CBI prodrug analogs of CC-1065 and the duocarmycins

Article abstract of DOI:10.1055/s-1999-3658

The preparation of a small series of CBI-indole₂ prodrugs is detailed.

Full text of DOI:10.1055/s-1999-3658

PAPER
1505
CBI Prodrug Analogs of CC-1065 and the Duocarmycins
Dale L. Boger,* Christopher W. Boyce, Robert M. Garbaccio, Mark Searcey, Qing Jin
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037, USA
Fax +1(858)7847550; E-mail: boger@scripps.edu
Received 12 April 1999
agents incorporating the natural CPI alkylation subunit of
Abstract: The preparation of a small series of CBI-indole2 prodrugs
CC-1065.3 (+)-CBI-indole2 (4), a simplified agent within
is detailed.
our early series of analogs, not only exhibited cytotoxic
Key words: prodrugs, cytoxicity, CBI-indole2, duocarmycins
potency comparable to that of the (+)-CC-1065 and great-
er (4×) than that of (+)-CPI-indole2 (U71,184),4 but it also
exhibited potent and efficacious in vivo antitumor activi-
ty.5 It is known that duocarmycin and CPI prodrugs
formed by acylation of the C4 phenol of appropriate seco
precursors such as 5 may show improved pharmacokinet-
ics, synthesis scaleup safety, storage stability and safety,
as well as improved efficacy6 and two such compounds,
KW-21897 and carzelesin (U-80,244),8 are currently un-
dergoing clinical development. Herein, we describe the
synthesis and evaluation of six prodrug derivatives of (+)-
CBI-indole2 which have become especially attractive for
their therapeutic properties.
CC-1065 and the duocarmycins (1–3) are the parent mem-
bers of a class of potent naturally occurring antitumor an-
tibiotics which derive their biological properties through
the sequence selective alkylation of duplex DNA.1,2 In the
course of our efforts on the evaluation of analogs bearing
deep-seated structural modifications in the alkylation sub-
unit, we described the first preparation and examination of
agents containing the 1,2,9,9a-tetrahydrocyclopro-
pa[c]benz[e]indol-4-one (CBI) alkylation subunit.3 In
these studies, the CBI-based analogs are chemically more
stable (4×), biologically more potent (4×), and consider-
ably more synthetically accessible than the corresponding
Synthesis
The N,N-dialkylcarbamoyl derivatives of seco-CBI-
indole2 (5)5 were prepared in good yields by treatment of
5 with 4-nitrophenyl chloroformate (Et3N, THF) to afford
H2N
O
N
OH
Me
Me
OMe
HN
NH
HN
N
N
O
O
N
N
O
O
N
O
OH
R
R
H
CPI
CBI
O
O
OMe
MeO2C
HN
(+)-1, (+)-CC-1065
OMe
N
O
H
N
N
O
N
N
O
H
OMe
H
O
O
N
OMe
H
MeO2C
Me
O
(+)- 2, (+)-duocarmycin SA
(+)-4, (+)-CBI-indole2
Cl
HN
OMe
H
N
O
N
N
HO
N
H
O
N
O
OMe
O
H
N
OMe
H
(+)-3, (+)-duocarmycin A
(+)-5, (+)-seco-CBI-indole2
Synthesis 1999, No. SI, 1505–1509 ISSN 0039-7881 © Thieme Stuttgart · New York

1506
D. L. Boger et al.
PAPER
Cl
to the DNA binding subunit including the safety issues
surrounding large scale intermediate handling and the ex-
amination of alternative right-hand subunits. Treatment of
133,5 with 4-nitrophenyl chloroformate (Et3N, CH2Cl2) af-
forded the carbonate intermediate which was reacted im-
mediately with 1-methylpiperazine (14, 47%). Similarly,
treatment of 13 with acetic anhydride (NaHCO3, CH2Cl2)
gave the acetate in good yield (15, 92%). Deprotection of
both 14 and 15 under acidic conditions (3.3 M HCl/
EtOAc) followed by direct coupling with 165 (EDCI,
DMF) gave the two prodrugs in good yield (42% for 7,
58% for 10).
indole2
N
O2N
OCOCl
Et3N, THF;
O
5
Me2NH, 97%
NMe2
O
6
O
Cl
indole2
O2N
OCOCl
N
O
Et3N, THF;
NMe
5
N
O
O
O
MeN
NH,
63%
7
O
O
O
Cl
indole2
Cl
Cl
N
O2N
OCOCl
47%
O
R
NBOC
N
PhNCO, Et3N
CH2Cl2, 86%
Et3N, THF;
NH,
O
5
NHPh
NMe
8
MeN
OH
N
O
13
16
Cl
indole2
O
N
14, R = OtBu
O
HCl/EtOAc;
16, EDCI, 42%
H
7, R = indole2
N
MeNCO, Et3N
CH2Cl2, 57%
N
H
CO2H
5
NHMe
O
N
H
9
Cl
Cl
Cl
indole2
N
R
N
O
NBOC
Ac2O, NaHCO3
CH2Cl2, 92%
Ac2O, Et3N
THF, 73%
O
5
Me
O
10
OH
Me
O
13
O
O
O
Cl
indole2
15, R = OtBu
N
CO2H
HCl/EtOAc;
16, EDCI, 58%
N
MeN
12
10, R = indole2
O
5
EDCI, DMAP
CH2Cl2, 89%
O
O
N
11
NMe
O
In Vitro Cytotoxicity Activity
Consistent with past observations, each of the prodrugs
exhibited an in vitro cytotoxic activity in the L1210 assay
that was essentially equivalent to that of 4 and 5. Since the
O-acylated or O-alkylated derivatives of 5 cannot as ef-
fectively alkylate DNA and would be expected to be
>100x less potent, the cytotoxicity of the derivatives 6–11
indicate that each prodrug is effectively hydrolyzed to re-
lease 5 which serves as the penultimate precursor to the
active constituent 4. The agents were further examined in
a human colon carcinoma cell line (HCT116) and two re-
sistant variants. HCT116/VM46 overexpresses the cell
surface protein gp 170 and embodies the MDR phenotype
while HCT116/VP35 is resistant to topoisomerase II in-
hibitors by virtue of its lower expression. In these cell
lines, the carbamate prodrugs incorporating a tertiary
amine were inactive presumably because of the lack of
the carbonate as an intermediate, followed by the addition
of dimethylamine (6, 97%) or 1-methylpiperazine (7,
63%). Reaction of 5 with phenyl or methyl isocyanate
(Et3N, CH2Cl2) gave the N-phenylcarbamoyl derivative 8
(86%) and N-methylcarbamoyl derivative 9 (57%). Treat-
ment of 5 with acetic anhydride (Et3N, THF, 73%) pro-
duced 10 while esterification of 5 with the acid 126 (EDCI,
DMAP, CH2Cl2, 89%) gave 11.
An alternative synthesis of the prodrugs of seco-CBI-
indole2 was also explored. There are a number of advan-
tages to an approach in which the prodrug substituent is
added to the alkylation subunit, followed by its coupling
Synthesis 1999, No. SI, 1505–1509 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
CBI Prodrug Analogs of CC-1065 and the Duocarmycins
1507
mL, 37 mmol) and stirred at 4 °C for 2.5 h under Ar. 1-Methylpiper-
azine (6.2 mL, 56 mmol) was added and the solution was allowed to
warm to 25 °C. After 12 h, the mixture was concentrated and direct-
ly subjected to chromatography (PTLC, 20 × 10 cm, THF) to yield
hydrolysis, but the remainder exhibited potent cytoxic ac-
tivity essentially equipotent or more potent, against both
the wild type and resistant cell lines. We had reported pre-
viously this behavior for 2,5 and the results suggest that
the agents may prove especially effective against resistant
variants of tumor cell lines and particularly useful in com-
bination therapy or in relapse chemotherapy. The results
of more detailed comparative in vitro and in vivo testing
of 4–11 will be disclosed in due course.
7 (1.5 mg, 63%) as a beige film, (+)-(1S)-7: [a]25 +24 (c = 0.08,
D
DMSO).
1H NMR (DMSO-d6, 400 MHz): d = 11.70 (s, 1H), 11.65 (s, 1H),
10.19 (s, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 8.07 (d, 1H, J = 9.5 Hz),
7.85 (d, 1H, J = 8.1 Hz), 7.69 (d, 1H, J = 8.1 Hz), 7.66 (m, 2H),
7.53 (m, 2H), 7.45 (d, 1H), 7.43 (s, 1H), 7.29 (s, 1H), 7.21 (dd, 1H,
J = 1.9, 8.4 Hz), 7.10 (dd, 1H, J = 1.9, 8.5 Hz), 4.92 (m, 1H), 4.67
(d, 1H, J = 9.2 Hz), 4.44 (s, 1H), 4.10 (m, 2H), 4.05 (m, 2H), 3.82
(m, 1H), 3.51 (m, 1H), 3.45 (m, 2H, obscured by H2O), 3.17 (d, 2H,
J = 7.0 Hz), 2.30 (s, 3H).
IR (film) nmax = 3310, 2925, 1734, 1653, 1559, 1478, 1405, 1368,
1335 cm-1.
FAB/HRMS (NBA/CsI) m/z = 661.2347 (M+H+, C37H33N6O4Cl re-
quires 661.2330).
3-[5’-(((1H-Indol-2”-yl)carbonyl)amino)-1H-indol-2’-yl)car-
bonyl]-1-(chloromethyl)-5-[[(phenylamino)carbonyl]oxy]-1,2-
dihydro-3H-benz[e]indole (8)
A solution of 5 (1.9 mg, 3.6 mmol) in CH2Cl2 (0.3 mL) was treated
with phenylisocyanate (1.7 mL, 16.0 mmol) and Et3N (2.5 mL, 18.0
mmol) and stirred at 25 °C for 6 h under Ar. The mixture was con-
centrated and directly subjected to chromatography (PTLC, 20 × 20
cm, 50% THF/hexanes) to yield 8 (2.0 mg, 86%) as a light yellow
film, (+)-(1S)-8: [a]25D +31 (c = 0.08, DMF); (–)-(1R)-8: [a]25D –35
(c = 0.02, DMF).
1H NMR (DMF-d7, 400 MHz): d = 11.79 (s, 1H), 11.77 (s, 1H),
10.56 (br s, 1H), 10.31 (s, 1H), 8.51 (s, 1H), 8.43 (s, 1H), 8.15 (d,
1H, J = 8.4 Hz), 8.10 (d, 1H, J = 8.4 Hz), 7.71 (m, 4H), 7.65 (d, 1H,
J = 8.4 Hz), 7.57 (m, 4H), 7.40 (t, 2H, J = 8.1 Hz), 7.37 (d, 1H,
J = 1.5 Hz), 7.27 (t, 1H, J = 7.0 Hz), 7.11 (m, 2H), 5.03 (t, 1H,
J = 10.7 Hz), 4.86 (dd, 1H, J = 1.8, 10.7 Hz), 4.53 (m, 1H), 4.23
(dd, 1H, J = 3.3, 11.0 Hz), 4.13 (dd, 1H, J = 7.0, 11.0 Hz).
3-[5’-(((1H-Indol-2”-yl)carbonyl)amino)-1H-indol-2’-yl)car-
bonyl]-1-(chloromethyl)-5-[[(dimethylamino)carbonyl]oxy]-
1,2-dihydro-3H-benz[e]indole (6)
IR (film): nmax = 3318, 2916, 2838, 1723, 1614, 1557, 1515, 1465,
1418, 1335, 1240 cm-1.
FAB/HRMS (NBA/CsI) m/z = 654.1932 (M+H+, C28H28N5O4Cl re-
quires 654.1908).;
A solution of 5 (2.8 mg, 5.2 mmol) in THF (0.3 mL) was treated with
4-nitrophenylchloroformate (2.8 mg, 14.0 mmol) and Et3N (1.6 mL,
11.2 mmol) and stirred at 25 °C for 2.5 h under Ar. Me2NH (8.4 mL,
2 M solution in THF, 16.8 mmol) was added and the solution was
stirred for an additional 3 h at 25 °C. The mixture was concentrated
and directly subjected to chromatography (PTLC, 20 × 20 cm, 50%
THF/hexanes) to yield 6 (3.1 mg, 97%) as a light yellow film. (+)-
(1S)-6: [a]25D +54 (c = 0.16, DMF).
1H NMR (DMF-d7, 400 MHz): d = 11.69 (s, 1H), 11.56 (s, 1H),
10.18 (s, 1H), 8.23 (d, 1H, J = 1.8 Hz), 8.17 (s, 1H), 7.90 (d, 1H,
J = 8.1 Hz), 7.78 (d, 1H, J = 8.8 Hz, partially obscured by DMF),
7.55 (dd, 1H, J = 1.8, 8.8 Hz), 7.46 (d, 1H, J = 7.4 Hz), 7.43 (m,
1H), 7.39 (s, 1H), 7.37 (m, 1H), 7.31 (m, 2H), 7.14 (d, 1H, J = 1.5
Hz), 7.05 (m, 1H), 6.88 (m, 1H), 4.79 (m, 1H), 4.62 (dd, 1H, J = 2.2,
10.6 Hz), 4.29 (m, 1H), 3.99 (dd, 1H, J = 3.3, 11.0 Hz), 3.91 (dd,
1H, J = 7.4, 11.0 Hz), 3.10 (s, 3H), 2.84 (s, 3H).
3-[5’-(((1H-Indol-2”-yl)carbonyl)amino)-1H-indol-2’-yl)car-
bonyl]-1-(chloromethyl)-5-[[(methylamino)carbonyl]oxy]-1,2-
dihydro-3H-benz[e]indole (9)
A sample of 5 (3.1 mg, 5.8 mmol) was dissolved in CH2Cl2 (0.3 mL)
and treated with methyl isocyanate (15 mL, 10% solution in CH2Cl2,
26.0 mmol) and Et3N (4 mL, 29.0 mmol). The resulting solution was
stirred at 25 °C for 12 h under Ar. The mixture was concentrated and
directly subjected to flash chromatography (silica gel, 1.5 × 5 cm,
75% THF/hexanes) to yield 9 (2.4 mg, 57%) as a beige film, (+)-
(1S)-9: [a]25D +56 (c = 0.11, THF).
1H NMR (DMF-d7, 400 MHz): d = 11.76 (s, 2H), 10.29 (s, 1H), 8.41
(s, 1H), 8.38 (s, 1H), 8.09 (d, 1H, J = 8.4 Hz), 7.98 (d, 1H, J = 8.4
Hz), 7.88 (m, 1H), 7.72 (dd, 1H, J = 1.8, 8.8 Hz), 7.69 (d, 1H,
J = 9.5 Hz), 7.60 (m, 3H), 7.51 (m, 2H), 7.33 (s, 1H), 7.25 (m, 1H),
7.09 (m, 1H), 4.99 (m, 1H), 4.82 (dd, 1H, J = 1.8, 11.0 Hz), 4.48 (m,
1H), 4.18 (dd, 1H, J = 3.0, 11.0 Hz), 4.08 (dd, 1H, J = 7.3, 11.0 Hz),
2.86 (d, 3H, J = 4.4 Hz).
IR (film) nmax = 3286, 2934, 1704, 1633, 1558, 1524, 1463, 1417,
1317, 1313, 1246, 1172 cm-1.
FAB/HRMS (NBA/CsI) m/z = 738.0862 (M+Cs+, C34H28N5O4Cl
requires 738.0864).
IR (film): nmax = 3290, 2952, 1738, 1633, 1615, 1557, 1520, 1417,
1315, 1246, 1139 cm-1.
3-[5’-(((1H-Indol-2”-yl)carbonyl)amino)-1H-indol-2’-yl)car-
bonyl]-1-(chloromethyl)-5-[[(4-methyl-1-piperazinyl)carbon-
yl]oxy]-1,2-dihydro-3H-benz[e]indole (7)
FAB/HRMS (NBA/CsI): m/z 724.0751 (M+Cs+, C33H26N5O4Cl re-
quires 724.0728).
A solution of 5 (2.0 mg, 3.7 mmol) in CH2Cl2 (0.1 mL) was treated
with 4-nitrophenylchloroformate (7.5 mg, 37 mmol) and Et3N (5.0
Synthesis 1999, No. SI, 1505–1509 ISSN 0039-7881 © Thieme Stuttgart · New York

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D. L. Boger et al.
PAPER
3-[5’-(((1H-Indol-2”-yl)carbonyl)amino)-1H-indol-2’-yl)car-
bonyl]-5-(acetyloxy)-1-(chloromethyl)-1,2-dihydro-3H-
benz[e]indole (10)
A sample of 5 (1.4 mg, 2.6 mmol) was dissolved in THF (0.1 mL)
and treated with Ac2O (1.2 mL, 13.1 mmol) and Et3N (0.7 mL, 5.2
mmol). The resulting solution was stirred at 25 °C for 8 h under Ar.
The mixture was concentrated and directly subjected to chromatog-
raphy (PTLC, 20 × 10 cm, 50% THF/hexanes) to yield 10 (1.1 mg,
73%) as a beige film. (+)-(1S)-10: [a]25D +42 (c = 0.12, DMF).
(s, 2H), 3.61 (s, 2H), 3.46 (t, 1H, J = 11.1 Hz), 2.52 (s, 2H), 2.49 (s,
2H), 1.66 (s, 3H), 1.59 (s, 9H).
IR (film): nmax = 2919, 1717, 1699, 1520, 1478, 1405, 1368, 1335
cm-1.
FAB/HRMS (NBA/CsI): m/z = 460.2018 (M+H+, C24H30N3O4Cl re-
quires 460.2003).
Alternative Synthesis of 7
Compound 14 (2.3 mg, 5.0 mmol) was treated with 3.3 M HCl/
EtOAc (0.3 mL) and stirred at 25 °C for 30 min. The solvent was
removed under a stream of N2 and the resulting salt was dried under
vacuum. This salt was dissolved in DMF (0.2 mL) and treated with
EDCI (2.9 mg, 15 mmol) and 16 (2.9 mg, 8.9 mmol) and stirred at 25
°C. After 16 h, the mixture was concentrated and directly subjected
to chromatography (PTLC, 20 × 20 cm, 10% CH3OH/CHCl3) to
give 7 (1.4 mg, 42%).
1H NMR (DMF-d7, 400 MHz): d = 11.79 (s, 1H), 11.77 (s, 1H),
10.32 (s, 1H), 8.43 (d, 1H, J = 1.9 Hz), 8.37 (s, 1H), 8.13 (d, 1H,
J = 8.4 Hz), 8.02 (m, 1H, obscured by DMF), 7.74 (dd, 1H, J = 2.0,
8.9 Hz), 7.70 (d, 1H, J = 8.6 Hz), 7.66 (m, 1H), 7.61 (s, 1H), 7.59
(m, 1H), 7.53 (m, 2H), 7.36 (d, 1H, J = 1.7 Hz), 7.28 (m, 1H), 7.10
(m, 1H), 5.02 (t, 1H, J = 10.8 H), 4.85 (dd, 1H, J = 2.3, 11.0 Hz),
4.51 (m, 1H), 4.21 (dd, 1H, J = 3.4, 11.3 Hz), 4.12 (dd, 1H, J = 7.0,
11.1 Hz), 2.56 (s, 3H).
IR (film): nmax = 3294, 2925, 1717, 1653, 1559, 1507, 1457, 1405,
5-(Acetyloxy)-3-(tert-butyloxycarbonyl)-1-(chloromethyl)-1,2-
dihydro-3H-benz[e]indole (15)
1368, 1335 cm-1.
FAB/HRMS (NBA/CsI): m/z = 709.0630 (M+Cs+, C33H25N4O4Cl
requires 709.0619).
A solution of 13 (3.1 mg, 9.1 mmol) in CH2Cl2 (0.3 mL) was treated
with Ac2O (13 mL, 93 mmol, 10 equiv) and NaHCO3 (7.8 mg, 93
mmol, 10 equiv) and stirred at 25 °C for 19 h. The mixture was con-
centrated and directly subjected to chromatography (PTLC, 20 × 20
cm, 10% EtOAc/hexanes) to give 15 (3.2 mg, 92%) as a colorless
film, (–)-(1S)-15: [a]25D –15 (c = 0.16, EtOAc).
3-[5’-(((1H-Indol-2”-yl)carbonyl)amino)-1H-indol-2’-yl)car-
bonyl]-1-(chloromethyl)-5-[4-(4-methyl-1-piperazinyl)-1,4-di-
oxobutoxy]-1,2-dihydro-3H-benz[e]indole (11)
1H NMR (CDCI3, 400 Mhz: d = 8.01 (br s, 1H), 7.78 (d, 1H, J = 8.5
Hz), 7.68 (d, 1H, J = 8.3 Hz), 7.49 (dd, 1H, J = 1.8, 8.3 Hz), 7.35
(dd, 1H, J = 1.9, 8.5 Hz), 4.30 (m, 1H), 4.14 (dd, 1H, J = 3.3, 10.5
Hz), 4.00 (dd, 1H, J = 7.4, 11.0 Hz), 3.91 (d, 1H, J = 11.0 Hz), 3.45
(t, 1H, J = 10.6 Hz), 2.42 (s, 3H), 1.56 (s, 9H).
A sample of 5 (3.5 mg, 5.8 mmol) was dissolved in CH2Cl2 (0.3 mL)
and treated with 126 (1.5 mg, 7.5 mmol), EDCI (2.6 mg, 13.0 mmol)
and catalytic dimethylaminopyridine (DMAP). The resulting solu-
tion was stirred at 25 °C for 2 h under Ar. The mixture was diluted
with H2O (5 mL), and extracted with EtOAc (3 × 5 mL). The organ-
ic layers were combined, washed with brine (5 mL), dried
(Na2SO4), and concentrated under reduced pressure. Semi-prepara-
tive reverse-phase HPLC (Waters Bondapak C-18 column, 300 Å,
25 × 100 mm, 70% CH3OH/30% (0.07% TFA/H2O), 10 mL/min)
afforded 11 (4.2 mg, 89%) as a beige film, (+)-(1S)-12: [a]25D +35
(c = 0.15, THF).
IR (film): nmax = 2979, 1769, 1703, 1630, 1595, 1478, 1406, 1368,
1332 cm-1.
FAB/HRMS (NBA/CsI): m/z = 375.1249 (M+, C20H22NO4Cl re-
quires 375.1237).
Alternative Synthesis of 10
1H NMR (DMF-d7, 400 MHz): d = 11.76 (s, 1H), 11.75 (s, 1H),
10.30 (s, 1H), 8.41 (s, 1H), 8.36 (s, 1H), 8.11 (d, 1H, J = 8.8 Hz),
7.98 (d, 1H, under DMF), 7.72 (dd, 1H, J = 1.8, 8.8 Hz), 7.69 (d,
1H, J = 9.5 Hz), 7.64 (m, 1H), 7.60 (m, 2H), 7.51 (m, 2H), 7.33 (s,
1H), 7.25 (m, 1H), 7.09 (m, 1H), 5.00 (m, 1H), 4.83 (dd, 1H, J = 1.7,
11.0 Hz), 4.51 (m, 1H), 4.20 (dd, 1H, J = 3.3, 11.4 Hz), 4.10 (dd,
1H, J = 7.0, 11.0 Hz), 3.5 (m, 3H, under H2O), 3.12 (m, 3H), 3.00
(m, 6H), 2.75 (s, 3H).
Compound 15 (2.7 mg, 7.2 mmol) was treated with 3.3 M HCl/
EtOAc (0.2 mL) and stirred at 25 °C for 30 min. The solvent was
removed under a stream of N2 and the resulting salt was dried under
vacuum. This salt was dissolved in DMF (0.2 mL) and treated with
EDCI (4.1 mg, 22 mmol) and 16 (2.8 mg, 8.6 mmol) and stirred at 25
°C. After 16 h, the mixture was concentrated and directly subjected
to chromatography (PTLC, 20 × 20 cm, 50% EtOAc/hexanes) to
give 10 (2.4 mg, 58%).
IR (film): nmax = 3282, 1757, 1653, 1521, 1465, 1418, 1314, 1202,
1138 cm-1.
FAB/HRMS (NBA/CsI): m/z 849.1594 (M+Cs+, C40H37N6O5Cl re-
Acknowledgment
quires 849.1568).
We gratefully acknowledge the financial support of the National In-
stitutes of Health (CA41986), the Skaggs Institute for Chemical
Biology, the award of an ACS Medicinal Division fellowship spon-
sored by Bristol-Myers Squibb (CWB), and the award of an ACS
Organic Division fellowship sponsored by Zeneca Pharmaceuticals
(RMG).
3-(tert-Butyloxycarbonyl)-1-(chloromethyl)-5-[[(4-methyl-1-
piperazinyl)carbonyl]oxy]-1,2-dihydro-3H-benz[e]indole (14)
A solution of 13 (3.0 mg, 9.0 mmol) in CH2Cl2 (0.3 mL) was treated
with 4-nitrophenyl chloroformate (3.6 mg, 18 mmol) and Et3N (3
mL, 21 mmol) and stirred at 25 °C for 2 h. 1-Methylpiperazine (15
mL, 0.13 mmol) was added and the mixture was stirred for 16 h, di-
luted with CH2Cl2 (10 mL) and washed with 10% aq NaHCO3 (5 x References
10 mL). The organic layer was dried (MgSO4), concentrated and
(1) Boger, D. L.; Johnson, D. S. Angew. Chem., Int. Ed. Engl.
subjected to chromatography (PTLC, 20 × 20 cm, 10% CH3OH/
EtOAc) to give 14 (2 mg, 47%) as a colorless film, (–)-(1S)-14: [a]
1996, 35, 1439.
Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Goldberg, J.
Chem. Rev. 1997, 97, 787.
Boger, D. L.; Johnson, D. S. Proc. Natl. Acad. Sci. U.S.A.
1995, 92, 3642.
Boger, D. L. Acc. Chem. Res. 1995, 28, 20.
Boger, D. L. Chemtracts: Org. Chem. 1991, 4, 329.
25
D –7.7 (c = 0.35, CH2Cl2).
1H NMR (CDCl3, 400 MHz): d = 8.22 (s, 1H), 7.83 (d, 1H, J = 8.5
Hz), 7.67 (d, 1H, J = 8.3 Hz), 7.47 (dd, 1H, J = 1.8, 8.3 Hz), 7.35
(dd, 1H, J = 1.9, 8.5 Hz), 4.22 (m, 1H), 4.11 (dd, 1H, J = 3.3, 10.5
Hz), 3.93 (dd, 1H, J = 7.4, 11.0 Hz), 3.91 (d, 1H, J = 11.0 Hz), 3.82
Synthesis 1999, No. SI, 1505–1509 ISSN 0039-7881 © Thieme Stuttgart · New York

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