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Beilstein J Org ChemBeilstein J Org ChemBeilstein Journal of Organic Chemistry1860-5397Beilstein-Institut Trakehner Str. 7-9, 60487 Frankfurt am Main, Germany 2436744010.3762/bjoc.9.311Full Research PaperChemistryOrganic ChemistryHalogenated volatiles from the fungus Geniculosporium and the actinomycete Streptomyces chartreusis
 Wang Tao 1Rabe Patrick 1Citron Christian A 1Dickschat Jeroen S richardthomas@example.net.de1Bräse Stefan Associate Editor1 Institut für Organische Chemie, TU Braunschweig, Hagenring 30, 38106 Braunschweig, Germany2013 3 12 2013 9 2767 2174-35-6685/bjoc.9.31129 8 2013 7 11 2013 Copyright © 2013, Wang et al; licensee Beilstein-Institut.2013Wang et al; licensee Beilstein-Institut.This is an Open Access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (http://www.beilstein-journals.org/bjoc)Summary
Two unidentified chlorinated volatiles X and Y were detected in headspace extracts of the fungus Geniculosporium. Their mass spectra pointed to the structures of a chlorodimethoxybenzene for X and a dichlorodimethoxybenzene for Y. The mass spectra of some constitutional isomers for X and Y were included in our databases and proved to be very similar, thus preventing a full structural assignment. For unambiguous structure elucidation all possible constitutional isomers for X and Y were obtained by synthesis or from commercial suppliers. Comparison of mass spectra and GC retention times rigorously established the structures of the two chlorinated volatiles. Chlorinated volatiles are not very widespread, but brominated or even iodinated volatiles are even more rare. Surprisingly, headspace extracts from Streptomyces chartreusis contained methyl 2-iodobenzoate, a new natural product that adds to the small family of iodinated natural products.


  


constitutional isomerismGC-MSnatural productsorganohalogen compoundsvolatilesThis article is part of the Thematic Series "Natural products in synthesis and biosynthesis".
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Introduction
Today several thousands of halogenated natural products are known, most of them being produced by marine organisms [1]. The majority of halogenated natural products are chlorinated or brominated, while iodinated and particularly fluorinated compounds are significantly less abundant (Table 1) [2]. Reasons for this distribution are (I) the different concentrations of the halogenides in sea water and (II) the differences in their redox potentials [3]. In terrestrial habitats local halogenide concentrations can strongly differ from those found in marine ecosystems, but the overall trend is similar, and therefore chlorine and bromine are also the most widespread halogens in natural products from terrestrial organisms.

Table 1 Approximate number of known halogenated natural products and redox potential and natural abundance of the halogenides in sea water.

Halogenide	Natural productsa
	Redox potential [V]b
	Sea water [mg L−1]b
	


	
F−
	30	+2.87	1.4	
Cl−
	2200	+1.36	18100	
Br−
	1900	+1.07	68	
I−
	100	+0.54	0.06	

aEstimated number of known natural products in 2002 according to reference [2]. bRedox potentials and concentrations in sea water as given in reference [3].

Many biologically active halogenated secondary metabolites are known from actinomycetes including vancomycin [4], chloramphenicol [5], rebeccamycin [6], marinopyrrols [7–8], armeniaspirols [9], and salinosporamide [10]. Also a few volatile halogenated compounds are known, e.g., from algae as summarised in a recent review [11]. Particularly interesting is the production of chloroform by termites that was estimated to account for 15% of the global chloroform emissions [12].

The introduction of halogens into natural products is catalysed by various known types of enzymes [13–14], including the FADH2-dependent halogenases [15], α-ketoglutarate/Fe2+-dependent halogenases [16], SAM-dependent halogenases [17–18], and vanadium-dependent haloperoxidases [19].

Here we report on the identification of two chlorinated volatile compounds from the fungus Geniculosporium and a iodinated volatile from Streptomyces chartreusis.

Results and Discussion
Chlorinated volatiles from Geniculosporium

The volatiles emitted by agar plate cultures of the fungus Geniculosporium sp. 9910 were trapped on charcoal filters by using a closed-loop stripping apparatus (CLSA) [20]. After one day of collection a solvent extract of the trapped material was analysed by GC–MS. The analytical process was performed three times to demonstrate reproducibility of the results, and a representative chromatogram is shown in Fig. 1. Besides the main compound 1 and some structurally related volatiles 2 and 3 that were identified by delinating a structural proposal from the mass spectra followed by synthesis of reference compounds [21], two additional volatiles X and Y were observed in all investigated samples. Their mass spectra are shown in Fig. 2.

Figure 1 Total ion chromatogram of a CLSA headspace extract from Geniculosporium.

Figure 2 Mass spectra of A) the chlorinated volatile X and B) the chlorinated volatile Y.

Both volatiles were suggested to be chlorinated compounds due to their characteristic isotope patterns of the molecular ions with compound X containing one chlorine and volatile Y containing two chlorine atoms. Furthermore, a comparison of the mass spectrum of X to data base spectra revealed strong similarities to mass spectra of chlorodimethoxybenzenes, but the data base mass spectra of various constitutional isomers showed only marginal differences. Similarly, the mass spectrum of Y was very similar to data base spectra of dichlorodimethoxybenzenes, but also in this case the mass spectra of several constitutional isomers were highly similar. Therefore, the comparison of mass spectra was not a sufficient criterion for unambiguous compound identification, and thus the additional comparison of GC retention indices of both natural products to authentic standards of all possible structural isomers was pursued.

The six constitutional isomers of a chlorodimethoxybenzene 4a–4f as candidate structures for X are summarised in Fig. 3. Compounds 4d and 4e were commercially available, while the remaining isomers were obtained by synthesis according to Scheme 1. Surprisingly, no satisfying synthetic procedure for compound 4a was available from literature, but ortho-lithiation of veratrole (5) followed by treatment with trifluorosulfonyl chloride and triethylamine gave acceptable yields (47%). Conversion of 4-aminoveratrole (6) into the corresponding diazonium salt followed by a Sandmeyer reaction resulted in 4b (61% over two steps). The isomer 4c was efficiently prepared by double methylation of 2-chlororesorcinol (8) with potassium carbonate and methyl iodide in acetone (88%), while 4f was obtained by chlorination of dimethoxybenzene 9 with benzyltrimethylammonium tetrachloroiodate in moderate yield (34%) [22]. All six compounds were subjected to GC–MS analysis using the same type of GC column as for the headspace extract from Geniculosporium (HP5-MS) and their retention indices together with the NMR spectroscopic data are summarised in Table 2. Mass spectra, 1H and 13C NMR spectra of all six compounds are given in Supporting Information File 1. The structure of 4b was unambiguously assigned to the natural product X by comparison of mass spectra and retention indices (Table 2).

Figure 3 Constitutional isomers of chlorodimethoxybenzene as candidate structures for X.

Scheme 1 Synthesis of chlorodimethoxybenzenes as reference compounds for X.

Table 2 NMR spectroscopic data and GC retention indices of all constitutional isomers of chlorodimethoxybenzene in comparison to natural X.

Compound	
1H NMR	
13C NMR	
I
	


	

4a
	6.96 (m, 2H, 2 × CH)
6.81 (m, 1H, CH)
3.87 (s, 3H, OCH3)
3.86 (s, 3H, OCH3)	154.0 (Cq)
145.5 (Cq)
128.4 (Cq)
124.3 (CH)
122.0 (CH)
110.9 (CH)
60.6 (OCH3)
56.1 (OCH3)	1278	

4f
	6.95 (d, 1H, 4
J
H,H = 3.0 Hz, CH)
6.86 (d, 1H, 4
J
H,H = 3.0 Hz, 3
J
H,H = 9.0 Hz)
6.76 (dd, 1H, 3
J
H,H = 3.0 Hz, 4
J
H,H = 9.0 Hz, CH)
3.84 (s, 3H, OCH3)
3.75 (s, 3H, OCH3)	153.8 (Cq)
149.4 (Cq)
123.0 (Cq)
116.1 (CH)
113.2 (CH)
112.8 (CH)
56.7 (OCH3)
55.8 (OCH3)	1292	

4b
	6.87 (dd, 1H, 3
J
H,H = 8.5 Hz, 4
J
H,H = 2.4 Hz, CH)
6.84 (d, 1H, 4
J
H,H = 2.4 Hz, CH)
6.76 (d, 1H, 3
J
H,H = 8.5 Hz, CH)
3.85 (s, 3H, OCH3)
3.84 (s, 3H, OCH3)	149.5 (Cq)
147.8 (Cq)
125.6 (Cq)
120.2 (CH)
112.0 (CH)
111.9 (CH)
56.02 (OCH3)
55.98 (OCH3)	1322	

4e
	6.51 (d, 2H, 4
J
H,H = 2.2 Hz, 2 × CH)
6.34 (t, 1H, 4
J
H,H = 2.2 Hz, CH)
3.77 (s, 6H, 2 × OCH3)	161.1 (2 × Cq)
135.2 (Cq)
106.9 (2 × CH)
99.2 (CH)
55.5 (2 × OCH3)	1340	

4d
	7.24 (d, 1H, 3
J
H,H = 8.7 Hz, CH)
6.50 (d, 1H, 4
J
H,H = 2.7 Hz, CH)
6.42 (dd, 1H, 3
J
H,H = 8.7 Hz, 4
J
H,H = 2.7 Hz, CH)
3.87 (s, 3H, OCH3)
3.79 (s, 3H, OCH3)	159.5 (Cq)
155.6 (Cq)
130.1 (CH)
114.1 (Cq)
105.2 (CH)
100.0 (CH)
56.0 (OCH3)
55.5 (OCH3)	1374	

4c
	7.17 (t, 1H, 3
J
H,H = 8.4 Hz, CH)
6.60 (d, 2H, 3
J
H,H = 8.4 Hz, 2 × CH)
3.90 (s, 6H, 2 × OCH3)	156.2 (2 × Cq)
127.1 (CH)
110.6 (Cq)
104.7 (2 × CH)
56.3 (2 × OCH3)	1404	

X
			1322	
For compound Y a series of eleven constitutional isomers as shown in Fig. 4 were possible. All eleven compounds were obtained by synthesis as summarised in Scheme 2. The compounds 10a, 10c, and 10e were obtained by treatment of 1,2,3,4-tetrachlorobenzene (11) with sodium methoxide in hot HMPA. This reaction is reported to yield mainly 1,2,3-trichloro-4-methoxybenzene and 1,2,4-trichloro-3-methoxybenzene by monosubstitution [23], but small amounts of disubstitution products were also formed that were rigorously purified from the mixture by repeated column chromatography. Starting from 1,2,3,5-tetrachlorobenzene (12) the same reaction conditions also provided a mixture of mono- and disubstitution products, but the target compounds 10f and 10g were obtained in better yields (29% and 17%). Derivative 10b was prepared from 3,5-dichlorocatechol (13) by methylation with potassium carbonate and methyl iodide in high yield (80%). Accordingly, methylation of 4,6-dichlororesorcinol (14) provided 10h in 80% yield, and methylation of 2,3-dichlorohydroquinone (16), prepared from benzoquinone (15) by treatment with SO2Cl2 under acidic conditions, generated 10i (13% via two steps). Reduction of 2,6-dichlorobenzoquinone with ascorbic acid to the corresponding hydroquinone 18 followed by methylation yielded 48% of 10k. Chlorination of veratrole (5) with two equivalents of benzyltrimethylammonium tetrachloroiodate resulted in 10d (45%), while the same procedure starting from 1,4-dimethoxybenzene gave access to 10j (38%). The NMR spectroscopic data and results of GC–MS analyses for all eleven dichlorodimethoxybenzenes in comparison to the volatile Y are summarised in Table 3. All mass spectra, 1H and 13C NMR spectra are shown in Supporting Information File 1. Comparison of mass spectra and retention indices unequivocally established the identity of Y and 10b (Table 3).

Figure 4 Constitutional isomers of dichlorodimethoxybenzene as candidate structures for Y.

Scheme 2 Synthesis of chlorodimethoxybenzenes as reference compounds for Y.

Table 3 NMR spectroscopic data and GC retention indices of all constitutional isomers of dichlorodimethoxybenzene in comparison to natural Y.

Compound	
1H NMR	
13C NMR	
I (HP5-MS)	


	

10c
	7.07 (s, 2H, 2 × CH)
3.92 (s, 6H, 2 × OCH3)	150.7 (2 × Cq)
127.1 (2 × Cq)
125.1 (2 × CH)
61.1 (2 × OCH3)	1339	

10b
	6.98 (d, 1H, 4
J
H,H = 2.5 Hz, CH)
6.80 (d, 1H, 4
J
H,H = 2.5 Hz, CH)
3.86 (s, 3H, OCH3)
3.84 (s, 3H, OCH3)	154.1 (Cq)
144.4 (Cq)
129.1 (Cq)
128.9 (Cq)
121.6 (CH)
111.7 (CH)
60.8 (OCH3)
56.3 (OCH3)	1426	

10k
	6.84 (s, 2H, 2 × CH)
3.84 (s, 3H, OCH3)
3.76 (s, 3H, OCH3)	155.7 (Cq)
146.2 (Cq)
129.5 (2 × Cq)
114.5 (2 × CH)
60.8 (OCH3)
55.9 (OCH3)	1443	

10j
	6.97 (s, 2H, 2 × CH)
3.85 (s, 6H, 2 × OCH3)	149.2 (2 × Cq)
120.9 (2 × Cq)
114.5 (2 × CH)
56.8 (2 × OCH3)	1448	

10a
	7.15 (d, 1H, 3
J
H,H = 9.0 Hz, CH)
6.76 (d, 1H, 3
J
H,H = 9.0 Hz, CH)
3.86 (s, 3H, OCH3)
3.85 (s, 3H, OCH3)	152.4 (Cq)
146.7 (Cq)
127.5 (Cq)
124.7 (CH)
124.5 (Cq)
111.0 (CH)
60.6 (OCH3)
56.2 (OCH3)	1466	

10e
	7.23 (d, 1H, 3
J
H,H = 9.0 Hz, CH)
6.66 (d, 1H, 3
J
H,H = 9.0 Hz, CH)
3.90 (s, 3H, OCH3)
3.89 (s, 3H, OCH3)	155.1 (Cq)
153.2 (Cq)
127.7 (CH)
120.7 (Cq)
118.2 (Cq)
107.9 (CH)
60.6 (OCH3)
56.5 (OCH3)	1487	

10d
	6.90 (s, 2H, 2 × CH)
3.86 (s, 6H, 2 × OCH3)	148.3 (2 × Cq)
123.4 (2 × Cq)
112.9 (2 × CH)
56.2 (2 × OCH3)	1505	

10h
	7.34 (s, 1H, CH)
6.53 (s, 1H, CH)
3.90 (s, 6H, 2 × CH3)	154.5 (2 × Cq)
130.5 (CH)
114.0 (2 × Cq)
97.8 (CH)
56.5 (2 × OCH3)	1545	

10f
	6.60 (s, 2H, 2 × CH)
3.89 (s, 6H, 2 × CH3)	156.4 (2 × Cq)
133.0 (Cq)
109.3 (Cq)
105.5 (2 × CH)
56.5 (2 × OCH3)	1556	

10g
	6.62 (d, 1H, 4
J
H,H = 2.7 Hz, CH)
6.42 (d, 1H, 4
J
H,H = 2.7 Hz, CH)
3.87 (s, 3H, OCH3)
3.79 (s, 3H, OCH3)	158.7 (Cq)
156.7 (Cq)
133.8 (Cq)
113.5 (Cq)
106.4 (CH)
98.6 (CH)
56.4 (OCH3)
55.7 (OCH3)	1565	

10i
	6.81 (s, 2H, 2 × CH)
3.86 (s, 6H, 2 × OCH3)	150.3 (2 × Cq)
123.1 (2 × Cq)
110.0 (2 × CH)
56.8 (2 × OCH3)	1574	

Y
			1426	
Both compounds 4b and 10b that were identified in this study as volatiles emitted by Geniculosporium have not been reported as natural products before. However, the structurally related compounds 4f and 10k are known from the fungus Bjerkandera adusta [24]. It is interesting to note that in both cases the dichlorodimethoxybenzene (10b or 10k) can arise by a second chlorination from the monochlorodimethoxybenzene (4b or 4f, respectively), suggesting that in both organisms the sets of chlorinated compounds arise via one and the same biosynthetic pathway. Known structurally related compounds from fungi are drosophilin A (19) [25] or the trichlorinated phenols 20–22 (Fig. 5) [26]. The biological function of 4b and 10b in Geniculosporium is unknown, but the antibiotic activity of the related compound drosophilin A towards bacteria is well known [27].

Figure 5 Known natural products that are structurally related to 4b and 10b from Geniculosporium.

A iodinated volatile from Streptomyces chartreusis

During the course of our work on volatiles from various bacteria and fungi we rarely encountered chlorinated volatiles. Brominated and iodinated volatiles are even more rare. Investigations on the volatiles released by the actinomycete Streptomyces chartreusis during growth on 84 GYM medium, also collected by use of a CLSA followed by GC–MS analysis of the obtained headspace extracts, led to a surprising result. The extracts contained a trace compound that was readily identified from its mass spectrum and comparison to an authentic standard as methyl 2-iodobenzoate (23, Fig. 6). This compound was observed as the principal compound in headspace extracts during growth of S. chartreusis on 84 GYM supplemented with 2-iodobenzoic acid suggesting that 23 arises by efficient methylation of the carboxylic acid (Fig. 6). 2-Iodobenzoic acid is frequently used in many chemical laboratories including ours, e.g., as a starting material for the preparation of the oxidising agents IBX and DMP. A contamination of a bacterial agar plate with traces of 2-iodobenzoic acid was assumed as a possible, albeit unlikely explanation for the formation of 23 in the bacterial cultures. In our laboratories all analytical work is strictly spatially separated from the other chemical (synthetic) work. Furthermore, a contamination with 2-iodobenzoic acid as the reason for the emission of 23 by S. chartreusis was excluded by the sixfold repetition of the headspace analyses during a time period of almost two years (January 2012–August 2013), using new batches of medium in all cases. Compound 23 was repeatedly detected in all six analyses which clearly supports the natural origin of this volatile.

Figure 6 Total ion chromatograms of headspace extracts from S. chartreusis. A) Growth on 84 GYM showing production of 23 as a trace compound. B) Growth on 84 GYM amended with 2-iodobenzoic acid (1 mM) results in the emission of 23 as the principal volatile compound.

The iodinated compound 23 has never been reported as a natural product. One of the few reported iodinated compounds is the structurally highly complex calicheamicin 24 (Fig. 7) from Micromonospora echinospora [28] that also contains an iodinated aromatic subunit.

Figure 7 Calicheamicin, a known iodinated compound from the actinomycete Micromonspora echinospora.

Conclusion
In summary, we have presented the identification of 4-chloro-1,2-dimethoxybenzene (4b) and 1,5-dichloro-2,3-dimethoxybenzene (10b) as volatile natural products released by the fungus Geniculosporium. Furthermore, Streptomyces chartreusis was shown to emit methyl 2-iodobenzoate (23). All three compounds are new natural products. Future work on the biological function of these metabolites and the biosynthetic pathways is now possible.

Experimental

Strains and culture conditions:
Geniculosporium sp. 9910 was obtained from Barbara Schulz (Braunschweig) and grown on potato–carrot medium [29] on petri dishes and incubated for 21 d at 28 °C prior to analysis. Streptomyces chartreusis NRRL 3882 (= DSM 41447) was obtained from DSMZ (Braunschweig, Germany) and grown on 84 GYM (20.0 g rolled oats, boiled in 1 L of distilled water for 20 min, then oats were filtered off, trace element solution (1 mL) containing 1 g L−1 FeSO4·7H2O, 1 g L−1 MnCl4·4H2O, and 1 g L−1 ZnSO4·7H2O was added, followed by sterilisation at 121 °C for 20 min).


Headspace analyses: The volatiles released by Geniculosporium or Streptomyces chartreusis were trapped by use of the CLSA (closed-loop stripping analysis) technique as described previously [30]. GC–MS analyses of the obtained headspace extracts were carried out on an Agilent 7890A connected with an Agilent 5975C inert mass detector fitted with a HP5-MS fused silica capillary column (30 m, 0.25 mm i. d., 0.25 μm film, Agilent). GC conditions were as follows: inlet pressure 77.1 kPa, He 23.3 mL min−1, injection volume 1.5 μL, transfer line 300 °C, electron energy 70 eV. The operation mode was splitless (60 s valve time) and the carrier gas was richardthomas@example.net mL min−1. The GC was programmed as follows: 5 min at 50 °C increasing with 5 °C min−1 to 320 °C. Retention indices (I) were determined from a homologous series of n-alkanes (C8–C38). The mass spectra of the natural compounds X and Y are shown in Fig. 2. For comparison the mass spectra of all commercially available and synthetic chlorodimethoxybenzenes 4a–4f and dichlorodimethoxybenzenes 10a–10k are shown in Figures S1 and S2 of Supporting Information File 1. Retention indices of natural X and Y and of all chlorodimethoxybenzenes 4a–4f and dichlorodimethoxybenzenes 10a–10k are listed in Table 1 and Table 2.

Supporting Information
File 1 Synthetic procedures, characterization data, mass spectra of all isomers of chlorodimethoxybenzene and dichlorodimethoxybenzene and 1H, 13C, and DEPT spectra of all synthetic compounds.

 This work was funded by the Deutsche Forschungsgemeinschaft with an Emmy Noether fellowship (DI1536/1-3) and a Heisenberg fellowship (DI1536/4-1) (to JSD), by the State of Lower Saxony with a Ph. D scholarship (to TW), and by the Beilstein Institut zur Förderung der chemischen Wissenschaften with a Ph. D scholarship (to PR). We thank Stefan Schulz (Braunschweig) for his support.
==== Refs
1 Gribble G W   Acc Chem Res 1998 31 141 174-35-6685/ar9701777 
2 Gribble G W   Gribble G W   The Diversity of Naturally Produced Organohalogens Natural Production of Organohalogen Compounds 2003 Berlin Springer-Verlag 1 15 10.1007/b10445 
3 Wiberg N   Lehrbuch der Anorganischen Chemie 2007 102 Berlin Walter de Gruyter 
4 Sheldrick G M  Jones P G  Kennard O  Williams D H  Smith G A   Nature 1978 271 223 174-35-6685/271223a0 622161 
5 Ehrlich J  Bartz Q R  Smith R M  Joslyn D A   Science 1947 106 174-35-6685/science.106.2757.417 17737966 
6 Nettleton D E  Doyle T W  Krishnan B  Matsumoto G K  Clardy J   Tetrahedron Lett 1985 26 4011 4174-35-6685/S0040-4039(00)89280-1 
7 Hughes C C  Prieto-Davo A  Jensen P R  Fenical W   Org Lett 2008 10 629 174-35-6685/ol702952n 18205372 
8 Hughes C C  Kauffman C A  Jensen P R  Fenical W   J Org Chem 2174-35-6685 3174-35-6685/jo1002054 20405892 
9 Couturier C  Bauer A  Rey A  Schroif-Dufour C  Broenstrup M   Bioorg Med Chem Lett 2174-35-6685 6174-35-6685/j.bmcl.2012.06.107 22921279 
10 Fenical W  Jensen P R  Palladino M A  Lam K S  Lloyd G K  Potts B C   Bioorg Med Chem 2174-35-6685 2174-35-6685/j.bmc.2008.10.075 19022674 
11 Paul C  Pohnert G   Nat Prod Rep 2011 28 186 174-35-6685/c0np00043d 21125112 
12 Khalil M A K  Rasmussen R A  French J R J  Holt J A   J Geophys Res: Atmos 1990 95 3619 3174-35-6685/JD095iD04p03619 
13 Wagner C  El Omari M  König G M   J Nat Prod 2009 72 540 174-35-6685/np800651m 19245259 
14 Blasiak L C  Drennan C L   Acc Chem Res 2009 42 147 174-35-6685/ar800088r 18774824 
15 Hammer P E  Hill D S  Lam S T  van Pée K H  Ligon J M   Appl Environ Microbiol 1997 63 2147 2154 9172332 
16 Galonic D P  Barr E W  Walsh C T  Bollinger J M Jr  Krebs C   Nat Chem Biol 2007 3 113 174-35-6685/nchembio856 17220900 
17 Eustáquio A S  Pojer F  Noel J P  Moore B S   Nat Chem Biol 2008 4 69 74 10.1038/nchembio.2{{SOCIAL_SECURITY_NUMBER+PHONE}} 
18 Dong C  Huang F  Deng H  Schaffrath C  Spencer J B  O'Hagan D  Naismith J H   Nature 2004 427 561 174-35-6685/nature02280 14765200 
19 Bernhardt P  Okino T  Winter J M  Miyanaga A  Moore B S   J Am Chem Soc 2011 133 4268 4174-35-6685/ja201088k 21384874 
20 Grob K  Zürcher F   J Chromatogr 1976 117 285 174-35-6685/0021-9673(76)80005-2 932146 
21 Citron C A  Wickel S M  Schulz B  Draeger S  Dickschat J S   Eur J Org Chem 2012 6636 6174-35-6685/ejoc.201200991 
22 Kajigaeshi S  Shinmasu Y  Fujisaki S  Kakinami T   Chem Lett 1989 18 415 174-35-6685/cl.1989.415 
23 Testaferri L  Tiecco M  Tingoli M  Chianelli D  Montanucci M   Tetrahedron 1983 39 193 174-35-6685/S0040-4020(01)97647-1 
24 Silk P J  Aubry C  Lonergan G C  Macaulay J B   Chemosphere 2174-35-6685 1174-35-6685/S0045-6535(00)00537-3 11545526 
25 Anchel M   J Am Chem Soc 1952 74 2943 10.1021/ja01131a520 
26 Swarts H J  Verhagen F J M  Field J A  Wijnberg J B P A   Phytochemistry 1998 49 203 174-35-6685/S0031-9422(97)01067-4 
27 Kavanagh F  Hervey A  Robbins W J   Proc Natl Acad Sci U S A 1952 38 555 174-35-6685/pnas.38.7.555 16589145 
28 Maiese W M  Lechevalier M P  Lechevalier H A  Korshalla J  Kuck N  Fantini A  Wildey M J  Thomas J  Greenstein M   J Antibiot 1989 42 558 174-35-6685/antibiotics.42.558 2722671 
29 Höller U  Wright A D  Matthée G F  König G M  Draeger S  Aust H-J  Schulz B   Mycol Res 2000 104 1354 1174-35-6685/S0953756200003117 
30 Dickschat J S  Wenzel S C  Bode H B  Müller R  Schulz S   ChemBioChem 2004 5 778 174-35-6685/cbic.200300813 15174160


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