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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5352_Библиотеки_им_академика_М_И_Перельмана
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162 Chemistry and Biology of Beta-Lactams
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electron charge with respect to the nucleus. The fourth pathway is due to the polarization of a material
that accumulates charges on the surface.
Thus, the material should have specic dielectric properties in order to be heated in the microwave
oven. The heating properties of a material depend on the ability to convert electromagnetic energy into
thermal energy. This ability is expressed as tan δ, the loss tangent. For rapid heating, solvents with high
tan δ are required. But solvents with low tan δ values can be used in microwave synthesis. The substrates
and the components of the reactions should be polar with low tan δ values. Reactants interact with microwaves in three main ways. The conducting materials (metals) reect microwaves, and therefore, heating
does not occur. Dielectric materials capture microwaves, and heating takes place. Water, acids, and polar
solvents absorb microwaves. Insulating materials are inert to microwave (polymers, quartz, or ceramics).
5.1.3 Differences Between Microwave and Conventional Heating
The temperature of the surface of the reaction container increases along with the internal components
during the conventional heating, and it is called wall heating. A large amount of energy is wasted. The
high surface temperature makes heat transfer from the outer part to the internal substances. An ununiform
sample temperature and higher thermal gradients are seen. It is known that heating through the conventional way is nonhomogeneous, and it depends on thermal conductivity power, heat capacity, and density
of substances. In contrast, microwave does not heat the whole materials. Electromagnetic enters into the
surface of a substance and causes double effects. A portion of the radiation reects from the outer surface,
and a part penetrates inside the material. The penetrated radiation interacts with the components (molecules and ions) of the substance. The radiation penetrates the materials at different depths depending
upon the nature of the substance. In microwave experiment, the penetration depth is crucial.
5.1.4 Benefits of Microwave Heating
Microwave heating has advantages compared to conventional heating. This method has no contact, minimized wall effect, precise electronic regulation, quick energy transfer, uniform heating, rapid reaction,
less side reactions, and excellent selectivity in product formation and operates in the absence of solvent.
5.1.5 Applications of Microwave Heating
Microwave heating has numerous applications in food business, industrial work, waste management,
medical treatment, analytical science, and above all organic and inorganic chemical synthesis. The
microwave-mediated synthetic methods have advantages compared to conventional methods in terms of
rapid reactions, better yield, less byproduct, better selectivity, being environmentally benign, and causing reduced pollution, and it also develops new reactions. Interestingly, reactions which were problematic
to conduct under conventional process were made possible with the microwave method.
Many synthetic methods using microwave under both homogeneous and heterogeneous conditions
to prepare compounds were conducted. The microwave-induced synthesis has been used to carry out
diverse organic reactions including cycloaddition, coupling, cyclization, rearrangement, organocatalysis,
condensation, cleavage, radical, hydrogenation, alkenylation, protection-deprotection, oxidation-reduction, hydrolysis, dehydration, epoxidation, esterication, Heck reaction, Diels–Alder reaction, Suzuki
reaction, and Mannich reaction.
Our research group has used microwave-assisted beta-lactam chemistry extensively.
5.2 Ultrasound-Assisted Reactions
Ultrasound-assisted synthesis (sonochemistry) was initiated in the early 20th century. The range of
ultrasound waves (20 kHz to several megahertz (MHz)) can change depending on the application and
the equipment. The choice of frequency depends on the reaction nature. Ultrasound-induced reactions
have demonstrated applications in organic chemistry, nanomaterials, pharmaceuticals, and materials
163Microwave and Ultrasound in Beta-Lactam Chemistry
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science. Ultrasound enhances mass transfer, accelerates dispersion, promotes cavitation, and helps to
create localized heat.
The ultrasound-assisted effects on reactions were rst noted by Sir William Ramsay and Sydney
Young in 1883. Later, Friedrich Heyl and Adolf Muckenfuss in 1933 showed an ultrasound-induced
enhanced reactivity of halogens. Kenneth S. Suslick conducted experiments on sonochemistry and identied the cause of enhancing chemical reactions. Many investigations studied the ultrasound-induced
effects of cavitation, streaming, and high-temperature/pressure environments. Ultrasound-mediated
organic synthesis received signicant attention. Many studies showed its power in accelerating process
and catalyzing reactions.
5.2.1 Development of Ultrasound-Assisted Reactions
The ultrasound in chemical reactions began to gain attention during 1950–1960. During 1970–1980,
scientists started investigating the ultrasound in pharmaceutical development. This was used to improve
reaction kinetics and yields of the products and to perform new synthetic research. Much progress was
made in realizing the mechanisms of sonochemistry during 1990–2000. Ultrasound-mediated drug synthesis was continued systematically in 2000 –2010. The application of ultrasound in synthetic chemistry
and drug synthesis has become established.
5.2.2 Ultrasound-Induced Principles
The ultrasound-assisted synthesis (sonochemistry or ultrasonic chemistry) applies high-frequency sound
waves to speed up chemical reactions. The main principles involved are cavitation, acoustic streaming,
and increased mass transfer [12, 13].
Cavitation: Cavitation helps the generation, growth, and collapse of microscopic bubbles in a liquid
induced by ultrasound. The quick collapse of the bubbles produces high temperatures and pressures
locally, creating substantial physical and chemical alterations.
Acoustic Streaming: It indicates the ow of liquid inuenced by ultrasound. This process creates
convection currents and accelerates appropriate mixing in the reaction medium.
Mass Transfer: Ultrasound creates agitation and turbulence inside the reaction mixture enhancing
mass transfer by increasing the diffusion rate of the reactants.
By combining these principles, ultrasound-mediated synthesis improves reaction rates and yields of
the products and becomes more selective.
5.2.3 Advantages of Ultrasound-Assisted Synthesis
Ultrasound has been used in the preparation of synthetic compounds, natural products, and bioactive
molecules. This wave accelerates chemical reactions signicantly. The cavitation promotes mixing,
improves collision frequency, and enhances kinetics. These help reactions to be conducted in milder conditions. The method is considered as green since it does not use hazardous reagents, minimizes waste,
and lowers energy consumption. It helps difculties by promoting selectivity. Using ultrasound-assisted
methods, our group has conducted research on beta-lactams. Obviously, ultrasound-induced methods are
not applied in beta-lactam research.
5.3 Crucial Beta-Lactams as Antibiotics
β-Lactam antibiotics were the best medicines against infection up to 1970. These antibiotics are classied into a few groups, some of which are as follows [14 –24]. Structurally, most of the β-lactam antibiotics are bicyclic although monocyclic and polycyclic β-lactam antibiotics are available. These types of
compounds have diverse stereostructures, and they can have cis- or trans-conguration. Many of these
drug molecules are stable in aqueous solution and at room temperature. Synthesis of these compounds or
fragments present in them has been conducted by diverse methods [25–33].
164 Chemistry and Biology of Beta-Lactams
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• Penicillin
• Cephalosporin (penam)
• Cephamycin (cephem)
• Oxacephem
• Monobactam
• Penem
• Oxapenam
• Carbapenem
• Nocardicin
5.4 Microwave-Induced Stereospecific Glycosylation
Toward Thienamycin β-Lactam
A naturally occurring carbapenem was isolated from the culture broth of S. cattleya, and this was thienamycin. Owing to its powerful activities against both gram-positive and gram-negative bacteria, attention to this antibiotic became very high.
A hydroxymethyl side chain at C6 position is present in this antibiotic [9]. Notably, penicillin and
cephalosporin have cis-stereostructures at the azetidine nucleus, but thienamycin has a trans-conguration. The rst total synthesis of (+/−)-thienamycin was achieved by Christensen at Merck research
laboratory. 4-Acetoxy-3-hydroxyethyl-2-azetedinone (Fig ure 5.1) can serve as a precursor in the total
synthesis of thienamycin and related carbapenems.
The various thienamycin-related structures are delineated (Figure 5.1) [34–42]. Microwave-induced
bismuth triate or bismuth nitrate-catalyzed reactions were employed to produce enantiomerically pure
1-hydroxyethyl side chain of thienamycin. This reaction was performed following Ferrier rearrangement
of racemic β-lactam alcohol and glycal.
Ferrier rearrangement is considered as one of the best methods for the preparation of glycosides. In
general, acidic catalysts are used as activators. This method produces 2,3-unsaturated glycosides with an
axial or equatorial bond. The conguration of the glycosidic bond may vary as the reaction depends on
the protecting groups of the glycals, the nucleophilic power of the alcohol, the temperature of the process, and the nature of the solvents used. Indium-induced process was identied for the stereoselective
FIGURE 5.1 Substituted thienamycin antibiotics.
SCHEME 5.1 Synthesis of a Beta-Lactam with the Thienamycin Side-Chain Structure.
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165Microwave and Ultrasound in Beta-Lactam Chemistry
FIGURE 5.2 Transition-state structures involved in the preparation of thienamycin.
preparation of glycosides. Stereoselective glycosylation of alcohol by iodine-induced rearrangement was
available.
Toward the synthesis of optically active side chain of thienamycin, rac-cis-3-(1-hydroxyethyl)-4-phenyl-N-p-anisyl-2-azetidinone was prepared. A reaction of rac-(±)-ethyl-3-hydroxy-butyrate and anisyl-
aldimine in anhydrous THF at −20°C to room temperature was conducted, and this reaction produced a
cis-β-lactam (Scheme 5.1).
A cis-stereochemistry was attributed due to the E-enolate followed by a specic transition state structure of the reaction (Figure 5.2).
The principal force for this type of transition state was due to stabilization through an effective hydrogen bonding between the hydroxyl and the ester group.
166 Chemistry and Biology of Beta-Lactams
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SCHEME 5.2 Microwave-Induced Glycosylation of Hydroxyethyl Side Chain by Bismuth Triate.
Microwave-induced Ferrier glycosylation of cis-azetidinone using acetyl-D-glucal was conducted in
the presence of Bi (OTf)3 (5–10 mol%) in anhydrous THF at 50°C for 5 min. Two products were isolated
in 70% yield (Scheme 5.2). Glycosylation with 3,4,5-tri-O-acetyl-D-galactal as glycosyl donor with the
racemic alcohol in the presence of bismuth triate did not produce glycosides. Interestingly, 3,4,5-tri-Obenzyl-D-glucose failed to react with the alcohol.
To establish the stereostructure of the anomeric center, the alkenyl bond in the pyranosides were
reduced with ammonium formate/10% Pd-C catalyst in ethanol in a domestic microwave oven.
Microwave-induced hydrogenation produced saturated compounds (Scheme 5.3).
The proton Nuclear Magnetic Resonance (NMR) data of the dideoxy compounds demonstrated small
couplings (1–2 Hz) for the anomeric hydrogens, and therefore, an axial glycoside bond was formed. A
167Microwave and Ultrasound in Beta-Lactam Chemistry
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SCHEME 5.3 Microwave-Induced Hydrogenolysis.
higher coupling constant (8–10 Hz) was expected for a β-glycosidic molecule. The sugar component was
removed using hydrochloric acid to produce optically active hydroxy β-lactams.
To know the absolute stereochemistry, the hydroxy-β-lactams obtained through deglycosylation
(Scheme 5.4) were converted to the alkenes by mesylation–elimination. The synthesis of the Z-olen
indicated the conguration of the hydroxy group and the ring hydrogens.
5.5 Carbapenem Antibiotics
The precursors of carbapenem antibiotics were prepared from 3-vinyl-β-lactams [43– 47] [Schemes 5.43-
5.47]. These unsaturated β-lactams were synthesized in a domestic microwave oven following cycloaddition of diarylimines and acid chlorides. Interestingly, several trans-3-vinyl-β-lactams were obtained
168 Chemistry and Biology of Beta-Lactams
CH
Ar
1
1
2
OH
O
1
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SCHEME 5.4 Deglycosylation and Acetylation.
SCHEME 5.5 Synthesis of Vinyl-β-Lactams.
SCHEME 5.6 Synthesis of Thienamycin Side Chain from Vinyl-β-Lactams in Racemic Form.
within 5–6 min of irradiation in chlorobenzene as the solvent (Scheme 5.5). The reaction produced a
mixture of cis- and trans-isomers with imines derived from aliphatic amines.
The alkene groups present in these molecules were epoxidized by m-chloroperbenzoic acid. The epoxide was transformed to bromo alcohol regioselectively by aqueous potassium bromide. The bromo group
was then removed by tributyltin hydride-induced radical reaction to afford the thienamycin side chain in
racemic form (Scheme 5.6).
The bromo alcohol was mesylated and converted to E- or Z-alkene by microwave-induced reaction.
The structure of these alkenes was helpful to establish the conguration of the bromo alcohol in the
β-lactams (Scheme 5.7).
The same process was investigated with imines obtained from diethylketomalonate under microwave
irradiation. A microwave irradiation of the reaction mixture of the Schiff base obtained from malonate
ester and aryl amine produced β-lactam. The removal of an ester by LICl/DMSO was also selectively
possible in the microwave oven. This selective ester removal process ultimately produced cis-β-lactam
Br
3
N
O
SnH
Ar
2
Ar
2
N
Ar
1
Ar
2
CH=CHCOCl
3
=Ar
Ar
=Aromatic
Ar
2
mClC
N
Ar
O
1
+
N
Ar
H
H
CO
4
6
3
TEA
Chlorobenzene
1
MW
O
N
O
Ar
Ar
2
KBr/H2O
1
O
Bu
AIBN
MW
OH
Ar
2
N
Ar
169Microwave and Ultrasound in Beta-Lactam Chemistry
1
OH
Br
O
O
EtOOC
t
COOEt
Me
ra
-(+/-)-
m
O
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Ar
2
CH
SO2Cl
N
Ar
CH
1
SO2Cl
3
O
3
TEA
TEA/MW
CH
3
Ar
2
N
Ar
1
SCHEME 5.7 Synthesis of E- and Z-Isomers of Alkenyl-β-Lactams.
COOEt
N
Ar
+
CH
CH=CHCOCl
3
TEA/MW
SCHEME 5.8 Synthesis of 3-Substituted 4-Carboethoxy-β-Lactams.
Ar
H
C
3
O
2
N
Ar
COOE
N
O
Ar
LiCl
DMSO
MW
Et
CO
2
N
Ar
c
-(+/-)-
O
S
O
O
O
HH
2
R
3
N
DMSO/MW
1
R
cis-beta-lactam
AcONa
rac
Me
C
O
O
trans
HH
2
R
3
N
R
1
-beta-lacta
SCHEME 5.9 Microwave-Induced Synthesis of trans-Monocyclic-β-Lactam.
that has alkyl group (Scheme 5.8). An extension of this method was helpful to obtain other cis-β-lactams
that have N-, S-, and O-containing groups at the C3 position of the ring.
5.6 Inversion of Configuration of the β-Lactams
A few cis-3-mesyl acetoxy β-lactams were prepared from racemic acetoxy and hydroxyl derivatives.
Reaction of mesylate with sodium acetate in DMSO under microwave irradiation method exclusively
produced trans-3-acetoxy β-lactams in good yield (Scheme 5.9).
Following a similar method, cis-3-mesyl-3R, 4S and cis-3-mesyl-3S, 4R were subjected to react with
sodium acetate. The product obtained from this route is trans-3-acetoxy-β-lactams (Scheme 5.10).
However, a reaction of cis-3-mesyl beta-lactams with sodium acetate and DMSO gave trans-acetoxy
product (Scheme 5.11) [48]. Interestingly, these reactions were successful by microwave-induced or
ultrasound-assisted reactions. The cis-3-acetoxy beta-lactams failed to react with NaOAC/DMSO. This
indicated that the leaving group property of the mesyl group is superior to that of acetoxy group in
beta-lactams.
170 Chemistry and Biology of Beta-Lactams
Me
(+)-cis
-beta-lactam
O
Me
(-)-
m
O
Me.C
LG
Leaving
Group
1
2
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O
S
O
SCHEME 5.10 Microwave-Induced Synthesis of Chiral trans-β-Lactam Enantiomers.
O
S
O
(-)-cis
SCHEME 5.11 Microwave-Induced or Ultrasound-Assisted Reaction of cis-Mesylate to trans-Acetate.
Me
O
LG
HH
O
3
N
O
-beta-lactam
HH
O
3
N
O
-beta-lactam
O
S
O
O
O
O
:
2
R
1
R
2
R
1
R
HH
3
N
AcONa
DMSO/MW
AcONa
DMSO/MW
2
R
1
R
inversion
SN
attack
at
Me
C
(+)-
Me
Me
2
C-3
position
trans
C
trans
O
3
O
O
3
O
-beta-lacta
O
OHHC
O
HH
2
R
N
R
1
HH
2
R
N
R
1
R
3
N
R
SCHEME 5.12 Plausible Mechanism of Concomitant Demesylation.
The mesylate functionality at the C3 position of the racemic and chiral derivatives underwent reaction
with the acetate anion. The departure of the mesylate group was possible because it has an excellent leaving group character. The process was responsible for an inversion of conguration at the C-center (Scheme
5.12). This represents an example of substitution nucleophilic bimolecular reaction. Remarkably, acetate
anion was unable to attack the beta-lactam carbonyl group under this condition of the experiment.
Sodium iodide also reacted with the acetate in beta-lactam through SN2 route. If the attacking reagent
was acetate anion, such reaction failed to produce the trans-isomer. This suggested that acetate compound produced a carbocation at the C3 center of the beta-lactam ring through a leaving process, and
this was stabilized by a hydride shift from the neighboring C4 position. The generated carbocation at C4
was stabilized by the aromatic system connected to it. This route allowed an attack of the C3 carbocation by acetate ion through an SN1 mechanism. The cation formation was feasible due to a common ion
effect (acetate was the leaving group and the nucleophile). But with the iodide ion, the reaction followed
an SN2 pat hway.
A reaction of cis-acetoxy isomer with NaI/DMSO produced trans-iodo compound (Scheme 5.13). The
mechanism of this process was explained by a nucleophilic substitution bimolecular pathway. The iodine
ion is an excellent nucleophile, and therefore, it attacked the acetate ion which is an excellent leaving
group. Microwave irradiation and ultrasound accelerated the process.
171Microwave and Ultrasound in Beta-Lactam Chemistry
Ar
1
Ar
A
MW
I
Ar
1
SPh
PhSC
1
PhSC
COOEt
O
LiCl/DMSO
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O
SPh
SPh
2
N
Ar
2
N
Ar
COOEt
N
Ar
N
1
MW
COOEt
Ar
1
O
N
EtOOC
Ar
2
+
1
N
COOEt
N
Ar
Ar
Ar
1
NaI
DMSO
2
TEA
O
MW
TEA
MW
cO
O
SCHEME 5.13 Microwave-Induced or Ultrasound-Assisted Inversion of Conguration: Acetoxy to Iodo Compound.
H2COCl
SCHEME 5 .14 Microwave-Induced or Ult ras ound-Assist ed Ster eosp eci c Synth esis of Trans -3-Thio-Substituted-β-Lactams.
H2COCl
+
SCHEME 5. 15 Microwave-Induced or Ult rasound-Assist ed Stereospe cic Synthe sis of Cis-3-Thio-Substituted-β-Lactams.
5.7 Microwave-Induced and Ultrasound-Assisted
Synthesis of 3-Thio-Substituted β-Lactams
Microwave irradiation was employed to prepare trans-3-thio-substituted β-lactams in chlorobenzene or
DMF at about 50°C. Staudinger cycloaddition of imines with phenylthioacetyl chloride in the presence
of a tertiary base afforded trans-β-lactams exclusively [49, 50]. An identical result was obtained when
the reaction was conducted using an ultrasound bath (Scheme 5.14). This reaction produced trans-compounds irrespective of the nature of the imines.
The above results indicated that preparation of cis-3 -thio -β-lactams is a challenging objective. The
cis-substituted 3-thio β-lactams were obtained by an indirect method by selective removal of a germinal
diester group. Thus, C4-dicarboethoxy β-lactams were made following a cycloaddition in a microwave
or in a sonicator. One of the ester groups was removed by LiCl/DMSO, and through this process, cisphenylthio β-lactams were prepared (Scheme 5.15).
5.8 Microwave-Induced and Ultrasound-Assisted
Synthesis of Pyrrole-Fused Beta-Lactams
Pyrroles are important organic compounds with numerous biological activities. Synthesis of chiral and
non-chiral C3-substituted pyrrole-containing beta-lactam is a crucial synthetic target from the 3-keto
beta-lactams.
Pyrrole-substituted beta-lactams were prepared using racemic 3-keto beta-lactams and hydroxyl proline in the presence of the catalytic amount of Bi(NO3)3.5H2O in reuxing ethanol in a microwave. This
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