Preparation of novel selenopenams by intramolecular homolytic substitution

Article abstract of DOI:10.3390/90600466

Photolyses of the thiohydroximate ester derivatives 13 and 21 of the 4-(benzyl-seleno)-2-azetidinoines 7 and 20, afford the 1-aza-7-oxo-4- selenabicyclo-[3.2.0]heptane ring systems 14 and 21 in good to moderate yield in processes that presumably involve i

Full text of DOI:10.3390/90600466

Molecules 2004, 9, 466-471
molecules
ISSN 1420-3049
http://www.mdpi.org
Preparation of Novel Selenopenams by Intramolecular
Homolytic Substitution
Michael W. Carland 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: 20 February 2004 / Published: 31 May 2004
Abstract: Photolyses of the thiohydroximate ester derivatives 13 and 21 of the 4-
(benzyl-seleno)-2-azetidinoines 7 and 20, afford the 1-aza-7-oxo-4-selenabicyclo-
[3.2.0]heptane ring systems 14 and 21 in good to moderate yield in processes that
presumably involve intramolecular homolytic substitution at selenium with expulsion of
benzyl radical. Extension of this methodology to the preparation of derivatives 24 of
12,2a-dihydro-1H,8H-azeto[2,1-b][1,3]benzoselenazin-1-one (22) is also described.
Keywords: Free radical, homolytic substitution, selenium, β-lactam.
Introduction
Free-radical homolytic substitution chemistry is rapidly gaining acceptance as a versatile
synthetic method [1]. Over the past few years, we have demonstrated the effectiveness of this
chemistry for the preparation of selenium and tellurium-containing higher heterocycles. Indeed, so
versatile is the free-radical approach that many classes of compound including some of hitherto
unknown structure have been successfully prepared. Among these are included 5-deoxy-5-seleno
pyranose sugars (eg. 1) [2], and novel selenium and tellurium analogues (eg. 2) [3] of the important
antioxidant, α-tocopherol.
It is generally appreciated that β-lactam based antibiotics have a limited future given increased
resistance demonstrated by many strains of bacteria [4]. There is an urgent need for the
development of new classes of antibiotic and many laboratories have made significant progress in
this area, especially with the introduction of peptide-based agents [5].

Molecules 2004, 9
467
Se
OH
HO
OBn
OBn
Se
OBn
1
2
A common mechanism of resistance in bacteria to the β-lactam class of antibiotics is through the
β-lactamase enzymes [6,7]. These enzymes hydrolyse β-lactam antibiotics, rendering them
impotent. Several β-lactamase inhibitors, such as sulbactam (3) and clavulanic acid (4) are known,
are able to be administered in conjunction with antibiotics susceptible to β-lactamase activity [8].
O
O
O
O
OH
S
O
Se
N
N
O
O
O
CO2H
CO2H
CO2H
3
4
5
In an attempt to extend the variety of available β-lactamase inhibitors, we considered that
substitution of the sulfur atom in the bicyclic core with selenium may provide an analogue (5) of
sulbactam that preserves its shape and electronic properties, but which may differ in reactivity, and
thus potency.
Selenium analogues of β-lactam antibiotics have been reported on previous occasions together
with limited biological testing data [9,10]. In each report the yields of the target molecules are
either poor, or the compounds prepared bear functionality that compromises biological activity.
New methods for the preparation of these interesting systems are therefore important objectives.
We now report that selenium analogues of β-lactam antibiotic nuclei are conveniently prepared by
extension of our previously established radical methodologies.
Results and Discussion
Our synthetic route began with commercially available 4-acetoxy-2-azetidinone (6) which was
reacted with, sodium benzylselenoate, prepared by treatment of dibenzyldiselenide and sodium
borohydride, to give 4-(benzylseleno)-2-azetidinone (7) in quantitative yield. Further reaction with
ethyl bromoacetate under alkaline conditions (LiHMDS) afforded ester 8 in good (88%) yield.
Ester 8 was further reacted with several equivalents of t-butyl bromoacetate under alkaline
conditions to provide the mixed diester 9 in 74% yield. Selective hydrolysis of the t-butyl ester in a
1:1 mixture of trifluoroacetic acid and dichloromethane afforded the monoacid 10 in quantitative
yield. Further reaction of 10 with N-hydroxypyridine-2-thione in the presence of
dicyclohexylcarbodiimide (DCC) afforded the pyridinethioneoxycarbonyl (PTOC, Barton)[11]
ester free radical precursor 11 (Scheme 1).

Molecules 2004, 9
468
Scheme 1.
OAc
SeBn
NH
SeBn
(BnSe)2 / NaBH4
i. LiHMDS
NH
N
O
O
O
ii. BrCH2CO2Et
6
7
8
CO2Et
i. LiHMDS
SeBn
S
t
ii BrCH2CO2 Bu
N
O
N
N
S
O
OH
EtO2C
O
SeBn
11
SeBn
THF / CH2Cl2
DCC
DCC
N
N
CO2H
CO2Et
CO2t-Bu
CO2Et
O
O
Me
S
SeBn
S
10
9
S
N
O
N
SMe
N
HO
Me
O
Me
EtO2C
O
13
The Barton ester proved to be quite labile and was not purified. Rather, a concentrated solution
of 11 was transferred into benzene, after which irradiation with a tungsten lamp for about two hours
resulted in a distinct colour change and the appearance of several components by TLC. The
dominant TLC spot was isolated and characterized and proved to be the required ethyl 1-aza-7-oxo-
4-selenabicyclo[3.2.0]heptane-2-carboxylate (12) which was isolated in 35% yield (based on 10) as
an inseparable mixture of diastereoisomers (Scheme 2). Attempts to improve the yield through
irradiation at 0° or at reflux, or thermolysis in the dark did not result in any significant
improvement. Presumably 12 arises through a mechanism involving intramolecular homolytic
substitution at selenium (Scheme 2).
We were pleasantly surprised, however, to find significant improvements through the use of the
thiohydroximate ester derivative 13 of compound 10 as described recently by Kim [12]. The
thiohydroximate ester 13 was prepared by the action of N-methylhydroxydithiocarbamate and
dicyclohexylcarbodiimide (DCC) on the carboxylic acid 10. It was stable to purification by column
chromatography, and was isolated as a thick yellow oil. When the radical precursor 13 was
irradiated in benzene as described above for 11, the required selenapenam 12 was isolated in 71%
yield.
Interestingly, the diastereomeric ratios ranged from 1:1 to 8:1 depending upon conditions,
however, upon standing, epimerization to a single diastereoisomer 14 was observed within 72 hours
77
(Scheme 2). Selenapenam 14 displayed a signal at δ 301.0 in its Se NMR spectrum, as well as a
doublet of doublets at δ 3.69 for the proton at position-2 in 14 in the 1H-NMR spectrum. Coupling
constants of 3.9 and 15.9 Hz for this proton are indicative of the relative stereochemistry depicted
in 14.

Molecules 2004, 9
469
Scheme 2.
Ph
Se
Se
Se
hν and/or ∆
¡
11 or 13
N
N
N
O
O
O
CO2Et
CO2Et
CO2Et
12
14
While the synthesis described above affords the general core structure of a β-lactamase
inhibitor, we were also interested in the preparation of selenium-containing analogues of penem
β-lactam antibiotics (eg. 15). To that end, the commercially available, optically pure, 4-acetoxy-
azetidinone 16 was converted into the benzylseleno derivative 17 as described above for the
preparation of 7, with complete retention of configuration (de > 98%). Because of the
susceptibility of the protecting group in 17 to acidic workup, it was necessary to subtly change the
order in which the subsequent steps were executed to that described in Scheme 1. The selenide 17
was reacted with t-butyl bromoacetate under alkaline conditions (LiHMDS) to afford the ester 18 in
86% yield. Subsequent reaction with ethyl bromoacetate and LiHMDS, followed by careful barium
hydroxide hydrolysis provided the acid 19 as a 7:1 mixture of diastereoisomers in 68% yield.
Further conversion of 19 into the thiohydroximate ester 20 and photolysis as described above
afforded the required selenapenam 21 in 35% yield (based on 19) (Scheme 3). Once again, NMR
spectroscopy provided evidence for the formation of 21, in particular, the penam displayed a signal
at δ 279.8 in its 77Se-NMR spectrum.
Scheme 3.
OTBDMS
H
OTBDMS
H
OTBDMS
H
OTBDMS
H
SeBn
OAc
SeBn
SeBn
t
NH
17
NH
16
N
N
CO2 Bu
CO2H
O
O
O
O
t
18
19
CO2 Bu
OTBDMS
Se
OTBDMS
SeBn
OTBDMS
Se
S
N
O
N
O
t
SMe
N
CO2 Bu
N
O
15
tBuO2C
O
O
Me
t
CO2 Bu
21
20
Finally, with the aim of exploring other biologically important selenium heterocycles, we
considered the feasibility of preparing benzo-fused systems such as that found in 12,2a-dihydro-
1H,8H-azeto[2,1-b][1,3]benzoselenazin-1-one (22). Therefore, 17 was reacted with 2-(bromo-
methyl)iodobenzene under alkaline conditions to afford the aromatic iodide 23 in 65% yield.
Reaction with triphenyltin hydride (0.015M) under standard radical conditions (AIBN, refluxing
benzene) afforded the required product 24 in 59% yield, together with the uncyclized (directly

Molecules 2004, 9
470
reduced) byproduct 25 demonstrating, once again, that intramolecular homolytic substitution
chemistry is a versatile method for the construction of selenium-containing rings (Scheme 4).
Selenide 24 exhibited a signal at δ 311.8 in its 77Se-NMR spectrum.
Scheme 4.
OTBDMS
OTBDMS
H
OTBDMS
H
Se
Br
SeBn
SeBn
Ph3SnH
I
N
O
N
NH
17
AIBN / PhH / ∆
LiHMDS
O
24
O
I
+
23
OTBDMS
H
SeBn
Se
N
O
N
O
22
25
Conclusions
We have presented work toward the preparation of novel selenium-containing compounds with
potential β-lactamase inhibitory properties and have demonstrated that intramolecular homolytic
substitution is an effective method for the preparation of these ring system that include the 1-aza-7-
oxo-4-selenabicyclo[3.2.0]heptane and 12,2a-dihydro-1H,8H-azeto[2,1-b][1,3]benzoselenazin-1-
one core structures.
Acknowledgements
Financial support from the Australian Research Council is gratefully acknowledged.
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