Synthesis of 2-[6-(2,4-Dinitrophenoxy)hexyl]oxiranecarboxylic acid: A selective carnitine palmitoyltransferase-1 inhibitor

Article abstract of DOI:10.1016/S0968-0896(98)00175-8

Carnitine palmitoyltransferases 1 and 2 (CPT-1 and CPT-2) catalyze the transfer of long chain fatty acids between carnitine and coenzyme A. Unlike CPT-2, CPT-1 exists in at least two isoforms with different physical and kinetic properties. Liver and skele

Full text of DOI:10.1016/S0968-0896(98)00175-8

BIOORGANIC &
MEDICINAL
CHEMISTRY
Bioorganic & Medicinal Chemistry 6 (1998) 2133±2138
Synthesis of 2-[6-(2,4-Dinitrophenoxy)hexyl]oxiranecarboxylic
Acid: A Selective Carnitine Palmitoyltransferase-1 Inhibitor
Tracy L. Hutchison and Wayne J. Brouillette*
Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
Received 1 May 1998; accepted 14 July 1998
AbstractÐCarnitine palmitoyltransferases 1 and 2 (CPT-1 and CPT-2) catalyze the transfer of long chain fatty acids
between carnitine and coenzyme A. Unlike CPT-2, CPT-1 exists in at least two isoforms with di€erent physical and
kinetic properties. Liver and skeletal muscle each contain a di€erent isoform of CPT-1. Cardiac muscle contains both
isoforms, and the minor component is identical to the isoform found in the liver. 2-[6-(2,4-Dinitrophenoxy)hexyl]ox-
iranecarboxylic acid (2) was reported to be a selective inhibitor for the liver isoform of CPT-1. A synthesis of 2 is
described here which involves the reaction of diethyl malonate with 1-bromo-6-phenoxyhexane. # 1998 Elsevier Science
Ltd. All rights reserved.
Introduction
CPT-1 exists in at least two isoforms that have di€erent
physical and kinetic properties. Weis and McGarry have
shown that liver and skeletal muscle each contain a
single isoform of CPT-1, while the heart contains two
isoforms.3 The major component of heart muscle is
identical to the skeletal muscle isoform (M-CPT-1),
while the minor component is identical to the liver iso-
form (L-CPT-1).
Carnitine (1, 3-hydroxy-4-trimethylammoniobutyrate)
serves as a substrate for a class of enzymes, the carnitine
acyltransferases, which catalyze the reversible transfer
of an acyl group between an acyl-CoA and the b-
hydroxy group of carnitine (Fig. 1). Di€erent carnitine
acyltransferases are selective for di€erent acyl chain
lengths. The most well understood function of carnitine
involves its substrate activity for the long chain acyl-
transferases, which is required for the transfer of long
chain fatty acids into the mitochondrial matrix where
they undergo b-oxidation (Fig. 2).1 Long chain acyl-
CoA esters are unable to cross the inner mitochondrial
matrix. Rather, the long chain fatty acyl-CoA is ester-
i®ed to carnitine by carnitine palmitoyltransferase-1
(CPT-1) to produce an acylcarnitine and free CoA. The
fatty acylcarnitine is then transported across the inner
mitochondrial membrane by the carnitine±acylcarnitine
translocase, and it is then converted back to carnitine
and the fatty acyl-CoA by carnitine palmitoyltransfer-
ase-2 (CPT-2). The fatty acyl-CoA can then enter into
b-oxidation for energy production.
The inhibition of CPT-1 has shown potential as a clin-
ical approach to the treatment of non-insulin-dependent
diabetes mellitus (NIDDM). NIDDM is characterized
by elevated levels of glucose (hyperglycemia) and excess
fatty acid oxidation. The excess free fatty acid oxidation
allows gluconeogenesis to proceed at elevated rates
without utilization of glucose.4,5 By inhibiting CPT-1,
the rate determining step in long chain fatty acid oxida-
tion, the rate of acetyl-CoA production is diminished.
This in turn lowers the rate of gluconeogenesis, which
allows glucose to be used for energy production in gly-
colysis, thus lowering hyperglycemia.
Prior to the ®nding that CPT-1 exists in two isoforms,
two glycolic acid derivatives were reported to be irre-
versible inhibitors of CPT-1. These inhibitors include
tetradecylglycidic acid (TDGA)6 and ethyl 2-[6-(4-
chlorophenoxy)hexyl]oxirane-2-carboxylic acid (Eto-
moxir).7,8 Both compounds were found to be e€ective
CPT-2 appears to exist as a single protein (&70 kDa) in
an individual species.2 Recently, it has been shown that
*Corresponding author. Tel: 205 934 4747; fax: 205 934 2543.
0968-0896/98/$ - see front matter # 1998 Elsevier Science Ltd. All rights reserved
PII: S0968-0896(98)00175-8

2134
T. L. Hutchison, W. J. Brouillette/Bioorg. Med. Chem. 6 (1998) 2133±2138
hypoglycemia, and thus were nonselective inhibitors.
Here we report a synthesis of 2 from phenol and 1,6-
dibromohexane.
Results and Discussion
Chemistry
As shown in Scheme 1, ether 4 was prepared from
phenol and excess 1,6-dibromohexane following
a
procedure used by Diana et al. for the preparation of
1-(2-chloro-4-methoxyphenoxy)-6-bromohexane from
2-chloro-4-methoxyphenol and 1,6-dibromohexane.10
Simple distillation of the crude reaction mixture pro-
vided pure 4. This intermediate was then converted to 5
by reacting 4 with diethyl malonate and sodium eth-
oxide following a procedure used by Ho et al. for react-
ing 1-bromotetradecane with diethyl malonate.11
Compounds 6 and 7 were also prepared by methods
reported by Ho et al. for similar compounds which do
not contain the aromatic ring.11 Hydrolysis of one of the
ester groups in 5 with one equivalent of potassium
hydroxide in ethanol gave the monoester 6. The acrylic
ester 7 was obtained by reacting 6 with diethylamine
and 37% formaldehyde. As a ®rst approach, ester 7 was
converted to the ethyl ester analogue of 11 (see Scheme
1), but attempts to hydrolyze the ethyl ester at the end
of the synthesis proved to be problematic. Attempted
ester hydrolysis under basic conditions displaced the
Figure 1. Reaction of carnitine with an acyl-CoA.
hypoglycemic agents in animals. However, neither com-
pound has been developed into a clinical treatment for
hyperglycemia, probably because they cause myocardial
hypertrophy in animals via the inhibition of M-CPT-1.9
Recently, two inhibitors selective for the liver isoform of
CPT-1 have been identi®ed. One of these, a long chain
phosphonate ester of carnitine, was reported to be a
reversible, competitive inhibitor of CPT-1 by Anderson
et al.9 The phosphonate did not cause myocardial
hypertrophy in vivo and was thus assumed to selectively
inhibit L-CPT-1. The other, 2-[6-(2,4-dinitrophenoxy)-
hexyl]oxirane-2-carboxylic acid (2), was reported to be
an irreversible inhibitor selective for L-CPT-1.3 Pre-
viously described glycolic acids (like etomoxir and
TDGA) caused myocardial hypertrophy as well as
Figure 2. The carnitine pathway.

T. L. Hutchison, W. J. Brouillette/Bioorg. Med. Chem. 6 (1998) 2133±2138
2135
Scheme 1.
dinitrophenol group, while hydrolysis under acidic con-
ditions opened the epoxide ring. Therefore, ethyl ester 7
was hydrolyzed to provide 8, which underwent reaction
with nitronium tetra¯uoroborate12 to provide 9 as a
solid. The tert-butyldiphenylsilyl ester, 10, was then
prepared from the corresponding acid and tert-butyldi-
phenylsilyl chloride.13 This ester was then epoxidized
with MCPBA followed by removal of the silyl ester
group using tetrabutylammonium ¯uoride to yield 2.
over magnesium ethoxide, methylene chloride was dis-
tilled over phosphorus pentoxide, and tetrahydrofuran
was distilled over sodium metal and benzophenone prior
to use. Benzene and 1,2-dichloroethane were distilled
over calcium hydride. Acetone was dried over potassium
permangenate followed by distillation from calcium
sulfate. All other solvents were reagent grade, obtained
from Fisher Scienti®c or Aldrich Chemical Company,
and were used without further puri®cation. Elemental
analyses were performed at Atlantic Microlab of
Atlanta, GA.
Experimental
General
6-Bromo-1-phenoxyhexane (4). A mixture of phenol (3,
22.1 g, 234 mmol), 1,6-dibromohexane (250 mL, 35.1 g,
1.63 mol), anhydrous K2CO3 (66.9 g, 400 mmol), and 18-
crown-6 (2.00 g, 757 mmol) in acetone (1.00 L) was
heated to re¯ux for 24 h. The reaction mixture was con-
centrated to dryness and ethyl acetate (200 mL) was
added. The ethyl acetate solution was washed with 5%
Na2CO3 (3Â100 mL), saturated NaCl (3Â100 mL) and
dried (Na2SO4). The solvent was removed in vacuo to
yield a mixture of 4 and 1,6-dibromohexane (203 g),
which was distilled to yield 4 (56.0 g, 90.4%) as an oil:
bp 104±106ꢀC/0.2 mm Hg (lit.14 126±130 ꢀC/2 mm Hg).
Melting points were determined on an electrothermal
melting point apparatus and are uncorrected. The 1H
and 13C NMR spectra were recorded on a Bruker DRX-
400 or a Bruker ARX-300 spectrometer. Chemical shifts
are referenced in ppm down®eld from internal TMS for
1H and 13C NMR spectra. IR spectra were obtained on
a Bruker Vector 22 FT-IR or a Perkin±Elmer 1310 IR
spectrometer. Mass spectra were recorded by electro-
spray on a Perkin±Elmer Sciex API-III spectrometer.
Flash chromatographic separations were on Baker silica
gel, 40 mm, and TLC was performed on Whatman brand
silica gel plates (250 mm layer, 5Â10 cm). HPLC separa-
tions were performed using a Rainin Dynamax silica
column on a Rainin Rabbit HPLC system. All liquid
reagents were distilled prior to use. Ethanol was distilled
Diethyl 2-(6-phenoxyhexyl)propanedioate (5). Diethyl
malonate (6.35 mL, 6.70 g, 41.8 mmol) was added drop-
wise to a freshly prepared mixture of sodium (0.850 g,
37.0 mmol) in dry ethanol (200 mL) under a nitrogen
atmosphere. Compound
4 (7.17 g, 27.9 mmol) was

2136
T. L. Hutchison, W. J. Brouillette/Bioorg. Med. Chem. 6 (1998) 2133±2138
added rapidly, and the reaction mixture was heated at
re¯ux for 2.5 h. The solvent was removed in vacuo to
yield a white residue which was dissolved in H2O
(100 mL) and extracted with ethyl acetate (3Â50 mL).
The combined organic layers were washed with satu-
rated NaCl solution (2Â50 mL) and dried (Na2SO4).
The solvent was removed in vacuo to yield 5 as an oil
(7.73 g, 82.4%), which was puri®ed by distillation: bp
173±174 ꢀC/0.4 mm Hg; Rf 0.63 (30% ethyl acetate/70%
(2Â50 mL), and dried (Na2SO4); then the solvent was
removed in vacuo to yield 7 as an oil (5.69 g, 91.9%),
which was puri®ed by distillation: bp 132±133 ꢀC/
0.2 mm Hg; Rf 0.71 (30% ethyl acetate/70% hexanes);
IR (neat) 1710 (C=O), 1620 (C=C), 1240 (asymmetric
1
C±O±C), 1030 (symmetric C±O±C) cm
;
1H NMR
(CDCl3) d 1.30 (t, 3H, OCH2CH3), 1.50±1.35 (m, 6H,
O(CH2)2CH2CH2CH2) 1.72±1.81 (m, 2H, OCH2CH2),
2.31 (t, 2H, CH2C(=C)CO2Et), 3.95 (t, 2H, OCH2),
4.20 (q, 2H, CO2CH2CH3), 5.51 (dd, 1H, C=CH2), 6.15
(d, 1H, C=CH2), 6.95±6.85 (m, 3H, aromatic), 7.23±
7.31 (m, 2H, aromatic); 13C NMR (CDCl3) d 167.3,
159.1, 141.0, 129.3, 124.1, 120.4, 114.5, 67.7, 60.5, 31.7,
29.2, 28.9, 28.3, 25.8, 14.2; MS (ES) m/z 277 (M+H)+.
Anal. calcd for C17H24O3: C, 73.88; H, 8.75. Found: C,
73.98; H, 8.78.
hexanes); IR (neat) 1732 and 1742 (C=O), 1245 (asym-
1
metric C±O±C), 1033 (symmetric C±O±C) cm
;
1H
NMR (CDCl3) d 1.25 (t, 6H, CO2CH2CH3), 1.30±1.50
(m, 6H, O(CH2)2CH2CH2CH2), 1.70±1.80 (m, 2H,
OCH2CH2), 1.90±2.00 (m, 2H, CH2CH(CO2Et)2), 3.30
(t, 1H, CH(CO2Et)2), 3.95 (t, 2H, OCH2), 4.20 (q, 4H,
CO2CH2CH3), 6.85±6.95 (m, 3H, aromatic), 7.20±7.30
(m, 2H, aromatic); 13C NMR (CDCl3) d 169.3, 158.9,
129.2, 120.3, 114.3, 67.4, 61.1, 51.8, 28.9, 28.8, 28.5,
27.1, 25.6, 13.9; MS (ES) m/z 337 (M + H)+. Anal.
calcd for C19H28O5: C, 67.83; H, 8.39. Found: C, 67.96;
H, 8.34.
2-Methylene-8-phenoxyoctanoic acid (8). A mixture of
2.0 N KOH/ethanol (10.0 mL, 20.0 mmol) and 7 (1.40 g,
5.07 mmol) was stirred at 25 ꢀC for 8 h. The solvent was
removed in vacuo to yield a white residue which was
dissolved in H2O (50 mL) and extracted with ethyl acet-
ate (3Â25 mL). The aqueous layer was acidi®ed (pH 3)
with 5% HCl and extracted with ethyl acetate
(3Â25 mL). The combined organic extracts were washed
with saturated NaCl (3Â25 mL) and dried (Na2SO4).
The solvent was removed in vacuo to yield 8 as a white
solid (1.12 g, 88.9%): mp 53±54 ꢀC (benzene); Rf 0.44
(30% ethyl acetate/70% hexanes); IR (KBr) 3500±2500
Ethyl 2-(6-phenoxyhexyl)propanedioate (6). Compound
5 (10.0 g, 29.7 mmol) was suspended in 1 N KOH/etha-
nol (40.0 mL, 40.0 mmol). The reaction mixture was
stirred at 25 ꢀC under a nitrogen atmosphere for 6 h.
The solvent was removed in vacuo to yield a white resi-
due which was taken up in H2O (75 mL) and extracted
with ether (3Â50 mL). The aq layer was acidi®ed with
5% HCl (pH 2) and extracted with ether (3Â50 mL).
The combined ether extracts were dried (Na2SO4) and
the solvent was removed in vacuo to yield 6 as an oil
(8.91 g, 97.3%), which was puri®ed by distillation: bp
148±149 ꢀC/0.3 mm Hg; Rf 0.34 (30% ethyl acetate/70%
hexanes); IR (neat) 3500±2500 (OH), 1712 and 1737
(OH), 1693 (C=O), 1625 (C=C), 1250 (asymmetric
1
C±O±C), 1034 (symmetric C±O±C) cm
;
1H NMR
(CDCl3) d 1.35±1.42 (m, 2H, O(CH2)3CH2), 1.42±1.60
(m, 4H, O(CH2)2CH2 and O(CH2)4CH2), 1.73±1.82 (p,
2H, OCH2CH2), 2.32 (t, 2H, O(CH2)5CH2), 3.95 (t, 2H,
OCH2), 5.65 (d, 1H, C=CH2), 6.28 (s, 1H, C=CH2),
6.85±6.95 (m, 3H, aromatic), 7.25±7.29 (m, 2H, aro-
matic); 13C NMR (CDCl3) d 172.3, 159.1, 140.1, 129.4,
127.0, 120.5, 114.5, 67.8, 31.5, 29.2, 29.0, 28.3, 25.9; MS
(ES) m/z 248 (M+H)+. Anal. calcd for C15H20O3: C,
72.55; H, 8.12. Found: C, 72.45; H, 8.15.
(C=O), 1245 (asymmetric C±O±C), 1033 (symmetric
1
C±O±C) cm
;
1H NMR (CDCl3) d 1.25 (t, 3H,
CO2CH2CH3), 1.35±1.40 (m, 4H, O(CH2)3CH2CH2),
1.40±1.50 (m, 2H, O(CH2)2CH2), 1.70±1.80 (p, 2H,
OCH2CH2), 1.90±2.00 (m, 2H, CHCH2), 3.35 (t, 1H,
CH(CO2Et)(CO2H)), 3.95 (t, 2H, OCH2), 4.20 (q, 2H,
OCH2CH3), 6.85±6.95 (m, 3H, aromatic), 7.21±7.29 (m,
2H, aromatic); 13C NMR (CDCl3) d 175.1, 169.5, 159.1,
129.4, 120.5, 114.5, 67.7, 61.7, 51.8, 29.2, 29.0, 28.8,
27.2, 25.8, 14.1; MS (ES) m/z 265 (M-CO2)+. Anal.
calcd for C17H24O5: C, 66.21; H, 7.84. Found: C, 66.29;
H, 7.92.
2-Methylene-8-(2,4-dinitrophenoxy)octanoic acid (9).
Compound 8 (2.00 g, 8.10 mmol) in anhydrous CH2Cl2
(200 mL) was cooled under a nitrogen atmosphere in an
ice bath for 30 min. NO2BF4 (6.81 g, 51.3 mmol) was
added to the cooled reaction mixture. After 1 h, the
reaction was quenched with cold H2O (50 mL) and
extracted with CH2Cl2 (3Â50 mL). The combined
organic extracts were washed with saturated NaCl
(2Â50 mL) and dried (Na2SO4). The solvent was
removed in vacuo to yield 9 as a yellow solid (2.55 g,
93.8%): mp 93±94 ꢀC (ether); Rf 0.45 (90% CH2Cl2/9%
hexanes/1% HOAc); IR (KBr) 3250±2500 (OH), 1694
(C=O), 1627 (C=C), 1518 (asymmetric NÁ Á ÁO), 1349
Ethyl 2-methylene-8-phenoxyoctanoate (7). Compound 6
(6.90 g, 22.4 mmol) was added to a mixture of diethyla-
mine (10.0 mL, 7.07 g, 96.7 mmol) and 37% for-
maldehyde (18.0 mL, 239 mmol) under
a nitrogen
atmosphere. The mixture was heated to re¯ux for
30 min, diluted with H2O (50 mL), and extracted with
ether (3Â50 mL). The combined ether layers were
washed with 5% HCl (3Â50 mL), saturated NaCl
1
(symmetric NÁ Á ÁO), 1073 (symmetric C±O±C) cm 1; H
NMR (CDCl3) d 1.35±1.43 (m, 2H, O(CH2)3CH2),

T. L. Hutchison, W. J. Brouillette/Bioorg. Med. Chem. 6 (1998) 2133±2138
2137
1.49±1.58 (m, 4H, O(CH2)2CH2 and O(CH2)4CH2),
1.85±1.95 (p, 2H, OCH2CH2), 2.32 (t, 2H, O(CH2)5
CH2), 4.25 (t, 2H, OCH2), 5.65 (d, 1H, C=CH2), 6.28
(d, 1H, C=CH2), 7.19 (d, 1H, aromatic H-6), 8.45 (dd,
1H, aromatic H-5), 8.75 (d, 1H, aromatic H-3); 13C
NMR (CDCl3) d 171.96, 156.90, 139.99, 139.82, 129.01,
127.19, 121.88, 114.23, 70.82, 31.41, 28.65, 28.59, 28.23,
25.49; MS (ES) m/z 338 (M+H)+. Anal. calcd for
C15H18N2O7: C, 53.25; H, 5.36; N, 8.28. Found: C,
53.15; H, 5.18; N, 8.09.
1536 (asymmetric NÁ Á ÁO), 1343 (symmetric NÁ Á ÁO)
cm 1; 1H NMR (CDCl3) d 1.12 (s, 9H, Si-C(CH3)3, 1.31±
1.42 (m, 2H, O(CH2)3CH2), 1.43±1.62 (m, 4H,
O(CH2)2CH2 and O(CH2)4CH2), 1.82±1.89 (p, 2H,
OCH2CH2), 2.34 (t, 2H, O(CH2)5CH2), 4.19 (t, 2H,
OCH2), 5.66 (d, 1H, C=CH2), 6.34 (d, 1H, C=CH2),
7.13 (d, 1H, aromatic), 7.34±7.44 (m, 6H, aromatic),
7.67±7.69 (dd, 4H, aromatic), 8.37 (dd, 1H, aromatic),
8.72 (d, 1H, aromatic); 13C NMR (CDCl3) d 168.06,
157.25, 142.31, 135.68, 132.35, 130.44, 129.35, 128.11,
126.31, 122.22, 114.59, 71.17, 32.25, 29.07, 28.92, 28.84,
27.34, 25.78; MS (ES) m/z 592 (M H). Anal. calcd for
C31H36N2O8Si: C, 62.82; H, 6.13; N, 4.72. Found: C:
63.06; H, 6.21; N, 4.89.
tert-Butyldiphenylsilyl 2-methylene-8-(2,4-dinitrophen-
oxy)octanoate (10). DBU (0.150 mL, 0.26 g, 1.00 mmol)
and t-butyldiphenylchlorosilane (0.25 mL, 0.96 mmol)
were added to a mixture of 9 (300 mg, 0.890 mmol) in
dry benzene (100 mL) under a nitrogen atmosphere. The
reaction was stirred at 25 ꢀC for 60 min and quenched
with H2O (80 mL). The organic layer was washed con-
secutively with 5% HCl (2Â50 mL), 5% NaHCO3
(2Â50 mL), and saturated NaCl (2Â50 mL) and then
was dried (Na2SO4). The solvent was removed in vacuo
to yield 10 (503 mg) as a mixture. The crude mixture was
chromatographed on a ¯ash silica gel column (3Â34 cm,
30% ethyl acetate/hexanes) to ®rst provide a mixture
(95 mg) of 10 and unreacted t-butyldiphenylchloro-
silane. Further elution gave 10 (380 mg, 74.3%) as a
light-yellow solid: mp 87±89 ꢀC; Rf 0.67 (30% ethyl
acetate/hexanes); IR (KBr) 1692 (C=O), 1607 (C=C),
2-[6-(2,4-Dinitrophenoxy)hexyl]oxiranecarboxylic acid
(2). Tetrabutylammonium ¯uoride (0.50 mL, 1.0 M in
anhydrous THF, 0.50 mmol) was added to a mixture of
11 (140 mg, 0.24 mmol) in dry THF (2.0 mL). This mix-
ture was stirred at 0 ꢀC for 30 min. The solvent was
removed under vacuum, ethyl acetate (20 mL) was
added, and the mixture was washed with cold 5%
NaHCO3 (3Â10 mL). The combined NaHCO3 extracts
were cooled in ice and acidi®ed with cold 5% HOAc
(pH 4). The acidic solution was extracted with ethyl
acetate (3Â20 mL), the combined organic layers were
dried (Na2SO4), and the solvent was removed in vacuo
to yield 2 (62 mg, 74%) as a solid: mp 101±103 ꢀC
(CH3OH/ether); 1H NMR (MeOH-d4) d 1.41±1.73 (m,
7H, hexyl H-1a, H-2, H-3, H-4), 1.86 (p, 2H, hexyl H-5),
2.10±2.23 (m, 1H, hexyl H-1b), 2.73 (d, 1H, OCH2), 2.93
(d, 1H, OCH2), 4.35 (t, 2H, hexyl H-6), 7.41 (d, 1H,
aromatic), 8.43 (dd, 1H, aromatic), 8.84 (d, 1H, aro-
matic); 13C NMR (MeOH-d4) 174.08, 157.98, 141.36,
130.09, 127.33, 122.30, 116.21, 71.93, 58.08, 52.63,
32.26, 30.05, 29.62, 26.58, 25.84; MS m/z 353 (M H);
Anal. calcd. for C15H18N2O8: C, 50.84; H, 5.13; N, 7.90.
Found: C, 51.15; H, 5.28; N, 8.14.
1530 (asymmetric NÁ Á ÁO), 1345 (symmetric NÁ Á ÁO)
1
cm
;
1H NMR (CDCl3) d 1.12 (s, 9H, SiC(CH3)3),
1.35±1.42 (m, 2H, O(CH2)3CH2), 1.45±1.55 (m, 4H,
O(CH2)2CH2 and O(CH2)4CH2), 1.80±1.90 (p, 2H,
OCH2CH2), 2.35 (t, 2H, O(CH2)5CH2), 4.18 (t, 2H,
OCH2), 5.68 (d, 1H, C=CH2), 6.37 (d, 1H, C=CH2),
7.12 (d, 1H, aromatic), 7.31±7.42 (m, 6H, aromatic),
7.65±7.71 (dd, 4H, aromatic), 8.38 (dd, 1H, aromatic),
8.72 (d, 1H, aromatic); 13C NMR (CDCl3) d 166.31,
156.87, 141.93, 139.94, 135.30, 131.97, 130.06, 128.97,
127.73, 125.93, 121.83, 114.21, 77.22, 70.79, 31.87,
28.69, 28.54, 28.46, 26.96, 25.41, 19.28; MS (ES) m/z
594 (M+NH4)+; Anal. calcd for C31H36N2O7Si: C,
64.56; H, 6.31; N, 4.86. Found: C, 64.33; H, 6.18, N,
4.78.
References
1. Bremer, J. Physiol. Rev. 1983, 63, 1420.
2. Weis, B. C.; Esser, V.; Foster, D. W.; McGarry, J. D. J.
Biol. Chem. 1994, 269, 18712.
tert-Butyldiphenylsilyl 2-[6-(2,4-dinitrophenoxy)hexyl]oxi-
ranecarboxylate (11). Compound 10 (770 mg, 1.34 mmol)
in dry 1,2-dichloroethane (60.0 mL) was combined
with MCPBA (1.45 g, 8.40 mmol) and 3-tert-butyl-4-
hydroxy-5-methyl-phenylsul®de (31.0 mg, 0.0865 mmol)
and heated to 60 ꢀC for 14 h. The heating was stopped
and the reaction mixture was cooled to room tempera-
ture followed by cooling in an ice bath. The cold solution
was washed with cold 5% Na2CO3 (3Â50 mL) and satu-
rated NaCl (2Â50 mL) and then dried (Na2SO4). The
solvent was removed in vacuo to yield 11 (760 mg, 96%)
as an oily solid. IR (KBr) 1707 (C=O), 1608 (C=C),
3. Weis, B. C.; Cowan, A. T.; Brown, N.; Foster, D. W.;
McGarry, J. D. J. Biol. Chem. 1994, 269, 26443.
4. DeFronzo, R. A. Diabetes 1988, 5, 271.
5. Golay, A.; Swislocki, A.; Chen, Y.-Di. I.; Reaven, G. M.
Metabolism 1987, 36, 692.
6. Tutwiler, G. F.; Ho, W.; Mohrbacher, R. J. Methods
Enzymol. 1981, 72, 533.
7. Lilly, K.; Chuang, C.; Kerner J.; VanRenterghern R.; Bie-
ber, L. L. Biochem. Pharmacology 1992, 43, 353.
8. Lopaschuk, G. D.; McNeil, G. F.; McVeigh, J. J., Mol. Cell.
Biochem. 1989, 88, 175.

2138
T. L. Hutchison, W. J. Brouillette/Bioorg. Med. Chem. 6 (1998) 2133±2138
9. Anderson, R. C.; Balestra, M.; Bell, R. A.; Deems, R. O.;
Fillers, W. S.; Foley, J. E.; Fraser, J. D.; Mann, W. R.; Rudin,
M.; Villhauer, E. B. J. Med. Chem. 1995, 38, 3448.
12. Prakash, G. K.; Wang, Q.; Li, X.; Olah, G. A. Helv. Chem.
Acta 1990, 73, 1167.
13. Davis, J. T.; Moore, R. N.; Imperiali, B.; Pratt, A. J.;
Kobayashi, K.; Masamune, S.; Sinskey, A. J.; Walsh, C.
T. J. Biol. Chem. 1987, 262, 82.
10. Diana, G. D., Salvador, J.; Xalay, E. S.; Carabateas, P. M.;
Williams, G. L.; Collins, J. C.; Pancid, F. J. Med. Chem. 1977,
20, 757.
11. Ho, W.; Tutwiler, G. F.; Cottrell, S. C.; Morgans, D. J.;
Tarhan, O.; Mohrbacher, R. J. J. Med. Chem. 1986, 29, 2184.
14. Illuminati, G.; Mandolini, L.; Masci, B. J. Org. Chem.
1974, 39, 2598.