Syntheses and antibacterial properties of iso-platencin, Cl-iso-platencin and Cl-platencin: Identification of a new lead structure

Article abstract of DOI:10.1002/chem.201000706

Platencin is a novel antibiotic which is active against multiresistant pathogens. We describe efficient syntheses of three platencin analogues of varying activities which allow further conclusions about the pharmacophoric part of the molecule. The unnatural antibiotic iso-platencin, which is about as active as natural platencin, but much more selective, was identified as a new lead structure.

Full text of DOI:10.1002/chem.201000706

DOI: 10.1002/chem.201000706
Syntheses and Antibacterial Properties of iso-Platencin, Cl-iso-Platencin and
Cl-Platencin: Identification of a New Lead Structure
Konrad Tiefenbacher, Andreas Gollner, and Johann Mulzer*[a]
Abstract: Platencin is a novel antibiotic which is active against multiresistant
pathogens. We describe efficient syntheses of three platencin analogues of varying
activities which allow further conclusions about the pharmacophoric part of the
molecule. The unnatural antibiotic iso-platencin, which is about as active as natural
platencin, but much more selective, was identified as a new lead structure.
Keywords: antibiotics
products · stereoselectivity · ter-
penoids · total synthesis
·
natural
The rise of multiresistant bacteria is a serious and urgent
threat, especially in hospitals, where antibiotics are perma-
nently used and bacteria strains easily evolve that withstand
multiple antibiotic classes. Infections by Gram-positive
pathogens such as methicillin-resistant Staphylococcus
aureus (MRSA), vancomycin-resistant enterococci (VRE)
and penicillin-resistant Streptococcus pneumonia (PRSP) are
particularly worrying.[1] From these observations the urgency
to develop new antibiotics is obvious. Since novel antibiotics
usually address well-known targets just at different binding
sites or through new binding modes, the discovery of platen-
cin[2] (1, Figure 1) and platensimycin[3] (2), has been hailed
as a breakthrough in antibiotics research.
inhibitors of bacterial fatty acid biosynthesis (Fab), which is
essential to the survival of the pathogens, distinct from the
mammalian pathway and generally highly conserved among
bacteria. While platensimycin is blocking the fatty acid con-
densing enzyme FabF selectively, platencin inhibits the en-
zymes FabF and FabH. Both compounds thus display a
broad-spectrum antibiotic activity against many drug-resist-
ant pathogens such as methycillin-, macrolide- and linezolid-
resistant S. aureus, vancomycin intermediate S. aureus, van-
comycin-resistant enterococci, and Streptococcus pneumo-
niae.[2] Owing to the unique mode of action, no cross-resis-
tances to existing drugs have been observed so far. In addi-
tion the toxicity profile seems to be good. However, the in
vivo efficacy is low, due to the limited metabolic stability, so
that suitable synthetic derivatives will have to be prepared
and investigated to find more promising drug candidates.[1]
Not surprisingly numerous synthetic approaches to platen-
cin[4] and platensimycin{5] have been uncovered. Meanwhile
also platensimycin B1–B4, platensimide A, homoplatensi-
mide A, platensic acid and its methyl ester, platencin A1
and platensimycin A1, which are all much less biologically
active or even inactive natural derivatives of platensimycin,
have been discovered.[6] In addition several analogues of
platensimycin with moderate to no biological activity have
been reported.[7] From these observations a simple guideline
to the platensimycin pharmacophore was delineated.[7c]
Modifications on the aromatic part heavily impact the bio-
logical profile. The removal of the carboxylic acid or one of
the two hydroxy groups renders the molecule inactive. On
the other hand modifications in the eastern part are more
tolerated. But so far no modification has resulted in a com-
parable or even better biological activity than the parent
structure platensimycin. As the only example of a platencin-
derivative, (ꢀ)-nor-platencin was published recently[8] and
Figure 1. Structures of platencin (1) and platensimycin (2).
This is due to the fact that compounds 1 and 2 address an
apparently ideal biological target. They are the first potent
[a] Dr. K. Tiefenbacher, Dr. A. Gollner, Prof. Dr. J. Mulzer
University of Vienna, Institute of Organic Chemistry
Wꢀhringerstrasse 38, 1090 Wien (Austria)
Fax : (+43)1-4277-52189
E-mail: johann.mulzer@univie.ac.at
Supporting information for this article is available on the WWW
1
under http://dx.doi.org/10.1002/chem.201000706: H and 13C NMR
spectra of all new compounds.
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FULL PAPER
showed moderate antibiotic activity (4–16 times less potent
than platencin).
8 and after saponification platensic acid (4) was obtained in
good overall yield.
Our goal was to synthesize new platencin derivatives to
shed further light on the structure–activity relationship. Spe-
cifically the influence of the double bond position (natural
exo position C15–C16 vs endo position C14–C15, Scheme 1)
Having secured practical routes to iso-platensic acid (3) as
well as to 4, we turned our attention to the western aromatic
units. The synthesis of the Cl-substituted amino acid 6
(Scheme 4) started from known methyl 5-chloro-2,4-dihy-
droxybenzoate[10] (12) which
was nitrated with 65% HNO3
in excellent yield and protected
as bis-benzyl ether to furnish
compound 13. Saponification of
the methyl ester, followed by
concomitant reduction of the
nitro group and bis-debenzyla-
tion, delivered the Cl-western
unit 6.
The analogous synthesis of
the F derivative was hampered
by the fact that several attempts
to introduce fluorine in methyl
Scheme 1. Envisaged sites of derivatization on platencin and required frag-
ments.
and the introduction of a halogen substituent on the C6’ po-
sition were investigated. The idea behind introducing an
inert substituent on C6’ was to improve the stability of the
aromatic system towards oxidation to the p-quinoid system.
The synthesis of iso-platensic acid (3) relies on our short
synthesis of platencin[4c,h] which delivers tricycle 8 in only
three steps and high yield (49%, Scheme 2). After methyla-
tion, the side chain was introduced via 1,4-addition to
methyl acrylate. Surprisingly
Scheme 3. Conversion of iso-platensic acid methyl ester 10 to platensic
acid 4.
the subtle changes caused by
the alkene endo-position led to
an excellent 10:1 diastereose-
lectivity of this addition com-
pared to the moderate 4:1
ratio[4h] in the case of the regu-
lar platencin core. Saponifica-
tion of the methyl ester yielded
iso-platensic acid (3).
Scheme 4. Synthesis of Cl-western unit 6.
2,4-dihydroxybenzoate failed. We therefore turned to the
known[11] introduction of fluorine into the more electron
rich resorcin core. The resulting crude mixture of fluorinat-
ed resorcin compounds was subjected to a Kolbe–Schmitt
reaction[12] and a subsequent double methylation delivered
compound 15 (Scheme 5) in low but sufficient yield. Selec-
tive demethylation with Lewis acid, followed by nitration
and bis-benzylation gave intermediate 16 which was pro-
cessed to the F-western unit 7 in the same way as the Cl-de-
rivative 13.
Scheme 2. Synthesis of iso-platensic acid 3.
With all required fragments in hand, only coupling via
amidation was left. iso-Platencin (17, Scheme 6) was ob-
tained from iso-platensic acid (3) and known[5p] amino acid 5
via optimized coupling conditions (HOBt, DMAP, EDC,
DMF) in 51% yield. For obtaining a clean product, an aque-
ous workup and the use of EDC instead of DCC proved es-
sential. Coupling of iso-platensic acid (3) with Cl-western
Encouraged by the improved 1,4-addition selectivity we
investigated the possibility to convert iso-platensic acid
methyl ester (10) to platensic acid (4, Scheme 3). Indeed the
transposition of the endo-alkene to the exo-position worked
well under the conditions[4h] developed earlier for substrate
Chem. Eur. J. 2010, 16, 9616 – 9622
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J. Mulzer et al.
additional benefit, our route to the key precursor platensic
acid 4 was optimized.
Experimental Section
All reactions were carried out in oven-dried glassware under an argon at-
mosphere, unless otherwise stated. Anhydrous CH2Cl2 was distilled from
CaH2 under argon. Anhydrous THF (tetrahydrofuran) and DMF (N,N-
dimethylformamide) was purchased from Acros. All other solvents were
HPLC grade. Reactions were magnetically stirred and monitored by thin
layer chromatography (TLC) with E. Merck silica gel 60-F254 plates.
Flash column chromatography was performed with Merck silica gel
(0.04–0.063 mm, 240–400 mesh) under pressure. Yields refer to chromato-
graphically and spectroscopically pure
Scheme 5. Synthesis of F-western unit 7.
compounds, unless otherwise stated.
NMR spectra were recorded on either
Bruker Avance DRX 400 or DRX
600 MHz spectrometer. All NMR
spectra were measured in CDCl3 or
MeOD solutions and referenced to the
residual CHCl3 signal (1H, d=
7.26 ppm; 13C, d=77.00 ppm) or
MeOH signal (1H, d=3.31 ppm; 13C,
d=49.00 ppm). All 1H and 13C shifts
are given in ppm (s=singlet; d=dou-
blet; t=triplet; q=quadruplet; m=
multiplet; b=broad signal). Assign-
ments of proton resonances were con-
firmed, when possible, by correlated
spectroscopy. Optical rotations were
measured on a P 341 Perkin–Elmer
Scheme 6. Syntheses of iso-platencin (17), Cl- iso-platencin (18) and Cl-platencin (19).
unit 6 under these conditions resulted in a sharp drop of
polarimeter. Mass spectra were measured on a Micro mass, trio 200 Fi-
sions Instruments. High resolution mass spectra (HRMS) were performed
with a Finnigan MAT 8230 with a resolution of 10000.
yield (17% of 18), whereas coupling with F-western unit 7
failed altogether. Thus, for the coupling of 4 with 6 we ex-
plored other conditions and found that HATU gave a slight-
ly better result (27% yield of 19). Even under these condi-
tions 4 and 7 just gave traces of the desired product.
Methyl 5-chloro-2,4-dihydroxy-3-nitrobenzoate (20):
A suspension of
methyl 5-chloro-2,4-dihydroxybenzoate[9] (1.20 g, 5.92 mmol) in CHCl3
(10 mL) was homogenized by the use of a ultrasonic bath (1 min) and
treated with 65% HNO3 (0.62 mL) at RT. After stirring for 100 min,
water (20 mL) was added and the aqueous layer was extracted two times
with CH2Cl2. The combined organic phases were dried over magnesium
sulfate, filtered and the solvent was removed under vacuum to yield
The biological data are summarized in Table 1. The modi-
fications on the aromatic system (Cl-platencin and Cl-iso-
platencin) resulted in a complete loss of antibacterial activi-
ty. This is in agreement with the simple guideline developed
for the platensimycin pharmacophore.[7c] On the other hand
the modification on the eastern part (iso-platencin) led to a
highly potent and selective derivate. In fact it is the first de-
rivate described so far that shows activity on a par with the
parent natural products platencin and platensimycin. Its in
vitro activity against various resistant staphylococci matches
those of platencin. Interestingly it is also highly selective for
staphylococci since it is ineffective against Enterococci.
1
phenol 20 (1.33 g, 90%) as a yellow crystalline solid. H NMR (400 MHz,
CDCl3): d=8.11 (s, 1H), 4.00 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d=169.1 (C), 158.2 (C), 156.3 (C), 136.0 (CH), 126.1 (C), 113.4 (C), 105.7
(C), 53.2 ppm (CH3); IR: n˜
= 3500 (br), 1674, 1539, 1440, 1349,
1177 cmꢀ1; HRMS(EI): m/z: calcd for C8H6ClNO6+: 246.9884, found:
246.9880 [M]+.
Methyl 2,4-bis(benzyloxy)-5-chloro-3-nitrobenzoate (13): To a solution of
phenol 20 (1.33 g, 5.37 mmol) in DMF (21 mL) was added K2CO3 (3.71 g,
26.9 mmol) and the suspension stirred for 15 min. After the addition of
benzyl bromide (1.47 mL, 12.4 mmol) the mixture was heated to 608C for
20 h. Additional benzyl bromide (1.47 mL, 12.4 mmol) was added and
stirring at 608C continued for 7 h. The suspension was filtered, diluted
with water (100 mL) and the aqueous layer was extracted three times
with ethyl acetate. The combined organic phases were washed with brine
and dried over magnesium sulfate, filtered and the solvent was removed
under vacuum. Purification by column chromatography (40 g silica gel)
using hexane/ethyl acetate 10:1 yielded 13 (1.12 g, 49%). 1H NMR
(400 MHz, CDCl3): d=8.10 (s, 1H), 7.47–7.32 (m, 10H), 5.21 (s, 2H),
5.12 (s, 2H), 3.91 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=163.3
(C), 150.5 (C), 150.2 (C), 135.4 (C), 134.9 (C), 134.3 (CH), 129.0 (CH),
128.7 (CH), 128.6 (CH, 2C), 128.6 (CH, 2C), 128.6 (CH, 2C), 128.6 (CH,
2C), 124.1 (C), 122.4 (C), 79.2 (CH2), 77.2 (CH2), 52.8 ppm (CH3); IR: n˜
Conclusion
In summary the synthesis of three new platencin analogs is
reported. iso-Platencin (17) is the first derivate to show
comparable activity to the parent natural product. Remarka-
bly the core, iso-platensic acid 3, was synthesized from peril-
laldehyde in only six steps. Therefore analogue 17 can be
obtained quickly and in good yield to serve as a lead struc-
ture in further biological investigations. Modification of the
aromatic section delivered inactive compounds only. As an
= 1733, 1545, 1372, 1292, 1252, 1147 cmꢀ1
.
2,4-Bis(benzyloxy)-5-chloro-3-nitrobenzoic acid (21): To a solution of
ester 13 (600 mg, 1.40 mmol) in THF (5.6 mL) was added water (1.4 mL)
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Chem. Eur. J. 2010, 16, 9616 – 9622

Platencin Derivatives
FULL PAPER
Table 1. MIC (minimum inhibitory concentration [mgmLꢀ1]) values for platencin, iso-platencin, Cl-platencin and Cl-iso-platencin (Fus=fusidic acid; Pen
G=Penicillin G; Van=Vancomycin;Doxy=doxycyclin; Linco=lincomycin; Cipro=ciprobay; Clarithro=clarithromycin R=resistant; S=sensitive).
BC-Code
Resistances
Platencin
Iso-platecin
CI-platencin
CI-iso-Platencin
Staphylococcus aureus (MSSA)
Staphylococcus aureus (MSSA)
Staphylococcus aureus (MSSA)
Staphylococcus aureus (MSSA)
Staphylococcus aureus (MSSA)
Staphylococcus aureus (MSSA)
Staphylococcus aureus (MRSA)
Staphylococcus haemolyticus
Staphylococcus aureus (MRSA)
Staphylococcus aureus (MRSA)
Staphylococcus aureus (MRSA)
Staphylocccus epidermidis (MRSE)
Staphylococcus epidermidis
Staphylococcus epidermidis
Staphylococcus haemolyticus
Enterococcus faecalis
FusR (fusB)
0.8
6.4
1.6
1.6
0.4
0.4
1.6
0.4
1.6
1.6
1.6
0.4
0.1
0.2
0.2
0.2
0.2
0.2
0.2
>25.6
>25.6
>25.6
>25.6
0.2
0.4
25.6
0.8
1.6
0.4
1.6
1.6
0.4
25.6
1.6
12.8
0.2
0.1
0.8
0.4
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>2.56
>2.56
>2.56
>2.56
>2.56
>2.56
>2.56
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>2.56
>2.56
>2.56
>2.56
>2.56
>2.56
>2.56
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>25.6
>2.56
>2.56
>2.56
>2.56
>2.56
>2.56
>2.56
PenGR AmpR
TiamulinR
TiamulinR LinezolidR
FusR (fusA)
MakrolidR LincoR TelithroR CiproR
MupirocinR
MakrolidR LincoR TelithroR CiproS
FusR (not fusB) MacrolidR LincoS TelithroS CiproS
MakrolidS LincoS TelithroS CiproS
MupirocinS OxaR VanS
MupirocinR OxaS VanS
FusR (not fusB) MupirocinS VanR
CiproR EryR PenGR
AmpS VanS MakrolidS
Enterococcus faecalis
VanS DoxyS MakrolidR
VanR DoxyR MakrolidR
VanR DoxyR MakrolidR
VanR DoxyR MakrolidR
VanR DoxyR MakrolidR
VanS DoxyR MakrolidR
AmpS VanS MakrolidS CiproR
BRO-1 b-lactamase
Enterococcus faecalis (VRE)
Enterococcus faecalis (VRE)
Enterococcus faecium (VRE)
Enterococcus faecium (VRE)
Enterococcus faecium
Enterococcus faecium
Moraxella catarrhalis
Moraxella catarrhalis
Escherichia coli
Streptococcus pneumoniae
Streptococcus pneumoniae
Streptococcus pneumoniae
Streptococcus pneumoniae
Streptococcus pneumoniae (MDR)
Streptococcus pneumoniae (MDR)
Streptococcus pneumoniae (MDR)
BRO-1 b-lactamase
0.2
>25.6
>2.56
>2.56
>2.56
>2.56
>2.56
>2.56
>2.56
no resistance
MakrolidR
PenGR ClarithroR
PenGR
MakrolidR VanI DoxyI
and LiOH·H2O (2.94 g, 70.1 mmol) and the suspension was stirred for
20 h at 458C. After acidification with 3n HCl and saturation of the solu-
tion with NaCl, the aqueous layer was extracted three times with CHCl3.
The combined organic phases were dried over sodium sulfate, filtered
and the solvent was removed under vacuum. Purification by column
chromatography (50 g silica gel) using ethyl acetate yielded 21 (490 mg,
(100 mL), the aqueous phase was extracted four times with diethyl ether.
The aqueous phase was acidified with HCl and extracted three times
with diethyl ether. The combined organic phases were dried over sodium
sulfate, filtered and the solvent was removed under vacuum to give crude
5-fluoro-2,4-dihydroxybenzoic acid (4.0 g). To a solution of the crude ma-
terial in DMF (42 mL) was added KHCO3 (2.56 g, 25.5 mmol) and after
5 min. methyl iodide (1.4 mL, 23.2 mmol). After stirring at RT for 20 h,
water (160 mL) was added and the aqueous phase was extracted three
times with ethyl acetate. The combined organic phases were washed with
brine and dried over magnesium sulfate, silica gel was added and the sol-
vent was carefully removed under vacuum. Purification of the adsorbed
material by column chromatography (70 g silica gel) using hexane/ethyl
acetate 7:1 ! 3:1 yielded ester 15 (624 mg, 7% over 3 steps). 1H NMR
(400 MHz, CDCl3): d=7.48 (d, J=11.6 Hz, 1H), 6.51 (d, J=7.1 Hz, 1H),
3.92 (s, 3H), 3.90 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=169.9
(C), 159.7 (C), 154.1 (d, J=12.6 Hz, C), 145.4 (d, J=239.3 Hz, C), 115.2
(d, J=20.7 Hz, CH), 103.4 (C), 101.2 (CH), 56.2 (CH3), 52.2 ppm (CH3);
IR: n˜ = 1659, 1444, 1362, 1273, 1196, 955, 909, 787, 749 cmꢀ1 ; HRMS
(EI): m/z: calcd for C9H9FO4+: 200.0485, found: 200.0483 [M]+.
1
84%). H NMR (400 MHz, CDCl3): d=8.24 (s, 1H), 7.47–7.34 (m, 10H),
5.25 (s, 2H), 5.16 (s, 2H); 13C NMR (100 MHz, CDCl3): d=165.3 (C),
151.5 (C), 150.4 (C), 135.1 (CH), 134.7 (C), 134.6 (C), 129.1 (CH), 129.1
(CH), 128.9 (CH, 2C), 128.8 (CH, 2C), 128.7 (CH, 2C), 128.7 (CH, 2C),
124.7 (C), 120.8 (C), 79.8 (CH2), 77.3 ppm (CH2); IR: n˜ = 1699, 1545,
ꢀ
1373, 1292, 696 cmꢀ1
;
HRMS (EI): m/z: calcd for C21H15ClNO6
:
412.0588, found: 412.0592 [MꢀH]ꢀ.
3-Amino-5-chloro-2,4-dihydroxybenzoic acid (6): To a solution of acid 21
(490 mg, 1.18 mmol) in methanol (12 mL) was added 5% Pd/C (84 mg)
and the suspension was stirred for 26 h under an atmosphere of hydro-
gen. After filtration, the solvent was removed under vacuum to give a
brownish solid. The crude material was taken up in boiling iPrOH
(100 mL), filtered and the solvent again removed under vacuum to yield
pure 6 (135 mg, 56%). 1H NMR (400 MHz, MeOD): d=7.31 ppm (s,
1H); 13C NMR (100 MHz, MeOD): d=173.2 (C), 151.5 (C), 147.2 (C),
Methyl 5-fluoro-2,4-dihydroxybenzoate (22): To a cooled (08C) suspen-
sion of AlCl3 (2.50 g, 18.7 mmol) in CH2Cl2 (12.5 mL) was added ester 15
(624 mg, 3.12 mmol) dissolved in CH2Cl2 (24 mL). The mixture was
stirred for 23 h at RT and quenched by the addition of water (100 mL) at
08C. The aqueous phase was extracted two times with ethyl acetate. The
combined organic phases were washed with brine, dried over magnesium
sulfate, filtered and the solvent was removed under vacuum. Purification
by column chromatography (20 g silica gel) using hexane/ethyl acetate
4:1 yielded bisphenol 22 (531 mg, 91%). 1H NMR (400 MHz, CDCl3):
d=7.53 (d, J=10.9 Hz, 1H), 6.57 (d, J=7.3 Hz, 1H), 3.92 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=169.7 (C), 159.7 (C), 150.3 (d, J=
124.0 (C), 121.1 (CH), 112.8 (C), 107.4 ppm (C); IR: n˜ = 3000 (br), 1628,
ꢀ
1448, 1375, 1301 cmꢀ1
;
HRMS (EI): m/z: calcd for C7H5ClNO4
:
201.9907, found: 201.9914 [MꢀH]ꢀ.
Methyl 5-fluoro-2-hydroxy-4-methoxybenzoate (15): To crude 4-fluoro-
benzene-1,3-diol (4.65 g; prepared from 4.9 g resorcinol according to lit-
erature)[11] was added water (47 mL) and KHCO3 (20.0 g) and the sus-
pension heated to reflux. A constant stream of CO2 was bubbled through
the refluxing reaction mixture for 10 h. After the addition of water
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J. Mulzer et al.
16.2 Hz, C), 144.3 (d, J=231.0 Hz, C), 115.3 (d, J=20.5 Hz, CH), 105.0
trated under vacuum. Purification by column chromatography (30 g silica
gel) using hexane/ethyl acetate 10:1 yielded compound 9 (325 mg, 80%).
[a]2D0 =ꢀ148.5 (c=1.55, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=6.90
(d, J=10.1 Hz, 1H), 5.93 (d, J=10.1 Hz, 1H), 5.77 (s, 1H), 2.42–2.38 (m,
1H), 2.31–2.22 (m, 1H), 1.81 (d, J=1.7 Hz, 3H), 1.79–1.70 (m, 2H),
1.65–1.53 (m, 2H), 1.41–1.23 (m, 2H), 1.17–1.10 (m, 1H), 1.13 ppm (d,
J=6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=202.4 (C), 155.9 (CH),
142.4 (C), 128.9 (CH), 128.0 (CH), 45.7 (CH), 44.0 (CH), 39.6 (C), 35.9
(CH), 31.4 (CH2), 27.4 (CH2), 26.0 (CH2), 20.1 (CH3), 12.8 ppm (CH3);
IR: 2935, 1676, 1445, 823 cmꢀ1; HRMS (EI): m/z: calcd for C14H18O:
202.1358, found: 202.1357 [M]+.
(CH), 104.3 (d, J=6.6 Hz, C), 52.3 ppm (CH3); IR: n˜ = 3562, 1663, 1632,
+
1437, 1363, 1286, 1250, 786 cmꢀ1; HRMS (EI): m/z: calcd for C8H7FO4
186.0328, found: 186.0326 [M]+.
:
Methyl 5-fluoro-2,4-dihydroxy-3-nitrobenzoate (23):
A suspension of
phenol 22 (500 mg, 2.69 mmol) in CHCl3 (4.5 mL) was homogenized by
the use of a ultrasonic bath (1 min) and treated with 65% HNO3
(0.28 mL) at RT. After stirring for 100 min. water (10 mL) was added and
the aqueous layer was extracted two times with CH2Cl2. The combined
organic phases were dried over magnesium sulfate, filtered and the sol-
vent was removed under vacuum to yield compound 23 (440 mg, 71%)
as a yellow crystalline solid. 1H NMR (400 MHz, CDCl3): d=7.85 (d, J=
10.4 Hz, 1H), 4.00 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=169.3
(C), 156.0 (C), 150.3 (d, J=15.3 Hz, C), 143.7 (d, J=242.6 Hz, C), 126.2
(C), 121.8 (d, J=19.9 Hz, CH), 103.4 (d, J=6.1 Hz, C), 53.2 ppm (CH3);
IR: n˜ = 3000 (br), 1669, 1541, 1447, 1364, 1290, 1252, 1173 cmꢀ1; HRMS
(EI): m/z: calcd for C8H6FNO6+: 231.0179, found: 231.0174 [M]+.
Methyl
3-[(5S,6R,8S)-5,9-dimethyl-4-oxotricyclo[6.2.2.01,6]dodeca-2,9-
dien-5- yl]propanoate (10): To a solution of 9 (200 mg, 0.99 mmol) in di-
ethyl ether (2.9 mL) and tert-butanol (2.9 mL) was added potassium tert-
butoxide (222 mg, 1.98 mmol) at 08C. After stirring at this temperature
for 5 min methyl acrylic ester (0.71 mL, 7.91 mmol) was added. After
40 min the reaction was quenched by the addition of saturated aq. NH4Cl
and the aqueous layer was extracted three times with diethyl ether. The
combined organic phases were dried over magnesium sulfate, filtered and
the solvent was removed under vacuum. Purification by column chroma-
tography (20 g silica gel) using hexane/ethyl acetate 10:1 yielded a crude
diastereomeric mixture of esters (220 mg, d.r. 10:1) as colorless oil. Pu-
rification by HPLC yielded ester 10 (180 mg, 63%) as an analytically
pure material. [a]2D0 =ꢀ84.7 (c=1.00, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=6.82 (d, J=10.1 Hz, 1H), 5.91 (d, J=10.1 Hz, 1H), 5.81 (s,
1H), 3.63 (s, 3H), 2.50–2.44 (m, 1H), 2.22–2.08 (m, 3H), 1.97–1.84 (m,
2H), 1.80 (d, J=1.7 Hz, 3H), 1.61–1.39 (m, 4H), 1.35–1.20 (m, 2H),
1.17 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=204.2 (C), 174.0 (C),
154.7 (CH), 141.1 (C), 131.1 (CH), 127.2 (CH), 51.5 (CH3), 47.2 (C), 42.4
(CH), 39.6 (C), 35.8 (CH), 31.6 (CH2), 29.5 (CH2), 27.6 (CH2), 26.0
(CH2), 25.5 (CH2), 20.4 (CH3), 20.2 ppm (CH3); IR: n˜ = 2931, 1739,
1674, 1436, 1174, 829 cmꢀ1; HRMS (EI): m/z: calcd for C18H24O3 +Na+:
311.1623, found: 311.1620 [M+Na]+.
Methyl 2,4-bis(benzyloxy)-5-fluoro-3-nitrobenzoate (16): To a solution of
compound 23 (440 mg, 1.90 mmol) in DMF (9.4 mL) was added 60%
NaH (182 mg, 4.56 mmol) at 08C and the suspension stirred for 10 min.
After the addition of benzyl bromide (0.60 mL, 5.02 mmol) the mixture
was stirred at RT for 50 h. After the addition of brine (5 mL) and water
(50 mL), the aqueous layer was extracted four times with diethyl ether.
The combined organic phases were dried over magnesium sulfate, filtered
and the solvent was removed under vacuum. Purification by column
chromatography (20 g silica gel) using hexane/ethyl acetate 10:1 yielded
ester 16 (420 mg, 54%). 1H NMR (400 MHz, CDCl3): d=7.80 (d, J=
12.6 Hz, 1H), 7.43–7.33 (m, 10H), 5.13 (d, J=1.9 Hz, 2H), 5.07 (s, 2H),
3.88 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=163.3 (C), 149.9 (d,
J=248.1 Hz, C), 147.7 (d, J=2.9 Hz, C), 142.3 (d, J=14.6 Hz, C), 135.6
(C), 134.8 (C), 129.0 (C), 128.7 (C, 2C), 128.6 (C), 128.5 (C, 4C), 128.4
(C, 2C), 120.8 (d, J=22.7 Hz, CH), 119.9 (d, J=6.6 Hz, C), 79.1 (CH2),
77.2 (CH2), 52.7 ppm (CH3); IR: n˜ = 1733, 1544, 1498, 1440, 1377, 1325,
1262, 1198, 735 cmꢀ1
.
Methyl
dien-5-yl]propanoic acid (3): To
3-[(5S,6R,8S)-5,9-dimethyl-4-oxotricyclo[6.2.2.01,6]dodeca-2,9-
a
solution of ester 10 (85 mg,
2,4-Bis(benzyloxy)-5-fluoro-3-nitrobenzoic acid (24): To a solution of
ester 16 (380 mg, 0.92 mmol) in THF (3.7 mL) was added water (0.9 mL)
and LiOH.H2O (1.93 g, 46.0 mmol) and the suspension was stirred for
20 h at 458C. After acidification with 3N HCl and saturation of the solu-
tion with NaCl, the aqueous layer was extracted three times with CHCl3.
The combined organic phases were dried over sodium sulfate, filtered
and the solvent was removed under vacuum to yield 24 (350 mg, 96%)
which was used without further purification. 1H NMR (400 MHz,
CDCl3): d=7.91 (d, J=12.3 Hz, 1H), 7.42–7.34 (m, 10H), 5.40 (d, J=
2.0 Hz, 2H), 5.11 ppm (s, 2H); 13C NMR (100 MHz, CDCl3): d=165.4
(C), 150.0 (d, J=249.6 Hz, C), 147.8 (d, J=2.9 Hz, C), 143.3 (d, J=
14.6 Hz, C), 141.8 (C), 134.6 (C), 129.1 (C), 129.1 (C), 128.9 (C, 2C),
128.7 (C, 4C), 128.4 (C, 2C), 121.5 (d, J=22.7 Hz, CH), 118.3 (d, J=
6.6 Hz, C), 79.7 (CH2), 76.6 ppm (CH2); IR: n˜ = 1701, 1546, 1499, 1375,
1204, 696 cmꢀ1; HRMS (EI): m/z: calcd for C21H15FNO6ꢀ: 396.0883,
found: 396.0873 [MꢀH]ꢀ.
0.294 mmol) in THF (3.5 mL) was added 1m aq. NaOH (3.5 mL) and
stirred for 23 h at RT. After the addition of water (30 mL) and brine
(15 mL) the mixture was washed with diethyl ether twice. The aqueous
phase was acidified with 1.2m HCl (formation of a white precipitate) and
extracted three times with diethyl ether. The combined organic phases
were dried over magnesium sulfate, filtered and the solvent was removed
under vacuum to give acid
3
(77 mg, 95%). [a]2D0 =ꢀ73.1 (c=0.55,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=6.83 (d, J=10.1 Hz, 1H), 5.92
(d, J=10.1 Hz, 1H), 5.81 (s, 1H), 2.51–2.45 (m, 1H), 2.23–2.14 (m, 3H),
1.97–1.84 (m, 2H), 1.80 (d, J=1.7 Hz, 3H), 1.61–1.39 (m, 4H), 1.34–1.20
(m, 2H), 1.17 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=204.3 (C),
178.7 (C), 154.8 (CH), 141.2 (C), 131.1 (CH), 127.2 (CH), 47.2 (C), 42.5
(CH), 39.6 (C), 35.8 (CH), 31.3 (CH2), 29.2 (CH2), 27.5 (CH2), 26.0
(CH2), 25.5 (CH2), 20.4 (CH3), 20.2 ppm (CH3); IR: n˜ = 2930, 1709,
1674, 1295, 414 cmꢀ1 HRMS (EI): m/z: calcd for C17H22O3 +Na+:
;
297.1467, found: 297.1465 [M+Na]+.
3-Amino-5-fluoro-2,4-dihydroxybenzoic acid (7): To a solution of acid 24
(350 mg, 0.88 mmol) in methanol (9 mL) was added 5% Pd/C (63 mg)
and the suspension was stirred for 25 h under an atmosphere of hydro-
gen. After filtration, the solvent was removed under vacuum to give
crude acid 7 (160 mg, 97%) which was used without further purification.
1H NMR (400 MHz, MeOD): d=7.01 ppm (d, J=11.1 Hz, 1H);
13C NMR (100 MHz, MeOD): d=173.6 (C), 149.2 (C), 146.5 (d, J=
229.1 Hz, C), 139.7 (d, J=19.0 Hz, C), 124.7 (C), 105.9 (d, J=21.2 Hz,
CH), 104.8 ppm (d, J=8.1 Hz, C); IR: n˜ = 3073 (br), 1577, 1511, 1466,
1307, 889, 740 cmꢀ1; HRMS (EI): m/z: calcd for C7H5FNO4ꢀ: 186.0203,
found: 186.0200 [MꢀH]ꢀ.
Methyl-3-[(5S,6R,8S)-5-methyl-9-methylidene-4-oxotricy-
clo[6.2.2.01,6]dodec-2-en-5-yl]propanoate (25): To a solution of ester 10
(295 mg, 1.02 mmol) in CH2Cl2 (5 mL) was added TFA (1.35 mL) at 08C
and stirred for 15 min at this temperature. The cooling bath was removed
and stirring continued for 2 h. Methanol (30 mL) and K2CO3 (3.6 g) were
added and the mixture stirred until complete consumption of the starting
material. The suspension was filtered, water was added and the aqueous
layer was extracted four times with CH2Cl2. The combined organic
phases were dried over magnesium sulfate, filtered and the solvent was
removed under vacuum. Purification by column chromatography (20 g
silica gel) using hexane/ethyl acetate 2:1 ! 1:1 yielded alcohol 11
(280 mg, 89%) as a inconsequential diastereomeric mixture, which was
directly used for the next step.
ACHTUNGTRENNUNG
(5S,6S,8S)-5,9-Dimethyltricyclo[6.2.2.01,6]dodeca-2,9-dien-4-one (9): To a
solution of enone 8 (380 mg, 2.02 mmol) in THF (25 mL) was added 0.5m
KHMDS in toluene (6.1 mL, 3.03 mmol) slowly at ꢀ788C. After 30 min.,
HMPA (5 mL) and MeI (1.00 mL, 16.1 mmol) was added sequentially.
After 4 h, the reaction was quenched by the addition of sat. aq. NaHCO3
solution and extracted with EtOAc (ꢂ3). The combined organic phase
was washed with water, brine, dried over magnesium sulfate and concen-
To a solution of alcohol 11 (280 mg, 0.91 mmol) in CH2Cl2 (5.7 mL) was
added a solution of Martinꢃs sulfurane (775 mg, 1.15 mmol) in CH2Cl2
(1.8 mL) at 08C. Stirring was continued for 1 h at 08C. The reaction mix-
ture was concentrated under vacuum and the residue purified by column
9620
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9616 – 9622

Platencin Derivatives
FULL PAPER
chromatography (30 g silica gel) using hexane/ethyl acetate 7:1, to yield
ester 25 (214 mg, 82%), which analytical data matched those reported in
our earlier publication.[4h]
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35, 388.
iso-Platencin (17): To a solution of acid 3 (14 mg, 0.051 mmol) in DMF
(0.75 mL) were added HOBt·H2O (10 mg, 0.065 mmol), DMAP (1 mg,
0.0082 mmol) and EDC (12 mg, 0.063 mmol). After 4 h, amine 5 (17 mg,
0.101 mmol) was added and stirring continued for 40 h. Water (10 mL)
was added and the pH adjusted to 4 by the addition of 1m HCl. The
aqueous layer was extracted four times with CH2Cl2. The combined or-
ganic phases were dried over sodium sulfate, filtered and the solvent was
removed under vacuum. Purification by column chromatography (5 g
silica gel) using EtOAc/hexane/AcOH/MeOH/H2O 60:40:0.5:1.0:0.5
yielded 17 (11 mg, 51%). [a]2D0 =ꢀ107.7 (c=0.35, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=8.19 (s, 1H), 7.62 (d, J=9.0 Hz, 1H), 6.83 (d, J=
10.1 Hz, 1H), 6.51 (d, J=9.0 Hz, 1H), 6.01 (d, J=10.1 Hz, 1H), 5.83 (s,
1H), 2.55–2.49 (m, 1H), 2.43–2.31 (m, 2H), 2.23–2.15 (m, 1H), 2.00–1.91
(m, 2H), 1.84–1.76 (m, 1H), 1.81 (d, J=1.6 Hz, 3H), 1.65–1.25 ppm (m,
5H), 1.24 (s, 3H); 13C NMR (100 MHz, CDCl3): d=206.2 (C), 174.1 (C),
173.1 (C), 156.7 (CH), 155.5 (C), 154.4 (C), 141.5 (C), 130.7 (CH), 128.3
(CH), 126.9 (CH), 114.4 (C), 111.3 (CH), 103.4 (C), 47.7 (C), 42.4 (CH),
39.8 (C), 35.7 (CH), 32.8 (CH2), 32.4 (CH2), 27.5 (CH2), 25.9 (CH2), 25.4
[2] a) J. Wang, S. Kodali, S. H. Lee, A. Galgoci, R. Painter, K. Dorso, F.
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L. Hernandez, J. Allocco, A. Basilio, J. R. Tormo, O. Genilloud, F.
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J. W. Becker, D. Cully, S. B. Singh, Nature 2006, 441, 358; b) S. B.
Singh, H. Jayasuriya, J. G. Ondeyka, K. B. Herath, C. Zhang, D. L.
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130, 11292; J. Am. Chem. Soc. (Addition/Correction) 2008, 130,
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Am. Chem. Soc. 2009, 131, 8413; n) N. A. McGrath, E. S. Bartlett, S.
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p) K. C. Nicolaou, A. Li, S. P. Ellery, D. J. Edmonds, Angew. Chem.
(CH2), 20.5 (CH3), 20.2 ppm (CH3); IR: n˜ = 2928, 1654, 1534, 1375 cmꢀ1
;
HRMS (EI): m/z: calcd for C24H27NO6 +Na+: 448.1736, found: 448.1729
[M+Na]+.
Cl-Platencin (19): To a solution of acid 4 (10 mg, 0.036 mmol) in DMF
(0.20 mL) were added NEt3 (25 uL, 0.18 mmol) and HATU (27 mg,
0.072 mmol). After 1 h, amine 6 (29 mg, 0.144 mmol) was added and stir-
ring continued for 54 h. Water (5 mL) was added and the pH adjusted to
4 by the addition of 1m HCl. The aqueous layer was extracted five times
with CH2Cl2. The combined organic phases were dried over sodium sul-
fate, filtered and the solvent was removed under vacuum. Purification by
column chromatography (4 g silica gel) using acetone/hexane/AcOH
2:1:0
!
70:30:0.5 yielded 19 (4.5 mg, 27%). [a]2D0 =ꢀ24.4 (c=0.09,
CHCl3); 1H NMR (400 MHz, CDCl3): d=8.28 (s, 1H), 7.74 (s, 1H), 6.59
(d, J=10.1 Hz, 1H), 5.93 (d, J=10.1 Hz, 1H), 4.87 (s, 1H), 4.69 (s, 1H),
2.51–1.25 (m, 14H), 1.23 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
206.2, 174.6, 171.6, 156.4, 152.8, 151.5, 148.2, 127.6, 125.9, 115.5, 107.8,
47.7, 44.4, 44.2, 39.5, 36.4, 35.8, 32.3, 31.0, 28.0, 26.6, 21.2 ppm; IR: n˜ =
2927, 1653, 1534, 1126, 889, 739 cmꢀ1
; HRMS (EI): m/z: calcd for
C24H26ClNO6ꢀ: 458.1370, found: 458.1378 [MꢀH]ꢀ.
Cl-isoplatencin (18): To a solution of acid 3 (20 mg, 0.072 mmol) in DMF
(0.80 mL) were added HOBt·H2O (14 mg, 0.086 mmol), DMAP (2.0 mg,
0.016 mmol) and EDC (16 mg, 0.086 mmol). After 7 h, amine 6 (30 mg,
0.144 mmol) was added and stirring continued for 72 h. Water (10 mL)
was added and the pH adjusted to 4 by the addition of 1m HCl. The
aqueous layer was extracted three times with CH2Cl2. The combined or-
ganic phases were dried over sodium sulfate, filtered and the solvent was
removed under vacuum. Purification by column chromatography (4 g
silica gel) using acetone/hexane/AcOH 2:1:0 ! 70:30:0.5 yielded 18
(5.5 mg, 17%). [a]2D0 =ꢀ70.8 (c=0.185, CHCl3); 1H NMR (400 MHz,
CDCl3): d=8.20 (s, 1H), 7.75 (s, 1H), 6.95 (d, J=10.1 Hz, 1H), 6.00 (d,
J=10.1 Hz, 1H), 5.82 (s, 1H), 2.52 (s, 1H), 2.46–2.27 (m, 2H), 2.19–2.15
(m, 1H), 2.00–1.87 (m, 2H), 1.81 (s, 3H), 1.81–1.72 (m, 1H), 1.64–1.52
(m, 2H), 1.52–1.28 (m, 2H), 1.27–1.25 (m, 1H), 1.24 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=206.2, 174.5, 172.0, 156.8, 152.7, 151.0,
141.5, 130.7, 127.6, 126.9, 115.4, 47.7, 42.5, 39.8, 35.7, 32.7, 32.4, 27.5, 25.9,
25.4, 20.4, 20.2 ppm; IR: n˜
= ;
2927, 1653, 1534, 1376, 878, 740 cmꢀ1
HRMS (EI): m/z: calcd for C24H26ClNO6ꢀ: 458.1370, found: 458.1375
[MꢀH]ꢀ.
Acknowledgements
The authors thank Mathias Ferencic and Nabriva Therapeutics AG for
biological testing.
Chem. Eur. J. 2010, 16, 9616 – 9622
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9621

J. Mulzer et al.
2009, 121, 6411; Angew. Chem. Int. Ed. 2009, 48, 6293. Short synthe-
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MacCoss, S. L. Colletti, Bioorg. Med. Chem. Lett. 2009, 19, 1623;
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Med. Chem. Lett. 2009, 19, 4601.
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Singh, Chem. Commun. 2008, 5034; b) K. B. Herath, C. Zhang, H.
Jayasuriya, J. G. Ondeyka, D. L. Zink, B. Burgess, J. Wang, S. B.
Singh, Org. Lett. 2008, 10, 1699; c) H. Jayasuriya, K. B. Herath, J. G.
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Received: March 19, 2010
Published online: May 18, 2010
9622
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