Synthesis of the benz[a]anthraquinone core of angucyclinone antibiotics

Article abstract of DOI:10.1021/ol0274920

A general method for the synthesis of benz[a]anthraquinones is reported. The key step is a catalytic cobalt-mediated [2+2+2]-cycloaddition of a triyne, which affords an angularly substituted tetracycle. Oxidation of this core gives the typical structure o

Full text of DOI:10.1021/ol0274920

ORGANIC
LETTERS
2003
Vol. 5, No. 6
843-844
Synthesis of the Benz[a]anthraquinone
Core of Angucyclinone Antibiotics
Aris Kalogerakis and Ulrich Groth*
Fachbereich Chemie, UniVersita¨t Konstanz, Fach M-720, UniVersitaetsstrasse 10,
78457 Konstanz, Germany
ulrich.groth@uni-konstanz.de
Received December 18, 2002
ABSTRACT
A general method for the synthesis of benz[a]anthraquinones is reported. The key step is a catalytic cobalt-mediated [2+2+2]-cycloaddition
of a triyne, which affords an angularly substituted tetracycle. Oxidation of this core gives the typical structure of angucyclinone antibiotics.
The angucyclines are a large class of antibiotics isolated from
several strains of Streptomyces. They display a broad
spectrum of biological properties including antiviral, anti-
fungal, antitumor, and enzyme inhibitor activity.1 Most of
these antibiotics feature a unique benz[a]anthraquinone
structure either with or without a 9-C-glycosidic moiety.
Members of this class of angucyclines without a glycosidic
moiety, the angucyclinones, have the benz[a]anthraquinone
structure either without a hydroxy group at C-6 such as (+)-
rubiginone B2 12 or with a hydroxy group at C-6 such as
(+)-hatomarubigin A 2.3 Some members of this class feature
a tertiary hydroxy group at C-3 such as (-)-tetrangomycin
34 and (-)-rabelomycin 4.5
metic-type reactions7 by employing polyketide condensations.
Herein we would like to present the first synthesis of the
benz[a]anthraquinone structure of the angucyclinone anti-
biotics via an intramolecular cobalt-mediated [2+2+2]-
cycloaddition8 of a triyne. The cyclization of triynes is a
powerful synthetic method to form several carbon-carbon
bonds in one step and provides access to polycyclic systems
with a newly formed highly substituted benzene nucleus. We
were able to synthesize a triyne-precursor 11 (Scheme 1)
which, after cobalt-mediated [2+2+2]-cycloaddition, gave
the anthracene structure 13 (Scheme 2).9 Cyclization experi-
ments with RhCl(PPh3)3 and RuCl2(dCHPh)(PCy3)2, which
Most general strategies for the construction of the an-
gucyclinone framework are based on Diels-Alder reaction
of a naphthoquinone with a vinylcyclohexene6 or on biomi-
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10.1021/ol0274920 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/27/2003

Scheme 1a
Scheme 2a
a Reagents and conditions: (a) (i) s-BuLi/TMEDA, THF, -80
°C, 1 h, (ii) ZnCl2, -80 °C, 1 h, (iii) CuCN‚2LiCl, -80 °C, 1 h,
(iv) (3-bromoprop-1-ynyl)trimethylsilane 5, -80 °C to room temp-
erature (85%). (b) DIBAL/BuLi, THF, 25 °C, 18 h (68%). (c) BuLi/
1-TMS-1,7-octadiyne, THF (82%). (d) (i) NH4F/Bu4NHSO4, CH2Cl2,
48 h, (ii) TBDMSOTf, 2,6-lutidine, CH2Cl2, 25 °C, 2 h (95%).
a Reagents and conditions: (a) 5% CpCo(ethene)2, Et2O, -80
°C to room temperature, 18 h, or 5% CpCo(CO)2, toluene, reflux,
hν, 4 h (66%). (b) 8 equiv of [Ag(Py)2]MnO4, CH2Cl2, 25 °C, 18
h (63%). (c) hν, air, CHCl3, 25 °C, 18 h (61%).
anthracene 13 (55% yield and 16% isolated starting material).
In the case of CpCo(CO)2 the reaction had been carried out
in toluene under reflux and irradiation with a tungsten lamp
(66% yield). Oxidation of 13 with the aid of the mild reagent
[Ag(Py)2]MnO4 gave the anthraquinone 14 (63% yield).18
We have also been trying to oxidize with CrO3 in AcOH,
but these conditions led to decomposition of the anthracene.
The introduction of the C-1 carbonyl was achieved by
photooxidation, a general method for the angucyclinones
developed by Krohn.19 Exposure of 14 to visible light
(tungsten lamp) gave the typical structure 15 of the angucy-
clinone antibiotics (61% yield).
In conclusion, the angucyclinone framework 15 was
synthesized from benzamide 6 in 8 steps and 11% yield
overall. This method provides a new access toward the
angucyclinone antibiotics, which do not have a hydroxy
group at C-6. The stereocenter at C-3 is not involved in the
[2+2+2]-cycloaddition, therefore this methodology offers
a good strategy for the enantioselective synthesis of this class
of antibiotics.
can also promote alkyne trimerization,10 were not successful
in our systems. Two-step oxidation of 13 led then to the
angucyclinone core 15.
The amide 611 was at first selectively ortho-lithiated with
s-BuLi/TMEDA.12b It was then transmetalated with ZnCl2
and then CuCN‚2LiCl and allowed to react with (3-
bromoprop-1-ynyl)trimethylsilane 5 to give the propynyl-
amide 7.12c This was directly reduced to benzaldehyde 8 with
the DIBAL/BuLi complex.13 After addition of lithiated
1-TMS-1,7-octadiyne14 to this aldehyde, the triple bonds of
the resulting triyne 9 were deprotected with NH4F15 (depro-
tection with TBAF in THF led to decomposition of the triyne
9). The hydroxy group was then transformed into its silyl
ether 11 with the aid of TBDMSOTf.16
For the cyclization of 11 we used CpCo(ethene)217and the
commercially available CpCo(CO)2. Reaction of 11 with 5%
CpCo(ethene)2 succeeded under mild conditions at low
temperature. Surprisingly we observed the loss of the
TBDMSO-group with concomitant aromatization to the
Acknowledgment. The authors are grateful to the Fonds
der Chemischen Industrie and the EU-Comission, Directorate
XII, for financial support.
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Supporting Information Available: Experimental pro-
cedures and analytical data for all compounds, 1H NMR and
13C NMR spectra for 13, 14, and 15. This material is
available free of charge via the Internet at http://pubs.acs.org.
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