An improved synthesis of ethyl cis-5-iodo-trans-2-methylcyclohexanecarboxylate, a potent attractant for the Mediterranean fruit fly

Article abstract of DOI:10.1016/S0040-4020(03)00853-6

Both racemic ethyl 5-iodo-2-methylcyclohexanecarboxylate (1), known as Mediterranean fruit fly attractant ceralure B₁, and its (-)-(1R,2R,5R) enantiomer 1a were conveniently synthesized from commercially available racemic trans-6-methyl-3-cyclohexenecarboxylic acid 2 or its (1R,6R) enantiomer 2a. Key steps included an asymmetric Diels-Alder reaction using a sultam auxiliary and cyclization of the unwanted trans-5-iodo-trans-2-methylcyclohexanecarboxylic acid (8) to the intermediate lactone 7 (or 8a to 7a). The new method may circumvent chromatographic separations and seems amenable to scale-up.

Full text of DOI:10.1016/S0040-4020(03)00853-6

Tetrahedron 59 (2003) 5475–5480
An improved synthesis of ethyl cis-5-iodo-trans-2-
methylcyclohexanecarboxylate, a potent attractant for the
Mediterranean fruit fly
a
b
Ashot Khrimian,a Armenak Kh. Margaryan and Walter F. Schmidt
,
*
aUSDA-ARS, Beltsville Agricultural Research Center, PSI, CAIBL, Bldg. 007, Rm. 301, Beltsville, MD 20705, USA
bUSDA-ARS, Beltsville Agricultural Research Center, EQL, Beltsville, MD 20705, USA
Received 28 April 2003; revised 15 May 2003; accepted 27 May 2003
Abstract—Both racemic ethyl 5-iodo-2-methylcyclohexanecarboxylate (1), known as Mediterranean fruit fly attractant ceralure B1, and its
(2)-(1R,2R,5R) enantiomer 1a were conveniently synthesized from commercially available racemic trans-6-methyl-3-cyclohexene-
carboxylic acid 2 or its (1R,6R) enantiomer 2a. Key steps included an asymmetric Diels–Alder reaction using a sultam auxiliary and
cyclization of the unwanted trans-5-iodo-trans-2-methylcyclohexanecarboxylic acid (8) to the intermediate lactone 7 (or 8a to 7a). The new
method may circumvent chromatographic separations and seems amenable to scale-up. Published by Elsevier Science Ltd.
1. Introduction
and Jang have conducted syntheses of both enantiomers as
well as of racemic ceralure B1 (1) and found that (2)-
(1R,2R,5R)-1a was a much better attractant than the (þ)
enantiomer and was 30–40% more active than the racemate
1.7,8
The Mediterranean fruit fly, or medfly, Ceratitis capitata
(Wiedemann), is a serious pest of over 253 varieties of fruits
and vegetables. The establishment of this exotic pest in the
continental United States would significantly increase
pesticide use and curtail fruit and vegetable exports, a
multibillion dollar industry.1 For more than 30 years,
conventional monitoring systems have utilized traps baited
primarily with trimedlure, a synthetic male medfly attrac-
tant.2 Trimedlure is a mixture of 16 regio- and stereoisomers
of tert-butyl esters of 4(5)-chloro-2-methylcyclohexane-
carboxylate, and over one million dispensers, each contain-
ing 2 g of trimedlure, are produced and sold annually for use
as baits. An iodo analog of trimedlure, ceralure, also a
mixture of 16 regio- and stereoisomers, has been found to be
more persistent and more potent than trimedlure.3 Field tests
with individual ceralure isomers demonstrated that ethyl
cis-5-iodo-trans-2-methylcyclohexanecarboxylate (ceralure
B1, 1) is the most active component in the mixture,4 and that
ceralure B1 is two to three times more attractive than
trimedlure.5
The enantioselective synthesis, based on a chiral Diels–
Alder reaction, utilized an expensive starting material,
D-phenylalanine, and provided an overall yield of 15% from
a nine step process.7 We now report a new synthesis,
amenable to both racemic (1) and (2)-ceralure B1 (1a)
production, that uses the relatively inexpensive (2)-
bornane-10,2-sultam 3 as a chiral auxiliary for the Diels–
Alder reaction. The new route provides better yields than
existing methods, is easy to perform, and seems suitable for
scale-up.
2. Results and discussion
As in the published syntheses,6,7 our starting material was
trans-6-methyl-3-cyclohexanecarboxylic acid (2, Siglure
acid), the racemic form of which is commercially available.
To prepare (2)-Siglure acid 2a, we employed a Diels–
Alder reaction using a chiral camphor-derived sultam
auxiliary developed by Oppolzer, et al.9 (Scheme 1).
Usually, the acylation of amides, and particularly crotonyl-
ation of sultam 3, requires a base such as sodium hydride.9
Recently, we succeeded in conducting a direct acylation of
sultam 3 with acryloyl chloride catalyzed by copper(II)
chloride,10 which rendered unnecessary the customary
trimethylsilylation of the sultam prior to a copper-catalyzed
A regioselective synthesis of racemic ceralure B1 that
produced a mixture of 1 with a trans-5-iodo isomer was
described.6 A chromatographic separation of two stereo-
isomers was reported,6 but in our hands flash chromato-
graphy failed to isolate 1 quantitatively, and the use of
HPLC deemed impractical for large scale synthesis. Raw
Keywords: medfly; ceralure; attractant; synthesis; racemic; asymmetric.
*
Corresponding author. Tel.: þ1-301-504-6138; fax: þ1-301-504-6580;
e-mail: khrimiaa@ba.ars.usda.gov
0040–4020/03/$ - see front matter Published by Elsevier Science Ltd.
doi:10.1016/S0040-4020(03)00853-6

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A. Khrimian et al. / Tetrahedron 59 (2003) 5475–5480
Scheme 1. Reagents and conditions: (a) trans-CH3CHvCHCOCl/Cu2þ, reflux; (b) CH2vCHCHvCH2, EtAlCl2, CH2Cl2, 250 to 08C; (c) 1. LAH, THF, rt;
(d) PDC, DMF, rt; (e) H2O2, LiOH, THF/H2O, rt.
acylation.11 We again were able to omit the silylation step,
as (2)-bornane-10,2-sultam (3) was directly acylated with
trans-crotonyl chloride in 92% yield in the presence of
CuCl2. A Lewis acid catalyzed Diels–Alder reaction of
(2)-N-acylated sultam 4 and butadiene was performed
using a protocol developed to suppress the polymerization
of the diene by adding the radical inhibitor galvinoxyl.12
Although in our hands some polymerization still occurred,
the crystalline adduct 5 was isolated in 85% yield and
.98% de judged from the absence of the signals of the other
diastereoisomer in 1H NMR spectrum. The stereochemistry
of the newly constructed ring was assigned based on a well-
documented sense of asymmetric induction expected from
(2)-bornane-10,2-sultam auxiliary.9,12
reagent of choice for regioselective hydrolysis of sterically
hindered carboximides.13,14 We found that unlike lithium
hydroxide, lithium hydroperoxide did hydrolyze adduct 5,
but the yields of both 2a and sultam 3 were low. The main
product was a water-soluble material identified on the basis
of 1H NMR and IR spectra as sulfonic acid 6, arising from a
somewhat unexpected cleavage of the S–N bond. The main
evidence from 1H NMR in favor of structure 6 was a
substantial difference in chemical shifts of the magnetically
non-equivalent protons in CHAHBSO2 (d 2.92 and 3.31),
similar to that of (þ)-10-camphorsulfonic acid (d 2.82 and
3.33). Furthermore, the IR spectrum showed absorptions
characteristic for structure 6 (See Section 3). For the
conversion of 5 to 2a, we used a slightly modified version of
a two-step procedure reported by Oppolzer et al.9 Adduct 5
was first reduced with LAH in THF to give sultam 3 and
intermediate 6-methyl-3-cyclohexenemethanol, and the
later was oxidized in situ with pyridinium dichromate in
DMF15 to give 2a. Extractive separation of the products
followed by chromatography afforded 71% (2)-Siglure acid
2a of .98% ee and 82% of 3. Thus, the chiral auxiliary
could be efficiently recovered for further use.
We encountered certain difficulties during the cleavage of
adduct 5 to (2)-Siglure acid 2a (and recovering chiral
auxiliary 3). An obvious solution would have been base-
catalyzed hydrolysis reported for the Diels–Alder adduct of
N-propenoyl-2,10-camphorsultam and butadiene.9,12 How-
ever, hydrolysis of 5 with lithium hydroxide in aqueous
THF9 was unsuccessful, as were attempts to use other bases
or to promote the reaction by ultrasound and/or phase-
transfer catalysis. Apparently, a methyl group in the newly
constructed ring exerts significant steric crowding in the
vicinity of carbonyl function, similar to the steric shielding
of the exocyclic carbonyl group in certain Diels–Alder
adducts with an oxazolidinone chiral auxiliary.13,14 In the
latter case, lithium hydroperoxide was reportedly the
The synthesis outlined in Scheme 2 was first developed
using racemic Siglure acid 2. The method was based on the
route of Avery et al.6 and was further improved by recycling
the unwanted stereoisomer. Sequential iodolactonization of
acid 2 and reduction of iodolactone according to published
methodology6,7 yielded lactone 7. For ring opening of 7, we
Scheme 2. Reagents and conditions: (a) KI3, NaHCO3; (b) (Bu)3Sn, AIBN, benzene, reflux; (c) 1. Cl3SiCH3/NaI, CH3,CN, reflux, 2. H2O; (d) K2CO3, THF;
(e) 1. (COCl)2, DMF, CH2Cl2. 2. EtOH, Py.

A. Khrimian et al. / Tetrahedron 59 (2003) 5475–5480
5477
used methyltrichlorosilane/sodium iodide mixture,16 which
appeared to be more efficient than chlorotrimethylsilane/
sodium iodide.6 Initially, acid 8 formed almost exclusively
(after hydrolysis of the intermediate silyl ester). Apparently,
cleavage of lactone 7 occurrs stereoselectively with
inversion of configuration at C-3. As the reaction advances,
acid 8 slowly isomerizes to acid 9, and continuing the
reaction for 3–4 h results in the two epimers in the ratio of
2:3. Longer runs gave rise to byproducts and did not seem to
change the proportion of stereoisomers. We found that
heating pure acid 9 in the presence of Cl3SiCH3 (1 equiv.)
and NaI (3 equiv.) in CH3CN, or just in a solution of NaI
(2 equiv.) in CH3CN, for 7–8 h resulted in mixtures of 9 and
8 containing 30–40% of the latter.† Similarly, ceralure B1 1
upon reflux with NaI (2 equiv.) in CH3CN for 12 h gave a
mixture of 1 and the trans-3-iodo epimer in the ratio of 2:1.†
We also found that heat itself did not cause epimerization, as
acid 9 melted at 1658C without change, and epimer 8 upon
melting at 898C partially cyclized to lactone 7 but did not
form acid 9. We therefore concluded that interconversion of
epimers 8 and 9 (as silyl esters) during cleavage of 7 is
catalyzed by iodide, apparently through an SN2 type
displacement of the existing iodine atom at C-3. The
5-cis-iodo isomer 9 appears to be thermodynamically more
stable than the 5-trans epimer 8. A minor side reaction
(Scheme 2) concurrently afforded 3–6% of 4-iodo regio-
isomer 10, evidently through an HI elimination–addition
sequence.
yield of 46% based on 2a, and 26% based on (2)-bornane-
10,2-sultam 3.
In summary, a convenient and easily scaleable synthesis of
both racemic and (2)-ceralure B1 was developed. Inasmuch
as racemic ceralure B11 is only 30–40% less attractive than
the (2)-enantiomer 1a, the former appears commercially
appealing. It is now being scaled-up to kilogram quantities
for larger field studies.
3. Experimental
3.1. General
Melting points and boiling points are uncorrected. 1H NMR
and 13C NMR spectra were recorded with TMS as an
internal standard on a Bruker QE-300 spectrometer. GC
analyses were performed on a Shimadzu 17A gas chro-
matograph using a 60 m£0.25 mm RTX-1701 column
(Restek Corporation) and H2 as a carrier gas. Optical purity
of (2)-2 was determined on Chiraldex B-DM GC column
(b-cyclodextrin, dimethyl), 30 m£0.25 mm (Advanced
Separation Technologies, Inc). Mass spectra were obtained
with a Hewlett–Packard 5971 GC–MS equipped with a
30 m£0.25 mm DB-5 (J&W Scientific) column. Combus-
tion analyses were conducted by Galbraith Laboratories.
Flash chromatography was carried out with 230–400 mesh
silica gel (Whatman). The reagents were bought from
Aldrich unless otherwise specified. (2)-Bornane-10,2-
sultam 3 was synthesized from (þ)-camphorsulfonic acid
by converting it to acyl chloride,17 a two-step trans-
formation to (2)-(camphorsulfonyl)imine,18 and reduction
with LAH.19 Mention of a proprietary company or product
does not imply endorsement by the US Department of
Agriculture.
It was mentioned earlier that the stereoisomer 1 was the
most attractive to the medfly among all regio- and
stereoisomers of the ceralure mixture, which necessitated
finding an efficient way of purifying acid 9. We found that a
short reflux of the acid mixture with potassium carbonate in
THF resulted in complete cyclization of epimer 8 to lactone
7, whereas 9 remained intact. Separation of acid 9 and
lactone 7 was easily achieved by partitioning between
aqueous K2CO3 (pH ,8–9) and ether/hexane (1:1).
Consequently, successive ring opening of lactone 7 and
reconverting the unwanted acid 8 to starting material
achieved a conversion of ,60% and provided acid 9 of
92–94% purity. In the last step, acid 9 was esterified to
Ceralure B1 which was isolated by flash chromatography in
80% yield based on reacted lactone 7. Alternatively, pure
acid 9 could be obtained by crystallization and subsequently
converted to ester 1 in 72% yield, thus excluding
chromatography throughout the synthesis. Notably, both
chromatography and crystallization conveniently removed
regioisomer 10 from the main product. The overall yield of
racemic ceralure B1 1 starting from Siglure acid was 58–
65%, compared to 30–35% yield achieved in previous
syntheses.
3.1.1. (2)-N-[(E)-20-Butenoyl]bornane-10,2-sultam (4).9
A
solution of (2)-bornane-10,2-sultam
3
(26.4 g,
0.123 mol), trans-crotonyl chloride (47.3 mL, 0.491 mol)
and anhydrous CuCl2 (1.64 g, 0.012 mol) in anhydrous
benzene (180 mL) was refluxed under N2 for 1 h. The
mixture was filtered while still warm, the reaction vessel
was washed with dichloromethane (80 mL), and the
combined filtrates were concentrated in vacuo to give a
solid product. Crystallization from methanol (250 mL)
yielded pure sultam (31.0 g, 89%) as white needles, mp
183–1858C. [a]D¼298.9 (c 1.60, CHCl3). Lit.9 mp 186–
1878C, [a]D¼299.5 (c 1.04, CHCl3). IR (KBr, cm 21):
2910, 1680, 1640, 1450, 1380, 1330, 1225, 1135, 975, 880,
1
780, 760. H NMR (CDCl3): 0.95 (s, 3H), 1.14 (s, 3H),
1.25–1.47 (m, 2H), 1.85–2.20 (m, 5H), 1.90 (dd, J¼7.0,
1.5 Hz, 3H), 3.42 (d, J¼14.0 Hz, 1H), 3.48 (1H, d,
J¼14.0 Hz), 3.90 (dd, J¼5.5, 7.0 Hz, 1H), 6.55 (dq,
J¼1.5, 15.0 Hz, 1H), 7.06 (dq, J¼7.0, 15.0 Hz, 1H).
3.1.2. (2)-N-[(10R,60R)-6-Methyl-3-cyclohexenylcar-
bonyl]bornane-10,2-sultam (5). To a dry 250 mL flask
equipped with a pressure-equalized dropping funnel, was
cannulated a solution of 4 (5.66 g, 20.0 mmol) in anhydrous
CH2Cl2 (43 mL) containing galvinoxyl (0.25 g). The
resulting red-brown solution was cooled to 2788C, and
EtAlCl2 (3.2 mL, 30.4 mmol) in anhydrous CH2Cl2 (10 mL)
Analogously to the achiral synthesis, (2)-2a was converted
to (þ)-(1R,2R,5R)-7a in 75% yield.7 Treatment of 7a with
Cl3SiCH3/NaI for 2 h followed by recycling of iodoacid 8a
using the described protocol afforded (2)-(1R,2R,5R)-
iodoacid 9a in 64% yield after crystallization from heptane.
Finally, 9a was esterified to (2)-ceralure B1 1a in an overall
†
50–60 mmol scale reactions were run and worked-up as described in
Section 3 and analyzed by GC.

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A. Khrimian et al. / Tetrahedron 59 (2003) 5475–5480
was added slowly via the dropping funnel keeping the
temperature at 2788C. The bright pink mixture was then
stirred at 2788C for 15–20 min after which time gaseous
butadiene (275.2 mmol corresponding to 24 mL of liquid)
was added via a cannula whose tip was submerged into the
reaction mixture. After addition was complete the mixture
was allowed to warm up to 08C and kept at this temperature
overnight. The resulting pink solution was transferred into
stirred ice-water (100 mL) to give a bright yellow mixture
from which the organic phase was separated and washed
with sat. brine (50 mL), sat. aq. NaHCO3 (50 mL) and more
brine (50 mL). The solution was dried (MgSO4), filtered and
concentrated to give a gummy yellow solid (8.07 g), which
was dissolved in boiling heptane (125 mL). On cooling,
Diels–Alder adduct 5 (4.90 g) crystallized as fine white
plates. The mother liquor was concentrated and the residual
gum chromatographed on silica gel (EtOAc/pet. ether, 1:8)
to give an additional 0.90 g 5 (total 5.80 g, 86%), mp
181–1838C, [a]D¼2159.3 (c 1.6, CHCl3). IR (KBr, cm21):
3020 m, 2960 s, 2890 m, 2840 w, 1685 s, 1655 s, 1460 w,
1415 w, 1325 s, 1275 s, 1245 s, 1220 s, 1140 m, 1065 m,
1005 w. 1H NMR (CDCl3): 0.95 (s, 3H), 0.96 (d, J¼6.0 Hz,
3H), 1.12 (s, 3H), 1.18–1.45 (m, 2H), 1.52–2.25 (m, 9H),
2.27–2.50 (m, 1H), 2.91 (ddd, J1¼5.5 Hz, J2¼J3¼10.5 Hz,
CHCvO), 3.41 (d, J¼14.0 Hz, CHAHBSO2), 3.49 (d,
J¼14.0 Hz, CHAHBSO2), 3.91 (dd, J1¼J2¼6.0 Hz, CHN),
5.55–5.93 (m, CH¼CHHzCH). Anal. Calcd for
C18H27NO3S: C, 64.00; H, 8.00; N, 4.14. Found: C, 63.99;
H, 7.97; N, 4.00.
solid lithium hydroxide monohydrate (0.42 g, 10 mmol).
The resulting solution was allowed to warm to room
temperature and was stirred for 17 h. The reaction mixture
was cooled to 08C, and a solution of sodium sulfite (3.53 g,
27.9 mmol) in water (15 mL) was added. After buffering to
pH 9–10 by addition of saturated aqueous NaHCO3 (2 mL),
the bulk of THF was removed in vacuo, and the resulting
mixture was extracted with methylene chloride (3£25 mL).
The combined methylene chloride extracts were dried
(MgSO4) and concentrated to yield a crude sultam 3
(0.37 g, 34%). The aqueous layer was acidified to pH 1–2
with 20% H2SO4 and extracted with ethyl acetate
(4£25 mL). The combined ethyl acetate extract was dried
(MgSO4), concentrated and purified by flash chromato-
graphy (EtOAc/methanol, 10:1) to give pure acid (2)-2
(0.16 g, 23%) and (þ)-(1S,2R)-2-[(10R,60R)-6-methyl-3-
cyclohexene-10-carbonyl]aminobornane-10-sulfonic acid
(6, 0.23 g, 13%), mp 2298C (dec). [a]D¼þ 89.7 (c 1.37,
CH3OH). IR (KBr, cm21): 3440 w, 3260 s and 3110 s (N–
H), 2900 s, 1660 w, 1600 s, 1280 s and 1250 m (SvO
asym.), 1080 m and 1050 s (SvO sym.), 975 m, 810 w, 680
1
m. H NMR (CD3OD): 0.95 (s, 3H), 1.01 (s, 3H), 1.02 (d,
J¼5.0 Hz, CH3CH), 1.13–1.30 (m, 1H), 1.60–2.35 (m,
11H), 2.44 (ddd, J1¼5.5 Hz, J2¼J3¼10.5 Hz, CHCvO),
2.92 (d, J¼15.0 Hz, CHAHBSO2), 3.31 (d, J¼15.0 Hz,
CHAHBSO2), 4.05 (dd, J¼4.0, 8.5 Hz, CHN), 5.55–5.77
(m, CHvCH). Anal. Calcd for C18H29NO4S: C, 60.76; H,
8.15; N, 3.93. Found: C, 60.65; H, 8.47; N, 3.91.
3.1.5. trans-2-Methyl-6-oxabicyclo[3.2.1]octan-7-one (7).
Was prepared from trans-6-methyl-3-cyclohexene-1-car-
boxylic acid (Siglure acid, Pharma Tech International
Corp.) via the iodolactonization–reduction sequence
described in the literature.6,7 Iodolactone of 98% purity
was obtained in 87% yield. MS (EI): 266 (Mþ), 139, 95
(100), 79, 77, 67 matched literature data.7 Crude iodo-
lactone (54.35 g, 0.20 mol) was reduced with tributyltin
hydride (68 mL, 0.25 mol) in benzene solution (250 mL) in
the presence of 2,20-azobisisobutyronitrile (70 mg) as
described7 to give crude lactone 7 (42.56 g). A sample
(1.01 g) of the product was purified by flash chromato-
graphy (hexane/ethyl acetate, 7:3) to give 7 (0.630 g) in
93% yield. The remainder was purified by distillation, bp
86–888C/0.6 torr, to give 7 (18.91 g) of . 98% purity. MS
(EI): 140 (Mþ), 112, 97, 81 (100), 55, 41. Mp 588C
(hexane).
3.1.3. (2)-(1R,6R)-6-Methyl-3-cyclohexenecarboxylic
acid (2a). To a stirred suspension of lithium aluminum
hydride (152 mg, 4.0 mmol) in anhydrous THF (10 mL) was
added dropwise a solution of 5 (1.38 g, 4.0 mmol) in
anhydrous THF (10 mL) under N2 over a period of 20 min.
The reaction mixture was stirred at room temperature for
4 h, then unreacted lithium aluminum hydride was
cautiously hydrolyzed by dropwise addition of 1N hydro-
chloric acid (30 mL). Layers were separated and the
aqueous phase was extracted with methylene chloride
(5£25 mL). The organic washings were combined with
the THF layer, dried with MgSO4 for 1 h and concentrated
to give a crude product (1.38 g) that was dissolved in DMF
(28 mL) and stirred with pyridinium dichromate (7.62 g,
20.2 mmol) for 4 h at room temperature. The reaction
mixture was diluted with water (70 mL) and extracted with
diethyl ether (5£100 mL). The combined extract was
concentrated to ,200 mL and washed with 10% aqueous
sodium carbonate (2£25 mL). The aqueous layer was
cooled in an ice-water bath, acidified with conc. HCl to
pH 1–2 and extracted with methylene chloride (5£ 50 mL).
The extract was dried with MgSO4, concentrated on a rotary
evaporator and flash chromatographed (EtOAc/hexane, 1:3)
to give acid (2)-2 (0.412 g, 72%) of .98 % ee determined
by analysis of methyl ester (CH2N2) on a chiral GC column.
The ether layer was dried (MgSO4), concentrated, and flash
chromatographed (acetone/hexane, 1:4) to recover pure
sultam 4 (0.716 g, 82%).
3.1.6. cis-5-Iodo-trans-2-methylcyclohexanecarboxylic
acid (9). To a solution of 7 (3.50 g, 25 mmol) and sodium
iodide (11.25 g, 75 mmol) in dry acetonitrile (80 mL),
methyltrichlorosilane (2.95 mL, 25 mmol) was added under
a N2 atmosphere. The mixture was refluxed for 2 h,
concentrated on rotary evaporator to remove most of the
acetonitrile, and partitioned between water (100 mL) and
ether (100 mL). The white precipitate was removed by
vacuum filtration and the aqueous layer was extracted with
ether (3£100 mL). The combined organic extracts were
washed with a small amount of 10% sodium thiosulfate
solution to remove the color, filtered under vacuum, and
dried with Na2SO4. Evaporation of the solvent left 6.4 g of
the acids 9 and 8 in the ratio 53:43, as determined by treating
an aliquot with diazomethane and GC analysis of the
corresponding methyl esters. The mixture of acids was
3.1.4. Hydrolysis of Diels–Alder adduct 5 with lithium
hydroperoxide. To a cold (08C) solution of 5 (1.69 g,
5.0 mmol), in 3:1 THF/water mixture (16 mL) was added
30% hydrogen peroxide (2.85 mL, 25 mmol), followed by

A. Khrimian et al. / Tetrahedron 59 (2003) 5475–5480
5479
dissolved in THF (100 mL), treated with anhydrous
potassium carbonate (1.73 g, 12.5 mmol), and refluxed
under N2 for ,1 h, or until GC analysis showed complete
conversion of acid 8 to starting lactone 7. Most of the THF
was removed under reduced pressure, water (50 mL) was
added to the remainder, and the mixture was cooled to 08C.
A solution of K2CO3 (15 mL, 10%) was added under
vigorous stirring bringing the pH to 8–9. The mixture was
extracted while cold with hexane/ether, 1:1 (4£30 mL), the
organic extract was neutralized with 2% H2SO4, dried with
Na2SO4 and evaporated to recover starting 7 (1.40 g,
10 mmol, 97% purity). Thus, the conversion after consecu-
tive ring opening and lactonization steps was 60%. The
aqueous layer was acidified with 10% H2SO4 to pH 2,
extracted with CH2Cl2 and dried with Na2SO4. Evaporation
of CH2Cl2 afforded crude acid 9 (3.78 g, 92% purity) as a
colorless solid, which was purified by crystallization from
heptane (136 mL) to afford .98% pure acid 9 (3.14 g, 78%
3.1.8. trans-5-Iodo-trans-2-methylcyclohexanecarboxylic
acid (8). To a solution of lactone 7 (1.00 g, 7.1 mmol) and
NaI (3.15 g, 21 mmol) in acetonitrile (20 mL) was added
under N2 chlorotrimethylsilane (2.7 mL, 21 mmol). The
mixture was refluxed for 30 min and quenched with ice-
water. The reaction products were extracted with ether
(3£20 mL), and the combined ether extracts were washed
with sodium thiosulfate and dried with Na2SO4. Evapor-
ation of the solvent provided a mixture of 32% starting
lactone 7, 5% acid 9 and 60% acid 8. The mixture was
suspended in water and treated with 10% K2CO3 at 08C to
pH ,9 and extracted with a 1:1 mixture of hexane and
ether (4£20 mL) to separate unreacted lactone from acids.
The aqueous layer was acidified with 10% H2SO4 to pH ,2
and extracted with CH2Cl2 (4£20 mL). After drying the
extract with Na2SO4, the residue was purified by flash
chromatography (hexane/ethyl acetate, 4:1, 0.01% trifluoro-
acetic acid) to afford 430 mg acid 8 of 97% purity, mp
868C. 1H NMR (300 MHz, CDCl3): 1.01 (d, J¼6.5 Hz,
CH3), 1.47–1.85 (m, 5H, H-2a, 3a, 3e, 4a, 6a), 2.06 (m,
1
yield based on reacted lactone 7). Mp 1658C. H NMR
(300 MHz, CDCl3): 0.91 (d, J¼6.5 Hz, CH3), 1.13 (dddd,
3
2
3
2
3J3a–2a< J3a–4a< J3a–3e<12.5 Hz, J3a–4e¼3.5, H-3a),
1H, H-4e), 2.25 (dm, J6e–6a¼14.5, H-6e), 2.55 (ddd,
3
3
1.64 (dm, H-3e), 1.75 (m, H-2a), 1.90–2.10 (m, 2H, H-1,
H-4a), 2.16 (ddd, J6a–1a< J6a–5a< J6a–6e¼12.5 Hz,
3J1a–6e¼3.0 Hz, J1a–2a< J1a–6a¼11.0 Hz, H-1a), 4.84
(m, 1H, H-5e), 11.15 (1H, OH). 13C NMR (76 MHz,
CDCl3): 20.1 (CH3), 30.2, 32.0, 33.7 (C-5), 35.6 (C-4),
38.8 (C-6), 47.4 (C-1), 181.5 (COOH). NMR spectra are
in close agreement with literature data of the correspond-
ing ethyl ester.20 Anal. Calcd for C8H13IO2: C, 35.80; H,
4.90. Found: C, 35.26; H, 4.99. Running the same
reaction for 7–8 h resulted in complete conversion of 7 to
a 42:53 mixture of 8 and 9.
3
3
2
2
H-6a), 2.42 (dm, J4a–4e¼12.0, H-4e), 2.61 (dm, H-6e),
3
3
3
4.03 (dddd, J5a–4a¼12.5 Hz, J5a–6e< J5a–4e<4.0 Hz,
H-5a). 13C NMR (76 MHz, CDCl3): 20.1 (CH3), 24.9
(C-5), 32.9 (C-2), 36.1 (C-3), 39.9 (C-4), 42.5 (C-6), 53.0
(C-1), 179.4 (COOH). NMR spectra are in close agreement
with literature data of the corresponding ethyl ester.20 Anal.
Calcd for C8H13IO2: C, 35.80; H, 4.90. Found: C, 36.09; H,
5.14.
3.1.9. (1)-(1R,2R,5R)-2-Methyl-6-oxabicyclo[3.2.1]-
octan-7-one (7a). Was prepared in overall 75% yield
from (2)-2a acid via iodolactonization–reduction
procedure described above for the racemic compound. Mp
588C (hexane). [a]D¼þ33.3 (c 0.94, CHCl3). Lit.7
[a]D¼þ31.3 (c 0.96, CHCl3).
3.1.7. Ethyl cis-5-iodo-trans-2-methylcyclohexanecar-
boxylate (1). To a solution of crude acid 9 (2.97 g, 92%
purity, 11 mmol) in CH2Cl2 (30 mL) was added oxalyl
chloride (1.93 mL, 22 mmol) at 08C followed by dimethyl-
formamide (10 mL). The mixture was stirred at room
temperature for 2 h and concentrated on rotary evaporator.
The remainder was taken into CH2Cl2 (18 mL), cooled to
2108C and treated with a mixture of ethanol (734 mL,
13 mmol) and pyridine (1.06 mL, 13 mmol). After stirring
for 2 h at rt, the mixture was diluted with CH2Cl2 (25 mL)
and washed with water, 5% HCl, water and dried with
Na2SO4. Evaporation of the solvent left Ceralure B1
(3.15 g) of 92% purity. A sample of crude product
(1.05 g) was flash chromatographed (hexane/ethyl acetate,
19:1) to afford 930 mg 1 (Rf¼0.4, 98% pure). The isolated
yield of Ceralure B1 based on a two-step process from 7 and
60% conversion was 80%. GC retention times and mass-
spectroscopy data of synthesized product and an authentic
sample were identical. MS (EI) m/z: 251 (2%), 169 (15),
123 (10), 95 (100), 81 (12), 67 (22), 55 (25). Continuing
elution with the same solvent furnished 30 mg ethyl
3.1.10. (2)-(1R,2R,5R)-5-Iodo-2-methylcyclohexane-
carboxylic acid (9a). To a solution of (þ)-7a (3.59 g,
25.64 mmol), and NaI (11.54 g, 76.92 mmol) in dry aceto-
nitrile (80 mL) was added methyltrichlorosilane (3.03 mL,
25.64 mmol) and the mixture was refluxed for 2 h. After the
work-up described for the racemic compound, the crude
mixture of acids 8a and 9a (7.67 g) was dissolved in THF
(90 mL) and refluxed in the presence of K2CO3 for 50 min.
Acid–base partitioning was conducted at 08C as described
above. Flash chromatography (hexane/ethyl acetate, 7:3) of
crude basic material (2.68 g), yielded 7a (1.27 g, 9.04 mmol).
Crystallization of the acidic product (3.49 g) from heptane
(120 mL) furnished pure 9a (2.68 g, 10.67 mmol) in 64%
yield based on reacted 7a. [a]D¼255.6 (c 0.70, CH2Cl2), mp
175–1778C.
cis-4-iodo-trans-2-methylcyclohexanecarboxylate
(10,
1
Rf¼0.3). H NMR (300 MHz, C6D6): 0.61 (m, H-3a), 0.69
(d, J¼6.5 Hz, CH3), 0.80 (m, H-5a), 0.86 (t, J¼6.0 Hz,
CH2CH3), 2.06 (dm, H-6e), 1.58–1.76 (m, 3H), 2.05 (dddd,
3.1.11. Ethyl (2)-(1R,2R,5R)-5-iodo-2-methylcyclo-
hexanecarboxylate (1a). Analogously to the achiral
synthesis, 9a (2.23 g, 8.32 mmol) in CH2Cl2 (23 mL) was
converted to acyl chloride using oxalyl chloride
(16.21 mmol) and DMF (10 mL). The crude acyl chloride
was esterified with EtOH (550 mL) in CH2Cl2 (14 mL) in
the presence of pyridine (795 mL) to 1a (2.34 g, 95% yield),
[a]D¼233.1 (c 0.80, CH2Cl2). Lit.7 [a]D¼229.0 (c 0.72,
CH2Cl2).
3
2
3J6a–1a< J6a–5a< J6a–6e¼11.5 Hz, 3J6a–5e¼3.5 Hz, H-6a),
2.32 (m, H-2a), 3.87 (q, CH2CH3), 4.16 (m, H-4e). 13C
NMR (76 MHz, CDCl3): 14.3 (CH3CH2), 19.4 (CH3), 26.0
(C-6), 30.4 (C-2), 32.8 (C-4), 35.5 (C-5), 43.7 (C-3), 50.7
(C-1), 60.2 (CH3CH2), 174.8 (CvO). 13C NMR data were
identical to those reported in the literature.20

5480
A. Khrimian et al. / Tetrahedron 59 (2003) 5475–5480
8. Jang, E. B.; Raw, A. S.; Carvalho, L. A. J. Chem. Ecol. 2001,
27, 235–242.
Acknowledgements
9. Oppolzer, W.; Chapuis, C.; Bernardinelli, G. Helv. Chim. Acta
1984, 67, 1397–1401.
We wish to thank our cooperating entomologist, Dr Eric
B. Jang, Hilo, Hawaii, for conducting field bioassays, and
Melissa Booth and Nikki Holtmeier for assistance in
syntheses.
10. Klun, J. A.; Khrimian, A.; Margaryan, A.; Kramer, M.;
Debboun, M. J. Med. Entomol. 2003, 40, 293–299.
11. Thom, C.; Kocienski, P. Synthesis 1992, 582–586.
12. Thom, C.; Kocienski, P.; Jarowicki, K. Synthesis 1993,
475–586.
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