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192 Chemistry and Biology of Beta-Lactams
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92. Banik BK, Raju VS, Manhas MS, Bose AK. Tetracyclic isoquinolones and quinazolones via aryl radical
cyclizations. Heterocycles. 1998;47:639–642.
93. Ng S, Banik I, Okawa A, Becker FF, Banik BK. Synthesis of tricyclic β-lactams via palladium acetate
mediated heck reaction. J Chem Res. 2001:118–119. d oi:10.3184/030823401103169199
94. Ghatak A, Becker FF, Banik BK. Indium-mediated facile synthesis of 3-unsubstituted ferrocenyl
β-lactams. Heterocycles. 2000;53:2769–2773.
95. Das A, Banik BK. Advances in heterocycles as DNA intercalating cancer drugs. Phys Sci Rev.
doi:10.1515/psr-2021-0065
96. Das A, Banik BK. Advances in heterocycles as DNA intercalating cancer drugs. In: Heterocyclic
Anticancer Agents. De Gruyter; 2022:111–160. doi:10.1515/9783110735772-0 04
97. Banik BK, Das A. Natural Products as Anticancer Agents. Elsevier; 2023.
98. Yadav RN, Srivastava AK, Banik BK. Microwave-induced bismuth nitrate-catalyzed michael reaction
of 3-amino beta-lactams with enones. Asian J Chem. 2020;32:233–236.
99. Das A, Yadav RN, Banik BK. Microwave-induced conversion of electromagnetic energy into heat
energy in different solvents: Synthesis of β-lactams. Chem J Mold. 2022;17(1):62–66. doi:10.19261/
cjm.2021.864
100. Das A, Banik BK. Dipole moment studies on beta lactams. In: Banik BK, ed. Green Approaches in
Medicinal Chemistry for Sustainable Drug Design. Elsevier; 2023.
101. Das A, Banik BK. β-Lactams: Geometry, dipole moment and anticancer activity. J Indian Chem Soc.
2020;97(11b):2461–2 467. d oi:10.5281/zenodo.5656689
102. Das A, Alqashqari AA, Banik BK. Quantum mechanical calculations of dipole moment of diverse
imines. J Indian Chem Soc. 2021;97(9b):1563–1566.
103. Das A, Banik BK. Dipole moment studies on α-hydroxy-β-lactam derivatives. J Indian Chem Soc.
2021;97(9b):1567–1571.
104. Das A, Banik BK. Dipole moment and anticancer activity of beta lactams. Indian J Pharm Sci.
2021;83(5):1071–1074. doi:10.36468/pharmaceutical-sciences.862
105. Das A, Banik BK. Computational studies of physicochemical parameters on optically active anticancer
β-lactams. Heterocycl Lett. 2023;13(1). doi:10.36468/pharmaceutical-sciences.862
106. Das A, Banik BK. Studies on dipole moment of penicillin isomers and related antibiotics. J Indian
Chem Soc. 2020;97:6.
107. Das A, Banik BK. Dipole moment in medicinal research: Green and sustainable approach. In: Banik
BK, ed. Green Approaches in Medicinal Chemistry for Sustainable Drug Design, Advances in Green
and Sustainable Chemistry. Elsevier; 2020:921–964.
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Approaches in Medicinal Chemistry for Sustainable Drug Design. Elsevier; 2024.
109. Das A, Das A, Banik BK. Inuence of dipole moments on the medicinal activities of diverse organic
compounds. J Indian Chem Soc. 2021;98(2):100005. doi:10.1016/j.jics.20 21.100005
6
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Solid Support-Mediated Beta-Lactam Synthesis
Bimal Krishna Banik1 and Aparna Das
1
Department of Mathematics and Natural Sciences, College of Sciences and
2
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: Bimal Krishna Banik, email: bimalbanik10 @gmail .c om;
bbanik @pmu .edu . sa; Aparna Das, email: aparnadasam @gmail . com
6.1 Introduction
Since Fleming discovered the primitive antibiotic penicillin, which has a unique beta-lactam (2-azetidinone) ring, in the year 1928,1 the importance of this class of compounds in human healthcare had been
continuously on the rise, improving the quality of healthcare as a whole since that time. As a matter of
fact, the beta-lactam skeleton can also be found in a wide variety of other antibiotics, such as cephalosporins, carbapenems, carbacephems, oxacephems, and monobactams, among them (Fig u re 6.1).
It is the combination of their potent antibacterial properties4, 5 and the exceptionally low toxicity6 of
these compounds to the host cells which has contributed to their widespread popularity in addition to
their effectiveness against a wide spectrum of Gram-positive and -negative pathogens. In subsequent
studies, they have also been shown to possess additional useful properties, such as their ability to lower
cholesterol absorption,7, 8 their antiviral properties, their anticancer properties,9, 10 and their effectiveness
in treating Parkinson’s disease and other neurological disorders. In spite of this, their uncontrolled usage,
often without adequate supervision, has resulted in the alarming situation where a number of pathogens
have developed beta-lactamase enzymes capable of deactivating the drug molecules, thus becoming
drug resistant. The high drug resistance of deadly pathogens has necessitated the development of novel
beta-lactam derivatives capable of overriding these drug resistance mechanisms.11 It has also been demonstrated that several beta-lactam compounds can be used as versatile synthons for the synthesis of a
variety of enantiopure amino acids and heterocyclic molecules.
There are various routes for the synthesis of beta-lactam rings, but the most common way is through
the Staudinger reaction,14 which was invented in the year 1907, which was a long time before penicillin
antibiotics were isolated from microorganisms. In recent decades, much effort has been spent by chemists around the globe to develop a wide variety of bioactive beta-lactams (mono-, bi-, and tricyclic) that
can be synthesized in highly diastereo- and enantioselective manner. The Staudinger reaction (reaction
between ketene and imine) is one of the most commonly used methods for preparing beta-lactam rings.
During the course of studies on beta-lactams, our research group has synthesized
dipole moments of these types of molecules.
Other methods include [2 + 2] cycloaddition of olens and isocyanates, cyclization of 3-aminopropanoic acid derivatives, carbonylative ring expansions, intramolecular ring expansion of three-membered
rings, and ring contraction of ve-membered rings (Scheme 6.1).
In the past, asymmetric synthetic approaches in solution have been reviewed by several authors.
a result of the increasing incidence of drug resistance among pathogens, efforts have been diverted toward
the development of suitable derivatives of the active compounds utilizing combinatorial approaches. As
18–24, 31–35
12, 13
15–30
2 ,3
and studied the
36, 37
As
DOI: 10.1201/9780367816339-6
193
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FIGURE 6.1 Various beta-lactam antibiotics.
SCHEME 6.1 A description of the steps toward the synthesis of a beta-lactam ring.
a result of the fact that solid state-mediated chemical reactions can generate asymmetric compounds
with little to no workup, thereby eliminating the need for cumbersome chromatography-based purication procedures, this eld soon attracted several chemists. It is also worth noting that the SPS synthesis
method allows the separation of excess reagents from resin-bound substrates/products by simple ltration. This allows the addition of large amounts of reagents to ensure that the reaction is completed and
that the unused reagents can be recovered efciently.
In addition to all of these aspects, the “pseudo-dilution effect” is achieved as a result of immobilization of the substrates to resins, which prevents unwanted homocouplings
38, 39
and intramolecular
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macrocyclizations.40 The focus of this chapter is on the development of solid-phase syntheses, which are
used to prepare a variety of beta-lactam derivatives.
6.2 Solid-Phase Synthesis of β-Lactams (2-Azetidinone)
6.2.1 Synthesis of β-Lactams Through Resin-Bound Ketenes
As Jarrahpour et al.41 showed, they used a different approach by immobilizing the ketene on Merrield
resin42 and treating it with a solution of imine-containing Vilsmeier reagent and triethyl amine to yield
excellent yields of polymer-tethered trans-beta-lactams. It was possible to easily separate the products
from the resin, resulting in either 4-carboxy phthalimido- or 3-amino beta-lactams by the use of TFA
or methyl hydrazine for cleavage. The key steps involved are as follows: attaching the carboxy end of
the trimellitic anhydride in the presence of triethyl amine, treating the same with glycine to yield phthaloyl glycine (toluene, reux, 24 hours), and performing the Staudinger reaction by combining appropriate imines, Vilsmeier reagent, and TEA in dry DCM as the solvent at room temperature to produce
trans-beta-lactams supported by a polymer (Scheme 6.2 and Scheme 6.3). It should be noted that cis-3phthalimido-beta-lactams can be exclusively prepared by cyclizing imines with activated acetic acidderived ketenes, which are the products of the cyclization of imines.
It has also been demonstrated that resin-bound ketenes can be used to synthesize multicyclic betalactam derivatives.44 A couple of compounds (Figure 6.2) have been noted for their potential potency
as beta-lactamase enzyme inhibitors and antibiotics,
45, 46
while another two are inhibitors of cholesterol
absorption (CAIs) as well as cytotoxic against human cancer cell lines (Figure 6.3).47 We have conducted a systematic analysis of a number of diverse organic compounds in order to determine whether
or not they have anticancer activities in various cell lines both in vitro and in vivo. There are a variety
of chemical structures of anticancer agents, and some of these molecules have chiral centers that have
cyclic or noncyclic rings within them.
48–62
To be able to create medicinally active compounds, theoretical
approaches have been found to be helpful. It is possible to prepare a large number of compounds with
anticancer effects by a variety of green methods, including organocatalysis.
reaction is used to make the methods faster, since it speeds up the reaction process.
43
63–66
A microwave-assisted
67–80
Additionally,
SCHEME 6.2 Reagents and condition: a) NH2CH2COOH; b) R1N=CHR2, Et3N; c) 10% TFA in CH2Cl2; d) MeNHNH2.
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SCHEME 6.3 Mechanism induced by Vilsmeier reagent and triethyl amine.
FIGURE 6.2 Beta-lactam derivatives with beta-lactamase enzyme inhibitory and antibiotic activity.
FIGURE 6.3 Beta-lactam derivatives with cytotoxic and CAI activity.
our group has demonstrated that tellurium can be used for the synthesis of organic compounds that are
similar to many natural anticancer agents that have been shown to possess anticancer properties.
81–92
Using resin-bound phenoxy acetic acid, activated with Mukaiyama reagent and phenanthridine, it
was initially demonstrated that it was possible to synthesize multicyclic carbacephem derivatives with a
yield of 57% (Scheme 6.4), which was much higher than the yield achieved under homogeneous reaction
conditions.
93
Interestingly, the stereochemistry of the ring fusion has been found to be trans, as expected for the
closure of multicyclic rings. A number of 1,2-benzofused carbacephems were synthesized later using
derivatives of 3,4-dihydroisoquinoline as imines in the synthesis. As a result, the nal removal of the
desired product from the resin was very difcult, regardless of the fact that the 3,4-dihydroisoquinoline
under SP conditions allowed the desired products to be formed readily. In contrast, it was possible to
easily separate products of other isoquinoline derivatives from the resin by using 10% TFA in DCM
(Scheme 6.5).
As a result of the Staudinger reaction between Merrield resin-bound imine and acid chloride in
CH2Cl2 at −78°C, followed by cleavage by sodium methoxide, cis-beta-lactam derivatives were obtained
(Scheme 6.6).
94
SCHEME 6.4 Reagents and condition: a) Mukaiyama reagent, Et3N; b) 10% TFA in CH2Cl2.
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197Solid Support-Mediated Beta-Lactam Synthesis
SCHEME 6.5 Reagents and condition: a) Mukaiyama reagent, Et3N; b) 10% TFA in CH2Cl2.
SCHEME 6.6 Reagents and condition: a) RCH2COCl, NEt3; b) NaOMe, MeOH:THF.
6.2.2 Synthesis of Beta-Lactams Through Resin-Bound Imines
Furthermore, Wang resin-bound imines were converted to beta-lactams via Staudinger reaction; these
beta-lactams were then cleaved from the resin with TFA and subsequently treated with thionyl chloride
to give the nal product (Scheme 6.7).
Scheme 6.7 Reagents and condition: a) RCH2OCH2COCl, NEt3; b) TFA; c) SOCl2.
The solid-phase asymmetric synthesis of 3,4-disubstituted beta-lactams using chiral auxiliary molecules has been described by Delpiccolo and Mata95 (Scheme 6.8–6.9). It has been shown that in the presence of triethyl amine, an asymmetric Staudinger reaction occurs between solid-supported imine and
acid chloride attached to oxazolidinone moiety as a chiral auxiliary. In order to produce the 3,4-substituted beta-lactams, the resultant solid-supported beta-lactams were cleaved using 10% TFA in CH2Cl2,
and their esterication was accomplished using diazomethane (Scheme 6.8).
An asymmetric Staudinger reaction has also been performed as shown in Scheme 16 between solidsupported chiral imines and acid chlorides using a similar approach.
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SCHEME 6.7 Reagents and condition: a) RCH2OCH2COCl, NEt3; b) TFA; c) SOCl2.
SCHEME 6.8 Reagents and condition: a) Et3N; b) i) TFA; ii) CH2N2.
SCHEME 6.9 Reagents and condition: a) R2COCl, Et3N; b) i) 10% TFA in DCM; ii) CH2N2.
SCHEME 6.10 Reagents and condition: a) R1CH2CO2H, Et3N, CHCl3; b) i) 10% TFA; ii) CH2N2.
In a comprehensive study, different commercially available resins have been evaluated for their efcacy
in the synthesis of 3,4-disubstituted beta-lactams.96 For the purpose of preparing libraries of 3,4-disubstituted beta-lactams, several in situ -synthesized ketenes were reacted with immobilized imines bound to
different resins (Scheme 6.10). As a result of these studies, Wang resin was found to be the most efcient
for these types of reactions.
With the help of Staudinger reaction, Ruhland et al. synthesized the structurally diverse beta-lactams on solid supports under a variety of conditions.96 The resin was modied with a photolabile amide
linker,97 and in order to release the beta-lactams from the resin, photolysis at a wavelength of 365 nm
was used (Scheme 6.11).
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SCHEME 6.11 Reagents and condition: a) 30% piperidine in NMP; b) R2CHO in 1:1 (MeO)3CH:CH2Cl2; c) R3CH2COCl,
NEt3; d) 3% TFA in DCM.
SCHEME 6.12 Reagents and condition: a) NaHCO3, DMSO; b) 4 Å MS, Dean–Stark trap, benzene, reux; c) Et3N,
Mukaiyama reagent; d) i) 10% TFA in DCM; ii) CH2N2.
It has been shown that aliphatic cross-metathesis reactions have been successfully conducted on the
appropriate solid-supported aliphatic moieties.
into aldehyde and then imine, followed by Staudinger reaction using appropriate carboxylic acid activated by Mukaiyama reagent in order to generate a library of trans-beta-lactams (Scheme 6.12) that will
be used for the evaluation of cholesterol absorption-lowering properties.
Another study described the synthesis of 1,3,4-trisubstituted beta-lactams via the conventional
Staudinger reaction. These beta-lactams were then converted into beta-thiolactams by the use of
Lawesson’s reagent (Scheme 6.13 and Scheme 6.14).
resin-bound beta-lactams from commercially available Fmoc-Gly-Wang resin via the classical Staudinger
reaction. To obtain resin-bound beta-thiolactams from beta-lactams, Lawesson’s reagent was used to thionate the beta-lactams.
After that, using CH2N2, the resultant free acid is esteried to give 1,3,4-trisubstituted beta-thiolactams.
There are a number of uses for beta-thiolactams, which are useful for the rapid generation of chemical
98, 99
This process involves the conversion of the product
100
101
Three steps were taken for the preparation of
102, 103
Using 10% TFA in CH2Cl2, the lactam was then cleaved from the resin.
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SCHEME 6.13 Reagents and condition: a) R2CHO, 1% v/v AcOH in DMF; b) Et3N, R1CH2COCl; c) Lawesson’s reagent,
toluene, 95°C; d) i) 10% TFA in CH2Cl2; ii) CH2N2.
SCHEME 6.14 Mechanism of thionation by Lawesson’s reagent.
libraries that can be used for conducting biological screenings. This was the rst report of synthesis of
beta-thiolactams on a solid support.
There have been reports describing the synthesis of 1,4,4-trisubstituted 2-azetidinones by two
approaches involving base-promoted intramolecular alkylations
anchored to solid supports (Scheme 6.15 and 6.16 ).
105
With the rst method, phenylalanine esters were
104
of N-chloroacetyl-Phe derivatives
loaded into the solid support through a reductive amination procedure using sodium cyanoborohydride
as a reducing agent. By treating the resultant amine with chloroacetyl chloride in the presence of propylene oxide (an HCl scavenger), the respective N-chloroacetyl Phe derivatives were generated, which were
further converted into resin-bound beta-lactams using phosphazene base BTPP as a cyclization agent.
Lastly, it was cleaved from the resin by using TFA in order to separate it (Scheme 6.15).
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SCHEME 6.15 Reagents and condition: a) i) H-L-Phe-OR1, DMF; ii) NaBH3CN, DMF; b) propylene oxide, ClCH2COCl,
DMF; c) BTTP, NMP; d) TFA.
A second approach relies on tethering the carboxylic acid of the Fmoc-Phe-OH as an ester resin, and
then following a similar procedure to that described above, the beta-lactams are synthesized by applying
a similar approach (Scheme 6.16).
It has been demonstrated that the Staudinger reaction can be used to synthesize beta-lactams in the
solid phase.
106
It is described how the Staudinger reaction can be used to synthesize cis-azetidinones
on solid supports. In the end, the products are obtained in high purity without the need for further
purication. The formation of azetidinones via the formation of imines from resin-bound aldehydes is
one method of synthesizing azetidinones. As a result of a reaction between several primary amines and
resin-bound paracarboxaldehyde, a component known as the imine component was formed. In anhydrous dichloromethane in the presence of molecular sieves or trimethylorthoformate, excess amine is
then added to the aldehyde in the presence of anhydrous dichloromethane, resulting in different types of
imines (Scheme 6.17).
By ltration, the resin-bound imines were isolated, excess amines were washed out with dichloromethane, and the resin was dried after which it was used for the subsequent formation of lactams. It
should be noted that the Staudinger reaction is achieved by treating the imine in dichloromethane with
acetoxyacetyl chloride in the presence of triethylamine for the formation of the desired azetidinone
at 0°C or at room temperature. When this cycloaddition occurs at 0°C in a solution phase, it typically
requires chromatographic purication; however, with solid-phase synthesis, this problem can be easily
overcome.
Based on the initial NMR studies of the Staudinger reaction products, it was found that only cisazetidinones were produced as a result of this reaction. A mild condition was used to remove the acetoxy
group by treating it with potassium carbonate in methanol and dichloromethane overnight at room temperature to remove the acetoxy group. The alcoholysis of the azetidinone ring was found to occur when
more than 1.3 equivalents of potassium carbonate were used in the reaction. It was also investigated
whether sodium methoxide could be used to remove the acetoxy group as well; however, this proved to
be less effective. As a result of NMR and mass spectrometry data, it was possible to conrm the structure of 3-hydroxy azetidinone derivative. The carbonate derivative was obtained by reacting azetidinone
with p-nitrophenyl chloroformate in dichloromethane with N,N-diisopropylethylamine present in the
mixture. As the nal step in the process, the carbamate was formed as a result of the treatment with
a primary or secondary amine in dichloromethane (Scheme 6.18). In general, this reaction was able to
tolerate a large excess of amine without causing any undesirable cleavage of the azetidinone amide bond
to occur in the reaction.
An overview of some of the preliminary results obtained by applying the methodology can be found
in Tab le 6.1. There is no doubt that the yields of the solid-phase synthesis of azetidinone indicate that
the synthesis can be carried out efciently. A range of amines including alkyls, aryls, and anilines
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