Synthesis of taiwaniaquinoids via Nazarov triflation

Article abstract of DOI:10.1021/ja062505g

A unified approach toward the taiwaniaquinoids that has yielded four natural products is described. A new variant of the Nazarov reaction with concomitant formation of an enol triflate serves as one of the key steps, considerably shortening the synthetic

Full text of DOI:10.1021/ja062505g

Published on Web 08/08/2006
Synthesis of Taiwaniaquinoids via Nazarov Triflation
Guangxin Liang, Yue Xu, Ian B. Seiple, and Dirk Trauner*
Department of Chemistry, UniVersity of California, Berkeley, Berkeley, California 94720-1460
Received April 11, 2006; E-mail: trauner@cchem.berkeley.edu
Scheme 1. Total Synthesis of Taiwaniaquinol B
The taiwaniaquinoids are a family of unusual tricyclic diterpe-
noids isolated from East Asian conifers with interesting biological
activities (Chart 1).1 Structurally, their members are marked by a
rare tricyclic [6-5-6] ring system, which is presumably formed by
an oxidative ring contraction of a more regular hydrophenanthrene
precursor.1a In some cases, one carbon has been lost in the course
of the biosynthesis to afford norditerpenoids such as taiwaniaquinol
B (2), taiwaniaquinone H (8) and dichroanone (9).
Several members of the taiwaniaquinoids have shown activity
as aromatase inhibitors and are currently under evaluation for their
potential as drug leads.1e-h Thus, it comes as no surprise that the
taiwaniaquinoids have attracted the interest of several synthetic
groups.2 Fillion reported a total synthesis of (()-taiwaniaquinol B
featuring an interesting domino acylation/alkylation step.2a Very
recently, Stoltz published a synthesis of (+)-dichroanone based on
a novel asymmetric palladium-catalyzed alkylation.2b Approaches
toward other members of the family based on intramolecular Heck
reactions have also been reported.2c-e
Chart 1. The Taiwaniaquinoids
to afford the highly unstable silyl enol ether 17, presumably through
the intermediacy of cation 16. Upon aqueous workup, this procedure
afforded the thermodynamically more favorable cis-indane product
18 as the only stereoisomer observed. It is important to note that
the use of solvents less polar than nitromethane gave little or no
cyclization.
Since 18 was featured as an intermediate in Fillion’s first total
synthesis of (()-taiwaniaquinol B,2a the overall sequence constitutes
a short formal total synthesis of the natural product. In a slightly
modified endgame, we found that selective deprotection, followed
by CAN-oxidation and sodium dithionite reduction upon workup4
afforded (()-taiwaniaquinol B (2) in comparable overall yield from
18.
We now report a concise and convergent synthetic approach
toward the taiwaniaquinoid family that hinges on Nazarov chem-
istry.3 Indeed, aromatic Nazarov reactions are well suited for the
construction of the central indanone or indene moieties of these
natural products. In the course of our studies we have developed a
new aromatic Nazarov cyclization that directly produces indenyl
triflates and could be of general use for the synthesis of substituted
indenes.
Our total synthesis of taiwaniaquinol B is outlined in Scheme 1.
Bromination of the known resorcinol derivative 10 gave aryl
bromide 11. Lithiation of this material (11 f 12), followed by
addition of the commercially available â-cyclocitral 13 afforded
aryl vinyl carbinol 14. This sensitive alcohol was oxidized
immediately to yield aryl vinyl ketone 15. Attempts to produce 15
more directly via Friedel-Crafts acylation, possibly with concomi-
tant Nazarov cyclization, failed.
Contemplating the mechanism of the key aromatic Nazarov
cyclization, we came to the conclusion that treatment of 15 with
triflic anhydride (instead of TMS triflate) should afford the
corresponding enol triflate.5 Indeed, heating of aryl vinyl ketone
15 with triflic anhydride in the presence of a hindered base (2,6-
di-tert-butylpyridine; 2,6-DTBP) cleanly gave trifloxy indene 20
(Scheme 2). This reaction is proposed to proceed through trifloxy
cation 19, which undergoes 4π electrocyclization followed by
deprotonation to yield 20. A systematic survey of substrates showed
that the reaction works reasonably well with electron-rich aryl vinyl
ketones but fails with most substrates bearing electron-withdrawing
substituents on the aryl ring (see Supporting Information). This
reflects general reactivity trends among aromatic Nazarov reactions.
Enol triflate 20 can serve as a key intermediate to access several
taiwaniaquinoids. Its use in a total synthesis of taiwaniaquinone H
(8) and dichroanone (9) is shown in Scheme 3. Palladium-catalyzed
reduction gave indene 21 in excellent yield. Because of steric
hindrance, the comparatively small ligand trimethyl phosphite was
After an extensive survey of conditions, we found that 15 could
be cyclized in the presence of trimethylsilyl triflate in nitromethane
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10.1021/ja062505g CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Nazarov Cyclization/Triflation
regioselective demethylation of the resultant aldehyde 24 and
oxidation/reduction gave (()-taiwaniaquinol D (4). In accordance
with the literature,8 the DIBAH reduction of unsaturated cyanide
23 proceeded cleanly but was difficult to drive to completion.
Attempts to perform the overall transformation 20 f 24 more
directly through palladium-catalyzed carbonylation failed.
In summary, we have described a concise, unified approach to
the taiwaniaquinoids that hinges on new variants of the aromatic
Nazarov reaction. Asymmetric versions of this reaction are currently
under investigation.
Acknowledgment. D.T. thanks the Alfred P. Sloan Foundation
for generous support. G.L. gratefully acknowledges Bristol-Myers
Squibb for a graduate fellowship. Financial support by Novartis,
Glaxo Smith Kline, Eli Lilly, Astra Zeneca, and Amgen is also
gratefully acknowledged.
Scheme 3. Total Syntheses of Taiwaniaquinone H and
Dichroanone
Supporting Information Available: Synthetic procedures and
spectroscopic data for compounds 11, 15, 18, 20, 21, 23, and 24, as
well as the natural products 2, 4, 8, and 9. Further investigations on
the Nazarov triflation are also described. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Lin, W.; Fang, J.; Cheng, Y. Phytochemistry 1995, 40, 871. (b) Lin,
W.; Fang, J.; Cheng, Y. Phytochemistry 1996, 42, 1657. (c) Kawazoe,
K.; Yamamoto, M.; Takaishi, Y.; Honda, G.; Fujita, T.; Sezik, E.; Yesilada,
E. Phytochemistry 1999, 50, 493. (d) Chang, C.; Chien, S.; Lee, S.; Kuo,
Y. Chem. Pharm. Bull. 2003, 51, 1420. (e) Chang, C.; Chang, J.; Kuo,
C.; Pan, W.; Kuo, Y. Planta Med. 2005, 71, 72. (f) Iwamoto, M.; Ohtsu,
H.; Tokuda, H.; Nishino, H.; Matsunaga, S.; Tanaka, R. Bioorg. Med.
Chem. 2001, 9, 1911. (g) Minami, T.; Iwamoto, M.; Ohtsu, H.; Ohishi,
H.; Tanaka, R.; Yoshitake, A. Planta Med. 2002, 68, 742. (h) Hanson, J.
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Scheme 4. Total Synthesis of Taiwaniaquinol D
(2) (a) Fillion, E.; Fishlock, D. J. Am. Chem. Soc. 2005, 127, 13144. (b)
McFadden, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 7738. (c)
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required to effectively carry out this reaction.6 Yields decreased
markedly if bulkier phosphine ligands were used. Global demethyl-
ation, followed by oxidation catalyzed by salcomine (22) gave (()-
dichroanone (9). Alternatively, a more selective demethylation and
oxidation led to (()-taiwaniaquinol H (8).
The further extension of this strategy toward the total synthesis
of taiwaniaquinol D (4) is shown in Scheme 4. A challenging
palladium-mediated cyanation of enol triflate 20 afforded nitrile
23.7 Reduction with diisobutylaluminum hydride, followed by
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