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

Article abstract of DOI:10.1021/jm040006p

Keto-substituted hydrocarbons with 11-19 methylene and bis-terminal hydroxyl and carboxyl groups have been synthesized and evaluated in both in vivo and in vitro assays 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 obese female Zucker fatty rats [Crl:(ZUC)-faBR] following 1 and 2 weeks of oral administration. The most active compounds were found to be symmetrical with four to five methylene groups separating the central ketone functionality and the gem dimethyl or methyl/aryl substituents. Furthermore, biological activity was found to be greatest in both in vivo and in vitro assays for the tetramethyl-substituted keto diacids and diols (e.g., 10c, 10g, 14c), and the least active were shown to be the bis(arylmethyl) derivatives (e.g., 10e, 10f, 14f). Compound 14c dose-dependently elevated HDL-cholesterol, reduced triglycerides, and reduced NEFA, with a minimum effective dose of 30 mg/kg/day. Compound 10g dose-dependently modified non-HDL-cholesterol, triglycerides, and nonesterified fatty acids, with a minimum effective dose of 10 mg/kg/day. At this dose, compound 10g elevated HDL-cholesterol levels 2-3 times higher than pretreatment levels, and a dose-dependent reduction of fasting insulin and glucose levels was observed.

Full text of DOI:10.1021/jm040006p

6082
J. Med. Chem. 2004, 47, 6082-6099
Long Hydrocarbon Chain Keto Diols and Diacids that Favorably Alter Lipid
Disorders in Vivo
Ralf Mueller,† Jing Yang,† Caiming Duan,† Emil Pop,† Otto J. Geoffroy,† Lian Hao Zhang,† Tian-Bao Huang,†
Sergey Denisenko,† Bruce H. McCosar,† Daniela C. Oniciu,*,‡ Charles L. Bisgaier,‡ Michael E. Pape,‡
Catherine Delaney Freiman,‡ Brian Goetz,‡ Clay T. Cramer,‡ Krista L. Hopson,‡ and Jean-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 January 13, 2004
Keto-substituted hydrocarbons with 11-19 methylene and bis-terminal hydroxyl and carboxyl
groups have been synthesized and evaluated in both in vivo and in vitro assays 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 obese female Zucker fatty rats [Crl:(ZUC)-faBR] following 1 and 2 weeks of oral administra-
tion. The most active compounds were found to be symmetrical with four to five methylene
groups separating the central ketone functionality and the gem dimethyl or methyl/aryl
substituents. Furthermore, biological activity was found to be greatest in both in vivo and in
vitro assays for the tetramethyl-substituted keto diacids and diols (e.g., 10c, 10g, 14c), and
the least active were shown to be the bis(arylmethyl) derivatives (e.g., 10e, 10f, 14f). Compound
14c dose-dependently elevated HDL-cholesterol, reduced triglycerides, and reduced NEFA, with
a minimum effective dose of 30 mg/kg/day. Compound 10g dose-dependently modified non-
HDL-cholesterol, triglycerides, and nonesterified fatty acids, with a minimum effective dose of
10 mg/kg/day. At this dose, compound 10g elevated HDL-cholesterol levels 2-3 times higher
than pretreatment levels, and a dose-dependent reduction of fasting insulin and glucose levels
was observed.
Introduction
morbidity and mortality in humans.9 In addition, both
the Helsinki Heart Study10 and the Veterans Affairs-
HDL-Cholesterol Intervention Trial (VA-HIT) showed
that gemfibrozil-treatment-related increases in HDL-C
predicted a significant reduction in secondary coronary
events.11 In addition, the VA-HIT trial showed that the
gemfibrozil treatment reduced the incidence of stroke.12
Epidemiological studies have demonstrated a strong
correlation between elevated serum cholesterol and
coronary artery disease (CAD).1,2 Specifically, the level
of blood cholesterol carried in the low density lipopro-
teins (LDL-C) is positively correlated with increased risk
of CAD in the human population. Conversely, several
epidemiological studies have demonstrated an inverse
relationship between blood high-density lipoprotein
cholesterol (HDL-C) levels and the risk of developing
CAD.3 Elevated blood triglyceride levels are also inde-
pendently associated with increased risk for CAD.4-6 In
the light of these data, intensive effort over the last 30
years has focused on identifying pharmacologic agents
that can alter blood lipid levels. The 1960s were marked
by the discovery that clofibrate possessed hypolipidemic
activity. Subsequent work in the 1970s resulted in the
synthesis of other hypolipidemic fibrates, including
bezafibrate, ciprofibrate, fenofibrate, and gemfibrozil.
Elucidation of the cholesterol de novo synthetic path-
way,7 coupled with the discovery of the low-density
lipoprotein receptor and the metabolic basis of its
regulation,8 led to rapid development in the late 1970s
and 1980s of the statin class of drugs targeted at
inhibiting HMG-CoA reductase. Clinical trials demon-
strated that the statins markedly reduced LDL-C and
While the fibrate and statin discovery efforts were
ongoing, several groups were pursuing alternative
chemical and biological approaches to identify lipid-
regulating agents. For example, Sircar and co-workers13
described a series of phenylenebis(oxy)bis[2,2,-dimeth-
ylpentanoic acid]s that blunted the HDL-C reduction
induced in rats fed a peanut oil, cholesterol, and cholic
acid containing diet. Furthermore, Bar-Tana and co-
workers14,15 initiated a program to design nonmetabo-
lizable long-chain fatty acid analogues as potential
hypolipidemic agents. The resultant series of compounds
was termed “MEDICA” for â,â′-methyl-R,ω-dicarboxylic
acids, and a prototype member of this family, 3,3,14,-
14-tetramethylhexadecanedioic acid (MEDICA 16), was
selected for biological evaluation. The biochemical de-
sign for this series was based on the idea that it would
mimic long-chain fatty acids and thus inhibit lipid
synthesis. Other structural features included (1) the
ω-carboxyl function, which was expected to interfere
with incorporation of fatty acids into neutral lipids and
phospholipids, and (2) the â,â′-substitution to prevent
the â-oxidative catabolism of MEDICA compounds by
either mitochondrial or peroxisomal â-oxidative systems.
* To whom correspondence should be addressed. Phone: (734) 222-
1825. Fax: (734) 332-0516. E-mail: Daniela.Oniciu@pfizer.com.
† Alchem Laboratories Corp.
‡ Esperion Therapeutics.
10.1021/jm040006p CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/27/2004

Keto Diols and Diacids that Alter Lipid Disorders
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 6083
Scheme 1. Synthesis of Ethyl ω-Bromoalkanoates and
ω-Bromoalkyloxy THP Ethersa
a Reagents: (a) LDA, Br(CH2)nBr, [THF/DMPU]; (b) LiBH4,
MeOH, [CH2Cl2]; (c) DHP, pTosOH, [CH2Cl2].
to be particularly important, since a central ether
moiety conferred HDL-C elevating properties to alkyl
ethers, while a methylene spacer chain of equivalent
length did not.24 Beginning with modifications of the
central moiety, we determined that substitution of an
ether with a ketone in compounds with terminal hy-
droxyl moieties resulted in nearly equivalent HDL-C
elevating activity in various models of dyslipidemia.27c
We then investigated a ketone series having the general
formula V and examined the influence of chain length
and symmetry, terminal groups, and substitution pat-
tern at the quaternary carbons R to the terminal
carboxyl and â to the terminal hydroxy moieties. It
should be noted that pharmacokinetic studies have
shown the interconversion between the ketone diols and
ketone diacids in vivo (unpublished observation). Since
a single, specific molecular target has not been positively
identified for long-chain hydrocarbon compounds in
general, their lipid-regulating activity could be ex-
plained by cumulative effects on multiple biological
targets with emphasis on the fatty acid synthesis
inhibition at the acetyl-CoA carboxylase (ACC) step via
an allosteric mechanism.27d For this reason, lipid syn-
thesis in primary rat hepatocytes and lipid serum
regulation in the dyslipidemic obese female Zucker rat
were tested to ensure efficacy through biochemical
pathways in complex systems (cells and whole animals).
Chemistry. A series of long hydrocarbon chain keto
diols and diacids was synthesized using as starting
templates bromides of types 5 and 7 (Scheme 1 and
Table 1).31 The side chains connected to the central
ketone functionality varied both in length (n, m ) 3-7)
and in the attached geminal modifying groups (R1, R2
) Me, Ph, 4-Me-C6H4, 4-iBu-C6H4). The majority of
target compounds fell in the category of either sym-
metrical keto diacids (10b-10g, 10i, 10j, Scheme 2) or
symmetrical keto diols (14a-14i, Scheme 3). A series
of unsymmetrical keto diols and diacids with chains of
different lengths or with a different substitution pattern
(17-19, Scheme 4; 25, 26, Scheme 5) was included in
this study as well. In addition, the aryl-bridged com-
pounds 31 and 32 with a benzophenone backbone
(Scheme 6) were prepared and examined for comparison.
The key step in the syntheses of all ketones with
aliphatic chains was the alkylation of tosylmethyl
isocyanide (TosMIC)32,33 with appropriately substituted
alkyl bromides (Schemes 2-5). These alkyl bromide
building blocks were generally synthesized via lithiation
of commercially available or readily accessible ethyl
Figure 1.
Bar-Tana and co-workers have described in detail the
effects of MEDICA compounds (e.g., I, Figure 1) on lipid
disorders including metabolic syndrome related dis-
orders.16-19 These studies have shown that, indeed,
MEDICA compounds are hypolipidemic, antidiabetic,
and antiatherosclerotic in addition to possessing anti-
obesity properties in relevant animal models. Another
series of compounds with similar biological activity to
the MEDICA series are 3-thia fatty acids (e.g., II, Figure
1) developed and studied by Berge, Bremer, and
colleagues.20-23 Finally, carboxyl- and hydroxylalkyl
ether compounds III24-26 and IV27 (Figure 1) were
shown to significantly raise HDL-C in rats in contrast
to MEDICA 16 and 3-thia fatty acid compounds that
tend to lower HDL-C or HDL-associated proteins in that
species. However, the effect of Gemcabene (III, Figure
1), a dialkyl ether (dicarboxylic acid), on serum HDL-C
and triglyceride levels (TG) was shown to be dependent
upon baseline TG levels and Gemcabene dose in patients
with low levels of HDL-C.26
To identify new compounds that may be useful for the
treatment of human dyslipidemias and associated dis-
orders such as metabolic syndrome, we synthesized
ketone derivatives of long-chain hydrocarbons by 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 assay and a long-term (2 weeks) in vivo
animal model. Since some long-chain hydrocarbon com-
pounds (e.g., I and II) have been shown to inhibit fatty
acid and sterol synthesis,20,28,29 we tested the ability of
compounds to inhibit lipid synthesis by assessing their
effects on the de novo incorporation of radiolabeled
acetate into lipids in primary cultures of rat hepato-
cytes. In addition to the short-term lipid synthesis assay,
the compounds were also tested for their ability to alter
serum lipid variables over a 2-week period of oral
administration in the obese female Zucker rat line Crl:
(ZUC)-faBR, a model of diabetic dyslipidemia.
Results and Discussion
Drug Design. Studies related to compounds I-IV
suggested that certain structural features of the poly-
functionalized long hydrocarbon chains conferred lipid
regulating activity.14,21,30 The central group appeared

6084 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24
Mueller et al.
Scheme 3. Synthesis of Symmetrical Keto Diolsa
Table 1. Synthesis of Ethyl ω-Bromoalkanoates and
ω-Bromoalkyloxy THP Ethers
yield
(%)
yield
(%)
no.
n
R1
R2
no.
n
R1
R2
2
-
-
-
3
3
4
4
4
4
5
5
6
7
3
Me Ph
72
6b
6c
6d
6e
6g
3
4
4
4
5
5
3
3
4
4
4
5
5
Me Ph
Me Me
Me Ph
98
99e
84
3
Me 4-Me-C6H4 86
4
Me 4-iBuC6H4 96
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
6a
Me Me
Me Ph
Me Me
Me Ph
85a
59b
Me 4-Me-C6H4 96
Me Me
Me Ph
Me Me
Me Ph
Me Me
Me Ph
Me 4-Me-C6H4 93
Me Me
Me Ph
98
98
90
95
83
70
98,a 72c 6h
99
7a
7b
7c
7d
7e
7g
7h
Me 4-Me-C6H4 90
Me 4-iBu-C6H4 88
Me Me
Me Ph
Me Me
Me Me
Me Me
44
57
52
46
76
45d
100
a As described in ref 53. b (+)-Enantiomer described in ref 54.
c As described in ref 36a. d Reaction performed at 0 °C and without
cosolvent. e Also prepared with DIBAL according to ref 36a in 82%
yield.
a Reagents: (a) TosMIC, NaH, NBu4I, [DMSO]; (b) aq HCl,
[MeOH/H2O]; (c) LiAlH4, [MTBE]; (d) aq NaOCl, [HOAc]; (e) 1,3-
propanedithiol, BF3-Et2O, [CH2Cl2]; (f) LiAlH4, [THF]; (g) concd
HCl, DMSO, dimethoxyethane.
Scheme 2. Synthesis of Symmetrical Keto Diacidsa
Scheme 4. Synthesis of Unsymmetrical Keto Diolsa
a Reagents: (a) TosMIC, NaH, NBu4I, [DMSO], 27%, or K2CO3,
NBu4I, [DMF], 69%; (b) for 17, 7a, NaH, NBu4I, [DMSO], then
concd HCl, [MeOH], 58%; for 18, 7d, NaH, NBu4I, [DMSO], then
concd HCl, [MeOH], 71%; for 19, 7g, NaH, NBu4I, [DMSO], then
concd HCl, [MeOH], 48%.
esters 5b-5g, 5i, and 5j in the presence of catalytic
amounts of tetrabutylammonium iodide (NBu4I)39 to
give the corresponding dialkylated TosMIC intermedi-
ates 8b-8g, 8i, and 8j. In most cases, these intermedi-
ates were not purified or characterized but directly treat-
ed with concentrated aqueous HCl in CH2Cl232a to give
keto diesters 9b-9g, 9i, and 9j in good yields after chro-
matographic purification (Table 2). Finally, hydrolysis
of the ester groups with KOH in aqueous EtOH and sub-
sequent acidification with concentrated HCl (steps c, d)
provided the target diacids 10b-10g and 10j in variable
yields ranging from 31 to 87%. According to a different
protocol, keto diacid 10i was prepared by simultaneous
hydrolysis of the tosyl isocyanide and the ester groups
in 8i with KOH in aqueous EtOH followed by acidifica-
tion with dilute H2SO4 (steps c, e) in 57% yield.
Scheme 3 illustrates three different strategies that
were studied for the synthesis of symmetrical keto diols.
The standard procedure used in most cases employed
the dialkylation protocol of TosMIC as described above.
Bromo THP ethers 7a-7e, 7g, and 7h were used as
electrophiles, and the resulting TosMIC intermediates
were directly hydrolyzed to give the keto diols 14a-14e,
14g, and 14h in acceptable yields after purification by
column chromatography (Table 3). An alternative path-
way was elected for the synthesis of keto diol 14i. In
a Reagents: (a) TosMIC, NaH, NBu4I, [DMSO]; (b) aq HCl,
[CH2Cl2]; (c) KOH, [EtOH/H2O]; (d) aq HCl; (e) aq H2SO4.
esters 1, 2,34 3,35 and 4 with LDA in anhydrous THF in
the presence of N,N′-dimethylpropyleneurea (DMPU) at
-78 °C, followed by subsequent reaction with an R,ω-
dibromoalkane36 of the required chain length (Scheme
1). Thus, bromo esters 5a-5j were obtained in moderate
to good yields (Table 1). Reduction of bromo esters with
LiBH4 and MeOH37 in refluxing CH2Cl2 afforded the
bromo alcohols 6a-6e, 6g, and 6h in excellent yields
and purities without affecting the bromide moiety.38
Reduction with LiAlH4 or NaBH4 on the other hand was
not chemoselective, and the reactions were not repro-
ducible. Another chemoselective reducing agent was
diisobutylaluminum hydride.36a Bromo alcohols were
treated with 3,4-dihydro-2H-pyran (DHP) and catalytic
amounts of p-toluenesulfonic acid (pTosOH)36a to give
the THP ethers 7a-7e, 7g, and 7h (Scheme 1, Table 1)
in moderate to good yields.
The synthesis of symmetrical keto diacids 10b-10g,
10i, and 10j from bromo esters 5b-5g, 5i, and 5j was
accomplished by employing TosMIC methodology33
(Scheme 2). Accordingly, TosMIC was deprotonated with
NaH in either DMSO or in a DMSO/Et2O mixture32a at
room temperature and then reacted with suitable bromo

Keto Diols and Diacids that Alter Lipid Disorders
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 6085
Table 2. Synthesis of Symmetrical Keto Diacids
Scheme 5. Synthesis of Unsymmetrical Keto Diacidsa
yield
(%) no.
yield
(%)
no.
n
R1
R2
n
R1
R2
9b
9c
9d
9e
9f
9g
9i
9j
3
4
4
4
4
5
6
7
Me Ph
Me Me
Me Ph
61
67
66
10b
10c
10d
10e
10f
10g
10i
10j
3
4
4
4
4
5
6
7
Me Ph
Me Me
Me Ph
31
86
87
Me 4-Me-C6H4 54
Me 4-Me-C6H4 39
Me 4-iBu-C6H4 82
Me 4-iBu-C6H4 86
Me Me
Me Me
Me Me
61
Me Me
Me Me
Me Me
57
40
57b
74
61a
a Intermediate 8j was purified by column chromatography;
b Prepared by direct base hydrolysis of 8i.
Table 3. Synthesis of Symmetrical Keto Diols
yield
(%) no.
yield
(%)
no.
n
R1
R2
n
R1
R2
11i
12f
13f
14a
14b
14c
5
4
4
3
3
4
Me Me
66
14d
14e
14f
14g
14h
14i
4
4
4
5
5
6
Me Ph
61
Me 4-iBu-C6H4 98
Me 4-Me-C6H4 21
Me 4-iBu-C6H4 94
Me 4-iBu-C6H4 83
Me Me
Me Ph
Me Me
30
38
68
Me Me
Me Ph
Me Me
79
56
35
a Reagents: (a) TosMIC, NaH, NBu4I, [DMSO], 12%; (b) for n
) 3, 7a, NaH, NBu4I, [DMSO], then aq H2SO4, [MeOH], 60%; (c)
for n ) 5, (1) TosMIC, NaH, NBu4I, [DMSO]; (2) 7g, NaH; (3) aq
H2SO4, [MeOH], 36%; (d) PDC, [DMF]; n ) 3, 79%; n ) 5, 68%;
(e) KOH, [EtOH/H2O]; n ) 3, 60%; n ) 5, 43%.
13f. Removal of the 1,3-dithiane protective group with
DMSO in dimethoxyethane and concentrated HCl42
afforded keto diol 14f (63% from 5f). Despite the
superior yields attained, this method was not generally
applied for the synthesis of 14a-14i because of the
malodorous reagent involved.
Scheme 6. Synthesis of Aryl-Bridged Compoundsa
Unsymmetrical keto diols 17-19 were prepared via
the mono-alkylated TosMIC derivative 15 (Scheme 4).
However, reaction of TosMIC with 1 equiv of 7c under
the previously utilized reaction conditions (NaH and
NBu4I in DMSO) gave a mixture of mono- and dialkyla-
ted products 15 and 16, which were separated by chro-
matography.43 Consequently, formation in the next step
of mixtures of 17 or 19, respectively, with 14c, practical-
ly impossible to separate, was prevented, but the yield
remained low (27%). When using K2CO3 in DMF, com-
pound 15 was produced in 69% yield without formation
of 16, even when an excess of 7c was used. Further al-
kylation of 15 with bromo THP ethers 7a, 7d, and 7g,
followed by deprotection with concentrated HCl in re-
fluxing MeOH furnished the unsymmetrical products
17-19.
Similar problems with an unwanted dialkylated
byproduct (8c, Scheme 5) were also encountered in the
synthetic route to diacids 25 and 26. Alkylation of
TosMIC with 5c by treatment with NaH and NBu4I in
DMSO led to a mixture of compounds 20 and 8c that
was very difficult to separate chromatographically.44 As
a result, the yield of pure 20 was only 12%. To ensure
the complete removal of the symmetrical keto diester
9c that results from intermediate 8c, compound 20 was
reacted with bromo THP ether 7a and subsequently
hydrolyzed to give hydroxy ester 21. Purification of 21
from traces of 9c was now easily accomplished by
chromatography (60% yield). Subsequent oxidation of
this alcohol with pyridinium dichromate (PDC) in
DMF45 afforded diacid monoester 23 (79%), which was
further saponified to provide 25 in 60% yield after
crystallization from Et2O/hexanes.
a Reagents: (a) Ethyl isobutyrate, LDA, [THF/DMPU], 89%; (b)
KOH, [EtOH/H2O], quantitative; (c) 1,3-propanedithiol, BF3-Et2O,
[CH2Cl2], 87%; (d) LiBH4, MeOH, [CH2Cl2], 85%; (e) CuO, CuCl2,
[acetone/DMF], 71%.
this case, keto diester 9i was first reduced to triol 11i
by treatment with LiAlH4 (66%). Selective oxidation of
the secondary alcohol moiety in 11i with aqueous NaOCl
solution in acetic acid40 then produced 14i in low yield
(35%). Better results were obtained when the ketone
functionality in the keto diester was protected prior to
the reduction of the esters. Thus, protection of 9f with
1,3-propanedithiol and BF3-Et2O41 led to formation of
12f, which was subsequently reduced with LiAlH4 to
The same strategy was applied for the synthesis of
unsymmetrical keto diacid 26. In this case, intermediate
20 was not isolated but further alkylated in situ with

6086 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24
Mueller et al.
Table 4. Effect of Keto Diacids and Diols on Lipid Synthesis in Primary Rat Hepatocytes
a Not active; inhibition of [14C]acetate incorporation into total lipids is less than 50% at 300 µM. b The confidence of the IC50 estimate
is insufficient to assign a value. However, the compound’s IC50 is between the stated concentrations.
bromo THP ether 7g. After deprotecting the ketone
group by acid treatment and purification of the crude
product by chromatography, hydroxy ester 22 was
isolated in 36% yield. In analogy to its shorter chain
homologue 21, oxidation of compound 22 with PDC in
DMF led to keto diacid monoester 24 (68%). Subsequent
hydrolysis of 24 with KOH in aqueous EtOH followed
by chromatographic purification and crystallization
furnished 26 in 43% yield.
lalated diol 32, the ketone moiety in intermediate 28
was first protected as S,S-acetal 29 (87%).41 Reduction
with LiBH4 and MeOH37b gave diol 30 in 85% yield.
Finaally, deprotection with CuO and CuCl2 in a reflux-
ing acetone/DMF solvent mixture47 afforded keto diol
32 in 71% yield.
Biological Activity. The aim of our structure-based
drug design in the ketone series was to determine the
influence of structural modifications on biological activ-
ity. Several specific structural features were explored
to determine their effects on biological activity, including
methylene spacer length from the central ketone to the
gem-dialkyl or gem-alkylaryl substituents, symmetry
around the central ketone, variation of gem substitu-
ents, and terminal functional groups (diacids and diols).
Tables 4-8 present in vitro and in vivo biological data in
Benzophenone derivative 2746 was used as starting
material for the synthesis of aryl-bridged ketones 31 and
32. Bromide displacement in 27 by reaction with lithio
ethyl isobutyrate in THF/DMPU at -78 °C produced the
diester 28 in 89% yield. Conversion of 28 to diacid 31
performed by saponification with KOH resulted in prac-
tically quantitative yield. For the synthesis of the re-

Keto Diols and Diacids that Alter Lipid Disorders
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 6087
Table 5. Effect of Keto Diacids and Diols in Obese Female Zucker Ratsa
a ND ) Compound not tested.
connection with lipid-regulating properties for the keto
diols and keto diacids described above. In vitro studies
tested the ability of compounds to inhibit the incorpora-
tion of [14C]acetate into total cellular lipids of primary rat
hepatocytes over a 4-h time period (Table 4). The com-
pounds were also tested for their ability to alter serum
lipid variables in an animal model of diabetic dyslipid-
emia, the obese female Zucker rat, over a 2-week period
at a single daily dose of 30 or 100 mg/kg/day (Table 5).
Select compounds (14c, 10c, and 10g) were further
evaluated in the same Zucker rat model by performing
a full dose-response study and measuring additional
serum variables including markers for diabetes (Tables
6-8).
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 the ketone series on total lipid
synthesis activity in that model using [14C]acetate as
the metabolic precursor.48,49 Table 4 summarizes the
biological effects of the keto diacid and keto diol
analogues in primary rat hepatocyte cultures.
Compounds with three methylene spacers on each
side of the central ketone moiety were inactive (10b) or
showed only marginal activity (14a, 14b). As the me-
thylene spacer chain length was increased to four or
five, the activity of keto diacids (10c and 10g) and keto
diols (14c and 14g) increased markedly (i.e., IC50 ) 3-4
µM). The activity of compounds with six or seven
Effect on Lipid Synthesis In Vitro. The rat hepa-
tocyte culture is a useful model for assessing de novo

6088 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24
Mueller et al.
methylene spacers (10i, 10j, 14i) was only slightly lower
(i.e., IC50 ) 2-9 µM). By replacing the methylene
spacers in the chain with aryl groups (such as in
benzophenone 32), lipid synthesis inhibitory activity
was reduced significantly (IC50 ) 52 µM).
Symmetry around the central ketone did not appear
to markedly affect biological activity. For example, the
unsymmetrical compounds 19 (keto diol) and 26 (keto
diacid) possessing chains of four and five methylene
spacer groups flanking the central ketone had activities
similar to the symmetrical compounds with two chains
of four or five methylene spacers (compounds 10c, 10g,
14c, 14g).
Regarding gem substitutions, the addition of a single
phenyl substituent to one of the gem sites on the
quaternary carbon (18) did not markedly change the
activity (IC50 ) 1 µM) compared to the tetramethyl-
substituted keto diol (14c, IC50 ) 4 µM). However,
substituting one of the methyl groups with aryl (10d-
10f, 14d-14f, 14h) on both quaternary carbons mark-
edly reduced activities (IC50 > 100 µM) compared to the
corresponding tetramethyl-substituted compounds (10c,
10g, 14c, 14g).
metrical ketones with two chains of five methylene
spacers (10g, 14g) were superior to symmetrical ketones
with two chains of four (10c, 14c) and unsymmetrical
ketones with chains of four and five (19, 26) methylene
spacers. Furthermore, compounds with six (14i) or
seven (10j) methylene spacers displayed a reduction in
activity compared to the five-methylene spacer com-
pounds (10g, 14g). No marked differences between the
corresponding diacid or diol forms of the active com-
pounds were noticed. Virtually all the aromatic substi-
tutions at the quaternary carbon rendered the com-
pounds relatively inactive with the exception of diacid
10f. However, the corresponding diol 14f was not active
in this particular set of experiments. Additional dose-
response studies are needed to confirm these differences.
A comparison of activities in the in vitro lipid syn-
thesis assay (Table 4) and the Zucker rat model (Table
5) indicated that 8 out of the 12 compounds with an IC50
below 10 µM in the lipid synthesis assay favorably
altered non-HDL-C, HDL-C, and triglycerides in the
Zucker rat (10c, 10g, 10j, 14c, 14g, 14i, 19, 26). Three
compounds showed discordance between the in vitro and
in vivo assays: diol 17 and diacid 25 are both unsym-
metrical ketones with chains of three and four methyl-
ene spacers flanking the central ketone; compound 18
contains two chains consisting of four methylene spacer
groups each and a phenyl substituent on one of the two
quaternary carbons. In addition, keto diacid 10f, which
has two four-methylene spacers and aromatic substit-
uents on both quaternary carbons, was not active in the
lipid synthesis assay but did display activity in the
Zucker rat model. These data demonstrate that the in
vitro lipid synthesis assay cannot predict all active
compounds in vivo but does show concordance with
respect to certain structural features (e.g., gem-dimethyl
substitutions and hydrocarbon chains but not R-(aryl-
methyl) substitution to the carboxyl).
Effect on Lipid Variables in the Obese Female
Zucker Rat: Dose-Response for Selected Com-
pounds. As noted previously, some long chain hydro-
carbon compounds (e.g., I and II, Figure 1) possess
insulin-sensitizing activity as well as lipid-regulating
properties. To confirm our single dose findings with
respect to lipids and determine ketone compound effects
on diabetes variables, a dose-response study for some
of the most active compounds (10c, 10g, 14c) was
performed. In regard to lipid variables, we specifically
focused on agents that lowered non-HDL-C, elevated
HDL-C, and lowered serum triglycerides with additional
measurements of glucose, insulin, and nonesterified
fatty acids (NEFA). It should be noted that animals used
to initiate these studies were between 10 and 12 weeks
of age, hyperinsulinemic, and generally mildly hyper-
glycemic, that is, they expressed symptoms of impaired
glucose tolerance. Data for 14c, 10c, and 10g are
presented in Tables 6, 7, and 8, respectively.
Both diacid 10c and diol 14c have two chains of four
methylene spacers attached to the central ketone and
gem-dimethyl substitution on both quaternary carbons.
As noted previously (Tables 4 and 5), our initial assess-
ment indicated little difference between diacids and
diols in the in vitro and in vivo assays. Indeed, both
compounds had similar activities in the dose-response
study (Tables 6 and 7). The only observed difference was
Regarding the terminal functional groups, there was
no significant difference in the in vitro activity between
diacids or diols (e.g., 10c vs 14c and 10g vs 14g).
Effect on Lipid Variables in the Obese Female
Zucker Rat. To test the lipid regulating activity of
these compounds, we used the obese Zucker fatty rat
[Crl:(Zuc)-faBR] 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 nonin-
sulin dependent diabetes mellitus (NIDDM) or type II
diabetes. Animals develop an age-dependent progression
of disease that includes hypertriglyceridemia, increased
VLDL-cholesterol (VLDL-C), decreased HDL-C, im-
paired insulin 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. It
is worthwhile to mention that, unlike a normal rat,
these animals have markedly elevated plasma triglyc-
erides and a significant amount of cholesterol as VLDL-
C. Their lipoproteins are also distinct from humans,
where most of the non-HDL-C is carried in the LDL
fraction.
Initially, the lipid-regulating activities of the ketone
compounds in this model were assessed by administer-
ing a single dose of 30 or 100 mg/kg/day 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 5 summarizes those serum lipid
changes induced by the keto diols and keto diacids.
Rather than favorably changing only one or two lipid
variables and maintaining marked changes throughout
the entire 2-week time course, active compounds favor-
ably altered all three serum lipid variables while
sustaining the effect for two weeks (10c, 10g, 10j, 14c,
14g, 19, 26). We generally defined active compounds as
those that markedly reduced non-HDL-C and triglyc-
erides while elevating HDL-C. Common features of
these compounds included methylene spacer chain
lengths equal to or greater than four and a gem dimethyl
substitution pattern at the quaternary carbon. Sym-

Keto Diols and Diacids that Alter Lipid Disorders
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 6089

6090 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24
Mueller et al.
that 10c appeared to dose-dependently reduce non-
HDL-C, with greater effects after 1 week than after 2
weeks, while 14c displayed little activity toward non-
HDL-C. However, both compounds dose-dependently
elevated HDL-C, reduced triglycerides, and reduced
NEFA. Neither compound affected fasting insulin or
glucose in the Zucker rat.
The extended chain length in 10g compared to 10c
significantly increased compound potency and efficacy.
Compound 10g dose-dependently modified non-HDL-C,
triglycerides, and NEFA with reductions of 88%, 92%,
and 52%, respectively, after 2 weeks of dosing at 100
mg/kg/day (Table 8). Furthermore, 10g elevated HDL-C
in a time- and dose-dependent manner, reaching HDL-C
levels that were 2-3 times higher than pretreatment
levels. In addition, the compound dose-dependently
reduced fasting insulin levels while only moderately
affecting fasting glucose levels, suggesting improved
insulin-sensitization in this diabetic model. Weight gain
was also measured in this experiment. Control animals
(n ) 27) gained 7.9 ( 0.4% of their initial body weight
(401.7 ( 5.7 g) over the 2-week study period. Animals
treated with compound 10g at doses of 10, 30, and 100
mg/kg/day gained 7.1 ( 0.5%, 4.6 ( 0.5%, and 1.1 (
0.9% of their initial body weights (407.9 ( 8.1 g, n )
22; 396.4 ( 5.8 g, n ) 18; and 413.3 ( 5.3 g, n ) 15),
respectively. The percent weight gain with compound
10g was significantly less at 30 (p < 0.005; n ) 18) and
100 mg/kg/day (p < 0.0001; n ) 15) compared to the
control group.
It is unclear why non-HDL-C is elevated at the 30
mg/kg/day dose for 14c and at 10 mg/kg/day for 10g.
However, since both compounds inhibit cholesterol
synthesis, the effect may be due to the well-known
cholesterol synthesis compensation mechanism earlier
described for statins as being operative in rodents.50
Conclusions
Our research effort was focused on identifying com-
pounds for the treatment of dyslipidemia, diabetes, and
obesity, all of which are major medical problems related
to premature development of cardiovascular diseases.
Common elements of these conditions include elevated
levels of triglycerides and low levels of HDL-C. The
current discovery effort has generated a series of novel
keto diol and keto diacid compounds with biological
properties that suggest utility for controlling these
serum variables in appropriate preclinical models. Sym-
metrical compounds possessing five methylene spacer
chains proved to be the most promising candidates for
further development. Overall, we have discovered a
series of novel agents that may have beneficial effects
on serum lipids while enhancing glycemic control with-
out causing weight gain. The combination of these
effects within a single agent may be highly desirable to
treat a host of diverse but related metabolic disorders.
Experimental Section
Chemistry. Chemical reagents from Sigma-Aldrich or
Lancaster were used without further purification. Ibuprofen
and silica gel for column chromatography (0.035-0.070 mm,
pore diameter ca. 6 nm) were obtained from Acros Organics.
ACS grade solvents from Fisher Scientific or Mallinckrodt were
routinely used for chromatographic purifications and extrac-
tions. Melting points (uncorrected) were determined on either

Keto Diols and Diacids that Alter Lipid Disorders
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 6091
a Thomas-Hoover capillary or Haake-Buchler melting point
of this oil (30.0 g) in CH2Cl2 (300 mL) and concentrated
aqueous HCl (40 mL) was stirred for 2 h at room temperature.
After extractive workup and flash chromatography (silica gel;
hexanes/EtOAc ) 10/1), 9d (5.0 g, 66%) was obtained as a clear
1
apparatus. H NMR spectra were recorded at 300 MHz and
13C NMR spectra 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 cali-
brated on the CDCl3 resonance at 77.23 ppm, unless otherwise
specified. Coupling constants (J) are given in Hz. The purity
of target compounds was analyzed using Shimadzu HPLC
systems equipped with UV and/or RI detection.
1
oil together with a less pure fraction (1.17 g, 16%). H NMR
(CDCl3): δ 7.40-7.10 (m, 10 H), 4.11 (q, 4 H, J ) 7.0), 2.34 (t,
4 H, J ) 7.1), 2.10-1.70 (m, 4 H), 1.6-1.4 (m, 4 H), 1.52 (s, 6
H), 1.30-1.00 (m, 10 H). 13C NMR (CDCl3): δ 210.7, 176.0,
143.8, 128.2, 126.5, 125.8, 60.6, 50.0, 42.4, 38.9, 24.3, 24.1, 22.6,
14.0. HRMS (LSIMS, nba): calcd for C31H43O5 (MH+) 495.3110,
found 495.3106. HPLC: Alltima C-18 column, 250 × 4.6 mm,
5 µm; 80% acetonitrile/20% 0.05 M KH2PO4, flow rate 1.2 mL/
min; RI, tR 13.00 min, 94.8% pure.
Representative Procedure for the Synthesis of Keto
Diesters: 2,2,12,12-Tetramethyl-7-oxotridecanedioic Acid
Diethyl Ester (9c). Under N2-atmosphere, to a solution of
5c (22.4 g, 89.2 mmol) in anhydrous DMSO (300 mL) was
added TosMIC (8.71 g, 44.6 mmol), NaH (60% w/w in mineral
oil, 4.28 g, 107.0 mmol), and NBu4I (3.30 g, 8.9 mmol) under
cooling with an ice bath. After the addition, the reaction
mixture was stirred for 23 h at room temperature, cooled with
an ice bath, and carefully hydrolyzed with water (300 mL).
The solution was extracted with CH2Cl2 (3 × 150 mL). The
combined organic layers were washed with water (100 mL)
and half-saturated aqueous NaCl solution (100 mL), dried over
anhydrous MgSO4, concentrated in vacuo, and dried in high
vacuo to give the crude intermediate 8c (26.2 g) as an oil [1H
NMR (CDCl3): δ 7.85 (d, 2 H, J ) 8.3), 7.42 (d, 2 H, J ) 8.3),
4.12 (q, 4 H, J ) 7.0), 2.49 (s, 3 H), 1.94 (m, 4 H), 1.60-1.34
(m, 8 H), 1.30-1.15 (m, 4 H), 1.25 (t, 6 H, J ) 7.0), 1.15 (s, 12
H). 13C NMR (CDCl3): δ 177.77, 164.08, 146.43, 131.20, 130.34,
129.96, 81.78, 60.37, 42.12, 40.27, 33.21, 25.25, 25.19, 24.97,
24.26, 21.86, 14.34]. To a solution of 8c (26.0 g) in CH2Cl2 (400
mL) was added concentrated HCl (100 mL) and the reaction
mixture was stirred for 45 min at room temperature. The
solution was diluted with water (400 mL), and the layers were
separated. The aqueous layer was extracted with CH2Cl2 (300
mL). The combined organic layers were washed with saturated
aqueous NaHCO3 solution (100 mL) and saturated aqueous
NaCl solution (100 mL). The organic phases were dried over
anhydrous MgSO4, concentrated in vacuo, and dried in high
vacuo. The residue was purified by flash chromatography
(silica gel; hexanes/EtOAc ) 95/5, then 90/10) to give 9c (11.0
2,12-Dimethyl-7-oxo-2,12-di-p-tolyltridecanedioic Acid
Diethyl Ester (9e). In analogy to the procedure described for
the synthesis of 9c, 5e (21.0 g, 64.2 mmol) was reacted with
NBu4I (2.37 g, 6.4 mmol), TosMIC (6.26 g, 32.1 mmol), and
NaH (60% dispersion in mineral oil, 3.24 g, 81.0 mmol) in
anhydrous DMSO (320 mL) and Et2O (110 mL) for 24 h at
room temperature. After hydrolysis and extraction, the crude
intermediate 8e was stirred in CH2Cl2 (500 mL) and concen-
trated HCl (140 mL) for 2 h at room temperature. Extraction
and purification by flash chromatography (silica gel; EtOAc/
hexanes ) 1/20, 1/9) afforded 9e (9.0 g, 54%) as a light
1
yellowish oil. H NMR (CDCl3): δ 7.10 (d, 4 H, J ) 7.9), 7.02
(d, 4 H, J ) 7.9), 4.05 (q, 4 H, J ) 7.0), 2.25 (t, 4 H, J ) 7.3),
2.20 (s, 6 H), 1.95-1.70 (m, 4 H), 1.42 (s, 6 H), 1.50-1.05 (m,
8 H), 1.08 (t, 6 H, J ) 7.0). 13C NMR (CDCl3): δ 211.10, 176.00,
141.00, 135.80, 128.50, 124.51, 60.50, 49.50, 42.01, 39.50,
24.28, 24.05, 22.10, 20.50, 13.00. HRMS (LSIMS, nba): calcd
for C33H47O5 (MH+) 523.3423, found 523.3405.
2,12-Bis(4-isobutylphenyl)-2,12-dimethyl-7-oxotride-
canedioic Acid Diethyl Ester (9f). Similar to the procedure
given for 9c, 5f (14.13 g, 38.3 mmol) was reacted with TosMIC
(3.73 g, 19.1 mmol), NBu4I (1.30 g, 3.5 mmol), and NaH (2.0
g, 60%, 50.0 mmol) in freshly distilled DMSO (200 mL) for 18
h at room temperature. The crude intermediate 8f obtained
after hydrolysis and extraction was stirred in CH2Cl2 (100 mL)
and concentrated HCl (50 mL) for 1 h at room temperature.
Extractive workup and purification by flash chromatography
(silica gel; EtOAc/hexanes ) 10/90, then 20/80) yielded 9f (9.49
1
g, 67%) as an oil. H NMR (CDCl3): δ 4.03 (q, 4 H, J ) 7.1),
1
2.31 (t, 4 H, J ) 7.5), 1.45 (m, 8 H), 1.20-1.08 (m, 4 H), 1.16
(t, 6 H, J ) 7.1), 1.07 (s, 12 H). 13C NMR (CDCl3): δ 211.14,
178.05, 60.34, 42.69, 42.20, 40.52, 25.24, 24.71, 24.30, 14.35.
HRMS (LSIMS, nba): calcd for C21H39O5 (MH+) 371.2797,
found 371.2763.
g, 82%) as a colorless oil. H NMR (CDCl3): δ 7.18 (d, 4 H, J
) 8.0), 7.07 (d, 4 H, J ) 8.0), 4.10 (q, 4 H, J ) 7.0), 2.43 (d, 4
H, J ) 7.0), 2.34 (t, 4 H, J ) 7.6), 2.10-1.92 (m, 2 H), 1.92-
1.78 (m, 4 H), 1.60-1.50 (m, 4 H), 1.50 (s, 6 H), 1.19-1.11 (m,
5 H), 1.17 (t, 3 H, J ) 7.0), 0.88 (d, 12 H, J ) 6.6). 13C NMR
(CDCl3): δ 211.06, 176.39, 141.36, 140.04, 129.16, 125.71,
60.77, 49.90, 45.06, 42.66, 39.18, 30.27, 24.59, 24.35, 22.86,
22.56, 14.23. HRMS (LSIMS, nba): calcd for C39H59O5 (MH+)
607.4362, found 607.4337.
2,10-Dimethyl-6-oxo-2,10-diphenylundecanedioic Acid
Diethyl Ester (9b). According to the procedure described for
the synthesis of 9c, 5b (25.0 g, 76.4 mmol), NBu4I (2.78 g, 7.5
mmol), and TosMIC (7.34 g, 37.6 mmol) in anhydrous DMSO
(400 mL) and Et2O (150 mL) were reacted with NaH (60%
dispersion in mineral oil, 3.80 g, 95.0 mmol) first under cooling
with an ice bath and then at room temperature for 24 h.
Hydrolysis and extraction afforded the intermediate 8b (28.0
g) as a brown oil. A portion of this crude intermediate (25.0 g)
was then treated with concentrated aqueous HCl (140 mL) in
CH2Cl2 (500 mL) for 2 h at room temperature. Aqueous
workup, extraction, and purification by flash chromatography
(silica gel; EtOAc/hexanes ) 1/20, 1/10) furnished 9b (9.5 g,
2,2,14,14-Tetramethyl-8-oxopentadecanedioic Acid Di-
ethyl Ester (9g). According to the procedure described for the
synthesis of 9c, a solution of 5g (32.3 g, 115.3 mmol), NBu4I
(3.69 g, 10.0 mmol), and TosMIC (9.80 g, 50.2 mmol) in
anhydrous DMSO (300 mL) was treated with NaH (4.80 g,
120.0 mmol, 60% in mineral oil) at room temperature for 20
h. The intermediary dialkylated TosMIC derivative 8g ob-
tained after aqueous workup (36.8 g) was then hydrolyzed with
concentrated HCl (110 mL) in CH2Cl2 (450 mL) at room
temperature for 1 h. Extractive workup and purification by
column chromatography (silica gel; hexanes/EtOAc ) 11/1)
afforded 9g (12.20 g, 61%) as a colorless oil. 1H NMR (CDCl3):
δ 4.11 (q, 4 H, J ) 6.9 Hz), 2.37 (t, 4 H, J ) 7.5), 1.58-1.47
(m, 8 H), 1.35-1.10 (m, 8 H), 1.24 (t, 6 H, J ) 7.2), 1.15 (s, 12
H). 13C NMR (CDCl3): δ 211.6, 178.3, 60.5, 43.1, 42.5, 40.9,
30.1, 25.5, 25.1, 24.1, 14.7. HRMS (LSIMS, gly): calcd for
C23H43O5 (MH+) 399.3110, found 399.3129.
2,2,18,18-Tetramethyl-10-oxononadecanedioic Acid Di-
ethyl Ester (9j). Under N2 atmosphere, NaH (60% w/w in
mineral oil, 1.21 g, 30.2 mmol) was added in portions to a
solution of TosMIC (2.43 g, 12.5 mmol) and NBu4I (0.462 g,
1.25 mmol) in dry DMSO (100 mL) while being vigorously
stirred and cooled with a water bath. After 15 min, 5j (7.65 g,
26.1 mmol) was added dropwise in 20 min. After 1 h, H2O (100
1
61%) as a light yellowish oil. H NMR (CDCl3): δ 7.40-7.10
(m, 10 H), 4.20-4.05 (m, 4 H), 2.38 (m, 4 H), 2.05-1.80 (m, 4
H), 1.60 (s, 6 H), 1.50-1.20 (m, 4 H), 1.22 (m, 6 H). 13C NMR
(CDCl3): δ 210.24, 176.06, 143.71, 128.42, 126.72, 125.97,
60.83, 50.13, 42.97, 38.91, 22.73, 22.47, 19.09, 14.13. HRMS
(LSIMS, nba): calcd for C29H39O5 (MH+) 467.2797, found
467.2772.
7-Oxo-2,12-dimethyl-2,12-diphenyltridecanedioic Acid
Diethyl Ester (9d). In analogy to the procedure described for
the synthesis of 9c, 5d (9.59 g, 30.6 mmol) in anhydrous DMSO
(50 mL) was reacted with TosMIC (3.02 g, 15.5 mmol), NaH
(60% w/w in mineral oil, 1.44 g, 36.0 mmol), and NBu4I (1.10
g, 3.0 mmol), first under cooling with a water bath and then
for 96 h at room temperature. Hydrolysis and extraction
afforded the crude intermediate 8d (30.0 g) as an oil. A solution

6092 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24
Mueller et al.
mL) was added dropwise and the resulting mixture was
extracted with Et2O (3 × 100 mL). The combined organic layers
were washed with brine (2 × 100 mL), dried over anhydrous
Na2SO4, and evaporated in vacuo. The residue was purified
by column chromatography (silica, heptane:EtOAc ) 6:1) to
give 8j (5.41 g) as a yellow oil. To a portion of this oil (5.03 g),
dissolved in CH2Cl2 (100 mL), was added aqueous HCl (concd,
30 mL) and the resulting mixture was stirred vigorously for
17.5 h. Water (100 mL) was added and the layers were
separated. The aqueous phase was extracted with CH2Cl2 (100
mL) and the combined organic layers were washed with
NaHCO3 solution (2 × 100 mL) and brine (100 mL), dried over
anhydrous Na2SO4, and evaporated in vacuo. The residue was
purified by column chromatography (silica, heptane:EtOAc )
7:1) to give 9j (3.21 g, 61%) as a colorless oil. 1H NMR
(CDCl3): δ 4.11 (q, J ) 7.2, 4 H), 2.37 (t, J ) 7.4, 4 H), 1.57-
1.46 (m, 8 H), 1.28-1.23 (m, 16 H), 1.24 (t, J ) 7.1, 6 H), 1.15
(s, 12 H). 13C NMR (CDCl3): δ 211.5, 178.0, 60.08, 60.07, 42.7,
42.1, 40.7, 29.9, 29.21, 29.15, 25.1, 24.8, 23.8, 14.2. HRMS:
calcd for C27H50O5 (MH+) 454.3658, found 454.3663.
9-Isocyano-2,2,16,16-tetramethyl-9-(tolyl-4-sulfonyl)-
heptadecanedioic Acid Diethyl Ester (8i). To a solution
of 5i (35.0 g, 125.4 mmol), NBu4I (4.6 g, 12.5 mmol), and
TosMIC (12.2 g, 62.5 mmol) in anhydrous DMSO (450 mL)
was added NaH (60% dispersion in mineral oil, 6.3 g, 158
mmol) under cooling with an ice-water bath and under N2
atmosphere. The reaction mixture was stirred for 23 h at
ambient temperature and then carefully hydrolyzed with ice-
water (500 mL) and extracted with MTBE (3 × 200 mL). The
organic layers were washed with water (300 mL) and brine
(150 mL), dried over anhydrous MgSO4, and concentrated in
vacuo to give crude 8i (37.0 g, 100%) as an oil. 1H NMR
(CDCl3): δ 7.88 (d, J ) 7.9, 2 H), 7.42 (d, J ) 7.9, 2 H), 4.10
(q, J ) 7.5, 4 H), 2.48 (s, 3 H), 2.05-1.75 (m, 3 H), 1.65-1.20
(m, 21 H), 1.15 (t, J ) 7.5, 6 H), 1.10 (s, 12 H). 13C NMR
(CDCl3): δ 177.89, 163.75, 146.23, 131.08, 130.28, 129.82,
81.79, 60.17, 42.09, 40.57, 33.09, 29.68, 29.31, 25.17, 24.78,
23.66, 21.08, 14.31. HRMS (LSIMS, gly): calcd for C37H54NO6S
(MH+) 592.3672, found 592.3667.
(LSIMS, nba): calcd for C35H50O5Na (MNa+): 573.355, found
573.3459. HPLC: Alltima phenyl column, 250 × 4.6 mm, 5
µm; 80% acetonitrile/20% 0.05 M KH2PO4, flow rate 1.2 mL/
min; RI, tR 6.33 min, 86.9% pure. Anal. (C35H50O5): C, H.
2,10-Dimethyl-6-oxo-2,10-diphenylundecanedioic Acid
(10b). According to the procedure given for 10f, 9b (14.5 g,
31.1 mmol) was saponified with KOH (85%, 7.2 g, 108.6 mmol)
in water (15 mL) and EtOH (45 mL) at reflux for 6 h. After
the usual extractive workup, the crude material was purified
by flash chromatography (silica gel; EtOAc/hexanes ) 1/20,
1/10, 1/2) to give 10b (4.0 g, 31%) as a white solid. Mp: 44-
1
46 °C. H NMR (CDCl3): δ 10.25 (br, 2 H), 7.35-7.22 (m, 10
H), 2.32 (m, 4 H), 1.94-1.86 (m, 4 H), 1.57 (s, 6 H), 1.51-1.22
(m, 4 H). 13C NMR (CDCl3): δ 210.64, 182.66, 142.69, 128.66,
127.18, 126.29, 50.07, 42.97, 38.62, 22.20, 19.11. HRMS
(LSIMS, gly): calcd for C25H31O5 (MH+) 411.2171, found
411.2144. HPLC: Alltima C-18 column, 250 × 4.6 mm, 5 µm;
60% acetonitrile/40% 0.05 M KH2PO4, flow rate 1.2 mL/min;
UV, tR 5.50 min, 95.2% pure.
7-Oxo-2,2,12,12-tetramethyltridecanedioic Acid (10c).
According to the procedure given for 10f, 9c (30.0 g, 81.0 mmol)
was saponified with KOH (85%, 18.9 g, 286 mmol) in EtOH
(143 mL) and water (48 mL) at reflux for 5 h. The solid product
obtained after extraction and drying was purified by flash
chromatography (silica; hexanes/EtOAc ) 90/10) to afford 10c
(22.0 g, 86%) as a white solid. Mp: 60-61.5 °C. 1H NMR
(CDCl3): δ 11.40 (br, 2 H), 2.41 (t, 4 H, J ) 7.3), 1.62-1.48
(m, 8 H), 1.32-1.18 (m, 4 H), 1.18 (s, 12 H). 13C NMR (CDCl3
) 77.0 ppm): δ 211.11, 184.74, 42.49, 42.14, 40.42, 24.92,
24.62, 23.99. HRMS (LSIMS, gly): calcd for C17H31O5 (MH+)
315.2171, found 315.2183. HPLC: Alltima phenyl column, 250
× 4.6 mm, 5 µm; 60% acetonitrile/40% 0.05 M KH2PO4,
flow rate 1.2 mL/min; RI, tR 5.08 min, 94.5% pure. Anal.
(C17H30O5): C, H.
2,12-Dimethyl-7-oxo-2,12-diphenyltridecanedioic Acid
(10d). According to the procedure given for 10f, 9d (3.93 g,
7.9 mmol) was hydrolyzed with KOH (85%, 4.0 g, 60.6 mmol)
in EtOH (60 mL) and water (10 mL) at reflux for 3 h and at
room temperature overnight. After the usual workup and
drying, 10d (3.0 g, 87%) was obtained as an oil. 1H NMR
(CDCl3): δ 7.40-7.10 (m, 10 H), 2.32 (t, 4 H, J ) 7.2), 2.10-
1.80 (m, 4 H), 1.60-1.45 (m, 4 H), 1.54 (s, 6 H), 1.25-1.10 (m,
4 H). 13C NMR (CDCl3): δ 211.1, 182.5, 142.8, 128.4, 126.9,
126.0, 49.9, 42.3, 38.7, 24.2, 24.0, 22.3. HRMS (LSIMS, nba):
calcd for C27H35O5 (MH+) 439.2484, found 439.2497. HPLC:
Alltima C-18 column, 250 × 4.6 mm, 5 µm; 60% acetonitrile/
40% 0.05 M KH2PO4, flow rate 1.2 mL/min; RI, tR 7.67 min,
93.7% pure.
2,12-Dimethyl-7-oxo-2,12-di-p-tolyltridecanedioic Acid
(10e). According to the procedure given for 10f, 9e (9.0 g, 17.2
mmol) was hydrolyzed with KOH (85%, 4.0 g, 60.6 mmol) in
water (10 mL) and EtOH (30 mL) at reflux for 6 h. After the
usual extractive workup, the crude material was purified by
flash chromatography (silica gel; EtOAc/hexanes ) 1/10, 1/6,
1/2) to give 10e (3.1 g, 39%) as a white solid. Mp: 48-50 °C.
1H NMR (CDCl3): δ 10.8-8.8 (br, 2 H), 7.22 (d, 4 H, J ) 8.1),
7.12 (d, 4 H, J ) 8.1), 2.36 (t, 4 H, J ) 7.5), 2.31 (s, 6 H),
1.98-1.80 (m, 4 H), 1.56-1.44 (m, 4 H), 1.51 (s, 6 H), 1.24-
1.15 (m, 4 H). 13C NMR (CDCl3): δ 211.63, 183.07, 140.40,
137.00, 129.58, 126.43, 50.02, 42.82, 39.10, 24.74, 24.50, 22.82,
21.39. HRMS (LSIMS, gly): calcd for C29H39O5 (MH+) 467.2797,
found 467.2785. HPLC: Alltima C-18 column, 250 × 4.6 mm,
5 µm; 60% acetonitrile/40% 0.05 M KH2PO4, flow rate 1.2 mL/
min; RI, tR 15.17 min, 92.4% pure. Anal. (C29H38O5): C, H.
2,2,16,16-Tetramethyl-9-oxoheptadecanedioic Acid Di-
ethyl Ester (9i). To a solution of 8i (12.0 g, 20.3 mmol) in
CH2Cl2 (200 mL) was added concentrated HCl (47 mL). The
reaction mixture was stirred for 80 min at room temperature
and diluted with water (200 mL). The layers were separated,
and the aqueous layer was extracted with CH2Cl2 (3 × 70 mL).
The combined organic layers were washed with saturated
NaHCO3 solution (3 × 40 mL) and brine (50 mL), dried over
anhydrous MgSO4, and concentrated in vacuo to yield the
crude product (7.52 g). Purification by column chromatography
(silica gel, EtOAc/hexanes ) 1/9) gave 9i (3.5 g, 40.0%) as a
1
colorless oil. H NMR (CDCl3): δ 4.14 (q, J ) 7.1, 4 H), 2.41
(t, J ) 7.0, 4 H), 1.66-1.45 (m, 8 H), 1.35-1.20 (m, 12 H),
1.25 (t, J ) 7.1, 6 H), 1.17 (s, 12 H). 13C NMR (CDCl3): δ
211.24, 177.89, 60.01, 42.69, 42.07, 40.64, 29.86, 29.07, 25.13,
24.73, 23.74, 14.24. HRMS (LSIMS, gly): calcd for C25H47O5
(MH+) 427.3423, found 427.3430.
Representative Procedure for the Saponification of
Keto Diesters: 2,12-Bis(4-isobutylphenyl)-2,12-dimethyl-
7-oxotridecanedioic Acid (10f). A solution of 9f (3.0 g, 4.95
mmol) and KOH (85%, 4.4 g, 66.7 mmol) in EtOH (40 mL)
and water (10 mL) was heated to reflux for 6 h. The EtOH
was removed under reduced pressure and the mixture was
diluted with water (200 mL). The solution was extracted with
Et2O (100 mL) and the aqueous layer was acidified with
concentrated HCl (10 mL) to pH 1. The product was extracted
with Et2O (2 × 100 mL). The ether fractions were combined,
dried over Na2SO4, concentrated, and dried in high vacuo to
yield 10f (2.35 g, 86%) as a light yellow foam. 1H NMR
(CDCl3): δ 10.02 (br, 2 H), 7.24 (d, 4 H, J ) 8.0), 7.09 (d, 4 H,
J ) 8.0), 2.43 (d, 4 H, J ) 7.0), 2.33 (t, 4 H, J ) 7.3), 2.05-
1.88 (m, 2 H), 1.96-1.77 (m, 4 H), 1.55-1.42 (m, 10 H), 1.22-
1.08 (m, 4 H), 0.88 (d, 12 H, J ) 6.6). 13C NMR (CDCl3): δ
211.48, 182.94, 140.43, 140.24, 129.27, 125.94, 49.71, 45.06,
42.58, 42.58, 38.91, 30.25, 24.45, 24.24, 22.58, 22.40. HRMS
2,2,14,14-Tetramethyl-8-oxopentadecanedioic Acid
(10g). According to the procedure given for 10f, 9g (8.54 g,
21.4 mmol) was saponified with KOH (85%, 4.53 g, 68.6 mmol)
in EtOH (13 mL) and water (5 mL) at reflux for 4 h. The solid
product obtained after usual workup was recrystallized from
Et2O/hexanes (50 mL/50 mL), affording 10g (4.16 g, 57%) as
1
colorless needles. Mp: 82-83 °C. H NMR (CDCl3): δ 11.53
(br, 2H), 2.39 (t, 4H, J ) 7.3), 1.60-1.50 (m, 8 H), 1.30-1.20
(m, 8 H), 1.18 (s, 12 H). 13C NMR (CDCl3): δ 211.7, 185.0, 42.8,
42.3, 40.4, 29.7, 25.1, 24.8, 23.8. HRMS (LSIMS, gly): calcd

Keto Diols and Diacids that Alter Lipid Disorders
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 6093
for C19H35O5 (MH+) 343.2484, found 343.2444. HPLC: Alltima
C-8 column, 250 × 4.6 mm, 5 µm; 60% acetonitrile/40% 0.05
M KH2PO4, flow rate 1.0 mL/min; RI, tR 6.50 min, 92.6% pure.
Anal. (C19H34O5): C, H.
mmol) and TosMIC (7.8 g, 40.0 mmol) in anhydrous DMSO
(200 mL) and THF (10 mL) was added NaH (3.8 g, 95.0 mmol,
60% in mineral oil) in five portions at 20-30 °C under cooling
with a water bath. After the addition of NBu4I (3.0 g, 8.1
mmol), the reaction mixture was stirred at room temperature
for 20 h and then hydrolyzed with water (400 mL). The
mixture was extracted with Et2O (3 × 100 mL). The combined
organic layers were washed with saturated aqueous NaCl
solution (100 mL), dried over MgSO4, and concentrated in
vacuo to yield the crude dialkylated intermediate (28.2 g) as
an orange oil, which was used without purification. To a
solution of this crude product (28.0 g) in MeOH (115 mL) was
added dilute H2SO4 (46 g, 12 mL of concd H2SO4 in 24 mL of
water) over a period of 10 min, and the mixture was stirred
for 80 min at room temperature. The solution was diluted with
water (120 mL) and extracted with CH2Cl2 (150 mL, 100 mL,
50 mL). The combined organic layers were washed with
saturated aqueous Na2CO3 solution (2 × 100 mL), saturated
aqueous NaHCO3 solution (100 mL), water (200 mL), and
saturated aqueous NaCl solution (150 mL). The organic extract
was dried over anhydrous MgSO4 and concentrated in vacuo.
The residue (18.4 g) was purified by column chromatography
(silica gel; hexanes, then CH2Cl2, then hexanes/EtOAc ) 4/3)
2,2,16,16-Tetramethyl-9-oxoheptadecanedioic Acid (10i).
To a solution of KOH (85%, 8.4 g, 127.3 mmol) in deionized
water (3.6 mL) and EtOH (11.5 mL) was added 8i (15.0 g, 25.3
mmol) and the mixture was heated to reflux for 7 h. The
reaction mixture was diluted with water (40 mL) and extracted
with MTBE (2 × 30 mL). The aqueous layer was cooled with
an ice bath and the pH was adjusted to 1 by addition of 5 N
H2SO4 (45 mL). The aqueous layer was extracted with MTBE
(3 × 30 mL), and the combined organic layers were washed
with brine (50 mL), dried over anhydrous MgSO4, and con-
centrated in vacuo to give a crude oil (12.5 g). Purification by
chromatography (silica gel, EtOAc/hexanes ) 10% to 100%)
and recrystallization from MTBE/hexanes (4 mL/50 mL)
yielded 10i (5.37 g, 57%) as a white powder. Mp: 74.5-76.0
°C. 1H NMR (CDCl3): δ 12.40-11.20 (br, 2 H), 2.39 (t, J )
7.3, 4 H), 1.62-1.48 (m, 8 H), 1.38-1.22 (m, 12 H), 1.11 (s, 12
H). 13C NMR (CDCl3 ) 77.02 ppm): δ 211.88, 184.93, 42.70,
42.19, 40.63, 29.63, 29.09, 24.96, 24.83, 23.83. HRMS (LSIMS,
gly): calcd for C21H39O5 (MH+) 371.2797, found 371.2804.
HPLC: Inertsil ODS2 column, 250 × 4.6 mm, 5 µm; 60%
acetonitrile/40% 0.05 M KH2PO4, flow rate 1.0 mL/min; RI, tR
10.95 min, 96.9% pure. Anal. (C21H38O5) C, H.
2,2,18,18-Tetramethyl-10-oxononadecanedioic Acid
(10j). To a solution of 9j (11.63 g, 25.6 mmol) in EtOH and
H2O (3:1, 200 mL) was added powdered KOH (85%, 4.31 g,
65.3 mmol). The resulting mixture was refluxed for 19 h and
concentrated in vacuo until all of the EtOH was removed.
Water (200 mL) was added and the resulting mixture was
extracted with Et2O (2 × 200 mL). The aqueous phase was
acidified with aqueous HCl (4 M) to pH ∼1 and extracted with
Et2O (3 × 200 mL). The combined Et2O layers of the latter
extraction were dried over anhydrous Na2SO4 and evaporated
in vacuo. The remaining white solid was recrystallized from
heptane/iPr2O to give 10j (7.56 g, 74%) as white crystals. Mp:
74.3-77.3 °C. 1H NMR (CD3OD): δ 2.43 (t, J ) 7.3, 4 H), 1.57-
1.50 (m, 8 H), 1.33-1.21 (m, 16 H), 1.14 (s, 12 H). 13C NMR
(CD3OD): δ 214.5, 182.1, 43.6, 43.2, 42.0, 31.2, 30.4, 30.38,
26.2, 25.9, 25.0. HRMS: calcd for C23H42O5 (M+): 398.3028,
found 398.3032. Anal. (C23H42O5): C, H.
1
to give 14g (9.97 g, 79%) as a colorless oil. H NMR (CDCl3):
δ 3.30 (s, 4 H), 2.39 (t, 4 H, J ) 7.2), 2.07 (br. s, 2 H), 1.60-
1.55 (m, 4 H), 1.28-1.17 (m, 12 H), 0.85 (s, 12 H). 13C NMR
(CDCl3): δ 212.0, 72.0, 43.0, 38.6, 35.2, 30.3, 24.0, 23.8. HRMS
(LSIMS, gly): calcd for C19H39O3 (MH+) 315.2899, found
315.2886. HPLC: Alltima C-18 column, 250 × 4.6 mm, 5 µm;
70% acetonitrile/30% water, flow rate 1.0 mL/min; RI, tR 8.10
min, 94.7% pure.
1,11-Dihydroxy-2,2,10,10-tetramethylundecan-6-one
(14a). In analogy to the procedure described for the synthesis
of 14g, 7a (40.0 g, 143.3 mmol) was reacted with TosMIC
(13.99 g, 71.7 mmol), NBu4I (5.28 g, 14.3 mmol), and NaH (6.86
g, 171.5 mmol) in anhydrous DMSO (400 mL). After extractive
workup and drying, the crude intermediate (47.9 g) was
dissolved in MeOH (200 mL) and water (40 mL) and treated
with concentrated sulfuric acid (20 mL) at room temperature.
Workup and purification by chromatography (silica gel; hex-
anes/EtOAc ) 90/10, 70/30, and then 50/50) afforded 14a (5.6
1
g, 30%) as an oil. H NMR (CDCl3): δ 3.30 (s, 4 H), 2.68 (br.
s, 2 H), 2.40 (t, 4 H, J ) 7.2), 1.53 (m, 4 H), 1.20 (m, 4 H), 0.86
(s, 12 H). 13C NMR (CDCl3 ) 77.0 ppm): δ 212.25, 70.99, 43.15,
37.69, 34.94, 23.89, 17.91. HRMS (LSIMS, gly): calcd for
C15H29O2 (MH+ - H2O) 241.2168, found 241.2169. HPLC:
Alltima C-8 column, 250 × 4.6 mm, 5 µm; 50% acetonitrile/
50% water, flow rate 1.0 mL/min; RI, tR 6.05 min, 96.7% pure.
2,2,16,16-Tetramethylheptadecane-1,9,17-triol (11i). Un-
der N2 atmosphere, MTBE (80 mL) was added to LiAlH4 (0.67
g, 17.65 mmol) and the suspension was stirred under cooling
with an ice-water bath. A solution of 9i (3.0 g, 7.03 mmol) in
MTBE (20 mL) was added dropwise, followed by additional
MTBE (40 mL). After 2 h at 0 °C, the reaction mixture was
carefully quenched by addition of EtOAc (8 mL) and allowed
to warm to room temperature overnight. The mixture was
cooled with an ice-water bath and carefully hydrolyzed by
addition of crushed ice (15 g) and water (15 mL). The pH was
adjusted to 1 by addition of 2 N H2SO4 (28 mL) and the solution
was stirred at room temperature for 15 min. The layers were
separated, and the aqueous layer was extracted with MTBE
(40 mL). The combined organic layers were washed with
deionized water (50 mL), saturated NaHCO3 solution (40 mL),
and brine (40 mL), dried over anhydrous MgSO4, concentrated
in vacuo, and dried in high vacuo. The crude product (2.65 g)
was purified by recrystallization from hot CH2Cl2 (20 mL). The
crystals were filtered, washed with ice-cold CH2Cl2 (20 mL),
and dried in high vacuo to furnish 11i (1.59 g, 66%) as a white
solid. Mp: 75-77 °C. 1H NMR (CDCl3): δ 3.57 (m, 1 H), 3.30
1,11-Dihydroxy-2,10-dimethyl-2,10-diphenylundecan-
6-one (14b). In analogy to the procedure given for 14g, to a
solution of 7b (25.0 g, 73.3 mmol), NBu4I (3.0 g, 8.2 mmol),
and TosMIC (7.23 g, 37.0 mmol) in anhydrous DMSO (350 mL)
was added NaH (60% dispersion in mineral oil, 3.73 g, 93.3
mmol) while the temperature was controlled with an ice bath.
After the addition of Et2O (100 mL), the mixture was stirred
at room temperature for 24 h, hydrolyzed, extracted, and dried
to afford the dialkylated TosMIC intermediate (28.0 g) as a
brown oil. This crude intermediate was heated to reflux for 3
h in MeOH (500 mL), concentrated HCl (60 mL), and water
(120 mL). Extractive workup and purification by flash chro-
matography (silica gel; hexanes, then EtOAc/hexanes ) 1/20,
1/10, 1/2, 1/1) gave 14b (5.3 g, 38%) as a light yellowish oil.
1H NMR (CDCl3): δ 7.38-7.30 (m, 8 H), 7.26-7.18 (m, 2 H),
3.62 (d, 2 H, J ) 10.5 Hz), 3.48 (d, 2 H, J ) 10.5 Hz), 2.25 (m,
6 H) 1.76-1.64 (m, 2 H), 1.58-1.16 (m, 6 H), 1.32 (s, 6 H). 13
C
(s, 4 H), 1.72 (br, 2 H), 1.50-1.16 (m, 25 H), 0.85 (s, 12 H). 13
C
NMR (CDCl3): δ 211.43, 144.84, 128.32, 126.58, 126.03, 71.79,
NMR (CDCl3): δ 72.09, 38.79, 37.61, 35.21, 30.70, 29.85, 25.78,
24.06, 23.92. HRMS (LSIMS, gly): calcd for C21H45O3 (MH+)
345.3369, found 345.3364. HPLC: Alltima C-18 column, 250
× 4.6 mm, 5 µm; 60% acetonitrile/40% water, flow rate 1.0
mL/min; RI, tR 17.88 min, 95.0% pure.
43.11, 42.89, 37.61, 21.68, 18.12. HRMS (LSIMS, nba): calcd
-
for C25H33O2 (MH+ H2O) 365.2481, found 365.2482. HPLC:
Alltima C-8 column, 250 × 4.6 mm, 5 µm; 50% acetonitrile/
50% water, flow rate 1.0 mL/min; RI, tR 14.00 min, 89.5% pure.
Representative Procedure for the Dialkylation of
TosMIC and Deprotection to Keto Diols: 1,15-Dihy-
droxy-2,2,14,14-tetramethylpentadecan-8-one (14g). Un-
der an argon atmosphere, to a solution of 7g (26.0 g, 84.6
1,13-Dihydroxy-2,2,12,12-tetramethyltridecan-7-one
(14c). Similar to the procedure given for the synthesis of 14g,
7c (13.0 g, 44.3 mmol) was treated with TosMIC (4.33 g, 22.17
mmol), NaH (60% dispersion in mineral oil, 2.13 g, 53.2 mmol),

6094 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24
Mueller et al.
and NBu4I (1.64 g, 4.4 mmol) in anhydrous DMSO (100 mL)
and anhydrous Et2O (50 mL) at room temperature overnight.
Hydrolysis and extraction afforded the dialkylated TosMIC
intermediate (15.5 g) as an oil that was dissolved in MeOH
(180 mL), concentrated HCl (20 mL), and water (40 mL) and
heated to reflux for 2 h. Extractive workup and purification
by flash chromatography (silica gel; hexanes/EtOAc ) 50/50)
furnished 14c (4.3 g, 68%) as a colorless oil. 1H NMR (CDCl3):
δ 3.28 (s, 4 H), 2.80 (br. m, 2 H), 2.42 (t, 4 H, J ) 7.3), 1.54
(m, 4 H), 1.25 (m, 8 H), 0.84 (s, 12 H). 13C NMR (CDCl3): δ
212.06, 71.24, 42.47, 38.11, 34.76, 24.45, 23.72, 23.25. HRMS
(LSIMS, gly): calcd for C17H35O5 (MH+) 287.2556, found
287.2585. HPLC: Alltima C-8 column, 250 × 4.6 mm, 5 µm;
58% acetonitrile/42% water, flow rate 1.0 mL/min; RI, tR 7.02
min, 97.5% pure. Anal. (C17H34O5): C, H.
(CDCl3): δ 211.68, 144.94, 128.56, 126.82, 126.23, 72.68, 43.50,
42.79, 38.42, 30.01, 23.74, 23.68, 21.62. HRMS (LSIMS, nba):
calcd for C29H43O3 (MH+) 439.3212, found 439.3207. HPLC:
Alltima C-8 column, 250 × 4.6 mm, 5 µm; 75% acetonitrile/
25% water, flow rate 1.0 mL/min; RI, tR 5.78 min, 95.3% pure.
2,12-Bis(4-isobutylphenyl)-2,12-dimethyl-7-([1,3]dithi-
anyl)tridecanedioic Acid Diethyl Ester (12f). Compound
9f (5.50 g, 9.06 mmol) was dissolved in CH2Cl2 (freshly distilled
from CaH2, 60 mL) with BF3-Et2O (0.45 mL, 0.50 g, 3.55
mmol) and 1,3-propanedithiol (1.0 mL, 1.08 g, 9.99 mmol). The
solution was stirred for 3 h at room temperature under a
nitrogen atmosphere. An additional volume of CH2Cl2 (100 mL)
was added and the solution was extracted with 5% NaOH
solution (2 × 50 mL) and water (100 mL). After drying with
anhydrous Na2SO4, filtration, and concentration, the product
was purified by flash chromatography (silica gel; EtOAc/
hexanes ) 10/90), affording 12f (6.16 g, 98%) as a colorless
1,13-Dihydroxy-2,12-dimethyl-2,12-diphenyltridecan-
7-one (14d). According to the procedure described for the
synthesis of 14g, 7d (10.0 g, 28.2 mmol) was reacted with
NBu4I (1.06 g, 2.9 mmol), TosMIC (2.34 g, 12.0 mmol), and
NaH (60% dispersion in mineral oil, 1.42 g, 35.5 mmol) in
anhydrous DMSO (100 mL) and anhydrous Et2O (50 mL) at
room temperature for 24 h. After aqueous workup and extrac-
tion, the dialkylated TosMIC intermediate (11.0 g) was heated
to reflux in a mixture of MeOH (180 mL), concentrated HCl
(20 mL), and water (40 mL) for 3 h. After extraction, the crude
oil was purified by flash chromatography (silica gel; hexanes/
EtOAc ) 80/20, then 60/40), affording 14d (3.0 g, 61%) as a
1
oil. H NMR (CDCl3): δ 7.20 (d, 4 H, J ) 8.0), 7.07 (d, 4 H, J
) 8.0), 4.10 (q, 4 H, J ) 7.0), 2.76 (t, 4 H, J ) 5.3), 2.43 (d, 4
H, J ) 7.0), 2.09-1.95 (m, 2 H), 1.94-1.78 (m, 10 H), 1.51 (s,
6 H), 1.46-1.36 (m, 4 H), 1.25-1.12 (m, 4 H), 1.18 (t, 6 H, J )
7.0), 0.88 (d, 12 H, J ) 6.5). 13C NMR (CDCl3): δ 176.42,
141.43, 140.00, 129.14, 125.74, 60.74, 53.30, 49.97, 45.05,
39.22, 38.29, 30.26, 26.10, 25.64, 25.17, 24.76, 22.99, 22.56,
14.26. HRMS (EI): calcd for C42H64O4S2 (M+) 696.4246, found
696.4234. HPLC: Alltima C-18 column, 250 × 4.6 mm, 5 µm;
95% acetonitrile/5% water, flow rate 1.0 mL/min; UV, tR 7.33
min, 96.2% pure.
1
colorless oil. H NMR (CDCl3): δ 7.37-7.28 (m, 8 H), 7.24-
7.17 (m, 2 H), 3.69 (dd, 2 H, J ) 10.9, 5.2), 3.52 (dd, 2 H, J )
10.9, 7.5), 2.26 (t, 4 H, J ) 7.3), 1.75 (m, 2 H), 1.61 (s, 2 H),
1.57-1.40 (m, 6 H), 1.33 (s, 6 H), 1.29-1.06 (m, 2 H), 1.04-
0.80 (m, 2 H). 13C NMR (CDCl3): δ 211.21, 144.72, 128.23,
126.50, 125.92, 72.17, 43.14, 42.38, 38.06, 24.27, 23.34, 21.42.
HRMS (LSIMS): calcd for C27H39O3 (MH+) 411.2899, found
411.2899. HPLC: Alltima phenyl column, 250 × 4.6 mm, 5
µm; 70% acetonitrile/30% water, flow rate 1.0 mL/min; UV, tR
8.10 min, 92.7% pure.
2,12-Bis(4-isobutylphenyl)-2,12-dimethyl-7-([1,3]dithi-
anyl)tridecane-1,13-diol (13f). A solution of 12f (5.81 g, 8.33
mmol) in freshly distilled THF (50 mL) was added dropwise
to a suspension of LiAlH4 (1.0 g, 26.4 mmol) in THF (50 mL)
at -78 °C under N2 atmosphere. The solution was warmed to
room temperature over 4 h, cooled back to -78 °C, and
quenched with EtOAc (5.0 mL). After warming to room
temperature, water (100 mL) was added and the product was
extracted with Et2O (2 × 100 mL). The ether extracts were
combined, dried with sodium sulfate, filtered, and concen-
trated. After drying under high vacuum for 4 h, 13f (4.80 g,
94%) was obtained as a colorless oil. 1H NMR (CDCl3): δ 7.20
(d, 4 H, J ) 8.0), 7.09 (d, 4 H, J ) 8.0), 3.64 (d, 2 H, J ) 10.7),
3.48 (d, 2 H, J ) 10.7), 2.71 (t, 4 H, J ) 5.1), 2.50-2.35 (m br,
2 H), 2.43 (d, 4 H, J ) 7.0), 1.90-1.80 (m, 4 H), 1.80-1.68 (m,
6 H), 1.58-1.42 (m, 2 H), 1.38-1.25 (m, 4 H), 1.30 (s, 6 H),
1.26-1.10 (m, 2H), 1.10-0.95 (m, 2 H), 0.89 (d, 12 H, J ) 6.6).
13C NMR (CDCl3): δ 141.94, 139.39, 129.20, 126.44, 72.48,
53.30, 44.97, 43.09, 38.45, 38.18, 30.21, 26.01, 25.64, 24.84,
24.09, 22.55, 21.64. HRMS (LSIMS, nba): calcd for C38H61O2S2
(MH+) 613.4113, found 613.4075. HPLC: Alltima C-18 column,
250 × 4.6 mm, 5 µm; 90% acetonitrile/10% water, flow rate
1.0 mL/min; UV, tR 8.37 min, 97.6% pure.
1,13-Dihydroxy-2,12-dimethyl-2,12-di-p-tolyltridecan-
7-one (14e). According to the procedure for the synthesis of
14g, 7e (21.5 g, 75.3 mmol) was reacted with NBu4I (2.36 g,
6.4 mmol), TosMIC (5.68 g, 29.1 mmol), and NaH (60%
dispersion in mineral oil, 2.94 g, 73.5 mmol) in anhydrous
DMSO (300 mL) and anhydrous Et2O (100 mL) at room
temperature for 24 h. The crude intermediate (18.4 g) obtained
after aqueous workup and extraction was then heated to reflux
in MeOH (300 mL), concentrated HCl (36 mL), and water (70
mL) for 3 h. Extractive workup and purification by flash
chromatography (silica gel; hexanes/EtOAc ) 20/1, 15/1, 10/
1
1, 5/1, and 1/1) gave 14e (2.72 g, 21%) as a colorless oil. H
NMR (CDCl3): δ 7.18 (d, 4 H, J ) 8.1), 7.12 (d, 4 H, J ) 8.1),
3.61 (d, 2H, J ) 11.0), 3.48 (d, 2 H, J ) 11.0 Hz), 2.31 (s, 6 H),
2.26 (t, 4 H, J ) 7.8), 1.78-1.40 (m, 10 H), 1.29 (s, 6 H), 1.24-
0.82 (m, 4 H). 13C NMR (CDCl3): δ 211.51, 141.75, 135.64,
129.23, 126.64, 72.54, 43.06, 42.65, 38.28, 24.53, 23.59, 21.66,
20.98. HRMS (LSIMS, gly): calcd for C29H43O3 (MH+) 439.3212,
found 439.3222. HPLC: Alltima C-8 column, 250 × 4.6 mm, 5
µm; 60% acetonitrile/40% water, flow rate 1.0 mL/min; RI, tR
15.32 min, 95.4% pure.
1,13-Dihydroxy-2,12-bis(4-isobutylphenyl)-2,12-dime-
thyltridecan-7-one (14f). To a mixture of 13f (4.50 g, 7.34
mmol) in dimethoxyethane (50 mL) and concentrated HCl (10
mL) was added dropwise DMSO (5.0 mL) over 5 min. The
solution was stirred for 30 min at room temperature and then
slowly poured into saturated aqueous NaHCO3 solution (100
mL) and extracted with Et2O (2 × 100 mL). The ether fractions
were combined, dried with anhydrous Na2SO4, filtered, and
concentrated. The product was purified by flash chromatog-
raphy (silica gel; EtOAc/hexanes ) 30/70), affording 14f (3.2
1,15-Dihydroxy-2,14-dimethyl-2,14-diphenylpentade-
can-8-one (14h). In analogy to the procedure of 14g, to a
solution of 7h (18.0 g, 63.1 mmol), NBu4I (2.0 g, 5.4 mmol),
and TosMIC (4.8 g, 24.6 mmol) in anhydrous DMSO (250 mL)
and Et2O (80 mL) was added NaH (60% dispersion in mineral
oil, 2.5 g, 62.5 mmol) while being cooled with an ice bath under
N2 atmosphere. After 24 h at room temperature, the mixture
was hydrolyzed and worked up by extraction to give the crude
intermediate (18.0 g) as a brown oil. This crude material was
heated to reflux in MeOH (300 mL), concentrated HCl (36 mL),
and water (70 mL) for 3 h. Extractive workup and purification
by flash chromatography (silica gel; hexanes/EtOAc/hexanes
) 10/1, 5/1, 2/1) yielded 14h (6.1 g, 56%) as a yellowish oil. 1H
NMR (CDCl3): δ 7.32-7.19 (m, 10 H), 3.68 (d, 2 H, J ) 10.8),
3.50 (d, 2 H, J ) 10.8), 2.26 (t, 4 H, J ) 7.50 H), 1.88-1.42
(m, 10 H), 1.25 (s, 6 H), 1.22-0.85 (m, 8 H). 13C NMR
1
g, 83%) as a colorless oil. H NMR (CDCl3): δ 7.19 (d, 4 H, J
) 8.0), 7.09 (d, 4 H, J ) 8.0), 3.63 (d, 2 H, J ) 11.0), 3.49 (d,
2 H, J ) 11.0), 2.43 (d, 4 H, J ) 7.0), 2.26 (t, 4 H, J ) 7.3),
1.88-1.66 (m, 4 H), 1.52-1.41 (m, 8 H), 1.29 (s, 6 H), 1.15-
1.10 (m, 2 H), 0.98-0.88 (m, 2 H), 0.89 (d, 12 H, J ) 6.6). 13
C
NMR (CDCl3): δ 211.47, 141.97, 139.51, 129.28, 126.45, 72.53,
45.02, 43.11, 42.69, 38.36, 30.26, 24.57, 23.63, 22.58, 21.72.
HRMS (LSIMS, nba): calcd for C35H55O3 (MH+) 523.4151,
found 523.4144. HPLC: Alltima C-8 column, 250 × 4.6 mm, 5
µm; 90% acetonitrile/10% water, flow rate 1.0 mL/min; UV, tR
5.78 min, 96.3% pure.
1,17-Dihydroxy-2,2,16,16-tetramethylheptadecan-9-
one (14i). To a solution of 11i (2.42 g, 7.02 mmol) in acetic

Keto Diols and Diacids that Alter Lipid Disorders
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 6095
acid (10 mL) was added dropwise NaOCl solution (1.76 mL,
ca. 3.5 mmol) at 18 °C. Additional NaOCl solution (3 × 1.0
mL, ca. 6.0 mmol) was added after 20, 40, and 60 min under
monitoring by TLC. The reaction was quenched with 2-pro-
panol (4 mL) and diluted with deionized water (100 mL). The
reaction mixture was extracted with EtOAc (3 × 60 mL). The
combined organic layers were washed with saturated NaHCO3
solution (3 × 60 mL), water (60 mL), and brine (60 mL); dried
over anhydrous MgSO4; and concentrated in vacuo. Purifica-
tion of the crude product (2.38 g) by column chromatography
(silica gel, EtOAc/hexanes ) 1/1) gave 14i (0.83 g, 35%) as a
C-18 column, 250 × 4.6 mm, 5 µm; 60% acetonitrile/40% water,
flow rate 1.0 mL/min; RI, tR 5.50 min, 91.4% pure.
1,13-Dihydroxy-2,2,12-trimethyl-12-phenyltridecan-7-
one (18). To a solution of 15 (5.3 g, 13.0 mmol) in anhydrous
DMSO (60 mL) was added NaH (0.62 g, 15.5 mmol, 60% in
mineral oil), 7d (4.6 g, 12.9 mmol), and NBu4I (0.48 g, 1.3
mmol). The reaction mixture was stirred at room temperature
overnight and hydrolyzed with water (100 mL). The product
was extracted with CH2Cl2 (3 × 100 mL), and the combined
organic phases were washed with water (100 mL) and half-
saturated aqueous NaCl solution (100 mL), dried over Na2-
SO4, and concentrated in vacuo to get the crude intermediate
(9.0 g). This crude material was heated to reflux in concen-
trated HCl (13.4 mL) and MeOH (60 mL) overnight. The
reaction mixture was poured into water (200 mL) and the
product was extracted with Et2O (3 × 60 mL). The combined
organic layers were washed with water (3 × 20 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue
was purified by column chromatography (silica gel; hexanes/
1
colorless wax. H NMR (CDCl3): δ 3.33 (s, 4 H), 2.41 (t, J )
7.4, 4 H), 1.85 (br, 2 H), 1.62-1.45 (m, 4 H), 1.35-1.18 (m, 16
H), 0.87 (s, 12 H). 13C NMR (CDCl3): δ 212.09, 72.10, 42.99,
38.75, 35.20, 30.48, 29.42, 24.05, 23.99, 23.82. HRMS (LSIMS,
gly): calcd for C21H43O3 (MH+) 343.3212, found 343.3208.
HPLC: Alltima C-8 column, 250 × 4.6 mm, 5 µm; 90%
acetonitrile/10% water, flow rate 1.0 mL/min; RI, tR 26.91 min,
93.5% pure.
1
2-[7-Isocyano-2,2-dimethyl-7-(tolyl-4-sulfonyl)heptyloxy]-
tetrahydropyran (15). Method A. To a solution of TosMIC
(9.75 g, 49.9 mmol) and NBu4I (1.69 g, 4.6 mmol) in anhydrous
DMSO (240 mL) was added NaH (2.2 g, 55.0 mmol, 60% in
mineral oil), while being cooled with an ice bath. 7c (14.65 g,
50 mmol) was added dropwise over 1 h, and the reaction
mixture was stirred at room temperature overnight. The
mixture was quenched with water (100 mL) and extracted with
CH2Cl2 (3 × 100 mL). The combined organic layers were
washed with water (100 mL) and half-saturated aqueous NaCl
solution (100 mL), dried over anhydrous Na2SO4, and concen-
trated in vacuo to afford the crude product (30 g), which was
purified by column chromatography (silica gel; hexanes/EtOAc
EtOAc ) 2/1), affording 18 (3.2 g, 71%) as a colorless oil. H
NMR (CDCl3): δ 7.38-7.16 (m, 5 H), 3.67 (d, 1 H, J ) 10.9),
3.52 (d, 1 H, J ) 10.9), 3.26 (s, 2 H), 2.40-2.20 (m, 4 H), 1.85-
1.60 (m, 3 H), 1.60-1.40 (m, 5 H), 1.33 (s, 3 H), 1.28-1.10 (m,
5 H), 1.10-0.90 (m, 1 H), 0.83 (s, 6 H). 13C NMR (CDCl3
)
77.0 ppm): δ 211.5, 144.6, 128.3, 126.6, 126.0, 72.3, 71.6, 43.3,
42.5, 38.2, 34.9, 24.6, 24.4, 23.8, 23.4, 21.5. HRMS (LSIMS,
gly): calcd for C22H37O3 (MH+) 349.2743, found 349.2731.
HPLC: Alltima C-8 column, 250 × 4.6 mm, 5 µm; 50%
acetonitrile/50% water, flow rate 1.0 mL/min; RI, tR 12.87 min,
84.9% pure.
1,14-Dihydroxy-2,2,13,13-tetramethyltetradecan-7-
one (19). According to the procedure described for the
synthesis of 17, 15 (6.98 g, 17.1 mmol) was reacted with NaH
(0.82 g, 20.5 mmol, 60% in mineral oil), 7g (5.8 g, 18.9 mmol),
and NBu4I (0.63 g, 1.7 mmol) in anhydrous DMSO (100 mL)
for 24 h at room temperature. The crude intermediate (10.9
g) obtained after aqueous workup was heated to reflux in
concentrated HCl (18 mL) and MeOH (100 mL) overnight.
After extraction and column chromatography (silica gel; hex-
anes/EtOAc ) 80/20), 19 (2.3 g, 48%) was obtained as a
1
) 90/10) to obtain 15 (5.4 g, 27%) as a colorless oil. H NMR
(CDCl3): δ 7.87 (d, 2 H, J ) 8.2), 7.43 (d, 2 H, J ) 8.2), 4.56-
4.40 (m, 2 H), 3.83 (t, 1 H, J ) 8.1), 3.58-3.38 (m, 1 H), 3.46
(d, 1 H, J ) 9.2), 2.97 (d, 1 H, J ) 9.2), 2.49 (s, 3 H), 2.30-
1.20 (m, 16 H), 0.88 (s, 6 H). 13C NMR (CDCl3): δ 164.7, 146.5,
131.1, 130.1, 99.1, 76.2, 62.0, 38.7, 34.1, 30.6, 28.3, 26.2, 25.5,
24.5, 23.0, 21.8, 19.5. HRMS (LSIMS, nba): calcd for C22H34-
NSO4 (MH+) 408.2209, found 408.2205.
1
Method B. To a solution of TosMIC (3.9 g, 20.0 mmol) in
anhydrous DMF (100 mL) was added K2CO3 (5.52 g, 39.9
mmol), 7c (11.72 g, 40.0 mmol), and NBu4I (0.74 g, 1.95 mmol).
The reaction mixture was stirred at room temperature for 20
h and then heated to 50 °C for 4 h. The reaction mixture was
poured into ice water (300 mL) and extracted with CH2Cl2 (3
× 60 mL). The combined organic layers were washed with
water (2 × 100 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo to afford the crude product, which was
purified by column chromatography (silica gel; hexanes/EtOAc
) 90/10) to give 15 (5.6 g, 69%) as a colorless oil.
colorless oil. H NMR (CDCl3): δ 3.30 (s, 4 H), 2.48-2.34 (m,
4 H), 1.85 (br, 2 H), 1.66-1.46 (m, 4 H), 1.24-1.14 (m, 10 H),
0.85 (s, 12 H). 13C NMR (CDCl3): δ 211.8, 71.8, 71.6, 42.7, 42.6,
38.4, 38.2, 34.9, 30.1, 24.6, 23.8, 23.8, 23.7, 23.6, 23.4. HRMS
(LSIMS, gly): calcd for C18H37O3 (MH+) 301.2743, found
301.2745. HPLC: Alltima C-8 column, 250 × 4.6 mm, 5 µm;
50% acetonitrile/50% water, flow rate 1.0 mL/min; RI, tR 15.32
min, 97.4% pure.
7-Isocyano-2,2-dimethyl-7-(tolyl-4-sulfonyl)heptano-
ic Acid Ethyl Ester (20). Under N2 atmosphere, to a stirred
solution of NBu4I (4.23 g, 11.5 mmol) and TosMIC (27.56 g,
141.2 mmol) in anhydrous DMSO (500 mL) was added NaH
(60% w/w in mineral oil, 5.80 g, 145.0 mmol), while the internal
temperature was kept between 10 and 15 °C. After the
dropwise addition of 5c (36.60 g, 145.7 mmol), the mixture was
stirred at room temperature for 20 h and then cooled with an
ice bath and carefully hydrolyzed with water (600 mL). The
solution was extracted with CH2Cl2 (4 × 150 mL). The
combined organic layers were washed with water (200 mL)
and half-saturated aqueous NaCl solution (200 mL), dried over
anhydrous MgSO4, and concentrated in vacuo to obtain the
crude product mixture (40.9 g) as an orange oil. A portion of
this crude product (13.0 g) was purified by column chroma-
tography (silica gel; hexanes/EtOAc ) 10/1, then 9/1), affording
20 (1.92 g, 12%) as a pale yellow oil, 8c (0.70 g, 3%) as a
colorless oil, and a mixture of both (2.50 g, ratio 9/1). 1H NMR
(CDCl3): δ 7.86 (d, 2 H, J ) 8.1), 7.43 (d, 2 H, J ) 8.1), 4.48
(dd, 1 H, J ) 7.2, 3.6), 4.11 (q, 2 H, J ) 7.2), 2.49 (s, 3 H),
2.21-2.16 (m, 1 H), 1.90-1.78 (m, 1 H), 1.56-1.50 (m, 4 H),
1.35-1.20 (m, 2 H), 1.25 (t, 3 H, J ) 7.2), 1.16 (s, 6 H). 13C
NMR (CDCl3): δ 177.8, 165.0, 146.7, 131.3, 130.3, 130.2, 72.9,
60.5, 42.2, 40.2, 28.3, 25.8, 25.3, 25.2, 24.2, 21.9, 14.4. HRMS
(LSIMS, nba): calcd for C19H28NO4S (MH+) 366.1739, found
366.1746.
1,12-Dihydroxy-2,2,11,11-tetramethyldodecan-6-one
(17). To a solution of 15 (6.5 g, 15.9 mmol) in anhydrous DMSO
(70 mL) was added NaH (0.77 g, 19.3 mmol, 60% in mineral
oil), 7a (4.91 g, 17.6 mmol), and NBu4I (0.59 g, 1.6 mmol). The
reaction mixture was stirred at room temperature for 24 h and
hydrolyzed with water (100 mL). The product was extracted
with CH2Cl2 (3 × 100 mL). The combined organic layers were
washed with water (3 × 100 mL), dried over anhydrous Na2-
SO4, and concentrated in vacuo to give the crude intermediate
(14.0 g). This crude material was heated to reflux in concen-
trated HCl (17 mL) and MeOH (100 mL) overnight. The
reaction mixture was poured into ice water (200 mL) and
extracted with Et2O (3 × 100 mL). The combined organic layers
were washed with 5% NaOH solution (60 mL) and water (2 ×
100 mL), dried over Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography (silica gel;
hexanes/EtOAc ) 80/20), affording 17 (2.5 g, 58%) as a
1
colorless oil. H NMR (CDCl3): δ 3.31 (s, 2 H), 3.28 (s, 2 H),
2.42-2.37 (m, 4 H), 2.4-1.8 (m br, 2 H), 1.56-1.48 (m, 4 H),
1.22-1.14 (m, 6 H), 0.85 (s, 6 H), 0.84 (s, 6 H). 13C NMR
(CDCl3): δ 212.0, 71.5, 71.1, 43.0, 42.7, 38.2, 37.7, 35.0, 34.9,
30.8, 24.6, 23.9, 23.8, 23.4, 17.8. HRMS (LSIMS, gly): calcd
for C16H33O3 (MH+) 273.2430, found 273.2422. HPLC: Alltima

6096 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24
Mueller et al.
Ethyl 12-Hydroxy-2,2,11,11-tetramethyl-7-oxodode-
canoate (21). Under N2 atmosphere, to a solution of 20 (1.72
g, 4.68 mmol), NBu4I (0.17 g, 0.46 mmol), and 7a (1.45 g, 5.19
mmol) in anhydrous DMSO (20 mL) was added NaH (60% w/w
in mineral oil, 0.19 g, 4.75 mmol), while the internal temper-
ature was kept between 10 and 15 °C. The reaction mixture
was stirred for 20 h at room temperature and then carefully
hydrolyzed with ice-water (100 mL). The mixture was ex-
tracted with CH2Cl2 (3 × 15 mL). The combined organic layers
were washed with water (40 mL) and saturated aqueous NaCl
solution (2 × 20 mL), dried over anhydrous MgSO4, and
concentrated in vacuo to obtain the crude intermediate (3.50
g) as brown oil. A solution of this intermediate in 48% H2SO4
(6 mL) and MeOH (12 mL) was stirred for 100 min at room
temperature. The mixture was diluted with water (50 mL) and
extracted with CH2Cl2 (3 × 15 mL). The combined organic
layers were washed with water (100 mL) and saturated
aqueous NaCl solution (100 mL), dried over anhydrous MgSO4,
and concentrated in vacuo to obtain the crude product (2.70
g) as yellow oil. A portion of the crude product (2.50 g) was
subjected to column chromatography (silica gel; hexanes/
EtOAc ) 80/20, then 75/25) to give 21 (0.82 g, 60%) as a pale
yellow oil. 1H NMR (CDCl3): δ 4.14-4.03 (m, 2 H), 3.31 (br s,
2 H), 2.42 (br, 1 H), 2.39 (m, 4 H), 1.54-1.48 (m, 6 H), 1.24-
1.18 (m, 7 H), 1.14 (s, 6 H), 0.86 (s, 6 H). 13C NMR (CDCl3): δ
211.7, 178.0, 71.2, 60.3, 43.2, 42.7, 42.1, 40.4, 37.9, 35.1, 25.2,
24.6, 24.2, 24.1, 18.0, 14.3. HRMS (LSIMS, gly): calcd for
C18H35O4 (MH+) 315.2535, found 315.2541.
Ethyl 14-Hydroxy-2,2,13,13-tetramethyl-7-oxotetrade-
canoate (22). According to the procedure for the synthesis of
20, 5c (45.6 g, 182 mmol) was reacted with TosMIC (35.2 g,
180 mmol), NBu4I (4.3 g, 11.6 mmol), and NaH (60% w/w in
mineral oil, 7.3 g, 183 mmol) in anhydrous DMSO (500 mL).
To this solution were added NBu4I (4.3 g, 11.6 mmol) and 7g
(43.8 g, 143 mmol) in anhydrous DMSO (20 mL) and then NaH
(7.4 g, 185 mmol, 60% w/w in mineral oil) at 10 °C. The
reaction mixture was stirred at room temperature for 20 h,
cooled with an ice bath, and carefully hydrolyzed with ice-
water (1000 mL). The product was extracted with CH2Cl2 (5
× 100 mL). The combined organic layers were dried over
anhydrous MgSO4 and concentrated in vacuo to obtain the
crude intermediate (115 g) as a red oil. This intermediate was
dissolved in 48% H2SO4 (147 mL) and MeOH (480 mL) and
the mixture was stirred for 100 min at room temperature.
After dilution with water (1500 mL), the product was extracted
with CH2Cl2 (2 × 150 mL, 100 mL, 50 mL). The combined
organic layers were washed with saturated aqueous Na2CO3
solution (150 mL) and saturated aqueous NaCl solution (150
mL), dried over MgSO4, filtered through a short column
(aluminum oxide; EtOAc), and concentrated in vacuo to obtain
the crude product (89 g) as a yellow oil. The crude product
was subjected to column chromatography (silica gel; hexanes/
EtOAc ) 6:1, then 3:1) to give 22 (17.6 g, 36%) as a pale yellow
oil. 1H NMR (CDCl3): δ 4.10 (q, 2 H, J ) 6.9), 3.30 (br. s, 2 H),
2.39 (t, 4 H, J ) 6.9), 1.98 (br, 1 H), 1.56-1.48 (m, 6 H), 1.27-
1.18 (m, 11 H), 1.14 (s, 6 H), 0.85 (s, 6 H). 13C NMR (CDCl3):
δ 211.5, 178.0, 71.9, 60.3, 42.9, 42.7, 42.2, 40.5, 38.6, 35.1, 30.3,
25.2, 24.7, 24.2, 24.0, 23.8, 14.4. HRMS (LSIMS, gly): calcd
for C20H39O4 (MH+) 343.2848, found 343.2846.
25.3, 25.0, 24.7, 24.3, 19.3, 14.4. HRMS (LSIMS, gly): calcd
for C18H33O5 (MH+) 329.2328, found 329.2330.
2,2,13,13-Tetramethyl-7-oxotetradecanedioicAcid1-Eth-
yl Ester (24). A mixture of 22 (10.53 g, 30.7 mmol) and PDC
(32.5 g, 86.4 mmol) in DMF (120 mL) was stirred at 30 °C for
40 h. The mixture was poured into 48% H2SO4 (50 mL) and
water (700 mL). The product was extracted with EtOAc (3 ×
200 mL, 2 × 100 mL). The combined organic layers were
washed with saturated aqueous NaCl solution (4 × 100 mL),
dried over anhydrous MgSO4, and concentrated in vacuo to
give the crude product (10.3 g) as a pale yellow oil. This crude
material was purified by column chromatography (silica gel;
hexanes/EtOAc ) 75/25) to afford 24 (7.40 g, 68%) as a
1
yellowish oil. H NMR (CDCl3): δ 4.10 (q, 2 H, J ) 7.5), 2.39
(m, 4 H), 1.56-1.49 (m, 8 H), 1.26-1.21 (m, 10 H), 1.18 (s, 6
H), 1.15 (s, 6 H). 13C NMR (CDCl3): δ 211.4, 184.2, 178.0, 60.3,
42.8, 42.7, 42.1, 40.5, 40.4, 29.7, 25.2, 24.8, 24.7, 24.3, 23.7,
14.3. HRMS (LSIMS, gly): calcd for C20H37O5 (MH+) 357.2641,
found 357.2641.
2,2,11,11-Tetramethyl-6-oxododecanedioic Acid (25).
According to the procedure given for 9f, 23 (2.50 g, 7.6 mmol)
was saponified with KOH (1.80 g, 27.3 mmol) in water (3 mL)
and EtOH (8 mL) at reflux for 4 h. After the usual workup,
the crude product (2.17 g) was recrystallized from Et2O/
hexanes (15 mL/25 mL) to give 25 (1.36 g, 60%) as white
needles. Mp: 72-73 °C. 1H NMR (CDCl3): δ 12.0-11.2 (br, 2
H), 2.41 (m, 4 H), 1.60-1.52 (m, 8 H), 1.29-1.24 (m, 2 H), 1.20
(s, 6 H), 1.18 (s, 6 H). 13C NMR (CDCl3): δ 211.2, 185.1, 184.9,
43.9, 42.7, 42.2, 40.3, 39.8, 25.1, 25.0, 24.7, 24.2, 19.3. HRMS
(LSIMS, gly): calcd for C16H29O5 (MH+) 301.2015, found
301.2023. HPLC: Alltima C-8 column, 250 × 4.6 mm, 5 µm;
60% acetonitrile/40% water, flow rate 1.0 mL/min; RI, tR 4.60
min, 95.8% pure. Anal. (C16H28O5): C, H.
2,2,13,13-Tetramethyl-7-oxotetradecanedioic Acid (26).
According to the procedure for the synthesis of 9f, a solution
of 24 (7.4 g, 20.8 mmol) and KOH (85%, 4.6 g, 69.6 mmol) in
water (5 mL) and EtOH (15 mL) was heated to reflux for 4 h.
The crude product (6.8 g) obtained after the usual workup was
purified by repeated column chromatography (silica gel; first
hexanes/EtOAc ) 2/1 and then 1/1 and second hexanes/EtOAc
) 1/) and crystallization (Et2O/hexanes, 20 mL/10 mL), af-
fording 26 (2.95 g, 43%) as colorless needles. Mp: 61-62 °C.
1H NMR (CDCl3): δ 11.91 (br, 2 H), 2.41 (t, 4 H, J ) 6.9), 2.39
(t, 4 H, J ) 6.9), 1.58-1.52 (m, 8 H), 1.30-1.22 (m, 6 H), 1.18
(s, 12 H). 13C NMR (CDCl3): δ 211.8, 184.5, 185.4, 43.0, 42.9,
42.5, 40.7, 40.6, 29.9, 25.4, 25.1, 25.0, 24.6, 23.9. HRMS
(LSIMS, gly): calcd for C18H33O5 (MH+) 329.2328, found
329.2324. HPLC: Alltima C-8 column, 250 × 4.6 mm, 5 µm;
60% acetonitrile/40% water, flow rate 1.0 mL/min; RI, tR 5.72
min, 93.5% pure. Anal. (C18H32O5) C, H.
3-{3-[3-Ethoxycarbonyl-2-methylpropyl)benzoyl]phe-
nyl}-2,2-dimethylpropionic Acid Ethyl Ester (28). Under
inert gas atmosphere and at -78 °C, to a stirred solution of
ethyl isobutyrate (9.78 g, 84.2 mmol) in anhydrous THF (30
mL) was added dropwise a solution of LDA (2.0 M, 42.2 mL,
84.4 mmol). After 1 h, 2746 (10.34 g, 28.1 mmol) was added,
followed by addition of DMPU (2.7 g, 21.1 mmol). The mixture
was stirred for 30 min and then allowed to warm to room
temperature over 30 min. The THF was distilled off under
reduced pressure. The residue was dissolved in saturated
aqueous NH4Cl solution (280 mL) and extracted with EtOAc
(3 × 100 mL). The combined organic layers were washed with
saturated aqueous NaCl solution (200 mL), 5% HCl (100 mL)
and saturated aqueous NaHCO3 solution (50 mL). Drying over
anhydrous Na2SO4 and concentration in vacuo afforded 28
(11.0 g, 89%) as an oil. 1H NMR (CDCl3): δ 7.8-7.2 (m, 8 H),
3.98 (q, 4 H, J ) 6.9), 2.83 (s, 4 H), 1.2-0.8 (m, 18 H). 13C
NMR (CDCl3 ) 77.0 ppm): δ 196.5, 176.8, 138.1, 137.2, 134.0,
131.4, 128.1, 127.7, 60.3, 45.7, 43.3, 24.8, 13.9.
2,2,11,11-Tetramethyl-7-oxododecanedioic Acid 1-Eth-
yl Ester (23). A mixture of 21 (3.26 g, 10.4 mmol) and PDC
(14.0 g, 37.2 mmol) in DMF (45 mL) was stirred at room
temperature for 46 h. The solution was diluted with 48% H2-
SO4 (30 mL) and water (300 mL) and extracted with EtOAc
(5 × 100 mL). The combined organic layers were washed with
saturated aqueous NaCl solution (5 × 100 mL), dried over
anhydrous MgSO4, and concentrated in vacuo to give the crude
product (3.19 g) as greenish oil. The crude product was
subjected to column chromatography (silica gel; hexanes/
EtOAc ) 3:1, 2:1), affording 23 (2.69 g, 79%) as a pale yellow
oil. 1H NMR (CDCl3): δ 11.30 (br, 1 H), 4.10 (q, 2 H, J ) 7.2),
2.39 (t, 4 H, J ) 7.2), 1.56-1.48 (m, 8 H), 1.25-1.15 (m, 2 H),
1.24 (t, 3 H, J ) 7.2), 1.20 (s, 6 H), 1.15 (s, 6 H). 13C NMR
(CDCl3): δ 210.9, 184.4, 178.1, 60.4, 43.1, 42.7, 42.2, 40.5, 39.8,
3-(3-{2-[3-(2-Ethoxycarbonyl-2-methylpropyl}phenyl]-
[1,3]dithian-2-yl}phenyl)-2,2-dimethylpropionic Acid Eth-
yl Ester (29). To a solution of 28 (6.2 g, 14.1 mmol) and 1,3-
propanedithiol (1.9 g, 17.6 mmol) in CH2Cl2 (100 mL) was
added BF3-Et2O (0.52 mL, 0.58 g, 4.1 mmol). The solution

Keto Diols and Diacids that Alter Lipid Disorders
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 6097
was stirred at room temperature overnight. After the addition
of 5% NaOH solution (17.5 mL), the organic layer was
separated, washed with water (50 mL), dried over anhydrous
Na2SO4, and evaporated to afford 29 (6.5 g, 87%) as an oil. 1H
NMR (CDCl3): δ 7.58-6.96 (m, 8 H), 4.10 (q, 4 H, J ) 7.2),
2.85 (s, 4 H), 2.76 (t, 4 H, J ) 5.6), 1.98 (m, 2 H), 1.22 (t, 6 H,
J ) 7.2) 1.13 (s, 12 H). 13C NMR (CDCl3 ) 77.0 ppm): δ 177.17,
142.18, 138.07, 131.12, 129.30, 127.84, 127.33, 60.35, 46.16,
43.48, 29.38, 24.90, 14.13.
3-(3-{2-[3-(3-Hydroxy-2,2-dimethylpropyl)phenyl][1,3]-
dithian-2-yl}phenyl)-2,2-dimethylpropan-1-ol (30). To a
suspension of LiBH4 (0.78 g, 35.8 mmol) in CH2Cl2 (55 mL)
was added MeOH (1.04 g, 32.5 mmol) at room temperature.
After the addition of 29 (6.5 g, 12.3 mmol), the reaction mixture
was heated to reflux for 6 h. After cooling to room temperature,
saturated aqueous NH4Cl solution (20 mL) and CH2Cl2 (15 mL)
were added and the layers were separated. The aqueous layer
was extracted with CH2Cl2 (2 × 10 mL). The combined organic
layers were dried over anhydrous Na2SO4 and concentrated
in vacuo to afford 30 (4.66 g, 85%) as an oil. 1H NMR (CDCl3):
δ 7.42 (s br, 2 H), 7.17 (m, 4 H), 6.97 (m, 2 H), 3.63 (s, 4 H),
3.16 (s, 4 H), 2.69 (m, 2 H), 2.47 (m, 4 H), 1.88 (m, 2 H), 0.75
(s, 12 H). 13C NMR (CDCl3): δ 142.39, 139.18, 131.69, 129.88,
128.05, 127.01, 71.12, 44.89, 43.74, 36.70, 29.63, 24.22.
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 deter-
mine total lipid synthesis, 170 µL of MicroScint-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 assessed by scintillation
spectroscopy in a Packard TopCount NXT. Lipid synthesis
rates were used to determine the IC50s of the compounds.
In Vivo Effects on Lipid Variables in Obese Female
Zucker Fatty Rats. Ten- to twelve-week old (400-500 g)
female Zucker fatty rats [Crl:(Zuc)-faBR] were obtained from
Charles River Laboratories. Animals were acclimated to the
laboratory environment for 7 days. During the acclimation and
study period, animals were housed by group in shoebox
polycarbonate cages on Cellu-Dri bedding. The temperature
and humidity in the animals’ quarters (68-78 °F; 30-75% RH)
were monitored, and the airflow in the room was sufficient to
provide several exchanges per hour with 100% fresh filtered
air. An automatic timing device provided an alternating 12-h
cycle of light and dark. Rats received pelleted Purina Labora-
tory Rodent Chow (5001) prior to and during the drug
intervention period except for a 6-h phase prior to blood
sampling. Freshwater was supplied ad libitum via an auto-
matic watering system. Compounds were dissolved and sus-
pended by mixing in a dosing vehicle consisting of 20% EtOH
and 80% poly(ethylene glycol)-200 (v/v). Dose volume of vehicle
or vehicle plus each compound was set at 0.25% of body weight
in order to deliver the appropriate dose. Doses were admin-
istered daily by oral gavage, approximately between 8 and 10
a.m. Regarding blood sampling, animals were fasted for 6 h
prior to all blood collections. To measure blood glucose levels,
blood from tail-pricked, unanesthetized animals was spotted
onto a glucometer (Bayer, Model 3952E). Subsequently, ad-
ditional blood samples were collected as follows. Prior to and
after 7 days of dosing, a 1.0-2.0 mL sample of blood was
collected by administering O2/CO2 anesthesia and bleeding
from the orbital venous plexus. Following 14 days of dosing,
blood was collected by cardiac puncture after euthanasia with
CO2. All blood samples were processed for separation of serum
and stored at -80 °C until analysis. Commercially available
kits were used to determine serum triglycerides (Roche
Diagnostic Corp., Kit No. 148899 or Boehringer Mannheim,
Kit No. 1488872), total cholesterol (Roche Diagnostic Corp.,
Kit No. 450061), nonesterified fatty acids (Wako Chemicals,
Kit No. 994-75409), and â-hydroxybutyrate (Wako Chemicals,
Kit No. 417-73501 or Sigma Kit. No. 310-0) on a Hitachi 912
Automatic Analyzer (Roche Diagnostic Corp.). Serum insulin
was determined using a commercial ELISA kit (Alpco Diag-
nostics, Windham, NH). 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 × 30 cm) column equipped with on-line
detection of total cholesterol as described by Kieft et al.52 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.
3-{3-[3-(2-Carboxy-2-methylpropyl)benzoyl]phenyl}-
2,2-dimethylpropionic Acid (31). According to the procedure
for the synthesis of 9f, a mixture of 28 (4.38 g, 10.0 mmol)
and KOH (85%, 1.57 g, 23.8 mmol) was heated to reflux in
water (1.5 mL) and EtOH (5 mL) for 3 h. After extraction and
drying in high vacuo, 31 (3.88 g, quantitative) was obtained
1
as a white solid. Mp: 46-48 °C. H NMR (CDCl3): δ 11.2-
10.6 (br, 2 H), 7.8-7.2 (m, 8 H), 2.83(s, 4 H), 1.25(s, 12 H). 13
C
NMR (CDCl3): δ 198.02, 183.86, 138.61, 137.73, 134.56,
130.54, 128.41, 128.10, 46.69, 43.77, 24.83. HRMS (LSIMS,
nba): calcd for C23H27O5 (MH+) 383.1858, found 383.1858.
HPLC: Alltima C-8 column, 250 × 4.6 mm, 5 µm; 55%
acetonitrile/45% water, flow rate 1.0 mL/min; RI, tR 8.62 min,
88.3% pure.
Bis[3-(3-hydroxy-2,2-dimethylpropyl)phenyl]metha-
none (32). A suspension of CuO (0.96 g, 12.1 mmol) and
anhydrous CuCl2 (3.2 g, 23.8 mmol) in acetone (80 mL) was
heated to reflux. A solution of 30 (4.44 g, 10.0 mmol) in acetone
(20 mL) and DMF (1.2 mL) was added dropwise over 5 min.
After 90 min at reflux temperature, the reaction mixture was
cooled to room temperature and filtered. The insoluble mate-
rial was washed with CH2Cl2 (3 × 20 mL). The combined
organic solutions were washed with aqueous 2 N Na2CO3
solution (50 mL), dried over anhydrous Na2SO4, and concen-
trated in vacuo. The residue was purified by column chroma-
tography (silica gel; hexanes/acetone ) 80/20) to give 32 (2.5
g, 71%) as an oil. 1H NMR (CDCl3): δ 7.68-7.30 (m, 8 H), 3.31
(s, 4 H), 3.03 (s br, 2 H), 2.65 (s, 4 H), 0.88 (s, 12 H). 13C NMR
(CDCl3 ) 77.00 ppm): δ 197.42, 139.06, 136.96, 134.60, 131.88,
127.78, 127.55, 70.39, 44.07, 36.30, 23.80. HRMS (LSIMS,
nba): calcd for C23H31O3 (MH+) 355.2273, found 355.2263.
HPLC: Alltima C-18 column, 250 × 4.6 mm, 5 µm; 55%
acetonitrile/45% water, flow rate 1.0 mL/min; RI, tR 13.37 min,
94.5% pure.
Biological Methods. In Vitro Measurement of Lipid
Synthesis in Isolated Hepatocytes. 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/day). Rat hepatocytes were isolated essentially as described
by the method of Seglen.51 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 was replaced
with the same media without serum. Cells were grown
overnight to allow formation of monolayer cultures. Lipid
Acknowledgment. We thank Dr. Edmund P. Woo
of Alchem Laboratories for his helpful suggestions.
Supporting Information Available: Details on the syn-
theses of intermediates 2, 3, 4, 5a-5j, 6a-6h, and 7a-7h and
spectral and elemental analysis data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.

6098 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24
Mueller et al.
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O. A.; et al. Metabolic effects of thia fatty acids. Curr. Opin.
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