Synthesis and biological evaluation of ferrocene-containing bioorganometallics inspired by the antibiotic platensimycin lead structure

Article abstract of DOI:10.1021/om100614c

The recent discovery of the natural product platensimycin (1) as a new antibiotic lead structure has triggered the synthesis of numerous organic derivatives for structure-activity relationships (SAR) in order to improve the poor in vivo efficacy of 1. The synthesis, characterization, and biological evaluation of the first four ferrocene-containing bioorganometallic compounds based on the platensimycin lead structure are reported herein, namely 3-(4,4-diferrocenoylpentanamido)-2,4-dihydroxybenzoic acid (2), 3-(4,4-diferrocenoylbutanamido)-2,4-dihydroxybenzoic acid (3), 3-{4-(acetylferrocenoyl)butanamido}-2,4-dihydroxybenzoic acid (4), and 3-(4-ferrocenoylbutanamido)-2,4-dihydroxybenzoic acid (5). All new compounds were unambiguously characterized by all common analytical methods, including ¹H and ¹³C NMR, mass spectrometry, IR spectroscopy, and elemental analysis. Furthermore, the single-crystal X-ray structures of methyl 4,4-diferrocenoylbutanoate (9), methyl 4,4-diferrocenoylpentanoate (10), 4,4-diferrocenoylpentanoic acid (14), 4,4-diferrocenoylbutanoic acid (15), and 4-(acetylferrocenoyl)butanoic acid (16) were also determined. Among 2-5 and their intermediate carboxylic acids tested, only 3 was found to inhibit selectively the growth of S. aureus Mu50 strain (VISA) at a minimum inhibitory concentration (MIC) value of 128 μg/mL.

Full text of DOI:10.1021/om100614c

4312 Organometallics 2010, 29, 4312–4319
DOI: 10.1021/om100614c
Synthesis and Biological Evaluation of Ferrocene-Containing
Bioorganometallics Inspired by the Antibiotic Platensimycin
Lead Structure
Malay Patra,† Gilles Gasser,†,‡ Michaela Wenzel,§ Klaus Merz,† Julia E. Bandow,§ and
Nils Metzler-Nolte*,†
†
€
Lehrstuhl fu€r Anorganische Chemie I, Fakultat fur Chemie und Biochemie, Ruhr-Universitat Bochum,
Gebaude NC 3 Nord, Universitatsstrasse 150, D-44801 Bochum, Germany, Institute of Inorganic
€
€
‡
€
€
§
Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland, and Lehrstuhl fu€r
Biologie der Mikroorganismen, Fakulta€t fu€r Biologie und Biotechnologie, Ruhr-Universita€t Bochum,
€
Universitatsstrasse 150, D-44801 Bochum, Germany
Received June 24, 2010
The recent discovery of the natural product platensimycin (1) as a new antibiotic lead structure has
triggered the synthesis of numerous organic derivatives for structure-activity relationships (SAR) in
order to improve the poor in vivo efficacy of 1. The synthesis, characterization, and biological
evaluation of the first four ferrocene-containing bioorganometallic compounds based on the
platensimycin lead structure are reported herein, namely 3-(4,4-diferrocenoylpentanamido)-
2,4-dihydroxybenzoic acid (2), 3-(4,4-diferrocenoylbutanamido)-2,4-dihydroxybenzoic acid (3),
3-{4-(acetylferrocenoyl)butanamido}-2,4-dihydroxybenzoic acid (4), and 3-(4-ferrocenoylbutan-
amido)-2,4-dihydroxybenzoic acid (5). All new compounds were unambiguously characterized by all
common analytical methods, including 1H and 13C NMR, mass spectrometry, IR spectroscopy, and
elemental analysis. Furthermore, the single-crystal X-ray structures of methyl 4,4-diferrocenoylbu-
tanoate (9), methyl 4,4-diferrocenoylpentanoate (10), 4,4-diferrocenoylpentanoic acid (14), 4,4-
diferrocenoylbutanoic acid (15), and 4-(acetylferrocenoyl)butanoic acid (16) were also determined.
Among 2-5 and their intermediate carboxylic acids tested, only 3 was found to inhibit selectively
the growth of S. aureus Mu50 strain (VISA) at a minimum inhibitory concentration (MIC) value of
128 μg/mL.
Introduction
ideal lead structure in antibiotic research for further drug
design and development.
The recent discovery of platensimycin (1; Figure 1) was an
important contribution to the search for new treatment
options against multidrug resistant pathogens.1 1 displays
potent activity against Gram-positive bacterial strains
(methicillin-resistant Staphylococcus aureus, vancomycin re-
sistant Enterococcus faecalis) by selectively inhibiting the
FabF enzyme in the bacterial fatty acid biosynthesis.2,3
Although 1 is not suited to become a drug, due to its low in
vivo efficacy, its impressive antibacterial activity and low
intrinsic toxicity toward mammalian cell lines makes 1 an
Since the discovery of 1, several synthetic routes to 1 and
its analogues were developed4-8 and the antibacterial acti-
vities of the analogues evaluated.9-12 To date, modifications
of the complicated tetracyclic cage were exclusively done by
replacing it with different isosteric organic moieties. Nota-
bly, Nicolaou et al. reported the two most potent analogues,
namely carbaplatensimycin (1b; Figure 1) and adamantapla-
tensimycin (1c; Figure 1), which showed activity similar to
(4) Nicolaou, K. C.; Li, A.; Edmonds, D. J. Angew. Chem., Int. Ed.
2006, 45, 7086–7090.
*To whom correspondence should be addressed. Fax: 0234 32-14378.
E-mail: Nils.Metzler-Nolte@rub.de.
(5) Yao, Y.-S.; Yao, Z.-J. Youji Huaxue 2008, 28, 1553–1560.
(6) Nicolaou, K. C.; Li, A.; Edmonds, D. J.; Tria, G. S.; Ellery, S. P.
J. Am. Chem. Soc. 2009, 131, 16905–16918.
(7) McGrath, N. A.; Bartlett, E. S.; Sittihan, S.; Njardarson, J. T.
Angew. Chem., Int. Ed. 2009, 48, 8543–8546.
(8) Kaliappan, K. P.; Palanichamy, K. Chem. Asian. J. 2010,
00, 00–00.
(9) Nicolaou, K. C.; Lister, T.; Denton, R. M.; Montero, A.;
Edmonds, D. J. Angew. Chem., Int. Ed. 2007, 46, 4712–4714.
(10) Nicolaou, K. C.; Tang, Y.; Wang, J.; Stepan, A. F.; Li, A.;
Montero, A. J. Am. Chem. Soc. 2007, 129, 14850–14851.
(11) Nicolaou, K. C.; Stepan, A. F.; Lister, T.; Li, A.; Montero, A.;
Tria, G. S.; Turner, C. I.; Tang, Y.; Wang, J.; Denton, R. M.; Edmonds,
D. J. J. Am. Chem. Soc. 2008, 130, 13110–13119.
(1) Wang, J.; Soisson, S. M.; Young, K.; Shoop, W.; Kodali, S.;
Galgoci, A.; Painter, R.; Parthasarathy, G.; Tang, Y. S.; Cummings, R.;
Ha, S.; Dorso, K.; Motyl, M.; Jayasuriya, H.; Ondeyka, J.; Herath, K.;
Zhang, C.; Hernandez, L.; Allocco, J.; Basilio, A.; Tormo, J. R.;
Genilloud, O.; Vicente, F.; Pelaez, F.; Colwell, L.; Lee, S. H.; Michael,
B.; Felcetto, T.; Gill, C.; Silver, L. L.; Hermes, J. D.; Bartizal, K.;
Barrett, J.; Schmatz, D.; Becker, J. W.; Cully, D.; Singh, S. B. Nature
2006, 441, 358–361.
(2) Wright, H. T.; Reynolds, K. A. Curr. Opin. Microbiol. 2007, 10,
447–453.
(3) Singh, S. B.; Jayasuriya, H.; Ondeyka, J. G.; Herath, K. B.;
Zhang, C.; Zink, D. L.; Tsou, N. N.; Ball, R. G.; Basilio, A.; Genilloud,
O.; Diez, M. T.; Vicente, F.; Pelaez, F.; Young, K.; Wang, J. J. Am.
Chem. Soc. 2006, 128, 11916–11920.
(12) Krauss, J.; Knorr, V.; Manhardt, V.; Scheffels, S.; Bracher, F.
Arch. Pharm. 2008, 341, 386–392.
r
pubs.acs.org/Organometallics
Published on Web 09/09/2010
2010 American Chemical Society

Article
Organometallics, Vol. 29, No. 19, 2010 4313
Figure 1. Structures of platensimycin (1), isoplatensimycin (1a), carbaplatensimycin (1b), adamentaplatensimycin (1c), platensimycin
A1 (1d), 11-methyl-7-phenyl platensimycin (1e), 7-phenyl platensimycin (1f), and ferrocene-containing bioorganometallics (2-5).
that of the parent compound against a number of Gram-
positive bacteria, including S. aureus.13,14 Interestingly, iso-
platensimycin (1a; Figure 1), which has a structure very
similar to that of the parent compound (1), exhibited
poor activity against different strains of S. aureus but showed
significant activity against E. faecium.15 Nonetheless, despite
the high degree of structural similarity between 1 and its
natural analogue platensimycin A1 (1d; Figure 1), 1d inhibits
the S. aureus growth at a minimum inhibitory concentration
(MIC) of 16 μg/mL while platensimycin exhibited a MIC
value of 0.5 μg/mL against the same bacterial strain.16 The
structure-activity relationship (SAR) study by Nicolaou
and co-workers showed that the tetracyclic cage of platensi-
mycin is somewhat tolerant to modifications, whilst any small
modification on the benzoic acid entity led to complete loss
of antibacterial activity.11 Very recently, Jang et al. reported
two analogues of platensimycin, 11-methyl-7-phenylplaten-
simycin (1e; Figure 1) and 7-phenylplatensimycin (1f;Figure1),
which were found to be more potent (MIC = 0.25 μg/mL) than
the parent compound platensimycin (MIC = 0.5 μg/mL)
against methicillin sensitive and resistant S. aureus strains.17
The poor antibacterial activity of 1a,d and excellent antibacter-
ial activity of 1e,f certainly reveals that very small changes in
the tetracyclic core may bring a dramatic change in the anti-
bacterial activity of 1.
the bioactivity of 1, we have recently reported the synthesis
and biological evaluation of Cr-bioorganometallics based on
the platensimycin lead structure.18 In this study, we have
replaced the synthetically challenging tetracyclic cage by
rather simple arene-Cr(CO)3 moieties.18,19 Unfortunately,
our most active compound was found to be less potent (MIC=
80 μg/mL against B. subtilis) than platensimycin. Interestingly,
however, the mode of action was found to be different from
that of the parent compound.20 This unexpected new mode of
action is highly encouraging, as the biomedical usefulness of
the intrinsic mode of action of platensimycin has been ques-
tioned. Indeed, very recently Brinster et al. reported that some
Gram-positive pathogens might overcome the drug-induced
inhibition of fatty acid biosynthesis in the presence of external
fatty acid sources such as human serum,21 although this does
not seem to be true for S. aureus.22
In recent years, ferrocene-containing biomolecules have
attracted much attention for medicinal applications, mainly
in anticancer and antimalarial research.23-28 For example,
ferroquine, a ferrocene derivative of the known antimalarial
(18) Patra, M.; Gasser, G.; Pinto, A.; Merz, K.; Ott, I.; Bandow, J. E.;
Metzler-Nolte, N. ChemMedChem 2009, 4, 1930–1938.
(19) For new metal-containing platensimycin analogues, a patent is
pending (EP09154125).
(20) Patra, M.; Wenzel, M.; Bandow, J. E.; Metzler-Nolte, N.
In preparation.
(21) Brinster, S.; Lamberet, B.; Staels, B.; Trieu-Cuot, P.; Gruss, A.;
Poyart, C. Nature 2009, 458, 83–86.
(22) Balemans, W.; Lounis, N.; Gilissen, R.; Guillemont, J.; Simmen,
Inspired by the possibility of replacing the tetracyclic cage
of 1 by organometallic cores and studying their influence on
(13) Nicolaou, K. C.; Lister, T.; Denton, R. M.; Montero, A.;
Edmonds, D. J. Angew. Chem., Int. Ed. 2007, 46, 4712–4714.
(14) Nicolaou, K. C.; Tang, Y.; Wang, J.; Stepan, A. F.; Li, A.;
Montero, A. J. Am. Chem. Soc. 2007, 129, 14850–14851.
K.; Andries, K.; Koul, A. Nature 2010, 463, E3.
(23) Hartinger, C. G.; Dyson, P. J. Chem. Soc. Rev. 2009, 38, 391–401.
(24) Jaouen, G. Bioorganometallics: Biomolecules, Labelling, Medi-
cine; Wiley-VCH: Weinheim, Germany, 2006.
€
(15) Jang, K. P.; Kim, C. H.; Na, S. W.; Kim, H.; Kang, H.; Lee, E.
(25) James, P.; Neudorfl, J.; Eissmann, M.; Jesse, P.; Prokop, A.;
Bioorg. Med. Chem. Lett. 2009, 19, 4601–4602.
Schmalz, H.-G. Org. Lett. 2006, 8, 2763–2766.
(26) Hillard, E.; Vessieres, A.; Thouin, L.; Jaouen, G.; Amatore, C.
Angew. Chem., Int. Ed. 2006, 45, 285–290.
(27) van Staveren, D. R.; Metzler-Nolte, N. Chem. Rev. 2004, 104,
5931–5985.
(16) Singh, S. B.; Jayasuriya, H.; Herath, K. B.; Zhang, C.; Ondeyka,
J. G.; Zink, D. L.; Ha, S.; Parthasarathy, G.; Becker, J. W.; Wang, J.;
Soisson, S. M. Tetrahedron Lett. 2009, 50, 5182–5185.
(17) Jang, K. P.; Kim, C. H.; Na, S. W.; Jang, D. S.; Kim, H.; Kang,
H.; Lee, E.
bmcl.2010.02.037.
Bioorg. Med. Chem. Lett. 2010, DOI: 10.1016/j.
(28) Gasser, G.; Ott, I.; Metzler-Nolte, N. J. Med. Chem. 2010,
accepted.

4314 Organometallics, Vol. 29, No. 19, 2010
Patra et al.
drug chloroquine, was found to have activity similar to that
of the parent compound against a chloroquine-sensitive
P. falciparum strain (HB3 5CQS), whereas comparison of
activity of ferroquine and chloroquine against chloroquine-
resistant P. falciparum (Dd2) shows that the former is 10
times more active than the latter.29,30 Ferroquine has recently
successfully passed the clinical trial phase II. Ferrocifens
(i.e., ferrocene-modified tamoxifen derivatives), developed by
Jaouen et al., are another successful example of medicinal
biorganometallic chemistry. They exhibit activity against
hormone-independent breast cancer cell lines, where hydro-
xytamoxifen and tamoxifens are inactive.26,31 With this in
mind, we envisioned replacing the synthetically challenging
tetracyclic cage of platensimycin with different bulky ferrocene
entities and to study their effects on the biological activity of 1.
Herein, we report the synthesis and biological evaluation
of four ferrocene-containing bioorganometallics inspired by
the antibiotic platensimycin lead structure, namely 3-(4,4-
diferrocenoylpentanamido)-2,4-dihydroxybenzoic acid (2),
3-(4,4-diferrocenoylbutanamido)-2,4-dihydroxybenzoic
acid (3), 3-{4-(acetylferrocenoyl)butanamido}-2,4-dihydro-
xybenzoic acid (4), and 3-(4-ferrocenoylbutanamido)-2,4-
dihydroxybenzoic acid (5) (see Figure 1 for their structures).
Scheme 1. Synthesis of Carboxylic Acid Derivatives 14-17,
Bearing Ferrocenyl Moietya
a Reagents and conditions: (a) 13, KOtBu, DMF; (b) K2CO3,
tBu4NBr, MeI, toluene or acetonitrile; (c) DBU, methyl acrylate,
DCM; (d) 10 equiv of aqueous NaOH, THF, or MeOH; (e) Me3SiI,
CH3CN; (f) DBU, methyl acrylate, DCM; (g) NaH, methyl 3-bromo-
propionate, THF; (h) NaH, MeI, THF; (i) 100 equiv of aqueous NaOH,
THF, or MeOH; (j) AlCl3, glutaric anhydride, DCM.
Results and Discussion
Synthesis and Spectroscopic Characterization of Com-
pounds 2-5. The synthesis sequence to obtain the desired
ferrocene-containing carboxylic acids 4,4-diferrocenoylpen-
tanoic acid (14), 4,4-diferrocenoyllbutanoic acid (15), and
4-(acetylferrocenoyl)butanoic acid (16) is outlined in Scheme 1.
The carboxylic acid 4-ferrocenoylbutanoic acid (17) was pre-
pared by following the literature procedure.32 Methyl ferro-
cenoate (6) was prepared from ferrocenecarboxylic acid via the
ferrocene carboxyl chloride intermediate.33,34
methyl acrylate in the presence of DBU provided 9 in good
yield (75%). The difference in reactivity of 7 and 8 arises
probably as a consequence of the presence of the methyl
group between the two keto groups in 8, which makes this
position more crowded and less accessible to DBU. Alter-
natively, 9 could also be obtained by refluxing the mixture of
7, NaH, and methyl 3-bromopropionate (∼20-30% yield).
Following literature procedures,35 the Claisen condensa-
tion of 6 with acetylferrocene (13) in the presence of lithium
diisopropylamide (LDA) afforded 7 in 30-40% yield to-
gether with an unknown impurity and the starting materials.
However, by changing the base from LDA to potassium tert-
butoxide (KOtBu), we were able to obtain 7 in 85%
yield.36 7 was treated with K2CO3 and MeI to afford 8 in 62%
1
The H NMR spectrum of 9 shows a singlet at 3.75 ppm
corresponding to the methyl ester group together with the
signals at 4.12-4.95 ppm from the ferrocenyl groups. Only a
trace of the enol isomer was observed in the 1H as well as in
the 13C NMR spectrum. A clean peak at m/z 549.03 corre-
sponding to [M þ Na]þ was observed in the electrospray
ionization mass spectrum (ESI-MS, positive detection mode).
The methyl ester 10 was finally prepared from 9 by refluxing a
mixture of 9, NaH, and MeI in 78% yield. As expected, a
singlet at 1.54 ppm corresponding to the CH3 group was found
in the 1H NMR spectrum. The carboxylic acids 14 and 15 were
obtained by treating the corresponding methyl esters 10 and 9
with 10 equiv of aqueous NaOH solution (yields of 80-88%),
respectively. Use of >30 equiv of NaOH or extending the
reaction time to more than 1.5 h produced undesired side
products (11 or 12 and ferrocenecarboxylic acid; Scheme 1)
together with the desired carboxylic acids 14 and 15, respec-
tively. A complete hydroxide-promoted cleavage of the 1,3-
ferrocenyl diketone functionality was possible by using >70
equiv of NaOH and stirring the reaction mixture overnight at
room temperature (Scheme 1). Alternatively, the carboxylic
acids 14 and 15 could also be obtained by treating the
corresponding methyl esters with 2.5 equiv of Me3SiI (yield
38-45%).
1
yield. The H NMR spectrum of 8 shows a doublet at 1.53
ppm and a quartet at 4.31 ppm corresponding to the CH3 and
(CO)2CH- groups present. No distinct signal for the enol
isomer was observed in either the 1H or 13C NMR spectrum.
All our efforts to make 10 by Michael addition of 8 to methyl
acrylate using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
were unsuccessful. On the other hand, a 1,4-addition of 7 to
(29) Delhaes, L.; Biot, C.; Berry, L.; Delcourt, P.; Maciejewski, L. A.;
Camus, D.; Brocard, J. S.; Dive, D. ChemBioChem 2002, 3, 418–423.
(30) Biot, C.; Glorian, G.; Maciejewski, L. A.; Brocard, J. S.; Domarle,
O.; Blampain, G.; Millet, P.; Georges, A. J.; Abessolo, H.; Dive, D.; Lebibi,
J. J. Med. Chem. 1997, 40, 3715–3718.
(31) Naguen, A.; Vessieres, A.; Hillard, E. A.; Top, S.; Pigeon, P.;
Jaouen, G. Chimia 2007, 61, 716–724.
(32) Apreutesei, D.; Lisa, G.; Akutsu, H.; Hurduc, N.; Nakatsuji, S.;
Scutaru, D. Appl. Organomet. Chem. 2005, 19, 1022–1037.
(33) Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Mazzanti, G.;
Ricci, A.; Alberti, A.; Macciantelli, D.; Marcaccio, M.; Roffia, S. Eur. J.
Org. Chem. 2002, 543–550.
The formation of 14 and 15 was confirmed by the disap-
pearance of the COOCH3 signal in the 1H NMR spectrum of
both compounds. Carboxylic acid 16 was prepared in a one-
step synthesis, using the Friedel-Crafts reaction of acetyl-
ferrocene (13) with glutaric anhydride. 16 showed a sharp
(34) Routaboul, L.; Chiffre, J.; Balavoine, G. G. A.; Daran, J.-C.;
Manoury, E. J. Organomet. Chem. 2001, 637, 364–371.
(35) (Ina) du Plessis, W. C.; Vosloo, T. G.; Swarts, J. C. J. Chem. Soc.,
Dalton Trans. 1998, 2507–2514.
(36) Nandurkar, N. S.; Bhanushali, M. J.; Patil, D. S.; Bhanage,
B. M. Synth. Commun. 2007, 37, 4111–4115.

Article
Organometallics, Vol. 29, No. 19, 2010 4315
Scheme 2. Preparation of the Ferrocene Bioorganometallics 2-5a
a Reagents and conditions: (a) HATU, DIPEA, DMF/CH3CN; (b) BBr3, CHCl3; (c) aqueous NaOH, MeOH/THF; (d) HATU, DIPEA, DMF; (e)
TASF, DMF; (f) HATU, DIPEA, DMF/CH3CN; (g) aqueous LiOH and THF and then 4 N HCl in dioxane. Abbreviations: TMSE =
(trimethylsilyl)ethyl, MOM = methoxymethyl, HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methana-
minium, DIPEA = diisopropylethylamine, TASF = tris(dimethylamino)sulfonium difluorotrimethylsilicate.
singlet at 2.38 ppm in the 1H NMR spectrum corresponding
to the COCH3 group together with the other expected signals
from the ferrocenoyl group.
22, as utilized by Nicolaou and co-workers in their synthesis
of platencin.38
Amide coupling of 22 with the carboxylic acids 14 and 15
afforded 23 and 24 in 60 and 64% yields, respectively.
Deprotection of the (trimethylsilyl)ethyl ester of 23 and 24
was achieved using TASF to give the desired bioorgano-
metallics 2 and 3, respectively. In ESI-MS (negative mode),
the signals at m/z 675.89 and 661.87, corresponding to the
[M - H]- species of 2 and 3, unambiguously confirmed the
formation of the expected compounds. The 1H NMR spec-
trum showed two distinct doublets and a broad singlet for the
CONH proton in the aromatic region along with all the
signals from the ferrocenoyl entities between 4 and 5 ppm.
Coupling of the carboxylic acids 16 and 17 with the methoxy-
methyl-protected amine 25 gave 26 and 27, respectively, in
good yields. 26 and 27 were then deprotected using LiOH and
then 4 M HCl in dioxane to obtain the desired compounds 4
and 5 respectively. As expected, the 1H NMR spectra showed
With all the ferrocene-containing carboxylic acids
(14-17) in hand, we then focused on coupling them with
different aromatic amines relevant for platensimycin chem-
istry (Scheme 2). The carboxylic acid 15 was first coupled
to the protected amine 18 using standard HATU-mediated
amide coupling.37 19 was isolated in 89% yield (Scheme 2).
Our attempts to carry out the deprotection of 19 using BBr3,
as used for the synthesis of sulfonamide analogues of pla-
tensimycin, gave only a trace of the desired compound 3 along
with 20 and some undesired impurities (confirmed by TLC
and ESI-MS spectrometry).37 When 20 was treated with
aqueous NaOH, cleavage of the 1,3-diketone functionality
was observed exclusively and, instead of 3, a mixture of 21
and ferrocenecarboxylic acid was obtained. However, the
synthesis of 2 and 3 was finally achieved by using the amine
(37) McNulty, J.; Nair, J. J.; Capretta, A. Tetrahedron Lett. 2009, 50,
4087–4091.
(38) Nicolaou, K. C.; Tria, G. S.; Edmonds, D. J. Angew. Chem., Int.
Ed. 2008, 47, 1780–1783.

4316 Organometallics, Vol. 29, No. 19, 2010
Patra et al.
No inhibition of E. coli W3110 or P. aeruginosa PA01 growth
was observed for any of the compounds up to 180 μg/mL.
Interestingly, however, among all the compounds tested,
only 3 selectively inhibits the Gram-positive S. aureus
Mu50 (VISA) growth at a MIC of 128 μg/mL.
Conclusion
In summary, we have synthesized and characterized four
new ferrocene-containg bioorganometallics (2-5) inspired
by the antibiotic platensimycin lead structure. Compounds
2-5 were found to be inactive against Gram-negative E. coli
and P. aeruginosa PA01. However, among all the new com-
pounds tested, compound 3, bearing a ferrocenoyl 1,3-diketone
functionality, inhibits S. aureus Mu50(VISA) growth selectively at a
MIC value of 128 μg/mL. Although the antibacterial activity is
moderate, this result is encouraging, as it demonstrates some activity
of an organometallic compound against a (partly) resistant strain.
Multistep syntheses of novel bioorganometallics based on
a natural product lead structure are highly demanding,
because of the sometimes limited stability toward various
reagents and reaction conditions of organometallic compounds
compared to purely organic compounds. In this report, we
have discussed the problems related to OH--induced cleavage
of the 1,3-ferrocenoyl diketone functionality during the
attempted synthesis of 3 from 19 which was resolved using an
alternative synthetic route that avoids the basic saponification
of the carboxylic ester functionality and the desired compound
3 was obtained in good yield. These efficient multistep synthetic
strategies reported herein can potentially be helpful for the
synthesis of other 1,3-ferrocenoyl diketone containing organo-
metallics based on natural product lead structures. We are
currently planning to use this multistep synthetic route to expand
our library of metal-containing bioorganometallics based on the
platensimycin lead structure for structure-activity relationship
(SAR) studies. These results will be published in due course.
Figure 2. ORTEP plot of methyl ester 10 (ellipsoids drawn at
the 50% probability level, hydrogen atoms omitted for clarity).
Selected bond lengths (A) and angles (deg): Fe(1)-centroid
Cp(C1-5)=1.638, Fe(1)-centroid Cp(C6-10)=1.650, Fe(2)-
centroid Cp(C12-16)=1.635, Fe(2)-centroid Cp(C17-21) =
1.644, average Fe-C Cp’s 2.034(7), Fe(1)-Fe(2) = 6.187;
C(2)-C(11)-C(23)=119.2(5), C(12)-C(22)-C(23)=119.7(5),
C(11)-C(23)-C(22) = 110.8(5).
˚
two distinct doublets and a broad singlet for the CONH
proton in the aromatic region together with all the signals
from the ferrocenoyl entity.
X-ray Crystal Structures of 9, 10, and 14-16. Single
crystals of 9, 10, and 14-16 suitable for X-ray diffraction
were grown by slow diffusion of pentane into a diethyl ether
solution of the respective compounds. The ORTEP plot of 10
is shown in Figure 2 (see Figures S1-S4 in the Supporting
Information for the ORTEP plots of 9 and 14-16). Both
compounds 10 and 16 crystallized in the monoclinic space
group P21/n, while compounds 9 and 14 crystallized in the
triclinic space group P1 and compound 15 in the monoclinic
space group P21/c. The asymmetric units of 9 and 14 contain
two crystallographically independent molecules.
Experimental Section
Materials. All chemicals were of reagent grade quality or
better, were obtained from commercial suppliers, and were used
without further purification. Solvents were used as received or
dried over molecular sieves. All preparations were carried out
using standard Schlenk techniques.
As expected for carboxylic acids, 14 forms head-to-head
dimers in the solid state through hydrogen bonding inter-
action between the carboxylic acid groups (Figure S5 in the
Supporting Information). Interestingly, compound 15 forms
dimeric units through intermolecular hydrogen-bonding
interactions between the carboxylic acid and the keto car-
bonyl group (Figure S5). In the crystal lattice of 16, the
molecules self-organize in a two-dimensional assembly
through water molecule mediated H-bonding interactions
(Figure S6 in the Supporting Information). Selected bond
distances and angles, crystallographic data, and parameters
for all the five compounds are presented in Tables S1 and S2
in the Supporting Information. The Fe-C distances for all
Instrumentation and Methods. 1H and 13C NMR spectra were
recorded in deuterated solvents on Bruker DRX 200, 250, 400,
and 600 spectrometers at 30 °C. The chemical shifts, δ, are
reported in ppm (parts per million). The residual solvent peaks
have been used as an internal reference. The abbreviations for
the peak multiplicities are as follows: s (singlet), d (doublet), dd
(doublet of doublets), t (triplet), q (quartet), m (multiplet), and
br (broad). For the compounds that exist as a mixture of keto
and enol forms in solution, in the 1H and 13C NMR spectra the
signals from the minor and the major isomers are abbreviated as
“min” and “maj”, respectively. Infrared spectra were recorded
on an ATR unit using a Bruker Tensor 27 FTIR spectro-
photometer at 4 cm-1 resolution. The signal intensity is abbre-
viated br (broad), s (strong), m (medium), and w (weak). ESI
mass spectra were recorded on a Bruker Esquire 6000. Melting
points were determined with a Buchi apparatus. Elemental
microanalyses were performed using a Fisons Carlo Erba
EA1108 instrument (CHNS version). High-resolution mass
spectra (HRMS) were measured using a LTQ Orbitrap XL
hybrid FTMS (ionization, ESI (4 kV at 3 μL/min flow rate);
mass accuracy, < 10 ppm; resolution, 60 000). Crystallographic
data for 9, 10, and 14-16 were collected using a Bruker-AXS
SMART 1000 CCD diffractometer. The structures were solved
˚
compounds fall in the same range between 1.63 and 1.65 A.
Antimicrobial Activity. The antimicrobial activities of the
new ferrocene-containing bioorganometallics 2-5 and their
corresponding carboxylic acid intermediates 14-17 were
tested against various bacterial strains, including Gram-
positive methicilline (MRSA) or vancomycin (VISA) resis-
tant strains (Staphylococcus aureus COL (MRSA), S. aureus
Mu50 (VISA), S. aureus ATCC43300 (MRSA), Bacillus
subtilis 168) and Gram-negative (E. coli W3110 and Pseudo-
monas aeruginosa PA01) bacterial strains up to 180 μg/mL.

Article
Organometallics, Vol. 29, No. 19, 2010 4317
by direct methods (SHELXS-9739) and refined against F2 with
all measured reflections (SHELXL-97,39 Platon-Squeeze40).
The crystal structures are deposited in the Cambridge Crystal-
lographic Data Centre (CCDC) and the CCDC numbers are
767283 (compound 9), 767281 (compound 10), 770379 (com-
pound 14), 767280 (compound 15), and 767282 (compound 16).
These data can be obtained free of charge from the CCDC via
www.ccdc.cam.ac.uk/data_request/cif.
chromatography (silica gel, hexane/EtOAc 4/1) yielded 9
(∼40%). The compound was recrystallized from an ethyl acet-
ate/hexanes mixture (1/2). Mp: 122-125 °C. Rf = 0.39 (silica
gel, hexanes/EtOAc 3/1). 1H NMR (400 MHz, CDCl3): δ (ppm)
2.45-2.50 (m, 4H, 2CH2), 3.71 (min) and 3.73 (maj) (s, 3H,
C(O)OCH3, keto and enol), 4.14 (maj) and 4.17 (min) (s, 10H,
C5H5, keto and enol), 4.53-4.56 (m, 5H, C5H4 and (CO)2CH-),
4.92-4.95 (maj) and 4.05 (min) (m, 4H, C5H4, keto and enol).
ESI-MS (positive mode): m/z (%) 549.03 (100) [M þ Na]þ.
HRMS (ESI, positive mode): m/z calcd for C27H27Fe2O4 [M þ
H]þ 527.0608, found 527.0608. Anal. Calcd for C27H26Fe2O4: C,
61.63; H, 4.98. Found: C, 61.52; H, 5.02.
Minimum Inhibitory Concentration (MIC) Determination.
Minimun inhibitory concentrations (MICs) against all bacterial
strains were determined in a microtiter plate assay containing
0.2 mL of Luria Broth medium and appropriate compound
concentrations up to 180 μg/mL. The tubes were inoculated with
105 cells/mL and incubated at 37 °C for 18 h. The MIC was
defined as the lowest concentration that inhibited visible growth.
Synthesis. 1, 3-Diferrocenyl-1, 3-propanedione (7).35,36 Po-
tassium tert-butoxide (KOtBu) (614 mg, 5.48 mmol) in 10 mL of
N,N-dimethylformamide (DMF) was heated to 50 °C under a
nitrogen atmosphere. Acetylferrocene (13; 500 mg, 2.19 mmol)
in 2 mL of DMF was added dropwise. After 5 min methyl
ferrocenecarboxylate (6; 802 mg, 3.28 mmol) in 2 mL of DMF
was added slowly and the progress of the reaction was mon-
itored by TLC. After 1.5 h 100 mL of ethyl acetate was added to
the reaction mixture, and this mixture was washed with 1 M HCl
(2 ꢀ 50 mL), water (2 ꢀ 50 mL), and brine (1 ꢀ 50 mL). The
organic layer was dried over anhydrous Na2SO4 and filtered,
and the solvent was evaporated. The residue was chromato-
graphed on silica using a 4:1 hexane and EtOAc mixture to give
820 mg of the desired product 7 as a deep red solid (yield 85%).
Compound 8. A mixture of 7 (200 mg, 0.45 mmol), K2CO3 (249
mg, 1.8 mmol), tBu4NBr (725 mg, 2.25 mmol), and MeI (2.6 g,
18 mmol) in 50 mL of toluene or acetonitrile was heated to 50 °C
for 25 h. The reaction mixture was then filtered, and 50 mL of
Et2O was added to the filtrate. The organic phase was washed
with water (2 ꢀ 50 mL) and brine (1 ꢀ 50 mL), dried over
anhydrous Na2SO4, and filtered. Solvent removal followed by
flash column chromatography on silica using 4/1 hexane/EtOAc
yielded 8 as a deep red solid (128 mg, 62%). Mp: 126-129 °C.
Rf = 0.50 (silica gel, hexanes/EtOAc 3/1). 1H NMR (200 MHz,
Methyl Ester 10. To a stirred solution of 9 (800 mg, 1.52
mmol) in 40 mL of anhydrous THF, was added NaH (73 mg,
3.04 mmol) slowly under an N2 atmosphere, and the mixture was
stirred for 20 min at room temperature. MeI (10.8 g, 76 mmol)
was then added, and the mixture was stirred for 16 h at 50 °C.
After completion of the reaction (checked by TLC, silica gel, 3/1
hexane/EtOAc), 60 mL of brine was added slowly and the
product was extracted with 2 ꢀ 30 mL of EtOAc. The organic
phase was dried over anhydrous Na2SO4 and filtered. Solvent
removal followed by flash column chromatography (silica gel,
hexane/EtOAc 3.5/1) yielded 10 (640 mg, 78%) as a red solid.
The compound was recrystallized from diethyl ether. Mp:
143-146 °C. Rf = 0.5 (silica gel, hexanes/EtOAc 3/1). 1H
NMR (400 MHz, CDCl3): δ (ppm) 1.67 (s, 3H, CH3), 2.33-
2.41 (m, 2H, CH2), 2.42-2.50 (m, 2H, CH2), 3.69 (maj) and 3.71
(min) (s, 3H, C(O)OCH3, rotamer), 4.09 (maj) and 4.21, 4.22
(min) (s, 10H, C5H5, rotamer), 4.40 (maj) and 4.51 (min) (s, br,
4H, C5H4, rotamer), 4.64 (maj), 4.77 (maj) and 4.79 (min), 4.80
(min) (s, br, 4H, C5H4, rotamer). ESI-MS (positive mode): m/z
(%) 539.92 (100) [M]þ. HRMS (ESI, positive mode): m/z calcd
for C28H28Fe2O4 [M]þ 540.0686, found 540.0686. Anal. Calcd
for C28H28Fe2O4: C, 62.25; H, 5.22. Found: C, 62.19; H, 5.26.
Carboxylic Acid 14. To a stirred solution of 10 (400 mg, 0.74
mmol) in 30 mL of THF was added 7.4 mL of 1 M aqueous
NaOH (7.4 mmol), and the mixture was stirred at room tem-
perature. The progress of the reaction was followed by TLC
(silica gel, EtOAc). After 1.5 h, 50 mL of water and 9 mL of 1 M
HCl was added to this solution. The product was then extracted
using EtOAc (2 ꢀ 30 mL). The combined organic phase was
washed with 50 mL of water and 30 mL of brine, dried over
anhydrous Na2SO4, and filtered. Solvent removal followed by
flash column chromatography (silica gel, EtOAc/MeOH 15/1)
yielded 14 (319 mg, 82%) as a deep red solid.
3
CDCl3): δ (ppm) 1.57 (d, 3H, CH3, J = 7 Hz), 4.04 (s, 10H,
C5H5), 4.31 (q, 1H, (CO)2CH-, 3J = 7 Hz), 4.42-4.49 (m, 4H,
C5H4), 4.79-4.88 (m, 4H, C5H4). ESI-MS (positive mode): m/z
(%) 453.86 (100) [M]þ, 492.80 (40) [M þ K]þ. HRMS (ESI,
positive mode): m/z calcd for C24H23Fe2O2 [M þ H]þ 455.0396,
found 455.0392. Anal. Calcd for C24H22Fe2O2: C, 63.48; H,
4.88. Found: C, 63.29; H, 5.12.
In an alternative procedure, to a stirred solution of 10
(108 mg, 0.20 mmol) in 7 mL of acetonitrile was added 0.06
mL of Me3SiI (0.40 mmol) under an N2 atmosphere. The
mixture was then refluxed (90 °C) for 2 h. The progress of the
reaction was monitored by TLC (silica gel, EtOAc). Water was
added to the mixture, and the product was extracted using
EtOAc (2 ꢀ 15 mL). The combined organic phase was washed
with 40 mL of water and 20 mL of brine, dried over anhydrous
Na2SO4, and filtered. Solvent removal followed by flash column
chromatography (silica gel, EtOAc/MeOH 15/1) yielded 14
(45 mg, 43%). Mp: 164-167 °C. Rf=0.53 (silica gel, EtOAc/MeOH
Methyl Ester 9. To a stirred solution of 1,3-diferrocenyl-1,3-
propanedione (7; 250 mg, 0.56 mmol) in 50 mL of dichloro-
methane was added DBU (400 mg, 2.8 mmol) at room tempera-
ture under an N2 atmosphere. The mixture was then stirred for
20 min. A solution of methyl acrylate (1.2 g, 14 mmol) in 20 mL
of DCM was then added dropwise and the mixture was refluxed
for 30 h. The progress of the reaction was followed by TLC
(silica gel, 4/1 hexane/EtOAc).The reaction mixture was evapo-
rated, and the residue was chromatographed on silica using 4/1
hexane/EtOAc to give 205 mg of the desired product 9 as a deep
red solid (yield 80%).
1
10/1). H NMR (250 MHz, CDCl3): δ (ppm) 1.68 (s, 1H, CH3),
In an alternative procedure, 7 (300 mg, 0.68 mmol) was added
to a suspension of NaH (21 mg, 0.88 mmol) in 15 mL of
anhydrous THF under an N2 atmosphere. Methyl 3-bromopro-
pionate (568 g, 3.4 mmol) was added, and the mixture was
stirred at reflux temperature for 45 h. A 50 mL portion of brine
was then added slowly, and the solution was extracted with
50 mL of Et2O. The organic phase was dried over anhydrous
Na2SO4 and filtered. Solvent removal followed by flash column
2.43-2.49 (m, 4H, 2CH2), 4.10 (s, 10H, C5H5), 4.42 (m, 4H, C5H4),
4.65 (m, 2H, C5H4), 4.79 (m, 2H, C5H4). ESI-MS (positive mode):
m/z (%) 525.97 (100) [M]þ. HRMS (ESI, positive mode): m/z calcd
for C27H27Fe2O4 [MþH]þ 527.0608, found 527.0610. Anal. Calcd
for C27H26Fe2O4: C, 61.63; H, 4.98. Found: C, 61.98; H, 5.12.
Carboxylic Acid 15. To a stirred solution of 9 (350 mg, 0.66
mmol) in 15 mL of MeOH was added 6.6 mL of 1 M aqueous
NaOH (6.6 mmol). The mixture was then stirred at room
temperature. The progress of the reaction was followed by
TLC (silica gel, hexane/EtOAc 3/2). After 1.5 h, 50 mL of water
and 8 mL of 1 M HCl were added and the product was extracted
using EtOAc. The combined organic phase was washed with
50 mL of water and 30 mL of brine, dried over anhydrous
€
€
(39) Sheldrick, G. M. SHELXL-97; University of Gottingen, Gottingen,
Germany, 1997.
(40) Spek, A. L. Acta Crystallogr., Sect. A: Found. Crystallogr. 1990,
46, C34.

4318 Organometallics, Vol. 29, No. 19, 2010
Patra et al.
Na2SO4, and filtered. Solvent removal followed by flash column
chromatography (silica gel, EtOAc/MeOH 10/1) yielded 15
(300 mg, 88%) as a deep red solid.
Amide 23.38 14 (200 mg, 0.38 mmol), 22 (306 mg, 1.14 mmol),
HATU (366 mg, 1.14 mmol), DIPEA (196 mg, 1.52 mmol), and
DMF (6 mL) were employed. After 34 h the reaction mixture
was worked up following the procedure mentioned above.
Column chromatography (silica gel, hexane/EtOAc 4/1 f 3/1)
yielded 23 (177 mg, 60%) as a red sticky solid. Rf = 0.44 (silica
gel, Hex/EtOAc 3/1). 1H NMR (400 MHz, CDCl3): δ (ppm) 0.03
(s, 9H, Si(CH3)3), 1.04-1.08 (m, 2H, CH2CH2Si), 1.65 (s, 3H,
CH3), 2.44-2.50 (m, 4H, 2CH2), 4.01 (s, 10H, 2C5H5),
4.30-4.36 (m, 6H, CH2CH2Si and C5H4), 4.55-4.59 (m, 2H,
C5H4), 4.71-4.75 (m, 2H, C5H4), 6.41 (d, 1H, benzene ring
proton), 7.49 (d, 1H, benzene ring proton), 8.02 (s, 1H, NH),
10.94 (s, br, 1H, OH), 11.73 (s, 1H, OH). ESI-MS (positive mode):
m/z (%) 799.91 (50) [M þ Na]þ, 776.95 (100) [M]þ. HRMS (ESI,
positive mode): m/z calcd for C39H43Fe2NO7Si [M]þ 777.1507,
found 777.1505. Anal. Calcd for C39H43Fe2NO7Si: C, 60.24; H,
5.57; N, 1.80. Found: C, 60.28; H, 5.90; N, 1.53.
In an alternative procedure, to a stirred solution of 9 (100 mg,
0.19 mmol) in 7 mL of acetonitrile was added 0.09 mL of Me3SiI
(0.58 mmol) under an N2 atmosphere and the mixture was
refluxed at 90 °C for 2 h. The progress of the reaction was
monitored by TLC (silica gel, EtOAc). Water was added to
the mixture, and the product was extracted using EtOAc (2 ꢀ
15 mL). The combined organic phases were washed with 40 mL
of water and 20 mL of brine, dried over anhydrous Na2SO4, and
filtered. Solvent removal followed by flash column chromatog-
raphy (silica gel, EtOAc/MeOH 15/1) yielded 15 (34 mg, 35%).
Mp: 148-151 °C. Rf = 0.51 (silica gel, EtOAc). 1H NMR (400
MHz, CDCl3): δ (ppm) 2.45-2.53 (m, 4H, 2CH2), 4.05 (maj)
and 4.09 (min) (keto and enol) (s, 10H, C5H5), 4.38 (m, 1H,
(CO)2CH-), 4.46 (m, 4H, C5H4), 4.85 (m, 4H, C5H4). ESI-MS
(negative mode): m/z (%) 510.91 (100) [M - H]-, 624.87 (20)
[M þ TFA - H]-. HRMS (ESI, positive mode): m/z calcd for
C26H25Fe2O4 [M þ H]þ 513.0451, found 513.0450. Anal. Calcd for
Amide 24.38 15 (100 mg, 0.19 mmol), 22 (157 mg, 0.58 mmol),
HATU (188 mg, 0.58 mmol), DIPEA (100 mg, 0.78 mmol), and
DMF (3 mL) were employed. After 34 h the reaction mixture
was worked up following the procedure mentioned above.
Column chromatography (silica gel, hexane/EtOAc 5/1 f 4/1)
yielded 24 (95 mg, 64%) as a red sticky solid. Rf = 0.31 (silica
C26H24Fe2O4 0.5H2O: C, 59.88; H, 4.83. Found: C, 60.00; H, 4.85.
3
Carboxylic Acid 16.32 To a stirred solution of acetylferrocene
(13; 500 mg, 2.19 mmol) and glutaric anhydride (250 mg, 2.19
mmol) in 50 mL of anhydrous DCM was added AlCl3 (1.4 g,
10.90 mmol) in small portions at 0-5 °C under an N2 atmo-
sphere. The mixture was stirred overnight at room temperature.
Then the reaction mixture was poured into 50 mL of ice water
containing 50 mL of 1 M HCl. The organic layer was separated,
and the aqueous layer was extracted with DCM (2 ꢀ 30 mL).
The combined organic layer was washed with water (4 ꢀ
100 mL) and brine (1 ꢀ 50 mL), dried over anhydrous Na2SO4,
and filtered. The solvent was evaporated to obtain 16 as a red
sticky solid (590 mg, 78%).The crude product was used for the
next step without further purification. The compound was
recrystallized from diethyl ether. Mp: 81-84 °C. Rf = 0.46
(silica gel, pure EtOAc). 1H NMR (400 MHz, CDCl3): δ
(ppm) 2.03-2.1 (m, 2H, CH2), 2.38 (s, 3H, CO-CH3) 2.55 (t,
2H, CH2, 3J = 6.91 Hz), 2.78 (t, 2H, CH2, 3J = 6.91 Hz), 4.53 (s,
4H, C5H4), 4.79 (s, 2H, C5H4), 4.82 (s, 2H, C5H4). ESI-MS
(negative mode): m/z (%) 341.03 (100) [M - H]-, 683.03 (40)
[2M- H]-. HRMS (ESI, positive mode): m/zcalcd for C17H19FeO4
[M þ H]þ 343.0632; found 343.0629. Anal. Calcd for C17H18FeO4:
C, 59.67; H, 5.30. Found: C, 59.92; H, 5.79.
1
gel, Hex/EtOAc 2/1). H NMR (400 MHz, CDCl3): δ (ppm)
(keto and enol isomeric mixture) 0.09 (keto and enol) (s, 9H,
Si(CH3)3), 0.80-0.95 (min) and 1.08-1.20 (maj) (keto and enol)
(m, 2H, CH2CH2Si), 1.27 (enol) (s, 1H, OH), 2.11-2.27 (min)
and 2.53-2.76 (maj) and 2.82-2.95 (min) (keto and enol) (m,
4H, 2CH2), 4.15 (maj) and 4.20 (min) (keto and enol) (s, 10H,
2C5H5), 4.35-4.47 (keto and enol) (m, 2H, CH2CH2Si), 4.5-
4.62 (keto and enol) (m, 5H, C5H4 and (CO)2CH), 4.80-4.84
(min) and 4.92-4.99 (maj) (keto and enol) (m, 4H, C5H4), 6.54
(keto and enol) (d, 1H, benzene ring proton), 7.57 (keto and
enol) (d, 1H, benzene ring proton), 8.01 (maj) and 8.10 (min)
(keto and enol) (s, 1H, NH), 11.08 (keto and enol) (s, br, 1H,
OH), 11.82 (keto and enol) (s, 1H, OH). ESI-MS (positive
mode): m/z (%) 762.99 (10) [M]þ, 346.14 (25) [M - (SiMe3) þ
2H]2þ, 310.18 (100) [M - (Me3SiCH2CH2CO2) þ 2H]2þ. HRMS
(ESI, positive mode): m/z calcd for C38H42Fe2NO7Si [M þ H]þ
664.1429; found 664.1430. Anal. Calcd for C38H41Fe2NO7Si: C,
59.78; H, 5.41; N, 1.83. Found: C, 60.00; H, 5.91; N, 2.32.
Amide 26. 16 (2 g, 5.84 mmol), 25 (2.35 g, 8.7 mmol), HATU
(4.4 g, 11.6 mmol), DIPEA (1.5 g, 11.6 mmol), DMF (15 mL),
and ACN (20 mL) were employed. After 60 h the reaction
mixture was worked up following the procedure mentioned
above. Column chromatography (silica gel, hexane/EtOAc
1/1.5 f 0/1) yielded 26 (1.67 g, 65%) as as a red sticky solid.
Rf = 0.29 (silica gel, pure EtOAc). 1H NMR (400 MHz, CDCl3):
δ (ppm) 2.0-2.18 (m, 2H, CH2), 2.35 (s, 3H, COCH3), 2.43-
2.66 (m, 2H, CH2), 2.73-2.89 (m, 2H, CH2), 3.51 (s, 3H, OCH3),
3.58 (s, 3H, OCH3), 3.87 (s, 3H, COCH3), 4.49-4.51 (m, 4H,
C5H4), 4.77 (s, br, 2H, C5H4), 4.83 (s, 2H, br, C5H4), 5.09 (s, 2H,
OCH2), 5.25 (s, 2H, OCH2), 7.03 (d, 1H, benzene ring proton),
7.45-7.61 (s, br, 1H, NH), 7.80 (d, 1H, benzene ring proton).
ESI-MS (positive mode): m/z (%) 618.14 (100) [M þ Na]þ.
HRMS (ESI, positive mode): m/z calcd for C29H34FeNO9 [M þ
H]þ 596.1583, found 596.1583.
General Procedure for the Amide Coupling. To a stirred
solution of the carboxylic acid in DMF were added HATU
and DIPEA, and the mixture was stirred for 30 min under an N2
atmosphere. The amine in a small volume of DMF or acetonitrile
was then added, and the mixture was stirred at room temperature
until TLC showed the reaction is complete. The volume of the
reaction mixture was then reduced under vacuum, brine was
added, and this mixture was then extracted with ethyl acetate.
The organic layer was washed with 0.5 M HCl, distilled water, and
brine.The organic phase was then dried over anhydrous Na2SO4
and filtered. Removal of solvent followed by flash column chro-
matography afforded the desired products.
Amide 19. 15 (600 mg, 1.17 mmol), 18 (495 mg, 2.34 mmol),
HATU (751 mg, 2.34 mmol), DIPEA (278 mg, 2.34 mmol),
DMF (15 mL), ACN (10 mL) were employed. After 70 h the
reaction mixture was worked up following the procedure men-
tioned above. Column chromatography (silica gel, hexane/
EtOAc 1/1) yielded 19 (740 mg, 89%) as as a red sticky solid.
Amide 27. 17 (1.3 g, 4.33 mmol), 25 (2.35 g, 8.66 mmol),
HATU (3.3 g, 8.66 mmol), DIPEA (1.12 g, 8.66 mmol), DMF
(15 mL), and ACN (20 mL) were employed. After 60 h the
reaction mixture was worked up following the procedure men-
tioned above. Column chromatography (silica gel, hexane/
EtOAc 1/1.5 f 0/1) yielded 27 (1.71 g, 73%) as as a red sticky
solid. Rf = 0.24 (silica gel, hexanes/EtOAc 1/1). 1H NMR (400
MHz, CDCl3): δ (ppm) 1.94-2.10 (m, 2H, CH2), 2.33-2.57 (m,
2H, CH2), 2.70-2.89 (m, 2H, CH2), 3.37 (min) and 3.38 (maj)
(rotamers, s, 3H, OCH3), 3.46 (s, 3H, OCH3), 3.76 (maj) and
3.81 (min) (rotamers, 3H, COCH3), 4.10 (s, 5H, C5H5), 4.39
(s, br, 2H, C5H4), 4.71 (s, 2H, br, C5H4), 4.98 (s, 2H, OCH2), 5.12
(s, 2H, OCH2), 6.62 (min) and 6.92 (maj) (rotamers, d, 1H,
1
Rf=0.68 (silica gel, EtOAc). H NMR (400 MHz, CDCl3): δ
(ppm) 2.54 (m, 4H, 2CH2), 3.79 (s, 3H, -OCH3), 3.81 (s, 3H,
-C(O)OCH3), 3.84 (s, 3H, -OCH3), 4.11 (s, 10H, C5H5), 4.51
(m, 4H, C5H4) 4.62 (m, 1H, (CO)2CH-), 4.91-4.95 (m, 4H,
C5H4), 6.71 (d, 1H, benzene ring proton), 6.98 (s, br, 1H, NH),
7.81 (d, 1H, benzene ring proton). ESI-MS (positive mode):
m/z (%) 704.92 (100) [M]þ, 727.87 (49) [M þ Na]þ, 743.81 (8)
[M þ K]þ. HRMS (ESI, positive mode): m/z calcd for C36H36-
Fe2NO7 [M þ H]þ 706.1190, found 706.1187.

Article
Organometallics, Vol. 29, No. 19, 2010 4319
benzene ring proton), 7.45-7.58 (s, br, 1H, NH), 7.62 (min) and
7.70 (maj) (rotamers, d, 1H, benzene ring proton). ESI-MS
(positive mode): m/z (%) 553.20 (100) [M]þ, 576.18 (25) [M þ
Na]þ. HRMS (ESI, positive mode): m/z calcd for C27H31FeNO8
[M]þ 553.1399, found 553.1386.
(d, 1H, benzene ring proton), 7.57 (d, 1H, benzene ring proton),
8.15 (s, 1H, NH), 11.12 (s, br, 1H, OH), 11.57 (s, br, 1H, OH).
ESI-MS (negative mode): m/z (%) 492.02 (100) [M - H]-.
HRMS (ESI, positive mode): m/z calcd for C24H24FeNO7 [M þ
H]þ 494.0904, found 494.0904. Anal. Calcd for C24H23FeNO7
3
Compound 2.38 To a stirred solution of amide 23 (150 mg, 0.19
mmol) in DMF (3 mL) was added tris(dimethylamino)-
sulfonium difluorotrimethylsilicate (TASF; 107 mg, 0.39 mmol)
at room temperature and the mixture was heated at 40 °C for
40 min. The reaction mixture was then cooled to room tempera-
ture and brine was added to it with EtOAc (3 ꢀ 40 mL). The
combined organic phase was dried over Na2SO4, filtered, and
concentrated. Flash column chromatography of the resulting
residue (EtOAc/MeOH/AcOH 20/1/0.05) gave compound 2
(126 mg, 96%) as an orange powder. Mp: 180-183 °C. Rf =
0.30 (silica gel, EtOAc/MeOH/AcOH 20/1/0.05). 1H NMR (400
MHz, DMSO-d6): δ (ppm) 1.65 (s, 3H, CH3) 2.37-2.42 (m, 4H,
2CH2), 4.15 (s, 10H, C5H5), 4.46-4.49 (m, 4H, C5H4), 4.50-
4.52 (m, 2H, C5H4), 4.60-4.62 (m, 2H, C5H4), 6.42 (d, 1H,
benzene ring proton), 7.57 (d, 1H, benzene ring proton), 9.02 (s,
1H, NH), 10.14 (s, br, 1H, OH). ESI-MS (negative mode): m/z
(%) 675.89 (100) [M - H]-. HRMS (ESI, positive mode): m/z
calcd for C34H31Fe2NO7 [M]þ 677.0798, found 677.0798. Anal.
2H2O: C, 54.46; H, 5.14; N, 2.65. Found: C, 53.97; H, 5.22; N, 2.46.
Compound 5. To a stirred solution of 9 (200 mg, 0.36 mmol) in
20 mL of a THF/H2O mixture (THF/H2O 4/1) was added
LiOH H2O (811 mg, 19.8 mmol) under an argon atmosphere.
3
The mixture was heated at 45 °C for 20 h (TLC shows complete
ester hydrolysis). Then the reaction mixture was evaporated to
dryness under vacuum and degassed 4 N HCl in dioxane was
added to make the pH of the reaction mixture near zero and this
mixture was stirred at room temperature. After 20 min the
reaction was complete (checked by TLC). A 50 mL portion of
brine was then added, and the mixture was extracted with
EtOAc (3 ꢀ 30 mL). The combined organic phase was washed
with distilled water (5 ꢀ 50 mL) and brine (2 ꢀ 25 mL), dried on
anhydrous Na2SO4, and filtered. Removal of the solvent gave a
red sticky solid. Flash column chromatography (silica gel,
EtOAc/MeOH/AcOH 1/0/0 f 20/1/0.1) was done. The volume
of the solvent was reduced to about 3 mL, and pentane was
added to it; the compound precipitated, and the pentane was
drained off to yield compound 5 as an orange powder (138.6 mg,
85%). Mp: 143-146 °C. Rf = 0.37 (silica gel, EtOAc/MeOH/
Calcd for C34H31Fe2NO7 1.5H2O: C, 57.93; H, 4.87; N, 1.99.
3
Found: C, 58.09; H, 5.18; N, 1.94.
Compound 3.38 To a stirred solution of amide 24 (80 mg, 0.10
mmol) in DMF (1.5 mL) was added tris(dimethylamino)-
sulfonium difluorotrimethylsilicate (TASF; 55 mg, 0.21 mmol)
at room temperature, and the mixture was heated at 40 °C for
40 min. The solution was then cooled to room temperature and
brine was added to it. The mixture was extracted with EtOAc
(3 ꢀ 25 mL), and the combined organic phase was dried over
Na2SO4, filtered, and concentrated. Flash column chromatog-
raphy of the resulting residue (EtOAc/MeOH/AcOH 20/1/0.05)
gave compound 3 (61 mg, 89%) as an orange powder. Mp:
134-137 °C. Rf = 0.30 (silica gel, EtOAc/MeOH/AcOH 20/
AcOH 20/1/0.1). H NMR (400 MHz, pyridine-d5): δ (ppm)
1
2.35-2.48 (m, 2H, CH2), 2.85-2.98 (m, 2H, CH2), 3.02-3.15
(m, 2H, CH2), 4.18 (s, 5H, C5H5), 4.45 (s, br, 2H, C5H4), 4.95 (s,
2H, br, C5H4), 6.94 (d, 1H, benzene ring proton), 8.12 (d, 1H,
benzene ring proton), 10.61 (s, 1H, OH), 10.75-11.34 (s, br, 1H,
NH). ESI-MS (negative mode): m/z (%) 449.98 (100) [M - H]-.
HRMS (ESI, positive mode): m/z calcd for C22H21FeNO6 [M]þ
451.0718, found 451.0717. Anal. Calcd for C22H21FeNO6: C,
58.56; H, 4.69; N, 3.10. Found: C, 58.33; H, 5.17; N, 3.04.
Abbreviations
1
1/0.0.1). H NMR (400 MHz, DMSO-d6): δ (ppm) 2.30-2.42
(m, 2H, CH2), 2.48-2.58 (m, 2H, CH2) (overlaps with DMSO-
d6), 4.22 (s, 10H, C5H5), 4.56-4.58 (min) and 4.62-4.68 (maj)
(m, 5H, C5H4 and (CO)2CH-, keto and enol), 4.80-4.83 (min)
and 4.86-4.92 (maj) (m, 4H, C5H4, keto and enol), 6.42 (d, 1H,
benzene ring proton), 7.56 (d, 1H, benzene ring proton), 9.09
(min) and 9.15 (maj) (s, 1H, NH, keto and enol), 10.27 (s, br, 1H,
OH). ESI-MS (negative mode): m/z (%) 661.87 (100) [M - H]-.
HRMS (ESI, positive mode) m/z calcd for C33H30Fe2NO7 [M þ
H]þ 664.0727, found 664.0721. Anal. Calcd for C33H29Fe2-
TMSE,(trimethylsilyl)ethyl; MOM, methoxymethyl; HATU,
2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hex-
afluorophosphate methanaminium; DIPEA, diisopropylethyla-
mine, TASF, tris(dimethylamino)sulfonium difluorotrimethyl-
silicate; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; Fc, ferrocene;
MIC, minimum inhibitory concentration; Cp, cyclopentadienyl.
Acknowledgment. We wish to acknowledge the Inter-
national Max Planck Research School for Chemical
Biology(fellowship to M.P.), the Alexander von Humboldt
Foundation (fellowship to G.G.), the Swiss National
Science Foundation (Ambizione Grant PZ00P2_126404
to G.G.), and the DFG-Deutsche Forschungsgemeinschaft
(FOR 630) for financial support of this project. Support
from the Research Department Interfacial System Chemis-
try (J.E.B. and N.M.-N.) is also gratefully acknowledged.
G.G. thanks Prof. Roger Alberto for generous access to all
the facilities of the Institute of Inorganic Chemistry of the
University of Zurich. We thank Dr. Dirk Wolters and
Benjamin Fraenzel from Ruhr-University Bochum for the
HRMS measurements.
NO7 H2O: C, 58.18; H, 4.59; N, 2.06. Found: C, 58.28; H,
5.12; N 2.22.
3
Compound 4. To a stirred solution of 8 (1 g, 1.68 mmol) in
40 mL of a THF/H2O mixture (THF/H2O 4/1) was added
LiOH H2O (3.78 g, 92.43 mmol) under an argon atmosphere.
3
The mixture was heated at 45 °C for 20 h (TLC shows complete
ester hydrolysis). The reaction mixture was then evaporated to
dryness under vacuum. Degassed 4 N HCl in dioxane was then
added slowly to adjust the pH of the reaction mixture to near
zero. The mixture was then stirred at room temperature. After
15 min the reaction was complete (checked by TLC) and 50 mL
of brine was added to the mixture, which was then extracted with
EtOAc (3 ꢀ 30 mL). The combined organic phases were washed
with distilled water (5 ꢀ 50 mL) and brine (2 ꢀ 25 mL), dried
over anhydrous Na2SO4, and filtered. Removal of the solvent
gave a red sticky solid. Flash column chromatography (silica gel,
EtOAc/MeOH/AcOH 1/0/0 f 20/1/0.2) was done. The volume
of the solvent was reduced to about 5 mL and pentane was added
to it; the compound precipitated, and the pentane was drained
off to yield compound 4 as an orange powder (500 mg, 60%). Mp:
57-60 °C. Rf=0.28 (silica gel, EtOAc/MeOH/AcOH 20/1/0.2).
1H NMR (400 MHz, CDCl3): δ (ppm) 2.10 (s, br, 2H, CH2), 2.29
(s, 3H, CH3), 2.65 (s, br, 2H, CH2), 2.75 (s, br, 2H, CH2), 4.46 (s,
br, 4H, C5H4), 4.72 (s, br, 2H, C5H4), 4.76 (s, br, 2H, C5H4), 6.48
Supporting Information Available: ORTEP plots of 9 and
14-16 (Figures S1-S6), selected bond distances, angles, crystal-
lographic data, and parameters for 9, 10, and 14-16 (Tables S1
and S2), text and figures giving 13C NMR and IR data and 1H
and 13C NMR spectra of all new compounds, and CIF files
giving X-ray crystallographic data for compounds 9, 10, and
14-16. This material is available free of charge via the Internet
at http://pubs.acs.org.