Tetrahedron Letters
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
⇑
12
the synthesis of cyclic zwitterionic piperidine compounds could
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0