Synthesis of macrosporin and related 9,10-anthraquinones by biomimetic polyketide aromatization and cyclization of 6-benzylresorcylates

Article abstract of DOI:10.1002/ejoc.201201480

This paper describes the synthesis of an array of 9,10-anthraquinones 2 by initial preparation of 6-benzylresorcylates 3 from oxo-dioxinone precursors 4 and their subsequent conversion to anthrones by cyclization and oxidation. Resorcylates 3 were obtained by an improved two-step procedure from oxo ester 5 and acyl chlorides 6. These methods were applied in a seven-step synthesis of the fungal natural product macrosporin (1). A new synthetic approach to 9,10-anthraquinones was developed. Selective Claisen condensation of an allyl γ-dioxinyl-β-oxo ester with arylacetyl chlorides, Pd-catalyzed deallylation, decarboxylation and aromatization gave 6-(arylmethyl)resorcylates. Subsequent acid-mediated cyclization and oxidation with CAN gave target anthraquinones, one of these being the fungal natural product macrosporin. Copyright

Full text of DOI:10.1002/ejoc.201201480

FULL PAPER
DOI: 10.1002/ejoc.201201480
Synthesis of Macrosporin and Related 9,10-Anthraquinones by Biomimetic
Polyketide Aromatization and Cyclization of 6-Benzylresorcylates
Jens Cordes[a] and Anthony G. M. Barrett*[a]
Keywords: Natural products / Quinones / Fused-ring systems / Annulation / Oxidation
This paper describes the synthesis of an array of 9,10-anthra-
quinones 2 by initial preparation of 6-benzylresorcylates 3
from oxo-dioxinone precursors 4 and their subsequent con-
version to anthrones by cyclization and oxidation. Resorcyl-
ates 3 were obtained by an improved two-step procedure
from oxo ester 5 and acyl chlorides 6. These methods were
applied in a seven-step synthesis of the fungal natural prod-
uct macrosporin (1).
which in turn should be available from known oxo ester
5[14] and acyl chloride 6 by Claisen reaction. The strategy
in Scheme 1 should easily allow the preparation of 1,3-dihy-
droxy-9,10-anthraquinones with diverse substitution pat-
terns and therefore should be of general utility.
Introduction
9,10-Anthraquinones[1] are an important class of natural
products that show various biological activities.[2] In 1957,
Suemitsu et al. reported the first isolation of the 9,10-
anthraquinone macrosporin (1, Figure 1) from the plant
pathogen fungus[3] Macrosporium porri,[4] followed by its
structure determination by degradation.[5] Over the years,
macrosporin (1) has been isolated from a number of other
phytopathogenic fungi[6] and shown to inhibit several pro-
tein kinases[6j] as well as having antiproliferative[6h,7] and
antibacterial activities.[6f,8]
Figure 1. Macrosporin (1).
Although the biosynthesis of 1 proceeds through the oc-
taketide pathway,[9,10] the only reported total synthesis of 1
utilized a Diels–Alder reaction of a 1,4-naphthoquinone
and a diene[11] to introduce the 9,10-anthaquinone unit.[12]
Building on our recent biomimetic syntheses of resorcylate
natural products,[13,14] we sought to explore an alternative
synthesis of 9,10-anthraquinones including 1 that utilizes a
polyketide-like construction of one of the arenes, with sub-
sequent intramolecular Friedel–Crafts acylation to close the
tricyclic array. This retrosynthetic analysis is outlined in
Scheme 1. We envisioned that key resorcylate 3 should be
available by biomimetic cyclization of dioxo-dioxinone 4,
Scheme 1. Retrosynthetic analysis of macrosporin-like 9,10-anthra-
quinones 2.
Results and Discussion
Selective Claisen condensation of acyl chlorides 6a–g[15]
with dioxinone oxo ester 5[14] gave dioxinone dioxo esters
7, which were subjected directly to Pd(PPh3)4-catalyzed de-
allylation and decarboxylation (Table 1). In this reaction,
morpholine was used both as a π-allyl scavenger[16] as well
as a base to catalyze cyclization of the resultant dioxo-diox-
inones 4 to generate 6-benzylresorcylates 8a–g in a one-pot
reaction in high yield (61–74% over two steps). This is a
[a] Department of Chemistry, Imperial College London,
South Kensington, London SW7 2AZ, England
Fax: +44-207-594-5805
E-mail: agm.barrett@imperial.ac.uk
Homepage: www3.imperial.ac.uk/people/agm.barrett
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201480.
1318
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Eur. J. Org. Chem. 2013, 1318–1326

Macrosporin and Related 9,10-Anthraquinones
significant improvement to previously reported multistep yields (42–63%, Table 2). As could be expected for a Frie-
methods.[13b–13d,14] Phenol methylation of 8a–g was carried del–Crafts-type reaction, yields were significantly higher for
out by using iodomethane and cesium carbonate to afford substrates with electron-donating substituents in positions
the corresponding ethers (91–96%). Attempts to cyclize ortho and/or para to the reacting arene carbon atom. Fi-
benzylresorcylates 3 directly to anthrones 10 were not suc- nally, oxidation with cerium ammonium nitrate (CAN)[17]
cessful, probably due to side reactions with the by-product gave 9,10-anthraquinones 2 in good yields (74–88%).
acetone. Thus, resorcylates 3a–g were transesterified to pro- The cyclization of 6-benzylresorcylates to anthrones in
vide methyl esters 9a–g by using methanolic potassium car- PPA worked well for methyl-protected phenols. It failed,
bonate in quantitative yields.
however, for benzyl-protected phenol 9a and led instead
only to decomposition. Deprotection by hydrogenation
using Pd/C gave phenol 9i (95%, Scheme 2). Attempts to
form anthrone 10i from this compound by heating in PPA
were again unsuccessful. To solve this problem, we exam-
ined other methods of cyclization and found that trimethyl-
silyl triflate in dichloromethane also catalyzed the desired
C-acylation. These slightly milder reaction conditions gave
anthrone 10i in 76% yield. With PPA, phenol phosphoryla-
tion is likely to occur, while we assume that trimethylsilyl
triflate gave an intermediate aryl trimethylsilyl ether, which
appears to be beneficial for the reaction. Although resorcyl-
ates 9b–g also contain unprotected phenol units, these seem
to be less reactive, presumably due to hydrogen bonding
with the adjacent carbonyl group. To our disappointment,
attempted oxidation of anthrone 10i with CAN to generate
the corresponding 9,10-anthraquinone 1 gave intractable
mixtures of products, again most likely due to side reactions
involving the unprotected phenol on C-7. This problem was
solved by the use of cupric bromide and oxygen instead,[18]
giving macrosporin 1 in 81% yield. The analytical data for
synthetically produced 1 are in full agreement with reported
values for the isolated natural product.[4a,6,9a,9b]
Table 1. Synthesis of 6-benzylresorcylates 9a–g.
Scheme 2. Synthesis of macrosporin (1).
Interestingly, an attempt to apply the reaction conditions
used for the cyclization of resorcylate 9i to yield anthrone
10i to substrate 9d failed to afford anticipated anthrone 10d.
[a] Isolated yield over two steps from 5. [b] Isolated yield. [c] Acyl
chloride 6a was prepared as described in ref.[15]
Initial attempts to cyclize resorcylates 9 to anthrones 10
catalyzed by Lewis acids were unsuccessful, as was the reac-
tion in concentrated sulfuric acid. However, heating in poly-
phosphoric acid (PPA)[17] gave anthrones 10b–h in moderate Scheme 3. Reaction of resorcylate 9d with trimethylsilyl triflate.
Eur. J. Org. Chem. 2013, 1318–1326
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J. Cordes, A. G. M. Barrett
FULL PAPER
Table 2. Synthesis of 9,10-anthraquinones 2b–h.
[a] Isolated yield. [b] Reaction of 9c gave a mixture of anthrones 10c and 10h, which were isolated and oxidized separately to anthra-
quinones 2c and 2h respectively.
In this case, a selective but incomplete deprotection and de- anthraquinones by intramolecular Friedel–Crafts acylation
carboxylation of the ester was observed, yielding benzyl- and oxidation. This strategy was applied in a seven-step
benzene 11 (Scheme 3). Although trimethylsilyl triflate synthesis of the fungal natural product macrosporin (1) in
worked well on substrate 9i, it seems to be even more sub- 40% overall yield.
strate-sensitive than PPA, which in this case, gave 38% of
cyclization product 10d. Consequently, these two conditions
Experimental Section
complement each other, PPA being the appropriate reagent
for most anthrones, and trimethylsilyl triflate being superior
for electron-rich phenols.
General Methods: All reactions were carried out in oven-dried
glassware under argon by using commercially supplied solvents and
reagents unless otherwise stated. Polyphosphoric acid (PPA) was
bought from Sigma–Aldrich (Hn+2PnO3n+1, 115% H3PO4 basis).
THF was redistilled from Na/Ph2CO. Hexanes refers to petroleum
spirit of boiling range 40–60 °C. Column chromatography was car-
ried out on silica gel by using flash techniques (eluents are given
Conclusions
We describe a versatile method for the synthesis of 6-
benzylresorcylates and their transformation into 9,10- in parentheses). Analytical TLC was performed with precoated sil-
1320 Eur. J. Org. Chem. 2013, 1318–1326
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Macrosporin and Related 9,10-Anthraquinones
ica gel F254 aluminum plates with visualization under UV light or
by staining with acidic vanillin or anisaldehyde spray reagents.
Melting points were measured with a hot stage apparatus. IR spec-
J = 7.8 Hz, 1 H, Ar-H), 6.79 (mc, 1 H, Ar-H), 6.75 (d, J = 7.6 Hz,
1 H, Ar-H), 6.72 (dd, J = 2.4, 8.3 Hz, 1 H, Ar-H), 6.20 (d, J =
2.4 Hz, 1 H, Ar-H), 6.18 (d, J = 2.3 Hz, 1 H, Ar-H), 4.40 (s, 2 H,
Ar-CH2-ArЈ), 3.72 (s, 3 H, OMe), 1.62 [s, 6 H, C(CH3)2] ppm. 13C
NMR (100 MHz, [D8]THF, 25 °C): δ = 164.2, 160.8, 159.8 (2 C),
148.8, 142.7, 129.7, 122.2, 115.7, 113.8, 112.0, 105.0, 104.8, 102.0,
55.0, 40.0, 25.5 (2 C) ppm. HR-MS (ESI): calcd. for C18H19O5 [M
+ H]+ 315.1232; found 315.1230. C18H18O5 (314.33): calcd. C
68.78, H 5.77; found C 68.65, H 5.78.
1
tra were recorded neat. H NMR spectra were recorded at 400 or
500 MHz, whereas 13C NMR spectra were recorded at 100 or
125 MHz. Chemical shifts (δ) are quoted in ppm.
Synthesis of 9,10-Anthraquinones 2b–h and the Macrosporin Precur-
sor 9a
General Procedure for the Synthesis of 5-Benzyl-7-hydroxy-2,2-di-
methyl-4H-benzo[d][1,3]-dioxin-4-ones 8a–g from Dioxinone Oxo
Ester 5 and Acyl chlorides 6a–g: Pyridine (0.90 mL, 11.2 mmol,
3.0 equiv.) and MgCl2 (355 mg, 3.73 mmol, 1.0 equiv.) were added
with stirring to 5[14] (1.00 g, 3.73 mmol, 1.0 equiv.) in CH2Cl2
(15 mL) at 0 °C. After 15 min, 6a–g[15] (4.85 mmol, 1.3 equiv.) was
added dropwise, and the resulting mixture was stirred at 0 °C for
1 h. Aqueous HCl (1 m; 40 mL) and CH2Cl2 (50 mL) were added
and the phases separated. The aqueous layer was extracted with
CH2Cl2 (2ϫ 50 mL), and the combined organic layers were dried
(MgSO4) and the volatiles rotary-evaporated. The resultant 7a–g
was dissolved in THF (19 mL), and morpholine (0.97 mL,
11.2 mmol, 3.0 equiv.) was added. The solution was degassed by
purging with argon for 15 min. Pd(PPh3)4 (86 mg, 74 μmol,
0.02 equiv.) was added at 20 °C, and, after 30 h, HCl (1 m; 40 mL)
and CH2Cl2 (50 mL) were added and the phases separated. The
aqueous layer was further extracted with Et2O (3ϫ 50 mL), and
the combined organic layers were dried (MgSO4) and the volatiles
rotary-evaporated. The crude product was chromatographed (hex-
anes/THF, 19:1 Ǟ 9:1 Ǟ 6:1 Ǟ 4:1) to afford 8a–g.
7-Hydroxy-5-(2-methoxybenzyl)-2,2-dimethyl-4H-benzo[d][1,3]di-
oxin-4-one (8d): White solid, 73% over 2 steps. Rf = 0.22 (hexanes/
THF, 3:1). M.p. 182–184 °C (CH Cl ). IR: ν = 1724, 1692, 1611,
˜
2
2
1584, 1493, 1447, 1284, 1268, 1243, 1205, 1165, 1107, 104 8, 1027,
1
832, 752, 718, 680 cm–1. H NMR (400 MHz, [D8]THF, 25 °C): δ
= 9.12 (s, 1 H, OH), 7.17 (ddd, J = 1.7, 8.1, 8.2 Hz, 1 H, Ar-H),
7.05 (dd, J = 1.6, 7.4 Hz, 1 H, Ar-H), 6.92 (d, J = 8.2 Hz, 1 H, Ar-
H), 6.83 (ddd, J = 1.0, 7.6, 7.8 Hz, 1 H, Ar-H), 6.15 (d, J = 2.4 Hz,
1 H, Ar-H), 6.07 (d, J = 2.4 Hz, 1 H, Ar-H), 4. (s, 2 H, Ar-CH2-
ArЈ), 3.75 (s, 3 H, OMe), 1.64 [s, 6 H, C(CH3)2] ppm. 13C NMR
(100 MHz, [D8]THF, 25 °C): δ = 164.1, 159.8, 159.7, 158.6, 149.0,
131.3, 129.5, 128.1, 120.9, 113.0, 111.0, 105.0, 104.8, 101.7, 55.4,
34.4, 25.6 (2 C) ppm. HR-MS (ESI): calcd. for C18H19O5 [M +
H]+ 315.1232; found 315.1233. C18H18O5 (314.33): calcd. C 68.78,
H 5.77; found C 68.83, H 5.79.
5-(3,4-Dimethoxybenzyl)-7-hydroxy-2,2-dimethyl-4H-benzo[d]-
[1,3]dioxin-4-one (8e): White solid, 74% over 2 steps. Rf = 0.29 (hex-
anes/Et O/CH Cl , 2:1:1). M.p. 150–152 °C (CH Cl ). IR: ν =
˜
2
2
2
2
2
1722, 1695, 1613, 1586, 1514, 1448, 1291, 1263, 1208, 1168, 1140,
1028 cm–1. 1H NMR (400 MHz, [D8]THF, 25 °C): δ = 9.20 (s, 1 H,
OH), 6.81 (s, 1 H, Ar-H), 6.80 (d, J = 8.0 Hz, 1 H, Ar-H), 6.70
(dd, J = 1.9, 8.2 Hz, 1 H, Ar-H), 6.16 (s, 2 H, 2 Ar-H), 4.35 (s, 2
H, Ar-CH2-ArЈ), 3.74 (s, 3 H, OMe), 3.72 (s, 3 H, OMe), 1.62 [s,
6 H, C(CH3)2] ppm. 13C NMR (100 MHz, [D8]THF, 25 °C): δ =
164.2, 159.8 (2 C), 150.5, 149.7, 149.0, 133.6, 122.0, 114.4, 113.5,
112.8, 104.9, 104.7, 101.8, 56.0, 55.9, 39.6, 25.5 (2 C) ppm. HR-
MS (ESI): calcd. for C19H21O6 [M + H]+ 345.1338; found 345.1354.
C19H20O6 (344.36): calcd. C 66.27, H 5.85; found C 66.17, H 5.78.
5-[4-(Benzyloxy)-3-methylbenzyl]-7-hydroxy-2,2-dimethyl-4H-
benzo[d][1,3]dioxin-4-one (8a): White solid, 72% over 2 steps. Rf =
0.44 (hexanes/Et O, 1:1). M.p. 170–172 °C (CH Cl ). IR: ν = 1687,
˜
2
2
2
1614, 1580, 1506, 1291, 1256, 1227, 1200, 1172 cm–1 1H NMR
.
(400 MHz, [D8]THF, 25 °C): δ = 9.26 (s, 1 H, OH), 7.44 (d, J =
7.4 Hz, 2 H, 2 Ar-H), 7.34 (t, J = 7.3 Hz, 2 H, 2 Ar-H), 7.26 (t, J
= 7.3 Hz, 1 H, Ar-H), 7.00 (d, J = 1.9 Hz, 1 H, Ar-H), 6.97 (dd, J
= 8.3, 2.0 Hz, 1 H, Ar-H), 6.86 (d, J = 8.3 Hz, 1 H, Ar-H), 6.18
(d, J = 2.3 Hz, 1 H, Ar-H), 6.17 (d, J = 2.3 Hz, 1 H, Ar-H), 5.05
(s, 2 H, Ph-CH2-OAr), 4.34 (s, 2 H, Ar-CH2-ArЈ), 2.21 (s, 3 H, Ar-
CH3), 1.61 [s, 6 H, C(CH3)2] ppm. 13C NMR (100 MHz, [D8]THF,
25 °C): δ = 164.2, 159.8 (2 C), 156.2, 149.7, 138.7, 133.0, 132.3,
128.9 (2 C), 128.3, 128.1, 127.7 (2 C), 127.0, 113.7, 111.8, 104.9,
104.7, 101.8, 70.3, 39.2, 25.5 (2 C), 16.4 ppm. HR-MS (ESI): calcd.
for C25H25O5 [M + H]+ 405.1702; found 405.1703. C25H24O5
(404.46): calcd. C 74.24, H 5.98; found C 74.24, H 5.97.
5-(2,5-Dimethoxybenzyl)-7-hydroxy-2,2-dimethyl-4H-benzo[d]-
[1,3]dioxin-4-one (8f): White solid, 61% over 2 steps. Rf = 0.48 (hex-
anes/Et O/CH Cl , 2:1:1). M.p. 197–199 °C (CH Cl ). IR: ν =
˜
2
2
2
2
2
1724, 1692, 1611, 1584, 1498, 1447, 1432, 1269, 1224, 1166, 1046,
1
1027, 857, 805, 715 cm–1. H NMR (400 MHz, [D8]THF, 25 °C): δ
= 9.12 (s, 1 H, OH), 6.83 (d, J = 8.7 Hz, 1 H, Ar-H), 6.72 (dd, J
= 3.1, 8.6 Hz, 1 H, Ar-H), 6.69 (d, J = 3.0 Hz, 1 H, Ar-H), 6.15
(d, J = 2.3 Hz, 1 H, Ar-H), 6.09 (d, J = 2.4 Hz, 1 H, Ar-H), 4.38
(s, 2 H, Ar-CH2-ArЈ), 3.70 (s, 3 H, OMe), 3.67 (s, 3 H, OMe), 1.64
[s, 6 H, C(CH3)2] ppm. 13C NMR (100 MHz, [D8]THF, 25 °C): δ
= 164.1, 159.8, 159.7, 154.7, 152.8, 148.9, 130.5, 117.5, 113.0, 112.2,
111.9, 105.0, 104.9, 101.7, 55.9, 55.4, 34.4, 25.6 (2 C) ppm. HR-
MS (ESI): calcd. for C19H21O6 [M + H]+ 345.1338; found 345.1343.
C19H20O6 (344.36): calcd. C 66.27, H 5.85; found C 66.18, H 5.91.
7-Hydroxy-5-(4-methoxybenzyl)-2,2-dimethyl-4H-benzo[d][1,3]di-
oxin-4-one (8b): White solid, 68% over 2 steps. Rf = 0.32 (hexanes/
Et O, 1:3). M.p. 122–124 °C (CH Cl ). IR: ν = 1687, 1611, 1577,
˜
2
2
2
1281, 1268, 1241, 1204, 1167, 1054, 1039, 838 cm–1 1H NMR
.
(400 MHz, [D8]THF, 25 °C): δ = 9.19 (s, 1 H, OH), 7.10 (d, J =
8.6 Hz, 2 H, 2 Ar-H), 6.80 (d, J = 8.7 Hz, 2 H, 2 Ar-H), 6.17 (d,
J = 2.4 Hz, 1 H, Ar-H), 6.16 (d, J = 2.4 Hz, 1 H, Ar-H), 4.35 (s, 2
H, Ar-CH2-ArЈ), 3.73 (s, 3 H, OMe), 1.61 [s, 6 H, C(CH3)2] ppm.
13C NMR (100 MHz, [D8]THF, 25 °C): δ = 164.2, 159.9, 159.7,
159.1, 149.6, 133.0, 130.9 (2 C), 114.2 (2 C), 113.7, 104.9, 104.7,
101.8, 55.1, 39.1, 25.5 (2 C) ppm. HR-MS (ESI): calcd. for
C18H19O5 [M + H]+: 315.1232; found 315.1235. C18H18O5 (314.33):
calcd. C 68.78, H 5.77; found C 68.69, H 5.74.
5-(3,5-Dimethoxybenzyl)-7-hydroxy-2,2-dimethyl-4H-benzo[d]-
[1,3]dioxin-4-one (8g): White solid, 62% over 2 steps. Rf = 0.36
(hexanes/Et O, 1:1). M.p. 154–156 °C (CH Cl ). IR: ν = 1694,
˜
2
2
2
1610, 1594, 1459, 1353, 1290, 1205, 1157, 1059, 839 cm–1. 1H NMR
(400 MHz, [D8]THF, 25 °C): δ = 9.21 (s, 1 H, OH), 6.38 (d, J =
2.3 Hz, 2 H, 2 Ar-H), 6.30 (t, J = 2.3 Hz, 1 H, Ar-H), 6.20 (d, J =
2.4 Hz, 1 H, Ar-H), 6.17 (d, J = 2.3 Hz, 1 H, Ar-H), 4.36 (s, 2 H,
7-Hydroxy-5-(3-methoxybenzyl)-2,2-dimethyl-4H-benzo[d][1,3]di-
oxin-4-one (8c): White solid, 74% over 2 steps. Rf = 0.37 (hexanes/
Ar-CH2-ArЈ), 3.70 (s, 6 H, 2 OMe), 1.63 [s, 6 H, C(CH3)2] ppm. 13
C
Et O, 1:1). M.p. 124–126 °C (CH Cl ). IR: ν = 1692, 1611, 1583,
NMR (100 MHz, [D8]THF, 25 °C): δ = 164.2, 161.9 (2 C), 159.8 (2
1H C), 148.8, 143.2, 113.6, 108.0 (2 C), 105.0, 104.8, 101.9, 98.7, 55.1
(2 C), 40.2, 25.5 (2 C) ppm. HR-MS (ESI): calcd. for C19H21O6 [M
˜
2
2
2
1489, 1449, 1390, 1355, 1296, 1265, 1209, 1168, 1052 cm–1
.
NMR (400 MHz, [D8]THF, 25 °C): δ = 9.23 (s, 1 H, OH), 7.14 (t,
Eur. J. Org. Chem. 2013, 1318–1326
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1321

J. Cordes, A. G. M. Barrett
FULL PAPER
+ H]+ 345.1338; found 345.1339. C19H20O6 (344.36): calcd. C
66.27, H 5.85; found C 66.19, H 5.92.
NMR (100 MHz, CDCl3, 25 °C): δ = 164.7, 160.2, 158.9, 157.5,
148.1, 130.4, 128.5, 127.6, 120.5, 112.2, 110.4, 105.1, 104.7, 99.1,
55.3 (2 C), 33.8, 25.6 (2 C) ppm. HR-MS (ESI): calcd. for
C19H21O5 [M + H]+ 329.1389; found 329.1384. C19H20O5 (328.36):
calcd. C 69.50, H 6.14; found C 69.38, H 6.16.
General Procedure for the Synthesis of 5-Benzyl-7-methoxy-2,2-di-
methyl-4H-benzo[d][1,3]-dioxin-4-ones 3a–g from 5-Benzyl-7-hy-
droxy-2,2-dimethyl-4H-benzo[d][1,3]-dioxin-4-ones 8a–g: Cs2CO3
(2.15 g, 6.60 mmol, 3.0 equiv.) and MeI (0.41 mL, 6.60 mmol,
3.0 equiv.) were added with stirring to 8a–g (2.20 mmol, 1.0 equiv.)
in THF (22 mL) at 20 °C. After 18 h, aqueous HCl (1 m: 40 mL)
and Et2O (50 mL) were added and the phases separated. The aque-
ous layer was further extracted with Et2O (2ϫ 50 mL), and the
combined organic layers were dried (MgSO4) and the volatiles ro-
tary-evaporated. The crude product was chromatographed on silica
(hexanes/Et2O, 3:1) to obtain 3a–g.
5-(3,4-Dimethoxybenzyl)-7-methoxy-2,2-dimethyl-4H-benzo[d]-
[1,3]dioxin-4-one (3e): White solid, 93%. Rf = 0.32 (hexanes/Et2O,
1:1). M.p. 108–110 °C (CH Cl ). IR: ν = 1720, 1609, 1575, 1278,
˜
2
2
1258, 1202, 1153, 1139, 1057, 1043, 1026, 727 cm–1 1H NMR
.
(400 MHz, CDCl3, 25 °C): δ = 6.79 (d, J = 1.3 Hz, 1 H, Ar-H),
6.78 (d, J = 7.0 Hz, 1 H, Ar-H), 6.72 (dd, J = 1.9, 8.3 Hz, 1 H, Ar-
H), 6.36 (d, J = 2.5 Hz, 1 H, Ar-H), 6.30 (d, J = 2.6 Hz, 1 H, Ar-
H), 4.41 (s, 2 H, Ar-CH2-ArЈ), 3.84 (s, 3 H, OMe), 3.83 (s, 3 H,
OMe), 3.76 (s, 3 H, OMe), 1.68 [s, 6 H, C(CH3)2] ppm. 13C NMR
(100 MHz, CDCl3): δ = 164.9, 160.2, 159.2, 148.8, 148.3, 147.4,
132.6, 121.1, 112.8, 112.7, 111.1, 104.9, 104.8, 99.3, 55.83, 55.79,
55.5, 39.2, 25.6 (2 C) ppm. HR-MS (ESI): calcd. for C20H23O6 [M
+ H]+ 359.1495; found 359.1483. C20H22O6 (358.39): calcd. C
67.03, H 6.19; found C 66.94, H 6.16.
5-[4-(Benzyloxy)-3-methylbenzyl]-7-methoxy-2,2-dimethyl-4H-
benzo[d][1,3]dioxin-4-one (3a): Colorless oil, 95%. Rf = 0.62 (hex-
anes/Et O, 1:1). IR: ν = 1726, 1610, 1577, 1503, 1279, 1156, 1132,
˜
2
1059 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.44 (d, J =
7.3 Hz, 2 H, 2 Ar-H), 7.38 (pt, J = 7.4 Hz, 2 H, 2 Ar-H), 7.31 (tt,
J = 2.4, 7.2 Hz, 1 H, Ar-H), 7.00 (d, J = 1.8 Hz, 1 H, Ar-H), 6.97
(dd, J = 1.9, 8.3 Hz, 1 H, Ar-H), 6.80 (d, J = 8.2 Hz, 1 H, Ar-H),
6.37 (d, J = 2.5 Hz, 1 H, Ar-H), 6.31 (d, J = 2.5 Hz, 1 H, Ar-H),
5-(2,5-Dimethoxybenzyl)-7-methoxy-2,2-dimethyl-4H-benzo[d]-
[1,3]dioxin-4-one (3f): Colorless oil, 96%. Rf = 0.60 (hexanes/Et2O,
5.05 (s, 2 H, Ph-CH2-OAr), 4.39 (s, 2 H, Ar-CH2-ArЈ), 3.77 (s, 3 1:1). IR: ν = 1726, 1611, 1577, 1499, 1434, 1389, 1280, 1226, 1157,
˜
H, OMe), 2.24 (s, 3 H, Ar-CH3), 1.68 [s, 6 H, C(CH3)2] ppm. 13C
1056, 855, 715 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 6.80
NMR (100 MHz, CDCl3, 25 °C): δ = 164.8, 160.2, 159.1, 155.3, (d, J = 8.8 Hz, 1 H, Ar-H), 6.72 (dd, J = 3.1, 8.8 Hz, 1 H, Ar-H),
148.7, 137.6, 132.0, 131.6, 128.4 (2 C), 127.7, 127.3, 127.1 (2 C), 6.63 (d, J = 3.0 Hz, 1 H, Ar-H), 6.31 (d, J = 2.6 Hz, 1 H, Ar-H),
126.9, 112.9, 111.4, 104.9 (2 C), 99.2, 69.9, 55.5, 38.8, 25.6 (2 C),
16.4 ppm. HR-MS (ESI): calcd. for C26H27O5 [M + H]+ 419.1858;
found 419.1868. C26H26O5 (418.48): calcd. C 74.62, H 6.26; found
C 74.58, H 6.33.
6.29 (d, J = 2.5 Hz, 1 H, Ar-H), 4.44 (s, 2 H, Ar-CH2-ArЈ), 3.75
(s, 3 H, OMe), 3.73 (s, 3 H, OMe), 3.71 (s, 3 H, OMe), 1.70 [s, 6
H, C(CH3)2] ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 164.8,
160.2, 158.9, 153.5, 151.9, 147.7, 129.8, 116.7, 112.4, 111.5 (2 C),
105.1, 104.8, 99.2, 56.1, 55.6, 55.3, 33.9, 25.6 (2 C) ppm. HR-MS
(ESI): calcd. for C20H23O6 [M + H]+ 359.1495; found 359.1500.
C20H22O6 (358.39): calcd. C 67.03, H 6.19; found C 66.93, H 6.21.
7-Methoxy-5-(4-methoxybenzyl)-2,2-dimethyl-4H-benzo[d][1,3]di-
oxin-4-one (3b): White solid, 95%. Rf = 0.65 (hexanes/Et2O, 1:1).
M.p. 72–74 °C (CH Cl ). IR: ν = 1727, 1611, 1577, 1512, 1435,
˜
2
2
1389, 1280, 1247, 1204, 1157, 1059, 1041 cm–1
.
1H NMR
5-(3,5-Dimethoxybenzyl)-7-methoxy-2,2-dimethyl-4H-benzo[d]-
[1,3]dioxin-4-one (3g): White solid, 93%. Rf = 0.53 (hexanes/Et2O,
(400 MHz, CDCl3, 25 °C): δ = 7.12 (d, J = 8.6 Hz, 2 H, 2 Ar-H),
6.82 (d, J = 8.7 Hz, 2 H, 2 Ar-H), 6.35 (d, J = 2.4 Hz, 1 H, Ar-H),
6.30 (d, J = 2.5 Hz, 1 H, Ar-H), 4.41 (s, 2 H, Ar-CH2-ArЈ), 3.78
1:1). M.p. 100–102 °C (CH Cl ). IR: ν = 1725, 1608, 1577, 1459,
˜
2
2
1430, 1328, 1280, 1203, 1155, 1059 cm–1 1H NMR (400 MHz,
.
(s, 3 H, OMe), 3.77 (s, 3 H, OMe), 1.67 [s, 6 H, C(CH3)2] ppm. 13
C
CDCl3, 25 °C): δ = 6.38 (d, J = 2.4 Hz, 1 H, Ar-H), 6.36 (d, J =
2.2 Hz, 2 H, 2 Ar-H), 6.32–6.30 (m, 2 H, 2 Ar-H), 4.41 (s, 2 H, Ar-
NMR (100 MHz, CDCl3, 25 °C): δ = 164.8, 160.2, 159.2, 158.0,
148.6, 132.1 (2 C), 130.2, 113.8 (2 C), 112.8, 104.9, 104.8, 99.3, CH2-ArЈ), 3.77 (s, 3 H, OMe), 3.75 (s, 6 H, 2 OMe), 1.68 [s, 6 H,
55.5, 55.2, 38.8, 25.6 (2 C) ppm. HR-MS (ESI): calcd. for C19H21O5
[M + H]+ 329.1389; found 329.1404. C19H20O5 (328.36): calcd. C
69.50, H 6.14; found C 69.48, H 6.23.
C(CH3)2] ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 164.8,
160.7 (2 C), 160.2, 159.1, 147.4, 142.4, 113.0, 107.3 (2 C), 104.9,
104.8, 99.4, 98.1, 55.5, 55.2 (2 C), 39.7, 25.6 (2 C) ppm. HR-MS
(ESI): calcd. for C20H23O6 [M + H]+ 359.1495; found 359.1513.
C20H22O6 (358.39): calcd. C 67.03, H 6.19; found C 66.93, H 6.21.
7-Methoxy-5-(3-methoxybenzyl)-2,2-dimethyl-4H-benzo[d][1,3]di-
oxin-4-one (3c): Colourless oil, 94%. Rf = 0.24 (hexanes/Et2O, 3:1).
IR: ν = 1723, 1609, 1576, 1488, 1433, 1389, 1329, 1277, 1261, 1203, General Procedure for the Synthesis of Methyl 6-Benzyl-2-hydroxy-
˜
1
1155, 1056 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 7.19 (t,
4-methoxybenzoates 9a–g from 5-Benzyl-7-methoxy-2,2-dimethyl-
J = 7.8 Hz, 1 H, Ar-H), 6.80–6.73 (m, 3 H, Ar-H), 6.38 (d, J = 4H-benzo[d][1,3]-dioxin-4-ones 3a–g: K2CO3 (829 mg, 6.00 mmol,
2.5 Hz, 1 H, Ar-H), 6.32 (d, J = 2.5 Hz, 1 H, Ar-H), 4.46 (s, 2 H,
Ar-CH2-ArЈ), 3.77 (s, 6 H, 2 OMe), 1.68 [s, 6 H, C(CH3)2] ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 164.8, 160.2, 159.6, 159.2,
3.0 equiv.) was added with stirring to 3a–g (2.00 mmol, 1.0 equiv.)
in dry MeOH (20 mL) at 20 °C. After 18 h, the solvent was evapo-
rated, and Et2O (60 mL) and HCl (1 m; 40 mL) were added to the
147.7, 141.6, 129.3, 121.6, 114.9, 113.0, 111.5, 104.9 (2 C), 99.4, resultant solid. The phases were separated, and the aqueous layer
55.5, 55.1, 39.6, 25.6 (2 C) ppm. HR-MS (ESI): calcd. for C19H21O5
[M + H]+ 329.1389; found 329.1377. C19H20O5 (328.36): calcd. C
69.50, H 6.14; found C 69.41, H 6.05.
was further extracted with Et2O (3ϫ 50 mL). The combined or-
ganic extracts were dried (MgSO4) and the volatiles rotary-evapo-
rated to obtain 9a–g in quantitative yields.
7-Methoxy-5-(2-methoxybenzyl)-2,2-dimethyl-4H-benzo[d][1,3]di-
oxin-4-one (3d): White solid, 91%. Rf = 0.71 (hexanes/Et2O, 1:1).
5-[4-(Benzyloxy)-3-methylbenzyl]-7-methoxy-2,2-dimethyl-4H-
benzo[d][1,3]dioxin-4-one (9a): White solid. Rf = 0.61 (hexanes/
M.p. 118–120 °C (CH Cl ). IR: ν = 1723, 1610, 1576, 1493, 1434, Et O, 3:1). M.p. 76–78 °C (CH Cl ). IR: ν = 1650, 1615, 1576,
˜
˜
2
2
2
2
2
1279, 1243, 1202, 1154, 1057, 1029, 754 cm–1. 1H NMR (400 MHz,
1503, 1434, 1327, 1252, 1204, 1158, 1131 cm–1 1H NMR
.
CDCl3, 25 °C): δ = 7.21 (ddd, J = 1.7, 7.9, 7.9 Hz, 1 H, Ar-H), (400 MHz, CDCl3, 25 °C): δ = 11.85 (s, 1 H, OH), 7.50 (d, J =
7.05 (dd, J = 1.4, 7.7 Hz, 1 H, Ar-H), 6.89–6.85 (m, 2 H, 2 Ar-H), 7.3 Hz, 2 H, 2 Ar-H), 7.43 (pt, J = 7.3 Hz, 2 H, 2 Ar-H), 7.36 (t,
6.30–6.29 (m, 2 H, 2 Ar-H), 4.48 (s, 2 H, Ar-CH2-ArЈ), 3.79 (s, 3 J = 7.2 Hz, 1 H, Ar-H), 6.96 (d, J = 1.7 Hz, 1 H, Ar-H), 6.90 (dd,
H, OMe), 3.73 (s, 3 H, OMe), 1.71 [s, 6 H, C(CH3)2] ppm. 13C
J = 2.0, 8.3 Hz, 1 H, Ar-H), 6.84 (d, J = 8.3 Hz, 1 H, Ar-H), 6.45
1322
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1318–1326

Macrosporin and Related 9,10-Anthraquinones
(d, J = 2.6 Hz, 1 H, Ar-H), 6.33 (d, J = 2.6 Hz, 1 H, Ar-H), 5.09
+ H]+ 333.1338; found 333.1321. C18H20O6 (332.35): calcd. C
(s, 2 H, Ph-CH2-OAr), 4.23 (s, 2 H, Ar-CH2-ArЈ), 3.84 (s, 3 H, 65.05, H 6.07; found C 65.05, H 6.12.
OMe), 3.82 (s, 3 H, OMe), 2.32 (s, 3 H, H, Ar-CH3) ppm. 13C
Methyl 2-(2,5-Dimethoxybenzyl)-6-hydroxy-4-methoxybenzoate
NMR (100 MHz, CDCl3, 25 °C): δ = 171.6, 165.7, 163.9, 155.0,
145.5, 137.5, 132.6, 130.9, 128.3 (2 C), 127.6, 127.0 (2 C), 126.7,
126.4, 111.9, 111.3, 104.9, 98.9, 69.8, 55.1, 51.6, 41.1, 16.3 ppm.
HR-MS (ESI): calcd. for C24H25O5 [M + H]+ 393.1702; found
393.1708. C24H24O5 (392.44): calcd. C 73.45, H 6.16; found C
73.36, H 6.18.
(9f): White solid. Rf = 0.34 (hexanes/Et2O, 3:1). M.p. 72–74 °C
(CH Cl ). IR: ν = 1651, 1615, 1578, 1499, 1434, 1327, 1253, 1216,
˜
2
2
1
1158, 1113, 1048, 1027 cm–1. H NMR (400 MHz, CDCl3, 25 °C):
δ = 11.76 (s, 1 H, OH), 6.80 (d, J = 8.8 Hz, 1 H, Ar-H), 6.69 (dd,
J = 3.1, 8.8 Hz, 1 H, Ar-H), 6.41 (d, J = 3.0 Hz, 1 H, Ar-H), 6.37
(d, J = 2.6 Hz, 1 H, Ar-H), 6.19 (d, J = 2.6 Hz, 1 H, Ar-H), 4.20
(s, 2 H, Ar-CH2-ArЈ), 3.79 (s, 3 H, OMe), 3.77 (s, 3 H, OMe), 3.74
(s, 3 H, OMe), 3.68 (s, 3 H, OMe) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 171.8, 165.7, 164.0, 153.6, 151.4, 144.8, 130.7,
116.2, 111.6, 110.8, 110.7, 105.2, 99.0, 55.9, 55.6, 55.2, 51.7,
36.1 ppm. HR-MS (ESI): calcd. for C18H21O6 [M + H]+ 333.1338;
found 333.1327. C18H20O6 (332.35): calcd. C 65.05, H 6.07; found
C 64.96, H 6.11.
Methyl 2-Hydroxy-4-methoxy-6-(4-methoxybenzyl)benzoate (9b):
White solid. Rf = 0.45 (hexanes/Et2O, 3:1). M.p. 48–50 °C
(CH Cl ). IR: ν = 1653, 1615, 1577, 1511, 1435, 1329, 1303, 1250,
˜
2
2
1
1219, 1204, 1158, 1046 cm–1. H NMR (400 MHz, CDCl3, 25 °C):
δ = 11.78 (s, 1 H, OH), 7.00 (d, J = 8.3 Hz, 2 H, 2 Ar-H), 6.82 (d,
J = 8.4 Hz, 2 H, 2 Ar-H), 6.40 (d, J = 2.1 Hz, 1 H, Ar-H), 6.27 (d,
J = 1.9 Hz, 1 H, Ar-H), 4.20 (s, 2 H, Ar-CH2-ArЈ), 3.79 (s, 3 H,
OMe), 3.78 (s, 3 H, OMe), 3.77 (s, 3 H, OMe) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 171.6, 165.7, 163.9, 157.7, 145.3,
132.7 129.2 (2 C), 113.6 (2 C), 111.8, 104.8, 99.0, 55.1, 55.0, 51.6,
41.1 ppm. HR-MS (ESI): calcd. for C17H19O5 [M + H]+ 303.1232;
found 303.1236. C17H18O5 (302.32): calcd. C 67.54, H 6.00; found
C 67.39, H 6.00.
Methyl 2-(3,5-Dimethoxybenzyl)-6-hydroxy-4-methoxybenzoate
(9g): White solid. Rf = 0.41 (hexanes/Et2O, 3:1). M.p. 72–74 °C
(CH Cl ). IR: ν = 1650, 1606, 1594, 1430, 1327, 1252, 1203, 1156,
˜
2
2
1
1066, 830 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 11.75 (s,
1 H, OH), 6.39 (d, J = 2.6 Hz, 1 H, Ar-H), 6.30 (t, J = 2.2 Hz, 1
H, Ar-H), 6.28 (d, J = 2.6 Hz, 1 H, Ar-H), 6.24 (d, J = 2.1 Hz, 2
H, 2 Ar-H), 4.18 (s, 2 H, Ar-CH2-ArЈ), 3.78 (s, 6 H, 2 OMe), 3.74
(s, 6 H, 2 OMe) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
171.5, 165.7, 163.9, 160.6 (2 C), 144.3, 143.2, 112.1, 106.6 (2 C),
104.9, 99.2, 97.5, 55.2, 55.1 (2 C), 51.6, 42.2 ppm. HR-MS (ESI):
calcd. for C18H21O6 [M + H]+ 333.1338; found 333.1335. C18H20O6
(332.35): calcd. C 65.05, H 6.07; found C 64.96, H 6.02.
Methyl 2-Hydroxy-4-methoxy-6-(3-methoxybenzyl)benzoate (9c):
White solid. Rf = 0.65 (hexanes/Et2O, 3:1). M.p. 48–52 °C
(CH Cl ). IR: ν = 1654, 1611, 1578, 1489, 1436, 1329, 1259, 1203,
˜
2
2
1
1159, 1048, 957, 775 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ
= 11.79 (s, 1 H, OH), 7.19 (t, J = 7.9 Hz, 1 H, Ar-H), 6.73 (dd, J
= 2.3, 8.1 Hz, 1 H, Ar-H), 6.69 (d, J = 7.8 Hz, 1 H, Ar-H), 6.64
(mc, 1 H, Ar-H), 6.41 (d, J = 2.6 Hz, 1 H, Ar-H), 6.30 (d, J =
2.6 Hz, 1 H, Ar-H), 4.24 (s, 2 H, Ar-CH2-ArЈ), 3.78 (s, 3 H, OMe),
3.77 (s, 3 H, OMe), 3.76 (s, 3 H, OMe) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 171.5, 165.7, 163.9, 159.5, 144.4, 142.4, 129.0,
120.7, 114.3 112.1, 110.7, 104.9, 99.1, 55.1, 54.9, 51.5, 42.0 ppm.
HR-MS (ESI): calcd. for C17H19O5 [M + H]+ 303.1232; found
303.1231. C17H18O5 (302.32): calcd. C 67.54, H 6.00; found C
67.62, H 6.01.
General Procedure for the Synthesis of 1-Hydroxy-3-methoxyan-
thracen-9(10H)-ones 10b–h from Methyl 6-Benzyl-2-hydroxy-4-
methoxybenzoates 9b–g: 9b–g (1.00 mmol) was dissolved in polyp-
hosphoric acid (PPA, 3.5 mL) and heated with stirring to 65 °C for
14 h. After cooling to 20 °C, iced water (35 mL) was added care-
fully. The aqueous layer was extracted with CH2Cl2 (3ϫ 50 mL),
and the combined organic layers were dried (Na2SO4) and the vola-
tiles rotary-evaporated. The residue was chromatographed (hex-
anes/CH2Cl2, 3:1 Ǟ 1:1 Ǟ CH2Cl2) to provide 10b–h.
Methyl 2-Hydroxy-4-methoxy-6-(2-methoxybenzyl)benzoate (9d):
White solid. Rf = 0.60 (hexanes/Et2O, 3:1). M.p. 76–78 °C
1-Hydroxy-3,7-dimethoxyanthracen-9(10H)-one (10b): Yellow solid,
(CH Cl ). IR: ν = 1649, 1614, 1575, 1433, 1325, 1241, 1222, 1202,
˜
2
2
45%. R = 0.68 (CH Cl ). M.p. 136–138 °C (CH Cl ). IR: ν = 1599,
˜
f 2 2 2 2
1155, 1047, 752 cm–1 1H NMR (400 MHz, CDCl3, 25 °C): δ =
.
1578, 1500, 1357, 1322, 1298, 1280, 1229, 1204, 1147 cm–1 1H
.
11.76 (s, 1 H, OH), 7.19 (ddd, J = 3.2, 5.9, 8.4 Hz, 1 H, Ar-H),
6.88 (d, J = 8.0 Hz, 1 H, Ar-H), 6.84–6.82 (m, 2 H, 2 Ar-H), 6.38
(d, J = 2.6 Hz, 1 H, Ar-H), 6.18 (d, J = 2.7 Hz, 1 H, Ar-H), 4.23
(s, 2 H, Ar-CH2-ArЈ), 3.84 (s, 3 H, OMe), 3.77 (s, 3 H, OMe), 3.74
(s, 3 H, OMe) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
171.9, 165.6, 164.0, 157.0, 145.1, 129.3 (2 C), 127.2, 120.5, 111.5,
110.0, 105.3, 99.0, 55.3, 55.2, 51.6, 35.9 ppm. HR-MS (ESI): calcd.
for C17H19O5 [M + H]+ 303.1232; found 303.1244. C17H18O5
(302.32): calcd. C 67.54, H 6.00; found C 67.66, H 5.99.
NMR (400 MHz, CDCl3, 25 °C): δ = 13.37 (s, 1 H, OH), 7.74 (d,
J = 2.8 Hz, 1 H, Ar-H), 7.29 (d, J = 8.5 Hz, 1 H, Ar-H), 7.15 (dd,
J = 2.8, 8.5 Hz, 1 H, Ar-H), 6.44 (mc, 1 H, Ar-H), 6.40 (d, J =
2.4 Hz, 1 H, Ar-H), 4.20 (s, 2 H, Ar-CH2-ArЈ), 3.90 (s, 3 H, OMe),
3.85 (s, 3 H, OMe) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
187.8, 165.7, 165.3, 158.6, 144.0, 132.8, 132.1, 129.3, 121.8, 110.9,
108.4, 105.9, 99.2, 55.5, 55.4, 32.0 ppm. HR-MS (ESI): calcd. for
C16H13O4 [M – H]+ 269.0814; found 269.0819.
1-Hydroxy-3,6-dimethoxyanthracen-9(10H)-one (10c): Yellow solid,
Methyl 2-(3,4-Dimethoxybenzyl)-6-hydroxy-4-methoxybenzoate 50% (isolated along with 11% of 10h and separated from this com-
(9e): White solid. Rf = 0.24 (hexanes/Et2O, 3:1). M.p. 83–85 °C pound by chromatography). Rf = 0.65 (CH2Cl2). M.p. 158–160 °C
(CH Cl ). IR: ν = 1650, 1615, 1576, 1513, 1435, 1328, 1252, 1220, (CH Cl ). IR: ν = 1598, 1500, 1364, 1303, 1250, 1155, 1022, 818,
˜
˜
2
2
2
2
1203, 1158, 1141, 1028 cm–1. H NMR (400 MHz, CDCl3, 25 °C): 673 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 13.52 (s, 1 H,
δ = 11.71 (s, 1 H, OH), 6.74 (d, J = 8.2 Hz, 1 H, Ar-H), 6.61 (d, J OH), 8.21 (d, J = 8.8 Hz, 1 H, Ar-H), 6.94 (dd, J = 2.5, 8.8 Hz, 1
= 1.9 Hz, 1 H, Ar-H), 6.56 (dd, J = 1.9, 8.2 Hz, 1 H, Ar-H), 6.35 H, Ar-H), 6.80 (d, J = 2.4 Hz, 1 H, Ar-H), 6.39 (d, J = 2.2 Hz, 1
1
1
(d, J = 2.6 Hz, 1 H, Ar-H), 6.21 (d, J = 2.5 Hz, 1 H, Ar-H), 4.16
(s, 2 H, Ar-CH2-ArЈ), (s, 2 H, Ar-CH2-ArЈ), 3.80 (s, 3 H, OMe),
3.78 (s, 3 H, OMe), 3.76 (s, 3 H, OMe), 3.73 (s, 3 H, OMe) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 171.4, 165.5, 163.8, 148.6,
147.0, 145.0, 133.1, 120.3, 111.8, 111.6, 111.0, 104.7, 98.9, 55.62,
55.59, 55.0, 51.5, 41.3 ppm. HR-MS (ESI): calcd. for C18H21O6 [M
H, Ar-H), 6.37 (d, J = 2.4 Hz, 1 H, Ar-H), 4.20 (s, 2 H, Ar-CH2-
ArЈ), 3.88 (s, 3 H, OMe), 3.84 (s, 3 H, OMe) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 187.2, 165.6, 165.0, 163.4, 143.2,
142.7, 129.2, 124.6, 113.9, 111.8, 110.7, 105.8, 99.2, 55.5, 55.4,
32.9 ppm. HR-MS (ESI): calcd. for C16H15O4 [M + H]+ 271.0970;
found 271.0984.
Eur. J. Org. Chem. 2013, 1318–1326
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1323

J. Cordes, A. G. M. Barrett
FULL PAPER
1-Hydroxy-3,5-dimethoxyanthracen-9(10H)-one (10d): Yellow solid,
vents were evaporated. The resultant solids were chromatographed
38%. R = 0.54 (CH Cl ). M.p. 158–162 °C (CH Cl ). IR: ν = 1579,
(CHCl3/hexanes, 1:1 Ǟ 3:1 Ǟ CHCl3/EtOH, 99:1) to render 2b–h.
˜
f
2
2
2
2
1315, 1285, 1154, 1085, 955, 820, 792, 709 cm–1 1H NMR
.
1-Hydroxy-3,7-dimethoxyanthracene-9,10-dione (2b): Yellow solid,
80%. Rf = 0.80 (CHCl3/EtOH, 99:1). M.p. 206–208 °C (CH2Cl2).
(400 MHz, CDCl3, 25 °C): δ = 13.40 (s, 1 H, OH), 7.90 (d, J =
8.4 Hz, 1 H, Ar-H), 7.40 (pt, J = 8.0 Hz, 1 H, Ar-H), 7.08 (dd, J
= 2.8, 8.5 Hz, 1 H, Ar-H), 6.49 (mc, 1 H, Ar-H), 6.40 (d, J =
2.4 Hz, 1 H, Ar-H), 4.12 (s, 2 H, Ar-CH2-ArЈ), 3.93 (s, 3 H, OMe),
3.86 (s, 3 H, OMe) ppm. 13C NMR (100 MHz, CDCl3): δ = 188.1,
165.6, 165.4, 156.2, 143.8, 132.0, 129.3, 127.3, 118.5, 113.5, 110.9,
106.2, 99.2, 55.6, 55.5, 27.7 ppm. HR-MS (ESI): calcd. for
C16H15O4 [M + H]+ 271.0970; found 271.0976.
IR: ν = 1588, 1571, 1337, 1284, 1214, 1101, 961, 837, 801, 702 cm–1.
˜
1H NMR (400 MHz, CDCl3, 25 °C): δ = 12.83 (s, 1 H, OH), 8.22
(d, J = 8.7 Hz, 1 H, Ar-H), 7.72 (d, J = 2.6 Hz, 1 H, Ar-H), 7.37
(d, J = 2.5 Hz, 1 H, Ar-H), 7.24 (dd, J = 2.7, 8.7 Hz, 1 H, Ar-H),
6.68 (d, J = 2.5 Hz, 1 H, Ar-H), 3.99 (s, 3 H, OMe), 3.94 (s, 3 H,
OMe) ppm; the 1H NMR signal for the OH proton matches the
value reported in the literature.[19] 13C NMR (125 MHz, CDCl3,
50 °C): δ = 186.8, 181.4, 166.6, 165.5, 164.7, 135.8, 135.5, 130.0,
127.3, 120.8, 111.1, 110.0, 107.7, 106.3, 56.0, 55.9 ppm. HR-MS
(EI): calcd. for C16H12O5 [M]+ 284.0685; found 284.0669.
1-Hydroxy-3,6,7-trimethoxyanthracen-9(10H)-one (10e): Yellow so-
lid, 63 %. Rf = 0.60 (CHCl3/EtOH, 99:1). M.p. 196–200 °C
(CH Cl ). IR: ν = 1628, 1594, 1579, 1419, 1380, 1299, 1272, 1224,
˜
2
2
1201, 1152, 1109, 820 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ
= 13.48 (s, 1 H, OH), 7.72 (s, 1 H, Ar-H), 6.80 (s, 1 H, Ar-H),
6.44–6.43 (m, 1 H, Ar-H), 6.41 (d, J = 2.3 Hz, 1 H, Ar-H), 4.21 (s,
2 H, Ar-CH2-ArЈ), 3.98 (s, 3 H, OMe), 3.97 (s, 3 H, OMe), 3.86 (s,
3 H, OMe) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 187.2,
165.4, 164.9, 153.6, 148.5, 143.5, 135.1, 124.4, 110.6, 109.4, 107.8,
105.9, 99.2, 56.1, 56.0, 55.5, 32.4 ppm. HR-MS (ESI): calcd. for
C17H17O5 [M + H]+ 301.1076; found 301.1073.
1-Hydroxy-3,6-dimethoxyanthracene-9,10-dione (2c): Yellow solid,
87%. Rf = 0.78 (CHCl3/EtOH, 99:1). M.p. 198–200 °C (CH2Cl2).
IR: ν = 1626, 1591, 1448, 1380, 1283, 1217, 1152, 979, 830,
˜
1
753 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 13.00 (s, 1 H,
OH), 8.23 (d, J = 8.7 Hz, 1 H, Ar-H), 7.70 (d, J = 2.7 Hz, 1 H,
Ar-H), 7.36 (d, J = 2.6 Hz, 1 H, Ar-H), 7.26 (dd, J = 2.8, 8.6 Hz,
1 H, Ar-H), 6.70 (d, J = 2.8 Hz, 1 H, Ar-H), 3.98 (s, 3 H, OMe),
3.93 (s, 3 H, OMe) ppm; the 1H NMR spectra match the data
reported in the literature.[20] 13C NMR (125 MHz, CDCl3, 45 °C):
δ = 186.2, 182.5, 166.0, 165.3, 164.5, 135.8, 135.3, 129.3, 127.0,
121.0, 110.7, 110.6, 107.6, 106.9, 56.0 (2 C) ppm. HR-MS (ESI):
calcd. for C16H13O5 [M + H]+ 285.0763; found 285.0762.
1-Hydroxy-3,5,8-trimethoxyanthracen-9(10H)-one (10f): Orange so-
lid, 60 %. Rf = 0.42 (CHCl3/EtOH, 99:1). M.p. 138–140 °C
(CH Cl ). IR: ν = 1627, 1581, 1500, 1480, 1430, 1299, 1270, 1249,
˜
2
2
1196, 1151, 1080, 972 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ
= 13.58 (s, 1 H, OH), 7.05 (d, J = 9.1 Hz, 1 H, Ar-H), 6.90 (d, J =
9.1 Hz, 1 H, Ar-H), 6.44–6.42 (m, 1 H, Ar-H), 6.38 (d, J = 2.4 Hz, 1
H, Ar-H), 4.12 (s, 2 H, Ar-CH2-ArЈ), 3.95 (s, 3 H, OMe), 3.88 (s,
3 H, OMe), 3.84 (s, 3 H, OMe) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 188.9, 165.4, 164.9, 155.1, 149.7, 142.5, 131.4, 120.8,
114.9, 111.9, 110.3, 105.2, 99.3, 56.5, 55.8, 55.4, 28.3 ppm. HR-MS
(ESI): calcd. for C17H17O5 [M + H]+ 301.1076; found 301.1075.
1-Hydroxy-3,5-dimethoxyanthracene-9,10-dione (2d): Yellow solid,
71%. Rf = 0.70 (CHCl3/EtOH, 99:1). M.p. 174–176 °C (CH2Cl2).
IR: ν = 1631, 1611, 1584, 1442, 1378, 1284, 1238, 1210, 1143,
˜
1
968 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 12.77 (s, 1 H,
OH), 7.97 (dd, J = 0.9, 7.5 Hz, 1 H, Ar-H), 7.73 (dd, J = 7.7,
8.4 Hz, 1 H, Ar-H), 7.34–7.32 (m, 2 H, 2 Ar-H), 6.66 (d, J = 2.5 Hz,
1 H, Ar-H), 4.05 (s, 3 H, OMe), 3.93 (s, 3 H, OMe) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 186.6, 181.7, 166.5, 164.9, 160.6,
136.6, 135.7, 135.2, 121.4, 119.3, 118.0, 110.3, 107.5, 105.6, 56.6,
56.0 ppm. HR-MS (ESI): calcd. for C16H13O5 [M + H]+ 285.0763;
found 285.0771.
1-Hydroxy-3,6,8-trimethoxyanthracen-9(10H)-one (10g): Orange so-
lid, 58%. R = 0.36 (CH Cl ). M.p. 150–152 °C (CH Cl ). IR: ν =
˜
f
2
2
2
2
1624, 1596, 1570, 1332, 1290, 1262, 1222, 1201, 1148, 1092 cm–1.
1H NMR (400 MHz, CDCl3, 25 °C): δ = 13.74 (s, 1 H, OH), 6.39
(d, J = 2.3 Hz, 1 H, Ar-H), 6.37 (d, J = 2.3 Hz, 1 H, Ar-H), 6.31
(d, J = 2.4 Hz, 1 H, Ar-H), 6.29–6.27 (m, 1 H, Ar-H), 4.15 (s, 2 H,
Ar-CH2-ArЈ), 3.93 (s, 3 H, OMe), 3.85 (s, 3 H, OMe), 3.79 (s, 3 H,
OMe) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 187.8, 165.3,
164.3, 164.0, 163.1, 145.5, 141.7, 114.2, 111.6, 104.6, 104.1, 99.3,
97.7, 56.0, 55.4, 55.3, 34.0 ppm. HR-MS (ESI): calcd. for C17H17O5
[M + H]+ 301.1076; found 301.1080.
1-Hydroxy-3,6,7-trimethoxyanthracene-9,10-dione (2e): Yellow so-
lid, 88 %. Rf = 0.78 (CHCl3/EtOH, 99:1). M.p. 226–228 °C
(CH Cl ). IR: ν = 1629, 1577, 14142, 1386, 1357, 1307, 1247, 1220,
˜
2
2
1
1104 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 12.81 (s, 1 H,
OH), 7.62 (s, 1 H, Ar-H), 7.61 (s, 1 H, Ar-H), 7.28 (d, J = 2.4 Hz,
1 H, Ar-H), 6.62 (d, J = 2.4 Hz, 1 H, Ar-H), 4.04 (s, 3 H, OMe),
4.03 (s, 3 H, OMe), 3.91 (s, 3 H, OMe) ppm. 13C NMR (100 MHz,
CDCl3): δ = 186.2, 181.6, 165.9, 165.0, 153.8, 153.7, 135.0, 128.4,
128.2, 110.5, 108.6 (2 C), 107.8, 106.1, 56.5 (2 C), 56.0 ppm. HR-
MS (ESI): calcd. for C17H15O6 [M + H]+ 315.0869; found 315.0873.
1-Hydroxy-3,8-dimethoxyanthracen-9(10H)-one (10h): Orange so-
lid, 11% (isolated along with 50% 10c and separated from this
compound by chromatography). Rf = 0.35 (CH2Cl2). M.p. 122–
124 °C (CH Cl ). IR: ν = 1623, 1594, 1572, 1498, 1430, 1383, 1294,
˜
1-Hydroxy-3,5,8-trimethoxyanthracene-9,10-dione (2f): Yellow so-
lid, 79 %. Rf = 0.45 (CHCl3/EtOH, 99:1). M.p. 210–215 °C
2
2
1261, 1205, 1164, 1146, 1082 cm–1. 1H NMR (400 MHz, CDCl3,
25 °C): δ = 13.55 (s, 1 H, OH), 7.47 (dd, J = 7.7, 8.4 Hz, 1 H, Ar-
H), 6.95 (dd, J = 0.8, 7.8 Hz, 1 H, Ar-H), 6.92 (d, J = 8.4 Hz, 1
H, Ar-H), 6.36 (s, 2 H, 2ϫ Ar-H), 4.25 (s, 2 H, Ar-CH2-ArЈ), 3.99
(s, 3 H, OMe), 3.82 (s, 3 H, OMe) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 188.7, 165.5, 164.8, 161.3, 143.3, 142.2, 134.0,
120.4, 120.3, 112.0, 110.0, 104.9, 99.3, 56.1, 55.4, 33.6 ppm. HR-
MS (ESI): calcd. for C16H15O4 [M + H]+ 271.0970; found 271.0971.
(CH Cl , decomp). IR: ν = 1623, 1442, 1331, 1290, 1226, 1201,
˜
2
2
1150, 979, 820 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 13.01
(s, 1 H, OH), 7.37 (d, J = 9.9 Hz, 1 H, Ar-H), 7.35 (d, J = 9.8 Hz,
1 H, Ar-H), 7.25 (d, J = 2.5 Hz, 1 H, Ar-H), 6.66 (d, J = 2.5 Hz,
1 H, Ar-H), 4.02 (s, 3 H, OMe), 4.00 (s, 3 H, OMe), 3.90 (s, 3 H,
OMe) ppm. 13C NMR (100 MHz, CDCl3): δ = 187.4, 182.6, 165.7,
164.6, 154.8, 154.6, 136.0, 122.8, 122.1, 120.7 (2 C), 111.2, 106.3,
105.9, 57.1, 57.0, 55.8 ppm. HR-MS (EI): calcd. for C17H14O6
[M]+ 314.0790; found 314.0809.
General Procedure for the Synthesis of 1-Hydroxy-3-methoxy-
anthracene-9,10-diones 2b–h from 1-Hydroxy-3-methoxyanthracen-
9(10H)-ones 10b–h: Water (2.0 mL) and cerium ammonium nitrate
1-Hydroxy-3,6,8-trimethoxyanthracene-9,10-dione (2g): Yellow so-
(CAN, 438 mg, 0.80 mmol, 4.0 equiv.) were added with stirring to lid, 74 %. Rf = 0.75 (CHCl3/EtOH, 99:1). M.p. 236–238 °C
10b–h (0.20 mmol) in THF (8.0 mL) at 20 °C. After 14 h, the sol- (CH Cl ). IR: ν = 1591, 1553, 1320, 1220, 1199, 1149, 1035, 946,
˜
2
2
1324
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1318–1326

Macrosporin and Related 9,10-Anthraquinones
878, 756 cm–1. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 13.38 (s, 1
H, OH), 7.47 (d, J = 2.3 Hz, 1 H, Ar-H), 7.30 (d, J = 2.7 Hz, 1 H,
Ar-H), 6.80 (d, J = 2.5 Hz, 1 H, Ar-H), 6.70 (d, J = 2.5 Hz, 1 H,
solution was purged with O2 for 15 min and then stirred under O2.
After 20 h, the solvents were evaporated, and the resultant solid
was chromatographed (hexanes/THF, 3:1) to yield 1 (18 mg,
Ar-H), 4.03 (s, 3 H, OMe), 3.99 (s, 3 H, OMe), 3.91 (s, 3 H, OMe) 0.06 mmol, 81%) as a yellow solid. Rf = 0.54 (hexanes/THF, 3:1).
1
ppm; the H NMR spectra match the data reported in the litera-
M.p. 300–302 °C (THF, decomp.; sublimation at 256–260 °C). IR:
ture.[21] 13C NMR (125 MHz, CDCl3, 25 °C): δ = 186.6, 182.8, ν = 3278, 2924, 1658, 1636, 1570, 1449, 1395, 1362, 1323, 1262,
165.2, 165.1, 165.0, 162.9, 137.5, 134.1, 115.2, 111.4, 107.5, 106.6,
˜
1214, 1163, 1101, 787, 625 cm–1. 1H NMR (400 MHz, [D8]THF,
104.9, 104.1, 56.6, 56.0, 55.9 ppm. HR-MS (ESI): calcd. for 25 °C): δ = 12.88 (s, 1 H, OH), 9.98 (s, 1 H, OH), 7.99 (s, 1 H, Ar-
C17H15O6 [M + H]+ 315.0869; found 315.0865.
H), 7.53 (s, 1 H, Ar-H), 7.27 (d, J = 2.5 Hz, 1 H, Ar-H), 6.71 (d,
J = 2.5 Hz, 1 H, Ar-H), 3.92 (s, 3 H, OMe), 2.32 (s, 3 H, Ar-CH3)
ppm. 13C NMR (100 MHz, [D8]THF, 25 °C): δ = 187.7, 181.0,
167.2, 166.2, 162.1, 136.4, 134.4, 132.8, 131.0, 126.7, 111.5, 111.4,
107.8, 105.9, 56.2, 16.3 ppm. HR-MS (CI): calcd. for C16H13O5 [M
+ H]+ 285.0763; found 285.0760. The spectra match the reported
data of the isolated natural product.[4a,6,9a,9b]
1-Hydroxy-3,8-dimethoxyanthracene-9,10-dione (2h): Yellow solid,
85%. Rf = 0.78 (CHCl3/EtOH, 99:1). M.p. 158–160 °C (CH2Cl2).
IR: ν = 1637, 1585, 1445, 1392, 1331, 1250, 1167, 978, 750 cm–1.
˜
1H NMR (400 MHz, CDCl3, 25 °C): δ = 13.23 (s, 1 H, OH), 7.95
(dd, J = 1.0, 7.6 Hz, 1 H, Ar-H), 7.72 (dd, J = 7.7, 8.4 Hz, 1 H,
Ar-H), 7.36 (d, J = 8.1 Hz, 1 H, Ar-H), 7.31 (d, J = 2.5 Hz, 1 H,
Ar-H), 6.71 (d, J = 2.6 Hz, 1 H, Ar-H), 4.07 (s, 3 H, OMe), 3.92
(s, 3 H, OMe) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
187.5, 182.7, 165.5, 165.3, 160.8, 135.7, 135.3, 134.2, 120.3, 120.2,
118.3, 111.7, 107.3, 106.5, 56.7, 55.9 ppm. HR-MS (ESI): calcd. for
C16H13O5 [M + H]+ 285.0763; found 285.0775.
Attempted Cyclization of Resorcylate 9d by Using Trimethylsilyl
Triflate
3-Methoxy-5-(2-methoxybenzyl)phenol (11): Trimethylsilyl triflate
(0.60 mL, 3.3 mmol, 10 equiv.) was added with stirring to 9d
(100 mg, 0.33 mmol) in CH2Cl2 (8.0 mL) at 20 °C. After 18 h,
CH2Cl2 (90 mL) and water (50 mL) were added and the phases
separated. The aqueous layer was further extracted with CH2Cl2
(4 ϫ 100 mL), and the combined organic layers were dried
(Na2SO4) and the volatiles rotary-evaporated. The resultant oil was
chromatographed on silica (hexanes/Et2O, 9:1 Ǟ 3:1) to give unre-
acted 9d (10 mg, 0.03 mmol, 10%) and benzylbenzene 11 (72 mg,
0.29 mmol, 89%) as a colorless oil. Rf = 0.20 (hexanes/Et2O, 3:1).
Synthesis of Macrosporin (1) from Resorcylate 9a
Methyl 2-Hydroxy-6-(4-hydroxy-3-methylbenzyl)-4-methoxybenzo-
ate (9i): Pd/C (10%, 35 mg) was added to 9a (352 mg, 0.90 mmol)
in EtOAc (18 mL) under argon, and the gas was changed to hydro-
gen. The mixture was stirred at 20 °C for 18 h, when the gas was
changed to nitrogen. Silica (2.0 g) was added, and the solvent was
evaporated. Chromatography of the resultant residue on silica (hex-
anes/Et2O, 1:1) gave 9i (257 mg, 0.85 mmol, 95%) as a white solid.
IR: ν = 1594, 1492, 1456, 1436, 1242, 1143, 1051, 1028, 752, 732,
˜
1
690 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 7.22 (ddd, J =
R = 0.20 (hexanes/Et O, 3:1). M.p. 84–86 °C (CH Cl ). IR: ν =
˜
f
2
2
2
1649, 1614, 1577, 1434, 1329, 1257, 1202, 1158, 1115, 1047 cm–1.
1H NMR (400 MHz, CDCl3, 25 °C): δ = 11.83 (s, 1 H, OH), 6.83
(d, J = 1.7 Hz, 1 H, Ar-H), 6.77 (dd, J = 1.9, 8.2 Hz, 1 H, Ar-H),
6.67 (d, J = 8.1 Hz, 1 H, Ar-H), 6.40 (d, J = 2.6 Hz, 1 H, Ar-H),
6.27 (d, J = 2.7 Hz, 1 H, Ar-H), 5.42 (s, 1 H, OH), 4.15 (s, 2 H,
Ar-CH2-ArЈ), 3.81 (s, 3 H, OMe), 3.78 (s, 3 H, OMe), 2.21 (s, 3 H,
OMe) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 171.7, 165.5,
163.9, 152.0, 145.6, 132.5, 131.0, 126.8, 123.6, 114.7, 111.9, 104.9,
98.9, 55.2, 51.7, 41.1, 15.7 ppm. HR-MS (EI): calcd. for C17H18O5
[M]+ 302.1154; found 302.1155. C17H18O5 (302.32): calcd. C 67.54,
H 6.00; found C 67.41, H 5.93.
1.7, 7.8, 7.8 Hz, 1 H, Ar-H), 7.09 (dd, J = 1.6, 7.3 Hz, 1 H, Ar-H),
6.91–6.85 (m, 2 H, 2 Ar-H), 6.39 (mc, 1 H, Ar-H), 6.27 (mc, 1 H,
Ar-H), 6.24 (t, J = 2.2 Hz, 1 H, Ar-H), 5.11 (s, 1 H, OH), 3.89 (s,
2 H, Ar-CH2-ArЈ), 3.82 (s, 3 H, OMe), 3.73 (s, 3 H, OMe) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 160.7, 157.2, 156.5, 143.8,
130.3, 129.1, 127.5, 120.5, 110.4, 108.4, 107.3, 98.9, 55.3, 55.2,
35.7 ppm. HR-MS (ESI): calcd. for C15H17O3 [M + H]+ 245.1172;
found 245.1166.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra for macrosporin (1),
anthraquinones 2b–h, resorcylates 3a–g, 8a–g, 9a–g and 9i,
anthrones 10b–i, and benzylbenzene 11.
1,7-Dihydroxy-3-methoxy-6-methylanthracen-9(10H)-one (10i): Tri-
methylsilyl triflate (0.60 mL, 3.3 mmol, 10 equiv.) was added with
stirring to 9i (100 mg, 0.33 mmol) in CH2Cl2 (8.0 mL) at 20 °C.
After 18 h, CH2Cl2 (90 mL) and water (50 mL) were added and
the phases separated. The aqueous layer was further extracted with
CH2Cl2 (4ϫ 100 mL), and the combined organic layers were dried
(Na2SO4) and the volatiles rotary-evaporated. The residue was
chromatographed on silica (hexanes/THF, 19:1 Ǟ 9:1 Ǟ 3:1) to
give 10i (68 mg, 0.25 mmol, 76%) as a pale-yellow solid. Rf = 0.30
Acknowledgments
We thank the European Research Council (ERC) for generous
grant support, GlaxoSmithKline for the Glaxo endowment and
P. R. Haycock and R. N. Sheppard for high-resolution NMR spec-
troscopy.
(hexanes/THF, 9:1). M.p. 230–234 °C (THF, decomp.). IR: ν =
˜
3415, 1624, 1596, 1572, 1463, 1420, 1371, 1355, 1290, 1098, 1056,
[1] R. H. Thomson in Naturally Occurring Quinones IV, Blackie
Academic & Professional, London, 1997, pp. 309–483.
[2] For some recent examples, see: a) Q. Huang, H.-M. Shen,
M. C. M. Chung, C. N. Ong, Med. Res. Rev. 2007, 27, 609–
630; b) M. R. Dhananjeyan, Y. P. Milev, M. A. Kron, M. G.
Nair, J. Med. Chem. 2005, 48, 2822–2830; c) M. Pickhardt, Z.
Gazova, M. von Bergen, I. Khlistunova, Y. Wang, A. Hascher,
E.-M. Mandelkow, J. Biernat, E. Mandelkow, J. Biol. Chem.
2005, 280, 3628–3635.
[3] For recent reviews on natural products from endophytic fungi,
see: a) A. H. Aly, A. Debbab, P. Proksch, Appl. Microbiol. Bio-
technol. 2011, 90, 1829–1845; b) A. H. Aly, A. Debbab, J. Kjer,
P. Proksch, Fungal Diversity 2010, 41, 1–16.
1
954, 8560 cm–1. H NMR (400 MHz, [D8]THF, 25 °C): δ = 13.44
(s, 1 H, OH), 8.65 (s, 1 H, Ar-H), 7.54 (s, 1 H, Ar-H), 7.16 (s, 1 H,
OH), 6.46–6.49 (m, 1 H, Ar-H), 6.36 (d, J = 2.4 Hz, 1 H, Ar-H),
4.17 (s, 2 H, Ar-CH2-ArЈ), 3.83 (s, 3 H, OMe), 2.27 (s, 3 H, Ar-
CH3) ppm. 13C NMR (125 MHz, [D8]THF, 25 °C): δ = 188.5,
166.6, 166.1, 155.6, 145.1, 132.7, 132.4, 130.8 (2 C), 111.4, 110.9,
106.1, 99.6, 55.6, 32.2, 16.4 ppm. HR-MS (CI): calcd. for C16H15O4
[M + H]+ 271.0970; found 271.0963.
1,7-Dihydroxy-3-methoxy-6-methylanthracene-9,10-dione (Macro-
sporin, 1): CuBr2 (17 mg, 0.08 mmol, 1.0 equiv.) was added with
stirring to 10i (21 mg, 0.08 mmol) in THF (1.5 mL) at 20 °C. The
Eur. J. Org. Chem. 2013, 1318–1326
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1325

J. Cordes, A. G. M. Barrett
FULL PAPER
[4] a) R. Suemitsu, Y. Matsui, M. Hiura, Bull. Agric. Chem. Soc.
Jpn. 1957, 21, 1–4; b) R. Suemitsu, M. Hiura, Bull. Agric.
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[5] R. Suemitsu, M. Nakajima, M. Hiura, Bull. Agric. Chem. Soc.
Jpn. 1959, 23, 547–551.
[11]
[12]
C. Brisson, P. Brassard, J. Org. Chem. 1981, 46, 1810–1814.
For reviews on strategies for the synthesis of 9,10-anthra-
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367–506; b) P. T. Gallagher, Contemp. Org. Synth. 1996, 3, 433–
446.
a) J. Cordes, F. Calo, K. Anderson, T. Pfaffeneder, S. Laclef,
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Received: November 6, 2012
Published Online: January 21, 2013
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