Synthesis and structural studies of a novel scaffold for drug discovery: A 4,5-dihydro-3H-spiro[1,5-benzoxazepine-2,4′-piperidine]

Article abstract of DOI:10.1016/j.tetlet.2003.11.079

We describe the three-step synthesis of a novel 4,5-dihydro-3H-spiro[1,5- benzoxazepine-2,4′-piperidine] scaffold from ortho-hydroxyacetophenone and N-benzylpiperidone. The structure of one disubstituted derivative, studied by NOESY NMR in an aqueous medi

Full text of DOI:10.1016/j.tetlet.2003.11.079

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1051–1054
Synthesis and structural studies of a novel scaffold for drug
discovery: a 4,5-dihydro-3H-spiro[1,5-benzoxazepine-2,40-
piperidine]q
Nicolas Willand,a,* Terence Beghyn,a Guy Nowogrocki,b Jean-Claude Gesquierea
and Benoit Depreza
aLaboratoire de chimie organique, UMR 8525, Facultꢀe des sciences Pharmaceutiques et biologiques,
3 rue du Pr. Laguesse, F-59006 Lille, France
bLaboratoire de Cristallochimie et Physicochimie du Solide, CNRS UMR 8012, ENSC Lille,
B.P. 108, 59652 Villeneuve dꢀAscq, France
Received 17 September 2003; revised 12 November 2003; accepted 18 November 2003
Abstract—We describe the three-step synthesis of a novel 4,5-dihydro-3H-spiro[1,5-benzoxazepine-2,40-piperidine] scaffold from
ortho-hydroxyacetophenone and N-benzylpiperidone. The structure of one disubstituted derivative, studied by NOESY NMR in an
aqueous medium and X-ray diffraction, demonstrates that this scaffold presents side chains in a well-defined orientation. The Boc
protected derivative represents a key intermediate for the combinatorial synthesis of drug-like molecules.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Privileged structures in drug discovery
collapseꢀ.3 With the generalisation of high throughput
screening in the drug discovery process, there has been
significant interest in the incorporation of structural
features (substructures or scaffolds) of privileged struc-
tures in the design of chemical libraries.4 It has been
shown that biological activity and specificity of com-
pounds based on privileged structures can easily be
modulated with minor changes in the nature of the
substituents.5;6
Privileged structures represent molecular frameworks
capable of binding to several diverse biological receptors
with high affinity. Since its introduction by Evans et al.1
for 1,4-benzodiazepine-2-ones, the term privileged
structures has appeared in the literature many times to
define structures as diverse as 1,4-dihydropyridines,
benzylpiperidines or even cyclic peptides. These struc-
tures need to be distinguished from ꢁfrequent hittersꢀ
such as those described by Roche et al.,2 which either
bind nonspecifically to a variety of targets or interfere
with the read-out of biological assays. A structural
rather than biological definition of a privileged structure
was thus provided by IUPAC as a ꢁsubstructural feature
which confers desirable (often drug like) properties on
compounds containing that feature. It often consists of a
semi-rigid scaffold, which is able to present multiple
hydrophobic residues without undergoing hydrophobic
1.1. 4,5-Dihydro-3H-spiro[1,5-benzoxazepine-2,40-
piperidine]: a new scaffold for library design
We report here the design of a scaffold suitable for the
preparation of combinatorial libraries. In designing our
new scaffold, our intention was to meet the IUPAC
requirements for a privileged structure. This scaffold
combines two substructures: 1,5-benzoxazepine and
spiro piperidine leading to the 4,5-dihydro-3H-spiro[1,5-
benzoxazepine-2,40-piperidine]
semi-rigid
scaffold
(structure A in Fig. 1). Although the preparation of
spirocyclic systems of this type has not yet been pub-
lished, related spirocycles endowed with various bio-
activities have been reported. Spiro[piperidine-pyrrolo[2,
1-c]-[1,4]-benzoxazepines] (type B) have been shown to
be analgesic and antihypertensive agents,7 whilst
Keywords: Benzoxazepine; Piperidine; Scaffold; Privileged structures;
X-ray.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2003.11.079.
* Corresponding author. Tel.: +33-3-20-96-4024; fax: +33-3-20-96-47-
09; e-mail: nwilland@pharma.univ-lille2.fr
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.079

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N. Willand et al. / Tetrahedron Letters 45 (2004) 1051–1054
H
N
O
O
O
H
N
O
H
N
CH3
OH
a
N
+
N
O
O
N
N
H
NH
O
A
B
C
1
2
3
Figure 1. Structures of scaffold type A and spiro scaffolds of types B
and C.
OH
H
N
N
b
spiro[benzoxazepine-2,40-piperidine] (type C) bind to
sigma receptors (Fig. 1).8
c
O
O
N
N
Due to the presence of two nitrogen atoms of well-
defined chemical reactivity, various substituents can be
attached and projected in a conformationally restricted
manner in the three spatial directions. Moreover the
HCl salt of 6, despite bearing two hydrophobic sub-
stituents, displays remarkable water solubility (>10 mg/
mL at pH ¼ 1 and >50 lg/mL at pH ¼ 7.4).
4
5
Me
N
O
d
N
6
2. Synthetic approach
Scheme 2. Reagents and conditions: (a) pyrrolidine, MeOH, reflux
18 h, 98%; (b) NH2OHÆHCl, pyridine, EtOH, reflux 2 h, 64%; (c) DI-
BAL-H, CH2Cl2, 0 ꢁC, 3 h then MeOH, H2O, 20% H2SO4 (30 min),
then 30% NaOH to pH 9, 50%; (d) 4-methylbenzaldehyde,
NaBH(OAc)3, CH2Cl2, 18 h, rt, 70%.
In our synthetic approach, we designed a strategy that
permits the rapid and efficient synthesis of derivatives
from simple and commercially available ortho-
hydroxyacetophenones
and
N-benzyl-piperidone
(Scheme 1). Compound 3 was obtained in quantitative
yield by refluxing bis-nucleophile 1 (1 equiv) with 2
(1 equiv) in methanol, in the presence of a catalytic
amount of pyrrolidine (0.5 equiv). Oxime 4 was formed
in a refluxing ethanolic solution of hydroxylamine
hydrochloride (2 equiv), pyridine (2 equiv) and com-
pound 3 (1 equiv). The key step for the preparation of 5
was the ring expansion. The one-pot synthesis of het-
erocyclic fused azepines using diisobutylaluminium hy-
dride (DIBAL-H) from oximes has been studied by Cho
et al.9 In contrast to the classical two-step Beckmann
synthesis, which requires the preparation of a lactam
intermediate and its reduction, this procedure yields the
desired oxazepine directly. However, when using the
described conditions, the product decomposed rapidly
during work-up. Exchanging potassium fluoride for 20%
sulfuric acid for the cleavage of the nitrogen–aluminium
complex, the desired compound 5 was recovered in
dichloromethane after basification to pH 9 using a 30%
sodium hydroxide solution. The target compound 5 was
obtained as an oil, which crystallised, in three steps with
an overall yield of 31% (Scheme 2).10
3. Structural studies
In order to exemplify the possibility of introducing an
additional substituent on the azepine nitrogen, 5 was
alkylated with 4-methylbenzaldehyde (1.1 equiv) and
sodium triacetoxyborohydride (2 equiv) in CH2Cl2 to
give 6 in 70% yield. The relative orientations of the
scaffold and the two side-chains in 6 were studied by 2D
NMR in CDCl3 and D2O/DCl and by X-ray crystal-
1
lography. The H NMR spectrum of compound 6, in
D2O/DCl and in CDCl3, showed only one set of signals
that could be attributed to 6a, one of the two possible
chair conformations of the piperidine illustrated in
Figure 2.
The H12ax and H16ax protons appeared as a multiplet,
showing one large geminal coupling (J2 ¼ 12:65 Hz),
one large trans-axial coupling with H13ax and H15ax
(J3 ¼ 12:04 Hz), and one cis coupling (J3 ¼ 4:71 Hz)
with H13eq and H15eq. In addition the H12eq, H16eq and
R1
O
H
N
N
O
O
CH3
+
Ar
Ar
Ar
N
OH
PG
O
N
N
PG
R2
Scheme 1.

N. Willand et al. / Tetrahedron Letters 45 (2004) 1051–1054
1053
ligands for diverse receptors (GPCRs, metallo-protease)
depending on the side-chains attached and other modi-
fications.
1
R
N
O
13ax
15ax
3
17
N
6a
6b
12ax
16ax
Supplementary material
12ax
16ax
Experimental procedures for syntheses of 3, 4, 6, 7 and
an ORTEP drawing of compound 6 (CCDC 224676).
O
N
17
3
13ax
15ax
N
R1
Acknowledgements
Figure 2. NOESY NMR spectrometry in CDCl3 and D2O/DCl. Solid
arrows: observed cross-signals, dotted lines: cross-signals not observed,
R1 ¼ 4-methylbenzyl.
ꢀ
The authors thank Gerard Montagne and Nathalie
Azaroual for NMR experiments and Andre Tartar for
helpful contributions.
H13eq, H15eq protons appeared as doublets showing one
large geminal coupling. In the NOESY spectrum, H3 of
the azepine ring gave cross-signals with H12ax and
H16ax. Both H17 protons gave cross-signals with H13ax
and H15ax. No cross-signals between H3 and H13ax, or
H15ax could be detected (Fig. 1). This experiment con-
firmed the presence of conformation 6a, which is ener-
getically favoured both in CDCl3 and D2O/DCl.
References and notes
1. Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber,
D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.;
Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.;
Springer, J. P.; Hirschfield, J. J. Med. Chem. 1988, 31,
2235.
2. Roche, O.; Schneider, P.; Zuegge, J.; Guba, W.; Kansy,
M.; Alanine, A.; Bleicher, K.; Danel, F.; Gutknecht,
E.-M.; Rogers-Evans, M.; Neidhart, W.; Stalder, H.; Dillon,
M.; Sjogren, E.; Fotouhi, N.; Gillespie, P.; Goodnow, R.;
Harris, W.; Jones, P.; Taniguchi, M.; Tsujii, S.; von der
Saal, W.; Zimmermann, G.; Schneider, G. J. Med. Chem.
2002, 45, 137.
Compound 6 also adopts the same conformation in the
crystal as shown by the ORTEP drawing of the X-ray
diffraction analysis. Thus 4,5-dihydro-3H-spiro[1,5-
benzoxazepine-2,40-piperidine] acts as a semi-rigid scaf-
fold, able to present various substituents without
undergoing hydrophobic collapse and behaves struc-
turally as a privileged structure.
3. Maclean, D. Pure Appl. Chem. 1999, 71, 2349.
4. Abrous, L.; Hynes, J.; Friedrich, R. S.; Smith, A. B., III,
Hirschmann, R. Org. Lett. 2001, 3, 1089.
5. Willoughby, C. A. et al. Bioorg. Med. Chem. Lett. 2002,
12, 93.
4. A key intermediate for combinatorial synthesis
6. Poulain, R.; Horvath, D.; Bonnet, B.; Eckhoff, C.;
Chapelain, B.; Bodinier, M.-C.; Deprez, B. J. Med. Chem.
2001, 44, 3391.
7. Effland, R. C.; Davis, L. B. L.; Kapples, K. J. European
Patent EP 0 301 426 A1, 1988.
8. (a) Radeke, H.; Resons, P.; Hauske, J. WO 01/12630 A1,
2001; (b) Cossy, J.; Poitevin, C.; Gomez Pardo, D. J. Org.
Chem. 1998, 63, 4554.
To exploit fully the potential of this scaffold in parallel
synthesis, compound 5 was debenzylated by Pd-cataly-
sed hydrogenation and selectively protected with a Boc
group, to yield compound 7 (Scheme 3). This scaffold is
currently being substituted with target-specific pharma-
cophores to demonstrate that it is able to provide
9. Cho, H.; Murakami, K.; Nakanishi, H.; Isoshima, H.;
Hayakawa, K.; Uchida, I. Heterocycles 1998, 43, 919.
10. Oxime 4 (3 g, 9.3 mmol, 1 equiv) was solubilised in
anhydrous dichloromethane (20 mL). The mixture was
stirred at 0 ꢁC for 30 min, and (1 N) diisobutylaluminium
hydride in dichloromethane (54 mL, 54 mmol, 5.8 equiv)
was added dropwise over 1 h. The mixture was stirred for
3 h under nitrogen at 0 ꢁC. The reaction was quenched by
slowly adding MeOH (9 mL), followed by distilled water
(9 mL) and 20% sulfuric acid (50 mL). The solution was
stirred for a further 20 min. The solution was basified to
pH 9 using a 30% sodium hydroxide solution. The
resulting mixture was extracted with ethyl acetate
(2 · 100 mL). The organic layer was dried (MgSO4) and
concentrated to give a yellow oil. The residue was purified
by chromatography on alumina oxide with cyclohexane/
ethyl acetate (1/1, v/v) to give 1.5 g of a yellow oil, which
H
N
H
N
a
O
O
N
N
O
O
CH3
CH3
5
7
H3C
Combinatorial Libraries
Scheme 3. Reagents and conditions: (a) (i) H2, Pd/C (10%), MeOH,
18 h; (ii) Boc2O (1.05 equiv), Et3N (2 equiv), DCM/dioxane, 2 h, 66%
(two steps).

1054
N. Willand et al. / Tetrahedron Letters 45 (2004) 1051–1054
crystallised. Yield: 52%. Mp: 99.0–101 ꢁC. 1H NMR
6.53 (dd, 1H, J ¼ 7:73 Hz, J ¼ 1:62 Hz); 6.63 (td, 1H,
J ¼ 7:55 Hz, J ¼ 1:59 Hz); 6.77 (td, 1H, J ¼ 7:45 Hz,
J ¼ 1:52 Hz); 6.87 (dd, 1H, J ¼ 7:78 Hz, J ¼ 1:55 Hz);
7.15–7.30 (m, 5H). 13C NMR d: 34.3; 40.2; 40.9; 48.7; 62.6;
117.7; 119.1; 123.0; 123.8; 126.2; 127.4; 127.4; 128.5; 137.7;
141.8. MS (MH)þ m=z 309 (100%).
(300 MHz, CDCl3) d: 1.54 (ddd, 2H, J ¼ 12:85 Hz,
J ¼ 12:60 Hz, J ¼ 4:62 Hz); 1.82 (t, 2H, J ¼ 5:16 Hz);
1.86
(dm,
2H,
J ¼ 12:60 Hz);
2.40
(ddm,
2H, J ¼ 12:60 Hz, J ¼ 11:41 Hz); 2.51 (dm, 2H,
J ¼ 11:41 Hz); 3.18 (t, 2H, J ¼ 5:16 Hz), 3.47 (s, 2H);