- An Unconventional Redox Cross Claisen Condensation-Aromatization of 4-Hydroxyprolines with Ketones
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Reaction of α-amino acids, particularly prolines and their derivatives with carbonyl compounds via decarboxylative redox process, is a viable strategy for synthesis of structurally diverse nitrogen centered heterocyclics. In these processes, the decarboxylation is the essential driving force for the processes. The realization of the redox process without decarboxylation may offer an opportunity to explore new reactions. Herein, we report the discovery of an unprecedented redox Claisen-type condensation aromatization cascade reaction of 4-substituted 4-hydroxyproline and its esters with unreactive ketones. We found that the use of propionic acid as a catalyst and a co-solvent can change the reaction course. The commonly observed redox decarboxylation and aldol condensation reactions are significantly minimized. Moreover, unreactive ketones can effectively participate in the Claisen condensation reaction. The new reactivity enables a redox cyclization via an unconventional Claisen-type condensation reaction of in situ formed enamine intermediates from ketone precursors with 4-substituted 4-hydroxyproline and its esters as electrophilic acylation partners. Under the reaction conditions, the cascade process proceeds highly regio- and stereoselectively to afford highly synthetically and biologically valued cis-2,3-dihydro-1H-pyrrolizin-1-ones with a broad substrate scope in efficient 'one-pot' operation, whereas such structures generally require multiple steps.
- Tang, Mi,Sun, Rengwei,Li, Hao,Yu, Xinhong,Wang, Wei
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- The selective O-acylation of hydroxyproline as a convenient method for the large-scale preparation of novel proline polymers and amphiphiles
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In this work we show how a direct O-acylation of trans-4-hydroxy-L-proline with acyl chlorides in trifluoroacetic acid makes a range of novel proline derivatives readily available on large-scale. No protecting groups or chromatographic techniques are involved in any of the procedures, and certain amphiphilic proline derivatives, which recently have received interest in synthesis, are now potentially some of the most readily accessible organocatalysts. The selective acylation was also utilized in the synthesis of a novel high-load proline polymer, poly(O-acryloyl-trans-4-hydroxy-L-proline), a polymer with the highest proline loading reported and for which classical methods failed for its preparation. Wiley-VCH Verlag GmbH & Co. KGaA, 2009.
- Kristensen, Tor E.,Hansen, Finn K.,Hansen, Tore
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- β-L-Arabinofuranosylation Conducted by 5-O-(2-pyridinecarbonyl)-L-arabinofuranosyl Trichloroacetimidate
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We describe a β-L-arabinofuranosylation method by employing the 5-O-(2-pyridinecarbonyl)-L-arabinofuranosyl trichloroacetimidate 10 as a donor. This approach allows a wide range of acceptor substrates, especially amino acid acceptors, to be used. Stereoselective synthesis of β-(1,4)-L-arabinofuranosyl-(2S, 4R)-4-hydroxy-L-proline (β-L-Araf-L-Hyp4) and its dimer is achieved readily by this method. Both the stereoselectivities and yields of the reactions are excellent. To demonstrate the utility of this methodology, the preparation of a trisaccharide in a one-pot manner was carried out.
- Li, Hong-Zhan,Ding, Jie,Cheng, Chun-Ru,Chen, Yue,Liang, Xing-Yong
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- L-proline-grafted mesoporous silica with alternating hydrophobic and hydrophilic blocks to promote direct asymmetric aldol and Knoevenagel-Michael cascade reactions
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Promotion of heterogeneous asymmetric catalysis is of major interest in the asymmetric catalysis field. In this work, a novel strategy for the synthesis of l-proline-grafted mesoporous silica with alternating hydrophobic and hydrophilic blocks to promote the heterogeneous asymmetric catalysis was reported. The surface synergies in the neat environment and the interface acceleration in aqueous medium thereby fostered high catalytic activities and enantioselectivity in the direct aldol reaction and the Knoevenagel-Michael cascade reaction. The l-proline loading could be reduced to as low as 0.63 mol %, giving 95% ee for anti-isomers and 81% ee for syn-isomers in the catalytic asymmetric aldol reaction of nitrobenzaldehyde and cyclohexanone, which was hard to accomplish on the homogeneous counterpart. In the direct asymmetric aldol reaction of ethyl-2-oxoacetate and cyclohexanone, 82% yield in 24 h and 90% ee were achieved. More exciting, the catalysts were applied to more exigent reactions. As an example, in the Knoevenagel-Michael cascade reaction, 85% yield in 10 h and up to 91% ee was achieved.
- An, Zhe,Guo, Ying,Zhao, Liwei,Li, Zhi,He, Jing
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- Chemical Probes Unravel an Antimicrobial Defense Response Triggered by Binding of the Human Opioid Dynorphin to a Bacterial Sensor Kinase
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Host-microbe communication via small molecule signals is important for both symbiotic and pathogenic relationships, but is often poorly understood at the molecular level. Under conditions of host stress, levels of the human opioid peptide dynorphin are elevated, triggering virulence in the opportunistic pathogenic bacterium Pseudomonas aeruginosa via an unknown pathway. Here we apply a multilayered chemical biology strategy to unravel the mode of action of this putative interkingdom signal. We designed and applied dynorphin-inspired photoaffinity probes to reveal the protein targets of the peptide in live bacteria via chemical proteomics. ParS, a largely uncharacterized membrane sensor of a two-component system, was identified as the most promising hit. Subsequent full proteome studies revealed that dynorphin(1-13) induces an antimicrobial peptide-like response in Pseudomonas, with specific upregulation of membrane defense mechanisms. No such response was observed in a parS mutant, which was more susceptible to dynorphin-induced toxicity. Thus, P. aeruginosa exploits the ParS sensing machinery to defend itself against the host in response to dynorphin as a signal. This study highlights interkingdom communication as a potential essential strategy not only for induction of P. aeruginosa virulence but also for maintaining viability in the hostile environment of the host.
- Wright, Megan H.,Fetzer, Christian,Sieber, Stephan A.
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- Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne
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The use of an interleukin β antibody is currently being investigated in the clinic for the treatment of acne, a dermatological disorder affecting 650M persons globally. Inhibiting the protease responsible for the cleavage of inactive pro-IL1β into active IL-1β, caspase-1, could be an alternative small molecule approach. This report describes the discovery of uracil 20, a potent (38 nM in THP1 cells assay) caspase-1 inhibitor for the topical treatment of inflammatory acne. The uracil series was designed according to a published caspase-1 pharmacophore model involving a reactive warhead in P1 for covalent reversible inhibition and an aryl moiety in P4 for selectivity against the apoptotic caspases. Reversibility was assessed in an enzymatic dilution assay or by using different substrate concentrations. In addition to classical structure-activity-relationship exploration, topical administration challenges such as phototoxicity, organic and aqueous solubility, chemical stability in solution, and skin metabolic stability are discussed and successfully resolved.
- Fournier, Jean-Fran?ois,Clary, Laurence,Chambon, Sandrine,Dumais, Laurence,Harris, Craig Steven,Millois, Corinne,Pierre, Romain,Talano, Sandrine,Thoreau, étienne,Aubert, Jérome,Aurelly, Michèle,Bouix-Peter, Claire,Brethon, Anne,Chantalat, Laurent,Christin, Olivier,Comino, Catherine,El-Bazbouz, Ghizlane,Ghilini, Anne-Laurence,Isabet, Tatiana,Lardy, Claude,Luzy, Anne-Pascale,Mathieu, Céline,Mebrouk, Kenny,Orfila, Danielle,Pascau, Jonathan,Reverse, Kevin,Roche, Didier,Rodeschini, Vincent,Hennequin, Laurent Fran?ois
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- Synthesis and DNA binding property of a novel peptide nucleic acid that contains cis-4-adeninyl-L-prolinol unit
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A novel oxy-peptide nucleic acid that contains a cis-4-adeninyl-L-prolinol unit in the main chain (PPNA) was synthesized. The peptide nucleic acid with nine adenine units [PPNA(A9)] hybridized with the complementary DNA (T9). The hybrid showed a very sharp melting curve with Tm = 34 °C.
- Shigeyasu, Masanori,Kuwahara, Masayasu,Sisido, Masahiko,Ishikawa, Teruhiko
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- Synthetic Marine Sponge Collagen by Late-Stage Dihydroxylation
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Based on the observation that an increased substrate size is paralleled by an enhanced diastereoselectivity, a late-stage dihydroxylation protocol toward the 21mer CMP (collagen model peptide) Ac-(Pro-Hyp-Gly)3-Pro-Dyp-Gly-(Pro-Hyp-Gly)3-NH2 is presented. C3 and C4 hydroxylation have a converse effect on the triple-helical stability of collagen. Their combined influence on the melting temperature was studied by NMR spectroscopy.
- Priem, Christoph,Geyer, Armin
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- The development of a new class of inhibitors for betaine-homocysteine S-methyltransferase
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Betaine-homocysteine S-methyltransferase (BHMT) is an important zinc-dependent methyltransferase that uses betaine as the methyl donor for the remethylation of homocysteine to form methionine. In the liver, BHMT performs to half of the homocysteine remethylation. In this study, we systematically investigated the tolerance of the enzyme for modifications at the "homocysteine" part of the previously reported potent inhibitor (R,S)-5-(3-amino-3-carboxy-propylsulfanyl)-pentanoic acid (1). In the new compounds, which are S-alkylated homocysteine derivatives, we replaced the carboxylic group in the "homocysteine" part of inhibitor 1 with different isosteric moieties (tetrazole and oxadiazolone); we suppressed the carboxylic negative charge by amidations; we enhanced acidity by replacing the carboxylate with phosphonic or phosphinic acids; and we introduced pyrrolidine steric constraints. Some of these compounds display high affinity toward human BHMT and may be useful for further pharmacological studies of this enzyme. Although none of the new compounds were more potent inhibitors than the reference inhibitor 1, this study helped to completely defi ne the structural requirements of the active site of BHMT and revealed the remarkable selectivity of the enzyme for homocysteine.
- Pi?ha, Jan,Vaňek, Václav,Budě??sińsky, Milo?,Mlad?ková, Jana,Garrow, Timothy A.,Ji??acek, Ji??i
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- Collagen labelling with an azide-proline chemical reporter in live cells
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We have developed a strategy for selective imaging of collagen in live foetal ovine osteoblasts. Our approach involves the incorporation of an azide-tagged proline in the biosynthesis of collagen followed by labelling using a strain-promoted [3+2] azide-alkyne cycloaddition reaction. This journal is
- Amgarten, Beatrice,Rajan, Rakesh,Martínez-Sáez, Nuria,Oliveira, Bruno L.,Albuquerque, Inês S.,Brooks, Roger A.,Reid, David G.,Duer, Melinda J.,Bernardes, Gon?alo J. L.
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- Locked conformations for proline pyrrolidine ring: Synthesis and conformational analysis of cis- and trans-4-tert-butylprolines
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The motional restrictions of the proline pyrrolidine ring allow this secondary amine amino acid to act as a turn inducer in many peptides and proteins. The pyrrolidine ring is known to exhibit two predominant pucker modes (i.e., C-4 (Cγ) exo and endo envelope conformers whose ratio can be controlled by proper substituents in the ring). In nature, the exo puckered 4(R)-hydroxy-L-proline plays a crucial role as a building block in collagen and collagen-like structures. It has been previously concluded that the electronegativity of the 4-cis-substituent increases the endo puckering while the electronegativity of the 4-trans-substituent favors the exo puckering. Here, we have introduced a sterically demanding tert-butyl group at C-4 in trans- and cis-configurations. In the case of trans-substitution, the induced puckering effect on the pyrrolidine ring was studied with X-ray crystallography and 1H NMR spectral simulations. Both cis- and trans-4-tert-butyl groups strongly favor pseudoequatorial orientation, thereby causing opposite puckering effects for the pyrrolidine ring, cis-exo and trans-endo for L-prolines, in contrast to the effects observed in the case of electronegative C-4 substituents. The syntheses and structural analysis are presented for the conformationally constrained 4-tert-butylprolines. The prolines were synthesized from 4-hydroxy-L-proline, substitution with t-BuCuSPhLi being the key transformation. This reaction gave N-Boc-trans-4-tert-butyl-L-proline tert-butyl ester in 94% ee and 57% de. Enantioselectivity was increased to 99.2% ee by crystallization of N-Boc-trans-4-tert-butyl-L-proline in the final step of the synthesis.
- Koskinen, Ari M. P.,Helaja, Juho,Kumpulainen, Esa T. T.,Koivisto, Jari,Mansikkamaeki, Heidi,Rissanen, Kari
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- Altering the sex pheromone cyclo(L-pro-l-pro) of the diatom seminavis robusta towards a chemical probe
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As a major group of algae, diatoms are responsible for a substantial part of the primary production on the planet. Pennate diatoms have a predominantly benthic lifestyle and are the most species-rich diatom group, with members of the raphid clades being motile and generally having heterothallic sexual reproduction. It was recently shown that the model species Seminavis robusta uses multiple sexual cues during mating, including cyclo(L-Pro-L-Pro) as an attraction pheromone. Elaboration of the pheromone-detection system is a key aspect in elucidating pennate diatom life-cycle regulation that could yield novel fundamental insights into diatom speciation. This study reports the synthesis and bio-evaluation of seven novel pheromone analogs containing small structural alterations to the cyclo(L-Pro-L-Pro) pheromone. Toxicity, attraction, and interference assays were applied to assess their potential activity as a pheromone. Most of our analogs show a moderate-to-good bioactivity and low-to-no phytotoxicity. The pheromone activity of azide-and diazirine-containing analogs was unaffected and induced a similar mating behavior as the natural pheromone. These results demonstrate that the introduction of confined structural modifications can be used to develop a chemical probe based on the diazirine-and/or azide-containing analogs to study the pheromone-detection system of S. robusta.
- Bonneure, Eli,De Baets, Amber,De Decker, Sam,Van den Berge, Koen,Clement, Lieven,Vyverman, Wim,Mangelinckx, Sven
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- Multipodal insulin mimetics built on adamantane or proline scaffolds
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Multi-orthogonal molecular scaffolds can be applied as core structures of bioactive compounds. Here, we prepared four tri-orthogonal scaffolds based on adamantane or proline skeletons. The scaffolds were used for the solid-phase synthesis of model insulin mimetics bearing two different peptides on the scaffolds. We found that adamantane-derived compounds bind to the insulin receptor more effectively (Kd value of 0.5 μM) than proline-derived compounds (Kd values of 15–38 μM) bearing the same peptides. Molecular dynamics simulations suggest that spacers between peptides and central scaffolds can provide greater flexibility that can contribute to increased binding affinity. Molecular modeling showed possible binding modes of mimetics to the insulin receptor. Our data show that the structure of the central scaffold and flexibility of attached peptides in this type of compound are important and that different scaffolds should be considered when designing peptide hormone mimetics.
- Hajduch, Jan,Fabre, Benjamin,Klopp, Benjamin,Pohl, Radek,Budě?ínsky, Milo?,?olínová, Veronika,Ka?i?ka, Václav,K?prülüoglu, Cemal,Eyrilmez, Saltuk Mustafa,Lep?ík, Martin,Hobza, Pavel,Mitrová, Katarína,Lubos, Marta,Hernández, María Soledad Garre,Jirá?ek, Ji?í
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- Design and synthesis of fluorinated peptides for analysis of fluorous effects on the interconversion of polyproline helices
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The unique interaction between fluorine atoms has been exploited to alter protein structures and to develop synthetic and analytical applications. To expand such fluorous interaction for novel applications, polyproline peptides represent an excellent molecular nanoscaffold for controlling the presentation of perfluoroalkyl groups on their unique secondary structure. We develop approaches to synthesis fluorinated peptides to systematically investigate how the number, location and types of the fluorous groups on polyproline affect the conformation by monitoring the transition between the two major polyproline structures PPI and PPII. This work provides valuable information on how fluorous interaction affects the peptide structure and also benefits the design of functional fluorous molecules.
- Horng, Jia-Cherng,Hsu, Kuang-Cheng,Li, Meng-Che,Lin, Chih-Wei,Lin, Tse-Hsueh,Liu, Ying-Jie,Wang, Sheng-Kai
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- Method for synthesizing tert-2-(3- (2S)-4- butyl)-1- ester of n-oxo-isothiazole alkyloxycarbonylpyrrolidinecarboxylic acid (by machine translation)
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The technical scheme of the present (2S) - 4 - invention is that the following) - 1 - technical scheme of the present invention, is that the compound is obtained. by the continuous production of the: compound having L - the following beneficial, effects: the Boc compound is obtained II, from the following technical scheme III, No.No. STR3, No.No. IV; The technical proposal of the present invention is the following technical proposal: II No.No. STR3 III. No., No. The following technical II, proposal III Boc - L - of the present, N - Boc - 4 - IV invention is the following (2S) - 4 -) - 1 - technical proposal: No.No. STR8. No. II No.No. :(1) STR8 III, No.No.No. STR8No.No.No.No. STR8No.No.No.No. STR8No.No.No.No. STR8No.No.No.No. STR8No.No.No.No. STR8No.No.No.No. STR2, No.No.No. STR8No.No.No.No. .(2) STR8No., No.No.No.. STR8No., No.No.No., STR2No.No.No. STR8No.No.No.No. STR8No.No.No.No. STR2No.No.No. STR8No.No.No.No. STR8No.No.No.No. STR2No.No.No. STR8No.No.No.No. STR8No.No.No.No. STR2No.No.No. STR8No.No.No.No. STR2No.No.No. STR8No.No.No.No. STR8No.No.No.No. STR2No.No.No. STR8No.No.No.No. STR2No.No.No. STR7No.No.No.No. STR2No.No.No. STR8No.No.No.No. STR2No.No.No. STR7No.No.No.No. STR2No.No.No. STR8No.No.No.No. STR2No.No.No. STR7No.No.No.No. STR2No.No.No. STR8No.No.No.No. STR2No.No.No. STR7No.No.No.No. STR2No.No.No. STR7No.No.No.No. STR2No.No.No. STR8No.No.No.No. STR2No.No.No. STR7No.No.No.No. STR2No.No.No. STR7No.No.No.No. STR2No.No.No. STR7No.No.No.No. ST (by machine translation)
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Paragraph 0038-0040; 0053-0055; 0066-0068
(2020/02/14)
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- Rational Design of Azastatin as a Potential ADC Payload with Reduced Bystander Killing
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Auristatins are a class of ultrapotent microtubule inhibitors, whose growing clinical popularity in oncology is based upon their use as payloads in antibody-drug conjugates (ADCs). The most widely utilized auristatin, MMAE, has however been shown to cause apoptosis in non-pathological cells proximal to the tumour (“bystander killing”). Herein, we introduce azastatins, a new class of auristatin derivatives encompassing a side chain amine for antibody conjugation. The synthesis of Cbz-azastatin methyl ester, which included the C2-elongation and diastereoselective reduction of two proteinogenic amino acids as key transformations, was accomplished in 22 steps and 0.76 % overall yield. While Cbz-protected azastatin methyl ester (0.13–3.0 nM) inhibited proliferation more potently than MMAE (0.47–6.5 nM), removal of the Cbz-group yielded dramatically increased IC50-values (9.8–170 nM). We attribute the reduced apparent cytotoxicity of the deprotected azastatin methyl esters to a lack of membrane permeability. These results clearly establish the azastatins as a novel class of cytotoxic payloads ideally suited for use in next-generation ADC development.
- Hartmann, Rafael W.,Fahrner, Raphael,Shevshenko, Denys,Fyrkn?s, M?rten,Larsson, Rolf,Lehmann, Fredrik,Odell, Luke R.
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p. 2500 - 2512
(2020/10/20)
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- Synthesis of 4-(Arylmethyl)proline Derivatives
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A synthesis of 4 - (arylmethyl)proline by using Suzuki cross-couplings was developed. The route permits access to a variety of 4-substituted proline derivatives bearing various aryl moieties that expand the toolbox of proline analogues for studies in chemistry and biology.
- Loosli, Simon,Foletti, Carlotta,Papmeyer, Marcus,Wennemers, Helma
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supporting information
p. 508 - 510
(2019/02/26)
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- Chiral aminophosphines derived from hydroxyproline and their application in allene–imine [4 + 2] annulation
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A robust synthetic route from l-hydroxyproline (l-Hyp) to phosphines has established an expandable library of six chiral aminophosphines, which were then applied to the phosphine-catalyzed [4 + 2] allene–imine annulation. The enantioinduction in the annulations—induced by a purely steric effect—were moderate (up to 57% ee). A switch of the reaction site from the γ- to the β′-carbon atom of the allenoate was observed during the annulations performed using sterically demanding chiral phosphines.
- Khong, San N.,Xie, Changmin,Wang, Xinyi,Tan, Hao,Kwon, Ohyun
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p. 389 - 396
(2019/04/08)
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- N-methyl-D-aspartate receptor modulators and methods of making and using same
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Disclosed are compounds having enhanced potency in the modulation of NMDA receptor activity. Such compounds are contemplated for use in the treatment of diseases and disorders, such as learning, cognitive activities, and analgesia, particularly in alleviating and/or reducing neuropathic pain. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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Page/Page column 55; 56
(2018/06/25)
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- Design and synthesis of plant cyclopeptide Astin C analogues and investigation of their immunosuppressive activity
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To further investigate on the structure-activity relationships of immunosuppressive Astin C, seventeen analogues 1–17 were designed and synthetized via amino acid substitution strategy by the solid-phase peptide synthesis method for the first time. In comparison with Astin C (IC50 = 12.6 ± 3.3 μM), only compounds 2 (IC50 = 38.4 ± 16.2 μM), 4 (IC50 = 51.8 ± 12.7 μM), 5 (IC50 = 65.2 ± 15.6 μM), and 8 (IC50 = 61.8 ± 12.4 μM) exhibited immunosuppressive activity in the Lymph node cells of mice. These results showed that the Astin C analogues containing D-amino acid residues, hydrophobic long-chain alkyl substituents, and aryl substituents performed better than those carrying hydrophilic amino acid residues and short-chain alkyl substituents. Moreover compounds 15, 16, and 17 had no immunosuppressive activity, which suggested that cis-3,4-dichlorinated proline played an important role in the immunosuppressive activity of Astin C.
- Li, Fei,Guo, Xi-Xi,Zeng, Guang-Zhi,Qin, Wei-Wei,Zhang, Bo,Tan, Ning-Hua
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supporting information
p. 2523 - 2527
(2018/06/06)
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- Ledipasvir preparation method
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The invention discloses a Ledipasvir preparation method. The Ledipasvir preparation method includes steps: (1) Ledipasvir intermediate product 1-LD-B preparation; (2) Ledipasvir intermediate product 2-LD-E preparation; (3) Ledipasvir intermediate product 3-LD-F preparation; (4) Ledipasvir intermediate product 4-LD-J preparation; (5) Ledipasvir intermediate product 5-LD-L preparation; (6) Ledipasvir-LD-Q preparation. The Ledipasvir preparation method has advantages of technical maturity and stability, product quality stability, safety and reliability in production process and suitableness for industrial production.
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Paragraph 0071; 0073; 0074; 0144; 0213
(2018/05/16)
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- Synthesis technology of N-Boc-4-oxo-L-proline tert-butyl ester
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The invention discloses a synthesis technology of N-Boc-4-oxo-L-proline tert-butyl ester, and relates to the technical field of medicine synthesis. The synthesis technology solves the problems that inthe prior art, the production cost is low, the product yield is low, and the synthesis technology is not suitable for industrial production. According to the synthesis technology, Boc anhydride is used to generate tert-butyl carbonate, special esterification reagents namely O-tert-butyl-N,N'-diisopropyl isourea and EDC condensation reagent are not used, and the production cost is reduced by morethan 70%. Sodium hypochlorite is directly used to replace ruthenium tetroxide and chromium trioxide to prepare oxidized hydroxyl and is safe and reliable, furthermore, the post treatment is simple, the environmental pollution is greatly reduced, the operation of the synthesis technology is easy to perform, the technological conditions are easy to control, the synthesis technology is suitable for massive production, and the yield of step three can reach 69% and is higher than that of a conventional technology.
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Paragraph 0018
(2018/07/30)
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- Preparation method of N-t-butyloxycarboryl-ketone-L-proline
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The invention relates to a preparation method of N-t-butyloxycarboryl-ketone-L-proline, and belongs to the technical field of synthesis of drug intermediates. In order to solve the problems that existing reaction is dramatic and low in safety and the product yield stability is low, the invention provides the preparation method of the N-t-butyloxycarboryl-ketone-L-proline. The method comprises thefollowing steps: under the existence of an inorganic alkaline reagent, enabling L-hydroxyproline to react with di-tert-butyl dicarbonate ester in a mixed solvent of water and a water-soluble organic solvent, and removing the organic solvent at the end of the reaction, thereby obtaining a residual aqueous solution containing an intermediate product carboxylate; and under the existence of a TEMPO catalyst, directly generating oxidizing reaction between the obtained intermediate product carboxylate and dihalide isocyanurate, and acidifying a product at the end of the reaction, thus obtaining theproduct N-t-butyloxycarboryl-ketone-L-proline. The preparation method can realize stable reaction, so as to achieve effects of increasing the yield and improving the purity.
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Paragraph 0023; 0024; 0027; 0030
(2018/09/12)
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- Methods for Treating Cognitive Disorders Using Inhibitors of Histone Deacetylase
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This disclosure relates to compounds for the inhibition of histone deacetylase and treatment of a cognitive disorder or deficit. More particularly, the disclosure provides for compounds of formula (I) wherein Q, J, L and Z are as defined in the specification.
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Paragraph 0568
(2017/01/23)
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- Preparation method for medical intermediate N-Boc-cis-4-hydroxy-L-proline
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The invention provides a preparation method for a medical intermediate N-Boc-cis-4-hydroxy-L-proline. The preparation method comprises the following steps: with L-hydroxyproline as a raw material, subjecting the raw material to Boc protection; then carrying out hydroxyl radical oxidation so as to obtain N-Boc-4-oxo-L-proline; dissolving N-Boc-4-oxo-L-proline in a solvent and successively carrying out reduction with a reducing agent and purification at a certain temperature so as to obtain the product N-Boc-cis-4-hydroxy-L-proline. The method has the advantages of good reaction selectivity, high product ee value and low preparation cost.
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Paragraph 0015; 0017-0018
(2017/04/26)
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- (L)-Prolinamide imidazolium hexafluorophosphate ionic liquid as an efficient reusable organocatalyst for direct asymmetric aldol reaction in solvent-free condition
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We have designed a new hydrophobic ionic liquid derived from bromoester of trans-4-hydroxy-(l)-prolinamide and N-methylimidazole. (l)-Prolinamide imidazolium hexafluorophosphate ionic liquid (2 mol%) found to be an excellent organocatalyst for direct asymmetric aldol reaction between 4-nitrobenzaldehyde and cyclohexanone using acetic acid (2 mol%) as an additive at -15 °C in solvent-free condition, the aldol product was afforded in excellent yield with diastereomeric ratio (anti/syn; 97:3) and 94% ee of anti-aldol product. Ionic liquids can catalyze the direct aldol reaction between benzaldehyde derivatives and cycloalkanones and the best dr (anti/syn; 99.9/0.01) and 99% ee was obtained for aldol product of 2-trifluoromethyl benzaldehyde and cyclohexanone. (l)-Prolinamide imidazolium hexafluorophosphate ionic liquid was reused up to 6 continuous cycles without decrease in the conversion of the product with 92% ee and found to be superior than its counterpart trans-4-hydroxy-(l)-prolinamide. Continuous cycle experiments do not require isolation of the catalyst after each cycle. The results of reusability of the ionic liquid catalyst were found to be better than most of other reported reusable catalysts.
- Yadav, Geeta Devi,Singh, Surendra
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p. 100459 - 100466
(2016/11/09)
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- (4S)-N-Boc-4-methoxymethyl-L-proline synthesis method
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The invention discloses a (4S)-N-Boc-4-methoxymethyl-L-proline synthesis method. The method comprises that 1, L-hydroxyproline as an initial raw material is subjected to Boc protection so that N-Boc-L-hydroxyproline is produced, 2, the N-Boc-L-hydroxyproline is dissolved in a solvent, the solution and 2, 2, 6, 6-tetramethyl-1-piperidinyloxy (TEMPO) undergo an oxidation reaction to produce (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid, 3, the (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid and (methoxymethyl)triphenylphosphonium chloride are dissolved in a solvent and undergo a wittig reaction to produce (2S)-N-Boc-4-methoxymethylenepyrrolidine-2-carboxylic acid, and 4, the (2S)-N-Boc-4-methoxymethylenepyrrolidine-2-carboxylic acid and tert-butylamine are dissolved in water and undergo a hydrogenation reaction to produce (4S)-N-Boc-4-methoxymethyl-L-proline. The method shortens reaction processes, is free of severe-toxicity cyanides, improves safety, reduces environmental protection pressure, improves atom economy, reduces waste discharge and greatly reduces a raw material cost.
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Paragraph 0045; 0046
(2016/10/31)
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- NOVEL BETULINIC PROLINE IMIDAZOLE DERIVATIVES AS HIV INHIBITORS
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The present invention relates to novel betulinic proline imidazole derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.
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Page/Page column 28; 29
(2016/01/25)
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- PROCESS FOR THE PREPARATION OF (4R)-1-(TERT-BUTOXYCARBONYL)-4-HYDROXY-L-PROLINE
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The present invention provides a process for the preparation of (4R)-1-(tert- butoxycarbonyl)-4-hydroxy-L-proline of Formula IV. The present invention also provides a process for the preparation of {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazin-1-yl] pyrrolidin-2-yl}(1,3-thiazolidin-3-yl) methanone of Formula II, or salts thereof, using (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline of Formula IV.
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Page/Page column 10 ; 11
(2016/06/20)
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- THERAPEUTIC COMPOUNDS AND METHODS OF USE THEREOF
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The invention provides compounds having the general Formula (I); and pharmaceutically acceptable salts thereof; wherein the variables RA, RAA, subscript n, subscript q, ring A, X2, L, subscript m, X1, R1, R2, R3, R4, R5, D and E have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.
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Page/Page column 166
(2016/01/25)
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- 4R- and 4S-iodophenyl hydroxyproline, 4R-pentynoyl hydroxyproline, and S-propargyl-4-thiolphenylalanine: Conformationally biased and tunable amino acids for bioorthogonal reactions
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Bioorthogonal reactions allow the introduction of new functionalities into peptides, proteins, and other biological molecules. The most readily accessible amino acids for bioorthogonal reactions have modest conformational preferences or bases for molecular interactions. Herein we describe the synthesis of 4 novel amino acids containing functional groups for bioorthogonal reactions. (2S,4R)- and (2S,4S)-iodophenyl ethers of hydroxyproline are capable of modification via rapid, specific Suzuki and Sonogashira reactions in water. The synthesis of these amino acids, as Boc-, Fmoc- and free amino acids, was achieved through succinct sequences. These amino acids exhibit well-defined conformational preferences, with the 4S-iodophenyl hydroxyproline crystallographically exhibiting β-turn (φ, ψ ～ -80°, 0°) or relatively extended (φ, ψ ～ -80°, +170°) conformations, while the 4R-diastereomer prefers a more compact conformation (φ ～ -60°). The aryloxyproline diastereomers present the aryl groups in a highly divergent manner, suggesting their stereospecific use in molecular design, medicinal chemistry, and catalysis. Thus, the 4R- and 4S-iodophenyl hydroxyprolines can be differentially applied in distinct structural contexts. The pentynoate ester of 4R-hydroxyproline introduces an alkyne functional group within an amino acid that prefers compact conformations. The propargyl thioether of 4-thiolphenylalanine was synthesized via copper-mediated cross-coupling reaction of thioacetic acid with protected 4-iodophenylalanine, followed by thiolysis and alkylation. This amino acid combines an alkyne functional group with an aromatic amino acid and the ability to tune aromatic and side chain properties via sulfur oxidation. These amino acids provide novel loci for peptide functionalization, with greater control of conformation possible than with other amino acids containing these functional groups.
- Forbes, Christina R.,Pandey, Anil K.,Ganguly, Himal K.,Yap, Glenn P. A.,Zondlo, Neal J.
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supporting information
p. 2327 - 2346
(2016/03/01)
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- SUBSTITUTED HETEROCYCLIC SULFONAMIDE COMPOUNDS USEFUL AS TRPA1 MODULATORS
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The invention is concerned with the compounds of formula I or II: and salts thereof. In addition, the present invention relates to methods of manufacturing and methods of using the compounds of formula I or II as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain.
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Paragraph 01322; 01323
(2015/04/28)
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- THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
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Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
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Page/Page column
(2015/03/31)
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- Direct asymmetric aldol reactions catalysed by trans-4-hydroxy-(S)-prolinamide in solvent-free conditions
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Direct asymmetric aldol reactions between 4-nitrobenzaldehyde and cyclohexanone were catalysed by trans-4-hydroxy-(S)-prolinamide (10 mol %) in the presence of CH3COOH (10 mol %) as the co-catalyst under solvent-free conditions at 15 °C. (2S,4R)-4-Hydroxy-N-((S)-1-phenylethyl)pyrrolidine-2-carboxamide 2 efficiently catalysed the asymmetric aldol reaction to afford the product in >99% yield and with 95% ee with an anti/syn ratio of 88:12 after 18 h. The additional trans-hydroxyl group on (S)-prolinamide and (S)-1-phenylethylamine both influenced the ee of the predominant anti aldol product. Different benzaldehyde derivatives with cyclohexanone gave the corresponding aldol products in 38-89% yields and with 56-94% ee with anti/syn (100:0-71:29). Catalyst 2 can be used up to 5 continuous cycles for asymmetric aldol reactions between 4-nitrobenzaldehyde and cyclohexanone with overall 91% yield and 86% yield of anti-product with anti/syn (98:2).
- Yadav, Geeta Devi,Singh, Surendra
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p. 1156 - 1166
(2015/10/28)
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- PROCESS FOR THE PREPARATION OF N-PROTECTED (5S)-5-(1,3-THIAZOLIDIN-3-YLCARBONYL)PYRROLIDIN-3-ONE
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The present invention provides a process for the preparation of an N-protected (55)-5-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one of Formula III. The invention also provides a process for the preparation of {(25',45)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5- yl)piperazin-l-yl]pyrrolidin-2-yl}(l,3-thiazolidin-3-yl)methanone, or salts thereof, using the N-protected (55)-5-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one of Formula III. (III)
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Page/Page column 8; 9
(2015/02/25)
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- Propargyloxyproline Regio- and Stereoisomers for Click-Conjugation of Peptides: Synthesis and Application in Linear and Cyclic Peptides
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The use of the click reaction for the introduction of conjugate groups, such as affinity or fluorescent labels, to a peptide for the study of peptide biochemistry and pharmacology is widespread. However, the nature and location of substituted 1,2,3-triazoles in peptide sequences may markedly affect conformation or binding as compared with native sequences. We have examined the preparation and application of propargyloxyproline (Pop) residues as a precursor to such peptide conjugates. Pop residues are available in a range of regio- and stereoisomers from hydroxyproline precursors and are readily prepared in Fmoc-protected form. They can be incorporated routinely in peptide synthesis and broadly retain the conformational properties of the parent proline containing peptides. This is exemplified by the preparation of biotin- and fluorophore-labelled peptides derived from linear and cyclic peptides.
- Northfield, Susan E.,Mountford, Simon J.,Wielens, Jerome,Liu, Mengjie,Zhang, Lei,Herzog, Herbert,Holliday, Nicholas D.,Scanlon, Martin J.,Parker, Michael W.,Chalmers, David K.,Thompson, Philip E.
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p. 1365 - 1372
(2015/09/15)
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- Synthesis of (1R,4R)-2,5-diazabicyclo[2.2.1]heptane derivatives by an epimerization-lactamization cascade reaction
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An epimerization-lactamization cascade of functionalized (2S,4R)-4-aminoproline methyl esters is developed and applied in synthesizing (1R,4R)-2,5-diazabicyclo[2.2.1]heptane (DBH) derivatives. (2S,4R)-4-Aminoproline methyl esters are likely to undergo 2-epimerization under basic conditions, followed by an intramolecular aminolysis of the (2R)-epimer to form the bridged lactam intermediates. Key factors identified for this cascade reaction include the electron-withdrawal N-protective group in the substrates and a strong base as the promoter.
- Cui, Benqiang,Yu, Jie,Yu, Fu-Chao,Li, Ya-Min,Chang, Kwen-Jen,Shen, Yuehai
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p. 10386 - 10392
(2015/01/30)
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- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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The present invention provides compounds of Formula (I) (Formula (I)) including pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention.
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Page/Page column 43-44
(2015/07/07)
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- Chemoselective synthesis of N-protected alkoxyprolines under specific solvation conditions
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N-Protected hydroxyprolines (Hyp) were transformed chemoselectively into alkoxyproline derivatives by direct O-alkylation. The starting Hyp was transformed into the corresponding dianion in a mixture of dimethyl sulfoxide and tetrahydrofuran (1:16 v/v) as solvent. Under these conditions, the carboxy-anion showed reduced nucleophilicity because it was specifically solvated, and the more reactive oxy-anion was selectively alkylated. N-Protected trans-4-alkoxy-, cis-4-alkoxy- and trans-3-alkoxyprolines were thus obtained in a single step in very high overall yields and with complete stability of the stereogenic center configuration. Copyright
- Mihali, Voichita,Foschi, Francesca,Penso, Michele,Pozzi, Gianluca
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supporting information
p. 5351 - 5355
(2014/10/15)
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- PERFLUORO-TERT-BUTYL HYDROXYPROLINE
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The present invention provides novel analogues of alpha amino acids, comprising a perfluoro-tert-butyl group, and molecules comprising the novel analogues. Also provided are a wide range of applications of the novel analogues in therapeutics, theranostics and pharmaceuticals as well as in imaging applications. In particular, the use of the novel analogues in detecting or modifying a target molecule is provided.
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Page/Page column 10
(2014/09/03)
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- Design, synthesis, and antileukemic activity of stereochemically defined constrained analogues of FTY720 (Gilenya)
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FTY720 functions as an immunosuppressant due to its effect on sphingosine-1-phosphate receptors. At doses well above those needed for immunosuppression, FTY720 also has antineoplastic actions. Our published work suggests that at least some of FTY720's anticancer activity is independent of its effects on S1P receptors and due instead to its ability to induce nutrient transporter down-regulation. Compounds that trigger nutrient transporter loss but lack FTY720's S1P receptor-related, dose-limiting toxicity have the potential to be effective and selective antitumor agents. In this study, a series of enantiomerically pure and stereochemically diverse O-substituted benzyl ethers of pyrrolidines was generated and tested for the ability to kill human leukemia cells. The stereochemistry of the hydroxymethyl was found to be a key determinant of compound activity. Moreover, phosphorylation of this group was not required for antileukemic activity.
- Fransson, Rebecca,McCracken, Alison N.,Chen, Bin,McMonigle, Ryan J.,Edinger, Aimee L.,Hanessian, Stephen
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supporting information
p. 969 - 973
(2013/10/22)
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- THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
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Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
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Page/Page column 97-98
(2013/07/31)
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- INHIBITORS OF CYTOCHROME P450
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The present application provides for a compound of formula I, or a salt thereof, compositions containing such compounds, therapeutic methods that include the administration of such compounds, and therapeutic methods that include the administration of such compounds with at least one additional therapeutic agent.
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Page/Page column 58-59
(2012/07/13)
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- INHIBITORS OF CYTOCHROME P450 (CYP3A4)
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The present application provides for a compound of formula I, and related compounds, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, compositions containing such compounds, therapeutic methods that include the administration of such compounds, and therapeutic methods that include the administration of such compounds with at least one additional therapeutic agent.
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Page/Page column 127-128
(2012/07/13)
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- Direct asymmetric aldol reactions in water catalysed by a highly active C2-symmetrical bisprolinamide organocatalyst
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A novel C2-symmetrical bisprolinamide organocatalyst was synthesised and used to facilitate asymmetric direct aldol reactions in a water emulsion. Reactions were performed at room temperature with very low catalyst loadings (1-2.5 mol%) without the required use of additives, co-catalysts or extended reaction times (24 h). This catalyst system was then used with a variety of aldehyde substrates showing good reaction generality for benzaldehydes with cyclohexanone (dr range 77/23 to 99/1, anti/syn; ee range 33% to 99%) and moderate scope with cyclopentanone (dr range 45/55 to 76/24, anti/syn; ee range 14% to 68%). Ultra-low catalysts loadings (0.1 and 0.05 mol%) were also investigated demonstrating catalyst turnover numbers in the order of 1000.
- Delaney, Joshua P.,Henderson, Luke C.
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supporting information; experimental part
p. 197 - 204
(2012/03/27)
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- Structure-reactivity studies of simple 4-hydroxyprolinamide organocatalysts in the asymmetric Michael addition reaction of aldehydes to nitroolefins
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A series of simple 4-hydroxyprolinamides was synthesised and they were found to act as organocatalysts for the asymmetric conjugate addition of aldehydes to nitroolefins in excellent yields (98%), with complete diastereoselectivity (99:1, syn:anti) and enantioselectivity (98% ee for syn). Furthermore, the use of low catalyst loadings (5mol%) and a low aldehyde molar excess (1.5equivalents) were achieved. Copyright
- Watts, John,Luu, Lien,McKee, Vickie,Carey, Ed,Kelleher, Fintan
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supporting information; experimental part
p. 1035 - 1042
(2012/05/20)
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- Heterogeneous asymmetric Henry-Michael one-pot reaction synergically catalyzed by grafted chiral bases and inherent achiral hydroxyls on mesoporous silica surface
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Highly efficient and enantioselective asymmetric Henry-Michael one-pot reaction has been achieved on bifunctional heterogeneous catalysts with inherent achiral hydroxyls as acidic sites and immobilized chiral amines as basic sites. Final products were afforded in yields of up to 85% and ee of 99%.
- Yang, Shanshan,He, Jing
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supporting information
p. 10349 - 10351,3
(2020/09/09)
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- Homo- and heterogeneous organocatalysis: Enantioselective Mannich addition of ketones to endocyclic carbon-nitrogen double bonds
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The proline-catalyzed Mannich addition of ketones to chalkogenazines is reported. Yields and enantioselectivities of the corresponding products were good to excellent, using different types of organocatalysts. Furthermore the immobilization of hydroxyproline into a readily synthesized polystyrene- copolymer was accomplished. The catalytic performance of this heterogeneous catalyst was successfully demonstrated in the discussed Mannich reaction. Copyright
- Schulz, Knut,Ratjen, Lars,Martens, Jürgen
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scheme or table
p. 546 - 553
(2011/03/18)
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- Dual kinetically controlled native chemical ligation using a combination of sulfanylproline and sulfanylethylanilide peptide
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Dual kinetically controlled native chemical ligation using a newly developed sulfanylproline-mediated reaction in combination with an N-sulfanylethylanilide peptide was successfully applied to a previously unreported sequential coupling of peptide fragments added simultaneously to the reaction.
- Ding, Hao,Shigenaga, Akira,Sato, Kohei,Morishita, Ko,Otaka, Akira
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supporting information; experimental part
p. 5588 - 5591
(2011/12/03)
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- Design and synthesis of simplified taxol analogs based on the T-Taxol bioactive conformation
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A series of compounds designed to adopt a conformation similar to the tubulin-binding T-Taxol conformation of the anticancer drug paclitaxel has been synthesized. Both the internally bridged analogs 37-39, 41 and the open-chain analogs 27-29 and 43 were prepared. The bridged analogs 37-39 and 41 were synthesized by Grubbs' metatheses of compounds 30-32 and 33, which, in turn, were prepared by coupling β-lactams 24-26 with alcohols 22 and 23. Both the bridged and the open-chain analogs showed moderate to good cytotoxicity.
- Zhao, Jielu,Bane, Susan,Snyder, James P.,Hu, Haipeng,Mukherjee, Kamalika,Slebodnick, Carla,Kingston, David G.I.
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experimental part
p. 7664 - 7678
(2012/01/05)
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- MELANOCORTIN RECEPTOR AGONISTS
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The present invention relates to a compound having a good agonistic activity to melanocortin receptor, or pharmaceutically acceptable salt or isomer thereof, and an agonistic composition for melanocortin receptor comprising the same as an active ingredient.
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Page/Page column 10
(2010/06/11)
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- DICYCLOAZAALKANE DERIVATES, PREPARATION PROCESSES AND MEDICAL USES THEREOF
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Disclosed are new dicycloazaalkane derivates represented by general formula (I), preparation processes and pharmaceutical compositions containing them, and the uses for treatment especially for dipeptidyl peptidase inhibitor (DPP-IV), in which each substitute group of general formula (I) is as defined in specification.
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Page/Page column 38-39
(2010/11/17)
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- Chiral amino amides for the ruthenium(II)-catalyzed asymmetric transfer hydrogenation reaction of ketones in water
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The chiral amino amide 3 was derived from L-proline and used for the [RuCl2(p-cymene)]2-catalyzed asymmetric transfer hydrogenation of prochiral ketones performed in water. Moderate to good chemical selectivities (up to 95% yield) and enantioselectivities (up to 90% ee) were obtained in the presence of 2 mol % of TBAB (n-Bu4NBr) as the phase transfer catalyst.
- Mao, Jincheng,Guo, Jun
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experimental part
p. 173 - 181
(2010/09/04)
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