Synthesis and HMG-CoA reductase inhibition of 2-cyclopropyl-4-thiophenyl-quinoline mevalonolactones

Article abstract of DOI:10.1016/j.bmc.2009.10.021

A novel series of 2-cyclopropyl-4-thiophenyl quinoline-based mevalonolactones were synthesized from the substituted anilines by several reactions. Among them, (4R,6S)-6-[(E)-2-(2-cyclopropyl-6-fluoro-4-(4-fluoro-thiophenyl)-quinoline-3-yl)-ethenyl]-3,4,5,

Full text of DOI:10.1016/j.bmc.2009.10.021

Bioorganic & Medicinal Chemistry 17 (2009) 7915–7923
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and HMG-CoA reductase inhibition of 2-cyclopropyl-4-thiophenyl-
quinoline mevalonolactones
a
b
Shikui Zhao a, , Weicheng Zhou , Jun liu
*
a State Key Lab of New Drug & Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, PR China
b Screening Center for New Drugs, China Pharmaceutical University, Nanjing 210009, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of 2-cyclopropyl-4-thiophenyl quinoline-based mevalonolactones were synthesized from
the substituted anilines by several reactions. Among them, (4R,6S)-6-[(E)-2-(2-cyclopropyl-6-fluoro-
4-(4-fluoro-thiophenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (1d),
(4R,6S)-6-[(E)-2-(2-cyclopropyl-6-fluoro-4-(3-methoxy-thiophenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-tetra-
hydro-4-hydroxy-2H-pyran-2-one (1f) and (4R,6S)-6-[(E)-2-(2-cyclopropyl-6-fluoro-4,7-di(3-methoxy-
thiophenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (1q) showed potent
HMG-CoA reductase inhibitory activity comparable with pitavastatin.
Received 5 September 2009
Revised 12 October 2009
Accepted 13 October 2009
Available online 30 October 2009
Keywords:
HMG-CoA reductase
Quinoline
Ó 2009 Elsevier Ltd. All rights reserved.
Mevalonolactone
Synthesis
1. Introduction
quinoline-based HMG-CoA reductase inhibitors, we designed the
2-cyclopropyl-4-phenylthioquinoline-based derivatives (com-
Hypercholesterolemia and cardiovascular disease are major
health problems. One approach to reduce hypercholesterolemia
is to use the medicines that inhibit the enzymes essential for cho-
lesterol biosynthesis. Hydroxymethylglutaryl-Coenzyme A (HMG-
CoA) reductase catalyzes the rate-limiting step in cholesterol
biosynthesis. When this synthesis is inhibited, the low density
lipoprotein cholesterol (LDL-c) receptor is upregulated and LDL-c
is rapidly cleared from the bloodstream.1 Quinoline-based pita-
vastatin as a HMG-CoA reductase inhibitor is a highly effective
therapeutic agent for the treatment of hypercholesterolemia.2
After a systematical QSAR study on quinoline compound A,3 Slisko-
vic and Suzuki et al. discovered that the desmethylmevalonic acid
portion was linked through a trans-ethylene group to position 3 in
quinoline ring, and 4-fluorophenyl and 2-cyclopropyl groups were
preferable substituents in order to get the best inhibition on HMG-
CoA reductase. The introduction of chloro, methyl or methoxy
group to the 6, 7, or 8-position of the quinoline nucleus may in-
crease the inhibitory potency.
pounds 1), in which the lactone moiety was connected to position
3 of the quinoline nucleus via a trans-ethylene spacer and the nu-
cleus was flanked at position 2 and 4 by cyclopropyl and substi-
tuted thiophenyl as the lipophilic groups, and at position 6, 7 by
different groups, such as H, F, OCH3, substituted thiophenyl
(Fig. 1). The inhibition on HMG-CoA reductase of these novel
2-cyclopropyl-4-phenylthio-quinoline derivatives will also be
reported.
F
R2
R3
OH OH
OH OH
R4
COOH
R
COONa
R5
OH
O
N
R1
N
pitavastatin
A
S
N
R1
R2
O
As part of our lab’s investigations on quinoline derivatives with
pharmacological interests,4 Cai5 introduced a sulfur atom between
the quinoline ring position 4 and 4-fluorophenyl to obtain a series
of novel compounds. Compounds B and C were found approxi-
mately three times more potent than rosuvastatin or pitavastatin
in inhibiting HMG-CoA reductase. Continuing our pursuit on new
H3CO
S
1
OH
OH
S
N
F
F
F
S
O
O
H3CO
O
O
N
C
F
B
* Corresponding author. Tel.: +86 21 55514600 820; fax: +86 21 35052484.
E-mail address: zhaosk2002@163.com (S. Zhao).
Figure 1. 2-Cyclopropyl-4-thiophenyl-quinolines (1).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.10.021

7916
S. Zhao et al. / Bioorg. Med. Chem. 17 (2009) 7915–7923
were defined as no significantly active ones and those (totally 10
2. Chemistry
compounds) giving less than 80% of decreased absorbance would
go to the secondary screening (IC50 determination).
The 2-cycloproyl-4-thiophenyl quinoline derivatives (1) were
synthesized in optically pure forms by the general method shown
in Scheme 1.
3.2. IC50 determination
The key intermediate ethyl 2-cyclopropyl-4-chloro-quinoline-
3-carboxylates (5) were synthesized from anilines and diethyl
[chloro(cyclopropyl)methylene]malonate (2, prepared from
diethyl malonate and cyclopanecarboxylic acid chloride)6 in three
steps. The aromatic nucleophilic substitution (SNAr) of 5 with
4-fluorothiophenol, 2-methoxythiophenol, 3-methoxythiophenol,
4-methoxythiophenol or 4-isopropylthiophenol was highly regio-
specific to afford the 4-monosubstituted (6a–o) or 4,7-disubsti-
tuted (6p–r) products by controlling the reaction temperature,
the type of the base, the solvents as well as the ratio of the
substrate to the nucleophile. Characterizations of 6 are shown in
Table1.
The concentration of an inhibitor required to inhibit 50% of
the HMG-CoA reductase under the above assay conditions was de-
fined as IC50. The UV absorbance was measured in eight levels
(5 ꢀ 10ꢁ4 M, 1 ꢀ 10ꢁ4 M, 5 ꢀ 10ꢁ5 M, 1 ꢀ 10ꢁ5 M, 5 ꢀ 10ꢁ6 M, 1 ꢀ
10ꢁ6 M, 5 ꢀ 10ꢁ7 M, 1 ꢀ 10ꢁ7 M at final concentration) for each
sample. A statistical analysis was performed by standard curve using
mean values of triplicate measurements (n = 3). The results are seen
in Table 3.
4. Results and discussion
Compounds 6 were reduced to the alcohols (7) by diisobutylalu-
minum hydride (DIBAL-H). Bromination of alcohols with PBr3 affor-
ded the bromides (8), which were converted to the corresponding
phosphorus compounds (9) with Ph2POEt in toluene. The trans-
olefins (11) were generated by Wittig–Horner reaction of 9 with
tert-butyl (3R, 5S)-6-oxo-3,5-dihydroxy-3,5-O-isopropylidene-hex-
anoate (10) under basic condition. The olefins were deprotected
and lactonized with CF3COOH in CH2Cl2 to give the target com-
pounds 1. Characterizations of 1a–r are shown in Table 2.
In the preliminary screening among the obtained 18 com-
pounds, 10 compounds were found to possess good or moderate
inhibition on HMG-CoA reductase. And the inhibition of three com-
pounds: 1d, 1f and 1q were more potent than that of pitavastatin.
In the early reports for quinoline-based mevalonolactones, it
was known that the preferable groups at position 2 and 4 are cyclo-
propyl and 4-fluorophenyl, respectively. Cai5 found that the 4-iso-
propylthiophenyl and 3-methoxythiophenyl were better potent
groups than 4-fluorothiophenyl when the sulfur was introduced
at position 4 and the 2-substituent was simplified into H. In this
paper, 4-fluorothiophenyl was found to be a better group for
HMG-CoA reductase inhibition than 4-methoxythiophenyl, 2-
methoxythiophenyl and 4-isopropylthiophenyl (1d vs 1e, 1d vs
1g, 1d vs 1h) and 3-methoxythiophenyl seemed better than 4-flu-
orothiophenyl (1f vs 1d, 1q vs 1p).
The potency was altered with the different R1 groups at position
6. The early report showed that replacement of H at position 6 by
some small groups, for example, Cl or OCH3, might enhance the
activity in the 4-fluorophenylquinolines.3b The present work dem-
onstrated that introduction of F to position 6 might generally give
more potency than the OCH3 or hydrogen counterparts (1d vs 1a,
1d vs 1i, 1f vs 1b, 1f vs 1j).
3. Biological activity
All the 18 synthesized target compounds 1, with pitavastatin as
the reference, were evaluated for inhibitory activity on rat liver
HMG-CoA reductase in vitro, following the method of Kleinsek7
where by the rate of decrease in absorbance at 340 nm due to
the oxidation of NADPH was measured. The enzyme preparation
and assay procedures used in this study were the same as those de-
scribed in the literature.5,8
3.1. The preliminary screening
At the same time, it was found that introduction of fluoro group
at position 7 might decreased the activity (1m vs 1f, 1l vs 1d).
When this post was substituted with the thiophenyl group, it is dif-
ficult to conclude the structure–activity relationship.
According to the protocol in experiment, the assay system with-
out any inhibitor was taken as the negative control. The test com-
pounds (6.6 ꢀ 10ꢁ5 M at final concentration) which gave the
decreased UV absorbance more than 80% of that in negative control
EtOOC
OH
N
Cl
N
R3
R1
R1
R3
COOEt
COOEt
COOEt
(a)
Cl
R1
R3
COOEt
R1
R3
COOEt
(b)
(c)
+
NH2
R
N
H
R
R
R
S
N
S
S
S
COOEt
CH2OH
CH2POPh2
(d)
(e)
R1
R2
(f)
R1
R2
(g) R1
CH2Br
R1
R2
N
R2
N
N
7a-r
8a-r
9a-r
6a-r
H3C CH3
R
O
O
R
OH
H3C CH3
COOt-Bu
OHC
S
N
S
N
O O
(i)
10
R1
R2
R1
R2
COOt-Bu
(h)
O
O
11a-r
Scheme 1. Reagents and conditions: (a) K2CO3/DMF, 16 h, 100 °C; (b) diphenyl ether, 0.5 h, 170–230 °C; (c) POCl3, toluene, 80 °C; (d) substituted thiophenols, NaH/THF or
K2CO3/DMF, 6–16 h; (e) DIBAL-H, toluene, 0 °C, 4 h; (f) PBr3, CH2Cl2, rt; (g) Ph2POEt, toluene, reflux; (h) n-BuLi, THF, 0 °C to rt; (i) CF3COOH, CH2Cl2, 0 °C to rt.

S. Zhao et al. / Bioorg. Med. Chem. 17 (2009) 7915–7923
7917
Table 1
Characterization of the ethyl ester 6a–o
R
S
COOEt
R1
R2
N
Compound R1
R2
H
R
Yield (%) Mp (°C) 1H NMR d ppm in CDCl3
6a
6b
6c
6d
6e
6f
H
H
H
F
p-F
87
76–78
75–77
Oil
8.23 (d, 1H, J = 8.4 Hz), 7.97 (d, 1H, J = 8.8 Hz), 7.66 (t, 1H, J = 7.6 Hz), 7.43 (t, 1H, J = 7.6 Hz),
7.28–6.90 (m, 4H), 4.47 (q, 2H, J = 7.2 Hz), 2.18–2.13 (m, 1H), 1.40–1.36 (m, 5H),
1.12–1.07 (m, 2H)
8.25 (d, 1H, J = 8.4 Hz), 8.01 (d, 1H, J = 8.4 Hz), 7.66 (t, 1H, J = 8.0 Hz), 7.44 (t, 1H, J = 8.0 Hz),
7.14–6.68 (m, 4H), 4.46 (q, 2H, J = 7.2 Hz), 3.71 (s, 3H), 2.20–2.16 (m, 1H), 1.43–1.38 (m, 2H),
1.36 (t, 3H, J = 7.2 Hz), 1.13–1.08 (m, 2H)
8.29 (d, 1H, J = 8.4 Hz), 8.02 (d, 1H, J = 8.0 Hz) 7.66 (t, 1H, J = 8.4 Hz), 7.44 (t, 1H, J = 8.0 Hz),
7.19–7.06 (m, 4H), 4.43 (q, 2H, J = 7.2 Hz), 2.85–2.81 (m, 1H), 2.19–2.14 (m, 1H),
1.42–1.38 (m, 2H), 1.35 (t, 3H, J = 7.2 Hz), 1.20 (d, 6H, J = 6.8 Hz), 1.12–1.07 (m,2H)
H
H
H
H
H
m-OCH3
83
p-CH(CH3)2 83
p-F
57
87
76
53
112–114 7.93 (dd, 1H, J = 9.2, 5.6 Hz), 7.82 (dd, 1H, J = 10, 2.8 Hz), 7.41–7.37 (m, 1H), 7.25–6.89 (m, 4H),
4.45 (q, 2H, J = 7.2 Hz), 2.13–2.09 (m, 1H), 1.35 (t, 3H, J = 7.2 Hz), 1.34–1.31 (m, 2H),
1.09–1.04 (m, 2H)
116–118 7.93 (dd, 1H, J = 9.2, 5.6 Hz), 7.84 (dd, 1H, J = 10, 2.8 Hz), 7.41–7.36 (m, 1H), 7.15–6.68 (m, 4H),
4.40 (q, 2H, J = 7.2 Hz), 3.92 (s, 3H), 2.15–2.10 (m, 1H), 1.35–1.33 (m, 2H), 1.28 (t, 3H, J = 7.2 Hz),
1.08–1.03 (m, 2H)
105–107 7.93 (dd, 1H, J = 9.2, 5.6 Hz), 7.84 (dd, 1H, J = 10, 2.8 Hz), 7.42–7.37 (m, 1H), 7.13–6.74 (m, 4H),
4.44 (q, 2H, J = 7.2 Hz), 3.69 (s, 3H), 2.14–2.10 (m, 1H), 1.35–1.31 (m, 2H), 1.32 (t, 3H, J = 7.2 Hz),
1.09–1.04 (m, 2H)
114–115 7.92–7.86 (m, 2H), 7.39–7.34 (m, 1H), 7.27–6.75 (m, 4H), 4.45 (q, 2H, J = 7.2 Hz), 3.73 (s, 3H),
2.12–2.08 (m, 1H), 1.37 (t, 3H, J = 7.2 Hz), 1.33–1.29 (m, 2H), 1.07–1.02 (m, 2H)
104–106 7.92 (dd, 1H, J = 9.2, 5.6 Hz), 7.87 (dd, 1H, J = 10, 2.8 Hz), 7.40–7.36 (m, 1H), 7.16–7.05 (m, 4H),
4.42 (q, 2H, J = 7.2 Hz), 2.83–2.79 (m, 1H), 2.25–2.21 (m, 1H), 1.33 (t, 3H, J = 7.2 Hz),
1.35–1.30 (m, 2H), 1.16 (d, 6H, J = 7.2 Hz), 1.08–1.03 (m, 2H)
F
o-OCH3
m-OCH3
p-OCH3
F
6g
6h
F
F
H
H
p-CH(CH3)2 88
6i
6j
OCH3
OCH3
H
H
p-F
89
81
95–97
7.89 (d, 1H, J = 9.2 Hz), 7.46 (d, 1H, J = 2.8 Hz), 7.31–6.91 (m, 5H), 4.48 (q, 2H, J = 7.2 Hz),
3.76 (s, 3H), 2.15–2.11 (m, 1H), 1.38 (t, 3H, J = 7.2 Hz), 1.35–1.31 (m, 2H), 1.08–1.03 (m, 2H)
7.90 (d, 1H, J = 9.2 Hz), 7.49 (d, 1H, J = 2.8 Hz), 7.30 (dd, 1H, J = 9.6, 2.8 Hz), 7.15–6.69 (m, 4H),
4.48 (q, 2H, J = 7.2 Hz), 3.74 (s, 3H), 3.70 (s, 3H), 2.17–2.13 (m, 1H), 1.37 (t, 3H, J = 7.2 Hz),
1.35–1.32 (m, 2H), 1.09–1.04 (m, 2H)
m-OCH3
80–82
6k
OCH3
H
p-CH(CH3)2 73
Oil
7.89 (d, 1H, J = 8.8 Hz), 7.48 (d, 1H, J = 2.8 Hz), 7.28 (dd, 1H, J = 8.8, 2.8 Hz), 7.22–7.07 (m, 4H),
4.46 (q, 2H, J = 7.2 Hz), 3.71 (s, 3H), 2.85–2.82 (m, 1H), 2.16–2.12 (m, 1H), 1.37 (t, 3H, J = 7.2 Hz),
1.34–1.31 (m, 2H), 1.20 (d, 6H, J = 6.8 Hz), 1.07–1.03 (m, 2H)
6l
F
F
F
F
F
F
p-F
89
84
87
114–116 7.96 (dd, 1H, J = 11.6, 8.4 Hz), 7.69 (dd, 1H, J = 11.2, 8.0 Hz), 7.26–6.92 (m, 4H), 4.46 (q, 2H,
J = 7.2 Hz), 2.12–2.08 (m, 1H), 1.36 (t, 3H, J = 7.2 Hz), 1.34–1.31 (m, 2H), 1.11–1.07 (m, 2H)
115–117 7.97 (dd, 1H, J = 11.6, 8.4 Hz), 7.75 (dd, 1H, J = 11.2, 8.0 Hz), 7.16–6.70 (m, 4H),
4.44 (q, 2H, J = 7.2 Hz), 3.72 (s, 3H), 2.14–2.10 (m, 1H), 1.38–1.32 (m, 5H), 1.13–1.08 (m, 2H)
110–112 7.94 (dd, 1H, J = 11.6, 8.8 Hz), 7.59 (dd, 1H, J = 11.2, 7.6 Hz), 7.22–6.70 (m, 4H),
4.39 (q, 2H, J = 7.2 Hz),
6m
6n
m-OCH3
p-OCH3
3.68 (s, 3H), 2.05–2.01 (m, 1H), 1.32 (t, 3H, J = 7.2 Hz), 1.27–1.23 (m, 2H), 1.03–0.98 (m, 2H)
6o
F
F
p-CH(CH3)2 76
90–92
8.00 (dd, 1H, J = 11.6, 8.4 Hz), 7.67 (dd, 1H, J = 11.2, 8.0 Hz), 7.17–7.07 (m, 4H),
4.42 (q, 2H, J = 7.2 Hz), 2.85–2.81 (m, 1H), 2.13–2.08 (m, 1H), 1.36–1.30 (m, 5H),
1.19 (d, 6H, J = 7.2 Hz), 1.10–1.05 (m, 2H)
6p
6q
F
F
S-C6H4-4-F p-F
84
87
93–95
Oil
7.81 (d, 1H, J = 10.8 Hz), 7.55–6.90 (m, 9H), 4.43 (q, 2H, J = 7.2 Hz), 2.08–2.04 (m, 1H),
1.34 (t, 3H, J = 7.2 Hz), 1.25–1.21 (m, 2H), 1.04–0.99 (m, 2H)
7.83 (d, 1H, J = 10.8 Hz), 7.56 (d, 1H, J = 7.6 Hz), 7.34–6.68 (m, 8H), 4.42 (q, 2H, J = 7.2 Hz),
3.79 (s, 3H), 3.71 (s, 3H), 2.10–2.06 (m, 1H), 1.34 (t, 3H, J = 7.2 Hz), 1.27–1.22 (m, 2H),
1.04–0.99 (m, 2H)
S-C6H4-3- m-OCH3
OCH3
6r
F
S-C6H4-4- p-CH(CH3)2 82
CH(CH3)2
Oil
7.85 (d, 1H, J = 10.8 Hz), 7.47–7.06 (m, 9H), 4.39 (q, 2H, J = 7.2 Hz), 2.98–2.94 (m, 1H),
2.84–2.80 (m, 1H), 2.10–2.06 (m, 1H), 1.35–1.17 (m, 17H), 1.01–0.97 (m, 2H)
pyran-2-one (1q) were found to possess the activity comparable to
5. Conclusion
pitavastatin in HMG-CoA reductase inhibition.
A series of 2-cyclopropyl-4-thiophenyl quinoline-based meval-
onolactones was synthesized to evaluate their inhibition on HMG-
CoA reductase in vitro. It was found that substitution with a variety
of thiophenyl groups at position 4 in quinoline resulted in retention
or enhancement of the inhibition, and the preferable groups were
4-fluorothiophenyl and 3-methoxythiophenyl. Additionally, the
introduction of fluoro group at position 6 of the quinoline nucleus
moderately increased the potency. (4R,6S)-6-[(E)-2-(2-Cyclopro-
pyl-6-fluoro-4-(4-fluoro-thiophenyl)-quinoline-3-yl)-ethenyl]-3,4,
5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (1d), (4R,6S)-6-[(E)-2-
(2-cyclopropyl-6-fluoro-4-(3-methoxy-thiophenyl)-quinoline-3-yl)-
ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (1f) and
(4R,6S)-6-[(E)-2-(2-cyclopropyl-6-fluoro-4,7-di(3-methoxy-thio-
phenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-
6. Experimental
Melting points were determined on an Electrothermal Melting
Point Apparatus and were uncorrected. 1H NMR spectra were re-
corded at 400 MHz on a Varian Inova-400 spectrometer in CDCl3
or DMSO-d6 with chemical shifts (d) given in ppm relative to
TMS as an internal standard. Mass spectra were recorded by an
Q-TOF Mass Spectrometer using electrospray ionization (ESI).
6.1. Diethyl [cyclopropyl(aniline)methylene]malonate (3a)
A mixture of aniline (11.16 g, 0.12 mol), 2 (24.7 g, 0.1 mol),
anhydrous K2CO3 (33.1 g, 0.24 mol), and DMF (130 mL) was stirred

7918
S. Zhao et al. / Bioorg. Med. Chem. 17 (2009) 7915–7923
Table 2
Characterization of the ethyl ester 1a–ra
R
OH
O
S
N
R1
R2
O
½ ꢂ
a 2D5
Compound
Yield (%) Mp (°C)
MS
1H NMR d ppm in CDCl3
(M+H)+
1a
ꢁ15.7, c 1, CHCl3 61
ꢁ22.8, c 1, CHCl3 60
ꢁ25.9, c 1, CHCl3 62
150–152 436
8.32 (d, 1H, J = 8.4 Hz), 7.98 (d, 1H, J = 8.4 Hz), 7.65 (t, 1H, J = 8.0 Hz), 7.44 (t, 1H, J = 8.0 Hz), 7.10
(dd, 1H, J = 16.4, 1.6 Hz), 7.02–6.88 (m, 4H), 5.97 (dd, 1H, J = 16.0, 6.0 Hz), 5.40–5.35 (m, 1H), 4.44–
4.39 (m, 1H), 2.83–2.65 (m, 2H), 2.49–2.43 (m, 1H), 2.06–1.81 (m, 3H, changed to 2H by addition of
D2O), 1.39–1.33 (m, 2H), 1.08–1.04 (m, 2H)
8.35 (d, 1H, J = 8.4 Hz), 7.96 (d, 1H, J = 8.4 Hz), 7.65 (t, 1H, J = 8.0 Hz), 7.44 (t, 1H, J = 8.0 Hz), 7.11–
6.53 (m, 4H), 5.96 (dd, 1H, J = 16.4, 6.0), 5.36–5.32 (m, 1H), 4.34 (br, 1H), 3.71 (s, 3H), 2.81–2.61 (m,
2H), 2.50–2.45 (m, 1H), 1.97–1.77 (m, 3H, changed to 2H by addition of D2O), 1.37–1.34 (m, 2H),
1.07–1.03 (m, 2H)
8.38 (d, 1H, J = 8.4 Hz), 7.99 (d, 1H, J = 7.6 Hz), 7.65 (t, 1H, J = 8.0 Hz), 7.44 (t, 1H, J = 8.0 Hz), 7.09
(dd, 1H, J = 16.4, 1.6 Hz), 7.06–6.91 (m, 4H), 5.96 (dd, 1H, J = 16.4, 6.0 Hz), 5.36–5.30 (m, 1H), 4.36–
4.34 (m, 1H), 2.86–2.81 (m, 1H), 2.80–2.61 (m, 2H), 2.52–2.45 (m, 1H), 1.96–1.74 (m, 3H, changed
to 2H by addition of D2O), 1.38–1.34 (m, 2H), 1.20 (d, 6H, J = 6.4 Hz), 1.08–1.04 (m,2H)
7.94–7.90 (m, 2H), 7.40–7.35 (m, 1H), 7.07 (dd, 1H, J = 16.0, 2.4 Hz), 7.00–6.87 (m, 4H), 5.95 (dd, 1H,
J = 16.0, 6.0 Hz) 5.37–5.32 (m, 1H), 4.40–4.38 (m, 1H), 2.80–2.62 (m, 2H), 2.44–2.39 (m, 1H), 2.03–
1.78 (m , 3H, changed to 2H by addition of D2O), 1.31–1.25 (m, 2H), 1.04–1.00 (m, 2H)
7.94–7.90 (m, 2H), 7.39–7.34 (m, 1H), 7.11–6.38 (m, 5H), 5.92 (dd, 1H, J = 16.0, 6.0 Hz), 5.31–5.28
(m, 1H), 4.29–4.27 (m, 1H), 3.92 (s,3H), 2.77–2.55 (m, 2H), 2.46–2.41 (m, 1H), 1.95–1.73 (m, 3H,
changed to 2H by addition of D2O), 1.32–1.27 (m, 2H), 1.05–1.00 (m, 2H)
1b
1c
36–38
448
125–127 460
1d
1e
1f
+3.3, c 1, CH2Cl2
ꢁ4.9, c 1, CH2Cl2
+3.5, c 1, CH2Cl2
+2.8, c 1, CH2Cl2
68
65
70
46
152–154 454
155–157 466
50–53
466
7.96–7.90 (m, 2H), 7.40–7.35 (m, 1H), 7.10–6.49 (m, 5H), 5.94 (dd, 1H, J = 16.0, 6.0 Hz), 5.34–5.29
(m, 1H), 4.32 (br, 1H), 3.69 (s, 3H), 2.77–2.58 (m, 2H), 2.46–2.40 (m, 1H), 1.96–1.74 (m, 3H, changed
to 2H by addition of D2O), 1.31–1.24 (m, 2H), 1.04–1.00 (m, 2H)
7.98 (dd, 1H, J = 10.4, 2.8 Hz), 7.90 (dd, 1H, J = 9.2, 5.2), 7.37–7.35 (m, 1H), 7.06 (dd, 1H, J = 16.4, 1.6),
7.00–6.72 (m, 4H), 5.95 (dd, 1H, J = 16.4, 6.0 Hz), 5.36–5.32 (m, 1H), 4.39–4.36 (m, 1H), 3.74 (s, 3H),
2.81–2.65 (m, 2H), 2.44–2.39 (m, 1H), 2.04–1.84 (m, 3H, changed to 2H by addition of D2O), 1.30–
1.27 (m, 2H), 1.03–0.99 (m, 2H)
1g
106–108 466
1h
1i
ꢁ9.5, c 1, CH2Cl2
58
111–113 500
7.98–7.89 (m, 2H), 7.39–7.34 (m, 1H), 7.07–6.88 (m, 5H), 5.94 (dd, 1H, J = 16.0, 6.0), 5.32–5.28 (m,
(M+Na) 1H), 4.33–4.31 (m, 1H), 2.84–2.77 (m, 1H), 2.77–2.58 (m, 2H), 2.46–2.40 (m, 1H), 1.94–1.71 (m, 3H,
changed to 2H by addition of D2O), 1.33–1.25 (m, 2H), 1.17 (d, 1H, J = 7.2, 6H), 1.04–1.00 (m, 2H)
ꢁ26.2, c 1, CHCl3 57
ꢁ34.6, c 1, CHCl3 60
ꢁ33.6, c 1, CHCl3 63
ꢁ11.4, c 1, CHCl3 81
ꢁ22.6, c 1, CHCl3 62
131–133 466
7.88 (d, 1H, J = 8.0 Hz), 7.57 (d, 1H, J = 2.8), 7.29 (dd, 1H, J = 8.0, 2.8 Hz), 7.11 (dd, 1H, J = 16.0,
1.2 Hz), 7.05–6.86 (m, 4H), 5.97 (dd, 1H, J = 16.0, 6.0 Hz), 5.40–5.35 (m, 1H), 4.42 (br, 1H), 3.79 (s,
3H), 2.84–2.65 (m, 2H), 2.45–2.38 (m, 1H), 2.06–1.83 (m, 3H, changed to 2H by addition of D2O),
1.32–1.26 (m, 2H), 1.04–1.00 (m, 2H)
7.86 (d, 1H, J = 9.2 Hz), 7.61 (s, 1H), 7.29 (dd, 1H, J = 8.0, 2.0), 7.12–6.58 (m, 5H), 5.96 (dd, 1H,
J = 16.0, 6.0 Hz), 5.36–5.33 (m, 1H), 4.36–4.34 (m, 1H), 3.79 (s, 3H), 3.71 (s, 3H), 2.82–2.61 (m, 2H),
2.45–2.41 (m, 1H), 1.99–1.84 (m, 3H, changed to 2H by addition of D2O), 1.32–1.30 (m, 2H), 1.04–
1.00 (m,2H)
7.94 (br, 1H), 7.59 (d, 1H, J = 2.8 Hz), 7.29 (dd, 1H, J = 8.0, 2.8 Hz), 7.12–6.97 (m, 5H), 5.96 (dd, 1H,
J = 16.4, 6.0 Hz), 5.38–5.33 (m, 1H), 4.38–4.35 (m, 1H), 3.75 (s, 3H), 2.87–2.79 (m, 1H), 2.76–2.63
(m, 2H), 2.46–2.42 (m, 1H), 2.02–1.76 (m, 3H, changed to 2H by addition of D2O), 1.37–1.33 (m,
2H), 1.20 (d, 6H, J = 7.2 Hz), 1.07–1.02 (m, 2H)
8.04 (dd, 1H, J = 11.6, 8.8 Hz), 7.66 (dd, 1H, J = 10.8, 7.6 Hz), 7.00–6.88 (m, 4H), 7.04 (dd, 1H, J = 16.0,
0.9 Hz), 5.94 (dd, 1H, J = 16.4, 6.0 Hz), 5.37–5.31 (m, 1H), 4.41–4.38 (m, 1H), 2.81–2.62 (m, 2H),
2.44–2.38 (m, 1H), 2.03–1.78 (m, 3H, changed to 2H by addition of D2O), 1.30–1.24 (m, 2H), 1.05–
1.02 (m, 2H)
8.07 (dd, 1H, J = 11.6, 8.4 Hz), 7.67 (dd, 1H, J = 10.8, 7.6 Hz), 7.11–6.49 (m, 4H), 7.04 (dd, 1H, J = 16.4,
0.9 Hz), 5.93 (dd, 1H, J = 16.4, 5.6 Hz), 5.34–5.30 (m, 1H), 4.33 (br, 1H), 3.71 (s, 3H), 2.78–2.59 (m,
2H), 2.44–2.40 (m, 1H), 1.96–1.74 (m, 3H, changed to 2H by addition of D2O), 1.31–1.25 (m, 2H),
1.05–1.02 (m, 2H)
8.10 (dd, 1H, J = 11.6, 8.8 Hz), 7.65 (dd, 1H, J = 11.2, 8.0 Hz), 7.02–6.74 (m, 4H), 7.04 (d, 1H, J = 16.4),
5.94 (dd, 1H, J = 16.4, 5.6), 5.37–5.32 (m, 1H), 4.41–4.38 (m, 1H), 3.75 (s, 3H), 2.82–2.63 (m, 2H),
2.04–1.81 (m, 3H, changed to 2H by addition of D2O), 2.43–2.39 (m, 1H), 1.30–1.24 (m, 2H), 1.04–
1.00 (m, 2H)
8.09 (dd, 1H, J = 11.6, 8.4 Hz), 7.68 (dd, 1H, J = 11.2, 7.6 Hz), 7.06–6.88 (m, 5H), 5.93 (dd, 1H, J = 16.4,
5.6 Hz), 5.33–5.30 (m, 1H), 4.34–4.32 (m, 1H), 2.84–2.76 (m, 1H), 1.18 (d, 6H, J = 6.8 Hz), 2.77–2.59
(m, 2H), 1.94–1.71 (m, 3H, changed to 2H by addition of D2O), 2.45–2.41 (m, 1H), 1.33–1.29 (m,
2H), 1.06–1.02 (m, 2H)
1j
132–134 478
135–137 490
158–160 472
1k
1l
1m
1n
1o
50–53
83–85
484
484
ꢁ4.1, c 1, CHCl3
59
ꢁ12.2, c 1, CHCl3 67
132–134 496
1p
1q
1r
ꢁ2.3, c 1, CHCl3
ꢁ5.6, c 1, CHCl3
ꢁ3.5, c 1, CHCl3
68
54
60
206–208 580
122–124 604
123–125 628
7.92 (d, 1H, J = 11.2 Hz), 7.46 (d, 1H, J = 7.2 Hz), 7.55–6.88 (m, 8H), 7.03 (dd, 1H, J = 16.0, 1.2 Hz),
5.93 (dd, 1H, J = 16.4, 6.0 Hz), 5.35–5.31 (m, 1H), 4.39 (br, 1H), 2.80–2.62 (m, 2H), 2.01v1.77 (m, 3H,
changed to 2H by addition of D2O), 2.39–2.35 (m, 1H), 1.28–1.20 (m, 2H), 1.01–0.97 (m, 2H)
7.95 (d, 1H, J = 11.2 Hz), 7.63 (d, 1H, J = 7.6 Hz), 7.32–6.50 (m, 9H), 5.93 (dd, 1H, J = 16.4, 5.6 Hz),
5.31–5.28 (m, 1H), 4.32–4.30 (m, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 2.77–2.58 (m, 2H), 2.41–2.37 (m,
1H), 1.94–1.76 (m, 3H, changed to 2H by addition of D2O), 1.24–1.21 (m, 2H), 1.00–0.97 (m,2H)
7.95 (d, 1H, J = 11.2 Hz), 7.52 (d, 1H, J = 7.2 Hz), 7.47–6.88 (m, 9H), 5.92 (dd, 1H, J = 16.4, 6.0 Hz),
5.30–5.27 (m, 1H), 4.31 (br, 1H), 2.97–2.94 (m, 1H), 2.83–2.80 (m, 1H), 2.76–2.58 (m, 2H), 2.40–
2.36 (m, 1H), 1.91–1.70 (m, 3H, changed to 2H by addition of D2O), 1.30–1.17 (m, 14H), 0.99–0.95
(m, 2H)
a
The definition of R, R1 and R2 is the same as Table 1.

S. Zhao et al. / Bioorg. Med. Chem. 17 (2009) 7915–7923
7919
Table 3
line or 3,4-difluoroaniline was used instead of aniline. Some phys-
ical properties are included in Table 4.
Inhibition of HMG-CoA reductase in vitro
R
OH
O
S
6.3. Ethyl 4-chloro-2-cyclopropyl-quinoline-3-carboxylate (5a)
R1
O
R2
N
Phosphorus oxychloride (15 mL, 0.16 mol) was added to a sus-
pension of 4a (20.5 g, 0.08 mol) in acetonitrile (150 mL) and the
mixture was heated at 75 °C for 6 h. The resulting light brown solu-
tion was poured into the aqueous solution saturated with sodium
bicarbonate (300 mL); the suspension was extracted with ethyl
acetate twice. The organic extracts were washed with water, dried
over Na2SO4 and concentrated to give 5a as a lightly yellow oil
(19.4 g, 88%). 1H NMR (400 MHz, CDCl3): d 8.16 (d, 1H, J = 8.4 Hz,
ArH), 7.93 (d, 1H, J = 8.4 Hz, ArH), 7.72–7.52 (m, 2H, ArH), 4.53
(q, 2H, J = 7.2 Hz, CH2), 2.13–2.09 (m, 1H, CHCH), 1.46 (t, 3H,
J = 7.2 Hz, CH3), 1.34–1.30 (m, 2H, 2 ꢀ CHCH2), 1.07–1.02 (m, 2H,
2 ꢀ CHCH2). MS (ESI): m/z = 276, 278 (M+H)+.
Compound
R
R1
R2
IC50 (lM)
1a
1c
1d
1f
4-F
H
H
F
F
OCH3
OCH3
F
F
F
F
H
H
H
H
H
H
F
62.4
11.3
6.93
5.61
25.7
41.3
359.6
759
45.7
7.1
4-CH(CH3)2
4-F
3-OCH3
4-F
1i
1k
1m
1o
1p
1q
4-CH(CH3)2
3-OCH3
4-CH(CH3)2
4-F
F
SC6H4-4-F
SC6H4-3-OCH3
3-OCH3
Pitavastatin calcium
8.9
Compounds 5b–d were prepared in the manner analogous to
the method described above. But the 5d was purified by silica gel
chromatography (petroleum ether–ethyl acetate, 100:1); 1H NMR
(400 MHz, CDCl3): d 7.90 (dd, 1H, J = 10.8, 8.4 Hz, ArH), 7.68 (dd,
1H, J = 11.2, 7.6 Hz, ArH), 4.53 (q, 2H, J = 7.2 Hz, CH2), 2.10–2.06
(m, 1H, 2 ꢀ CHCH), 1.45 (t, 3H, J = 7.2 Hz, CH3), 1.31–1.27 (m, 2H,
2 ꢀ CHCH2), 1.09–1.04 (m, 2H, 2 ꢀ CHCH2). MS (ESI): m/z = 312,
314 (M+H)+.
at 100 °C (oil bath temperature) for 16 h. When it was cooled to
room temperature, the inorganic material was removed by filtra-
tion and washed with ethyl acetate. The resulting solution was
transferred to a separatory funnel, and ethyl acetate and water
were added. The organic layer was separated, washed with brine
(200 mL), dried over Na2SO4, and concentrated to give yellow oil
(29.64 g, 98%) which was used for the next step without further
purification. It was purified by silica gel chromatography (petro-
leum ether–ethyl acetate, 10:1) to provide 3a as an analytical sam-
ple: colorless oil; 1H NMR (400 MHz, CDCl3): d 11.08 (s, 1H, NH),
7.33–7.13 (m, 5H, ArH), 4.25–4.20 (m, 4H, 2 ꢀ CH2), 1.98–1.91
(m, 1H, CHCH), 1.32–1.29 (m, 6H, 2 ꢀ CH3), 0.72–0.67 (m, 2H,
2 ꢀ CHCH2), 0.46–0.42 (m, 2H, 2 ꢀ CHCH2).
The physical properties of 5a–d are shown in Table 5.
6.4. Ethyl 2-cyclopropyl-4-(4-fluorothiophenyl)-quinoline-3-
carboxylate (6a)
A mixture of 4-fluorothiophenol (1.13 g, 8.8 mmol), 5a (2.0 g,
7.25 mmol), anhydrous K2CO3 (1.22 g, 8.8 mmol), and DMF
(20 mL) was stirred for 20 h at room temperature. The inorganic
material was removed by filtration and washed with ethyl
acetate. The resulting mixture was transferred to a separatory
funnel, and ethyl acetate and water were added. The organic
layer was separated, washed with brine, dried over Na2SO4, and
concentrated to dryness to give an yellow solid, which was
recrystallized from n-hexane to give 6a (2.31 g, 87%) as a lightly
yellow powder: mp 76–78 °C; 1H NMR (400 MHz, CDCl3): d 8.23
(d, 1H, J = 8.4 Hz), 7.97 (d, 1H, J = 8.8 Hz), 7.66 (t, 1H, J = 7.6 Hz),
7.43 (t, 1H, J = 7.6 Hz), 7.28–6.90 (m, 4H), 4.47 (q, 2H, J = 7.2 Hz),
2.18–2.13 (m, 1H), 1.40–1.36 (m, 5H), 1.12–1.07 (m, 2H).
Compounds 6b–k were prepared in manner analogous to the
method described above. Some physical properties are included
in Table 1.
6.2. Ethyl 2-cyclopropyl-4-hydroxyquinoline-3-carboxylate (4a)
The crude 3a (29.0 g, 0.96 mol) was added to diphenyl ether
(400 mL) and heated at 220 °C for 0.5 h. After the solution cooled,
the precipitate was filtered off, washed with petroleum ether
(4 ꢀ 100 mL), and dried. The obtained solid was recrystallized from
95% ethanol to give the colorless needle-like crystals 4a (21.3 g,
87%): mp 248–250 °C. 1H NMR (400 MHz, DMSO-d6): d 10.88 (s,
1H, OH), 8.03 (d, 1H, J = 8.4 Hz, ArH), 7.69 (d, 1H, J = 8.4 Hz, ArH),
7.64 (dd, 1H, J = 6.8, 1.6 Hz, ArH), 7.32 (t, 1H, J = 7.2 Hz, ArH),
4.25 (q, 2H, J = 6.8 Hz, CH2), 2.08–2.06 (m, 1H, CHCH), 1.28 (t, 3H,
J = 7.2 Hz, CH3), 1.08–1.05 (m, 4H, 4 ꢀ CHCH2).
Compounds 4b–d were prepared in the manner analogous to
the method described above when 4-fluoroaniline, 4-methoxyani-
Table 4
Physical properties and yield of 4a–d
OH
N
R1
R3
COOEt
Compound R1
R3 Formula
Reaction
temp. (°C) (%)
Yield* Mp (°C)
1H NMR d ppm in DMSO-d6
4a
H
H
C15H15NO3
190–220
85
248–250
10.88 (s, 1H), 8.03 (d, 1H, J = 8.4 Hz), 7.69 (d, 1H, J = 8.4 Hz), 7.64 (dd, 1H, J = 6.8, 1.6 Hz),
7.32 (t, 1H, J = 7.2 Hz), 4.25 (q, 2H, J = 6.8 Hz), 2.08–2.06 (m, 1H), 1.28 (t, 3H, J = 7.2 Hz),
1.08–1.05 (m, 4H)
4b
4c
F
H
H
C15H14FNO3
C16H17NO4
200–220
170–200
83
84
279–280
256–258
10.67 (s, 1H), 7.87 (dd, 1H, J = 8.8, 2.8 Hz), 7.68 (dd, 1H, J = 9.2, 5.2 Hz), 7.31–7.25 (m, 1H),
4.36 (q, 2H, J = 7.2 Hz), 2.25–2.20 (m, 1H), 1.37 (t, 3H, J = 7.2 Hz), 1.11–1.05 (m, 4H)
10.88 (s, 1H), 7.66 (d, 1H, J = 9.2 Hz), 7.45 (d, 1H, J = 2.8 Hz), 7.29 (dd, 1H, J = 9.2, 2.8 Hz),
4.25 (q, 2H, J = 7.2 Hz), 3.83 (s, 3H), 2.10–2.06 (m, 1H), 1.28 (t, 3H, J = 7.2 Hz), 1.06–1.04 (m,
4H)
OCH3
4d
F
F
C15H13F2NO3 200–230
71
280–282
10.63 (s, 1H), 7.99 (dd, 1H, J = 10.8, 8.8 Hz), 7.53 (dd, 1H, J = 10.8, 6.8 Hz), 4.36 (q, 2H,
J = 7.2 Hz), 2.23–2.18 (m, 1H), 1.37 (t, 3H, J = 7.2 Hz), 1.10–1.06 (m, 4H)
*
The yields were calculated from 2.

7920
S. Zhao et al. / Bioorg. Med. Chem. 17 (2009) 7915–7923
6.5. Ethyl 2-cyclopropyl-6,7-difluoro-4-(4-fluorothiophenyl)
quinoline-3-carboxylate (6l)
4.81 mmol) was added. The mixture was stirred at ice bath for
4 h. After completion the reaction mixture was transferred to a
separatory funnel, then ethyl acetate and water were added. The
organic layer was separated, washed with brine, dried over Na2SO4
and concentrated to dryness. The residue was recrystallized from
n-hexane to give 6l (1.73 g, 89%) as a lightly yellow powder: mp
4-Fluorothiophenol (0.678 g, 5.29 mmol) was added to a mix-
ture of NaH (0.127 g, 5.29 mmol, 60%) in THF (15 mL) at 0 °C. The
resulting mixture was stirred for 0.5 h, and then 5d (1.5 g,
Table 5
Physical properties and yield of 5a–d
Cl
N
R1
R3
COOEt
Compound R1
R3 Formula
Yield Mp
MS
1H NMR d ppm in CDCl3
(%)
(°C)
(M+H)
5a
5b
5c
5d
H
H
H
H
F
C15H14ClNO2
89
Oil
276, 278 8.16 (d, 1H, J = 8.4 Hz), 7.93 (d, 1H, J = 8.4 Hz), 7.72–7.52 (m, 2H), 4.53 (q, 2H, J = 7.2 Hz),
2.13–2.09 (m, 1H), 1.46 (t, 3H, J = 7.2 Hz), 1.34–1.30 (m, 2H), 1.07–1.02 (m, 2H)
F
C15H13ClFNO2
C16H16ClNO3
94
86
65–67 294, 296 7.93 (dd, 1H, J = 8.8, 5.2 Hz), 7.68 (dd, 1H, J = 9.2, 2.8 Hz), 7.49–7.44 (m, 1H), 4.53 (q, 2H,
J = 7.2 Hz), 2.12–2.07 (m, 1H), 1.46 (t, 3H, J = 7.2 Hz), 1.32–1.28 (m, 2H), 1.07–1.02 (m, 2H)
85–87 306, 308 7.88 (d, 1H, J = 8.8 Hz), 7.43–7.37 (m, 2H), 4.55 (q, 2H, J = 7.2 Hz), 3.97 (s, 3H),
2.13–2.09 (m, 1H), 1.48 (t, 3H, J = 7.2 Hz), 1.32–1.28 (m, 2H), 1.06–1.01 (m, 2H)
68–70 312, 314 7.90 (dd, 1H, J = 10.8, 8.4 Hz), 7.68 (dd, 1H, J = 11.2, 7.6 Hz), 4.53 (q, 2H, J = 7.2 Hz),
2.10–2.06 (m, 1H), 1.45 (t, 3H, J = 7.2 Hz), 1.31–1.27 (m, 2H), 1.09–1.04 (m, 2H)
OCH3
F
C15H12ClF2NO2 67a
a
Purified by silica gel column chromatography (petroleum ether–ethyl acetate, 100:1).
Table 6
Physical properties and yield of 2-cyclopropyl-4-substituted-thiophenyl-quinoline-3-methanol (7a–r)a
R
S
CH2OH
R1
R2
N
Compound Formula
Yield (%) Mp (°C)
1H NMR d ppm in CDCl3
7a
7b
7c
C19H16FNOS
98
90
88
137–139 8.35 (d, 1H, J = 8.4 Hz), 8.09 (d, 1H, J = 8.4 Hz), 7.67 (t, 1H, J = 8.0 Hz), 7.47 (t, 1H, J = 8.0 Hz), 7.11–6.90 (m, 4H),
5.36 (s, 2H), 2.66–2.60 (m, 1H), 1.84 (s, 1H), 1.44–1.42 (m, 2H), 1.18–1.13 (m, 2H)
C20H19NO3
C22H23NOS
154–156 8.38 (d, 1H, J = 8.4 Hz), 8.01 (d, 1H, J = 8.4 Hz), 7.66 (t, 1H, J = 8.0 Hz), 7.46 (t, 1H, J = 8.0 Hz), 7.13–6.60 (m, 4H),
5.34 (d, 2H, J = 6.4 Hz), 3.70 (s, 1H), 2.66–2.60 (m, 1H), 1.83 (br, 1H), 1.42–1.38 (m, 2H), 1.16–1.11 (m, 2H)
108–110 8.43 (d, 1H, J = 8.4 Hz), 8.01 (d, 1H, J = 7.6 Hz), 7.66 (t, 1H, J = 8.0 Hz), 7.46 (t, 1H, J = 8.0 Hz), 7.09–7.01 (m, 4H),
5.34 (d, 2H, J = 6.4 Hz), 2.87–2.81 (m, 1H), 1.74 (br, 1H), 2.65–2.59 (m, 1H), 1.40–1.39 (m, 2H), 1.23 (d, 6H,
J = 6.8 Hz), 1.14–1.10 (m, 2H)
7d
7e
7f
C19H15F2NOS
94
64
92
81
82
97
89
87
150–152 7.96–7.92 (m, 2H), 7.41–7.36 (m, 1H), 7.08–6.88 (m, 4H), 5.32 (d, 2H, J = 6.4 Hz), 2.59–2.54 (m, 1H), 1.81 (t, 1H,
J = 6.4 Hz), 1.34–1.30 (m, 2H), 1.11–1.07 (m, 2H)
168–170 7.96–7.92 (m, 2H), 7.39–7.34 (m, 1H), 7.15–6.54 (m, 4H), 5.29 (d, 2H, J = 6.4 Hz), 3.89 (s, 3H), 2.62–2.57 (m, 1H),
1.98 (t, 1H, J = 6.4 Hz), 1.34–1.30 (m, 2H), 1.11–1.06 (m, 2H)
170–172 7.99-7.92 (m, 2H), 7.41–7.36 (m, 1H), 7.12–6.57 (m, 4H), 5.30 (d, 2H, J = 6.4 Hz), 3.69 (s, 3H), 2.59–2.56 (m, 1H),
1.82 (br, 1H), 1.34–1.30 (m, 2H), 1.11–1.06 (m, 2H)
128–130 8.04 (dd, 1H, J = 10.4, 2.8 Hz), 7.92 (dd, 1H, J = 9.2, 5.6 Hz), 7.40–7.35 (m, 1H), 7.11–6.74 (m, 4H), 5.32 (d, 2H,
J = 6.4 Hz), 3.73 (s, 3H), 2.59–2.53 (m, 1H), 1.74 (t, 1H, J = 6.4 Hz), 1.32–1.28 (m, 2H), 1.09–1.05 (m, 2H)
132–134 8.04–7.92 (m, 2H), 7.41–7.37 (m, 1H), 7.08–6.99 (m, 4H), 5.31 (s, 2H), 2.84–2.80 (m, 1H), 2.58 (br, 1H), 1.72 (br,
1H), 1.32 (br, 2H), 1.17 (d, 6H, J = 6.4 Hz), 1.10–1.08 (m, 2H)
C
20H18FNO2S
C20H18FNO2S
C20H18FNO2S
C22H22FNOS
7g
7h
7i
C
20H18FNO2S
116–118 7.88 (d, 1H, J = 9.2 Hz), 7.59 (d, 1H, J = 2.8 Hz), 7.29 (d, 1H, J = 9.2 Hz), 7.12–6.90 (m, 4H), 5.35 (s, 2H), 3.79 (s, 3H),
2.61–2.54 (m, 1H), 1.94 (br, 1H), 1.36–1.32 (m, 2H), 1.12–1.08 (m, 2H)
7j
C21H21NO3S
C23H25NO2S
97–99
7.91 (d, 1H, J = 8.4 Hz), 7.63 (d, 1H, J = 2.8 Hz), 7.29 (d, 1H, J = 9.2 Hz), 7.14–6.64 (m, 4H), 5.33 (d, 2H,J = 6.0 Hz),
3.79 (s, 3H), 3.70 (s, 3H), 2.55–2.51 (m, 1H), 1.88 (br, 1H), 1.35–1.32 (m, 2H), 1.11–1.07 (m, 2H)
7k
105–107 7.88 (d, 1H, J = 9.2 Hz), 7.65 (d, 1H, J = 2.4 Hz), 7.28 (d, 1H, J = 9.2 Hz), 7.09–7.04 (m, 4H), 5.33 (d, 2H, J = 6.0 Hz),
3.78 (s, 3H), 2.87–2.80 (m, 1H), 2.55–2.55 (m, 1H), 1.83 (br, 1H), 1.34 (br, 2H), 1.20 (d, 6H, J = 7.2 Hz), 1.12–1.07
(m, 2H)
7l
C19H14F3NOS
98
117–119 8.08 (dd, 1H, J = 11.8, 8.6 Hz), 7.74 (dd, 1H, J = 11.2, 8.0 Hz), 7.08–6.90 (m, 4H), 5.31 (s, 2H), 1.81 (br, 1H), 2.60–
2.54 (m, 1H), 1.36–1.32 (m, 2H), 1.14–1.10 (m, 2H)
7m
7n
7o
7p
7q
7r
C20H17F2NO2S 94
C20H17F2NO2S 59
144–146 8.09 (dd, 1H, J = 11.6, 8.8 Hz), 7.71 (dd, 1H, J = 10.8, 7.6 Hz), 7.13–6.56 (m, 4H), 5.28 (s, 2H), 3.70 (s, 3H), 2.60–2.56
(m, 1H), 1.76 (br, 1H), 1.35–1.31 (m, 2H), 1.13–1.08 (m, 2H)
118–119 8.16 (dd, 1H, J = 12.0, 8.8 Hz), 7.66 (dd, 1H, J = 11.2, 8.0 Hz), 7.10–6.75 (m, 4H), 5.31 (d, 2H, J = 6.4 Hz), 3.74 (s, 3H),
2.57–2.53 (m, 1H), 1.72 (t, 1H, J = 6.4 Hz), 1.32–1.27 (m, 2H), 1.10–1.06 (m, 2H)
C22H21F2NOS
25H18F3NOS2 82
C27H24FNO3S2 82
C31H32FNOS2 92
81
90–92
8.16 (dd, 1H, J = 11.4, 9.0 Hz), 7.70 (dd, 1H, J = 10.8, 7.6 Hz), 7.28–7.00 (m, 4H), 5.31 (s, 2H), 2.86–2.82 (m, 1H),
2.60–2.57 (m, 1H), 1.72 (s, 1H), 1.34–1.28 (m, 2H), 1.20 (d, 6H, J = 7.2 Hz), 1.13–1.10 (m, 2H)
C
143–145 7.93 (d, 1H, J = 10.8 Hz), 7.55–6.89 (m, 8H), 7.45 (d, 1H, J = 7.2 Hz), 5.28 (s, 2H), 2.55–2.51 (m, 1H), 1. 85 (s, 1H),
1.25–1.21 (m, 2H), 1.07–1.02 (m, 2H)
141–143 7.97 (d, 1H, J = 10.8 Hz), 7.63 (d, 1H, J = 7.2 Hz), 7.33–6.57 (m, 8H), 5.26 (d,2H, J = 6.4 Hz), 3.79 (s, 3H), 3.70 (s, 3H),
2.56–2.52 (m,1H), 1.75 (t, 1H, J = 6.4 Hz), 1.27–1.23 (m, 2H), 1.07–1.02 (m, 2H)
102–104 8.00 (d, 1H, J = 10.8 Hz), 7.53 (d, 1H, J = 7.6 Hz), 7.48–6.98 (m, 8H), 5.26 (d, 2H, J = 4.8 Hz), 2.98–2.94 (m, 1H),
2.84–2.80 (m, 1H), 2.55–2.50 (m, 1H), 1.68 (br, 1H), 1.31–1.16 (m, 14H), 1.05–1.01 (m, 2H)
a
The definition of R, R1 and R2 is the same as Table 1.

S. Zhao et al. / Bioorg. Med. Chem. 17 (2009) 7915–7923
7921
114–116 °C; 1H NMR (400 MHz, CDCl3): d 7.96 (dd, 1H, J = 11.6,
8.4 Hz), 7.69 (dd, 1H, J = 11.2, 8.0 Hz), 7.26–6.92 (m, 4H), 4.46 (q,
2H, J = 7.2 Hz), 2.12–2.08 (m, 1H), 1.36 (t, 3H, J = 7.2 Hz), 1.34–
1.31 (m, 2H), 1.11–1.07 (m, 2H).
Table 7
Physical properties and yield of yield of 2-cyclopropyl-4-substituted-thiophenyl-3-
bromomethyl (or 3-diphenyl-oxo-phosphonyl-methyl)-quinolines (8a–r or 9a–r)a
R
Compounds 6m–o were prepared in the manner analogous to
the method described above. Some physical properties are in-
cluded in Table 1.
S
8a-r
9a-r
: X=Br
: X=POPh2
CH2X
R1
R2
N
Compound
Formula
Yield (%)
Mp (°C)
6.6. Ethyl 2-cyclopropyl-6-fluoro-4,7-di(4-fluorothiophenyl)
quinoline-3-carboxylate (6p)
8a
8b
8c
8d
8e
8f
8g
8h
8i
C19H15BrFNS
C20H18BrNOS
93
93
97
97
81
91
91
98
93
97
96
93
93
94
83
91
79
96
82
95
81
91
94
93
84
88
91
96
88
91
86
88
87
89
93
85
128–130
131–133
Oil
C
22H22BrNS
A mixture of 4-fluorothiophenol (1.30 g, 10.1 mmol), 5d (1.5 g,
4.81 mmol), anhydrous K2CO3 (1.39 g, 10.1 mmol), and DMF
(15 mL) was stirred at 50 °C for 20 h. When it was cooled to room
temperature, the inorganic material was removed by filtration and
washed with ethyl acetate. The resulting mixture was transferred
to a separatory funnel, and ethyl acetate and water were added.
The organic layer was separated, washed with brine, dried over
Na2SO4, and concentrated to dryness. The residue was purified by
silica gel column chromatography (petroleum ether–ethyl acetate,
60:1) to provide 6p (2.06 g, 84%) as a yellow solid: mp 93–95 °C; 1H
NMR (400 MHz, CDCl3): d 7.81 (d, 1H, J = 10.8 Hz), 7.55–6.90 (m,
9H), 4.43 (q, 2H, J = 7.2 Hz), 2.08–2.04 (m, 1H), 1.34 (t, 3H,
J = 7.2 Hz), 1.25–1.21 (m, 2H), 1.04–0.99 (m, 2H).
C19H14BrF2NS
C20H17BrFNOS
C20H17BrFNOS
C20H17BrFNOS
C22H21BrFNS
C20H17BrFNOS
C21H20BrNO2S
146–148
174–176
102–104
135–137
116–118
122–124
122–124
Oil
105–107
99–101
129–131
97–99
152–154
103–105
137–139
215–217
238–240
217–219
244–246
204–206
240–242
259–261
253–255
236–238
201–202
243–245
266–267
239–241
277–279
267–269
251–253
226–228
276–278
8j
8k
8l
C23H24BrNOS
C19H13BrF3NS
C20H16BrF2NOS
C20H16BrF2NOS
C22H20BrF2NS
C25H17BrF3NS2
C27H23BrFNO2S2
C31H31BrFNS2
C31H25FNOPS
C32H28NO2PS
C34H32NOPS
C31H24F2NOPS
C32H27FNO2PS
C32H27FNO2PS
C32H27FNO2PS
C34H31FNOPS
8m
8n
8o
8p
8q
8r
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
Compounds 6q and 6r were prepared in the manner analogous
to the method described above. Some physical properties are in-
cluded in Table 1.
6.7. 2-Cyclopropyl-4-(4-fluorothiophenyl)quinoline-3-methanol
(7a)
C
32H27FNO2PS
To a solution of 6a (2.0 g, 5.44 mmol) in toluene (5 mL), at 0 °C
under an atmosphere of nitrogen, was added DIBAL-H (13.6 mL,
13.6 mmol, 1 mol/L) in toluene. The resulting solution was stirred
for 2 h at ice bath before quenching with 6 M HCl. The mixture
was added to EtOAc and the organic layer was separated, washed
with water, dried over Na2SO4 and concentrated to give the title
compound as a white solid 7a (1.73 g, 98%), mp: 137–139 °C; 1H
NMR (400 MHz, CDCl3): d 8.35 (d, 1H, J = 8.4 Hz), 8.09 (d, 1H,
J = 8.4 Hz), 7.67 (t, 1H, J = 8.0 Hz), 7.47 (t, 1H, J = 8.0 Hz),
7.11–6.90 (m, 4H), 5.36 (s, 2H), 2.66–2.60 (m, 1H), 1.84 (s, 1H,
disappeared by addition of D2O), 1.44–1.42 (m, 2H), 1.18–1.13
(m, 2H).
C33H30NO3PS
C35H34NO2PS
C31H23F3NOPS
C32H26F2NO2PS
C32H26F2NO2PS
C34H30F2NOPS
9m
9n
9o
9p
9q
9r
C
37H27F3NOPS2
C39H33FNO3PS2
C43H41FNOPS2
a
The definition of R, R1 and R2 is the same as Table 1.
Compounds 7b–r were prepared in the manner analogous to
the method described above. Some physical properties are in-
cluded in Table 6.
fluxed for 2 h during which time the precipitated solid
developed. After cooling to room temperature, the solid was iso-
lated by filtration and washed with petroleum ether. The product
was then dried to afford the title compound (1.84 g, 82%), mp:
215–217 °C.
Compounds 9b–r were prepared in the manner analogous to
the method described above. Some physical properties are in-
cluded in Table 7.
6.8. 2-Cyclopropyl-4-(4-fluorothiophenyl)-3-bromomethyl-
quinoline (8a)
A solution of PBr3 (0.95 mL, 10.1 mmol) in CH2Cl2 (6 mL) was
added to the mixture of 7a (1.65 g, 5.07 mmol) in CH2Cl2 (10 mL)
at 0 °C. The resulting mixture was stirred for 3 h at room temper-
ature before quenching with saturated aqueous NaHCO3 solution
to pH 8. The mixture was added to CH2Cl2 and the organic layer
was separated, washed with water, dried over Na2SO4, concen-
trated to give the title compound as an off-white solid (1.83 g,
93%), mp: 128–130 °C.
6.10. tert-Butyl (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorothi-
ophenyl)-quinoline-3-yl]-3,5-O-isoproylidene-6-heptenoate
(11a)
A hexane solution of n-BuLi (1.6 mL, 4.29 mmol, 2.7 M) was
added to a solution 9a (1.82 g, 3.57 mmol) in anhydrous THF
(50 mL) at 0 °C and stirred for 0.5 h under an atmosphere of nitro-
gen. 10 (1.11 g, 4.29 mmol) in anhydrous THF (5 mL) was added to
the solution and stirred for 10 h at room temperature, and then
quenched with 2 M HCl solution at 0 °C. The resulting mixture
was added to EtOAc and the organic layer was separated, washed
with brine, dried over Na2SO4, concentrated to dryness. The residue
was purified by silica gel column chromatography (petroleum
ether–ethyl acetate, 20:1) to give 11a (0.98 g, 50%) as a lightly yel-
Compounds 8b–r were prepared in the manner analogous to
the method described above. Some physical properties are in-
cluded in Table 7.
6.9. 2-Cyclopropyl-4-(4-fluorothiophenyl)-3-(diphenyl-oxo-phos-
phonyl-methyl)-quinoline (9a)
A
solution of 8a (1.70 g, 4.38 mmol) and ethyl diph-
enylphosphinite (1.2 mL, 5.69 mmol) in toluene (20 mL) was re-

7922
S. Zhao et al. / Bioorg. Med. Chem. 17 (2009) 7915–7923
low powder: mp 103–105 °C; ½a D25
ꢂ
= +8.9 (c 1, CHCl3); 1H NMR
d 8.36 (d, 1H, J = 8.4 Hz), 7.96 (d, 1H,
6.11. (4R,6S)-6-[(E)-2-[2-Cyclopropyl-4-(4-fluorothiophenyl)-
quinoline-3-yl]-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-
pyran-2-one (1a)
(400 MHz, CDCl3):
J = 8.8 Hz), 7.63 (t, 1H, J = 7.6 Hz), 7.44 (t, 1H, J = 7.6 Hz), 7.05–
6.86 (m, 5H), 5.91 (dd, 1H, J = 16.4, 5.6 Hz), 4.57–4.53 (m, 1H),
4.36–4.32 (m, 1H), 2.52–2.31 (m, 3H), 1.63–1.02 (m, 21H).
Compounds 11b–r were prepared in the manner analogous to
the method described above. Their physical properties are included
in Table 8.
A solution of 11a (0.95 g, 1.73 mmol) and CF3COOH (2.6 mL,
34.6 mmol) in CH2Cl2 (13 mL) was stirred at 0 °C for 2 h before
quenching with a saturated aqueous NaHCO3 solution. The mixture
was added to EtOAc and the organic layer was separated, washed
Table 8
Physical properties and yield of yield of (3R,5S, 6E)-tert-butyl-7-(2-cyclopropyl-4-substituted-thiophenyl-quinoline-3-yl)-3,5-dihydroxy-3,5-O-isoproylidene-6-heptenoates
(11a–r)a
R
H3C CH3
S
N
O O
R1
R2
COOt-Bu
1H NMR d ppm in CDCl3
½ ꢂ
a 2D5
Compound
Formula
Yield
(%)
Mp
(°C)
11a
C32H36FNO4S
+8.9, c 1, CHCl3
+7.0, c 1, CHCl3
+1.5, c 1, CHCl3
+11.4, c 1, CH2Cl2
+4.1, c 1, CH2Cl2
+13.0, c 1, CH2Cl2
+14.1, c 1, CH2Cl2
+10.5, c 1, CH2Cl2
+8.9, c 1, CHCl3
+1.6, c 1, CHCl3
+1.0, c 1, CHCl3
+10.8, c 1, CHCl3
+5.8, c 1, CHCl3
+7.7, c 1, CHCl3
ꢁ4.0, c 1, CHCl3
50
25
64
47
29
17
23
31
55
58
69
75
31
34
54
103–105
35–36
40– 42
Oil
8.36 (d, 1H, J = 8.4 Hz), 7.96 (d, 1H, J = 8.8 Hz), 7.63 (t, 1H, J = 7.6 Hz), 7.44 (t, 1H,
J = 7.6 Hz), 7.05–6.86 (m, 5H), 5.91 (dd, 1H, J = 16.4, 5.6 Hz), 4.57–4.53 (m, 1H), 4.36–
4.32 (m, 1H), 2.52–2.31 (m, 3H), 1.63–1.02 (m, 21H)
8.34 (d, 1H, J = 8.4 Hz), 7.96 (d, 1H, J = 8.0 Hz), 7.62 (t, 1H, J = 7.6 Hz), 7.42 (t, 1H,
J = 7.6 Hz), 7.10–6.57 (m, 5H), 5.94 (dd, 1H, J = 16.4, 5.6 Hz), 4.57–4.52 (m, 1H), 4.34–
4.31 (m, 1H), 3.69 (s, 3H), 2.54–2.29 (m, 3H), 1.62–1.03 (m, 21H)
8.38 (d, 1H, J = 8.4 Hz), 7.96 (br, 1H), 7.62 (t, 1H, J = 7.6 Hz), 7.42 (t, 1H, J = 7.6 Hz),
7.05– 6.95 (m, 5H), 5.92 (dd, 1H, J = 16.4, 5.6 Hz), 4.56–4.52 (m, 1H), 4.36–4.32 (m,
1H), 2.85–2.81 (m, 1H), 2.54–2.29 (m, 3H), 1.64–1.03 (m, 27H)
7.96 (dd, 1H, J = 10.4, 2.8 Hz), 7.90 (dd, 1H, J = 9.2, 5.6 Hz), 7.38–7.33 (m, 1H), 7.02–
6.85 (m, 5H), 5.90 (dd, 1H, J = 16.4, 5.2 Hz), 4.54–4.50 (m, 1H), 4.33–4.29 (m, 1H),
2.47–2.27 (m, 3H), 1.64–0.99 (m, 21H)
7.93 (dd, 1H, J = 10.4, 2.8 Hz), 7.89 (dd, 1H, J = 9.2,5.6 Hz), 7.36–7.31 (m, 1H), 7.10–
6.43 (m, 5H), 5.91 (dd, 1H, J = 16.4, 5.2 Hz), 4.53–4.48 (m, 1H), 4.29–4.24 (m, 1H),
3.89 (s, 3H), 2.51–2.24 (m, 3H), 1.54–0.98 (m, 21H)
7.94 (dd, 1H, J = 10.4, 2.8 Hz), 7.90 (dd, 1H, J = 9.2, 5.2 Hz), 7.37–7.32 (m, 1H), 7.08–
6.54 (m, 5H), 5.92 (dd, 1H, J = 16.4, 5.2 Hz), 4.54–4.49 (m, 1H), 4.31–4.28 (m, 1), 3.67
(s, 3H), 2.49–2.26 (m, 3H), 1.60–0.98 (m, 21H)
8.01 (dd, J = 10.4, 2.8 Hz), 7.88 (dd, 1H, J = 9.2,5.6 Hz), 7.36–7.31 (m, 1H), 7.03–6.71
(m, 5H), 5.91 (dd, 1H, J = 16.4, 5.2 Hz), 4.56–4.52 (m, 1H), 4.33–4.29 (m, 1H), 3.73 (s,
3H), 2.47–2.28 (m, 3H), 1.66–0.86 (m, 21H)
7.98 (dd, 1H, J = 10.4, 2.8 Hz), 7.89 (dd, 1H, J = 9.2, 5.6 Hz), 7.36–7.32 (m, 1H), 7.03–
6.84 (m, 5H), 5.91 (dd, 1H, J = 16.4, 5.2 Hz), 4.54–4.50 (m, 1H), 4.34–4.28 (m, 1H),
2.84–2.77 (m, 1H), 2.50–2.27 (m, 3H), 1.62–0.96 (m, 27H)
7.86 (d, 1H, J = 8.4 Hz), 7.61 (d, 1H, J = 2.8 Hz), 7.28 (dd, 1H, J = 8.4, 2.8 Hz), 7.07–6.87
(m, 5H), 5.92 (dd, 1H, J = 16.4, 5.6 Hz), 4.58–4.54 (m, 1H), 4.36–4.33 (m, 1H), 3.80 (s,
3H), 2.51–2.31 (m, 3H), 1.67–0.99 (m, 21H)
7.85 (br, 1H), 7.60 (d, 1H, J = 2.8 Hz), 7.26 (dd, J = 9.2, 3.2), 7.11–6.59 (m, 5H), 5.94
(dd, 1H, J = 16.4, 5.2), 4.58–4.54 (m, 1H), 4.34–4.32 (m, 1H), 3.77 (s, 3H), 3.68 (s, 3H),
2.49–2.29 (m, 3H), 1.64–0.99 (m, 21H)
7.84 (br, 1H), 7.60 (d, 1H, J = 2.8 Hz), 7.25 (dd, 1H, J = 9.2, 2.8 Hz), 7.04–6.99 (m, 5H),
5.93 (dd, 1H, J = 16.4, 5.2 Hz), 4.58–4.54 (m, 1H), 4.35–4.31 (m, 1H), 3.75 (s, 3H),
2.85–2.80 (m, 1H), 2.49–2.30 (m, 3H), 1.66–1.00 (m, 27H)
8.08 (dd, 1H, J = 11.6, 8.4 Hz), 7.65 (dd, 1H, J = 10.8, 7.6 Hz), 7.02–6.86 (m, 5H), 5.87
(dd, 1H, J = 16.4, 5.2 Hz), 4.52–4.49 (m, 1H), 4.32–4.29 (m, 1H), 2.47–2.27 (m, 3H),
1.62–0.99 (m, 21H)
8.06 (dd, 1H, J = 12.0, 8.8 Hz), 7.67 (dd, 1H, J = 11.2, 7.6 Hz), 7.10–6.52 (m, 5H), 5.90
(dd, 1H, J = 16.4, 5.2 Hz), 4.54–4.48 (m, 1H), 4.31–4.26 (m, 1H), 3.67 (s, 3H), 2.48–2.25
(m, 3H), 1.59–1.01 (m, 21H)
8.13 (dd, 1H, J = 12.0, 8.8 Hz), 7.65 (dd, 1H, J = 11.2, 7.6 Hz), 7.04–6.72 (m, 5H), 5.89
(dd, 1H, J = 16.4, 5.2 Hz), 4.56–4.52 (m, 1H), 4.34–4.30 (m, 1H), 3.73 (s, 3H), 2.48–2.29
(m, 3H), 1.66–0.99 (m, 21H)
8.10 (dd, 1H, J = 12.0, 8.4 Hz), 7.64 (dd, 1H, J = 10.8, 7.6 Hz), 7.05–6.91 (m, 5H), 5.90
(dd, 1H, J = 16.0, 5.2 Hz), 4.54–4.50 (m, 1H), 4.33–4.29 (m, 1H), 2.84–2.80 (m, 1H),
2.48–2.70 (m, 3H), 1.63–1.00 (m, 27H)
11b
11c
11d
11e
11f
C33H39NO5S
C35H43NO4S
C32H35F2NO4S
C33H38FNO5S
C33H38FNO5S
C33H38FNO5S
C35H42FNO4S
C33H38FNO5S
C34H41NO6S
C36H45NO5S
C32H34F3NO4S
C33H37F2NO5S
C33H37F2NO5S
C35H41F2NO4S
Oil
Oil
11g
11h
11i
Oil
Oil
47–49
Oil
11j
11k
11l
50–51
107–109
94–96
132–134
119–121
11m
11n
11o
11p
11q
C38H38F3NO4S2
C40H44FNO6S2
+7.1, c 1, CHCl3
+11.2, c 1, CHCl3
24
13
120–122
Oil
7.96 (d, 1H, J = 10.8 Hz), 7.54–6.85 (m, 10H), 5.88 (dd, 1H, J = 16.4, 5.6 Hz), 4.52–4.48
(m, 1H), 4.32–4.28 (m, 1H), 2.47–2.27 (m, 3H), 1.62–0.95 (m, 21H)
7.95 (d, 1H, J = 11.2 Hz), 7.65 (d, 1H, J = 7.2 Hz), 7.31–6.53 (m, 9H), 5.91 (dd, 1H,
J = 16.4, 5.2 Hz), 4.53–4.48 (m, 1H), 4.30–4.27 (m, 1H), 3.79 (s, 3H), 3.69 (s, 3H), 2.45–
2.25 (m, 3H), 1.59–0.96 (m, 21H)
11r
C44H52FNO4S2
+17.5, c 1.2, CHCl3
26
Oil
7.92 (d, 1H, J = 11.6 Hz), 7.49–6.97 (m, 9H), 6.88 (d, 1H, J = 16.4 Hz), 5.87 (dd, 1H,
J = 16.0, 5.2 Hz), 4.62–4.59 (m, 1H), 4.27–4.24 (m, 1H), 2.98–2.95 (m, 1H), 2.82–2.79
(m, 1H), 2.41–2.20 (m, 3H), 1.61–0.95 (m, 33H)
a
The definition of R, R1 and R2 is the same as Table 1.

S. Zhao et al. / Bioorg. Med. Chem. 17 (2009) 7915–7923
7923
with water, dried over Na2SO4, concentrated to dryness. The resi-
due was purified by silica gel column chromatography (petroleum
ether–ethyl acetate, 1:1) to give 1a (0.46 g, 61%) as a lightly yellow
The solution obtained was added to the assay system at multicon-
centration levels. The enzymatic reaction was initiated by addition
of HMG-CoA. After the solution was incubated for 30 min at 37 °C,
the reaction was terminated and the rate of decreased absorbance
at 340 nm was measured.
powder: mp 150–152 °C; ½a D25
ꢂ
=ꢁ15.7 (c 1, CHCl3); 1H NMR
(400 MHz, CDCl3):
d 8.32 (d, 1H, J = 8.4 Hz), 7.98 (d, 1H,
J = 8.4 Hz), 7.65 (t, 1H, J = 8.0 Hz), 7.44 (t, 1H, J = 8.0 Hz), 7.10 (dd,
1H, J = 16.4, 1.6 Hz), 7.02–6.88 (m, 4H), 5.97 (dd, 1H, J = 16.0,
6.0 Hz), 5.40–5.35 (m, 1H), 4.44–4.39 (m, 1H), 2.83–2.65 (m, 2H),
2.49–2.43 (m, 1H), 2.06–1.81 (m, 3H, changed to 2H by addition
of D2O), 1.39–1.33 (m, 2H), 1.08–1.04 (m, 2H).
Acknowledgments
The work was supported by ‘‘New Drug Innovation
2009X09301-007” by Ministry of Science and Technology of China.
The other 3,5-dihydroxy-3,5-O-isopropylidene-6-heptenoates
were converted to the corresponding pyran-2-ones in the
similar method. The physical properties of 1a–r are shown in
Table 2.
References and notes
1. (a) Watanabe, M.; Koike, H.; Ishiba, T.; Okade, T.; Seo, S.; Hiri, K. Bioorg. Med.
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Sekerke, C.; Unangst, P. C.; Trivedi, B. K. Bioorg. Med. Chem. 2007, 15, 5576.
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H.; Tushima, M.; Sasaki, J.; Ogawa, N.; Goto, Y. Atherosclerosis 2002, 162, 373.
3. (a) Sliskovic, D. R.; Picard, J. A.; Roark, W. H.; Roth, B. D.; Ferguson, E.; Krause, B.
R.; Newton, R. S.; Sekerke, C.; Shaw, M. K. J. Med. Chem. 1991, 34, 367; (b) Suzuki,
M.; Iwasaki, H.; Fujikawa, Y.; Sakashita, M.; Kitahara, M.; Sakoda, R. Bioorg. Med.
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6.12. HMG-CoA reductase inhibition assay in vitro
The HMG-CoA reductase inhibitory activity was assayed spec-
trophotometrically, following the method of Kleinsek et al.7 where-
by the rate of decrease in absorbance at 340 nm due to the
oxidation of NADPH was measured. The standard assay mixture
contained 0.1 mM HMG-CoA, 0.2 mM NADPH, 0.2 mM KCl, 4 mM
EDTA, 10 mM dithiothreitol, and 160 mM potassium phosphate
buffer (pH 7.0) in a total volume of 140
lL.
The reaction mixture containing the enzyme (100–150
lL) and
7. Kleinsek, D. A.; Dugan, R. E.; Baker, T. A.; Porter, J. W. Methods Enzymol. 1981, 71,
462.
8. (a) Kuroda, M.; Endo, A. Biochem. Biophys. Acta 1977, 486, 70; (b) Kleinsek, D. A.;
Ranfanathan, S.; Porter, J. W. Proc. Natl. Acad. Sci. 1977, 74, 1431; (c) Heller, R. A.;
Shrewsbury, M. A. J. Biol. Chem. 1976, 251, 3815; (d) Kim, H.-J.; Lee, D.-H.;
Hwang, Y.-Y.; Lee, K.-S.; Lee, J.-S. J. Agric. Food. Chem. 2005, 53, 5882.
all components except HMG-CoA were prior monitored to detect
any HMG-CoA independent oxidation of NADPH.
Before bioassay, the test compounds were dissolved in 0.1 mol/
L NaOH/THF (1/1) (during the process, the lactone was hydrolyzed
into the sodium salt of dihydroxy acid) and diluted with the buffer.