Toward pyridine-fused selenium-containing antioxidants

Article abstract of DOI:10.3390/90600472

Photolysis of the thiohydroximate ester derivative 21 of 2-carboethoxy-2-(2-(benzylseleno)pyridin-3-yl)tridecylcarboxylic acid (20) affords 2-dodecyl-2-carboethoxy-2,3-dihydroselenolo[2,3-b]pyridine (22) in 89% yield in a process presumably involving intr

Full text of DOI:10.3390/90600472

Molecules 2004, 9, 472-479
molecules
ISSN 1420-3049
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Toward Pyridine-Fused Selenium-Containing Antioxidants
Tahli Fenner and Carl H. Schiesser*
School of Chemistry, Bio21 Molecular Science and Biotechnology Institute, The University of
Melbourne, Victoria, Australia, 3010. Tel. (+61)-3-8344-4180, Fax (+61)-3-9347-5180.
* Author to whom correspondence should be addressed; e-mail: carlhs@unimelb.edu.au.
Received: 17 February 2004 / Accepted: 21 February 2004 / Published: 31 May 2004
Abstract: Photolysis of the thiohydroximate ester derivative 21 of 2-carboethoxy-2-(2-
(benzylseleno)pyridin-3-yl)tridecylcarboxylic
acid
(20)
affords
2-dodecyl-2-
carboethoxy-2,3-dihydroselenolo[2,3-b]pyridine (22) in 89% yield in a process
presumably involving intramolecular homolytic substitution by a tertiary alkyl radical at
selenium with loss of a benzyl radical. Work toward extending this methodology to the
preparation of pyridine-fused selenium analogues of antioxidants is described.
Keywords: Free radical, homolytic substitution, selenium, antioxidants.
Introduction
Interest in selenium containing therapeutics has grown over the last thirty years [1]. Simple
organoselenium compounds have been prepared, such as selenazolopyrimidone (1), that show
antitumor activity against mouse leukemia [2]. (Aminoethyl)phenylselenide (2) shows excellent
antihypertensive activity and selenazine derivatives such as 3 show both antibacterial and antitumor
activity [3]. Despite this, the major therapeutic benefit that selenium currently offers appears to be
in the form of dietary supplements [4]. Selenium is an essential trace element and dietary
deficiency can lead to ailments including gum disease, as well as debilitating conditions such as
Keshan’s disease [4e]. The biochemistry and pharmacology of selenium is of intense current
interest. Selenium is now know to be intimately involved in the activity of enzymes such as
glutathione peroxidase and thioredoxin reductase, that catalyse chemistry essential to the protection
of biomolecules against oxidative stress and free radical damage [5].

Molecules 2004, 9
473
O
N
Se
NH2
Se
N
N
Se
N
HO
1
2
3
Reactive oxygen species (ROS) are a byproduct of normal aerobic metabolism [6]. Superoxide
is formed when electrons leaked from the electron transport chain react with molecular oxygen and
is also the product of some enzymatic processes [6b,7]. Superoxide dismutase converts superoxide
to hydrogen peroxide, which can, in turn, lead to the formation of hydroxyl and lipid peroxyl
radicals [6b,7]. Hydroxyl radicals are extremely reactive and can cause damage to important
biomolecules that include DNA, while lipid peroxidation has been implicated in diseases such as
atherosclerosis [6a,8]. Reactive oxygen species do have some positive roles in biology, such as
providing defense against infection [6a,9], however, excessive concentrations of ROS can lead
oxidative stress [6a,9]. Nature has evolved clever methods for controlling ROS. Preventative
antioxidant enzymes such as glutathione peroxidase remove ROS through redox cycling [5], while
chain breaking antioxidants such as Vitamin E, interrupt the chain reactions responsible for the
formation of radical species [10]. It should be noted that Vitamin E refers to a family of related
compounds known as tocopherols of which α-tocopherol (4) is most potent [10b].
HO
O
4
In recent years there has been much interest in developing new, more potent antioxidants such as
Ebselen (5), that also acts as a glutathione peroxidase mimic and is due to be released for human
use as a non-steroidal anti-inflammatory [11]. Water-soluble Vitamin E analogues that have been
prepared include Trolox (6) [12], while our group has used intramolecular homolytic substitution
chemistry to prepare a selenium containing analogue 7 of Vitamin E that possesses dual mode of
action [13].
O
HO
HO
N Ph
Se
CO2H
O
Se
5
6
7
Work in our laboratories has also been directed at the development of water-soluble, dual acting,
tocopherol/ebselen hybrids such as 8 and to pyridine-fused tocopherol systems such as 9. Our
recent efforts towards the synthesis of the latter system are described below.

Molecules 2004, 9
474
R
R
O
HO
R
HO
R
n
( )
N
Se
Se
N
R
N
R
9
8
Results and Discussion
Preliminary investigations began with the attempted preparation of model compound 10 that
contained many of the salient feature of structures 8 and 9. To that end ethyl 2-chloronicotinate
(11) was reacted with sodium benzylselenoate, generated in situ by reduction of dibenzyl diselenide
with sodium borohydride, to give ethyl 2-(benzylseleno)nicotinate (12) in 64% yield (Scheme 1).
Scheme 1.
NaBH4
CO2Et
Cl
CO2Et
(SeBn)2
OH
LiAlH4
91%
N
64%
N
SeCH2Ph
N
SeCH2Ph
11
12
13
MsCl
92%
O
O
CO tBu
/ NaH
2
Cl
SeCH2Ph
CO2tBu
SeCH2Ph
96%
N
N
14
15
conc. HCl
N
Se
86%
O
10
OH
MgBr
N
16
SeCH2Ph
86%
N
SeCH2Ph
17
Further reduction with lithium aluminium hydride afforded alcohol 13 in 91% yield. It is
interesting to note that the alternative sequence of reactions, namely reduction of the ester 11
followed by treatment with sodium benzylselenoate proceeded only very poorly. We attribute this
observation to the electrophilicity of the pyridine ring in the various substrates, specifically that the
electron-withdrawing ester substituent is able to increase ring reactivity in a manner that the
alcohol can not. The alcohol 13 was further reacted with methanesulfonyl chloride to give the
chloride 14 in 92% yield, which was subsequently reacted with t-butyl acetoacetate and base to

Molecules 2004, 9
475
give the ketoester 15 following the procedure developed by Malmström [13]. Treatment of 15 with
concentrated hydrochloric afforded the required ketone 16 in excellent overall yield. Finally,
reaction of 16 with n-butylmagnesium bromide gave the desired tertiary alcohol 17 in 86% yield
(Scheme 1).
Following our previously published work, we expected that alcohol 17 could be converted into
the PTOC oxalate ester, originally described by Barton and Crich as a suitable precursor for the
generation of carbon-centred radicals from tertiary alcohols. To our surprise, reaction of 17 with
oxalyl chloride , followed by sodium omadine®, afforded none of the desired cyclized product 10,
despite the reaction being carried out under a number of different conditions. 1H-NMR
spectroscopy of the only identified product suggested strongly that elimination has occurred to
afford a mixture of isomeric alkenes (Scheme 2).
Scheme 2.
OH
1. Base
(COCl)2
S
2.
N
SeCH2Ph
N
SeCH2Ph
N
SeCH2Ph
N
NaO
17
Given the problems associated with the methodology described above, it became apparent that
an alternative method for the generation of the required radical was needed. Following a
modification of the procedure described in Scheme 1, chloride 14 was reacted with t-butyl ethyl
malonate to afford selenide 18 in moderate (54%) yield (Scheme 3).
Scheme 3.
O
O
CO2Et
CO2tBu
(CH2)11CH3
SeCH2Ph
CO2Et
CO2tBu
CH3(CH2)11Br
NaH
EtO
OtBu
NaH
54%
N
N
SeCH2Ph
14
72%
19
18
TFA
67%
Me
S
Me
S
S
S
O
N
EtO2C
CO2Et
Me
N
O
HO
Me
hv
89%
CO2H
(CH2)11CH3
CO2Et
(CH2)11CH3
SeCH2Ph
(CH2)11CH3
DCC, DMAP
70%
Se
N
N
N
SeCH2Ph
22
21
20

Molecules 2004, 9
476
Further treatment with sodium hydride and 1-bromododecane provided diester 19 in 72% yield,
which was selectively deprotected by the action of trifluoroacetic acid to afford 2-carboethoxy-2-
(2-(benzylseleno)pyridin-3-yl)tridecylcarboxylic acid (20), suitable for conversion into a radical
precursor.
Kim recently described a new method for generating carbon-centred radicals from
thiohydroximate esters of carboxylic acids and we have generally found this precursor to be
superior to those described by Barton and coworkers [14] for reasons including stability, especially
in tertiary systems [15]. Therefore, reaction of N-methyl-hydroxydithiocarbamate and
dicyclohexylcarbodiimide (DCC) with 20 afforded precursor 21 which was isolated as a yellow oil
after column chromatography. Photolysis of 21 in heptane afforded the target 2-dodecyl-2-
carboethoxy-2,3-dihydroselenolo[2,3-b]pyridine (22) in 89% yield. The dihydroselenolo[2,3-b]-
pyridine 22 displayed a 77Se-NMR signal at δ 547.6, characteristic of the structurally related
selenium heterocycles [16]. Having successfully demonstrated that tertiary carbon-centred radicals,
such as 23 are capable of undergoing intramolecular homolytic substitution to afford
dihydroselenolo[2,3-b]pyridines such as 22, we next turned our attention to the preparation of a
precursor for the synthesis of a six-membered ring such as that found in the initial target compound
10.
EtO2C
(CH2)11CH3
N
Se
Ph
23
To that end, 2-chloronicotinaldehyde (25) was added to a solution of ethyl propiolate and
lithium hexamethyldisilazine in THF at –78°C (Scheme 4).
Scheme 4.
O
O
OH
CO2Et
-78oC
1. H2 10% Pd/C
2. PCC
LiHMDS
CO2Et
H
CO2Et
36%
N
Cl
N
Cl
N
Cl
73%
25
26
27
NaBH4
(SeBn)2
75%
O
OH
O
N2H4
NH
OH
NaBH4
85%
N
CO2Et
KOH
63%
N
SeBn
N
SeBn
N
SeBn
29
28
30

Molecules 2004, 9
477
After stirring at –78°C for 4 hours, the reaction was quenched using saturated ammonium
chloride solution to give the acetylinic alcohol 26 in 73% yield after purification. It is important
that the reaction mixture is quenched at low temperature, as significantly lower yields were
obtained when the mixture was allowed to warm addition of the ammonium chloride solution.
Hydrogenolysis of alcohol 26 followed by PCC oxidation afforded ketone 27 in poor (36%) yield.
Significant amounts of by-product appeared to accompany this transformation. Despite this, ketone
(27 was further reacted with sodium benzylselenoate, generated as described above, to afford ethyl
3-oxo-3-(2-(benzylseleno)pyridin-3-yl)butyrate (28) in acceptable yield.
With 28 in hand, the next task was the removal of the ketone functional group. We envisaged
that Wolff-Kischner or Clemenson techniques would result in the required compound.
Unfortunately, the action of zinc-mercury amalgam (Clemenson reduction) returned only 28, while
reaction with alkaline hydrazine (Wolff-Kischner reduction) afforded a single product that was
isolated in 63% yield and that was eventually assigned to be pyradizinone 30. The formation of 30
can be rationalized by the nucleophilic capture of the initial ketone/hydrazine adduct by the
proximate ester moiety, with subsequent dehydration.
R
R
O
O
Se
CH2Ph
N
N
Se
CH2Ph
28
31
Ketone 28 proved to surprisingly difficult to reduce using standard techniques. Treatment with a
large excess of sodium borohydride at room temperature resulted in no reduction, however in
refluxing ethanol, clean conversion to the diol 29 was observed after several hours. Single crystal
x-ray analysis of 28 provided interesting structural information that may help in our understanding
of the relative inertness of the ketone moiety in 28 to reduction (Figure 1).
Figure 1 Perspective diagram of 28
Se
2.680(3)Å
O

Molecules 2004, 9
478
There appears to be a remarkably short oxygen-selenium separation in 28, which at 2.68Å is
suggestive of significant contribution of resonance structure 31 to the overall bonding in 28.
Indeed, the O–Se separation in 28 is, to the best of our knowledge, the shortest such interaction
reported, being some 0.04Å shorter than the previous “record” of 2.72Å reported by us recently
[17].
Conclusions
We have presented work toward the preparation of novel pyridine-fused, selenium-containing
antioxidants and anti-inflammatory agents and have demonstrated that, in a model compound,
intramolecular homolytic substitution is an effective method for the preparation of these ring
systems. The unusual reactivity of ethyl 3-oxo-3-(2-(benzylseleno)pyridin-3-yl)butyrate (28) is
attributed to strong non-bonded O–Se interactions that are supported by x-ray analysis
Acknowledgements
Financial support from the Australian Research Council is gratefully acknowledged.
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