Design and synthesis of a novel series of 1,2-disubstituted cyclopentanes as small, potent potentiators of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) receptors

Article abstract of DOI:10.1021/jm0105474

2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) potentiators are ligands that act as positive allosteric modulators at the AMPA receptors. We recently disclosed a novel series of 2-arylpropylsulfonamides that were potent potentiators of responses mediated through AMPA receptors. To further define the structural requirements for activity in this series, new ring-constrained analogues were prepared and a new stereocenter was introduced. The potentiating activity was highly dependent on the stereochemistry at the 2-position of the disubstituted cyclopentane and was independent of the relative stereochemistry at the 1-position. Compound (R,R)-10 represents a potent, novel potentiator of iGluR4 flip receptors (EC₅₀ = 22.6 nM).

Full text of DOI:10.1021/jm0105474

J . Med. Chem. 2002, 45, 2101-2111
2101
Design a n d Syn th esis of a Novel Ser ies of 1,2-Disu bstitu ted Cyclop en ta n es a s
Sm a ll, P oten t P oten tia tor s of
2-Am in o-3-(3-h yd r oxy-5-m eth yl-isoxa zol-4-yl)p r op a n oic Acid (AMP A) Recep tor s
Timothy A. Shepherd,* J ames A. Aikins, David Bleakman, Buddy E. Cantrell, J ohn P. Rearick,†
Richard L. Simon, Edward C. R. Smith, Gregory A. Stephenson, and Dennis M. Zimmerman
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285
Allan Mandelzys, Keith R. J arvie, Ken Ho, Michelle Deverill, and Rajender K. Kamboj
NPS Allelix Corporation, 6850 Goreway Drive, Mississaugua, Ontario L4V 1V7, Canada
Received December 3, 2001
2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) potentiators are ligands
that act as positive allosteric modulators at the AMPA receptors. We recently disclosed a novel
series of 2-arylpropylsulfonamides that were potent potentiators of responses mediated through
AMPA receptors. To further define the structural requirements for activity in this series, new
ring-constrained analogues were prepared and a new stereocenter was introduced. The
potentiating activity was highly dependent on the stereochemistry at the 2-position of the
disubstituted cyclopentane and was independent of the relative stereochemistry at the
1-position. Compound (R,R)-10 represents a potent, novel potentiator of iGluR4 flip receptors
(EC50 ) 22.6 nM).
In tr od u ction
The neurotransmitter glutamate is the principal
mediator of fast excitatory transmission in the central
nervous system (CNS). It is believed that defects in
glutamatergic neurotransmission are associated with
many human neurological and psychiatric disorders.
F igu r e 1.
AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)-
propanoic acid) receptors are a subset of ionotropic
controlled synthesis of a set of substituted monoaryl cis
glutamate receptors. Activation of AMPA receptors is
and trans cyclopentanes and examine the effects on
critical for expression and maintenance of long-term
AMPA potentiator activity by varying the phenyl ring
potentiation, an enduring form of synaptic plasticity
substituents and cyclopentane ring stereochemistry.
that may be associated with certain forms of learning
When compared to our previously reported series,7,8
and memory.1 AMPA receptor protein subunits have
these compounds are significantly more potent.
been cloned and identified as GluR1-4.2 These subunits
are thought to form tetrameric or pentameric ion
Ch em istr y
channel complexes. In addition, there are also amino
Two general approaches have been reported for the
acid sequence variants of the subunit, the two splice
synthesis of 2-phenylcyclopentylamines. Early efforts
variant isoforms, flip and flop.3,4
focused on the preparation of 2-phenylcyclopentanone,
Several molecules known as AMPA receptor potentia-
formation of the oxime, and reduction, typically giving
tors such as 1 (IDRA-21) and 2 (CX-516)5,6 (Figure 1)
mixtures of difficult to separate cis and trans 2-phenyl-
have been shown to positively modulate ion influx
cyclopentylamines. One noted exception is the work of
through recombinant and neuronal AMPA receptors via
Wiehl, who was able to make enantiomerically pure cis
an allosteric mechanism of action. We have recently
amines by using a chiral amine for oxime formation.9
described a novel class of 2-arylpropylsulfonamides
The second approach involved the opening of cyclopen-
(Figure 2, 3a -d ) as AMPA receptor potentiators.7,8 In
tene oxide with an aryl Grignard reagent and subse-
an effort to further expand our understanding of the
quent conversion of the alcohol to an amine.10 This
structural requirements for activity within this series,
method has the advantage of producing only the trans
we proposed new ring-constrained analogues. By bridg-
aryl adduct, and subsequent manipulation to either the
ing the methyl group with the methylene unit, we
cis or the trans amine is possible. We chose the latter
introduced an additional stereocenter in the form of a
method for both its simplicity and the current com-
1-amino-2-aryl-cyclopentane, allowing the possibility of
mercial availability of many substituted aryl Grignard
four diastereomers. In this article, we will detail the
reagents.
Scheme 1 outlines the synthesis of cis-2-aryl-1-amino-
cyclopentanes. Reaction of commercially available aryl
Grignard reagents (4a -h ) with cyclopentene oxide
* To whom correspondence should be addressed. Tel.: (317)276-
5164. Fax: (317)277-2035. E-mail: Shepherd_Timothy@Lilly.com.
† Purdue University Summer Intern.
10.1021/jm0105474 CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/17/2002

2102 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 10
Shepherd et al.
F igu r e 2.
Sch em e 1. Synthesis of cis-2-Phenyl-1-Amino-Cyclopentanesa
a
Reagents: (a) CuI, THF, 2 h. (b) Phthalimide, DIAD, Ph3P, THF. (c) Hydrazine or 2-aminoethanol. (d) i-Pr-SO2Cl, DBU, CH2Cl2. (e)
Chiral chromatography using Chiralcel AD column. (f) HOAc, H2SO4, I2, I2O5. (g) Zn(CN)2, PdCl2(dppf), DMF. (h) NaNO3, TFA.
provides the trans cyclopentanols 6a -h exclusively. The
Mitsunobu reaction with phthalimide proceeds with
complete inversion to give cis compounds 7a -h . Ami-
nolysis with hydrazine or hydroxyethylamine afforded
the amines 8a -h in good yield. Substitution of the
amine as the isopropylsulfonamide was found to be
optimal in our previously published series and so was
also exclusively retained throughout this series.
To have a versatile intermediate for further chemical
manipulations, the selective para iodination of the
phenyl derivative 9a was examined. We found moderate
success using periodic acid and iodine but later found
the method of Brazdil (diiodine pentoxide, iodine) to give
the cleanest, highest yield of compound 10.11 The cis
enantiomers were separated by chiral chromatography
using a Chiralcel AD column to give compounds (R,R)-
10 and (S,S)-10. The iodo-containing intermediates were
converted to the cyano-containing compounds using zinc
cyanide and palladium catalysis to yield compounds
(R,R)-12 and (S,S)-12.12 Alternatively, para nitration of
9a was accomplished with sodium nitrate and trifluo-
roacetic acid to yield compound 11. For three of these
cis analogues (9a ,f,h ), we chose to separate enantiomers
by chiral chromatography using a Chiralcel OD column.
A smaller set of compounds was made in the trans
series by two approaches that are outlined in Schemes

Novel AMPA Receptor Potentiator
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 10 2103
Sch em e 2. Synthesis of trans-2-Phenyl-1-Amino-Cyclopentanesa
a
Reagents: (a) Benzoic acid, DEAD, Ph3P, THF. (b) NaOH, MeOH, 3 h. (c) Phthalimide, DEAD, THF. (d) Hydrazine, toluene. (e)
i-Pr-SO2Cl, DBU, CH2Cl2. (f) Chiral chromatography using Chiralcel OD column.
Sch em e 3. Alternate Synthesis of trans-2-Phenyl-1-Amino-Cyclopentanesa
a
Reagents: (a) BH2Cl‚SMe2, CH2Cl2. (b) Me3Al, hexanes. (c) NH2OSO3H, THF. (d) i-Pr-SO2Cl, DBU, CH2Cl2. (e) Chiral chromatography
using Chiralcel OD column. (f) HOAc, H2SO4, I2, I2O5, 90 °C, 22 h.
2 and 3. The route in Scheme 2 follows the same general
approach as for the cis analogues but with the addition
of an inversion step for the secondary alcohol. The
inversion of the alcohol in 6h was accomplished with
benzoic acid by a Mitsunobu reaction. The ester 13 was
hydrolyzed to the cis alcohol 14 using sodium hydroxide.
The remainder of the synthesis is analogous to that
described above for the cis series.
An interesting alternate approach to the trans-2-
phenyl-1-amino-cyclopentanes is shown in Scheme 3.
Following the pioneering work of H. C. Brown, the
selective hydroboration of commercially available 1-phe-
nylcyclopentene 18 yielded exclusively the trans amine
19.13 The overall transformation for the synthesis of 19
is shown in Scheme 4 involving three air-sensitive steps.
Beginning with the addition of monochloroborane di-
methyl sulfide complex across the double bond, a
dimeric product has been proposed. Replacement of the
chlorine with a methyl group using trimethylaluminum
facilitates the replacement of boron for amine using
commercially available hydroxylamine-O-sulfonic acid
(HSA). The overall yield is moderate, and the procedure
is labor intensive, but because no intermediates must
be isolated, the sequence can be executed much more
rapidly than a stepwise one. Sulfonylation and selective
iodination were carried out as previously described.
Chiral chromatographic separation was achieved for all
three trans analogues prepared (17, 20, and 21). As-
signment of the absolute configuration was based on an
X-ray structure determination of (1S,2R)-2014 and made
possible by anomalous dispersion techniques using the
heavy atom sulfur. In all cases, the later-eluting chro-
matographic peak, including (1S,2R)-20 (see Experi-
mental Section), was the more active isomer; therefore,
the assignment of the R configuration at the 2-position
of the remaining enantiomeric pairs was made.
P h a r m a cology
All new compounds were evaluated for their ability
to potentiate responses mediated by 100 µM L-glutamate
in HEK293 cells expressing homomeric iGluR4 flip
receptors.15 The activities at various concentrations
were expressed as a percentage of responses evoked by
100 µM cyclothiazide, and EC50 values were then
calculated (Tables 1 and 2). This report will only show
results on the cloned human form of GluR4flip. Data are
shown for both racemates and individual enantiomeric
pairs in selected cases.
It was quickly recognized that this series of com-
pounds was more potent than our previously disclosed

2104 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 10
Sch em e 4. Hydroboration of 1-Phenylcyclopentene
Shepherd et al.
Ta ble 1. Summary of EC50 Values for AMPA Receptor
Potentiators: Cis Derivatives
Ta ble 2. Summary of EC50 Values for AMPA Receptor
Potentiators: Trans Derivatives
GluR4flip EC50
GluR4flip EC50
compd
(()-20
(1R,2S)-20
(1S,2R)-20
(()-17
(1R,2S)-17
(1S,2R)-17
(()-21
(1R,2S)-21
(1S,2R)-21
R
( SEM (nM)a,b
compda
R
( SEM (nM)b,c
4-H
4-H
4-H
4-Br
4-Br
4-Br
4-I
70% ( 11 (n ) 4)
6%
551 ( 13
130 ( 16
2%
82.1 ( 18.8
93.1 ( 15.4
12%
(()-3a
290 ( 100
520
0%
26%
48% ( 5 (n ) 6)
2%
(()-3b
(()-3c
(()-3d
(()-9a
4-H
4-H
4-H
4-Me
4-F
(S,S)-9a
(R,R)-9a
(()-9b
1740 ( 880
434 ( 109
57% ( 4 (n ) 4)
621 ( 56
1100 ( 550
281 ( 97
5%
118 ( 20
247 ( 26
147 ( 37
27%
68 ( 11
45.8 ( 2.8
34%
22.6 ( 2.5
190 ( 11
17%
4-I
4-I
32.8 ( 1.9
(()-9c
(()-9d
3-F
a
Human transfected HEK293 cells. Values represent mean
(()-9e
3,4-di-F
3,5-di-F
3,5-di-F
3,5-di-F
4-Cl
4-Br
4-Br
4-Br
EC50 values determined from at least three separate experi-
(()-9f
ments.15 Those compounds not achieving an EC50 are repre-
b
(S,S)-9f
(R,R)-9f
(()-9g
sented as a percent potentiation (n ) 1) at the highest dose tested
(3 µM).
(()-9h
(S,S)-9h
(R,R)-9h
(()-10
potentiator than the 4-F-substituted compound 9c. A
further enhancement in potency was seen with the 3,5-
difluorinated compound 9f (EC50 ) 281 nM). The most
potent racemic compound disclosed to date in the
2-arylpropylsulfonamide series is (()-3a , with an EC50
) 290 nM. In Table 1, we show four racemic compounds
that are more potent, including 4-chloro, 4-bromo, and
4-iodo. We observe a preference for large halogens in
the para position over unsubstituted, methyl, nitro, or
cyano substituents. Five pairs of cis enantiomers were
separated, and the data were reported in Table 1. The
vast majority of the potentiating activity of these
compounds was in a single enantiomer. The most potent
enantiomer was the 4-iodo (R,R)-10 with an EC50 ) 22.6
nM.
4-I
4-I
4-I
(S,S)-10
(R,R)-10
(()-11
(S,S)-12
(R,R)-12
4-NO2
4-CN
4-CN
403 ( 84
a
b
See Figure 2 for the structures of 3a -d . Human transfected
HEK293 cells. Values represent mean EC50 values determined
from at least three separate experiments.15 c Those compounds
not achieving an EC50 are represented as a percent potentiation
(n ) 1) at the highest dose tested (3 µM).
potentiators. For comparison purposes, we have in-
cluded in Table 1 results for four compounds from our
earlier structure-activity relationship studies. For in-
stance, the unsubstituted phenyl compound 3c in the
2-arylpropylsulfonamide series was inactive at the
highest concentration tested (0% at 3 µM), whereas
compound (()-9a was measurably more active (48% at
3 µM). Likewise, the 4-bromo derivative in the 2-aryl-
propylsulfonamide series (()-3d (26% at 3 µM) was
significantly less active than the cyclopentane derivative
(()-9h (EC50 ) 147 nM). The effect of various fluorine
substituents was particularly interesting. The 3-F-
substituted compound 9d was a more potent AMPA
In Table 2, a smaller set of trans compounds is
reported. It is interesting that the activity of the trans
isomers is essentially indistinguishable from the cis. For
instance, the 4-Br cis compound (()-9h and trans
compound (()-17 had EC50 values of 147 and 130 nM,
respectively. The results indicate that either the R or S
isomer can be tolerated at the 1-position of the cyclo-
pentane ring, but the R isomer is required at the
2-position. Until we know more about the receptor

Novel AMPA Receptor Potentiator
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 10 2105
(300 mL, 300.0 mmol) and copper iodide (3.8 g, 20.0 mmol).
To this reaction mixture was then added cyclopentene oxide
(25.23 g, 300.0 mmol) dissolved in THF (50.0 mL) dropwise
over a period of 60 min (reaction was quite exothermic,
reaching THF reflux by the end of addition). The reaction
mixture was then stirred to room temperature and quenched
with a 25% solution of ammonium chloride (200.0 mL). Ether
was added (80.0 mL), and the upper organic layer was
separated. The organic layer was washed with 25% ammonium
chloride solution, dried with anhydrous magnesium sulfate,
filtered, and concentrated to a filtrate to provide 6a (47.7 g,
binding site for these molecules, the significance of these
observations will be open to speculation.
Con clu sion
We have reported new syntheses of 2-phenylcyclo-
pentylamines with complete control of cis vs trans
stereochemistry. These compounds have allowed us to
examine the effect of constraining our previously pub-
lished 2-arylpropylsulfonamide series (Figure 2). Where
direct comparisons can be made, these cyclopentyl
analogues are more potent AMPA potentiators than our
previous series. The activities of the cis vs trans cyclo-
pentyl isomers are equipotent within the limited set
shown here. However, for the enantiomers, a clear
preference for the R configuration at position 2 is seen
(Tables 1 and 2). The most potent potentiators were
those with halogen substituents, for example, (R,R)-10
(EC50 ) 22.6 nM); the potent activity of the 3,5-difluoro
analogue (R,R)-9f (EC50 ) 118 nM) is also noteworthy.
These compounds are the most potent small molecule
AMPA potentiators that have been reported to date. The
expansion of this series will be reported in due course.
1
98%) as a brown oil. H NMR (CDCl3): δ 7.4-7.2 (aromatic,
5H), 4.16-4.13 (m, 1H), 2.88-2.80 (m, 1H), 2.2-2.0 (m, 2H),
1.8-1.6 (m, 4H). 13C NMR (CDCl3): δ 144.05, 129.25, 128.11,
127.10, 81.11, 55.13, 34.64, 32.57, 22.46.
(()-tr a n s-2-p-Tolyl-cyclop en ta n ol (6b). The title com-
pound was prepared in a manner analogous to the procedure
for 6a , starting with 10.0 mL of a 1 M ethereal solution of
p-tolylphenylmagnesium bromide (100 mmol). The same work-
up gave 1.7 g of a crude yellow oil. The title compound was
purified by radial chromatography eluting with 25:75 EtOAc:
1
hexanes to give 1.48 g of 6b (84%) as a colorless oil. H NMR
(CDCl3): δ 7.17-7.09 (aromatic, 4H), 4.13-4.07 (m, 1H), 2.85-
2.78 (m, 1H), 2.30 (s, 3H), 2.2-2.0 (m, 2H), 1.84-1.6 (m, 4H).
(()-tr a n s-2-(4-F lu or o-p h en yl)cyclop en ta n ol (6c). The
title compound was prepared from 4-fluorophenylmagnesium
bromide and cyclopentene oxide in a manner analogous to the
procedure described above for 6a in 26% yield. 1H NMR
(CDCl3): δ 7.31 (m, 2H), 7.10 (m, 2H), 4.21 (m, 1H), 2.96 (m,
1H), 2.30-2.18 (m, 2H), 2.00-1.75 (m, 4H).
(()-tr a n s-2-(3-F lu or o-p h en yl)cyclop en ta n ol (6d ). The
title compound was prepared from 3-fluorophenylmagnesium
bromide and cyclopentene oxide in a manner analogous to the
procedure described above for 6a in 73% yield. 1H NMR
(CDCl3): δ 7.22 (m, 1H), 7.00 (m, 1H), 6.90 (m, 2H), 4.12 (m,
1H), 2.86 (m, 1H), 2.20-2.00 (m, 2H), 1.90-1.60 (m, 4H).
(()-tr a n s-2-(3,4-Diflu or o-ph en yl)cyclopen tan ol (6e). The
title compound was prepared from 3,4-difluorophenylmagne-
sium bromide and cyclopentene oxide in a manner analogous
to the procedure described above for 6a in 70% yield. 1H NMR
(CDCl3): δ 7.20 (s, 1H), 7.00 (m, 2H), 4.04 (m, 1H), 2.79 (m,
1H), 2.15-2.00 (m, 2H), 1.83-1.50 (m, 4H).
(()-tr a n s-2-(3,5-Diflu or o-ph en yl)cyclopen tan ol (6f). The
title compound was prepared from 3,5-difluorophenylmagne-
sium bromide and cyclopentene oxide in a manner analogous
to the procedure described above for 6a in 30% yield. 1H NMR
(CDCl3): δ 6.72 (m, 2H), 6.60 (m, 1H), 4.05 (m, 1H), 2.81 (m,
1H), 2.15-2.00 (m, 2H), 1.82-1.56 (m, 4H). FDMS ) 198.
(()-tr a n s-2-(4-Ch lor op h en yl)cyclop en ta n ol (6g). The
title compound was prepared from p-chlorophenylmagnesium
bromide and cyclopentene oxide in a manner analogous to the
procedure described above for 6a in 31% yield. 1H NMR
(CDCl3): δ 7.27 (d, 2H, J ) 8.5 Hz), 7.17 (d, 2H, J ) 8.2 Hz),
4.12 (m, 1H), 3.70 (m, 1H), 2.05 (m, 2H), 1.90-1.63 (m, 4H).
13C NMR (CDCl3): δ 143.00, 132.25, 129.86, 121.00, 80.98,
54.40, 32.45, 22.38.
(()-tr a n s-2-(p-Br om o-p h en yl)cyclop en ta n ol (6h ). The
title compound was prepared from p-bromophenylmagnesium
bromide and cyclopentene oxide in a manner analogous to the
procedure described above for 6a in 26% yield. 1H NMR
(CDCl3): δ 7.31 (m, 2H), 7.10 (m, 2H), 4.21 (m, 1H), 2.96 (m,
1H), 2.30-2.18 (m, 2H), 2.00-1.75 (m, 4H).13C NMR (CDCl3):
δ 143.00, 132.25, 129.86, 121.00, 80.98, 54.40, 32.45, 22.38.
(()-cis-2-(2-P h en yl-cyclopen tyl)isoin dole-1,3-dion e (7a).
A 500 mL three-necked round-bottom flask equipped with a
mechanical stirrer, thermometer, reflux condenser, addition
funnel, and a nitrogen blanket is charged with triphenylphos-
phine (16.19 g, 61.73 mmol) and THF (200 mL). To the solution
at 0 °C was added dropwise a solution of diisopropyl azodi-
carboxylate (12.15 mL, 61.73 mmol) dissolved in THF (30 mL)
over a period of 10 min. A massive precipitate formed im-
mediately after addition. To the slurry was then added solid
phthalimide (9.08 g, 61.7 mmol), followed by a solution of 6a
(10.0 g, 61.7 mmol) dissolved in THF (30 mL) over a period of
Exp er im en ta l Section
Gen er a l. All reactions were performed under a positive N2
flow with commercially available solvents. All Grignard re-
agents were from commercial sources (Rieke Metals) with the
exception of p-Br-phenylmagnesium bromide, which can be
made from 1,4-dibromobenzene according to literature meth-
ods. 1-Phenylcyclopentene was purchased from Chemsampco,
Trenton, NJ . Proton nuclear magnetic resonance spectra (1H
NMR) were obtained on either a Varian Mercury-400 or
General Electric QE-300 spectrometer. Fast atom bombard-
ment high-resolution mass spectra (FAB-HRMS) were ob-
tained on a VG Analytical VGZAB-2SE mass spectrometer.
Field desorption mass spectra (FDMS) were obtained on a VG
Analytical VG70SE mass spectrometer. Combustion analyses
were performed on a Control Equipment Corporation 440
elemental analyzer and were within 0.4% of the calculated
values unless otherwise noted. Electrospray mass spectra were
obtained on a Micromass Platform LCZ mass spectrometer
using a Gilson 215 flatbed autosampler and HP1100 pump
system. Medium-pressure liquid chromatography (MPLC) was
performed using PrepPak silica gel cartridges on a Waters
Prep LC/System 500A. Flash chromatography was performed
over silica gel 60 (230-400 mesh ASTM). Preparative cen-
trifugal thin-layer chromatography (TLC) was performed on
a Harrison model 7924 chromatotron with Merck silica gel 60
PF254 containing CaSO4‚0.5H2O binder.
Assa y Meth od . Calcium measurements in iGluR4 trans-
fected HEK293 cells were performed as described in Miu et
al.15 Briefly, 96 well plates containing confluent monolayers
of HEK293 cells stably expressing human AMPA receptors
were prepared. Cells were incubated in buffer solution (10 mM
glucose, 138 mM sodium chloride, 1 mM magnesium chloride,
5 mM potassium chloride, 5 mM calcium chloride, and 10 mM
N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid, adjusted
to pH 7.1-7.3) containing 20 µM Fluo3-AM dye (obtained from
Molecular Probes Inc.) for 60 min. Cells were washed with
buffer solution, and fluorescence measurements were made
using a FLUOROSKAN II fluorometer (Labsystems) that
indicated changes in fluorescence upon influx of calcium into
cells upon stimulation by glutamate (100 µM) in the presence
of cyclothiazide (100 µM) or compound. Compound applications
preceded glutamate additions by 5 min, and fluorescent
measurements were made immediately prior to the addition
of glutamate and 3 min following glutamate addition.
(()-tr a n s-2-P h en yl-cyclop en ta n ol (6a ). A 1 L three-
necked round-bottom flask equipped with a mechanical stirrer,
addition funnel, and thermometer was charged with 1 M
tetrahydrofuran (THF) solution of phenylmagnesium bromide

2106 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 10
Shepherd et al.
20 min, maintaining temperature at 0-5 °C (the reaction
mixture went into solution by the end of alcoholic substrate
addition). The reaction was then stirred at 0 °C for 4 h and
brought to room temperature overnight for convenience. The
reaction was quenched with water (200 mL), and the organics
were extracted with chloroform (200 mL). The organic layer
was washed with water (100 mL) and dried with anhydrous
magnesium sulfate. Subsequent filtration and concentration
under reduced pressure afforded an oil that solidified on
equilibrating to room temperature. To the precipitate was then
added hexane (250 mL) with vigorous stirring. The triph-
enylphosphine oxide precipitate was filtered off, and the
filtrate was concentrated to an oil. Silica gel plug filtration of
the oil with 1:1 ethyl acetate:hexanes and subsequent concen-
tration of product fractions afforded 7a (12.5 g, 70%) as an
off-white precipitate. 1H NMR (CDCl3): δ 7.64-7.52 (aromatic,
4H), 7.15-6.9 (aromatic, 5H), 5.1-5.0 (m, 1H), 3.50-3.39 (m,
1H), 2.68-2.40 (m, 2H), 2.35-2.20 (m, 2H), 2.1-2.0 (m, 1H),
1.8-1.6 (m, 1H). 13C NMR (CDCl3): δ 168.86, 139.68, 131.67,
128.41, 128.01, 126.44, 122.89, 54.60, 50.34, 30.56, 28.89, 25.4.
Anal. (C19H17NO2) C, H, N.
(CDCl3): δ 168.43, 138.48, 133.67, 131.23, 130.79, 129.83,
122.78, 119.96, 54.00, 49.59, 30.58, 28.93, 25.17.
(()-cis-2-P h en yl-cyclop en tyla m in e (8a ). A 1000 mL
three-necked flask equipped with a mechanical stirrer, ther-
mometer, addition funnel, and a reflux condenser was charged
with 7a (27.3 g, 93.9 mmol) and toluene (400 mL). To this
solution was added anhydrous hydrazine (29.48 mL, 939.1
mmol) dropwise over a period of 15 min. The reaction was
stirred at room temperature for 60 min, and then, it was
heated at 90-95 °C for 6 h. The reaction was cooled to room
temperature, the precipitates were filtered, the cake was
washed with toluene (50.0 mL), and the filtrate was concen-
trated to provide 8a (15.1 g, 100%) as an oil. 1H NMR
(CDCl3): δ 7.35-7.19 (aromatic, 5H), 3.7-3.4 (m, 1H), 3.10-
3.05 (m, 1H), 2.1-2.0 (m, 2H), 2.0-1.9 (m, 2H), 1.69-1.63 (m,
1H), 1.6-1.5 (m, 1H), 0.8-0.6 (m, 1H). 13C NMR (CDCl3): δ
142.00, 129.20, 128.96, 126.86, 56.68, 51.75, 34.98, 27.96,
23.05.
(()-cis-2-p-Tolyl-cyclop en tyla m in e (8b). To 7b (582 mg,
1.91 mmol) was added ethanolamine (5 mL), and the solution
was heated to 80 °C and stirred for 30 min. ES-MS indicated
that the reaction was not complete, and the reaction was
heated to 90 °C for 30 min. The reaction was diluted with ethyl
ether and washed with dilute sodium hydroxide and brine, and
the organic layer was dried over sodium sulfate. The filtrate
was concentrated to provide 313 mg (94%) of 8b as a colorless
oil. The oil was used directly without further characterization.
Mass spectrum (ES-MS): M + 1 ) 176.
(()-cis-2-(2-p-Tolyl-cyclopen tyl)isoin dole-1,3-dion e (7b).
The title compound was prepared in a manner analogous to
the procedure for 7a from 6b (1.48 g, 8.4 mmol). The title
compound was purified by radial chromatography eluting with
ethyl acetate and then again eluting with methylene chloride
to give 0.69 g (27%) of 7b as an oil, which solidified under
1
vacuum. H NMR (CDCl3): δ 7.62-7.52 (m, 4H), 7.00 (d, 2H,
(()-cis-2-p-F lu or op h en yl-cyclop en tyla m in e (8c). The
title compound was prepared in a manner analogous to the
procedure for 8b from 7c to give 61% of 8c as a colorless oil.
Mass spectrum (ES-MS): M + 1 ) 180.
J ) 9 Hz), 6.82 (d, 2H, J ) 9 Hz), 5.01-4.95 (m, 1H), 3.41-
3.32 (m, 1H), 2.6-2.4 (m, 2H), 2.22-2.15 (m, 2H), 2.10 (s, 3H),
2.03-1.88 (m, 1H), 1.73-1.6 (m, 1H). Anal. (C20H19NO2‚
0.2H2O) C, H, N.
(()-cis-2-m -F lu or op h en yl-cyclop en tyla m in e (8d ). The
title compound was prepared in a manner analogous to the
procedure for 8b from 7d to give 92% of 8d as a colorless oil.
(()-cis-2-(2-p-F lu or op h en yl-cyclop en tyl)isoin d ole-1,3-
d ion e (7c). The title compound was prepared in a manner
analogous to the procedure for 7a from 6c to give 47% of 7c
as an oil. 1H NMR (CDCl3): δ 7.58 (m, 4H), 7.08 (m, 2H), 6.74
(m, 2H), 4.98 (m, 1H), 3.39 (m, 1H), 2.50 (m, 2H), 2.20 (m,
2H), 2.03 (m, 1H), 1.69 (m, 1H).
1
Mass spectrum (ES-MS): M + 1 ) 180. H NMR (CDCl3): δ
7.25 (m, 1H), 7.02-6.85 (m, 3H), 3.52 (m, 1H), 3.05 (m, 1H),
2.00 (m, 4H), 1.69 (m, 1H), 1.55 (m, 1H), 1.25 (brs, 2H).
(()-cis-2-(3,4-Diflu or op h en yl)cyclop en tyla m in e (8e).
The title compound was prepared in a manner analogous to
the procedure for 8b from 7e to give 80% of 8e as an oil. Mass
spectrum (ES-MS): M + 1 ) 198.
(()-cis-2-(2-m -F lu or op h en yl-cyclop en tyl)isoin d ole-1,3-
d ion e (7d ). The title compound was prepared in a manner
analogous to the procedure for 7a from 6d to give 43% of 7d
1
as a light yellow solid. H NMR (CDCl3): δ 7.58 (m, 4H), 6.99
(()-cis-2-(3,5-Diflu or oph en yl)cyclopen tylam in e (8f). The
title compound was prepared in a manner analogous to the
procedure for 8b from 7f to give 100% of 8f as an oil. Mass
spectrum (ES-MS): M + 1 ) 198.
(m, 1H), 6.88 (d, 1H, J ) 7 Hz), 6.82 (d, 1H, J ) 9 Hz), 6.63
(m, 1H), 5.00 (m, 1H), 3.40 (m, 1H), 2.48 (m, 2H), 2.20 (m,
2H), 2.05 (m, 1H), 1.68 (m, 1H). FDMS ) 309. Anal. (C19H16
FNO2‚0.3H2O) C, H, N.
-
(()-cis-2-(4-Ch lor op h en yl)cyclop en t yla m in e Oxa la t e
(8g). The title compound was prepared in a manner analogous
to the procedure for 8a from 7g to give 75% of 8g as an oil.
The free base was dissolved in ethyl acetate and treated with
oxalic acid (1.0 eq). The slurry was stirred for 60 min and
filtered, and the off-white precipitate was dried under house
(()-cis-2-(2-(3,4-Diflu or op h en yl)cyclop en tyl)isoin d ole-
1,3-d ion e (7e). The title compound was prepared in a manner
analogous to the procedure for 7a from 6e to give 94% of 7e
1
as a yellow solid. H NMR (CDCl3): δ 7.58 (m, 4H), 6.90 (m,
1H), 6.78 (m, 2H), 4.94 (m, 1H), 3.33 (m, 1H), 2.43 (m, 2H),
2.17 (m, 2H), 1.98 (m, 1H), 1.68 (m, 1H).
1
vacuum at 35 °C to provide 8g. H NMR (DMSO): δ 7.90 (m,
(()-cis-2-(2-(3,5-Diflu or op h en yl)cyclop en tyl)isoin d ole-
1,3-d ion e (7f). The title compound was prepared in a manner
analogous to the procedure for 7a from 6f to give 53% of 7f as
an oil. 1H NMR (CDCl3): δ 7.60 (m, 4H), 6.64 (m, 2H), 6.39
(m, 1H), 5.00 (m, 1H), 3.37 (m, 1H), 2.43 (m, 2H), 2.20 (m,
2H), 2.04 (m, 1H), 1.68 (m, 1H). FDMS ) 327. Anal. (C19H15F2-
NO2‚0.3H2O) C, H, N.
4H), 7.39 (d, 2H, J ) 8.2 Hz), 7.29 (d, 2H, J ) 8.5 Hz), 3.72
(m, 1H), 3.18 (m, 1H), 2.12 (m, 2H), 1.90 (m, 2H), 1.70 (m,
2H). Anal. (C11H14ClN‚1.1C2H2O4) C, H, N.
(()-cis-2-(4-Br om op h en yl)cyclop en tyla m in e (8h ). The
title compound was prepared in a manner analogous to the
procedure for 8b from 7h to give 27% of 8h as an oil. 1H NMR
(CDCl3): δ 7.4 (d, 2H), 7.10 (d, 2H), 3.5 (m, 1H), 3.00 (m, 1H),
2.0-1.8 (m, 4H), 1.79-1.60 (m, 1H), 1.60-1.50 (m, 1H), 0.86
(m, 2H). 13C NMR (CDCl3): δ 141.00, 132.00, 131.00, 128.00,
120.00, 36.20, 31.00, 28.00, 21.3. The free base was dissolved
in ethyl acetate and treated with oxalic acid (1.0 equiv). The
slurry was stirred for 60 min and filtered, and the off-white
precipitate was dried under house vacuum at 35 °C to provide
8g. Anal. (C11H14ClN‚1.1C2H2O4) C, H, N.
(()-cis-P r op a n e-2-su lfon ic Acid (2-P h en yl-cyclop en -
tyl)a m id e (9a ). A 250 mL three-necked round-bottom flask
equipped with a magnetic stirrer is charged with 8a (8.72 g,
54.2 mmol), methylene chloride (80 mL), triethylamine (14.8
mL, 106 mmol), and (dimethylamino)pyridine (0.33 g, 2.71
mmol) with stirring. The reaction solution was then cooled to
0 °C (ice/water bath), and then, isopropylsulfonyl chloride (5.96
(()-cis-2-(2-(4-Ch lor op h en yl)isoin d ole-1,3-d ion e (7g).
The title compound was prepared in a manner analogous to
the procedure for 7a from 6g to give 19% of 7g as an off-white
1
solid. H NMR (CDCl3): δ 7.58 (m, 4H), 7.08 (d, 2H, J ) 8.5
Hz), 7.04 (d, 2H, J ) 8.7 Hz), 5.05 (m, 1H), 3.19 (m, 1H), 2.50
(m, 2H), 2.24 (m, 2H), 2.07 (m, 1H), 1.75-1.61 (m, 1H). 13C
NMR (CDCl3): δ 169.31, 138.75, 134.46, 132.56, 132.03,
130.23, 128.63, 123.55, 54.70, 50.17, 31.21, 29.50, 25.79.
(()-cis-2-(2-(4-Br om op h en yl)cyclop en tyl)isoin d ole-1,3-
d ion e (7h ). The title compound was prepared in a manner
analogous to the procedure for 7a from 6h to give 27% of 7h
as an oil that solidified. 1H NMR (CDCl3): δ 7.67-7.57 (m,
4H), 7.2 (d, 2H), 7.00 (d, 2H), 3.32-2.35 (m, 2H), 2.27-2.16
(m, 2H), 2.09-2.00 (m, 1H), 1.77-1.03 (m, 1H). 13C NMR

Novel AMPA Receptor Potentiator
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 10 2107
pared in a manner analogous to the procedure for 9b from 8e
mL, 53.07 mmol) dissolved in methylene chloride (20 mL) was
added dropwise over a period of 30 min. The reaction was then
stirred at 0 °C for 60 min and brought to room temperature.
It was then stirred for 1.5 h and quenched with 1 N HCl (150
mL). The lower organic layer was separated, and the aqueous
layer was back-extracted with methylene chloride (50 mL). The
combined organic layer was then dried with anhydrous
magnesium sulfate, filtered, and concentrated to 9a (9.06 g,
64%) as a tan solid. 1H NMR (CDCl3): δ 7.31 (m, 2H), 7.21
(m, 3H), 3.95 (m, 1H), 3.71 (d, 1H, J ) 8 Hz), 3.29 (m, 1H),
2.82 (m, 1H), 2.15-1.70 (m, 6H), 1.18 (d, 3H, J ) 7 Hz), 0.98
(d, 3H, J ) 7 Hz). 13C NMR (CDCl3): δ 140.28, 128.90, 128.81,
127.23, 59.10, 53.78, 48.70, 33.76, 28.62, 21.79, 16.56. Anal.
(C14H21NO2S) C, H, N.
(S,S)-P r op a n e-2-su lfon ic Acid (2-P h en yl-cyclop en tyl)-
a m id e ((S,S)-9a ). The racemic cis compound 9a was separated
into individual enantiomers by chiral chromatography. The
semiprep column used was 1 cm × 25 cm Chiralcel OD eluting
with 10% IPA in heptane containing 0.2% dimethylethylamine
at a flow rate of 4.0 mL/min monitoring at UV of 250 nm. The
analytical column was 0.46 cm × 25 cm Chiralcel OD eluting
with 10% IPA in heptane containing 0.2% dimethylethylamine
at a flow rate of 1.0 mL/min monitoring at UV of 250 nm. The
early-eluting compound had a retention time of 7.03 min.
Enantiomeric excess was estimated to be 99% by high-
1
to give 42% of 9e as a white solid. H NMR (CDCl3): δ 7.20-
6.93 (m, 5H), 3.98 (m, 1H), 3.50 (m, 1H), 3.28 (m, 1H), 2.92
(m, 1H), 2.11 (m, 2H), 1.92 (m, 2H), 1.77 (m, 2H), 1.22 (d, 3H,
J ) 7 Hz), 1.12 (d, 3H, J ) 7 Hz). Mass spectrum (ES-MS): M
- 1 ) 302. Anal. (C14H19F2NO2S) C, H, N.
(()-cis-P r op a n e-2-su lfon ic Acid (2-(3,5-Diflu or op h e-
n yl)cyclop en tyl)a m id e (9f). The title compound was pre-
pared in a manner analogous to the procedure for 9b from 8f
1
to give 65% of 9f as a white solid. H NMR (CDCl3): δ 6.80-
6.66 (m, 5H), 3.98 (m, 1H), 3.51 (d, 1H, J ) 8 Hz), 3.28 (m,
1H), 2.93 (m, 1H), 2.10 (m, 2H), 1.91 (m, 2H), 1.78 (m, 2H),
1.23 (d, 3H, J ) 7 Hz), 1.12 (d, 3H, J ) 7 Hz). Mass spectrum
(ES-MS): M - 1 ) 302. Anal. (C14H19F2NO2S) C, H, N.
(S,S)-cis-P r op a n e-2-su lfon ic Acid (2-(3,5-Diflu or op h e-
n yl)cyclop en tyl)a m id e ((S,S)-9f). The racemic cis compound
(570 mg) 9f was separated into individual enantiomers by
chiral chromatography. The prep column used was 8 cm × 27
cm Chiralcel OD eluting with 90% heptane/10% IPA at a flow
rate of 330 mL/min monitoring at a UV wavelength of 255 nm.
The analytical column was 0.46 cm × 25 cm Chiralcel OD-H
eluting with 90% heptane/10% IPA at a flow rate of 1.0 mL/
min monitoring at a UV wavelength of 220 nm. The early-
eluting compound had a retention time of 6.9 min. The yield
was 263 mg. Enantiomeric excess was estimated to be 99% by
HPLC.
performance liquid chromatography (HPLC). Anal. (C14H21
NO2S) C, H, N.
-
(R,R)-cis-P r op a n e-2-su lfon ic Acid (2-(3,5-Diflu or op h e-
n yl)cyclop en tyl)a m id e ((R,R)-9f). The racemic cis com-
pound (570 mg) 9f was separated into individual enantiomers
by chiral chromatography. The prep column used was 8 cm ×
27 cm Chiralcel OD eluting with 90% heptane/10% IPA at a
flow rate of 330 mL/min monitoring at a UV wavelength of
255 nm. The analytical column was 0.46 cm × 25 cm Chiralcel
OD-H eluting with 90% heptane/10% IPA at a flow rate of 1.0
mL/min monitoring at a UV wavelength of 220 nm. The late-
eluting compound had a retention time of 11.1 min. The yield
was 265 mg. Enantiomeric excess was estimated to be 99% by
HPLC.
(R,R)-P r op a n e-2-su lfon ic Acid (2-P h en yl-cyclop en tyl)-
a m id e ((R,R)-9a ). The racemic cis compound 9a was sepa-
rated into individual enantiomers by chiral chromatography.
The semiprep column used was 1 cm × 25 cm Chiralcel OD
eluting with 10% IPA in heptane containing 0.2% dimethyl-
ethylamine at a flow rate of 4.0 mL/min monitoring at UV of
250 nm. The analytical column was 0.46 cm × 25 cm Chiralcel
OD eluting with 10% IPA in heptane containing 0.2% dim-
ethylethylamine at a flow of 1.0 mL/min monitoring at UV of
250 nm. The later-eluting compound had a retention time of
7.84 min. Enantiomeric excess was estimated to be 98% by
HPLC. Anal. (C14H21NO2S) C, H, N.
(()-cis-P r op a n e-2-su lfon ic Acid (2-p-Ch lor op h en yl-cy-
clop en tyl)a m id e (9g). The title compound was prepared in
a manner analogous to the procedure for 9b from 8g to give
(()-cis-P r op a n e-2-su lfon ic Acid (2-p-Tolyl-cyclop en -
tyl)a m id e (9b). A 100 mL round-bottom flask equipped with
a magnetic stirrer was charged with 8b (313 mg, 1.79 mmol)
and methylene chloride (5.0 mL), and the solution was cooled
to 0 °C. DBU (0.32 mL, 2.14 mmol) and isopropylsulfonyl
chloride (0.24 mL, 2.14 mmol) were added. The reaction was
then stirred at 0 °C for 60 min and brought to room temper-
ature with stirring overnight. The reaction was diluted with
methylene chloride and washed with aqueous ammonium
chloride and brine, and the organic layer was dried over
sodium sulfate. The title compound was purified by radial
chromatography eluting with methylene chloride to give 250
1
55% of 9g as a white solid. H NMR (CDCl3): δ 7.29 (d, 2H, J
) 8 Hz), 7.14 (d, 2H, J ) 8 Hz), 3.93 (m, 1H), 3.42 (d, 1H, J )
8 Hz), 3.28 (m, 1H), 2.90 (m, 1H), 2.08 (m, 2H), 1.90 (m, 2H),
1.75 (m, 2H), 1.20 (d, 3H, J ) 7 Hz), 1.09 (d, 3H, J ) 7 Hz).
Mass spectrum (ES-MS): M - 1 ) 300. Anal. (C14H20ClNO2S)
C, H, N.
(()-cis-P r op a n e-2-su lfon ic Acid (2-p-Br om op h en yl-cy-
clop en tyl)a m id e (9h ). The title compound was prepared in
a manner analogous to the procedure for 9b from 8h to give
1
45% of 9h as a white solid. H NMR (CDCl3): δ 7.42 (d, 2H, J
1
mg (50%) of 9b. H NMR (CDCl3): δ 7.13-7.05 (m, 4H), 3.90
) 8 Hz), 7.08 (d, 2H, J ) 8 Hz), 3.93 (m, 1H), 3.58 (d, 1H, J )
8 Hz), 3.25 (m, 1H), 2.88 (m, 1H), 2.05 (m, 2H), 1.90 (m, 2H),
1.72 (m, 2H), 1.19 (d, 3H, J ) 7 Hz), 1.08 (d, 3H, J ) 7 Hz).
(m, 1H), 3.50 (d, 1H, J ) 8 Hz), 3.30-3.25 (m, 1H), 2.95-2.83
(m, 1H), 2.30 (s, 3H), 2.1-1.7 (m, 6H), 1.20 (d, 3H, J ) 8 Hz),
1.02 (d, 3H, J ) 8 Hz). Anal. (C15H23NO2S) C, H, N.
Mass spectrum (ES-MS): M - 1 ) 344, 346. Anal. (C14H20
-
(()-cis-P r op a n e-2-su lfon ic Acid [2-(4-F lu or o-p h en yl)-
cyclop en tyl]a m id e (9c). The title compound was prepared
in a manner analogous to the procedure for 9b from 8c to give
BrNO2S) C, H, N. Exact mass calcd for (M + H) C14H21BrNO2S,
346.0476; found, 346.0486.
(S,S)-cis-P r op a n e-2-su lfon ic Acid (2-p-Br om op h en yl-
cyclop en tyl)a m id e ((S,S)-9h ). The racemic cis compound
(233 mg) 9h was separated into individual enantiomers by
chiral chromatography. The semiprep column used was 1 cm
× 25 cm Chiralcel AD eluting with a gradient of 5-50% IPA/
heptane over 30 min at a flow rate of 5.0 mL/min monitoring
at a UV wavelength of 260 nm. The analytical column was
0.46 cm × 25 cm Chiralcel AD eluting with a gradient of
5-50% IPA/heptane over 30 min at a flow rate of 1.0 mL/min
monitoring at a UV wavelength of 220 nm. The early-eluting
compound had a retention time of 9.1 min. The yield was 109
mg. Enantiomeric excess was estimated to be 97% by HPLC.
(R,R)-cis-P r op a n e-2-su lfon ic Acid (2-p-Br om op h en yl-
cyclop en tyl)a m id e ((R,R)-9h ). The racemic cis compound
(233 mg) 9h was separated into individual enantiomers by
chiral chromatography. The semiprep column used was 1 cm
× 25 cm Chiralcel AD eluting with a gradient of 5-50% IPA/
1
65% of 9c as a colorless oil. H NMR (CDCl3): δ 7.18 (m, 2H),
7.00 (m, 2H), 3.93 (m, 1H), 3.44 (m, 1H), 3.29 (m, 1H), 2.88
(m, 1H), 2.08 (m, 2H), 1.92 (m, 2H), 1.75 (m, 2H), 1.20 (d, 3H,
J ) 7 Hz), 1.07 (d, 3H, J ) 7 Hz). Mass spectrum (ES-MS): M
+ 1 ) 286. Anal. (C14H20FNO2S‚0.1H2O) C, H, N.
(()-cis-P r op a n e-2-su lfon ic Acid [2-(3-F lu or o-p h en yl)-
cyclop en tyl]a m id e (9d ). The title compound was prepared
in a manner analogous to the procedure for 9b from 8d to give
1
55% of 9d as a white solid. H NMR (CDCl3): δ 7.31 (m, 1H),
7.03 (d, 1H, J ) 8 Hz), 6.95 (m, 2H), 3.99 (m, 1H), 3.51 (d, 1H,
J ) 8 Hz), 3.31 (m, 1H), 2.91 (m, 1H), 2.12 (m, 2H), 1.96 (m,
2H), 1.80 (m, 2H), 1.22 (d, 3H, J ) 7 Hz), 1.09 (d, 3H, J ) 7
Hz). Mass spectrum (ES-MS): M + 1 ) 286. Anal. (C14H20
FNO2S) C, H, N.
-
(()-cis-P r op a n e-2-su lfon ic Acid [2-(3,4-Diflu or o-p h e-
n yl)cyclop en tyl]a m id e (9e). The title compound was pre-

2108 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 10
Shepherd et al.
heptane over 30 min at a flow rate of 5.0 mL/min monitoring
at a UV wavelength of 260 nm. The analytical column was
0.46 cm × 25 cm Chiralcel AD eluting with a gradient of
5-50% IPA/heptane over 30 min at a flow rate of 1.0 mL/min
monitoring at a UV wavelength of 220 nm. The late-eluting
compound had a retention time of 10.4 min. The yield was 109
mg. Enantiomeric excess was estimated to be 88% by HPLC.
Tris(dibenzylideneacetone)dipalladium(0) (8 mg), and zinc
cyanide (20 mg) were added, and the reaction was heated to
130 °C with stirring overnight. The reaction was diluted with
methylene chloride and washed with dilute sodium bicarbon-
ate. The organic layer was dried over sodium sulfate and
concentrated to a crude brown oil. The title compound was
purified by radial chromatography eluting with methylene
chloride to 2% MeOH/methylene chloride to give 21 mg (22%)
(()-cis-P r op a n e-2-su lfon ic Acid [2-(4-Iod o-p h en yl)cy-
clop en tyl]a m id e (10). Compound 9a (1.8 g, 6.7 mmol) was
dissolved in 20 mL of glacial acetic acid, and 0.7 mL (7.1 mmol)
of concentrated sulfuric acid was added followed by 2 mL of
water. To this solution were added periodic acid (0.35 g, 1.6
mmol) and iodine (0.77 g, 3.0 mmol). The resulting mixture
was heated to 60 °C for 3 h. The reaction was cooled to room
temperature, and 20 mL of a 10% aqueous solution of sodium
bisulfite was added. The product was extracted into ethyl
acetate and then washed with water and dilute sodium
bicarbonate and dried over magnesium sulfate. This was then
filtered and concentrated in vacuo to 2.2 g of crude yellow oil.
This oil was purified by reverse phase chromatography to give
1
of (S,S)-12 as a colorless oil. H NMR (CDCl3): δ 7.63 (d, 2H,
J ) 8 Hz), 7.38 (d, 2H, J ) 8 Hz), 4.05 (m, 1H), 3.58 (d, 1H, J
) 8 Hz), 3.37 (m, 1H), 2.90 (m, 1H), 2.15 (m, 2H), 1.95 (m,
2H), 1.78 (m, 2H), 1.20 (d, 3H, J ) 7 Hz), 1.11 (d, 3H, J ) 7
Hz). Mass spectrum (ES-MS): M - 1 ) 291. Exact mass calcd
for (M + Na) C15H20N2O2S, 315.1143; found, 315.1146.
(R,R)-cis-P r op a n e-2-su lfon ic Acid [2-(4-Cya n o-p h en yl)-
cyclop en tyl]a m id e ((R,R)-12). Compound (R,R)-10 (131 mg,
0.33 mmol) was dissolved in 4 mL of DMF and 0.5 mL of water
and degassed. Zinc cyanide (70 mg, 0.60 mmol), Tris(diben-
zylideneacetone)dipalladium(0) (15 mg, 0.02 mmol), and 1,1′-
Bis(diphenylphosphino)ferrocene (22 mg, 0.04 mmol) were
added, and the reaction was heated to 135 °C with stirring
overnight. The reaction was diluted with methylene chloride
and washed with dilute sodium bicarbonate. The organic layer
was dried over sodium sulfate and concentrated to a crude
brown oil. The title compound was purified by radial chroma-
tography eluting with 0.2% MeOH/methylene chloride to 2%
MeOH/methylene chloride to give 75 mg (77%) of (R,R)-12 as
1
341 mg (13%) of the title compound as a white solid. H NMR
(CDCl3): δ 7.65 (d, 2H, J ) 8 Hz), 6.98 (d, 2H, J ) 8 Hz), 3.97
(m, 1H), 3.45 (d, 1H, J ) 8 Hz), 3.28 (m, 1H), 2.92 (m, 1H),
2.10 (m, 2H), 1.93 (m, 2H), 1.77 (m, 2H), 1.22 (d, 3H, J ) 7
Hz), 1.11 (d, 3H, J ) 7 Hz). Mass spectrum (ES-MS): M - 1
) 392. Anal. (C14H20INO2S) C: calcd, 42.76; found, 43.23. H,
N.
(S,S)-cis-P r op a n e-2-su lfon ic Acid [2-(4-Iod o-p h en yl)-
cyclop en tyl]a m id e ((S,S)-10). The racemic cis compound 10
was separated into individual enantiomers by chiral chroma-
tography. The prep column used was 8 cm × 28 cm Chiralcel
AD eluting with 100% 3A alcohol at a flow rate of 300.0 mL/
min monitoring at a UV wavelength of 275 nm. The analytical
column was 0.46 cm × 25 cm Chiralcel AD eluting with 100%
3A alcohol at a flow rate of 1.0 mL/min monitoring at UV of
220 nm. The early-eluting compound had a retention time of
4.69 min. Enantiomeric excess was estimated to be 99% by
HPLC.
(R,R)-cis-P r op a n e-2-su lfon ic Acid [2-(4-Iod o-p h en yl)-
cyclop en tyl]a m id e ((R,R)-10). The racemic cis compound 10
was separated into individual enantiomers by chiral chroma-
tography. The prep column used was 8 cm × 28 cm Chiralcel
AD eluting with 100% 3A alcohol at a flow rate of 300.0 mL/
min monitoring at a UV wavelength of 275 nm. The analytical
column was 0.46 cm × 25 cm Chiralcel AD eluting with 100%
3A alcohol at a flow rate of 1.0 mL/min monitoring at UV of
220 nm. The late-eluting compound had a retention time of
5.91 min. Enantiomeric excess was estimated to be 99% by
HPLC.
1
a light yellow oil. H NMR (CDCl3): δ 7.63 (d, 2H, J ) 8 Hz),
7.38 (d, 2H, J ) 8 Hz), 4.05 (m, 1H), 3.58 (d, 1H, J ) 8 Hz),
3.37 (m, 1H), 2.90 (m, 1H), 2.15 (m, 2H), 1.95 (m, 2H), 1.78
(m, 2H), 1.20 (d, 3H, J ) 7 Hz), 1.11 (d, 3H, J ) 7 Hz). Mass
spectrum (ES-MS): M - 1 ) 291. Exact mass calcd for (M +
Na) C15H20N2O2S, 315.1143; found, 315.1138.
(()-cis-Ben zoic Acid 2-(4-Br om o-p h en yl)cyclop en tyl
Ester (13). Into a 250 mL three-necked flask fitted with a
stirrer and thermometer were placed 5.00 g (24.7 mmol) of
DEAD and 3.50 g (28.7 mmol) of benzoic acid in THF (50 mL).
A total of 5.78 g (24.0 mmol) of the alcohol (()-6h and 7.50 g
(28.6 mmol) of triphenylphosphine in THF (50 mL) were added
dropwise while stirring at 0 °C under a nitrogen atmosphere.
After 2 h at this temperature, the TLC showed that the
reaction was complete. The solution was allowed to warm to
room temperature and then concentrated under reduced
vacuum to yield 9.14 g of an oil. This material was purified
via silica gel chromatography employing the Water’s prep.
2000 and eluting with an isocratic solvent of hexane/methylene
chloride 1:1 to yield 3.74 g (45%) of 13 as a slowly crystallizing
1
oil. H NMR (CDCl3): δ 7.80 (d, 2H, J ) 8 Hz), 7.50 (m, 2H),
7.37 (m, 3H), 7.18 (d, 2H, J ) 8 Hz), 5.58 (m, 1H), 3.22 (m,
1H), 2.25-1.60 (m, 6H). Mass spectrum (ES-MS): M - 1 )
344. Anal. (C18H17BrO2) C, H.
(()-cis-P r op a n e-2-su lfon ic Acid [2-(4-Nitr o-p h en yl)-
cyclop en tyl]a m id e (11). Compound 9a (560 mg, 2.1 mmol)
was dissolved in 10 mL of trifluoroacetic acid, and 534 mg (6.3
mmol) of sodium nitrate was added. The reaction was stirred
for 5 h at room temperature. The reaction was diluted with
methylene chloride and washed with water and dilute sodium
bicarbonate. The organic layer was dried over sodium sulfate
and concentrated in vacuo to 620 mg of a crude yellow oil. This
oil was purified by radial chromatography eluting with 98:2
methylene chloride:ethyl acetate to give 120 mg (18%) of 11
as a white solid and also 400 mg (62%), which contained a
(()-cis-2-(4-Br om o-p h en yl)cyclop en ta n ol (14). To com-
pound 13 (3.70 g, 10.7 mmol) was added 5% NaOH/MeOH (75
mL, excess) in a 250 mL single-necked flask and stirred at
room temperature for 3 h. The reaction mixture was then
concentrated under reduced pressure to yield a semisolid. This
material was taken into ether and washed once with water,
dried over potassium carbonate, and concentrated under
reduced vacuum to yield 3.01 g of an oil. This material was
purified via silica gel chromatography employing the Water’s
prep. 2000 and eluting with an isocratic solvent of hexane/
methylene chloride 1:1 to yield 2.31 g (90%) of 14 as a clear
1
small amount of ortho nitrated product. H NMR (CDCl3): δ
8.12 (d, 2H, J ) 8 Hz), 7.38 (d, 2H, J ) 8 Hz), 4.01 (m, 2H),
3.35 (m, 1H), 2.82 (m, 1H), 2.13 (m, 2H), 1.96 (m, 2H), 1.77
(m, 2H), 1.13 (d, 3H, J ) 7 Hz), 1.03 (d, 3H, J ) 7 Hz). Anal.
(C14H20N2O4S) C, H, N. Mass spectrum (ES-MS): M - 1 )
311.
1
oil. H NMR (CDCl3): δ 7.42 (d, 2H, J ) 8 Hz), 7.18 (d, 2H, J
) 8 Hz), 4.28 (m, 1H), 2.98 (m, 1H), 2.10-1.67 (m, 6H), 1.18
(brs, 1H). Mass spectrum (ES-MS): M + 1 ) 241. Anal.
(C11H13BrO) C, H.
(S,S)-cis-P r op a n e-2-su lfon ic Acid [2-(4-Cya n o-p h en yl)-
cyclop en tyl]a m id e ((S,S)-12). Compound (S,S)-10 (128 mg,
0.33 mmol) was dissolved in 4 mL of dimethylformamide
(DMF) and degassed. Zinc cyanide (23 mg, 0.20 mmol) and
[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) com-
plex with dichloromethane 1:1 (21 mg, 0.03 mmol) were added,
and the reaction was heated to 125 °C with stirring overnight.
The reaction had not progressed far, and so, 0.5 mL of water,
(()-tr a n s-2-[2-(4-Br om o-p h en yl)cyclop en tyl]isoin d ole-
1,3-Dion e (15). Into a 500 mL 3 N flask fitted with a stirrer
and thermometer, 8.49 g (42.0 mmol) of DEAD in THF (25
mL) was added dropwise to 10.4 g (42.0 mmol) of triph-
enylphosphine in THF (175 mL) while stirring at 0 °C under
a nitrogen atmosphere. A white precipitate formed. At this
same temperature, 6.18 g (42.0 mmol) of phthalimide in THF
(25 mL) was added dropwise followed by 10.2 g (42.0 mmol) of

Novel AMPA Receptor Potentiator
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 10 2109
14 in THF (25 mL) added dropwise at 0 °C. The reaction was
then stirred at this temperature for 4 h and then allowed to
warm to room temperature. The mixture was poured into
water, and the desired material was extracted with ethyl
acetate. The organic layer was washed once with water, dried
over potassium carbonate, and concentrated under reduced
vacuum to yield 27.3 g of a semisolid. This material was
extracted with 3-500 mL portions of hexanes and filtered. The
filtrate was concentrated under reduced vacuum to yield 14.7
g of a yellow solid. This material was purified via silica gel
chromatography employing the Water’s prep. 2000 and eluting
with an isocratic solvent of hexane/ethyl acetate 9:1 to yield
25 cm Chiralcel OD-H eluting with 90% heptane/10% IPA at
a flow rate of 1.0 mL/min monitoring at a UV wavelength of
240 nm. The late-eluting compound had a retention time of
8.5 min. The yield was 4.9 g. Enantiomeric excess was
estimated to be 98% by HPLC.
Ch lor o-bis-(2-p h en yl-cyclop en tyl)bor a n e. This used a
modification of H. C. Brown et al.13 1-Phenylcyclopentene
(commercial 96%) (10.0 g, 69.4 mmol) was placed in an oven-
dried flask under nitrogen and diluted with 60 mL of dry
methylene chloride. The solution was cooled to 0 °C and
monochloroborane-methyl sulfide complex (3.6 mL, 35 mmoL)
was added dropwise via syringe. The solution was allowed to
warm to room temperature and stirred overnight. The solvent
was removed by aspirator vacuum under a nitrogen atmo-
sphere to provide a crude colorless oil. This oil was used
directly in the next step without further characterization.
1
5.20 g (34%) of 15 as a white solid. H NMR (CDCl3): δ 7.75
(m, 2H), 7.65 (m, 2H), 7.32 (d, 2H, J ) 8 Hz), 7.10 (d, 2H, J )
8 Hz), 4.70 (m, 1H), 3.90 (m, 1H), 2.40-1.70 (m, 6H). Mass
spectrum (ES-MS): M + 2 ) 372. Anal. (C19H16BrNO2)
C, H, N.
Meth yl-bis-(2-p h en yl-cyclop en tyl)bor a n e. Chloro-bis-(2-
phenyl-cyclopentyl)borane from above was diluted with 60 mL
of dry hexanes under nitrogen. The solution was cooled to 0
°C, and a 2 M solution of trimethylaluminum in hexanes (5.8
mL) was added dropwise causing the reaction to turn orange.
The reaction was allowed to warm to room temperature and
stirred for 1.5 h. During this time, a red-brown mass precipi-
tated out of solution, leaving a yellow supernatant. The
hexanes supernatant was transferred via cannula to a nitrogen-
flushed separatory funnel containing 50 mL of saturated
aqueous ammonium chloride. The organic phase became
colorless and was transferred via cannula to a dry flask
containing sodium sulfate for drying. The solution was then
transferred via cannula to a dry, nitrogen-flushed flask, and
the solvent was removed under aspirator vacuum and nitro-
gen. The clear oil was used directly without further charac-
terization.
(()-tr a n s-2-P h en yl-cyclop en tyla m in e (19). Methyl-bis-
(2-phenyl-cyclopentyl)borane (theoretical 34.7 mmoL) from
above was diluted with 40 mL of dry THF. A 8.3 g (73 mmol)
amount of HSA was slurried in a separate dry flask in 60 mL
of THF, and small portions were transferred via cannula to
control the exothermic reaction. The cloudy white solution was
stirred at room temperature for 24 h. The reaction mixture
was filtered, and the THF was removed in vacuo. The residue
was treated with 30 mL of concentrated HCl, 15 mL of
methanol, 20 mL of water, and 60 mL of diethyl ether and
stirred at room temperature for 30 min. The aqueous phase
was collected, and the organic phase was washed with water
and combined with the aqueous phase. The aqueous phase was
cooled to 0 °C, layered with diethyl ether, and made strongly
basic with sodium hydroxide pellets. The organic phase was
separated, and the aqueous phase was extracted with diethyl
ether (2×) and ethyl acetate (1×). The organic phases were
combined and dried over sodium sulfate. The filtrate was
concentrated to 5.96 (53%) of 19 as a yellow oil. 1H NMR
(CDCl3): δ 7.31-7.15 (m, 5H), 3.19 (m, 1H), 2.57 (m, 1H), 2.08
(m, 2H), 1.80 (m, 6H), 1.49 (m, 1H). Mass spectrum (ES-MS):
M + 1 ) 162.
(()-tr a n s-P r op a n e-2-su lfon ic Acid (2-P h en yl-cyclop en -
tyl)a m id e (20). Compound 19 (5.95 g, 37.0 mmol) was
dissolved in dry methylene chloride and cooled to 0 °C under
a nitrogen atmosphere. A 6.1 mL (41 mmol) amount of DBU
was added followed by dropwise addition of 2-propanesulfonyl
chloride (4.6 mL, 41 mmol). The reaction was allowed to warm
to room temperature and stirred overnight. The reaction was
judged incomplete by TLC, and an additional 20% of DBU and
2-propanesulfonyl chloride were added. Stirring at room
temperature was continued for 3 days. The reaction was
diluted with methylene chloride and washed (1 × 100 mL) with
1 N HCl. The organic phase was dried over sodium sulfate,
filtered, and concentrated in vacuo to 9.3 g. The product was
purified on silica by Chromatotron eluting with 99:1 methylene
chloride:ethyl acetate to yield 5.7 g (31%) of 20 as a white solid.
1H NMR (CDCl3): δ 7.29 (m, 2H), 7.22 (m, 3H), 3.99 (d, 1H, J
) 8 Hz), 3.67 (m, 1H), 2.72 (m, 1H), 2.60 (m, 1H), 2.35 (m,
1H), 2.12 (m, 1H), 1.80 (m, 3H), 1.61 (m, 1H), 1.12 (d, 3H, J )
7 Hz), 0.90 (d, 3H, J ) 7 Hz). Anal. (C14H21NO2S) C: calcd,
(()-tr a n s-2-(4-Br om o-p h en yl)cyclop en t yla m in e (16).
Into a 250 mL 3 N flask fitted with a stirrer, thermometer,
and condenser was placed 5.10 g (14.0 mmol) of 15 in toluene
(60 mL). To this mixture was added dropwise 4.50 g (140
mmol) of hydrazine in toluene (20 mL) while it was stirred at
room temperature under a nitrogen atmosphere. The reaction
was then heated at 95 °C for 6 h. The reaction was cooled to
room temperature and stirred overnight. The precipitate that
had formed was filtered, and the filtrate was dried over
potassium carbonate and then concentrated under reduced
vacuum to yield 3.41 g of an oil. This material was purified
via silica gel chromatography employing the Water’s prep.
2000 and eluting with an isocratic solvent of methylene
chloride/methanol 9:1 to yield 16 (3.30 g, 98%) as a light oil.
1H NMR (CDCl3): δ 7.42 (d, 2H, J ) 8 Hz), 7.10 (d, 2H, J ) 8
Hz), 3.15 (m, 1H), 2.52 (m, 1H), 2.11 (m, 2H), 1.77 (m, 6H),
1.44 (m, 1H). Mass spectrum (ES-MS): M - 1 ) 239. Anal.
(C11H14NBr‚0.4H2O) C, N, H calcd, 6.03; found, 5.50.
(()-tr a n s-P r op a n e-2-su lfon ic Acid [2-(4-Br om o-p h e-
n yl)cyclop en tyl]a m id e (17). Into a 250 mL three-necked
flask fitted with a stirrer and thermometer, 3.73 g (15.4 mmol)
of 2-propanesulfonyl chloride was added dropwise to 3.30 g
(14.0 mmol) of 16 and 4.23 g (16.8 mmol) DBU in methylene
chloride (90 mL) while it was stirred at 0 °C under a nitrogen
atmosphere. The reaction was then allowed to warm to room
temperature and stirred overnight. The mixture was diluted
with methylene chloride (100 mL), washed once with water,
dried over potassium carbonate, and concentrated under
reduced vacuum to yield 5.63 g of a solid. This material was
purified via silica gel chromatography employing the Water’s
prep. 2000 and eluting with an isocratic solvent of hexane/
ethyl acetate 7:3 to yield 3.54 g (73%) of 17 as a white solid.
1H NMR (CDCl3): δ 7.42 (d, 2H, J ) 8 Hz), 7.14 (d, 2H, J ) 8
Hz), 4.15 (d, 1H, J ) 8 Hz), 3.62 (m, 1H), 2.70 (m, 2H), 2.32
(m, 1H), 2.13 (m, 1H), 1.80 (m, 2H), 1.62 (m, 2H), 1.18 (d, 3H,
J ) 7 Hz), 1.01 (d, 3H, J ) 7 Hz). Mass spectrum (ES-MS): M
+ ) 346. mp 128°-130 °C. Anal. (C14H20BrNO2S) C, H, N.
(1R,2S)-tr a n s-P r op a n e-2-su lfon ic Acid [2-(4-Br om o-
p h en yl)cyclop en tyl]a m id e ((1R,2S)-17). The racemic trans
compound 17 (11.2 g) was separated into individual enanti-
omers by chiral chromatography. The prep column used was
8 cm × 29 cm Chiralcel OD eluting with 90% heptane/10%
IPA at a flow rate of 330 mL/min monitoring at a UV
wavelength of 250 nm. The analytical column was 0.46 cm ×
25 cm Chiralcel OD-H eluting with 90% heptane/10% IPA at
a flow rate of 1.0 mL/min monitoring at a UV wavelength of
240 nm. The early-eluting compound had a retention time of
6.7 min. The yield was 4.6 g. Enantiomeric excess was
estimated to be 99% by HPLC. Anal. (C14H20BrNO2S) C, H,
N.
(1S,2R)-tr a n s-P r op a n e-2-su lfon ic Acid [2-(4-Br om o-
p h en yl)cyclop en tyl]a m id e ((1S,2R)-17). The racemic trans
compound 17 (11.2 g) was separated into individual enanti-
omers by chiral chromatography. The prep column used was
8 cm × 29 cm Chiralcel OD eluting with 90% heptane/10%
IPA at a flow rate of 330 mL/min monitoring at a UV
wavelength of 250 nm. The analytical column was 0.46 cm ×

2110 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 10
62.89; found, 62.38. H, N. Exact mass calcd for (M + NH4)
Shepherd et al.
retention time of 12.28 min. The yield was 172 mg. Enantio-
meric excess was estimated to be 98% by HPLC. Mass
spectrum (ES-MS): M - 1 ) 392.
C
14H25N2O2S, 285.1637; found, 285.1629.
(1S,2R)-tr a n s-P r op a n e-2-su lfon ic Acid (2-P h en yl-cy-
clop en tyl)a m id e ((1S,2R)-20). The racemic trans compound
20 was separated into individual enantiomers by chiral
chromatography. The semiprep column used was 1 cm × 25
cm Chiralcel OD eluting with 10% IPA in heptane containing
0.2% dimethylethylamine at a flow rate of 4.0 mL/min moni-
toring at UV of 250 nm. The analytical column was 0.46 cm ×
25 cm Chiralcel OD eluting with 10% IPA in heptane contain-
ing 0.2% dimethylethylamine at a flow rate of 1.0 mL/min
monitoring at UV of 250 nm. The later-eluting compound had
Ack n ow led gm en t. We thank J oseph H. Kennedy,
Scott Sharp, and Kurt Hostettler for chiral purifications.
We also thank Dr. Andy Fray for helpful discussions
and the Lilly Research Labs analytical department.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data for (1S,2R)-20. This material is available free of
charge at http://pubs.acs.org.
a
retention time of 8.97 min. Enantiomeric excess was
estimated to be 99% by HPLC. Mass spectrum (ES-MS): M -
1 ) 266. Anal. (C14H21NO2S) C, H, N.
Refer en ces
(1R,2S)-tr a n s-P r op a n e-2-su lfon ic Acid (2-P h en yl-cy-
clop en tyl)a m id e ((1R,2S)-20). The racemic trans compound
20 was separated into individual enantiomers by chiral
chromatography. The semiprep column used was 1 cm × 25
cm Chiralcel OD eluting with 10% IPA in heptane containing
0.2% dimethylethylamine at a flow rate of 4.0 mL/min moni-
toring at UV of 250 nm. The analytical column was 0.46 cm ×
25 cm Chiralcel OD eluting with 10% IPA in heptane contain-
ing 0.2% dimethylethylamine at a flow rate of 1.0 mL/min
monitoring at UV of 250 nm. The early-eluting compound had
(1) Lees, G. J . Pharmacology of AMPA/Kainate Receptor Ligands
and Their Therapeutic Potential in Neurological and Psychiatric
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(2) Bleakman, D.; Lodge, D. Neuropharmacology of AMPA and
kainate receptors. Neuropharmacology 1998, 37, 1187-1204.
(3) Sommer, B.; Keinanen, K.; Verdoorn, T. A.; Wisden, W.; Bur-
nashev, N.; Herb, A.; Kohler, M.; Takagi, T.; Sakmann, B.;
Seeburg, P. H. Flip and Flop: a cell-specific functional switch
in glutamate-operated channels of the CNS. Science 1990, 249,
1580-1585.
(4) Partin, K. M.; Fleck, M. W.; Mayer, M. L. AMPA receptor flip/
flop mutants affecting deactivation, desensitization, and modu-
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science 1996, 16, 6634-6647.
(5) Bertolino, M.; Baraldi, M.; Parenti, M.; Braghiroli, D.; DiBella,
M.; Vicini, S.; Costa, E. Modulation of AMPA/kainate receptors
by analogues of diazoxide and cyclothiazide in thin slices of rat
hippocampus. Recept. Channels 1993, 1, 267-278.
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G. A.; Lynch, G. A. A drug that facilitates glutamatergic
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(7) Zarrinmayeh, H.; Bleakman, D.; Gates, M. R.; Yu, H.; Zimmer-
man, D. M.; Ornstein, P. L.; McKennon, T.; Arnold, M. B.;
Wheeler, W. J .; Skolnick, P. [3H]N-2-(4-(N-Benzamido)phenyl)-
propyl-2-propanesulfonamide: A Novel AMPA Receptor Poten-
tiator and Radioligand. J . Med. Chem. 2001, 44, 302-304.
(8) Ornstein, P. L.; Zimmerman, D. M.; Arnold, M. B.; Bleisch, T.
J .; Cantrell, B.; Simon, R.; Zarrinmayeh, H.; Baker, S. R.; Gates,
M.; Tizzano, J . P.; Mandelzys, A.; J arvie, K.; Ho, K.; Deverill,
M.; Kamboj, R.; Bleakman, D. Biarylpropylsulfonamides as
Novel, Potent Potentiators of 2-Amino-3-(5-methyl-3-hydroxy-
isoxazol-4-yl)propanoic Acid (AMPA) Receptors. J . Med. Chem.
2000, 43, 4354-4358.
a
retention time of 6.82 min. Enantiomeric excess was
estimated to be 99% by HPLC. Anal. (C14H21NO2S) C: calcd,
62.89; found, 62.46. H, N. Mass spectrum (ES-MS): M - 1 )
266.
(()-tr a n s-P r op a n e-2-su lfon ic Acid [2-(4-Iod o-p h en yl)-
cyclop en tyl]a m id e (21). Racemic 20 (0.52 g, 1.5 mmol) was
dissolved in 30 mL of glacial acetic acid. To this solution was
added concentrated sulfuric acid (0.16 mL, 1.6 mmol) at room
temperature followed by iodine (0.19 g, 0.74 mmol) and
diiodine pentoxide (0.20 g, 0.59 mmol). The reaction was then
protected from light and heated to 90 °C and stirred for 22 h.
To the dark brown reaction mixture was slowly added 10%
aqueous sodium bisulfite. The mixture was cooled to 0 °C for
1 h, and a light brown solid was collected by filtration. The
solid was dissolved in warm diethyl ether and washed with
water (2×) and then saturated sodium bicarbonate (1×). The
organic layer was separated, dried (Na2SO4), filtered, and
concentrated in vacuo to give 435 mg (75%) of 21. 1H NMR
(CDCl3): δ 7.60 (d, 2H, J ) 8 Hz), 6.98 (d, 2H, J ) 8 Hz), 4.05
(d, 1H, J ) 8 Hz), 3.62 (m, 1H), 2.70 (m, 2H), 2.30 (m, 1H),
2.10 (m, 1H), 1.80 (m, 2H), 1.62 (m, 2H), 1.15 (d, 3H, J ) 7
Hz), 0.98 (d, 3H, J ) 7 Hz). Anal. (C14H20INO2S) C, H, N. Mass
spectrum (ES-MS): M - 1 ) 392. Exact mass calcd for (M +
NH4) C14H24IN2O2S, 411.0603; found, 411.0611.
(1R,2S)-tr a n s-P r op a n e-2-su lfon ic Acid [2-(4-Iod o-p h e-
n yl)cyclop en tyl]a m id e ((1R,2S)-21). The racemic trans
compound 21 (400 mg) was separated into individual enanti-
omers by chiral chromatography. The semiprep column used
was 1 cm × 25 cm Chiralcel OD eluting with 90% heptane/
10% IPA containing 0.2% dimethylethylamine at a flow rate
of 4.0 mL/min monitoring at a UV wavelength of 260 nm. The
analytical column was 0.46 cm × 25 cm Chiralcel OD eluting
with 90% heptane/10% IPA containing 0.2% dimethylethy-
lamine at a flow rate of 1.0 mL/min monitoring at a UV
wavelength of 220 nm. The early-eluting compound had a
retention time of 9.32 min. The yield was 200 mg. Enantio-
meric excess was estimated to be 99% by HPLC. Mass
spectrum (ES-MS): M - 1 ) 392.
(9) Wiehl, W.; Frahm, A. W. Asymmetric reductive amination of
cycloalkanones. 5. Synthesis and absolute configuration of
2-substituted cyclopentanamines. Chem. Ber. 1986, 119, 2668-
2677.
(10) Seemayer, R.; Schneider, M. P. Enzymatic hydrolysis and
esterification. Routes to optically pure cyclopentanols. Recl. Trav.
Chim. Pays-Bas 1991, 110, 171-174.
(11) Brazdil, L. C.; Cutler, C. J . Selective Production of Diiodobenzene
and Iodobenzene from Benzene. J . Org. Chem. 1996, 61, 9621-
9622.
(12) Maligres, P. E.; Waters, M. S.; Fleitz, F.; Askin, D. A Highly
Catalytic Robust Palladium-Catalyzed Cyanation of Aryl Bro-
mides. Tetrahedron Lett. 1999, 40, 8193-8195.
(13) Brown, H. C.; Malhotra, S. V.; Ramachandran, P. V. Organobo-
ranes for Synthesis 17. Generality of Hydroboration-Amination
for the Conversion of Terpenes into Enantiomerically Pure
Terpenylamines. Their Utility for Gas Chromatographic Analysis
of Chiral Caroboxylic Acids. Tetrahedron: Asymmetry 1996, 7,
3527-3534.
(14) Stephenson, G. Lilly Research Laboratories; see details in the
Supporting Information.
(15) Miu, P.; J arvie, K. R.; Radhakrishnan, V.; Gates, M. R.; Ogden,
A.; Ornstein, P. L.; Zarrinmayeh, H.; Ho, K.; Peters, D.; Grabell,
J .; Gupta, A.; Zimmerman, D. M.; Bleakman, D. Novel AMPA
receptor potentiators LY392098 and LY404187: effects on
recombinant human AMPA receptors in vitro. Neuropharma-
cology 2001, 40, 976-983. Calcium influx measurements: 96
well plates containing confluent monolayers of HEK293 cells
stably expressing human AMPA receptors were prepared. Cells
were incubated in buffer solution (10 mM glucose, 138 mM
sodium chloride, 1 mM magnesium chloride, 5 mM potassium
chloride, 5 mM calcium chloride, and 10 mM N-2-hydroxyeth-
ylpiperazine-N-2-ethanesulfonic acid, adjusted to pH 7.1-7.3)
containing 20 µM Fluo3-AM dye (obtained from Molecular
Probes Inc., Eugene, OR) for 60 min. Cells were washed with
(1S,2R)-tr a n s-P r op a n e-2-su lfon ic Acid [2-(4-Iod o-p h e-
n yl)cyclop en tyl]a m id e ((1S,2R)-21). The racemic trans
compound 21 (400 mg) was separated into individual enanti-
omers by chiral chromatography. The semiprep column used
was 1 cm × 25 cm Chiralcel OD eluting with 90% heptane/
10% IPA containing 0.2% dimethylethylamine at a flow rate
of 4.0 mL/min monitoring at a UV wavelength of 260 nm. The
analytical column was 0.46 cm × 25 cm Chiralcel OD eluting
with 90% heptane/10% IPA containing 0.2% dimethylethy-
lamine at a flow rate of 1.0 mL/min monitoring at a UV
wavelength of 220 nm. The late-eluting compound had a

Novel AMPA Receptor Potentiator
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 10 2111
buffer solution, and fluorescence measurements were made using
a FLUOROSKAN II fluorometer (Labsystems, Needham Heights,
MA) that indicated changes in fluorescence upon influx of
calcium into cells upon stimulation by glutamate (100 µM) in
the presence of cyclothiazide (100 µM) or compound. Compound
applications preceded glutamate additions by 5 min, and fluo-
rescent measurements were made immediately prior to addition
of glutamate and 3 min following glutamate addition.
J M0105474