Syntheses of tetrahydrothiophenes and tetrahydrofurans and studies of their derivatives as melanocortin-4 receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2007.11.128

Piperazinebenzylamine derivatives from trans-4-(4-chlorophenyl)tetrahydrothiophene-3-carboxylic acid 6 and its S-oxide 7 and sulfone 8, and the tetrahydrofuran 9 and its two regioisomers 11 and 13 were synthesized and studied for their binding affinities at the human melanocortin-4 receptor. These five-membered ring constrained compounds possessed similar or lower potency compared to the acyclic analogs.

Full text of DOI:10.1016/j.bmcl.2007.11.128

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 1124–1130
Syntheses of tetrahydrothiophenes and tetrahydrofurans and
studies of their derivatives as melanocortin-4 receptor ligands
Joe A. Tran,a Caroline W. Chen,a Fabio C. Tucci,a,
Wanlong Jiang,a Beth A. Fleckb and Chen Chena,*
aDepartment of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA
bDepartment of Pharmacology, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA
Received 25 October 2007; revised 28 November 2007; accepted 30 November 2007
Available online 5 December 2007
Abstract—Piperazinebenzylamine derivatives from trans-4-(4-chlorophenyl)tetrahydrothiophene-3-carboxylic acid 6 and its S-oxide
7 and sulfone 8, and the tetrahydrofuran 9 and its two regioisomers 11 and 13 were synthesized and studied for their binding affin-
ities at the human melanocortin-4 receptor. These five-membered ring constrained compounds possessed similar or lower potency
compared to the acyclic analogs.
Ó 2007 Elsevier Ltd. All rights reserved.
The melanocortin-4 receptor (MC4R) is a member of
the G-protein-coupled receptor (GPCR) superfamily
and plays an important role in regulating feeding behav-
ior.1 While MC4R agonists are pursued for reducing
body weight,2 MC4R antagonists are able to reverse
lean body mass loss as well as food intake reduction in
animal models,3 indicating the potential utility in the
treatment of cancer cachexia.4,5
methyl group. We speculate that in the low-energy con-
formations of 1–4, the ‘correct’ positioning of the 4-
chlorophenyl ring relative to the benzylamine moiety is
critical for the interaction of these molecules with the
receptor, and a small group such as methyl at the a-po-
sition of the propionyl moiety contributes to the orienta-
tion of this 4-chlorophenyl functionality.
To further explore and understand the structure–activity
relationship (SAR) of these compounds, we cyclized the
a-position of the 4-chlorophenylpropionyl group of 1 to
the adjacent benzylic carbon by a five-membered ring,
and this eliminated the flexibility of the carbon–carbon
bond between the benzylic and a-carbon and limited
the free rotation of 4-chlorophenyl functionality. Based
on the X-ray crystal structure of the MC4R agonist 5a
(Fig. 1), the 4-chlorophenyl ring is almost parallel to
the piperidine plane in the solid state.7 Preliminary
computational studies indicate the position of the
4-chlorophenyl ring favors this conformation in a five-
membered constrained system such as tetrahydrofuran.
Ujjainwalla has recently reported that a series of pyrrol-
idines are potent MC4R agonists.8 For example, com-
pound 5b has an IC50 of 14 nM in a binding assay
although this is a functional agonist with an EC50 of
2 nM. Here we report the synthesis of tetrahydrothioph-
enes and tetrahydrofurans and the SAR investigation of
their derivatives as MC4R ligands.
In our efforts to find small molecule MC4R antagonists,
we have found that a series of acylpiperazinebenzylam-
ines exemplified by R-2 and 3 possess potent binding
affinities. In the course of these studies, we have ob-
served that introducing an R-configured methyl group
at the a-position of the 2,4-dichlorophenylpropionyl
moiety of 1 (Ki = 74 nM, Fig. 1) improves its potency
(R-2, Ki = 26 nM) and an S-methyl slightly does the
opposite (S-2, Ki = 140 nM).6 While these steric effects
may seem insignificant, incorporating an additional
methyl to the a-position of R-methyl compound 3
(Ki = 31 nM) reduces its binding affinity over 25-fold
(4, Ki = 810 nM), demonstrating a profound role of this
Keywords: Synthesis; Tetrahydrothiophene; Tetrahydrofuran; Mela-
nocortin-4 receptor; Cyclization; Heterocycle; Piperazinebenzylamine;
Stereoisomer; Binding affinity.
*
Corresponding author. Tel.: +1 858 617 7634; fax: +1 858 617
7602; e-mail: cchen@neurocrine.com
Present address: Department of Medicinal Chemistry, Tanabe
Research Laboratories, USA, Inc., 4540 Towne Centre Ct., San
Diego, CA 92121, USA.
Methyl trans-4-(4-chlorophenyl)-2,3,4,5-tetrahydrothio-
phene-3-carboxylate 16 was synthesized based on a
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.11.128

J. A. Tran et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1124–1130
R Cl
1125
F
F3C
F
Cl
N
R'
R"
N
N
NH2
N
N
O
N
N
NH
N
O
O
O
O
N
O
1: R = Cl, R' = R" = H: Ki = 74 nM
-2: R = Cl, R' = Me, R"= H: Ki = 26 nM
-2: R = Cl, R' = H, R" = Me: Ki = 140 nM
3: R = H, R' = Me, R" = H: Ki = 31 nM
4: R = H, R' = R" = Me: Ki = 810 nM
R
S
HN
5a
5b
Figure 1. Chemical structures of MC4R ligands 1–5.
procedure similar to that described by Hosomi et al.9 as
shown in Scheme 1. Thus, chloromethyl trimethylsilyl-
methyl sulfide 15, prepared from trimethylsilylmethyl
sulfide 14, trioxane, and HCl gas, was cyclized with
methyl trans-4-chlorocinnamate to give 16, which was
oxidized to the corresponding sulfoxide 17 using hydro-
gen peroxide in hexafluoroisopropanol.10 Alternatively,
sulfone 18 was obtained from 16 by an oxidation with
mCPBA in dichloromethane.11 Hydrolysis of 16–18 un-
der basic conditions (aq NaOH) afforded the corre-
sponding acids 6–8 in good yields.12
in methanol, to give the target ester 21 as a mixture
of trans- and cis-isomers (85:15 ratio), which could
be separated by chromatography. Hydrolysis of 21
afforded the corresponding acid 9.
trans-2-Oxo-4-(4-chlorophenyl)tetrahydrofuran-3-car-
boxylate 2314 was synthesized via ethyl 2-oxo-4-(4-chlo-
rophenyl)-2,5-dihydrofuran-3-carboxylate,15 which was
prepared by cyclization of 4-chlorophenacylbromide 22
with malonic acid monoethyl ester potassium salt in
DMSO. Reduction of the resulting intermediate with so-
dium borohydride, followed by a basic hydrolysis, pro-
vided the corresponding acid 10 in a moderate overall
yield (Scheme 3).16
The synthesis of 4-(4-chlorophenyl)-2,3,4,5-tetrahydro-
furan-3-carboxylic acid 9 is described in Scheme 2.
Methyl 4-oxotetrahydrofuran-3-carboxylate, prepared
from methyl acrylate and methyl glycolate 19 under
basic conditions,13 was converted to the triflate 20,
which was subjected to a palladium-catalyzed coupling
reaction with 4-chlorophenylboronic acid, followed by
a nickel-catalyzed reduction with sodium borohydride
The synthesis of trans- and cis-2-(4-chlorophenyl)tetra-
hydrofuran-3-carboxylic acid 11 is shown in Scheme 4
and uses a procedure similar to that described by Mak-
osza and Judka.17 Thus, c-butyrolactone 24 was con-
verted to tert-butyl 4-chlorobutyrate 25 using thionyl
Cl
Cl
a
b
e
S(O)n
S(O)n
Si
SH
Si
S
Cl
HO
MeO
O
O
14
15
16: n = 0
17: n = 1
18: n = 2
trans-6: n = 0
trans-7: n = 1
trans-8: n = 2
c
d
Scheme 1. Reagents and conditions: (a) HCl (gas)/trioxane/À10 to 0 °C, 16 h, 53%; (b) methyl trans-4-chlorocinnamate/TBAF/THF/rt, 1 h,
quantitative; (c) H2O2/(CF3)2CHOH/rt, 1 h, 67 %; (d) mCPBA/CH2Cl2/rt, 2 h, 25%; (e) NaOH/THF/MeOH/H2O, 90–96%.
Cl
+
Cl
Cl
c,d
OH
b
a
TfO
MeO
MeO
O
O
O
O
HO
HO
RO
O
O
O
O
O
20
19
21: R = Me
9: R = H
d
cis-9
trans-9
Scheme 2. Reagents and conditions: (a) i—Methyl acrylate/NaH/DMSO/0 °C to rt, 1 h, 26%; ii—NaH/Tf2O/Et2O/0 °C to rt, 1.5 h, 23%; (b) i—4-
ClPhB(OH)2/Pd(PPh3)4/Et3N/DMF/100 °C, 12 h, 40%; ii—NiCl2/NaBH4/MeOH/0 °C to rt, 6 h, 76%; (c) chromatography separation on silica gel;
(d) NaOH/MeOH/65 °C, 3 h, ꢀ97%.

1126
J. A. Tran et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1124–1130
Cl
Cl
Cl
a
b
Br
O
O
O
EtO
HO
O
O
O
23
O
22
10
Scheme 3. Reagents and conditions: (a) i—EtOOCCH2COOK/DMSO/rt, 80 min, then NH4OAc/rt, 8 h; ii—AcOH/NaBH4/0 °C to rt, 3 h; (b)
NaOH/MeOH/H2O/rt, 8 h, 21% overall yield.
Cl
Cl
O
O
b
a
Cl
O
+
O
O
O
O
HO
HO
25
24
O
cis-11
O
trans-11
Cl
O
c
O
O
HO
O
O
12
26
Scheme 4. Reagents and conditions: (a) i—SOCl2/ZnCl2/55 °C, 12 h, 74%; ii—t-BuOH/Py/rt, 4 h, 25%; (b) i—4-ClC6H4CHO/t-BuOK/THF/À30 °C,
0.5 h, 15%; ii—Chromatography; iii—TFA/CH2Cl2/rt, 1 h, quantitative; (c) 4-ClC6H4CHO/NaOAc/toluene/reflux, 10 h, 33%.
chloride and zinc chloride,18 which was cyclized with 4-
chlorobenzaldehyde promoted by potassium tert-butox-
ide to give a tert-butyl ester intermediate as a mixture of
trans- and cis-isomers. These isomers were separated by
chromatography on silica gel and then converted to the
corresponding acids trans-11 and cis-11 by a trifluoro-
acetic acid treatment.
The eight heterocyclic acids 6–13 were then coupled with
several piperazine derivatives 31–34 which were ob-
tained from the double-protected precursors 29–30.21
Selective removal of the Boc group of 29–30 gave the
piperazines 31–32, which were coupled with the acids
6–11 to afford the final products 35–42 after an HCl/
MeOH treatment to remove the sulfinyl group.22 Alter-
natively, selective deprotection of the sulfinyl group of
29–30 with HCl/MeOH provided the benzylamines
which were coupled with N,N-dimethyl-b-alanine to give
the intermediates 33–34 after Boc-deprotection with tri-
fluoroacetic acid. Coupling reactions of 33–34 with the
acids 6–13 afforded the final compounds 41–54 after
purification. Several amides 43–49 were also prepared
from 35–42 by a coupling reaction with an N-Boc amino
acid followed by a TFA treatment (Scheme 6).
2-(4-Chlorophenyl)-5-oxotetrahydrofuran-3-carboxylic
acid 12 was obtained by a condensation and cycliza-
tion process between 4-chlorobenzaldehyde and succi-
nic anhydride in the presence of sodium acetate.19
Its ratio of trans- and cis-isomers was not
determined.
Ethyl 2,5-anhydro-3,4-dideoxy-3-(4-chlorophenyl)pent-
onate 28 was prepared from 2-(4-chlorophenyloxetane
27 using a procedure similar to that reported by Nozaki
and coworkers.20 Separation by chromatography on sil-
ica gel followed by hydrolysis of 28 under basic conditions
gave the desired acids trans-13 and cis-13 in good yield
(Scheme 5).
The binding affinities of the final compounds 35–54 were
determined in HEK293 cells stably expressing human
melanocortin-4 receptors, using [125I]-NDP-MSH as the
radiolabeled ligand,23 and the results are listed in Tables
1 and 2.
Cl
Cl
Cl
Cl
b
a
O
+
HO
EtO
HO
O
O
O
27
O
O
O
cis-13
trans-13
28
Scheme 5. Reagents and conditions: (a) N2CH2COOEt/CuSO4/80 °C, 4 h, 80%; (b) i—Chromatography separation on silica gel; ii—NaOH/MeOH/
H2O/rt, 6 h, ꢀ 90%.

J. A. Tran et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1124–1130
R1
1127
R1
Cl
R1
a
b,c
N
Z
N
N
Y
N
O
NH
R2
NH
R2
N
R2
NH2
NH
X
S
O
S
O
O
O
35-40: R2 = iBu
41-42: R2 = iPr
29: R = iBu
30: R = iPr
31: R = iBu
32: R = iPr
c,d,a
e,a
R1
R1
Cl
Cl
b
N
Z
N
NH
Z
Y
R2
N
NH
R2
NH
R3
X
Y
HO
X
O
O
O
O
41-49: R2 = iBu
N
33: R = iBu
34: R = iPr
6-13
50-54: R2 = iPr
Scheme 6. Reagents and conditions: (a) TFA/CH2Cl2/rt, 0.5 h, quantitative; (b) 6–13/EDC/HOBt/Et3N/DMF/rt, 1–16 h, various yields, conditions
were not optimized; (c) HCl/MeOH/rt, 1 h; (d) Me2NCH2CH2COOH/EDC/HOBt/Et3N/CH2 Cl2/rt, 8 h, 60–90%; (e) R3COOH/EDC/HOBt/Et3N/
CH2Cl2, rt, 8 h, 20–60%.
The tetrahydrothiophene trans-35 (Ki = 280 nM) as a
pair of diastereoisomers was significantly less potent
than the R-configured a-methylpropionyl analog 3
(Ki = 31 nM). The corresponding S-oxide trans-36
(Ki = 120 nM) as a mixture of S- and R-isomers was
slightly more potent than trans-35, while the sulfone
trans-37 (Ki = 38 nM) was 7-fold better compared to
trans-35, and similar to 3 in binding affinity (Table
1). The tetrahydrofuran (THF) 38 as a trans/cis mix-
ture (85:15) exhibited similar binding affinity to
trans-35, which also matched with the lactone 39.
The fact that the trans-2-(4-chlorophenyl)tetrahydrofu-
ran-3-carboxamide trans-40a possessed a similar Ki va-
lue to its isomeric THF 38 (mainly trans-isomer)
suggests that the trans-THF ring may distort a pre-
ferred conformation in which the 4-chlorophenyl ring
is parallel to the piperazine plane and opposite to
the basic benzylamine based on the X-ray crystal
structure of a close analog of 3.24 Similar binding
affinity was also obtained from the THF trans-40b
with a 4-chlorophenylpiperazine group.
Ki = 71 M). In comparison, the lactone derivatives
47a–b displayed similar binding affinity to their par-
ent 39.
For the second THF analog trans-40a with a CF3-
group at the left-side molecule, incorporating a b-
alanine had a minimal effect (trans-48a). However,
a 4-fold increase from trans-40b was observed for
trans-48. The cis-48 possessed a Ki value of 87 nM
which was similar to that of trans-48 and the lac-
tone 49.
The benzylamines 41 (Ki = 790 nM) with an a-isopropyl
group had significantly lower affinity than the THF 38
(Ki = 280 nM) as a mixture of 85:15 trans-/cis-iso-
mers,26 but incorporating a b-alanine side chain in-
creased its potency by almost 20-fold (51, Ki = 40 nM,
Table 2). More detailed studies showed that the binding
affinity of the cis-isomer was not significantly different
from that of the trans-analog. Thus, trans-51 or cis-51
exhibited a very similar Ki value (30 and 28 nM, respec-
tively). For the THF analogs 42b, the trans-compound
was slightly more potent than the cis-isomer, and incor-
porating a b-alanine side chain improved the binding
affinity of the cis-isomer (cis-42b, Ki = 2100 nM) by
4-fold (cis-53, Ki = 480 nM). Similar results were also
obtained for the 4-methyl analogs cis-42a and cis-52
(Table 2). However, for the THF compounds 54, the
cis-isomer (cis-54, Ki = 10 nM) was about 4-fold better
than the trans-analog (trans-54, Ki = 43 nM). The over-
all conformations of these THF stereoisomers were not
significantly different except the THF rings (Fig. 2).
The individual isomers of the trans-sulfone 50 were sep-
arated by HPLC and studied for their stereo-effects.
Thus, one isomer (trans-50–2, Ki = 37 nM) was 10-fold
more potent than the other (trans-50–1, Ki = 380 nM).
We have previously found that incorporating an ami-
no acid side chain to the benzylamine such as 2 in-
creases potency by 5- to 10-fold.25 For the current
study, adding a flexible amino side chain might refine
the relationship between the 4-chlorophenyl group
and the basic amine. However, incorporating various
amino amides (trans-43a–d) to the benzylamine of tet-
rahydrothiophene trans-35 had a minimal effect. A
similar result (trans-44, Ki = 230 nM) was also ob-
served for the S-oxide trans-35. For the sulfone
trans-37, this change decreased its binding affinity
(trans-45a–d). For the THF analog 38, however, a
4-fold increase in binding affinity was observed after
incorporating
an
N,N-dimethyl-b-alanine
(46,

1128
J. A. Tran et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1124–1130
Table 1. SAR of compounds 35–40 and 43–49 at hMC4Ra
Cl
Cl
R1
R1
Z
Z
N
N
Y
Y
N
N
X
X
NH
R3
NH2
O
O
O
43-49
R3
35-40
Compound
R1
X
Y
Z
Ki (nM)
trans-35
4-CF3
4-CF3
4-CF3
4-CF3
4-CF3
CH2
CH2
CH2
CH2
CH2
S
S
S
S
S
CH2
CH2
CH2
CH2
CH2
280
130
170
130
250
trans-43a
trans-43b
trans-43c
trans-43d
CH2CH2NMe2
CH2CH2NHMe
R-CH(Me)NH2
CH2NHMe
trans-36b
trans-44b
4-CF3
4-CF3
CH2
CH2
SO
SO
CH2
CH2
120
230
CH2CH2NMe2
trans-37
4-CF3
4-CF3
4-CF3
4-CF3
4-CF3
CH2
CH2
CH2
CH2
CH2
SO2
SO2
SO2
SO2
SO2
CH2
CH2
CH2
CH2
CH2
38f
170
190
100
180
trans-45a
trans-45b
trans-45c
trans-45d
CH2CH2NMe2
CH2CH2NHMe
R-CH(Me)NH2
CH2NHMe
38c
46c
4-CF3
4-CF3
CH2
CH2
O
O
CH2
CH2
280
71
CH2CH2NMe2
39d
47ad
47bd
4-CF3
4-CF3
4-CF3
CO
CO
CO
O
O
O
CH2
CH2
CH2
260
290
180
CH2CH2NMe2
CH2CH2NH2
trans-40a
trans-48a
4-CF3
4-CF3
CH2
CH2
CH2
CH2
O
O
330
200
CH2CH2NMe2
trans-40b
trans-48b
cis-48b
4-Cl
4-Cl
4-Cl
CH2
CH2
CH2
CH2
CH2
CH2
O
O
O
280
74
CH2CH2NMe2
CH2CH2NMe2
87
49e
4-CF3
CH2
CO
O
CH2CH2NH2
110
a Data are average of two or more independent measurements; the affinity measurements for each compound differed by less than 3-fold, resulting in
an average coefficient of variance of 25% for the binding assay Ki values.
b The sulfoxide consisted of about 1:1 S-and R-isomers.
c The ratio of trans/cis was 85:15 based on NMR analysis.
d The trans–cis isomers are interchangeable.
e Stereochemistry was not determined.
f Dose-dependently inhibited a-MSH-stimulated cAMP release with an IC50 of 690 nM.
Although the absolute stereochemistry was not deter-
mined for these compounds, it could be speculated
that trans-50–2 had a R,R-configuration to match with
the R-configured 2 which is more active than the S-iso-
mer 3.
on the modification of related compounds will be re-
ported in due course.
In conclusion, we synthesized a series of cyclized analogs
of 4-chlorophenylpropionylpiperazine benzylamines and
their derivatives, which were subsequently investigated
for their interaction with the human melanocortin-4
receptor. These constrained compounds did not show
improved binding affinity over the open-chain propionyl
analogs. In addition, none of these tetrahydrothiophene
and tetrahydrofuran derivatives showed significant
cAMP stimulation in cells expressing melanocortin-4
receptor (data not shown). In contrast, 4-(4-chloro-
phenyl)pyrrolidine-3-carboxamide analogs have been
found to be potent MC4R agonists.27 These SAR results
provide further information for the active pharmaco-
phore of small molecule MC4R antagonists and
agonists.
Compounds trans-37 and cis-54 were found to dose-
dependently inhibit a-MSH-stimulated cAMP release
in the in vitro functional assay with IC50 values of
690 and 530 nM, respectively, demonstrating func-
tional antagonism. Based on the above results, it
seems that for the a-isobutylbenzylamines with a lipo-
philic trifluoromethyl group (compounds 35–40a),
incorporating an amino acid side chain has a minimal
and even negative effect on their binding affinity. In
comparison, the a-isopropylbenzylamines 41–42 are
more sensitive to such change. Thus, the Ki values in
Table 2 range from 10 to 2100 nM. Further studies

J. A. Tran et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1124–1130
1129
Table 2. SAR of compounds 41–42 and 50–54 at hMC4Ra
4. Scarlett, J. M.; Marks, D. L. Expert Opin. Investig. Drugs
2005, 14, 1233.
5. Foster, A. C.; Chen, C.; Markison, S.; Marks, D. L.
IDrugs 2005, 8, 314.
R1
Cl
R1
Cl
6. Chen, C. W.; Tran, J. A.; Jiang, W.; Tucci, F. C.;
Arellano, M.; Wen, J.; Fleck, B. A.; Marinkovic, D.;
White, N. S.; Pontillo, J.; Saunders, J.; Madan, A.; Foster,
A. C.; Chen, C. Bioorg. Med. Chem. Lett. 2006, 16, 4800.
7. Mutulis, F.; Yahorava, S.; Mutule, I.; Yahorau, A.;
Liepinsh, E.; Kopantshuk, S.; Veiksina, S.; Tars, K.;
Belyakov, S.; Mishnev, A.; Rinken, A.; Wikberg, J. E. S.
J. Med. Chem. 2004, 47, 4613.
Z
Z
N
N
Y
Y
N
N
X
X
NH
NH2
O
O
O
50-54
41-42
N
8. Ujjainwalla, F. 230thACS National Meeting, Washington,
DC, USA. 2005, MEDI 275.
9. Hosomi, A.; Matsuyama, Y.; Sakurai, H. Chem. Commun.
1986, 1073.
10. The sulfoxide 17 consisted of about 1:1 S- and R-isomers
based on TLC analysis. They were not separated.
11. For experimental detail, see: Chen, C.; Tran, J. A.; Tucci,
F. C.; Chen, C. W.; Jiang, W.; Marinkovic, D.; Arellano,
M.; White, N. S. WO 2005/040109.
Compound
R1
X
Y
Z
Ki (nM)
trans-50–1
trans-50–2
6-F
6-F
CH2
CH2
SO2
SO2
CH2
CH2
380
37
41b
51b
6-F
6-F
CH2
CH2
O
O
CH2
CH2
790
40
trans-51
cis-51
30
28
12. Synthesis of trans-4-(4-chlorophenyl)-3-tetrahydrothio-
phenecarboxylic acid (trans-6). HCl (g) was bubbled into
a mixture of trimethylsilylmethyl sulfide (14, 4.98 g,
41.4 mmol) and trioxane (1.28 g, 14.2 mmol) at À10 °C
for 80 min. The reaction mixture was kept at 0 °C for 16 h
and the organic layer was separated and treated with
CaCl2 for 2 h. The crude product was distilled under
reduced pressure (ꢀ 10 mmHg, bp 60 °C) to afford
chloromethyl trimethylsilylmethyl sulfide 15 as a colorless
oil (3.70 g, 53% yield).
trans-42a
cis-42a
cis-52
4-Me
CH2
CH2
O
410
590
120
4-Me
6-F
CH2
CH2
CH2
CH2
O
O
trans-42b
cis-42b
cis-53
1100
2100
480
6-F
CH2
CH2
O
trans-54
cis-54
4-Me
4-Me
O
O
CH2
CH2
CH2
CH2
43
10c
a Data are average of two or more independent measurements; the
affinity measurements for each compound differed by less than 3-fold,
resulting in an average coefficient of variance of 25% for the binding
assay Ki values.
b The ratio of trans/cis was 85:15 based on NMR analysis.
c Dose-dependently inhibited a-MSH-stimulated cAMP release with an
IC50 of 530 nM.
To a solution of 15 (1.00 g, 5.9 mmol) and trans-methyl 4-
chlorocinnamate (900 mg, 4.6 mmol) in THF (23 mL) was
added TBAF (1.0 M in THF, 6.9 mmol). The reaction was
stirred at rt for 16 h, quenched with H2O, and extracted
with EtOAc. The organic phase was washed with 10% aq
HCl twice and brine, dried over MgSO4, filtered, and
concentrated in vacuo to give methyl trans-4-(4-chloro-
phenyl)-3-tetrahydro-thiophenecarboxylate trans-16 as a
clear oil (1.192 g, ꢀ80% yield).
To a mixture of 16 (700 mg, 2.75 mmol) in H2O/THF/
MeOH (14 mL, 14 mL, 10 mL) was added aq NaOH (50%,
0.2 mL). This solution was stirred at rt for 2 h and then
concentrated in vacuo. The residue was dissolved in H2O
and extracted with Et2O. The aqueous phase was acidified
with 10% aq HCl and the product was extracted with EtOAc
twice. The extract was dried over Na2SO4, filtered, and
concentrated in vacuo to afford trans-4-(4-chlorophenyl)-3-
tetrahydrothiophenecarboxylic acid (trans-6) (625 mg,
96% yield).
13. Gianturco, M. A.; Friedel, P.; Giammarino, A. S. Tetra-
hedron 1964, 20, 1763.
14. Nymann, K.; Svendsen, J. S. Acta Chem. Scand 1998, 52,
338.
15. Park, K. H.; Kim, S. Y.; Chung, Y. K. Org. Biomol. Chem.
2005, 3, 395.
16. The trans–cis isomers are interchangeable Hussain, S. A.
M. T.; Ollis, W. D.; Smith, C.; Stoddart, J. F. Perkin
Transact. 1975, 1, 1480.
17. Makosza, M.; Judka, M. Chemistry 2002, 8, 4234.
18. Kuo, G.-H.; Prouty, C.; Wang, A.; Emanuel, S.; DeAn-
gelis, A.; Zhang, Y.; Song, F.; Beall, L.; Connolly, P. J.;
Karnachi, P.; Chen, X.; Gruninger, R. H.; Sechler, J.;
Fuentes-Pesquera, A.; Middleton, S. A.; Jolliffe, L.;
Murray, W. V. J. Med. Chem. 2005, 48, 4892.
19. Lawlor, J. M.; McNamee, M. B. Tetrahedron Lett. 1983,
24, 2211.
Figure 2. The overlay of the low-energy conformers of cis-54 (green)
and trans-54 (violet) indicates no significant difference in conforma-
tions between these two stereoisomers. The 4-chlorophenyl group in
both isomers is almost parallel to the piperazine ring.
References and notes
1. Cone, R. D. Nat. Neurosci. 2005, 8, 571.
2. Yang, Y. K. Obes. Rev. 2003, 4, 239.
3. Deboer, M. D.; Marks, D. L. Trends Endocrinol. Metab.
2006, 17, 199.
20. (a) Nozaki, H.; Takaya, H.; Noyori, R. Tetrahedron 1966,
22, 3393; (b) Ito, K.; Katsuki, T. Chem. Lett. 1994, 1857;

1130
J. A. Tran et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1124–1130
(c) Lo, M. M.-C.; Fu, G. C. Tetrahedron 2001, 57, 2621;
(d) Ito, K.; Yoshitake, M.; Katsuki, T. Heterocycles 1996,
42, 305.
The above compound in MeOH (5 mL) was treated with
HCl (4.0 M in 1,4-dioxane, 0.2 mL) for 0.5 h and the
solution was concentrated in vacuo. One-fifth of the
product was purified by HPLC to afford the titled
compound trans-35 (27.8 mg, 43% yield).
21. Jiang, W.; Chen, C.; Marinkovic, D.; Tran, J. A.; Chen, C.
W.; Arellano, L. M.; White, N. S.; Tucci, F. C. J. Org.
Chem. 2005, 70, 8924.
23. Nickolls, S. A.; Cismowski, M. I.; Wang, X.; Wolff, M.;
Conlon, P. J.; Maki, R. A. J. Pharmacol. Exp. Ther. 2003,
304, 1217.
24. Chen, C.; Jiang, W.; Tucci, F. C.; Tran, J. A.; Fleck, B. A.;
Hoare, S. R.; Joppa, M.; Markison, S.; Wen, J.; Sai, Y.;
Johns, M.; Madan, A.; Chen, C. W.; Marinkovic, D.;
Arellano, M.; Saunders, J.; Foster, A. C. J. Med. Chem.
2007, 50, 5249.
25. Jiang, W.; Tucci, F. C.; Chen, C. W.; Arellano, M.; Tran,
J. A.; White, N. S.; Marinkovic, D.; Pontillo, J.; Fleck, B.
A.; Wen, J.; Saunders, J.; Madan, A.; Foster, A. C.; Chen,
C. Bioorg. Med. Chem. Lett. 2006, 16, 4674.
26. Based on our previous work, there is only a small (2-fold)
affinity difference between the 6-fluorophenylpiperazine
and the 4-(trifluoromethyl)phenylpiperazine analogs. See
Ref. 6.
22. Synthesis of 1-[2-[(1S)-1-amino-3-methylbutyl]-4-(trifluo-
romethyl)phenyl]-4-{[trans-4-(4-chlorophenyl)tetrahydro-
3-thiophenyl]carbonyl}piperazine trifluoroacetate (trans-35).
To a mixture of trans-6 (305 mg, 1.26 mmol) and 1-[2-
[(1S)-1-(S-tert-butylsulfinyl amino)-3-methylbutyl]-4-(tri-
fluoromethyl)phenyl]-4-{[trans-4-(4-chlorophenyl)tetrahydro-
3-thiophenyl]carbonyl}piperazine (31a, 480 mg, 1.14mmol)
were added HOBt (0.5 M in DMF, 3.1 mL), HBTU
(590 mg, 1.90 mmol), and DIEA (0.36 mL, 2.28 mmol).
The reaction mixture was stirred at rt for 16 h and then
quenched with saturated aq NaHCO3. The product was
extracted with CH2Cl2, and the extract was dried over
Na2SO4, filtered, and concentrated in vacuo. The
product 1-[2-[(1S)-1-(S-tert-butylsulfinylamino)-3-meth-
ylbutyl]-4-(trifluoromethyl)
phenyl]-4-{[trans-4-(4-chloro-
phenyl)-tetrahydro-3-thiophenyl] carbonyl}piperazine was
obtained by flash column chromatography (hexane/EtOAc
9:1–1:1) as a white foam (319 mg, 43 % yield).
27. Tran, J. A.; Chen, C. W.; Jiang, W.; Tucci, F. C.; Fleck, B.
A.; Marinkovic, D.; Arellano, M.; Chen, C. Bioorg. Med.
Chem. Lett. 2007, 17, 5165.