Towards a general synthesis of 3-metal-substituted β-lactams

Article abstract of DOI:10.1002/chem.201301114

Joining metals and antibiotics: Studies towards a general method for the synthesis of β-lactams that have a metal complex moiety attached to the C3-position are reported (see scheme). The cis/trans selectivity of the reactions ranges from low in complexes containing the alkyne moiety joined directly to the cyclopentadienyl ring to complete when the metal moiety is separated from the reactive alkyne by an alkynyl-aryl fragment. Copyright

Full text of DOI:10.1002/chem.201301114

COMMUNICATION
Antibiotics
B. Baeza, L. Casarrubios,*
M. A. Sierra* .................. &&&& — &&&&
Towards a General Synthesis of 3-
Metal-Substituted b-Lactams
Joining metals and antibiotics: Studies
towards a general method for the syn-
thesis of b-lactams that have a metal
complex moiety attached to the C3-
position are reported (see scheme).
The cis/trans selectivity of the reac-
tions ranges from low in complexes
containing the alkyne moiety joined
directly to the cyclopentadienyl-ring to
complete when the metal moiety is
separated from the reactive alkyne by
an alkynyl–aryl fragment.
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

DOI: 10.1002/chem.201301114
Towards a General Synthesis of 3-Metal-Substituted b-Lactams
Beatriz Baeza, Luis Casarrubios,* and Miguel A. Sierra*[a]
Molecules containing simultaneously an organometallic
ganometallic entities.[8] This structural diversity of the bioor-
ganometallic 2-azetidinones may be of high relevance.
Nowadays the preparation of novel b-lactam antibiotics is a
priority due to the apparition of pathogens with multidrug
resistance,[9] in particular those containing enzymes capable
of hydrolyzing the four-membered ring of these antibiotics
(metallo-b-lactamases or mbs).[10] This resistance renders the
antibiotic inactive and it is a cause of worldwide alarm.
Moreover, it seriously questions our ability to fight the
never-ending war of man against pathogenic germs. This is
especially true since the discovery of the New Delhi mbs
(NDM-1) conferring nearly complete resistance to most of
the standard b-lactam antibiotics.[11] So far there are no
known inhibitors to these class B b-lactamases as these en-
zymes are named.[12]
moiety and a b-lactam nucleus are scarce.[1] Most of these
compounds are coordination complexes of well-known anti-
bacterial agents, and the remaining are mainly metallocene-
containing 2-azetidinones.[2] Our interest in the synthesis of
novel classes of metalla-b-lactams has resulted to date in the
preparation of ferrocenyl-2-azetidinones 1,[3] diverse penicil-
lin and cephalosporin derivates 2 and 3 containing pendant
chromium(0) carbene moieties,[4] and the first example of a
6-ruthenocenylpenicillin, 4.[5] Macrocyclic bis-b-lactams con-
Additionally, the synthesis of new 2-azetidinones contain-
ing unprecedented structures is pursued due to the fact that
it is now known that 2-azetidinone-derived drugs show bio-
logical properties of interest apart from their antibacterial
activity. For example, it has been reported that they exhibit
strong activity as inhibitors of mammalian serine proteas-
es,[13] cholesterol absorption inhibitors,[14] inhibitors of the
human cytomegalovirus (HCMV, a b-herpes virus),[15] and
neuroprotectors.[16] Herein, we report results that demon-
strate not only the suitability of using the Kinugasa reaction
to access to b-lactams containing diverse metal substituents
at the C3-position, but also some insights into the mecha-
nism of this reaction.
taining the metal moiety embedded in the macrocycle have
also been reported from these laboratories.[6] Within this
context, we devised an alternative entry to the nucleus of 2-
azetidinone-containing organometallic substituents by using
a Kinugasa reaction,[7] namely the reaction of a metal com-
plex bearing the alkyne moiety and a nitrone. This led to a
new type of general entry to compounds containing the
metal complex moiety attached to the C3-position of the b-
lactam.
Ethynylferrocene 5a was used as the substrate to tune-up
the reaction conditions. Thus, the reactions of compound 5a
with diphenylnitrone 6a (Scheme 1) were carried out in the
In this regard, in addition to expanding the potential to
produce new entities, the inclusion of organometallic moiet-
ies in well-known biologically active templates will highly
enhance the structural diversity of the corresponding bioor-
Scheme 1. Synthesis of 3-metallocenyl-2-azetidinones.
[a] B. Baeza, Prof. L. Casarrubios, Prof. M. A. Sierra
Dpto. de Quꢁmica Orgꢂnica, Facultad de Quꢁmica
Universidad Complutense, 28040 Madrid (Spain)
Fax : (+34)913944310
presence of different bases (Et3N, Cy2NMe), Cu sources
(CuCl, CuI, Cu-2-thienylcarboxylate), additives (indaBOX
7, Phen 8, Diox 9), and temperatures. While 3-ferrocenyl-2-
azetidinone 10a was obtained under all the different condi-
tions tested, the combination 2.5% CuCl/50% Cy2NMe/
E-mail: luis_casarrubios@quim.ucm.es
sierraor@quim.ucm.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301114.
&
2
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Towards a General Synthesis of 3-Metal-Substituted b-Lactams
COMMUNICATION
Scheme 2. Synthesis of 2-azetidinones containing a half-sandwich metal
substituent at C3.
2.75% indaBOX (percentages referred to the amount of ni-
trone) was the optimum.[17] b-Lactam 10a was obtained in
73% isolated yield as a 1:0.35 cis/trans mixture (Scheme 1).
The conditions used to obtain compound 10a were used to
prepare 3-ruthenocenyl-2- azetidinone 10b (70% isolated
yield, 1:0.35 cis/trans mixture) from ethynylruthenocene 5b
(Scheme 1).
The analysis of the enantiomeric excess for compounds 10
was done through conventional 1H NMR spectroscopy in
the presence of [EuACTHNUTRGNE(UNG hfc)3] (hfc=3-(heptafluoropropylhy-
droxymethylene)-(+)-camphorate) by using cis/trans mix-
tures of compounds 10a and 10b. The calculated enantio-
meric excess (ee) for both compounds was lower than
15%.[18]
Scheme 3. Different nitrones tested in the Kinugasa reaction of complex
5a.
The half-sandwich alkynes 11a and 11b were next reacted
with nitrone 6a under analogous reaction conditions to
those used for the preparation of b-lactams 10. The corre-
sponding 2-azetidinones 12a and 12b containing half-sand-
wich Mn- or Re-derived substituents attached to the C3-po-
sition of the four-membered ring were obtained in 75 and
74% isolated yields and as 0.45:1 and 0.67:1 cis/trans mix-
tures, respectively (Scheme 2). Again, both diastereomers of
compound 12b were obtained with ee values of <15%.[18]
The compatibility of the basic conditions and the Cu cata-
lysts required to effect the Kinugasa reaction with the sensi-
tive ruthenocene 5b and half-sandwich Mn- and Re- com-
plexes 11a–b is remarkable.
Alkynes 14 containing the triple bond separated from a
sensitive Group 6 metal–carbene center either by aryl or al-
kynyl–aryl moieties were next tested. Again, the mixture
2.5% CuCl/50% Cy2NMe/2.75% indaBOX in a 1.5:1 car-
bene complex/nitrone ratio was the optimum for the prepa-
ration of the corresponding 2-azetidinones. b-lactams 15
were obtained as single cis isomers in 48–60% isolated
yields, which is notable due to the presence of the chromi-
um(0)–carbene moiety prone to both oxidation[19] and trans-
metallation (Scheme 4).[20]
However, the use of the less
stable Me-substituted nitrone
6b or cyclic nitrone 6c pro-
duced only complex mixtures
when reacted with complexes 5
or 11. The corresponding prod-
ucts derived from the self-cou-
pling of the alkyne were tenta-
tively identified in the reaction
mixtures, but their isolation
was elusive. More successful
was the reaction of chiral ni-
trone 6d with ethynylferrocene
5a, which leads to 3-ferrocen-
yl-2-azetidinone 13 in 78%
yield as a 1:1 cis/trans mixture
(Scheme 3). Each diastereomer
of compound 13 was obtained
as a single enantiomer. Clearly,
in this case the chirality of the
nitrone is responsible for the
observed enantioselectivity of
the reaction.
Scheme 4. Synthesis of b-lactams containing a tethered Cr0 or W0 Fischer carbene moiety.
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

L. Casarrubios, M. A. Sierra, and B. Baeza
It is worth noting the complete cis selection observed
during the formation of b-lactams 15. Apparently, the place-
ment of the metal complex directly bonded to the alkyne (at
the emerging C3 of the four-membered ring) diminishes the
cis/trans selectivity, whereas separating the metal fragment
from the reactive alkyne by a tether resulted in a totally se-
lective reaction. Additionally, compounds 15 were obtained
in low but appreciable enantioselectivities (35 for 15a, 24
for 15b, and 21% ee for 15c).[18] Both the complete cis selec-
tivity and the increase in enantioselectivity observed when
the metal-center is placed away from the reaction center
pointed to a pivotal role of the metal fragment in determin-
ing the selectivity of the reaction.
The low cis/trans selectivity obtained in the synthesis of
compounds 10 and 12 is usual in the Kinugasa reaction.[7] It
is generally accepted that the cis/trans selectivity of the Ki-
nugasa reaction is defined either during the protonation of
the intermediate Cu species 16, according to the original
proposal of Ding and Irwin,[21] or by protonation of the Cu
enolate 17 formed during the collapse of the aminoketene
18. Both reaction pathways share a common intermediate 19
formed upon addition of the nitrone to the Cu acetyli-
de.[22]Additionally, it has been proposed[7,21] that the thermo-
dynamic trans isomer may arise from the deprotonation of
the kinetic cis product by the base present in the reaction
media to form the intermediate anion at the C3-position of
the four-membered ring (Scheme 5).
of 10a. No epimerization was observed after 72 h of reac-
tion. Therefore, at least under the conditions that we used,
the origin of the cis/trans selectivity should be different from
the epimerization of the final products. In fact, the diaster-
eoselectivity should reflect the selectivities in the protona-
tion event of either intermediate species 16 or 17. The cis/
trans selectivity is not attributable to the indaBOX ligand
since it is a common additive for all reactions. The use of
chiral nitrone 6d overcomes the low enantioselectivity of
these reactions but not the low cis/trans selectivity during its
reaction with ethynylferrocene 5a to form 13. This is a
known behavior of chiral nitrones in the Kinugasa reac-
tion.[23] Finally, for the sake of comparison, the reported re-
action between nitrone 6a and phenylacetylene catalyzed by
indaBOX using Cy2NH as the base and CuCl as the catalyst
(20%) renders the corresponding 2-azetidinone in 58%
yield as a 95:5 cis/trans mixture (53% ee for the cis
isomer).[17]
The bulkiness of the [M(Cp)2] or [M(CO)3Cp] (Cp= cy-
clopentadienyl) moieties should be responsible for these re-
sults. Thus, the protonation of either intermediate species 16
or 17 by the face opposite to the adjacent Ph-ring would
À
place the two substituents at C3 and C4, namely the Ph
and metal fragments, in a cis disposition, the kinetic favorite
pathway for nonsterically demanding substituents. However,
À
the strong steric interaction between the Ph and the bulky
metal moiety would favor the competitive protonation by
the same face of the adjacent Ph-ring leading to the trans
isomer. The Ph-moieties of complexes 14 containing the
sterically demanding metal substituents tethered to the aro-
matic ring by a linear alkyne group, and, therefore unable to
interfere with the protonation step, lead to the exclusive for-
mation of the cis isomers. The origin of the low enantiose-
lectivities observed remains unclear.[24]
To discard the hypothesis that the cis/trans ratio reflected
the formation of the thermodynamically more stable trans
isomer, due to epimerization of the C3-position of the 2-aze-
tidinone ring by the amine present in the reaction media,
pure cis-10a was reacted with an excess of Cy2NMe under
identical reaction conditions to those used in the synthesis
To conclude, a method to efficiently prepare b-lactams
containing metal fragments at the C3-position of the azetidi-
none ring has been developed. The approach uses a Kinuga-
sa reaction between terminal alkynes substituted by metal
fragments, including sandwich, half-sandwhich, and arene-
tethered metal–carbene (Fischer) complexes. The method is
compatible with metal fragments that are sensitive to oxida-
tion and transmetallation. As usual for the Kinugasa reac-
tion, the cis/trans selectivity of the formation of the b-lactam
ring is low for complexes containing the alkyne moiety
joined directly to the Cp ring, whereas it is complete when
the metal moiety is separated from the reactive alkyne by
an aryl–akynyl fragment. The enantioselectivities of the
processes are low, increasing slightly when the metal frag-
ment is separated from the reactive alkyne. A model to ra-
tionalize the cis/trans selectivity based on the interaction be-
tween the substituent in the emerging C3 and the substitu-
ent in the nitrone carbon atom is proposed. While much
work remains to fully control the selectivity in the synthesis
of these new classes of compounds, the structures available
represent potential biologically active b-lactams. Efforts to
achieve these endeavors are underway in our laboratories.
Scheme 5. Two proposed reaction pathways for the Kinugasa reaction.
&
4
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Towards a General Synthesis of 3-Metal-Substituted b-Lactams
COMMUNICATION
3706; c) T. R. Paul, N. G. Halligan, L. C. Blaszczak, T. R. Parr, Jr.,
T. J. Beveridge, J. Bacteriol. 1992, 174, 4689; d) S. Wçckel, J. Gale-
zowska, S. Dechert, F. Meyer, Inorg. Chem. 2012, 51, 2486; e) A.
Dauth, J. A. Love, Dalton Trans. 2012, 41, 7782; f) L. Dreesen, C,
Silien, C. Volcke, Y. Sartenaer, P. A. Thiry, A. Peremans, J. Grugier,
J. Marchand-Brynaert, A. Brans, S. Grubisic, B. Joris, ChemPhy-
sChem 2007, 8, 1071; g) D. Kumar, A. Syamal, A. Kumar, D. Dass,
A. Gupta, Asian J. Chem. 2009, 21, 7345; h) M. J. Zaworotko, H. H.
Hammud, I. Abbas, V. C. Kravtsov, M. S. Masoud, J. Coord. Chem.
2006, 59, 65; i) J. R. Anacona, E. M. Figueroa, J. Coord. Chem. 1999,
48, 181; j) N. E. A. El-Gamel, J. Coord. Chem. 2010, 63, 534;
k) Z. H. Chohan, C. T. Supuran, A. Scozzafava, J. Enzyme Inhib.
Med. Chem. 2004, 19, 79; l) G. G. Mohamed, W. M. Hosny, M. A.
Abd El-Rahim, Synth. React. Inorg. Met.-Org. Chem. 2002, 32, 1501;
m) T. Kupka, Spectrochim. Acta Part A 1997, 53, 2649.
Experimental Section
General procedure for the Kinugasa reaction: A Schlenk tube was charg-
ed with CuCl (2.5 mol% related to the nitrone) and indaBOX (2.75%
mmol related to the nitrone) dissolved in MeCN (0.01 mL). The mixture
was allowed to stir at room temperature for 1 h. Cy2NMe (0.50 mmol)
was added and the mixture was transferred via cannula to a Schlenk tube
containing a 0.2m solution of the corresponding nitrone (1.00 mmol) in
MeCN. The reaction was cooled to 08C and a 0.3m solution of the alkyne
(1.50 mmol) in MeCN was added dropwise. The solution was slowly al-
lowed to reach RT and stirred at this temperature until TLC analysis
showed the total consumption of the starting nitrone. The solvent was
then evaporated under vacuum and the thus-obtained crude was analyzed
1
by H NMR spectroscopy to evaluate the cis/trans b-lactam ratio, and pu-
rified as indicated for each case.
[2] a) K. Kumar, P. Singh, L. Kremer, Y. Guerardel, C. Biot, V. Kumar,
Dalton Trans. 2012, 41, 5778; b) J. Balogh, R. Skoda-Foeldes, K.
Vazdar, I. Habus, J. Organomet. Chem. 2012, 697, 51; c) J. Balogh, T.
Kegl, L. Parkanyi, L. Kollar, F. Ungvary, R. Skoda-Foeldes, J. Orga-
nomet. Chem. 2011, 696, 1394; d) K. Radolovic, K. Molcanov, I.
Habus, J. Mol. Struct. 2010, 966, 8; e) V. Kovac, K. Radolovic, I.
Habus, D. Siebler, K. Heinze, V. Rapic, Eur. J. Inorg. Chem. 2009,
389; f) T. Poljak, K. Molcanov, A. Visnjevac, I. Habus, V. Kovac, V.
Rapic, J. Mol. Struct. 2005, 751, 60; g) L. Bernardi, B. F. Bonini, M.
Comes-Franchini, G. Dessole, M. Fochi, A. Ricci, Eur. J. Org. Chem.
2005, 3326; h) B. F. Bonini, C. Femoni, M. Comes-Franchini, M.
Foschi, G. Mazzanti, A. Ricci, G. Varchi, Synlett 2001, 1092; i) A.
Ghatak, F. F. Becker, B. K. Banik, Heterocycles 2000, 53, 2769; j) N.-
Y. Fu, M.-S. Liu, Chin. J. Org. Chem. 2010, 30, 499.
[3] a) M. A. Sierra, M. J. MancheÇo, R. Vicente, M. Gꢄmez-Gallego, J.
Org. Chem. 2001, 66, 8920; b) M. A. Sierra, M. Rodrꢁguez-Fernꢂn-
dez, L. Casarrubios, M. Gꢄmez-Gallego, C. P. Allen, M. J. Manche-
Ço, Dalton Trans. 2009, 8399.
[4] M. A. Sierra, M. Rodrꢁguez-Fernꢂndez, L. Casarrubios, M. Gꢄmez-
Gallego, M. J. MancheÇo, Eur. J. Org. Chem. 2009, 2998.
b-Lactam 10a: By following the general procedure, from nitrone 6a
(80 mg, 0.40 mmol) and ethynylferrocene 5a (126 mg, 0.60 mmol), and
after 3 d at RT, a crude containing 10a (cis/trans 1:0.35) was obtained.
The insoluble solid material was taken up with MeCN yielding pure cis-
10a (84 mg, 0.2 mmol, 50%) as a yellow solid. Evaporation of the MeCN
and purification of the residue by SiO2 flash chromatography (hexanes)
yielded pure trans-10a, (37 mg, 0.09 mmol, 23%) as a pale-yellow oil.
b-Lactam cis-10a: 1H NMR (300 MHz, CDCl3): d=7.44–7.35 (m, 2H),
7.34–7.24 (m, 2H), 7.19–7.01 (m, 6H), 5.25 (d, 1H, J=6.1 Hz), 4.75 (d,
1H, J=6.1 Hz), 4.26 (s, 5H), 4.01–3.98 (m, 1H), 3.92–3.87 (m, 2H), 3.80–
3.76 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d=165.6, 137.9, 134.7,
129.0, 128.0, 127.7, 126.9, 123.8, 117.1, 78.2, 69.1, 68.3, 68.2, 68.0, 67.6,
60.2, 57.0 ppm; IR (film): n˜ =1753 cmÀ1; HRMS ESI: m/z: calcd for
C25H21FeNO: 408.1046 [M+H]+; found: 408.1059 [M+H]+.
b-Lactam trans-10a: 1H NMR (300 MHz, CDCl3): d=7.44–7.32 (m, 7H),
7.29 (s, 1H), 7.26–7.22 (m, 1H), 7.08–7.02 (m, 1H), 4.89 (d, 1H, J=
2.5 Hz), 4.31–4.26 (m, 1H), 4.22–4.18 (m, 3H), 4.19 (s, 5H), 3.98 ppm (d,
1H, J=2.5 Hz); 13C NMR (75 MHz, CDCl3): d=165.3, 137.7, 137.6,
129.2, 129.1, 128.5, 125.9, 123.8, 116.9, 81.6, 68.8, 68.3, 68.1, 67.4, 66.7,
63.0, 60.2 ppm; IR (film): n˜ =1752 cmÀ1; HRMS ESI: m/z: calcd for
C25H21FeNO: m/z: 408.1046 [M+H]+; found: 408.1043 [M+H]+.
[5] M. L. Lage, I. Fernꢂndez, M. J. MancheÇo, M. Gꢄmez-Gallego,
M. A. Sierra, Chem. Eur. J. 2009, 15, 593.
[6] D. Pellico, M. Gꢄmez-Gallego, P. Ramꢁrez-Lꢄpez, M. J. MancheÇo,
M. A. Sierra, M. R. Torres, Chem. Eur. J. 2009, 15, 6940.
b-Lactam 15b: By following the general procedure, from 6a (39.4 mg,
0.20 mmol) and carbene complex 14b (108 mg, 0.30 mmol), and after
24 h at RT, a crude containing exclusively cis-15b was obtained. SiO2
chromatography (hexanes to hexanes/AcOEt 4:1) yielded pure cis-15b
(68 mg, 0.12 mmol, 60%) as a pale-orange solid. 1H NMR (300 MHz,
CDCl3): d=8.74 (brs, 1H), 7.43 (d, 2H, J=8.0 Hz), 7.36–7.21 (m, 2H),
7.20–7.04 (m, 10H), 5.51 (d, 1H, J=6.1 Hz), 5.02 (d, 1H, J=6.1 Hz),
3.42 ppm (d, 3H, J=5.0 Hz); 13C NMR (75 MHz, CDCl3): d=256.3,
223.3, 217.1, 164.8, 137.4, 133.8, 133.0, 132.3, 131.3, 131.0, 130.7, 129.5,
129.4, 129.1, 128.4, 128.2, 127.0, 124.3, 121.4, 117.2, 88.8, 60.1, 59.5,
39.4 ppm; IR (film): n˜ =2054, 1928, 1752 cmÀ1; HRMS ESI: m/z: calcd
for C30H20CrN2O6: 557.0804 [M+H]+; found: 557.0806 [M+H]+.
[7] M. Kinugasa, S. Hashimoto, J. Chem. Soc. Chem. Commun. 1972,
466. For reviews. see: a) B. Mandal, B. Basu, Top. Heterocycl. Chem.
2012, 30, 85; b) R. Pal, S. C. Ghosh, K. Chandra, A. Basak, Synlett
2007, 2321; c) J. Marco-Contelles, Angew. Chem. 2004, 116, 2248;
Angew. Chem. Int. Ed. 2004, 43, 2198. For general methods in the
synthesis of b-lactams, see: d) A. Brandi, S. Cicchi, F. M. Cordero,
Chem. Rev. 2008, 108, 3988.
[8] For an overview of this field, see: a) R. Dagani, Chem. Eng. News
2002, 80, 23; b) special issue on bioorganometallic chemistry, J. Or-
ganomet. Chem. 1999, 589, 1.
[9] Treatment of bacteria with low concentrations of bactericidal antibi-
otics generates multidrug resistance: a) see, among many others, the
monographic issue of Nature Reviews Microbiology 2010, 8. The fol-
lowing articles give a description of the appealing necessity of ob-
taining new antibacterial agents: b) C. T. Walsh, G. Wright, Chem.
Rev. 2005, 105, 391; c) J. F. Fisher, S. O. Meroueh, S. Mobashery,
Chem. Rev. 2005, 105, 395; d) D. J. Payne, Science 2008, 321, 1644;
e) F. von Nussbaum, M. Brands, B. Hinzen, S. Weigand, D. H.
Hꢅbich, Angew. Chem. 2006, 118, 5194; Angew. Chem. Int. Ed. 2006,
45, 5072.
Acknowledgements
Financial support from the Spanish MINECO: Projects CTQ-2010–
20414-C02–01/BQU, Consolider Ingenio 2010 (CSD2007—00006), and
the Comunidad de Madrid (S2009/PPQ-1634-AVANCAT) is acknowl-
edged.
[10] For reviews, see, among many others: a) G. Schenk, N. Mitꢆc, L. R.
Gahan, D. L. Ollis, R. P. McGeary, L. W. Ruddat, Acc. Chem. Res.
2012, 45, 1593; b) G. Cornaglia, H. Giamarellou, G. M. Rossolini,
Lancet Infect. Dis. 2011, 11, 381; c) T. R. Walsh, M. A. Toleman, L.
Poirel, P. Nordmann, Clin. Microbiol. Rev. 2005, 18, 306; d) D. L. Pa-
terson, R. A. Bonomo, Clin. Microbiol. Rev. 2005, 18, 657.
Keywords: alkynyl metals · antibiotics · Kinugasa reaction ·
lactams · nitrones
[11] See: a) K. K. Kumarasamy, M. A. Toleman, T. R. Walsh, J. Bagaria,
F. A. Butt, R. Balakrishnan, U. Chaudhary, M. Doumith, C. G.
Giske, S. Irfan, P. Krishnan, A. V. Kumar, S. Maharjan, S. Mushtaq,
T. Noorie, D. L. Paterson, A. Pearson, C. Perry, R. Pike, B. Rao, U.
[1] a) J. D. Buynak, L. Vogeti, H. Chen, Org. Lett. 2001, 3, 2953; b) E.
Hevia, J. Pꢃrez, V. Riera, D. Miguel, P. Campomanes, M. I. Menꢃn-
dez, T. L. Sordo, S. Garcꢁa-Granada, J. Am. Chem. Soc. 2003, 125,
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!

L. Casarrubios, M. A. Sierra, and B. Baeza
Ray, J. B. Sarma, M. Sharma, E. Sheridan, M. A. Thirunarayan, J.
Turton, S. Upadhyay, M. Warner, W. Welfare, D. M. Livermore, N.
Woodford, Lancet Infect. Dis. 2010, 10, 597; b) For a review in the
emerging NDM carbapenemases, see: P. Nordmann, L. Poirel, T. R.
Walsh, D. M. Livermore, Trends Microbiol. 2011, 19, 588.
py in the presence of increasing amounts of [EuACTHGNUTRENNU(G hfc)3] (1 mg x up to
5 times) and checked against a reaction mixture obtained in the
presence of the achiral ligand 1,10-phenantroline. The given values
through this work were obtained by careful integration of the well-
resolved signals of either C3 or C4 hydrogen atoms corresponding
to each enantiomer. This method was applicable to all compounds
10–15 except for compound 12a for which no unfolded signals were
[12] Selected revisions on the synthesis and biology of b-lactams:
a) M. T. Aranda, P. Perez-Faginas, R. Gonzꢂlez-Muniz, Curr. Org.
Synth. 2009, 6, 325; b) N. Fu, T. T. Tidwell, Tetrahedron 2008, 64,
10465; c) T. T. Tidwell, Top. Heterocycl. Chem. 2012, 30, 111; d) I.
Fernꢂndez, M. A. Sierra, Top. Heterocycl. Chem. 2012, 30, 65; e) M.
Gꢄmez-Gallego, M. J. MancheÇo, M. A. Sierra, Tetrahedron 2000,
56, 5743; f) E. L. Setti, R. G. Micetich, Curr. Med. Chem. 1998, 5,
101; g) S. Brickner, J. Chem. Ind. (London) 1997, 4, 131; h) G. N.
Rolinson, J. Antimicrob. Chemother. 1998, 41, 589; i) K.-F. Kong, L.
Schneiper, K. Mathee, APMIS 2010, 118, 1; j) A. L. Demain, R. P.
Elander, A. van Leeuwenhoek, J. Microbiol. 1999, 75, 5.
[13] a) O. A. Pierrat, K. Strisovsky, Y. Christova, J. Large, K. Ansell, N.
Bouloc, E. Smiljanic, M. Freeman, ACS Chem. Biol. 2011, 6, 325;
b) J. Mulchande, R. Oliveira, M. Carrasco, L. Gouveia, R. C.
Guedes, J. Iley, R. Moreira, J. Med. Chem. 2010, 53, 241; c) R. An-
nunziata, M. Benaglia, M. Cinquini, F. Cozzi, A. Puglisi, Bioorg.
Med. Chem. 2002, 10, 1813; d) G. Veinberg, M. Vorona, I. Shestako-
va, I. Kanepe, E. Lukevics, Curr. Med. Chem. 2003, 10, 1741.
[14] a) C. M. L. Delpiccolo, S. A. Testero, F. N. Leyes, D. B. Boggian,
C. M. Camacho, E. G. Mata, Tetrahedron 2012, 68, 10780; b) Y.
Wang, H. Qian, J. Zhou, H. Zhang, J. Ji, W. Huang, Med. Chem.
2011, 7, 534; c) Y. Wang, H. Zhang, H. Qian, W. Huang, Zhongguo
Yaoke Daxue Xuebao 2011, 42, 213; d) G. J. Morriello, R. J. Devita,
S. G. Mills, C. R. Moyes, P. Lin, PCT Int. Appl., 2010, WO
2010056788 A1 20100520; e) J.-F. Ji, W.-L. Huang, H.-B. Zhang,
Yaoxue Jinzhan 2007, 31, 342; f) D. A. Burnett, Curr. Med. Chem.
2004, 11, 1873.
[15] a) G. Gerona-Navarro, M. J. Perez de Vega, M. T. Garcia-Lopez, G.
Andrei, R. Snoeck, E. De Clercq, J. Balzarini, R. Gonzalez-Muniz,
J. Med. Chem. 2005, 48, 2612; b) P. R. Bonneau, F. Hasani, C.
Plouffe, E. Malenfant, S. R. LaPlante, I. Guse, W. W. Ogilvie, R.
Plante, W. C. Davidson, J. L. Hopkins, M. M. Morelock, M. G. Cor-
dingley, R. Dꢃziel, J. Am. Chem. Soc. 1999, 121, 2965 and references
cited therein; c) A. D. Borthwick, G. Weingarten, T. M. Haley, M.
Tomaszewski, W. Wang, Z. Hu, J. Bedard, H. Jin, L. Yuen, T. S.
Mansour, Bioorg. Med. Chem. Lett. 1998, 8, 365; d) G. Gerona-Nav-
arro, M. J. Perez de Vega, M. T. Garcia-Lopez, G. Andrei, R.
Snoeck, R. Snoeck, J. Balzarini, E. De Clercq, R. Gonzalez-Muniz,
Bioorg. Med. Chem. Lett. 2004, 14, 2253.
[16] a) E. Hedlund, Experimental neurology 2011, 231, 14; b) M. I. Kona-
klieva, B. J. Plotkin, T. Herbert, Anti-Infect. Agents Med. Chem.
2009, 8, 28; c) U. Holzgrabe, Pharm. Unserer Zeit 2006, 35, 387;
d) J. D. Rothstein, S. Patel, M. R. Regan, C. Haenggeli, Y. H.
Huang, D. E. Bergles, L. Jin, M. D. Hoberg, S. Vidensky, D. S.
Chung, S. V. Toan, L. I. Bruijn, Z.-z. Su, P. Gupta, P. B. Fisher,
Nature 2005, 433, 73.
observed when treating with [EuACTHNURTGNENG(U hfc)3].
[19] Group 6 metal–carbene complexes are sensitive to oxygen and oxi-
dizing agents. In fact, these complexes experience the stepwise addi-
tion of oxygen to the M=C bond, followed by the cycloreversion of
the metalla-dioxetane thus formed generating the corresponding
ester and (CO)4Cr=O. See, among others: a) M. Gibert, M. Ferrer,
A.-M. Lluch, F. Sꢂnchez-Baeza, A. Messeguer, J. Org. Chem. 1999,
64, 1591. This process is easy and it is the basis of the oxidative de-
metalation of Group 6 metal–carbene complexes, a standard tool to
remove the metal fragment. See, for example: b) dimethyldioxirane:
A.-M. Lluch, L. Jordi, F. Sꢂnchez-Baeza, S. Ricart, F. Camps, A.
Messeguer, J. M. Moretꢄ, Tetrahedron Lett. 1992, 33, 3021; c) ceric
ammonium nitrate (CAN): N. Luo, Z. Zheng, Z. Yu, Org. Lett.
2011, 13, 3384; d) S/NaBH4: C. Sandoval-Chꢂvez, J. G. Lopez-
Cortes, A. I. Gutierrez-Hernandez, M. C. Ortega-Alfaro, A. Tosca-
no, C. Alvarez-Toledano, J. Organomet. Chem. 2009, 694, 3692;
e) SCO or SeCO: Z. Zheng, J. Chen, N. Luo, Z. Yu, X. Han, Orga-
nometallics 2006, 25, 5301; f) methyl(trifluoromethyl)dioxirane
(TFMD): J. Barluenga, R.-M. Canteli, J. Florez, S. Garcia-Granda,
A. Gutierrez-Rodriguez, J. Am. Chem. Soc. 1994, 116, 6949;
g) PyNO: V. Capriati, S. Florio, R. Luisi, F. M. Perna, J. Barluenga,
J. Org. Chem. 2005, 70, 5852; h) I2: B. C. Soderberg, B. A. Bowden,
Organometallics 1992, 11, 2220; i) Electrochemical oxidation: M. K.
Lloyd, J. A. McClever, D. G. Orchard, J. A. Connor, M. B. Hall, H.
Hillier, E. M. Jones, G. K. McEven, J. Chem. Soc. Dalton Trans.
1973, 1743.
[20] Review: a) M. Gꢄmez-Gallego, M. J. MancheÇo, M. A. Sierra, Acc.
Chem. Res. 2005, 38, 44; b) For a theoretical study: I. Fernꢂndez,
M. J. MancheÇo, R. Vicente, L. A. Lopez, M. A. Sierra, Chem. Eur.
J. 2008, 14, 11222.
[21] L. K. Ding, W. J. Irwin, J. Chem. Soc. Perkin Trans. 1 1976, 2382.
[22] a) R. Shintani, G. C. Fu, Angew. Chem. 2003, 115, 4216; Angew.
Chem. Int. Ed. 2003, 42, 4082; b) M.-C. Ye, J. Zhou, Y. Tang, J. Org.
Chem. 2006, 71, 3576.
[23] For examples including chiral nitrones, chiral alkynes, or both, see:
a) A. Mames, S. Stecko, P. Mikozajczyk, M. Soluch, B. Furman, M.
Chmielewski, J. Org. Chem. 2010, 75, 7580; b) S. Stecko, A. Mames,
B. Furman, M. Chmielewski, J. Org. Chem. 2008, 73, 7402; c) Ibid, J.
Org. Chem. 2009, 74, 3094; d) R. K. Khangarot, K. P. Kaliappan,
Eur. J. Org. Chem. 2011, 6117; e) S. Masamune, W. Choy, J. S. Pe-
tersen, L. R. Sita, Angew. Chem. 1985, 97, 1; Angew. Chem. Int. Ed.
Engl. 1985, 24, 1.
[24] It would be appealing to hypothesize that the steric interference be-
tween the bulky metal moiety and the chiral ligand attached to Cu,
reflected in an equalization of the energies required for the protona-
tion by each diasterotopic face of either intermediate 16 or 17
(Scheme 5), leading to the enantiomers of the cis isomer, as respon-
sible for the lack of selectivity, an argument that is also applicable
to the trans isomer. The increase in the enantioselectivity observed
in the formation of 2-azetidinones 15, containing sterically less de-
manding substituents in the alkyne moiety may support the argu-
ment above. Nevertheless, due to the low levels of enantioselectivity
observed any conclusion based on these arguments is at the very
least speculative.
[17] This is interesting since indaBOX has been reported mainly as a
ligand for the CuII-catalyzed Kinugasa reaction, see: T. Saito, T. Ki-
kuchi, H. Tanabe, J. Yahiro, T. Otani, Tetrahedron Lett. 2009, 50,
4969. In spite of the fact that these authors reported that indaBOX
formed 2-azetidinones also in the presence of CuI, the role of CuII –
indaBOX was proposed to be a Lewis acid, which leads to a mecha-
nism involving a CuII –acetylide, which is slightly different from the
two usually proposed for the Kinugasa reaction catalyzed by CuI.
Our results coupled to the ones reported by these authors pointed
better to the “in situ” reduction of CuII to CuI and hence to the ac-
cepted mechanisms involving CuI –acetylide species.
[18] The protocol for the determination of the ee of the compounds syn-
thesized through this work follows: 5 mg of pure b-lactams obtained
in the presence of indaBOX were analyzed by 1H NMR spectrosco-
Received: March 22, 2013
Revised: June 10, 2013
Published online: && &&, 0000
&
6
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!