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52 Chemistry and Biology of Beta-Lactams
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2
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Monocyclic Beta-Lactams: Stereocontrolled
Synthesis by Diverse Methods
Bimal Krishna Banik1 and Aparna Das
“1
Department of Mathematics and Natural Sciences, College of Sciences and
Human Studies, Deanship of Research Development, Prince Mohammad
Bin Fahd University, Al Khobar 31952, Kingdom of Saudi Arabia.
2
Department of Mathematics and Natural Sciences, College of Sciences and Human Studies,
Prince Mohammad Bin Fahd University, Al Khobar 31952, Kingdom of Saudi Arabia.
*Corresponding authors: Aparna Das, email: aparnadasam @gmail .c om;
BimalKrishna Banik, email: bimalbanik10 @gmail .c om; bbanik @pmu .edu .sa
2
2.1 Introduction
Heterocyclic molecules have a great impact on medicines,1 which are associated with their ability to
interact with proteins.2 The discovery of β-lactams has been considered as the most important nding
of the 20th century. This has become the high-utility tool for humans to ght against diverse diseases.
2-Azetidinone, the chemical name of β-lactams, has remained as the most useful heterocycle since the
discovery of penicillin antibiotics.3 Many other analogues of penicillins have been included in the class
of antibiotics, for example, cephalosporins, monobactams, nocardicins, carbapenems, clavulanic acid,
sulbactams, and tazobactams.
Researchers have focused on the antibacterial activities of 2-azetidinones at the initial stage of research
on these types of molecules. Many other pharmacological functions of β-lactams have been discovered,
and therefore, interests in this eld have grown signicantly. For example, β-specic lactams have been
reported as antifungal, anti-inammatory, anti-diabetic, anti-HIV, anticancer, and anti-parkinsonian
agents.5 They have shown inhibition towards serine proteases and been found to act as luteinizing hormone–releasing hormone (LHRH) antagonist.5 They have found applications as thrombin inhibitor, cholesterol absorption inhibitor, human leukocyte elastase inhibitor, and inhibitors of viruses such as herpes
virus and Picornaviridae.5 The β-lactams have utility as synthetic intermediates in organic synthesis.6
The core structure of β-lactam is shown in Figure 2.1.
4
2.2 Classification of β-Lactams
The β-lactam derivatives have been classied under different categories. Different types of β-lactams are
available. For example, monocyclic, bicyclic, tricyclic, tetracyclic, biscyclic, spirocyclic, and heterocyclic
β-lactams are available (Figure 2.2).
2.3 Biological Activities of β-Lactams
As stated already, various biological activities have been seen in β-lactams (Figure 2.3).
DOI: 10.1201/9780367816339-2
55
56 Chemistry and Biology of Beta-Lactams
N1
C3 C4
Monocyclic
Bis -lactams
d
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N
O
FIGURE 2.1 General skeleton of β-lactam.
3
1
R
O
R2R
N
-lactams
4
R
5
R
N
O
Heteroaryl substitute
X
n
O
-lactams
X
n
N
X
n
NH
O
N
O
Bicyclic -lactams
FIGURE 2.2 Different types of β-lactams.
Antiviral
Antidiabetic
Anticancer
Antitubercular
O
HLE
inhibitor
N
O
N
O
Spirocyclic -lactams
N
N
O
Thrombin
inhibitor
-LactamAntimicrobial
Chymase &
Tryptase
inhibitor
Vasopressin
antagonist
Cholesterol
absorption
inhibitor
Antiparkinsonian
Antiinflammatory
& Analgesic
FIGURE 2.3 Diverse biological activities of β-lactams.
2.4 Construction of β-Lactams
Signicant research has been conducted in exploring various synthetic aspects of β-lactams.1 Most of the
methods for the construction of β-lactams are classied under two categories: cycloaddition and cyclization reactions.
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2.4.1 Cycloaddition Reactions
Cycloaddition reactions have exceptional contribution in organic synthesis. These reactions are useful
due to their excellent efciency. The synthesis of β-lactams can be performed using different types of
cycloaddition reactions. A few best methods include Staudinger cycloaddition, nitrone-alkyne cycloaddition, ester enolate-imine condensation, and isocyanate-alkene cycloadditions (Figure 2.4).
2
The ketene-imine cycloaddition reaction is the common method for the preparation of β-lactams.3 This
is because of the mild reaction conditions and accessibility of various substrates with different functional
groups.
2.4.2 Cyclization Reactions
These methods are useful. A few cyclization reactions can lead to a β-lactam ring that involves N1–C2
bond formation, N1–C4 bond formation, and C3–C4 bond formation.
2
The N1–C2 bond formation is achieved by cyclization of β-amino esters or β-amino alcohols.7 Some
bases such as LDA and LHMDS are required. In addition, cyclization of α-aminoketenes under basic or
photochemical conditions gives β-lactams.
The other cyclization for the formation of β-lactam ring is via N1–C4 bond formation.8 This method
needs β-haloenamide, β-amino alcohols, and β-hydroxamate esters.
The β-lactams can also be formed by a cyclization of C3–C4 bond, known as C-alkylation method
(Figure 2.5).
9
2.4.3 Other Methods
Some other strategies are also reported, such as metal-catalyzed carbonylation, ring expansion reactions,
C–H insertion reactions, and multi-component reactions.
10, 11
FIGURE 2.4 Synthesis of β-lactams by diverse methods.
58 Chemistry and Biology of Beta-Lactams
H
H
H
H
H
Aztreonam
OH
Tigemonam
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FIGURE 2.5 Synthesis of β-lactams via diverse cyclization methods.
R
N
OH
N
R
O
HOOC
Nocardicins
O
S
N
C
N
O
H
N
C
H
H
H
OCH
N
O SO
O
N
N
3
FIGURE 2.6 Clinically active monocyclic β-lactams.
O
S
H2N
3
-
+
Na
3
N
HOOC
N
O SO
Monobactams
O
NH
N
O
O O
-
+
Na
3
N
S
O
O
2.5 Monocyclic β-Lactams
Interestingly, nocardicin 1 is the rst β-lactam antibiotic containing monocyclic β-lactam ring, which
demonstrates that bicyclic ring in β-lactam antibiotics is not required. Other antibiotics that belong to
this group from this class are monobactams, aztreonam, and tigemonam (Figure 2.6).
Bhat et al.12 carried out synthesis of 2-(4- metho xyphe nylam ino)a cetam ido-s ubsti tuted 3-chloro-β-
lactams. These were subjected to in vitro antimicrobial test against four bacterial strains and one fungal
strain. These compounds showed good activity, and β-lactam with 4-nitroaryl group at C4 demonstrated
maximum potency.
Bagherwal et al.13 investigated monocyclic 3-chloro-β-lactam substituted with naphthylaminoacetamide and screened for potential antibacterial and antifungal activities. These compounds showed antimicrobial activities with maximum potency against Gram-positive strain. The β-lactams with 4-ClC6H4,
4-OMeC6H4, and 4-NMe2C6H4 demonstrated excellent antimicrobial activity (Figure 2 .7).
Rokade et al.14 reported the synthesis and antimicrobial evaluation of β-naphthol-derived 2-azetidinones. The antibacterial activity was screened against S. aureus, E. coli, and P. aeruginosa, while antifungal function was checked against A. niger. The chloro-, methyl-, and methoxy-substituted aryl groups
at C4 demonstrated excellent activity.
Gawande et al.15 reported microwave irradiation method for the synthesis of 2-azetidinone derivatives
followed by antibacterial test against a panel of Gram-positive and Gram-negative bacterial strains. The
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FIGURE 2.7 N-hydrazide/hydrazone-β-lactams.
SAR study revealed that electron-withdrawing property of C4 aryl substituents is responsible for the
antibacterial function. The bromo derivative was the most and the methyl derivative was the least active
in a series.
Patel et al.16 prepared benzamide-substituted β-lactam derivatives. The in vitro antibacterial test was
done against B. cereus, E. coli, B. subtilis, and S. aureus. β-Lactam derivatives with 4-hydroxyphenyl
group showed excellent results.
A few 4-ary l-3-c hloro -N-(3 ,4,5- trihy droxy benza mido) -2-az etidi nones were prepared by Ilango et al.17
Some activities were investigated against B. subtilis, S. aureus, S. mutant, E. coli, K. pneumonia, P. aeru-
ginosa, C. albicans, A. niger, and M. tuberculosis. The β-lactams with chlorophenyl and dimethylamino
group exhibited excellent activity with Minimal Inhibitory Concentration (MIC) values of 1.56–12.5 μg/
mL (antimicrobial) and 0.57–0.83 μg/mL (antitubercular). It was found that the electron-withdrawing
nature and bulky groups signicantly enhance the activities.
Halve et al.18 reported the synthesis and antimicrobial screening of N1–C4-substituted β-lactam. The
in vitro antimicrobial test was performed against anthracis, S. typhi, S. aureus, A. niger, A. fumigates,
and C. albicans. The β-lactams with m-Cl, p-Cl, and m-NO2 aryl groups showed good antibacterial and
antifungal activities. In addition, β-lactam with p-ClC6H4 group showed the best inhibitory function
against C. albicans (MIC 31.25 μg/mL). The azo derivatives of β-lactams were found to be less active.
A series of gallic acid-derived 2-azetidinones were prepared via cycloaddition reaction by Cao et
al.19 The authors investigated preliminary studies on these molecules for insecticidal activity against H.
60 Chemistry and Biology of Beta-Lactams
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armigera and P. xylostella. The compounds were found to be totally inactive against P. xylostella. Four
β-lactams displayed insecticidal activity against H. armigera at a dosage level of 200 μg/mL. β-Lactams
with Ph and iPr groups showed moderate activity. An introduction of electron-withdrawing groups (F,
Cl, and CF3) decreased the activities.
A few β-lactam derivatives anchored with 3,4,5-trimethoxyphenyl ring were described by Swamy et
al.20 These were synthesized via ketene-imine cycloaddition between 4-chlorophenoxyacetyl chloride
and hydrazide-hydrazones. All these compounds were screened against various bacterial strains for antibacterial activity. The results demonstrated that β-lactams with 3-NO2-4-F-C6H3 and 2-methylpyridine
groups have good potency.
Shah et al.21 synthesized 4-[(4 -(car boxyp henyl )-oxy )]-3, 3-die thyl- 1-[[( pheny lmeth yl)am ino]c arbon
yl]-2 -azet idino nes. The lead compound with two alkyl groups at C3 was stable with good inhibitory
activity. A few modications of this compound were conducted. These new β-lactam derivatives were
examined for in vitro as well as in vivo HLE inhibition. The results indicated that the methylene groups
between urea-N and aromatic ring improve enzyme inhibition. The presence of Me or OMe group at the
fourth position of phenyl ring improved in vitro and in vivo results. It was concluded that in vitro activities were improved in comparison to in vivo.
Green et al.22 synthesized, studied, and discussed the mechanism of human leukocyte elastase
(HLE) inhibition by monocyclic 3,3-dialkyl-β-lactams. The formation of reversible enzyme-inhibitor
complex and subsequent formation of acyl-enzyme complex were depended on the partition ratio
(k
, i.e., enzyme turnover and inactivation). The study indicated that substitution of urea at N1
cat/kinac
controls the stability of the molecule-derived HLE-I complexes. But the nature of C4 group did not
alter the stability of complex. The structural model β-lactam-generated acyl-enzyme complexes indicated different stabilities. This was explained due to an interaction with hydrophobic pocket and orientation of residue.
Borthwick et al.23 designed and synthesized 3-substituted/unsubstituted 2-azetidinones as human
cytomegalovirus (HCMV) protease inhibitors. The SAR investigations on N-urea-β-lactams identied
a compound with good aqueous solubility (Ki 5.7 μM) and stability (t
22.8). Moreover, the potent
1/2
β-lactam showed excellent selectivity for δAla HCMV (IC50 17 μM) in comparison to viral enzymes,
viz. acetylcholine esterase, elastase, and chymotrypsin (IC50 >10 0 μM). The anti-HCMV activity was
dependent on size, bulk of substituents, and relative stereochemistry (Figure 2.8).
Stereospecic synthesis of 4-[(4 -carb oxyph enyl) oxyl] -3,3- dialk yl-l- [[(l- pheny lalky l)-am ino]c arbon yl]
az etidi n-2-o ne was described by Finke et al.24 In this study, hydrolytic stability, in vitro inhibition for
HLE, and in vivo oral efcacy were investigated. A (4S)-β-lactam showed excellent inhibition. On the
other hand, t-butyl esters were more potent but less viable because of metabolic instability and aqueous
insolubility. In addition, racemic 3-β-ethyl β-lactam exhibited improved activity. It was concluded that
4R isomer of all the β-lactam shows poor activity. Also, increasing the size of the substituent diminished
the activ i t y.
Turos et al.9 investigated N-thiolated β-lactam antibiotics as anti-bacillus agent. The SAR studies
indicate to balance the lipophilic character of C3–C4 substituents of β-lactam ring to obtain optimal
anti-bacillus activity. 3-Allyloxy/propyloxy-β-lactams demonstrated better activity than the 3-methoxyβ-lactam, while benzoyl ester was weaker. The 3-arylsulfonyl-β-lactam was more active against Bacillus
microbes with respect to methanesulfonyl derivatives. The polar side chains had a detrimental effect,
which was seen in C3 amino derivatives. Moreover, replacement of the methoxy group at C3 with chloro
group increased anti-Bacillus activity, whereas iodo or azido groups exhibited lower activity. The m-
and p-substituted aryl systems at C4 demonstrated superior activity than o-substituted aromatic groups,
while no major change in activity was observed in different substitution patterns. Importantly, N-secbutylthio-β-lactam was proven to be most active.
Many series of N-thiolated β-lactams were tested for antifungal activity.10 Antifungal activity test was
performed against various Candida sp. These investigations proved that halogens (F or Cl) at para position of C4 aryl group on β-lactam nucleus were less active compared to ortho-substituted compound.
The presence of multiple halo groups signicantly improved the antifungal function. But changing the
C3 methoxy group with other alkoxy groups (PhO or AcO) decreased the antifungal activity. In addition,
increasing the bulk of N1 substituents of β-lactam ring (sec-butyl S and methyl S) decreased the activity.9
61Monocyclic Beta-Lactams
https://t.me/med1917
FIGURE 2.8 N-urea-β-lactams.
The antifungal activity of N-thiolated β-lactams was due to the cytostatic effects, which leads to the
disruption of structure of cytoplasmic membrane.
Cervellati et al.
11b
ty
against Gram-positive and Gram-negative strains including strains from cystic brosis (MRSA and
11a
investigated monocyclic N-methylthio-β-lactams with excellent antibacterial activi-
MSSA). The study was conducted to identify molecules with dual action (antibacterial and antioxidant).
The results indicated that β-lactams with polyphenolic substituents activated radical scavenging ability
against DPPH, ABTS, and HOO. The dual property was found in β-lactam bearing phenolic moieties on
hydroxyethyl side chains. The authors disafrmed the involvement of sulfur groups towards antioxidant
activity using CV measurements. The redox potential of β-lactams with sulfur substituents was found
to be 0.82–0.88 V in comparison to the redox potential of couples such as DPPH/DPPH (0.28 V) and
ABTS+/ABTS (0.68 V). This suggested that N-methylthio substituent is not prone to oxidation and so
phenolic groups are responsible for their activity (Figure 2.9).
McKittrick et al.
25a
synthesized and evaluated a series of C3 heteroatom-substituted β-lactams as
CAIs. These β-lactams were synthesized by introducing isosteric and isoelectronic groups (S, SO, SO2,
PO2Me, POOH) at 1’ and 3’ positions of the C3 side chain of SCH 56524. It was found that an alteration
at 3’ position of the C3 side chain lowers the activity, while changes at 1’ position resulted in increased
CAI. In addition, optically pure cis- and trans-β-lactams were prepared, and some of the compounds
showed multi-fold CAI activity (Figure 2.10).
Deziel et al.
25b
synthesized two novel peptidyl series and non-peptidic series of β-lactams. In a study,
26b
it was shown that C3 peptidyl β-lactams have good inhibition of HCMV protease (IC50 33 μM). So, SAR
studies were conducted by introducing C4 peptidic pharmacophore unit on β-lactam ring. The structural
alterations led to the identication of a β-lactam as the most potent inhibitor (IC50 0.07 μM) having a
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