Total Synthesis of the Ambigols: A Cyanobacterial Class of Polyhalogenated Natural Products

Article abstract of DOI:10.1021/acs.orglett.0c03784

The first total synthesis of all members of the cyanobacterial natural product class of the ambigols is described. Key steps of the synthetic strategy are the formation of sterically demanding mono- and bis-iodonium salts to install the required biaryl ether structural elements and Suzuki cross-coupling giving straightforward access to the biaryl bonds. The synthetic methods are also utilized to construct unnatural or hypothetical ambigols that are still awaiting discovery from Nature.

Full text of DOI:10.1021/acs.orglett.0c03784

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Letter
Total Synthesis of the Ambigols: A Cyanobacterial Class of
Polyhalogenated Natural Products
Tobias M. Milzarek and Tobias A. M. Gulder*
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ABSTRACT: The first total synthesis of all members of the
cyanobacterial natural product class of the ambigols is described.
Key steps of the synthetic strategy are the formation of sterically
demanding mono- and bis-iodonium salts to install the required
biaryl ether structural elements and Suzuki cross-coupling giving
straightforward access to the biaryl bonds. The synthetic methods
are also utilized to construct unnatural or hypothetical ambigols
that are still awaiting discovery from Nature.
Fischerella ambigua6 or structurally related polybrominated
diphenyl/s ethers (6 and 7, PBBs/DEs) from the marine γ-
proteobacteria Pseudoalteromonas spp.7 All these compounds
not only bear multiple chlorine/bromine substituents but also
have biaryl (Scheme 1, yellow) and/or biaryl ether (Scheme 1,
blue) structural elements in common. We have previously
shown that two cytochrome P450 enzymes, ab2 and ab3,
which are part of the 14.3 kb ab biosynthetic gene cluster,
selectively install these structural features found in the
ambigols using dichlorophenol building blocks (Scheme 1a),8
olychlorinated organic compounds are known not only for
Ptheir structural and functional diversity but also for their
negative environmental impact.1 Compounds such as the man-
made polychlorinated diphenyl ethers (PCDEs) and biphenyls
(PCBs) accumulate as persistent and bioaccumulative
substances in the human food chain and can ultimately lead
to deleterious health effects in animals and humans, e.g.,
causing liver damage, teratogenicity, and immunotoxicity.2−5
In addition to chlorinated substances of anthropogenic
origin, Nature offers diverse biological sources, such as the
ambigols (1−5, Figure 1) from the terrestrial blue-green alga
Scheme 1. (a) Biosynthetic Assembly of Ambigols A (1) and
B (2) and (b) Retrosynthetic Analysis
Received: November 13, 2020
Figure 1. Structures of natural products produced by the terrestrial
cyanobacterium Fischerella ambigua (1−5) and the marine γ-
proteobacteria Pseudoalteromonas spp. (6, 7).
© XXXX The Authors. Published by
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a
Scheme 2. Synthesis of Ambigol A (1) and B (2)
a
C−O−C biaryl ether (blue) and C−C biphenyl (yellow) bond formation.
in analogy to previous work by Moore et al. on PBDE
biosynthesis.9
applied in PBDE synthesis.16,17 Most importantly, these
hypervalent iodine compounds are directly accessible by one-
pot reactions by oxidation of the corresponding iodinated
precursor (hence giving fast access to all required regioiso-
meric iodonium salts), are stable, and can be readily purified
due to their high polarity.18−21 This compound class is thus
perfectly suited for a streamlined synthesis of all ambigols.
The route to ambigols A (1) and B (2) started with the
selective ortho double iodination of 3,5-dichlorophenol (8) by
electrophilic aromatic substitution (SEAr) using NaH/I2 to
give 9 in 56% yield.22 After O-protection of the aryl diiodide 9
using potassium carbonate and iodomethane (97%), oxidation
of 10 using mCPBA, p-toluenesulfonic acid, and trimethoxy-
benzene (TMB) provided direct access to bisiodonium salt 12
in 80% yield.23−26 The following arylation reaction of 12 with a
nucleophile (here phenol 13) takes place via a T-shaped Ar2I-
Nu intermediate, leading to an aryl iodine side product and the
desired biaryl ether by reductive elimination.27,28 When using
λ3-iodonium salt with unsymmetric substitution at the
iodonium center(s), such as 12, two theoretical T-shaped
intermediates are possible. However, chemoselectivity studies
have shown that in general the less electron-rich and/or
sterically demanding aryl group (ortho effect) is transferred to
the nucleophile.28 Accordingly, when subjecting 12 to an aryl
transfer reaction with 2,4-dichlorophenol (13) as the
nucleophile, the central 3,5-dichlorophenol of 12 is transferred
to the nucleophile with the electron-rich trimethoxybenzene
serving as a “dummy group”. The aryl transfer reaction led to
the monoarylated main product 14 in 65% yield and the
double-arylated trimeric 15 in 27% yield (Scheme 2). This
reaction thus conveniently gave access to the two central
intermediates 14 and 15 for ambigol A (1) and B (2)
synthesis, respectively. Deprotection of 15 by BBr3-mediated
O-demethylation delivered 2 in 76% yield. The formation of
the biphenyl bond present in ambigol A (1) was realized by
Suzuki reaction. The reaction conditions were initially
optimized for such electronically demanding substrates using
a structurally related model system (coupling of 1,5-dichloro-3-
iodo-2-methoxybenzene to (3,5-dichlororo-2-methoxyphenyl)
boronic acid; see Supporting Information, Chapter 2.3) by
The ambigols are interesting not only from a structural point
of view but also in terms of biological effects. Ambigol A (1) is
a strong inhibitor of cyclooxygenase (in the range of the drug
indometacin), a relevant activity in the development of
nonsteroidal antirheumatic drugs.6 In addition, 1 exhibits
antibiotic (against B. megaterium and subtilis), antiviral (HIV-1
reverse transcriptase inhibition), and cytotoxic (L6 myoblast
cells) activities. Interestingly, ambgiol B (2) shows generally
lower biological activities in the above indications.10 Ambigol
C (3), which is structurally very similar to 2, but with a
different substitution pattern at the central building block,
exhibits strong antibacterial activity against B. megaterium
(IC50: 7.0 ng/mL) and has weak antiplasmodial and
trypanocidal effects.11 Ambigols D (4) and E (5), which
were recently isolated by Niedermeyer et al., were shown to
increase prodigiosin production in Serratia spp.12 In-depth
investigations of all these biological effects are impeded by low
production titers and long fermentation times (30 to 40 days
of incubation) of the natural producer F. ambigua. Synthetic
access to the ambigols has the potential to solve these
problems and to enable future functional evaluation of this
interesting natural product class. We thus set out to develop
chemical routes to all known ambigols.
Results and Discussion. From a synthetic perspective, the
biaryl cross-links in the ambigols can be established by
transition-metal catalyzed cross-coupling reactions. In the
structurally related but only dimeric PBBs and PBDEs (e.g.,
6 and 7, Figure 1) this was successfully achieved by Suzuki
cross-coupling reactions (Scheme 1b, yellow),12,13 thus also
rendering this the method of choice for ambigol assembly. For
the installation of the biaryl ether bonds a number of different
established reactions is available. This includes copper-
catalyzed Ullmann coupling, palladium-catalyzed Buchwald−
Hartwig reaction, and nucleophilic aromatic substitution
(SNAr).14,15 In this work, the formation of the biaryl ether
bonds by aryl transfer reaction using electrophilic λ3-iodonium
salts was applied. The use of iodonium salts in aryl transfer
reactions offers many advantages and has also successfully been
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Scheme 3. Dual Approach for the Total Synthesis of Ambigol C (3) and C−C Coupled Analogue 30
extensive screening of the catalyst system, base, solvent, and
additives (Table S1). The reaction outcome was evaluated
after 24 h by HPLC analysis (Figure S1). In summary,
approximately 60% of the tested reaction conditions resulted in
exclusive substrate protodeboronation. Product formation was
observed with PdCl2(dppf) or Pd2(dba)3 in combination with
phosphine ligands as the catalyst system and 1,4-dioxane as the
solvent (Table S1, entries 14, 15, 17, 18, 22, 23). However,
protodeboronation was also observed in these reactions. Use of
Pd2(dba)3 and DavePhos showed the best results (Tables S1,
entry 23). The reaction was performed with silver(I) oxide as
the additive to increase the transmetalation rate of Pd and to
facilitate halogen-hydroxide exchange.29,30 The ambigol A
precursor (17) was obtained in a yield of 41% (55% based on
reisolated starting material = brsm). Final O-demethylation of
17 with BBr3 delivered ambigol A (1) in a yield of 95%.
Ambigol A (1) and other members of this natural product
family contain biaryl axes with three ortho substituents, which
might thus be rotationally stable. As this aspect has not been
covered in the literature, we set out to test rotational stability,
exemplarily for 1. Sufficient separation of the atropoisomers
indeed succeeded by HPLC on chiral reversed-phase material
at low temperature (5 °C; see Supporting Information),
permitting isolation of enriched fractions of both rotational
isomers. Reanalysis of this material under identical chromato-
graphic conditions over time revealed a fast equilibration
within only 1−2 h at room temperature (Figure S96).
Ambigol C (3) was accessible in analogy to ambigol B (2),
by using 2,4-dichloro-1,5-diiodo-3-methoxybenzene (21) in
the formation of the symmetric bisiodonium salt 22 (Scheme
3). The starting material can be obtained in 74% yield from a
double directed silylation of anisole 20 followed by
iododesilylation with iodine chloride.31,32 The subsequent
aryl transfer with the iodonium salt led to 66% of the
monoarylated species 23 and to only 4% of the desired
diarylated intermediate 24. The latter was O-demethylated
with BBr3 furnishing ambigol C (3) in 75% yield. To our
surprise, the NMR data of synthetic 3 were markedly different
from the published data of the corresponding natural
product.10 In particular, the chemical shift at position 4
showed significant differences: δH = 6.01 ppm, δC = 101.9 ppm
(reported: δH = 7.18 ppm, δC = 121.8 ppm). Interestingly, the
reported shifts at that position correspond almost perfectly to
the signals found in ambigol B (2) (Supporting Information
(SI), Chaper 2.2). However, in-depth 2D NMR analysis (see
SI, Figures S33−35) of synthetic 3 was in good agreement with
the targeted published natural product structure. Given the
differences in NMR data of synthetic and published 3, along
with the unsatisfactory low yield in the aryl transfer reaction,
we decided to establish an additional, alternative route to 3 for
unambiguous structural verification. The starting material 26
for this approach was obtained by esterification of
phloroglucinol (25) with acetyl chloride under basic
conditions. However, almost only the triacetylated product
was obtained when the reaction was carried out at room
temperature. Heating the reaction shifted the product outcome
in favor of the mono- (26, 18%, 30% brsm) and diacetylated
compound (26%, 40% brsm). Regioselective chlorination of
monoacetylated phloroglucinol (26) with N-chlorosuccinimide
(NCS) in hexafluoro-2-propanol (HFIP) delivered dichlori-
nated compound 27 (30% yield, 70% brsm).33 This reaction
had to be stopped prior to completion to circumvent
increasing formation of the trichlorinated byproduct over
time (15% after 22 h). The final aryl transfer using 2,4-
dichloro-1-iodobenzene-containing iodonium salt 28 directly
provided ambgiol C (3) in a yield of 14%. The analytical data
of 3 from both synthetic routes matched perfectly, hence firmly
corroborating that the published structure of 3 was indeed
synthesized. Despite the low overall yield of the second
synthesis of 3, it is an important alternative to the route using
bisiodonium salt 22, particularly due to low step count and
cheap starting materials.
The main product of the aryl transfer reaction of 22 and 13,
biaryl ether 23, was readily converted into a new ambigol
analogue 30. This was achieved by Suzuki coupling to give 29
followed by O-demethylation with BBr3, delivering ambigol
analogue 30 in 43% yield over two steps.
The total synthesis of ambigol D (4) commenced with 1,3-
dichloro-2-iodo-5-methoxybenzene (31) which was synthe-
sized as described previously (Scheme 4A).8,34 The regiose-
lective iodination to 32, its conversion into bisiodonium salt
33, aryl transfer reaction to 34, Suzuki coupling to 35, and final
methoxy deprotection to ambigol D (4) was performed in
analogy to ambigol A−C (1−3) synthesis. The selective
formation of the monoarylated 34 can be achieved by adjusting
the stoichiometry of 2,4-dichlorophenol (13) and 33.
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Scheme 4. Total Synthesis of Ambigol D (4) and E (5)
Scheme 5. Synthesis of the Structural Analogue 47 Only
Consisting of 2,4-Dichlorophenol Units
compound 43. Upon deacetylation to 44 in 92% yield, the
liberated phenol is arylated using iodonium salt 28, analogous
to ambigol C (3) and E (5) synthesis, to furnish biaryl ether
45 in 46% yield. In the last two steps, biaryl bond formation by
Suzuki coupling to 16 followed by O-demethylation leads to
the desired analog 47 in 20% over two steps. The novel
ambigol derivative 47 was thus accessible in six steps with a
combined yield of 8%.
In conclusion, we report the first total synthetic access to all
five natural ambigols: ambgiol A (1) in a six-step synthesis with
an overall yield of 15%, ambgiol B (2) in a five-step synthesis
with an overall yield of 9%, ambgiol C (3) in five steps with a
yield of 2% or in three steps with a yield of 3%, ambigol D (4)
and ambigol E (5), each in a five-step synthesis with an overall
yield of 8%. The strategic combination of aryl transfer
reactions with λ3-iodonium salts and Suzuki cross-coupling
chemistry to install biaryl ether and biaryl cross-links,
respectively, thus gives direct access to a structurally diverse
natural product family and further yet unknown synthetic
analogs, such as 30, 40, and 47. Application of these synthetic
routes therefore contributes to broadening the structural space
covered by the ambigols. Our work sets the stage for future in-
depth studies on biological effects of the ambigol natural
product class and novel analogs, work currently pursued in our
laboratory.
Furthermore, the site in relative ortho-position to the methoxy
group is also stereoelectronically preferred.
Just as ambigol D (4), ambigol E (5) contains a C−O−C
biaryl ether and a C−C biaryl bridge (Scheme 4B). The only
difference between these two natural products is the altered
connectivity at the central phenol building block. However, the
direct synthesis of the required double-chlorinated precursor
using NCS was not possible in this case. We therefore changed
our strategy by applying a regioselective silver-catalyzed
iodination of 2-chloro-3-methoxyphenol (36) to 37. The latter
was used in an aryl transfer reaction with 28, delivering 38 in
54% yield. Subsequent Suzuki coupling furnished 39 in 54%
yield (74% brsm), which upon deprotection gave dechloro
ambigol E analogue 40. Installation of the still missing
substituent was realized by final chlorination. To achieve
this, the phenol was activated by deprotonation using sodium
hydride and NCS was employed as the chlorinating agent,
ultimately giving ambigol E (5) in 51% yield.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03784.
As shown for 26 and 40, our synthetic strategy is also an
enabling tool to prepare new-to-Nature ambigols. An
interesting addition to this natural product class would be
analogues exclusively composed of 2,4-dichlorophenol building
blocks, which do not yet have any natural counterparts.
Such a new analogue can readily be prepared from 2-
methoxyphenol (41, Scheme 5). Acetylation of the free phenol
using AcCl and NEt3 gives 42 (99%) and facilitates subsequent
regioselective dichlorination (69%) in relative ortho- and para-
positions to the activating methoxy group, leading to
Experimental procedures, supplementary figures, and
NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Tobias A. M. Gulder − Chair of Technical Biochemistry,
Technical University of Dresden, 01069 Dresden, Germany;
orcid.org/0000-0001-6013-3161; Email: tobias.gulder@
tu-dresden.de
D
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Tobias M. Milzarek − Chair of Technical Biochemistry,
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orcid.org/0000-0001-7512-9093
̈
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Complete contact information is available at:
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Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
T.M.M. thanks the Stiftung der Deutschen Wirtschaft (sdw)
for funding. We thank the DFG for generous financial support
of the work in our laboratory (Emmy Noether Program (GU
1233/1-1)).
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