Stereoselective synthesis of novel C-3 functionalized 3-sulfonyl-β-lactams: Promising biologically active heterocyclic scaffolds

Article abstract of DOI:10.1016/j.tetlet.2017.02.011

An efficient and operationally simple strategy for the stereoselective synthesis of novel C-3 functionalized 3-sulfonyl-β-lactam heterocycles is described. The C-3 functionalized 3-phenyl/benzylsulfonyl-β-lactams 3/3′, 5/5′ has been synthesized via Michael addition using different Michael acceptors on trans-3-phenyl/benzylsulfonyl-β-lactams 2(a–f) using K₂CO₃as a base and acetonitrile/DMF as solvents. The reaction furnished exclusively cis-β-lactam adducts 3(a–r) using sterically less hindered Michael acceptors. Further, the effect of steric bulk and chiralilty of Michael acceptors was explored to achieve target C-3 functionalized β-lactams 3(s-u)/3′(s-u) and 5(a–c)/5′(a–c). The structural and stereochemical analysis of novel β-lactams were carried out using FT-IR, NMR (¹H,¹³C,¹H-¹H COSY,¹H-¹³C COSY and¹³C DEPT-135), elemental analysis (CHNS), mass spectrometry (EIMS and LCMS) in representative cases and single crystal X-ray crystallographic studies (3e). The cis or trans configuration of the Michael acceptor (E) at C-3 was assigned with respect to C4-H.

Full text of DOI:10.1016/j.tetlet.2017.02.011

Accepted Manuscript
Stereoselective synthesis of novel C-3 functionalized 3-sulfonyl-β-lactams:
promising biologically active heterocyclic scaffolds
Aman Bhalla, Garima Modi, Shamsher S. Bari, Anu Kumari, Shiwani Berry,
Geeta Hundal
PII:
S0040-4039(17)30176-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.011
TETL 48622
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 December 2016
1 February 2017
4 February 2017
Please cite this article as: Bhalla, A., Modi, G., Bari, S.S., Kumari, A., Berry, S., Hundal, G., Stereoselective synthesis
of novel C-3 functionalized 3-sulfonyl-β-lactams: promising biologically active heterocyclic scaffolds, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.011
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Graphical Abstract
Stereoselective synthesis of novel C-3
Leave this area blank for abstract info.
functionalized 3-sulfonyl-β-lactams: promising
biologically active heterocyclic scaffolds
Aman Bhallaa,*, Garima Modia, Shamsher S. Baria, Anu Kumaria, Shiwani Berrya, Geeta Hundalb
aDepartment of Chemistry, Panjab University and Centre of Advanced Studies in Chemistry, Chandigarh 160014, U. T., India
bDepartment of Chemistry, Guru Nanak Dev University, Amritsar, India
R
O
O
O
S
S
H
H
N
H
E
R1
R2
R1
R2
R
O
Michael acceptors (E)
O
N
aq. K2CO3/acetonitrile or anhyd. K2CO3/DMF,
O
O
O
O
R3
OR*
;
R* =
OC2H5
OCH3
4
N
,
;
,
R
O
,
R3, R4 = CH , H
,
,
,
3
E =
O
O
O
O
(-)-Menthol
(-)-8-Phenylmenthol

1
Tetrahedron Letters
Stereoselective synthesis of novel C-3 functionalized 3-sulfonyl-β-lactams: promising
biologically active heterocyclic scaffolds
Aman Bhallaa,  Garima Modia, Shamsher S. Baria, Anu Kumaria, Shiwani Berrya, Geeta Hundalb
aDepartment of Chemistry, Panjab University and Centre of Advanced Studies in Chemistry, Chandigarh 160014, U. T., India
bDepartment of Chemistry, Guru Nanak Dev University, Amritsar 143005, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and operationally simple strategy for the stereoselective synthesis of novel C-3
functionalized 3-sulfonyl-β-lactam heterocycles is described. The C-3 functionalized 3-
phenyl/benzylsulfonyl--lactams 3/3ʹ, 5/5ʹ has been synthesized via Michael addition using
different Michael acceptors on trans-3-phenyl/benzylsulfonyl-β-lactams 2(a-f) using K2CO3 as a
base and acetonitrile/DMF as solvents. The reaction furnished exclusively cis-β-lactam adducts
3(a-r) using sterically less hindered Michael acceptors. Further, the effect of steric bulk and
chiralilty of Michael acceptors was explored to achieve target C-3 functionalized β-lactams 3(s-
u)/3ʹ(s-u) and 5(a-c)/5ʹ(a-c). The structural and stereochemical analysis of novel β-lactams were
carried out using FT-IR, NMR (1H, 13C, 1H-1H COSY, 1H-13C COSY and 13C DEPT-135),
elemental analysis (CHNS), mass spectrometry (EIMS and LCMS) in representative cases and
single crystal X-ray crystallographic studies (3e). The cis or trans configuration of the Michael
acceptor (E) at C-3 was assigned with respect to C4-H.
Available online
Keywords:
trans-3-Phenyl/benzylsulfonyl-β-lactams
C-3 functionalization
Michael addition
cis-β-Lactam adducts
Michael acceptors
2017 Elsevier Ltd. All rights reserved.
.
Asymmetric induction
-rmacologist in the development of new methodologies for
designing new functionalized β-lactams.
The dynasty of -lactam continued to possess the most widely
used clinical agents1 with admissible safety profile. Beside the
pharmaceutical applications, -lactams are also used as synthetic
intermediates in enantiomerically pure amino-acid synthesis2.
However, the alarming increase in bacterial resistance against β-
lactam antibiotics possess a serious threat for the mankind.3 The
main reason behind this resistance is β-lactamase production by
bacteria. To overcome this, various groups4-6 have synthesized
sulfone-β-lactamase inhibitors (I-III) called suicide inhibitors
(Figure 1) which functions as mechanism-based inactivators of β-
lactamases.
Sulfone derivatives are another widely accepted important
class of bioactive compounds possessing wide spectrum of
activities such as antibacterial,7a antifungal,7b antihepatitis,7c
antitumor,7d anti-inflammatory,7e anticancer,7f anti-HIV-1,7g and
antitubercular.7h Further, C-3 unsymmetrically disubstituted β-
lactams8 such as cholesterol absorption inhibitors (IV, V) and
prostate specific antigen inhibitor VI (Figure 1) having a variety
of alkyl/aryl substituents and the Structure-Activity Relationship
(SAR) of the β-lactam heterocyclic nucleus has been well
documented by Clader et al.9a Recently, Sardarian et al.9b
reported the synthesis of functionalized β-lactam nanoparticles
VII (Figure 1) for the enhancement of antibacterial activity of β-
lactams. These reports refreshed the interest of chemists and pha-
Figure 1. Potential inhibitors of β-Lactamase (I-III), cholesterol
acyltransferase (IV, V), prostate specific antigen VI and antibacterial β-
lactam nanoparticles VII
———
 Corresponding author. Tel.: +91-172-253-4417; fax: +91-172-254-5074.
E-mail: amanbhalla@pu.ac.in (A. Bhalla).

2
Tetrahedron
Table 2
In literature, a number of strategies have been listed for the
C-3 functionalized 3-sulfoyl-β-lactams 3(a-r)a
Entry
1
synthesis and functionalization of -lactams.2b,8-10 However, the
intermediacy of organosulfones in C-3 functionalization of -
lactams via Michael addition is not yet explored. The synthetic
potential of organosulfones including their use as an auxiliary
were reported especially in making carbon-carbon bond thus
establishing these “chemical chameleons” as activating groups in
various synthetic building blocks.11,12
In our earlier studies towards the β-lactam scaffold, we have
synthesized novel β-lactam precursors, 3-thio/seleno-β-lactams
and their Lewis acid mediated functionalization, stereoselective
cis- and trans-alkoxy-β-lactams α-keto-β-lactams, bicyclic-β-
lactams, spirocyclic-β-lactams, 4-pyrazolyl-β-lactams, 4-
pyrazolylspirocyclic-β-lactams and (E)- and (Z)-3-allylidene-β-
lactams.13 In continuance of above, and considering the
importance of sulfonyl-substituted β-lactams, we investigated C-
3 functionalization of trans-3-phenyl/benzylsulfonyl-β-lactams
2(a-f) via Michael addition reactions using simple and milder
bases i.e. aqueous or non-aqueous NaHCO3/K2CO3 in
acetonitrile/DMF as the solvents.
Starting substrate trans-3-phenyl/benzylthio-β-lactams 1(a-f)
were prepared from potassium phenyl/benzylthioacetate and
appropriate Schiff’s bases using our reported procedure.8 Further,
β-lactams 1(a-f) were subjected to oxidation with hydrogen
peroxide (30%) in glacial acetic acid to furnish 2(a-f)16 (Scheme
1) and the results are summarized in Table 1. 1(a-f) and 2(a-f)
were purified by column chromatography (ethyl acetate : hexane)
and crystallization using dichloromethane : hexane and their
structures were confirmed by various spectroscopic techniques
such as IR, 1H NMR, 13C NMR and elemental analysis.16
Time
Yieldb
(%)
E
2
-Lactam 3
40 min
78
2a
3a
O
O
O
O
2
3
4
45 min
1.5 h
1 h
79
70
85
2b
2c
2d
3b
3c
3d
5
6
7
8
9
3 h
3ec
3f
69
66
63
80
81
2a
2b
2c
2d
2a
OCH3
OCH3
OCH3
OCH3
O
3.5 h
4 h
O
O
O
3g
3h
3i
3.5 h
2.5 h
OCH2CH3
O
O
O
O
10
11
12
3 h
4 h
69
71
81
2b
2c
2d
3j
3k
3l
OCH2CH3
OCH2CH3
OCH2CH3
Scheme 1. Synthesis of trans-3-phenyl/benzylsulfonyl--lactams 2(a-f).
3.5 h
Table 1
Synthesis of trans-3-phenyl/benzylsulfonyl--lactams 2(a-f)a
Entry
R
R1
R2
Yieldb
(%)
69
1
-Lactam
13
14
15
16
17
30 min
40 min
1 h
90
89
86
85
69
2a
2b
2c
2d
2e
3m
3n
3o
3p
3q
N
2
1
2
3
4
5
6
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H4OCH3
C6H5
1a
1b
1c
1d
1e
1f
2a
N
N
N
80
67
78
64
67
2b
2c
2d
2e
2f
C6H4OCH3 C6H4OCH3
2 h
C6H5
CH2C6H5
C6H5
2.5 h
CH2C6H5 C6H5
O
CH2C6H5 C6H4OCH3 C6H4OCH3
18
19
1h
-
72
-
2f
3r
N
a Reaction conditions: 1 (1 mmol), 30% H2O2 (33 mmol), stirring at r.t.
b Isolated yields after chromatographic purifications.
-
2e
OCH3
O
Initially, trans-3-phenylsulfonyl--lactam 2a was subjected to
Michael addition with methyl vinyl ketone in solvents such as
THF, methanol, dichloromethane and acetonitrile using aqueous
saturated NaHCO3/K2CO3 as base at room temperature or
refluxing temperature to optimize the reaction conditions.
20
-
-
-
2f
OCH2CH3
O
a Reaction conditions: 2 (1 mmol), Michael acceptor (3.0-6.0 mmol), aq.
K2CO3 (4.0-10.0 mmol), stirring at 50-60 ºC.
b Isolated yields after chromatographic purifications.
c Structure established on the basis of X-ray crystallographic study.
However, the reaction afforded complete conversion of
reactants into products using aqueous K2CO3 in acetonitrile at 50-
60 ºC temperature, in high yield with lesser time. The reaction
afforded the exclusive formation of cis-1-(4ʹ-methoxyphenyl)-3-
benzenesulfonyl-3-(3ʹ-oxo-butyl)-4-phenyl-azetidin-2-one
3a
(Scheme 2, Table 2, entry 1). Furthermore, the feasibility and
Scheme 2. C-3 Functionalization of 2(a-f) via Michael addition.

3
methacrylate and ethyl crotonate. However, they failed to give
desired products under optimized reaction condition.
generality of this reaction in terms of various substrates 2(b-f)
and Michael acceptors was evaluated using these optimized
reaction conditions. The reaction furnished C-3 functionalized 3-
sulfonyl-β-lactams 3(b-r)17 (Scheme 2) and the results are listed
in Table 2.
When trans-3-benzylsulfonyl-β-lactams 2(e-f) were subjected
to Michael addition using methyl vinyl ketone (Table 2, entry 17)
and acrylonitrile (Table 2, entry 18), the reaction yielded 3q and
3r respectively. However, methyl acrylate and ethyl acrylate
(Table 2, entries 19 and 20) failed to afford target β-lactams. This
can be attributed that 3-benzylsulfonyl moiety preferably
allowing the methyl vinyl ketone and acrylonitrile in comparison
to slightly bulkier methyl acrylate and ethyl acrylate on the basis
of stability and steric effects. Further, studies are underway with
different substrates and Michael acceptors to investigate and
propose the mechanistic aspects. All these newly synthesized 3-
phenyl/benzylsulfonyl-β-lactams 3(a-r) were purified by column
chromatography (ethyl acetate : hexane). The structure of novel
C-3 functionalized 3-sulfonyl-β-lactams was established using
Scheme 3. Synthesis of trans- and cis-C-3 functionalized 3-sulfonyl-β-
lactams 3(s-u)/3ʹ(s-u).
1
1
FT-IR, NMR (1H, 13C, H-1H COSY, H-13C COSY and 13C
DEPT-135), elemental analysis (CHNS), and mass spectrometry
(EIMS and LCMS) in representative cases.17.
In literature, the acidity of the proton at -position to the
phenylsulfonyl group has been well demonstrated.14 Therefore, it
was envisaged that DMF and NaHCO3 / K2CO3 at higher
temperature may help to overcome this problem. The reaction
resulted in the formation of a mixture of trans- and cis-isomers
3(s-u)/3ʹ(s-u) in DMF using K2CO3 under anhydrous conditions
at 80 oC (Scheme 3)17 and the results are summarized in Table 3.
However, the mixture was found to be inseparable by column
chromatography and was analyzed by various spectroscopic
techniques such as IR, NMR (1H, 13C, DEPT-135) and elemental
analysis. It is evident from the results listed in Table 3, that in
case of sterically demanding Michael acceptors and R3, higher
temperature favours the formation of trans-isomer in majority
than the cis-isomer. Further, investigation on mechanistic route is
underway in laboratory.
Table 3
Michael addition of ethyl methacrylate and ethyl crotonate on 2(a–c)a
Entry
R3
R4
β-Lactams 3/3ʹ
(trans : cis)
3s/3ʹs (2 : 1)
3t/3ʹt (1 : 1)
3u/3ʹu (3 : 1)
Yieldsb
(%)
55
65
58
2
Figure 2. ORTEP diagram of 3e18,19
1
2
3
CH3
H
CH3
H
CH3
H
2a
2b
2c
Furthermore, structural confirmation of these β-lactams 3 was
done by single crystal X-ray structure analysis of (methyl 3-((3S,
4R)-1-(4-methoxyphenyl)-2-oxo-4-phenyl-3-(phenylsulfonyl)
azetidin-3-yl)propanoate) 3e (Figure 2)18,19 where the Michael
acceptor (E+) and the C4–H have cis stereochemistry to each
other. It was crystallized from dichloromethane-hexane (1:3) as
colorless crystalline solids suitable for single crystal X-ray
diffraction.
Presumably, after the abstraction of proton at C-3 by base, the
approach of electrophile (E+) from below gets blocked by the aryl
substituent on C-4 (VI) and thus, the Michael acceptor prefers to
approach C-3 from the side of C4–H i.e from above leading to
the formation of exclusively cis isomer (Figure 3).
a
Reaction conditions: 2 (1 mmol), Michael acceptor (5.0-6.0 mmol), K2CO3
(5.0-10.0 mmol) stirring at 70-80 ºC.
b Isolated yields after chromatographic purifications.
Furthermore, to investigate the versatility of this reaction in
asymmetric induction we examined the use of cyclohexyl based
chiral auxiliaries. The reaction of chiral acrylic acid esters,
prepared using the chiral auxiliaries (1R, 2S, 5R)-(-)-menthol and
(1R, 2S, 5R)-(-)-8-phenylmenthol with 2(a-b) was explored. The
synthesis of Michael acceptors 4(a-b) was carried out by
esterification of chiral auxiliaries with acryloyl chloride using
reported procedure15 (Scheme 4).
Scheme 4: Synthesis of Michael acceptors 4(a-b).
Figure 3. Favoured approach of the Michael acceptor at C-3 resulting into
cis-β-lactams
After purification by column chromatography, chiral Michael
acceptors 4(a-b) were treated with equivalent amount of trans-3-
phenylsulfonyl-β-lactams 2(a-b) in the presence of aq. K2CO3 in
To further explore the potential of this reaction for sterically
demanding Michael acceptors, 2(a-c) were treated with ethyl

4
Tetrahedron
acetonitrile at room temperature (Scheme 5)17 to afford pair of
The synthesized C-3 functionalized 3-phenyl/benzylsulfonyl-
β-lactams have been submitted for their molecular docking, in
silico as well as in vitro studies. Furthermore, desulfonylation of
these C-3 functionalized 3-sulfonyl-β-lactams 3(a-r) and
explorative studies of chiral and sterically demanding Michael
acceptors are in progress. In addition, studies have been pursued
for the transformation of these novel C-3 functionalized β-
lactams to their nanocomposites in relation to recent reports.9b
cis-diastereomers 5(a-c)/5ʹ(a-c) in moderate yields and the
results are listed in Table 4.
Acknowledgements
AB gratefully acknowledges the financial support for this
work from Department of Science and Technology (DST), New
Delhi, Government of India, Project No. SR/FT/CS-037/2010
dated 28-10-2010, FIST-II/PURSE-II (DST), and UGC-CAS,
Panjab University, Chandigarh. GM, AK and SB acknowledges
the financial support from Council of Scientific and Industrial
Research (CSIR) and University Grant Commission (UGC), New
Delhi vides Award No-F.No.09/135/(0437)2002-EMR-I,
F.No.09/135/(0679)/2012-EMR-I, 201112-RGNF-ST-HIM-9284
respectively.
Scheme 5. Synthesis of pair of cis-C-3 functionalized 3-sulfonyl-β-lactam
diastereomers 5(a-c)/5ʹ(a-c).
1H NMR analysis revealed the preference for one of the cis-
isomers in case of menthol as the chiral auxiliary (Table 4,
entries 1 and 2), however, for 8-phenylmenthol, no such
selectivity was observed (Table 4, entry 3).
Supplementary Materials
Supplementary data [general experimental, spectral data (2(a-
Table 4.
1
e), 3(b-r), 3(s-u)/3ʹ(s-u), 5(a-c)/5ʹ(a-c)), copies of H, 13C, 13C
Reaction of 2(a-b) with chiral Michael acceptors 4(a-b)a
Entry
1
2
Michael acceptor 4 (R5)
4a (R5=H)
cis-β-Lactams 5/5ʹ
5a/5ʹa (1 : 2)
Yieldb (%)
55
66
62
DEPT-135 spectra of representative β-lactams (2(a, f), 3(a, d, f,
2
1
1
g, i, j, m, p, r), 3s/3ʹs and 5b/5ʹb), H-1H COSY, H-13C COSY
(HSQC) NMR spectra of 3m, 5b/5ʹb, EIMS spectra of 3c and
LCMS of 3j β-lactams] associated with this article can be found,
2a
2b
2c
4a (R5=H)
5b/5ʹb (1 : 1)
5c/5ʹc (1 : 1)
3
4b (R5=Ph)
a
Reaction conditions: 2 (1 mmol), 4 (3.0-6.0 mmol), K2CO3 (5.0-6.0 mmol)
stirring at r.t.
in
the
online
version,
at
b Isolated yields after chromatographic purifications.
http://dx.doi.org/10.1016/j.tetlet.2017_______.
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M. G. P.; Specklin, J. –L.; Winkler, F. K. J. Med. Chem. 1996, 39, 3712;
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Figure 4. Preferred conformation of 5c using 8-phenylmenthol ester as chiral
auxillary.
A possible rationalization of these results can be sought in
terms of diastereofacial selection during the reaction which is
attributed to the system (Figure 4). Because of its possible
confirmation, system contains more than one proximal resident
asymmetric carbon atoms which render the two faces of the
system diastereotopic. The π-e- cloud of phenyl ring stacks with
π-e- cloud of carbonyl group and due to this π stacking one face
of the system is blocked, thus, decreasing the possibility of the
formation of the trans-isomer and hence, the ratio 1:1. In all
these cases, 1,4-addition process proceeded efficiently relative to
the 1,2-addition at C-3 and no 1,2-addition product was obtained.
In conclusion, we have presented herein a new synthetic route
for C-3 functionalization of trans-3-phenyl/benzylsulfonyl-β-
lactams via Michael addition using mild base K2CO3. The
reaction afforded stereoselective formation of cis-C-3-
functionalized 3-sulfonyl-β-lactams 3(a-r) under aqueous/organic
media with sterically less hindered Michael acceptors. Further,
formation of trans- and cis-β-lactams 3(s-u)/3ʹ(s-u) was
investigated using sterically demanding acceptors. In addition,
chiral Michael acceptors were also subjected to these optimized
conditions to furnish a pair of cis-diastereomers of β-lactam
adducts 5(a-c)/5ʹ(a-c). The X-ray crystallographic analysis of
compound 3e allowed establishment of the stereochemistry at C-
3 of cis-β-lactams 3, 5.
8. (a) Bhalla, A.; Madan, S.; Venugopalan, P.; Bari, S. S. Tetrahedron 2006,
62, 5054 and refrerences cited therein; (b) Van der Veen, J. M.; Bari, S.
S.; Krishanan, L.; Manhas, M. S.; Bose, A. K. J. Org. Chem. 1989, 54,

5
5758; (c) Bhalla, A.; Venugopalan, P.; Bari, S. S. Eur. J. Org. Chem.
2006, 2006, 4943 and refrerences cited therein; (d) Adlington, R. M.;
Baldwin, J. E.; Becker, G. W.; Chen, B.; Cheng, L.; Cooper, S. L. J. Med.
Chem. 2001, 44, 1491.
Cambridge Crystallographic Data Centre as supplementary publication
number CCDC, 650917. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB@ 1EZ,
UK[Fax: (internet) +44 1223 336033: e-mail: deposit@ccdc.cam.ac.uk].
19. Sheldrick, G. M. SHELXTL-PC. Siemens, XSCANS, X-ray Single
Crystal Analysis System, Version 5.05; Siemens Analytical Instruments
Inc., Madison. WI, 1994.
9. (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. Jr. J. Med. Chem. 1996, 39, 3684; (b)
Esmaeilpour, M.; Sardarian, A. R.; Jarrahpour, A.; Ebrahimi, E.; Javidi,
J. RSC Adv. 2016, 6, 43376.
10. (a) Ojima, I. Adv. Asym. Synth. 1995, 1, 95; (b) Alcaide, B.; Almedros, P.
Org. Prep. Proced. Int. 2001, 33, 317; (c) Alcaide, B.; Almendros, P.;
Aragonillo, C. Chem. Rev. 2007, 107, 4437; (d) Brandi, A.; Cicchi, S.;
Cordero, F. M. Chem. Rev. 2008, 108, 3988; Xu, J. Arkivoc 2009, ix, 21.
11. For general reviews see: (a) The Chemistry of Sulfones and Sulfoxides;
Rappoport, Z.; Sterling, C. Eds.; J. Wiley and Sons: Chichester, 1988; (b)
Trost, B. M. Bull. Chem. Soc. Jpn. 1988, 61, 107; (c) Simpkins, N. S.
Sulphones in Organic Synthesis; Pergamon Press: Oxford, 1993; (d) The
Synthesis of Sulfones, Sulfoxides and Cyclic Sulfides; Patai, S.;
Rappoport, Z. Eds.; J. Wiley and Sons: Chichester, 1994.
12. For specific reviews see: (a) Sulfones as Cationic Reagents; Chinchilla,
R.; Najera, C. Recent Res. Develop. Org. Chem. 1997, 1, 437; (b)
Sulfones as anionic reagents; Najera, C.; Sansano, J. M. Recent Res.
Develop. Org. Chem. 1998, 2, 637.
13. Bhalla, A.; Bari, S. S.; Vats, S.; Bhalla, J. Sharma, K.; Narula, D.
Tetrahedron Lett. 2016, 57, 47 and references cited therein.
14. Kundig, E. P.; Cunningham, A. F., Jr. Tetrahedron 1988, 44, 6855.
15. Sukopp, M.; Schwab, R.; Marinelli, L.; Biron, E.; Heller, M.; Várkondi,
E.; Pap, Á.; Novellino, E.; Kéri, G.; Kessler, H. J. Med. Chem. 2005, 48,
2916.
16. General procedure for the synthesis of 2(a-f): To a well stirred solution of
1a–f (1 mmol) in 20 mL glacial acetic acid was added 30% hydrogen
peroxide (1 mL) and the contents were stirred at room temperature. The
progress of the reaction was monitored by TLC. After completion of the
reaction, the reaction mixture was poured in 25 mL of water. A white
solid precipitated out which was kept for 24h. Solid was removed by
filtration to give the crude product, which was purified by silica gel
column chromatography (12% EtOAc : hexanes) and then crystallized
from dichloromethane
:
hexanes. trans-1-(4′-Methoxyphenyl)-3-
benzylsulfonyl-4-(4′-methoxyphenyl)azetidin-2-one (2f). White solid;
1
yield: 67%; mp 130–134 °C; Rf (30% EtOAc–n-hexane) 0.38; H NMR
(300 MHz, CDCl3) δ 7.46–6.67 (m, 13H, Ar-H), 5.32 (d, J = 2.4 Hz, 1H,
C3–H), 4.57 (d, J = 14.1 Hz, 1H, CH2S), 4.28 (d, J = 14.1 Hz, 1H,
CH2S), 4.00 (d, J = 2.4 Hz, 1H, C4–H), 3.668 (s, 3H, OCH3), 3.661 (s,
3H, OCH3); 13C NMR (75 MHz, CDCl3) δ 160.3, 156.8, 155.6, 131.3,
130.3, 129.18, 128.12, 127.6, 127.2, 126.6, 118.8, 114.8, 114.4, 72.6,
59.6, 55.2, 55.1, 54.3; IR (CHCl3): 1754 cm-1 (C=O); 1300, 1149 cm-1
(S=O); empirical formula: C24H23NO5S; anal. calcd: C, 65.88; H, 5.29; N,
3.20; found: C, 65.79; H, 5.20; N, 3.16.
17. General procedure for the synthesis of 3(a-r), 3(s-u)/3ʹ(s-u) and 5(a-
c)/5ʹ(a-c): To a well-stirred solution of 2(a-f) in acetonitrile, 2(a-c) in
dry DMF and 2(a-b) in acetonitrile (1 mmol) was added the suitable
Michael acceptor/chiral Michael acceptor (3.0–6.0 mmol) followed by
aq. satd. K2CO3/ K2CO3/ aq. satd. K2CO3 (4.0–10.0 mmol) and the
contents were stirred at 50–60 oC/ 70–80 oC/ room temperature,
respectively. The progress of the reaction was monitored by TLC, which
showed the appearance of spot lower to the starting compound. After the
completion of the reaction, water was added to it and extracted with
dichloromethane, washed successively with water and brine and then
dried over anhydrous Na2SO4. The residue after solvent evaporation in
vacuo, was purified by silica gel column chromatography (12% EtOAc :
hexanes). cis-3-Benzenesulfonyl-1-(4′-Methoxyphenyl)-3-(3′-oxo-butyl)-
4-phenylazetidin-2-one (3a). White fluffy solid; yield: 78%; mp 200–201
°C; Rf (30% EtOAc–n-hexane) 0.46; 1H NMR (300 MHz, CDCl3) δ 7.65–
6.74 (m, 14H, Ar-H), 5.23 (s, 1H, C4-H), 3.73 (s, 3H, OCH3), 2.85–2.77
(m, 2H, CH2C=O), 2.44–2.38 (m, 2H, CH2), 2.16 (s, 3H, CH3); 13C NMR
(75 MHz, CDCl3) δ 206.0, 159.7, 156.8, 137.7, 133.9, 130.5, 129.9,
129.5, 128.9, 128.8, 128.1, 119.0, 114.4, 81.2, 64.5, 55.3, 38.3, 30.0, 25.2
(DEPT-135) δ 133.9 (+), 129.5 (+), 128.9 (+), 128.8 (+), 128.1 (+), 119.0
(+), 114.4 (+), 64.5 (+), 55.3 (+), 38.3 (–), 30.0 (+), 25.2 (–).; IR (CHCl3):
1756 cm-1 (C=O), 1718 cm-1 (ketone) 1301, 1150 cm-1 (S=O); empirical
formula: C26H25NO5S; anal. calcd: C, 67.36; H, 5.44; N, 3.02; found: C,
67.30; H, 5.36; N, 2.96.
18. Crystal data for 3e. C26H25NO6S, V = 2447.9 (16) Å3, Mr = 479.53, Z = 4,
Monoclinic, space group P 21/n, Dcacld = 1.301 g cm-3, a = 11.879 (5), b =
12.343(5), c = 17.3111(5) Å, T = 295(2) K, α = 90, β = 105.330 (5), γ =
90. Full matrix least-square on F2; R1 = 0.0932, wR2 = 0.1908 for 4565
observed reflections [I>2σ(I)] and R1 = 0.2535, wR2 = 0.2872 for all 4812
reflections; GOF = 0.968. Crystallographic data (excluding structure
factors) for the structure 3e in this letter have been deposited with

6
Tetrahedron
Highlights:
Title: Stereoselective synthesis of novel C-3
functionalized 3-sulfonyl-β-lactams: promising
biologically active heterocyclic scaffolds
Aman Bhalla*, Garima Modi, Shamsher S. Bari,
Anu Kumari, Shiwani Berry, Geeta Hundal
 Stereoselective synthesis of novel C-3
functionalized 3-sulfonyl-β-lactams.
 Simple, efficient and fast (30 min-4 h)
strategy for mild C-3 functionalization via
Michael addition.
 Exploration of steric bulk and chirality of
Michael acceptor on C-3 functionalization.
 Stereochemistry at C-3 of 3-functionalized
sulfonyl β-lactams 3e was established by X-
ray structural analysis.
 C-3 functionalized β-lactams: potential
synthons and promising biologically active
heterocyclic scaffolds.