Oxygen analogues of the benzodiazepine alkaloids sclerotigenin and circumdatin F

Article abstract of DOI:10.1002/jhet.5570390218

A new type of fused oxazepinones 9a and 9b, which are analogues of sclerotigenin and circumdatin F, were obtained in a two step synthesis from 2-(2-amino-benzoylamino)-benzoic acid or the corresponding methyl ester. Secondly a new synthesis of circumdatin F arose from this work, where 2-(2-propionylaminobenzoylamino)-benzoic acid methyl ester was used as an intermediate.

Full text of DOI:10.1002/jhet.5570390218

Mar-Apr 2002
Oxygen Analogues of the Benzodiazepine Alkaloids Sclerotigenin
and Circumdatin F
351
Anette Witt and Jan Bergman*
Unit for Organic Chemistry, Department of Biosciences, Karolinska Institute and
Södertörn University College, Novum Research Park, SE-141 57 Huddinge, Sweden
Received July 30, 2001
A new type of fused oxazepinones 9a and 9b, which are analogues of sclerotigenin and circumdatin F,
were obtained in a two step synthesis from 2-(2-amino-benzoylamino)-benzoic acid or the corresponding
methyl ester. Secondly a new synthesis of circumdatin F arose from this work, where 2-(2-propionylamino-
benzoylamino)-benzoic acid methyl ester was used as an intermediate.
J. Heterocyclic Chem., 39, 351 (2002).
Introduction.
and sclerotigenin (6). Furthermore one of the intermediates
8a could be used in a synthesis of sclerotigenin (6) and also
a new approach was used in a synthesis of circumdatin F (1).
In 1999, several new fused benzodiazepine alkaloids were
isolated from a terrestrial isolate of the fungus Aspergillus
ochraceus. Circumdatin F (1) and C (2) are two prototypical
members (Figure 1) [1]. Recently, a new metabolite, cir-
cumdatin G (3), has been isolated from the same fungus [2].
The related alkaloid, asperlicin (4), produced by Aspergillus
alliaceus, is a potent cholecystokinin antagonist [3], and
benzomalvin A (5), isolated from a fungus culture of
Penicillium sp, showed inhibitory activity against substance
P of the guinea pig, rat and human neurokinin NK1 recep-
tors, respectively [4]. Sclerotigenin (6) was recently isolated
from organic extracts of sclerotia of Penicillium scleroti-
genum (NRRL 3461) [5], a potential antiinsectan benzodi-
azepine alkaloid. The total syntheses of circumdatin F (1)
[6,7], circumdatin C (2) [6], asperlicin (4) [8] and benzoma-
lvin A (5) [9], have been reported and the synthesis of scle-
rotigenin (6) [10] was reported already 20 years ago, i.e
before its identification as a natural product. No synthesis of
circumdatin G (3) has yet been published. Now we wish to
report a synthesis of oxygen analogues of circumdatin F (1)
Results and Discussion.
The ester 7a [11], readily obtained from methyl anthrani-
late and N-sulfinylanthraniloyl chloride [12], was used as a
key intermediate. The sulfinyl chloride, previously incor-
rectly described as a sulfinamide [13], was prepared from
anthranilic acid and thionyl chloride. The acid 7b [14] was
synthesised from isatoic anhydride and anthranilic acid.
When compounds 7a,b were treated with bromoacetyl bro-
mide in dioxane the corresponding bromoacetyl com-
pounds 8a,c were isolated in 81% and 76% yield, respec-
tively (Scheme 1). Analogously with the latter compounds
8b,d were isolated in 92% and 80% yield, when com-
pounds 7a,b were treated with 2-bromopropionyl bromide.
When the acids 8c,d were heated at reflux in DMF for 3
hours and overnight, the O-sclerotigenin 9a and O-circum-
datin F 9b were isolated after recrystallisation from ethanol
in 20% yields, respectively. A reasonable mechanism,
using compounds 8c,d, involves an initial cyclisation to the
quinazolinone followed by an intramolecular O-alkylation.
Scheme 1
Figure 1

352
A. Witt and J. Bergman
Vol. 39
When compounds 8a,b were heated overnight at reflux in
DMF, the O-sclerotigenin 9a was only isolated in 1−2%
yield and O-circumdatin F 9b was isolated in 15% yield.
Addition of base such as triethylamine did not improve the
yields for the reaction with the methyl esters 8a,b.
If compounds 8a,b could be specifically cyclised to the
quinazolinone adducts 10 or 14, these latter compounds
could serve as precursors for sclerotigenin (6) and circum-
datin F (1). Compound 8a could be cyclised using p-TSA
in toluene at reflux to the quinazolinone 10 [10] in 43%
yield (Scheme 2), previously synthesised via bromination
of the 2-methyl analogue of compound 10. The quinazoli-
none 10 when treated with ammonia in ethanol at 60° gave
6 [10] in 38% yield. Compound 8b could not analogously
be cyclised to the quinazolinone 14, and therefore an alter-
native approach towards compound 14 was investigated
starting with the benzoxazinone 11 [15].
The benzoxazinone 11 [15], was heated at reflux with
methyl anthranilate in acetic acid for 3 hours and compound
12 could be isolated in 12% yield (Scheme 3). The low yield
might be due to hydrolysis of the starting material 11, but
the cyclised adduct 13 [16] could also be isolated as a co-
product in 5% yield. Optimisation assays towards direct
cyclisation from 11 to the quinazolin-4-one 13 gave no satis-
factory results in our hands. Instead was compound 12 then
heated at reflux in DMF for 65 hours and the quinazolinone
adduct 13 was isolated in 39% yield. The total yield was
only 4.7% yield in two steps, but prior synthesis of com-
pound 13 has been obtained by allowing the appropriate
imidate ester to stand for 15 months [16]. Introduction of an
α-bromine atom in 2-ethylquinazolinone using bromine and
NaOAc in acetic acid is known [17]. When using this
methodology on compound 13 the expected product 14 was
isolated in 87% yield, as a diastereomeric mixture (7:3)
1
according to H NMR. The interesting stereochemistry of
Scheme 2
compound 14 is probably due to the chiral axis, which arises
from restricted rotation about the amide nitrogen to aryl
methyl ester bond. This phenomenon was not further inves-
tigated at this point. It is well known that chiral axes are
important in asymmetric catalysis [18]. The diastereomeric
mixture was separated by flash chromatography in 47% and
32% yield, respectively. The total yield decreased, because
the separation was not complete between the diastereomers.
When the quinazolinone 14 was treated with ammonia in
ethanol, no clean reaction could be observed. Instead the
purified quinazolinone 14 was allowed to react with NaN
3
in 2-propanol at reflux overnight and subsequently hydro-
genated using 5% Pd/C in ethanol for 7 hours to compound
Scheme 3

Mar-Apr 2002
Oxygen Analogues of the Benzodiazepine Alkaloids Sclerotigenin and Circumdatin F
353
mp 144−145°; ir (KBr): 3307, 3103, 1689, 1586, 1535, 1432,
15, which could be cyclised without purification in refluxing
acetonitrile overnight and after treatment with diethyl ether
circumdatin F (1) was isolated in 32% yield (3 steps). The
synthesis was completed with both diastereomers separately
and 1 was isolated as racemate. The amine 15 was not char-
acterised, because it could not be subjected to purification
such as chromatography.
-1
1
1269, 1096, 757 cm ; H-nmr (DMSO-d ): δ 1.74 (d, 3H, J =
6
6.8, CH ), 3.85 (s, 3H, OCH ), 4.79 (d, 1H, J = 6.8, CH), 7.27
3
3
(ddd, 1H, J = 8.0, 7.0, 1.0), 7.34 (ddd, 1H, J = 8.1, 7.1, 1.0), 7.61
(ddd, 1H, J = 8.5, 7.1, 1.4), 7.69 (ddd, 1H, J = 8.6, 7.0, 1.6), 7.85
(dd, 1H, J = 7.8, 1.3), 7.99 (dd, 1H, J = 7.9, 1.6), 8.10 (d, 1H, J =
8.2), 8.40 (d, 1H, J = 8.3), 10.99 (s, 1H, NH), 11.33 (s, 1H, NH);
13
C-nmr (DMSO-d ): δ 21.6 (q), 44.7 (d), 52.6 (q), 118.2 (s),
6
In conclusion, a synthesis of a new type of fused
oxazepinones 9a,b has been attained in 2 steps and 15−
16% overall yield from 7a,b. A new synthesis of circum-
datin F (1) has been achieved in 6 steps in an overall yield
of 1% from 11.
121.7 (d), 122.3 (d), 123.9 (d), 124.5 (d), 124.8 (s), 128.1 (d),
130.6 (d), 132.3 (d), 134.1 (d), 137.0 (s), 139.5 (s), 166.2 (s),
167.6 (s), 167.7 (s).
Anal. Calcd. for C
H BrN O : C, 53.35; H, 4.23; N, 6.91.
18 17 2 4
Found: C, 53.46; H, 4.27; N, 6.82.
2-[2-(2-Bromo-ethanoyl)-benzoylamino]-benzoic Acid (8c).
EXPERIMENTAL
Compound 8c was prepared similarly to compound 8a using 2-
(2-benzoylamino)-benzoic acid 7b [14]. Yield; 76 % as a white
solid, mp 180−182°; ir (KBr): 3017, 2967, 1666, 1606, 1583,
General Aspects. NMR spectra were recorded on a Bruker
-1
1
1
1532, 1450, 1406, 1253, 1229, 750 cm ; H-nmr (DMSO-d ): δ
Avance DPX 300 spectrometer, operating at 300 MHz for H-
6
13
4.19 (s, 2H, CH ), 7.24 (ddd, 1H, J = 8.2, 7.1, 1.1), 7.33 (ddd, 1H,
nmr and 75 MHz for C-nmr respectively; δ values are given in
2
J = 8.1, 7.1, 0.9), 7.60 (ddd, 1H, J = 8.5, 7.1, 1.4), 7.67 (ddd, 1H,
J = 8.7, 7.0, 1.6), 7.84 (dd, 1H, J = 7.9, 1.4), 8.04 (dd, 1H, J = 7.9,
1.6), 8.12 (d, 1H, J = 8.3), 8.58 (dd, 1H, J = 8.3, 0.6), 11.00 (s,
ppm. J-Values are given in Hz. IR spectra were recorded on a
Perkin-Elmer 1600 FT-IR instrument. Mass spectra were
recorded on a Hewlett-Packard GC/MS system (HP 6890 series
GC system / HP 5973 mass selective detector) equipped with a
capillary column (HP-5MS column with 5% phenyl methyl silox-
ane) operating in the electron impact (EI) mode at 70 eV. Only
fragments larger than 20% of the base peak are given. Element
analyses were performed by H. Kolbe Mikroanalytisches
Laboratorium, Mülheim an der Ruhr, Germany. HRMS analyses
were performed by E. Nilsson, University of Lund, Sweden.
Melting points were determined on a Büchi Melting Point B-545
(capillary method) and are uncorrected. All solvents were puri-
fied by distillation or were HPLC grade. Flash chromatography
was carried out on silica gel 60 (230−400 mesh ASTM, Merck),
13
1H, NH), 11.89 (s, 1H, NH), 13.67 (br s, 1H, COOH); C-nmr
(DMSO-d ): δ 30.33 (t), 117.5 (s), 120.6 (d), 122.4 (d), 123.4 (d),
6
124.5 (d), 124.9 (s), 128.0 (d), 131.1 (d), 132.2 (d), 134.1 (d),
137.0 (s), 140.4 (s), 164.9 (s), 166.1 (s), 169.7 (s).
Anal. Calcd. for C
H BrN O : C, 50.95; H, 3.47; N, 7.43.
16 13 2 4
Found: C, 50.76; H, 3.42; N, 7.28.
2-[2-(2-Bromo-propanoyl)-benzoylamino]-benzoic Acid (8d).
Compound 8d was prepared similarly to compound 8a using
2-bromopropionyl bromide and compound 7b [14]. Yield; 80%
as a light beige solid, mp 192−193°; ir (KBr): 2982, 1683, 1583,
1
1535, 1450, 1230, 758; H-nmr (DMSO-d ): δ 1.74 (d, 3H, J =
TLC analyses were run on Merck Silica Gel 60 F
plates.
6
254
6.7, CH ), 4.78 (q, 1H, J = 6.7, CH), 7.23 (dd, 1H, J = 7.8, 7.3),
3
2-[2-(2-Bromo-ethanoyl)-benzoylamino]-benzoic Acid Methyl
Ester (8a).
7.33 (dd, 1H, J = 7.7, 7.4), 7.60 (ddd, 1H, J = 8.3, 7.4, 1.0), 7.67
(ddd, 1H, J = 8.5, 7.3, 1.4), 7.83 (dd, 1H, J = 7.8, 0.9), 8.04 (dd,
1H, J = 7.9, 1.4), 8.09 (d, 1H, J = 8.2), 8.58 (d, 1H, J = 8.3), 10.97
Bromoacetyl bromide (3.01 g, 15 mmol) was added to a solu-
tion of compound 7a (2.70 g, 10 mmol) in dioxane (55 mL) at 0°
under a nitrogen atmosphere. The reaction mixture was stirred at
room temperature for 2 hours and then diluted with water until a
precipitate appeared, which was collected and washed with water
to give compound 8a (3.17 g, 81%) as a white solid, mp 145−
146°; ir (KBr): 3305, 3116, 2957, 1687, 1665, 1608, 1586, 1540,
13
(s, 1H, NH), 11.87 (s, 1H, NH), 13.70 (br s, 1H, COOH); C-
nmr (DMSO-d ): δ 21.6 (q), 44.7 (d), 117.4 (s), 120.6 (d), 122.4
6
(d), 123.4 (d), 124.5 (d), 125.1 (s), 128.1 (d), 131.1 (d), 132.2 (d),
134.1 (d), 137.0 (s), 140.5 (s), 166.1 (s), 167.7 (s), 169.6 (s).
7,7-Dihydro-quinazolino[3,2-a][4,1]benzoxazepine-5,13-dione
(9a).
-1
1
1450, 1275, 757 cm ; H-nmr (DMSO-d ): δ 3.86 (s, 3H,
6
OCH ), 4.16 (s, 2H, CH ), 7.28 (ddd, 1H, J = 8.1, 7.2, 0.9), 7.35
(ddd, 1H, J = 8.1, 7.1, 0.9), 7.61 (ddd, 1H, J = 8.5, 7.1, 1.4), 7.69
(ddd, 1H, J = 8.6, 7.1, 1.6), 7.85 (dd, 1H, J = 7.8, 1.4), 7.99 (dd,
Compound 8c (570 mg, 1.5 mmol) was heated at reflux for 3
hours in dry DMF (12.5 mL). The solution was poured into water
(~20 mL) and a yellow precipitate was collected after 1 hour,
which was recrystallised from ethanol to give compound 9a (83
mg, 20%) as a yellow solid, mp 233−235°; ir (KBr): 1739, 1697,
3
2
1H, J = 7.9, 1.6), 8.12 (d, 1H, J = 8.3), 8.39 (d, 1H, J = 8.3), 10.99
13
(s, 1H, NH), 11.34 (s, 1H, NH); C-nmr (DMSO-d ): δ 30.3 (t),
6
-1
1
52.5 (q), 118.4 (s), 121.8 (d), 122.2 (d), 123.9 (d), 124.5 (d),
124.7 (s), 128.1 (d), 130.6 (d), 132.2 (d), 134.0 (d), 137.0 (s),
139.4 (s), 164.9 (s), 166.2 (s), 167.6 (s).
1650, 1448, 1350, 1107, 785, 764 cm ; H-nmr (DMSO-d ): δ
6
5.01 and 5.26 (AB q, 2H, J = 13.3, CH ), 7.60−7.69 (m, 2H),
2
7.73−7.84 (m, 3H), 7.86 (dd, 1H, J = 7.7, 1.4), 7.93 (ddd, 1H, J =
13
Anal. Calcd. for C
H
BrN O : C, 52.19; H, 3.86; N 7.16.
8.4, 6.9, 1.5), 8.22 (dd, 1H, J = 7.9, 1.2); C-nmr (DMSO-d ): δ
17 15
2
4
6
Found: C, 52.28; H, 3.88; N, 7.12.
69.7 (t), 121.5 (s), 125.9 (s), 126.9 (d), 127.4 (d), 128.1 (d), 128.5
(d), 129.0 (d), 131.2 (d), 132.5 (d), 133.3 (s), 135.2 (d), 145.8 (s),
150.9 (s), 160.4 (s), 167.0 (s); gc/ms (EI) m/z (rel.intensity) 279
2-[2-(2-Bromo-propanoyl)-benzoylamino]-benzoic Acid Methyl
Ester (8b).
+
+
(M +1, 18%), 278 (M , 100), 277 (47), 249 (49), 221 (24).
Compound 8b was prepared similarly to compound 8a using
2-bromopropionyl bromide. Yield; 92% as a light yellow solid,
HRMS (EI) for C
m/z 278.0694.
H N O requires M, 278.0691. Found:
16 10 2 3

354
A. Witt and J. Bergman
Vol. 39
Anal. Calcd. for C
H
N O : C, 69.06; H, 3.62; N, 10.07.
The resulting precipitate was collected and purified by flash chro-
16 10
2 3
matography (33% ethyl acetate in hexane as eluent, r = 0.42) to
Found: C, 69.16; H, 3.74; N, 10.15.
f
give compound 12 (410 mg, 12%) as a white solid, mp 133−136°;
7-Methyl-7H-quinazolino[3,2-a][4,1]benzoxazepine-5,13-dione
(9b).
-1
1
ir (KBr): 3269, 3204, 1700, 1583, 1540, 1261, 753 cm ; H-nmr
(DMSO-d ): δ 1.05 (t, 3H, J = 7.5, CH ), 2.33 (q, 2H, J = 7.5,
6
3
CH ), 3.85 (s, 3H, OCH ), 7.23−7.32 (m, 2H), 7.56 (ddd, 1H, J =
Compound 8d (400 mg, 1.0 mmol) was heated at reflux
overnight in dry DMF (12 mL). The solution was poured into
water (~20 mL). The resulting precipitate was collected and
recrystallised from ethanol to give compound 9b (60 mg, 20%) as
light brown crystals, mp 224−225°; ir (KBr): 3001, 2941, 1723,
2
3
8.5, 7.1, 1.4), 7.68 (ddd, 1H, J = 8.6, 7.0, 1.6), 7.81 (dd, 1H, J =
7.8, 1.4), 7.99 (dd, 1H, J = 7.9, 1.5), 8.14 (d, 1H, J = 8.3), 8.39 (d,
13
1H, J = 8.3), 10.51 (s, 1H, NH), 11.31 (s, 1H, NH); C-nmr
(DMSO-d ): δ 9.4 (q), 30.0 (t), 52.5 (q), 118.3 (s), 121.7 (d), 122.1
6
-1
1
(d), 123.6 (d), 123.8 (d), 124.1 (s), 128.0 (d), 130.6 (d), 132.2 (d),
134.1 (d), 137.9 (s), 139.5 (s), 166.6 (s), 167.7 (s), 171.9 (s).
1698, 1619, 1313, 1262, 774, 760 cm ; H-nmr (DMSO-d ): δ
6
1.69 (d, 3H, J = 6.2, CH ), 5.43 (q, 1H, J = 6.2, CH), 7.59−7.83
3
(m, 5H), 7.86 (dd, 1H, J = 7.7, 1.5), 7.93 (ddd, 1H, J = 8.3, 6.9,
Anal. Calcd. for C H N O : C, 66.25; H, 5.56; N, 8.58.
Found: C, 66.17; H, 5.49; N, 8.50.
18 18 2 4
13
1.4), 8.21 (dd, 1H, J = 7.9, 1.3); C-nmr (DMSO-d ): δ 15.8 (q),
6
73.9 (d), 121.5 (s), 126.6 (s), 126.9 (d), 127.7 (d), 128.1 (d),
128.8 (d), 129.0 (d), 130.7 (d), 132.4 (d), 132.9 (s), 135.2 (d),
145.5 (s), 152.2 (s), 160.6 (s), 166.8 (s); gc/ms (EI) m/z (rel.inten-
2-(2-Ethyl-4-oxo-4H-quinazolin-3-yl)-benzoic Acid Methyl
Ester (13).
+
+
sity) 293 (M +1, 6%), 292 (M , 33), 248 (26), 247 (100).
Compound 12 (1.16 g, 3.6 mmol) was heated at reflux in dry
DMF (35 mL) for 65 hours. The dark solution was poured into
water (~50 mL) and a precipitate was collected after 1 hour to
give compound 13 (430 mg, 39%) as a yellow solid, mp 151−
152° (lit. [16] 146.5−147°); ir (KBr): 2981, 2938, 1720,1677,
HRMS (EI) for C
H N O requires M, 292.0848. Found:
17 12 2 3
m/z 292.0843.
Anal. Calcd. for C
H N O : C, 69.86; H, 4.14; N, 9.58.
17 12 2 3
Found: C, 69.74; H, 4.22; N, 9.62.
-1
1
1604, 1595, 1275, 1084, 780, 766 cm ; H-nmr (DMSO-d ): δ
6
2-(2-Bromomethyl-4-oxo-4H-quinazolin-3-yl)-benzoic Acid
Methyl Ester (10).
1.13 (t, 3H, J = 7.3, CH ), 2.13-2.45 (m, 2H, CH ), 3.63 (s, 3H,
3
2
OCH ), 7.51 (dd, 1H, J = 7.8, 7.2), 7.62 (d, 1H, J = 7.8), 7.66−
3
7.75 (m, 2H), 7.81−7.89 (m, 2H), 8.08 (d, 1H, J = 7.8), 8.14 (d,
Compound 8a (850 mg, 2.2 mmol) and a catalytic amount of p-
TSA were dissolved in toluene (15 mL) and heated at reflux in a
Dean-Stark for 60 hours. The solution was concentrated to an oily
residue and purified by flash chromatography (gradient from 25−
40% ethyl acetate in hexane as eluent) to give compound 10 (350
mg, 43%) as a yellow solid, mp 198−201° (lit. [10] 200−203°); ir
13
1H, J = 7.5); C-nmr (DMSO-d ): δ 10.4 (q), 28.4 (t), 52.3 (q),
6
120.3 (s), 126.2 (d), 126.3 (d), 126.9 (d), 127.5 (s), 129.7 (d),
130.7 (d), 131.4 (d), 134.2 (d), 134.6 (d), 137.3 (s), 147.3 (s),
157.3 (s), 161.4 (s), 164.4 (s).
2-[2-(1-Bromo-ethyl)-4-oxo-4H-quinazolin-3-yl]-benzoic Acid
Methyl Ester (14).
-1
1
(KBr): 3059, 2996, 1716, 1679, 1604, 1593, 1278, 775 cm ; H-
nmr (DMSO-d ): δ 3.62 (s, 3H, OCH ) 4.11 and 4.25 (AB q, 2H,
6
3
J = 11.0, CH ) 7.61 (ddd, 1H, J = 7.9, 7.1, 0.8), 7.67−7.81 (m, 3H),
Bromine (400 mg, 2.5 mmol) in acetic acid (5 mL) was added
during 15 minutes to a solution of compound 13 (780 mg, 2.5
mmol) and NaOAc (220 mg, 2.7 mmol) in acetic acid (20 mL) at
60°. The reaction mixture was stirred for 1.5 hours. Whereupon
the reaction mixture was slowly poured into cold water and the
precipitate formed was collected, washed with water to give com-
pound 14 (850 mg, 87%) as a yellow solid; diastereomeric mix-
2
7.83−7.97 (m, 2H), 8.12 (dd, 1H, J = 7.9, 1.4), 8.18 (dd, 1H, J = 7.8,
13
1.5); C-nmr (DMSO-d ): δ 30.3 (t), 52.3 (q), 120.6 (s), 126.5 (d),
6
127.3 (d), 127.6 (s), 127.7 (d), 130.2 (d), 131.2 (d), 131.5 (d), 134.0
(d), 135.0 (d), 136.0 (s), 146.8 (s), 151.8 (s), 161.3 (s), 164.2 (s).
6,7,7-Trihydro-quinazolino[3,2-a][1,4]benzodiazepine-5,13-
dione (6).
1
ture (7:3) according to H NMR. The diastereomeric mixture of
Compound 10 (210 mg, 0.56 mmol) was heated at 60° with
compound 14 (530 mg, 1.4 mmol) was separated by flash chro-
presaturated NH in ethanol (10 mL). After 3 hours the solution
matography (60% ethyl acetate in hexane as eluent).
3
was cooled at 0° and a precipitate was collected. The mother liq-
uid was allowed to stand and yellow crystals were collected to
give sclerotigenin (6) (60 mg, 38%), mp 310−313° (lit. [10],
The First Diastereoisomer.
This compound (r = 0.42), 250 mg (47%) was obtained as a
f
-1
312−315 °C); ir (KBr): 3317, 1668, 1610, 1350, 1230, 760 cm ;
white solid, mp 149−150°; ir (KBr): 2950, 1724, 1680, 1595,
1
-1 1
H-nmr (DMSO-d ): δ 4.00 (dd, 1H, J = 15.0, 6.7, CH ), 4.19
1275, 1064, 780 cm ; H-nmr (DMSO-d ): δ 1.94 (t, 3H, J = 6.5,
6
2
6
(dd, 1H, J = 15.0, 5.2, CH ), 7.53−7.68 (m, 4H), 7.72 (d, 1H, J =
CH ), 3.63 (s, 3H, OCH ), 4.49 (q, 1H, J = 6.5, CH), 7.54−7.67
3 3
2
8.1), 7.80 (d, 1H, J 7.2), 7.90 (dd, 1H, J 8.2, 7.0), 8.19 (d, 1H, J
(m, 2H), 7.69−7.83 (m, 2H), 7.83−7.96 (m, 2H), 8.10 (dd, 1H, J =
13
13
7.3), 8.96 (br t, 1H, J = 5.8, NH); C-nmr (DMSO-d ): δ 46.2 (t),
7.9, 1.0), 8.14 (dd, 1H, J = 7.8, 1.4); C-nmr (DMSO-d ): δ 22.8
6
6
121.0 (s), 126.9 (d), 127.1 (d), 127.6 (d), 128.5 (d), 128.8 (d),
129.3 (d), 130.6 (s), 130.7 (d), 133.4 (s), 135.2 (d), 146.1 (s),
154.8 (s), 161.0 (s), 167.0 (s); gc/ms (EI) m/z (rel.intensity) 278
(q), 43.8 (d), 52.5 (q), 120.7 (s), 126.5 (d), 127.5 (d), 127.6 (s),
127.7 (d), 130.3 (d), 131.6 (2 × d), 133.9 (d), 135.1 (d), 135.4 (s),
146.6 (s), 155.4 (s), 161.1 (s), 164.7 (s).
+
+
(M +1, 18%), 277 (M , 100), 276 (53), 249 (27), 248 (23).
The Second Diastereoisomer.
2-(2-Propionylamino-benzoylamino)-benzoic Acid Methyl Ester
(12).
This compound (r = 0.30), 170 mg (32%) was obtained as a
f
white solid, mp 176−178°; ir (KBr): 2951, 1723, 1681, 1592,
-1
1
Compound 11 [15] (1.78 g, 10 mmol) and methyl anthranilate
(1.69 g, 11 mmol) were heated at reflux in acetic acid (40 mL) for
3 hours. The cooled solution was poured into water (~100 mL).
1265, 1092, 776, 695 cm ; H-nmr (DMSO-d ): δ 1.96 (d, 3H,
6
J = 6.5, CH ), 3.56 (s, 3H, OCH ), 4.57 (q, 1H, J = 6.5, CH), 7.59
3
3
(dd, 1H, J = 7.9, 7.1), 7.67−7.81 (m, 3H), 7.81−7.96 (m, 2H),

Mar-Apr 2002
Oxygen Analogues of the Benzodiazepine Alkaloids Sclerotigenin and Circumdatin F
355
[2] J-R. Dai, B. K. Carté, P. J. Sidebottom, A. Lee Sek Yew, S-
B. Ng, Y. Huang and M. S. Butler, J. Nat. Prod., 64, 125 (2001).
[3a] M. A. Goetz, M. Lopez, R. L. Monaghan, R. S. L. Chang,
V. J. Lotti and T. B. Chen, J. Antibiot., 38, 1633 (1985); [b] J. M.
Liesch, O. D. Hensens, J. P. Springer, R. S. L. Chang and V. J. Lotti,
J. Antibiot., 38, 1638 (1985); [c] H. H. Sun, S. J. Byard and R.
Copper, J. Antibiot., 47, 599 (1994).
[4] H. H. Sun, C. J. Barrow, D. M. Sedlock, A. M. Gillum and
R. Copper, J. Antibiot., 47, 515 (1994).
[5] B. K. Joshi, J. B. Gloer, D. T. Wicklow and P. F. Dowd, J.
Nat. Prod., 62, 650 (1999).
[6] A. Witt and J. Bergman, J. Org. Chem., 66, 2784 (2001).
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(2001).
[8] F. He, B. M. Foxman and B. B. Snider, J. Am. Chem. Soc.,
120, 6417 (1998).
13
8.13 (dd, 1H, J = 7.9, 0.8), 8.17 (d, 1H, J = 7.8); C-nmr
(DMSO-d ): δ 23.3 (q), 43.0 (d), 52.1 (q), 120.7 (s), 126.5 (d),
6
127.4 (d), 127.6 (d), 128.0 (s), 130.1 (d), 130.9 (d), 131.6 (d),
134.2 (d), 134.9 (d), 136.1 (s), 146.7 (s), 153.9 (s), 161.4 (s),
163.9 (s).
Anal. Calcd. for C
H BrN O : C, 55.83; H, 3.90; N, 7.23.
18 15 2 3
Found: C, 55.79; H, 3.89; N, 7.15.
6,7-Dihydro-7-methyl-quinazolino[3,2-a][1,4]benzodiazepine-
5,13-dione (1).
Sodium azide (100 mg, 1.5 mmol) dissolved in water (2 mL)
was added to a mixture of compound 14 (285 mg, 0.74 mmol) in
2-propanol (10 mL). The mixture was heated at reflux overnight.
The solution was concentrated to an oily residue and treated with
water/ethyl acetate (1:1). The aqueous phase was extracted with
ethyl acetate (25 mL×2), the combined organic phases were dried
[9] T. Sugimori, T. Okawa, S. Eguchi, A. Kakehi, E. Yashima
and Y. Okamoto, Tetrahedron, 54, 7997 (1998).
(MgSO ) and concentrated to give an yellow oil. The crude oil
4
was dissolved in ethanol (20 mL) and hydrogenated in a Parr
apparatus with 220 psi at room temperature using 5% Pd/C as
catalyst for 7 hours. After solvent concentration, the crude amino
compound 15 was dissolved in acetonitrile (10 mL) and heated at
reflux overnight. The solution was concentrated and treated with
diethyl ether. The resulting precipitate was collected to give cir-
cumdatin F (1) (69 mg, 32%) as a light grey solid. The spectral
data of 1 were identical with those previously published [1,6,7].
[10] D. R. Harrison, P. D. Kennewell and J. B. Taylor, J.
Heterocyclic Chem., 14, 1191 (1977).
[11] V. P. Kamat and J. K. Kirtany, Org. Prep. Proced. Int., 26,
494 (1994).
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Tetrahedron Lett., 32, 3263 (1991).
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and K. Fukumoto, J. Am. Chem. Soc., 98, 6186 (1976).
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Stephanatou and J. F. Stoddart, J. Chem. Soc., Perkin Trans 1, 1649
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[1959]; [c] A. Mohr, J. Prakt. Chem., 79, 281 (1909).
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Chemistry, Academic Press, London, 1968, pp 121−122.
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Heterocycles, 37, 903 (1994).
Acknowledgement.
We thank Mr. Patrik Rhönnstad, a student from Södertörn
University College, for his help with part of the synthetic work.
REFERENCES AND NOTES
[1a] L. Rahbæk, J. Breinholt, J. C. Frisvad and C.
Christophersen, J. Org. Chem., 64, 1689 (1999); [b] L. Rahbæk and
J. Breinholt, J. Nat. Prod., 62, 904 (1999).
[18] For recent review, see: M. McCarthy and P. J. Guiry,
Tetrahedron, 57, 3809 (2001).