A synthesis of trisquinones

Full text of DOI:10.1021/jo980680c

5726
J . Org. Chem. 1998, 63, 5726-5727
Communications
A Syn th esis of Tr isqu in on es
J ingjun Yin and Lanny S. Liebeskind*
Sanford S. Atwood Chemistry Center, Emory University,
1515 Pierce Drive, Atlanta, Georgia 30322
Received April 14, 1998
Exceptionally high and selective anti-HIV activity in a
variety of cellular in vitro tests was reported for the trimeric
naphthoquinone conocurvone (Figure 1).1 Because tereti-
folione B, the monomer comprising the two noncentral
quinone units of conocurvone, was devoid of antiviral activ-
ity, the observed biological activity was attributed to the
trisquinone structure.2 The development of a general syn-
thetic entry to trisquinones (and oligoquinones) is therefore
of considerable interest because it could lead to a new source
of biologically active compounds.
F igu r e 1.
Sch em e 1
Although a wide variety of quinones are known and
quinone syntheses have been extensively reviewed,3,4 very
few oligoquinones have been reported.5-7 The few ap-
proaches to oligoquinones that are documented suffer from
very low overall yields and poor solubilities of the products.
For example, in 1990, a light-sensitive trisnaphthoquinone
was prepared in approximately 1% overall yield from com-
mercially available starting materials.5 Other simple oli-
gobenzoquinones and their derivatives have also been
reported,7 but they are also unstable to varying degrees and
are poorly soluble. To date, there is no competent and
general synthetic approach to trisquinones.
In the past decade, a mild and general synthesis of
substituted quinones was developed (Scheme 1).8,9 It relies
upon maleoyl- (1) or phthaloylcobalt (2) complexes that,
depending upon the nature of the ligand “L” on cobalt, are
activated either thermally or photochemically and react with
a large variety of alkynes to give quinone complexes 3 in
high yields. The intermediate cobalt-quinone π-complexes
are readily demetalated, either directly under the reaction
conditions or upon brief treatment with ceric ammonium
nitrate (CAN). The mild reaction conditions and functional
group compatibility of the maleoyl/phthaloylmetal procedure
seemed ideally suited to the construction of sensitive tris-
quinones from alkynes that bear suitable quinone or quinone
precursor substituents. This notion was reduced to practice,
which established the first general synthetic route to
substituted trisquinones. Although only symmetric tris-
quinones 4 were synthesized in this initial study, unsym-
metrically substituted ones should also be available via this
protocol.
1,2-Diarylalkynes (5a -e, Table 1) were easily prepared
from bis(tri-n-butylstannyl)acetylene and 2 equiv of the
corresponding iodoarene using a cross-coupling procedure.10
Reaction of diarylalkynes 5a ,b,d with maleoylcobalt complex
6 in 1,2-dichloroethane at 80 °C for 24 h in a sealed tube8
provided the trisquinone precursor cobalt complexes 7a ,b,d ,
respectively, in high yields (Table 1). Photochemical activa-
tion of phthaloylcobalt complex 6′ in the presence of 5b,d ,e
produced the trisquinone precursors 7b′,d ′,e′, respectively,
which were directly isolated as the corresponding 2,3-
diarylnaphthoquinones in good yields. In contrast to the
robust CpCo(benzoquinone) complexes, spontaneous de-
metalation of the more weakly ligated CpCo(naphtho-
quinone) complexes is known to occur under the reaction
conditions.8 Both the cobalt complexes 7 and the demeta-
lated 2,3-diarylnaphthoquinones show two sets of signals in
their 1H NMR spectra due to atropisomerism; coalescence
of signals for demetalated 7d ′ was not observed up to 120
°C in DMSO. The 13C NMR spectra of the trisquinone
precursors are also very complex, especially those with cobalt
attached. This was not unexpected since the natural product
conocurvone also exhibits spectral data complicated by
atropisomerism.1
* To whom correspondence should be addressed. Tel.: (404) 727-6604.
Fax: (404) 727-0845. E-mail: CHEMLL1@emory.edu.
(1) Decosterd, L. A.; Parsons, I. C.; Gustafson, K. R.; Cardellina, J . H.,
II.; McMahon, J . B.; Cragg, G. M.; Murata, Y.; Pannell, L. K.; Steiner, J .
R.; Clardy, J .; Boyd, M. R. J . Am. Chem. Soc. 1993, 115, 6673.
(2) Cannon, J . R.; J oshi, K. R.; McDonald, I. A.; Retallack, R. W.;
Sierakowske, A. F.; Wong, L. C. H. Tetrahedron Lett. 1975, 32, 2795.
(3) Naruta, Y.; Maruyama, K. In Recent Advances in the Synthesis of
Quinonoid Compounds; Naruta, Y., Maruyama, K., Eds.; J ohn Wiley &
Sons: New York, 1988; Vol. II, p 241.
(4) Gallagher, P. T. Contemp. Org. Synth. 1996, 3, 433.
(5) Laatsch, H. Liebigs Ann. Chem. 1990, 433.
(6) Pummerer, R.; Lu¨ttringhaus, A.; Fick, R.; Pfaff, A.; Riegelbauer, G.;
Rosenhauer, E. Chem. Ber. 1938, 71, 2569.
Following a literature procedure,8 when 7a ,b,d were
treated with 10 equiv of CAN at 0 °C for 30 min (for
demetalation) and then at room temperature (for oxidative
demethylation), complicated mixtures were formed. How-
(7) Erdtman, H.; Granath, M.; Schultz, G. Acta Chem. Scand. 1954, 8,
1442.
(8) Liebeskind, L. S.; J ewell, C. F., J r. J . Organomet. Chem. 1985, 285,
305.
(9) Liebeskind, L. S.; Baysdon, S. L.; South, M. S.; Iyer, S.; Leeds, J . P.
Tetrahedron 1985, 41, 5839.
(10) Cummins, C. H. Tetrahedron Lett. 1994, 35, 857.
S0022-3263(98)00680-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/05/1998

Communications
Ta ble 1. Syn th eses of Tr isqu in on es
J . Org. Chem., Vol. 63, No. 17, 1998 5727
studies are needed to probe the introduction of substituents
R3 * H in 4, as in the natural product conocurvone, since
such substituents will stabilize the acyclic trisquinones from
undesired cyclization.11
The trisquinones are yellow solids, soluble in organic
solvents such as CH2Cl2, THF, and EtOAc. Upon exposure
to air and light, the solids quickly darken, but the majority
of the mass remains unchanged. Decomposition in solution
is faster but still slow enough that chromatography or
recrystallization can be carried out without noticeable
decomposition. Unlike their precursors that displayed
complicated NMR spectra due to atropisomerism in solution,
all of the trisquinones showed a single set of NMR spectral
signals. A broad peak was observed in the 1H NMR spectra
between 6.4 and 6.8 ppm, which is typical of the quinone
ring C-H, and absorbances were seen between 182 and 186
ppm for the carbonyl carbons in the 13C NMR spectra. One
or two very strong absorptions were observed in the carbonyl
region of the IR spectra (1654-1673 cm-1). The 1H NMR
and IR spectra and the melting point of the known tris-
naphthoquinone 4d ′ were in agreement with the data
reported in the literature.5
In conclusion, a simple and mild new method for the
synthesis of trisquinones has been developed. The com-
pounds prepared in this study have been submitted for
biological assay.
Ack n ow led gm en t. This investigation was supported
by Grant No. CA40157, awarded by the National Cancer
Institute, DHHS. We also acknowledge the use of a VG
70-S mass spectrometer purchased through funding from
the National Institutes of Health, S10-RR-02478.
a
Reaction conditions. Maleoylcobalt complex 6: 1,2-dichloro-
ethane, 80 °C, 24 h. Phthaloylcobalt complex 6′: 1,2-dichloro-
ethane, UV irradiation, 25 °C, 36 h. Demetalation to the 2,3-
b
diarylnaphthoquinone occurs under the reaction conditions. Iso-
lated as the demetalated 2,3-diarylnaphthoquinone. c Unavailable.
Su p p or tin g In for m a tion Ava ila ble: A complete description
of the synthesis and characterization of all compounds in the
manuscript (50 pages).
ever, when 7a ,b,b′,d ,d ′,e′ were treated with 10 equiv of CAN
at room temperature and subjected to workup after 3 min,
the corresponding trisquinones 4a ,b,b′,d ,d ′,e′ were isolated
as yellow solids in high yields. Perhaps due to the increased
steric hindrance about the triple bond, diarylalkynes 5c and
5f failed to react with cobalt complexes 6 and 6′. Further
J O980680C
(11) Brockmann, H. Liebigs Ann. Chem. 1988, 1.