A R T I C L E S
Ling et al.
example, avarol (1) and avarone (2) were shown to inhibit HIV-1
reverse transcriptase,7 while their methoxylated relatives 4 and
5 are reported to have tyrosine kinase modulatory properties.4c
On the other hand, the strong antiviral, antimitotic, and
antiinflammatory activities of ilimaquinone (6)8 may be con-
nected to its ability to promote a reversible vesiculation of the
Golgi apparatus and interfere with intracellular protein traffick-
ing.9 Furthermore, the most recently identified member of this
family, nakijiquinone A (3), was reported to have excellent
activity as an inhibitor of the erbB-2 protooncogene that is
frequently implicated in the development of breast cancer.10
Although the chemical origins of these biological properties
remain obscure, the redox properties of the hydroquinone-
quinone system present in all of these compounds may account
for their diverse medicinal profiles.11
Intrigued with the interesting chemical structures and biologi-
cal activities, we sought to design a “unified” synthetic approach
to these quinone metabolites. Central to this strategy is a novel
radical-based addition method that serves to connect the decalin
fragment with the quinone unit. Herein we present the chemo-
and regioselectivity of this reaction, expand upon its concept,
and define its overall scope and limitations. Moreover, we
demonstrate the synthetic value of this new method with
enantioselective syntheses of avarol (1),12 avarone (2),12 meth-
oxyavarones (4, 5), ilimaquinone (6),13 and smenospongidine
(7).
Figure 2. Radical decarboxylation and quinone addition reaction.
been published. A common characteristic to all these synthetic
strategies is the assembly of the entire backbone of the molecule
by constructing the C9-C15 bond. This is achieved by a
reductive alkylation (Li/NH3) of a suitably functionalized enone
with an appropriately substituted benzyl bromide. A conse-
quence of this approach is that the quinone unit is attached on
the decalin core relatively early during the synthesis, substan-
tially restricting access to different natural products from a
common intermediate. Moreover, due to functional group
incompatibility issues, the quinone ring has to be introduced as
an aromatic unit in which the phenolic groups are masked with
robust protecting groups. Consequently, the final deprotection
steps afford the natural product(s) in rather low yields.
The above observations led us to consider an alternative
disconnection centered around the formation of the C15-C16
bond. In principle, this connection could be accomplished by
reacting a C15 carbon-centered radical with a quinone such as
10 (Figure 2). The concept of this method, herein referred to as
the radical decarboxylation and quinone addition reaction, is
based on generating radical 9 from thiopyridone derivative 817
and trapping it with quinone 10 by a radical-chain process.18
The newly formed semiquinone 11 was expected to undergo
tautomerization to hydroquinone 12, thus protecting the second
double bond of the semiquinone from further attack by carbon
radicals. A slow oxidation of 11 or 12 in the presence of excess
10 could then produce the desired quinone 13.19
Retrosynthetic Analysis and Strategic Bond Disconnec-
tions. The combination of a challenging structure and intriguing
biological applications has prompted several research groups
to investigate the synthesis of the quinone sesquiterpenes. In
fact, the first synthetic entry to these compounds, a racemic
synthesis of avarone (1), was reported in the literature in 1982,14
and since then several syntheses of 1,15 2,15 3,16 and 616 have
(7) (a) Mu¨ller, W. E. G.; Sladic, D.; Zahn, R. K.; Ba¨ssler, K.-H.; Dogovic,
N.; Gerner, H.; Gasic, M. J.; Schro¨der, H. C. Cancer Res. 1987, 47, 6565-
6571. (b) Loya, S.; Hizi, A. FEBS Lett. 1990, 269, 131-134. (c) Schro¨der,
H. C.; Begin, M. E.; Klo¨cking, R.; Matthes, E.; Sarma, A. S.; Gasic, M.
Mu¨ller, W. E. G. Virus Res. 1991, 21, 213-223. (d) De Clercq, E. Med.
Res. ReV. 2000, 5, 323-349.
(8) (a) Loya, S.; Tal, R.; Kashman, Y.; Hizi, A. Antimicrob. Agents Chemother.
1990, 2009-2012. (b) Loya, S.; Hizi, A. J. Biol. Chem. 1993, 268, 9323-
9328. (c) Rangel, H. R.; Dagger, F.; Compagnone, R. S. Cell Biol. Intern.
1997, 21, 337-339.
(9) (a) Takizawa, P. A.; Yucei, J. K.; Veit, B.; Faulkner, J. D.; Deerinck, T.;
Soto, G.; Ellisman, M.; Malhotra, V. Cell 1993, 73, 1079-1090. (b) Jamora,
C.; Takizawa, P. A.; Zaarour, R. F.; Denesvre, C.; Faulkner, J. D.; Malhotra,
V. Cell 1997, 91, 617-626. (c) Wang, H.; Benlimame, N.; Nabi, I. R. J.
Cell Sci. 1997, 110, 3043-3053. (d) Pou¨s, C.; Chabin, K.; Drechou, A.;
Barbot, L.; Phung-Koskas, T.; Settegrana, C.; Bourguet-Kondracki, M. I.;
Maurice, M.; Cassio, D.; Guyot, M.; Durand, G. J. Cell Biol. 1998, 142,
153-165. (e) Radeke, H. S.; Digits, C. A.; Casaubon, R. L.; Snapper, M.
L. Chem. Biol. 1999, 6, 639-647. (f) Radeke, H. S.; Snapper, M. L. Bioorg.
Med. Chem. Lett. 1998, 6, 1227-1232. (g) Casaubon, R. L.; Snapper, M.
L. Bioorg. Med. Chem. Lett. 2001, 11, 133-136.
(10) For an interesting account on the synthesis and biological investigation of
this natural product, see (a) Stahl, P.; Waldmann, H. Angew. Chem. 1999,
38, 3710-3713. (b) Stahl, P.; Kissau, L.; Mazitschek, R.; Huwe, A.; Furet,
P.; Giannis, A.; Waldmann, H. J. Am. Chem. Soc. 2001, 123, 11586-
11593.
A general retrosynthetic scheme based on the above discon-
nection is shown in Figure 3. Photochemical decarboxylation
of thiocarbonyl derivative 16 and trapping of the derived C15
radical with appropriately substituted quinone 10 could produce
adduct 15. It was expected that further functionalization
(reductive desulfurization and/or addition-elimination) of the
thiopyridyl group of 15 would allow access to all structures of
(16) For other syntheses of 6, see (a) Bruner, S. D.; Radeke, H. S.; Tallarico, J.
A.; Snapper, M. L. J. Org. Chem. 1995, 60, 1114-1115. (b) Radeke, H.
S.; Digits, C. A.; Bruner, S. D.; Snapper, M. L. J. Org. Chem. 1997, 62,
2823-2831. (c) Poigny, S.; Guyot, M.; Samadi, M. J. Org. Chem. 1998,
63, 5890-5894.
(17) For selected reviews on the photochemical decarboxylation of thiopyridone
derivatives, see (a) Crich, D. Aldrichim. Acta 1987, 20, 35-49. (b) Barton,
D. H. R. Pure Appl. Chem. 1994, 66, 1943-1954. (c) Barton, D. H. R.
Tetrahedron 1992, 48, 2529-2544.
(11) (a) Miguel del Corral, J. M.; Gordaliza, M.; Castro, M. A.; Mahiques, M.
M.; Chamorro, P.; Molinari, A.; Garcia-Cravalos, M. D.; Broughton, H.
B.; San Feliciano, A. J. Med. Chem. 2001, 44, 1257-1267. (b) Molinari,
A.; Oliva, A.; Aguilera, N.; Miguel del Corral, J. M.; Castro, M. A.;
Gordaliza, M.; Garcia-Cravalos, M. D.; San Feliciano, A. Bioorg. Med.
Chem. 2000, 8, 1027-1032.
(12) For a preliminary communication on the synthesis of 1 and 2, see Ling,
T.; Xiang, A. X.; Theodorakis, E. A. Angew. Chem. 1999, 38, 3089-3091.
(13) For a preliminary communication on the synthesis of 6, see Ling, T.;
Poupon, E.; Rueden, E. J.; Theodorakis, E. A. Org. Lett. 2002, 4, 819-
822.
(14) Sarma, A. S.; Chattopadhyay, P. J. Org. Chem. 1982, 47, 1727-1731.
(15) For other syntheses of avarol and avarone, see (a) Locke, E. P.; Hecht, S.
M. Chem. Commun. 1996, 2717-2718. (b) An, J.; Wiemer, D. F. J. Org.
Chem. 1996, 61, 8775-8779.
(18) (a) Barton, D. H. R.; Sas, W. Tetrahedron 1990, 46, 3419-3430. (b) Barton,
D. H. R.; Bridon, D.; Zard, S. Z. Tetrahedron 1987, 43, 5307-5314.
(19) This oxidation can be mechanistically explained if we consider that alkyl-
substituted quinones are known to have lower oxidation potentials than
the nonsubstituted counterparts. For recent reviews on this topic see (a)
The Chemistry of the Quinonoid Compounds, Volumes 1 and 2; Patai, S.,
Rappoport Z., Eds.; Wiley: New York, 1988. (b) Naturally Occurring
Quinones IV: Recent AdVances, 4th ed.; Thomson, R. H., Eds.; Blackie
Academic & Professional: London, 1997.
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