Total Syntheses of Prenylated Isoflavones from Erythrina sacleuxii and Their Antibacterial Activity: 5-Deoxy-3′-prenylbiochanin A and Erysubin F

Article abstract of DOI:10.1021/acs.jnatprod.0c00932

The prenylated isoflavones 5-deoxyprenylbiochanin A (7-hydroxy-4′-methoxy-3′-prenylisoflavone) and erysubin F (7,4′-dihydroxy-8,3′-diprenylisoflavone) were synthesized for the first time, starting from mono- or di-O-allylated chalcones, and the structure of 5-deoxy-3′-prenylbiochanin A was corroborated by single-crystal X-ray diffraction analysis. Flavanones are key intermediates in the synthesis. Their reaction with hypervalent iodine reagents affords isoflavones via a 2,3-oxidative rearrangement and the corresponding flavone isomers via 2,3-dehydrogenation. This enabled a synthesis of 7,4′-dihydroxy-8,3′-diprenylflavone, a non-natural regioisomer of erysubin F. Erysubin F (8), 7,4′-dihydroxy-8,3′-diprenylflavone (27), and 5-deoxy-3′-prenylbiochanin A (7) were tested against three bacterial strains and one fungal pathogen. All three compounds are inactive against Salmonella enterica subsp. enterica (NCTC 13349), Escherichia coli (ATCC 25922), and Candida albicans (ATCC 90028), with MIC values greater than 80.0 μM. The diprenylated natural product erysubin F (8) and its flavone isomer 7,4′-dihydroxy-8,3′-diprenylflavone (27) show in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300) at MIC values of 15.4 and 20.5 μM, respectively. In contrast, the monoprenylated 5-deoxy-3′-prenylbiochanin A (7) is inactive against this MRSA strain.

Full text of DOI:10.1021/acs.jnatprod.0c00932

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Article
Total Syntheses of Prenylated Isoflavones from Erythrina sacleuxii
and Their Antibacterial Activity: 5‑Deoxy-3′-prenylbiochanin A and
Erysubin F
George Kwesiga, Alexandra Kelling, Sebastian Kersting, Eric Sperlich, Markus von Nickisch-Rosenegk,
and Bernd Schmidt*
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sı Supporting Information
ABSTRACT: The prenylated isoflavones 5-deoxyprenylbiochanin
A (7-hydroxy-4′-methoxy-3′-prenylisoflavone) and erysubin F
(
7,4′-dihydroxy-8,3′-diprenylisoflavone) were synthesized for the
first time, starting from mono- or di-O-allylated chalcones, and the
structure of 5-deoxy-3′-prenylbiochanin A was corroborated by
single-crystal X-ray diffraction analysis. Flavanones are key
intermediates in the synthesis. Their reaction with hypervalent
iodine reagents affords isoflavones via a 2,3-oxidative rearrange-
ment and the corresponding flavone isomers via 2,3-dehydrogen-
ation. This enabled a synthesis of 7,4′-dihydroxy-8,3′-diprenyl-
flavone, a non-natural regioisomer of erysubin F. Erysubin F (8), 7,4′-dihydroxy-8,3′-diprenylflavone (27), and 5-deoxy-3′-
prenylbiochanin A (7) were tested against three bacterial strains and one fungal pathogen. All three compounds are inactive against
Salmonella enterica subsp. enterica (NCTC 13349), Escherichia coli (ATCC 25922), and Candida albicans (ATCC 90028), with MIC
values greater than 80.0 μM. The diprenylated natural product erysubin F (8) and its flavone isomer 7,4′-dihydroxy-8,3′-
diprenylflavone (27) show in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300) at MIC values
of 15.4 and 20.5 μM, respectively. In contrast, the monoprenylated 5-deoxy-3′-prenylbiochanin A (7) is inactive against this MRSA
strain.
soflavonoids are secondary plant metabolites mainly found
lallyldiphosphate (DMAPP) to phenolic groups to form prenyl
ethers or to the activated positions of the aromatic core to
form C-prenylated products, processes that require prenyl-
1
−3
I
in the Leguminosae.
They share a characteristic 3-
4
arylbenzopyran skeleton that results biosynthetically from
flavanones, via an oxidative migration of the aryl substituent
from C-2 to C-3 in the presence of isoflavone synthase (IFS), a
1
6
transferases. Compared to their parent flavonoids, the
prenylated derivatives are more lipophilic and can thus
permeate more rapidly through cell membranes and bind
5
−8
cytochrome P450 hydroxylase.
17
Flavonoids and isoflavonoids play various roles in plants.
more efficiently to target proteins. Increased lipophilicity is
13,18,19
They can quench reactive oxygen species and protect the plant
thus often associated with increased bioactivities.
9
against environmental stressors (e.g., UV light), modulate
The Erythrina genus is a particularly important source of
10,11
symbiotic interactions with microbes in the rhizosphere,
take part in allelopathic interactions with other plants, or act as
3
prenylated isoflavones. Erythrina species are distributed in
tropical and subtropical areas all over the world and have
found many uses in ethnopharmacology, in particular for the
12
antimicrobial phytoalexins. Apart from their essential effects
on the plants themselves several bioactivities have been
reported. Some isoflavanoids that act as phytoestrogens
20−22
treatment of inflammation and infectious diseases,
23
including malaria. Comparatively little is known about the
13,14
occur in plants relevant for human nutrition, e.g., soybeans.
anti-infective activities of isoflavonoids isolated from Erythrina
For several isoflavonoids anti-inflammatory effects have been
24
24
sp.: isoflavonoids from E. stricta, E. subumbrans, E.
reported, and their regular dietary intake is believed to prevent
15
many diseases resulting from chronic inflammation.
Received: August 24, 2020
In the most recent review on the isolation of isoflavonoids
from natural sources, 391 new compounds were reported for
the period from 2012 to 2017. Among these 391 novel
isoflavonoids, the prenylated isoflavones represent the largest
3
subgroup, with 94 new compounds. Prenylation occurs
biosynthetically by transfer of prenyl groups from dimethy-
©
XXXX American Chemical Society and
American Society of Pharmacognosy
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A
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2
5,26
27
28
abyssinica,
E. latissima, and E. sacleuxii were reported to
compounds are among the strongest binding phytochemicals
investigated in the docking study, with calculated docking
energies in the same range as those of the known inhibitor
M9P, a synthetic guanidin derivative. Erysubin F (8) has been
be active against Plasmodium falciparum. Some isoflavonoids
29
30
31
from E. variegata, E. zeyheri, and E. poeppigiana showed
activity against methicillin-resistant Staphylococcus aureus and
vancomycin-resistant enterococci.
Erythrina sacleuxii is a tree found exclusively in Kenya and
Tanzania. Root bark and leaves are traditionally used for the
treatment of microbial infections and malaria. Few reports
describe the isolation and structural characterization of
isoflavonoids in general and prenylated isoflavonoids in
particular from this species. The first phytochemical inves-
tigation of E. sacleuxii by Yenesew et al. led to the isolation and
structural characterization of four isoflavones, two of which (1
38
29
39
isolated from E. suberosa, E. variegata, E. poeppigiana, E.
2
8
40
19
41
sacleuxii, E. subumbrans, E. addisoniae, and E. brucei. In
vitro bioactivity tests revealed antiplasmodial activity against P.
32
2
4,28
falciparum at micromolar concentrations,
activity against Mycobacterium tuberculosis (MIC 32.0 μM),
antibacterial
24
and growth inhibitory activity against methicillin-resistant S.
29
aureus. Erysubin F (8) also showed inhibitory activity to
protein tyrosine phosphatase 1B (PTP1B), a potential drug
target in the therapy of breast and ovarian cancers, at
33
and 2) were prenylated and one (3) formylated at C-3′.
19
micromolar concentrations.
Later, 2,3-dehydrokievitone (4) was isolated from the same
To date, no chemical syntheses of either 5-deoxy-3′-
3
4
source. Recently, erysacleuxins A (5) and B (6), which are
oxidation products of 5′-prenylpratensein (2), were isolated
prenylbiochanin A (7a) or erysubin F (8) has been reported.
42
While most syntheses of isoflavone natural products start
35
from E. sacleuxii. 5-Deoxyisoflavones are comparatively rare
in this species. Two prenylated 5-deoxyisoflavones (5-deoxy-
from deoxybenzoins, only a few use the more conveniently
43
available chalcones as precursors. The conversion of
3
′-prenylbiochanin A (7a) and erysubin F (8)) have been
chalcones into isoflavones requires not only an oxidation but
also an aryl migration step after the cyclization, which is
biosynthetically accomplished by the IFS enzymes. For
chemical syntheses, Tl-(III)-acetate was demonstrated to
isolated from E. sacleuxii (Figure 1).
4
4,45
induce oxidative aryl migrations of chalcones.
Although
4
6−54
the method has been improved upon over the years,
the
toxicity of the Tl-salts, which have to be used in excess, and
occasionally poor selectivities remain serious drawbacks.
Since the mid 1980s hypervalent iodine compounds have
55
emerged as a less hazardous alternative to Tl−III-salts, but
the oxidative rearrangement method has nevertheless found
surprisingly little application in the synthesis of isoflavones.
Only one example where this method has been used as a key
step in the total synthesis of the prenylated isoflavone
wighteone has been described. In this synthesis the prenyl
substituent was introduced after the oxidative rearrangement
5
6
through a Pd-catalyzed coupling. One reason for the
restricted utilization of the oxidative rearrangement method
could be the confusing and sometimes contradictory literature
precedence: isoflavones, flavones, and benzofurans or mixtures
of these products have been reported to arise from the reaction
5
4−65
of flavanones with hypervalent iodine reagents.
A
plausible mechanism for the formation of all three types of
products is shown in Scheme 1 for the reaction of an
unsubstituted flavanone A with the hypervalent iodine reagent
54,64
[bis(trifluoroacetoxy)iodo]benzene (BTI).
The initial step
is an electrophilic iodination of A at C-3 that presumably
proceeds via the enol B. The 3-iodinated product C is the
central intermediate for all possible products: isoflavones are
formed via migration of the C-2-aryl substituent with
intramolecular substitution of the iodo substituent and
deprotonation at C-3 (black arrows), flavones result from β-
elimination (blue arrow), and benzofurans result from a ring
contraction (red arrow) and nucleophilic trapping of the
oxocarbocation (G) with MeOH.
Herein, the chemical syntheses of two prenylisoflavones
from E. sacleuxii, 5-deoxy-3′-prenylbiochanin A (7) and
erysubin F (8), using the oxidative rearrangement method
are reported. The antimicrobial activities of both natural
products and their non-natural flavone regioisomers, which
were obtained as side products from the 2,3-oxidative
rearrangements, were investigated and compared.
Figure 1. Prenylated isoflavones from Erythrina sacleuxii.
2
8
Compound 7a has only been isolated from E. sacleuxii, but
it was previously synthesized by hydrolysis of its naturally
36
occurring glucoside. To date, 5-deoxy-3′-prenylbiochanin A
7a) has only been tested for its activity against chloroquine-
resistant and -sensitive strains of Plasmodium falciparum and
(
28
was found to be active at concentrations of ca. 20 μM (IC ).
5
0
5
′-Prenylpratensein (2) and 5-deoxy-3′-prenylbiochanin A
7a) are two of 120 isoflavonoids that have been included in
a computational molecular docking study to the dengue virus
(
37
protease DENV NS2B-NS3, a potential drug target. Both
B
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Scheme 1. Mechanistic Rationale for the Formation of
Isoflavones, Flavones, and Benzofurans
valuable and convenient-to-handle cross-metathesis partner for
the regioselective construction of prenyl substituents and was
72−75
also used in this study.
The 3′-allylisoflavone 16a was
converted into 5-deoxy-3′-prenylbiochanin A (7a) in the
presence of 5 mol % of second-generation Grubbs catalyst
76
(
A) in high yield and 100% regioselectivity. THF was used as
a solvent because 16a is sparingly soluble in CH Cl , which
2
2
would normally be the solvent of choice for metathesis
reactions. The cross metathesis of the MOM-ether 16b, which
was obtained together with 16a via oxidative rearrangement of
1
5a without in situ cleavage of the MOM group, was also
investigated. In this case, CH Cl was used as a solvent and the
2
2
MOM-protected cross-metathesis product 7b was isolated in
nearly quantitative yield. Nevertheless, this route was discarded
because subsequent cleavage of the MOM-ether requires
carefully controlled conditions to avoid undesired Markovni-
kov addition of MeOH to the prenyl substituent, which gives
77
methyl ether 18 as a side product.
The molecular structure of 5-deoxy-3′-prenylbiochanin A
7a) was unambiguously corroborated by single-crystal X-ray
(
diffraction analysis (Figure 2). In the solid state, noncovalent
intermolecular interactions (hydrogen bonds between O-1−H
and O-3; π-stacking interactions between both rings of the
benzopyrone moieties) lead to the formation of molecule
chains.
The synthesis of erysubin F (8) started from the same
aldehyde 11 that was previously used to synthesize 5-deoxy-3′-
prenylbiochanin A (7). MOM protection and Claisen−
6
7
Schmidt condensation with acetophenone 20 afforded
chalcone 21. Chalcone 21 was subjected to a microwave-
promoted one-pot Claisen rearrangement/oxa-Michael addi-
tion to furnish flavanone 22. Oxidative rearrangement of 22
gave a mixture of the targeted isoflavone 23 and its flavone
regioisomer 24, which could be separated by column
chromatography on silica. Both compounds were susceptible
to double cross metathesis with 2-methyl-2-butene in CH Cl
RESULTS AND DISCUSSION
■
Synthesis and Crystal Structure of 5-Deoxy-3′-
prenylbiochanin A. For the synthesis of 5-deoxy-3′-
prenylbiochanin A (7) via oxidative rearrangement, the 3′-
allylflavanone 15 was envisaged as a key intermediate in the
synthesis (Scheme 2). 4-Hydroxybenzaldehyde (9) was
allylated, and the resulting allyl ether 10 was subjected to
microwave irradiation at 250 °C to furnish 11 via Claisen
rearrangement. This transformation has previously been
accomplished by conventional heating at 200 °C in a similar
2
2
to yield MOM-protected isoflavone 25 and flavone 26,
respectively. Deprotection gave erysubin F (8) and flavone
2
7, which has thus far not been described as a natural product
66
(Scheme 3).
yield but in a notably shorter reaction time. Methylation of
As mentioned in the introduction, information about
antimicrobial activities of prenylated (iso)flavonoids isolated
from Erythrina sp. is scarce, although a considerable amount of
information on antibacterial activities of flavonoids in general
1
1 and Claisen−Schmidt condensation of the resulting
benzaldehyde 12 with acetophenone 13 (available via
regioselective MOM-etherification of 2,4-dihydroxyacetophe-
6
7,68
none)
afforded the chalcone 14, which underwent base-
7
8,79
and their structure−activity relationships is available.
In a
catalyzed cyclization to 15a.
previous report, the MIC value of erysubin F (8) against M.
tuberculosis was determined to be 32.0 μM. In another report,
erysubin F (8) was found to be virtually inactive against
methicillin-resistant S. aureus strains (MIC = 256.1 μM). To
assess the antimicrobial activities of the prenylated isoflavones
The MOM-protected flavanone 15a was converted into the
deprotected 3′-allylisoflavone 16a in a one-pot sequence of
oxidative rearrangement and acid-mediated cleavage of the
MOM group. A combination of BTI and trimethyl
orthoformate gave the highest yield of isoflavone 16a after
24
2
9
69
5
-deoxy-3′-prenylbiochanin A (7a) and erysubin F (8), their
MIC values against methicillin-resistant S. aureus (ATCC
3300), Salmonella enterica subsp. enterica (NCTC 13349),
Escherichia coli (ATCC 25922), and Candida albicans (ATCC
0028) were determined. As the flavone 7,4′-dihydroxy-8,3′-
some optimization. Small amounts of the flavone regioisomer
7 (11%), resulting from competing oxidation without 2,3-aryl
1
4
migration and deprotected, starting material 15b (16%) were
also isolated. Isoflavone 16a, flavone 17, and deprotected
starting material 15b were separated by column chromatog-
raphy. For the introduction of the prenyl group, an olefin cross
9
diprenylflavone (27) was also obtained in notable quantities in
the course of the synthesis of erysubin F, this non-natural
erysubin F isomer was included in the antimicrobial testing to
investigate if and how a switch from an isoflavone to a flavone
structure would affect the bioactivity when all other structural
features are retained. The results from the antimicrobial assays
are summarized in Table 1.
70
metathesis reaction was used. Occasionally, coordinating
groups in the substrate can lead to catalyst inhibition through
71
coordination to the metathesis catalyst. This has also been
67
observed with phenols, but was not expected to be a problem
in this case because the phenolic group is not in proximity to
the allyl substituent. 2-Methyl-2-butene has emerged as a
C
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Scheme 2. Synthesis of 5-Deoxy-3′-prenylbiochanin A (7)
To some extent the observations in the current study are in
line with previously published results, but there are also some
notable discrepancies. It was shown that the antibacterial
activity of various natural flavanones and flavones strongly
depends on a well-balanced lipophilicity and that Gram-
positive bacteria are susceptible to a wider lipophilicity range
80
than Gram-negative ones. This may explain why the Gram-
negative bacteria investigated in this study are not affected by
any of the compounds tested. It may also explain why the
presumably less lipophilic 5-deoxy-3′-prenylbiochanin A (7a)
is much less active against MRSA than erysubin F (8) and its
flavone analogue 27. Another important factor is the position
of prenylation: when 30 prenylated flavonoids and isoflavo-
noids were tested against the Gram-positive bacterium Listeria
monocytogenes, significant differences were observed between
C-6-, C-8- and C-3′-prenylated isoflavones. The C-8
prenylated isoflavone lupiwighteone was inactive (MIC >
Figure 2. Single-crystal X-ray structure analysis of 5-deoxy-3′-
prenylbiochanin A (7a).
All prenylated flavonoids were inactive against the Gram-
negative bacteria S. enterica subsp. enterica and E. coli as well as
the fungal pathogen C. albicans. 5-Deoxy-3′-prenylbiochanin A
147.8 μM), whereas the C-6 prenylated isomer wighteone
showed high activity (MIC = 29.6 μM) and the C-3′
prenylated isomer isowighteone was moderately active (MIC
(
7a) was also inactive against Gram-positive MRSA, but
8
1
=
59.1 μM) (Figure 3). A similar effect of the prenylation
interestingly both erysubin F (8) and the non-natural flavone
isomer 27 showed similar activities against this MRSA strain,
with MIC values of 15.4 and 20.5 μM, respectively. These
results suggest that the isoflavone structure with the sterically
less hindered electrophilic C-2 is apparently less decisive for
antibiotic activity than the increased lipophilicity caused by the
presence of two prenyl groups.
82
pattern on antibacterial activity was observed with MRSA.
The low activity of 5-deoxy-3′-prenylbiochanin A (7a), which
has no prenyl substituent at C-6 or C-8, is in line with these
literature reports. The high activity of erysubin F (8), however,
is somewhat surprising against this background, because a C-8
prenyl group would normally be considered to be detrimental.
D
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Scheme 3. Synthesis of Erysubin F (8) and Its Flavone Regioisomer 27
Table 1. Antimicrobial Activities of 7, 8, and 27
MIC (μM)
MRSA
S. enterica subsp.
enterica (NCTC
13349)
E. coli
(ATCC
25922)
C. albicans
(ATCC
90028)
(
ATCC
compound
43300)
7
8
2
a
>154.6
15.4
20.5
>190.3
>82.0
>82.0
>95.1
>82.0
>82.0
>95.1
>82.0
>82.0
0.5
7
amphotericin B
vancomycin
ampicillin
0.5
11.4
11.4
DMSO
no growth inhibition
Figure 3. Structures of antimicrobial isoflavones and their
bioactivities.
31,81
The C-6 prenylated isomer of erysubin F is unknown, and
therefore no data are available for comparison.
The most notable difference between our and previously
published results concerns the MIC value of erysubin F (8).
Tanaka et al. reported an MIC value of 256.1 μM against
MRSA for erysubin F (8) that was isolated from the roots of E.
variegata. The MIC value determined by us (15.4 μM) for
synthetic erysubin F (8) is reproducible between 1 and 2
orders of magnitude lower (Table 1). The possibility that the
high antibacterial activity is an artifact caused by impurities
from the chemical synthesis can be excluded, because
essentially the same synthetic methods and reagents were
also used for 5-deoxy-3′-prenylbiochanin A (7a), which is
inactive against MRSA. In a later study Sato et al. screened six
isoflavones for their activity against MRSA and found that
isolupalbigenin (Figure 3) is the most active compound, with
MIC values between 3.8 and 7.7 μM. As isolupalbigenin is
the C-5-hydroxylated analogue of erysubin F (8), the authors
reasoned that a phenolic group at C-5 of the A-ring is an
2
9
31
E
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essential requirement for anti-MRSA activity in isoflavones”,
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Article
3
1
“
extracted with EtOAc (3 × 30 mL). The organic extract was dried
with MgSO , the solvent was evaporated, and the residue was
a conclusion that should be reconsidered in light of our results.
Finally, the surprisingly small effect of the basic isoflavone
skeleton on the antibacterial activity should be mentioned. The
MIC values of the isoflavone erysubin F (8) (15.4 μM) and its
non-natural flavone isomer 27 (20.5 μM) differ only slightly.
Although several reports on the relationship of antibacterial
activity and molecular structure of flavonoids and isoflavonoids
4
redissolved in MeOH (40 mL). Aqueous HCl (6 M, 1 mL, 6.0 mmol)
was added, and the mixture was heated to reflux at 60 C for 2 h. The
solvent was evaporated, and water (50 mL) was added to the residue.
It was extracted with EtOAc (3 × 30 mL). The combined organic
extracts were dried with MgSO , the solvent was evaporated, and the
residue was purified by column chromatography on silica, using
hexanes−EtOAc mixtures (3:1 to 2:3) as eluent to afford the
isoflavone 16a (155 mg, 0.50 mmol, 25%), flavone 17 (65 mg, 0.21
mmol, 11%), and the MOM-deprotected flavanone 15b (100 mg,
ο
4
7
8,79
exist,
there seems to be no study where flavone and
isoflavone constitutional isomers with otherwise identical
substitution patterns were tested for their antibacterial activity
under comparable conditions. Several modes of actions have
0
.32 mmol, 16%).
Compound 16a: colorless crystals, mp 206−207 °C; H NMR
1
8
3
(300 MHz, DMSO-d ) δ 10.78 (s, 1H), 8.30 (s, 1H), 7.96 (d, J = 8.8
6
been discussed for antibacterial plant (iso)flavonoids,
Hz, 1H), 7.40 (dd, J = 8.5, 2.2 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H), 7.01
including interference with bacterial topoisomerase. The latter
mechanism has been particularly emphasized for isoflavones,
which structurally resemble the clinically used 4-quinolone
(
d, J = 8.5 Hz, 1H), 6.94 (dd, J = 8.8, 2.1 Hz, 1H), 6.86 (d, J = 2.1 Hz,
H), 5.96 (ddt, J = 17.0, 10.2, 6.6 Hz, 1H), 5.05 (dm, J = 17.0 Hz,
1
1
2
H), 5.01 (dm, J = 10.2 Hz, 1H), 3.81 (s, 3H), 3.34 (d, J = 6.6 Hz,
82
1
3
1
topoisomerase inhibitors. Our results point toward a mode of
action that does not necessarily rely on an isoflavone skeleton,
but a detailed mechanistic investigation is required before any
conclusions can be drawn.
H); C{ H} NMR (75 MHz, DMSO-d ) δ 174.6, 162.5, 157.4,
6
156.6, 153.1, 136.7, 130.1, 128.0, 127.3, 127.3, 124.0, 123.3, 116.6,
115.7, 115.1, 110.4, 102.1, 55.5, 33.8; IR (ATR) ν 3205 (m), 1625
(s), 1567 (s), 1497 (m), 1237 (s), 1029 (m); HRMS (ESI) calcd for
̃
+
C H O [M + H] 309.1127, found 309.1123.
In summary, the first syntheses of the naturally occurring 5-
deoxyisoflavones 5-deoxy-3′-prenylbiochanin A (7a) and
erysubin F (8), using a 2,3-oxidative rearrangement of
flavanones and a regioselective olefin cross metathesis as key
steps, are reported. A hitherto unknown flavone regioisomer of
erysubin F was obtained as a byproduct in notable quantities;
this flavone and the natural products erysubin F (8) and 5-
deoxy-3′-prenylbiochanin A (7a) were tested for antimicrobial
activity. While all compounds were inactive against S. enterica
subsp. enterica (NCTC 13349), E. coli (ATCC 25922), and C.
albicans (ATCC 90028), both erysubin F (8) and its flavone
isomer 27 were active against methicillin-resistant S. aureus
19 17
4
1
Compound 17: colorless crystals, mp 204−205 °C; H NMR (400
MHz, DMSO-d ) δ 7.91 (dd, J = 8.7, 2.5 Hz, 1H), 7.86 (d, J = 8.7 Hz,
6
1
H),7.79 (d, J = 2.5 Hz, 1H), 7.11 (d, J = 8.7 Hz, 1H), 6.97 (d, J = 2.3
Hz, 1H), 6.91 (dd, J = 8.7, 2.3 Hz, 1H), 6.74 (s, 1H), 5.99 (ddt, J =
1
1
7.0, 10.2, 6.6 Hz, 1H), 5.06 (dm, J = 17.0 Hz, 1H), 5.05 (dm, J =
0.2 Hz, 1H), 3.86 (s, 3H), 3.38 (d, J = 6.6 Hz, 2H); C{ H} NMR
13
1
(100 MHz, DMSO-d ) δ 176.4, 162.7, 162.2, 159.7, 157.5, 136.4,
6
128.6, 127.5, 126.5, 126.3, 123.2, 116.2, 116.0, 114.9, 111.2, 105.1,
102.6, 55.8, 33.8; IR (ATR) ν
̃
2843 (w), 2599 (w), 1603 (m), 1548
(
[
m), 1521 (s), 1255 (s), 1243 (m); HRMS (ESI) calcd for C H O
19 17
4
+
M + H] 309.1127, found 309.1113.
-(3-Allyl-4-methoxyphenyl)-7-hydroxychroman-4-one (15b):
2
1
pale yellow solid, mp 152−153 °C; H NMR (400 MHz, acetone-
(
ATCC 43300) with MIC values of 15.4 and 20.5 μM,
d ) δ 9.39 (s, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.39 (dd, J = 8.4, 2.4 Hz,
6
respectively.
1
8
H), 7.34 (d, J = 2.4 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.58 (dd, J =
.7, 2.3 Hz, 1H), 6.43 (d, J = 2.3 Hz, 1H), 6.00 (ddt, J = 17.0, 10.0,
EXPERIMENTAL SECTION
General Experimental Procedures. All reactions were carried
out in dry reaction vessels. All solvents were purified by standard
6.7 Hz, 1H), 5.46 (dd, J = 13.0, 2.9 Hz, 1H), 5.06 (dm, J = 17.0 Hz,
■
1
2
H), 5.00 (dm, J = 10.0 Hz, 1H), 3.86 (s, 3H), 3.39 (dm, J = 6.6 Hz,
H), 3.05 (dd, J = 16.8, 13.0 Hz, 1H), 2.68 (dd, J = 16.8, 2.9 Hz, 1H);
1
3
1
C{ H} NMR (100 MHz, acetone-d ) δ 190.5, 165.2, 164.5, 158.3,
procedures. NMR spectra were obtained using Bruker Avance-300,
6
Bruker NEO-400, and Bruker Avance-500 instruments at 300, 400, or
137.7, 132.2, 129.5, 129.4, 129.0, 126.7, 115.8, 115.2, 111.2, 111.2,
103.7, 80.5, 55.9, 44.7, 35.0; IR (ATR) ν 2936 (w), 1647 (w), 1566
1
5
7
00 MHz (for H NMR spectroscopy) in CDCl with CHCl (δ =
̃
3
3
.26) as a calibrant. Coupling constants are given in hertz (Hz).
C{ H} NMR spectra were recorded at 75, 100, or 125 MHz in
(s), 1499 (m), 1234 (s), 1116 (m); HRMS (EI) calcd for C19
H
18
O
4
1
3
1
+
[M ] 310.1205, found 310.1211.
5
-Deoxy-3′-prenylbiochanin A (7a). To a solution of 16a (38
CDCl with CDCl (δ = 77.1) as a calibrant. Whenever the solubility
3
3
mg, 0.12 mmol) in dry THF (5 mL) at 20 °C was added 2-methyl-2-
butene (1.2 mL, 11.3 mmol) and second-generation Grubbs catalyst
A (5 mg, 5 mol %). The reaction mixture was stirred at 20 °C under a
nitrogen atmosphere for 48 h. After completion of the reaction, the
solvent was evaporated and the residue purified by column
chromatography on silica, using a hexanes−EtOAc mixture (7:3) to
afford 7a (35 mg, 0.10 mmol, 86%). Crystals suitable for X-ray
crystallographic analysis were obtained by recrystallization from
of the sample was insufficient in CDCl , it was replaced by either
3
1
acetone-d (acetone-d as a calibrant for H NMR spectroscopy, δ =
6
5
1
3
1
2
2
.05; acetone-d as a calibrant for C{ H} NMR spectroscopy, δ =
9.9) or DMSO-d6 (DMSO-d5 as a calibrant for H NMR
spectroscopy, δ = 2.50; DMSO-d as a calibrant for C{ H} NMR
6
1
1
3
1
6
spectroscopy, δ = 39.5). IR spectra were recorded as ATR-FTIR
spectra using a PerkinElmer UART TWO FT-IR-spectrometer.
−
1
Wavenumbers (ν) are given in cm . The peak intensities are defined
̃
1
MeOH: colorless crystals, mp 197−199 °C; H NMR (500 MHz,
as strong (s), medium (m), or weak (w). Low- and high-resolution
mass spectra were obtained by EI-TOF (70 eV) or ESI-Q-TOF using
Waters Micromass (Manchester, UK) instruments. Melting points
were measured using a SMP-10 instrument from Bibby Scientific
acetone-d ) δ 8.13 (s, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.42 (dd, J = 8.4,
6
2.3 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 6.99 (dd, J = 8.7, 2.3 Hz, 1H),
6.98 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 2.3 Hz, 1H), 5.32 (tm, J = 7.3
Hz, 1H), 3.87 (s, 3H), 3.33 (d, J = 7.3 Hz, 2H), 1.72 (s, 3H), 1.70 (s,
(
Stuart).
1
3
1
3-(3-Allyl-4-methoxyphenyl)-7-hydroxy-4H-chromen-4-one
3H); C{ H} NMR (125 MHz, acetone-d
158.1, 153.3, 132.5, 130.9, 130.3, 128.6, 128.5, 125.4, 125.3, 123.6,
118.6, 115.7, 111.0, 103.2, 55.8, 29.3, 25.9, 17.8; IR (ATR) ν 3219
6
) δ 175.7, 163.3, 158.8,
(
16a) and 2-(3-Allyl-4-methoxy-phenyl)-7-hydroxy-4H-chro-
men-4-one (17). To a solution of 15a (710 mg, 2.00 mmol) in
̃
trimethyl orthoformate (20 mL) was added concentrated H SO (40
(m), 2633 (w), 1622 (s), 1582 (m), 1493 (m), 1233 (s), 1125 (m);
HRMS (EI) calcd for C H O [M ] 336.1362, found 336.1368.
2
4
ο
+
μL), and the mixture was stirred at 20 C for 5 min. To the mixture
2
1
20
4
was added dropwise a solution of BTI (1.290 g, 3.00 mmol) in
Analytical data match those previously reported for the natural
ο
28
trimethyl orthoformate (5 mL). The mixture was stirred at 20 C for
product.
2
4 h. The solvent was evaporated, and water (40 mL) was added to
8-Allyl-3-[3-allyl-4-(methoxymethoxy)phenyl]-7-(methoxy-
methoxy)-4H-chromen-4-one (23) and 8-Allyl-2-[3-allyl-4-
ο
the residue. The mixture was further stirred at 20 C for 2 h. It was
F
https://dx.doi.org/10.1021/acs.jnatprod.0c00932
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
pubs.acs.org/jnp
Article
(
methoxymethoxy)phenyl]-7-(methoxymethoxy)-4H-chro-
Hz, 1H), 3.36 (d, J = 7.4 Hz, 2H), 1.83 (s, 3H), 1.73 (s, 3H), 1.70 (s,
1
3
1
men-4-one (24). Following the procedure given above for the
synthesis of 16a, compound 22 (424 mg, 1.00 mmol) was converted
3
1
1
2
H), 1.66 (s, 3H); C{ H} NMR (100 MHz, acetone-d ) δ 176.3,
60.1, 156.6, 155.7, 153.3, 132.5, 132.3, 131.2, 128.5, 128.5, 125.3,
25.0, 124.6, 123.8, 122.5, 118.8, 116.3, 115.5, 114.8, 29.2, 25.9, 25.9,
6
into 23 (85 mg, 0.20 mmol, 20%) and 24 (75 mg, 0.18 mmol, 18%).
1
Compound 23: yellow oil; H NMR (300 MHz, acetone-d ) δ 8.26
6
2.6, 18.0, 17.9; IR (ATR) ν
m), 1430 (s), 1271 (s), 1159 (m); HRMS (EI) calcd for C H O
4
̃
3245 (w), 2912 (w), 1616 (m), 1587
(
=
s, 1H), 8.07 (d, J = 9.0 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.44 (dd, J
8.9, 2.3 Hz, 1H), 7.29 (d, J = 8.9 Hz, 1H), 7.13 (d, J = 9.0 Hz, 1H),
(
2
5
26
+
[
M ] 390.1831, found 390.1821. Analytical data match those
6
5
3
.10−5.94 (m, 2H), 5.39 (s, 2H), 5.27 (s, 2H), 5.15−5.05 (m, 2H),
38
previously reported for the natural product.
.04−4.97 (m, 2H), 3.65 (d, J = 6.2 Hz, 2H), 3.48 (s, 3H), 3.46 (s,
1
3
1
7,4′-Dihydroxy-8,3′-diprenylflavone (27). Following the pro-
cedure given above for the synthesis of erysubin F (8), compound 26
H), 3.43 (d, J = 6.5 Hz, 2H); C{ H} NMR (75 MHz, acetone-d )
6
δ 176.1, 159.7, 156.1, 155.7, 154.0, 138.0, 136.3, 131.6, 129.8, 129.0,
(
134 mg, 0.28 mmol) was converted into 27 (67 mg, 0.17 mmol,
1
9
1
26.6, 126.0, 124.8, 120.1, 117.6, 115.9, 115.8, 114.7, 113.0, 95.4,
5.2, 56.7, 56.3, 35.3, 27.9; IR (ATR) ν 3076 (w), 2906 (w), 1639(s),
498 (m), 1432 (s), 1252 (s), 1150 (m); HRMS (EI) calcd for
1
̃
61%): yellow solid, mp 216−218 °C; H NMR (400 MHz, acetone-
) δ 9.64 (s, 1H), 9.23 (s, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.84 (d, J =
d
6
+
C H O [M ] 422.1729, found 422.1717.
2.3 Hz, 1H), 7.76 (dd, J = 8.4, 2.3 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H),
7.04 (d, J = 8.7 Hz, 1H), 6.63 (s, 1H), 5.44−5.36 (m, 2H), 3.70 (d, J
= 7.2 Hz, 2H), 3.42 (d, J = 7.2 Hz, 2H), 1.84 (s, 3H), 1.75 (s, 3H),
25
26
6
1
Compound 24: colorless solid, mp 129−130 °C; H NMR (300
MHz, acetone-d ) δ 7.96 (d, J = 8.9 Hz, 1H), 7.90 (dd, J = 8.9, 2.3
Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 7.27 (d, J
=
6
13
1
1
1
1
2
(
[
.75 (s, 3H), 1.66 (s, 3H); C{ H} NMR (100 MHz, acetone-d ) δ
6
8.9 Hz, 1H), 6.67 (s, 1H), 6.14−6.01 (m, 2H), 5.40 (s, 2H), 5.35
78.1, 164.2, 160.4, 159.2, 156.5, 133.5, 132.6, 129.8, 128.6, 126.4,
24.6, 124.1, 122.9, 122.9, 118.0, 116.7, 116.3, 114.7, 106.2, 29.0,
5.9, 25.9, 23.0, 18.2, 17.9; IR (ATR) ν
m), 1561 (m), 1382 (s), 1255 (s); HRMS (EI) calcd for C H O
4
M ] 390.1831, found 390.1827.
X-ray Crystallographic Data of 7a. From a MeOH solution,
(
s, 2H), 5.19−5.00 (m, 4H), 3.77 (d, J = 6.3 Hz, 2H), 3.50 (d, J = 6.6
13 1
Hz, 2H), 3.49 (s, 3H), 3.48 (s, 3H); C{ H} NMR (75 MHz,
̃
3125 (w), 2912 (w), 1621
acetone-d ) δ 177.5, 163.5, 159.7, 158.4, 155.9, 137.3, 136.5, 130.8,
1
1
6
2
5
26
28.7, 126.7, 125.9, 125.1, 119.1, 117.7, 116.4, 115.7, 114.9, 112.7,
06.2, 95.3, 95.0, 56.6, 56.4, 35.0, 28.2; IR (ATR) ν 2957 (w), 1635
+
̃
(
s), 1601 (s), 1499 (m), 1248 (s), 1024 (s); HRMS (EI) calcd for
+
compound 7 crystallized as colorless plates. Crystallographic data
were collected at 288 K on a Stoe imaging plate diffraction system
IPDS-II, using Mo Kα radiation (λ = 0.710 73 Å). Afterward, a
C H O [M ] 422.1729, found 422.1720.
25
26
6
7-(Methoxymethoxy)-3-[4-(methoxymethoxy)-3-(3-methyl-
but-2-en-1-yl)phenyl]-8-(3-methylbut-2-en-1-yl)-4H-chromen-
4
84
-one (25). Following the procedure given above for the synthesis of
spherical absorption correction (STOE LANA) and an extinction
correction were performed. The structure was solved with SHELXS-
7
b, compound 23 (300 mg, 0.70 mmol) was converted into 25 (215
1
mg, 0.45 mmol, 64%): yellowish oil; H NMR (400 MHz, CDCl ) δ
85
2
3
2013/1 using direct methods and refined against F by full-matrix
8
7
1
=
3
.14 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 7.36 (dd, J = 8.9, 2.3 Hz, 1H),
.35 (d, J = 2.3 Hz, 1H), 7.19 (d, J = 8.9 Hz, 1H), 7.12 (d, J = 9.0 Hz,
H), 5.33 (tm, J = 7.2 Hz, 1H), 5.32 (s, 2H), 5.24 (s, 2H), 5.23 (tm, J
86
least-squares procedures with SHELXL-2014/7. The non-hydrogen
atoms were refined anisotropically. For the visualization of the
87
structure, the graphic program DIAMOND was used.
7.2 Hz, 1H), 3.59 (d, J = 7.2 Hz, 2H), 3.50 (s, 3H), 3.49 (s, 3H),
The crystallographic data can be obtained free of charge via
https://www.ccdc.cam.ac.uk/structures/ or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
.39 (d, J = 7.2 Hz, 2H), 1.84 (s, 3H), 1.73 (s, 3H), 1.73 (s, 3H), 1.69
s, 3H); 1 C{ H} NMR (100 MHz, CDCl ) δ 176.5, 158.6, 155.3,
3
1
(
3
1
1
2
55.0, 152.5, 132.6, 132.5, 131.0, 130.4, 127.8, 125.4, 125.2, 124.6,
22.7, 121.5, 119.5, 118.7, 113.9, 112.1, 94.5, 94.4, 56.4, 56.1, 29.0,
1
EZ, UK; fax (+44) 1223-336-033; or via e-mail: deposit@ccdc.cam.
ac; deposit number: CCDC 2013149.
, M = 336.37 g/mol, 1.00 × 0.60 × 0.20 mm ,
5.9, 25.9, 22.4, 18.0, 18.0; IR (ATR) ν
s), 1599 (m), 1431 (s), 1252(s), 1149 (s); HRMS (EI) calcd for
̃
2962 (w), 2911 (w), 1643
3
(
C H O
21 20 4
+
C H O [M ] 478.2355, found 478.2339.
monoclinic, space group P2 /n (no. 14), a = 14.8274(4) Å, b =
29
34
6
1
7
-(Methoxymethoxy)-2-[4-(methoxymethoxy)-3-(3-methyl-
8.16970(10) Å, c = 15.5656(4) Å, β = 114.139(2)°, V = 1720.67(7)
but-2-en-1-yl)phenyl]-8-(3-methylbut-2-en-1-yl)-4H-chromen-
3
3
Å , Z = 4, D = 1.298 mg/cm , 22 586 reflections measured (3.2° ≤ 2θ
c
4
-one (26). Following the procedure given above for the synthesis of
b, compound 24 (140 mg, 0.33 mmol) was converted into 26 (148
mg, 0.31 mmol, 94%): colorless solid, mp 81−82 °C; H NMR (300
MHz, CDCl ) δ 8.04 (d, J = 9.0 Hz, 1H), 7.74 (dd, J = 9.0, 2.4 Hz,
H), 7.73 (d, J = 2.4 Hz, 1H), 7.20−7.13 (m, 2H), 6.69 (s, 1H),
.35−5.28 (m, 2H), 5.31 (s, 2H), 5.28 (s, 2H), 3.68 (d, J = 7.2 Hz,
H), 3.50 (s, 3H), 3.50 (s, 3H), 3.40 (d, J = 7.2 Hz, 2H), 1.84 (s,
H), 1.76 (s, 3H), 1.73 (s, 3H), 1.68 (s, 3H); C{ H} NMR (75
MHz, CDCl ) δ 178.5, 163.4, 158.8, 157.7, 155.2, 133.8, 132.5, 131.6,
≤
55°), 3955 unique (Rint = 0.0281, Rsigma = 0.0133), which were used
7
in all calculations. The final R was 0.040 (I > 2σ (I)) and wR was
1
1
2
0.117 (all data).
3
Antimicrobial Assay. The MIC of compounds 7, 8, and 27 was
1
5
2
3
determined using a standardized agar dilution method. Three
bacterial strains and one pathogenic yeast strain were utilized in
these experiments: S. enterica subsp. enterica (NCTC 13349),
methicillin-resistant S. aureus (ATCC 43300), E. coli (ATCC
25922), and C. albicans (ATCC 90028). Each test compound was
dissolved in DMSO, and 2-fold serial dilutions in the solvent were
prepared. These dilutions were added to Mueller Hinton agar
medium or, for C. albicans, to yeast extract peptone dextrose (YPD)
1
3
1
3
1
1
(
27.6, 125.5, 125.3, 124.4, 121.7, 121.6, 118.8, 118.8, 113.8, 111.9,
05.9, 94.5, 94.2, 56.4, 56.3, 28.7, 25.9, 25.9, 22.8, 18.1, 17.9; IR
ATR) ν
̃
2912 (w), 1645 (s), 1597 (m), 1377 (s), 1256 (s), 1069 (s);
+
HRMS (EI) calcd for C H O [M ] 478.2355, found 478.2343.
2
9
34
6
Erysubin F (8). To a solution of 25 (180 mg, 0.38 mmol) in
MeOH (10 mL) was added aqueous HCl (4 M, 0.57 mL, 2.28 mmol),
and the mixture was heated to reflux at 65 °C for 2 h. The mixture
was cooled to room temperature and quenched with water (30 mL).
It was extracted with EtOAc (3 × 20 mL), and the combined organic
(
1% v/v) to give the final test concentration. The antibiotics
vancomycin (S. aureus) and ampicillin (S. enterica and E. coli) and the
antimycotic amphotericin B (C. albicans) were used as positive
controls and to verify that MIC values of each individual strain were
in agreement with known MIC ranges. Agar plates containing only
DMSO (1% v/v) served as negative controls. Inocula of all test
organisms were prepared using overnight cultures, photometrically
adjusted to approximate 10 CFU/mL for bacteria and 10 CFU/mL
for C. albicans. Agar plates were incubated aerobically at 37 °C for 18
h with the three bacterial strains and 30 °C for 48 h with C. albicans.
The MICs were defined as the lowest concentrations of compound to
prevent visible growth after incubation.
extracts were dried with MgSO . The solvent was evaporated under
4
reduced pressure, and the residue purified by column chromatography
on silica, using hexanes−EtOAc mixtures (7:3 to 1:1) as eluent to
8
7
afford 8 (120 mg, 0.31 mmol, 81%): yellow solid, mp 162−163 °C;
1
H NMR (400 MHz, acetone-d ) δ 9.47 (s, 1H), 8.35 (s, 1H), 8.21 (s,
6
1H), 7.93 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.30 (dd, J =
8.4, 2.3 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H),
5.38 (tm, J = 7.4 Hz, 1H), 5.29 (tm, J = 7.2 Hz, 1H), 3.57 (d, J = 7.2
G
https://dx.doi.org/10.1021/acs.jnatprod.0c00932
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
pubs.acs.org/jnp
Article
(
10) Sugiyama, A.; Yamazaki, Y.; Hamamoto, S.; Takase, H.; Yazaki,
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.jnatprod.0c00932.
■
K. Plant Cell Physiol. 2017, 58, 1594.
*
(
(
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Experimental details and characterization data for all
1
13
1
(14) Baber, R. J. In Isoflavones: Chemistry, Analysis, Function and
Effects; Preedy, V. R., Ed.; The Royal Society of Chemistry:
Cambridge, 2013; p 3.
compounds; copies of H and C{ H} NMR spectra of
all compounds; crystallographic details and refinement
data; tables of atomic coordinates, bond lengths, and
angles (PDF)
Details and documentation for antimicrobial test
experiments (PDF)
(
(
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AUTHOR INFORMATION
Corresponding Author
Bernd Schmidt − Institut fuer Chemie, Universitaet Potsdam,
D-14476 Potsdam-Golm, Germany; orcid.org/0000-
■
(19) Nguyen, P. H.; Sharma, G.; Dao, T. T.; Uddin, M. N.; Kang, K.
W.; Ndinteh, D. T.; Mbafor, J. T.; Oh, W. K. Bioorg. Med. Chem.
2012, 20, 6459.
(20) Kokwaro, J. O. Medicinal Plants of East Africa; University of
0
002-0224-6069; Phone: +49-331-977-5187;
Email: bernd.schmidt@uni-potsdam.de; Fax: +49-331-
77-5059
Nairobi Press: Nairobi, 2009.
(21) Mitscher, L. A.; Drake, S.; Gollapudi, S. R.; Okwute, S. K. J.
Nat. Prod. 1987, 50, 1025.
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Authors
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(23) Kaur, K.; Jain, M.; Kaur, T.; Jain, R. Bioorg. Med. Chem. 2009,
17, 3229.
George Kwesiga − Institut fuer Chemie, Universitaet Potsdam,
D-14476 Potsdam-Golm, Germany
Alexandra Kelling − Institut fuer Chemie, Universitaet
Potsdam, D-14476 Potsdam-Golm, Germany
Sebastian Kersting − Fraunhofer Institute for Cell Therapy
and Immunology, Branch Bioanalytics and Bioprocesses
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(
2
(
(
Fraunhofer IZI-BB), D-14476 Potsdam-Golm, Germany
Eric Sperlich − Institut fuer Chemie, Universitaet Potsdam, D-
4476 Potsdam-Golm, Germany
Heydenreich, M.; Peter, M. G.; Akala, H.; Wangui, J.; Liyala, P.;
Waters, N. C. Phytochemistry 2004, 65, 3029.
1
Markus von Nickisch-Rosenegk − Fraunhofer Institute for
Cell Therapy and Immunology, Branch Bioanalytics and
Bioprocesses (Fraunhofer IZI-BB), D-14476 Potsdam-Golm,
Germany
(
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The Ph.D. scholarship (2018−2021) for G.K. (57381412)
from German Academic Exchange Service (DAAD) is
gratefully acknowledged. We thank Dr. M. Heydenreich and
Prof. H. Mo
spectroscopic characterization).
̈
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