Late stage Fe(CO)5 promoted double bond migration: Total synthesis of limazepines C and D

Article abstract of DOI:10.1016/j.tetlet.2015.06.051

The first total syntheses of limazepines C and D were accomplished from inexpensive and readily available starting materials using an iron pentacarbonyl promoted allylamide-enamide double bond migration as a key step. The obtained limazepine C was found to be unstable and undergoes oxidation to limazepine D.

Full text of DOI:10.1016/j.tetlet.2015.06.051

Tetrahedron Letters 56 (2015) 4767–4769
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Late stage Fe(CO)5 promoted double bond migration: total synthesis
of limazepines C and D
⇑
Guna Sakaine, Gints Smits, Ronalds Zemribo
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, Latvia
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total syntheses of limazepines C and D were accomplished from inexpensive and readily
available starting materials using an iron pentacarbonyl promoted allylamide–enamide double bond
migration as a key step. The obtained limazepine C was found to be unstable and undergoes oxidation
to limazepine D.
Received 27 April 2015
Revised 15 June 2015
Accepted 17 June 2015
Available online 23 June 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Natural products
Double bond migration
Transition metals
Iron pentacarbonyl
Limazepine
Pyrrolo[1,4]benzodiazepines
Introduction
often this transformation has been effected by rhodium hydrides,11
however use of nickel,12 iron,13 iridium,14 ruthenium,15 and
Pyrrolo[1,4]benzodiazepines (PBDs) are an important class of
antitumor antibiotic due to their ability to covalently bind to the
C-2 amino group of guanine residues within the minor groove of
DNA.1 Most PBDs possess a condensed three ring system which
is right-hand twisted between the aromatic and pyrrolidine ring
allowing them to fit within the backbone of DNA (Fig. 1).
PBDs have been known since the 1960s since the isolation of
anthramycin 1.2 Since then a vast amount of information3 has been
published including the isolation and characterization of new nat-
ural products, synthetic pathways, and applications. Moreover, one
PBD class member SJG-136 has shown good potential in the
treatment of ovarian carcinoma and is currently in Phase II clinical
studies.4 Anthramycin 1, as well as several other PBD natural prod-
ucts (2,5 3,6 47) possess a C2–C3 enamide double bond. The previ-
ously reported syntheses of C2–C3 unsaturated PBDs have involved
enolization of the C2 ketone to the corresponding enol triflate, fol-
lowed by a palladium catalyzed coupling to introduce the C2 sub-
stituent8 or direct Horner–Wadsworth–Emmons reaction of the C2
ketone with the corresponding phosphonate.9
osmium16 complexes is also reported in the literature. In the
course of our studies toward the total synthesis of PBD natural
products we envisioned that the C2–C3 enamide double bond
could be introduced by a double bond migration of the C2 ethyli-
dene group in intermediate 6, which had been successfully used
in our total synthesis of limazepine E 7 (Scheme 1).17 Herein, we
report the total synthesis of limazepines C and D via a late stage,
transition metal catalyzed double bond migration as the key step.
Results and discussion
To prove the concept, we initially examined the migration reac-
tion of an appropriately protected PBD dilactam 10, which was
available from the previous total synthesis of limazepine
E
(Scheme 2).17 The screening results of several commercially avail-
able catalysts are shown in Table 1.
Attempts using Ru (Entry 1) or Rh (Entry 2) complexes to effect
the double bond migration from allylamide 10 to enamide 11 failed
and only formation of undesired byproducts was observed. The use
of Fe(CO)5 catalyst however gave traces of the desired product 11.
Interestingly, by switching to the related Fe2(CO)9 catalyst, forma-
tion of the desired product 11 was again not observed.
Nowadays, a well-established method for the introduction of
enamide functionality involves the transition metal catalyzed
migration of an allylamide to the corresponding enamide.10 Most
We elected to further optimize the Fe(CO)5 promoted double
bond migration reaction of allylamide 10 (Table 2). Formation of
the desired product was not observed upon simply changing the
⇑
Corresponding author. Tel.: +371 67014901.
E-mail address: ronalds@osi.lv (R. Zemribo).
http://dx.doi.org/10.1016/j.tetlet.2015.06.051
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

4768
G. Sakaine et al. / Tetrahedron Letters 56 (2015) 4767–4769
Table 2
OH
9a
OH
H
N
OMe
H
N
O
9
Optimization of reaction conditions and solvent for the Fe(CO)5 promoted double
bond migration of 10 (Scheme 2)
Me
Me
H
10B 1111a
H
8
7
1
A
5
C
5a
N
N
6
4
2
3
Entry
Solvent
Temperature (°C)
Time (h)
Yield (%)
CONH2
O
O
1
anthramycin
2
limazepine G
1
2
3
4
5
Toluene
Dioxane
THF
THF
THF
100
100
100
150
150
18
18
18
3
—
—
OH
OH
Tracea
45b
71b
H
N
OMe
N
MeO
Me
O
H
H
18
N
N
O
O
Conditions: sealed tube, 5 mg of 10, 3 equiv of Fe(CO)5.
O
OH
4
sibiromycin
3
limazepine C
a
MeHN
HO
HPLC/MS.
b
Isolated yield.
N
N
O
O
H
N
H
(Scheme 3). Protection of the phenol group of nitrobenzoic acid
N
OMe
MeO
12, followed by ester hydrolysis and condensation of the interme-
diate benzoic acid with trans-4-hydroxy-L-proline methyl ester
O
O
SJG-136
Figure 1. Representative structures of PBDs.
gave amide 13 in good overall yield. Over three steps the nitro
group of amide 13 was reduced to give the intermediate anthrani-
lic amide which underwent cyclization under acidic conditions to
the PBD dilactam which was protected to give the desired alcohol
14. Dess–Martin oxidation of the hydroxyl group in 14 followed by
Julia-Kocienski olefination gave alkene 10 as a 5:1 mixture of E/Z
double bond isomers. The obtained mixture of isomers E-10 and
Z-10 was treated with Fe(CO)5 under our optimized conditions to
give the desired enamide 11 in fairly good yield. This implied that
the double bond geometry in 10 did not influence the outcome of
the migration step. Finally, reduction of the C11 amide gave lima-
zepine C 3 which tended to undergo spontaneous oxidation19 to
limazepine D 9. Only by careful work-up20 of the reaction mixture
could limazepine C 3 be obtained in satisfactory amounts and pur-
ity. Even immediately after the column chromatography ca. 10% of
limazepine D was observed. Upon storage of limazepine C 3 in the
refrigerator for one month, 50% of the material underwent oxida-
tion to limazepine D 9. Furthermore, limazepine D 9 could be
directly obtained by evaporation of the reaction mixture after the
protecting group cleavage step (step h (ii) in Scheme 3). The
Previous work:
OH
OH
OH
H
N
O
H
N
MeO
MeO
H
H
MeO2C
N
N
N
H
N
7
5
6
O
O
limazepine E
OH
[cat]
This work:
N
MeO
H
O
N
MeO
H
O
N
3
limazepine C
8
O
OH
N
MeO
N
O
9
limazepine D
Scheme 1. Total synthesis of limazepines C-E.
OH
OBn
Ph
N
Ph
N
MeO
MeO
NO2
MeO
MeO
NO2
CO2Me
O
O
d
a, b, c
O
O
H
MeO
MeO
H
[Catalyst]
CO2Me
N
OH
12
13
O
N
N
solvent
100 oC, 36 h
Ph
Ph
11
10
O
O
O
O
O
N
O
N
Scheme 2. Double bond migration studies of PBD dilactam 10.
H
H
e
f
N
N
OH
O
14
15
11
O
O
Table 1
Ph
Ph
Catalyst screening for double bond migration in allylamide 10 (Scheme 2)
O
O
O
Entry
Catalyst (50 mol %)
Solvent
Yielda (%)
O
H
N
MeO
MeO
N
MeO
MeO
H
g
h
1
2
3
4
RuCl2*3PPh3
RhCl*3PPh3
Fe(CO)5
Toluene
Toluene
THF
—
—
Trace
—
N
N
N
10
O
O
E/Z 5:1
Fe2(CO)9
THF
OH
OH
N
N
H
N
Conditions: 100 °C, 36 h, sealed tube.
i
a
HPLC/MS.
O
O
3
9
limazepine C
limazepine D
solvent from THF to dioxane (Entry 2) or toluene (Entry 1).
However in THF, after increasing the temperature, the desired dou-
ble bond migration product 11 was formed in a fairly good yield
(Entry 5). These conditions were selected for further utilization
in the total synthesis of limazepines C and D.
Scheme 3. Total syntheses of limazepine C and D. Reagents and conditions: (a)
BnBr, K2CO3, DMF, 96%; (b) LiOH, THF/H2O/MeOH; (c) trans-4-hydroxy- -proline
L
methyl ester hydrochloride, EDC, HOBt, TEA, DMF, 71% over 2 steps; (d) (i) H2, 10%
Pd/C, EtOH; (ii) cat. HCl, THF/H2O; (iii) cat. TsOH, PhCH(OMe)2, 64%; (e) DMP, DCM,
82%; (f) 5-(ethylsulfonyl)-1-phenyl-1H-tetrazole, NaHMDS, THF, 67%, E/Z 5:1; (g)
Fe(CO)5 (3 equiv), THF, 68%; (h) (i) NaBH4, MeOH; (ii) AcOH, H2O, MeCN, 40%; (i)
Work-up, 19%.
A shorter reaction sequence for the synthesis of dilactam 10
was also developed starting from known nitrobenzoic acid 1218

G. Sakaine et al. / Tetrahedron Letters 56 (2015) 4767–4769
4769
9, 1; (c) Kamal, A.; Rao, M. V.; Laxman, N.; Ramesh, G.; Reddy, G. S. K. Curr. Med.
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recorded NMR spectra of both synthetic samples of limazepines C 3
and D 9 were in a good agreement with the literature values.
In conclusion, the first total synthesis of limazepines C 3 and D 9
has been accomplished using transition metal promoted ally-
lamide–enamide double bond migration as the key step. The
migration was effected by cheap and readily available Fe(CO)5.
Limazepine C 3 turned out to be unstable and tended to undergo
oxidation to limazepine D 9.
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Acknowledgments
The authors acknowledge the European Social Fund (ESF) (pro-
ject No. 1DP/1.1.1.2.0/13/APIA/VIAA/003, EU) and Latvian IOS
internal Grant for G. Sakaine (IG-2014-05) for the financial support.
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Supplementary data
Supplementary data (detailed experimental analysis and spec-
tral analysis including 1H, 13C, and HRMS) associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/10.
1016/j.tetlet.2015.06.051.
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