- Synthesis of enantiomerically pure δ-benzylproline derivatives
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The (2S,5R) stereoisomer of 5-benzylproline, i.e. the l-proline analogue that bears a δ-benzyl substituent cis to the carbonyl function, has been prepared in enantiomerically pure form and excellent global yield. The procedure involves the construction of
- Rodríguez, Isabel,Calaza, M. Isabel,Jiménez, Ana I.,Cativiela, Carlos
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- Synthesis method of chiral N-Boc-3-amino-4-aryl-butyric acid
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The invention relates to a synthesis method of chiral N-Boc-3-amino-4-aryl-butyric acid. The method is as below: 1, conducting a cross metathesis reaction, an asymmetric conjugate addition reaction and an oxidation reaction on starting materials including an allyl aromatic compound and crotonaldehyde by a continuous reaction one-pot method to synthesize an N-Boc-3-aryl methyl-5-oxo isoxazole intermediate; or conducting an asymmetric conjugate addition reaction and an oxidation reaction on a starting material (E)-4-aryl-2-crotonaldehyde by a continuous reaction one-pot method to synthesize an N-Boc-3-aryl methyl-5-oxo isoxazole intermediate; and 2, subjecting (3R)-N-Boc-3-aryl methyl-5-oxo isoxazole intermediate by high-pressure hydrogenation to directly prepare the chiral N-Boc-3-amino-4-aryl-butyric acid. The synthesis method provided by the invention has the advantages of simple operation, mild reaction conditions, target product yield reaching 60-69%, and ee value of the target product reaching as high as 96%. The synthetic route has industrialization prospect.
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Paragraph 0032; 0033; 0034; 0035; 0036
(2017/08/28)
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- Protein-protein interface mimicry by an oxazoline piperidine-2,4-dione
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Representative minimalist mimics 1 were prepared from amino acids. Scaffold 1 was not designed to mimic any particular secondary structure, but simulated accessible conformations of this material were compared with common ideal secondary structures and with >125000 different protein-protein interaction (PPI) interfaces. This data mining exercise indicates that scaffolds 1 can mimic features of sheet-turn-sheets, somewhat fewer helical motifs, and numerous PPI interface regions that do not resemble any particular secondary structure.
- Li, Xun,Taechalertpaisarn, Jaru,Xin, Dongyue,Burgess, Kevin
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supporting information
p. 632 - 635
(2015/03/05)
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- A multifaceted secondary structure mimic based on piperidine-piperidinones
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Minimalist secondary structure mimics are typically made to resemble one interface in a protein-protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1, simulation of its solution-state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side-chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non-ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus dld-1-faf crystallized in a conformation that is estimated to be 0.91 kcal-mol-1 above the minimum energy solution state. Do we know, when designing a new peptidomimetic scaffold like the one shown, how it can resemble secondary structures? Design and modular synthesis of this elongated mimic is reported, and the structure is related to ideal and real structures at PPI interfaces.
- Xin, Dongyue,Perez, Lisa M.,Ioerger, Thomas R.,Burgess, Kevin
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p. 3594 - 3598
(2014/04/17)
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- Antiplasmodial activity of new 4-aminoquinoline derivatives against chloroquine resistant strain
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Emergence and spread of multidrug resistant strains of Plasmodium falciparum has severely limited the antimalarial chemotherapeutic options. In order to overcome the obstacle, a set of new side-chain modified 4-aminoquinolines were synthesized and screened against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of P. falciparum. The key feature of the designed molecules is the use of methylpiperazine linked α, β3- and γ-amino acids to generate novel side chain modified 4-aminoquinoline analogues. Among the evaluated compounds, 20c and 30 were found more potent than CQ against K1 and displayed a four-fold and a three-fold higher activity respectively, with a good selectivity index (SI = 5846 and 11,350). All synthesized compounds had resistance index between 1.06 and >14.13 as against 47.2 for chloroquine. Biophysical studies suggested that this series of compounds act on heme polymerization target.
- Sinha, Manish,Dola, Vasanth R.,Agarwal, Pooja,Srivastava, Kumkum,Haq, Wahajul,Puri, Sunil K.,Katti, Seturam B.
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p. 3573 - 3586
(2014/07/07)
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- Continuous flow synthesis of β-amino acids from α-amino acids via Arndt-Eistert homologation
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A fully continuous four step process for the preparation of β-amino acids from their corresponding α-amino acids utilizing the Arndt-Eistert homologation approach is described. the Partner Organisations 2014.
- Pinho, Vagner D.,Gutmann, Bernhard,Kappe, C. Oliver
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p. 37419 - 37422
(2014/12/09)
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- Chirality and template-mediated induction of helical preferences in achiral β-peptides
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This study describes chirality- or template-mediated helical induction in achiral β-peptides for the first time. A strategy of end capping β-peptides derived from β-hGly (the smallest achiral β-amino acid) with a chiral β-amino acid that possesses a carbo
- Sharma, Gangavaram V. M.,Kodeti, Srinivas Reddy,Dutta, Samit K.,Velaparthi, Subash,Narsimulu, Kongari,Anjaiah, Gonuguntla,Basha, Shaik Jeelani,Kunwar, Ajit C.
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supporting information
p. 16046 - 16060
(2013/02/23)
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- TAPP analogs containing β3-homo-amino acids: Synthesis and receptor binding
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β-Amino acids containing α,β-hybrid peptides show great potential as peptidomimetics. In this paper, we describe the synthesis and affinity to μ-opioid and δ-opioid receptors of α,β-hybrids, analogs of the tetrapeptide Tyr- d-Ala-Phe-Phe-NH2 (TAPP). Each amino acid was replaced with an l- or d-β3-h-amino acid. All α,β-hybrids of TAPP analogs were synthesized in solution and tested for affinity to μ-opioid and δ-opioid receptors. The analog Tyr-β3h- d-Ala-Phe-PheNH2 was found to be as active as the native tetrapeptide.
- Podwysocka,Kosson,Lipkowski,Olma, Aleksandra
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p. 556 - 559
(2012/11/07)
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- Stabilization of β-hairpin structures via inter-strand π-π and hydrogen bond interactions in α-, β-, γ-hybrid peptides
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Synthesis and conformational studies of α-, β-, γ-hybrid peptides containing a pyrrole amino acid (Paa, 1) and a furan amino acid (Faa, 2), namely Boc-β-Phe-Faa-d-Pro-Gly-Paa-β-HGly-Faa-OMe (3) and Boc-Paa-β-Phe-Faa-d-Pro-Gly-Paa-β-HGly-Faa-OMe (4), were
- Chakraborty, Tushar K.,Srinivasa Rao,Udaya Kiran,Jagadeesh
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scheme or table
p. 4350 - 4353
(2009/10/26)
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- General and practical conversion of aldehydes to homologated carboxylic acids
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(Chemical Equation Presented) The reaction of aldehydes with trichloromethide followed by sodium borohydride or sodium phenylseleno(triethyl) borate under basic conditions affords homologated carboxylic acids in high yields. This operationally simple procedure provides a practical, efficient alternative to other homologation protocols. The approach is compatible with sensitive aldehydes including enals and enolizable aldehydes. It also offers convenient access to α-monodeuterated carboxylic acids.
- Cafiero, Lauren R.,Snowden, Timothy S.
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supporting information; experimental part
p. 3853 - 3856
(2009/07/01)
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- Wolff rearrangement of Nα-Boc-/Z-protected aminodiazoketones to the corresponding β-amino acids under microwave irradiation
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The Wolff rearrangement of Nα-Boc-/Z-protected aminodiazoketones in the presence of silver benzoate under microwave irradiation is described. The reaction is found to be rapid, efficient and complete. It results in the isolation of Boc-/Z- prot
- Kantharaju,Patil, Basanagoud S.,Suresh Babu, Vommina V.
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p. 2611 - 2613
(2007/10/03)
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- Synthesis of β-amino acids: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (TBTU) for activation of Fmoc-/Boc-/Z-α-amino acids
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A new and efficient method for the homologation of urethane protected α-amino acids to its β-homomers by the Arndt-Eistert method using TBTU as a coupling agent is described. Several Fmoc-/Boc-/Z-protected α-amino diazoketone derivatives have been obtaine
- Patil, Basanagoud S.,Vasanthakumar, Ganga-Ramu,Suresh Babu
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p. 3089 - 3096
(2007/10/03)
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- β-hairpins generated from hybrid peptide sequences containing both α- and β-amino acids
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The incorporation of the β-amino acid residues into specific positions in the strands and β-turn segments of peptide hairpins is being systematically explored, The presence of an additional torsion variable about the C(α)-C(β) bond (θ) enhances the confor
- Gopi, Hosahudya N.,Roy, Rituparna S.,Raghothama, Srinivasa R.,Karle, Isabella L.,Balaram, Padmanabhan
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p. 3313 - 3330
(2007/10/03)
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- Endomorphin-1 analogues containing β-proline are μ-opioid receptor agonists and display enhanced enzymatic hydrolysis resistance
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In this paper we describe the synthesis and affinity toward the μ-opioid receptor of some tetrapeptides obtained from endomorphin-1, H-Tyr-Pro-Trp-Phe-NH2 (1), by substituting each amino acid in turn with its homologue. The ability to bind μ -opioid receptors depends on the β-amino acid, and in particular 4, which contains β-L-Pro, has a KI, in the nanomolar range. The peptides 4 and 5 are significantly more resistant to enzymatic hydrolysis than 1. The same compounds, as well as the μ-opioid receptor agonist DAMGO, produced a concentration-dependent inhibition of forskolin-stimulated cyclic AMP formation, thus behaving as μ-opioid agonists. These features suggest that this novel class of endomorphin-1 analogues may represent suitable candidates for the in vivo investigation as potential μ-opioid receptor agonists.
- Cardillo, Giuliana,Gentilucci, Luca,Qasem, Ahmed R.,Sgarzi, Fabio,Spampinato, Santi
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p. 2571 - 2578
(2007/10/03)
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- β3-Amino acids by nucleophilic ring-opening of N-nosyl aziridines
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N-Nosyl aziridines can be easily prepared from 1,2-amino alcohols derived from α-amino acids. Nucleophilic ring-opening of N-nosyl aziridines with cyanide ions followed by hydrolysis of the corresponding nitriles lead to N-nosyl β3-amino acids, which can be readily converted into a variety of derivatives bearing adequate functionality for peptide synthesis. The proposed methodology is simple, efficient, and amenable to large-scale preparations.
- Farràs, Jaume,Ginesta, Xavier,Sutton, Peter W,Taltavull, Joan,Egeler, Frank,Romea, Pedro,Urpí, Fèlix,Vilarrasa, Jaume
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p. 7665 - 7674
(2007/10/03)
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- Pseudoaxially disubstituted cyclo-β3-tetrapeptide scaffolds
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An N,N-disubstituted cyclo-β3-tetrapeptide, identified as a potential molecular scaffold, has been synthesised on a multigram scale from β-homophenylalanine by employing a nosylate-based protection strategy. C2-Symmetric derivatives containing pseudoaxial, combinatorially addressable functionalities have been prepared from the parent cyclopeptide. (C) 2000 Elsevier Science Ltd.
- Sutton, Peter W.,Bradley, Adrian,Farràs, Jaume,Romea, Pedro,Urpí, Fèlix,Vilarrasa, Jaume
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p. 7947 - 7958
(2007/10/03)
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- Trifluoroacetic acid-mediated intramolecular formal N-H insertion reactions with amino-α-diazoketones: A facile and efficient synthesis of optically pure pyrrolidinones and piperidinones
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Trifluoroacetic acid (TFA) was found to promote intramolecular formal N-H insertion reactions. Upon treatment with TFA, optically pure N-Boc-β′-amino-α-diazoketones (5a-c) and N-Boc-γ′-amino-α-diazoketones (10a-d) can be converted, with retention of chira
- Yang, Hua,Jurkauskas, Valdas,Mackintosh, Nicole,Mogren, Tobias,Stephenson, Corey R. J.,Foster, Katherine,Brown, William,Roberts, Edward
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p. 800 - 808
(2007/10/03)
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- Solid-phase synthesis of a β-dodecapeptide with seven functionalized side chains and CD-spectroscopic evidence for a dramatic structural switch when going from water to methanol solution
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An all-β3-dodecapeptide with a protected N-terminal thiol-anchoring group and with seven side chains has been synthesized in multi-mg amounts by the manual solid-phase technique, applying Fmoc methodology and the Wang resin. The sequence is β-H
- Schreiber, Juerg V.,Seebach, Dieter
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p. 3139 - 3152
(2007/10/03)
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- The cyclo-β-tetrapeptide (β-HPhe-β-HThr-β-HLys-β-HTrp): Synthesis, NMR structure in methanol solution, and affinity for human somatostatin receptors
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The known solid-state structure (Fig. 1, top) of cyclo(β-HAla)4 was used to model the structure of the title compound 1 as a prospective somatostatin mimic (Fig. 1, bottom). The synthesis started with the N-protected natural amino acids Boc-Phe-OH, Boc-Trp-OH, Boc-Lys(2-Cl-Z)-OH, and Boc-Thr(OBn)-OH, which were homologated to the corresponding β-amino-acid derivatives (Scheme 1) and coupled to the β-tetrapeptide Boc-β-HTrp-β-HPhe-β-HThr(OBn)-β-HLys(2-Cl-Z)-OMe (16); the (N-Me)-β-HThr-(N-Me)-β-HPhe analog 17 was also prepared. C- and N-terminal deprotection and cyclization through the pentafluorophenyl ester gave the insoluble β-tetrapeptide with protected Thr and Lys side chains (18). Solubilization and debenzylation could only be effected in LiCl-containing THF (ca. 10% yield; with ca. 55% recovery). HPLC Purification provided a sample of the title compound 1, the structure of which, as determined by NMR-spectroscopy (Fig. 2, left) was drastically different from the 'theoretical' model (Fig. 1). There is a transannular H-bond dividing the macrocyclic 16-membered ring, thus forming a ten- and a twelve-membered H-bonded ring, the former mimicking, or actually being superimposable on, an α-peptidic so-called β-turn. Still, the four side chains occupy equatorial positions on the ring, as planned, albeit with somewhat different geometry as compared to the 'original'. The cyclo-β-tetrapeptide has micromolar affinities to the human somatostatin receptors (hsst 1-5). Thus, we have demonstrated for the first time that it is possible to mimic a natural peptide hormone with a small β-peptide. Furthermore, we have discovered a simple way to construct the ubiquitous β-turn motif with β-peptides (which are known to be stable to mammalian peptidases).
- Gademann, Karl,Ernst, Martin,Seebach, Dieter,Hoyer, Daniel
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- Synthesis of optically active β-amino acid N-carboxyanhydrides
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(Equation presented) Methodology has been developed for the general synthesis of optically active β-amino acid N-carboxyanhydrides (β-NCAs) through cyclization of Nβ-Boc or Nβ-Cbz β-amino acids using phosphorus tribromide. The format
- Cheng, Jianjun,Ziller, Joseph W.,Deming, Timothy J.
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p. 1943 - 1946
(2007/10/03)
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- Design and synthesis of a novel cyclo-β-tetrapeptide
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N-Substituted tetralactams (cyclo-β-tetrapeptides) have been identified as potential molecular scaffolds by computer-aided design; compound 2, arising from L-β-homophenylalanine, has been prepared as a model system and its structure elucidated by single c
- Sutton, Peter W.,Bradley, Adrian,Elsegood, Mark R. J.,Farras, Jaume,Jackson, Richard F. W.,Romea, Pedro,Urpi, Felix,Vilarrasa, Jaume
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p. 2629 - 2632
(2007/10/03)
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- 2,2'-dithiobisbenzamides derived from α-, β- and γ-amino acids possessing anti-HIV activities: Synthesis and structure-activity relationship
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Nucleocapsid protein (NCp7), which contains highly conserved retroviral zinc fingers, is essential in the early as well as the late phase of human immunodeficiency virus (HIV) life cycle and constitutes a novel target for AIDS therapy. HIV-1 NCp7 is a basic 55 amino acid protein containing two C(X)2C(X)4H(X)4C motif zinc fingers flanked by basic amino acids on each side. 2,2'-dithiobisbenzamides have previously been reported to release zinc from these NCp7 zinc fingers and also to inhibit HIV replication. Specifically, 2,2'-dithiobisbenzamides derived from simple amino acids showed good antiviral activities. The benzisothiazolone 3, the cyclic derivative of 2, was selected for clinical trials as an agent for AIDS therapy. Herein we report the syntheses and antiviral activities, including therapeutic indices, of 2,2'-dithiobisbenzamides derived from α-, β- and γ-amino acids. Electrospray ionization mass spectrometry was used to study the zinc-ejection activity of these compounds. Among the α-amino acid derived 2,2'-dithiobisbenzamides, analogues containing alkyl side chains were found to be antivirally active with good therapeutic indices. 2,2'-Dithiobisbenzamides, derived from β- and γ-amino acids, were found to possess better antiviral and therapeutic efficacies than the α-amino acid analogues. Thus compound 59 was found to possess an EC50 of 1.9μM with a therapeutic index of >50. Interestingly, 2,2'-dithiobisbenzamides derived from α-amino acids containing a protected acid function and polar side chains also exhibited very good antiviral activity. Copyright (C) 1998 Elsevier Science Ltd.
- Vara Prasad,Loo, Joseph A.,Boyer, Frederick E.,Stier, Michael A.,Gogliotti, Rocco D.,Turner, William J.,Harvey, Patricia J.,Kramer, Melissa R.,Mack, David P.,Scholten, Jefferey D.,Gracheck, Stephen J.,Domagala, John M.
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p. 1707 - 1730
(2007/10/03)
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- A general route to "carba" peptide bond replacements: Unequivocal synthesis of Boc-L-Phe-ψ(CH2-CH2)-L-Ala-OH and Boc-L-Phe-ψ(CH2-CH2)-D-Ala-OH
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An unambiguous synthesis of Boc-L-Phe-ψ(CH2-CH2)-L-Ala-OH and BocL-Pheψ(CH2-CH2)-D-AlaOH from Boc-L-phenylalanine, through lactame intermediates (3R,6R)-3-m
- Rodriguez, Marc,Aumelas, Andre,Martinez, Jean
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p. 5153 - 5156
(2007/10/02)
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- Retro-inverso concept applied to the complete inhibitors of enkephalin-degrading enzymes
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Peptide retro-inverso modification was applied to the complete hydroxamate inhibitors of the three zinc metallopeptidases (neutral endopeptidase 24-11 (NEP, EC 3.4.24.11), aminopeptidase N (APN, EC 3.4.11.2), and a dipeptidylaminopeptidase (DAP) involved in the in vitro enkephalin degradation by brain tissues. Compounds corresponding to the general formula RN(OH)CO(CH2)(n)CH(CH2Ph)NHCOCH(R')COOH (n=0, 1) were synthesized. In the first series of inhibitors (n=0), the 'retro-inverso' modification induced a large decrease in inhibitory potency for NEP as compared to that of the parent compounds. In contrast, the presence of a methylene group between the hydroxamate and CHα in the second series (n=1) led to derivatives with inhibitory potencies in the nanomolar range, similar to their analogues with a natural amide bond. On the other hand, the retro-inverso modification led to a slight improvement in the inhibition of DAP and APN, in the first series of inhibitors, while the inverse result occurred in the second series. Thus, compounds containing an α-amino acid moiety in P'1 position behave as weak inhibitors of the three enzymes, with IC50 values in the micromolar range, and compounds bearing a β-amino acid moiety in the same position are more specific than the parent compounds for NEP inhibition.
- Hernandez,Soleilhac,Roques,Fournie-Zaluski
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p. 1825 - 1831
(2007/10/02)
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- SYNTHESIS OF DIAZOKETONES DERIVED FROM α-AMINO ACIDS; PROBLEM OF SIDE REACTIONS
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Optimum conditions of synthesis of eight diazoketones derived from optically active N-(t-butyloxycarbonyl)- and N-benzyloxycarbonylamino acids have been described.The problem of formation of by-products during Arndt-Eistert synthesis of β-homoamino acids at the stage of reaction of mixed anhydride with a weak nucleophile-diazomethane - has been discussed.
- Plucinska, Krystyna,Liberek, Bogdan
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p. 3509 - 3518
(2007/10/02)
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