Novel construction of highly-substituted xanthones

Full text of DOI:10.1021/ja962920g

J. Am. Chem. Soc. 1996, 118, 12473-12474
12473
Scheme 1
Novel Construction of Highly-Substituted
Xanthones
Lijun Sun and Lanny S. Liebeskind*
Sanford S. Atwood Chemistry Center, Emory UniVersity
1515 Pierce DriVe, Atlanta, Georgia 30322
ReceiVed August 19, 1996
The xanthone core 1 is present in a large family of natural
products with broad biological activities.1-4 Many polyoxy-
genated, naturally-occurring xanthones possess intriguing bio-
logical properties, a factor that has led to interest in the
development of new synthetic methodologies for construction
of the ring system and to the total synthesis of various xanthone-
based natural products.5-25
Deconstruction of the highly-substituted xanthone core reveals
a concise synthetic strategy that generates the key dithiane-
protected benzopyrone-fused cyclobutenedione 5 by fusing a
dianion derived from the salicylaldehyde 2, protected as the
dithiane 3, to a squaric acid derivative 4 (Scheme 1). Reaction
of 5 with alkenyl, aromatic, and heteroaromatic lithiates should
provide, after thermolysis and hydrolysis, the highly-oxygenated
xanthones 1 following well-established cyclobutenedione-based
technology.26-31
Table 1. Synthesis of Dithiane-Protected Benzopyrone-Fused
Cyclobutenediones 5
The synthesis of five dithiane-protected benzopyrone-fused
cyclobutenediones is depicted in Table 1. A variety of 2-(o-
hydroxyphenyl)-1,3-dithianes 3 was prepared, each in high yield
from the corresponding salicylaldehyde under standard condi-
tions.32,33 Each of the dithianes 3 was dissolved in THF and
entry
R1
R2
R3
cmpd, %
4
6, %
5, %
1
2
3
4
5
H
H
H
H
Cl
H
MeO
H
3a, 95
3b, 90
3c, 95
3d, 98
3e, 91
4a 6a, 87 5a, 82
4a 6b, 94 5b, 76
4b 6c, 89 5c, 80
4b 6d, 77 5d, 79
4b 6e, 86 5e, 46
H
H
H
MeO
H
MeO MeO
(1) Bennett, G. J.; Lee, H.-H. Phytochemistry 1989, 28, 967.
(2) Afzal, M.; Al-Hassan, J. M. Heterocycles 1980, 14, 1173.
(3) Sultanbawa, M. U. S. Tetrahedron 1980, 36, 1465.
(4) Roberts, J. C. Chem. ReV. 1961, 61, 591.
(5) Asano, J.; Chiba, K.; Tada, M.; Yoshii, T. Phytochemistry 1996, 41,
815.
(6) Fernandes, E. R.; Carvalho, F. D.; Remia˜o, F. G.; Bastos, M. L.;
Pinto, M. M.; Gottlieb, O. R. Pharm. Res. 1995, 12, 1756.
(7) Lin, C.-N.; Liou, S.-S.; Lai, S.-C.; Lin, H.-C.; Ko, F.-N.; Liu, H.-
W.; Teng, C.-M. J. Pharm. Pharmacol. 1995, 47, 588.
(8) Sakai, S.-i.; Katsura, M.; Takayama, H.; Aimi, N.; Chokethaworn,
N.; Suttajit, M. Chem. Pharm. Bull. 1993, 41, 958.
(9) Chang, C.-C.; Lin, C.-N.; Lin, J.-Y. AntiViral Res. 1992, 19, 119.
(10) Liou, S.-S.; Shieh, W.-L.; Cheng, T.-H.; Won, S.-J.; Lin, C.-N. J.
Pharm. Pharmacol. 1993, 45, 791.
(11) Rao, A. V. R.; Yadav, J. S.; Reddy, K. K.; Upender, V. Tetrahedron
Lett. 1991, 32, 5199.
(12) Parker, K.; Ruder, S. M. J. Am. Chem. Soc. 1989, 111, 5948.
(13) Kelly, T. R.; Jagoe, C. T.; Li, Q. J. Am. Chem. Soc. 1989, 111,
4522.
(14) Mehta, G.; Shah, S. R. Tetrahedron Lett. 1991, 32, 5195.
(15) Mehta, G.; Venkateswarlu, Y. J. Chem. Soc., Chem. Commun. 1988,
1200.
(16) Rao, A. V. R.; Reddy, K. K.; Yadav, J. S.; Singh, A. K. Tetrahedron
Lett. 1988, 29, 3991.
(17) Omura, S.; Nakagawa, A.; Kushida, K.; Lukacs, G. J. Am. Chem.
Soc. 1986, 108, 6088.
(18) Omura, S.; Iwai, Y.; Hinotozawa, K.; Takahashi, Y.; Kato, J.;
Nakagawa, A.; Hirano, A.; Shimizu, H.; Haneda, K. J. Antibiot. 1982, 35,
645.
(19) Bekaert, A.; Andrieux, J.; Plat, M. Tetrahedron Lett. 1992, 33, 2805.
(20) Bergeron, D.; Brassard, P. Heterocycles 1992, 34, 1835.
(21) Letcher, R. M.; Yue, T. Y. J. Chem. Soc., Chem. Commun. 1992,
1310.
(22) Hauser, F. M.; Hewawasam, P.; Baghadanov, V. M. J. Org. Chem.
1988, 53, 223.
(23) Kjaer, D.; Kjaer, A.; Risbierg, E. J. Chem. Soc., Perkin Trans. 1
1983, 2815.
treated with 2.2 equiv of t-BuLi in pentane at -78 °C, and the
resulting solution was warmed to 0 °C to generate a slurry of
the corresponding O-, C-dianion. Reaction of the dianions with
the dialkyl squarates (4) took place at 0 °C to afford the 1,2-
adducts 6 in excellent yield in all cases.
The choice of squarate ester 4 was dictated by the ability to
promote the transformation of 6 into 5 using p-toluenesulfonic
acid monohydrate (pTSA) in CH2Cl2 at room temperature (6a,
10 mol % of pTSA for 72 h; 6b, 20 mol % of pTSA for 12 h
and then an additional 10 mol % of pTSA for 12 h). Notably,
the purification of 5a,b was achieved by simple trituration in
ether and hexanes, thus avoiding a tedious chromatography.
Under a variety of conditions, the adducts derived from
diisopropyl squarate and the methoxylated phenyldithianes (3c-
e) did not efficiently transform into the corresponding ring-
fused cyclobutenediones 5. To overcome this limitation adducts
6c-e derived from dimethyl squarate, although not stable
enough for complete characterization (their structures were
1
confirmed by H NMR spectra, alone), were obtained in good
yields and did undergo the desired acid-promoted reaction to
provide 5c-e in moderate to very good yields (Table 1, entries
3-5). It is noteworthy that these reactions can be conducted
on a large scale. Thus, without chromatography, 7.5 g of
diisopropyl squarate 4a and 7.3 g of dithiane 3a gave 13.5 g of
adduct 6a (87%), of which 7.0 g in turn was transformed into
4.1 g (82%) of cyclobutenedione 5a, again without chromatog-
raphy.
(24) Barton, D. H. R.; Cottire, L.; Freund, K.; Luini, F.; Magnus, P. D.;
Salazar, I. J. Chem. Soc., Perkin Trans. 1 1976, 499.
(25) Kato, T.; Katagiri, N.; Nakano, J.; Kawamura, H. J. Chem. Soc.,
Perkin Trans. 1 1981, 2710.
(26) Turnbull, P.; Moore, H. W. J. Org. Chem. 1995, 60, 3274.
(27) Koo, S.; Liebeskind, L. S. J. Am. Chem. Soc. 1995, 117, 3389.
(28) Gurski-Birchler, A.; Liu, F.; Liebeskind, L. S. J. Org. Chem. 1994,
59, 7737.
Efficient nucleophilic addition of different alkenyl (styrene,
dihydropyran), aryl (benzene, substituted benzenes, naphtha-
lenes), and heteroaryl (furan, thiophene, pyrrole, indole) lithiates
(32) Page, P. C. B.; van Niel, M. B.; Prodger, J. Tetrahedron 1989, 45,
(29) Liebeskind, L. S.; Wang, J. Y. J. Org. Chem. 1993, 58, 3550.
(30) Moore, H. W.; Yerxa, B. R. Chemtracts: Org. Chem. 1992, 5, 273.
(31) Liebeskind, L. S. Tetrahedron (Symposia in Print) 1989, 45, 3053.
7643.
(33) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965, 4,
1075.
S0002-7863(96)02920-4 CCC: $12.00 © 1996 American Chemical Society

12474 J. Am. Chem. Soc., Vol. 118, No. 49, 1996
Communications to the Editor
Table 2. Highly-Substituted Xanthones From Dithiane Protected Benzopyrone-fused Cyclobutenediones
entry
5a
organolithium reagent
phenyllithium
2-naphthyllithium
X
R4
R5
cmpd, %
cmpd, %
1
2
3
4
5
6
7
8
9
10
11
12
13
14
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
5b
5c
5d
5e
-CHdCH-
-CHdCH-
o-phenylene
-CHdCH-
NNMe2
NMe
H
H
7a, 81
7b, 89
7c, 75
7d, b
7e, 57
7f, 76
7g, 50
8a, b
7h, 41
7i, 55
8b, 66
7j, b
7k, 71
8c, 73
9a, 77
9b, 71
9c, 80
9d, 33c
9e, 81
9f, 56
9g, 67
10a, 21c
9h, 68
9i, 54
10b, 62
9j, 41c
9k, 88
10c, 53
benzo
benzo
1-naphthyllithium
H
H
H
H
OMe
H
p-methoxyphenyllithium
2-((1-dimethylamino)pyrrolyl)lithium
2-(1-methylindolyl)lithium
2-thienyllithium
(E)-â-styrenyllithium
2-thienyllithium
2-((5-trimethylsilyl)furanyl)lithium
2-dihydropyranyllithium
p-(dimethylamino)phenyllithium
2-(1-(dimethylamino)pyrrolyl)lithium
3-furanyllithium
S
H
H
H
H
H
Ph
S
O
H
SiMe3
-(CH2)3O-
H
NMe2
H
H
NNMe2
H
-OCHdCH-
a Refer to Table 1 for a listing of substituents R1 to R3 of 5. b Not purified; the crude product was directly exposed to the dithiane hydrolysis
conditions. c Overall yield from 5.
to the dithiane-protected γ-benzopyrone-fused cyclobutenedi-
ones 5 took place exclusively at the carbonyl group opposite
the bulky dithiane moiety (Table 2).34 The 1,2-adducts (brack-
eted structure in Table 2) were exceptionally prone to benzan-
nulation; even at room temperature the aromatized products
slowly formed, and the alkenyl adducts were so reactive toward
benzannulation that they were seen only by TLC. Although
the O-acetylated 1,2-adducts derived from phenyl and substi-
tuted phenyl lithiates had longer lifetimes and could be isolated
in pure form in some cases, facile room temperature benzan-
nulation in solution and in the solid state prevented their
comprehensive characterization. It proved most efficient to
isolate the benzannulated products 7 or 8 directly, after heating
THF solutions of the crude 1,2-adducts for about 2 h. Following
this protocol, the dithiane-protected xanthones 7 or 8 could be
easily obtained in moderate to excellent yields in pure form by
chromatographic purification, in most cases. However, attempts
to obtain analytically pure 7d, 7j, and 8a were not successful.
Nevertheless, the corresponding analytically pure xanthones 9d,
9j, and 10a could be obtained after hydrolysis of the crude
dithiane-protected products. In these three cases, overall yields
are reported on the basis of the cyclobutenediones 5 used in
those reactions. In all other cases, the targeted xanthone struc-
tures 9 and 10 were obtained in moderate to excellent yields
after chromatographic purification when a standard HgCl2-
promoted deprotection protocol32,33was applied to compounds
7 and 8 (Table 2).
In conclusion, a concise and synthetically flexible approach
to highly-substituted xanthones has been demonstrated which
relies on the versatility of cyclobutenediones as scaffolds for
the construction of a diverse range of molecular structures.
Dithiane-protected γ-benzopyrone-fused cyclobutenediones 5,
easily prepared on a large scale from dialkyl squarates and the
dianions of 2-(o-hydroxyphenyl)-1,3-dithianes, are the key to
accessing in a regiocontrolled fashion a variety of highly-
substituted xanthones and xanthones fused to aromatic and
heteroaromatic rings.
Acknowledgment. This investigation was supported by Grant No.
CA40157, awarded by the National Cancer Institute, DHHS. We
acknowledge the use of a VG 70-S mass spectrometer purchased
through funding from the National Institutes of Health, (S10-RR-02478)
and a 300 and 360 MHz NMR purchased through funding from the
National Science Foundation (NSF CHE-85-16614 and NSF CHE-
8206103, respectively).
(34) The regiochemistry of the nucleophilic addition was assigned on
the basis of two factors: (1) nucleophilic addition to cyclobutenediones is
known to occur with high regioselectivity at the nonvinylogous ester (or
vinylogous amide) carbonyl group and (2) an extensive but yet unpublished
study has demonstrated highly selective nucleophilic attack at the cy-
clobutenedione carbonyl group most distant from sterically encumbering
substituents at the 3- or 4-position of the cyclobutenedione ring.
Supporting Information Available: A complete description of the
synthesis and characterization of all compounds in the manuscript (23
pages). See any current masthead page for ordering and Internet access
instructions.
JA962920G