Staudinger ketene-imine cycloaddition, RCM approach to macrocrocyclic bisazetidinones

Article abstract of DOI:10.1021/jo9006392

(Chemical Equation Presented) Application of Staudinger ketene-imine cycloaddition reaction to bis-o-allyloxyarylideneamines afforded the corresponding bisallyloxyazetidinones as the cis-cis diastereomers, exclusively obtained as a mixture of cis-syn-cis

Full text of DOI:10.1021/jo9006392

Staudinger Ketene-Imine Cycloaddition, RCM Approach to
Macrocrocyclic Bisazetidinones
Yehia A. Ibrahim,* Talal F. Al-Azemi, Mohamed D. Abd El-Halim, and Elizabeth John
Chemistry Department, Faculty of Science, Kuwait UniVersity, P.O. Box 5969, Safat 13060, Kuwait
yehiaai@kuc01.kuniV.edu.kw
ReceiVed March 27, 2009
Application of Staudinger ketene-imine cycloaddition reaction to bis-o-allyloxyarylideneamines afforded
the corresponding bisallyloxyazetidinones 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 the corresponding
macrocyclic bisazetidinones in good yields. The cis-anti-cis bisazetidinones are readily identified by 1H
NMR using Eu(hfc)3 chiral shift reagent.
Introduction
The obtained macrocyclic bisazetidinones are potenial starting
materials for the synthesis of highly functionalized macro-
cycles 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 aza-crown ethers, macrocyclic bisamides, and
macrocyclic ꢀ-amino acids.4
Crown compounds, aza-crown compounds, and crown
ethers incorporating amide groups find many interesting
applications in diverse fields of supramolecular chemistry.6
During our recent studies of the synthesis of macrocyclic
polyether moiety, we and others successfully applied the
RCM technique to efficiently synthesize a large number of
macrocycles of variable ring sizes.6
The Staudinger 2 + 2 ketene-imine cycloaddition reaction
is considered as one of the most important synthetic
approaches to ꢀ-lactams (2-azetidinones), which have im-
portantapplicationinpharmaceuticalandsyntheticchemistry.1-3
Recently, this reaction has been used to construct macrocyclic
bisazetidinone polyethers by the reaction of the appropriate
ketene precursors with macrocyclic diimines (Scheme 1).4,5
* Corresponding author. Fax: +965-24816482.
(1) de Kimpe, N. ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: London, 1996; Vol. 8, pp
507-512.
(2) Staudinger, H. Ann. 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, 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.
(6) (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. Tetrahedron 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: Chem. 2006, 254, 43–52. (h) Malhas, R. N.;
Ibrahim, Y. A. Synthesis 2006, 3261–3269.
(4) Sierra, M. A.; Pellico, D.; Go´mez-Gallego, M. Mancheno, M. J.; Rosario,
T. J. Org. Chem. 2006, 71, 8787–8793, and references cited therein.
(5) Arumugam, N.; Raghunathan, R. Tetrahedron Lett. 2006, 47, 8855–8857,
and references cited therein.
10.1021/jo9006392 CCC: $40.75
Published on Web 05/05/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4305–4310 4305

Ibrahim et al.
SCHEME 1
SCHEME 2
1
TABLE 1. Ketene-Imine Cycloaddition Products, Isolated Yield, Ratio of Anti and Syn, and Characteristic Azetidinone H and 13C NMR
Signals
substrates
products
yield (%), anti/syn
δ H3 (C3)
δ H4 (C4)
J (H3, H4)
1a + PhOCH2COCl
2a, 5a
3a, 6a
4a, 7a
2b, 5b
3b, 6b
4b, 7b
85, 53:47
91, 51:49
93, 51:49
75, 52:48
90, 50:50
80, 50:50
5.51 (82.5), 5.32 (81.9)
5.74 (82.8), 5.50 (82.4)
5.68 (82.4), 5.48 (82.0)
5.44 (81.8), 5.41 (81.8)
5.65 (82.1), 5.62 (82.1)
5.60 (82.0), 5.57 (81.9)
5.84 (55.5), 5.44 (55.8)
5.95 (55.6), 5.54 (56.1)
5.98 (55.4), 5.58 (55.8)
5.58 (56.6), 5.57 (56.6)
5.68 (56.9), 5.67 (56.9)
5.71 (56.7), 5.71 (56.7)
4.4, 4.2
4.4, 4.6
4.4, 4.4
4.2, 4.8
4.8, 4.8
4.2, 4.2
1a + R-NaphOCH2COCl
1a + ꢀ-NaphOCH2COCl
1b + PhOCH2COCl
1b + R-NaphOCH2COCl
1b + ꢀ-NaphOCH2COCl
TABLE 2. RCM of 2a with Different Ratios of Grubbs’ Catalysts
I and II
Results and Discussion
In the present work, we describe the sequential application
of Staudinger 2 + 2 ketene-imine cycloaddition followed by
RCM reactions as a route to functionalized macrocycles of
possible use as starting materials for further functionalization
of macrocyclic aza-crown ethers (Scheme 2). Thus, treatment
of 1,2-bis-o-allyloxybenzylideneamines 1a,b with aryloxyacetyl
chloride in CH2Cl2 in the presence of triethylamine gave a
mixture of cis-anti-cis (racemic) 2a,b, 3a,b, and 4a,b and cis-
syn-cis (meso) 5a,b, 6a,b, and 7a,b diastereomers. These two
isomers were separated by chromatography for all products
isolated from 1a. However, the isomeric mixtures synthesized
from 1b could not be isolated and were used as such in the
next RCM reactions. Table 1 shows the diastereomeric ratio
obtained and the characteristic 1H and 13C NMR signals of these
novel acyclic isomeric bisazetidinone derivatives.
entry
substrate/catalyst (%)
yield (%) (Z/E)a
1
2
3
4
5
6
7
8
9
2a/I (1)
2a/I (2)
2a/I (3)
2a/I (4)
2a/I (5)
2a/II (1)
2a/II (2)
2a/II (3)
2a/II (4)
32 (30:70)
60 (27:73)
72 (25:75)
83 (23:77)
98 (17:83)
67 (30:70)
72 (21:79)
75 (24:76)
88 (18:82)
a No more product was detected after 1-2 h, and the remaining
percent is a recovered unreacted starting material 2a. Yield of product,
percent of unreacted 2a, and E/Z ratio were determined by H NMR.
1
I (1%), the reaction proceeds for 1 h and stops to give 32% of
the product 8a as an E/Z mixture. Increasing the ratio of I to
2%, 3%, 4%, and 5% led to an increased yield of the RCM
products to 60%, 73%, 83%, and 98%, respectively, as an E/Z
(70-83:30-17) mixture (Table 2). On the other hand, similar
RCM of 2a was investigated using each of Grubbs’ catalysts
I and II in dichloromethane at reflux. Table 2 shows the results
obtained using different ratios of catalysts I and II. With catalyst
4306 J. Org. Chem. Vol. 74, No. 11, 2009

Staudinger Ketene-Imine Cycloaddition
1
1
TABLE 3. RCM Products, Yield, Ratio of Z and E Isomers, and Characteristic H, 13C NMR of Azetidinones and H NMR of CHd
δ H3/C3 δ H4/C4 1H NMR OCH2CHd
entrya
substrate/ product
yield (%), Z/E ratio
Z
E
Z
E
Z
E
1
2
3
4
2a/8a
5a/11a
3a/9a
6a/12a
4a/10a
7a/13a
2b/8b
5b/11b
3b/9b
98, 1:5
98, 1:5
4.73/81.4
5.44/81.8
4.92/81.5
5.32/82.1
4.85/81.4
5.67/81.6
5.39/82.1
5.48/82.1
5.55/82.3
5.65/82.4
5.45/82.0
5.45/82.1
5.17/81.5
5.43/81.9
5.35/81.6
5.59/82.1
5.32/81.5
5.61/81.9
5.45/82.0
5.48/82.1
5.54/82.2
5.56/82.3
5.60/81.9
5.63/82.1
5.42/56.0
5.56/55.7
5.56/55.9
5.68/55.7
5.54/56.1
5.76/55.7
5.59/56.8
5.68/56.6
5.66/56.8
5.74/56.6
5.62/56.7
5.62/56.5
5.36/55.7
5.48/55.8
5.50/55.9
5.65/56.0
5.48/55.7
5.65/55.8
5.69/56.2
5.70/56.6
5.67/56.2
5.68/56.6
5.83/56.3
5.85/56.5
6.18
6.08
6.19
6.08
6.33
6.32
5.95
5.87
5.89
5.81
5.63
5.63
5.97
5.98
6.02
5.97
6.01
6.02
6.17
6.08
5.97
5.91
6.21
6.09
95, 1:3.85
98, 1:4.17
57, 1:2.94
60, 1:1.56
82, 1:1.72
1:1.89
80, 1:2.17
1:1.54
75, 1:1.79
1:1.4
5
6
7b
8b
9b
6b/12b
4b/10b
7b/13b
a Reaction conditions: substrate (0.03 mmol) in DCM (10 mL) and catalyst I (1.2 mg, 5 mol % for entries 1-9) or II (1.3 mg, 5 mol % for entries
b
1
10-12) were heated under reflux for 1 h. Identified from their characteristic H NMR and compared with their samples prepared as shown in Scheme
3; with catalyst II, only the E isomers were obtained in 90-94% yield. Yields were determined by 1H NMR and agree with the isolated yields within
(5% (cf. the experimental data in the Supporting Information).
SCHEME 3
RCM of 2a with different ratios (1-4%) of catalyst II was found
to lead to the formation of the corresponding product 8a in
67-88% yield with a better trans stereoselectivity (E/Z ≈ 80:
20 ratio) (Table 2), after which the catalyst showed no further
activity and the remainder was unreacted starting material 2a.
From the results obtained in Table 2, RCM reactions of the
other derivatives 2-7 were successfully accomplished to give
57-98% yields of the corresponding macrocycles 8-13 using
catalyst I (5%) (Scheme 2). Table 3 illustrates the RCM products
obtained by Grubbs’ catalyst I together with Z/E ratio of the
formed double bond and the characteristic 1H and 13C NMR of
the azetidinone ring and olefinic protons. Interestingly, RCM
of 2b-7b with Grubbs’ catalyst II (5%) led to complete
disappearance of the starting materials and formation of the
corresponding 22 membered macrocyclic bisazetidinones
8b-13b in over 90% yield with only E stereochemistry.
The stereochemistry of the formed ethylenic double bond in
the RCM reaction was proved by preparing samples of 8b, 9b,
10b, 11b, 12b, and 13b by the reaction sequence illustrated in
Scheme 3. Thus, reacting (E)-1,4-bis(o-formylphenoxy)-2-
butene 14 with 1,8-diamino-3,6-dioxaoctane gave the corre-
sponding macrocyclic (E)-bisimine 15. The latter was reacted
J. Org. Chem. Vol. 74, No. 11, 2009 4307

Ibrahim et al.
FIGURE 1. 1H NMR (600 MHz, CDCl3) spectra of cis-anti-cis compound 2a (racemic): (a) before and (b) after addition of chiral shift reagent
Eu(hfc)3.
TABLE 4. Isomerization of Z-8b, Z-11b into E-8b, E-11b
for stereochemical reasons. Presumably, some of the syn isomers
lead to the formation of polymer instead of the corresponding
macrocycles, thus leading to loss of their relative abundances
in the product mixture.
entrya
catalyst (%)
overall yield (%) (E-8b:E-11b)
1
2
3
I (1)
II (1)
II (3)
0
54 (29:25)
95 (52:48)
The structure and stereochemistry of 2a, 5a, 8a, and 11a were
fully assigned using different NMR techniques (cf. the Sup-
porting Information). It is found that azetidinone H-3 and H-4
appear more upfield in the syn (meso) isomer 5a than in the
corresponding anti isomer 2a; in addition, the methylene CH2N
protons appear as two doublets for the anti isomer 2a and as
two multiplets for the syn isomer 5a. To confirm the assignment
of the cis-anti-cis and cis-syn-cis isomers (2a, 5a) by NMR
spectral analysis, a chiral shift reagent [Eu(hfc)3] was added.
1H NMR spectra for both isomers 2a and 5a before and after
addition of Eu(hfc)3 are shown in Figures 1 and 2. The
azetidinone protons H-3 and H-4 of compound 2a are shown
as doublets at 5.45 and 5.77 ppm (Figure 1a); after the addition
of the chiral shift reagent, the two protons are shifted downfield
and each proton split into a doublet, resulting in four doublets
at 5.58, 5.61, 5.87, and 5.89 ppm (Figure 1b), which confirms
that the cis-anti-cis isomer 2a is a racemic mixture. For
compound 5a, the two doublets at 5.29 and 5.42 ppm for the
azetidinone protons H-3 and H-4 (Figure 2a) appeared downfield
at 5.63 and 5.63 ppm after the addition of the chiral shift reagent
without further splitting (Figure 2b), which indicates that cis-
syn-cis 5a is the meso isomer. The results are in agreement with
the reported NMR data for acyclic bisazetidinones prepared from
bisbenzylideneaminoethane where the stereochemistry is con-
firmed by X-ray crystallography.7
a A solution of Z-8b, Z-11b mixture (0.03 mmol) in DCM (10 mL)
and Grubb’s catalyst (1-3 mol %) was heated under reflux for 1 h (no
change in yield or percent distribution of all isomers after this time).
with the appropriate aryloxyketene generated in the reaction
medium from the corresponding aryloxyacetyl chloride to give
a mixture of the corresponding anti-E-bisazetidinones 8b, 9b,
and 10b together with their corresponding syn-E-isomers 11b,
12b, and 13b, respectively. The corresponding Z-isomers were
also prepared by reacting (Z)-1,4-bis(o-formylphenoxy)-2-butene
16 with 1,8-diamino-3,6-dioxaoctane to give the corresponding
macrocyclic (Z)-bisimine 17. Reaction of the latter with the
appropriate aryloxyketene gave a mixture of the corresponding
anti-(Z)-bisazetidinones 8b, 9b, and 10b together with their
corresponding syn-Z-isomers 11b, 12b, and 13b, respectively
(Scheme 3). The Z-8b and Z-11b isomers were readily isomer-
ized to the corresponding E-8b and E-11b isomers upon
refluxing in CH2Cl2 with Grubbs’ catalyst II. This isomerization
was complete using 3 mol % of the catalyst; however, using 1
mol % of the catalyst led only to 54% isomerization.
Attempted isomerization of the Z isomeric mixture 8b, 11b
to the E isomers using Grubbs’ catalyst I failed and led to
complete recovery of the starting Z-isomers (Table 4). Similar
observations were reported6h and were attributed to the higher
tolerance of Grubbs’ catalyst II to the steric effect of substituted
alkenes. It was also observed during this isomerization reaction
that the ratio of the anti isomer increases more in the product
than in the reactant. Since this isomerization involves ring-
opening/ring-closing metathesis, it is clear that the ring closure
of the anti isomer is more favorable than that of the syn isomer
The opposite occurs with the corresponding macrocyclic
bisazetidinones 8a and 11a, where H-3 and H-4 appear more
downfield in the syn (meso) isomer 11a than in the corresponding
(7) Karupaiyan, K.; Puranik, V. G.; Deshmukh, A. R. A. S.; Bhawal, B. M.
Tetrahedron 2000, 56, 8555–8560.
4308 J. Org. Chem. Vol. 74, No. 11, 2009

Staudinger Ketene-Imine Cycloaddition
FIGURE 2. 1H NMR (600 MHz, CDCl3) spectra of cis-syn-cis compound 5a (meso): (a) before and (b) after addition of chiral shift reagent
Eu(hfc)3.
(5 mL) was added dropwise with a syringe. The mixture was stirred
for 30 min, and a solution of the corresponding diimine 1a,b, 15,
and 17 (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 occurred and then
dried over anhydrous Na2SO4. The solvent was removed in vacuo,
and the crude product was separated by chromatography. All anti
products 2a, 3a, 4a were readily separated from their corresponding
syn isomers 5a, 6a, 7a. The other anti and syn isomers could not
be separated and were identified as a mixture of each of these two
anti isomer 8a; in addition, the methylene CH2N protons appear
as two doublets for the anti isomer 8a and as two multiplets for
the syn isomer 11a. Similar splitting of the racemic mixture of the
macrocycle 8a with the chiral shift reagent was observed (cf.
the Supporting Information). Again, this is in agreement with the
reported NMR data for cyclic bisazetidinones where the stereo-
chemistry has been proved by X-ray crystallography.4,5
Conclusion
The present study offers synthetic routes toward macrocyclic
aza-crown ethers condensed with bisazetidinones via bridgehead
(ring junction) nitrogens through the sequential application of
Staudinger [2 + 2] ketene-imine cycloaddition followed by RCM
reactions in an overall yield of these two steps amounting to 83%,
while the other approach in which the macrocyclic bis-imines 15
and 17 were prepared followed by Staudinger [2 + 2] ketene-
imine cycloaddition gave the corresponding macrocyclic bisaze-
tidinones 8b-13b in an overall yield of these two steps
amounting to 71%. Comparison of these two approaches clearly
indicates that the Staudinger-RCM approach gave overall
comparable or better yield of the desired macrocyclic bisaze-
tidinones. Moreover, attempts to prepare the precursor cyclic
bis-imines with X ) CH2CH2 by reacting 14 and 16 with 1,2-
ethylenediamine was completely impossible due to the formation
of polymeric gummy material, which is a further advantage of
the RCM technique. These macrocyclic bisazetidinones are
potential starting materials useful for further functionalization
of macrocyclic aza-crown ethers.
1
isomers where H NMR is almost completely identical except for
the azetidinones ring, which is assigned for each isomer.
Compound 2a. Yield: 0.28 g (45%). Colorless crystals. Mp:
130-132 °C. Rf ) 0.54 (petroleum ether/EtOAc 1:1). MS m/z )
616 (M+, 5). IR: 3067, 3040, 2969, 2929, 1759, 1600, 1590, 1494,
1
1415, 1353, 12407, 1231, 1055, 1002, 926, 752, 691. H NMR
(CDCl3): δ 2.90 (d, 2H, J 11.4), 3.90 (d, 2H, J 10.8), 4.34 (dd, 2H,
J 13.2, 4.8), 4.50 (dd, 2H, J 13.2, 4.8), 5.34 (dd, 2H, J 10.8, 1.2),
5.48 (dd, 2H, J 17.7, 1.2), 5.51 (d, 2H, J 4.4), 5.84 (d, 2H, J 4.4),
6.06 (m, 2H), 6.73 (d, 2H, J 8.4), 6.80 (d, 4H, J 7.8), 6.87 (t, 2H,
J 7.2), 6.94 (t, 2H, J 7.8), 7.11 (t, 4H, J 7.2), 7.20 (dt, 2H, J 7.8,
1.2), 7.32 (dd, 2H, J 7.8, 1.2). 13C NMR (CDCl3): δ 37.9, 55.5,
68.7, 82.5, 111.4, 115.6, 117.4, 120.4, 121.4, 121.7, 127.9, 128.9,
129.4, 133.0, 156.9, 157.0, 167.4. HRMS ) 616.2568 (C38H36N2O6
requires 616.2567).
Compound 5a. Yield: 0.25 g (40%). Yellow oil. Rf ) 0.39
(petroleum ether/EtOAc 1:1). MS: m/z ) 616 (M+, 5). IR: 3068,
3015, 2917, 2850, 1761, 1599, 1590, 1493, 1455, 1408, 1357, 1291,
1
1238, 997, 753, 691. H NMR (CDCl3): δ 3.11 (m, 2H), 3.85 (m,
2H), 4.28 (ddt, 2H, J 12.6, 5.4, 1.2), 4.44 (ddt, 2H, J 12.6, 5.4,
1.8), 5.29 (ddd, 2H, J 10.2, 2.0, 1.2), 5.32 (d, 2H, J 4.2), 5.38 (ddd,
2H, J 17.4, 2.4, 1.2), 5.44 (d, 2H, J 4.2), 6.00 (m, 2H), 6.71 (m,
6H), 6.86 (t, 2H, J 7.2), 6.98 (t, 2H, J 7.8), 7.09 (dt, 4H, J 7.2,
1.8), 7.22 (dt, 2H, J 8.4, 1.8), 7.30 (dd, 2H, J 7.8, 1.8). 13C NMR
(CDCl3): δ 37.7, 55.8, 68.5, 81.9, 111.3, 115.2, 117.4, 120.4, 120.5,
121.5, 128.1, 128.7, 129.4, 132.7, 156.5, 156.6, 166.0. HRMS )
616.2568 (C38H36N2O6 requires 616.2567).
Experimental Section
Synthesis of ꢀ-Lactams 2-7 by Staudinger Reaction:
General Procedure. A solution of aryloxyacetyl chloride (4 mmol)
in dry CH2Cl2 (5 mL) was purged with nitrogen and cooled to
0 °C, and then a solution of triethylamine (8 mmol) in dry CH2Cl2
J. Org. Chem. Vol. 74, No. 11, 2009 4309

Ibrahim et al.
General Procedures of the RCM. To a solution of the
appropriate ꢀ-lactam 2-7 (1 mmol) in DCM (10 mL) was added
Grubbs’ catalyst I or II (mol % indicated in Tables 2 and 3). The
reaction mixture was heated under reflux (for the time indicated in
Tables 2 and 3), and the solvent was removed in vacuo and the
product was purified by column chromatography with eluent DCM/
petroleum ether (60-80)/EtOAc.
25). HRMS ) 588.2256 (C36H32N2O6 requires 588.2261). IR: 3063,
3013, 2926, 1771, 1599, 1493, 1456, 1406, 1360, 1236, 1047, 866,
1
752, 690. trans-11a. H NMR (CDCl3): δ 2.95 (m, 2H), 3.78 (m,
2H), 4.62 (d, 2H, J 14.0), 4.75 (d, 2H, J 14.0), 5.43 (d, 2H, J 4.5),
5.48 (d, 2H, J 4.5), 5.95 (s, 2H), 6.78 (m, 6H), 6.89 (m, 4H), 7.15
(m, 6H), 7.28 (dd, 2H, J 7.6, 1.6). trans-11a. 13C NMR (CDCl3):
δ 38.2, 55.8, 68.6, 81.9, 114.4, 115.5, 121.4, 121.9, 122.1, 128.9,
129.1, 129.4, 129.7, 156.6, 157.0, 166.2. cis-11a. 1H NMR (CDCl3):
δ 2.93 (m, 2H), 3.97 (m, 2H), 4.46 (dd, 2H, J 10.4, 5.6), 4.64 (dd,
2H, J 10.4, 5.6), 5.44 (d, 2H, J 4.5), 5.56 (d, 2H, J 4.5), 6.22
(t, 2H, J 5.6), 6.78 (m, 6H), 6.89 (m, 4H), 7.15 (m, 6H), 7.28 (dd,
2H, J 7.6, 1.6). cis-11a. 13C NMR (CDCl3): δ 38.0, 55.7, 63.6,
81.8, 112.3, 115.6, 121.1, 121.6, 121.7, 128.8, 129.0, 129.8, 130.7,
156.9, 157.2, 166.5.
Compound 8a. Yield: 0.56 g (95%) isolated as cis/trans (8:92)
mixture after column chromatography [of RCM reaction with
Grubbs’ I (5 mol %)] as colorless crystals. Mp 123-125 °C. Rf )
0.61 (DCM/petroleum ether/EtOAc 1:1:1). MS: m/z ) 588 (M+,
25). HRMS ) 588.2254 (C36H32N2O6 requires 588.2254). IR: 3065,
3041, 2922, 2853, 1764, 1599, 1590, 1492, 1456, 1404, 1355, 1237,
1
912, 752, 734. trans-8a. H NMR (CDCl3): δ 3.06 (d, 2H, J 9.6),
3.58 (d, 2H, J 9.6), 4.58 (dd, 2H, J 11.0, 2.8), 4.71 (dd, 2H, J 11.0,
2.8), 5.17 (d, 2H, J 4.6), 5.36 (d, 2H, J 4.6), 5.96 (t, 2H, J 2.8),
6.70 (d, 4H, J 7.8), 6.86 (m, 4H), 7.00 (t, 2H, J 7.2), 7.11 (m, 4H),
7.22 (td, 2H, J 8.4, 1.2), 7.39 (dd, 2H, J 7.8, 1.2). trans-8a. 13C
NMR (CDCl3): δ 39.1, 55.7, 68.4, 81.5, 114.7, 115.3, 121.6, 121.7,
122.6, 129.1, 129.3, 129.75, 129.9, 156.6, 156.9, 166.6. cis-8a. 1H
NMR (CDCl3): δ 3.32 (d, 2H, J 13.0), 3.73 (d, 2H, J 13.0), 4.63
(dd, 2H, J 11.0, 4.0), 4.67 (dd, 2H, J 11.0, 4.0), 4.73 (d, 2H, J
4.6), 5.42 (d, 2H, J 4.6), 6.18 (t, 2H, J 4.0), 6.64 (d, 4H, J 7.8),
6.86 (m, 4H), 7.06 (t, 2H, J 7.3), 7.12 (m, 4H), 7.27 (td, 2H, J 8.0,
2.0), 7.35 (dd, 2H, J 7.7, 1.6). cis-8a. 13C NMR (CDCl3): δ 39.4,
56.0, 64.6, 81.4, 111.9, 115.5, 121.4, 121.68, 121.8, 128.9, 129.2,
129.6, 129.8, 156.5, 156.7, 166.3.
Acknowledgment. The support of the University of Kuwait
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.
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 8a (racemic) (a) before and
(b) after addition of chiral shift reagent Eu(hfc)3; 1H, 13C NMR,
and 15N full spectral assignment of 2a, 5a, 8a, and 11a and
1
copies of H NMR and 13C NMR spectra. This material is
Compound 11a. Yield: 0.55 g (94%) isolated as cis/trans (11:
89) mixture after column chromatography [of RCM reaction with
Grubbs’ I (5 mol %)] as white crystals. Mp: 123-125 °C. Rf )
0.69 (DCM/petroleum ether/EtOAc 1:1:1). MS: m/z ) 588 (M+,
available free of charge via the Internet at http://pubs.acs.org.
JO9006392
4310 J. Org. Chem. Vol. 74, No. 11, 2009