Synthesis and antimicrobial evaluation of novel platensimycin analogues

Article abstract of DOI:10.1002/ardp.201100455

Since the isolation of the natural products platensimycin and platencin as new antibiotic lead structures, several total syntheses as well as syntheses of derivatives have been developed. Most of these approaches are very laborious and the target molecule

Full text of DOI:10.1002/ardp.201100455

Arch. Pharm. Chem. Life Sci. 2012, 000, 1–6
1
Full Paper
Synthesis and Antimicrobial Evaluation of Novel
Platensimycin Analogues
Eva Plesch, Franz Bracher, and Ju¨rgen Krauss
Center of Drug Research, Department of Pharmacy, Ludwig-Maximilians University, Munich, Germany
Since the isolation of the natural products platensimycin and platencin as new antibiotic lead
structures, several total syntheses as well as syntheses of derivatives have been developed. Most of
these approaches are very laborious and the target molecules are often produced in only poor overall
yields. The following approach describes the synthesis of rather simple platensimycin analogues
focussing on some structure elements that have previously been identified as being essential for
binding to the Fab F enzyme in fatty acid biosynthesis. Two of the new analogues show significant
antimicrobial activities.
Keywords: Antimicrobial activity / Corey–Seebach reaction / Dithiane / Platensimycin
Received: December 16, 2011; Revised: March 13, 2012; Accepted: March 15, 2012
DOI 10.1002/ardp.201100455
Introduction
docking protocol and the docking experiments as well
as a comparison of binding to the Fab F complex of
platensimycin, platencin and adamantaplatensimycin were
described in Ref. [18].
The natural products platensimycin (1) and platencin (Fig. 1),
isolated from Streptomyces platensis in 2006 by researchers at
Merck [1–4], are interesting leads for the development of new
antibiotic drugs. These compounds exhibit potent activity
against Gram-positive bacteria by a new mechanism of
action, namely by inhibiting the Fab F enzyme in bacterial
fatty acid synthesis. Prior to this, only two antimicrobial
The complex enone partial structure of the side chain was
to be replaced by a simple open-chain enone or a phenyl
ketone moiety, moreover, the effect of a deletion of the
carboxylate group was investigated.
drugs targeted this biosynthesis pathway, triclosan and iso- Results and discussion
niazid (INH). But triclosan is only used in topical formu-
lations, and INH is used only against mycobacteria
(antituberculosis drug) [5].
Chemistry
Both benzaldehyde (2a) and trans-crotonaldehyde (2b) were
reacted with propane-1,3-dithiol to give the corresponding
1,3-dithianes 3a/3b. These dithianes have been used as build-
ing blocks in organic synthesis previously [19, 20]. Using the
Corey–Seebach method [21], dithianes 3a/3b were lithiated
with n-butyllithium and alkylated with trimethyl 4-bromoor-
thobutyrate to give, after aqueous workup, the methyl esters
4a/4b. The orthoester group avoids undesired reaction of the
lithiated dithiane with the ester moiety [22]. After alkaline
hydrolysis of the esters 4a/4b with Na2CO3 the resulting
carboxylic acids 5a/5b were converted to the anilides
6a–6d with aniline or methyl 3-aminobenzoate using N,N0-
dicyclohexylcarbodiimide (DCC) and N-hydroxybenzotriazole
(HOBt) [23]. Subsequent cleavage of the dithiane groups with
BF3-etherate and mercuric oxide [24] gave the target ketones
7a–d. Exemplarily the ester 7c was hydrolysed to the corre-
sponding carboxylic acid 8c (Scheme 1).
Since 2006 several total syntheses of platensimycin and
platencin have been described, but all these syntheses are
laborious and expensive [6–12]. Moreover, a number of
derivatives of platensimycin and platencin have been syn-
thesised [13–17].
In continuation of our efforts on the development of novel
simple platensimycin analogues [17] we focused on com-
pounds containing the anilide group and the ketone,
both identified as being essential for binding of the active
components to the Fab F complex (Fig. 2). The complete
Correspondence: Dr. Ju¨rgen Krauss, Center of Drug Research,
Department of Pharmacy, Ludwig-Maximilians University, Butenandtstr. 5-
13, 81377 Munich, Germany.
E-mail: hjkra@cup.uni-muenchen.de
Fax: þ49-89-218077171
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

2
E. Plesch et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–6
OH
O
H
OH
O
Thr270
N
O
O
HO
Ala309
HO
N
O
NH
HO
N
H
O
OH
H
O
O
OH
Ala207
OH
O
O
O
Thr307
Platensimycin
H
Platencin
O
Phe400
Asp265
N
H2O
O
HO
Figure 1. Structures of the antibiotics platensimycin (1) and platencin.
HO
OH
H2O
OH
H
N+
O
Thr305
Antimicrobial activity
O
The target compounds 7a–d and 8c and the precursors 6a–d
were tested in a standardised (DIN) agar diffusion assay [25]
against several Gram-negative bacteria (Escherichia coli
and Pseudomonas antimicrobia), Gram-positive bacteria
(Staphylococcus equorum and Streptococcus entericus) and some
fungi (Table 1). The ketones 7a and 7b showed a broad
spectrum of antibacterial activity comparable to the anti-
biotic tetracycline.
O
Phe398
H2O
H2N
H
N
HN
O
H
N
Gly399
His303
N
His340
Gln163
Figure 2. Schematic diagram showing the key interactions
between platensimycin (red) and Fab F [18]. Most prominent inter-
actions take place with the carboxylate, amide and side chain enone
moieties.
Exemplarily the cytotoxicity of the compounds 6b and
7a–7d was evaluated in an MTT assay [26] against a HL 60
cell line. The compounds showed only poor to moderate
cytotoxicities with IC50 values between 32 and 41 mM.
following the Corey–Seebach method. Both phenyl ketone
7a and propenyl ketone 7b showed high activity against
Gram-negative, Gram-positive bacteria and a few yeasts
and fungi (Candida glabrata and Hyphopichia burtonii).
Surprisingly, the analogues 7c and 7d containing additional
Conclusion
Highly simplified analogues of the antibiotic platensimycin
were synthesised starting from appropriate 1,3-dithianes
O
O
Br
SH SH
a
O
R1
S
R1
b
S
O
2a: R1 = Ph
3a: R1 = Ph
3b: R1 = trans H3C-CH=CH-
2b: R1 = trans H3C-CH=CH-
O
O
O
NH
R1
S
O
R1
S
OH
R1
S
S
d
c
S
S
R2
4a: R1 = Ph
5a: R1 = Ph
5b: R1 = trans H3C-CH=CH-
6a: R1 = Ph, R2 = H
4b: R1 = trans H3C-CH=CH-
6b: R1 = trans H3C-CH=CH-, R2 = H
6c: R1 = Ph, R2 = COOCH3
6d: R1 = trans H3C-CH=CH-, R2 = COOCH3
O
O
NH
NH
1
1
R
O
f
e
R
O
R2
Scheme 1. (a) Methanol, BF3-etherate; (b)
THF, n-BuLi, then trimethyl 4-bromoorthobu-
tyrate; (c) K2CO3, methanol; (d) DCC, HOBt,
dichloromethane; (e) BF3-etherate, HgO,
THF, H2O; (f) K2CO3, methanol.
R2
7a: R1 = Ph, R2 = H
8c: R1 = Ph, R2 = COOH
7b: R1 = trans H3C-CH=CH-, R2 = H
7c: R1 = Ph, R2 = COOCH3
7d: R1 = trans H3C-CH=CH-, R2 = COOCH3
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–6
Synthesis of Novel Platensimycin Analogues
3
Table 1. Agar diffussion assay (te: tetracycline, cl: clotrimazol, 50 mg/disc)
6a
6b
6c
6d
7a
7b
7c
7d
8c
te
cl
Escherichia coli
0
0
0
0
0
0
0
0
0
0
6
0
0
0
0
0
0
0
0
0
0
0
0
0
0
8
0
10
0
7
11
14
0
16
20
0
10
10
11
14
17
6
0
0
0
0
8
0
0
6
0
7
6
9
0
8
0
6
0
0
0
0
8
0
0
0
25
23
23
12
nt
nt
nt
nt
0
0
9
11
15
15
20
17
Pseudomonas antimicrobia
Staphylococcus equorum
Streptococcus entericus
Candida glabrata
Aspergillus niger
Yarrowia lipolytica
Hyphopichia burtonii
0
0
0
10
7
15
Zones of inhibition (in mm). nt, not tested, 0, no measurable zone of inhibition.
to warm up to 08C. After 12 h the mixture was cooled to ꢁ408C
again, and 1.2 equivalents of trimethyl 4-bromoorthobutyrate
were added dropwise. After stirring for 1 h at ꢁ408C the
mixture was allowed to warm up to 08C and stirred at this
temperature for 36 h. The mixture was quenched with water,
2 M HCl were added to reach pH 5 and the solution was
extracted with diethyl ether (3 ꢀ 30 mL). The combined organic
layers were dried over Na2SO4 and the solvent was evaporated.
The residue was purified by flash column chromatography
(isohexane/ethyl acetate 10:1).
ester groups at the anilide moiety, and compound 8c con-
taining a carboxylic acid group in analogy to the arene
substitution pattern of platensimycin, did not show signifi-
cant activities. This is in contrast to the proposed central role
of the carboxylate group in the binding of platensimycin to
the target Fab F complex. In contrast to the natural product
platensimycin with highest activities against Gram-positive
bacteria our compounds 7a and 7b showed a broad spectrum
of antimicrobial activities. Unspecific cytotoxic effects of the
active compounds can, however, be excluded due to the poor
cytotoxicity against a HL cell line.
General procedure 3
Methyl ester 4a/4b was dissolved in 50 mL 5% methanolic K2CO3
solution (50 mL/mmol) and the mixture refluxed for 24 h.
The solvent was evaporated, the residue was dissolved in
30 mL H2O and 10 mL aqueous 10% HCl. The mixture was
extracted with diethyl ether (3 ꢀ 30 mL) and the combined
organic layers were dried over Na2SO4. The solvent was evapor-
ated and the residue purified by flash column chromatography
(isohexane/ethyl acetate 1:1).
Experimental
M.p. (uncorr.) Bu¨chi B-540; IR-Spectra: Perkin-Elmer FT-IR Paragon
1000; MS: Hewlett Packard MS-Engine, electron ionisation (EI)
70 eV, chemical ionisation (CI) with CH4 (300 eV); NMR: Jeol GSX
400 (1H: 400 MHz, 13C: 100 MHz); GLC-MS: Shimadzu GC 17 A;
flash column chromatography: silica gel 60 (230–400 mesh, E.
Merck, Darmstadt).
General procedure 4
Carboxylic acid 5a/5b was dissolved in CH2Cl2 (30 mL/mmol). At
08C equimolar amounts of DCC and HOBt were added. The
solution was stirred at 08C for 30 min under N2 atmosphere,
then 1.5 equivalents of the aniline (dissolved in 5 mL CH2Cl2 per
mmol) were added and the solution was stirred for 30 min at 08C
and 12 h at room temperature. The resulting suspension was
filtered and the filtrate was extracted with 6 M aqueous HCl and
6 M aqueous NaOH. The organic layer was dried over Na2SO4, the
solvent was evaporated and the residue was purified by FSC
(isohexane/ethyl acetate 1:1).
Agar diffusion assay
The bacteria and fungi were cultivated on an AC agar (Sigma).
The substances were placed on 6 mm paper discs on the agar,
each impregnated with 50 mg of the test compound or 50 mg of
the reference drugs. The bacteria media were incubated for 24 h
at 328C, the fungi media for 48 h at 288C, and the diameters of
the zones of inhibition (mm) were registrated.
General procedure 1
About 10 mmol of aldehyde and 1.05 equivalents of propane-1,3-
dithiol were dissolved in 20 mL CHCl3 and 0.2 mmol of
BF3 ꢀ Et2O was added. The solution was stirred for 3 h at 08C,
then 10% aqueous KOH (20 mL) was added and the organic
layer was separated. After drying over Na2SO4 the solvent
was evaporated and the residue was purified by flash column
chromatography (isohexane/ethyl acetate 5:1).
General procedure 5
Dithiane 6a/6b/6c/6d was dissolved in THF/H2O (7:3; 50 mL/
mmol) and 3 equivalents of red HgO and 3 equivalents of
BF3 ꢀ Et2O were added. After stirring for 30 min at room
temperature 50 mL of CH2Cl2 was added and the mixture was
extracted with 100 mL ethyl acetate. The organic layer was dried
over Na2SO4, the solvent was evaporated and the residue was
purified by flash column chromatography (isohexane/ethyl
acetate 5:1).
General procedure 2
Dithiane 3a/3b was dissolved in dry THF (7 mL/mmol dithiane)
and under N2 atmosphere at ꢁ408C 1.5 equivalents of 1.6 M
n-butyllithium solution in n-hexane were added dropwise.
The solution was stirred for 30 min at ꢁ408C and then allowed
2-Phenyl-1,3-dithiane 3a
The compound was prepared according to General procedure 1
from 1.107 g (0.01043 mol) benzaldehyde, 1.19 g (0.0110 mol)
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4
E. Plesch et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–6
propane-1,3-dithiol and 0.305 g (2.15 mmol) BF3 ꢀ Et2O to give
1.95 g (95%) of 3a as colourless crystals. M.p.: 72.28C. IR (KBr): n
(cmꢁ1) ¼ 3067, 3031, 2948, 2929, 2890, 2810, 1581, 1494, 1480,
1450, 1422, 1411, 1274, 1170, 1071, 1024, 908, 881, 725, 695, 673.
HRMS: C10H12S2. Calcd.: 196.0381. Found: 196.0392. MS (CI)
m/z (%) ¼ 197 ([Mþ1]þ, 100). MS (EI) m/z (%) ¼ 196 ([M]þ, 74),
177 (80), 149 (40), 121 (96), 83 (56), 69 (66), 57 (100), 55 (84).
1H NMR (400 MHz, CDCl3) d (ppm) ¼ 2.18 (m, 2 H, CH2), 2.91
(m, 4 H, 2 CH2), 5.17 (s, 1 H, CH), 7.38 (m, 5 H, CH, aromat.). 13C NMR
(100 MHz, CDCl3) d (ppm) ¼ 25.11 (CH2), 32.11 (2 CH2), 51.48 (CH),
127.75 (2 aromat. CH), 128.43 (aromat. CH), 128.73 (2 aromat. CH),
139.07 (quart. C). This compound has been described in several
publications [20, 21], but not with a complete dataset.
d (ppm) ¼ 1.35 (m, 2 H, CH2), 1.77 (dd, J ¼ 1.3 Hz, J ¼ 6.6 Hz,
3 H, CH3), 1.83 (m, 4 H, 2 CH2), 2.29 (t, J ¼ 7.4 Hz, 2 H, 2-H), 2.68
(m, 2 H, CH2), 2.83 (m, 2 H, CH2), 3.65 (s, 3 H, OCH3), 5.42 (dd,
J ¼ 1.3 Hz, J ¼ 15.2 Hz, 10-H), 5.88 (dq, J ¼ 6.6 Hz, J ¼ 15.2 Hz,
1 H, 20-H). 13C NMR (100 MHz, CDCl3) d (ppm) ¼ 17.57 (CH3), 19.69
(CH2), 25.41 (CH2), 26.98 (2 CH2), 33.88 (CH2), 40.95 (CH2), 51.54
(CH3), 54.11 (quart. C), 129.38 (CH), 133.22 (CH), 173.64 (quart. C).
4-(2-Phenyl-1,3-dithian-2-yl)-butanoic acid 5a
The compound was prepared according to General procedure 3
from 0.169 g (0.571 mmol) 4a to give 0.152 g (94%) of 5a as white
crystals. M.p.: 1168C. IR (NaCl, film): n (cmꢁ1) ¼ 3053, 3029, 2953,
2902, 2756, 2697, 2607, 2540, 1693, 1441, 1432, 1411, 1281,
1272, 946, 762, 698. HRMS: C14H18O2S2. Calcd.: 282.0748.
Found: 282.0743. MS (CI) m/z (%) ¼ 283 ([Mþ1]þ, 30), 197 (28),
195 (100), 175 (28) MS (EI) m/z (%) ¼ 282 ([M]þ, 28), 195 (100), 129
(34), 121 (74), 85 (34), 77 (40). 1H NMR (400 MHz, CDCl3)
d (ppm) ¼ 1.59 (m, 2 H, CH2), 1.94 (m, 2 H, CH2), 2.05 (m, 2 H,
CH2), 2.22 (t, J ¼ 7.7 Hz, 2 H, CH2), 2.69 (m, 4 H, 2 CH2), 7.27
(m, 1 H, aromat. CH), 7.38 (t, J ¼ 7.6 Hz, 2 H, 2 aromat. CH),
7.89 (d, J ¼ 7.6 Hz, 2 H, 2 aromat. CH). 13C NMR (100 MHz, CDCl3)
d (ppm) ¼ 19.30 (CH2), 25.15 (CH2), 27.56 (2 CH2), 33.36 (CH2),
44.05 (CH2), 58.52 (quart. C), 127.05 (aromat. CH), 128.57 (2 aro-
mat. CH), 128.71 (2 aromat. CH), 141.36 (quart. C), 178.35 (quart.
C).
((E)-Prop-2-en-1-yl)-1,3-dithiane 3b
The compound was prepared according to General procedure
1
from 0.972 g (0.0139 mol) trans-crotonaldehyde, 1.57 g
(0.0145 mol) propane-1,3-dithiol and 0.422 g (2.97 mmol)
BF3 ꢀ Et2O to give 2.16 g (97%) of 3b as a colourless oil. IR
(NaCl, film): n (cmꢁ1) ¼ 3022, 2931, 2912, 1677, 1447, 1422,
1275, 1041, 961. HRMS: C7H12S2. Calcd.: 160.0381. Found:
160.0421. MS (CI) m/z (%) ¼ 161 ([Mþ1]þ, 100). MS (EI)
m/z (%) ¼ 160 ([M]þ, 22), 119 (50), 113 (80), 108 (100), 85 (98).
1H NMR (400 MHz, CDCl3) d (ppm) ¼ 1.72 (d, J ¼ 6.5 Hz, 3 H,
CH3), 2.09 (m, 2 H, CH2), 2.87 (m, 4 H, 2 CH2), 4.62 (d, J ¼ 7.9 Hz,
1 H, CH), 5.53 (m, 1 H, CH), 5.87 (m, 1 H, CH). 13C NMR (100 MHz,
CDCl3) d (ppm) ¼ 17.83 (CH3), 25.19 (CH2), 30.47 (2 CH2), 47.72
4-[2-((E)-Prop-2-en-1-yl)-1,3-dithian-2-yl]-butyric acid 5b
The compound was prepared according to General procedure 3
from 0.307 g (1.18 mmol) 4b to give 0.245 g (84%) of 5b as a pale
yellow oil. IR (NaCl, film): n (cmꢁ1) ¼ 3021, 2934, 2912, 2670,
1707, 1422, 1413, 1276, 969, 907. HRMS: C11H18O2S2. Calcd.:
246.0748. Found: 246.0747. MS (CI) m/z (%) ¼ 247 ([Mþ1]þ,
100), 159 (12), 139 (22). MS (EI) m/z (%) ¼ 246 ([M]þ, 52), 159
(52). 139 (28), 100 (27), 85 (100). 1H NMR (400 MHz, CDCl3)
d (ppm) ¼ 1.20 (t, J ¼ 7.2 Hz, 2 H, CH2), 1.79 (d, J ¼ 7.2 Hz,
3 H, CH3), 1.88 (m, 4 H, 2 CH2), 2.35 (t, J ¼ 7.2 Hz, 2 H, CH2),
2.69 (m, 2 H, CH2), 2.84 (ddd, J1 ¼ 12.4 Hz, J2 ¼ 10.4 Hz,
J3 ¼ 3.4 Hz, 2 H, CH2), 5.43 (dd, J1 ¼ 15.2 Hz, J2 ¼ 1.5 Hz, 1 H,
CH), 5.89 (m, 1 H, CH). 13C NMR (100 MHz, CDCl3) d (ppm) ¼ 17.57
(CH3), 19.40 (CH2), 25.39 (CH2), 26.98 (2 CH2), 33.84 (CH2), 40.80
–
–
–
(CH), 127.70 ( CH–), 130.13 ( CH–). The compound has been
–
described in several publications [19], but not with a complete
dataset.
Methyl 4-(2-phenyl-1,3-dithian-2-yl)-butanoate 4a
The compound was prepared according to General procedure 2
from 0.503 g (2.57 mmol) 2-phenyl-1,3-dithiane (3a), 2.4 mL
1.6 M n-butyllithium solution in THF (3.84 mmol) and 0.706 g
(3.11 mmol) trimethyl 4-bromoorthobutyrate to give 0.42 g (55%)
of 4a as a colourless oil. IR (NaCl, film): n (cmꢁ1) ¼ 3056, 2949,
2906, 2360, 2342, 1736, 1442, 1256, 1173, 701.
HRMS: C15H20O2S2. Calcd.: 296.0905. Found: 296.0901. MS (CI)
m/z (%) ¼ 297 ([Mþ1]þ, 100), 195 (25). MS (EI) m/z (%) ¼ 296 ([M]þ,
29), 195 (100), 129 (56), 121 (66), 115 (34), 106 (40), 91 (20), 77 (34),
55 (26). 1H NMR (400 MHz, CDCl3) d (ppm) ¼ 1.57 (m, 2 H, CH2),
1.93 (m, 2 H, CH2), 2.03 (m, 2 H, CH2), 2.18 (t, J ¼ 7.5 Hz, 2 H, CH2),
2.69 (m, 4 H, 2 CH2), 3.60 (s, 3 H, CH3), 7.25 (m, 1 H, CH, aromat.),
7.37 (t, J ¼ 7.9 Hz, 2 H, 2 aromat. CH), 7.89 (d, J ¼ 7.5 Hz, 2 H,
2 aromat. CH). 13C NMR (100 MHz, CDCl3) d (ppm) ¼ 19.55 (CH2),
25.14 (CH2), 27.66 (2 CH2), 33.76 (CH2), 44.16 (CH2), 51.50 (CH3),
58.55 (quart. C), 126.98 (aromat. CH), 128.52 (2 aromat. CH),
128.70 (2 aromat. CH), 141.41 (quart. C) 173.43 (quart. C).
–
–
(CH ), 54.07 (quart. C), 129.47 ( CH–), 133.17 ( CH–), 179.59
2
–
–
(quart. C).
N-Phenyl-4-(2-phenyl-1,3-dithian-2-yl)-butyramide 6a
The compound was prepared according to General procedure 4
from 0.139 g (0.493 mmol) 5a, 0.1086 g (0.526 mmol) DCC,
0.0695 g (0.514 mmol) HOBt and 0.083 g (0.89 mmol) aniline
to give 0.1595 g (91%) of 6a as a pale yellow oil IR (NaCl, film):
n (cmꢁ1) ¼ 3302, 3057, 2932, 2906, 1662, 1599, 1544, 1498, 1442,
1310, 755, 700. HRMS: C20H23NOS2. Calcd. 357.1221. Found:
357.1229. MS (CI) m/z (%) ¼ 358 ([Mþ1]þ, 100), 265 (32), 195
(34). MS (EI) m/z (%) ¼ 357 ([M]þ, 4), 251 (100), 195 (34), 121
(32), 93 (94), 77 (28), 55 (48). 1H NMR (400 MHz, CDCl3)
d (ppm) ¼ 1.69 (m, 2 H, CH2), 1.94 (m, 2 H, CH2), 2.09 (m, 2 H,
CH2), 2.21 (t, J ¼ 7.6 Hz, 2 H, CH2), 2.70 (m, 4 H, 2 CH2), 6.99
(s, 1 H, NH), 7.08 (t, J ¼ 7.5 Hz, 1 H, aromat. CH), 7.28 (m, 3 H,
3 aromat. CH), 7.38 (t, J ¼ 7.8 Hz, 2 H, 2 aromat. CH), 7.45
(d, J ¼ 7.8 Hz, 2 H, 2 aromat. CH), 7.91 (d, J ¼ 7.8 Hz, 2 H, 2
aromat. CH). 13C NMR (100 MHz, CDCl3) d (ppm) ¼ 19.42 (CH2),
24.31 (CH2), 26.76 (2 CH2), 36.59 (CH2), 43.34 (CH2), 57.76 (quart. C),
118.86 (2 aromat. CH), 123.34 (aromat. CH), 126.23 (aromat. CH),
Methyl 4-[2-((E)-prop-2-en-1-yl)-1,3-dithian-2-yl]-
butanoate 4b
The compound was prepared according to General procedure 2
from 0.533 g (3.33 mmol) 3b, 3.2 mL 1.6 M n-butyllithium
solution in THF (5.12 mmol) and 0.899 g (3.96 mmol) trimethyl
4-bromoorthobutyrate to give 0.417 g (1.60 mmol) (48%) of 4b as
a pale yellow oil. IR (NaCl, film): n (cmꢁ1) ¼ 3019, 2950, 2913,
2855, 1738, 1435, 1423, 1253, 1169, 970. HRMS: C12H20O2S2.
Calcd.: 260.0905. Found: 260.0913. MS (CI) m/z (%) ¼ 261
([Mþ1]þ, 100), 159 (18). MS (EI) m/z (%) ¼ 260 ([M]þ, 48), 159
(100), 147 (66), 119 (58), 85 (90). 1H NMR (400 MHz, CDCl3)
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–6
Synthesis of Novel Platensimycin Analogues
5
127.77 (2 aromat. CH), 127.91 (2 aromat. CH), 128.10 (2 aromat.
CH), 136.89 (quart. C), 140.56 (quart. C), 169.47 (quart. C).
2.69 (m, 2 H, CH2), 2.85 (m, 4 H, 2 CH2), 3.90 (s, 3 H, OCH3), 5.45
(d, J ¼ 15.4 Hz, 1 H, CH), 5.91 (m, 1 H, CH), 7.33 (s, 1 H, NH), 7.39
(dd, J1 ¼ 7.9 Hz, J2 ¼ 7.9 Hz, 1 H, CH), 7.77 (d, J ¼ 7.9 Hz, 1 H,
CH), 7.90 (d, J ¼ 7.9 Hz, 1 H, CH), 8.01 (s, 1 H, CH). 13C NMR
(100 MHz, CDCl3) d (ppm) ¼ 17.62 (CH3), 20.28 (CH2), 25.44 (CH2),
27.05 (2 CH2), 37.46 (CH2), 41.10 (CH2), 52.27 (OCH3), 54.25 (quart.
C), 120.55 (CH), 124.31 (CH), 125.26 (CH), 129.19 (CH), 129.60 (CH),
130.82 (quart. C), 133.22 (CH), 138.06 (quart. C), 166.72 (CO),
170.83 (CO).
N-Phenyl-4-[2-((E)-prop-2-en-1-yl)-1,3-dithian-2-yl]-
butyramide 6b
The compound was prepared according to General procedure 4
from 0.165 g (0.671 mmol) 5b, 0.141 g (0.683 mmol) DCC,
0.093 g (0.69 mmol) HOBt and 0.105 g (1.13 mmol) aniline
to give 0.1738 g (80%) of 6b pale yellow oil. IR (NaCl, film):
n (cmꢁ1) ¼ 3300, 3196, 3136, 3019, 2933, 2912, 1661, 1600, 1544,
1499, 1442, 1310, 1256, 969, 755, 692. HRMS: C17H23NOS2. Calcd.:
321.1221. Found: 321.1215. MS (CI): m/z (%) ¼ 322 ([Mþ1]þ, 100), 229
(28). MS (EI): m/z (%) ¼ 321 ([M]þ, 26), 246 (30), 215 (56), 93 (100),
55 (48). 1H NMR (400 MHz, CDCl3) d (ppm) ¼ 1.25 (m, 2 H, CH2), 1.78
(d, J ¼ 7.0 Hz, 3 H, CH3), 1.88 (m, 4 H, 2 CH2), 2.35 (t, J ¼ 7.0 Hz, 2 H,
CH2), 2.69 (d, J ¼ 14.0 Hz, 2 H, CH2), 2.84 (ddd, J1 ¼ 14.0 Hz,
J2 ¼ 10.4 Hz, J3 ¼ 2.8 Hz, 2 H, CH2), 5.44 (d, J ¼ 14.0 Hz, 1 H,
CH), 5.90 (m, 1 H, CH), 7.09 (t, J ¼ 8.0 Hz, 1 H, aromat. CH), 7.22
(s, 1 H, NH), 7.31 (t, J ¼ 8.0 Hz, 2 H, 2 aromat. CH), 7.50
(d, J ¼ 8.0 Hz, 2 H, 2 aromat. CH). 13C NMR (100 MHz, CDCl3)
d (ppm) ¼ 17.57 (CH3), 20.38 (CH2), 25.44 (CH2), 27.05 (2 CH2),
5-Oxo-5-phenylpentanoic acid phenylamide 7a
The compound was prepared according to General procedure 5
from 0.123 g (0.344 mmol) of 6a, 0.281 g (1.30 mmol) HgO and
0.175 g (1.23 mmol) BF3 ꢀ Et2O to give 0.0.079 g (86%) of 7a as
pale yellow oil. IR (NaCl, film): n (cmꢁ1) ¼ 3302, 3057, 2932, 2906,
1662, 1599, 1544, 1498, 1442, 1310, 755, 700. HRMS: C20H23NOS2.
Calcd.: 357.1221. Found: 357.1229. MS (CI) m/z (%) ¼ 358
([M þ 1]þ, 100), 265 (32), 195 (34). MS (EI) m/z (%) ¼ 357 ([M]þ,
1
4), 251 (100), 195 (34), 121 (32), 93 (94), 77 (28), 55 (48). H NMR
(400 MHz, CDCl3) d (ppm) ¼ 1.69 (m, 2 H, CH2), 1.94 (m, 2 H, CH2),
2.09 (m, 2 H, CH2), 2.21 (t, J ¼ 7.6 Hz, 2 H, CH2), 2.70 (m, 4 H,
2 CH2), 6.99 (s, 1 H, NH), 7.08 (t, J ¼ 7.5 Hz, 1 H, aromat. CH), 7.28
(m, 3 H, 3 aromat. CH), 7.38 (t, J ¼ 7.8 Hz, 2 H, 2 aromat. CH), 7.45
(d, J ¼ 7.8 Hz, 2 H, 2 aromat. CH), 7.91 (d, J ¼ 7.8 Hz, 2 H, 2 aromat.
CH) 13C NMR (100 MHz, CDCl3) d (ppm) ¼ 19.42 (CH2), 24.31 (CH2),
26.76 (2 CH2), 36.59 (CH2), 43.34 (CH2), 57.76 (quart. C), 118.86
(2 aromat. CH), 123.34 (aromat. CH), 126.23 (aromat. CH), 127.77
(2 aromat. CH), 127.91 (2 aromat. CH), 128.10 (2 aromat. CH),
136.89 (quart. C), 140.56 (quart. C), 169.47 (quart. C).
–
37.53 (CH ), 41.10 (CH ), 54.24 (quart. C), 119.78 ( CH–), 124.20
–
2
2
–
( CH–), 128.97 (2 aromat. CH), 129.48 (aromat. CH), 133.28
–
(2 aromat. CH), 137.84 (quart. C), 170.57 (quart. C).
Methyl 3-[4-(2-phenyl-1,3-dithian-2-yl)-butanoylamino]-
benzoate 6c
The compound was prepared according to General procedure 4
from 327 mg (1.16 mmol) 5a, 263 mg (1.74 mmol) methyl 3-
aminobenzoate, 239 mg (1.16 mmol) DCC and 157 mg
(1.16 mmol) HOBt to give 478 mg (99%) of 6c as colourless crys-
tals. M.p. 1258C. IR (NaCl, film): n (cmꢁ1) ¼ 3415, 3305, 3213,
3089, 3030, 2950, 2931, 2901, 2362, 2345, 1719, 1670, 1596,
1550, 1427, 1300, 1273, 1230, 756. HRMS: C22H25NO3S2. Calcd.:
415.1276. Found: 415.1305. MS (CI) m/z (%) ¼ 416 ([Mþ1]þ, 100),
265 (34), 225 (28). MS (EI) m/z (%) ¼ 415 ([M]þꢂ, 6), 309 (100). 1H NMR
(400 MHz, CDCl3) d (ppm) ¼ 1.68 (m, 2 H, CH2), 1.92 (m, 2 H, CH2),
2.07 (m, 2 H, CH2), 2.23 (t, J ¼ 7.2 Hz, 2 H, CH2), 2.67 (m, 4 H, 2 CH2),
3.87 (s, 3 H, O–CH3), 7.25 (m, 1 H, CH), 7.35 (m, 2 H, 2 CH), 7.52
(s, 1 H, CH), 7.73 (d, J ¼ 7.2 Hz, 1 H, CH), 7.83 (d, J ¼ 7.2 Hz, 1 H,
CH), 7.89 (d, J ¼ 7.2 Hz, 2 H, 2 CH), 7.97 (s, 1 H, CH). 13C NMR
(100 MHz, CDCl3) d (ppm) ¼ 20.12 (CH2), 25.13 (CH2), 27.57 (2 CH2),
37.19 (CH2), 44.17 (CH2), 52.25 (OCH3), 58.06 (quart. C), 120.57
(aromat. CH), 124.33 (aromat. CH), 125.15 (aromat. CH), 127.07
(aromat. CH), 128.60 (2 aromat. CH), 128.73 (2 aromat. CH), 129.08
(aromat. CH), 130.69 (quart. C), 138.10 (quart. C), 141.39 (quart. C),
166.77 (CO), 170.80 (CO).
(E)-5-Oxo-oct-6-enoic acid phenylamide 7b
The compound was prepared according to General procedure 5
from 0.133 g (0.414 mmol) 6b, 0.279 g (1.29 mmol) HgO and
0.181 g (1.28 mmol) BF3 ꢀ Et2O to give 0.047 g (49%) of 7b as
a pale yellow solid. M.p.: 83.48C. IR (KBr): n (cmꢁ1) ¼ 3341, 3053,
3010, 2964, 2941, 2896, 1670, 1596, 1524, 1443, 1380, 1316,
1175, 968, 754, 691, 500. HRMS: C14H17NO2. Calcd.: 231.1259.
Found: 231.1270. MS (CI) m/z (%) ¼ 232 ([Mþ1]þ, 100), 139 (64). MS
(EI) m/z (%) ¼ 231 ([M]þ, 6), 139 (32), 111 (38), 93 (100), 69 (48),
55 (22). 1H NMR (400 MHz, CDCl3) d (ppm) ¼ 1.87 (d, J ¼ 7.0 Hz,
3 H, CH3), 2.01 (tt, J1 ¼ 7.0 Hz, J2 ¼ 7.0 Hz, 2 H, CH2), 2.38
(t, J ¼ 7.0 Hz, 2 H, CH2), 2.66 (t, J ¼ 7.0 Hz, 2 H, CH2), 6.10
(d, J ¼ 15.7 Hz, 1 H, CH), 6.87 (m, 1 H, CH), 7.07 (t, J ¼ 7.2 Hz,
1 H, aromat. CH), 7.29 (t, J ¼ 7.2 Hz, 2 H, 2 aromat. CH), 7.52
(t, J ¼ 7.2 Hz, 2 H, 2 aromat. CH), 7.94 (s, 1 H, NH). 13C NMR
(100 MHz, CDCl3) d (ppm) ¼ 18.35 (CH3), 20.06 (CH2), 36.51 (CH2),
–
–
–
38.50 (CH ), 119.91 ( CH–), 124.23 ( CH–), 129.05 (2 aromat. CH),
–
2
131.89 (2 aromat. CH), 138.05 (quart. C), 143.77 (aromat. CH),
171.09 (quart. C), 200.49 (quart. C).
Methyl 3-{4-[2-((E)-prop-2-en-1-yl)-1,3-dithian-2-yl]-
butanoylamino}-benzoate 6d
Methyl 3-(5-oxo-5-phenyl-pentanoylamino)-benzoate 7c
The compound was prepared according to General procedure 5
from 470 mg (1.13 mmol) 6c, 733 mg (3.39 mmol) HgO and
480 mg (3.40 mmol) BF3 ꢀ Et2O to give 320 mg (87%) of 7c as
colourless crystals. IR (NaCl, film): n (cmꢁ1) ¼ 3347, 2926, 2850,
1715, 1680, 1588, 1529, 1428, 1229, 754, 687. HRMS: C19H19NO4.
Calcd.: 325.1314. Found: 325.1289. MS (CI) m/z (%) ¼ 326 ([Mþ1]þ,
44), 225 (100), 175 (52). MS (EI) m/z (%) ¼ 325 ([M]þꢂ, 4), 175 (52),
151 (54), 105 (62), 56 (100). 1H NMR (400 MHz, CDCl3)
d (ppm) ¼ 2.18 (quint., J ¼ 7.3 Hz, 2 H, CH2), 2.51 (t, J ¼ 7.3 Hz,
2 H, CH2), 3.14 (t, J ¼ 7.3 Hz, 2 H, CH2), 3.90 (s, 3 H, OCH3), 7.40
The compound was prepared according to General procedure
4 from 241 mg (0.98 mmol) 5b, 224 mg (1.48 mmol) methyl
3-aminobenzoate, 201 mg (0.97 mmol) DCC and 139 mg
(1.0 mmol) HOBt to give 140 mg (38%) of 6d as pale yellow oil.
IR (NaCl, film): n (cmꢁ1) ¼ 3300, 3017, 2933, 2855, 1723, 1551,
1488, 1442, 1299, 1107, 755. HRMS: C19H25NO3S2. Calcd.:
379.1276. Found: 379.1238. MS (CI) m/z (%) ¼ 380 ([Mþ1]þ,
100), 229 (30), 120 (38). MS (EI) m/z (%) ¼ 379 ([M]þꢂ, 62), 309
(60), 273 (78), 151 (76), 55 (100). 1H NMR (400 MHz, CDCl3)
d (ppm) ¼ 1.79 (dd, J1 ¼ 6.6 Hz, J2 ¼ 1.6 Hz, 3 H, CH3), 1.88
(m, 2 H, CH2), 1.91 (m, 2 H, CH2), 2.38 (t, J ¼ 7.0 Hz, 2 H, CH2),
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

6
E. Plesch et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–6
(t, J ¼ 8.0 Hz, 1 H, CH), 7.46 (t, J ¼ 7.4 Hz, 2 H, 2 CH), 7.57
(t, J ¼ 8.0 Hz, 1 H, CH), 7.77 (d, J ¼ 7.4 Hz, 1 H, CH), 7.90
(d, J ¼ 8.0 Hz, 1 H, CH), 7.97 (d, J ¼ 8.0 Hz, 2 H, 2 CH), 8.08
(s, 1 H, CH). 13C NMR (100 MHz, CDCl3) d (ppm) ¼ 20.01 (CH2),
36.39 (CH2), 37.24 (CH2), 52.28 (CH3), 120.61 (CH), 124.01 (CH),
125.20 (CH), 128.12 (CH), 128.70 (CH), 129.15 (CH), 130.81 (quart.
C), 133.36 (CH), 136.59 (quart. C), 138.26 (quart. C), 166.79 (CO),
171.18 (COO), 200.23 (CO).
Cummings, S. Ha, K. Dorso, M. Motyl, H. Jayasuriya, J.
Ondeyka, K. Herath, C. Zhang, L. Hernandez, J. Allocco, A.
Basilio, J. R. Tormo, O. Genilloud, F. Vicente, F. Pelaez, L.
Colwell, S. H. Lee, B. Michael, T. Felcetto, C. Gill, L. L. Silver,
J. D. Hermes, K. Bartizal, J. Barrett, D. Schmatz, J. W. Becker,
D. Cully, S. B. Singh, Nature 2006, 441, 358–361.
[2] S. B. Singh, J. G. Ondeyka, K. B. Herath, C. Zhang,
H. Jayasuriya, D. L. Zink, G. Parthasarathy, J. W. Becker,
J. Wang, S. M. Soisson, Bioorg. Med. Chem. Lett. 2009, 19,
4756–4759.
Methyl 3-((E)-5-oxooct-6-enoylamino)-benzoate 7d
The compound was prepared according to General procedure 5
from 139 mg (0.343 mmol) 6d, 273 mg (1.26 mmol) HgO and
192 mg (1.35 mmol) BF3 ꢀ Et2O to give 22 mg (22%) of 7d as a
yellow oil. IR (NaCl, film): n (cmꢁ1) ¼ 3323, 3144, 3035, 2932,
2855, 1723, 1667, 1594, 1549, 1488, 1442, 1299, 1222, 1107, 970,
756. HRMS C16H19NO4. Calcd.: 289.1314. Found: 289.1284. MS (CI)
[3] C. Zhang, J. Ondeyka, Z. Guan, L. Dietrich, B. Burgess,
J. Wang, S. B. Singh, J. Antibiot. 2009, 62, 699–702.
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951–954.
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447–453.
m/z (%) ¼ 290 ([Mþ1]þ, 86), 139 (100). MS (EI) m/z (%) ¼ 289 ([M]þꢂ
,
8), 151 (100), 139 (84), 111 (100), 69 (100), 55 (54). 1H NMR
(400 MHz, CDCl3) d (ppm) ¼ 1.89 (dd, J1 ¼ 6.9 Hz, J2 ¼ 1.6 Hz,
3 H, CH3), 2.03 (quint., J ¼ 7.0 Hz, 2 H, CH2), 2.42 (t, J ¼ 7.0 Hz, 2
H, CH2), 2.68 (t, J ¼ 7.0 Hz, 2 H, CH2), 3.89 (s, 3 H, OCH3), 1.11
(dd, J1 ¼ 15.8 Hz, J2 ¼ 1.6 Hz, 1 H, CH), 6.88 (m, 1 H, CH), 7.37
(dd, J1 ¼ 8.0 Hz, J2 ¼ 8.0 Hz, 1 H, CH), 7.75 (d, J ¼ 8.0 Hz, 1 H,
CH), 7.90 (d, J ¼ 8.0 Hz, 1 H, CH), 8.06 (s, 1 H, CH), 8.09 (s, 1 H, NH).
13C NMR (100 MHz, CDCl3) d (ppm) ¼ 18.37 (CH3), 19.95 (CH2),
36.37 (CH2), 38.32 (CH2), 52.26 (OCH3), 120.56 (aromat. CH),
124.26 (aromat. CH), 125.14 (aromat. CH), 129.12 (aromat. CH),
130.78 (quart. C), 131.78 (CH), 138.30 (quart. C), 143.74 (CH),
166.81 (CO), 171.22 (CO), 200.47 (CO).
[6] K. C. Nicolaou, Y. Tang, J. Wang, Chem. Commun. 2007, 1922–
1923.
[7] K. C. Nicolaou, A. Li, D. J. Edmonds, Angew. Chem., Int. Ed.
2006, 45, 2548–2555.
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6294–6295.
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Edmonds, Angew. Chem., Int. Ed. 2007, 46, 4712–4714.
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J. Am. Chem. Soc. 2009, 131, 16905–16918.
[11] D. C. J. Waalboer, M. C. Schaapman, F. L. van Delft,
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6578.
3-(5-Oxo-5-phenylpentanoylamino)-benzoic acid 8c
Of 7c, 258 mg (0.79 mmol) was dissolved in 50 mL methanol,
45.1 mg (0.33 mmol) K2CO3 was added and the suspension was
refluxed for 24 h. Then 20 mL 10% aqueous HCl was added and
the solution was extracted with diethyl ether (3 ꢀ 30 mL). The
combined organic layers were dried over Na2SO4, the solvent
was evaporated and the residue was purified by flash column
chromatography to give 239 mg (97%) of 8c as colourless crystals.
M.p.: 1918C. IR (NaCl, film): n (cmꢁ1) ¼ 3293, 3062, 2927, 2850,
2359, 2341, 1973, 1908, 1689, 1653, 1591, 1537, 1455, 1415,
1307, 1270, 1179, 963, 756, 688, 679. MS (ESI) m/z (%) ¼ 312.1
([Mþ1]þ), 225.2. MS (CI) m/z (%) ¼ 225 (100). MS (EI) m/z (%) ¼ 224
(12), 143 (14), 99 (24), 62 (34), 56 (100). 1H NMR (400 MHz, CDCl3) d
(ppm) ¼ 1.94 (quint., J ¼ 7.2 Hz, 2 H, CH2), 2.44 (t, J ¼ 7.2 Hz,
2 H, CH2), 3.10 (t, J ¼ 7.2 Hz, 2 H, CH2), 7.40 (t, J ¼ 8.1 Hz, 1 H,
CH), 7.52 (t, J ¼ 8.1 Hz, 2 H, 2 CH), 7.59 (d, J ¼ 8.0 Hz, 1 H, CH),
7.63 (t, J ¼ 7.4 Hz, 1 H, CH), 7.85 (d, J ¼ 8.0 Hz, 1 H, CH), 7.96
(s, 1 H, NH), 7.97 (d, J ¼ 8.0 Hz, 2 H, 2 CH), 8.27 (s, 1 H, CH), 10.31
(s, 1 H, OH). 13C NMR (100 MHz, CDCl3) d (ppm) ¼ 19.56 (CH2),
35.29 (CH2), 37.18 (CH2), 117.72 (CH), 123.08 (CH), 123.65 (CH),
127.78 (2 CH), 128.64 (2 CH), 128.76 (CH), 131.08 (quart. C), 133.04
(CH), 136.50 (quart. C), 139.47 (quart. C), 167.10 (COOH), 171.15
(CO), 199.59 (CO).
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C. Zhang, D. L. Zink, N. N. Tsou, R. G. Ball, A. Basilio,
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The authors have declared no conflict of interest.
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ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com