- Enantioselective Synthesis of Chiral Substituted 2,4-Diketoimidazolidines and 2,5-Diketopiperazines via Asymmetric Hydrogenation
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An enantioselective hydrogenation of 5-alkylidene-2,4-diketoimidazolidines (hydantoins) and 3-alkylidene-2,5-ketopiperazines catalyzed by the Rh/f-spiroPhos complex under mild conditions has been developed, which provides an efficient approach to the highly enantioselective synthesis of chiral hydantoins and 2,5-ketopiperazine derivatives with high enantioselectivities up to 99.9% ee.
- Xiao, Guiying,Xu, Shuang,Xie, Chaochao,Zi, Guofu,Ye, Weiping,Zhou, Zhangtao,Hou, Guohua,Zhang, Zhanbin
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p. 5734 - 5738
(2021/08/01)
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- En Route to a Heterogeneous Catalytic Direct Peptide Bond Formation by Zr-Based Metal-Organic Framework Catalysts
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Peptide bond formation is a challenging, environmentally and economically demanding transformation. Catalysis is key to circumvent current bottlenecks. To date, many homogeneous catalysts able to provide synthetically useful methods have been developed, while heterogeneous catalysts remain largely restricted to the studies addressing the prebiotic formation of peptides. Here, the catalytic activity of Zr6-based metal-organic frameworks (Zr-MOFs) toward peptide bond formation is investigated using dipeptide cyclization as a model reaction. Unlike previous catalysts, Zr-MOFs largely tolerate water, and reactions are carried out under ambient conditions. Notably, the catalyst is recyclable and no additives to activate the COOH group are necessary, which are common limitations of previous methods. In addition, a broad reaction scope tolerates substrates with bulky and Lewis basic groups. The reaction mechanism was assessed by detailed mechanistic and computational studies and features a Lewis acid activation of carboxylate groups by Zr centers toward amine addition in which an alkoxy ligand on adjacent Zr sites assists in lowering the barrier of key proton transfers. The proposed concepts were also used to study the formation of intermolecular peptide bond formation. While intrinsic challenges associated with the catalyst structure and water removal limit a more general intermolecular reaction scope under current conditions, the results suggest that further design of Zr-MOF catalysts could render these materials broadly useful as heterogeneous catalysts for this challenging transformation.
- Conic, Dragan,De Azambuja, Francisco,Harvey, Jeremy N.,Loosen, Alexandra,Parac-Vogt, Tatjana N.,Van Den Besselaar, Maxime
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p. 7647 - 7658
(2021/06/30)
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- Immobilized Carbodiimide Assisted Flow Combinatorial Protocol to Facilitate Amide Coupling and Lactamization
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Through a screen of over one hundred and 30 permutations of reaction temperatures, solvents, carbodiimide resins, and carbodiimide molar equivalences, in the presence, absence, or combination of diisopropylamine and benzotriazole additives, a convenient and first reported carbodiimide polymer-assisted flow approach to effect amide coupling and lactamization was developed. The protocol entails injecting a single solution (1:9 dimethylformamide: dichloromethane) containing a carboxylic acid and an amine or linear peptide sequence into a continuous stream of dichloromethane. The protocol remained viable in the absence of base, did not require carboxylate preactivation which, and in concert with minimal workup requirements, enabled the isolation of products in high yields. Compared to the utilization of untethered carbodiimide reagents, the flow procedure was also observed to provide a degree of racemization safety.
- Aldrich-Wright, Janice R.,Dankers, Christian,Gordon, Christopher P.,Harman, David G.,Nguyen, Thanh V.,Tadros, Joseph
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supporting information
p. 255 - 267
(2020/06/05)
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- Anti-biofilm and anti-adherence properties of novel cyclic dipeptides against oral pathogens
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Microorganisms embedded in a biofilm are significantly more resistant to antimicrobial agents and the defences of the human immune system, than their planktonic counterpart. Consequently, compounds that can inhibit biofilm formation are of great interest for novel therapeutics. In this study, a screening approach was used to identify novel cyclic dipeptides that have anti-biofilm activity against oral pathogens. Five new active compounds were identified that prevent biofilm formation by the cariogenic bacterium Streptococcus mutans and the pathogenic fungus Candida albicans. These compounds also inhibit the adherence of microorganisms to a hydroxylapatite surface. Further investigations were conducted on these compounds to establish the structure–activity relationship, and it was deduced that the common cleft pattern is required for these molecules to act effectively against biofilms.
- Simon, Ga?lle,Bérubé, Christopher,Voyer, Normand,Grenier, Daniel
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p. 2323 - 2331
(2018/12/11)
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- Water-Tolerant and Atom Economical Amide Bond Formation by Metal-Substituted Polyoxometalate Catalysts
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A simple, safe, and inexpensive amide bond formation directly from nonactivated carboxylic acids and free amines is presented in this work. Readily available Zr(IV)- and Hf(IV)-substituted polyoxometalates (POM) are shown to be catalysts for the amide bond formation reaction under mild conditions, low catalyst loading, and without the use of water scavengers, dry solvents, additives for facilitating the amine attack, or specialized experimental setups commonly employed to remove water. Detailed mechanistic investigations revealed the key role of POM scaffolds which act as inorganic ligands to protect Zr(IV) and Hf(IV) Lewis acidic metals against hydrolysis and preserve their catalytic activity in amide bond formation reactions. The catalysts are compatible with a range of functional groups and heterocycles useful for medicinal, agrochemical, and material chemists. The robustness of the Lewis acid-POM complexes is further supported by the catalyst reuse without loss of activity. This prolific combination of Zr(IV)/Hf(IV) and POMs inaugurates a powerful class of catalysts for the amide bond formation, which overcomes key limitations of previously established Zr(IV)/Hf(IV) salts and boron-based catalysts.
- De Azambuja, Francisco,Parac-Vogt, Tatjana N.
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p. 10245 - 10252
(2019/11/03)
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- Interfacial supramolecular biomimetic epoxidation catalysed by cyclic dipeptides
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We synthesised a library of cis- and trans-cyclic dipeptides and evaluated their efficacy as catalysts in the asymmetric Weitz-Scheffer epoxidation of trans-chalcone. A thorough investigation relying on structure-activity studies and computational studies provided insights into the mechanism of the process. Our results revealed some structural features required for efficient conversion and for introduction of chirality into the product. The cyclic dipeptide acts as a catalyst by templating a supramolecular arrangement at the aqueous-organic interface required for efficient transformations to occur. Among all cyclic dipeptides investigated, cyclo(Leu-Leu) was the most efficient supramolecular catalyst.
- Bérubé, Christopher,Barbeau, Xavier,Cardinal, Sébastien,Boudreault, Pierre-Luc,Bouchard, Corinne,Delcey, Nicolas,Lagüe, Patrick,Voyer, Normand
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p. 330 - 349
(2017/03/15)
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- A general method for the facile synthesis of optically active 2-substituted piperazines via functionalized 2,5-diketopiperazines
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Upon utilization of some common methods described in the literature for the synthesis of chiral, 2-substituted 2,5-diketopiperazines, extensive racemization was observed. Further investigation showed that heating in the presence of a mild base racemized the chiral center in the product diketopiperazines. A generalized, readily scalable route was sought and, after investigating the effect of base and temperature, conditions were identified that promoted cyclization without erosion of enantiomeric excess. An array of functionalization was tolerated and this procedure serves as a useful and reliable method for the facile synthesis of this important class of compounds.
- Ashton, Kate S.,Denti, Mitchell,Norman, Mark H.,St. Jean Jr., David J.
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supporting information
p. 4501 - 4504
(2014/08/05)
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- Synthesis and conformational characterization of diketopiperazines bearing a benzyl moiety
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Diketopiperazines bearing a benzyl moiety with different para-substituents were synthesized and analyzed by 1HNMR spectroscopy. All of these diketopiperazines were found to adopt a folded conformation according to the upfield chemical shift of the cis-proton (cis to the benzyl moiety) due to a shielding effect in the 1HNMR spectra. An intramolecular CH-π interaction appears to be an important factor for the folded conformation due to the effects of para-substituents on the benzyl group.
- Nakao, Michiyasu,Toriuchi, Yuriko,Fukayama, Shintaro,Sano, Shigeki
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p. 340 - 342
(2014/03/21)
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- Phenylalanine-containing cyclic dipeptides-the lowest molecular weight hydrogelators based on unmodified proteinogenic amino acids
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Cyclic dipeptides (diketopiperazines-DKPs) that are based on the proteinogenic amino acid phenylalanine in combination with serine, cysteine, glutamate, histidine and lysine are described as simple and remarkable low molecular weight hydrogelators. Blends
- Kleinsmann, Alexander J.,Nachtsheim, Boris J.
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supporting information
p. 7818 - 7820
(2013/09/02)
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- Efficient synthesis of 2,5-diketopiperazines by Staudinger-mediated cyclization
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Solution- and solid-phase Staudinger-mediated cyclizations were assessed to efficiently prepare hetero-2,5-diketopiperazines from their protected azido dipeptide thioesters under microwave irradiation. Short reaction time, good yields and ease of purification are the main assets of this methodology. Georg Thieme Verlag Stuttgart · New York.
- Beagle, Lucas K.,Hansen, Finn K.,Monbaliu, Jean-Christophe M.,Desrosiers, Michael P.,Phillips, Angela M.,Stevens, Christian V.,Katritzky, Alan R.
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supporting information
p. 2337 - 2340
(2013/07/11)
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- Synthesis and phytotoxicity of structural analogues of thaxtomin natural products
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Structural analogues of the phytotoxic thaxtomin natural products have been synthesized by building upon a piperazinedione core and from l-phenylalanine. The compounds were evaluated for their phytotoxic activity against Arabidopsis thaliana seedlings and some of the key features for activity have been identified. CSIRO 2010.
- Molesworth, Peter P.,Gardiner, Michael G.,Jones, Roderick C.,Smith, Jason A.,Tegg, Robert S.,Wilson, Calum
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experimental part
p. 813 - 820
(2011/08/03)
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- Stereoselective ring contraction of 2,5-diketopiperazines: An innovative approach to the synthesis of promising bioactive 5-membered scaffolds
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Ring contraction of 2,5-diketopiperazines by TRAL-alkylation led us to the stereoselective synthesis of original pyrrolidine-2,4-diones, a novel series of promising molecules with moderate anti-proliferative activity on breast cancer cells.
- Coursindel, Thibault,Restouin, Audrey,Dewynter, Georges,Martinez, Jean,Collette, Yves,Parrot, Isabelle
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experimental part
p. 210 - 217
(2010/10/01)
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- Herbicidally Active Composition
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The present invention relates to herbicidally active compositions comprising at least one piperazinedione compound of the formula I in which: Rx, Ry are each hydrogen or together are a chemical bond; R1 is cyano or nitro; R2 is hydrogen, fluorine, chlorine, C1-C2-alkyl, ethenyl or C1-C2-alkoxy; R3 is fluorine or hydrogen; R4 is methyl; R5 is hydrogen, methyl or ethyl; R6 is hydrogen, methyl or ethyl; and R7 is hydrogen or halogen; and at least one further active compound selected from the group consisting of b1) lipid biosynthesis inhibitors; b2) acetolactate synthase inhibitors (ALS inhibitors); b3) photosynthesis inhibitors; b4) protoporphyrinogen-IX oxidase inhibitors, b5) bleacher herbicides; b6) enolpyruvyl shikimate 3-phosphate synthase inhibitors (EPSP inhibitors); b7) glutamine synthetase inhibitors; b8) 7,8-dihydropteroate synthase inhibitors (DHP inhibitors); b9) mitose inhibitors; b10) inhibitors of the synthesis of very long chain fatty acids (VLCFA inhibitors); b11) cellulose biosynthesis inhibitors; b12) decoupler herbicides; b13) auxin herbicides; b14) auxin transport inhibitors; b15) other herbicides, and C) safeners.
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Page/Page column 56
(2010/08/07)
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- Structure-activity relationships for dipeptide prodrugs of acyclovir: Implications for prodrug design
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A series of water-soluble dipeptide ester prodrugs of the antiviral acyclovir (ACV) were evaluated for their chemical stability, cytotoxicity, and antiviral activity against several strains of Herpes Simplex-1 and -2, vaccinia, vesicular stomatitis, cytom
- Santos, Cledir R.,Capela, Rita,Pereira, Claudia S.G.P.,Valente, Emilia,Gouveia, Luis,Pannecouque, Christophe,De Clercq, Erik,Moreira, Rui,Gomes, Paula
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body text
p. 2339 - 2346
(2009/12/07)
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- Efficient microwave assisted syntheses of 2,5-diketopiperazines in aqueous media
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Aqueous in situ one-pot N-Boc-deprotection-cyclization of Nα-Boc-dipeptidyltert-butyl and methyl esters under microwave irradiation afforded 2,5-diketopiperazines (DKPs) in excellent yields. This protocol is rapid, safe, environmentally friendly, and high
- Perez-Picaso, Lemuel,Escalante, Jaime,Olivo, Horacio F.,Rios, Maria Yolanda
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experimental part
p. 2836 - 2849
(2009/12/06)
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- Biomimetic catalysis of diketopiperazine and dipeptide syntheses
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Modular supramolecular catalysts with a coiled-coil peptide scaffold, designed to mimic nonribosomal peptide synthetases, catalyze the formation of diketopiperazines and linear dipeptides for several aminoacyl substrates (see scheme). The nature of the ac
- Huang, Zheng-Zheng,Leman, Luke J.,Ghadiri, M. Reza
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supporting information; experimental part
p. 1758 - 1761
(2009/02/06)
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- COMPOUNDS WHICH MODULATE THE CB2 RECEPTOR
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Compounds are provided which bind to and are agonists, antagonists or inverse agonists of the CB2 receptor, the compounds having the general formula (I) wherein, R1, R2, A, Y, X, Ar1 and Ar2 have the meanings given in the specification, and the preparation and use thereof. The compounds are valuable CB2 receptor modulators.
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Page/Page column 74-75
(2008/06/13)
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- Microwave-assisted synthesis of 2,5-piperazinediones under solvent-free conditions
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A general, efficient and environmentally friendly procedure for the synthesis of 2,5-piperazinediones is described, involving the microwave irradiation of N-Boc dipeptide esters. Georg Thieme Verlag Stuttgart.
- Lopez-Cobenas, Alberto,Cledera, Pilar,Sanchez, J. Domingo,Lopez-Alvarado, Pilar,Ramos, M. Teresa,Avendano, Carmen,Menendez, J. Carlos
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p. 3412 - 3422
(2007/10/03)
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- Solvent-free, efficient synthesis of 2,5-piperazinediones from Boc-protected dipeptide esters under microwave irradiation
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Microwave irradiation allows the efficient, solvent-free transformation of N-Boc dipeptide esters into 2,5-piperazinediones. The microwave-assisted conditions were found to be much better than traditional heating in terms of reaction time, yield and stere
- López-Cobe?as, Alberto,Cledera, Pilar,Sánchez, J. Domingo,Pérez-Contreras, Rafael,López-Alvarado, Pilar,Ramos, M. Teresa,Avenda?o, Carmen,Menéndez, J. Carlos
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p. 1158 - 1160
(2007/10/03)
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- Cyclization-activated prodrugs. Synthesis, reactivity and toxicity of dipeptide esters of paracetamol
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Dipeptide esters of paracetamol were prepared in high yields. These compounds are quantitatively hydrolyzed to paracetamol and corresponding 2,5-diketopiperazines at pH 7.4 and 37°C. The reactivity is increased in sarcosine and proline peptides and decreased by bulky side chains at both the N- and C-terminal residues of the dipeptide carrier. Moreover, dipeptide esters of paracetamol did not affect the levels of hepatic glutathione. Thus, dipeptides seem promising candidates as carriers for cyclization-activated prodrugs.
- Santos, Cledir,Mateus, Maria Luisa,Dos Santos, Ana Paula,Moreira, Rui,De Oliveira, Eliandre,Gomes, Paula
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p. 1595 - 1598
(2007/10/03)
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- 2, 3, 6-TRISUBSTITUTED-4-PYRIMIDONE DERIVATIVES
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A pyrimidone derivative having tau protein kinase 1 inhibitory activity which is represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof; useful for prventive and/or therapeutic treatment of diseass such as neurodegenerative diseases (e.g. Alzheimer disease); wherein Q represents CH or nitrogen atom; R represents a C1-C12 alkyl group; the ring of Formula (I): represents piperazine ring or piperidine ring; each X independently represents a C1-C8 alkyl group, an optionally partially hydrogenated C6-C10 aryl ring, an indan ring or the like; m represents an integer of 1 to 3; each Y independently represents a halogen atom, a hydroxy group, a cyano group, a C1-C6 alkyl group or the like; n represents an integer of 0 to 8; when X and Y or two Y groups are attached on the same carbon atom, they may combine to each other to form a C2-C6 alkylene group.
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- Phenylahistin and the phenylahistin analogs, a new class of anti-tumor compounds
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A compound, its pharmaceutically acceptable salts, and/or its pro-drug esters, in isolated form, and methods for isolating, for formulating, and for administering the compound, salt, and/or pro-drug ester as an antitumor agent, wherein the compound, salt,
- -
-
Example 7,18
(2008/06/13)
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- Synthesis and biological activities of phenylahistin derivatives
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X-ray crystallographic analysis was performed and several phenylahistin derivatives were synthesized to elucidate the structural components necessary for the anti-microtubule activity of phenylahistin. We primarily focused on the unique isoprenylated dehy
- Kanoh, Kaneo,Kohno, Shinkichi,Katada, Jun,Takahashi, Junko,Uno, Isao,Hayashi, Yoshio
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p. 1451 - 1457
(2007/10/03)
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- An Optically Active Nucleophile That Catches Its Substrate By Two Points
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Two diastereomeric cyclic dipeptides are obtained by coupling L or D-His with L-(crowned DOPA).The kinetic data on the reaction of p-nitrophenyl esters of protonated amino-acids and peptides with these His derivatives are reported.
- Janus, Stephan,Sonveaux, Etienne
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p. 3757 - 3760
(2007/10/02)
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- SYNTHESIS OF DIPEPTIDE ESTERS OF METRONIDAZOLE AND EVALUATION OF THEIR HYDROLYTIC STABILITY
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Amino acid and dipeptide esters of metronidazole were synthesized and evaluated on their hydrolytic stability in various buffers and culture media.The hydrolytic susceptibility of the different esters was minimal in the pH range 3-5.In the alkaline region, pH 6.5-8, the half-lifes were of the order of 1-6.6 hrs.At alkaline pH the dipeptide esters were more susceptible towards hydrolysis.At pH 8.8 the observed half-life for the gly-gly and the gly-phe esters was 0.2 h, whereas for the gly and the phe ester it was 1.1 h, respectively 2.7 h.It was demonstrated that the increased rate of hydrolysis for the dipeptide esters was due to an intramolecular aminolysis with the formation of a diketopiperazine accompanied by the release of free metronidazole.
- Permentier, Dirk,Vansteenkiste, Stefan,Schacht, Etienne,Vermeersch, Hans,Remon, Jean Paul
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p. 701 - 708
(2007/10/02)
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- N-Hydroxy Amides. Part 6. Synthesis and Spectroscopic Properties of 1-Hydroxypiperazine-2,5-diones
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1-Hydroxypiperazine-2,5-diones (3a-f) are prepared in good yields, starting with Boc-L-amino acids and N-benzyloxyglycine methyl ester.The rate of cyclisation for N-hydroxy and N-benzyloxydipeptide methyl esters are 38-77 times as large as that of phenyla
- Akiyama, Masayasu,Katoh, Akira,Tsuchiya, Yuko
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p. 235 - 239
(2007/10/02)
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- A Mechanism for bitter Taste Sensibility in Peptides
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To estimate the steric distance between the bitter taste determinant sites in peptides, some cyclic dipeptides, amino acid anilides, amino acid cyclohexylamides, and benzoyl amino acids were synthesized and their tastes were evaluated.The diketopiperazine ring of cyclic dipeptides acted as a bitter taste determinant site due to its hydrophobicity.The steric distance between 2 sites was estimated as 4.1 Angstroem from the molecule models of cyclic dipeptides composed of typical amino acids in the bitter peptides.Due to the hypothesis of two bitter taste determinant sites, which bind with the bitter taste receptor via a "binding unit" and a "stimulating unit," a mechanism for the bitterness in peptides was postulated.
- Ishibashi, Norio,Kouge, Katsushige,Shinoda,Ichizo,Kanehisa, Hidenori,Okai, Hideo
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p. 819 - 828
(2007/10/02)
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- Ring Current Shielding and Molecular Motions in Piperazine-2,5-diones
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In 3-(phenylmethyl)piperazine-2,5-dione(cyclo(Phe-Gly)) the C6 methylene hydrogens are shielded by the aromatic ring which lies above them.As the temperature is raised, this shielding is reduced but the aromatic ring retains its gross position with respec
- Frigerio, Ian J.,Rae, Ian D.,Wong, Margaret G.
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p. 1609 - 1614
(2007/10/02)
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- 15N NMR Spectroscopy. 19 - Spectroscopic Characterization of Cyclodipeptides (2,5-Dioxopiperazines)
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Various cyclodipeptides containing glycine, alanine, leucine, valine, phenylalanine, phenylglycine and sarcosine units were synthesized by cyclization of dipeptide pentachlorophenyl esters.The 13C and natural abundance 15N NMR spectra of these heterocycles were measured in trifluoroacetic acid and compared with the spectra of the corresponding amino acids and polypeptides.The 13C NMR carbonyl signals of all cyclodipeptides show a 1.5-4.0 ppm upfield shift relative to the corresponding polypeptides.The 15N NMR signals show no such consistent relationship.The substituent effects and the neighbouring residue effects observed in the 15NMR spectra of the cyclodipeptides are different from those of polypeptides, while the one bond N-H coupling constant of cis and trans amide groups was almost identical.The nitrogen and the carbonyl signal of the Gly units in cyclo-Gly-Phe show an extraordinary downfield shift, reflecting the interaction of the phenyl group with the 2,5-dioxopiperazine ring.
- Kricheldorf, Hans R.
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