Total synthesis of rac-γ-indomycinone by Baker-Venkataraman rearrangement

Article abstract of DOI:10.1002/ejoc.200700015

The total synthesis of racemic γ-indomycinone (rac-3) was achieved by Baker-Venkataraman rearrangement of ester 11 to the diketone 12, acid-catalyzed cyclization to the anthrapyranone 13, followed by methyl ether cleavage and acetylation to 16, selective bromination of the branched side chain with simultaneous S_N1-type hydroxy substitution to 23 and transesterification to rac-3. The corresponding γ-indomycin-one 11-methyl ether (rac-20) was prepared in a similar reaction sequence. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700015

FULL PAPER
DOI: 10.1002/ejoc.200700015
Total Synthesis of rac-γ-Indomycinone by Baker–Venkataraman
Rearrangement
Karsten Krohn,*[a] Hoan Trang Tran-Thien,[a] Jürgen Vitz,[a] and Anne Vidal[a]
Dedicated to Professor Burchard Franck on the occasion of his 80th birthday
Keywords: Total synthesis / Anthrapyranone antibiotics / γ-Indomycinone / Baker–Venkataraman rearrangement / Radical
bromination
The total synthesis of racemic γ-indomycinone (rac-3) was
achieved by Baker–Venkataraman rearrangement of ester 11
transesterification to rac-3. The corresponding γ-indomycin-
one 11-methyl ether (rac-20) was prepared in a similar reac-
to the diketone 12, acid-catalyzed cyclization to the anthra- tion sequence.
pyranone 13, followed by methyl ether cleavage and acety-
lation to 16, selective bromination of the branched side chain
with simultaneous SN1-type hydroxy substitution to 23 and
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
γ-Indomycinone[1] is a member of the large family of an-
thrapyran antibiotics which mostly occur as the C-glyco-
sides such as the pluramycines, hedamycines, riboflavines,
altromycines and indomycines.[2,3] These antibiotics found
renewed interest in structural biology[4] due to their selec-
tive binding to DNA and their specific alkylation of gua-
nine.[5,6] In addition to the C-glycosides, a number of agly-
cones with the anthra[b]pyran skeleton are also found in
nature. Some of these have a C-6 side chain at C-2 such as
β-indomycinone (1)[7] and δ-indomycinone (2)[7,8] or a C-4
side chain, exemplified by γ-indomycinone (3),[1] kidamyci-
none (4),[9] the antihepatitic antibiotic AH-1763 IIa (5),[10]
and the neuroprotective espicufolin (6)[11] (Figure 1). The
remarkable biological properties of some derivatives have
aroused great interest, which recently resulted in several
syntheses including those of premithramycinone,[12] espicu-
folin,[13,14] altromycinone and kidamycinone,[15] and AH-
1763 IIa.[16] The recent publication of the synthesis of ent-
γ-indomycinone by Tietze et al.[17] prompted us to disclose
our alternative synthesis of rac-3. In the syntheses published
to date, the construction of the appropriately substituted
skeleton and the attachment of the C-2 side chain have
found different solutions. Diels–Alder reactions[13,14,16,17] or
biomimetic-type dianion condensations[12,15] were mainly
used for the construction of the anthra[b]pyran skeleton.
Carbanion methodology, not possible at the anthraquinone
level, was often employed on naphthalene derivatives for
[a] Department of Chemistry, University of Paderborn,
Warburger Straβe 100, 33098 Paderborn, Germany
Fax: +49-5251603245
Figure 1. Representative anthrapyranone antibiotics with C-6 or C-
4 side chains.
E-mail: k.krohn@uni-paderborn.de
Eur. J. Org. Chem. 2007, 1905–1911
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1905

K. Krohn, H. T. Tran-Thien, J. Vitz, A. Vidal
FULL PAPER
the attachment of the side chains.[13–17] Alternatively, in our the cyclization of the open-chain β-diketone 12 to the an-
approach, we used an acyl transfer of the Baker–Venkatara- thra[b]pyran skeleton. Simple solution in trifluoroacetic
man-type for chain elongation to avoid the reduction and/ acid induced this transformation and the 2Ј-deoxy-γ-indo-
or oxidation steps connected with the organometallic reac- mycinone methyl ether 13 was isolated in 75% yield. At this
tions on the anthraquinone skeleton.[12,18]
point, we wanted to test the cleavage of the methyl ether at
C-11. Interestingly, using boron tribromide, the bromina-
tion product 15 (56%) was isolated in addition to the ex-
pected phenol 14 (34%). This side reaction has to be kept
Results and Discussion
The synthesis of rac-γ-indomycinone started from the in mind generally in the employment of boron tribromide in
known 2-acetyl-1-hydroxy derivative 7, prepared in a biomi- phenol methyl ether cleavage. Not unexpectedly, the methyl
metic-type dianion reaction during the synthesis of ak- ether cleavage using boron trichloride went without forma-
lanonic acid.[19] The first task was the decarboxylation of tion of any side products and the phenol 14 was isolated in
the ester group to obtain the methyl group at C-5 as present 86%. Acetylation of the phenol 14 afforded the acetate 16
in γ-indomycinone (3). To this end, the tert-butyl ester 7 in 95% yield, providing another molecule in addition to 13
was dissolved in trifluoroacetic acid to afford the acid 8 for subsequent bromination experiments (see below).
in 89% yield (Scheme 1). As communicated earlier,[18] the
A key feature of our synthesis was the exploitation of
decarboxylation of the acid 8 was particularly rapid in rig- selective brominations of the side chains of 13 to introduce
orously dried DMF solutions, and the decarboxylated the missing hydroxy groups. We expected that the tertiary
anthraquinone 9 was isolated in 79% yield after stirring for position of the branched side chain at C-2Ј would be at-
12 h at 40 °C. The poor nucleophilicity of the strongly che- tacked more rapidly than the C-5 methyl group. In fact,
lated phenolic hydroxy group at C-1 in 9 in the esterification this assumption turned out to be true, in agreement with
with the racemic α-branched acyl chloride 10[20] was over- theory.[22] We tried two different conditions for the bromi-
come by addition of 4-(dimethylamino)pyridine (DMAP)[21] nation reactions. In the first experiment, rigorously dried
to afford the ester 11 in 95% yield. The key step was the tetrachloromethane and a sixfold excess of bromine was
subsequent Baker–Venkataraman rearrangement induced used in the light induced bromination. After consumption
by heating of the ester 11 under reflux with lithium hydride of the starting material, an approximate 3.3:2.3:1 ratio (45,
to afford the anthraquinone 12 with a branched β-diketo 32, and 13% yield, respectively) of the monobromide 17,
side chain in 97% yield. The NMR spectra clearly showed the dibromide 18, and the tribromide 19 was isolated
that the β-diketone 12 existed in a tautomeric equilibrium (Scheme 2). In the second series of experiments, moist tetra-
with the enol form in CDCl3 solution. The next task was chloromethane was used as a solvent, only a twofold excess
Scheme 1. Synthesis of the basic anthrapyranone skeletons 13–16 by Baker–Venkataraman rearrangement of 12.
1906
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Eur. J. Org. Chem. 2007, 1905–1911

Total Synthesis of rac-γ-Indomycinone
FULL PAPER
Scheme 2. Synthesis of rac-20 and the natural product rac-3 by transesterification in basic methanol of 21 and 23, respectively.
of bromine was used, and the irradiation time was limited stage (Scheme 1). The bromination reaction of 16 in moist
to ca. 90% of starting material conversion. Under these tetrachloromethane was run with a reduced excess of bro-
conditions, in addition to the expected monobromination mine (2 equiv.) and incomplete conversion of the starting
product 17, the γ-indomycinone methyl ether (20) was material (TLC monitoring) to yield the monobromide 24
simultaneously formed (38%). A similar in situ bromine- (20%), the alcohol 23 (24%) and starting material 16 at
hydroxy group exchange was observed in the dealkyl mum- 50% conversion. As described for 20, the transesterification
baistatin synthesis.[23] In fact, the tertiary bromide proved in basic methanol afforded the racemic γ-indomycinone
to be easily exchanged by SN1-type substitution in moist (rac-3) quantitatively. The product was identical except for
solvents. For instance, the formation of the corresponding chiroptical properties with an authentic sample of the natu-
hydroxy compounds could be observed by TLC analysis of ral product.[24]
the CDCl3 solution from NMR measurement. An alterna-
tive exchange of the bromine atom in the monobromide 17
was realized by the two step procedure via the acetate 21,
formed by treating bromide 17 with silver acetate in DMF
(85%), followed by transesterification with basic methanol
Experimental Section
General: For general methods and instrumentation see ref.[25]
to yield γ-indomycinone methyl ether (15) quanitatively. It 2-(3-Acetyl-4-hydroxy-5-methoxy-9,10-dioxo-9,10-dihydro-
anthracen-2-yl)acetic Acid (8): Trifluoroacetic acid (3 mL) was
added to a solution of the tert-butyl ester 7[19] (520 mg, 1.27 mmol)
in dry CH2Cl2 (30 mL), followed by stirring under reflux for 1 h.
Dichloromethane (15 mL) was then added and the solvent was re-
moved under reduced pressure. The procedure was repeated twice
to remove traces of trifluoroacetic acid. The precipitate was puri-
fied by recrystallization from ethanol to afford the acid 8 as light
yellow crystals (400 mg 89%, m.p. 237 °C). 1H NMR (200 MHz,
CDCl3): δ = 2.56 (s, 3 H, CH3), 3.71 (s, 2 H, CH2), 3.97 (s, 3 H,
OCH3), 7.34 (dd, J6Ј,7Ј = 8.6 Hz, J6Ј,8Ј = 1.0 Hz, 1 H, 6Ј-H), 7.54
is worth mentioning that the dibromide 18 may serve to
prepare a 1Ј-hydroxy analogue of the neuroprotective espic-
ufolin (6).
Having established a route to the rac-γ-indomycinone
methyl ether (20), the final task was the methyl ether cleav-
age in 20 to yield the natural product rac-3. However, elimi-
nation of the hydroxy group in 20 might be possible using
either boron tribromide or boron trichloride for this reac-
tion. We therefore decided to use the acetate 16, produced
by cleavage of the methyl ether and acetylation at an earlier (s, 1 H, 1Ј-H), 7.70 (dd, J6Ј,7Ј = 8.6 Hz, J7Ј,8Ј = 7.8 Hz, 1 H, 7Ј-H),
Eur. J. Org. Chem. 2007, 1905–1911
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1907

K. Krohn, H. T. Tran-Thien, J. Vitz, A. Vidal
FULL PAPER
7.84 (dd, J7Ј,8Ј = 7.8 Hz, J6Ј,8Ј = 1.0 Hz, 1 H, 8Ј-H) ppm. 13C NMR tals (266 mg, 95%, m.p. 158 °C). 1H NMR (200 MHz, CDCl3): δ
(50 MHz, CDCl3): δ = 35.9 (q, CH3), 43.1 (t, CH2), 60.9 (q, OCH3), = 1.10 (t, J3Ј,4Ј = 7.5 Hz, 3 H, 4Ј-H), 1.40 (d, J2Ј,5Ј = 7.0 Hz, 3 H,
120.7 (s, C-4aЈ), 123.1 (d, C-6Ј), 123.1 (s, C-3Ј), 123.2 (s, C-10aЈ),
124.6 (d, C-1Ј), 124.7 (s, C-8aЈ), 125.5 (d, C-8Ј), 137.0 (s, C-9aЈ), COCH3), 2.54 (s, 3 H, CH3), 2.87 (m, 1 H, 2Ј-H), 4.00 (s, 3 H,
139.6 (s, C-2Ј), 140.8 (d, C-7Ј), 144.9 (s, C-5Ј), 165.4 (s, C-4Ј), 176.3 OCH3), 7.33 (dd, J6,7 = 8.4 Hz, J5,7 = 1.0 Hz, 1 H, 7-H), 7.70 (dd,
5Ј-H), 1.68 (m, 1 H, 3αЈ-H), 1.97 (m, 1 H, 3βЈ-H), 2.43 (s, 3 H,
(s, C-1), 186.6 (s, C-9Ј, C-10Ј), 208.6 (s, CO) ppm. IR (KBr): ν = J5,6 = 7.7 Hz, J6,7 = 8.4 Hz, 1 H, 6-H), 7.89 (dd, J5,6 = 7.7 Hz, J5,7
˜
3446, 3165, 1747, 1734, 1689, 1670, 1626, 1595, 1583, 1566, 1468,
1444, 1392, 1363, 1352, 1284, 1275, 1236, 1213, 1182, 1038, 962,
835, 752, 611 cm–1. UV (MeOH): λmax (lgε) = 415 (4.34) cm–1. MS
= 1.0 Hz, 1 H, 5-H), 8.03 (d, J4,1ЈЈЈ = 0.5 Hz, 1 H, 4-H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 11.8 (q, C-4Ј), 16.3 (q, C-5Ј), 19.7 (q,
C-1ЈЈЈ), 26.5 (t, C-3Ј), 32.3 (q, C-2ЈЈ), 41.3 (d, C-2Ј), 57.1 (q,
(EI, 70 eV): m/z (%) = 354 (4) [M+], 310 (70) [M+ – CO2], 295 OCH3), 119.0 (d, C-7), 119.8 (d, C-5), 123.3 (s, C-9a), 125.6 (s, C-
(100), 252 (10), 224 (4), 196 (3), 168 (6), 139 (6), 44 (7). HRMS (EI,
70 eV, 200 °C): C19H14O7 calcd. for 354.07395; found 353.97786.
C19H14O7 (354.31): calcd. C 64.41, H 3.98; found C 64.29, H 3.74.
8a), 126.8 (d, C-4), 134.1 (s, C-10a), 135.1 (d, C-6), 135.2 (s, C-4a),
140.6 (s, C-2), 142.5 (s, C-3), 146.2 (s, C-1), 160.4 (s, C-8), 174.8 (s,
C-1Ј), 181.5 (s, C-9), 183.2 (s, C-10), 202.6 (s, C-1ЈЈ) ppm. IR (KBr):
ν = 3431, 2972, 2939, 2925, 1763, 1707, 1672, 1657, 1589, 1466,
˜
2-Acetyl-1-hydroxy-8-methoxy-3-methylanthracene-9,10-dione (9):
The acid 8 (340 mg, 0.96 mmol) was dissolved in dry DMF (5 mL,
addition of 1 g of 4-Å molecular sieves) and the reaction mixture
was stirred overnight under protective gas at 40 °C. Ethyl acetate
(40 mL) was added and the organic phase was washed successively
with HCl (2 mol/L, 2 ϫ 30 mL), saturated NaHCO3 solution
(2ϫ20 mL), water (20 mL), and brine (20 mL). The solution was
dried with MgSO4, filtered and the solvents were removed under
reduced pressure. The crude product was purified by recrystalli-
zation from ethanol to afford the methyl anthraquinone 9 as orange
crystals (226 mg, 76%, m.p. 238 °C). 1H NMR (200 MHz, CDCl3):
δ = 2.41 (s, 3 H, COCH3), 2.65 (s, 3 H, CH3), 4.11 (s, 3 H, OCH3),
7.41 (dd, J6,7 = 8.3 Hz, J5,7 = 1.0 Hz, 1 H, 7-H), 7.64 (s, 1 H, 4-
H), 7.79 (dd, J5,6 = 7.8 Hz, J6,7 = 8.3 Hz, 1 H, 6-H), 8.00 (dd, J5,6
= 7.8 Hz, J5,7 = 1.0 Hz, 1 H, 5-H), 13.30 (s, 1 H, OH) ppm. 13C
NMR (50 MHz, CDCl3): δ = 20.5 (q, CH3), 32.3 (q, COCH3), 57.1
(q, OCH3), 115.6 (s, C-9a), 118.8 (d, C-4), 120.7 (d, C-7), 121.2 (d,
C-5), 132.6 (s, C-8a), 136.0 (s, C-2), 136.4 (d, C-6), 136.7 (s, C-10a,
C-4a), 144.2 (s, C-3), 160.0 (s, C-8), 161.4 (s, C-1), 182.8 (s, C-10),
1446, 1360, 1331, 1313, 1279, 1265, 1227, 1186, 1119, 1111, 1092,
1076, 1034, 1014, 993, 943, 791, 752, 742 cm–1. UV (MeOH): λmax
(lgε) = 382 (3.74). MS (EI, 70 eV, 200 °C): m/z (%) = 394 (12) [M+],
310 (100), 295 (64), 252 (5), 167 (10), 149 (22), 113 (5), 85 (20), 57
(65), 43 (8). HRMS (EI, 70 eV): C23H22O6 calcd. for 394.14164:
found 394.14191. C23H22O6 (394.42): calcd. C 70.04, H 5.62; found
C 69.57, H 5.30.
1-Hydroxy-8-methoxy-3-methyl-2-(4-methyl-3-oxohexanoyl)anthra-
cene-9,10-dione (12): A solution of the phenol ester 11 (341 mg,
0.94 mmol) in THF (20 mL) was treated at 0 °C with LiH
(10 mmol, 80 mg) and the suspension was refluxed for 20 h (TLC
monitoring). The mixture was carefully neutralized at 0 °C by ad-
dition of HCl (2 mol/L, 2 mL), reduced to one fifth of its volume
under reduced pressure, and diluted with dichloromethane
(100 mL). The organic phase was washed successively with HCl
(2 mol/L, 2ϫ40 mL) and water (40 mL), dried with MgSO4, fil-
tered and concentrated under reduced pressure to afford the dike-
tone 12 (215 mg, mmol, 97%, m.p. 155 °C) as yellow crystals after
crystallization from dichloromethane/ethanol (1:1). 1H NMR
(500 MHz, CDCl3): δ (enol) = 0.98 (t, J5Ј,6Ј = 7.5 Hz, 3 H, 6Ј-H),
1.23 (d, J4Ј,7Ј = 6.8 Hz, 3 H, 7Ј-H), 1.56 (m, 1 H, 5αЈ-H), 1.75 (m,
1 H, 5βЈ-H), 2.39 (m, 1 H, 4Ј-H), 2.47 (s, 3 H, CH3), 4.09 (s, 3 H,
OCH3), 5.84 (s, 1 H, 2Ј-H), 7.40 (d, J6,7 = 8.3 Hz, 1 H, 7-H), 7.64
(s, 1 H, 4-H), 7.78 (dd, J5,6 = 7.7 Hz, J6,7 = 8.3 Hz, 1 H, 6-H), 7.98
(dd, J5,6 = 7.7 Hz, J5,7 = 0.8 Hz, 1 H, 5-H), 13.34 (s, 1 H, OH),
15.63 (br. s, 1 H, OH) ppm. 13C NMR (125 MHz, CDCl3): δ (enol)
= 11.7 (q, C-6Ј), 16.9 (q, C-7Ј), 20.5 (q, C-1ЈЈ), 27.1 (t, C-5Ј, CH2),
44.0 (d, C-4Ј), 56.7 (q, OCH3), 101.9 (d, C-2Ј), 115.3 (s, C-9a),
118.4 (d, C-7), 120.2 (d, C-5), 120.5 (d, C-4), 120.8 (s, C-8a), 132.3
(s, C-2), 132.5 (s, C-4a), 135.6 (s, C-10a), 135.8 (d, C-6), 145.3 (s,
C-3), 160.0 (s, C-1), 161.0 (s, C-8), 182.5 (s, C-10), 185.8 (s, C-1Ј),
188.9 (s, C-9), 203.9 (s, CO) ppm. IR (KBr): ν = 3437, 2981, 2927,
˜
2848, 1685, 1631, 1585, 1487, 1468, 1446, 1352, 1286, 1271, 1230,
1184, 1068, 1036, 1012, 962, 849, 750 cm–1. UV (MeOH): λmax (lgε)
= 415 (3.59). MS (EI, 70 eV): m/z (%) = 310 (25) [M+], 295 (45),
279 (4), 252 (5), 167 (4), 149 (10), 98 (100), 84 (10), 57 (14), 43
(10). HRMS (EI, 70 eV): C18H14O5 calcd. for 310.08412; found
310.08414. C18H14O5 (310.30): calcd. C 69.67, H 4.55; found C
69.32, H 4.05.
2-Methylbutanoyl Chloride (10):[20] 2-Methylbutanoic acid (20.0 g,
196 mmol) was treated with thionyl chloride (26.2 g, 220 mmol,
16.0 mL) and a few drops of DMF. The reaction started spontane-
ously and the mixture was stirred for 2 h at 40 °C. The crude prod-
uct was distilled to afford the acid chloride as a colorless oil (17.4 g,
188.4 (s, C-9), 198.5 (s, C-3Ј) ppm. IR (KBr): ν = 3446, 2966, 2929,
˜
1
85%, b.p. 32 °C/1 mbar (ref.[20] b.p. 118 °C). H NMR (500 MHz,
2875, 1674, 1653, 1626, 1585, 1558, 1491, 1473, 1466, 1456, 1446,
1437, 1352, 1277, 1240, 1186, 1066, 1039, 976, 858, 796, 752 cm–1.
UV (MeOH): λmax (lgε) = 418 (5.08). MS (EI, 70 eV): m/z (%) =
394 (22) [M+], 379 (8), 337 (8), 310 (50), 295 (100), 252 (10), 57
(12). HRMS (EI, 70 eV): C23H22O6 calcd. for 394.14164; found
394.14314. C23H22O6 (394.42): calcd. C 70.04, H 5.62; found C
69.74, H 5.74.
CDCl3): δ = 1.00 (t, J3,4 = 7.4 Hz, 3 H, 4-H), 1.31 (d, J2,1Ј = 6.9 Hz,
3 H, 1Ј-H), 1.63 (m, 1 H, 3α-H), 1.86 (m, 1 H, 3β-H), 2.84 (m, 1
H, 2-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 11.5 (q, C-4), 16.9
(q, C-1Ј), 26.9 (t, C-3), 53.3 (d, C-2), 178.1 (s, CO) ppm.
2-Acetyl-8-methoxy-3-methyl-9,10-dioxo-9,10-dihydroanthracen-1-yl
2-Methylbutanoate (11): A solution of the phenol 9 (220 mg,
0.71 mmol) in dry dichloromethane (5 mL) was treated at 0 °C suc-
cessively with pyridine (0.1 mL, 1.12 mmol), acid chloride 10
2-sec-Butyl-11-methoxy-5-methyl-4H-naphtho[2,3-h]chromene-
4,7,12-trione (13): Trifluoroacetic acid (5 mL) was added to the di-
(0.1 mL, 1.12 mmol), and DMAP (3 mol-%). The mixture was ketone 12 (45 mg, 0.114 mmol) and the solution was stirred at room
stirred for 6 h at 20 °C (TLC monitoring). Water was then added
(20 mL) and the aqueous phase was extracted with dichlorometh-
ane (2ϫ50 mL). The combined organic phases were washed with
saturated NaHCO3 solution (20 mL), dilute HCl (2 mol/L, 20 mL),
water (20 L), and brine (30 mL), dried with MgSO4, filtered and
concentrated under reduced pressure. The crude product was puri-
fied by crystallization (CH2Cl2) to give the ester 11 as yellow crys-
temperature for 1 h. Dichloromethane (15 mL) was then added and
the solvent was removed under reduced pressure. The procedure
was repeated twice to remove the trifluoroacetic acid. The crude
product was dissolved in dichloromethane (50 mL) and successively
washed with saturated NaHCO3 solution (20 mL), dilute HCl
(2 mol/L, 20 mL), water (20 L), and brine (30 mL), dried with
MgSO4, filtered, and concentrated under reduced pressure.
1908
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Eur. J. Org. Chem. 2007, 1905–1911

Total Synthesis of rac-γ-Indomycinone
FULL PAPER
Crystallization (toluene/ethanol) afforded the product as yellow
crystals (32 mg, 75%, m.p. 219 °C). H NMR (500 MHz, CDCl3):
11), 172.9 (s, C-2), 179.1 (s, C-4), 181.4 (s, C-7), 187.0 (s, C-12)
ppm. IR (KBr): ν = 3853, 3423, 3075, 2972, 2924, 2874, 2363, 2331,
˜
1
δ = 1.00 (t, J2Ј,3Ј = 7.6 Hz, 3 H, 3Ј-H), 1.43 (d, J1Ј,4Ј = 7.1 Hz, 3 H, 1661, 1580, 1460, 1416, 1378, 1335, 1313, 1264, 1210, 1106, 1068,
4Ј-H), 1.78 (m, 1 H, 2αЈ-H), 1.96 (m, 1 H, 2βЈ-H), 2.77 (m, 1 H, 1Ј- 932, 840, 742 cm–1. MS (EI, 70 eV): m/z (%) = 440 (100) [M+], 362
H), 2.98 (s, 3 H, CH3), 4.06 (s, 3 H, OCH3), 6.23 (s, 1 H, 3-H),
7.37 (dd, J9,10 = 8.3 Hz, J8,10 = 1.0 Hz, 1 H, 10-H), 7.70 (dd, J8,9
(72), 281 (30), 243 (12), 196 (8), 167 (12), 139 (18), 85 (10), 57
(26), 43 (50), 28 (30). HRMS (EI, 70 eV): calcd. for C22H17BrO5
440.0259; found 440.0259.
= 7.7 Hz, J9,10 = 8.3 Hz, 1 H, 9-H), 7.88 (dd, J8,9 = 7.7 Hz, J8,10
=
1.0 Hz, 1 H, 8-H), 7.92 (s, 1 H, 6-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 11.6 (q, C-3Ј), 17.9 (q, C-4Ј), 23.9 (q, CH3), 27.3 (t,
C-2Ј), 40.2 (d, C-1Ј), 56.8 (q, OCH3), 110.8 (d, C-3), 118.5 (d, C-
10), 119.3 (d, C-8), 122.6 (s, C-12a), 123.6 (s, C-11a), 124.4 (d, C-
6), 126.5 (s, C-4a), 134.4 (d, C-9), 134.5 (s, C-7a), 135.0 (s, C-6a),
147.2 (s, C-5), 156.0 (s, C-12b), 159.7 (s, C-11), 173.2 (s, C-2), 179.6
11-Acetoxy-2-sec-butyl-5-methyl-4H-naphtho[2,3-h]chromene-
4,7,12-trione (16): The phenol 14 (15.0 mg, 0.04 mmol) was treated
at room temperature under argon for 2 h with acetic anhydride
(0.3 mL), pyridine (0.3 mL), and a catalytic amount of DMAP
(5 mg). After addition of water, the mixture was extracted with
dichloromethane, the combined organic phases were washed with
saturated sodium hydrogen carbonate, dilute hydrochloric acid, and
brine, and dried with anhydrous magnesium sulfate. The solvents
were removed under reduced pressure and the crude product puri-
fied by preparative TLC (dichloromethane) to afford the acetate 16
as an orange solid (17.6 mg, 95 %, m.p. 191 °C). 1H NMR
(500 MHz, CDCl3.): δ = 0.98 (t, J2Ј,3Ј = 7.6 Hz, 3 H, 3Ј-H), 1.41
(d, J1Ј,4Ј = 7.1 Hz, 3 H, 4Ј-H), 1.76 (m, 1 H, 2αЈ-H), 1.97 (m, 1 H,
2βЈ-H), 2.67 (s, 3 H, CH3), 2.71 (m, 1 H, 1Ј-H), 3.01 (s, 3 H, CH3),
6.24 (s, 1 H, 3-H), 7.45 (dd, J9,10 = 8.3 Hz, J8,10 = 1.0 Hz, 1 H, 10-
H), 7.76 (dd, J8,9 = 7.7 Hz, J9,10 = 8.3 Hz, 1 H, 9-H), 7.98 (dd, J8,9
= 7.7 Hz, J8,10 = 1.0 Hz, 1 H, 8-H), 8.21 (s, 1 H, 6-H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 11.7 (q, C-3Ј), 17.6 (q, C-4Ј), 20.7
(q, CH3), 23.9 (q, CH3), 27.3 (t, C-2Ј), 40.5 (d, C-1Ј), 111.2 (d, C-
3), 121.6 (s, C-12a), 124.64 (d, C-6), 125.2 (s, C-11a), 126.5 (s, C-
4a), 130.2 (d, C-8), 134.0 (s, C-7a), 134 (d, C-9) 135.0 (s, C-6a),
148.32 (s, C-5), 156.8 (s, C-1a), 161.2 (s, C-11), 169.1 (q, CH3),
169.5 (q, CH3), 172.6 (s, C-2), 179.4 (s, C-4), 182.3 (s, C-7), 205.3
(s, C-12), 180.5 (s, C-4), 183.2 (s, C-7) ppm. IR (KBr): ν = 3431,
˜
2968, 2925, 2877, 1676, 1653, 1647, 1628, 1587, 1466, 1446, 1387,
1281, 1227, 1076, 1039, 947, 752 cm–1. UV (MeOH): λmax (lgε) =
386 (4.10). MS (EI, 70 eV): m/z (%) = 376 (100) [M+], 359 (32), 347
(8), 330 (15), 310 (48), 295 (78), 279 (15), 266 (20), 252 (12), 205
(9), 167 (22), 149 (43), 139 (11), 97 (13), 85 (16), 57 (62), 43 (28).
HRMS (EI, 70 eV): C23H20O5 calcd. for 376.13107; found
376.13116. C23H20O5 (376.40): calcd. C 73.39, H 5.36; found C
72.83, H 4.84.
2-sec-Butyl-11-hydroxy-5-methyl-4H-naphtho[2,3-h]chromen-4,7,12-
trione (14): A solution of boron trichloride in dichloromethane
(1.7 mL, 1 mol/L) was added dropwise under argon at –70 °C to a
solution of the methoxy compound 13 (24 mg) in dry dichloro-
methane (5 mL). The temperature was allowed to rise to –20 °C
during 1 h (TLC monitoring). The mixture was diluted with dichlo-
romethane, the organic phase washed with saturated sodium hydro-
gen carbonate, water, dried with anhydrous MgSO4, and the solvent
was removed under reduced pressure to afford phenol 14 (20 mg,
86%, m.p. 186–188 °C). 1H NMR (500 MHz, CDCl3.): δ = 0.98 (t,
J2Ј,3Ј = 7.6 Hz, 3 H, 3Ј-H), 1.43 (d, J1Ј,4Ј = 7.1 Hz, 3 H, 4Ј-H), 1.78
(m, 1 H, 2αЈ-H), 1.96 (m, 1 H, 2βЈ-H), 2.74 (m, 1 H, 1Ј-H), 3.01
(s, C-12) ppm. IR (KBr): ν = 3423, 3059, 2966, 2924, 2352, 1764,
˜
1647, 1585, 1466, 1384, 1308, 1280, 1215, 1025, 911, 753 cm–1. MS
(EI, 70 eV): m/z (%) = 404 (70) [M+], 362 (100), 334 (19), 281 (50),
243 (12), 202 (16), 168 (14), 149 (130), 85 (30), 58 (53), 43 (60),
28 (16). HRMS (EI, 70 eV): calcd. for C24H20O5 404.1260; found
404.1255.
(s, 3 H, CH3), 6.24 (s, 1 H, 3-H), 7.35 (dd, J9,10 = 8.3 Hz, J8,10
=
1.0 Hz, 1 H, 10-H), 7.70 (dd, J8,9 = 7.7 Hz, J9,10 = 8.3 Hz, 1 H, 9-
H), 7.82 (dd, J8,9 = 7.7 Hz, J8,10 = 1.0 Hz, 1 H, 8-H), 8.04 (s, 1 H,
6-H), 13.64 (s, 1 H, OH) ppm. 13C NMR (125 MHz, CDCl3): δ =
11.7 (q, C-3Ј), 17.8 (q, C-4Ј), 24.2 (q, C-1ЈЈ), 27.3 (t, C-2Ј), 40.5 (d,
C-1Ј), 111.3 (d, C-3), 116.8 (s, C-11a), 119.2 (s, C-12a), 119.5 (d,
C-8), 125.3 (d, C-10), 125.5 (d, C-6), 126.6 (s, C-4a), 132.3 (s, C-
7a) 136.2 (d, C-9), 139.5 (s, C-6a), 149.8 (s, C-5), 156.8 (s, C-1a),
162.6 (s, C-11), 172.9 (s, C-2), 179.3 (s, C-4), 182.0 (s, C-7), 187.2
Bromination of Anthrapyranone 13: A solution of the anthrapy-
ranone 13 (15 mg, 0.040 mmol) in moist CCl4 (10 mL) was treated
with a solution of Br2 in CCl4 (0.08 mmol, 0.08 mmol/mL, 1 mL).
The solution was irradiated under nitrogen (normal 100-W daylight
lamp) until the starting material was almost consumed (ca. 95%,
TLC monitoring, 1–2 h). The solvent was removed under reduced
pressure and the crude products were separated by column
chromatography on silica gel (CH2Cl2) to afford the bromide 17
from the less polar fraction (6 mg, 33 %, m.p. 192 °C) and the
alcohol 20 from the polar fraction (6 mg, 38%).
(s, C-12) ppm. IR (KBr): ν = 3847, 3431, 3064, 2966, 2924, 2352,
˜
1650, 1647, 1580, 1460, 1373, 1352, 1319, 1265, 1221, 1074, 1010,
906, 829 cm–1. MS (EI, 70 eV): m/z (%) = 362 (18) [M+], 307 (2),
279 (20), 243 (19), 198 (3), 167 (48),149 (100), 85 (38), 57 (78), 43
(50), 28 (38). HRMS (EI, 70 eV): calcd. for C22H18O5 362.1154;
found 362.1144.
2-(1-Bromo-1-methylpropyl)-11-methoxy-5-methyl-4H-naphtho-
1
[2,3-h]chromene-4,7,12-trione (17): H NMR (500 MHz, CDCl3): δ
10-Bromo-2-sec-butyl-11-hydroxy-5-methyl-4H-naphtho[2,3-h]chro-
mene-4,7,12-trione (15): 60 mg of 13 (0.16 mmol) was treated as
described for 14 but with boron tribromide instead of boron tri-
= 1.11 (t, J2Ј,3Ј = 7.3 Hz, 3 H, 3Ј-H), 2.25 (s, 3 H, 4Ј-H), 2.59–2.66
(m, 2 H, 2Ј-H), 2.98 (d, J6,1ЈЈ = 0.7 Hz, 3 H, CH3), 4.08 (s, 3 H,
OCH3), 6.61 (s, 1 H, 3-H), 7.45 (dd, J9,10 = 8.3 Hz, J8,10 = 1.0 Hz,
1 H, 10-H), 7.76 (dd, J8,9 = 7.7 Hz, J9,10 = 8.3 Hz, 1 H, 9-H), 7.90
chloride to yield the phenol 14 (23 mg, 40%) and the bromophenol
1
15 (39 mg, 56%, m.p. 210 °C). H NMR (500 MHz, CDCl3.): δ = (dd, J8,9 = 7.7 Hz, J8,10 = 1.0 Hz, 1 H, 8-H), 8.00 (d, J6,1ЈЈ = 0.7 Hz,
0.98 (t, J2Ј,3Ј = 7.6 Hz, 3 H, 3Ј-H), 1.43 (d, J1Ј,4Ј = 7.1 Hz, 3 H, 4Ј- 1 H, 6-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 10.2 (q, C-3Ј),
H), 1.77 (m, 1 H, 2αЈ-H), 1.96 (m, 1 H, 2βЈ-H), 2.73 (m, 1 H, 1Ј-
H), 3.01 (s, 3 H, CH3), 6.25 (s, 1 H, 3-H), 7.67 (d, J8,9 = 8 Hz, 1
23.5 (q, C-1ЈЈ), 27.8 (q, C-4Ј), 36.0 (t, C-4Ј), 56.7 (q, OCH3), 63.1
(s, C-1Ј), 110.4 (d, C-3), 118.9 (d, C-8/10), 119.0 (d, C-8/10), 123.3
H, 9-H), 7.94 (d, J8,9 = 8 Hz, 1 H, 8-H), 8.02 (s, 1 H, 6-H), 13.64 (s, C-12a), 123.7 (s, C-11a), 124.5 (d, C-6), 126.1 (s, C-4a), 134.5
(s, 1 H, OH) ppm. 13C NMR (125 MHz, CDCl3): δ = 11.7 (q, C- (d, C-9), 135.4 (s, C-6a, C-7a), 146.9 (s, C-5), 155.6 (s, C-12b), 159.9
3Ј), 17.8 (q, C-4Ј), 24.2 (q, C-1ЈЈ), 27.3 (t, C-2Ј), 40.4 (d, C-1Ј),
111.4 (d, C-3), 117.1 (s, C-11a), 119.4 (s, C-12a), 119.5 (d, C-8),
120.3 (d, C-10), 125.5 (d, C-6), 126.6 (s, C-4a),131.3 (s, C-7a) 135.7
(d, C-9), 139.5 (s, C-6a), 150 (s, C-5), 156.8 (s, C-1a), 159.0 (s, C-
(s, C-11), 167.9 (s, C-2), 176.5 (s, C-12), 179.5 (s, C-4), 183.0 (s, C-
7) ppm. IR (KBr): ν = 2966, 2924, 1670, 1647, 1585, 1462, 1452,
˜
1363, 1329, 1277, 1228, 1101, 1036, 951 cm–1. MS (EI, 70 eV):
m/z (%) = 454 (4) [M+], 376 (100), 359 (38), 330 (12), 295 (38), 266
Eur. J. Org. Chem. 2007, 1905–1911
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1909

K. Krohn, H. T. Tran-Thien, J. Vitz, A. Vidal
(26), 152 (8), 80 (24) [Br], 57 (6). HRMS (EI, 70 eV): C23H19BrO5 C-11), 169.0 (s, C-2), 179.1 (s, C-4), 179.5 (s, C-12), 181.8 (s, C-
FULL PAPER
calcd. for 454.04159; found 454.04400.
7) ppm. IR (KBr): ν = 2924, 2852, 1683, 1653, 1636, 1617, 1457,
˜
1276 cm–1. MS (EI, 70 eV): m/z (%) = 614 (1) [M+], 612 (1) [M+],
548 (2), 502 (1), 453 (1), 412 (16), 368 (10), 167 (29), 82 (98), 80
(100). HRMS calcd. for C23H1779Br281BrO5 611.8605; found
611.8605.
2-(1-Hydroxy-1-methylpropyl)-11-methoxy-5-methyl-4H-naphtho-
1
[2,3-h]chromene-4,7,12-trione (20): H NMR (500 MHz, CDCl3): δ
= 0.97 (t, J = 7.2 Hz, 3 H, 3Ј-H), 1.67 (s, 3 H, 4Ј-H), 1.98 and 2.11
(2 dd, J = 14.4 Hz, J = 7.6 Hz, 2 H, 2Ј-H), 2.99 (s, 3 H, 1ЈЈ-H),
4.05 (s, 3 H, OCH3), 6.48 (s, 1 H, 3-H), 7.37 (m, 1 H, 8-H or 10-
H), 7.71 (dd, J = 8.3 Hz, J = 7.7 Hz, 1 H, 9-H), 7.90 (dd, J =
7.6 Hz, J = 1.0 Hz, 1 H, 10-H or 8-H), 7.97 (d, J = 0.9 Hz, 1 H,
6-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 8.1 (q, C-3Ј), 23.8
(q, C-1ЈЈ), 25.8 (q, C-4Ј), 33.8 (t, C-2Ј), 56.8 (q, OCH3), 74.1 (s, C-
1Ј), 109.4 (d, C-3), 118.7 and 119.4 (2d, C-8, C-10), 123.3 (s), 124.7
(d, C-6), 126.3 (s), 134.5 (s), 134.6 (d, C-9), 147.6 (s), 152.9 and
155.5 (2s), 159.9 (s), 171.6 (s), 179.6 and 180.7 (2s) ppm. IR (KBr):
1-(11-Methoxy-5-methyl-4,7,12-trioxo-1,4,7,12-tetrahydrobenz[a]-
anthracen-2-yl)-1-methylpropyl Acetate (21): The monobromide 17
(9.1 mg, 0.02 mmol) was dissolved in dry dimethylformamide
(1 mL), and silver acetate (20 mg) was added under argon at room
temperature. The mixture was stirred overnight at room tempera-
ture, the silver salts were filtered off and washed with dichloro-
methane, and the solvents were removed under reduced pressure.
Purification by preparative TLC (dichloromethane/diethyl ether,
95:5) afforded the acetate 21 (7.4 mg, 85%) as an orange solid with
m.p. 225–227 °C. 1H NMR (500 MHz, CDCl3): δ = 0.97 (t, J =
7.6 Hz, 3 H, 3Ј-H), 1.89 and 2.20 (2s, each 3 H, 4Ј-H, COCH3),
2.22 (m, 2 H, 2Ј-H), 2.97 (d, J = 1.0 Hz, 3 H, 1ЈЈ-H), 4.02 (s, 3 H,
OCH3), 7.35 (dd, J = 8.5 Hz, J = 1.1 Hz, 1 H, 8-H or 10-H), 7.69
(dd, J = 8.5 Hz, J = 7.7 Hz, 1 H, 9-H), 7.88 (dd, J = 7.7 Hz, J =
1.1 Hz, 1 H, 10-H or 8-H), 7.94 (m, 1 H, 6-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 7.9 (q, C-3Ј), 21.6 and 22.4 (2q, C-4Ј,
COCH3), 23.8 (q, C-1ЈЈ), 56.6 (q, OCH3), 81.2 (s, C-1Ј), 109.9 (d,
C-3), 118.6 and 119.3 (2d, C-8, C-10), 122.8 (s), 123.7 (s), 124.6 (d,
C-6), 126.4 (s), 134.4 (d, C-9), 134.5, 135.2, 147.2, 155.2, 159.2,
169.1, 169.9, 179.3, 180.3 and 183.1 (3s, C-4, C-7, C-12) ppm. IR
ν = 3379, 2925, 2854, 1738, 1720, 1682, 1651, 1587, 1464, 1446,
˜
1379, 1333, 1306, 1273, 1230, 1188, 1097, 1038, 951 cm–1. MS (EI,
70 eV): m/z (%) = 392 (40) [M+], 376 (30), 363 (100), 344 (30), 333
(10), 319 (10), 295 (32), 266 (12), 252 (10), 152 (10), 125 (10), 97
(22), 57 (34). HRMS (EI, 70 eV): C23H20O6 calcd. for 392.12599;
found 392.12612.
Procedure B: The acetate 21 (4.3 mg, 0.01 mmol) was dissolved in
dry methanol, 10 mg potassium carbonate was added, and the mix-
ture was stirred at 21 °C until the starting material was consumed
(ca. 10 h, TLC monitoring). The solution was filtered and the sol-
vent removed under reduced pressure to afford the alcohol 20
(3.9 mg, quantitative) as a yellow solid.
(KBr): ν = 2923, 2851, 1740, 1674, 1645, 1587, 1465, 1446, 1331,
˜
1305, 1247, 1227, 949 cm–1. MS (EI, 70 eV): m/z (%) = 434 (100)
[M+], 392 (60), 363 (80), 359 (64), 295 (58), 266 (22), 57 (22).
HRMS calcd. for C25H22O7 434.1366; found 434.1365.
5-Bromomethyl-2-(1-bromo-1-methylpropyl)-11-methoxy-1-oxabenz-
[α]anthracene-4,7,12-trione (18): In a related bromination, the an-
thrapyranone 13 (75.2 mg, 0.2 mmol) was brominated in dry tetra-
chloromethane with an excess of 6 equiv. of bromine. The irradia-
tion was continued until the starting material was consumed (TLC
monitoring). In addition to 41 mg (45%) of monobromide 17, the
dibromide 18 (33.5 mg, 32%) and the tribromide 19 (16 mg, 13%)
were isolated after chromatographic separation. M.p. 150 °C (de-
11-Acetoxy-2-(1-bromo-1-methylpropyl)-5-methyl-4H-naphtho-
[2,3-h]chromene-4,7,12-trione (24): A dilute solution of bromine in
carbon tetrachloride (1 mL, 0.04 mmol, 0.04 mol/L) was added to a
solution of the acetate (7.0 mg, 0.02 mmol) in carbon tetrachloride
(3 mL). The solution was irradiated for 2 h under argon, at room
temperature with a 100-W daylight lamp. The solvent was removed
under reduced pressure. Purification by preparative TLC on silica
gel (dichloromethane/diethyl ether, 95:5) afforded the monobrom-
ide 24 (2.0 mg, 20%) and the alcohol 23 (2.0 mg, 24%) in addition
to 3.2 mg of starting material 21. M.p. 192 °C. 1H NMR
(500 MHz, CDCl3.): δ = 1.07 (t, J = 7.6 Hz, 3 H, 3Ј-H), 2.17 (s, 3
H, 4Ј-H), 2.48 (s, 3 H, COCH3), 2.54 (q, J = 7.4 Hz, 2 H, 2Ј-H),
2.99 (s, 3 H, 1ЈЈ-H), 6.60 (s, 1 H, 3-H), 7.46 (dd, J = 7.8 Hz, J =
1.3 Hz, 1 H, 8-H or 10-H), 7.78 (dd, J = 7.8 Hz, 1 H, 9-H), 8.00
(m, 1 H, 6-H), 8.20 (dd, J = 7.8 Hz, J = 1.3 Hz, 1 H, 10-H or 8-
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 10.4 (q, C-3Ј), 21.1 (q,
COCH3), 23.8 (q, C-1ЈЈ), 28.0 (q, C-4Ј), 36.0 (t, C-2Ј), 62.4 (s, C-
1Ј), 110.7 (d, C-3), 120.3 (s, C-12a), 121.5 (s, C-6a), 125.0 (d, C-6),
125.2, 129.6 (2d, C-8, C-10), 126.1 (s, C-4a), 126.5 (s, C-11a), 133.9
(s, C-7a), 134.4 (d, C-9), 148.3 (s, C-5), 149.8 (s, C-11), 155.6 (s, C-
12b), 168.1 (s, C-2), 169.5 (s, COCH3), 179.6 (s, C-34), 180.0 (s, C-
1
composition). H NMR (500 MHz, CDCl3): δ = 1.08 (s, 3 H, 3Ј-
H), 2.21 (s, 3 H, 4Ј-H), 2.57 (qd, J = 7.2 Hz, J = 1.5 Hz, 2 H, 2Ј-
H), 4.05 (s, 3 H, OCH3), 5.33 (dd, J = 11.3 Hz, J = 0.4 Hz, 1 H,
1ЈЈ-H), 5.35 (dd, J = 11.3 Hz, J = 0.4 Hz, 1 H, 1ЈЈ-H), 6.70 (s, 1 H,
3-H), 7.39 (dd, J = 8.2 Hz, J = 1.0 Hz, 1 H, 8-H or 10-H), 7.73
(dd, J = 8.2 Hz, J = 7.7 Hz, 1 H, 9-H), 7.90 (dd, J = 7.7 Hz, J =
1.0 Hz, 1 H, 10-H or 8-H), 8.23 (s, 1 H, 6-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 10.4 (q, C-3Ј), 28.4 (q, C-4Ј), 29.7 (t, C-
1ЈЈ), 31.0 (t, C-2Ј), 56.9 (q, OCH3), 62.6 (s, C-1Ј), 111.0 (d, C-3),
118.9 and 119.5 (2d, C-8, C-10), 123.4 and 124.6 (2s, C-11a, C-
12a), 124.8 (s, C-4a), 125.2 (d, C-6), 134.3 and 136.1 (2s, C-6a, C-
7a), 134.8 (d, C-9), 144.4 (s, C-5), 155.5 (s, C-11), 159.8 (s, C-12b),
168.7 (s, C-2), 178.8, 179.8 and 182.3 (3s, C-4, C-7, C-12) ppm. IR
(KBr): ν = 2924, 2852, 1676, 1653, 1647, 1637, 1278 cm–1. MS (EI,
˜
70 eV): m/z (%) = 534 (5) [M+], 454 (8), 374 (42), 362 (80), 310
(22), 281 (72), 133 (28), 79 (100), 57 (77). HRMS calcd. for
C23H1779Br81BrO5 533.9501; found 533.9498.
12), 182.1 (s, C-7) ppm. IR (KBr): ν = 2924, 2852, 1683, 1676,
˜
2-(1-Bromo-1-methylpropyl)-5-dibromomethyl-11-methoxy-1-oxa-
benz[α]anthracene-4,7,12-trione (19): M.p. 174–176 °C. H NMR
1653, 1647, 1636, 1458, 1182, 625, 582 cm–1. MS (EI, 70 eV): m/z
(%) = 484 (10) [M+], 482 (10) [M+], 442 (9), 440 (9), 404 (16), 402
(16), 362 (58), 361 (46), 349 (14), 281 (100), 149 (18), 111 (22),
97 (34), 83 (38), 71 (45), 57 (78). HRMS (EI, 70 eV): calcd. for
C2 4 H 1 9 7 9 Br O 6 4 8 2 . 0 3 6 5 , fo u n d 4 8 2 . 0 3 7 0 , c a l c d . fo r
C24H1981BrO6 484.0344; found 484.0335.
1
(500 MHz, CDCl3): δ = 1.08 (t, J = 7.2 Hz, 3 H, 3Ј-H), 2.21 (s, 3
H, 4Ј-H), 2.56 (q, J = 7.2 Hz, 2 H, 2Ј-H), 4.05 (s, 3 H, OCH3), 6.71
(s, 1 H, 3-H), 7.40 (m, 1 H, 10-H), 7.74 (m, 1 H, 9-H), 7.93 (m, 1
H, 8-H), 8.78 (s, 1 H, 1ЈЈ-H), 8.97 (s, 1 H, 6-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 10.4 (q, C-3Ј), 28.4 (q, C-4Ј), 36.1 (t, C-
2Ј), 36.9 (d, C-1ЈЈ), 56.9 (q, OCH3), 62.3 (s, C-1Ј), 111.0 (d, C-3),
119.0 (d, C-10), 119.6 (d, C-8), 121.3 (s, C-4a), 123.3 (s, C-11a),
11-Acetoxy-2-(1-hydroxy-1-methylpropyl)-5-methyl-4H-naphtho-
[2,3-h]chromene-4,7,12-trione (23): 1H NMR (500 MHz, CDCl3.): δ
125.0 (s, C-6a/C-12a), 125.7 (d, C-6), 134.2 (s, C-7a), 134.9 (d, C- = 0.97 (t, J = 7.5 Hz, 3 H, 3Ј-H), 1.66 (s, 3 H, 4Ј-H), 1.94 (dq, J =
9), 136.6 (s, C-12a/C-6a), 147.6 (s, C-5), 154.2 (s, C-12b), 159.9 (s, 13.9 Hz, J = 7.5 Hz, 1 H, 2Ј-H), 2.08 (dq, J = 13.9 Hz, J = 7.5 Hz,
1910
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1905–1911

Total Synthesis of rac-γ-Indomycinone
FULL PAPER
[6]
[7]
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1 H, 2Ј-H), 2.48 (s, 3 H, COCH3), 3.00 (s, 3 H, 1ЈЈ-H), 6.49 (s, 1
H, 3-H), 7.46 (dd, J = 7.9 Hz, J = 1.2 Hz, 1 H, 8-H or 10-H), 7.79
(d, J = 7.8 Hz, 1 H, 9-H), 8.00 (m, 1 H, 6-H), 8.22 (dd, J = 7.7 Hz,
J = 1.2 Hz, 1 H, 10-H or 8-H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 8.0 (q, C-3Ј), 21.2 (t, COCH3), 23.9 (q, C-1ЈЈ), 25.8 (q, C-4Ј),
33.8 (t, C-2Ј), 74.1 (s, C-1Ј), 109.5 (d, C-3), 124.0, 125.4 (2d), 130.3
[9]
[10]
(d), 134.6 (d) ppm. IR (NaCl, film): ν = 2955, 2923, 2853, 1678,
˜
1650, 1640, 1463, 1370, 1306, 1267 cm–1. MS (EI, 70 eV): m/z (%)
= 420 (72) [M+], 349 (99), 281 (82), 236 (16), 197 (10), 167 (32),
149 (58), 83 (55), 57 (100). HRMS (EI, 70 eV): calcd. for C24H20O7
420.1209; found 420.1206.
[11]
J. S. Kim, K. Shin-Ya, J. Eishima, K. Furihata, H. Seto, J. Anti-
biot. 1996, 49, 947–948.
[12]
[13]
K. Krohn, J. Vitz, Eur. J. Org. Chem. 2004, 209–219.
H. Uno, K. Sakamoto, E. Honda, N. Ono, Chem. Commun.
1999, 1005–1106.
H. Uno, K. Sakamoto, E. Honda, K. Fukuhara, N. Ono, J.
Tanaka, M. Sakanaka, J. Chem. Soc. Perkin Trans. 1 2001,
229–238.
γ-Indomycinon (rac-3): A solution of the alcohol 23 (2.0 mg) in dry
methanol (1 mL) was stirred at room temperature with 5 mg of
potassium carbonate. The reaction was monitored by TLC and af-
ter consumption of the starting material the suspension was filtered
and the solvent removed at reduced pressure. Comparison with an
authentic sample proved the identity with natural γ-indomycinon.
[14]
[15]
Z. Fei, F. E. McDonald, Org. Lett. 2005, 7, 3617–3620.
[16] L. F. Tietze, K. M. Gericke, R. S. Singidi, Angew. Chem. 2006,
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[17] L. F. Tietze, R. R. Singidi, K. M. Gericke, Org. Lett. 2007, 8,
5873–5876.
Acknowledgments
[18] K. Krohn, A. Vidal, J. Vitz, B. Westermann, M. Abbas, I.
Green, Tetrahedron: Asymmetry 2007, 18, 3051–3057.
[19] K. Krohn, E. Roemer, M. Top, Liebigs Ann. 1996, 271–277.
[20] R. Leimu, Ber. Dtsch. Chem. Ges. 1937, 70, 1040–1053.
[21] A. V. Kalinin, V. Snieckus, Tetrahedron Lett. 1998, 39, 4999–
5002.
We thank Prof. H. Laatsch (Univ. of Göttingen) for a sample of
natural γ-indomycinone, the Deutsche Forschungsgemeinschaft
(DFG) (Project KR 595/10-4) for financial support and the BASF
AG, Ludwigshafen, for a gift of chemicals.
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[24] A sample of natural γ-indomycinone was kindly provided by
Prof. H. Laatsch (Univ. of Göttingen). No melting points are
given for the naturally occurring γ-indomycinone[1] or the syn-
thetic product.[17] In our hands, all 1Ј-hydroxylated products
(3, 20, 23) decomposed around 250 °C, depending upon the
speed of heating.
[4] M. R. Hansen, L. H. Hurley, Acc. Chem. Res. 1996, 29, 249– [25] K. Krohn, D. Gehle, O. Kamp, T. van Ree, J. Carbohydr. Chem.
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Received: January 8, 2007
Published Online: February 28, 2007
3581–3583.
Eur. J. Org. Chem. 2007, 1905–1911
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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