Asymmetric modular synthesis of a semirigid dipeptide mimetic by cascade cycloaddition/ring rearrangement and borohydride reduction

Article abstract of DOI:10.1021/jo500237j

A new semirigid dipeptide mimetic was prepared on multigram scale, in good yield, and in a stereocontrolled way, starting from commercially available and unexpensive reagents, i.e., N-benzylpiperidone, tosyl azide, and proline methyl ester. The optimized multicomponent process consisted of a cascade click cycloaddition and a ring rearrangement reaction, followed by a reductive step. Theoretical calculations were performed to elucidate the reaction mechanism and support the stereochemical outcome of the reduction. Finally, the new scaffold was used for the preparation of model peptidomimetics, whose β turn conformation was confirmed by dynamic NMR experiments.

Full text of DOI:10.1021/jo500237j

Article
pubs.acs.org/joc
Asymmetric Modular Synthesis of a Semirigid Dipeptide Mimetic by
Cascade Cycloaddition/Ring Rearrangement and Borohydride
Reduction
Sara Pellegrino,*,† Alessandro Contini,† Maria Luisa Gelmi,† Leonardo Lo Presti,‡,§ Raffaella Soave,‡,§
and Emanuela Erba†
†Universita
‡Universita
̀
̀
degli Studi di Milano, DISFARM-Sez. Chimica Generale e Organica “A.Marchesini”, via Venzian 21, 20133 Milano, Italy
degli Studi di Milano, Dipartimento di Chimica, Via Golgi 19, 20133 Milano, Italy
§CNR- Istituto di Scienze e Tecnologie Molecolari, Via Golgi 19, 20133 Milano, Italy
S
* Supporting Information
ABSTRACT: A new semirigid dipeptide mimetic was
prepared on multigram scale, in good yield, and in a
stereocontrolled way, starting from commercially available
and unexpensive reagents, i.e., N-benzylpiperidone, tosyl azide,
and proline methyl ester. The optimized multicomponent
process consisted of a cascade click cycloaddition and a ring
rearrangement reaction, followed by a reductive step.
Theoretical calculations were performed to elucidate the reaction mechanism and support the stereochemical outcome of the
reduction. Finally, the new scaffold was used for the preparation of model peptidomimetics, whose β turn conformation was
confirmed by dynamic NMR experiments.
a cascade click cycloaddition and ring rearrangement reactions,
followed by a reductive step, was developed. Our challenge was
the preparation of 1 on a gram scale, controlling the
stereochemistry of the new stereocenters and without the
isolation of any intermediates (Scheme 1). Theoretical
INTRODUCTION
■
Peptidomimetics are small synthetic molecules able to mimic
peptides and protein fragments. Intense research has been
made on their development in the early 21st century.1 The
design and preparation of peptidomimetics able to selectively
perturb protein−protein interactions (PPI) is, in particular, an
important challenge for both chemical biology and medicinal
chemistry.2 The most applied approach is the use of rigid
scaffolds mimicking the secondary structure of the binding
portion involved in PPI.3 On the other hand, extreme rigidity is
desirable only if the obtained molecular shape is exactly
complementary to the binding partner, but most often PPIs rely
on an induced fit of the two interacting units. In order to fit in
the target, it is now commonly assessed that peptidomimetics
should have several kinetically and thermodynamically
accessible local minima representing conformations. As a result,
the use of semirigid mimetics of secondary protein structures is
a much more convenient approach.4
Scheme 1. Retrosynthesis of Reverse-Turn Peptidomimetic
calculations were performed to elucidate the reaction
mechanism and supported the stereochemical outcome. Finally,
compound 1 was used for the preparation of model
peptidomimetics, whose conformation was studied by NMR
technique.
The most prevalent nonrepetitive motif observed in proteins
is the four residues β turn, in which Pro and Gly are generally
found in the i+1 and i+2 positions.5 Many rigid scaffolds
mimicking this structural motif have been developed,6 and the
Pro-D-Pro or D-Pro-Pro sequences have demonstrated the
effective semirigid reverse turn nucleators.7 More recently, the
D-Pro-Pro motif has also been inserted into several peptides to
be used as low-loading organocatalysts, providing higher
catalytic activity and stereoselectivity than proline itself.8
In this work, a semirigid dipeptide mimetic 1, containing
piperidine and a NH-tosyl-functionalized pyrrolidine, was
designed and synthesized. An efficient protocol, consisting of
RESULTS AND DISCUSSION
■
Synthesis of Dipeptide Mimetics. Our researches have
been focused on the reactions between sulfonylazides and
enamines for a long time.9 We recently reported on a
multicomponent click reaction between morpholine, 1-
methyl-4-piperidone, and tosyl azide affording azacycloalkene
N-monosulfonyl diamines, formed through a 5-amino-1,2,3-
triazoline rearrangement.9a As proline is involved in β turn
Received: January 30, 2014
Published: March 17, 2014
© 2014 American Chemical Society
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Scheme 2. Mechanism of Multicomponent Reaction
induction, we envisioned the possibility to use this amino acid
as a secondary amine instead of morpholine, in order to obtain
enantiopure compound 1 (Scheme 1).
reduction stereochemical outcome; thus, we tested different
reducing agents.
The robustness of the above reaction was checked using
commercially available N-benzylpiperidone, tosyl azide, and
proline methyl ester hydrochloride. First, the hydrochloride salt
was neutralized using TEA (1 equiv) in 1,2 dichloroethane. N-
Benzylpiperidone, molecular sieves, and after 1 h, tosyl azide (1
equiv) were added to the mixture, but the reaction did not
occur. In order to overcome eventual issues in the formation of
the enamine, a catalytic amount of InCl3 was added to the
initial mixture of the ketone and the free amine. The sulfonyl
azide was then dropped, and the reaction was complete after 45
min (TLC analysis). Any attempt to purify the crude reaction
mixture by crystallization failed, while it was possible to isolate
only a mixture of diasteroisomeric amidines 2 (20%) by column
chromatography (Scheme 2).
The compound 2 isolation was proof that the cycloaddition/
ring rearrangement reactions were effective. As in the recently
reported mechanism for morpholino derivatives,9a proline
reacts first with keto compound (leading to enamine A) and
then reacts with tosyl azide, affording cycloadduct B in
equilibrium with its conformer B′. Amidines 2 are formed
through a concerted transposition of the piperidine ring bond
and nitrogen elimination (path a). As the main products were
degraded during the workup, our hypothesis is that, starting
from conformer B, the concerted transposition of proline
moiety and nitrogen elimination (path b) gives imine 3. The
latter equilibrates to azacycloalkene diamine derivative 4, which
was not stable during the purification on silica gel (Scheme 2).
Since compounds 5 were our synthetic targets, we reasoned
that the direct treatment of the multicomponent reaction
mixture with a reducing agent could give access to a more stable
piperidine ring. (Scheme 2) In compounds 3/4, the reduction
of the double bond of could give four isomers: two having a
trans substitution pattern and the others with cis disposition,
respectively (Figure 1). Our interest was the control of the
Figure 1. Possible stereoisomers of 5.
We first performed a catalytic hydrogenation using Pd/C in
MeOH (1 atm, 25 °C), which actually led to a complex mixture
(1H NMR). Molecular weights, corresponding to amidines 2
and piperidines 5, together with their N-debenzylated
derivatives, were detected in the mass spectrum of the crude.
In order to avoid the formation of mixtures and the N-benzyl
deprotection side reaction, we then turned to borohydride
reducing agents.10 As reported,10b by tuning the sterical and
electronical properties of the substituents on the boron atom, it
could be possible to control the diastereoselection in the
formation of the new stereocenters.
A series of reducing borohydrides were tested. The reactions
were directly performed on the crude click reaction mixture,
operating at 25 °C for 10 h. Using NaBH(OAc)3 (2.5 equiv),
the reaction was successful (40% overall yield), leading
exclusively to 5a and 5b isomers, together with amidine 2
1
(5a/5b/2, 2:1:1 ratio, H NMR and HPLC analyses, see the
Supporting Information). The same stereochemical outcome
was found with NaBH3CN (2.5 equiv), obtaining the only 5a
and 5b isomers, although their distribution was found not
completely reproducible. Only degradation products were
observed using NaBH4 (2.5 equiv). The reaction did not
occur with 2.5 equiv of hindered L-Selectride. A complex
reaction mixture was obtained by increasing the equivalents (5
equiv) of the reducing agent (2/5a/5b/5c,d 3:2:1:1, LC/MS
analysis of the crude).
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Scheme 3. Scale up of Multicomponent Reaction
NaBH(OAc)3 was thus selected as the best catalyst to
control the diastereoselection. In order to enhance the yield, we
increased the amount of the reducing agent (5 eq instead of 2.5
equiv), obtaining compounds 5 in 75% yield (5a/5b, 2:1).
Finally, the entire protocol was carried out on a multigram
scale (4 g of proline). The multicomponent reaction between
the proline, N-benzylpiperidone, and tosyl azide was first
performed. After removal of the solvent and molecular sieves,
dichloroethane and NaBH(OAc)3 (5 equiv) were added, and
the mixture was allowed to sit for 10 h at 25 °C under stirring.
After column chromatography, compound 5a was isolated in
good yield (50%) with the minor isomer 5b (25%) and amidine
2 (20%) (Scheme 3).
stability of the 3′R and 3′S diastereoisomeric imides 3, which
are in equilibrium due to tautomerization between 3 and 4.
Our interest focuses on theoretical analyses of chemical
reactions,9a,11 and DFT calculations were thus done to explain
the reasons for the observed stereochemistry. Indeed, a study
on the mechanism and diastereoselectivity of NaBH4 reduction
of ketones was published by Suzuki and co-workers.12 They
reported that DFT calculations were able to describe the
geometry and energy of the stationary point along the reaction
path and correctly predict the diastereoisomeric ratio of the
reduction of 4-methylcyclohexanone, which showed a prefer-
ence for the trans isomer, and 2-tert-butylcyclohexanone, where
diastereoselectivity was almost eliminated. In these cases,
diastereoselection was observed to be dependent from the
difference in energy between the two transition states (TS)
obtained from the axial or equatorial attack of the hydride on
cyclohexanone. Interestingly, the authors reported that the
inclusion of the Na+ counterion in the theoretical models was
essential to reproduce the experimental results. Indeed, they
demonstrated that NaBH4 is associated and Na+ ion takes an
active part in the TS even by using methanol as the solvent.
Starting from these findings, we thought of applying to our
system the model by Suzuki et al. Some approximations needed
to be done for reasons of feasibility. In particular, to reduce
both the size and degrees of freedom of the system, the benzyl
at N1 and the tolyl at SO2 were replaced by methyl groups. The
effect of this simplification was evaluated by performing a
conformational search, at the molecular mechanics (MM) level,
on the approximated model of 5a (M5a) and by comparing the
results with the X-ray structure of 5a. A root-mean-square
deviation (RMSD) of 0.52 Å was obtained between the heavy
atoms of M5a most stable conformation and the corresponding
atoms of 5a, suggesting that such approximation is not critical
(Figure S9, Supporting Information). TS models for both the
axial and equatorial hydride attack on models (3′R)-3 and
(3′S)-3, leading to all possible diastereoisomers, were located
by considering NaBH3CN as the reducing agent. By using
NaBH(OAc)3, convergence time was unacceptably long. Since
the two reactants substantially led to comparable stereo-
chemical results, our simplification can be considered accept-
able. Single-point energy calculations were performed on
optimized geometries at the mPW1B95/6-311G(2d,p) level
both in the gas phase and in dichloroethane.
The stereochemistry of compounds 5a and 5b was assigned
by NMR analyses. The NOESY spectrum of 5a showed a
spatial proximity between H3′ and NHTos protons, suggesting
a trans configuration of the Pro and NHTos substituents on the
piperidine ring. On the other hand, this spatial proximity was
not found for isomer 5b. X-ray analysis on 5a confirmed the
trans configuration of the substituents, indicating a R
configuration of both C3′ and C4′ stereocenters and the S
configuration of Cα of Pro (see the Supporting Information,
Figure S1). On the contrary, crystal structure of stereoisomer
5b showed the S and the R configuration of the C3′ and the
C4′, respectively (see the Supporting Information, Figure S6).
Thus, stereoisomers 5a and 5b possess the same stereo-
chemistry at C4′.
To explain the stereochemical outcome on the reduction,
insights on the reaction mechanism were acquired.
First, it can be safely assumed that between tautomers 3 and
4 the former is the most reactive toward hydrides, as the
negative charge deriving from the nucleophilic attack at 3-C4′
can be delocalized on the more electronegative sulfonamide
group, while on 4 it would be delocalized on carbon (Scheme
4). Second, it can be hypothesized that the hydride only attacks
at the Re face, thus leading to the R configuration of C4′. The
variability at C3′ should instead depend on the thermodynamic
Scheme 4. Hypothesized Mechanism for Hydride Attack on
Tautomers 3 and 4
The obtained relative energies are summarized in Table 1
(see the Supporting Information for absolute energies), while
selected geometrical parameters are reported in Table 2.
Geometries of all TSs deriving from either the axial or the
equatorial attack of the hydride are depicted in Figure 2.
First of all, the most stable structures, TS-3′R,4′R-ax and TS-
3′S,4′R-ax, led to the actually isolated compounds 5a and 5b,
although gas-phase calculations predict both TSs to be
energetically equivalent. Conversely, single-point energy
calculations conducted in solution by using the PCM model
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interactions between the Na+ ion and (i) the partially negative
charged sulfonamide nitrogen (see Scheme 4), (ii) the proline
nitrogen, (iii) the carbonyl group, (iv) the SO2 oxygen, and (v)
the electron-rich CN group of the borohydride (see Table 2).
Conversely, in the equatorial TS, the two substituents at C3′
and C4′ are both axial, and only three stabilizing interactions
are found between the Na+ ion and electron-rich groups (see
Figure 3 and Table 2). Moreover, the equatorial approach of
the reducing agent to the substrate is hampered by steric
hindrances of the methoxycarbonyl group of proline, the SO2
group, and the axial hydrogen at C5′ (see Figure S10,
Supporting Information).
For TS-3′S,4′R, no particular differences are observed among
axial and equatorial TSs on the steric hindrance, hampering the
approach of the reducing agent to the substrate. However, in
the equatorial TS geometry the S(O2)N···CN distance is
2.81 Å, while 3.31 Å is measured in the axial TS. This would
suggest that there is on the former TS, a stronger repulsive
effect between the electron-rich sulphonamide nitrogen and the
CN group. Moreover, steric interferences are also observed
between the proline hydrogen atoms at Cα and Cδ and those at
C2′, C3′, and C4′ of the piperidine ring, less relevant in the
corresponding axial TS (Figure S11, Supporting Information).
Concerning TS-3′R,4′S, which does not lead to exper-
imentally isolated products, the two approaches, axial and
equatorial, are closer in terms of relative activation energies.
The former is favored by 1.4 kcal/mol in the gas phase and the
second is favored by 0.8 kcal/mol in solution and only 1.4 kcal/
mol less stable than TS-3′R,4′R. Although the difference is
small, it is enough to make it impossible to obtain
experimentally the product, according to the Arrhenius
equation.13 Both axial and equatorial TSs pay an energy toll
probably due to unfavorable steric contacts that are between
the methoxycarbonyl and sulfonamide methyl groups and
between the boron-linked hydrogen and the proline Hα (see
Figure 3).
Table 1. Relative Gibbs Free Energies (kcal/mol) Computed
at the mPW1B95/6-311G(2d,p) Level for TSs Leading to
(3′R,4′R), (3′S,4′R′), (3′R,4′S), and (3′S,4′S)
a
Configurations of M5
model
ΔΔG⧧
ΔΔG⧧
gas
DCE
TS-3′R,4′R-ax
TS-3′R,4′R-eq
TS-3′S,4′R-ax
TS-3′S,4′R-eq
TS-3′R,4′S-ax
TS-3′R,4′S-eq
TS-3′S,4′S-ax
TS-3′S,4′S-eq
0.0
10.1
0.0
0.0
2.3
0.5
5.0
2.2
1.4
4.9
3.3
6.2
1.6
3.0
9.2
9.3
a
Gibbs free energies are computed by single-point calculations at the
mPW1B95/6-311G(2d,p) level on geometries optimized at the
mPW1B95/6-31G(d) level in the gas phase and include thermochem-
ical corrections from vibrational analysis conducted at the same level of
theory in standard conditions (1 atm, 298.15 K). Relative activation
free energies are obtained as the difference between the energy
computed for the considered TS and that of the most stable one.
provide excellent concordance with the experiments, with a
ΔΔG⧧ = 0.5 kcal/mol in favor of the most abundant
regioisomer 5a (5a:5b = 2:1).
The second observation deriving from theoretical results is
that the axial attack of the hydride is the most favored for all the
examples in the gas phase, while the axial attack is still favored
in solution for those paths leading to the experimentally
obtained compounds 5a and 5b. Considering that, for the
herein reported examples, NaBH(OAc)3 and NaBH3CN
provided comparable results in terms of product stereo- and
regiochemistry, a similar mechanism of attack could be
hypothesized. Our findings are thus apparently in contrast
with the general observation that bulky reducing agents usually
favor equatorial attack.10b However, our results are probably
due to the peculiar substitution pattern of the substrate.
Concerning TS-3′R,4′R, in the most favored axial TS, the bulky
substituents at C3′ and C4′ are both in an equatorial position
(Figure 3), and no evident steric interference is found by
analyzing the TS geometry (see Figure S10, Supporting
Information). Moreover, the TS is stabilized by electrostatic
Even for the least stable TS-3′S,4′S, the axial TS is predicted
as slightly favored in the gas phase, while in solution the
equatorial attack is preferred, although it is still 3.3 kcal/mol
less stable than the most favored TS-3′R,4′R axial. Probably, the
higher energy is mainly due to the stabilizing interaction
Table 2. Selected Geometrical Parameters of Optimized TSs
TS-3′R,4′R
TS-3′S,4′R
TS-3′R, 4′S
TS-3′S,4′S
axial
equat
axial
equat
axial
equat
axial
1.12
equat
distances (Å)
C4′−H
H4′−B
B−NSO2
S(O2)N−Na
OSO−Na
1.12
1.12
2.09
3.56
2.33
2.23
2.39
5.92
6.70
1.13
1.12
1.97
2.78
2.31
2.30
2.53
2.73
2.27
1.12
1.12
2.06
3.77
2.31
2.40
2.78
2.66
2.33
1.12
2.09
3.66
2.34
2.23
2.38
5.89
7.01
2.03
2.78
2.38
2.32
2.50
2.93
2.24
2.09
3.70
2.39
2.25
2.48
4.24
2.24
2.09
3.72
2.46
2.25
2.43
4.21
2.23
2.07
2.80
2.36
2.25
2.50
2.51
5.32
CN−Na
N(Pro)−Na
CO−Na
angles (deg)
C4′−H4′−B
CO−Na
CN−Na
C3′−N(Pro)−Na
C4′−N−Na
SO−Na
126.0
141.8
79.8
161.8
129.0
120.0
95.4
163.3
163.9
108.8
106.7
109.8
116.3
92.2
125.7
152.6
95.6
116.2
96.7
129.3
119.0
63.2
115.3
119.4
67.2
47.0
95.6
112.9
32.3
116.4
35.4
106.4
124.0
94.1
106.0
125.4
96.2
112.2
113.6
94.9
131.6
95.8
130.9
97.0
130.4
97.4
128.5
95.4
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Figure 2. Geometries of all of the possible TSs deriving from either the axial or equatorial attack of the hydride.
orientation of the chains and to develop the most efficient
protocol for peptidomimetic synthesis. Starting from 5a, the
“one pot” catalytic hydrogenation/acetylation reaction was
performed using toluene as the solvent and adding Ac2O (2
equiv) to the reaction mixture. Compound 6 was obtained in
moderate yield (40%) and then treated with MeNH2 in EtOH
at 0 °C affording 7 (50%, Scheme 5).
Scheme 5. Synthesis of Dipeptide Model 7
Figure 3. β-Turn-like geometry of dipeptide model 7 obtained by
conformational search.
between the methoxycarbonyl group and the Na+ ion, which is
missing in both the axial and equatorial TSs: a singularity
among the cases analyzed herein.
Taken together, the theoretical data suggest that the stereo-
and regiochemical outcome observed experimentally can be
ascribed to a fine balance of steric and electronic factors. The
latter is dependent from the interactions between the electron-
rich functional groups and the Na+ ion, whose role is again
predicted to be extremely relevant as suggested by Suzuki et
al.12
Peptidomimetic Synthesis. From the crystal structure of
both compounds 5a and 5b (Figure S1 and S6, Supporting
Information), it was evidenced that the carboxylic group of Pro
and the benzyl substituent on the piperidine ring were oriented
in the same direction. The spatial proximity between Cα of Pro
and the benzyl group suggested that both scaffolds could act as
a β turn nucleator when inserted into a peptide sequence. A
preliminary conformational search conducted on the dipeptide
model 7, deriving from the major isomer 5a, encouraged us to
pursue this idea, since a top-ranked conformation presented a β
turn-like geometry with an H-bond between the proline amide
NH and the acetamide carbonyl group at N1′ forming a 10-
membered ring (Figure 3). Furthermore, the computed phy
and psi values of Pro, were in the range of a type VIII β turn.
In order to confirm this hypothesis, the preparation of
dipeptide 7 was planned both to ascertain by NMR the correct
To improve the yield, we tested a second synthetic protocol,
consisting first of the functionalization of the carboxylic group
and then of the deprotection of nitrogen. Compound 5a was
thus treated with MeNH2 in EtOH at 0 °C obtaining
compound 8 (96%) and then deprotected with H2, Pd/C in
toluene. The obtained free amine 9 (96%) was acetylated using
Ac2O, affording compound 7 (64%). When the reduction was
carried out in the presence of Ac2O, the yield was increased
(95% instead of 60% in two steps) (Scheme 5).
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Scheme 6. Synthesis of Peptidomimetic 13
We tested the possibility of using compound 5a in the
synthesis of short peptide models. According to the above best
synthetic protocol, peptidomimetic 12 was synthesized by
hydrolysis of compound 5a (6 M HCl), affording free
carboxylic acid 10 (99%). Its coupling with H-Val-NH2 using
HOBT, EDC as coupling reagents, DIPEA as the base, and
CH2Cl2 as the solvent (10 h) (Scheme 6) gave compound 11
(72%). The latter was then debenzylated to derivative 12
(76%). Peptidomimetic 13 (45%) was finally obtained by
coupling of 12 with N-Ac-Ala-OH using the above conditions
(Scheme 6).
conformation is active for isomer 7, which is stabilized by the
hydrogen bond. The latter consideration is also supported by
the observation that compound 6, which possesses an acetyl
group on piperidine ring and an ester function on Pro, exists as
a single conformer in solution and shows no significant
Overhauser effect in the NOESY experiments, thus lacking a
reverse-turn conformation.
Peptidomimetic 13 is present in solution as a mixture of two
conformers 13/13′ (1:1 ratio, Figure 5, Tables S3 and S4,
NMR Discussion. Compound 7 was characterized by means
of 1D and 2D NMR experiments (20 mM in CD3CN, 25 °C,
500 MHz), as well as by dynamic NMR experiments (0−60 °C
1
temperature range in CD3CN). The 1D H spectrum showed
the presence of two different conformers 7 and 7′ (1:1 ratio,
Figure 5 and Table S1 and S2, Supporting Information).
1
Performing the H NMR analysis in DMSO, the complete
coalescence of the signals was observed at 80 °C. Dynamic
NMR experiments in CD3CN showed in both isomers a high
temperature coefficient for NHTos, while NHMe was involved
in a medium-weak hydrogen bond only in 7 (see Tables S2 and
S3, Supporting Information). In the NOESY experiments, both
conformers showed spatial proximities between the Hα of Pro
and H6′, while an NOE effect between Hα of Pro and H2′ was
observed only for the hydrogen bonded isomer 7. On the other
hand, the isomer 7′ showed a spatial proximity between Hα of
Pro and NHMe (Figure 4) From these findings, we can
postulate that the two conformers 7 and 7′ could correspond to
the rotamers of the acetamide bond, as typically found in
similar compounds.14 We suggested that a reverse turn
Figure 5. Schematic representation of conformers 13 and 13′
supported by NOE experiments.
Supporting Information). In isomer 13, NH-Val and the NH-
acetyl are involved in medium-weak hydrogen bonds (see
Tables S3 and S4, Supporting Information), while none of the
amidic protons of 13′ showed low temperature coefficients. In
the NOESY experiments, both conformers 13 and 13′ showed
spatial proximity between the Hα of Ala and H2′ and H6′. On
the contrary, Overhauser effects between Hα of Pro and H2′
and H6′ were present only for the hydrogen bonded conformer
13, while spatial proximity between Hα of Pro and NH-Val was
found in isomer 13′. These findings suggested that a β turn
conformation is present in conformer 13, while 13′ possesses
an extended conformation.
In conclusion, starting from commercially available cheap
reagents, through a multicomponent/cascade process, the new
scaffold 5a was prepared in multigram scale, in good yield, and
with a good control in the formation of two new stereocenters.
When inserted into a peptide chain, compound 5a acts as a β
turn nucleator, representing a promising building block that
contains an additional amino group on the piperidine ring,
which could be used for further functionalization of the ring.
Figure 4. Schematic representation of conformers 7 and 7′ supported
by NOE experiments.
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S-Methyl 1-[(3S,4R)-1-Benzyl-4-tosylamidopiperidin-3-yl]-
pyrrolidine-2-carboxylate (5b). Yellow solid: mp 95−97 °C (i-
Pr2O); [α]D = (c, 20 °C); IR (KBr) 3256, 2921, 1736 cm−1; NMR
(CDCl3, 500 MHz) δ 1.37−1.42 (m, 1H), 1.67−1.72 (m, 1H), 1.79−
2.10 (m, 6H), 2.43 (s, 3H), 2.59−2.63 (m, 1H), 2.70−2.75 (m, 1H),
2.85−2.94 (m, 3H), 2.96−3.00 (m, 1H), 3.48 (s, 2H), 3.60 (s, 3H),
3.63 (dd, J 7.7, 3.7 Hz, 1H), 5.85 (bs, 1H), 7.20−7.35 (m, 7H), 7.78
(d, J 7.2 Hz, 2H). 13C NMR (CDCl3, 125 MHz) δ 21.5, 23.8, 29.6,
30.5, 49.3, 51.4, 51.5, 52.0, 54.1, 60.0, 60.3, 62.8, 127.2, 127.3, 128.3,
129.0, 129.4, 137.7, 138.4, 143.1, 175.6; MS (ESI) M+ 472. Anal. Calcd
for C25H33N3O4S: C, 63.67; H, 7.05; N, 8.91. Found: C, 63.40; H,
7.30; N, 8.61.
S-Methyl 1-[(3R,4R)-1-Acetyl-4-tosylamidopiperidin-3-yl]-
pyrrolidine-2-carboxylate (6). To a solution of 5a (0.2 g, 0.4
mmol) and acetic anhydride (0.052 g, 0.44 mmol) in toluene (20 mL)
was added Pd/C (10%, 0.1 g), and the obtained suspension was stirred
under H2 at room temperature for 12h. The mixture was filtered
through a Celite pad, and the solvent was removed under vacuum
affording pure compound 6 (0.07 g, 40%) as a colorless gum: IR
(KBr) 320, 1740 cm−1; 1H NMR (CDCl3, 300 MHz) δ 1.30−1.62 (m,
3H, 1.66−1.85 (m, 2H), 1.99−2.11 (m, 1H), 2.05 (s, 3H), 2.32−2.60
(m, 4H), 2.44 (s, 3H), 2.82−3.10 (m, 2H), 3.77 (s, 3H), 3.40−3.78
(m, 2H), 4.55 (d, J 9.6 Hz, 1H), 7.00 (bs, 1H, exch), 7.30 (d, J 9.9 Hz,
2H), 7.79 (d, J 6.4 Hz, 2H); 13C NMR (CDCl3, 50 MHz) δ 21.7, 21.9,
24.9, 30.7, 34.2, 40.5, 44.3, 45.2, 52.8, 54.1, 58.4, 62.4, 127.6, 129.4,
137.6, 137.7, 143.4, 169.5, 176.6; MS (ESI) M+ 423. Anal. Calcd for
C20H29N3O5S: C, 56.72; H, 6.90; N, 9.92. Found: C, 56.55; H, 7.10;
N, 9.73.
Furthermore, the semirigid structure of compound 5a is an
added value for its use in the preparation of PPI modulators.
EXPERIMENTAL SECTION
■
Materials and solvents were purchased from common commercial
sources and used without additional purification. H NMR spectra
1
were recorded at 200, 400, or 500 MHz and 13C NMR spectra at 50,
70, or 125 MHz using TMS as internal standard. The following
abbreviations were used to describe peak patterns where appropriate:
singlet (s), doublet (d), triplet (t), multiplet (m), broad resonances
(br). Coupling constants (J) are reported in hertz. Mass spectra were
recorded under electron spray interface (ESI) conditions. Infrared
spectra were recorded on a FTIR spectrometer. [α]D values were
measured using CHCl3 as the solvent, if not differently reported.
Theoretical Calculations. Transition states were fully optimized
at the mPW1B95/6-31G(d) level of theory.15 Different conformations
were evaluated for each structure, and only the most stable was further
considered. Vibrational frequencies were computed at the same level
of theory in order to verify the presence of unique imaginary frequency
corresponding to the vibrational stretching of the forming/breaking
bonds and to calculate zero-point and thermochemical corrections to
electronic energies (1 atm, 298.15 K, unscaled frequencies). Single-
point calculations were then performed at the 6-311G(2d,p) level,
both in the gas phase and in solution, by using the PCM solvent model
for dichloroethane.16 All quantum chemical calculations were
performed with the Gaussian09 software package.17 Conformational
searches were conducted in the gas phase by using the MOE software
with the MMFF94x force field and default parameters.
S-N-Methyl 1-[(3R,4R)-1-Acetyl-4-tosylamido)piperidin-3-yl]-
pyrrolidine-2-carboxamide (7). Method A: Operating at 0 °C and
under N2 atmosphere, pure isomer 6 (0.34g, 0.85 mmol) was dissolved
in CHCl3 (2 mL), and then methylamine (8 M in EtOH, 15 mL) was
added. After 1 h, the mixture was warmed at room temperature and
the stirring was continued overnight. The solvent was evaporated, and
pure compound 7 was obtained after crystallization from hexane (0.17
g, 50%). Method B: To a solution of 8 (0.36 g, 0.75 mmol) in toluene
(20 mL) were added acetic anhydride (0.153 g, 1.5 mmol) and Pd/C
(10%, 0.08g). The suspension was stirred under H2 atmosphere at
room temperature for 12 h. The reaction mixture was filtered through
a Celite pad, and the solvent was removed under vacuum. Pure
compound 7 (0.33 g, 95%) was obtained as a white powder after
crystallization from hexane. Method C: Pure compound 9 (58 mg,
0.15 mmol) was dissolved in CH2Cl2 (10 mL) and Ac2O (51 mg, 1
mmol) was added. The solution was left under stirring at room
temperature for 5 h. The solvent was removed affording and pure 7
was obtained after crystallization from hexane (40 mg, 64%): IR (KBr)
3425, 3271, 1659 cm−1; [α]D = −62.1 (c 0.3, 20 °C); mp 60−62 °C
(hexane); 1H NMR (CD3CN, 300 MHz) 1:1 mixture of conformers, δ
1.21−1.80 (m, 4H), 1.99−2.55 (m, 6H), 2.00 (s, 3H), 2.44 (s, 3H),
2.73, 2.75 (2 s, 3H), 2.81−3.30 (m, 2H), 3.33−3.46 (m, 1H), 3.65−
3.87 (m, 1H), 4.43−4.53 (m, 1H), 6.99, 7.11 (2 bs, 1H, exch), 7.15
(bs, 1H, exch.), 7.39 (d, J 8.0 Hz, 2H), 7.79 (d, J 8.2 Hz, 2H); 13C
NMR (CD3CN, 75 MHz) 1:1 mixture of conformers δ 20.9, 24.5
(24.6), 25.6, 30.8 (30.9), 33.9, 40.0, 44.3 (44.4), 44.9, 53.9 (54.0),
58.8, 59.6, 64.0, 127.0, 129.9, 138.5, 143.7, 168.9, 175.9; MS (ESI) M+
423. Anal. Calcd for C20H30N4O4S: C, 56.85; H, 7.16; N, 13.26.
Found: C, 56.68; H, 7.30; N, 13.01.
S-N-Methyl1-[(3R,4R)-1-Benzyl-4-tosylamidopiperidin-3-yl]-
pyrrolidine-2-carboxamide (8). Pure isomer 5a (0.4 g, 0.85 mmol)
was dissolved in CHCl3 (2 mL). Methylamine (8 M in EtOH, 15 mL)
was added at 0 °C and under N2 atmosphere. After 1 h, the ice bath
was removed and the stirring continued overnight. The solvent was
evaporated to yield pure compound 8 (0.38g, 98%) as a yellow powder
after crystallization from Et2O: IR (KBr) 3307, 3087, 1655 cm−1; [α]D
= −75.0 (c 0.4, 20 °C); mp 80−82 °C (Et2O); 1H NMR (CDCl3, 200
MHz) δ 1.37−2.25 (m, 7H), 2.40 (s, 3H), 2.42−2.95 (m, 5H), 2.8 (d,
J 5.14 Hz, 3H), 3.00−3.22 (m, 1H), 3.41 (d, J 11.0 Hz, 1H), 3.47 (d, J
11.0 Hz, 1H), 5.28 (bs, 1H), 7.18−7.38 (m, 7H), 7.62 (bs, 1H, exch),
7.77 (d, J 8.1 Hz, 2H); 13C NMR (CDCl3, 50 MHz) δ 21.7, 25.1, 26.1,
31.4, 32.5, 45.4, 51.9, 52.1, 54.2, 60.5, 62.9, 64.4, 127.1, 127.5, 128.5,
Multicomponent Reaction Procedure. To a suspension of
proline methyl ester hydrochloride (4 g, 24 mmol) in 1,2
dichloroethane (40 mL) was added TEA (3.36 mL, 1 equiv). After
15 min, under N2 atmosphere, 4-benzylpiperidone (4.2 mL, 24.0
mmol) and molecular sieves (5 g) were added to the solution. After 30
min, a catalytic amount of InCl3 (0.53 g, 0.1 equiv) was added, and
stirring was continued for 45 min. The reaction mixture was cooled at
10 °C, and tosyl azide (4.76 g, 24.0 mmol) dissolved in dichloroethane
(20 mL) was added. After 45 min (TLC analysis: CH2Cl2/CH3OH,
20:1), (AcO)3BHNa (25.4 g, 5 equiv) was added to the crude that was
allowed to stir for 12 h at 25 °C (TLC analysis: CH2Cl2/AcOEt, 1:1).
The reaction mixture was filtered, washed with water (3 × 30 mL),
and dried with Na2SO4, and the solvent was removed under vacuum.
The crude was crystallized with CH3OH obtaining pure 5a (2.2 g,
20%). The mother liquor was purified by column chromatography
(CH2Cl2/AcOEt from 100:0 to 50:50) affording a further amount of
5a (3.2 g, 30%), together with amidine 2 (2.15 g, 20%) and 5b (2.19 g,
20%).
S-Methyl 1-[(1-Benzylpirrolidin-3-yl-(tosylimido)methyl)]-
pyrrolidine-2-carboxylate (2). Mixture of inseparable diaster-
eoisomers: IR (KBr) 3247, 2917, 2250, 1740 cm−1; 1H NMR
(CDCl3, 200 MHz) δ 1.60−1.98 (m, 2H), 1.99−2.35 (m, 3H), 2.36−
2.54 (m, 2H), 2.40 (s, 3H), 2.55−2.75 (m, 1H), 3.00−3.20 (m, 2H),
3.45 (s, 3H), 3.55−3.95 (m, 3H), 4.05−4.35 (m, 1H), 4.36−4.55 (m,
2H), 7.20−7.41 (m, 7H), 7.72 (d, J 7.4 Hz, 2H); 13C NMR (CDCl3,
50 MHz) δ 21.6, 25.7 (25.4), 28.6, 29.9, 40.6, 48.9, 52.0, 54.5, 55.2,
59.9, 62.3, 126.4, 127.5 (127.7), 128.6, 128.9, 129.1 (130.1), 138.6
(C), 141.9 (141.6) (C), 167.8 (C), 172.1 (C); MS (ESI) M+ 470.
Anal. Calcd for C25H31N3O4S: C, 63.94; H, 6.65; N, 8.95. Found: C,
63.72; H, 6.77; N, 8.72.
S-Methyl 1-[(3R,4R)-1-Benzyl-4-tosylamido-piperidin-3-yl]-
pyrrolidine-2-carboxylate (5a). White solid; mp 156−157 °C
(MeOH); [α]D = 108.3 (c 0.4, 20 °C); IR (KBr) 3202, 2937, 1739
1
cm−1; H NMR (CDCl3, 500 MHz) δ 1.34−1.45 (m, 1H),1.49−1.72
(m, 2H), 1.73−2.10 (m, 5H), 2.22−2.38 (m, 2H), 2.42 (s, 3H), 2.57−
2.64 (m, 1H), 2.68−2.84 (m, 3H), 3.40−3.59 (m, 3H), 3.79 (s, 3H),
6.82 (bs, 1H), 7.15−7.31 (m, 7H), 7.80 (d, J 8.2 Hz, 2H); 13C NMR
(CDCl3, 125 MHz) δ 20.8, 23.7 (CH2), 29.1, 32.1, 43.5, 50.9, 51.1,
51.7, 52.9, 57.8, 61.3, 62.3, 126.5, 126.6, 127.6, 128.2, 128.6, 136.8,
137.1, 142.1, 175.4; MS (ESI) M+ 472. Anal. Calcd for C25H33N3O4S:
C, 63.67; H, 7.05; N, 8.91. Found: C, 63.49; H, 7.46; N, 8.67.
3100
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The Journal of Organic Chemistry
Article
129.1, 129.8, 137.7, 138.7, 143.4, 176.2 MS (ESI) M+ 471. Anal. Calcd
for C25H32N4O4S: C, 61.96; H, 6.66; N, 11.56. Found: C, 61.81; H,
6.89; N, 11.32.
17.8, 19.2, 20.7, 23.5, 24.6, 30.6, 31.2, 43.7, 44.6, 45.3, 54.7, 57.3, 60.0,
63.5, 126.8, 128.5, 140.2, 143.4, 175.0, 175.4; MS (ESI) M+ 466. Anal.
Calcd for C22H35N5O4S: C, 56.75; H, 7.58; N, 15.04. Found: C, 56.50;
H, 7.90; N, 14.85.
S-N-Methyl-1-[(3R,4R)-4-Tosylamido)piperidin-3-yl]pyrrolidine-2-
carboxamide (9). To a solution of 8 (0.29 g, 0.63 mmol) in toluene
(20 mL) was added Pd/C (10%, 0.13 g), and the suspension was
stirred for 12h under H2 at room temperature. The crude was filtered
through a Celite pad, and the solvent was removed under vacuum
obtaining pure compound 9 (0.2g, 96%) after crystallization from
toluene: IR (KBr) 3436, 3271, 3176, 1658 cm−1; [α]D = −55.6 (c 0.6,
(S)-1-((3R,4R)-1-((S)-2-Acetamidopropanoyl)-4-(tosylamidopiper-
idino-3-yl)-N-((S)-1-amino-3-methyl-1-oxobutan-2-yl)pyrrolidine-2-
carboxamide (13). To a cooled solution of N-acetyl-(S)-alanine (16
mg, 0.121 mmol) in CH2Cl2 (5 mL) were added HOBT (16 mg, 0.121
mmol) and EDC (23 mg, 0.121 mmol). The mixture was stirred for 1
h, and 12 (47 mg, 0.101 mmol) was added. The solution was stirred
overnight at room temperature, washed with water (10 mL) and a
saturated solution of NaHCO3 (10 mL), and then dried over Na2SO4.
The solvent was evaporated under vacuum affording 13 (26 mg, 45%)
as a white powder: [α]D = +34.5 (c 0.5, 20 °C); mp 62−64 °C (Et2O);
1H NMR 1:1 mixture of conformers (CD3CN, 300 MHz) δ 0.83 (d, J
6.7 Hz, 3H), 0.97 (d, J 6.7 Hz, 3H),1.15−1.19 (m, 3 H),1.49−1.55 (m,
1H), 1.66−1.70 (m, 2H), 1.91 (s, 3H) 2.04−2.13 (m, 2H), 2.19−2.35
(m, 3H), 2.38 (s, 3H), 2.41−2.54 (m, 3H), 2.91−3.01 and 2.97−3.12
(two m, 1H), 3.18−3.23 and 3.23−3.38 (two m, 1H), 3.43−3.68 (m,
1H), 3.74−3.85 and 3.86−3.98 (two m, 1H), 4.24−4.36 (m, 1H),
4.31−4.38 and 4.45−4.56 (two m, 1H), 4.66−4.76 (m, 1H), 6.11 (bs,
1H, exch), 6.60 (bs, 1H, exch), 6.75 (d, J 7.2 Hz, 1H, exch), 7.28 (bs,
1H, exch), 7.38 (d, J 8.0 Hz, 2H), 7.76 and 7.87 (two bs, 1H, exch),
7.78 (d, J 6.6 Hz, 2H); 13C NMR (CD3CN, 75 MHz) δ 17.9, 18.3,
19.3, 20.9, 22.3, 24.7 (24.8), 30.7 (30.9), 31.5 (31.4), 34.5 (33.5), 39.7
(41.1), 43.4 (44.1), 44.7 (44.6), 45.1 (45.2), 54.4 (54.2), 57.6 (57.4),
58.7 (59.2), 63.5 (63.4), 127.1, 130.0, 139.8, 143.7, 169.5 (169.2),
171.0, 174.8, 175.2; MS (ESI) M+ 577.5. Anal. Calcd for
C27H42N6O6S: C, 56.04; H, 7.31; N, 14.52. Found: C, 55.81; H,
7.60; N, 14.32.
1
20 °C); mp 195−197 °C (toluene); H NMR (CDCl3, 300 MHz) δ
1.25−1.45 (m, 1H), 1.55−1.73 (m, 2H), 1.75−1.91 (m, 2H), 1.95−
2.13 (m, 1H), 2.22 (bs, 2H), 2.31−2.50 (m, 2H), 2.44 (s, 3H), 2.51−
2.71 (m, 2H), 2.74−2.86 (m, 1H), 2.73 (d, J 4.9 Hz, 3H), 2.86−2.97
(m, 1H), 3.0−3.12 (m, 1H), 3.20 (dt,, J 9.1, 4.7 Hz, 1H), 3.40 (dd, J
9.6, 4.0 Hz, 1H), 7.32 (d, J 8.1 Hz, 2H), 7.64 (bs, 1H, exch), 7.80 (d, J
8.3 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 21.9, 25.2, 26.3, 31.6,
34.9, 44.8, 45.5, 45.7, 54.7, 61.8, 64.8, 127.3, 130.1, 138.8, 143.8, 176.2;
MS (ESI) M+ 381. Anal. Calcd for C18H28N4O3S: C, 56.82; H, 7.42;
N, 14.72. Found: C, 56.59; H, 7.70; N, 14.48.
S 1-[(3R,4R)-1-Benzyl-4-tosylamidopiperidin-3-yl]pyrrolidine-2-
carboxylic Acid HCl (10). In a sealed tube, pure isomer 5a (0.1 g,
0.21 mmol) was dissolved in 6 N HCl (2 mL) and heated at 110 °C in
oil bath. The solution was stirred for 4 h and then evaporated yielding
pure compound 10 (0.95g, 99%) as a white solid: FTIR (KBr) 3435,
3270, 1631 cm−1; [α]D = −35 (c 0.6 in MeOH, 20 °C); mp 95−97 °C
1
(Et2O); H NMR (D2O, 200 MHz) δ 1.42−1.63 (m, 2H), 1.79−2.19
(m, 3H), 2.30 (s, 3H), 2.22−2.33 (m, 1H), 2.78−3.00 (m, 1H), 3.19−
3.45 (m, 2H), 3.50−3.82 (m, 3H), 4.19−4.25 (m, 1H), 4.26, (d, J 13.2
Hz, 1H), 4.33 (d, J 13.2 Hz, 1H), 7.25−7.50 (m, 7H), 7.70 (d, J 8.5
Hz, 2H); 13C NMR (D2O, 50 MHz) δ 21.0, 24.0, 27.1, 28.8, 48.3, 49.7,
50.3, 50.4, 60.0, 61.4, 67.3, 127.1, 129.8, 130.8, 131.0, 131.6, 127.8,
135.4, 146.4, 172.1; MS (ESI) M+ 458. Anal. Calcd for C24H29N3O5S:
C, 61.13; H, 6.20; N, 8.91. Found: C, 60.81; H, 6.53; N, 8.65.
(S)-N-((S)-1-Amino-3-methyl-1-oxobutan-2-yl)-1-((3R,4R)-1-ben-
zyl-4-tosylamidopiperidin-3-yl)pyrrolidine-2-carboxamide (11). To
a solution of 10 (99 mg, 0.22 mmol) in CH2Cl2 (15 mL) and DMF (2
mL) were added HOBT (35 mg, 0.26 mmol) and EDC (49 mg, 0.26
mmol). The solution was stirred for 1 h at 0 °C. (S)-Valinamide (36
mg, 0.24 mmol) and DIPEA (0.15 g, 87 mmol) were added. The
mixture was stirred overnight at room temperature and washed with
water (10 mL) and with a saturated solution of NaHCO3 (10 mL).
The organic layer was dried with Na2SO4 and evaporated under
vacuum to yield 11 (0.89g, 73%) as a yellow powder: FTIR (KBr)
3435, 2962, 1661 cm−1; [α]D = −53 (c 0.3, 20 °C); mp 70−73 °C
(Et2O); 1H NMR (CD3CN, 300 MHz) δ 0.94 (d, J 6.7 Hz, 3H), 0.97
(d, J 6.7 Hz, 3H), 1.40−1.85 (m, 5H), 1.86−2.25 (m, 3H), 2.42 (s,
3H), 2.40−2.60 (m, 2H), 2.68−2.75 (m, 1H), 2.85−3.10 (m, 1H),
3.20−3.35 (m, 2H), 3.38−3.75 (m, 2H), 4.22−4.29 (m, 1H), 6.17 (bs,
1H), 6.68 (bs, 1H), 7.25−7−55 (m, 8H), 7.77 (d, J 8.2 Hz, 2H), 7.88
(bs, 1H); 13C NMR (CD3CN, 75 MHz) δ 18.0, 19.4, 20.9, 24.7, 30.7,
31.3, 33.5, 44.8, 51.0, 51.9, 54.2, 57.6, 58.7, 62.2, 63.6, 127.0, 127.7,
128.7, 129.5, 130.0, 138.2, 140.1, 143.6, 174.9, 175.5; MS (ESI) M+
556. Anal. Calcd for C29H41N5O4S: C, 62.68; H, 7.44; N, 12.60.
Found: C, 62.92; H, 7.21; N, 12.43.
ASSOCIATED CONTENT
■
S
* Supporting Information
X-ray data for 5a and 5b (CIF); tables with significant NMR
data for compounds 7, 7′, 13, and 13′; HPLC spectra of
multicomponent reaction and of compounds 2, 5a, and 5b; 1H,
13C NMR spectra for all new compounds; NOESY spectra of
compounds 7 and 13; computational details; crystallographic
description; tables of the atomic coordinates of compounds 5a
and 5b. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sara.pellegrino@unimi.it.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding for this work was provided by MIUR (PRIN 2010-
2011 - prot. 2010NRREPL).
(S)-N-((S)-1-Amino-3-methyl-1-oxobutan-2-yl)-((3R,4R)-4-tosyla-
midopiperidin-3-yl)pyrrolidine-2-carboxamide (12). To a solution of
11 (50 mg, 0.09 mmol) in toluene (5 mL) Pd/C (10%, 0.05 g) was
added. The suspension was stirred under H2 atmosphere at room
temperature for 30 h. The catalyst was filtered through a Celite pad
that was carefully washed with methanol (20 mL). The solvent was
evaporated under vacuum yielding pure compound 12 (0.032g, 76%)
as a light yellow powder after crystallization from hexane: IR (KBr)
3435, 2963, 1662 cm−1; [α]D = −24.3 (c 0.2, 20 °C); mp 57−59
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(hexane); H NMR (CD3CN, 200 MHz) δ 0.94 (d, J 6.7 Hz, 3H),
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8.4 Hz, 2H), 7.90 (d, J 10.2 Hz, 1H); 13C NMR (CD3CN, 50 MHz) δ
3101
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The Journal of Organic Chemistry
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