Takeshi Kitahara
*
1Agricultural Chemicals Research Laboratory, Sumitomo Chemical
Co., Ltd., Takarazuka, Hyogo, Japan
2Department of Applied Biological, Graduate School of Agricultural and
Biological Sciences, The University of Tokyo, Tokyo, Japan
ABSTRACT
Syntheses of eight stereoisomers of methyl norchrysanthemate, (1R)-
trans-(Z)-isomer and (1R)-trans-(E)-isomer from (1R)-trans-chrysan-
themic acid, and other six isomers from (þ)-3-carene, are described.
Key Words: Norchrysanthemic acid; Pyrethroids; Metofluthrin; Nor-
chrysanthemic acid.
Norchrysanthemic acid (1), or 2,2-dimethyl-3-(1-propenyl)cyclopropane-
carboxylic acid, was first synthesized by Staudinger et al. in 1924 by the
*
Correspondence: Kazuya Ujihara, Agricultural Chemicals Research Laboratory,
Sumitomo Chemical Co., Ltd., 4-2-1 Takatsukasa, Takarazuka, Hyogo 665-8555,
Japan; E-mail: ujihara@sc.sumitomo-chem.co.jp.
1001
DOI: 10.1081/SCC-120028630
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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pyrolytic decarboxylation of chrysanthemum dicarboxylic acid (2). Some
esters of norchrysanthemic acid were evaluated and revealed to be equipotent
to the corresponding chrysanthemates.[2–8] However, no commercial use of
norchrysanthemic acid was attained as an acid moiety of synthetic pyrethroids
owing to the difficulty of the synthesis. Recently one of the present authors has
invented metofluthrin[9] (5), or (2,3,5,6-tetrafluoro-4-methoxymethylphenyl)-
methyl (1R,3R)-2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylate and
profluthrin[9] (6), or (2,3,5,6-tetrafluoro-4-methylphenyl)methyl (1R,3R)-2,2-
dimethyl-3-(1-propenyl)cyclopropanecarboxylate as novel pyrethroid insecti-
cides for environmental health use. They have potent vapor action against
household insect pests and both contain norchrysanthemic acid as an acid
moiety. In order to clarify the relationship between stereochemistry and
insecticidal activity of two new synthetic pyrethroids, it is required to establish
the synthetic methods of all eight stereoisomers of norchrysanthemic acid. We
now report the stereoselective syntheses of (1R)-trans-(Z)-norchrysanthemic
methyl ester (1a) and (1R)-trans-(E)-norchrysanthemic acid methyl ester (1b)
starting from (1R)-trans-chrysanthemic acid (3), and other six isomers,
(1R)-cis-(Z)-norchrysanthemic acid methyl ester (1c), (1R)-cis-(E)-norchry-
santhemic acid methyl ester (1d), (1S)-trans-(Z)-norchrysanthemic acid
methyl ester (1e), (1S)-trans-(E)-norchrysanthemic acid methyl ester (1f),
Figure 1.

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Figure 2.
(1S)-cis-(Z)-norchrysanthemic acid methyl ester (1g) and (1S)-cis-(E)-
norchrysanthemic acid methyl ester (1h) from (þ)-3-carene (4).
We planned to introduce a 1-propenyl side chain at the C-3 position by the
Wittig-type reaction with caronaldehydic acids or the corresponding esters
7a–7d on the last step. Thus (1R)-trans-caronaldehydic methyl ester (7a,
R55Me) can be prepared by ozonolysis of (1R)-trans-chrysanthemic acid (3).
For cis-isomers, (þ)-3-carene (4) was transformed to (1R)-cis-caronaldehydic
acid (7b, R55H) and (1S)-cis-caronaldehydic acid (7c, R55H) according to
Dev’s and Ho’s procedures. (1S)-trans-isomer (7d, R55Me) could be prepared
by epimerization at the C-3 carbon atom of 7c (R55Me).
Synthesis of (1R)-trans-(Z)- and (E)-Isomers
Syntheses of these isomers were reported by Crombie[3] and Elliott[4]
staring from (1R)-trans-chrysanthemic acid by means of the Wittig reaction.
Their method were convenient to obtain (Z)-isomer (Sch. 1, step a) but not
appropriate for the synthesis of (E)-isomer because of the (Z)-selective nature
of the Wittig reaction. It was very difficult to obtain the pure (E)-isomer out of
the (E)- and (Z)-mixture. This problem was overcome by use of the Takai’s

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Scheme 1. (a) CH3CH55PPh3, THF; (b) CH3CHl2, CrCl2, THF, rt.
method (Sch. 1, step b).[11] The (E)-selectivity of the double bond was fairly
high (E : Z ¼ 89 : 11).
Synthesis of (1R)-cis-(Z)- and (E)-Isomers
These isomers were synthesized as shown in Sch. 2. (1R)-cis-Caron-
aldehydic acid hemiacetal 9b, which is the equivalent of (1R)-cis-caronalde-
hydic acid 10b, could be prepared from (þ)-3-carene (4) according to Dev’s
procedure.[12] The Wittig reaction of hemiacetal 9b under ice-cooling gave not
only desired (1R)-cis-(Z)-norchrysanthemic acid 11c but also undesired
.
Scheme 2. (a) CH3CH2PPh3 Br, t-BuOK, THF, 2408C to 08C; (b) MeOH, i-
PrOCO–N55N–CO2i-Pr, Ph3P, THF; (c) CH3CHl2, CrCl2, THF, rt.

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(1R)-trans-isomer (cis : trans ¼ 80 : 20). Fortunately, this epimerization was
prevented by performing the reaction at the lower temperature. Thus the
Wittig reaction of hemiacetal 9b with CH3CH55PPh3 at 2408C gave (1R)-cis-
(Z)-norchrysanthemic acid 11c free from the trans-isomer. The acid was
converted to the corresponding methyl ester 1c using the Mitsunobu reaction.
(1R)-cis-(E)-isomer was prepared using the same procedure as the (1R)-trans-
(E)-isomer via the Takai’s method. However, the reaction resulted in the lower
stereoselectivity (E : Z ¼ 72 : 28) because of the more steric hindrance of the
(E)-isomer with the ester group.
Synthesis of (1S)-cis-(Z)-, (1S)-cis-(E)-, (1S)-trans-(Z)-, and
(1S)-trans-(E)-isomers
These isomers were synthesized as shown in Sch. 3. According to the
Lajunen’s procedure, (þ)-3-carene was converted to a mixture of allyl
Scheme 3. (a) t-BuOK, DMSO, 1008C; (b) PCC, CH2Cl2; (c) MeOH, i-PrOCO-
N55N-CO2 i-Pr, Ph3P, THF; (d) MeONa, MeOH.

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alcohols 12 and 13 (9 : 1) in totally 60% yield.[14] The mixture was subjected
to a basic condition to obtain the pure allyl alcohol 13 via the isomerization of
the double bond. Subsequently the alcohol 13 was oxidized with PCC to give
2-caren-4-one 14. The carenone was converted to (1S)-cis-caronaldehydic
acid hemiacetal 9d, which is an antipode of 9b, according to Ho’s
procedure.[13] The (1S)-hemiacetal was transformed to the (1S)-cis-(Z)- and
(1S)-cis-(E)-isomers according to the same procedures as (1R)-cis-isomers.
For trans-isomers, the methyl ester 8d was epimerized at the C-3 position to
give the (1S)-trans-isomer by sodium methoxide. (1S)-trans-(Z)- and (1S)-
trans-(E)-norchrysanthemic acid methyl esters were obtained as the same
manner described in Sch. 1.
In conclusion, all of the eight isomers of norchrysanthemic acid methyl
esters were synthesized in stereoselective manner from (1R)-trans-
chrysanthemic acid or (þ)-3-carene. All stereoisomers of metofluthrin and
profluthrin were synthesized in our laboratory. Their relationship between
stereochemistry and insecticidal activity will be published elsewhere.
EXPERIMENTAL
(1R)-trans-caronaldehydic acid methyl ester was prepared by the
Crombie’s method.[3] (1R)-cis-caronaldehydic acid hemiacetal was prepared
by the Martel’s method.[15] (1S)-cis-caronaldehydic acid hemiacetal was
prepared by the Ho’s method.[13] A mixture of (1R,3RS,6S)-7,7-dimethyl-4-
methylenebicyclo[4.1.0]heptan-3-ol
and
(1R,3R,6R)-4,7,7-trimethylbi-
cyclo[4.1.0]hept-4-en-3-ol was prepared by the Lajunen’s method.[14] E/Z
ratios were determined by GC-EIMS spectra. 1H-NMR spectra were recorded
in JEOL JNM-AL400 NMR spectrum meter with tetramethylsilane as an
internal standard. IR spectra were recorded in Hitachi 270–30 infrared
spectrometer. GC-EIMS spectra were recorded in Agilent 6890/5973 System
(Agilent 19091S-433 HP-5MS 0.25 mm  30 m  0.25 mm; 3008C; flow rate
1.0 mL/min).
(1R,3R)-2,2-Dimethyl-3-((1Z)-
propenyl)cyclopropanecarboxylic acid methyl ester (1a)
This compound was prepared in 92% from (1R)-trans-caronaldehydic
acid methyl ester according to the known procedure[16] to give a 90 : 10
mixture of 1a and 1b. [a]D24 þ 6.58 (c ¼ 2.4, CHCl3). NMR dH (CDCl3): 1.14
(s, 3H), 1.27 (s, 3H), 1.45 (d, 1H), 2.75 (dd, 1H), 3.68 (s, 3H), 5.05–5.18
(m, 1H), 5.52–5.68 (m, 1H). IR nmax (neat): 2990, 1740, 1440, 1230,
1170 cm21. EIMS m/z: 168 (Mþ, 13), 153 (8), 109 (100).

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(1R,3R)-2,2-Dimethyl-3-((1E)-
propenyl)cyclopropanecarboxylic Acid Methyl Ester (1b)
To a stirring mixture of chromium(II) chloride (0.85 g, 6.9 mmol) in
tetrahydrofuran (20 ml) was added a mixture of (1R)-trans-caronaldehydic
acid methyl ester (0.16 g, 1.0 mmol) and 1,1-diiodomethane (0.60 g,
2.1 mmol) in tetrahydrofuran (5 mL). The mixture was stirred for 15 hr. It
was filtered on a Celite pad, the filtrate was poured onto water and then
extracted with t-butyl methyl ether, washed with brine, dried over sodium
sulfate and concentrated under reduced pressure. The residue was chromato-
graphed on silica gel with t-butyl methyl ether þ hexane (1 þ 100 by volume)
as eluant to give a 93 : 7 mixture of the methyl esters 1b and 1a (0.11 g, 63%)
as a colorless oil. [a]D24 þ 318 (c ¼ 2.4, CHCl3). NMR dH (CDCl3): 1.14
(3H, s), 1.24 (3H, s), 1.48 (1H, d, J ¼ 5.3), 1.68 (3H, dd, J ¼ 6.5, 1.6), 2.00
(1H, dd, J ¼ 5.3, 8.2), 3.66 (3H, s), 5.24 (1H, ddq, J ¼ 15.2, 8.2, 3.1), 5.61
(1H, dq, J ¼ 15.2, 6.5). IR nmax (neat): 2990, 1740, 1450, 1220, 1180 cm21
EIMS m/z: 168 (Mþ, 14), 153 (10), 109 (100).
.
(1R,3S)-2,2-Dimethyl-3-((1Z)-
propenyl)cyclopropanecarboxylic Acid Methyl Ester (1c)
A solution of potassium tert-butoxide (42 g, 380 mmol) in tetrahydrofuran
(500 mL) was dropped to a stirring mixture of (ethyl)triphenylphosphonium
bromide (150 g, 400 mmol) and tetrahydrofuran (500 mL) over 30 min under
nitrogen atmosphere at 2408C for 15 min. (1R)-cis-Caronaldehydic acid
hemiacetal (25.0 g, 176 mmol) was dropped to the mixture over 30 min at the
same temperature and was left to stand at room temperature for 2 hr. The
reaction mixture was poured onto 10% aqueous hydrochloric acid and then
extracted with t-butyl methyl ether, washed with brine, dried over magnesium
sulfate to give the crude acid. The acid was diluted with tetrahydrofuran
(500 mL) and methanol (50 mL), and triphenylphosphine (46 g, 176 mmol)
was added to the solution. To the mixture was added a solution of diisoporopyl
azodicarboxylate (40% in toluene, 90 mL, 178 mmol) over 5 min and the
resulting mixture was stirred for 1 hr at 08C. It was then concentrated under
reduced pressure, and the residue was chromatographed on silica gel with
ethyl acetate þ hexane (1 þ 4 by volume) as eluant to give a 93 : 7 mixture
of the methyl esters 1c and 1d (23.7 g, 80%) as a colorless oil. [a]2D4 þ 978
(c ¼ 2.5, CHCl3). NMR dH (CDCl3): 1.22 (3H, s), 1.26 (3H, s), 1.70 (3H, d,
J ¼ 5.1), 1.71 (1H, d, J ¼ 8.3), 1.98 (1H, t, J ¼ 8.3), 3.63 (3H, s), 5.6–5.7
(2H, m). IR nmax (neat): 2990, 1740, 1450, 1180 cm21. EIMS m/z: 168 (Mþ,
14), 153 (10), 109 (100).

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(1R,3S)-2,2-Dimethyl-3-((1E)-
propenyl)cyclopropanecarboxylic Acid Methyl Ester (1d)
A solution of diisoporopyl azodicarboxylate (40% in toluene, 105 mL,
208 mmol) was dropped to a stirring mixture of (1R)-cis-caronaldehydic acid
hemiacetal (28 g, 200 mmol), methanol (50 mL) and triphenylphosphine (55 g,
210 mmol) in tetrahydrofuran (500 mL) over 5 min at 08C. After stirring for
2 hr, the mixture was concentrated under reduced pressure. The residue was
chromatographed on silica gel with ethyl acetate þ hexane (1 þ 4 by volume)
as eluant to give methyl ester 8b (17.8 g, 57%). The methyl ester was mixed
with 1,1-diiodoethane (41 g, 145 mmol) and tetrahydrofuran (400 mL), then
the resulting solution was added to a stirring mixture of chromium(II) chloride
(48 g, 391 mmol) in tetrahydrofuran (500 mL) under nitrogen atmosphere. The
stirring was continued for 12 hr. It was filtered on a celite pad, and then poured
into water and extracted with t-butyl methyl ether. The extract was washed
with brine, dried over sodium sulfate and concentrated under reduced pres-
sure. The residue was chromatographed on silica gel with ethyl acetate þ
hexane (1 þ 20 by volume) as eluant to give a 72 : 28 mixture of the methyl
esters 1d and 1c (10.4 g, 64%) as a colorless oil. [a]2D4 þ 558 (c ¼ 2.5, CHCl3).
NMR dH (CDCl3): 1.14 (3H,s), 1.27 (3H, s), 1.63 (1H, d, J ¼ 8.8), 1.80 (1H, t,
J ¼ 9.0), 3.63 (3H, s), 5.60–5.66 (1H, m), 5.75 (1H, ddd, J ¼ 13.8, 8.6, 0.8).
IR nmax (neat): 3000, 1740, 1450, 1190, 1160 cm21. EIMS m/z: 168 (Mþ, 14),
153 (10), 109 (100).
(1E,6R)-4,7,7-Trimethyl-bicyclo[4.1.0]hept-4-en-3-one (14)
Potassium tert-butoxide (0.25 g, 2.2 mmol) was added to a 9 : 1 mixture
of (1R,3RS,6S)-7,7-dimethyl-4-methylenebicyclo[4.1.0]heptan-3-ol 6 and
(1R,3R,6R)-4,7,7-trimethylbicyclo[4.1.0]hept-4-en-3-ol 7 (302 mg, 2.0 mmol)
in dimethylsulfoxide (3 mL), and the mixture was heated to 1208C for 3 hr. It
was poured onto water and then extracted with t-butyl methyl ether, washed
with brine, dried over sodium sulfate and concentrated under reduced pressure
to give a crude (1R,3RS,6R)-4,7,7-trimethylbicyclo[4.1.0]hept-4-en-3-ol 13,
which was diluted with dichloromethane (20 mL) and then cooled to 08C.
Pyridinium chlorochromate (0.5 g, 2.5 mmol) was added to the mixture. The
resulting mixture was stirred for 2 hr. It was passed through a Florisil pad, and
the filtrate was concentrated under reduced pressure. The residue was
chromatographed on silica gel with ethyl acetate þ hexane (1 þ 20 by
volume) as eluant to give enone 14 (142 mg, 47%). The enone was identified
by 1H-NMR spectrum.[17]

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(1S,3R)-3-Formyl-2,2-dimethylcyclopropanecarboxylic Acid
Methyl Ester (8c)
A 28% solution of sodium methoxide in methanol (0.5 mL) was added to
(1S, 3S)-3-formyl-2,2-dimethylcyclopropanecarboxylic acid methyl ester 8d
(156 mg, 1.0 mmol) at 08C and stood for 5 min. It was poured onto saturated
aqueous ammonium chloride and then extracted with t-butyl methyl ether,
washed with brine, dried over sodium sulfate and concentrated under reduced
pressure. The residue was chromatographed on silica gel with ethyl
acetate þ hexane (1 þ 4 by volume) as eluant to give the methyl ester 8c
(128 mg, 82%). [a]2D4 2118 (c ¼ 2.6, CHCl3). NMR dH (CDCl3): 1.31 (1H, s),
1.35 (1H, s), 2.45–2.50 (2H, m), 3.71 (1H, s), 9.59 (1H, d, J ¼ 2.0).
The following compounds were prepared by the same procedures with
their antipodes.
(1S,3S)-2,2-Dimethyl-3-((1Z)-propenyl)cyclopropanecarboxylic acid
methyl ester (1e). [a]2D4 2 6.08 (c ¼ 2.4, CHCl3).
(1S,3S)-2,2-Dimethyl-3-((1E)-propenyl)cyclopropanecarboxylic acid
methyl ester (1f). [a]2D4 2 318 (c ¼ 2.4, CHCl3).
(1S,3R)-2,2-Dimethyl-3-((1Z)-propenyl)cyclopropanecarboxylic acid
methyl ester (1g). [a]2D4 2 948 (c ¼ 2.4, CHCl3).
(1S,3R)-2,2-Dimethyl-3-((1E)-propenyl)cyclopropanecarboxylic acid
methyl ester (1h). [a]2D4 2 588 (c ¼ 2.5, CHCl3).
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¨
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´ ´ ´
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Received in Japan August 18, 2003

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