Intramolecular vinyl quinone Diels-Alder reactions: Asymmetric entry to the cordiachrome core and synthesis of (-)-isoglaziovianol

Article abstract of DOI:10.1021/ol401787n

A short and asymmetric entry to the core structure of the cordiachromes has been developed, allowing access to (-)-isoglaziovianol in seven steps. Our synthesis includes a Trost asymmetric allylic alkylation and a reaction cascade triggered by a vinyl quinone Diels-Alder reaction and followed by intramolecular nucleophilic interception.

Full text of DOI:10.1021/ol401787n

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Intramolecular Vinyl Quinone DielsÀAlder
Reactions: Asymmetric Entry to the
Cordiachrome Core and Synthesis of
(À)-Isoglaziovianol
€
Florian Lobermann, Lara Weisheit, and Dirk Trauner*
Department of Chemistry and Center of Integrated Protein Science, University of
Munich, Butenandtstraße 5À13 (F4.086), 81377 Munich, Germany
dirk.trauner@lmu.de
Received June 24, 2013
ABSTRACT
A short and asymmetric entry to the core structure of the cordiachromes has been developed, allowing access to (À)-isoglaziovianol in seven
steps. Our synthesis includes a Trost asymmetric allylic alkylation and a reaction cascade triggered by a vinyl quinone DielsÀAlder reaction and
followed by intramolecular nucleophilic interception.
The cordiachromes are an unusual class of meroterpe-
noids that have been isolated either in the quinone or
quinol form. They all feature a hydroanthracene skeleton
that is further oxidized to varying degrees (Figure 1).1,2
Most of them possess a cis-fused decalin moiety with one
remarkable exception: glaziovianol 1, which is the only
member of the family known to date that features a trans-
fused decalin. This natural product was isolated from the
trunk heartwood of Auxemma glazioviana, a tree endemic
in the region of northeastern Brazil.3 The wood of this tree
is resistant to fungi and termite attacks and thus often used
for civil construction.3 In folk medicine, cuts and wounds
are treated with the trunk bark.4
The intriguing tetracyclic structure of glaziovianol in-
cludes four contiguous stereocenters, one of which is qua-
ternary, thus rendering it a challenging target for total
synthesis. To date only cordiachrome B 2 has been
(1) Moir, B. M.; Thomson, R. H. J. Chem. Soc., Chem. Commun.
1972, 14, 363–364.
(2) Moir, B. M.; Aberdeen, O. J. Chem. Soc., Perkin Trans. 1 1973,
1556–1561.
Figure 1. The cordiachrome family of natural products (shown
with arbitrary absolute configuration).
(3) Da Costa, G. M.; De Lemos, T. L.; Pessoa, O. D. L.; Monte,
F. J. Q.; Braz-Filho, R. J. Nat. Prod. 1999, 62, 1044–1045.
(4) Braga, R. Plantas do Nordeste, Especialmente do Ceara, 2nd ed.;
Imprensa Oficial: Fortaleza, Ceara, Brasil, 1960.
(5) Watabe, T.; Hosoda, Y.; Okada, K.; Oda, M. Bull. Chem. Soc.
Jpn. 1987, 60, 3801–3802.
synthesized, albeit in racemic form.5 To the best of our
knowledge, no asymmetric entry to this class of natural
products has been reported.
r
10.1021/ol401787n
XXXX American Chemical Society

Our retrosynthetic analysis of glaziovianol 1 (Scheme 1)
was based on biosynthetic consideration and commences
with the disconnection of the tetrahydrofuran ring at the
benzylic position, which would result in isoquinone methide
3. Intermediate 3 bears the retron of an intramolecular vinyl
quinone DielsÀAlder (VQDA)6,7 reaction with neutral elec-
tron demand, the implementation of which yields alkenyl
hydroquinone 4. According to our synthetic plan, the enone
functionality in 4 would be introduced through a singlet
oxygen ene reaction in the side chain, while the alkenyl
hydroquinone moiety would be assembled from aryl halide
5 with tertiary allylic alcohol 6.
Figure 2. Relative configuration of (À)-21.
internal nucleophile, whereas the tertiary radical is further
oxidized to a cation and then intercepted by water.
Our second generation, asymmetric approach, which
drew from lessons learned in the racemic series, is shown in
Scheme 3. It commenced with a Trost asymmetric alkyla-
tion of para-methoxybenzyl alcohol 10 with the known
racemic vinyl epoxide 11. Employing the S,S-DACH
phenyl ligand, we obtained tertiary allylic ether 12 with
high regio- and enantioselectivity (85% isolated yield and
93% ee).9 Heck-coupling of 12 with protected ortho-bro-
mohydroquinone 13 then gave alkenyl hydroquinone 14.10
A TPP sensitized singlet-oxygen ene reaction of 14, fol-
lowed by acetylation and elimination, gave the desired
R,β-unsaturated ketone 15.11 It should be noted that this
reaction mode could also occur in the biosynthesis of the
cordiachromes.
Scheme 1. Retrosynthetic Analysis of Glaziovianol, 1
In the key sequence of our synthesis, the acetyl protect-
ꢀ
ing groups were removed under Zemplen deacetylation
conditions, and the resulting phenol was oxidized to the
corresponding quinone 16 under mild conditions.12 This
vinyl quinone, however, could not be isolated since it rapidly
underwent VQDA reaction at room temperature, presum-
ably via the endo transition state 17, followed by nucleo-
philic interception of the resulting isoquinone methide 18.
Further oxidation of the resulting hydroquinone 19
upon workup afforded the tetracyclic quinone 20 in 39%
overall yield. Oxidative removal of the PMB group and
reduction then gave hydroquinone 21, which bears the
constitution of glaziovianol.
Our synthetic studies commenced with a model system
shown in Scheme 2. Heck-coupling of myrcene-derived
diol 68 with bromo hydroquinonedimethyl ether 7 gave
tertiary allylic alcohol 8 (Scheme 2). This compound turned
out to be very sensitive toward acid, complicating our efforts
to oxidize it to the corresponding vinyl quinone. Interest-
ingly, when subjecting methoxyether 8 to radical oxidation
conditions such as buffered CAN or DDQ, compound 9
was observed as the only isolable product. The relative
configuration of compound 9 was established through
NOE measurements (see Supporting Information).
Unfortunately, 21 turned out to be an isomer of the
natural product glaziovianol with respect to the decalin
junction, which is cis-fused instead of trans-fused. The
stereochemistry of (À)-21 was elucidated through detailed
NOE measurements. We were able to observe NOE signals
beteween the methine protons at C1 and C2, as well as
signals between C2 and the angular methyl group (Figure 2).
Scheme 2. Formation of Unexpected Cyclization Product 9
€
(6) Lobermann, F.; Mayer, P.; Trauner, D. Angew. Chem., Int. Ed.
2010, 49, 6199–6202.
(7) Zhang, Z.; Chen, J.; Yang, Z.; Tang, Y. Org. Lett. 2010, 12, 5554–
5557.
(8) Fauchet, V.; Miguel, B. A.; Taran, M.; Delmond, B. Synth.
Commun. 1993, 23, 2503–2510.
(9) Trost, B. M.; McEachern, E. J.; Toste, F. D. J. Am. Chem. Soc.
1998, 120, 12702–12703.
(10) Trost, B. M.; Andersen, N. G. J. Am. Chem. Soc. 2002, 124,
14320–14321.
(11) Mihelich, E. D.; Eickhoff, D. J. J. Org. Chem. 1983, 48, 4135–
4137.
(12) Tohma, H.; Morioka, H.; Harayama, Y.; Hashizume, M.; Kita,
Y. Tetrahedron Lett. 2001, 42, 253–270.
This unusual cyclization presumably involves the initial
formation of a stabilized benzylic radical cation, which under-
goes stereoselective cyclization to yield a benzylic cation and
a tertiary radical. The benzylic cation is quenched by the
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Synthesis of Isoglaziovianol through a VQDA Cascade Reaction
In addition, the chemical shift of the methyl group in 21,
which we propose to call isoglaziovianol, is in better agree-
ment with the cis-fused “regular” cordiachromes than with
trans-fused glaziovianol (1.27 ppm vs 0.94 ppm).3 Attempts
to overcome the undesired diastereoselectivity of the
DielsÀAlder reaction and favor an exo-transition state,
e.g. by employing catalysts or using an allylic alcohol
instead of an enone as the dienophile, proved fruitless.
In conclusion we have developed an asymmetric synth-
esis of (À)-isoglaziovianol that emphasizes the uniqueness
of glaziovianol in the cordiachrome series. Our short
synthesis raises interesting biosynthetic questions, since
an uncatalyzed VQDA reaction does not appear to be
involved, indicating that an enzyme might be required for
the formation of the trans-decalin moiety. Alternatively,
it is conceivable that isoglaziovianol is indeed a natural
product, which is epimerized at its quaternary sterocenter
to glaziovianol via a photochemical reaction, similar to the
epimerization of estrone to lumiestrone.13
Acknowledgment. We thank Prof. Wolfgang Steglich
€
(LMU Munchen) forstimulating discussions regarding the
biosynthesis of glaziovianol and undergraduate research-
€
ers M. Ilg (LMU Munchen) and A. Großmann (LMU
Munchen) for skillful experimental assistance. We thank
€
the Deutsche Forschungsgemeinschaft (SFB 749) for
financial support.
Supporting Information Available. Detailed experimen-
tal procedures, characterization data, and NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Wehrli, H.; Schaffner, K. Helv. Chim. Acta 1962, 45, 385–389.
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
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