Asymmetric synthesis of β-lactams by [2+2] cycloaddition using 1,4:3,6-dianhydro-d-glucitol (isosorbide) derived chiral pools

Article abstract of DOI:10.1016/j.tet.2007.02.022

Highly diastereoselective synthesis of cis-β-lactams via [2+2] cycloaddition reactions of imines derived from a chiral bicyclic aldehyde and ketenes is described. The chiral bicyclic aldehyde as well as chiral acids were prepared from commercially available inexpensive isosorbide. The cycloaddition reaction was found to be highly diastereoselective; in some cases giving a single diastereomer of cis-azetidin-2-one in very good yields. A moderate diastereoselectivity was observed with chiral ketenes derived from isosorbide.

Full text of DOI:10.1016/j.tet.2007.02.022

Tetrahedron 63 (2007) 3380–3388
Asymmetric synthesis of b-lactams by [2D2] cycloaddition using
1,4:3,6-dianhydro-D-glucitol (isosorbide) derived chiral pools
A. L. Shaikh,a A. S. Kale,a Md. Abrar Shaikh,a Vedavati G. Puranikb and A. R. A. S. Deshmukhc,
*
aDivision of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune-411 008, Maharashtra, India
bCentre for Materials Characterization, National Chemical Laboratory, Pune-411 008, Maharashtra, India
cEmcure Pharmaceuticals Limited, API R&D, ARC-H, P-2, I.T.-B.T. Park, Phase-II, M.I.D.C., Hinjwadi, Pune-411 057,
Maharashtra, India
Received 2 October 2006; revised 21 January 2007; accepted 8 February 2007
Available online 13 February 2007
Abstract—Highly diastereoselective synthesis of cis-b-lactams via [2+2] cycloaddition reactions of imines derived from a chiral bicyclic
aldehyde and ketenes is described. The chiral bicyclic aldehyde as well as chiral acids were prepared from commercially available inexpensive
isosorbide. The cycloaddition reaction was found to be highly diastereoselective; in some cases giving a single diastereomer of cis-azetidin-2-
one in very good yields. A moderate diastereoselectivity was observed with chiral ketenes derived from isosorbide.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
stereoselection were achieved when the b-carbon of the chi-
ral aldehyde is attached to a hetero-atom.7 In recent years,
several researchers have studied different approaches to op-
tically pure b-lactams of predictable absolute stereochemis-
try.8,9 It has been shown that the reaction of an acid chloride
(or equivalent) with a Schiff’s base derived from an optically
active aldehyde and an achiral amine, in the presence of
triethylamine leads to a very high level of diastereoselectiv-
ity. In some cases, a single, optically pure, cis-b-lactam is
obtained.10d,e,f
The b-lactam skeleton is the key structural unit responsible
for the antibacterial property of the most widely employed
antibacterial agents.1 The resistance developed by the micro-
organisms against the most traditional b-lactam antibiotic
drugs, maintained the interest of organic chemists for the
development of new b-lactam drugs displaying broader
antibacterial activity.2 As a consequence, a large number of
synthetic methods for b-lactams are now available, and the
topic has been reviewed on more than one occasion.3 The
most convenient procedure for the synthesis of the b-lactam
ring skeleton is the [2+2] cyclocondensation of ketenes to
the imines, known as the Staudinger reaction.4 In particular,
this method has provided useful and economical entries to b-
lactams, mainly due to the ready availability of both Schiff’s
bases and ketenes. In this context, in spite of the high level of
achievement reached in the Staudinger reaction, the subject
still continues to be an active area of research.5 Over the past
few years, asymmetric versions of this reaction has been
extensively developed using a combination of either chiral
ketenes and achiral imines or achiral ketenes and chiral
imines, generally providing good diastereoselectivity.6
2. Results and discussion
We have been studying the Staudinger reaction for the
diastereoselective construction of the b-lactam ring for
several years.10 In this publication we wish to report our
work on the application of isosorbide derived optically
pure (3aR,4S,6aR)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]-
dioxole-4-carbaldehyde, a bicyclic aldehyde (5) (Scheme 1),
2-((3R,3aR,6S,6aR)-6-acetoxy-hexahydrofuro[3,2-b]furan-3-
yloxy)acetic acid (14) (Scheme 3) and 2-((3S,3aR, 6R,6aR)-
6-methoxy-hexahydrofuro[3,2-b]furan-3-yloxy)acetic acid,
bicyclic acid (21) (Scheme 5) for the synthesis of variously
substituted chiral cis-b-lactams via the Staudinger reaction.
In the diastereoselective synthesis of b-lactams, chiral
starting materials such as aldehydes, acids/acid halides and
amines have been widely used. High levels of
Isosorbide is commercially available in large quantities as
a by-product from the starch industry and it is obtained by
dehydration of D-sorbitol.11 Apart from its nitro derivatives
being used in medicine as vasodilators,12 benzamidines as
factor Xa inhibitors,13 and in spite of its commercial avail-
ability, it has not been fully exploited in the asymmetric
Keywords: Asymmetric synthesis; Staudinger reaction; Ketenes; Imines;
Azetidinones.
* Corresponding author. Tel.: +91 20 39821300; fax: +91 20 39821445;
e-mail: abdulrakeeb.deshmukh@emcure.co.in
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.022

A. L. Shaikh et al. / Tetrahedron 63 (2007) 3380–3388
3381
HO
O
O
O
O
O
a)
b)
I
O
O
O
O
OH
OH
3 (72%)
1
2 (99%)
c)
O
O
O
O
d)
OH
CHO
5 (82%)
O
O
Figure 1. Molecular model of Schiff’s base 7a.
OH
4 (60%)
Scheme 1. Reagents and conditions: (a) TMSCl, NaI, acetone, rt, 12 h; (b)
NaH, THF, rt, 5 h; (c) NaOH, THF reflux, 48 h; (d) NaIO4, SiO2, CH2Cl2,
rt, 6 h.
O
O
a)
5
+
RNH2
6
H
organic syntheses. However, there are some sporadic in-
stances, where it has been transformed to a chiral phase
transfer catalyst,14 chiral aminoalcohols,15 and also used
as a chiral auxiliary.16
O
N
R1
7
6a, R = PMP
6b, R = Bn
6c, R = 4-Cl-Ph
b)
As a part of our ongoing research programme on the appli-
cation of commercially available inexpensive chiral mate-
O
O
10a,c,d,f,17
rials for asymmetric synthesis of b-lactams
we
R2
O
H
H
have used isosorbide as a chiral source for the synthesis of
b-lactams. Isosorbide was stereoselectively transformed to
an iodoalcohol 2 by a known procedure,18 which was further
converted to epoxide 3 by treating with sodium hydride in
THF at 0 ꢀC. The epoxide 3 on reaction with aqueous so-
dium hydroxide in refluxing THF gave diol 4 as a white crys-
talline solid. Our attempt to convert iodoalcohol 2 to diol 4
directly by the treatment with aqueous sodium hydroxide
was unsuccessful. The diol 4 on oxidative cleavage with so-
dium metaperiodate gave (3aR,4S,6aR)-2,2-dimethyl-tetra-
hydrofuro[3,4-d][1,3]dioxole-4-carbaldehyde (5), a chiral
bicyclic aldehyde, in very good overall yield. We envisaged
that the Schiff’s base derived from 5 would give a good dia-
stereoselectivity in the cycloaddition reaction with ketene as
it has a hetero-atom on the b-carbon atom and also the rigid
cis-fused bicyclic ring structure would provide very good fa-
cial selectivity. This is clear from the molecular structure
shown in Figure 1.19 In fact the Schiff’s base derived from
this bicyclic aldehyde 5 on reaction with ketene derived
from methoxyacetyl chloride and triethylamine, gave exclu-
sively a single diastereomer of cis-b-lactam (9a) (Scheme 2).
No trace of the other diastereomer was detected either in the
1H NMR spectrum or from HPLC analysis of the crude reac-
tion product.20 The cis stereochemistry of the b-lactam ring
was ascertained from the coupling constant of the b-lactam
ring protons (J¼5.4 Hz for cis-isomer). The absolute stereo-
chemistry of the newly formed chiral centres was established
as 3S, 4R from the single crystal X-ray analyses21,22 of the b-
lactam 9a (Fig. 2), which was obtained by recrystallization
from ethyl acetate/petroleum ether as colourless cubes.
The generality of this reaction was established by preparing
large number of b-lactams in very good yields and excellent
optical purities (Table 1).
O
N
R1
9a-k
Scheme 2. Reagents and conditions: (a) MgSO4, CH2Cl2, rt, 15 h; (b)
R2OCH2COCl (8), Et3N, CH2Cl2, 0 ꢀC to rt, 15 h.
After establishing the excellent diastereoselectivity in the
cycloaddition reaction of imines derived from isosorbide
and ketenes we were also interested to know the
Figure 2. ORTEP diagram for compound 9a.

3382
A. L. Shaikh et al. / Tetrahedron 63 (2007) 3380–3388
Table 1. Synthesis of azetidin-2-ones (9a–k)
AcO
AcO
HO
H
HO
H
H
H
O
O
O
Entry no. Compd R1
R2
HPLCb purity Yieldc (%)
O
a)
O
O
O
O
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
9g
9h
9i
PMPa
PMP
PMP
PMP
CH2Ph
CH2Ph
CH2Ph
CH2Ph
OCH3 98
74
78
75
75
67
70
60
61
68
71
62
H
H
H
OAc
H
OH
OAc
OH
OBn
OPh
OAc
99
97
97
1
10
11
12
major (60%)
OCH3 95
OBn
OPh
OAc
96
96
96
O
O
H
O
H
O
O
c)
b)
OH
9
10
11
4-Cl-Ph OCH3 98
4-Cl-Ph OBn
4-Cl-Ph OPh
10
O
O
9j
9k
98
97
H
H
OAc
OAc
14 (55%)
13 (87%)
a
PMP¼p-methoxyphenyl.
b
Purity was determined by HPLC analysis on Chromsphere Chromsep 5 C-
18, 250ꢁ4.6 mm (5 mm) column; solvent system (v/v): MeCN/H2O
(60:40), flow rate 1.5 mL/min.
Scheme 3. Reagents and conditions: (a) AcOH, CH2Cl2/DMAP/DCC, rt,
3 h; (b) allyl bromide, Ag2O, CaSO4, 2 days, dark rt; (c) RuCl3, NaIO4,
CH3CN, CCl4, H2O, 0 ꢀC, 6 h.
c
Isolated yields.
as secondary oxidant in CH3CN/CCl4/H2O (2:2:3)25 for
12 h at 0 ꢀC to furnish the desired chiral bicyclic acid 14
in 53% yield (Scheme 3). The Staudinger reaction of this
endo-chiral bicyclic acid 14 with imine 15a in the presence
of Et3N, triphosgene as an acid activator26 in dichloro-
methane at 0 ꢀC to room temperature for 15 h gave a dia-
stereomeric mixture of b-lactams 16a and 17a (w80:20,
diastereoselectivity in the cycloaddition reaction of chiral
ketenes derived from isosorbide and achiral imines. It has
been shown that the two hydroxyl groups present in iso-
sorbide have different reactivities as they are sterically and
electronically different. The C-5 endo-hydroxyl group is in-
volved in intramolecular H-bonding while the other C-2 exo-
hydroxyl group is free (Fig. 3).23 One can selectively acylate
the C-2 hydroxyl groups.24 We have exploited this reactivity
difference and prepared two chiral acetic acid derivatives
from isosorbide and used them as ketene precursors in the
synthesis of b-lactams using Staudinger cycloaddition reac-
tion with various imines.
1
from H NMR of the crude product) (Scheme 4). All our
efforts to purify the major diastereomer by flash column
were unsuccessful. However, the major diastereomer 16a
was obtained in pure form as a white crystalline solid by
crystallization from methanol. The cis stereochemistry of
the b-lactam ring was ascertained from the coupling con-
stant of the ring protons (J¼5.4 Hz for cis-isomer). The
absolute stereochemistry of the newly formed chiral centres
was further established as 3R, 4S from the single crystal
X-ray analyses27 of 16a (Fig. 4).
endo
Hb
O
O
1
5
4
6
2
3
O
OHa
exo
H
H
Figure 3. Structure of isosorbide 1.
The acylation of isosorbide with acetic acid using DCC gave
a mixture monoacetates 10, 11 and diacetate 12 of which the
pure major monoacetate 10 (60%) was separated by column
chromatography. All our efforts to alkylate C-5 endo-hy-
droxyl with ethylbromoacetate using sodium hydride under
various reaction conditions were unsuccessful. Therefore, it
was reacted with allyl bromide in the presence of silver
oxide and calcium sulfate to get the O-allyl-monoacetate-
isosorbide 13 in very good yield. The O-allyl-monoacetate
13 was further oxidized with catalytic RuCl3 and NaIO4
Figure 4. ORTEP diagram for compound 16a.
R2
H
R2
H
R1
H
O
R1
H
O
N
N
H
H
H
H
O
O
O
R1
a)
O
+
N
R2
14
+
O
O
OAc
OAc
15a R1 = Ph, R2 = Ph
15b R1 = 4-Cl-Ph, R2 = Ph
17a R1 = Ph, R2 = Ph
16a R1 = Ph, R2 = Ph (65%)
16b R1 = 4-Cl-Ph, R2 = Ph (68%)
17b R1 = 4-Cl-Ph, R2 = Ph
Scheme 4. Reagents and conditions: (a) triphosgene, Et3N, DCM, 0 ꢀC to rt, 15 h.

A. L. Shaikh et al. / Tetrahedron 63 (2007) 3380–3388
3383
MeO
MeO
MeO
MeO
H
H
H
H
H
H
H
H
O
O
O
O
d)
c)
b)
a)
HO
10
O
O
O
O
O
O
O
OH
OAc
18 (92%)
19 (86%)
21 (51%)
20 (98%)
Scheme 5. Reagents and conditions: (a) CH3I, Ag2O, CaSO4, 2 days, dark rt; (b) KOH, EtOH, 30 min, 50 ꢀC; (c) allyl bromide, Ag2O, CaSO4, 2 days, dark rt; (d)
KMnO4, K2CO3, acetone, rt, 3 h.
As there was moderate selectivity in the cycloaddition
reaction of ketenes derived from endo-acid 14, we also
wanted to examine the selectivity with acid 21 possessing
an exo-acetic acid side chain on C-2 oxygen of the isosor-
bide. This exo-acid 21 can be easily prepared by a synthetic
manipulation as shown in Scheme 5. The monoacetate 10
was methylated using methyl iodide and Ag2O in the pres-
ence of calcium sulfate to get methoxyacetate 18 in 92%
yield. This methoxyacetate 18 was further hydrolysed
with ethanolic potassium hydroxide to give methoxy-
alcohol 19, which was alkylated with allyl bromide under
similar reaction conditions used in the synthesis of 13 to
get an allyl ether 20 in excellent yield. It was oxidized
with KMnO4 in acetone in the presence of K2CO3 to get
chiral bicyclic exo-acid 21 in 51% yield. The asymmetric
Staudinger reaction of chiral bicyclic acid 21 with achiral
imine 15a afforded an inseparable diastereomeric mixture
of two cis-b-lactams 22 and 23 (Scheme 6). In this case
there was no diastereoselectivity in the b-lactam formation
4. Experimental section
4.1. General
1H NMR and 13C NMR spectra were recorded in CDCl3
solution on a Bruker AV 200 or AV 400 spectrometers and
chemical shifts are reported in parts per million downfield
1
from tetramethylsilane for H NMR. Infrared spectra were
recorded on Perkin–Elmer infrared spectrophotometer,
Model 599-B or Shimadzu FTIR-8400 using sodium chlo-
ride optics. Melting points were determined on a Thermonik
Campbell melting point apparatus and were uncorrected.
MS analyses were performed on a Peseiex API QSTAR
Pulsar with an electrospray ionization mass spectrometer
(LC-MS), using MeOH as a solvent (m/z, fragmentor 70 V).
The microanalyses were performed on a Carlo-Erba, CHNS-
O EA 1108 elemental analyzer. Optical rotations were
recorded on an ADP-200 polarimeter under standard condi-
tions. HPLC: HP-1050 Ti series pump, JASCO 970 detector,
at 254 nm connected to HP 3396 series-II integrator;
column: Chromsphere Chromsep 5 C-18, 250ꢁ4.6 mm
(5 mm); solvent system (v/v): MeCN/H2O (60:40), flow
rate 1.5 mL/min.
1
(w50:50 from H NMR of the crude product). All our at-
tempts to separate these isomers either by flash column
chromatography or recrystallization were unsuccessful. A
low diastereoselectivity in the b-lactam formation in case
of exo-ketene was expected, as there is no facial differen-
tiation in the transition state during the ketene–imine
cycloaddition reaction. However, in case of endo-ketene
generated from acid 14, the rigid bicyclic framework of
the isosorbide has considerable effect on the diastereo-
selectivity in the cycloaddition reaction with imine.
4.1.1. (S)-1-((3aR,4R,6aR)-2,2-Dimethyl-tetrahydro-
furo[3,4-d][1,3]dioxol-4-yl)ethane-1,2-diol (4). To the
solution of epoxide 3 (0.5 g, 2.66 mmol) in a mixture of
THF (10 mL) and water (5 mL) was added aqueous NaOH
(1 M, 3.5 mL) and refluxed for 48 h. The THF was then
removed under reduced pressure and the aqueous layer acid-
ified dropwise with dilute HCl (pH¼2) and extracted with
ethyl acetate (3ꢁ10 mL). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated under
reduced pressure to give diol 4 as a white solid (0.330 g,
60%); mp 89–90 ꢀC [Found: C, 52.84; H, 7.82. C9H16O5 re-
quires C, 52.93; H, 7.89%]; [a]2D6 ꢂ40.0 (c 1.0, CHCl3); nmax
(CHCl3) 3433, 1382, 1215 cmꢂ1; dH (200 MHz, CDCl3)
1.32 (3H, s, CH3), 1.49 (3H, s, CH3), 2.45 (2H, br s, OH),
3.47–3.54 (2H, m, CH2OH), 3.79 (2H, t, J 3.6 Hz,
CHCH2O), 4.06–4.13 (2H, m, OCHCHOH), 4.72 (1H,
dd, J 6.2, 3.6 Hz, OCHCH), 4.81 (1H, dd, J 6.2, 3.6 Hz,
OCHCH2O); dC (50 MHz, CDCl3) 24.4, 25.8, 63.5, 70.7,
72.6, 80.6, 81.3, 82.2, 112.4; MS: m/z 204 (M+).
MeO
MeO
H
H
O
O
a)
71%
O
O
Ph
O
O
+
+
21
N
Ph
H
H
O
O
N
N
Ph
H
Ph
H
H
H
Ph
Ph
15a
22
23
Scheme 6. Reagents and conditions: (a) triphosgene, Et3N, DCM, 0 ꢀC to rt,
15 h.
3. Conclusion
In conclusion, we have synthesized bicyclic chiral aldehyde
from isosorbide and the imines derived from this aldehyde
were used in the synthesis of azetidin-2-ones via [2+2] cy-
cloaddition reaction with ketenes. The reaction was highly
stereoselective and in most of the cases a single diastereomer
was obtained in very good yields. The endo-chiral ketene de-
rived from isosorbide also showed diastereoselectivity in the
Staudinger cycloaddition reaction. However, no selectivity
was observed when exo-chiral ketene was used in the cyclo-
addition reaction.
4.1.2. (3aR,4S,6aR)-2,2-Dimethyl-tetrahyrdofuro[3,4-
d][1,3]dioxole-4-carbaldehyde (5). To a vigorously stirred
suspension of chromatographic grade silica (3.3 g) in di-
chloromethane (15 mL) in a 100 mL flask was added aque-
ous solution (0.65 M) of NaIO4 (3.5 mL) dropwise with
stirring. Diol 4 (0.330 g, 1.61 mmol) in dichloromethane
(15 mL) was then added dropwise and the reaction was
stirred at room temperature. The reaction was stirred until
the disappearance of the starting material (5 h, by TLC).

3384
A. L. Shaikh et al. / Tetrahedron 63 (2007) 3380–3388
The reaction mixture was filtered and the filtrate was washed
with water (10 mL), dried over anhydrous Na2SO4 and the
solvent removed under reduced pressure to afford pure bi-
cyclic aldehyde 5 as oil (0.228 g, 82%); [a]2D6 ꢂ97.1 (c
0.2, CHCl3) [Found: C, 55.73; H, 6.96. C8H12O4 requires
C, 55.80; H, 7.02%]; nmax (CHCl3) 1215, 1350,
1737 cmꢂ1; dH (200 MHz, CDCl3) 1.31 (3H, s, CH3), 1.46
(3H, s, CH3), 3.63 (1H, dd, J 10.7, 3.6 Hz, CHaHbOH),
3.97 (1H, d, J 4.8 Hz, CHaHbOH), 4.23 (1H, d, J 10.7 Hz,
OCHCH2O), 4.86 (1H, dd, J 5.9, 3.6 Hz, OCHCH), 5.03
(1H, dd, J 5.9, 4.8 Hz, CHCHO), 9.67 (1H, d, J 1.3 Hz,
CHO); dC (50 MHz, CDCl3) 24.5, 25.8, 73.3, 80.7, 81.8,
85.9, 113.2, 198.4; MS: m/z 172 (M+).
successively with water (2ꢁ10 mL), satd NaHCO3 (10 mL)
and brine (10 mL). The organic layer was dried over anhy-
drous Na2SO4 and concentrated under reduced pressure.
The crude product on purification by flash column chroma-
tography using 20% ethyl acetate/petroleum ether as an elu-
ent gave a single diastereomer, cis-b-lactam 9a as white
crystalline solid (0.300 g, 74%); mp 155–156 ꢀC [Found:
C, 61.70; H, 6.57; N, 4.00. C18H23NO6 requires C, 61.86;
H, 6.64; N, 4.01%]; Rf (20% ethyl acetate/petroleum ether)
0.52; [a]2D6 ꢂ138.8 (c 0.8, CHCl3); nmax (CHCl3)
1745 cmꢂ1; dH (200 MHz, CDCl3) 1.36 (3H, s, CH3), 1.56
(3H, s, CH3), 3.43 (1H, dd, J 10.9, 3.7 Hz, CHaHbOCH),
3.68 (3H, s, OCH3), 3.70 (1H, dd, J 7.5, 3.7 Hz,
CHaHbOCH), 3.79 (3H, s, PhOCH3), 4.09 (1H, d, J
10.9 Hz, OCHCH), 4.52 (1H, dd, J 8.7, 5.4 Hz, C4H), 4.69
(1H, d, J 5.4 Hz, C3H), 4.78 (1H, dd, J 6.1, 3.7 Hz,
OCHCH2), 4.91 (1H, dd, J 6.1, 3.7 Hz, OCHCH), 6.85
(2H, d, J 9.8 Hz, Ar-H), 7.64 (2H, d, J 9.8 Hz, Ar-H); dC
(50 MHz, CDCl3) 24.7, 26.1, 55.4, 58.9, 59.8, 72.7, 80.8,
82.7, 83.1, 112.2, 113.9, 119.5, 131.3, 156.4, 165; MS: m/z
349 (M+).
4.1.3. (E)-N-(((3aS,4R,6aR)-2,2-Dimethyl-tetrahydro-
furo[3,4-d][1,3]dioxol-4-yl)methylene)-4-methoxybenz-
enamine (6a). To a solution of aldehdye 5 (0.210 g,
1.22 mmol) in dichloromethane (20 mL) and anhydrous
MgSO4 (0.307 g, 2.44 mmol) was added p-anisidine
(0.165 g, 1.34 mmol) in dichloromethane (10 mL) at room
temperature and the mixture stirred for 15 h. Then the
reaction mixture was filtered through Celite and the filtrate
was concentrated under reduced pressure to give imine 6a
(0.320 g, 94%) as brown oil; nmax (CHCl3) 1689, 1600,
1500, 1244 cmꢂ1; dH (200 MHz, CDCl3) 1.41 (3H, s,
CH3), 1.50 (3H, s, CH3), 3.75–3.83 (5H, m, CHCH2O and
OCH3), 4.43–4.91 (3H, m, OCHCH2, OCHCHCH]N,
OCHCHCH]N), 6.85–7.06 (2H, m, Ar-H), 7.43–7.48
(2H, m, Ar-H), 8.34 (1H, d, J 1.6 Hz, OCHCHCH]N).
Following the similar procedure other cis-b-lactam 9b–k
were synthesized.
4.1.7. (3S,4R)-3-(Benzyloxy)-4-((3aS,4R,6aR)-2,2-di-
methyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1-(-4-meth-
oxyphenyl)azetidin-2-one (9b). It was purified by flash
column chromatography (20% ethyl acetate/petroleum
ether); yield 78%; colourless oil [Found: C, 67.53; H,
6.28; N, 3.12. C24H27NO6 requires C, 67.74; H, 6.40; N,
3.29%]; Rf (20% ethyl acetate/petroleum ether) 0.47; [a]D26
4.1.4. (E)-N-(((3aS,4R,6aR)-2,2-Dimethyl-tetrahydro-
furo[3,4-d][1,3]dioxol-4-yl)methylene) (phenyl methan-
amine) (6b). Yield 95%; pale yellow oil; nmax (CHCl3)
1683, 1558, 1456, 1217 cmꢂ1; dH (200 MHz, CDCl3)
1.28 (3H, s, CH3), 1.46 (3H, s, CH3), 3.51 (1H, dd, J 10.8,
3.2 Hz, CHCHaHbO), 3.82 (2H, s, CH2Ph); 3.96–4.11
(1H, m, CHCHaHbO), 4.55–4.85 (3H, m, OCHCH2,
OCHCHCH]N, OCHCHCH]N), 7.15–7.30 (5H, m, Ar-
H), 7.89 (1H, d, J 1.6 Hz, OCHCHCH]N).
ꢂ118.1 (c 1, CHCl3); nmax (neat) 1751 cmꢂ1
; dH
(200 MHz, CDCl3) 1.39 (3H, s, CH3), 1.57 (3H, s, CH3),
3.41 (1H, dd, J 10, 3.3 Hz, CHaHbOCH), 3.71–3.77 (1H,
m, CHaHbOCH), 3.79 (3H, s, PhOCH3), 4.12 (1H, d, J
11.5 Hz, OCHaHbPh), 4.55 (1H, d, J 5.4 Hz, C4H), 4.75
(1H, dd, J 5.4, 4.4 Hz, C3H), 4.85 (1H, d, J 11.5 Hz,
OCHaHbPh), 4.92–5.04 (3H, m, OCHCH2, OCHCH,
OCHCH), 6.86 (2H, d, J 8.8 Hz, Ar-H), 7.35–7.41 (5H, m,
Ar-H), 7.67 (2H, d, J 8.8 Hz, Ar-H); dC (50 MHz, CDCl3)
24.6, 26.0, 55.3, 59.0, 72.5, 73.6, 80.7, 83.0, 112.0, 113.8,
119.4, 127.7, 127.9, 128.4, 131.3, 137.2, 156.3, 165; MS:
m/z 425 (M+).
4.1.5. (E)-4-Chloro-N-(((3aS,4R,6aR)-2,2-dimethyl-tetra-
hydrofuro[3,4-d][1,3]dioxol-4-yl)methylene)benzen-
amine (6c). Yield 96%; yellow oil; nmax (CHCl3) 1681,
1600, 1495, 1269 cmꢂ1; dH (200 MHz, CDCl3) 1.45 (3H,
s, CH3), 1.54 (3H, s, CH3), 3.31–4.95 (5H, m, CHCH2O,
OCHCH2, OCHCHCH]N, OCHCHCH]N), 6.53–6.68
(2H, m, Ar-H), 7.09–7.33 (2H, m, Ar-H), 8.35 (1H, d, J
1.6 Hz, OCHCHCH]N).
4.1.8. (3S,4R)-4-((3aS,4R,6aR)-2,2-Dimethyl-tetrahydro-
furo[3,4-d][1,3]dioxol-4-yl)-1-(4-methoxyphenyl)-3-phen-
oxyazetidin-2-one (9c). It was purified by flash column
chromatography (15% ethyl acetate/petroleum ether); yield
75%; white solid; mp 177–178 ꢀC [Found: C, 67.09; H,
6.08; N, 3.28. C23H25NO6 requires C, 67.13; H, 6.13; N,
3.41%]; Rf (15% ethyl acetate/petroleum ether) 0.66; [a]D26
ꢂ224.3 (c 1.2, CHCl3); nmax (nujol) 1747 cmꢂ1; dH
(200 MHz, CDCl3) 1.29 (3H, s, CH3), 1.56 (3H, s, CH3),
3.49 (1H, dd, J 10, 3.5 Hz, CHaHbOCH), 3.81 (3H, s,
PhOCH3), 3.91 (1H, dd, J 8.7, 3.5 Hz, CHaHbOCH), 4.12
(1H, d, J 10.8 Hz, OCHCH), 4.71–4.82 (2H, m, OCHCH2,
OCHCH), 4.95 (1H, dd, J 5.4, 3.6 Hz, C4H), 4.46 (1H, d,
J 5.4 Hz, C3H), 6.88 (2H, d, J 8.6 Hz, Ar-H), 7.35–7.41
(5H, m, Ar-H), 7.72 (2H, d, J 8.6 Hz, Ar-H); dC (50 MHz,
CDCl3) 24.3, 26.0, 55.3, 58.7, 72.8, 80.0, 80.7, 82.8,
112.0, 113.8, 116.2, 119.5, 122.5, 129.4, 131.1, 156.4,
157.8, 163.4; MS: m/z 411 (M+).
The imines 6a–c were used without purification for the next
step.
4.1.6. Typical procedure for the synthesis of (3S,4R)-4-
((3aS,4R,6aR)-2,2-dimethyl-tetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)-3-methoxy-1-(4-methoxyphenyl)aze-
tidin-2-one (9a). A solution of the methoxyacetyl chloride
(0.188 g, 1.73 mmol) in dichloromethane (10 mL) was added
to a cooled solution of imine 6a (0.320 g, 1.15 mmol) and
triethylamine (0.350 g, 3.46 mmol) in anhydrous dichloro-
methane (15 mL) at 0 ꢀC. It was then allowed to warm to
room temperature and stirred for 15 h. The reaction mixture
was then diluted with dichloromethane (10 mL) and washed

A. L. Shaikh et al. / Tetrahedron 63 (2007) 3380–3388
3385
4.1.9. (2R,3S)-2-((3aS,4R,6aR)-2,2-Dimethyl-tetrahydro-
furo[3,4-d][1,3]dioxol-4-yl)-1-(4-methoxyphenyl)-4-oxo-
azetidin-3-yl acetate (9d). It was purified by flash column
chromatography (20% ethyl acetate/petroleum ether); yield
75%; thick oil [Found: C, 60.38; H, 6.08; N, 3.65.
C19H23NO7 requires C, 60.47; H, 6.14; N, 3.71%]; Rf
(20% ethyl acetate/petroleum ether) 0.38; [a]2D6 ꢂ134.1 (c
0.9, CHCl3); nmax (CHCl3) 1750 cmꢂ1; dH (200 MHz,
CDCl3) 1.31 (3H, s, CH3), 1.52 (3H, s, CH3), 2.19 (3H, s,
CH3COO), 3.5 (1H, dd, J 11, 3 Hz, CHaHbOCH), 3.44–
3.79 (1H, m, CHaHbOCH and 3H, s, PhOCH3), 4.31 (1H,
d, J 10.8 Hz, OCHCH), 4.59–4.63 (1H, m, OCHCH2),
4.72–4.89 (2H, m, OCHCH and C4H), 6.24 (1H, d,
J 5.4 Hz, C3H), 6.85 (2H, d, J 8.8 Hz, Ar-H), 7.65 (2H, d,
J 8.8 Hz, Ar-H); dC (50 MHz, CDCl3) 20.6, 24.4, 25.9,
55.3, 58.9, 72.3, 72.7, 80.6, 82.8, 112.5, 113.9, 119.5,
130.9, 156.6, 162.3, 168.3; MS: m/z 377 (M+).
(3H, s, CH3), 3.48 (1H, dd, J 10.8, 3.4 Hz, CHaHbOCH),
3.78 (1H, dd, J 8.8, 3.4 Hz, CHaHbOCH), 4.10–4.19 (2H,
m, OCHCH and OCHCH2), 4.34 (1H, d, J 14.5 Hz,
NCHaHbPh), 4.56–4.58 (1H, m, NCHaHbPh), 4.71–4.82
(2H, m, C4H and OCHCH), 5.26 (1H, d, J 5.5 Hz, C3H),
6.90–7.39 (10H, m, Ar-H); dC (50 MHz, CDCl3) 24.6,
25.9, 30.8, 45.5, 56.5, 73.0, 80.5, 81.0, 82.7, 112.2, 114.6,
116.0, 122.0, 122.2, 127.6, 128.5, 128.8, 137.7, 165.3;
MS: m/z 395 (M+).
4.1.13. (2R,3S)-1-Benzyl-2-((3aS,4R,6aR)-2,2-dimethyl-
tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-4-oxoazetidin-3-
yl acetate (9h). It was purified by flash column chromato-
graphy (15% ethyl acetate/petroleum ether); yield 61%;
thick oil [Found: C, 63.07; H, 6.26; N, 3.78. C19H23NO6 re-
quires C, 63.15; H, 6.41; N, 3.88%]; Rf (15% ethyl acetate/
petroleum ether) 0.33; [a]2D6 ꢂ37.7 (c 1.1, CHCl3); nmax
(neat) 1747 cmꢂ1; dH (200 MHz, CDCl3) 1.27 (3H, s,
CH3), 1.37 (3H, s, CH3), 2.14 (3H, s, CH3COO), 3.48 (1H,
dd, J 10.7, 3.5 Hz, CHaHbOCH), 3.69 (1H, dd, J 8.8,
3.5 Hz, CHaHbOCH), 4.10 (1H, dd, J 8.8, 5.2 Hz, OCHCH),
4.25 (1H, d, J 14.6 Hz, NCHaHbPh), 4.40 (1H, d, J 14.6 Hz,
NCHaHbPh), 4.61–4.78 (3H, m, C4H, OCHCH and
OCHCH2), 5.95 (1H, d, J 5.1 Hz, C3H), 7.27–7.37 (5H, m,
Ar-H); dC (50 MHz, CDCl3) 20.5, 24.5, 25.8, 45.4, 56.1,
72.7, 73.9, 80.3, 81.0, 82.6, 112.6, 127.6, 128.5, 128.7,
164.5, 168.6; MS: m/z 361 (M+).
4.1.10. (3S,4R)-1-Benzyl-4-((3aS,4R,6aR)-2,2-dimethyl-
tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-3-methoxyazeti-
din-2-one (9e). It was purified by flash column chromato-
graphy (10% ethyl acetate/petroleum ether); yield 67%;
thick oil [Found: C, 64.72; H, 6.88; N, 4.13. C18H23NO5 re-
quires C, 64.84; H, 6.95; N, 4.20%]; Rf (10% ethyl acetate/
petroleum ether) 0.33; [a]2D6 ꢂ65.0 (c 1.0, CHCl3); nmax
(CHCl3) 1751 cmꢂ1; dH (200 MHz, CDCl3) 1.30 (3H s,
CH3), 1.39 (3H, s, CH3), 3.42 (1H, dd, J 10.8, 3.4 Hz,
CHaHbOCH), 3.53–3.58 (1H, m, CHaHbOCH), 3.59 (3H,
s, OCH3), 3.91 (1H, dd, J 8.8, 3.4 Hz, OCHCH), 4.04–4.09
(1H, m, OCHCH2), 4.25 (1H, d, J 14 Hz, NCHaHbPh),
4.51 (1H, d, J 4.5 Hz, C3H), 4.70 (1H, d, J 14 Hz,
NCHaHbPh), 4.74–4.76 (2H, m, OCHCH and C4H), 5.25–
5.31 (5H, m, Ar-H); dC (50 MHz, CDCl3) 24.8, 25.9, 45.1,
56.6, 59.4, 72.8, 80.5, 81.0, 83.0, 83.3, 111.3, 127.4,
128.5, 128.8, 167.2; MS: m/z 333 (M+).
4.1.14. (3S,4R)-1-(4-Chlorophenyl)-4-((3aS,4R,6aR)-2,2-
dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-3-me-
thoxyazetidin-2-one (9i). It was purified by flash column
chromatography (10% ethyl acetate/petroleum ether); yield
68%; thick oil [Found: C, 57.68; H, 5.61; N, 3.87; Cl, 9.79.
C17H20NO5Cl requires C, 57.77; H, 5.71; N, 3.97; Cl,
9.90%]; Rf (10% ethyl acetate/petroleum ether) 0.44;
[a]2D6 ꢂ128.0 (c 0.5, CHCl3); nmax (CHCl3) 1749 cmꢂ1
;
4.1.11. (3S,4R)-1-Benzyl-3-(benzyloxy)-4-((3aS,4R,6aR)-
2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)aze-
tidin-2-one (9f). It was purified by flash column chromato-
graphy (15% ethyl acetate/petroleum ether); yield 70%;
thick oil [Found: C, 70.29; H, 6.54; N, 3.33. C24H27NO5 re-
quires C, 70.38; H, 6.65; N, 3.42%]; Rf (15% ethyl acetate/
petroleum ether) 0.32; [a]2D6 ꢂ58.0 (c 1.0, CHCl3); nmax
(neat) 1757 cmꢂ1; dH (200 MHz, CDCl3) 1.31 (3H, s,
CH3), 1.40 (3H, s, CH3), 3.43 (1H, dd, J 11.7, 3.3 Hz,
CHaHbOCH), 3.65 (1H, dd, J 8.3, 3.3 Hz, CHaHbOCH),
3.95 (1H, dd, J 8.3, 5.1 Hz, OCHCH), 4.09 (1H, d, J
10.6 Hz, NCHaHbPh), 4.25 (1H, d, J 14.6 Hz, OCHaHbPh),
4.71–4.77 (5H, m, C3H, C4H, OCHCH2, OCHCH,
NCHaHbPh), 4.92 (1H, d, J 11.6 Hz, OCHaHbPh), 7.26–
7.37 (10H, m, Ar-H); dC (50 MHz, CDCl3) 24.7, 25.9,
45.1, 56.8, 72.7, 73.1, 80.5, 80.9, 81.3, 83.0, 112.1, 127.4,
127.6, 127.8, 128.2, 128.5, 128.7, 136.0, 137.7, 167.3;
MS: m/z 409 (M+).
dH (200 MHz, CDCl3) 1.28 (3H, s, CH3), 1.48 (3H, s,
CH3), 3.35 (1H, dd, J 10.9, 3.4 Hz, CHaHbOCH), 3.60
(3H, s, OCH3), 3.63–3.68 (1H, m, CHaHbOCH), 4.12
(1H, d, J 10.9 Hz, OCHCH), 4.45 (1H, dd, J 8.7, 5.4 Hz,
C4H), 4.62 (1H, d, J 5.4 Hz, C3H), 4.69–4.74 (1H, m,
OCHCH), 4.80–4.89 (1H, m, OCHCH2), 7.18 (2H, d, J
8.6 Hz, Ar-H), 7.59 (2H, d, J 8.6 Hz, Ar-H); dC (50 MHz,
CDCl3) 24.6, 26.1, 59.0, 59.9, 72.7, 80.7, 80.8, 82.8,
83.0, 112.2, 119.4, 128.7, 129.3, 136.3, 165.5; MS: m/z
353 (M+).
4.1.15. (3S,4R)-3-(Benzyloxy)-1-(4-chlorophenyl)-4-
((3aS,4R,6aR)-2,2-dimethyl-tetrahydrofuro[3,4-d]-
[1,3]dioxol-4-yl)azetidin-2-one (9j). It was purified by
flash column chromatography (10% ethyl acetate/petro-
leum ether); yield 71%; thick oil [Found: C, 64.21; H,
5.73; N, 3.19; Cl, 8.09. C23H24NO5Cl requires C, 64.32;
H, 5.64; N, 3.26; Cl, 8.15%]; Rf (10% ethyl acetate/petro-
leum ether) 0.28; [a]2D6 ꢂ117.1 (c 0.7, CHCl3); nmax
(CHCl3) 1755 cmꢂ1; dH (200 MHz, CDCl3) 1.30 (3H, s,
CH3), 1.50 (3H, s, CH3), 3.33 (1H, dd, J 11, 3.4 Hz,
CHaHbOCH), 3.62–3.69 (2H, m, CHaHbOCH, OCHCH),
4.01 (1H, d, J 9.6 Hz, OCHaHbPh), 4.47–4.69 (1H, m,
OCHaHbPh), 4.67–4.72 (1H, m, OCHCH), 4.78–4.94
(3H, m, C3H, C4H and OCHCH2), 7.16–7.58 (7H, m, Ar-
H), 7.60 (2H, d, J 8.6 Hz, Ar-H); dC (100 MHz, CDCl3)
24.6, 26.1, 59.2, 72.6, 73.8, 80.7, 80.8, 83.0, 112.1,
4.1.12. (3S,4R)-1-Benzyl-4-((3aS,4R,6aR)-2,2-dimethyl-
tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-3-phenoxyazeti-
din-2-one (9g). It was purified by flash column chromato-
graphy (5% acetone/petroleum ether); yield 60%; thick
oil [Found: C, 69.73; H, 6.29; N, 3.44. C23H25NO5 requires
C, 69.84; H, 6.38; N, 3.54%]; Rf (5% acetone/petroleum
ether) 0.30; [a]D26 ꢂ70.0 (c 1.0, CHCl3); nmax (neat)
1758 cmꢂ1; dH (200 MHz, CDCl3) 1.23 (3H, s, CH3), 1.40

3386
A. L. Shaikh et al. / Tetrahedron 63 (2007) 3380–3388
119.4, 127.8, 128.0, 128.1, 128.5, 128.7, 129.3, 136.3,
137.0, 165.6; MS: m/z 429 (M+).
ethyl acetate/petroleum ether) to get diastereomeric mixture
of cis-b-lactams 16a and 17a (80:20). A major diastereomer
of white solid 16a (0.153 g, 65%) was obtained in pure form
by recrystallization of diastereomeric mixture from metha-
nol; mp 72–73 ꢀC [Found: C, 67.47; H, 5.66; N, 3.42.
C23H23NO6 requires C, 67.38; H, 5.55; N, 3.35%]; Rf
(30% ethyl acetate/petroleum ether) 0.34; [a]2D6 +66.0 (c
0.20, CHCl3); nmax (CHCl3) 1743, 1735, 1238 cmꢂ1; dH
(200 MHz, CDCl3) 2.06 (3H, s, COOCH3), 3.13–3.28 (3H,
m, OCHCH2 and OCHCH), 3.74 (1H, dd, J 10.5, 5.4 Hz,
OCHCHAc), 3.95 (2H, br d, J 2.8 Hz, OCH2CH), 4.33
(1H, d, J 5.2 Hz, C4H), 5.07 (1H, t, J 2.4 Hz, HCOCHC]O),
5.21 (2H, dd, J 8.2, 5.2 Hz, C3H and HCOCH2COOMe),
7.03–7.43 (10H, m, Ar-H); dC (125 MHz, CDCl3) 20.9,
61.8, 70.6, 73.7, 77.2, 78.3, 78.8, 81.0, 83.1, 86.2, 117.5,
124.5, 128.1, 128.6, 129.1, 133.4, 137.1, 163.3, 170.0; MS:
m/z 410 (M+).
4.1.16. (3S,4R)-1-(4-Chlorophenyl)-4-((3aS,4R,6aR)-2,2-
dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-3-phen-
oxyazetidin-2-one (9k). It was purified by flash column
chromatography (10% ethyl acetate/petroleum ether); yield
62%; thick oil [Found: C, 63.48; H, 5.22; N, 3.29; Cl,
8.45. C22H22NO5Cl requires C, 63.54; H, 5.33; N, 3.37;
Cl, 8.52%]; Rf (10% ethyl acetate/petroleum ether) 0.34;
[a]2D6 ꢂ117.9 (c 0.6, CHCl3); nmax (CHCl3) 1764 cmꢂ1; dH
(200 MHz, CDCl3) 1.23 (3H, s, CH3), 1.50 (3H, s, CH3),
3.43 (1H, dd, J 10.0, 3.6 Hz, CHaHbOCH), 3.84 (1H, dd,
J 10.0, 3.6 Hz, CHaHbOCH), 4.08 (1H, d, J 11.0 Hz,
OCHCH), 4.69–4.76 (2H, m, OCHCH and OCHCH2),
4.90 (1H, dd, J 5.8, 3.6 Hz, C4H), 5.41 (1H, d, J 5.8 Hz,
C3H), 6.77–7.31 (7H, m, Ar-H), 7.66 (2H, d, J 8.9 Hz, Ar-
H); dC (100 MHz, CDCl3) 24.4, 26.0, 58.9, 72.9, 80.2,
80.7, 80.8, 112.3, 114.6, 115.2, 119.6, 121.8, 122.7, 128.8,
129.6, 136.2, 169.5; MS: m/z 415 (M+).
4.1.19. (3S,3aR,6R,6aR)-6-((3R,4S)-1-(4-Chlorophenyl)-
2-oxo-4-phenylazetidin-3-yloxy)hexahydrofuro[3,2-b]-
furan-3-yl acetate (16b). A single diastereomer was
obtained by flash column chromatography; yield 68%; thick
oil [Found: C, 62.16; H, 4.87; N, 3.08; Cl, 7.91.
C23H22NO6Cl requires C, 62.24; H, 4.99; N, 3.15; Cl,
7.99%]; Rf (30% ethyl acetate/petroleum ether) 0.44; [a]D26
+73 (c 0.2, CHCl3); nmax (CHCl3) 1747, 1737, 1494,
1244 cmꢂ1; dH (200 MHz, CDCl3) 2.15 (3H, s, COOCH3),
3.74–4.15 (4H, m, OCHCH2 and OCH2CH), 4.55–4.66
(2H, m, OCHCH and OCHCHCAc), 4.68 (1H, d, J 4.8 Hz,
C4H), 4.90 (1H, t, J 3.8 Hz, HCOCHC]O), 5.18–5.26
(2H, m, C3H and HCOCH2COOMe), 7.33–7.48 (9H, m,
Ar-H); dC (100 MHz, CDCl3) 20.9, 64.0, 70.2, 73.9, 77.2,
78.0, 78.3, 85.9, 86.0, 90.2, 118.8, 126.1, 129.1, 129.4,
129.6, 135.4, 135.6, 163.7, 170.0; MS: m/z 444 (M+).
4.1.17. ((3R,3aR,6S,6aR)-6-Acetoxy-hexahydrofuro[3,2-
b]furan-3-yloxy)acetic acid (14). To a solution of the 2-
O-acetyl-5-O-allyl-1,4:3,6-dianhydro-D-glucitol 13 (1.0 g,
4.38 mmol) in the mixture of solvent CH3CN/CCl4/H2O
(2:2:3, 30 mL), powdered NaIO4 (2.8 g, 13.2 mmol) was
added followed by catalytic amount of hydrated RuCl3
(5 mg) at 0 ꢀC. The reaction mixture was stirred for 6 h at
this temperature. After completion of the reaction (TLC),
the reaction mixture was diluted with water (10 mL) and ex-
tracted with dichloromethane (3ꢁ10 mL). The organic layer
was washed with saturated NaHCO3 (10 mL) and the alka-
line extract was neutralized with dilute HCl (10%) and again
extracted with ethyl acetate (3ꢁ10 mL). The organic layer
was washed with water (10 mL), brine (10 mL) and dried
over anhydrous Na2SO4. The solvent was removed under re-
duced pressure to get pure endo-bicyclic acid 14 (0.57 g,
53%) as pale yellow oil [Found: C, 48.78; H, 5.73.
C10H14O7 requires C, 48.71; H, 5.64%]; [a]2D6 +89.7 (c
4.1.20. (3S,3aR,6R,6aR)-3-(Allyloxy)-6-methoxy-hexa-
hydrofuro[3,2-b]furan (20). To a solution of 2-O-methyl-
5-O-hydroxy-1,4:3,6-dianhydro-D-glucitol
19
(3.7 g,
23.12 mmol) in freshly distilled allyl bromide (40 mL)
were added Ag2O (7.07 g, 30.52 mmol) and CaSO4 (15 g).
The resulting suspension was stirred for 2 days in the dark
at room temperature, then diluted with ether (100 mL),
filtered through Celite and concentrated under reduced pres-
sure to give the crude product as a brown oil. It was purified
by column chromatography (20% ethyl acetate/petroleum
ether) to get 2-O-methyl-5-O-allyl-1,4:3,6-dianhydro-D-glu-
citol 20 (4.54 g, 98%) as a pale yellow oil [Found: C, 59.87;
H, 7.95. C10H16O4 requires C, 59.98; H, 8.05%]; Rf (40%
ethyl acetate/petroleum ether) 0.64; [a]2D6 +91 (c 0.37,
CHCl3); nmax (neat) 1735, 1647, 1463, 1220 cmꢂ1; dH
(200 MHz, CDCl3) 3.46 (3H, s, OCH3), 3.52–3.63 (1H,
m, OCHCH), 3.87–4.05 (7H, m, OCHCH2, OCH2CH,
OCHCHO-olefin and OCH2CH]C), 4.52 (1H, dd, J 4.2,
1.0 Hz, HCOMe), 4.67 (1H, t, J 4.2 Hz, HCO-olefin),
5.15–5.33 (2H, m, HC]CH2), 5.79–5.98 (1H, m, HC]
CH2); dC (50 MHz, CDCl3) 57.9, 69.4, 70.2, 73.4, 79.6,
81.5, 83.4, 86.0, 117.1, 133.9; MS: m/z 201 (M+).
0.75, CHCl3); nmax (CHCl3) 3300, 1731, 1371, 1238 cmꢂ1
;
dH (200 MHz, CDCl3) 2.08 (3H, s, COOCH3), 3.80–4.29
(7H, m, OCHCH2, OCH2CH, OCH2COOH, OCHCH),
4.51 (1H, d, J 4.3 Hz, OCHCH), 4.75 (1H, t, J 4.3 Hz,
HCOCH2COOH), 5.19–5.20 (1H, m, HCOCH2COOMe),
6.91 (1H, br s, OH); dC (50 MHz, CDCl3) 20.8, 68.1, 70.9,
73.8, 78.1, 80.5, 81.2, 86.0, 170.0, 172.5; MS: m/z 247 (M+).
4.1.18. (3S,3aR,6R,6aR)-6-((3R,4S)-2-Oxo-1,4-diphenyl-
azetidin-3-yloxy)hexahydrofuro[3,2-b]furan-3-yl acetate
(16a). To a stirred solution of the endo-bicyclic acid 14
(0.142 g, 0.57 mmol), imine 15a (0.104 g, 0.57 mmol) and
dry triethylamine (0.174 g, 1.73 mmol) in anhydrous di-
chloromethane (10 mL), a solution of triphosgene (0.085 g,
0.29 mmol) in dichloromethane was added dropswise at
0 ꢀC. The reaction mixture was allowed to come to room
temperature and stirred at this temperature for 15 h. After
completion of the reaction (TLC), the reaction mixture was
diluted with dichloromethane (10 mL) and washed succes-
sively with water (3ꢁ10 mL), saturated bicarbonate solution
(3ꢁ10 mL) and brine (15 mL), and the organic layer was
dried over anhydrous Na2SO4. The solvent was removed un-
der reduced pressure to get the crude product as a brown oil,
which was purified by flash column chromatography (30%
4.1.21. ((3S,3aR,6R,6aR)-6-Methoxy-hexahydrofuro[3,2-
b]furan-3-yloxy)acetic acid (21). 2-O-Methyl-5-O-allyl-
1,4:3,6-dianhydro-D-glucitol 20 (0.5 g, 2.50 mmol) was
dissolved in anhydrous acetone (10 mL) and potassium
carbonate (0.025 g) was added. This mixture was cooled to

A. L. Shaikh et al. / Tetrahedron 63 (2007) 3380–3388
3387
0 ꢀC and then powdered potassium permanganate (1.0 g,
6.32 mmol) was added portionwise with stirring for about
1–2 h at 0–5 ꢀC. The reaction mixture was stirred at room
temperature for 3 h and filtered through Buchner funnel.
The manganese dioxide residue was washed with acetone
and then extracted with hot water (3ꢁ10 mL). The aqueous
alkaline extract was cooled and acidified with 10% concd
HCl, saturated with NaCl and extracted with dichlorome-
thane (3ꢁ20 mL). The dichloromethane extract was washed
with saturated brine solution (10 mL), dried over anhydrous
Na2SO4 and concentrated under reduced pressure to get pure
exo-bicyclic acid 21 (0.280 g, 51%) as colourless oil [Found:
C, 49.48; H, 6.40. C9H14O6 requires C, 49.54; H, 6.46%];
[a]2D6 +35.9 (c 0.27, CHCl3); nmax (neat) 3469, 1741, 1647,
1463, 1217 cmꢂ1; dH (200 MHz, CDCl3) 3.45 (3H, s,
OCH3), 3.52–3.63 (1H, m, OCHCH), 3.89–4.17 (7H, m,
OCHCH2, OCH2CH, OCHCHOCH2COOH and OCH2-
COOH), 4.58 (1H, d, J 4.3 Hz, HCOMe), 4.71 (1H, t, J
4.3 Hz, HCCH2COOH), 6.62 (1H, br s, OH); dC (50 MHz,
CDCl3) 58.2, 69.8, 73.1, 75.7, 79.9, 81.6, 84.9, 85.8,
177.2; MS: m/z 219 (M+).
A.S.K. thank Council of Scientific and Industrial Research
(CSIR), New Delhi, for Research Fellowships.
References and notes
€
1. For reviews on b-lactam antibiotics, see: (a) Durkheimer, W.;
Blumbach, J.; Lattrell, R.; Scheunemann, K. H. Angew.
Chem., Int. Ed. Engl. 1985, 24, 180–202; (b) Chemistry and
Biology of b-Lactam Antibiotics; Morin, R. B., Gorman, M.,
Eds.; Academic: New York, NY, 1982; Vols. 1–3; (c)
Coulton, S.; Hunt, E. Recent Progress in the Chemical
Synthesis of Antibiotics and Related Microbial Products;
Lukacs, G., Ed.; Springer: Berlin, 1993; Vol. 2, p 621; (d)
Southgate, R. Contemp. Org. Synth. 1994, 1, 417–431.
2. The Chemistry of b-lactams; Page, M. I., Ed.; Chapman and
Hall: London, 1992.
3. For comprehensive general reviews, see: (a) Koppel, G. A.
Small Ring Heterocycles; Hasner, A., Ed.; Wiley: New York,
NY, 1983; Vol. 42, p 219; (b) Backes, J. Houben-Weyl,
Methoden der Organischem Chemie; Muller, E., Bayer, O.,
Eds.; Thieme: Stuttgart, 1991; Band E16B, p 31; (c)
DeKimpe, N. Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Padwa, A.,
Eds.; Pergamon: Oxford, 1996; Vol. 1B, p 507; (d) Alcaide,
B.; Almendros, P. Curr. Org. Chem. 2002, 6, 245–264.
4. Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51–123.
5. (a) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Curr.
Med. Chem. 2004, 11, 1837–1872; (b) Singh, G. S. Tetrahedron
2003, 59, 7631–7649 and references cited therein; (c) Alcaide,
B.; Almendros, P. Chem. Soc. Rev. 2001, 30, 226–240; (d)
Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oirabide, M. Eur. J.
Org. Chem. 1999, 8, 3223–3235; (e) Palomo, C.; Aizpurua,
J. M. Chem. Heterocycl. Compd. 1998, 34, 1222–1236; (f)
Palomo, C.; Aizpurua, J.; Mielgo, A.; Linden, A. J. Org.
Chem. 1996, 61, 9186–9195.
4.1.22. Diastereomeric mixture of b-lactams 22 and 23.
To a stirred solution of the exo-bicyclic acid 21 (0.145 g,
0.66 mmol), imine 15a (0.120 g, 0.66 mmol) and dry tri-
ethylamine (0.201 g, 1.99 mmol) in anhydrous dichloro-
methane (10 mL), a solution of triphosgene (0.098 g,
0.33 mmol) in dichloromethane was added dropswise at
0 ꢀC. The reaction mixture was allowed to come to room
temperature and stirred at this temperature for 15 h. After
completion of the reaction (TLC), the reaction mixture
was diluted with dichloromethane (10 mL) and washed suc-
cessively with water (3ꢁ10 mL), saturated bicarbonate solu-
tion (3ꢁ10 mL) and brine (15 mL), and the organic layer
was dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure to get the crude product as a yellow
solid. It was purified by flash column chromatography (30%
ethyl acetate/petroleum ether) to get diastereomeric mixture
of b-lactams 22 and 23 (0.180 g, 71%). After recrystalliza-
tion through methanol, it was obtained as a white solid, which
was an inseparable diastereomeric mixture of b-lactams
(50:50); Rf (30% ethyl acetate/petroleum ether) 0.60; mp
175–176 ꢀC; nmax (CHCl3) 1757, 1500, 1338 cmꢂ1; dH
(400 MHz, CDCl3) 3.27 (1H, dd, J 10.3, 2.0 Hz, OCHaCH),
3.37 (3H, s, OCH3), 3.41 (3H, s, OCH3), 3.42–3.54 (3H, m,
OCHCH2, OCHaHbCH), 3.68–3.72 (1H, m, OCHaHbCH),
3.77–4.02 (9H, m, OCHCH2, OCH2CH, OCHbCH, OCH-
CHa, OCHCHb, HaCOCHC]O and C4Ha), 4.52 (1H, t,
J 4.2 Hz, HbCOCHC]O), 4.59 (1H, d, J 4.2 Hz, C4Hb),
5.05 (2H, dd, J 13.3, 4.7 Hz, C3Ha and HaCOMe), 5.25
(2H, dd, J 7.5, 4.7 Hz, C3Hb and HbCOMe), 7.24–7.42
(20H, m, Ar-H); dC (100 MHz, CDCl3) 58.0, 58.1, 62.0,
62.4, 69.6, 69.7, 73.0, 73.4, 77.2, 79.5, 79.9, 81.6, 81.7,
82.7, 83.3, 84.6, 85.6, 85.9, 86.0, 117.6, 124.6, 128.0,
128.3, 128.6, 128.8, 128.9, 129.1, 133.1, 133.5, 136.9,
163.6, 163.8.
6. For reviews on asymmetric Staudinger reaction, see: (a)
Cooper, R. D. G.; Daugherty, B. W.; Boyd, D. B. Pure Appl.
Chem. 1987, 59, 485–492; (b) Van der Steen, F. H.; Van
Koten, G. Tetrahedron 1991, 47, 7503–7524; (c) Georg, G. I.;
Ravikumar, V. T. The Organic Chemistry of b-lactams; VCH:
New York, NY, 1993; p 295.
7. (a) Bose, A. K.; Womelsdorf, J. F.; Krishnan, L.; Urbanczyk-
Lipkowska, Z.; Shelly, D. C.; Manhas, M. S. Tetrahedron
1991, 47, 5379–5390; (b) Kawabata, T.; Kimura, Y.; Ito, Y.;
Tereshima, S.; Sasaki, A.; Sanagawa, M. Tetrahedron 1988,
44, 2149–2165.
8. Bose, A. K.; Manhas, M. S.; Van derVeen, J. M.; Bari, S. S.;
Wagle, D. R. Tetrahedron 1992, 48, 4831–4844.
9. (a) Hubschwerlen, C.; Schmid, G. Helv. Chim. Acta 1983, 66,
2206–2209; (b) Bose, A. K.; Manhas, M. S.; Van derVeen,
J. M.; Bari, S. S.; Wagle, D. R. Tetrahedron Lett. 1985, 26,
33–36; (c) Palomo, C.; Cossio, F. P.; Cuevas, C. Tetrahedron
Lett. 1991, 32, 3109–3110.
10. (a) Jayaraman, M.; Deshmukh, A. R. A. S.; Bhawal, B. M.
J. Org. Chem. 1994, 59, 932–934; (b) Srirajan, V.;
Deshmukh, A. R. A. S.; Puranik, V. G.; Bhawal, B. M.
Tetrahedron: Asymmetry 1996, 7, 2733–2738; (c) Bhawal,
B. M.; Joshi, S. N.; Krishnaswamy, D.; Deshmukh,
A. R. A. S. J. Indian Inst. Sci. 2001, 81, 265–276; (d) Arun,
M.; Joshi, S. N.; Puranik, V. G.; Bhawal, B. M.; Deshmukh,
A. R. A. S. Tetrahedron 2003, 59, 2309–2316; (e) Jayanthi,
A.; Puranik, V. G.; Deshmukh, A. R. A. S. Synlett 2004,
Acknowledgements
The authors thank Department of Science and Technology
(DST), New Delhi for financial support and Mrs. S. S. Kunte
for the HPLC analyses of all new b-lactams. A.L.S. and

3388
A. L. Shaikh et al. / Tetrahedron 63 (2007) 3380–3388
1249–1253; (f) Jayanthi, A.; Thiagrajan, K.; Puranik, V. G.;
on Bruker SMART APEX CCD diffractometer using Mo Ka
radiation with fine focus tube with 50 kV and 30 mA. Crystal
to detector distance was 6.05 cm, 512ꢁ512 pixels/
frame, hemisphere data acquisition. Total scans¼3, total
frames¼1271, oscillation/frame ꢂ0.3ꢀ, exposure/frame¼
5.0 s/frame, maximum detector swing angle¼ꢂ30.0ꢀ, beam
centre¼(260.2, 252.5), in plane spot width¼1.24, SAINT inte-
gration, q range¼2.23–25.00ꢀ, completeness to q of 25.00ꢀ is
99.9%. C18H23NO6, M¼349.37. Crystals belong to orthorhom-
bic, space group P212121, a¼12.4688(7), b¼10.7999(6),
Bhawal, B. M.; Deshmukh, A. R. A. S. Synthesis 2004, 18,
2965–2974; (g) Shaikh, A. L.; Puranik, V. G.; Deshmukh,
A. R. A. S. Tetrahedron 2005, 61, 2441–2451; (h) Shaikh,
A. L.; Puranik, V. G.; Deshmukh, A. R. A. S. Tetrahedron
Lett. 2006, 47, 5993–5996.
11. (a) Sheldon, R. A. Chirotechnology: Industrial Synthesis of
Optically Active Compounds; Marcel Dekker: New York, NY,
ꢀ
1993; pp 145–146; (b) Fleche, G.; Huchette, H. Starch/sta€rke
1986, 38, 26–30.
3
3
˚
˚
12. (a) Thatcher, G. R. J. Curr. Top. Med. Chem. 2005, 5, 597–601;
(b) Ravikumar, K. S.; Chadrasekaran, S. Synthesis 1994, 1032–
1034; (c) Seemayer, R.; Bar, N.; Schneider, M. P. Tetrahedron:
Asymmetry 1992, 3, 1123–1126; (d) Sandrock, K; Gunther, C.
German Patent 2903927, 1980; Sanol Schwarz Monheim
GmbH. Chem. Abstr. 1980, 93, 239846; (e) Stoss, P.
European Patent 57847, 1981; Heinrich Mack Nachf. Chem.
Abstr. 1983, 98, 54395; (f) Stoss, P. German Patent 3124410,
1981; Heinrich Mack Nachf. Chem. Abstr. 1983, 98, 161103.
13. (a) Volger, M.; Koert, U.; Dorsch, D.; Gleitz, J.; Raddatz, P.
Synlett 2003, 1683–1687; (b) Volger, M.; Koert, U.; Harms,
K.; Dorsch, D.; Gleitz, J.; Raddatz, P. Synthesis 2004,
1211–1228.
14. Kumar, S.; Ramachandran, U. Tetrahedron 2005, 61, 4141–
4148.
15. Tamion, R.; Marsais, F.; Ribereau, P.; Queguiner, G.;
Abenhaim, D.; Loupy, A.; Munnier, L. Tetrahedron:
Asymmetry 1993, 4, 1879–1890.
16. (a) Loupy, A.; Monteux, D. A. Tetrahedron 2002, 58, 1541–
1549; (b) Xu, Ming-Hua; Wang, W.; Xia, Li-Jun; Lin, G.-Q.
J. Org. Chem. 2001, 66, 3953–3962; (c) Loupy, A.; Monteux,
D. A. Tetrahedron Lett. 1996, 37, 7023–7026; (d) Tamion,
R.; Marsais, F.; Ribereau, P.; Queguiner, G. Tetrahedron:
Asymmetry 1993, 4, 2415–2418.
c¼13.3993(8) A, V¼1804.4(2) A , Z¼4, Dc¼1.286 Mg/m ,
m(Mo Ka)¼0.097 mmꢂ1, T¼293(2) K, out of 9153 collected,
3170 are unique reflections [I>2s(I)]. All the data were
corrected for Lorentzian, polarization and absorption effects.
The structure was solved by direct methods using
SHELXTL. SHELX-97 (ShelxTL)22 was used for structure so-
lution and full matrix least squares refinement on F2. Hydrogen
atoms were included in the refinement as per the riding model.
Least squares refinement of scale, positional and anisotropic
thermal parameters for non-hydrogen atom converged to
R¼0.0406, wR2¼0.0985 for 3170 unique observed reflections.
X-ray analysis revealed the stereochemistry of the compound
to be 3S, 4R at C3 and C4, respectively. The crystal structure
for 9a has been deposited at the Cambridge Crystallographic
Data Centre and allocated the deposition number CCDC
606925.
22. Sheldrick, G. M. SHELX-97 Program for Crystal Structure
Solution and Refinement; University of Gottingen: Gottingen,
Germany, 1997.
23. Abenhaim, D.; Loupy, A.; Munnier, L.; Tamion, R.; Marsais,
F.; Queguiner, G. Carbohydr. Res. 1994, 261, 255–266.
24. Cekovic, Z.; Tokic, Z. Synthesis 1989, 610–612.
25. Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J. Org. Chem. 1981, 46, 3936–3938.
17. (a) Srirajan, V.; Puranik, V. G.; Deshmukh, A. R. A. S.; Bhawal,
B. M. Tetrahedron 1996, 52, 5579–5584; (b) Jayaraman, M.;
Deshmukh, A. R. A. S.; Bhawal, B. M. Tetrahedron 1996,
52, 8989–9004; (c) Shinkre, B. A.; Puranik, V. G.; Bhawal,
B. M.; Deshmukh, A. R. A. S. Tetrahedron: Asymmetry
2003, 14, 453–459.
18. (a) Ejjiyar, S.; Saluzzo, C.; Amouroux, R.; Massoui, M.
Tetrahedron Lett. 1997, 38, 1575–1576; (b) Ejjiyar, S.;
Saluzzo, C.; Amouroux, R. Org. Synth. 2000, 77, 91–97.
19. This molecular structure is drawn by using software pro-
gramme Chem 3D Pro.
20. The purity of all new b-lactams was determined by HPLC:
HP-1050 Ti series pump; detector: JASCO 970 (at 254 nm)
connected to integrator: HP-3396 series-II; column: Chrom-
sphere Chromsep 5 C-18, 250ꢁ4.6 mm (5 mm); solvent system
(v/v): MeCN/H2O (60:40), flow rate 1.5 mL/min.
21. X-ray diffraction data for compound 9a: Single crystals of the
compound 9a were grown by slow evaporation of ethyl acetate
and petroleum ether (8:2) solution. Colourless cubes of approx-
imate size 0.45ꢁ0.40ꢁ0.40 mm were used for data collection
26. Krishnaswamy, D.; Bhawal, B. M.; Deshmukh, A. R. A. S.
Tetrahedron Lett. 2000, 41, 417–419.
27. X-ray diffraction data for compound 16a: X-ray structure deter-
mination of C23H23NO6: colourless needles 0.33ꢁ0.02ꢁ
0.02 mm grown from methanol. M¼409.42, orthorhombic,
˚
˚
˚
ꢂ1
P212121, a¼6.623(2) A, b¼9.627(3) A, c¼32.182(10) A,
3
3
˚
V¼2052.0(12) A , Z¼4, D¼1.325 Mg/m , m¼0.096 mm
,
F(000)¼864, T¼293 K. Data were collected on SMART
APEX CCD single crystal X-ray diffractometer using Mo Ka
ꢀ
˚
radiation (l¼0.7107 A) to a maximum q range of 23.49 . The
structure was solved by direct methods using SHELXTL.22
Least squares refinement of scale, positional and anisotropic
thermal parameters for non-hydrogen atom converged to
R¼0.0898, Rw¼0.1746 for 3039 unique observed reflections.
Hydrogen atoms were geometrically fixed. The refinements
were carried out using SHELXL-97. X-ray analysis revealed
the stereochemistry of the compound to be 3R, 4S at C3 and
C4, respectively. The crystal structure for 16a has been depos-
ited at the Cambridge Crystallographic Data Centre and allo-
cated the deposition number CCDC 620045.