Synthesis and biological evaluation of fluorinated analogues of ripostatin A

Article abstract of DOI:10.1039/C8OB02890G

Several monocyclic derivatives of 14,14′-difluororipostatin A were prepared using a catalytic Mukaiyama aldol reaction, a ring-closing metathesis reaction and a late stage click reaction as key steps. The biological activity of the produced compounds was assessed in vivo using a panel of pathogenic microorganisms. Moderate antibiotic activity was observed for 11-OMe-ripostatin A and 11-OMe-14,14′-difluororipostatin A.

Full text of DOI:10.1039/C8OB02890G

Organic &
Biomolecular Chemistry
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COMMUNICATION
Synthesis and biological evaluation of fluorinated
analogues of ripostatin A†
Cite this: DOI: 10.1039/c8ob02890g
a,b
Vladyslav Shendermana and Evgeny V. Prusov
*
Received 19th November 2018,
Accepted 10th December 2018
DOI: 10.1039/c8ob02890g
rsc.li/obc
Several monocyclic derivatives of 14,14’-difluororipostatin A were 14,14′-difluororipostatin A using a last-stage click chemistry
prepared using a catalytic Mukaiyama aldol reaction, a ring-closing approach.
metathesis reaction and a late stage click reaction as key steps. The
Starting from 3-butyn-1-ol, vinyl iodide 7 was prepared by
biological activity of the produced compounds was assessed carboalumination/iodination and converted into alcohol 8
in vivo using a panel of pathogenic microorganisms. Moderate (90% ee)‡ via DMP oxidation and Brown allylation
antibiotic activity was observed for 11-OMe-ripostatin
A
and (Scheme 1).6 Subsequent methylation of the hydroxyl group
11-OMe-14,14’-difluororipostatin A.
Ripostatins are 14-membered, polyene-rich macrolactones iso-
lated from the myxobacterium Sorangium cellulosum Soce 377.1
Both ripostatin A and ripostatin B possess antibiotic activity
against Gram-positive bacteria and their cellular target was
established as the “switch region” of the bacterial RNA-poly-
merase (Fig. 1).2
The presence of the synthetically challenging skipped
polyene motif in the molecule of ripostatins prompted efforts
from several groups towards the total3 and partial4 synthesis of
these natural products. The synthesis and biological evalu-
ation of some structurally modified ripostatins were also
reported.5 Notably, the fluorinated analogue of ripostatin A
was found to be roughly thousand times less potent than the
corresponding derivative of ripostatin B. Such a difference in
the RNAP inhibitory activity can be explained by the fact that
difluororipostatin A exists almost exclusively as a bicyclic hemi-
acetal, whereas difluororipostatin B is a monocyclic macrolac-
tone with a flexible side-chain.
Fig. 1 Ripostatins A, B and their fluorinated analogues.
To test this hypothesis, we decided to prepare monocyclic
analogues of ripostatin A and difluororipostatin A in which the
formation of the hemiacetal is blocked by the methylation of
the C-11 hydroxyl group (Fig. 2). We were also interested in
generating some heterocycle-containing analogues of 11-OMe-
aHelmholtz Centre for Infection Research, Inhoffen Str. 7, 38124 Braunschweig,
Germany
bInstitute for Organic Chemistry, Leibniz Universität Hannover, Schneiderberg 1B,
30167 Hannover, Germany
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob02890g
Fig. 2 Monocyclic fluorinated analogues of ripostatin A.
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primary TBS ether followed by two oxidation reactions pro-
vided the desired acid 6.
Using a similar synthetic strategy, the Weinreb amide 14
was extended with the alkyne building block 22 to ketone 23
and then elaborated to macrolactone 26 (Scheme 3). We found
that it was necessary to retain the TMS protecting group at the
Scheme 1 Synthesis of Weireb amide 14.
and dihydroxylation provided diol 9, from which aldehyde 10
was accessed via Stille cross-coupling and periodate cleavage.
The Mukaiyama aldol reaction between acetal 11 and aldehyde
10 performed according to the procedure originally reported
by Iseki7 produced the desired adduct in a rather moderate
yield and low diastereoselectivity. After optimization of the
catalyst preparation and reaction conditions,§ we were able to
obtain the aldol product 13 in 66% yield and a 9 : 1 diastereo-
meric ratio. The ester functionality in 13 was easily converted
into the Weinreb amide using an excess of lithium N-methoxy-
N-methylamide.8
The reaction of the Weinreb amide 14 with the organo-
lithium reagent generated from iodide 15 by metal/halogen
exchange produced hydroxyketone 16 in
a good yield
(Scheme 2). Then, the iodoacrylic acid fragment was attached
using a modified Yamaguchi procedure. After the installation
of the second allyl group in the acrylate moiety by the Stille
cross-coupling reaction, the indenyl-based ring-closing
metathesis catalyst 20 developed by Fürstner9 was used to
build-up the macrolactone. Finally, deprotection of the
Scheme 3 Click-chemistry approach to synthesize the heterocyclic
analogues of 11-O-Me-14,14’-difluororipostatin A.
Scheme 2 Synthesis of 11-O-Me-14,14’-difluororipostatin A.
Scheme 4 Synthesis of 11-O-Me-ripostatin A.
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Table 1 Biological activity of the ripostatin A derivatives
Acknowledgements
Micrococcus
luteus
Bacillus
subtilis
Nematosp.
coryli
We thank Prof. Dr M. Kalesse for many helpful discussions
and valuable pieces of advice. We are also indebted to
W. Collisi for performing the biological activity tests.
Financial support of this work from the Deutsche
Forschungsgemeinschaft (Grant PR1328/1-2 to P. E. V.) is grate-
fully acknowledged.
Compound
S. aureus
5
6
28
29
33
17
67
67
17
4
67
—
67
17
—
—
—
—
67
67
triple bond until the RCM step in order to prevent the for-
mation of enyne metathesis byproducts. Removal of the pro-
tecting groups by sequential treatment with TBAF and the
Et3N·3HF complex and application of the two-step oxidation
protocol produced the penultimate acid 27, which was then
introduced into the Cu-catalyzed cycloaddition reactions10
with several azides to give the triazole-containing analogues of
ripostatin A.
Notes and references
‡According to the 1H NMR of the Mosher ester.
§It was crucial to prepare the oxazaborolidinone catalyst in THF and not in
nitroethane as described in the original protocol. Also, the use of a borane–di-
methylsulfide complex instead of a borane–THF complex produced significantly
more consistent results at the aldol step.
For comparison purposes, we also synthesized 11-OMe-
ripostatin A (Scheme 4). The polyketide fragment was obtained
using the Paterson aldol reaction11 between ketone 31 and
aldehyde 33. Construction of the macrolactone was performed
as described earlier without any difficulties. However, the
methylated analogue of ripostatin A was found to be unstable
under basic conditions due to the macrolactone opening
through β-elimination.
Biological evaluation of the produced compounds revealed
that 11-O-methylated ripostatins and their heterocyclic deriva-
tives are weakly active against some bacterial species. The
lowest MIC value was observed for 11-OMe-difluororipostatin A
against Bacillus subtilis (Table 1).
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Conclusions
As a result of our studies, an efficient synthetic approach to
various fluorinated analogues of ripostatin A containing
heterocyclic fragments in the side chain was developed. The
produced compounds were found to be less potent than the
derivatives of ripostatin B, but still active against some organ-
isms. Further studies on the SAR of ripostatins with modifi-
cations around the macrolactone fragment may produce more
promising compounds suitable for development into clinical
candidates.
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Conflicts of interest
There are no conflicts to declare.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem.