Concise preparation of 1,8-diazaanthracene-2,7,9,10-tetraones. Two alternative syntheses of the natural antifolate diazaquinomycin A

Article abstract of DOI:10.1016/S0040-4020(00)00371-9

Treatment of compounds bearing one or two 1-dimethylamino-1,4- dihydropyridine moieties with the urea-hydrogen peroxide complex (UHP) led to their efficient aromatization. Double N-oxidation of 1,8-diazaanthraquinones thus obtained is the first example of a double N-oxidation of a diaza heterocycle by UHP in trifluoroacetic acid. Treatment of the crude double N- oxides with tosyl chloride in acetonitrile-water afforded 1,8- diazaanthracene-2,7,9,10-tetraones (including diazaquinomycin A) in 25-40% overall yields. An alternative synthesis of diazaquinomycin A was also devised, whose key steps are the hetero Diels-Alder reaction between 2- methyl-2-hexenal dimethylhydrazone and 3-methyl-4-propyl-2H-quinoline-2,5,8- trione and the oxidative functionalization of the 1,8-diazaanthracene-2,9,10- trione derivative thus obtained. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00371-9

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4575±4583
Concise Preparation of 1,8-Diazaanthracene-2,7,9,10-Tetraones.
Two Alternative Syntheses of the Natural Antifolate
Diazaquinomycin A
*
   Â
Ä
Jose Marõa Perez, Pilar Lopez-Alvarado, Eva Pascual-Alfonso, Carmen Avendano
*
Â
and J. Carlos Menendez
  Â
Departamento de Quõmica Organica y Farmaceutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain.
Received 2 February 2000; revised 6 April 2000; accepted 27 April 2000
AbstractÐTreatment of compounds bearing one or two 1-dimethylamino-1,4-dihydropyridine moieties with the urea-hydrogen peroxide
complex (UHP) led to their ef®cient aromatization. Double N-oxidation of 1,8-diazaanthraquinones thus obtained is the ®rst example of a
double N-oxidation of a diaza heterocycle by UHP in tri¯uoroacetic acid. Treatment of the crude double N-oxides with tosyl chloride in
acetonitrile±water afforded 1,8-diazaanthracene-2,7,9,10-tetraones (including diazaquinomycin A) in 25±40% overall yields. An alternative
synthesis of diazaquinomycin A was also devised, whose key steps are the hetero Diels±Alder reaction between 2-methyl-2-hexenal
dimethylhydrazone and 3-methyl-4-propyl-2H-quinoline-2,5,8-trione and the oxidative functionalization of the 1,8-diazaanthracene-
2,9,10-trione derivative thus obtained. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
As part of an effort to study the biological activity of
bacterial secondary metabolites, Omura's group1 described
the isolation from a Streptomyces strain of a compound with
antibacterial properties, which they named diazaquino-
mycin A. Further research from the same group2 allowed
them to attribute the antibiotic activity to inhibition of
thimidylate synthase. This ®nding made diazaquinomycin
A an attractive lead compound in the ®eld of cancer
chemotherapy, although the natural product itself lacked
antitumour activity because of its poor pharmacokinetic
properties.3 Diazaquinomycin A is also interesting because
its 1,8-diazaanthracene-2,7,9,10-tetraone structure is
unique, although related natural products, like nibomycin
A,4 are known. The only prior total synthesis of diazaquino-
mycin A was that by Kelly and coworkers, and featured a
double Knorr cyclization as the key step.5
tetraones. Alternatively, these compounds could also be
prepared by N-oxidation and rearrangement of the products
obtained in the hetero Diels±Alder reaction7 between
1-dimethylamino-1-azadienes and 2,5,8(1H)-quinoline-
triones (Scheme 1).
The rearrangement of pyridine and quinoline N-oxides to
the corresponding unsaturated d-lactams is a well-known
transformation.6 Therefore, we envisaged that a double rear-
rangement of double N-oxides derived from 1,8-diazaan-
thraquinones would provide an ef®cient entry into
symmetrically substituted 1,8-diazaanthracene-2,7,9,10-
Results and Discussion
N-oxidation of nitrogen atoms that are deactivated by the
presence of electron-withdrawing groups requires the use of
very strong oxidants. For instance, the preparation of
N-oxides of polyhalogenated pyridines and pyrazines
Keywords: N-oxides; rearrangements; lactams; quinones; Diels±Alder
reactions.
* Corresponding authors. Tel. 134-91-3941-821; fax: 134-91-3941-822;
e-mail: josecm@eucmax.sim.ucm.es
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00371-9

Â
J. M. Perez et al. / Tetrahedron 56 (2000) 4575±4583
4576
Scheme 1.
required the use of 90% hydrogen peroxide in acidic
media.8 In order to avoid the dangers inherent to this
reagent, a number of alternatives have been proposed, like
peroxyimidic acid,9 magnesium monoperoxyphthalate,10
and several compounds where hydrogen peroxide is
hydrogen-bonded to a variety of molecules containing
electron donors. Among these, hydrogen peroxide±urea
adduct (UHP, percarbamide)11 is the most widely used
and has been successfully employed on very deactivated
substrates, including heterocyclic quinones;12 recent
advances in the use of UHP include the development of a
solid-state protocol suitable for liquid or low-melting
substrates.13 However, double N-oxidations using this
reagent are unknown; for instance, an attempt to use UHP
to transform quinoxaline into its double N-oxide was
unsuccessful, while magnesium monoperoxyphthalate
gave a 72% yield of the desired product.14
bis(dimethylamino) intermediate 2e to UHP in tri¯uoro-
acetic acid at room temperature afforded compound 3e in
73% overall yield. This aromatization can be explained
through the N-oxidation of the dimethylamino group of
compound 2e followed by an aza-Cope elimination
(Scheme 2); the N-oxidation step is probably very fast,
which prevents decomposition of the acid-sensitive starting
material under the conditions employed. In fact, addition of
neat tri¯uoroacetic acid to 2e in the absence of UHP led to
its rapid decomposition. This aromatization of 2e was of
interest to us because of the mildness of the reaction con-
ditions and the good yield obtained, and could be extended
to other examples, as shown in Table 1 for the preparation of
3c,d from 2c,d, and also for the transformation of compound
417 into the natural product cleistopholine 5.17,18 On the
other hand, several attempts to aromatize 8-chloro-1-
dimethylamino-4-methyl-1,4-dihydro-1,5-diazaanthracene-
9,10-dione19 by this method led to intractable mixtures,
probably as a consequence of the sensitivity of the 4-chloro-
pyridine subunit to tri¯uoroacetic acid.
The 1,8-diazaanthraquinones 3a±d used as starting
materials for our study were prepared through literature
methods,15 by double hetero Diels±Alder reactions of
1-dimethylamino-1-azadienes and 2,6-dibromobenzo-
quinone16 followed by aromatization under thermal condi-
tions. However, 3,6-dimethyl-4,5-dipropyl-1,8-diaza-
anthraquinone 3e, the starting material required for the
preparation of diazaquinomycin itself, was not available
by this route because of failure of the aromatization step,
probably due to the steric compression between the C4- and
C5-alkyl groups and the C10 carbonyl in the desired product.
Fortunately, we discovered that brief exposure of the
Owing to the above mentioned lack of precedent on double
N-oxidations with UHP, in our ®rst experiments we
attempted to oxidize 3,6-dimethyl-1,8-diazaanthraquinone
with magnesium monoperoxyphthalate under several
literature conditions,20 but these reactions afforded only
recovered starting material, even after very prolonged treat-
ments. Use of UHP under standard conditions (reaction at
room temperature in tri¯uoroacetic acid, followed by basi-
®cation with ammonium hydroxide and extraction) was also
Scheme 2. Reagents and conditions: i. R.t., 5 min (ref. 15). ii. R.t., Et3N, 15 min (ref. 15). iii. 1108C, 0.1 Torr, 2 h (ref. 15). iv. H2O2-urea, F3C-CO2H, r.t.,
10 min.

Â
J. M. Perez et al. / Tetrahedron 56 (2000) 4575±4583
4577
Table 1. Aromatization of 1-dimethylamino-1,4-dihydropyridine rings in the presence of UHP (TFA, rt, 10 min)
Starting material
Product
Yield (%)
77
73
80
unsuccessful, in agreement with the above mentioned pre-
cedent.14 While performing these experiments, we noticed
that only a small fraction of the mass of the starting material
was recovered, suggesting that the failure of the reaction
might be due to dif®culties in the extraction of the double
N-oxide. Therefore, we decided to use a different workup
procedure, consisting of evaporation of the tri¯uoroacetic
acid and extraction of the solid residue with chloroform. As
shown in Scheme 3, this method allowed the transformation
of compounds 3 into the double N-oxides 6, which were
characterized by 1H NMR and treated without further puri-
®cation with tosyl chloride in acetonitrile-water, yielding
the desired 1,8-diazaanthracene-2,7,9,10-tetraones 7 in
25±40% overall yields. The rearrangement step could be
controlled to yield the monolactam N-oxides 8 by use of a
shorter reaction time. Compound 7e was identical in all
respects to natural diazaquinomycin A.21
Finally, in order to explore the alternative route to diaza-
quinomycin A mentioned in the introduction, we prepared
3-methyl-4-propyl-2,5,8(1H)-quinolinetrione 14 by the
method outlined in Scheme 4.22 Regioselective alkylation23
of the C-4 position of the dianion derived from S-tert-butyl
acetothioacetate 924 with ethyl bromide afforded a 74%
yield of thioester 10, which was methylated at its C-2 posi-
tion via its monoanion to yield compound 11 in 62% yield.
Scheme 3. Reagents and conditions: i. H2O2-urea, F3C-CO2H, r.t., 24 h. ii. TsCl, CH3CN, H2O, 608C, 24 h. iii. TsCl, CH3CN, H2O, 608C, 18 h.

Â
J. M. Perez et al. / Tetrahedron 56 (2000) 4575±4583
4578
Scheme 4. Reagents and conditions: i. NaH, DME, 208C, 15 min. ii. BuLi, DME, 2208C, 10 min. iii. EtBr, DME 08C, 80 min. iv. NaH, DME, 208C, 15 min.
v. Mel, DME, 08C, 14 h. vi. AgCF3CO2, DME, r.t., 15 h. vii. 96% H2SO4, r.t., 3 h. viii. (NH4)2Ce(NO3)6, CH3CN, H2O, r.t., 3 h.
Scheme 5. Reagents and conditions: i. Dimethylhydrazine, Et2O, cat. AcOH, 458C, 30 min. ii. Silica gel, CH2Cl2, r.t., 1 min, then chromatography. iii. MnO2,
CH2Cl2, r.t., 30 min. iv. H2O2-urea, F3C-CO2H, r.t., 18 h. v. TsCl, CH3CN, H2O, 608C, 24 h. vi. H2O2-urea, F3C-CO2H, r.t., 24 h.
Amidation of 11 with 2,5-dimethoxyaniline in the presence
of silver tri¯uoroacetate25 afforded anilide 12 in 49% yield
(97% based on unrecovered starting material). Knorr
cyclization of 12 under strongly acidic conditions led to
carbostyril 13 in quantitative yield, and oxidative demethyl-
ation of the latter with cerium ammonium nitrate afforded
quinone 14 in 85% yield.
between 1e and quinone 14 was carried out in a silica gel
support, followed by immediate chromatography in order to
prevent the addition of dimethylamine to the starting
quinone,28 a very common problem in the reactions between
1-dimethylamino-1-azadienes and quinones,29 and afforded
the 5,8-dihydro-1,8-diazaanthracene-2,9,10-trione 15 as the
major product (46%), together with its aromatic derivative
16 (14%). Compound 15 was independently aromatized to
16 in 85% yield by oxidation with manganese dioxide. In
order to link this route with the previous one, we also exam-
ined the transformation of 1,8-diazaanthraquinone 3e into
compound 16. Thus, treatment of 3e with UHP in tri¯uoro-
acetic acid for 18 h gave the mono N-oxide 17, which upon
The azadiene necessary for the planned hetero Diels±Alder
reaction, namely 2-methyl-2-hexenal dimethylhydrazone
(1e), was prepared in 95% yield from the corresponding
aldehyde26 by treatment with dimethylhydrazine in the
presence of a catalytic amount of acetic acid.27 The reaction

Â
J. M. Perez et al. / Tetrahedron 56 (2000) 4575±4583
4579
rearrangement in the presence of tosyl chloride±water
afforded 16 in 31% overall yield from 3e. Finally,
compound 16 was transformed into diazaquinomycin A in
26% yield by a similar N-oxidation/rearrangement sequence
(Scheme 5).
(231 mg, 1.5 mmol, 2 equiv.) and triethylamine (0.21 mL,
152 mg, 1.5 mmol, 2 equiv.). The solution was stirred at
room temperature for 1 min and evaporated. The residue
was washed with Et2O (3£25 mL) yielding 306 mg
(99%) of 1,8-bis-(dimethylamino)-3,6-dimethyl-4,5-dipro-
pyl-1,4, 5,8-tetrahydro-1,8-diazaanthraquinone (2e),30
which was suf®ciently pure to be used without further
puri®cation.
Experimental
All reagents were of commercial quality (Aldrich, Fluka,
SDS, Probus) and were used as received with the exception
of 2,5-dimethoxyaniline, which was puri®ed by ®ltration
through silica gel, eluting with ethyl ether. Solvents (SDS,
Scharlau) were dried and puri®ed using standard techniques.
`Petroleum ether' refers to the fraction boiling at 40±608C.
S-tert-butyl acetothioacetate (11) was prepared according to
Ref. 24b. Reactions were monitored by thin layer chromato-
graphy, on aluminium plates coated with silica gel with
¯uorescent indicator (Macherey±Nagel Alugram Sil
G/UV254). Separations by ¯ash chromatography were
performed on silica gel (SDS 60 ACC, 230±400 mesh and
Scharlau Ge 048). Melting points were measured in open
capillary tubes using a BuÈchi inmersion apparatus, or on a
Reichert 723 hot stage microsope, and are uncorrected.
Infrared spectra were recorded on a Perkin±Elmer Paragon
1000 FT-IR spectrophotometer, with solid compounds
compressed into KBr pellets and liquid compounds
examined as ®lms on NaCl disks. NMR spectra were
Aromatization of 1-dimethylamino-1,4-dihydropyridine
rings in the presence of UHP
General procedure. To a solution of the starting material in
TFA (5 mL per mmol) was added solid UHP (3.8 equiv.).
The solution was stirred at room temperature for 10 min and
tri¯uoroacetic acid was then evaporated under reduced pres-
sure. The residue was dissolved in 20% aqueous NH4OH
(1 mL) and extracted with CHCl3 (3£25 mL). The
combined organic layers were dried (Na2SO4) and evapo-
rated under reduced pressure. The residue was washed with
Et2O (3£25 mL), yielding compounds 3c±e and 5.
4,5-Dimethyl-1,8-diazaanthraquinone (3c). Starting from
50 mg (0.15 mmol) of compound 2c, a yield of 28 mg (77%)
of 3c15 was obtained, as a pale yellow solid.
4,5-Diethyl-3,6-dimethyl-1,8-diazaanthraquinone (3d).
Starting from 131 mg (0.34 mmol) of compound 2d, a yield
1
obtained on Bruker AC-250 (250 MHz for H, 63 MHz for
1
13C) and Varian VXR-300 (300 MHz for H, 75 MHz for
of 73 mg (73%) of 3d15 was obtained, as a pale yellow solid.
13C) spectrometers, with CDCl3, DMSO-d6, CF3COOD,
pyridine-d5, and acetone-d6 as solvents (Servicio de
3,6-Dimethyl-4,5-dipropyl-1,8-diazaanthraquinone (3e).
Starting from 340 mg (0.82 mmol) of 2e, a yield of
193 mg (73%) of 3e was obtained, as a pale yellow solid.
[Found: C, 74.20; H, 6.76; N, 8.43. C20H22N2O2 requires C,
74.51; H, 6.88; N, 8.69]; mp .3008C; nmax (KBr)
1677 cm21; dH (250 MHz, CDCl3) 8.72 (s, 2H, H-2,7),
3.06 (t, 4H, Jˆ8.0 Hz, C4,5±CH2±CH2±CH3), 2.45 (s, 6H,
C3,6±CH3), 1.64 (m, 4H, C4,5±CH2±CH2±CH3), 1.07 (t, 6H,
Jˆ7.2 Hz, C4,5±CH2±CH2±CH3); dC (63 MHz, CDCl3)
188.0 (C-9), 181.8 (C-10), 154.8 (C-2,7), 152.3 (C-8a,9a),
147.5 (C-10a,4a), 138.4 (C-4,5), 130.6 (C-3,6), 31.7
(C4,5±CH2±CH2±CH3), 22.9 (C4,5±CH2±CH2±CH3), 17.1
(C3,6±CH3), 14.7 (C4,5±CH2±CH2±CH3).
Â
Espectroscopõa, Universidad Complutense). When neces-
sary, assignments were aided by DEPT, COSY and 13C-1H
correlation experiments. Elemental analyses were deter-
Â
mined by the Servicio de Microanalisis, Universidad
Complutense.
2-Methyl-2-hexenal dimethylhydrazone (1e)
To a solution of 2-methyl-2-hexenal26 (0.68 g, 6.07 mmol)
in Et2O (10 mL) was added N,N-dimethylhydrazine (0.73 g,
0.92 mL, 12.14 mmol, 2 equiv.) and glacial AcOH
(0.2 mL). The reaction mixture was re¯uxed under a
CaCl2 tube at 458C for 30 min and then was warmed to
room temperature and washed with aqueous NaHCO3
(2£10 mL). The ether layer was dried (Na2SO4) and evapo-
rated under reduced pressure at room temperature to give
0.884 g (95%) of dimethylhydrazone 6c as a pale yellow oil.
[Found: C, 69.93; H, 11.58; N, 17.92. C9H18N2 requires C,
70.08; H, 11.76; N, 18.16]; nmax (NaCl) 1572 cm21. dH
(250 MHz, CDCl3) 7.03 (s, 1H, H-1), 5.54 (t, 1H, Jˆ
7.4 Hz, H-3), 2.79 (s, 6H, NMe2), 2.12 (q, 2H, Jˆ7.4 Hz,
H-4), 1.81 (s, 3H, C2±CH3), 1.42 (sext, 2H, Jˆ7.2 Hz, H-5),
0.91 (t, 3H, Jˆ7.2 Hz, H-6). dC (63 MHz, CDCl3) 140.82
(C-1), 134.48 (C-3), 133.49 (C-2), 43.32 (NMe2), 30.35
(C-4), 22.80 (C-5), 13.97 (C-6), 11.79 (C2±CH3).
4-Methyl-1-azaanthraquinone (cleistopholine) (5). Start-
ing from 45 mg (0.18 mmol) of compound 4,17 a yield of
30 mg (80%) of 517,18 was obtained, as a pale yellow solid.
Double N-oxidation of 1,8-diazaanthraquinones
General procedure. A solution of the suitable 1,8-diazaan-
thraquinone 3 (95±130 mg, 0.39±0.93 mmol) and UHP
(118±282 mg, equivalent to 1.25±2.99 mmol of H2O2) in
TFA (0.85±1.15 mL) was stirred at room temperature for
4 h, with periodic additions of UHP (118±282 mg each
hour, in one portion). The reaction mixture was stirred for
additional 20 h and evaporated. The residue was triturated
with CHCl3 (8£25 mL) and the combined chloroform layers
were ®ltered through celite and evaporated. The bis(N-oxides)
Reaction of 2-methyl-2-hexenal dimethylhydrazone with
2,6-dibromobenzoquinone
1
6 were characterized by H NMR spectroscopy31 and used
To a solution of 2,6-dibromobenzoquinone16 (200 mg,
0.75 mmol) in CHCl3 (10 mL) was added the azadiene 1e
without further puri®cation.

Â
J. M. Perez et al. / Tetrahedron 56 (2000) 4575±4583
4580
Rearrangements of 1,8-diazaanthracene-9,10-dione bis-
(N-oxides) 6
6H, Jˆ7.4 Hz, C3,5±CH2CH3); dC (63 MHz, F3C±CO2D)
180.6 (C-9), 173.3 (C-10), 166.3 (C-2,7), 146.4 (C-3,6),
136.3 (C-8a,9a), 135.4 (C-4,5); 119.9 (C-10,4a), 24.8
(C3,5±CH2CH3), 11.5 (C3,5±CH2CH3).
General procedures. Single rearrangement of 6a to 8a.
To a suspension of compound 6a (45 mg, 0.17 mmol) in
CH3CN (13 mL) at room temperature was added tosyl chlo-
ride (25 mg, 0.13 mmol). The suspension was slowly heated
to 608C until complete dissolution, and water (0.64 mL,
35.0 mmol) was added. The reaction mixture was stirred
for 4 h, with periodic additions of tosyl chloride (25 mg,
0.13 mmol each hour). The solution was stirred for addi-
tional 14 h and cooled. A precipitate was ®ltered off; the
®ltrate was evaporated and the residue was washed with
chloroform, and the orange crystalline residue was identi-
®ed as compound 8a (30 mg, 67%). [Found: C, 61.98; H,
3.57; N, 10.10. C14H10N2O4 requires C, 62.22; H, 3.73; N,
10.37]; mp .3008C. nmax (KBr) 3423, 1676, 1640,
1188 cm21. dH (250 MHz, F3CCO2D) 8.00 (br. s, 1H, H-4),
7.44 (d, 1H, Jˆ7.5 Hz, H-7), 7.02 (d, 1H, Jˆ7.5 Hz, H-5),
2.13 (br. s, 6H, 2 CH3). dC (63 MHz, F3CCO2D) 181.2 (C-9),
173.5 (C-10), 166.9 (C-2), 147.5 (C-8a), 146.5 (C-10a), 141.2
(C-3), 137.8 (C-7), 136.8 (C-9a), 131.2 (C-4), 127.4 (C-5),
122.8 (C-4a), 21.4 (C3±CH3), 17.5 (C6±CH3).
Data for 8b. [Found: C, 64.21; H, 4.97; N, 9.19. C16H14N2O4
requires C, 64.42; H, 4.73; N, 9.39]; mp .3008C; nmax
(KBr) 3419, 1654 cm21; dH (250 MHz, CD3OD) 8.84 (s,
1H, H-4), 8.45 (s, 1H, H-7), 8.00 (s, 1H, H-5), 2.94 (q,
2H, Jˆ7.4 Hz, C6±CH2CH3), 2.70 (q, 2H, Jˆ7.4 Hz, C3±
CH2CH3), 1.43 (t, 3H, Jˆ7.4 Hz, C6±CH2CH3), 1.33 (t, 3H,
Jˆ7.4 Hz, C3±CH2CH3); dC (75 MHz, CD3OD) 182.0
(C-9), 172.1 (C-10), 163.3 (C-2), 147.4 (C-8a), 147.0
(C-10a), 142.0 (C-6), 138.9 (C-3), 135.2 (C-9a), 134.7 (C-7),
132.1 (C-4), 131.5 (C-5), 119.8 (C-4a), 27.2 (C6±CH2CH3),
25.0 (C3±CH2CH3), 15.1 (C6±CH2CH3), 12.8 (C3±CH2CH3).
Rearrangement of 6c. Starting from crude bis(N-oxide) 6c,
previously obtained from 3c (100 mg, 0.42 mmol), a yield
of 28 mg (25% overall from 3c) of 4,5-dimethyl-1H,8H-1,8-
diazaanthracene-2,7,9,10-tetraone (7c) was obtained.
[Found: C, 62.23; H, 3.61; N, 10.08. C14H10N2O4 requires
C, 62.22; H, 3.73; N, 10.37]; mp .3008C; nmax (KBr) 3420,
1670, 1637 cm21; dH (250 MHz, 1:1 F3CCO2D1CDCl3)
8.77 (br. s, 2H, NH), 8.08 (s, 2H, H-3,5), 2.96 (s, 6H, 2
CH3). dC (63 MHz, 1:1 F3CCO2D1CDCl3) 176.6 (C-9),
175.6 (C-10), 166.2 (C-2,7), 142.6 (C-4,5), 136.7 (C-
8a,9a), 134.5 (C-3,6), 127.3 (C-10a,4a), 21.5 (CH3).
Double rearrangement to compounds 7. To a suspension
of the suitable compound 6 (0.28±0.38 mmol) in CH3CN
(25±35 mL), was added tosyl chloride (54±74 mg, 0.28±
0.38 mmol) at room temperature. The suspension was slowly
heated to 608C until complete dissolution, and water (1.35±
1.85 mL, 75±103 mmol) was added. The reaction mixture
was stirred for 4 h, with periodic additions of tosyl chloride
(54±74 mg, 0.28±0.38 mmol each hour). The solution was
stirred for an additional period of 20 h and was cooled. The
red precipitate (compounds 7) was ®ltered, washed with
methanol and dried under reduced pressure. In the reaction
starting from 6b, a 13% yield of compound 8b was obtained
from the ®ltrate (see below).
Rearrangement of 6d. Starting from crude bis(N-oxide)
6d, previously obtained from 3d (115 mg, 0.39 mmol), a
yield of 51 mg (40% overall from 3d) of 4,5-diethyl-3,6-
dimethyl-1H,8H-1,8-diazaanthracene-2,7,9,10-tetraone (7d)
was obtained. [Found: C, 66.20; H, 5.21; N, 8.54.
C18H18N2O4 requires C, 66.25; H, 5.56; N, 8.58]; mp
.3008C; nmax (KBr) 3430, 1671, 1637 cm21
; dH
±
(250 MHz, F3CCO2D) 3.05 (q, 4H, Jˆ7.5 Hz, C4,5
CH2CH3), 2.18 (s, 6H, C3,6±CH3), 1.12 (t, 6H, Jˆ7.5 Hz,
C4,5±CH2CH3); dC (63 MHz, F3CCO2D) 181.9 (C-9), 173.9
(C-10), 161.1 (C-2,7), 138.0 (C-3,6), 135.2 (C-8a,9a),122.2
(C-10a,4a), 25.2 (C4,5±CH2CH3), 12.8 (C3,5±CH3), 12.5
(C4,5±CH2CH3).
Rearrangement of 6a. Starting from the crude bis(N-oxide)
6a, previously obtained from 3a (53 mg, 0.22 mmol), a
yield of 20 mg (33% overall from 3a) of 3,6-dimethyl-
1H,8H-1,8-diazaanthracene-2,7,9,10-tetraone (7a) was
obtained. [Found: C, 62.35; H, 3.57; N, 10.40.
C14H10N2O4 requires C, 62.22; H, 3.73; N, 10.37]; mp
.3008C; nmax (KBr) 3432, 1677, 1639 cm21; dH (250
MHz, F3CCO2D) 8.20 (s, 2H, H-4,5), 2.37 (s, 6H, 2 CH3);
dC (63 MHz, F3C±CO2D) 178.1 (C-9), 171.7 (C-10), 163.5
(C-2,7), 139.6 (C-3,6), 135.5 (C-4,5), 134.8 (C-8a,9a),
117.7 (C-10a,4a), 16.9 (2 CH3).
Rearrangement of 6e. Synthesis of diazaquinomycin A
(7e, 1)
Starting from the crude bis(N-oxide) 6e (130 mg,
0.40 mmol), a yield of 43 mg of 7e (1) was obtained (30%
overall from 3e). This material was identical in all respects
to a natural sample;32 mp 290±2958C, lit.1 291±2958C; nmax
(KBr) 1671, 1625 cm21; dH (250 MHz, F3CCO2D) 2.99 (t,
4H, Jˆ7.7 Hz, C4,5±CH2CH2CH3), 2.17 (s, 6H, C3,6±CH3),
1.44 (quint, 4H, Jˆ7.5 Hz, C4,5±CH2CH2CH3), 0.92 (t, 6H,
Jˆ7.4 Hz, C4,5±CH2CH2CH3); dC (75 MHz, F3CCO2D)
181.1 (C-9), 173.0 (C-10), 158.9 (C-2,7), 137.1 (C-3,6),
Rearrangement of 4b. Starting from crude bis(N-oxide)
6b, previously obtained from 3b (100 mg, 0.38 mmol), a
yield of 28 mg (25% overall from 3b) of 3,6-diethyl-
1H,8H-1,8-diazaanthracene-2,7,9,10-tetraone (7b) was
obtained. Evaporation of the methanol washes followed
by trituration with CHCl3 afforded a precipitate of 3,6-
diethyl-1H-1,8-diazaanthracene-2,9,10-trione-8-oxide (8b)
(15 mg, 13%), as an orange solid.
134.3 (C-8a,9a), 121.4 (C-10a,4a), 32.9 (C4,5
±
CH2CH2CH3), 24.1 (C4,5±CH2CH2CH3), 13.3 (C3,5±CH3),
11.8 (C4,5±CH2CH2CH3).
Data for 7b. [Found: C, 64.31; H, 4.36; N, 9.21. C16H14N2O4
requires C, 64.42; H, 4.73; N, 9.39]; mp .3008C; nmax
(KBr) 3446, 1639 cm21; dH (250 MHz, F3CCO2D) 8.04 (s,
2H, H-4,5), 2.53 (q, 4H, Jˆ7.4 Hz, C3,5±CH2CH3), 1.08 (t,
S-tert-Butyl-3-oxohexanethioate (10)
To a slurry of petrol-washed (2£10 mL) sodium hydride
(0.76 g of a 60% dispersion in mineral oil, 18.96 mmol,

Â
J. M. Perez et al. / Tetrahedron 56 (2000) 4575±4583
4581
1.1 equiv.) in dry 1,2-dimethoxyethane (70 mL) under a
nitrogen atmosphere at 2208C, was added dropwise, via
cannula, a solution of 922b (3.00 g; 17.24 mmol) in dry
dimethoxyethane (50 mL). The solution was left to warm
to 08C for 5±10 min, and then was cooled to 2408C. After
15 min at this temperature, butyl lithium (11.85 mL of a
1.6 M solution in hexanes, 18.97 mmol, 1.1 equiv.) was
added dropwise, and the solution turned from yellow to
dark red. The reaction was warmed to 2208C, in order to
complete anion formation. After stirring for 10 min more at
this temperature, it was cooled again to 2408C, and ethyl
bromide (1.97 g, 18.10 mmol, 1.05 equiv.) was added. After
30 min at 08C, the reaction mixture was quenched with
saturated aqueous NH4Cl (2£50 mL), extracted with diethyl
ether (2£100 mL) and washed again with aqueous NH4Cl
(50 mL) and brine (2£50 mL), dried (Na2SO4), and evapo-
rated under reduced pressure to give an orange oil. Chro-
matography (99% petroleum ether/ethyl ether) yielded
2.58 g (74%) of S-tert-butyl-3-oxohexanethioate 10 as a
colourless oil. [Found: C, 59.16; H, 8.72. C10H18SO2
requires C, 59.37; H, 8.97]; nmax (NaCl) 1732 (CvO, a),
1684 (tBuS±CvO, a), 1624 (CvC, b) cm21; dH (CDCl3,
250 MHz, 81% oxo (a) and 19% enol (b)) 12.80 (br. s, 1H,
OH, b), 5.25 (s, 1H, H-2, b), 3.48 (s, 2H, H-2, a), 2.44 (t, 2H,
Jˆ7.2 Hz, H-4, a), 2.03 (t, 2H, Jˆ7.2 Hz, H-4, b), 1.53
dimethoxyaniline (0.34 g; 2.24 mmol; 1.05 equiv.) in 1,2-
dimethoxyethane (10 mL) was added freshly prepared silver
tri¯uoroacetate33 (0.38 g; 1.72 mmol). After 10 min at room
temperature, more silver salt (0.19 g, 0.86 mmol, totalling
1.2 equiv.) was added, and the suspension was stirred over-
night at room temperature (the reaction was complete in ca.
90 min by TLC, but longer reaction times favoured the
precipitation of silver species and facilitated the puri®cation
process). The dark-brown suspension was decanted from the
precipitate of silver salts, which was washed with petrol
(3£20±50 mL). The combined organic phases were evapo-
rated under reduced pressure to give a black oil. Chromato-
graphy (neat dichloromethane to neat ethyl ether) yielded
0.23 g of recovered 11 and 0.29 g (49% isolated, 97% based
on recovered starting material) of 12, as a colourless oil.
[Found: C, 64.59; H, 7.59; N, 5.09. C15H21NO4 requires C,
64.50; H, 7.58; N, 5.01]; nmax (NaCl) 3380 (NH), 1732
(CvO), 1692 (CO±N), 1232 (OCH3) cm21; dH (CDCl3,
250 MHz) 8.61 (br. s, 1H, NH), 8.03 (d, 1H, Jˆ3.0 Hz,
H-60), 6.76 (d, 1H, Jˆ8.9 Hz, H-30), 6.54 (dd, 1H, Jˆ8.9
0
0
0
and 3.0 Hz, H-4 ), 3.82 (s, 3H, C5 ±OMe), 3.73 (s, 3H, C2 ±
OMe), 3.55 (q, 1H, Jˆ7.2 Hz, H-2), 2.55 (td, 2H, Jˆ7.2 and
2.5 Hz, H-4), 1.59 (sext, 2H, Jˆ7.3 Hz, H-5), 1.45 (d, 3H,
Jˆ7.2 Hz, C2±CH3), 0.87 (t, 3H, Jˆ7.4 Hz, H-6); dC
(CDCl3, 63 MHz) 209.1 (C-3), 167.4 (C-1), 153.6 (C-50),
t
(sext, 2H, Jˆ7.3 Hz, H-5, a), 1.43 (s, 9H, Bu, b), 1,40 (s,
142.3 (C-20), 127.8 (C-10), 110.7 (C-30), 108.7 (C-40), 105.9
t
0
(C-4), 16.6 (C-55), 14.9 (C2±CH3), 13.4 (C-6).
0
(C-6 ), 56.2 (C2 ±OMe), 55.5 (C2 ±OMe), 55.3 (C-2), 43.3
0
9H, Bu, a), 1.23±1.14 (m, 2H, H-5, b), 0.84 (t, 3H;
Jˆ7.4 Hz, H-6, a and b); dC (CDCl3, 63 MHz) 202.3 (C-3,
a), 196.1 (C-3, b), 192.6 (C-1, b), 176.3 (C-1, b), 99.6 (C-2,
b), 58.4 (C-2, a), 48.9 (C(CH3)3, a), 48.1 (C(CH3)3, b), 44.9
(C-4, a), 36.8 (C-4, b), 30.2 (C(CH3)3, b), 29.6 (C(CH3)3, a),
19.6 (C-5, b), 16.9 (C-5, a), 13.6 (C-6, b), 13.5 (C-6, a).
3-Methyl-4-propyl-5,8-dimethoxy-2(1H)-quinolinone
(13)
A solution of compound 12 (0.15 g, 0.54 mmol) in 96%
H2SO4 (2 mL) was stirred at room temperature for 3 h,
and was then quenched with ice, basi®ed with 25% aqueous
NH4OH and extracted with CHCl3 (3£25±50 mL). The
combined organic layers were washed with brine (25±
50 mL), dried (Na2SO4) and evaporated under reduced
pressure to give an off-white solid. Chromatography (50%
ethyl ether/ethyl acetate to neat ethyl acetate) afforded
0.14 g (100%) of compound 13 as white crystals. [Found:
C, 68.68; H, 7.31; N, 5.18. C15H19NO3 requires C, 68.94; H,
7.33; N, 5.36]; mp 171±1738C; nmax (KBr) 3190 (NH), 1644
(CvO), 1268 (OCH3) cm21; dH (CDCl3, 250 MHz) 9.27
(br. s, 1H, NH), 6.79 (d, 1H, Jˆ8.8 Hz, H-7), 6.50 (d, 1H,
Jˆ8.8 Hz, H-6), 3.88 and 3.84 (2 s, 6H, 2OMe), 3.05 (t, 2H,
Jˆ7.9 Hz, C4±CH2), 2.24 (s, 3H, C3±CH3), 1.55 (sext, 2H,
Jˆ7.9 Hz, C4±CH2±CH2), 1.03 (t, 3H, Jˆ7.3 Hz, C4±CH2±
CH2±CH3); dC (CDCl3, 63 MHz) 161.6 (C-2), 151.1 (C-5),
148.9 (C-8), 139.6 (C-4), 128.4 (C-8a), 127.1 (C-3), 111.3
(C-4a), 108.4 (C-7), 102.2 (C-6), 56.1 and 55.7 (2 OMe),
34.1 (CH2±CH2±CH3), 22.8 (CH2±CH2±CH3), 14.5 (CH2±
CH2±CH3), 12.2 (C3±CH3).
S-tert-Butyl 2-methyl-3-oxothiohexanoate (11)
To a slurry of petrol-washed (2£10 mL) sodium hydride
(0.26 g of a 60% dispersion in mineral oil, 6.50 mmol) in
a nitrogen
dry 1,2-dimethoxyethane (40 mL) under
atmosphere at 2208C, was added dropwise, via cannula, a
solution of 10 (1.25 g, 6.19 mmol) in dry 1,2-dimethoxy-
ethane (5 mL). The solution was left to warm to 08C for
5±10 min, and methyl iodide (0.92 g, 6.50 mmol,
1.05 equiv.) was added. After 14 h at room temperature,
the reaction mixture was quenched with saturated aqueous
NH4Cl (50 mL), extracted with diethyl ether (2£100 mL)
and washed again with aqueous NH4Cl (50 mL) and brine
(2£50 mL), dried (Na2SO4), and evaporated under reduced
pressure to give an orange oil. Chromatography (99%
petroleum ether/ethyl ether) yielded 0.83 g (62%) of 11 as
a colourless oil. [Found: C, 60.96; H, 9.13. C11H20SO2
requires C, 61.07; H, 9.32]; nmax (NaCl) 1725 (CvO),
1673 (tBuS±CvO) cm21; dH (CDCl3, 250 MHz) 3.63 (q,
1H, Jˆ6.9 Hz, H-2), 2.50 (t, 2H, Jˆ7.3 Hz, H-4), 1.57
t
(sext, 2H, Jˆ7.3 Hz, H-5), 1.46 (s, 9H, Bu), 1.35 (d, 3H,
Jˆ7.0 Hz, C2±CH3), 0.88 (t, 3H, Jˆ7.4 Hz, H-6). dC
(CDCl3, 63 MHz) 204.5 (C-3), 196.8 (C-1), 61.8 (C-2),
48.4 (C(CH3)3), 42.8 (C-4), 29.4 (C(CH3)3), 16.7 (C-5),
13.3 and 13.2 (C6 and C2±CH3).
3-Methyl-4-propyl-1H-2,5,8-quinolinetrione (14)
To a solution of compound 13 (0.18 g, 0.70 mmol) in a
mixture of CH3CN (10 mL) and H2O (5 mL) was added
cerium ammonium nitrate (1.16 g, 2.10 mmol, 3 equiv.).
The solution was stirred at room temperature for 3 h, and
was then diluted with H2O (15 mL) and extracted with
CHCl3 (3£30 mL). The chloroform layer was washed with
H2O (2£40 mL), dried (Na2SO4) and evaporated under
N-(2,5-Dimethoxyphenyl)-2-methyl-3-oxohexanamide
(12)
To a solution of compound 11 (0.46 g, 2.13 mmol) and 2,5-

Â
J. M. Perez et al. / Tetrahedron 56 (2000) 4575±4583
4582
reduced pressure to give a red residue. Sublimation at
0.1 torr yielded 0.14 g (87%) of quinone 14 as a dark orange
solid. [Found: C, 67.56; H, 5.83; N, 5.80. C13H13NO3
requires C, 67.52; H, 5.67; N, 6.06]; mp 144±1468C; nmax
(KBr) 3450 (NH), 1652 (CvO) cm21; dH (CDCl3,
250 MHz) 9.47 (br. s, 1H, NH); 6.84 (d, 1H, Jˆ10.2 Hz,
H-7), 6.76 (d, 1H, Jˆ10.2 Hz, H-6), 2.99 (t, 2H, Jˆ7.9 Hz,
C4±CH2), 2.22 (s, 3H, C3±CH3), 1.49 (sext, 2H, Jˆ7.8 Hz,
C4±CH2±CH2±CH3), 1.06 (t, 3H, Jˆ7.3 Hz, C4±CH2±
CH2±CH3); dC (CDCl3, 63 MHz) 183.8 (C-8), 179.5
(C-5), 161.2 (C-2), 150.0 (C-4), 140.3 (C-6), 136.1 (C-8a),
134.9 (C-3), 132.4 (C-7), 113.9 (C-4a), 31.7(C4±CH2), 22.2
(C4±CH2±CH2±CH3), 14.34 (C4±CH2±CH2±CH3), 12.35
(C3±CH3).
117.9 (C-4a), 32.1 and 31.6 (C4±CH2 and C5±CH2), 22.6
and 22.5 (C4±CH2±CH2 and C5±CH2±CH2), 17.2 (C6±
CH3), 14.5 and 14.3 (C4±CH2±CH2±CH3 and C5±CH2±
CH2±CH3), 12.7 (C3±CH3).
Preparation of (16) by aromatization of (15)
To a solution of compound 15 (25 mg, 0.07 mmol) in
CH2Cl2 (10 mL) was added 38 mg (0.39 mmol, 5 equiv.)
of activated 85% manganese dioxide. The suspension was
stirred at room temperature for 30 min and then was ®ltered
through celite, which was washed twice with CHCl3
(30 mL). The combined organic layers were evaporated
under reduced pressure to give a brown residue. Chromato-
graphy (ethyl acetate) afforded 16 mg (65%) of the aromatic
compound 16 as a yellow solid.
Reaction of 3-methyl-4-propyl-1H-2,5,8-quinolinetrione
(14) with 2-methyl-2-hexenal dimethylhydrazone (1e)
Alternative synthesis of compound (16) from (3e)
Silica gel (125 mg) was added to a solution of quinone 14
(40 mg, 0.17 mmol) in CHCl3 (10 mL). The suspension was
stirred at room temperature for 15 min and evaporated to
dryness. The silica gel-supported quinone was placed on the
top of a chromatography column containing silica gel (6 g)
and was covered with a layer of sand. Neat 2-methyl-2-
hexenal dimethylhydrazone 1e (53 mg, 0.35 mmol,
2 equiv.) was added and covered with a second layer of
sand. The diene was allowed to permeate the sand and
contact the silica gel layer over 1 min. The column was
then eluted with a gradient from dichloromethane to 1:1
dichloromethane-ethyl acetate, to yield recovered azadiene
1e, 27 mg (46%) of 5,8-dihydro-3,5-dimethyl-4,5-dipropyl-
1H-1,8-diazaanthracene-2,9,10-trione (15) as a green solid
and 14 mg (24%) of 3,5-dimethyl-4,5-dipropyl-1,8-diaza-
anthracene-2,9,10-trione (16) as a yellow solid.
A solution of compound 3e (60 mg, 0.19 mmol) and UHP
(54.6 mg, equivalent to 0.58 mmol of H2O2) in tri¯uoro-
acetic acid (0.5 mL) was stirred at room temperature for
4 h, with periodic additions of fresh UHP (54.6 mg each
hour). Stirring at room temperature was prolonged for addi-
tional 14 h. The reaction mixture was then evaporated and
the residue was trirurated with CHCl3 (8£25 mL). The
combined organic layers were ®ltered through celite and
evaporated, affording compound 17 as an orange solid,
1
which was identi®ed by H RMN and used without further
puri®cation. The crude compound 1734 was dissolved in
TFA (1 mL) and submitted to the general procedure for
the rearrangement of N-oxides to lactams described above,
yielding compound 16 (20 mg, 31% overall).
Synthesis of diazaquinomycin A from (16)
Data for 15. [Found: C, 70.38; H, 6.95; N, 8.01. C20H24N2O3
requires C, 70.57; H, 7.11; N, 8.23]; mp 179±1808C; nmax
(KBr) 3420 (NH), 1654, 1636 (CvO) cm21; dH (CDCl3,
250 MHz) 9.79 (br. s, 1H, NH), 6.64 (br. s, 1H, H-8), 6.06
(d, 1H, Jˆ4.2 Hz, H-7), 3.62 (t, 1H, Jˆ4.7 Hz, H-5), 3.21±
2.95 (m, 2H, C4±CH2), 2.23 (s, 3H, C3±CH3), 1.74 (s, 3H,
C6±CH3), 1.51±1.42 (m, 4H, C4±CH2±CH2 and C5±CH2±
CH2), 1.34±1.24 (m, 2H, C5±CH2), 1.06 (t, 3H, Jˆ7.1 Hz,
C4±CH2±CH2±CH3), 0.94±0.76 (m, 3H, C5±CH2±CH2±
CH3); dC (CDCl3, 63 MHz) 183.5 (C-9), 175.9 (C-10),
161.2 (C-2), 151.1 (C-4), 136.5, 135.8 and 134.2 (C8a, C9a
and C3), 119.37 (C-7), 116.00 (C-6), 114.83 (C-4a), 112.6
(C-10a), 35.9 (C4±CH2), 35.6 (C-5), 32.2 (C5±CH2), 22.6
(C4±CH2±CH2), 18.9 (C5±CH2±CH2±CH3), 18.6 (C6±
CH3), 14.6 and 14.4 (C4±CH2±CH2±CH3 and C5±CH2±
CH2±CH3), 12.82 (C3±CH3).
A solution of compound 16 (19 mg, 0.056 mmol) and UHP
(17.3 mg, equivalent to 0.18 mmol of H2O2) in TFA
(0.15 mL) was stirred at room temperature for 4 h, with
hourly additions of fresh UHP (17.3 mg each time). Stirring
at room temperature was prolonged for additional 14 h; the
reaction mixture was then evaporated and the residue was
triturated with CHCl3 (8£25 mL). The combined organic
layers were evaporated and the residue was suspended in
CH3CN (5 mL). The suspension was treated with tosyl
chloride (10.8 mg, 0.056 mmol) and the temperature was
raised to 608C, until dissolution. Water (0.3 mL,
16.6 mmol) was added, and the solution was stirred at
608C for 4 h, with hourly additions of tosyl chloride
(10.8 mg each time). After an additional reaction time of
20 h at 608C, the solution was cooled. A red precipitate was
®ltered, washed with methanol and dried in vacuo. This
material (6 mg, 30% overall from 16) was identical in all
respects to natural diazaquinomycin A.
Data for 16. [Found: C, 70.75; H, 6.53; N, 7.99. C20H22N2O3
requires C, 70.99; H, 6.55; N, 8.28]; mp 170±1728C; nmax
(KBr) 3421 (NH), 1654 and 1636 (CvO) cm21; dH (CDCl3,
250 MHz) 9.67 (br. s, 1H, NH), 8.69 (s, 1H, H-7), 3.12±2.99
(m, 4H, C4±CH2 and C5±CH2), 2.46 (s, 3H, C6±CH3), 2.26
(s, 3H, C3±CH3), 1.67±1.45 (m, 4H, C4±CH2±CH2 and C5±
CH2±CH2), 1.10 and 1.08 (2 t, 6H, Jˆ7.3 and 7.1 Hz, C4±
CH2±CH2±CH3 and C5±CH2±CH2±CH3). dC (CDCl3,
63 MHz) 184.3 (C-9), 177.1 (C-10), 160.9 (C-2), 154.2
(C-7), 152.8 (C-4), 149.9 (C-5), 145.4 (C-8a), 139.6
(C-9a), 136.3 and 136.1 (C-6 and C-3), 129.5 (C-10a),
Acknowledgements
We thank Professor S. Omura for generously providing a
sample of natural diazaquinomycin A for reference
purposes. Financial support from CICYT (grant PTR-95-
0230) is also gratefully acknowledged.

Â
J. M. Perez et al. / Tetrahedron 56 (2000) 4575±4583
4583
20. (a) Ames, D. E.; Archibald, J. L. J. Chem. Soc. 1962,
1475±1481. (b) Klemm, L. H.; Wang, J.; Sur, S.K. J. Heterocycl.
Chem. 1990, 27, 1537±1541.
References
1. (a) Omura, S.; Iwai, K.; Hinotozawa, K.; Tanaka, H.;
Takahashi, Y.; Nakagawa, A. J. Antibiot. 1982, 35, 1425±1429.
(b) Omura, S.; Nakagawa, A.; Hinotozawa, K.; Sano, H.
Tetrahedron Lett. 1983, 24, 3643±3646.
21. Preliminary account of the synthesis of diazaquinomycin A:
  Â
Perez, J. M.; Lopez-Alvarado, P.; AvendanÄo, C.; Menendez, J. C.
Tetrahedron Lett., 1998, 39, 673±676.
22. This method has been previously applied to the synthesis of
2. (a) Omura, S.; Murata, M.; Kimura, K.; Matsakura, S.;
Nishihara, T.; Tanaka, H. J. Antibiot. 1985, 38, 1016±1024. (b)
Murata, M.; Miyasaka, T.; Tanaka, H.; Omura, S. J. Antibiot. 1985,
38, 1025±1033.
Â
analogues of 14: Lopez-Alvarado, P.; AvendanÄo, C.; Menendez,
Â
J. C. Synthesis, 1998 186±194.
23. (a) Booth, P. M.; Fox, C. M. J.; Ley, S. V. J. Chem. Soc. Perkin
Trans. 1 1987, 121±129. (b) Booth, P. M.; Broughton, H. B.; Ford,
M. J.; Fox, C. M. J.; Ley, S. V.; Slawin, A. M. Z.; Williams, D. J.;
Woodward, P. R. Tetrahedron 1989, 45, 7565±7580.(c) Ley, S. V.;
Trudell, M.; Wadsworth, D. J. Tetrahedron 1991, 47, 8285±8296.
24. (a) Fox, C. M. J.; Ley, S. V.; Org. Synth. 1987, 66, 108±115.
3. Omura, S. Microbiol. Rev. 1986, 50, 259±279.
4. (a) Forbis, R. M.; Rinehart, R. L.; J. Am. Chem. Soc. 1973, 95,
5003±5013. (b) Lee, H.; Anderson, W. K. Tetrahedron Lett. 1990,
31, 4405±4408.
5. Kelly, T. R.; Field, J. A.; Li, Q. Tetrahedron Lett. 1988, 29,
3545±3546.
 Â
(b) Lopez-Alvarado, P.; AvendanÄo, C.; Menendez, J. C. Synth.
6. For some recent examples, see: (a) Miura, Y.; Takaku, S.;
Humana, M. Heterocycles 1992, 34, 1055±1063. (b) Kitahara,
Y.; Nakahara, S.; Shimizu, M.; Yonezawa, T.; Kubo, A.
Heterocycles 1993, 36, 1909±1924. (c) OcanÄa, B.; Espada, M.;
AvendanÄo, C. Tetrahedron 1995, 51, 1253±1258.
Commun. 1992, 22, 2329±2333.
25. Woodward, P. R.; Ley, S. V. Tetrahedron Lett. 1987, 32,
2431±2432.
26. Satsumabayashi, S.; Nakajo, K.; Soneda, R.; Motoki, S. Bull.
Chem. Soc. Jpn. 1970, 43, 1586±1588.
27. Waldner, A. Helv. Chim. Acta 1988, 71, 486±492.
 Â
28 Perez, J. M.; AvendanÄo, C.; Menendez, J. C. Tetrahedron Lett.
1996, 37, 6955±6958.
7. For reviews, see: (a) Boger, D. L. Tetrahedron 1983, 39, 2869±
2939. (b) Boger, D. L. Chem. Rev. 1986, 86, 781±793. (c) Boger,
D. L.; Weinreb, S. M. In Hetero Diels±Alder Methodology in
Organic Synthesis; Academic Press: New York, 1987. (d) Boger,
D. L. In Comprehensive Organic Synthesis; Paquette. L. A., Ed.;
(Trost, B. M., Fleming, I. General editors). Pergamon Press: New
Â
York, 1991; Vol. 5, pp 451±512. (e) Barluenga, J.; Tomas, M. Adv.
Heterocycl. Chem. 1993, 57, 1. (f) Tietze, L. F.; Kettschau, G.,
Topics Curr. Chem. 1997, 189, 1±80.
29. See, for instance: (a) Potts, K. T.; Walsh; E. B.; Bhattacharjee,
D. J. Org. Chem. 1987, 52, 2285±2292. (b) Nebois, P.; Cherkaoui,
O.; Benameur, L.; Fillion, H. Tetrahedron 1994, 50, 8457±8464.
(c) Chaker, L.; Pautet, F.; Fillion, H. Heterocycles 1995, 41, 1169±
 Â
1179. (d) Perez, J. M.; AvendanÄo, C.; Menendez, J. C. Tetrahedron
1995, 51, 6573±6586.
8. Chirers, G. E.; Suschitzky, H. J. Chem. Soc. (C) 1971, 2867±
2871.
30. dH (250 MHz, CDCl3) 6.04 (s, 2H), 3.40 (t, 2H, Jˆ4.5 Hz),
2.58 (s, 6H), 1.66 (s, 6H), 1.12 (m, 4H), 1.01 (m, 4H), 0.81 (t, 6H,
Jˆ7.5 Hz).
9. Katritzky, A. R.; Rasala, D.; Brito-Palma, F. J. Chem. Res. (S)
1988, 42±43.
31. dH (250 MHz, CDCl3): 4a: 8.41 (s, 2H, H-2,7), 7.99 (s, 2H,
H-4,5), 2.54 (s, 6H, C3,6±CH3); 4b: 8.36 (s, 2H, H-2,7), 7.94 (s, 2H,
10. Broughman, P.; Cooper, M. S.; Cummerson, M. S.; Heaney,
H.; Thompson, N. Synthesis 1987, 1015±1017.
11. Cooper, M. S.; Heaney, H.; Newbold, A. J.; Sanderson, W. R.
Synlett 1990, 533±535.
12. OcanÄa, B.; Espada, M.; AvendanÄo, C. Tetrahedron 1994, 50,
9505±9510.
H-4,5), 2.77 (m, 4H, C3,6-CH2±CH3), 1.28 (t, 6H, Jˆ6.2 Hz, C3,6
±
CH2-CH3). 4c: 7.90 (d, 2H, Jˆ8.5 Hz, H-2,7), 7.07 (d, 2H,
Jˆ8.5 Hz, H-3,6), 2.83 (s, 6H, C4,5±CH3), 4d: 8.35 (s, 2H,
H-2,7), 3.06 (m, 4H, C4,5±CH2±CH3), 2.44 (s, 6H, C3,6±CH3),
1.30 (t, 6H, Jˆ7.1 Hz, C4,5±CH2-±CH3); 4e: 8.26 (s, 2H, H-2,7),
2.88 (m, 4H, C4,5±CH2±CH2±CH3), 2.38 (m, 4H, C4,5±CH2±CH2±
CH3), 2.13 (s, 6H, C3,6±CH3), 1.07 (t, 6H, Jˆ7.1 Hz, C4,5±CH2±
CH2±CH3).
13. Varma, R. S.; Naicker, K. P. Org. Lett. 1999, 1, 189±191.
14. Heaney, H. Aldrichim. Acta 1993, 26, 35±45.
 Â
15. (a) Perez, J. M.; AvendanÄo, C.; Menendez, J. C. Tetrahedron
Â
Lett., 1997, 26, 4717±4720. (b) Perez, J. M.; Lopez-Alvarado, P.;
Â
32. The synthetic material was directly compared with a natural
sample. Literature NMR data for diazaquinomycin A (Ref. 1b)
were obtained in an unspeci®ed mixture of CD3OD and CDCl3,
which explains the slight differences with our data.
Â
AvendanÄo, C.; Menendez, J. C. Tetrahedron 2000, 56, 1561±1567.
16. Perumal, P. T.; Bhat, M. V. Synthesis 1979, 205±206.
17. Bracher, F. Liebigs Ann. Chem. 1989, 87±88.
18. Goulart, M. O. F.; Santana, A. E. G.; de Oliveira, A. B.; de
Oliveira, G. G.; Maia, J. G. S. Phytochemistry 1986, 25, 1691±
1695.
33. Janssen, D. E.; Wilson, C. V. Org. Synth. 1956, 36, 46±48.
34. dH (CDCl3, 250 MHz) 8.72 (s, 1H, H-7), 8.29 (s, 1H, H-2),
2.85 (m, 4H, 2 CH2CH2CH3), 2.43 (s, 3H, C6±CH3), 2.35 (s, 3H,
C3±CH3), 1,55 (m, 4H, 2 CH2CH2CH3), 1.10 (m, 6H, 2
CH2CH2CH3).
Â
Â
19. AvendanÄo, C.; Blanco, M. M.; Menendez, J. C.; Garcõa-
 Â
Gravalos, M. D.; de la Fuente, J. A.; Martõn, J. M. International
Patent Application PCT/GB99/01613 (21-May-1999).