Sequential staudinger ketene-imine cycloaddition, RCM approach to highly rigid macrocrocyclic bisazetidinones

Article abstract of DOI:10.1021/jo100679d

(Figure presented) An efficient approach to highly rigid macrocyclic bisazetidinones with interesting structural feature was achieved via sequential Staudinger ketene-imine cycloaddition of o-allyloxyphenoxyketene and bis-arylidenediamines followed by RCM

Full text of DOI:10.1021/jo100679d

pubs.acs.org/joc
Sequential Staudinger Ketene-Imine Cycloaddition, RCM Approach to
Highly Rigid Macrocrocyclic Bisazetidinones
Yehia A. Ibrahim,* Talal F. Al-Azemi, and Mohamed D. Abd El-Halim
Chemistry Department, Faculty of Science, Kuwait University, P.O. Box 5969, Safat 13060, Kuwait
yehiaai@kuc01.kuniv.edu.kw
Received April 9, 2010
An efficient approach to highly rigid macrocyclic bisazetidinones with interesting structural feature
was achieved via sequential Staudinger ketene-imine cycloaddition of o-allyloxyphenoxyketene and
bis-arylidenediamines followed by RCM. The ketene-imine cycloaddition afforded the correspond-
ing bis-o-allyloxyphenoxyazetidinones as the cis-cis diastereomers, exclusively obtained as a mixture
of cis-syn-cis and cis-anti-cis. RCM of the latter using Grubbs’ catalysts afforded good yields of the
corresponding novel macrocyclic bisazetidinones. The cis-anti-cis bisazetidinones are readily identi-
fied by 1H NMR using Eu(hfc)3 chiral shift reagent. 1H NMR indicated the high shielding effect of the
aryl substituents on one of the ortho-H’s of the condensed phenylene ring, and VT 1H NMR indicates
the highly restricted rotation of the aryl groups, thus offering a highly rigid system.
Introduction
synthesize a large number of macrocycles of variable ring
sizes.1
Crown compounds, azacrown compounds, and crown
ethers incorporating amide groups find many interesting
applications in diverse fields of supramolecular chemistry.1
During our recent interest in the synthesis of macrocyclic
polyethers moiety, we and others successfully applied the
ring-closing metathesis (RCM) technique to efficiently
The Staudinger [2 þ 2] ketene-imine cycloaddition reaction
is considered as one of the most important synthetic app-
roaches to β-lactams (2-azetidinones), which have important
applications in pharmaceutical and synthetic chemistry.2-4
(2) Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51–123.
(3) (a) Tidwell, T. T. Eur. J. Org. Chem. 2006, 563–568. (b) Fu, N.;
Tidwell, T. T. Tetrahedron 2008, 64, 10465–10496. (c) Xu, J. Arkivoc 2009,
No. iv, 21–44. (d) Jiao, L.; Zhang, Q. F.; Liang, Y.; Zhang, S. W.; Xu, J. X.
J. Org. Chem. 2006, 71, 815–818. (e) Wang, Y.; Liang, Y.; Jaoo, L.; Du, D-M;
Xu, J. X. J. Org. Chem. 2006, 71, 6983–6990. (f) Jiao, L.; Liang, Y.; Zhang,
Q.; Zhang, S.; Xu, J. Synthesis 2006, 659–665. (g) Jiao, L.; Liang, Y.; Xu, J. X.
J. Am. Chem. Soc. 2006, 128, 6060–6069. (h) Liang, Y.; Zhang, S. W.; Xu,
J. X. J. Org. Chem. 2005, 70, 334–337. (i) Lee, E. G.; Hodous, B. L.; Bergan,
E.; Shih, C.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 11586–11587.
(1) (a) Ibrahim, Y. A.; Behbehani, H.; Ibrahim, M. R. Tetrahedron Lett.
2002, 43, 4207–4210. (b) Behbehani, H.; Ibrahim, M. R.; Ibrahim, Y. A.
Tetrahedron Lett. 2002, 43, 6421–6426. (c) Ibrahim, Y. A.; Behbehani, H.;
Ibrahim, M. R.; Abrar, N. M. Tetrahedron Lett. 2002, 43, 6971–6974.
(d) Ibrahim, Y. A.; Behbehani, H.; Ibrahim, M. R.; Malhas, R. N. Tetra-
hedron 2003, 59, 7273–7282. (e) Ibrahim, Y. A.; Behbehani, H.; Khalil, N. S.
Tetrahedron 2004, 60, 8429–8436. (f) Ibrahim, Y. A.; John, E. Tetrahedron
2006, 62, 1001–1014. (g) Ibrahim, Y. A. J. Mol. Catal. A: Chemical 2006, 254,
43–52. (h) Malhas, R. N.; Ibrahim, Y. A. Synthesis 2006, 3261–3269.
ꢀ
(4) Sierra, M. A.; Pellico, D.; Gomez-Gallego, M.; Mancheno, M. J.;
Torres, R. J. Org. Chem. 2006, 71, 8787–8793. and references therein.
4508 J. Org. Chem. 2010, 75, 4508–4513
Published on Web 06/10/2010
DOI: 10.1021/jo100679d
r
2010 American Chemical Society

Ibrahim et al.
JOCArticle
SCHEME 1
SCHEME 2
This reaction has been used to construct macrocyclic bisaze-
tidinone polyethers by the reaction of the appropriate ketene
precursors with macrocyclic diimines (Scheme 1).4,5
fused to the macrocycle through the 1,3-positions of the
azetidinone ring (Scheme 3). Thus, treatment of N,N0-bis-
aryliden-1,2-ethanediamines 1a, 2a, 3a, 4a, and 5a with
o-allyloxyphenoxyacetyl chloride in CH2Cl2 in the presence
of triethylamine gave a mixture of cis-anti-cis (racemic) 6a, 7a,
8a, 9a, and 10a and cis-syn-cis (meso) 11a, 12a, 13a, 14a, and
15a diastereomers. These stereoisomers were successfully
separated by column chromatography. On the other hand,
similar treatment of N,N0-bis-arylidene-3,6-dioxaoctane-
1,8-diamines 1b, 3b, and 4b gave inseparable mixtures of
the corresponding cis-anti-cis (racemic) 6b, 8b, and 9b and
cis-syn-cis (meso) 11b, 13b, and 14b diastereomers. Table 1
shows the diastereomeric ratio obtained and the character-
istic 1H and 13C NMR signals of these novel acyclic isomeric
bisazetidinone derivatives.
RCM of 6a-15a was succefully achieved with Grubbs’ cata-
lyst I to give a mixture of the corresponding E,Z isomers at the
olefinic double bond, which were readily characterized from
their 1H and 13C NMR (Table 2, entries 2, 4, 6, 8, 10, 12, 14, 16,
18, 20). On the other hand RCM with Grubbs’ catalyst II gave
only the corresponding E isomers (Table 2, entries 1, 3, 5, 7, 9,
11, 13, 15, 17, 19). The E,Z isomers of the olefinic double bonds
were readily assigned, and their ratios were determined from
the 1H NMR and 13C NMR spectra. The E isomers show the
characteristic 13C signal of the OCH2 (of the OCH2CHd
CHCH2O) at frequency lower than that for the corresponding
Z isomer (cf. the experimental data in Supporting Information).
Similar RCM results were obtained when the mixture of
each of the enatiomers 6b, 11b and 8b, 13b and 9b, 14b were
treated with either Grubbs’ I or Grubbs’ II catalysts. How-
ever, because of the complexity of the four products mix-
tures obtained in each case with Grubbs’ I catalyst, results
Recently, we reported the sequential application of
Staudinger [2 þ 2] ketene-imine cycloaddition followed by
RCM to construct macrocyclic bisazetidinone polyethers
(Scheme 2).6 Subsequently the same procedure has then been
applied for the synthesis of macrocyclic bisazetidinone poly-
ethersincorporating ferrocene moietyinsidethe macrocycles.7
Moreover, bis-β-lactams were macrocyclized via Cu-catalyzed
alkyne-azide cycloadditions8a or via M-CorM-N(M=Pd
or Pt) bonds.8b
The obtained macrocyclic bisazetidinones are potenial
starting materials for the synthesis of highly functionalized
macrocycles through the chemical transformation of the
azetidinone ring moiety,4 thus leading to macrocyclic crown
compounds containing suitable functionalities of potential
applications in supramolecular chemistry. This includes the
transformation to macrocyclic azacrown ethers, macrocyclic
bisamides, and macrocyclic β-aminoacids.4,7
Results and Discussion
In the present work we describe an alternative sequential
application of Staudinger [2 þ 2] ketene-imine cycloaddi-
tion followed by RCM reactions as a route to novel macro-
cyclic azacrown ethers incorporating the azetidinone ring
(5) Arumugam, N.; Raghunathan, R. Tetrahedron Lett. 2006, 47, 8855–
8857. and references therein.
(6) Ibrahim, Y. A.; Al-Azemi, T. F.; Abd El-Halim, M. D.; John, E.
J. Org. Chem. 2009, 74, 4305–4310.
(7) Sierra, M. A.; Fernandez, M. R.; Casarrubios, L.; Gallego, M. G.;
Allen, C. P.; Mancheno, M. J. Dalton Trans. 2009, 8399–8405.
J. Org. Chem. Vol. 75, No. 13, 2010 4509

Ibrahim et al.
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SCHEME 3
reported previously.6,8,9 Generally, the H-3 signal of the
azetidinone ring appears at lower frequency than the H-4
signal in all of the present new acyclic and macrocyclic
derivatives except in cases of 1-naphthyl and 9-anthracenyl
derivatives where the opposite occurs (Table 1, entries 3, 5, 7;
Table 2, entries 9-12, 17-20; Table 3, entry 2). This is clearly
attributed to the more anisotropic effect of the 1-naphthyl
and 9-anthracenyl substituents. All H-3 and H-4 signals have
been assigned on the basis of their cross correlation with
their respective carbon signals in HSQC-NMR experiments
where the C-3 signal appears at δ = 83-87 and the C-4 signal
appears at δ = 59-64.
TABLE 1. Products 6-15 Obtained by the Reaction of o-Allyloxy-
phenoxyketene with 1-5a
yield,b
entry substrates products anti:syn
δ H3 (C3)
δ H4 (C4)
1
2
3
4
5
6
7
8
1a
2a
3a
4a
5a
1b
3b
4b
6a
11a
7a
12a
8a
13a
9a
14a
10a
15a
6b
11b
8b
13b
9b
14b
85%
47:53
80%
35:45
80%
50:50
75%
44:56
75%
40:35
75%
49:51
80%
45:55
85%
34:66
5.44 (83.7)
5.26 (83.4)
5.40 (83.6)
5.24 (83.4)
5.71 (84.4)
5.03 (83.7)
5.52 (83.9)
5.28 (83.6)
5.96 (85.9)
4.79 (84.9)
5.47 (83.4)
5.45 (83.3)
5.71 (83.9)
5.57 (83.9)
5.20 (61.1)
4.77 (62.1)
5.16 (60.8)
4.76 (61.6)
6.08 (57.4)
5.51 (57.9)
5.39 (61.4)
4.93 (62.3)
6.89 (58.1)
5.65 (58.2)
5.00 (63.0)
4.98 (63.0)
5.79 (59.1)
5.64 (59.1)
The 1H NMR spectra of the anti isomers 6a-10a and the
corresponding syn isomers 11a-15a showed the diastereo-
topic NCH2CH2N proton signals at two δ values. The Δδ in
the former are larger (Δδ ≈ 1 except for 10a Δδ = 1.34) than
in the latter (Δδ ≈ 0.6 except for 15a Δδ = 1.02). Similarly,
all anti macrocycles isomers 16a-20a whether E or Z
showed the NCH2CH2N proton signals at two δ values with
Δδ ≈ 1.1 except for 20a with Δδ = 1.38, 1.34 for the E and Z
isomers, respectively. On the other hand, the corresponding
macrocyclic syn isomers 21a-25a showed the NCH2CH2N
proton signals at two δ values with Δδ ≈ 0.34-0.7 except for
25a with Δδ = 1.30, 1.38 for E and Z isomers, respectively.
Although these findings are characteristic for the anti and
syn isomers in the present study, they are opposite to what
has been reported recently by Pellico et al.8a In addition to
our previous work6 this Δδ of the diastereotopic NCH2
signals cannot be taken as a generalization for assigning
the anti and syn bis-azetidinones. Additionally in all of the
cis-anti-cis the two diastereotopic NCH2 signals have sig-
nificantly different appearance than the cis-syn-cis deriva-
tives (cf. Figure 1 and 1H NMR spectra in Supporting
Information).
5.48 (83.43) 5.11 (63.1)
5.44 (83.40) 5.08 (63.1)
aReaction conditions: substrate (1 mmol) in DCM (5 mL) was added
to a solution of o-allyloxyphenoxyketene [prepared from o-allyloxyphen-
oxyacetyl chloride, (4 mmol)] at -78 °C and stirred overnight at room
temperature (cf. the experimental data in Supporting Information). The
crude product was separated (for entries 1-5) and purified as a mixture
(for entries 6-8) by chromatography. bYields were determined by 1H
NMR and agree with the isolated yields within (5% (cf. the experi-
mental data in Supporting Information).
obtained only from Grubbs’ II catalyst were recorded in
Table 3 and in the Experimental Section.
NMR of the Products. The cis stereochemistry of all of
these new bis-β-lactams 6-15 and their corresponding
macrocycles 16-25 were established on the basis of the
azetidinones 3J(H3,H4) coupling constant of 4.4-4.9 Hz as
(8) (a) Pellico, D.; Gomez-Gallego, M.; Ramirez-Lopez, P.; Mancheno,
M. J.; Sierra, M. A.; Torres, M. R. Chem.;Eur. J. 2010, 16, 1592–1600.
(b) Pellico, D.; Gomez-Gallego, M.; Ramirez-Lopez, P.; Mancheno, M. J.;
Sierra, M. A.; Torres, M. R. Chem.;Eur. J. 2009, 15, 6940.
(9) Singh, G. S.; D’hooghe, M.; De Kimpe, N. Azetidines, Azetines and
Azetes: Monocyclic. In Comprehensive Heterocyclic Chemistry III; Katritzky,
A. R., Ramsdem, C. A., Scriven, E. F. V., Eds.;Elsevier: Amsterdam, 2008;
Vol. 2, pp 1-110.
As reported previously,6 the chiral shift reagent Eu(hfc)3
was used to confirm the assignment of the cis-anti-cis and
cis-syn-cis isomers of compounds 6a and 11a from NMR
spectral analysis. The two methylene CH2N bridge and
azetidinone H-3 and H-4 proton signals appear at δ 2.85,
4510 J. Org. Chem. Vol. 75, No. 13, 2010

Ibrahim et al.
JOCArticle
TABLE 2. RCM Products of 6a-15a with Grubbs’ I and Grubbs’ II
TABLE 3. RCM Product of 6b, 11b, 8b, 13b, 9b, 14b with Grubbs’ II
Catalysta
Catalystsa
1H NMR of Z/E
NMR of products
δ H3 (C3) δ H4 (C4)
product ArHc
substrate
(anti:syn)
pro-
duct
yield,b
anti:syn
δ H3 δ H4
(C3) (C4) OCH2CH=
δ
substrate yield,b
entry product Z:E ratio
entry
1
Z
E
Z
E
Z
E
6b, 11b (49:51) 16b 95%, 49:51 5.07 5.48
84.5 63.2
5.07 5.51
84.3 63.1
8b, 13b (45:55) 18b 90%, 47:53 5.84 5.93
5.86
5.85
5.88
6.00
5.56
5.68
1
6a
16a
6a
97%
0:1
98%
5.78
5.07
5.49
85.1
5.41 5.78 5.05 5.07 5.86
61.4
21b
2
5.49
6.29
6.29
5.63
5.63
6.35
6.35
4.95
4.95
5.92
5.92
5.43
5.43
6.26
6.26
5.01
5.01
6.05
6.05
16a
11a
21a
11a
21a
7a
1:4.9 85.6 85.1 61.3 61.4
2
3
3
98%
0:1
98%
5.77
84.4
5.60 5.77 4.96 4.98 6.48
4.98
63.3
85.1 59.8
23b
5.90 5.93
84.8 59.1
9b, 14b (34:66) 19b 80%, 53:47 5.25 5.55
4
1:7.3 84.3 84.4 63.2 63.3
5
98%
0:1
97%
5.72
85.0
5.39 5.72 4.98 5.01 5.94
5.01
60.9
83.8 63.3
5.28 5.60
84.8 63.5
17d
7a
24b
6
aReaction conditions: substrate (0.03 mmol) in DCM (10 mL) and
Grubbs’ II (1.2 mg, 5 mol %) were heated under reflux for 1 h. bOnly E
isomers were formed under these conditions as identified from their
characteristic 1H NMR. Yields were determined by 1H NMR and agree
with the isolated yields within (5% (cf. the experimental data in
Supporting Information).
17d
12a
22a
12a
22a
8a
1:2.7 85.5 85.0 60.8 60.9
7
97%
0:1
90%
5.73
84.3
5.54 5.73 4.93 4.97 6.50
4.97
62.8
8
1:3.0 84.2 84.3 62.7 62.8
9
92%
0:1
90%
5.97
85.8
5.76 5.97 5.94 6.11 5.43
6.11
58.5
18a
8a
10
11
12
13
14
15
16
17
18
19
20
18a
13a
23a
13a
23a
9a
1:2.8 86.2 85.8 58.2 58.5
high frequency at δ 5.49 for the anti isomer 16a and shows at
δ 6.29 for the syn isomer 21a (See Figure 1). This is due to the
diamagnetic anisotropic shielding caused by the phenyl ring
alignment to the aromatic proton in the macrocyclic system
of the anti isomer 16a. NOE-difference spectroscopy con-
firmed further the assignment of this high-frequency aro-
matic proton signal. Thus, irradiation of this proton
enhanced the two ortho phenyl proton signals in compounds
E-16a and E-17a (cf. Supporting Information). Replacing
the phenyl ring in the azetidinone system by a 1-naphthyl or
9-anthracenyl ring in anti isomers 18a, 20a increases the
diamagnetic anisotropic shielding effect, which resulted in
further shielding of the aromatic proton to δ 4.95, 5.01,
respectively (Table 2, entries 9, 17, Figure 1). The 2-naphthyl
derivatives do not affect markedly the position of this high
frequency aromatic proton signal.
97%
0:1
98%
5.84
85.1
5.82 5.84 5.90 6.05 6.07
6.05
59.70
1:4.3 85.0 85.1 59.74 59.70
96%
0:1
97%
5.89
85.4
5.53 5.89 5.23 5.26 5.84
5.26
63.5
19a
9a
19a
14a
24a
14a
24a
10a
20a
10a
20a
15a
25a
15a
25a
1:3.8 85.8 85.4 61.55 61.62
97%
0:1
97%
5.86
84.71
5.19
63.5
5.68 5.86 5.19 5.19 6.47
1:6.7 84.74 84.71 63.4 63.5
98%
0:1
98%
6.33
86.8
6.02 6.33 6.66 6.66 5.54
6.66
59.4
1:2.6 87.1 86.8 58.9 59.4
95%
0:1
95%
6.22
86.5
6.35 6.22 6.68 6.58 6.03
6.58
60.6
Interestingly, the aromatic proton signal of the macro-
cyclic anti Z isomers are shifted to lower frequency
compared to their anti E isomer counterparts (Table 2).
Apparently these systems are highly rigid as evidenced
from the 1H NMR experiments preformed at different
temperatures in pyridine-d6 for the anti isomer 16a (see
Supporting Information). At 298 K the aromatic proton
signal in the macrocyclic system shows at δ 5.87, upon
increasing the temperature to 378.4 K the aromatic proton
signal shifted to lower frequency at δ 6.09. When the
temperature was lowered to 232.5 K, the proton signal
shifted to high frequency at δ 5.69. The differences in
aromatic proton signal shift of approximately (0.2 ppm
from the experiment carried out at room temperature in-
dicate that there is no significant conformational rearrange-
ment in the macrocyclic system. It also indicates that there is
some flexibility in the phenyl ring rotation, which may be
only swinging. At higher temperature this swinging has a
larger amplitude so that, on average, its position for an
effective shielding is somewhat diluted.
1:6.6 86.8 86.5 59.4 60.6
aReaction conditions: substrate (0.03 mmol) in DCM (10 mL) and
Grubbs’ II (1.2 mg, 5 mol % for entries 1, 3, 5, 7, 9, 11, 13, 15, 17, 19) or
Grubbs’ I (1.3 mg, 5 mol % for entries 2, 4, 6, 8, 10, 12, 14, 16, 18, 20)
were heated under reflux for 1 h. bIdentified from their characteristic
1H NMR; with Grubbs’ II, only the E isomers were obtained in
90-98% yield. Yields were determined by 1H NMR and agree with
the isolated yields within (5% (cf. the experimental data in Supporting
Information). cThis ArH is the highest frequency proton signals ortho to
the azetidinone ring of the condensed benzene ring.
1
3.84, 5.20, 5.44, respectively, in the H NMR spectrum of
the anti isomer 6a (see Supporting Information). After the
addition of the chiral shift reagent the two signals of
the diastereotopic methylene (CH2N) bridge and azetidinone
H-3 and H-4 proton signals shifted to lower frequency, and
each proton signal splits resulting in eight signals at δ 2.97,
3.02, 4.01, 4.09, 5.47, 5.45, 5.71, and 5.77, which confirms
that 6a is a racemic mixture. As for compound 11a, after the
addition of the chiral shift reagent the two H-3 and H-4
proton signals of the azetidinone appear at δ 4.77 and 5.26
shifted to lower frequency without splitting, which indicates
that 11a is the meso isomer.
On subjecting the anthracenyl derivative E-20a to cycload-
dition reaction with N-phenylmaleimide, an almost quanti-
tative yield of the corresponding cycloadduct 26 was
Another significant difference between the syn and the anti
isomers is that one of the aromatic proton signals appears at
1
obtained. The H NMR of 26 shows the high frequency
J. Org. Chem. Vol. 75, No. 13, 2010 4511

Ibrahim et al.
JOCArticle
FIGURE 1. 1H NMR (400 MHz, CDCl3) spectra: (a) cis-anti-cis isomer of compound 16a; (b) cis-syn-cis isomer of compound 21a; (c) cis-anti-
cis isomer of compound 18a.
aromatic proton signal at δ 5.16, which has not been affected
significantly by such structural modification.
literature. Cycloaddition of N-phenylmaleimide and E-20a were
done following literature procedure.15
Synthesis of β-Lactams 6-15 by Staudinger Reaction: General
Procedure. A solution of o-allyloxyphenoxyacetyl chloride
(4 mmol) in dry CH2Cl2 (5 mL) was purged with nitrogen and
cooled to -78 °C, and then a solution of Et3N (8 mmol) in dry
CH2Cl2 (5 mL) was added dropwise with a syringe. The mixture
was stirred for 30 min, and a solution of the corresponding
diimine 1-5 (1 mmol) in dry CH2Cl2 (5 mL) was added dropwise
over a period of 2 h. The reaction mixture was then stirred
overnight at room temperature. The organic layer was washed
with water and Na2CO3 solution (10%) until no effervescence
and then dried over anhydrous Na2SO4. The solvent was
removed in vacuo. The crude product was separated or purified
by chromatography. All anti products 6a, 7a, 8a, 9a, and 10a
were readily separated from their corresponding syn isomers
11a, 12a, 13a, 14a, and 15a.
Compound 6a. Yield 0.30 g (40%); yellow oil, Rf = 0.36 (pet.
ether/EtOAc 2:1). MS: m/z = 616 (Mþ, 5%). IR: 3065, 3033,
2973, 2925, 1755, 1499, 1455, 1406, 1354, 1256, 1209, 747, 700.
1H NMR (CDCl3): δ 2.85 (d, 2H, J 11.0), 3.84 (d, 2H, J 11.0),
4.30 (dt, 4H, J 5.2, 1.5), 5.13 (ddd, 2H, J 10.5, 2.8, 1.5), 5.20 (d,
2H, J 4.8), 5.22 (ddd, 2H, J 17.2, 3.2, 1.5), 5.44 (d, 2H, J 4.8), 5.88
(m, 2H), 6.74 (m, 6H), 6.83 (m, 2H), 7.31 (m, 6H), 7.38 (dd, 4H,
J 8.0, 1.6). 13C NMR (CDCl3): δ 37.2, 61.1, 69.8, 83.7, 115.2,
116.9, 117.1, 121.2, 122.8, 128.3, 128.4, 128.5, 133.1, 133.2,
Conclusion
The present study offers alternative synthetic routes to-
ward macrocyclic azacrown ethers condensed with bisazeti-
dinones via bridgehead (ring junction) nitrogens through the
sequential application of Staudinger [2 þ 2] ketene-imine
cycloaddition followed by RCM reactions in an overall yield
of these two steps amounting to 83%. The new macrocyclic
bisazetidinones were proved to be conformationaly rigid
systems and also are not expected to be efficiently otherwise
accessible using other synthetic approaches.
Experimental Section
The starting compounds 1a,10 2a,10 3a,11 4a,11 5a,12 1b,13 3b,13
4b,14 and o-allyloxyphenol1e were prepared as reported in the
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Ibrahim et al.
JOCArticle
147.1, 148.4, 167.3. 15N NMR (CDCl3): δ 139.6. HRMS =
616.2565 (C38H36N2O6 requires 616.2567).
(d, 2H, J 10.8), 4.70 (d, 2H, J 9.6), 4.74 (d, 2H, J 9.6), 5.05 (d, 2H,
J 4.6), 5.41 (d, 2H, J 4.6), 5.86 (dd, 2H, J 7.8, 1.6), 6.22 (t, 2H,
J 4.7), 6.58 (td, 2H, J 7.6, 1.3), 6.90 (dd, 2H, J 8.0, 1.3), 6.98 (td,
2H, J 7.8, 1.6), 7.41 (m, 10H). 13C NMR (CDCl3): δ 36.8, 61.3,
62.2, 85.6, 112.6, 120.7, 122.8, 124.9, 128.2, 128.3, 128.5, 128.7,
131.2, 146.2, 150.0, 167.7.
Compound 11a. Yield 0.33 g (45%); colorless crystals, mp
149 °C, Rf = 0.23 (pet. Ether/EtOAc 2:1). MS: m/z = 616 (Mþ,
5%). IR: 3065, 3034, 2984, 2922, 2860, 1759, 1500, 1455, 1407,
1357, 1258, 1212, 744, 702. 1H NMR(CDCl3): δ 3.10 (m 2H), 3.71
(m, 2H), 4.30 (dt, 4H, J 5.1, 1.6), 4.77 (d, 2H, J 4.6), 5.15 (ddd, 2H,
J 10.6, 2.8, 1.6), 5.21 (ddd, 2H, J 17.2, 3.2, 1.6), 5.26 (d, 2H, J 4.6),
5.87 (m, 2H), 6.66 (dd, 2H, J 8.5, 1.6), 6.75 (m, 4H), 6.84 (dt, 2H,
J 1.5, 7.2), 7.34 (m, 10H). 13C NMR (CDCl3): δ 37.9, 62.1, 70.0,
83.4, 115.4, 117.1, 117.2, 121.3, 123.0, 128.5, 128.6, 128.9, 133.0,
133.3, 147.2, 148.5, 166.4. 15N NMR (CDCl3): δ 139.3. HRMS =
616.2567 (C38H36N2O6 requires 616.2567).
General Procedures of the RCM. (Condition A) To a solution
of each of the appropriate β-lactams 6-15 (0.03 mmol) in DCM
(10 mL) was added Grubb’s catalyst II (1.2 mg, 5 mol %). The
reaction mixture was heated under reflux for 1 h, the solvent was
removed in vacuo, and the product was purified by column
chromatography with eluent DCM/pet. ether (60-80)/EtOAc
to give the corresponding E isomers 16-25. (Condition B) To a
solution of each of the appropriate β-lactams 6-15 (0.03 mmol)
in DCM (10 mL) was added Grubb’s catalyst I (1.2 mg,
5 mol %). The reaction mixture was heated under reflux for
1 h, the solvent was removed in vacuo, and the product was
purified by column chromatography with eluent DCM/pet.
ether (60-80)/EtOAc to give mixture of the coresponding
E and Z isomer. 1H NMR and 13C NMR data of the Z isomer
were extracted from the mixed spectra by comparison with the
pure E isomer.
Compound 21a-E. Yield 0.58 g (98%) (Condition A), 0.52 g
(88%) (Condition B), colorless oil, Rf = 0.46 (DCM/pet. ether/
EtOAc 1:1:1). MS: m/z = 588 (Mþ, 25%). HRMS = 588.2254
(C36H32N2O6 requires 588.2254). IR: 3064, 2957, 2928, 2860,
1
1762, 1729, 1497, 1460, 1381, 1272, 1124, 1072, 745, 702. H
NMR (CDCl3): δ 3.10 (m, 2H), 3.63 (m, 2H), 4.63 (m, 4H), 4.98
(d, 2H, J 4.6), 5.77 (d, 2H, J 4.6), 6.29 (dd, 2H, J 8.0, 1.5), 6.44 (t,
2H, J 2.5), 6.65 (td, 2H, J 7.7, 1.5), 6.85 (dd, 2H, J 8.2, 1.7), 6.90
(td, 2H, J 8.0, 1.5), 7.31-7.38 (m, 6H), 7.42 (m, 4H). 13C NMR
(CDCl3): δ 38.9, 63.3, 68.4, 84.4, 113.8, 120.1, 121.1, 123.7,
128.1, 128.4, 128.7, 128.8, 133.7, 146.4, 149.2, 167.3. 15N NMR
(CDCl3): δ 138.6.
Compound 21a-Z. Formed in 12% with 21a-E (Condition B),
1H NMR (CDCl3): δ 3.16 (m, 2H), 3.50 (m, 2H), 4.73 (dd, 2H,
J 11.0, 4.3), 4.76 (dd, 2H, J 11.0, 4.3), 4.96 (d, 2H, J 4.8), 5.60 (d,
2H, J 4.8), 6.18 (t, 2H, J 4.3), 6.48 (dd, 2H, J 8.2, 1.6), 6.71 (td,
2H, J 7.8, 2.0), 6.90 (dd, 2H, J 8.0, 1.5), 6.92 (td, 2H, J 7.8, 2.0),
7.31-7.38 (m, 6H), 7.42 (m, 4H). 13C NMR (CDCl3): δ 38.8,
63.2, 64.4, 84.3, 114.8, 119.8, 121.5, 123.8, 128.3, 128.5, 128.8,
128.9, 134.3, 147.1, 149.2, 167.0.
Acknowledgment. The support of the University of Ku-
wait received through research grant no. SC02/07 and the
facilities of ANALAB and SAF (grants no. GS01/01, GS01/
03, GS03/01) are gratefully acknowledged.
Compound 16a-E. Yield 0.57 g (97%) (Condition A), 0.48 g
(83%) (Condition B), colorless oil, Rf = 0.41 (DCM/pet. ether/
EtOAc 1:1:1). MS: m/z = 588 (Mþ, 25%). HRMS = 588.2253
(C36H32N2O6 requires 588.2254). IR: 3061, 3029, 2926, 2852,
1764, 1751, 1597, 1496, 1453, 1410, 1257, 1213, 1114, 1040, 745,
Supporting Information Available: General experimental
methods and full experimental details for all reactions; char-
acterization data for all products; 1H NMR (600 MHz, CDCl3)
spectra of cis-anti-cis compound 6a (racemic) and cis-syn-cis
compound 11a (meso) (a) before addition of chiral shift reagent,
Eu(hfc)3 and (b) after addition of chiral shift reagent, Eu(hfc)3;
1H, 13C NMR and 15N full spectral assignment of 6a and
1
700. H NMR (CDCl3): δ 2.80 (d, 2H, J 11.2), 3.93 (d, 2H,
J 11.2), 4.56 (d, 2H, J 10.8), 4.61 (d, 2H, J 10.8), 5.07 (d, 2H,
J 4.5), 5.49 (dd, 2H, J 7.9, 1.6), 5.78 (d, 2H, J 4.5), 6.38 (t, 2H,
J 2.4), 6.48 (td, 2H, J 7.7, 1.4), 6.83 (dd, 2H, 8.1, 1.3), 6.93 (td,
2H, J 7.6, 1.6), 7.43 (m, 10H). 13C NMR (CDCl3): δ 37.4, 61.4,
67.6, 85.1, 112.4, 120.4, 122.9, 124.8, 127.4, 128.5, 128.7(2C),
134.2, 145.1, 150.4, 168.0. 15N NMR (CDCl3): δ 138.5.
11a and copies of H NMR and 13C NMR spectra and some
1
Compound 16a-Z. Formed in 17% as mixture with 4a-E
(Condition B), H NMR (CDCl3): δ 2.78 (d, 2H, J 10.8), 3.88
representative 2D NMR. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
J. Org. Chem. Vol. 75, No. 13, 2010 4513