Stereocontrolled synthesis of anticancer β-lactams via the Staudinger reaction

Article abstract of DOI:10.1016/j.bmc.2005.03.044

Stereocontrolled synthesis of novel β-lactams using polyaromatic imines following the Staudinger reaction has been accomplished. The effects of domestic microwave irradiation on this type of reaction have been investigated. Formation of trans-β-lactams has been explained through isomerization of the enolates formed during the reaction of acid chloride (equivalent) with imines in the presence of triethylamine. A donor-acceptor complex pathway is believed to be involved in the formation of cis-β-lactams. The effect of a peri hydrogen has been found to be significant in controlling the stereochemistry of the resulting β-lactams. SAR has identified β-lactams with anticancer activity. The presence of an acetoxy group has proven obligatory for their anticancer activity.

Full text of DOI:10.1016/j.bmc.2005.03.044

Bioorganic & Medicinal Chemistry 13 (2005) 3611–3622
Stereocontrolled synthesis of anticancer b-lactams via the
Staudinger reaction
Bimal K. Banik,a,* Indrani Banikb and Frederick F. Beckerb
aDepartment of Chemistry, University of Texas-Pan American, 1201 West University Drive, Edinburg, TX 78541, USA
bThe University of Texas, M. D. Anderson Cancer Center, Department of Molecular Pathology, Houston, TX 77030, USA
Received 22 January 2005; revised 15 March 2005; accepted 24 March 2005
Available online 12 April 2005
Dedicated to Professor R. L. Dutta of Burdwan University, India for his remarkable lifetime contributions in teaching University students
Abstract—Stereocontrolled synthesis of novel b-lactams using polyaromatic imines following the Staudinger reaction has been
accomplished. The effects of domestic microwave irradiation on this type of reaction have been investigated. Formation of trans-
b-lactams has been explained through isomerization of the enolates formed during the reaction of acid chloride (equivalent) with
imines in the presence of triethylamine. A donor–acceptor complex pathway is believed to be involved in the formation of cis-b-lac-
tams. The effect of a peri hydrogen has been found to be significant in controlling the stereochemistry of the resulting b-lactams.
SAR has identified b-lactams with anticancer activity. The presence of an acetoxy group has proven obligatory for their anticancer
activity.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
bacterial and have other medically important properties
will continue.9–11
The enchanted b-lactams has had a variety of medicinal
applications. In addition to the well-known penicillins
and cephalosporins antibiotics, a number of other bio-
logically relevant enzymes have been targeted by b-lac-
tams.1 The need for potent and effective b-lactam
antibiotics as well as more effective b-lactamase inhibi-
tors has motivated chemists to design new b-lactams.2
These compounds have served as starting materials in
the preparation of various heterocyclic compounds of
biological significance.3 Substituted hydroxy b-lactams
have been the starting materials in the semi-synthesis
of paclitaxel (Taxol) and docetaxel (Taxotere).4 The
medicinal use of some b-lactams as therapeutic agents
for lowering plasma cholesterol levels has been docu-
mented.5 Studies of human leukocyte elastase inhibitory
mechanisms and the biological activity of this class of
compounds have also been published.6 There have been
a few other remarkable developments, such as catalytic
asymmetric7 and polymer-supported8 synthesis of b-lac-
tams. As a result of this general trend of b-lactam use,
the searches for clinically useful b-lactams that are anti-
We have demonstrated various methods for the synthe-
sis of b-lactams12 and several biologically active com-
pounds.13,14 In continuation of our research in this
area, we describe herein a full account of our stereocon-
trolled synthesis of novel anticancer b-lactams starting
from imines, with pendent polyaromatic substituents.14
In previous publications, we demonstrated synthesis and
biological evaluation of some derivatives of polyaro-
matic amines, which were open-chain amides to which
the polycyclic residue was bound (e.g., 1 and 2, Fig.
1).13 Structures 1 and 2 suggest that a ring formation
using N1 and C4 would result in b-lactam 3. With regard
to the above, we envisioned that b-lactam 3 of the gen-
eral structure shown in Figure 1 would serve as a con-
formationally constrained analogue of our open-chain
compounds (1 and 2) that have been shown to have anti-
cancer activity. The initial impetus for this study was to
prepare substituted amines and amides, particularly
including compounds with polyaromatic substituents,
with the goal of investigating such compounds for po-
tential anticancer activity. It was then decided to extend
the scope to include a variety of cyclic amides, including
b-lactams. Therefore, our goal has been targeted to de-
velopthe synthesis of these types of molecules.
Keywords: b-Lactams; Anticancer agents; Staudinger reaction.
*
Corresponding author. Tel.: +1 956 380 8741; fax: +1 956 384
5006; e-mail: banik@panam.edu
0968-0896/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.03.044

3612
B. K. Banik et al. / Bioorg. Med. Chem. 13 (2005) 3611–3622
Scheme 2.
used reaction for this purpose. The conditions described
using mixed acids are not ecologically friendly. How-
ever, our recent work culminated in facile synthesis of
polyaromatic nitro derivative 9 starting from polyaro-
matic hydrocarbons (PAHs) 8 through the use of bis-
muth nitrate impregnated with clay (Scheme 2).23 The
advantages of this method over the classical method
are numerous. The presence of clay is essential for the
success of this reaction.
Figure 1.
Several methodologies can be used to prepare polyaro-
matic amines from polyaromatic nitro compounds.
For example, catalytic hydrogenation, catalytic transfer
hydrogenation, and several new methods have been
found to be suitable for the reduction of polyaromatic
nitro compound 9 to polyaromatic amine 10. These
methods are not convenient with PAH derivatives.
Our recently described indium-24 and samarium-in-
duced25 reduction methods offer additional opportuni-
ties to achieve this purpose. For example, the indium-
induced reaction can be performed in water in the pres-
ence of ammonium chloride, while the samarium-in-
duced reaction can elicit a product within a few
minutes using ultrasound (Scheme 3). The indium-in-
duced method can be accomplished in 10 g scale. We
have reduced 6-nitro chrysene to 6-aminochrysene in
more than 90% yield in 10 g scale. The most common
hydrogenation using Pd/C has not proved to be success-
ful. Preparation of polyaromatic aldehydes, particularly
phenanthrene 12a, chrysene 12b, and dibenzofluorene
12c, has been accomplished using a previously described
method26a from their respective hydrocarbons 11a,b,
and 11c. Synthesis of dibenzofluorene hydrocarbon 11c
has been achieved by following our one-pot method by
reacting b-tetralone 13 and naphthyl bromide 14 in the
presence of sodium hydride in benzene and subsequent
acid treatment (Scheme 4).26b This process involves
alkylation, cyclodehydration, and aromatization in a
one-pot method.27
We are aware from the literature that conformationally
constrained molecules often have a greater effect on bio-
logical properties when compared to the relatively flexi-
ble open-chain compounds.15–22 On the basis of this
hypothesis, we anticipated that conformationally con-
strained analogues of our open-chain diamides (1 and
2) may increase potency. It has been established that
b-lactams are more effective at lowering cholesterol in
human plasma when compared to open-chain sub-
strates.5 Therefore, synthesis of b-lactams of type 3
and related compounds is necessary in order to investi-
gate a comparative study with diamides 1 and 2.
2. Results and discussion
2.1. Synthesis of novel b-lactams with polyaromatic
imines
The Staudinger reaction has been used extensively for
the synthesis of monocyclic b-lactams (Scheme 1, e.g.,
6 and 7).12c This reaction requires an imine 5, a tertiary
base (triethylamine), and acid chloride 4 (or equivalent).
While many monocyclic aromatic amines and aldehydes
required for the synthesis of imines are commercially
available, polycyclic aromatic amines and aldehydes
are not. Therefore, preparation of these starting materi-
als is necessary for studying this reaction. In general, ni-
tro compounds are the precursors of the amines.
Therefore, an important task is to prepare polycyclic
aromatic nitro compounds, particularly those of chry-
sene, phenanthrene, pyrene, and dibenzofluorene in
good yield. Nitration of these hydrocarbons by concen-
trated nitric acid in sulfuric acid or acetic acid is a widely
We initiated preparation of b-lactams by following the
Staudinger reaction using these specific amine 10, alde-
hyde 12, and commercially available compounds. The
stereochemistry of resulting b-lactams including, cis,
trans, and a cis–trans mixture, varies depending on the
Scheme 1.
Scheme 3.

B. K. Banik et al. / Bioorg. Med. Chem. 13 (2005) 3611–3622
3613
The preparation of b-lactams using the Staudinger reac-
tion was discovered more than 90 years ago. Surpris-
ingly, there has not been a precedent recorded in the
literature regarding the use of tetracyclic or pentacyclic
aromatic systems in imine components. Notably, the
formation of trans-b-lactams as seen in the present
investigation also has not been described in the
literature.12c Some previous studies were aimed at the
formation of trans-b-lactams. However, the experimen-
tal conditions in those investigations were clearly differ-
ent from those in the present one. For example,
synthesis of some trans-b-lactams was achieved using
high-power microwave irradiation and changing the or-
der in which the reagents were added.29d,e Furthermore,
in two cases, trans-b-lactams were formed in low yield as
the only isolated products using cyclic imines, but they
were not derived from aromatic amines.29a,b Struc-
turally, those cyclic imines are completely different
than the imines used in this study. The situation became
more complicated when a sterically congested cyclic
imine produced cis-b-lactam.29c Since microwave irradia-
tion was helpful in achieving the synthesis of trans-b-
lactams, we wanted to test this approach under this
condition.
Scheme 4.
2.2. Microwave-induced synthesis of b-lactams
substituents present in imine 5 and acid chloride 4 and
the conditions of the reactions (Scheme 1). In general,
the reaction of acyloxy, alkoxy, and nitrogen-containing
acid chloride with diaryl imines produces cis-b-lactams
under Staudinger reaction conditions.28 However, reac-
tion of polyaromatic imines (15, 17, 19, 21, 23, and
25) with acetoxy, phenoxy, and phthalimido acid chlo-
ride in the presence of triethyl amine at ꢀ78 °C to room
temperature produced exclusively trans-b-lactams in
reasonably good yields (16, 18, 20, 22, 24, and 26,
Scheme 5), which contrasts sharply with the observation
described above. According to earlier results, cis-b-lac-
tams were expected.28 The trans stereochemistry of the
products has been verified from the NMR data (Section
4). The coupling constant of the C3 and C4 hydrogens in
the cis-compounds is higher than that of in the trans-
products. Also, isomeric polyaromatic imines (27, 29,
and 31) in which the aromatic moieties were inter-
changed produced exclusively cis-b-lactams (28, 30,
and 32) in good yield (Scheme 6). Interestingly, imine
21e derived from cinnamaldehyde and 1-amino pyrene
also afforded cis-b-lactam 33 as the only product
(Scheme 7).
The use of domestic microwave in organic synthesis is
well established. This is particularly very interesting be-
cause of the unconventional set upfor conducting the
reaction to take advantage of the specific nature of
microwave energy. Irradiation of a solution of imines
15, 17, and 23 with acetoxyacetyl chloride in chloroben-
zene using a domestic microwave oven30,31 afforded
trans-b-lactams 16a, 18a, and 24a, respectively, in com-
parable yield (Scheme 9).
A large Erlenmeyer flask was the reaction vessel in
unmodified domestic microwave oven. Polar solvents
like chlorobenzene and DMF can be used. The boiling
points of these solvents are much higher than the pro-
jected temperature of the reaction. The temperature of
the reaction mixture was kept below 110 °C by the prop-
er adjustments of the on–off cycle and a Ôheat sinkÕ. Since
microwave energy is absorbed by all of the polar mole-
cules effectively, there is no need for a stirrer. A reflux
condenser is not required. When irradiated in a micro-
wave oven using chlorobenzene and triethylamine, cis-
b-lactams 37 and 39 did not isomerize to the more stable
trans-b-lactams 36 and 38. Also, the cis-b-lactams did
not change to trans-b-lactams when they were refluxed
using ethylene dichloride and triethylamine. These
experiments established that there was no isomerization
of the cis-b-lactams to the more thermodynamically sta-
ble trans-b-lactams during reaction of imines with acid
chlorides (equivalent) at a high temperature and/or un-
der microwave irradiation.
The critical aspect of the Staudinger reaction, however,
was observed when isomeric naphthalenyl (1- and 2-
substituted) and anthracenyl (1- and 2-substituted) imi-
nes were employed. While the 1-substituted compounds
(15 and 17) produced only the trans isomers (16 and 18),
the 2-substituted compounds (34 and 35) produced a
mixture of cis (37 and 39) and trans isomers (36 and
38) in a ratio of 1:1. The only structural difference in
these compounds was the location of a peri hydrogen
in these derivatives (15 and 17) and (34 and 35) (Scheme
8). The peri hydrogen in 15 and 17 was closer to the
C@N bond than it was in 34 and 35.
The surprising observation is that irradiation of 15, 17,
and 23 with 4 under identical conditions afforded the
trans product 16a, 18a, and 24a as the only isomers.
However, irradiation of 34 and 35 with 4 in chloroben-
zene produced mostly trans-b-lactams (36 and 38).

3614
B. K. Banik et al. / Bioorg. Med. Chem. 13 (2005) 3611–3622
Scheme 5.
Therefore, the present study clearly indicates that micro-
wave irradiation can accelerate the synthesis of b-lactams
with comparable yield. These reactions were performed
in unmodified domestic microwave ovens in a matter of
minutes using very limited amounts of solvents.
observations, cis-b-lactam was found to be the exclusive
or major product when acid chloride (equivalent) was
added dropwise at low to room temperature to the solu-
tion of imines and a tertiary base. On the other hand, a
trans-b-lactam is the major or exclusive product when a
tertiary base is slowly added to the imine and acid chlo-
ride (equivalent) solution at room to high temperature.
Based on the large amount of data in the literature,
some predictions concerning their stereoselectivity have
been made. For instance, Georg and Ravikumar estab-
lished some empirical rules regarding stereoselectivity
in the formation of b-lactam rings.28 Also, computer-as-
sisted theoretical calculations have been advanced to ex-
plain the stereochemical outcome.32,33 Cossio and co-
workers32 and Sordo and co-workers33 explained the
stereochemical results on the basis of torquoelectronic
2.3. Mechanism of b-lactam formation with polyaromatic
imines
While the mechanism of b-lactam formation has been
investigated extensively, the rationale for the observed
diastereoselectivity in certain cases remains unknown.
It has been shown that the stereoselectivity depends on
a number of factors: the structure of the imine, acid
chloride (equivalent), sequence of reagent addition, sol-
vent, temperature, and bases. In a large number of

B. K. Banik et al. / Bioorg. Med. Chem. 13 (2005) 3611–3622
3615
Scheme 6.
Scheme 7.
Scheme 8.
effects. Low-temperature infrared spectroscopy was used
by Lynch et al. to identify the reactive intermediates.34
In general, two mechanisms have been proposed to ex-
plain the product distribution in the b-lactam formation
reaction. One of these, the ketene mechanism, was ob-
served in a low-temperature infrared spectroscopy
study34 while the other, the acylation of imine mecha-
nism, was believed to be involved as described previ-
ously.28 Both mechanisms have been supported by
numerous lines of evidence in several studies. In partic-
ular, it has been hypothesized that cycloaddition of the
imine occurs from the least hindered side of the ketene,
a process that generates zwitterionic intermediates; con-
rotatory cyclization of these intermediates can then pro-
vide cis- and trans-b-lactams. In addition, the latter
mechanism proposes acylation of the imine by the acid

3616
B. K. Banik et al. / Bioorg. Med. Chem. 13 (2005) 3611–3622
speculated. The formation of a trans isomer as observed
in the present study can be rationalized through isomeri-
zation of the enolates (Scheme 10, A to B). The electron-
withdrawing polyaromatic group at the nitrogen stabi-
lizes the iminium ion. This process allows rotation of
the bond (A to B) and results in the formation of
trans-b-lactam C. This observation is similar to that de-
scribed by Just et al., in which formation of a trans-iso-
mer having electron-withdrawing nitro-substituted
imines was performed.35 In contrast, the exclusive form-
ation of a cis-b-lactam having a polyaromatic group and
cinnamyl at C4 prompted us to develop a hypothesis
regarding a mechanism previously described by Doyle
et al.36 In this context, extended conjugation of the cinn-
amyl and polyaromatic system stabilizes the acylimin-
ium ion D. Furthermore, the presence of the cinnamyl
or polyaromatic system at C4 outweighs the contribu-
tion of the N-polyaromatic system, resulting in cis-b-lac-
tam formation. Subsequent proton abstraction from
complex D would lead to cis-b-lactam G through E
(90° bond rotation and closure) or F (anion inversion
and closure). This hypothesis is further strengthened
by the possible formation of donor–acceptor complex
H as suggested by Bose et al.37 This complex formation
effectively stabilizes the transition states of the reaction.
Scheme 9.
chloride to form N-acyliminium chloride, which pro-
duces zwitterionic intermediates (Scheme 10).
Our current thoughts regarding the likely mechanisms
by which this cycloaddition proceeds are described be-
low in brief. Infra-red spectra have shown a strong band
at 2200 cmꢀ1 when 4 and 23 were reacted in the presence
of triethylamine within 30 min after the start of the reac-
tion. This band mostly disappeared after 24 h of reac-
tion. Therefore, involvement of a ketene species is
Scheme 10.

B. K. Banik et al. / Bioorg. Med. Chem. 13 (2005) 3611–3622
3617
In an elegant study, Cossio et al.32a described that the
SN2 intramolecular mechanism favored the preferential
or exclusive formation of trans-b-lactams, particularly
when the reactions were allowed to take place in the ab-
sence of a tertiary base in the initial stages of the reac-
tion. Triethylamine was used as one of the reactants at
the beginning of our experiment, yet the product was a
trans-b-lactam in many cases as described above. The
use of diisopropylethyl amine as the base could not im-
prove the yield of our products. However, the
stereochemistry of the products remained identical. In
a recent paper, Lassaletta and co-workers38 explained
the stereoselectivity of trans-b-lactam on the basis of ste-
ric effects. This paper postulated the isomerization of
C@N bond prior to ring closure as a result of severe ste-
ric interactions between bulky N-benzyloxycarbonyl-N-
benzylamino groupand the alkyl groupof hydrazone.
Undoubtedly, this mechanism explained our trans-selec-
tivity, but could not explain cis selectivity with similar-
types of compounds. Formation of a mixture of cis-
and trans-isomers with naphthalenyl and anthracenyl
imines as observed cannot be explained even when using
the mechanisms described above.32–38 If the electron-
withdrawal properties or the steric crowding of the N-
polyaromatic system are solely responsible for the
trans-b-lactam formation, then an identical stereochem-
ical distribution would have been observed in the iso-
meric naphthalenyl and anthracenyl compounds.
Comparison of these results and examination of the N-
polyaromatic systems with which (19, 21, 23, and 25)
trans isomers were the only products revealed a struc-
tural similarity. As stated above, these imines 15 and
17 have a peri hydrogen very close to the C@N bond,
whereas this peri hydrogen is relatively distant from
the same bond in imines 34 and 35. Whether this peri
hydrogen is accountable for the difference in stereo-
chemical behavior is unknown at this time. However,
a critical role for a peri nitrogen atom in the biological
activity of a number of carboxamides has been demon-
strated. But, it has been established that microwave irra-
diation can alter the stereochemical distribution when
naphthalenyl and anthracenyl imines 34 and 35 were
used irrespective of the absence of the peri hydrogen.
In contrast, several other imines (21e, 27, 29, and 31)
with extended conjugation never produced trans-b-lac-
tams even after performing the reactions under forcing
conditions.29e In this respect, it appears that stabiliza-
tion of the positive charge by the extended conjugation
is the major contributor in dictating the stereochemistry
of the final b-lactams.36 These extensive results also indi-
cate that it is the nature of the C4 groupthat controls the
isomer distribution in this type of reaction. Therefore, it
is conceivable that the mechanism of b-lactam forma-
tion reaction by Staudinger reaction is not only very
complex, but also unique since it varies considerably
with minor structural changes and conditions.
2.4. Anticancer activities of the b-lactams
These b-lactams were tested using nine human cancer
cell lines with cisplatin and diamide 1b as controls.
The results are depicted in Table 1.
The structure–activity study revealed that regardless of
the structure or configuration of the b-lactam compo-
nent, neither naphthalene (16), anthracene (18) nor
pyrene derivatives (22) demonstrated activity against
any of these cell lines. Their maximum activity was
determined to be at concentrations in excess of 20 lM/
mL (a level not considered to have a significant effect).
The trans-acetoxy phenanthrene and chrysene deriva-
tives (20a, 24a, and 24d) demonstrated activity. Phenoxy
and phthalimido (20b, 24b, and 24c) b-lactams were
inactive. Specifically, on the breast cancer cell line
MCF-7, three compounds (cisplatin, 20a, and 24a) had
almost identical activity, while on the colon cancer cell
line HT-29; 24a was approximately three times as active
as cisplatin. Selective differences in cytotoxicity were
also evident on the ovarian cancer cell line OVCAR,
where cisplatin and 24a had almost identical activity
and 20a had little.
Several conclusions can be derived from the results of
the in vitro studies. It is a evident that the minimal struc-
tural requirement of the aromatic moiety for cytotoxi-
city is at least three aromatic rings in an angular
configuration. Thus, only phenanthrene 20a and two
chrysene derivatives 24a and 24d demonstrated cytotoxi-
city against the tumor cell lines. The comparable naph-
thalenes, anthracenes, and pyrene compounds (16, 18,
20b, 22, 24b–c, 28, and 30) were inactive. Also, the pres-
ence of the acetoxy groupproved to be obligatory. Acet-
oxy is a well-established leaving groupfor reactions with
a wide range of nucleophiles. This suggests that an enzy-
matic or other alteration at this site was involved in the
activation of these compounds (20a, 24a, and 24d).
Furthermore, only the trans-b-lactams (20a and 24a vs
28a and 30a) were proved to have antitumor activity.
This study supports that certain conformationally re-
stricted compounds, indeed, can give better activity in
biological systems.5,15–22 In the present study, it has
been confirmed that 20a, 24a, and 24d are more potent
Table 1. In vitro cytotoxicity of b-lactams on human cancer cell lines (lM)
Compounds
BRO
MCF-7
MDA-231
OVCAR
SKOV
PC-3
4.66
HL-60
K-562
HT-29
Cisplatin
1b
7.66
10.05
40.0
12.33
12.23
12.49
11.98
14.46
>20
3.99
18.11
18.0
4.17
—
5.99
11.05
18.00
6.88
1.66
9.41
5.21
3.64
2.5
2.33
12.70
4.0
16.99
16.70
10.49
5.66
33.64
10.48
10.84
11.00
27.29
9.3
16.32
20a
24a
10.09
9.81
4.33
2.5
24d
16, 18, 20b, 22, 24b–c, 28, 30, 33
14.93
>20
9.0
—
>20
15.90
>20
>20
>20
>20
>20
>20
All of the in vitro cytotoxicity assays were performed using MTT assay.

3618
B. K. Banik et al. / Bioorg. Med. Chem. 13 (2005) 3611–3622
than 1b in many cancer lines in vitro. However, neither
the target nor the mechanism of the subsequent antitu-
mor activity of these agents has been identified.14b
4.4. Microwave-assisted preparation of the b-lactam
(general procedure)
The following caution is recommended. It is standard
practice in our laboratories to place the microwave oven
inside the hood. Many commercial microwave ovens are
equipped with a timer such that heating can be started
after the operator has moved away from the hood con-
taining the microwave oven.
3. Conclusion
We have demonstrated facile synthesis of a number of
new anticancer active b-lactams starting from polyaro-
matic imines. The b-lactam derivatives described herein
are unique and they demonstrate reasonable in vitro
antitumor cytotoxicity. The stereochemical outcome of
the Staudinger reaction as reported herein may offer
our laboratory and others many additional opportuni-
ties to use b-lactams in the synthesis of biologically ac-
tive compounds.39
The same amount of imine, acid chloride, and triethyl-
amine was placed in an Erlenmeyer flask (125 mL capac-
ity) containing chlorobenzene (2 mL). The flask was
then capped with a glass funnel and placed in a micro-
wave oven (G. E. Model, 1450 W). A 500 mL beaker
containing 200 mL of water was placed in the oven next
to the reaction flask to serve as a Ôheat sinkÕ. The mixture
was irradiated for 3 min at intervals of 1 min each. After
the usual work upas described above, the b-lactam was
isolated (60–70% yield).
4. Experimental
4.1. General methods
4.5. trans-N-(1-Naphthalenyl)-3-acetoxy-4-phenyl-2-aze-
tidine-2-one (16a)
All of the solvents and reagents were obtained from
commercial sources and used without purification.
Reactions were monitored by TLC using pre-coated sil-
ica gel aluminum plates containing a fluorescence indi-
Mp136–138 °C; IR cmꢀ1 (neat) 1757, 1745, 1596, 1576,
1510, 1465, 1456, 1409, 1367, 1340, 1222; 1H NMR
1
cator. Chemical shifts of H NMR spectra were given
(CDCl3):
d
(ppm) 2.26 (s, 3H), 5.33–5.34 (d,
in parts per million with respect to TMS, and the cou-
pling constant J was measured in hertz. Data are re-
ported as follows: chemical shifts, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet). 1H NMR spectra were recorded in
CDCl3 and CD3OD using tetramethylsilane as an inter-
nal standard. IR spectra were expressed as wave num-
bers (cmꢀ1).
J = 1.94 Hz, 1H), 5.66–5.67 (d, J = 1.96 Hz, 1H), 7.21–
7.39 (m, 7H), 7.52–7.66 (m, 2H), 7.72–7.75 (d, 1H),
7.84–7.85 (d, 1H), 8.22–8.25 (d, 1H). Anal. Calcd for
C21H17NO3: C, 76.12; H, 5.17; N, 4.23. Found: C,
76.15; H, 5.19; N, 4.20.
4.6. trans-N-(1-Naphthalenyl)-3-phenoxy-4-phenyl-2-
azetidine-2-one (16b)
For the preparation of the nitro compound, see Ref. 25.
For the preparation of the aldehyde, see Ref. 26.
Mp215–217 °C; IR cmꢀ1 (neat) 1760, 1596, 1576, 1510,
1494, 1465, 1456, 1406, 1368, 1339, 1290, 1228; 1H
NMR (CDCl3): d (ppm) 5.30–5.31 (d, J = 1.81 Hz,
1H), 5.38–5.39 (d, J = 1.8 Hz, 1H), 6.95–7.06 (m, 3H),
7.23–7.44 (m, 9H), 7.51–7.57 (m, 1H), 7.59–7.67 (m,
1H), 7.72–7.74 (d, 1H), 7.84–7.87 (d, 1H), 8.25–8.27
(d, 1H). Anal. Calcd for C25H19NO2: C, 82.17; H,
5.24; N, 3.83. Found: C, 82.2; H, 5.18; N, 3.79.
4.2. Preparation of imine (general procedure)
To a solution of the amine (10 mmol) in toluene (40 mL)
was added aldehyde (10 mmol) and the mixture was re-
fluxed overnight using a Dean–Stark water separator
(monitored by TLC). When the reaction was over, tolu-
ene was evaporated under reduced pressure, and the
crude product was used as such for the next reaction.
4.7. trans-N-(1-Anthracenyl)-3-acetoxy-4-phenyl-2-azeti-
dine-2-one (18a)
4.3. Preparation of b-lactam (general procedure)
Mp298–300 °C; IR cmꢀ1 (neat) 1752, 1672, 1583, 1457,
1370, 1315, 1273, 1218; 1H NMR (CDCl3): d (ppm) 2.28
(s, 3H), 5.41–5.42 (d, J = 1.95 Hz, 1H), 5.74–5.75 (d,
J = 1.99 Hz, 1H), 7.18–7.20 (d, 1H), 7.26–7.42 (m,
6H), 7.51–7.54 (m, 2H), 7.88–7.91 (d, 1H), 7.99–8.02
(m, 1H), 8.14–8.17 (m, 1H), 8.44 (s, 1H), 8.83 (s, 1H).
Anal. Calcd for C25H19NO3: C, 78.72; H, 5.02; N,
3.67. Found: C, 78.69; H, 5.05; N, 3.59.
A solution consisting of acid chloride (1.5 mmol) in
dichloromethane (10 mL) was added dropwise to a stir-
red solution containing imine (1 mmol) and distilled tri-
ethylamine (3 mmol) in dry dichloromethane (10 mL) at
ꢀ78 °C. The reaction mixture was then stirred overnight
at room temperature, washed with saturated sodium
bicarbonate solution (10 mL), dilute hydrochloric acid
(10%, 10 mL), brine (10 mL), dried with anhydrous so-
dium sulfate, and evaporated to obtain the crude prod-
uct. Proton NMR was performed to calculate the ratio
of the isomeric b-lactams. The pure product (47–80%)
was then isolated via column chromatography over sil-
ica gel using ethyl acetate–hexanes (1:4) as the solvent.
4.8. trans-N-(1-Anthracenyl)-3-phenoxy-4-phenyl-2-aze-
tidine-2-one (18b)
Mp146–148 °C; IR cmꢀ1 (neat) 1761, 1622, 1598, 1592,
1541, 1493, 1458, 1406, 1385, 1367, 1339, 1290, 1231; 1H
NMR (CDCl3): d (ppm) 5.38–5.39 (d, J = 1.81 Hz, 1H),

B. K. Banik et al. / Bioorg. Med. Chem. 13 (2005) 3611–3622
3619
5.47–5.48 (d, J = 1.79 Hz, 1H), 6.99–7.08 (m, 3H), 7.20–
7.36 (m, 7H), 7.44–7.56 (m, 4H), 7.88–7.91 (d, 1H),
7.98–8.01 (m, 1H), 8.14–8.18 (m, 1H), 8.44 (s, 1H),
8.85 (s, 1H). Anal. Calcd for C29H21NO2: C, 83.83; H,
5.09; N, 3.3.37. Found: C, 83.79; H, 5.1; N, 3.4.
C31H18N2O4: C, 77.17; H, 3.76; N, 5.81. Found: C,
76.68; H, 3.45; N, 5.53.
4.14. trans-N-(6-Chrysenyl)-3-acetoxy-4-phenyl-2-azeti-
dine-2-one (24a)
Mp174–176 °C; IR cmꢀ1 (neat) 1755, 1595, 1515, 1486,
4.9. trans-N-(9-Phenanthrenyl)-3-acetoxy-4-phenyl-2-
azetidine-2-one (20a)
1456, 1440, 1394, 1373, 1314, 1283, 1219; 1H NMR
(CDCl3):
d
(ppm) 2.36 (s, 3H), 5.54–5.55 (d,
Mp152–154 °C; IR cmꢀ1 (neat) 1754, 1625, 1599, 1528,
1498, 1455, 1401, 1369, 1280, 1219; 1H NMR (CDCl3): d
(ppm) 2.27 (s, 3H), 5.43–5.44 (d, J = 1.92 Hz, 1H), 5.70–
5.71 (d, J = 1.96 Hz, 1H), 7.27–7.29 (m, 3H), 7.40–7.42
(m, 2H), 7.52–7.63 (m, 3H), 7.73–7.78 (m, 3H), 8.29–
8.32 (m, 1H), 8.62–8.64 (d, 1H), 8.70–8.73 (m, 1H).
Anal. Calcd for C25H19NO3: C, 78.72; H, 5.02; N,
3.67. Found: C, 78.69; H, 5.17; N, 3.70.
J = 1.91 Hz, 1H), 5.77–5.78 (d, J = 1.94 Hz, 1H), 7.26–
7.31 (m, 3H), 7.46–7.49 (m, 2H), 7.60–7.71 (m, 2H),
7.77–7.80 (m, 2H), 7.95–7.99 (m, 2H), 8.38–8.41 (m,
1H), 8.45 (s, 1H), 8.50–8.53 (d, 1H), 8.63–8.66 (d, 1H),
8.79–8.82 (m, 1H). Anal. Calcd for C29H21NO3: C,
80.72; H, 4.91; N, 3.25.12. Found: C, 80.69; H, 4.89;
N, 3.19.
4.15. trans-N-(6-Chrysenyl)-3-phenoxy-4-phenyl-2-azeti-
dine-2-one (24b)
4.10. trans-N-(9-Phenanthrenyl)-3-benzyloxy-4-phenyl-2-
azetidine-2-one (20b)
Mp180–182 °C; IR cmꢀ1 (neat) 1761, 1596, 1515, 1494,
1456, 1439, 1392, 1346, 1315, 1235; 1H NMR (CDCl3): d
(ppm) 5.42–5.43 (d, J = 1.8 Hz, 1H), 5.59–5.60 (d,
J = 1.74 Hz, 1H), 7.0–7.09 (m, 3H), 7.28–7.38 (m, 5H),
7.52–7.55 (m, 2H), 7.59–7.70 (m, 2H), 7.76–7.79 (m,
2H), 7.94–7.98 (m, 2H), 8.41–8.43 (m, 1H), 8.48 (s,
1H), 8.50–8.52 (d, 1H), 8.62–8.65 (d, 1H), 8.78–8.81
(m, 1H). Anal. Calcd for C33H23NO2: C, 85.14; H,
4.98; N, 3.01. Found: C, 85.09; H, 4.79; N, 2.99.
IR cmꢀ1 (neat) 1760, 1624, 1597, 1528, 1497, 1482, 1453,
1400, 1368, 1346, 1277, 1208; 1H NMR (CDCl3): d
(ppm) 4.80 (d, J = 1.87 Hz, 1H), 4.94 (d, J = 11 Hz,
1H), 5.32 (d, J = 1.85 Hz, 1H), 7.21–7.26 (m, 6H),
7.34–7.44 (m, 5H), 7.70–7.75 (m, 5H), 8.27–8.30 (m,
1H), 8.61 (d, J = 8 Hz, 1H), 8.66–8.71 (m, 1H). Anal.
Calcd for C30H23NO2: C, 83.89; H, 5.39; N, 3.26.
Found: C, 83.80; H, 4.89; N, 3.50.
4.16. trans-N-(6-Chrysenyl)-3-phthalimido-4-phenyl-2-
azetidine-2-one (24c)
4.11. trans-N-(1-Pyrenyl)-3-acetoxy-4-phenyl-2-azeti-
dine-2-one (22a)
IR cmꢀ1 (neat) 3050, 1760, 1605, 1550; 1H NMR
(CDCl3): d (ppm) 5.67 (d, J = 2.8 Hz, 1H), 5.95 (d,
J = 2.8 Hz, 1H), 7.23–7.30 (m, 3H), 7.46–7.49 (m, 2H),
7.62 (m, 2H), 7.77 (m, 4H), 7.92 (m, 4H), 8.50 (m,
2H), 8.60 (m, 2H), 8.75 (m, 1H). Anal. Calcd for
C35H22N2O3: C, 81.07; H, 4.28; N, 5.40. Found: C,
81.0; H, 4.25; N, 5.35.
Mp130–132 °C; IR cmꢀ1 (neat) 1760, 1745, 1601, 1509,
1457, 1410, 1372, 1315, 1283, 1224; 1H NMR (CDCl3): d
(ppm) 2.29 (s, 3H), 5.52–5.53 (d, J = 1.19 Hz, 1H), 5.75–
5.76 (d, J = 1.93 Hz, 1H), 7.24–7.27 (m, 3H), 7.41–7.44
(m, 2H), 7.77–7.80 (d, 1H), 7.97–8.10 (m, 4H), 8.19–
8.25 (m, 3H), 8.41–8.44 (d, 1H). Anal. Calcd for
C27H19NO3: C, 79.98; H, 4.72; N, 3.45. Found: C,
80.0; H, 4.7; N, 3.5.
4.17. trans-N-(6-Chrysenyl)-3-acetoxy-4-(20-pyridyl)-2-
azetidine-2-one (24d)
4.12. trans-N-(1-Pyrenyl)-3-phenoxy-4-phenyl-2-azeti-
dine-2-one (22b)
Mp162–164 °C; IR cmꢀ1 (neat) 1760, 1600, 1510, 1485,
1
1450, 1390; H NMR (CDCl3): d (ppm) 2.29 (s, 3H),
Mp186–187 °C; IR cmꢀ1 (neat) 1757, 1599, 1590, 1509,
1493, 1456, 1438, 1410, 1379, 1315, 1276, 1263, 1241,
1227; 1H NMR (CDCl3): d (ppm) 5.40–5.39 (d,
J = 1.79 Hz, 1H), 5.57–5.58 (d, J = 1.68 Hz, 1H), 6.99–
7.06 (m, 3H), 7.26–7.34 (m, 5H), 7.46–7.49 (dd, 2H),
7.79–7.81 (d, 1H), 7.97–8.09 (m, 4H), 8.18–8.24 (m,
3H), 8.44–8.47 (d, 1H). Anal. Calcd for C31H21NO2: C,
84.72; H, 4.82; N, 3.19. Found: C, 84.7; H, 4.8; N, 3.2.
5.30 (d, J = 1.5 Hz, 1H), 5.58 (d, J = 1.5 Hz, 1H), 7.16
(dd, J1 = 5.1 Hz, J2 = 6.9 Hz, 9H), 7.27 (d, J = 9 Hz,
1H), 7.50–7.98 (m, 7H), 8.36–8.81 (m, 6H). Anal. Calcd
for C28H20N2O3: C, 77.76; H, 4.66; N, 6.48. Found: C,
77.43; H, 4.35; N, 6.18.
4.18. trans-N-(20-Dibenzofluorenyl)-3-acetoxy-4-phenyl-
2-azetidine-2-one (26)
4.13. trans-N-(1-Pyrenyl)-3-phthalimido-4-phenyl-2-
azetidine-2-one (22c)
UV (EtOH): kmax 260 (log e 4.57), 355 (log e 4.26); IR
cmꢀ1 (CH2Cl2) 3054, 1755, 1590, 1496, 1456; 1H
NMR (CDCl3): d (ppm) 2.28 (s, 3H), 4.00 (1H, ABq,
J = 22.68 Hz), 5.42, (d, J = 1.2 Hz, 1H), 5.70 (d,
J = 1.2 Hz, 1H), 7.23–7.40 (m, 8H), 7.67–7.87 (m, 2H),
7.88–7.90 (m, 3H), 8.35–8.38 (m, 2H), 8.42–8.50 (m,
1H); 13C NMR (CDCl3): d (ppm) 20.67, 36.29, 65.29,
81.03, 117.50, 121.41, 124.04, 124.08, 124.62, 125.61,
1
IR cmꢀ1 (CH2Cl2) 3060, 1760, 1600, 1555; H NMR
(CDCl3): d (ppm) 2.21 (s, 3H), 5.43 (d, J = 2.04 Hz,
1H), 6.10 (d, J = 2.05 Hz, 1H), 6.25 (dd, J1 = 10 Hz,
J2 = 14 Hz, 1H), 6.42 (d, J = 3.8 Hz, 1H), 7.80 (d,
J = 9 Hz, 1H), 8.05–8.31 (m, 9H). Anal. Calcd for

3620
B. K. Banik et al. / Bioorg. Med. Chem. 13 (2005) 3611–3622
125.78, 126.50, 126.91, 127.68, 127.82, 128.59, 129.01,
129.99, 130.19, 131.82, 135.28, 136.96, 141.28, 141.13,
163.29, 169.77. Anal. Calcd for C32H23NO3: C, 81.86;
H, 4.94; N, 2.98. Found: C, 81.58; H, 5.02; N, 3.09.
J2 = 8 Hz), 6.12 (d, J = 5.2 Hz, 1H), 6.25–6.38 (m, 1H),
6.65–6.70 (m, 1H), 7.8–8.38 (m, 14H). Anal. Calcd for
C29H21NO3: C, 80.72; H, 4.91; N, 3.25. Found: C,
80.69; H, 4.89; N, 3.19.
4.19. cis-N-(1-Phenyl)-3-acetoxy-4-phenanthrenyl-2-
azetidine-2-one (28a)
4.24. cis-N-(1-Pyrenyl)-3-benzyloxy-4-cinnamyl-2-azeti-
dine-2-one (33b)
1
Mp192–194 °C; IR cmꢀ1 (neat) 1761, 1599, 1497, 1451,
1408, 1372, 1265, 1217; 1H NMR (CDCl3): d (ppm) 1.40
(s, 3H), 6.11–6.13 (d, J = 5.17 Hz, 1H), 6.53–6.54 (d,
J = 5.22 Hz, 1H), 7.11–7.16 (m, 1H), 7.26–7.33 (m,
2H), 7.45–7.49 (m, 2H), 7.54–7.59 (m, 1H), 7.65–7.78
(m, 5H), 7.97–8.0 (d, 1H), 8.67–8.7 (d, 1H), 8.76–8.79
(d, 1H). Anal. Calcd for C25H19NO3: C, 78.72; H,
5.02; N, 3.67. Found: C, 78.69; H, 4.99; N, 3.59.
IR cmꢀ1 (CH2Cl2): 3055, 1756, 1600, 1550; H NMR
(CDCl3): d (ppm) 4.80 (dd, J1 = 9 Hz, J2 = 12 Hz, 2H),
5.12 (dd, J1 = 4 Hz, J2 = 8 Hz, 1H), 5.20 (d, J = 5.5
Hz, 1H), 6.46–6.62 (m, 2H), 7.18–7.45 (m, 8H), 7.84–
8.24 (m, 11H). Anal. Calcd for C34H25NO2: C, 85.15;
H, 5.25; N, 2.92. Found: C, 84.89; H, 5.01; N, 2.75.
Acknowledgements
4.20. cis-N-(1-Phenyl)-3-phenoxy-4-phenanthrenyl-2-
azetidine-2-one (28b)
We gratefully acknowledge the partial financial support
for this research from The University of Texas, M. D.
Anderson Cancer Center. B.K.B. is grateful to The Uni-
versity of Texas—Pan American for academic and re-
search facilities.
IR cmꢀ1 (neat) 1752, 1596, 1493, 1452, 1435, 1405, 1375,
1264, 1227; H NMR (CDCl3): d (ppm) 5.80–5.82 (d,
J = 5.39 Hz, 1H), 6.17–6.19 (d, J = 5.32 Hz, 1H), 6.68–
6.71 (m, 2H), 6.83–6.88 (m, 1H), 7.04–7.14 (m, 3H),
7.30–7.35 (m, 2H), 7.50–7.77 (m, 8H), 7.96–7.98 (d,
1H), 8.68–8.71 (d, 1H), 8.78–8.81 (d, 1H). Anal. Calcd
for C29H21NO2: C, 83.83; H, 5.09; N, 3.37. Found: C,
83.79; H, 5.1; N, 3.33.
1
References and notes
1. For recent examples, see: (a) Southgate, R.; Branch, C.;
Coulton, S.; Hunt, E. In Recent Progress in the Chemical
Synthesis of Antibiotics and Related Microbial Products;
Lukacs, G., Ed.; Springer: Berlin, 1993; Vol. 2, p 621; (b)
Kidwai, M.; Sapra, P.; Bhushan, K. R. Curr. Med. Chem.
1999, 6, 195–215; (c) Bose, A. K.; Manhas, M. S.; Banik,
B. K.; Srirajan, V. In The Amide Linkage: Selected
Structural Aspects in Chemistry, Biochemistry, and Mate-
rial Science; Greenberg, A., Breneman, C. M., Liebman, J.
F., Eds.; Wiley-Interscience: New york, 2000, pp 157–214,
Chapter 7 (b-Lactams: Cyclic Amides of Distinction); (d)
b-Lactams: Synthesis, Stereochemistry, Synthons and Bio-
logical Evaluation; Current Medicinal Chemistry; Banik,
B. K., Ed.; ; Bentham Science, 2004; Vol. 11.
2. Buynak, J. Curr. Med. Chem. 2004, 11, 1951–1964.
3. (a) Manhas, M. S.; Banik, B. K.; Mathur, A.; Vincent, J.
E.; Bose, A. K. Tetrahedron 2000, 56, 5587–5601; (b) Bose,
A. K.; Mathur, C.; Wagle, D. R.; Manhas, M. S.
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307–309.
4.21. cis-N-(1-Phenyl)-3-acetoxy-4-chrysenyl-2-azetidine-
2-one (30)
IR cmꢀ1 (neat) 1755, 1748, 1598, 1497, 1383, 1368, 1264,
1
1255, 1216; H NMR (CDCl3): d (ppm) 8.89–8.56 (d,
1H), 8.73–8.70 (d, 1H), 8.64 (s, 1H), 8.41–8.37 (m,
1H), 8.11–8.09 (d, 1H), 8.05–8.02 (d, 1H), 7.98–7.95
(m, 1H), 7.79–7.95 (m, 1H), 7.79–7.72 (m, 2H), 7.62–
7.58 (m, 2H), 7.59–7.52 (m, 1H), 7.51–7.29 (t, 2H),
7.14–7.10 (t, 1H), 6.59–6.57 (d, J = 5.2 Hz, 1H), 6.28–
6.26 (d, J = 5.18 Hz, 1H), 1.37 (s, 3H); 13C NMR
(CDCl3): d (ppm) 169.1, 162.6, 136.9, 132.1, 130.8,
130.2, 129.4, 129.3, 128.4, 128.3, 128.1, 127.1, 127.0,
126.9, 126.8, 126.6, 126.42, 124.9, 123.9, 123.1, 122.8,
120.7, 120.4, 117.6, 75.2, 59.2, 19.7. Anal. Calcd for
C29H21NO3: C, 80.72; H, 4.91; N, 3.25. Found: C,
80.52; H, 4.69; N, 3.0.
4.22. cis-N-(1-Phenyl)-3-acetoxy-4-(2-dibenzofluorenyl)-
2-azetidine-2-one (32)
4. Suffness, M. Taxol Science and Applications; CRC: Boca
Raton, FL, 1995.
1
IR cmꢀ1 (CH2Cl2): 3050, 1758, 1590, 1490, 1456; H
NMR (CDCl3): d (ppm) 8.98–8.69 (d, 1H), 8.58–8.55
(d, 1H), 8.11–7.93 (m, 5H), 7.74–7.46 (m, 5H), 7.35–
7.30 (t, 3H), 7.15–7.10 (t, 1H), 6.50–6.48 (d, J = 5.17
Hz, 1H), 6.24–6.22 (d, J = 5.03 Hz, 1H), 4.25–4.24 (d,
2H), 1.42 (s, 3H). Anal. Calcd for C32H23NO3: C,
81.86; H, 4.94; N, 2.98. Found: C, 81.58; H, 5.02; N, 3.09.
5. (a) Clader, J. W.; Burnett, D. A.; Caplen, M. A.;
Domalski, M. S.; Dugar, S.; Vaccaro, W.; Sher, R.;
Browne, M. E.; Zhao, H.; Burrier, R. E.; Salisbury, B.;
Davis, H. R. J. Med. Chem. 1996, 39, 3684–3693; (b)
Burnett, D. A.; Caplen, M. A.; Darris, H. R., Jr.; Burrier,
R. E.; Clader, J. W. J. Med. Chem. 1994, 37, 1734–1736;
(c) Burnett, D. A. Curr. Med. Chem. 2004, 11, 1873–1887;
(d) Clader, J. W. J. Med. Chem. 2004, 47, 1–9.
6. Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.;
Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hand, K.
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Weston, H.; Davies, P.; Doherty, J. B. J. Med. Chem.
1995, 38, 2449–2462, and earlier references.
4.23. cis-N-(1-Pyrenyl)-3-acetoxy-4-cinnamyl-2-azeti-
dine-2-one (33a)
1
IR cmꢀ1 (CH2Cl2): 3070, 1755, 1600, 1558; H NMR
(CDCl3): d (ppm) 2.21 (s, 3H), 5.30 (dd, J1 = 5 Hz,

B. K. Banik et al. / Bioorg. Med. Chem. 13 (2005) 3611–3622
3621
7. For catalytic asymmetric synthesis, see: (a) Taggi, A. E.;
Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J., III;
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American Chemical Society (ACS) National Meeting,
Orlando, FL, April 2002, MEDI-213. We sent this paper
for presentation to the ACS on October 31, 2001 and it
was accepted on December 16, 2001. The drug synthesis
and chemistry branch of the NCI tested 24a in their 60 cell
lines and sent us the report on August 8, 2001. This
indicates that we are the pioneer in this field.
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15. It has also been demonstrated that UAB-8, a conforma-
tionally constrained analogue of retinoic acid, has a
favorable toxicological profile relative to the original
molecule. For example, see: Lin, T. H.; Rogers, T. S.; Hill,
D. L.; Simpson-Herren, L.; Farnell, D. R.; Kochhar, D.
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3622
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some examples of indium-induced reactions from our
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