Total Syntheses of Cystobactamids and Structural Confirmation of Cystobactamid 919-2

Article abstract of DOI:10.1002/anie.201705387

The cystobactamids are a family of antibacterial natural products with unprecedented chemical scaffolds that are active against both Gram-positive and Gram-negative pathogens. Herein, we describe the first total synthesis of cystobactamid 919-2 from three fragments. Our convergent synthesis enabled both the confirmation of the correct structure and the determination of the absolute configuration of cystobactamid 919-2.

Full text of DOI:10.1002/anie.201705387

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Accepted Article
Title: Total Syntheses of Cystobactamids and Structural Confirmation
of Cystobactamid 919-2
Authors: Dirk Trauner, Bichu Cheng, and Rolf Müller
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Angewandte Chemie International Edition
10.1002/anie.201705387
COMMUNICATION
Total Syntheses of Cystobactamids and Structural Confirmation
of Cystobactamid 919-2
Bichu Cheng,* Rolf Müller, and Dirk Trauner*
Abstract: The cystobactamids are a family of antibacterial natural
products with unprecedented chemical scaffolds that are active
against both Gram positive and negative pathogens. Herein, we
describe the first total synthesis of cystobactamid 919-2 from three
fragments. Our convergent synthesis both confirmed the correct
structure and determined the absolute configuration of
cystobactamid 919-2.
More recently, cystobactamid 919-2 was reisolated by Kim
from cultures of myxobacteria Corallococcus coralloides M23,
[
6]
together with coralmycins
A
(5) and B.
Comparison of
spectroscopic data of 2 with coralmycin A revealed ambiguities
regarding NOE correlations and optical rotation data (see below)
which lead to a revision of the relative stereochemistry of the β-
methoxyasparagine moiety in cystobactamid 919-2 (4).
Possessing an additional hydroxy group on the benzoic acid unit,
coralmycin
A is even more potent against Gram-negative
The development of antibiotics has been a milestone in the
history of modern medicine. Many lifesaving drugs, such as the
penicillins, the erythromycins, and vancomycin, were found
during the “golden age” of antibiotics between 1940 and 1960.
However, new discoveries have plummeted from the 1980s
onward. Most antibiotics approved for use in patients today are
derived from a limited number of antibiotic types that were
pathogens than cystobactamid 919-2 (Figure 1).
O
CO2H
OH HN
[
1]
O
established by the mid-1980s. The increasing rate of multiple
drug resistance (MDR) and the low rate of new antibiotic
development endanger public health, and put us at risk of
returning to the pre-antimicrobial era. The development of new
antibiotics faces a severe crisis in finding novel chemical
scaffolds with activity against Gram-negative and multiresistant
pathogens, especially “ESKAPE” pathogens (Enterococcus
faecium, Staphylococcus aureus, Klebsiella pneumoniae,
Acinetobacter baumannii, Pseudomonas aeruginosa, and
O
cystobactamid 919-1
HN
(1)
CO H
2
O
O
O
HN
MeO S
HO
O
NH
O
O
HN S
NH2
O
O
O
[
2]
NH
Enterobacter species).
N
H
cystobactamid 507
Natural products have historically been a valuable resource
NH2
(3)
[
3]
O N
2
in the identification and development of antibacterial agents.
MeO S
H N
2
O
O
The cystobactamids (1−3) are a novel class of antibacterial
natural products recently isolated from Cystobacter sp. by Müller
HN
S
[
4]
et al. They are highly active against several Gram-positive
pathogens, with cystobactamid 919-2 (2) being the most potent.
More importantly, 2 also efficiently inhibited the growth of
several Gram-negative pathogens, such as E. coli and A.
baumannii. These compounds have been identified as inhibitors
of bacterial type IIa topoisomerases, and the potency of 2 is
HN
O
O
O
N
H
O
HN
OH
O N
2
originally-proposed structure
of cystobactamid 919-2 (2)
O
O
HN
NH2
comparable to or even exceeds that of ciprofloxacin,
a
5
MeO R
fluoroquinolone antibiotic currently used in the clinic, thus
offering exciting new alternatives for type II topoisomerase
4
1
O
O
CO H
2
HN S
[
5]
inhibitors.
HN
O
O
O
N
H
O
HN
OH
[*]
Dr. B. Cheng, Prof. Dr. D. Trauner
Department of Chemistry, University of Munich
Butenandtstr. 5-13, Haus F, 81377 Munich, Germany;
and
O N
2
O
O
(
(
4) R = H: Kim's revised structure of
cystobactamid 919-2
5) R = OH: coralmycin A
HN
R
Department of Chemistry, New York University
100 Washington Square East, Room 712
CO H
2
New York, NY 10003 USA
E-mail: dirktrauner@nyu.edu
Figure 1. Structures of the cystobactamids and coralmycin A.
bc2548@nyu.edu
Prof. Dr. R. Müller
Department of Microbial Natural Products, Helmholtz Institute for
Pharmaceutical Research Saarland, Helmholtz Center for Infection
Research, Saarland University, 66123 Saarbrücken, Germany
The isolation of cystobactamids from the natural producer
is difficult and yields are very low. For further development,
compound supply must be sustained by an optimised
biotechnological approach or scalable chemical synthesis.
Supporting information for this article is given via a link at the end of
the document.
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Angewandte Chemie International Edition
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COMMUNICATION
Both cystobactamids and coralmycins are nonribosomal
peptides that consist of six unnatural amino acids, including one
acidic or basic conditions led to partial epimerization.
Alternatively, the azide group was first reduced via
hydrogenation to the primary amine. Acidic hydrolysis of the
diester afforded the corresponding dicarboxylic acid without
epimerization. Finally, treatment of the acid with trifluoroacetic
anhydride (TFAA) afforded the cyclic anhydride fragment 7 with
concomitant protection of the amine as its trifluoroacetamide
[
4]
β-methoxyasparagine and five aromatic moieties.
aminobenzoic acid (PABA) chain scaffold is unique, and has not
The p-
[
7]
been found before in natural products. Furthermore, both the
[
8]
nitro group
and the isopropyl ether of the 3-hydroxy-4-
[
9]
aminobenzoic acid moieties are rare amongst natural products.
Synthetic challenges of cystobactamids include the efficient
synthesis of the monomeric PABA derivatives and their low
reactivity in amide bond formation. Incorporation of the β-
methoxyasparagine unit was also found to be nontrivial. Another
unforeseen problem is the difficulty in separating the
diastereoisomers at a late stage due to their poor solubility and
tendency to aggregate.
[
12]
(Scheme 2).
O
O
O
OH
O
OC6F5
a
N
H
N
H
gram scale
O N
9
O N
6
2
2
Herein we describe the total syntheses of cystobactamids
O
O
O
O
O
5
07 (3) and 919-2. Since the originally proposed structures of
MeO
HN
HO
HO
HO
N3
cystobactamid 919-1 (1) and 919-2 (2) are a pair of regioisomers,
and the stereochemistry of the β-methoxyasparagine moiety was
in dispute, we developed a divergent route that could lead to a
range of cystobactamids. Retrosynthetically, we envisioned that
Kim’s revised structure of cystobactamid 919-2 (4) could be
made from three fragments: activated ester 6, cyclic anhydride
fragment 7 and aniline derivative 8 (Scheme 1).
OEt
OEt
OEt
OEt
b-e
gram scale
2
steps
Ref. 11
O
O
F3C
O
1
0
11
7
Scheme 2. Synthesis of activated ester
CF CO 5, pyridine, DMF (quant.); b) MeI, Ag
d) HCl (6 M), 100 °C; e) TFAA, rt (quant., 2 steps).
6
and cyclic anhydride 7. a)
O (99%); c) Pd/C, H (91%);
3
2
C
6
F
2
2
NH2
MeO
O
Regioselective alkylation of 2,3-dihydroxybenzaldehyde (12)
[
13]
with 2-PrBr at the 3-OH position
and subsequent acetylation
O
HN
of the 2-OH afforded the corresponding protected aldehyde.
HN
[14]
Regioselective nitration followed by oxidation of the aldehyde
O
O
[
15]
®
O
with Oxone gave the carboxylic acid 13. The structure of 13
was confirmed by X-ray crystallographic analysis of a single
crystal (supporting information). The second fragment 15 was
prepared from 3-hydroxy-4-nitrobenzoic acid (14). Esterification
N
H
O
HN
OH
O N
2
(
4) Kim's revised structure of
O
cystobactamid 919-2
O
[
16]
of 14 with t-BuOH,
alkylation of the phenol with 2-PrI and
HN
reduction of the nitro group afforded aniline 15. Direct coupling
of acid 13 and aniline 15 under standard amide coupling
conditions worked poorly. Therefore, acid 13 was first
transformed into the corresponding acid chloride and further
reaction with aniline 15 under Schotten-Baumann conditions
afforded the amide product in good yield. Reduction of the nitro
group by hydrogenation gave aniline 16. Amidation of 16 with 4-
nitrobenzoyl chloride and another hydrogenation afforded the
trimeric aniline fragment 8. Removal of both the acetyl and the t-
butyl group afforded cystobactamid 507 (3). The spectroscopic
data of synthetic 3 match with those reported in the literature
H N
2
NO2
CO H
2
O
NH
O
MeO
O
+
O
+
O
NH
OAc
NH
HN
F3C
O
O
O
O
7
8
O
OC6F5
6
CO t-Bu
2
[
4,17]
(
Scheme 3).
Scheme 1. Retrosynthetic analysis of Kim’s revised structure of cystobactamid
19-2 (4).
9
The activated ester fragment
6
was prepared by
with pentafluorophenyl
). The cyclic anhydride fragment
was prepared from the readily available L-diethyl tartrate 10.
Compound 10 was transformed into the azido alcohol 11 in two
esterification of the known acid
9
[
10]
3 2 6 5
trifluoroacetate (CF CO C F
7
[
11]
steps following a literature procedure.
alcohol under almost neutral conditions (Ag
Methylation of the
O/MeI) afforded the
2
methyl ether product. Attempted hydrolysis of the ester under
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Angewandte Chemie International Edition
10.1002/anie.201705387
COMMUNICATION
OH
O
H
O N
2
With ample amounts of fragments 6–8 in hand, we
investigated the fragment coupling (Scheme 4). Reaction of
aniline 8 with cyclic anhydride 7 in toluene cleanly afforded a
a-c
O
O
OAc
HO
OH
1
2
1
3
2
.8:1 regioisomeric mixture of the ring-opened carboxylic acid
+
[
18]
products. The carboxylic acids from the ring-opening reaction
Ot-Bu
OH
O
d-f
H N
were esterified with trimethyl orthoacetate to form the
2
O N
2
O
[19]
corresponding methyl esters 17 and 17’.
The major product
O
HO 14
15
1
7’ was separated from its regioisomer by flash column
chromatography and was isolated in 69% yield. It was identified
g, h
to be the β-isomer of ring opening, as confirmed by X-ray
H N
NH2
analysis of
a
single crystal (Scheme
4 an supporting
2
[
20]
O
information).
Apparently, the additional methoxy group
O
O
changed the regioselectivity, which usually favours the α-isomer
HN
OAc
O
AcO
[
12a, 18]
in similar reactions of aspartic anhydride with anilines.
O
O
NH
O
i, j
gram scale
Ot-Bu
HN
8
k
O
t-BuO
O
cystobactamid 507 (3)
1
6
Scheme 3. Synthesis of fragment 8 and cystobactamid 507 (3). a) NaH, DMF;
-PrBr; Ac O (34%); b) NaNO , TFA, TFAA, DCM, −40 to 0 °C; c) Oxone®,
DMF (71%, 2 steps); d) Boc O, t-BuOH; piperidine; e) 2-PrI, K CO ; f) Pd/C,
(69%, 3 steps); g) (COCl) ; NaHCO (aq.); h) Pd/C, H (74%, 2 steps); i) 4-
NO PhCOCl, 2,6-lutidine (91%); j) Pd/C, H , (91%); k) HCl (conc.), then
Na CO , CH OH (95%).
2
2
3
2
2
3
H
2
2
3
2
2
2
2
3
3
OMe
CO t-Bu
2
O
MeO
HN
F3C
O
O
O
N
H
OAc
O
N
H
HN
O
O
H
N
HN
MeO
HN
F3C
a
H
N
O
O
7
+ 8
O
+
1
7/17’
1:2.8
O
17'
≡
=
17
OAc O
O
O
OMe
O
Ot-Bu
NH2
NH
2
1H⎻13C HMBC
1H⎻15N HMBC
H
MeO
presumably via
MeO
O
O
O
O
O
MeO
H N
AcHN
2
b
c
N
Ar
HN
N
H
HN
O
O
O
O
O
O
3
F C
HN
OH
HN
OAc
1
9
NH2
O
O
O
5
O
20
MeO R
18
4
1
HN
O
O
HN
d
HN
S
CO t-Bu
CO t-Bu
2
2
HN
O
O
O
N
O
H
HN
OH
2
O N
O
O
2
1: R = t-Bu
e
HN
4
: R = H
cystobactamid 919-2
CO R
2
Scheme 4. Fragment coupling and synthesis of cystobactamid 919-2 (4). a) toluene, rt; then MeC(OMe)
3
3
, 80 °C, 69% (isolated yield of 17’); b) NH (aq.), toluene,
0
°C to rt, 79% from 17’, 60% from 17; c) Ac O, pyridine, quantitative; d) 6, N-methylmorpholine, DMF, 83%; e) TFA, Et
2
3
SiH, 98%.
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Angewandte Chemie International Edition
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COMMUNICATION
Remarkably, aminolysis of either methyl ester 17 or 17’
exhibited very similar antibacterial activities against several
strains of bacteria to those of the natural product (Table 2).
3
using aqueous NH in toluene afforded the same major product,
primary amide 18, with concomitant removal of both the acetyl
and the trifluoroacetyl groups. We therefore conclude that the
reaction occurred via the aspartimide intermediate 19, a known
Table 2. Minimum inhibitory concentrations (MICs in µg/mL) of natural and
[a]
synthetic cystobactamid 919-2 and ciprofloxacin.
[
21]
complication in peptide synthesis.
A β-selective ring opening
Indicator strain
Cys919-2
Cys919-2
(synthetic)
ciprofloxacin
(
natural)
of 19 with NH then afforded 18, the structure of which was
3
1
13
1
15
elucidated by H– C- and H– N HMBC analysis of its acetate
A. baumannii DSM-30008
E. coli DSM-1116
4
4
4
8
0.5
0.013
1.5
derivative 20 (Figure S9−S13). The choice of organic co-solvent
3
is critical for this reaction. The reaction in THF or CH OH
became homogeneous and a significant amount of byproducts
formed, while the reaction in toluene became heterogeneous
and the product precipitated from the solution. Only a small
amount of by-products was observed under these basic
conditions. Separation of 18 from by-products by silica gel flash
column chromatography was found to be difficult, due to their
E. faecalis ATCC-29212
S. aureus ATCC-29213
0.5
0.25
0.5
0.25
0.2
[
a] MIC values were determined as described in ref. 4.
f
similar retention factors (R ), poor solubility and aggregation
[
22]
behaviour on column. It was found that trituration of the solid
product mixture with hexanes/ethyl acetate (1:1) could afford
analytically pure amine 18. Coupling of amine 18 with carboxylic
acid 9 under amide coupling conditions (i.e. EDC, HOBT) did not
afford a clean product due to the influence of the free phenolic
hydroxy group. However, coupling of 18 with the third fragment 6
occurred readily in DMF to give compound 21, and subsequent
The CD spectrum also matches the reported one, but,
surprisingly, the specific rotation [+68° (c = 0.047, CH OH); +46°
c = 0.10, CH Cl /CH OH 1:1); +24° (c = 0.33, THF)] is of the
opposite sign to that of the literature values [–14.3° (c = 0.057,
3
(
2
2
3
[
4]
[6]
3 3
CH OH); −14.4° (c = 0.08, CH OH) ], which originally lead the
Müller group, in combination with NOE data, to assign the
stereochemical configuration as shown for 1 and 2. Kim et al.
also observed discrepancies regarding the optical rotation data
and concluded that the “determination of the absolute
stereochemistry by optical rotation was difficult for
cystobactamids”. Even though cystobactamid 919-2 and
[
23]
removal of the t-butyl group with TFA
afforded acid 4.
1
13
The spectroscopic data ( H and C NMR, Figure S1−S3) of
synthetic 4 fully match with those of the natural cystobactamid
[
4,6]
9
19-2 in both CD
3
OD and DMSO-d
6
.
The NMR data of the β-
1
13
methoxyasparagine moiety are highly characteristic and listed in
Table 1.
coralmycins A have very similar spectroscopic data ( H,
NMR and CD) and proposed structures (see 4 and 5), opposite
C
[
6]
1
13
specific rotations were determined. A careful investigation of
our measurement showed that due to the low solubility of
cystobactamid 919-2 (4), trace amount of insoluble sample
greatly influenced the optical rotation. A consistent positive value
was obtained only after filtration of the solution. In addition, the
advanced intermediates in our synthesis also have positive
specific rotation values. Therefore, we propose that the absolute
configuration (2S, 3R) of cystobactamid 919-2 (4) is correct like
assigned by Kim et al, but the specific rotation value should be
revised. The CD spectrum and specific rotation (after filtration) of
an authentic sample confirmed our proposal (Figure S7). Indeed,
configurational analysis of cystobactamids is not trivial and
requires thorough examination. Consequently, total synthesis
was crucial to remove any possible doubts.
Table 1. Comparison of the H and C NMR spectroscopic data of β-
methoxyasparagine moiety in synthetic and natural cystobactamid 919-2.
position
1
2
3
4
5
synthetic
5.06,
d (7.4)
4.17,
d (7.4)
3.49,
s
a
Kim
Muller
synthetic
Kim
5.06,
d (8.0)
4.18,
d (8.0)
3.50,
s
δ
H
5.08,
d (7.4)
4.18,
d (7.4)
3.50,
s
NH
.49, d
4.92, t
(8.1)
4.10,
d (8.0)
NH
7.49/7.58
2
3.31,
s
8
8
8
b
NH
.46, d
4.92, t
(8.0)
4.09,
d (8.0)
NH
7.47/7.54
2
3.31,
s
δ
δ
H
Muller
NH
.46, d
4.92,
m
4.09,
d (7.9)
NH
7.48/7.55
2
3.31,
s
In summary, we have completed total syntheses of
cystobactamid 507 (3) and cystobactamid 919-2 (4). Our
synthesis unequivocally established both the correct structure
and absolute configuration of cystobactamid 919-2. The
convergent nature of our synthesis and scalable syntheses of
each fragment would also make the supply of compounds for
further biological study possible. Syntheses of other isomeric
natural products in this family and study of their structure-activity
relationship are in progress. Further “azologization” of these
natural products for photopharmacological studies will also be
synthetic
Kim
168.74
168.6
168.4
55.77
55.7
55.4
79.97
79.7
79.8
170.92
170.8
170.6
57.75
57.7
57.4
b
C
Muller
[
a] in CD
3
6
OD. [b] in DMSO-d .
1
For further confirmation, the NMR spectra ( H and 2D) and
HPLC co-injection of a mixed sample of synthetic and natural
cystobactamid 919-2 were also measured. Only one set of
peaks was observed (Figure S4−S6), thus confirming the identity
of the natural product. The synthetic cystobactamid 919-2 (4)
[
24]
investigated.
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Angewandte Chemie International Edition
10.1002/anie.201705387
COMMUNICATION
[
9]
Y. Wang, B. Schnell, S. Baumann, R. Müller, T. P. Begley, J. Am.
Chem. Soc. 2017, 139, 1742–1745.
Acknowledgements
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(
ERC Advanced Grant 268795 to D.T.) and the Deutsche
1
4, 3301–3312.
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assistance in H– N HMBC measurement, Dr. Stephan Hüttel
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the optical rotation and CD spectrum of the natural and mixing
samples, Dr. Viktoria Schmitt for the bioassay, and Dr. Frits
Kamp and Ms. Brigitte Nuscher for assistance in the
measurement of circular dichroism spectra. We also thank Mr.
Ben Williams for helpful discussions during the preparation of
this manuscript.
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Angewandte Chemie International Edition
10.1002/anie.201705387
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
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COMMUNICATION
A convergent total synthesis of the
Bichu Cheng,* Rolf Müller and Dirk
novel bacterial type IIa
R
Trauner*
NH
2
topoisomerases inhibitor
HN
O
MeO
HN
MeO
MeO
HN
O
O
cystobactamids 919-2 has been
achieved. Our synthesis confirmed the
correct relative and established the
absolute configuration of the unusual
peptide.
O
O
NH
3
N Ar
Page No. – Page No.
2
H N
O
HN
OMe
F
C
O
F
3
C
O
3
Total Syntheses of Cystobactamids
and Structural Confirmation of
Cystobactamid 919-2
R
NH
2
MeO
HN
R
O
O
HN
O
O
O
N
H
O
HN
OH
2
O N
O
cystobactamid 919-2
O
HN
COOH
Layout 2:
Page No. – Page No.
((Insert TOC Graphic here))
This article is protected by copyright. All rights reserved.