General approach to anthrapyran antibiotics exemplified by the synthesis of rac-γ-indomycinone

Article abstract of DOI:10.1002/ejoc.201100093

A new general route to the anthrapyran antibiotics is presented, which allows the attachment of various branched side chains. A key step is the Baker-Venkataraman rearrangement of the propionate 9 to the diketone 10. Acid-catalyzed cyclization gives the ethyl-branched anthrapyranone 11, serving as the starting material for further side-chain elongation. For example, the ethyl-substituted anthrapyranones 12a,b,c, the corresponding bromides 13b,c, the phosphonium salts 14b,c, the olefins 22a,c, and the epoxides 23a,c are prepared by starting from 11. A first example demonstrating the potential of this route is the synthesis of the naturally occurring γ-indomycinone (24b), prepared bycuprate-mediated opening of the epoxide 23a. A general route to the anthrapyran antibiotics is presented, which allows the attachment of various branched side chains. In a first example, an ethyl-branched anthrapyranone, prepared in a Baker-Venkataraman rearrangement, was used to obtain a 1-methylvinyl-substituted anthrapyranone that was transformed into rac-indomycinone via an intermediate epoxide in a cuprate-mediated epoxide opening. Copyright

Full text of DOI:10.1002/ejoc.201100093

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100093
General Approach to Anthrapyran Antibiotics Exemplified by the Synthesis of
rac-γ-Indomycinone
Karsten Krohn,*[a] Hoan Trang Tran-Thien,[a] and Ishtiaq Ahmed[a]
Keywords: Anthrapyran antibiotics / Biomimetic synthesis / Dianion reaction / Olefination / Epoxidation / Cuprate
addition
A new general route to the anthrapyran antibiotics is pre-
sented, which allows the attachment of various branched
side chains. A key step is the Baker–Venkataraman re-
arrangement of the propionate 9 to the diketone 10. Acid-
catalyzed cyclization gives the ethyl-branched anthrapy-
ranone 11, serving as the starting material for further side-
chain elongation. For example, the ethyl-substituted anthra-
pyranones 12a,b,c, the corresponding bromides 13b,c, the
phosphonium salts 14b,c, the olefins 22a,c, and the epoxides
23a,c are prepared by starting from 11. A first example dem-
onstrating the potential of this route is the synthesis of the
naturally occurring γ-indomycinone (24b), prepared by
cuprate-mediated opening of the epoxide 23a.
Introduction
The decaketide-derived anthrapyran antibiotics (indomy-
cinones, kidamycinones, rubiflavinones, pluramycinones,
hedamycinones)[1] have recently also aroused the interest of
synthetic chemists.[2–10] Side chains with different lengths
are attached to C-2 of the anthrapyran core. Unfortunately,
to date a common approach to the different aglycon cores
with one, two, four, or six carbon atoms in the side chain at
C-2 is missing. In this communication, we disclose a general
approach to the anthrapyran antibiotics, which is exem-
plified by the synthesis of rac-γ-indomycinone (24b). The
first steps follow the linear route of Yamaguchi et al.;[11,12]
however, the synthesis is shortened, and the overall yield is
improved from 40% to 87% by starting from hydroxyglut-
arate 1 via enones 2 to the phenol 3, skipping an intermedi-
ate conversion of the hydroxy group into the acetate, and
instead employing the acid-catalyzed elimination of water
(Scheme 1). Another shortcut was the direct one-step con-
version of the di-tert-butyl ester 4, obtained by silver oxide
mediated methylation of phenol 3 in 96% to the mono-
methyl ester 5 by treatment of 4 with acidic methanol
(93%).
Scheme 1. (a) (1) LDA, tert-butyl acetate (TBA), THF, 78 °C; (2)
Ca(OAc)2, MeOH; (b) toluene, reflux, 87%; (c) MeI, Ag2O, 96 %;
(d) (1) trifluoroacetic acid (TFA), CH2Cl2; (2) MeOH, 93%; (e)
LDA, tert-butyl acetoacetate (TBAA), THF, –78 °C, 83%; (f) (1)
NaH, THF; (2) LDA, acetylacetone (AA), THF, –78 °C, 78%; (g)
CuBr2, THF, O2, 94%; (h) TFA, CH2Cl2, 91%; (i) DMF, 40 °C,
90%.
According to earlier procedures,[2] the anthrone 7 was
isolated in two subsequent biomimetic dianion reactions
(78%) via the isocoumarin 6 (83%). This anthrone was then
oxidized with air in the presence of copper bromide to an
intermediate anthraquinone 8a (94%), which was subjected
to acid-catalyzed cleavage of the tert-butyl ester, followed by
decarboxylation in dry DMF at 40 °C to the corresponding
methylanthraquinone 8b in 91% overall yield.
In the following stages the synthetic route deviated from
earlier procedures.[10] The aim was to incorporate the
methyl branching of the side chain, present in most natu-
rally occurring anthrapyran antibiotics,[1] at an early stage
of the synthesis maintaining the flexibility in the nature of
the final side chain. For that purpose, the propionyl ester 9
[a] Department of Chemistry, University of Paderborn,
Warburger Straße 100, 33098 Paderborn, Germany
Fax: +49-525-1603245
E-mail: k.krohn@uni-paderborn.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100093.
Eur. J. Org. Chem. 2011, 2223–2225
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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K. Krohn, H. T. Tran-Thien, I. Ahmed
SHORT COMMUNICATION
was prepared (98%) from 8b and subjected to a lithium hoped that preferential bromination of the ethyl side chain
hydride catalyzed Baker–Venkataraman rearrange- would take place, so that these monobromides could be
ment[6,13,14] to afford the ethyl diketone 10 in 92% yield. used in subsequent Wittig reactions to attach missing parts
This established an ethyl side chain in the subsequent acid- of different side chains such as in rubiflavinone (16) (see
catalyzed cyclization to the anthrapyran 11. Since boron Scheme 2). In the first experiment, by using the most solu-
tribromide cleavage of aryl methyl ethers is prone to bromi- ble n-butanoic ester 12c, a mixture of the monobromide 13c
nation of the aromatic nucleus,[10] the methyl ether in 11 (36%) and the dibromide 14c (32%) was isolated. When
was cleaved to the phenol 12a by employing boron trichlo- the bromination of the acetate 12b was conducted to a less
ride (93%).
complete conversion, the formation of 50% of almost pure
Anthraquinones have notoriously low solubility in apolar monobromide 13b in addition to starting material was ob-
solvents. Therefore, the corresponding acetate 12b and the served. The monobromides 13b and 13c were then trans-
n-butanoic ester 12c were prepared from the phenol 12a formed almost quantitatively into the phosphonium salts
according to standard methods to increase the solubility in 15b and 15c by boiling with triphenylphosphane in toluene.
CCl4, the best solvent for radical brominations. It was
Olefinations by the Augustine Method
The Wittig reaction was postponed, and the C–C cou-
pling according to Augustine et al.[15,16] was tested first, be-
cause no selective monobromination of the alkylated an-
thrapyran core 12 was required. Reaction components in
the Augustine procedure are strongly polarized compounds
such 1,1-dihalides. Augustine et al. used gem-dibromo-
methyl-substituted aromatic compounds in a kind of Knoe-
venagel–Doebner reaction to prepare α,β-unsaturated alde-
hydes efficiently.[15,16] Augustine et al.[15] proposed a reac-
tion mechanism via the intermediate formation of pyrid-
inium salt 18, starting from the dihalide 17 (Scheme 3).
Subsequently, the nucleophilic reaction takes place between
the bis(pyridinium) cation 18 and the pyranone 19 to form
the adduct 20, which eliminates pyridinium hydrochloride
to form the double bond of the pyranone 21.
In our reaction, a methylene group could be introduced
into 12a and 12c by employing diiodomethane, dibro-
momethane or bromochloromethane. A clean olefination
reaction took place by using bromochloromethane with
catalytic amounts of DMAP and DMF in pyridine to af-
ford the olefins 22a and 22c in 76 and 79% yield, respec-
tively (Scheme 4).
The epoxidation of the double bond in the pyranones
22a,c by using meta-chloroperbenzoic acid afforded the
somewhat more polar compounds 23a and 23c in 93% and
89% yield, respectively (Scheme 4). These epoxides now
open the door to the preparation of a variety of anthra-
pyran antibiotics by employing nucleophilic openings of the
epoxides for instance with Grignard reagents or cup-
rates.[17,18] In this work, we started with the investigation
Scheme 2. (a) Propionyl chloride, pyridine, 4-(dimethylamino)pyr-
idine (DMAP), CH2Cl2, 98%; (b) LiH, THF, 92%; (c) TFA, 76%;
(d) BCl3, CH2Cl2, –10 °C, 93%; (e) Ac2O, pyridine, DMAP,
CH2Cl2, 91%; (f) valeric chloride, pyridine, DMAP, CH2Cl2, 72%;
(g) CCl4, Br2, hν; (h) P(Ph)3, toluene, 4 h, reflux; 13b (50%), 13c
(36%), 14c (32%); 15b (95%), 15c (93%).
Scheme 3. Postulated reaction mechanism of the olefination according to Augustine et al.[15]
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Eur. J. Org. Chem. 2011, 2223–2225

Synthesis of rac-γ-Indomycinone
ethyl-substituted anthrapyranones 12a,b,c, the correspond-
ing bromides 13b,c, the phosphonium salts 14b,c, and the
epoxides 23a,c were provided. The possibilities were first
exemplified in the synthesis of the naturally occurring γ-
indomycinone (24b) starting from 12a via the olefin 22a and
the epoxide 23a.
Supporting Information (see footnote on the first page of this arti-
cle): Procedures for compounds 3–24b and their spectroscopic data
1
including H and 13C NMR data are reported.
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Received: January 21, 2011
Conclusion
We presented a new general route to anthrapyran anti-
biotics, which allowed the attachment of various branched
side chains. As starting materials for these reactions the
Published Online: February 18, 2011
Eur. J. Org. Chem. 2011, 2223–2225
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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