Total Synthesis and Structural Reassignment of Aspergillomarasmine A

Article abstract of DOI:10.1002/anie.201509960

The increase and spread of Gram-negative bacteria that resistant are to almost all currently available β-lactam antibiotics is a major global health problem. The primary cause for drug resistance is the acquisition of metallo-β-lactamases such as metallo-β-lactamase-1 (NDM-1). The fungal natural product aspergillomarasmine A (AMA), a fungal natural product, is an inhibitor of NDM-1 and has shown promising in vivo therapeutic potential in a mouse model infected with NDM-1-expressing Gram-negative bacteria. The first total synthesis and stereochemical configuration reassignment of aspergillomarasmine A is reported. The synthesis highlights a flexible route and an effective strategy to achieve the required oxidation state at a late stage. This modular route is amenable to the efficient preparation of analogues for the development of metallo-β-lactamase inhibitors to potentiate β-lactam antibiotics.

Full text of DOI:10.1002/anie.201509960

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International Edition: DOI: 10.1002/anie.201509960
German Edition: DOI: 10.1002/ange.201509960
Antibiotics
Total Synthesis and Structural Reassignment of
Aspergillomarasmine A
Daohong Liao+, Shaoqiang Yang+, Jianyu Wang, Jian Zhang, Benke Hong, Fan Wu, and
Xiaoguang Lei*
Abstract: The increase and spread of Gram-negative bacteria
that resistant are to almost all currently available b-lactam
antibiotics is a major global health problem. The primary
cause for drug resistance is the acquisition of metallo-b-
lactamases such as metallo-b-lactamase-1 (NDM-1). The
fungal natural product aspergillomarasmine A (AMA),
a fungal natural product, is an inhibitor of NDM-1 and has
shown promising in vivo therapeutic potential in a mouse
model infected with NDM-1-expressing Gram-negative bac-
teria. The first total synthesis and stereochemical configuration
reassignment of aspergillomarasmine A is reported. The syn-
thesis highlights a flexible route and an effective strategy to
achieve the required oxidation state at a late stage. This
modular route is amenable to the efficient preparation of
analogues for the development of metallo-b-lactamase inhib-
itors to potentiate b-lactam antibiotics.
Several effective small-molecule inhibitors of serine-lacta-
mases are clinically available, such as clavulanic acid and
sulbactam, and these are used in combination with b-lactam
antibiotics.[6] The second class is metallo-b-lactamases
(MBLs), such as New Delhi metallo-b-lactamase-1 (NDM-
1),[7] which are ZnII-dependent enzymes. Unfortunately, no
corresponding inhibitors for MBLs have so far been devel-
oped for clinical use.[8] Given the recent emergence of MBLs
as a major driving force for the rapid spread of resistance in
Gram-negative bacteria, which is significant clinical threat,[9]
there is a pressing need for the development of potent and
safe small-molecule inhibitors of MBLs.
Natural products have played a central role in antibiotic
drug discovery,[10] which is further emphasized by the
identification of the fungal natural product aspergillomaras-
mine A (AMA) as a potent inhibitor of NDM-1.[11] In 2014,
Wright and co-workers reported that AMA could overcome
metallo-b-lactamase antibiotic resistance by inhibiting NDM-
1 (IC50 = 4.0 Æ 1.0 mm).[11a] AMA also showed good selectivity
for MBLs over serine b-lactamases. Moreover, AMA has
shown promising in vivo therapeutic potential in a mouse
model infected with NDM-1-expressing Gram-negative bac-
teria.[11a]
AMA was originally identified and characterized in the
early 1960s.[12] The molecule was first evaluated for its
inhibitory effect against human angiotensin-converting
enzyme (ACE).[13] Notably, the three stereogenic centers of
the original structure 1, proposed by Lederer and co-workers,
were determined to be (2’’R,2’R,2S) on the basis of degra-
dation studies, as well as the fact that both the 2’ and 2’’ amino
groups of AMA are unreactive to Crotalus adamantus l-
amino acid oxidase and are therefore derived from d-amino
acids (Figure 1).[12] All of the following studies on this natural
product adopted this originally proposed structure (1). Møller
and co-workers have since suggested that AMA might have
(2’’S,2’S) configurations at C2’ and C2“ based on their
biosynthetic studies.[14] However, no direct and conclusive
evidence supported their hypothesis. Therefore, total syn-
thesis represents the only practical means by which the
S
ince the landmark discovery of penicillin in 1928, anti-
biotics have become one of the most successful forms of
chemotherapy in the history of human medicine.[1] However,
the increase and spread of antibiotic resistance has become
a severe global public health problem in the past two
decades.[2] Among the most important and widely used classes
of antibiotics, the b-lactams, which include penicillins, ceph-
alosporins, and carbapenems, account for about half of all
antibacterial drugs prescribed, and are essential for the
treatment of serious infections caused by Gram-negative
bacteria.[3] However, bacteria have developed a number of
mechanisms to generate significant resistance against b-
lactams, such as the acquisition of b-lactamases, enzymes
that hydrolyze the b-lactam ring.[4] There are two major types
of b-lactamase. The first class comprises serine-dependent
enzymes, such as extended-spectrum b-lactamase (ESBL).[5]
[*] D. Liao,[+] S. Yang,[+] J. Wang, J. Zhang, B. Hong, F. Wu, Prof. Dr. X. Lei
Beijing National Laboratory for Molecular Sciences, Key Laboratory
of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education, Department of Chemical Biology
College of Chemistry and Molecular Engineering
Synthetic and Functional Biomolecules Center
and Peking-Tsinghua Center for Life Sciences
Peking University, Beijing 100871 (China)
E-mail: xglei@pku.edu.cn
Homepage: http://www.chem.pku.edu.cn/leigroup/
S. Yang,[+] B. Hong
School of Pharmaceutical Science and Technology, Tianjin University
Tianjin 300072 (China)
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201509960.
Figure 1. Proposed (1) and revised (2) structures of aspergillomaras-
mine A.
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correct structure of AMA can be elucidated unambigu-
ously.[15] Herein, we report the first total synthesis of AMA
through a modular approach that is amenable to derivatiza-
tion for analogue synthesis. Our synthetic studies also enabled
us to revise the originally proposed structure of AMA
(Figure 1).
commercially available 2-butene-1,4-diol in 43% yield over
four steps,[18] to afford aldehyde 12 in 85 % yield with93% ee
(Scheme 2).[19] Reductive amination of aldehyde 12 with the
The chemical syntheses of AMA and related natural
products have proven to be challenging. The Ohfune group
has investigated the total synthesis of this family of natural
products.[16] Unfortunately, they failed to achieve the total
synthesis of AMA.[16a] As depicted in Scheme 1A, Ohfune
Scheme 2. Attempted synthesis of AMA from alkenes. IBX=2-iodoxy
benzoic acid, CbzCl=benzyl carbonochloridate, EA=ethyl acetate.
known amine 13, which was obtained from commercially
available material in three steps with 65% yield and 99%
ee,[20] and subsequent in situ Cbz protection of the newly
formed secondary amine moiety smoothly generated diol 14
in 51% yield over two steps. Oxidative cleavage of diol 14
with NaIO4 in a mixture of THF and H2O provided the crude
aldehyde 15, which was used directly in the next reductive
Scheme 1. Previous synthetic studies and our synthetic plan.
and co-workers successfully coupled three amino acid equiv-
alent building blocks, including d-serine derivative 3 and an
l-aspartic acid derivative to afford diol 4, but they were
unable to achieve the late-stage oxidation of both hydroxy
groups of 4 and were only able to produce 5, despite
examination of various oxidation conditions.[16a]
t
amination step involving treatment with either Bn- or Bu-
protected aspartic acids 16 and 17, respectively. Unfortu-
nately, all of these attempts failed to deliver the desired
product 18. Instead, during the reductive amination process,
we always observed a complex mixture of byproducts. Based
on the preliminary NMR and LC–MS analysis, we postulated
that the major byproduct might be 19, which was presumably
generated via dienamine 20 through migration of the terminal
double bond under acidic conditions, followed by sequential
1,4- and 1,2-reductions of the iminum species.
In order to avoid the alkene isomerization problem, we
proposed that diol 9 may be a better carboxylic acid synthon.
Accordingly, the revised synthetic route commenced with
Dess–Martin oxidation of the reported chiral alcohol 21,
which was obtained from commercially available 4,4-
Dimethyl-3,5,8-trioxabicyclo[5.1.0]octane in four steps with
50% yield and 99% ee,[21] to afford the desired aldehyde 22
(Scheme 3). To our delight, the first reductive amination
between aldehyde 22 and the readily available amine 13
proceeded smoothly to furnish the desired amine 24 without
any racemization (within our limits of detection). Compound
24 was protected in situ with Cbz to afford 25 in 74% yield
over three steps. The free diol moiety of 25 was subsequently
protected with 2,2-dimethoxylpropene to generate alkene 26
in 95% yield. Ozonolysis of the alkene efficiently afforded
We therefore recognized during our synthetic planning
that the selection of suitable carboxylic acid precursors would
be critical. The presence of a carboxylic acid group from an
early stage was precluded by the expected racemization of
compound 6 during oxidation from serine 7. Consequently, we
decided to use alkene 8 and protected diol 9 as carboxylic acid
synthons to be unmasked after conjugation of the three amino
acid derivatives (Scheme 1B). The strategy for N-alkyl bond
formation was also carefully considered: the presence of
several nitrogen atoms in a target molecule is known to
complicate total syntheses owing to the basicity of nitrogen
atoms and their susceptibility to oxidation.[17] We envisaged
that reductive amination would serve as the key conjugation
reaction. The mild reaction conditions would prevent race-
mization and facilitate sequential transformations with min-
imal requirements for workup and purification. The selection
of suitable protecting groups would be essential for the
success of the synthesis, considering the presence of various
polar and reactive functionalities.
Our initial attempts began with IBX oxidation of the
readily available chiral alcohol 11, which was prepared from
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Scheme 3. Total synthesis and structural reassignment of aspergillomarasmine A. DMP=Dess–Martin periodinane, (+)-CSA=(+)-camphorsul-
fonic acid, 2,2-DMP=2, 2-dimethoxylpropene, Jones reagent=a solution of chromium trioxide in dilute sulfuric acid and water.
the crude aldehyde, which was directly used for the following
reductive amination with Bu-protected aspartic acid 17 to
promote the deprotection process. Ultimately it was discov-
ered that treatment of 30 with CF3SO3H[22] and anisole in
dichloromethane effected a clean and complete global
deprotection in one vessel to afford the desired (R,R,S)-
AMA (1) in 95% yield. We anticipate that this mild and
robust global deprotection method will find further applica-
tions in peptide synthesis.
t
generate amine 27, followed by in situ Cbz protection to
afford 28 in 46% yield over three steps. Selective removal of
two acetonide groups with AcOH afforded tetraol 29 in 70%
yield. Subsequent oxidative cleavage of the vicinal diol group
with NaIO4 in a mixture of acetone and H2O furnished the
crude aldehyde intermediate, which was oxidized using the
Jones reagent to generate the desired di-acid 30 in 36% yield.
With compound 30 in hand, we were in a position to
complete the synthesis after global deprotection to remove
the three Cbz groups and two tert-butyl groups (Scheme 3).
However, this process proved challenging. Initially, we sought
to remove the tert-butyl groups with TFA to generate the
desired tetra-acid first, followed by hydrogenolysis of the Cbz
group with a Pd catalyst. A number of conditions (Pd black,
Pd/C, Pd(OH)2/C, etc.) were examined, yet few were success-
ful. We then decided to explore the possibility of removing
both the tert-butyl and Cbz groups under acidic conditions. A
variety of acids, including CH3SO3H, HCl, CF3COOH,
CF3SO3H, and AlCl3, were surveyed for their ability to
Unfortunately, the 1H and 13C NMR spectra, as well as the
optical rotation value of synthetic (R,R,S)-AMA (1) were not
identical to those reported for the natural product,[11a,19] which
suggested that structural reassignment is required. In agree-
ment with Møller and co-workersꢀ suggestion that C2’ and
C2’’ of aspergillomarasmine A have an S configuration, we
postulated that AMA has the revised (S,S,S) structure 2.
Accordingly, we conducted the chemical synthesis of the
proposed new structure for AMA by following our previously
established synthetic route (Scheme 3). As a result, (S,S,S)-
AMA (2) was efficiently generated from ent-21. To our
delight, synthetic (S,S,S)-AMA (2) exhibited 1H and 13C NMR
spectra indistinguishable from those reported for the natural
isolate.[11a,19] In addition, the optical rotation value of 2
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([a]D23 = À51.2, c = 0.8, pH 7 phosphate buffer) was consis-
Acknowledgements
tent with that of the natural product ([a]D20 = À48, c = 1, pH 7
phosphate buffer), which unambiguously establishes the
absolute configurations of AMA. Moreover, we applied the
same synthetic route to obtain the other two possible isomers
(R,S,S)-AMA and (S,R,S)-AMA. The 1H and 13C NMR
spectra of these two isomers did not fully match those of
the natural isolate.[19] Collectively, the results unambiguously
show that the configuration of AMA should be reassigned as
(S,S,S).
We thank Prof. Gerard Wright (McMaster University) for
generously providing us the authentic natural product sample
for spectra comparison. We also thank Dr. Alexander Jones,
Dr. Chao Li, and Dr. Houhua Li for helpful discussions, as
well as Prof. Changwen Jin and Prof. Hongwei Li (Peking
University) for the assistance with 600 MHz NMR analysis.
Financial support from the National High Technology Project
973 (2015CB856200) and NNSFC (21222209, 91313303, and
21472010) is gratefully acknowledged.
Wright and co-workers have demonstrated that the
natural product AMA has good in vitro dose-dependent
inhibition against metallo-b-lactamase NDM-1 and related
MBLs such as VIM-2.[11a] To validate the NDM-1 inhibition
activity of our synthetic samples, we performed an enzyme
inhibition assay with the purified NDM-1 protein and nitro-
cefin as a substrate (Figure 2).[19] As expected, the revised
Keywords: antibiotics · aspergillomarasmine A ·
metallo-b-lactamase · structural reassignment · total synthesis
How to cite: Angew. Chem. Int. Ed. 2016, 55, 4291–4295
Angew. Chem. 2016, 128, 4363–4367
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dependent inhibition of NDM-1. Interestingly, the originally
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NDM-1 whatsoever. Thus, both our biological and chemical
studies confirm that natural AMA should have the reassigned
structure 2. Furthermore, this interesting result provides
initial leads for the development of more effective AMA-
derived antibiotics.
In summary, we have accomplished the first total synthesis
of the natural product aspergillomarasmine A, a potent and
selective inhibitor of NDM-1. In the course of our synthetic
studies, we reassigned the stereochemical configurations of
the originally proposed structure of AMA. The structurally
revised synthetic AMA was confirmed to have same inhib-
itory effect on NDM-1 as the naturally occurring AMA. We
have also developed an effective late-stage oxidation strategy
and a robust global deprotection method that might find
further synthetic application in peptide natural product
synthesis. Notably, our synthesis features a convergent, flex-
ible, and stereocontrolled route that is amenable to the
efficient preparation of analogues. Studies towards the
development of more potent and selective metallo-b-lacta-
mase inhibitors based on AMA are currently ongoing in our
laboratory.
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Received: October 25, 2015
Published online: November 23, 2015
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