Efficient enantiodivergent total synthesis of (+) and (-)-bromoxone

Article abstract of DOI:10.1016/j.tetasy.2009.12.016

The total synthesis of (+)-bromoxone and a formal synthesis of (-)-bromoxone were performed in a simple chemoenzymatic manner, starting from bromobenzene, and using an enantiodivergent strategy. The usefulness of chiral cyclohexadienediols derived from the biotransformations of monosubstituted-aromatic compounds as building blocks for the preparation of natural epoxyenones was confirmed.

Full text of DOI:10.1016/j.tetasy.2009.12.016

Tetrahedron: Asymmetry 21 (2010) 153–155
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Efficient enantiodivergent total synthesis of (+) and (ꢀ)-bromoxone
*
Maitia Labora, Enrique M. Pandolfi, Valeria Schapiro
Departamento de Química Orgánica, Facultad de Química, Universidad de la República, General Flores 2124, CP 11800, Montevideo, Uruguay
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis of (+)-bromoxone and a formal synthesis of (ꢀ)-bromoxone were performed in a sim-
ple chemoenzymatic manner, starting from bromobenzene, and using an enantiodivergent strategy. The
usefulness of chiral cyclohexadienediols derived from the biotransformations of monosubstituted-aro-
matic compounds as building blocks for the preparation of natural epoxyenones was confirmed.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 30 November 2009
Accepted 21 December 2009
Available online 27 January 2010
1. Introduction
enantiomers to reach (+)-bromoxone. In 2003, two reports have
been published concerning this synthetic target. Tachihara and Kita-
In the last few years, we have been engaged in research con-
cerning the preparation of natural epoxyenones and analogues.1,2
Our starting materials are cis-cyclohexadienediols of microbial ori-
gin,3 and provide the source of chirality for our syntheses. These
are well established building blocks in the asymmetric synthesis
of natural products.4–6Among the natural epoxyenones7 (Fig. 1)
some lack side chains, such as (+)-bromoxone 1a,8 or exhibit sim-
ple chains, such as epiepoformin 2 and isoepoxydon.9 Others, while
still retaining a simple epoxyenone core, bear more complex side
chains as jesterone,10 panepoxydon,11 and ambuic acid 3.12 Finally,
some natural epoxyenones stand out for their complexity such as
panepophenathrin 4,13 hexacyclinol 5,14 torreyanic acid,15 and
epoxyquinols,16 which exhibit a wide range of biological activities
such as antifungal, antiproliferative, and antiangiogenic agents.7,17
We have previously focused our attention on ambuic acid 3 and
wereportedthepreparationof a modelmolecule,1 whichconstitutes
the first application of microbial cis-cyclohexadienediols in the syn-
thesis of this type of molecules. We also reported methodology con-
cerning the introduction of side chains to the epoxyenone core
through Stille’s reactions.2 Herein, we disclose the chemoenzymatic
and enantiodivergent synthesis of (+) and (ꢀ)-bromoxone, using the
biotransformation of bromobenzene as the first step of the strategy.
Bromoxone 1a was isolated along with its acetate 1b from marine
acornwormsin1987. Acetate1bhasprovedtobea potentantitumor
agent in vitro.8 A few synthetic efforts have been published concern-
ing 1a and 1b. A racemic synthesis of bromoxone has been reported
in 1994,18 and in 1995, Miller and Johnson19 who synthesized both
bromoxone enantiomers starting with p-benzoquinone and per-
forming a lipase-mediated resolution in the fourth step of their
route. Five years later, Altenbach20 also used a lipase to resolve an
enantiomeric mixture during a synthesis, and used one of these
hara21 prepared (+)-bromoxone among other epoxyenones, utilizing
´
a chiral building block obtained with the aid of a bakers yeast reduc-
tion while Barros et al.22 obtained it with a chiral building block
derived from (ꢀ)-quinic acid. Afterwards, in their route to (+)-
hexacyclinol 5, Porco et al.23 also synthesized (ꢀ)-bromoxone using
a chiral building block prepared by themselves through a tartrate-
mediated asymmetric epoxidation. During the preparation of this
manuscript, Banwell reported the synthesis of (ꢀ)-bromoxone from
cis-cyclohexadienediols.24 Three months ago, we reported our preli-
minary results in the preparation of (+) and (ꢀ)-bromoxone using
these starting materials.25
2. Results and discussion
Bromobenzene was converted into cyclohexadienediol 6 with
high enantiomeric purity, through whole-cell oxidation using
Pseudomonas putida F39/D.3 After protection of the diol functional-
ity, compound 8 was obtained under selective iodohydroxylation
conditions previously described for this type of compounds.26
Selective hydrolysis of the acetonide enabled oxirane ring closure
under basic medium affording the key intermediate 10 (Scheme 1).
(+)-Bromoxone was prepared as shown in Scheme 2. Epoxide 10
was successfully debrominated to yield compound 11 which, after
convenient protection–deprotection steps, was oxidized to
epoxyenone 14. The hydroxy group on carbon 4 was deprotected
and subsequently treated under Mitsunobu conditions to give 16.
a
-Bromination of the inverted compound 16 under addition–elim-
ination conditions and further hydrolysis of the p-nitrobenzoate
provided (+)-bromoxone, which was confirmed by spectroscopic
and polarimetric analysis.
The enantiodivergence of the route is originated in the fact that,
as shown in Scheme 3, (ꢀ)-bromoxone can also be generated from
epoxide 10, which was the key intermediate of our strategy.
Efficient removal of the acetate group from epoxide 10 afforded
* Corresponding author. Tel.: +5982 924 4066; fax: +5982 924 1906.
E-mail address: vschapir@fq.edu.uy (V. Schapiro).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.12.016

154
M. Labora et al. / Tetrahedron: Asymmetry 21 (2010) 153–155
OH
O
O
O
Br
HO
H3C
O
O
O
COOH
OR
OH
1a:
1b:
2
R=H, (+)-Bromoxone
R=Ac
3
Epiepoformin
Ambuic acid
OH
O
O
O
OH
O
O
O
H
O
O
H
OH
H
OH
O
OH
O
5
4
Panepophenanthrin
Hexacyclinol
Figure 1. Naturally occurring epoxyenones.
Br
Br
Br
OH
OH
DMP, acetone
p-TsOH, 0ºC
88%
AcOH, AcOAg
Pseudomonas putida F39/D
O
O
I2, rt
87%
ee > 99 %
6
7
Br
Br
Br
O
O
OH
OH
AcOH 50%
reflux
Bu4NHSO4, NaOH
OH
CH2Cl2, rt
79%
AcO
AcO
AcO
O
94%
I
I
8
9
10
Scheme 1. Synthesis of key intermediate 10.
OH
OTHS
OTHS
THSCl, Imidazole
HSnBu3, ABCC
MeOH, K2CO3
10
AcO
HO
THF, reflux
100%
DMF, 0 ºC
AcO
rt
O
O
O
100%
79%
11
13
12
NO2
OTHS
OH
HF, CH3CN
IBX, DMF
PPh3, DIAD
O
rt
O
rt
PNBA, benzene, rt
63%
O
O
O
85%
71%
O
O
14
15
O
16
NO2
Br
OH
K2CO3 / MeOH
Br2 / CCl4
Br
O
O
rt
43%
rt
50%
O
O
O
O
1a: (+)-bromoxone
17
Scheme 2. Total synthesis of (+)-bromoxone ABCC: 1, 10-azobis(cyclohexanecarbonitrile) THSCl: chlorodimethylhexylsilane.
compound 18. Banwell reported the preparation of (ꢀ)-bromoxone
from 18,24 thus converting the preparation of this dihydroxy epox-
ide into the formal total synthesis of the enantiomer of the natural
product. All compounds were purified by column chromatography,
their specific rotations were determined and they were fully char-
acterized by spectroscopic methods.

M. Labora et al. / Tetrahedron: Asymmetry 21 (2010) 153–155
155
Br
Br
O
OH
K2CO3 / MeOH
formal synthesis
10
HO
(-)-bromoxone
rt
94%
O
HO
O
18
Scheme 3. Formal synthesis of (ꢀ)-bromoxone.
5. Johnson, R. A. Org. React. 2004, 63, 117–264.
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3. Conclusion
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We demonstrated the applicability of cis-cyclohexadienediols of
microbial origin to prepare suitable building blocks, such as the
key intermediate 10, for the synthesis of natural and unnatural
epoxyenones. We completed the first total synthesis of the natural
product (+)-bromoxone from these starting materials and a formal
synthesis of the enantiomer was established in an enantiodiver-
gent manner. Further applications of this strategy for the prepara-
tion of the central core of these target molecules are currently
under research in our laboratory and will be reported in due
course.
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Acknowledgments
The authors are grateful to PEDECIBA (PNUD/URU/06/004) and
CSIC-UdelaR for financial support of this work. Maitia Labora
thanks PEDECIBA and ANII for a doctoral fellowship. We are also
grateful to Dr. Gabriel Cavalli for helpful discussions.
References and notes
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