Synthesis of 1,2,3,12a,12b-hexahydrocyclopropa-[1,2-d]benzo[f]pyrrolo[1,2- b]isoquinolin-5,7-dione related to duocarmycins and anthramycin

Article abstract of DOI:10.1002/jhet.5570420220

Structural features of the Duocarmycins and Anthramycin were incorporated into 1,2,3,12a,12b-hexa-hydro-cyclopropa[1,2-d]benzo[f]pyrrolo[1,2-b] isoquinolin-5,7-dione. The synthesis of the cis and trans diastereomers was accomplished using a benzyne Diels-

Full text of DOI:10.1002/jhet.5570420220

March 2005
297
Synthesis of 1,2,3,12a,12b-Hexahydrocyclopropa-
[1,2-d]benzo[f]pyrrolo[1,2-b]isoquinolin-5,7-dione Related to
Duocarmycins and Anthramycin
Atigadda Venkatram, Tara Colley, Jack DeRuiter, Forrest Smith*
Harrison School of Pharmacy, Auburn University, Auburn, Alabama 36849
Received June 9, 2004
Structural features of the Duocarmycins and Anthramycin were incorporated into 1,2,3,12a,12b-hexa-
hydro-cyclopropa[1,2-d]benzo[f]pyrrolo[1,2-b]isoquinolin-5,7-dione. The synthesis of the cis and trans
diastereomers was accomplished using a benzyne Diels-Alder reaction and an imine-anhydride cyclization
as key steps.
J. Heterocyclic Chem., 42, 297 (2005).
The anti-tumor agent (+)-CC-1065 was first isolated in
1978 and structure elucidation revealed a complex mole-
cule composed of 3 pyrrolo-indole subunits that are capable
of alkylating DNA [1-5]. While (+)-CC-1065 proved to be
active against a variety of cancers, in vivo studies revealed
intolerable hepatic toxicity [6]. Subsequent efforts led to
the duocarmycins and related compounds that have shown
high levels of cytotoxicity and have been of interest as anti-
neoplastic agents (Figure I) [7-9]. The mechanism of cyto-
toxicity has been shown to involve site specific binding
within the minor groove of DNA followed by alkylation
involving nucleophilic attack on the cyclopropyl ring with
resulting aromatization of the cyclohexadienone system to
give the phenol [3]. The property of site specific alkylation
offers the potential to target specific oncogenes and possi-
bly reduce the indiscriminate toxicity associated with tradi-
tional alkylating agents. Duocarmycins and (+)-CC-1065
analogs are generally specific for A-T rich sequences of
DNA. This has been related to hydrophobic bonding within
the minor groove and the complementary shape of the com-
pound and receptor [3-5].
was demonstrated with alkylation occurring as a result of
nucleophilic attack of the 2-amino group of guanine at the
carbinolamine carbon (C11) as the carbinolamine, imine or
as a ring opened aldehyde [13,14].
Given the sequence selective alkylation of these two
groups of compounds albeit at different sites and different
sequences within the minor groove of DNA, it was of
interest to combine several of the structural features. With
this in mind, the synthesis of Compound 1 was undertaken
(Figure 2). Compound 1 incorporated the cyclopropyl
spiro-fused cyclohexadienone system of the duo-
carmycins amide linked to the pyrrolidine ring system,
which would approximate the pyrroline ring of
anthramycin. It was believed that the amide linkage would
stabilize the cyclohexadienone and give a less reactive
and more selective agent. To the contrary however;
Compound 1 could be synthesized but was too unstable to
completely characterize. Therefore Compound 2 was tar-
geted since it was known that in the duocarmycins that
fusion of the cyclohexadienone system with an aromatic
ring increased stability.
Figure 1
The synthesis begins with the generation of benzyne by
the nitrosation of anthranilic acid and subsequent Diels-
Alder reaction with the previously prepared furan 4
(Scheme 1) [15-16]. This gave the unstable diester 5 in 50%
yield which was immediately purified by flash chromatog-
Anthramycin was first isolated in the 1950's by Tendler
and subsequently purified and crystallized by Leimgruber
in 1965 [10,11]. In vivo testing revealed antibacterial and
antitumor properties that were mediated by the ability of
the compound to alkylyate DNA within the minor groove
[12]. Sequence selectivity for G-C rich regions of DNA
raphy and allowed to react with BF to give the phenol 6 in
3

298
A. Venkatram, T. Colley, J. DeRuiter, F. Smith
Vol. 42
quantitative yield. Benzylation was accomplished under
standard conditions followed by hydrolysis to give the
diacid 8 and conversion to the anhydride 9 was accom-
plished by refluxing in acetyl chloride [17-20].
Condensation of the anhydride with the 1-pyrroline trimer
gave 10 in quantitative yield as a 50:50 mixture of cis and
trans isomers [21,22]. The diastereomers were identified on
1
13
the basis of their respective H and C-NMR spectra. In the
case of the cis isomer, the C-12 proton appeared at δ 4.48
with J
= 5.0 Hz. The trans isomer C-12 proton
12-12a

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Synthesis of 1,2,3,12a,12b-Hexahydrocyclopropa-
299
[1,2-d]benzo[f]pyrrolo[1,2-b]isoquinolin-5,7-dione
1-Carboxymethyl-2-carboxy-1,4-dihydro-1,4-epoxynaphthalene
Diethylester (5).
appeared at δ 4.12 with J
= 11.8 Hz. The diastereomers
12-12a
could be separated by fractional recrystallization however
the recovery was low and it was found to be more efficient
to separate after the following step. Reduction of the acid to
the alcohol could be accomplished with diborane. This
worked well in the case of the cis isomer; however in the
case of the trans isomer the acid reduction was slow and
amide reduction began to compete significantly lowering
the yield. In order to gain entry into the trans compound, the
acid as a mixture of cis and trans isomers was converted to
the acid chloride. The acid chlorides were then reduced with
A solution of 4 (3 g, 13.27 mmol) and isoamyl nitrite (1.95 g,
16.6 mmol) in 10 mL of dry THF was treated dropwise with
anthranilic acid (1.82 g, 13.27 mmol) in 25 mL of dry THF over
a period of 45 minutes while heating at reflux. After the addition
was complete, the reaction mixture was stirred at reflux for 45
minutes. The THF was removed under vacuum. Chromatography
(silica gel 66% pet ether-ether) afforded pure 5 (2 g, 50%) as an
1
oil which was used immediately in the subsequent reaction; H
NMR (CDC1 ): δ 7.6 (s, 1H), 7.26 (m, 2H), 7.03 (m, 2H), 5.7 (d,
3
1H, J=1.9Hz), 4.15 (dq, 4H), 3.9 (d, 2H, J=16.3Hz), 3.25 (dd, 1H,
J=16.5, 0.78Hz), 1.25 (dt, 6H); MS (EI): 302 (m/z), 257, 228,
204, 200, 172, 155, 131.
NaBH to give the alcohols, which could be separated by
4
spinning band chromatography [22]. In the conversion of
the acids to the acid chlorides, some epimerization occurred
so that the trans alcohol was the predominant product
(60/40: trans/cis). Mesylation of the alcohols occurred
under standard conditions. The benzyl protecting group was
then removed via hydrogenolysis in THF to give the unsta-
ble phenol-mesylate 13. Cyclization to give the cyclopropyl
ring was accomplished under basic conditions (NaH) in dry
THF to give a clean product which was extracted and
recrystallized from ether to give the final compounds.
3-Carboxy-4-carboxymethyl-l-naphthol diethylester (6).
A solution of 5 (3.5 g, 11.6 mmol) in 25 mL of chloroform was
treated with boron trifluoride etherate (6.5 g, 45.7 mmol) and
stirred for 30 minutes at room temperature. The reaction mixture
was washed with water, dried and concentrated under reduced
pressure to give pure 6 (3.45 g, 100%) as an oil which solidified
upon standing and recrystallized from ether-pet ether; mp
105-107 °C; ir: (KBr) 3396, 3074, 2989, 1739, 1679, 1599, 1478,
-1 1
1433, 1385, 1335, 1259 cm ; H NMR (CDC1 ): δ 7.95 (m, 2H),
3
7.5 (m, 2H), 6.9 (s, 1H), 4.46 (s, 2H), 4.3 (dq, 4H) , 1.3 (dt, 6H);
13
C NMR: δ 172.9, 167.8, 151.2, 133.6, 128.3, 127.2, 126.6,
126.4, 124.5, 124.41, 122.6, 108.7, 61.2 (2 C) , 34.3, 14.2, 14.1;
MS (EI): 302 (m/z), 256, 228, 201, 157, 127, 115.
EXPERIMENTAL
Anal. Calcd. for C
67.33; H, 6.00.
H O : C, 67.54; H, 5.96. Found: C,
17 18 5
Melting points were determined in open capillary tubes with a
1
Thomas-Hoover melting point apparatus and are uncorrected. H
1-Benzyloxy-3-carboxy-4-carboxymethyl Naphthalene
Diethylester (7).
13
and C NMR spectra were recorded on a Bruker (250 and 400
MHz) NMR spectrometer unless otherwise indicated with
tetramethysilane as an internal standard. Elemental analyses were
performed by Atlantic Microlab, Inc., Norcross, Georgia and are
within ± 0.4 of the theoretical percentages. Common reagent
grade chemicals were purchased from Aldrich Chemical
Company. All the reactions were carried out under a nitrogen
atmosphere. High-resolution mass specta were obtained on a
7070 Micromass magnetic sector mass spectrometer.
A solution of 6 (2.0 g, 6.6 mmol) in 25 mL of acetone was
treated with anhydrous K CO (0.92 g, 6.6 mmol) and benzyl
bromide (1.24 g, 7.2 mmol). The resulting mixture was stirred at
reflux for 24 hours. The K CO was removed by filtration.
Acetone was removed under reduced pressure and the resulting
oily material was crystallized from ether/pet ether to give pure 7
(2.5 g, 98%). mp 80-81 °C; ir (KBr): ν 3436, 2986, 1731, 1708,
1596, 1369, 1242, 1199 cm ; H NMR (CDC1 ): δ 8.37 (m, 1H),
8.02 (m, 1H), 7.55 (m, 4H), 7.37 (m, 4H), 5.23 (s, 2H), 4.46 (s,
2
3
2
3
-1 1
3
Ethyl 2-Ethoxycarbonylmethylfuran-3-carboxylate (4).
13
A suspension of diethyl 1,3-acetonedicarboxylate (1 g, 4.9
2H), 4.39 (q, 2H), 4.15 (q, 2H), 1.4 (t, 3H), 1.21 (t, 3H);
C
mmol) in 3 mL of 3 N Na CO was cooled in an ice bath and
NMR (CDC1 ): δ 171.3, 167.8, 153.4, 136.6, 133.5, 128.4 (2 C),
2
3
3
treated with 50% chloroacetaldehyde (0.38 g, 4.9 mmol) over a
period of 1 hour. The mixture was stirred at room temperature for
6 hours. The solution was acidified and extracted with chloro-
form (3 X 10 mL) washed with water, dried and concentrated
under vacuum. The resulting oily material in 2 mL of dioxane
was treated with 0.1 mL of concentrated HCl and stirred at room
termperature for 2 hours. The reaction mixture was diluted with
water and extracted with chloroform. The organic layer was
washed with water, dried and concentrated under vacuum.
Chromatography (silica gel, 66% pet ether-ether) afforded pure 4
(550 mg, 50%) as an oil. bp 148-150 °C at 1.0 Torr (bp 86-90 °C
128.3 (2 C), 127.9 (2 C), 127.4 (2 C), 126.8, 125.8, 124.6, 122.5,
105.1, 79.1, 61.1, 60.6, 34.3, 14.1, 14.0; MS (EI): 392 (m/z), 347,
319, 255, 200, 155, 127, 91.
Anal. Calcd. for C
H O : C, 73.46; H, 6.12. Found: C,
24 24 5
73.33; H, 6.19.
1-Benzyloxy-3-carboxy-4-carboxymethyl Naphthalene (8).
A solution of 7 (2.5 g, 6.3 mmol) in 25 mL of 3 N methanolic
KOH was heated at reflux for 6 hours. The methanol was
removed in vacuo. The residue was dissolved in 10 mL of water,
washed with ether, and acidified with HCl. The resulting precipi-
tate was filtered, washed with water and dried to give 8 which
was recrystallized from ethanol/ether (2 g, 95% yield), mp
191-193 °C ; ir (KBr): ν 2953, 2625, 1713, 1679, 1596, 1513,
1
at 0.2 Torr) [15]; H NMR (CDC1 ): δ 7.32 (d, 1H, J = 1.9 Hz),
3
6.69 (d, 1H, J = 1.9 Hz), 4.28 (q, 2H), 4.16 (q, 2H), 4.05, (s, 2H),
13
1.33 (t, 3H), 1.25 (t, 3H); C NMR: δ 168.2, 163.0, 153.9,
1
1
141.4, 115.4, 110.5, 60.9, 60.0, 33.5, 13.9, 13.7; IR (film): ν
1411, 1367, 1259, 1096 cm- ; H NMR (CDC1 /DMSO): δ 8.17
3
-1
3130, 2983, 1742, 1707, 1614, 1517, 1307, 1261, 1182 cm ; MS
(m, 1H), 7.94 (m, 1H), 7.41 (m, 4H), 7.26 (s, 1H), 7.2 (m, 3H),
13
(EI): 226 (m/z), 181, 153, 125, 108.
5.08 (s, 2H), 4.3 (s, 2H);
C NMR: δ 172.7 , 169.8, 152.6,

300
A. Venkatram, T. Colley, J. DeRuiter, F. Smith
Vol. 42
136.0, 133.0, 128.4 (2 C), 127.9 (2 C), 127.3 (2 C), 126.8, 126.7,
126.2, 125.5, 124.4, 121.8, 104.8, 69.4, 34.0; MS (EI): 336 (m/z),
318, 274, 155, 127, 91.
1
190-191 °C ; H NMR (CDC1 ): δ 8.37 (m, 1H), 8.09 (m, 1H),
3
7.51 (m, 5H), 7.38 (m, 3H), 5.21 (s, 2H), 4.04 (m, 1H), 3.83 (m,
3H), 3.68 (m, 1H), 3.5 (m, 1H), 2.75 (br s, 1H), 2.38 (m, 1H),
2.18 (m, 1H) , 2.05 (m, 1H) , 1. 8 (m, 1H); C NMR: δ 163.4,
153.8, 136.8, 131.1, 129.0, 128.5, 127.8 (2 C), 127.6, 127.5 (2
C), 127.3 (2 C), 126.6, 124.0, 123.0, 102.4, 70.1, 61.3, 58.7, 45.2,
39.0, 29.1, 23.3; EIHRMS: m/z 373.1679 (C H NO requires
13
Anal. Calcd for C H O : C, 71:43; H, 4.76. Found: C, 71.21;
20 16
5
H, 4.92.
9-Benzyloxybenzo[f]isochroman-1,3-dione (9).
24 23
3
A solution of acid 8 (2.5 g, 7.4 mmol) in 45 mL of acetyl chlo-
ride was heated at reflux for 12 hours. Acetyl chloride was
removed under reduced pressure and the residue was recrystallized
from benzene/pet ether to give 9 as a light green precipitate (2.1 g,
89%) which was used immediately in the subsquent reaction, mp
204-206°C; IR (KBr) 3456, 3107, 1784, 1738, 1659, 1594, 1374
373.1678).
Anal. Calcd. for C H NO (1/10 H O): C, 76.70; H, 6.18; N,
3.73. Found: C, 76.77; H, 6.19; N, 3.62.
Trans isomer: mp 200-201 °C H NMR (CDC1 /DMSO): δ
8.4 (m, 1H), 8.15 (m, 1H), 7.74 (s, 1H), 7.55 (m, 4H), 7.37 (m,
3H), 5.29 (s, 2H), 4.24 (m, 1H), 4.05 (m, 1H), 3.9 (m, 2H), 3.68
(m, 1H), 3.35 (m, 1H), 2.5 (br s, 1H), 2.08 (m, 1H), 1.9 (m, 2H),
24 23
3
2
1
3
-1 1
cm ; H NMR (CDC1 ): δ 8.41 (m, 1H), 7.99 (m, 1H), 7.76 (m,
3
13
2H), 7.37-7.57 (m, 7H) 5.34 (s, 2H), 4.50 (s, 2H).
1.52 (m, 1H); C NMR: δ 163.7, 158.7, 153.4, 136.6, 131.5,
128.3 (2 C), 127.7, 127.3 (2 C), 126.7, 126.5, 126.3, 126.2,
123.9, 122.7, 102.5, 69.9, 65.9, 58.3, 44.5, 39.0, 30.8, 21.5;
1,2,3,12,12a-Tetrahydro-12-carboxy-7-benzyloxybenzo[f]-
pyrrolo[1,2-b]isoquinoline-5-one (10).
EIHRMS: m/z 373.1686 (C H NO requires 373.1678).
24 23
3
A solution of 9 (2.0 g, 6.3 mmol) in 20 mL of dry CH Cl was
Anal. Calcd. for C H NO (1/10 H O): C, 76.70; H, 6.18; N,
2
2
24 23
3
2
treated with 1-pyrroline trimer (0.48 g, 2.3 mmol) dissolved in 5
mL of CH Cl [21]. The resulting solution was stirred at reflux
3.73. Found: C, 76.66; H, 6.24; N, 3.59.
2
2
1,2,3,12,12a-Tetrahydro-7-benzyloxy-12-(methanesulfonyloxy-
methyl)benzo[f]pyrrolo[1,2-b]isoquinoline-5-one (12).
for 1 hour during which time a precipitate formed. Stirring was
continued for an additional 2 hours at room temperature. The
reaction mixture was diluted with ether, cooled and filtered to
give 2.4 g (100%) of acid 10 as an equal mixture of cis and trans
A solution of cis alcohol 11 (150 mg, 0.4 mmol) and triethy-
lamine (82 mg, 0.8 mmol) in 15 mL of dry CH C1 was treated
2
2
1
isomers. Cis isomer: H NMR(CDC1 /DMSO): δ 8.4 (m, 1H),
with methanesulfonyl chloride (69 mg, 0.6 mmol). The resulting
mixture was stirred at room temperature for 18 hours. The reac-
3
8.16 (m, 1H), 7.6 (s, 1H), 7.56 (m, 4H), 7.42 (m, 3H), 5.20-5.23
(m, 2H), 4.48 (d, 1H, J=5.0 Hz), 4.17 (m, 1H) , 3.88 (m, 1H), 3.62
tion mixture was diluted with CH C1 , washed with 1 N HC1,
2
2
13
(m, 1H), 2.33 (m, 1H), 2.15 (m, 2H), 1.95 (m, 1H); C NMR: δ
saturated NaHCO solution, water, dried and concentrated under
3
170.8 161.6, 153.0, 135.7, 130.3, 127.6, 127.5, 126.9, 126.57,
126.4, 126.1, 125.7, 124.8, 123.1, 121.6, 101.9, 69.0, 56.4, 44.0,
42.8, 39.9,, 39.6, 39.2, 38.9, 38.6, 38.2, 29.0, 22.0. Trans isomer:
reduced pressure. Chromatography (silica gel, 9% ethanol-ether)
afforded the pure mesylate 12 as a solid (170 mg, 95%); H NMR
1
(CDC1 ): δ 8.42 (m, 1H), 8.1 (m, 1H), 7.6 (m, 5H), 7.36 (m, 3H),
3
1
H NMR(CDC1 /DMSO): δ 8.33 (m, 1H), 7.95 (m, 1H), 7.55 (s,
5.25-5.28 (m, 2H), 4.37 (dd, 1H, J=10.8, 7.3 HZ), 4.26 (dd, 1H,
J=10.8, 3.3 HZ), 4.07 (m, 2H), 3.88 (m, 1H), 3.62 (m, 1H), 2.79
3
1H), 7.52 (m, 4H), 7.34 (m, 3H), 5.30-5.33 (m, 2H), 4.12 (d, 1H,
J=11.8 Hz), 4.02 (m, 1H), 3.77 (m, 1H), 3.54 (m, 1H), 2.32 (m,
13
(s, 3H), 2.25 (m, 1H), 2.13 (m, 1H), 1.84 (m, 1H); C NMR: δ
13
1H), 2.0 (m, 3H); C NMR: δ 173.8, 160.5, 152.0, 135.0, 129.7
162.8, 154.4, 136.5 (2C), 130.7, 128.5 (2C), 128.4, 127.9, 127.8,
127.6 (2C), 127.4, 126.9, 126.0, 123.4, 123.1, 102.4, 70.1, 66.7,
58.1, 45.1, 37.1, 36.4, 29.1, 23.2.
(2 C), 126.8, 126.7, 126.2 (2 C), 125.7, 125.6, 125.3, 125.0,
124.6, 122.6, 120.9, 101.0, 68.2, 57.6, 48.8, 43.2, 30.6, 20.6; MS
(EI): 343 (387-COOH), 274, 252, 155, 127, 91; MS (CI, NH ):
Anal. Calcd. for C H NO S: C, 66.50; H, 5.58; N, 3.10.
3
25 25
5
344 (m/z), 238, 183, 137.
Found: C, 66.32; H, 5.54; N, 3.07.
Simarily prepared was the trans isomer. H NMR (CDC1 ): δ
1
Anal. Calcd. for C H NO (+ 3/4 H O) : C, 71.9; H, 5.6; N,
24 21
4
2
3
3.5. Found: C, 72.1; H, 5.37; N, 3.5.
8.43 (m, 1H), 8.09 (m, 1H), 7.75 (s, 1H), 7.6 (m, 4H), 7.39 (m,
3H), 5.30 (s, 2H), 4.58 (m, 1H), 4.28 (m, 3H), 3.915 (m, 1H),
3.35 (m, 1H), 2.92 (s, 3H), 2.1 (m, 2H), 1.9 (m, 2H); C NMR: δ
163.7, 154.5, 137.0, 136.6, 131.3, 128.3, 127.8, 127.7, 127.3 (2
C), 126.9, 126.8 (2 C), 123.1, 123.0, 122.9, 102.9, 71.8, 70.3,
58.2, 44.9, 37.4, 36.5, 30.5, 21.7; EIHRMS: m/z 451.1448
1,2,3,12,12a-Tetrahydro-7-benzyloxy-12-hydroxymethyl-benzo-
[f]pyrrolo[1,2-b]isoquinoline-5-one (11).
13
A solution of 10 (500 mg, 1.29 mmol) in 20 mL of benzene
was treated with thionyl chloride (10.0 mL) and the solution was
stirred at reflux for 1 hour. The resulting orange-brown solution
was evaporated to dryness to remove excess thionyl chloride. An
addditional 10 ml of benzene was added and the solution again
evaporated to dryness. The residue was then dissolved in 30 mL
of dry THF and sodium borohydride (782 mg, 20.6 mmol) was
added. The mixture was stirred at room temperature overnight
(C H NO S requires 451.1453).
25 25
5
Anal. Calcd. for C H NO S: C, 66.50; H, 5.58; N, 3.10.
25 25
5
Found: C, 66.40; H, 5.37; N, 2.99.
1,2,3,12,12a-Tetrahydro-7-hydroxy-12-(methanesulfonyloxy-
methyl)benzo[f]pyrrolo[1,2-b]isoquinoline-5-one (13).
after which time 25 mL of H O was added and the product
A mixture of cis-12 (160 mg, 0.35 mmol) and 10% Pd/C (90
2
extracted into ethyl acetate (100 mL). The organic layer was sep-
arated, dried and evaporated. The crude product was purified by
spinning band chromotography (silica gel 9% ethanol-ether) to
give the cis (124 mg, 26%) and trans (185 mg, 38%) isomers ini-
tially as oils however both solidified upon the addition of ether.
Cis isomer: mp
mg) in THF (10 mL) was shaken under H for 10 hours. The
mixture was filtered and concentrated under reduced pressure.
The product was crystallized upon addition of ether to give pure
2
phenol 13 (113 mg, 90%) which was used immediately in the
1
subsquent reaction. Cis isomer: H NMR (CDC1 ): δ 9.8 (s, 1H),
3
8.38 (d, 1H, J=8.29Hz), 8.07 (d, 1H, J=8.4Hz), 7.6 (s, 1H), 7.58

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Synthesis of 1,2,3,12a,12b-Hexahydrocyclopropa-
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[1,2-d]benzo[f]pyrrolo[1,2-b]isoquinolin-5,7-dione
REFERENCES AND NOTES
(m, 2H), 4.4 (dd, 1H, J=7.7, 10.7Hz), 4.27 (dd, 1H, J=3.2,
10.7Hz), 4.11 (m, 2H), 3.88 (m, 1H), 3.6 (m, 1H), 2.82 (s, 3H),
2.28 (m, 2H), 2.19 (m, 1H), 1.89 (m, 1H); CIHRMS (CH ): m/z
[1] L. J. Hanka, A. Dietz, S. A. Gerpheide, S. L. Kuentze and
D.G. Martin, J. Antibiot., 31 1211 (1978).
4
362.10635 (C H NO S requires 362.1062).
18 20
5
Similarily prepared was the trans isomer which was used
[2] C. G. Chidester, W. C. Krueger, S. A. Mizsak, D. J. Duchamp
and D. G. Martin, J. Am. Chem. Soc., 103, 7629 (1981).
[3] D. H. Swenson, L. H. Li, L. H. Hurley, J. S. Rokem, G. L.
Petzold, B. D. Dayton, T. L. Wallace, A. H. Lin and W. K Krueger,
Cancer Res., 42, 2021 (1982).
1
immediately in the subsequent reaction. H NMR (CDC1 ): δ
3
8.89 (br s, 1H), 8.4 (m, 1H), 8.2 (s, 1H), 8.0 (m, 1H), 7.6 (m, 2H),
4.58 (m, 1H), 4.28 (m, 3H), 3.97 (m, 1H), 3.45 (m, 1H), 2.9 (s,
13
3H), 2.2 (m, 1H), 1.9 (m, 2H), 1.6 (m, 1H); C NMR: δ 163.6,
[4] L. H. Hurley, V. L. Reynolds, D. H. Swenson, G. L. Petzold
and T. A. Scahill, Science, 226, 843 (1984).
[5] V. L. Reynolds, I. J. Molineaux, D. J. Kaplan, D. H. Swenson
and L. H. Hurley, Biochemistry, 24, 6220 (1985).
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J. Antibiot., 37, 63 (1984).
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Kroeger, J. P. McGovern, S. A. Mizsk, G. L. Neil, J. C. Stewart and J.
Visser, J. Antibiot., 34, 1119 (1981).
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35, 1438 (1996).
[9] D. L. Boger, C. W. Boyce, R. M. Garbaccio and J. A.
Goldberg, Chem. Rev., 97, 787, (1997).
[10] M. D. Tendler and S. Korman, Nature, 199, 501, (1963).
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Am. Chem. Soc., 87, 5791 (1965).
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L. H. Hurley, Biochemistry, 25, 1249 (1986).
153.1, 131.1, 127.1, 126.0, 125.0, 123.2, 123.1, 120.8, 117.1,
105.2, 71.8, 67.4, 58.1, 44.6, 37.8, 29.3, 21.5.
1,2,3,12a,12b-Hexahydro-cyclopropa[1,2-d]benzo[f]pyrrolo-
[1,2-b]isoquinolin-5,7-dione (2).
Sodium hydride (13 mg of 60% in mineral oil, 0.32 mmol) was
washed with petroleum ether (3 X 1 mL) and suspended in 2 mL
of dry THF. A solution of cis 13 (90 mg, 0.25 mmol) in 1 mL of
THF and 0.1 mL of DMF was added to the suspension of sodium
hydride and the resulting solution protected from light was stirred
for 30 minutes at room temperature. A solution of phosphate
buffer (pH 7, 5 mL) was added. The mixture was extracted with
ethyl acetate (3 X 5 mL). The combined organic layers were
dried and concentrated under reduced pressure. The resulting oily
material was crystallized from ether to give pure 2 (61 mg, 92%)
1
as off white plates. Cis Isomer: mp 160-162 °C ; H NMR
(CDC1 ): δ 8.22 (dd, 1H, J= 1.0, 7.8 Hz), 7.58 (m, 1H), 7.40 (m,
3
1H), 7.2 (s, 1H) , 7.01 (d, 1H, J= 8.0 Hz), 4.05 (m, 1H), 3.65 (m,
1H), 3.49 (m, 1H), 2.71 (m, 1H), 2.33 (m, 1H), 2.08 (m, 1H), 1.92
13
(m, 4H); C NMR (CDC1 ): δ 184.7, 161.5, 149.0, 143.2, 132.9,
3
[15] T. Reichstein and H. Zschokke, Helv. Chim. Acta., 15, 268
(1932).
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Laikos and V. M. Vishwanath, J. Org. Chem., 49, 4107 (1984).
[18] F. T. Smith and R. V. Atigadda, J. Heterocyclic Chem., 28,
1813 (1991).
132.0, 129.0, 126.6, 126.5, 121.1, 55.5 , 45.4, 32.3, 31.0, 27.4,
23.3, 22.4; EIHRMS: m/z 265.1095 (C
265.1103).
H NO requires
17 15 2
Anal. Calcd. for C H NO (+ 1/3 H O) : C, 75.00; H, 5.75;
17 15
2
2
N, 5.14. Found: C, 74.85; H, 5.88; N, 5.08.
The trans isomer was prepared in a similar manner; H NMR
1
(CDC1 ): δ 8.25 (d, 1H, J= 8.0 Hz), 7.61 (m, 1H), 7.49 (m, 1H),
3
7.28 (s, 1H) , 7.01 (d, 1H, J= 8.0 Hz), 4.19-4.30 (m, 1H), 3.81-
3.97 (m, 1H), 3.11-3.28 (m, 1H), 2.81-2.88 (m, 1H), 0.81-2.15
[19] M. A. Haimova, N. M. Nolov, S. C. Ivanova, A. I. Dimitrova
and V. I. Ognyanov, Tetrahedron, 33, 331 (1971).
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[21] X. Y. Jiao, M. Borloo, C. Verbuggen and A. Haemers,
Tetrahedron Lett., 35, 1103, 1994.
13
(m, 5H), 1.40-1.50(m, 1H); C NMR (CDC1 ): δ 185.2, 160.9,
3
146.8, 144.0, 133.2, 132.7, 130.4, 126.8 (2 C) 120.8, 58.8, 44.4,
31.1, 29.0, 27.9, 27.3, 22.0.
Anal. Calcd. for C H NO (+ 2/3 H O): C, 73.64; H, 5.88;
N, 5.05. Found: C, 73.50; H, 5.70; N, 5.05.
[22] F. T. Smith, J. DeRuiter and D. A. Carter, J. Heterocyclic
Chem., 26, 1815 (1989).
17 15
2
2