Structural revision and synthesis of altechromone A

Article abstract of DOI:10.1021/np1005604

The chromone "altechromone A" was synthesized as a substructure in the course of natural product synthesis. Its architecture was verified by X-ray analysis, but spectroscopic data showed a strong deviation from the reported data. By comparison with the sy

Full text of DOI:10.1021/np1005604

2064
J. Nat. Prod. 2010, 73, 2064–2066
Structural Revision and Synthesis of Altechromone A
P. Ko¨nigs,† B. Rinker,† L. Maus,† M. Nieger,‡ J. Rheinheimer,§ and S. R. Waldvogel*,†,⊥
Kekule´-Institut fu¨r Organische Chemie und Biochemie, Rheinische Friedrich-Wilhelms-UniVersita¨t Bonn, Gerhard-Domagk-Strasse 1,
53121 Bonn, Germany, Laboratory of Inorganic Chemistry, Department of Chemistry, P.O. Box 55 FI-00014, UniVersity of Helsinki, Finland,
BASF SE, GVA/FO-A030, Carl-Bosch-Strasse 38, 67056 Ludwigshafen, Germany, and Institut fu¨r Organische Chemie, Johannes
Gutenberg-UniVersita¨t, Duesbergweg 10-14, 55128 Mainz, Germany
ReceiVed August 17, 2010
The chromone “altechromone A” was synthesized as a substructure in the course of natural product synthesis. Its
architecture was verified by X-ray analysis, but spectroscopic data showed a strong deviation from the reported data.
By comparison with the synthesized isomers the structure of altechromone A was revised.
In 1992 a chromone derivative was isolated from Alternaria sp.
and consequently named altechromone A (1) (Figure 1). The
1
structural assignment was performed by a complete set of H and
13C NMR data. Additional NOE data made the suggestion of this
rather simple natural product plausible.1 Further analytical data such
as UV and IR spectra as well as microanalysis confirmed its identity.
5-Hydroxy-2,7-dimethylchromone (1) was first mentioned by
Ahluwalia and Kumar 16 years earlier.2 Although 1 was claimed
Figure 1. Originally assigned structures of altechromone A (1) and
to be synthesized, only the melting point and IR data were
published. More recently, altechromone A was isolated from several
fungi including Hypoxylon truncatum,3 Ascomycota sp.,4 and
Alternaria brassicicola.5 The isolated compound showed remarkable
biological activity such as root growth promotion1 and inhibition
of bacterial proliferation.4 These authors referred to 1, which was
isolated almost 20 years ago.1
altechromone B (2).
Several natural products originating from fungal sources contain
1 as substructure. Chloromonilicin (3) was isolated from Monilia
fructicola in 1985,6 coniochaeton A (4) from Coniochaeta sacer-
doi,7 and remisporin A (5) from the marine fungus Remispora
maritima (Figure 2).8
Figure 2. Secondary metabolites containing the altechromone
In the course of our synthetic efforts on 3-5 we envisaged using
altechromone A as an intermediate. Our synthesis of 1 commenced
with 2,6-dihydroxy-4-methylacetophenone (6), which is readily
available by a simple Friedel-Crafts acylation of orcinol.9 The
bis(trimethylsilyl) ether 7 is formed almost quantitatively under the
prevailing conditions (Scheme 1).
substructure.
Scheme 1. Synthesis of 5-Hydroxy-2,7-dimethylchromone (1)a
Aldol reaction of 7 with ethyl acetate affords chromone 1 directly
after acidic workup and purification by column chromatography
on silica. This represents rapid access to the chromone derivative.
Compound 1 was properly characterized. In addition, suitable single
crystals of 1 allowed X-ray analysis, which confirmed the antici-
pated molecular structure.10 Since the chromone system is planar
(mean deviation from the least-squares plane 0.023 Å), the
molecules form close π-stacks parallel to the a-axis with alternating
intermolecular distances of 3.33 and 3.45 Å. The piles are cross-
linked via weak intermolecular hydrogen bonds involving the
carbonyl oxygen, acting as a trifurcating acceptor atom. Further-
more, the molecular structure confirms the hydrogen bonding
between the C-4 carbonyl functionality and the 5-hydroxy group
(O5-H5 0.84(2) Å, H5-O4 1.82(2) Å, O5-O4 2.599(1) Å,
O5-H5-O4 155(2)°) (Figure 3).
a Reagents and conditions: (a) HMDS, TMSCl, 140 °C, 5 h, > 99%; (b) NaH,
EtOAc, THF, 75 °C, 6 h, then rt, 16 h, 69%.
isomeric congeners of 1. First, the aromatic substituents were
switched. Starting with 2,4-dihydroxy-6-methylacetophenone 8, a
synthetic approach similar to the previous one was employed
(Scheme 2). Compound 8 is accessible by a Gattermann-type
acetylation reaction of orcinol with acetonitrile and zinc chloride.11
Blocking of the hydroxy moieties by trimethylsilyl groups is
accomplished in quantitative yield. The subsequent aldol reaction
and cyclization via acidic conditions furnished 7-hydroxy-2,5-
dimethylchromone (10) in good yield (61%, two steps).
However, since the NMR data of 1 strongly deviated from the
reported data of altechromone A,1 we were prompted to synthesize
In order to exclude the possibility of a coumarin architecture,
we synthesized the analogous coumarin derivative 11 (Figure 4).
5-Hydroxy-4,7-dimethylcoumarin (11) was accessible in low yield
by a Von Pechmann-type condensation of orcinol with methyl
acetoacetate.12 Since the analytical data of 11 and altechromone A
showed distinct differences, this coumarin can definitely be excluded
as a candidate structure.
* To whom correspondence should be addressed. Tel: +49 (0)6131
3926069. Fax: +49 (0)6131 3926777. E-mail: waldvogel@uni-mainz.de.
† Rheinische Friedrich-Wilhelms-Universita¨t Bonn.
‡ University of Helsinki.
§ BASF SE, Ludwigshafen.
⊥ Johannes Gutenberg-Universita¨t Mainz.
10.1021/np1005604  2010 American Chemical Society and American Society of Pharmacognosy
Published on Web 11/17/2010

Notes
Journal of Natural Products, 2010, Vol. 73, No. 12 2065
Figure 5. Chromones from plant material.
7-Hydroxy-2,5-dimethylchromone (10) is a well-known constitu-
ent of plant material. First synthesized and characterized in 1974,13
it was recently isolated from different plant families such as
Polygonaceae, Lamiaceae, Fabaceae, and Hypericaceae.14 Al-
though the structural similarity to aleosone (12) and 5,7-dihydroxy-
2-methylchromone (13) (Figure 5), both products of the polyketide
pathway, is obvious, 7-hydroxy-2,5-dimethylchromone as a typical
fungal metabolite presumably has its origin in endophytic fungi.
This seems possible as recent reports describe the compound as
a fungal secondary metabolite (“altechromone A”).3-5 These
species often exist in mutualistic interaction with a host plant,
protecting it from grazing livestock, invertebrate herbivores, and
pathogenic microorganisms.
In conclusion, the structure of altechromone A has to be
reassigned as 7-hydroxy-2,5-dimethylchromone. A fast and reliable
synthesis of 1 was established in 67% overall yield starting from
2-acetyl orcinol. The use of this intermediate in the synthesis of
other natural products will be reported in due course.
Experimental Section
General Experimental Procedures. All reagents were used in
analytical grade. Solvents were dried if necessary by standard methods.
Melting points were determined with an SMP 3 melting point apparatus
(Bibby Sterilin LTD, Stone, Staffordshire) and were uncorrected.
Microanalysis was performed with a Vario EL (Elementar-Analysen-
systeme, Hanau, Germany). NMR spectra were recorded with a Bruker
AM 300 and AM 400 (Analytische Messtechnik, Karlsruhe, Germany)
by calibration in CHCl3 with δ ) 7.26 or DMSO-d6 (δ ) 2.50) for
1H NMR; chemical shifts were expressed in ppm. Mass spectra were
obtained on a MAT8200 (Finnigan, Bremen, Germany) employing
EI or on a MS50 (Kratos, Manchester, England) or MAT95XL
(Finnigan, Bremen, Germany) employing HRMS. All reactions were
monitored by TLC, and visualization was effected by UV and heating
with a 1% aqueous solution of Ce(SO4)2 ·4H2O containing 2.5% of
molybdatophosphoric acid and 6% of H2SO4. Column chromatography
was performed on silica gel (particle size 63-200 µm, Merck,
Darmstadt, Germany) using mixtures of cyclohexane with EtOAc as
eluents.
Figure 3. (Top) Molecular structure of 1 showing the intramolecular
hydrogen bond (displacement parameters are drawn at 50%
probability). (Bottom) Crystal packing of 1 showing the weak
intermolecular hydrogen bonds.10
Scheme 2. Preparation of Isomeric Chromone 10a
a Reagents and conditions: (a) 1. HMDS, TMSCl, 140 °C, 5 h, > 99%; (b) 1.
NaH, EtOAc, THF, 75 °C, 6 h, then rt, 16 h, 2. HCl conc., THF, rt, 16 h, 61%
(two steps).
5-Hydroxy-2,7-dimethylchromone (1): colorless solid; 69% yield;
1
mp 82-83 °C; Rf (cyclohexane-EtOAc, 90:10) 0.26; H NMR and
13C NMR data see Table 1; HREIMS m/z 190.0637 (calcd for C11H10O3,
190.0630); anal. C 69.46, H 5.30%, calcd for C11H10O3, C 69.14, H
5.12%.
Crystal Data for 1: formula C11H10O3, M ) 190.19, a ) 6.9503(2)
Å, b ) 16.4718(4) Å, c ) 8.2909(2) Å, ꢀ ) 102.266(1)°, V ) 927.51(4)
Å3, Fcalc ) 1.362 g cm-3, µ ) 0.099 mm-1, no absorption correction,
Z ) 4, monoclinic, space group P21/c (No. 14), T ) 123 K, ω and ꢁ
scans, 15 639 reflections collected, 2112 unique (Rint ) 0.0591); 132
parameters, 1 restraint, R ) 0.0602, wR2 ) 0.1479 (both for all data),
max. residual electron density 0.322 (-0.252) e Å-3. The hydrogen
atoms were localized by difference Fourier synthesis and refined using
a riding model. H(O) was refined free.
Figure 4. Related coumarin derivative 11.
The best fit of 1H and 13C NMR data with the isolated compound
of Kimura et al.1 is given by 10. In contrast, the data of 1 do not
fit those of altechromone A at all. Most striking is the signal at
12.53 ppm, which indicates an intramolecular hydrogen bonding.
The melting point reported by Kimura et al.1 (250-252 °C) only
deviates slightly from the one originally reported by Ahluwalia
(245-248 °C, dec).2 The melting point we determined for 1 is
totally different (82-83 °C). Further reports dealing with 13-5 did
not report melting points for altechromone A. In contrast, 5-hy-
droxy-4,7-dimethylcoumarin (11) melts at 243 °C with decomposi-
tion. Consequently, the melting points and NMR data support our
hypothesis that the structure of altechromone A has to be revised
to 7-hydroxy-2,5-dimethylchromone (10).
7-Hydroxy-2,5-dimethylchromone (10): light yellow solid; 61%
yield; mp 252 °C; 1H NMR and 13C NMR data see Table 1; HREIMS
m/z 190.0633 (calcd for C11H10O3, 190.0630).
5-Hydroxy-4,7-dimethylcoumarin (11): light brown solid; 8%
1
yield; mp 243 °C (dec); H NMR and 13C NMR data see Table 1;
HREIMS m/z 190.0628 (calcd for C11H10O3, 190.0630).
Acknowledgment. The authors highly appreciate the financial
support by BASF SE and collaboration with the Kompetenzzentrum
der Integrierten Naturstoff-Forschung (University of Mainz).

2066 Journal of Natural Products, 2010, Vol. 73, No. 12
Notes
References and Notes
Table 1. Comparison of NMR Data
1H NMR Shifts (400 MHz for 1 and 10, 300 MHz for 11, DMSO-d6)
(1) Kimura, Y.; Mizuno, T.; Nakajima, H.; Hamasaki, T. Biosci. Bio-
technol. Biochem. 1992, 56, 1664–1665.
(2) Ahluwalia, V. K.; Kumar, D. Indian J. Chem. 1976, 14B, 326–328.
(3) Gu, W.; Ge, H. M.; Song, Y. C.; Ding, H.; Zhu, H. L.; Zhao, X. A.;
Tan, R. X. J. Nat. Prod. 2007, 70, 114–117.
altechromone A
1
10
11
entry δH (J in Hz) δH (J in Hz) δH (J in Hz)
δH (J in Hz)
(4) Shushni, M. A. M.; Mentel, R.; Lindequist, U.; Jansen, R. Chem.
BiodiVersity 2009, 6, 127–137.
1
2
3
4
5
6
2.27, s
2.67, d (0.5)
5.97, s
6.60, d (1.5)
6.62, d (1.5)
10.53, s
2.34, s
2.37, s
6.23, s
2.26, d (0.8)
2.64, b
5.96, s
2.27, dd (0.7, 0.7)
2.54, d (1.3)
6.04, q (1.3)
(5) Gu, W. World J. Microbiol. Biotechnol. 2009, 25, 1677–1683.
(6) Sassa, T.; Kachi, H.; Nukina, M. J. Antibiot. 1985, 38, 439–441.
(7) Wang, H.; Gloer, J. B. Tetrahedron Lett. 1995, 36, 5847–4850.
(8) Kong, F.; Carter, G. T. Tetrahedron Lett. 2003, 44, 3119–3122.
(9) Tsujihara, K.; Hongu, M.; Saito, K.; Kawanishi, H.; Kuriyama, K.;
Matsumoto, M.; Oku, A.; Ueta, K.; Tsuda, M.; Saito, A. J. Med. Chem.
1999, 42, 5311–5324.
6.58, d (0.6) 6.61, dq (0.8, 2.3) 6.57, dq (0.7, 1.7)
6.78, d (0.6) 6.65, d (2.3)
12.53, s 10.55, b
6.62, dq (0.7, 1.7)
10.50, s
13C NMR Shifts (100 MHz for 1 and 11, 75 MHz for 10, DMSO-d6)
(10) Crystallographic data for the structure reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre (CCDC
783508). Copies of the data can be obtained, free of charge, on
application to the Director, CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
(11) Hoesch, K. Chem. Ber. 1915, 48, 1122–1133.
(12) Sethna, S. M.; Shah, R. C. J. Indian Chem. Soc. 1940, 17, 211–214.
(13) Hirata, T.; Suga, T. Bull. Chem. Soc. Jpn. 1974, 47, 244–245.
(14) See for example: (a) Auamcharoen, W.; Kijjoa, A.; Chandrapatya,
A.; Pinto, M. M.; Silva, A. M. S.; Naengchomnong, W.; Herz, W.
Biochem. Syst. Ecol. 2009, 37, 690–692. (b) Kjer, J.; Wray, V.; Edrada-
Ebel, R.; Ebel, R.; Pretsch, A.; Lin, W.; Proksch, P. J. Nat. Prod.
2009, 72, 2053–2057. (c) Aly, A. H.; Edrada-Ebel, R.; Indriani, I. D.;
Wray, V.; Mueller, W. E. G.; Totzke, F.; Zirrgiebel, U.; Schaechtele,
C.; Kubbutat, M. H. G.; Lin, W. H.; Proksch, P.; Ebel, R. J. Nat.
Prod. 2008, 71, 972–980. (d) Wang, X.; Sun, W.; Sun, H.; Lv, H.;
Wu, Z.; Wang, P.; Liu, L.; Cao, H. J. Pharm. Biomed. Anal. 2008,
46, 477–490. (e) Kametani, S.; Kojima-Yuasa, A.; Kikuzaki, H.;
Kennedy, D. O.; Honzawa, M.; Matsui-Yuasa, I. Biosci. Biotechnol.
Biochem. 2007, 71, 1220–1229. (f) Kashiwada, Y.; Nonaka, G.;
Nishioka, I. Chem. Pharm. Bull. 1984, 32, 3493–3500.
altechromone A
1
10
11
entry
δC, mult.
δC, mult.
δC, mult.
δC
1
2
3
4
5
6
7
8
19.3, CH3
22.3, CH3
100.5, CH
110.7, CH
114.2, C
116.4, CH
141.4, C
159.1, C
20.0, CH3
21.7, CH3
107.3, CH
107.6, C
108.4, CH
111.5, CH
147.0, C
156.1, C
159.6, C
168.5, C
182.6, C
19.3, CH3
22.4, CH3
100.5, CH
110.7, CH
114.2, C
116.5, CH
141.4, C
159.1, C
21.0
23.3
106.4
107.6
111.8
111.9
142.6
154.4
154.7
156.4
159.7
9
10
11
160.8, C
163.7, C
178.2, C
160.9, C
163.8, C
178.3, C
Supporting Information Available: Full experimental details,
copies of the spectra, and the crystallographic information file (CCDC-
783508 (1)). This material is available free of charge via the Internet
at http://pubs.acs.org.
NP1005604