Synthesis of azafluorenone antimicrobial agents

Article abstract of DOI:10.1021/np100536a

A flexible synthesis of the azafluorenone alkaloids 1, 2, 3, and 4 is described.

Full text of DOI:10.1021/np100536a

J. Nat. Prod. 2010, 73, 1967–1968
1967
Synthesis of Azafluorenone Antimicrobial Agents
George A. Kraus* and Aaron Kempema
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011, United States
ReceiVed July 30, 2010
A flexible synthesis of the azafluorenone alkaloids 1, 2, 3, and 4 is described.
The azafluorenones constitute a growing class of alkaloids.1
Representative natural products of this class include compounds
1-5 as shown. Onychine (1) was active against C. albicans B311
with a MIC of 3.12 µg per milliliter.2 In addition, compound 1
also exhibited antimicrobial activity against S. aureus NCTC 8530,
B. subtilis IFO 3007, Escherichia coli IFO 3545, and Saccharo-
myces cereVisiae IFO 0203 in the range 50 to >100 µg per
milliliter.3 Polyfothine (2) shows DNA-damaging activity.4 Isour-
suline (5) exhibited antimalarial activity against Plasmodium
falciparum at micromolar concentrations.5 Both compounds 1 and
2 have been synthesized by Koyama using an acid-catalyzed
rearrangement of the oxime O-allyl ether of an indanone.6
Compound 1 has also been synthesized by way of intramolecular
Friedel-Crafts reactions and organometallic coupling reactions.7,8
Of particular note is the novel boronic acid coupling developed by
Snieckus and co-workers.9
Scheme 1. Retrosynthetic Analysis
Scheme 2. First Approach to Azafluorenone Skeleton
Scheme 3. Model System Results
Scheme 4. General Synthesis of Azafluorenones
Our retrosynthetic analysis is depicted below in Scheme 1. The
starting materials, substituted pyridines 6 and bromobenzaldehydes
7, are either commercially available or are readily available in a
few steps.
Initially, we envisioned a one-pot synthesis of the tricyclic
skeleton 9 from 3-lithio-2-bromopyridine (8) and isovanillin, as
shown in Scheme 2. Although the first step was successful, the
intramolecular cyclization failed. Attempted cyclization of the
corresponding benzophenone, prepared by Jones oxidation of
the alcohol, also failed.
Scheme 5. Synthesis of 4 from 2
Interestingly, bromo ketone 10, prepared in two steps from 8,
underwent an intramolecular Heck reaction to afford 11 in 40%
yield, as shown in Scheme 3. This reaction was regioselective,
providing only the isomer shown, as evidenced by the singlets for
the para-hydrogens in the aromatic ring of 11.
In order to develop a more general approach, the three-step
synthesis illustrated in Scheme 4 was developed. It began with the
reaction of an aldehyde with the anion derived by metal-halogen
exchange between bromopyridine 12 and n-butyllithium.10 This
reaction afforded an unstable alcohol that was readily oxidized using
manganese dioxide to generate ketone 13 in 86% yield over two
steps, as shown in Scheme 4. An intramolecular Heck reaction11
on bromo benzophenones 13a-13c cleanly provided azafluorenones
1, 2, and 3 in 53%, 47%, and 50% yields, respectively.
Natural product 4 was isolated from the stem barks of Onco-
dostigma monosperma.12 This compound can be readily prepared
from azafluorenone 2 using hydrochloric acid, as illustrated in
Scheme 5.13
In conclusion, the synthesis of four azafluorenones has been
achieved in three steps in good overall yields. Our synthesis of
azafluorenones 1 and 2 is strategically distinct from previous
syntheses. Our synthetic approach to azafluorenones is flexible and
will permit the synthesis of a variety of analogues for additional
antibacterial testing.
Experimental Section
General Experimental Procedures. Unless otherwise noted, materi-
als were obtained from commercial suppliers and used without
purification. Bromobenzaldehydes were made on the basis of literature
* To whom correspondence should be addressed. Tel: 515-294-7794.
Fax: 515-294-0105. E-mail: gakraus@iastate.edu.
10.1021/np100536a  2010 American Chemical Society and American Society of Pharmacognosy
Published on Web 10/21/2010

1968 Journal of Natural Products, 2010, Vol. 73, No. 11
Notes
procedures without further modification. Tetrahydrofuran was distilled
from sodium and benzophenone. All experiments were performed under
an argon atmosphere unless otherwise noted. Nuclear magnetic
resonance experiments were performed with either a Varian 300 MHz
or a Varian 400 MHz instrument. Coupling constants (J) are reported
in Hz with abbreviations s ) singlet, d ) doublet, t ) triplet, q )
quartet, m ) multiplet. High-resolution mass spectra were recorded
on a Kratos model MS-50 spectrometer. Standard grade silica gel (60
Å, 32-63 µm) was used for flash column chromatography.
General Procedure for the Synthesis of 1-3. To a solution of
3-bromo-4-methylpyridine (12) (1 equiv) in THF (0.05 M) was added
n-BuLi (1 equiv) at -100 °C. The mixture was stirred at this
temperature for 10 min followed by the addition of bromobenzaldehyde
(1 equiv) as a solution in THF. The reaction was warmed to 78 °C for
2 h and then stirred at rt for 8 h. The reaction was quenched with water
and extracted with EtOAc. The organic phase was then washed with
brine and dried over MgSO4, followed by filtration and concentration
in vacuo.
Acknowledgment. We thank the Department of Chemistry at Iowa
State University for partial support of this work.
Supporting Information Available: Experimental procedures and
characterization data; 1H and 13C NMR for 10, 11, 13a, 13b, 13c, and
3. This material is available free of charge via the Internet at http://
pubs.acs.org.
References and Notes
(1) Prachayasittikul, S.; Manam, P.; Chinworrungsee, M.; Isarankura-Na-
Ayudhya, C.; Ruchirawat, S.; Prachayasittikul, V. Molecules 2009,
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(2) Hufford, C. D.; Liu, S.; Clark, A. M.; Oguntimein, B. O. J. Nat. Prod.
1987, 50, 961–964.
(3) Koyama, J.; Morita, I.; Kobayashi, N.; Osakai, T.; Usuki, Y.;
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(4) Lago, J. H. G.; Chaves, M. H.; Ayres, M. C. C.; Agripino, D. G.;
Young, M. C. M. Planta Med. 2007, 292–295.
(5) Mueller, D.; Davis, R. A.; Duffy, S.; Avery, V. M.; Camp, D.; Quinn,
R. J. J. Nat. Prod. 2009, 72, 1538–1540.
To the unpurified alcohol was added activated MnO2 (5 equiv) in
50 mL of benzene. The solution was heated to reflux with a Dean-Stark
trap for 18 h. The MnO2 was filtered, and the solution was concentrated
in vacuo. The residue was purified with silica gel flash chromatography
(3:1-1:2 hexanes-EtOAc).
(6) Koyama, J.; Okatani, T.; Tagahara, K. Heterocycles 1989, 29, 1649–
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Padmakumar, R. Synth. Commun. 1998, 28, 2071–2075.
(8) Shiao, M. J.; Liu, K. H.; Lin, P. Y. Heterocycles 1993, 36, 507–518.
(9) Alessi, M.; Larkin, A. L.; Ogilvie, K. A.; Green, L. A.; Lai, S.; Lopez,
S.; Snieckus, V. J. Org. Chem. 2007, 72, 1588–1594.
(10) Frenette, R.; Blouin, M.; Brideau, C.; Chauret, N.; Ducharme, Y.;
Friesen, R. W.; Hamel, P.; Jones, T. R.; Laliberte, F.; Li, C.; Masson,
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(11) Ames, D. E.; Opalko, A. Tetrahedron 1984, 40, 1919–1925.
(12) Sinclair, J. Sarawak Mus. J. 1951, 5, 605.
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A solution of bromo-keto pyridine (1 equiv), TBAC (1.5 equiv),
Pd(OAc)2 (0.1 equiv), and base (1.5 equiv) in DMF (0.05 M) was heated
and stirred until completion (TLC). After the reaction was complete,
the solution was extracted with diethyl ether and washed with water,
followed by brine, and dried over MgSO4. The organic phase was
filtered and concentrated in vacuo. The residue was purified with silica
gel flash chromatography (1:1-1:3 hexanes-EtOAc) to afford 1-3.
1
Characterization Data H and 13C NMR for 10, 11, 13a, 13b,
13c, and 3. Further details of the preparation and characterization and
1
the H and 13C NMR data for compounds 10, 11, 13a, 13b, 13c, and
3 are provided in the Supporting Information.
NP100536A