A conformationally restricted GABA analogue based on octahydro-1H-cyclopenta[b]pyridine scaffold

Article abstract of DOI:10.1007/s00726-018-2660-1

An approach to rel-(4aS,6R,7aR)-octahydro-1H-cyclopenta[b]pyridine-6-carboxylic acid—a bicyclic conformationally restricted γ-aminobutyric acid (GABA) analogue was developed. The eight-step sequence relied on the reaction of 2,3-bis(chloromethyl)pyridine and a C₁-binucleophile and the catalytic reduction of the pyridine ring as the key steps and allowed for the preparation of the title compound in 9.0% overall yield. Assessment of the octahydro-1H-cyclopenta[b]pyridine scaffold geometry showed that this template can be considered truly three-dimensional.

Full text of DOI:10.1007/s00726-018-2660-1

Amino Acids
https://doi.org/10.1007/s00726-018-2660-1
ORIGINAL ARTICLE
A conformationally restricted GABA analogue based
on octahydro‑1H‑cyclopenta[b]pyridine scaꢀold
Kostiantyn P. Melnykov1,2 · Dmitriy M. Volochnyuk · Sergey V. Ryabukhin · Eduard B. Rusanov ·
3
2
3
Oleksandr O. Grygorenko1,2
Received: 6 September 2018 / Accepted: 29 September 2018
©
Springer-Verlag GmbH Austria, part of Springer Nature 2018
Abstract
An approach to rel-(4aS,6R,7aR)-octahydro-1H-cyclopenta[b]pyridine-6-carboxylic acid—a bicyclic conformation-
ally restricted γ-aminobutyric acid (GABA) analogue was developed. The eight-step sequence relied on the reaction of
2
,3-bis(chloromethyl)pyridine and a C -binucleophile and the catalytic reduction of the pyridine ring as the key steps and
1
allowed for the preparation of the title compound in 9.0% overall yield. Assessment of the octahydro-1H-cyclopenta[b]
pyridine scaꢀold geometry showed that this template can be considered truly three-dimensional.
Keywords Conformational restriction · Amino acids · Bicyclic compounds · Pyridine · Hydrogenation · GABA analogues
Introduction
Ordóñez 2009; Trabocchi et al. 2008; Sorochinsky et al.
013a, b; Aceña et al. 2014; Fülöp et al. 2006; Kiss et al.
2
Conformational restriction is a tool which is widely used
in diꢀerent areas of chemistry, especially those related to
molecular interactions with biological macromolecules. It
is recognized that conformationally restricted molecules
have advantages with respect to their potency and selectivity
towards biological targets as compared to their ꢁexible coun-
terparts (Mann 2008; Fang et al. 2014). Compounds with
reduced conformational ꢁexibility—analogs of natural com-
pounds are of special interest to bioorganic and medicinal
chemistry, and of these, conformationally restricted amino
acids have attracted most interest over the last two decades
2015; Wang et al. 2017). γ-Aminobutyric acid (GABA, 1),
which is a chief neurotransmitter in mammalian, is an attrac-
tive target for molecular design based on reducing confor-
mational ꢁexibility (Fig. 1) (Ordóñez and Cativiela, 2007).
Conformationally restricted GABA analogues (e.g, 2–4)
were used in the studies of various GABA-related biological
activities such as GABA receptors binding, GABA uptake
or GABA aminotransferase inhibition (Witiak et al. 1986;
Crittenden et al. 2006; Pingsterhaus et al. 1999; Mortensen
et al. 2004; Chebib et al. 2001; Kobayashi et al. 2014).
In this work, we report the synthesis of novel bicyclic
conformationally restricted GABA analogue, octahydro-
1H-cyclopenta[b]pyridine-6-carboxylic acid (5) (Fig. 2).
Notably, derivatives of octahydro-1H-cyclopenta[b]pyridine
have already shown their utility for the design of biologically
relevant molecules, e.g., local anesthetic rodocaine (6) (Van
Bever et al. 1973), bone resorption inhibitor 7 (Szabo et al.
(
Vagner et al. 2008; Janecka and Kruszynski 2005; Komarov
et al. 2004; Gellman 1998; Soloshonok 2002; Cativiela and
Handling Editor: V. Soloshonok.
*
Oleksandr O. Grygorenko
gregor@univ.kiev.ua
2
2
002), nitric oxide synthase inhibitor 8 (Guthikonda et al.
005).
http://www.enamine.net
1
2
3
Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094,
Ukraine
Results and discussion
National Taras Shevchenko University of Kyiv,
Volodymyrska Street, 60, Kyiv 01601, Ukraine
Our approach to the synthesis of 5 commenced from the
dichloride 9, which is known in the literature and can be
prepared from commercially available quinolinic acid (10)
Institute of Organic Chemistry, National Academy
of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660,
Ukraine
Vol.:(0
1
123456789)
3

K. P. Melnykov et al.
O-
O-
in three steps (Scheme 1) (Grimm et al. 2002). Construc-
tion of the cyclopentane ring was expected to proceed via
+
+
H N
+
3
H N
3
O
O
double alkylation of a C -binucleophile with 9. Several
1
2
4
C -binucleophiles 11 were tested for that purpose (Table 1).
1
GABA (1)
O-
Optimization of the reaction conditions showed that using
NaH in DMSO gave the highest yields of the bicyclic
adducts as compared to other systems studied, e.g., NaH—
DMF or EtONa—EtOH. In the latter case, considerable
formation of the products resulting from the side reaction
at the 1:2 ratio of 9 and the corresponding binucleophile
O-
H N
+
2
H N
O
2
O
3
1
Fig. 1 GABA and its conformationally restricted analogues
was observed according to H NMR and LC–MS. Varia-
tion of the structure of C -binucleophile revealed that the
1
yield of the target product 12 depended strongly on the pK
a
O
O
value of the corresponding CH-acid (Bordwell 1988). The
best results were obtained with malonic acid derivatives
O-
N
N
H
N
H
+
(pK = 11–17); the corresponding bicyclic adducts 12c–f
2
Cl
a
5
6
were isolated and characterized.
O
O-
The product 12e obtained from diethyl malonate was sub-
jected to acidic hydrolysis, leading to the carboxylic acid
13 (isolated as a hydrochloride in 90% yield). Surprisingly,
hydrogenation of 13 obtained by this method did not give
reproducible results; the rate of the reaction and the diastere-
omeric ratio varied signiꢂcantly, possibly due to the poison-
ing of the catalyst by traces of sulfur which remained in the
H
P
OH
OH
P
N
+
HN
N
H
O
2
OH
H
H
8
7
Fig. 2 Octahydro-1H-cyclopenta[b]pyridine derivatives
Scheme 1 Synthesis of amino
acid 5
O
O
O
NaBH4
OH
OH
O
O
OH MeOH
OH H SO
CaCl , EtOH
2
2
4
N
N
N
68%
7
2%
O
1
0
98% SOCl
2
−
−
XCH Y
(11)
Cl
2
Cl
O
X
aq HCl
0%
(X = Y =
CO Et)
Cl
Cl
9
Y
NaH,
DMSO
OH
N
N
H
N
H
+
+
1
3
12
see Table 1
9
=
2
2-
C
H
2
, Pd(OH)
MeOH
O
O
O
+
H
2
H
H
O
−
N
C
l
O
H
aq HCl
62%
ArC(O)Cl
−
Et N
3
Cl
H
OH
5
2% (for
N
O
NH2+
2
steps)
17
Ar
1
4
15
1
1c, 12c: X = Y = CN; 11d, 12d: X = CN, Y = CO Et
2
Ar = C H (4-NO )
6
4
2
1
1e, 12e: X = Y = CO Et; 11f, 12f: X = Y = CO iPr
2
2
1
3

A conformationally restricted GABA analogue based on octahydro-1H-cyclopenta[b]pyridine…
Table 1 Reaction of dichloride 9 with C -binucleophiles 11
Analysis of the 1,6-disubstituted octahydro-
H-cyclopenta[b]pyridine scaffold geometry using the
1
1
#
Binucleophile pKa
X
Y
Yield of 12, %
exit vector plot (EVP) tool (Grygorenko et al. 2016, 2018)
(applied to the X-Ray diꢀraction study data for 16) showed
that this bicyclic template can be considered as truly three-
dimensional (Fig. 4). The main idea behind the EVP tool is
based on simulation of the two functional groups attached
to the scaꢀold by exit vectors. Relative spatial orientation
of these vectors is then described by four geometric param-
eters (r, φ , φ , and θ). These parameters can discriminate
1
2
3
4
5
6
7
8
11a
11b
11c
11d
11e
11f
7.3 CH OCMe OCH
9.1 NO2
11.1 CN
13.1 CN
0
2
2
2
a
CO Et 27
2
CN
72
CO Et 68
CO Et 77
CO i-Pr 55
2
15.7 CO Et
2
2
17.3 CO i-Pr
2
2
a
11 g
11e
21.9 CN
Ph
32
1
2
b
15.7 CO Et
CO Et 65
2
2
various spatial arrangements of the exit vectors, i.e., linear
φ /φ ~ 0°), ꢁattened (θ ~ 0/180°), and three-dimensional
(
1
2
Conditions: NaH, DMSO, 50 °C, overnight
a
1
(φ /φ and θ are far from the aforementioned values). In
1 2
Yield by H NMR
b
the case of 16, the corresponding values were r= 3.75 Å,
φ =46°, φ =49°, and θ=134°. These data show that the
DMF was used as the solvent instead of DMSO (see the text)
1
2
title scaꢀold is larger than the common saturated rings [e.g.,
for the compounds 2 ((a) Kaneda et al. 1980; Woll et al.
2001) and 3 (Mora et al. 2005), the corresponding data
points are located in the typical α–ε areas of EVPs] and falls
into the three-dimensional category. It should be noted that
the φ /φ —θ plot (Fig. 4b) demonstrates some geometrical
sample of 13 even after the chromatographic puriꢂcation. We
have used another sample of 13, which was obtained from
the batch of 12 prepared via alkylation of diethyl malonate
by 9 over NaH in DMF instead of DMSO. Although the
yield of 12 prepared by this method was slightly lower
1
2
(
65%), in this case, hydrogenation over Pd(OH) -C was suc-
similarity between the 1,6-disubstituted rel-(4aS,6R,7aR)-
octahydro-1H-cyclopenta[b]pyridine and trans-1,3-disub-
stituted cyclopentane scaꢀolds (in 16 and a peptidomimetic
derived from trans-2, respectively).
2
cessful and gave the corresponding methyl ester 14 as ca.
1
8
5:15 mixture of stereoisomers (according to H NMR). All
attempts to separate this mixture were unfruitful; therefore,
it was used in the next step without characterization. Moreo-
ver, chromatographic separation of the corresponding acetyl,
Boc, and Cbz derivatives also was not successful. We have
then prepared the p-nitrobenzoyl derivative of 14, aiming at
its puriꢂcation by recrystallization. Although the recrystal-
lization was not fruitful, the rel-(4aS,6R,7aR) diastereomer
1
5 could be isolated in a pure form after column chromatog-
raphy (52% yield from 13). Its relative stereochemistry was
established using X-Ray diꢀraction studies with the corre-
sponding carboxylic acid 16, prepared by alkaline hydrolysis
of 15 (Fig. 3). Acidic hydrolysis of 15 gave the target amino
acid hydrochloride 17 in 62% yield.
≡
Fig. 4 Geometric parameters of the 1,6-disubstituted octahydro-
1
H-cyclopenta[b]pyridine scaꢀold shown in a r − θ plot (polar coor-
Fig. 3 ORTEP diagram and molecular structure of the compound 16
dinates); b θ − φ /φ plot. Colored areas correspond to the α–ε areas
1 2
(
thermal ellipsoids are shown at 50% probability level)
of EVPs (see Grygorenko et al. 2018)
1
3

K. P. Melnykov et al.
+
+
Conclusions
70.62, H 4.45, N 25.04. MS (EI): 169 (M ), 168 (M –H),
+
+
1
1
43 (M –CN), 142 (M –HCN). H NMR (500 MHz,
An approach to the synthesis of novel conformation-
ally restricted GABA analogues based on octahydro-
CDCl3) δ 8.56 (d, J=4.2 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H),
7.30–7.25 (dd, J = 7.6, 4.2 Hz, 1H), 3.86 (s, 2H), 3.81 (s,
1
3
1H-cyclopenta[b]pyridine scaꢀold was developed. This amino
2H). C NMR (126 MHz, CDCl3) δ 171.2, 161.1, 148.4,
acid can be used in the studies of various GABA-related bio-
logical activities, and also as a three-dimensional building
block for design of lead-oriented compound libraries in drug
discovery.
133.3, 132.0, 121.7, 41.7, 38.3, 29.6.
Ethyl 6‑cyano‑6,7‑dihydro‑5H‑cyclopenta[b]
pyridine‑6‑carboxylate (12d)
Materials and methods
Yield 64 mg (68%). Yellowish oil. Anal. Calcd. for
C H N O C 66.65, H 5.59, N 12.95. Found C 66.38, H
1
2
12
2
2
+
+
General
5.37, N 13.33. MS (EI): 216 (M ), 189 (M –HCN), 143
+
1
(
M –CO Et). H NMR (500 MHz, DMSO-d ) δ 8.48 (d,
2 6
The solvents were puriꢂed according to the standard proce-
dures. All starting materials were obtained from Enamine
Ltd. Analytical TLC was performed using Polychrom SI
F254 plates. Column chromatography was performed using
Kieselgel Merck 60 (230–400 mesh) as the stationary phase.
J=4.6 Hz, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.29 (dd, J=7.3,
4.6 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.86 (d, J=17.0 Hz,
1H), 3.78 (d, J = 17.0 Hz, 1H), 3.75 (d, J = 15.8 Hz, 1H),
1
3
3.63 (d, J=15.8 Hz, 1H), 1.34 (t, J=7.1 Hz, 3H). C NMR
(126 MHz, CDCl3) δ 167.8, 158.0, 147.2, 134.4, 133.2,
123.2, 119.6, 63.7, 45.3, 43.5, 40.9, 13.9.
1
13
19
H, C, and F NMR spectra were recorded on a Bruker
1
70 Avance 500 spectrometer (at 500 MHz for Protons and
26 MHz for Carbon-13) and Varian Unity Plus 400 spec-
1
Diethyl 5,7‑dihydro‑6H‑cyclopenta[b]
pyridine‑6,6‑dicarboxylate (12e)
trometer (at 400 MHz for protons, 101 MHz for Carbon-13,
1
13
and 376 MHz for Fluorine-19). Tetramethylsilane ( H, C) or
19
C F ( F) were used as standards. Elemental analyses were
Yield 6.60 g (77%).Yellowish oil. Anal. Calcd. for
C14H17NO4 C 63.87, H 6.51, N 5.32. Found C 64.17, H 6.31,
6
6
performed at the Laboratory of Organic Analysis, Institute of
Organic Chemistry, National Academy of Sciences of Ukraine,
their results were found to be in good agreement (± 0.4%) with
the calculated values. Mass spectra were recorded on Agilent
+
1
N 5.65. MS (EI): 263 (M ), 189, 117. H NMR (400 MHz,
CDCl3) δ 8.35 (d, J=4.9 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H),
7.05 (dd, J=7.2, 4.9 Hz, 1H), 4.20 (q, J=7.1 Hz, 4H), 3.67
1
3
1
100 LCMSD SL instrument [chemical ionization (APCI)]
(s, 2H), 3.57 (s, 2H), 1.24 (t, J = 7.1 Hz, 6H). C ЯMP
(126 MHz, CDCl3), δ 171.2, 161, 148.4, 133.3, 132, 121.7,
61.9, 41.7, 38.3, 22.7, 14.0.
and Agilent 5890 Series II 5972 GCMS instrument [electron
impact ionization (EI)].
General procedure for the preparation of 12c–f
Diisopropyl 5,7‑dihydro‑6H‑cyclopenta[b]
pyridine‑6,6‑dicarboxylate (12f)
Sodium hydride (60% in mineral oil) (600 mg, 15 mmol)
was suspended in DMSO (50 mL), and the compound
yield 75 mg (55%). Yellowish solid. Mp 87–89 °C. Anal.
Calcd. for. C16H21NO4 C 65.96, H 7.27, N 4.81. Found
1
1 (4.7 mmol) was added upon vigorous stirring. The
+
1
resulting mixture was stirred for additional 10 min, and
C 65.63, H 6.98, N 5.14. MS (CI): 292 (MH ). H NMR
(500 MHz, CDCl3) δ 8.37 (d, J = 4.8 Hz, 1H), 7.48 (d,
J = 7.5 Hz, 1H), 7.06 (dd, J = 7.5, 4.8 Hz, 1H), 5.06
(sept, J = 6.2 Hz, 2H), 3.67 (s, 2H), 3.56 (s, 2H), 1.24 (d,
2
4
5
,3-bis(chloromethyl)pyridine hydrochloride (9·HCl) (1 g,
.7 mmol) was added. The resulting mixture was stirred at
0 °C overnight, then cooled, and ice-cold H O (50 mL) was
2
1
3
added. The mixture was extracted with Et O (3×15 mL), the
J = 6.2 Hz, 12H). C NMR (126 MHz, CDCl3) δ 170.8,
161.2, 148.4, 133.4, 132.0, 121.7, 69.4, 58.0, 41.7, 38.2,
21.5.
2
combined organic extracts were dried over Na SO and evapo-
2
4
rated in vacuo. The crude product was puriꢂed by column
chromatography (EtOAc—Hexanes (2:1) as eluent).
Diethyl 5,7‑dihydro‑6H‑cyclopenta[b]
pyridine‑6,6‑dicarboxylate (12e) (alternative
method)
5
,7‑Dihydro‑6H‑cyclopenta[b]
pyridine‑6,6‑dicarbonitrile (12c)
Yield 64 mg (72%). Yellowish solid. Mp 109–112 °C. Anal.
Calcd. for C H N C 70.99, H 4.17, N 24.84. Found C
The procedure was essentially the same as the general
method described above, except DMF was used as the sol-
vent instead of DMSO. Yield 24.7 g, 65%.
1
0
7
3
1
3

A conformationally restricted GABA analogue based on octahydro-1H-cyclopenta[b]pyridine…
6
,7‑Dihydro‑5H‑cyclopenta[b]pyridine‑6‑carboxylic
rel‑(4aS,6R,7aR)‑1‑(4‑Nitrobenzoyl)
octahydro‑1H‑cyclopenta[b]pyridine‑6‑carboxylic
acid (16)
acid, hydrochloride (13)
The diester 12e (10.0 g, 3.8 mmol) was dissolved in con-
centrated aq HCl (10 mL), and the mixture was reꢁuxed
for 24 h, then cooled and evaporated to dryness, the residue
To a solution of 15 (100 mg, 0.300 mmol) in MeOH (2 mL),
NaOH (14 mg, 0.35 mmol) in H O (0.1 mL) was added. The
2
was treated with Et O and ꢂltered to give 13. Yield 6.81 g
reaction mixture was stirred at rt for 8 h. Then MeOH was
2
(
90%). Greyish solid. Mp 162–166 °C (dec.). Anal. Calcd.
evaporated in vacuo, and H O (2 mL) and CH Cl (1 mL)
2
2
2
for. C H ClNO C 54.15, H 5.05, Cl 17.76, N 7.02. Found
were added. The layers were separated, and the aqueous
layer was acidiꢂed with 10% aq HCl to pH 2. The prod-
uct was extracted with CH Cl (2 × 1 mL). The combined
9
10
2
+
C 53.94, H 5.39, Cl 17.46, N 6.67. MS (CI): 164 (MH ),
+
1
1
18 (M –COOH). H NMR (500 MHz, D O) δ 8.41 (d,
2
2
2
J=6.2 Hz, 1H), 8.30 (d, J=7.6 Hz, 1H), 7.72 (dd, J=7.6,
organic layers were dried over Na SO and evaporated in
2 4
6
3
1
1
.2 Hz, 1H), 3.69–3.61 (m, 1H), 3.56 (d, J= 7.8 Hz, 2H),
.47 (dd, J=17.3, 9.2 Hz, 1H), 3.36 (dd, J=17.3, 6.5 Hz,
vacuo. Yield 90 mg, 94%. White solid. Mp 124–125 °C.
Anal. Calcd. for C H N O : C, 60.37; H, 5.70; N, 8.80.
1
6
18
2
5
1
3
+
H). C NMR (126 MHz, D O) δ 177.7, 142.7, 142.4,
Found: C, 60.04; H, 6.00; N, 8.77. MS (CI): 341 (MNa ),
2
+
+
+
38.3, 131.9, 125.1, 41.2, 33.9, 33.7.
319 (MH ) (positive mode), 301 (MH –H O); 317 (M–H )
2
(
negative mode). The compound had double set of broad-
ened signals in the NMR spectra due to some exchange
1
rel‑(4aS,6R,7aR)‑Methyl 1‑(4‑nitrobenzoyl)
process (possibly rotamers at the amide bond). H NMR
octahydro‑1H‑cyclopenta[b]pyridine‑6‑carboxylate
(500 MHz, DMSO-d , 40 °C) δ 8.26 (d, J = 8.0 Hz, 2H),
6
(15)
7.63 (d, J = 8.0 Hz, 2H), 4.81 (br s, 0.5H), 4.40 (s, 0.5H),
3
.72 (s, 0.5H), 3.54–3.13 (m, 1H), 3.08 (br s, 0.5H), 2.87
Compound 13 (1.00 g, 5.01 mmol) was dissolved in MeOH
15 mL). 20% Pd(OH) on charcoal (50 mg) was added,
(br s, 1H), 2.26–1.78 (br m, 4H), 1.59 (br s, 3H), 1.35 (br s,
1
(
2H); COOH is exchanged with HDO. H NMR (500 MHz,
2
and the mixture was hydrogenated in an autoclave at 50 bar
and 35 °C for 8 h. The catalyst was ꢂltered oꢀ, washed with
MeOH (5 mL), and the ꢂltrate was evaporated in vacuo
to give crude 14. The residue was suspended in CH Cl
DMSO-d , 80 °C) δ 8.26 (d, J = 8.0 Hz, 2H), 7.63 (d,
6
J=8.0 Hz, 2H), 4.84–3.00 (br m, 2H), 3.55–2.87 (br m, 1H),
2.75 (br s, 1H), 2.29–2.08 (br m, 1H), 1.97 (br s, 3H), 1.61
(br s, 3H), 1.37 (br s, 2H); COOH is exchanged with HDO.
2
2
1
3
(
25 mL), and triethylamine (1.14 g, 11.3 mmol) was added.
C NMR (126 MHz, DMSO-d , 80 °C) δ 177.0, 168.4,
6
The reaction mixture was stirred at rt for 10 min and cooled
to 0 °C. 4-Nitrobenzoyl chloride (0.930 g, 5.01 mmol) was
added to the reaction mixture. The mixture was stirred at
rt overnight, and then diluted with 10% aq citric acid. The
organic layer was separated, washed with brine (10 mL),
dried over Na SO and evaporated. The residue was puri-
148.4, 143.7, 128.2, 124.1, 55.8 (br s), 38.7 (br s), 39.5,
1
3
36.2, 33.2, 28.9, 27.1, 24.7. C NMR (101 MHz, CDCl )
3
δ 181.2 and 180.6, 169.0, 148.3, 142.6, 127.7 and 127.4,
123.9, 59.2 and 53.5, 43.4 and 37.1, 39.3, 36.6 and 36.0,
33.1 and 32.5, 28.7 and 27.8, 26.8, 25.2 and 24.5. Final
atomic coordinates, geometrical parameters and crystal-
lographic data for the compound 16 have been deposited
with the Cambridge Crystallographic Data Centre, 11 Union
Road, Cambridge, CB2 1EZ, UK (E-mail: deposit@ccdc.
cam.ac.uk; fax: +44 1223 336033) and are available on
request quoting the deposition number CCDC 1864063.
2
4
ꢂed by column chromatography (hexanes: EtOAc (2:1) as
eluent) Yield 0.859 g, 52%. White solid, mp 114–118 °C.
Anal. Calcd. for. C H N O C 61.44, H 6.07, N 8.43.
1
7
20
2
5
+
Found C 61.27, H 5.64, N 8.38. MS (CI): 355 (MNa ), 333
+
+
+
(
MH ), 301 (MH –MeOH), 150 (4-O NC H C≡O ). The
2 6 4
compound had double set of broadened signals in the NMR
spectra due to some exchange process (possibly rotamers at
rel‑(4aS,6R,7aR)‑Octahydro‑1H‑cyclopenta[b]
pyridine‑6‑carboxylic acid, hydrochloride (17)
1
the amide bond). H NMR (500 MHz, DMSO-d , 80 °C) δ
6
8
.25 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 4.75–3.47
(
br m, 2H), 3.63 (s, 3H), 2.97 (br s, 1H), 2.84 (br s, 1H), 2.16
Compound 15 (200 mg, 0.600 mmol) was suspended in
(
app. q, J=11.6 Hz, 1H), 2.11–1.88 (m, 3H), 1.68–1.53 (m,
10% aq HCl (2 mL). The mixture was stirred at 85–90 °C
1
3
3
H), 1.44–1.30 (m, 2H). C NMR (126 MHz, DMSO-d ,
for 16 h, then cooled to rt, and CHCl (2 mL) was added.
6
3
8
0 °C) δ 176.2, 168.5, 148.4, 143.7, 128.2, 124.2, 56.7 (br
The precipitate was ꢂltered oꢀ, and the layers were sepa-
rated. The aqueous layer was evaporated and dried in vacuo.
Yield 77 mg, 62%. White solid, mp 188–190 °C (dec.). Anal.
Calcd. for. C H ClNO C 52.56, H 7.84, Cl 17.24, N 6.81.
1
3
s), 52.0, 40.0 (br s), 39.3, 36.1, 33.1, 28.9, 27.1, 24.6.
C
NMR (101 MHz, CDCl , rt) δ 176.8 and 176.1, 168.7, 148.2,
3
1
3
2
42.9, 127.8 and 127.3, 123.9, 59.2 and 53.3, 52.0, 43.2 and
7.2, 39.3 and 39.0, 36.6 and 35.9, 33.2 and 32.6, 29.1 and
7.9, 26.9, 25.2 and 24.4.
9
16
2
Found C 52.50, H 7.63, Cl 16.93, N 7.15. MS (CI): 170
+
1
(MH ). H NMR (400 MHz, D O) δ=3.61–3.47 (m, 1H),
2
1
3

K. P. Melnykov et al.
3
2
1
5
.25–3.12 (m, 1H), 3.06–2.92 (m, 1H), 2.91–2.78 (m, 1H),
.37–2.18 (m, 2H), 2.17–2.05 (m, 1H), 2.03–1.92 (m, 1H),
disubstituted saturated rings. New J Chem 42:8355–8365. https
:
//doi.org/10.1039/c7nj05015a
Guthikonda RN, Shah SK, Pacholok SG, Humes JL, Mumford RA,
Grant SK, Chabin RM, Green BG, Tsou N, Ball R, Fletcher DS,
Luell S, Euan MacIntyre D, Maccoss M (2005) Bicyclic amidine
inhibitors of nitric oxide synthase: discovery of perhydro-imino-
pyrindine and perhydro-iminoquinoline as potent, orally active
inhibitors of inducible nitric oxide synthase. Bioorg Med Chem
Lett 15:1997–2001. https://doi.org/10.1016/j.bmcl.2005.02.067
Janecka A, Kruszynski R (2005) Conformationally restricted peptides
as tools in opioid receptor studies. Curr Med Chem 12:471–481.
https://doi.org/10.2174/0929867053362983
1
3
.79–1.52 (m, 5H). C NMR (126 MHz, D O) δ 180.8,
2
7.5, 42.7, 40.9, 36.8, 31.9, 31.3, 22.0, 17.7.
Acknowledgements The authors thank Prof. Andrey A. Tolmachev
for his encouragement and support and Ms. Yuliya Kuchkovska for her
help with preparation of Fig. 3.
Compliance with ethical standards
Kaneda M, Nakamura S, Iitaka Y (1980) Absolute structure of ami-
dinomycin. J Antibiot 33:778–780. https://doi.org/10.7164/antib
iotics.33.778
Conflict of interest The authors declare no conꢁict of interests.
Funding The work was funded by Enamine Ltd.
Kiss L, Cherepanova M, Fülöp F (2015) Recent advances in the stere-
2,3
oselective syntheses of acyclic disubstituted β -amino acids. Tet-
rahedron 71:2049–2069. https://doi.org/10.1016/j.tet.2015.01.060
Kobayashi T, Suemasa A, Igawa A, Ide S, Fukuda H, Abe H, Arisawa
M, Minami M, Shuto S (2014)Conformationally restricted gaba
with bicyclo[3.1.0]hexane backbone as the ꢂrst highly selective
BGT-1inhibitor. ACS Med Chem Lett 5:889–893. https://doi.
org/10.1021/ml500134k
Ethical approval This article does not contain any studies with human
participants or animals performed by any of the authors.
Komarov IV, Grigorenko AO, Turov AV, Khilya VP (2004) Confor-
mationally rigid cyclic α-amino acids in the design of peptidomi-
metics peptide models and biologically active compounds. Russ
Chem Rev 73:785–810. https://doi.org/10.1070/RC2004v073
n08ABEH000912
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