First enantioselective total synthesis and structure determination of the anthrapyran metabolite γ-indomycinone

Article abstract of DOI:10.1021/ol062492b

(Diagram presented) The first total synthesis of (R)-γ-indomycinone has been achieved which allowed the determination of the configuration of the stereogenic center of natural γ-indomycinone as (S). The approach stands out for its generality and efficienc

Full text of DOI:10.1021/ol062492b

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5873-5876
First Enantioselective Total Synthesis
and Structure Determination of the
Anthrapyran Metabolite
γ-Indomycinone
Lutz F. Tietze,* Ramakrishna Reddy Singidi, and Kersten M. Gericke
Institute of Organic and Biomolecular Chemistry, Georg-August-UniVersity,
Tammannstr. 2, D-37077 Go¨ttingen, Germany
ltietze@gwdg.de
Received October 10, 2006
ABSTRACT
The first total synthesis of (R)-γ-indomycinone has been achieved which allowed the determination of the configuration of the stereogenic
center of natural -indomycinone as (S). The approach stands out for its generality and efficiency.
γ
γ-Indomycinone (1) has recently been isolated as a new
member of the pluramycin class of antibiotics from the
culture broth of an actinomycete identified as Streptomyces
sp.1,2 [marine (B5543) and terrestrial (GW3/1130)] along with
the known compounds rubiflavinone C-13 and â-indomyci-
none.4 These antibiotics contain a 4H-anthra[1,2-b]pyran-
4,7,12-trione nucleus, typical for the pluramycin antibiotics,5
which are known for their potent anticancer activity due to
a specific alkylation at N-7 of the guanine base in the DNA.
However, they differ from the pluramycin group antibiotics
by the absence of an aminosugar moiety attached to the
chromophore by a C-glycosidic bond.
Figure 1. Proposed structure of γ-indomycinone (1).
The constitution of γ-indomycinone (1) (Figure 1) was
established by spectroscopic methods, but its absolute
configuration remains unknown so far. Because it was
isolated in only minute amounts, a chemical total synthesis
was needed for the determination of the configuration of the
stereogenic center as well as of its bioactivity.
Despite the excellent work of Hauser,6a,b Uno,6c,d Krohn,6e
McDonald,6f and their co-workers, a general approach to the
anthrapyran antibiotics, especially those with stereogenic
centers in the side chain, has only recently been accomplished
within the total synthesis of the natural product AH-1763
IIa.7
(1) Schumacher, R. W.; Davidson, B. S.; Montenegro, D. A.; Bernan,
V. S. J. Nat. Prod. 1995, 58, 613-617.
(2) Laatsch, H.; Abdelfattah, M. New Secondary Metabolites from
Bacteria: Seitomycin with high Anti-Helicobacter pylori Activity, Exfo-
liazone B, new Steffimycinones, Espicufolin B, Flavomarine A and B, and
BS-46 with a Novel Carbon Skeleton, Ph.D. thesis, University of Go¨ttingen,
Go¨ttingen, 2004.
(3) Nadig, H.; Se´quin, U. HelV. Chim. Acta 1987, 70, 1217-1228.
(4) Brockmann, H. Angew. Chem. 1968, 7, 493; Angew. Chem., Int. Ed.
1968, 39, 481.
(5) (a) Eckardt, K. Quinones and Other Carbocyclic Antitumor Antibiotics
in Antitumor Compounds of Natural Origin. In Chemistry and Biology;
Aszalos, A., Ed.; CRC Press: Boca Raton, 1981; Vol. II. (b) Se´quin, U.
The Antibiotics of the Pluramycin Group (4H-Anthra[1,2-b]pyran Antibiot-
ics) In Progress in the Chemistry of Organic Natural Products; Zechmeister,
L., Ed.; Springer, Wien: New York, 1986; Vol. 50, pp 58-122.
10.1021/ol062492b CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/15/2006

Here, we describe the first enantioselective total synthesis
of (R)-γ-indomycinone (R-1), which also allowed us to
determine the stereochemistry of the natural compound. Its
retrosynthetic analysis is outlined in Scheme 1. The first
element directing the carbon-carbon bond formation during
the Diels-Alder reaction.10 The following regioselective
ortho-bromination of anthraquinone 9 was feasible due to
the strong ortho-directing effect of the hydroxyl group. Thus,
treatment of 9 with NBS in dichloromethane in the presence
of a catalytic amount of a secondary amine11 gave the
monobromoanthraquinone 10 in nearly quantitative yield. To
complete the synthesis of the building block 3 (Scheme 2),
Scheme 1. Retrosynthetic Analysis of (R)-γ-Indomycinone
(R-1)
Scheme 2. Synthesis of the Building Block 3
disconnection in the pyrone ring moiety envisions an intra-
molecular 6-endo-dig cyclization of the chiral ynone 2, which
in turn should result from a nucleophilic attack of an aryl
lithium species generated from the bromodimethoxyanthra-
cene derivative 3 on the enantiopure propargylic aldehyde
4. Compound 3 should be accessible from the two fragments
5 and 6 employing a Diels-Alder reaction, and the aldehyde
4 could be obtained from the enantiopure dioxolanone 7.
Recently, we have shown that anthraquinones can be
obtained in an operationally simple way via a regioselective
Diels-Alder reaction,7 which is highly advantageous com-
pared to the known procedure. Thus, cycloaddition of
3-bromojuglone benzyl ether 58 as a dienophile and 1-meth-
oxy-3-methyl-1-trimethylsiloxy-1,3-butadiene 69 as a diene
led to adduct 8, which without isolation yielded the anthra-
quinone 9 by treatment with silica gel as a mild acid in 94%.
The bromo atom at C-3 in 5 acts as a regiochemical control
both the hydroxyl group and the quinone moiety had to be
protected. Following an orthogonal protecting-group strategy,
the hydroxyl group of bromoanthraquinone 10 was protected
as its isopropyl ether 11 in 90% yield by treatment with i-PrI
and Cs2CO3 in a mixture of acetone and N,N-dimethylfor-
mamide.12 Finally, reductive methylation of the quinone
moiety in 11 using the phase-transfer method13 with aq
sodium dithionite followed by treatment with KOH and
dimethyl sulfate led to the desired dimethoxyanthracene 3
in 90% overall yield. 3 is sensitive to light in the presence
of air. Under these conditions, a partial formation of the
corresponding anthraquinone takes place. The building block
3 has the advantage, over the already used corresponding
building block with two isopropyl ether moieties as protecting
groups,7 that deprotection as one of the last steps does not
cause any problems.
(6) (a) Hauser, F. M.; Rhee, R. P. J. Am. Chem. Soc. 1979, 101, 1628-
1629. (b) Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1980, 45, 3061-3068.
(c) Uno, H.; Sakamoto, K.; Honda, E.; Ono, N. Chem. Commun. 1999,
1005-1006. (d) Uno, H.; Sakamoto, K.; Honda, E.; Fukuhara, K.; Ono,
N.; Tanaka, J.; Sakanaka, M. J. Chem. Soc., Perkin Trans. 1 2001, 229-
238. (e) Krohn, K.; Vitz, J. Eur. J. Org. Chem. 2004, 209-219. (f) Fei, Z.;
McDonald, F. E. Org. Lett. 2005, 7, 3617-3620.
(7) Tietze, L. F.; Gericke, K. M.; Singidi, R. R. J. Angew. Chem. 2006,
118, 7146-7150; Angew. Chem., Int. Ed. 2006, 45, 6990-6993.
(8) (a) Takeya, T.; Kajiyama, M.; Nakumara, C.; Tobinaga, S. Chem.
Pharm. Bull. 1999, 47, 209-219. (b) Wheeler, A. S; Naiman, B. J. Am.
Chem. Soc. 1922, 44, 2331-2334. (c) Thomson, R. H. J. Org. Chem. 1948,
13, 377-383. (d) Hannan, R. L.; Barber, R. B.; Rapoport, H. J. Org. Chem.
1979, 44, 2153-2158. (e) Tietze, L. F.; Gu¨ntner, C.; Gericke, K. M.;
Schuberth, I.; Bunkoczi, G. Eur. J. Org. Chem. 2005, 2459-2467.
(9) Savard, J.; Brassard, P. Tetrahedron 1984, 40, 3455-3464.
(10) Grunwell, J. R.; Karipides, A.; Wigal, C. T.; Heinzman, S. W.;
Parlow, J.; Surso, J. A.; Clayton, L.; Fleitz, F. J.; Daffner, M.; Stevens, J.
E. J. Org. Chem. 1991, 56, 91-95.
(11) (a) Fujisaki, S.; Eguchi, H.; Omura, A.; Okamoto, A.; Nishida, A.
Bull. Chem. Soc. Jpn. 1993, 66, 1576-1579. (b) Krohn, K.; Bernhard, S.;
Floerke, U.; Hayat, N. J. Org. Chem. 2000, 65, 3218-3222. (c) Nicolaou,
K. C.; Gray, D.; Tae, J. Angew. Chem. 2001, 113, 3791-3795; Angew.
Chem., Int. Ed. 2001, 40, 3679-3683. (d) Bringmann, G.; Menche, D.;
Kraus, J.; Mu¨hlbacher, J.; Peters, K.; Peters, E.-M.; Brun, R.; Bezabih, M.;
Abegaz, B. M. J. Org. Chem. 2002, 67, 5595-5610.
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714.
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A. J. Chem. Soc., Perkin Trans. 1 1998, 3, 575 -582.
5874
Org. Lett., Vol. 8, No. 25, 2006

The synthesis of the needed propargylic aldehyde 4
(Scheme 3) started from the ester 12, which is easily
Scheme 4. Synthesis of (R)-γ-Indomycinone (R-1) from 3 and
4
Scheme 3. Synthesis of the Propargylic Aldehyde 4
accessible from enantiomerically pure dioxolanone 7 ac-
cording to a known procedure.14 Reduction of 12 with LAH
yielded the primary alcohol 13 in 80% yield, which on
oxidation utilizing the very mild IBX15 reagent furnished the
aldehyde 14. Finally, a Corey-Fuchs homologation16 to give
15 was followed by treatment with n-BuLi and N,N-
dimethylformamide17 to furnish the desired propargylic
aldehyde 4 in 80% yield.
Having successfully synthesized both the building blocks
3 and 4 in a convenient and highly efficient manner, we
focused on the coupling of these intermediates as the next
task. After conversion of 3 into the lithium derivative by
metalation using n-BuLi, the subsequent reaction with the
propargylic aldehyde 4 proceeded smoothly to give the
corresponding alcohol 16 in 86% yield as a mixture of both
possible diastereomers in a ratio of 1:1 (Scheme 4) according
to the NMR spectra of the product. The missing selectivity
has no consequences because the formed stereogenic center
is later removed by oxidation. However, it should be noted
that the aldehyde should be added in one batch immediately
after generation of the organolithium compound to get good
results. Oxidative cleavage of the 7,12-dimethoxy groups
present in 16 was accomplished in 90% yield using silver-
(II) oxide in dilute nitric acid18 to give the anthraquinone
derivative 17, which was subsequently subjected to IBX
oxidation15 to afford the ynone 18 in 93% yield. First, we
had planned to remove the protecting groups at the anthra-
quinone moiety and perform the ring closure under acidic
conditions in a domino process.19 However, treatment of 18
in acetic acid at 55 °C with a catalytic amount of sulfuric
acid led only to a cleavage of the benzyl and isopropyl ethers
at the anthraquinone to give 2, but not to a cyclization. Both
raising the temperature and increasing the reaction time did
not provide the desired product but induced an elimination
of the benzyloxy group in the side chain. However, an
efficient formation of the γ-pyrone ring system was possible
by an intramolecular 6-endo-dig cyclization of 2 under basic
conditions. Thus, treatment of 2 in acetone with Cs2CO3
yielded the tetracycle 19 in 65% yield.20 Formation of a
furanone was not detected. The final step in the synthesis of
(R)-γ-indomycinone (R-1) was the removal of the benzyl
protecting group in the side chain, which was effected in
85% yield by treatment of 19 with TiCl4 in CH2Cl2 at -78
°C and then by slow warming to -20 °C.11d
(14) (a) Seebach, D.; Naff, R.; Calderari, G. Tetrahedron 1984, 40,
1313-1324. (b) Lee, M.; Kim, D. H. Bioorg. Med. Chem. 2000, 8, 815-
823.
(15) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999,
64, 4537-4538.
(16) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769-3772.
(17) Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tetsuaki, T.;
Takemoto, Y.; Ibuka, T. J. Org. Chem. 2001, 66, 4904-4914.
(18) (a) Snyder, C. D.; Rapoport, H. J. Am. Chem. Soc. 1972, 94, 227-
231. (b) Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1980, 45, 3061-3068.
(19) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2006, (ISBN: 3-527-29060-5).
The 1H NMR spectra of the isolated natural product1,2 and
synthetic compound 1 are identical in all respects, including
(20) Mzhel’skaya, M. A.; Moroz, A. A.; Shvartsberg, M. S. Seriya
Khimicheskaya 1991, 7, 1469-1472.
Org. Lett., Vol. 8, No. 25, 2006
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chemical shifts as well as coupling constant values. The
absolute configuration of the stereogenic center in the natural
product was determined by comparison of the optical
cinone (R-1) and which allowed us to determine the natural
γ-indomycinone as (S)-1.
Acknowledgment. The authors are grateful to the Fonds
der Chemischen Industrie for supporting this work, and
R.R.S. thanks the Alexander von Humboldt Foundation for
a postdoctoral grant.
rotation. The [R]25 value of the synthetic compound (R)-1
D
was determined as +4.0 (c 0.1, DMSO), which is opposite
in sign to a natural sample with [R]D ) -5.5 (c 0.11,
DMSO), which was provided by Prof. Laatsch at the
University of Go¨ttingen.2 This clearly indicates that natural
γ-indomycinone has an (S)-configuration at the stereogenic
center.
In conclusion, we have developed a new general strategy
for the synthesis of anthrapyran antibiotics, which resulted
in the first enantioselective total synthesis of (R)-γ-indomy-
Supporting Information Available: Full experimental
procedures and detailed spectral data of all key compounds
1
are reported. Copies of H and 13C spectra are additionally
provided, along with HRMS data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL062492B
5876
Org. Lett., Vol. 8, No. 25, 2006