Synthesis of (-)-ilimaquinone via a radical decarboxylation and quinone addition reaction.

Article abstract of DOI:10.1021/ol025501z

[reaction: see text] A stereoselective synthesis of (-)-ilimaquinone (4) is presented. The synthetic strategy is based on a novel radical decarboxylation and quinone addition methodology that produces quinone 7 from reaction of thiohydroxamic acid derivat

Full text of DOI:10.1021/ol025501z

ORGANIC
LETTERS
2002
Vol. 4, No. 5
819-822
Synthesis of (−)-Ilimaquinone via a
Radical Decarboxylation and Quinone
Addition Reaction
Taotao Ling, Erwan Poupon, Erik J. Rueden, and Emmanuel A. Theodorakis*
Department of Chemistry and Biochemistry, UniVersity of California,
San Diego, 9500 Gilman DriVe, La Jolla, California 92093-0358
etheodor@ucsd.edu
Received January 1, 2002
ABSTRACT
A stereoselective synthesis of (−)-ilimaquinone (4) is presented. The synthetic strategy is based on a novel radical decarboxylation and
quinone addition methodology that produces quinone 7 from reaction of thiohydroxamic acid derivative 8 with benzoquinone (9). Final
functionalization of 7 to ilimaquinone (4) is achieved by exploring the electronic effects of the residual thiopyridyl group.
Marine organisms represent a rich source of natural products
that often possess novel chemical structures and interesting
biological and pharmacological properties.1 Among these
products is included a family of quinone sesquiterpenes,
selected members of which are avarol (1),2 avarone (2),2
nakijiquinone A (3),3 ilimaquinone (4),4 smenospongine (5),5
and smenospongidine (6)5 (Figure 1).
All members of this family are distinguished by a common
chemical architecture in which the C9 position of a trans-
decalin ring is attached to a variably hydroxylated (or
heteroatom substituted) quinone or hydroquinone unit.
Interestingly, this nearly identical structural motif translates
to a variety of exciting biological properties often unique to
each family member. For example, avarol (1) and avarone
(2) have been shown to exhibit anti-HIV properties,6 while
nakijiquinone A (3) was found to inhibit selectively the Her-
2/Neu protooncogene.3,7 On the other hand, ilimaquinone (4)
was found to exhibit anti-HIV, antimitotic, and antiinflam-
matory activities,8 in addition to promoting a reversible
vesiculation of the Golgi apparatus and interfering with
intracellular protein trafficking.9
(1) Biomedical Importance of Marine Organisms; Fautin, D. G., Ed.;
Memoirs Calif. Acad. Sci 13. 1988, 1-158. Capon, R. J. Eur. J. Org. Chem.
2001, 633-645.
(6) 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. Loya, S.; Hizi, A. FEBS 1990, 269, 131-134. 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. De Clercq, E. Med. Res. ReV. 2000, 5,
323-349.
(7) For an interesting account on the synthesis and biological investigation
of this natural product, see: Stahl, P.; Waldmann, H. Angew. Chem., Int.
Ed. 1999, 38, 3710-3713. Stahl, P.; Kissau, L.; Mazitschek, R.; Huwe,
A.; Furet, P.; Giannis, A.; Waldmann, H. J. Am. Chem. Soc. 2001, 123,
11586-11593.
(2) Minale, L.; Ricio, R.; Sodano, G. Tetrahedron Lett. 1974, 38, 3401-
3404. DeRosa, S.; Minale, L.; Riccio, R.; Sodano, G J. Chem. Soc., Perkin
Trans. I 1976, 1408-1414. Puliti, R.; deRosa, S.; Mattia, C. A. Acta
Crystallogr. Sect. C 1994, C50, 830-833. Stewart, M.; Fell, P. M.; Blunt,
J. W.; Munro, M. H. G. Aust. J. Chem. 1997, 50, 341-347.
(3) Shigemori, H.; Madono, T.; Sasaki, T.; Mikami, Y.; Kobayashi, J.
Tetrahedron 1994, 50, 8347-8354. Kobayashi, J.; Madono, T.; Shigemori,
H. Tetrahedron 1995, 51, 10867-10874.
(4) Luibrand, R. T.; Erdman, T. R.; Vollmer, J. J.; Scheuer, P. J.; Finer,
J.; Clardy, J. C. Tetrahedron 1979, 35, 609-612. Capon, R. J.; MacLeod,
J. K. J. Org. Chem. 1987, 52, 5059-5060. Carte´, B.; Rose, C. B.; Faulkner,
D. J. J. Org. Chem. 1985, 50, 2785-2787.
(5) Kondracki, M.-L.; Guyot, M. Tetrahedron Lett. 1987, 28, 5815-
5818. Kondracki, M.-L.; Guyot, M. Tetrahedron 1989, 45, 1995-2004.
(8) Loya, S.; Tal, R.; Kashman, Y.; Hizi, A. Antimicrob. Agents
Chemother. 1990, 1990, 2009-2012. Loya, S.; Hizi, A. J. Biol. Chem. 1993,
268, 9323-9328. Rangel, H. R.; Dagger, F.; Compagnone, R. S. Cell Biol.
Intern. 1997, 21, 337-339.
10.1021/ol025501z CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/12/2002

Figure 2. Retrosynthetic analysis of ilimaquinone (4).
Figure 1. Selected structures of quinone sesquiterpenes.
At the onset of our studies we were concerned with the
regiochemistry of the sodium methoxide addition as well as
the replacement of the thiopyridyl group by a hydroxide
anion. In principle, sodium methoxide can either replace the
thiopyridyl group at the C17 carbon center of 7 via an
addition-elimination process or add in a conjugate fashion
on the C19-20 double bond (ilimaquinone numbering). In
the latter case one could envision the formation of two
regioisomers arising from addition at the C19 or C20 centers,
the ratio of which would be dependent on the relative
reactivity of the two carbonyl groups. To examine the sodium
methoxide addition, we investigated its reaction with a
similarly functionalized quinone, 1112 (R ) cyclohexyl
group, PyS ) thiopyridyl group). Our initial studies revealed
that this addition produces a mixture of hydroquinone adducts
that are slowly oxidized upon exposure to air to the
corresponding quinones (Scheme 1). To facilitate the prod-
ucts isolation and characterization, we decided to treated the
mixture with excess MnO2, thus driving the oxidation process
to completion. This sequence afforded best results using 5
equivs of sodium methoxide at -20 °C followed by acid
extraction and subsequent treatment with 5 equiv of MnO2.
Under these conditions we obtained a mixture of isomeric
quinones 14 and 15 in a 4.9:1 ratio in favor of 14 (71%
combined yield).13 Formation of the major product 14 is
proposed to occur via the intermediacy of adducts 12 (or
13), in which the crucial addition of methoxide anion to the
C20 center has been accomplished. The regioselectivity of
the methoxide addition can be mechanistically rationalized
by comparing the relative electron deficiency of the C18 and
Inspired by the interesting chemical structures and promis-
ing biological activities, we sought to design a “unified”
approach to these quinone sesquiterpenes. Our synthetic
strategy is based on a novel radical decarboxylation and
quinone addition method, the validity of which was initially
demonstrated with the synthesis of avarol (1) and avarone
(2).10 Herein we further expand this method to the synthesis
of ilimaquinone (4).11
The retrosynthetic analysis of ilimaquinone is shown in
Figure 2 and rests upon a photochemical decarboxylation of
thiohydroxamic ester 8 and trapping of the derived C15
radical with benzoquinone (9) to produce quinone 7. It was
expected that further functionalization of adduct 7 by
introducing a methoxy group at the C20 carbon center and
replacing the thiopyridyl group at C17 with a hydroxide
species could form the ilimaquinone structure. Starting
material for this venture would then be the Wieland-
Miescher enone 10, which upon additional funtionalizations
could provide activated ester 8.
(9) Takizawa, P. A.; Yucei, J. K.; Veit, B.; Faulkner, J. D.; Deerinck,
T.; Soto, G.; Ellisman, M.; Malhotra, V. Cell 1993, 73, 1079-1090. Jamora,
C.; Takizawa, P. A.; Zaarour, R. F.; Denesvre, C.; Faulkner, J. D.; Malhotra,
V. Cell 1997, 91, 617-626. Wang, H.; Benlimame, N.; Nabi, I. R. J. Cell
Sci. 1997, 110, 3043-3053. 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.
Radeke, H. S.; Digits, C. A.; Casaubon, R. L.; Snapper, M. L. Chem. Biol.
1999, 6, 639-647. Radeke, H. S.; Snapper, M. L. Bioorg., Med. Chem.
Lett. 1998, 6, 1227-1232. Casaubon, R. L.; Snapper, M. L. Bioorg., Med.
Chem. Lett. 2001, 11, 133-136.
(10) Ling, T.; Xiang, A. X.; Theodorakis, E. A. Angew. Chem., Int. Ed.
1999, 38, 3089-3091.
(11) For other syntheses of 4, see: Bruner, S. D.; Radeke, H. S.; Tallarico,
J. A.; Snapper, M. L. J. Org. Chem. 1995, 60, 1114-1115. Radeke, H. S.;
Digits, C. A.; Bruner, S. D.; Snapper, M. L. J. Org. Chem. 1997, 62, 2823-
2831. Poigny, S.; Guyot, M.; Samadi, M. J. Org. Chem. 1998, 63, 5890-
5894.
(12) For the synthesis of 11, see Supporting Information.
(13) The structures of the quinone addition products were assigned by
NOE and HMBC experiments. See Supporting Information for details.
820
Org. Lett., Vol. 4, No. 5, 2002

Scheme 1. Studies on the Regiochemistry of the Sodium
Scheme 2. Total Synthesis of Ilimaquinone (4)a
Methoxide Addition to Quinonesa
a Reagents and conditions: [R ) cyclohexyl]; (a) 5.0 equiv of
MeONa (0.5 M in MeOH), THF, -20 °C, 2 h; then aqueous NH4Cl,
AcOEt, 5.0 equiv of MnO2, 25 °C, 1 h, 59% for 14 and 12% for
15; (b) 3.0 equiv of MeONa (0.5 M in MeOH), MeOH, 50 °C, 1
h; 77%; (c) 3.0 equiv of KOH, MeOH/H2O (1/1), 65%.
C21 carbonyl groups. Among them, the C21 carbonyl group
is electronically richer due to the electron-donating effect
of the thiopyridyl group at the C17 center (vinylogous ester
functionality).14 By virtue of this effect, the C18 carbonyl
group is more electronically deficient and consequently the
C20 center becomes a better electrophilic center for conjugate
additions. Hence, the preferred site for the methoxide addition
is the C20 carbon atom (Scheme 1).15
The next task was the exchange of the thiopyridyl group
with a hydroxyl equivalent. However, all attempts to perform
this displacement in a direct way, by reacting 14 with
hydroxide anion, led to formation of multiple products,
arising presumably by reaction of hydroxide anions both at
the C17 and C20 centers. This problem was circumvented
by using a two-step procedure that involved reaction of 14
with sodium methoxide (3 equiv at 50 °C) to afford
dimethoxy quinone 16 (77% yield), followed by selective
monodeprotection of the C17 center to produce the desired
compound 18 (Scheme 1). The selectivity observed during
the last step may be explained by considering the relative
stability of the tetrasubstituted enolate 17 versus the less
a Reagents and conditions: (a) 0.1 N HCl, THF, 3 h, 25 °C,
93%; (b) 3.0 equiv of CH3PPh3Br, 2.5 equiv of NaHMDS, THF,
65 °C, 10 h, 92%; (c) 1.2 equiv of Dess-Martin periodinane,
CH2Cl2, 1 h, 25 °C, 96%; (d) 2.0 equiv of NaClO2, 2.0 equiv of
NaH2PO4, 2.0 equiv of CH3CHdC(CH3)2, tBuOH/H2O: 2/1 25 °C,
1 h, 89%; (e) 1.0 equiv of 21, 1.0 equiv of 22, 1.0 equiv of DCC,
CH2Cl2, 12 h, 25 °C, (dark), 94%; (f) 3.0 equiv of 9, CH2Cl2, hν
(2 × 500 W), 2 h, 0 °C, 75%; (g) 5.0 equiv of MeONa (0.5 M in
MeOH), MeOH, -20 °C, 2 h; then aqueous NH4Cl, CH2Cl2, 5.0
equiv of MnO2, 1 h, 65% for 24 and 16% for C19-adduct; (h) 3.0
equiv of MeONa (0.5 M in MeOH), MeOH, 50 °C, 1 h; 77%; (i)
1.2 equiv of oHClO4 (70% aq.), THF, 25 °C, 4 h, 78%.
(14) The “vinylogous ester” effect of alkoxy groups in benzoquinone
and related compounds has been explored in regioselective Diels-Alder
reactions. For selected reviews on this topic, see: Oppolzer, W. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, New York, 1991; pp 315-399. Woodward, R. B.; Katz, T. J.
Tetrahedron 1959, 5, 70-89.
(15) For a related study on vicinally substituted quinones, see: Cox, A.
L.; Johnston, J. N. Org. Lett. 2001, 3, 3695-3697.
Org. Lett., Vol. 4, No. 5, 2002
821

substituted one arising from conjugate addition at the C20
center.16
identical with the literature values, thereby supporting the
prediction that the methoxide functionalities were ap-
propriately incorporated at the C20 and C17 centers.11
Selective hydrolysis of 25 at the C17 center was then
attempted under basic conditions (aqueous KOH). Despite
our encouraging results in model studies (see Scheme 1) this
reaction produced a complex mixture of quinones, containing
ilimaquinone 4 in 34% yield (calculated by NMR). Gratify-
ingly, treatment of 26 under dilute perchloric acid conditions
produced the desired natural product 4 in 78% yield.21
Compound 4 was spectroscopically and analytically identical
with the natural ilimaquinone.22
In conclusion, we have developed an efficient synthesis
of (-) ilimaquinone (4). Our synthesis is based on a novel
radical decarboxylation and quinone addition methodology
that was used to construct the carbocyclic framework of the
natural product. Taking advantage of both the electronic
effects and the leaving ability of the residual thiopyridyl
group we developed conditions for sequential regioselective
oxygenations of the quinone ring. Our strategy extends the
scope, applicability, and versatility of the above methodology
and opens the way for the construction of differentially
substituted derivatives of the natural product.
Application of the above strategy to the synthesis of
ilimaquinone (4) is illustrated in Scheme 2. Enantiomerically
enriched enone 10 was converted to alcohol 19,10 which upon
acid-catalyzed deprotection of the C4 ketal and Wittig
methylenation afforded compound 20 (86% combined yield).
The C15 hydroxyl group of 20 was then oxidized to the
corresponding carboxylic acid 21 (Dess-Martin periodi-
nane17 and sodium chlorite, 85% combined yield), which
upon DCC-induced coupling with commercially available
N-hydroxy-2-thiopyridone (22) furnished adduct 8 (94%
yield).18 Light-induced decarboxylation (>350 nm) of 8 in
the presence of excess benzoquinone (9) produced the
substituted quinone 7 in 75% yield.19 The structure of 7 can
be mechanistically explained by considering an initial
formation of a semiquinone adduct that is further oxidized
to 7 with an excess of 9.20 Treatment of adduct 7 with sodium
methoxide at -20 °C followed by one-pot oxidation with
MnO2 afforded quinone 24, presumably via intermediate 23,
in 65% yield. Under these conditions the C19-methoxylated
adduct was also isolated as a minor product (16% yield) and
was chromatographically separated from the desired com-
pound 24. Furher exposure of 24 with excess of sodium
methoxide at 50 °C produced dimethoxyquinone 25 in 72%
yield. The spectroscopic and analytical data of 25 were
Acknowledgment. Financial support from the NIH
(CA086079) is gratefully acknowledged. We also thank
Professor D. John Faulkner (Scripps Institute of Oceanog-
raphy) for a sample of natural ilimaquinone and for critical
suggestions on the spectroscopic analysis of quinone rings.
(16) Although the regioselective hydrolysis of a more hindered methoxy
group under basic conditions has been reported in the literature (ref 7), no
explanation for this effect was offered.
Supporting Information Available: 1H NMR and 13C
NMR spectra for compounds 4, 7-8, 11, 14-16, 18-21,
and 24-25. Experimental procedures for compounds 8 and
11. This material is available free of charge via the Internet
at http://pubs.acs.org.
(17) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287. Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(18) For selected reviews on the photochemistry of thiohydroxamic acid
derivatives, see: Crich, D. Aldrichimica Acta 1987, 20, 35-49. Barton, D.
H. R. Pure Appl. Chem. 1994, 66, 1943-1954. Barton, D. H. R. Tetrahedron
1992, 48, 2529-2544.
(19) Barton, D. H. R.; Sas, W. Tetrahedron 1990, 46, 3419-3430.
Barton, D. H. R.; Bridon, D.; Zard, S. Z. Tetrahedron 1987, 43, 5307-
5314.
OL025501Z
(20) Alkyl-substituted quinones are known to have a lower oxidation
potential than the nonsubstituted counterparts. For recent reviews on this
topic, see: (a) The Chemistry of the Quinonoid Compounds; Patai, S.,
Rappoport, Z., Eds.; Wiley: New York, 1988; Vol. 1, p 2. (b) Naturally
Occuring Quinones IV: Recent AdVances, 4th ed.; Thomson, R. H., Ed.;
Blackie Academic & Professional: London, 1997.
(21) Fukuyama, Y.; Kiriyama, Y.; Kodama, M. Chem. Pharm. Bull. 1998,
46, 1770-1775. Kubo, I.; Kamikawa, T.; Miura, I. Tetrahedron Lett. 1983,
24, 3825-3828.
(22) A sample of natural ilimaquinone was obtained by Professor D.
John Faulkner (Scripps Institute of Oceanography).
822
Org. Lett., Vol. 4, No. 5, 2002