The spiropiperidine-3,3′-oxindole scaffold: a type II β-turn peptide isostere

Article abstract of DOI:10.1016/j.tet.2010.04.077

An unprecedented chiral spiropiperidine oxindole system was synthesized starting from enantiopure quaternary 3-aminooxindole and relying on a ring closing metathesis as the key step. This compound acts as an highly constrained Freidinger γ-lactam, adopting a type II β-turn conformation in solution, as assessed by modelling and spectroscopical studies.

Full text of DOI:10.1016/j.tet.2010.04.077

Tetrahedron 66 (2010) 4474e4478
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The spiropiperidine-3,30-oxindole scaffold: a type II
b-turn peptide isostere
,
Giordano Lesma a, Nicola Landoni a, Alessandro Sacchetti b, Alessandra Silvani a
*
a Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, via G. Venezian 21, 20133 Milano, Italy
b Politecnico di Milano, Dipartimento di Chimica, Materiali ed Ingegneria Chimica ‘Giulio Natta’, via Mancinelli 7, 20131 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
An unprecedented chiral spiropiperidine oxindole system was synthesized starting from enantiopure
quaternary 3-aminooxindole and relying on a ring closing metathesis as the key step. This compound
Received 5 February 2010
Received in revised form 30 March 2010
Accepted 19 April 2010
acts as an highly constrained Freidinger
g
-lactam, adopting a type II
b
-turn conformation in solution, as
assessed by modelling and spectroscopical studies.
Available online 24 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Peptidomimetics
Spiro compounds
Metathesis
Conformation analysis
Oxindole
1. Introduction
oxindoles are important targets in organic synthesis7 due to their
frequent occurrence in natural products8 and biologically relevant
molecules9 (Fig. 1). Diverse oxindole derivatives were used as non-
peptide scaffolds10 in the search for peptidomimetics either as
enzyme inhibitors or as ligands of G-protein-coupled receptors.11
b-turns represent an important recognition element of peptides
and proteins and are considered as initiation sites for protein
folding.1 Consequently, it is not surprising that a major challenge in
the field of peptidomimetics is the design and synthesis of con-
formationally constrained analogues that mimic these essential
O
Cl
Me
secondary structural elements.2 Nowadays,
b-turn based pharma-
N
N
cophore design has become a central topic in medicinal chemistry.3
A general approach to the synthesis of peptidomimetic com-
pounds involves the use of non-peptide building blocks, which
N
MeO
O
Br
N
N
N
H
Br
H
1
2
: Chartelline C
: Horsfiline
enforce or stabilize a particular type of
a peptide chain. A pioneer in this field is Freidinger, who developed
dipeptide -, -, -lactams as constrained scaffolds to stabilize turn
b-turn, when inserted into
OH
g
d 3
TolHN
HN
O
N
conformations.4 In his approach, the lactam ring acts as the
bridging element of the betagenicd(iþ1)ꢀ(iþ2)dcentral residue
and can bring recognition groups for interaction with the receptor
or enzyme active site. In particular, hydrophobic and aromatic
moieties often play an important role in recognition and activation
of receptors possessing lipophilic domains, and this is why many
ligand mimics contain these elements.
HO
O
O
N
NHTol
Cl
R
N
CONMe2
O
O
O
O
N
S
N
O
OEt
OEt
H
O
O
3: gastrin/CCK-B receptor 4: vasopressin VIb receptor 5: HIV protease inhibitor
antagonist AG-041R antagonist SSR-149415
In the course of a program directed towards the search for new
methodologies to access pharmaceutically relevant heterocyclic
scaffolds,5 we recently developed a new protocol for the asymmetric
synthesis of quaternary 3-aminooxindoles.6 3,30-Disubstituted
Figure 1. Representative 3,30-disubstituted oxindole-containing natural products (1
and 2) and drugs (3e5).
For instance, in searching for new HIV-1 protease inhibitors that
maintain their potencies against mutant strains of HIV, a series of
novel oxyindole-derived HIV-1 protease inhibitors were designed
and synthesized and the effects of substituents, spirocyclic rings
* Corresponding author. Tel.: þ39 02 50 31 40 80; fax: þ39 02 50 31 40 78; e-mail
address: alessandra.silvani@unimi.it (A. Silvani).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.077

G. Lesma et al. / Tetrahedron 66 (2010) 4474e4478
4475
and ring sizes on the activity have been investigated.12 Besides, the
oxindole framework is the essential feature of orally active non-
peptide arginine-vasopressin receptor antagonists, such as SSR-
149415 and of growth hormone secretagogue (ghrelin) receptors
agonists.13 At the end, the 3-aminooxindole structure is the key
pharmacophore in compound AG-041R, a potent gastrin/CCK-B
receptor antagonist.14
definition of
of the amide backbone for the global minimum of 6, ascribes this
compound to a type II -turn (Table 2). The same global minimum
b-turn types, the analysis of the dihedral angle values
b
was found, both in vacuo and in water, the latter being implicitly
represented by a solvation model.19
Table 2
Calculated values of selected geometrical parameters for the MM/MC lowest energy
conformer of 6
2. Results and discussion
Compd
F(iþ1)
(deg)
;
j(iþ1)
F(iþ2)
(deg)
;
j(iþ2)
d(C
(Å)
a
(i)/Ca(iþ3)
)
b
(deg)
9.65
The light of the relevance of the oxindole nucleus, mainly as key
framework of non-peptidic ligands for G-protein-coupled re-
ceptors, we report here the synthesis of the spiropiperidine-3,30-
6
ꢀ52.00; 126.53 101.71; ꢀ30.37 5.472
-turn (ideal) ꢀ60; 120 80; 0 4.745
II
b
ꢀ1.95
oxindole-based peptide isostere 6, acting as a potent type II b-turn
The similarity between 6 and a type II b-turn model was eval-
mimetic (Fig. 2). Spiro compounds having cyclic structures fused at
a central carbon are of recent interest due to their structural
implications on biological systems.15 Compound 6 can be regarded
uated by superimposing their amide backbone. An alignment score
of 0.9520 was obtained, thus confirming the good ability of 6 to
mimic such a secondary structure (Fig. 3).
as an highly constrained Freidinger
g-lactam, bearing a fused
aromatic ring as recognition group and a spiropiperidine ring as
further element of conformational restriction.
n
C
N
2
C
1
C1
O
O
N
C
H
3
N4
C
4
O
n from 0 to 3
For n=2, compound 6
Figure 2. Parameters for the characterization of
based scaffolds.
b-turn propensity of spirooxindole-
Figure 3. Lowest energy conformer for 6 obtained by MC/MM calculations. Superim-
position with standard type II b-turn (in green) is shown.
The reverse turn mimicry ability of spirooxindole scaffolds was
firstly evaluated by performing a computer-assisted16 conforma-
tional analysis on compounds like 6, as a function of the dimension
of the spiro ring in position 3 of the oxindole skeleton. The com-
On the basis of predictions from computational studies, we then
focused our attention to the synthesis of compound 6, according to
the Scheme 1. We recently developed the diastereoselective
Grignard addition of imines derived from isatine.6 Following the
described protocol, amine 7 could be obtained in good yield as a 3S
single enantiomer. Acetylation of 7 with acetic anhydride to give 8,
followed by allylation of the amide nitrogen with allyl bromide,
afforded diene 9 in good overall yields. Diene 9 was submitted to
a ring closing metathesis reaction (RCM) with Grubbs’ second
generation catalyst in refluxing toluene.21 The spirooxindole 10 was
obtained in 79% yield after chromatographic purification. 1H NMR
investigation revealed the metal-promoted shift to enamide of the
newly formed double bond. Hydrogenation of the double bond to
puted main geometric features of
tance d (C
torsion angle
b-turns are the interatomic dis-
a
a1eCa4), which should be less than 7 Å, the virtual
b
(C1eC
a
2eC
a
3eN4), which should be j
b
j <30ꢁ and
the possible presence of the characteristic hydrogen bond
C1O/HN4, that was estimated by means of the ‘hydrogen bonds’
function implemented in the software.17 The computational
procedure consisted in an unconstrained Monte Carlo/Energy
Minimization conformational search using the molecular
mechanics MMFF94 force field18 in vacuo. For each compound only
conformations within 6 kcal/mol of the global minimum were kept.
Results are reported in Table 1 as percentage of conformers, which
meet the requirements for a generic b-turn.
Table 1
MC/EM conformational analysis for spirooxindole-based scaffoldsa
N
No. of conf. <6 kcal/mol
% da<7 Å
% j
b
j<30ꢁ
% H bond
0
1
2
3
8
4
6
4
50
50
67
50
50
50
67
50
25
50
67
50
a
Results are reported as percentage of conformers, which meet the indicated
requirement.
The highest percentage of conformers having a b-turn geometry
is achieved by oxindole 6, bearing a spiropiperidine ring (n¼2). For
this structure, 67% of conformers have d
show a ten membered intramolecular hydrogen bond. According to
a
<7 Å, j
b
j <30ꢁ and also
Scheme 1.

4476
G. Lesma et al. / Tetrahedron 66 (2010) 4474e4478
give 11 was followed by removal of PMB protecting group with
CF3SO2H/anisole. The resulting 12 was subjected to alkylation with
methyl bromoacetate to afford 13, and then treated with methyl-
amine to give the desired tetrapeptide mimetic 6.
d
¼0 ppm for 1H NMR and to CDCl3 at
d
¼77.16 ppm for 13C NMR.
High-resolution MS spectra were recorded using a FT-ICR (Fourier
Transform Ion Ciclotron Resonance) instrument, equipped with ESI
source, or a standard MS instrument, equipped with EI source. IR
spectra were recorded using a FTIR instrument.
The spiropiperidine oxindole 6 was fully characterized by means
of 1D- and 2D-dimensional NMR spectroscopy. The study of con-
formational behaviour was conducted in CDCl3, at 2.0 mM con-
centration to avoid intermolecular aggregation, in order to assess
the presence of the intramolecular hydrogen bond.22 The partici-
pation of the NH amide proton in intramolecular hydrogen bonding
was first estimated by evaluation of its chemical shift value and of
the temperature coefficient, recording five spectra from 303 K to
343 K with increments of 10 K. Downfield chemical shift value
(7.80 ppm at 303 K) and small temperature coefficient (ꢀ3.6 ppb/K)
were found, thus supporting the involvement of NH in an equilib-
rium between a hydrogen-bonded and a non-hydrogen-bonded
state. Besides, DMSO titration studies in CDCl3 indicate that the
chemical shift of NH in 6 is almost constant up to 30% of the
hydrogen bond-acceptor solvent DMSO (chemical shift difference
of 0.16 ppm in absolute value), thus confirming the presence of
a rather stable intramolecular H-bonded conformation. From NMR
4.1.1. N-[(S)-3-Allyl-1-(4-methoxy-benzyl)-2-oxo-2,3-dihydro-1H-
indol-3-yl]-acetamide (8). To
0.23 mmol,1 equiv) in dry CH2Cl2 (3 mL) at 0 ꢁC and under nitrogen
atmosphere, i-Pr2NEt (59 L, 0.34 mmol,1.5 equiv) and Ac2O (32 L,
0.34 mmol, 1.5 equiv) were added. The solution was stirred for 2 h
at room temperature before addition of 5% aq H3PO4 solution
(5 mL). Then the aqueous layer was extracted twice with CH2Cl2
(10 mL). The collected organic phases were dried over Na2SO4 and
evaporated under reduced pressure to afford 8 (65 mg, 85%) as
a solution of amine 7 (70 mg,
m
m
a clear oil, which was used in the next step without any further
25
purification. Rf¼0.38 (EtOAc). [
a]
ꢀ32.6 (c 1.0, CHCl3). 1H NMR
D
(400 MHz, CDCl3,
d
) 7.35 (d, J¼8.6 Hz, 2H), 7.22 (dd, J¼7.5, 0.6 Hz,
1H), 7.16 (ddd, J¼7.8, 7.5, 1.1 Hz, 1H), 7.03 (ddd, J¼7.8, 7.5, 0.6 Hz,
1H), 6.89 (d, J¼8.6 Hz, 2H), 6.69 (d, J¼7.8 Hz, 1H), 6.26 (s, 1H), 5.81
(ddt, J¼17.3, 10.0, 7.5 Hz, 1H), 5.29 (dd, J¼17.3, 1.4 Hz, 1H), 5.25 (br d,
J¼10.0 Hz, 1H), 4.96 (d, J¼15.8 Hz, 1H), 4.93 (d, J¼15.8 Hz, 1H), 3.79
(s, 3H), 2.70 (dd, J¼13.4, 7.6 Hz, 1H), 2.54 (dd, J¼13.4, 7.2 Hz, 1H),
spectra,
a prevalent rotamer seems to be present for the
acetylepiperidine moiety; further, the NOESY experiment high-
lights a strong NOE interaction between the acetyl group and the
NeCH2 protons of the piperidine ring, only detectable in a
H-bonded conformation similar to that shown in Figure 3. Finally,
a further probe of a constrained conformation for 6 was derived
from 1H NMR analysis of the AB system of the geminal glycyl res-
idue,23 comparing the chemical shift difference in CDCl3 between
0
2.00 (s, 3H). 13C NMR (100 MHz, CDCl3,
d) 176.0, 168.9, 158.9, 142.6,
130.3, 129.6, 128.7, 128.5 (2C), 127.8, 122.5, 122.4, 121.3, 114.1 (2C),
109.5, 60.7, 55.2, 43.6, 41.8, 22.7. HRMS (EI) calcd for C21H22N2O3
350.1630, found 350.1626.
4.1.2. N-Allyl-N-[(S)-3-allyl-1-(4-methoxy-benzyl)-2-oxo-2,3-dihy-
the two
a
-protons, Dda a , in the case of non-hydrogen bonded
dro-1H-indol-3-yl]-acetamide (9). A solution of
0.23 mmol, 1 equiv), Bu4NBr (73 mg, 0.23 mmol, 1 equiv) and allyl
bromide (96 L, 1.14 mmol, 5 equiv) in dry DMF (5 mL) was stirred
8
(80 mg,
/
compound 13 and in the case of hydrogen bonded compound 6.
This difference was found 0.72 ppm for 13 and 0.92 ppm for 6, thus
suggesting the strong preference of 6 for a turn state.
The FT-IR spectrum of a 2.0 mM solution of 6 in CHCl3 showed
a strong absorption band at 3350 cmꢀ1 for an hydrogen-bonded NH
stretching together with a weak band at 3438 cmꢀ1 for the non-
hydrogen-bonded NH stretching, in accordance with the preva-
lence of a conformational constrained state in this molecule.
m
for 20 min at 0 ꢁC under a nitrogen atmosphere. After that time,
95% NaH (16 mg, 0.68 mmol, 3 equiv) was added and the solution
was stirred at room temperature for 1 h. The reaction was then
diluted with water (10 mL) and extracted three times with ethyl
acetate (15 mL). The organic phase was dried over Na2SO4 and
evaporated under reduced pressure, to give a crude product, which
was purified with flash chromatography (hexane/EtOAc 1:7) to
25
3. Conclusions
afford 9 (62 mg, 70% yield), as a clear oil. Rf¼0.31 (EtOAc). [
a]
D
ꢀ41.9 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3,
) 7.38 (d, J¼8.7 Hz,
d
In summary, we have prepared a spiropiperidine oxindole-
based peptide isostere, with the purpose of exploring its confor-
mational behaviour. The synthesis starts from
described enantiopure quaternary 3-aminooxindole and relies on
a ring closing metathesis as the key step for attaining the
spiropiperidine ring. Conformational analysis by means of model-
ling and NMR and IR spectroscopies assesses a type II
conformation for this compound. Work is now underway to eval-
uate the application of this novel spirocyclic peptide isostere to the
2H), 7.15 (d, J¼7.2 Hz, 1H), 7.14 (ddd, J¼7.7, 7.2, 0.9 Hz, 1H), 6.98
(ddd, J¼7.7, 7.2, 0.6 Hz, 1H), 6.87 (d, J¼8.7 Hz, 2H), 6.65 (d, J¼7.7 Hz,
1H), 6.07 (dddd, J¼17.2, 10.6, 5.2, 4.0 Hz, 1H), 5.69 (d, J¼17.2, 1H),
5.44 (d, J¼10.6, 1H), 5.18 (ddt, J¼17.1, 9.8, 7.0 Hz, 1H), 4.99 (d, J¼17.1,
1H), 4.94 (d, J¼16.1, 1H), 4.88 (d, J¼9.8, 1H), 4.81 (d, J¼16.1, 1H), 4.39
(ddt, J¼18.8, 4.0, 1.9 Hz, 1H), 4.30 (ddt, J¼18.8, 5.2, 1.6 Hz, 1H), 3.80
(s, 3H), 2.86 (dd, J¼12.4, 7.0, 1H), 2.80 (dd, J¼12.4, 7.0, 1H), 2.10 (s,
a previously
b-turn
3H). 13C NMR (100 MHz, CDCl3,
d) 176.1, 170.8, 158.8, 143.4, 135.0,
134.3, 129.9, 129.2, 128.8 (2C), 128.3, 122.1, 121.6, 120.2, 117.6, 113.9
(2C), 108.8, 66.1, 55.2, 47.6, 43.7, 40.0, 22.5. HRMS (EI) calcd for
C24H26N2O3 390.1943, found 390.1956.
synthesis of b-turned ligands for G-protein-coupled receptors.
4. Experimental section
4.1. General methods
4.1.3. (S)-10-Acetyl-1-(4-methoxy-benzyl)-30,4’-dihydro-spiro[indo-
line-3,20-pyridin]-2-one (10). To a solution of 9 (140 mg, 0.36 mmol,
1 equiv) in dry toluene (3 mL) under nitrogen atmosphere, second
generation Grubbs’ catalyst (31 mg, 10% mol) was added and the
solution was heated to reflux for 24 h. The solution was then
evaporated under reduced pressure and the crude product was
All solvents were distilled and properly dried, when necessary,
prior to use. All chemicals were purchased from commercial sour-
ces and used directly, unless indicated otherwise. All reactions were
run under N2, unless otherwise indicated. All reactions were
monitored by thin layer chromatography (TLC) on precoated silica
gel 60 F254; spots were visualized with UV light or by treatment
with 1% aqueous KMnO4 solution. Products were purified by flash
chromatography on silica gel 60 (230e400 mesh). 1H and 13C NMR
spectra were recorded using 300 and 400 MHz spectrometers.
purified by flash chromatography (hexane/EtOAc 1:9) to afford 10
25
(100 mg, 79%), as a brown oil. Rf¼0.31 (EtOAc). [
a
]
D
ꢀ17.6 (c 1.0,
CHCl3). 1H NMR (400 MHz, CDCl3,
d
) 7.37 (d, J¼8.6 Hz, 2H), 7.17 (d,
J¼7.1 Hz, 1H), 7.16 (ddd, J¼7.6, 7.1, 1.2 Hz, 1H), 6.97 (ddd, J¼7.6, 7.1,
0.8 Hz, 1H), 6.89 (d, J¼8.6 Hz, 2H), 6.84 (dd, J¼7.8, 1.4 Hz, 1H), 6.70
(d, J¼7.6 Hz, 1H), 5.19 (br t, J¼7.8 Hz, 1H), 4.99 (d, J¼15.8 Hz, 1H),
4.92 (d, J¼15.8 Hz, 1H), 3.80 (s, 3H), 2.43e2.35 (m, 1H), 2.34e2.25
Chemical shifts (d) are expressed in ppm relative to TMS at

G. Lesma et al. / Tetrahedron 66 (2010) 4474e4478
4477
(m, 2H), 2.19 (s, 3H),1.77e1.70 (m, 1H). 13C NMR (100 MHz, CDCl3,
176.2, 167.3, 158.9, 142.1, 131.1, 128.5 (3C), 128.1, 126.4, 122.5, 122.2,
114.1 (2C), 109.3, 106.3, 61.2, 55.2, 43.6, 31.2, 21.7, 18.0. HRMS (EI)
calcd for C22H22N2O3 362.1630, found 362.1622.
d)
under reduced pressure affording pure 6 (20 mg, 93%), as a pale
25
yellow foam. Rf¼0.29 (EtOAc). [
(CHCl3) 3438.46, 3350.71, 1669.09, 1644.98, 1601.59, 1467.56,
1380.78, 1096.33. 1H NMR (400 MHz, CDCl3,
) 7.73 (br s, 1H),
a]
ꢀ17.0 (c 1.0, CHCl3). FTIR nmax
D
d
7.33e7.27 (m, 2H), 7.08 (ddd, J¼8.0, 7.5, 1.0 Hz, 1H), 6.83 (dd, J¼8.0,
0.9 Hz, 1H), 4.89 (d, J¼17.2 Hz, 1H), 3.97 (d, J¼17.2 Hz, 1H), 3.94 (dt,
J¼13.0, 5.0 Hz, 1H), 3.69 (dt, J¼13.0, 7.4 Hz, 1H), 2.74 (d, J¼4.7 Hz,
3H), 2.10 (s, 3H), 2.08e1.94 (m, 4H), 1.89e1.78 (m, 1H), 1.71 (dt,
4.1.4. (S)-10-Acetyl-1-(4-methoxy-benzyl)spiro[indoline-3,20-piper-
idin]-2-one (11). To a solution of 10 (100 mg, 0.28 mmol, 1 equiv)
in MeOH (5 mL), 10% Pd/C (10 mg) was added and the reaction
was stirred at room temperature under a hydrogen atmosphere
for 3 days. The suspension was then filtered through a pad of
J¼13.7, 4.7 Hz, 1H). 13C NMR (100 MHz, CDCl3,
d) 170.8, 167.6, 141.4,
130.8, 128.7, 122.8, 122.3, 108.6, 62.1, 44.1, 43.5, 32.6, 29.6, 26.1, 23.4,
22.3, 16.5. HRMS (EI) calcd for C17H21N3O3 315.1583, found
315.1588.
Celite and evaporated under reduced pressure to afford 11
25
(98 mg, 97%), as a pale yellow oil. Rf¼0.47 (EtOAc). [
a
]
ꢀ39.0 (c
D
1.0, CHCl3). 1H NMR (400 MHz, CDCl3,
d
) 7.34 (d, J¼8.6 Hz, 2H),
7.27 (d, J¼7.6 Hz, 1H), 7.14 (ddd, J1¼J2¼7.6 Hz, J3¼1.0 Hz, 1H), 6.96
(dd, J1¼J2¼7.6 Hz, 1H), 6.88 (d, J¼8.6 Hz, 2H), 6.68 (d, J¼7.6 Hz,
1H), 5.00 (d, J¼15.6 Hz, 1H), 4.86 (d, J¼15.6 Hz, 1H), 3.95 (dt,
J¼12.6, 5.1 Hz, 1H), 3.79 (s, 3H), 3.71e3.62 (m, 1H), 2.16e1.90 (m,
4H), 2.10 (s, 3H), 1.88e1.65 (m, 1H), 1.68 (dt, J¼13.5, 4.3 Hz, 1H).
References and notes
1. (a) Marcelino, A. M. C.; Gierasch, L. M. Biopolymers 2008, 89, 380e391 and
references therein; (b) Ball, J. B.; Hughes, R. A.; Alewood, P. F.; Andrews, P. R.
Tetrahedron 1993, 49, 3467e3478.
13C NMR (100 MHz, CDCl3,
d) 177.7, 171.3, 159.5, 143.0, 132.3, 129.1
2. For selected references about reverse-turn mimics, see: (a) Beierle, J. M.;
Horne, W. S.; van Maarseveen, J. H.; Waser, B.; Reubi, J. C.; Ghadiri, M. R. Angew.
Chem., Int. Ed. 2009, 48, 4725e4729; (b) Molteni, M.; Bellucci, M. C.; Bigotti, S.;
Mazzini, S.; Volonterio, A.; Zanda, M. Org. Biomol. Chem. 2009, 7, 2286e2296;
(c) Trabocchi, A.; Sladojevich, F.; Guarna, A. Chirality 2009, 21, 584e594; (d)
Arbor, S.; Kao, J.; Wu, Y.; Marshall, G. R. Biopolymers 2008, 90, 384e393; (e)
Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Benito, A.; Cuerdo, L.; Fratila, R. M.;
Jimenez, A.; Loinaz, I.; Miranda, J. I.; Pytlewska, K. R.; Micle, A.; Linden, A. Org.
Lett. 2004, 6, 4443e4446; (f) Gutierrez-Rodriguez, M.; Garcia-Lopez, M. T.;
Herranz, R. Tetrahedron 2004, 60, 5177e5183.
(3C), 128.7, 122.6, 122.4, 114.8 (2C), 110.0, 62.8, 55.8, 44.8, 44.2,
34.1, 24.4, 22.9, 17.6. HRMS (EI) calcd for C22H24N2O3 364.1787,
found 364.1792.
4.1.5. (S)-10-Acetylspiro[indoline-3,20-piperidin]-2-one (12). To a mix-
ture of 11 (30 mg, 0.08 mmol,1 equiv)and anisole (135
15 equiv) in dry CH2Cl2 (2 mL), at 0 ꢁC and under nitrogen atmo-
sphere, CF3SO2H (73 L, 0.82 mmol, 10 equiv) was added and the
mL,1.26 mmol,
3. Tyndall, J. D. A.; Pfeiffer, B.; Abbenante, G.; Fairlie, D. P. Chem. Rev. 2005, 105,
793e826.
m
4. (a) Freidinger, R. M. J. Med. Chem. 2003, 46, 5553e5566; (b) Freidinger, R. M.;
Perlow, D. S.; Veber, D. F. J. Org. Chem. 1982, 47, 104e109; (c) Freidinger, R. M.;
Veber, D. F.; Hirschmann, R.; Paege, L. M. Int. J. Pept. Protein Res. 1980, 16,
464e470.
5. (a) Lesma, G.; Landoni, N.; Pilati, T.; Sacchetti, A.; Silvani, A. J. Org. Chem. 2009,
74, 8098e8105; (b) Lesma, G.; Landoni, N.; Sacchetti, A.; Silvani, A. J. Org. Chem.
2007, 72, 9765e9768; (c) Lesma, G.; Meschini, E.; Recca, T.; Sacchetti, A.; Silvani,
A. Tetrahedron 2007, 63, 5567e5578.
reaction was stirred at room temperature for 3 h. The solution was
thenbasifiedwithsaturatedaqNaHCO3 solution (5 mL)and extracted
twice with CH2Cl2 (10 mL). The organic layer was separated, dried
over Na2SO4 and evaporated under reduced pressure. The crude was
purified with flash chromatography (EtOAc), to afford 12 (16 mg,
80%), asa paleyellowoil. Rf¼0.47 (EtOAc). [
a
]
25 ꢀ12.4 (c 1.0, CHCl3).1H
D
NMR (400 MHz, CDCl3,
d
) 7.55 (br s, 1H), 7.26 (d, J¼7.5 Hz, 1H), 7.24
6. Lesma, G.; Landoni, N.; Pilati, T.; Sacchetti, A.; Silvani, A. J. Org. Chem. 2009, 74,
4537e4541.
(dd, J¼7.7, 7.5 Hz, 1H), 6.99 (dd, J¼7.7, 7.5 Hz, 1H), 6.87 (d, J¼7.7 Hz,
1H), 3.93 (dt, J¼12.9, 4.8 Hz, 1H), 3.64 (ddd, J¼12.9, 9.0, 5.3 Hz, 1H),
2.11 (s, 3H), 2.10e2.05 (m, 1H), 2.05e1.89 (m, 3H), 1.87e1.76 (m, 1H),
7. (a) Ackermann, L.; Vicente, R.; Hofmann, N. Org. Lett. 2009, 11, 4274e4276; (b)
Felpin, F.-X.; Ibarguren, O.; Nassar-Hardy, L.; Fouquet, E. J. Org. Chem. 2009, 74,
1349e1352; (c) Qiao, X.-C.; Zhu, S.-F.; Zhou, Q.-L. Tetrahedron: Asymmetry 2009,
20, 1254e1261; (d) Kamisaki, H.; Yasui, Y.; Takemoto, Y. Tetrahedron Lett. 2009,
50, 2589e2592; (e) Arnott, G.; Brice, H.; Clayden, J.; Blaney, E. Org. Lett. 2008, 10,
3089e3092; (f) Kouznetsov, V. V.; Bello Forero, J. S.; Amado Torres, D. F. Tet-
rahedron Lett. 2008, 49, 5855e5857; (g) Shanmugam, P.; Viswambharan, B.;
Madhavan, S. Org. Lett. 2007, 9, 4095e4098; (h) Teng, D.; Zhang, H.; Mendonca,
A. Molecules 2006, 11, 700e706.
1.72 (dt, J¼13.4, 4.3 Hz,1H). 13C NMR (100 MHz, CDCl3,
d) 178.4,170.9,
140.4, 131.9, 128.3, 122.5, 121.9, 109.9, 62.2, 44.2, 33.2, 23.8, 22.4, 17.0.
HRMS (EI) calcd for C14H16N2O2 244.1212, found 244.1223.
4.1.6. (S)-Methyl 2-(10-acetyl-2-oxospiro[indoline-3,20-piperidine]-1-
yl)acetate (13). To a solution of 12 (35 mg, 0.14 mmol, 1 equiv) in
dry DMF (3 mL), NaH (7 mg, 0.28 mmol, 2 equiv) and methyl bro-
8. (a) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748e8758; (b)
Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209e2219.
9. (a) Kumar, R. R.; Perumal, S.; Senthilkumar, P.; Yogeeswari, P.; Dharmarajan, S. J.
Med. Chem. 2008, 51, 5731e5735; (b) Mendel, D. B.; Laird, A. D.; Xin, X. H.;
Louie, S. G.; Christensen, J. G.; Li, G. M.; Schreck, R. E.; Abrams, T. J.; Ngai, T. J.;
Lee, L. B.; Murray, L. J.; Carver, J.; Chan, E.; Moss, K. G.; Haznedar, J. O.; Suk-
buntherng, J.; Blake, R. A.; Sun, L.; Tang, C.; Miller, T.; Shirazian, S.; McMahon,
G.; Cherrington, J. M. Clin. Cancer Res. 2003, 9, 327e337; (c) Sun, L.; Liang, C.;
Shirazian, S.; Zhou, Y.; Miller, T.; Cui, J.; Fukuda, J. Y.; Chu, J. Y.; Nematalla, A.;
Wang, X. Y.; Chen, H.; Sistla, A.; Luu, T. C.; Tang, F.; Wei, J.; Tang, C. J. Med. Chem.
2003, 46, 1116e1119.
10. Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.; Gao, W.; Stuckey, J.;
Krajewski, K.; Roller, P. P.; Tomita, Y.; Parrish, D. A.; Deschamps, J. R.; Wang, S. J.
Am. Chem. Soc. 2005, 127, 10130e10131.
11. Blakeney, J. S.; Reid, R. C.; Le, G. T.; Fairlie, D. P. Chem. Rev. 2007, 107, 2960e3041.
12. Ghosh, A. K.; Schiltz, G.; Perali, R. S.; Leshchenko, S.; Kay, S.; Walters, D. E.; Koh,
Y.; Maedad, K.; Mitsuyad, H. Bioorg. Med. Chem. Lett. 2006, 16, 1869e1873.
13. Tokunaga, T.; Hume, W. E.; Umezome, T.; Okazaki, K.; Ueki, Y.; Kumagai, K.;
Hourai, S.; Nagamine, J.; Seki, H.; Taiji, M.; Noguchi, H.; Nagata, R. J. Med. Chem.
2001, 44, 4641e4649.
moacetate (27 mL, 0.28 mmol, 2 equiv) were added and the solution
was stirred for 2 h at 50 ꢁC. The reaction was then quenched with
saturated aq NH4Cl solution (4 mL) and extracted twice with EtOAc
(10 mL). The organic phase was then washed with brine (10 mL).
The organic layer was dried over Na2SO4 and evaporated under
reduced pressure, to afford 13 (31 mg, 67%), as a yellow oil, which
was used in the next step without further purification. Rf¼0.29
(EtOAc). [
a
]
25 ꢀ48.7 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3,
d) 7.30
D
(d, J¼7.7 Hz, 1H), 7.27 (dd, J¼7.9, 7.7 Hz, 1H), 7.03 (dd, J¼7.9, 7.7 Hz,
1H), 6.74 (d, J¼7.9 Hz, 1H), 4.91 (d, J¼17.7 Hz,1H), 4.20 (d, J¼17.7 Hz,
1H), 3.93 (dt, J¼12.9, 5.0 Hz, 1H), 3.78 (s, 3H), 3.70e3.61 (m, 1H),
2.12 (s, 3H), 2.10e1.88 (m, 4H), 1.87e1.80 (m, 1H), 1.77 (dt, J¼14.0,
4.1 Hz, 1H). 13C NMR (100 MHz, CDCl3,
d) 177.4, 171.5, 169.2, 142.5,
14. Sato, S.; Shibuya, M.; Kanoh, N.; Iwabuchi, Y. J. Org. Chem. 2009, 74, 7522e7524
and references cited therein.
15. Pradhan, R.; Patra, M.; Behera, A. K.; Mishra, B. K.; Behera, R. K. Tetrahedron
2006, 62, 779e828.
131.9, 128.9, 122.9 (2C), 108.8, 62.7, 53.0, 44.8, 42.1, 33.9, 24.3, 22.8,
17.5. HRMS (EI) calcd for C17H20N2O4 316.1423, found 316.1431.
16. Spartan’08, Wavefunction, Irvine, CA.
4.1.7. (S)-2-(10-Acetyl-2-oxospiro[indoline-3,20-piperidine]-1-yl)-N-
methylacetamide (6). To a solution of 13 (26 mg, 0.08 mmol,
1 equiv) in dry ethanol (3 mL), under nitrogen atmosphere and at
0 ꢁC, an 8 M solution of MeNH2 in EtOH (3 mL) was added. After
removing the cooling bath, the reaction mixture was stirred at
room temperature overnight. The solution was then evaporated
17. Hydrogen bonds are defined as non-bonded contacts between a nitrogen or
oxygen and an hydrogen attached to nitrogen or oxygen, separated by a dis-
tance ranging from 1.6 Å to 2.1 Å and making an XeHeY (X, Y¼N, O) angle
>120ꢁ.
18. Halgren, T. A. J. Comput. Chem. 1996, 17, 490e519.
19. The empirical solvation model SM.4 implemented in Spartan’08 was applied.
This model estimates the aqueous solvation energy. See also Chambers, C. C.;

4478
G. Lesma et al. / Tetrahedron 66 (2010) 4474e4478
Hawkins, G. D.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem.
16385e16398.
20. Score is reported as obtained by alignment score function implemented in the
Spartan ’08 software. The score is defined as [(1-R2)/N], where R2 is the rms.
distance between template and molecule centres and N is the number of
similarity centres.
A
1996, 100,
21. (a) Brik, A. Adv. Synth. Catal. 2008, 350,1661e1675; (b) Kotha, S.; Sreenivasachary,
N.; Mohanraja, K.; Durani, S. Bioorg. Med. Chem. Lett. 2001, 11, 1421e1423.
22. (a) Belvisi, L.; Gennari, C.; Mielgo, A.; Potenza, D.; Scolastico, C. Eur. J. Org. Chem.
1999, 389e400; (b) Gellman, S. H.; Dado, G. P.; Liang, G.; Adams, B. R. J. Am.
Chem. Soc. 1991, 113, 1164e1173 and references cited therein.
23. Tonan, K.; Ikawa, S. Spectrochim. Acta, Part A 2003, 59, 111e120.