Novel nonadride, heptadride and maleic acid metabolites from the byssochlamic acid producer Byssochlamys fulva IMI 40021-an insight into the biosynthesis of maleidrides

Article abstract of DOI:10.1039/c5cc06988b

The filamentous fungus Byssochlamys fulva strain IMI 40021 produces (+)-byssochlamic acid 1, its novel dihydroanalogue 2 and four related secondary metabolites. Agnestadrides A, 17 and B, 18 constitute a novel class of seven-membered ring, maleic anhydride-containing (hence termed heptadride) natural products. The putative maleic anhydride precursor 5 for both nonadride and heptadride biosynthesis was isolated as a fermentation product for the first time and its structure confirmed by synthesis. Acid 5 undergoes facile decarboxylation to anhydride 6. The generic term maleidrides is proposed to encompass biosynthetically-related compounds containing maleic anhydride moieties fused to an alicyclic ring, varying in size and substituents.

Full text of DOI:10.1039/c5cc06988b

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COMMUNICATION
Novel nonadride, heptadride and maleic acid metabolites from the
byssochlamic acid producer Byssochlamys fulva IMI 40021 – an
insight into the biosynthesis of maleidrides
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
b
Agnieszka J. Szwalbe , Katherine Williams , Daniel E. O’Flynn , Andrew M. Bailey , Nicholas P.
c
c
a
a,d
a
DOI: 10.1039/x0xx00000x
Mulholland , Jason L. Vincent , Christine L. Willis , Russell J. Cox* and Thomas J. Simpson* .
www.rsc.org/
8
The filamentous fungus Byssochlamys fulva strain IMI40021 synthesis of (+)–byssochlamic acid.
produces (+)-byssochlamic acid 1, its novel dihydroanalogue 2 and
All three metabolites, 1, 3 and 4, were hypothesised to be
biosynthesised via alternative dimerisation modes of a C
novel class of seven-membered ring, maleic maleic acid precursor 5 and/or 6, and evidence for this was
four related secondary metabolites. Agnestadrides A, 17 and B, 18
constitute
9
/C10-
a
9
anhydride-containing (hence termed heptadride) natural obtained by feeding studies with radiolabelled 6. Many more
products. The putative maleic anhydride precursor 5 for both nonadride metabolites have since been reported, e.g. heveadride
10
7
,
an isomer of 1, and others which are expected to be
nonadride and heptadride biosynthesis was isolated as
a
biosynthesised through dimerisation of differently substituted
fermenation product for the first time and its structure confirmed
by synthesis. Acid 5 undergoes facile decarboxylation to anhydride
1
1
maleic anhydride units, including scytalidin 8, and castaneolide
1
2
9
.
More complex examples include rubratoxin A 10, and its
6
.
The generic term maleidrides is proposed to encompass
13
dihydro-analogue rubratoxin B 11, and phomoidrides A 12 and B
3. Cornexistin 14, is a nonadride unique in having a single
biosynthetically-related compounds containing maleic anhydride
moieties fused to an alicyclic ring, varying in size and substituents.
14
1
15
16
17
anhydride unit. Viburspiran 15 and zopfiellin 16, feature 8-
membered carbocyclic rings and so have been classed as
octadrides. Notably, all of the compounds belonging to this family
reported so far have been isolated from fungi.
The collective name “nonadrides” was introduced by Barton and
Sutherland for fungal metabolites containing a nine-membered ring
1
fused to one or two maleic anhydride moieties in 1965. The first of
1'
O
these, glaucanic acid 3 and glauconic acid 4 were isolated from
O
2
'
3
12
2
O
B
O
O
O
Penicillium glaucum, by Wijkman and reported in 1931. Soon
2
4
O
1
3
1
R
5
O
*
afterwards the pseudo-symmetrical analogue, byssochlamic acid 1
was isolated from the common food contaminant Byssochlamys
9
O
R
7
6
R
O
O
1
0
A
8
R
O
O
5'
O
O
O
3
11
O
4'
O
fulva by Raistrick and coworkers. However the structures of 1 and
3'
R = O
R = H,OH
O
O
1
2
5
6
R = CO
R = H
2
H
7 R = O
3
4
R = H
R = OH
4
were only established some 30 years later by X-ray
4
,5
O
OH
HO
O
analysis. Barton and coworkers subsequently reisolated
from Penicillium purporogenum and began considering the
O
OH
O
H
2
HO C
OH
H
4
O
O
R
O
O
6
biosynthesis of the nonadrides. The cis relative stereochemistry of
O
O
O
O
O
O
R
OH
12
the ethyl and propyl groups of byssochlamic acid was confirmed by
O
O
O
O
O
H
O
5
HO
HO2
C
X-ray analysis of the bis-p-bromophenylhydrazide. The absolute
O
O
8
9
R = H
R = OH
10 R = O
11 R = H, OH
O
configuration of
1
was established by classical degradative
O
7
O
13
methods,
and subsequently confirmed by enantiospecific
O
O
O
O
OH
O
OH
H
O
H
O
H
O
O
O
OH
O
O
OH
15
O
O
O
O
1
4
16
Pursuing a general interest in the biosynthesis of nonadrides and
other related fungal compounds, we re-analysed the secondary
metabolite profile of B. fulva to assess its nonadride-related
metabolites in greater detail. This has led to isolation and
characterisation of a new analogue, dihydro-byssochlamic acid 2;
two novel metabolites agnestadride A 17 and agnestadride B 18,
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1
2
4
9
10
O
3
5
11
O
O
8
7
12
O
O
6
O
3
O
15
O
14
17
O
O
1
OH
1
O
6
O
O
18
O
17
1
8
19
weight as byssochlamic acid 1 but a slightly different UV spectrum.
It was isolated by HPLC (~1 mg.L culture) and HRESIMS confirmed
Figure 1. HPLC (DAD) chromatogram of B. fulva extract.
-1
20 6
both containing 7 membered rings which we have therefore termed it to have the same molecular formula (C18H O ) as byssochlamic
1
heptadrides; and as a natural product for the first time, the acid. However, H NMR analysis (Table S2) showed the presence of
proposed nonadride precursor, maleic anhydride 5 along with its a 1-butenyl side chain. The HSQC spectrum revealed only nineteen
decarboxylated derivative 6.
hydrogens attached to carbon, suggesting that the other belonged
to a hydroxyl. The presence of a further propyl substituent linked to
an otherwise uncoupled CH, and two mutually coupled methylenes
were obvious from the COSY spectrum (Figure 2a). The
characteristic signals for one maleic anhydride were apparent at
3
B. fulva, was grown as described by Raistrick in static culture in
Czapek-Dox liquid medium with glucose as the sole carbon source
for between 7 and 30 days. The crude ethyl acetate extracts were
analysed by LCMS. Byssochlamic acid 1 (C18
20 6
H O ) was detectable
1
43.3 (C-11), 165.3 (C-12), 164.8 (C-13) and 144.9 (C-14) ppm. The
after 7 days of static fermentation (Figure 1, 15.4 min.) and large
-1
remaining 4 carbons resonances at 168.5 (C-6), 127.0 (C-5), 153.4
(C-8) and 104.0 (C-7) ppm were indicative of an α,β-unsaturated
ester/lactone and an acetal, consistent with the hydroxylactone
moiety indicted in bold in Figure 2a. Further detailed analysis of the
HMBC data (Figure 2b) was consistent with the seven-membered
carbocycle, which we name agnestadride A 17. The key correlations
were seen from the butenyl H-4 (6.08 ppm) to C-5, C-6 and C-8, and
amounts (> 50 mg
•
L ) could be isolated after 4 weeks. Its identity
1
was confirmed as (+)-byssochlamic acid by comparison of 1D H and
1
3
C NMR spectra, and optical rotation comparison with literature
8
values. Detailed analysis of 2D NMR spectra (COSY, HSQC and
1
13
HMBC) allowed all signals in the H and C NMR spectra to be fully
assigned for the first time (Table S1).
The second-most abundant component of the extract eluted at 11.3 from H-16 (3.54 ppm) to C-7, and 9-CH (3.01/2.66 ppm) to C-5, C-7
2
min. (Figure 1). The new compound had
a UV absorption and C-8 to firmly locate the hydroxylactone ring. Similarly,
characteristic for nonadrides (λmax 211, 260 nm), ionized well in the correlations from 9-CH2 to C-10 (20.6 ppm) and C-11, and 10-CH2
negative ESIMS mode and had the same fragmentation pattern as (3.05/2.52 ppm) to C-11, C-12 and C-13 locate the maleic anhydride
byssochlamic acid 1 – the only difference being that all of the peaks moiety.
appeared at m/z values two units higher. HRESIMS analysis
A less polar new compound was detected (18.4 min. in Figure 1)
22 6
confirmed the molecular formula to be C18H O , corresponding to a
-
1)
and was isolated (1mg.L using mass-directed preparative HPLC. It
reduced form of 1. Dihydrobyssochlamic acid 2 was purified by
mass-directed preparative HPLC. The NMR spectra (Table S1) were
compared with those of byssochlamic acid 1. A new peak at 95.9
-
had a mass of 314 (peak of m/z 313 [M-H] in the negative ESIMS
spectrum), corresponding to a dehydrated derivative of 17. The
formula was confirmed by HRESIMS analysis to be C18H O . In
18 5
1
3
ppm in the C NMR spectra correlated (HSQC) to H-10 at 5.71 ppm
confirmed the presence of a hemi-acetal in 2. Consistent with the
loss of the carbonyl, the resonances of C-11 and C-9 appeared at
higher chemical shifts (172.2 and 160.7 ppm respectively), and the
C-8 resonance moved upfield to 130.6 ppm. Key HMBC signals
contrast with other colourless metabolites isolated from B. fulva
1
compound 18 was bright yellow. The H NMR spectrum revealed
that 18 also contained a pendant 1-butenyl side chain. A total of 18
1
protons were observed in the H NMR spectrum (Table S2). There
1
3
were three C NMR resonances (166.2, 164.6 and 163.1 ppm)
characteristic for anhydride/ unsaturated lactone carbonyls, and 6
quaternary olefinic carbons. The C-7 acetal and C-15 methine
signals in 18 were absent, being replaced by two quaternary olefinic
carbons. This data is fully consistent with compound 18, named
agnestadride B, being a dehydrated form of agnestadride A. The
structure is supported by HMBC correlations, from H-4 to C-5 and C-
2
included correlations between 1-CH protons (2.42/2.32 ppm) and
C-8, C-9 and C-10; C-9, C-8 and C-11 but not C-10 correlated also to
H-7 (2.81 ppm), consistent with the lactol hydroxyl being attached
2
to C-10. Moreover, 6-CH (3.03/2.60ppm) showed correlations with
C-8, C-4, C-5 and C-13 (130.1, 139.1, 139.9 and 168.5 ppm
respectively) but not C-11 or C-9 (171.8 and 160.3 ppm).
1
Interestingly, closer inspection of the H NMR spectrum showed the
6
2
, as well as from 17-CH to C-15. To our knowledge, no heptadrides
presence of one major singlet at 5.71 ppm consistent with the
hemi-acetal adopting one major configuration (68%) but three
other singlet methine signals were apparent at 5.80 (16%), 5.84
have been previously reported as natural products. Baldwin and co-
workers, investigating biomimetic dimerisation of putative
nonadride maleic anhydride monomers isolated
a heptadride
(
5%), and 5.93 (11%) ppm respectively. While one of these minor
structure 19 which was also reported as being an intense yellow
components is likely to be due to the epimeric lactol, the other two
signals may be due to regioisomeric lactols. Other nonadride lactol
1
9
compound.
1
3
analogues are known, e.g. rubratoxin B 11 and dihydro- and
tetrahydroepiheveadrides (e.g. 7 = H, OH, * = S) have been isolated
O
O
O
O
1
8
from Wicklowia aquatica, along with the corresponding lactones.
O
O
In phomoidride A 12, one of the anhydrides is found as a hemi-
acetal due to a transannular C-C bond, and in phomoidride B 13 as a
O
O
HO
OH
O
O
1
4
(a)
(
b)
full acetal due to further linkage to a side chain hydroxyl.
17
Figure 2. (a) COSY correlations of three isolated spin systems of 17.
b) HMBC correlations.
LCMS chromatograms of extracts from older cultures of B. fulva (ca.
(
3
0 days) showed a new peak at 13.3 min. with the same molecular
2
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1
O
O
B
O
O
O
OTBS
O
2
4
present in the H NMR spectrum of the impure naturally occurring 5
matched those of the synthetic analogue (Table S3). Interestingly
anhydride 6, did not show any signal by ELS (Evaporative Light
Scattering) detection and attempts to purify it by HPLC resulted in
yields much lower than anticipated. This was attributed to volatility
of 5, and was confirmed by HPLC of a sample that had been allowed
to evaporate at room temperature. On re-addition of solvent HPLC
analysis showed that ca. 96% of the compound had evaporated.
Br
Br
22
Br
t
(a)
O Bu
(c)
tBuO
C
2
O
O
(b)
O
O
Br
Br
OH
OTBS
OTBS
OTBS
2
0
21
23
25
(
d)
O
O
O
HO
2
C
(f)
t
BuO2
C
O
(e)
t
BuO2C
O
O
O
O
OH
5
27
2
6
Byssochlamic acid 1 exists in equilibrium with its mono-hydrated
Scheme 1. Synthesis of anhydride 5. Reagents and conditions; (a) diacid forms which appear together at 9.8 min in the LCMS
TBSCl (1.2 eq), imidazole (1.5 eq), DMAP (0.05 eq), DCM:DMF (6:1), r.t, 22 h,
chromatogram (1a/1b in Figure 1), as indicated by the characteristic
7
9%; (b) (E)-2-(but-1-en-1-yl)benzo[d][1,3,2]dioxaborole 22 (1.2 eq),
Pd(PPh Cl (0.05 eq), KOAc (2 eq), PhMe, H O, reflux, 16 h 79%; (c) 1-(tert-
butyldimethylsilyloxy)-1-tert-butoxyethylene (2.04 eq), Pd(PTol Cl (0.05
-
[
M + H O - H] ion (m/z 349.2) in the negative ESIMS spectrum. This
2
3
)
2
2
2
peak appeared in chromatograms of purified byssochlamic acid 1
and of a purified mixture of 1a/1b. When re-injected, this reforms
3
)
2
2
eq), KOAc (2 eq), THF, reflux, 16 h, 93%; (d) HF-Py (70:30) (3 eq), THF, 0 °C to
r.t, 18 h, 46%; (e) DMP (3 eq), DCM, 0 °C to r.t, 16 h, 86%; (f) TFA (excess),
1
an equilibrium mixture with byssochlamic acid 1. H NMR spectra
6
6%.
showed that the ring-closed form 1 is preferred in organic solvent,
while the ring-open forms 1a/1b are also present in aqueous
Barton and coworkers suggested that maleic anhydride 6 is the solvents. Similar behaviour is observed for other maleic anhydride
6
precursor of 1. Although indirect and direct evidence has containing metabolites including the compound 5 (see peaks at 11.3
6
,20,21
accumulated for this hypothesis,
observed as a component of B. fulva fermentations. Subsequent acid 2, and for related maleic anhydrides isolated from P. variotii.
anhydride 6 has never been and 4.9 min in Figure 1), and 6 (Figure S3) and dihydrobyssochlamic
25
feeding studies on the phomoidrides utilising synthetic precursor
26
Previous work had provided evidence for biosynthesis of
byssochlamic acid via dimerisation of maleic anhydride 6 the
decarboxylated form of 5. However, it would appear likely that 5 is
the actual precursor, decarboxylation providing the exo-methylene
intermediate 28 necessary for cyclisation with a second molecule of
22
analogues by Sulikowski and coworkers indicated that the
monomeric nonadride precursor unit may be a carboxylated
species, e.g. 5 for byssochlamic acid. In an attempt to find 5 or 6 in
extracts of B. fulva, we searched extracted ion chromatograms of
fresh extracts and identified a candidate peak at 7.7 min. (Figure 1).
This metabolite formed ions of m/z 209.5, 165.5 in the negative
5
as indicated in Scheme 2 (pathway a). Tautomerisation of the first
formed macrocycle leads to byssochlamic acid 1. The heptadrides,
agnestadrides A and B can be accounted for by a different mode of
dimerisation of these intermediates as indicated in Scheme 2
-
ESIMS, which matched masses of ions expected for 5 ([M-H] and
-
[
(
M-H-CO
2
] respectively) and m/z 211.5, 193.3 in the positive ESIMS
+
+
2
[M+H] and [M+H-H O] respectively). This compound was purified,
(
pathway b). Formal Michael addition of the anion derived by
but identification by full NMR (Table S3) and HRESIMS analysis
surprisingly showed it to be 6, the decarboxylated form of 5.
Reinjection of 6 into the LCMS showed that it had a different
retention time to 5, suggesting that it had decarboxylated during
purification and/or subsequent analysis. So to confirm the structure
and study its stability maleic anhydride 5 was synthesised as shown
decarboxylation of 5 now occurs on the other end of the diene
system of 28. In the in vitro studies leading to 19 strong base was
19
required to trigger dimerisation. Although presented in Scheme 2
as synchronous processes, stepwise mechanisms are equally valid
at this stage. Interestingly diene 28 has been isolated as
waquafranone B, along with waquafranone A 29 and several
2
2
in Scheme 1 based on previous work by Sulikowski. Commercially
available mucobromic acid 20 was protected as silyl ether 21 in 79%
yield. (E)-2-(But-1-en-1-yl)benzo[d][1,3,2]dioxaborole 22 prepared
18
epiheveadrides from W. aquatica. Also, the exo-methylene
compound 30 has been isolated, as tubingenoic acid, from
27
Aspergillus tubingensis, along with the hexyl analogue of 5, itself a
2
3
via the hydroboration of 1-butyne with catecholborane
26, 28, 29
metbolite of several Aspergillus species.
underwent Suzuki cross-coupling with 21 to give bromide 23 regio-
selectively (as proven by HMBC). No bis-coupling was observed and
the trans-geometry of the alkene was confirmed by a 16 Hz
O
O
1
O
O
O
H
coupling constant in the H NMR spectrum. Palladium-catalysed
O
O
O
O
H
H
+
coupling of the bromide 23 with silyl enol ether 24 (prepared
pathway
a
-
CO
2
O
OH
O
1
2
4
O
separately by treatment of tert-butyl acetate with LDA and TBSCl)
O
O
O
H
+
O
O
afforded ester 25 in an excellent yield of 93%. Removal of the TBS
group with HF-pyridine was sluggish, giving yields of 26 typically
between 30-46%. The resulting lactol 26 was then oxidised
efficiently by Dess-Martin periodinane to 27 and final ester
5
O
2
8
O
O
H
O
O
O
O
O
29
2
- H O
O
pathway
b
1
8
hydrolysis with TFA generated anhydride 5 in 66% yield
.
O
O
O
O
O
O
O
OH
O
O
H
+
O
The identity of naturally occurring 5 was confirmed by comparing its
LCMS characteristics with the data collected for the synthetic
O
17
30
product. The synthetic compound was observed to undergo Scheme 2. Proposed biosynthesis of nonadride and heptadrides via
decomposition to spontaneously and decomposition was common intermediates.
6
complete in under 48 h. The less polar peak at 20.6 min (Figure S2)
had a similar UV spectrum to 5, however it did not ionize well (the -
ESI spectrum shows a m/z 165 with a m/z of 209 but only in very
concentrated samples), which was consistent with the loss of the
ionisable carboxylate group. In addition the chemical shifts of peaks
Our work with B. fulva has led to the isolation of 5 new maleic
anhydride-containing compounds in addition to byssochlamic acid.
These include dihydrobyssochlamic acid, but more significantly, two
novel 7-membered ring analogues which we have termed
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heptadrides by analogy to nine-membered nonadrides and eight- 18 T. Hosoe, J.B. Gloer, D. T. Wicklow, H. A. Raja and C.A.
membered octadrides. Heptadrides have never been reported
previously as natural products. In addition, the putative
Shearer, Heterocycles, 2010, 81, 2123.
‡
1
9 J. E. Baldwin, A. Beyeler, R. J. Cox, C. Keats, G. J. Pritchard, M.
Adlington, D. J. Watkin, Tetrahedron, 1999, 55, 7363.
0 C. E. Moppett, J. K. Sutherland, Chem. Commun., 1966, 772.
1 G. A. Sulikowski, F. Agnelli, P. Spencer, J. M. Koomen, D. H.
monomeric maleic anhydride intermediate previously proposed to
undergo macrocyclisation via dimerisation to give byssochlamic acid
and other nonadrides, has also been isolated for the first time. A
scheme for the biosynthesis of both the nonadrides and
heptadrides is proposed. Work is in progress to establish details of
the biosynthesis, as well as the identification of the biosynthetic
gene cluster.
2
2
Russell, Org. Lett., 2002,
2 G. A. Sulikowski, F. Agnelli, R. M. Corbett, J. Org. Chem.,
000, 65, 337.
3 J. D. White, Y. Choi, Helv. Chim. Acta, 2002, 85, 4306
4, 1447
2
2
2
24 S. Danishefsky, K. Vaughan, R. Gadwood, K. J. Tsuzuki, Am.
Chem.Soc., 1981, 103, 4136.
5 D. C. Aldridge, R. M. Carman, R. B. Moore, J. Chem. Soc.,
Perkin Trans. 1, 1980, 2134.
6 R. K. Huff, C. K. Moppett, J. K. Sutherland, Chem. Comm.
To account for diversity among nonadride-like natural products, we
propose the generic name maleidrides to denote biosynthetically
related compounds, with one (monomaleidrides) or two
2
2
(bismaleidrides) maleic anhydride units anchored on a diversely
1
968, 1192.
substituted ring. Production of the anhydride 5 by B. fulva, along 27 L. Koch, A. Lodin, I. Herold, M. Ilan, S. Carmeli, O. Yarden,
with hepta- and nonadrides, indicates that the diversity among
Mar. Drugs, 2014, 12, 4713.
maleidrides very likely arises not only from diversely substituted 28 G. Mondal, P. Dureja, B. Sen, Ind. J. Exp. Biology, 2000, 84.
2
9 H.-L. Winderemüller, F. Cavagna, H.-W. Fehlhaber, P. Präve,
Tetrahderon Lett., 1972, 3519.
anhydride precursors, but also from alternative dimerisation
modes.
We thank Prof. Matthew Crump for help with acquiring 600 MHz
NMR data, Dr. Craig Butts and Paul Lawrence for assistance with
500 MHz-cryo NMR instrument and Dr. Paul Gates from Bristol
University Mass Spectrometry Service for help with obtaining HRMS
data. Financial support (AJW and KW) was provided by BBSRC and
Syngenta (BB/J006289/1), and the EPSRC (CDT award forDEO’F).
Notes and References
‡
Tropolone metabolites, e.g. stipitatonic and puberlonic acids,
contain maleic anhydride moieties fused to 7-membered
aromatic polyketide-derived rings, in contrast to the alicyclic
rings found in the nonadride and related metabolites.
1
2
3
4
J.K. Sutherland, Fortschr. Chem. Org. Naturst., 1967, 25, 131.
N. Wijkman, Liebeigs Ann. Chem., 1931, 485, 61.
H. Raistrick, G. Smith, Biochem. J., 1933, 27, 1814.
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