Cobalt(III)-Catalyzed C?H Amidation of Dehydroalanine for the Site-Selective Structural Diversification of Thiostrepton

Article abstract of DOI:10.1002/anie.201911886

Thiostrepton is a potent antibiotic against a broad range of Gram-positive bacteria, but its medical applications have been limited by its poor aqueous solubility. In this work, the first C(sp²)?H amidation of dehydroalanine (Dha) residues was applied to the site selective modification of thiostrepton to prepare a variety of derivatives. Unlike all prior methods for the modification of thiostrepton, the alkene framework of the Dha residue is preserved and with complete selectivity for the Z-stereoisomer. Additionally, an aldehyde group was introduced by C?H amidation, enabling oxime ligation for the installation of an even greater range of functionality. The thiostrepton derivatives generally maintain antimicrobial activity, and importantly, eight of the derivatives displayed improved aqueous solubility (up to 28-fold), thereby addressing a key shortcoming of this antibiotic. The exceptional functional group compatibility and site selectivity of Co^III-catalyzed C(sp²)?H Dha amidation suggests that this approach could be generalized to other natural products and biopolymers containing Dha residues.

Full text of DOI:10.1002/anie.201911886

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Co(III)-Catalyzed C-H Amidation of Dehydroalanine for the Site-
Selective Structural Diversification of Thiostrepton
Authors: Ryan J Scamp, Edward deRamon, Eric K Paulson, Scott J
Miller, and Jonathan Anthony Ellman
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201911886
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10.1002/anie.201911886
Angewandte Chemie International Edition
RESEARCH ARTICLE
Co(III)-Catalyzed C–H Amidation of Dehydroalanine for the
Site-Selective Structural Diversification of Thiostrepton
Ryan J. Scamp, Edward deRamon, Eric K. Paulson, Scott J. Miller,* and Jonathan A. Ellman*[a]
Abstract: Thiostrepton is a potent antibiotic against a broad
range of Gram-positive bacteria, but its medical applications
have been limited by its poor aqueous solubility. In this work,
the first C(sp2)–H amidation of dehydroalanine (Dha) residues
was applied to the site selective modification of thiostrepton
to prepare a variety of derivatives. Unlike all prior methods for
the modification of thiostrepton, the alkene framework of the
Dha residue is preserved and with complete selectivity for the
Z-stereoisomer. Additionally, an aldehyde group was
introduced by C–H amidation, enabling oxime ligation for the
installation of an even greater range of functionality. The
thiostrepton derivatives generally maintain antimicrobial
activity, and importantly, eight of the derivatives displayed
improved aqueous solubility (up to 28-fold), thereby
addressing
a key shortcoming of this antibiotic. The
exceptional functional group compatibility and site selectivity
of Co(III)-catalyzed C(sp2)–H Dha amidation suggests that
this approach could be generalized to other natural products
and biopolymers containing Dha residues.
Introduction
Thiostrepton 1 (Figure 1, top) is a potent antibiotic
synthesized by several strains of Gram-positive
microbes.1,2 Although it is used as an active component in
topical veterinary antibiotics, applications to human
medicine are limited owing to poor physicochemical
properties, particularly low aqueous solubility.1a Although
site-specific modification of 1 is a possible approach for
improving its aqueous solubility, architectural complexity
and a high density of delicate functionalities provide a
formidable barrier to successful, site-selective chemical
modification.3,4
The dehydroalanine (Dha) residues characteristic of 1
and other thiopeptides are reactive sites, most notably as
Michael acceptors for a variety of nucleophilic species.5
Previously, several studies have been carried out on
additions to the Dha residues in 1 (Figure 1, middle).6,7
Variable Dha site selectivity was observed depending on
the transformation and reaction conditions, with notable
site and diastereoselectivity achieved for Rh-catalyzed
arylboronic acid additions.6b Importantly, many of the
synthesized thiostrepton derivatives maintained potent
antibacterial activity with only moderate reductions relative
Figure 1. Thiostrepton 1 and applicability of Dha residues as scaffolds
for analog synthesis.
to 1. However, hydrophobic functionality has generally
been introduced, including in recent work involving
cycloaddition to the Dha residues,7a and aqueous
solubility has not been reported for any of these
derivatives of 1. Moreover, physicochemical properties of
derivatives of 1 have not been characterized, except for
studies by Honek and coworkers on several thiol Michael
adducts showing qualitative increases in overall polarity
by RP-HPLC and improvements in theoretical logP.6d
[a]
Dr. R. J. Scamp, E. deRamon, Dr. E. K. Paulsen, Prof. Dr. S. J.
Miller* , Prof. Dr. J. A. Ellman*
Department of Chemistry, Yale University
225 Prospect St., New Haven, CT 06520 (USA)
E-mail: jonathan.ellman@yale.edu, scott.miller@yale.edu
Supporting information for this article is given via a link at the
end of the document.
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10.1002/anie.201911886
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RESEARCH ARTICLE
Figure 2. Optimization of reaction conditions for thiostrepton C–H amidation. (a) Reaction scheme and generated regioisomers. (b) Conditions screened
for C–H amidation. (c) Crude UPLC chromatogram for optimized conditions (entry 8).
The previously investigated chemical modifications of
the Dhas in 1 resulted in loss of the alkene framework to
give modified residues with sp3 rather than sp2
hybridization. We sought a complementary method that
instead maintains the unsaturated character of the Dha
residue through catalytic C(sp2)–H functionalization.8 This
type of modification also avoids epimeric mixtures that can
complicate isolation of pure stereoisomers for biological
studies. We specifically pursued methods to install polar
functionality that would be beneficial to aqueous solubility.
Evaluation of a number of catalysts and coupling partners
was required to achieve this goal.
Here we report the first application of C(sp2)–H
amidation of Dhas for the site selective introduction of
amide functionality at the terminal Dha residue of 1 (Dha1;
Figure 1, bottom). In addition to defining a new threshold
for functional group tolerance in Cp*Co(III)-catalyzed C–H
functionalization reactions, a wide range of functionality
could be incorporated by C–H amidation using
dioxazolone coupling partners. Moreover, by introducing
an aldehyde group with C–H amidation, oxime ligation
could be employed to install an even greater range of
functionality. Many of the analogs maintained potent
antibacterial activity with only a moderate reduction
relative to thiostrepton perhaps because Dha1 is located
solubility of all previously reported thiostrepton derivatives
prepared by semisynthetic or biosynthetic methods.2
Results and Discussion
For C(sp2)–H functionalization of the Dhas of 1, we
evaluated
a range of coupling partners, including
isocyanates9 and electrophilic alkenes such as enones,8
acrylates, and maleimides.10 Unfortunately, under a
variety of conditions and with different transition metal
catalysts, little to no desired products were obtained, often
with significant degradation of the natural product.
Relevant to these studies, thiostrepton completely
degraded in the presence of Cu(OAc)2 or AgOAc,
stoichiometric oxidants that are commonly used in C–H
functionalization reactions.
We then directed our attention to 1,4,2-dioxazolones
as potential amidation reagents. Chang and coworkers
initially demonstrated that these reagents are particularly
effective coupling partners for C–H amidation,11 and they
have since been employed by many research labs for a
range of different applications.12 We hypothesized that
due to the inherently polar character of amide functionality,
selective C–H amidation of Dha C(sp2)–H bonds could
provide new analogs of thiostrepton with improved
aqueous solubility. Significantly, β-amidated Dhas are
found in stable bioactive natural products, suggesting that
the amidated thiostrepton analogs would also be stable.13
in
a solvent exposed region of thiostrepton with
modifications to this region generally well-tolerated.6b-d,7a
Most importantly, many analogs showed significantly
greater solubility in pH 7.2 aqueous solution with up to 28-
fold improvement to 83 μg/mL, surpassing the aqueous
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10.1002/anie.201911886
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RESEARCH ARTICLE
While C(sp2)–H amidation of Dha residues have not
previously been reported, structurally, Dhas bear aspects
of both acrylamides and enamides, motifs that have been
modified by C(sp2)–H functionalization. Specifically, Li and
co-workers had shown that N-methoxyacrylamides were
viable substrates for C–H amidations with dioxazolones.12i
Although the C(sp2)–H amidation of enamides has not
been reported, we had previously found that enamides are
effective substrates for other types of C(sp2)–H
functionalization under mild conditions.14
could be effectively synthesized with respectable yields
and regioselectivities. Furthermore, MOM and MEM
ethers (2k-l) were incorporated to give the respective
ether-substituted amides with superb regioselectivities.
An optimized reaction system with 10 equiv of 3-
phenyl-1,4,2-dioxazolone
[Cp*Co(MeCN)3][SbF6]2
and
50
mol
%
of
15
proved to be effective for
conversion of 1 to amidation products. A 71% overall yield
of amidated derivatives of 1 was obtained in 9:1 solvent
mixture of 1,2-DCE/TFE based on crude UPLC analysis
(Figure 2B, entry 1, see Table 1).16 Dha1 was determined
to be the predominant site for C–H amidation as
determined by NMR analysis (see Supporting
Information). A mixed solvent system was found to be
important for the desired reactivity; neat fluorinated
alcohols such as HFIP led to consumption of 1 without
detection of products by UPLC (entry 2). Negligible
conversions were observed with 1,2-DCE and 1,4-dioxane
as solvents owing to insolubility of 1 and the Co catalyst in
those solvents, respectively (entries 3-4). Other mixed
solvent systems allowed for significant product formation,
but in lower yields relative to the DCE/TFE system
(compare entry 1 with entries 5-6).
Upon determination of optimal solvent conditions, we
further evaluated the importance of other components of
the reaction system. Minimal conversion to product
occurred at 25 °C (Figure 2B, entry 7). No loss in yield was
observed upon lowering the dioxazolone loading to 5
equivalents (entry 8), but the yield was reduced when 2
equivalents of the amidating agent was used (entry 9).
Finally, the importance of the Co catalyst and its loading
amount was established through use of an analogous Rh
catalyst as well as a 10% loading of the Co catalyst, with
both reactions showing negligible conversion of 1 (entries
10-11). Relatively high catalyst loading is needed likely
due to sequestration by the plethora of functionalities
within 1; however, the use of an earth abundant cobalt
catalyst diminishes concern about this higher loading, and
product purification was unimpeded by the presence of
somewhat higher catalyst concentration.
Scheme 1. Scope of thiostrepton C–H amidation.
Having demonstrated the ability to synthesize analogs
of 1 through mild, single-step C–H amidation, we then
explored the potential of these analogs to serve as
platforms for the modular introduction of additional
functionality. Carbonyl groups are known handles for
bioorthogonal oxime formation to enable a broad range of
applications, including alteration of physicochemical
properties and drug targeting.17 However, standard
conditions for oxime formation from ketone-containing
peptides17 caused extensive degradation of the
thiostrepton derivative 2f appended with a ketone. We
therefore explored alternate strategies for oxime synthesis
that might be more compatible with the delicate nature of
thiosteptron.
With effective C–H amidation conditions in hand, we
next evaluated a broader set of dioxazolone substrates for
derivatization of 1 (Scheme 1). In addition to the phenyl
substituent used for reaction optimization (vide supra),
anisole (2b) and halobenzene (2c-d) substituents were
readily
installed
with
moderate
yields
and
regioselectivities. Although an inductively-withdrawing
CF3 group at the para position gave only trace amount of
2e, electron withdrawing substituents at the meta-position
of the phenyl ring were tolerated, as exemplified by analog
2f with the meta-acetyl group. The method also enabled
the introduction of nonaromatic amide groups; analogs
containing alkyl chains (2g-i) and a tethered ester (2j)
We expected the greater reactivity of aldehydes
relative to ketones to enable oxime formation under milder
conditions, and to that end we synthesized dioxazolone 4.
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Amidation of 1 with 4 generated crude mixtures that could
be immediately used for oxime formation with an
assortment of O-substituted hydroxylamines (Scheme 2).
In addition to the synthesis of O-methyl oxime (5a) and
hydroxime (5b) analogs, oxime tethering proved
competent for the installation of various unprotected protic
functionalities. Carboxylic acids (5c-d) and an alcohol (5e)
were introduced in moderate yields over two steps, as
determined by UPLC. A PEG3 chain was also appended
to thiostrepton by the amidation-condensation sequence
(5f). Finally, synthesis of 5g demonstrated that even
unprotected glycosyl units could be introduced.
important for achieving pronounced effects on solubility.
These results validate C–H amidation as a potential tool
for improving physicochemical properties of bioactive
molecules, such as solubility in the case of 1.
Site-specific modification in the tail region of
thiostrepton should also likely beneficial for maintaining
antibacterial activity. X-ray structural determination of
thiostrepton bound to the 50S ribosomal subunit have
established that the tail region is solvent exposed,18 with
modifications to this region generally well tolerated.6b-d,7a
Analogs 2a-l and 4a-g were consequently evaluated for
activity against a broad spectrum of Gram-positive
bacteria (Table 2). Many analogs demonstrated activity
within 2-5 times the MICs observed for 1 (Table 2, bolded
entries). Importantly, except for 4g, all compounds were
We next evaluated the effects of the pendant amide
substituents at Dha1 on the aqueous solubility of
thiostrepton derivatives (Table 1). The thermodynamic
solubility of 1 was first assessed in 10 mM aqueous MOPS
buffer (pH 7.2) and was found to be 3.0 ± 0.2 μg/mL (see
Supplemental Information for details). Products 2g and 2i-
2l each showed substantial improvements in solubility,
with 2g giving the highest solubility (83 ± 5 μg/mL; 28-fold
increase). The benzamide derivatives 2a, 2c, and 2e
showed poor solubilities below detection limits on UPLC,
indicating that an aromatic ring was a poor fit for improving
solubility as a key pharmacokinetic parameter, likely
owing to an overall enhancement of lipophilic character
relative to 1. Although oxime derivatives 4a-b and 4e also
showed an overall reduction in aqueous solubility, the
polar groups of 4c (carboxylic acid), 4f (PEG), and 4g
(hexose) successfully compensated for the lipophilic aryl
ring to effect substantial improvements in solubility relative
to 1.
generally competitive with vancomycin,
a
potent
compound currently used for treating bacterial
infections.19 Only VSE E. faecium showed consistent
vulnerability to vancomycin over the derivatives of 1. The
most active analogs, including 2c, 4a, and 4c, possessed
relatively nonpolar amides. In contrast, compounds with
the smallest alkyl (2g-h) or a polar carbohydrate group
(4g) had the poorest activity.
Table 1. Aqueous solubility of thiostrepton derivatives.
Entry
Compound
Solubility (μg/mL)[a]
1
2
1
3.0 ± 0.2
<1.0
2a
2c
2e
2g
2h
2i
3
<1.0
4
1.1 ± 0.2
83 ± 5
<1.0
5
6
7
16.2 ± 0.6
22 ± 2
28 ± 4
19 ± 1
<1.0
8
2j
9
2k
2l
10
11
12
13
14
15
16
5a
5b
5c
5e
5f
<1.0
20 ± 1
1.4 ± 0.4
4.3 ± 0.4
11 ± 1
5g
Bolded entries indicate improvements in solubility relative to 1.
[a]Aqueous concentration after 24 h stirring in 10 mM aqueous MOPS
buffer (average of two measurements).
Scheme 2. Oxime synthesis from a C-H amidation-condensation
sequence.
Given the large size of thiostrepton, it is somewhat
surprising that a wide range of solubilities were observed
for the thiostrepton derivatives. The site-specific
modification of a solvent-exposed Dha site was perhaps
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10.1002/anie.201911886
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RESEARCH ARTICLE
Table 2. Antibacterial activity of 1 and derivatives.
MIC (μg/mL) for Gram-positive organisms
Compound
S. aureus
(MSSA)
S. aureus
(MRSA)
E. faecalis
(VSE)
E. faecalis
(VRE)
E. faecium
(VSE)
E. faecium
(VRE)
S. pneumoniae
S. pyogenes
1
0.06
1
0.12
2
0.12
1
0.12
1
0.12
0.5
1
0.06
0.5
1
<0.001
0.008
0.004
<0.001
<0.001
0.004
0.06
<0.001
0.002
0.004
0.002
<0.001
0.004
0.06
2b
2b
1
2
2
1
2c
0.25
1
0.5
1
0.25
0.5
1
0.25
0.5
1
0.25
0.5
1
0.12
0.5
0.5
2
2d
2f
1
2
2g
2
4
4
4
4
2h
2
4
4
4
4
2
0.06
0.06
2i
0.5
0.5
1
0.5
1
0.5
1
1
1
0.25
0.5
1
0.004
0.015
0.015
<0.001
0.002
0.015
0.015
0.004
0.002
0.25
0.004
0.008
0.015
<0.001
0.004
0.015
0.015
0.004
0.004
0.25
2k
1
1
2l
1
1
1
1
5a
0.5
0.5
1
0.5
0.5
1
0.5
1
0.25
0.5
1
0.25
0.5
2
0.25
0.5
1
5b
5c
2
5d
1
1
2
1
1
1
5e
0.5
0.5
16
1
0.5
1
0.5
1
0.5
0.5
16
>32
1
0.5
0.5
8
5f
5g
1
16
1
16
2
16
0.25
vancomycin
>32
0.12
0.25
amines. Hergenrother and coworkers have recently
reported that appending amines to antibiotics can result in
dramatic improvements in accumulation and cytotoxicity
for Gram-negative bacteria along with beneficial effects for
Gram-positive bacteria.20 The preparation of derivatives of
1 that incorporate basic amines should improve aqueous
solubility while maintaining and potentially improving
activity against Gram-positive bacteria. These analogs
could possibly even elicit activity against Gram-negative
bacteria for which thiostrepton is inactive. The introduction
of amine functionality will therefore be the focus of future
work.
Beyond the immediate applications in thiostrepton
derivatization, these first examples of Dha C(sp2)–H
functionalization could feasibly be extended to other
natural products as well as peptides and proteins that
contain Dha residues.
Conclusion
We have disclosed the site-selective modification of
Dha1 of the natural product thiostrepton (1) by Cp*-
catalyzed C–H amidation with dioxazolone coupling
partners. This approach, which represents the first
example of C–H functionalization of Dha residues to
maintain the alkene character of the Dha residue, enabled
the preparation of a number of novel analogs of 1. In
addition, by using this approach to introduce a formyl
group, the modular introduction of diverse functional
groups by bioorthogonal oxime formation was also
accomplished. Antibiotic activity was broadly maintained,
and many of the derivatives showed greatly improved
aqueous solubility. These results demonstrate the
potential of Dha C(sp2)–H amidation for the synthesis of
bioactive analogs of thiostrepton with improved
physicochemical properties.
Acknowledgements
The current set of thiostrepton derivatives incorporate
a variety of polar functionality, but none incorporate basic
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10.1002/anie.201911886
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RESEARCH ARTICLE
Support from the NIH is gratefully acknowledged,
R35GM122473 to JAE and R35GM132092 to SJM.
Park, Y. Hwang, Y. B. Kim, M.-H. Baik, S. Chang, Science 359,
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See Section V and Table S1 of the Supporting Information for
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compound.
Keywords: C–H activation • cobalt • antibiotic •
chemoselectivity • natural product
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10.1002/anie.201911886
Angewandte Chemie International Edition
RESEARCH ARTICLE
R. J. Scamp, E. deRamon, E. K. Paulsen,
S. J. Miller,* and J. A. Ellman*
Page No. – Page No.
Site-Selective Co(III)-Catalyzed C-H
Amidation
Enabling
Diversification of Thiostrepton
of
Rapid
Dehydroalanine
Structural
Text for Table of Contents
Co(III)-catalyzed C-H amidation was used for the site-selective modification of the
antibiotic thiostrepton. A range of amide groups was installed with 1,4,2-dioxazolone
coupling partners. The introduction of an aldehyde group by C-H amidation enabled
modular incorporation of additional functionality by oxime formation. A number of the
thiostrepton derivatives showed greatly improved aqueous solubility while maintaining
antibacterial activity.
This article is protected by copyright. All rights reserved.