Total synthesis and antibiotic activity of dehydrohomoplatencin

Article abstract of DOI:10.1002/chem.201001744

Expanding antibiotics: A concise synthesis of dehydrohomoplatencin a novel derivative of the naturally occurring antibiotic platencin has been realized (see scheme). Notably the synthesis of the ketolide portion of the molecule was achieved in only two exceedingly simple steps. Compared to platencin dehydrohomoplatencin showed virtually equipotent antibacterial activity against Gram-positive bacteria and may serve as a novel lead structure for the development of new antibiotics.

Full text of DOI:10.1002/chem.201001744

COMMUNICATION
DOI: 10.1002/chem.201001744
Total Synthesis and Antibiotic Activity of Dehydrohomoplatencin
Dennis C. J. Waalboer,[a] Stefan H. A. M. Leenders,[a] Tanja Schꢀlin-Casonato,[b]
Floris L. van Delft,[a] and Floris P. J. T. Rutjes*[a]
The emergence of resistant pathogens is a rapidly increas-
ing concern to society and has been identified by the World
Health Organization (WHO) as one of the three greatest
threats to human health. Unfortunately, the pressing need
for new classes of antibiotics is still poorly met by the phar-
maceutical industry,[1] as illustrated by the recent call by the
Infectious Diseases Society of America (IDSA) for a global
commitment to develop ten new antibiotics by 2020.[2] In
this respect, the recent discovery of two new antibiotics, pla-
tensimycin[3] (1) and platencin[4] (2), represented a potential
breakthrough in antibiotic research.
ty, which has culminated in an impressive number of formal
and total syntheses given the relatively short time frame.[6]
In contrast to 1, the synthesis of platencin derivatives has re-
ceived little attention. Norplatencin (3),[7] and very recently
isoplatencin[8] and derivatives thereof, are the only closely
related synthetic analogues of platencin that have been re-
ported. Of these derivatives only isoplatencin demonstrated
potent antibiotic activity. Herein, we report a concise total
synthesis of dehydrohomoplatencin (4) of which the core
structure can be synthesized in enantiopure form in two ex-
ceedingly simple steps. Furthermore, we will demonstrate
that this analogue displays potent antibacterial activity.
Both compounds are potent inhibitors of the fatty acid
synthesis in Gram-positive bacteria and even eradicate noto-
riously resistant bacteria such as methicillin-resistant Staphy-
lococcus aureus (MRSA) and vancomycin-resistant Entero-
coccus faecalis (VREF). Interestingly, the validity of this
target and hence the in vivo efficacy of 1 and 2 is still under
debate.[5] The valuable properties of these natural products
immediately caught the attention of the synthetic communi-
In our research toward a formal total synthesis of platen-
cin (2),[6h] we isolated an unexpected side product in the re-
action of alkene 7 with TsOH and ethylene glycol in reflux-
ing benzene (Scheme 1). Extensive 2D NMR spectroscopy
studies eventually revealed structure 9, which might be
formed by initial acid-mediated isomerization of the isopro-
penyl group to an isopropylidene group followed by attack
[a] D. C. J. Waalboer, S. H. A. M. Leenders, Dr. F. L. van Delft,
Prof. Dr. F. P. J. T. Rutjes
Institute for Molecules and Materials, Radboud University Nijmegen
Heyendaalseweg 135, 6525 AJ Nijmegen (The Netherlands)
Fax : (+31)24-365-3393
E-mail: f.rutjes@science.ru.nl
[b] Dr. T. Schꢀlin-Casonato
Department of Medical Microbiology
Radboud University Nijmegen Medical Centre
P.O. Box 9101, 6500 HB Nijmegen (The Netherlands)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001744.
Scheme 1. Unexpected formation of acetal 9 in the protection of ketone
7. a) TsOH, ethylene glycol, benzene, reflux, 16 h. Ts=para-toluenesul-
fonyl.
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of this double bond in a 1,4-manner to the protonated unsa-
turated ketone. Loss of a proton from the resulting cation
reformed the isopropenyl group. Subsequent protection of
the ketone then afforded tricyclic acetal 9.[9]
Intrigued by this mechanism, we attempted to reproduce
the reaction with the precursor of alkene 7, aldehyde 6, in
the absence of ethylene glycol and with more TsOH
(0.5 equiv) to accelerate the reaction (Scheme 2). To our
surprise, a completely different reaction occurred to afford
diene 10 in 48% yield. By shortening the reaction time to
30 min the yield of diene 10 was increased to 67%.
rather rare and to the best of our knowledge none have
been reported that yield a diene.
The unique structure of diene 10 was unambiguously con-
firmed by X-ray crystallographic analysis (Scheme 2) and
shows great similarity to the core structure of 2.[12] An over-
lay of ketones 10 and 15 clearly shows that the increased
ring size of diene 10 does not alter the overall shape of the
molecule compared to core structure 15 and only seems to
affect the orientation of the exocyclic double bond
(Figure 1).
Scheme 2. Synthesis and ORTEP plot of diene 10 derived from X-ray
crystallographic analysis (non-hydrogen atoms are shown with ellipsoids
at 50% probability). a) TsOH, benzene, 808C, 0.5 h, 67%. Ts=para-tol-
uenesulfonyl.
Figure 1. Overlay of the core structure of platencin (15) and diene 10.
Energies of conformations and overlap were minimized (MM2).
The significant structural resemblance of core structures
10 and 15, and the exceptionally short synthesis of diene 10
sparked our interest in the antibiotic properties of a platen-
cin analogue incorporating core structure 10.
Most likely, the formation of diene 10 proceeds through
an acid-mediated Prins cyclization[10] of aldehyde 6 to give
the tertiary cation 12 (Scheme 3). Molecular modeling
(MM2) indicates that formation of the endo double bond is
According to the methodology developed by Nicolaou
and co-workers,[6d,13] diene 10 was methylated by using
KHMDS and MeI in 93% yield and in an inconsequential
diastereomeric ratio (d.r.) of 1:7 (Scheme 4). Subsequent al-
lylation with allyl iodide proceeded smoothly and afforded
alkene 16 in 76% yield and a d.r. of 3:10. The inseparable
diastereomeric mixture was reacted in a cross-metathesis re-
action with vinylboronic acid pinacol ester. The reaction re-
turned a mixture of E and Z isomers that was treated with
trimethylamine-N-oxide in THF at reflux to afford the cor-
responding aldehyde in 35% yield over two steps based on
the 3:10 diastereomeric ratio of alkene 16. Finally, oxidation
of the aldehyde was achieved by a Pinnick oxidation to give
carboxylic acid 17 in 91% yield.
Scheme 3. Proposed reaction mechanism for the formation of diene 10.
energetically favored, giving rise to allylic alcohol 13 as the
thermodynamic product. Subsequent protonation and elimi-
nation of the alcohol will lead to the highly stabilized allylic
cation 14, which after elimination affords diene 10. Al-
though a carbonyl ene[11] pathway would also be possible,
this seems less likely, since in the high-pressure Diels–Alder
reaction leading to aldehyde 6 no carbonyl ene products are
observed.[6h] It is interesting to note that examples of seven-
membered ring formation through a Prins cyclization are
Scheme 4. a) KHMDS, THF, ꢀ788C, 45 min, then HMPA, MeI, 1 h,
93%, d.r. 1:7; b) KHMDS, THF, ꢀ788C, 45 min, then HMPA, allyl
iodide, 30 min, 76%, d.r. 3:10; c) Vinylboronic acid pinacol ester, Grubbs
2nd generation cat., benzene, 808C, 1 h; d) Me3NO, THF, 708C, 1.5 h,
35% (2 steps); e) 2-methyl-2-butene, NaH2PO4, NaClO2, H2O, tBuOH,
RT, 15 min, 91%. KHMDS=potassium bis(trimethylsilyl)amide,
HMPA=hexamethylphosphoramide.
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Chem. Eur. J. 2010, 16, 11233 – 11236

Dehydrohomoplatencin
COMMUNICATION
(40 mL), dried over Na2SO4, and the solvent was evaporated in vacuo.
The crude product was purified by flash chromatography (silica gel,
EtOAc/heptane 1:20 to 1:5) to give diene 10 as a pale yellow oil that sol-
idified upon storage in the freezer (1.22 g, 67%). A sample for X-ray
crystallographic analysis was obtained by dissolving diene 10 in heptane
and subsequent slow evaporation of most of the solvent. The remaining
mother liquor was removed by pipette and the process was repeated
again to give diene 10 as colorless rodlike crystals. [a]2D0 =ꢀ42.4 (c 1.07,
CH2Cl2); 1H NMR (CDCl3, 400 MHz): d=6.67 (d, J=10.1 Hz, 1H), 6.14
(dd, J=1.6, 10.8 Hz, 1H), 5.91 (dd, J=1.0, 10.1 Hz, 1H), 5.73 (d, J=
10.8 Hz, 1H), 4.82 (m, 1H), 4.77 (m, 1H), 2,60–2.65 (m, 1H), 2.48–2.57
(m, 1H), 2.39 (ddd, J=0.8, 5.1, 16.2 Hz, 1H), 2.30 (dd, J=13.7, 16.2 Hz,
1H), 2.12 (tdd, J=2.4, 9.4, 13.9 Hz, 1H), 1.76–1.94 (m, 4H), 1.43 ppm
(ddd, J=4.4, 7.3, 13.7 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=199.6,
157.4, 153.2, 139.0, 132.8, 126.6, 112.8, 43.1, 40.0, 39.3, 38.6, 35.6, 28.4,
26.4 ppm; IR (neat): n˜ =3076, 3018, 2930, 2858, 1679, 1635, 1620,
1592 cmꢀ1; HRMS (EI+): m/z calcd for C14H16O: 200.1201 [M]+; found:
200.1204.
The synthesis of dehydrohomoplatencin (4) was efficiently
completed by the coupling of carboxylic acid 17 to aniline
18[6d] and subsequent deprotection of the TMSE ester with
TASF (Scheme 5).
Scheme 5. a) HATU, Et3N, DMF, RT, 70%; b) TASF, DMF, RT!408C,
57%. TMSE=2-(trimethylsilyl)ethyl, HATU=O-(7-azabenzotriazol-1-
yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate, TASF=tris(di-
methylamino)sulfonium difluorotrimethylsilicate.
With derivative 4 in hand, we could determine its antibi-
otic profile. Much to our delight, dehydrohomoplatencin (4)
proved virtually equipotent to 2 and only lacked activity
against Streptococcus pneumoniae (Table 1).[14]
Acknowledgements
This research has been financially supported (in part) by the Council for
Chemical Sciences of The Netherlands Organization for Scientific Re-
search (NWO-CW). We would like to thank J. M. M. Smits (Institute for
Molecules and Materials, Radboud University Nijmegen) for the crystal-
lographic analysis.
Table 1. Minimum inhibitory concentration (mgmLꢀ1) of dehydrohomo-
platencin (4) compared to the reported values for platensimycin (1) and
platencin (2).
Keywords: antibiotics · medicinal chemistry · platencin ·
Prins reaction · total synthesis
Organism and resistance
4
2[a]
1[a]
S. aureus (MSSA)
S. aureus (MRSA)
S. aureus (MRSA, Macrolid)
E. faecalis
E. faecium (vancomycin)
CNS (MRSE)
0.5
1
1
0.5
1
1
2
<0.06
ND[b]
4
0.5
0.5
0.5
1
0.1
ND[b]
1
2
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0.12
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[a] Values taken from literature.[3,4a] [b] ND=not determined.
In conclusion, we have developed an exceedingly short
enantiopure synthesis to core structure 10 using a novel
Prins cyclization as the key step. By this easy two-step pro-
tocol using commercially available starting materials, we are
now able to routinely synthesize diene 10 on a multigram
scale. This structure was elaborated to derivative 4, which
proved to be virtually equipotent to 2. Currently, we are ex-
ploiting the concise synthesis of diene 10 to quickly assem-
ble a library of derivatives with modified aromatic frag-
ments for structure–activity relationship (SAR) studies.
Experimental Section
Diene 10: TsOH (0.789 g, 4.58 mmol) was added in one portion to a solu-
tion of aldehyde 6 (2.00 g, 9.16 mmol) in benzene (70 mL) under an
argon atmosphere. The reaction flask was placed in a preheated oil bath
at 808C and stirred for 30 min. At that time TLC analysis showed com-
plete consumption of aldehyde 6 and the reaction mixture was cooled to
RT using a water bath. The reaction mixture was diluted with diethyl
ether (40 mL) and washed with water (80 mL). The water layer was ex-
tracted with diethyl ether (2ꢂ40 mL) and the combined organic layers
were washed with saturated aqueous NaHCO3 (40 mL) and brine
Chem. Eur. J. 2010, 16, 11233 – 11236
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[12] CCDC-783495 contains the supplementary crystallographic data for
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[14] See the Supporting Information for a full overview of MIC values of
derivative 4.
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[8] During the preparation of this manuscript a synthesis of isoplatencin
was reported: K. Tiefenbacher, A. Gollner, J. Mulzer, Chem. Eur. J.
2010, DOI: 10.1002/chem.201000706.
[9] A scheme of the proposed reaction mechanism has been included in
the Supporting Information.
Received: June 20, 2010
Published online: August 16, 2010
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Chem. Eur. J. 2010, 16, 11233 – 11236