The total synthesis of the fungal metabolite diversonol

Article abstract of DOI:10.1002/anie.200502913

(Chemical Equation Presented) Mission accomplished. The fungal metabolite diversonol has been synthesized for the first time. A key step in the total synthesis was the domino oxa-Michael-aldol condensation of salicylic aldehyde 1 and 4-hydroxycyclohexenon

Full text of DOI:10.1002/anie.200502913

Angewandte
Chemie
Natural Product Synthesis
other—which would require an efficient protecting-group
strategy. Furthermore, control over the relative stereochem-
istry of the substituents is mandatory for a successful syn-
thesis. Based on the synthetic access to tetrahydroxanthe-
nones developed in our group, diversonol (2) can be reduced
retrosynthetically to a substituted salicylic aldehyde and 4-
DOI: 10.1002/anie.200502913
The Total Synthesis of the Fungal Metabolite
Diversonol**
[
5]
hydroxycyclohexenone (4). The tetrahydroxanthenone 5
formed by a domino oxa-Michael–aldol condensation should
then be transformed to diversonol (2) in few steps
Carl F. Nising, Ulrike K. Ohnemüller (nØe Schmid) , and
Stefan Bräse*
[
6]
(Scheme 1).
Dedicated to Professor Burchard Franck
Mycotoxins, which are secondary metabolites produced by
fungi, are a source of substances with interesting biological
[
1]
activity. The secalonic acids (1) represent a class of
substances produced by Claviceps purpurea as well as various
[
2]
other fungi. The secalonic acids are symmetrical or unsym-
metrical tetrahydroxanthenone dimers possessing a 2,2’-biaryl
unit. Since other mycotoxins with a similar structure have
been isolated recently, many of which show promising
biological activity, an efficient synthetic access to this
[
3]
substance class would be very useful. In the course of our
studies towards the total synthesis of the secalonic acids, we
were also interested in the synthesis of the secondary
metabolite diversonol (2), which was isolated by Turner
from Penicillium diversum and whose structural motif can
also be found in some of the substances mentioned above. The
absolute configuration of naturally occurring diversonol is not
Scheme 1. Modification of tetrahydroxanthenone 5: a) imidazole, diox-
ane/H O, sonication, 7 d, 61%; b) MEMCl, iPr NEt, CH Cl , RT, 3 h,
2
2
2
2
7
5%; c) tetrabutylammonium tribromide, THF/H O, RT, 5 h, 52%;
2
d) DABCO, dioxane, RT, 16 h, 53%; e) TPAP, NMO, CH Cl /CH CN,
2
2
3
sonication, 40%; f) MeLi, CuCN, Et O, À788C, 5 h, 52%. MEMCl=(2-
2
methoxyethoxy)methyl chloride, DABCO=1,4-diazabicyclo-
[2.2.2]octane, TPAP=tetrapropylammonium perruthenate.
[
4]
known to date.
As the structure of diversonol is very similar to that of the
secalonic acid monomers, the total synthesis of diversonol
would also be a step towards the total synthesis of the
secalonic acids. The synthesis of diversonol was expected to
be challenging owing to the high density of functional
groups—all four hydroxy groups are located close to each
We now report on the first total synthesis of diversonol in
racemic form. Starting from orcinol, salicylic aldehyde 3 could
[
7]
be prepared in a three-step procedure with excellent yields.
4-Hydroxycyclohexenone (4) could be synthesized on a
multigram-scale according to a procedure optimized in our
[
8]
group and starting from p-benzoquinone.
With these building blocks in hand, we set out to optimize
the key domino oxa-Michael–aldol condensation. When
imidazole was used as the base, tetrahydroxanthenone 5
could be isolated in a yield of 61% and as a 1.5:1 mixture of
the two possible diastereoisomers, whereas the bases
DABCO and K CO used in former tetrahydroxanthenone
[
*] Dipl.-Chem. C. F. Nising, Dipl.-Chem. U. K. Ohnemüller (nØe
Schmid) , Prof. Dr. S. Bräse
Institut für Organische Chemie
Universität Karlsruhe (TH)
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
Fax: (+49)721-608-8581
E-mail: braese@ioc.uka.de
2
3
[
5]
syntheses only led to decomposition of the cyclohexenone.
Protection of the free hydroxy functionality as a MEM
[
**] We thank the Fonds der Chemischen Industrie (grant for C.F.N.)
and the Landesgraduiertenförderung Baden-Württemberg (grant for
U.K.O.).
[
9]
ether, followed by the stereoselective formation of bromo-
hydrin 7 now set the stage for the synthesis of the conjugated
system 8 by elimination of hydrogen bromide from 7. The
moderate yields of steps b–d in Scheme 1 result from the fact
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2006, 45, 307 –309
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
307

Communications
that the trans diastereoisomers (C4-OR and H4a trans) of
In summary, we have developed a flexible route to
tetrahydroxanthenone mycotoxins by applying a domino
tetrahydroxanthenones 5–7 are almost unreactive; after
elimination of HBr from 7 allylic alcohol 8 was isolated as a
single diastereoisomer. The halogenation of the aromatic
moiety, which inevitably takes place during bromohydrin
formation, could be used for palladium-catalyzed aryl–aryl
coupling since dimeric analogues of diversonol bearing a
[
5]
oxa-Michael–aldol condensation. In this context, we were
able to achieve the first total synthesis of the secondary
metabolite diversonol (2) in racemic form and in a sequence
of 14 synthetic steps. The application of this methodology to
the total synthesis of the secalonic acids (1) and an evaluation
of the biological activity of diversonol (2) are currently
underway in our laboratory.
[
10]
biaryl unit have been reported recently. The subsequent
oxidation of compound 8 was unexpectedly difficult since the
allylic alcohol proved to be acid- and base-sensitive. Of a
number of different oxidation protocols, only oxidation under
Received: August 16, 2005
Revised: October 4, 2005
Published online: December 9, 2005
[
11]
Ley conditions using tetrapropylammonium perruthenate
TPAP) as a catalytic oxidizing agent gave diketone 9 in
(
acceptable yield. The subsequent cuprate addition could be
performed diastereoselectively and with good yield by a
Keywords: diversonol · domino reactions · fungal metabolites ·
natural products · total synthesis
.
[
12]
protocol developed by Gabbutt et al. After dehalogenation
of 10 by halogen–metal exchange followed by protonation,
the hydroxy functionality on C9a was introduced by diaste-
reoselective hydroxylation of enol 11 using magnesium
monoperoxophthalate (Scheme 2).
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2
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[
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[
4] a) W. B. Turner, J. Chem. Soc. Perkin Trans. 1 1978, 1621; in this
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Scheme 2. Concluding stages of the total synthesis of rac-diversonol
[
(
2): a) tBuLi, THF, À788C, NaHCO , 4 h, 93%; b) magnesium mono-
3
peroxophthalate, EtOH, RT, 5 h, 57%; c) BBr , CH Cl , RT, 7 h, 40%;
3
2
2
d) NaBH , MeOH, À788C, 20 min, 66%.
4
2005, 4, 555 – 562; for an independent study see: K. Y. Lee, J. M.
Kim, J. N. Kim, Bull. Korean Chem. Soc. 2003, 24, 17 – 18.
[
6] For a review of domino reactions see: L. F. Tietze, Chem. Rev.
To our delight, the diastereoselectivity of this step could
1996, 96, 115 – 136.
[
13]
be influenced by varying the reaction conditions.
After
[
7] Details of this synthesis can be found in the Supporting
Information.
deprotection of compound 12 at the phenolic and secondary
hydroxy functionalities, diversonol (2) was obtained by
diastereoselective reduction of the unconjugated carbonyl
function using sodium borohydride. The analytical data are in
complete agreement with those reported for the natural
[8] M. Oda, T. Kawase, T. Okada, T. Enomoto, Org. Synth. 1996, 73,
53 – 261; A. P. Marchand, D. Xing, Y. Wang, S. G. Bott,
2
Tetrahedron: Asymmetry 1995, 6, 2709 – 2714; U. K. Ohnemüller,
S. Bräse, unpublished results.
[
9] E. J. Corey, J.-L. Gras, P. Ulrich, Tetrahedron Lett. 1976, 809 –
[
4]
product except for the optical rotation, which remains
unknown to date.
812.
[
10] M. Stewart, R. J. Capon, J. M. White, E. Lacey, S. Tennant, J. H.
Gill, M. P. Shaddock, J. Nat. Prod. 2004, 67, 728 – 730; for the
3
08
www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 307 –309

Angewandte
Chemie
synthesis of symmetrical biaryls see: C. F. Nising, U. K. Schmid,
M. Nieger, S. Bräse, J. Org. Chem. 2004, 69, 6830 – 6833.
[
[
[
11] S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis
1994, 639 – 666.
12] C. D. Gabbutt, J. D. Hepworth, M. W. J. Urquhart, L. M. Vaz-
quez de Miguel, J. Chem. Soc. Perkin Trans. 1 1997, 1819 – 1824.
13] Both of the two possible diastereoisomers could be synthesized
selectively by using either meta-chloroperbenzoic acid or
magnesium monoperoxophthalate as the oxidizing agent. The
possibility of controlling the diastereoselectivity could be proved
by X-ray structure analyses of model compounds; C. F. Nising,
M. Nieger, S. Bräse, unpublished results.
Angew. Chem. Int. Ed. 2006, 45, 307 –309
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
309