Letter Cite This: Org. Lett. 2018, 20, 3250−3254
pubs.acs.org/OrgLett
Synthesis of [1,2,4]Triazolo[4,3‑a]piperazin-6-ones: An Approach to the Triazole-Fused Ketopiperazine Scaffold Khoubaib Ben Haj Salah,† Baptiste Legrand,† Mathieu Bibian,† Emmanuel Wenger,‡ Jean-Alain Fehrentz,† and Séverine Denoyelle*,† †
IBMM, Université de Montpellier, CNRS, ENSCM, Faculté de Pharmacie, 34093 Montpellier Cedex 5, France CRM2 (UMR UL-CNRS 7036), Faculté des Sciences et Technologies, Université de Lorraine, 54506 Vandoeuvre-lès-Nancy, France
‡
S Supporting Information *
ABSTRACT: A stereoconservative synthesis to access the triazole-fused ketopiperazine (TKP) scaffold is presented. This underexplored platform offers a wide range of structural modulations with several points of diversity and chiral centers. A series of [1,2,4]triazolo[4,3-a]piperazin-6-ones was synthesized from optically pure dipeptides. The methodology was then successfully applied to access the pyrrolo[1,2-a]triazolo[3,4-c]piperazin-6-one tricycle. Importantly, the crystal structures of representative TKPs confirmed that the configuration of the chiral centers was controlled during the synthetic route and facilitated description of the orientation of the substituents depending on their nature and position on the TKP scaffold.
C
antiviral,5 antifungal,6 antibacterial,7 and neuroprotective8 activities. Since 1,2,4-triazole derivatives have been used as mimics of the amide bond in an attempt to increase the bioavailability of the parent bioactive molecules,9 triazole-fused ketopiperazines (TKPs) could be considered as isosteres of the diketopiperazine scaffold, making them potential candidates for the rational development of new therapeutic agents (Figure 1). Only a few heterocycle-fused ketopiperazines have been reported so far, including triazole- and tetrazole-fused ketopiperazines. The latter have been described as potential bioisosteres of the scaffold of Epelsiban, a DKP developed for the treatment of premature ejaculation in men,10 while the former have only been listed in a patent with only a brief characterization and no stereochemical details.11 Over the past decade, we have been focusing our efforts on the design and pharmacological evaluation of trisubstituted [1,2,4]triazoles in order to find selective and potent ligands of the Ghrelin receptor (a GPCR that controls growth hormone secretion, body homeostasis, and reward-seeking behaviors). We reported several SAR studies showing that we were capable of (i) elaborating potent and highly selective ligands of the receptor12 and (ii) controlling the conformation of the [1,2,4]triazole scaffold while bearing chiral centers.13 With the view to design a new series of heterocyclic compounds, we fused together the triazole and the ketopiperazine rings. The resulting triazoloketopiperazinone scaffold offered a new point
yclic peptides are a class of privileged structures that exhibit a wide spectrum of biological activities.1 Because of their increased enzymatic stability, receptor selectivity, and improved pharmacodynamic properties, cyclic peptides offer potential advantages as therapeutic candidates compared to their linear counterparts.2 Composed of only two amino acids, diketopiperazines (DKPs), also known as piperazin-2,5-diones, are the smallest bioactive cyclic peptides (Figure 1) that have the ability to bind to a wide range of receptors such as the oxytocin receptor, CCR5 (C−C chemokine receptor type 5) or BCRP (breast cancer resistance protein) and to inhibit enzymes such as PDE5 (phosphodiesterase-5), PAI-1 (plasmogen activator-inhibitor 1), or MMPs (matrix metalloproteases).3
Figure 1. General structure of 2,5-diketopiperazines (DKPs) and triazole-fused ketopiperazines (TKPs).
Their small and conformationally constrained heterocyclic scaffold not only gives them high stability against proteolysis but also offers the possibility of introducing diversity and controlling the stereochemistry of the chiral centers. Therefore, they have attracted substantial interest with respect to the wide spectrum of their biological properties, including antitumor,4 © 2018 American Chemical Society
Received: April 9, 2018 Published: May 15, 2018 3250
DOI: 10.1021/acs.orglett.8b01112 Org. Lett. 2018, 20, 3250−3254
Letter
Organic Letters of diversity at position 3 that allowed the possibility of introducing substituents R3 and R4 (Figure 1), and the stiffness induced by the triazole ring remained interesting from a structural point of view. Based on our expertise on the design of substituted [1,2,4]triazoles, we elaborated an efficient synthesis to access a series of substituted [1,2,4]triazolo[4,3-a]piperazin6-ones (Scheme 1). We structurally modulated positions 3, 5, and 8 by introducing several substituents R1, R2, R3, and R4. We fully characterized all final compounds after purification on reversed-phase preparative HPLC. Importantly, we verified by a crystallographic structural study whether the configuration of the chiral centers was controlled during the synthetic route. Eventually, we investigated the orientation of the substituents depending on their nature and position on the TKP scaffold.
Table 1. Synthetic Access to Thioamides 2a−i, 3Benzyl[1,2,4]triazoles 3a−i, and 3-Benzyl[1,2,4]triazolo[4,3a]piperazin-6-ones 4a−i
entry
R1
C*
2, yield (%)
3, yield (%)
4, yield (%)
1 2 3 4 5 6 7 8 9
methyl methyl benzyl benzyl 1H-indol-3-ylmethyl 1H-indol-3-ylmethyl isobutyl (S)-1-methylpropyl (R)-1-benzyloxyethyl
S R S R S R S S Ra
2a, 83 2b, 84 2c, 79 2d, 75 2e, 80 2f, 78 2g, 76 2h, 79 2i, 72
3a, 45 3b, 50 3c, 80 3d, 88 3e, 70 3f, 65 3g, 65 3h, 71 3i, 55
4a, 96 4b, 98 4c, 95 4d, 94 4e, 96 4f, 97 4g, 92 4h, 95 4i, 91
Scheme 1. Synthetic Strategies To Build Triazole- and Tetrazole-Fused Ketopiperazines
Configuration of the C* is R for the final compound 4i and the [1,2,4,]-triazole 3i, while it is S for the thioamide 2i. a
equiv) and acetic acid (3 equiv) in dichloromethane at room temperature as described by Bibian et al.16 Removal of the silver salts on a Celite pad and purification on silica gel using a mixture of EtOAc/hexane led to 3-benzyl[1,2,4]triazoles 3a−i in moderate to good yields (45−88%). This step proved to be the most limiting of the synthetic process. Although the purifications were intricate due to the presence of silver salts difficult to remove, the yield also seemed to depend on the nature of the R1 substituent. For instance, while R1 was a methyl group (compounds 3a and 3b) or a (R)-1benzyloxyethyl group (compounds 3i), the yield dropped around 50%. Nevertheless, no rationale could enlighten why such a decrease was observed with these substituents. To allow the final cyclization, the Boc protecting group was hydrolyzed using a 4 N HCl solution in dioxane at 60 °C. After removal of the solvent under vacuum, the reaction mixture was solubilized in methanol and the pH was adjusted to 9 by adding DIEA. These conditions led to spontaneous intramolecular cyclization into 3-benzyl[1,2,4]triazolo[4,3-a]piperazin-6-ones 4a−i (Figure 2). All of these final compounds were obtained in high yields (91−98%) after purification on reversed-phase preparative HPLC, regardless of the configuration of the chiral carbon bearing the R1 substituent. In the second set of [1,2,4]triazolo[4,3-a]piperazin-6-ones 4j−n, position 8 was decorated with a benzyl group, and the chiral carbon was kept in the S configuration (Table 2). We decided to modulate substituents at position 3 and we introduced methyl groups at position 5, highlighting a new point of diversity. Following the same procedure previously described, we were able to bring diversity at position 3 by using hydrazides that were properly substituted.17 Diversity at position 5 resulted from the nature of the C-terminal αamino acid’s side chain of the starting dipeptide. Initially, we planned to introduce one methyl group (compounds 4j and 4k) then two (compound 4l). Unfortunately, we were not capable of going through the entire synthesis of compound 4l. Indeed, not only did the
Previously described strategies leading to [1,2,3]triazole- and [1,2,3,4]tetrazole-fused ketopirazines used the Ugi multicomponent reaction (Scheme 1).14 Knowing that the main drawback of this reaction is the lack of stereochemical control,15 we envisioned a new strategy to access our target substituted [1,2,4]triazolo[4,3-a]piperazin-6-ones. This strategy started from optically pure dipeptides that were cyclized into [1,2,4]triazole heterocycles via two steps: first, thionation of the amide bond, and second, condensation of substituted hydrazides. Final removal of the Boc protecting group followed by basic treatments allowed the intramolecular cyclization into the piperazinone ring. Two sets of TKPs were designed. First, only one position was modulated. We decided to investigate position 8 as it was the most easily chemically modifiable position of the piperazinone ring. Then, two new positions were modulated, position 3 (present on the triazole ring) and position 5. In the first set of substituted [1,2,4]triazolo[4,3-a]piperazin-6-ones 4a−i, only the nature of the R1 substituent was modulated, while position 3 was decorated with a benzyl group and position 5 consisted of a methylene bridge (Table 1). Various R1 substituents were introduced depending on the nature of the N-terminal α-amino acid of the starting dipeptide (Ala, Phe, Trp, Leu, Ile, or Thr), and we varied the configuration of the chiral center C*. The synthesis started with thionation of the amide bond on dipeptides 1a−i using Lawesson’s reagent (0.5 equiv) in 1,2-dimethoxyethane at 85 °C. Under these conditions, we obtained thioamides 2a−i in good yields (72− 84%). The thionation was followed by the [1,2,4]triazole cyclization induced by the condensation of phenylacetic hydrazide (1.2 equiv) in the presence of silver benzoate (2 3251
DOI: 10.1021/acs.orglett.8b01112 Org. Lett. 2018, 20, 3250−3254
Letter
Organic Letters
Scheme 2. Access to Pyrrolo[1,2-a]triazolo[3,4,c]piperazin6-one Tricycle 4o
interesting to investigate this tricycle scaffold, no suitable crystal for X-ray study could be obtained.
Figure 2. Series of novel substituted TKPs 4a−n.
presence of two methyl groups limit the thionation of the amide bond (compound 2l), but it also prevented the cyclization into triazole ring (compound 3l). This result may suggest that a steric hindrance resulting from the presence of two substituents could not be tolerated at this position. Concerning compounds 4m and 4n, we introduced a new point of diversity at position 3 by grafting a benzyl group bearing an amine function orthogonally protected by a carboxybenzyloxyl group. After deprotection under classical conditions, this amine could be reacted with a panel of new substituents, providing access to additional structural modulations. Finally, in an attempt to rigidify even further the TKP scaffold, we decided to design a tricycle by introducing a pyrrole ring at positions 7 and 8 (Scheme 2). At that point, we wanted to investigate the potential impact of the pyrrole ring on both the TKP scaffold and the spatial orientation of its substituents. Following the general procedure, the thionation of the amide bond of dipeptide Boc-Pro-Gly-OEt 1o led to thioamide 2o in good yield (80%). Cyclization into a triazole ring (compound 3o) followed by cyclization into a ketopiperazine ring (compound 4o) were completed in 50% and 92% yields, respectively, providing access to pyrrolo[1,2a]triazolo[3,4-c] piperazin-6-one 4o. With these newly characterized TKPs in hands, we were able to crystallize compounds 4c, 4d, 4g, 4i, and 4n. The X-ray crystal structures confirmed that the configuration of the chiral centers was retained during the cyclization steps (Figure 3A). Concerning compound 4o, although it would have been
Figure 3. (A) Crystal structures of 4c (in green), 4d (in orange), 4g (in cyan), 4i (in yellow), and 4n (in pink). Hydrogen bonds are shown as cyan dashed lines. (B, C) Superimposition of the TKPs derivatives 4c, 4d, and 4g (B) and 4c, 4i, and 4n (C). Hydrogen atoms have been omitted for clarity. (D) Superimposition of the TKP bicycle scaffolds of 4c, 4d, 4g, 4i, and 4n.
The crystallographic structural study revealed that the crystal asymmetric unit of 4i comprised eight independent molecules with similar structures stacked in two columns (Figure S1). A zigzag hydrogen bond network alternatively connected molecules from each column. Concerning compounds 4c and 4d, a water solvent molecule was hydrogen-bonded to the TKP carbonyl group (Figure 3A). Both compounds shared similar substituents, while the configuration of the chiral center C* in position 8 was S and R, respectively. In this context, the TKP
Table 2. Synthetic Access to Substituted 8-Benzyl[1,2,4]triazolo[4,3-a]piperazin-6-ones 4j−n
entry
R2
C*
2, yield (%)
R3
R4
1 2 3 4 5
methyl methyl dimethyl H H
R S
2j, 82 2k, 79 2l, 50 2c, 79 2c, 79
phenyl phenyl phenyl benzyl benzyl
H H H NHCbz NHCbz
3252
C*
3, yield (%)
4, yield (%) 4j, 95 4k, 92
R S
3j, 80 3k, 72 3l, 0 3m, 55 3n, 59
4m, 87 4n, 89 DOI: 10.1021/acs.orglett.8b01112 Org. Lett. 2018, 20, 3250−3254
Organic Letters
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rings of 4c and 4d exhibited mirror geometries with comparable torsion angles of opposite signs, and the R1 benzyl groups were oriented on opposite faces (Table 3, Figure 3B). Importantly, in both 4c and 4d, the two benzyl substituents were projected on the same side of the TKP and were stabilized by a T-shaped interaction. Such aromatic interaction influenced the orientation of the R3 substituent. Indeed, when the benzyl (R1) was replaced by an isobutyl group in 4g, R3 was projected on the other side of the TKP scaffold. In contrast, when a benzyloxyethyl group was incorporated in position 8, a Tstacking occurred similarly to 4i and, R1 and R3 pointed on the same side of the TKP (Figure 3C). When a larger chain bearing a R4 substituent was incorporated in position 3 (compound 4n), an aromatic−aromatic interaction also occurred between R1 and the R4 benzyl group, while the benzyl in R3 pointed in the other direction (Figure 3C).
Letter
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01112. X-ray data, synthetic details, characterizations, 1H and 13 C NMR spectra, and LC−MS analyses (PDF) Accession Codes
CCDC 1832933−1832937 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Table 3. Torsion Angle Values of the TKP Rings
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Khoubaib Ben Haj Salah: 0000-0002-2313-2773 Séverine Denoyelle: 0000-0002-5661-8382 angle (deg)
4c
4d
4g
4i
4n
ϕ1 ψ1 ω1 ϕ2 ψ2 ω2
30.7 −27.2 −10.2 27.9 −17.7 −7.8
−30.0 26.8 −4.1 −18.1 −15.5 −9.7
26.8 −22.2 5.6 10.2 −7.0 −12.7
37.8 −34.0 9.1 16.4 −16.4 −13.7
27.0 −26.2 4.6 18.6 −18.6 −5.0
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the Labex EpiGenMed, an “Investissements d’avenir” program, reference ANR-10-LABX12-01. We also thank the Plateforme de Mesures de Diffraction X of the University of Lorraine for providing access to crystallographic facilities, and the Institut of Biomolecules Max Mousseron, the University of Montpellier and the Centre National de la Recherche Scientifique (CNRS) for additional financial support.
Finally, we compared the TKP torsion angle values (Table 3) and showed that its puckering was only slightly impacted by the nature of the substituents, but mainly by the configuration of the asymmetric carbon in position 8 (R1) (Figure 3D). However, the up and down orientation of the substituent in position 3 was modulated by the nature of R1, R3, and R4 and the chirality of the carbon in position 8. Therefore, interactions between substituents (driven by the chemical nature of these latter) have proven to be the key input in predicting their relative orientations on the TKP scaffold. In conclusion, an original, efficient, and stereoconservative methodology to synthesize a new class of triazole-fused ketopiperazines has been developed. This easy-to-handle three-step sequence starting from optically pure dipeptides led to substituted [1,2,4]triazolo[4,3-a]piperazin-6-ones in good yields. The crystal structures of some representative compounds confirmed that the configuration of the chiral centers was retained during the synthetic process. Moreover, the X-ray crystallographic study allowed us to describe the conformation of the TKP scaffold and the orientation of the substituents depending on their nature and position on the bicycle, which is mandatory to rationally design compounds for therapeutic applications. In this context, a SAR study is underway to evaluate both the affinity and efficiency of this new series of molecules toward the GHS-R1a receptor.
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DOI: 10.1021/acs.orglett.8b01112 Org. Lett. 2018, 20, 3250−3254
