Synthesis of analogue structures of the p-quinone methide moiety of kendomycin

Article abstract of DOI:10.1021/ol048825r

(Chemical Equation Presented) The synthesis of two model p-quinone methide ring systems of the antibiotic and antiosteoporotic compound kendomycin is reported. Two approaches were examined in detail, and the two-step (i) demethylation and (ii) DMDO oxidat

Full text of DOI:10.1021/ol048825r

ORGANIC
LETTERS
2004
Vol. 6, No. 18
3131-3134
Synthesis of Analogue Structures of the
p-Quinone Methide Moiety of
Kendomycin
Martin P. Green, Stefan Pichlmair, Maria M. B. Marques, Harry J. Martin,
Oliver Diwald,† Thomas Berger,† and Johann Mulzer*
Institut fu¨r Organische Chemie, Wa¨hringerstrasse 38, A-1090 Wien, Austria
johann.mulzer@uniVie.ac.at
Received June 21, 2004
ABSTRACT
The synthesis of two model p-quinone methide ring systems of the antibiotic and antiosteoporotic compound kendomycin is reported. Two
approaches were examined in detail, and the two-step (i) demethylation and (ii) DMDO oxidation were found to be reliable and generally
applicable. Additionally, it was found that oxidation of a benzofuran by NaIO on silica produced a long-lived semiquinone radical.
4
Kendomycin [(-)-TAN 2162] 1, a novel ansamycin com-
pound isolated from several different Streptomyces species,
has been shown to be a potent endothelin receptor antagonist
and an antiosteoporotic compound with remarkable anti-
bacterial and cytostatic activity.1 The challenging structure
and diverse pharmacological profile of kendomycin has
motivated us and other groups to carry out studies toward
its synthesis.2
product, it is thought that the highly electrophilic C16 of
the quinone methide is crucial for its pharmacological
activity.1d As part of our ongoing studies toward the synthesis
of this challenging natural product, we recently carried out
some model work on the construction of this previously
unknown quinone methide.
The most common approach for the synthesis of p-quinone
methides, as developed by Trammel for the synthesis of
puupehenone,3 involves the oxidation of a catechol to an
o-quinone followed by tautomerization. Initial experiments
confirmed our expectations that these and other literature
conditions4 would be unsuitable for the synthesis of the
quinone methide moiety found in 1, mainly because of
complications arising from the presence of the hemiketal. It
was therefore essential to develop a new strategy specifically
designed for our purposes.
The most intriguing feature of kendomycin is the unique
and structurally interesting p-quinone methide chromophore.
As well as being the source of the yellow color of the natural
† Institut fu¨r Materialchemie, Technische Universita¨t Wien, Veterina¨r-
platz 1/GA, A-1210, Wien, Austria.
(1) (a) Funahashi, Y.; Kawamura, N.; Ishimaru, T. Jpn. Patent 08231551
[A2960910], 1996; Chem. Abstr. 1997, 126, 6553. (b) Funahashi, N.;
Kawamura, N. Jpn. Patent 08231552, 1996; Chem. Abstr. 1996, 125,
326518. (c) Su, M. H.; Hosken, M. I.; Hotovec, B. J.; Johnston, T. L. U.S.
Patent 5728727, 1998; Chem. Abstr. 1998, 128, 239489. (d) Bode, H. B.;
Zeeck, A. J. Chem. Soc., Perkin Trans. 1 2000, 323. (e) Bode, H. B.; Zeeck,
A. J. Chem. Soc., Perkin Trans. 1 2000, 2665.
(2) (a) Martin, H. J.; Drescher, M.; Ka¨hlig, H.; Schneider, S.; Mulzer, J.
Angew. Chem. 2001, 113, 3287. (b) Marques, M. M. B.; Pichlmair, S.;
Martin, H. J.; Mulzer, J. Synthesis 2002, 18, 276. (c) Pichlmair, S.; Marques,
M. M. B.; Green, M. P.; Martin, H. J.; Mulzer, J. Org. Lett. 2003, 24,
4657. (d) Mulzer, J.; Pichlmair, S.; Green, M. P.; Marques, M. M. B.; Martin,
H. J. Proc. Natl. Acad. Sci. U.S.A. 2004, in press. (e) Sengoku, T.; Arimoto,
H.; Uemura, D. Chem. Commun. 2004, 1220.
As a result of the chemical sensitivity of the quinone
methide in 1, we planned to introduce it late in the total
synthesis, perhaps by oxidation of a suitably functionalized
benzofuran 2 (Scheme 1). The benzofuran moiety is ideally
(3) Trammel, G. L. Tetrahedron Lett. 1978, 18, 1525.
(4) Angle, S. R.; Arnaiz, D. O. J. Org. Chem. 1992, 57, 5937.
10.1021/ol048825r CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/31/2004

Our model study began with the synthesis of substrate 7
from known aryl Grignard 9.2c Reaction with isobutene oxide
in the presence of copper iodide gave ketone 10 after Swern
oxidation. Acid-catalyzed MOM deprotection and benzofuran
formation of 10 was followed by reprotection of the phenolic
OH to give 11. ortho-Lithiation of 11 and reaction with
methyl iodide then gave 7 after MOM deprotection (Scheme
3).
Scheme 1. Benzofuran Oxidation as Last Step in the
Synthesis of Kendomycin
Scheme 3. Synthesis of Benzofuranes
suited as a quinone methide precursor because it can be intro-
duced early in our current route to the natural product and
should be able to withstand the rest of the synthetic sequence
with little requirement for protecting group chemistry.
At the outset of this work, we considered two alternative
strategies for the required oxidation (Scheme 2). First, we
Scheme 2. Oxidation Strategies
Various conditions for the direct oxidation of 7 to the
corresponding o-quinone 13 were studied. Unfortunately, our
initial efforts to apply several known procedures for the
oxidation of monoquinol ethers and monocatechol ethers to
quinones, including CAN,6 DDQ,7 AgO,8 and NaIO4,9
resulted in complex mixtures of products. Upon further
examination of the literature we found a report that sodium
periodate adsorbed onto silica could be used for the oxidation
of quinols and catechols to quinones.10 Application of these
conditions to the oxidation of 7 resulted in conversion of
the starting material to a strongly blue colored compound.
Although we were unable to purify this compound, 1H NMR
analysis of the crude material showed that the phenolic OMe
had been removed and that the signal for the furan proton
had shifted from 6.3 to 5.8 ppm. This initially led us to
believe that we had produced the desired o-quinone; however,
this did not explain the strong blue color observed. We
realized at this point that we might have in fact produced a
stable semiquinone radical 12 resulting from single-electron
oxidation with NaIO4. Evidence for this hypothesis came
from the EPR spectrum, which clearly showed the presence
of a radical (Figure 2).
planned to oxidize an arene such as 3 to an o-quinone 4 and
have the latter undergo a 1,6-addition of water to give the
quinone methide 5. Alternatively, we proposed that in a
Rubottom-type oxidation5 epoxidation of the furan double
bond could be followed by 1,6-elimination to give the
quinone methide.
To examine these two approaches in detail we decided to
carry out a study using two relatively simple model substrates
7 and 8. In both cases, the catechol was monomethylated,
because this protecting group is used in our current approach
to the synthesis of kendomycin.
(5) Rubottom, G. M.; Gruber, J. M.; Juve, H. D., Jr. Org. Synth. 1985,
64, 118.
(6) Jacob, P., III; Callery, P. S.; Shulgin, A. T.; Castagnoli, N., Jr. J.
Org. Chem. 1976, 41, 3627.
(7) Becker, H.-D. J. Org. Chem. 1965, 30, 982.
(8) Rapoport, H. J. Am. Chem. Soc. 1972, 94, 227.
(9) Adler, E.; Magnusson, R. Acta Chem. Scand. 1959, 13, 505.
(10) Daumas, M.; Vo-Quang, L.; Le Goffic, F. Synthesis 1989, 64.
Figure 1. Substrates chosen for model study.
3132
Org. Lett., Vol. 6, No. 18, 2004

Scheme 5. Synthesis of Benzofuran 8
Figure 2. EPR spectrum of semiquinone radical 12.
treatment with this model substrate with NaIO4 on SiO2 a
blue color was once again observed, although it was apparent
from H NMR spectroscopy that a complex mixture of
1
We found that the redox potential of semiquinone radical
is dependent on pH, as on treatment of an acetonitrile solution
of the radical species with aqueous 0.1 N HCl we observed
a rapid color change from blue to yellow. After workup we
were able to isolate the quinone methide 14 in a moderate
20% yield. Presumably, formation of the o-quinone 13 occurs
through either auto-oxidation or disproportionation of the
semiquinone radical, followed by acid-catalyzed 1,6-addition
of water to the quinone to give the p-quinone methide 14
(Scheme 4).
products had been produced. Attempted acid-catalyzed
oxidation and hydrolysis, as used previously, resulted in loss
of the blue color, but no p-quinone methide 17 could be
identified.
Given the low yield for the formation of 14 and the
unsuccessful conversion of 8 to quinone methide 17, we
continued to seek a general procedure for the required
benzofuran oxidation. As stated earlier, we believed that it
would be possible to functionalize the furan double bond of
the benzofuran by epoxidation. This would be followed by
rearrangement to give the quinone methide. There was some
precedent for this transformation in the literature in which
Adam et al.11 converted a range of benzofurans into their
corresponding epoxides by treatment with dimethyldioxirane
(DMDO) at -78 °C. The resulting strained epoxides were
found to be unstable and rapidly decomposed above -20
°C.
Scheme 4. Quinone Methide Formation via o-Quinone
Preliminary experiments in which our monomethylated
model substrates 7 and 8 were treated with DMDO12 or
m-CPBA at various temperatures resulted only in the
Scheme 6. Quinone Methide Formation by Rubottom
Oxidation
Having fortuitously achieved a first synthesis of the desired
quinone methide, we then sought to apply these conditions
to the slightly more complex model substrate 8. We were
able to access the model system using conditions similar to
those before. In this case though, MOM deprotection with
aqueous HCl in the presence of methanol was accompanied
by exchange of the benzylic alcohol with OMe via the
intermediate ortho-quinone methide 16 (Scheme 5). Upon
Org. Lett., Vol. 6, No. 18, 2004
3133

decomposition of starting material. We then sought to remove
the OMe protecting group, which we believed was preventing
the necessary rearrangement reaction. After numerous ex-
periments we found that the demethylation of both of these
substrates could be carried out cleanly by treatment with a
1:1 mixture of boron tribromide and 2,6-lutidine in CH2Cl2
at 0 °C for 10 h (Scheme 6).13 The resulting catechols 18
and 19 were quite unstable with respect to column chroma-
tography on silica and were therefore used in crude form
for the next reaction. To our delight, treatment of 18 and 19
with DMDO at -78 °C for 20 min resulted in the expected
epoxidation and spontaneous rearrangement reactions to give
the yellow colored kendomycin-like p-quinone methides 14
and 17 in good yields over two steps.
In summary, we have developed a novel and reliable two-
step procedure for the synthesis of p-quinone methide ring
systems similar to that found in kendomycin. We are now
examining its application to the total synthesis of kendomycin
and these results will be published in due course.
Acknowledgment. We are grateful to the Austrian
Science Foundation (FWF, projects M674 and P14729-CHE)
for financial support.
(11) Adam, W.; Bialas, J.; Hadjiarapoglou, L.; Sauter, M. Chem. Ber.
1992, 125, 231.
(12) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991, 124,
2377.
(13) Platzek, J.; Beckmann, W.; Geisler, J.; Kirstein, H.; Niedballa, U.;
Ottow, E.; Radau, S.; Schulz, C.; Wessa, T. (SCHERING AG) PCT Int.
Appl. WO2003033461 A1, 2003.
Supporting Information Available: Experimental details
and characterization of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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