Highly Stereoselective Synthesis of Saccharin-Substituted β-Lactams via in Situ Generation of a Heterosubstituted Ketene and a Zwitterionic Intermediate as Potential Antibacterial Agents

Article abstract of DOI:10.1021/acs.orglett.5b01309

Highly stereoselective synthesis of saccharin derivatives containing functionalized 2-azetidinone moiety was achieved starting from saccharin as an available precursor. The approach to these valuable heterocyclic scaffolds involves a formal [2π + 2π] cycloaddition between Schiff bases and the saccharinylketene as a novel ketene which was generated in situ and an electrocyclic reaction of a zwitterionic intermediate. The identification of the ketene was confirmed by reaction with the stable free radical TEMPO (TO?). Also, the antimicrobial activities of some new substituted saccharin against nine standard bacteria, four bacteria which were isolated from clinical samples and one yeast, were evaluated.

Full text of DOI:10.1021/acs.orglett.5b01309

Letter
pubs.acs.org/OrgLett
Highly Stereoselective Synthesis of Saccharin-Substituted β‑Lactams
via in Situ Generation of a Heterosubstituted Ketene and a
Zwitterionic Intermediate as Potential Antibacterial Agents
Zahra F. A. Mortazavi,† Mohammad R. Islami,*,† and Moj Khaleghi‡
†Department of Chemistry, Shahid Bahonar University of Kerman, 22 Bahman Avenue, 76169 Kerman, Iran
‡Department of Biology, Shahid Bahonar University of Kerman, 76169 Kerman, Iran
S
* Supporting Information
ABSTRACT: Highly stereoselective synthesis of saccharin
derivatives containing functionalized 2-azetidinone moiety was
achieved starting from saccharin as an available precursor. The
approach to these valuable heterocyclic scaffolds involves a
formal [2π + 2π] cycloaddition between Schiff bases and the
saccharinylketene as a novel ketene which was generated in situ and an electrocyclic reaction of a zwitterionic intermediate. The
identification of the ketene was confirmed by reaction with the stable free radical TEMPO (TO•). Also, the antimicrobial
activities of some new substituted saccharin against nine standard bacteria, four bacteria which were isolated from clinical samples
and one yeast, were evaluated.
Scheme 1. Synthesis of Four- and Six-Membered Rings by
Reaction of the Ketenes
β-Lactams (2-azetidinones) have been recognized as the central
motif of antibiotics such as penicillins, cephalosporins, and
carbapenems.1−4 The history of the first synthetic β-lactam
dates back to 1907, when H. Staudinger reported that he added
zinc powder to 2-chloro-2,2-diphenylacetyl chloride in the
presence of an imine and 2-azetidinone was formed as the final
product.5 There are many reports in the literature about the
synthesis and application of such compounds.6−9 Practical
chemistry for introducing new organic molecules with func-
tional groups as potential synthons for new drug discovery is
also an important current need in medicinal chemistry.10−12
One of the most important methods for the synthesis of 2-
azetidinones is the use of ketenes. Ketenes are highly reactive
species in many organic reactions and are usually used in
organic synthesis to prepare four- and six-membered rings
(Scheme 1).13−17
Ketenes are remarkable for the variety of ways in which they
can be prepared18−21 and also for the range of useful products
from their reactions with unsaturated compounds.22,23 They
have long been known for their unique reactivity in [2 + 2]
cycloaddition reactions.24,25 Saccharin, benzisothiazole deriva-
tive, is the foundation for many low-calorie and sugar-free
products around the world.26,27 It is used as sweeteners, baked
goods, jams, chewing gum, canned fruit, candy, dessert
toppings, and salad dressings.26,28 It has been used in medicinal
chemistry29 and is a substituent in several drug molecules such
as Ipsapirone (Figure 1).30−32
To the best of our knowledge, saccharin has not been
employed as a substituent for the synthesis of β-lactam (2-
azetidinone). In this present work, we have synthesized new
saccharins including a β-lactam ring, as the central motif for
antimicrobial properties, in a highly stereoselective manner by
in situ producing the corresponding ketene and trapping it by
different Schiff bases and from a zwitterionic intermediate. It is
important to note that in this plan we used saccharin as a
precursor which is safe for human consumption and there is an
urgent need for new antibiotic capable of treating infection
Received: May 5, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01309
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Synthesis of 9 from Saccharinylacetyl Chloride
Figure 1. Ipsapirone drug.
caused by bacteria. Herein we would like to report the results of
our investigation about novel heterocyclic compounds
including two parts, saccharin and 2-azetidinone rings, as
potential antibacterial compounds.
To prepare saccharinylacetic acid 4 as a precursor by
modified Gabriel synthesis, potassium saccharin 2 was mixed
with 2-bromoacetic acid 3 and heated until they melted then
heating was continued for 6 h. Upon cooling to room
temperature, the desired product 4 was formed as a solid and
recrystallized from water and was used in the next reactions
(Scheme 2).
toluene and hexane at reflux condition in a 64% and 49%,
respectively (Table 1, entries 5 and 6). The best result was
obtained when the reaction was run in two steps using an acid/
reagent/base/Schiff base ratio of 2.0:2.1:2.0:2.0 in 80% yield
(Table 1, entry 3).
The reaction of N-saccharinylacetic acid 4 and Mukaiyama
reagent 6 with Et3N 5 in CH2Cl2 in the presence of imines 8
led to the formation of azetidinones 9. The reaction was found
to be highly stereoselective, and the trans-isomers were formed
as the only products (Table 2).
Scheme 2. Synthesis of Saccharinylacetic Acid 4
Table 2. Saccharin Derivatives 9 from N-Saccharinylktene 7
and Imines
a
9
Ar2
Ar1
yield (%) trans
9a
9b
9c
9d
9e
9f
Ph
Ph
Ph
Ph
Ph
Ph
80
65
55
50
77
69
67
63
51
56
86
4-BrC6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
Ph
4-ClC6H4
4-MeC6H4
4-MeOC6H4
Ph
Several methods are used for activating carboxylic acids. In
many cases where a carboxylic acid with strongly sensitive
functional groups to acid media such as amide group, the use of
Mukaiyama reagent 6 is better than other reagents. We
previously used this reagent for the synthesis of 2-azetidinones
at room temperature.33,34 While this method is certainly very
promising and provides the mentioned products, it suffers from
one or more disadvantages such as low yield of products. For
overcoming this problem, we investigated the effect of reagent
ratios. Our studies commenced with the reaction of saccharinyl-
acetic acid 4, Mukaiyama reagent 6, and benzylidenephenyl-
amine 8 in the presence of Et3N 5 in CH2Cl2 at room
temperature, and the corresponding β-lactam was obtained in a
20% yield (Table 1, entry 1). Then the mentioned reaction was
run in two steps: first, compound 4 was heated under reflux
conditions with Mukaiyama reagent 6 in the presence of Et3N
for time t1 and then Schiff base and the base were added and
the reaction continued to reflux for t2 (Table 1, entries 2 and
3). Also, the preparation of the same β-lactam was performed in
toluene and hexane by the reaction of saccharinyl acetyl
chloride 10 with compound 8 in the presence of triethylamine
5 at different temperatures (Scheme 3). The results revealed
that the corresponding product was not observed in hexane at
room temperature (Table 1, entry 4) and it was obtained in
9g
9h
9i
Ph
Ph
Naphthyl
Naphthyl
Naphthyl
9j
4-MeC6H4
4-MeOC6H4
9k
a
Isolated yield of pure product.
The structure of the products was fully characterized by IR
and H and 13C NMR spectra along with elemental analysis
data. 1H NMR spectroscopy is generally used for distinguishing
between cis and trans-isomers of β-lactam using H−H coupling
constants. The J value is smaller (2−2.5 Hz) in a trans-isomer
than in a cis-isomer (5−6 Hz).24 1H NMR spectra of products
exhibiting the trans-β-lactams were formed as the only product.
1
1
The H NMR spectrum of 9a exhibited two doublets at δ =
5.49 and 5.04 ppm (3JHH= 2.6 Hz) for vicinal methine protons
along with a multiplet at δ = 8.11−7.13 ppm for phenyl ring
protons. The H-decoupled 13C NMR spectrum of 9a showed
1
18 distinct resonances in agreement with the suggested
structure; partial assignment of these resonances is given in
the Supporting Information (SI). Characteristic 13C NMR
signals were shown due to two carbonyl groups at δ = 159.79
and 158.38 ppm and signals at δ = 63.11 and 61.08 ppm for CH
Table 1. Optimization of Reaction Conditions for the Synthesis of 9
entry
compd
ratio (4 or 10)/(6)/(5)/(8)
solvent
base
t1 (h)
conditions
t2 (h)
yield (%)
1
2
3
4
5
6
4
2.0:2.4:5.0:2.4
2.0:2.1:2.0:1.0
2.0:2.1:2.0:2.0
1.5:0.0:1.6: 2.2
1.5:0.0:1.6:2.2
1.5:0.0:1.6:2.2
CH2Cl2
CH2Cl2
CH2Cl2
hexane
hexane
toluene
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
17
10
10
17
0.5
0.5
rt
0
10
10
0
20
70
80
0
4
reflux
reflux
rt
4
10
10
10
reflux
reflux
0
49
64
0
B
DOI: 10.1021/acs.orglett.5b01309
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
groups, respectively. The 1H NMR and 13C NMR spectroscopic
data of compounds 9b−k are presented in the SI. It is not clear
to us why the reaction efficiency increases when the reaction
take places in two steps. It seems the reaction goes in different
paths. Two possible explanations for the formation of products
are shown in Schemes 4 and 6. In the first mechanism, salt I is
by an electrocyclic ring closure reaction via conrotatory mode
(Scheme 6). In the last mechanism, ketene has not been
generated and the zwitterion intermediate II has completely
converted to β-lactams 9.
Scheme 6. Zwitterion Formation in β-Lactam Formation
Scheme 4. Synthesis of β-Lactam from Ketene as an
Intermediate
formed as an intermediate from the reaction of saccharinyl-
acetic acid 4 and Mukaiyama reagent 6 in the presence of Et3N
and then the saccharinylketene 7 is actually formed as an
intermediate.
The stereochemistry in the cycloaddition reaction between
ketene and imine involves initial attack of the imine onto the
ketene with formation of intermediate 11a which can undergo
ring closure to the cis-β-lactam 9 or it can convert to the less
crowded intermediate 11b and ring closure to trans-β-lactam 9
(Scheme 5).
To identify the saccharinylketene as an intermediate in the
synthesis of β-lactam ring, we have undertaken further reaction
of the mentioned ketene with aminoxyl radicals. Reaction of N-
saccharinylacetic acid 4 with Mukaiyama reagent 6 and Et3N in
the presence of TEMPO 12 [(2,2,6,6-tetramethyl-piperidin-1-
yl) oxyl] in CH2Cl2 at room temperature leads to capture of
ketene 7 by addition of two TEMPO radicals forming 14
(Scheme 7). 1H NMR spectrum of 14 showed signals in
agreement with the suggested structure. This spectrum
exhibited clearly one single proton at 5.95 ppm for methine
group.
Scheme 5. A Plausible Mechanism for Highly Stereoselective
Formation of trans-β-Lactam from Saccharinyl Ketene
Scheme 7. Reaction of N-Saccharinylacetic Acid with
TEMPO 12
Ketene 7 reacts with the stable free radical TEMPO (TO•)
by initial attack of the radical on the carbonyl carbon of the
ketene forming intermediate enolic radical 13, followed by
addition of a second TEMPO giving the 1,2-di-addition
product 14 (Scheme 8).
Five of the 11 β-lactams 9b, 9c, 9e, 9f, and 9g have been
screened for their antimicrobial activities. The results showed
Because saccharin is a large group, steric hindrance between
Ar of the imine and the saccharin side chain of the ketene in the
intermediate 11a causes k3 to be enhanced relative to k2 (k3 ≫
k2), trans-β-lactam 9 formed as the only isomer.
Scheme 8. Reaction Mechanism of TEMPO Radical
In the second possible mechanism, the reaction of imine 8
with salt I generates a zwitterionic intermediate II, which
proceeds onto lactam products. Zwitterionic intermediate II is
converted to an equilibrium mixture of IIIa and IIIc involving
IIIb. The trans-β-lactam is formed as an only product from IIIc
C
DOI: 10.1021/acs.orglett.5b01309
Org. Lett. XXXX, XXX, XXX−XXX

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ASSOCIATED CONTENT
* Supporting Information
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Detailed experimental procedures, compound characterization
1
data, H and 13C NMR spectra of compounds 9a−9k and
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compound 14. Antibacterial procedure and the SAS system
calculation. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01309.
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AUTHOR INFORMATION
Corresponding Author
■
(29) Banerjee, R.; Bhatt, P. M.; Ravindra, N. V.; Desiraju, G. R. Cryst.
Growth Des. 2005, 5, 2299−2309.
*E-mail: mrislami@uk.ac.ir. Phone: +98-343-322-2033.
Notes
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J.; Schweiger, U.; Hohagen, F.; Hajak, G. Neuropsychopharmacology
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors express appreciation to the Shahid Bahonar
University of Kerman Faculty Research committee funds for its
support of this investigation.
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(34) Zigheimat, F.; Islami, M. R.; Nourmohammadian, F. Synlett
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D
DOI: 10.1021/acs.orglett.5b01309
Org. Lett. XXXX, XXX, XXX−XXX