Highly Efficient Total Synthesis of Closthioamide
ca. 73% (3b Ǟ 1a), ca. 70% (7 Ǟ 1a) over all steps]. It hexathionation, but also provides the basis for a large vari-
should be highlighted that the entire route to 1a afforded ety of prospective modifications. Bioactivity tests have con-
only a single flash-chromatographic purification (5b).
firmed the impressive activity of 1a against multiresistant
The two hexathioamides 1a and 1b were subjected to bacterial pathogens. Our protocol provides efficient access
standardized antimicrobial assays to evaluate the antimicro- to a variety of closthioamides and thus sets the stage for
bial activity.[15] The antibiotic activity of synthetic clos- studying their mode of action and structure–activity rela-
thioamide (1a) was verified in comparison to the natural tionships – important prerequisites for the further develop-
product (Table 1).[3] The activity of synthetic closthioamide ment of this novel class of antibiotics.
was shown to be equivalent to the activity of the bacterial
metabolite, thus giving direct evidence for the potency of
the hexathioamide. In contrast, monothioamides, exam-
plarily represented by 4-hydroxythiobenzamide, exhibit neg-
ligible antimicrobial activities (Table 1). Surprisingly, de-
spite the common hexathioamide backbone, the Chx ether
protected derivative 1b is nearly inactive against the test or-
ganisms. It appears that the phenyl substituent (OH, ChxO)
plays an eminent role for the antibiotic potency and bioac-
tivity profiles of the thioamides. Ongoing studies will pro-
vide more information about structure–activity relation-
ships and address the biological target of the closthioam-
ides.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures and product characteriza-
tion.
Acknowledgments
We thank A. Perner and F. Rhein for MS and NMR measurements
and C. Weigel for performing biological assays. This work was fin-
ancially supported by the Pakt für Forschung und Innovation.
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Table 1. Antimicrobial activity (MIC values and zones of inhibi-
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[12] The use of trifluoroacetic acid for deprotection showed also
good applicability since the reaction proceeds faster (within
minutes). However, the corresponding trifluoroacetates require
a more careful workup (anion exchange, removal of excess
acid).
[13] This reagent was synthesized according to a reported method,
but is also commercially available from various suppliers (Sup-
porting Information).
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[a] Ec: Escherichia coli; MRSA: methicillin-resistant Staphylococcus
aureus; VRE: vancomycin-resistant Enterococcus faecalis; Mv: My-
cobacterium vaccae; nat.: natural isolate.
Conclusions
We have developed a highly efficient and simple pro-
cedure for the first de novo synthesis of closthioamide start-
ing from readily available starting material. The convergent
synthetic route not only allows the multigram synthesis of
the unique polythioamide antibiotic involving a one-pot
Received: December 16, 2010
Published Online: February 3, 2011
Eur. J. Org. Chem. 2011, 1429–1431
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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