Preparation of highly substituted γ-lactam follicle stimulating hormone receptor agonists

Article abstract of DOI:10.1016/j.bmc.2005.07.025

An unusual combination of Weinreb amidation and Mitsunobu lactam formation was used to prepare highly substituted γ-lactam analogues of a thiazolidinone follicle stimulating hormone receptor agonist. The analogue synthesis was stereoselective and the fina

Full text of DOI:10.1016/j.bmc.2005.07.025

Bioorganic & Medicinal Chemistry 13 (2005) 5986–5995
Preparation of highly substituted c-lactam follicle
stimulating hormone receptor agonists
Jeffrey C. Pelletier,a,* John Rogers,a Jay Wrobel,a M. Claudia Perezb and Emily S. Shenb
aDepartment of Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
bDepartment of Womenꢀs Health and Musculoskeletal Biology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
Received 26 April 2005; revised 7 July 2005; accepted 7 July 2005
Available online 15 August 2005
Abstract—An unusual combination of Weinreb amidation and Mitsunobu lactam formation was used to prepare highly substituted
c-lactam analogues of a thiazolidinone follicle stimulating hormone receptor agonist. The analogue synthesis was stereoselective and
the final products were chemically stable. Biological properties of the target molecules were nearly identical to those of the lead
compound.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
testing of the separable diastereomers indicated that
the more active species had the syn configuration. In
addition to this, after separation to pure diastereomers
both compounds tended to isomerize upon standing.
Follicle stimulating hormone (FSH) is a 38 kDa protein
that triggers maturation of ovarian follicles in women
and spermatogenesis in men. It is released from the ante-
rior pituitary gland, following stimulation by gonado-
tropin-releasing hormone (GnRH), and serves as the
naturally occurring agonist of the FSH receptor
(FSHR).1 The receptors are located on granulosa cells
in females and Sertoli cells in males. Natural or recom-
binant FSH is used as a fertility treatment in women.2
Its expense and method of administration (injection in
a clinical setting), however, make compliance difficult.
A small molecule FSH agonist could offer considerable
mitigation of these circumstances.3,4
Chemical instability, observed in 1, is presumed to orig-
inate from the activated hydrogen at the 5-position and/
or the thioaminal carbon via a ring opening and closure
equilibrium mechanism. In an attempt to overcome this
situation, we designed a new compound, 2a (Fig. 1), that
has a methylene group in the place of the ring sulfur
atom, as well as a methyl group replacing hydrogen at
position 5. These changes were expected to impart chem-
ical stability by locking the resulting c-lactam in the
active syn configuration. Structural similarity to
compound 1 also suggests that biological activity should
remain in this compound.
A recent disclosure described the preparation and FSH
agonist activity of thiazolidinones, such as 1.4a Com-
pounds were initially prepared using split–mix combina-
torial synthesis technology and were tested as mixtures,
following resin cleavage of the products, in a luciferase
reporter gene assay dependent on FSHR activation
(compound 1 EC50 = 14 nM).5 Despite the ease of thia-
zolidinone preparation, little control over relative
stereoselectivity at the 2,5-positions on the heterocyclic
ring could be achieved. In our hands, this also occurred
during resynthesis of the discrete compounds. In gener-
al, the anti isomer predominated, while additional
The proposed method of preparation for the target
compound is shown in the retrosynthetic analysis
(Fig. 2). The key step would be the proposed conversion
of lactone 4 to highly substituted lactam 6 in a stereo-
selective fashion. An interesting way to implement this
transformation would be amide formation (from the
corresponding lactone) via Weinreb methodology,6
followed by an intramolecular Mitsunobu cyclization
of 5 to the lactam. It is desirable that this closure occur
with inversion of configuration since the stereochemistry
a to the carbonyl in lactone 4 will be opposite to that
desired in the final compound 2. Mitsunobu alkylation
of primary and secondary amides generally occur with
Keywords: Follicle stimulating hormone; FSH; Mitsunobu reaction.
*
Corresponding author. E-mail: pelletj@wyeth.com
0968-0896/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.07.025

J. C. Pelletier et al. / Bioorg. Med. Chem. 13 (2005) 5986–5995
5987
2
O
H2N
O
Oxidation, amide formation,
hydrolysis
O
O
O
NH
CN
N
S
O
N
O
RO
1 (FSH Reporter EC50 = 14 nM)
6
Intramolecular Mitsunobu
O
OH
H
H2N
O
N
CN
O
O
RO
O
O
NH
5
N
RO
Weinreb amide formation
O
2a, R = Bn
2b, R = n-Bu
O
Figure 1. FSHR agonist 1 and the proposed structure 2.
RO
4
the more acidic versions.7 There are a few instances,
however, of lactam formation via intramolecular
cyclization,8 while stereoselective examples are rare.9
Figure 2. Retrosynthetic analysis of 2.
Conversion to the final product
accomplished by standard techniques.
2
should be
9b:10b, 67:9 yield ratio). The mixtures were allylated at
the 3-position under conditions similar to those used
for the previous reaction to provide the single isomers
4a, b in 68% and 61% yields, respectively. The presumed
relative stereochemistry of the products most likely
resulted from phenyl group steric hindrance directing
the nucleophilic attack from the opposite face of the
lactones.
In addition to 2a, compound 2b was also prepared under
the expectation (a priori) that biological activity of the
n-butyl analogue of the benzyl compound 2a would
not differ significantly from the parent structure. With
lower molecular weight (636 for 2a, 602for 2b) and a
ClogP closer to 5.0 (5.99 for 2a, 5.80 for 2b), this com-
pound may show better drug-like properties in future
studies.
Key intermediate lactams 6a and b were prepared, as
shown in Scheme 2. Hence, lactones 4a and b were treat-
ed with the aluminate of 3-cyanoaniline under Weinreb
conditions.6 Isolation of product 5a from aluminum
salts was difficult, so a one-pot procedure involving ami-
dation and closure to the key intermediate lactam, via
intramolecular Mitsunobu reaction, was attempted.
Following amide formation, the intermediate 5a was
treated with triphenylphosphine (TPP) and diethylazo-
dicarboxylate (DEAD) in toluene and stirred at
room temperature. The reaction was followed by
LC/MS and was complete in 1 h. Product isolation
Preparation of intermediate 4 is shown in Scheme 1. The
commercially available oxobutyric acid 3 reacted with
benzyl bromide in the presence of potassium carbonate
to give the ester 7a in good yield, while 7b was available
commercially. Ketone reduction of 7a, b with sodium
borohydride provided the expected alcohols, which then
spontaneously cyclized to lactones 8a, b during workup
procedures (see Section 2). The lactones were methylat-
ed under standard conditions to provide a separable
mixture of diastereomers (9a:10a, 50:8 yield ratio and

5988
J. C. Pelletier et al. / Bioorg. Med. Chem. 13 (2005) 5986–5995
CO2H
O
CO2Bn
O
O
O
a
RO
4a, b
HO
RO
3
7a, b
a
O
c
b
O
OH
RO
8a, b
H
N
CN
O
O
O
O
RO
O
5a, b
+
RO
RO
10a, b
9a, b
b
d
O
O
NC
RO
O
NC
RO
N
N
O
+
H
Noe
6a, b
RO
4a, b
11a, b
Scheme 1. Reagents: (a) BnBr, K2CO3, H2O, DMF (7a, R = Bn, 59%);
(b) NaBH4, NaOEt, EtOH (8a, R = Bn, 67%; 8b, R = n-Bu, 64%); (c)
LiHMDS, MeI, THF (9a, R = Bn, 50%; 10a, 8%; 9b, R = n-Bu, 67%;
10b, 9%); (d) LiHMDS, allyl bromide, THF (4a, R = Bn, 68%; 4b,
R = n-Bu, 61%).
Scheme 2. Reagents: (a) AlMe3, 3-cyanoaniline, toluene; (b) (Ph)3P,
DEAD, toluene (6a, R = Bn, 67%; 6b, R = n-Bu, 39%; 11a, R = Bn,
10%; 11b, R = n-Bu, 0%).
fluorophosphate (HATU) as the coupling reagent to
provide the expected exocyclic amides 13a and b.
Finally, the nitriles were hydrolyzed under Evans condi-
tions (LiOH, H2O2)11 to give targets 2a and b in 45%
and 97% yields, respectively, over two steps. NMR
analysis of the products indicated little change in struc-
ture and purity after standing for two weeks, thus con-
firming the expected increase in stability of 2a, b in
comparison to 1.
and purification were considerably easier at this stage.
The separable diastereomers 6a and 11a were isolated
in a ratio of nearly 7:1 (total yield = 77%). NOE exper-
iments confirmed the relative stereochemistry of lactam
6a. This also confirmed that intramolecular Mitsunobu
lactam formation can occur stereoselectively, even with
a sensitive substrate, such as 5a, which possesses an epi-
merizable benzylic alcohol para to the benzyloxy func-
tion. Transformation of the lactone 4b to lactam 6b
under identical conditions occurred in modest yield
but the diastereomer 11b could not be detected.
Compounds 1 and 2a, b were tested in agonist mode on
a Chinese hamster ovary (CHO) cell line that expresses
recombinant human FSHR and a luciferase reporter
gene regulated by a cAMP response element (CRE).5
EC50s of 14, 25, and 27 nM were obtained for these ana-
logues, respectively (Table 1). All compounds clearly
possessed cell-based agonist activity. No compounds
were active when the luciferase assay was run in antag-
onist mode (data not shown). The three compounds
were also tested on a CHO-cell line that overexpressed
Conversion of lactams 6a and b to the final products 2a
and b (Scheme 3) began with oxidation of the olefins of 6
to the acids 11 (95% and 92% yields, respectively) under
Sharpless conditions.10 The acids were reacted with
3-ethoxy-4-methoxyphenethylamine using O-(7-aza-
benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium hexa-

J. C. Pelletier et al. / Bioorg. Med. Chem. 13 (2005) 5986–5995
5989
and efficacy levels (Table 1). In antagonist mode, they
were inactive (data not shown). In addition, analogues
1 and 2a, b were tested on CHO cells that did not
express the FSHR by measuring cAMP production.
The compounds were inactive, indicating the lack of a
nonspecific effect (data not shown).
CN
O
N
Additional functional selectivity studies were performed
in a CHO-cell line overexpressing the recombinant
human thyroid stimulating hormone receptor (TSHR).
The receptor shares significant homology with the
FSHR, indicating cross-reactivity as a potential safety
issue. The ability of lactams 1 and 2a, b to induce or
inhibit cAMP production in this TSHR cell line was
negative (data not shown). Comparison of biological
activity profiles for 1 and 2a, b indicates similarity
between them, which confirms that structural changes
designed to enhance chemical stability have not been
deleterious to desired FSH agonist activity.
RO
6a, b
a
CN
O
N
CO2H
To conclude, a-methyl lactam analogues of a thiazolid-
inone FSH receptor agonist were prepared using a nov-
RO
12a, b
el,
stereoselective,
intramolecular
Mitsunobu
cyclization. Relative stereochemistry was confirmed by
2D NMR. Lactams 2a and b possessed FSH agonist
activity similar to compound 1 in functional potency,
efficacy, and selectivity over the TSHR.
b
2. Experimental
R'
2.1. General methods
O
O
N
Appropriate safety practices were observed 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 Aldrich Chemical
Co. and used without further treatment. Microanalyses
were performed by Robertson Microlit Labs (Madison,
NJ). High-resolution mass spectra were taken on a
Waters LC–TOFMS instrument. Accurate masses were
measured to within 5 ppm of the calculated values. Pro-
O
N
H
O
RO
13a, b R' = CN
c
2a, b R' = CONH2
Scheme 3. Reagents: (a) RuO2, NaIO4, CCl4, AcCN, H2O (12a,
R = Bn, 95%; 12b, R = n-Bu, 92%); (b) 30-ethoxy-40-methoxyphenyl-
ethylamine, HATU, DIPEA, DMF (R = Bn, 48%; R = n-Bu, 68%); (c)
30% H2O2, LiOHÆH2O, H2O, THF (2a, R = Bn, 45%; 2b, R = n-Bu,
97%).
1
ton H and 13C NMR were taken on a Bruker DPX300
(300 MHz) instrument and delta values (d) were mea-
sured in parts per million using tetramethylsilane as an
internal standard (d = 0 ppm). High performance liquid
chromatography (HPLC) was performed with an Agilent
1100F series instrument with autosampler, thermoregu-
lated column oven, and a diode array detector. The fol-
lowing method was used to determine the purity and
retention times for intermediates and the final product:
the FSHR for the ability to induce cAMP production.12
The analogues 1 and 2a, b had EC50s of 166 nM (76%
efficacy compared to FSH), 400 nM (87% efficacy com-
pared to FSH), and 400 nM (80% efficacy compared to
FSH), respectively, indicating similar functional potency
Table 1. A comparison of functional FSH activity of 1 and 2a, b
Compound
EC50 (nM) (% efficacy compared to FSH)
FSHR-dependent CRE LUC
cAMP production
1
14.4 3.4 (n = 2; 92%)
24.8 11.8 (n = 2; 86%)
26.5 + 6.5 (n = 2; 111%)
166.7 116.8 (n = 3; 76%)
400 (n = 1; 87%)
400 (n = 1; 80%)
2a
2b
Data represent means SEM for replicate experiments as indicated in parentheses. EC50 values for luciferase and cAMP production for compound 1
and 2a, b were not statistically significant as determined by t-test (P > 0.05).

5990
J. C. Pelletier et al. / Bioorg. Med. Chem. 13 (2005) 5986–5995
Flow rate: 1.2mL/min
Detection: 210–370 nm
Temperature: 30 ꢁC
Column: Xterra RP18, 3.5 Um, 150 · 4.6 mm 85/15–5/
95 (Ammonium formate buffer, pH 3.5/1:1 AcCN/
MeOH) for 10 min, hold 4 min.
NaBH4 (3.15 g, 83 mmol) and 21% NaOEt/EtOH solu-
tion (7 mL, 64 mmol) were added under nitrogen and
the reaction mixture was heated to 50 ꢁC. After 2h,
the reaction was complete, as judged by TLC. The reac-
tion mixture was partitioned between ethyl acetate
(200 mL) and brine (200 mL), the organic layer was
washed further with brine (2· 200 mL), dried (MgSO4),
and the solvent was removed in vacuo. The crude prod-
uct was purified by silica gel chromatography (eluted
with 10% ethyl acetate/hexane) to yield the title com-
O
1
O
pound 8a (1.8 g (67%), 6.7 mmol). H NMR (CDCl3):
d = 7.28–7.49 (m, 7H), 7.06 (dd, J = 6.8, 1.9 Hz, 2H),
5.47 (dd, J = 9.0, 6.5 Hz, 1H), 5.12 (s, 2H), 2.52–2.75
(m, 3H), 2.14 (m, 1H) MS (ESI-POS): [M+H]+ = 269.
Anal. Calcd for C17H16O3: C, 76.1, H, 6.01. Found: C,
75.29, H, 6.31.
O
O
O
O
2.2. 4-(4-Benzyloxyphenyl)-4-oxo-butyric acid benzyl
ester (7a)
Commercially available 4-(4-hydroxyphenyl)-4-oxo-bu-
tyric acid (3, 3.2g, 17 mmol) was dissolved in DMF
(200 mL). Potassium carbonate (8.83 g, 64 mmol) dis-
solved in water (60 mL) was added. Benzyl bromide
(11.1 g, 64 mmol) was then added dropwise and after
1 h, the reaction was complete, as judged by TLC. The
reaction mixture was partitioned between ethyl acetate
(200 mL) and brine (200 mL). The organic layer was fur-
ther washed with brine (3· 200 mL), dried (MgSO4), and
evaporated. The crude product was chromatographed
on silica gel with 15% ethyl acetate/hexane to yield the
title compound 7a (3.8 g, 10.2mmol, 59%). 1H NMR
(CDCl3): d = 7.96 (d, J = 8.8 Hz, 2H), 7.32–7.44 (m,
10H), 7.01 (d, J = 8.8 Hz, 2H), 5.15 (s, 2H), 5.13 (s,
2H), 3.28 (t, J = 6.6 Hz, 2H), 2.80 (t, J = 6.6 Hz, 2H).
13C NMR (CDCl3): 196.52, 172.91, 162.69, 136.12,
135.90, 130.32, 129.81, 128.70, 128.54, 128.26, 128.19,
127.48, 114.58, 70.12, 66.47, 32.96, 28.36. MS (ESI-
POS): [M+H]+ = 375. Anal. Calcd for C24H22O4: C,
76.99, H, 5.92. Found: C, 77.00, H, 5.73.
O
2.4. (cis)- and (trans)-5-(4-(Benzyloxy)phenyl)-3-methyl-
dihydrofuran-2(3H)-one (9a and 10a)
5-[4-(Benzyloxy)phenyl]dihydrofuran-2(H)-one
(8a,
1.17 g, 4.3 mmol) was dissolved in THF (66 mL)
and the solution was cooled to ꢀ78 ꢁC under a nitro-
gen atmosphere. Lithium hexamethyldisilylamide
(LiHMDS, 4.8 mL of a 1.0 M solution in tetrahydro-
furan, 4.8 mmol) was added and the solution was
allowed to stir for 5 min. Methyl iodide (0.68 g,
4.8 mmol) was added. After 1 h, the reaction was
complete, as judged by TLC. Methanol (5 mL) was
added to quench the reaction. The solvent was re-
moved under vacuum and the crude mixture was sub-
jected to column chromatography on silica gel (eluted
with 15% ethyl acetate/hexane) to provide the title
compound 9a (600 mg (50%), 2.2 mmol): 1H NMR
(DMSO-d6): d = 7.28–7.47 (m, 7H), 7.04 (dd,
J = 2.0, 6.9 Hz, 2H), 5.57 (dd, J = 7.3, 5.9 Hz, 1H),
5.11 (s, 2H), 2.82 (m, 1H), 2.23–2.43 (m, 2H), 1.21
(d, J = 7.3 Hz, 3H). MS (ESI-POS): [M+H]+ = 283.
Anal. Calcd for C17H16O3: C, 76.57, H, 6.43. Found:
C, 76.74, H, 6.49. A small amount of the cis isomer
O
O
O
10a,
5-[4-(benzyloxy)phenyl]-3-methyldihydrofuran-
2(3H)-one, was also obtained (92mg (8%),
0.33 mmol): 1H NMR (DMSO-d6): d = 7.31–7.49 (m,
7H), 7.04 (d, J = 8.7 Hz, 2H), 5.35 (dd, J = 10.9, 5.4
5Hz, 1H), 5.12 (s, 2H), 2.92 (m, 1H), 2.70 (m, 1H),
1.81 (q, J = 12.2 Hz, 1H), 1.21 (d, J = 7.0 Hz, 3H).
MS (ESI-POS): [M+H]+ = 283. Anal. Calcd for
2.3. 5-(4-Benzyloxyphenyl)-dihydro-furan-2-one (8a)
4-(4-Benzyloxyphenyl)-4-oxo-butyric acid benzyl ester
(7, 3.8 g, 10 mmol) was dissolved in ethanol (200 mL).

J. C. Pelletier et al. / Bioorg. Med. Chem. 13 (2005) 5986–5995
5991
C17H16O3: C, 76.57, H, 6.43. Found: C, 76.53, H,
6.50.
trimethylaluminum (0.600 mL of a 2.0 M solution in
heptane, 1.2mmol) was added. This suspension was
allowed to stir for 30 s. A solution of the lactone
(150 mg, 0.43 mmol) in toluene (12mL) was added
with stirring. After 1 h, the reaction was complete,
as judged by TLC. The solvent was removed, and
the residue was partitioned between ethyl acetate
(100 mL) and 3 N HCl (50 mL). The organic layer
was washed further with brine, dried over MgSO4,
and evaporated to leave the crude product contami-
nated with aluminum salts. Toluene (15 mL) was add-
ed, followed by triphenylphosphine (524 mg, 2 mmol)
and diethylazodicarboxylate (350 mg, 2mmol). After
1 h, the reaction was judged complete by LC/MS.
The solvent was removed and the crude product was
purified by column chromatography on silica gel elut-
ed with 20% ethyl acetate/hexane to yield the title
compound 6a (121 mg (67%), 0.28 mmol): 1H NMR
(DMSO-d6): d = 7.90 (d, J = 12.7 Hz, 1H), 7.65 (m,
1H), 7.28–7.56 (m, 7H), 7.20 (m, 2H), 6.90 (d,
J = 8.7 Hz, 2H), 5.81–5.95 (m, 1H), 5.42–5.50 (m,
1H), 5.07–517 (m, 2H), 5.00 (s, 2H), 2.51 (m, 1H),
2.31 (m, 2H), 1.92 (dd, J = 12.7, 9.2 Hz, 1H), 1.20
(s, 3H). MS (ESI-POS): [M+H]+ = 423.
O
O
O
2.5. 3-Allyl-5-[4-(benzyloxy)phenyl]-3-methyldihydrofuran-
2(3H)-one (4a)
The isomeric mixture of 5-(4-(benzyloxy)phenyl)-3-
methyldihydrofuran-2(3H)-one (9a and 10a, 260 mg,
0.92mmol) was dissolved in THF (20 mL), which was
cooled to ꢀ78 ꢁC. Lithium hexamethyldisilylamide
(1.4 mL of a 1.0 M tetrahydrofuran solution, 1.4 mmol)
was added slowly and the reaction mixture was allowed
to stir for 5 min. Allyl bromide (890 mg, 7.4 mmol) was
added and the reaction mixture was allowed to stir for
1 h. MeOH (3 mL) was added to quench the reaction
and the solvent was removed. The crude product was
chromatographed on silica gel (eluted with 12% ethyl
acetate/hexane) to provide the title compound 4a
(220 mg (68%), 0.63 mmol). 1H NMR (DMSO-d6):
d = 7.33–7.49 (m, 7H), 7.03 (d, J = 11.5 Hz, 2H), 5.85
(m, 1H), 5.50 (dd, J = 10.0, 6.3, 1H), 5.18 (m, 2H),
5.12 (s, 2H), 2.58 (m, 1H), 2.38 (m, 2H), 2.01 (dd,
J = 13.0, 10.1 Hz, 1H), 1.18 (s, 3H). 13C NMR (CDCl3):
180.13, 158.28, 136.85, 134.95, 133.06, 131.44, 128.33,
127.71, 127.57, 119.24, 114.71, 77.19, 69.09, 43.89,
41.93, 38.54, 22.28. MS (ESI-POS): [M+H]+ = 323.
Anal. Calcd for C21H22O3: C, 78.23, H, 6.88. Found:
C, 78.08, H, 6.89.
A small amount of the opposite diastereomer 11a 3-
allyl-5-[4-(benzyloxy)phenyl]-3-methyl-2-oxopyrrolidin-
1-yl}benzonitrile was obtained (18 mg (10%),
0.043 mmol): 1H NMR (DMSO-d6): d = 7.90 (m,
1H), 7.68 (m, 1H), 7.32–7.55 (m, 7H), 7.22 (d,
J = 8.7 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 5.78–5.92
(m, 1H), 5.40–5.47 (dd, J = 7.7 Hz, 1H), 5.08–5.16
(m, 2H), 5.01 (s, 2H), 2.54–2.60 (m, 1H), 2.18–2.41
(m, 2H), 1.64–1.73 (dd, J = 13.1, 8.2Hz, 1H), 1.22
(s, 3H). MS (ESI-POS): [M+H]+ = 423. HRMS
(ES-POS) calculated for C28H27N2O2: 423.2073.
Found: 423.2058 (ꢀ3.4 ppm). Analytical HPLC:
75.5% purity at wavelengths 210–370, retention time:
10.9 min.
O
N
OH
N
O
N
N
O
O
O
2.7. 5-[4-(Benzyloxy)phenyl]-1-(3-cyanophenyl)-3-methyl-
2-oxopyrrolidin-3-ylacetic acid (12a)
2.6. 3-Allyl-5-[4-(benzyloxy)phenyl]-3-methyl-2-oxopyrro-
lidin-1-yl benzonitrile (6a, 11a)
3-Allyl-5-[4-(benzyloxy)phenyl]-3-methyl-2-oxopyrrolidin-
1-ylbenzonitrile (6, 80 mg, 0.19 mmol) in CCl4 (1 mL) and
acetonitrile (3 mL) under a nitrogen atmosphere was
treated with NaIO4 (490 mg, 2.3 mmol) in water
3-Aminobenzonitrile (4a, 142mg, 1.2mmol) was
dissolved in toluene (12mL) under nitrogen and

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J. C. Pelletier et al. / Bioorg. Med. Chem. 13 (2005) 5986–5995
(4 mL) and stirred rapidly. RuO2 (12mg, 0.09 mmol)
was added after a few minutes. After 4 h, the reaction
was complete, as judged by LC/MS. The reaction mix-
ture was dissolved in ethyl acetate (50 mL), washed with
3 N HCl (3· 25 mL), brine (25 mL), dried over MgSO4,
and evaporated to provide the title compound 12a
(80 mg, 0.18 mmol, 95%). 1H NMR (DMSO-d6):
d = 12.2–12.4 (br s, 1H), 7.78 (d, J = 8.6 Hz, 1H),
7.60–7.66 (m, 1H), 7.29–7.57 (m, 7H), 7.18 (d,
J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 5.45–5.52
(m, 1H), 5.00 (s, 2H), 2.54–2.83 (dd, J = 40.0, 4.2Hz,
2H), 2.39 (m, 1H), 2.12 (m, 1H), 1.21 (s, 3H). MS
(ESI-NEG): [MꢀH]ꢀ = 439. HRMS (ES-POS) calcd
for C27H24N2O4: 441.1814. Found: 441.1820 (1.3 ppm).
Analytical HPLC: 100% purity at wavelengths 210–
370, retention time: 9.0 min.
Analytical HPLC: 97% purity at wavelengths 210–
370 nM, retention time: 10.4 min.
O
HN
O
O
O
N
H2N
O
O
O
O
O
NC
N
N
H
O
O
2.9. 5-[4-(Benzyloxy)phenyl]-3-(2-{[2-(3-ethoxy-4-methoxy-
phenyl) ethyl]amino}-2-oxoethyl)-3-methyl-2-oxopyrrolidin-
1-yl]benzamide (2)
2.8. 5-(4-Benzyloxyphenyl)-1-(3-cyano-phenyl)-3-methyl-
2-oxo-pyrrolidin-3-yl]-N-[2-(3-ethoxy-4-methoxyphenyl)-
ethyl]-acetamide (13a)
5-(4-Benzyloxyphenyl)-1-(3-cyano-phenyl)-3-methyl-2-
oxo-pyrrolidin-3- yl]-N-[2-(3-ethoxy-4-methoxyphenyl)-
ethyl]-acetamide from above (40 mg, 0.070 mmol) was
dissolved in tetrahydrofuran (1 mL) under nitrogen.
Hydrogen peroxide (0.032mL of a 30% solution) and
lithium hydroxidemonohydrate (9 mg, 0.21 mmol) were
dissolved in water (0.400 mL). The peroxide solution
was combined with the THF solution. The reaction mix-
ture was allowed to stir for 18 h. The solution was par-
titioned between ethyl acetate (50 mL) and water
(25 mL). The organic layer was further washed with
brine (25 mL), dried (MgSO4), and evaporated to pro-
vide the title compound 2 (20 mg, 45%, 0.030 mmol).
1H NMR (DMSO-d6): d = 7.99 (br t, J = 5.5 Hz, 1H),
7.90 (br s, 1H), 7.85 (s, 1H), 7.54 (d, J = 7.7 Hz, 1H),
7.26–7.43 (m, 10H), 6.89 (d, J = 8.6 Hz, 2H), 6.72–6.80
(m, 2H), 6.63–6.69 (dd, J = 8.1, 1.7 Hz, 1H), 5.38 (m,
1H), 4.98 (s, 2H), 3.96 (q, J = 6.9 Hz, 2H), 3.69 (s,
3H), 3.15–3.40 (m, 2H), 2.63 (t, J = 7.1 Hz, 2H), 2.35–
2.54 (dd, J = 40.8, 14.8 Hz, 2H), 2.29 (m, 1H), 2.12
(m, 1H), 1.32(t, J = 6.9 Hz, 3H), 1.18 (s, 3H). 13C
NMR (CDCl3): d = 177.35, 169.63, 167.26, 157.46,
147.61, 147.15, 138.10, 136.84, 134.16, 133.45, 131.70,
128.39, 128.27, 127.82, 127.69, 126.31, 123.33, 122.93,
120.25, 114.44, 113.43, 111.74, 68.99, 63.34, 58.43,
55.27, 42.82, 42.55, 41.71, 22.71, 14.69. MS (ESI-POS):
5-[4-(Benzyloxy)phenyl]-1-(3-cyanophenyl)-3-methyl-2-
oxopyrrolidin-3- yl]acetic acid (12, 80 mg, 0.18 mmol)
was dissolved in DMF (4 mL). Diisopropylethylamine
(46 mg, 0.36 mmol) and 3-ethoxy-4-methoxyphenethyl-
amine (70 mg, 0.36 mmol) were added. O-(7-Aza-
benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium hexa-
fluorophosphate (HATU, 137 mg, 0.36 mmol) was
added under nitrogen. The reaction mixture was
allowed to stir for 1 h and then the solution was par-
titioned between ethyl acetate (50 mL) and brine
(25 mL). The organic layer was washed further with
brine (2· 25 mL), 1 N HCl (25 mL), and brine again
(25 mL). The solvent was dried over MgSO4 and re-
moved under reduced pressure. The crude product
was purified by column chromatography on silica gel
(eluted with 90% ethyl acetate/hexane) to provide the
title compound (43 mg, 0.070 mmol, 48%). 1H NMR
(DMSO-d6): d = 8.01 (m, 1H), 7.78 (s, 1H), 7.62(m,
1H), 7.28–7.50 (m, 8H), 6.92 (d, J = 8.7 Hz, 2H),
6.72–6.80 (m, 2H), 6.65–6.70 (m, 1H), 5.40–5.46 (m,
1H), 5.00 (s, 2H), 3.95 (q, J = 7.0 Hz, 4H), 3.69 (s,
3H), 2.62 (t, J = 9.2 Hz, 2H), 2.33–2.54 (dd, J = 41.2,
14.9 Hz, 2H), 2.26 (m, 1H), 2.12 (m, 1H), 1.28 (t,
J = 7.0 Hz, 3H), 1.18 (s, 3H). MS (ESI-POS):
[M+H]+ = 618.
C38H39N3O5: 618.2968. Found: 618.2938 (ꢀ4.8 ppm).
HRMS
(ES-POS)
calcd
for
[M+H]+ = 636.
C38H42N3O6: 636.3074. Found: 636.3070 (ꢀ0.6 ppm).
HRMS
(ES-POS)
calcd
for

J. C. Pelletier et al. / Bioorg. Med. Chem. 13 (2005) 5986–5995
5993
Analytical HPLC: 100% purity at wavelengths 210–
370 nM, retention time: 9.6 min.
dry THF (15 mL) in dry glassware, and the reaction ves-
sel was cooled to ꢀ78 ꢁC. LiHMDS (1.5 mL of 1.0 M
solution in hexanes, 1.5 mmol) was added dropwise un-
der nitrogen. This solution was allowed to stir for
10 min. Methyl iodide (2.84 g, 2.0 mmol) was added
dropwise to the cooled solution. After 1 h, the reaction
was complete. The solvent was removed under vacuum,
and the residue was taken up in ethyl acetate. The
organic solution was washed with a saturated solution
of sodium bicarbonate (3·), brine, and dried over
MgSO4. The solvent was removed under reduced pres-
sure and the crude mixture was purified by silica gel
chromatography (10% ethyl acetate/hexane) to yield
the pure products as a trans-(9b, 170 mg, 67%),
0.86 mmol) and cis-(10b, 35 mg, 9%) isomers.
O
O
O
Compound 9b: 1H NMR (CDCl3): d = 7.33 (d,
J = 11 Hz, 2H), 6.94 (d, J = 11 Hz, 2H), 5.54 (t,
J = 6 Hz, 1H), 4.01 (t, J = 5 Hz, 2H), 2.85–3.02 (m,
1H), 2.60–2.75 (m, 1H), 1.65–1.90 (m, 3H), 1.40–1.53
(m, 2H), 1.22 (d, J = 7 Hz, 3H), 0.97 (t, J = 7 Hz, 3H);
13C NMR (CDCl3): d = 14.00, 15.66, 19.38, 31.41,
36.67, 40.05, 67.92, 79.50, 144.77, 127.33, 131.05,
159.27, 179.41. MS (ESI-POS): [M+H]+ = 249. Anal.
Calcd for C15H20O3: C, 72.55, H, 8.12. Found: C,
72.56, H, 8.34.
2.10. 5-(4-Butoxyphenyl)-dihydro-furan-2-one (8b)
Commercially available 4-(4-butoxyphenyl)-4-oxo-bu-
tyric acid methyl ester (7b, 264 mg, 1.0 mmol) was dis-
solved in ethanol (1 mL). NaBH4 (44 mg, 1.2mmol)
and 21% NaOEt/EtOH solution (0.12 mL, 1.1 mmol)
were added under nitrogen. After 2h, there was no
starting material observed by thin layer chromotogra-
phy. The reaction mixture was partitioned between ethyl
acetate and brine. The organic layer was washed twice
with brine, dried over MgSO4, and the solvent was re-
moved. The crude product was purified by silica gel
chromatography (10% ethyl acetate/hexane) to yield
the title compound (170 mg, 0.64 mmol, 64%). 1H
NMR (CDCl3): d = 7.31 (d, J = 11 Hz, 2H), 6.96 (d,
J = 11 Hz, 2H), 5.44 (t, J = 6 Hz, 1H), 4.01 (t,
J = 5 Hz, 2H), 2.85–3.02 (m, 3H), 2.08–2.15 (m, 1H),
1.65–1.90 (m, 2H), 1.40–1.53 (m, 2H), 0.97 (t,
J = 7 Hz, 3H); 13C NMR (CDCl3): d = 14.06, 19.43,
29.46, 31.12, 31.46, 67.98, 81.64, 114.85, 127.13,
131.06, 159.56, 177.20. MS (ESI-POS): [M+H]+ = 235.
Anal. Calcd for C14H18O3: C, 71.77, H, 7.74. Found:
C, 71.86, H, 7.72.
Compound 10b: 1H NMR (CDCl3): d = 7.43 (d,
J = 11 Hz, 2H), 6.94 (d, J = 11 Hz, 2H), 5.34 (dd,
J = 6 Hz, 1H), 4.01 (t, J = 5 Hz, 2H), 2.85–3.02 (m,
1H), 2.60–2.75 (m, 1H), 1.65–1.90 (m, 3H), 1.40–1.53
(m, 2H), 1.22 (d, J = 7 Hz, 3H), 0.97 (t, J = 7 Hz, 3H);
13C NMR (CDCl3): d = 14.04, 15.15, 19.41, 31.45,
36.72, 40.05, 67.95, 79.50, 114.80, 127.36, 130.73,
159.58, 179.44. (ESI-POS): [M+H]+ = 249. Anal. Calcd
for C15H20O3: C, 72.55, H, 8.12. Found: C, 72.30, H,
7.82.
O
O
O
O
O
2.12. 3-Allyl-5-(4-n-butoxyphenyl)-3-methyldihydrofuran-
2(3H)-one (4b)
O
The 5-(4-n-butoxyphenyl)-3-methyldihydro-2(3H)-fura-
none mixture (9b and 10b, 400 mg, 1.6 mmol) was
dissolved in dry THF (20 mL) under a nitrogen atmo-
sphere and cooled to ꢀ78 ꢁC. LDA (0.900 mL of a
2M solution, 1.8 mmol) was added dropwise and the
reaction mixture was allowed to stir for 5 min. Allyl
bromide (242mg, 2mmol) was added. After 2h, the
reaction was complete as judged by TLC. The solvent
was removed under reduced pressure and the residue
was partitioned between ethyl acetate and 3 N HCl.
2.11. trans- and cis-5-(4-Butoxyphenyl)-3-methyldihydro-
2(3H)-furanone (9b, 10b)
The 5-(4-n-butoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-
furan-2-one (8b, 300 mg, 1.3 mmol) was dissolved in

5994
J. C. Pelletier et al. / Bioorg. Med. Chem. 13 (2005) 5986–5995
The organic layer was washed with 3 N HCl and brine,
followed by drying over MgSO4 and solvent removal in
vacuo. The crude product was purified by silica gel chro-
matography with 5% ethyl acetate/hexane to yield the
title compound (280 mg, 0.97 mmol, 61%). 1H NMR
(CDCl3): d = 7.24 (d, J = 12Hz, 2H), 6.92 (d,
J = 12 Hz, 2H), 5.76–5.95 (m, 1H), 5.16–5.40 (m, 2H),
3.98 (t, J = 7 Hz, 2H), 2.60–2.72 (m, 1H), 2.34–2.52
(m, 1H), 1.70–1.81 (m, 2H), 1.50–1.71 (m, 2H), 0.99 (t,
J = 7 Hz, 3H). MS (ESI-POS): [M+H]+ = 289. Anal.
Calcd for C18H24O5: C, 74.97, H, 8.39. Found: C,
73.17, H, 8.14. HRMS (ES-POS) calcd for C18H24O3:
289.1800. Found: 289.1799 (ꢀ0.2ppm). Analytical
HPLC: 93.8% purity at 210 nm; 96.8% at 230 nm , reten-
tion time: 25.2 min. NMR (DMSO-d6): 180.85, 159.41,
133.81, 131.81, 128.38, 119.93, 115.07, 77.97, 67.82,
44.62, 42.71, 41.05, 31.36, 23.08, 19.37, 14.32.
O
O
OH
N
N
O
2.14. [5-(4-n-Butoxyphenyl)-1-(3-cyanophenyl)-3-methyl-
2-oxopyrrolidin-3-yl]-acetic acid (12b)
O
The
3-[3-allyl-5-(4-n-butoxyphenyl)-3-methyl-2-oxo-
pyrrolidin-1-yl]- benzonitrile (6b, 500 mg, 1.3 mmol)
was dissolved in CCl4 (6 mL) and acetonitrile (18 mL).
A solution of NaIO4 (3.41 g, 16 mmol) in water
(22 mL) was added. To this heterogeneous mixture,
RuO2 (86 mg, 0.5 mmol) was added. The mixture was
stirred at 40 ꢁC for 20 h, followed by solvent removal
in vacuo. The resulting crude mixture was partitioned
between ethyl acetate and water. After separation, the
organic layer was dried over MgSO4 and the solvent
was removed under reduced pressure to provide the title
N
N
O
2.13. 3-Allyl-5-(4-n-butoxyphenyl)-3-methyl-2-oxo-pyrro-
lidin-1-yl]-benzonitrile (6b)
compound (470 mg, 1.2mmol, 92%).
(CDCl3): d = 11.0–13.0 (br s, 1H), 7.72(s, 1H), 7.54–
7.63 (m, 1H), 7.32(d, J = 6 Hz, 2H), 7.04 (d,
1H NMR
The
3-allyl-5-(4-n-butoxyphenyl)-3-methyldihydrofu-
ran-2(3H)-one (4b, 670 mg, 2.3 mmol) was dissolved
in toluene (60 mL) and set aside. 3-Aminobenzonitrile
(390 mg, 3.3 mmol)) was dissolved in toluene (60 mL)
under nitrogen and trimethylaluminum (1.7 mL of a
2M solution, 3.3 mmol) was added and stirred several
minutes. The two solutions were combined. After 5 h,
the reaction was complete, as judged by TLC. The
solvent was removed under vacuum and the residue
was partitioned between ethyl acetate and 1 N HCl.
The organic layer was washed with 1 N HCl (2·)
and brine and then dried over MgSO4 followed by
solvent removal in vacuo. The residue was dissolved
in toluene (60 mL). Triphenylphosphine (2.33 g,
8.8 mmol) was added to the reaction mixture, fol-
lowed by diethylazodicarboxylate (1.44 g, 8.7 mmol).
The reaction was complete after 2h as judged by
TLC. The solvents were removed in vacuo and the
resulting crude product was chromatographed on sili-
ca gel with 15% ethyl acetate/hexane to provide the
title compound as a single diastereomer (350 mg,
1.0 mmol, 39%). 1H NMR (CDCl3): d = 7.69 (s,
1H), 7.54–7.61 (m, 1H), 7.30 (m, 2H), 7.07 (d,
J = 10 Hz, 2H), 6.80 (d, J = 10 Hz, 2H), 5.72–5.90
(m, 1H), 5.05–5.20 (m, 3H) 3.90 (t, J = 4 Hz, 2H),
2.50 (m, 1H), 2.23–2.40 (m, 2H), 2.01–2.10 (m, 1H),
1.67–1.81 (m, 2H), 1.38–150 (m, 2H), 0.98 (t, 3H).
MS (ESI-POS): HRMS (ES-POS) calcd for
C18H24O3: 389.2240. Found: 389.2225 (ꢀ4.0 ppm).
Analytical HPLC: 94.2% purity at wavelengths 210–
370 nm, retention time: 11.0 min.
J = 10 Hz, 2H), 6.80 (d, J = 10 Hz, 2H), 5.17 (m, 1H),
3.93 (t, J = 4 Hz, 2H), 2.50 (m, 3H), 2.23–2.40 (m,
2H), 2.01–2.10 (m, 2H), 1.67–1.81 (m, 2H), 1.38–150
(m, 2H), 0.98 (t, 3H). MS (ESI-POS): HRMS (ES-
POS) calcd for C24H26N2O4: 407.1954. Found:
407.1974 (5.0 ppm). Analytical HPLC: 100% purity at
wavelengths 210–370 nm, retention time: 12.8 min.
2.15. 2-[5-(4-n-Butoxyphenyl)-1-(3-cyanophenyl)-3-methyl-
2-oxo-pyrrolidin-3-yl]-N-[2-(3-ethoxy-4-methoxyphenyl)-
ethyl]-acetamide (13b)
O
HN
O
O
O
N
N
O

J. C. Pelletier et al. / Bioorg. Med. Chem. 13 (2005) 5986–5995
5995
1
The [5-(4-n-butoxyphenyl)-1-(3-cyanophenyl)-3-methyl-
2-oxopyrrolidin-3-yl]- acetic acid (12b, 210 mg,
0.5 mmol) was dissolved in DMF (16 mL). Diisopropyl-
ethylamine (129 mg, 1 mmol) and 30-ethoxy-40-methoxy-
phenethylamine (195 mg, 1 mmol) were added. O-(7-
Azabenzotriazol-1-yl)-N,N,N0,N0- tetramethyluronium
hexafluorophosphate (HATU, 380 mg, 1 mmol) was
added under nitrogen. The reaction mixture was allowed
to stir for 1 h under nitrogen. The reaction solution was
partitioned between ethyl acetate and brine, the organic
layer was washed further with brine (2·), 1 N HCl, and
brine again. The solvent was then dried (MgSO4), and
evaporated under reduced pressure. The crude product
was subjected to column chromatography and eluted
with 60% ethyl acetate/hexane to yield the title com-
3.0 mmol, 97%). H NMR (DMSO-d6): 7.96 (m, 1H),
7.87 (s, 1H), 7.82(m, 1H), 7.24–7.61 (m, 5H), 6.74–
6.82(m, 3H), 6.64 (m, 1H), 5.35 (m, 1H), 3.98 (t,
J = 4 Hz, 2H), 3.80–3.86 (m, 5H), 3.42–3.52 (m, 2H),
2.54 (m, 3H), 2.23–2.40 (m, 2H), 2.01–2.10 (m, 2H),
1.67–1.81 (m, 2H), 1.38–1.47 (m, 2H), 0.92 (t, 3H).
MS (ESI-POS): HRMS (ES-POS) calcd for
C35H43N3O6: 602.3230. Found: 602.3233 (0.5 ppm).
Analytical HPLC: 100% purity at wavelengths 210–
370 nm, retention time: 16.4 min.
Acknowledgments
The authors thank Rebecca Dooley for obtaining 2D
NMR, and Jamin Chi, Ed Meade, and Gi-Chung Chen
for performing pharmacology experiments.
1
pound (200 mg, 0.34 mmol, 68%). H NMR (CDCl3):
7.94 (s, 1H), 7.57 (s, 1H), 7.43 (m, 1H), 7.28 (d,
J = 5 Hz, 2H), 7.05 (d, J = 9 Hz, 2H), 6.64–6.78 (m,
5H), 6.04 (m, 1H), 5.05 (m, 1H), 3.98 (t, J = 4 Hz,
2H), 3.80–3.86 (m,5H), 3.42–3.52 (m, 2H), 2.54 (m,
3H), 2.23–2.40 (m, 2H), 2.01–2.10 (m, 2H), 1.67–1.81
(m, 2H), 1.38–1.50 (m, 2H), 0.92 (t, 3H). MS (ESI-
POS): HRMS (ES-POS) calcd for C35H31N3O5:
584.3124. Found: 584.3126 (0.3 ppm). Analytical
HPLC: 100% purity at wavelengths 210–370 nm, reten-
tion time: 4.7 min.
References and notes
1. Chappel, S.; Buckler, D.; Kelton, C.; El Tayer, N. Hum.
Reprod. 1998, 13(Suppl. 3), 1998.
2. Out, H. J. Excerpts in Human Reproduction, 1st ed.; NV
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3. For examples of small molecule FSH antagonists see:
Wrobel, J.; Green, D.; Jetter, J.; Kao, W.; Rogers, J.;
Perez, M. C.; Hardenburg, J.; Deecher, D. C.; Lopez, F.
J.; Arey, B. J.; Shen, E. S. Bioorg. Med. Chem. 2002, 10,
639–656.
O
4. (a) For examples of small molecule FSH agonists see:
MacLean, D.; Holden, F.; Davis, A. F.; Scheuerman, R.
A.; Yanofsky, S.; Holmes, C. P.; Fitch, W. L.; Tsutsui, K.;
Barrett, R. W.; Gallop, M. A. J. Comb. Chem. 2004, 6,
196–206; (b) Guo, T.; Adang, A. E. P.; Dolle, R. E.; Dong,
G.; Fitzpatrick, D.; Geng, P.; Ho, K.-K.; Kultgen, S. G.;
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van Straten, N. C. R.; Xie, D.; Webb, M. L. Bioorg. Med.
Chem. Lett. 2004, 14, 1717–1720.
HN
O
O
O
N
H2
N
O
O
5. Albanese, C.; Christin-Mautre, S.; Sluss, P. M.; Crowley,
W. F.; Jameson, J. L. Mol. Cell. Endocrinol. 1994, 101,
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7. Defacqz, N.; Tran-trieu, V.; Cordi, A.; Marchand-Bryna-
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2.16. 3-[5-(4-n-Butoxyphenyl)-3-{[2-(3-ethoxy-4-methoxy-
phenyl)-ethylcarbamoyl]-methyl}-3-methyl-2-oxopyrrolidin-
1-yl]-benzamide (2b)
8. (a) Townsend, C. A.; Nguyen, L. T. Tetrahedron Lett.
1982, 23, 4859–4862; (b) Kadow, J. F.; Vyas, D. M.;
Doyle, T. W. Tetrahedron Lett. 1989, 30, 3299–3302; (c)
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Chmielewski, M. Carbohydr. Res. 1998, 307, 33–43; (d)
Bell, I. M.; Beshore, D. C.; Gallicchio, S. N.; Williams, T.
M. Tetrahedron Lett. 2000, 41, 1141–1145.
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Page, M. I. J. Chem. Soc., Perkin Trans. 1 1997, 503–509.
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B. J. Org. Chem. 1981, 46, 3936–3938.
2-[5-(4-Butoxyphenyl)-1-(3-cyano-phenyl)-3-methyl-2-oxo-
pyrrolidin-3- yl]-N-[2-(3-ethoxy-4-methoxyphenyl)-eth-
yl]-acetamide (13b, 181 mg, 0.31 mmol) was dissolved
in THF (2mL) under nitrogen. Hydrogen peroxide
(0.068 mL of a 30% solution in water, 0.62mmol) and
LiOH monohydrate (15 mg, 0.37 mmol) were dissolved
in water (0.5 mL). The peroxide solution was combined
with the THF solution. The reaction mixture was al-
lowed to stir for 18 h. The solution was partitioned be-
tween ethyl acetate and water. The organic layer was
further washed with water, brine, dried (MgSO4), and
evaporated to provide the title compound (180 mg,
11. Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron
Lett. 1987, 28, 6141–6144.
12. Stevis, P. E.; Deecher, D. C.; Lopez, F. J.; Frail, D. E.
Endocrine 1999, 10, 153.