Long hydrocarbon chain ether diols and ether diacids that favorably alter lipid disorders in vivo

Article abstract of DOI:10.1021/jm0400395

Long hydrocarbon chain ethers with bis-terminal hydroxyl or carboxyl groups have been synthesized and evaluated for their potential to favorably alter lipid disorders including metabolic syndrome. Compounds were assessed for their effects on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes as well as for their effects on lipid and glycemic variables in female obese Zucker fatty rats following 1 and 2 weeks of daily oral administration. The most active compounds were found to be symmetrical with four to five methylene groups separating the central ether functionality and the gem dimethyl or methyl/aryl substituents. Biological activity was found to be greatest for tetramethyl-substituted ether diols (e.g., 28 and 31), while bis(arylmethyl) derivatives (e.g., 10, 11, and 27), diethers (e.g., 49, 50, and 56), and diphenyl ethers (e.g., 35 and 36) were the least active. For the most biologically active compound 28, we observed as much as a 346% increase in serum HDL-cholesterol and a 71% reduction in serum triglycerides at the highest dose administered (100 mg/kg) after 2 weeks of treatment. For compound 31 we observed a 69% reduction in non-HDL-cholesterol, accompanied by a 131% increase in HDL-cholesterol and an 84% reduction in serum triglycerides under the same treatment conditions.

Full text of DOI:10.1021/jm0400395

J . Med. Chem. 2004, 47, 5183-5197
5183
Lon g Hyd r oca r bon Ch a in Eth er Diols a n d Eth er Dia cid s Th a t F a vor a bly Alter
Lip id Disor d er s in Vivo
Ralf Mueller,† J ing Yang,† Caiming Duan,† Emil Pop,† Lian Hao Zhang,† Tian-Bao Huang,† Anna Denisenko,†
Olga V. Denisko,† Daniela C. Oniciu,*,‡ Charles L. Bisgaier,‡ Michael E. Pape,‡ Catherine Delaney Freiman,‡
Brian Goetz,‡ Clay T. Cramer,‡ Krista L. Hopson,‡ and J ean-Louis H. Dasseux‡
Alchem Laboratories Corporation, 13305 Rachael Boulevard, Alachua, Florida 32615, and Esperion Therapeutics, A Division
of Pfizer Global Research and Development, 3621 South State Street, 695 KMS Place, Ann Arbor, Michigan 48108
Received February 17, 2004
Long hydrocarbon chain ethers with bis-terminal hydroxyl or carboxyl groups have been
synthesized and evaluated for their potential to favorably alter lipid disorders including
metabolic syndrome. Compounds were assessed for their effects on the de novo incorporation
of radiolabeled acetate into lipids in primary cultures of rat hepatocytes as well as for their
effects on lipid and glycemic variables in female obese Zucker fatty rats following 1 and 2
weeks of daily oral administration. The most active compounds were found to be symmetrical
with four to five methylene groups separating the central ether functionality and the gem
dimethyl or methyl/aryl substituents. Biological activity was found to be greatest for
tetramethyl-substituted ether diols (e.g., 28 and 31), while bis(arylmethyl) derivatives (e.g.,
10, 11, and 27), diethers (e.g., 49, 50, and 56), and diphenyl ethers (e.g., 35 and 36) were the
least active. For the most biologically active compound 28, we observed as much as a 346%
increase in serum HDL-cholesterol and a 71% reduction in serum triglycerides at the highest
dose administered (100 mg/kg) after 2 weeks of treatment. For compound 31 we observed a
69% reduction in non-HDL-cholesterol, accompanied by a 131% increase in HDL-cholesterol
and an 84% reduction in serum triglycerides under the same treatment conditions.
Sch em e 1. Synthesis of Symmetrical Ether Diols
In tr od u ction
Starting from Dihalo Ethersa
We have previously shown that keto-substituted
hydrocarbons with hydroxyl or carboxyl termini can
favorably alter lipids in an animal model of metabolic
syndrome.1a,b Here, we have extended those studies to
ether derivatives of long-chain hydrocarbons with vary-
ing chain length, symmetry, terminal groups, and
quaternary carbon substitutions. To assess biological
activity, compounds were tested in both a short-term
(hours) in vitro total lipid synthesis assay and a long-
term (weeks) in vivo animal model in which we deter-
mined serum lipid changes over a 2-week period in the
obese female Zucker rat, a model of diabetic dyslipi-
demia.
Resu lts a n d Discu ssion
Dr u g Design . We have investigated a series of ethers
and examined the influence of chain length, aromatic
rings, symmetry, terminal groups, and substitution
pattern at the quaternary carbons R to the terminal
carboxyl or â to the hydroxyl moieties. Since a single,
specific molecular target has not been positively identi-
fied for long-chain hydrocarbon compounds in general,
their lipid regulating activity could be explained by
cumulative effects on multiple targets. For this reason,
biological activity was tested in cell-based as well as in
animal models in order to ensure a full complement of
operative biochemical pathways.
a
Reagents: (a) HBr, H2SO4, 13%; (b) HCl; (c) EtOH, H2SO4;
(d) LiAlH4 [THF], 66%; (e) PBr3, 55%; (f) for 6, ethyl isobutyrate,
LDA [THF/DMPU], 69%; for 7, ethyl 2-phenylpropionate, LDA
[THF/DMPU], 27%; for 8, ethyl 2-phenylpropionate, LDA [THF/
DMPU], 94%; (g) for 9, LiAlH4 [Et2O], 79%; for 10, LiAlH4 [THF],
82%; for 11, LiBH4, MeOH [CH2Cl2], 95%.
Ch em istr y. A series of long hydrocarbon chain ether
diols was synthesized. The side chains connected to the
central ether functionality varied both in the number
of methylene spacer units (n ) 3-5) and in the attached
geminal modifying groups (R ) Me, Ph), resulting in
ether diols of either the symmetrical (9-11, Scheme 1;
28 and 31, Scheme 2) or the unsymmetrical (26, 27, 29,
* To whom correspondence should be addressed. Phone: (734) 222-
1825. Fax: (734) 332-0516. E-mail: Daniela.Oniciu@pfizer.com.
† Alchem Laboratories Corporation.
‡ Esperion Therapeutics, A Division of Pfizer Global Research and
Development.
10.1021/jm0400395 CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/10/2004

5184 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21
Mueller et al.
Sch em e 2. Symmetrical and Unsymmetrical Ether
Sch em e 4. Synthesis of Cyclic Ether Diolsa
Diols via Williamson Ether Synthesisa
a
Reagents: (a) K2CO3 [DMSO/H2O]; (b) NaH [THF]; (c) con-
centrated HCl [MeOH].
Sch em e 3. Synthesis of Diaryl Ethersa
a
Reagents: (a) Mg [THF], succinaldehyde, 92%; (b) pTosOH
[toluene], H2SO4 [MeOH/H2O], 35%; (c) TsCl, pyridine [CH2Cl2],
∆ [pyridine/HMPA], H2SO4 [MeOH/H2O], 38%; (d) Mg [THF],
glutaric aldehyde, 55%; (e) H2SO4 [MeOH/H2O], 80%; (f) pTosOH
[toluene], 55%.
Sch em e 5. Synthesis of Ether Diacid 45 via
Wittig-Horner Reactiona
a
Reagents: (a) NBS, benzoyl peroxide [CCl4]; (b) ethyl iso-
butyrate, LDA [THF/DMPU]; (c) KOH [EtOH/H2O]; (d) LiAlH4
[THF].
and 30, Scheme 2) category. In addition, the aryl-
bridged diacid 35 and diol 36 (Scheme 3) as well as the
diols 38 and 41 with cyclic ether structures (Scheme 4)
were synthesized and examined for comparison. Also
included in this study were the ether diacid 45 (Scheme
5) with γ,γ,γ′,γ′-tetramethyl substitution, the THP-
protected derivatives 22 and 46 (Scheme 6), compounds
49, 50, 55, and 56 with a diether structural element
(Schemes 7, 8), and finally the hydrocarbon chain
analogues 61-63 (Scheme 9).
a
Reagents: (a) SO3-Py, NEt3 [DMSO], 63%; (b) (EtO)2P(O)-
CH2CO2Me, NaH [DMF]; (c) H2, 10% Pd-C [EtOH]; (d) KOH
[MeOH/H2O], 56%.
Sch em e 6. Synthesis of THP-Protected Ether Diols 22
and 46a
The synthesis of long hydrocarbon chain ether diols
was accomplished by two different methods.1c,d Accord-
ing to the first procedure (Scheme 1), bis(ω-haloalkyl)
ethers were reacted with lithiated ethyl esters and the
resulting diesters were reduced to the target diols. For
n ) 3, the starting dibromo ether 4 was first prepared
by condensing 1,3-propanediol (1) with 48% aqueous
HBr and concentrated H2SO4.2 However, the yield for
this reaction was only 13%, and purification of 4 was
difficult (fractional distillation). A better overall yield
(36%) was obtained when dinitrile 2 was converted via
a three-step reaction sequence consisting of saponifica-
tion (concentrated HCl),3 esterification (EtOH, concen-
a
Reagents: (a) pTosOH, 3,4-dihydro-2H-pyran [CH2Cl2]; 22,
21%; 46, 32%.
trated H2SO4),4 and reduction (LiAlH4) to diol 3 (66%),4
which was then transformed to 4 with PBr3 (55%).5
Bromide substitution in 4 with lithio ethyl isobutyrate
and lithio ethyl 2-phenylpropionate1,6 in THF and
cosolvent dimethylpropyleneurea (DMPU) gave diesters
6 and 7 in 69% and 27% yield, respectively. Reduction

Ether Diols and Ether Diacids
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21 5185
Sch em e 7. Synthesis of Diether Compounds 49 and 50a
Ta ble 1. Symmetrical and Unsymmetrical Ether Diols via
Williamson Ether Synthesis
compd
n
m
R1
R2
yield (%)
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3
3
4
4
5
CH3
Ph
CH3
Ph
a
a
a
a
CH3
a
4
4
5
4
4
4
4
4
5
4
4
4
4
4
5
CH3
Ph
CH3
CH3
Ph
CH3
CH3
CH3
CH3
CH3
Ph
CH3
CH3
CH3
CH3
99b
38
83b
3
3
4
4
5
5
3
3
4
4
5
5
CH3
Ph
CH3
Ph
CH3
CH3
CH3
Ph
CH3
Ph
63
c
c
c
34
c
a
Reagents: (a) 1-bromo-3-chloropropane, LDA [THF/DMPU],
64%; (b) (1) HO(CH2)2OH, KOtBu [DMAc]; (2) KOtBu, 18-crown-
6, 47, 65-85 °C, 23%; (c) LiAlH4 [MTBE], 52%; (d) KOH [EtOH/
H2O], 44%.
51 (32d)
44d
37d
Scheme 4 illustrates the synthesis of cyclic ether diols
38 and 41. Reaction of the Grignard reagent of bromo-
THP ether 12 with freshly prepared succinaldehyde14,15
in THF gave diol 37 (92%).16 The cyclodehydration17 and
deprotection to tetrahydrofuran derivative 38 were then
accomplished by two different methods: first, 37 was
condensed by treatment with p-toluenesulfonic acid
(pTosOH) in toluene under azeotropic removal18 of the
reaction water. Subsequent removal of the THP groups
(aqueous H2SO4/MeOH) furnished cyclic ether diol 38
in moderate yield (35%). Alternatively, 37 was mono-
tosylated (1.1 equiv of TsCl, Py)19 and then cyclized
under basic conditions (Py, HMPA). After deprotection
of the terminal alcohols (aqueous H2SO4/MeOH) and
purification by chromatography, 38 was obtained in 38%
yield. A methodology similar to the one used for the
synthesis of 38 was utilized to access tetrahydropyranyl
diol 41. Reaction of the Grignard reagent of 12 with
glutaric aldehyde15 gave compound 39 (55%). Deprotec-
tion (aqueous H2SO4/MeOH) furnished tetraol 40 that
could conveniently be purified by crystallization from
CH2Cl2/hexanes (80%). Finally, dehydration of 40 under
acidic conditions (pTosOH, toluene, Dean-Stark) led to
41 in 55% yield.
The synthesis of the γ,γ,γ′,γ′-tetramethyl-substituted
ether diacid 45 began with the oxidation of diol 28 to
dialdehyde 42 using SO3-pyridine complex and NEt3
in DMSO (63%, Scheme 5).20 The R,â-unsaturated ester
43 was then prepared from 42 by the Wittig-Horner
reaction with methyl diethylphosphonoacetate in the
presence of NaH in DMF.21,22 Subsequent hydrogenation
to 44 (Pd-C)22 followed by saponification of the ester
groups (KOH, MeOH/H2O)23 furnished the target com-
pound 45 (yield 56% from 42).
The mono- and bis-THP ethers 22 and 46 (Scheme 6)
were found as trace impurites in the kilogram-scale
synthesis of ether diol 28 (Scheme 2).9 Pure samples of
these compounds were required in order to evaluate
their biological properties. Treatment of 28 with 3,4-
dihydro-2H-pyran (DHP, 1 equiv) and catalytic amounts
of pTosOH in CH2Cl2 produced a mixture of 22, 28,
and 46 that was separated by chromatography to yield
THP ethers 22 (21%) and 46 (32%).
The synthesis of diether diol 49 and diether diacid
50 is shown in Scheme 7. Alkylation of lithiated ethyl
isobutyrate with 1-bromo-3-chloropropane in THF/
DMPU gave chloro ester 47 (64%). Ethylene glycol was
then deprotonated with potassium tert-butoxide (KOt-
24d
CH3
CH3
90 (31d)
30d
a
b
Synthesis described in ref 1. Used without purification for
step b. c Directly used for step c. Overall yield for steps b and c.
d
of the esters with LiAlH4 afforded ether diols 97 and 10
(79% and 82%) after purification by distillation or
chromatography. For n ) 4, the same methodology
starting with diiodide 58 via diester 8 was used and
ether diol 11 was obtained by reduction with LiBH4 and
9
MeOH in CH2Cl2 (86% over both steps).
According to the second method, symmetrical and
unsymmetrical ether diols 26-31 were prepared via
Williamson reaction10 of THP-protected bromo alcohols
12-161 with the sodium salts of alcohols 17-19 (Scheme
2, Table 1). Therefore, bromides 14-16 were hydrolyzed
with K2CO3 in a DMSO/water mixture at reflux11 to
afford alcohols 17-19 in varying yields (38-99%).
Alcohol 17 was deprotonated with NaH in THF at reflux
temperature and condensed with bromo-THP ethers 12
and 16, leading to protected ether intermediates 20 and
24 (60% and 34%), respectively, which were both puri-
fied by column chromatography. Deprotection of 20 and
24 with concentrated HCl in MeOH at reflux furnished
the two unsymmetrical ether diols 26 (51%) and 30
(90%). The yields over both steps for these compounds,
however, were similar (32% and 31%, Table 1). The
synthesis of ethers 27-29 and 30 from alcohols 17-19
and bromides 13-16 followed the same protocol; how-
ever, the protected intermediates 21-23 and 25 were
not purified but directly deprotected to the final ether
diols. The moderate yields obtained over both steps (24-
44%) were in the same range as those with purification
of the THP-protected intermediates, and the differences
in the synthesis of symmetrical (28 and 31) and unsym-
metrical (26, 27, 29, and 31) ether diols were not
significant.
The synthesis of diaryl ethers 35 and 36 is depicted
in Scheme 3. Dibromide 3312 (prepared from diphenyl
ether 3213 via bromination with NBS and benzoyl
peroxide in CCl4) was reacted with lithio ethyl iso-
butyrate in THF/DMPU to give diester 34 (59%).
Saponification of 34 with KOH in aqueous EtOH led to
diacid 35, which was purified by crystallization from
heptane (72%). Reduction of 34 with LiAlH4 afforded
ether diol 36 as an oil (80%).
24

5186 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21
Sch em e 8. Synthesis of Diether Compounds 55 and 56a
Mueller et al.
Sch em e 9. Synthesis of Hydrocarbon Chain Analoguesa
a
Reagents: (a) for n ) 9, 1,9-dibromononane, LDA [THF/
DMPU], 79%; for n ) 11, 1,11-dibromoundecane, LDA [THF/
DMPU], 94%; (b) for n ) 9, LiAlH4 [Et2O], 62%; for n ) 11, LiBH4/
MeOH [CH2Cl2], 51%; (c) KOH [EtOH/H2O], 69%.
a
Reagents: (a) tert-butyl bromoacetate, NBu4HSO4 [aqueous
NaOH/toluene], 72%; (b) LiAlH4 [MTBE], 62%; (c) PBr3, Py
[toluene], 61%; (d) ethyl isobutyrate, LDA [THF/DMPU], 66%; (e)
LiAlH4 [MTBE], 91%; (f) KOH [aqueous EtOH], 98%.
properties for the ether diols and ether diacids described
above as well as for their hydrocarbon analogues. In
vitro studies tested the ability of the compounds to
inhibit the incorporation of 14C-acetate into total cellular
lipids of primary rat hepatocytes over a 4-h time period
(Table 2). The compounds were also tested for their
ability to alter serum lipid variables in an animal model
of diabetic dyslipidemia, the obese Zucker rat, over a
2-week period at a single daily dose of 30 or 100 mg/kg
(Table 3). Selected compounds (28 and 31) were further
evaluated in the Zucker rat by performing a full dose
response and measuring additional serum variables
including markers for diabetes (Tables 4 and 5).
Effect on Lip id Syn th esis In Vitr o. The rat hepa-
tocyte culture is a useful model for assessing de novo
lipid synthesis activity. Key hepatic functions include
the de novo synthesis of both cholesterol and triglycer-
ides from fatty acids that are incorporated into nascent
very low density lipoprotein (VLDL). Therefore, we
studied the effects of ether type compounds and their
analogues on total lipid synthesis activity in that model
using 14C-acetate as the metabolic precursor.29,30 Table
2 summarizes the biological effects of the compounds
in primary rat hepatocyte cultures.
All of the hydrocarbon chain analogues (61-63) with
9 or 11 methylene spacers between the gem substitu-
tions proved to be very active by inhibiting lipid
synthesis with IC50 values of e7 µM. When the central
methylene moiety was replaced with an oxygen atom,
the resulting ethers, 28 and 31, were also quite active
with IC50 values of 11 and 4 µM, respectively; the
shorter chain homologue 9, which contains three
methylenes on both sides of the oxygen, was inactive.
The unsymmetrical ethers 30 and 26 showed activity
with IC50 values of 11 and 17 µM, respectively. These
data indicate that at least nine bonds between the two
carbons with the gem substitutions are needed in order
to induce lipid synthesis inhibition; there is little
difference in the inhibitory activity between ethers and
aliphatic compounds with gem dimethyl substitutions.
Previous studies have indicated no difference in inhibi-
tory activity between terminal diols and diacids in a
related series of ketone compounds.1a,b
Bu, 1.5 equiv) in dimethylacetamide (DMAc) and re-
acted with 47 (1.5 equiv) at 65 °C.25 Further reaction of
this mixture with 47 (1.5 equiv), KOtBu (1.5 equiv), and
catalytic amounts of 18-crown-6 at 65-85 °C afforded
diester 48 (23%). Subsequent reduction of 48 with
LiAlH4 in MTBE led to diol 49 (52%), while its saponi-
fication (KOH, aqueous EtOH) produced diacid 50
(44%).
A different approach was chosen for the synthesis of
the related diether compounds 55 and 56 (Scheme 8).
Alkylation of 1,3-propanediol with an excess of tert-butyl
bromoacetate under phase-transfer conditions26 (NBu4-
HSO4, aqueous NaOH/toluene) furnished diester 51 in
72% yield. Reduction of 51 with LiAlH4 gave diol 52
(62%),27 which was subsequently transformed to dibro-
mide 53 by reaction with PBr3 and pyridine (61%).28
Substitution of the bromides in 53 with lithio ethyl
isobutyrate24 led to diethyl ester 54 (66%), which was
reduced (LiAlH4, 91%) to diether diol 55 as well as
saponified (KOH, aqueous EtOH, 98%) to afford diether
dicarboxylic acid 56.
The hydrocarbon chain analogues to the ether com-
pounds described in this work were synthesized by
reaction of lithio ethyl isobutyrate with dibromides 57
and 58 in THF/DMPU to furnish diesters 59 and 60
(79% and 94%), respectively (Scheme 9). Reduction of
the shorter chain homologue 59 with LiAlH4 in Et2O
produced diol 61 (62%), whereas the longer chain
homologue 60 was reduced with LiBH4 and MeOH in
CH2Cl2 to 62 (51%).9 The tetramethyl-substituted diacid
63, finally, was synthesized from 60 via ester hydrolysis
with KOH in aqueous EtOH (69%).
Biologica l Activity. The structure-based drug de-
sign initiated earlier1a,b has been extended here to the
ether series. The influence of structural modifications
on biological activity has been examined. Specifically,
the effects of the methylene spacer length from the
central ether oxygen to the gem substitutions on the
quarternary carbons, symmetry around the central
ether, kind of the gem substitutions (methyl or phenyl)
and of the terminal functional groups (diols or diacids)
were studied. Tables 2-5 present in vitro and in vivo
biological data in connection with lipid regulating
The cyclic ethers (38 and 41) and the aryl-bridged
ethers (35 and 36) displayed IC50 values ranging from

Ether Diols and Ether Diacids
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21 5187
Ta ble 2. Effect of Ether Diols and Ether Diacids on Lipid
Synthesis in Primary Rat Hepatocytes
or both sides of the central ether were essentially
inactive in vitro, while the monophenyl-substituted
compound 29 was quite active (IC50 ) 5 µM). The diacid
with gem dimethyl substitutions in γ-positions (45) was
active with an IC50 of 22 µM. Mono- and bis-THP ethers
46 and 22 were also active, displaying IC50 values of 11
and 20 µM, respectively.
To demonstrate that the decreased incorporation of
acetate into lipids is not due to a general compound
effect on the cell, we assayed the culture medium for
the release of the cytosolic enzyme lactate dehydroge-
nase (LDH).31 Release of LDH into the media correlates
with plasma membrane damage, an early event in loss
of cell function. Compound-dependent increases in
media LDH are compared to vehicle-treated cultures.
The data for compounds active for inhibition of [1-14C]
acetate incorporation into lipids did not show general
effects on membrane integrity.
Effect on Lip id Va r ia bles in th e Obese F em a le
Zu ck er Ra t. To test the lipid-regulating activity of
these compounds, we used the obese Zucker fatty rat
as a model of diabetic dyslipidemia. The Zucker rat has
a mutation in the leptin receptor that leads to a
metabolic disorder similar to human non-insulin-de-
pendent diabetes mellitus (NIDDM) or type II diabetes.
Animals develop an age-dependent progression of dis-
ease that includes hypertriglyceridemia, increased VLDL-
cholesterol (VLDL-C), decreased HDL-C, impaired in-
sulin sensitivity, hyperphagia, and marked weight gain
leading to obesity. The non-HDL-C in this model is
mainly VLDL-C with essentially no LDL-C. Initially, the
lipid-regulating activities of the ether compounds in this
model were assessed by administering a single dose of
30 or 100 mg/kg every day for up to 2 weeks. Compounds
were evaluated for their ability to produce a less
atherogenic serum lipid profile, that is, reduce non-
HDL-C, elevate HDL-C, and reduce triglycerides. Table
3 summarizes those serum lipid changes induced by the
ether derivatives and their analogues.
The alkyl compounds (61-63) were all very effective
at lowering serum triglyceride levels as evidenced by
the >70% reductions compared to pretreatment values.
Both 61 and 63 consistently reduced non-HDL-C levels,
while only 61 elevated HDL-C. Thus, it appears that
nine methylene spacers are optimum for favorably
affecting all three lipid variables. In the corresponding
ethers, both 28 and 31 markedly reduced serum tri-
glycerides >70% while also significantly elevating HDL-
C. In fact, 28 elevated HDL-C about 5-fold compared to
pretreatment levels. Compound 31 markedly lowered
non-HDL-C, while 28 did not appear to have much effect
on that variable. A direct comparison of compounds with
identical chain topology of the aliphatic or ether variety
(62 vs 31 and 61 vs 28) indicated that of the compounds
with 10 spacer bonds between the two quarternary
carbons, compound 61 with nine methylene groups was
more effective at lowering non-HDL-C than compound
28 in which the central methylene is replaced by oxygen;
however, 28 was significantly more effective at elevating
HDL-C. With respect to compounds with 12 bonds
between the two quarternary carbons, ether 31 was
effective at favorably altering all three lipid variables
while the aliphatic compound 62 only lowered triglyc-
erides. The unsymmetrical 9-bond spacer ether 26 was
a
Not active; inhibition of 14C-acetate incorporation into total
lipids is less than 50% at 300 µM. r2 is the goodness of fit of the
data to the nonlinear sigmoidal model.
b
9 to 98 µM. The aryl-bridged ethers 35 and 36 were very
weak inhibitors with IC50 values of 53 and 98 µM,
respectively, as was the dihydropyran 41 (IC50 ) 39 µM).
The tetrahydrofuran 38 showed relatively potent activ-
ity with an IC50 of 9 µM compared to the tetrahydro-
pyran analogue 41 with an IC50 of 39 µM, while the
compounds containing a diether in the backbone (49 and
50) were relatively weak or inactive in this assay.
Regarding gem substitutions, the diphenyl-substi-
tuted ethers (10 and 27) with three methylenes on one

5188 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21
Mueller et al.
Ta ble 3. Effect of Ether Diols and Ether Diacids in Female Obese Zucker Rats
a
100% represents a 2-fold increase from pretreatment value.
weakly active in vivo in our animal model. Altogether,
these data indicate that within the ether compounds, a
spacer of 12 bonds between quarternary carbons (31)
was more effective at lowering non-HDL-C and triglyc-
erides, while a 10-bond spacer (28) was better at
elevating HDL-C. Furthermore, a minimum spacer
length of 10 bonds is required for activity. Diacid 45,
however, did not affect the HDL-C dramatically but

Ether Diols and Ether Diacids
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21 5189

5190 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21
Mueller et al.
showed significant triglyceride lowering. Compounds 38
and 41 (in which the central ether is part of a ring that
induces restricted rotation of the hydrocarbon chain)
showed significant HDL-C elevation, but relevant lipid
lowering activity is only shown in tetrahydropyran 41.
In this animal model, compounds 49, 50, and 56 with
two ether moieties placed symmetrically in the hydro-
carbon chain showed a weak triglyceride lowering but
no HDL-C elavation. When the ether moiety connects
two aromatic rings as in compounds 35 and 36, a modest
HDL-C elevation and triglyceride lowering were ob-
served compared to compound 28. There are no signifi-
cant differences between the activities of the diacid/diol
pairs (e.g., 35 vs 36, 49 vs 56, and 62 vs 63).
A comparison of activities in the in vitro lipid syn-
thesis assay (Table 2) and the Zucker rat model (Table
3) indicated that all compounds that lowered non-
HDL-C or triglycerides by about 70% had IC50 < 39 µM
in the lipid synthesis inhibition assay. However, some
compounds active in the in vitro assay (26, IC50 ) 17
µM; 22, IC50 ) 20 µM) were poorly active in vivo in the
Zucker rat model.
study is 28, which contains a spacer of 10 bonds between
the gem dimethyl substitutions and hydroxyl terminal
groups. This compound was exceptional at elevating
HDL-C and also lowered serum triglycerides and non-
esterified fatty acids.
Exp er im en ta l Section
Ch em istr y. Chemical reagents were purchased from Sigma-
Aldrich or Lancaster and were used without further purifica-
tion. Silica gel for column chromatography (0.035-0.070 mm,
pore diameter ca. 6 nm) was obtained from Acros Organics.
ACS grade solvents from Fisher Scientific or Mallinckrodt were
routinely used for chromatographic purifications and extrac-
tions. Melting points were determined on either a Thomas-
Hoover capillary or Haake-Buchler melting point apparatus
and are uncorrected. 1H NMR spectra were recorded at 300
MHz, and 13C NMR spectra were recorded at 75 MHz and
ambient temperature on Varian NMR spectrometers. Chemical
shifts for proton NMR are given in parts per million downfield
from an internal tetramethylsilane standard, and 13C chemical
shifts are calibrated on the CDCl3 resonance at 77.23 ppm,
unless otherwise specified. Coupling constants (J ) are given
in Hz. The purities of target compounds were analyzed using
Shimadzu HPLC systems with UV and RI detection.
Bis(3-br om op r op yl) Eth er (4). Under N2 atmosphere,
PBr3 (7.2 mL, 20.5 g, 75.8 mmol) was added dropwise over 1
h to 34 (10.14 g, 75.6 mmol), causing self-heating to reflux.
The reaction mixture was stirred overnight at room temper-
ature, then distilled in vacuo to give an oil. This oil was
dissolved in CH2Cl2 (100 mL), washed with water (100 mL),
dried over Na2SO4, and concentrated in vacuo, affording 4 (10.9
g, 55%) as a clear, colorless oil. Bp 68-70 °C/0.2 mmHg. 1H
NMR (CDCl3): δ 3.56 (t, 4 H, J ) 5.8), 3.51 (t, 4 H, J ) 6.4),
2.10 (m, 4 H). 13C NMR (CDCl3 ) 77.00 ppm): δ 68.17, 32.68,
30.59.
5-(4-E t h oxyca r bon yl-4-m et h ylp en t yloxy)-2,2-d im et h -
ylp en ta n oic Acid Eth yl Ester (6). Under N2 atmosphere and
at -78 °C, to a stirred solution of ethyl isobutyrate (6.5 g, 55.9
mmol) in anhydrous THF (30 mL) was added dropwise a
solution of LDA (30 mL, 60.0 mmol, 2.0 M in heptane/THF/
ethylbenzene). After 1 h, a solution of 42 (6.76 g, 26.0 mmol)
and DMPU (2 mL) in THF (15 mL) was added dropwise, and
the reaction temperature was kept at -78 °C for an additional
30 min. The reaction mixture was allowed to warm to room
temperature and stirred overnight, then quenched with a
mixture of ice (10 g) and concentrated HCl (10 mL). The
product was extracted with Et2O (2 × 30 mL). The combined
ether phases were washed with 5% aqueous NaHCO3 solution
(30 mL), dried over MgSO4, and concentrated in vacuo to
furnish the crude product (10.9 g), which was distilled in high
vacuo to give pure 6 (5.96 g, 69%) as an oil. Bp 115-120 °C/
0.5 mmHg. 1H NMR (CDCl3): δ 4.11 (q, 4 H, J ) 7.0), 3.37
(m, 4 H), 1.62-1.43 (m, 8 H), 1.25 (t, 4 H, J ) 7.0), 1.17 (s, 12
H). 13C NMR (CDCl3 ) 77.00 ppm): δ 177.62, 70.85, 60.06,
41.75, 36.89, 25.14, 24.96, 14.09.
Effect on Lip id Va r ia bles in th e Obese F em a le
Zu ck er Ra t: Dose Resp on se for Selected Com -
p ou n d s. To further investigate the active ether com-
pounds 28 and 31, we performed a complete dose
response study in the Zucker rat (Tables 4 and 5). The
10-bond spacer compound 28 dose-dependently elevated
HDL-C at a minimum effective daily dose of 3 mg/kg.
Compound 28 also reduced serum triglycerides and non-
esterified fatty acids (NEFA) at daily doses of 30 and
100 mg/kg. The compound had no effect on fasting
serum glucose or insulin levels. The 12-bond spacer
compound 31 dose-dependently elevated HDL-C as well,
with a minimal effective daily dose of 10 mg/kg. The
compound also lowered non-HDL-C (100 mg/kg/day) and
triglycerides (30 and 100 mg/kg/day); minimal effects
on NEFA were observed, while glucose and insulin were
not altered.
The mechanism of action (MoA) is clearly a key
component of drug discovery, and our in vivo structure
optimization approach implies that multiple MoAs could
be responsible for the biological activity in the whole
animal. A similar approach has been reported recently
by other research groups.32 We have determined that a
major MoA in this class of compounds is inhibition of
fatty acid synthesis (FAS) at the acetyl-CoA carboxylase
(ACC) step (within minutes of dosing) via an allosteric
mechanism.33 We have also found that these compounds
rapidly block de novo cholesterol synthesis at a step
between acetoacetyl-CoA formation and HMG-CoA,33
inferring that the compounds are dual inhibitors of lipid
synthesis.
5-(5-Hydr oxy-4,4-d im eth ylp en tyloxy)-2,2-dim eth ylp en -
ta n -1-ol (9). Under N2 atmosphere, to a solution of LiAlH4 in
Et2O (55 mL, 1.0 M, 55 mmol) was added dropwise a solution
of 6 (5.62 g, 17.0 mmol) in anhydrous Et2O (25 mL) at such a
rate as to prevent the ether from boiling. The mixture was
stirred for 30 min, then hydrolyzed by subsequent slow
addition of distilled water (30 mL) and 25% H2SO4 (35 mL).
The product was extracted with Et2O (5 × 75 mL). The
combined ether extracts were washed with 5% NaHCO3
solution (2 × 25 mL), dried over MgSO4, and concentrated
under reduced pressure to give an oil (4.95 g). Purification by
vacuum distillation afforded 9 (3.3 g, 79%) as an almost
colorless, very viscous oil. Bp 130-140 °C/0.5 mmHg (lit.7 mp
Con clu sion s
Our research was focused on identifying compounds
for the treatment of dyslipidemia, a major medical
problem related to premature development of cardio-
vascular diseases. A common dyslipidemic patient pre-
sents elevated levels of triglycerides and low levels of
HDL-C. The current discovery effort has generated a
series of novel ether compounds with biological proper-
ties that suggest utility for controlling these serum
variables. The most promising ether compound in this
1
30-32 °C). H NMR (CDCl3): δ 3.41 (t, 4 H, J ) 6.3), 3.28 (s,
4 H), 3.11 (br s, 2 H), 1.60-1.48 (m, 4 H), 1.33-1.24 (m, 4 H),
0.86 (s, 12 H). 13C NMR (CDCl3 ) 77.00 ppm): δ 71.65, 70.55,
34.78, 34.34, 24.06, 23.88. HRMS (CI) Calcd for C14H31O3
(MH+): 247.2273. Found: 247.2265. HPLC: Alltima C-8

Ether Diols and Ether Diacids
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21 5191
column, 250 mm × 4.6 mm, 5 µm; 58% acetonitrile, 42% water,
0.84 (s, 12 H). 13C NMR (CDCl3): δ 99.23, 76.68, 76.58, 71.95,
71.04, 62.03, 39.35, 35.56, 34.40, 34.20, 30.83, 25.75, 24.71,
24.63, 20.78, 19.60. HRMS (LSIMS, nba) Calcd for C25H47O5
[(M - 2H) + H+]: 427.3423. Found: 427.3428.
flow rate 1.0 mL/min; RI, retention time 4.95 min, 86.3% pure.
5-(5-Hyd r oxy-4-m eth yl-4-p h en ylp en tyloxy)-2-m eth yl-
2-p h en ylp en ta n -1-ol (10). According to the procedure given
for the synthesis of 9, 7 (4.2 g, 9.2 mmol) was reduced with
LiAlH4 (1.7 g, 44.8 mmol) in anhydrous Et2O (100 mL) at room
temperature overnight. Hydrolysis with acid, extraction, and
drying afforded pure 10 (2.8 g, 82%) as a colorless oil. 1H NMR
(CDCl3): δ 7.45-7.10 (m, 10 H), 3.70 (d, 2 H, J ) 11.0), 3.58
(d, 2 H, J ) 11.0), 3.28 (t, 4 H, J ) 6.3), 1.90-1.15 (m, 10 H),
1.34 (s, 6 H). 13C NMR (CDCl3 ) 77.00 ppm): δ 144.75, 128.41,
126.62, 126.11, 71.91, 71.21, 43.09, 34.60, 24.16, 21.87. HRMS
(LSIMS, gly) Calcd for C24H35O3 (MH+): 371.2586. Found:
371.2581. HPLC: Alltima C-8 column, 250 mm × 4.6 mm, 5
µm; 60% acetonitrile, 40% water, flow rate 1.0 mL/min; RI,
retention time 8.50 min, 93.9% pure.
Gen er a l P r oced u r e for t h e Dep r ot ect ion of THP
E t h er s:
6-(5-Hyd r oxy-4,4-d im et h ylp en t yloxy)-2,2-d i-
m eth ylh exa n -1-ol (26). A solution of 20 (8.0 g, 18.7 mmol)
in MeOH (80 mL) and concentrated HCl (8 mL) was heated to
reflux for 4 h, then poured into ice-water (40 mL). The
solution was neutralized with saturated NaHCO3 solution (100
mL) and extracted with EtOAc (3 × 100 mL). The combined
organic layers were washed with saturated NH4Cl solution
(100 mL) and brine (100 mL), dried over Na2SO4, and
concentrated in vacuo. The residue (7.4 g) was purified by
chromatography (silica gel; EtOAc/hexanes ) 20/80) to furnish
1
26 (2.5 g, 51%) as a colorless oil. H NMR (CDCl3): δ 3.35 (m,
4 H), 3.23 (s, 4 H), 2.54 (br, 2 H), 1.47 (m, 4 H), 1.22 (m, 6 H),
0.79 (s, 12 H). 13C NMR (CDCl3 ) 77.23 ppm): δ 71.77, 71.43,
71.07, 70.98, 38.25, 35.18, 35.06, 34.68, 30.45, 24.23, 20.63.
HRMS (LSIMS, gly) Calcd for C15H33O3 (MH+): 261.2430.
Found: 261.2413. HPLC: Alltima C-8 column, 250 mm × 4.6
mm, 5 µm; 50% acetonitrile, 50% water, flow rate 1.0 mL/min;
RI, retention time 7.43 min, 96.4% pure.
6-(6-Hyd r oxy-5-m eth yl-5-p h en ylh exyloxy)-2-m eth yl-2-
p h en ylh exa n -1-ol (11). Under N2 atmosphere and at room
temperature, to a suspension of LiBH4 (6.3 g, 289 mmol) in
CH2Cl2 (210 mL) was added dropwise MeOH (8.8 g, 275 mmol)
over 30 min. The reaction mixture was heated to reflux, and
8 (44.0 g, 91.2 mmol) was added. After the mixture was
refluxed overnight and cooled to room temperature, saturated
NH4Cl solution (100 mL) was added and the layers were
separated. The aqueous layer was extracted with CH2Cl2 (3 ×
50 mL). The combined organic layers were washed with 2 N
HCl (100 mL) and saturated NaCl solution (100 mL), dried
over MgSO4, and concentrated in vacuo. The crude product
was purified by flash chromatography (silica; hexanes/EtOAc
) 80/20), affording 11 (34.4 g, 95%) as an oil. 1H NMR
(CDCl3): δ 7.36-7.14 (m, 10 H), 3.67 (d, 2 H, J ) 10.7), 3.52
(d, 2 H, J ) 10.7), 3.27 (t, 4 H, J ) 6.6), 1.82-1.70 (m, 2 H),
1.60-1.10 (m, 10 H), 1.33 (s, 6 H), 1.05-0.95 (m, 2 H). 13C
NMR (CDCl3 ) 77.00 ppm): δ 144.84, 128.37, 126.63, 126.05,
72.35, 70.57, 43.34, 38.21, 30.25, 21.56, 20.44. HRMS (LSIMS,
nba) Calcd for C26H39O3 (MH+): 399.2899. Found: 399.2903.
7-(6-Hyd r oxy-5,5-d im eth ylh exyloxy)-2,2-d im eth ylh ep -
ta n -1-ol (30). According to the method given for the synthesis
of 26, 24 (5.0 g, 10.9 mmol) was heated to reflux in MeOH (60
mL) and concentrated HCl (6 mL) for 4 h. Extractive workup
gave a crude product that was purified by chromatography
(silica gel; EtOAc/hexanes ) 20/80), affording 30 (2.85 g, 90%)
1
as a colorless oil. H NMR (CDCl3): δ 3.34 (m, 4 H), 3.21 (s, 4
H), 2.26 (br, 2 H), 1.60-1.40 (m, 4 H), 1.34-1.10 (m, 10 H),
0.78 (s, 12 H). 13C NMR (CDCl3): δ 71.83, 71.67, 71.06, 70.86,
38.68, 38.42, 35.17, 30.53, 29.73, 27.22, 24.02, 23.76, 20.58.
HRMS (LSIMS, gly) Calcd for C17H37O3 (MH+): 289.2743.
Found: 289.2739. HPLC: Alltima C-8 column, 250 mm × 4.6
mm, 5 µm; 60% acetonitrile, 40% water, flow rate 1.0 mL/min;
RI, retention time 7.63 min, 95.7% pure.
Gen er a l P r oced u r e for th e Hyd r olysis of ω-Br om o- to
ω-Hyd r oxya lk yl THP Eth er s: 6,6-Dim eth yl-7-(tetr a h y-
d r op yr a n -2-yloxy)h ep ta n -1-ol (19). A mixture of 16 (11.0
g, 35.8 mmol), K2CO3 (10.0 g, 72.4 mmol), water (100 mL), and
DMSO (50 mL) was heated to reflux for 24 h. After cooling to
room temperature, the mixture was diluted with water (150
mL) and neutralized by addition of concentrated HCl (5 mL)
and 1 N HCl (15 mL). The solution was extracted with Et2O
(4 × 100 mL). The combined organic layers were washed with
saturated NH4Cl solution (100 mL) and saturated NaCl
solution (100 mL), dried over MgSO4, and concentrated in
vacuo to furnish 19 (7.3 g, 83%) as a colorless oil, which was
Gen er a l P r oced u r e for th e Willia m son Eth er Syn th e-
sis F ollow ed by THP Dep r otection : 6-(5-Hyd r oxy-4-
m et h yl-4-p h en ylp en t yloxy)-2-m et h yl-2-p h en ylh exa n -1-
ol (27). Under Ar atmosphere, to a suspension of NaH (60%,
600 mg, 15 mmol) in anhydrous THF (100 mL) was added
dropwise a solution of 18 (3.3 g, 11.3 mmol) in anhydrous THF
(25 mL). After 30 min of stirring at room temperature, the
mixture was heated to reflux for 1 h and cooled to room
temperature, and a solution of 131b (3.8 g, 11.1 mmol) in
anhydrous THF (25 mL) was added dropwise. The reaction
mixture was heated to reflux for 22 h and hydrolyzed by
addition of ice (100 g) and saturated NH4Cl solution (200 mL).
The mixture was extracted with EtOAc (3 × 300 mL). The
combined organic layers were washed with saturated NH4Cl
solution (3 × 300 mL), dried over MgSO4, and concentrated
in vacuo to give 21 (10.6 g). A solution of this residue in MeOH
(200 mL) and concentrated HCl (20 mL) was heated to reflux
for 6 h. The reaction mixture was diluted with water (50 mL),
and the MeOH was evaporated under reduced pressure. The
solution was extracted with CH2Cl2 (4 × 100 mL). The
combined organic layers were washed with saturated NaHCO3
solution (3 × 400 mL), dried over MgSO4, and evaporated to
give the crude product (6.5 g). Purification by flash chroma-
tography (silica gel; hexanes/EtOAc ) 50/50) afforded 27 (1.88
1
used without further purification for the next step. H NMR
(CDCl3): δ 4.55 (m, 1 H), 3.84 (m, 1 H), 3.61 (t, 2 H, J ) 6.5),
3.51-3.30 (m, 1 H), 3.45 (d, 1 H, J ) 9.1), 2.98 (d, 1 H, J )
9.1), 2.26 (br s, 1H), 1.98-1.40 (m, 8 H), 1.40-1.10 (m, 6 H),
0.88 (s, 6 H). 13C NMR (CDCl3 ) 77.20 ppm): δ 99.17, 76.61,
62.89, 61.95, 39.38, 34.28, 32.87, 30.75, 26.79, 25.66, 24.65,
23.81, 19.50. HRMS (LSIMS, nba) Calcd for C14H29O3 (MH+):
245.2117. Found: 245.2119.
Gen er a l P r oced u r e for th e Willia m son Eth er Syn th e-
sis: 2-{6-[4,4-Dim eth yl-5-(tetr a h yd r op yr a n -2-yloxy)p en -
tyloxy]-2,2-d im eth ylh exyloxy}tetr a h yd r op yr a n (20). Un-
der Ar atmosphere, to a suspension of NaH (95%, 0.76 g, 30
mmol) in anhydrous THF (80 mL) was added dropwise 17 (7.93
g, 34.4 mmol) over 10 min at room temperature. The reaction
mixture was heated to reflux overnight before 12 (9.30 g, 33.3
mmol) was added dropwise, and heating to reflux was contin-
ued for 4 h. After cooling to room temperature, the mixture
was hydrolyzed by adding ice (20 g) and saturated NH4Cl
solution (30 mL). The layers were separated, and the aqueous
layer was extracted with EtOAc (3 × 50 mL). The combined
organic layers were washed with saturated NH4Cl solution (3
× 50 mL), dried over MgSO4, and concentrated in vacuo.
Purification by flash chromatography (silica gel, EtOAc/
hexanes ) 20/80) furnished 20 (9.0 g, 63%) as a yellowish oil.
1H NMR (CDCl3): δ 4.49 (m, 2 H), 3.79 (m, 2 H), 3.39 (m, 8
H), 2.94 (m, 2 H), 1.90-1.38 (m, 14 H), 1.28-1.16 (m, 8 H),
1
g, 44%) as a colorless oil. H NMR (CDCl3): δ 7.36-7.15 (m,
10 H), 3.68 (m, 2 H), 3.55 (m, 2 H), 3.27 (m, 4 H), 1.85-1.30
(m, 10 H), 1.36 (s, 3 H), 1.33 (s, 3 H). 13C NMR (CDCl3): δ
145.07, 144.97, 128.61, 126.85, 126.31, 126.28, 72.52, 72.24,
71.40, 70.75, 43.55, 43.33, 38.38, 34.84, 30.44, 24.36, 22.03,
21.84, 20.70. HRMS (LSIMS, gly) Calcd for C25H37O3 (MH+):
385.2743. Found: 385.2749. HPLC: Alltima C-18/cation col-
umn, 250 mm × 4.6 mm, 5 µm; 60% acetonitrile, 40% water,
flow rate 1.0 mL/min; RI, retention time 9.10 min, 90.1% pure.
6-(6-Hyd r oxy-5-m eth yl-5-p h en ylh exyloxy)-2,2-d im eth -
yl-h exa n -1-ol (29). According to the procedure provided for
the synthesis of 27, 17 (10.57 g, 45.9 mmol) was treated with
NaH (95%, 1.01 g, 40.0 mmol) and 15 (14.95 g, 42.1 mmol) in

5192 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21
Mueller et al.
anhydrous THF (105 mL). After workup by hydrolysis and
extraction, the crude intermediate 23 (21.8 g) was heated to
reflux in MeOH (80 mL) and concentrated HCl (8 mL)
overnight. After extractive workup, the volatile impurities
were distilled off (195 °C/0.5 mmHg) and the residue was
purified by column chromatography (silica; CH2Cl2/acetone )
g, 178 mmol) in anhydrous THF (150 mL) was added dropwise
a solution of LDA (2.0 M in heptane/THF/ethylbenzene, 89 mL,
178 mmol) over 50 min at - 78 °C. The mixture was stirred
for 40 min, and a solution of 33 (prepared from diphenyl ether
3213 via bromination with NBS and benzoyl peroxide,12 25.4
g, 71.2 mmol) in THF (50 mL) was added dropwise over 20
min, keeping the reaction temperature below - 45 °C. DMPU
(20 mL) was added dropwise over 10 min, and the reaction
mixture was allowed to warm to room temperature overnight.
The mixture was poured into half-saturated aqueous NH4Cl
solution (250 mL) and extracted with EtOAc (2 × 200 mL).
The combined organic layers were washed with 1 N aqueous
HCl (250 mL) and saturated NaCl solution (2 × 100 mL), dried
over anhydrous MgSO4, and concentrated in vacuo. The
residue was purified by column chromatography (silica, hep-
tane/EtOAc ) 90/10) to afford 34 (17.9 g, 59%) as a yellowish
1
15:1) to furnish 29 (3.2 g, 24%) as an oil. H NMR (CDCl3): δ
7.38-7.16 (m, 5H), 3.70 (dd, 1 H, J ) 10.7, 4.4), 3.55 (dd, 1 H,
J ) 10.7, 7.7), 3.42-3.18 (m, 6 H), 1.76 (m, 2 H), 1.64-0.95
(m, 15 H), 0.85 (s, 6 H). 13C NMR (CDCl3 ) 77.00 ppm): δ
144.86, 128.31, 126.60, 125.98, 72.23, 71.58, 70.69, 70.58,
43.32, 38.20, 34.97, 30.35, 30.22, 23.88, 21.62, 20.42. HRMS
(LSIMS, gly) Calcd for C21H37O3 (MH+): 337.2743. Found:
337.2751. HPLC: Alltima C-18 column, 250 mm × 4.6 mm, 5
µm; 70% acetonitrile, 30% 0.05 M KH2PO4, flow rate 1.2 mL/
min; UV, retention time 5.83 min, 94.8% pure.
1
oil. H NMR (CDCl3): δ 7.20 (t, 2 H, J ) 7.8), 6.83 (t, 4 H, J
7-(7-Hyd r oxy-6,6-dim eth ylh ep tyloxy)-2,2-d im eth ylh ep -
ta n -1-ol (31). According to the procedure provided for the
synthesis of 27, 19 (1.83 g, 7.5 mmol) was treated with NaH
(60% w/w dispersion in mineral oil, 0.6 g, 15 mmol) and 16
(2.3 g, 7.5 mmol) in anhydrous THF (50 mL). The residue
obtained after extractive workup was heated to reflux in
MeOH (20 mL) and concentrated HCl (2 mL) for 4 h. Workup
and purification by column chromatography (silica; hexanes/
EtOAc ) 10/1 to 3/1) afforded 31 (0.68 g, 30%) as a yellow oil.
1H NMR (CDCl3): δ 3.40 (t, 4 H, J ) 6.6), 3.31 (s, 4 H), 1.71-
1.50 (m, 6 H), 1.40-1.17 (m, 12 H), 0.86 (s, 12 H). 13C NMR
(CDCl3 ) 77.00 ppm): δ 71.90, 70.90, 38.60, 34.98, 29.66,
27.15, 23.84, 23.66. HRMS (LSIMS, gly) Calcd for C18H39O3
(MH+): 303.2899. Found: 303.2907. HPLC: Alltima C-18
column, 250 mm × 4.6 mm, 5 µm; 60% acetonitrile, 40% water,
flow rate 1.0 mL/min; RI, retention time 15.73 min, 91.8%
pure. Anal. (C18H38O3) C, H.
6-(6-Hydr oxy-5,5-dim eth ylh exyloxy)-2,2-dim eth ylh exan -
1-ol (28). Under N2 atmosphere, NaH (60% w/w dispersion in
mineral oil, 150 g, 3.75 mol) was washed with hexanes (3 ×
0.5 L) and anhydrous THF (3 × 0.5 L), then suspended in THF
(2 L). A solution of 17 (496 g, 2.15 mol) in THF (1.5 L) was
added, and the mixture was stirred for 30 min at room
temperature. After heating to 60 °C for 17 h, the suspension
was cooled to 0 °C and a solution of 14 (639 g, 2.18 mol) in
THF (1.5 L) was added dropwise, keeping the internal tem-
perature below 35 °C. The mixture was heated to reflux for
10 h, stirred at room temperature for 17 h, and hydrolyzed by
addition of ice (0.5 L) and saturated NH4Cl solution (1.5 L).
The layers were separated, and the aqueous layer was
extracted with EtOAc (2 L, 2 × 0.5 L). The combined organic
phases were washed with saturated NH4Cl solution (2 × 0.6
L), dried over Na2SO4, and concentrated in vacuo to give 22
as a yellow, oily residue. A solution of this residue in MeOH
(2 L) and concentrated HCl (0.3 L) was heated to reflux for 48
h. The reaction mixture was cooled to room temperature,
diluted with water (1 L), and neutralized with saturated
NaHCO3 solution (1.1 L). The mixture was extracted with
EtOAc (3 × 0.7 L). The combined organic extracts were washed
with saturated NH4Cl solution (0.5 L) and saturated NaCl
solution (0.5 L), dried over Na2SO4, and concentrated in vacuo.
The volatiles were removed by distillation under high vacuum
at 35-70 °C/5 mmHg. The residue was dissolved in MeOH
(0.5 L) and concentrated HCl (50 mL) and heated to reflux for
17 h. The residual oil obtained after extractive workup as
above was distilled in high vacuo, affording 28 (216 g, 37%)
as a colorless oil. Bp 155-159 °C/0.03 mmHg; 160-162 °C/
0.15 mmHg. 1H NMR (CDCl3): δ 3.42 (t, 4 H, J ) 6.8), 3.32 (s,
4 H), 1.88 (br, 2 H), 1.55 (m, 4 H), 1.40-1.30 (m, 8 H), 0.86 (s,
12H). 13C NMR (CDCl3 ) 77.00 ppm): δ 71.58, 70.70, 38.16,
34.99, 30.33, 23.90, 20.43. HRMS (LSIMS, nba) Calcd for
C16H35O3 (MH+): 275.2586. Found: 275.2568. HPLC: Alltima
C-8 column, 250 mm × 4.6 mm, 5 µm; 55% acetonitrile, 45%
water, flow rate 1.0 mL/min; RI, retention time 8.83 min,
98.0% pure. Anal. (C16H34O3) C, H.
) 6.6), 6.76 (s, 2 H), 4.06 (q, 4 H, J ) 7.2), 2.82 (s, 4 H), 1.20
(t, 6 H, J ) 7.2), 1.17 (s, 12 H). 13C NMR (CDCl3): δ 176.95,
156.65, 139.73, 128.89, 124.82, 120.39, 116.62, 60.31, 45.98,
43.38, 24.95, 14.12. HRMS (LSIMS, nba) Calcd for C26H35O5
(MH+): 427.2484. Found: 427.2443.
3-{3-[3-(2-Ca r boxy-2-m eth ylp r op yl)p h en oxy]p h en yl}-
2,2-d im eth ylp r op ion ic Acid (35). A mixture of 34 (8.5 g,
19.9 mmol) and KOH (85%, 4.6 g, 69.8 mmol) in EtOH (30
mL) and water (30 mL) was heated to reflux for 4 h. The
mixture was cooled to room temperature, diluted with deion-
ized water (100 mL), and extracted with MTBE (50 mL). The
aqueous layer was acidified with concentrated HCl (5 mL) to
pH 1 and extracted with MTBE (2 × 50 mL). The organic
layers were washed with saturated NaCl solution (50 mL),
dried over anhydrous MgSO4, and concentrated in vacuo. The
residue was recrystallized from hot heptane (40 mL) to furnish
35 (5.3 g, 72%) as a white powder. Mp 87 °C. 1H NMR
(CDCl3): δ 11.0-9.0 (br, 2 H), 7.29 (t, 2 H, J ) 8.1), 7.00 (m,
2 H), 6.91 (m, 2 H), 6.59 (s, 2 H), 2.77 (s, 4 H), 1.26 (s, 12 H).
13C NMR (CDCl3): δ 183.61, 156.72, 139.29, 129.14, 125.23,
118.35, 118.31, 47.46, 43.81, 24.82. HRMS (CI) Calcd for
C22H26O5 (M+): 370.1780. Found: 370.1750. HPLC: Alltima
phenyl column, 250 mm × 4.6 mm, 5 µm; 60% acetonitrile,
40% 0.05 M KH2PO4, flow rate 1.2 mL/min; RI, retention time
6.67 min, 92.5% pure. Anal. (C22H26O5) C, H.
3-{3-[3-(3-H y d r o x y -2,2-d im e t h y lp r o p y l)p h e n o x y ]-
p h en yl}-2,2-d im eth ylp r op a n -1-ol (36). Under Ar atmo-
sphere, to a solution of LiAlH4 (1.0 M in THF, 41 mL, 41 mmol)
was added dropwise a solution of 34 (8.76 g, 20.5 mmol) in
anhydrous THF (50 mL) over 1 h under cooling with an ice
bath. The solution was stirred at room temperature for 3 h,
cooled with an ice bath, and carefully hydrolyzed with water
(25 mL) and 25% aqueous H2SO4 (100 mL). The mixture was
extracted with MTBE (3 × 50 mL). The combined organic
layers were washed with water (100 mL), saturated NaHCO3
solution (50 mL), and saturated NaCl solution (50 mL). The
solution was dried over anhydrous MgSO4 and concentrated
in vacuo. The residue (8.1 g) was purified by column chroma-
tography (silica, heptane/EtOAc ) 75/25, 70/30) to furnish 36
(5.65 g, 80%) as a very viscous, colorless oil. 1H NMR (CDCl3):
δ 7.21 (t, 2 H, J ) 7.7), 6.89 (d, 2 H, J ) 7.7), 6.80 (d, 2 H, J
) 7.7), 6.82 (s, 2 H), 3.29 (s, 4 H), 2.53 (s, 4 H), 2.34 (s br, 2
H), 0.86 (s, 12 H). 13C NMR (CDCl3): δ 156.81, 140.89, 129.00,
125.47, 120.94, 116.38, 71.09, 44.70, 36.61, 24.25. HRMS
(LSIMS, gly) Calcd for C22H31O3 (MH+): 343.2273. Found:
343.2257. HPLC: Alltima C-8 column, 250 mm × 4.6 mm, 5
µm; 80% acetonitrile, 20% water, flow rate 1.0 mL/min; RI,
retention time 5.03 min, 94.6% pure.
1,14-Bis(t e t r a h yd r op yr a n -2-yloxy)-2,2,13,13-t e t r a -
m eth yltetr a d eca n -6,9-d iol (37). A mixture of 2,5-dimethoxy-
tetrahydrofuran (26.4 g, 0.2 mol) and 0.6 N HCl (160 mL) was
stirred at room temperature for 1.5 h. The mixture was
neutralized with NaHCO3 (8.4 g, 0.10 mol) and extracted with
CH2Cl2 (3 × 50 mL). The aqueous phase was acidified with
concentrated HCl (10 mL), stirred for 1.5 h, neutralized with
NaHCO3 (10.1 g), and extracted with CH2Cl2 (3 × 50 mL). This
sequence of acidification, neutralization, and extraction was
3-{3-[3-(2-Eth oxyca r bon yl-2-m eth ylp r op yl)-p h en oxy]-
p h en yl}-2,2-d im eth ylp r op ion ic Acid Eth yl Ester (34).
Under Ar atmosphere, to a solution of ethyl isobutyrate (20.7

Ether Diols and Ether Diacids
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21 5193
repeated two more times. The combined organic extracts were
dried over MgSO4, and the solvent was distilled off under
atmospheric pressure. Distillation of the residue under reduced
pressure gave succinaldehyde14 (5.71 g, 33%) as a foul-
smelling, colorless liquid (bp 75-77 °C/15 mmHg; lit.15 bp 55-
60 °C/12 mmHg). Under N2 atmosphere, to a suspension of
Mg powder (3.65 g, 0.15 mol) in anhydrous THF (100 mL) was
added dropwise a solution of 121b (27.9 g, 0.10 mol) in THF
(100 mL). The reaction mixture was heated to reflux for 2 h.
Under cooling with an ice bath, a solution of freshly distilled
succinaldehyde (3.44 g, 40.0 mmol) in THF (30 mL) was added
dropwise, and the reaction mixture was stirred at room
temperature overnight. The solution was decanted from excess
Mg and poured into aqueous saturated NH4Cl solution (300
mL). After acidification to pH 1-2 with 2 N HCl, the reaction
mixture was extracted with diethyl ether (2 × 100 mL). The
combined organic extracts were washed with saturated NaCl
solution (100 mL), dried over MgSO4, and concentrated in
vacuo to give a residue that was purified by flash column
chromatography (silica, EtOAc/hexanes ) 25/75, then 50/50),
affording 37 (18.0 g, 92%) as an almost colorless, very viscous
1,15-Bis(t e t r a h yd r op yr a n -2-yloxy)-2,2,14,14-t e t r a -
m eth ylp en ta d eca n -6,10-d iol (39). An aqueous solution of
glutaric aldehyde (25 mL, 50% w/w) was extracted with CH2-
Cl2 (4 × 50 mL). The organic extracts were dried over MgSO4,
and the solvent was removed by distillation under atmospheric
pressure. The residue was distilled in vacuo to give glutaric
dialdehyde (7.97 g, 64%, bp 65-66 °C/5 mmHg; lit.15 bp 68-
69 °C/25 mmHg) as a malodorous, colorless liquid. According
to the procedure given for the synthesis of 36, the Grignard
reagent prepared from 121b (36.9 g, 0.13 mol) and Mg powder
(4.8 g, 0.20 mol) in anhydrous THF was reacted with a solution
of freshly distilled glutaric aldehyde (6.0 g, 60 mmol) in THF.
After workup and concentration, the residue was purified by
flash column chromatography (silica, EtOAc/hexanes ) 1/5 to
1/1) to afford 39 (16.67 g, 55%) as an almost colorless, very
1
viscous oil. H NMR (CDCl3): δ 4.53 (m, 2 H), 3.85 (m, 2 H),
3.63 (br s, 2 H), 3.48 (pseudo-t, 4 H, J ) 8.6), 3.00 (d, 1 H, J
) 9.1), 2.99 (d, 1 H, J ) 9.1), 1.90-1.20 (m, 32 H), 0.90 (s, 6
H), 0.89 (s, 6 H). 13C NMR (CDCl3 ) 77.00 ppm): δ 99.34,
99.15, 76.26, 71.76, 71.47, 62.29, 62.03, 39.24, 38.93, 38.24,
37.38, 34.22, 30.66, 25.53, 24.83, 24.65, 24.44, 21.73, 19.99,
19.83, 19.68, 19.51. HRMS (LSIMS, gly) Calcd for C29H57O6
(MH+): 501.4155. Found: 501.4152.
1
oil. H NMR (CDCl3): δ 4.54-4.50 (m, 2 H), 3.89-3.82 (m, 2
H), 3.66 (br s, 2 H), 3.48 (pseudo-t, 4 H, J ) 9.6), 2.99 (dd, 2
H, J ) 9.1, 3.5), 2.60 (br s, 2 H), 1.90-1.20 (m, 28 H), 0.90-
0.88 (m, 12 H). 13C NMR (CDCl3 ) 77.00 ppm): δ 99.38, 99.15,
76.40, 76.14, 72.14, 71.67, 71.29, 62.39, 62.05, 39.19, 38.77,
38.30, 38.17, 34.18, 33.35, 30.74, 30.64, 25.51, 24.93, 24.65,
24.48, 24.37, 20.04, 19.74, 19.51. HRMS (LSIMS, gly) Calcd
for C28H55O6 (MH+): 487.3998. Found: 487.3995.
2,2,14,14-Tetr am eth ylpen tadecan e-1,6,10,15-tetr aol (40).
A solution of 39 (5.75 g, 11.5 mmol) in MeOH (100 mL) and
diluted aqueous H2SO4 (1 mL of concentrated H2SO4/9 mL of
water) was stirred at room temperature for 5 h. After dilution
with water (20 mL), the MeOH was removed under reduced
pressure. The obtained aqueous phase was extracted with
EtOAc (3 × 50 mL). The combined organic extracts were
washed with water (30 mL) and brine (30 mL). The combined
aqueous extracts were saturated with NaCl and reextracted
with EtOAc (3 × 50 mL). The organic phases were washed
with water (20 mL) and brine (20 mL). Saturation with NaCl
and reextraction of the aqueous layer were repeated, and the
combined organic extracts were dried over MgSO4. After
solvent removal under reduced pressure, the residue was
dissolved in the minimal amount of CH2Cl2, treated with
hexanes for 15 min, and crystallized at room temperature. The
crystals were filtered and washed with hexanes to afford 40
(3.06 g, 80%) as a white solid. Mp 85-86 °C. 1H NMR (DMSO-
d6): δ 4.40 (t, 2 H, J ) 5.3), 4.20 (d, 2 H, J ) 5.5), 3.40-3.30
(m, 2 H), 3.06 (d, 4 H, J ) 5.3), 1.50-1.05 (m, 18 H), 0.77 (s,
12 H). 13C NMR (DMSO-d6): δ 69.87, 69.72, 38.36, 37.52, 34.83,
24.10, 21.67, 19.72. HRMS (LSIMS, gly) Calcd for C19H41O4
(MH+): 333.3005. Found: 333.2997.
5-[5-(5-Hyd r oxy-4,4-d im eth ylp en tyl)tetr a h yd r ofu r a n -
2-yl]-2,2-d im eth ylp en ta n -1-ol (38). Meth od A. A solution
of 37 (6.18 g, 12.7 mmol) and pTosOH monohydrate (0.3 g,
1.6 mmol) in toluene (300 mL) was heated under reflux with
azeotropic removal of water for 3 h. The reaction mixture was
cooled to room temperature and concentrated under reduced
pressure. The residue was dissolved in MeOH (100 mL) and 3
N H2SO4 (30 mL) and stirred at room temperature overnight.
The MeOH was distilled under reduced pressure, and the
aqueous phase was extracted with EtOAc (3 × 75 mL). The
combined organic extracts were washed with water (75 mL)
and saturated NaCl solution (75 mL), dried over MgSO4, and
concentrated under reduced pressure. The residue was purified
by column chromatography (twice; silica, EtOAc/hexanes ) 75/
25, then 50/50) to give 38 (1.35 g, 35%) as a light-yellow oil.
Meth od B. Under N2 atmosphere, a solution of 37 (3.79 g,
7.8 mmol), tosyl chloride (1.64 g, 8.6 mmol), and pyridine (1.0
mL, 12.4 mmol) in CH2Cl2 (40 mL) was stirred at room
temperature for 21 h. The solvent was removed under reduced
pressure, and the residue was dissolved in pyridine (3 mL)
and HMPA (5 mL). The mixture was heated to 70-75 °C for
4 h, cooled to room temperature, diluted with water (100 mL),
and extracted with CH2Cl2 (3 × 50 mL). The organic extracts
were washed with 2 N HCl (until the washings were acidic)
and with water and dried over MgSO4. The residue obtained
after solvent removal was dissolved in MeOH (40 mL) and
aqueous H2SO4 (2 mL of concentrated H2SO4/5 mL of water)
and stirred at room temperature overnight. The MeOH was
removed under reduced pressure. The residue was diluted with
water (40 mL) and extracted with EtOAc (3 × 50 mL). The
combined organic layers were washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified
by column chromatography (silica, EtOAc/hexanes ) 25/75,
then 50/50) to give 38 (0.9 g, 38%, mixture of diastereomers
in a ratio of ca. 60/40) as a yellow oil. 1H NMR (CDCl3): δ
3.96 (m, 2 H), 3.86 (m, 2 H), 3.30 (m, 8 H), 2.41 (s br, 4 H),
2.05-1.91 (m, 4 H), 1.57-1.18 (m, 28 H), 0.86 (s, 12 H), 0.85
(s, 12 H). 13C NMR (CDCl3 ) 77.00 ppm): δ 79.20, 78.53, 71.13,
37.99, 36.69, 36.48, 35.02, 32.16, 31.12, 24.23, 24.00, 23.95,
20.47. HRMS (LSIMS, gly) Calcd for C18H37O3 (MH+): 301.2743.
Found: 301.2743. HPLC: Alltima C8 column, 250 mm × 4.6
mm, 5 µm; 50% acetonitrile, 50% water, flow rate 1.0 mL/min;
RI, retention time 11.58 min, 53.3%, retention time 12.00 min,
43.8%; combined, 97.1% pure. Anal. (C18H36O3) C, H.
5-[6-(5-Hyd r oxy-4,4-d im eth ylp en tyl)tetr a h yd r op yr a n -
2-yl]-2,2-d im eth ylp en ta n -1-ol (41). A suspension of 40 (3.06
g, 9.2 mmol) and pTosOH monohydrate (0.59 g, 3.1 mmol) in
toluene (350 mL) was heated to reflux under azeotropic water
removal for 7 h. The solvent was evaporated, and the residual
oil was purified by column chromatography (silica, first,
EtOAc/hexanes ) 1/5 to 1/3; second, EtOAc/hexanes ) 1/3),
1
affording 41 (1.58 g, 55%) as a very viscous, colorless oil. H
NMR (CDCl3): δ 3.69 (br s, 2 H), 3.31 (s, 4 H), 2.10-2.00 (m,
2 H), 1.75-1.50 (m, 6 H), 1.50-1.18 (m, 12 H), 0.86 (s, 12 H).
13C NMR (CDCl3 ) 77.00 ppm): δ 71.50, 70.61, 38.51, 35.02,
34.03, 30.28, 24.10, 23.91, 20.02, 18.72. HRMS (LSIMS, gly)
Calcd for C19H39O3 (MH+): 315.2899. Found: 315.2899.
HPLC: Alltima C-8 column, 250 mm × 4.6 mm, 5 µm; 50%
acetonitrile, 50% water, flow rate 1.0 mL/min; RI, retention
time 14.80 min, 88.3% pure. Anal. (C19H38O3) C, H.
6-(5,5-Dim et h yl-6-oxoh exyloxy)-2,2-d im et h ylh exa n a l
(42). Under N2 atmosphere, to a solution of 28 (1.63 g, 5.9
mmol) and freshly distilled NEt3 (2.8 mL) in anhydrous DMSO
(10 mL) was added a solution of SO3-pyridine complex (3.3 g,
20.7 mmol) in anhydrous DMSO (10 mL) at room temperature.
The mixture was stirred for 4 h, and additional NEt3 (5.6 mL)
and SO3-pyridine complex (3.3 g, 20.7 mmol) were added. The
mixture was stirred at room temperature overnight, poured
into ice-water (100 mL), and stirred for 20 min. The mixture
was extracted with Et2O (4 × 30 mL), and the combined
organic layers were washed with 10% citric acid (2 × 20 mL),
water (2 × 20 mL), and saturated NaHCO3 solution (2 × 20

5194 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21
Mueller et al.
mL). Drying over MgSO4, concentration under reduced pres-
sure, and purification by column chromatography (silica;
hexanes/EtOAc ) 5/1 to 3/1) afforded 42 (1.0 g, 63%) as a
colorless oil, which should be used as soon as possible for the
99.03, 76.47, 70.87, 61.80, 39.14, 34.18, 30.62, 30.60, 25.53,
24.48, 24.41, 20.55, 19.37. HRMS (LSIMS, nba) Calcd for
C26H49O5 (M - H+): 441.3567. Found: 441.3610. HPLC:
Alltima phenyl column, 250 mm × 4.6 mm, 5 µm; 70%
acetonitrile, 30% water, flow rate 1.0 mL/min; RI, retention
time 7.40 min, 93.5% pure. Anal. (C26H50O5) C, H.
46. 1H NMR (CDCl3): δ 4.53 (t, 1 H, J ) 3.3), 3.88-3.78
(m, 1H), 3.52-3.44 (m, 1H), 3.45 (d, 1 H, J ) 9.1), 3.41 (t, 2 H,
J ) 6.5), 3.39 (t, 2 H, J ) 6.5), 3.30 (s br, 2 H), 2.99 (d, 1 H, J
) 9.1), 1.90-1.40 (m, 12 H), 1.40-1.20 (m, 7 H), 0.89 (s, 3 H),
0.88 (s, 3 H), 0.84 (s, 6 H). 13C NMR (CDCl3 ) 77.00 ppm): δ
98.48, 76.02, 70.94, 70.48, 70.38, 61.25, 38.84, 38.11, 34.65,
33.83, 30.24, 30.19, 25.22, 24.21, 24.17, 23.61, 20.22, 20.16,
18.92. HRMS (LSIMS, nba) Calcd for C21H42O4 (M + 1):
359.3161. Found: 359.3161. HPLC: Alltima phenyl column,
250 mm × 4.6 mm, 5 µm; 70% acetonitrile, 30% water, flow
rate 1.0 mL/min; RI, retention time 5.05 min, 93.6% pure.
Anal. (C21H42O4) C, H.
5-Ch lor o-2,2-d im eth ylp en ta n oic Acid Eth yl Ester (47).
To a solution of ethyl isobutyrate (130 g, 1.13 mol) and DMPU
(5 mL) in THF (160 mL) was added a solution of LDA (790
mL, 2 M in THF/heptane, 1.58 mol) at -50 to -78 °C. The
mixture was stirred for 1 h at -78 °C. 1-Bromo-3-chloropro-
pane (250 g, 1.58 mol) was added, and the mixture was stirred
overnight, gradually warming to room temperature. The
reaction mixture was poured into a mixture of aqueous HCl
(6 N, 250 mL), water (500 mL), and ice (500 g) and diluted
with saturated NH4Cl solution (400 mL). The solution was
extracted with MTBE (250 mL, 2 × 150 mL). The combined
organic layers were washed with saturated NaCl solution (200
mL), dried over MgSO4, and concentrated under vacuum to
give 47 (248 g) as a colorless oil. Distillation under vacuum
furnished pure product (140 g, 64%, bp 73-75 °C/2 mmHg)
as a colorless oil. 1H NMR (CDCl3): δ 4.14 (q, 2 H, J ) 7.1
Hz), 3.53 (t, 2 H, J ) 6.1 Hz), 1.74-1.69 (m, 4 H), 1.27 (t, 3 H,
J ) 7.1 Hz), 1.21 (s, 6 H). 13C NMR (CDCl3): δ 177.2, 60.2,
45.1, 41.7, 37.8, 28.3, 25.1, 14.2. HRMS (EI) Calcd for C9H17O2-
Cl (M+): 192.0917. Found: 192.0915.
5-[2-(4-E t h oxyca r b on yl-4-m et h ylp en t yloxy)et h oxy]-
2,2-d im eth ylp en ta n oic Acid Eth yl Ester (48). To a solution
of ethylene glycol (13.6 g, 220 mmol) in anhydrous DMAc (250
mL) was added KOtBu (40 g, 360 mmol) under N2 atmosphere.
The mixture was stirred at 80 °C for 18 h. A solution of 47 (70
g, 363 mmol) in DMAc (30 mL) and 18-crown-6 (0.35 g, 1.3
mmol) was added, and the mixture was stirred at 65 °C for 30
h. Second portions of KOtBu (40 g, 360 mmol) and, 3 h later,
of 47 (70 g, 363 mmol) were added, and stirring was continued,
first at 65 °C for 63 h and then at 85 °C for 28 h. The reaction
mixture was poured into ice-water (1300 mL), and the crude
product was extracted with MTBE (4 × 250 mL). The combined
organic layers were washed with saturated NaHCO3 solution
(100 mL) and saturated NaCl solution (100 mL) and dried over
anhydrous MgSO4. The solution was evaporated to yield the
crude product as a colorless oil (112 g). The crude product (110
g) was subjected to column chromatography on silica gel,
eluting with hexanes/EtOAc (9:1) to give 48 (19.1 g, 23%) as a
colorless oil. 1H NMR (CDCl3): δ 4.16 (q, 4 H, J ) 7.1 Hz),
3.61 (s, 4 H), 3.49 (t, 4 H, J ) 6.7 Hz), 1.61-1.58 (m, 8 H),
1.29 (t, 6 H, J ) 7.1 Hz), 1.22 (s, 12 H). 13C NMR (CDCl3): δ
177.6, 71.5, 69.9, 60.1, 41.8, 36.8, 25.1, 25.0, 14.1. HRMS (EI)
Calcd for C20H38O6 (M+): 374.2668. Found: 374.2664.
1
next step. H NMR (CDCl3): δ 9.45 (s, 2 H), 3.38 (t, 4 H, J )
6.4), 1.62-1.38 (m, 8 H), 1.38-1.14 (m, 4 H), 1.05 (s, 1 2H).
13C NMR (CDCl3 ) 77.00 ppm): δ 206.17, 70.36, 45.65, 36.89,
30.08, 21.11, 20.90. HRMS (LSIMS, gly) Calcd for C16H31O3
(MH+): 271.2273. Found: 271.2279.
4,4,14,14-Tetr am eth yl-9-oxah eptadecan e-1,17-dioic Acid
(45). To a solution of methyl diethylphosphonoacetate (12.0
g, 57.1 mmol) in anhydrous DMF (60 mL) was added NaH
(60% w/w dispersion in mineral oil, 3.3 g, 82.5 mmol) at room
temperature under N2 atmosphere, resulting in an exothermic
reaction. This mixture was stirred for 30 min, 42 (7.4 g, 24.7
mmol) was added, and stirring was continued overnight. The
mixture was hydrolyzed by addition of deionized water (100
mL) and extracted with Et2O (4 × 50 mL). The combined
organic layers were dried over MgSO4 and concentrated in
vacuo at 40-50 °C to give crude 43 (11.2 g) as an oil, which
was used for the next step without further purification. 1H
NMR (CDCl3): δ 6.91 (d, 2 H, J ) 16.1), 5.71 (d, 2 H, J )
16.1), 3.73 (s, 6 H), 3.36 (t, 4 H, J ) 6.4), 1.65-1.15 (m, 12 H),
1.04 (s, 12 H). 13C NMR (CDCl3 ) 77.00 ppm): δ 167.54,
158.54, 117.32, 70.68, 51.41, 42.10, 36.75, 30.26, 26.25, 21.28.
HRMS (LSIMS, gly) Calcd for C22H39O5 (MH+): 383.2797.
Found: 383.2789. A portion of crude 43 (2.0 g) was hydroge-
nated under elevated H2 pressure (38 psi) on 10% Pd/C (0.5 g)
in EtOH (50 mL) for 20 h. The catalyst was removed by
filtration through Celite (1 cm bed) and washed with some
EtOH. The filtrate was concentrated under reduced pressure
1
to give crude 44 (1.76 g) as a colorless oil. H NMR (CDCl3):
δ 3.66 (s, 6 H), 3.40 (t, 4 H, J ) 6.4), 2.25 (m, 4 H), 1.63-1.45
(m, 6 H), 1.40-1.10 (m, 10 H), 0.85 (s, 12 H). 13C NMR (CDCl3
) 77.00 ppm): δ 174.67, 70.70, 51.38, 41.44, 36.34, 32.27,
30.43, 29.28, 26.60, 20.51. HRMS (LSIMS, nba) Calcd for
C22H43O5 (MH+): 387.3110. Found: 387.3116. A solution of 44
(1.76 g) and KOH (85%, 1.5 g, 22.7 mmol) in MeOH (50 mL)
and deionized water (10 mL) was stirred at room temperature
overnight under N2 atmosphere. MeOH was removed under
reduced pressure, and the residue was diluted with deionized
water (50 mL). The solution was extracted with Et2O (4 × 20
mL), and the ethereal layers were discarded. The aqueous
layer was acidified with 2 N HCl (11 mL) to pH 2 and extracted
with Et2O (4 × 20 mL). The combined organic layers were
washed with saturated NaCl solution (20 mL), dried over
MgSO4, and concentrated and dried in vacuo to afford 45 (0.89
g, 56%) as a colorless oil. A sample of 350 mg was further
purified by flash chromatography (silica, heptane/EtOAc ) 70/
30, 50/50) to give a sample (220 mg) that was used for
combustion analysis. 1H NMR (CDCl3): δ 9.8-8.8 (br, 2 H),
3.42 (t, 4 H, J ) 6.4), 2.29 (m, 4 H), 1.67-1.40 (m, 8 H), 1.40-
1.08 (m, 8 H), 0.86 (s, 12 H). 13C NMR (CDCl3 ) 77.00 ppm):
δ 180.59, 70.75, 41.45, 36.11, 32.37, 30.41, 29.42, 26.71, 20.55.
HRMS (LSIMS, gly) Calcd for C20H39O5 (MH+): 359.2797.
Found: 359.2788. HPLC: Inertsil ODS2 column, 250 mm ×
4.6 mm, 5 µm; 50% acetonitrile, 50% water, flow rate 1.0 mL/
min; RI, retention time 23.22 min, 93.6% pure. Anal. (C20H38O5)
C, H.
2-{6-[5,5-Dim eth yl-6-(tetr a h yd r op yr a n -2-yloxy)h exyl-
oxy]-2,2-d im et h ylh exyloxy}t et r a h yd r op yr a n (22) a n d
6-[5,5-Dim et h yl-6-(t et r a h yd r op yr a n -2-yloxy)h exyloxy]-
2,2-d im eth ylh exa n -1-ol (46). Under N2 atmosphere and at
0 °C, to a solution of 28 (85.3 g, 0.31 mol) and pTosOH hydrate
(0.35 g, 1.8 mmol) in CH2Cl2 (400 mL) was added dropwise
DHP (26.3 g, 0.31 mol) over 1.5 h. The reaction mixture was
stirred at room temperature for 20 h and concentrated in
vacuo. The residue was purified twice by column chromatog-
raphy (silica; CH2Cl2/acetone ) 95/5) to afford 22 (29.0 g, 21%)
and 46 (35.7 g, 32%) as colorless oils.
5-[2-(5-Hyd r oxy-4,4-d im eth ylp en tyloxy)eth oxy]-2,2-d i-
m eth ylp en ta n -1-ol (49). Under Ar atmosphere, LiAlH4 (4.55
g, 120 mmol) was added in portions to MTBE (200 mL) and
the suspension was stirred at room temperature for 1 h. A
solution of 48 (11.2 g, 30 mmol) in MTBE (40 mL) was added
slowly. The mixture was heated to 45 °C for 3 h, then stirred
at room temperature for 60 h. The excess of LiAlH4 was
destroyed by dropwise addition of a solution of EtOAc (50 mL)
in MTBE (50 mL) at 0-10 °C. The mixture was stirred at room
temperature for 1 h, then hydrolyzed with aqueous HCl (6 N,
100 mL) and water (50 mL). The solution was extracted with
EtOAc (3 × 100 mL). The combined organic layers were
washed with saturated NaCl solution (2 × 200 mL), dried over
22. 1H NMR (CDCl3): δ 4.47 (t, 2 H, J ) 3.3), 3.77 (m, 2 H),
3.44 (m, 2 H), 3.39 (d, 2 H, J ) 9.1), 3.33 (t, 4 H, J ) 6.6), 2.91
(d, 2 H, J ) 9.1), 1.81-1.40 (m, 16 H), 1.30-1.19 (m, 8 H),
0.82 (s, 6 H), 0.81 (s, 6 H). 13C NMR (CDCl3 ) 77.00 ppm): δ

Ether Diols and Ether Diacids
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21 5195
MgSO4, and concentrated under vacuum to give the crude
product (9.0 g) as a colorless oil. This residue was subjected
to column chromatography on silica using hexanes/EtOAc (2:
1, then 1:1) as eluent to afford 49 (4.52 g, 52%) as a colorless
mixture was stirred vigorously for 1 h. The supernatant was
decanted from the white granular residue and concentrated
under vacuum to give pure 55 (7.20 g, 91%) as a colorless oil.
1H NMR (CDCl3): δ 3.54-3.47 (m, 10H), 3.26 (d, 4H, J ) 5.4),
1.84 (quint, 2 H, J ) 6.3), 1.55 (t, 4H, J ) 5.7), 0.90 (s, 12H).
13C NMR (CDCl3): δ 71.4, 68.1, 67.9, 39.4, 35.1, 30.0, 25.3.
HRMS (LSIMS, gly) Calcd for C15H33O4 (MH+): 277.2379.
Found: 277.2387. HPLC: Alltech Alltima C-8 column, 250 mm
× 4.6 mm, 5 µm; 65% acetonitrile, 35% water, flow rate 1.0
mL/min; RI, retention time 4.30 min, 99.9% pure. Anal.
(C15H32O4) C, H.
1
oil. H NMR (CDCl3): δ 3.63 (br s, 2 H), 3.58 (s, 4 H), 3.46 (t,
4 H, J ) 6.5 Hz), 3.27 (s, 4 H), 1.59-1.54 (m, 4 H), 1.31-1.21
(m, 4 H), 0.87 (s, 6 H), 0.86 (s, 6 H). 13C NMR (CDCl3): δ 72.0,
70.7, 69.8, 34.7, 34.3, 24.0, 23.9. HRMS (LSIMS, nba) Calcd
for C16H35O4 (MH+): 291.2535. Found: 291.2534. HPLC:
Alltima C-18, 4.6 mm × 250 mm; 60% acetonitrile, 40% water,
flow rate 1.0 mL/min, 35 °C; RI detection at 254 nm, retention
time 5.37 min, 99.1% pure. Anal. (C16H34O4) C, H.
4-[3-(4-Ca r boxy-3-m eth ylbu toxy)p r op oxy]-2,2-d im eth -
ylbu tyr ic Acid (56). A solution of 54 (8.06 g, 22.4 mmol) and
KOH (85%, 5.90 g, 89.5 mmol) in EtOH (15 mL) and water (7
mL) was heated to reflux for 4 h. MTBE (100 mL) was added,
and the mixture was stirred for 16 h. The aqueous solution
was acidified with 6 N HCl (ca. 17 mL) to pH 1 and extracted
with CH2Cl2 (3 × 80 mL). The organic extracts were washed
with saturated NaCl solution (200 mL), dried over Na2SO4,
and concentrated in a vacuum to give 56 (6.66 g, 98%) as a
5-[2-(4-Ca r b oxy-4-m e t h ylp e n t yloxy)e t h oxy]-2,2-d i-
m eth ylp en ta n oic Acid (50). A solution of 48 (15.1 g, 40.3
mmol) and KOH (85%, 9.4 g, 142.0 mmol) in EtOH (28 mL)
and water (12 mL) was heated to reflux for 4 h. Most of the
EtOH was evaporated under reduced pressure. The residue
was diluted with water (50 mL). The solution was extracted
with Et2O (50 mL), and the ether extracts were discarded. The
aqueous solution was acidified with aqueous 6 N HCl to pH 1
and extracted with MTBE (3 × 50 mL) and CH2Cl2 (2 × 50
mL). The combined organic layers were washed with saturated
NaCl (50 mL), dried over MgSO4, and concentrated in a
vacuum to get the crude product (12.0 g) as a pale-yellow solid.
The residue was subjected to column chromatography (silica
gel, hexanes/EtOAc ) 2:1, 1:1) to give 50 (5.6 g, 44%) as a
colorless oil, which solidified upon standing to give a white
solid. Mp 60-61 °C. 1H NMR (CDCl3): δ 11.93 (br s, 2 H),
3.60 (s, 4 H), 3.49 (br s, 4 H), 1.61-1.60 (m, 8 H), 1.21 (s, 12
H). 13C NMR (CDCl3): δ 184.4, 71.5, 70.0, 41.8, 36.7, 25.1, 24.9.
HRMS (LSIMS, gly) Calcd for C16H31O6 (MH+): 319.2121.
Found: 319.2117. HPLC: Luna C-18, 4.6 mm × 250 mm; 55%
acetonitrile, 45% 25 mM aqueous KH2PO4, 25 °C; RI detection
at 224 nm, flow rate 1.0 mL/min, retention time 5.03 min,
99.3% pure. Anal. (C16H30O6) C, H.
(3-ter t-Bu toxyca r bon ylm eth oxyp r op oxy)a cetic Acid
ter t-Bu tyl Ester (51). A mixture of 1,3-propanediol (2.69 g,
35.4 mmol), tert-butyl bromoacetate (58.0 g, 297.4 mmol), and
NBu4HSO4 (1.2 g, 3.5 mmol) in aqueous NaOH solution (50%
w/w, 175 mL, 265 g, 3.3 mol) and toluene (175 mL) was stirred
at room temperature for 16 h. The reaction mixture was
diluted with ice-water (750 mL), and the crude product was
extracted with MTBE (3 × 150 mL). The combined organic
layers were washed with saturated NaCl solution (2 × 150
mL) and dried over anhydrous MgSO4. The solution was
evaporated to yield the crude product as a colorless oil, which
was purified by column chromatography (silica gel; heptane/
EtOAc ) 10:1) to give 51 (7.75 g, 72%) as a colorless oil. 1H
NMR (CDCl3): δ 3.96 (s, 4 H), 3.64 (t, 4 H, J ) 6.3), 1.94 (quint,
2 H, J ) 6.3), 1.48 (s, 18 H). 13C NMR (CDCl3): δ 169.6, 81.5,
68.9, 68.5, 30.2, 28.3.
2-[3-(2-Hyd r oxyeth oxy)p r op oxy]eth a n ol (52).28 Under
Ar atmosphere, LiAlH4 (3.87 g, 102 mmol) was added in
portions to MTBE (150 mL). The mixture was stirred at room
temperature for 1 h. A solution of 51 (7.75 g, 25.5 mmol) in
MTBE (20 mL) was added slowly. The mixture was stirred at
room temperature for 16 h and heated to reflux for 3 h. The
excess of LiAlH4 was destroyed at 0-10 °C by slowly adding
water (4 mL), 20% aqueous NaOH solution (3 mL), and water
(12 mL). The suspension was stirred at room temperature for
4 h. The ether solution was decanted and concentrated under
vacuum to give 52 (2.60 g, 62%) as a colorless oil. 1H NMR
(CDCl3): δ 3.76-3.54 (m, 12 H), 3.58 (s, 2 H), 1.89 (quint, 2
H, J ) 6.3). 13C NMR (CDCl3): δ 72.0, 68.1, 61.3, 29.6. HRMS
(LSIMS, gly) Calcd for C7H17O4 (MH+): 165.1127. Found:
165.1127.
4-[3-(4-H yd r oxy-3,3-d im et h ylb u t oxy)p r op oxy]-2,2-d i-
m eth ylbu ta n -1-ol (55). Under Ar atmosphere, to a suspen-
sion of LiAlH4 (3.51 g, 92.4 mmol) in MTBE (100 mL) was
added dropwise a solution of 54 (10.4 g, 28.8 mmol) in MTBE
(50 mL). The reaction mixture was stirred at room temperature
for 64 h, then heated to reflux for 2 h. The excess of LiAlH4
was destroyed by adding water (3.7 mL), aqueous NaOH
solution (20%, 2.8 mL), and water (13 mL). The reaction
1
pale-yellow oil. H NMR (CDCl3): δ 11.25 (br s, 2H), 3.49 (t,
4H, J ) 6.3), 3.42 (t, 4H, J ) 6.3 Hz), 1.86 (t, 4H, J ) 6.3),
1.75 (quint, 2H, J ) 6.3), 1.22 (s, 12H). 13C NMR (CDCl3): δ
184.4, 67.9, 67.5, 40.7, 40.2, 30.4, 25.4. HRMS (LSIMS, gly)
Calcd for
C
15H29O6 (MH+): 305.1964. Found: 305.1966.
HPLC: Luna C-18 column, 4.6 mm × 250 mm; 55% acetoni-
trile, 45% 25 mM aqueous KH2PO4, flow rate 1.0 mL/min, 35
°C; RI detection at 224 nm, retention time 4.50 min, 99.2%
pure. Anal. (C15H28O6) C, H.
2,2,12,12-Tetr a m eth yl-1,13-tr id eca n ed iol (61). Under N2
atmosphere, to a stirred suspension of LiAlH4 (0.80 g, 21.1
mmol) in Et2O (20 mL) was added dropwise a solution of 59
(6.35 g, 17.8 mmol) in Et2O (15 mL) at room temperature. The
reaction mixture was heated to reflux for 3 h, cooled with an
ice bath, and carefully hydrolyzed by addition of water (10 mL)
and aqueous 2 N HCl (5 mL). The layers were separated, and
the aqueous layer was extracted with Et2O (3 × 40 mL). The
combined organic extracts were dried over Na2SO4 and con-
centrated in vacuo. The residue was distilled in high vacuum
to afford 61 (3.0 g, 62%) as an oil, which solidified upon
standing. Bp 150-151 °C/0.08 mmHg. Mp 52-54 °C. 1H NMR
(CDCl3): δ (ppm) 3.29 (s, 4 H), 1.50 (s, 2 H), 1.23 (m, 18 H),
0.85 (s, 12 H). 13C NMR (CDCl3): δ (ppm) 72.0, 38.7, 35.0, 30.5,
29.6, 23.8. HRMS (LSIMS, nba) Calcd for C17H37O2 (MH+):
273.2794. Found: 273.2796. HPLC: Alltech Alltima C-8
column, 250 mm × 4.6 mm, 5 µm; 52% acetonitrile, 48% water,
flow rate 1.0 mL/min; RI, retention time 39.40 min, 97.2%
pure. Anal. (C17H36O2) C, H.
2,2,14,14-Tetr a m eth ylp en ta d eca n e-1,15-d iol (62). Un-
der N2 atmosphere, MeOH (4.2 g, 131.1 mmol) was added
dropwise to a stirred suspension of LiBH4 (2.9 g, 133.1 mmol)
in methylene chloride (200 mL), followed by addition of 60
(17.0 g, 44.2 mmol). The reaction mixture was heated to reflux
overnight. Water (80 mL) and saturated aqueous NH4Cl
solution (80 mL) were added. The organic phase was separated,
and the aqueous layer was extracted with CH2Cl2 (2 × 50 mL).
The organic solutions were combined, washed with saturated
aqueous NaHCO3 solution (50 mL) and brine (80 mL), and
dried over MgSO4. The solvent was partially evaporated,
EtOAc (10 mL) was added, and the formed crystals were
filtered, affording 62 (6.8 g, 51%). Mp 45-47 °C. 1H NMR
(CDCl3): δ (ppm) 3.31 (br s, 4 H), 1.71 (br s, 2 H), 1.27-1.23
(m, 22 H), 0.86 (s, 12 H). 13C NMR (CDCl3): δ (ppm) 72.0, 38.7,
35.0, 30.6, 29.6, 23.8. HRMS (LSIMS, nba) Calcd for C19H41O2
[M + 1]+: 301.3107. Found: 301.3106. HPLC: Alltech Alltima
C-8 column, 250 mm × 4.6 mm, 5 µm; 70% acetonitrile, 30%
water, flow rate 1.0 mL/min; RI, retention time 15.87 min,
100% pure. Anal. (C19H40O2) C, H.
2,2,14,14-Tetr a m eth ylp en ta d eca n ed ioic Acid (63). A
solution of 60 (11.0 g, 28.6 mmol) and KOH (85%, 4.8 g, 72.7
mmol) in EtOH (70 mL) and water (30 mL) was heated to
reflux for 20 h. The EtOH was evaporated in vacuo, and the
remaining mixture was diluted with water (100 mL). After
acidification with dilute aqueous HCl, crystals formed, which

5196 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21
Mueller et al.
were filtered and dissolved in EtOAc. The solution was dried
over MgSO4 and reduced in volume. The crystals formed were
filtered and dried to give 63 (6.5 g, 69%). Mp 95-96 °C. 1H
NMR (CDCl3): δ (ppm) 1.57-1.52 (m, 4 H), 1.30-1.25 (m, 18
H), 1.20 (s, 12 H). 13C NMR (CDCl3): δ (ppm) 185.3, 42.2, 40.7,
30.0, 29.5, 29.5, 29.4, 25.0, 24.9. HRMS (LSIMS, gly) Calcd
for C19H37O4 [M + 1]+: 329.2692. Found: 329.2678. Anal.
(C19H36O4) C, H.
no. 310-0) on
a
Hitachi 912 automatic analyzer (Roche
Diagnostic Corporation). In some instances, an in-house
cholesterol reagent was used to determine total serum cho-
lesterol levels. Serum lipoprotein cholesterol levels were
determined by lipoprotein profile analysis. Lipoprotein profiles
were analyzed using gel-filtration chromatography on a Su-
perose 6HR (1 cm × 30 cm) column equipped with on-line
detection of total cholesterol as described by Kieft et al.35 The
total cholesterol content of each lipoprotein was calculated by
multiplying the independent values determined for serum total
cholesterol by the percent area of each lipoprotein in the
profile.
Biologica l Meth od s. In Vitr o Mea su r em en t of Lip id
Syn th esis in Isola ted Hep a tocytes. Compounds were tested
for inhibition of lipid synthesis in primary cultures of rat
hepatocytes. Male Sprague-Dawley rats were anesthetized
with intraperitoneal injection of sodium pentobarbital (80 mg/
kg). Rat hepatocytes were isolated essentially as described by
the method of Seglen.34 Hepatocytes were suspended in
Dulbecco’s modified Eagles medium containing 25 mM d-
glucose, 14 mM HEPES, 5 mM L-glutamine, 5 mM leucine, 5
mM alanine, 10 mM lactate, 1 mM pyruvate, 0.2% bovine
serum albumin, 17.4 mM nonessential amino acids, 20% fetal
bovine serum, 100 nM insulin, and 20 µg/mL gentamycin) and
plated at a density of 1.5 × 105 cells/cm2 on collagen-coated
96-well plates. Four hours after plating, media were replaced
with the same media without serum. Cells were grown
overnight to allow formation of monolayer cultures. Lipid
synthesis incubation conditions were initially assessed to
ensure the linearity of [1-14C]-acetate incorporation into hepa-
tocyte lipids for up to 4 h. Hepatocyte lipid synthesis inhibitory
activity was assessed during incubations in the presence of
0.25 µCi [1-14C]-acetate/well (final radiospecific activity in
assay is 1 Ci/mol) and 0, 1, 3, 10, 30, 100, or 300 µM of
compounds for 4 h. At the end of the 4 h incubation period,
medium was discarded and cells were washed twice with ice-
cold phosphate buffered saline and stored frozen prior to
analysis. To determine total lipid synthesis, 170 µL of Micro-
Scint-E and 50 µL of water were added to each well to extract
and partition the lipid-soluble products to the upper organic
phase containing the scintillant. Lipid radioactivity was as-
sessed by scintillation spectroscopy in a Packard TopCount
NXT. Lipid synthesis rates were used to determine the IC50
values of the compounds.
Ack n ow led gm en t. We thank Dr. Edmund P. Woo
of Alchem Laboratories for his helpful suggestions. The
assistance in the preparation of some intermediates and
target compounds by Dr. Sergey Denisenko, Bruce H.
McCosar, and Dr. George Nikonov of Alchem Labora-
tories is also greatly appreciated. The authors acknowl-
edge Sandra Drake, Michelle Washburn, Rose Acker-
mann, Terri Bancero, and Janell Lutostanski of Esperion
Therapeutics for collection, analysis of biological samples,
and fruitful discussions.
Su p p or tin g In for m a tion Ava ila ble: Details on the syn-
theses of intermediates 7, 8, 17, 18, 24, 53, 54, 59, and 60
and elemental analysis results. This material is available free
of charge via the Internet at http://pubs.acs.org.
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