Synthesis of cis bis-β-lactams via Staudinger cycloaddition reaction using C2-symmetric 1,2-diamines

Article abstract of DOI:10.1016/j.tet.2005.01.031

An efficient stereoselective synthesis of bis-β-lactams via cycloaddition reaction (Staudinger reaction) of ketenes with bisimines derived from C₂-symmetric 1, 2-diamines is described. The reaction provided diastereomeric mixture of meso and C₂-symmetric cis-bis-β- lactams with higher selectivity for meso-bis-β-lactams.

Full text of DOI:10.1016/j.tet.2005.01.031

Tetrahedron 61 (2005) 2441–2451
Synthesis of cis bis-b-lactams via Staudinger cycloaddition
reaction using C2-symmetric 1,2-diamines
Aarif L. Shaikh,a Vedavati G. Puranikb and A. R. A. S. Deshmukha,
*
aDivision of Organic Chemistry (Synthesis) National Chemical Laboratory, Pune 411 008, India
bCenter for Materials and Characterization, National Chemical Laboratory, Pune 411 008, India
Received 7 September 2004; revised 26 November 2004; accepted 7 January 2005
Available online 2 February 2005
Abstract—An efficient stereoselective synthesis of bis-b-lactams via cycloaddition reaction (Staudinger reaction) of ketenes with bisimines
derived from C2-symmetric 1, 2-diamines is described. The reaction provided diastereomeric mixture of meso and C2-symmetric cis-bis-b-
lactams with higher selectivity for meso-bis-b-lactams.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
for the diastereoselective construction of the b-lactam ring
for several years.9 In this publication, we wish to report our
work on the synthesis of bis-b-lactams from bisimines and
ketenes using the Staudinger cycloaddition reaction.
The b-lactam skeleton is the key structural unit of the most
widely employed b-lactam antibiotics.1 The constant need
for new drugs displaying broader antibacterial activity and
the necessity for new b-lactam antibiotics to combat the
microorganisms that have built up resistance against the
most traditional drugs,2 have maintained the interest of
organic chemists in b-lactams for decades. In addition to its
use in the synthesis of variety of b-lactam antibiotics, the
b-lactam skeleton has been recognized as a useful building
block by exploiting its strain energy associated with four-
member ring.3 Efforts have been made in exploring such
new aspects of b-lactam chemistry using enantiomerically
pure b-lactams as versatile intermediates for organic
syntheses.3c,g–h,4 Ojima et al.5 have shown the utility of
bis-b-lactams for the synthesis of peptides. The synthesis of
bis-b-lactams, in general, has been reported by a step-wise
construction of b-lactam rings.6
2. Results and discussion
We selected trans-1,2-diaminocyclohexane for the prepa-
ration of various bisimines from different aldehydes and
these imines were used for the stereoselective construction
of bis-b-lactams. trans-1,2-Diaminocyclohexane is one of a
few vicinal diamines commercially available in both the
enantiomeric forms with wide applications in stereoselec-
tive synthesis10 and chemotherapy.11 Bisimines derived
from trans-1,2-diaminocyclohexane have been used as
chiral ligands for asymmetric epoxidation,12 cyclopropana-
tion,13 Diels–Alder reaction,14 asymmetric alkylation15 and
several other asymmetric reactions.16 Gawronski et al.17
have shown that out of four different conformations of
N,N-dibenzylidine-1, 2-diaminocyclohexane, syn–syn-bi-
simine A is the most favored conformation (Fig. 1). We
were interested in studying the effect of this conformational
preference on the product formation during [2C2] cyclo-
addition reaction of bisimine and ketene.
In continuation of our work on synthesis of bis-b-lactams,7
we were interested in building bis-b-lactams from C2-sym-
metric vicinal bisimines using the Staudinger cycloaddition
reaction. Among the various methods available for the
synthesis of b-lactams, the Staudinger cycloaddition reac-
tion (ketene–imine cycloaddition reaction) is the most
widely used,8 mainly because of the simplicity in reaction
procedures and predictability of stereochemical output. We
have been studying the Staudinger cycloaddition reaction
The bisimines 3a–c were prepared by stirring (G) trans-1,2-
diaminocyclohexane with freshly distilled excess aldehydes
(benzaldehyde, 4-methoxybenzaldehyde and cinnamalde-
hyde) in the presence of anhydrous MgSO4 or anhydrous
K2CO3 in dry dichloromethane for about 15 h at room
temperature. The unreacted aldehyde was removed by
washing the crude reaction product with 10% ethyl
Keywords: Stereoselective synthesis; Ketenes; Imines; Staudinger cyclo-
addition reaction.
* Corresponding author. Fax: C91 20 25893153/25893355;
e-mail: arasd@dalton.ncl.res.in
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.031

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A. L. Shaikh et al. / Tetrahedron 61 (2005) 2441–2451
Figure 1. Conformations of N,N0-dibenzylidinecyclohexane-1,2-diamine.
Scheme 1.
acetate–pet ether solution to get bisimines 3a–c (Scheme 1)
in very good yields.
spectra showed two doublets at d 5.27 and 5.39 for cis-b-
lactam ring protons (JZ4.7 Hz for cis b-lactam protons). A
single broad doublet at d 3.97 for both the methyne protons of
cyclohexane ring with JZ9 Hz was observed. 13C NMR
spectra also showed a single peak for both the methyne
carbons of cyclohexane ring at 53.91 ppm; two peaks for
b-lactam carbons of both the rings at 61.4 ppm (C–4H) and
81.6 ppm (C–3H); and a single peak for both the carbonyl
carbons at 167.7 ppm. This was further confirmed by single
crystal X-ray spectroscopic analysis of 5a (Fig. 2).18
Bisimines 3a–c on cycloaddition reaction (Staudinger
reaction) with ketenes generated from various acid chlorides
(phenoxyacetyl chloride, benzyloxyacetyl chloride and
methoxyacetyl chloride) in the presence of triethylamine
gave diastereomeric mixtures of cis-bis-b-lactams 5a–g and
6a–g in good to excellent yields (Scheme 2, Table 1). The
1
TLC and H NMR spectra of the crude reaction mixture
showed the presence of two diastereomers. These dia-
stereomers were separated by flash column chromatography.
The C2-symmetric structure for bis-b-lactam 5a was assigned
The meso structure was assigned to the other diastereomer
1
6a as H NMR spectra showed two doublets at d 5.05 and
5.40 (JZ4.7 Hz) for one cis-b-lactam ring protons; and two
1
1
on the basis of H NMR spectral analysis. The H NMR
Scheme 2.

A. L. Shaikh et al. / Tetrahedron 61 (2005) 2441–2451
Table 1. Synthesis of bis-b-lactams 5a–i and 6a–i
2443
b-Lactams
Ra
R1
Ratio of 5 and 6b
Yield (%)c
Mp of 5 (8C)d
Mp of 6 (8C)d
5a, 6a
5b, 6b
5c, 6c
5d, 6d
5e, 6e
5f, 6f
5g, 6g
5h, 6h
5i, 6i
–Ph
–Ph
–Ph
–PMP
–PMP
–PMP
–Styryl
–Styryl
–Styryl
–OPh
–OBn
–OMe
–OPh
–OBn
–OMe
–OPh
–OBn
–OMe
34:66
34:66
23:77
22:78
28:72
24:76
36:64
46:54
42:56
90
87
86
93
80
73
88
81
86
231–232
111–112
247–248
158–159
194–195
229–230
245–246
179–180
211–212
82–83
72–73
191–192
209–210
123–124
84–85
175–176
61–62
79–80
a PMPZp-methoxyphenyl; BnZ benzyl.
b The ratio of the diastereomers 5 and 6 was determined by 1H NMR.
c Isolated yields of the diastereomeric mixture of 5 and 6.
d Pure diastereomers were obtained by flash column chromatography.
analysis (Fig. 3).18 The structures for other C2-symmetric
bis-b-lactams 5b–i and meso bis-b-lactams 6b–i were
assigned by correlating the spectral data with that of 5a
and 6a, respectively. Higher selectivity for meso bis-b-
lactam formation was observed in the cycloaddition reaction
(Table 1).
We believe that mono-b-lactam is initially formed by the
reaction of the most stable syn–syn bis-imine conformer A
with ketene. The approach of the ketene in the Staudinger
cycloaddition reaction is such that the steric interaction
between the aryl group of the imine and phenoxy group of
the ketene is minimum in the transition state (Scheme 3)
resulting in the formation of cis-b-lactam. However, the
formation of trans-b-lactam is unfavorable due to severe
steric interaction between the aryl group of imine and
phenoxy group of ketene in the transition state. The mono-
b-lactam 7 further undergoes cycloaddition reaction with
the second molecule of ketene to give bis-b-lactam (Scheme
4). The approach of the second ketene towards the syn-imine
7 is from the opposite site of the preformed azetidinone ring
to give C2-symmetric bis-b-lactam 5a. However, meso bis-
b-lactam 6a is formed by the cycloaddition of anti-imine 11
with the second molecule of ketene from opposite site of the
preformed b-lactam ring as shown in Scheme 4. To
substantiate this, cycloaddition reaction of bis-imine 3a
with 1 equiv of phenoxyketene, generated in situ from
phenoxyacetyl chloride and triethylamine, was carried out.
Figure 2. ORTEP diagram of 5a.
doublets at d 5.47 and 5.56 (JZ4.6 Hz) for other cis-b-
lactam ring protons due to non-equivalence of both the
b-lactam rings. Two multiplets at d 3.55–3.60 and 3.71–3.76
for two non-equivalent methyne protons of cyclohexane
ring were observed for meso bis-b-lactam 6a. Similarly 13
C
NMR spectra showed two sets of carbon signals for both
the azetidin-2-one rings as well as carbonyl carbons. The
structure was further confirmed by single crystal X-ray
1
The H NMR of the crude reaction product showed the
formation of two diastereomers of mono-b-lactams 7 and 8
in equal amount along with traces of bis-b-lactams 5a and
6a. However, all our attempts to separate the diastereomers
were unsuccessful. This mixture was further subjected to
Staudinger reaction with 1 equiv of phenoxyketene to get
mixture of bis-b-lactams 5a and 6a in good yield.
Other C2-symmetric vicinal diamines, such as 1,2-diphenyl-
ethylenediamine (12a)20 and 2,3-diaminobutane (12b),21
were also used for the preparation of bis-imines 13a,b.
These imines were used for the Staudinger reaction (Scheme
5). Here too, a mixture of C2-symmetric 14a–d and meso
bis-b-lactams 15a–d, with higher selectivity for meso
isomer, was obtained in very good yields (Table 2). The
diastereomers 14a–d and 15a–d were separated by flash
column chromatography and characterized by spectral
analyses.
The Staudinger cycloaddition reaction conditions were also
Figure 3. ORTEP diagram of 6a.

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A. L. Shaikh et al. / Tetrahedron 61 (2005) 2441–2451
Scheme 3.
Scheme 4.
employed for the asymmetric synthesis of bis-b-lactams (5j,
6j Scheme 2 and 14e, 15e Scheme 5) from chiral bis-imine
derived from optically pure (C)-1R,2R-trans-1,2-diamino-
cyclohexane,22 (K)-1S,2S-diphenylethylenediamine23 and
benzaldehyde; and in situ generated phenoxyketene from
phenoxyacetyl chloride. The cycloaddition reaction gave a
mixture of C2-symmetric 5j, 14e and meso 6j, 15e bis-b-
lactams (Table 3). Both C2-symmetric and meso b-lactams
were separated by careful flash column chromatography and
characterized by spectral analyses.
3. Conclusion
In conclusion we have shown the application of Staudinger
cycloaddition reaction for the synthesis of bis-b-lactams

A. L. Shaikh et al. / Tetrahedron 61 (2005) 2441–2451
2445
Scheme 5.
Table 2. Synthesis of bis-b-lactams 14a–d and 15a–d
Compounds
R
R1
R2
Ratio of 14 and
15a
Yield (%)b
Mp of 14 (8C)c
Mp of 15 (8C)c
14a, 15a
14b, 15b
14c, 15c
14d, 15d
–Ph
–Ph
–Ph
–Ph
–OPh
–OBn
–OMe
–OPh
–Ph
–Ph
–Ph
–Me
42:58
44:56
40:60
30:70
81
84
88
91
197–198
190–191
194–195
69–70
201–202
79–80
201–202
175–176
a The ratio of the diastereomers 14 and 15 was determined by 1H NMR.
b Isolated yields of the diastereomeric mixture of 14 and 15.
c Pure diastereomers were obtained by flash column chromatography.
Table 3. Asymmetric synthesis of bis-b-lactams 5j, 6j, 14e and 15e
Compound
R
R1
R2
Ratioa
Yield (%)b
76
[a]D (CHCl3)c
Configuration
1R,2R,30S,40R 300S,400R
1R,2R,30S,40R 300R,400S
1S,2S,30R,40S 300R,400S
1S,2S,30R,40S 300S,400R
5j
6j
14e
15e
–Ph
–Ph
–Ph
–Ph
–OPh
–OPh
–OPh
–OPh
5j/6j 40:60
K146.9 (c, 0.80)
K53.83 (c, 1.00)
C3.03 (c, 0.99)
C6.15 (c, 0.65)
–Ph
–Ph
14e/15e 36:64
80
a The ratio of the diastereomers 5j/6j and 14e/15e was determined by 1H NMR.
b Isolated yields of the diastereomeric mixture.
c Pure diastereomers were obtained by flash column chromatography.
from C2-symmetric 1,2-diamines in excellent yields. Both
C2-symmetric as well as meso bis-b-lactams were formed in
the reaction, which could be easily separated. The reaction
was also employed for asymmetric synthesis of bis-b-
lactams using enantiomerically pure (C)-1R,2R-trans-1,2-
diaminocyclohexane and (K)-1S,2S-1,2-diphenylethylene-
diamine.
a Thermonik Campbell melting point apparatus and were
uncorrected. The microanalyses were performed on a Carlo-
Erba, CHNS-O EA 1108 elemental analyzer. Optical
rotations were recorded on a JASCO-181 digital polarimeter
under standard conditions.
4.2. General procedure for the preparation of imines
3a–c
4. Experimental
4.1. General
A mixture of freshly distilled aldehyde (2.78 g, 26.3 mmol),
(G) trans-1,2-diaminocyclohexane (1.0 g, 8.8 mmol) and
anhydrous MgSO4 or anhydrous K2CO3 (2.20 g,
17.5 mmol) in dry dichloromethane (30 mL) was stirred
for 15 h at room temperature. The reaction mixture was then
filtered through a bed of celite and solvent was removed
under reduced pressure. The residue was then treated with
10% solution of ethyl acetate in pet ether to remove
unreacted aldehyde and filtered to give required bis-imine
(2.00 g, 80%). Following this procedure bisimines 3a–c
were prepared in excellent yield.
1H NMR and 13C NMR Spectra were recorded in CDCl3
solution on a Bruker AC 200 or Bruker MSL 300
spectrometers and chemical shifts are reported in ppm
downfield from tetramethylsilane for 1H NMR. Infrared
spectra were recorded on Perkin–Elmer Infrared Spectro-
photometer, Model 599-B or Shimadzu FTIR-8400 using
sodium chloride optics. Melting points were determined on

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A. L. Shaikh et al. / Tetrahedron 61 (2005) 2441–2451
4.2.1. N,N0-Dibenzylidenecyclohexane-1,2-diamine (3a).
It was obtained as a white solid, recrystallized from EtOAc–
petroleum ether (90:10) as needles, yield 80%; mp 129–
130 8C; [found C, 82.58; H, 7.54; N, 9.53 C20H22N2 requires
C, 82.72; H, 7.63; N, 9.64]; nmax (Nujol) 1462, 1578,
1641 cmK1; dH (200 MHz, CDCl3) 1.03–2.07 (m, 8H, CH2,
Cyclohexane), 3.21–3.45 (m, 2H, CH, Cyclohexane), 7.12–
7.64 (m, 10H, Ar), 8.15 (s, 2H, –N]CH); dC (75.48 MHz,
CDCl3) 24.5, 32.9, 73.7, 127.9, 128.2, 130.0, 136.5, 160.8;
MS (m/z): 290 (MC).
Cyclohexane), 3.97 (br d, JZ9 Hz, 2H, CH, Cyclohexane),
5.27 (d, JZ4.7 Hz, 2H, C4H), 5.39 (d, JZ4.7 Hz, 2H,
C3H), 6.48–7.73 (m, 20H, Ar); dC (75.48 MHz) 24.4, 30.1,
54.0, 61.4, 81.6, 115.7, 121.9, 128.0, 128.6, 128.9, 129.1,
134. 9, 156.8, 167.7; MS (m/z): 588 (MC).
4.3.2. 1-(30-Phenoxy-40-phenylazetidin-20-one-10-yl)-2-
(300-phenoxy-400-phenylazetidin-200-one-100-yl)cyclohex-
ane (6a). It was obtained as a white solid, which was
recrystallized from methanol, white needles, mp 82–83 8C;
[found C, 77.23; H, 5.96; N, 4.78 C36H34N2O4 requires C,
77.39, H, 6.13; N, 5.01]; Rf (30% ethyl acetate/pet ether)
0.25; nmax (CHCl3) 1753 cmK1; dH (500 MHz, CDCl3)
0.83–2.06 (m, 8H, CH2, Cyclohexane), 3.55–3.60 (m, 1H,
CH, Cyclohexane), 3.71–3.76 (m, 1H, CH, Cyclohexane),
5.005 (d, JZ4.7 Hz, 1H, C4H), 5.40 (d, JZ4.7 Hz, 1H,
C4 H), 5.47 (d, JZ4.6 Hz, 1H, C3H), 5.56 (d, JZ4.6 Hz,
1H, C30H), 6.72–7.55 (m, 20H, Ar); dC (125 MHz) 24.1,
29.2, 31.3, 53.4, 55.2, 61.2, 62.2, 81.1, 81.3, 115.7, 121.8,
122.0, 128.0, 128.4, 128.6, 129.0, 129.1, 133.6, 134.8,
157.0, 166.4, 166.5; MS (m/z): 588 (MC).
4.2.2. N,N0-Bis (4-methoxybenzylidene)cyclohexane-1,2-
diamine (3b). It was isolated as a white solid and
recrystallized from EtOAc–petroleum ether (90:10) to
give white needles; yield 90%; mp 166–1678C; [found C,
75.36; H, 7.38; N, 7.86 C22H26N2O2 requires C, 75.48; H,
7.49; N, 8.00]; nmax (CHCl3) 1253, 1512, 1606, 1643 cmK1
;
dH (200 MHz, CDCl3) 1.20–1.97 (m, 8H, CH2, Cyclohex-
ane), 3.27–3.42 (m, 2H, CH, Cyclohexane), 3.78 (s, 6H,
OCH3), 6.82 (d, JZ9 Hz, 4H, Ar), 7.54 (d, JZ9 Hz, 4H,
Ar), 8.13 (s, 2H, –N]CH); dC (75.48 MHz, CDCl3) 24.5,
33.0, 55.2, 73.7, 113.7, 129.2, 129.4, 160.3, 161.2; MS
(m/z): 352 (MC).
4.3.3. 1,2-Bis (30-benzyloxy-40-phenylazetidin-20-one-10-
yl)cyclohexane (5b). It was obtained as a white solid, which
was recrystallized from dichloromethane–methanol, white
crystalline solid, mp 111–112 8C; [found C, 77.56; H, 6.35;
N, 4.87 C38H38N2O4 requires C, 77.79, H, 6.53; N, 4.77]; Rf
4.2.3. N,N0-Bis (styrylmethylene)cyclohexane-1,2-dia-
mine (3c). It was isolated as a brown oil; yield 85%;
[found C, 84.08; H, 7.57; N, 8.04 C24H26N2 requires C,
84.17; H, 7.65; N, 8.18]; nmax (neat) 1253, 1448, 1632, 1677,
2854, 2929 cmK1; dH (200 MHz, CDCl3) 1.22–1.84 (m, 8H,
CH2, Cyclohexane), 3.06–3.23 (m, 2H, CH, Cyclohexane),
6.70–6.80 (m, 4H, CH-olefin), 7.05–7.55 (m, 10H, Ar),
7.80–7.90 (m, 2H, –N]CH); dC (75.48 MHz, CDCl3) 24.3,
33.0, 73.7, 127.0, 127.9, 128.3, 128.9, 131.0, 135.7, 141.3,
152.4, 162.4; MS (m/z): 342 (MC).
(30% ethyl acetate/pet ether) 0.48; nmax (CHCl3) 1747 cmK1
;
dH (200 MHz, CDCl3) 0.72–1.84 (m, 8H, CH2, Cyclohex-
ane), 3.92 (br d, JZ9 Hz, 2H, CH, Cyclohexane), 4.01 (d,
JZ10.9 Hz, 2H, CH2Ph), 4.31 (d, JZ10.9 Hz, 2H, CH2Ph),
4.89 (d, JZ4.3 Hz, 2H, C4H), 5.11 (d, JZ4.3 Hz, 2H,
C3H), 6.81–7.68 (m, 20H, Ar); dC (75.48 MHz) 24.0, 24.4,
29.7, 30.1, 53.4, 61.0, 72.3, 72.5, 83.8, 81.6, 127.8, 128.1,
128.2, 128.5, 128.8, 129.3, 135.6, 136.3, 167.5, 168.3; MS
(m/z): 586 (MC).
4.3. A typical procedure for the preparation of b-lactams
5a and 6a
4.3.4. 1-(30-Benzyloxy-40-phenylazetidin-20-one-10-yl)-2-
(300-benzyloxy-400-phenylazetidin-200-one-100-yl)cyclohex-
ane (6b). It was obtained as a white solid, which was
recrystallized from methanol, white needles, mp 72–73 8C;
[found C, 77.62; H, 5.40; N, 4.65 C38H38N2O4 requires C,
77.79, H, 5.33; N, 4.77]; Rf (30% ethyl acetate/pet ether)
0.35; nmax (CHCl3) 1749 cmK1; dH (200 MHz, CDCl3)
0.82–2.0 (m, 8H, CH2, Cyclohexane), 3.41–3.73 (m, 2H,
CH, Cyclohexane), 4.07 (d, JZ11.0 Hz, 1H, CHPh), 4.16
(d, JZ11.0 Hz, 1H, CHPh), 4.27 (d, JZ7.8 Hz, 1H, CHPh),
4.33 (d, JZ7.8 Hz, 1H, CHPh), 4.85 (d, JZ4.7 Hz, 1H,
C4H), 4.88 (d, JZ4.7 Hz, 1H, C40H), 4.98 (d, JZ4.3 Hz,
1H, C3H), 5.29 (d, JZ4.3 Hz, 1H, C30H), 6.88–7.66 (m,
20H, Ar); dC (125 MHz) 24.0, 29.3, 31.4, 52.9, 54.7, 60.7,
61.7, 72.3, 82.4, 83.0, 128.2, 128.5, 129.0, 129.2, 134.2,
135.4, 136.2, 136.4, 167.2, 167.5; MS (m/z): 586 (MC).
A solution of the phenoxyacetyl chloride 4a (0.350 g,
3.0 mmol) in dry methylene chloride (10 mL) was added
slowly to a solution of the imine 3a (0.200 g, 1.0 mmol) and
triethylamine (0.96 mL, 10.0 mmol) in CH2Cl2 (10 mL) at
0 8C. After the addition was complete, the reaction mixture
was allowed to warm up to room temperature and stirred for
15 h. The reaction mixture was then washed with water (2!
10 mL), saturated sodium bicarbonate solution (10 mL) and
saturated brine solution (10 mL). The organic layer was then
dried over anhydrous Na2SO4, and concentrated to give
the crude diastereomeric mixture (0.350 g, 90%) The
diastereomers were separated by flash column chroma-
tography (petroleum ether–ethyl acetate 7:3) to give pure
diastereomer of b-lactams (5a and 6a). Following this
procedure other b-lactams 5b–i and 6b–i were also
prepared.
4.3.5. 1,2-Bis (30-methoxy-40-phenylazetidin-20-one-10-
yl)cyclohexane (5c). It was obtained as a white solid,
which was recrystallized from methanol, white crystalline
solid, mp 247–248 8C; [found C, 71.59; H, 6.71; N, 6.22
C26H30N2O4 requires C, 71.86, H, 6.96; N, 6.45]; Rf (30%
ethyl acetate/pet ether) 0.44; nmax (CHCl3) 1743 cmK1; dH
(200 MHz, CDCl3) 0.52–1.95 (m, 8H, CH2, Cyclohexane),
3.01 (s, 6H, OCH3), 3.73 (br d, JZ9 Hz, 2H, CH,
Cyclohexane), 4.49 (d, JZ4.3 Hz, 2H, C4H), 4.92 (d, JZ
4.3.1. 1,2-Bis (30-phenoxy-40-phenylazetidin-20-one-10-
yl)cyclohexane (5a). It was isolated as a white solid from
diastereomeric mixture by flash column chromatography
and recrystallized from dichloromethane–petroleum ether,
white crystalline solid, mp 231–232 8C; [found C, 77.19; H,
5.88; N, 4.84 C36H34N2O4 requires C, 77.39, H, 6.13; N,
5.01]; Rf (30% ethyl acetate/pet ether) 0.42; nmax (CHCl3)
1745 cmK1; dH (200 MHz, CDCl3) 0.69–1.80 (m, 8H, CH2,

A. L. Shaikh et al. / Tetrahedron 61 (2005) 2441–2451
2447
4.3 Hz, 2H, C3H), 7.16–7.42 (m, 10H, Ar); dC (50.32 MHz)
24.3, 29.9, 53.4, 58.0, 60.8, 85.1, 123.3, 128.1, 128.7, 135.4,
168.5; MS (m/z): 434 (MC).
72.4, 83.6, 113.5, 127.5, 127.8, 128.2, 129.9, 136.4, 159.8,
168.3; MS (m/z): 648 (MC).
4.3.10. 1-[30-Benzyloxy-40-(p-methoxyphenyl)azetidin-20-
one-10-yl]-2-[300-benzyloxy-400-(p-methoxyphenyl)azeti-
din-200-one-100-yl]cyclohexane (6e). It was obtained as a
white solid, which was recrystallized from dichloro-
methane–methanol, white crystalline solid, mp 123–
124 8C; [found C, 74.17; H, 6.45; N, 4.28 C40H42N2O6
requires C, 74.28, H, 6.54; N, 4.33]; Rf (30% ethyl acetate/
pet ether) 0.24; nmax (CHCl3) 1751 cmK1; dH (200 MHz,
CDCl3) 0.77–1.92 (m, 8H, CH2, Cyclohexane), 3.72–3.86
(m, 2H, CH, Cyclohexane), 3.83, 3.85 (s, 6H, OCH3), 4.01–
4.33 (m, 4H, CH2Ph), 4.76 (d, JZ4.7 Hz, 1H, C4H), 4.89 (d,
JZ4.7 Hz, 1H, C40H), 4.91 (d, JZ4.3 Hz, 1H, C3H), 5.21
(d, JZ4.3 Hz, 1H, C30H), 6.80–7.49 (m, 18H, Ar); dC
(125 MHz) 24.0, 29.1, 31.4, 52.6, 54.6, 55.2, 60.2, 61.1,
72.2, 82.3, 82.8, 113.5, 113.9, 125.9, 127.2, 127.7, 127.8,
128.2, 130.2, 130.4, 136.3, 136.5, 159.7, 160.1, 167.3,
167.5; MS (m/z): 648 (MC).
4.3.6. 1-(30-Methoxy-40-phenylazetidin-20-one-10-yl)-2-
(300-methoxy-400-phenylazetidin-200-one-100-yl)cyclohex-
ane (6c). It was obtained as a white solid, which was
recrystallized from methanol, white needles, mp 191–
192 8C; [found C, 71.63; H, 6.73; N, 6.33 C26H30N2O4
requires C, 71.86, H, 6.96; N, 6.45]; Rf (30% ethyl acetate/
pet ether) 0.33; nmax (CHCl3) 1747 cmK1; dH (200 MHz,
CDCl3) 0.45–1.91 (m, 8H, CH2, Cyclohexane), 3.01 (s, 6H,
OCH3), 3.18–3.54 (m, 2H, CH, Cyclohexane), 4.47 (d, JZ
4.3 Hz, 1H, C4H), 4.56 (d, JZ4.3 Hz, 1H, C40H), 4.64 (d,
JZ4.7 Hz, 1H, C3H), 5.06 (d, JZ4.7 Hz, 1H, C30H), 7.04–
7.42 (m, 10H, Ar); dC (75.48 MHz) 24.0, 29.2, 31.3, 53.1,
55.0, 58.0, 60.5, 61.8, 84.6, 84.8, 128.0, 128.4, 128.8, 128.8,
129.0, 134.1, 135.4, 167.4; MS (m/z): 434 (MC).
4.3.7. 1,2-Bis [30-phenoxy-40-(p-methoxyphenyl)azetidin-
20-one-10-yl]cyclohexane (5d). It was obtained as a white
solid, which was recrystallized from dichloromethane–
methanol, white needles, mp 158–159 8C; [found C, 73.71;
H, 6.03; N, 4.52 C38H38N2O6 requires C, 73.77, H, 6.19; N,
4.52]; Rf (30% ethyl acetate/pet ether) 0.59; nmax (CHCl3)
1747 cmK1; dH (200 MHz, CDCl3) 0.67–1.82 (m, 8H, CH2,
Cyclohexane), 3.93 (br d, JZ9 Hz, 2H, CH, Cyclohexane),
3.76 (s, 6H, OCH3), 5.22 (d, JZ4.7 Hz, 2H, C4H), 5.34 (d,
JZ4.7 Hz, 2H, C3H), 6.54–7.47 (m, 18H, Ar); dC
(50.32 MHz) 24.3, 29.9, 29.7, 30.1, 53.7, 55.0, 60.9, 81.4,
113.3, 114.6, 115.5, 121.8, 126.5, 129.1, 129.5, 129.9,
156.7, 159.7, 167.6; MS (m/z): 620 (MC).
4.3.11. 1,2-Bis [30-methoxy-40-(p-methoxyphenyl) azeti-
dine-20-one-10-yl]cyclohexane (5f). It was obtained as a
white solid, which was recrystallized from methanol to get
white crystalline solid, mp 229–230 8C; [found C, 67.88; H,
6.83; N, 5.56 C28H34N2O6 requires C, 67.99, H, 6.92; N,
5.66]; Rf (60% ethyl acetate/pet ether) 0.52; nmax (CHCl3)
1743 cmK1; dH (200 MHz, CDCl3) 0.60–1.94 (m, 8H, CH2,
Cyclohexane), 3.03 (s, 6H, OCH3), 3.79 (br d, JZ9 Hz, 2H,
CH, Cyclohexane), 3.82 (s, 6H, PhOCH3), 4.55 (d, JZ
4.3 Hz, 2H, C4H), 4.96 (d, JZ4.3 Hz, 2H, C3H), 6.89 (d,
JZ8.6 Hz, 4H, Ar), 7.34 (d, JZ8.6 Hz, 4H, Ar); dC
(125.76 MHz) 24.5, 30.2, 53.3, 55.2, 58.0, 60.4, 85.2,
113.6, 127.5, 129.8, 159.9, 167.9; MS (m/z): 496 (MC).
4.3.8. 1-[30-Phenoxy-40-(p-methoxyphenyl)azetidin-20-
one-10-yl]-2-[300-phenoxy-400- (p-methoxyphenyl)azeti-
din-200-one-100-yl]cyclohexane (6d). It was obtained as a
white solid, which was recrystallized from dichloro-
methane–methanol, white needles, mp 209–210 8C; [found
C, 73.59; H, 6.07; N, 4.28 C38H38N2O6 requires C, 73.77, H,
6.19; N, 4.52]; Rf (30% ethyl acetate/pet ether) 0.47; nmax
(CHCl3) 1753 cmK1; dH (200 MHz, CDCl3) 0.83–2.06 (m,
8H, CH2, Cyclohexane), 3.49–3.71 (m, 2H, CH, Cyclohex-
ane), 3.75, 3.79 (s, 6H, OCH3), 5.01 (d, JZ4.7 Hz, 1H,
C4H), 5.37 (d, JZ4.7 Hz, 1H, C40H), 5.46 (d, JZ4.3 Hz,
1H, C3H), 5.50 (d, JZ4.3 Hz, 1H, C30H), 6.70–7.55 (m,
18H, Ar); dC (50.32 MHz) 23.9, 29.0, 31.4, 53.0, 55.0, 55.1,
60.7, 61.5, 81.0, 81.1, 113.4, 113.8, 115.6, 121.7, 121.9,
125.2, 126.6, 129.1, 130.4, 157.0, 159.7, 160.0, 166.4,
166.5; MS (m/z): 620 (MC).
4.3.12. 1-[30-Methoxy-40-(p-methoxyphenyl)azetidin-20-
one-10-yl]-2-[300-methoxy-400-(p- ethoxyphenyl)azetidin-
200-one-100-yl]cyclohexane (6f). It was obtained as a white
solid, which was recrystallized from methanol to get white
crystalline solid, mp 84–85 8C; [found C, 67.86; H, 6.85; N,
5.49 C28H34N2O6 requires C, 67.99, H, 6.92; N, 5.66]; Rf
(60% ethyl acetate/pet ether) 0.44; nmax (CHCl3) 1745 cmK
1; dH (200 MHz, CDCl3) 0.72–1.93 (m, 8H, CH2, Cyclohex-
ane), 3.09 (s, 6H, OCH3), 3.35–3.65 (m, 2H, CH,
Cyclohexane), 3.82, 3.84 (s, 6H, PhOCH3), 4.60 (d, JZ
4.7 Hz, 1H, C4H), 4.70 (d, JZ4.7 Hz, 1H, C40H), 4.76 (d,
JZ4.3 Hz, 1H, C3H), 5.22 (d, JZ4.3 Hz, 1H, C30H), 6.85–
7.01 (m, 4H, Ar), 7.34–7.48 (m, 4H, Ar); dC (75 MHz) 23.9,
24.0, 28.9, 31.3, 52.7, 54.7, 55.1, 55.2, 57.92, 59.9, 61.0,
84.4, 84.5, 113.4, 113.9, 125.7, 127.1, 130.2, 159.7, 160.0,
167.3, 167.5; MS (m/z): 496 (MC).
4.3.9. 1,2-Bis [30-benzyloxy-40-(p-methoxyphenyl)azeti-
din-20-one-10-yl]cyclohexane (5e). It was obtained as a
white solid, which was recrystallized from dichloro-
methane–methanol, white needles, mp 194–195 8C; [found
C, 74.14; H, 6.38; N, 4.15 C40H42N2O6 requires C, 74.28, H,
6.54; N, 4.33]; Rf (30% ethyl acetate/pet ether) 0.40; nmax
(CHCl3) 1755 cmK1; dH (200 MHz, CDCl3) 0.68–1.81 (m,
8H, CH2, Cyclohexane), 3.79 (br d, JZ9 Hz, 2H, CH,
Cyclohexane), 3.83 (s, 6H, OCH3), 3.98 (d, JZ10.9 Hz, 2H,
CH2Ph), 4.24 (d, JZ10.9 Hz, 2H, CH2Ph), 4.78 (d, JZ
4.3 Hz, 2H, C4H), 5.01 (d, JZ4.3 Hz, 2H, C3H), 6.83–7.47
(m, 18H, Ar); dC (50.32 MHz) 24.4, 30.1, 53.3, 55.3, 60.5,
4.3.13. 1-(30-Phenoxy-40-styrylazetidin-20-one-10-yl)-2-
(300-phenoxy-400-styrylazetidin-200-one-100-yl)cyclohexane
(5g). It was obtained as a white solid, which on
recrystallization from methanol gave white needles, mp
245–246 8C; [found C, 78.57; H, 6.16; N, 4.51 C40H38N2O4
requires C, 78.66, H, 6.27; N, 4.58]; Rf (30% ethyl acetate/
pet ether) 0.68; nmax (CHCl3) 1747 cmK1; dH (200 MHz,
CDCl3) 1.07–2.01 (m, 8H, CH2, Cyclohexane), 3.83–3.95
(m, 2H, CH, Cyclohexane), 4.88 (dd, JZ4.7, 8.2 Hz, 2H,
C4H), 5.29 (d, JZ4.7 Hz, 2H, C3H), 6.28 (dd, JZ8.2,
16 Hz, 2H, HC]CH), 6.77 (d, JZ16 Hz, 2H, ]CHPh),

2448
A. L. Shaikh et al. / Tetrahedron 61 (2005) 2441–2451
6.91–7.44 (m, 20H, Ar); dC (75.48 MHz) 24.7, 30.2, 53.5,
60.5, 82.0, 115.8, 122.2, 125.0, 126.7, 128.2, 128.6, 129.4,
136.0, 136.2, 157.4, 166.6; MS (m/z): 610 (MC).
C30H34N2O4 requires C, 74.05, H, 7.04; N, 5.75]; Rf (40%
ethyl acetate/pet ether) 0.49; nmax (CHCl3) 1741 cmK1; dH
(200 MHz, CDCl3) 1.01–1.96 (m, 8H, CH2, Cyclohexane),
3.41 (s, 6H, OCH3), 3.78–3.81 (m, 2H, CH, Cyclohexane),
4.49 (d, JZ4.3 Hz, 2H, C4H), 4.62 (dd, JZ4.3, 9.4 Hz, 2H,
C3H), 6.27 (dd, JZ9.4, 16 Hz, 2H, HC]CH), 6.77 (d, JZ
16 Hz, 2H, ]CHPh), 7.25–7.50 (m, 10H, Ar); dC
(75.48 MHz) 24.6, 30.3, 52.9, 58.6, 60.0, 85.3, 125.7,
126.6, 128.2, 128.6, 135.2, 136.2, 167.5; MS (m/z): 486
(MC).
4.3.14. 1-(30-Phenoxy-40-styrylazetidin-20-one-10-yl)-2-
(300-phenoxy-400-styrylazetidin-200-one-100-yl)cyclohexane
(6g). It was obtained as a white solid, which was
recrystallized from methanol to get white crystalline solid,
mp 175–176 8C; [found C, 78.49; H, 6.27; N, 4.58
C40H38N2O4 requires C, 78.66, H, 6.27; N, 4.58]; Rf (30%
ethyl acetate/pet ether) 0.40; nmax (CHCl3) 1753 cmK1; dH
(200 MHz, CDCl3) 1.05–2.09 (m, 8H, CH2, Cyclohexane),
3.72–3.93 (m, 2H, CH, Cyclohexane), 4.67 (dd, JZ4.4,
9.4 Hz, 1H, C4H), 5.16 (dd, JZ4.4, 9.4 Hz, 1H, C40H), 5.38
(dd, JZ4.7, 9.4 Hz, 2H, C3H and C30H), 6.27 (dd, JZ9.4,
16 Hz, 1H, HC]CH), 6.67–6.87 (m, 3H, HC]CH and
]CHPh), 6.89–7.70 (m, 20H, Ar); dC (75.48 MHz) 24.2,
24.4, 28.4, 31.1, 52.2, 54.8, 60.3, 60.6, 81.6, 81.7, 115.6,
115.8, 121.8, 122.0, 124.0, 125.3, 126.6, 127.0, 128.0,
128.2, 128.5, 129.2, 135.8, 136.0, 136.2, 136.5, 157.4,
165.7, 166.2; MS (m/z): 610 (MC).
4.3.18. 1-(30-Methoxy-40-styrylazetidin-20-one-10-yl)-2-
(300-methoxy-400-styrylazetidin-200-one-100-yl)cyclohexane
(6i). It was obtained as a white solid, which was
recrystallized from methanol to get white needles, mp 79–
80 8C; [found C, 73.88; H, 6.92; N, 5.65 C30H34N2O4
requires C, 74.05, H, 7.04; N, 5.75]; Rf (40% ethyl acetate/
pet ether) 0.38; nmax (CHCl3) 1749 cmK1; dH (200 MHz,
CDCl3) 1.01–1.99 (m, 8H, CH2, Cyclohexane), 3.43, 3.44
(s, 6H, OCH3), 3.60–3.73 (m, 2H, CH, Cyclohexane), 4.34–
4.45 (m, 1H, C4H), 4.60 (dd, JZ4.7, 9.40Hz, 2H, C40H and
C3H), 4.92 (dd, JZ4.7, 9.4 Hz, 1H, C3 H), 6.28 (dd, JZ
9.4, 16 Hz, 1H, HC]CH), 6.62–6.89 (m, 3H, HC]CH
and]CHPh), 7.24–7.67 (m, 10H, Ar); dC (75.48 MHz)
24.3, 24.4, 28.5, 31.2, 51.8, 54.3, 58.4, 58.5, 59.9, 60.3,
84.8, 85.1, 124.6, 126.1, 126.6, 127.1, 128.0, 128.1, 128.6,
135.1, 135.8, 136.1, 136.3, 166.6, 167.3; MS (m/z): 486
(MC).
4.3.15. 1-(30-Benzyloxy-40-styrylazetidin-20-one-10-yl)-2-
(300-benzylxy-400-styrylazetidin-200-one-100-yl)cyclohexane
(5h). It was obtained as a white solid, which was
recrystallized from methanol to get white crystalline solid,
mp 179–180 8C; [found C, 78.86; H, 6.55; N, 4.29
C42H42N2O4 requires C, 78.97, H, 6.63; N, 4.39]; Rf (20%
ethyl acetate/pet ether) 0.54; nmax (CHCl3) 1743 cmK1; dH
(200 MHz, CDCl3) 1.01–1.91 (m, 8H, CH2, Cyclohexane),
3.71–3.82 (m, 2H, CH, Cyclohexane), 4.58 (d, JZ10.2 Hz,
2H, CH2Ph), 4.63 (d, JZ10.2 Hz, 2H, CH2Ph), 4.65 (dd,
JZ4.3, 9.4 Hz, 2H, C4H), 4.73 (d, JZ4.3 Hz, 2H, C3H),
6.31 (dd, JZ9.4, 16 Hz, 2H, HC]CH), 6.72 (d, JZ16 Hz,
2H, ]CHPh), 7.15–7.51 (m, 20H, Ar); dC (75.48 MHz)
24.6, 30.3, 52.9, 60.3, 73.0, 83.7, 126.0, 126.7, 127.9, 128.2,
128.3, 128.6, 135.1, 136.2, 136.8, 167.5; MS (m/z): 638
(MC).
4.3.19. Procedure for the preparation of mono-b-lactams
(7 and 8). Phenoxy acetyl chloride 4a (0.1 mL, 1.0 mmol) in
dry methylene chloride (10 mL) was added slowly to a
solution of the bis-imine 3a (0.20 g, 1.0 mmol) and
triethylamine (0.96 mL, 10.0 mmol) in CH2Cl2 (10 mL) at
0 8C. After the addition was complete, the reaction mixture
was allowed to warm up to room temperature and stirred for
15 h. The reaction mixture was then washed with water (2!
10 mL), saturated sodium bicarbonate solution (10 mL) and
saturated brine solution (10 mL). The organic layer was then
dried over anhydrous Na2SO4 and concentrated to give the
crude diastereomeric mixture 7 and 8 (0.22 g).
4.3.16. 1-(30-Benzyloxy-40-styrylazetidin-20-one-10-yl)-2-
(300-benzylxy-400-styrylazetidin-200-one-100-yl)cyclohexane
(6h). It was obtained as a white solid, which on
recrystallization from methanol gave white crystalline
solid, mp 61–62 8C; [found C, 78.91; H, 6.48; N, 4.32
C42H42N2O4 requires C, 78.97, H, 6.63; N, 4.39]; Rf (20%
ethyl acetate/pet ether) 0.44; nmax (CHCl3) 1745 cmK1; dH
(200 MHz, CDCl3) 1.00–2.10 (m, 8H, CH2, Cyclohexane),
3.62–3.73 (m, 2H, CH, Cyclohexane), 4.32–4.41 (m, 1H,
C4H), 4.60 (d, JZ11.3 Hz, 2H, CH2Ph), 4.66 (d, JZ
11.3 Hz, 2H, CH2Ph), 4.76 (d, JZ4.7 Hz, 1H, C40H), 4.86
(d, 0 JZ4.3 Hz, 1H, C3H), 4.93 (dd, JZ4.7, 9.4 Hz, 1H,
C3 H), 6.31 (dd, JZ9.4, 15.7 Hz, 1H, HC]CH), 6.62–6.85
(m, 3H, HC]CH and ]CHPh), 7.18–7.65 (m, 20H, Ar); dC
(75.48 MHz) 24.3, 24.4, 28.6, 31.3, 51.8, 54.4, 60.1, 60.5,
72.5, 72.8, 82.7, 83.5, 124.9, 126.7, 127.5, 127.9, 128.2,
128.3, 128.6, 135.0, 135.7, 136.2, 136.4, 137.0, 166.9,
167.2; MS (m/z): 638 (MC).
Data for diastereomeric mixture of mono-b-lactams 7 and 8.
White solid; nmax (CHCl3) 1645, 1749 cmK1; dH (200 MHz,
CDCl3) 1.28–2.25 (m, 16H), 3.10–3.95 (m, 4H), 4.73 (d, JZ
4.7 Hz, 2H), 4.83 (d, JZ4.3 Hz, 1H), 5.04 (d, JZ4.3 Hz,
2H), 5.18 (d, JZ4.7 Hz, 1H), 6.58–7.83 (m, 30H), 8.33 (s,
1H), 8.45 (s, 1H); dC (125 MHz) 23.9, 24.3, 24.7, 25.2, 29.7,
29.9, 33.5, 33.8, 53.8, 58.2, 59.4, 61.3, 64.1, 69.9, 72.2,
96.0, 115.5, 121.7, 127.9, 128.0, 128.2, 128.6, 128.8, 129.0,
130.8, 131.0, 133.9, 136.1, 156.8, 161.4, 165.5, 167.6.
4.3.20. N,N0-Dibenzylidene-1,2-diphenylethane-1,2-dia-
mine (13a). This bis-imine 13a was prepared from
(G)1,2-diphenylethylenediamine and benzaldehyde follow-
ing the same procedure as described for 3a–c. It was isolated
as a white solid and recrystallized from EtOAc–petroleum
ether (10:90). White needles; yield 82%; mp 158–159 8C;
[found C, 86.43; H, 6.13; N, 7.06 C28H24N2 requires C,
86.56; H, 6.22; N, 7.21] nmax (CHCl3) 1643 cmK1; dH
(200 MHz, CDCl3) 4.67 (s, 2H, CHPh), 7.03–7.90 (m, 20H,
Ar), 8.22 (s, 2H, –N]CH) dC (75.48 MHz, CDCl3) 81.3,
4.3.17. 1-(30-Methoxy-40-styrylazetidin-20-one-10-yl)-2-
(300-methoxy-400-styrylazetidin-200-one-100-yl)cyclohexane
(5i). It was obtained as a white solid, which was
recrystallized from methanol to get white crystalline solid,
mp 211–212 8C; [found C, 73.92; H, 6.95; N, 5.68

A. L. Shaikh et al. / Tetrahedron 61 (2005) 2441–2451
2449
126.8, 127.8, 128.1, 128.3, 128.4, 130.3, 136.4, 141.1,
161.7; MS (m/z): 388 (MC).
4.3.25. 1,2-Diphenyl-1,2-bis(30-methoxy-40-phenylazeti-
din-20-one-10-yl)ethane (14c). It was obtained as a white
solid, which was recrystallized from methanol to get white
crystalline solid, mp 194–195 8C; [found C, 76.49; H, 5.88;
N, 5.10 C34H32N2O4 requires C, 76.67, H, 6.05; N, 5.26]; Rf
Following the typical procedure described for 5a, 6a bis-b-
lactams 14a–c and 15a–c were prepared.
(30% ethyl acetate/pet ether) 0.55; nmax (CHCl3) 1747 cmK1
;
4.3.21. 1,2-Diphenyl-1,2-bis(30-phenoxy-40-phenylazeti-
din-20-one-10-yl)ethane (14a). It was obtained as a white
solid, which was recrystallized from methanol to get white
crystalline solid, mp 197–198 8C; [found C, 78.81; H, 5.78;
N, 4.50 C40H36N2O4 requires C, 78.92, H, 5.96; N, 4.60]; Rf
dH (200 MHz, CDCl3) 3.01 (s, 6H, OCH3), 4.47 (d, JZ
5.1 Hz, 2H, C4H), 4.53 (d, JZ5.1 Hz, 2H, C3H), 5.60 (d,
JZ10.3 Hz, 2H, CHPh), 7.00–7.68 (m, 20H, Ar); dC
(50 MHz) 57.9, 61.3, 67.2, 85.0, 127.2, 127.7, 127.9,
128.0, 128.2, 128.3, 128.5, 128.6, 129.1, 130.7, 133.6,
136.4, 138.2, 140.9, 162.3; MS (m/z): 532 (MC).
(30% ethyl acetate/pet ether) 0.63; nmax (CHCl3) 1757 cmK1
;
dH (500 MHz, CDCl3) 5.19 (s, 2H, CHPh), 5.34 (d, JZ
4.1 Hz, 2H, C4H), 5.55 (d, JZ4.1 Hz, 2H, C3H), 6.69–7.30
(m, 30H, Ar); dC (125 MHz) 59.9, 60.9, 73.1, 111.5, 118.0,
123.3, 123.6, 124.0, 124.1, 124.2, 125.0, 125.1, 125.7,
125.8, 125.9, 152.7, 167.2; MS (m/z): 608 (MC).
4.3.26. 1,2-Diphenyl-1-(30-methoxy-40-phenylazetidin-20-
one-10-yl)-2-(300-methoxy-400-phenylazetidin-200-one-100-
yl)ethane (15c). It was obtained as a white solid, which was
recrystallized from methanol to get white crystalline solid,
mp 201–202 8C; [found C, 76.53; H, 5.83; N, 5.07
C34H32N2O4 requires C, 76.67, H, 6.05; N, 5.26]; Rf (30%
ethyl acetate/pet ether) 0.47; nmax (CHCl3) 1743 cmK1; dH
(200 MHz, CDCl3) 3.06, 3.09 (s, 6H, OCH3), 4.66 (d, JZ
4.3 Hz, 2H, C4H and C40H),04.80 (d, JZ4.7 Hz, 1H, C3H),
5.08 (d, JZ4.7 Hz, 1H, C3 H), 5.22 (q, JZ11.8 Hz, 2H,
CHPh), 6.76–7.47 (m, 20H, Ar); dC (50 MHz) 57.9, 58.1,
60.6, 61.2, 61.4, 63.4, 84.7, 85.0, 127.5, 127.8, 127.9, 128.1,
128.3, 128.5, 128.8, 129.1, 132.8, 133.7, 136.5, 137.2,
167.0, 167.8; MS (m/z): 532 (MC).
4.3.22. 1,2-Diphenyl-1-(30-phenoxy-40-phenylazetidin-20-
one-10-yl)-2-(300-phenoxy-400-phenylazetidin-200-one-100-
yl)ethane (15a). It was obtained as a white solid, which was
recrystallized from methanol to get white crystalline solid,
mp 209–210 8C; [found C, 78.85; H, 5.74; N, 4.53
C40H36N2O4 requires C, 78.92, H, 5.96; N, 4.60]; Rf (30%
ethyl acetate/pet ether) 0.52; nmax (CHCl3) 1751 cmK1; dH
(200 MHz, CDCl3) 5.24–5.34 (m, 2H, CHPh), 4.85 (d, JZ
4.7 Hz, 1H, C4H), 5.43 (d, JZ4.7 Hz, 1H, C40H), 5.33 (d,
JZ4.3 Hz, 1H, C3H), 5.57 (d, JZ4.3 Hz, 1H, C30H), 6.67–
7.40 (m, 30H, Ar); dC (75 MHz) 61.0, 61.8, 61.9, 64.0, 81.2,
81.6, 115.6, 115.8, 121.8, 122.0, 127.2, 127.6, 127.9, 128.3,
128.5, 128.6, 129.1, 129.2, 129.4, 132.4, 133.2, 136.4,
137.2, 157.0, 157.1, 165.8, 166.9; MS (m/z): 608 (MC).
4.3.27. N,N0-Dibenylidenebutane-2, 3-diamine (13b).
This bis-imine 13b was prepared from (G) 2,3-diamino-
butane and benzaldehyde following the same procedure as
described for 3a–c. It was isolated as an oil; yield 83%; nmax
(CHCl3) 1583, 1596, 1643 cmK1; dH (200 MHz, CDCl3)
1.30 (d, JZ5.8 Hz, 6H, CH3), 3.38–3.53 (m, 2H, CH),
7.17–7.92 (m, 10H, Ar), 8.16 (s, 2H, –N]CH).
4.3.23. 1,2-Diphenyl-1,2-bis(30-benzyloxy-40-phenylazeti-
din-20-one-10-yl)ethane (14b). It was obtained as a white
solid, which was recrystallized from methanol to get white
crystalline solid, mp 190–191 8C; [found C, 79.05; H, 6.23;
N, 4.28 C42H40N2O4 requires C, 79.21, H, 6.33; N, 4.39]; Rf
Following the typical procedure described for 5a, 6a bis-b-
lactams 14d and 15d were prepared from bisimine 13b and
phenoxyacetyl chloride.
(20% ethyl acetate/pet ether) 0.56; nmax (CHCl3) 1741 cmK1
;
4.3.28. 2,3-Bis [30-Phenoxy-40-phenylazetidin-20-one-10-
yl]butane (14d). It was obtained as a white solid, which was
recrystallized from methanol to get white crystalline solid,
mp 69–70 8C; [found C, 76.55; H, 6.05; N, 5.16
C34H32N2O4 requires C, 76.67, H, 6.05; N, 5.26]; Rf (30%
ethyl acetate/pet ether) 0.50; nmax (CHCl3) 1755 cmK1; dH
(200 MHz, CDCl3) 0.81 (d, JZ6.6 Hz, 6H, CH3), 4.08–4.17
(m, 2H, CHCH3), 5.26 (d, JZ4.7 Hz, 2H, C4H), 5.40 (d,
JZ4.7 Hz, 2H, C3H), 6.62–7.52 (m, 20H, Ar); dC
(125 MHz) 15.9, 51.2, 61.3, 81.3, 111.5, 127.9, 128.0,
128.6, 128.9, 129.1, 134.4, 156.6, 167.4; MS (m/z): 532
(MC).
dH (200 MHz, CDCl3) 4.11 (d, JZ10.3 Hz, 2H, CHPh),
4.54 (d, JZ4.3 Hz, 2H, C4H), 4.70 (d, JZ4.7 Hz, 2H,
C3H), 5.63 (d, JZ11 Hz, 4H, CH2Ph), 6.98–7.62 (m, 30H,
Ar); dC (50 MHz) 59.2, 61.5, 62.9, 63.8, 72.2, 72.8, 82.2,
82.8, 127.7, 127.9, 128.0, 128.1, 128.2, 128.3, 128.4, 128.5,
128.6, 129.2, 130.7, 136.0, 136.4, 138.0, 138.3, 138.6,
139.5, 141.0, 166.8; MS (m/z): 636 (MC).
4.3.24. 1,2 Diphenyl-1-(30-benzyloxy-40-phenylazetidin-
20-one-10-yl)-2-(300-benzyloxy-400-phenylazetidin-200-one-
100-yl)ethane (15b). It was obtained as a white solid, which
on recrystallization from methanol gave white crystalline
solid, mp 79–80 8C; [found C, 79.09; H, 6.20; N, 4.30
C42H40N2O4 requires C, 79.21, H, 6.33; N, 4.39]; Rf (20%
ethyl acetate/pet ether) 0.44; nmax (CHCl3) 1753 cmK1; dH
(200 MHz, CDCl3) 4.02–4.32 (m, 2H, CHPh), 4.61 (d, JZ
4.3 Hz, 1H, C4H), 4.84 (d, JZ4.3 Hz, 1H, C40H), 4.98 (d,
JZ4.7 Hz, 1H, C3H), 5.12 (d, JZ4.7 Hz, 1H, C30H), 5.14–
5.23 (q, JZ11.8 Hz, 4H, CH2Ph), 6.72–7.55 (m, 30H, Ar);
dC (75 MHz) 60.8, 61.5, 63.8, 63.9, 72.2, 72.3, 82.9, 83.1,
127.5, 127.6, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2,
128.3, 128.7, 128.9, 129.1, 129.4, 133.3, 134.1, 136.4,
136.8, 137.5, 167.0, 167.8; MS (m/z): 636 (MC).
4.3.29. 2-(30-Phenoxy-40-phenylazetidin-20-one-10-yl)-3-
(300-phenoxy-400-phenylazetidin-200-one-100-yl)butane
(15d). It was obtained as a white solid, which was
crystallized from methanol to get white crystalline solid,
mp 175–176 8C; [found C, 76.48; H, 6.03; N, 5.08
C34H32N2O4 requires C, 76.67, H, 6.05; N, 5.26]; Rf (30%
ethyl acetate/pet ether) 0.35; nmax (CHCl3) 1755 cmK1; dH
(200 MHz, CDCl3) 0.88 (d, JZ6.6 Hz, 3H, CH3), 1.32 (d,
JZ6.6 Hz, 3H, CH3), 3.71–3.90 (m, 2H, CHCH3), 4.95 (d,
JZ4.7 Hz, 1H, C4H), 5.37 (d, JZ4.7 Hz, 1H, C40H), 5.40

2450
A. L. Shaikh et al. / Tetrahedron 61 (2005) 2441–2451
(d, JZ4.3 Hz, 1H, C3H), 5.50 (d, JZ4.3 Hz, 1H, C30H),
6.60–7.57 (m, 20H, Ar); dC (125 MHz) 15.8, 17.1, 51.7,
52.4, 61.5, 62.6, 80.9, 115.6, 121.8, 122.0, 128.0, 128.4,
128.7, 129.2, 133.0, 134.4, 156.8, 166.3, 166.4; MS (m/z):
532 (MC).
Heterocycles 1988, 27, 1755–1802. (c) Ojima, I. In The
Chemistry of b-Lactams; Georg, G. I., Ed.; VCH: New York,
1993; p 197. (d) Ojima, I. Acc. Chem. Res. 1995, 28, 383–389.
(e) Srirajan, V.; Deshmukh, A. R. A. S.; Bhawal, B. M.
Tetrahedron 1996, 52, 5585–5590. (f) Srirajan, V.; Deshmukh,
A. R. A. S.; Puranik, V. G.; Bhawal, B. M. Tetrahedron:
Asymmetry 1996, 7, 2733–2738. (g) Palomo, C.; Aizpurua, J.;
Ganboa, I. In Enantioselective Synthesis of Beta-Amino Acids;
Juaristi, E., Ed.; VCH: New York, 1997; p 279; and references
cited therein. (h) For a review on this subject see: Ojima, I.;
Delaloge, F. Chem. Soc. Rev. 1997, 26, 377–386. (i) Alcaide,
B.; Almendros, P. Chem. Soc. Rev. 2001, 30, 226–240.
(j) Alcaide, B.; Almendros, P. Synlett 2002, 381–393.
(k) Deshmukh, A. R. A. S.; Bhawal, B. M.; Krishnaswamy,
D.; Govande, V. V.; Shinkre, B. A.; Jayanthi, A. Curr. Med.
Chem. 2004, 11, 1889–1920 and references cited therein.
(l) Alcaide, B.; Almendros, P. Curr. Med. Chem. 2004, 11,
1921–1949 and references cited therein.
4.3.30. Procedure for asymmetric synthesis of bis-b-
lactams (5j, 6j, 14e and 15e). Following the typical
procedure described for 5a, 6a the bis-b-lactams 5j, 6j, 14e
and 15e were prepared from chiral bis-imines derived from
optically pure (C)-1R,2R-trans-1, 2-diaminocyclohexane,
(K)-1S,2S-diphenylethylenediamine and benzaldehyde;
and phenoxyacetyl chloride.
4.3.30.1. (1R,2R,30S,40R,300S,400R)-1,2-Bis (30-phenoxy-
40-phenylazetidin-20-one-10-yl)cyclohexane (5j). It was
obtained as a white crystalline solid; mp 231–232 8C;
[a]2D5ZK146.9 (c, 0.80, CHCl3); spectral data same as for
5a.
4. Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Curr.
Med. Chem. 2004, 11, 1837–1872 and references cited therein.
5. (a) Ojima, I.; Hatanaka, N.; Yoda, N.; Abe, R.; Yatabe, M.;
Yanashita, M. In Peptide Chemistry; Sakakibara, S., Ed.;
Protein Research Foundation: Osaka, 1983; pp 29–34.
(b) Yamashita, M.; Abe, R.; Hatanaka, N.; Ojima, I. In
Peptide Chemistry; Sakakibara, S., Ed.; Protein Research
Foundation: Osaka, 1983; pp 85–90.
4.3.30.2. (1R,2R,30S,40R,300R,400S)-1-(30-Phenoxy-40-
phenylazetidin-20-one-10-yl)-2-(300-phenoxy-400-phenyl-
azetidin-200-one-100-yl)cyclohexane (6j). It was obtained as
a white crystalline solid, mp 82–83 8C; [a]2D5ZK53.83 (c,
1.00, CHCl3); spectral data same as for 6a.
4.3.30.3. (1S,2S,30R,40S,300R,400S)-1,2-Diphenyl-(30-
phenoxy-40-phenylazetidin-20-one-10-yl)ethane (14e). It
was obtained as a white amorphous solid, mp 197–198 8C;
[a]2D5ZC3.03 (c, 0.99, CHCl3); spectral data same as for
14a.
6. (a) Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K.;
Yamashita, M.; Abe, R. J. Org. Chem. 1991, 56, 5263–5277.
(b) Ojima, I.; Nakahashi, K.; Branstadter, S. M.; Hatanaka, N.
J. Am. Chem. Soc. 1987, 109, 1798–1805. (c) Bose, A. K.;
Womensdors, J. F.; Krishnan, L.; Urbanczyk-Lipkowska, Z.;
Shelly, D. C.; Manhas, M. S. Tetrahedron 1991, 47,
5379–5390. (d) Jayaraman, M.; Puranik, V. G.; Bhawal,
B. M. Tetrahedron 1996, 52, 9005–9016.
4.3.30.4. (1S,2S,30R,40S,300S,400R)-1,2-Diphenyl-1-(30-
phenoxy-40-phenylazetidin-20-one-10-yl)-2-(300-phenoxy-
400-phenylazetidin-200-one-100-yl)ethane (15e). It was
obtained as a white amorphous solid, mp 209–210 8C;
[a]2D5ZC6.15 (c, 0.80, CHCl3); spectral data same as for
15a.
7. (a) Jayaraman, M.; Deshmukh, A. R. A. S.; Bhawal, B. M.
J. Org. Chem. 1994, 59, 932–934. (b) Karupaiyan, K.; Puranik,
V. G.; Deshmukh, A. R. A. S.; Bhawal, B. M. Tetrahedron
2000, 56, 8555–8560.
8. (a) Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51–123.
(b) George, G. I.; Ravikumar, V. T. In The Organic Chemistry
of b-Lactams; George, G. I., Ed.; VCH: New York, 1993;
p 295. (c) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide,
M. Eur. J. Org. Chem. 1999, 3223–3235. (d) van der Steen,
F. H.; van Koten, G. Tetrahedron 1991, 47, 7503–7524.
9. (a) Jayaraman, M.; Deshmukh, A. R. A. S.; Bhawal, B. M.
Synlett 1992, 749–750. (b) Jayaraman, M.; Srirajan, V.;
Deshmukh, A. R. A. S.; Bhawal, B. M. Tetrahedron 1996,
52, 3741–3756. (c) Srirajan, V.; Deshmukh, A. R. A. S.;
Bhawal, B. M. Tetrahedron 1996, 52, 5585–5590. (d) Arun,
M.; Joshi, S. N.; Puranik, V. G.; Bhawal, B. M.; Deshmukh,
A. R. A. S. Tetrahedron 2003, 59, 2309–2316.
Acknowledgements
Authors thank DST, New Delhi, for financial support and
A. L. S. thanks CSIR, New Delhi, for research fellowship.
References and notes
1. For reviews on b-lactam antibiotics, see: (a) Du¨rkheimer, W.;
Blumbach, J.; Lattrell, R.; Scheunemann, K. H. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 180–202. (b) Morin, R. B., Gorman,
M., Eds.; Chemistry and Biology of b-Lactam Antibiotics;
Academic: New York, 1982; Vols. 1–3. (c) Coulton, S.; Hunt,
E. In Lukacs, G., Ed.; Recent Progress in the Chemical
Synthesis of Antibiotics and Related Microbial Products;
Springer: Berlin, 1993; Vols. 1–3, p 621. (d) Southgate, R.
Contemp. Org. Synth. 1994, 1, 417–432.
10. (a) Bennani, Y. l.; Hanessian, S. Chem. Rev. 1997, 97,
3161–3195. (b) Lucet, D.; Le gall, T.; Mioskowski, C. Angew.
Chem., Int. Ed. 1998, 37, 2581–2627.
11. (a) Wasserman, E.; Sutherland, W.; Cvitkovic, E. Clin.
Colorectal Cancer 2001, 1, 149–153. (b) Raymond, E.; Faivre,
S.; Chaney, S.; Woynarowski, J.; Cvitkovic, E. Mol. Cancer
Therapeutics 2002, 1, 227–235. (c) Mani, S.; Graham, M. A.;
Bregman, D. B.; Ivy, P.; Chaney, S. G. Cancer Invest. 2002,
20, 246–263. (d) Di Francesco, A. M.; Ruggiero, A.; Riccardi,
R. Cell. Mol. Life Sci. 2002, 59, 1914–1927.
2. The Chemistry of b-Lactams; Page, M. I., Ed.; Chapman &
Hall: London, 1992.
3. (a) Manhas, M. S.; Amin, S. G.; Bose, A. K. Heterocycles
1976, 5, 669–699. (b) Manhas, M. S.; Wagle, D. R.; Chiang, J.
12. (a) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J.
Am. Chem. Soc. 1990, 112, 2801–2803. (b) Jacobsen, E. N.;

A. L. Shaikh et al. / Tetrahedron 61 (2005) 2441–2451
2451
Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem.
Soc. 1991, 113, 7063–7064. (c) Larrow, J. F.; Jacobsen, E. N.;
Gao, Y.; Hong, Y.; Nie, X.; Zepp, C. M. J. Org. Chem. 1994,
59, 1939–1942. (d) Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.;
Katsuki, T.; Gilheany, D. G. Tetrahedron Lett. 1990, 31,
7345–7348. (e) Katsuki, T. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; Wiley-VCH: New York, 2000. (f) Katsuki, T.
Adv. Synth. Catal. 2002, 344, 131.
Least squares refinement of scale, positional and anisotropic
thermal parameters for non hydrogen atom converged to RZ
0.0470. RwZ0.0971 for [IO2s(I)], 2604 unique observed
reflections out of 13786 measured. Largest diff. peak and hole
-3
˚
0.142 and K0.145 e A . Compound 6a. C36 H34 N2 O4.
Colorless needles 0.78!0.18!0.08 mm grown from metha-
nol. MZ558.65, Monoclinic, space group P21/c, aZ13.722
˚
(1), bZ18.657 (1), cZ12.768 (1) A, bZ111.342(1)8 VZ
3
3044.4(4) A , ZZ4, DZ1.219 g cmK3
,
mZ0.079 mm-1,
13. Yao, X.; Qiu, M.; Lu, W.; Chen, H.; Zheng, Z. Tetrahedron:
Asymmetry 2001, 12, 197–204.
˚
F(000)Z1184. Least squares refinement of scale, positional
and anisotropic thermal parameters for non-hydrogen atom
converged to RZ0.0460. RwZ0.0970 for [IO2s(I)], 5361
unique observed reflections out of 21,926 measured. Largest
14. (a) Evans, D. A.; Lectka, T.; Miller, S. J. Tetrahedron Lett.
1993, 34, 7027–7030. (b) Schaus, S. E.; Branalt, J.; Jacobsen,
E. N. J. Org. Chem. 1998, 63, 403–405.
15. Belokon, Y. N.; North, M.; Churkina, T. D.; Ikonnikov, N. S.;
Maleev, V. I. Tetrahedron 2001, 57, 2491–2498.
diff. peak and hole 0.143 and K0.144 e AK3. ORTEP diagram
˚
of the molecule along with the crystallographic numbering of
atoms. Ellipsoids are drawn with 40% probability. The crystal
structures for 5a and 6a have been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition
numbers CCDC 249721 and 249722, respectively.
19. Sheldrick, G. M. SHELX-97: Program for Crystal Structure
Solution and Refinement; University of Gottingen: Germany,
1997.
16. (a) Kuhnert, N.; Strabnig, C.; Lopez-Periago, A. M.
Tetrahedron: Asymmetry 2002, 13, 123–128. (b) Kuhnert,
N.; Lopez-Periago, A. M. Tetrahedron Lett. 2002, 43,
3329–3332. (c) Kwit, M.; Garwronski, J. Tetrahedron:
Asymmetry 2003, 14, 1303–1308.
17. Kwit, M.; Garwronski, J. Tetrahedron 2003, 59, 9323–9331.
18. X-ray diffraction study. Data for both the compounds were
collected at TZ295 K, on SMART APEX CCD Single Crystal
20. Corey, E. J.; Lee, D.; Sarshar, S. Tetrahedron: Asymmetry
1995, 6, 3–6.
˚
X-ray diffractometer using Mo Ka radiation (lZ0.7107 A) to
a maximum q range of 25.008. The structures were solved by
direct methods using SHELXTL. All the data were corrected
for Lorentzian, polarisation and absorption effects. SHELX-97
(ShelxTL)19 was used for structure solution and full matrix
least squares refinement on F2. Hydrogen atoms were included
in the refinement as per the riding model. The refinements
were carried out using SHELXL-97. Compound 5a. C36 H34
N2 O4. Colorless needles 0.69!0.57!0.06 mm grown from
21. Nantz, M. H.; Lee, D. A.; Bender, D. M.; Roohi, A. H. J. Org.
Chem. 1992, 57, 6653–6657.
22. Optically pure (C)-1R,2R-trans-1,2-diaminocyclohexane was
obtained by resolution of racemic compound following the
reported procedure: Schanz, H.; Linseis, M.; Gilheany, D.
Tetrahedron: Asymmetry 2003, 14, 2763–2769.
23. Optically pure (K)-1S,2S-diphenylethylenediamine was
obtained by resolution of racemic compound following the
reported procedure: Pikul, S.; Corey, E. J. Org. Synth. 1992,
71, 22–29.
methanol. MZ558.65, orthorhombic, space group Pccn, aZ
3
˚
˚
24.698(2), bZ6.423(1), cZ18.595(2) A, VZ2949.8(5) A ,
ZZ4, DZ1.258 g cm-3, mZ0.082 mmK1
, F(000)Z1184.