Total Synthesis of Premithramycinone H and Related Anthrapyran Antibiotics

Article abstract of DOI:10.1002/ejoc.200300451

Two approaches are described for the preparation of 2-(1',3'-dioxoalkyl)-substituted 1-hydroxyanthraquinones 10a-d and 20a-c, which were cyclized in a biomimetic-type reaction to the anthra[1,2-b]pyran skeletons 11a-d and 21a-c of the heydamcin- or pluram

Full text of DOI:10.1002/ejoc.200300451

FULL PAPER
Total Synthesis of Premithramycinone H and Related
Anthrapyran Antibiotics
[a]
[a]
Karsten Krohn* and Jürgen Vitz
Keywords: Antibiotics / Natural products / Total synthesis / Antitumor agents
Two approaches are described for the preparation of 2-(1Ј,3Ј-
dioxoalkyl)-substituted 1-hydroxyanthraquinones 10a−d and
methyl ethers afforded the natural product premithramyci-
none H (2). The simple derivative 11b showed inhibition of
the A431 cell line in µmolar concentrations.
20a−c, which were cyclized in a biomimetic-type reaction to
the anthra[1,2-b]pyran skeletons 11a−d and 21a−c of the
heydamycin- or pluramycin-type antibiotics. Cleavage of the
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
Results and Discussion
The 4H-anthra[1,2-b]pyran antibiotics of the heydamycin
We now report our work on the synthesis of premithra-
or pluramycin types (for the basic structure 1 of the plura- mycinone H (2) and related, simpler anthrapyran anti-
mycins see Scheme 1) are known for their antibacterial and biotics. Our goal was to make this class of compounds read-
antitumor activity. Their chemistry, biochemistry and bio- ily available and in substantial amounts for biological test-
[
1,2]
logical activity was extensively reviewed some time ago.
ing and for the investigation of the structural requirements
More recently, the pluramycins have again attracted interest for antitumor activity. To this end, three approaches were
in biology as described in the account of Hansen and Hur- employed. The key steps in the first two approaches in-
ley: ‘‘Pluramycins. Old Drugs Having Modern Friends in cluded a Marschalk alkylation reaction of hydroxylated
Structural Biology.’’[ One reason for this renewed import- anthraquinones
3]
[10,11]
followed by
or aldol-type chain elongation and then an
into DNA, resulting in a specific alkylation of guanine at acid-catalyzed cyclization of ring A as shown by the discon-
a
BakerϪVenkata-
[
12,13]
ance was the discovery of the highly specific intercalation raman
[
4]
[
5]
N-7, making the pluramycins valuable tools for the de- nections A in Scheme 2. In the third approach, we used the
[
14]
[15]
tailed investigation of the structure of DNA.
methodology of Harris
and Yamaguchi
to construct
Our interest in the total synthesis was stimulated as a anthraquinones with ester and acyl side chains such as 19,
result of a recent report by Rohr and Sal a´ s et al., describing followed by a BakerϪVenkataraman rearrangement and a
the remarkable antitumor activity of premithramycinone H cyclization to the 4H-anthra[1,2-b]pyrans as shown by the
(
2), a metabolic shunt product discovered in the course of disconnections B in Scheme 2. The procedure culminated
the biosynthetic investigations of the aureolic acid anti- with the total synthesis of premithramycinone H (2)
biotic mithramycin.[ Another report described the inter- (Scheme 5).
6]
In the original version of the Marschalk reaction,[10] phe-
an anthrapyran isolated from a Streptomyces species. Re- nolic dihydroanthraquinones are alkylated in the position
lated naphthopyranones (TMC-256A1 and -C1) were found ortho to the phenolic hydroxy group by heating to reflux
esting neuronal cell protecting properties of espicufolin (3),
[
7]
[
8]
to be potent inhibitors of IL-4 signal transduction. Inter- with aldehydes under basic conditions. At low temperatures,
estingly however, only one major synthesis of the kidamyci- however, the originally introduced hydroxyalkyl group may
none methyl ether (4) by Hauser and Rhee has been re- be preserved if the intermediate hydroquinones are rapidly
ported in the literature in which the selenium dioxide me- re-oxidized to the quinones using hydrogen peroxide in an
[
11]
diated cyclization of ring A in the hydroquinone methyl alkaline reaction medium.
This reaction was used to in-
[9]
ether 5 was a key step (Scheme 1).
troduce hydroxyethyl side chains into the three initially
selected hydroxyanthraquinones 6aϪc to form the hydroxy-
ethyl compounds 7aϪc (Scheme 3). The reaction tempera-
tures had to be adjusted for the different reactivities of the
corresponding hydroquinones of the hydroxyanthraqui-
nones 6aϪc and were varied between 5 and 20 °C. At 20
[
a]
Department Chemie, Universität Paderborn,
Warburger Str. 100, 33098 Paderborn, Germany
E-mail: kk@chemie.upb.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
°
C, reduction occurred to some extent to the corresponding
ethyl anthraquinones, which were easily removed by chro-
Eur. J. Org. Chem. 2004, 209Ϫ219
DOI: 10.1002/ejoc.200300451
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
209

K. Krohn, J. Vitz
FULL PAPER
Scheme 1. Structure of some 4H-anthra[1,2-b]pyran antibiotics and synthesis of the kidamycinone methyl ether (4)
Scheme 2. Disconnections used in the construction of the 4H-anthra[1,2-b]pyran skeleton
matography or crystallization. The subsequent PCC oxi- was then extended by an aldol reaction with acetone to
[
16]
dations to the ketones 8aϪc were uneventful as were the yield the alcohol 9d which was oxidized to the diketone 10d
subsequent acetylations to the acetates 9aϪc. Several bases by repetition of the MnO oxidation procedure (Scheme 4).
2
were used to initiate the subsequent intramolecular acyl-
We experienced no problems with the unsaturated side
ation (BakerϪVenkataraman reaction). In our hands, lith- chains as encountered by Hauser and Rhee in their syn-
ium hydride in boiling THF[17] gave the best results and the thesis of kidamycinone methyl ether (4), so that the acid-
corresponding β-diketones 10aϪc were isolated in yields of catalyzed cyclization of the diketones 10aϪd was attempted
[9]
between 40 and 95 %.
next. Mechanistically, the reaction can be easily understood
Alternatively, the required side chain could also be intro- as a reversible hemiketal formation involving the phenolic
duced with a comparable overall yield by attachment of the group and the 3Ј-oxo group, followed by irreversible water
C and C units as exemplified by the phenolic anthraqui- elimination to form the pyranone ring. We found that hy-
1
3
[
18]
[20]
none 6d. The anthraquinone 6d was thus reduced to the drochloric acid in acetic acid gave varying yields and that
dihydro form and hydroxymethylated with formaldehyde to simply dissolving the phenolic β-diketones in trifluoroacetic
7
d, after oxidation with H O . The latter was oxidized with acid induced cyclization to the corresponding 4H-
2 2
[19]
active manganese dioxide to the aldehyde 8d.
The chain anthra[1,2-b]pyrans 11aϪd in nearly quantitative yields.
www.eurjoc.org Eur. J. Org. Chem. 2004, 209Ϫ219
210
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Total Synthesis of Premithramycinone H
FULL PAPER
constructing the carbocyclic ring in an aldol-type reac-
[
22]
tion and the 4H-anthra[1,2-b]pyran antibiotics in the for-
[
9]
mation of the heterocyclic pyranone ring. The requisite
monoacid 16 for premithramycinone H (2) was first pre-
[
23]
[24]
pared by Kjaer
and Henderson
by a different route.
A method more appropriate for larger scale preparation,
however, was the DielsϪAlder reaction of the 3-methoxyke-
tene acetals 12a or 12b with the allene diester 13, a reaction
[
25]
which proceeds with remarkable regioselectivity.
In the
reaction of diene 12a with the ketene 13, however, a mixture
of phenol 14a and the dimethyl ether 14b was produced.
The monophenol can be methylated to the dimethyl ether
14b using methyl iodide and silver oxide (basic conditions
lead to C-methylation of the benzylic position). The exclus-
ive formation of the required monomethoxy diester 14a was
achieved when the corresponding mixed tert-butoxy-OTMS
ketene acetal was used in the DielsϪAlder reaction, as pre-
[
26]
viously observed in related reactions.
Silylketene acetals
[
27]
are very often used in DielsϪAlder reactions.
The use
of the tert-butoxy-OTMS ethers such as 12b for selective
synthesis of phenols (instead of mixtures with methyl
ethers) is therefore of general importance for DielsϪAlder
Scheme 3. Synthesis of anthra[1,2-b]pyrans by the Marschalk alky-
lation followed by a BakerϪVenkataraman chain elongation and reactions with ketene acetals.
an acid catalyzed cyclization
The best way to produce the desired monoester 16 was
by saponification of the diester 14b to the diacid 15, fol-
lowed by efficient monoesterification of the phenylacetic
acid moiety. The regioselectivity of the reaction was con-
firmed by comparison of the spectroscopic data of 16 with
[
23,24]
those of an authentic sample
and independently by
selective BH reduction of the acid in the presence of the es-
3
[
28]
ter.
The subsequent construction of the benzopyranone 17
was achieved by selective deprotonation of the monoacid
16 using sodium hydride and subsequent ester condensation
with the dianion of tert-butyl acetoacetate (TBAA). The py-
ranone ring was probably formed by hemiketal formation
followed by the β-elimination of water. In the next reaction,
the electrophilicity of the β-oxo ester side chain was reduced
by deprotonation to form the stabilized enolate, and the
dianion of acetylacetone only attacked the pyranone car-
bonyl group. The intermediate oligoketide then underwent
Scheme 4. Synthesis of 10d by sequential attachment of C
3
1
and
C
units
Having achieved the synthesis of the simple 4H- cyclization to the anthrone 18 (for mechanistic consider-
[
17]
anthra[1,2-b]pyrans which are interesting models for ations and intermediates see ref. ) Oxidation to the
structureϪactivity studies of antitumor activity (see below), anthraquinone 19a was best achieved by copper-catalyzed
[
29]
we turned our attention to the synthesis of premithramy- air oxidation,
followed by acetylation to 19b. A
cinone H (2) and other derivatives with acetic ester side BakerϪVenkataraman rearrangement to produce 20a was
chains on the anthraquinone core (Scheme 5). Fortunately, then induced by treatment of the acetate 19b with lithium
1
in this context, we profited from our previous studies on hydride. At this stage, two more compounds, 20b (R ϭ Me;
2
1
2
aklanonic acid which is a presumed late intermediate in R ϭ H) and 20c (R ϭ Et; R ϭ H), prepared earlier in
anthracycline biosynthesis.[ The synthesis of the oxo ester connection with aklanonic acid synthesis were ready for
precursors such as 18 or 19 (Scheme 5) was achieved using acid-catalyzed cyclization to 4H-anthra[1,2-b]pyrans. In
successive condensations of the monoester 16 with the di- fact, treatment with trifluoroacetic acid induced cyclization
anions of acetoacetate and 2,4-pentanedione by the pro- as well as cleavage of the tert-butyl ester. The intermediate
anthraquinoneacetic acids were prone to decar-
The BakerϪVenkataraman reaction can again be used suc- boxylation
17]
[17]
cedure pioneered by Harris[ and later by Yamaguchi.
21]
[15]
[
17]
and were therefore immediately esterified by
cessfully for chain elongation. Interestingly, the same or treatment with diazomethane to afford the esters 21aϪc.
similar intermediate decaketides are biosynthetically used The structure of the chloroform-soluble dimethyl ether 21a
for both groups of natural products: the anthracyclines in was elucidated by extensive NMR experiments, including
Eur. J. Org. Chem. 2004, 209Ϫ219
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
211

K. Krohn, J. Vitz
FULL PAPER
Scheme 5. Synthesis of premithramycinone (2) using the dianion approach followed by chain elongation and TFA-catalyzed cyclization
an assignment of all hydrogen and carbon atoms (see Exp. The three anthra[1,2-b]pyrans 11b, 11d, and 21b were selec-
[
30]
Sect.) which was supported by 2D spectra. Cleavage to af- ted for antitumor activity in our tests.
The compounds
ford the fermentation product premithramycinone H (2) were tested on human A 431 cells/P-glycoprotein (3 d expo-
was then achieved by treatment of the corresponding di-
methyl ether 21a with boron tribromide, yielding the mono-
Table 1. Antitumor activity of compounds 11b,d (Scheme 3) and
phenol 22d as an isolable intermediate. The published
21b (Scheme 5)
[
6]
NMR spectroscopic data (DMSO/1 % TFA solution) are
in good agreement with those of the synthetic product.
Compound
A431
IC50
MaTu/Adr
IC50
MTT
inhibition
Antitumor Activity
11b
11d
21b
8.8 µ
Ͼ 30 µ
Ͼ 30 µ
21 µ
Ϫ
Ϫ
20 %
20 %
Ϫ
The antitumor activity of premithramycinone H (2)
against four different cell lines was reported by Rohr et al.
[
6]
212
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 209Ϫ219

Total Synthesis of Premithramycinone H
FULL PAPER
sure) and with overexpressed MaTu/Adr cells (3 d expo- 1-Hydroxy-2-(1-hydroxyethyl)-8-methoxyanthraquinone (7b): Start-
ing material 1-hydroxy-8-methoxyanthraquinone (6b) (3.0 g,
sure). In addition, the activity against mitochondria was
tested (MTT assay, 4 h exposure). Whereas 11d and 21d
showed low activity (IC50 Ͼ 30 µm), the growth of A 431
1
1.8 mmol), product 7b, yellow crystals (1.4 g, 40 %; m.p. 69Ϫ71
1
°C). H NMR (200 MHz, CDCl
3
): δ ϭ 1.60 (d, J1Ј,2Ј ϭ 6.50 Hz, 3
), 5.30 (q, J1Ј,2Ј ϭ 6.50 Hz, 1 H,
H, CH
3
, 2Ј-H), 4.12 (s, 3 H, OCH
3
cells was significantly inhibited by derivative 11b (IC50
.8 µm) (Table 1).
ϭ
1
6
Ј-H), 7.40 (d, J6,7 ϭ 8.40 Hz, 1 H, 7-H), 7.79 (m, 3 H, 3-H, 4-H,
-H), 8.00 (d, J5,6 ϭ 7.66 Hz, 1 H, 5-H), 13.51 (s, 1 H, OH) ppm.
8
Ϫ1
IR (KBr, cm ): ν˜ ϭ 3450 (OH), 2975 (CH), 2929 (CH), 2841
OCH ), 1672 (CO), 1631 (CO), 1589 (aryl), 1429, 1274, 1233. MS
(EI, 80 eV): m/z (%) ϭ 298 (86) [M ], 283 (100) [M Ϫ CH
(
3
ϩ
ϩ
Conclusion
3
], 265
OH], 255 (80), 240 (38), 237 (10), 223 (4), 212 (5),
93 (5), 165 (12), 149 (18), 139 (15), 97 (16), 84 (22), 49 (42), 43
(298.29): calcd. C 68.45, H 4.73; found C 68.15,
ϩ
(
1
(
25) [M Ϫ CH
3
In a biomimetic-type reaction, several 2-(1Ј,3Ј-dioxoal-
kyl)-substituted 1-hydroxyanthraquinones 10aϪd and
24). C17
H
14
O
5
H 4.43.
20aϪc were cyclized to the anthra[1,2-b]pyran skeleton of
the heydamycin- or pluramycin-type antibiotics including 1,4-Dihydroxy-2-(1-hydroxyethyl)anthraquinone (7c):[34] Dihydro-
quinizarin (leucoquinizarin) (10 g, 46 mmol) afforded orange crys-
the naturally occurring premithramycinone H (2). Of the
compounds tested for antitumor activity, the simple deriva-
tive 11b showed IC50 in µmolar concentrations.
[
35]
[34]
tals (6.5 g, 54 %, m.p. 133Ϫ135 °C, ref. 136Ϫ137 °C, ref. 105
°
1
(
1
3
C). C NMR (50 MHz, CDCl
Ј), 125.5 (d, C-3), 127.4 (d), 133.7 (s), 133.9 (s), 134.8 (d), 134.9
d), 147.3 (s), 155.8 (s, C-1), 158.4 (s, C-4), 186.7 (s, C-9), 187.6 (s,
3
): δ ϭ 23.1 (q, C-2Ј), 65.8 (d, C-
C-10) ppm.
Experimental Section
Oxidation of (Hydroxyethyl)anthraquinones 7a,b with PCC. General
General: For general methods and instrumentation see ref.[31]
NMR: ‘‘E’’ indicates ‘‘enol’’ tautomer and ‘‘K’’ the ‘‘keto’’ tau-
tomer.
Procedure: Solutions of the (hydroxyethyl)anthraquinones 7a,b
(
1.53 mmol) in dry dichloromethane (100 mL) were treated with
PCC (2.09 mmol) and stirred at room temperature until the starting
materials had been converted (ca. 2 h, TLC control). The solids
were removed by filtration and the organic phases were concen-
trated under reduced pressure. The crude products were purified by
Hydroxyethylation of Anthraquinone Monophenols 6aϪc. General
Procedure: Using a modification[ of the Marschalk
11]
[10]
reaction,
a solution of the hydroxyanthraquinones 6aϪc (6.7 mmol) [6a and
2 2
flash column chromatography on silica gel (6 g, CH Cl ) to afford
6
c are commercially available, for 1-hydroxy-8-methoxyanthraqui-
the 2-acetylanthraquinones 8a,b.
[
32,33]
none (6b) see refs.
] in methanol (40 mL) was first treated at 0
2
(
1
-Acetyl-1-hydroxyanthraquinone (8a):[36] Starting material 7a
410 mg, 1.53 mmol), product 8a (300 mg, 1.13 mmol, 73 %, m.p.
°
C with an aqueous NaOH solution (10 mL, 1 ) and then under
nitrogen with a solution of sodium dithionite (20 mL, 0.5 ). The
color changed from purple-red to brownish-yellow after the di-
thionite reduction. Acetaldehyde (35.4 mmol, 2 mL) was then ad-
ded and stirring at 5 °C (7a, 7b at 20 °C) was continued until the
starting material was almost (ca. 90 %) consumed (TLC control,
ca. 2 h). The solution was diluted with water and hydrogen peroxide
81 °C, ref.[ 166 °C), yellow solid. H NMR (200 MHz, CDCl
36]
1
):
3
δ ϭ 2.79 (s, 3 H, 2Ј-H), 7.81Ϫ7.90 (m, 3 H, 4-H, 6-H, 7-H), 8.17
(
d, J3,4 ϭ 7.99 Hz, 1 H, 3-H), 8.26Ϫ8.35 (m, 2 H, 5-H, 8-H), 13.64
1
3
(s, 1 H, OH) ppm. C NMR (50 MHz, CDCl
3
): δ ϭ 32.3 (q, C-
Ј), 117.5 (s, C-9a), 119.0 (d, C-4), 127.5 (d, C-8), 127.9 (d, C-5),
32.4 (s, C-2), 133.4 (s, C-10a), 133.6 (s, C-8a), 134.9 (d, C-6), 135.5
2
1
(3 %, ca. 10 mmol) was added for re-oxidation of the hydroanthra-
(
1
d, C-5), 136.4 (s, C-4a), 138.2 (d, C-3), 162.7 (s, C-1), 182.3 (s, C-
0), 189.3 (s, C-9), 198.2 (s, C-1Ј) ppm.
quinones to the anthraquinones. The solution was acidified with
HCl (10 mL, 1 ), the precipitate collected by filtration and the
aqueous phase extracted with dichloromethane (10 mL). The dried
2-Acetyl-1-hydroxy-8-methoxyanthraquinone (8b): Starting material
precipitate and the residue from the extraction were combined and 7b (80 mg, 0.27 mmol), product 8b (50 mg, 0.17 mmol, 63 %, m.p.
1
purified by column chromatography on silica gel (30 g; CH
by crystallization to afford the (hydroxyethyl)anthraquinones
2
Cl
2
) or
212Ϫ213 °C), yellow solid. H NMR (200 MHz, CDCl ): δ ϭ 2.80
3
(s, 3 H, CH ), 4.13 (s, 3 H, OCH ), 7.43 (d, J ϭ 8.05 Hz, 1 H,
3
3
6,7
7
aϪc.
7-H), 7.83Ϫ8.15 (m, 4 H, 3-H, 4-H, 5-H, 6-H), 14.00 (s, 1 H, OH)
1
3
ppm. C NMR (50 MHz, CDCl
ЈЈ), 118.3 (d, C-7), 118.9 (d, C-6), 120.7 (d, C-4), 120.9 (s, C-8a,
C-9a), 133.0 (s, C-2), 135.6 (s, C-10a), 135.8 (s, C-4a), 136.7 (d, C-
3
): δ ϭ 32.3 (q, C-2Ј), 57.2 (q, C-
1
6
2
6
-Hydroxy-2-(1-hydroxyethyl)anthraquinone (7a): Starting material
a (1.0 g, 6.7 mmol), product 7a, yellow crystals (0.53 g, 44 %, m.p.
93Ϫ294 °C). H NMR (200 MHz, CDCl
.50 Hz, 3 H, 2Ј-H), 5.30 (q, J1Ј,2Ј ϭ 6.50 Hz, 1 H, 1Ј-H), 7.75Ϫ7.96
1
1
3
): δ ϭ 1.61 (d, J1Ј,2Ј
ϭ
5
1
), 137.2 (d, C-3), 161.5 (s, C-1), 162.8 (s, C-8), 182.8 (s, C-10),
89.6 (s, C-9), 198.8 (s, C-1Ј) ppm. MS (EI, 70 eV): m/z (%) ϭ 296
13
(
(
m, 4 H), 8.29Ϫ8.35 (m, 2 H), 13.07 (s, 1 H, OH) ppm. C NMR
50 MHz, CD Cl ): δ ϭ 23.65 (q, C-2Ј), 51.84 (d, C-1Ј), 116.02 (s,
ϩ
ϩ
(
199) [M ], 281 (68) [M Ϫ CH
7), 126 (20), 115 (5), 77 (4), 63 (12), 43 (29). IR (KBr, cm ): ν˜ ϭ
450 (OH), 3100 (CH), 3002 (CH), 2940 (CH), 2842 (OCH ), 1667
CO), 1631 (CO), 1600 (aryl), 1584 (aryl), 1486, 1269, 1228, 1191.
UV (CH CN): λmax (lg ε) ϭ 269 (2.25) nm. C17 (296.28):
calcd. C 68.92, H 4.08; found C 68.74, H 3.80.
3
], 250 (18), 238 (10), 210 (5), 152
2
2
Ϫ1
(
3
(
C-9a), 119.06 (d, C-4), 127.01 (d, C-8), 127.25 (d, C-5), 132.46 (s,
C-2), 133.55 (s, C-4a), 133.89 (s, C-8a), 134.43 (d, C-6), 134.90 (d,
C-7), 135.58 (s, C-10a), 135.99 (d, C-3), 160.48 (s, C-1), 182.85 (s,
3
12 5
H O
Ϫ1
3
C-10), 189.00 (s, C-9) ppm. IR (KBr, cm ): ν˜ ϭ 3556, 3417, 3097,
1
1
674, 1633, 1589, 1435, 1362, 1313, 1298, 1201, 1184, 1157, 1030,
016, 787, 729, 679, 598, 499. UV (CH
CN): λmax (lg ε) ϭ 271 2-Acetyl-1,4-dihydroxyanthraquinone (8c):[37]
A solution of 7c
3
ϩ
(
(
(
4.52), 414 (2.05) nm. MS (EI, 70 eV): m/z (%) ϭ 268 (8) [M ], 250 (200 mg, 0.70 mmol) in dry THF (20 mL) was treated with IBX {1-
5
15), 237 (15), 222 (10), 207 (10), 192 (26), 163, 18), 149 (30), 109
32), 83 (52), 57 (50), 43 (40), 28 (100). HRMS (EI, 70 eV, mol/L, 5 mL) and stirred at 50Ϫ60 °C (45 min, TLC control). The
): calcd. 268.07356, found 268.07281. solution was filtered and the solvent removed under reduced press-
hydroxy-1-oxo-1H-1λ -benzo[d][1,2]iodoxol-3-one} in DMSO (0.14
16 12 4
C H O
Eur. J. Org. Chem. 2004, 209Ϫ219
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
213

K. Krohn, J. Vitz
):
FULL PAPER
ure. The crude product was purified by flash column chromatogra-
1
from dichloromethane/diethyl ether. H NMR (200 MHz, CDCl
δ ϭ 2.55 (s, 3 H, CH , 2-H), 2.64 (s, 3 H, CH , 2ЈЈ-H), 4.04 (s, 3
), 7.36 (d, J6Ј,7Ј ϭ 8.29, 1 H, 7Ј-H), 7.71 (dd, J6Ј,7Ј ϭ 8.29,
5Ј,6Ј ϭ 7.55 Hz, 1 H, 6Ј-H), 7.89 (d, J5Ј,6Ј ϭ 7.55 Hz, 1 H, 5Ј-H),
8.03 (d, J3Ј,4Ј ϭ 8.01 Hz, 1 H, 4Ј-H), 8.23 (d, J3Ј,4Ј ϭ 8.01 Hz, 1 H,
3
phy on silica gel (4 g, CH
2
Cl
2
) to afford 8c as an orange solid
3
3
[37]
(
148 mg, 0.53 mmol, 75 %, m.p. 199Ϫ201 °C, ref. 200Ϫ202 °C). H, OCH
C NMR (50 MHz, CDCl
3
1
3
3
): δ ϭ 32.1 (q, C-2Ј), 114.5 (s, C-9a),
J
115.8 (d, C-3), 127.7 (s, C-4a), 127.7 (d, C-8), 130.1 (d, C-5), 133.6
1
3
(
(
s, C-2), 133.8 (s, C-10a), 135.3 (d, C-7, C-6), 137.7 (s, C-8a), 156.8 3Ј-H) ppm. C NMR (50 MHz, CDCl
s, C-4), 157.1 (s, C-1), 187.5 (s, C-9), 187.8 (s, C-10), 197.8 (s, C- (q, C-2ЈЈ), 57.2 (q, OCH ), 119.0 (d, C-7Ј), 119.8 (d, C-6Ј), 123.2
(s, C-8aЈ), 125.2 (d, C-5Ј), 127.8 (s, C-9aЈ), 133.8 (d, C-4Ј), 135.0
3
): δ ϭ 21.9 (q, C-2), 30.8
3
1Ј) ppm.
(
(
s, C-2Ј), 135.4 (d, C-3Ј), 136.5 (s, C-10aЈ), 138.8 (s, C-4aЈ), 148.5
s, C-1Ј), 160.5 (s, C-8Ј), 169.8 (s, C-1Ј), 181.5 (s, C-10Ј), 182.9 (s,
1
-Hydroxy-5,8-dimethoxy-3-methyl-9,10-dioxo-9,10-dihydroanthra-
[19]
cene-2-carbaldehyde (8d): A solution of 7d (0.500 g, 1.52 mmol)
in CH Cl (150 mL) was treated with activated MnO (2.65 g,
0.48 mmol) and stirred at 22 °C (overnight, TLC control). Silica
C-9Ј), 198.0 (s, C-1ЈЈ) ppm. MS (EI, 70 eV): m/z (%) ϭ 338 (20)
2
2
2
ϩ
ϩ
[
M ], 296 (100) [M Ϫ C
18), 182 (12), 153 (14), 139 (42), 76 (12), 43 (6). IR (KBr, cm ):
ν˜ ϭ 3095 (CH), 2924 (CH), 2857 (OCH
), 1760 (CO), 1703 (CO),
678 (CO), 1584 (Aryl.), 1481, 1455, 1378. UV (CH CN): λmax (lg
(338.31):
2 2
H O], 281 (95), 251 (80), 238 (60), 210
3
Ϫ1
(
gel (5 g) was added and the solvent was removed under reduced
pressure. The crude product was purified by flash column chroma-
3
1
3
tography on silica gel (20 g, CH
0.480 g, 1.46 mmol, 96 %, m.p. 210Ϫ213 °C). H NMR (300 MHz,
CDCl ): δ ϭ 2.71 (s, 3 H, CH ), 4.02 (s, 3 H, OCH ), 4.05 (s, 3 H,
OCH
2 2
Cl ) to afford 8d as an orange solid
14 6
ε) ϭ 275 (3.51), 327 (3.22), 384 (3.11) nm. C19H O
1
(
calcd. C 67.45, H 4.17; found C 67.03, H 3.99.
3
3
3
), 7.42 (s, 2 H, 6-H, 7-H), 7.51 (s, 1 H, 4-H), 10.76 (s, 1 H, 4-Acetoxy-2-acetyl-9,10-dioxo-9,10-dihydroanthracen-1-yl Acetate
CHO), 13.58 (s, 1 H, OH) ppm. IR (KBr, cm ): ν˜ ϭ 1695, 1675, (9c): Prepared according to method B. Starting material 8c
3
Ϫ1
1
1
640, 1605, 1590, 1570, 1495, 1440, 1410, 1350, 1285, 1255, 1235,
195, 1130, 1095, 1065, 1010, 985, 880, 825. UV (CH Cl
): λmax (lg 0.92 mmol, 90 %, m.p. 161 °C) after crystallization from chloro-
(288 mg, 1.02 mmol) afforded red crystals of 9c (338 mg,
2
2
1
ε) ϭ 225 (4.57), 251 (4.25), 450 (3.99) nm. MS (EI, 70 eV): m/z
(
2
(
form/petroleum ether. H NMR (200 MHz, CDCl
H, CH ), 2.54 (s, 3 H, CH ), 2.63 (s, 3 H, CH ), 7.74 (s, 1 H, 3Ј-
H), 7.75Ϫ7.81 (m, 2 H, 5Ј-H, 8Ј-H), 8.13Ϫ8.21 (m, 2 H, 6Ј-H, 7Ј-
3
): δ ϭ 2.49 (s, 3
ϩ
%) ϭ 326 (62) [M ], 298 (100), 268 (9), 255 (17), 237 (9), 223 (4),
09 (6), 181 (6), 165 (5), 152 (6), 127 (7), 97 (7), 83 (7), 71 (9), 57
13), 43 (11). HRMS (EI, 70 eV, C18
): calcd. 326.0790, found H) ppm. C NMR (50 MHz, CDCl
(326.30): calcd. C 66.25, H 4.32; found C
CH ), 30.8 (q, C-2ЈЈ), 127.3 (d, C-3Ј), 127.5 (d, C-8Ј), 128.7 (s, C-
4aЈ, C-9aЈ), 131.0 (d, C-5Ј), 133.5 (s, C-2Ј), 133.9 (s, C-10aЈ), 134.7
d, C-6Ј), 134.8 (d, C-7Ј), 139.4 (s, C-8aЈ), 146.7 (s, C-1Ј), 148.2 (s,
C-4Ј), 169.5 (s, C-1), 169.8 (s, C-1ЈЈЈ), 181.5 (s, C-9Ј), 181.7 (s, C-
3
3
3
1
3
H
14
O
6
3 3
): δ ϭ 21.5 (q, CH ), 21.7 (q,
326.0790. C18
H
14
O
6
3
6
5.90, H 4.23.
(
Acetylation of the Phenols 8aϪc. General Procedures. Method A: A
suspension of the phenol (10 mmol) in acetic anhydride (30 mL)
was treated with three drops of pyridine and the solution stirred at
Ϫ1
1
2
1
0Ј), 196.3 (s, C-1ЈЈ) ppm. IR (KBr, cm ): ν˜ ϭ 3070, 3028, 2927,
854, 1766, 1709, 1674, 1589, 1431, 1396, 1365, 1319, 1254, 1176,
157, 1080, 1011. UV (CH CN): λmax (lg ε) ϭ 267 (4.91), 383 (4.30)
3
nm. MS (CI, 120 eV): m/z (%) ϭ 367 (10) [M ϩ 1], 351 (6), 325
100), 282 (18), 267 (4), 57 (88), 43 (26). C20 (366.33): calcd.
C 65.57, H 3.85; found C 65.73, H 3.69.
8
0 °C for 2 h. The mixture was then poured into ice-cold water,
stirred for 20 min, and then extracted with dichloromethane
80 mL). The organic phase was washed with water (4 ϫ 10 mL),
dried with MgSO and the solvent removed under reduced pressure.
ϩ
(
(
14 7
H O
4
The crude product was isolated as a red solid, which was purified
as detailed below. Method B: To a solution of the phenol (10 mmol)
in dry dichloromethane (40 mL), pyridine (4.0 mL), acetyl chloride
1
-Hydroxy-2-(1-hydroxy-3-oxobutyl)-5,8-dimethoxy-3-methyl-
[19]
anthraquinone (9d):
A solution of 8d (500 mg, 1.53 mmol) in
THF (150 mL) was treated with an NaOH solution (1 mol/L,
0 mL) and water (50 mL) and cooled to 0 °C. Acetone (25 mL)
was added and the solution was stirred at 0Ϫ5 °C under argon
(3.5 mL, 50 mmol) and DMAP (3 mol %) were added successively.
2
The solution was stirred at 20 °C for approximately 2 h (TLC con-
trol). The solution was then diluted with dichloromethane (100 mL)
and poured into ice-cold HCl (2 mol/L, 100 mL). The phases were
separated and the organic phase was first washed with dilute aque-
(
(
7 h, TLC control). The solution was poured into ice-cold water
100 mL), acidified to pH ϭ 5, extracted with CH Cl (3 ϫ 60 mL)
SO . The solvent was removed under reduced
pressure and the crude product purified by column chromatogra-
phy on silica gel (20 g, CH Cl /MeOH, 98:2) to afford 9d as an
orange solid (418 mg, 1.09 mmol, 71 %, m.p. 184 °C). H NMR
400 MHz, CDCl ): δ ϭ 2.22 (s, 3 H, COCH ), 2.54 (s, 3 H, CH ),
2.92 (dd, Jgem ϭ 16.5, Jvic ϭ 5 Hz, 1 H, 2Ј-H), 3.33 (dd, Jgem
16.5, Jvic ϭ 8.5 Hz, 1 H, 2Ј-H), 3.96 (d, J ϭ 10 Hz, 1 H, 1Ј-OH),
.37 mmol) afforded red crystals of 9a (372 mg, 1.21 mmol, 88 %, 4.00 (s, 3 H, OCH ), 4.03 (s, 3 H, OCH ), 5.51 (ddd, J
ϭ 10,
2
2
and dried with Na
2
4
ous NaHCO
The organic phase was dried with MgSO
under reduced pressure and the resultant crude product purified as
described below.
3
solution (2 ϫ 40 mL) and then with brine (50 mL).
, the solvent removed
4
2
2
1
(
3
3
3
2
-Acetyl-9,10-dioxo-9,10-dihydroanthracen-1-yl Acetate (9a):[36]
Prepared according to method B. Starting material 8a (365 mg,
ϭ
1
3
3
H,OH
[
36]
m.p. 165 °C, ref. 167Ϫ168 °C) after crystallization from chloro- Jvic ϭ 8.5, Jvic ϭ 5 Hz, 1 H, 1Ј-H), AB-signal (δA ϭ 7.37, δB
ϭ
1
form/petroleum ether. H NMR (200 MHz, CDCl
H, 2ЈЈ-H), 2.65 (s, 3 H, 2-H), 7.74Ϫ7.86 (m, 2 H), 8.10 (d, J ϭ
.13 Hz, 1 H), 8.17Ϫ8.34 (m, 3 H) ppm. 13C NMR (50 MHz, 1495, 1405, 1275, 1245, 1235, 1195, 1130, 1100, 1055, 1005. UV
CDCl ): δ ϭ 21.8 (q, C-2ЈЈ), 30.9 (q, C-2), 125.8 (d, C-8Ј), 127.4 (CH Cl ): λ
(lg ε) ϭ 231 (4.65), 260 (4.30), 451 (4.06). MS (EI,
d, C-5Ј), 127.8 (d, C-4Ј), 132.8 (s, C-9aЈ), 134.6 (d, C-6Ј), 134.9 (d, 70 eV): m/z (%) ϭ 384 (10) [M ], 327 (85), 298 (100), 267 (7), 255
C-7Ј), 135.1 (d, C-3Ј), 137.4 (s, C-2Ј, C-10aЈ), 138.6 (s, C-4aЈ, C- (13), 237 (7), 139 (5), 58 (5), 43 (18). C H O (384.38): calcd. C
3
): δ ϭ 2.55 (s, 3
7.41, J ϭ 9 Hz, 2 H, 6-H, 7-H), 7.51 (s, 1 H, 4-H), 13.64 (s, 1 H,
OH) ppm. IR (KBr, cm ): ν˜ ϭ 3500, 2945, 1720, 1665, 1630, 1565,
Ϫ1
8
3
2
2
max
ϩ
(
2
1
20
7
8aЈ), 149.0 (s, C-1Ј), 169.6 (s, C-1), 181.8 (s, C-9Ј), 182.3 (s, C-10Ј),
65.62, H 5.24; found C 65.47, H 5.21.
197.7 (s, C-1ЈЈ) ppm.
Baker؊Venkataraman Rearrangement of 9aϪc. General Procedure:
2
-Acetyl-8-methoxy-9,10-dioxo-9,10-dihydroanthracen-1-yl Acetate LiH (10 mmol) was added at 0 °C to a solution of 9aϪc (3 mmol)
in dry THF (300 mL) and the suspension was heated to reflux un-
crystals of 9b (42 mg, 75 %, m.p. 172Ϫ173 °C) after crystallization der argon for ca. 20 h (TLC control). After cooling to 20 °C, the
(9b): Prepared according to method A. 8b (50 mg) afforded orange
214
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 209Ϫ219

Total Synthesis of Premithramycinone H
FULL PAPER
solution was neutralized at 0 °C by addition of HCl (2 , 6 mL).
The solvent was removed under reduced pressure, the residue redis-
solved in dichloromethane (100 mL), the organic phase washed
with HCl (2 , 2 ϫ 20 mL) and water (2 ϫ 20 mL), dried with
(enol): δ ϭ 2.23 (s, 3 H, CH
OCH ), 4.07 (s, 3 H, OCH ), 5.86 (s, 1 H, 2Ј-H), 7.43 (br. s, 2 H,
6-H, 7-H), 7.59 (s, 1 H, 4-H), 13.12 (s, 1 H, OH) ppm. C NMR
(50 MHz, CDCl ) (enol): δ ϭ 21.1 (q, C-1ЈЈ), 25.8 (q, C-4), 57.7
(q, OCH ), 57.7 (q, OCH ), 104.2 (d, C-3Ј), 116.6 (s, C-9a), 116.7
3 3
), 2.48 (s, 3 H, CH ), 4.05 (s, 3 H,
3
3
1
3
3
Na
2
SO
4
and filtered. The solvent was removed under reduced
3
3
pressure and the crude product was purified as described below.
(s, C-8a), 116.9 (s, C-10a), 120.5 (d, C-7), 121.5 (d, C-6), 122.4 (d,
C-4), 135.1 (s, C-2, C-4a), 146.1 (s, C-3), 155.3 (s, C-5), 155.9 (s,
C-8), 159.9 (s, C-1), 186.2 (s, C-1Ј), 189.3 (s, C-9, C-10), 193.1 (s,
1
9
0
-Hydroxy-2-(3-oxobutyryl)anthraquinone (10a): Starting material
a (350 mg, 1.14 mmol), product 10a pale yellow crystals (274 mg,
Ϫ1
C-3Ј) ppm. IR (KBr, cm ): ν˜ ϭ 1670, 1630, 1580, 1565, 1490,
.90 mmol, 74 %, m.p. 189Ϫ191 °C) after crystallization from di-
1
(
(
405, 1345, 1275, 1230, 1185, 1135, 1065, 980, 875, 820. UV
CH Cl ): λmax (lg ε) ϭ 228 (4.56), 272 (4.39), 454 (4.07) nm. MS
EI, 70 eV): m/z (%) ϭ 382 (52) [M ], 367 (16), 339 (100), 325 (33),
67 (5), 191 (6), 97 (10), 69 (12), 57 (18). C21 (382.36): calcd.
C 65.96, H 4.74; found C 64.75, H 4.74.
1
chloromethane/diethyl ether. H NMR (200 MHz, CDCl
3
) (enol):
2
2
δ ϭ 2.31 (s, 3 H, 4Ј-H), 6.85 (s, 1 H, 2Ј-H), 7.86Ϫ7.95 (m, 3 H, 4-
H, 6-H, 7-H), 8.32Ϫ8.42 (m, 3 H, 3-H, 5-H, 8-H), 13.97 (s, 1 H,
ϩ
2
18 7
H O
OH), 16.06 (br. s, 1 H, OH) ppm. 13C NMR (50 MHz, CDCl
)
3
(enol): δ ϭ 27.4 (q, C-4Ј), 103.2 (d, C-2Ј), 116.9 (s, C-9a), 119.3 (d,
C-4), 127.6 (d, C-8), 127.9 (d, C-5), 129.2 (s, C-2), 133.4 (s, C-10a),
Acid-Catalyzed Ring Closure of β-Diketones 10aϪd to Anthrapyr-
anones. General Procedure. Method A: Concd. HCl (0.2 mL) was
added to a solution of 10aϪc (3 mmol) in acetic acid (15 mL). The
solution was stirred at 100Ϫ110 °C for ca. 6 h (TLC control). After
cooling to 20 °C, ethyl acetate (200 mL) was added and the solution
was washed successively with water (3 ϫ 30 mL) and a dilute aque-
1
1
(
33.8 (s, C-4a, C-8a), 134.9 (d, C-6), 135.5 (d, C-7), 137.7 (d, C-3),
62.3 (s, C-1), 176.4 (s, C-3Ј), 182.3 (s, C-10), 189.7 (s, C-9), 197.9
s, C-1Ј) ppm. IR (KBr, cmϪ1): ν˜ ϭ 3444, 3093, 3062, 2924, 1670,
1
1
635, 1589, 1547, 1477, 1419, 1350, 1331, 1304, 1265, 1107, 1045,
022. UV (CH CN): λmax (lg ε) ϭ 270 (3.80), 406 (3.15) nm. MS
3
ϩ
(
EI, 70 eV): m/z (%) ϭ 308 (4) [M ], 266 (40), 251 (100), 223 (5),
97 (2), 181 (2), 167 (20), 139 (30), 111 (12), 97 (18), 71 (24), 57
36), 43 (28), 28 (50). C18 (308.28): calcd. C 70.13, H 3.92;
ous NaHCO
3
solution (3 ϫ 30 mL). The organic phase was dried
4
, filtered, and the solvent was removed under reduced
1
(
with Na SO
2
12 5
H O
pressure. The crude product was purified as described below.
Method B: The β-diketone 10d (0.2 mmol) was dissolved at 0 °C in
trifluoroacetic acid (1.5 mL). After 20 min, the solution was
warmed to 20 °C for 10 min. Dichloromethane (10 mL) was then
added and the solvent removed under reduced pressure. The pro-
cedure was repeated twice to remove traces of trifluoroacetic acid.
The crude product was purified as described below.
found C 69.30, H 3.54.
1-Hydroxy-8-methoxy-2-(3-oxobutyryl)anthraquinone (10b): The
starting material 9b (100 mg, 0.30 mmol) afforded a crude product
(
(
(
50 mg) which was purified by PTLC to yield 10b as yellow crystals
40 mg, 0.12 mmol, 40 %, m.p. 218.5Ϫ219.5 °C). H NMR
1
200 MHz, CDCl
), 6.83 (s, 1 H, 2Ј-H), 7.43 (d, J6,7 ϭ 8.21 Hz, 1 H, 7-H), 7.84
m, 2 H, 4-H, 6-H), 8.00 (d, J5,6 ϭ 7.49 Hz, 1 H, 5-H), 8.33 (d,
3
) (enol): δ ϭ 2.30 (s, 3 H, 4Ј-H), 4.13 (s, 3 H,
OCH
(
3
2
-Methyl-1-oxabenzo[a]anthracene-4,7,12-trione (11a):[36] Prep-
aration according to method A. 10a (252 mg, 0.82 mmol) afforded
pale yellow crystals of 11a after crystallization from dichlorometh-
ane/diethyl ether (120 mg, 0.42 mmol, 51 %, m.p. 288Ϫ290 °C,
J
3,4 ϭ 8.11 Hz, 1 H, 3-H), 14.31 (s, 1 H, OH), 16.09 (s, 1 H, OH)
) (enol): δ ϭ 27.4 (q, CH ), 57.2
), 103.2 (d, C-2Ј), 118.4 (d, C-7), 118.9 (d, C-6), 120.7 (d,
ppm. 13C NMR (50 MHz, CDCl
3
3
(q, OCH
3
ref.[ 293 °C). H NMR (200 MHz, CDCl
36]
1
): δ ϭ 2.57 (s, 3 H, 1Ј-
H), 6.34 (s, 1 H, 3-H), 7.81Ϫ7.85 (m, 2 H, 9-H, 10-H), 8.26Ϫ8.35
m, 3 H, 6-H, 8-H, 11-H), 8.57 (d, J5,6 ϭ 8.24 Hz, 1 H, 5-H) ppm.
3
C-4), 129.5 (s, C-2, C-8a, C-9a), 135.8 (s, C-4a, C-10a), 136.7 (d,
C-5), 136.8 (d, C-3), 161.5 (s, C-1), 162.4 (s, C-8), 176.8 (s, C-3Ј),
(
182.7 (s, C-10), 189.7 (s, C-9), 197.9 (s, C-1Ј) ppm. UV (CH
3
CN):
1
3
3 3
C NMR (50 MHz, CDCl ): δ ϭ 21.2 (q, CH ), 111.6 (d, C-3),
λ
max (lg ε) ϭ 274 (4.52), 422 (4.04) nm. MS (EI, 70 eV): m/z (%) ϭ
1
1
22.8 (s, C-12a), 123.5 (d, C-6), 127.5 (d, C-11), 127.7 (d, C-8),
28.1 (s, C-4a), 132.2 (d, C-5), 132.5 (s, C-7a), 134.6 (d, C-9), 134.7
ϩ
3
38 (36) [M ], 295 (100), 281 (70), 252 (12), 238 (20), 210 (10), 182
8), 154 (8), 139 (22), 76 (5), 63 (5), 43 (38). HRMS (EI, 70 eV,
): calcd. 338.0790, found 338.0849. C19 (338.20):
calcd. C 67.45, H 4.17; found C 66.92, H 3.76.
(
C
(
(
s, C-11a), 135.3 (d, C-10), 138.1 (s, C-6a), 155.2 (s, C-12b), 169.2
s, C-2), 177.5 (s, C-4), 181.85 (s, C-7), 182.8 (s, C-12) ppm.
19
H
14
O
6
14 6
H O
1
1-Methoxy-2-methyl-1-oxabenzo[a]anthracene-4,7,12-trione (11b):
Preparation according to method A. Starting material 10b (40 mg,
.12 mmol) afforded a crude product which was purified by PTLC
silica gel, CH Cl /MeOH, 98:2) to yield 11b as yellow crystals
(35 mg, 0.11 mmol, 92 %, m.p. 263Ϫ264 °C). H NMR (200 MHz,
CDCl ): δ ϭ 2.58 (s, 3 H, CH ), 4.09 (s, 3 H, OCH ), 6.32 (s, 1 H,
-H), 7.40 (d, J9,10 ϭ 8.31 Hz, 1 H, 10-H), 7.74 (dd, J8,9 ϭ 7.74,
1,4-Dihydroxy-2-(3-oxobutyryl)anthraquinone (10c): The starting
material 9c (338 mg, 0.92 mmol) afforded a crude product (304 mg)
which was purified by crystallization from dichloromethane/diethyl
0
(
2
2
ether to yield 10c as yellow crystals (286 mg, 0.88 mmol, 95 %, m.p.
1
1
1
56Ϫ159 °C). H NMR (200 MHz, CDCl
3
) (enol): δ ϭ 2.52 (s, 3
3
3
3
H, CH
3
), 6.14 (s, 1 H, 2Ј-H), 8.08 (s, 1 H, 3-H), 8.24Ϫ8.29 (m, 2
3
J
8
H, 5-H, 8-H), 8.34Ϫ8.39 (m, 2 H, 6-H, 7-H), 14.10 (s, 1 H, OH),
Ϫ1
9,10 ϭ 8.31, 1 H, 9-H), 7.91 (dd, J8,9 ϭ 7.74, J8,10 ϭ 1.05 Hz, 1 H,
-H), 8.22 (d, J5,6 ϭ 8.24 Hz, 1 H, 6-H), 8.53 (d, J5,6 ϭ 8.24 Hz, 1
1
1
9
4.20 (s, 1 H, OH) ppm. IR (KBr, cm ): ν˜ ϭ 3433, 2924, 1770,
674, 1635, 1589, 1431, 1354, 1277, 1246, 1196, 1161, 1084, 1011,
45, 829, 798, 725, 420. MS (CI, isobutane, 200 eV): m/z (%) ϭ 325
5) [M ϩ 1], 225 (3), 113 (8), 57 (100), 39 (6).
1
3
H, 5-H) ppm. C NMR (50 MHz, CDCl
57.1 (q, OCH ), 111.7 (d, C-3), 118.9 (d, C-10), 119.8 (d, C-9),
22.7 (d, C-8), 123.3 (s, C-11a), 124.8 (s, C-12a), 128.4 (s, C-2Ј),
3 3
): δ ϭ 21.4 (q, CH ),
ϩ
3
(
1
1
-Hydroxy-5,8-dimethoxy-3-methyl-2-(3-oxobutyryl)anthraquinone
131.2 (d, C-6), 134.8 (s, C-7a), 135.2 (d, C-5), 137.0 (s, C-6a), 154.7
(
10d): A solution of 9d (150 mg, 0.39 mmol) in CH Cl (40 mL)
2
2
(s, C-1Ј), 160.2 (s, C-11), 168.7 (s, C-2), 177.2 (s, C-4), 181.3 (s, C-
Ϫ1
was treated with activated MnO
2
(1.70 g, 19.50 mmol) and stirred 7), 183.3 (s, C-12) ppm. IR (KBr, cm ): ν˜ ϭ 3089 (CH), 2929
at room temp. (24 h, TLC control). Silica gel (5 g) was added and
the solvent was removed under reduced pressure. The crude prod-
uct was purified by flash column chromatography on silica gel (5 g,
(CH), 2841 (CH), 1693 (CO), 1651, 1585, 1470, 1388, 1320, 1295,
1222. UV (CH Cl ): λmax (lg ε) ϭ 278 (4.5), 375 (2.5) nm. MS (EI,
80 eV): m/z (%) ϭ 320 (100) [M ], 291 (16), 274 (22), 251 (22), 234
2
2
ϩ
CH
2
Cl
2
/diethyl ether, 95:5) to afford 10d as an orange solid (54 mg,
(8), 206 (8), 163 (6), 138 (26), 125 (8), 63 (12), 39 (38). C19
(320.07): calcd. C 71.25, H 3.78; found C 69.65, H 3.45.
12 5
H O
1
0.14 mmol, 36 %, m.p. 184 °C). H NMR (200 MHz, CDCl )
3
Eur. J. Org. Chem. 2004, 209Ϫ219
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
215

K. Krohn, J. Vitz
FULL PAPER
6
-Hydroxy-2-methyl-1-oxabenzo[a]anthracene-4,7,12-trione (11c):
Preparation according to method A. Starting material 10c (192 mg,
.59 mmol) afforded pale yellow crystals of 11c after crystallization
from CH Cl /diethyl ether (144 mg, 0.47 mmol, 79 %, m.p.
Dimethyl Penta-2,3-dienedioate (13):[41] Triethylamine (22 mL, 0.16
mol) was added slowly (over 10 min) to a solution of dimethyl 3-
chloropent-2-enedioate[
42]
(28.34 g, 0.15 mol) in dry THF
0
2
2
1
(100 mL). The solution was stirred at 0Ϫ5 °C for 18 h and the
), precipitate which formed was filtered and washed with diethyl ether
(3 ϫ 75 mL). The ethereal phases were combined and extracted
2
6
37Ϫ240 °C). H NMR (200 MHz, CDCl
3 3
): δ ϭ 2.56 (s, 3 H, CH
.28 (s, 1 H, 3-H), 7.85Ϫ7.98 (m, 2 H, 9-H, 10-H), 8.05 (s, 1 H, 5-
1
3
H), 8.27Ϫ8.37 (m, 2 H, 8-H, 11-H), 12.68 (s, 1 H, OH) ppm.
C
successively with HCl (1 , 3 ϫ 75 mL) and brine (3 ϫ 75 mL).
The organic phase was dried with MgSO and the solvent was re-
s, C-12a), 120.74 (d, C-5), 122.1 (s, C-4a), 127.2 (d, C-8/C-11), moved under reduced pressure to give 13 as a colorless viscous
NMR (50 MHz, CDCl
(
3
): δ ϭ 21.0 (q, CH
3
), 110.1 (d, C-3), 120.0
4
[41]
1
27.6 (d, C-8/C-11), 130.9 (s, C-6a), 132.3 (s, C-7a/C-11a), 134.6 (s, oil (22.69 g, 0.14 mol, 97 %, b.p. 65 °C/0.10 mbar, ref.
58 °C/
): δ ϭ 3.76 (s, 6 H, 2 ϫ
), 6.04 (s, 2 H, 2-H, 4-H) ppm. C NMR (50 MHz, CDCl ):
/C-12), 189.5 (s, C-4) ppm. IR (KBr, cm ): ν˜ ϭ 1763, 1670, 1647, δ ϭ 53.0 (q, 2 ϫ CH
), 92.5 (d, C-2, C-4), 164.1 (s, C-1, C-5), 220.1
589, 1562, 1431, 1392, 1350, 1292, 1246, 1223, 1200, 1173, 1149, (s, C-3) ppm.
022. UV (CH CN): λmax (lg ε) ϭ 270 (2.75) nm. MS (EI, 70 eV):
1
C-7a/C-11a), 134.7 (d, C-9/C-10), 136.0 (d, C-9/C-10), 148.6 (s, C-
0.03 mbar). H NMR (200 MHz, CDCl
3
1
3
1
7
1
1
2b), 158.2 (s, C-6), 169.9 (s, C-2), 176.9 (s, C-7/C-12), 181.2 (s, C- CH
3
3
Ϫ1
3
3
Diels؊Alder Reaction between the Allene 13 and the Ketene Acetals
ϩ
m/z (%) ϭ 306 (80) [M ], 282 (82), 267 (80), 239 (20), 211 (10), 182
25]
1
2a,b. General Procedure:[ The ketene acetals 12a,b (120 mmol)
(12), 167 (14), 149 (20), 111 (18), 84 (34), 57 (70), 43 (100). HRMS
(EI, 70 eV, C18 ): calcd. 306.0528, found 306.0525. C18
(306.27): calcd. C 70.59, H 3.29; found C 69.84, H 2.82.
were added at 0 °C to the allene 13 (100 mmol) and the mixtures
were stirred at this temperature for 5 h. For aromatisation of the
intermediate adducts, methanolic HCl (1.54 mmol/mL) was added
slowly and addition was stopped when the color changed to light
yellow. The solvents were then removed under reduced pressure and
H
10
O
5
10 5
H O
8,11-Dimethoxy-2,5-dimethyl-1-oxabenzo[a]anthracene-4,7,12-trione
(11d): Preparation according to method B. Starting material 10d
(
17 mg, 0.044 mmol) afforded a crude product which was purified the crude products were purified by column chromatography on
Cl /MeOH, 98:2) to afford
silica gel (CH Cl ). Method A: The allene 13 (8.0 g, 51.3 mmol) and
1d as yellow crystals (14 mg, 0.038 mg, 85 %, m.p. 300Ϫ302 °C).
by flash chromatography (silica gel; CH
2
2
2
2
1
the ketene acetal 12a (14.0 g, 69 mmol) afforded 14a and 14b as a
1
H NMR (200 MHz, CDCl
3
): δ ϭ 2.52 (s, 3 H, CH
3
), 2.94 (s, 2 H, mixture which was separated by chromatography (14a: 5.2 g,
20.5 mmol, m.p. 77Ϫ80 °C, ref.[ 75Ϫ77 °C; 14b: 4.6 g, 17.2 mmol,
43]
CH ), 4.03 (s, 6 H, 2 ϫ OCH
9
ppm. C NMR (50 MHz, CDCl
1
1
3
3
), 6.23 (s, 1 H, 3-H), 7.32 (d, J9,10
ϭ
.34 Hz, 1 H), 7.39 (d, J9,10 ϭ 9.34 Hz, 1 H), 7.87 (s, 1 H, 6-H) colorless oil; overall yield: 74 %). Method B: The allene 13 (8.0 g,
13
3
): δ ϭ 20.8 (q, C-1Ј), 24.4 (q, C-
51.3 mmol) and the ketene acetal 12b (17.9 g, 69 mmol) afforded
14a (10.5 g, 41.3 mmol, 80 %, m.p. 77Ϫ80 °C, ref.[ 75Ϫ77 °C) as
43]
ЈЈ), 57.3 (q, OCH
3
), 57.5 (q, OCH ), 113.1 (d, C-3), 119.2 (d, C-
3
0), 121.0 (d, C-9), 122.4 (s, C-12a), 124.9 (d, C-6), 125.5 (s, C-7a, colorless crystals.
C-11a), 125.9 (s, C-4a), 137.4 (s, C-6a), 147.6 (s, C-5), 153.3 (s, C-
Methylation of 14a:[43] MeI (2 mL) and Ag
were added to a solution of 14a (1.69 g, 6.65 mmol) in dry acetone
20 mL) and the reaction was monitored by TLC. The solution was
filtered and the solvent evaporated under reduced pressure. Flash
O (0.54 g, 2.33 mmol)
2
8
1
1
1
3
), 153.9 (s, C-12b), 155.6 (s, C-11), 166.3 (s, C-2), 179.8 (s, C-12),
81.8 (s, C-7), 183.1 (s, C-4) ppm. IR (KBr, cm ): ν˜ ϭ 2924, 2846,
678, 1651, 1631, 1585, 1566, 1466, 1385, 1335, 1265, 1227, 1188,
Ϫ1
(
111, 1061, 980, 841, 825. UV (CH
3
CN): λmax (lg ε) ϭ 273 (4.23),
2 2
chromatography on silica gel (20 g, CH Cl ) afforded 14b (1.73 g,
66 (1.15), 428 (1.43) nm. MS (EI, 70 eV): m/z (%) ϭ 364 (85)
ϩ
6.46 mmol, 97 %) as a colorless oil.
[M ], 335 (35), 307 (28), 278 (24), 265 (26), 240 (62), 199 (12), 183
(
(
100), 155 (26), 139 (12), 105 (12), 76 (35), 57 (50), 43 (96). HRMS
EI, 70 eV, C21 ): calcd. 364.0947, found 364.0920.
Methyl 2-Hydroxy-4-methoxy-6-(methoxycarbonylmethyl)benzoate
H
16
O
6
[43] 1
(
14a):
3 3
H NMR (200 MHz, CDCl ): δ ϭ 3.70 (s, 3 H, OCH ),
Preparation of the Ketene Acetals 12a,b. General Procedure:[38]
solution of the unsaturated ester (100 mmol) in dry THF (30 mL)
was added at Ϫ80 °C over a period of 30 min to a solution of LDA
A
3.82 (s, 3 H, OCH ), 3.84 (s, 2 H, CH ), 3.87 (s, 3 H, OCH ), 6.31
3
2
3
(
d, J3,5 ϭ 2.55 Hz, 1 H, 3-H), 6.44 (d, J3,5 ϭ 2.55 Hz, 1 H, 5-H),
1
1
1.67 (s, 1 H, OH) ppm. 3C NMR (50 MHz, CDCl
C-1ЈЈ), 52.2 (q, OCH ), 52.4 (q, OCH ), 55.8 (q, OCH
C-3), 105.3 (d, C-5), 113.3 (s, C-1), 138.4 (s, C-6), 164.5 (s, C-2),
66.5 (s, C-4), 171.4 (s, C-1Ј), 172.3 (s, C-2ЈЈ) ppm.
3
): δ ϭ 43.2 (t,
), 100.5 (d,
(105 mmol) in dry THF (100 mL). After 30 min, chlorotrimethylsil-
3
3
3
ane (120 mmol) in THF (15 mL) was added and the temperature
was raised to 20 °C over 90 min. The solution was then concen-
trated under reduced pressure and cold hexane was added to form
a white precipitate. The suspension was filtered through a fritted
glass funnel and the solvent was removed under reduced pressure to
give the ketene acetal which was used without further purification.
1
[44]
Methyl 2,4-Dimethoxy-6-(methoxycarbonylmethyl)benzoate (14b):
1
H NMR (200 MHz, CDCl
3
): δ ϭ 3.68 (s, 2 H, CH
), 3.84 (s, 3 H, OCH ), 3.88 (s, 3 H,
), 6.41 (d, J3,5 ϭ 2.23 Hz, 1 H, 3-H), 6.44 (d, J3,5 ϭ 2.23 Hz,
2
), 3.70 (s, 3 H,
OCH
OCH
3
), 3.83 (s, 3 H, OCH
3
3
3
1
3
(
1
1,3-Dimethoxybuta-1,3-dienyloxy)trimethylsilane [1,3-Dimethoxy-
1 H, 5-H) ppm. C NMR (50 MHz, CDCl
3
): δ ϭ 40.1 (t, C-1ЈЈ),
), 56.4 (q, OCH ),
-(trimethylsilyloxy)buta-1,3-diene] (12a):[
39]
Starting material 52.5 (q, OCH ), 52.5 (q, OCH ), 55.9 (q, OCH
3
3
3
3
methyl 3-methoxybut-2-enoate (10.0 g, 77 mmol) afforded 12a
98.2 (d, C-3), 108.0 (d, C-5), 116.2 (s, C-1), 135.6 (s, C-6), 159.5 (s,
57Ϫ62 °C/ C-2), 162.2 (s, C-4), 168.2 (s, C-1Ј), 171.7 (s, C-2ЈЈ) ppm.
[
39]
(
1
12.9 g, 65 mmol, 85 %, b.p. 54 °C/0.7 mbar, ref.
.0 mbar) as a colorless oil. 13C NMR (50 MHz, CDCl
), 54.5 (q, OCH ), 55.4 (q, OCH ), 76.0 (d, C-2), 79.0
t, C-4), 159.1 (s, C-1, C-3) ppm.
3
): δ ϭ 0.7
2
-(Carboxymethyl)-4,6-dimethoxybenzoic Acid (15):[44] KOH (2 g)
was added to a solution of 14b (1.64 g, 4.7 mmol) in ethanol
20 mL) and water (20 mL). The solution was heated to reflux for
-tert-Butoxy-3-methoxy-1-(trimethylsilyloxy)buta-1,3-diene 8 h. After cooling, the solution was neutralized with dilute HCl
(q, 3 ϫ CH
3
3
3
(
(
1
[
40]
(12b):
Starting material tert-butyl 3-methoxybut-2-enoate
(1 ) and the ethanol was removed under reduced pressure. The
(
13.0 g, 75.6 mmol) afforded 12b (17.9 g, 73.3 mmol, 97 %) as a precipitate was purified by recrystallization from ethanol to give 15
13
colorless oil. C NMR (50 MHz, CDCl
2
8
3
): δ ϭ 0.9 (q, 3 ϫ CH
), 80.1 (s, C-1Ј), 80.2 (t, C-4),
7.7 (d, C-2), 154.0 (s, C-3), 159.2 (s, C-1) ppm.
3
),
as colorless crystals (1.06 g, 4.4 mmol, 94 %, m.p. 172Ϫ173 °C,
45] 1
8.8 (q, 3 ϫ CH
3
), 54.5 (q, OCH
3
ref.[ 172Ϫ173 °C). H NMR (200 MHz, CDCl
H, CH ), 3.85 (s, 3 H, OCH ), 3.90 (s, 3 H, OCH
3
3
): δ ϭ 3.79 (s, 2
), 6.47 (br. s, 2
2
3
216
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 209Ϫ219

Total Synthesis of Premithramycinone H
FULL PAPER
H, 3-H, 5-H) ppm. 13C NMR (50 MHz, CDCl
3
2 4
): δ ϭ 40.7 (t, CH ), dried with MgSO and the solvents were removed under reduced
5
5.6 (q, OCH
3 3
), 56.3 (s, OCH ), 98.0 (d, C-5), 108.9 (d, C-3), 114.6 pressure. Crystallization from ethanol afforded 18 (351 mg,
1
(s, C-1), 137.5 (s, C-2), 159.6 (s, C-6), 162.4 (s, C-4), 169.4 (s, C-
0.8 mmol, 37 %, m.p. 177 °C) as pale yellow crystals. H NMR
(200 MHz, CDCl ): δ ϭ 1.49 (s, 9 H, 3 ϫ CH ), 2.64 (s, 3 H, CH ),
.68 (s, 2 H, 2-H), 3.95 (s, 3 H, OCH ), 3.99 (s, 3 H, OCH ), 4.33
s, 2 H, 9Ј-H), 6.52 (d, J6Ј,8Ј ϭ 2.22 Hz, 1 H, 8Ј-H), 6.56 (d, J6Ј,8Ј
.22 Hz, 1 H, 6Ј-H), 6.75 (s, 1 H, 1Ј-H), 14.20 (s, 1 H, OH) ppm.
1
Ј), 173.7 (s, C-2ЈЈ) ppm.
3
3
3
3
3
3
2
,4-Dimethoxy-6-(methoxycarbonylmethyl)benzoic Acid (16):[23] p-
(
ϭ
Toluenesulfonic acid (10 mg) was added to a solution of 15 (1.06 g,
.4 mmol) in dichloromethane (30 mL) and methanol (5 mL) and
2
4
13
C NMR (50 MHz, CDCl
4.1 (t, C-9Ј), 40.7 (t, C-2), 56.1 (q, OCH
s, C(CH
3
): δ ϭ 28.2 (q, 3 ϫ CH
3
), 32.2 (q, CH
3
),
the solution was stirred at reflux for 2 h. The dichloromethane was
removed under reduced pressure and methanol (8 mL) was added.
The solution was heated for 0.5 h to complete the esterification.
The solvents were removed under reduced pressure and the crude
product was crystallized from dichloromethane/petroleum ether
3
[
3
), 56.4 (q, OCH
3
), 81.4
3
)
3
], 98.1 (d, C-8Ј), 104.8 (d, C-6Ј), 114.5 (s, C-10aЈ), 116.9
(
s, C-4aЈ), 120.7 (d, C-1Ј), 128.2 (s, C-3Ј), 139.7 (s,C-2Ј), 142.3 (s,
C-8aЈ), 146.2 (s, C-9aЈ), 161.6 (s, C-4Ј), 163.9 (s, C-5Ј), 165.2 (s, C-
7
7
Ј), 170.3 (s, C-1), 188.9 (s, C-10Ј), 203.9 (s, CϭO) ppm. MS (EI,
0 eV): m/z (%) ϭ 426 (60) [M ], 370 (90), 353 (58), 311 (85), 281
(2 mL/5 mL) to afford 16 as white crystals (1.08 g, 4.2 mmol, 95 %,
ϩ
[
23]
13
m.p. 122 °C, ref.
δ ϭ 42.2 (t, CH
128Ϫ129 °C). C NMR (50 MHz, CDCl
), 56.0 (q, OCH ), 57.3 (q, OCH
3
):
),
(
20), 267 (15), 239 (10), 211 (8), 181 (8), 163 (14), 139 (10), 85 (4),
7 (88), 43 (100), 28 (16). IR (KBr, cm ): ν˜ ϭ 3442, 2978, 2933,
850, 1734, 1684, 1610, 1569, 1500, 1458, 1419, 1412, 1400, 1367,
2
), 52.4 (q, OCH
3
3
3
Ϫ1
5
2
1
98.6 (d, C-3), 111.3 (s, C-1), 111.6 (d, C-5), 141.8 (s, C-6), 160.6 (s,
C-2), 163.4 (s, C-4), 166.3 (s, C-1Ј), 172.2 (s, C-2ЈЈ) ppm.
354, 1331, 1254, 1221, 1157, 1092, 964, 837, 602. UV (CH
max (lg ε) ϭ 269 (2.11), 343 (1.89) nm. C24 (426.46): calcd.
C 67.59, H 6.15; found C 66.87, H 5.76.
3
CN):
λ
26 7
H O
tert-Butyl 4-(6,8-Dimethoxy-1-oxo-1H-isochromen-3-yl)-3-oxobut-
anoate (17): A suspension of the sodium salt prepared from the
monoester 16 (720 mg, 2.82 mmol) in dry THF (40 mL) was added
slowly at Ϫ80 °C under argon to a solution of the tert-butyl ace-
toacetate dianion prepared from tert-butyl acetoacetate (1.10 mL,
tert-Butyl (3-Acetyl-4-hydroxy-5,7-dimethoxy-9,10-dioxo-9,10-dihy-
droanthracen-2-yl)acetate (19a): A solution of the anthrone 18
(
(
286 mg, 0.68 mmol) in THF (50 mL) was treated with CuBr
80 mg), and then water (5 mL) was added. The resultant suspen-
2
6.63 mmol) and LDA (14 mmol) in dry THF (60 mL). The mixture
was warmed to 20 °C over 1.5 h, acetic acid (1.5 mL) was then
added dropwise at Ϫ10 °C and the solvent removed under reduced
pressure. The residue was dissolved in ethyl acetate (60 mL) and
extracted with HCl (1 , 2 ϫ 40 mL). The organic phase was dried
with MgSO , concentrated under reduced pressure and the residue
4
treated with acetic anhydride (10 mL) at 0 °C for 16 h. The solvent
sion was stirred at 20 °C under oxygen for 3 h. The solvent was
removed under reduced pressure and the residue dissolved in a mix-
ture of dichloromethane (20 mL) and H
phase was washed with H O (3 ϫ 10 mL) to remove the copper
salts. The organic phase was dried with MgSO , filtered, concen-
2
O (10 mL). The organic
2
4
trated under reduced pressure and the residue was crystallized from
was evaporated under reduced pressure and the residue was crys-
tallized from ethanol at Ϫ20 °C to afford 17 as pale yellow crystals
ethanol to afford 19a (288 mg, 0.67 mmol, 97 %, m.p. 189 °C) as
1
1
orange crystals. H NMR (200 MHz, CDCl
3
): δ ϭ 1.49 (s, 9 H, 3
), 4.03 (s, 3 H, OCH ),
), 6.83 (d, J6Ј,8Ј ϭ 2.47 Hz, 1 H, 6Ј-H), 7.49 (d,
6Ј,8Ј ϭ 2.47 Hz, 1 H, 8Ј-H), 7.63 (s, 1 H, 1Ј-H), 13.64 (s, 1 H, OH)
(420 mg, 1.16 mmol, 41 %, m.p. 117Ϫ118 °C). H NMR (200 MHz,
ϫ CH
3
), 2.69 (s, 3 H, CH
3
), 3.78 (s, 2 H, CH
2
3
CDCl
3
): δ ϭ 1.50 (s, 9 H, 3 ϫ CH
), 3.99 (s, 3 H, OCH
Ј-H), 6.38 (d, J5Ј,7Ј ϭ 2.09 Hz, 1 H, 7Ј-H), 6.50 (d, J5Ј,7Ј ϭ 2.09 Hz,
H, 5Ј-H) ppm. 13C NMR (50 MHz, CDCl
): δ ϭ 28.4 (q, 3 ϫ
), 47.3 (t, C-2), 50.6 (t, C-4), 56.1 (q, OCH ), 56.7 (q, OCH ),
2.9 [s, C(CH ], 99.3 (d, C-7Ј), 100.6 (d, C-4Ј), 103.5 (s, C-8aЈ),
3
), 3.53 (s, 2 H, 4-H), 3.72 (s, 2
4
.07 (s, 3 H, OCH
3
H, 2-H), 3.92 (s, 3 H, OCH
4
1
3
3
), 6.30 (s, 1 H,
J
1
3
ppm. C NMR (50 MHz, CDCl
q, CH ), 40.5 (t, CH ), 56.6 (q, OCH
C(CH ], 104.7 (d, C-8Ј), 105.3 (d, C-6Ј), 116.5 (s, C-10aЈ), 121.5
d, C-1Ј), 132.9 (s, C-4aЈ), 136.8 (s, C-3Ј), 137.8 (s, C-2Ј), 140.6 (s,
3
): δ ϭ 28.4 (q, 3 ϫ CH
3
), 32.2
3
(
3
2
3
), 57.1 (q, OCH ), 82.3 [s,
3
CH
3
3
3
3 3
)
8
1
1
3 3
)
(
07.2 (d, C-5Ј), 141.9 (s, C-4aЈ), 151.1 (s, C-3Ј), 159.3 (s, C-1Ј),
63.7 (s, C-8Ј), 166.0 (s, C-6Ј), 166.4 (s, C-1), 197.9 (s, C-3) ppm.
C-8aЈ, C-9aЈ), 160.7 (s, C-4Ј), 163.6 (s, C-5Ј), 166.1 (s, C-7Ј), 169.9
(s, C-1), 182.6 (s, C-9Ј), 187.9 (s, C-10Ј), 204.1 (s, CϭO) ppm. IR
(KBr, cm ): ν˜ ϭ 3435, 2976, 2846, 1728, 1720, 1697, 1674, 1633,
ϩ
MS (CI, isobutane, 120 eV): m/z (%) ϭ 363 (66) [M ], 307 (34),
Ϫ1
Ϫ1
2
2
1
63 (28), 113 (4), 57 (100), 43 (18). IR (KBr, cm ): ν˜ ϭ 3421,
1
1
595, 1556, 1489, 1458, 1431, 1367, 1354, 1335, 1321, 1277, 1248,
213, 1151, 1130, 1113, 1065. UV (CH CN): λmax (lg ε) ϭ 270
): calcd.
(440.44): calcd. C 65.45, H
976, 2940, 2910, 2848, 1749, 1735, 1712, 1670, 1599, 1569, 1458,
429, 1375, 1352, 1271, 1213, 1167, 1115, 1066. UV (CH
3
3
CN): λmax
(362.37): calcd. C
(
24 8
2.89), 425 (1.47) nm. HRMS (EI, 70 eV, C24H O
(lg ε) ϭ 270 (2.60), 322 (1.96) nm. C19
H
22
O
7
4
5
40.1471, found 440.1474. C24
.49; found C 65.39, H 5.25.
24 8
H O
6
2.97, H 6.12; found C 62.87, H 5.67.
tert-Butyl
(3-Acetyl-4-hydroxy-5,7-dimethoxy-10-oxo-9,10-dihy-
droanthracen-2-yl)acetate (18): A suspension of the sodium salt of
tert-Butyl (4-Acetoxy-3-acetyl-5,7-dimethoxy-9,10-dioxo-9,10-dihy-
oxo ester 17 (2.2 mmol, 800 mg), and NaH (60 %, 4.6 mmol, droanthracen-2-yl)acetate (19b): A solution of 19a (0.45 mmol,
184 mg) in dry THF (50 mL) was added slowly at Ϫ80 °C under
200 mg) in dry dichloromethane (15 mL) was treated at 0 °C suc-
argon by means of a syringe pump to a solution of the acetylace-
cessively with pyridine (7 mmol, 0.5 mL), acetyl chloride (7 mmol,
tonate dianion, prepared from acetylacetone (12 mmol, 1.25 mL) 0.5 mL) and DMAP (5 mol %). The mixture was stirred at 20 °C
and LDA (30 mmol) in THF (60 mL). The mixture was warmed to
0 °C and was stirred at this temperature for 1 h. The mixture was
for 3 h (TLC control). HCl (2 , 20 mL) was then added and the
aqueous phase was extracted with dichloromethane (2 ϫ 40 mL).
2
acidified with HCl (2 , 60 mL) at Ϫ10 °C and extracted with ethyl The combined organic phases were washed with water (20 mL) and
acetate (2 ϫ 60 mL). The organic phase was washed with brine brine (20 mL), dried with MgSO , filtered and concentrated under
50 mL) and the solvent was removed under reduced pressure. The reduced pressure. The crude product was purified by flash column
residue was redissolved in methanol (40 mL) and calcium acetate chromatography on silica gel (CH Cl ) to give 19b as orange crys-
12 g) was added. This suspension was heated at 45 °C under argon tals (0.44 mmol, 210 mg, 96 %, m.p. 121Ϫ123 °C). H NMR
4
(
2
2
1
(
for 10 min. After cooling, HCl (2 ) was added to neutralize the
mixture. The mixture was extracted with ethyl acetate (2 ϫ 40 mL)
(200 MHz, CDCl
2.59 (s, 3 H, CH
3
): δ ϭ 1.48 (s, 9 H, 3 ϫ CH
), 3.78 (s, 2 H, 2-H), 4.00 (s, 6 H, 2 ϫ OCH
3
), 2.52 (s, 3 H, CH
3
),
),
3
3
and dichloromethane (40 mL). The combined organic phases were 6.82 (d, J6Ј,8Ј ϭ 2.44 Hz, 1 H, 6Ј-H), 7.41 (d, J6Ј,8Ј ϭ 2.44 Hz, 1 H,
Eur. J. Org. Chem. 2004, 209Ϫ219 www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 217

K. Krohn, J. Vitz
FULL PAPER
8
2
Ј-H), 8.07 (s, 1 H, 1Ј-H) ppm. 13C NMR (50 MHz, CDCl
1.8 (q, CH ), 28.4 (q, 3 ϫ CH ), 32.0 (q, CH
), 57.2 (q, OCH ), 82.5 [s, C(CH ], 103.3 (d, C-8Ј), 105.8
d, C-6Ј), 117.4 (s, C-10aЈ), 125.6 (s, C-4aЈ), 127.7 (d, C-1Ј), 134.3 the solution was warmed to 20 °C for 10 min. Dichloromethane
s, C-3Ј), 136.8 (s, C-2Ј), 138.2 (s, C-8aЈ), 142.6 (s, C-9aЈ), 147.2 (s, (10 mL) was then added and the solvent was removed under re-
3
): δ ϭ Methyl (9,11-Dimethoxy-2-methyl-4,7,12-trioxo-7,12-dihydro-4H-1-
), 40.0 (t, C-2), 56.4 oxabenzo[a]anthracen-5-yl)acetate (21a): 20a (0.149 mmol, 72 mg)
was dissolved in trifluoroacetic acid (1 mL) at 0 °C. After 20 min,
3
3
3
(
(
(
q, OCH
3
3
3 3
)
C-4Ј), 162.9 (s, C-5Ј), 165.0 (s, C-7Ј), 169.4 (s, CϭO), 169.6 (s, Cϭ duced pressure. The procedure was repeated twice to remove traces
O), 182.9 (s, C-9Ј, C-10Ј), 202.7 (s, CϭO) ppm. UV (CH CN): λmax of trifluoroacetic acid. The crude product was dissolved in di-
chloromethane (10 mL) and treated with a CH solution
O], 384 (18), (0.30 mmol/mL, 0.50 mL) to esterify the carboxylic acid group. The
3
ϩ
(
4
lg ε) ϭ 269 (3.25) nm. MS (EI, 70 eV): m/z (%) ϭ 482 (4) [M ],
2 2
N
ϩ
ϩ
40 (14) [M Ϫ C
2
H
2
O], 409 (2) [C24
H
24
O
8
Ϫ CH
3
3
67 (6), 338 (15), 300 (4), 285 (5), 252 (4), 239 (7), 210 (5), 178
solvent was removed under reduced pressure and the crude product
7 7 2 26 9
H O ]. HRMS (EI, 70 eV, C26H O ): was purified by crystallization from dichloromethane/diethyl ether
ϩ
(30), 150 (18), 123 (10) [C
calcd. 482.1577, found 482.1578.
to afford 21a as orange crystals (0.142 mmol, 60 mg, 95 %, m.p.
1
2
3
4
95 °C). H NMR (200 MHz, CDCl
3
): δ ϭ 2.55 (s, 3 H, 13Ј-H),
), 4.02 (s, 3 H, OCH ), 4.06 (s, 3 H, OCH ),
.35 (s, 2 H, 2-H), 6.24 (s, 1 H, 3Ј-H), 6.87 (d, J8Ј,10Ј ϭ 2.44 Hz, 1
tert-Butyl [4-Hydroxy-5,7-dimethoxy-9,10-dioxo-3-(3-oxobutyryl)-
,10-dihydroanthracen-2-yl]acetate (20a): A solution of the phenol
.76 (s, 3 H, OCH
3
3
3
9
ether 19b (0.41 mmol, 200 mg) in THF (30 mL) was treated at 0 °C
with LiH (4 mmol, 32 mg) and the suspension was heated to reflux
for 20 h (TLC control). The mixture was carefully neutralized at 0
H, 10Ј-H), 7.40 (d, J8Ј,10Ј ϭ 2.44 Hz, 1 H, 8Ј-H), 7.98 (s, 1 H, 6Ј-
H) ppm. 13C NMR (50 MHz, CDCl
3
): δ ϭ 20.9 (q, C-13Ј), 42.2 (t,
C-2), 52.5 (q, OCH ), 56.5 (q, OCH ), 57.1 (q, OCH ), 103.0 (d,
3
3
3
°
C by addition of HCl (2 , 1 mL), reduced to one fifth of its
volume under reduced pressure and diluted with dichloromethane
40 mL). The organic phase was washed successively with HCl (2
, 2 ϫ 10 mL) and water (10 mL), dried with MgSO , filtered and
concentrated under reduced pressure to afford 20a (0.33 mmol,
58 mg, 81 %, m.p. 167 °C) as orange crystals after crystallization
C-8Ј), 106.0 (d, C-10Ј), 112.7 (d, C-3Ј), 118.0 (s, C-11aЈ), 124.1 (s,
C-12aЈ), 125.9 (d, C-6Ј), 126.9 (s, C-4aЈ), 135.6 (s, C-5Ј), 136.3 (s,
C-7aЈ), 141.4 (s, C-6aЈ), 156.4 (s, C-12bЈ), 162.4 (s, C-11Ј), 164.8 (s,
(

4
C-2Ј), 167.2 (s, C-9Ј), 171.4 (s, C-1), 179.2 (s, C-4Ј), 180.0 (s, C-7Ј),
ϩ
1
3
1
2
1
1
4
83.3 (s, C-12Ј) ppm. MS (EI, 70 eV): m/z (%) ϭ 422 (60) [M ],
1
90 (100), 362 (80); 334 (20), 305 (25), 276 (10), 233 (5), 181 (16),
67 (18), 138 (5), 44 (5), 28 (4). IR (KBr, cm ): ν˜ ϭ 3437, 3082,
989, 2952, 2846, 1736, 1678, 1653, 1624, 1591, 1558, 1466, 1437,
392, 1373, 1344, 1325, 1302, 1279, 1240, 1215, 1200, 1182, 1165,
1
from dichloromethane/ethanol (1:1). H NMR (200 MHz, CDCl
3
)
Ϫ1
(enol): δ ϭ 1.48 (s, 9 H, 3 ϫ CH
3
), 2.21 (s, 3 H, 4ЈЈ-H), 3.78 (s, 2
H, 2-H), 4.03 (s, 3 H, OCH
3
3
), 4.07 (s, 3 H, OCH ), 5.98 (s, 1 H, 2ЈЈ-
H), 6.83 (d, J6Ј,8Ј ϭ 2.34 Hz, 1 H, 6Ј-H), 7.48 (d, J6Ј,8Ј ϭ 2.34 Hz, 1
140, 1113, 1065, 1043. HRMS (EI, 70 eV, C23
22.1001, found 422.1018.
18 8
H O ): calcd.
13
H, 8Ј-H), 7.69 (s, 1 H, 1Ј-H), 13.71 (s, 1 H, OH) ppm. C NMR
50 MHz, CDCl ) (enol): δ ϭ 25.5 (q, C-4ЈЈ), 28.4 (q, 3 ϫ CH ),
1.1 (t, C-2), 56.6 (q, OCH ), 57.1 (q, OCH ), 82.1 [s, C(CH ],
(
3
3
4
1
1
1
1
3
3
3 3
)
Methyl
anthracen-5-yl)acetate (21b): The ring closure of 20b (0.187 mmol,
9 mg) was carried out as described for 21a to afford red crystals
(2-Methyl-4,7,12-trioxo-7,12-dihydro-4H-1-oxabenzo[a]-
04.4 (d, C-2ЈЈ), 104.6 (d, C-8Ј), 105.3 (d, C-6Ј), 115.4 (s, C-10aЈ),
16.4 (s, C-4aЈ), 121.4 (d, C-1Ј), 132.7 (s, C-3Ј), 133.0 (s, C-2Ј),
37.8 (s, C-8aЈ), 141.6 (s, C-9aЈ), 160.7 (s, C-4Ј), 163.6 (s, C-5Ј),
7
1
of 21b (0.166 mmol, 60 mg, 89 %, m.p. 197Ϫ204 °C). H NMR
200 MHz, CDCl ): δ ϭ 2.58 (s, 3 H, CH ), 3.77 (s, 3 H, CH ),
.40 (s, 2 H, 2-H), 6.29 (s, 1 H, 3Ј-H), 7.81Ϫ7.93 (m, 2 H, 8Ј-H,
1Ј-H), 8.11 (s, 1 H, 6Ј-H), 8.30Ϫ8.37 (m, 2 H, 9Ј-H, 10Ј-H) ppm.
66.1 (s, C-7Ј), 169.8 (s, C-3ЈЈ), 182.6 (s, C-1), 185.5 (s, C-1ЈЈ), 187.7
(
3
3
3
Ϫ1
(
s, C-9Ј), 191.8 (s, C-10Ј) ppm. IR (KBr, cm ): ν˜ ϭ 3427, 2979,
4
1
2
1
932, 2845, 1734, 1628, 1595, 1559, 1487, 1455, 1368, 1324, 1251,
212, 1150, 1113, 1063, 1040, 974. UV (CH CN): λmax (lg ε) ϭ 281
3
13
C NMR (50 MHz, CDCl
3 3 2
): δ ϭ 20.3 (q, CH ), 42.0 (t, CH , C-
ϩ
(4.76), 431 (1.79) nm. MS (EI, 70 eV): m/z (%) ϭ 483 (20) [M
ϩ
2
4
7
1
1
), 52.2 (q, OCH ), 112.5 (d, C-3Ј), 121.9 (s, C-12bЈ), 126.3 (s, C-
3
1
], 465 (4), 427 (25), 383 (20), 365 (2), 169 (5), 85 (3), 57 (100)
aЈ), 126.5 (d, C-6Ј), 127.1 (d, C-11Ј), 127.5 (d, C-8Ј), 132.2 (s, C-
aЈ), 134.3 (s, C-6aЈ), 134.6 (d, C-9Ј), 135.1 (d, C-10Ј), 136.5 (s, C-
1aЈ), 142.7 (s, C-5), 156.8 (s, C-12bЈ), 167.5 (s, C-2Ј), 171.2 (s, C-
ϩ
[C
4
H
9
]. HRMS (EI, 70 eV, C26
H
26
O
9
): calcd. 482.1577, found
4
6
82.1578. C26
4.43, H 4.99.
H O (482.48): calcd. C 64.72, H 5.43; found C
26 9
), 179.2 (s, C-12Ј), 181.2 (s, C-7Ј), 182.4 (s, C-4Ј). UV (CH
3
CN):
λ
max (lg ε) ϭ 279 (4.28), 373 (1.97) nm. MS (EI, 70 eV): m/z (%) ϭ
tert-Butyl [4-Hydroxy-9,10-dioxo-3-(3-oxobutanoyl)-9,10-dihydro-
ϩ
[17]
362 (32) [M ], 330 (64), 302 (48), 274 (52), 248 (30), 231 (22), 205
14 6
(24), 165 (10), 151 (16), 109 (8), 91 (24), 57 (10), 28 (28). (C21H O ,
anthracen-2-yl]acetate (20b):
The rearrangement reaction of
9b (0.23 mmol, 96 mg) was carried out as described for 20a and
afforded orange crystals of 20b (0.20 mmol, 85 mg, 80 %, m.p. 180
[
17]
1
362.33): calcd. C 69.61, H 3.89; found C 68.93, H 3.49.
[
17]
1
°
(
1
8
C, ref. 183 °C). H NMR (200 MHz, CDCl
s, 9 H, 3 ϫ CH ), 2.21 (s, 3 H, CH ), 3.81 (s, 2 H, 2-H), 5.99 (s,
H, 2ЈЈ-H), 7.77 (s, 1 H, 1Ј-H), 7.83Ϫ7.89 (m, 2 H, 6Ј-H, 7Ј-H),
3
) (enol): δ ϭ 1.48
Methyl
(2-Ethyl-4,7,12-trioxo-7,12-dihydro-4H-1-oxabenzo[a]-
3
3
anthracen-5-yl)acetate (21c): The ring closure of 20c (0. 071 mmol,
28 mg) was carried out as described for 21a to afford red crystals
of 21c (0.048 mmol, 18 mg, 68 %, m.p. 268Ϫ270 °C). H NMR
.27Ϫ8.37 (m, 2 H, 5Ј-H, 8Ј-H) ppm. 1 C NMR (50 MHz, CDCl
3
3
)
1
(enol): δ ϭ 25.5 (q, CH
3
), 28.4 (q, 3 ϫ CH ), 41.3 (t, C-2), 82.2 (s,
3
(
(
200 MHz, CDCl
q, J1ЈЈ,2ЈЈ ϭ 7.52 Hz, 2 H, 1-HЈЈ), 3.72 (s, 3 H, OCH
), 6.26 (s, 1 H, 3-H), 7.76Ϫ7.90 (m, 2 H, 9-HЈ, 10-HЈ), 8.06
3
): δ ϭ 1.44 (t, J1ЈЈ,2ЈЈ ϭ 7.52 Hz, 3 H, 2-HЈЈ), 2.81
C-1tBu), 104.4 (d, C-2ЈЈ), 115.7 (s, C-4aЈ), 122.3 (d, C-1Ј), 127.5 (d,
C-5Ј), 127.9 (d, C-8Ј), 132.3 (s, C-3Ј), 133.5 (s, C-8aЈ), 133.8 (s, C-
3
), 4.34 (s, 2
H, CH
2
1
2
0aЈ), 134.9 (d, C-7Ј), 135.4 (d, C-6Ј), 143.3 (s, C-9aЈ), 160.6 (s, C-
Ј), 169.5 (s, C-4Ј), 182.2 (s, C-1), 184.9 (s, C-3ЈЈ), 188.8 (s, C-9Ј,
1
3
(
s, 1 H, 6-HЈ), 8.24Ϫ8.32 (m, 2 H, 8-HЈ, 11-HЈ) ppm. C NMR
50 MHz, CDCl ): δ ϭ 11.2 (q, C-2ЈЈ), 27.8 (t, C-1ЈЈ), 42.3 (t, C-
), 52.5 (q, OCH ), 111.2 (d, C-3Ј), 122.2 (s, C-12aЈ), 126.6 (d, C-
[4-Hydroxy-9,10-dioxo-3-(3-oxopentanoyl)-9,10-dihydro- 6Ј), 127.4 (d, C-8Ј/C-11Ј), 127.7 (d, C-8Ј/C-11Ј), 132.4 (s, C-4aЈ),
(
2
3
C-10Ј), 191.9 (s, C-1ЈЈ) ppm.
3
Methyl
[17]
anthracen-2-yl]acetate (20c):
The rearrangement reaction of
134.4 (d, C-9Ј/C-10Ј), 134.9 (s, C-7aЈ, C-11aЈ), 135.3 (d, C-9Ј/C-
10Ј), 136.7 (s, C-5Ј), 142.9 (s, C-6aЈ), 171.4 (s, C-12bЈ), 172.0 (s, C-
2Ј), 179.5 (s, C-7Ј, C-12Ј), 181.3 (s, C-1), 182.7 (s, C-4Ј) ppm. IR
methyl (3-acetyl-9,10-dioxo-4-propoxy-9,10-dihydroanthracen-2-yl)-
[
17]
acetate (0.091 mmol, 36 mg) was carried out as described for 20a
Ϫ1
and afforded orange crystals of 20c (0.076 mmol, 30 mg, 81 %, m.p. (KBr, cm ): ν˜ ϭ 3521, 3460, 2916, 2850, 1747, 1716, 1674, 1651,
[
17]
1
26 °C, ref. 127 °C).
1589, 1466, 1439, 1389, 1369, 1346, 1323, 1284, 1254, 1200, 1173.
www.eurjoc.org Eur. J. Org. Chem. 2004, 209Ϫ219
218
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Total Synthesis of Premithramycinone H
FULL PAPER
F. Lomb o´ , E. Künzel, L. Prado, A. F. Brana, K. U. Bindseil,
J. Frevert, J. Bearden, C. Mendez, J. Sal a´ s, J. Rohr, Angew.
Chem. Int. Ed. 2000, 39, 796Ϫ799.
J. S. Kim, K. Shin-Ya, J. Eishima, K. Furihata, H. Seto, J.
Antibiot. 1996, 49, 947Ϫ948.
M. Sakurai, J. Kohno, K. Yamamoto, T. Okuda, M. Nishio,
K. Kawano, T. Ohnuki, J. Antibiot. 2002, 55, 685Ϫ692.
F. M. Hauser, R. P. Rhee, J. Org. Chem. 1980, 45, 3061Ϫ3068.
C. Marschalk, F. Koenig, N. Ouroussoff, Bull. Soc. Chim. Fr.
[
6]
UV (CH
HRMS (EI, 70 eV, C22
3
CN): λmax (lg ε) ϭ 275 (4.32), 335 (1.74), 372 (1.57) nm.
): calcd. 376.0947, found 376.0849.
16 6
H O
C
22
H
16
O
6
(376.36): calcd. C 70.21, H 4.29; found C 69.91, H 4.44.
[
[
[
7]
8]
9]
Methyl
(11-Hydroxy-9-methoxy-2-methyl-4,7,12-trioxo-7,12-di-
hydro-4H-1-oxabenzo[a]anthracen-5-yl)acetate (22d): To a solution
of 21a (2.2 mg, 0.0053 mmol) in dry CH Cl (10 mL) was added a
solution of BBr in CH Cl (1 mmol/mL, 4 mL) and the solution
stirred for 3 h. Dichloromethane (30 mL) was added and the solu-
tion washed successively with a concd. NaHCO solution (10 mL)
and water (10 mL), dried with MgSO , filtered, and concentrated
under reduced pressure to afford 22d as red crystals (1.6 mg,
.0040 mmol, 75 %, m.p. 252Ϫ254 °C). 1H NMR (200 MHz,
CDCl ): δ ϭ 2.56 (s, 3 H, CH ), 3.78 (s, 3 H, OCH ), 3.99 (s, 3 H,
OCH ), 6.29 (s, 1 H, 3Ј-H), 6.81 (d, J8Ј,10Ј ϭ 2.57 Hz, 1 H, 10Ј-H),
.40 (d, J8Ј,10Ј ϭ 2.57 Hz, 1 H, 8Ј-H), 8.08 (s, 1 H, 6Ј-H), 13.07 (s,
2
2
3
2
2
[10]
1
936, 3, 1545Ϫ1575.
3
[11]
[12]
K. Krohn, C. Hemme, Liebigs Ann. Chem. 1979, 19Ϫ34.
I. C. Badhwar, K. S. Kang, K. Venkataraman, J. Chem. Soc.
1932, 1107Ϫ1112.
W. B a ke r, J. Chem. Soc. 1933, 1381Ϫ1389.
T. M. Harris, C. M. Harris, K. B. Hindley, Fortschr. Chem. Org.
Naturst. 1974, 31, 217Ϫ282.
4
[13]
0
[14]
3
3
3
3
[
[
15]
16]
M. Yamaguchi, Stud. Nat. Prod. Chem. 1992, 11, 113Ϫ149.
E. J. Corey, J. W. Suggs, Tetrahedron Lett. 1975, 16,
7
1
4
1
H, OH) ppm. 1 C NMR (50 MHz, CDCl
1.7 (t, CH ), 51.9 (q, OCH ), 55.9 (q, OCH
07.5 (d, C-10Ј), 111.2 (d, C-3Ј), 112.3 (s, C-11aЈ), 121.2 (s, C-4aЈ,
3
3
): δ ϭ 29.5 (q, CH
3
),
2647Ϫ2650.
2
3
3
), 107.2 (d, C-8Ј),
[17]
[18]
[19]
K. Krohn, E. Roemer, M. Top, Liebigs Ann. 1996, 271Ϫ277.
K. Krohn, Tetrahedron Lett. 1980, 21, 3557Ϫ3560.
Hans-Jürgen Köhle, Untersuchungen zur Synthese der Aglykone
des Nogalamycins und seiner Derivate, Dissertation,
Braunschweig, 1987.
C-12aЈ), 126.3 (d, C-6Ј), 133.4 (s, C-7aЈ), 136.1 (s, C-6aЈ), 142.7 (s,
C-5Ј), 156.3 (C-12bЈ), 165.3 (s, C-11Ј), 165.7 (s, C-9Ј), 166.4 (s, C-
2Ј), 170.5 (s, C-1), 178.3 (s, C-12Ј), 181.4 (s, C-7Ј), 185.2 (s, C-4Ј)
ϩ
[20]
ppm. MS (EI, 70 eV): m/z (%) ϭ 408 (20) [M ], 376 (48), 348 (92),
20 (34), 306 (12), 277 (6), 249 (6), 221 (5). HRMS (EI, 70 eV,
): calcd. 408.0845, found 408.0847.
I. Hirao, M. Yamaguchi, M. Hamada, Synthesis 1984, 12,
1076Ϫ1078.
3
[21]
Th. M. Harris, Ph. J. Wittek, J. Am. Chem. Soc. 1975, 97,
22 16 8
C H O
3270Ϫ3271.
Premithramycinone H (2):[6] A solution of BBr
mL, 4 mL) was added to a solution of 21a (122 mg, 0.29 mmol) in
dry CH Cl (30 mL). After stirring for 6 h, dichloromethane
30 mL) was added and the solution washed successively with
concd. NaHCO solution (20 mL) and water (20 mL), dried with
MgSO , filtered, and concentrated under reduced pressure to yield
as red crystals (84 mg, 0.21 mmol, 74 %), m.p. 254Ϫ260 °C. H
NMR (200 MHz, CDCl ): δ ϭ 2.56 (s, 3 H, CH ), 3.73 (s, 3 H,
OCH ), 4.38 (s, 2 H, CH ), 6.28 (s, 1 H, 3Ј-H), 7.47 (s, 2 H, 8Ј-H,
0Ј-H), 8.09 (s, 1 H, 6Ј-H), 13.69 (s, 1 H, OH) ppm. 1H NMR
200 MHz, [D ]DMSO): δ ϭ 2.44 (d, J3Ј,13Ј ϭ 0.7 Hz, 3 H, CH ),
.56 (s, 3 H, OCH ), 4.12 (s, 2 H, CH ), 6.38 (d, J3Ј,13Ј ϭ 0.7 Hz,
H, 3Ј-H), 6.93 (d, J8Ј,10Ј ϭ 2.8 Hz, 1 H, 10Ј-H), 7.19 (d, J8Ј,10Ј
.8 Hz, 1 H, 8Ј-H), 7.94 (s, 1 H, 6Ј-H), 10.32 (s, 1 H, OH), 13.02
[22]
K. Krohn, Eur. J. Org. Chem. 2002, 8, 1351Ϫ1362.
A. Kjaer, D. Kjaer, Acta Chem. Scand., Ser. B 1982, 36,
3
2 2
in CH Cl (1 mmol/
[23]
417Ϫ419.
2
2
[24]
G. B. Henderson, R. A. Hill, J. Chem. Soc., Perkin Trans. 1
982, 1111Ϫ1116.
W. R. Roush, M. Murphy, J. Org. Chem. 1992, 57, 6622Ϫ6629.
K. Krohn, H. Markus, H. P. Kraemer, W. Frank, Liebigs Ann.
Chem. 1988, 1033Ϫ1041.
F. Fringuelli, A. Taticchi, Dienes in the DielsϪAlder Reaction,
John Wiley & Sons, New York, 1990.
K. Furuta, Y. Miwa, K. Iwanaga, H. Yamamoto, J. Am. Chem.
Soc. 1988, 110, 6254Ϫ6255.
M. Iwata, H. Kuzuhara, Bull. Chem. Soc. Jpn. 1985, 58,
(
1
3
[25]
[26]
4
1
2
[27]
3
3
3
2
[28]
1
(
6
3
[
[
29]
30]
3
1
2
3
2
1609Ϫ1610.
ϭ
We thank Dr. R. Lichtner and Dr. R. Metternich from Scher-
ing AG, Berlin, Germany, for conducting the antitumor tests.
K. Krohn, D. Gehle, O. Kamp, T. van Ree, J. Carbohydr. Chem.
ϩ
(s, 1 H, OH) ppm. MS (EI, 70 eV): m/z (%) ϭ 394 (10) [M ], 368
[31]
(5), 348 (6), 279 (10), 177 (10), 167 (12), 149 (30), 96 (45), 69 (56),
2003, 22, 377Ϫ383.
[
[
32]
33]
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Received July 22, 2003
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www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
219