Chiral cyclic zwitterionic bipyridinium-4-olates for the diastereoselective synthesis of (R,S)- A nd (S,R)-trozamicol

Article abstract of DOI:10.1016/j.tetlet.2016.03.029

A series of new chiral enantiopure cyclic zwitterionic bipyridinium-4-olates compounds were prepared in four steps starting from the corresponding primary chiral amine. With these intermediates, a convenient methodology has been developed for the synthesis of cis-3-piperidinyl-4-hydroxypiperidines. Specifically, the utility of this chiral zwitterionic type intermediate has been demonstrated by the synthesis of (R,S)- A nd (S,R)-trozamicol.

Full text of DOI:10.1016/j.tetlet.2016.03.029

Tetrahedron Letters 57 (2016) 1683–1686
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Tetrahedron Letters
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Chiral cyclic zwitterionic bipyridinium-4-olates for the
diastereoselective synthesis of (R,S)- and (S,R)-trozamicol
a
a
a
a
a
Ricardo López-González , Araceli Zárate , David M. Aparicio , Angel Mendoza , Dino Gnecco ,
a
b
a
a,
⇑
Jorge R. Juárez , Nancy Romero-Ceronio , Laura Orea , Joel L. Terán
a
Centro de Química del Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Edif. IC7, Complejo de Ciencias, C.U., 72570 Puebla, Pue., Mexico
División Académica de Ciencias Básicas, Universidad Juárez Autónoma de Tabasco, Km 1, Carretera Cunduacán-Jalpa de Méndez, 86690, Cunduacán, Tab., Mexico
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new chiral enantiopure cyclic zwitterionic bipyridinium-4-olates compounds were prepared
in four steps starting from the corresponding primary chiral amine. With these intermediates, a conve-
nient methodology has been developed for the synthesis of cis-3-piperidinyl-4-hydroxypiperidines.
Specifically, the utility of this chiral zwitterionic type intermediate has been demonstrated by the synthe-
sis of (R,S)- and (S,R)-trozamicol.
Received 15 February 2016
Revised 2 March 2016
Accepted 3 March 2016
Available online 10 March 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Chiral cyclic zwitterionic
Bipyridinium
cis-3-Piperidinyl-4-hydroxypiperidines
Trozamicol
Introduction
F
H
N
Piperidine ring are important structure which are immerse in a
wide broad of important compounds. More specifically, 3-amino-
I
N
N
N
4
-hydroxypiperidines are one of the important architectures
OH
N
N
because it appears in several natural products, or pharmacologi-
Ph
OH
OH
cally active compounds.1 In these sense, the (R,R)-trozamicol (a
Ph
Ph
3
-amino-4-hydroxypiperidine) and its analogues present a
r
1
Trozamicol
MIBT
Ki-VAChT = 0.13 nM
FBT
2
Ki-VAChT = 0.22 nM
i-σ1 = 21.6 nM
i-σ2 = 35.9 nM
receptor binding affinities. The
1
r receptors are considered as
3
4
K
i-σ1 = 92 nM
K
K
a therapeutic target for the treatment of depression, anxiety,
K
i-σ2 = 190 nM
schizophrenia and Alzheimer’s disease.6 Therefore, a continuous
interest exists in the development of new methodologies for
asymmetric synthesis of this six-membered azaheterocycle
5
Figure 1. Trozamicol and analogues those are potent for r1 receptors.
2
,7
(Fig. 1).
Surprisingly the synthesis of (R,S)- and (S,R)-trozamicol
different reaction conditions with a view to study the reactivity
and regioselectivity.
stereoisomers has not been explored. These strongly suggest that
these isomers could also possess interesting pharmacological
properties.
9
On the other hand, it is well known that pyridinium zwitterions
are usually very reactive species, which should be kept at low tem-
peratures and in an inert atmosphere. The majority of these zwit-
terions are synthesized by first preparing the pyridinium salt,
3
-Amino-4-substituted piperidines commonly are prepared
through a regio- and stereoselective hetero nucleophilic addition
to a piperidinylaziridine,8 or via epoxide ring-opening of 3,4-
epoxypiperidines with an appropriate nucleophile to afford a
regioisomeric opening mixture of trans-vicinal aminoalcohol under
10
followed by the elimination of an acid in the reaction with a base.
Since pyridinium salts derived from
a-halogenocarbonyl com-
pounds are easily deprotonated to give pyridinium zwitterions,
which are prone to be high potential synthons and undergo versa-
1
1
tile reactions, we envisioned that our previously methodology to
⇑
Corresponding author. Tel.: +52 222 229 5500x7277; fax: +52 222 229 5551.
E-mail address: joel.teran@correo.buap.mx (J.L. Terán).
12
the synthesis of cyclic zwitterionic piperidine compounds could
http://dx.doi.org/10.1016/j.tetlet.2016.03.029
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0

1
684
R. López-González et al. / Tetrahedron Letters 57 (2016) 1683–1686
∗
R
N
O
O
H
2
, Pd-C
THF, rt, 22 h
∗
∗
∗
R
R
N
R
O
N
O
O
N
O
S(CH
3
)
2
KOH, CH CN
3
previous work
O
CH CN, 12 h
O
3
rt, 12h
S(CH3)
Br
S(CH
3
)
2
2
∗
R
N
OMe
OMe
Br
O
Br
2
, NEt
4
, rt, 6 h
3
CCl
SCH
3
OH
∗
∗
∗
R
N
R
N
R
N
H
N
O
O
O
4 steps
Py
base, solvent
temperature
this work
O
solvent, temperature
O
Br
Py
Py
N
R
OMe
OMe Br
O
OH
trozamicol derivatives
R*= (S)-pheny-ethyl, (R)-2-phenyl-ethanol
Scheme 1. Previous studies and this work.
R
NH
R
N
R
NH
O
R*
N
R*
N
i
ii
95-99%
O
neat conditions
O
N
2
O
O
ultrasound activation
Br
R1
O
OMe
2a,b
OMe
O
Br
1
a,b
3a,b
R1
OMe Br
OMe
3a,b
N
a R= (S)-phenyl-ethyl
b R= (R)-2-phenyl-ethanol
(
1,1 eq)
a R*= (S)-phenyl-ethyl
b R*= (R)-2-phenyl-ethanol
Scheme 2. Reagents and conditions: (i) methyl acrylate (1.2 equiv), methanol,
reflux, 3 h, 95–98% yield. (ii) Bromoacetyl bromide (1.2 equiv), for 3a: K CO
2 equiv), DCM/H O 1:1, 0 °C, 1 h; for 3b: NEt (1 equiv), DCM, 0 °C, 1 min.
2
3
H
3
C
Ph
Br
H
3
C
Ph
H C
Ph
(
2
3
3
N
O
N
N
O
N
N
O
Ph
O
O
O
O
O
Et
N
Br
Br
OMe
Ph
OMe
Ph
OMe
Ph
be applied to the synthesis of chiral zwitterionic bipyridinium-
olates that could be used on the preparation of trozamicol and
its derivatives (Scheme 1).
4a
5a
6a
OH
O
OH
OH
O
N
N
O
N
Ph
Results and discussion
O
Et
N
N
N
Br
Br
4b
Br
OMe
OMe
Ph
OMe
6b
Chiral bromoacyl amides were prepared as follow. Firstly the
corresponding chiral amine was condensed with methyl acrylate
allowing the formation of aminoester 2a,b; then, the resulting ami-
noester was reacted with bromoacetyl bromide to afford the
desired bromoacyl amide 3a,b (Scheme 2).
Next, diverse pyridines were condensed with 3a,b. Best results
were obtained when the reaction was carried out under ultrasonic
activation and neat conditions. The desired pyridinium salt was
obtained as a dynamic rotameric mixture in quantitative yields
5b
3
H C
H
3
C
Ph
O
H
3
C
Ph
N
N
O
N
O
OH
O
Br
O
O
CHO
N
N
N
Br
Br
OMe Br
OMe
OMe
Ph
8a
Ph
9a
7a
Ph
OH
O
OH
O
OH
O
N
N
N
(Scheme 3).
OH
O
CHO
O
Br
O
We then turned our attention to the intramolecular cyclization.
To this end, pyridinium salt 4a was treated with diverse bases. The
best result was obtained when 4a was treated with KOH (6 equiv)
N
N
N
Br
Br
8b
OH
Br
OMe
OMe
OMe
9b
7
b
in MeOH, allowing the formation of the desired cyclic zwitterion
H
3
C
Ph
Ph
3
1
1a in quasi quantitative yield in a few minutes (Table 1).1
N
O
N
N
O
Encouraged by the above finding, we attempted to synthesize
more functionalized zwitterion intermediates derived from substi-
tuted pyridine compounds. Pleasingly, a broad range of 2-, 3- and
O
O
N
OMe
Br
0b
Ph
OMe
Ph
10a
1
4
-substituted pyridinium salts gave the expected cyclic intermedi-
ates in good chemical yields. However, pyridinium salt derived
Scheme 3. Synthesis of several pyridinium salts.

R. López-González et al. / Tetrahedron Letters 57 (2016) 1683–1686
1685
Table 1
H
C
Ph
H
C
Ph
H
3
C
Ph
3
3
Intramolecular cyclization of pyridinium salt 4a
N
O
N
N
O
N
O
N
4
NaBH , MeOH
H
3
C
Ph
H C
Ph
3
N
N
O
N
Base,
N
O
O
N
OH
19a
OH
19a'
OH
18a
solvent
Ph
65%
Ph
Ph
O
:
rt, time
OMe Br
dr: 65:35
only cis
diastereoisomers
4
a
11a
Entry
Solvent
CH CN
MeOH
MeOH
MeOH
Base
Time (h)
Yield (%)
1
2
3
4
3
KOHa
NaOMe
KOH
KOH (6 equiv)
16 h
1 h
1 h
80
50
98
98
a
a
10 min
a
2
equiv of the base were used.
19a
major
diastereoisomer
Scheme 5. Diastereoselective reduction of compound 18a.
Table 2
Chiral cyclic zwitterionic derivatives obtained from intramolecular cyclization of
pyridinium salts
H
3
C
Ph
H
3
C
Ph
H C
Ph
3
H
3
C
Ph
N
O
N
N
O
O
N
O
O
N
from 2-phenylpyridine and (R)-(ꢀ)-2-phenylglycinol gave the
desired cyclic zwitterionic compound 12b in traces and the corre-
sponding oxazepanone compound as a major product (not show on
Table 2). This result could be attributed to the more favourable
intramolecular transesterification reaction.
Interestingly, cyclic zwitterions 12(a+a ) and 14(a+a ) were
obtained as an inseparable atropisomeric mixture, while zwitteri-
ons 12b, 13b, 14a, 15a and 15b were obtained as a separable
atropisomeric mixture in a 2:1 diastereomeric ratio. It is important
to mention that zwitterion 13a, 16a and 16b were obtained as a
sole atropisomer in a high chemical yield. All zwitterions were iso-
lated in its betaine form (Table 2).
Ph
N
O
O
N
N
Et
O
Ph
1
1a
12a + 12a'
1
3a
9
7% 10 min
100%, 10min
dr= 60:40
1
00%, 1h
Ph
0
0
Ph
Ph
HO
HO
HO
N
O
N
N
O
N
N
O
N
Ph
Et
O
1
O
O
2b
traces
13b + 13b'
1
1b
9
7%, 16h
8
3%, 1h
2h
dr =73:27
H
3
C
Ph
H
3
C
Ph
H
3
C
Ph
Continuing with our research aimed to apply these intermedi-
ates to the synthesis of trozamicol, we oriented our attention to
the reduction of the aromatic pyridinium ring. To this end, zwitte-
rion 17a was submitted to different catalytic hydrogenation condi-
N
O
N
N
O
O
N
O
O
N
OH
CHO
Br
N
O
1
4a + 14a'
15a + 15a'
16a
2
tions including Pd/C (20% mol), PtO (20% mol), etc. Excellent yield
5
6%, 10 min,
80%, 10 min,
93%, 10min
was obtained when the hydrogenation was carried out with Raney
Ni catalyst in EtOH at room temperature. The confirmation of the
reducing compound 18a was corroborated from the NMR spectrum
of the crude reaction which shows the characteristic piperidine
ring signals around 1.5–3.2 ppm (see Supplementary material)
dr = 83:16
dr= 85:15
Ph
Ph
Ph
HO
HO
HO
N
O
N
N
O
N
N
O
N
OH
CHO
Br
O
O
O
1
4b + 14b'
15b + 15b'
16b
(Scheme 4).
5
7%, 10 min
99%, 10 min,
99%, 10 min
Thereafter, the enol function of compound 18a was reduced
dr 85:15
H
3
C
Ph
Ph
with NaBH
to afford exclusively the cis diastereomeric mixture
4
HO
0
N
O
O
N
N
O
N
of the corresponding vicinal aminoalcohols 19(a+a ), which were
easily separated by chromatographic purification. Fortunately,
major diastereoisomer 19a crystallized, enabling the unequivocal
configuration at C-3 and C-4 as (S,S) respectively by X-ray diffrac-
O
Ph
Ph
17a
17b
1
4
9
8%, 1h
85%, 1h
tion analysis (Scheme 5).
Then, the amide function was reduced with LiAlH 15
to afford
4
the desired piperidine compound. Finally, the corresponding
piperidine was subject to hydrogenolysis process delivering the
1
6
(
R,S)- and (S,R)-trozamicol (Scheme 6).
Conclusion
In summary, we proved that chiral non-racemic zwitterionic
H
3
C
Ph
H
3
C
Ph
Raney Ni (20% mol),
2
N
O
O
N
O
H
, Ethanol, rt, 16 h
N
N
OH
bipyridinium-4-olates are valuable starting material for the prepa-
ration of trozamicol derivatives, and represent a novel methodol-
ogy to regiospecific synthesis of cis-3-piperidinyl-4-hydroxy
piperidine intermediates. This new, versatile, and scalable access
Ph
98%
Ph
1
7a
18a
Scheme 4. Reduction of zwitterionic compound 17a.

1
686
R. López-González et al. / Tetrahedron Letters 57 (2016) 1683–1686
H
3
C
Ph
H
3
C
Ph
H
N
N
O
N
+
N
H
2, Pd/C/H , EtOH
LiAlH
4
N
THF,
N
OH
0°C to reflux
9
0%
OH
OH
Ph
Ph
Ph
8
0%
1
9a
20a
(R,S)-trozamicol
20
[α]
D
= -5.8 (c = 1.0, CH
2
Cl
2
)
H
3
C
Ph
H
3
C
Ph
H
N
N
O
N
+
N
H2, Pd/C/H , EtOH
LiAlH
4
N
THF,
N
8
5%
OH
0°C to reflux
OH
OH
Ph
Ph
Ph
60%
1
9a'
20a'
(S,R)-trozamicol
2
0
[
α]
D
= +5.4 (c = 1.0, CH
2
Cl
2
)
Scheme 6. Synthesis of (ꢀ)-(R,S)-trozamicol and (+)-(S,R)-trozamicol.
to trozamicol derivatives opens the route to the pharmacological
investigation of these promising compounds as well as the design
of analogues.
7. Efange, S. M. N.; Mach, R. H.; Smith, C. R.; Khare, A. B.; Foulon, C.; Akella, S. K.;
Childers, S. R.; Parsons, S. M. Biochem. Pharmacol. 1995, 49, 791.
8
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Hu, X. E. Tetrahedron Lett. 2002, 43, 5315; Hu, X. E.; Kim, N. K.; Ledoussal, B.;
Colson, A.-O. Tetrahedron Lett. 2002, 43, 4289.
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Acknowledgments
We are grateful to VIEP-BUAP and CONACYT (Project No.
2
52435) for financial support, R.L.G. thanks to CONACyT for the
scholarship (383470).
2
015, 71, 6907.
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1
2
Supplementary data
1
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.03.
Zh. Org. Chem. 1997, 33, 903.
2. Palillero, A.; Terán, J. L.; Gnecco, D.; Juárez, J. R.; Orea, M. L.; Castro, A.
1
1
1
1
1
Tetrahedron Lett. 2009, 50, 4208.
0
29.
3. The formation of a cyclic zwitterion compound was confirmed by the 1H NMR
a
spectrum 9a, wherein the benzylic C–H resonates at d = 5.97 ppm.
4. Crystal structure was deposited at the Cambridge Crystallographic Data Centre.
Deposit number: CCDC 1451876.
References and notes
5. Efange, S. M. N.; Khare, A.; Parsons, S. M.; Bau, R.; Metzenthin, T. J. Med. Chem.
1.
2.
3.
Källström, S.; Leino, R. Bioorg. Med. Chem. 2008, 16, 601; Hopkins, B. T.; Cai, X.;
Chan, T. R.; Conlon, P.; Humora, M.; Jenkins, T. J.; Mac-Phee, J. M.; Shi, X.; Miller,
R. A.; Thompson, A. WO 2013185082 A2 2013. CAM. 160:69958.
Mach, R. H.; Voytko, M. L.; Ehrenkaufer, R. L.; Nader, M. A.; Tobin, J. R.; Efange,
S. M. N.; Parson, S. M.; Gage, H. D.; Smith, C. R.; Morton, T. E. Synapse 1997, 25,
1
993, 36, 985.
6. (ꢀ)-(R,S)-Trozamicol yield 90%, colorless oil. [
NMR (500 MHz, CDCl
dd, J = 3.8, 12.2 Hz, 1H), 1.74 (dd, J = 3.8, 12.3 Hz, 1H), 1.86 (m, 2H), 1.98 (ddd,
J = 2.65, 5.5, 14.1 Hz, 1H), 2.09 (td, J = 2.3, 11.8 Hz, 1H), 2.23 (td, J = 2.45,
20
); 1
a
]
D
= ꢀ5.8 (c = 1.0, CH
2
Cl
2
H
3
) d 1.61 (dddd, J = 2.75, 5.05, 10.26, 12.6 Hz, 1H), 1.69
(
3
68.
Fishback, J. A.; Robson, M. J.; Xu, Y. T.; Matsumoto, R. R. Pharmacol. Ther. 2010,
27, 271.
1
2
1
1.5 Hz, 1H), 2.28 (ddd. J = 2.75, 4.7, 11.1 Hz, 1H). 2.54 (tt, J = 3.7, 12.2 Hz, 1H),
.73 (ddd, J = 1.2, 4.6, 12.0 Hz, 1H), 2.77 (t, J = 11.3 Hz, 1H), 2.89 (td, J = 2.75,
2.4 Hz, 1H), 3.06 (m, 2H), 3.29 (m, 1H), 4.14 (br, 1H), 7.19–7.32 (m, 5H);
1
13
C
4
5
.
.
Matsumoto, R. R. Expert. Rev. Clin. Pharmacol. 2009, 2, 351.
NMR (125 MHz, CDCl
1
2
3
) d 31.4, 33.6, 33.7, 40.0, 42.6, 44.3, 49.4, 51.0, 62.9, 63.4,
26.2, 126.8, 128.4, 146.1 HRMS (FAB): Calcd for C16 O: 260.1889. Found:
60.1888. (+)-(S,R)-trozamicol. Yield 85%, colorless oil. [
Cl ).
Maestrup, E. G.; Wiese, C.; Schepmann, D.; Hiller, A.; Fischer, S.; Scheunemann,
M.; Brust, P.; Wünsch, B. Bioorg. Med. Chem. 2009, 17, 3630.
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24 2
H N
20
D
a] = +5.4 (c = 1.0,
6
.
CH
2
2