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Synthesis of Platensimycin Analogues and Their Antibiotic Potency.

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386
Arch. Pharm. Chem. Life Sci. 2008, 341, 386 – 392
Full Paper
Synthesis of Platensimycin Analogues and Their Antibiotic
Potency
Jrgen Krauss, Veronika Knorr, Vera Manhardt, Stefanie Scheffels, and Franz Bracher
Pharmaceutical Chemistry, Department of Pharmacy – Center of Drug Research, LMU Munich, Munich,
Germany
Platensimycin is a natural product isolated from various strains of Streptomyces platensis which
exhibits antimicrobial activity against Gram positive bacteria, including vancomycin- and linezolide-resistant species. Analogues of platensimycin were synthesized from 3-aminobenzoic acid or
other aniline derivatives and several alkyl- and aryl-carboxylic acids. The resulting compounds
were tested in an agar diffusion assay against several bacteria and fungi.
Keywords: Antibiotics / Natural products / Platensimycin /
Received: August 22, 2007; accepted: January 18, 2008
DOI 10.1002/ardp.200700177
Introduction
Platensimycin (Fig. 1) was isolated in 2006 by Wang et. al.
from a culture of Streptomyces platensis. The compound
showed significant antibiotic activity especially against
Gram positive species (MIC 0.5 – 1.0 lg/mL). The mechanism of action is the inhibition of the bacterial FabF/B
enzyme complex which results in an impaired fatty acid
synthesis. As this is a completely new target, the substance showed no cross resistance with other antibiotics.
Moreover, platensimycin did not show any significant
cytotoxicity against human cell lines so far [1, 2]. In 2006,
Nicolaou et al. developed the first total synthesis of the
compound in more than fifteen steps [3]. Nicolaou et al.
also published the synthesis and antimicrobial evaluation of the platensimycin derivative adamanta platensimycin in 2007 [4]. Thus, it is of great interest to find derivatives which show equal or even higher antibiotic activity while being easier to synthesize. Recently, Singh et al.
reported on the chemistry of platensimycin and the synthesis of various derivatives of this compound [5].
Results and discussion
Figure 1. Chemical structure of platensimycin.
Correspondence: Jrgen Krauss, Pharmaceutical Chemistry, Department of Pharmacy – Center of Drug Research, LMU Munich, Butenandtstr. 5-13, D-81377 Mnchen, Germany.
E-mail: hjkra@cup.uni-muenchen.de
Fax: +49 89 2180-77171
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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chemistry
The core of platensimycin is the hydroxy anilide structure. Therefore, the first series of analogues was prepared
from 3-amino benzoic acid 1a and several alkyl- or arylcarboxylic acid chlorides 2 to give the resulting anilides 3
(Scheme 1). Chlorides which were not commercially
available were prepared from the corresponding acids
with oxalyl chloride or thionyl chloride.
In a second series, 3-fluoro aniline 1b, aniline 1c, and 3hydroxy aniline 1d were reacted with the same carbonic
acid chlorides 2 to give the resulting anilides 3
(Scheme 1).
In a third series (Scheme 2), 3-amino benzoic acid was
esterified either with methanol or ethanol in the presence of sulphuric acid or with benzyl alcohol using the
Arch. Pharm. Chem. Life Sci. 2008, 341, 386 – 392
Platensimycin Analogues and Their Antibiotic Potency
387
Scheme 1. Synthesis of carbonic anilides and fluoro anilides 1a – d, 2a – h, and 3a – p.
Scheme 2. Synthesis of the esters 4a – c, 5b, and 5c.
Scheme 3. Synthesis route of the hydroxy amino benzoic acids.
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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2008, 341, 386 – 392
Table 1. Agar diffusion assay.
Compound
E. coli
Pseudomonas
antimicrobial
Staphylococcus Streptococcus Yarrowia
equorum
entericus
lipolytica
Aspergillus
niger
Candia
glabrata
Hypopichia
burtonii
DSM
1b
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
4a
4b
4c
5b
5c
6a
6b
7a
7b
Tetracycline
Penicillin
Clotrimazol
426
0
8
11
0
nt
0
8
16
0
nt
0
0
0
0
0
0
0
0
0
0
0
0
0
0
nt
0
30
20
17
8361
0
11
0
13 (GI)
nt
12
15
8
0
nt
0
0
8
28 (GI)
8 [10]
10
0
10
0
7
7
0
0
14
nt
14
24
45
8
20675
0
11
0
11
nt
10
12
7
6
nt
0
0
0 [10 GI]
0 [14 GI]
0 [20 GI]
10
0
12
0
0
0
0
0
0
nt
0
30
50
12
1988
0
0
0
0
nt
0
0
0
0
nt
0
0
0
0
0
0
0
0
0
0
0
0
0
0
nt
0
11226
0
0
0
0
nt
12
14
0
0
nt
0
0
7 [10]
0
10
20
0
0
0
0
0
0
0
0
nt
0
70663
0
0
0
0
nt
0
0
0
0
nt
0
0
0
0
0
0
0
0
0
0
0
0
0
0
nt
0
0
14
0
20
0
28
14446
0
0
0
0
nt
9
9
6
0
nt
0
0
6
0
10 GI [12]
10
0
0
0
0
0
0
0
0
nt
0
30
10
1345
0
0
0
0
nt
0
8
0
0
nt
0
0
0
0
0
0
0
0
0
0
0
0
0
0
nt
0
32
0
18
Agar diffusion assay (50 lg/disc [100 lg/disc], diameter of inhibition [mm]); te: tetracycline; cl: clotrimazol (25 lg/disc); 0 mm: no
effect in test concentration. GI: growth inhibition; nt: not tested.
Mitsunobu reaction [6]. Both reactions convert the acid
quantitatively into the esters 4. The resulting esters were
reacted with octanoyl chloride or 3-phenyl propionic
acid chloride to the corresponding anilides 5b/5c.
As in the first and second series, octanoyl amides
showed the highest activities. In a fourth series, benzoic
acid was replaced by hydroxy benzoic acid derivatives
(Scheme 3) to further increase the activity. Therefore,
commercially available 6-nitro salicylic acid was reacted
with methanol to give ester 4d. The nitro group of 4d was
reduced under a H2 atmosphere with Pd/C to the corresponding amino ester 5d, which was then reacted with
one equivalent of octanoyl chloride to give the amide 6a.
Cleavage of the methyl ester with methanolic aqueous
KOH led to the carboxylic acid 7a. Compound 7b was
built up in a similar way. Therefore, commercially available 4-hydroxy-3-amino benzoic acid was esterified with
methanol to afford the methyl ester 5e. The following
reaction with one equivalent of octanoyl chloride gave
the anilide 6b. Subsequent hydrolysis of the methyl ester
gave the carboxylic acid 7b [9 – 13].
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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Table 2. Cytotoxicity of the tested compounds against HL 60 cell
line.
Compound
IC50 (lM)
3e
3f
3n
Cisplatin
312
64
474
5
Almost all compounds were tested against Gram positive and Gram negative bacteria and some fungi in agar
diffusion assays (Table 1) [7, 8]. All cultures were ordered
from the German collection of microorganisms and cell
cultures (http://www.dsmz.de). The compounds showed
weak or partially no activities against Gram positive and
Gram negative bacteria and the fungi. Derivatives with an
octanoyl anilide structure showed weak antibiotic activities against some of the bacteria species.
The cytotoxicity of the most promising compounds 3e,
3f, and 3n was determined in an MTT assay on a human
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Arch. Pharm. Chem. Life Sci. 2008, 341, 386 – 392
leukaemia cell line (HL-60). The compounds showed no or
weak cytotoxicity against HL-60 cells [14] (Table 2).
Discussion
The resulting compounds showed only weak or no significant antimicrobial activities in the agar diffusion assay.
In order to investigate whether the antimicrobial effects
of 3e, 3f, and 3n were caused by an unspecific cytotoxic
mechanism, the cytotoxicity was evaluated in an MTT
assay on HL-60 cells. Only compound 3f showed a notable
cytotoxicity with an IC50 about 60 lM, thus 3e and 3n are
interesting leads. The poor solubility of the compounds
might be a limiting factor. Therefore, work is in progress
to build up more hydrophilic compounds.
The authors have declared no conflict of interest.
Experimental
Material and spectroscopy
IR-Spectra: Perkin-Elmer FT-IR Paragon 1000 (Perkin-Elmer, Norwalk, CT, USA); MS: Hewlett Packard MS-Engine, electron ionisation (EI) 70 eV, chemical ionisation (CI) with CH4 (300 eV) (Hewlett Packard, Palo Alto, CA, USA); NMR (400 MHz): Jeol GSX 400,
1
H: 400 MHz (JEOL, Tokyo, Japan); 13C: 100 MHz: GLC-MS: Shimadzu GC 17 A (Shimadzu, Tokyo, Japan); flash column chromatography (FCC): silica gel 60 (230 – 400 mesh, E. Merck, Darmstadt, Germany).
Agar diffusion assay
The bacteria and fungi were cultivated on an AC agar (SigmaAldrich, Munich, Germany), Aspergillus niger on a potato dextrose broth agar (Sigma). The substances were placed on 6 mm
paper discs on the agar each impregnated with 100 lg of the
tested compound or 50 lg of the reference drugs. The bacteria
media were incubated for 24 h at 328C, the fungi media for 48 h
at 288C and the diameter of the zone of inhibition [mm] was registered.
General procedure 1 for the preparation of amides
The aniline derivative (5.0 mmol) was dissolved in 20 mL dry toluene and 7.5 mmol of the acid chloride and 5 mL EDMA were
added. The solution was stirred for 5 h at room temperature.
Then, it was quenched with 20 mL brine and extracted with
ethyl acetate (3630 mL). The combined organic layers were
dried over Na2SO4 and the solvent was evaporated. The residue
was purified by flash column chromatography (n-hexane/ethyl
acetate 1 : 1) or crystallization.
N-(3-Fluoro-phenyl)-3-phenyl-propionamide 3a
The compound was prepared following general procedure 1
from 550 mg (5 mmol) 3-fluoro aniline and 1.26 g (7.5 mmol) 3phenyl propionic acid chloride to give 990 mg (82%) of 3a as a
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Platensimycin Analogues and Their Antibiotic Potency
389
brown solid. Elemental analysis C15H14FNO (243.28). Calcd.: C:
74.06. H: 5.80. N: 5.76. Found: C: 74.16. H: 5.80. N: 5.33. Mp.:
81.18C. MS (CI): m/z (%) = 244 [M+ + 1] (100), 111 (10). HR-MS:
Calcd.: 243.1059. Found: 243.1033. 1H-NMR (CDCl3) d (ppm) =
2.63 (t, J = 7.7 Hz, 2 H, CH2), 2.99 (t, J = 7.7 Hz, 2 H, CH2), 6.75 (dd, J
= 10.4 Hz, J = 8.3 Hz, 1 H, aromat. CH), 7.07 (d, J = 7.2 Hz, 1 H, aromat. CH), 7.17 (m, 4 H, 3 aromat. CH), 7.24 (m, 2 H, 2 aromat. CH),
7.40 (d, J = 10.4 Hz, 1 H, aromat. CH), 7.84 (s, 1 H, NH). 13C-NMR
(CDCl3) d (ppm) = 31.24 (CH2), 39.32 (CH2), 106.30 (d, J = 26 Hz, aromat. CH), 109.85 (d, J = 22 Hz, aromat. CH), 114.00 (aromat. CH),
126.46 (aromat. CH), 128.34 (2 aromat. CH), 128.66 (2 aromat.
CH), 128.88 (d, J = 9.6 Hz, aromat. CH), 139.22 (quart. C), 140.41
(quart. C), 163.01 (d, J = 246 Hz, quart. C), 170.81 (CO).
3-(3-Phenyl-propionylamino)-benzoic acid 3b
The compound was prepared following general procedure 1
from 685 mg (5 mmol) 3-amino benzoic acid and 1.26 g
(7.5 mmol) 3-phenyl propionic acid chloride to give 995 mg
(74%) of 3b. Elemental analysis C16H15NO3 (269.30). Calcd.: C:
71.36. H: 5.61. N: 5.20. Found: C: 67.60. H: 5.30. N. 4.69. H-NMR (dDMSO) d (ppm) = 2.66 (t, J = 7.8 Hz, 2 H, CH2), 2.99 (t, J = 7.8 Hz, 2
H, CH2), 7.25 (m, 5 H, 5 aromat. CH), 7.33 (dd, J = 7.9 Hz, J = 7.6 Hz,
5 – H), 7.65 (d, J = 7.6 Hz, 1 H, aromat. CH), 7.89 (d, J = 7.9 Hz, 1 H,
aromat. CH), 8.16 (s, 1 H, 2-H), 9.90 (s, 1H, NH). 13C-NMR (d-DMSO)
d (ppm) = 30.72 (CH2), 37.91 (CH2), 119.79 (aromat. CH), 122.76
(aromat. CH), 123.72 (aromat. CH), 125.80 (aromat. CH), 128.11 (2
aromat. CH), 128.17 (2 aromat. CH), 128.55 (aromat. CH), 131.84
(quart. C), 139.22 (quart. C), 141.00 (quart. C), 167.26 (CO), 170.43
(CO).
(E)-N-(3-Fluoro-phenyl)-3-phenyl-acrylamide 3c
The compound was prepared following general procedure 1
from 550 mg (5 mmol) 3-fluoro aniline and 1.2 g (7.5 mmol) phenyl acryloyl chloride to give 970 mg (73%) of 3c. Elemental analysis C15H12FNO (241.27). Calcd.: C: 74.68. H: 5.01. N: 5.81. Found:
C: 74.20. H: 4.78. N: 5.79. MS (CI): m/z (%) = 242 [M+ + 1] (100), 131
(28). MS (EI): m/z (%) = 241 [M+] (30), 131 (100), 103 (72). 1H-NMR (dDMSO) d (ppm) = 6.85 (m, 2 H, 2 aromat. CH), 7.40 (m, 5 H, 5 aromat. CH), 7.62 (m, 3 H, 3 aromat. CH), 7.76 (ddd, J = 11.6 Hz, J =
2.1 Hz, J = 2.1 Hz, 1 H, aromat. CH), 10.38 (s, 1H, NH). 13C-NMR (dDMSO) d (ppm) = 106.18 (d, J = 25 Hz, aromat. CH), 109.65 (d, J =
21 Hz, aromat. CH), 114.92 (quart. C), 121.88 (aromat. CH),
127.70 (2 aromat. CH), 128.89 (2 aromat. CH), 130.12 (d, J =
9.8 Hz, aromat. CH), 130.15 (aromat. CH), 140.67 (aromat. CH),
141.03 (d, J = 12 Hz, quart. C), 162.22 (d, J = 243 Hz, quart. C),
163.80 (CO).
3-Octanoylamino benzoic acid 3e
The compound was prepared following general procedure 1
from 685 mg (5 mmol) 3-amino benzoic acid and 1.2 g
(7.5 mmol) octanoyl acid chloride to give 1.2 g (93%) of 3e. Elemental analysis C15H21NO3 (263.34). Calcd.: C: 68.42. H: 8.04. N:
5.32. Found: C: 68.94. H: 8.49. N: 4.95. MS (CI): m/z (%) = 264 [M+ +
1] (100). 1H-NMR (d-DMSO) d (ppm) = 0.86 (t, J = 7.0 Hz, 3 H, CH3),
1.28 (m, 8 H, 4 CH2), 1.60 (m, 2 H, CH2), 2.31 (t, J = 7.4 Hz, 2 H,
CH2), 7.41 (dd, J = 8.0 Hz, J = 8.0 Hz, 1 H, 5-H), 7.60 (ddd, J = 8.0 Hz,
J = 1.1 Hz, J = 1.1 Hz, 1 H, aromat. CH), 7.82 (ddd, J = 8.0 Hz, J =
1.1 Hz, J = 1.1 Hz, 1 H, aromat. CH), 8.23 (dd, J = 1.1 Hz, J = 1.1 Hz,
1 H, 2-H), 10.06 (s, 1 H, NH), 12.91 (s, 1 H, OH). 13C-NMR (d-DMSO) d
(ppm) = 13.93 (CH3), 22.07 (CH2), 25.05 (CH2), 28.32 (CH2), 28.60
(CH2), 31.16 (CH2), 36.39 (CH2), 119.74 (aromat. CH), 123.03 (arowww.archpharm.com
390
J. Krauss et al.
mat. CH), 123.73 (aromat. CH), 128.88 (aromat. CH), 131.29
(quart. C), 139.52 (quart. C), 167.21 (CO), 171.52 (quart. C).
Octanoic acid (3-fluoro-phenyl)amide 3f
The compound was prepared following general procedure 1
from 550 mg (5 mmol) 3-fluoro aniline and 1.2 g (7.5 mmol) octanoyl chloride to give 745 mg (63%) of 3f. Elemental analysis
C14H20FNO. Calcd.: C: 70.86. H: 8.49. N: 5.90. Found: C: 70.13. H:
8.74. N. 5.21. MS (CI): m/z (%) = 238 [M+ + 1] (100), 111 (55). 1H-NMR
(CDCl3) d (ppm) = 0.88 (t, J = 7.1 Hz, 3 H, CH3), 1.29 (m, 8 H, 4 CH2),
1.72 (tt, J = 7.5 Hz, J = 7.5 Hz, 2 H, CH2), 2.35 (t, J = 8.0 Hz, 2 H,
CH2), 6.78 (ddd, J = 1.7 Hz, J = 8.3 Hz, J = 8.3 Hz, 1 H, aromat. CH),
7.20 (m, 2 H, 2 aromat. CH), 7.52 (d, J = 11.6 Hz, 1 H, aromat. CH),
7.70 (s, 1 H, NH). 13C-NMR (CDCl3) d (ppm) = 14.07 (CH3), 22.61
(CH2), 25.54 (CH2), 28.97 (CH2), 29.11 (CH2), 29.22 (CH2), 31.68
(CH2), 114.84 (aromat. CH), 110.60 (d, aromat. CH), 107.04 (d, aromat. CH), 129.95 (d, aromat. CH), 139.70 (d, quart. C), 163.00 (d,
quart. C), 171.71 (CO).
3-Undec-10-enoylamino benzoic acid 3g
The compound was prepared following general procedure 1
from 685 mg (5 mmol) 3-amino benzoic acid and 1.5 g
(7.5 mmol) undec-10-enoyl chloride to give 833 mg (55%) of 3g.
Elemental analysis C18H25NO3 (303.40). MS (CI): m/z (%) = 304 [M+ +
1] (12), 200 (100), 182 (24), 138 (26). HR-MS: Calcd.: 303.1834.
Found: 303.1834. 1H-NMR (d-DMSO) d (ppm) = 1.27 (m, 10, 5 CH2),
1.58 (m, 2 H, CH2), 2.00 (m, 2 H, CH2), 2.30 (t, J = 7.3 Hz, 2 H, CH2),
4.96 (m, 2 H, =CH2), 5.78 (ddt, J = 6.5 Hz, J = 10.5 Hz, J = 17.3 Hz, 1
H, -CH=), 7.40 (dd, J = 7.6 Hz, J = 7.8 Hz, 1 H, aromat. CH), 7.59 (d, J
= 7.6 Hz, 1 H, aromat. CH), 7.81 (d, J = 7.8 Hz, 1 H, aromat. CH),
8.22 (s, 1 H, 2-H), 10.04 (s, 1 H, NH), 12.86 (s, 1 H, OH). 13C-NMR (dDMSO) d (ppm) = 24.98 (CH2), 28.19 (CH2), 28.42 (CH2), 28.56 (CH2),
28.64 (CH2), 28.68 (CH2), 33.10 (CH2), 36.34 (CH2), 114.59 (=CH2),
119.71 (aromat. CH), 123.04 (aromat. CH), 123.69 (aromat. CH),
131.18 (quart. C), 138.78 (-CH=), 139.50 (quart. C), 167.15 (CO),
171.50 (CO).
Arch. Pharm. Chem. Life Sci. 2008, 341, 386 – 392
Calcd.: 207.0895. Found: 207.0895. 1H-NMR (CDCl3) d (ppm) =
0.93 (t, J = 7.5 Hz, 3 H, CH3), 1.63 (tq, J = 7.5 Hz, J = 7.5 Hz, 2 H,
CH2), 2.30 (t, J = 7.5 Hz, 2 H, CH2), 7.39 (dd, J = 7.6 Hz, J = 8.7 Hz, 1
H, H-5), 7.60 (d, J = 7.6 Hz, 1 H, aromat. CH), 7.83 (d, J = Hz, 8.7 Hz,
1 H, aromat. CH), 8.22 (s, 1 H, H-2), 10.02 (s, 1 H, OH). 13C-NMR
(CDCl3) d (ppm) = 13.58 (CH3), 18.49 (CH2), 38.31 (CH2), 119.82 (aromat. CH), 123.02 (aromat. CH), 123.69 (aromat. CH), 128.69 (aromat. CH), 139.44 (quart. C), 168.92 (CO), 171.27 (CO).
N-(3-Fluorophenyl)acetamide 3j
The compound was prepared following general procedure 1
from 550 mg (5 mmol) 3-fluoro aniline and 590 mg (7.5 mmol)
acetyl chloride to give 424 mg (55%) of 3j. Elemental analysis
C8H8FNO (153.16). Mp.: 81.18C. MS (CI): m/z (%) = 154 [M+ + 1]
(100). HR-MS: Calcd.: 153.0590. Found: 153.0581. 1H-NMR (CDCl3)
d (ppm) = 2.16 (s, 3 H, CH3), 6.78 (dd, J = 8.2 Hz, J = 8.2 Hz, J =
1.9 Hz, 1 H, aromat. CH), 7.18 (dd, J = 7.0 Hz, J = 8.2 Hz, 1 H, aromat. CH), 7.22 (dd, J = 1.6 Hz, J = 7.0 Hz, 1 H, aromat. CH), 7.48
(ddd, J = 11.1 Hz, J = 1.9 Hz, J = 1.6 Hz, 1 H, aromat. CH), 8.31 (s, 1
H, NH). 13C-NMR (CDCl3) d (ppm) = 24.55 (CH3), 107.35 (d, J =
27.4 Hz, 1 H, aromat. CH), 110.95 (d, J = 20.2 Hz, 1 H, aromat. CH),
115.04 (aromat. CH), 130.05 (m, aromat. CH), 139.50 (d, J = 9.0 Hz,
quart. C), 162.99 (d, J = 243.1 Hz, quart. C), 168.72 (CO).
3-Acetylamino benzoic acid 3k
The compound was prepared following general procedure 1
from 685 mg (5 mmol) 3-amino benzoic acid and 590 mg
(7.5 mmol) acetyl chloride to give 537 mg (60%) of 3k as brown
solid. Elemental analysis C9H9NO3 (179.18). MS (CI): m/z (%) = 180
[M+ + 1] (100). HR-MS: Calcd.: 179.0582. Found: 179.0590. 1H-NMR
(d-DMSO) d (ppm) = 2.05 (s, 3 H, CH3), 7.40 (dd, J = 7.8 Hz, J =
8.3 Hz, 1 H, 5-H), 7.60 (d, J = 7.8 Hz, 1 H, aromat. CH), 7.80 (d, J =
8.3 Hz, 1 H, aromat. CH), 8.21 (s, 1 H, 2-H), 10.11 (s, 1 H, NH),
11.87 (s, 1 H, OH). 13C-NMR (d-DMSO) d (ppm) = 23.37 (CH3), 119.10
(aromat. CH), 122.42 (aromat. CH), 123.17 (aromat. CH), 128.25
(aromat. CH), 130.61 (quart. C), 138.89 (quart. C), 166.57 (CO),
167.57 (CO).
Undec-10-enoic acid (3-fluoro-phenyl)amide 3h
The compound was prepared following general procedure 1
from 550 mg (5 mmol) 3-fluoro aniline and 1.5 g (7.5 mmol)
undec-10-enoyl chloride to give 830 mg (60%) of 3h. Elemental
analysis C17H24FNO (277.39). Calcd.: C: 73.61. H: 8.72. N: 5.05.
Found: C: 73.23. H: 8.89. N. 4.60. MS (CI): m/z (%) = 278 [M+ + 1]
(100), 111 (38). HR-MS: Calcd.: 277.1842. Found: 277.1838. 1HNMR (CDCl3) d (ppm) = 1.32 (m, 12 H, 6 CH2), 1.70 (m, 2 H, CH2),
2.03 (m, 2 H, CH2), 2.35 (t, J = 7.8 Hz, 2 H, CH2), 4.93 (m, 1 H, =CH2),
4.99 (m, 1 H, =CH2), 5.80 (ddt, J = 17.2 Hz, J = 10.5 Hz, J = 6.8 Hz, 1
H, -CH=), 6.78 (ddd, J = 8.3 Hz, J = 8.3 Hz, J = 1.7 Hz, 1 H, aromat.
C), 7.19 (m, 1 H, aromat. CH), 7.23 (m, 1 H, aromat. CH), 7.51 (d, J
= 11.2 Hz, 1 H, 2-H), 7.87 (s, 1 H, NH). 13C-NMR (CDCl3) d (ppm) =
25.58 (CH2), 28.89 (CH2), 29.07 (CH2), 29.12 (CH2), 29.33 (CH2),
30.95 (CH2), 33.78 (CH2), 37.72 (CH2), 106.06 (aromat. CH), 109.41
(aromat. CH), 112.91 (=CH2), 128.63 (aromat. CH), 138.00 (=CH-),
138.41 (quart. C), 163.00 (d, J = 245 Hz, quart. C), 171.95 (CO).
3-Buturylamino benzoic acid 3i
The compound was prepared following general procedure 1
from 685 mg (5 mmol) 3-amino benzoic acid and 795 mg
(7.5 mmol) butyryl chloride to give 670 mg (65%) of 3i. Elemental
analysis C11H13NO3 (207.23). MS (EI): m/z (%) = 207 [M+] (16), 137
(100), 71 (18). MS (CI): m/z (%) = 208 [M+ + 1] (100), 137 (16). HR-MS:
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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Octanoic acid phenyl amide 3l
The compound was prepared following general procedure 1
from 930 mg (10 mmol) aniline and 1.63 g (10.0 mmol) octanoyl
chloride to give 2.07 g (94%) of 3l as white solid. Elemental analysis C14H21NO (219.33). MS (CI): m/z (%) = 220 [M+ + 1] (100). HR-MS:
Calcd.: 219.1623. Found: 219.1584. 1H-NMR (d-DMSO) d (ppm) =
0.88 (t, J = 6.7 Hz, 3 H, CH3), 1.31 (m, 8 H, 4 CH2), 1.72 (m, 2 H,
CH2), 2.35 (t, J = 7.4 Hz, 2 H, CH2), 7.09 (dd, J = 7.4 Hz, J = 7.4 Hz, 1
H, aromat. CH), 7.31 (dd, J = 7.7 Hz, J = 8.2 Hz, 2 H, 2 aromat. CH),
7.52 (d, J = 8.3 Hz, 2 H, 2 aromat. CH). 13C-NMR (d-DMSO) d (ppm) =
14.09 (CH3), 22.62 (CH2), 25.66 (CH2), 29.05 (CH2), 29.24 (CH2),
31.69 (CH2), 37.86 (CH2), 119.75 (2 aromat. CH), 124.14 (aromat.
CH), 128.98 (2 aromat. CH), 137.98 (quart. C), 171.47 (CO). The
compound is also described in Lit. [12, 13].
Octanoic acid (3-hydroxyphenyl)amide 3m
The compound was prepared following general procedure 1
from 1.09 g (10 mmol) 3-hydroxy aniline and 1.63 g (10.0 mmol)
octanoyl chloride to give 330 mg (14%) of 3m as brown solid. Elemental analysis C14H21NO2 (235.33). MS (EI): m/z (%) = 235 [M+] (8),
151 (10), 109 (100). 13C-NMR (d-DMSO) d (ppm) = 14.00 (CH3), 22.35
(CH2), 25.52 (CH2), 28.83 (CH2), 29.02 (CH2), 31.46 (CH2), 37.03
(CH2), 106.77 (aromat. CH), 110.30 (aromat. CH), 110.32 (aromat.
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Arch. Pharm. Chem. Life Sci. 2008, 341, 386 – 392
CH), 129.07 (aromat. CH), 140.21 (quart. C), 157.56 (quart. C),
171.62 (COOH). The compound is also described in Lit [11].
3-(2-Bicyclo[2.2.1]hept-2-yl-acetylamino)benzoic acid 3n
The compound was prepared following general procedure 1
from 631 mg (4.6 mmol) 3-amino benzoic acid and 794 mg
(4.6 mmol) 2-norbornylethanoyl chloride to give 0.8 g (64%) of
3n as pale brown solid after crystallization from methanol /
water. Elemental analysis C16H19NO3 (273.33). MS (CI): m/z (%) =
274 [M+ + 1] (38), 210 (82), 155 (94), 137 (100). HR-MS: Calcd.:
273.1365. Found: 273.1359. 1H-NMR (d-DMSO) d (ppm) = 1.22 –
2.03 (m, 3 CH, 5 CH2), 7.39 (dd, J = 8.0 Hz, J = 8.0 Hz, 1 H, H-5), 7.58
(d, J = 8.0 Hz, 1 H, aromat. CH), 7.80 (d, J = 8.0 Hz, 1 H, aromat.
CH), 8.22 (s, 1 H, H-2), 10.04 (s, 1 H, NH), 12.68 (s, 1 H, OH). 13CNMR (d-DMSO) d (ppm) = 32.96 (CH2), 34.07 (CH2), 39.38 (CH2),
40.83 (CH), 41.72 (CH2), 43.27 (CH), 45.14 (CH), 48.08 (CH2), 119.77
(aromat. CH), 123.08 (aromat. CH), 123.78 (aromat. CH), 128.92
(aromat. CH), 131.23 (quart. C), 139.51 (quart. C), 167.22 (CO),
170.87 (CO).
3-(2-Cyclohexyl-acetylamino)benzoic acid 3o
The compound was prepared following general procedure 1
from 1.37 g (10 mmol) 3-amino benzoic acid and 1.6 g (10 mmol)
2-phenyl acetyl chloride to give 1.9 g (73%) of 3o as white solid.
Elemental analysis: C15H19NO3 (261.32). MS (CI): m/z (%) = 262 [M+
+ 1] (100). HR-MS: Calcd.: 261.1365. Found: 261.1360. 1H-NMR (dDMSO) d (ppm) = 0.98 (m, 2 H, CH2), 1.19 (m, 3 H, CH2, CH), 1.69
(m, 6 H, 3 CH2), 2.20 (d, J = 6.8 Hz, 1 H, H-2'), 7.40 (dd, J = 7.6 Hz, J =
8.2 Hz, 1 H, 5-H), 7.60 (d, J = 7.6 Hz, 1 H, aromat. CH), 7.82 (d, J =
8.2 Hz, 1 H, aromat. CH), 8.24 (s, 1 H, H-2), 10.04 (s, 1 H, NH),
12.92 (s, 1 H, OH). 13C-NMR (d-DMSO) d (ppm) = 25.58 (2 CH2),
25.79 (CH2), 32.47 (2 CH2), 34.76 (CH), 44.27 (CH2), 119.77 (aromat.
CH), 123.04 (aromat. CH), 123.70 (aromat. CH), 128.66 (aromat.
CH), 131.14 (quart. C), 139.40 (quart. C), 167.15 (CO), 170.67 (CO).
Octanoic acid 3-octanoylamino phenyl ester 3p
The compound was isolated as by-product by the synthesis of 3m
as a pale brown oil: 780 mg (22%). Elemental analysis: C22H35NO3
(361.53). MS (CI): m/z (%) = 362 [M+ + 1] (100). HR-MS: Calcd.:
361.2617. Found: 361.2589. 1H-NMR (d-DMSO) d (ppm) = 0.89 (m,
6 H, 2 CH3), 1.31 (m, 16 H, 8 CH2), 1.74 (m, 4 H, 2 CH2), 2.29 (t, J =
7.5 Hz, 2 H, CH2), 2.51 (t, J = 7.4 Hz, 2 H, CH2), 6.79 (d, J = 8.1 Hz, 1
H, NH), 7.23 (m, 3 H, 2 aromat. CH), 7.49 (m, 2 H, 2 aromat. CH).
13
C-NMR (d-DMSO) d (ppm) = 14.08 (2 CH3), 22.64 (CH2), 24.92
(CH2), 25.53 (CH2), 28.94 (CH2), 29.07 (CH2), 29.08 (2 CH2), 29.23
(CH2), 31.66 (CH2), 31.69 (CH2), 34.39 (CH2), 37.70 (CH2), 113.28
(aromat. CH), 116.75 (aromat. CH), 116.99 (aromat. CH), 129.49
(aromat. CH), 139.20 (quart. C), 151.06 (quart. C), 171.53 (CO),
172.50 (CO).
3-Aminobenzoic acid ethyl ester 4b
3-Amino benzoic acid (5.0 g) were dissolved in 50 mL dry ethanol
and 5 mL sulphuric acid (98%) were added. The mixture was
heated for 2 h, the solvent was evaporated and the residue was
suspended in 50 mL aqueous NaOH (10%). The aqueous layer was
extracted with ethyl acetate (3650 mL) and the combined
organic layers were dried over Na2SO4. The solvent was evaporated to give 4b as a pale yellow oil without further purification.
1
H-NMR (CDCl3) d (ppm) = 1.38 (t, J = 6.9 Hz, 3 H, CH3), 3.35 (s, 2 H,
NH2), 4.35 (q, J = 6.9 Hz, 2 H, CH2), 6.86 (ddd, J = 0.8 Hz, J = 2.5 Hz,
J = 8.1 Hz, 1 H, aromat. CH), 7.21 (dd, J = 8.1 Hz, J = 7.9 Hz, 1 H,
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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Platensimycin Analogues and Their Antibiotic Potency
391
aromat. CH), 7.37 (dd, J = 2.4 Hz, J = 2.5 Hz, 1 H, aromat. CH), 7.44
(ddd, J = 0.8 Hz, J = 1.1 Hz, J = 7.9 Hz, 1 H, aromat. CH). 13C-NMR
(CDCl3) d (ppm) = 14.32 (CH3), 60.89 (CH2), 115.84 (aromat. CH),
119.41 (aromat. CH), 129.23 (aromat. CH), 131.50 (quart. C),
146.29 (quart. C), 166.81 (CO). The compound is also described in
Lit [9].
3-Amino benzoic acid benzyl ester 4c
3-Amino benzoic acid (1.37 g; 10 mmol), 1.2 g (11 mmol) benzyl
alcohol 3.1 g (12 mmol) triphenylphosphine were dissolved in
dry toluene. 2.4 g (12 mmol) DIAD (diisopropylazodicarboxylate)
were added dropwise and the solution was stirred for 5 h. The
organic solvent was evaporated and the residue was separated
by flash column chromatography (hexane/ethyl acetate 1 : 1) to
give 1.97 g (87%) of 4c as a pale yellow oil. Elemental analysis
C14H13NO2 (227.27). 1H-NMR (CDCl3) d (ppm) = 5.29 (s, 2 H, CH2O),
7.62 (m, 9 H, 9 aromat. CH). 13C-NMR (CDCl3) d (ppm) = 65.16
(CH2O), 114.36 (aromat. CH), 116.74 (aromat. CH), 118.55 (aromat. CH), 128.61 (2 aromat. CH), 131.92 (aromat. CH), 133.00
(quart. C), 131.52 (2 aromat. CH), 136.27 (quart. C), 148.18 (quart.
C), 165.45 (CO). The compound is also described in Lit [10].
3-(3-Phenylpropionylamino)benzoic acid ethyl ester 5b
The compound was prepared following general procedure 1
from 825 mg (5 mmol) 4b and 1.26 g (7.5 mmol) phenyl propionyl acid chloride to give 1.43 g (96%) of 5b as a brown oil. Elemental analysis C18H19NO3 (297.36). MS (EI): m/z (%) = 297 [M+]
(30), 252 (16), 165 (100). HR-MS: Calcd.: 297.1365. Found:
297.1357. 1H-NMR (CDCl3) d (ppm) = 1.38 (t, J = 7.1 Hz, 3 H, CH3),
2.69 (t, J = 7.7 Hz, 2 H, CH2), 3.07 (t, J = 7.7 Hz, 2 H, CH2), 4.36 (q, J =
7.1 Hz, 2 H, CH2), 7.27 (m, 6 H, 6 aromat. CH), 7.77 (d, J = 7.6 Hz. 1
H, aromat. CH), 7.88 (d, J = 7.9 Hz, 1 H, aromat. CH), 7.92 (s, 1 H,
aromat. CH). 13C-NMR (CDCl3) d (ppm) = 14.26 (CH3), 31.48 (CH2),
39.17 (CH2), 61.15 (CH2), 115.72 (aromat. CH), 120.77 (aromat.
CH), 124.52 (aromat. CH), 125.11 (aromat. CH), 126.31 (aromat.
CH), 128.33 (2 aromat. CH), 128.46 (aromat. CH), 128.59 (2 aromat. CH), 129.01 (quart. C), 129.22 (quart. C), 133.99 (quart. C),
166.38 (CO), 171.06 (CO).
3-Octanoylamino benzoic acid benzyl ester 5c
The compound was prepared following general procedure 1
from 600 mg (2.6 mmol) 4c and 650 mg (4 mmol) octanoic acid
chloride to give 650 mg (71%) of 5c. Elemental analysis
C22H27NO3 (353.47) MS (CI):m/z (%) = 354 [M+ + 1] (100), 210 (54). 1HNMR (CDCl3) d (ppm) = 0.88 (t, J = 6.8 Hz, 3 H, CH3), 1.28 (m, 8 H, 4
CH2), 1.72 (tt, J = 7.4 Hz, J = 7.4 Hz, 2 H, CH2), 2.36 (t, J = 8.2 Hz, 2
H, CH2), 5.35 (s, 2 H, CH2O), 7.39 (m, 4 H, 4 aromat. CH), 7.44 (d, J =
6.9 Hz, 2 H, 2 aromat. CH), 7.80 (d, J = 8.3 Hz, 1 H, aromat. CH),
7.96 (s, 1 H, aromat. CH), 8.01 (d, J = 7.8 Hz, 1 H, aromat. CH). 13CNMR (CDCl3) d (ppm) = 14.07 (CH3), 22.57 (CH2), 25.51 (CH2), 29.04
(CH2), 29.20 (CH2), 30.96 (CH2), 31.65 (CH2), 66.89 (CH2O), 120.52
(aromat. CH), 124.51 (aromat. CH), 125.31 (aromat. CH), 128.26 (2
aromat. CH), 128.31 (aromat. CH), 128.62 (2 aromat. CH), 129.23
(aromat. CH), 130.79 (quart. C), 135.91 (quart. C), 138.23 (quart.
C), 166.03 (CO), 171.68 (CO).
2-Hydroxy-3-octanoylamino benzoic acid methyl ester 6a
The compound was prepared following general procedure 1
from 835 mg (5 mmol) 5d and 813 mg (5 mmol) octanoic acid
chloride to give 454 mg (31%) of 6a. 1H-NMR (CDCl3) d (ppm) =
0.88 (t, J = 7.1 Hz, 3 H, CH3), 1.29 (m, 8 h, 4 CH2), 1.74 (tt, J = 7.8 Hz,
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392
J. Krauss et al.
J = 7.8 Hz, 2 H, CH2), 2.42 (t, J = 7.8 Hz, 2 H, CH2), 3.96 (s, 3 H, CH3),
6.89 (dd, J = 8.2 Hz, J = 8.2 Hz, 1 H, aromat. CH), 7.53 (dd, J =
8.2 Hz, J = 1.4 Hz, 1 H, aromat. CH), 7.81 (s, 1 H, NH), 8.59 (dd, J =
8.2 Hz, J = 1.4 Hz, 1 H, aromat. CH), 11.28 (s, 1 H, OH). 13C-NMR
(CDCl3) d (ppm) = 14.07 (CH3), 22.62 (CH2), 25.59 (CH2), 29.04
(CH2), 29.19 (CH2), 29.71 (CH2), 31.68 (CH2), 52.52 (CH3), 111.61
(quart. C), 127.52 (quart. C), 119.22 (aromat. CH), 123.50 (aromat.
CH), 125.04 (aromat. CH), 171.15 (CO), 171.59 (CO).
4-Hydroxy-3-octanoylamino benzoic acid methyl ester 6b
The compound was prepared following general procedure 1
from 835 mg (5 mmol) 5e and 813 mg (5 mmol) octanoic acid
chloride to give 351 mg (24%) of 6b as pale brown solid. Mp.:
122 – 1288C. Elemental analysis C16H23NO4 (293.37). MS (CI): m/z
(%) = 294 [M+ + 1] (100), 167 (20). HR-MS: Calcd.: 293.1627. Found:
293.1622. 1H-NMR (CDCl3) d (ppm) = 0.88 (t, J = 6.8 Hz, 3 H, CH3),
1.28 (m, 8 H, 4 CH2), 1.74 (tt, J = 6.8 Hz, J = 6.8 Hz, 2 H, CH2), 2.48
(t, J = 7.3 Hz, 2 H, CH2), 3.86 (s, 3 H, CH3), 7.01 (d, J = 8.1 Hz, 1 H,
aromat. CH), 7.77 (dd, J = 8.6 Hz, J = 1.8 Hz, 1 H, aromat. CH), 7.80
(s, 1 H, aromat. CH), 8.07 (s, 1 H, NH). 13C-NMR (CDCl3) d (ppm) =
14.03 (CH3), 22.56 (CH2), 25.69 (CH2), 28.93 (CH2), 29.08 (CH2),
31.59 (CH2), 36.88 (CH2), 52.07 (OCH3), 119.62 (aromat. CH),
121.82 (quart. C), 124.18 (aromat. CH), 125.76 (quart. C), 128.73
(aromat. CH), 153.39 (quart. C), 166.73 (CO), 174.32 (CO).
2-Hydroxy-3-octanoylamino benzoic acid 7a
Compound 6a (200 mg; 0.7 mmol) was dissolved in 20 mL methanolic aqueous KOH and stirred under N2 atmosphere for 12 h.
The solvent was evaporated, the residue dissolved in 20 mL 10%
aqueous HCl and extracted with ethyl acetate (3620 mL). The
combined organic layers were dried over Na2SO4, the solvent was
evaporated and the residue was purified by flash column chromatography (n-hexane / ethyl acetate 1 : 1) to give 156 mg (80%)
of 7a. 1H-NMR (CDCl3) d (ppm) = 0.81 (t, J = 7.1 Hz, 3 H, CH3), 1.22
(m, 6 H, 3 CH2), 1.69 (m, 2 H, CH2), 2.39 (t, J = 7.5 Hz, 2 H, CH2),
6.87 (dd, J = 8.1 Hz, J = 8.0 Hz, 1 H, 5-H), 7.56 (dd, J = 8.1 Hz, J =
1.5 Hz, 1 H, aromat. CH), 7.78 (s, 1 H, OH), 8.55 (dd, J = 8.0 Hz, J =
1.5, 1 H, aromat. CH). 13C-NMR (CDCl3) d (ppm) = 13.05 (CH3),
21.59 (CH2), 24.63 (CH2), 27.80 (CH2), 28.15 (CH2), 30.64 (CH2),
37.00 (CH2), 110.10 (quart. C), 118.43 (aromat. CH), 123.68 (aromat. CH), 125.00 (aromat. CH), 126.30 (quart. C), 149.81 (quart.
C), 171.15 (CO), 172.87 (CO).
4-Hydroxy-3-octanoylamino benzoic acid 7b
An amount of 200 mg (0.7 mmol) of 6b was dissolved in 20 mL
methanolic aqueous KOH and stirred under N2 atmosphere for
12 h. The solvent was evaporated, the residue dissolved in 20 mL
10% aqueous HCl and extracted with ethyl acetate (3620 mL).
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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Chem. Life Sci. 2008, 341, 386 – 392
The combined organic layers were dried over Na2SO4, the solvent
was evaporated and residue was purified by flash column chromatography (n-hexane/ethyl acetate 1 : 1) to give 148 mg of 7b
(76%). MS (CI): m/z (%) = 280 [M+ + 1] (82), 262 (34), 236 (80). 1HNMR (d-DMSO) d (ppm) = 0.88 (t, J = 6.8 Hz, 3 H, CH3), 1.29 (m, 4 H,
2 CH2), 1.61 (m, 2 H, CH2), 2.40 (t, J = 7.9 Hz, 2 H, CH2), 6.90 (d, J =
8.4 Hz, 1 H, aromat. CH), 7.56 (d, J = 8.4 Hz, 1 H, aromat. CH), 8.39
(s, 1 H, aromat. CH), 9.21 (s, 1 H, OH), 10.59 (s, 1 H, OH), 12.33 (s, 1
H, OH). 13C-NMR (d-DMSO) d (ppm) = 13.80 (CH3), 22.01 (CH2),
25.15 (CH2), 28.43 (CH2), 28.64 (CH2), 31.12 (CH2), 35.95 (CH2),
115.14 (aromat. CH), 121.37 (quart. C), 123.47 (aromat. CH),
126.23 (aromat. CH), 126.00 (quart. C), 151.68 (quart. C), 167.03
(CO), 171.96 (CO).
References
[1] J. Wang, S. M. Soisson, K. Young, W. Shoop, et al., Nature
2006, 441, 358 – 361; H. T. Wright, K. A. Reynolds, Curr.
Opin. Microbiol. 2007, 10, 447 – 453.
[2] S. B. Singh, H. Jayasuriya, J. G. Ondeyka, K. B. Herath, et al.,
J. Am. Chem. Soc. 2006, 128, 11916 – 11920.
[3] K. C. Nicolaou, A. Li, D. J. Edmonds, Angew. Chem. Int. Ed.
2006, 45, 7086 – 7090.
[4] K. C. Nicolaou, T. Lister, R. M. Denton, A. Montero, D. J.
Edmonds, Angew. Chem. Int. Ed. 2007, 46, 4712 – 4714.
[5] S. B. Singh, K. B. Herath, J. Wang, N. Tsou, R. G. Ball, Tetrahedron Lett. 2007, 48, 5429 – 5433.
[6] O. Mitsunobu, Synthesis 1981, 1, 1 – 28.
[7] DIN – Norm 58940.
[8] H. E. Ungnade, A. S. Henick, J. Am. Chem. Soc. 1942, 64,
1737 – 1738.
[9] W. Blackburn, M. Danzig, H. Hubinger, D. Soisson, H. P.
Schulz, J. Org. Chem. 1961, 26, 2805 – 2809.
[10] H. A. Shonle, P. Q. Row, J. Am. Chem. Soc. 1921, 43, 361 –
365.
[11] Y. Hayakawa, M. Satomura, U. S. (1973), 12. CODEN: USXXAM US 3756818 19730904 CAN 80:42916 AN 1974:42916;
Y. Hayakawa, M. Satomura, Fr. (1969), 38. CODEN: FRXXAK
FR 1574759 19690718 CAN 72:138336 AN 1970:138336.
[12] T. Ogawa, T. Hikasa, T. Ikegami, N. Ono, H. Suzuki, J. Chem.
Soc. Perkin Trans I 1994, 23, 3473 – 3478.
[13] W. R. Lang, J. O. Woodhouse, J. Chem. Soc. Trans. 1908, 93,
1037 – 1040.
[14] T. J. Mosmann, J. Immunol. Methods 1983, 65, 55 – 63.
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