5-Alkylated thiazolidinones as follicle-stimulating hormone (FSH) receptor agonists

Article abstract of DOI:10.1016/j.bmc.2006.04.012

We prepared analogs of potent thiazolidinone-based follicle-stimulating hormone (FSH) agonists 1, that is, 3 that contained an additional 5-alkyl substituent. This extra substituent was added to reduce synthetic problems that arose during preparation of a

Full text of DOI:10.1016/j.bmc.2006.04.012

Bioorganic & Medicinal Chemistry 14 (2006) 5729–5741
5-Alkylated thiazolidinones as follicle-stimulating
hormone (FSH) receptor agonists
Jay Wrobel,a,* James Jetter,a Wenling Kao,a John Rogers,a Li Di,a Jamin Chi,b
b
b
b
´
M. Claudia Perez, Gi-Chung Chen and Emily S. Shen
aChemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
bWomen’s Health & Musculoskeletal Biology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
Received 28 February 2006; revised 4 April 2006; accepted 6 April 2006
Available online 3 May 2006
Abstract—We prepared analogs of potent thiazolidinone-based follicle-stimulating hormone (FSH) agonists 1, that is, 3 that
contained an additional 5-alkyl substituent. This extra substituent was added to reduce synthetic problems that arose during
preparation of analogs of 1. These compounds (3) were evaluated in a Chinese hamster ovary (CHO) cell line that
expressed recombinant human FSH receptor (FSHR) and a luciferase reporter gene regulated by a cAMP response element
(CRE). Selected compounds were also tested on a CHO-cell line that over expressed the FSHR for the ability to induce
cAMP production. When the 5-alkyl substituent was a methyl group as in analog 16a, similar FSH activity (i.e.,
EC50 = 51 nM, 100% efficacy relative to hFSH) to the analogous 5-hydrogen series compound (e.g., 2) was observed; thus,
proving that a small 5-alkyl substituent was well tolerated. New derivatives of 3, in which the potentially hydrolytically
labile secondary amide function of 1 (–CONH–) was modified to other moieties (e.g., –CH2NH–, –CH2S–, and –CH2O-
CONH–), were also prepared and evaluated. These congeners (namely 21, 22, and 24) also displayed good potency in
the CRE-luciferase assay.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
tion) have spurred the need to find small molecule ago-
nists that could be taken orally. Conversely, orally
active small molecule antagonists of FSH action could
lead to a new class of non-steroidal contraceptive agents.1
Follicle-stimulating hormone (FSH) is a 38 kDa glyco-
protein that is synthesized and released, as with luteiniz-
ing hormone (LH), from the anterior pituitary gland
under the control of gonadotropin-releasing hormone
(GnRH). These hormones bind to their respective
membrane receptors (FSHR, LHR), which are G pro-
tein-coupled receptors that stimulate adenylyl cyclase
resulting in the activation of a cAMP signaling cascade.
FSH and LH act directly on the ovary to promote the
development of selected follicles by stimulating granulo-
sa and theca cell proliferation and differentiation,
leading to ovulation. Recombinant human FSH (hFSH)
has been used clinically for fertility treatment in women;
however, its expense and mode of administration (injec-
Several series of small molecule modulators of the
FSHR have been reported. (Bis)sulfonic acids2 and
monosulfonic acids3 were shown to be functional antag-
onists that displaced FSH in receptor binding assays.
However, these compounds suffered from poor cell per-
meability and absorption properties, precluding their
ability to be used successfully in vivo.
Recently, a more ‘drug-like’ class of 6-amino-4-phenyl-
tetrahydroquinoline derivatives4 displayed excellent
antagonist activity in several hFSH-based cellular as-
says, but unlike the sulfonic acid class, they were not
able to compete with FSH in a receptor binding assay.
The authors4 offered a possible explanation for this pro-
file in that these antagonists interacted with the seven
transmembrane region of the G protein-coupled FSHR
and, thereby, induced a conformational change that
disrupted normal activation.
Keywords: Follicle-stimulating hormone; FSH; FSH receptor agonist;
Thiazolidinone.
*
Corresponding author. Tel.: +1 484 8652480; fax: +1 484 865 9399;
e-mail: wrobelj@wyeth.com
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.04.012

5730
J. Wrobel et al. / Bioorg. Med. Chem. 14 (2006) 5729–5741
Several different series of small molecule FSHR ago-
nists have also been reported recently through screen-
ing of large encoded combinatorial libraries. Gao5
described an approach that led to the identification
of several potential sub-series of biaryl urea-containing
compounds. A subsequent report6 described the opti-
mization of one of the sublibraries of biaryl diketopi-
perazines. These compounds showed high potency in
a human FSHR (hFSHR) luciferase reporter assay
and, in addition, stimulated cAMP accumulation in
hFSHR-transfected Chinese hamster ovary (CHO)
cells. These reports did not disclose any binding data
for the compounds.
O
HN
O
R'
R
O
O
HN
O
R
5
O
O
O
S
N
H2N
2
H2N
S
N
2, R = H
5, R = alkyl
R"'
1, R = H
3, R = alkyl
O
R
HN
O
R'
O
NHR'
O
M
O
O
O
O
"R
H2N
S
N
S
N
Thiazolidinone-based compounds 1 were also identi-
fied as hFSHR agonists via screening of encoded
combinatorial libraries.7 One representative, 3-((2S*,
5R*)-2-(4-benzyloxy-phenyl)-5-{[2-(3-ethoxy-4-methoxy-
phenyl)-ethylcarbamoyl]-methyl}-4-oxo-thiazolidin-3-yl)-
benzamide 2, was recently profiled.8 It was a potent
activator of human and rat FSHRs based on lucifer-
ase reporter gene screens and also caused hFSH-de-
pendent cAMP accumulation, as well as estradiol
secretion in rat granulosa cells. However, like the 6-
amino-4-tetrahydroquinoline antagonists,4 it too failed
to compete with FSH in a standard radioligand
receptor binding assay leading to the speculation that
this compound and analogs were allosteric activa-
tors.9 A c-lactam analog of thiazolidinone congener
2 that possessed similar FSH agonist activity was
recently described.10
6
4
O
O
2. Chemical syntheses
As outlined in Scheme 1, condensation of methyl-3-
aminobenzoate, 4-benzyloxybenzaldehyde, and merca-
ptosuccinic acid led to the desired 2,3,5-trisubstituted
thiazolidinone 7 in 95% yield that was predominantly
the trans isomer (>9:1). All attempts to alkylate 7
failed, thus, the 5-acetic acid group of 7 was converted
to the benzotriazole ester using the BOP reagent and
this ester was reduced with sodium borohydride to
the 5-ethanol derivative 8. Compound 8 was treated
with slightly more than 2 equiv of lithium hexamethyl-
disilazide and lithium chloride at low temperature, and
the resultant enolate was further reacted with methyl
iodide to form 9 in 39% yield or allyl bromide to form
11 in 37% yield. An NOE correlation experiment con-
firmed a coupling through space between the 5-methyl
group on thiazolidinone central ring and the 2-proton
that was attached to this same ring, confirming these
groups were cis to one another. A large amount of
starting material 8 was also recovered from these reac-
tions. Primary amide 10 was prepared in 66% yield
upon reaction of ester 9 with ammonium hydroxide.
Primary alcohols 9–11 were oxidized to the correspond-
ing carboxylic acids 12–14 using Jones reagent (40–70%
yields). These acids in turn were converted to amide
target compounds 15, 16 and 18, respectively, using
standard amidation methods (HATU, DIEA, 60–95%
yields). The ester 18 was transformed in 84% yield to
primary amide 19 with ammonium hydroxide. The sul-
fone 17 could be prepared upon reaction of 16 with m-
CPBA (83% yield).
The thiazolidinone series, however, suffered from syn-
thetic liabilities since the undesired trans isomer of 1 pre-
dominated over the desired cis isomer regardless of the
synthetic method attempted. In addition, cis/trans iso-
mer separation by chromatography or crystallization
leading to 1 was difficult, except on small scale by
HPLC, and this was sometimes further complicated by
epimerization at the 5-position of purified cis
compounds.
With this in mind, we sought the preparation of
analogs of 1, that is, 3 with an additional 5-alkyl
substituent that would lock the two different pharma-
cophore side chains (at positions 2 and 5) into the
syn orientation and impede epimerization at the 5-po-
sition. The desired syn configuration could be
achieved via alkylation of the enolate of intermediate
4. The 2-benzyloxyphenyl substituent of 4 should ste-
rically drive alkylation predominantly to the opposite
face of the thiazolidinone ring forcing a syn relation-
ship between the pharmacophore units. Furthermore,
straightforward synthetic manipulation of the side
chains would produce the desired target compounds.
Herein, we describe the preparation and FSH agonist
activity of several 5-alkyl analogs of 2 (e.g., 5).11 In
addition, new derivatives of 5 in which the secondary
amide function (–CONH–) was modified to other
Referring to Scheme 2, primary alcohol 10 was convert-
ed to the mesylate 20 (56% yield) and then reacted with a
primary amine to provide secondary amine target com-
pounds 21 in 63% yield. Alternatively, amines 21 could
be prepared via a three-step procedure involving oxida-
tion of alcohol 9 with PCC to the corresponding alde-
hyde (62% yield), reductive amination of this aldehyde
moieties (e.g., –CH2NH–, –CH2S–), and
sub-series of carbamate analogs 6 were prepared
a new
and evaluated.

J. Wrobel et al. / Bioorg. Med. Chem. 14 (2006) 5729–5741
5731
OH
R
O
O
Z
O
CH3O2C
a
9, R" = OCH3, R = CH3
10, R'' = NH2, R = CH3
11, R" = OCH3, R = allyl
CO2CH3
CHO
R"
S
S
N
N
d
c
NH2
7, Z = CO2H
and
OCH2Ph
b
PhCH2O
OCH2Ph
8, Z = CH2OH
HO2CCH(SH)CH2CO2H
OH
O
NHR'
R
R
O
O
O
O
e
O
S(O)n
f
R"
R"
S
N
N
15, R" = OCH3, R = CH3, n = 0
16, R' = NH2, R = CH3, n = 0
17, R' = NH2, R = CH3, n =2
18, R" = OCH3, R = allyl, n = 0
19, R" = NH2, R = allyl, n = 0
12, R" = OCH3, R = CH3
13, R'' = NH2, R = CH3
14, R" = OCH3, R = allyl
OCH2Ph
OCH2Ph
g
d
˚
Scheme 1. Reagents and conditions: (a) CH3CN, molecular sieves 4 A, 80 ꢁC; (b) BOP, DIEA, THF for 6 h then reduced with 1.15 equiv NaBH4;
(c) LiCl, LiNTMS2, RX, ꢁ78 ꢁC to ꢁ40 ꢁC; (d) NH4OH, CH3OH; (e) Jones oxidation, 0 ꢁC; (f) R0NH2, HATU, DIEA, DMF; (g) m-CPBA,
NMP, 60 ꢁC.
pounds were active when the luciferase assay was run in
21, Y = NHR'
Y
b
c
antagonist mode (data not shown). Selected compounds
were also tested for the ability to induce cAMP produc-
tion in a receptor-dependent manner using a CHO cell
line that overexpressed the FSHR gene.2,13 These selected
compounds were tested subsequently in CHO cells that
did not express the FSHR by measuring cAMP produc-
tion. The compounds were inactive suggesting the lack
of a FSHR-independent, nonspecific effect (data not
shown). A few compounds were further evaluated in
additional functional activity assays (Table 3), including
compound-induced estradiol production in rat primary
ovarian granulosa cells and progesterone secretion in a
clonal mouse adrenal Y1 cell line that was engineered to
stably express the hFSHR gene.2,3 In all assays agonist
efficacies are reported relative to hFSH. Like the thiazo-
lidinone analogs (1 and 2) on which these compounds are
based,7–9 none of the compounds here were able to dis-
place [125I]hFSH from hFSHR in a standard receptor
binding assay.
CH3
O
O
20, Y = OMs
H2N
a (to 20)
S
N
22,Y = SR'
10
9
or g (to 23)
23, Y = OCO(pNO2Ph)
24, Y = OCONHR'
h
OCH2Ph
d, e, f
21
Scheme 2. Reagents and conditions: (a) MsCl, pyridine, 0 ꢁC; (b)
R0NH2, benzene, reflux; (c) R0SH, NaH, DMF, 55 ꢁC; (d) pyridinium
chlorochromate, 0 ꢁC; (e) R0NH2, NaBH(OAc)3, HOAc, CH2Cl2, rt;
(f) NH4OH, CH3OH; (g) 4-nitrophenyl chloroformate, pyridine,
CH2Cl2, 0 ꢁC; (h) R0NH2, CH2Cl2, 0 ꢁC.
with the requisite primary amine, and then final conver-
sion of the methyl ester group to the carboxamide (26%
yield from the aldehyde). Thioether analogs 22 were pre-
pared from mesylate 20 via displacement of the mesyl
moiety with the appropriate thiol reagent (19–62%
yields). The carbamate analogs 24 were obtained by
reacting the p-nitrophenyl carbonate 23 with various
primary amines (ꢀ80% yields). The carbonate 23 was
derived from alcohol 10 via reaction with 4-nitrophenyl
chloroformate (83% yield).
Referring to Table 1, we were gratified to find that the
analog of direct comparison to 2, namely 16a, which dif-
fers only in the replacement of the 5-hydrogen of 2 with
a 5-methyl moiety, was equally efficacious in luciferase
reporter gene and cAMP assays, and nearly as potent
(EC50 of 51 vs 13 nM). Similarly, compound 19 with a
larger allyl moiety in the 5-position also displayed full
agonist efficacy and was only 2-fold less potent than
16a. Thus, small substituents in the 5-position of 1 lead-
ing to 3 were tolerated.
3. Results and discussion
The compounds in Tables 1 and 2 were tested in the ago-
nist mode in a CHO cell line that expressed recombinant
hFSHR and a luciferase reporter gene regulated by a
cAMP response element (CRE).9,12 None of the com-
The primary amide moieties of 16a or 19 (R00 = NH2)
were not essential for the molecule’s FSH agonist activ-

5732
J. Wrobel et al. / Bioorg. Med. Chem. 14 (2006) 5729–5741
Table 1.
CH3
O
O
CH3
HN
O
R
O
O
R"
S(O)n
N
O
Compound
R
R00
n
EC50 (nM) (% efficacy compared to FSH)
hFSHR-dependent CRE-LUC
hFSHR cAMP production
2
15
16a
17
18
19
H
CH3
NH2
0
0
0
2
0
0
14 3 (n = 5, 100%)
170 (n = 1, 73%)
167 117 (n = 3, 76%)
800 (n = 1, 50%)
100 (n = 1, 91%)
900 (n = 1, 100%)
NT
OCH3
NH2
NH2
CH3
CH3
51 42 (n = 4, 100%)
20 (n = 1, 73%)
CH2CH@CH2
CH2CH@CH2
OCH3
NH2
1750 (n = 1, 93%)
106 (n = 1, 100%)
NT
Data represent means SEM for replicate experiments (n) as indicated in parentheses.
NT, not tested.
ity. The corresponding methyl ester-containing com-
pounds (R00 = OCH3) 15 and 18 were also effective ago-
nists in the luciferase reporter gene assay, although there
was a 3- to10-fold drop in potency relative to the amide
congeners. The thiazolidinone ring sulfur of 16a could
be oxidized to the sulfone moiety to afford 17. Although
this compound retained agonist efficacy and potency, it
was highly unstable and rapidly degraded (over 24 h
period at 37 ꢁC) to a multitude of ring-opened products
under a variety of mild conditions,14 including simulated
fluids SGF (simulated gastric fluid), SIF (simulated
intestinal fluid), and SIBLM (simulated bile/lecithin
mixture) as well as rat plasma.15 Under identical condi-
tions, compound 16a was completely stable for the
length of the test period (24 h).
ducts 16b–16d were less potent by an order of magnitude
over the phenethylamine congeners such as 2 or 16a.
Conversion of the secondary amide of 16a to a second-
ary amine led to analogs 21a and 21b. These compounds
were also full agonists but approximately 3- to 7-fold
weaker in both functional assays. The thio ethers 22a
and 22b retained potency and efficacy relative to 16b
in the luciferase assay but 22a was less active and effica-
cious in the cAMP assay (22b not tested).
We also took advantage of intermediate 10 to prepare a
new sub-series of carbamate-containing compounds
24a–24f. These carbamates differed structurally from
the amide congeners in that they were longer in length
by the addition of a –CH2O– linkage. Compound 24a
with the same 3-ethoxy-4-methoxy-phenethylamine
appendage as 16a was slightly less potent than 16a in
the luciferase assay. To assess whether a shorter chain
length would result in greater activity, we prepared the
corresponding benzylamine analog 24b. In fact, lucifer-
ase potency did increase with the shorter chain length
to an EC50 value (30 nM), on par with 16a. This
prompted the preparation of a library of approximately
50 carbamate analogs, the most potent of which are 24c–
24g. These compounds generally showed good potency
and were full or nearly full agonists in the luciferase as-
say. However, this sub-series showed much weaker
potency (EC50s in low micromolar range) and/or partial
agonism in the cAMP assay as compared to 16a.
Previous investigators found that substituted-pheneth-
ylamine amides of the 5-acetic acid moiety of 1 provid-
ed the best hFSH potency. The optimum appendage
found among these substituted phenethylamine was
the 3-ethoxy-4-methoxy-phenethylamine moiety that
compound 2 contains.7,9 We decided to extend this
SAR (Table 2) and looked at a few substituted benzyl-
amine adducts (16b–16d). However, since amides are
often the site of hydrolytic and/or metabolic instability,
we also wanted to replace the secondary amide group
of 3 with other moieties, namely secondary amines
(21a and 21b), thioethers (22a and 22b), and carba-
mates (24a–24g).
What is apparent immediately upon perusal of Table 2 is
that an amide side chain emanating from the thiazolid-
inone 5-position was essential for FSH activity. The syn-
thetic precursors to 16, ethyl alcohol 10, and acetic acid
11 were devoid of activity in the luciferase assay. In
agreement with the previous investigations into the
SAR of 1 that found substituted phenethylamines to
be optimum for activity, substituted benzylamine ad-
Several of the better analogs were further evaluated in
additional hFSH-based functional assays as shown in
Table 3. The standard 2 and close derivative 16a were
of approximately equal activity in the Y1 adrenal and
granulosa cell assays. The two additional compounds
that were tested in the Y1 assay, the secondary amine
21b and carbamate 24d, lost potency and were partial

J. Wrobel et al. / Bioorg. Med. Chem. 14 (2006) 5729–5741
5733
Table 2.
CH3
A
O
H2NOC
S
N
O
Compound
A
EC50 (nM) (% efficacy compared to FSH)
hFSHR-dependent CRE-LUC activity
cAMP production
10
11
>30,000 (n = 1)
NT
NT
OH
OH
O
O
>30,000 (n = 1)
O
O
16a
51 42 (n = 4, 100%)
100 (n = 1, 91%)
N
H
O
N
H
O
16b
16c
605 20 (n = 2, 90%)
290 (n = 1, 100%)
NT
NT
O
O
N
H
O
CF3
O
16d
780 (n = 1, 98%)
NT
N
H
O
O
O
O
21a
21b
22a
22b
24a
165 35 (n = 2, 93%)
210 40 (n = 2, 99%)
60 (n = 1, 87%)
710 (n = 1, 65%)
400 (n = 1, 96%)
820 (n = 1, 50%)
NT
N
H
N
H
O
O
O
S
S
O
O
40 (n = 1, 100%)
O
O
O
110 30 (n = 2, 99%)
1800 (n = 1, 100%)
O
N
H
O
O
O
N
H
24b
24c
24d
30 (n = 1, 76%)
NT
NT
O
O
O
O
O
N
H
30 (n = 1, 82%)
O
44 13 (n = 2, 97%)
1000 (n = 1, 42%)
O
N
H
(continued on next page)

5734
J. Wrobel et al. / Bioorg. Med. Chem. 14 (2006) 5729–5741
Table 2 (continued)
Compound
A
EC50 (nM) (% efficacy compared to FSH)
hFSHR-dependent CRE-LUC activity
cAMP production
O
O
N
H
24e
24f
24g
205 35 (n = 2, 91%)
1800 (n = 1, 24%)
N
S
N
O
O
O
80 (n = 1, 100%)
370 (n = 1, 100%)
2300 (n = 1, 63%)
O
O
N
H
CF3
I
NT
N
H
Data represent means SEM for replicate experiments (n) as indicated in parentheses.
NT = not tested.
Table 3.
Compound
EC50 (nM) (% efficacy compared to FSH)
hFSHR-dependent CRE-LUC activity
hFSHR cAMP production
Y1 adrenal (progesterone)
granulosa (aromatase)
2
14 3 (n = 5, 100%)
51 42 (n = 4, 100%)
210 40 (n = 2, 99%)
40 (n = 1, 100%)
167 117 (n = 3, 76%)
100 (n = 1, 91%)
400 (n = 1, 96%)
NT
530 390 (n = 3, 93%)
<300 (n = 1, 99%)
1300 (n = 1, 47%)
NT
70 6 (n = 2, 77%)
107 39 (n = 2, 94%)
NT
16a
21b
22b
24d
24f
26 (n = 1, 78%)
410 (n = 100%)
120 10 (n = 2, 62%)
44 13 (n = 2, 97%)
80 (n = 1, 100%)
1000 (n = 1, 42%)
2300 (n = 1, 63%)
1310 (n = 1, 56%)
NT
Data represent means SEM for replicate experiments as indicated in parentheses.
NT = not tested.
agonists in the Y1 assay. Thioether 22b, and carbamates
24d and 24f were tested in the granulosa cell assay and
were generally in the same activity range as acetic acid
amides 2 and 16a.
Aldrich Chemical Co. and used without further treat-
ment. Microanalyses were performed by Robertson
Microlit Labs (Madison, NJ). High-resolution mass
spectra were taken on a Waters LC-TOFMS instru-
ment. Accurate masses were measured to within
5 ppm of the calculated values. Proton (1H) was taken
on a Bruker DPX300 (300 MHz) instrument and delta
values (d) were measured in ppm using tetramethylsi-
lane as an internal standard (d = 0 ppm). High-perfor-
mance liquid chromatography (HPLC) was performed
with an Agilent 1100F series instrument with autosam-
pler, thermoregulated column oven, and a diode array
detector.
To conclude, we demonstrated the straightforward prep-
aration of 5-alkylated analogs (3) of potent thiazolidi-
none-based FSH agonist 1. These compounds (3 and
5) were designed to reduce synthetic problems that arose
in the preparation of analogs of 1. FSH activity data for
specific 5-methyl analogs (e.g., 16a) were similar to cor-
responding 5-hydrogen-containing compounds (e.g., 2).
We also prepared derivatives of 3 that replaced the sec-
ondary amide functional group with other, potentially
less hydrolytically unstable groups. In this fashion, sec-
ondary amine (21), thioethers (22), and carbamate (24)
analogs were made and evaluated for FSH activity. All
these analogs retained good FSH activity, although in
certain circumstances either potency or efficacy was
reduced.
4.1. [(2S*, 5S*)-3-[3-(Methoxycarbonyl)phenyl]-2-[4-
(benzyloxy)phenyl]-4-oxo-1,3-thiazolidin-5-yl]acetic acid
(7)
At room temperature under N2, methyl-3-aminobenzo-
ate (18.12 g, 119.865 mmol), 4-benzyloxybenzaldehyde
(25.44 g, 119.865 mmol), and mercaptosuccinic acid
(27.00 g, 179.798 mmol) in acetonitrile (200 mL) were
heated at reflux for 4 days. The resulting brown solution
was concentrated in vacuo. The brown syrup was parti-
tioned between 1:1 water: CH2Cl2 (800 mL). The
CH2Cl2was dried over MgSO4 and concentrated in vac-
uo to a brown syrup. SiO2 gravitational chromatogra-
phy elution with hexane/EtOAc (3:1, 2 L), (2:1, 2 L),
(1:1, 4 L), (1:1.5, 2 L) afforded an orange powder
4. Experimental
General methods: Appropriate safety practices were ob-
served during all laboratory functions. General solvents
and chemicals were purchased from VWR and used
without further treatment. Anhydrous and deuterated
solvents as well as fine chemicals were purchased from

J. Wrobel et al. / Bioorg. Med. Chem. 14 (2006) 5729–5741
5735
1
(48.57 g, 85% yield). H NMR (DMSO-d6) d 2.93 (dd,
disilazane in THF (182 mL solution) was added to a
solution of methyl 3-[(2S*,5S*)-2-[4-(benzyloxy)phen-
yl]-5-(2-hydroxyethyl)-4-oxo-1,3-thiazolidin-3-yl]benzo-
ate (8, 24.27 g, 52.573 mmol), lithium chloride (8.91 g,
210.290 mmol) in THF (350 mL) at ꢁ45 ꢁC at a rate
where the reaction temperature was kept at ꢁ45 3 ꢁC
(about 4 min). The resulting dark brown mixture was
stirred at ꢁ78 ꢁC for 3.5 h. To the dark brown solution
was added iodomethane (7.18 g, 262.863 mmol) at
ꢁ78 ꢁC and the reaction mixture was stirred at this tem-
perature for 2.5 h. The resulting dark purple solution
was warmed to ꢁ40 ꢁC and then quenched with saturat-
ed aqueous NH4Cl (500 mL). The resulting brown solu-
tion was partitioned with EtOAc (500 mL). The
aqueous layer was further extracted with EtOAc
(500 mL). All organic layers were combined, washed
with brine (300 mL), dried over MgSO4, filtered, and
concentrated in vacuo to a dark brown syrup. Biotage
Flash-75 (75-L cartridge) elution schedule: hex-
ane:EtOAc/3:1 (16 L), 2:1 (12 L), 1:1 (16 L), 0:1 (8 L).
Collection of the clean fractions afforded a yellow foam
(9.71 g, 39% yield) of the title compound and recovered
starting material (12.18 g). 1H NMR (DMSO-d6) d 1.63
(s, 3H), 1.92 (m, 1H), 2.14 (m, 1H), 3.56 (m, 4H), 3.81
(s, 3H), 4.67 (t, J = 3.11 Hz, 1H), 4.99 (s, 2H), 6.61 (s,
1H), 6.83 (d, J = 8.68 Hz, 2H), 7.29 (m, 2H), 7.34 (m,
3H), 7.38 (m, 1H), 7.41 (d, J = 8.68 Hz, 1H), 7.53 (d,
J = 8.68 Hz, 1H), 7.88 (s, 1H). An NOE correlation
experiment confirmed a coupling through space be-
tween the 5-methyl group on thiazolidinone central ring
and the 2-proton that was attached to this same ring,
confirming these groups were cis to one another.
HRMS calcd for C27H27NO5S+H+, 478.16827; found
(ESI, [M+H]+), 478.1665. HPLC purity 89% at
210 nm; 91.8% at 230 nm; tR = 20.6 min; Capcell Pak,
UG120, 4.6 · 150 mm column, 1 mL/min, gradient:
(A) water; (B) acetonitrile.
J = 8.37, 8.38 Hz, 1H), 3.04 (dd, J = 17.26, 3.95 Hz,
1H), 3.83 (s, 3H), 4.51 (ddd, J = 5.42, 3.94, 1.48 Hz,
1H), 5.00 (s, 2H), 6.47 (d, J = 1.48 Hz, 1H), 6.90 (d,
J = 8.87 Hz, 2H), 7.31 (d, J = 6.90 Hz, 1H), 7.34 (m,
6H), 7.43 (t, J = 7.88 Hz, 1H), 7.53 (dd, J = 7.89,
0.99 Hz, 1H), 7.73 (d, J = 7.89 Hz, 1H), 7.94 (t,
J = 1.48 Hz, 1H), 12.66 (br s, 1H). Anal. HRMS Calcd
for C26H23NO6S+H+, 478.13189; found (ESI,
[M+H]+), 478.133. HPLC purity 91.9% at 210–370 nm,
9.8 min; Xterra RP18, 3.5 lm, 150 · 4.6 mm column,
1.2 mL/min, 85/15–5/95 (ammon. form. buff. Ph = 3.5/
ACN+MeOH) for 10 min, hold 4 min.
4.2. Methyl-3-[(2S*,5S*)-2-[4-(benzyloxy)phenyl]-5-(2-
hydroxyethyl)-4-oxo-1,3-thiazolidin-3-yl]benzoate (8)
At room temperature under N2, benzotriazol-1-yloxy-
tris(dimethylamino)phosphonium hexafluorophosphate
(5.0 g, 11.305 mmol) and diisopropylethylamine
(2.33 mL, 13.360 mmol) were added to a solution of
[(2S*,5S*)-3-[3-(methoxycarbonyl)phenyl]-2-[4-(benzyl-
oxy)phenyl]-4-oxo-1,3-thiazolidin-5-yl]acetic acid. Com-
pound 7 (4.90 g, 10.277 mmol) in THF (200 mL) and the
reaction mixture was stirred for 6 h. The brown solution
was cooled to 0 ꢁC upon which NaBH4 (450 mg,
11.819 mmol) was added. Gas evolution persisted for
about 0.5 h, after which the slightly cloudy brown solu-
tion was stirred at room temperature for 60 h. The solu-
tion was concentrated in vacuo to a brown syrup and
partitioned between 1:1 EtOAc: cold aqueous 2 N HCl
(500 mL). The aqueous layer was further extracted with
EtOAc (2· 100 mL). All organic layers were combined
and extracted with ice-cold saturated aqueous NaHCO3
(200 mL), water (150 mL), and brine (100 mL). The
organic layer was dried over MgSO4, filtered, and con-
centrated in vacuo to a brown syrup. Biotage SiO2 chro-
matography (40 M cartage), 3:1/hexane:EtOAc (1 L),
2:1/hexane:EtOAc (3 L), afforded the title compound
4.4. 3-[(2S*,5R*)-2-[4-(Benzyloxy)phenyl]-5-(2-hydroxy-
ethyl)-5-methyl-4-oxo-1,3-thiazolidin-3-yl]benzamide (10)
1
as a light brown powder (2.81 g, 63% yield). H NMR
(DMSO-d6) d 1.17 (m, 1H), 2.22 (m, 1H), 3.53 (m,
1H), 3.64 (m, 1H), 3.83 (s, 3H), 4.32 (dd, J = 4.02,
0.72 Hz, 1H), 4.72 (t, J = 5.13 Hz, 1H), 5.01 (s, 2H),
6.55 (s, 1H), 6.88 (q, d, J = 8.79, 1.83 Hz, 2H), 7.30
(m, 7H), 7.43 (t, J = 8.05 Hz, 1H), 7.55 (dd, J = 6.95,
1.10 Hz, 1H), 7.12 (d, J = 8.06 Hz, 1H), 7.95 (t,
J = 2.20 Hz, 1H). HRMS calcd for C26H25NO5S+H+,
464.15262; found (ESI, [M+H]+), 464.1524. HPLC puri-
ty 74% at 210 nm; 72% at 230 nm; tR = 25.9 min; Prime-
sphere, 5 lm, C18-HC, 4.6 · 250 mm column, 1 mL/
min, gradient: (A) water; (B) acetonitrile.
Ammonium hydroxide (20 mL, 30% aqueous solution)
was added to a solution of methyl 3-[(2S*,5R*)-2-[4-
(benzyloxy)phenyl]-5-(2-hydroxyethyl)-5- methyl-4-oxo-
1,3-thiazolidin-3-yl]benzoate (9, 1.00 g, 2.094 mmol) in
methyl alcohol (15 mL) at room temperature in a coated
flask opened to the atmosphere. The resulting brown
cloudy mixture was sealed with a TeflonTM screw cap
and stirred for 4 days. The yellow solution was concen-
trated in vacuo to a brown syrup. Biotage SiO2 chroma-
tography (5% MeOH:CH2Cl2) afforded the title
1
compound as a yellow foam (640 mg, 66% yield). H
4.3. Methyl-3-[(2S*,5R*)-2-[4-(benzyloxy)phenyl]-5-(2-
hydroxyethyl)-5-methyl-4-oxo-1,3-thiazolidin-3-yl]benzo-
ate (9)
NMR (DMSO-d6) d 1.62 (s, 3H), 2.00 (qd, J = 8.02,
2.82 Hz, 1H), 2.16 (q, J = 8.02 Hz, 1H), 3.62 (m, 1H),
3.71 (m, 1H), 4.66 (t, J = 5.31 Hz, 1H), 4.99 (s, 2H),
6.51 (s, 2H), 6.87 (d, J = 8.85 Hz, 2H), 7.30 (m, 7H),
7.40 (dq, J = 7.78, 0.05 Hz, 2H), 7.63 (dt, J = 7.78,
1.41 Hz, 1H), 7.80 (t, J = 1.77 Hz, 1H), 7.93 (br s, 2H).
HRMS calcd for C26H26N2O4S+H+, 463.16860; found
(ESI, [M+H]+), 463.1689. HPLC purity 98.2% at
210 nm; 99.1% at 230 nm; tR = 16.8 min; Capcell Pak,
UG120, 4.6 · 150 mm column, 1 mL/min, gradient: (A)
water; (B) acetonitrile.
n-Butyl lithium (48.37 mL, 120.917 mmol, 2.0 M solu-
tion in hexane) was added to THF (100 mL) at 0 ꢁC un-
der N2, by syringe. After 5 min, 1,1,1,3,3,3-hexamethyl
disilazane (32.00 g, 115.66 mmol) was added to the pale
yellow solution over 3 min producing gas evolution. The
resulting colorless solution was stirred at 0 ꢁC for
25 min. This solution of lithium 1,1,1,3,3,3,-hexamethyl-

5736
J. Wrobel et al. / Bioorg. Med. Chem. 14 (2006) 5729–5741
4.5. Methyl-3-[(2S*,5R*)-5-allyl-2-[4-(benzyloxy)phenyl]-5-
(2-hydroxy ethyl)-4-oxo-1,3-thiazolidin-3-yl]benzoate (11)
J = 7.89 Hz, 1H), 7.94 (t, J = 1.48 Hz, 1H), 12.66 (br s,
1H). HRMS calcd for C26H24N2O5S+H+, 477.14787;
found (ESI, [M+H]+), 477.1483. HPLC purity 84.3% at
210 nm, tR = 13.9 min 85.4% at 230 nm, tR = 13.9 min;
Inertsil ODS2, 5 lm, 4.6 · 150 mm column, 1.0 mL/min,
gradient: (A) 10 mM NH4H2PO4 (pH 3); (B) acetonitrile.
Using the procedure for compound 9 except using allyl
bromide as the alkylating agent afforded the title com-
pound as a yellow powder (790 mg, 36% yield). 1H
NMR (DMSO-d6) d 1.94 (m, 1H), 2.10 (m, 1H), 3.56
(m, 4H), 2.58 (m, 2H), 3.64 (m, 2H), 3.92 (s, 3H), 4.66
(t, J = 3.11 Hz, 1H), 4.99 (s, 2H), 5.15 (dd,
J = 10.70 Hz, 1H), 5.19 (dd, J = 10.70 Hz, 1H), 5.97 (m,
1H), 6.41 (s, 1H), 6.86 (d, J = 8.68 Hz, 2H), 7.29 (m,
2H), 7.34 (m, 2H), 7.38 (m, 1H), 7.51 (d, J = 8.68 Hz,
1H), 7.70 (d, J = 8.68 Hz, 1H), 7.83 (s, 1H). MS (ESI)
m/z 504; HPLC purity 98.7% at 210 nm; 99.0% at
230 nm; tR = 24.8 min; Inertsil, ODS3, 8 lm, 4.6 ·
250 mm column, 1 mL/min, gradient: (A) water; (B) ace-
tonitrile. Anal. Calcd for C29H29NO5S: C, 69.16; H, 5.80;
N, 2.78. Found: C, 69.13; H, 6.06; N, 2.74.
4.8. {(2S*,5R*)-5-Allyl-2-[4-(benzyloxy)phenyl]-3-[3-
(methoxycarbonyl)phenyl]-4-oxo-1,3-thiazolidin-5-yl}ace-
tic acid (14)
Using the Jones oxidation procedure to produce
compound 13, methyl 3-[(2S*,5R*)-5-allyl-2-[4-(benzyl-
oxy)phenyl]-5-(2-hydroxy ethyl)-4-oxo-1,3-thiazolidin-
3-yl]benzoate (11, 400 mg, 0.794 mmol) was converted
to the title compound: yellow foam (275 mg, 67% yield).
1H NMR (DMSO-d6): 2.52–2.60 (q and s, J = 7 Hz,
5H), 2.61–2.67 (t, J = 7 Hz, 2H), 2.75–2.89 (dd, J =
15.07, 15.07 Hz, 2H), 3.69 (s, 3H), 4.95–4.97 (d, J =
12 Hz, 1H), 5.15 (s, 3H), 5.13–5.23 (ddd, J = 19.04,
10.30, 1.99 Hz, 1H), 5.94–6.01 (m, 1H), 6.29 (s, 1H),
6.780–6.83 (m, 3H), 7.27–7.38 (m, 5H), 7.39–7.45 (m,
4H), 7.60–7.61 (d, J = 2 Hz, 1H), 7.78 (s, 1H), 7.90–7.91
(br s, 1H), 8.09–8.05 (t, J = 6 Hz, 1H). MS (ESI) [M+H]+
518. HPLC purity 94.0% at 230 nm, tR = 26.5 min; Inertsil
ODS 3, 4.6 · 250 mm, 8 lm column, 1 mL/min, gradient:
(A) 0.1% TFA in water; (B) acetonitrile.
4.6. {(2S*,5R*)-2-[4-(Benzyloxy)phenyl]-3-[3-(methoxy-
carbonyl)phenyl]-5-methyl-4-oxo-1,3-thiazolidin-5-yl}ace-
tic acid (12)
Methyl-3-[(2S*,5R*)-2-[4-(benzyloxy)phenyl]-5-(2-hydroxy-
ethyl)-5-methyl-4-oxo-1,3-thiazolidin-3-yl]benzoate (9) (160
mg, 0.32 mmol) was oxidized with Jones reagent accord-
ing to the procedure for 13 above. Chromatography of
the crude product on silica gel and elution with 1% meth-
anol in CH2Cl2 afforded 70 mg (44% yield) of the title
compound as a foam; 1H NMR (CDCl3): d 1.79 (s, 3H);
3.30, 3.00 (dd, J = 16 Hz, 2H), 3.82 (s, 3H), 6.20 (s, 1H)
4.83 (s, 2H), 7.9–6.7(m, 13H), 9.7 (br, 1H); MS (ES-
positive): [M+H]+ 492. HPLC purity 80.5% at 210 nm,
81.6% at 230 nm, tR = 17.7 min; INERTSIL ODS-2,
4.6 · 150 mm column, 1 mL/min, 10 mM NH4H2PO4
(pH 3)/ACN.
4.9. Methyl-3-[(2S*,5R*)-2-[4-(benzyloxy)phenyl]-5-(2-
{[2-(3-ethoxy-4-methoxy-phenyl)ethyl]amino}-2-oxoeth-
yl)-5-methyl-4-oxo-1,3-thiazolidin-3-yl]benzoate (15)
{(2S*,5R*)-2-[4-(Benzyloxy)phenyl]-3-[3-(methoxycar-
bonyl)phenyl]-5-methyl-4-oxo-1,3-thiazolidin-5-yl}ace-
tic acid (12, 240 mg, 0.49 mmol) was dissolved in DMF
(15 mL) and treated at room temperature under N2 with
diisopropylethylamine (76 mg, 0.59 mmol) and 3-eth-
oxy-4-methoxyphenethylamine (114 mg, 0.59 mmol) in
DMF (0.5 mL). To this solution O-(7-azabenzotriazole-
1-yl)-N,N,N0,N0-tetra-methyl uronium hexafluorophos-
phate (233 mg, 0.59 mmol) was added. The resulting solu-
tion was stirred at rt/N2 for 20 h. It was diluted with ethyl
acetate (220 mL), washed with brine (3· 20 mL/extrac-
tion), dried with MgSO4 and evaporated. Chromatogra-
phy of the crude product on silica gel and elution with
1.5% methanol in CH2Cl2 afforded 250 mg (76% yield)
of the title compound as a white solid; 1H NMR (CDCl3):
d 3.58, 3.50 (2m, 2H), 3.87, 3.84 (2s, 3H each), 4.04 (m,
2H), 4.95 (s, 2H), 6.17 (s, 1H), 7.9–6.6 (m, 16H); MS
(ES-positive): [M+H]+ 669. HPLC purity 82% at
210 nm, 85% at 230 nm, tR = 17.5 min; Inertsil, 5 ODS2,
4.6 · 150 mm column, 1 mL/min, gradient: (A) water;
(B) acetonitrile.
4.7. {(2S*,5R*)-3-[3-(Aminocarbonyl)phenyl]-2-[4-(ben-
zyloxy)phenyl]-5-methyl-4-oxo-1,3-thiazolidin-5-yl}acetic
acid (13)
3-[(2S*,5R*)-2-[4-(Benzyloxy)phenyl]-5-(2-hydroxyeth-
yl)-5-methyl-4-oxo-1,3-thiazolidin-3-yl]benzamide (10,
200 mg, 0.43 mmol) was dissolved in acetone (25 mL)
and cooled to ꢁ10 ꢁC/N2. To this solution 1.4 M Jones re-
agent (0.5 mL) was added over a period of 5 min. The or-
ange colored mixture was stirred at ꢁ10 ꢁC for 2 h. The
mixture was treated consecutively with methanol
(1 mL), saturated aqueous solution of sodium bicarbon-
ate (2 mL) and acetic acid (1 mL) and then filtered. After
evaporation, the residue was diluted with water (15 mL)
and extracted four times with CH2Cl2 (40 mL/extraction).
The CH2Cl2 solution was washed with water, dried with
MgSO4, and evaporated. Chromatography of the crude
product on silica gel and elution with 4% methanol in
CH2Cl2 afforded 100 mg (40% yield) of the title com-
The following compounds were prepared using the pro-
cedure of compound 15:
1
1
pound as a white solid; H NMR (DMSO-d6): d H
NMR (DMSO-d6) d 2.93 (dd, J = 8.37, 8.38 Hz, 1H),
3.04 (dd, J = 17.26, 3.95 Hz, 1H), 4.51 (ddd, J = 5.42,
3.94, 1.48 Hz, 1H), 5.00 (s, 2H), 6.47 (d, J = 1.48 Hz,
1H), 6.90 (d, J = 8.87 Hz, 2H), 7.31 (d, J = 6.90 Hz,
1H), 7.34 (m, 6H), 7.43 (t, J = 7.88 Hz, 1H), 7.44 (m,
2H) 7.53 (dd, J = 7.89, 0.99 Hz, 1H), 7.73 (d,
4.10. 3-[(2S*,5R*)-2-[4-(Benzyloxy)phenyl]-5-(2-{[2-(3-
ethoxy-4- methoxyphenyl)-ethyl]amino}-2-oxoethyl)-5-
methyl-4-oxo-1,3-thiazolidin-3-yl]benzamide (16a)
From 13 and 3-ethoxy-4-methoxyphenethylamine.
Chromatography of the crude product on silica gel

J. Wrobel et al. / Bioorg. Med. Chem. 14 (2006) 5729–5741
5737
and elution with 3% methanol in CH2Cl2 afforded 74 mg
(60% yield) of the title compound as a white powder; 1H
NMR (DMSO-d6): d 1.57 (s, 3H), 2.63 (q, 2H), 2.81(s,
2H), 3.69 (s, 3H), 3.82 (m, 2H), 4.96 (s, 2H), 6.46 (s,
1H), 8.2–6.7 (m, 16H): HRMS calcd for
C37H39N3O6S+H+, 654.26323; found (ESI, [M+H]+),
654.2607. HPLC purity 97.1% at 210 nm, 98.0% at
230 nm, tR = 19.5 min; Capcell PAK C19 4.6 · 150 mm
column, 1 mL/min, acetonitrile/water.
1,3-thiazolidin-3-yl]benzamide (18, 770 mg, 1.18 mmol)
was dissolved in 1-methyl-2-pyrrolidinone (20 mL) and
treated with 3-chloroperoxy-benzoic acid (2 g, 60%purity,
7 mmol). The resulting solution was stirred at 60 ꢁC /N2
for 2 days. All the solvent was removed at 60 ꢁC under re-
duced pressure. The residue was dissolved in ethyl acetate
(400 mL), washed with 10% aqueous sodium sulfite solu-
tion (45 mL), saturated aqueous sodium bicarbonate solu-
tion (45 mL), brine, and dried with MgSO4. After
evaporation of the solvent, the crude product was purified
by chromatography on silica gel. Elution with 3% metha-
nol in CH2Cl2 afforded 695 mg (83% yield) of the title
compound as a white solid; 1H NMR (DMSO-d6): d
1.29 (t, 3H), 1.67 (s, 3H), 2.64 (q, 2H), 2.97 (m, 2H),
3.30 (m, 2H), 3.71 (s, 3H), 3.97 (q, 2H), 5.02 (s, 2H),
6.80 (s, 1H), 8.24–6.71 (m, 16H); MS (ES-positive):
[M+H]+ 686. HRMS calcd for C37H39N3O8S+H+,
686.25306; found (ESI, [M+H]+), 686.2548. HPLC purity
86% at 210 nm; 87% at 230 nm; tR = 22.7 min; Inertsil,
ODS3, 8 lm, 4.6 · 250 mm column, 1 mL/min, gradient:
(A) water; (B) acetonitrile.
4.11. 3-((2S*,5R*)-2-[4-(Benzyloxy)phenyl]-5-{2-[(3-eth-
oxy-4-methoxybenzyl)amino]-2-oxoethyl}-5-methyl-4-
oxo-1,3-thiazolidin-3-yl)benzamide (16b)
From 13 and 3-ethoxy-4-methoxybenzylamine. 1H NMR
(DMSO-d6) d 1.14 (t, J = 6.24 Hz, 3H), 1.62 (s, 3H), 2.94
(d, J = 4.50 Hz, 2H), 3.69 (s, 3H), 3.71 (q, J = 6.24 Hz,
2H), 4.23 (qd, J = 27.6, 5.44 Hz, 2H), 4.96 (s,
J = 4.5 Hz, 2H), 6.48 (s, 1H), 6.78 (d,d and s, J = 8.55,
1.65, 5H), 7.24 (m, 10H), 7.59 (d, J = 8.55, 1H), 7.80 (s,
1H), 7.89 (s, 1H), 8.63 (t, J = 5.95 Hz, 1H). HRMS calcd
for C36H37N3O6S+H+, 640.24758; found (ESI, [M+H]+),
640.2462. HPLC purity 92.7% at 210 nm, 93.1% at
230 nm; tR = 18.7 min; Xterra MS C18, 5 l, 4.6 · 150 mm
column, 1.0 mL/min, gradient: (A) water; (B) ACN.
4.15. Methyl-3-[(2S*,5R*)-5-allyl-2-[4-(benzyloxy)phen-
yl]-5-(2-{[2-(3-ethoxy-4-methoxyphenyl)ethyl]amino}-2-
oxoethyl)-4-oxo-1,3-thiazolidin-3-yl]benzoate (18)
4.12. 3-[(2S*,5R*)-2-[4-(Benzyloxy)phenyl]-5-methyl-4-
oxo-5-(2-oxo-2-{[3-(trifluoromethoxy)benzyl]amino}eth-
yl)-1,3-thiazolidin-3-yl]benzamide (16c)
From 14 and 3-ethoxy-4-methoxyphenethylamine. Yel-
low powder (290 mg, 94% yield). 1H NMR (DMSO-
d6): 1.24–1.27 (t, J = 7 Hz, 3H), 2.52–2.60 (q and s,
J = 7 Hz, 5H), 2.61–2.67 (t, J = 7 Hz, 2H), 2.75–2.89
(dd, J = 15.07, 15.07 Hz, 2H), 3.16–3.21 (m, 1H), 3.38–
3.43 (m, 1H), 3.69 (s, 2H), 3.86–3.93 (m, 1H), 4.95–
4.97 (d, J = 12 Hz, 1H), 5.15 (s, 3H), 5.23–5.33 (ddd,
J = 19.04, 10.30, 1.99 Hz, 1H), 5.94–6.01 (m, 1H), 6.29
(s, 1H), 6.68–6.6.72 (m, 2H), 6.780–6.83 (m, 3H), 7.27–
7.38 (m, 5H), 7.39–7.45 (m, 5H), 7.60–7.61 (d,
J = 2 Hz, 1H), 7.78 (s, 1H), 7.90–7.91 (br s, 1H), 8.09–
8.05 (t, J = 6 Hz, 1H). MS (ESI) [M+H]+ 695. HPLC
purity 88% at 210 nm; 91% at 230 nm; tR = 24.5 min;
Inertsil, 5 ODS2, 4.6 · 150 mm column, 1 mL/min, gra-
dient: (A) water; (B) acetonitrile.
From 13 and 3-trifluoromethoxybenzylamine. 1H NMR
(DMSO-d6) d 1.62 (s, 3H), 2.94 (s, 2H), 4.23 (qd,
J = 27.6, 5.44 Hz, 2H), 4.96 (s, 2H), 6.48 (s, 1H), 6.79
(d, J = 8.55, 2H), 7.18 (d, J = 8.55, 1H), 7.28 (s, 1H),
7.21 (m, 12H), 7.59 (d, J = 8.55, 1H), 7.80 (s, 1H), 7.89
(s, 1H), 8.63 (t, J = 5.95 Hz, 1H). HRMS calcd for
C34H30F3N3O5S+H+, 650.19310; found (ESI, [M+H]+),
650.1922. HPLC purity 89.4% at 210 nm, 89.6%
at 230 nm; tR = 21.4 min; Xterra MS C18, 5 lm,
4.6 · 150 mm column, 1.0 mL/min, gradient: (A) water;
(B) ACN.
4.13. 3-((2S*,5R*)-2-[4-(Benzyloxy)phenyl]-5-{2-[([1,10-
biphenyl]-3-ylmethyl)amino]-2-oxoethyl}-5-methyl-4-oxo-
1,3-thiazolidin-3-yl)benzamide (16d)
4.16. 3-[(2S*,5R*)-5-Allyl-2-[4-(benzyloxy)phenyl]-5-(2-
{[2-(3-ethoxy-4-methoxyphenyl)ethyl]amino}-2-oxoeth-
yl)-4-oxo-1,3- thiazolidin-3-yl]benzamide (19)
From 13 and 3-phenylbenzylamine. 1H NMR (DMSO-d6) d
1.62 (s, 3H), 2.94 (s, 2H), 3.69 (s, 3H), 4.23 (qd, J = 27.6,
5.44 Hz, 2H), 4.96 (s, J = 4.5 Hz, 2H), 6.48 (s, 1H), 6.78
(d,d and s, J = 8.55, 1.65 Hz, 2H), 7.24 (m, 16H), 7.59 (d,
J = 8.55, 1H), 7.80 (s, 1H), 7.89 (s, 1H), 8.63 (t,
J = 5.95 Hz, 1H). HRMS calcd for C39H35N3O4S+H+,
642.24210; found (ESI, [M+H]+), 642.2433. HPLC purity
81.7% at 210 nm, 81.9% at 230 nm; tR = 21.9 min; Xterra
MS C18, 5 lm, 4.6 · 150 mm column, 1.0 mL/min, gradi-
ent: (A) water; (B) ACN.
Compound 18 (230 mg, 0.331 mmol) was stirred with
ammonia in methanol to afford the title compound as
a
yellow syrup (190 mg, 84% yield). 1H NMR
(DMSO-d6): 1.24–1.27 (t, J = 7 Hz, 3H), 2.52–2.60 (q
and s, J = 7 Hz, 5H), 2.61–2.67 (t, J = 7 Hz, 2H), 2.75–
2.89 (dd, J = 15.07, 15.07 Hz, 2H), 3.16–3.21 (m, 1H),
3.38–3.43 (m, 1H), 3.69 (s, 2H), 3.86–3.93 (m, 1H),
4.95–4.97 (br s, 2H), 5.13–5.23 (ddd, J = 19.04, 10.30,
1.99 Hz, 1H), 5.94–6.01 (m, 1H), 6.29 (s, 1H), 6.68–
6.6.72 (m, 2H), 6.780–6.83 (m, 3H), 7.27–7.38 (m, 5H),
7.39–7.45 (m, 5H), 7.60–7.61 (d, J = 2 Hz, 1H), 7.78 (s,
1H), 7.90-7.91 (br s, 1H), 8.09–8.05 (t, J = 6 Hz, 1H).
HRMS calcd for C39H41N3O6S+H+, 680.27888; found
(ESI, [M+H]+), 680.2758. HPLC purity 98% at
210 nm; 98% at 230 nm; tR = 20.9 min; Inertsil, 5
ODS2, 4.6 · 150 mm column, 1 mL/min, gradient: (A)
water; (B) acetonitrile.
4.14. 3-[(2S*,5R*)-2-[4-(benzyloxy)phenyl]-5-(2-{[2- (3-eth-
oxy-4-methoxy-phenyl)ethyl]amino}-2-oxoethyl)-5-methyl-
1,1-dioxido-4-oxo-1,3-thiazolidin-3-yl]benzamide (17)
3-[(2S*,5R*)-2-[4-(Benzyloxy)phenyl]-5-(2-{[2-(3-ethoxy-4-
methoxyphenyl)-ethyl]amino-2-oxoethyl)-5-methyl-4-oxo-

5738
J. Wrobel et al. / Bioorg. Med. Chem. 14 (2006) 5729–5741
4.17. Methanesulfonic acid 2-[(2S*,5R*)-2-(4-benzyloxy-
phenyl)-3-(3-carbamoyl-phenyl)-5-methyl-4-oxo-thiazoli-
din-5-yl]-ethyl ester (20)
1.74 (s, 3H), 3.26 (s, 2H), 3.88 (s, 3H), 5.03 (s, 2H),
6.70 (s, 1H), 6.90 (d, J = 8.06, 2H), 7.35 (m, 7H), 7.46
(t, J = 8.06 Hz, 1H), 7.62 (d, J = 7.87 Hz, 1H), 7.76
(dd, J = 7.63, 0.78 Hz, 1H), 7.98 (s, 1H), 9.82 (s, 1H).
MS (ESI) [M+H]+ 476.
Methanesulfonyl chloride (148 mg, 1.29 mmol) was
added to a stirred solution of 3-[(2S*,5R*)-2-[4-(benzyl-
oxy)phenyl]-5-(2-hydroxyethyl)-5-methyl-4-oxo-1,3-thiaz-
olidin-3-yl]benzamide (10, 200 mg, 0.433 mmol) in
pyridine (5 mL) at 0 ꢁC under N2. The resulting red solu-
tion was stirred at 0 ꢁC for 2 h. The red solution was con-
centrated in vacuo to a red syrup. Biotage SiO2
chromatography 3% MeOH:CH2Cl2 afforded a yellow
powder (130 mg, 56% yield). 1H NMR (DMSO-d6) d
1.66 (s, 3H), 2.29 (m, 1H), 2.45 (m, 1H), 2.50 (s, 3H),
4.44 (m, 2H), 5.00 (s, 2H), 6.58 (s, 1H), 6.86 (d,
J = 8.65 Hz, 2H), 7.32 (m, 6H), 7.44 (m, 2H), 7.63 (d,
J = 7.68 Hz, 1H), 7.82 (s, 1H), 7.89 (s, 1H), 8.57 (br s,
2H). MS (ESI) [M+H]+ 541.
Sodium triacetoxyborohydride (67 mg, 0.315 mmol),
3-ethoxy-4-methoxy phenethylamine (45 mg, 0.231
mmol), and glacial acetic acid (12 lL) were added to a
solution of this aldehyde (100 mg, 0.210 mmol) in
dichloroethane (5 mL) at room temperature under N2.
The resulting yellow mixture was stirred at room tem-
perature for 90 min and quenched with saturated aque-
ous NaHCO3 (10 mL). More CH2Cl2 was added and the
solution was washed with water and dried over MgSO4.
Concentration in vacuo afforded a brown syrup. Biotage
SiO2 (40 s) chromatography 3.5% MeOH:CH2Cl2
afforded methyl 3-[(2S*,5R*)-2-[4-(benzyloxy)phenyl]-
5-(2-{[2-(3-ethoxy-4-methoxyphenyl)ethyl]amino}ethyl)-5-
methyl-4-oxo-1,3-thiazolidin-3-yl]benzoate as a brown
4.18. 3-[(2S*,5R*)-2-[4-(Benzyloxy)phenyl]-5-(2-{[2-(3,4-
dimethoxy phenyl)ethyl]amino}ethyl)-5-methyl-4-oxo-1,3-
thiazolidin-3-yl]benzamide (21a)
1
powder (68 mg, 58% yield). H NMR (DMSO-d6) d 1.26
(t, J = 6.95 Hz, 3H), 1.61 (s, 3H), 1.90 (m, 1H), 2.11 (m,
1H), 2.63 (m, 6H), 3.35 (br s, 1H), 3.70 (s, 3H), 3.81 (s,
3H), 3.92 (q, J = 6.95 Hz, 2H), 4.98 (s, 2H), 6.59 (s, 1H),
6.69 (d, J = 8.09 Hz, 1H), 6.80 (m, 4H), 7.18 (m, 8H),
7.54 (d, J = 8.18 Hz, 1H), 7.69 (d, J = 7.69 Hz, 1H), 7.91
(s, 1H). MS (ESI) [M+H]+ 655. This compound
(250 mg, 0.382 mmol) was reacted with ammonia in meth-
anol to afford the title compound as a yellow powder
(110 mg, 45% yield). 1H NMR (DMSO-d6) d 1.26 (t,
J = 6.95 Hz, 3H), 1.61 (s, 3H), 1.90 (m, 1H), 2.11 (m,
1H), 2.63 (m, 6H), 3.35 (br s, 1H), 3.81 (s, 3H), 3.92 (q,
J = 6.95 Hz, 2H), 4.98 (s, 2H), 6.59 (s, 1H), 6.69 (d,
J = 8.09 Hz, 1H), 6.80 (m, 4H), 7.18 (m, 8H), 7.54 (d,
J = 8.18 Hz, 1H), 7.69 (d, J = 7.69 Hz, 1H), 7.91 (s, 1H),
7.97 (br s, 2H). HRMS calcd for C37H41N3O5S+H+,
640.28397; found (ESI, [M+H]+), 640.2835. HPLC purity
94.1% at 210 nm, 94.1% at 230 nm, tR = 13.25 min; Inert-
sil, 5 ODS2, 4.6 · 150 mm column, 1 mL/min, gradient:
(A) 10 mM NH4H2PO4 (pH 3.0); (B) acetonitrile.
3,4-Dimethoxy phenethylamine (200 mg, 1.104 mmol)
was added to a stirred solution of methanesulfonic acid
2-[(2S*,5R*)-2-(4-benzyloxy-phenyl)-3-(3-carbamoyl-
phenyl)-5- methyl-4-oxo-thiazolidin-5-yl]-ethyl ester (20,
110 mg, 0.204 mmol) in DMF (10 mL) at room temper-
ature under N2. The resulting yellow solution was heat-
ed at 75 ꢁC for 6 h and then concentrated in vacuo to a
brown syrup. Gravitational SiO2 chromatography 4%
MeOH:CH2Cl2 afforded the title compound as a yellow
powder (80 mg, 63% yield). 1H NMR (DMSO-d6) d 0.24
(br s, 1H), 1.64 (s, 3H), 2.04 (m, 1H), 2.18 (m, 1H), 2.72
(m, 6H), 3.70 (s, 3H), 3.73 (s, 3H), 4.99 (s, 2H), 6.57 (s,
1H), 6.74 (dd, J = 8.11, 1.53 Hz, 1H), 6.84 (m, 4H), 7.28
(m, 9H), 7.63 (d, J = 7.56 Hz, 1H), 7.86 (s, 1H), 7.97 (br
s, 2H). HRMS calcd for C36H39N3O5S+H+, 626.26832;
found (ESI, [M+H]+), 626.2673. HPLC purity 88% at
210 nm; tR = 15.9 min; Primesphere, C18-HC, 5 lm,
4.6 · 250 mm column, 1 mL/min, gradient: (A) 10 mM
NH4H2PO4 (pH 3.0); (B) acetonitrile.
4.20. 3-[(2S*,5R*)-2-[4-(Benzyloxy)phenyl]-5-(2-{[2- (3,4-
dimethoxy phenyl)ethyl]thio}ethyl)-5-methyl-4-oxo-1,3-
thiazolidin-3- yl]benzamide (22a)
4.19. 3-[(2S*,5R*)-2-[4-(Benzyloxy)phenyl]-5-(2-{[2-(3-
ethoxy-4-methoxy phenyl)ethyl]amino}ethyl)-5-methyl-4-
oxo-1,3-thiazolidin-3-yl]benzamide (21b)
Sodium hydride (20 mg, 0.509 mmol) was added to a
solution of 3,4-dimethoxyphenethane thiol (97 mg,
0.489 mmol) in DMF (4 mL) at room temperature
under N2. After 30 min, this solution was added to a
solution of methanesulfonic acid 2-[(2S*,5R*)-2-(4-
benzyloxy-phenyl)-3-(3-carbamoyl-phenyl)-5- methyl-4-
oxo-thiazolidin-5-yl]-ethyl ester (20, 110 mg, 0.205
mmol) in DMF (30 mL) and the reaction mixture was
heated at 55 ꢁC for 3 hrs. The resultant yellow solution
was cooled to room temperature and quenched with 2 N
HCl (50 mL). The reaction mixture was diluted with
CH2Cl2 (40 mL), washed with water, dried over MgSO4,
filtered, and concentrated in vacuo. Biotage SiO2 chro-
matography 2% MeOH:CH2Cl2 afforded the title com-
pound as a yellow powder (410 mg, 19% yield). 1H
NMR (DMSO-d6) d 1.63 (s, 3H), 2.00 (m, 1H), 2.21
(m, 1H), 2.54 (m, 1H), 2.73 (m, 5H), 3.69 (s, 3H), 3.70
(s, 3H), 4.98 (s, 2H), 6.56 (s, 1H), 6.73 (dd, J = 8.18,
Pyridinium chlorochromate (4.51 g, 20.941 mmol) was
added to CH2Cl2 (100 mL) at 0 ꢁC under N2. To the
orange mixture was added methyl 3-[(2S*,5R*)-2-[4-
(benzyloxy)phenyl]-5-(2-hydroxyethyl)-5-methyl-4-oxo-1,
3-thiazolidin-3-yl]benzoate (9, 1.00 g, 2.094) in CH2Cl2
(60 mL) dropwise over 30 min. The resulting dark
brown mixture was stirred at 0 ꢁC 2 h and then
quenched with water (150 mL), diluted with CH2Cl2
(100 mL), and filtered through Celite. The organic layer
was extracted with water (2· 150 mL), dried over
MgSO4, filtered, and concentrated in vacuo to a dark
brown syrup. Biotage SiO2 chromatography (40 s
cartridge) 1:1/hexane:EtOAc afforded methyl 3-
[(2S*,5R*)-2-[4-(benzyloxy)phenyl]-5- methyl-4-oxo-5-
(2-oxoethyl)-1,3-thiazolidin-3-yl]benzoate as a yellow
1
powder (617 mg, 62% yield). H NMR (DMSO-d6) d

J. Wrobel et al. / Bioorg. Med. Chem. 14 (2006) 5729–5741
5739
1.47 Hz, 1H), 6.83 (t, J = 9.93 Hz, 1H); MS (ESI)
[M+H]+ 643. HPLC purity 90.6% at 210 nm; 91.9% at
230 nm; tR = 17.6 min; Inertsil, 5 ODS2, 4.6 · 150 mm
column, 1 mL/min, gradient: (A) water; (B) acetonitrile.
CHN C36H38N2O5SÆ1/10H2O: Calcd C, 67.05; H, 5.97;
N, 4.34. Found: C, 67.37; H, 6.24; N, 4.52.
phenethyl-amine (200 mg, 1.03 mmol) in CH2Cl2
(2 mL) at ꢁ10 ꢁC /N2. After stirring at 0 ꢁC under N2
for 5 h, it was diluted with aqueous 1 N hydrochloric
acid (50 mL) and extracted with CH2Cl2 (4 · 50 mL).
The CH2Cl2 solution was washed with water, dried with
MgSO4, and evaporated. Chromatography of the crude
product on silica gel and elution with 2% methanol in
CH2Cl2 afforded 204 mg (90% yield) of the title com-
4.21. 3-[(2S*,5R*)-2-[4-(Benzyloxy)phenyl]-5-(2-{[2-(3-
ethoxy-4-methoxyphenyl)ethyl]thio}ethyl)-5-methyl-4-
oxo-1,3-thiazolidin-3-yl]benzamide (22b)
1
pound as a white solid; H NMR (DMSO-d6): d 1.29
(t, 3H), 1.64 (t, 3H), 2.20 (m, 2H), 2.62 (t, 2H), 3.18 (m,
2H) 3.69 (s, 3H), 3.96 (q, 2H), 4.20 (m, 2H), 4.98 (s, 2H),
6.55 (s, 1H), 8.0–6.6 (m, 16H); HRMS calcd for
C38H41N3O7S+H+, 684.27380; found (ESI, [M+H]+),
684.2755. HPLC purity 92.6% at 210 nm; 93.4% at
230 nm; tR = 21.4 min; Inertsil, 5 ODS2, 4.6 · 150 mm
column, 1 mL/min, gradient: (A) water; (B) acetonitrile.
Anal. Calcd for C37H39N3O7S: C, 66.74; H, 6.04; N,
6.14. Found: C, 66.75; H, 6.23; N, 6.07.
Using the procedure of the above example (22a) and
substituting 4-ethoxy-3-methoxyphenethane thiol for
3,4-dimethoxyphenylethane thiol afforded the title com-
pound as a yellow powder (220 mg, 62% yield). 1H
NMR (DMSO-d6) d 1.27 (t, J = 7.23 Hz, 3H), 1.63 (s,
3H), 2.01 (td, J = 13.88, 4.36 Hz, 1H), 2.22 (td,
J = 13.88, 4.36 Hz, 1H), 2.54 (td, J = 13.88, 4.36 Hz,
1H), 2.57 (td, J = 13.88, 4.36 Hz, 1H), 2.71 (m, 1H)
2.77 (s, 3H), 2.82 (td, J = 13.88, 4.36 Hz, 1H), 3.71 (s,
3H), 3.94 (q, J = 7.23 Hz, 2H), 4.98 (s, 2H), 6.55 (s,
1H), 6.72 (dd, J = 9.92, 1.98 Hz, 1H), 6.83 (2d,
J = 5.16,1.19 Hz, 2H), 6.87 (d, J = 5.16 Hz, 2H), 7.29
(d, J = 5.95 Hz, 2H), 7.34 (d, J = 7.94 Hz, 2H), 7.40
(d, J = 6.35 Hz, 2H), 7.41 (br s, 2H), 7.43 (dd,
J = 7.92, 1.19 Hz, 1H), 7.64 (d, J = 7.92 Hz, 1H), 7.83
(m, J = 1.19 Hz, 1H), 7.93 (br s, 1H); MS (ESI)
[M+H]+ 657. HPLC purity 86.8% at 210 nm, 86.5% at
230 nm, tR = 24.2 min; Capcell PAK C18 4.6 · 150 mm
column, 1 mL/min, water/acetonitrile. Anal. Calcd for
C37H40N2O5S2: C, 67.66; H, 6.14; N, 4.26. Found: C,
67.28; H, 6.32; N, 4.20.
4.24. 2-{(2S*,5R*)-3-[3-(Aminocarbonyl)phenyl]-2-[4-
(benzyloxy)phenyl]-5-methyl-4-oxo-1,3-thiazolidin-5-
yl}ethyl 3,4,5-trimethoxybenzylcarbamate (24b)
Ethoxy-4-methoxybenzaldehyde (3.6 g, 20 mmol) and
methyl hydroxylamine HCl salt (4.0 g, 48 mmol) were
dissolved in dry pyridine (15 mL) and stirred for 5 h at
room temperature under N2. The resulting suspension
was filtered and filtrate was evaporated at 40 ꢁC under
reduced pressure to give a light brown solid. The solid
material was dissolved in methanol (25 mL), diluted
with water (25 mL), and was cooled at 0 ꢁC to induce
crystallization. The white crystalline material was col-
lected by filtration, rinsed with methanol, and dried in
vacuum to give 2.75 g (66% yield) of 3-ethoxy-4-meth-
oxybenzaldehyde methoxyoxime as a white powder;
1H NMR (DMSO-d6) d 1.32 (t, 3H), 3.78 (s, 3H), 3.85
(s, 3H), 4.00 (q, 2H), 6.90–7.30 (m, 3H), 8.11(s, 1H);
MS (ES-positive): [M+H]+ 210. HPLC determined that
this compound 99% purity.
4.22. 2-{(2S*,5R*)-3-[3-(Aminocarbonyl)phenyl]-2-[4-
(benzyloxy)phenyl]-5-methyl-4-oxo-1,3-thiazolidin-5-
yl}ethyl 4-nitrophenyl carbonate (23)
A solution of 3-[(2S*,5R*)-2-[4-(benzyloxy)phenyl]-5-(2-
hydroxyethyl)-5-methyl-4-oxo-1,3-thiazolidin-3-yl]benz-
amide (10, 1.7 g, 3.8 mmol) in CH2Cl2 (50 mL)/pyridine
(5 mL) was treated with 4-nitrophenyl chloroformate
(1.1 g, 5.7 mmol) at 0 ꢁC under N2. After stirring at
room temperature under N2 for 1.5 h, it was diluted with
water (100 mL) and extracted with CH2Cl2 (4· 50 mL).
The combined CH2Cl2 solution was washed with water,
dried with MgSO4, and evaporated. Chromatography of
the crude product on silica gel and elution with 2%
methanol in CH2Cl2 afforded 1.9 g (83% yield) of the ti-
tle compound as a white solid; 1H NMR (DMSO-d6): d,
1.69 (s, 3H), 2.62, 2.20 (mm, 2H), 2.62, 2.20 (mm, 2H),
4.59 (m, 2H), 4.99 (s, 2H), 6.61 (s, 1H), 8.40–6.80 (m,
17H, aromatic); MS (ES-positive): [M+H]+ 628; Anal.
Calcd for C33H29N3O8S: C, 63.15; H, 4.66; N, 6.69.
Found: C, 62.86; H, 4.55; N, 6.47.
This compound (2.51 g) was dissolved in THF (15 mL)
and treated with 1 M diborane in THF (36 mL,
36 mmol) at rt/N2. The solution was heated under reflux
for 2 h, then cooled to 0 ꢁC, and treated with water
(10 mL) and 20% KOH aqueous solution (10 mL). The
mixture was heated under reflux for 1.5 h and extracted
with CH2Cl2. Evaporation of CH2Cl2extract and chro-
matography of crude product on silica gel afforded
2.1 g (62% yield) of 3-ethoxy-4-methoxybenzylamine as
1
a light brown oil; H NMR (DMSO-d6) d 1.31 (t, 3H),
3.71 (s, 3H), 3.97 (q, 2H), 4.28 (s, 2H), 6.70–7.00 (m, 3H).
Using the procedure of compound 24a and substituting 3-
ethoxy-4-methoxybenzylamine, the title compound was
1
obtained as a white solid; H NMR ( DMSO-d6) d 1.26
4.23. 2-{(2S*,5R*)-3-[3-(Aminocarbonyl)phenyl]-2-[4- (ben-
zyloxy)phenyl]-5-methyl-4-oxo-1,3-thiazolidin-5-yl}ethyl
2-(3-ethoxy-4-methoxyphenyl)ethylcarbamate (24a)
(t, 3H), 1.64 (s, 3H), 2.25 (m, 2H), 3.69 (s, 3H), 3.90 (q,
2H), 4.12 (d, J = 7.5 Hz, 2H), 4.25 (m, 2H), 4.97 (s, 2H),
6.55 (s, 1H), 6.70–8.00 (m, 16H); MS (ES-positive):
[M+H]+ 670. HRMS calcd for C37H39N3O7S+H+,
670.25815; found (ESI, [M+H]+), 670.2587. HPLC purity
88.5% at 210 nm, 90.3% at 230 nm, tR = 20.3 min; Xterra
MS, C18, 5 lm, 4.6 · 150 mm column, 1 mL/min, gradi-
ent: (A) water; (B) acetonitrile.
2-{(2S*,5R*)-3-[3-(Aminocarbonyl)phenyl]-2-[4-(benzyl-
oxy)phenyl]-5-methyl-4-oxo-1,3-thiazolidin-5-yl}ethyl 4-
nitrophenyl carbonate (23, 200 mg, 0.31 mmol) in
CH2Cl2 (10 mL) was treated with 3-ethoxy-4-methoxy-

5740
J. Wrobel et al. / Bioorg. Med. Chem. 14 (2006) 5729–5741
4.25. 2-{(2S*,5R*)-3-[3-(Aminocarbonyl)phenyl]-2-[4-
(benzyloxy)phenyl]-5-methyl-4-oxo-1,3-thiazolidin-5-
yl}ethyl 3,4,5-trimethoxybenzylcarbamate (24c)
(s, 1H), 6.80–8.00 (m, 17H); HRMS calcd for
C35H32F3N3O6S+H+,
680.20367; found (ESI,
[M+H]+), 680.204. HPLC purity 93.9% at 210 nm,
93.9% at 230 nm, tR = 22.6 min; Xterra MS C18,
4.6 · 150 mm, 5 lm column, 1 mL/min, gradient: (A)
water; (B) ACN. Anal. Calcd for C35H32F3N3O6S: C,
61.85; H, 4.75; N, 6.18. Found: C, 61.75; H, 4.82; N,
6.09.
Using the procedure of compound 24a and substituting
3,4,5-trimethoxybenzylamine in place of 3-ethoxy-4-
methoxyphenethyl-amine, the title compound was ob-
1
tained as a white solid: H NMR (DMSO-d6) d 1.62 (s,
3H), 2.11 (m, 1H), 2.29 (m, 1H), 3.59 (s, 1H), 2.58 (m,
2H), 3.58 (s, 3H), 3.62 (s, 6H), 4.11 (d, J = 5.35 Hz, 1H),
4.21 (m, 1H), 4.99 (s, 2H), 6.84 (d, J = 6.11 Hz, 3H),
6.84 (d, J = 8.68 Hz, 2H), 7.29 (m, 2H), 7.34 (m, 5H),
7.38 (m, 1H), 7.58 (m, 1H), 7.70 (s, 1H), 7.83 (s, 1H).
HRMS calcd for C37H39N3O8S+H+, 686.25306; found
(ESI, [M+H]+), 686.2535. HPLC purity 89.4% at
210 nm, 91.0% at 230 nm; tR = 19.6 min; Xterra MS
C18 4.6 · 150 mm column, 1 mL/min, gradient: (A)
water; (B) ACN.
4.29. 2-{(2S*,5R*)-3-[3-(Aminocarbonyl)phenyl]-2-[4-
(benzyloxy)phenyl]-5-methyl-4-oxo-1,3-thiazolidin-5-
yl}ethyl 3-iodobenzylcarbamate (24g)
Using the procedure of compound 24a and substituting
3-iodobenzylamine, the title compound was obtained as
1
a white solid; H NMR (DMSO-d6) d 1.65 (s, 3H), 2.25
(m, 2H), 4.17 (m, 4H), 4.98 (s, 2H), 6.55 (s, 1H), 6.70–
8.15 (m, 17H); MS (ES-positive): [M+H]+ 722. HPLC
purity 90.4% at 210 nm, 91.3% at 230 nm; tR = 22.3 min;
Xterra MS C18, 4.6 · 150 mm column, 1 mL/min, gradi-
ent: (A) water; (B) ACN. Anal. Calcd for C34H32I-
N3O5S: C, 56.59; H, 4.47; N, 5.82. Found: C, 56.91;
H, 4.60; N, 5.53.
4.26. 2-{(2S*,5R*)-3-[3-(aminocarbonyl)phenyl]-2-[4-
(benzyloxy)phenyl]-5-methyl-4-oxo-1,3-thiazolidin-5-
yl}ethyl [1,10-biphenyl]-3-ylmethylcarbamate (24d)
Using the procedure of compound 24a and substituting 3-
phenyl-benzylamine in place of 3-ethoxy-4-methoxy-
phenethyl-amine, the title compound was obtained as a
Acknowledgment
1
white solid: H NMR (DMSO-d6) d 1.67 (s, 3H), 2.13
(m, 2H), 4.18 (m, 4H), 4.99 (s, 2H), 6.56 (s, 1H), 6.82 (d,
J = 8.85 Hz, 2H), 7.24 (m, 9H), 7.39 (m, 4H), 7.47 (t,
J = 8.07 Hz, 2H), 7.52 (d, J = 6.27 Hz, 1H), 7.60 (m,
3H), 7.74 (t, J = 6.07 Hz, 1H), 7.81 (s, 1H), 7.91 (s, 1H).
HRMS calcd for C40H37N3O5S+H+, 672.25267; found
(ESI, [M+H]+), 672.251. HPLC purity 91.9% at 210 nm,
93.1% at 230 nm, tR = 17.1 min; X Terra MS C18, 5 lm,
4.6 · 150 mm column, 1 mL/min, gradient: (A) water;
(B) ACN.
We are grateful to the Discovery Analytical Chemistry
Department of Wyeth for elemental analyses, 1H
NMR, mass spectroscopy, and HPLC data.
References and notes
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4.27. 2-{(2S*,5R*)-3-[3-(Aminocarbonyl)phenyl]-2-[4-
(benzyloxy)phenyl]-5-methyl-4-oxo-1,3-thiazolidin-5-
yl}ethyl 4-(1,2,3-thiadiazol-5-yl)benzylcarbamate (24e)
Using the procedure of 24a and substituting 4-(1,2,3-
thiadiazol-5-yl)benzylamine, the title compound was ob-
1
tained as a white solid; H NMR (DMSO-d6) d 1.66 (s,
3H), 2.18 (m, 1H), 2.32 (m, 1H), 4.16 (m, 1H), 4.27 (d,
J = 6.18 Hz, 2H), 4.28 (m, 1H), 4.96 (s, 2H), 6.57 (s,
1H), 6.82 (d, J = 8.56 Hz, 2H), 7.25 (m, 8H), 7.38 (m,
4H), 7.61 (d, J = 7.65 Hz, 1H), 7.78 (t, J = 6.18 Hz,
1H), 7.81 (s, 1H), 7.96 (s, 1H), 8.20 (d, J = 8.08 Hz,
2H), 9.59 (s, 1H). HRMS calcd for C36H33N5O5S2+H+,
680.19959; found (ESI, [M+H]+), 680.201. HPLC purity
94.2% at 210 nm, 94.8% at 230 nm, tR = 20.2 min; X
Terra MS C18, 5 lm, 4.6 · 150 mm column, 1 mL/
min, gradient: (A) water; (B) ACN.
7. Maclean, D.; Holden, F.; Davis, A. M.; Scheuerman, R.
A.; Yanofsky, S.; Holms, C. R.; Fitch, W. L.; Tsutsui, K.;
Barrett, R. W.; Gallop, M. A. J. Comb. Chem. 2004, 6,
196–206.
4.28. 2-{(2S*,5R*)-3-[3-(Aminocarbonyl)phenyl]-2-[4-
(benzyloxy)phenyl]-5-methyl-4-oxo-1,3-thiazolidin-5-
yl}ethyl 3-(trifluoromethoxy)benzylcarbamate (24f)
8. Shen, E. S.; Wrobel, J.; Ruhland, B.; Scheuerman, R. A.;
Holmes, C. P.; Yanofsky, S.; Wu, M. M.; Meade, E. H.;
Perez, M. C.; Chen, G.-C.; Arey, B. J.; Chi, J. C.;
Winneker, R. C. In Activation of the Follicle-Stimulating
Hormone (FSH) Receptor Signalling Pathway by a Novel
Using the procedure of compound 24a and substituting
3-trifluoromethoxybenzylamine, the title compound was
obtained as a white solid; H NMR (DMSO-d6) d 1.65
(s, 3H), 2.20 (m, 2H), 4.25 (m, 4H), 5.00 (s, 2H), 6.55
1

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