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132 Chemistry and Biology of Beta-Lactams
https://t.me/med1917
(b) Structure–activity relationships (SARs) of newly synthesized β-lactams and a study of their
activities were compared with the lead compound and clinically active drugs to study the
genomic effects of these compounds (small-molecule screening technology) in order to better
identify their specic cellular targets and to rene the SARs. Since some of these compounds
inhibited the G2/M transition point in cancer cell lines, cell cycle analysis and studies of apoptosis were a constant part of their evaluations. The new data was analyzed and compared with
in vitro cytotoxicity data obtained using standard, sensitive, and resistant human tumor cell
lines as well as non-transformed human cell lines.
(c) The antitumor activities of β-lactams in vivo against a few ovarian, breast, and pancreatic can-
cer cell lines were conducted.
4.2 Specific Research Area: β-Lactams as Anticancer Agents
The search for new and novel organic compounds for the treatment of cancers is the aim of intense study.
Over the past decades, chemotherapy, either alone or in association with surgery and radiotherapy, has
represented the major approach for the treatment of cancers. However, despite the progress in research,
the morbidity and mortality of cancer remain a major health problem worldwide. The effectiveness of
currently available anticancer drugs is limited by their high toxicities and their intrinsic or acquired drug
resistance.1 Therefore, it is essential to identify novel chemotherapeutic molecules with high potency,
low toxicity, and mutagenicity with selective anticancer activity that are able to overcome frequently
developed tumor resistance to conventional anticancer drugs. An additional problem is that many of the
currently available drugs are unable to differentiate between normal and neoplastic cells. Selective activation of cell death pathways in cancer cells, but not in normal cells, is essential as one novel strategy for
the development of chemotherapeutic agents. Although cancer has been considered a disease of uncontrolled cell division, abnormal resistance to apoptosis is recognized to contribute to tumor initiation,
progression, and resistance to chemotherapy. Many anticancer agents induce apoptosis in normal as well
as malignant cells.2 Although the chemistry, biology, pharmacology, and medicinal values of β-lactams
are extremely well studied, reports of these molecules as anticancer agents are very limited. Based on
the limitation of the conventional anticancer agents under therapeutic situations, studies of β-lactams as
new chemotherapeutic agents are signicant, timely, and useful. The role of β-lactam antibiotics for the
treatment of different types of infections has been well established for the past several decades.3 Since
many β-lactams have been widely used as crucial and safe antibacterial agents, the hypothesis was that
novel β-lactam drugs can be synthesized that will have an enhanced anticancer activity, low toxicity to
normal tissues, and preclinical efcacy. On this basis, our goal was to develop the synthesis of β-lactams
of different structures and to study their anticancer activity in vitro and in vivo as compared with our
current lead compounds and clinically active medicines, particularly their effects against specic cellular targets.
4.3 Rationale for Synthesizing β-Lactams as Anticancer Agents
We designed, synthesized, and tested a number of novel anticancer β-lactams in racemic and optically
active forms and have shown that they possess excellent antitumor activity in vitro against a number
of human cancer cell lines such as ovarian, melanoma, breast, colon, leukemia, and pancreatic including against GEM-resistant cancer cell lines at micromolar level and in a few animal tumor models.4,
5
Turos et al. also investigated novel β-lactams as anticancer agents.6 In many instances, this activity
exceeded that of cisplatin and adriamycin in vitro. Biochemical studies of some of these β-lactams demonstrated an extremely active blockade of the G2/M checkpoint in cancer cell lines. In addition, it was
found that these β-lactams are relatively nontoxic to mice and non-mutagenic when tested in bacterial
and animal systems. Experiments conrmed that these compounds have good bioavailability and cell
permeability. Clearly, these results appeared to be of considerable interest in cancer therapy, much of
which was focused upon seeking new compounds that “target” specic and obligate pathways in tumor
133Polyaromatic Beta-Lactams
O
Ar
X
O
https://t.me/med1917
metabolism and control. Our studies on diverse anticancer products had a remarkable similarity with
synthetic β-lactams.
7
4.4 Results and Discussions
We reported the synthesis and biological evaluation of a number of planar molecules using lipophilic
polycyclic aromatic amines as their nucleus for a systematic examination of modications of structure,
shape, charge, basicity, and other characteristics that might result in the killing of cancer cells (Scheme
4.1).8 From the literature, it was known that conformationally constrained molecules have a much greater
effect on the biological properties compared to the relatively exible open-chain compounds in many
examples.
This was supported by the fact that conformationally restricted amides (β-lactams) are more effective
at lowering cholesterol in human plasma compared to open-chain substrates.6 Restriction of conformational freedom in a small organic molecule had signicant changes in assay performances. Many
examples were known in which restricted compounds have shown excellent and better biological proles
compared to relatively exible analogues.
Banik’s research group demonstrated synthesis and biological evaluation of a few derivatives of
polyaromatic amines, which were open-chain amides to which the polycyclic reside was bound.7 These
structures suggested that a ring formation using N1 and C4 would end up with a β-lactam. On this basis,
we envisioned that β-lactam would serve as a conformationally constrained analogue of open-chain
diamides that have shown promising anticancer activity.4 Therefore, synthesis of a number of novel
β-lactams was conducted, and these were evaluated against several cancer cell lines. As usual, many new
β-lactams were proven to be totally inactive. However, some of them demonstrated excellent antitumor
activity in vitro against a number of cancer cell lines and in animal tumor model systems (diverse ovarian
cancer cell lines, pancreatic cell lines, and colon cancer cell lines).
In cancer research, DNA is the most challenging bio-receptor for many small organic compounds and
a target of choice for the control of gene expression.1, 2 However, it is known that DNA binding is not
sufcient to confer cytotoxic activities. Conformational restriction in some molecules gives them signicance as anticancer agents. Interaction of organic molecules with DNA is also offered as a mechanism of
cytotoxic effects. Groove binders and intercalators are the main categories of DNA-binding compounds.
The intercalators are very important class of anticancer DNA-binding agents. In general, insertion of
planar aromatic or heteroaromatic rings in between DNA base pairs is the characteristic feature of these
types of compounds (anthracyclines, ellipticines, camptothecin, and acridines). Many of these types
of compounds are also excellent topoisomerase inhibitors. Hydrogen bonding and π-stacking are also
crucial in the stabilization of the compound-DNA complex, which causes inhibition of the replication
process and cell death. Anticancer activity is discovered in polycyclic aromatic hydrocarbon-bearing
compounds. Interestingly, DNA-intercalating drugs (doxorubicin) have also been shown to interact with
cell membranes effectively. We have synthesized and identied a few active polycyclic aromatic anticancer agents that are highly effective in inhibiting cancer cell growth without affecting normal cells. As
an extension of our research on these types of small molecules, we designed, synthesized, and tested a
number of novel, non-mutagenic, and nontoxic β-lactams.4 The physicochemical properties of some of
these β-lactams were investigated.
5
O
1
N
2
H
SCHEME 4.1 Hypothesis-based Anticancer β-Lactams.
=
Ar
4
3
X
N
5
6
6-chrysenyl,
=
Ar
6-chrysenyl,
=
Ar
2-chrysenyl,
=
Ar
2-chrysenyl,
=
X
CH
2
=
X
NCH
3
=
X
CH
2
=
X
NCH
3
3
O
6
4
N
5
1
N
2
Ar
134 Chemistry and Biology of Beta-Lactams
Ar
Ar
1
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4.4.1 Preparation of Imines
We prepared structurally diverse β-lactams using imines derived from 9-aminophenanthrene, 2-amino(9,10)-dihydrophenanthrene, 6-aminochrysene, 5-amino-1,10-phenanthroline, and benzylic polyaromatic amines. Benzylic polyaromatic and heteroaromatic amino compounds are more basic than
polyaromatic amino compounds, and therefore, these types of compounds were also used.
A facile synthesis of polyaromatic nitro derivatives starting from polyaromatic hydrocarbons through
the use of bismuth nitrate (and other metal nitrate salts) impregnated with solid support was demonstrated.9 Bismuth nitrate-induced nitration produced nitro aromatics with excellent regioselectivity. It was
a better reagent in nitrating the polyaromatic hydrocarbons than conventional nitric acid or nitronium
tetrauoroborate. Indium-induced reduction was used for the facile preparation of aromatic amine in
water in the presence of ammonium chloride.10 Samarium metal-induced reduction of the aromatic nitro
compounds was also acheived.11 Hydrogenation by palladium-charcoal and catalytic transfer hydrogenation (Pd/C and ammonium formate) were also performed to obtain the polyaromatic amino compounds.
The amines were condensed with diverse carbonyl compounds in toluene (and in benzene) as the solvent
using a Dean–Stark water separator to afford imines in excellent yield. Due to the less basicity of the
polyaromatic amines compared to primary aromatic amines, this reaction required a longer time under
reux conditions (Scheme 4.2).
4.4.2 Stereocontrolled Synthesis of Disubstituted β-Lactams
A facile preparation of several β-lactams was achieved by indium-induced reactions.12 Indium-mediated
reactions were also used by our group.13 Synthesis of several new 3,4-disubstituted β-lactams with
polyaromatic imines was demonstrated.14 An unprecedented stereochemical aspect of the Staudinger
reaction was identied. Reaction of the diaryl imine derived from monocyclic aromatic amine with acid
chloride in the presence of triethylamine produced exclusively cis-β -lactams. However, in contrast to the
literature, diaryl imine derived from polyaromatic amine under identical conditions with acid chloride
(equivalent) afforded the trans-β-lactam as the exclusive or major product in many examples (Scheme
4.3). On the other hand, imines derived from conjugated carbonyl compounds produced mostly cis-β-
lactams or a mixture of trans- and cis-isomers under these conditions. It was known that conjugated
imines derived from conjugated carbonyl compound produce cis-β-lactams. In contrast, however, a procedure was developed by which it is possible to prepare a number of trans-β-lactams at high temperature
H
1
SCHEME 4.2 Preparation of Imines from Polyaromatic Amines.
Clay
B
other metal nitrates
Ar
d:
Ar
5H
i(NO
=
1
2
=
O
2
3)3
or
a:
3
aromatic and heteroaromatic
2
CHO
N
Ar
5
9
In/NH4Cl
H
O/EtOH
2
Reflux
9
f:
groups
c:
Ar
1NO2
3
b:
e:
Ar
6
6
1NH2
g:
Ar
2
Toluene
Reflux
N
N
135Polyaromatic Beta-Lactams
Ar
Ar
Z
Ar
2
Z
1
Tr
Z=OAc, OPh, OMe, Phthalimido;
Cis and
Z=OAc, OPh, OMe; Ar2=Cinnamyl and conjugated cinnamyl
Ar
AcO
Ar
HO
Ar
2
H
CO2SO
1
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2
ZCH
COCl
2
ans Beta Lactams only: Ar1=Chrysenyl, Phenanthrenyl and Pyrenyl;
Trans Beta Lactams Mixtures: Ar1=Chrysenyl, Phenanthrenyl and Pyrenyl;
SCHEME 4.3 Synthesis of β-Lactams Using Polyaromatic Compounds.
2
N
O
SCHEME 4.4 Preparation of Hydroxy and Mesylate Derivatives of the β-Lactams.
Ar
1
Ar1=Chrysenyl, Phenanthrenyl and Pyrenyl; Ar2=Aromatic and Heteroaromatic
NaOH
THF, H
+
N
Ar
Ar2=Aromatic and Heteroaromatic
O
2
(110°C and/or microwave-induced method) using conjugated imines. Following this method, a number
of 3,3-disubstituted β-lactams were prepared. Dihydrophenanthrenyl imines produced a mixture of cis-
and trans-β-lactams at room temperature. However, trans-β-lactams were the major products at high
temperature and/or microwave-induced method. Microwave-assisted reactions were able to control the
stereochemistry of β-lactam formation reaction. Rapid exposure of heat and radiation by microwave gave
trans-β-lactams in some examples. Interestingly, the same reaction without microwave produced cisisomers. The cis-products failed to undergo isomerization when these were treated with a tertiary base
in a microwave at a relatively high temperature. This indicated that synthesis of β-lactams followed two
distinct pathways: one is favored at cold–room temperature and the other proceeds at high temperature.
Hydroxy β-lactams were prepared through a mild hydrolysis of the acetate group in the presence
of dilute sodium hydroxide solution or hydrogenolysis of the benzyloxy group (Scheme 4.4). However,
hydrolysis method under controlled conditions to prepare the hydroxy compound was preferred since this
reaction produced products without cleaving the N1–C2 or N1–C4 bonds. The hydroxyl compound was
converted to mesylate, tosylate, O-esters, and S-esters. This reaction proceeded well irrespective of the
conguration of the ring systems.
Although hydrogenolysis in the presence of Pd/C was able to cleave the N1–C4 bond in certain examples, no bond cleavage in N-multicyclic aromatic systems was observed in many instances. An excess
amount of Pd/C in the presence of large amounts of hydrogen donor (ammonium formate, sodium
formate, and hydrazine) cleaved the N1–C4 bond producing amides. On this basis as an alternative,
hydrogenolysis of the benzyloxy group was also performed for the preparation of the hydroxy β-lactam.
Hydrogen gas in the presence of palladium catalyst is used extensively for hydrogenation and hydrogenolysis. The removal of O-benzyl group was possible by hydrogen and Pd-C (10%).15 However, catalytic
transfer hydrogenation or catalytic hydrogenation failed to remove the N-benzyl group connected to the
β-lactam ring. Catalytic transfer hydrogenation was a rapid procedure compared to catalytic hydrogenation experiment (Scheme 4.5).
A mild acylation method for the esterication of the OH group to a long-chain ester derivative was
conducted (Scheme 4.6). Fatty acids (saturated and unsaturated) were converted to acid chloride derivatives and reacted with 3-hydroxy β-lactams in the presence of a base to afford the esters. This reaction
was successfully conducted with cis- as well as with trans-β-lactams.
Unsaturated acid chlorides were used in the cycloaddition for the preparation of β-lactams with imines
obtained from monocyclic and aliphatic amines. Interestingly, an identical reaction of the same acid
1
O
CH2Cl
TEA, 0-5
2
N
Ar
1
SO
Cis
2
Ar
+
1
3
N
Cl
2
O
Trans
O
N
Ar
N
Ar
2
C
o
O
CH
3
TEA
136 Chemistry and Biology of Beta-Lactams
HO
2
1
O
N
Ar
1
Ar
BnO
Ar
2
HO
1
N
1
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2
HCOONH
N
O
Ar
Pd-C,
1
Ar1=Ar2=Aromatic, aliphatic
SCHEME 4.5 Preparation of Hydroxy β-Lactams by Catalytic Transfer Hydrogenation.
Ar
2
(CH2)nCOCl
CH
+
N
O
Ar
1
3
SCHEME 4.6 Esterication of the Hydroxyl β-Lactams with Long-Chain Fatty Acids.
EtOH
TEA
4
N
O
Ar
n
(H
C)
2
H
C
3
O
O
Ar
N
Ar
SCHEME 4.7 Attempted Synthesis of Vinyl β-Lactams.
SCHEME 4.8 Attempted Synthesis of Optically Active β-Lactams from Chiral Aldehydes and Polyaromatic Amines.
chloride with imines derived from polyaromatic amines did not produce the β-lactams under a variety
of conditions (Scheme 4.7).
Similarly, optically active imines obtained from multicyclic aromatic amines (pyrene, phenanthrene,
and chrysene) and chiral aldehydes did not produce β-lactams even in satisfactory yields (Scheme 4.8).
Bis-imines obtained from 3,8-phenanthrene amino compounds on cycloaddition afforded trans-βlactams in excellent yield at room temperature–high temperature. At ice-cold conditions, a mixture of
cis- and trans-products was formed. This reaction indicated that the stereochemistry of the β-lactam ring
can be controlled even with multicyclic ring, which is not fully aromatic (Scheme 4.9).
The trans-hydroxy β-lactam was oxidized to the ketone, and it was then reduced to a cis-alcohol. The
alcohol was converted to acetate. Thus, the synthesis of trans- as well as cis-hydroxy β-lactam with
N-polyaromatic system was available (Scheme 4.10).
2
+
CH
CH=CHCOCl
3
TEA
Ar
O
O
TEA
+
ZCH
COCl
N
Ar
1
O
O
2
TEA
+
PhSCH
COCl
2
Ar
137Polyaromatic Beta-Lactams
Z
O
Z=OPh, OBn, OAc
HO
Ar
O
HO
Ar
2
AcO
https://t.me/med1917
N
Ph
2
1
NaBH
EtOH
CH
TEA
2Cl2
4
Ph
O
N
O
Z
Ar
2
TEA
Ac
O,
2
N
Ar
1
+
N
Ph
SCHEME 4.9 Synthesis of β-Lactams from Partially Aromatic Multicyclic Compounds.
Ar
2
[O]
N
Ar
O
Ar1=PAH
SCHEME 4.10 Synthesis of cis-Hydroxy and cis-Acetoxy β-Lactams from Polyaromatic Compounds R=p-anisyl, p-toyl,
phenyl, benzyl.
1
ZCH2COCl
O
N
Ar
N
Ph
N
Ar
O
1
4.4.3 Computer-Assisted Mechanism Study β-Lactam Formation Reaction
Computer-assisted mechanism study explained the observed unprecedented stereoselectivity of β-lactam
formation reaction.16 It was veried that the zwitterionic intermediate can be formed by either rotation
about the N1–C4 bond or nucleophilic attack of (Z)-imine on the sp-hybridized carbon atom of ketene.
The corresponding fully optimized saddle points were calculated. In the past, studies were aimed for
the preparation of a few trans-β-lactams. But the experimental conditions in these investigations were
different than our present method. The mechanism of the β-lactam preparation is discussed in a different
chapter in this book.
4.5 Cytotoxicity of β-Lactams
Several of these β-lactams were screened against nine human cancer cell lines in vitro using cisplatin and
diamides as controls.4 Structure–activity study revealed that β-lactams containing phenyl, para-anisyl,
naphthalene, anthracene, dibenzouorene, uorene, and pyrene-groups at N1 demonstrated no growth
inhibitory activity. But the trans-3-acetoxy phenanthrene, trans-3-mesylate phenanthrene, trans-3-acetoxy dihydrophenanthrene, trans-3-mesylate dihydrophenanthrene, trans-3-acetoxy chrysene, trans3-mesylate chrysene, and trans-3-amino chrysene β-lactam derivatives demonstrated excellent activity
against nine cancer cell lines. 3,3-Disubstituted-4-substituted β-lactams with acetoxy group at C3 also had
anticancer activities against these cancer cell lines. Tra n s -phenoxy, methoxy, benzyloxy, or phthalimido
compounds were inactive. Therefore, the anticancer activities of these β-lactams were highly specic,
and the data identied the antitumor β-lactams with novel structural features. The β-lactam with trans-
acetoxy chrysene had activity in vivo against ovarian (SKOV-3) and colon cancer (HT-29) cell lines. This
in vitro cytotoxicity data indicated that the mesylate compounds are more potent than the acetoxy compounds. Data for a few selected compounds are given here as IC50 values (µM). Assays were conducted
using 72-h continuous exposure to the compound; relative cell growth was determined using the MTT
method. The nal concentration of solvent was <0.625%, which is not toxic to the cells.17 All dilutions
were made in RPMI 1640 with 10% FBS. There was no problem of solubility under these conditions.
138 Chemistry and Biology of Beta-Lactams
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In vitro cytotoxicity of β-lactams on human tumor cell lines (µM): Trans-3-acetoxy-4-aryl β -lactams
with N-phenanthrene and N-chrysenyl system demonstrated an average IC50 of 5–10 µM with respect to
clinically active medicine cisplatin (IC50 1–7 µM) against a number of cancer cell lines in vitro. Aromatic
and heteroaromatic groups at C4 position of the ring demonstrated anticancer activity. In general, BRO
(melanoma), MCF-7 (breast), OVCAR-3 (ovarian), SKOV-3 (ovarian), PC-3 (prostate), HL-60 (leukemia),
A549 (non-small cell carcinoma of the lung), K-562 (leukemia), and HT-29 (colon) were used in this
investigation. However, similar compounds with methoxy, phenoxy, benzyloxy, and phthalimido group
at the C3 had no anticancer activity.
4.6 Asymmetric Synthesis of β-Lactams
4.6.1 Asymmetric Synthesis by Glycosylation of the Hydroxy β-Lactams
A few specically oriented glycals on reaction with alcohol and an acidic catalyst form 2,3-unsaturated
glycosides through Ferrier rearrangement.18 Different types of Bronsted and Lewis acids are employed
for this reaction. This method may produce a mixture of products depending upon the conditions of the
experiments and nature of the reactants. The reaction of tri-O-acetyl-D-glucal with a glycolic acid ester
was conducted using BF3.Et2O as the promoter, and both anomeric products were obtained.19 Iodinecatalyzed reactions were conducted with alcohols.20 The reaction of tri-O-acetyl-D-glucal with the glycolic ester and iodine produced exclusively a glycoside. Hydrogenation21 was conducted to determine the
conguration of the anomeric bond. The coupling constant of the anomeric proton indicated an axial
bond.20 This procedure was applied in the chemistry of β-lactam.
Iodine-catalyzed glycosylation was performed with chiral 3-hydroxy β-lactam and a glycal derived
from glucose. A single glycoside was formed. The reaction of the acetylated compound containing
β-lactam with sodium methoxide produced the dihydroxy molecule in good yields (Scheme 4.11).
To identify the conguration of the anomeric center, the coupling constant of the unsaturated glycosides was investigated. However, this data was not helpful as the carbohydrate system in this structure
has a twisted-chair conformation. On the other hand, to identify the conguration of the anomeric proton
in a saturated carbohydrate system was easy. Therefore, a saturated compound was used for this purpose.
The unsaturated glycoside was hydrogenated by transfer hydrogenation method with ammonium formate
and Pd/C.15 A few hydrogen donors (hydrazine, formic acid, sodium formate, and cyclohexane) with
Pd/C gave the products. But ammonium formate was selected as the best hydrogen donor. The Nuclear
Magnetic Resonance (NMR) data of the saturated glycoside indicated a small coupling constant data
(2.0 Hz) for the anomeric proton, and therefore, an axial glycosidic bond was proven. For an equatorial
glycosidic bond, a higher coupling constant of the anomeric proton was expected.
The glycosylation process was conducted with other hydroxy β-lactams that have multiple chiral centers. A reaction with a compound that has a ketal group produced products with good yield. But the
reaction with a compound with double ketal groups gave low yield (Scheme 4.12). Iodine was not able to
break the ketal group in these examples.
Two enantiomers of β -lactams were prepared following this method. Thus, glycosylation of racemic
cis-3-hydroxy-4-phenyl-2-azetidinone was conducted, and two diastereomers were obtained in 55:45
ratios (Scheme 4.13). The conguration of the two hydrogens at the C3 and C4 centers of these two diastereomers was opposite to each other.
The alkene group was removed by hydrogenation, and this experiment conrmed the conguration of
the products (Scheme 4.9). The NMR data of the anomeric hydrogen showed a small coupling constant
(about 1.0 Hz) in the saturated glycosides indicating an axial glycosidic bond.
The diastereomers were separated by column chromatography. A treatment of these diastereomers
with aqueous dilute acid or bismuth nitrate solution was able to remove the sugar part. The glycosidic
bond was not stable even in the presence of a mild acid. Under this condition, the β-lactam ring remained
intact. The hydroxy β-lactams were converted to acetates following a standard method (Scheme 4.14).
The reaction of racemic hydroxy β-lactam with a glycal derived from arabinose sugar in the presence of catalytic amounts of iodine produced two diastereomers in almost equal proportions. After the
HO
OAc
O
R
R=p-anisyl, p-toyl, phenyl, benzyl
https://t.me/med1917
O
H H
139Polyaromatic Beta-Lactams
O
OAc
OAc
O
O
H H
OH
O
O
N
O
R
NaOMe,
MeOH
OAc
THF
I
,
2
O
H
O
N
R
O
H
+
OAc
SCHEME 4.11 Glycosylation of Chiral β-Lactams.
OH
O
O
H H
N
O
H
separation by column chromatography, the individual glycosides on hydrogenation produced amides
through the cleavage of the ring. A partial deacetoxylation was also observed. The scission of the
β-lactam ring under reductive conditions was reported by Ojima et al. and our group. It was interesting to
note the results of the catalytic transfer hydrogenation experiments as described here. The steric crowding of the glycosides with arabinose was less compared to the glycosides with glucose. This reaction was
able to cleave the N1–C4 bond with C4-aryl β-lactam and deacetoxylate one of the acetates of the sugar
units. The sterically congested aryl group and a nonaromatic group at the C4 position of the β-lactam ring
inhibited cleavage (Scheme 4.15).
To explore other glycals, rhamnal acetate was allowed to react with the hydroxy β-lactam. Following
an identical route, two diastereomeric compounds were produced with an identical axial conguration
at the anomeric bond (Scheme 4.16). These series of reactions with different glycals produced glycosides
with axial linkages indicating a common mechanism. Perhaps, the cyclic nature of the β-lactam ring was
responsible for attacking the unsaturated sugar of different structures from a specic side only. The presence of an acetoxy and methyl group with different orientations at the C5 position as well as unsubstituted
C5 sugar derivative produced products with an identical conguration.
An aqueous hydrochloric acid was able to convert the two diastereomers into optically active 3-hydroxy2-azetidinones. The cleavage of the anomeric bond was also conducted with an aqueous bismuth nitrate
solution.23 The 3-hydroxy β-lactam was used to synthesize acetoxy compounds with acetic anhydride
and pyridine (Scheme 4.17). These compounds are designated as the side chain of Taxol and Taxotere.
140 Chemistry and Biology of Beta-Lactams
OAc
OAc
3
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OAc
OAc
O
OAc
O
+
OCH
OAc
O
O
O
H H
O
3
O
H
N
OCH
3
OAc
OAc
O
O
O
H H
O
O
H
N
O
O
H H
O
O
H
HCOONH
4
Pd-C
10%
N
EtOH
90%
OCH
3
OAc
O
+
HO
O
O
HH
N
O
H
O
,
OAc
THF
OH
I
2
R
70%
O
O
OAc
O
HH
N
O
H
O
OH
R
O
HO
O
H H
O
O
H
O
OAc
+
N
OAc
OCH
OAc
I
THF
,
2
O
O
H H
O
O
H
N
OCH
3
SCHEME 4.12 Glycosylation of Chiral Hydroxy β -Lactams R=p-anisyl, phenyl, p-tolyl and benzyl.
The trans-β-lactam was prepared from cis-hydroxy β-lactam through tosylation and inversion methods (Scheme 4.18). Direct displacement of the hydroxyl group was not possible. The intermediate tosylate
produced acetate with inversion of stereochemistry through a backside attack.
To extend the scope of this method, a few other glycals were also examined. The reaction of 3,4,5-triO-acetyl D-galactal with β-lactam alcohol did not go through. Moreover, tri-O-benzyl D-glucose failed
to yield the desired products. These experiments indicated that the nature of the glycal is crucial for an
efcient reaction (1). The protecting group and stereochemistry in the sugars inuenced iodine-catalyzed
glycosylation reaction.
The iodine-catalyzed glycosylation method was conducted with a diol connected with a β-lactam system. Only the primary alcohol reacted with sugar in the presence of the secondary, and the desired product was formed. This observation was conrmed by an oxidation experiment of the product to a ketone.
The glycosylation as described above was successfully performed with a β-lactam that has a hydroxyethyl side chain at the C3 position of the ring (Scheme 4.20). This type of side chain is present in
thienamycin and carbapenem antibiotics. A reaction of cis-3-(1 -hydr oxyet hyl)- 4-phe nyl-N -p-an isyl- 2
141Polyaromatic Beta-Lactams
HO
AcO
AcO
Ph
https://t.me/med1917
OAc
HH
O
Ph
+
N
R
OAc
OAc
O
THF
I
,
2
OAc
AcO
OAc
R=p-anisyl, phenyl, p-tolyl and benzyl
O
O
H
O
O
O
O
,
2
EtOH
Pd-C
HH
N
HH
N
O
NH
EtOH
or
2
2
O
4
OH
OH
,
O
O
Pd-C
HH
HH
O
O
Ph
N
R
N
R
OAc
Ph
+
R
HCO
2
CH
CH
AcO
Ph
R
SCHEME 4.13 Synthesis of Optically Active Glycosides.
azetidinone using D-glucal in the presence of Bi(OTf)3 afforded two products. These were separated,
and individual isomers were obtained. During this investigation, bismuth nitrate was also found to be an
excellent promoter for this type of glycosylation.
The above glycosylation method was not successful when hydroxy compounds obtained from polyaromatic systems were used as substrates. Therefore, alternative methods to obtain sugar-containing
β-lactam structures were necessary to study their anticancer affects, and these were achieved by different methods (below).
4.6.1.1 Mechanism of the Glycosylation Reaction
The mechanism of Ferrier rearrangement was investigated, and a rationale was established. The principal pathway followed an allylic isomerization process of the unsaturated sugar glycal to a 2,3-didehydro
intermediate (Scheme 4.21). To establish the mechanism of this reaction, NMR studies were conducted.
The glycosylation was accelerated when a higher concentration of catalyst was used. A few reactions with
different amounts of the catalysts were performed to know the optimum amount of promoter required for
this reaction. An increase of the reaction time with an acidic catalyst reduced the yield of the products
considering that the glycosidic bond is not stable under acidic conditions. The reaction failed to produce
product in the absence of a catalyst, iodine. The titration of the reaction mixture showed no consumption because of iodine due to this reaction. The 13CNMR showed all the peaks for the desired product
and the starting materials: glycal and the hydroxy compound. The corresponding peaks of the iodinated
intermediates or iodinated products were not located. Thus, the intermediates probably were spontaneously converted into the product. It must be stated that the reaction of glycal with alcohol in the presence of N-iodosuccinimide or iodonium dicollidinium perchlorate gave a deoxy-2-beta-iodo-3-glycoside.
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