The sequential building of chiral macrocyclic Bis-β-Lactams by double staudinger-Cu-Catalyzed azide-Alkyne Cycloadditions

Article abstract of DOI:10.1002/chem.200902685

A novel approach for the synthesis of macrocyclic bis-β-lactams based on the Cu-catalyzed alkyne-azide cycloaddition (CuAAC) is reported. The procedure is general and allows access to a full range of diastereomerically or enantiomerically pure macrocyclic cavities in good yields. The incorporation of chiral oxazolidinone fragments at C3 in the β-lactam rings allows the total enantiocontrol of the process.

Full text of DOI:10.1002/chem.200902685

DOI: 10.1002/chem.200902685
The Sequential Building of Chiral Macrocyclic Bis-b-Lactams by Double
Staudinger–Cu-Catalyzed Azide–Alkyne Cycloadditions
Daniel Pellico,[a] Mar Gꢀmez-Gallego,*[a] Pedro Ramꢁrez-Lꢀpez,[b]
Marꢁa Josꢂ MancheÇo,[a] Miguel A. Sierra,*[a] and M. Rosario Torres[c]
Abstract: A novel approach for the synthesis of macrocyclic bis-b-lactams based
on the Cu-catalyzed alkyne–azide cycloaddition (CuAAC) is reported. The proce-
dure is general and allows access to a full range of diastereomerically or enantio-
merically pure macrocyclic cavities in good yields. The incorporation of chiral oxa-
zolidinone fragments at C3 in the b-lactam rings allows the total enantiocontrol of
the process.
Keywords: azides · copper · cyclo-
addition · lactams · macrocycles
Introduction
dines.[5] Therefore, the design of new molecules framing b-
lactams in a macrocyclic structure could, at the same time,
lead to new types of potentially biologically active mole-
cules[6] and to highly versatile synthetic intermediates for
the preparation of diversely functionalized macrocycles.
The synthetic approaches to building macrocyclic struc-
tures that embed 2-azetidinone rings are summarized in
Scheme 1.[7] The first approach relies on the construction of
the b-lactam rings on a preformed macrocycle.[8] Thus, we
reported the synthesis of a series of macrocyclic b-lactams 2
starting from macrocyclic diimines 1 through a double Stau-
dinger ketene–imine cycloaddition reaction. These com-
pounds have been further used to obtain macrocyclic bis-b-
aminoacids, bis-azetidines, and bis-amides with defined ste-
reochemistry within the diversity-oriented synthesis (DOS)
concept.[8c] Our methodology has been useful for the prepa-
ration of other structurally related macrocyclic bis-b-lac-
tams,[8b,9] and has also been applied to acyclic diimines in
combination with ring-closing metathesis (RCM) for the clo-
sure of the cycle in the last step.[9]
The synthesis of different types of macrocyclic entities has
been frequently achieved during the last two decades.
Today, different synthetic methodologies that allow an effi-
cient access to this class of compounds are available.[1,2]
Nevertheless, the development of approaches for the synthe-
sis of macrocycles containing b-lactam moieties has been
somewhat neglected. This fact is appealing since 2-azetidi-
nones are highly relevant organic molecules, not only for
their role as structural components of the b-lactam antibac-
terial agents,[3,4] but also as intermediates in the preparation
of many other compounds, such as b-aminoacids and azeti-
[a] D. Pellico, Prof. M. Gꢀmez-Gallego, Prof. M. J. MancheÇo,
Prof. M. A. Sierra
Departamento de Quꢁmica Orgꢂnica, Facultad de Quꢁmica
Universidad Complutense, 28040 Madrid (Spain)
Fax : (+34)91-3944310
The second approach employs the multiple multicompo-
nent macrocyclization (MiB) strategy. This approach re-
quires starting from precursors that have the right geometry
to warrant further macrocyclic assembly.[10] Thus, the Stau-
dinger reaction of mixtures of dialdehydes 3 and diamines 4
affords macrocyclic tetra-b-lactams 5 in a one-pot process
(Scheme 1).[11] In this case, the reaction products are ob-
tained as inseparable mixtures of all the possible diastereo-
isomers. Finally, we have recently reported a different meth-
odology that relies on the assembling of the macrocyclic b-
E-mail: margg@quim.ucm.es
sierraor@quim.ucm.es
[b] Dr. P. Ramꢁrez-Lꢀpez
Instituto de Quꢁmica Orgꢂnica
Consejo Superior de Investigaciones Cientꢁficas (CSIC)
Juan de la Cierva 3, 28006 Madrid (Spain)
[c] Dr. M. R. Torres+
Laboratorio de Difracciꢀn de Rayos X, Facultad de Quꢁmica
Universidad Complutense, 28040 Madrid (Spain)
[+] To whom inquiries regarding the X-ray structure determination of
compounds 19n, 21, and (+)-26a should be addressed.
À
À
lactam structure by means of M C and M N (M=Pd, Pt)
bonds. The structures 6 and 7 obtained through this proce-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902685.
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FULL PAPER
cally controlled cyclization pro-
cesses frequently lead (irrever-
sibly) to the kinetic and statistic
distribution of products, includ-
ing a collection of linear/cyclic
oligomers and polymers of dif-
ferent chain length, thus inevi-
tably resulting in poor yields of
the desired macrocycles. In
these processes, taking advant-
age of the geometry and preor-
ganization of the precursors is
essential for the successful out-
come of the reaction.[15] Here
we benefit from the rigid 2-aze-
tidinone templates embedded
in the starting bis-alkynyl frag-
ment to effect the double
CuAAC. Therefore, our ap-
proach starts from a series of
bis-alkynes 8 that already hold
the preformed b-lactam moiet-
ies. The subsequent reaction
with different bis-azides
allows the obtention of the
ring-closure products 10
9
(Scheme 2). Reported herein is
the successful implementation
of this methodology to prepare
either racemic or enantiopure
bis-b-lactam cavities.
Results and Discussion
The synthesis of the starting
bis-alkynyl-b-lactams
follows
Scheme 1. A summary of the synthetic approaches used to build macrocyclic structures embedding 2-azetidi-
none rings (OTf=trifluoromethanesulfonate, dppe=1,2-bis(diphenylphosphino)ethane).
our previous reported method
dure combine the rigid 2-azeti-
dinone rings with ligand-tuna-
ble metal centers that have cis-
square-planar geometry.[12]
In the present work we de-
velop an alternative approach
to the synthesis of macrocyclic
bis-b-lactams that relies on the
sequential double Staudinger–
CuI-catalyzed 1,3-dipolar cyclo-
Scheme 2. Synthetic planning for 10.
addition
reaction
(CuAAC).[13,14] The double cycloaddition ring closure was
carried out on a bis-b-lactam that has the appropriate al-
kynes tethered to the C4 positions of the 2-azetidinone
rings. The success of the proposed methodology requires
overcoming the problem of ring closure versus oligomeriza-
tion (or cyclo-oligomerization). This is a key point, as kineti-
(Scheme 3).[12] Thus, diimines 14a–e were prepared in quan-
titative yields from diamines 13 and p-trimethylsilylethynyl-
benzaldehyde 11 or m-trimethylsilylethynylbenzaldehyde 12,
respectively.[16] Diimines 14 were then reacted with phenox-
yacetyl chloride in the presence of NEt3 to yield 1:1 mix-
tures of diastereomeric bis-b-lactams 15 and 16 (61–66%
[17]
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M. Gꢀmez-Gallego, M. A. Sierra et al.
pure bis-alkynyl–bis-b-lactams 17 and 18. In all cases the cis-
stereochemistry of the b-lactam rings was ensured by the
coupling constants of H3,H4 protons (average J
ACHTUNGTRENN(UNG H3,H4)=
4.4 Hz for compounds 17 and 18).[18]
The syn/anti (meso/racemic) stereochemistry of the bis-al-
kynyl–bis-b-lactams in Table 1 was determined by means of
X-ray analysis and/or spectroscopic methods. The geometry
of 16a had been already established by X-ray diffraction.[8a]
The study of the 1H NMR spectrum of this compound
showed the signals of the diastereotopic NCH2 protons as
two doublet of triplets, dt, at d=3.39 and 3.05 ppm, respec-
tively (Dd=0.34 ppm). This multiplicity pattern is also ob-
served in the corresponding syn (meso) isomer 15a, al-
though the signals of the dt are now clearly far apart (d=
3.46 and 2.98 ppm; Dd=0.48 ppm) (Figure 1A). The same
1
pattern for the NCH2 protons was observed in the H NMR
Scheme 3. Synthesis of the starting bis-alkynyl–b-lactams.
average yield) that were separated by chromatography on
silica gel (Table 1). The isomers were reacted independently
with tetrabutylammonium fluoride (TBAF) to remove quan-
titatively the trimethylsilyl (TMS) groups, thereby affording
Figure 1. 1H NMR spectra for compounds A) anti-16a and syn-15a, and
B) anti-16d and syn-15d.
Table 1. Bis-b-lactams 15 (R=TMS), 16 (R=TMS), 17 (R=H), and 18 (R=H) and the yields in which they
were produced (in parentheses).
spectra of the structurally relat-
ed syn/anti couple of bis-b-lac-
tams 15d and 16d, and their re-
spective configurations were as-
signed in consequence. Thus,
the anti isomer 16d showed the
NCH2 signals at d=3.42 and
3.07 ppm, respectively (Dd=
0.35 ppm), whereas these pro-
tons in the syn isomer appeared
at d=3.52 and 2.96 ppm (Dd=
0.56 ppm) (Figure 1B). These
characteristic changes in the
1H NMR spectra of syn/anti iso-
mers have been also observed
in other structurally related
macrocyclic bis-b-lactams.[8a]
15a (30%)
15b (31%)
17b (98%)
15c (26%)
17c (98%)
17a (97%)[a]
16a (32%)
16b (33%)
18b (97%)
16c (31%)
18c (98%)
18a (96%)[a]
The stereochemistry of the
bis-b-lactams having a 1,3-m-di-
aminobenzene bridge 15b/16b
was determined by X-ray dif-
15d (29%)
17d (98%)
15e (35%)
17e (97%)
–
–
fraction analysis of
a single
crystal of the azetidine deriva-
tive 21, which was obtained by
reduction of bis-b-lactam 16b
16d (33%)
18d (98%)
16e (33%)
18e (96%)
–
–
with
chloralane
(AlCl2H;
Scheme 4). The structure of 21
showed a C2 axis (Figure 2), as
expected for the anti (racemic)
[a] See ref. [12].
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Chiral Macrocyclic Bis-b-Lactams
FULL PAPER
Treatment of either syn or
anti
bis-alkynyl–bis-b-lactams
17 and 18 with a range of bis-
azides having different tethers
9a–d[19] in DMF in the presence
of CuI at room temperature af-
forded macrocycles 19a–n and
20a–n in yields ranging from 14
to 64% (Table 2, Scheme 5). In
all cases the reaction yielded
the expected macrocycles as the
Scheme 4. Synthesis of azetidine derivative 21.
Table 2. Macrocyclic bis-b-lactams 19 and 20 and the yields in which they
were produced (in parentheses).
9a
9b
9c
9d
syn-17a
syn-17b
syn-17c
syn-17d
syn-17e
anti-18a
anti-18b
anti-18c
anti-18d
anti-18e
19a (22%)
19b (40%)
19c (60%)
19d (59%)
19h (50%)
19i (15%)
–
19e (30%)
19 f (35%)
19g (55%)
[a]
[a]
[b]
19j (24%)
–
20a (23%)
19k (37%)
19m (41%)
20b (38%)
19l (62%)
19n (61%)
20c (60%)
–
20d (55%)
20h (64%)
20i (14%)
–
–
20e (25%)
20 f (39%)
20g (57%)
[a]
[a]
[b]
20j (19%)
–
20k (35%)
20m (47%)
20l (52%)
20n (51%)
[a] No signals of the macrocyclic ring were observed in the 1H NMR
spectra of the crude reaction mixtures. [b] <10% determined from
1H NMR spectra of the crude reaction mixtures.
Figure 2. ORTEP plot of 21 with 25% probability. Hydrogen atoms are
omitted for clarity, with an exception made for H3, H4, H3’, and H4’
bonded to the chiral carbon atoms. The asymmetric unit is one half of
the molecule.
diastereoisomer, which unequivocally established the stereo-
chemistry of the precursor 16b. In the case of the couple
(15e)17e/ACHTUNGTRENNUNG(16e)18e, the syn/anti stereochemistry was estab-
lished by X-ray diffraction analysis of the macrocyclic bis-b-
lactam 19n, derived from the CuAAC reaction of syn-17e
(Figure 3, see below).
Finally, for bis-b-lactams (15c)17c/ACTHNUTRGNEUNG(16c)18c that have an
ethylenediamine bridge, the syn/anti stereochemistry was es-
1
tablished by a H NMR spectroscopic study of the signals of
the H3,H4 b-lactam protons in the presence of [EuACHTNUTRGNEUNG(hfc)3]
(hfc=[(tris(3-(heptafluoropropylhydroxymethylene)-d-cam-
phorate)]). After the addition of the chiral shift reagent to
18c (CDCl3), the signals of the former CH duplets clearly
split, in accordance with a racemic (anti) diastereoisomer. In
a similar experiment carried out with 17c, the CH signals
did not separate, as expected for the meso (syn) isomer. The
stereochemical assignment is in full agreement with the data
reported for other structurally related compounds.[9]
Scheme 5. Synthesis of macrocycles 19 and 20.
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M. Gꢀmez-Gallego, M. A. Sierra et al.
sole reaction products (together with polymeric material of
unknown composition). No traces of other macrocyclic
structures were detected in the crude reaction mixtures. The
structural characterization of the products was based on an-
alytical and spectroscopic data (see the Experimental Sec-
tion and the Supporting Information). In the case of 19n, a
single crystal obtained by slow evaporation in CHCl3 al-
lowed the structural X-ray diffraction analysis (Figure 3)
that unequivocally confirmed the syn arrangement of the
precursor bis-b-lactam 17e (see above).
the lowest yields were observed when ortho-bis-azide 9a
(with the shortest tether) was used (19–30%).
Compounds 19/20 in Scheme 5 constitute a range of dia-
stereomerically pure macrocyclic cavities containing 2-azeti-
dinones as motifs of biological relevance. To go further, the
synthesis of enantiomerically pure macrocyclic cavities was
pursued next. The sequence of reactions followed is shown
in Scheme 6. Thus, enantiomerically pure bis-b-lactam (+)-
Scheme 6. Synthesis of enantiomerically pure macrocyclic bis-b-lactams
(+)-24a–c.
Figure 3. ORTEP plot of 19n with 25% probability. Hydrogen atoms are
omitted for clarity, with an exception made for H3, H4, H3’, and H4’
bonded to the chiral carbon atoms.
22 was prepared in 95% yield by the reaction of imine 14a
with (S)-(+)-(2-oxo-4-phenyloxazolydin-3-yl)acetic acid and
phenyldichlorophosphate in NEt3.[20] Compound (+)-22 was
obtained as a single product, thereby demonstrating that the
reaction occurs with total enantio- and diastereoselectivity.
The cis stereochemistry of the b-lactam rings was estab-
From the results in Table 2, it can be concluded that the
formation of the macrocycles 19 and 20 is not influenced by
the syn/anti stereochemistry of the starting bis-alkynyl li-
gands. Thus, for a given bis-azide 9 the yields of the cycliza-
tion products are similar with both isomers. The position
para (17a–c/18a–c) or meta (17d,e/18d,e) of the alkynyl
groups in the aromatic rings of the precursor bis-alkynyl–b-
lactams has also little influence on the progression of the
cyclization. However, the length of the tether between the
nitrogen atoms in the starting bis-alkynyl ligands 17 and 18
has more effect on the outcome of the process. Oligomeriza-
tion is the main reaction with bis-b-lactams (17c and 18c),
which have the short (CH2)2 chain as a tether, whereas for a
given bis-azide, there is hardly any difference in yields when
the tether is a flexible (CH2)3 chain or a more rigid 1,3-m-di-
aminobenzene bridge. Finally, the structure of the bis-azides
9 has also to be considered. The best yields (50–64%) were
obtained with the structurally related and more preorgan-
ized meta-bis-azides 9c and 9d, whereas the results are
poorer with ferrocenyl bis-azide 9b (35–47%). In all cases,
lished by the H3,H4 coupling constants (JACTHNUGRTENUNG(H3,H4)=4.5 Hz),
and the anti stereochemistry of (+)-22 was unambiguously
established by X-ray diffraction analysis of a macrocyclic de-
rivative ((+)-26a; Figure 4, see below). After removal of
the TMS groups (TBAF, 08C, 5 min, (+)-23, 97%) and re-
action with the most efficient bis-azides 9b–d, enantiomeri-
cally pure macrocyclic bis-b-lactams (+)-24a–c were ob-
tained in 30–58% yields (Scheme 6).
The experimental conditions used in the removal of the
TMS group in (+)-22 are critical. The reaction is very fast
(TBAF, 08C, THF, 5 min), and bis-alkynyl–bis b-lactam (+)-
23 is obtained quantitatively after workup. However, if the
reaction is carried out at room temperature for 45 min, the
complete cis/trans isomerization of the b-lactam rings
smoothly occurs and the anti,trans bis-alkynyl–bis-b-lactam
(À)-25 is obtained in 97% isolated yield (Scheme 7). The
trans stereochemistry of (À)-25 was established by the new
H3,H4 coupling constants (J
cis/trans isomerization of the b-lactam rings under the mild
(H3,H4)=2.3 Hz).[18] The clean
ACHTUNGTRENNUNG
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Chiral Macrocyclic Bis-b-Lactams
FULL PAPER
the expected enantiopure macrocyclic b-lactam cavities (+)-
26 in 35–62% yields (Scheme 7). Further structural confir-
mation of the products was gained by X-ray diffraction anal-
ysis of a single crystal obtained by slow evaporation of mac-
rocyclic bis-b-lactam (+)-26a in MeCN (Figure 4). By
means of this structure, the stereochemistry of anti,trans bis-
alkynyl–bis-b-lactam precursor (À)-25 was unequivocally es-
tablished. Furthermore, and considering that (À)-25 is very
likely formed by the exclusive epimerization of the more
acidic C3 positions of the b-lactam rings, the anti,cis stereo-
chemistry of its precursor (+)-22 could be also assigned (see
above).
The structures in Figures 3 and 4 show flexible macrocy-
clic cavities of 10ꢄ5 and 11ꢄ5 ꢅ, respectively, with distan-
ces of 4–5 ꢅ between the triazole rings. Chiral cavities are
of great importance in the field of molecular and anion rec-
ognition and their properties are valuable in different areas
such as organic chemistry; biochemistry and molecular biol-
ogy; polymer science; and supramolecular chemistry.[24] Our
procedure allows easy access to enantiomerically pure cavi-
ties by just placing the right substituent (with defined ste-
reochemistry) at C3 in the precursor bis-b-lactam fragment,
and also incorporates two triazole rings into the structure
that could have interesting properties for anion recogni-
tion.[25] Our method also leaves open the possibility of incor-
porating other chiral elements, either in the tether of the
bis-alkynyl–b-lactam fragment, or in the bis-azide to build
more complex chiral macrocycles.[25,26]
Scheme 7. Synthesis of enantiopure macrocyclic b-lactam cavities (+)-26.
Conclusion
A novel approach to the synthesis of macrocyclic bis-b-lac-
tams based on the sequential double Staudinger reaction–
Cu-catalyzed alkyne–azide (CuAAC) cycloaddition has
been developed. The procedure is general and allows access
to a full range of diastereomerically or enantiomerically
pure macrocyclic cavities in good yields. The incorporation
of chiral oxazolidinone fragments at C3 in the b-lactam
rings allows total enantiocontrol of the process. Eventually,
we have found an efficient procedure for the cis/trans iso-
merization of the 2-azetidinone moieties under smooth con-
ditions. The structures of the compounds prepared through
this work have been unambiguously determined by X-ray
diffraction studies and are flexible macrocyclic cavities of
10ꢄ5 and 11ꢄ5 ꢅ, respectively, with distances of 4–5 ꢅ be-
tween the triazole rings. The use of these chiral cavities in
different molecular recognition processes will be further
pursued in our laboratories.
Figure 4. ORTEP plot of (+)-26a with 25% probability. Hydrogen atoms
are omitted for clarity, with an exception made for H3, H4, H3’, and H4’
bonded to the chiral carbon atoms.
conditions used to remove the TMS groups deserves further
discussion. Generally, cis/trans isomerizations in 2-azetidi-
nones are carried out by C3 epimerization in the presence
of a base.[21] The reported procedures usually require high
concentrations of base, prolonged reaction times, and the
yields are low due to partial destruction of the starting ma-
terial during the reaction. Other methods that have been de-
scribed to achieve the ring cis/trans isomerization use UV
light irradiation,[22] or are restricted to 2-azetidinones that
have specific structural features.[23] In contrast, if the reac-
tion reported here would be of general applicability, it could
be clearly an advantageous procedure over the known meth-
ods. Therefore, the study of the scope of this new isomeriza-
tion procedure and its application to other sensitive b-
lactam derivatives requires further study.
Experimental Section
General procedures: Bis-b-lactams 15a, 16a, 17a, and 18a[12] and bis-
azides 9a–d[19] were prepared following literature procedures. Full experi-
mental procedures for the synthesis of dimines 14, compounds 15c–e,
16c–e, 17b–e, 18b–e, 19a–m, and 20a–n; crystallographic data; and
Finally, the reaction of anti,trans bis-alkynyl–bis-b-lactam
(À)-25 with azides 9b–d under the conditions above yielded
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M. Gꢀmez-Gallego, M. A. Sierra et al.
copies of NMR spectra of all new complexes discussed in the text are
available in the Supporting Information. 1H and 13C NMR spectra were
recorded at 228C using Bruker Avance 700 (700.1 and 176.0 MHz), 500
(500.1 and 125.7 MHz), 300 (300.1 and 75.5 MHz), or Bruker 200-AC
(200.1 and 50 MHz) spectrometers. Chemical shifts are given in ppm rela-
tive to CHCl3 (1H, d=7.27 ppm) and CDCl3 (13C, d=77.0 ppm), DMF
(1H, d=8.02 ppm) and [D7]DMF (13C, d=163.2 ppm), DMSO (1H, d=
2.50 ppm) and [D6]DMSO (13C, d=39.5 ppm), and CD3CN (1H, d=
1.95 ppm) and CD3CN (13C, d=118.0 ppm). IR spectra were recorded
using a Bruker Tensor 27 (MIR 8000–400 cmÀ1) spectrometer of a solid
film of pure compound. Mass spectra were recorded using a QSTAR pul-
sar I (hybrid analyzed QTOF, applied biosystems) (ESI), or a MAT 95
XP ThermoFinnigan (FAB) apparatus. CH2Cl2 was distilled from calcium
hydride and THF from sodium benzophenone. Flame-dried glassware
and standard Schlenk techniques were used for moisture-sensitive reac-
tions. Merck silica gel (230–400 mesh) was used as the stationary phase
for purification of crude reaction mixtures by flash column chromatogra-
phy. Identification of the products was made by TLC (Kiesegel 60F-254).
UV light (l=254 nm) was used to develop the plates.
silica gel (CH2Cl2/AcOEt 9:1). Bis-azetidine 21 (561 mg, 98%) was ob-
tained as
(300 MHz, CDCl3): d=7.49 (d, J=8.2 Hz, 4H; ArH), 7.41 (d, J=8.2 Hz,
4H; ArH), 7.23–7.08 (m, 8H; ArH), 6.84 (t, J=7.3 Hz, 2H; ArH), 6.58
a
crystalline solid. M.p. 112–1148C (CHCl3); 1H NMR
À
(d, J=8.4 Hz, 4H; ArH), 4.94 (t, J=5.8 Hz, 2H; CH O), 4.48 (d, J=
À
À
5.8 Hz, 2H; CH N), 3.84 (d, J=13.0 Hz, CH2 Ar), 3.58–3.49 (m, 4H;
À
À
À
CH2 N+CH2 Ar), 3.34–3.26 (m, 2H; CH2 N), 0.27 ppm (s, 18H; TMS);
13C NMR (75.5 MHz, CDCl3): d=157.3, 137.6, 137.4, 131.9, 129.2, 129.1,
ꢀ
À
128.4, 128.0, 127.5, 121.9, 120.7, 114.9 (ArC), 105.3, 93.7 ( C), 71.5 (CH
À
À
À
O), 64.3 (CH N), 60.8 (CH2 Ar), 57.1 ppm (CH2 N); IR (film): n˜max
3287, 3061, 3039, 2949, 2105, 1694, 1598, 1494, 1457, 1237, 1103, 1026,
795, 753 cmÀ1
=
.
General procedure for the synthesis of macrocycles: The bis-azide and
(+)-sodium l-ascorbate was added to a stirred solution of the corre-
sponding bis-b-lactam in DMF. The mixture was purged with Ar for
15 min and then CuSO4·5H2O was added in one portion. The molar ratio
of bis-b-lactam/bis-azide/l-ascorbate/CuSO4·5H2O was 1:1:0.4:0.2. The
reaction was stirred overnight at room temperature and the solvent was
removed under reduced pressure. The crude product was solved in
CH2Cl2 (40 mL), washed with water (2ꢄ20 mL), the organic layer dried
over MgSO4, and the solvent removed under reduced pressure. The pure
macrocycles were obtained after chromatography on silica gel (CH2Cl2/
AcOEt/MeOH, 8:2:0.1).
Synthesis of bis-b-lactams 15b/16b: A solution of phenoxyacetyl chloride
(1.30 g, 7.2 mmol) in dry CH2Cl2 (20 mL) was purged with argon and
cooled at À788C. Then a solution of triethylamine (1.40 g, 14.4 mmol) in
dry CH2Cl2 (10 mL) was added dropwise. The mixture was stirred for
30 min at À788C, and a solution of diimine 14b (1.20 g, 2.4 mmol) in dry
CH2Cl2 (10 mL) was added dropwise by means of a syringe pump for 2 h,
with the temperature maintained at À788C. The reaction was stirred at
room temperature for 16 h, and then quenched with a MeOH/water/ice
mixture (25 mL). The organic layer was washed with HCl (0.5m; to
remove the excess of triethylamine) and brine, and then dried with
MgSO4. The desiccant was removed by filtration and the solvent was
evaporated at reduced pressure. The crude solid was suspended in Et2O,
filtered with cold Et2O, and dried, thus yielding a 1:1 mixture of syn- and
anti-bis-b-lactams 15b/16b (1.46 g, 79%) that were separated by chroma-
tography on silica gel (hexane/AcOEt 7:3). Syn-bis-b-lactam 15b was ob-
tained as a crystalline solid (574 mg, 31%). M.p. 228–2318C (CHCl3);
1H NMR (300 MHz, CDCl3): d=7.37 (d, J=8.2 Hz, 4H; ArH), 7.28 (t,
J=7.7 Hz, 1H; ArH), 7.21–7.07 (m, 10H; ArH), 6.90 (s, 1H; ArH), 6.87
(t, J=7.2 Hz, 2H; ArH), 6.69 (d, J=7.8 Hz, 4H; ArH), 5.38 (d, J=
Synthesis of 19n: From bis-b-lactam 17e (50 mg, 79 mmol), bis-azide 9c
(15 mg, 79 mmol), (+)-sodium l-ascorbate (6 mg, 30 mmol), and
CuSO4·5H2O (4 mg 16 mmol) in DMF (100 mL), 19n (40 mg, 61%) was
obtained as a pale yellow crystalline solid. M.p. 176–1788C (CHCl3 +
MeOH); 1H NMR (300 MHz, CDCl3): d=8.26 (s, 2H; =CH), 7.95 (t, J=
7.7 Hz, 1H; ArH), 7.66–7.61 (m, 4H; ArH), 7.57–7.50 (m, 2H; ArH),
7.32–7.24 (m, 1H; ArH), 7.21–7.07 (m, 10H; ArH), 6.86–6.74 (m, 7H;
À
À
ArH), 5.79–5.66 (m, 6H; CH2 Ar+CH O), 4.92 (d, J=4.4 Hz, 2H;
À
À
CH N), 4.62 (d, J=15.4 Hz, 2H; CH2 N), 4.03 ppm (d, J=15.4 Hz, 2H;
CH2 N); 13C NMR (75.5 MHz, CDCl3): d=165.0 (C=O), 156.3, 154.2
(ArC), 145.9 (C), 138.7, 135.1, 134.0, 130.2, 129.2, 128.9, 128.3, 128.2,
À
127.4, 127.1, 125.5, 125.0, 122.9, 121.6 (ArC), 121.5 (=CH), 114.9 (ArC),
À
À
À
À
81.4 (CH O), 61.0 (CH N), 54.1 (CH2 Ar), 43.6 ppm (CH2 N); IR
(film): n˜max =3137, 3062, 2926, 1757, 1597, 1493, 1457, 1352, 1231, 1077,
1047, 864, 755 cmÀ1; FABMS: m/z: 818.9 [M+H]+; HRMS (ESI): m/z:
calcd for C49H30N9O4 [M+H]+: 818.3203; found: 818.3202.
À
À
4.4 Hz, 2H; CH O), 4.73 (d, J=14.9 Hz, 2H; CH2 N), 4.69 (d, J=
À
À
4.4 Hz, 2H; CH N), 3.90 (d, J=14.9 Hz, 2H; CH2 N), 0.22 ppm (s, 18H;
CH3); 13C NMR (75.5 MHz, CDCl3): d=165.3 (C=O), 156.5, 135.3, 133.0,
Synthesis of (+)-24a: From bis-b-lactam (+)-23 (50 mg, 71 mmol), bis-
azide 9b (21 mg, 71 mmol), (+)-sodium l-ascorbate (6 mg, 30 mmol), and
CuSO4·5H2O (4 mg, 16 mmol) in DMF (100 mL), (+)-24a (21 mg, 30%)
was obtained as a pale yellow crystalline solid. M.p. 2008C (CHCl3 +
MeOH; decomp); [a]D25 =+638 (c=0.001 in CH2Cl2); 1H NMR
(300 MHz, CD3CN): d=8.05 (s, 2H; =CH), 7.69 (d, J=8.1 Hz, 4H;
ArH), 7.43–7.32 (m, 10H; ArH), 7.30–7.19 (m, 4H; ArH), 5.23 (d, J=
15.2 Hz, 2H; CH2-Cp), 5.16 (d, J=15.2 Hz, 2H; CH2-Cp), 4.85 (d, J=
ꢀ
131.7, 129.4, 129.1, 128.5, 128.4, 128.1, 123.4, 122.0, 115.2 (ArC), 104.3 (
ꢀ
À
À
À
C), 95.2 ( C), 82.0 (CH O), 61.4 (CH N), 44.1 (CH2 N), À0.1 ppm
(CH3); IR (film): n˜max =3041, 2959, 2157, 1762, 1703, 1598, 1494, 1397,
1234, 1084, 953, 863, 753 cmÀ1
; HRMS (ESI): m/z: calcd for
C48H49N2O4Si2 [M+H]+: 773.3230; found 773.3217. Anti-bis-b-lactam 16b
was obtained as a crystalline solid (610 mg, 33%). M.p. 225–2278C
(CHCl3); 1H NMR (300 MHz, CDCl3): d=7.36 (d, J=8.3 Hz, 4H; ArH),
7.27 (t, J=7.8 Hz, 1H; ArH), 7.17 (d, J=8.3 Hz, 4H; ArH), 7.14–7.07
(m, 6H; ArH), 6.92 (s, 1H; ArH), 6.87 (t, J=7.4 Hz, 2H; ArH), 6.70 (d,
À
À
5.0 Hz, 2H; CH N), 4.42–4.33 (m, 4H; CH N), 4.25–4.13 (m, 6H;
À
CpH), 4.05 (t, J=8.8 Hz, 2H; CH2 O), 3.90 (brs, 2H; CpH), 3.88–3.79
(m, 2H; CH2 O), 3.47 (dt, 1J=14.4 Hz, J=7.0 Hz, 2H; CH2 N), 3.11
2
À
À
À
J=8.2 Hz, 4H; ArH), 5.44 (d, J=4.5 Hz, 2H; CH O), 4.73 (d, J=
2
(dt, 1J=14.4 Hz, J=7.0 Hz, 2H; CH2 N), 1.82 ppm (q, J=7.0 Hz, 2H;
À
À
À
14.8 Hz, 2H; CH2 N), 4.72 (d, J=4.5 Hz, 2H; CH N), 3.91 (d, J=
CH2); 13C NMR (75 MHz, CDCl3): d=164.5, 156.0 (C=O), 145.7 (C),
137.8, 134.7, 130.0, 129.0, 128.7, 128.2, 127.1, 124.8 (ArC), 121.9 (=CH),
14.8 Hz, 2H; CH2 N), 0.21 ppm (s, 18H; CH3); 13C NMR (75.5 MHz,
CDCl3): d=165.5 (C=O), 156.6, 135.4, 133.0, 131.8, 129.2, 128.5, 128.4,
À
À
84.3 (CpC), 69.5 (CH2 O), 68.9, 68.6, 68.6, 68.5 (CpC), 63.2, 62.9, 58.6
ꢀ
ꢀ
À
128.3, 128.1, 123.4, 122.1, 115.3 (ArC), 104.3 ( C), 95.3 ( C), 82.1 (CH
À
À
(CH N), 48.3, 40.6 (CH2 N), 28.0 ppm (CH2); IR (film): n˜max =3132,
2924, 1758, 1672, 1450, 1414, 1225, 1078, 1043, 881, 757 cmÀ1; ESIMS:
m/z: 1001.7 [M+H]+; HRMS (ESI): m/z: calcd for C55H49FeN10O6
[M+H]+: 1001.3185; found: 1001.3212.
À
À
O), 61.6 (CH N), 44.2 (CH2 N), À0.1 ppm (CH3); IR (film): n˜max =3039,
3960, 2920, 2160, 1764, 1597, 1495, 1399, 1353, 1237, 1083, 954, 844,
755 cmÀ1. HRMS (ESI): m/z: calcd for C48H49N2O4Si2 [M+H]+: 773.3230;
found: 773.3245.
Synthesis of (+)-24b: From bis-b-lactam (+)-23 (50 mg, 71 mmol), bis-
azide 9b (13 mg, 71 mmol), (+)-sodium l-ascorbate (6 mg,30 mmol), and
CuSO4·5H2O (4 mg, 16 mmol) in DMF (100 mL), (+)-24b (36 mg, 58%)
Synthesis of bis-azetidine 21: A solution of AlCl3 (103 mg, 0.77 mmol) in
dry THF (5 mL) was added with a cannula to a stirred suspension of
LiAlH4 (26 mg, 0.77 mmol) in dry THF (10 mL) at 08C and under Ar.
The mixture was stirred for 30 min at room temperature and then cooled
to 08C before the addition (also with a cannula) of a solution of bis-b-
lactam 16d (100 mg, 0.13 mmol) in dry THF (10 mL). After 20 min at
room temperature, the reaction was quenched with ice and extracted
with Et2O (3ꢄ20 mL). The organic phases were washed with brine and
water and dried over MgSO4. The solvent was removed under reduced
pressure and the crude product was purified by flash chromatography on
was obtained as
a crystalline solid. M.p. 2508C (CHCl3 +MeOH;
decomp); [a]2D5 =+768 (c=0.001 in CH2Cl2); 1H NMR (300 MHz,
CDCl3): d=7.87 (t, J=7.7 Hz, 1H; ArH), 7.83 (s, 2H; =CH), 7.69 (d, J=
8.1 Hz, 4H; ArH), 7.52 (d, J=7.7 Hz, 2H; ArH), 7.41–7.33 (m, 6H;
ArH), 7.31 (d, J=8.1 Hz, 4H; ArH), 7.23–7.13 (m, 4H; ArH), 5.73 (d,
À
À
J=14.9 Hz, 2H; CH2 Ar), 5.67 (d, J=14.9 Hz, 2H; CH2 Ar), 4.72 (d,
À
À
J=4.8 Hz, 2H; CH N), 4.38 (d, J=4.8 Hz, 2H; CH N), 4.16–4.04 (m,
1598
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1592 – 1600

Chiral Macrocyclic Bis-b-Lactams
FULL PAPER
4H; CH N+CH2 O), 3.87 (t, J=12.2 Hz, 2H; CH2 O), 3.56 (dt, 1J=
was obtained as
a crystalline solid. M.p. 2008C (CHCl3 +MeOH;
À
À
À
14.2 Hz, J=6.9 Hz, 2H; CH2 N), 3.12 (dt, 1J=14.2 Hz, 2J=6.9 Hz, 2H;
decomp); [a]2D5 =+818 (c=0.001 in CH2Cl2); 1H NMR (300 MHz,
CDCl3 +CD3OD): d=8.32 (s, 2H; =CH), 7.60–7.38 (m, 7H; ArH), 7.36–
2
À
CH2 N), 1.79 ppm (q, J=6.9 Hz, 2H; CH2); 13C NMR (175 MHz,
[D6]DMSO): d=164.2, 155.9 (C=O), 154.3 (ArC), 145.9 (C), 138.7, 137.7,
134.3, 130.1, 129.0, 128.7, 128.1, 127.1, 124.8, 122.7, (ArC), 121.5 (=CH),
À
À
7.12 (m, 11H; ArH), 7.06 (d, J=8.1 Hz, 4H; ArH), 5.62 (s, 4H; CH2
À
À
Ar), 5.12–4.97 (m, 2H; CH2 O), 4.80–4.67 (m, 4H; CH N), 4.28–4.10
(m, 4H; CH2 O+CH N), 3.09 (dt, 1J=14.1 Hz, J=7.2 Hz, 2H; CH2
2
À
À
À
À
À
À
À
69.4 (CH2 O), 63.1, 62.7, 58.7 (CH N), 53.9 (CH2 Ar), 40.3 (CH2 N),
27.6 ppm (CH2); IR (film): n˜max =2924, 1757, 1458, 1418, 1368, 1226,
1120, 1044, 882, 761 cmÀ1; ESIMS: m/z: 894.5 [M+H]+; HRMS (ESI):
m/z: calcd for C50H44N11O6 [M+H]+: 894.3475; found: 894.3507.
À
N), 2.70 (dt, J1 =14.1 Hz, J2 =7.2 Hz, 2H; CH2 N), 1.37 ppm (q, J=
7.2 Hz, 2H; CH2); 13C NMR (75.5 MHz, CDCl3 +CD3OD): d=169.3,
163.0 (C=O), 154.3 (ArC), 144.5 (C), 136.1, 134.6, 133.8, 128.5, 127.3,
À
126.8, 126.7, 125.6, 125.2, 125.1, 123.2 (ArC), 118.8 (=CH), 68.2 (CH2
Synthesis of (+)-24c: From bis-b-lactam (+)-23 (50 mg, 71 mmol), bis-
azide 9d (13 mg, 71 mmol), (+)-sodium l-ascorbate (6 mg, 30 mmol), and
CuSO4·5H2O (4 mg, 16 mmol) in DMF (100 mL), (+)-24c (32 mg, 52%)
À
À
À
O), 65.5, 58.0, 57.9 (CH N), 51.1 (CH2 Ar), 40.2 (CH2 N), 29.4 ppm
(CH2); IR (film): n˜max =3011, 2957, 1755, 1667, 1457, 1417, 1222, 1187,
1044, 754 cmÀ1; FABMS: m/z: 893.5 [M+H]+; HRMS (ESI): m/z: calcd
for C51H44N10O6 [M+H]+: 893.3523; found: 893.3542.
was obtained as
a crystalline solid. M.p. 2108C (CHCl3 +MeOH;
decomp); [a]2D5 =+758 (c=0.001 in CH2Cl2); 1H NMR (700 MHz,
[D6]DMSO) d=8.46 (s, 2H; =CH), 7.64 (d, J=8.0 Hz, 4H; ArH), 7.53–
7.46 (m, 3H; ArH), 7.42–7.33 (m, 6H; ArH), 7.31 (d, J=8.0 Hz, 4H;
ArH), 7.26 (d, J=7.3 Hz, 4H; ArH), 7.01 (s, 1H; ArH), 5.67 (s, 4H;
À
À
À
Acknowledgements
CH2 Ar), 4.90 (d, J=5.0 Hz, 2H; CH N), 4.43–4.40 (m, 4H; CH2 O+
À
À
À
CH N), 4.03 (t, J=8.8 Hz, 2H; CH2 O), 3.86–3.83 (m, 2H; CH N), 3.38
(dt, 1J=14.3 Hz, J=7.3 Hz, 2H; CH2 N), 3.12 (dt, J1 =14.3 Hz, J2 =
2
À
Support for this work under grants CTQ2007-67730-C02-01/BQU and
CSD2007-00006 (Programa Consolider-Ingenio 2010) from the MEC
(Spain) and CCG07-UCM/PPQ-2596 from the Comunidad de Madrid is
gratefully acknowledged. P. Ramꢁrez-Lꢀpez is a Juan de la Cierva Fellow.
7.3 Hz, 2H; CH2 N), 1.70 ppm (q, J=7.3 Hz, 2H; CH2); 13C NMR
À
(175 MHz, [D6]DMSO): d=164.4, 155.9 (C=O), 146.4 (C), 137.7, 136.8,
134.5, 130.1, 129.2, 129.0, 128.7, 128.1, 128.0, 127.1, 126.3, 124.8 (ArC),
À
À
À
121.1 (=CH), 69.5 (CH2 O), 63.0, 62.7, 58.7 (CH N), 52.7 (CH2 Ar),
À
40.6 (CH2 N), 27.8 ppm (CH2); IR (film): n˜max =3136, 2959, 1756, 1457,
1417, 1363, 1260, 1225, 1119, 1080, 1042, 802, 756 cmÀ1; ESIMS: m/z:
893.8 [M+H]+; HRMS (ESI): m/z: calcd for C51H45N10O6 [M+H]+:
893.3523; found: 893.3556.
[1] a) L. A. Wessjohann, C. K. Z. Andrade, O. E. Vercillo, D. G. Rivera,
Targets Heterocycl. Syst. 2006, 10, 24; b) F. von Nussbaum, M.
Brands, B. Hinzen, S. Weingand, D. Hꢆbich, Angew. Chem. 2006,
118, 5194; Angew. Chem. Int. Ed. 2006, 45, 5072; c) S. E. Gibson, C.
Lecci, Angew. Chem. 2006, 118, 1392; Angew. Chem. Int. Ed. 2006,
45, 1364; d) L. A. Wessjohann, E. Ruijter, Top. Curr. Chem. 2005,
243, 137; e) D. Kahne, C. Leimkuhler, W. Lu, C. Walsh, Chem. Rev.
2005, 105, 425; f) L. A. Wessjohann, E. Ruijter, D. G. Rivera, W.
Brandt, Mol. Diversity 2005, 9, 171; g) U. Nubbemeyer, Top. Curr.
Chem. 2001, 216, 125; h) V. J. Hruby, F. Al-Obeidi, W. Kazmierski,
Biochem. J. 1990, 268, 249; i) H. Kessler, Angew. Chem. 1982, 94,
509; Angew. Chem. Int. Ed. Engl. 1982, 21, 512.
[2] General references for supramolecular chemistry: a) J. M. Lehn,
Supramolecular Chemistry, Wiley-VCH, Weinheim, 1995; b) F.
Vçgtle, Supramolecular Chemistry, Wiley, New York, 1991; c) D. J.
Cram, M. J. Cram, Container Molecules and their Guests, RSC, Cam-
bridge, 1997.
[3] a) Chemistry and Biology of b-Lactam Antibiotics, Mode of Action,
Vol. 1: Penicillins and Cephalosporins (Ed.: D. B. Boyd), Academic
Press, New York, 1982; b) M. Takasuka, J. Nishikawa, K. Tori, J. An-
tibiot. 1982, 35, 1729; c) D. B. Boyd, J. Med. Chem. 1983, 26, 1010;
d) K. Bush, S. Mobashery in Resolving Antibiotic Paradox, Vol. 456
(Eds.: B. P. Rosen, S. Mobashery), Kluwer Academic, New York,
1998; e) J. M. Thomson, A. M. Distler, F. Pratl, R. A. Bonomo, J.
Biol. Chem. 2006, 281, 26734.
[4] For other uses of b-lactams, see, for example: a) A. D. Borthwick, G.
Weingarten, T. M. Haley, M. Tomaszewsky, W. Wang, Z. Hu, J.
Bedard, H. Jim, L. Yuen, T. S. Mansour, Bioorg. Med. Chem. Lett.
1998, 8, 365; b) W. D. Vaccaro, H. R. Davis, Bioorg. Med. Chem.
Lett. 1998, 8, 313; c) R. M. Adlington, J. E. Baldwin, S. L. Cooper,
W. McCoull, G. J. Pritchard, T. J. Howe, Bioorg. Med. Chem. Lett.
1997, 7, 1689.
Synthesis of (+)-26a: From bis-b-lactam (À)-25 (50 mg, 71 mmol), bis-
azide 9a (21 mg, 71 mmol), (+)-sodium l-ascorbate (6 mg, 30 mmol), and
CuSO4·5H2O (4 mg, 16 mmol) in DMF (100 mL), (+)-26a (25 mg, 35%)
was obtained as a pale yellow crystalline solid. M.p. 1958C (CHCl3 +
MeOH; decomp); [a]D25 =+308 (c=0.001 in CH2Cl2); 1H NMR
(300 MHz, CD3CN): d=8.03 (s, 2H; =CH), 7.57 (d, J=8.2 Hz, 4H;
ArH), 7.32–7.24 (m, 4H; ArH), 7.22–7.14 (m, 6H; ArH), 7.07 (d, J=
8.2 Hz, 4H; ArH), 5.22 (d, J=15.2 Hz, 2H; CH2-Cp), 5.15 (d, J=
À
15.2 Hz, 2H; CH2-Cp), 4.98–4.89 (m, 2H; CH2 O), 4.77–4.67 (m, 4H;
À
À
À
CH N), 4.25–4.15 (m, 6H; CH2 O+CpH), 4.10 (d, J=2.3 Hz, 2H; CH
À
N), 4.04 (brs, 2H; CpH), 3.99 (brs, 2H; CpH), 3.04–2.83 (m, 4H; CH2
N), 1.53 ppm (q, J=7.2 Hz, 2H; CH2); 13C NMR (175 MHz, [D6]DMSO):
d=165.0, 156.2 (C=O), 145.7 (C), 138.2, 136.0, 130.2, 128.7, 128.5, 127.3,
À
127.1, 125.1 (ArC), 121.9 (=CH), 84.3 (CpC), 70.1 (CH2 O), 68.8, 68.7,
À
À
68.6 (CpC), 67.1, 59.8, 59.7 (CH N), 48.2 (CH2-Cp), 38.9 (CH2 N),
26.1 ppm (CH2); IR (film): n˜max =2925, 2854, 1754, 1496, 1457, 1418,
1109, 1081, 1042, 830, 757 cmÀ1; FABMS: m/z: 1001.6 [M+H]+; HRMS
(ESI): m/z: calcd for C55H49FeN10O6 [M+H]+: 1001.3185; found:
1001.3195.
Synthesis of (+)-26b: From bis-b-lactam (À)-25 (50 mg, 71 mmol), bis-
azide 9b (13 mg, 71 mmol), (+)-sodium l-ascorbate (6 mg, 30 mmol), and
CuSO4·5H2O (4 mg, 16 mmol) in DMF (100 mL), (+)-26b (39 mg, 62%)
was obtained as
a crystalline solid. M.p. 2208C (CHCl3 +MeOH;
1
decomp); [a]2D5 =+298 (c=0.001 in CH2Cl2); H NMR (300 MHz, CDCl3)
d=7.87 (t, J=7.6 Hz, 1H; ArH), 7.78 (s, 2H; =CH), 7.53 (d, J=7.6 Hz,
2H; ArH), 7.45 (d, J=7.5 Hz, 4H; ArH), 7.15 (brs, 10H; ArH), 6.81 (d,
À
J=7.5 Hz, 4H; ArH), 5.74 (d, J=14.4 Hz, 2H; CH2 Ar), 5.63 (d, J=
À
À
14.4 Hz, 2H; CH2 Ar), 4.90–4.79 (m, 2H; CH N), 4.75–4.61 (m, 4H;
À
À
À
À
CH N+CH2 O), 4.28–4.14 (m, 2H; CH2 O), 3.96 (brs, 2H; CH N),
[5] a) M. S. Manhas, D. R. Wagle, J. Chiang, A. K. Bose, Heterocycles
1988, 27, 1755; b) G. I. Georg, The Organic Chemistry of b-Lactams,
VCH, Weinheim, 1992; c) I. Ojima, Adv. Mol. Struct. Res. 1995, 1,
95; d) I. Ojima, F. Delagoge, Chem. Soc. Rev. 1997, 26, 377; e) B. Al-
caide, P. Almendros, Chem. Soc. Rev. 2001, 30, 226; f) B. Alcaide, P.
Almendros, Curr. Med. Chem. 2004, 11, 1921; g) B. Alcaide, P. Al-
mendros, C. Aragoncillo, Chem. Rev. 2007, 107, 4437.
[6] The following article gives an up-to-date description of the appeal-
ing necessity of obtaining new antibacterial agents: a) C. T. Walsh,
G. Wright, Chem. Rev. 2005, 105, 391; b) J. F. Fisher, S. O. Meroueh,
S. Mobashery, Chem. Rev. 2005, 105, 395; c) D. J. Payne, Science
2008, 321, 1644.
3.13–2.90 (m, 4H; CH2 N), 1.57–1.44 ppm (m, 2H; CH2); 13C NMR
À
(75.5 MHz, CDCl3): d=165.7, 156.6 (C=O), 153.9 (ArC), 147.1 (C),
139.0, 137.1, 135.7, 130.5, 129.3, 129.2, 126.8, 126.7, 125.8, 123.3 (ArC),
À
À
À
120.0 (=CH), 70.4 (CH2 O), 68.1, 61.1, 60.8 (CH N), 55.0 (CH2 Ar),
À
39.5 (CH2 N), 26.4 ppm (CH2); IR (film): n˜max =3451, 3010, 1756, 1674,
1597, 1458, 1417, 1224, 1045, 756 cmÀ1; FABMS: m/z: 894.5 [M+H]+;
HRMS (ESI): m/z: calcd for C50H44N11O6 [M+H]+: 894.3475; found:
894.3473.
Synthesis of (+)-26c: From bis-b-lactam (À)-25 (50 mg, 71 mmol), bis-
azide 9c (13 mg, 71 mmol), (+)-sodium l-ascorbate (6 mg, 30 mmol), and
CuSO4·5H2O (4 mg, 16 mmol) in DMF (100 mL), (+)-26c (32 mg, 50%)
Chem. Eur. J. 2010, 16, 1592 – 1600
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1599

M. Gꢀmez-Gallego, M. A. Sierra et al.
[7] Although there is an early report in which an isomeric mixture of
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JACHTUNGTRENNUNG(H3,H4) cis value is approximately 4.5–6 Hz, whereas JCAHTUNGTRENN(UGN H3,H4)
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Received: September 29, 2009
Published online: December 18, 2009
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