вход по аккаунту


The Total Synthesis of the Fungal Metabolite Diversonol.

код для вставкиСкачать
Natural Product Synthesis
DOI: 10.1002/anie.200502913
The Total Synthesis of the Fungal Metabolite
Carl F. Nising, Ulrike K. Ohnemller (ne Schmid) , and
Stefan Brse*
other—which would require an efficient protecting-group
strategy. Furthermore, control over the relative stereochemistry of the substituents is mandatory for a successful synthesis. Based on the synthetic access to tetrahydroxanthenones developed in our group, diversonol (2) can be reduced
retrosynthetically to a substituted salicylic aldehyde and 4hydroxycyclohexenone (4).[5] The tetrahydroxanthenone 5
formed by a domino oxa-Michael–aldol condensation should
then be transformed to diversonol (2) in few steps
(Scheme 1).[6]
Dedicated to Professor Burchard Franck
Mycotoxins, which are secondary metabolites produced by
fungi, are a source of substances with interesting biological
activity.[1] The secalonic acids (1) represent a class of
substances produced by Claviceps purpurea as well as various
other fungi.[2] 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
substance class would be very useful.[3] 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
known to date.[4]
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
[*] Dipl.-Chem. C. F. Nising, Dipl.-Chem. U. K. Ohnem=ller (n>e
Schmid) , Prof. Dr. S. Br@se
Institut f=r Organische Chemie
Universit@t Karlsruhe (TH)
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
Fax: (+ 49) 721-608-8581
[**] We thank the Fonds der Chemischen Industrie (grant for C.F.N.)
and the LandesgraduiertenfFrderung Baden-W=rttemberg (grant for
Supporting information for this article is available on the WWW
under or from the author.
Angew. Chem. Int. Ed. 2006, 45, 307 –309
Scheme 1. Modification of tetrahydroxanthenone 5: a) imidazole, dioxane/H2O, sonication, 7 d, 61 %; b) MEMCl, iPr2NEt, CH2Cl2, RT, 3 h,
75 %; c) tetrabutylammonium tribromide, THF/H2O, RT, 5 h, 52 %;
d) DABCO, dioxane, RT, 16 h, 53 %; e) TPAP, NMO, CH2Cl2/CH3CN,
sonication, 40 %; f) MeLi, CuCN, Et2O, 78 8C, 5 h, 52 %. MEMCl = (2methoxyethoxy)methyl chloride, DABCO = 1,4-diazabicyclo[2.2.2]octane, TPAP = tetrapropylammonium perruthenate.
We now report on the first total synthesis of diversonol in
racemic form. Starting from orcinol, salicylic aldehyde 3 could
be prepared in a three-step procedure with excellent yields.[7]
4-Hydroxycyclohexenone (4) could be synthesized on a
multigram-scale according to a procedure optimized in our
group and starting from p-benzoquinone.[8]
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 K2CO3 used in former tetrahydroxanthenone
syntheses[5] only led to decomposition of the cyclohexenone.
Protection of the free hydroxy functionality as a MEM
ether,[9] followed by the stereoselective formation of bromohydrin 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
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
that the trans diastereoisomers (C4-OR and H4a trans) of
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
biaryl unit have been reported recently.[10] 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
Ley conditions[11] 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
protocol developed by Gabbutt et al.[12] After dehalogenation
of 10 by halogen–metal exchange followed by protonation,
the hydroxy functionality on C9a was introduced by diastereoselective hydroxylation of enol 11 using magnesium
monoperoxophthalate (Scheme 2).
Scheme 2. Concluding stages of the total synthesis of rac-diversonol
(2): a) tBuLi, THF, 788 C, NaHCO3, 4 h, 93 %; b) magnesium monoperoxophthalate, EtOH, RT, 5 h, 57 %; c) BBr3, CH2Cl2, RT, 7 h, 40 %;
d) NaBH4, MeOH, 78 8C, 20 min, 66 %.
To our delight, the diastereoselectivity of this step could
be influenced by varying the reaction conditions.[13] After
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
product[4] except for the optical rotation, which remains
unknown to date.
In summary, we have developed a flexible route to
tetrahydroxanthenone mycotoxins by applying a domino
oxa-Michael–aldol condensation.[5] 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.
Received: August 16, 2005
Revised: October 4, 2005
Published online: December 9, 2005
Keywords: diversonol · domino reactions · fungal metabolites ·
natural products · total synthesis
[1] a) B. Franck, Angew. Chem. 1984, 96, 462 – 474; Angew. Chem.
Int. Ed. Engl. 1984, 23, 493 – 505; b) L. Roth, H. Frank, K.
Kormann, Pilzgifte, Nikol, Hamburg, 1990; c) I. F. H. Purchase,
Mycotoxins, Elsevier, Amsterdam, 1974; d) W. B. Turner, Fungal
Metabolites, Academic Press, New York, 1971; e) W. B. Turner,
D. C. Aldridge, Fungal Metabolites II, Academic Press, New
York, 1983; f) K. Krohn, J. Dai, U. FlGrke, H.-J. Aust, S. DrHger,
B. Schulz, J. Nat. Prod. 2005, 68, 400 – 405.
[2] a) B. Franck, G. Baumann, U. Ohnsorge, Tetrahedron Lett. 1965,
2031 – 2037; b) B. Franck, E. M. Gottschalk, U. Ohnsorge, G.
Baumann, Angew. Chem. 1964, 76, 438 – 439; Angew. Chem. Int.
Ed. Engl. 1964, 3, 441 – 442; c) B. Franck, E. M. Gottschalk, U.
Ohnsorge, F. HIper, Chem. Ber. 1966, 99, 3842 – 3862; d) “The
Biosynthesis of the Ergochromes”: B. Franck in The Biosynthesis
of Mycotoxins: A Study in Secondary Metabolism (Ed.: P. S.
Steyn), Academic Press, New York, 1980.
[3] a) M. Wagenaar, J. Clardy, J. Nat. Prod. 2001, 64, 1006 – 1009;
b) M. Isaka, A. Jaturapat, K. Rukseree, K. Danwisetkanjana, M.
Tanticharoen, Y. Thebtaranonth, J. Nat. Prod. 2001, 64, 1015 –
1018; biological activity: c) I. Kurobane, S. Iwahashi, A. Fukuda,
Drugs Exp. Clin. Res. 1987, 13, 339 – 344; d) A. Stoll, J. Renz, A.
Brack, Helv. Chim. Acta 1952, 35, 2022 – 2034; e) F. McPhee, P. S.
Caldera, G. W. Bemis, A. F. McDonagh, I. D. Kuntz, C. S. Craik,
Biochem. J. 1996, 320, 681 – 686.
[4] a) W. B. Turner, J. Chem. Soc. Perkin Trans. 1 1978, 1621; in this
publication, the question whether the isolated compound was a
racemate or an enantiomerically pure compound remains
unanswered; b) diversonolic esters: J. S. Holker, E. OLBrien,
T. J. Simpson, J. Chem. Soc. Perkin Trans. 1 1983, 1365 – 1368.
[5] B. Lesch, S. BrHse, Angew. Chem. 2004, 116, 118 – 120; Angew.
Chem. Int. Ed. 2004, 43, 115 – 118; benzpyran synthesis: B.
Lesch, J. TorHng, S. Vanderheiden, S. BrHse, Adv. Synth. Cat.
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.
1996, 96, 115 – 136.
[7] Details of this synthesis can be found in the Supporting
[8] M. Oda, T. Kawase, T. Okada, T. Enomoto, Org. Synth. 1996, 73,
253 – 261; A. P. Marchand, D. Xing, Y. Wang, S. G. Bott,
Tetrahedron: Asymmetry 1995, 6, 2709 – 2714; U. K. OhnemIller,
S. BrHse, unpublished results.
[9] E. J. Corey, J.-L. Gras, P. Ulrich, Tetrahedron Lett. 1976, 809 –
[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
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 307 –309
synthesis of symmetrical biaryls see: C. F. Nising, U. K. Schmid,
M. Nieger, S. BrHse, 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. Vazquez 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. BrHse, unpublished results.
Angew. Chem. Int. Ed. 2006, 45, 307 –309
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Без категории
Размер файла
95 Кб
synthesis, tota, metabolico, diversonol, fungal
Пожаловаться на содержимое документа