1222
Chemistry Letters Vol.37, No.12 (2008)
Cyclopropanation Reactions for the Synthesis of 2-Azabicyclo[4.1.0]heptane Derivatives
with Nitric Oxide Synthase Inhibitory Activity
1
1
1
2
´
´
´
Irene Suarez del Villar, Ana Gradillas, Angel Gomez-Ovalles, Riꢀc1ardo Martınez-Murillo,
2
´
´
Alfredo Martınez, and Javier Perez-Castells
1Dept. of Chemistry, Facultad de Farmacia, Universidad San Pablo-CEU, Boadilla del Monte, 28668-Madrid, Spain
2Dept. of Cellular, Molecular, and Developmental Neurobiology, Instituto Cajal, CSIC, 28002-Madrid, Spain
(Received September 25, 2008; CL-080921; E-mail: jpercas@ceu.es)
Synthesis of new bicyclic structures containing cyclopro-
panes, related to selective iNOS inhibitor ONO-1714, is describ-
ed. We have evaluated the effect of the compounds obtained on
the production of nitric oxide in lipopolysaccharide and inter-
feron-gamma stimulated mouse peritoneal macrophages and
on in vitro iNOS activity assays.
H2N
R
R
R
O
(i), (ii)
(iii) (iv)
+
O
N
O
O
N
O
O
PMB
OCH3
PMB
4 a,b
1a: R = H
1b: R = CH3
2
3 a,b
PMB = p-methoxybenzyl
Nitric oxide (NO) and the enzymes that produce it, nitric
oxide synthases (NOS), regulate numerous physiological proc-
esses.1 Among the NOS subclasses, the iNOS is induced by in-
flammatory stimuli, which may result in an excessive production
of NO. It has been suggested that iNOS could be part of the phys-
iopathology of a number of diseases such as septic shock, inflam-
mation, and carcinogenesis.2
The search for more active and selective inhibitors of a par-
ticular NOS isoform is a challenge.3 Recently, a new iNOS
inhibitor, ONO-1714, has been described (Figure 1).4
This compound is a potent and selective inhibitor of iNOS
and is currently undergoing evaluation in a Phase II clinical trial
in Japan.5 We have been engaged in new structural modifications
of this compound. Thus, we have synthesized and evaluated new
compounds in which a polar side chain has been attached to the
cyclopropane ring.
Synthesis of the test compounds was planned using a cyclo-
propanation reaction of cyclic enamides 4 with ethyl diazoace-
tate (EDA). 4a and 4b were obtained by aminolysis of 1 follow-
ing a procedure described by Kawanaka et al.4 which formed the
imides 3. We carried out the reduction of 3 with DIBAL, and de-
hydrated the resulting intermediate using mesyl chloride, which
formed 4 in 85–87% yield (Scheme 1).
The cyclopropanation reaction with EDA was first done
with rhodium acetate (Table 1). In the reactions with compound
4a, trans- and cis-5a were isolated jointly with unreacted starting
material and insertion product 6a. Major product was trans-5a.
The conditions shown in Entry 1 were then used with chiral cop-
per complexes, observing an improvement in yields keeping a
high diastereomeric ratio. These catalysts were prepared in situ
treating CuOTf with ligands A or B. As shown in Entries 2
and 3 these ee are not completely satisfactory although it is in-
teresting that the major enantiomer is different in reactions of
Entries 2 and 3, which will make it possible to have information
on biological activity of both enantiomers.
Scheme 1. Synthesis of olefins 4a and 4b. (i) THF, rt; (ii) Et3N,
Ac2O (90–95% in two steps); (iii) DIBAL, CH2Cl2, ꢁ78 ꢂC (80–
85%); (iv) Et3N, MsCl, CH2Cl2, 0 ꢂC (85–87%).
Table 1. Cyclopropanation of 4a with EDAa
H
metal catalyst
COOEt
+
COOEt
H
O
N
N2CHCO2Et
slow addition
O
N
O
N
H
PMB
PMB
PMB
4a
6a
5a
Me Me
O
N
O
O
O
Cat: Rh2(OAc)4, Cu OTf,
Ph
Ph
N
N
N
Ph
Ph
Ph
Ph
B
A
mol
Yield/%
% drb
ee %
Entry Catalyst
% cat. 4a trans-5a cis-5a 6a trans:cis trans-5ac
1
2
3
Rh2(OAc)4
CuOTf:A6
CuOTf:B7
4
25
45
52
62
5
4
10
5
7
5
90:10
87:13
78:22
—
75d
55d
1:1 28
1:1 18
aAll reactions in DCM, at rt, with 2 equivalents of EDA slowly added with a
pump syringe over 4 h; relative stereochemistry of products determined by
NOE experiments, see Supporting Information. Yields are given for pure
products after chromatographic separation. b% dr was determined by
c
1H NMR of the crude mixture. % ee was determined by HPLC analysis.
dMajor enantiomer was the first eluted in reaction of Entry 2 and the second
in Entry 3.
Our next target was the cyclopropanation of 4-methyl-sub-
stituted lactam 4b.4 The starting material was racemic but we de-
cided to use chiral catalysts, in addition to rhodium acetate, as
they gave better yields in the case of 4a, and a kinetic resolution
could be envisioned. Thus, 4b was treated under the conditions
indicated in Table 2, giving mixtures of the four possible diaster-
eomers 5b. In all cases the anti–trans isomer was the major prod-
uct. A small amount of insertion compound 6b was also ob-
tained. This time, insertion of EDA occurred in position 5 of
the ring. The best result was achieved with complex catalyst
CuOTf:A, in terms of total yield and diastereoselectivity (Entry
3, Table 2). The major product, anti–trans-5b was isolated in
50% yield as a pure scalemic compound (18% ee). Overall yield
of this reaction was 82%. All the isomers could be separated by
CH3
H
H
Cl
HN
N
H
H
Figure 1. Structure of ONO-1714.
Copyright ꢀ 2008 The Chemical Society of Japan
Del Villar, Irene Suarez
