Tetrahedron Letters
An improved synthesis of hemichrysophaentin-AB fragment of
chrysophaentin A
a
a,b,c,
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Christopher R. Fullenkamp , Gary A. Sulikowski
a
Department of Chemistry, Vanderbilt University, Nashville, TN, USA
Department of Pharmacology, Vanderbilt University, Nashville, TN, USA
Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN, USA
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthetic fragments of chrysophaentin A, a rare antimicrobial marine natural product, were required to
support structure-activity and mechanism of action studies. Hemichrysophaentin, a synthetic fragment
of chrysophaentin A showed antimicrobial activity against Gram-positive bacteria, presumably acting
through the inhibition of the microbial tubulin-like protein FtsZ. Here in, we report a concise and scalable
Received 6 February 2020
Revised 11 March 2020
Accepted 16 March 2020
Available online 18 March 2020
1
1-step synthesis of hemichrysophaentin featuring a stereo- and regiocontrolled installation of an E-
chloroalkene followed by a Lewis acid promoted O to C migration.
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Stannylcupration
O to C rearrangement
Natural product derivative
Antimicrobial
FtsZ inhibition
Introduction
[6]. However, inconsistency in reported mechanisms [7] and the
labor and time intensive total syntheses required for study of nat-
ural product inhibitors, has made the detailed investigation into
FtsZ inhibition as an antimicrobial target difficult.
The need for new antibiotics and the identification of new
pathogen cellular targets is at the forefront of antibiotic research.
We are entering an era where a growing number of bacterial infec-
tions are resistant to our ‘‘last resort” antibiotics. However, antibi-
otic development has slowed in the recent years with many
pharmaceutical companies abandoning their antimicrobial pro-
grams. In the past thirty years only three new classes of antibiotics
have been approved and many of the newly approved antibiotics
are derivatives of previously released antibiotics [1]. The need for
new antibiotics and antimicrobial targets is of utmost importance.
Bacterial cell division has not been successfully targeted by an
approved antibiotic and would represent a novel target for the
development of new therapeutics [2]. One essential cell division
protein that has garnered the attention of researchers is FtsZ. This
protein is preserved across bacterial species and serves as a bacte-
rial homologue of eukaryotic tubulin [3,4] and is essential for cell
division. The clinical success of tubulin inhibitors as anticancer
therapies [5] provides hope that inhibition of FtsZ could lead to
the development of new therapeutics to fight pathogenic infec-
tions. Numerous compounds have been described as FtsZ inhibi-
tors including synthetic small molecules and natural products
In 2012, the Wipf group, reported the synthesis of hemichryso-
phaentin (2), a truncated derivative of the natural product chryso-
phaentin A (1) in support of SAR studies aimed at identification of
the minimal pharmacophore of the parent natural product (Fig. 1A)
[8]. Chrysophaentin A was shown to be a competitive inhibitor of
FtsZ [9]. Hemichrysophaentin had slightly reduced antimicrobial
activity compared to the chrysophaentin A, however it was demon-
strated to be a competitive inhibitor of GTPase activity of FtsZ and
inhibited the polymerization of FtsZ in vitro [8,9b]. However, no
further investigation into the mechanism of action of hemichryso-
phaentin or synthetic derivatives have been reported.
The previously reported 12 step synthesis of hemichrysophaen-
tin [8], featured a Negishi coupling between vinyl iodide 3 and
benzylzinc bromide 4 to form the trisubstituted chloroalkene.
Vinyl iodide 3 was generated as a 2:1 mixture of E and Z isomers
by the addition of iodine monochloride to the corresponding
alkyne. Benzylzinc bromide 4 was synthesized in four steps from
2,4-dimethoxychlorobenzene. The two fragments were coupled
under Negishi conditions. Following removal of the pivalate ester
groups the mixture of geometric isomer were separated by Super-
critical Fluid Chromatography (SFC) to afford pure samples of
hemichrysophaentin (2) and the corresponding Z-isomer (Fig. 1B).
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040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
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