Synthesis and evaluation of N-substituted nipecotic acid derivatives with an unsymmetrical bis-aromatic residue attached to a vinyl ether spacer as potential GABA uptake inhibitors

Article abstract of DOI:10.1016/j.bmc.2013.02.056

γ-Amino butyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system (CNS). A malfunction of the GABAergic neurotransmission is connected to several neuronal disorders like epilepsy, Alzheimer's disease, neuropathic

Full text of DOI:10.1016/j.bmc.2013.02.056

Bioorganic & Medicinal Chemistry 21 (2013) 3363–3378
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and evaluation of N-substituted nipecotic acid derivatives
with an unsymmetrical bis-aromatic residue attached to a vinyl ether
spacer as potential GABA uptake inhibitors
⇑
Gabriele Quandt, Georg Höfner, Klaus T. Wanner
Ludwig-Maximilians-University Munich, Department Pharmacy, Center for Drug Research, Butenandtstr. 7, 81377 Munich, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 2 April 2013
c
-Amino butyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous
system (CNS). A malfunction of the GABAergic neurotransmission is connected to several neuronal disor-
ders like epilepsy, Alzheimer’s disease, neuropathic pain, and depression. One possibility to enhance
GABA levels in the synaptic cleft is to inhibit mGAT1, one of the four known plasma membrane bound
GABA transporters, which is considered the most important GABA transporter subtype, being in charge
of the removal of GABA from the synaptic cleft after a neuronal impulse. Lipophilic derivatives of nipe-
cotic acid like Tiagabine (GabitrilÒ), an approved drug used in add-on therapy of epilepsy, are known
to inhibit uptake of mGAT1 with high subtype selectivity and affinity. We synthesized new N-substituted
nipecotic acid derivatives with a vinyl ether spacer and an unsymmetrical bis-aromatic residue, which
carries fluorine substituents at various positions of the aromatic ring-system. The new compounds were
characterized with respect to their potency and subtype selectivity as mGAT1 inhibitors.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
GABA uptake
Chelation-controlled Heck reaction
Fries rearrangment
Aromatic fluoro-compounds
SAR study
1. Introduction
also be useful in the sense of a species independent nomenclature.
However, as the biological test system employed in our group is
The regulation of neuronal signal transduction in the mamma-
lian central nervous system (CNS) is mainly controlled by the inter-
play of the major excitatory neurotransmitter glutamate and the
based on GABA transporters originating from murine cells, we will
refer to these transporters in this paper as mGAT1–4.
mGAT1 is the most abundant GABA transporter in the brain ex-
pressed throughout most regions of this organ whereas the expres-
sion of mGAT4 is lower and limited mostly to the retina, olfactory
bulb, brainstem, and diencephalon.8,9 For mGAT2 and mGAT3 main
expressions were shown to refer to kidney and liver. In contrast to
former assumptions these transporters do not play a significant
role in GABA inactivation in the brain, displaying significant con-
centrations on the leptomeninges and some cerebral blood vessels
only.6,10–12 Being expressed closely along GABAergic pathways and
in particular on presynaptic neurons, mGAT1 is considered as the
most important transporter for neuronal GABA uptake and as an
interesting drug target.13
Nipecotic acid (2), a cyclic amino acid which can be considered
as a conformationally restricted b-alanine analog, shows high
in vitro activity as inhibitor of [3H]GABA uptake.14 However, it can-
not cross the blood brain barrier (BBB) due to its polar, zwitterionic
structure.15 Through N-alkylation, usually with a bis-aromatic
moiety, provided with a C4 carbon unit as spacer, the lipophilicity
of 2 is raised, allowing penetration of the BBB. Nipecotic acid deriv-
atives with such a lipophilic side chain also show a significantly in-
creased potency compared to their parent amino acid 2, which is
usually also combined with an improved subtype selectivity to-
wards mGAT1. SKF 89976A (3) and Tiagabine (GabitrilÒ, 4), a drug
major inhibitory neurotransmitter
c-amino butyric acid (GABA,
1). A malfunction of either one of these neurotransmitter systems
can lead to severe neurological disorders. Low GABA levels are con-
nected with epilepsy,1 Alzheimer’s disease,2 neuropathic pain,3 and
depression.4 Enhancing the amount of GABA in the synaptic cleft is
believed to be beneficial in the treatment of these diseases. One ap-
proach for GABA upregulation is the inhibition of particular sub-
types of the plasma membrane bound GABA transporters (GATs),
which are in charge of the removal of GABA from the synaptic cleft
after a neuronal impulse. Four subtypes of GABA transporters have
been identified. They are described by different nomenclatures,
depending on the origin of the cells they were cloned from. When
cloned from rat or human cells, they are denoted as GAT-1, BGT-1,
GAT-2, and GAT-3,5,6 with a prefix indicating the individual species
(e.g., rGAT-1 or hGAT-1) while the respective murine transporters
are named mGAT1–4.7 The Human Genome Organization (HUGO)
suggested a nomenclature, which describes the transporters as
GAT1 (slc6a1), BGT1 (slc6a12), GAT2 (slc6a13), and GAT3
(slc6a11)8 which though—strictly speaking—refers to human might
⇑
Corresponding author. Tel.: +49 89 2180 77249; fax: +49 89 2180 77247.
E-mail address: klaus.wanner@cup.uni-muenchen.de (K.T. Wanner).
0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2013.02.056

3364
G. Quandt et al. / Bioorg. Med. Chem. 21 (2013) 3363–3378
used in add-on therapy of epilepsy, are two examples for a success-
ful realization of this concept (see Table 1).16 Selectivity towards
mGAT2–4 can also be achieved depending on the structure of the
side chain, but as these compounds are not subject of this paper,
they will not be described here (see Table 1).17
affinity and subtype selectivity of the target compounds 7 and 8 to-
wards mGAT1 and potentially contribute to a better understanding
of the protein–ligand interactions relevant for this system.
2. Results and discussion
2.1. Chemistry
In a series of SAR studies, Andersen et al. developed several very
potent new compounds inhibiting GABA uptake. Many of them are
nipecotic acid derivatives with a lipophilic N-substituent consist-
ing of an alkyl spacer and a bis-aromatic residue attached to the
end of that spacer.19–24 Several different structural elements were
introduced to those compounds in order to improve selectivity and
affinity. Among those structural elements, two were particularly
interesting and seemed to be beneficial for uptake inhibition: a vi-
nyl ether or an ether unit embedded in the spacer combined with
either a symmetrical or an unsymmetrical substitution pattern in
the bis-aromatic residue as exemplified by 5 and 6 (Fig. 1).21,24
The oxygen atom of the vinyl ether in the spacer may be able to
participate in hydrogen bonding and also increase the flexibility
of the chain.17 Thus, for example, compound 5 (Fig. 1, pIC50
(GAT1) = 7.85), shows an enhanced potency towards mGAT1 com-
pared to compound 4 (pIC50 (GAT1) = 6.88), though it differs from
the latter only by an additional oxygen atom in the spacer chain
and an extended chain length resulting therefrom.21 Another po-
tent inhibitor is compound 6 (Fig. 1, pIC50 (GAT1) = 7.00), which
exhibits the same spacer as compound 5, however, in saturated
form in this case. Also in contrast to inhibitors like 3, 4, and 5, in
which two identical aromatic rings are attached symmetrically to
the terminal position of the spacer, compound 6 displays a 2-ben-
zylphenyl moiety representing the terminal bis-aromatic residue
exerting an unsymmetrical substitution pattern.24
We decided to create nipecotic acid derivatives similar to 6, but
with a vinyl ether unit being part of the spacer as in 5, in which the
two aromatic rings of the asymmetrically attached bis-aromatic
residue (Fig. 1, 7 and 8, ring 1 and ring 2) are connected either
via a methanone (Fig. 1, 7, Y = O) or a methylene bridge (Fig. 1, 8,
Y = H2). Since fluorine, as the most electronegative atom, has a
strong influence on several physicochemical properties of a com-
pound and can have an indirect or a direct influence on protein–li-
gand interactions, our aim was also to insert fluorine substituents
at various positions of the aromatic rings of the aforementioned
target compounds. Introduction of fluorine substituents can for
example result in a pKA shift, depending on their position relative
to the acidic or basic group in the molecule. Also, fluorine can
polarize neighboring oxygen atoms, which leads to stronger hydro-
gen bonds and a decrease in lipophilicity. The electronegative fluo-
rine atom can also directly participate in hydrogen bonding or
interact with carbonyl groups of proteins.25,26 Thus, the presence
of fluorine could be expected to significantly effect the binding
Retrosynthetic analysis revealed a C–C-bond formation be-
tween the b-position of the vinyl ether moiety of the nipecotic acid
scaffold 9 or its ester 20 and the respective aryl halides or triflates
to represent an efficient and at the same time flexible approach to
the target compounds (Fig. 2).
Being known to proceed with high b-regioselectivity, a chela-
tion-controlled Heck reaction was expected to be well suited for
this purpose. This method for controlling regioselectivity has been
established by Hallberg and co-workers who performed chelation-
controlled Heck arylations of (2-vinyloxyethyl)dimethylamine
with various aryl triflates and aryl iodides.27–30 The b-selectivities
Hallberg et al. observed for these reactions are a result of the
geometry of the reactive intermediate that forms upon coordina-
tion of palladium to the vinylic double bond and to the amino
nitrogen of the substrate (see 21, Scheme 5). As the same structural
motif, a vinylether moiety and an amino group linked by an ethyl-
ene bridge, is present in 9 (or its ester 20) as well, it was expected
that this concept might be successful here, too.
2.1.1. Synthesis of the triflates
At first, a convenient method for the synthesis of the various
fluorine substituted triflates as educts for the intended Heck reac-
tion had to be established. The Fries rearrangement was considered
to give a flexible access to the phenols and thus to the correspond-
ing triflates required for the Heck reaction. The starting material
for the Fries rearrangement was prepared by esterification of fluor-
ophenols 12a–c with fluorobenzoyl chlorides 13a–c (Scheme 1,
conditions a).31 The reactions provided 14a–i with high yields
(83–99%, Table 2).
The obtained esters 14a–f were subsequently transformed to
the corresponding ketones 15a–f (Table 2) by Fries rearrangement
with AlCl3 as catalyst. When heated to 200 °C for short reaction
times (20 min to 1 h; Scheme 1, conditions b),32,33 the 2-substi-
tuted rearrangement products 15a–f were formed almost exclu-
sively and with high yields (78–90%) (Scheme 2, Table 3).
To our regret, the rearrangement of the 2-fluorophenyl benzo-
ates 14g–i (R0 = F) did not lead to the desired 2-substituted prod-
ucts 15g–i, but almost exclusively to the 4-substituted
compounds 17a–c (Scheme 3). This is, however, in line with the
O
O
O
OH
OH
OH
O
N
O
N
R2
R1
1
X
6
N
OH
OH
5
2
ring 1
R2
O
Y
Y
N
α
4
O
Y
N
3
+
O
R2
R1
6
R3
R4
1
ortho
meta
β
5
O
S
2
O
4
α
R1
3
ring 2
R3
R3
R4
R5
ortho
meta
β
para
S
R4
9
R5
R5
para
R1-5 = F or H
R1-5 = F or H
X = halide or triflate
R1-5 = F or H
5
6
7 (Y = O) or 8 (Y = H2)
7 (Y = O) or 8 (Y = H2)
10 (Y = O) or 11 (Y = H2)
Figure 1. Template structures 5 and 6 and target structures 7 and 8.
Figure 2. Retrosynthesis of 7 and 8.

G. Quandt et al. / Bioorg. Med. Chem. 21 (2013) 3363–3378
3365
Table 1
Table 3
pIC50 values of compounds 1–4
Methanones 15a–f
O
O
Compound
Ring 1
Ring 2
R4
Yield (%)
OH
R1
R2
R3
R5
OH
O
N
N
15a
15b
15c
15d
15e
15f
F
F
F
H
H
H
H
H
H
F
F
F
H
H
F
H
H
F
H
F
H
H
F
F
80
83
90
78
78
86
O
H2N
OH
H
H
F
H
H
OH
N
S
H
S
H
1
2
3
4
Compound
GABA-uptake-inhibition (pIC50 SEM)a
OH
mGAT1
mGAT2
mGAT3
mGAT4
F
O
R3
OH
O
R3
R4
R5
1
2
3
4
5.14 0.09 4.56 0.06
5.07 0.02 3.28 0.05
6.16 0.05 3.43 0.07
4.94 0.09
4.71 0.04
3.71 0.04
5.18 0.13
4.79 0.05
3.56 0.06
AlCl3, 200 °C
R4
R5
O
F
F
+
O
6.88 0.12 100
lM/
100
l
M/
100
lM/
R3
R5
50.3%b
64.1%b
73.4%b
R4
> 80%
R3 R4 R5
Shown values were measured with a standard assay run in our group.18
a
traces
Remaining [3H]GABA uptake in presence of 100
lM test compound.
b
R3 R4 R5
14g-i
17a
H
H
F
H
F
H
H
15g
H
H
F
H
F
H
H
17b H
17c F
15h H
15i
O
R3
F
OH
R4
R5
O
R3
O
R'
R2
Scheme 3. Fries rearrangement of 14g–i.
R4
R5
a
R'
R2
+
Cl
R1
quent coupling reactions, whereas the 4-substituted products
displaying the wrong substitution pattern were of no value for
the present study.
R1
R' R1 R2
R3 R4 R5
14a-i
12a H
12b H
12c F
F
H
F
13a H
13b H
13c F
H
F
F
In the next step, for the preparation of the 2-benzyl substituted
phenols 16a–f (Table 4), ketones 15a–f were deoxygenated by
treatment with sodium borohydride and trifluoroacetic acid
(Scheme 4, conditions c).35 The deoxygenation proceeded with
moderate to high yields (54–94%). Reaction of 15a–f and 16a–f
with triflic anhydride in the presence of 2,4,6-collidine led to the
desired triflates 10a–f and 11a–f, respectively (Scheme 4), which
were then introduced to the Heck reaction in the following step.
In both cases, triflate syntheses had proceeded with high yields
(88–99%, Table 5).
H
H
H
H
H
H
Scheme 1. Reagents and conditions: (a) NEt3/DMAP, CH2Cl2, reflux, 1 h, 83–99%.
Table 2
Esters 14a–i
Compound
Ring 1
R2
Ring 2
R4
Yield (%)
R1
R’
R3
R5
14a
14b
14c
14d
14e
14f
14g
14h
14i
F
F
F
H
H
H
H
H
H
H
H
H
F
F
F
H
H
H
H
H
H
H
H
H
F
H
H
F
H
H
F
H
H
F
H
F
H
H
F
H
H
F
F
99
93
96
88
83
90
94
92
94
H
H
F
H
H
F
2.1.2. Synthesis of the carboxylic acids
The nipecotic acid derivative with a vinyl ether side chain 20 re-
quired for the Heck reaction was conveniently obtained by N-alkyl-
ation of the commercially available ethyl nipecotate (18) with 2-
(vinyloxy)ethyl tosylate (19),30 the yield amounting to 80%
(Scheme 5).
The chelation-controlled Heck-reaction with ethyl 1-(2-(vinyl-
oxy)ethyl)nipecotate (20) and the fluorine substituted (2-ben-
zoyl)phenyl triflates 10a–f or (2-benzyl)phenyl triflates 11a–f,
respectively, was performed at 80 °C using Pd(OAc)2 as a precata-
lyst, NEt3 as a base, and DMF as solvent. Depending on the reactiv-
ity of the triflate, we either worked under ligand-free conditions or
F
F
H
H
H
O
R3
OH
R1
O
R3
R4
R5
R4
R5
O
b
R'
R2
R2
R1
Table 4
Phenols 16a–f
14a-f
15a-f
Compound
Ring 1
Ring 2
R4
Yield (%)
Scheme 2. Reagents and conditions: (b) AlCl3, 200 °C, 20 min to 1 h, 78–90%.
R1
R2
R3
R5
16a
16b
16c
16d
16e
16f
F
F
F
H
H
H
H
H
H
F
F
F
H
H
F
H
H
F
H
F
H
H
F
F
96
80
94
81
53
86
general observation according to which Fries rearrangements lead
preferentially to the thermodynamically more stable 4-substituted
product as soon as one of the 2-positions is occupied.34 Being
formed in trace amounts only, the available quantities of 2-substi-
tuted phenols 15g–i were too low to be employed in the subse-
H
H
F
H
H
H

3366
G. Quandt et al. / Bioorg. Med. Chem. 21 (2013) 3363–3378
the triflate to the Pd(0) complex and is therefore added when less
reactive, electron-rich aryl triflates are used.36
OH
R1
O
R3
OTf
R1
O
R3
R4
R5
R4
R5
d
We added PPh3 as a ligand when coupling the electron-richer
and less reactive (2-benzyl)phenyl triflates 11a–f to 20 (Scheme 6,
conditions g, method B, 23a–f). This resulted in increased yields
and shorter reaction times. When working under so called li-
gand-free conditions, only traces of the products 23a–f were ob-
tained. The (2-benzoyl)phenyl triflates 10a–f appeared to be
more reactive probably due to the presence of the electron-with-
drawing carbonyl function, and led to higher yields (Table 6). As
these could not be enhanced through addition of phosphine ligand,
the reactions were performed under ligand-free conditions
(Scheme 6, conditions f, method A). In contrast to the Heck reac-
tions with 11a–f (Table 6, 23a–f), all triflates 10a–f could be suc-
cessfully coupled with the scaffold 20 with reasonable to good
yields (Table 6, 22a–f). Compared to the yields for the syntheses
of 22a–f, those for 23a–f were generally lower at similar reaction
times, even though PPh3 was added. Enhancing the reaction times
or the temperature also did not lead to significantly higher yields.
The lowest yields were obtained, when ring 1 carried a fluorine
substituent in 4-position (11a–c, R1 = F, Table 5 ? 23a–c, Table 6).
Considering the higher energy of the 4-fluoro-substituted benzene
anion as compared to its 3-substituted analog,37 this is likely due
to the fact that the electron density diminishing effect on the 1-po-
sition carrying the triflate moiety resulting from the fluorine sub-
stituent is less pronounced when the latter is located in the 4-
instead in the 3-position. Besides, the position of the fluorine sub-
stituent in ring 2 has been found to have an influence on the reac-
tivity of the (2-benzyl)phenyl triflate. Thus, in case of the reaction
of 20 with 11b, carrying a fluorine substituent in meta-position of
ring 2, only trace amounts of the desired coupling product 23b
could be detected. As even modification of the reaction conditions,
higher temperatures or longer reaction times did not improve
yields, the product could not be isolated.
R2
R2
15a-f
10a-f
c
OH
R3
OTf
R3
R4
R5
R4
R5
d
R2
R2
R1
R1
16a-f
11a-f
Scheme 4. Reagents and conditions: (c) NaBH4/TFA, CH2Cl2, 0 °C to rt, 53–94%, (d)
Tf2O, 2,4,6-collidine, CH2Cl2, 0 °C to rt, 88–99%.
I
O
I
c
10g
11g
Scheme 5. Reagents and conditions: (c) NaBH4/TFA, CH2Cl2, 0 °C to rt, 99%.
Table 5
Triflates 10a–f and 11a–f
Compound
Y
Ring 1
Ring 2
R4
Yield (%)
R1
R2
R3
R5
10a
10b
10c
10d
10e
10f
11a
11b
11c
11d
11e
11f
O
O
O
O
O
O
H2
H2
H2
H2
H2
H2
F
F
F
H
H
H
F
F
F
H
H
H
F
F
F
H
H
H
F
F
F
H
H
F
H
H
F
H
H
F
H
H
F
H
F
H
H
F
H
H
F
H
H
F
F
95
88
88
94
94
90
99
91
88
96
87
89
H
H
F
H
H
F
H
H
F
H
H
When synthesizing the parent compounds 22g and 23g, being
devoid of fluorine substituents in the bis-aromatic moiety, only
trace amounts of the product were obtained through the reaction
with the unsubstituted triflates. This indicates that the presence
of fluorine substituents has a significant influence on the electron
density of the triflate and on their reactivity. Since the correspond-
ing, unsubstituted iodides were easily available, we decided to test
whether they would allow to perform the desired Heck reaction. Of
the two starting materials required, 2-iodobenzophenone (10g) is
commercially available and 2-benzyl-1-iodo benzene (11g) was
found to be easily accessible from the former in an excellent yield
H
H
H
H
in the presence of PPh3 as a ligand. The phosphine ligand is known
to accelerate the reduction of the Pd(II) precatalyst to the active
Pd(0) species, but it can also promote the oxidative addition of
O
O
O
O
OH
O
O
O
N
e
f , g or h
N
R
R
i
N
O
OTs
N
L
+
O
Pd
N
H
Ar
O
Y
O
Y
O
L = PPh3, OAc, Cl
R5
R4
R5
R4
18
19
20
21
R1
R2
R1
R2
R3
R3
R1-5 = F or H
22a-g (Y = O)
23a-g (Y = H2)
R1-5 = F or H
7a-g (Y = O)
8a, 8c-g (Y = H2)
Scheme 6. Reagents and conditions: (e) 7 h, rt, 80%, (f) Method A: 10a–f, Pd(OAc)2/NEt3, DMF, 80 °C, 20 h, 39–78%; (g) Method B: 11a–f, Pd(OAc)2/PPh3/NEt3, DMF, 80 °C,
20 h, 19–55%; (h) Method C: 10g or 11g, Pd(OAc)2/LiCl/NaOAc/K2CO3, DMF/H2O (v/v = 10:1), 80 °C, 20 h, 65–83%; (i) (1) 12 M NaOH or 2 M LiOH, EtOH, 0 °C to rt, 0.5–6.5 h; (2)
phosphate buffer (50 mM, pH 6), CH2Cl2, 0 °C to rt, 78–99%.

G. Quandt et al. / Bioorg. Med. Chem. 21 (2013) 3363–3378
3367
Table 6
Conditions and yields for the coupling products 22a–g and 23a–g
Compd Ar
Method (E)/(Z) Isolated
Yield ((E)/(Z))b (%) Compd Ar
Method (E)/(Z) Isolated
Yieldb ((E)/(Z)) (%)
yielda (%)
yielda (%)
O
O
O
22a
A
A
A
60:40 40
71:29 56
57:43 38
20/6
8/5
23a
23b
23c
B
B
B
74:26 19
8/4
F
F
F
F
F
F
F
22b
22c
n.d.
Traces
n.d.
19/6
F
F
F
F
7/7
71:29 30
F
O
O
O
22d
22e
A
A
60:40 40
60:40 37
20/8
23d
23e
B
B
71:29 46
71:29 42
28/6
23/2
F
F
F
F
F
F
F
F
F
17/12
F
F
22f
A
C
71:29 78
29:71 83
51/17
24/11
23f
B
C
75:25 55
40:60 65
32/13
21/22
F
O
22g
23g
a
Isolated yield of the (E)/(Z)-mixture.
Isolated yield of the isomers after FCC.
b
of 99% by deoxygenation with NaBH4/TFA in analogy to the synthe-
ses of 16a–f (Scheme 5, conditions c).35
of the tested compounds. When the potency was low and the com-
pounds were not able to reduce [3H]GABA uptake to a value of be-
When coupling of the iodides 10g and 11g with the vinylether
20 was attempted by following the above described methods A
and B, requiring anhydrous conditions, exclusively the undesired
low 50% at 100
l
M (pIC50 <4.00), only the percentage is given,
representing the remaining specific [3H]GABA uptake at 100
lM.
In the following, the inhibitory potencies at as well as selectiv-
ities for mGAT1 as a function of the position of the fluorine substit-
uents in ring 1 (Fig. 2, 4-position or 5-position) and ring 2 (Fig. 2,
ortho, meta, or para) of the bis-aromatic residue attached to the vi-
nyl ether spacer of the N-alkylated nipecotic acid derivatives 7a–g,
8a and 8c–g are described. As compared to the potencies at
mGAT1, all compounds tested were only weak to very weak inhib-
itors at mGAT2-4, the pIC50 values for these transporters ranging in
most cases far below 5. Therefore, besides being mentioned with
respect to the subtype selectivity in favor of mGAT1, these data
did not appear to be sufficiently important to be included in the
following discussion.
a-coupling products were formed.
But the reactions could be successfully performed under aque-
ous conditions comprising Pd(OAc)2, K2CO3, LiCl, and NaOAc in
DMF/H2O (Scheme 6, conditions h, method C), conditions that
had also been introduced by Hallberg and co-workers for b-selec-
tive coupling of aryl iodides with a vinyl ether scaffold.30
All coupling products were obtained as (E)/(Z)-mixtures in ra-
tios ranging from 57:43 to 29:71 ((E)/(Z)), depending on the reac-
tion conditions and reactants. But all isomers could be separated
by flash-column chromatography (Et2O + 1% NEt3) and were ob-
tained in reasonable amounts in pure form.
In the last step of the synthesis, the ethyl esters 22a–g and 23a–
g were hydrolyzed with an excess of 12 M NaOH or 2 M LiOH,
respectively, at 0 °C to room temperature. After complete conver-
sion (after 30 min to 8.5 h) and workup (phosphate buffer pH 6,
extraction with dichloromethane), the target compounds, the car-
boxylic acids 7a–g, 8a, and 8c–g were obtained in yields of 78–99%.
Regarding compounds 7a–f (Table 7, entries 3–14), in which
ring 1 and ring 2 are connected with a methanone bridge (Fig. 1,
7, Y = O), the unsubstituted compounds (E)- and (Z)-7g (Table 7,
entries 1 and 2) serve as references. (E)-7g (pIC50 4.60, Table 7, en-
try 1) and (Z)-7g (pIC50 5.15, Table 7, entry 2) both displayed mod-
erate to poor inhibitiory potency and an acceptable selectivity
towards mGAT1, the (Z)-isomer being slightly more potent at and
selective for mGAT1. With regard to the (E)-isomers bearing a fluo-
rine substituent at the 4-position of ring 1 (R1 = F, Table 7, entry 3,
5 and 7), the inhibitory potency and subtype selectivity is signifi-
cantly enhanced compared to (E)-7g when ring 2 is substituted
with fluorine at the para-position (see (E)-7a, pIC50 5.73, Table 7,
entry 3). When ring 2 carries a fluorine substituent in the meta-po-
sition (see (E)-7b, pIC50 64.00, Table 7, entry 5), the inhibitory po-
2.2. Biological evaluation
Uptake inhibition and subtype selectivity towards all four mur-
ine transporter subtypes mGAT1–4 were determined for all syn-
thesized carboxylic acids using a standardized [3H]GABA uptake
assay based on HEK cell lines, each stably expressing one of the
four GATs.18 pIC50 values were determined as a measure of potency

3368
G. Quandt et al. / Bioorg. Med. Chem. 21 (2013) 3363–3378
Table 7
GABA-uptake inhibition of 7a–g, 8a, and 8c–g
O
OH
N
O
R
7a-g, 8a or 8c-g
Entry
Compound
R
GABA-uptake inhibition (pIC50 SEM)
mGAT2 mGAT3
mGAT1
4.60b
mGAT4
M/67.5 %a
100
100
l
M/55.9 %a
100
100
l
M/79.8 %a
O
O
1
(E)-7g
100
100
l
2
(Z)-7g
5.15 0.07
l
M/72.3 %a
l
M/59.8 %a
l
M/72.4 %a
O
M/71.4 %a
100
l
M/68.8 %a
100 l
M/72.7 %a
F
3
(E)-7a
5.73 0.14
100
l
F
O
M/73.0 %a
100
l
M/59.8 %a
100 l
M/44.8 %a
F
4
(Z)-7a
6.47 0.08
100
l
F
M/67.5 %a
100
100
l
M/62.9 %a
100
100
l
M/51.5 %a
100
100
l
M/67.6 %a
O
5
6
7
(E)-7b
(Z)-7b
(E)-7c
100
l
F
F
F
F
M/56.9 %a
l
M/52.7 %a
l
M/45.2 %a
O
6.10 0.04
l
4.97 0.17
3.85b
3.43b
4.17 0.02
O
F
F

G. Quandt et al. / Bioorg. Med. Chem. 21 (2013) 3363–3378
3369
Table 7 (continued)
Entry
Compound
R
GABA-uptake inhibition (pIC50 SEM)
mGAT1
mGAT2
mGAT3
mGAT4
8
(Z)-7c
6.12 0.13
4.18b
100
l
M/43.5 %a
100
l
M/45.1 %a
O
F
F
F
O
9
(E)-7d
4.68 0.02
100
l
M/61.2 %a
100
l
M/97.7 %a
100
l
M/94.3 %a
F
F
O
10
(Z)-7d
5.12 0.08
100
l
M/70.2 %a
100
l
M/79.5 %a
100
l
Mv82.2 %a
F
F
F
4.22b
3.47b
3.70b
O
11
(E)-7e
4.53 0.13
F
Mv96.1 %a
M/68.6 %a
M/74.5 %a
M/60.2 %a
M/68.6 %a
100
100
100
l
Mv83.6 %a
M/57.6 %a
M/83.2 %a
100
100
100
l
M/52.1 %a
M/52.1 %a
M/86.3 %a
O
12
13
14
15
16
(Z)-7e
(E)-7f
(Z)-7f
(E)-8g
(Z)-8g
5.58 0.13
5.09 0.04
5.52 0.08
5.38 0.10
6.40 0.09
100
100
100
100
100
l
F
F
F
O
l
l
l
l
l
l
l
l
F
O
F
4.43b
4.50b
100
l
M/56.0 %a
100
l
M/66.0 %a
(continued on next page)

3370
G. Quandt et al. / Bioorg. Med. Chem. 21 (2013) 3363–3378
Table 7 (continued)
Entry
Compound
R
GABA-uptake inhibition (pIC50 SEM)
mGAT2 mGAT3
mGAT1
mGAT4
M/71.6 %a
100
l
M/49.3 %a
100 l
M/63.7 %a
F
17
(E)-8a
5.34 0.05
100
l
F
M/64.8 %a
4.46b
4.59b
F
18
(Z)-8a
5.93 0.05
100
l
F
19
20
(E)-8c
(Z)-8c
5.57 0.12
100
100
l
M/57.5 %a
100
l
M/80.1 %a
4.23b
F
F
F
6.20 0.11
l
M/80.1 %a
4.71b
4.22b
F
F
21
(E)-8d
5.05 0.12
100
l
M/58.1 %a
100
l
M/62.0 %a
4.03b
F
F
F
22
(Z)-8d
5.96 0.04
4.04b
4.30b
100 l
M/50.3 %a
F
F
23
(E)-8e
5.17 0.07
100
l
M/70.5 %a
100
l
M/59.3 %a
100
l
M/51.8 %a
F
F
24
(Z)-8e
6.52 0.09
100
l
M/60.3 %a
4.70b
100
l
M/56.0 %a

G. Quandt et al. / Bioorg. Med. Chem. 21 (2013) 3363–3378
3371
Table 7 (continued)
Entry
Compound
R
GABA-uptake inhibition (pIC50 SEM)
mGAT2 mGAT3
mGAT1
mGAT4
F
25
(E)-8f
4.99 0.08
100
100
l
M/47.8 %a
100
l
M/83.7 %a
100 l
M/53.8 %a
F
F
F
26
(Z)-8f
6.52 0.14
l
M/71.1 %a
4.55b
4.31b
Remaining [3H]GABA uptake in presence of 100
At low pIC50 values, only one measurement was performed in triplicate. Therefore, no SEM could be calculated.
l
M test compound.
a
b
tency and subtype-selectivity was lower than that of (Z)-7g. A fluo-
rine substituent in the ortho-position (see (E)-7c, pIC50 4.97, Ta-
ble 7, entry 7), on the other hand did not enhance the selectivity
or the potency significantly. The (Z)-isomers with a fluorine substi-
tuent in the 4-position of ring 1 (R1 = F, Table 7, entry 4, 6, and 8)
all showed significantly higher inhibitory potencies and also en-
hanced subtype selectivities towards mGAT1 than (Z)-7g (Table 7,
entry 2). The most potent compound of this series and also of all
the tested methanone bridged compounds was found to be (Z)-
7a (pIC50 6.47, Table 7, entry 4), which carries a fluorine substitu-
ent in the para-position of ring 2. It also exhibits an excellent selec-
tivity towards mGAT1. When ring 2 carries the fluorine substituent
in the meta-position (see (Z)-7b, pIC50 6.10, Table 7, entry 6), or in
the ortho-position (see (Z)-7c, pIC50 6.12, Table 7, entry 8), lower,
insignificantly different pIC50 values for mGAT1 together with sim-
ilar mGAT1-selectivities are observed. Regarding the (E)-isomers
(E)-7d–(E)-7f with a fluorine substituent at the 5-position of ring
1 (R2 = F, Table 7 entries 9, 11 and 13), (E)-7d (pIC50 4.68, Table 7,
entry 9), which bears a fluorine substituent at the para-position of
ring 2 and (E)-7e (pIC50 4.53, Table 7, entry 11), with a fluorine sub-
stituent at the meta-position of ring 2, both do not show significant
changes in inhibitory potency or mGAT1-selectivity compared to
the unsubstituted (E)-7g. (E)-7f (pIC50 5.09, Table 7, entry 13), in
which the fluorine substituent in ring 2 is attached at the ortho-po-
sition, is slightly more potent and also slightly more mGAT1-selec-
tive than (E)-7g. When comparing the (Z)-isomers (Z)-7d–(Z)-7f
with a fluorine substituent in 5-position of ring 1 (R2 = F, Table 7,
entries 10, 12 and 14), it is found that the potency of (Z)-7d
(pIC50 5.12, Table 7, entry 10), in which the fluorine substituent
is attached to the para-position of ring 2, does not significantly dif-
fer from that of the unsubstituted compound (Z)-7g and that the
subtype selectivities of the two compounds are very similar, too.
(Z)-7e (pIC50 5.58, Table 7, entry 12), with a fluorine substituent
at the meta-position of ring 2, and (Z)-7f (pIC50 5.52, Table 7, entry
14), with a fluorine substituent at the ortho-position of ring 2, both
show only slightly enhanced inhibitory potencies and mGAT1-
selectivities compared to (Z)-7g.
tency and subtype selectivity, the potency at and the subtype
selectivity for mGAT1 displayed by (Z)-8g (pIC50 6.40, Table 7, en-
try 16) are quite pleasing. Actually, the potency of this compound
(Z)-8g is the same, the differences of the pIC50 values being insig-
nificant, as that of (Z)-7a, the most potent compound of all meth-
anone bridged derivatives.
Of the methylene bridged derivatives, the two (E)-isomers with
a fluorine substituent in 4-position of ring 1 (R1 = F, Table 7, entries
17 and 19), (E)-8a, exhibiting a fluorine in para-position of ring 2
(pIC50 5.34, Table 7, entry 17), and (E)-8c with fluorine in the
ortho-position of ring 2 (pIC50 5.57, Table 7, entry 19) display
potencies at mGAT1 that are identical or somewhat higher than
that of the unsubstituted (E)-8g, combined with a slightly im-
proved subtype selectivity for this transporter. In case of the (Z)-
isomers carrying a fluorine substituent in 4-position of ring 1
(R1 = F, Table 7, entries 18 and 20), potency and mGAT1-selectivity
were lower as those of the unsubstituted counterpart (Z)-8g when
the fluorine substituent was present in para-position ((Z)-8a, pIC50
5.93, Table 7, entry 18). The subtype selectivity was also lower for
(Z)-8c with a fluorine in the ortho-position of ring 2 (pIC50 6.20, Ta-
ble 7, entry 20), but the potency displayed by this compound at
mGAT1 was only numerically but not significantly lower that that
of the reference compound (Z)-8g. Regarding the (E)-isomers carry-
ing a fluorine substituent in 5-position of ring 1 (R2 = F, Table 7, en-
tries 21, 23 and 25), (E)-8d (pIC50 5.05, Table 7, entry 21), with a
fluorine substituent at the para-position, as well as (E)-8e (pIC50
5.17, Table 7, entry 23), which is fluorine substituted at the
meta-position of ring 2, and (E)-8f (pIC50 4.99, Table 7, entry 25),
which carries a fluorine substituent at the ortho-position of ring
2, all show similar or slightly decreased potencies at mGAT1 and
similar mGAT1-selectivities as compared to their unsubstituted
counterpart (E)-8g. The (Z)-isomers with a fluorine substituent at
the 5-position of ring 1 (R2 = F, Table 7, entries 22, 24 and 26), show
to some extent strong differences with regard to their potencies
and good to high subtype selectivities. Thus, (Z)-8d (pIC50 5.96, Ta-
ble 7, entry 22), in which ring 2 is substituted with fluorine at the
para-position, is clearly the least potent inhibitor in this series, its
pIC50 ranging almost a half log unit below that of the unsubstituted
counterpart (Z)-8g. On the other hand, (Z)-8e (pIC50 6.52, Table 7,
entry 24), which bears a fluorine substituent at the meta-position,
and (Z)-8f (pIC50 6.52, Table 7, entry 26), with a fluorine substitu-
ent at the ortho-position of ring 2, show potencies towards mGAT1
that are identical and nominally even slightly higher than that of
the unsubstituted counter part (Z)-8g. Furthermore, with pIC50 val-
Compounds 8a and 8c–f (Table 7, entries 17–26), in which
ring 1 and ring 2 are connected with a methylene bridge (Fig. 1,
8, Y = H2), were referenced to the unsubstituted compounds (E)-
and (Z)-8g (Table 7, entries 15 and 16). Both of these compounds,
(E)-8g and (Z)-8g, show enhanced potency compared to their
methanone bridged counterparts (E)-7g and (Z)-7g. Whereas (E)-
8g (pIC50 5.38, Table 7, entry 15) shows still only poor mGAT1-po-

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G. Quandt et al. / Bioorg. Med. Chem. 21 (2013) 3363–3378
ues amounting to 6.52, they also represent, along with (Z)-7a and
(Z)-8g, the most potent uptake inhibitors at mGAT1 of all com-
pounds studied, the subtype selectivities of these compounds in fa-
vor of mGAT1 being reasonable as well.
4. Experimental
4.1. Chemistry
Unless otherwise noted, all reactions were performed in oven-
dried glassware under moisture-free conditions and argon atmo-
sphere. All commercial reagents were used without further purifi-
cation. For the reactions, dried and freshly distilled solvents were
used. NEt3 was dried over sodium and distilled under nitrogen
when needed. CH2Cl2 was distilled from CaH2 under nitrogen and
DMF was stored over molecular sieves (4 Å) prior to use. For chro-
matographic purposes, only distilled solvents were used. Flash col-
umn chromatography (FCC) was performed according to Still38
using silica gel (0.040–0.063 mm, Acros and Merck). NMR spectra
were measured with a Jeol Eclipse +400 (400 MHz) and a Jeol
Eclipse +500 (500 MHz) spectrometer. The coupling constants
were stated with an accuracy of 0.5 Hz. MestreNova was used for
further analysis of the spectra. IR spectra were recorded with a
FT-IR spectrometer Paragon 1000 (Perkin–Elmer) and Spectrum
v2.00 software (Perkin–Elmer) was used for analysis. Mass spectra
were measured with a Mass Spectrometer 59827A with 59980 Par-
ticle Beam LC/MS Interface (Hewlett Packard) or an Applied LC–
MS/MS Mass Spectrometer API 2000. High resolution mass spec-
trometry (HRMS) was accomplished with an LTQ FT (ThermoFinn-
igan) or a JMS GCmate II (Jeol). Microanalytical data for carbon,
hydrogen, nitrogen, and sulfur was determined using an Elementar
Vario Micro Cube or an Elementar Vario EL analyzer.
3. Conclusion
In conclusion, the b-selective, chelation-controlled Heck-reac-
tion was found a convenient and versatile method to synthesize
a series of new lipophilic N-alkylated nipecotic acid derivatives
with a vinyl ether unit embedded in the spacer and an unsymmet-
rical bis-aromatic residue attached to the terminal position of that
spacer. Most of the compounds display reasonable to good poten-
cies at and selectivities for mGAT1. Differences in uptake-inhibi-
tion depending on whether the two aromatic rings were
connected by a methanone (Fig. 1, 7, Y = O) or a methylene bridge
(Fig. 1, 8, Y = H2) were observed. Thus, the methylene bridged com-
pounds bearing no fluorine substituents appeared to be more po-
tent than their unsubstituted methanone bridged counterparts.
Additionally, the influence of the presence and the position of fluo-
rine substituents in the bis-aromatic residue concerning potency
and selectivity of the new compounds could be defined by compar-
ing the pharmacological profiles of those compounds without sub-
stituents in the bis-aromatic residue with those bearing fluorine
substituents in both aromatic rings.
Generally, all (Z)-isomers of the synthesized compounds are
more potent than their corresponding (E)-isomers. The influence
of fluorine substituents on GAT1 uptake inhibition is generally
more severe for those compounds, in which the two aromatic rings
are linked by a methanone bridge (Y = O, (E)/(Z)-7a–g). Here, both,
the (E)- and the (Z)-isomer of the unsubstituted compound ((E)/
(Z)-7g) exhibit very poor potencies, but the potencies of most of
the (Z)-isomers are significantly enhanced through the attachment
of fluorine substituents to the two aromatic rings. A substitution
with fluorine in 4-position of ring 1 (R1 = F) and an additional fluo-
rine substituent at the para-position of ring 2 is the most beneficial
combination for uptake inhibition of this series leading to com-
pound (Z)-7a, one of the most potent compounds of the whole ser-
ies. When the two rings of the bis-aromatic residue are connected
by a methylene bridge (Y = H2, (E)/(Z)-8a, (E)/(Z)-8c–g), attachment
of fluorine substituents does not have a big impact on uptake inhi-
bition. (Z)-8g, the (Z)-isomer of the unsubstituted derivative, is al-
ready a good inhibitor and displays even higher potency than most
of its fluorine-substituted counterparts. The best inhibitors of all
tested compounds are the compounds (Z)-8e and (Z)-8f, which
both show nominally a slightly enhanced, but almost identical po-
tency towards mGAT1 compared to their parent compound (Z)-8g.
For economical reasons, only the racemic compounds have been
synthesized, though Andersen et al. focused on the preparation and
biological testing of the pure (R)-nipecotic acid derivatives, in line
with former studies according to which for GAT1 inhibitors derived
from nipecotic acid the higher potency resides in general in the (R)-
configured isomer.19–24 Thus, also for the GAT1 inhibitors devel-
oped in this study that had so far been prepared in racemic form
only, it can be expected that their (R)-enantiomers display still
higher potencies.
For each general procedure (GP) the full characterization of at
least one compound, which is not known in literature, is given in
this paper. For the biologically tested compounds, those exhibiting
the highest pIC50 values are characterized. All other compounds
can be found in the Supplementary data.
4.1.1. General procedure for the synthesis of fluorophenyl-
fluorobenzoates (GP1)
The respective fluorobenzoyl chloride 13a–c (1.00 equiv) was
added dropwise to a solution of the corresponding fluorophenol
12a–c (1.00 equiv) and NEt3 (1.20 equiv) in CH2Cl2. The solution
was stirred under reflux for 1 h. After cooling to rt, the solution
was diluted with CH2Cl2 and washed with sat NaHCO3 solution
and water. The organic layer was washed with brine, dried over
MgSO4 and the solvent was removed in vacuo to give the crude
product.
4.1.1.1. 3-Fluorophenyl 3-fluorobenzoate (14e).
According
to GP1. 3-Fluorobenzoylchloride (13b) (7.90 g, 6.10 mL,
50.0 mmol), 3-fluorophenol (12b) (5.60 g, 4.00 mL, 50.0 mmol),
and NEt3 (6.10 g, 8.30 mL, 60.0 mmol) in CH2Cl2 (125 mL) were
used. The crude product was purified via FCC (cyclohexane/
EtOAc = 5:1) to yield 14e (9.67 g, 83%) as colorless solid: mp
35.0 °C. IR (KBr): 3079, 1743, 1593, 1487, 1445, 1252, 1188,
1155, 1123, 1074, 953, 913, 893 cmꢀ1 1H NMR (400 MHz, CDCl3):
.
d 6.98–7.04 (m, 3H, OCCHarCHarCHarCFCHar), 7.36 (td, J = 8.3/2.8 Hz,
1H, OOCCCHarCFCHar), 7.40 (td, J = 8.3/6.8 Hz, 1H, OCCHarCHar),
7.50 (td, J = 8.0/5.5 Hz, 1H, OOCCCHarCHar), 7.87 (ddd, J = 9.0/2.3/
1.5 Hz, 1H, OOCCCHarCFCHar), 7.99 (ddd, J = 7.8/2.5/1.5 Hz, 1H,
OOCCCHarCHar) ppm. 13C NMR (100 MHz, CDCl3): d 109.8 (d,
Future work will aim at the expansion of the library of com-
pounds described in this study and at the synthesis and biological
evaluation of similar compounds bearing only one fluorine substi-
tuent at either one of the rings. This can be expected to deepen the
already achieved knowledge of the influence of the position of the
fluorine substituents on mGAT1 binding, which can potentially
lead to even more potent mGAT1-inhibitors and also to a better
understanding of the binding mode of these inhibitors in the bind-
ing pocket of mGAT1.
JCF = 24.6 Hz, OCarCarHCarF), 113.2 (d, JCF = 21.1 Hz, OCarCarHCarF-
CarH), 117.1 (d, JCF = 23.3 Hz, OOCCarCarHCarF), 117.4 (OCarCarH-
CarH), 121.0 (d, JCF = 21.4 Hz, OOCCarCarHCarFCarH), 126.0
(OOCCarCarHCarH), 130.3 (d, JCF = 9.6 Hz, OOCCarCarHCarH), 130.4
(d, JCF = 7.6 Hz, OCarCarHCarH), 131.3 (d, JCF = 7.6 Hz, OOCCar),
151.5 (d, JCF = 10.9 Hz, OCar), 162.6 (d, JCF = 249 Hz, OOCCarCarH-
CarF), 163.0 (d, JCF = 249 Hz, OCarCarHCarF), 163.7 (COO) ppm. M
(C13H8F2O2) = 234.20. MS (CI, CH5+) m/z (%): 235 (100, [M+H]+),

G. Quandt et al. / Bioorg. Med. Chem. 21 (2013) 3363–3378
3373
123 (24), 141 (7). HRMS (EI+): M+ calcd for C13H8F2O2 234.0492;
found: 234.0497.
35.35 (CH2), 103.4 (d, JCF = 24.4 Hz, HOCarCarH), 107.7 (d, JCF
=
21.0 Hz, HOCarCarHCarFCarH), 113.3 (d, JCF = 21.0 Hz, CarHCarHCarH-
CarF), 115.5 (d, JCF = 21.5 Hz, CarHCarHCarHCarFCarH), 122.2 (d,
4.1.2. General procedure for the Fries rearrangement (GP2)
The fluorophenyl benzoate 14a–f (1.0 equiv) was liquefied
through heating and AlCl3 (1.2 equiv) was added. The mixture
was stirred at 200 °C for 20 min to 1 h. After cooling to rt, the
glass-like material was grinded to a powder and added slowly to
a mixture of 12 M HCl (25 equiv), crushed ice and water. The
resulting suspension was extracted several times with Et2O. The
combined organic layers were washed with water and dried over
MgSO4. The solvent was removed in vacuo to give the crude
product.
J
CF = 3.30 Hz, HOCarCarCH2), 124.2 (d, JCF = 2.80 Hz, CarHCarHCarH-
CarFCarH), 130.0 (d, JCF = 8.40 Hz, CarHCarHCarHCarF), 131.7 (d,
CF = 9.70 Hz, HOCarCarHCarFCarHCarH), 142.5 (d, JCF = 7.20 Hz, HO-
J
CarCarCH2Car), 154.4 (d, JCF = 10.7 Hz, HOCar), 162.3 (d, JCF = 245 Hz,
HOCarCarHCarF), 163.1 (d, JCF = 246 Hz, H2CCarCHarCarF) ppm. M
(C13H10F2O) = 220.22. MS (CI, CH5+) m/z (%): 109 (41), 125 (74),
221 (100, [M+H]+). HRMS (EI+): M+ calcd for C13H10F2O,
220.06998; found: 220.06948. C13H10F2O (220.22): calcd C 70.90,
H 4.58; found: C 70.62, H 4.61.
4.1.4. General procedure for the synthesis of triflates (GP4)
The phenol (15a–f or 16a–f, 1.0 equiv) and 2,4,6-collidin
(4.0 equiv) were dissolved in CH2Cl2 and cooled to 0 °C. At this
temperature, triflic anhydride was added dropwise. The solution
was stirred at rt until TLC control revealed completion of the reac-
tion. After dilution with Et2O, the mixture was washed twice with
water, the organic layer was separated and the aqueous layer ex-
tracted with Et2O. The combined organic layers were washed sev-
eral times with satd CuSO4 solution and dried over MgSO4.
Evaporation of the solvent gave the crude product.
4.1.2.1.
none (15e).
(4-Fluoro-2-hydroxyphenyl)(3-fluorophenyl)-metha-
According to GP2 with 14e (8.00 g, 34.2 mmol)
and AlCl3 (5.47 g, 41.4 mmol). The reaction time was 20 min. The
crude product was purified via FCC (cyclohexane/EtOAc = 9:1) to
yield 15e (6.25 g, 78%) as yellow solid: mp 74.7 °C. IR (KBr):
3447, 3075, 1699, 1634, 1616, 1683, 1506, 1479, 1439, 1263,
965, 851, 834, 803, 778, 706 cmꢀ1 1H NMR (500 MHz, CDCl3): d
.
6.62 (ddd, J = 9.2/8.2/2.5 Hz, 1H, HOCCHarCFCHar), 6.77 (dd,
J = 10.4/2.4 Hz, 1H, HOCCHar), 7.30 (tdd, J = 8.4/2.7/1.1 Hz, 1H,
CHarCHarCHarCF), 7.36 (ddd, J = 8.8/2.4/1.6 Hz, 1H, CHarCHarCHarCF-
CHar), 7.43 (dt, J = 7.6/1.2 Hz, 1H, CHarCHarCHarCF), 7.50 (td, J = 7.9/
5.5 Hz, 1H, CHarCHarCHarCF), 7.60 (dd, J = 8.8/6.4 Hz, 1H, HOCC-
CHar), 12.3 (s, 1H, OH) ppm. 13C NMR (125 MHz, CDCl3): d 105.3
(d, JCF = 23.9 Hz, HOCarCarH), 107.3 (d, JCF = 22.8 Hz, HOCarCarHCarF-
CarH), 116.0 (d, JCF = 22.9 Hz, CarHCarHCarHCarFCarH), 115.9 (HOCar-
CarCO), 119.1 (d, JCF = 21.3 Hz, CarHCarHCarHCarFCarH), 124.7 (d,
4.1.4.1.
(10e).
5-Fluoro-2-(3-fluorobenzoyl)phenyl
According to GP4 with 15e (2.00 g, 8.50 mmol), 2,4,6-
triflate
collidin (4.16 g, 4.60 mL, 34.3 mmol) and triflic anhydride (2.88 g,
1.70 mL, 10.2 mmol) in CH2Cl2 (42.5 mL). After 19 h, more triflic
anhydride (1.19 g, 0.70 mL, 4.25 mmol) was added. The total reac-
tion time was 20.5 h. The crude product was purified via FCC
(cyclohexane/EtOAc = 9:1) to yield 10e (2.94 g, 94%) as colorless
oil: IR (KBr): 3103, 3080, 1676, 1611, 1589, 1430, 1409, 1300,
J
CF = 3.00 Hz, CarHCarHCarHCarFCarH), 130.26 (d, JCF = 7.80 Hz, CarH-
CarHCarHCarFCarH), 135.8 (d, JCF = 11.8 Hz, HOCarCarCarH), 139.7 (d,
CF = 6.70 Hz, HOCarCarCOCar), 162.5 (d, JCF = 250 Hz, CarHCarHCarH-
J
1271, 1215, 1139, 1073, 987, 964, 833, 762 cmꢀ1 1H NMR
.
CarFCarH), 165.9 (d, JCF = 14.5 Hz, HOCar), 167.7 (d, JCF = 259 Hz, HO-
CarCarHCarF), 199.0 (ArCOAr) ppm. M (C13H8F2O2) = 234.20. MS (CI,
CH5+) m/z (%): 315 (18), 235 (100, [M+H]+), 215 (9), 139 (8). HRMS
(EI+): M+ calcd for C13H8F2O2, 234.0492; found: 234.0470.
(500 MHz, CDCl3): d 7.19 (dd, J = 8.3/2.3 Hz, 1H, TfOCCHar), 7.24
(ddd, J = 8.8/7.5/2.3 Hz, 1H, TfOCCHarCFCHar), 7.34 (tdd, J = 8.3/
2.5/1.0 Hz, 1H, CHarCHarCHarCF), 7.46–7.49 (td, J = 7.9/5.3 Hz, 1H,
CHarCHarCHarCF), 7.51 (ddd, J = 8.8/2.5/1.5 Hz, 1H, CHarCHarCHarCF-
CHar), 7.54 (ddd, J = 8.0/1.5/1.0 Hz, 1H, CHarCHarCHarCF), 7.62 (dd,
J = 8.8/6.3 Hz, 1H, TfOCCHarCFCHarCHar) ppm. 13C NMR (125 MHz,
CDCl3): d 111.2 (d, JCF = 25.8 Hz, TfOCarCarH), 115.6 (d, JCF = 21.3 Hz,
TfOCarCarHCarFCarH), 116.6 (d, JCF = 22.7 Hz, CarHCarHCarHCarFCarH),
118.4 (q, JCF = 321 Hz, CF3), 121.0 (d, JCF = 21.5 Hz, CarHCarHCarH-
CarF), 126.0 (d, JCF = 3.00 Hz, CarHCarHCarHCarF), 128.3 (d,
C13H8F2O2 (234.20): calcd C 66.67, H 3.44; found: C 66.37, H 3.30.
4.1.3. General procedure for the deoxygenation (GP3)
NaBH4 pellets (6–7 equiv) were added to cooled (0 °C) TFA and
stirred at this temperature until it was almost completely dis-
solved. A solution of the methanone 15a–f in CH2Cl2 was added
within 30 min and the mixture was stirred at rt until TLC control
revealed completion of the reaction. If necessary, more NaBH4
was added after 15 h. The reaction was quenched with an excess
of water and NaOH pellets were added under ice bath cooling until
the solution showed a basic pH. The mixture was then extracted
several times with Et2O and the combined organic layers were
washed with water and brine and dried over MgSO4. Evaporation
of the solvent gave the crude product.
J
CF = 4.20 Hz, TfOCarCarCO), 130.4 (d, JCF = 7.80 Hz, CarHCarHCarH-
CarF), 132.9 (d, JCF = 9.60 Hz, TfOCarCarHCarFCarHCarH), 138.5 (d,
CF = 6.40 Hz, TfOCarCarCOCar), 147.6 (d, JCF = 11.0 Hz, TfOCar),
J
162.7 (d, JCF = 250 Hz, CarHCarHCarHCarF), 164.2 (d, JCF = 258 Hz,
TfOCarCarHCarF), 190.4 (CO) ppm. M (C14H7F5O4S) = 366.27. MS
(CI, CH5+) m/z (%): 123 (9), 367 (100, [M+H]+). HRMS (EI+): M+ calcd
for C14H7F5O4S, 365.99853; found: 365.99924. C14H7F5O4S
(366.27): calcd C 45.91, H 1.93; found: C 45.98, H 1.99.
4.1.3.1. 15-Fluoro-2-(3-fluorobenzyl) phenol (16e).
Accord-
4.1.5. Synthesis of ethyl 1-(2-(vinyloxy)ethyl)nipecotate (20)
Compound 18 (4.74 g, 4.65 mL, 30.2 mmol) was added dropwise
and under stirring to 19 (1.00 g, 4.13 mmol). The solution was stir-
red at rt for 4.5 h, until the completion of the reaction (TLC). The
reaction was quenched with water (2.50 mL) and the mixture ex-
tracted several times with pentane. The combined organic layers
were dried over K2CO3 and the solvent was evaporated. The crude
product was purified via FCC (cyclohexane/EtOAc = 3:1 + 1% NEt3)
to yield 20 (761 mg, 80%) as colorless oil: IR (KBr): 3117, 2942,
2870, 2790, 1731, 1635, 1616, 1467, 1453, 1370, 1319, 1274,
ing to GP3 with NaBH4 (1.02 g, 27.0 mmol, 1.00 pellet) in TFA
(20.3 mL) and 15e (949 mg, 4.05 mmol) in CH2Cl2 (12.2 mL). After
15 h, another NaBH4 pellet (1.04 g, 27.4 mmol) was added. The to-
tal reaction time was 40 h. The crude product was purified via FCC
(cyclohexane/EtOAc = 9:1) to yield 16e (458 mg, 51%) as colorless
solid: mp 44.3 °C. IR (KBr): 3332, 3070, 2956, 2934, 2858, 1614,
1594, 1485, 1443, 1427, 1272, 1250, 1234, 1149, 1139, 1091,
973, 848, 753 cmꢀ1 1H NMR (500 MHz, CDCl3): d 3.93 (s, 2H,
.
CH2), 4.86 (s, 1H, OH), 6.53 (dd, J = 10.0/2.5 Hz, 1H, HOCCHar),
6.61 (td, J = 8.5/2.5 Hz, 1H, HOCCHarCFCHar), 6.90 (m, 2H, CHarCH-
arCHarCFCHar), 6.98 (d, J = 7.5 Hz, 1H, CHarCHarCHarCFCHar), 7.04
(dd, J = 8.5/6.5 Hz, 1H, HOCCHarCFCHarCHar), 7.24 (q, J = 7.8 Hz,
1H, CHarCHarCHarCFCHar) ppm. 13C NMR (125 MHz, CDCl3): d
1201, 1155, 1030, 1000, 964 cmꢀ1 1H NMR (500 MHz, CDCl3): d
.
1.25 (t, J = 7.3 Hz, 3H, CH3), 1.44 (ddd, J = 16.8/11.8/4.2 Hz, 1H,
NCH2CH2CH2,ax), 1.56–1.65 (m, 1H, NCH2CH2,axCH2), 1.69–1.76
(m, 1H, NCH2CH2,eqCH2), 1.91–1.98 (m, 1H, NCCH2CH2CH2,eq),

3374
G. Quandt et al. / Bioorg. Med. Chem. 21 (2013) 3363–3378
2.07 (td, J = 11.2/2.9 Hz, 1H, NCH2,axCH2CH2), 2.23 (t, J = 10.8 Hz,
1H, NCH2,axCH), 2.59 (tt, J = 10.9/3.9 Hz, 1H, NCH2CH), 2.64–2.74
(m, 2H, NCH2CH2O), 2.83 (d, J = 11.2 Hz, 1H, NCH2,eqCH2CH2), 3.04
(d, J = 11.2 Hz, 1H, NCH2,eqCH), 3.81 (t, J = 5.8 Hz, 2H, NCH2CH2O),
4.00 (dd, J = 6.8/2.1 Hz, 1H, OCHCH2,cis), 4.13 (q, J = 7.1 Hz, 2H,
CH2CH3), 4.18 (dd, J = 14.4/2.1 Hz, 1H, OCHCH2,trans), 6.50 (dd,
J = 14.4/6.8 Hz, 1H, OCHCH2) ppm. 13C NMR (125 MHz, CDCl3): d
12.71 (CH3), 23.04 (NCH2CH2CH2), 25.37 (NCH2CH2CH2), 40.31
(NCH2CH), 52.55 (NCH2CH2CH2), 54.27 (NCH2CH), 55.84
(NCH2CH2O), 58.80 (CH2CH3), 63.74 (NCH2CH2O), 84.91 (OCHCH2),
150.25 (OCHCH2), 172.65 (COOEt) ppm. MS (CI, CH5+) m/z (%): 228
(87, [M+H]+), 184 (90), 170 (100). HRMS (EI+): M+ calcd for
CarCarHCarF), 149.61 (OCHCH), 160.41 (d, JCF = 247.6 Hz,
COCarCarHCarF), 166.00 (d, JCF = 256.7 Hz, COCarCarHCarHCarF),
174.08 (COOEt), 195.55 (ArCOAr) ppm. M (C25H27F2NO4) 443.50.
MS (CI, CH5+) m/z (%): 444 (53, [M+H]+) , 243 (5), 170 (100), 185
(94). HRMS (EI+): M+ calcd for C25H27F2NO4 443.1908; found:
443.1939.
Compound (Z)-22a: Pale yellow oil. 40.2 mg (6%). 1H NMR
(500 MHz, CDCl3): d 1.24 (t, J = 7.0 Hz, 3H, CH3), 1.45 (qd, J = 11.5/
3.8 Hz, 1H, NCH2CH2CH2,ax), 1.50–1.61 (m, 1H, NCH2CH2,axCH2),
1.68–1.75 (m, 1H, NCH2CH2,eqCH2), 1.89–1.97 (m, 1H,
NCH2CH2CH2,eq), 2.12 (td, J = 10.8/2.8 Hz, 1H, NCH2,axCH2CH2),
2.30 (t, J = 10.8 Hz, 1H, NCH2,axCH), 2.54 (tt, J = 10.3/3.9 Hz, 1H,
NCH2CH), 2.64 (t, J = 6.0 Hz, 2H, NCH2CH2O), 2.75 (dbr, J = 11.0 Hz,
1H, NCH2,eqCH2CH2), 2.98 (dbr, J = 10.5 Hz, 1H, NCH2,eqCH), 3.95 (t,
J = 6.0 Hz, 2H, NCH2CH2O), 4.12 (qd, J = 7.2/1.5 Hz, 2H, CH2CH3),
5.14 (d, J = 7.5 Hz, 1H, OCHCH), 6.10 (d, J = 7.5 Hz, 1H, OCHCH),
6.97 (dd, J = 8.5/2.5 Hz, 1H, COCCHarCF), 7.13 (t, J = 8.8 Hz, 2H, COC-
CHarCHarCFCHar), 7.15 (dd, J = 8.5/3.0 Hz, 1H, COCCHarCFCHar), 7.84
(dd, J = 9.0/5.5 Hz, 2H, COCCHarCHarCFCHarCHar), 8.09 (dd, J = 9.0/
5.5 Hz, 1H, OCHCHCCHar) ppm. 13C NMR (125 MHz, CDCl3): d
14.20 (CH3), 24.61 (NCH2CH2CH2), 26.69 (NCH2CH2CH2), 41.86
(NCH2CH), 54.11 (NCH2CH2CH2), 55.80 (NCH2CH), 57.74
(NCH2CH2O), 60.37 (CH2CH3), 71.38 (NCH2CH2O), 101.3 (OCHCH),
114.6 (d, JCF = 22.8 Hz, COCarCarHCarF), 115.7 (d, JCF = 21.9, 2C, CO-
CarCarHCarHCarFCarH), 117.0 (d, JCF = 20.8 Hz, COCarCarHCarFCarH),
130.1 (d, JCF = 3.5 Hz, OCHCHCar), 131.6 (d, JCF = 7.4 Hz, OCH-
CHCarCarH), 133.0 (d, JCF = 9.5 Hz, 2 C, COCarCarHCarHCarFCarHCarH),
133.4 (d, JCF = 2.9 Hz, COCarCarHCarHCarF), 138.5 (d, JCF = 5.8 Hz, CO-
CarCarHCarF), 147.4 (OCHCH), 159.9 (d, JCF = 246.3 Hz, COCarCarH-
CarF), 166.0 (d, JCF = 254.4 Hz, COCarCarHCarHCarF), 174.0 (COOEt),
195.6 (ArCOAr) ppm. 19F NMR (470 MHz, CDCl3): d ꢀ104.2,
ꢀ115.7 ppm. M (C25H27F2NO4) 443.50. MS (CI, CH5+) m/z (%): 444
(100, [M+H]+), 184 (31), 170 (45). HRMS (EI+): M+ calcd for
C12H21NO3, 227.1521; found: 227.1478. C12H21NO3 (227.31): calcd
C 63.41, H 9.31, N 6.16; found: C 63.22, H 9.32, N 6.55.
4.1.6. General procedures for the Heck reaction (GP5)
Method A (Scheme 5, conditions f): The aryl triflate 10a–f
(1.0 equiv) was dissolved in DMF and the reactants were added
in the following order: (1) Pd(OAc)2 (3–10 mol %), (2) NEt3
(1.5 equiv), and (3) 20 (1.5 equiv). The reaction mixture was stirred
for 20 h at 80 °C. After cooling to rt, the black solution was diluted
with CH2Cl2 and washed with water and brine. The organic layer
was dried over K2CO3, filtered, and the solvent was removed in
vacuo.
Method B (Scheme 5, conditions g): Pd(OAc)2 (10 mol %) and
PPh3 (20 mol %) were dissolved in DMF and the reactants were
added in the following order: (1) aryl triflate 11a–f (1.0 equiv),
(2) NEt3 (1.5 equiv), and 20 (1.5 equiv). The reaction mixture was
stirred at 80 °C for 20 h and work up was performed according to
method A.
Method C (Scheme 5, conditions h): The aryl iodide (1.0 equiv)
was dissolved in DMF and the reactants were added in the follow-
ing order: (1) 20 (2.0 equiv), (2) Pd(OAc)2 (10 mol%), (3) NaOAc
(1.2 equiv), (4) LiCl (2.0 equiv), (5) K2CO3 (1.2 equiv), and water
(DMF/H2O (v/v) = 10:1). The reaction mixture was stirred at 80 °C
for 20 h and work up was performed according to method A.
C25H27F2NO4 443.1908; found: 443.1920.
4.1.6.2. Ethyl 1-(2-{2-[4-fluoro-2-(4-fluorobenzyl)phenyl]-vinyl-
oxy}ethyl)nipecotate (23a). According to GP5 (method B)
4.1.6.1. Ethyl 1-(2-{2-[4-fluoro-2-(4-fluorobenzoyl)phenyl]-
using 11a (1.06 g, 3.00 mmol), 20 (1.02 g, 4.50 mmol), NEt3
(455 mg, 0.620 mL, 4.50 mmol), Pd(OAc)2 (67.4 mg, 0.300 mmol),
and PPh3 (157 mg, 0.600 mmol) in DMF (12.0 mL). The crude prod-
uct was purified by FCC (cyclohexane/MTBE = 2.5:1 + 1% NEt3) to
yield 23a (250 mg, 19%) as (E)/(Z)-mixture. The isomers were sep-
arated via FCC (Et2O + 1% NEt3).
vinyloxy}ethyl)nipecotate (22a).
A) using 10a (549 mg, 150 mol) in DMF (6.00 mL), Pd(OAc)2
(10.2 mg, 45.0 mol), NEt3 (228 mg, 310 L, 225 mol), and 20
(511 mg, 225 mol). The crude product was purified by FCC (cyclo-
According to GP5 (method
l
l
l
l
l
hexane/EtOAc = 5:1 + 1% NEt3) to yield 22a (268 mg, 40%) as (E)/
(Z)-mixture. The isomers were separated by FCC (Et2O + 1% NEt3).
Compound (E)-22a: 134 mg (20%). Pale yellow oil. 1H NMR
(500 MHz, CDCl3): d 1.24 (t, J = 7.0 Hz, 3H, CH3), 1.41 (ddd,
J = 24.5/11.9/4.1 Hz, 1H, NCH2CH2CH2,ax), 1.57 (m, 1H,
NCH2CH2,axCH2), 1.70 (dt, J = 13.5/3.5 Hz, 1H, NCH2CH2,eqCH2),
1.94 (dd, J = 12.9/3.8 Hz, 1H, NCH2CH2CH2,eq), 2.00 (td, J = 11.2/
2.9 Hz, 1H, NCH2,eqCH2CH2), 2.17 (t, J = 10.8 Hz, 1H, NCH2,axCH),
2.55 (m, 1H, NCH2CH), 2.60 (m, 2H, NCH2CH2O), 2.75 (d,
J = 11.2 Hz, 1H, NCH2,eqCH2CH2), 2.97 (d, J = 11.0 Hz, 1H,
NCH2,eqCH), 3.75 (t, J = 5.7 Hz, 2H,NCH2CH2O), 4.12 (q, J = 7.1 Hz,
2H, CH2CH3), 5.77 (d, J = 12.9 Hz, 1H, OCHCH), 6.84 (d, J = 12.9 Hz,
1H, OCHCH), 7.01 (dd, J = 8.5/2.5 Hz, 1H, COCCHarCF), 7.12 (td,
J = 8.3/3.0 Hz, 1H, COCCHarCFCHar), 7.13 (t, J = 8.8 Hz, 2H, COC-
CHarCHarCFCHar), 7.39 (dd, J = 8.8/5.3 Hz, 1H, OCHCHCCHar), 7.81
(dd, J = 8.5/5.5 Hz, 2H, COCCHarCHarCFCHarCHar) ppm. 13C NMR
(125 MHz, CDCl3): d 14.21 (CH3), 24.51 (NCH2CH2CH2), 26.83
(NCH2CH2CH2), 41.79 (NCH2CH), 53.98 (NCH2CH2CH2), 55.73
(NCH2CH), 57.30 (NCH2CH2O), 60.34 (CH2CH3), 66.98 (NCH2CH2O),
102.34 (OCHCH), 115.34 (d, JCF = 22.7 Hz, COCarCarH), 115.81 (d,
Compound (E)-23a: 101 mg (8%) Colorless oil. 1H NMR
(500 MHz, CDCl3): d 1.25 (t, J = 7.3 Hz, 3H, CH3), 1.44 (qd, J = 12.0/
4.1 Hz, 1H, NCH2CH2CH2,ax), 1.56–1.66 (m, 1H, NCH2CH2,axCH2),
1.73 (dt, J = 13.5/3.6 Hz, 1H, NCH2CH2,eqCH2), 1.93–2.00 (m, 1H,
NCH2CH2CH2,eq), 2.06 (td, J = 11.1/3.0 Hz, 1H, NCH2,axCH2CH2),
2.23 (t, J = 10.8 Hz, 1H, NCH2,axCH), 2.59 (tt, J = 10.8/3.8 Hz, 1H,
NCH2CH), 2.69 (td, J = 5.6/1.8 Hz, 2H, NCH2CH2O), 2.82 (dbr
,
J = 11.0 Hz, 1H, NCH2,eqCH2CH2), 3.04 (dbr J = 10.0 Hz, 1H,
,
NCH2,eqCH), 3.87 (t, J = 5.8 Hz, 2H, NCH2CH2O), 3.94 (s, 2H, ArCH2-
Ar), 4.13 (q, J = 7.0 Hz, 2H, CH2CH3), 5.83 (d, J = 12.5 Hz, 1H,
OCHCH), 6.75 (d, J = 13.0 Hz, 1H, OCHCH), 6.76 (dd, J = 9.8/2.8 Hz,
1H, CH2CCHarCF), 6.87 (td, J = 8.4/2.8 Hz, 1H, CH2CCHarCFCHar),
6.97 (t, J = 8.8 Hz, 2H, CHarCHarCFCHarCHar), 7.07 (dd, J = 8.5/
5.5 Hz, 2H, CHarCHarCFCHarCHar), 7.23 (dd, J = 8.8/5.8 Hz, 1H,
CH2CCHarCFCHarCHar) ppm. 13C NMR (125 MHz, CDCl3): d 14.21
(CH3), 24.52 (NCH2CH2CH2), 26.84 (NCH2CH2CH2), 38.52 (ArCH2-
Ar), 41.75 (NCH2CH), 54.08 (NCH2CH2CH2), 55.76 (NCH2CH),
57.47 (NCH2CH2O), 60.37 (CH2CH3), 67.16 (NCH2CH2O), 102.8
(OCHCH), 113.5 (d, JCF = 20.9 Hz, CH2CarCarHCarFCarH), 115.3 (d,
J
CF = 21.9 Hz, 2 C, COCarCarHCarHCarFCarH), 117.72 (d, JCF = 21.4 Hz,
J
CF = 21.0 Hz, 2 C, CarHCarHCarFCarHCarH), 116.7 (d, JCF = 21.4 Hz,
CH2CarCarHCarF), 127.1 (d, JCF = 7.8 Hz, CH2CarCarHCarFCarHCarH),
130.1 (d, CF = 7.9 Hz, C, CarHCarHCarFCarHCarH), 131.2 (d,
CF = 3.1 Hz, OCHCHCar), 135.4 (d, JCF = 3.1 Hz, CH2CarCarHCarHCarF-
COCarCarHCarFCarH), 127.28 (d, JCF = 7.4 Hz, OCHCHCarCarH),
131.31 (OCHCHCar), 132.91 (d, JCF = 9.6 Hz, 2 C, COCarCarHCarHCarF-
CarHCarH), 133.47 (COCarCarHCarHCarF), 137.88 (d, JCF = 5.8 Hz, CO-
J
2
J

G. Quandt et al. / Bioorg. Med. Chem. 21 (2013) 3363–3378
3375
CarHCarH), 139.2 (d, JCF = 6.9 Hz, OCHCHCarCarCH2), 148.7 (OCHCH),
161.4 (d, CF = 242.9 Hz, CarHCarHCarFCarHCarH), 161.5 (d,
CF = 243.3 Hz, CH2CarCarHCarF), 174.1 (COOEt) ppm. 19F NMR
(NCH2CH2O), 103.8 (OCHCH), 125.4 (OCHCHCarCarH), 125.5 (OCH-
CHCarCarHCarHCarH), 128.8 (2 C, CarHCarHCarHCarHCarH), 129.3
(OCHCHCarCarHCarHCarHCarH), 130.5 (2 C, CarHCarHCarHCarHCarH),
130.8 (OCHCHCarCarHCarH), 133.5 (CarHCarHCarHCarHCarH), 135.7
(OCHCHCar), 137.2 (OCHCHCarCarCO), 138.2 (OCHCHCarCarCOCar),
J
J
(470 MHz, CDCl3):
d
ꢀ116.7, ꢀ116.9 ppm.
M (C25H29F2NO3)
429.51. MS (CI, CH5+) m/z (%): 430 (64, [M+H]+), 184 (100), 170
(67). HRMS (EI+): M+ calcd for C25H29F2NO3 429.2116; found:
429.2151.
150.1 (OCHCH), 174.3 (COOEt), 198.7 (ArCOAr) ppm.
M
(C25H29NO4) 407.51. MS (CI, CH5+) m/z (%): 408 (100, [M+H]+),
Compound (Z)-23a: 49.1 mg (4%). Colorless oil. 1H NMR
(500 MHz, CDCl3): d 1.23 (t, J = 7.0 Hz, 3H, CH3), 1.45 (dq, J = 11.7/
3.6 Hz, 1H, NCH2CH2CH2,ax), 1.51–1.62 (m, 1H, NCH2CH2,axCH2),
1.71 (dt, J = 13.0/3.6 Hz, 1H, NCH2CH2,eqCH2), 1.91–1.94 (m, 1H,
NCH2CH2CH2,eq), 2.13 (td, J = 10.9/2.8 Hz, 1H, NCH2,axCH2CH2),
2.31 (t, J = 10.8 Hz, 1H, NCH2,axCH), 2.55 (tt, J = 10.5/3.9 Hz, 1H,
NCH2CH), 2.69 (t, J = 5.8 Hz, 2H, NCH2CH2O), 2.78 (dbr, J = 11.0 Hz,
1H, NCH2,eqCH2CH2), 3.01 (dbr, J = 10.0 Hz, 1H, NCH2,eqCH), 3.95 (s,
2H, ArCH2Ar), 3.99 (t, J = 6.0 Hz, 2H, NCH2CH2O), 4.11 (qd, J = 7.1/
1.3 Hz, 2H, CH2CH3), 5.21 (d, J = 7.0 Hz, 1H, OCHCH), 6.18 (d,
J = 7.5 Hz, 1H, OCHCH), 6.74 (dd, J = 9.8/2.8 Hz, 1H, OCH-
CHCCHarCHarCFCHar), 6.90 (td, J = 8.5/2.5 Hz, 1H, OCH-
CHCCHarCHar), 6.96 (t, J = 8.8 Hz, 2H, CHarCHarCFCHarCHar), 7.06
(dd, J = 8.3/5.8 Hz, 2H, CHarCHarCFCHarCHar), 7.94 (dd, J = 8.8/
184 (34), 170 (11), 83 (29), 79 (21). HRMS (EI+): M+ calcd for
C
25H29NO4 407.2097; found: 407.2088.
Compound (Z)-22g: 135 mg (11%). Colorless oil. 1H NMR
(500 MHz, CD2Cl2): d 1.20 (t, J = 7.3 Hz, 3H, CH3), 1.42, (qd,
J = 11.8/3.7 Hz, 1H, NCH2CH2CH2,ax), 1.48–1.58 (m, 1H,
NCH2CH2,axCH2), 1.64–1.73 (m, 1H, NCH2CH2,eqCH2), 1.84–1.91
(m, 1H, NCH2CH2CH2,eq), 2.10 (td, J = 10.9/2.7 Hz, 1H,
NCH2,axCH2CH2), 2.27 (t, J = 10.5 Hz, 1H, NCH2,axCH), 2.51 (tt,
J = 10.3/4.0 Hz, 1H, NCH2CH), 2.56–2.66 (m, 2H, NCH2CH2O), 2.73
(dbr, J = 11.0 Hz, 1H, NCH2,eqCH2CH2), 2.96 (dbr, J = 9.0 Hz, 1H,
NCH2,eqCH), 3.93 (t, J = 5,8 Hz, 2H, NCH2CH2O), 4.02–4.13 (m, 2H,
CH2CH3), 5.21 (d, J = 7.0 Hz, 1H, OCHCH), 6.15 (d, J = 7.5 Hz, 1H,
OCHCH), 7.20 (td, J = 7.5/1.0 Hz, 1H, OCHCHCCHarCHarCHar), 7.25
(dd, J = 7.5/1.5 Hz, 1H, OCHCHCCHarCHarCHarCHar), 7.41–7.47 (m,
3H, OCHCHCCHarCHar und CHarCHarCHarCHarCHar), 7.58 (tt, J = 7.5/
1.5 Hz, 1H, CHarCHarCHarCHarCHar), 7.76–7.80 (m, 2H, CHarCHarCH-
arCHarCHar), 8.11 (d, J = 8.0 Hz, 1H, OCHCHCCHar) ppm. 13C NMR
(100 MHz, CD2Cl2): d 14.54 (CH3), 25.17 (NCH2CH2CH2), 27.26
(NCH2CH2CH2), 42.41 (NCH2CH), 54.58 (NCH2CH2CH2), 56.39
(NCH2CH), 58.32 (NCH2CH2O), 60.72 (CH2CH3), 71.92 (NCH2CH2O),
102.4 (OCHCH), 125.5 (OCHCHCarCarHCarHCarH), 128.5 (OCH-
CHCarCarHCarHCarHCarH), 128.9 (2 C, CarHCarHCarHCarHCarH), 130.1
(OCHCHCarCarH), 130.4 (OCHCHCarCarHCarH), 130.7 (2 C, CarHCarH-
CarHCarHCarH), 133.6 (CarHCarHCarHCarHCarH), 134.6 (OCHCHCar),
137.8 (OCHCHCarCarCO), 138.3 (OCHCHCarCarCOCar), 148.5
(OCHCH), 174.4 (COOEt), 198.8 (ArCOAr) ppm. M (C25H29NO4)
407.51. MS (CI, CH5+) m/z (%): 408 (100, [M+H]+), 184 (32), 170
(16). HRMS (EI+): M+ calcd for C25H29NO4 407.2097; found:
407.2105.
v
6.3 Hz, 1H, OCHCHCCHar) ppm. (125 MHz, CDCl3): d 14.20 (CH3),
24.62 (NCH2CH2CH2), 26.71 (NCH2CH2CH2), 38.49 (ArCH2Ar),
41.88 (NCH2CH), 54.13 (NCH2CH2CH2), 55.82 (NCH2CH), 57.82
(NCH2CH2O), 60.36 (CH2CH3), 71.27 (NCH2CH2O), 101.5 (OCHCH),
113.1 (d, JCF = 20.7 Hz, OCHCHCarCarHCarH), 115.3 (d, JCF = 21.3 Hz,
2
C, CarHCarHCarFCarHCarH), 116.5 (d, JCF = 21.5 Hz, OCH-
CHCarCarHCarHCarFCarH), 130.1 (d, JCF = 7.88 Hz, 2 C, CarHCarHCarF-
CarHCarH), 130.2 (d, JCF = 3.33 Hz, OCHCHCar), 131.1 (d,
J
CF = 7.78 Hz, OCHCHCarCarH), 135.5 (d, JCF = 3.13 Hz, OCH-
CHCarCarCH2Car), 139.2 (d, JCF = 6.87 Hz, OCHCHCarCarCH2), 146.6
(OCHCH), 160.9 (d, JCF = 246 Hz, OCHCHCarCarHCarHCarF), 161.4 (d,
J
CF = 245 Hz, CarHCarHCarFCarHCarH), 174.1 (COOEt) ppm. 19F NMR
(470 MHz): d ꢀ116.1, ꢀ117.1 ppm. M (C25H29F2NO3) 429.51. MS
(CI, CH5+) m/z (%): 430 (100, [M+H]+), 184 (36), 170 (44). HRMS
(EI+): M+ calcd for C25H29F2NO3 429.2116; found: 429.2108.
C25H29F2NO3 (429.51): calcd C 69.91, H 6.81, N 3.26; found: C
68.67, H 6.40, N 2.96.
4.1.7. General procedure for the ester hydrolysis (GP6)
The ethyl ester (22a–g, 23a, 23c–g, 1.0 equiv) was dissolved in
EtOH and cooled to 0 °C. An excess of 12 M NaOH or 2.0 M LiOH
(6.0–10 equiv) was added dropwise at this temperature. After the
reaction was complete (TLC), the solution was diluted with CH2Cl2
and phosphate buffer (0.4 M, pH 6.0) was added until a clear solu-
tion with a pH of 6.0 was obtained. The aqueous layer was ex-
tracted with CH2Cl2 several times, the combined organic layers
were dried with MgSO4 and the solvent was removed in vacuo to
give the pure neutral form of the desired carboxylic acid.
4.1.6.3. Ethyl 1-(2-{2-[2-benzoylphenyl]vinyloxy}ethyl) nipeco-
tate (22g).
According to GP5 (method C) using 10g (924 mg,
0.57 mL, 3.00 mmol) in DMF (12.0 mL), 20 (1.36 g, 6.00 mmol)
Pd(OAc)2 (67.3 mg, 0.300 mmol), NaOAc (295 mg, 3.60 mmol),
K2CO3 (498 mg, 3.60 mmol), LiCl (254 mg, 6.00 mmol), and H2O
(1.32 mL). The crude product was purified via FCC (cyclohexane/
MTBE = 2.5:1 + 1% NEt3) to yield 22g (1.02 g, 83%) as (E)/(Z)-mix-
ture. The isomers were separated by FCC (Et2O + 1% NEt3).
Compound (E)-22g: 291 mg (24%). Colorless oil. 1H NMR
(500 MHz, CD2Cl2):
d
1.21 (t, J = 7.3 Hz, 3H, CH3), 1.40 (qd,
4.1.7.1. 1-(2-{(E)-2-[4-Fluoro-2-(4-fluorobenzoyl)phenyl]vinyl-
J = 11.8/3.8 Hz, 1H, NCH2CH2CH2,ax), 1.46–1.57 (m, 1H,
NCH2CH2,axCH2), 1.63–1.70 (m, 1H, NCH2CH2,eqCH2), 1.84–1.91
(m, 1H, NCH2CH2CH2,eq), 2.01 (td, J = 11.0/2.5 Hz, 1H,
NCH2,axCH2CH2), 2.17 (t, J = 10.5 Hz, 1H, NCH2,axCH), 2.49 (tt,
J = 10.3/3.8 Hz, 1H, NCH2CH), 2.52–2.60 (m, 2H, NCH2CH2O), 2.69
(dbr, J = 11.0 Hz, 1H, NCH2,eqCH2CH2), 2.90 (dbr, J = 8.0 Hz, 1H,
NCH2,eqCH), 3.73 (t, J = 5.5 Hz, 2H, NCH2CH2O), 4.08 (q, J = 7.0 Hz,
2H, CH2CH3), 5.85 (d, J = 13.0 Hz, 1H, OCHCH), 6.92 (d, J = 12.5 Hz,
oxy}ethyl)nipecotic acid ((E)-7a).
According to GP6 with
(E)-22a (40.0 mg, 0.090 mmol) and 12 M NaOH (0.080 mL,
0.900 mmol) in EtOH (0.500 mL). The reaction time was 1 h.
Compound (E)-7a: 35.7 mg (96%). Colorless oil. 1H NMR
(500 MHz, CD2Cl2): d 1.58–1.69 (m, 2H, NCH2CH2,axCH2,ax), 1.70–
1.82 (m, 1H, NCH2CH2,eqCH2), 1.83–1.93 (m, 1H, NCH2CH2CH2,eq),
2.30–2.41 (m, 1H, NCH2,axCH2CH2), 2.42–2.54 (m, 1H, NCH2,axCH),
2.59–2.65 (m, 1H, NCH2CH), 2.74 (t, J = 5.3 Hz, 2H, NCH2CH2O),
2.82–2.92 (m, 1H, NCH2,eqCH2CH2), 2.93–3.03 (m, 1H, NCH2,eqCH),
3.80 (t, J = 5.3 Hz, 2H, NCH2CH2O), 5.79 (d, J = 12.5 Hz, 1H, OCHCH),
6.84 (d, J = 13.0 Hz, 1H, OCHCH), 7.03 (dd, J = 8.8/2.8 Hz, 1H, COC-
CHarCF), 7.15 (t, J = 8.8 Hz, 2H, CHarCHarCFCHarCHar), 7.13–7.18
(m, 1H, OCHCHCCHarCHar), 7.44 (dd, J = 8.8/5.3 Hz, 1H, OCH-
CHCCHarCHar), 7.80 (dd, J = 9.0/5.5 Hz, 2H, CHarCHarCFCHarCHar)
ppm. 13C NMR (125 MHz, CD2Cl2): d 22.72 (NCH2CH2CH2), 26.78
(NCH2CH2CH2), 40.85 (NCH2CH), 53.75 (NCH2CH2CH2), 55.49
(NCH2CH), 56.58 (NCH2CH2O), 66.26 (NCH2CH2O), 103.7 (OCHCH),
1H,
CHCCHarCHarCHarCHar), 7.30 (dd, J = 8.0/1.5 Hz, 1H, OCH-
CHCCHarCHarCHarCHar), 7.41 (td, J = 7.6/1.3 Hz, 1H,
OCHCH),
7.22
(td,
J = 7.4/1.3 Hz,
1H,
OCH-
OCHCHCCHarCHarCHarCHar), 7.44–7.48 (m, 3H, OCHCHCCHar and
CHarCHarCHarCHarCHar), 7.58 (tt, J = 7.5/1.5 Hz, 1H, CHarCHarCH-
arCHarCHar), 7.74–7.77 (m, 2H, CHarCHarCHarCHarCHar) ppm. 13C
NMR (100 MHz, CD2Cl2): d 14.42 (CH3), 24.99 (NCH2CH2CH2),
21.18 (NCH2CH2CH2), 42.23 (NCH2CH), 54.35 (NCH2CH2CH2),
56.17 (NCH2CH), 57.72 (NCH2CH2O), 60.58 (CH2CH3), 67.84

3376
G. Quandt et al. / Bioorg. Med. Chem. 21 (2013) 3363–3378
115.9 (d, JCF = 22.8 Hz, COCarCarHCarF), 116.2 (d, JCF = 22.0 Hz, 2 C,
CarHCarHCarFCarHCarH), 118.2 (d, JCF = 21.4 Hz, OCHCHCarCarHCarH),
128.0 (d, JCF = 7.38 Hz, OCHCHCarCarHCarH), 131.6 (d, JCF = 3.38 Hz,
OCHCHCar), 133.4 (d, JCF = 9.50 Hz, 2 C, CarHCarHCarFCarHCarH),
134.1 (d, JCF = 2.88 Hz, COCarCarHCarHCarF),138.5 (d, JCF = 5.75 Hz,
OCHCHCarCarCO), 149.5 (OCHCH), 161.0 (d, JCF = 245 Hz, CHCarCarH-
CarF), 166.5 (d, JCF = 254 Hz, CarHCarHCarFCarHCarH), 176.5 (COOH),
195.7 (ArCOAr) ppm. 19F NMR (470 MHz, CD2Cl2): d ꢀ105.0,
ꢀ116.9 ppm. M (C23H23F2NO4) 415.44. MS (CI, CH5+) m/z (%): 416
(21, [M+H]+), 156 (20), 142 (100). HRMS (EI+): M+ calcd for
CarFCarHCarHCarH), 130.4 (d, JCF = 3.50 Hz, OCHCHCar), 130.7 (d,
CF = 7.63 Hz, CarHCarFCarHCarHCarH), 132.2 (d, JCF = 7.38 Hz, OCH-
CHCarCarH), 138.7 (d, JCF = 5.88 Hz, OCHCHCarCarCO), 139.6 (d,
J
J
CF = 6.25 Hz, OCHCHCarCarCOCar), 147.3 (OCHCH), 160.4 (d,
CF = 246 Hz, OCHCHCarCarHCarHCarF), 163.1 (d, JCF = 246 Hz, CarH-
J
CarFCarHCarHCarH), 176.6 (COOH), 195.8 (ArCOAr) ppm. 19F NMR
(470 MHz, CD2Cl2):
d
ꢀ112.6, ꢀ116.0 ppm.
M (C23H23F2NO4)
415.44. MS (CI, CH5+) m/z (%): 416 (100, [M+H]+), 261 (22), 247
(23), 174 (69), 156 (85), 142 (61), 130 (29). HRMS (EI+): M+ calcd
for C23H23F2NO4 415.1595; found: 415.1583.
C23H23F2NO4 415.1595; found: 415.1591.
4.1.7.4. 1-(2-{(Z)-2-[4-Fluoro-2-(2-fluorobenzoyl)phenyl]vinyl-
4.1.7.2. 1-(2-{(Z)-2-[4-Fluoro-2-(4-fluorobenzoyl)phenyl]vinyl-
oxy}ethyl)nipecotic acid ((Z)-7a). According to GP6 with
oxy}ethyl)nipecotic acid ((Z)-7c).
According to GP6 with
(Z)-22c (29.3 mg, 0.066 mmol) and 12 M NaOH (0.060 mL,
0.660 mmol) in EtOH (0.500 mL). The reaction time was 1 h.
Compound (Z)-7c: 23.4 mg (85%). Colorless oil. 1H NMR
(500 MHz, CD2Cl2): d 1.58–1.71 (m, 2H, NCH2CH2,axCH2,ax), 1.74–
1.85 (m, 1H, NCH2CH2,eqCH2), 1.85–1.95 (m, 1H, NCH2CH2CH2,eq),
2.32–2.45 (m, 1H, NCH2,axCH2CH2), 2.47–2.59 (m, 1H, NCH2,axCH),
2.62–2.68 (m, 1H, NCH2CH), 2.74–2.88 (m, 2H, NCH2CH2O), 2.89–
3.00 (m, 1H, NCH2,eqCH2CH2), 3.01–3.13 (m, 1H, NCH2,eqCH), 4.04
(t, J = 5.3 Hz, 2H, NCH2CH2O), 5.48 (d, J = 7.5 Hz, 1H, OCHCH), 6.14
(d, J = 7.5 Hz, 1H, OCHCH), 7.04 (dd, J = 9.0/3.0 Hz, 1H, COCCHarCF),
7.13 (ddd, J = 10.6/8.4/1.1 Hz, 1H, CHarCHarCHarCHarCF), 7.19 (td,
J = 8.5/2.8 Hz, 1H, OCHCHCCHarCHar), 7.26 (td, J = 7.8/1.2 Hz, 1H,
CHarCHarCHarCHarCF), 7.57 (dddd, J = 8.4/7.3/5.3/1.9 Hz, 1H,
CHarCHarCHarCHarCF), 7.63 (td, J = 7.5/1.5 Hz, 1H, CHarCHarCHarCH-
arCF), 8.02 (dd, J = 8.8/5.8 Hz, 1H, OCHCHCCHar) ppm. 13C NMR
(125 MHz, CD2Cl2): d 22.62 (NCH2CH2CH2), 26.60 (NCH2CH2CH2),
40.77 (NCH2CH), 53.71 (NCH2CH2CH2), 55.68 (NCH2CH), 57.12
(NCH2CH2O), 70.27 (NCH2CH2O), 102.4 (OCHCH), 115.8 (d,
(Z)-22a (31.3 mg, 0.070 mmol) and 12 M NaOH (0.060 mL,
0.700 mmol) in EtOH (0.500 mL). The reaction time was 30 min.
Compound (Z)-7a: 27.2 mg (94%). Colorless oil. 1H NMR
(500 MHz, CD2Cl2): d 1.58–1.71 (m, 2H, NCH2CH2,axCH2,ax), 1.75–
1.86 (m, 1H, NCH2CH2,eqCH2), 1.89–1.97 (m, 1H, NCH2CH2CH2,eq),
2.33 (t, J = 10.5 Hz, 1H, NCH2,axCH2CH2), 2.47 (d, J = 11.5 Hz, 1H,
NCH2,axCH), 2.63–2.69 (m, 1H, NCH2CH), 2.71–2.83 (m, 2H,
NCH2CH2O), 2.94–3.03 (m, 1H, NCH2,eqCH2CH2), 3.05–3.13 (m,
1H, NCH2,eqCH), 3.96–4.06 (m, 2H, NCH2CH2O), 5.18 (d, J = 7.0 Hz,
1H, OCHCH), 6.11 (d, J = 7.0 Hz, 1H, OCHCH), 6.98 (dd, J = 8.8/
2.8 Hz, 1H, COCCHarCF), 7.15 (t, J = 8.8 Hz, 2H, CHarCHarCFCHarCHar),
7.19 (td, J = 8.9/3.0 Hz, 1H, COCCHarCFCHar), 7.83 (dd, J = 9.0/5.5 Hz,
2H, CHarCHarCFCHarCHar), 8.07 (dd, J = 8.8/5.8 Hz, 1H, OCHCHCCHar)
ppm. 13C NMR (125 MHz, CD2Cl2): d 22.72 (NCH2CH2CH2), 26.79
(NCH2CH2CH2), 40.88 (NCH2CH), 53.82 (NCH2CH2CH2), 55.79
(NCH2CH), 57.26 (NCH2CH2O), 70.40 (NCH2CH2O), 102.5 (OCHCH),
115.2 (d, JCF = 22.8 Hz, COCarCarHCarF), 116.2 (d, JCF = 22.0 Hz, 2 C,
CarHCarHCarFCarHCarH), 117.5 (d, JCF = 20.8 Hz, COCarCarHCarFCarH),
130.3 (d, JCF = 3.38 Hz, OCHCHCar), 132.3 (d, JCF = 7.50 Hz, OCH-
CHCarCarH), 133.5 (d, JCF = 9.50 Hz, 2 C, CarHCarHCarFCarHCarH),
134.1 (d, JCF = 2.75 Hz, OCHCHCarCarCOCar), 139.3 (d, JCF = 5.75 Hz,
OCHCHCarCarCO), 147.3 (OCHCH), 160.6 (d, JCF = 246 Hz, COCarCarH-
CarF), 166.5 (d, JCF = 254 Hz, CarHCarHCarFCarHCarH), 175.4 (COOH),
J
CF = 22.8 Hz, COCarCarHCarF), 117.0 (d, JCF = 21.9 Hz, CarHCarHCarH-
CarHCarF), 118.2 (d, JCF = 21.0 Hz, OCHCHCarCarHCarH), 124.8 (d,
CF = 3.63 Hz, CarHCarHCarHCarHCarF), 127.2 (d, JCF = 11.1 Hz, COCar-
J
CarF), 130.6 (d, JCF = 3.38 Hz, OCHCHCar), 132.1 (d, JCF = 1.75 Hz,
CarHCarHCarHCarHCarF), 132.4 (d, JCF = 7.25 Hz, OCHCHCarCarH),
135.1 (d,
J
CF = 8.75 Hz, CarHCarHCarHCarHCarF), 139.6 (d,
CF = 6.13 Hz, OCHCHCarCarCO), 147.2 (OCHCH), 160.5 (d,
CF = 245 Hz, COCarCarHCarF), 161.6 (d, JCF = 255 Hz, CarHCarHCarH-
195.8 (ArCOAr) ppm. 19F NMR (470 MHz, CD2Cl2):
d
ꢀ105.1,
J
J
ꢀ116.0 ppm. M (C23H23F2NO4) 415.44. MS (CI, CH5+) m/z (%): 416
(23, [M+H]+), 201 (16), 156 (33), 142 (100), 123 (24). HRMS
(EI+): M+ calcd for C23H23F2NO4 415.1595; found: 415.1595.
CarHCarF), 176.3 (COOH), 194.0 (ArCOAr) ppm. 19F NMR
(470 MHz, CD2Cl2):
d
ꢀ111.0, ꢀ116.2 ppm.
M (C23H23F2NO4)
415.44. MS (CI, CH5+) m/z (%): 416 (100, [M+H]+), 261 (16), 247
(14), 174 (27), 156 (75), 142 (31), 130 (12). HRMS (EI+): M+ calcd
for C23H23F2NO4 415.1595; found: 415.1582.
4.1.7.3. 1-(2-{(Z)-2-[4-Fluoro-2-(3-fluorobenzoyl)phenyl]vinyl-
oxy}ethyl)nipecotic acid ((Z)-7b).
According to GP6 with
(Z)-22b (33.3 mg, 0.075 mmol) and 12 M NaOH (0.060 mL,
0.750 mmol) in abs EtOH (0.500 mL). The reaction time was 1.5 h.
Compound (Z)-7b: 27.8 mg (89%). Colorless oil. 1H NMR
(500 MHz, CD2Cl2): d 1.59–1.70 (m, 2H, NCH2CH2,axCH2,ax), 1.72–
1.84 (m, 1H, NCH2CH2,eqCH2), 1.84–1.93 (m, 1H, NCH2CH2CH2,eq),
2.31–2.43 (m, 1H, NCH2,axCH2CH2), 2.48–2.58 (m, 1H, NCH2,axCH),
2.60–2.67 (m, 1H, NCH2CH), 2.70–2.83 (m, 2H, NCH2CH2O), 2.84–
2.96 (m, 1H, NCH2,eqCH2CH2), 2.96–3.08 (m, 1H, NCH2,eqCH), 4.00
(t, J = 5.3 Hz, 2H, NCH2CH2O), 5,20 (d, J = 7.0 Hz, 1H, OCHCH), 6.13
(d, J = 7.0 Hz, 1H, OCHCH), 6.99 (dd, J = 8.8/2.8 Hz, 1H, OCH-
CHCCHarCHarCFCHar), 7.20 (td, J = 8.5/3.0 Hz, 1H, OCH-
4.1.7.5. 1-(2-{(Z)-2-[4-Fluoro-2-(4-fluorobenzyl)phenyl]vinyl-
oxy}ethyl)nipecotic acid ((Z)-8a).
According to GP6 with
(Z)-23a (32.2 mg, 0.075 mmol) and 12 M NaOH (0.060 mL,
0.700 mmol) in abs EtOH (0.500 mL). The reaction time was 4 h.
Compound (Z)-8a: 33.4 mg (99%). Colorless oil. 1H NMR
(500 MHz, CD2Cl2): d 1.49–1.62 (m, 2H, NCH2CH2,axCH2,ax), 1.64–
1.76 (m, 1H, NCH2CH2,eqCH2), 1.77–1.86 (m, 1H, NCH2CH2CH2,eq),
2.23–2.36 (m, 1H, NCH2,axCH2CH2), 2.38–2.48 (m, 1H, NCH2,axCH),
2.54–2.59 (m, 1H, NCH2CH), 2.68–2.79 (m, 2H, NCH2CH2O), 2.81–
2.93 (m, 1H, NCH2,eqCH2CH2), 2.94–3.05 (m, 1H, NCH2,eqCH), 3.88
(s, 2H, ArCH2Ar), 3.96 (t, J = 5.3 Hz, 2H, NCH2CH2O), 5.22 (d,
J = 7.5 Hz, 1H, OCHCH), 6.10 (d, J = 7.5 Hz, 1H, OCHCH), 6.70 (dd,
J = 10.0/3.0 Hz, 1H, CH2CCHarCF), 6.84 (td, J = 8.6/2.8 Hz, 1H, OCH-
CHCCHarCHar), 6.89 (t, J = 8.8 Hz, 2H, CHarCHarCFCHarCHar), 7.01
(dd, J = 8.5/5.5 Hz, 2H, CHarCHarCFCHarCHar), 7.81 (dd, J = 8.5/
6.0 Hz, 1H, OCHCHCCHar) ppm. 13C NMR (125 MHz, CD2Cl2): d
22.74 (NCH2CH2CH2), 26.73 (NCH2CH2CH2), 38.91 (ArCH2Ar),
40.91 (NCH2CH), 53.90 (NCH2CH2CH2), 55.82 (NCH2CH), 57.33
(NCH2CH2O), 70.29 (NCH2CH2O), 102.7 (OCHCH), 113.6 (d,
CHCCHarCHar),
7.31
(tdd,
J = 8.3/2.8/1.1 Hz,
1H,
CHarCFCHarCHarCHar), 7.45 (td, J = 8.0/5.5 Hz, 1H, CHarCFCHarCH-
arCHar), 7.51 (ddd, J = 9.5/2.5/1.5 Hz, 1H, CHarCFCHarCHarCHar),
7.55 (dt, J = 8.0/1.4 Hz, 1H, CHarCFCHarCHarCHar), 8.05 (dd, J = 8.8/
5.8 Hz, 1H, OCHCHCCHar) ppm. 13C NMR (125 MHz, CD2Cl2): d
22.74 (NCH2CH2CH2), 26.68 (NCH2CH2CH2), 40.93 (NCH2CH),
53.74 (NCH2CH2CH2), 55.76 (NCH2CH), 57.15 (NCH2CH2O), 70.32
(NCH2CH2O), 102.3 (OCHCH), 115.2 (d, JCF = 22.9 Hz, OCH-
CHCarCarHCarHCarFCarH), 116.8 (d, JCF = 22.3 Hz, CarHCarFCarHCarH-
CarH), 117.7 (d, JCF = 20.9 Hz, OCHCHCarCarHCarH), 120.8 (d,
JCF = 20.6 Hz, OCHCHCarCarHCarH), 115.7 (d, JCF = 21.1 Hz, 2 C, CarH-
JCF = 21.5 Hz, CarHCarFCarHCarHCarH), 126.7 (d, JCF = 2.88 Hz, CarH-
CarHCarFCarHCarH), 116.9 (d, JCF = 21.4 Hz, CH2CarCarHCarF), 130.5 (d,

G. Quandt et al. / Bioorg. Med. Chem. 21 (2013) 3363–3378
3377
JCF = 3.00 Hz, OCHCHCar), 130.7 (d, JCF = 7.88 Hz, 2 C, CarHCarHCarF-
CarHCarH), 131.9 (d, JCF = 7.75 Hz, OCHCHCarCarH), 136.4 (d,
JCF = 7.80 Hz, 2 C, CarHCarHCarFCarHCarH), 131.8 (d, JCF = 8.30 Hz,
OCHCHCarCarHCarFCarHCarH), 133.3 (d, JCF = 2.90 Hz, OCH-
CHCarCarCH2), 136.1 (d, JCF = 8.70 Hz, OCHCHCar), 136.9 (d,
J
CF = 3.13 Hz, CH2CarCarHCarHCarF), 140.3 (d, JCF = 7.00 Hz, OCH-
CHCarCarCH2), 146.5 (OCHCH), 161.5 (d, JCF = 243 Hz, CH2CarCarH-
CarF), 161.9 (d, JCF = 242 Hz, CarHCarHCarFCarHCarH), 176.5 (COOH)
ppm. 19F NMR (470 MHz, CD2Cl2): d ꢀ112.2, ꢀ113.5 ppm. M
(C23H25F2NO3) 401.46. MS (CI, CH5+) m/z (%): 402 (100, [M+H]+),
156 (58), 142 (53). HRMS (EI+): M+ calcd for C23H25F2NO3
401.1803; found: 401.1806.
J
CF = 2.90 Hz, OCHCHCarCarCH2Car), 147.6 (OCHCH), 161.7 (d,
CF = 242 Hz, CarHCarHCarFCarHCarH), 161.8 (d, JCF = 241 Hz, OCH-
J
CHCarCarHCarF), 176.3 (COOH) ppm. 19F NMR (470 MHz, CD2Cl2):
d 117.2, ꢀ118.1 ppm. M (C23H25F2NO3) 401.46. MS (CI, CH5+) m/z
(%): 402 (100, [M+H]+), 174 (53), 156 (42), 142 (47). HRMS (EI+):
M+ calcd for C23H25F2NO3 401.1803; found: 401.1803.
4.1.7.6. 1-(2-{(Z)-2-[4-Fluoro-2-(2-fluorobenzyl)phenyl]vinyl-
4.1.7.8. 1-(2-{(Z)-2-[5-Fluoro-2-(3-fluorobenzyl)phenyl]vinyl-
oxy}ethyl)nipecotic acid ((Z)-8c).
According to GP6 with
oxy}ethyl)nipecotic acid ((Z)-8e).
According to GP6 with
(Z)-23c (29.0 mg, 0.070 mmol) and 12 M NaOH (0.060 mL,
0.720 mmol) in EtOH (0.500 mL). The reaction time was 2 h.
Compound (Z)-8c: 24.8 mg (88%). Colorless oil. 1H NMR
(500 MHz, CD2Cl2): d 1.49–1.63 (m, 2H, NCH2CH2,axCH2,ax), 1.66–
1.78 (m, 1H, NCH2CH2,eqCH2), 1.79–1.88 (m, 1H, NCH2CH2CH2,eq),
2.24–2.34 (m, 1H, NCH2,axCH2CH2), 2.36–2.48 (m, 1H, NCH2,axCH),
2.54–2.60 (m, 1H, NCH2CH), 2.68–2.81 (m, 2H, NCH2CH2O), 2.84–
2.96 (m, 1H, NCH2,eqCH2CH2), 2.98–3.09 (m, 1H, NCH2,eqCH), 3.92
(s, 2H, ArCH2Ar), 3.97 (t, J = 5.3 Hz, 2H, NCH2CH2O), 5.26 (d,
J = 7.0 Hz, 1H, OCHCH), 6.13 (d, J = 7.5 Hz, 1H, OCHCH), 6.68 (dd,
J = 9.8/2.8 Hz, 1H, CH2CCHarCF), 6.85 (td, J = 8.5/3.0 Hz, 1H, OCH-
CHCCHarCHar), 6.91 (td, J = 7.8/2.0 Hz, 1H, CHarCHarCHarCHarCF),
6.97 (td, J = 7.4/1.2 Hz, 1H, CHarCHarCHarCHarCF), 6.98 (ddd,
J = 9.9/8.4/1.4 Hz, 1H, CHarCHarCHarCHarCF), 7.11–7.17 (m, 1H,
CHarCHarCHarCHarCF), 7.80 (dd, J = 8.8/6.3 Hz, 1H, OCHCHCCHar)
ppm. 13C NMR (125 MHz, CD2Cl2): d 22.67 (NCH2CH2CH2), 26.73
(NCH2CH2CH2), 32.48 (dd, JCF = 3.5/1.5 Hz, ArCH2Ar), 40.86
(NCH2CH), 53.89 (NCH2CH2CH2), 55.80 (NCH2CH), 57.19
(NCH2CH2O), 70.29 (NCH2CH2O), 102.7 (OCHCH), 113.6 (d,
(Z)-23e (13.0 mg, 0.030 mmol) and 12 M NaOH (0.030 mL,
0.300 mmol) in EtOH (0.500 mL). The reaction time was 1.5 h.
Compound (Z)-8e: 10.5 mg (87%). Colorless oil. 1H NMR
(500 MHz, CD2Cl2): d 1.56–1.71 (m, 2H, NCH2CH2,axCH2,ax), 1.75–
1.86 (m, 1H, NCH2CH2,eqCH2), 1.89–1.97 (m, 1H, NCH2CH2CH2,eq),
2.32–2.41 (m, 1H, NCH2,axCH2CH2), 2.45–2.52 (m, 1H, NCH2,axCH),
2.62–2.68 (m, 1H, NCH2CH), 2.81–2.86 (m, 2H, NCH2CH2O), 2.97–
3.06 (m, 1H, NCH2,eqCH2CH2), 3.07–3.16 (m, 1H, NCH2,eqCH), 3.99
(s, 2H, ArCH2Ar), 4.02–4.12 (m, 2H, NCH2CH2O), 5.30 (dd, J = 7.3/
1.3 Hz, 1H, OCHCH), 6.23 (d, J = 7.0 Hz, 1H, OCHCH), 6.76–6.80
(m, 1H, CHarCFCHarCHarCHar), 6.85 (td, J = 8.3/2.8 Hz, 1H, OCH-
CHCCHarCFCHar), 6.88 (td, J = 8.3/3.0 Hz, 1H, CHarCFCHarCHarCHar),
6.90–6.93 (m, 1H, CHarCFCHarCHarCHar), 7.09 (dd, J = 8.3/6.3 Hz,
1H, OCHCHCCHarCFCHarCHar), 7.24 (td, J = 8.0/6.0 Hz, 1H, CHarCF-
CHarCHarCHar), 7.69 (dd, J = 11.0/3.0 Hz, 1H, OCHCHCCHar) ppm.
13C NMR (125 MHz, CD2Cl2):
d 22.53 (NCH2CH2CH2), 26.61
(NCH2CH2CH2), 38.74 (ArCH2Ar), 40.72 (NCH2CH), 53.91
(NCH2CH2CH2), 55.61 (NCH2CH), 57.17 (NCH2CH2O), 70.66
(NCH2CH2O), 102.6 (d, JCF = 2.13 Hz, OCHCH), 113.2 (d,
J
CF = 20.6 Hz, OCHCHCarCarHCarH), 115.6 (d, JCF = 21.9 Hz, CarHCarH-
CarHCarHCarF), 116.7 (d, JCF = 21.6 Hz, CH2CarCarHCarF), 124.7 (d,
CF = 3.63 Hz, CarHCarHCarHCarHCarF), 127.3 (d, JCF = 15.6 Hz, CH2Car-
CarF), 128.6 (d, JCF = 7.88 Hz, CarHCarHCarHCarHCarF), 130.6 (d,
CF = 3.13 Hz, OCHCHCar), 131.3 (d, JCF = 4.38 Hz, CarHCarHCarHCarH-
J
CF = 21.2 Hz, 2 C, OCHCHCarCarHCarFCarH and CarHCarFCarHCarH-
CarH), 115.6 (d, JCF = 21.3 Hz, CarHCarFCarHCarHCarH), 116.4 (d,
CF = 22.8 Hz, OCHCHCarCarH), 124.7 (d, JCF = 2.63 Hz, CarHCarFCarH-
CarHCarH), 130.2 (d, JCF = 8.25 Hz, CarHCarFCarHCarHCarH), 131.9 (d,
CF = 8.50 Hz, OCHCHCarCarHCarFCarHCarH), 132.7 (d, JCF = 3.00 Hz,
OCHCHCarCarCH2), 136.2 (d, JCF = 8.75 Hz, OCHCHCar), 143.9 (d,
J
J
J
J
CarF), 131.8 (d, JCF = 7.75 Hz, OCHCHCarCarH), 139.1 (d, JCF = 6.63 Hz,
OCHCHCarCarCH2), 146.5 (d, JCF = 1.75 Hz, OCHCH), 161.4 (d,
J
CF = 7.75 Hz, OCHCHCarCarCH2Car), 147.7 (OCHCH), 161.9 (d,
CF = 241 Hz, OCHCHCarCarHCarF), 163.4 (d, JCF = 243 Hz, CarHCarF-
J
CF = 243 Hz, CH2CarCarHCarF), 161.6 (d, JCF = 243 Hz, CarHCarHCarH-
J
CarHCarF), 176.5 (COOH) ppm. 19F NMR (470 MHz, CD2Cl2): d
ꢀ116.5, ꢀ118.1 ppm. M (C23H25F2NO3) 401.46. MS (CI, CH5+) m/z
(%): 402 (41, [M+H]+), 249 (15), 170 (15), 156 (100), 142 (62).
HRMS (EI+): M+ calcd for C23H25F2NO3 401.1803; found: 401.1799.
CarHCarHCarH), 176.2 (COOH) ppm. 19F NMR (470 MHz, CD2Cl2): d
ꢀ114.2, ꢀ117.0 ppm. M (C23H25F2NO3) 401.46. MS (CI, CH5+) m/z
(%): 402 (8, [M+H]+), 145 (13), 127 (12), 109 (11), 85 (81), 83
(100), 79 (25). HRMS (EI+): M+ calcd for C23H25F2NO3 401.1803;
found: 401.1802.
4.1.7.7. 1-(2-{(Z)-2-[5-Fluoro-2-(4-fluorobenzyl)phenyl]vinyl-
oxy}ethyl)nipecotic acid ((Z)-8d).
According to GP6 with
4.1.7.9. 1-(2-{(Z)-2-[5-Fluoro-2-(2-fluorobenzyl)phenyl]vinyl-
(Z)-23d (70.9 mg, 0.165 mmol) and 12 M NaOH (0.140 mL,
1.65 mmol) in EtOH (1.00 mL). The reaction time was 6.5 h.
Compound (Z)-8d: 60.7 mg (92%). Colorless oil. 1H NMR
(400 MHz, CD2Cl2): d 1.58–1.73 (m, 2H, NCH2CH2,axCH2,ax), 1.74–
1.87 (m, 1H, NCH2CH2,eqCH2), 1.87–1.97 (m, 1H, NCH2CH2CH2,eq),
2.34–2.47 (m, 1H, NCH2,axCH2CH2), 2.48–2.59 (m, 1H, NCH2,axCH),
2.62–2.71 (m, 1H, NCH2CH), 2.86 (t, J = 5.6 Hz, 2H, NCH2CH2O),
2.95–3.06 (m, 1H, NCH2,eqCH2CH2), 3.06–3.17 (m, 1H, NCH2,eqCH),
3.96 (s, 2H, ArCH2Ar), 4.08 (t, J = 5.2 Hz, 2H, NCH2CH2O), 5.31 (dd,
J = 7.6/1.6 Hz, 1H, OCHCH), 6.23 (d, J = 7.6 Hz, 1H, OCHCH), 6.84
(td, J = 8.2/2.9 Hz, 1H, OCHCHCCHarCFCHar), 6.96 (t, J = 8.6 Hz, 2H,
CHarCHarCFCHarCHar), 7.06 (dd, J = 8.6/5.8 Hz, 2H, CHarCHarCF-
CHarCHar), 7.07 (dd, J = 8.6/6.2 Hz, 1H, OCHCHCCHarCFCHarCHar),
7.69 (dd, J = 11.2/2.8 Hz, 1H, OCHCHCCHar) ppm. 13C NMR
(100 MHz, CD2Cl2): d 22.53 (NCH2CH2CH2), 26.54 (NCH2CH2CH2),
38.19 (ArCH2Ar), 40.69 (NCH2CH), 53.88 (NCH2CH2CH2), 55.60
(NCH2CH), 57.16 (NCH2CH2O), 70.53 (NCH2CH2O), 102.6 (d,
oxy}ethyl)nipecotic acid ((Z)-8f).
According to GP6 with
(Z)-23f (36.0 mg, 0.084 mmol) and 12 M NaOH (0.100 mL,
1.20 mmol) in EtOH (0.500 mL). The reaction time was 6.5 h.
Compound (Z)-8f: 30.0 mg (89%). Colorless oil. 1H NMR
(500 MHz, CD2Cl2): d 1.57–1.73 (m, 2H, NCH2CH2,axCH2,ax), 1.75–
1.86 (m, 1H, NCH2CH2,eqCH2), 1.87–1.96 (m, 1H, NCH2CH2CH2,eq),
2.37–2.47 (m, 1H, NCH2,axCH2CH2), 2.48–2.58 (m, 1H, NCH2,axCH),
2.64–2.70 (m, 1H, NCH2CH), 2.86 (t, J = 5.3 Hz, 2H, NCH2CH2O),
2.97–3.06 (m, 1H, NCH2,eqCH2CH2), 3.07–3.16 (m, 1H, NCH2,eqCH),
3.99 (s, 2H, ArCH2Ar), 4.09 (t, J = 5.3 Hz, 2H, NCH2CH2O), 5.35 (dd,
J = 7.0/1.0 Hz, 1H, OCHCH), 6.25 (d, J = 7.0 Hz, 1H, OCHCH), 6.83
(td, J = 8.4/2.8 Hz, 1H, CH2CCHarCHarCF), 6.93 (td, J = 7.7/1.8 Hz,
1H, CHarCHarCHarCHarCF), 7.01–7.08 (m, 3H, CH2CCHarCHarCF and
CHarCHarCHarCHarCF), 7.17–7.23 (m, 1H, CHarCHarCHarCHarCF),
7.68 (dd, J = 11.3/2.8 Hz, 1H, OCHCHCCHar) ppm. 13C NMR
(125 MHz, CD2Cl2): d 22.54 (NCH2CH2CH2), 26.57 (NCH2CH2CH2),
31.67 (d,
JCF = 3.38 Hz, ArCH2Ar), 40.71 (NCH2CH), 53.91
J
CF = 2.30 Hz,
CHCarCarHCarFCarH), 115.4 (d, JCF = 21.1 Hz, 2 C, CarHCarHCarFCarH-
CarH), 22.7 (d, JCF 116.3 Hz, OCHCHCarCarH), 130.3 (d,
OCHCH),
113.2
(d,
JCF = 21.3 Hz,
OCH-
(NCH2CH2CH2), 55.60 (NCH2CH), 57.15 (NCH2CH2O), 70.48
(NCH2CH2O), 102.6 (OCHCH), 113.2 (d, JCF = 21.1 Hz, CH2CarCarH-
CarHCarF), 115.4 (d, JCF = 21.9 Hz, CarHCarHCarHCarHCarF), 116.3 (d,
=

3378
G. Quandt et al. / Bioorg. Med. Chem. 21 (2013) 3363–3378
2. Rissman, R. A.; De Blas, A. L.; Armstrong, D. M. J. Neurochem. 2007, 103, 1285.
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5. Guastella, J.; Nelson, N.; Nelson, H.; Czyzyk, L.; Keynan, S.; Miedel, M.;
Davidson, N.; Lester, H.; Kanner, B. Science 1990, 249, 1303.
6. Borden, L. A.; Smith, K. E.; Hartig, P. R.; Branchek, T. A.; Weinshank, R. L. J. Biol.
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8. Madsen, K. K.; White, H. S.; Schousboe, A. Pharmacol. Ther. 2010, 125, 394.
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10. Palacín, M.; Estevéz, R.; Bertran, J.; Antonio, Z. Physiol. Rev. 1998, 78, 969.
11. Zhou, Y.; Holmseth, S.; Guo, C.; Hassel, B.; Höfner, G.; Huitfeldt, H. S.; Wanner,
K. T.; Danbolt, N. C. J. Biol. Chem. 2012, 287, 35733.
JCF = 22.9 Hz, OCHCHCarCarH), 124.5 (d, JCF = 3.50 Hz, CarHCarHCarH-
CarHCarF), 127.9 (d, JCF = 15.6 Hz, CH2CarCarF), 128.3 (d, JCF = 8.00 Hz,
CarHCarHCarHCarHCarF), 131.0 (d, JCF = 4.38 Hz, CarHCarHCarHCarH-
CarF), 131.6 (d, JCF = 8.50 Hz, CH2CarCarHCarHCarF), 132.2 (d,
J
CF = 3.00 Hz, OCHCHCarCarCH2), 136.2 (d, JCF = 8.63 Hz, OCHCHCar),
147.6 (OCHCH), 161.2 (d, CF = 243 Hz, CH2CarCarF), 161.8 (d,
CF = 240 Hz, CH2CarCarHCarHCarF), 176.1 (COOH) ppm. 19F NMR
J
J
(470 MHz, CD2Cl2):
d
ꢀ117.2, ꢀ118.2 ppm.
M (C23H25F2NO3)
401.46. MS (ESI+) m/z (%): 402 ([M+H]+), 424 ([M+Na]+). HRMS
(EI+): M+ calcd for C23H25F2NO3 401.1803; found: 401.1805.
12. Zhou, Y.; Holmseth, S.; Hua, R.; Lehre, A. C.; Olofsson, A. M.; Poblete-Naredo, I.;
Kempson, S. A.; Danbolt, N. C. Am. J. Physiol.-Renal Physiol. 2012, 302, F316.
13. Borden, L. A. Neurochem. Int. 1996, 29, 335.
4.1.7.10. 1-(2-{(Z)-2-[2-Benzylphenyl]vinyloxy}ethyl) nipecotic
acid ((Z)-8g).
According to GP6 with (Z)-23g (32.8 mg,
14. Johnston, G. A. R.; Allan, R. D.; Kennedy, S. M. G.; Twitchin, B. In GABA-
Neurotransmitter: Pharmacochemical, Biochemical and Pharmacological Aspect;
Krogsgaard-Larsen, P., Scheel-Krüger, J., Kofoed, H., Eds.; Munksgaard:
Copenhagen, 1978; pp 147–164.
15. Myers, R. D. In Handbook of Pharmacology; Iversen, L. L., Iversen, S. D., Snyder, S.
H., Eds.; Plenum: New York, 1975; pp 1–28.
16. Borden, L. A.; Dhar, T. G. M.; Smith, K. E.; Weinshank, R. L.; Branchek, T. A.;
Gluchowski, C. Eur. J. Pharm. Mol. Pharmacol. Sect. 1994, 269, 219.
17. Hog, S.; Greenwood, J. R.; Madsen, K. B.; Larsson, O. M.; Frolund, B.; Schousboe,
A.; Krogsgaard-Larsen, P.; Clausen, R. P. Curr. Top. Med. Chem. 2006, 6, 1861.
18. Kragler, A.; Höfner, G.; Wanner, K. T. Eur. J. Med. Chem. 2008, 43, 2404.
19. Andersen, K. E.; Braestrup, C.; Groenwald, F. C.; Joergensen, A. S.; Nielsen, E. B.;
Sonnewald, U.; Soerensen, P. O.; Suzdak, P. D.; Knutsen, L. J. S. J. Med. Chem.
1993, 36, 1716.
20. Andersen, K. E.; Begtrup, M.; Chorghade, M. S.; Lee, E. C.; Lau, J.; Lundt, B. F.;
Petersen, H.; Sørensen, P. O.; Thøgersen, H. Tetrahedron 1994, 50, 8699.
21. Knutsen, L. J. S.; Andersen, K. E.; Lau, J.; Lundt, B. F.; Henry, R. F.; Morton, H. E.;
Nærum, L.; Petersen, H.; Stephensen, H.; Suzdak, P. D.; Swedberg, M. D. B.;
Thomsen, C.; Sørensen, P. O. J. Med. Chem. 1999, 42, 3447.
22. Andersen, K. E.; Sørensen, J. L.; Huusfeldt, P. O.; Knutsen, L. J. S.; Lau, J.; Lundt, B.
F.; Petersen, H.; Suzdak, P. D.; Swedberg, M. D. B. J. Med. Chem. 1999, 42, 4281.
23. Andersen, K. E.; Sørensen, J. L.; Lau, J.; Lundt, B. F.; Petersen, H.; Huusfeldt, P. O.;
Suzdak, P. D.; Swedberg, M. D. B. J. Med. Chem. 2001, 44, 2152.
24. Andersen, K. E.; Lau, J.; Lundt, B. F.; Petersen, H.; Huusfeldt, P. O.; Suzdak, P. D.;
Swedberg, M. D. B. Bioorg. Med. Chem. 2001, 9, 2773.
25. Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-
Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637.
26. Hardegger, L. A.; Kuhn, B.; Spinnler, B.; Anselm, L.; Ecabert, R.; Stihle, M.; Gsell,
B.; Thoma, R.; Diez, J.; Benz, J.; Plancher, J.-M.; Hartmann, G.; Banner, D. W.;
Haap, W.; Diederich, F. Angew. Chem., Int. Ed. 2011, 50, 314.
0.083 mmol) and 12 M NaOH (0.070 mL, 0.830 mmol) in EtOH
(0.500 mL). The reaction time was 3 h.
Compound (Z)-8g: 26.8 mg (88%). Colorless oil. 1H NMR
(400 MHz, CD2Cl2): d 1.55–1.70 (m, 2H, NCH2CH2,axCH2,ax), 1.72–
1.86 (m, 1H, NCH2CH2,eqCH2), 1.86–1.95 (m, 1H, NCH2CH2CH2,eq),
2.31–2.42 (m, 1H, NCH2,axCH2CH2), 2.46–2.56 (m, 1H, NCH2,axCH),
2.59–2.65 (m, 1H, NCH2CH), 2.75–2.89 (m, 2H, NCH2CH2O), 2.90–
3.03 (m, 1H, NCH2,eqCH2CH2), 3.03–3.61 (m, 1H, NCH2,eqCH), 4.01
(s, 2H, ArCH2Ar), 4.04 (t, J = 5.4 Hz, 2H, NCH2CH2O), 5.38 (d,
J = 7.2 Hz, 1H, OCHCH), 6.18 (d, J = 7.2 Hz, 1H, OCHCH), 7.09–7.13
(m, 4H, OCHCHCCHarCHarCHarCHar and CH2CCHarCHarCHarCHarCH-
ar), 7.14–7.22 (m, 2H, OCHCHCCHarCHar and CH2CCHarCHarCHarCH-
arCHar), 7.25 (t, J = 7.4 Hz, 2H, CH2CCHarCHarCHarCHarCHar), 7.90 (d,
J = 7.6 Hz, 1H, OCHCHCCHar) ppm. 13C NMR (100 MHz, CD2Cl2): d
22.58 (NCH2CH2CH2), 26.57 (NCH2CH2CH2), 39.72 (ArCH2Ar),
40.78 (NCH2CH), 53.73 (NCH2CH2CH2), 55.69 (NCH2CH), 57.18
(NCH2CH2O), 70.71 (NCH2CH2O), 103.7 (OCHCH), 126.3 (OCH-
CHCarCarHCarH), 126.6 (CH2CarCarHCarHCarHCarHCarH), 126.7 (OCH-
CHCarCarHCarHCarH), 128.7 (2 C, CH2CarCarHCarHCarHCarHCarH),
129.0 (2 C, CH2CarCarHCarHCarHCarHCarH), 130.1 (OCHCHCarCarH),
130.6 (OCHCHCarCarHCarHCarHCarH), 134.3 (OCHCHCar), 137.8
(OCHCHCarCarCH2), 141.4 (OCHCHCarCarCH2Car), 146.5 (OCHCH),
176.5 (COOH) ppm. M (C23H27NO3) 365.48. MS (CI, CH5+) m/z (%):
366 (100, [M+H]+), 156 (62), 142 (37). HRMS (EI+): M+ calcd for
27. Andersson, C. M.; Larsson, J.; Hallberg, A. J. Org. Chem. 1990, 55, 5757.
28. Larhed, M.; Andersson, C. M.; Hallberg, A. Acta Chem. Scand. 1993, 47, 212.
29. Larhed, M.; Andersson, C. M.; Hallberg, A. Tetrahedron 1994, 50, 285.
30. Nilsson, P.; Larhed, M.; Hallberg, A. J. Am. Chem. Soc. 2001, 123, 8217.
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32. Kaplan, J. P.; Raizon, B. M.; Desarmenien, M.; Feltz, P.; Headley, P. M.; Worms,
P.; Lloyd, K. G.; Bartholini, G. J. Med. Chem. 1980, 23, 702.
C23H27NO3 365.1991; found: 365.1995.
Supplementary data
33. Krause, M.; Rouleau, A.; Stark, H.; Luger, P.; Lipp, R.; Garbarg, M.; Schwartz, J.
C.; Schunack, W. J. Med. Chem. 1995, 38, 4070.
34. Martin, R. Org. Prep. Proced. Int. 1992, 24, 369.
35. Gribble, G. W.; Kelly, W. J.; Emery, S. E. Synthesis 1978, 763.
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Supplementary data (experimental data for 14a-d, 14f–i, 15a-d,
15f, 16a-d, 16f, 10a-d, 10f, 11a–g, 11g, 22b–f, 23c–g, (E)-7b, (E)-7c,
7d-g, (E)-8a, (E)-8c, (E)-8d, (E)-8e, (E)-8f, (E)-8g) associated with
this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.bmc.2013.02.056.
´
37. Clot, E.; Megret, C.; Eisenstein, O.; Perutz, R. N. J. Am. Chem. Soc. 2009, 131,
7817.
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References and notes
1. Treiman, D. M. Epilepsia 2001, 42, 8.