Enantiomeric Resolution and Absolute Configuration of a Chiral δ-Lactam, Useful Intermediate for the Synthesis of Bioactive Compounds
Abstract
:1. Introduction
2. Results
2.1. Synthesis
2.2. Chiral Resolution
2.3. Single Crystal X-ray Diffraction Study
3. Discussion
4. Materials and Methods
4.1. General
4.2. Synthesis of 2-(4-Bromophenyl)-1-isobutyl-6-oxopiperidin-3-carboxylic Acid (trans-1)
4.3. Chiral Chromatographic Resolution of Trans-1
4.4. X-ray Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
- Batool, M.; Ahmad, B.; Choi, S. A Structure-Based Drug Discovery Paradigm. Int. J. Mol. Sci. 2019, 20, 2783. [Google Scholar] [CrossRef] [Green Version]
- Tambuyzer, E.; Vandendriessche, B.; Austin, C.P.; Brooks, P.J.; Larsson, K.; Miller Needleman, K.I.; Valentine, J.; Davies, K.; Groft, S.C.; Preti, R.; et al. Therapies for rare diseases: Therapeutic modalities, progress and challenges ahead. Nat. Rev. Drug Discov. 2020, 19, 93–111. [Google Scholar] [CrossRef]
- Jasial, S.; Hu, Y.; Bajorath, J. Assessing the Growth of Bioactive Compounds and Scaffolds over Time: Implications for Lead Discovery and Scaffold Hopping. J. Chem. Inf. Model. 2016, 56, 300–307. [Google Scholar] [CrossRef]
- Zdrazil, B.; Guha, R. The Rise and Fall of a Scaffold: A Trend Analysis of Scaffolds in the Medicinal Chemistry Literature. J. Med. Chem. 2018, 61, 4688–4703. [Google Scholar] [CrossRef]
- Scannell, J.W.; Blanckley, A.; Boldon, H.; Warrington, B. Diagnosing the decline in pharmaceutical R&D efficiency. Nat. Rev. Drug Discov. 2012, 11, 191–200. [Google Scholar] [CrossRef]
- Wang, C.Y.; Kim, D.; Zhu, Y.K.; Oh, D.-C.; Huang, R.Z.; Wang, H.-S.; Liang, D.; Lee, S.K. Glechomanamides A–C, Germacrane Sesquiterpenoids with an Unusual Δ8-7,12-Lactam Moiety from Salvia scapiformis and Their Antiangiogenic Activity. J. Nat. Prod. 2019, 82, 3056–3064. [Google Scholar] [CrossRef]
- Vartak, A.P.; Skoblenick, K.; Thomas, N.; Mishra, R.K.; Johnson, R.L. Allosteric Modulation of the Dopamine Receptor by Conformationally Constrained Type VI β-Turn Peptidomimetics of Pro-Leu-Gly-NH2. J. Med. Chem. 2007, 50, 6725–6729. [Google Scholar] [CrossRef] [Green Version]
- Saldívar-González, F.I.; Lenci, E.; Trabocchi, A.; Medina-Franco, J.L. Exploring the chemical space and the bioactivity profile of lactams: A chemoinformatic study. RSC Adv. 2019, 9, 27105–27116. [Google Scholar] [CrossRef] [Green Version]
- Chatterjee, N.R. On the chemical aspects of penicillin activity. Hindustan Antibiot. Bull. 1972, 14, 184–190. [Google Scholar]
- Syed, Y.Y. Lenalidomide: A Review in Newly Diagnosed Multiple Myeloma as Maintenance Therapy After ASCT. Drugs 2017, 77, 1473–1480. [Google Scholar] [CrossRef]
- Giagounidis, A.; Mufti, G.J.; Fenaux, P.; Germing, U.; List, A.; MacBeth, K.J. Lenalidomide as a disease-modifying agent in patients with del(5q) myelodysplastic syndromes: Linking mechanism of action to clinical outcomes. Ann. Hematol. 2014, 93, 1–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Blair, H.A. Dolutegravir/Rilpivirine: A Review in HIV-1 Infection. Drugs 2018, 78, 1741–1750. [Google Scholar] [CrossRef]
- Altamura, A.C.; Moliterno, D.; Paletta, S.; Maffini, M.; Mauri, M.C.; Bareggi, S. Understanding the pharmacokinetics of anxiolytic drugs. Expert Opin. Drug Metab. Toxicol. 2013, 9, 423–440. [Google Scholar] [CrossRef]
- Lepovitz, L.T.; Meis, A.R.; Thomas, S.M.; Wiedeman, J.; Pham, A.; Mensa-Wilmot, K.; Martin, S.F. Design, synthesis, and evaluation of novel anti-trypanosomal compounds. Tetrahedron 2020, 76, 131086. [Google Scholar] [CrossRef]
- Wang, S.; Han, X.; Yang, Y.; Zhou, C.; Luo, D.; He, W.; Zhu, Q.; Xu, Y. Discovery of deoxylimonin δ-lactam derivative with favorable anti-inflammation and antinociception efficacy from chemical modified limonin/deoxylimonin analogs. Bioorganic Chem. 2020, 100, 103886. [Google Scholar] [CrossRef]
- Song, D.; Cao, X.; Wang, J.; Ke, S. Discovery of γ-lactam derivatives containing 1,3-benzodioxole unit as potential anti-phytopathogenic fungus agents. Bioorg. Med. Chem. Lett. 2020, 30, 126826. [Google Scholar] [CrossRef]
- de Almeida, J.; Pimenta, A.L.; Pereira, U.A.; Barbosa, L.C.A.; Hoogenkamp, M.A.; van der Waal, S.V.; Crielaard, W.; Felippe, W.T. Effects of three γ-alkylidene-γ-lactams on the formation of multispecies biofilms. Eur. J. Oral Sci. 2018, 126, 214–221. [Google Scholar] [CrossRef]
- Barrett, S.D.; Holt, M.C.; Kramer, J.B.; Germain, B.; Ho, C.S.; Ciske, F.L.; Kornilov, A.; Colombo, J.M.; Uzieblo, A.; O’Malley, J.P.; et al. Difluoromethylene at the γ-Lactam α-Position Improves 11-Deoxy-8-aza-PGE1 Series EP4 Receptor Binding and Activity: 11-Deoxy-10,10-difluoro-8-aza-PGE1 Analog (KMN-159) as a Potent EP4 Agonist. J. Med. Chem. 2019, 62, 4731–4741. [Google Scholar] [CrossRef]
- Delong, W.; Lanying, W.; Yongling, W.; Shuang, S.; Juntao, F.; Xing, Z. Natural α-methylenelactam analogues: Design, synthesis and evaluation of α-alkenyl-γ and δ-lactams as potential antifungal agents against Colletotrichum orbiculare. Eur. J. Med. Chem. 2017, 130, 286–307. [Google Scholar] [CrossRef]
- Davoren, J.E.; Garnsey, M.; Pettersen, B.; Brodney, M.A.; Edgerton, J.R.; Fortin, J.-P.; Grimwood, S.; Harris, A.R.; Jenkinson, S.; Kenakin, T.; et al. Design and Synthesis of γ- and δ-Lactam M1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M1-Selective PAM with Weak Agonist Activity. J. Med. Chem. 2017, 60, 6649–6663. [Google Scholar] [CrossRef]
- Nasti, R.; Rossi, D.; Amadio, M.; Pascale, A.; Unver, M.Y.; Hirsch, A.K.H.; Collina, S. Compounds Interfering with Embryonic Lethal Abnormal Vision (ELAV) Protein-RNA Complexes: An Avenue for Discovering New Drugs. J. Med. Chem. 2017, 60, 8257–8267. [Google Scholar] [CrossRef] [PubMed]
- Vasile, F.; Volpe, S.D.; Ambrosio, F.A.; Costa, G.; Unver, M.Y.; Zucal, C.; Rossi, D.; Martino, E.; Provenzani, A.; Hirsch, A.K.H.; et al. Exploration of ligand binding modes towards the identification of compounds targeting HuR: A combined STD-NMR and Molecular Modelling approach. Sci. Rep. 2018, 8, 1–11. [Google Scholar] [CrossRef] [PubMed]
- Della Volpe, S.; Nasti, R.; Queirolo, M.; Unver, M.Y.; Jumde, V.K.; Dömling, A.; Vasile, F.; Potenza, D.; Ambrosio, F.A.; Costa, G.; et al. Novel Compounds Targeting the RNA-Binding Protein HuR. Structure-Based Design, Synthesis, and Interaction Studies. ACS Med. Chem. Lett. 2019, 10, 615–620. [Google Scholar] [CrossRef] [PubMed]
- Hong, S. RNA Binding Protein as an Emerging Therapeutic Target for Cancer Prevention and Treatment. J. Cancer Prev. 2017, 22, 203–210. [Google Scholar] [CrossRef] [Green Version]
- Talman, V.; Amadio, M.; Osera, C.; Sorvari, S.; af Gennäs, G.B.; Yli-Kauhaluoma, J.; Rossi, D.; Govoni, S.; Collina, S.; Ekokoski, E.; et al. The C1 domain-targeted isophthalate derivative HMI-1b11 promotes neurite outgrowth and GAP-43 expression through PKCα activation in SH-SY5Y cells. Pharmacol. Res. 2013, 73, 44–54. [Google Scholar] [CrossRef]
- Campos-Melo, D.; Droppelmann, C.A.; Volkening, K.; Strong, M.J. RNA-binding proteins as molecular links between cancer and neurodegeneration. Biogerontology 2014, 15, 587–610. [Google Scholar] [CrossRef]
- Filatov, V.; Kukushkin, M.; Kuznetsova, J.; Skvortsov, D.; Tafeenko, V.; Zyk, N.; Majouga, A.; Beloglazkina, E. Synthesis of 1,3-diaryl-spiro[azetidine-2,3′-indoline]-2′,4-diones via the Staudinger reaction: cis- or trans-diastereoselectivity with different addition modes. RSC Adv. 2020, 10, 14122–14133. [Google Scholar] [CrossRef] [Green Version]
- Meazza, M.; Companyó, X.; Rios, R. Syntheses of Lactams by Tandem Reactions. Asian J. Org. Chem. 2018, 7, 1934–1956. [Google Scholar] [CrossRef]
- Castagnoli, N. Condensation of succinic anhydride with N-benzylidene-N-methylamine. Stereoselective synthesis of trans- and cis-1-methyl-4-carboxy-5-phenyl-2-pyrrolidinone. J. Org. Chem. 1969, 34, 3187–3189. [Google Scholar] [CrossRef]
- Castagnoli, N.; Cushman, M. Condensation of succinic anhydrides with Schiff bases. Scope and mechanism. J. Org. Chem. 1971, 36, 3404–3406. [Google Scholar] [CrossRef]
- González-López, M.; Shaw, J.T. Cyclic Anhydrides in Formal Cycloadditions and Multicomponent Reactions. Chem. Rev. 2009, 109, 164–189. [Google Scholar] [CrossRef] [PubMed]
- Dar’in, D.; Bakulina, O.; Chizhova, M.; Krasavin, M. New Heterocyclic Product Space for the Castagnoli–Cushman Three-Component Reaction. Org. Lett. 2015, 17, 3930–3933. [Google Scholar] [CrossRef] [PubMed]
- Lepikhina, A.; Dar’in, D.; Bakulina, O.; Chupakhin, E.; Krasavin, M. Skeletal Diversity in Combinatorial Fashion: A New Format for the Castagnoli–Cushman Reaction. ACS Comb. Sci. 2017, 19, 702–707. [Google Scholar] [CrossRef] [PubMed]
- Ryabukhin, S.V.; Panov, D.M.; Granat, D.S.; Ostapchuk, E.N.; Kryvoruchko, D.V.; Grygorenko, O.O. Toward Lead-Oriented Synthesis: One-Pot Version of Castagnoli Condensation with Nonactivated Alicyclic Anhydrides. ACS Comb. Sci. 2014, 16, 146–153. [Google Scholar] [CrossRef] [PubMed]
- Caruano, J.; Muccioli, G.G.; Robiette, R. Biologically active γ-lactams: Synthesis and natural sources. Org. Biomol. Chem. 2016, 14, 10134–10156. [Google Scholar] [CrossRef] [PubMed]
- Tan, T.-D.; Ye, L.-W. Chiral γ-lactam synthesis via asymmetric C–H amidation. Nat. Catal. 2019, 2, 182–183. [Google Scholar] [CrossRef]
- Alkadi, H.; Jbeily, R. Role of Chirality in Drugs: An Overview. Infect. Disord. Drug Targets 2018, 18, 88–95. [Google Scholar] [CrossRef]
- Calcaterra, A.; D’Acquarica, I. The market of chiral drugs: Chiral switches versus de novo enantiomerically pure compounds. J. Pharm. Biomed. Anal. 2018, 147, 323–340. [Google Scholar] [CrossRef]
- Brooks, W.H.; Guida, W.C.; Daniel, K.G. The Significance of Chirality in Drug Design and Development. Curr. Top. Med. Chem. 2011, 11, 760–770. [Google Scholar] [CrossRef]
- Saha, D.; Kharbanda, A.; Yan, W.; Lakkaniga, N.R.; Frett, B.; Li, H.-Y. The Exploration of Chirality for Improved Druggability within the Human Kinome. J. Med. Chem. 2020, 63, 441–469. [Google Scholar] [CrossRef]
- Kroon, E.; Schulze, J.O.; Süß, E.; Camacho, C.J.; Biondi, R.M.; Dömling, A. Discovery of a Potent Allosteric Kinase Modulator by Combining Computational and Synthetic Methods. Angew. Chem. 2015, 127, 14139–14142. [Google Scholar] [CrossRef]
- Farah, A.O.; Rabah, M.; Beng, T.K. Transition metal-free domino acyl substitution/Michael addition of alkenyl Grignard reagents to lactam esters: Synthesis of lactam-bearing homoallylic ketones. RSC Adv. 2020, 10, 22454–22459. [Google Scholar] [CrossRef]
- Braunstein, H.; Langevin, S.; Khim, M.; Adamson, J.; Hovenkotter, K.; Kotlarz, L.; Mansker, B.; Beng, T.K. Modular access to vicinally functionalized allylic (thio)morpholinonates and piperidinonates by substrate-controlled annulation of 1,3-azadienes with hexacyclic anhydrides. Org. Biomol. Chem. 2016, 14, 8864–8872. [Google Scholar] [CrossRef] [PubMed]
- Cavalloro, V.; Russo, K.; Vasile, F.; Pignataro, L.; Torretta, A.; Donini, S.; Semrau, M.S.; Storici, P.; Rossi, D.; Rapetti, F.; et al. Insight into GEBR-32a: Chiral Resolution, Absolute Configuration and Enantiopreference in PDE4D Inhibition. Molecules 2020, 25, 935. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gaggeri, R.; Rossi, D.; Collina, S.; Mannucci, B.; Baierl, M.; Juza, M. Quick development of an analytical enantioselective high performance liquid chromatography separation and preparative scale-up for the flavonoid Naringenin. J. Chromatogr. A 2011, 1218, 5414–5422. [Google Scholar] [CrossRef]
- Della Volpe, S.; Listro, R.; Parafioriti, M.; Di Giacomo, M.; Rossi, D.; Ambrosio, F.A.; Costa, G.; Alcaro, S.; Ortuso, F.; Hirsch, A.K.H.; et al. BOPC1 Enantiomers Preparation and HuR Interaction Study. From Molecular Modeling to a Curious DEEP-STD NMR Application. ACS Med. Chem. Lett. 2020, 11, 883–888. [Google Scholar] [CrossRef]
- Desiraju, G.R. Supramolecular Synthons in Crystal Engineering—A New Organic Synthesis. Angew. Chem. Int. Ed. Engl. 1995, 34, 2311–2327. [Google Scholar] [CrossRef]
- Etter, M.C. Encoding and decoding hydrogen-bond patterns of organic compounds. Acc. Chem. Res. 1990, 23, 120–126. [Google Scholar] [CrossRef]
- Groom, C.R.; Bruno, I.J.; Lightfoot, M.P.; Ward, S.C. The Cambridge Structural Database. Acta Crystallogr. Sect. B Struct. Sci. Cryst. Eng. Mater. 2016, 72, 171–179. [Google Scholar] [CrossRef]
- Chan, T.-L.; Kwong, S.-S.; Mak, T.C.W.; Kwok, R.; Chen, X.-M.; Shi, K.-L. Crystal structure of a non-stoichiometric channel inclusion complex of 1-benzyl-6-phenylpiperidin-2-one-5-carboxylic acid with acetonitrile. J. Incl. Phenom. 1988, 6, 507–513. [Google Scholar] [CrossRef]
- Campello, H.R.; Parker, J.; Perry, M.; Ryberg, P.; Gallagher, T. Asymmetric Reduction of Lactam-Based β-Aminoacrylates. Synthesis of Heterocyclic β2-Amino Acids. Org. Lett. 2016, 18, 4124–4127. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lepikhina, A.; Bakulina, O.; Dar’in, D.; Krasavin, M. The first solvent-free synthesis of privileged γ- and δ-lactams via the Castagnoli–Cushman reaction. RSC Adv. 2016, 6, 83808–83813. [Google Scholar] [CrossRef] [Green Version]
- Rossi, D.; Nasti, R.; Collina, S.; Mazzeo, G.; Ghidinelli, S.; Longhi, G.; Memo, M.; Abbate, S. The role of chirality in a set of key intermediates of pharmaceutical interest, 3-aryl-substituted-γ-butyrolactones, evidenced by chiral HPLC separation and by chiroptical spectroscopies. J. Pharm. Biomed. Anal. 2017, 144, 41–51. [Google Scholar] [CrossRef] [PubMed]
- Rossi, D.; Pedrali, A.; Marra, A.; Pignataro, L.; Schepmann, D.; Wünsch, B.; Ye, L.; Leuner, K.; Peviani, M.; Curti, D.; et al. Studies on the enantiomers of RC-33 as neuroprotective agents: Isolation, configurational assignment, and preliminary biological profile. Chirality 2013, 25, 814–822. [Google Scholar] [CrossRef]
- Rossi, D.; Nasti, R.; Marra, A.; Meneghini, S.; Mazzeo, G.; Longhi, G.; Memo, M.; Cosimelli, B.; Greco, G.; Novellino, E.; et al. Enantiomeric 4-Acylamino-6-alkyloxy-2 Alkylthiopyrimidines As Potential A3 Adenosine Receptor Antagonists: HPLC Chiral Resolution and Absolute Configuration Assignment by a Full Set of Chiroptical Spectroscopy. Chirality 2016, 28, 434–440. [Google Scholar] [CrossRef] [Green Version]
- Rossi, D.; Tarantino, M.; Rossino, G.; Rui, M.; Juza, M.; Collina, S. Approaches for multi-gram scale isolation of enantiomers for drug discovery. Expert Opin. Drug Discov. 2017, 12, 1253–1269. [Google Scholar] [CrossRef]
- Flack, H.D.; Bernardinelli, G. The use of X-ray crystallography to determine absolute configuration. Chirality 2008, 20, 681–690. [Google Scholar] [CrossRef]
- Parsons, S.; Wagner, T. Use of intensity quotients and differences in absolute structure refinement. Acta Crystallogr. B Struct. Sci. Cryst Eng. Mater. 2013, 11, 249–259. [Google Scholar] [CrossRef] [Green Version]
- Bruker. SAINT Software Reference Manual, Version 6; Bruker AXS Inc.: Madison, WI, USA, 2003. [Google Scholar]
- Krause, L.; Herbst-Irmer, R.; Sheldrick, G.M.; Stalke, D. Comparison of silver and molybdenum microfocus X-ray sources for single-crystal structure determination. J. Appl. Crystallogr. 2015, 48, 3–10. [Google Scholar] [CrossRef] [Green Version]
- Altomare, A.; Burla, M.C.; Camalli, M.; Cascarano, G.L.; Giacovazzo, C.; Guagliardi, A.; Moliterni, A.G.G.; Polidori, G.; Spagna, R. SIR97: A new tool for crystal structure determination and refinement. J. Appl. Crystallogr. 1999, 32, 115–119. [Google Scholar] [CrossRef]
- Sheldrick, G.M. Crystal structure refinement with SHELXL. Acta Crystallogr. Sect. C Struct. Chem. 2015, 71, 3–8. [Google Scholar] [CrossRef] [PubMed]
CSPs | ||||||||
---|---|---|---|---|---|---|---|---|
Chiralpak IA b,c | Chiralpak IC c | |||||||
Eluent a | k1 | k2 | α | RS | k1 | k2 | α | RS |
A | 1.39 | 2.17 | 1.56 | 4.28 | 4.15 | 5.47 | 1.32 | 3.91 |
B | 0.74 | 1.15 | 1.56 | 3.19 | 0.94 | 1.37 | 1.45 | 2.99 |
C | 0.49 | 0.75 | 1.53 | 2.20 | 1.44 | 1.87 | 1.30 | 2.33 |
D | 0.53 | 0.80 | 1.51 | 1.59 | 1.16 | 1.54 | 1.33 | 1.75 |
E | 0.32 | 0.47 | 1.44 | 1.01 | 0.93 | 1.22 | 1.31 | 1.48 |
F | 0.19 | 0.28 | 1.46 | 0.81 | 0.36 | 0.49 | 1.35 | - |
G d | 0.24 | - | - | - | 0.47 | - | - | - |
H d | 0.24 | - | - | - | 0.48 | - | - | - |
I | 0.65 | 0.99 | 1.53 | 2.01 | 0.68 | 0.78 | 1.14 | - |
L | 0.86 | 1.36 | 1.57 | 2.67 | 0.94 | 1.08 | 1.15 | - |
M | 1.43 | 2.16 | 1.51 | 3.38 | 1.93 | 2.20 | 1.14 | 0.99 |
(2R,3R/2S,3S)-1 | ||||
---|---|---|---|---|
CSP | Eluent (v/v/v/v) | Flow Rate | Injection Volume | Concentration |
Chiralpak IA (1 cm × 25 cm, 5 μm) | n-Hex/EtOH/TFA/DEA 90:10:0.1:0.3 | 2.5 mL/min | 1 mL | 3 mg/mL |
Sample Availability: Samples of all compounds are available from the authors. |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Listro, R.; Rossino, G.; Della Volpe, S.; Stabile, R.; Boiocchi, M.; Malavasi, L.; Rossi, D.; Collina, S. Enantiomeric Resolution and Absolute Configuration of a Chiral δ-Lactam, Useful Intermediate for the Synthesis of Bioactive Compounds. Molecules 2020, 25, 6023. https://doi.org/10.3390/molecules25246023
Listro R, Rossino G, Della Volpe S, Stabile R, Boiocchi M, Malavasi L, Rossi D, Collina S. Enantiomeric Resolution and Absolute Configuration of a Chiral δ-Lactam, Useful Intermediate for the Synthesis of Bioactive Compounds. Molecules. 2020; 25(24):6023. https://doi.org/10.3390/molecules25246023
Chicago/Turabian StyleListro, Roberta, Giacomo Rossino, Serena Della Volpe, Rita Stabile, Massimo Boiocchi, Lorenzo Malavasi, Daniela Rossi, and Simona Collina. 2020. "Enantiomeric Resolution and Absolute Configuration of a Chiral δ-Lactam, Useful Intermediate for the Synthesis of Bioactive Compounds" Molecules 25, no. 24: 6023. https://doi.org/10.3390/molecules25246023