Fused bicyclic pyrrolizinones as new scaffolds for human NK1 antagonists

Article abstract of DOI:10.1016/j.bmc.2007.11.081

Previous work on human NK₁ antagonists in which the core of the structure is a substituted pyrrolidine has been disclosed. These compounds showed good binding affinity and functional IP activity, however, many did not exhibit the necessary brai

Full text of DOI:10.1016/j.bmc.2007.11.081

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 2156–2170
Fused bicyclic pyrrolizinones as new scaffolds
for human NK1 antagonists
Gregori J. Morriello,a,* Robert J. DeVita,a Sander G. Mills,a Jonathan R. Young,a
Peter Lin,a George Doss,a Gary G. Chicchi,b Julie DeMartino,b Marc M. Kurtz,b
Kwei-Lan C. Tsao,b Emma Carlson,c Karen Townson,c Alan Wheeldon,c Susan Boyce,c
Neil Collinson,c Nadia Rupniakc and Stephen Moorec
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA
bDepartment of Immunology, Merck Research Laboratories, Terlings Park, UK
cDepartment of Behavioral Neuroscience, Merck Research Laboratories, Terlings Park, UK
Received 25 September 2007; accepted 30 November 2007
Available online 5 December 2007
Abstract—Previous work on human NK1 antagonists in which the core of the structure is a substituted pyrrolidine has been dis-
closed. These compounds showed good binding affinity and functional IP activity, however, many did not exhibit the necessary
brain penetration for good in vivo activity. The discovery and preparation of a novel 5,5-fused pyrrolidine core is presented in this
paper. This scaffold maintains the excellent binding affinity and functional IP activity of the previously reported compounds, but
also exhibits excellent brain penetration as observed in a gerbil foot-tapping assay. The determination of the core structural stereo-
chemistry, which eventually led to the final synthesis of a single active diastereomer, is described.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
tivity for the hNK1 receptor. In vitro assessment of new
compounds can readily be carried out by determining
their binding affinity to the hNK1 receptor.3 In vivo
activity and the ability of compounds to gain access to
NK1 receptors in the brain was studied in the gerbil, a
species whose NK1 receptors have pharmacology similar
to humans. Specifically, the ability of a test compound
to inhibit the vigorous hindlimb thumping (foot tap-
ping) elicited by central administration of an NK1 ago-
nist was measured.4 This foot-tapping response has been
shown to be NK1 agonist specific since NK2 and NK3
receptor agonists do not induce this response and this
response is specifically inhibited by peripheral adminis-
tration of potent, brain-penetrant NK1 receptor
antagonists.5
The therapeutic potential of tachykinin receptor antago-
nists has become a focal point of research in recent
years. Animal studies with NK1 antagonists indicate
several prospective disease treatments, such as CNS dis-
orders, pain, emesis, and GI disorders.1 The ability of
human NK1 (hNK1) receptor antagonists to inhibit
emesis has been documented with the FDA approval
of Emendꢁ (aprepitant) as a treatment for chemother-
apy induced nausea and vomiting (CINV).2 Research
into a new class of hNK1 antagonists was driven by
the potential of other novel therapies that target the cen-
tral nervous system (CNS).
The ability of these hNK1 antagonists to penetrate the
brain is a pre-requisite for their potential use for the
clinical treatment of various CNS mediated disorders.
Therefore, it was important to discover highly potent
antagonists with good brain penetration and high selec-
Much research has been done on hNK1 antagonists with
piperidine, morpholine, pyrrolidine, and other heterocy-
clic and cycloalkyl core structures.6,7 This paper will
present hNK1 antagonists featuring a novel fused bicy-
clic pyrrolidine scaffold that have subnanomolar binding
affinity and good central activity in the gerbil foot-tap-
ping assay (see Fig. 1).
*
Corresponding author. Tel.: +1 732 594 3867; fax: +1 732 594
5350; e-mail: greg_morriello@merck.com
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.11.081

G. J. Morriello et al. / Bioorg. Med. Chem. 16 (2008) 2156–2170
2157
3. Chemistry
3.1. Chemistry of 2,3,4-substituted pyrrolidines
CF3
CF3
O
CF3
O
CF3
N
R'
N
The hydroxymethyl substituent at the pyrrolidine 2-po-
sition was envisioned to be a useful intermediate for
cyclization to different bicyclic ring systems. Thus,
chemistry was first developed using commercially avail-
able racemic methyl 3,4-dehydroprolinate (1). Schemes 1
and 2 outline the syntheses of the different diastereomers
which were assayed to screen for the isomer with highest
affinity on the hNK1 receptor assay (see below).
R
R
(H,F)
(H,F)
Reported hNK1 antagonists
Figure 1. Fused bicyclic idea.
target hNK1 antagonists
2. Background
1,3,4-Trisubstituted pyrrolidine-based hNK1 antago-
nists have been reported to display good bioavailability
and efficacy profiles; although, many of these com-
pounds show substantial shifts in binding in the pres-
ence of human serum.7 To improve this property, it
was decided that a more rigid structure might be advan-
tageous since substituents at the 2-position of the pyrrol-
idine were tolerated.8 In addition, the success of fused
bicyclic tetrahydroquinoline hNK1 antagonists9 inspired
our interest in fused bicyclic pyrrolidines. Thus, the deci-
sion was made to cyclize the 2-position substituent of
the pyrrolidine to the pyrrolidine nitrogen. The hope
was that this modification would retain hNK1 binding
affinity and improve on other physical and pharmacoki-
netic properties.
c,d
a, b
Boc
N
HN
O
OH
OMe
2
1
3a,b: R = H
4a,b: R = TBDMS
Boc
N
Boc
N
O
+
syn (+/-)
OR
O
anti(+/-)
OR
b
a
2 : 1 ratio
Scheme 1. Reagents and conditions: (a) Boc2O, TEA, DCM; (b)
DiBAL-H, THF À78 ꢂC; (c) m-CPBA, DCM, rt, overnight; (d) tert-
butyldimethylsilyl chloride, imidazole, DCM.
Boc
N
O
Boc
N
O
(+/-)
(+/-)
TBDMSO
TBDMSO
4b
4a
(+/-) for all structures
(H,F)
(+/-) for all structures
e
e
(H,F)
OH
OH
Boc
N
Boc
N
Boc
N
Boc
N
OH
TBDMSO
OH
TBDMSO
TBDMSO
(H,F)
TBDMSO
6b1
6b2
5a1
f, g, h, i
5a2
f, g, h, i
f, g, h, i
F3C
(H,F)
(H,F)
CF3
O
CF3
Boc
HO
N
Boc
N
CF3
CF3
Boc
N
O
O
HO
HO
(H,F)
CF3
10b-1 methyl (S)
10b-2 methyl (R)
9a1-1 (S)-methyl
9a1-2 ( )-methyl
9a2-1 (
S
)-methyl
R
9a2-2 (
R
)-methyl
Scheme 2. Reagents and conditions: (e) phenyl- or 4-fluorophenylmagnesium bromide, copper(I) iodide, THF 0 ꢂC, rt; (f) bis-3,5-trifluorometh-
ylbenzoyl chloride, triethylamine (TEA), DCM, rt; (g) Tebbeꢁ reagent, THF À40 ꢂC to rt; (h) 10% palladium on carbon, H2 atmosphere, ethanol; (i)
1.0 M TBAF in THF, rt, 1 h.

2158
G. J. Morriello et al. / Bioorg. Med. Chem. 16 (2008) 2156–2170
The commercially available pyrrolidine 1 was protected
with tert-butylcarboxyl (Boc) via standard conditions
and its methyl ester reduced to the alcohol 2 by treat-
ment with DiBAL-H in THF at À78 ꢂC. The double
bond was then epoxidized with m-CPBA to give racemic
syn (3a) and anti (3b) isomers, relative to the 2-hydroxy-
methyl substituent.10 The epoxides were separated by
column chromatography and the hydroxyl group of
each isomer was protected as its silyl ether (4a,b).
romethylbenzoyl chloride, followed by treatment with
l-chloro-l-methylene[bis(cyclopentadienyl) titanium]-
dimethylalum inum (Tebbeꢁ reagent)11, produced the
corresponding vinyl ethers. Hydrogenation with 10%
palladium on carbon in ethanol afforded the desired
ethers as stereochemical mixtures at the benzylic ether
position.
The ether intermediates were then treated with TBAF in
THF to remove the silyl protecting groups to afford the
desired alcohols 9a1, 9a2, and 10b. Careful separation of
each isomeric pair by Horizon MPLC silica gel chroma-
tography afforded six separate products in racemic form
in both the 4-H and 4-fluoro series. The problem of the
relative stereochemistry of the 2-substitution needed to
be resolved since potentially eight diastereomers and
their enantiomers could have been formed by this se-
quence. The possible isomers obtained are shown in
the two figures below (Figs. 2 and 3).
The two epoxides (4a,b) were then reacted separately
with either phenyl- or 4-fluorophenylmagnesium bro-
mide and copper(I) iodide to produce the 3,4-disubsti-
tuted pyrrolidine intermediates 5a1, 5a2 (Scheme 2a
and 6b1, 6b2) (Scheme 2b). The reaction products
were separated by careful column chromatography.
1HNMR analysis of the intermediates indicated that
compound 6b1 was a by-product that did not possess
the aryl moiety. The three isolated phenyl substituted
products were utilized to produce three of the possible
four 2-hydroxymethyl substituted diastereomers. Acyl-
ation of the C-3 hydroxyl groups with bis-3,5-trifluo-
The R/S-methyl stereochemistry was first determined by
hNK1 binding activity, since the S-methyl derivatives
O
O
O
N
N
O
O
O
OH
OH
OH
Ar
Ar
OH
OH
Ar
O
O
Ar
O
O
O
O
O
O
+
N
and
N
N
N
and
R= t-BDMS
OH
OR
OR
OR
OR
5a2
5a1
CF3
R' =
CF3
R'
Ar
O
R'
O
O
Ar
O
O
O
O
N
R'
O
O
O
O
+
N
R'
N
N
+
O
Ar
Ar
OH
OH
OH
OH
and
and
and
and
R'
(S)
R'
Ar
O
Ar
O
O
O
O
O
O
R'
O
N
(R)
N
R'
(R)
N
N
O
O
O
Ar
(S)
O
Ar
OH
OH
OH
9a2-1
OH
9a1-1
9a1-2
9a2-2
Figure 2. All potential products derived from syn epoxide (3a).

G. J. Morriello et al. / Bioorg. Med. Chem. 16 (2008) 2156–2170
2159
O
O
O
O
N
O
O
N
OH
O
OH
OH
obtained
as other
product
HO
N
N
O
R= t-BDMS
Ar
OH
Ar
OH
Ar
OH
Ar
O
O
O
O
O
O
N
N
and
and
N
+
OH
O
O
OR
OR
OR
OR
6b2
6b1 (not isolated)
CF3
X
R' =
CF3
R'
Ar
O
R'
O
Ar
O
O
O
O
O
O
O
N
N
N
N
+
+
R'
O
O
Ar
R'
Ar
O
OH
OH
OH
and
OH
and
and
and
Ar
O
Ar
O
R'
O
O
R'
O
O
O
O
N
N
N
N
R'
R'
O
O
O
Ar
O
Ar
OH
OH
(10b-1)
Figure 3. All potential products derived from anti epoxide (3b).
OH
OH
(not obtained)
(10b-2)
CF3
CF3
are known to be much less potent than the R-methyl
analogs. Then the relative stereochemistry was based
on chemical reactivity observations and the regiochem-
istry was determined by H1 and 2D TOCSY NMR spec-
troscopy. The desired active isomers shown in boxes
were determined by these methods. However, the fused
bicyclic structures, produced by further chemical manip-
ulations, were more rigorously characterized by spectro-
scopic methods since they exhibited first order spectra
(vide infra).
O
CF3
O
CF3
HCl
HN
j
Boc
N
OH
11a2-2
OH
(H,F)
(H,F)
9a2-2
CF3
O
CF3
k
O
N
3.2. Chemistry of the fused bicyclic carbamates
O
The synthesis of the fused bicyclic carbamates was a
simple two-step process, as outlined in Scheme 3 for iso-
mer 9a2-2. The three isomers were treated with 4 N HCl
in dioxane to remove the BOC protecting group and the
resulting hydroxy methyl pyrrolidines were reacted with
phosgene to form the bicyclic carbamate compounds
12a1-2, 12a2-2, and 13b-2.
(H,F)
12a2-2
same chemistry with isomers 9a1-2 and 10b-2 to yield 12a1-2 and 13b-2
Scheme 3. Reagents and conditions: (j) 4 N HCl in dioxane, rt, 1 h; (k)
phosgene, N-ethyl-N,N-diisopropylamine (DIEA), DCM, rt,
overnight.

2160
G. J. Morriello et al. / Bioorg. Med. Chem. 16 (2008) 2156–2170
F3C
(m, 3.36-3.32)
(ddd, 4.14)
CF3
4
7
H
5
H
N
H
(dd's, 3.90 & 3.62)6
H
H
O
H
O
O
(dd, 4.06)
3
O
H
CF3
CF3
N
(dd, 3.11)
H8
O
O
H
10
H
H
9
2
H
1
H
H
(ddd, 4.30)
(m, 4.60-4.55)
12a1-1
(ddd, 4.05)
(dd's, 4.49 & 4.28)
12a2-2
Figure 4. Chemical shifts and coupling constants of bicyclic compounds 12a1-1 and 12a2-2.
3.3. Stereochemical analysis
with this structural assignment is that of the ether’s loca-
tion next to the unsubstituted pyrrolidine carbon and the
phenyl substituted carbon. Therefore, we were comfort-
able with the stereochemical assignments of bicyclic ana-
logs 12a1-1 and 12a2-2 (see Fig. 4).
The NMR spectra of isomers 12a1-1 and 12a2-2 were
first order and allowed more rigorous stereochemical
assignments. For the 12a1-1 isomer, one may conclude
that the ether was adjacent to the 2-pyrrolidine substitu-
ent since H-3 couples to H-2 and H-4 and is further
downfield than H-4. Small ‘W’ coupling of H-3 to the
downfield hydrogens H-1 was also observed which sup-
ports this assignment. The chemical shifts for H-1 and
H-3 hydrogens all appeared in the downfield region,
consistent with their assignment to a carbon possessing
an oxygen substituent. H-2 couples only to downfield
hydrogens (d = 4.60–4.55 and 4.06), assigned hydrogens
H-1 and H-3. To further confirm this, we examined H-4
(the most upfield proton not including the methyl
group) and determined that it is coupled to the hydro-
gens H-5 and downfield proton H-3.
For the remaining isomer 13b-2, the 2D TOCSY readily
provided data that allowed the regio-stereochemical
assignment. Examining the ether hydrogens H-13, we
observed a pronounced coupling to H-12 and H-14,
and also small coupling to hydrogens H-11 and H-15.
The hydrogen (H-13) appears to couple with all the
hydrogens around the two fused rings. We reasoned that
H-13 exhibits ‘W’ coupling to both hydrogens H-11 and
H-15. The one possible structure that is consistent with
these data possesses an ether at the 3-position adjacent
to both the 4-phenyl and 2-pyrrolidine substituent. If
one considers the reverse regiochemistry with the phenyl
adjacent to both substituents, H-13 would not be able to
have any coupling to hydrogens H-11. Therefore, the
ether must be adjacent to the two substituents for it to
be possible to have ‘W’ coupling to the hydrogens of
H-11 and H-15 consistent with the assigned regio-chem-
istry of 13b-2. The relative stereochemistry of each iso-
mer was assigned solely on the basis of which epoxide
(3a) or (3b) it was derived from (see Fig. 5).
With the structure of isomer 12a1-1 assigned, the only
other regioisomer possible for 12a2-2 is that of the phenyl
adjacent to the hydroxymethyl substituent. 2D TOCSY
spectrum was examined to confirm this and the results
agreed with our regiochemical assignment. The hydrogen
of the ether (H-7 in this case) is coupled only to the three
upfield protons H-6 and H-8. One other important feature
was the coupling pattern. In isomer 12a1-1, the ether
hydrogen (H-3) is a clean dd, and therefore, was only cou-
pled to two hydrogens. The one possibility that remains is
that the ether must be the substituent between the phenyl
and the 2-pyrrolidine substituent. For isomer 12a2-2, the
ether hydrogen (H-7) is a ddd, therefore, it must be cou-
pled with three hydrogens. The one possibility consistent
The relative stereochemistry of the most active isomer
(12a2-2), see section on biological results and discussion,
was further supported by 2D NOESY experiments.12
3.4. Chemistry discussion: fused bicyclic ureas
We desired only the active enantiomer of 12a2-2 for fur-
ther analog synthesis, therefore, an asymmetric synthesis
was investigated. To that end, the racemic methyl 3,4-
dehydroproline acetate was resolved enzymatically to
obtain the desired (R)-methyl ester enantiomer as de-
scribed in the literature.13 The recovered (S)-acid was
recycled by re-esterification, then racemization with
LHMDS in THF. The recovered racemate could be
enzymatically resolved again to obtain more of the de-
sired (R)-methyl ester which gave an 82% yield of the de-
sired (R)-isomer after three recycles. The (R)-ester was
reduced by treatment with DIBAL-H in THF to afford
the (R)-hydroxylmethyl intermediate (2). After epoxida-
tion with m-CPBA, the stereoisomers were separated by
(app q, 3.40)
14
H
(dd's, 3.80 & 3.67)
15
H
H
O
(br dd, 3.91)
N
13
H
O
O
H
H
12
H
11
CF3
(ddd, 4.09)
(dd's, 4.69 & 4.40)
F3C
13b-2
Figure 5. Chemical shifts and coupling constants of bicyclic compound
13b-2.

G. J. Morriello et al. / Bioorg. Med. Chem. 16 (2008) 2156–2170
2161
OH
Boc
f, g, h
N
d, e
Boc
N
O
O
Si
F
OH
3a (R)-hydroxy methyl
5a2 (Fluoro-only)
F3C
collect
F3C
O
CF3
+
O
CF3
isomer 7a2-1
Boc
N
Boc
ONLY
N
l
O
Si
O
Si
F
F
4 : 1
7a2-2
7a2-1
F3C
F3C
O
CF3
O
CF3
Boc
N
i
Boc
N
O
Si
F
OH
F
9a2-2: single active isomer
7a2-2
Scheme 4. Reagent and conditions: (d) tert-butyldimethylsilyl chloride, imidazole, DCM; (e) 4-fluorophenylmagnesium bromide, copper(I) iodide,
THF 0 ꢂC, rt; (f) bis-3,5-trifluoromethylbenzoyl chloride, triethylamine (TEA), DCM, rt; (g) Tebbeꢁ reagent, THF À40 ꢂC to rt; (h) 10% palladium
on carbon, H2 atmosphere, ethanol; (i) 1.0 M TBAF in THF, rt, 1 h; (l) 1.0 M potassium tert-butoxide in THF 40 ꢂC, 4 h.
F3C
F3C
O
CF3
O
CF3
m
n
Boc
N
Boc
N
OH
9a2-
O
F
F
2
15
F3C
F3C
O
CF3
O
CF3
Boc
N
O
N
o, p
N
q
H
NH
F
F
16
17
F3C
F3C
O
O
CF3
CF3
r
O
O
N
N
HN
N
H
H
F
F
19
18
Scheme 5. Reagents and conditions: (m) oxalyl chloride, DMF; then TEA, THF À78 ꢂC to rt; (n) benzylamine, sodium triacetoxyborohydride, TEA,
DCM; (o) 4 N HCl in dioxane, 1 h; (p) phosgene, DIEA, DCM; (q) 10% palladium on carbon, 1 equiv HCl, H2, methanol; (r) NaH, MeI, THF À40 ꢂC.

2162
G. J. Morriello et al. / Bioorg. Med. Chem. 16 (2008) 2156–2170
F3C
F3C
O
CF3
O
CF3
s
t, u
Boc
N
Boc
N
O
F
F
O
O
O
15
20
F3C
F3C
O
CF3
HCl HN
O
v
O
CF3
N
F
H
F
OH
22
21
Scheme 6. Reagents and conditions: (s) (tert-butoxycarbonylmethylene)triphenyl phosphorane, DCM; (t) 10% palladium on carbon, H2 atmosphere,
ethanol; (u) 4 N HCl in dioxane, 1 h; (v) EDC, DMAP, DIEA, DCM, rt, overnight.
Table 1. NK-1 binding activity for the hydroxymethyl intermediates 9
and 10
column chromatography and the desired higher Rf iso-
mer (3a) was used to complete the synthesis. Similarly,
a
Compound p-Benzyl substituents hNK-1 binding IC50 (nM)
the opening of the epoxide with 4-fluorophenylmagne-
sium bromide produced two diastereomers of which,
after separation, the desired less polar isomer (5a2)
was further utilized. The chemistry described earlier
was used to produce the (R) and (S)-a-methyl benzyl
ethers in 1:4 ratio. Separation of the benzylic ether iso-
mers was then performed. Unfortunately, the major iso-
mer was of the undesired (S)-ether configuration.
However, epimerization of the benzylic methyl was
examined and it was found that treatment with t-BuOK
in THF at 40 ꢂC for 4 h gave complete epimerization of
the methyl group to give a 1:1 ratio. The two isomers
were then separated via careful column chromatography
and the undesired (S)-isomer was again epimerized to
provide the desired (R)-methyl ether in reasonable over-
all yield (81%). The silyl group was then removed with
TBAF in THF to give the desired active single enantio-
mer, 9a2-2 (see Scheme 4).
9a1-1
H
F
13% at 0.1 lM
39% at 0.1 lM
9a1-2
H
F
7.8 nM
4.4 nM
9a2-1
H
F
26% at 0.1 lM
92% at 0.1 lM
9a2-2
H
0.63 nM
0.28 nM
F
10b-1
H
F
26% at 0.1 lM
41% at 0.1 lM
10b-2
H
F
3.6 nM
1.2 nM
a See Ref. 18.
tion15 gave the precursor useful to prepare the cyclized
amide analogs. Hydrogenation of this a,b-unsaturated
ester 20 was accomplished using H2 with 10% palladium
on carbon, followed by treatment with 4 N HCl in diox-
ane to simultaneously remove the tert-butyl ester and
the N-Boc protecting group. The resulting amino acid
intermediate 21 was then cyclized via standard EDC
coupling procedures16 to afford the fused bicyclic amide
22 (see Scheme 6).
Simple chemical manipulations gave the desired fused
bicyclic ureas and amide with this enantiomerically pure
intermediate in hand. First, the alcohol 9a2-2 was oxi-
dized to the aldehyde 15 via Swern oxidation.14 This
intermediate was then immediately used without purifi-
cation in a reductive amination with benzylamine to ob-
tain intermediate 16. Treatment of intermediate 16 with
4 N HCl in dioxane gave the amino pyrrolidine which
was then cyclized to the urea 17 with phosgene. Hydro-
genation of N-benzyl urea 17 gave the unsubstituted cyc-
lic urea 18 which was then converted to the N-methyl
urea 19 via treatment with sodium hydride and addition
of methyl iodide (see Scheme 5).
4. Biological results and discussion
Table 1 contains the hNK1 binding data3 for the
hydroxymethyl target intermediates; six each from the
phenyl or 4-fluorophenyl series. The data show that
one isomer (9a2-2) in both phenyl and 4-fluorophenyl
series clearly possessed the highest binding affinity;
therefore, these were chosen as the primary intermedi-
3.5. Chemistry discussion: fused bicyclic amides
The cyclic amide synthesis began with the same aldehyde
intermediate 15 as for the cyclic ureas. A Wittig reac-

G. J. Morriello et al. / Bioorg. Med. Chem. 16 (2008) 2156–2170
Table 2. NK1 assay results for bicyclic carbamates
2163
Human serum shift + 50% HSb
GFT brain % inhc
a
hNK-1 binding IC50 (nM)
Compound
p-Benzyl substituents
12a1-2
H
F
1.5
1.0
31% at 0.1 lM
na
na
na
12a2-2
13b-2
H
F
0.27
0.14
37 nM
37 nM
2.5%
49%
H
F
1.3
0.33
25% at 0.1 lM
57 nM
na
na
a,b See Ref. 18.
c GFT: measure of brain penetration analyzed at 0 h at 1 mpk iv; see Refs. 5 and 6d.
Table 3. NK1 assay results for bicyclic urea series
F3C
O
CF3
O
R
N
N
F
Human serum shift + 50%HSb
GFT Brain % inhc
a
hNK-1 binding IC50 (nM)
Compound
R
17
18
19d
Bn
CH3
H
2.7
na
32 nM
2 nM
na
na
0.88
0.06
100%
a,b See Ref. 18.
c GFT: measure of brain penetration analyzed at 0 h at 1 mpk iv; see Refs. 5 and 6d.
d GFT for this compound was also determined at 24 h for a 3 mpk dosage and was found to have ꢀ8% brain penetration.
Table 4. Bicyclic amide assay results
nists showed two- to threefold improved hNK1 binding
affinity as compared to the parent phenyl analogs. The
gerbil foot-tapping data also demonstrate that the 4-
fluorophenyl analogs have improved efficacy as com-
pared to the unsubstituted-phenyl compounds of the
same relative stereochemistry. As a result of these data,
the 4-fluorophenyl series of analogs with the 12a2-2 rel-
ative stereochemistry were investigated further with
other fused bicyclic systems.
F3C
O
CF3
O
N
H
F
22
In Table 3, the hNK1 binding affinity relationship of
substituents on the nitrogen of the bicyclic ureas shows
that less bulky groups are clearly preferred. The benzyl
is not tolerated as compared to the smaller methyl with
a threefold decrease in potency. However, the unsubsti-
tuted cyclic urea was much more active and also had a
decreased human serum shift relative to the N-substi-
tuted ureas. Gerbil foot-tapping efficacy was improved
for the unsubstituted cyclic urea 19, 100% inhibition at
0 h at 1 mg/kg iv as compared to 49% inhibition for
the 4-fluorophenyl cyclic carbamate, 12a2-2, in the same
assay. However, no activity was observed at 24 h for
compound 19. This compound lacked the duration of
central activity we desired to be considered for further
evaluation (see Table 4).
hNK1 binding
Human serum shift
Gerbil foot tapping
0.06 nM
2.2 nM
100 % inh at 0 h, 1 mg/kg
100 % inh at 24 h 3 mg/kg
0.03 mg/kg 0 h
Titration (ID50
)
ates to prepare the initial fused bicyclic designs. This re-
sult was in clear agreement with the reported results in
the previous pyrrolidine and cyclopentane series.6,7
Table 2 below contains the hNK1 binding results, with-
out and in the presence of 50% human serum,17 and ger-
bil foot-tapping (GFT) data for the bicyclic carbamates.
One isomer, 12a2-2, had superior binding affinity with a
minimal shift in binding in the presence of 50% human
serum as compared to the other stereoisomers. The 4-
fluorophenyl compounds of this series of hNK1 antago-
The cyclic amide 22 was equipotent in the hNK1 binding
assay with similar human serum shift as compared to
both the urea and carbamate analogs. However, central

2164
G. J. Morriello et al. / Bioorg. Med. Chem. 16 (2008) 2156–2170
tions unless otherwise noted. Chemical shifts (d) are re-
F3C
F3C
ported in parts-per-million (ppm) downfield from
tetramethylsilane and coupling constants (J values) are
given in hertz. Carbon-13 nuclear magnetic resonance
(13C NMR) spectra were recorded at 50.103 MHz on
the above mentioned Varian Associates Unity+ 500 or
Inova 600 instrument in deuteriochloroform solutions
unless otherwise noted. Fast-atom bombardment
(FAB-MS) and electron spray ionization mass spectra
(ESI-MS) were obtained with a Hewlett Packard Series
1100MSD LC-MS. The positive ion peaks are given in
units of mass/charge (m/z). High pressure liquid chroma-
tography (HPLC) purifications were performed on the
Gilson diode array detector HPLC using a stepwise gra-
dient of 1:9–9:1 acetonitrile/water with 0.1% TFA buffer
as the eluant.
O
O
CF3
CF3
O
N
Boc
N
O
H
H
OH
F
F
9a2-2
0.28 nM
12a2-2
Compound:
hNK1 IC50
:
0.14 nM
GFT data:
16%inh. @ 0h (1 mpk iv.)
0%inh. @ 24h (3 mpk iv.)
49%inh. @ 0h (1 mpk iv.)
0%inh. @ 24h (3 mpk iv.)
F3C
F3C
O
CF3
O
O
CF3
O
N
Precoated silica gel plates (E. Merck 60) were used for
analytical thin-layer chromatography. Pre-coated silica
gel preparative plates (E. Merck 500 or 1000 lM) or
SupelCo SupelCleanTM LC-Si SPE 3 mL tubes were
used for small quantity purification. E. Merck silica
gel (230–400 mesh) was employed for flash column
chromatography. All solvents and reagents were ob-
tained from either Aldrich Chemical Co. or Fisher
Scientific Co. All reactions except those in aqueous
solutions or otherwise noted were run under nitrogen
atmosphere.
N
HN
H
H
F
F
19
22
0.06 nM
Compound:
hNK1 IC50
GFT data:
:
0.06 nM
100%inh. @ 0h (1 mpk iv.)
8%inh. @ 24h (3 mpk iv.)
100%inh. @ 0h (1 mpk iv.)
100%inh. @ 24h (3 mpk iv.)
Figure 6. hNK1 binding and gerbil foot-tapping results for best
compounds in each series.
6.1.1. Racemic: tert-butyl-4-{1-[3,5-bis(trifluoromethyl)
phenyl]ethoxy}-2-(hydroxymethyl)-3-phenylpyrrolidine-1-
carboxylate
efficacy was improved as determined in the GFT assay:
100% inhibition at both 0 and 24 h time points at our
screening dosages (1 mg/kg and 3 mg/kg, respectively).
Titration at 0 and 24 h showed that compound 22 had
excellent potency and useful duration of action for cen-
tral antagonist activity in this in vivo model. These re-
sults opened a new series of fused bicyclic heterocycles
as centrally active hNK1 antagonists.
6.1.1.1. tert-Butyl-2-(hydroxymethyl)-2,5-dihydro-1H-
pyrrole-1-carboxylate (2). To
a solution of 10 g
(44 mmol) 1-tert-butyl-2-methyl 2,5-dihydro-1H-pyr-
role-1,2-dicarboxylate (prepared according to the proce-
dure of Sturmer, R.; Schafer, B.; Wolfart, V.; Stahr, H.;
Kazmaier, U.; Helmchen, G. Synthesis 2001 (1), 46–48)
in 150 mL dry THF under nitrogen atmosphere at
À78 ꢂC was added dropwise over 30 min 100 mL
(100 mmol) of a 1.0 M solution of DIBAL in cyclohex-
ane. The reaction mixture was stirred at À78 ꢂC for
15 min and then warmed to room temperature. Upon
completion of the reaction (as monitored by TLC), the
reaction mixture was quenched with excess water and
transferred to a separatory funnel. The reaction mixture
was extracted with EtOAc (2· 200 mL) and then meth-
ylene chloride (100 mL). The combined organic extracts
were dried over anhydrous sodium sulfate, filtered, and
evaporated under vacuum. The resulting thick yellow oil
was purified by silica gel chromatography eluting with
gradient hexanes–EtOAc (9/1) to hexanes–EtOAc (2/8).
The product fractions were combined and evaporated
5. Conclusion
Figure 6 shows the most interesting analogs of each
fused bicyclic pyrrolidine series and the most potent
open hydroxymethyl compound (9a2-2). The gerbil
foot-tapping results revealed that the bicyclic fused car-
boxamide had the most promising properties for a CNS
penetrant hNK1 antagonist and that the fused core in-
deed provides the necessary brain penetration needed
for an hNK1 antagonist. The binding affinity was subn-
anomolar and a low dose of compound 22 completely
inhibits the icv agonist induced activity (foot-tapping re-
sponse) in the gerbil model. Other bicyclic carboxamide
analogs will be described in the future.
1
under vacuum to give 16.3 g of the title compound. H
(500 MHz, CDCl3) d 5.82 (dd, J = 1.3, 4.6 Hz, 1H);
5.66–5.62 (m, 1H); 4.75 (br s, 1H); 4.20 (dd, J = 1.9,
15.6 Hz, 1H); 4.10 (ddd, J = 2.0, 5.5, 15.6 Hz, 1H);
3.80 (dd, J = 2.1, 11.4 Hz, 1H); 3.58 (dd, J = 7.5,
11.4 Hz, 1H), 1.52 (s, 9H) ppm.
6. Experimental
6.1. General
Proton nuclear magnetic resonance (1H NMR) spectra
were obtained with a Varian Associates Unity+ 500 or
Inova 600 instrument by using deuteriochloroform solu-
6.1.1.2. tert-Butyl-2-(hydroxymethyl)-6-oxa-3-aza bicy-
clo[3.1.0]hexane-3-carboxylate (3). To a solution 16.3 g
(81.9 mmol) 2 in 500 mL methylene chloride was added

G. J. Morriello et al. / Bioorg. Med. Chem. 16 (2008) 2156–2170
2165
163.7 mmol (2 equiv) MCPBA. The reaction mixture
was stirred at ambient T for 24 h. The reaction mixture
was quenched with excess Ca(OH)2 and stirred vigor-
ously for 30 min. The reaction mixture was filtered,
washed with methylene chloride, and the solvent of the
filtrate removed under vacuum. The residue was purified
by chromatography on silica gel eluting with a hexanes–
EtOAc (100/0 to 10/90) gradient system to provide two
isomeric products; 6.57 g of the major less polar isomer
vacuum. The resulting oil was purified by preparative
TLC eluting with EtOAc–hexanes (25/75) to provide
two isomeric products (isomer 5a2 major). More polar
isomer by TLC: 130 mg (37%). 1H NMR (500 MHz,
CDCl3): d 7.35 (app t, J = 7.5 Hz, 2H), 7.28–7.24 (m,
1H), 7.16 (br d dd, J = 7.55, 10.5 Hz, 2H); 4.44 (dd,
J = 2.4, 10.6 Hz, 1H); 4.24–4.16 (m, 1H); 4.04 (br s,
1H), 3.76–3.70 (m, 1H); 3.67 (d, J = 10.6 Hz, 1H); 3.48
(dd, J = 12.4, 15.6 Hz, 1H); 3.37 (s, 1H); 1.53 (s, 9H);
0.96 (s, 9H); 0.17 (s, 6H). MS: 408 (M+H), 308
(M+H-Boc) (isomer 5a1 minor). Minor less polar iso-
mer by TLC: 103 mg (34%). 1H NMR (500 MHz,
CDCl3): d 7.38–7.35 (m, 2H); 7.34–7.25 (m, 3H); 4.44
(dd, J = 8.45, 16 Hz, 1H); 4.24 (dd, J = 4.0, 10.9 Hz,
0.5H), 4.10–4.02 (m, 2H); 3.97–3.92 (m, 0.5H); 3.82
(dd, J = 8.5, 16.4 Hz, 1H), 3.52–3.36 (m, 3H), 1.52 (s,
3.5H); 1.48 (s, 5.5H), 0.96 (s, 9H); 0.14 (s, 6H). MS:
408 (M+H), 308 (M+H-Boc).
1
1 (syn-isomer, 3a). H NMR (500 MHz, CDCl3): d 3.98
(d, J = 10.8 Hz, 1H); 3.94–3.82 (m, 2H); 3.77 (br s, 1H);
3.74 (d, J = 13 Hz, 1H); 3.62 (s, 1H); 3.42 (d, J = 13 Hz,
1H); 1.46 (s, 9H). 13C (125 MHz, CDCl3) 158.02, 64.19,
61.90, 58.58, 53.75, 49.71, 28.57 ppm. Also obtained
3.44 g of the minor more polar isomer 2 (anti-isomer,
3b). 1H NMR (500 MHz, CDCl3):
d
4.17 (t,
J = 5.2 Hz, 0.5H), 4.03 (t, J = 4.2 Hz, 0.5H), 3.88 (d,
J = 13 Hz, 0.5H), 3.86–3.74 (m, 3H), 3.70–3.65 (m,
1H), 3.60 (d, J = 3.0 Hz, 0.5H), 3.37 (dd, J = 1.2,
13 Hz, 1H), 1.45 (br s, 9H). 13C (125 MHz, CDCl3): d
156.11 (154.96), 80.88 (80.62), 62.86 (62.37), 60.18
(60.07), 58.08 (57.29), 55.35 (54.89), 47.81 (47.75),
28.69 (28.62).
6.1.1.5. tert-Butyl-4-{[3,5-bis(trifluoromethyl)benzoyl]
oxy}-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-phenyl-
pyrrolidine-1-carboxylate. To a solution 3.0 g (7.37
mmol) of the more polar isomer (5a2) in 60 mL dry meth-
ylene chloride under nitrogen atmosphere was added
2.27 mL (16.2 mmol) DIPEA followed by 1.47 mL
(8.1 mmol) 3,5-bis(trifluoromethyl)benzoyl chloride.
The resulting mixture was stirred at ambient T for 16 h
and then partitioned between aq 1 N HCl (5 mL). The
layers were separated and the organic layer was washed
with satd aq sodium bicarbonate (5 mL) then brine
(5 mL), dried over anhydrous sodium sulfate, filtered,
and the solvent removed under vacuum. The residue
was purified by chromatography on silica gel eluting with
EtOAc/hexanes gradient (0–40% EtOAc) to afford 4.52 g
6.1.1.3. tert-Butyl-2-({[tert-butyl(dimethyl)silyl]ox-
y}methyl)-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxyl-
ate (4a). To a solution of 6.56 g (30.5 mmol) of major
isomer 1(3a) in 45 mL dry DMF under nitrogen atmo-
sphere was added 4.17 g (61 mmol) imidazole followed
by 4.6 g (30.5 mmol) tert-butylchlorodimethylsilane.
The reaction mixture was stirred for 16 h and then di-
luted with water. The mixture was transferred to a
separatory funnel and extracted with ether (3· 50 mL).
The combined ether extracts were washed with water
(2· 25 mL), dried over magnesium sulfate, filtered, and
the solvent removed under vacuum. The residue was
purified by chromatography on silica gel eluting with a
hexanes–EtOAc gradient (95/5 to 40/60) to provide
9.04 g of the title compound. 1H NMR (500 MHz,
CDCl3): d 4.33 (br s, 0.5H); 4.15 (br s, 0.5H); 3.90 (t,
J = 2.5 Hz, 1H); 3.88–3.76 (m, 1H); 3.72 (br d,
J = 14.2 Hz, 1H); 3.65 (d, J = 12.5 Hz, 1H); 3.60–3.52
(m, 1H); 3.46 (d, J = 12.5 Hz, 1H); 1.46 (br s, 9H);
0.93 (s, 9H); 0.12 (s, 6H) ppm.
1
of the title compound. H NMR (500 MHz, CDCl3): d
8.46 (s, 2H); 8.10 (s, 1H); 7.38 (app t, J = 7.4 Hz, 2H);
7.34–7.26 (m, 3H); 5.92–5.45 (br m, 1H); 4.25 (dd,
J = 6.4, 12.1 Hz, 1H); 4.10 (br s, 1H); 4.08–4.00 (m,
1H); 3.92 (br d, J = 7.0 Hz, 2H); 3.80 (br s, 1H); 3.58
(d, 10.7 Hz, 0.5H); 3.48–3.42 (m, 0.5H); 1.53 (s, 9H);
0.90 (s, 5H); 0.88 (s, 4H), 0.07 (s, 2.5H); 0.04 (s,
3.5H) ppm. MS: 670 (M+Na), 548 (M+H-Boc).
6.1.1.6. tert-Butyl-4-({1-[3,5-bis(trifluoromethyl)phenyl]
vinyl}oxy)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-
phenylpyrrolidine-1-carboxylate. In a pressure tube was
placed a solution of 1.0 g (1.55 mmol) of the intermedi-
ate tert-Butyl-4-{[3,5-bis(trifluoromethyl)benzoyl]oxy}-
2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-phenylpyrr-
olidine-1-carboxylate in 30 mL dry toluene. To this
solution was added 6.2 mL (6.2 mmol) of a 1.0 M solu-
tion of Petasis reagent in toluene. The pressure tube
was purged several times with nitrogen, sealed, and
heated at 70 ꢂC for 16 h. The reaction vessel was
cooled to room temperature and filtered through a plug
of silica gel eluting with EtOAc–hexanes (20/80) to af-
ford 500 mg (50%) of the title compound. MS: 668
(M+Na), 547 (M+H-Boc).
6.1.1.4.
6.1.1.4.1. tert-Butyl-2-({[tert-butyl(dimethyl)silyl]oxy}-
methyl)-4-hydroxy-3-phenylpyrrolidine-1-carboxylate (more
polar isomer) (isomer 5a2 major)
6.1.1.4.2. tert-Butyl-2-({[tert-butyl(dimethyl)silyl] oxy}
methyl)-3-hydroxy-4-phenylpyrrolidine-1-carboxylate (less
polar isomer) (5a1 minor). To a slurry of 25 mg
(0.13 mmol) CuI in 2 mL dry THF cooled to 0 ꢂC in
an ice/MeOH bath was added dropwise by syringe
1.31 mL (1.31 mmol) of a 1.0 M solution of phenylmag-
nesium bromide in THF. The resulting mixture was stir-
red for 10 min. at which time a solution of 250 mg
(0.87 mmol) of 4a in 1 mL THF was added. The result-
ing reaction mixture was stirred for 5 h at ambient T.
The mixture was quenched by the addition of 2 mL
water and extracted with ether 93· 10 mL. The com-
bined organic extracts were dried over anhydrous so-
dium sulfate, filtered, and the solvent removed under
6.1.1.7. tert-Butyl-4-{1-[3,5-bis(trifluoromethyl)phenyl]
ethoxy}-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-phe-
nylpyrrolidine-1-carboxylate (7a2). To a solution of
50 mg (0.077 mmol) of the intermediate tert-butyl-4-

2166
G. J. Morriello et al. / Bioorg. Med. Chem. 16 (2008) 2156–2170
({1-[3,5-bis(trifluoromethyl)phenyl]vinyl}oxy)-2-({[tert-
butyl(dimethyl)silyl]oxy}methyl)-3-phenylpyrrolidine-1-
carboxylate in 3 mL MeOH was added 5 mg (0.1 by wt)
10% Pd–C. The resulting mixture was degassed and then
stirred under hydrogen balloon atmosphere for 3 h. The
reaction mixture was filtered and the solvent of the fil-
trate removed under vacuum. The residue was purified
by prep TLC eluting with EtOAc–hexanes (1/9). Less
polar diastereomer (7a2-1): 24 mg (48%); 1H NMR
(500 MHz, CDCl3): d 7.68 (s, 1H); 7.43 (s, 2H); 7.20–
7.15 (m, 3H); 7.07 (d, J = 6.4 Hz, 2H); 4.38 (q,
J = 6.2 Hz, 1H); 4.12 (dd, J = 6.8, 10.0 Hz, 1H); 4.04–
3.91 (m, 2H); 3.70 (br s, 1H); 3.64 (d, 10.5 Hz, 0.5H);
3.52–3.39 (m, 1.5H); 3.30 (dd, J = 8.0, 10.3 Hz, 1H);
1.52 (s, 2.5 H); 1.48 (s, 6.5 H); 1.38 (d, J = 6.2 Hz,
3H); 0.91 (s, 9H); 0.12 (s, 6H) ppm. More polar diaste-
reomer (7a2-2); 26 mg (52%): 1H NMR (500 MHz,
CDCl3): d 7.72 (s, 1H); 7.52 (s, 1H); 7.49 (s, 1H);
7.27–7.21 (m, 3H); 7.07 (d, J = 6.4 Hz, 2H); 4.54–4.45
(m, 1H); 4.12 (dd, J = 6.8, 10.0 Hz, 1H); 4.04–3.95 (m,
1H); 3.91 (d, J = 7.0 Hz, 1H); 3.82–3.78 (m, 0.5H);
3.73 (br s, 0.5 H); 3.64 (d, 10.5 Hz, 0.5H); 3.60–3.50
(m, 1.5H); 3.30 (dd, J = 8.0, 10.3 Hz, 1H); 1.52 (s, 3.5
H); 1.48 (s, 5.5 H); 1.40 (d, J = 7.6 Hz, 3H); 0.94 (s,
9H); 0.17 (s, 3H); 0.15 (s, 3H) ppm.
resulting orange mixture was cooled to room tempera-
ture and the solids removed by filtration. The solids
were washed with water (2· 20 mL) and ether. The fil-
trate was extracted with ether (3· 150 mL) and the sol-
vent removed under vacuum to afford the 1-tert-butyl-
2-methyl (2R)-2,5-dihydro-1H-pyrrole-1,2-dicarboxyl-
ate. The 1-tert-butyl (2S)-2,5-dihydro-1H-pyrrole-2-car-
boxylate could be recovered by acidification of the
aqueous layer and extracting with an organic solvent
as described in the original reference.
6.1.2.2. tert-Butyl-(2R)-2-(hydroxymethyl)-2,5-dihydro-
1H-pyrrole-1-carboxylate (2, R-hydroxy methyl). The title
compound was prepared from 1-tert-butyl-2-methyl
(2R)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate accord-
1
ing to the procedure in the prior racemic synthesis. H
(500 MHz, CDCl3) d 5.82 (dd, J = 1.3, 4.6 Hz, 1H);
5.66–5.62 (m, 1H); 4.75 (br s, 1H); 4.20 (dd, J = 1.9,
15.6 Hz, 1H); 4.10 (ddd, J = 2.0, 5.5, 15.6 Hz, 1H);
3.80 (dd, J = 2.1, 11.4 Hz, 1H); 3.58 (dd, J = 7.5,
11.4 Hz, 1H), 1.52 (s, 9H) ppm.
The same procedures in the prior racemic synthesis were
used to give the intermediates needed to synthesize 9a2-2
as the only isomer obtained. A modification in the final
procedures was done and is included below.
6.1.1.8. tert-Butyl-4-{1-[3,5-bis(trifluoromethyl)phenyl]
ethoxy}-2-(hydroxymethyl)-3-phenylpyrro-lidine-1-carbox-
ylate (9a2-2). The more polar intermediate Step G,
90 mg (0.14 mmol) was dissolved in ꢀ2 mL (ꢀ2 mmol)
of a 1.0 M solution of TBAF in THF. The reaction mix-
ture was stirred at room temperature for 2 h and then
the solvent was removed under vacuum. The residue
was taken up in methylene chloride (ꢀ50 mL), washed
with water (2· 5 mL), dried over anhydrous sodium sul-
fate, filtered, and the solvent removed under vacuum
The residue was purified by prep. TLC eluting with hex-
anes–EtOAc (4/6) to afford 68 mg of the title compound.
1H NMR (500 MHz, CDCl3): d 7.72 (s, 1H); 7.46 (s,
2H); 7.27–7.24 (m, 3H); 7.08 (dd, J = 2.0, 7.2 Hz, 2H);
4.45 (app q, J = 6.3 Hz, 1H); 4.00 (dd, J = 2.3,
11.0 Hz, 2H) 3.99 (overlapping br s, 1H); 3.72 (br s,
2H), 3.38 (app t, J = 11.2 Hz, 1H), 2.92 (br s, 1H);
1.53 (s, 9H); 1.41 (d, J = 6.2 Hz, 3H) ppm. MS: 556
(M+Na), 434 (M+H-Boc).
6.1.2.3. tert-Butyl (2R,3S,4R)-4-{(1R)-1-[3,5-bis(tri-
fluoromethyl)phenyl]ethoxy}-2-({[tert-butyl(dimethyl)silyl]
oxy}methyl)-3-(4-fluorophenyl)pyrrolidine-1-carboxylate
(7a2-2). To a solution of 39 g (58.7 mmol) tert-butyl
(2R,3S,4R)-4-({1-[3,5-bis(trifluoromethyl)phenyl]vinyl}
oxy)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(4-fluo-
rophenyl)pyrrolidine-1-carboxylate in 400 mL EtOH
was added 2 g (0.05 by wt) 10% Pd–C. The resulting
mixture was hydrogenated in two 500 mL pressure
vessels at 40PSI and room temperature for 2 h.
The reaction mixture was filtered and the solvent of
the filtrate removed under vacuum to give an approxi-
mately 4:1 mixture of undesired (7a1-2): desired product
(7a2-2).
The undesired less polar isomer (7a1-2) can be isomer-
ized to a 1:1 mixture of isomers in which the desired
tert-butyl-(2R,3S,4R)-4-{(1R)-1-[3,5-bis(trifluoromethyl)-
phenyl]ethoxy}-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-
3-(4-fluorophenyl)pyrrolidine-1-carboxylate can be
obtained after separation of the isomers by chromatog-
raphy on silica gel. Several recycles of the undesired less
polar isomer afforded the major desired isomer with
highly improved yields. The procedure below explains
the racemization of the benzylic ether methyl
substituent.
All other isomers (9a1-1, 9a1-2, 9a2-2, 10b1, and 10b2)
were synthesized in the same manner as described above
for 9a2-2.
6.1.2. Single isomer: tert-butyl (2R,3S,4R)-4-{(1R)-1-[3,5-
bis(trifluoromethyl)phenyl]ethoxy}-2-(hydroxymethyl)-3-
(4-fluorophenyl)pyrrolidine-1-carboxylate
6.1.2.1. 1-tert-Butyl-2-methyl (2R)-2,5-dihydro-1H-
pyrrole-1,2-dicarboxylate (1, R-ester). (Prepared accord-
ing to the procedure of Sturmer, R.; Schafer, B.; Wolf-
art, V.; Stahr, H.; Kazmaier, U.; Helmchen, G.
Synthesis 2001 (1), 46–48). To a mixture of 8 g
(35.2 mmol) 1-tert-butyl-2-methyl (2RS)-2,5-dihydro-
1H-pyrrole-1,2-dicarboxylate in 200 mL distilled water
was added 1.6 g (19.3 mmol) sodium bicarbonate fol-
lowed by 1.6 g Novozyme 435ꢁ. The resulting suspen-
sion was heated at 50 ꢂC in an oil bath for 18 h. The
To 120 mL (120 mmol) of a 1.0 M solution of potas-
sium tert-butoxide in THF under nitrogen atmo-
sphere, cooled to À78 ꢂC, was added a solution of
ꢀ39 g of the above crude product in 400 mL dry
THF dropwise over 30 min. The reaction mixture
was slowly warmed in an ice/water bath then to room
temperature. After the temperature reached room tem-
perature, the mixture was heated at 40 ꢂC for 3 h. The
reaction mixture was cooled to room temperature,

G. J. Morriello et al. / Bioorg. Med. Chem. 16 (2008) 2156–2170
2167
quenched with saturated aqueous ammonium chloride,
and extracted with excess EtOAc. The combined ex-
tracts were washed with water, dried over anhydrous
sodium sulfate, filtered, and the residue was purified
by column chromatography on silica gel eluting with
EtOAc/hexanes gradient (0/100 to 20/80) to provide
7.4 g (19%) tert-butyl (2R,3S,4R)-4-{(1R)-1-[3,5-bis(tri-
fluoromethyl)phenyl]ethoxy}-2-({[tert-butyl(dimethyl)-
silyl]oxy}methyl)-3-(4-fluorophenyl)pyrrolidine-1-car-
boxylate, desired more polar 7a2-2. 1H NMR
(500 MHz, CDCl3): d 7.73 (s, 1H); 7.52 (s, 2H); 7.02
(dd, J = 6.2, 8.3 Hz, 2H); 7.00–6.94 (m, 2H); 4.45–
4.34 (m, 1H); 4.12 (dd, J = 6.8, 10.0 Hz, 1H); 4.04–
3.95 (m, 1H); 3.92–3.80 (m, 2H); 3.82–3.78 (m, 1H);
3.70–3.62 (m, 1H); 3.56 (app t, J = 7.2, 1H); 3.50 (d,
J = 9 Hz, 1H); 3.24–3.30 (m, 1H); 1.52 (s, 3.5H);
1.48 (s, 4.5H); 1.42 (d, J = 6.6 Hz, 3H), 0.94 (s, 9H);
0.06 (s, 3H); 0.04 (s, 3H) ppm. In addition, mixed
fractions containing 4.6 g of >95% pure desired more
polar were isolated and 16 g of a mixture containing a
majority of undesired less polar diastereomer which
could be further recycled to desired product by isom-
erization. Undesired less polar diastereomer (7a1-2):
1H NMR (500 MHz, CDCl3): d 7.80 (s, 1H); 7.58 (s,
2H); 7.24–7.16 (m, 2H); 7.04 (dd, J = 6.2, 8.4 Hz,
2H); 4.50–4.40 (m, 1H); 4.08 (br d, J = 6.0 Hz, 1H);
3.92–3.83 (m, 2H); 3.80–3.76 (m, 1H); 3.72 (br s,
1H); 3.68–3.55 (m, 2H); 3.26–3.20 (m, 1H); 3.15 (br
t, J = 9.2 Hz, 1H); 1.46 (s, 3.5H); 1.44 (s, 4.5H);
1.36 (d, J = 6.6 Hz, 3H), 0.94 (s, 9H); 0.07 (s, 3H);
0.05 (s, 3H) ppm.
0.06 mL (0.340 mmol) of DIEA, followed by 22 mg
(0.085 mol) of disuccinimidyl-carbonate (DSC) and the
resulting solution stirred at room temperature over-
night. The mixture was concentrated in vacuo and puri-
fied via preparative TLC plate eluting with 70% ethyl
acetate in hexane to afford 17 mg, (48% yield) of the title
compound. 1H NMR (500 MHz, CDCl3): d 7.74 (s, 1H);
7.50 (s, 2H); 7.06 (dd, J = 5.2, 8.6 Hz, 2H); 6.97 (dd,
J = 8.7, 7.9 Hz, 2 H); 4.51 (app q, J = 6.3 Hz, 1H);
4.49 (dd, J = 2.3, 9.1 Hz, 1H) 4.28 (dd, J = 3.2, 9.1 Hz,
1H), 4.14 (ddd, J = 4.3, 6.6, 10.9 Hz, 1H), 4.05 (ddd,
J = 3.1, 8.0, 11.2 Hz, 1H), 3.90 (dd, J = 4.1, 12.1 Hz,
1H), 3.62 (dd, 6.4, 12.2 Hz, 1H), 3.11 (dd, J = 6.9,
9.0 Hz, 1H), 1.44 (d, J = 6.6 Hz, 3H).
The other two diastereomers, 12a1-2 and 13b-2, were
also prepared in similar fashion as described for 12a2-
2. Below are the H NMR results for these compounds.
1
6.1.5.1. (6S,7R,7aR)-7-{(1R)-1-[3,5-Bis(trifluorometh-
yllphenyl)]ethoxy}-6-phenyltetrahydro-1H-pyrrolo[1,2-c]
[1,3]oxazol-3-one (12a1-2). 1H NMR (500 MHz,
CDCl3): d 7.81 (s, 1H); 7.70 (s, 2H); 6.98–6.92 (m,
4H); 4.65 (q, J = 6.4 Hz, 1 H); 4.60–4.55 (m, 2 H) 4.30
(ddd, J = 5.0, 7.3, 9.9 Hz, 1 H), 4.06 (dd, J = 7.3,
11.2 Hz, 1 H), 3.95 (dd, J = 3.0, 4.4 Hz, 1 H), 3.39 (d,
J = 5.2 Hz, 1H), 3.36–3.32 (m, 1H), 1.54 (d,
J = 6.4 Hz, 3H).
6.1.5.2. (6S,7R,7aS)-7-{(1R)-1-[3,5-Bis(trifluoromethyl)
phenyl]ethoxy}-6-phenyltetrahydro-1H-pyrrolo[1,2-c][1,3]
oxazol-3-one (13b-2). 1H NMR (500 MHz, CDCl3): d 7.79
(s, 1H); 7.65 (s, 2H); 7.06 (dd, J = 5.2, 8.6 Hz, 2H); 6.97
(dd, J = 8.7, 7.9 Hz, 2H); 4.69 (dd, J = 2.2, 9.1 Hz, 1H),
4.60 (d, J = 3.2 Hz, 1H), 4.54 (q, J = 6.5 Hz, 1H), 4.40
(dd, J = 6.8, 9.0 Hz, 1H), 4.09 (ddd, J = 5.0, 6.8, 8.6 Hz,
1H), 3.91 (br dd, J = 3.0, 5.4 Hz, 1H), 3.80 (dd, J = 4.1,
5.5 Hz, 1H), 3.67 (dd, J = 6.3, 9.1 Hz, 1H), 3.40 (app q,
J = 6.3 Hz, 1H), 1.44 (d, J = 6.7 Hz, 3H).
6.1.3. tert-Butyl (2R,3S,4R)-4-{(1R)-1-[3,5-bis(trifluoro-
methyl)phenyl]ethoxy}-3-(4-fluorophenyl)-2-(hydroxy-
methyl)pyrrolidine-1-carboxylate (9a2-2). The title
compound was prepared from tert-butyl (2R,3S,4R)-4-
{(1R)-1-[3,5-bis(trifluoromethyl) phenyl]ethoxy}-2-({[tert-
butyl(dimethyl)silyl]oxy}methyl)-3-(4-fluorophenyl)pyr-
rolidine-1-carboxylate (7a2-2) according to the proce-
dure in the prior racemic synthesis. 1H NMR
(500 MHz, CDCl3): d 7.72 (s, 1H); 7.46 (s, 2H); 7.06
(dd, J = 5.2, 8.6 Hz, 2H); 6.97 (dd, J = 8.7, 7.9 Hz,
2H); 4.45 (app q, J = 6.3 Hz, 1H); 4.00 (dd, J = 2.3,
11.0 Hz, 2H) 3.99 (overlapping br s, 1H); 3.72 (br s,
2H), 3.38 (dd, J = 7.7, 10.6 Hz, 1H), 2.92 (br s, 1H);
1.53 (s, 9H); 1.41 (d, J = 6.6 Hz, 3H) ppm. MS: 574
(M+Na), 451 (M+H-Boc).
6.1.6. tert-Butyl-4-{1-[3,5-bis(trifluoromethyl)phenyl]eth-
oxy}-2-formyl-3-phenylpyrrolidine-1-carboxylate
(15).
To a stirred solution of 0.016 mL (0.19 mmol) oxalyl
chloride in 4 mL dry methylene chloride under nitrogen
atmosphere at À78 ꢂC was added 0.025 mL (0.372
mmol) DMSO dropwise over 5 min by syringe. After
10 min, to this mixture was added a solution of 50 mg
(0.093 mmol)
tert-butyl-4-{1-[3,5-bis(trifluoromethyl)
6.1.4. (2R,3S,4R)-4-{(1R)-1-[3,5-Bis(trifluoromethyl)phen-
yl]ethoxy}-3-(4-fluorophenyl)-2-(hydroxyl methyl)pyrroli-
dine hydrochloride (11a2-2). The title compound was
prepared by treatment of 50 mg of tert-butyl
(2S,3S,4R)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]
ethoxy}-3-(4-fluorophenyl)-2-(hydroxymethyl)pyrroli-
dine-1-carboxylate (9a2-2) with 2 mL of 4 N HCl in
dioxane for 1 h at room temperature. Concentration in
vacuo afforded 42 mg of the title compound; no further
purification was necessary. MS: 434 (M+H).
phenyl]ethoxy}-2-(hydroxymethyl)-3-phenylpyrrolidine-
1-carboxylate (9a2-2) in 1 mL dry methylene chloride.
The reaction mixture was stirred at À78 ꢂC for 1 h, then
0.104 mL (0.744 mmol) TEA was added by syringe. The
reaction mixture was stirred at À78 ꢂC for 15 min, then
warmed to room temperature and stirred an additional
hour. The reaction mixture was quenched with aq 1 N
HCL (ꢀ5 mL) and transferred to a separatory funnel.
The reaction mixture was extracted with EtOAc (2·
5 mL). The combined organic extracts were washed with
water (5 mL) then brine (5 mL), dried over anhydrous
sodium sulfate, filtered, and evaporated under vacuum
to afford 45 mg of the title compound. The resulting
crude product (15) was used without further
purification.
6.1.5. (6R,7S)-6-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]
ethoxy}-7-phenyltetrahydro-1H-pyrrolo[1,2-c] [1,3]oxa-
zol-3-one (12a2-2). To a solution of 40 mg (0.085 mmol)
of (11a2-2) in dichloromethane (3 mL) was added

2168
G. J. Morriello et al. / Bioorg. Med. Chem. 16 (2008) 2156–2170
6.1.7. tert-Butyl-2-[(benzylamino)methyl]-4-{1-[3,5-bis(tri-
fluoromethyl)phenyl]ethoxy}-3-phenylpyrrolidine-1-car-
boxylate hydrochloride (16). To a stirred solution of
45 mg (0.085 mmol) of 15 and 0.010 mL (0.085 mmol)
benzylamine in 5 mL dry methylene chloride under
nitrogen atmosphere at room temperature were added
ꢀ50 mg 4A molecular sieves followed by 90 mg
(0.423 mmol) NaBH(OAc)3. The reaction mixture was
stirred at room temperature. for 16 h, then quenched
with satd aq sodium bicarbonate (ꢀ10 mL) and trans-
ferred to a separatory funnel. The reaction mixture
was extracted with methylene chloride (2· 10 mL). The
combined organic extracts were dried over anhydrous
sodium sulfate, filtered, and evaporated under vacuum.
The resulting crude product was purified by prep TLC
eluting with hexanes–EtOAc (65/45) to afford 30 mg of
the free base of the title compound. The isolated free
base was converted to the hydrochloride salt by treat-
ment with HCL to afford the title compound. 1H
NMR (500 MHz, CDCl3): d 7.79 (s, 1H); 7.62 (s, 2H);
7.40 (br d, J = 7.1 Hz, 3H); 7.34 (d, J = 7.1 Hz, 2H);
7.29–7.26 (m, 3H); 7.15–7.11 (m, 2H); 4.68 (app q,
J = 6.2 Hz, 1H); 4.25 (d, J = 13.0 Hz, 1H); 4.13 (t,
J = 8.3 Hz, 1H); 4.10–4.05 (m, 1H); 4.04 (d,
J = 13.0 Hz, 1H); 3.42–3.35 (m, 1H); 3.33 (dd, J = 1.6,
3.2 Hz, 2H); 3.19 (d, J = 13.3 Hz, 1H); 3.11 (t,
J = 7.6 Hz, 1H); 1.54 (s, 9H); 1.37 (d, J = 6.3 Hz,
3H) ppm. MS: 623 (M+H).
1 mL MeOH and 2 equiv of 2 M HCl/ether was added
2.5 mg (0.25 by wt) 10% Pd–C. The resulting mixture
was degassed and then stirred under hydrogen balloon
atmosphere for 3 h. The reaction mixture was filtered
and the solvent of the filtrate removed under vacuum.
The residue was purified by prep TLC eluting with
EtOAc–hexanes (1/1) to afford 8 mg of the title com-
1
pound (18). H NMR (500 MHz, CD3OD): d 7.70 (s,
1H), 7.50 (s, 2H), 7.30–7.22 (m, 2H overlapped by
CDCl3 signal), 7.08 (app t, J = 8.7 Hz, 2H), 4.58 (s,
1H), 4.49 (q, J = 6.5 Hz, 1H), 4.14 (ddd, J = 4.6, 7.0,
11.2 Hz, 1H), 3.90 (ddd, J = 2.3, 7.8, 10.0 Hz, 1H),
3.86 (dd, 4.3, 12.1 Hz, 1H), 3.57 (t, J = 8.5 Hz, 1H),
3.52 (dd, J = 6.6, 12.1 Hz, 1H), 3.32 (dd, J = 2.2,
9.2 Hz, 1H), 3.04 (dd, J = 7.1, 9.5 Hz, 1H), 1.41 (d,
J = 6.5 Hz, 1H). MS: 477 (MH)+; 499 (M+Na)+.
6.1.11. (6R,7S)-6-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]
ethoxy}-2-methyl-7-phenylhexahydro-3H-pyrrolo[1,2-c]imi-
dazol-3-one (19). To a solution of 4 mg (0.01 mmol) of
18 in DMF (0.5 mL) under nitrogen, cooled to 0 ꢂC
via ice bath, was added NaH (1 mg, 0.04 mmol) and
the resulting solution stirred for 30 min. After aging
for 30 min, MeI (1 lL, 0.02 mmol) was added to the
reaction mixture and the solution was stirred overnight
allowing to warm to room temperature. The reaction
mixture was quenched with aqueous NH4Cl and ex-
tracted with ethyl acetate (3· 2 mL). The organics were
combined, dried over sodium sulfate, filtered, and con-
centrated in vacuo. Preparative plate purification
(250 lM plate) eluting with ethyl acetate–hexane (1/1)
afforded 3.25 mg (80%) of 19 as a clear film. 1H
NMR (500 MHz, CD3OD): d 7.70 (s, 1H), 7.50 (s,
2H), 7.30–7.22 (m, 2H overlapped by CDCl3 signal),
7.08 (app t, J = 8.7 Hz, 2H), 4.49 (q, J = 6.5 Hz, 1H),
4.14 (ddd, J = 4.6, 7.0, 11.2 Hz, 1H), 3.90 (ddd,
J = 2.3, 7.8, 10.0 Hz, 1H), 3.86 (dd, 4.3, 12.1 Hz, 1H),
3.57 (t, J = 8.5 Hz, 1H), 3.52 (dd, J = 6.6, 12.1 Hz,
1H), 3.32 (dd, J = 2.2, 9.2 Hz, 1H), 3.12 (s, 3H), 3.04
(dd, J = 7.1, 9.5 Hz, 1H), 1.41 (d, J = 6.5 Hz, 1H).
MS: 491 (MH)+; 513 (M+Na)+.
6.1.8. 2-(Benzylamino)methyl-4-{1-[3,5-bis(trifluoromethyl)-
phenyl]ethoxy}-3-phenylpyrrolidine hydrochloride. The
title compound was prepared by treatment of 30 mg of
tert-Butyl-2-[(benzylamino)
methyl]-4-{1-[3,5-bis(tri-
fluoromethyl)phenyl]ethoxy}-3-phenylpyrrolidine-1-car-
boxylate hydrochloride (16) with 1 mL of 4 N HCl in
dioxane for 1 h at room temperature. Concentration in
vacuo afforded 14 mg of the title compound; no further
purification was necessary. MS: 523 (M+H).
6.1.9. (6R,7S)-2-Benzyl-6-{(1R)-1-[3,5-bis(trifluoromethyl)
phenyl]ethoxy}-7-phenylhexahydro-3H-pyrrolo[1,2-c]imi-
dazol-3-one (17). To a solution of 2-(benzylamino)methyl-
4-{1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-phenyl-
pyrrolidine hydrochloride (25 mg, 0.04 mmol) and DIEA
(30 mL, 0.16 mmol) in dichloromethane (1 mL) was
added phosgene (20% solution, 24 mL, 0.05 mmol) and
the resulting solution stirred overnight at room tempera-
ture. The solution was transferred directly to a prepara-
tive TLC plate and purified by eluting with 30% ethyl
acetate in hexane to afford 12 mg of 17. 1H NMR
(500 MHz, CD3OD): d 7.77 (s, 1H), 7.54 (s, 2H), 7.43
(br d, J = 7.1 Hz, 3H); 7.33 (d, J = 7.1 Hz, 2H); 7.29–
7.24 (m, 3H); 7.15–7.09 (m, 2H); 4.65 (app q,
J = 6.2 Hz, 1H), 4.49 (q, J = 6.5 Hz, 1H), 4.14 (ddd,
J = 4.6, 7.0, 11.2 Hz, 1H), 3.90 (ddd, J = 2.3, 7.8,
10.0 Hz, 1H), 3.86 (dd, 4.3, 12.1 Hz, 1H), 3.57 (t,
J = 8.5 Hz, 1H), 3.52 (dd, J = 6.6, 12.1 Hz, 1H), 3.32
(dd, J = 2.2, 9.2 Hz, 1H), 3.04 (dd, J = 7.1, 9.5 Hz, 1H),
1.41 (d, J = 6.5 Hz, 1H). MS: 566 (MH)+; 588 (M+Na)+.
6.1.12. tert-Butyl-(2S,3S,4R)-4-{(1R)-1-[3,5-bis(trifluoro-
methyl)phenyl]ethoxy}-3-(4-fluorophenyl)-2-[(1E)-3-tert-
butoxy-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate (20).
To
a solution of 977 mg (1.78 mmol) tert-butyl-
(2R,3S,4R)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]
ethoxy}-3-(4-fluorophenyl)-2-formyl pyrrolidine-1-car-
boxylate (15) in 30 mL dry methylene chloride under
nitrogen atmosphere was added 670 mg (1.78 mmol)
(tert-butoxycarbonylmethylene) triphenyl phosphorane.
The resulting mixture was stirred at room temperature
for 16 h. The solvent was removed under vacuum and
the residue purified by Horizon MPLC using a gradient
eluting system of 0–20% ethyl acetate in hexane to afford
1.01 g (88%) of the title compound. MS: 648.2 (MH+).
6.1.13. tert-Butyl-(2S,3S,4R)-4-{(1R)-1-[3,5-bis(trifluoro-
methyl)phenyl]ethoxy}-3-(4-fluorophenyl)-2-(3-tert-butoxy-
3-oxopropyl)pyrrolidine-1-carboxylate. To a solution of
1.01 g of 20 in 30 mL ethanol under nitrogen atmo-
sphere was added 100 mg 10% Pd–C catalyst. The
resulting mixture was stirred under hydrogen balloon
6.1.10. (6R,7S)-6-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]
ethoxy}-7-phenylhexahydro-3H-pyrrolo[1,2-c]imidazol-3-
one (18). To a solution of 10 mg (0.02 mmol) of 17 in

G. J. Morriello et al. / Bioorg. Med. Chem. 16 (2008) 2156–2170
2169
atmosphere at room temperature. After several hours,
the catalyst was filtered through filter aid and the solvent
was removed under vacuum to afford 945 mg (94%) of
References and notes
1. (a) Boyce, S. J.; Laird, M. A.; Tattersall, F. D.; Rupniak,
N. M. J.; Hargreaves, R. J.; Hill, R. G. I. A. S. P.
Publications Congress Abstracts 1993, 231; (b) Tattersall,
F. D.; Rycroft, W.; Hargreaves, R. J.; Hill, R. G. Eur. J.
Pharmacol. 1993, R5, 250; (c) Swain, C.; Rupian, N. M. J.
Annu. Rep. Med. Chem. 1999, 34, 51.
2. (a) Campos, D.; Pereira, J. R.; Reinhardt, R. R.; Carra-
cedo, C.; Poli, S.; Vogel, C., et al. J. Clin. Oncol. 2001, 19,
1759; (b) Poli-Bigelli, S.; Rodrigues-Pereira, J.; Carides, A.
D.; Ma, G. J.; Eldridge, K.; Hipple, A., et al. Cancer
2003, 97, 3090.
1
the title compound. H NMR (500 MHz, CD3OD): d
7.78 (s, 1H); 7.66 (s, 2H); 7.12 (dd, J = 5.3, 8.5 Hz,
2H); 6.98 (app t, J = 8.6 Hz, 2H); 4.72 (q, J = 6.4 Hz,
1H); 4.14 (ddd, J = 2.7, 7.3, 12.0 Hz, 1H) 3.90 (dd,
J = 7.1, 14.2 Hz, 1H); 3.81 (br s, 1H), 3.28 (br s, 1H),
(br m, 1H), 2.20 (br app dd, J = 6.6, 7.5 Hz, 2H);
2.06–1.96 (m, 2H); 1.50 (s, 9H), 1.43 (s, overlapping a
d, 9H) 1.43 (d, J = 6.4 Hz, 3H). MS: 650(MH)+, 594
(M-56; M-tert-bu)+, 550 (M-100; M-BOC)+.
3. (a) Patacchini, R.; Maggi, C. A. Arch. Int. Pharmacodyn.
1995, 329, 161; (b) Maggi, C. A.; Patacchini, R.; Rovero,
P., et al. J. Auton. Pharmacol. 1993, 13, 23; (c) Otsuka,
M.; Yoshioka, K. Physiol. Rev. 1993, 73, 229.
4. (a) Graham, E. A.; Turpin, M. P.; Stubbs, C. M.
Neuropeptides 1993, 109, 713; (b) Bristow, L. J.; Young,
L. Eur. J. Pharmacol. 1994, 253, 245.
6.1.14. 3-[(2S,3S,4R)-4-{(1R)-1-[3,5-Bis(trifluoromethyl)
phenyl]ethoxy}-3-(4-fluorophenyl)pyrrolidin-2-yl]prop-
anoic acid hydrochloride (21). The title compound was
prepared by treatment of tert-butyl (2S,3S,4R)-4-
{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-
fluorophenyl)-2-(3-tert-butoxy-3-oxopropyl)pyrrolidine-
1-carboxylate with 30 mL of 4 N HCl in dioxane for 1 h
at room temperature. Concentration in vacuo afforded
770 mg of the title compound; no further purification
5. Rupniak, N. M. J.; Williams, A. R. Eur. J. Pharmacol.
1994, 265, 179.
6. (a) Ward, P.; Armour, D. R.; Bays, D. E.; Evans, B.;
Giblin, G. M. P.; Heron, N.; Hubbard, T.; Liang, K.;
Middlemiss, D., et al. J. Med. Chem. 1995, 38, 4985; (b)
Caron, S.; Massett, S. S.; Bogle, D. E.; Castaldi, M. J.;
Braish, F. Org. Process Res. Dev. 2001, 5, 254; (c) Desai,
M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K.; Snider,
M. R. J. Med. Chem. 1992, 35, 4911; (d) Rupniak, N. M. J.;
Tattersall, D. F.; Williams, A. R.; Rycroft, W.; Carlson, E.
J.; Cascieri, M. A.; Sadowski, S.; Ber, E.; Hale, J. J.; Mills,
S. G.; MacCoss, M.; Steward, E.; Huscroft, I.; Owen, S.;
Swain, C. J.; Hill, R. G.; Hargreaves, R. J. Eur. J.
Pharmacol. 1997, 326, 201; (e) Meurer, L. C.; Finke, P. E.;
Owens, K. A.; Tsou, N. N.; Ball, R. G.; Mills, S. G.;
MacCoss, M.; Sadowski, S.; Cascieri, M. A.; Tsao, K.-L.;
Chicchi, G. G.; Egger, L. A.; Luell, S.; Metzger, J. M.;
MacIntyre, E.; Rupniak, N. M.; Williams, A. R.; Harg-
reaves, R. Biol. Med. Chem. Lett. 2006, 16, 4505.
7. (a) Lin, P.; Chang, L.; DeVita, R. J.; Young, J. R.; Eid, R.;
Tong, X.; Zheng, S.; Ball, R. G.; Tsou, N. N.; Chicchi, G.;
Kurtz, M.; Tsao, K.-L. C.; Wheeldon, A.; Carlson, E. J.;
Eng, W.; Burns, D. H.; Hargreaves, R. J.; Mills, S. G.
Biol. Med. Chem. Lett. 2007, 17, 5191; (b) Lin, P.; Young,
J. R.; DeVita, R. J.; Eid, R.; Mills, S. G.; MacCoss, M.;
Chang, L. World Patent 2005/032464, 2005.
1
was necessary. H NMR (500 MHz, CD3OD): d 7.78
(s, 1H); 7.64 (s, 2H); 7.21 (dd, J = 5.0, 8.7 Hz, 2H);
7.20 (app t, J = 8.7 Hz, 2H); 4.72 (app q, J = 6.2 Hz,
1H); 4.22 (ddd, J = 2.7, 7.3, 12.0 Hz, 1H) 3.82 (dd,
J = 7.3, 12.2 Hz, 1H); 3.66 (ddd, J = 3.2, 4.6, 12.0 Hz,
1H), 3.50 (dd, J = 4.6, 12.3 Hz, 1H), 3.14 (dd, J = 7.4,
12.0 Hz, 1H), 2.35 (app dd, J = 6.8, 12.7 Hz, 2H);
2.06–1.96 (m, 1H); 1.98–1.87 (m, 1H); 1.43 (d,
J = 6.7 Hz, 3H). MS: 494 (MH)+; 516 (M+Na)+.
6.1.15. (6R,7S,7aS)-6-{(1R)-1-[3,5-Bis(trifluoromethyl)
phenyl]ethoxy}-7-(4-fluorophenyl)hexahydro-3H-pyrroli-
zin-3-one (22). To a solution of 768 mg of 21, 20 mg
(0.15 mmol) DMAP, and 253 lL (1.45 mmol) DIEA in
75 mL dichloromethane under nitrogen atmosphere
was added 556 mg (2.90 mmol) EDC and the resulting
solution stirred overnight at room temperature. The
reaction mixture was washed with 1 N HCl solution
(20 mL), followed by saturated NaHCO3 solution
(20 mL) and then brine (30 mL). The organic solution
was dried over sodium sulfate, filtered through a fritted
funnel, and concentrated in vacuo. The residue was
purified by eight preparative TLC plates eluting with
ethyl acetate to afford 600 mg (88%) of the title com-
8. Jiang, J. et al. World Patent 2006/060390, 2006.
9. (a) Devita, R.; Mills, S. G.; Jiang, J.; et al. World Patent
2006/060344, 2006; (b) Devita, R.; Mills, S. G.; Jiang, J.;
et al. World Patent 2006/060346, 2006.
10. Oliveira, D. F.; Severino, E. A.; Correia, C. R. D.
Terahedron Lett. 1999, 40, 2083.
1
pound. H NMR (500 MHz, CDCl3): d 7.72 (s, 1H),
7.45 (s, 2H), 7.06 (dd, J = 5.3, 8.7 Hz, 2H), 6.98 (app
t, J = 8.7 Hz, 2H), 4.46 (q, J = 6.5 Hz, 1H), 4.17 (ddd,
J = 5.8, 7.4, 13.8 Hz, 1H), 3.89 (ddd, J = 6.9, 10.1,
13.9 Hz, 1H), 3.70 (dd, J = 6.0, 11.9 Hz, 1H), 3.60
(ddd, J = 1.2, 7.3, 11.9 Hz, 1H), 2.84 (dd, J = 8.4,
9.9 Hz, 1H), 2.67 (dd, J = 9.9, 16.9 Hz, 1H), 2.53 (dddd,
J = 2.5, 9.9, 12.4, 16.8 Hz, 1H), 2.25–2.17 (m, 1H), 1.93–
1.83 (m, 1H), 1.42 (d, J = 6.7 Hz, 3H). MS: 476 (MH)+;
498 (M+Na)+.
11. (a) Tebbe, F. N. G.; Parshall, W.; Reddy, G. S. J. Am.
Chem. Soc. 1978, 100, 3611; (b) Pine, S. H.; Shen, G. S.;
Hoang, H. Synthesis 1991, 2, 165.
12. 2D NOESY performed by Dr. George Doss. Crucial cross
couplings observed that determined relative stereochemis-
try of compound 12a2-2: H9 to H7; coupling of H7 and
H9 to one of the o-hydrogens on the phenyl substituent;
slight coupling of H8 to benzylic ether hydrogen; slight
coupling of H7 to benzylic methyl hydrogens; observed no
coupling for H8 to either H7 or H9.
13. (a) Sanchez, V. M.; Rebolledo, F.; Gotor, V. J. Org.
Chem. 1999, 64, 1464; (b) Sturmer, R.; Schafer, B.;
Wolfart, V.; Stahr, H.; Kazmaier, U.; Helmchen, G.
Synthesis 2001, 1, 46.
14. (a) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem.
1978, 43, 2480; (b) Mancuso, A. J.; Swern, D. Synthesis
1981, 3, 165.
Acknowledgments
The authors thank Christopher Moyes and Paul Finke
for their help in the preparation of this manuscript.
Their assistance was greatly appreciated.

2170
G. J. Morriello et al. / Bioorg. Med. Chem. 16 (2008) 2156–2170
15. (a) Wittig, G.; Geissler, G. Liebigs Ann. Chem. 1953, 580,
44; (b) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem.
Soc. 1961, 7, 1733.
Watt, A. P.; Chicchi, G. G.; Keohane, C.; Hora, D.
F.; Chiu, S.-H. L. Drug Metab. Dispos. 2003, 31,
785.
16. (a) Sehgal, D.; Ik, V. Anal. Biochem. 1994, 218, 87; (b)
Marder, O.; Albericio, F. Chim. OGGI/Chem. 2003, 21, 35.
17. Huskey, S-E. W.; Dean, B. J.; Bakhtiar, R.; Sanchez,
R. I.; Tattersall, F. D.; Rycroft, W.; Hargreaves, R.;
18. Cascieri, M. A.; Ber, E.; Fong, T. M.; Sadowski, S.;
Bansal, A.; Swain, C. J.; Seward, E. M.; Frances, B.;
Burns, D.; Strader, C. D. Mol. Pharmacol. 1992, 42,
458.