Scheme 1
Scheme 2. Biosynthesis of Maldoxin
dihydromaldoxin (RES-1214-2, pestheic acid, 7b).2,4,5
A second oxidative cyclization could thenlead to maldoxin
(1b).2 A similar oxidative cleavage of physcion (4a) would
give isosulochrin (5a),4,6 which could be oxidatively cy-
clized to give dechlorodihydromaldoxin (RES-1214-1,
7a).2,5 Although only dihydromaldoxin was isolated by
Liu and Che from Pestalotiopsis fici,1 isosulochrin (5a),
chloroisosulochrin (5b), and dihydromaldoxin (pestheic
acid, 7b) were all isolated from Pestalotiopsis theae,4 both
dechlorodihydromaldoxin (RES-1214-1, 7a) and dihydro-
maldoxin (RES-1214-2, 7b) were isolated from Pestalo-
tiopsis sp. RES-1214,5 and dechlorodihydromaldoxin (7a),
dihydromaldoxin (7b), and maldoxin (1b) were all isolated
fromanunidentifiedXylaria species.2 The isolation of both
chlorinated and unchlorinated 5 and 7 from the same
source suggests that chlorination might occur after oxida-
tive cleavage of anthraquinone 4. RES-1214-1 (7a) and -2
(7b) selectively inhibit ET-1 binding to endothelin type A
receptor (ETA receptor) with IC50 values of 1.5 and 20 μM,
respectively.5 They also inhibit the increase in intracellular
Ca2þ concentration elicited by 1 nM ET-1 in A10 cells.5
We planned to synthesize chloroisosulochrin (5b)
and convert it to maldoxin (1b) by the biomimetic se-
quence shown in Scheme 2. The oxidative cyclization of 2,
20-dihydroxybenzophenones analogous to 5 to give spir-
ofuranones analogous to 6 and acid-catalyzed hydrolysis
of the spirofuranones to provide 2-(2-hydroxyphenoxy-
)benzoic acids analogous to 7 are well precedented.7 The
oxidative cyclization of 2-(4-hydroxyphenoxy)benzoic
acids to give benzo[d][1.3]dioxin-4-ones spiro fused at the
4-position to 2,5-cyclohexadienones is known,8 but the
analogous preparation of benzo[d][1.3]dioxin-4-ones such
as maldoxin that are spiro fused at the 6-position to 2,4-
cyclohexadienones is unknown, possibly because of the
susceptibility of such dienones to dimerization.9
We started with resorcinol 8,10 an intermediate in
Katoh’s synthesis of geodin. Selective methylation of the
less hindered hydroxy group of 8 provided phenol 9a in
92% yield (see Scheme 3). We needed to selectively chlor-
inate 9a ortho to the phenol. Unfortunately, ortho chlor-
ination of complex phenols has proved to be very
challenging.11 Our initial attempt with NCS and benzoyl
peroxide in CCl4 provided a disappointing 1:8 mixture of
the desired ortho chlorophenol 9b and the para chloro-
phenol 10. Gnaim and Sheldon reported that phenol can
be selectively ortho chlorinated with SO2Cl2 and primary
or secondary amines in toluene.12 They suggested that the
high regioselectivity with phenol results from the in situ
formation of an N-chloroamine, which hydrogen bonds to
the phenol forming a complex that delivers chlorine in-
tramolecularly to the ortho position. We were disap-
pointed to find that chlorination of 9a with SO2Cl2 and
tert-butylamine in toluene provided only a 1:2.6 mixture of
9b and 10, although these conditions provide an 11.4:1
ortho/para mixture from phenol itself.12b Presumably,
(5) Ogawa, T.; Ando, K.; Aotani, Y.; Shinoda, K.; Tanaka, T.;
Tsukuda, E.; Yoshida, M.; Matsuda, Y. J. Antibiot. 1995, 48, 1401–
1406.
(6) (a) Assante, G.; Camarda, L.; Nasini, G. Gazz. Chim. Ital. 1980,
110, 629–631. (b) Hamasaki, T.; Kimura, Y. Agric. Biol. Chem. 1983, 47,
163–165.
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F.; Deffieux, D.; Pouysegu, L.; Quideau, S. Tetrahedron 2007, 63, 6493–
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(10) Katoh, T.; Ohmuri, O.; Iwasaki, K.; Inoue, M. Tetrahedron
2002, 58, 1289–1299.
(11) Mal, D.; Dey, S. Tetrahedron 2006, 62, 9589–9602.
(12) (a) Smith, K.; Butters, M.; Nay, B. Tetrahedron Lett. 1988, 29,
1319–1322. (b) Gnaim, J. M.; Sheldon, R. A. Tetrahedron Lett. 1995, 36,
3893–3896. (c) Gnaim, J. M.; Sheldon, R. A. Tetrahedron Lett. 2004, 45,
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(7) (a) Hendrickson, J. B.; Ramsay, M. V. J.; Kelly, T. R. J. Am.
Chem. Soc. 1972, 94, 6834–6843. (b) Sala, T.; Sargent, M. V. J. Chem.
Soc., Perkin Trans. 1 1981, 855–869. (c) Sala, T.; Sargent, M. V. J. Chem.
Soc., Perkin Trans. 1 1981, 877–882. (d) Coomber, M. F.; Sargent, M. V.;
Skelton, B. W.; White, A. H. J. Chem. Soc., Perkin Trans 1 1989, 441–
448. (e) Pulgarin, C.; Tabbachi, R. Helv. Chim. Acta 1989, 72, 1061–1065
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(8) Hassall, C. H.; Lewis, J. R. J. Chem. Soc. 1961, 2312–2315.
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