Enantioselective synthesis of ceralure B1, ethyl cis-5-iodo-trans-2- methylcyclohexane-1-carboxylate

Article abstract of DOI:10.1016/S0040-4020(00)00219-2

Ethyl (1R, 2R, 5R)-5-iodo-2-methylcyclohexane-1-carboxylate is a potent attractant for the Mediterranean fruit fly. This compound was stereoselectively synthesized on a multigram scale in nine steps in 15% yield. Key steps of the synthesis involved an asymmetric Diels-Alder reaction, iodolactonization, stereoselective reduction of the carbonyl, and inversion of configuration with iodide. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00219-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3285±3290
Enantioselective Synthesis of Ceralure B1,
Ethyl cis-5-Iodo-trans-2-methylcyclohexane-1-carboxylate
b,²
Andre S. Rawa, and Eric B. Jang
*
aUSDA-ARS-PSI Insect Chemical Ecology Laboratory, Beltsville, MD 20705, USA
bUSDA-ARS Tropical Fruit and Vegetable Research Laboratory, Hilo, HI 96720, USA
Received 23 February 2000; accepted 13 March 2000
AbstractÐEthyl (1R, 2R, 5R)-5-iodo-2-methylcyclohexane-1-carboxylate is a potent attractant for the Mediterranean fruit ¯y. This
compound was stereoselectively synthesized on a multigram scale in nine steps in 15% yield. Key steps of the synthesis involved an
asymmetric Diels±Alder reaction, iodolactonization, stereoselective reduction of the carbonyl, and inversion of con®guration with iodide.
Published by Elsevier Science Ltd.
Introduction
5)-iodo-2-methylcyclohexane-1-carboxylate has been found
to be a more persistent and potent attractant than TML.7 A
®eld study designed to measure the relative attractiveness of
these racemates, which were tediously separated by HPLC,
demonstrated that ethyl cis-5-iodo-trans-2-methylcyclo-
hexane-1-carboxylate (CER B1) (4) is most active.8
The Mediterranean fruit ¯y, Ceratitis capitata (Wiedemann)
commonly known as the med¯y, is a worldwide pest that
feeds on 253 fruits and vegetables.1 The establishment of
this exotic pest into the continental United States would
signi®cantly increase pesticide use and curtail fruit and
vegetable exports, a multi-billion dollar industry.2 For
more than 30 years trimedlure (TML), a mixture of sixteen
regio- and stereoisomers of tert-butyl esters of 4 (and 5)-
chloro-2-methylcyclohexane-1-carboxylate (1) has been
widely used as an attractant in traps used to monitor and
detect male med¯y.3 HPLC separation of these isomers
made possible a ®eld study of the relative attractiveness of
these racemates toward the Mediterranean fruit ¯y.4 Of
these isomers, TML-C (2) was shown to be most active.
Particularly noteworthy is the ability of the med¯y to dis-
criminate among the two enantiomers of TML-C, with the
(1S, 2S, 4R) con®guration being most attractive.5,6
We sought to develop an ef®cient enantioselective synthesis
of CER B1 which is amenable to multigram scale, for
various reasons. Firstly, to our knowledge, despite various
attempts, no stereoselective synthesis of the most active
stereoisomer of CER or even TML has been developed.
Secondly, we wanted to ascertain which enantiomer of
CER B1 is most attractive. Finally and most importantly,
an ef®cient synthesis of the most active compound within
the 16 component CER mixture should provide a signi®-
cantly improved tool for monitoring infestations of the
Mediterranean fruit ¯y.
Our synthetic plan for developing an enantioselective
synthesis of 4 is shown in Scheme 1. We envisaged that
the construction of the cyclohexane ring via an asymmetric
Diels±Alder reaction between butadiene and (E)-crotonic
acid would establish the trans stereochemistry between
the carboxylate and the methyl group with absolute stereo-
chemical control. Iodolactonization, followed by reduc-
tion and transesteri®cation should in effect provide for
Recently, an iodo analog of trimedlure, ceralure (CER) (3),
also a mixture of 16 regio- and stereoisomers of ethyl 4 (and
Keywords: insects; asymmetric synthesis; regiochemistry.
* Corresponding author. Tel.: 301-504-6138; fax: 301-504-6580; e-mail:
araw@asrr.arsusda.gov
²
E-mail: ejang@pbarc.arsusda.gov
0040±4020/00/$ - see front matter. Published by Elsevier Science Ltd.
PII: S0040-4020(00)00219-2

3286
A. S. Raw, E. B. Jang / Tetrahedron 56 (2000) 3285±3290
Scheme 1. Synthetic plan for enantioselective synthesis of 4.
regioselective and stereoselective addition of water across
the double bond. Inversion of con®guration of the hydroxyl,
followed by SN2 displacement with iodide, should provide
(4) in optically pure form.
re¯uxing benzene.13 Finally, ring-opening of the lactone
with sodium ethoxide in ethanol generated 10 in quanti-
tative yield. Hence the synthetic sequence 5 to 10 was, in
effect, equivalent to the regio- and stereoselective addition
of water across the ole®n. However, the con®guration of the
hydroxyl was opposite to that desired. Hence, inversion of
the hydroxyl was required. Mitsunobu inversion of a
hydroxyl in the cyclohexane ring was plagued with dif®-
culties, due to the propensity of elimination as well as low
reactivity resulting from steric hindrance of an approaching
nucleophile. Accordingly, in an alternate approach, the
hydroxyl in 10 was oxidized with PCC15 in methylene
chloride to generate the ketone (11) in high yield (95%).
Stereoselective reduction of the ketone should provide the
desired alcohol 12 with inverted stereochemistry. As the
cyclohexanone ring in 11 should exist in a distorted chair
conformation with the ethyl ester and methyl groups
occupying equatorial positions, reduction of the ketone
with hydride from an equatorial trajectory should provide
the desired alcohol 12 with inverted stereochemistry. In fact,
reduction of 11 with NaBH4 gave predominantly 10
(dsˆ9:1), most likely as a result of approach of compara-
tively unhindered borohydride from the axial position.
Interestingly, reduction of the ketone with the sterically
encumbered reducing agent LiAlH(OC(CH3)3)3 also gave
a preponderance of 10 (ds.99:1). However, reduction of
11 with K-Selectridew16 in THF at 2788C followed by
oxidation of the trialkylborane with hydrogen peroxide
under neutral conditions, generated the desired axial alcohol
12 with high stereoselectivity (ds.25:1). Alcohol 12 could
then be isolated in pure form by simple ¯ash chroma-
tography (86%).
Results and Discussion
We sought to utilize an asymmetric Diels±Alder reaction to
obtain the enantiomers of sigluric acid 5. This would avoid
the tedious multistep chiral resolution of 5, used previously
for the synthesis of the enantiomers of TML.6 Evans has
described the asymmetric Diels±Alder technique with
chiral a,b-unsaturated N-acyloxazolidinones.9,10 Most
appealing is the ready availability of both enantiomers of
the benzyloxazolidinone chiral auxiliary. Hence, treatment
of the chiral oxazolidinone derived from d-phenylalanine
with n-butyllithium followed by addition of (E)-crotonyl
chloride generated the chiral a,b-unsaturated N-acyloxazo-
lidinone 6 in 90% yield. The asymmetric reaction of 6 with
butadiene in the presence of 2.0 equiv. of the Lewis acid
catalyst diethylaluminum chloride at 2158C generated
the adduct 7 with high diastereoselectivity (ds.97:1).
Galvinoxyl was employed in this procedure to prevent the
polymerization of butadiene under the reaction conditions.11
Without puri®cation, 7 was subject to contrasteric carboxi-
mide hydrolysis with lithium hydroperoxide12 to afford (1R,
6R)-6-methyl-3-cyclohexene-1-carboxylic acid 5 in 51%
overall yield from 6. The optical purity of 5 was judged to
be 97% ee on a chiral cyclodextrin column. The chiral
auxiliary was also recovered in 87% yield. The absolute
con®guration of 5 is based on precedent of analogous
reactions documented by Evans.9 Additionally, the literature
value for the rotation of 5 ([a]Dˆ284.28) con®rms the
stereochemical assignment.6
Activation of the hydroxyl, followed by nucleophilic dis-
placement with iodide should generate the desired 4a stereo-
isomer. However, this last step of the sequence proved to be
quite dif®cult. A variety of conditions were attempted,
including Ph3P/DEAD/CH3I, Ph3P/N-iodosuccinimide,
Ph3P/DEAD/ZnI2, I2SiH2, and o-phenylene phosphochlori-
dite/I2, all of which proved unsuccessful. In these instances,
starting material was recovered, along with 4a and elimi-
nation product. We attribute this to the steric hindrance of
the axial hydroxyl in 12 for activation. If activation were to
occur, facile E-2 elimination of the activated axial hydroxyl
would compete with nucleophilic attack by iodide. Other
Iodolactonization of 5 with I2, KI and NaHCO3 provided 8
in a highly regioselective manner in 87% yield.13,14
Attempted hydrogenolysis of the iodolactone with various
heterogeneous metal catalysts, including Pd/C, Pt/C, or Pt/
Al2O3, proved to be unsuccessful. Unreacted starting
material or products resulting from over reduction were
obtained. However, reduction of iodolactone 8 to lactone
9 proceeded smoothly in 94% yield with tributyltin hydride
in the presence of catalytic azobisisobutyronitrile (AIBN) in

A. S. Raw, E. B. Jang / Tetrahedron 56 (2000) 3285±3290
3287
Scheme 2. Enantioselective synthesis of Ceralure B1 (4a).
reagents, including P2I4, Me3SiCl/NaI, Cl3SiMe/NaI, and
trimethylsilylpolyphosphate/NaI, did yield 4a, albeit in
poor stereoselectivity, most likely due to the highly ionic
nature of the intermediates involved. After modi®cation of
previously reported conditions, we found that Ph3P-imida-
rial may justify the use of this attractant as a replacement of
TML that is annually used in over 100,000 baited detection
traps for monitoring infestations of the Mediterranean fruit
¯y in the U.S.
17
zole-I2 in a 2:1 carbon tetrachloride/methylene chloride
mixture at room temperature did give CER B1 (4a) in fair
yield (55%) and in high stereoselectivity (ds.50:1)
(Scheme 2). Fortunately, the elimination side product
Experimental
Melting points were uncorrected. 1H NMR and
13C{1H}NMR spectra were recorded with TMS as an inter-
nal standard in CDCl3 on a Bruker QE-300 spectrometer
1
could easily be removed by ¯ash chromatography. The H
and 13C NMR spectra of 4a synthesized in this manner were
identical to those of an authentic racemic sample previously
isolated from the mixture of CER stereoisomers by HPLC.8
Synthesis of CER B1 (4a) in high optical purity by this route,
yielded material on a 6.0-g scale. The opposite enantiomer
(4b) was also generated from the readily available benzyl-
oxazolidinone chiral auxiliary derived from l-phenyl-
alanine. Both enantiomers of CER B1 (4) were determined
to be 97% ee on a chiral GC column.
1
unless otherwise stated. H NMR coupling constants are
reported in Hz. Mass spectra were obtained with a
Hewlett±Packard 5971 GC±MS equipped with a 30 m
DB-5 (J&W Scienti®c) fused silica column. IR spectra
were obtained with a Hewlett±Packard Series 6890 gas
chromatograph (equipped with a 60-m DB-Waxter (J&W
Scienti®c) fused silica column) coupled to a Bio Rad IRD
II Infrared Detector. Optical rotations were recorded using a
Perkin±Elmer Model 241 automatic polarimeter operated at
the sodium-D (589 nm) wavelength. Gas chromatography
was performed on a Shimadzu Model 14A gas chromato-
graph using hydrogen as the carrier gas. Combustion
analyses were conducted by Galbraith Laboratories, Inc.,
Knoxville, TN.
Conclusions
In summary, a convenient nine-step stereoselective synthe-
sis of the enantiomers of CER B1 (4) has been described.
The synthesis was accomplished in 15% overall yield and is
amenable to large scale. Preliminary ®eld tests on cotton
wicks conducted in Hawaii demonstrated that the
1R,2R,5R enantiomer (4a) is very attractive to the Medi-
terranean fruit ¯y and that the 1S,2S,5S enantiomer (4b) is
signi®cantly less active. Preliminary results demonstrate
that 4a caught as many as ten and twenty times more ¯ies
than the standard TML and CER mixtures, respectively.
Thus the increased ef®ciency of trapping per dose of mate-
Analytical thin layer chromatography (TLC) was carried out
on silica gel (J. T. Baker IB-F). Flash chromatography was
performed as previously described on E. Merck silica gel
(230±400 mesh).18 Tetrahydrofuran (THF) was distilled
from sodium/benzophenone; methylene chloride and ben-
zene were distilled from CaH2 and purged with nitrogen
before using. Unless otherwise noted, materials were
obtained from commercial suppliers and were used without

3288
A. S. Raw, E. B. Jang / Tetrahedron 56 (2000) 3285±3290
further puri®cation. All reactions were carried out under a
nitrogen atmosphere. Mention of a proprietary company or
product does not imply endorsement by the US Department
of Agriculture.
yield) of the recovered benzyloxazolidinone auxiliary. The
aqueous layer was acidi®ed to pH 1±2 with 12 M HCl and
extracted with ethyl acetate (5£300 mL). The combined
ethyl acetate extracts were dried (Na2SO4) and the volatiles
were removed in vacuo to yield an oil that was puri®ed by
¯ash chromatography (1:1 ethyl acetate/hexane, 0.3% acetic
acid) to give 5 as a solid (20.2 g, 51% overall yield from 6).
The optical purity of the methyl ester of 5 was shown to be
97% ee (30 m Chiraldex BD-A column, 708C isothermal,
25 psi, tr major 31.4 min, tr minor 33.0 min). Rf 0.40 (ethyl
acetate/hexane 1:1); mp 65±668C; 1H NMR (300 MHz,
CDCl3) d 10.2±11.8 (b, 1H), 5.61±5.69 (m, 2H). 2.12±
2.33 (m, 4H), 1.89±2.00 (m, 1H), 1.67±1.77 (m, 1H), 1.02
(d, Jˆ6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 182.3,
126.3, 124.5, 46.8, 32.9, 30.3, 28.7, 19.7; MS (EI) m/z
140 (M1, 21), 122 ([M2H2O]1, 16), 111 (14), 95 (100),
79 (75), 67 (49); [a]Dˆ299.08 (cˆ4.89, CHCl3).
(4R)-3-((E)-2-Butenoyl)-4-(phenylmethyl)-2-oxazolidinone
(6) was synthesized according to a literature procedure.9
The product was recrystallized from ethanol to yield a
white solid (156.4 g, 90%). Rf 0.20 (ethyl acetate/hexane
1
1:9); mp 79±818C; H NMR (300 MHz, CDCl3) d 7.14±
7.35 (m, 7H), 4.67±4.75 (m, 1H), 4.10±4.21 (m, 2H), 3.30
(dd, Jˆ3.4 Hz, 13.2 Hz, 1H), 2.79 (dd, Jˆ9.5 Hz, 13.2 Hz,
1H), 1.97 (d, Jˆ5.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
164.6, 153.2, 146.3, 135.2, 129.2, 128.6, 127.0, 121.7, 65.8,
54.9, 37.5, 18.2; MS (EI) m/z 245 (M1, 10), 230 (11), 154
(12), 133 (4), 91 (9), 69 (100), 41 (11); [a]Dˆ 278.38
(cˆ3.83, CHCl3).
(4R)-3-((40R,50R)-Cyclohexene-40-carbonyl)-4-(phenyl-
methyl)-2-oxazolidinone (7).10 In a fume hood, a 3 L, 3-
neck round-bottomed ¯ask equipped with a dry-ice con-
denser, was charged with oxazolidinone 6 (70.0 g, 0.286
mol), galvinoxyl (500 mg, 1.2 mmol), and 400 mL of
methylene chloride. After cooling to 2788C, butadiene
(800 mL, 9.6 mol), dried by passage through Drierite was
condensed into the solution. Diethylaluminum chloride
(0.570 mol, 1.8 M in toluene) was added over 10 min and
the solution was stirred overnight at 215 to 2108C. The
reaction was quenched by addition to 1 M HCl (1000 mL),
and stirred for 60 min at room temperature to allow the
butadiene to evaporate. The layers were separated and the
aqueous layer was extracted with methylene chloride
(4£250 mL). The combined organics were neutralized by
stirring with solid NaHCO3, dried (MgSO4) and the volatiles
were removed in vacuo to give a crude oil (103.9 g, 107%
crude yield), that was carried onto the next step without
puri®cation. A portion of the sample was puri®ed by ¯ash
chromatography (1:4 ethyl acetate/hexane), to give a solid;
(1R,2R,4S,5S)-4-Iodo-2-methyl-6-oxabicyclo[3.2.1]octan-
7-one (8).14 To a solution of optically active 5 (16.8 g,
120 mmol) in methylene chloride (200 mL) and water
(400 mL), were added NaHCO3 (20.1 g, 240 mmol), KI
(120 g, 720 mmol) and iodine (91.0 g, 360 mmol). The
resulting mixture was protected from light and stirred for
24 h. The solution was cooled (08C), and sodium thiosulfate
was carefully added until the dark iodine color disappeared.
It was then extracted with diethyl ether (4£300 mL). The
combined organics were dried (MgSO4) and the volatiles
were removed in vacuo to give crude 8 as a yellowish
solid (27.8 g, 87% yield). This was carried onto the next
step without further puri®cation. Rf 0.33 (ethyl acetate/
1
hexane 1:9); mp 99±1008C; H NMR (300 MHz, CDCl3)
d 4.86 (dd, Jˆ3.6 Hz, 5.9 Hz, 1H), 4.35±4.38 (m, 1H),
2.90 (m, 1H), 2.63±2.73 (m, 1H), 2.49±2.52 (m, 1H),
2.20±2.36 (m, 2H), 1.95±2.00 (m, 1H). 1.38 (d, Jˆ
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 178.2, 81.6,
43.8, 34.3, 29.3, 27.8, 19.5, 19.1; MS (EI) m/z 266 (M1,
4), 139 ([M2I]1, 80), 95 (100), 79 (16), 67 (26), 55 (29);
[a]Dˆ23.608 (cˆ2.22, CHCl3).
1
Rf 0.25 (1:9 ethyl acetate/hexane); mp 79±808C; H NMR
(300 MHz, CDCl3) d 7.19±7.36 (m, 5H), 5.69±5.73 (m,
2H), 4.68±4.76 (m, 1H), 4.14±4.24 (m, 2H), 3.70 (dt,
Jˆ5.5 Hz, 10.2 Hz, 1H), 3.26 (dd, Jˆ3.2 Hz, 13.5 Hz,
1H), 2.79 (dd, Jˆ9.5 Hz, 13.5 Hz, 1H), 2.35±2.43 (m,
1H), 2.02±2.27 (m, 3H), 1.75±1.86 (m, 1H), 0.97 (d, Jˆ
6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 176.4, 153.1,
135.3, 129.4, 128.9, 127.3, 126.3, 124.6, 66.0, 55.3, 44.2,
37.9, 33.0, 30.3, 29.0, 19.5; MS (EI) m/z 299 (M1, 13), 284
(1), 178 (25), 122 (100), 95 (46), 79 (30); [a]Dˆ2141.58
(cˆ1.48, CHCl3).
(1R, 6R)-6-Methyl-3-cyclohexene-1-carboxylic acid (5).6
To a cold (08C) solution of 7 (103.9 g, 0.286 mol), in 4:1
THF/water (500 mL) was added 30% hydrogen peroxide
(160 mL, 1.40 mol), followed by addition of solid lithium
hydroxide (27.4 g, 0.652 mol). The resulting mixture was
allowed to slowly warm to room temperature, and after
4 h the reaction was complete. The solution was cooled
(08C) and sodium sul®te (202 g, 1.6 mol) was added. The
bulk of the THF was removed in vacuo, and the resulting
mixture (pH 12±13) was extracted with methylene chloride
(5£200 mL) to remove the chiral auxiliary. The combined
methylene chloride extracts were dried (MgSO4) and the
volatiles were removed in vacuo to yield 44.0 g (87%
(1R,2R,5R)-2-Methyl-6-oxabicyclo[3.2.1]octan-7-one (9).14
A solution of 8 (26.8 g, 101 mmol), tributyltin hydride
(29.8 mL, 111 mmol), and AIBN (200 mg) in benzene
(300 mL) was re¯uxed overnight. After removing the ben-
zene in vacuo, diethyl ether (250 mL) and 10% aqueous KF
(250 mL) were added. Stirring for 30 min precipitated a
tributyltin ¯ouride polymer. The polymer was removed by
®ltration, and the ®ltrate was extracted with methylene
chloride (3£100 mL). The combined organics were dried
(MgSO4) and the volatiles were removed in vacuo to yield
an oil that was puri®ed by ¯ash chromatography (using
eluent gradient 1:20 ethyl acetate/hexane to 3:7 ethyl
acetate/hexane) to give 9 as a yellowish solid (13.2 g,
94% yield). Rf 0.26 (ethyl acetate/hexane 1:9); mp 62±
638C; IR (gas phase) cm21 2975, 2888, 1811, 1347, 1156;
1H NMR (300 MHz, CDCl3) d 4.76±4.80 (m, 1H), 2.43±
2.46 (m, 1H), 2.12±2.25 (m, 2H), 2.01±2.05 (m, 1H), 1.89±
1.98 (m, 2H), 1.62±1.70 (m, 1H), 1.41±1.47 (m, 1H), 1.13
(d, Jˆ6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 179.1,
78.1, 44.5, 31.0, 28.1, 24.8, 24.4, 17.5; MS (EI) m/z 140
(M1, 3), 112 ([M2CO]1, 3), 97 (28), 81 (100), 70 (38), 55
(48); [a]Dˆ131.38 (cˆ0.968, CHCl3); Analysis calcd for
C8H12O2: C, 68.54; H, 8.63. Found: C, 68.15; H, 8.60.

A. S. Raw, E. B. Jang / Tetrahedron 56 (2000) 3285±3290
3289
1
Ethyl
(1R,2R,5R)-5-hydroxy-2-methyl-1-carboxylate
cm21 3655, 2938, 2895, 1746, 1240, 1158, 1041; H NMR
(300 MHz, CDCl3) d 4.45±4.54 (m, 1H), 4.10 (q, Jˆ7.2 Hz,
2H), 2.34±2.44 (m, 1H), 2.00±2.30 (b, 1H), 1.26±1.91 (m,
7H), 1.22 (t, Jˆ7.2 Hz, 3H), 0.89 (d, Jˆ6.4 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 176.1, 65.4, 60.0, 45.1, 35.8,
33.9, 32.0, 27.6, 20.2, 14.2; MS (EI) m/z 186 (M1, 3), 168
([M2H2O]1, 37), 141 ([M2OCH2CH3]1, 25), 130 (12), 95
(100), 73 (27), 55 (34); [a]Dˆ227.48 (cˆ1.10, CH2Cl2).
Analysis calcd for C10H18O3: C, 64.49; H, 9.74. Found: C,
64.19; H, 9.62.
(10). Sodium (5.0 g, 217 mmol) was dissolved in anhydrous
ethanol (250 mL) at room temperature. Lactone 9 (13.2 g,
94.3 mmol) was added and the solution was allowed to stir
at room temperature for one hour, whereupon the reaction
was judged to be complete by TLC. The mixture was diluted
with saturated ammonium chloride (300 mL) and extracted
with methylene chloride (3£100 mL). The combined organics
were dried (MgSO4) and the volatiles were removed in
vacuo to give 10 as a crude oil (17.3 g, 99% yield) that
was carried onto the next step without further puri®cation.
Rf 0.25 (ethyl acetate/hexane 3:7); IR (gas phase) cm21
3650, 2941, 2869, 1748, 1244, 1171, 1032; 1H NMR
(300 MHz, CDCl3) d 4.11 (q, Jˆ7.2 Hz, 2H), 3.52±3.61
(m, 1H), 1.92± 2.08 (m, 4H), 1.69±1.78 (m, 1H), 1.56±
1.69 (m, 1H), 1.39±1.50 (m, 1H), 1.26±1.36 (m, 1H), 1.23
(t, Jˆ7.2 Hz, 3H), 0.97±1.11 (m, 1H), 0.86 (d, Jˆ6.4 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 174.9, 69.8, 60.2, 49.7,
38.2, 35.0, 33.6, 32.4, 19.6, 14.2; MS (EI) m/z 186 (M1, 3),
168 ([M2H2O]1, 57), 141 ([M2OCH2CH3]1, 16), 129
(29), 95 (100), 73 (21), 55 (30); [a]Dˆ226.68 (cˆ1.10,
CH2Cl2). Analysis calcd for C10H18O3: C, 64.49; H, 9.74.
Found: C, 64.68; H, 9.51.
Ethyl (1R,2R,5R)-5-iodo-2-methyl-1-carboxylate (4a). To
a cold (08C) solution of 12 (8.28 g, 44.5 mmol) in 1:2 meth-
ylene chloride/carbon tetrachloride (400 mL) was added
triphenylphosphine (14.0 g, 53.4 mmol), imidazole
(3.63 g, 53.4 mmol), and iodine (13.5 g, 54.4 mmol). The
reaction mixture was allowed to warm to room temperature
and stirred overnight. The reaction was quenched by
addition of saturated sodium thiosulfate (300 mL) and
stirred until the solution became clear. The layers were
separated and the aqueous layer was extracted with methyl-
ene chloride (2£200 mL). The combined organics were
washed with sodium thiosulfate (200 mL), brine (200 mL),
dried (Na2SO4), and the volatiles were removed in vacuo to
yield a solid that was puri®ed by ¯ash chromatography
(toluene) to give 4a as an oil (7.0 g, 53% yield). Analysis
on a 60 m SPB-608 column19 indicated production of 4a in
high diastereoselectvity (.40:1). Rf 0.76 (ethyl acetate/
hexane 3:7); IR (gas phase) cm21 2961, 2936, 1748, 1319,
1279, 1180, 1140, 1036; 1H NMR (300 MHz, CDCl3) d 4.13
Ethyl (1R,2R)-2-methyl-5-one-1-carboxylate (11). To a
suspension of pyridinium chlorochromate (36.0 g, 167
mmol) in methylene chloride (200 mL) was added 10
(17.27 g, 92.8 mmol), whereupon the mixture became a
dark homogeneous solution. The reaction was stirred over-
night. Diethyl ether (3£300 mL) was added, and the product
was passed through a short column of Florisilw to remove
the chromium salts. Removal of the solvent in vacuo gave
11 as an oil (15.9 g, 93% yield), that was carried onto the
next step without further puri®cation. Rf 0.61 (ethyl acetate/
hexane 3:7); IR (gas phase) cm21 2972, 2940, 1744, 1166,
J
(q, ˆ7.2 Hz, 2H), 4.00±4.09 (m, 1H), 2.51±2.58 (m, 1H),
2.37±2.45 (m, 1H), 2.10±2.22 (m, 1H), 1.95±2.09 (m, 2H),
1.69±1.80 (m, 1H), 1.59±1.67 (m, 1H), 1.26 (t, Jˆ7.2 Hz,
3H), 1.06±1.12 (m, 1H), 0.86 (d, Jˆ6.4 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 173.4, 60.4, 53.3, 42.7, 39.9, 36.2, 33.1,
25.8, 20.0, 14.2; MS (EI) m/z 251 ([M2OCH2CH3]1, 2),
169 ([M2I]1, 21), 123 (11), 95 (100), 81 (8), 67 (14), 55
(17); [a]Dˆ229.08 (cˆ0.72, CH2Cl2).
1
1035; H NMR (300 MHz, CDCl3) d 4.18 (dq, Jˆ1.1 Hz,
7.2 Hz, 2H), 2.35±2.63 (m, 5H), 2.01±2.19 (m, 2H), 1.42±
1.53 (m, 1H), 1.28 (t, Jˆ7.2 Hz, 3H), 1.03 (d, Jˆ6.4 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 208.9, 173.5, 60.6, 50.5,
42.7, 40.3, 33.4, 33.2, 19.0, 14.1; MS (EI) m/z 184 (M1, 23),
169 ([M2CH3]1, 3), 155 ([M2CH2CH3]1, 8), 139
([M2OCH2CH3]1, 8), 128 (35), 111 (100), 99 (46). 55
(50); [a]Dˆ246.98 (cˆ1.00, CH2Cl2). Analysis calcd for
C10H16O3: C, 65.19; H, 8.75. Found: C, 65.06; H, 8.73.
Ethyl (1S,2S,5S)-5-iodo-2-methyl-1-carboxylate (4b) was
produced in an analogous manner from the oxazolidinone
derived from l-Phe. [a]Dˆ128.88 (cˆ0.65, CH2Cl2).
Ethyl (1SR, 2SR, 5SR)-5-iodo-2-methyl-1-carboxylate (4)
was generated in an analogous manner from racemic (1RS,
6RS)-6-methyl-3-cyclohexene-1-carboxylic acid.
Ethyl
(1R,2R,5S)-5-hydroxy-2-methyl-1-carboxylate
(12). To a cold (2788C) solution of 11 (14.9 g, 80.8
mmol) in THF (250 mL) was added K-Selectridew (95.0
mmol, 1.0 M in THF). After addition was complete, the
mixture was allowed to warm to 2508C and was stirred
for an additional 4 h, whereupon the reaction was judged
to be complete by TLC. The reaction was quenched by
addition to 2.2 M NaH2PO4/K2HPO4 buffer (300 mL, pH
7). The mixture was cooled (08C) and 30% hydrogen
peroxide (42 mL, 370 mmol) was added and the mixture
was allowed to stir overnight. The layers were separated
and the aqueous layer was extracted with ethyl acetate
(4£200 mL). The combined organics were washed with
brine (300 mL), 1.0 M sodium sul®te (300 mL), dried
(MgSO4) and the volatiles were removed in vacuo to yield
an oil that was further puri®ed by ¯ash chromatography (3:7
ethyl acetate/hexane) to give 12 as an oil (12.48 g, 83%
yield). Rf 0.35 (ethyl acetate/hexane 3:7); IR (gas phase)
Acknowledgements
The assistance of Lori Carvalho in conducting the bioassay
is gratefully acknowledged.
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