Discovery of a highly orally bioavailable c-5-[6-(4-Methanesulfonyloxyphenyl)hexyl]-2-methyl-1,3-dioxane-r-2-carbo xylic acid as a potent hypoglycemic and hypolipidemic agent

Article abstract of DOI:10.1016/j.bmcl.2008.08.112

A series of novel 1,3-dioxane-2-carboxylic acid derivatives containing alkyl chain tether and substituted phenyl group as a lipophilic tail have been prepared as agonists of PPARα and γ. c-5-[6-(4-Methanesulfonyloxyphenyl)hexyl]-2-methyl-1,3-dioxane-r-2-carbo xylic acid 13c exhibited potent hypoglycemic and lipid lowering activity with high oral bioavailability in animal models.

Full text of DOI:10.1016/j.bmcl.2008.08.112

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5586–5590
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a highly orally bioavailable c-5-[6-(4-Methanesulfonyloxyphenyl)-
hexyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid as a potent hypoglycemic and
hypolipidemic agent q
a
b
a
a
a
Harikishore Pingali a,b, , Mukul Jain , Shailesh Shah , Sujay Basu , Pankaj Makadia , Amitgiri Goswami ,
Pandurang Zaware a, Pravin Patil a, Atul Godha a, Suresh Giri a, Ashish Goel a, Megha Patel a,
Harilal Patel a, Pankaj Patel a
*
a Zydus Research Centre, Sarkhej-Bavla N.H 8A Moraiya, Ahmedabad 382210, India
b Department of Chemistry, Faculty of Science, M. S. University of Baroda, Vadodara 390002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 1,3-dioxane-2-carboxylic acid derivatives containing alkyl chain tether and substituted
Received 27 June 2008
Revised 24 August 2008
Accepted 29 August 2008
Available online 3 September 2008
phenyl group as a lipophilic tail have been prepared as agonists of PPARa and c. c-5-[6-(4-Methanesulfo-
nyloxyphenyl)hexyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid 13c exhibited potent hypoglycemic and
lipid lowering activity with high oral bioavailability in animal models.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Type 2 diabetes
PPAR agonist
1,3-Dioxane-2 carboxylic acid
Metabolic disorders
Prevalence of Type 2 diabetes and adverse cardiovascular condi-
tions associated with this disease are increasing world wide and
are considered as a major threat to human health in the 21st cen-
tury.1 The defects in lipid and carbohydrate metabolism are the
main causes of this disease and the nuclear hormone receptors
dual agonists are marketed including Farglitazar,4 Ragaglitazar,5
Tesaglitazar6 and Muraglitazar7 which were dropped from late
clinical development due to adverse effects like edema, carcino-
gencity in rodent toxicity models, heart failure or cardiovascular
deaths and elevated serum creatinine. The unsuccessful efforts to
develop dual agonist and recent research findings that activation
PPAR
the treatment of diabetes and dyslipidemia.2 PPAR
tified as a key regulator for insulin sensitivity, and two PPAR
a
and PPAR
c
agonists have shown therapeutic benefits in
has been iden-
ago-
c
of PPAR
tizing effects8 led to the discovery of potent and selective activa-
tors of PPAR as remedy for disorders mediated by lipid and
a lower triglycerides, elevate HDL and exert insulin-sensi-
c
nists, Rosiglitazone and Pioglitazone have demonstrated clinical
success in the treatment of Type 2 diabetes. Unfortunately, these
agents are found to cause adverse effects including weight gain,
edema and anemia in both animal models and humans. Fibrate
class of compounds have been shown to lower plasma lipid, tri-
glyceride (TG), levels and have been in clinical use for the treat-
ment of dyslipidemia. However these are poor activators of
a
carbohydrate metabolism. A potent and selective PPAR
a agonist
NS-2209 is reported to exert hypoglycemic and lipid modulating
effects in animal models but the further development of this com-
pound is discontinued for unknown reasons. Another compound K-
111,10 a relatively weak PPAR
a agonist is presently undergoing
clinical trials for the treatment of Type 2 diabetes. As a part of
our research in the field of PPAR,11 we have recently reported a ser-
ies of oxazole containing 1,3-dioxane-2-carboxylic acid derivatives
PPAR
with PPAR
treatment of hyperglycemia and hyperlipidemia in animal models
a
and need high doses to exert therapeutic effect. Treatment
c
and PPAR dual agonists found to be useful in the
a
as PPARa/c
dual agonist.12 In this communication we report a ser-
and a number of PPAR
a
/
c
dual agonists have been discovered and
ies of novel 1,3-dioxane carboxylic acid derivatives designed by the
hybridization of the compounds NS-220 and K-111 and mimicking
Tesaglitazar (Fig. 1) in order to optimize the lead candidate.
The synthesis of compounds 7a–e is outlined in Scheme 1.
Starting materials 1a–e, procured from commercial sources were
reduced initially with Zn/Hg to compounds 2a–e which were
further reduced with LiAlH4 to yield the hydroxy compounds
evaluated by different research groups.3 Till date none of these
q
ZRC communication.240.
* Corresponding author. Tel.: +91 2717 250801; fax: +91 2717 250603.
E-mail addresses: pingalihk@rediffmail.com (H. Pingali), shailesh-chem@
msubaroda.ac.in (S. Shah).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.08.112

H. Pingali et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5586–5590
5587
O
Cl
O
N
O
O
O
OH
Cl Cl
K-111
NS-220
O
O
O
S
O
O
COOH
OEt
O
S
O
O
O
O
O
OH
13c
TESAGLITAZAR
Figure 1. Structures of PPAR agonists.
O
OH
i
ii
OH
OH
O
O
R
R
R
3a-e
2a-e
1a-e
OH
OH
a; R=Me
b; R=F
c; R=SMe
d; R=OMe
e; R=Cl
iii
iv, v
OMs
O
R
R
5a-e
4a-e
O
COOH
COOMe
vi
vii
O
O
R
R
7a-e
6a-e
Scheme 1. Reagents and conditions: (i) Zn/Hg, Toluene, AcOH, H2O, reflux, 4 h; (ii) LiAlH4, THF, 0–10 °C, 1 h; (iii) CH3SO2Cl, Et3N, CH2Cl2, 0–10 °C, 30 min; (iv) diethyl
malonate, NaH, THF, 60 °C, 48 h; (v) LiAlH4, THF, 0-10 °C, 2 h; (vi) BF3ꢀetherate, methyl pyruvate, CH3CN, 25 °C, 2 h; (vii) LiOH.H2O, H2O, THF, MeOH, 25 °C, 18 h.
3a–e. These compounds (3a–e) were converted to their corre-
sponding mesylate derivatives (4a–e) and treated with diethyl-
malonate in the presence of sodium hydride. The diesters so
obtained were reduced with LiAlH4 to diols 5a–e. These diols
when reacted with methylpyruvate in the presence of borontri-
fluoride etherate in acetonitrile yielded the esters as a mixture
of diastereomeric isomers. The mixture was separated by chro-
matography to get the cis-isomers 6a–e which showed a chem-
ical shift pattern in 1H NMR identical to that of the other cis
derivatives reported.13 These esters 6a–e were hydrolyzed using
aqueous NaOH to obtain the acids 7a–e. Compounds 7f and 7g
were synthesized as illustrated in Scheme 2. Sulfanyl derivative
6c when treated with 1.2 molar equivalent of m-CPBA gave cor-
responding sulfinyl derivative which on hydrolysis gave the acid
O
O
COOH
COOMe
O
i, iii
O
S
O
S
6c
7f
ii, iii
O
COOH
O
O
S
O
7g
Scheme 2. Reagents and conditions: (i) m-CPBA (1.2 equiv), CHCl3, 0–10 °C, 30 min; (ii) m-CPBA (3 equiv), CHCl3, 25 °C, 1 h; (iii) LiOH, H2O, THF, MeOH, 25 °C, 18 h.

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H. Pingali et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5586–5590
7f where as the same compound 6c on treatment with 3 molar
equivalents of m-CPBA gave the sulfonyl derivative which upon
hydrolysis yielded the acid 7g. The synthesis of compounds 9,
11, and 13a–c was as illustrated in Scheme 3. Compounds 8a–
O
O
COOMe
COOH
i
O
O
n
n
BnO
BnO
8a; n=3
9; n=3
8b; n=4
8c; n=5
ii
O
O
i
COOMe
COOH
O
O
n
n
HO
HO
10a; n=3
10b; n=4
10c; n=5
11; n=3
iii
O
O
i
COOMe
COOH
O
O
n
n
H3CO2SO
H3CO2SO
13a; n=3
13b; n=4
13c; n=5
12a; n=3
12b; n=4
12c; n=5
Scheme 3. Reagents and conditions: (i) LiOH, H2O, THF, MeOH, 25 °C, 18 h; (ii) HCOONH4, Pd/C (10%), MeOH, reflux, 2 h; (iii) CH3SO2Cl, Et3N, CH2Cl2, 0–10 °C, 30 min.
Table 1
In vitro hPPAR transactivation and TG reducing activity of compounds 7a–g, 9, 11, and 13a
R
O
O
OH
O
Compound
R
hPPAR transactivationa,b
% Change in TG in SAMc
a
(10
l
M)
c
(0.2
l
M)
d (0.2 lM)
7a
7b
7c
7d
7e
7f
7g
9
Me
F
3.2
2.3
4
2.5
2.6
2
1.5
1.1
1.2
1.9
1.2
2.2
1.8
2.2
1.0
1.4
1.0
1.0
ND
ND
5.6
ꢁ22
ꢁ9
2.1
1.9
1.2
2.2
1.8
2.2
1.0
1.4
1.0
1.0
SMe
OMe
Cl
SOMe
SO2Me
OBn
OH
ꢁ14
ꢁ11
ꢁ10
ꢁ12
ꢁ7
1
2.3
1.2
3.0
1.0
3.3
ND
ND
ꢁ25
ꢁ15
ꢁ32
0.0
ND
ND
11
13a
Vehicle
WY-14643
Rosiglitazone
GW-501516
OSO2Me
ND
10.2
ND
a
HepG2 cells were transfected with pSG5 expression vector containing the cDNA of hPPAR
a
or hPPARc or hPPARd and cotransfected with PPRE3-TK-luc. The Luciferase
activity was determined using commercial fire-fly luciferase assay and b-galactosidase activity was determined in ELISA reader. Activities are presented by fold induction of
PPAR and activation. IA denotes inactive.
a
c
b
In hPPARd transactivation assay, any of these compounds did not show any activation above basal level.
The test compounds were administered orally at a dose of 10 mg/kg/day to male swissalbino mice (SAM) of 6–8 weeks of age for 6 days. Mean values (n = 6) are the %
c
change in serum triglyceride (TG) concentration of the compound-treated mice versus vehicle controls. All values are the mean of n = 6. ND denotes not determined.

H. Pingali et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5586–5590
5589
Table 2
1,3-dioxane acidic head with an alkyl tether. Phenyl ring has been
substituted at para-position as the activity of these compounds is
sensitive to substituent at this position. In vitro hPPAR transactiva-
tion is reported as fold induction and their ability to reduce plasma
triglycerides (TG) in male swiss albino mice (SAM) which is a mod-
erately hyperlipidemic model and the results are shown in Table 1.
These results reveal that the substitution at para-position on the
phenyl ring contributes significantly to the in vitro as well as
in vivo triglyceride lowering activity of these compounds. Based
on these results 13a was selected for further modifications. We
fixed the tail group as para-methanesulfonyloxy phenyl group
and opted to optimize the tether length. Compounds 13b and
13c were synthesized by elongating the tether length to pentam-
ethylene and hexamethylene, respectively. PPAR in vitro activities
of these compounds (13b–c) and their TG lowering activity in SAM
model are summarized in Table 2. Compound 13b containing pen-
tamethylene chain as tether found inferior to 13a but surprisingly
compound 13c containing hexamethylene chain as tether reduced
plasma TG significantly (71%). The transient transactivation results
of these compounds are reported as EC50 (Table 2) which shows
that the compound 13c is a moderate activator of PPAR. Having
surprised and encouraged with the initial results of compound
13c, we evaluated it in db/db mice and high cholesterol fed Spra-
gue–Dawley rats (HC fed SD rats). In db/db mice model the com-
pound 13c showed excellent plasma glucose and TG reductions
which are comparable to NS-220 (Table 3). In HC fed SD rat model
the same compound exhibited excellent reduction in TG and cho-
lesterol superior to NS-220 (Table 4). To further understand and
to draw correlation between moderate in vitro potency and high
in vivo efficacy of compound 13c we evaluated its pharmacokinetic
parameters which are presented in Table 5. Compound 13c showed
In vitro hPPAR transactivation and TG reducing activity of compounds 13a–c
O
COOH
O
O
n
H3C
S
O
O
Compound
n
hPPAR transactivation EC50
(
lM)
% Change in TG in SAM
a
c
13a
13b
13c
NS-220
Tesaglitazar
3
4
5
20
2.5
IA
IA
ꢁ32
ꢁ28
ꢁ71
ꢁ67
ꢁ79
2
15
7
0.013
0.05
0.82
Table 3
Hypoglycemic and hypolipidemic activities of compound 13c in db/db micea
Compound
Dose (mg/kg/day)
% Change
TG
PG
13c
NS-220
Tesaglitazar
3
3
3
ꢁ50
ꢁ54
ꢁ60
ꢁ53
ꢁ44
ꢁ54
a
Male db/db mice of 6–8 weeks old were dosed with test compounds daily for 6
days and Plasma glucose, triglycerides were measured. Values reported are %
change of compound-treated mice versus vehicle controls.
Table 4
Hypolipidemic activity of compound 13c in HC fed SD ratsa
Compound
Dose (mg/kg/day)
% Change
LDL-C
Cmax of 127 lg/mL and an AUC of 1491 h lg/mL when adminis-
TG
TC
HDL-C
tered orally to male wistar rat at a dose of 30 mg/kg body weight.
These results clearly established the compound 13c as highly effi-
cacious and bioavailable hypoglycemic and hypolipidemic agent
with moderate in vitro potency and this compound is currently
undergoing pre-clinical toxicity studies in order to evaluate the
other effects of this compound in animal models.
In summary c-5-[(phenyl)-alkyl]-2-methyl-1,3-dioxane-r-2-
carboxylic acid derivatives have been prepared with substitutions
on phenyl ring and are evaluated in vitro for their PPAR agonistic
potential followed by in vivo hypoglycemic and hypolipidemic
activities. Lead compound c-5-[6-(4-Methanesulfonyloxyphe-
nyl)hexyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid 13c showed
excellent hypoglycemic and hypolipidemic activities with very
modest in vitro potency and has exhibited high oral bioavailability.
13c
NS-220
Tesaglitazar
3
3
3
ꢁ63
ꢁ54
ꢁ51
ꢁ56
ꢁ49
ꢁ59
ꢁ46
ꢁ68
ꢁ31
51
88
18
a
Male Sprague–Dawley (SD) rats were fed with diet containing high cholesterol
for 15 days then dosed with vehicle or the indicated doses of test compound daily
for 4 days by oral gavage. Serum triglycerides (TG), total cholesterol (TC), LDL-
cholesterol (LDL-C) and HDL-cholesterol (HDL-C) were measured. Values reported
are % change versus control group.
Table 5
Mean pharmacokinetic parametersa of 13c in fasted male wistar rat
Compound Route Dose
Tmax
Cmax
g/mL)
T1/2
(h)
AUC(0-/)
(h g/mL)
(mg/kg) (h)
(
l
l
13c
NS-220
Oral
Oral
30
30
4( 0.0)
0.67( 0.0) 41( 3.8)
127( 4.6)
12( 0.9)
1.5( 0.3) 99( 5.2)
1491( 78)
Acknowledgments
a
Values indicate mean SD for n = 6.
Authors are grateful to Dr. B.B. Lohray, Dr. V.B. Lohray for valu-
able suggestions, management of Zydus Group for encouragement,
and the analytical department for support.
c are prepared following the procedures similar to those de-
scribed in Scheme 1. Compound 8a was hydrolyzed to obtain
the compound 9 where as the compounds 8a–c were debenzy-
lated under hydrogen transfer reaction condition to yield the
compounds 10a–c. Compound 10a was hydrolyzed to compound
11 while 10a–c were treated with mathanesulfonyl chloride to
obtain the compounds 12a–c which were subsequently hydro-
lyzed to compounds 13a–c.
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hPPAR
ted HepG2 cells. WY-14643, Rosiglitazone and GW501516 were
used as PPAR and d controls, respectively. Initial compounds
a, c and d agonistic activity by using PPAR receptor transfec-
a, c
7a–g, 9, 11, and 13a are designed by hybridizing the structures
of NS-220 and K-111 wherein the phenyl ring is connected with

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and 4.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H); 13C NMR
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97.48, 113.90, 129.07, 133.98, 157.27, 171.32; ESI-MS m/z: 309.3 (M+H)+.7e: c-
5-[4-(4-Chloro-phenyl)-butyl]-r-2-methyl-1,3-dioxane-2-carboxylic acid: White
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;
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3.93 (dd, J = 11.6 and 4.2 Hz, 2H,), 7.52 (d, J = 8.07 Hz, 2H), 7.6 (d, J = 8.0 Hz,
2H); 13C NMR (100 MHz, DMSO-d6): d 25.18, 25.55, 27.22, 30.86, 32.77, 34.59,
43.20, 67.24, 97.48, 123.60, 129.10, 143.46, 145.26, 171.33; ESI-MS m/z: 341.1
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11. (a) Lohray, B. B.; Bhushan, V.; Reddy, A. S.; Rao, P. B.; Reddy, N. J.; Harikishore,
P.; Vikramadityan, R. K.; Chakrabarti, R.; Rajagopalan, R.; Katneni, K. J. Med.
Chem. 1999, 42, 2569; (b) Reddy, K. A.; Lohray, B. B.; Bhushan, V.; Reddy, A. S.;
Harikishore, P.; Rao, V. V.; Saibaba, V.; Bajji, A. C.; Rajesh, B. M.; Reddy, K. V.;
Chakrabarti, R.; Rajagopalan, R. Bioorg. Med. Chem. Lett. 1998, 8, 999; (C) Tudor,
C.; Feige, J. N.; Harikishore, P.; Lohray, V. B.; Wahli, W.; Desvergne, B.;
Engelborghs, Y.; Gelman, L. J. Biol. Chem. 2007, 282, 4417.
HPLC; IR (KBr): 3020, 2933, 1743, 1299, 1134, 1118, 763 cmꢁ1 1H NMR
;
(300 MHz, CDCl3): d 1.04–1.11 (m, 2H), 1.26–1.36 (m, 2H), 1.56 (s, 3H), 1.59–
1.67 (m, 2H), 2.01–2.06 (m, 1H), 2.68 (t, J = 7.6 Hz, 2H), 3.05 (s, 3H), 3.45 (t,
J = 11.5 Hz, 2H), 3.93–3.99 (dd, J = 11.9 and 4.4 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H),
7.84 (d, J = 8.3 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): d 25.22, 25.60, 27.25,
30.72, 32.81, 34.72, 67.28, 97.58, 127.01, 129.21, 138.31, 148.59, 171.43; ESI-
MS m/z: 379.2 (M+Na)+.9: c-5-[4-(4-Benzyloxy-phenyl)-butyl]-r-2-methyl-1,3-
dioxane-r-2-carboxylic acid: White solid; mp: 102–104 °C; Yield: 84%; Purity:
99% by HPLC; IR (KBr): 3020, 2929, 1728, 1510, 1236, 1047, 746 cmꢁ1 1H NMR
;
(300 MHz, CDCl3): d 1.04-1.09 (m, 2H), 1.23–1.33 (m, 2H), 1.50–1.62 (m, 5H),
1.97–2.03 (m, 1H), 2.50 (t, J = 7.5 Hz, 2H), 3.40 (t, J = 11.5 Hz, 2 H), 3.94-3.99
(dd, J = 11.8 and 4.4 Hz, 2H), 5.03 (s, 2H), 6.87 (d, J = 8.4 Hz, 2H), 7.04 (d,
J = 8.4 Hz, 2H), 7.29–7.44 (m, 5H); 13C NMR (100 MHz, DMSO-d6): d 25.17,
25.61, 27.32, 31.36, 32.85, 34.02, 67.31, 69.13, 97.56, 114.56, 127.66, 128.42,
129.18, 134.34, 137.30, 156.43, 171.42, 185.15; ESI-MS m/z: 402.3
12. Pingali, H.; Jain, M.; Shah, S.; Makadia, P.; Zaware, P.; Goel, A.; Patel, M.; Giri, S.;
Patel, H.; Patel, P. Bioorg. Med. Chem. 2008, 16, 7117.
13. Asaki, T.; Aoki, T.; Hamamoto, T.; Sugiyama, Y.; Ohmachi, S.; Kuwabara, K.;
Murakami, K.; Todo, M. Bioorg. Med. Chem. 2008, 16, 981.
(M+NH4)+.11:
c-5-[4-(4-Hydroxy-phenyl)-butyl]-2-methyl-1,3-dioxane-r-2-
carboxylic acid: White solid; mp: 157–159 °C; Yield: 86%; Purity: 99% by
HPLC; IR (KBr): 3073, 2933, 1720, 1514, 1228, 1136, 813 cmꢁ1 1H NMR
;
(300 MHz, DMSO-d6): d 0.92–1.00 (m, 2H), 1.13–1.22 (m, 2H), 1.31 (s, 3H),
1.38–1.52 (m, 2H), 1.75–1.83 (m, 1H), 2.37 (t, J = 7.5 Hz, 2H), 3.22 (t, J = 11.5 Hz,
2H), 3.76–3.82 (dd, J = 11.7 and 4.4 Hz, 2H), 6.61 (d, J = 8.3 Hz, 2H), 6.91 (d,
J = 8.2 Hz, 2H), 9.06 (br s, 1H); 13C NMR (100 MHz, DMSO-d6): d 25.32, 25.63,
27.42, 31.39, 32.99, 34.03, 67.07, 98.07, 114.97, 128.60, 132.10, 155.24, 171.60;
ESI-MS m/z: 317.1 (M+Na)+.13a: c-5-[5-(4-Methanesulfonyloxy-phenyl)-butyl]-
2-methyl-1,3-dioxane-r-2-carboxylic acid: White solid; mp: 140–142 °C; Yield:
84%; Purity: 98% by HPLC; IR (KBr): 3020, 2927, 1753, 1506, 1346, 1261, 1170,
14. Spectroscopic analysis of the compounds 7a–7g, 9, 11, 13a–13c:7a: 2-Methyl-
c-5-(4-(4-methylphenyl)-butyl)-1,3-dioxane-r-2-carboxylic acid; White solid;
mp: 111–113 °C; Yield: 86%; Purity: 99% by HPLC; IR (KBr): 3003, 2923,
1716, 1284, 1207, 1047 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.02–1.09 (m, 2H),
;
1.23–1.31 (m, 2H), 1.51–1.64 (m, 5H), 1.95–2.05 (m, 1H), 2.31 (s, 3H), 2.54 (t,
J = 7.5 Hz, 2H), 3.44 (t, J = 11.6 Hz, 2H), 3.94–3.99 (dd, J = 11.8 and 4.6 Hz, 2H),
7.01–7.09 (m, 4H); 13C NMR (100 MHz, DMSO-d6): d 20.63, 25.34, 25.63, 27.38,
31.24, 32.92, 34.54, 67.32, 97.76, 128.11, 128.61, 134.44, 139.04, 171.46; ESI-
MS m/z: 310.2 (M+NH4)+.7b: c-5-[4-(4-Fluoro-phenyl)-butyl]-2-methyl-1,3-
dioxane-r-2-carboxylic acid: White solid; mp: 90–92 °C; Yield: 88%; Purity:
987 cmꢁ1 1H NMR (300 MHz, CDCl3), d 1.03–1.10 (q, J = 7.5 Hz, 2H), 1.28–1.34
;
(m, 2H), 1.53 (s, 3H), 1.98–2.04 (m, 1H), 2.59 (t, J = 7.5 Hz, 2H), 3.13 (s, 3 H),
3.44 (t, J = 11.6 Hz, 2H), 3.93–3.99 (dd, J = 4.7 and 11.9 Hz, 2H), 7.18 (s, 4H); 13C
NMR (100 MHz, DMSO-d6): d 25.20, 25.56, 27.25, 30.94, 32.80, 34.19, 37.23,
67.26, 97.50, 121.91, 129.72, 141.51, 147.15, 171.34; ESI-MS m/z: 395.0
98% by HPLC; IR (KBr): 3020, 2923, 2852, 1716, 1284, 1209, 806 cmꢁ1 1H NMR
;
(300 MHz, CDCl3): d 1.02–1.10 (m, 2H), 1.23–1.31 (m, 2H), 1.51–1.64 (m, 5H),
1.95–2.05 (m, 1H), 2.55 (t, J = 7.5 Hz, 2H), 3.44 (t, J = 11.5 Hz, 2H), 3.94–3.99
(dd, J = 11.8 and 4.6 Hz, 2H), 6.94 (t, J = 8.6 Hz, 2H), 7.06–7.14 (m, 2H); 13C NMR
(100 MHz, DMSO-d6): d 25.33, 25.65, 27.47, 31.41, 33.05, 33.93, 67.07, 98.07,
115.01, 128.64, 132.14, 155.25, 171.60; ESI-MS m/z: 313.6 (M+NH4)+.7c: 2-
Methyl-c-5-[4-(4-methylsulfanyl-phenyl)-butyl]-1,3-dioxane-r-2-carboxylic acid:
White solid; mp: 103–105 °C; Yield: 90%; Purity: 98% by HPLC; IR (KBr): 3040,
(M+Na)+.13b:
c-5-[5-(4-Methanesulfonyloxy-phenyl)-pentyl]-2-methyl-1,3-
dioxane-r-2-carboxylic acid: White solid; mp: 102–104 °C; Yield: 94%; Purity:
98% by HPLC; IR (KBr): 3036, 2930, 1720, 1498, 1363, 1290, 1211, 1168, 1145,
974, 867, 775, 538, 526 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.0 (m, 2H), 1.2 (m,
;
4H), 1.5 (m, 5H), 2.0 (m, 1H), 2.6 (t, J = 7.4 Hz, 2H), 3.1 (s, 3H), 3.4 (t, J = 11.6 Hz,
2H), 3.9 (dd, J = 12.0 and 4.5 Hz, 2H), 7.2 (m, 4H); 13C NMR (100 MHz, DMSO-
d6): d 25.34, 25.54, 27.41, 28.71, 30.54, 32.86, 34.33, 37.22, 67.27, 97.49,
121.86, 129.70, 141.54, 147.12, 171.32; ESI-MS m/z: 409.0 (M+Na)+.13c: c-5-[6-
(4-Methanesulfonyloxy-phenyl)-hexyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid:
White solid; mp: 104–106 °C; Yield: 93%; Purity: 97.5% by HPLC; IR (KBr):
2931, 1720, 1492, 1284, 1043 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.02–1.09
;
(m, 2H), 1.25–1.33 (m, 2H), 1.51–1.61 (m, 5H), 1.98–2.02 (m, 1H), 2.46 (s, 3H),
2.51 (t, J = 7.6 Hz, 2H), 3.40 (t, J = 11.8 Hz, 2H), 3.94–3.99 (dd, J = 11.8 and
4.4 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H); 13C NMR (100 MHz,
DMSO-d6): d 15.09, 25.14, 25.57, 27.27, 31.03, 32.82, 34.27, 67.26, 97.50,
126.30, 128.87, 134.72, 139.07, 171.35; ESI-MS m/z: 342.2 (M+NH4)+.7d: c-5-
[4-(4-Methoxy-phenyl)-butyl]-r-2-methyl-1,3-dioxane-2-carboxylic acid: White
solid; mp: 84–86 °C; Yield: 80%; Purity: 98% by HPLC; IR (KBr): 3020, 2938,
3026, 2922, 1755, 1467, 1259, 1147 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.02-
;
1.05 (m, 2H), 1.27 (bm, 6H), 1.57 (bm, 5H), 1.98–2.06 (m, 1H), 2.59 (t, J = 7.6 Hz,
2H), 3.12 (s, 3H), 3.46 (t, J = 11.6 Hz, 2H), 3.96–4.00 (dd, J = 12.0 and 4.4 Hz,
2H), 7.16–7.28 (m, 4H); 13C NMR: (100 MHz, DMSO-d6): d 25.60, 26.72, 28.46,
29.02, 32.47, 33.06, 34.46, 37.23, 67.35, 97.13, 121.64, 129.47, 141.35, 147.50,
171.40; ESI-MS m/z: 423.0 (M+Na)+.
1727, 1556, 1228, 1136, 823 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.02–1.09 (m,
;
2H), 1.23–1.30 (m, 2H), 1.50–1.52 (m, 2H), 1.60 (s, 3H), 1.98–2.0 (m, 1H), 2.52