Stereoselective synthesis of original spirolactams displaying promising folded structures

Article abstract of DOI:10.1039/c3ob40643a

Access to diastereoisomeric forms of original spirolactam frameworks and investigation of their folded potentials are depicted here. Taking advantage of a stereoselective ring-contraction reaction, the Transannular Rearrangement of Activated Lactams (TRAL), followed by two unprecedented tandem reactions, we describe here an efficient access to elegant spirocyclic scaffolds. After dimerization, NMR analyses, circular dichroism, SEM and molecular modelling indicated the existence of an attractive edifice able to fold and behave as a PPII helix, a common yet neglected peptidic secondary structure. is

Full text of DOI:10.1039/c3ob40643a

Organic &
Biomolecular Chemistry
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Stereoselective synthesis of original spirolactams
displaying promising folded structures†
Cite this: Org. Biomol. Chem., 2013, 11,
4719
Guilhem Chaubet,a Thibault Coursindel,a Xavier Morelli,b Stéphane Betzi,b
Philippe Roche,b Yannick Guari,c Aurélien Lebrun,a Loïc Toupet,d Yves Collette,b
Isabelle Parrot*a and Jean Martinez*a
Access to diastereoisomeric forms of original spirolactam frameworks and investigation of their folded
potentials are depicted here. Taking advantage of a stereoselective ring-contraction reaction, the Trans-
annular Rearrangement of Activated Lactams (TRAL), followed by two unprecedented tandem reactions,
we describe here an efficient access to elegant spirocyclic scaffolds. After dimerization, NMR analyses,
circular dichroism, SEM and molecular modelling indicated the existence of an attractive edifice able to
fold and behave as a PPII helix, a common yet neglected peptidic secondary structure.
Received 1st April 2013,
Accepted 21st May 2013
DOI: 10.1039/c3ob40643a
www.rsc.org/obc
pathologies29,30 have recently stimulated a few chemists to syn-
thesize PPII mimics.31 They essentially concern the synthesis
Introduction
Spirocycle moieties are encountered in many natural of polyimide-based foldamers,32–34 PTAAs,35–37 triproline
products1–6 which made these particular bicycles key platforms mimics,38,39 Ser-Pro dipeptide40 or Pro-Pro dipeptide
for medicinal chemists.7–10 Due to their highly constrained mimics.41 However, compared to the ever-growing field of
structures,11–13 spirocompounds were also described as having α-helices or β-turn mimics, only a few approaches have been
interesting properties as folded materials14–16 efficient cata- described to emulate the PPII structure. Then, the discovery of
lysts17 or molecular actuators.18 However, very few articles have pertinent PPII scaffolds to target protein–protein molecular
reported their use as peptidomimetics or tools to explore interactions is still completely relevant to understand their bio-
protein–protein interactions19–23 which are largely mediated by logical significance.
the recognition of proline-rich modules generally described to
In this context, we wish here to present the access to
be structured in polyproline II helices (PPII). They represent dimeric spirolactam structures, one of which was capable of
attractive targets for the medicinal chemist,24–28 being the behaving as a polyproline II helix. We report our first steps in
architectural hallmark of linear sequences recognizing the development of a new class of artificial bio-inspired PPII
protein–protein interaction modules such as SH3, WW and compounds, part of a challenging study on pertinent tools for
EVH1 domains.24–26,29 Formerly neglected, the significance of the understanding of protein–protein interactions.
this unique extended structure and its implication in crucial
In order to build spirolactam platforms, the Transannular
Rearrangement of Activated Lactams (TRAL) has proven to be a
central and optimal tool. More particularly, we describe in this
article a careful study on the stereochemical potential of this
rearrangement for the design of unprecedented heterocyclic
frameworks. Starting from N,N′-bis-Boc-activated diketopiper-
azines (DKP), the six- to five-membered ring-contraction yielded
aminotetramate scaffolds with high stereoselectivity.42 The
broad interest of the reaction was previously demonstrated by
the preparation of diverse scaffolds such as statins or pentacin
analogues.43–45 While protonation in an aqueous medium
yielded the TRAL product, addition to the reaction mixture of
an alkylating agent allowed the formation and isolation of the
TRAL–alkylation product (Scheme 1).
aInstitut des Biomolécules Max Mousseron, IBMM UMR 5247 CNRS-Université
Montpellier I-Université Montpellier II, Pl. E. Bataillon, 34095 Montpellier Cedex 5,
France. E-mail: jean.martinez@um1.fr, isabelle.parrot@um2.fr;
Fax: (+33)467144866; Tel: (+33)467144986
bCentre de Recherche en Cancérologie de Marseille, CRCM UMR 7258-INSERM U
1068 CNRS-Université Aix-Marseille, Institut Paoli-Calmettes, 13009 Marseille,
France. E-mail: xavier.morelli@inserm; Fax: (+33)486977499; Tel: (+33)491164501
cInstitut Charles Gerhardt Montpellier, UMR 5253, Chimie Moléculaire et
Organisation du Solide, Université Montpellier II, Pl. E. Bataillon, 34095 Montpellier
Cedex 5, France. E-mail: yannick.guari@um2.fr; Fax: (+33)467143852;
Tel: (+33)467144224
dInstitut de Physique de Rennes, UMR 6251 CNRS Université Rennes 1, 35042
Rennes cedex, France. E-mail: loic.toupet@univ-rennes1.fr; Fax: (+33)223236717;
Tel: (+33)223236497
In the present work, we deliberately chose the commercially
available Shöllkopf’s DKP, given the exceptional stereo-
†Electronic supplementary information (ESI) available. CCDC 751234. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3ob40643a
selectivity of the TRAL, as
a model to further access
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Scheme 1 Proposed mechanism for the TRAL and the TRAL–alkylation.
spirolactam moieties. We herein report a preliminary pathway
to such constrained structures in a first part, using the TRAL–
alkylation tandem reaction, the quickest way to prepare substi-
tuted pyrrolidine-2,4-diones. In the second part of our manu-
script, we then disclose an alternative access to spirolactam
constructs, highlighting an attractive edifice able to fold and
behave as a PPII helix.
Results and discussion
First route to spirolactam scaffolds
The TRAL–alkylation gave substituted pyrrolidine-2,4-diones
with a high to total diastereoselectivity, depending on the
steric hindrance of the starting DKP’s side-chain. After a pre-
liminary protection/activation step of the lactams using Boc2O
and DMAP, the resulting activated N,N′-bis-Boc-cyclo-[Gly-(D)-
Val] model was submitted to the TRAL–alkylation conditions
using ethyl 2-(bromomethyl)acrylate as the alkylating agent
(Scheme 2). The reaction proceeded with a total diastereo-
selectivity furnishing the R,R-diastereoisomer 2 with a yield of
38%. As we recently reported,44 it is always difficult to propose
a predictable and rational chemical reactivity for the TRAL–
alkylation, the major by-product here resulting from a direct
alkylation of the starting DKP.
Scheme 2 Synthesis of spirolactams using the TRAL–alkylation reaction.
After a facile deprotection of the Boc-moieties allowing iso-
lation of the trifluoroacetate salt of the primary amine, we
chose to increase the functional diversity on our scaffold.
Taking advantage of the acrylate moiety, a benzylamino group
was incorporated in the following step via a suitable aza-
Michael addition. At this stage we observed the 1,4-addition of
benzylamine, concomitant with the spirocyclisation, without
any detectable trace of 1,2-addition. An excess of benzylamine
under microwave irradiation triggered a one-pot spirocyclisa-
tion concomitant with an aza-Michael addition. This tandem
reaction led to 95% conversion of the starting material into
the functionalized original spirolactam 3. Concurrently, the
presence of a keto group caused the formation of a Schiff base
which needed to be further hydrolysed with aqueous 1 N HCl.
This unprecedented reaction which is in fact a combination of
three different synthetic steps – a 1,4-addition of benzylamine
on the ethyl acrylate moiety, and an intramolecular cyclization
concomitant with a Schiff base formation – allowed access to
innovative spirolactam scaffolds with excellent yield.
Only one epimer was isolated (3a, for details, please refer to
ESI†), which then underwent a stereocontrolled reduction
using sodium borohydride to provide a crystalline spirolactam 4.
NOESY experiments performed on compound 4, revealing
strong correlations between hydrogen 7, 16 and 17, allowed us
to confirm the 9R,11R,16S,17S configuration for this com-
pound. Access to the crystal structure permitted us to validate
those NMR data, certifying the relative stereochemistry of the
stereogenic centre created during the aza-Michael addition
and the configuration of the asymmetric quaternary carbon
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11, previously generated during the TRAL–alkylation. The
stereoselectivity of the reduction step could be supported by
the literature which described the reduction of substrates
bearing a hydrogen bond donor (HBD) on an asymmetric
carbon in the α-position of the carbonyl to reduce.46 The
hydride source, supposedly positioned in the same plane as
the HBD, could explain the produced selectivity during
the reduction step, thanks to a dihydrogen bond formation.47
A second plausible explanation for the observed total stereo-
selectivity could also be the steric hindrance at the Si face gen-
erated by both alkyl groups in α and α′ positions of the ketone.
Consequently, the attack of the hydride would occur at the less
hindered Re face, yielding only the 17S diastereoisomer.
Benefiting from these results, we decided to turn our atten-
tion to the simple version of the TRAL, which presents the
advantage of a quantitative yield. Thus switching from the
TRAL–alkylation to the TRAL reaction followed by an appropri-
ate alkylation step, we envisioned to apply the precedent syn-
thetic pathway.
Second route to spirolactam scaffolds
The activated N,N′-bis-Boc-cyclo-[Gly-(D)-Val] model was sub-
mitted to the TRAL conditions, allowing the synthesis of the
aminotetramate 5. When O-alkylation conditions, using ethyl
2-(bromomethyl)acrylate, were applied to the TRAL product, a
concomitant and opportune Claisen rearrangement took
place, giving us access to compound 6 in a single step
(Scheme 3).
Based on a previous study on O-alkylation of aminotetra-
mates,43 we postulated that the reaction did not proceed
through a direct C-alkylation. We could notice here that the
subsequent Claisen rearrangement was completed at room
temperature without any addition of catalyst, which is unusual
for such a sigmatropic rearrangement.48 The main advantage
of this step lies in its total diastereoselectivity, which could be
explained by a representation of the Zimmerman–Traxler
Scheme 4 Synthesis of spirolactam diastereoisomeric mixture 8.
chain-like transition state (Scheme 3).48 The isopropyl side
chain creates a strong steric hindrance, preventing the for-
mation of the R,R isomer. Compound 6 was prepared with a
greatly improved yield of 70% compared to its diastereoiso-
meric construct synthesized by the first route.
Following our preliminary study, Boc protecting groups
were removed in pure TFA before neutralizing the TFA salt,49
to generate compound 7 (Scheme 4). The tandem reaction
described for the first route, involving a spirocyclisation conco-
mitant with an aza-Michael addition and an imine formation,
was then applied to this pyrrolidine-2,4-dione yielding, after a
suitable acidic work-up, a functionalized spirolactam 8 (95%
yield). Purification of the mixture of the two diastereoisomers
allowed us to isolate 8a and 8b in 40% and 45% yield,
respectively.
Compound 8a was then submitted to a stereoselective
reduction step to yield 10a, unfortunately we were unable to
crystalize the product. Unexpectedly, cautious 2D-NMR experi-
ments performed on compound 10a and meticulous compari-
son with data obtained earlier during the synthesis of product
4 led us to discover a remarkable epimerisation of the asym-
metric carbon bearing the isopropyl group.
We were intrigued to observe in this second route, and not
in the first one using the TRAL–alkylation (Scheme 2), a quasi-
total inversion of configuration of one stereogenic center
(>90% de), instead of a more expected partial loss of stereo-
chemistry due to the imine–enamine intermediate
equilibrium.
Regarding opposite and equal specific rotations, but also
identical 1D NMR spectra, of 10a and 4, it appeared obvious
that two enantiomers were present. Careful NOESY experi-
Scheme 3 Diastereoselective O-alkylation–Claisen rearrangement tandem
ments confirmed those data by highlighting
a strong
reaction.
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correlation between H17 and H16 and between H17 and NH7 En route to the construction of folded edifices
while no signs of correlations between H16 with H10 and H10′
Having efficient access to spirolactam building blocks, helpful
were detected. We found it of interest to develop arguments to
explain this serendipitous epimerisation, which seemed to be
related to the formation of the undesired imine during the
tandem reaction.
To understand precisely at which step this epimerisation
exactly occurred, we performed similar NOESY experiments on
the spirolactam 9, prepared by simply heating primary amine 7
in absolute ethanol, using microwave irradiation, without any
for the construction of folded edifices, we then intended (i) to
firstly take advantage of the hydroxyl group generated pre-
viously for crystallization, thinking that this additional point
of functionalization could be useful to decrease the keto reac-
tivity but also to further build larger structures, (ii) to secondly
remove the benzyl protecting group to release a free amino
group in order to link the two spirolactam units, (iii) to finally
proceed to the dimerisation itself.
Reduction of the spirocycles 8a or 8b using sodium boro-
hydride furnished monomers 10a and 10b with an excellent
yield and a total diastereoselectivity, while a hydrogenolysis of
8a or 8b, using Pd/C 10% under a hydrogen atmosphere in an
acidic medium, easily led to the desired primary amines 11a
and 11b. The linking of the two monomers 10 and 11 was then
performed on each diastereoisomer by creating a urea bond in
the presence of triphosgene and DIPEA.50 Dimers 12a and 12b
were finally isolated with good yields after purification by pre-
parative HPLC (Scheme 6).
addition of benzylamine. NMR analyses of compound
9
revealed no correlation this time between H11 and NH5, con-
firming the retention of the configuration of C11 during the
heating step. The same epimerisation could be further
observed, with an identical diastereomeric excess, only when
the spirolactam 9 was converted into compound 8 in the pres-
ence of benzylamine under microwave heating. As a first con-
clusion, the epimerisation seemed to be clearly induced by the
presence of benzylamine and could find its explanation in the
Schiff base formation.
A proposed mechanism which could explain the high
stereoselectivity of this epimerisation process is depicted in
Scheme 5. We suggested here that in the imine–enamine equi-
librium, the C11 could switch from sp3 to sp2 allowing us to
easily consider a potential epimerisation of the product. To
explain the observed quasi total inversion, promoting the for-
mation of one epimer in favour of another, we proposed a peri-
cyclic reaction involving the lactam group borne by cycle A and
the enamine group of the cycle B. In the representation pro-
posed in Scheme 5, due to the bottom face localization of the
lactam, the sp2 carbon C11 seems to have no choice but to
acquire the NH proton via the same Re face to become sp3
again, resulting in the inversion of the configuration of C11.
This postulated mechanism is also coherent with the absence
of epimerisation observed initially for spirolactam 4. Following
a similar representation, the lactam would be located, this
time, at the top face of cycle A, the pericyclic reaction resulting
in the retention of the configuration of C11.
To summarize this chemical part of our report, TRAL reac-
tion products were used as spirolactam precursors and helped
us to confirm an unprecedented total inversion of the con-
figuration based on a pericyclic reaction. An elegant 6-step
pathway was developed, providing us access to innovative con-
strained dimeric spirocyclic constructs with a good overall
yield of 47–49%.
To gain information on local secondary structures of our
dimers, we then decided to use the circular dichroism (CD)
analytical technique. Obviously, this is the most popular tech-
nique to determine spatial arrangement of chiral molecules,
especially conformations of proteins, peptides and more par-
ticularly polyproline II secondary structures.24,51
Scheme 5 Proposed pathway for the highly stereoselective epimerisation
process.
Scheme 6 Dimerisation of spirolactams 8a and 8b to access 12a and 12b.
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CD results of the synthesized spirolactam constructs will be correlated with the presence of a benzyl moiety or a cis-con-
then presented afterward to explore the conformational state figuration of amide bonds in lactams.
of the synthesized spirolactam constructs, although our struc-
To reinforce this first assumption of a similar behaviour in
tures were not related to peptides and we were aware of the CD between our molecule and a natural PPII, extensive CD
fact that CD spectra interpretation can be misleading when studies involving the effect of increasing temperature, and
dealing with non-peptidic structures.
more specifically the concentration effect in the presence of a
chaotropic agent, were performed revealing a bio-inspired PPII
conformation of dimer 12a. Regarding the literature,29,30,51–53
among the helical structures, PPII helix has been known for
decades to be more resistant to an increase of temperature
than any other helix. Additional temperature-based variation
analyses by CD revealed a PPII characteristic temperature
effect on the CD spectrum of 12a (Fig. 1). The conformational
change between two forms occurring at 50 °C, indicated by the
presence of an isodichroic point, is reversible since we
recorded, at 5 °C, after this experiment, the same spectrum as
before heating. This point clearly indicated that the dimeric
construct could assume a preferred folded state. Comparable
results were obtained when performing CD studies in a less
polar solvent such as TFE.
The most striking observation was nevertheless the typical
intensification of 12a molar ellipticity, similar to that of the
hexaproline, in the presence of increasing concentrations of a
chaotropic agent, a typical behavior only displayed by a PPII
helix among natural secondary structures.30,51–53 The compar-
able comportment of our dimer and a natural PPII in the pres-
ence of a chaotropic agent,52 displayed through a signal
Folded potential of compound 12a
CD spectra of monomers and dimers were recorded, analyzed
and compared with the CD spectrum of the hexapeptide
H-(Pro)6-NH2 synthesized in our laboratory. The CD spectrum
of H-(Pro)6-NH2 in phosphate buffer, as PPII helices, showed a
positive π–π* band around 204 nm and a negative n–π* band
around 226 nm. The spectral features were extremely characteri-
stic, easy to differentiate from other secondary structures, and
typically intensified in the presence of a chaotropic agent such
as guanidine hydrochloride, which favored the PPII structure
(for details refer to ESI†).30,51–53
As expected, CD spectra of all monomers presented data
which were not in favour of a PPII folded potential but which
could be more qualified as unordered forms (for details refer
to ESI†). However, the behaviour of our artificial dimer 12a in
CD analyses was remarkably similar to that observed with the
well-known PPII hexaproline.30,51–55
In phosphate buffer, a negative band followed by a positive
one of lower magnitude was observed, with an exact batho-
chromic effect compared to PPII spectra, which could be
Fig. 1 CD experiments in phosphate buffer; A and B: effect of the increasing temperature on the global shape of 12a and 12b signals respectively; C and D: effect
of increasing concentrations of guanidinium chloride on the global shape of 12a and 12b signals, respectively.
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reinforcement, which is exceptional with chemical compounds
Although the correlation between the spirocyclic structures
unrelated to peptides, are strong arguments in favour of a bio- and proline moieties seems unusual, molecular modelling
inspired PPII conformation of 12a. Even though this dimer studies suggested that the two nitrogens of each spiro group
exhibited some of the properties of the PPII helix, we could could be correlated to two consecutive nitrogens of a Pro–Pro
not affirm that 12a literally mimics a PPII helix.
sequence (Fig. 2). The resulting construct could possibly be
To confirm that CD spectra do not result from the sum of seen as a series of two over-constrained proline bio-inspired
the CD spectra of each building block, the same experiments structures linked by a flexible arm, increasing the extended
were performed with an equimolar mixture of 10a and 11a PPII-structural ability of the edifice.
corroborating the importance of the carbamide linker in the
PPII-like behaviour of the dimer 12a (for details refer to ESI†).
Inspired by biological systems, chemists have managed to
design and synthesize artificial oligomers able to spon-
As polyproline II conformation is critical for the majority of taneously fold into well-defined edifices.57 Recently, H.-S. Lee
protein–protein interaction modules, molecular modelling et al. introduced the concept of “foldectures” where artificial
analysis was also initiated to illustrate how such a chemical protein fragments with particular secondary structure self-
entity could recognize an SH3 domain. Consequently, com- assembled to provide original 3D molecular architectures.58,59
pound 12a was docked on the 3D structure of a relevant SH3 To learn more about the “foldecture” potential of our edifice
domain without applying any restraints to the system and having a specific rigidity and folding predisposition to act as a
using a flexible algorithm to illustrate how such conformers PPII helix, we undertook Scanning Electron Microscopy (SEM)
could interact and recognize SH3 domains.
experiments under solvophobic conditions. The SEM images
Then, a 3D model of a PPII-bound conformation was revealed the 3D shape of diverse rods and sticks, which are ca.
achieved by a flexible docking of the spiro-compound 12a onto 75 μm in length for the longest one with widths of ca. 8.5 μm
the SH3 domain of the Fyn kinase, a very well described PPII (Fig. 3).
interacting partner (PDB code 1EFN).56 The top solutions from
the docking simulation were filtered using NMR restraints
observed in aqueous solution (for details refer to ESI†) and the
most representative conformation was compared to a penta-
proline (Fig. 2). The resulting conformation of this polyproline
demonstrated the potentiality of our heterocyclic framework to
mimic the three-dimensionality of PPII helices with a con-
served shape, end-to-end distances and 3D-pharmacophoric
properties (Fig. 2).
According to our first results, we have discovered here
efficient access to chemical constructions able to fold into arti-
ficial structures hypothetically acting as natural polyproline
oligomers.
Fig. 3 SEM images of the self-assembled structure of dimer 12a.
Fig. 2 (A) Representation from modelling studies of PPII bio-inspired spirocyclic dimers 12a (right) and a pentaproline in PPII conformation (left) (modelled from
PDB code 1EFN). (B) Representation of the crystallographic structure between Nef polyproline (sticks with atoms colour-coded option) and SH3 from Fyn kinase
protein (PDB code 1EFN, Conolly-type surface representation with depth-colour coded option). The side chains of the pXXp from Nef (residues XX-XX) have been
replaced by prolines; (C) docking mode of action of 8a after a fully flexible docking by surflex-GeomX and compatibility assessment with NMR restraints observed in
solution; (D) schematic analysis of the relative orientation of the spiro groups (orange) with the N- and C-term Pro–Pro (yellow).
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Only a biological evaluation of optimized compounds actu- interactions but also be more generally useful for molecular
ally under investigation would permit us to conclude if 12a recognition, catalysis or nanoscience.
indeed behaves as the natural PPII helix does and if specific
moieties of the molecule are more active than others, such as
the carbonyl moieties for example.
Acknowledgements
For this purpose, the affinity of the dimer needs to be
improved by adding specific amino acid sequences on the This work was supported by the “Ministère de l’Enseignement
compounds side chain to possibly bind specific receptors and Supérieur et de la Recherche” and the CNRS. The authors are
crystallize the compound in the presence of a biological target particularly grateful to Dr C. Baraguey for fruitful discussions
such as the SH3 domain.
regarding the structure elucidation of compounds 12a and
12b.
Folded potential of compound 12b
Unexpectedly, analysis of CD spectra of dimer 12b, whose
structure differs from 12a only by the configuration of two
stereogenic centres, was incompatible with PPII helix features.
The CD spectrum displayed a weak negative band around
208 nm and a strong positive band at 227 nm, the signature of
a folded state. One can tentatively compare the shape of the
signal with the one of a class B β-turn, exhibiting a weak nega-
tive band around 187 nm and a strong positive band around
209 nm, a well-known secondary structure.54 A bathochromic
effect compared to class B β-turn spectra could here again be
correlated with the presence of a benzyl moiety or a cis-con-
figuration of amide bonds in lactams. The folding propensity
of 12b could be easily disturbed by a chaotropic agent or by
increasing the temperature above 25 °C as proven by the loss
of its signature, a completely opposite behaviour compared to
12a. This peculiarity was hypothetically consistent with a
possible β-turn conformation, acknowledged to be stabilized
by intramolecular hydrogen bonds. It is important to note that
for both dimers, the conformational changes induced by the
heating were reversible, since we noticed the reappearance of
the exact same spectrum when cooling back to room tempera-
ture. To confirm that CD spectra do not result from the sum of
the CD spectra of each building block, the same experiments
were performed with an equimolar mixture of 10b and 11b
corroborating the importance of the carbamide linker in the
folding potential of the dimer 12b (for details refer to ESI†).
While an ever-growing interest in β-turn mimics makes this
work perhaps less relevant compared with neglected PPII
mimics, additional studies are actually under investigation to
confirm this hypothesis.
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