A mechanochemical approach to access the proline-proline diketopiperazine framework

Article abstract of DOI:10.3762/bjoc.13.217

Ball milling was exploited to prepare a substituted proline building block by mechanochemical nucleophilic substitution. Subsequently, the mechanocoupling of hindered proline amino acid derivatives was developed to provide proline-proline dipeptides under solvent-free conditions. A deprotection-cyclization sequence yielded the corresponding diketopiperazines that were obtained with a high stereoselectivity which could be explained by DFT calculations. Using this method, an enantiopure disubstituted Pro-Pro diketopiperazine was synthesized in 4 steps, making 5 new bonds using a ball mill.

Full text of DOI:10.3762/bjoc.13.217

A mechanochemical approach to access the proline–proline
diketopiperazine framework
Nicolas Pétry1, Hafid Benakki1,2, Eric Clot3, Pascal Retailleau4, Farhate Guenoun2,
Fatima Asserar2, Chakib Sekkat2, Thomas-Xavier Métro*1, Jean Martinez1
and Frédéric Lamaty*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 2169–2178.
1Institut des Biomolécules Max Mousseron (IBMM), UMR 5247,
CNRS, Université de Montpellier, ENSCM, Campus Triolet, Place
Eugène Bataillon, 34095 Montpellier Cedex 5, France, 2Laboratory of
Chemistry Biology Applied to the Environment, Faculty of Sciences,
Moulay Ismail University BP: 11201 Zitoune Meknès, Morocco,
3Institut Charles Gerhardt, UMR 5253 CNRS-UM-ENSCM, Université
de Montpellier, Place Eugène Bataillon, cc 1501, 34095 Montpellier
Cedex 5, France and 4Institut de Chimie des Substances Naturelles,
CNRS UPR 2301, Université Paris-Saclay, 1 Avenue de la Terrasse,
91198 Gif-sur-Yvette, France
doi:10.3762/bjoc.13.217
Received: 30 May 2017
Accepted: 21 September 2017
Published: 19 October 2017
This article is part of the Thematic Series "Mechanochemistry".
Guest Editor: J. G. Hernández
© 2017 Pétry et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Thomas-Xavier Métro* - thomas-xavier.metro@umontpellier.fr;
Frédéric Lamaty* - frederic.lamaty@umontpellier.fr
* Corresponding author
Keywords:
ball mill; DFT calculations; diketopiperazine; mechanochemistry;
pyrrolidine
Abstract
Ball milling was exploited to prepare a substituted proline building block by mechanochemical nucleophilic substitution. Subse-
quently, the mechanocoupling of hindered proline amino acid derivatives was developed to provide proline–proline dipeptides
under solvent-free conditions. A deprotection–cyclization sequence yielded the corresponding diketopiperazines that were obtained
with a high stereoselectivity which could be explained by DFT calculations. Using this method, an enantiopure disubstituted
Pro–Pro diketopiperazine was synthesized in 4 steps, making 5 new bonds using a ball mill.
Introduction
2,5-Diketopiperazines (DKPs) are heterocyclic structures, [3]. Consequently, medicinal chemists have used DKPs exten-
usually derived from dipeptides, which find many applications sively as a synthetic platform, easily synthesized and stereo-
in chemistry and biology, and have attracted attention in the last chemically controlled, for the preparation of small bioactive
years [1,2]. The diketopiperazine backbone can be found in molecules [4,5]. DKPs have also been considered as chiral
many natural products exhibiting various biological activities auxiliaries in asymmetric synthesis [6]. Furthermore, the
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Beilstein J. Org. Chem. 2017, 13, 2169–2178.
rigidity of the DKPs is a unique feature, used for the prepara- has been extensively used [1], involving milder conditions and
tion of biologically active peptides and peptidomimetics [7], for provides access to unsymmetrical dipeptides and DKPs.
applications in organocatalysis [8-10], and for the preparation Furthermore, substituted prolines could be obtained by nucleo-
of novel materials [11,12].
philic substitution of benzylamine from dimethyl dibromoadi-
pate, allowing the addition of functional groups on the Pro–Pro-
An interesting sub-family of these compounds are DKPs based framework [17]. Recently, mechanochemistry has
derived from the amino acid proline and its analogues, which become a powerful synthetic technique for making new organic
provide a useful rigid structure. During the course of our proj- molecules [18,19]. In the course of this project, we applied
ect on the exploitation of dimethyl dibromoadipate as a synthon mechanochemistry to a nucleophilic substitution and the effi-
to access original molecules [13,14], we thought that it could cient coupling of two proline residues.
provide an original access to the DKP Pro–Pro framework.
More specifically, this type of framework has been used as a Results and Discussion
scaffold for the preparation of small compound libraries [15]. First we studied the preparation of simple Pro–Pro DKP as a
model compound. The use of ball milling in peptide synthesis
The Pro–Pro diketopiperazine can be prepared directly by has drawn some attention in the recent years [20-28]. We took
dimerization of unprotected proline in a one-pot transformation, advantage of our extensive experience in peptide mechanosyn-
generally under harsh conditions [16]. Good results were indeed thesis [20,23-25,27] to prepare the Pro–Pro dipeptide from the
reported, although this procedure gives access only to symmet- corresponding amino acid derivatives. We investigated the cou-
rical products and can be detrimental for more fragile mole- pling of proline N-hydroxysuccinimide ester with proline
cules such as substituted enantiomerically pure compounds. As methyl ester in a vibrating ball mill (vbm, Scheme 2) [23].
shown by a retrosynthetic analysis (Scheme 1), a classical
milder approach would consist in preparing first the dipeptide, Surprisingly, while the coupling of various other amino acids
followed by an intramolecular ester aminolysis. This strategy previously used yielded the corresponding dipeptides [23], no
Scheme 1: Retrosynthesis of the Pro–Pro DKP framework.
Scheme 2: Coupling with N-hydroxysuccinimide-activated amino acids.
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Beilstein J. Org. Chem. 2017, 13, 2169–2178.
reaction occurred in the case of the two prolines 1 and 2, even (Table 1, entry 3) did not provide much improvement. Finally
by varying the reaction conditions. To verify the reactivity of supplementing the reaction mixture with oxyma (Table 1,
either Boc–Pro–OSu (1) or H–Pro–OMe (2) in the mechanocou- entries 4–7) increased the yield up to 85–90% depending on the
pling, we reacted HCl·H–Phe–OMe or Boc–Phe–OSu with re- protection on the proline nitrogen (Boc or Z). Both of the bases
spectively Boc–Pro–OSu and HCl·H–Pro–OMe. In both cases, gave similar yields (Table 1, entry 5 vs 7 and entry 4 vs 6).
the reaction proceeded smoothly to give good yields of dipep- Eventually, as proposed before [25], NaH2PO4 was preferred
tides 3 and 4 (95% of Boc–Pro–Phe–OMe and 82% of since it would avoid a potential pressure build-up (release of
Boc–Phe–Pro–OMe, respectively). Most probably, this method CO2) which could occur with NaHCO3. Noteworthy, no epi-
was less adapted to hindered amino acid derivatives such as merization could be detected by NMR or HPLC analyses.
proline.
Both peptides 7 and 8 were then deprotected and cyclized into
As an alternative approach, we tested the optimal conditions de- the corresponding diketopiperazine 9. Palladium-catalyzed
veloped previously for peptide mechanosynthesis [25], starting hydrogenolysis of the Z group of 7, in the presence of NaHCO3,
with unactivated amino acids together with a coupling agent. in MeOH, provided the DKP 9 in 83% yield. Compound 8 was
We had indeed reported two successful examples of couplings deprotected with gaseous HCl, and the resulting dipeptide was
involving proline amino esters. The initial conditions, using cyclized in the presence of NaHCO3, in MeOH, yielding 70%
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), ethyl of 9 (Scheme 3).
cyano(hydroxyimino)acetate (oxyma) in the presence of a base
and a liquid additive, were adapted to the preparation of Then, as proposed above, we expanded this method to the prep-
Z–Pro–Pro–OMe (7) and Boc–Pro–Pro–OMe (8, Table 1). It aration of substituted Pro–Pro DKPs. For this purpose, we
consisted in ball milling the two amino acid derivatives 5 or 6 considered using dimethyl (2R,5S)-pyrrolidine-2,5-dicarboxy-
with 2 in the presence of EDC (coupling agent), a base and a late (cis-11) as a building block in the synthesis of dipeptides
small amount [29] of EtOAc as liquid grinding assistant. The and diketopiperazines. This building block was used in a very
role of oxyma was mainly to suppress amino acid epimeriza- limited number of cases for the formation of DKP in combina-
tion during the coupling, a limited problem in the case of tion with an amino acid derivative [30,31]. Original preparative
proline. Consequently, our first experiments did not involve this conditions of the protected compound 11 consisted in per-
reagent (Table 1, entries 1–3). Gratifyingly, the initial results forming a nucleophilic substitution of benzylamine with meso
showed that this method was adequate to prepare the Pro–Pro dimethyl-2,5-dibromohexanedioate (10) in benzene or toluene
dipeptide 7 albeit in fair yield (Table 1, entry 1). Adding more as solvent, yielding two diastereomers cis-11 (meso) and trans-
starting material 6 (Table 1, entry 2) and changing the base 11 (racemic), which could be separated by crystallization or
Table 1: Optimization of the Pro-Pro couplinga.
Entry
PG
equiv of 5 or 6
Base (equiv)
Activating agent (equiv) Reaction time
Yield (%)
1
2
3
4
5
6
7
Boc
Boc
Boc
Boc
Z
1.2
NaHCO3 (3)
NaHCO3 (3)
NaH2PO4 (3)
NaHCO3 (4)
NaHCO3 (4)
NaH2PO4 (4)
NaH2PO4 (4)
EDC (1.2)
1 h
65
68
66
78
90
85
88
1.2 + 0.5
1.2 + 0.5
1.2
EDC (1.5)
2 × 45 min
2 × 45 min
1 h
EDC (1.5)
EDC/oxyma (1.2)
EDC/oxyma (1.2)
EDC/oxyma (1.2)
EDC/oxyma (1.2)
1.2
1 h
Boc
Z
1.2
1 h
1.2
1 h
aReactions performed under air, in a vibrating ball mill (vbm) at 30 Hz with EtOAc (as a liquid grinding assistant).
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Beilstein J. Org. Chem. 2017, 13, 2169–2178.
Scheme 3: Synthesis of Pro–Pro DKP.
column chromatography [17,32,33]. Trying to avoid as much as mill (pbm) with the advantage of its capacity to produce more
possible the use of (toxic) solvents, we considered extending the material. In this case (Table 2, entry 8), using cheaper K2CO3,
known nucleophilic substitution in a ball mill [34-41] to this full conversion was obtained and cis-11 was isolated in 75%
reaction system (Table 2).
yield and a larger amount of cis-11 could be prepared. Interest-
ingly the cis/trans ratio (cis-11/trans-11) was different when the
For sake of comparison, we first performed the reaction be- reaction was performed in solution (Table 2, entry 1) or in the
tween meso-10 and benzylamine in toluene (Table 2, entry 1) ball mill (Table 2, entries 2–9) with a higher selectivity in the
providing a full conversion into the expected product 11 with a latter case [42].
78:22 cis/trans ratio. Then we studied the mechanosynthesis of
these compounds (Table 2, entries 2–8), starting by mixing an With this building block in hands, the preparation of a variety of
equimolar amount of the starting materials together with a base DKPs could be envisaged (Scheme 4).
(K2CO3) in a vibratory ball mill at 25 Hz (Table 2, entry 2).
This resulted in a lower conversion compared to that obtained in Pyrrolidine cis-11 is an N-protected amino ester, which can be
solution. Using an excess of base increased the conversion to used in the synthesis of diketopiperazines by deprotecting either
62% (Table 2, entry 3). Switching to Cs2CO3 resulted in an in- the amino group or the ester function. Hydrogenolysis of the
creased conversion of 74% (Table 2, entry 4), further improved benzyl group of cis-11 provided the nitrogen-free pyrrolidine
to 82% when the milling frequency was adjusted to 30 Hz derivative 12 in excellent yield and purity after filtration of the
(Table 2, entry 5). Adding EtOAc as liquid grinding assistant catalytic system. 12 was engaged without further purification in
did not improve the conversion, with either K2CO3 or Cs2CO3 a coupling reaction with Z-proline (5) and Boc-proline (6), in
(Table 2, entries 6 and 7). Finally, we tested the planetary ball the solvent-free conditions described above. In both cases, the
Table 2: Optimization of the substitution reaction.
Entry
equiv BnNH2
Base (equiv)
Conditions
Conversiona
cis/trans-11 ratio
1
2
3
4
5
6
7
8
3
–
toluene, 16 h, reflux
vbm, 1 h, 25 Hz
vbm, 1 h, 25 Hz
vbm, 1 h, 25 Hz
vbm, 1 h, 30 Hz
vbm, 1 h, 30 Hzb
vbm, 1 h, 30 Hzb
pbm, 2 h, 500 rpmb
100
40
62
74
82
49
59
97
78:22
96:04
98:02
91:09
94:06
98:02
87:13
97:03
1
K2CO3 (1.2)
K2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
K2CO3 (3)
Cs2CO3 (3)
K2CO3 (2.2)
1
1.1
1.1
1.1
1.1
1.3
aMeasured by 1H NMR bEtOAc was used as liquid grinding assistant.
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Beilstein J. Org. Chem. 2017, 13, 2169–2178.
Scheme 4: Synthesis of substituted Pro–Pro DKP 15a.
dipeptides 13 and 14 were obtained in good yields (78 and 61%, of the reaction mechanism have been carried out. DFT calcula-
respectively). Deprotection followed by cyclization provided tions were applied to the various pathways starting from the
the corresponding diketopiperazine 15a in 95% yield (from 13) deprotected amine 16 and reaction pathways leading to either
or 80% yield (from 14). In this case, two carboxymethyl groups product 15a, resulting from nucleophilic attack of the amine on
could participate in the cyclization providing two possible dia- Ca, or to product 15b resulting from attack on Cb, were consid-
stereomers 15a and 15b (Scheme 5).
ered (Scheme 5).
To our delight, this stereodivergent cyclization was selective The first step was to study if there was any preferential interac-
and only one diastereomer was obtained, as supported by ana- tion between the free nitrogen atom and either Ca or Cb before
lytical data. X-ray analysis of the product confirmed the stereo- the C–N bond formation. Both optimized structures are shown
chemistry of the three chiral centres and the structure of 15a.
in Figure 1, and compound 16a is computed to be less stable
than 16b by ΔG = 2.7 kcal mol−1. The C···N bond distance is
To shed more light on the origin of the selectivity observed in slightly shorter in 16b (2.673 Å) than in 16a (2.682 Å). Many
the deprotection–cyclization transformation, DFT calculations attempts to locate a transition state structure for the C–N bond
Scheme 5: Potential isomers yielded by cyclization of 16.
Figure 1: Optimized geometries for the two conformers presenting interactions with either Ca (16a) or Cb (16b). H atoms were omitted for clarity.
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Beilstein J. Org. Chem. 2017, 13, 2169–2178.
formation starting from either 16a or 16b failed. Even though with ΔG = −17.3 kcal mol−1 and the geometry of 15a-solv
the geometry optimizations were performed with implicit inclu- (Figure 2) had the stereochemistry expected for 15a
sion of the solvent influence (SMD model with methanol), the (Scheme 5).
zwitterionic character developing in the C–N bond formation
could not be stabilized. However, the protic methanol solvent
Table 3: Selected bond distances (Å) for the structures optimized
could act both as a base to abstract the proton from the nitrogen
atom, and as an acid to facilitate the C–OMe bond cleavage.
Transition state structures with combined implicit (SMD model)
and explicit inclusion of the solvent were thus searched for.
along the transformation 16a-solv→15a-solv.
Bond
16a-solv
TS-16a-solv 15a-solv
N–H
1.077
2.153
0.970
1.925
1.340
2.464
1.167
1.341
1.226
1.117
1.935
1.500
2.310
0.965
1.761
0.979
3.784
1.343
NH···O
MeO–H
H···OMe
C–OMe
N–C
The geometry of 16a allowed the creation of a network of stabi-
lizing interactions between an explicit methanol solvent mole-
cule and both the N–H proton and the OMe group (N–H···O =
2.153 Å, H···OMe = 1.925 Å; see 16a-solv in Figure 2).
16a-solv was computed to be less stable than 16a by
ΔG = 9.3 kcal mol−1. This higher Gibbs free energy was due
only to entropic factors as 16a-solv was computed to be more
stable than 16a by ΔE = −4.0 kcal mol−1. Interestingly, upon The geometry of 16b did not allow creating a similar network
interaction with an explicit methanol molecule the C···N dis- of H-bonding interactions when one explicit molecule of
tance in 16a-solv had been reduced to 2.464 Å compared to methanol was considered. The N–H bond is pointed in a direc-
a value of 2.682 Å in 16a. A transition state structure, tion of space remote from the methoxy group of the ester
TS-16a-solv, corresponding to a concerted C–N bond forma- functionality. Rotation by 180° around the C–C bond of the
tion and a C–OMe bond cleavage could be located (Figure 2). ester led to a geometry in which a methanol molecule could
Table 3 collects selected bond distances associated to the trans- interact with both groups as illustrated in 16b-solv (Figure 3).
formation. In the transition state, the C–OMe bond cleavage This structure was computed to be more stable than 16a-solv by
was well advanced and the C–N bond formation was also ΔG = −3.8 kcal mol−1, probably because in addition to the ex-
almost complete. This indicated that the transformation was pected H-bonds between N–H and O (N–H···O = 2.123 Å), and
concerted and that the explicit methanol molecule only acted as between O–H and OMe (H···OMe = 2.488 Å), there existed an
a relay to accept the proton from the amine and to facilitate the additional H-bond with the other ester functionality (H···OC =
departing of the methoxy group by transferring a proton. The 1.873 Å). However, despite the greater stability of 16b-solv, the
activation energy from 16a-solv was computed to be concerted formation of C–N and cleavage of the C–OMe bond
ΔG# = 22.8 kcal mol−1, in good agreement with an easy reac- through TS-16b-solv was associated to a higher activation
tion at room temperature. The reaction was strongly exoergic barrier with ΔG# = 30.0 kcal mol−1 and a less exoergic reaction
Figure 2: Optimized geometries of the extrema located along the pathway for formation of 15a with explicit participation of one solvent molecule. Most
H atoms were omitted for clarity.
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Beilstein J. Org. Chem. 2017, 13, 2169–2178.
Figure 3: Optimized geometries of the extrema located along the pathway for formation of 15b with explicit participation of one solvent molecule.
Most H atoms were omitted for clarity.
(ΔG = −2.6 kcal mol−1). Selected bond distances in Table 4
Table 4: Selected bond distances (Å) for the structures optimized
clearly show that the formation of C–N and cleavage of C–O
are both well advanced in TS-16b-solv, similarly to the situa-
tion observed in TS-16a-solv. The essential difference was the
significant longer C···N distance in 16b-solv (2.625 Å vs 2.464
Å in 16a-solv), and the longer H-bond between the methanol
molecule and the methoxy group in 16b-solv (2.488 Å) com-
pared to that observed in 16a-solv (1.925 Å). The origin of
these differences lied in the presence of an H-bond between the
methanol molecule and the carbonyl group of the other ester
functionality. This interaction stabilized a geometry with a
longer C···N distance, and destabilized the transition state struc-
along the transformation 16b-solv→15b-solv.
Bond
16b-solv
TS-16b-solv 15b-solv
N–H
1.018
2.123
0.973
2.488
1.326
2.625
1.165
1.342
1.212
1.182
1.940
1.521
2.014
0.971
1.751
0.979
3.333
1.365
NH···O
MeO–H
H···OMe
C–OMe
N–C
ture as it needed to be lost in TS-16b-solv (H···OC = 3.326 Å vs TS-16a-solv and TS-16b-solv were significantly different, and
1.873 Å in 16b-solv).
this could be the origin of the stability of the former. Therefore
a transition state structure leading to 15b with the methanol
There was thus a significant energetic preference for the forma- molecule in an “exo” position was optimized (TSbis-16b-solv,
tion of 15a with respect to 15b with a ΔΔG# = 7.3 kcal mol−1. Figure 4). This transition state was less stable than TS-16b-solv
However, the positions of the methanol molecule in by 2.9 kcal mol−1. Alternatively, a transition state structure
Figure 4: Optimized geometries for the transition states associated to alternate position of the methanol molecule. Most H atoms were omitted for
clarity.
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Beilstein J. Org. Chem. 2017, 13, 2169–2178.
leading to 15a with a methanol molecule in an “endo” position tive cyclization, which was clearly supported by DFT calcula-
was located (TSbis-16a-solv, Figure 4). This structure was tions is noteworthy. Further developments and applications of
computed to be less stable than TS-16a-solv by 3.9 kcal mol−1. these scaffolds are currently underway.
The calculations thus clearly indicated that there was a
low lying pathway for the formation of 15a consisting in a
Supporting Information
concerted C–N bond formation and C–OMe bond cleavage
mediated by a solvent methanol molecule acting as both a
Experimental procedures and characterization of new
proton acceptor from N–H and a proton donor to OMe. All the
compounds, X-ray data including CCDC numbers and CIF
alternative pathways were associated to transition states lying at
files.
significantly higher energy not to be observed experimentally.
Supporting Information File 1
Experimental part.
This was in agreement with the experimental formation of only
15a.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-217-S1.pdf]
As mentioned above, another possibility to exploit meso pyrrol-
idine cis-11 would be to desymmetrize [43] the ester functions
by selective hydrolysis. The corresponding carboxylic acid
could then be engaged in a peptide coupling. Pig liver esterase
(PLE)-catalyzed enzymatic hydrolysis of meso cis-11 provided
selectively the N-protected amino acid 17 as one enantiomer
[33,44,45]. Mechanocoupling of 17 with pyrrolidine 12 provi-
ded the dipeptide 18 in excellent yield. Removal of the benzyl
group by hydrogenation in the presence of Pd(OH)2/C followed
by cyclization provided unprecedented DKP 19 in 52% yield. In
this case again, spectral data and X-ray analysis showed the
selective formation of diketopiperazine 19 as only one isomer
(Scheme 6).
Supporting Information File 2
Crystallographic data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-217-S2.pdf]
Supporting Information File 3
X-ray of meso-10.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-217-S3.cif]
Supporting Information File 4
X-ray of 15a.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-217-S4.cif]
Conclusion
In summary, we have developed an efficient synthesis of two
enantiopure substituted diketopiperazines based on the
proline–proline framework. The synthetic schemes included
two key reactions, which were performed under mechanochem-
ical conditions, including a peptide coupling leading to the for-
mation of Pro–Pro dipeptides, and a nucleophilic substitution
furnishing substituted proline derivatives. The diastereoselec-
Supporting Information File 5
X-ray of 19.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-217-S5.cif]
Scheme 6: Synthesis of diketopiperazine 19.
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Beilstein J. Org. Chem. 2017, 13, 2169–2178.
24.Métro, T.-X.; Colacino, E.; Martinez, J.; Lamaty, F. Amino Acids and
Peptides in Ball Milling. In Ball Milling Towards Green Synthesis:
Applications, Projects, Challenges; Stolle, A.; Ranu, B., Eds.; RSC
Green Chem. Ser., Vol. 31; Royal Society of Chemistry: Cambridge,
UK, 2015; pp 114–150. doi:10.1039/9781782621980-00114
25.Porte, V.; Thioloy, M.; Pigoux, T.; Métro, T.-X.; Martinez, J.; Lamaty, F.
Eur. J. Org. Chem. 2016, 3505–3508. doi:10.1002/ejoc.201600617
26.Landeros, J. M.; Juaristi, E. Eur. J. Org. Chem. 2017, 687–694.
doi:10.1002/ejoc.201601276
Acknowledgements
The authors thank the Centre National de la Recherche Scien-
tifique (CNRS) and Université de Montpellier for financial
support.
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