Unexpected syntheses of seco-cyclopropyltetrahydroquinolines from a radical 5-exo-trig cyclization reaction: Analogs of CC-1065 and the duocarmycins

Article abstract of DOI:10.3390/90300125

Analogs of the seco-cyclopyrroloindoline (seco-CPI), the DNA alkylation pharmacophore of CC-1065 and the duocarmycins, can be prepared through a 5-exo-trig radical cyclization of a free radical and a 3-chloro-2-allylic moiety. This manuscript reports an unexpected discovery that, depending on the structure and stability of the free radical, the cyclization process leads to the production of an appreciable amount of seco-cyclopropyltetrahydroquinolines 7a-d along with the seco-cyclopropoyltetrahydroindoline products (6a-e). For instance, free radical reaction of the bromoallylic chloride 5a produced an equal amount of 6-benzyloxy-N-t-butoxycarbonyl-3-(chloromethyl)furano[e]indoline (6a), and 7-benzyloxy-N-t-butoxycarbonyl-3-chloro-1,2,3,4-tetrahydrofurano[f] quinoline (7a). Three other examples that produced mixtures of indoline and quinoline products are provided. In only one of the examples reported in this manuscript, the 6-benzyloxy-N-t-butoxycarbonyl-3-(chloromethyl)benzo[e]indoline, was a seco-CBI precursor 6e formed exclusively, consistent with literature precedents.

Full text of DOI:10.3390/90300125

Molecules 2004, 9, 125-133
molecules
ISSN 1420-3049
http://www.mdpi.org
Unexpected Syntheses of seco-Cyclopropyltetrahydroquinolines
From a Radical 5-Exo-Trig Cyclization Reaction: Analogs of
CC-1065 and the Duocarmycins
Hari Pati, Tiffany Howard, Heather Townes, Brian Lingerfelt, LuAnne McNulty and Moses
Lee*
Department of Chemistry, Furman University, Greenville, SC 29613, USA.
*Author to whom correspondence should be addressed: email: moses.lee@furman.edu
Received: 13 January 2004; in revised form 28 January 2004 / Accepted: 29 January 2004 /
Published: 28 February 2004
Abstract: Analogs of the seco-cyclopyrroloindoline (seco-CPI), the DNA alkylation
pharmacophore of CC-1065 and the duocarmycins, can be prepared through a 5-exo-trig
radical cyclization of a free radical and a 3-chloro-2-allylic moiety. This manuscript
reports an unexpected discovery that, depending on the structure and stability of the free
radical, the cyclization process leads to the production of an appreciable amount of seco-
cyclopropyltetrahydroquinolines 7a-d along with the seco-cyclopropoyltetra-
hydroindoline products (6a-e). For instance, free radical reaction of the bromoallylic
chloride 5a produced an equal amount of 6-benzyloxy-N-t-butoxycarbonyl-3-
(chloromethyl)furano[e]indoline (6a), and 7-benzyloxy-N-t-butoxycarbonyl-3-chloro-
1,2,3,4-tetrahydrofurano[f]quinoline (7a). Three other examples that produced mixtures
of indoline and quinoline products are provided. In only one of the examples reported in
this manuscript, the 6-benzyloxy-N-t-butoxycarbonyl-3-(chloromethyl)benzo[e]indoline,
was a seco-CBI precursor 6e formed exclusively, consistent with literature precedents.
Keywords:
seco-Cyclopropyltetrahydroquinoline,
CC-1065,
duocarmycins,
(chloromethyl)furano[e]indoline, (chloromethyl)furano[f]tetrahydroquinoline.

Molecules 2004, 9
126
Introduction
CC-1065 (1) and the duocarmycins [such as duocarmycin SA (2), duocarmycin C1 (3) and
duocarmycin C2 (4)], whose structures are given in Figure 1, are members of an extremely potent
group of anticancer agents that contain an interesting cyclopropylpyrroloindolone (CPI) DNA
alkylating functionality. These compounds also consist of a non-covalently active portion, the
phosphoidiesterase inhibitor (PDE) moiety in CC-1065 and the 5,6,7-trimethoxyindole-2-carbonyl
group in the duocarmycins [1,2]. Upon binding within the minor groove of AT-rich sequences of
DNA, notably at 5-TTA-3’, the reactivity of the cyclopropane is enhanced by a million fold for
reaction with the adenine-N3 atoms to form a covalent bond [3]. Two mechanisms have been proposed
for the DNA-binding enhancement in reactivity of the cyclopropane with nucleophiles: the alkylation
[4] and non-covalent driven model [5]. Covalent interaction of CC-1065 and the duocarmycins with
DNA has been found to kill cancer cells by inducing the cells to undergo apoptosis [6].
Figure 1. Structures of CC-1065 (1) and the duocarmycins, such as duocarmycin SA (2),
duocarmycin C1 (3) and duocarmycin C2 (4).
NH2
N
OCH3
O
OCH3
OH
N
OCH3
OCH3
O
N
H
N
O
O
N
H
CH3O2C
H3C
OCH3
H3C
N
N
N
H
H
OH
O
O
N
Duocarmycin A, 2
H
O
CC-1065, 1
OCH3
OCH3
OCH3
Cl
Cl
OCH3
OCH3
OCH3
O
N
O
O
N
H
CH3O2C
H3C
N
CH3O2C
H3C
N
H
N
O
N
H
OH
H
OH
Duocarmycin C2, 4
Duocarmycin C1, 3
Due to their potent anticancer properties, CC-1065 and the duocarmycins have enjoyed significant
levels of attention. This attention has led to the development of several analogs that have superior
activity over CC-1065 and the duocarmycins, and several analogs have been selected for clinical
evaluation. Examples of such compounds include adozelesin [5], carzelesin [6], KW5189 [7], and
bizelesin [8]. However, due to their severe toxicity to the bone marrow, currently only bizelesin
remains in clinical evaluation. In an attempt to design novel analogs of the duocarmycins and CC-1065
with reduced toxicity to bone marrow cells, a wide range of analogs of the cyclopropyl-
pyrrolo[e]indolone (CPI) subunit were synthesized and tested. Examples of such analogs,

Molecules 2004, 9
127
cyclopropylbenzo[e]indolone (CBI) [9], cyclopropylpyrazolo[e]indolone (CPzI) [10], cyclopropyl-
furano[e]indolone (CFI) [11], and cyclopropylindolone (CI) [12], are given in Figure 2. We have
contributed to this list of analogs by the design and synthesis of an iso-cyclopropylfurano[e]indolone
(iso-CFI) pharmacophore, a highly cytotoxic pharmacophore that is significantly less toxic to murine
bone marrow cells than the corresponding CBI analogs [13]. As depicted in Figure 3, synthesis of the
iso-CFI intermediate relied on the free radical 5-exo-trig cyclization in refluxing toluene of the
bromoallylic chloride 5a in the presence of 2,2'-azobisisobutyronitrile (AIBN) and tributyltin hydride.
To our surprise, radical cyclization of compound 5a gave not only the iso-CFI precursor, indoline 6a,
but it also afforded an equal amount of a CFQ precursor, quinoline 7a. In order to further explore
whether the unexpected ring closure process that led to the production of quinoline products is more
common, or whether the formation of compound 7a represented an exceptional behavior, the 5-exo-
trig radical cyclizations of five different bromoallylic chlorides 5a-e were studied.
Figure 2. Strucutres of the cyclopropylpyrrolo[e]indolone (CPI), cyclopropylbenzo-
[e]indolone (CBI), cyclopropylpyrazolo[e]indolone (CPzI), cyclopropylfurano[e]-
indolone (CFI), and cyclopropylindolone (CI) analogs.
H3C
H3C
N
R
R
N
N
R
R'
N
O
O
O
N
H
N
H
O
O
O
CPzI
CPI
CBI
R
N
R
N
CH3O2C
O
O
O
O
O
CFI
CI
Results and Discussion
Syntheses of the benzofuran bromoallylic chlorides 5a and 5b were accomplished according to a
procedure recently published from our laboratory [13]. Using a similar approach, and an appropriate
starting material, such as thiophene-2-carboxaldehyde and 3-bromobenzaldehyde, the corresponding
bromoallylic chlorides 5c and 5d were prepared. The naphthalene bromoallylic chloride 5e was
prepared according to a literature process [14]. With the five compounds 5a-e at hand, their free radical
promoted ring closure reactions were carried out as depicted in Figure 3. Each compound 5a-e was
treated with 0.33 mole-equivalents of AIBN and 2.5 mole-equivalents of tributyltin hydride. The
mixture was dissolved in freshly distilled (over sodium) toluene or benzene and the solution was
thoroughly deoxygenated by degassing the same under vacuum and opening the flask to nitrogen (three

Molecules 2004, 9
128
times). The resulting clear solutions were heated to reflux under a nitrogen atmosphere for 5 hours, at
which time the reactions were completed as monitored by TLC analyses. Because of their different
structures, the indoline compounds (6) were separated readily from the more polar quinoline
compounds (7) by chromatography. In all cases the unpurified products, as well as the silica gel
1
column purified compounds (6 and 7) were analyzed by 500 MHz H-NMR. As indicated in the
Experimental section, the indoline and quinoline compounds gave characteristic spectra, each bearing
peaks in the 3.5-4.5 ppm region. As depicted in Figure 4A, the spectrum of indoline 6a gave four sets
of peaks in this region, with two distinct triplet-like patterns at 3.6 and 4.2 ppm. Quinoline 7a, as
shown in Figure 4B, gave a simpler spectrum in this region, with one distinct triplet in the 4.2 ppm
position and a multiplet at 3.6 ppm. As illustrated in Figure 4C, the spectrum for the unpurified
material indicated a mixture of 6a and 7a, at a ratio of 1:1.2. The products for reactions of compounds
5b-e are summarized in Table 1.
Table 1. Summary of the percent yields and product ratios resulting from the radical
cyclizations of bromoallylic chlorides 5a-e.
Reactant
Indoline (6)
Quinoline (7)
Ratio of 6:7
1:1.2
5a
5b
5c
5d
5e
40%
37
35
29
48%
32
32
19
1.2:1
1.1:1
1.5:1
86
none isolated
not calculated
Formation of substantial amounts of the seco-cyclopropyltetrahydroquinoline products 7a-d, in
addition to their 5-exo-trig (seco-iso-CFI) counterparts 6a-d, is noteworthy. This type of radical
cyclization process on a diverse range of structures, including compound 5e, has been widely reported
[14]. In all of the reported cases, the indoline or 5-exo-trig products were obtained exclusively [11b,
14], including the formation of a seco-CBI precursor (indoline 6e) from bromoallylic chloride 5e. We
propose that formation of the quinolines 7a-d is due to the generation of a stabilized radical
intermediate, formed via a 5-exo-trig ring closure reaction. Instead of immediately reacting with
tributyltin hydride, the radical intermediate undergoes a ring expansion reaction to produce a more
stable intermediate, which has a six-membered ring (quinoline) structure. The free radical is further
stabilized by conjugation of the radical at the benzylic position. Subsequent reaction of the seco-CFQ
radical with tributyltin hydride afforded products 7a-d.

Molecules 2004, 9
Figure 3. Free radical promoted cyclization of bromo-allylic chlorides 5a-e
129
Cl
Cl
Cl
Br
NHBOC
AIBN
NBOC
X
NBOC
X
X
R
R
R
Bu SnH
3
heat
OBn
OBn
OBn
7, quinoline compounds
a, X = O, R = H
6, indoline compounds
5, bromo-allylic chlorides
a, X = O, R = H
a, X = O, R = H
b, X = O, R = CH3
c, X = S, R = H
b, X = O, R = CH3
c, X = S, R = H
b, X = O, R = CH3
c, X = S, R = H
Cl
Cl
Cl
Br
NHBOC
AIBN
R
R
NBOC
NBOC
R
Bu SnH
3
heat
OBn
OBn
OBn
7, quinoline compounds
d, R = CO2Bu
6, indoline compounds
d, R = CO2Bu
e, R = H
5, bromo-allylic chlorides
d, R = CO2Bu
e, R = H
With both quinoline (7) and indoline (6) products available, they were conjugated to a 5,6,7-
trimethoxyindole-2-carboxylic acid moiety, thereby forming analogs of the duocarmycins. Conjugates
of compounds 6a,b and 7a,b to the trimethoxyindole moiety were found to have significant, yet
similar, cytotoxicity against the growth of cancer cells grown in culture. The IC50 values for these
compounds derived from a three-day drug exposure against murine B16 melanoma are 0.04 – 0.09 µM
[13].
Figure 4. Expanded 500 MHz 1H-NMR spectra of indoline 6a (A), quinoline 7a (B)
and an unpurified sample of 6a and 7a (C).
A
B
C
ppm

Molecules 2004, 9
130
Acknowledgements
The authors acknowledge support from the NSF-REU, NIH (RR16461-10) from the BRIN Program,
and Furman University.
Experimental
General
Instruments, etc
General Procedure for the Free Radical 5-Exo-Trig Cyclization
6-Benzyloxy-N-t-butoxycarbonyl-3-(chloromethyl)furano[e]indoline (6a) and 7-benzyloxy-N-t-butoxy-
carbonyl-3-chloro-1,2,3,4-tetrahydronfurano[f]quinoline (7a). To a mixture of cis and trans bromo
allylic-chloride 5a (1.37 g, 2.59 mmol) was added 2,2'-azobisisobutyronitrile (AIBN) (250 mg, 1.52
mmol). The reagents were then dissolved in freshly distilled toluene (140 mL), and nBu3SnH (1.87
mL, 6.95 mmol) was added. The solution was degassed with nitrogen and heated in an oil bath (90°C)
for 2 hours. The toluene was removed in vacuo to produce a light yellow oil which was dissolved in
CH2Cl2 and loaded on a hexane/silica gel column. The products were eluted with 1% EtOAc/hexane
with the composition of EtOAc gradually increased to 5%. Fractions containing the products were
concentrated in vacuo. The expected indoline product 6a was obtained as a colorless clear oil (430 mg,
1.03 mmol, 40%); TLC (10% EtOAc/hexane) Rf = 0.52; IR (KBr, cm-1) 3070, 3024, 2971, 2927, 1701,
1652, 1634, 1617, 1559, 1541, 1493, 1457, 1417, 1368, 1342, 1257, 1155, 1080, 1049, 1023, 978, 929,
903, 858, 823, 788, 739, 712; 1H-NMR (CDCl3) 7.57 (s br, 1H), 7.41 (d br, 8.0, 2H), 7.35 (d, 2.5, 1H),
7.33 (t, 8.0, 2H), 7.28 (t, 8.0, 1H), 6.77 (d, 2.5, 1H), 5.13 (s, 2H), 4.15 (dd, 9.5, 10.0, 1H), 4.02 (dd,
4.0, 11.0, 1H), 3.98 (m, 1H), 3.92 (dt, 4.0, 10.0, 1H), 3.54 (t, 10.5, 1H), 1.51 (s, 9H); EI-MS (m/z rel.
35
+
:
intensity) 413 (M , 14); Accurate mass for C23H24NO4 Cl calcd. 413.1394, obsd. 413.1381.
In addition to the inoline product 6a, an unexpected quinoline substance 7a was isolated as a
colorless clear oil (513 mg, 1.24 mmol, 48%); TLC (10% EtOAc/hexane) Rf = 0.51; IR (KBr, cm-1)
3122, 3069, 2971, 2927, 1701, 1639, 1612, 1493, 1457, 1417, 1368, 1342, 1258, 1222, 1160, 1138,
1
1084, 1071, 1049, 1023, 903, 858, 832, 756, 734, 694; H-NMR (CDCl3) 7.57 (s br, 1H), 7.41 (d br,
7.5, 2H), 7.36 (d, 2.0, 1H), 7.33 (t, 7.5, 2H), 7.27 (t, 7.5, 1H), 6.76 (d, 2.0, 1H), 5.13 (s, 2H), 4.17 (t,
+
+
9.5, 2H), 3.5-3.65 (m, 3H), 1.49 (s, 9H); EI-MS (m/z, rel. intensity) 413 (M , 4), 379 (M + H-Cl, 20);
Accurate mass for C23H24NO4 Cl: calcd. 413.1394, obsd. 413.1384.
35
Note: The radical cyclization of pure cis or trans isomer of compound 5a gave similar mixtures of
products 6a and 7a.

Molecules 2004, 9
131
6-Benzyloxy-N-t-butoxycarbonyl-3-(chloromethyl)-5-methylfurano[e]indoline (6b), and 7-benzyloxy-
N-t-butoxycarbonyl-3-chloro-1,2,3,4-tetrahydro-5-methylfurano[f]quinoline (7b). The products were
purified by silica gel column chromatography using 10% EtOAc/petroleum ether as eluent to give
compounds 6b and 7b in 37% and 32% yield, respectively. Indoline 6b was isolated as an off-white
-1
solid. Mp. 170-172°C; TLC (10% EtOAc/petroleum ether) Rf = 0.44; IR (KBr, cm ) 3045, 2965,
2927, 2856, 1701, 1638, 1621, 1493, 1457, 1417, 1368, 1342, 1258, 1213, 1164, 1146, 1058, 1027,
1
934, 898, 752; H-NMR (CDCl3) 7.58 (s br, 1H), 7.43 (d br, 2H), 7.38 (t, 8.0, 2H), 7.24 (t, 8.0, 1H),
6.45 (s, 1H), 5.23 (s, 2H), 4.20 (dd, 9.5, 10.0, 1H), 4.10 (dd, 4.0, 10.0, 1H), 4.06 (m, 1H), 3.97 (dt, 4.0,
10.0, 1H), 3.59 (t, 10.0, 1H), 2.41 (s, 3H), 1.61 (s, 9H); EIMS m/z (rel. intensity) 427 (M+, 15), 371
(67), 91 (100).
Quinoline product 7b: Yellowish oil; TLC (10% EtOAc/petroleum ether) Rf = 0.40; IR (KBr, cm-1)
3040, 2964, 2927, 1701, 1639, 1497, 1458, 1417, 1458, 1417, 1368, 1342, 1320, 1213, 1164, 1142,
1049, 974, 934, 898, 832, 761, 734, 694; 1H-NMR (CDCl3) 7.59 (s br, 1H), 7.47 (s br, 2H), 7.39 (t, 7.5,
sH), 7.34 (d, 7.5, 1H), 6.44 (s, 1H), 5.17 (s, 2H), 4.22 (t, 9.5, 2H), 3.65 (m, 3H), 2.41 (s, 3H), 1.60 (s,
9H); EIMS m/z (rel. intensity) 427 (M+, 2), 393 (30), 337 (100).
6-Benzyloxy-N-t-butoxycarbonyl-3-(chloromethyl)thiopheno[e]indoline (6c) and 7-benzyloxy-N-t-
butoxycarbonyl-3-chloro-1,2,3,4-tetrahydrothiopheno[f]quinoline (7c). The products were putified by
column chromatography using 5% ethyl acetate/petroleum ether as eluent. Both products were viscous
and colorless oils. Indoline 6c: TLC (5% EtOAc/petroleum ether) Rf = 0.62; IR (KBr, cm-1) 3010,
1
2963, 1705, 1697, 1438, 1461, 1394, 1368, 1337, 1293, 1257, 1223, 1164, 1142, 1116; H-NMR
(CDCl3) 7.45 (m, 6H), 7.32 (t, 7.5, 1H), 7.17 (d, 5.0, 1H), 5.21 (s, 2H), 4.21 (m, 2H), 4.05 (dd, 2.0, 9.9,
1H), 3.87 (m, 1H), 3.62 (t, 10.5, 1H), 1.59 (s, 9H); EIMS m/z (rel. intensity) 430 [M+, 10].
Quinoline 7c: TLC (5% EtOAc/petroleum ether) Rf = 0.55; IR (KBr, cm-1) 3007, 1953, 1700, 1607,
1483, 1461, 1394, 1368, 1332, 1292, 1142 and 1120; 1H-NMR (CDCl3) 7.54 (s, 7.0, 2H), 7.53 (d, 5.0,
1H), 7.44 (t, 7.0, 1H), 7.36 (t, 7.0, 1H), 7.16 (d, 5.0, 1H), 5.23 (s, 2H), 4.28 (t, 6.0, 2H), 3.68 (m, 1H),
3.61 (m, 2H), 1.59 (s, 9H); EIMS m/z (rel. intensity) 430 [M+, 6].
Butyl 5-[6-benzyloxy-N-t-butoxycarbonyl-3-(chloromethyl)benzo[e]indoline]carboxylate (6d) and
butyl
5-[7-benzyloxy-N-t-butoxycarbonyl-3-chloro-1,2,3,4-tetrahydrobenzo[f]quinoline]carboxylate
(7d). Silica gel column chromatography purification of the crude product using 5% EtOAc/hexane as
eluent afforded compounds 6d and 7d in 29% and 19%, respectively. Compound 6d was isolated as a
white solid. Mp 146-149°C; TLC (10% EtOAc/hexane) Rf = 0.55; IR (KBr, cm-1) 2961, 1701, 1409,
1363, 1329, and 1141; 1H-NMR (CDCl3, 500 MHz) 8.38 (d, 2.0, 1H), 8.33 (d, 8.0, 1H), 7.90 (dd, 2.0,
8.0, 1H), 7.54 (d, 8.0, 1H), 7.42 (m, 5H), 5.30 (s, 2H), 4.40 (t, 6.0, 2H), 4.30 (m, 1H), 4.18 (m, 1H),
4.08 (m, 1H), 3.93 (dd, 2.5, 11.1, 1H), 3.50 (t, 11.0, 1H), 1.81 (quintet, 6.0, 2H), 1.61 (s, 9H), 1.53
(quintet, 6.0, 2H), 1.02 (t, 6.0, 3H); EIMS m/z (rel. intensity) 523 [M+, 10]; Accurate mass calcd. for
C30H34NO535C l 525.2126, obsd. 525.2137.

Molecules 2004, 9
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Quinoline 7d: Colorless oily residue; TLC (10% EtOAc-Hexane) Rf = 0.51; IR (KBr, cm-1) 2991,
1704, 14062, 1368, 1328, and 1147; 1H-NMR (CDCl3, 500 MHz) 8.56 (d, 2.0, 1H), 8.36 (d, 8.0, 1H),
8.03 (s br, 1H), 7.94 (dd, 2.0, 8.0, 1H), 7.54 (d, 8.0, 7H), 7.48 (t, 8.0, 2H), 7.39 (t, 8.0, 1H), 5.30 (s,
2H), 4.40 (t, 6.0, 2H), 4.21 (t, 6.0, 2H), 3.80 (m, 3H), 1.82 (quintet, 6.0, 2H), 1.60 (s, 9H), 1.50
(quintet, 6.0, 2H), 0.98 (t, 6.0, 3H); EIMS m/z (rel. intensity) 523 [M+, 7].
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