Aziridines as a Protecting and Directing Group. Stereoselective Synthesis of (+)-Bromoxone

Article abstract of DOI:10.1021/ol035576i

(Equation presented) The directing ability of an aziridine group for the epoxidation of adjacent double bonds is demonstrated. The aziridine group is also used to effectively protect a double bond in a cycloenone system for a short synthesis of the title

Full text of DOI:10.1021/ol035576i

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4321-4323
Aziridines as a Protecting and Directing
Group. Stereoselective Synthesis of
(+)-Bromoxone
,‡
M. Teresa Barros,† Pedro M. Matias,‡ Christopher D. Maycock,* and
M. Rita Ventura‡
Departamento de Qu´ımica, Faculdade de Cieˆncias e Tecnologia da UniVersidade NoVa
de Lisboa, 2825 Monte da Caparica, and Instituto de Tecnologia Qu´ımica e Biolo´gica,
UniVersidade NoVa de Lisboa, Apartado 127, 2780 Oeiras, Portugal
maycock@itqb.unl.pt
Received August 21, 2003
ABSTRACT
The directing ability of an aziridine group for the epoxidation of adjacent double bonds is demonstrated. The aziridine group is also used to
effectively protect a double bond in a cycloenone system for a short synthesis of the title compound.
(+)-Bromoxone 1 and its acetate were isolated in 1987 from
a species of acorn worm belonging to the genus Ptychodera
found in deep underwater caves on the island of Maui.1 The
acetate of bromoxone shows potent antitumor activity against
P388 cells in vitro. These compounds belong to the bioactive
polyoxygenated cyclohexenone family. Bromoxone also
provides an entry to more complex members of this family
such as Manumycin A and Asukamycin via cross-coupling
reactions. Several syntheses of 1 have been developed.
Racemic syntheses of 1 have been reported by the groups
of Taylor2 and enantioselective syntheses by Altenbach,3
Johnson,4 and Kitahara.5
The chiral enone 3 derived from (-)-quinic acid 26 was
used as the starting material, having the required cyclohexane
skeleton, a 1,4-oxygen functionality suitable for synthesis
of the necessary hydroxyl, and carbonyl groups in these
positions of the target compound. In fact, it has already been
used to synthesize several members of the polyoxygenated
cyclohexane metabolite family.6-8 R-Iodocycloenone 4 was
† Faculdade de Cieˆncias e Tecnologia da Universidade Nova de Lisboa.
‡ Instituto de Tecnologia Qu´ımica e Biolo´gica.
(1) Higa, T.; Okuda, R. K.; Severns, R. M.; Scheur, P. J.; He, C.-H.;
Changfu, X.; Clardy, J. Tetrahedron 1987, 43, 1063.
(2) Gautier, E. C. L.; Lewis, N.; McKillop, A.; Taylor, R. J. K.
Tetrahedron Lett. 1994, 35, 8759.
Figure 1.
(3) (a) Adelt, S.; Plettenburg, O.; Stricker, R.; Reiser, G.; Altenbach,
H.-J.; Vogel, G. J. Med. Chem. 1999, 42, 1262. (b) Altenbach, H.-J. In
Antibiotics and AntiViral Compounds; Krohn, K., Kirst, H., Maas, H., Eds.;
VCH: Weinheim, 1993, 359-372. (c) Block, O.; Klein, G.; Altenbach,
H.-J.; Brauer, D. J. Org. Chem. 2000, 65, 716.
(4) Johnson, C. R.; Miller, M. W. J. Org. Chem. 1995, 60, 6674.
(5) Tachihara, T.; Kitahara, T. Tetrahedron 2003, 59, 1773.
obtained from enone 3, which in turn was obtained from
quinic acid in five steps.6 We have recently described a
general method to prepare aziridines from R-iodocycloenones
in very good yield, by a Michael addition/cyclization
10.1021/ol035576i CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/11/2003

(Gabriel-Cromwell) process using only a slight excess of
primary amine and Cs2CO3 as a base at 95 °C.9
Scheme 2a
R-Iodocycloenone 4 was employed as the substrate for
aziridination, and we postulated that the presence of an
adjacent asymmetric center on a cyclohexane nucleus should
induce stereoselectivity to the process.9 The aziridination
reaction with 4-methoxybenzylamine afforded, however, two
diastereoisomers 5 and 6 in a 4:1 ratio (84% yield, Scheme
1), accompanied by an aromatic byproduct 7. The configu-
Scheme 1a
a Reaction conditions: (a) NaOH 0.5 N, THF, 0 °C, 88%. (b)
TBDMSCl, DMAP, (i-Pr)2NEt, CH2Cl2, rt, 80%. (c) H2O2, Triton
B, THF 0 °C, 90%. (d) HBr, MeOH, rt, 80%. (e) HF 40%, MeCN,
rt, 89%.
a Reaction conditions: (a) I2, DMAP, Pyr/CC4I, rt, 80%. (b)
4-Methoxybenzylamine, Cs2CO3, 1,10-phenanthroline, xylene, 95
°C, 84%.
more, care was needed to avoid aromatization and the degree
of purity of the aziridine was very important for the
successful outcome of this reaction. To induce the formation
of the epoxide with the correct stereochemistry, the free
hydroxyl group in 8, which in previous syntheses8 had been
shown to have a strong influence in directing the cis epoxide
formation, was protected with TBDMSCl, a bulky group, to
afford 9. Epoxidation of the enone system of 9 with hydrogen
peroxide and catalytic Triton B afforded exclusively the
epoxide 10 (80%). Surprisingly the epoxidation of 8, and
silylation of the resulting epoxide, afforded the same
compound 10. It was thus concluded that in this case, it was
not the hydroxyl group that exerted the strongest orientating
effect but the nitrogen atom of the aziridine group. This was
also confirmed by performing the same sequence of reactions
on the minor diastereoisomer 6; in this case, the epoxide
formed was syn with respect to the adjacent bulky TBDMS
ether group.
ration of aziridine 5 was confirmed by X-ray crystallographic
studies. We also attempted this reaction with other amines,
Figure 2.
with differing results. For benzylamine, only one diastereo-
isomer was obtained, with the aziridine below the plane of
the molecule (60%), along with an aromatic byproduct, which
contaminated the aziridine. When n-butylamine was used,
the two diastereoisomers of the aziridine were obtained in a
1:1 ratio (70%). As before, aromatic byproduct was also
formed.
Resuming the synthesis, at this stage, we had a molecule
with five asymmetric centers and two three-membered rings
on opposite sides of the cyclohexane ring, a highly strained
molecule.
The next step was critically important, since we were
dependent upon the exclusive opening of the benzylaziridine
in the presence of the epoxide. This proved to be rather easy
to accomplish employing 0.1 M HBr in MeOH at rt, and
TBDMS-protected bromoxone 11 was efficiently obtained
in 80% yield (Scheme 2), [R]20D +99.3 (c 1.03, CHCl3) (lit.
Treatment of aziridine 5 with catalytic NaOH 0.5 N
afforded the alcohol 8 (Scheme 2) in good yield (88%). Once
(6) Barros, M. T.; Maycock, C. D.; Ventura, M. R. J. Org. Chem. 1997,
62, 3984.
(7) Barros, M. T.; Maycock, C. D.; Ventura, M. R. Tetrahedron 1999,
55, 3233.
[R]20 +98.9 (c 0.79, CHCl3),5 mp 46-47 °C (lit. 49-50
D
°C).5
(8) Barros, M. T.; Maycock, C. D.; Ventura, M. R. Chem. Eur. J. 2000,
6, 3991.
(9) Barros, M. T.; Maycock, C. D.; Ventura, M. R. Tetrahedron Lett.
2002, 43, 4329.
Hydrolysis of the silyl protecting group afforded (+)-
bromoxone 1 (89%), [R]20 +205.7 (c 0.32, acetone) (lit.
D
[R]20 +204.0 (c 0.21, acetone),5 [R]22 +220 (c 0.09,
D
D
4322
Org. Lett., Vol. 5, No. 23, 2003

3. It is the only asymmetric synthesis of bromoxone that does
not rely on an enzymatic resolution.
Scheme 3
The aziridine ring could also be opened with HN3 in the
presence of the epoxide ring to afford R-azido enone 12
(Scheme 3), which represents a novel and short route to (-)-
LL-C10037 R 13. These studies are currently being carried
out.
Acknowledgment. We thank Fundac¸a˜o para a Cieˆncia e
a Tecnologia for a grant conceded to M.R.V.
CHCl3),1 [R]25 +203 (c 2.5, acetone)3c, mp 125-126 °C
Supporting Information Available: Experimental pro-
cedures and spectrosocopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
D
(lit. 123-127 °C,1 124-125 °C,5 138-139 °C,4 131-132
°C3c). This is an efficient asymmetric synthesis of (+)-
bromoxone, with an overall yield of 24%, starting from enone
OL035576I
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