Chloriolide, a 12-membered macrolide from Chloridium virescens var. chlamydosporum (NRRL 37636)

Article abstract of DOI:10.1021/np0504964

A new 12-membered macrolide (chloriolide; 1) was obtained from solid-substrate fermentation cultures of Chloridium virescens var. chlamydosporum that was originally isolated from decayed wood. The structure of 1 was determined by analysis of ID NMR, 2D NMR, and MS data and confirmed by X-ray crystallographic analysis. The absolute configuration of 1 was assigned by application of the modified Mosher method using the (R)- and (S)-MTPA derivatives of a rearrangement product obtained under standard acylation conditions. The assignment made by analysis of the corresponding Δδ values was verified by X-ray crystallographic analysis of the (S)-MTPA derivative.

Full text of DOI:10.1021/np0504964

636
J. Nat. Prod. 2006, 69, 636-639
Chloriolide, a 12-Membered Macrolide from Chloridium Wirescens var. chlamydosporum (NRRL
37636)
Ping Jiao,† Dale C. Swenson,† James B. Gloer,*,† and Donald T. Wicklow‡
Department of Chemistry, UniVersity of Iowa, Iowa City, Iowa 52242, and Mycotoxin Research Unit,
Agricultural Research SerVice, National Center for Agricultural Utilization Research, USDA, Peoria, Illinois 61604
ReceiVed NoVember 29, 2005
A new 12-membered macrolide (chloriolide; 1) was obtained from solid-substrate fermentation cultures of Chloridium
Virescens var. chlamydosporum that was originally isolated from decayed wood. The structure of 1 was determined by
analysis of 1D NMR, 2D NMR, and MS data and confirmed by X-ray crystallographic analysis. The absolute configuration
of 1 was assigned by application of the modified Mosher method using the (R)- and (S)-MTPA derivatives of a
rearrangement product obtained under standard acylation conditions. The assignment made by analysis of the corresponding
∆δ values was verified by X-ray crystallographic analysis of the (S)-MTPA derivative.
In the course of our ongoing studies of mycoparasitic and
fungicolous fungi as sources of new bioactive natural products,1-4
chemical investigation of solid-substrate fermentation cultures of
Chloridium Virescens var. chlamydosporum (J.F.H. Beyma) W.
Gams & Holubova-Jechova (anamorph: Lasiosphaeriaceae) led to
the isolation of a new 12-membered macrolide, chloriolide (1), along
with two other known macrolides. Details of the isolation, structure
elucidation, and stereochemical assignment of chloriolide (1) are
presented here.
The isolate of C. Virescens var. chlamydosporum employed in
this work (MYC-1299 ) NRRL 37636) was obtained from an area
of conspicuous fungal colonization on the underside of a decaying
hardwood branch collected in a Florida pine-oak forest and was
C12H18O4 (four unsaturations). The NMR data (Table 1) indicated
the presence of two 1,2-disubstituted olefin moieties and one
carboxy carbon, requiring chloriolide to be monocyclic. The H-
considered to be a fungicolous isolate. The term “fungicolous” is
sometimes used to refer specifically to fungi found as colonists of
macromycetes, but can also be employed more widely to embrace
a range of fungus-fungus relationships.5 Hawksworth observed that
saprophytic Hyphomycetes may be found growing intermixed with
one another, and in some instances overgrowth or facultative
parasitism may be exhibited, as with C. botryoideum (Corda)
Hughes on various dematiaceous fungal species on wood.5 C.
Virescens var. chlamydosporum is most commonly isolated from
wood in advanced stages of decay and from forest soils rich in
organic matter.6,7 The fungus was one of five Hyphomycetes shown
to increase in frequency with the decomposition of fallen logs of
Picea glauca that were also colonized by Basidiomycetes.8 There
are no prior reports of chemistry from this species and only one
report of chemistry from any member of the genussan unrelated
compound described from an unidentified Chloridium spp.9
The EtOAc extract of solid-substrate fermentation cultures of
C. Virescens var. chlamydosporum exhibited activity against As-
pergillus flaVus and Fusarium Verticillioides and was fractionated
by Sephadex LH-20 column chromatography, followed by flash
silica gel chromatography and HPLC, to afford a new 12-membered
macrolide (1) and the known bioactive macrolides monorden
(radicicol)10,11 and pochonin B.12 The known compounds were
identified by comparison of their spectroscopic data with published
values.10-12
1
1H COSY spectra, together with chemical shift data, revealed a
single spin-system corresponding to the C2-C12 unit in 1. The
geometries of the C2-C3 and C5-C6 double bonds were assigned
as E and Z, respectively, on the basis of 1H-1H coupling constants
(JH2-H3 ) 16 Hz, JH5-H6 ) 12 Hz). HMBC correlations observed
from olefinic proton H-2 and deshielded oxymethine proton H-11
to carboxy carbon C-1 established the location of the ester linkage,
leading to the gross structure of 1 as shown.
The geometry of the double bonds in 1 was confirmed, and the
relative configurations at C-4, C-7, and C-11 were assigned by
X-ray crystallographic analysis. Colorless prisms of 1 were obtained
from CH2Cl2/CH3OH. X-ray diffraction analysis of 1 revealed the
relative configuration as shown in Figure 1. Intermolecular hydrogen
bonding was observed between the two hydroxyl groups in the
crystal structure.
a
Table 1. NMR Data for Chloriolide (1) in CDCl3
position
δH
δC
HMBC (H f C#)
1
2
3
4
5
6
7
166.7
119.8
152.7
68.2
126.8
140.5
69.9
6.15 (dd, 16, 2.2)
7.20 (dd, 16, 2.5)
4.80 (dt, 7.3, 2.5)
5.75 (dd, 12, 7.3)
5.55 (dd, 12, 8.2)
4.60 (br t, 8.2)
1, 3, 4
1, 2, 4
2, 3, 5, 6
3, 4, 6
4, 5
Results and Discussion
5, 8, 9
7, 9, 10
7, 8, 10, 11
8, 9, 11
1, 10
8
9
10
11
12
1.69 (m), 1.58 (m)
1.83 (m), 1.22 (m)
1.78 (m), 1.45 (dt, 13, 8.4)
5.20 (m)
36.8
21.5
34.4
74.1
Chloriolide (1) was obtained as a white powder that afforded
NMR and EIMS data consistent with the molecular formula
* To whom correspondence should be addressed. Tel: 319-335-1361.
Fax: 319-335-1270. E-mail: james-gloer@uiowa.edu.
† University of Iowa.
1.35 (d, 6.4)
19.8
10, 11
1
a Recorded at 300 MHz for H NMR, 100 MHz for 13C NMR, and
‡ National Center for Agricultural Utilization Research.
600 MHz for HMBC.
10.1021/np0504964 CCC: $33.50
© 2006 American Chemical Society and American Society of Pharmacognosy
Published on Web 02/14/2006

12-Membered Macrolide from Chloridium Virescens
Journal of Natural Products, 2006, Vol. 69, No. 4 637
Figure 2. ∆δ values ()δS - δR; in ppm) obtained for (S)- and
(R)-MTPA esters 4 and 3.
Figure 1. X-ray crystal structure of chloriolide (1).
Efforts to determine the absolute configuration of compound 1
using the modified Mosher’s method13 were undertaken. Although
two secondary hydroxyl groups are present in 1, 1 equiv of (S)-
MTPACl [R-methoxy-R-(trifluoromethyl)phenylacetyl chloride] was
added in an effort to prepare a monoacyl derivative. Two major
products were obtained. The EIMS molecular ion peak at m/z 442
for one product (2) was consistent with the result expected for a
1
monoacylated product. However, the H NMR spectrum showed
that the core structure of 1 had changed during the reaction. The
two olefinic protons of the C2-C3 E-double bond were replaced
by a methine triplet at δH 5.30 and a methylene doublet at δH 2.95,
which were mutually coupled, as indicated by homonuclear
decoupling experiments. The C5-C12 portion of the molecule
remained the same as in compound 1, but this spin-system was
insulated from the new unit. Analysis of these data suggested that
the product had undergone a double-bond rearrangement ac-
companied by a monoacylation to give structure 2.
Figure 3. X-ray crystal structure of (S)-MTPA ester 4.
Fortunately, a crystal of 4 was obtained from EtOAc/hexanes. X-ray
diffraction analysis revealed that the new enol ester double bond
has the Z geometry and also provided independent confirmation of
the absolute configuration assignment for 4 arrived at by the
modified Mosher protocol, and therefore for 1-3 as well.
1
The H NMR and MS data for the second product (3) clearly
revealed that two MTPA units had been added and that the same
double-bond rearrangement had occurred. The diastereotopic proton
resonances of the new methylene group appeared at slightly different
positions in this case. In addition, the signal for H-7 was shifted
significantly downfield relative to that of 1, indicating that the
hydroxyl group at C-7 was acylated in 3. HMBC and HMQC data
were obtained for 3 in order to verify the proposed structure. These
experiments allowed assignment of three new carbon signals around
δC 114.7, 144.5, and 32.0. The HMBC correlations observed from
H-3 to C-4, from H-5 to C-3, and from H-6 to C-4 indicated that
the double bond formed involving carbons at δC 114.7 and 144.5
(C-3 and C-4) was conjugated with the Z-double bond of the C5-
C12 unit. Correlations between the methylene protons and the ester
carbonyl confirmed the occurrence of the double-bond rearrange-
ment.
In an effort to prevent the occurrence of the double-bond
rearrangement, a different acylation reaction of 1 under somewhat
milder conditions using R-MPAOH (R-methoxyphenylacetic acid)
with EDC [1-ethyl-3-(3-dimethylaminopropyl)carbodiimide]14 as the
coupling reagent was conducted. However, only products displaying
the same double-bond rearrangement were observed, as exemplified
by diacylation product 5, which was isolated and characterized. At
the same time, a blank control experiment carried out exposing 1
only to DMAP resulted in little if any reaction, with only a possible
trace of the keto form of the nonacylated version of 2-4 being
observed. Treatment of 1 with dilute HCl resulted in no rearrange-
ment product, but instead afforded NMR signals consistent with
hydrolytic cleavage of the lactone ring. The reason for the
prevalence of this rearrangement under acylation reaction conditions
is not clear, although limited molecular modeling calculations
(CambridgeSoft Chem 3D Pro version 9.0.1) indicate that the
products arising from the double-bond rearrangement are somewhat
more stable than their unrearranged counterparts.
Upon treatment of 1 with 2 equiv of (R)-MTPACl, bis-(S)-MTPA
1
ester 4 was obtained as the major product. H-1H COSY data
enabled assignment of the proton signals for 4, and comparison of
these results with the 1D and 2D NMR data for 3 allowed
assignment of the corresponding signals for 3. Analysis of the ∆δS-R
values for the two diastereomeric esters 3 and 4 (Figure 3)13 enabled
assignment of the absolute configuration at C-7 as R. 4S and 11S
configurations could then be assigned to 1 on the basis of the
knowledge of the relative configuration from the X-ray structure.
However, the geometry of the new C3-C4 double bond formed in
2-4 proved to be difficult to assign unambiguously by NMR.
Chloriolide is a member of a family of polyketide-derived fungal
macrolactones. The closest known analogues are patulolides A-C
from Penicllium urticae15,16 and cladospolides A-D produced by
Cladosporium spp.17-19 These precedents also possess 12-membered
lactone rings, but with different arrangements in functionality.
Interestingly, the 11S configuration assigned to 1 is different from

638 Journal of Natural Products, 2006, Vol. 69, No. 4
Jiao et al.
that reported for the analogous centers in monorden,11 pochonin
B,12 patulolides A-C,15,16 and cladospolides A-D,17-19 although
it does match the configuration recently assigned at the correspond-
ing center in iso-cladospolide B and pandangolides 1 and 1a.20
Table 2. NMR Data for Mosher Esters 2 and 3 in CDCl3
2
3
a
c
d
position
δH
δH
δC
1
2
169.3
32.0
Although the related cladospolides and patulolides have been
reported to show antifungal and antibacterial activity,15-17 chlori-
olide (1) was inactive against Aspergillus flaVus (NRRL 6541) and
Fusarium Verticillioides (NRRL 25457) in standard disk assays1
at 200 µg/disk. Chloriolide (1) was also inactive in antibacterial
disk assays against Staphylococcus aureus (ATCC 29213), Es-
cherichia coli (ATCC 25922), and Bacillus subtilis (ATCC 6051).
The antifungal activity of the original extract in this case was
attributed to the presence of the well-known antifungal metabolite
monorden. Monorden (also known as radicicol) is produced by
Monicillium nordinii, a mycoparasite isolated from fungi that attack
forest trees, as well as a variety of other fungi.1,21
2.95 (d, 8.3)
5.30 (t, 8.3)
2.97 (ddd, 17, 8.3, 1.1)
2.89 (ddd, 17, 8.3, 1.1)
5.47 (td, 8.3, 1.1)
3
4
5
6
7
8
114.5
144.5
124.5
139.0
73.3
6.00 (d, 10)
5.77 (dd, 10, 6.9)
4.80 (m)
6.19 (br d, 11)
5.80 (dd, 11, 6.5)
6.12 (m)
2.02 (tdd, 13, 4.6, 3.0),
1.71 (m)
1.55 (m), 1.16 (m)
1.72 (m), 1.39 (ddd, 15,
10, 4.5)
2.0-1.2b
33.0
9
10
2.0-1.2b
2.0-1.2b
32.0
30.5
11
12
5.10 (m)
1.22 (d, 6.5)
5.05 (m)
1.19 (d, 6.4)
72.5
17.4
a Recorded at 300 MHz. b Methylene signals H2-8-H2-10 in 2 were
not specifically assigned due to extensive overlap. c Recorded at 600
MHz. d These 13C NMR shifts were assigned on the basis of 600-MHz
HMBC data.
Experimental Section
General Experimental Procedures. The optical rotation was
determined with a Rudolph automatic polarimeter, model AP III 589,
and UV data were recorded with a Varian Cary III UV-visible
spectrophotometer. 1H and 13C NMR spectra were acquired on Bruker
DPX-300 and DRX-400 spectrometers, respectively. HMQC and
HMBC data were obtained on a Bruker Avance-600. HPLC was carried
out using a Beckman system Gold instrument with a model 166 UV
detector. Other general procedures and instrumentation have been
described previously.22
35% level. No other restraints or constraints were applied. The final
refinement gave R1 ) 0.0273, wR2 ) 0.0692.
Preparation of (R)-MTPA Esters 2 and 3. To a solution of 1 (1.5
mg, 0.067 mmol) in CH2Cl2 (1 mL) was added (S)-MTPACl (1.7 mg,
0.067 mmol) and DMAP (1 crystal). After stirring at ambient
temperature for 14 h, saturated aqueous NaHCO3 was added. The
reaction mixture was extracted with CH2Cl2 (3 × 1 mL), and the organic
layer was collected, evaporated to dryness, and subjected to RP-HPLC
(Alltech HS BDS 8 µm C18 column, 250 × 10 mm; flow rate 2 mL/
min, UV detection at 215 nm, eluent MeCN/H2O, 30-100% over 30
min) to afford 2 (0.5 mg) and 3 (0.7 mg). Compound 2: white solid;
1H NMR data, see Table 2; EIMS m/z 442 (M+; 7), 387 (14), 189
(100). Compound 3: white solid; 1H and 13C NMR data, see Table 2;
selected key HMBC data, H-2 f C-1, 3, 4; H-3 f C-1, 4, 5; H-5 f
C-3, 7; H-6 f C-4; H-7 f C-5; ESIMS m/z 676 [M + NH4]+, 681 [M
+ Na]+, 697 [M + K]+.
Fungal Material. A culture of C. Virescens var. chlamydosporum
(MYC-1299) was isolated from a visibly decayed portion of a dead
hardwood branch collected from a long-leaf pine-oak forest at Wakulla
Springs State Park near Crawfordsville, Florida, in May 2002. A
subculture has been deposited in the Agricultural Research Service
(ARS) collection at the NCAUR with the accession number NRRL
37636. General fermentation procedures used have been published
elsewhere.2,22 The culture was incubated on rice (3 × 50 g) at 25 °C
for 30 days and extracted with EtOAc (3 × 500 mL). The combined,
filtered EtOAc solution was evaporated to dryness, yielding 389 mg
of crude extract.
Preparation of (S)-MTPA Ester 4. A sample of 1 (1.7 mg, 0.0075
mmol) was treated with (R)-MTPACl (3.8 mg, 0.0015 mmol), and the
reaction mixture was processed in the same fashion as described above
to afford the (S)-MTPA ester 4 (2.4 mg). Compound 4: white solid;
1H NMR (300 MHz, CDCl3) δ 6.14 (m, H-7), 6.10 (d, J ) 11 Hz,
H-5), 5.67 (dd, J ) 11, 6.3 Hz, H-6), 5.55 (t, J ) 8.3 Hz, H-3), 5.07
(m, H-11), 3.07 (dd, J ) 17, 8.3 Hz, H-2), 2.89 (dd, J ) 17, 8.3 Hz,
H-2), 2.08 (m, H-8), 1.82 (m, H-10), 1.76 (m, H-8), 1.74 (m, H-9),
1.51 (m, H-10), 1.45 (m, H-9), 1.19 (d, J ) 6.5 Hz, H-12).
Extraction and Isolation. The crude extract (389 mg) was parti-
tioned between hexane and MeCN. The MeCN fraction (242 mg) was
chromatographed using a Sephadex LH-20 column to yield 20 fractions.
Fraction 12 consisted of essentially pure monorden (27 mg). Fraction
14 (26 mg) was further purified by flash silica column chromatography
by gradient elution with hexanes/EtOAc. Subfractions 7, 8, 9, and 10
from fraction 14 were combined to afford chloriolide (1; 15 mg). Further
purification of fraction 15 (20 mg) by HPLC (MeCN/H2O, 40-50%
over 15 min, 50-100% over 10 min) on an Alltech HS BDS 8-µm C18
column (10 × 250 mm) at a flow rate of 2 mL/min with UV detection
at 215 nm gave pochonin B (2.7 mg).
X-ray Crystallographic Analysis of (S)-MTPA Ester 4.23
A
colorless prism (0.24 × 0.24 × 0.20 mm; triclinic; space group P1)
obtained from 1:2 EtOAc/hexanes was selected having cell dimensions
a ) 8.9862(9) Å, b ) 9.1107(9) Å, c ) 10.8325(11) Å. Data were
collected on a Nonius Kappa CCD diffractometer (Mo ΚR radiation,
graphite monochromator) at 190(2) Κ (cold N2 gas stream) using
standard CCD techniques, yielding 15 580 data. Lorentz and polarization
corrections were applied. A correction for absorption using the multiscan
techinique was also applied (Tmax ) 0.9757, Tmin ) 0.9710). Equivalent
data were averaged, yielding 3531 unique data (Rint ) 0.024, 2698 F
> 4σ(F), Friedel pairs averaged). The computer program from the HKL
package was used for data reduction. All other programs are in the
SHELXTL v6.1 package, and the data were otherwise processed as
described above for 1. Due to the weak anomalous signal with Mo
radiation and the fact that only determination of relative configuration
was needed from the X-ray data for 1 and 4, no absolute structure
parameter (e.g., the Flack parameter) was refined in either case, and
the Freidel pairs were averaged for the final cycles of refinement. The
final refinement in this instance gave R1 ) 0.0391, wR2 ) 0.0940.
Preparation of (R)-MPA Ester 5. To a solution of 1 (1.6 mg, 0.071
mmol) with EDC (1.7 mg, 0.086 mmol) and DMAP (1 crystal) in
CH2Cl2 (0.5 mL) was added (R)-MPAOH (1.4 mg, 0.084 mmol). After
1 h at ambient temperature, water was added. The resulting mixture
was evaporated to dryness and directly subjected to reversed-phase
HPLC (Alltech Apollo 5-µm C18 column, 250 × 10 mm; flow rate 2
mL/min, UV detection at 215 nm, eluting with MeCN/H2O, 30-100%
Chloriolide (1): white powder; [R]25 +107 (c 0.2, CH2Cl2); UV
D
(MeOH) λmax (log ꢀ) 270 (4.76); H and 13C NMR data, see Table 1;
1
COSY data, H-2 f H-3, 4; H-3 f H-2, 4; H-4 f H-3, 5, 6; H-5 f
H-4, 6, 7; H-6 f H-5, 7; H-7f H-5, 8; H-8 f H-9, 10; H-9 f H-8,
10; H-10 f H-9, 11; H-11 f H-10, 12; H-12 f H-10, 11; ESIMS
m/z 475 [2M + Na]+, 249 [M + Na]+.
X-ray Crystallographic Analysis of Chloriolide (1).23 A colorless
crystal of 1 was obtained from CH2Cl2/MeOH (0.47 × 0.40 × 0.19
mm) that proved to be monoclinic (space group P21) with cell
dimensions a ) 5.0243(5) Å, b ) 7.2167(7) Å, c ) 16.7328(17) Å.
Crystallographic data were collected on a Nonius Kappa CCD diffrac-
tometer (Mo KR radiation, graphite monochromator) at 190(2) Κ (cold
N2 gas steam) using standard CCD techniques, yielding 10 090 data.
Lorentz and polarization corrections were applied. A multiscan empiri-
cal absorption correction was also applied (Tmax ) 0.9826, Tmin
)
0.9578). The data were averaged, yielding 1488 independent data (1437
> 4σ(Fo), R(int) ) 0.025). The computer programs from the HKL
package were used for data reduction. The preliminary model of the
structure was obtained using XS, a direct method program. Least-
squares refining of the model versus the data was performed with the
XL computer program. All of these programs are in the SHELXTL
V5.1 package. Thermal ellipsoids shown in the illustration are at the

12-Membered Macrolide from Chloridium Virescens
Journal of Natural Products, 2006, Vol. 69, No. 4 639
over 30 min) to afford 5 (0.8 mg). Compound 5: white solid; 1H NMR
(300 MHz, CDCl3) δ 5.86 (m, H-7), 5.80 (d, J ) 11 Hz, H-5), 5.39
(dd, J ) 11, 6.5 Hz, H-6), 5.33 (t, J ) 7.8 Hz, H-3), 5.00 (m, H-11),
2.65 (d, J ) 7.8 Hz, H-2), 2.10-1.20 (m, H8-H10), 1.18 (d, J ) 6.5
Hz, H-12).
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Acknowledgment. Financial support from the National Science
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or e-mail: deposit@ccdc.cam.ac.uk).
NP0504964