Volatiles from the ascomycete: Daldinia cf. childiae (Hypoxylaceae), originating from China

Article abstract of DOI:10.1039/c9md00083f

The volatiles from an isolate of the fungus Daldinia cf. childiae, obtained from a specimen collected in China, were collected by use of a closed-loop stripping apparatus and analysed by GC-MS. A total number of 33 compounds from different classes were ri

Full text of DOI:10.1039/c9md00083f

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ARTICLE
Volatiles from the ascomycete Daldinia cf. childiae
(
Hypoxylaceae), originating from China
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
b
a
Lukas Lauterbach, Tao Wang, Marc Stadler and Jeroen S. Dickschat*
DOI: 10.1039/x0xx00000x
The volatiles from an isolate of the fungus Daldinia cf. childiae, obtained from a specimen collected in China, were
collected by use of a closed-loop stripping apparatus and analysed by GC-MS. A total number of 33 compounds from
different classes were rigorously identified by comparison of mass spectra to library spectra and of retention indices to
tabulated data from the literature. For unknown compounds structural suggestions were delineated from the mass spectra
and verified by chemical synthesis of reference materials. Through this approach two 2-alkylated furan derivatives were
identified, demonstrating that the genus Daldinia continues to be an interesting source for the discovery of novel
www.rsc.org/
1
3
2
secondary metabolites. Feeding experiments with sodium (1,2- C )acetate were performed to investigate the biosynthesis
of the polyketide 5-hydroxy-2-methyl-4-chromanone that are in favour of a non-enzymatic cyclisation step.
species isolated from China,12 came into our focus. The strain
had already been included in a study containing preliminary
data on its GC-MS profile, but the main focus of this study was
Introduction
The Xylariales are an order of mostly saprophytic ascomycete
fungi that grow on decaying wood. They are rich producers not
only of volatile secondary metabolites, but also of larger
polyoxygenated natural products from diverse compound
on the discovery and description of the new species Daldinia
1
3
hawksworthii. The bouquet of D. cf. childiae was found to
contain several natural products that could not be easily
identified from their mass spectra. Here we report on a re-
investigation of the volatiles from D. cf. childiae with a special
emphasis on the extended chemical space observed in this
organism.
1
2
classes that often exhibit interesting biological activities. One
of the first characterised xylarialean volatile compounds
(Figure 1) is 2-butyl-3-methylbut-2-en-4-olide (1) from
3
Hypoxylon serpens (currently valid name: Nemania serpens), a
compound that was also found in an endophytic isolate
assigned to the genus Geniculosporium (the asexual state of
A)
O
O
O
4
Nemania). In N. serpens it is accompanied by its isomer 2-
O
O
3
butyl-3-methylenebutan-4-olide (2). With respect to terpenes,
1
,8-cineol (3) has been reported from endophytic species of
1
2
3
5
,6
the genus Hypoxylon, and the monoterpene synthase for this
compound has recently been identified. Among non-volatile
B)
OH
O
7
O
O
secondary metabolites compounds from many classes can be
8
H
O
found, such as the xylariterpenoids A (4a) and B (4b), or the
9
HO
daldinones as represented by daldinone A (5a) and daldionin
H
HO
O
(
5b) that exhibits moderate antimicrobial activity against
OH
1
0
1
0
Gram-positive bacteria. Daldinone A was initially obtained as
a minor metabolite from the fruiting bodies of Daldinia
concentrica, but it is also present in other Hypoxylaceae, e. g. it
is extremely frequent in Annulohypoxylon where it constitutes
the major stromatal pigments of many species. Following our
continuous effort in the identification of volatile secondary
metabolites from fungi, Daldinia cf. childiae MUCL 53761, a
HO
OH
OH
4a (10R)
b (10S)
5a
5b
4
1
1
Figure 1: Volatile and non-volatile secondary metabolites from Xylariales.
Results and Discussion
Headspace analysis
a. Kekulé-Institut für Organische Chemie, Universität Bonn, Gerhard-Domagk-Straße
1
, 53121 Bonn, Germany. Email: dickschat@uni-bonn.de.
b.
Abteilung Mikrobielle Wirkstoffe, Helmholtz-Zentrum für Infektionsforschung,
Inhoffenstraße 7, 38124 Braunschweig, Germany.
The volatile organic compounds emitted by agar plate cultures
of Daldinia cf. childiae were collected on charcoal filters with a
closed-loop stripping apparatus (CLSA) as described by Grob
Electronic Supplementary Information (ESI) available: Table of identified
compounds in headspace extracts. See DOI: 10.1039/x0xx00000x
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and Zürcher.14 After one day the trapped compounds were compounds included the widespread volatiles 2-phenyVlieewthAartnicolelO(1nl8in)e,
extracted with dichloromethane and the obtained headspace its isomer 1-phenylethanol (16) and theDOcoI:r1r0e.s10p3o9n/dCi9nMgDk0e0t0o8n3eF
extracts were analysed by gas chromatography-mass acetophenone (17).
spectrometry (GC-MS). The detected compounds were
O
O
OH
O
identified from their mass spectra by comparison to mass
1
5
spectral libraries, and from their retention indices by
comparison to literature data for the same (HP5-MS) or similar
GC column type of same polarity (polydimethylsiloxane coating
with 5% phenyl groups). Positive compound identification was
assumed for a good mass spectral match and deviation
between measured and reported retention index of no more
than 10 points. If library mass spectra or retention index
literature data were not available, an authentic reference
compound was used for unambiguous compound
identification. As will be reported here, for a few compounds
that were not commercially available structural suggestions
were made based on the recorded mass spectral
fragmentation patterns and the chromatographic behaviour.
The structural suggestions were then verified or disproven by
synthesis of a reference compound.
6
7
8
OH
O
OH
O
O
9
10
11
12
OH
N
N
S
O
N
N
1
3
14
15
16
R
O
O
OH
O
OH
17
18
19 (R=H)
0 (R=OH)
Identification of volatiles from Daldinia cf. childiae
2
A total number of 33 different compounds representing
various compound classes were identified in the headspace
extracts from D. cf. childiae (Figures 2 and 3, Table S1)
including the biosynthetically related aliphatic compounds 4-
methylhexan-3-one (6), manicone (7) and (4R,5R,6S)-5-
R
O
O
OH
O
OMe OMe
O
21 (R=H)
23
24
hydroxy-4,6-dimethyloctan-3-one
(8).
The
absolute
22 (R=OH)
O
configuration of compound 8 was recently determined for the
same compound produced by Daldinia clavata by comparison
to all eight synthetic stereoisomers through GC using a chiral
stationary phase.16 Furthermore, the widespread typical
mushroom odour oct-1-en-3-ol (9, matsutake alcohol) and
traces of cyclohexanol (10) and cyclohexanone (11) were
detected.
O
O
n
n
27 (n=1)
8 (n=2)
2
2
5 (n=1)
6 (n=2)
2
H
OH
29
30
31
HO
O
32 (cis)
33 (trans)
Figure 3: Volatiles from Daldinia cf. childiae. The absolute configuration of compounds
, 7, 9 and 16 is unknown.
6
The main volatile 5-hydroxy-2-methyl-4-chromanone (22) from D.
cf. childiae was also found in liquid culture extracts and isolated for
unambiguous identification by NMR spectroscopy (Figures S1 – S3).
The chromanone 22 is a small polyketide that was first reported
Figure 2: Total ion chromatogram of a CLSA headspace extract from Daldinia cf.
childiae MUCL 53761. The bold compound numbers at peaks correspond to those in
Table S1 and in Figure 3.
Small heterocyclic compounds were represented by 2-acetylfuran from the plant pathogenic fungus Phialophora gregata21 and is also
(
12), 2-acetylthiazole (13), 2,5-dimethylpyrazine (14) and 2,4,6- known from other species of the genus Daldinia22,23 and the related
trimethylpyridine (15). While 12 – 14 are widespread volatiles, genera Thamnomyces24 and Phylacia.25 Its optical rotation of []
20
D
2 2
compound 15 is rare and has only occasionally been reported as a = –0.1 (c 1.6, CH Cl ) pointed to a racemic sample, as verified by GC
constituent of plant essential oils17-19 and from bacteria of the on a chiral stationary phase (Figure S4), while for 22 from
genus Collimonas,20 but never from fungal sources before. Aromatic Nodulisporium a slight enrichment of the (R) enantiomer was
2
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Journal Name
ARTICLE
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DOI: 10.1039/C9MD00083F
A)
MT
MT
DH
KR
DH
KR
KS AT
ACP
S
KS AT
ACP
S
OH
O
OH
O
O
ChrA
ChrB
KR
O
O
O
O
O
2
-
H O
2
OH
OH
O
3
4 (2)
35
22
O
B)
MT
DH
KR
KS AT
ACP
S
OH
O
O
OH
O
O
OH
O
O
ChrA
O
OH
-
H O
2
-
2 H O
2
OH
OH
O
36
37
23
O
O
Scheme 1: Chromanone biosynthesis in Daldinia by the partially reducing polyketide synthase (PR-PKS) ChrA in conjunction with the discrete ketoreductase ChrB. Biosynthetic
models for A) 5-hydroxy-2-methyl-4-chromanone (22) and B) 5-hydroxy-2-methyl-4H-chromen-4-one (23). ACP: acyl carrier protein, AT: acyl transferase, DH: dehydratase, KR:
ketoreductase, KS: ketosynthase, MT: methyltransferase.
2
5
2 2
= +6, c 0.19, CH Cl
, 6% ee for (R)-22).26 The (C-4a/C-5, C-6/C-7 and C-8/C-8a) which is explainable by the C2v
reported ([]
D
corresponding compounds 2-methyl-4-chromanone (21) and 5- symmetric intermediate 34. The equal peak integrals for both
hydroxy-2-methyl-4H-chromen-4-one (23) were also detected as coupling patterns also suggest that the conversion from 34 to 22 is
minor constituents. The polyketide synthase ChrA for chromane likely not under control of the PKS or any other enzyme, which is
biosynthesis was recently reported from Daldinia eschscholtzii and also reflected by the racemic nature of 22. Liquid culture extracts
2
7
acts together with a discrete ketoreductase ChrB (Scheme 1).
also yielded 1-(2,6-dihydroxyphenyl)butan-1-one (35, Figures S6 –
The biosynthetic model for the main compound 22 (Scheme 1A) S8), a compound that was previously reported inter alia from an
1
0,23,28
includes the formation of a pentaketide chain from an acetyl-CoA endophytic Nodulisporium and D. eschscholtzii,
whose
starter unit and malonyl-CoA extender units with ketoreduction and formation can be explained by full reduction in the first PKS
elimination of water during the first chain extension step. extension step. This compound was neither present in the
Reduction of the 3-oxo group of the ACP-bound pentaketide by the headspace nor the liquid culture extracts from the feeding
1
3
ketoreductase ChrB and cyclisation by Dieckmann condensation experiment with sodium (1,2- C
leads to 1-(2,6-dihydroxyphenyl)but-2-en-1-one (34) that can
undergo spontaneous cyclisation to 22. The minor compound 23 is
similarly formed from a pentaketide in which only the 3-oxo group
is reduced to the alcohol, followed by cyclisation to 1-(2,6-
dihydroxyphenyl)butane-1,3-dione (36) and spontaneous formation
of the hemiacetal 37 and elimination of water to 23 (Scheme 1B).
This biosynthetic model was supported by a feeding experiment
2
)acetate.
1
3
with sodium (1,2- C
labelling (14% incorporation rate) and up to five labelled C
Figure S5). The coupling pattern in the 13C-NMR spectrum of
2
)acetate, resulting in a good incorporation of
2
units
(
labelled 22 (Figure 4) demonstrates that the labelled acetate units
in the pseudosymmetric aromatic ring are oriented in a clockwise
(C-4a/C-8a, C-8/C-7 and C-6/C-5) or counterclockwise arrangement
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(
Scheme S1) is excluded by the observed incorporation pattern
View Article Online
DOI: 10.1039/C9MD00083F
1
3
2
from sodium (1,2- C )acetate, because for this alternative
mechanism the C-2/C-3 unit of 22 should arise from one acetate.
Figure 4: Expansions of the 13C-signals for all carbons of labelled 22 obtained in the
feeding experiment with sodium (1,2-13
2 2
C )acetate. The intact labelled C units are
shown as bold arrows in different colours. The corresponding 13C,13C couplings are
indicated in the 13C-spectra by the same colour. The coupling pattern in the aromatic
ring can be explained by either clockwise or counterclockwise incorporation of labelled
2
C units.
The compounds 36 and 37 have also previously been reported from
2
9
Daldinia, which further supports the biosynthetic hypothesis. The
methyl esters methyl salicylate (19) and methyl 2,6-
dihydroxybenzoate (20) found in the headspace extracts exhibit the
Figure 5: EI mass spectra of A) 2-nonylfuran (25) and B) 2-undecylfuran (26), and the
unidentified furan derivatives with unsaturated side chains C) X and D) Y.
same aromatic ring substitution patterns as observed for 21 and 22 The second most abundant volatile from D. clutidae was
and may arise by degradation of these chromanones. An alternative identified as 1,8-dimethoxynaphthalene (24). This compound
biosynthetic hypothesis in which the coenzyme A esters of salicylic has been previously reported from other fungi including D.
acid and 2,6-dihydroxybenzoic acid would serve as starter units eschscholtzii,30 Hypoxylon invadens31 and Hypoxylon
4
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griseobrunneum32 that all belong to the family Hypoxylaceae.33 the production of X and Y was too low for derivVaietwisAartticiloenOsnlinine
The corresponding compound 1,8-dihydroxynaphthalene (1,8- microreactions. Biosynthetically, the fuDrOaIn: s10.m10a39y/Ca9rMisDe00f0ro83mF
DHN), which is likely the biosynthetic precursor of 24, also fatty acids, and for this reason we assumed that the double
3
4
serves as a building block of 1,8-DHN melanin in ascomycota.
bond for X may be located in the -6 position and Z configured
For compounds 25 and 26 no reference mass spectra were as in linolenic acid. However, synthetic (Z)-2-(non-3-en-1-
included in our mass spectral libraries, but the fragmentation yl)furan (41) prepared by alkylation of furan with (Z)-1-
pattern pointed to the structures of 2-alkylated furans by the iodonon-3-ene (40) showed a different mass spectrum and
strong fragment ions at m/z = 81 and 95, representing the retention index than X (Figure S15, NMR spectra are shown in
furan moiety by - and -cleavage (Figures 5A and 5B). Figures S16 – S18). As an alternative, 2-(non-1-en-1-yl)furan
Together with the molecular ions at m/z = 194 and 222 the (45) and 2-(undec-1-en-1-yl)furan (46), compounds that can be
structures of 2-nonylfuran (25) and 2-undecylfuran (26) were expected to elute later than 25 and 26, respectively, due to
suggested. Both compounds were synthesised by alkylation of their conjugated double bond systems, were prepared by
furan with the corresponding alkyl halogenides 38 and 39 Wittig reaction of furfural (42) with octyl and
(Scheme 2, for NMR spectra cf. Figures S9 – S14). The obtained decyltriphenylphosphonium salts (43 and 44). These reactions
products showed identical mass spectra and retention times to yielded the Z stereoisomers as the main products along with
the volatiles from D. cf. childiae, thus giving unambiguous minor amounts of the E isomers, but also these furans
evidence for the suggested structures. 2-Nonylfuran has been exhibited different mass spectra and retention indices than X
3
5
reported as an essential oil constituent of Bifora radians,
and Y (Figure S15, for NMR spectra cf. Figures S19 – S24). The
while 2-undecylfuran is known from tonka beans (Dipteryx structures of X and Y remain currently unclear and their
odorata),36 but both compounds have not been described as a identification will require the synthesis of further reference
fungal natural product before.
compounds or isolation from culture extracts.
-Heptyl-2H-pyran-2-one (27), known as a volatile organic
6
3
8
compound from Trichoderma viride, was also found in trace
amounts. Significantly larger amounts were observed for 6-
nonyl-2H-pyran-2-one (28), a compound that we have recently
i) BuLi, THF
O
1
6
ii) X
reported from D. clavata. Furthermore, a few terpenes were
n
found including the widespread trisnor-sesquiterpene geosmin
1
,39
3
3
4
8 (X=Br, n=1)
(29),
-bisabolene (30), trans--bergamotene (31), and cis-
9 (X=I, n=2)
0 (X=I, n=1, 3)
and trans-linalool oxide (32 and 33). The sesquiterpenes 30
and 31 are biosynthetically linked through the bisabolyl cation
A (Scheme 3) and may potentially arise from the same
sesquiterpene synthase. Notably, the combination of 30 and
O
n
4
0
3
1 has recently also been reported from Aspergillus fischeri.
2
2
4
5 (X=Br, n=1), 53%
6 (X=I, n=2), 26%
3
1 (X=I, n=1,  ), 28%
H
BuLi, THF
O
O
O
Ph3P
-OPP-
OPP
n
X-
4
4
3 (X=Br, n=1)
4 (X=I, n=2)
OPP
42
FPP
NPP
A
-
H+
n
H
4
4
5 (n=1), 88%, Z/E 7:1
6 (n=2), 80%, Z/E 3:1
Scheme 2: Synthesis of 2-alkyl and 2-alkenylfurans.
B
-
H+
Two more trace compounds X and Y eluted slightly later than
5 and 26 and showed very similar mass spectra, but the
30
2
molecular ions were 2 Da lower with m/z = 192 and 220,
suggesting an additional unsaturation in the side chain (Figures
5
C and 5D). It is difficult to determine the positions of double
31
bonds in long alkenyl chains from mass spectral fragmentation Scheme 3: Cyclisation of farnesyl diphosphate (FPP) via nerolidyl diphosphate (NPP)
and the bisabolyl cation (A) as last common intermediate towards 30 and 31.
patterns. To solve this problem the iodine catalysed addition
3
7
of dimethyl disulfide to olefins is often used. This method
yields bis(methylthio) ethers that show strong -
fragmentations of the chain between the thioether groups, but
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was grown in YMG liquid medium (4 g/L yeast extract, 10 g/L
malt extract, 4 g/L glucose, pH 7.2) at 25°C with agitation or on
YMG agar plates.
Conclusions
View Article Online
DOI: 10.1039/C9MD00083F
The previous study of the same strain had tentatively revealed
compounds like 5-methoxy-1,3-dimethyl-1H-pyrazole, 7-
methoxy-1-naphthol,
guaia-1(10),11-diene,
5-ethyl-4-
Analysis of volatiles
methylhept-4-en-3-one, and 6,6-dimethylhepta-1,3-dien-5-ol
as major detectable metabolites, but only with poor mass
spectral accordance values of ca. 60% according to the NIST
The volatiles released by Daldinia cf. childiae MUCL 53761 agar
plate cultures were trapped on charcoal filters using a closed-
loop stripping apparatus (CLSA) as described by Grob and
1
3
database and without a comparison of retention indices.
1
4
Zürcher for 24 h at room temperature with natural light-dark
rhythm. The adsorbed volatiles were extracted from the filter
Moreover, the chromane (23) was detected with confidence as
a major metabolite, relying on an available standard. The fact
that none of the above mentioned compounds except for 23
was confirmed to be present in the volatilome of the fungus
during the course of the current study should give rise to take
such preliminary data more cautiously, because only a
2 2
traps with CH Cl (50 L, HPLC grade) and the obtained
extracts were subjected to GC/MS analysis.
GC/MS
relatively small number of volatiles derived from fungi are GC/MS analyses were carried out with a coupled 7890A GC –
contained in the NIST database. On the other hand, the 5975C mass selective detector system (Agilent, Hewlett-
current work shows that it may be rewarding to study fungi Packard Company, Wilmington, USA). The GC was equipped
more intensively with the goal of obtaining new fungal with a HP5-MS fused silica capillary column (30 m, 0.25 mm i.
volatiles with potentially interesting functions in fungal d., 0.25 m film, Agilent). The GC/MS settings were inlet
ecology. The profile of fungal volatiles is also interesting, pressure: 77.1 kPa, He 23.3 mL min−1; injection volume: 1.5 L;
because the presence of some compounds may point to the injector operation mode: splitless (60 s valve time); carrier gas:
production of functionalised non-volatile metabolites with He at 1.2 mL min−1; GC program: 5 min at 50 °C, then
interesting medicinal properties, e. g. trans--bergamotene increasing with 5 °C min-1 to 320 °C; transfer line 300 °C;
(
31) is the parent hydrocarbon of the xylariterpenoids A (4a) electron energy 70 eV. Retention indices (I) were calculated
and
B
(4b), and 1,8-dimethoxynaphthalene (24) is according to Kovats15 from retention times of the analytes in
biosynthetically linked to the pseudo-dimeric structures of comparison to those of alkane standards in a homologous
daldinones such as 5a and daldionin (5b). In future studies we series of n-alkanes (C –C ).
8
38
will continue to investigate the interesting chemical space of
fungal volatiles.
GC on chiral stationary phase
The enantiomeric composition of 22 was determined on an
Agilent 7820A GC system equipped with an FID detector and a
Cyclosil B column (30 m, 0.25 mm diameter, 0.25 m film). The
GC was programmed as follows: start temperature 110 °C, held
for 5 min, followed by a temperature ramp of 40 °C/min to 130
Conflicts of interest
There are no conflicts to declare.
°
°
C, then a ramp of 2.5 °C/min to 220°C. Inlet temperature: 250
C, injection volume: 1 L, carrier gas: H , gas flow: 2.3
Experimental Part
2
Strain and culture conditions
mL/min.
The culture of Daldinia cf. childiae was originally obtained from
ascospores of a specimen that was collected by Cony Decock in
Compound isolation from liquid culture extracts
China (Yunnan Province, Chu Xiong, Zi Xi Shan Nature Reserve) Daldinia cf. childiae MUCL 53761 was grown in YMG liquid
from Prunus on 17 September 2008, and is deposited at the medium (6 L) for two days. After centrifugation the
Mycothéque de l’ Universite Catholique de Louvain supernatant was extracted with diethyl ether (3x). The
(
BCCM/MUCL), Louvain-la-Neuve (Belgium), under the combined organic layers were dried with MgSO
4
and
accession number MUCL 53761. Its taxonomy has been concentrated under reduced pressure to yield the crude
previously reported in the course of the last world monograph extract (0.4 g). Column chromatography on silica gel with
1
2
of the genus Daldinia. The specimen showed a highly similar diethyl ether/pentane (5:1) yielded two fractions (F1 and F2).
morphology as compared to Daldinia childiae, but differed Fraction F1 was further purified by a second column
from typical material of this extremely frequently occurring chromatography on silica gel with diethyl ether/pentane (1:5)
species in having a deviating stromatal morphology and to yield pure 22 (15 mg) as a colourless oil and five fractions
slightly larger ascospores with aberrant germ slit morphology. (F1.1 – F1.5). Fraction 1.2 was purified by preparative TLC
Its anamorphic characteristics and HPLC profile were the same (silica gel, toluene/ethyl acetate 10:1) to give pure 35 (7.4 mg)
as in D. childiae from other localities, and the ITS sequence as a colourless oil.
also did not deviate. For these reasons, and because only a 5-Hydroxy-2-methyl-4-chromanone (22). TLC (pentane/diethyl
1
single specimen has so far become available, the fungus has ether 5:1): R
f
= 0.4. H NMR (700 MHz, C
6
D
6
):  = 12.35 (br s,
3
3
not yet been formally assigned to a new species. The strain 1H, OH), 6.91 (dd, JH,H = 8.3, 8.3 Hz, 1H, CH), 6.51 (dd, JH,H
=
6
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3
8
.3 Hz, 4JH,H = 0.9 Hz, 1H, CH), 6.30 (dd, JH,H = 8.2 Hz, 4JH,H = 0.9 assigned as s (strong), m (medium), and w (weak). UV/Vis
View Article Online
DOI: 10.1039/C9MD00083F
3
Hz, 1H, CH), 3.68 (ddq, JH,H = 9.9, 6.2, 6.2 Hz, 1H, CH), 1.94- spectra were recorded on a Cary 100 UV/Vis spectrometer
13
1
.89 (m, 2H, CH
NMR (175 MHz, C
38.2 (CH), 109.5 (CH), 108.5 (C
CH ), 20.4 (CH
2
), 0.83 (d, 3JH,H = 6.3 Hz, 3H, CH
):  = 198.5 (CO), 163.1 (C
3
) ppm.
C
),
(Agilent).
D
6 6
q
), 162.1 (C
q
1
(
q
), 107.2 (CH), 73.6 (CH), 43.4 Synthesis of 2-alkyl and 2-alkenylfurans by alkylation of furan
) ppm. HR-APCI-MS: calcd. for C10
79.0703; found 179.0702. IR (ATR): /c = 2980 (w), 1646 (s),
627 (m), 1579 (m), 1388 (s), 1349 (m), 1226 (s), 1161 (w),
147 (w), 1111 (w), 1060 (m), 1012 (w), 939 (w), 903 (w), 870
+
2
3
H O
11 3
-1
To a solution of furan (1 eq.) in anhydrous THF (3 mL mmol of
1
1
1
(
=
furan), a solution of n-BuLi (1.6 M in hexane, 1 eq.) was added
dropwise at –78 °C, followed by stirring for 30 minutes. Then, a
solution of the corresponding alkyl or alkenyl halogenide (1
-1
w), 801 (m), 730 (m), 578 (w) cm . UV-Vis (CH
2
Cl
351 (3.28), 270 (3.66), 227 (3.59), 202 (3.86) nm.
-(2,6-Dihydroxyphenyl)butan-1-one (35).
2
): max (log )
-1
eq.) in dry THF (0.3 mL mmol of alkyl or alkenyl halogenide)
was added. The mixture was stirred at room temperature for
another 3 hours. Distilled water was added and the aqueous
layer was extracted with diethyl ether (3x). The collected
1
TLC
1
(pentane/diethyl ether 2:1): R
f
= 0.35. H NMR (700 MHz,
):  = 9.05 (br s, 2H, 2 x OH), 6.78 (t, JH,H = 8.2 Hz, 1H, CH),
.97 (d, JH,H = 8.1 Hz, 2H, 2 x CH), 2.86 (t, JH,H = 7.2 Hz, 2H,
3
C
5
CH
CH
1
D
6 6
4
organic layers were dried over MgSO and concentrated in
3
3
vacuo. The residue was purified by flash column
chromatography on silica gel to yield the 2-alkyl and 2-
alkenylfurans as colourless oils.
3
3
2
), 1.65 (tq, JH,H = 7.3 Hz, 2H, CH
) ppm. 13C NMR (175 MHz, C
):  = 207.2 (CO), 161.8 (C
), 108.5 (2 x CH), 46.7 (CH
13 3
) ppm. HR-APCI-MS: calcd. for C10H O
2
), 0.86 (t, JH,H = 7.4 Hz, 3H,
3
D
6 6
q
),
35.4 (2 x CH), 110.5 (C
q
2
), 18.0
2
7
0
-Nonylfuran (25). Prepared from nonyl bromide (38, 1.51 g,
+
(CH ), 14.0 (CH
2
3
.3 mmol). Yield: 757 mg (3.90 mmol, 53%). TLC (hexane): R
f
=
1
2
1
1
(

81.0859; found 181.0859. IR (ATR): /c = 3276 (w), 2962 (w),
929 (w), 2873 (w), 1628 (m), 1586 (s), 1510 (w), 1448 (s),
385 (w), 1356 (w), 1339 (w), 1297 (w), 1234 (m), 1214 (s),
196 (s), 1165 (w), 1106 (w), 1037 (m), 980 (m), 901 (w), 871
1
3
.51. H NMR (400 MHz, CDCl
3
, TMS):  = 7.30 (dd, JH,H = 1.9
Hz, JH,H = 0.9 Hz, 1H, CH), 6.28 (dd, 3JH,H = 1.9, 3.1 Hz, 1H, CH),
4
.97 (m, 1H, CH), 2.62 (t, 3JH,H = 7.6 Hz, 2H, CH
5
CH
CH
2
), 1.64 (m, 2H,
), 0.89 (t, JH,H = 6.6 Hz, 3H,
3
2
), 1.39-1.22 (m, 12H, 6 x CH
2
-1
w), 794 (m), 725 (m), 595 (w), 534 (w) cm . UV-Vis (CH
2
Cl
2
):
13
3
) ppm. C NMR (100 MHz, CDCl
3
, TMS):  = 156.7 (C
), 29.5 (CH ), 29.4
), 28.0 (CH ), 22.7 (CH ),
22O+ 194.1665;
) ppm. HR-ESI-MS: calcd. for C13
q
),
max (log ) = 254 (4.93), 212 (4.93) nm.
1
(
1
40.6 (CH), 110.0 (CH), 104.5 (CH), 31.9 (CH
CH ), 29.3 (CH ), 29.2 (CH ), 28.1 (CH
4.1 (CH
2
2
2
2
2
2
2
2
1
3
2
Feeding experiment with sodium (1,2- C )acetate
3
H
Daldinia cf. childiae MUCL 53761 was grown in YMG liquid found 194.1667. IR (ATR): /c = 2924 (m), 2854 (m), 1597 (w),
1
3
medium (250 mL) supplemented with sodium (1,2- C
210 mg, 2.5 mmol, 10 mM) for two days. After centrifugation 924 (w), 885 (w), 794 (w), 723 (s), 599 (w) cm . UV-Vis
the supernatant was extracted with diethyl ether (3x). The (CH Cl ): max (log ) = 277 (2.85), 229 (4.56) nm.
combined organic layers were dried with MgSO and 2-Undecylfuran (26). Prepared from undecyl iodide (39, 680
2
)acetate 1507 (w), 1464 (w), 1379 (w), 1146 (w), 1077 (w), 1006 (w),
-1
(
2
2
4
concentrated under reduced pressure to yield the crude mg, 2.5 mmol). Yield: 150 mg (0.65 mmol, 26%). TLC
1
extract that was directly analysed by NMR spectroscopy.
(cyclohexane): R
(
f
= 0.90. H NMR (500 MHz, CDCl
3
):  = 7.29
dd, JH,H = 1.6 Hz, 4JH,H = 0.6 Hz, 1H, CH), 6.27 (dd, JH,H = 1.9,
3
3
3
4
General synthetic methods
3.1 Hz, 1H, CH), 5.97 (dd, JH,H = 3.1 Hz, JH,H = 0.7 Hz, 1H, CH),
3
2
1
.61 (t, JH,H = 7.6 Hz, 2H, CH
2
), 1.63 (m, 2H, CH
2
), 1.37-1.22 (m,
Starting materials were obtained from commercial suppliers
3
13
6H, 8 x CH
2
), 0.88 (t, JH,H = 6.9 Hz, 3H, CH
3
) ppm. C NMR
(Thermo Fisher Scientific, Waltham, USA; Sigma Aldrich, St.
(
(
(
(
125 MHz, CDCl
CH), 32.0 (CH ), 29.69 (CH
), 29.39 (CH ), 29.2 (CH
), 14.2 (CH
3
):  = 156.7 (C
), 29.67 (CH
), 28.1 (CH
q
), 140.6 (CH), 110.0 (CH), 104.5
), 29.60 (CH ), 29.42
), 28.0 (CH
Louis, USA or TCI, Tokyo, Japan) and used without purification.
Flash column chromatography was performed on silica
2
2
2
2
CH
CH
2
2
2
2
2
2
), 22.7
(Geduran Si 60, 40 – 63 m, Merck, Darmstadt, Germany).
+
3
27
) ppm. HR-APCI-MS: calcd. for C15H O
Solvents for column chromatography were distilled prior to
use. All reactions were carried out in flame dried glassware
under Ar atmosphere in solvents dried by standard
procedures. All reactions and chromatographic steps were
monitored by TLC (silica, Polygram SIL G/UV254, Macherey-
Nagel, Düren, Germany). Phosphomolybdic acid in EtOH (10
g/100 mL) was used for staining. NMR spectra were recorded
on Bruker instruments (Billerica, USA), Avance III HD Prodigy
2
1
1
23.2056; found 223.2056. IR (ATR): /c = 2924 (s), 2854 (s),
597 (w), 1508 (w), 1466 (w), 1376 (w) 1229 (w), 1216 (w),
008 (w), 794 (w), 725 (m), 599 (w) cm . UV-Vis (CH Cl ): max
2 2
-1
(log ) = 213 (3.81) nm.
(
3
Z)-2-(Non-3-en-1-yl)furan (41). Prepared from (Z)-1-iodonon-
-ene (40, 0.63 g, 2.50 mmol). Yield: 134 mg (0.70 mmol, 28%).
= 0.85. H NMR (500 MHz, CDCl
.30 (dd, JH,H = 1.8 Hz, 4JH,H = 0.8 Hz, 1H, CH), 6.28 (dd, JH,H
3.1, 1.9 Hz, 1H, CH), 5.99 (dd, JH,H = 3.1 Hz, JH,H = 0.9 Hz, 1H,
CH), 5.45-5.35 (m, 2H, 2 x CH), 2.67 (t, JH,H = 7.5 Hz, 2H, CH
1
TLC (cyclohexane): R
f
3
3
):  =
3
7
=
(
500 MHz) or Avance III HD Cryo (700 MHz). Spectra were
3
4
1
referenced against solvent signals ( H-NMR, residual proton
signals: CDCl
3
 = 7.16 ppm; 1 C-NMR:
3
2
),
),
3
 = 7.26 ppm, C
D
6 6
3
2
1
.41-2.36 (m, 2H, CH
.36-1.23 (m, 6H, 3 x CH
3
2
), 2.01 (dt, 2H, JH,H = 6.8 Hz, 2H, CH
2
CDCl  = 77.16 ppm, C
3
D
6 6
 = 128.06 ppm). Optical rotations
3
2
), 0.89 (t, JH,H = 7.0 Hz, 3H, CH
3
) ppm.
), 140.8 (CH), 131.1
CH), 128.1 (CH), 110.1 (CH), 104.9 (CH), 31.5 (CH ), 29.3 (CH ),
were recorded on a P8000 Polarimeter (Krüss Optronic,
Hamburg, Germany). IR spectra were measured with a Bruker
Alpha FT-IR spectrometer. The intensities of the peaks were
1
3 q
C NMR (125 MHz, CDCl ):  = 155.9 (C
(
2
2
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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2 2 2 2 3
), 27.2 (CH ), 25.8 (CH ), 22.6 (CH ), 14.1 (CH
View Article Online
) ppm. isomer), 6.18 (d, 3JH,H = 11.8 Hz, 1H, CH, Z isomer), 6.12 (d, JH,H
3
2
8.2 (CH
+
3
DOI: 10.1039/C9MD00083F
HR-APCI-MS: calcd. for C13
(
1
1
H
21O 193.1587; found 193.1587. IR = 3.3 Hz, 1H, CH, E isomer), 5.56 (dt, JH,H = 11.7, 7.3 Hz, 1H,
ATR): /c = 3008 (w), 2957 (s), 2926 (s), 2857 (s), 1799 (w), CH, Z isomer), 2.43 (ddt, JH,H = 7.3, 7.3 Hz, 4JH,H = 1.6 Hz, 2H,
3
3
2 2
597 (w), 1507 (w), 1458 (w), 1261 (w), 1147 (w), 1104 (w), CH , Z isomer), 2.17 (dt, JH,H = 7.1, 7.1 Hz, 2H, CH , E isomer),
-1
3
3
078 (w), 1009 (m), 923 (w), 797 (w), 727 (m), 599 (w) cm . 1.47 (q, JH,H = 7.3 Hz, 2H, CH
Cl ): max (log ) = 214 (3.92) nm. 2H, CH , E isomer), 1.39 – 1.22 (m, 24H, 12 x CH
.89 (t, 3JH,H = 7.2 Hz, 6H, 2 x CH , E + Z isomer) ppm. 13C NMR
(175 MHz, CDCl ):  = 153.6 (C , E isomer), 153.6 (C , Z isomer),
41.3 (CH, E isomer), 141.3 (CH, Z isomer), 131.7 (CH, Z
2
, Z isomer), 1.45 (q, JH,H = 7.5 Hz,
UV-Vis (CH
2
2
2
2
, E + Z isomer),
0
3
Synthesis of 2-(alk-1-en-1-yl)furans by Wittig reaction
3
q
q
1
To a solution of alkyltriphenylphosphonium halide (1.0 eq) in
-1
isomer), 130.5 (CH, E isomer), 118.6 (CH, E isomer), 117.3 (CH,
Z isomer), 111.2 (CH, E isomer), 111.2 (CH, Z isomer), 108.8
anhydrous THF (5 mL mmol of halide), a solution of n-BuLi
1.6 M in hexanes, 1.0 eq) was added dropwise at –35 °C. The
(
(
CH, Z isomer), 106.0 (CH, E isomer), 33.0 (CH
2 x CH , E + Z isomer), 29.7 (CH , Z isomer), 29.7 (CH
, Z isomer), 29.7 (2 x CH
2
, E isomer), 32.0
, E
, E + Z isomer), 29.6
red ylide mixture was stirred for 30 minutes followed by
dropwise addition of 2-furaldehyde (1.0 eq) in anhydrous THF
(
2
2
2
-1
isomer), 29.7 (CH
CH , Z isomer), 29.5 (2 x CH
isomer), 29.4 (CH
2
2
(4 mL mmol of aldehyde). The mixture was warmed to room
(
2
2
, E + Z isomer), 29.4 (CH
, E isomer), 29.4 (CH , E isomer), 22.8 (CH
2 2
2
, Z
, Z
3
, E + Z isomer) ppm. HR-APCI-MS: calcd.
temperature overnight. Distilled water was added and the
aqueous phase was extracted with ethyl acetate (3 x). The
combined organic phases were dried and concentrated in
vacuo. The residue was purified by flash column
2
isomer), 14.3 (2 x CH
+
for C15
H
25O 221.1900; found 221.1897. IR (ATR): /c = 2956
m), 2925 (s), 2854 (s), 1492 (w), 1465 (w), 1150 (w), 1120 (w),
086 (w), 1039 (w), 1013 (w), 959 (w), 936 (w), 922 (w), 884
w), 800 (w), 723 (s), 654 (w), 622 (w), 595 (w) cm . UV-Vis
CH Cl ): max (log ) = 274 (3.76), 263 (3.93) nm.
(
1
chromatography (SiO
yl)furans as yellow oils.
-(Non-1-en-1-yl)furan
octyltriphenylphosphonium bromide (43, 1.1 g, 2.42 mmol).
2
, cyclohexane) to yield 2-(alk-1-en-1-
-1
(
(
2
(45).
Prepared
from
2
2
Yield: 407 mg (2.11 mmol, 88%, Z/E 7:1). TLC (cyclohexane): R
f
1
3
=
0.80. H NMR (700 MHz, CDCl
3
):  = 7.37 (d, JH,H = 1.7 Hz, 1H,
Acknowledgements
3
CH, Z isomer), 7.30 (d, JH,H = 1.7 Hz, 1H, CH, E isomer), 6.39
3
3
This work was funded by the DFG (DI1536/9-1). The authors
thank Cony Decock and Jacques Fournier for providing the
specimen and the morphological study and for their
continuous support during the monographic work on Daldinia
and other Hypoxylaceae in the past years. Technical assistance
by Neran Reuber is gratefully acknowledged.
(dd, JH,H = 3.3, 1.7 Hz, 1H, CH, Z isomer), 6.33 (dd, JH,H = 3.2,
3
1
.7 Hz, 1H, CH, E isomer), 6.25 (d, JH,H = 3.3 Hz, 1H, CH, Z
3
3
isomer), 6.19 (d, JH,H = 11.9 Hz, 1H, CH, Z isomer), 6.12 (d, JH,H
3
=
3.2 Hz, 1H, CH, E isomer), 5.56 (dt, JH,H = 11.8, 7.3 Hz, 1H,
CH, Z isomer), 2.44 (ddt, JH,H = 7.4, 7.4 Hz, 4JH,H = 1.6 Hz, 2H,
3
3
CH
1
7
2
, Z isomer), 2.17 (dt, JH,H = 7.0, 7.0 Hz, 2H, CH
, Z isomer), 1.45 (quin, 3JH,H
2
, E isomer),
.48 (quin, 3JH,H = 7.4 Hz, 2H, CH
=
2
.4 Hz, 2H, CH
2
, E isomer), 1.38 – 1.24 (m, 16H, 8 x CH
2
, E + Z
3
) ppm. 13C NMR (175
Notes and references
isomer), 0.89 (t, JH,H = 7.0 Hz, 6H, 2 x CH
MHz, CDCl ):  = 153.6 (C , E isomer), 153.6 (C
41.3 (CH, E isomer), 141.3 (CH, Z isomer), 131.7 (CH, Z
3
q
, Z isomer),
1
2
J. S. Dickschat, Nat. Prod. Rep., 2017, 34, 310.
3
q
S. E. Helaly, B. Thongbai and M. Stadler, Nat. Prod. Rep.,
1
2
018, 35, 992.
isomer), 130.5 (CH, E isomer), 118.6 (CH, E isomer), 117.3 (CH,
Z isomer), 111.2 (CH, E isomer), 111.2 (CH, Z isomer), 108.8
3
4
5
R. L. Edwards and A. J. S. Whalley, J. Chem. Soc., Perkin
Trans. 1, 1979, 803.
C. A. Citron, S. M. Wickel, B. Schulz, S. Draeger and J. S.
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Fernandez, P. Lappe-Oliveras, G. Roque-Flores, G. Duarte-
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Microbiol., 2016, 121, 380.
J. J. Shaw, T. Berbasova, T. Sasaki, K. Jefferson-George, D. J.
Spakowicz, B. F. Dunican, C. E. Portero, A. Narvaez-Trujillo
and S. A. Strobel, J. Biol. Chem., 2015, 290, 8511.
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0 E. C. Barnes, J. Jumpathong, S. Lumyong, K. Voigt and C.
Hertweck, Chem. Eur. J., 2016, 22, 4551.
(
(
CH, Z isomer), 106.0 (CH, E isomer), 33.0 (CH
2 x CH , E + Z isomer), 29.7 (CH , Z isomer), 29.5 (CH
, E + Z isomer), 29.4 (CH , E isomer), 29.4
, Z isomer), 29.3 (CH , E isomer), 29.3 (CH , E isomer), 22.8
, E + Z isomer) ppm. HR-APCI-MS:
2
, E isomer), 32.0
2
2
2
, Z
isomer), 29.4 (2 x CH
2
2
(
(
CH
CH
2
2
2
2
, Z isomer), 14.3 (2 x CH
3
6
7
+
calcd. for C13
H21O 193.1587; found 193.1587. IR (ATR): /c =
3
1
1
5
026 (w), 2956 (m), 2925 (s), 2855 (s), 1735 (w), 1583 (w),
492 (w), 1459 (w), 1256 (w), 1218 (w), 1175 (w), 1150 (w),
058 (w), 1013 (m), 960 (w), 923 (w), 885 (w), 804 (w), 729 (s),
-1
2 2
95 (w) cm . UV-Vis (CH Cl ): max (log ) = 274 (3.61), 263
(
2
3.83) nm.
-(Undec-1-en-1-yl)furan
decyltriphenylphosphonium iodide (44, 2.65 g, 5.00 mmol).
8
9
1
1
(46).
Prepared
from
Yield: 881 mg (4.00 mmol, 80%, Z/E 3:1). TLC (cyclohexane): R
f
1
3
=
0.85. H NMR (700 MHz, CDCl
3
):  = 7.34 (d, JH,H = 1.7 Hz, 1H,
3
CH, Z isomer), 7.30 (d, JH,H = 1.5 Hz, 1H, CH, E isomer), 6.39
1 E. Kuhnert, E. B. Sir, C. Lambert, K. D. Hyde, A. I. Hladki, A. I.
Romero, M. Rohde and M. Stadler, Fungal Divers., 2017, 85,
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(
dd, JH,H = 3.3, 1.8 Hz, 1H, CH, Z isomer), 6.34 (dd, 3JH,H = 3.3,
3
1
.8 Hz, 1H, CH, E isomer), 6.25 (d, 3JH,H = 3.3 Hz, 1H, CH, Z
8
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
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