Vinyl quinones as Diels-Alder dienes: Concise synthesis of (-)-halenaquinone

Article abstract of DOI:10.1021/ja8035042

A concise asymmetric synthesis of (-)-halenaquinone is described. The synthesis features a diastereoselective Heck cyclization to set a quaternary center as well as a novel intramolecular inverse-electron-demand Diels-Alder reaction involving a vinyl quinone. The synthesis is highly convergent and features a minimal amount of protecting group manipulations. Copyright

Full text of DOI:10.1021/ja8035042

Published on Web 06/13/2008
Vinyl Quinones as Diels-Alder Dienes: Concise Synthesis of
(-)-Halenaquinone
Michael A. Kienzler, Sandy Suseno, and Dirk Trauner*
Department of Chemistry, UniVersity of California, Berkeley, California 94720-1460
Received May 11, 2008; E-mail: trauner@cchem.berkeley.edu
Eight decades after its discovery, the synthetic appeal of the
Diels-Alder reaction has not diminished, and new modes continue
to be discovered. The versatility of the reaction and the ease with
which its components can be modified is indeed remarkable.
Quinones, for instance, are classical electron-deficient dienophiles,
yet relatively little is known about their role in neutral or inverse-
electron-demand Diels-Alder reactions. With appropriate substitu-
tion, however, they can be part of an electron-deficient diene system
that can readily engage in cycloadditions. Indeed, vinyl-p-quinones
are known to dimerize thermally to yield hydrophenathrenes with
excellent regio- and chemoselectivity (1f2; Scheme 1).1,2 Ad-
ditionally, Noland and Kedrowski have shown that extremely
electron-deficient vinyl nitroquinones undergo facile cycloadditions
to electron-rich furans and indoles (e.g., 3f4).3
Although these modes of reactivity provide rapid access to highly
functionalized ring systems, they appear to have never been
exploited in total synthesis.4 We now report a concise, asymmetric
synthesis of (-)-halenaquinone, which is based on an intramolecular
inverse-electron-demand Diels-Alder reaction involving a vinyl
quinone.
In one of the key steps of our synthesis, the quaternary
stereocenter of (-)-halenaquinone was formed through an intramo-
lecular Heck cyclization.12 This reaction proceeded with high
diastereoselectivity to afford furanocyclohexanol 11 as the major
isomer (dr ) 7:1). Interestingly, in the absence of the 2-formyl
group, the reaction proceeded with opposite (and lower)
diastereoselectivity.11a This observation points to a role of the
formyl group as a coordinating ligand in a palladium(II) intermedi-
ate. The relative configuration of the furanocyclohexanol 11 could
not be determined directly but was ultimately proven by its
conversion to (-)-halenaquinone, whose absolute stereochemistry
is known.8
Addition of an organolithium compound derived from the vinyl
stannane 12 to aldehyde 11 afforded the acid-sensitive vinyl furyl
carbinol 13 in excellent yield.13 Subsequent desilylation of 13,
followed by oxidation of both secondary alcohols, gave hydro-
quinone ether 14. This intermediate was converted into the key
vinyl quinone 15 by oxidative demethylation with silver(II) oxide
and nitric acid.
Scheme 1. Diels-Alder Reactions of Vinyl-p-quinones
With vinyl quinone 15 in hand, we explored the inverse-electron-
demand Diels-Alder reaction under various conditions. We found
that the reaction proceeded even at room temperature in dichlo-
romethane solution, albeit slowly, to afford the sparingly soluble
pentacyclic hydroquinone 17. Higher temperatures or the addition
of Lewis acids, such as Sc(OTf)3, increased reaction rates but had
little effect on the yields. High-pressure conditions, however, gave
the most satisfactory results; subjecting 15 to 10 kbar of pressure
at room temperature afforded 17 in 78% yield. In all cases
investigated, vinyl hydroquinone 17 was the only isolated isomer.
In the final step of our synthesis, 17 was oxidized and aromatized
to afford (-)-halenaquinone (ent-5).3a,14 This oxidative endgame
could be combined with the cycloaddition in a single operation:
heating of quinone 15 with DDQ afforded halenaquinone directly,
albeit in low yield.
(+)-Halenaquinone (5), the natural enantiomer, is a pentacyclic
natural product that has attracted considerable interest in the
synthetic and medicinal chemistry communities due its unusual
structure and multifaceted bioactivity.5,6 To date, two asymmetric
syntheses of the molecule have been reported by Shibasaki7 and
Harada,8 whereas a total synthesis of the racemic natural product
was achieved by Rodrigo et al.9 A thiophene derivative of (()-
halenaquinone (6) was recently synthesized by Wipf et al. to study
the contribution of the diacyl furan system to the bioactivity of the
natural product.10
Our total synthesis of (-)-halenaquinone starts with iodofuran
9 (Scheme 2), which was previously developed for our synthesis
of guanacastepene E and heptemerone B.11 Enantiomerically
enriched 9 can be obtained in three simple steps from diiodofuran
7 and the unsaturated aldehyde 8. Protection of 9 as a silyl ether
was then followed by a regioselective deprotonation and formylation
to afford iodofurfural 10 in excellent yield.
Synthetic (-)-halenaquinone was identical in all respects to the
natural product, with the exception of its optical rotation, which
had the opposite sign but a similar absolute value ([R]25D -22.7°,
c 0.25, CH2Cl2; [R]Lit. +22.2°, c 0.124, CH2Cl2).5
D
The key Diels-Alder step of our synthesis warrants further
analysis in terms of its simple and induced diastereoselectivity. The
latter can be inferred from the relative stereochemistry of 17, which
was elucidated by detailed NMR studies (see Supporting Informa-
tion).
9
8604 J. AM. CHEM. SOC. 2008, 130, 8604–8605
10.1021/ja8035042 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Total Synthesis of (-)-Halenaquinonea
Scheme 3. Transition States of the Key Diels-Alder Reaction
of the Diels-Alder reaction. The viability of vinyl quinones as
dienes in intramolecular versions of this reaction has been
demonstrated, and potential transition states have been explored
with DFT calculations. Other notable features of our convergent
synthesis include the regioselective lithiation and formylation of a
3-iodofuran enabling a highly diastereoselective intramolecular
Heck cyclization. The further application of vinyl quinone cycload-
ditions in total synthesis is under investigation in our laboratories.
Acknowledgment. We thank Novartis and Roche Biosciences
for generous funding of our synthetic program. We also thank Dr.
Kathy Durkin and Dr. Jamin Krinsky for assistance with the
calculations.
Supporting Information Available: Experimental procedures and
compound characterization data. B3LYP coordinates and electronic
energies of TSs and products. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Reagents and conditions: (a) TBDPSCl, imidazole, DMAP, DMF
(93%); (b) n-BuLi, DMF, THF (94%); (c) Pd(OAc)2, TBAB, Et3N, MeCN
(95%); (d) 12, n-BuLi, THF, then 11 (92%); (e) TBAF, THF (85%); (f)
TPAP, NMO, (64%); (g) AgO, HNO3, dioxane (65%); (h) DCM, 10 kbar
(78% from 14); (i) MnO2, PhH (60%); (j) AgO, HNO3, dioxane; then DDQ,
dioxane (12%).
References
(1) Irngartinger, H.; Stadler, B. Eur. J. Org. Chem. 1998, 605–626.
(2) Iwamoto, H.; Takuwa, A.; Hamada, K.; Fujiwara, R. J. Chem. Soc., Perkin
Trans. 1 1999, 575–581.
In contrast to the examples shown in Scheme 1, the initial
cycloaddition product (e.g., 16) could not be isolated because it
underwent rapid tautomerization to vinyl hydroquinone 17 under
all conditions tested. Therefore, the simple diastereoselectivity (exo/
endo selectivity) of the reaction could not be determined directly.
Density functional theory (DFT) calculations at the B3LYP/6-
31G** level were able to locate both the exo transition state (TS-
1) and the endo transition state (TS-2) of the reaction (Scheme
3).15 According to these calculations, TS-1, which yields diaste-
reomer 16a, is 26.0 kcal/mol higher in energy than the lowest-
energy conformer of 15. The more congested TS-2, which could
be relevant at high pressures and leads to 16b, is energetically less
favorable (∆Erel ) 28.9 kcal/mol). Both transition states are marked
by essentially synchronous bond formations and fall well within
the regime of classical Diels-Alder reactions. Thermodynamically,
the reaction was found to be highly exothermic and essentially
irreversible (cf. Scheme 3).
(3) (a) Noland, W. E.; Kedrowski, B. L. J. Org. Chem. 1999, 64, 596–603.
(b) Noland, W. E.; Kedrowski, B. L. J. Org. Chem. 2002, 67, 8366–8373.
(4) For synthetic studies involving vinylquinone ketals, see: Parker, K. A.;
Ruder, S. M. J. Am. Chem. Soc. 1989, 111, 5948–5949.
(5) Roll, D. M.; Scheuer, P. J.; Matsumoto, G. K.; Clardy, J. J. Am. Chem.
Soc. 1983, 105, 6177–6178.
(6) Wipf, P.; Halter, R. J. Org. Biomol. Chem. 2005, 3, 2053–2061, and
references therein.
(7) Kojima, A.; Takemoto, T.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1996,
61, 4876–4877.
(8) Harada, N.; Sugioka, T.; Ando, Y.; Uda, H.; Kuriki, T. J. Am. Chem. Soc.
1988, 110, 8483–8487.
(9) Sutherland, H. S.; Souza, F. E. S.; Rodrigo, R. G. A. J. Org. Chem. 2001,
66, 3639–3641.
(10) Wakefield, B.; Halter, R. J.; Wipf, P. Org. Lett. 2007, 9, 3121–3124.
(11) (a) Hughes, C. C.; Kennedy-Smith, J. J.; Trauner, D. Org. Lett. 2003, 5,
4113–4115. (b) Miller, A. K.; Hughes, C. C.; Kennedy-Smith, J. J.; Gradl,
S. N.; Trauner, D. J. Am. Chem. Soc. 2006, 128, 17057–17063.
(12) Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945–2963.
(13) Stannane 12 was derived from the corresponding vinyl bromide: Manecke,
G.; Zerpner, D. Chem. Ber. 1972, 105, 1943. See Supporting Information.
(14) Tominaga, Y.; Lee, M. L.; Castle, R. N. J. Heterocycl. Chem. 1981, 18,
967–972.
(15) Jaguar, version 6.5; Schro¨dinger, LLC: New York, NY, 2006; see
Supporting Information for more complete references.
In summary, we have achieved a concise asymmetric synthesis
of (-)-halenaquinone that hinges on a previously unexploited mode
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