Stereoselective synthesis of cis-bis-β-lactams linked with an ethylene bridge

Article abstract of DOI:10.1016/S0040-4020(00)00800-0

An efficient synthesis of (±)-cis-bis-β-lactams (5 and 6) via cycloaddition reaction of bisimines (3a-c) with acid chlorides (4) in the presence of triethylamine in very good yield is described. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00800-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8555±8560
Stereoselective Synthesis of cis-Bis-b-lactams Linked with an
Ethylene Bridge
K. Karupaiyan,a V. G. Puranik,b A. R. A. S. Deshmukha and B. M. Bhawala,
*
aDivision of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
bDivision of Physical Chemistry, National Chemical Laboratory, Pune 411 008, India
Received 5 June 2000; revised 14 August 2000; accepted 30 August 2000
AbstractÐAn ef®cient synthesis of (^)-cis-bis-b-lactams (5 and 6) via cycloaddition reaction of bisimines (3a±c) with acid chlorides (4) in
the presence of triethylamine in very good yield is described. q 2000 Published by Elsevier Science Ltd.
Although b-lactam derivatives are well known for their
antibiotic activities,1 recently they have also been used as
a synthon for the synthesis of various natural and unnatural
products.2 Ojima has shown the utility of bis-b-lactams for
the synthesis3 of peptides. The synthesis of bis-b-lactams, in
general, have been reported by step-wise construction of
b-lactam rings.4 In continuation of our work on synthesis
of bis-b-lactams,4d,5 we were interested in building bis-b-
lactams with spacer groups. Herein, we report the synthesis
of bis-b-lactams in single step from bisimines derived from
bis-amines.
reaction) with various acid chlorides (4a±c) in the presence
of triethylamine gave diastereomeric mixtures of (^)-cis-
bis-b-lactams9 (5a±g and 6a±g) in good to excellent yields
(Scheme 2, Table 1). The TLC and 1H NMR spectral
analysis of the crude reaction mixture showed the presence
two diastereomers. These diastereomers were separated by
¯ash column chromatography. The C-symmetric structure
1
for bis-b-lactams 5a±g was assigned from the H NMR
spectral analysis. The 1H NMR spectra of all these
compounds showed two doublets at about d 2.8 and 3.8
with geminal coupling of 11±12 Hz for the protons of the
methylene group joining two b-lactam rings. The meso
structure was assigned to the other diastereomers 6a±g as
1H NMR spectra of all compounds in this series showed two
multiplets (d ,3.0 and 3.5) due to non-equivalence of two
methylenes joining two b-lactam rings.
The starting N,N0-bis-(p-anisylmethylene)ethane diamine
(3a)6 and N,N0-bis-(phenylmethylene)ethane diamine (3b)7
were prepared in excellent yields by stirring a mixture of the
aromatic aldehydes (2a,b), ethylenediamine and anhydrous
MgSO4 in dry dichloromethane (Scheme 1). The bisimine
N,N0-bis-(styrylmethylene)ethane diamine (3c)8 was
prepared in quantitative yield by re¯uxing ethanolic
solution of ethylenediamine and cinnamaldehyde.
The structures for both C2-symmetric and meso bis-b-
lactams (5a±g and 6a±g) were further con®rmed by single
crystal X-ray analysis of the representative compounds 5b
and 6c. The X-ray crystal analysis of isomer (^)-5b showed
C2-symmetry in the molecule and the relative stereo-
chemistry of b-lactam ring centres was assigned as 3S,
4R, 30S, 40R or 3R, 4S, 30R, 40S (Fig. 1).
The bisimines 3a±c on cycloaddition reaction (Staudinger
The meso stereochemistry of the isomer (^)-6c was
established from its X-ray structure and the relative stereo-
chemistry of b-lactam ring centres was assigned as 3S, 4R,
30R, 40S or 3R, 4S, 30S, 40R (Fig. 2).
We have extended the above methodology to the asym-
metric synthesis of bis-b-lactams. To achieve the stereo-
selectivity in b-lactam ring formation via ketene±imine
cycloaddition reaction, a sterically demanding chiral acid
7, derived from camphor sultam (Oppolzer's sultam) was
chosen as a ketene precursor. The starting acid 7 was
obtained in overall 70% yield from camphor sultam in
Scheme 1.
Keywords: cycloaddition reaction; azetidinones; Staudinger reaction;
bisimines; bis-b-lactams.
* Corresponding author. Tel.: 191-20-5893153; fax: 191-20-5893355;
e-mail: bhawal@dalton.ncl.res.in
0040±4020/00/$ - see front matter q 2000 Published by Elsevier Science Ltd.
PII: S0040-4020(00)00800-0

8556
K. Karupaiyan et al. / Tetrahedron 56 (2000) 8555±8560
Scheme 2.
Table 1. Synthesis of bis-b-lactams 5 and 6
Compound
R1
R2
Compound 5 and 6
Yielda (%)
Ratiob of 5 and 6
mp of 5c (8C)
mp of 6c (8C)
a
b
c
d
e
f
Anisyl
Anisyl
Anisyl
Ph
Ph
Styryl
Styryl
Ph
Bn
Ac
Ph
Bn
Bn
Ph
80
86
75
79
85
60
66
42:58
55:45
51:49
38:62
30:70
58:42
61:39
204±205
138±139
184±185
212±213
128±129
Semisolid
196±198
182±183
227±228
194±195
195±196
242±243
151±153
195±196
g
a Isolated yields of diastereomeric mix of 5 and 6.
b The diastereomeric ratio of 5 and 6 was determined from 1H NMR spectral data.
c The diastereomers 5 and 6 were separated by ¯ash column chromatography.
Figure 1. ORTEP diagram of bis-b-lactam 5b without solvent molecule.
Figure 2. ORTEP diagram of bis-b-lactam 6c.

K. Karupaiyan et al. / Tetrahedron 56 (2000) 8555±8560
8557
Scheme 3.
two steps using our earlier reported procedure.10 The
cycloaddition reaction of ketene derived from the acid 7
with imine 3a in the presence of triethylamine and phenyl-
dichlorophosphate, as an acid activator, furnished stereo-
speci®cally bis-b-lactam 8 in excellent yield (Scheme 3).
The formation of a single diastereomer was evident from 1H
NMR and HPLC analysis of the crude reaction mixture. The
C2-symmetric structure was assigned to bis-b-lactam 8
based on its 1H NMR spectrum, which compares very
N,N0-Bis(p-methoxyphenylmethylene)ethane-1,2-diamine
3a. It was obtained as a white solid, crystallized from
EtOAc:petroleum ether (90:10) as needles, yield 88%; mp
109±1108C [lit. mp6 110±1118C]; nmax (CHCl3) 830, 1010,
1450, 1630 cm21; dH (200 MHz, CDCl3) 3.74 (s, 6H); 3.84
(s, 4H); 6.78 (d, Jˆ8 Hz, 4H); 7.50 (d, Jˆ8 Hz, 4H); 8.06 (s,
2H).
N,N0-Bis(phenylmethylene)ethane-1,2-diamine 3b. It was
isolated as a white solid and crystallized from EtOAc:
petroleum ether (90:10) to give white needles; yield 84%;
mp 52±538C [lit. mp7 51.5±538C]; nmax (CHCl3) 960, 1000,
1350, 1430, 1610 cm21; dH (200 MHz, CDCl3) 3.88 (s, 4H);
6.92±7.88 (m, 10H); 8.14 (s, 2H).
1
well with the H NMR spectra of C2-symmetric bis-b-
lactams 5 obtained earlier. The absolute stereochemistry
for this bis-b-lactam 8 was assigned as 3R, 4S, 30R, 40S
based on our earlier work on asymmetric synthesis of
b-lactams10 using ketene derived from Oppolzer's sultam
and imines.
Preparation of N,N0-bis(styrylmethylene)ethane-1,2-di-
amine 3c
Experimental
A solution of freshly distilled cinnamaldehyde (14.18 g,
0.107 mol) and ethylenediamine (3 g, 0.05 mol) in ethanol
(40 mL) was re¯uxed for 1 h. The solvent was removed by
distillation under reduced pressure and the residue was puri-
®ed by crystallization from ethyl acetate:petroleum ether
(90:10) to yield 14.38 g (100%) of pure bisimine 3c as a
crystalline pale yellow solid, mp 108±1098C [lit. mp8
1098C]; nmax (CHCl3) 979, 1164, 1218, 1450, 1635, 2846,
2939 cm21; dH (200 MHz, CDCl3) 3.80 (s, 4H); 6.70±6.95
(m, 4H); 7.15±7.55 (m, 10H); 7.95 (d, Jˆ6.6 Hz, 2H).
General
1H NMR Spectra were recorded in CDCl3 solution on a
Bruker AC 200 spectrometer at 200 MHz and chemical
shifts are reported in ppm down®eld from tetramethylsilane.
13C NMR spectra were recorded in CDCl3 solution on a
Bruker AC 200 and Bruker MSL 300 instruments and
chemical shifts were reported in ppm relative to the center
line of CDCl3 (77.0 ppm). Infrared spectra were recorded on
a Perkin-Elmer Infracord Spectrophotometer Model 599-B
using sodium chloride optics. Melting points were deter-
mined on 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.
Typical procedure for the preparation of b-lactams 5a±g
and 6a±g
A solution of the acid chlorides (4a±c, 2.53 mmol) in dry
CH2Cl2 (15 mL) was slowly added to a solution of imines
(3a±c, 3.5 mmol) and triethylamine (10 mmol) in CH2Cl2
(15 mL) at 08C. The reaction mixture was then allowed to
warm to room temperature and stirred for 15 h. It was then
washed with water (2£20 mL), satd NaHCO3 (15 mL), brine
(15 mL) and dried (Na2SO4). The removal of organic
solvent by distillation under reduced pressure gave crude
product of a diastereomeric mixture. The diastereomers
were separated by ¯ash column chromatography (silica
gel, 230±400, petroleum ether:ethyl acetate, 3:1) to give
pure diastereomer of b-lactams (5a±g and 6a±g).
General procedure for imines 3a and 3b
A mixture of freshly distilled aldehyde (0.15 mol), ethylene-
diamine (0.05 mol), anhydrous MgSO4 (24 g) and dry
dichloromethane (200 mL) was stirred for 15 h at room
temperature. The reaction mixture was then ®ltered through
a bed of celite and the solvent from the ®ltrate was removed
by distillation under reduced pressure. The residue was then
treated with a 10% solution of ethyl acetate in petroleum
ether (60±80) to remove unreacted aldehyde and ®ltered to
give required imines 3a,b in excellent yield as a crystalline
solid.
1,2-Bis[30-phenoxy-40-(p-methoxyphenyl)azetidin-20-one-
10-yl]ethane 5a. It was isolated as white solid from dia-
stereomeric mixture by ¯ash column chromatography and

8558
K. Karupaiyan et al. / Tetrahedron 56 (2000) 8555±8560
crystallized from dichloromethane:petroleum ether, mp
204±2058C; [Found: C, 72.40; H, 5.49; N, 4.69.
C34H32N2O6 requires C, 72.32; H, 5.71; N, 4.96%]; nmax
(Nujol) 1735 cm21; dH (300 MHz, CDCl3) 2.80 (d,
Jˆ11.4 Hz, 2H); 3.75 (s, 6H); 3.82 (d, Jˆ11.4 Hz, 2H);
5.17 (d, Jˆ6.5 Hz, 2H); 5.34 (d, Jˆ6.5 Hz, 2H); 6.60±
6.93 (m, 12H); 7.02±7.33 (m, 6H); dC (75.2 MHz, CDCl3)
37.36, 55.24, 60.76, 82.55, 113.93, 116.86, 129.16, 129.80,
155.37, 160.14, 166.82; m/z (EI) 121(100%), 134, 148, 161,
226.
41.27, 55.36, 60.13, 76.26, 77.26, 77.62, 113.98, 124,97,
129.74, 159.85, 161.39, 165.40, 168.66; m/z (EI)
121(100%), 161, 262, 304.
1-[3-Acetoxy-4-(p-methoxyphenyl)azetidin-20-one-10-yl]-
2-[30-Acetoxy-40-(p-meth-oxyphenyl)azetidin-200-one-100-
yl]ethane 6c. The title compound 6c was obtained as a white
crystalline solid, crystallized from ethyl acetate: petroleum
ether, mp 194±1958C; [Found: C, 62.62; H, 5.69; N, 5.50.
C26H28N2O8 requires C, 62.89; H, 5.68; N, 5.64]; nmax
(Nujol) 1758 cm21; dH (200 MHz, CDCl3) 1.73 (s, 6H);
3.02±3.18 (m, 2H); 3.46±3.67 (m, 2H); 3.83 (s, 6H); 4.85
(d, Jˆ5.4 Hz, 2H); 5.65 (d, Jˆ5.4 Hz, 2H); 6.92 (d,
Jˆ9.7 Hz, 4H); 7.14±7.30 (m, 4H); dC (75.2 MHz,
CDCl3) 19.84, 38.45, 55.24, 61.31, 77.43, 113.93, 123.82,
129.65, 160.14, 165.26, 168.92; m/z (EI) 150 (100%), 121,
135.
1-[3-Phenoxy-4-(p-anisyl)azetidin-20-one-10yl]-2-[31-phen-
oxy-41-(p-methoxy-phenyl)-azetidin-200-one-100-yl]ethane
6a. It was obtained as a white solid, which was crystallized
from dichloromethane:petroleum ether, mp 182±1838C;
[Found: C, 72.50; H, 5.76; N, 4.76. C34H32N2O6 requires
C, 72.32; H, 5.71; N, 4.96]; nmax (Nujol) 1740 cm21; dH
(200 MHz CDCl3) 3.00±3.24 (m, 2H); 3.50±3.75 (m, 2H);
3.78 (s, 6H); 4.88 (d, Jˆ5.4 Hz, 2H); 5.24 (d, Jˆ5.4 Hz,
2H); 6.57±7.42 (m, 18H); dC (75.2 MHz, CDCl3) 38.24,
55.27, 61.68, 82.16, 113.99, 116.80, 129.16, 129.86,
155.37, 160.23, 165.84; m/z (EI) 245 (100%), 148, 161,
226, 254.
1,2-Di-[30-Phenoxy-40-phenylazetidin-20-one-10-yl]ethane
5d. It was obtained as a white crystalline solid, crystallized
from dichloromethane:petroleum ether; mp 212±2138C;
[Found: C, 76.05; H, 5.30; N, 5.40. C32H28N2O4 requires
C, 76.17; H, 5.59; N, 5.55]; nmax (CHCl3) 1752 cm21; dH
(300 MHz, CDCl3) 2.86 (d, Jˆ11.5 Hz, 2H); 3.88 (d,
Jˆ11.5 Hz, 2H); 5.22 (d, Jˆ3.9 Hz, 2H); 5.38 (d,
Jˆ3.9 Hz, 2H); 6.58±7.39 (m, 20H). dC (75.2 MHz,
CDCl3) 37.54, 61.16, 82.62, 115.64, 116.92, 128.49,
129.01, 129.13, 132.45, 155.28, 166.85; m/z (EI) 230
(100%), 196, 224.
1,2-Bis[30-benzyloxy-40-(p-methoxyphenyl)azetidin-20-one-
10-yl]ethane 5b. It was obtained as a white solid, crystal-
lized from dichloromethane:petroleum ether, mp 138±
1398C; [Found: C, 72.69; H, 6.22; N, 4.58. C36H36N2O6
requires C, 72.95; H, 6.12; N, 4.72]; nmax (Nujol)
1735 cm21; dH (200 MHz, CDCl3) 2.72 (d, Jˆ10.8 Hz,
2H); 3.72 (d, 10.79 Hz, 2H); 3.81 (s, 6H); 4.14 (d,
Jˆ8.1 Hz, 2H); 4.30 (d, Jˆ8.1 Hz, 2H); 4.82 (d,
Jˆ4.2 Hz, 2H); 5.00 (d, Jˆ4.2 Hz, 2H); 6.73±7.04 (m,
8H); 7.12±7.41 (m, 10H); dC (50.3 MHz, CDCl3) 37.34,
55.64, 60.99, 72.65, 84.69, 114.34, 125.77, 128.16,
128.39, 128.52, 130.12, 136.85, 160.32, 168.32; m/z (EI)
91(100%), 149, 261, 281, 331, 484, 501(M1-Bn).
1-[30-Phenoxy-40-phenylazetidin-20-one-10-yl]-2-[300-phen-
oxy-400-phenylazetidin 200-one-100-yl]ethane 6d. It was
isolated as a white solid, crystallized from dichloro-
methane:petroleum ether, mp 195±1968C; [Found: C,
76.30; H, 5.36; N, 5.31. C32H28N2O4 requires C, 76.17; H,
5.59; N, 5.55]; nmax (CHCl3) 1729 cm21; dH (200 MHz,
CDCl3) 3.00±3.23 (m, 2H); 3.55±3.79 (m, 2H); 4.87 (d,
Jˆ4.2 Hz, 2H); 5.22 (d, Jˆ4.2 Hz, 2H); 6.52±6.73 (m,
4H); 6.97±7.20 (m, 4H); 7.20±7.43 (m, 12H); dC
(75.2 MHz, CDCl3) 38.30, 62.08, 82.16, 116.80, 128.55,
129.16, 132.27, 155.28, 165.81; m/z (EI) 230 (100%), 196.
1-[3-Benzyloxy-4-(p-methoxyphenyl)azetidin-20-one-10yl]-
2-[30-benzyloxy-40-(p-methoxyphenyl)azetidin-200-one-100-
yl]ethane 6b. The title compound 6b was obtained as a
white solid, crystallized from dichloromethane:petroleum
ether, mp 227±2288C; [Found: C, 72.76; H, 6.17; N, 4.85.
C36H36N2O6 requires C, 72.95; H, 6.12; N, 4.72]; nmax
(Nujol) 1750 cm21; dH (200 MHz, CDCl3) 2.81±3.02 (m,
2H); 3.41±3.62 (m, 2H); 3.82 (s, 6H); 4.14 (d, Jˆ10.8, Hz,
2H); 4.26 (d, Jˆ10.8 Hz, 2H); 4.58 (d, Jˆ4.2 Hz, 2H); 4.70
(d, Jˆ4.2 Hz, 2H); 6.78±7.02 (m, 8H); 7.12±7.33 (m, 10H);
dC (75.2 MHz, CDCl3) 37.81, 55.48, 61.59, 72.33, 83.77,
114.17, 125.22, 128.00, 128.24, 128.36, 129.92, 136.54,
160.22, 167.34; m/z (EI) 90 (100%), 148, 240, 268, 501
(M1-Bn).
1,2-Di[30-benzyloxy-40-phenylazetidin-20-one-10-yl]ethane
5e. It was obtained from the diastereomeric mixture by
column chromatography (silica gel, 230±400) and crystal-
lized from dichloromethane:petroleum ether, mp 128±
1298C; [Found: C, 76.43; H, 6.16; N, 4.98. C34H32N2O4
requires C, 76.67; H, 6.05; N, 5.26]; nmax (Nujol)
1740 cm21; dH (200 MHz, CDCl3) 2.75 (d, Jˆ10.9 Hz,
2H); 3.80 (d, Jˆ10.9 Hz, 2H); 4.12 (d, Jˆ10.8 Hz, 2H);
4.29 (d, Jˆ10.8 Hz, 2H); 4.90 (d, Jˆ4.4 Hz, 2H); 5.08 (d,
Jˆ4.4 Hz, 2H); 6.94 (m, 4H); 7.18±7.46 (m, 16H); dC
(50.3 MHz, CDCl3) 37.29, 61.32, 69.19, 72.64, 80.16,
81.13, 82.98, 83.11, 84.73, 86.08, 90.09, 128.03, 128.25,
128.38, 128.72, 133.90, 136.56, 166.11, 168.21, 175.39.
1,2-Bis[30-acetoxy-40-(p-methoxyphenyl)azetidin-20one-
10-yl]ethane 5c. It was obtained as a white solid, crystal-
lized from ethyl acetate:petroleum ether, mp 184±1858C.
[Found: C, 62.77; H, 5.72; N, 5.77. C26H28N2O8 requires
C, 62.90; H, 5.68; N, 5.64]; nmax (Nujol) 1755 cm21; dH
(200 MHz, CDCl3) 1.72 (s, 6H); 2.88 (d, Jˆ10.3 Hz, 2H);
3.79 (d, Jˆ10.3 Hz, 2H); 3.82 (s, 6H); 5.13 (d, Jˆ4.5 Hz,
2H); 5.74 (d, Jˆ4.5 Hz, 2H); 6.89 (d, Jˆ8.69 Hz, 4H);
7.17±7.32 (m, 4H); dC (50.3 MHz, 1:1DMSO:CDCl3)
19.98, 38.23, 38.77, 39.18, 39.59, 40.01, 40.43, 40.85,
1-[30-Benzyloxy-40-phenylazetidin-20-one-10-yl]-2-[300-
benzyloxy-400-phenylazetidin-200-one-100-yl]ethane 6e. It
was obtained as a white solid, crystallized from dichloro-
methane:petroleum ether, mp 242±2438C; [Found: C,
76.51; H, 6.31; N, 5.27. C34H32N2O4 requires C, 76.67; H,
6.05; N, 5.26]; nmax (Nujol) 1750 cm21; dH (200 MHz,
CDCl3) 2.90±3.10 (m, 2H); 3.51±3.71 (m, 2H); 4.12 (d,

K. Karupaiyan et al. / Tetrahedron 56 (2000) 8555±8560
8559
Jˆ10.3 Hz, 2H); 4.24 (d, Jˆ10.34 Hz, 2H);.59 (d,
Jˆ4.3 Hz, 2H); 4.68 (d, Jˆ4.3 Hz, 2H); 6.84±6.97 (m,
4H); 7.14±7.54 (m, 16H); dC (75.2 MHz, CDCl3) 37.72,
61.95, 72.24, 83.71, 127.88, 128.21, 128.46, 128.58,
128.79, 133.34, 136.24, 167.09.
8.86 mmol), triethylamine (0.6 mL) and dry CH2Cl2
(10 mL), a solution of phenyl dichlorophosphate (2 mL,
0.013 mol) in dry CH2Cl2 (40 mL) was added at 08C. The
reaction mixture was allowed to warm to room temperature
and stirred further for 15 h. The reaction mixture was
diluted with CH2Cl2 (30 mL) and successively washed
with water (30 mL), satd. NaHCO3 solution (30 mL),
brine (30 mL) and dried (Na2SO4). The CH2Cl2 solution
was concentrated to give the crude product, which was
column chromatographed (silica gel, 60±120, petroleum
ether:ethyl acetate) to furnish 1.9 g (93%) of pure 8 as a
white crystalline solid, mp 229±2318C; [Found: C, 62.32;
H, 6.54; N, 6.85. C42H54N4O8S2 requires C, 62.51; H, 6.74;
N, 6.94]; [a]D25ˆ196.56 (c 0.99, CHCl3); nmax (CHCl3)
1757 cm21; dH (200 MHz, CDCl3) 0.36 (s, 6H); 0.76 (s,
6H); 1.15±1.52 (m, 4H); 1.60±1.90 (m, 10H); 2.80±3.12
(m, 6H); 3.47±3.62 (m, 2H); 3.78 (s, 6H); 3.84 (d, Jˆ
10.8 Hz, 2H); 4.94 (d, Jˆ4.8 Hz, 2H); 5.02 (d, Jˆ4.8 Hz,
2H); 6.88 (d, Jˆ8.7 Hz, 4H); 7.19 (d, Jˆ8.7 Hz, 4H); dC
(50.3 MHz, CDCl3) 19.97, 20.27, 26.99, 32.94, 38.27,
39.10, 45.41, 47.62, 48.92, 50.30, 55.62, 59.71, 63.60,
66.36, 114.38, 126.53, 129.24, 160.17, 165.15; m/z (EI)
121 (100%), 228, 459.
1-[30-Benzyloxy-40-styrylazetidin-20-one-10-yl]-2-[300-ben-
zyloxy-400-styrylazetidin-200-one-100-yl]ethane 5f. Isolated
as a semisolid material. [Found: C, 78.17; H, 6.13; N,
4.54. C38H36N2O4 requires C, 78.06; H, 6.20; N, 4.79];
nmax (CHCl3) 1747 cm21; dH (200 MHz, CDCl3) 3.00 (d,
Jˆ11.8 Hz, 2H); 3.62 (d, Jˆ11.8 Hz, 2H); 4.52 (dd,
Jˆ4.4, 9.2 Hz, 2H); 4.62 (d, Jˆ7.3 Hz, 2H); 4.68 (d,
Jˆ7.3 Hz, 2H); 4.83 (d, Jˆ4.4 Hz, 2H); 6.23 (dd, Jˆ9.2,
16.1 Hz, 2H); 6.72 (d, Jˆ16.1 Hz, 2H); 7.15±7.50 (m,
20H); dC (75.2 MHz, CDCl3) 37.89, 60.53, 72.59, 83.65,
122.69, 126.37, 127.84, 128.02, 128.31, 135.44, 136.40,
167.17. m/z 494 (M1-90), 236, 91(100%).
1-[30-Benzyloxy-40-styrylazetidin-20-one-10-yl]-2-[300-ben-
zyloxy-400-styrylazetidin-200-one-100-yl]ethane 6f. The title
compound 6f was obtained as a white solid, crystallized
from dichloromethane/methanol, mp 158±1598C; [Found:
C, 77.87; H, 6.41; N, 4.84. C38H36N2O4 requires C, 78.06;
H, 6.20; N, 4.79]; nmax (CHCl3) 1747 cm21; dH (200 MHz,
CDCl3) 3.10±3.27 (m, 2H); 3.39±3.50 (m, 2H); 4.37 (dd,
Jˆ4.4, 9.5 Hz, 2H); 4.53 (d, Jˆ11.0 Hz, 2H); 4.64 (d,
Jˆ10.8 Hz, 2H); 4.76 (d, Jˆ4.4 Hz, 2H); 6.30 (dd, Jˆ9.5,
15.4 Hz, 2H); 6.63 (d, Jˆ15.4 Hz, 2H); 7.15±7.50 (m,
20H); dC (75.2 MHz, CDCl3) 38.39, 61.31, 72.82, 83.68,
123.54, 126.87, 128.00, 128.21, 128.39, 128.73, 135.93,
136.51, 136.76, 167.31; m/z (EI) 494 (M1-90), 236, 91
(100%).
X-Ray diffraction study
X-Ray structure determination of 5b [C37H36N2O8]: Single
crystals of compound 5b were grown by slow evaporation of
dichloromrthane:petroleum ether.
A crystal of size
0.60£0.47£0.06 mm was used for data collection on an
Enaraf Nonius CAD-4 single crystal X-ray diffractometer
Ê
using CuKa radiation (lˆ1.5406 A) and v-2u scan mode
to a maximum u range of 658. Mˆ636.68, monoclinic,
space group C2/c, aˆ23.944 (3), bˆ10.716(3), cˆ
Ê
Ê 3
1-[30-Phenoxy-40-styrylazetidin-20-one-10-yl]-2-[300-phen-
oxy-400-styrylazetidin-200-one-100-yl]ethane 5g. It was
obtained as a white solid, crystallized from dichloro-
methane/methanol, mp 196±1988C; [Found: C, 77.56; H,
5.71; N, 4.89. C36H32N2O4 requires C, 77.67; H, 5.79; N,
5.03]; nmax (CHCl3) 1755 cm21; dH (200 MHz, CDCl3) 3.12
(d, Jˆ11.3 Hz, 2H); 3.76 (d, Jˆ11.7 Hz, 2H); 4.80 (dd,
Jˆ4.9, 9.3 Hz, 2H); 5.40 (d, Jˆ4.9 Hz, 2H); 6.25 (dd,
Jˆ9.3, 15.6 Hz, 2H); 6.80 (d, Jˆ15.6 Hz, 2H); 6.90±7.60
(m, 20H); dC (75.2 MHz, CDCl3) 37.57, 38.67, 38.94,
25.821(3) A, bˆ95.47(2)8, Vˆ6595(2) A , Zˆ8, Dcˆ
1.282 Mg m23. The structure was solved by direct methods
using shelxs and re®ned by full-matrix least-squares on F2
using shelxl-97.11 Empirical absorption correction was
applied. Least squares re®nement of scale, positional and
anisotropic thermal parameters of non-hydrogen atoms was
carried out while the positions of hydrogen atoms was held
®xed. Each H atom was assigned the same isotropic thermal
parameter as the atom to which it was bonded. The re®ne-
ment with number of re®ned parameters 410, converged
to R1ˆ0.0665, Rwˆ0.190, wˆ1/s2[(Fo2)1(0.1513P)21
1.199P] where Pˆ(Fo212Fc2)/3 from 5977 unique re¯ec-
tions ([I.2s(I)]), from a total of 6806 collected. The
residual density in the difference map for peak and hole is
39.22,
59.70, 81.15,
114.42,
121.13, 121.34,
125.65,.127.36, 127.60, 128.46, 134.65, 136.12, 156.14,
164.93; m/z (EI) 292, 222, 128 (100%).
Ê 23
1-[30-Phenoxy-40-styrylazetidin-20-one-10-yl]-2-[300-phen-
oxy-400-styrylazetidin-200-one-100-yl]ethane 6g. It was
obtained as white solid, crystallized from dichloro-
methane/methanol, mp 195±1968C. [Found: C, 77.45; H,
5.68; N, 4.81. C36H32N2O4 requires C, 77.67; H, 5.79; N,
5.03]; nmax (CHCl3) 1757 cm21; dH (200 MHz, CDCl3) 3.27±
3.67 (m, 4H); 4.75 (dd, Jˆ4.3, 9.2 Hz, 2H); 5.42 (d, Jˆ
4.4 Hz, 2H); 6.37 (dd, Jˆ9.2, 15.6 Hz, 2H); 6.75 (d, Jˆ
15.6 Hz, 2H); 6.88±7.55 (m, 20H); dC (75.2 MHz, CDCl3)
38.33, 39.31, 3958, 39.86, 60.89, 81.61, 114.17, 115.09,
121.68, 122.20, 126.35, 127.94, 128.18, 128.97, 135.32,
136.64, 156.78, 165.63. m/z (EI) 292, 222, 128 (100%).
0.390 and -0.612 e A , respectively.
X-Ray structure determination of 6c [C26H28N2O8]: Single
crystals of compound 6c were grown by slow evaporation of
methylene chloride/petroleum ether. A crystal of size
0.62£0.5£0.2 mm was used for data collection on Enaraf
Nonius CAD-4 single crystal X-ray diffractometer using
Ê
CuKa radiation (lˆ1.5406 A) and v-2u scan mode to a
maximum u range of 658. Mˆ496.50, Triclinic, space group
Ê
P-1, aˆ6.425 (2), bˆ14.161 (2), cˆ14.811(3) A, aˆ106.45
Ê 3
(2), bˆ100.58 (2), gˆ98.76 (2)8, Vˆ1240.3 (5) A , Zˆ2,
Dcˆ1.330 Mg m23. The structure was solved by direct
methods using shelxs and re®ned by full-matrix least-
squares on F2 using shelxl-97.11 Empirical absorption
correction was applied. Least squares re®nement of
Preparation of bis-b-lactam 8. To a stirred mixture of
bisimine 3a (0.75 g, 2.53 mmol), acid
7 (2.418 g,

8560
K. Karupaiyan et al. / Tetrahedron 56 (2000) 8555±8560
Deshmukh, A. R. A. S.; Bhawal, B. M. Tetrahedron 1996, 52,
5585. (f) Srirajan, V.; Deshmukh, A. R. A. S.; Puranik, V. G.;
Bhawal, B. M. Tetrahedron: Asymmetry 1996, 7, 2733.
3. (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. (a) Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K.; Yamashita,
M.; Abe, R. J. Org. Chem. 1991, 56, 5263. (b) Ojima, I.;
Nakahashi, K.; Branstadter, S. M.; Hatanaka, N. J. Am. Chem.
Soc. 1987, 109, 1798. (c) Bose, A. K.; Womensdors, J. F.;
Krishnan, L.; Urbanczyk-Lipkowska, Z.; Shelly, D. C.; Manhas,
M. S. Tetrahedron 1991, 47, 5379. (d) Jayaram, M.; Puranik, V. G.;
Bhawal, B. M. Tetrahedron 1996, 52, 9005.
scale, positional and anisotropic thermal parameters of non-
hydrogen atoms was carried out while the positions of
hydrogen atoms was held ®xed. Each H atom was assigned
the same isotropic thermal parameter as the atom to which it
was bonded. The re®nement with number of re®ned para-
meters 326, converged to R1ˆ0.0532, Rwˆ0.168, wˆ1/
s2[(Fo2)1(0.1075P)210.5243P] where Pˆ(Fo212Fc2)/3
from 3934 unique re¯ections ([I.2s(I)]), from a total of
4516 collected. The residual density in the difference map
Ê 23
for peak and hole is 0.362 and -0.252 e A , respectively.
Acknowledgements
One of the authors (K. K.) thanks CSIR for ®nancial
support.
5. Jayaram, M.; Deshmukh, A. R. A. S.; Bhawal, B. M. J. Org.
Chem. 1994, 59, 932.
6. Billman, J. H.; Chen Ho, J. Y.; Caswell, L. R. J. Org. Chem.
1952, 17, 1375.
References
7. Szabo, J. L.; Edwards, C. D.; Bruce, W. F. Antibiotics and
Chemotheraphy 1951, 1, 499±503; Chem. Abstr. 1953, 47, 3850d.
8. Ferguson, L. N.; Branch, G. E. K. J. Am. Chem. Soc. 1944, 66,
1467.
1. (a) Nagahara, T.; Kametani, T. Heterocycles 1987, 25, 729.
(b) Thomas, R. C. In Recent Progress in the Chemical Synthesis
of Antibiotics; Lukacs, G., Ohno, M., Eds.; Springer: Berlin, 1990,
p 553. (c) Palamo, C. In Recent Progerss in the Chemical Synthesis
of Antibiotics; Lukacs, G., Ohno, M., Eds.; Springer: Berlin, 1990,
p 565. (d) Van der Steen, F. H.; Van Koten, G. Tetrahedron 1991,
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2. (a) Manhas, M. S.; Amin, S. G.; Bose, A. K. Heterocycles 1976,
5, 699. (b) Manhas, M. S.; Wagle, D. R.; Chiang, J. Heterocycles
1988, 27, 1755. (c) Ojima, I. In The Organic Chemistry of
b-Lactams, Georg, G. I., Ed.; VCH: New York, 1993; p 197.
(d) Ojima, I. Acc. Chem. Res. 1995, 28, 383. (e) Srirajan, V.;
9. The formation of only cis-isomers was con®rmed from the
1
coupling constant (4±5 Hz) of the b-lactam ring protons in H
NMR of the crude reaction mixture.
10. Srirajan, V.; Deshmukh, A. R. A. S.; Bhawal, B. M.
Tetrahedron 1996, 52, 5579 and references cited therein.
11. (a) Sheldrick, G. M. shelxs-93 Program for crystal structure
È
solution and re®nement, University of Gottingen, Germany, 1993.
(b) Sheldrick, G. M. shelxl-97 Program for crystal structure
È
solution and re®nement, University of Gottingen, Germany, 1997.