2275
G. Smits, R. Zemribo
Letter
Synlett
References and Notes
O
H
H
N
N
H
H
(1) Leimgruber, W.; Batcho, A. D.; Czajkowski, R. C. J. Am. Chem. Soc.
1968, 90, 5641.
(2) Thurston, D. E. In Molecular Aspects of Anticancer Drug–DNA
Interactions; Vol. 1; Neidle, S.; Waring, M. J., Eds.; The Macmil-
lan Press Ltd: London, 1993, 54.
NaBH4, TFA
N
N
THF, 14%
O
O
oxoprothracarcin (19)
boseongazepine C (23)
(3) For reviews, see: (a) Antonow, D.; Thurston, D. E. Chem. Rev.
2011, 111, 2815. (b) Cipolla, L.; Araujo, A. C.; Airoldi, C.; Bini, D.
Anti-Cancer Agents Med. Chem. 2009, 9, 1. (c) Kamal, A.; Rao, M.
V.; Laxman, N.; Ramesh, G.; Reddy, G. S. K. Curr. Med. Chem.:
Anti-Cancer Agents 2002, 2, 215. (d) Thurston, D. E.; Bose, D. S.
Chem. Rev. 1994, 94, 433.
NaH, SEMCl
DMF, 79%
NaBH4, MeOH
27% in 2 steps
SEM
O
NaBH4, MeOH, then
RP prep. LC/MS
N
N
H
H
N
N
(5) (a) Jiao, R. H.; Xu, H.; Cui, J. T.; Ge, H. M.; Tan, R. X. J. Appl. Micro-
biol. 2013, 114, 1046. (b) Antonow, D.; Jenkins, T. C.; Howard, P.
W.; Thurston, D. E. Bioorg. Med. Chem. 2007, 15, 3041.
(c) Kamal, A.; Reddy, K. L.; Devaiah, V.; Shankaraiah, N.; Reddy,
G. S. K.; Raghavan, S. J. Comb. Chem. 2007, 9, 29. (d) Biel, M.;
Deck, P.; Giannis, A.; Waldmann, H. Chem. Eur. J. 2006, 12, 4121.
(6) Smits, G.; Zemribo, R. Org. Lett. 2013, 15, 4406.
O
O
21
prothracarcin (22)
Scheme 3 Total synthesis of boseongazepine C
The reported method15 for selective reduction of the
N10-C11 amide group gave very low yields of the desired
boseongazepine C (23) and the reaction was also not repro-
ducible. A reduction of the double bond was also observed
using these conditions. To increase the yield of the reduc-
tion we applied the described3d concept by introducing an
N10 nitrogen protecting group to lower the electron densi-
ty on nitrogen N10, thereby increasing the electrophilicity
of the C11-carbonyl. Although the N10 protecting group
was successfully installed, the subsequent reduction se-
quence was again low yielding. Nevertheless, the spectro-
scopic data of boseongazepine C (23) obtained by either re-
duction method were in a good agreement with the litera-
ture data.
In summary, we have developed a convenient and high
yielding method for the synthesis of pyrrolo[1,4]benzodiaz-
epine dilactams in one step from unprotected anthranilic
acids and proline ester derivatives. Notably, a number of
functional groups are tolerated, even unprotected hydroxyl
and phenol groups. The broad number of commercially
available proline esters and anthranilic acids makes this
method a valuable tool for the synthesis of large PBD dilact-
am libraries in short time.
(7) Yang, B. V.; O’Rourke, D.; Li, J. Synlett 1993, 195.
(8) General Procedure for Synthesis of PBD Dilactams: To a
stirred solution of anthranilic acid (2.2 mmol, 2 equiv), BOP
reagent (2.2 mmol, 2 equiv) and HOBt hydrate (2.2 mmol, 2
equiv) in anhyd DMF (10 mL) was added Et3N (10.9 mmol, 10
equiv). After stirring for 15 min, proline ester hydrochloride
(1.1 mmol, 1 equiv) was added and the resultant mixture was
stirred for 16 h. The volatiles were removed in vacuo and the
residue was partitioned between CH2Cl2 and brine. The organic
phase was dried over anhyd Na2SO4, filtered and concentrated
in vacuo. The residue was purified by flash column chromatog-
raphy (EtOAc–MeOH) or reversed-phase flash column chroma-
tography (MeOH + 0.5% HCOOH–H2O + 0.5% HCOOH).
(S)-9-Bromo-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]-
diazepine-5,11(10H,11aH)-dione (23): colorless solid; [α]D
+423 (c = 0.1, MeOH). 1H NMR (300 MHz, CDCl3): δ = 7.95 (d, J =
7.9 Hz, 1 H), 7.69–7.81 (m, 2 H), 7.14 (t, J = 7.9 Hz, 1 H), 4.05 (d, J
= 6.2 Hz, 1 H), 3.76–3.91 (m, 1 H), 3.50–3.70 (m, 1 H), 2.67–2.86
(m, 1 H), 1.92–2.18 (m, 3 H). 13C NMR (100 MHz, CDCl3): δ =
170.0, 164.4, 136.0, 133.1, 130.9, 129.2, 126.0, 115.5, 56.8, 47.5,
26.4, 23.5. HRMS–ESI: m/z [M + H] calcd for C12H12N2O2Br:
295.0082; found: 295.0090.
(S)-8-(Trifluoromethyl)-2,3-dihydro-1H-benzo[e]pyrrolo-
[1,2-a][1,4]diazepine-5,11(10H,11aH)-dione (24): yellowish
solid; Lit. 9: [α]D +41 (c = 0.1, MeOH). 1H NMR (400 MHz,
DMSO): δ = 7.93 (dd, J = 7.9, 1.5 Hz, 1 H), 7.76 (br s, 1 H), 7.73
(dd, J = 7.9, 1.5 Hz, 1 H), 7.12 (t, J = 7.9 Hz, 1 H), 4.03 (d, J = 6.0
Hz, 1 H), 3.72–3.88 (m, 1 H), 3.52–3.69 (m, 1 H), 2.66–2.85 (m, 1
H), 1.95–2.14 (m, 3 H). 13C NMR (100 MHz, DMSO): δ = 170.7,
163.4, 137.1, 131.9, 131.9 (q, J = 32.2 Hz), 129. 8, 123.5 (q, J =
272.8 Hz), 119.9, 118.1, 56.1, 47.0, 25.7, 23.0. HRMS–ESI: m/z
[M + H] calcd for C13H12N2O2F3: 285.0851; found: 285.0855.
(S,E)-2-Ethylidene-10-{[2-(trimethylsilyl)ethoxy]methyl}-
2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-
5,11(10H,11aH)-dione (21): To a stirred solution of oxoprothra-
carcin (140 mg, 0.6 mmol, 1 equiv) in anhyd DMF (1.5 mL)
under an argon atmosphere was added NaH (80% in mineral oil,
21 mg, 0.7 mmol, 1.2 equiv) at 0 °C. After stirring for 30 min
SEM-Cl (118 mg, 0.7, 1.2 equiv) was added and the mixture was
allowed to warm to r.t. overnight and then partitioned between
CH2Cl2 and brine. The organic phase was dried over anhyd
Na2SO4, filtered and concentrated in vacuo. The residue was
Acknowledgment
We thank the European Social Fund (ESF) for financial support (proj-
ect No. 1DP/1.1.1.2.0/13/APIA/VIAA/003).
Supporting Information
Supporting information for this article is available online at
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2272–2276