Synthesis of Natural Rubrolides B, I, K, L, M, O and Analogues

Article abstract of DOI:10.1002/ejoc.202100526

The chlorinated natural products, rubrolides B, I, K, L, M and O and analogues were synthesized in only five steps employing a robust and divergent synthetic strategy. The synthesis is performed without using protecting groups starting from a key intermediate, which can be synthesized from commercially available tetronic acid in only two steps. Selective halogenation and vinylogous aldol condensation enable the efficient synthesis of highly halogenated natural occurring rubrolides as well as synthetic analogues to build up a compound library for antiviral and antibiofilm testing. All synthesized compounds were then tested for their activity against the two influenza A virus strains pH1N1 and H3N2 as well as for their antibiofilm activity. Naturally occurring as well as synthetic analogues showed promising antiviral and antibiofilm activities.

Full text of DOI:10.1002/ejoc.202100526

Communications
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Synthesis of Natural Rubrolides B, I, K, L, M, O and
Analogues
Jessica de Vries,[a] Maik Assmann,[a] Jasmin Janneschütz,[a] Judith Krauß,[a] Mirja Gudzuhn,[b]
Stephanie Stanelle-Bertram,[c] Gülsah Gabriel,[c, d] Wolfgang R. Streit,[b] and
Nina Schützenmeister*[e]
In memory of Professor Dr. Dr. h.c. mult. Wittko Francke (1940–2020).
The chlorinated natural products, rubrolides B, I, K, L, M and O
Introduction
and analogues were synthesized in only five steps employing a
robust and divergent synthetic strategy. The synthesis is
performed without using protecting groups starting from a key
intermediate, which can be synthesized from commercially
available tetronic acid in only two steps. Selective halogenation
and vinylogous aldol condensation enable the efficient syn-
thesis of highly halogenated natural occurring rubrolides as
well as synthetic analogues to build up a compound library for
antiviral and antibiofilm testing. All synthesized compounds
were then tested for their activity against the two influenza A
virus strains pH1N1 and H3N2 as well as for their antibiofilm
activity. Naturally occurring as well as synthetic analogues
showed promising antiviral and antibiofilm activities.
Marine-derived tunicates have proven to be a valuable source
of natural products with distinct biological activities and
chemical features, which cannot be found in terrestrial
organisms.[1]
Rubrolides are a marine natural product class bearing so far
21 polysubstituted butenolides with β-aryl and γ-benzylidene
groups as substituents at the furanone core.[2–10] These small
molecules mostly differ in their halogenation grade at the
aromatic substituents except rubrolides E, R and S, which are
not halogenated at all. The biological activities of the members
of the natural product class range from antibacterial,[2,3,5,7] anti-
inflammatory,[4] antiviral[8,11] to aldose-reductase inhibition[10]
with a so far unknown mode of action. Most rubrolides contain
brominated phenol groups, and some also have a chloro
substituent in α-position of the furanone ring (Figure 1).
Some of the natural abundant rubrolides were already
synthesized employing various protocols,[11–25] since the bio-
logical activities, especially of higher halogenated rubrolides, is
considered promising for the discovery of novel antiinfective
agents. Therefore, a robust and divergent synthetic protocol for
the construction of a suitable substance library is highly
desirable. The synthetic strategy employs the synthesis of
privileged intermediates, which then can be transferred into
halogenated analogues by simple procedures. Intermediate 9
can be synthesized in two steps employing a robust Suzuki-
Miyaura cross-coupling reaction starting from tetronic acid
10.[11] This product 9 can be selectively chlorinated in 3-position
[a] J. de Vries, Dr. M. Assmann, J. Janneschütz, J. Krauß
Department of Chemistry, Institute of Pharmacy,
Universität Hamburg,
Bundesstrasse 45, 20146 Hamburg, Germany
[b] M. Gudzuhn, Prof. Dr. W. R. Streit
Department of Microbiology and Biotechnology,
Universität Hamburg,
Ohnhorststrasse 18, 22609 Hamburg, Germany
[c] Dr. S. Stanelle-Bertram, Prof. Dr. G. Gabriel
Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology,
Martinistrasse 52, 20251 Hamburg, Germany
[d] Prof. Dr. G. Gabriel
Institute for Virology, University for Veterinary Medicine Hannover,
Buenteweg 17, 30559 Hannover, Germany
[e] Prof. Dr. N. Schützenmeister
Department of Pharmaceutical Chemistry,
University of Vienna, Althanstrasse 14, 1090 Vienna, Austria
E-mail: nina.schuetzenmeister@univie.ac.at
https://pharmchem.univie.ac.at/home/research-groups/staff-members-
by-name/schuetzenmeister-nina/
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100526
Part of the “YourJOC Talents” Special Collection.
© 2021 The Authors. European Journal of Organic Chemistry published by
Wiley-VCH GmbH. This is an open access article under the terms of the
Creative Commons Attribution Non-Commercial NoDerivs License, which
permits use and distribution in any medium, provided the original work is
properly cited, the use is non-commercial and no modifications or adap-
tations are made.
Figure 1. Selected structures of natural rubrolides 1–6.
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Ass.-Prof. Dr. Nina Schützenmeister obtained her
Mirja Gudzuhn obtained her BSc in Biology in
2015 and her MSc in Molecular Biology and
Evolution in 2018, both in the group of Prof.
Schmitz-Streit at Kiel University (Germany). She
then started as a PhD student in the group of
Prof. Streit at the Universität Hamburg (Ger-
many) in 2018. Her research focuses on biofilm
PhD in the group of Prof. L. F. Tietze from the
Georg-August University Göttingen (Germany) in
2012. From 2012–2013 she was a postdoc in the
group of Prof. C. Griesinger (Göttingen, Ger-
many) and from 2013–2015 in the group of Prof.
V. K. Aggarwal FRS (Bristol, UK). From 2015–2020
she was Juniorprofessor at the Pharmaceutical
Institute of the Universität Hamburg (Germany)
and since 2020 she is Assistant Professor (TT) at
the Department for Pharmaceutical Science at
the University of Vienna (Austria). In 2021, she
received the Innovation Award for Medicinal and
Pharmaceutical Chemistry. Her research interest
focuses on the synthesis of antiviral and anti-
bacterial natural products for drug development.
research
with
the
model
organism
Stenotrophomonas maltophilia and strategies to
combat its biofilm.
Dr. Stephanie Stanelle-Bertram is a Senior Scien-
tist at the department Viral Zoonoses – One
Health at the Leibniz Institute for Experimental
Virology (HPI) in Hamburg. She studied Biology
at the Universität Hamburg and obtained her
PhD in 2011 at the Institute of Virology of the
Hannover Medical School (MHH) and the Leibniz
University of Hannover, Germany. From 2011–
2013 she held the position of Postdoctoral
Fellow within the Infection Biology Unit at the
German Primate Center, Göttingen. In 2012 she
received the Jürgen Wehland Preis awarded
from the German Helmholtz Center for Infection
Research (HZI), Braunschweig. Her research focus
is to understand influenza A virus and coronavi-
rus pathogenesis in animal models.
Jessica de Vries completed an apprenticeship as
biological-technical assistant in 2012 and worked
in the group of Dr. R. Meijers at the EMBL
Hamburg. Afterwards, she studied chemistry at
the Universität Hamburg, where she obtained
her BSc (2016) and her MSc (2019) in the group
of Prof. Dr. N. Schützenmeister. In 2019, she
started her Ph.D. at the Universität Hamburg and
2021 she moved to the University of Vienna. Her
research focuses on the synthesis as well as
biological testing of natural products.
Prof. Dr. Gülsah Gabriel is head of the depart-
ment Viral Zoonoses - One Health at the Leibniz
Institute for Experimental Virology (HPI) in Ham-
burg and professor for virology at the University
of Veterinary Medicine in Hannover. Her research
focus is to understand the molecular basis of
influenza A virus interspecies transmission and
its pathophysiology in high-risk groups. She has
received many prestigious awards for her re-
search, e.g. the Robert-Koch Förderpreis
awarded from the Robert-Koch Foundation, the
Best Minds Award from the Leibniz Association
and the DZIF Award for Translational Infection
Research from the German Center for Infection.
Gülsah Gabriel is Vice-president of the European
Scientific Working Group on Influenza (ESWI).
Dr. Maik Assmann studied chemistry at the
Philipps University at Marburg (Germany), where
he has done his bachelor thesis about the
boron-induced cross-coupling towards the bisin-
dole of Cladoniamide G in the group of Prof. Dr.
U. Koert. Afterwards, he successfully completed
his master’s degree with his thesis regarding
PNP-stabilized iron complexes in unusual oxida-
tion states under supervision of Prof. Dr. R.
Langer. For his PhD, he subsequently moved to
the UniversitätHamburg (Germany), where he
examined the synthesis of rubrolides and their
analogues in the group of Prof. Dr. N. Schützen-
meister. Since 2021, he is part of the R&D
department of Heliatek (Ulm; Germany) to
contribute to the development of organic solar
films.
Prof. Dr. Wolfgang Streit received his PhD in
Biology in 1994 from the University of Marburg,
Germany. From 1996–1997 he was a postdoc at
UC Davis, CA (USA). From there he moved to the
University of Göttingen, Germany where he did
his habilitation in 2002. He was associate
professor for enzyme biotechnology at the
University of Duisburg-Essen (Germany) from
2004–2006. In 2006, he was appointed as chair
of the department of Microbiology and Biotech-
nology at the UniversitätHamburg (Germany).
Research in the lab focuses on functional
metagenomics, biotechnology, bacterial genet-
ics, biofilm research and cell-cell communication.
Jasmin Janneschütz studied chemistry at the
Universität Hamburg (Germany). She obtained
her BSc in 2017 working in the group of Prof. Dr.
N. Schützenmeister and her MSc in 2019 in the
group of Dr. T. Hackl. In 2020, she started her
PhD in the group of Prof. Dr. N. Schützenmeister
in at the Universität Hamburg (Germany) and
recently moved to the University of Vienna
(Austria) to continue her studies on the total
syntheses of antiviral and antibacterial natural
products.
Judith Krauß obtained her Bachelor’s degree in
Chemistry at the Universität Regensburg (Ger-
many) in the group of Prof. Dr. J. Wegener in
2019. After a three-month research stay with Dr.
A. Wijeyesekera (Reading, UK) she joined the
group of Prof. Dr. N. Schützenmeister for
a
research internship at the Universität Hamburg
(Germany) to work on the synthesis of antiinfec-
tive compounds. Currently she is completing her
Master’s degree in Prof. Dr. J. Wegener’s group
at the Universität Regensburg in the fields of
bioanalytical chemistry and molecular biology.
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of the furanone ring. Further halogenation of the aromatic
substituent and final vinylogous aldol condensation with differ-
ent benzaldehyde derivatives will allow for the synthesis of α-
chlorinated members (7) of the natural product class and
further halogenated analogues without employing protecting
groups (Scheme 1).
Results and Discussion
The required β-aryl butenolide 9 starting from tetronic acid
10[26] were synthesized using a literature-known protocol.[11] The
privileged intermediate 9 was selectively chlorinated in α-
position of the furanone ring using substoichiometric amounts
of N-chlorosuccinimid (NCS) and triflic acid (TfOH) in dioxane to
yield butenolide 11 in 79%. Increase of the equivalents of NCS
to 2.5 equivalents yielded the dichlorinated compound 12 in
88%. Further chlorination of the aromatic substituent was not
observed. The synthesized compounds 11 and 12 were then
brominated using an adapted literature-known procedure,[14]
which gave inseparable mixtures. Selective monobromination
of 11 was achieved by treatment with 2.0 equivalents of Br2,
1.0 equivalents of KBr and 10 mol% of (nBu)4NBr in CH2Cl2
yielding 13 in 78%. For a selective monobromination the
absence of water is crucial. Otherwise, complex mixtures of the
mono- and dibrominated products 13 and 14 were observed.
Dibromination was achieved by increase of the equivalents of
Br2 to 3.0 and decrease of the quantity of KBr to a catalytic
amount of 10 mol% giving 14 in quantitative yield. In order to
achieve complete conversion towards the dibrominated prod-
uct, the presence of water was crucial and therefore, a solvent
mixture of CH2Cl2/water (6:1) was used. Also, the dichlorinated
intermediate 12 was brominated using (nBu)4NBr3 as mild
bromine source giving building block 15 in 96% yield
(Scheme 2).
Scheme 2. Synthesis of chlorinated butenolides 13–15: a) NCS (0.98 equiv.),
TfOH (1.1 equiv.), 1,4-dioxane, room temp., 16 h, 79%; b) NCS (2.5 equiv.),
°
TfOH (1.1 equiv.), 1,4-dioxane, 35 C, 16 h, 88%; c) Br2 (2.0 equiv.), KBr
°
(1.0 equiv.), (nBu)4NBr (10 mol%), CH2Cl2, 90 C (microwave), 3 h, 78%; d) Br2
°
(3.0 equiv.), KBr (10 mol%), CH2Cl2/H2O (6:1), 60 C (microwave), 1 h, quant.;
°
e) (nBu)4NBr3 (1.2 equiv.), MeOH, 60 C (microwave), 1 h, 96%.
With the β-aryl butenolides 13–15 in hand, a vinylogous
aldol condensation between commercially available benzalde-
hyde derivatives 16–18 was employed in order to synthesize
the naturally occurring rubrolides B 1, I 2, K 3, L 4, M 5, O 6 and
nine
rubrolide
analogues
19–27.
As
reported
previously,[11,13,14,15,18] the vinylogous aldol condensation was
conducted in a three-step one-pot synthesis, using TBSOTf,
DIPEA (a) or Et3N (b) as base depending on the desired
°
derivative and CH2Cl2 at 0 C for 30 min in the first step.
Afterwards, the p-hydroxy benzaldehyde derivative (16, 17 or
18) is added to the reaction mixture and stirred for another
24 h at room temperature. Finally, DBU and H2O were added,
and the mixture was stirred for another 16 h (Scheme 3).
The aldol reaction delivered the rubrolides and their
analogues as E/Z-mixtures, which were separated in order to
obtain the pure Z-isomer. The double bond configuration was
analyzed by NOESY experiments. In addition, the structures of
rubrolide I 2, K 3, O 6, and analogues 21–24 were unambigu-
ously determined using single-crystal X-ray crystallography
(Scheme 3).
Biological Evaluation
Rubrolides B 1, I 2, K 3, L 4, M 5, O 6 and the synthesized
analogues were tested for their antibiofilm and antiviral proper-
ties. Investigating the reduction of virus replication of two
different influenza A virus subtypes[28,29] and biofilm formation
of Stenotrophomonas maltophilia.[30–32] For the virus inhibition,
MDCK (Madin-Darby canine kidney) cells were infected with
pH1N1 or H3N2 influenza A viruses and cotreated with Ribavirin
Scheme 1. Retrosynthesis of chlorinated rubrolides.
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°
Scheme 3. Vinylogous aldol condensation: a) TBSOTf, DIPEA, CH2Cl2, 0 C, 30 min, then p-hydroxy benzaldehyde derivative (16–18), room temp., 24 h, then
°
DBU/H2O, room temp., 16 h; b) TBSOTf, NEt3, CH2Cl2, 0 C, 30 min, then p-hydroxy benzaldehyde derivative (16–18), room temp., 24 h, then DBU/H2O, room
temp., 16 h. X-ray crystal structures: Thermal ellipsoids are shown at 50% probability level. Hydrogen atoms are omitted for clarity.
or the synthesized rubrolides (for all data see Supporting
Information). The viral titer of infected and PBS (phosphate
buffer saline) (Ctrl 1) or 0.1% DMSO (Ctrl 2) treated cells served
as negative control. Data are shown as logarithmic mean of
plaque forming units/mL (log p.f.u./mL) with standard deviation
of three independent experiments (Figure 1). Rubrolides 5, 19,
22, 26 and 27 were pretested and showed cytotoxic effects
towards MDCK cells (for all data see Supporting Information).
Rubrolides 3, 4, 20 and 23 showed significant reduction of 1–
3 log steps compared to the controls for both influenza A virus
strains. Rubrolides 3 and 4 showed a cytotoxic effect at 100 μM
when testing H3N2 influenza A virus, still having a significant
reduction of the virus titer at 1–10 μM. Very good reduction of
pH1N1 was also observed for 4 with a reduction of virus titer of
3 log steps. Rubrolide 20 showed a reduction by 2 log steps for
H3N2 virus replication. A complete inhibition of virus replication
was observed with a concentration of 100 μM 3 at total cell
viability. To our delight, the rubrolides were even more effective
against the virus replication of pH1N1 then H3N2. The treat-
ment of the cells and virus with ribavirin, which is a guanosine
analog and used as inhibitor for viral RNA synthesis, did not
result in a significant reduction of virus replication anymore due
to development of resistances (Figure 2).
Furthermore, all synthesized natural rubrolides B 1, I 2, K 3,
L 4, M 5, O 6 and their synthetic analogues 19–25 and 27 had a
significant antibiofilm activity against Stenotrophomonas malto-
philia K279a. The treatment of S. maltophilia biofilms is very
important since it is an emerging and highly multidrug resistant
pathogen, which is often co-isolated from wounds, catheters
and other medical devices together with P. aeruginosa, S. aureus
and other relevant pathogens.[32,33] The strongest effect was
achieved by rubrolide B 1, which reduced the biofilm formation
by 84.6�15.0% at 100 μg/mL. The biofilm was analyzed as
previously described.[32–34]
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Figure 2. Plaque reduction assay of rubrolides 3, 4, 20 and 23 on virus replication. MDCK cells were infected with either H3 N2 (A) or pH1 N1 (B) influenza
virus. Sample concentration measured in 1–100 μM. Results of three independent experiments. Ctrl 1 – untreated; Ctrl 2 – 0.1% DMSO added, n.p. – no
plaques detected, × – no viable cells detected.
Keywords: Antiviral agents · Halogenation · Natural products ·
Rubrolides · Total synthesis
Conclusion
In summary, the syntheses of the natural products rubrolide
B 1, I 2, K 3, L 4, M 5, O 6 as well as their synthetic analogues
19–27 were reported with satisfying total yields over five steps
starting from tetronic acid. Furthermore, the structures of
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sized compounds showed promising antiviral activities for 3, 4,
20, 23 against the seasonal flu H3N2 as well as the pandemic
swine flu virus pH1N1. Furthermore, rubrolides B 1, I 2, K 3, L 4,
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The authors declare no conflict of interest.
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