- Recoverable Dendritic Phase-Transfer Catalysts that Contain (+)-Cinchonine-Derived Ammonium Salts
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Four new phosphorus dendrimeric phase-transfer catalysts are prepared that contain 12 (+)-cinchoninium salts on the surface obtained by the quaternisation of the quinuclidinic N atom. The asymmetric alkylation of a glycinate Schiff base with benzyl bromide is used as a benchmark reaction, and the dendrimeric catalyst that contains an allyl group on the O-9 hydroxy group of the cinchonine units is the most active. The recovery and reuse of the catalyst are possible for five consecutive runs without loss of activity and with only a slight decrease in enantioselectivity. If other electrophiles are used, substituted benzyl bromides give better results than other activated alkyl bromides to afford the corresponding R amino acid derivatives. A comparison of these results with those reported previously for similar cinchoninium salts shows that dendrimers could be a better support than other polymers for this type of organocatalysis.
- Rull, Jordi,Jara, José Juan,Sebastián, Rosa M.,Vallribera, Adelina,Nájera, Carmen,Majoral, Jean-Pierre,Caminade, Anne-Marie
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p. 2049 - 2056
(2016/07/07)
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- Dual Chemical Modification of a Polytheonamide Mimic: Rational Design and Synthesis of Ion-Channel-Forming 48-mer Peptides with Potent Cytotoxicity
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Polytheonamide B (1) is a natural peptide that displays potent cytotoxicity against P388 mouse leukemia cells (IC50=0.098 nm). Linear 48-mer 1 is known to form monovalent cation channels on binding to lipid bilayers. We previously developed a fully synthetic route to 1, and then achieved the design and synthesis of a structurally simplified analogue of 1, namely, dansylated polytheonamide mimic 2. Although the synthetically more accessible 2 was found to emulate the channel function of 1, its cytotoxicity was decreased 120-fold. Herein, the chemical preparation and biological evaluation of seven analogues 3-9 of 2 are reported. Compounds 3-9 were modified at their N terminus and/or the side chain of residue 44 of 2 to alter their physicochemical properties. The total synthesis of 3-9 was accomplished in a unified fashion by a combination of solid-phase and solution-phase chemistry. Systematic evaluation of the hydrophobicities, single-channel currents, ion-exchange activities, and cytotoxicities of 3-9 revealed that their hydrophobicities are correlated with the total magnitude of ion exchange and determine their cytotoxic potency. Consequently, the most hydrophobic analogue 9 exhibited the lowest IC50 value, which is comparable to that of 1. Therefore, these results clarified that the bioactivity of the polytheonamide-based peptides can be rationally controlled by changing their hydrophobicity at the N and C termini of the 48-amino-acid sequence.
- Hayata, Atsushi,Itoh, Hiroaki,Matsutaka, Shoko,Inoue, Masayuki
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supporting information
p. 3370 - 3377
(2016/03/05)
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- A practical aryl unit for azlactone dynamic kinetic resolution: Orthogonally protected products and a ligation-inspired coupling process
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The first strategy for bringing about enantioselective azlactone dynamic kinetic resolution to generate orthogonally protected amino acids has been developed. In the presence of a C2-symmetric squaramide-based catalyst, benzyl alcohol reacts with novel yet readily prepared tetrachloroisopropoxycarbonyl-substituted azlactones to generate trapped phthalimide products of significant synthetic interest with excellent enantiocontrol. These materials are masked amino acids which are demonstrably orthogonally protected: cleavage of the phthalimide can be achieved in the presence of the ester and vice versa. This process could be utilized to bring about a highly stereoselective ligation-type coupling of protected serines (at stoichiometric loadings) with racemic azlactones derived from both natural and abiotic amino acids. After deprotection, a subsequent base-mediated Oa??N acyl transfer occurs to form a dipeptide.
- Tallon, Sean,Manoni, Francesco,Connon, Stephen J.
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supporting information
p. 813 - 817
(2015/02/19)
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- Polyimide precursor, polyimide, and liquid crystal aligning agent
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To provide a novel diamine which is useful as the starting material of a novel polyimide precursor or polyimide which can provide a liquid crystal alignment film having a low volume resistivity, a liquid crystal aligning agent containing these polymers, a
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Paragraph 0198
(2014/12/09)
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- Structural permutation of potent cytotoxin, polytheonamide B: Discovery of cytotoxic peptide with altered activity
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Polytheonamide B (1) is an ion-channel forming natural peptide with a d,l-alternating 48 amino acid sequence, which is an exceedingly potent cytotoxin. We recently designed and synthesized a simplified dansylated polytheonamide mimic 2, in which six amino
- Itoh, Hiroaki,Inoue, Masayuki
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- Design, synthesis and functional analysis of dansylated polytheonamide mimic: An artificial peptide ion channel
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We report herein the design, total synthesis, and functional analysis of a novel artificial ion channel molecule, designated as dansylated polytheonamide mimic (3). The channel 3 was designed based on an exceptionally potent cytotoxin, polytheonamide B (1
- Itoh, Hiroaki,Matsuoka, Shigeru,Kreir, Mohamed,Inoue, Masayuki
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p. 14011 - 14018
(2012/10/29)
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- Synthesis and biological evaluation of triazole analogues of antillatoxin
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Antillatoxin 1, a cyclic lipopeptide, is known as an activator of voltage-gated sodium channels and exhibits potent neurotoxicity toward Neuro 2a mouse neuroblastoma cells. To investigate the biological effects of the side-chain structures at C5 and C5′ i
- Goto, Ryosuke,Okura, Ken,Sakazaki, Hayato,Sugawara, Tatsuya,Matsuoka, Shigeru,Inoue, Masayuki
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experimental part
p. 6659 - 6672
(2011/10/01)
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- Studies directed toward the synthesis of the scabrosins: validation of a tandem enyne metathesis approach
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A synthetic approach to the scabrosin family of antibiotics using a ruthenium carbene-catalyzed tandem metathesis and?a Pd(II)-catalyzed cyclization is described. The chiral propargyl amino acid is furnished through enantioselective phase-transfer proparg
- Middleton, Mark D.,Peppers, Brian P.,Diver, Steven T.
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p. 10528 - 10540
(2007/10/03)
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- Chloroanalyland propargylglycyl dipeptides. Suicide substrate containing antibacterials
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A set of dipeptides containing the amino acid residues β-chloroalanine and propargylglycine, which are mechanism-based inactivators of purified microbial enzymes (alanine racemase and cystathionine γ-synthase, respectively), have been synthesized, and their antibacterial properties in vitro have been evaluated. Dipeptides containing a single β-chloro-L-alanyl residue (e.g., 3, 5, 9, and 10) or a single L-propargylglycyl residue (e.g., 12 and 15) are potent antibacterials. The in vitro antibiotic activity of β-chloro-L-alanine and of L-propargylglycine is increased as much as 4000-fold by incorporation of these residues into a dipeptide. Compounds that contain only a single enzyme-inactivating amino acid together with a second L-alanyl residue (3, 5, 12, and 15) have a restricted range of activity: of the species tested, only Streptococcus agalactiae, Staphylococcus aureus, and Staphylococcus epidermidis are sensitive. However, peptides that contain two suicide-substrate residues [e.g., β-Cl-LAla-β-Cl-LAla (8) or LppGly-LppGly (18)] are broad-spectrum antibacterials; as many as 12 different species of the 16 surveyed are sensitive. Dipeptides that contain an amino-terminal L-methionyl (9) or an L-norvalyl (10) residue and a carboxy-terminal β-chloro-L-alanyl unit are also effective against a large number of organisms; the spectra of activity are like those seen for 8 and 18. A 'mixed' dipeptide [β-Cl-LAla-LppGly, (21)] gives apparent synergism of antibiotic action of β-chloro-L-alanine and of L-propargylglycine when these two residues are incorporated into a single structure. Peptides of the D,D configuration (4, 6, 13, 16, and 20) and ones of L,D stereochemistry (e.g., 7) are not antibacterials. Peptides containing one (11 and 14) and two (17) D,L-propargylglycyl residues are unresolved sets of diastereomers; the mixtures of compounds are between two- and fourfold less active than the corresponding resolved L,L dipeptides (12, 15, and 18). These findings are consistent with a mechanism of action for these antibiotics involving stereoselective processing of the peptidyl unit in vivo.
- Cheung, Kam Sing,Wasserman, Steven A.,Dudek, Edward,Lerner, Stephen A.,Johnston, Michael
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p. 1733 - 1741
(2007/10/02)
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- The synthesis of [4-carboranylalanine,5-leucine]-enkephalin
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The title compound, an analogue of [Leu5]-enkephalin with L-O-carboranylalanine replacing L-phenylalanine in position 4, was prepared by fragment condensation. The analogue has a 3-fold higher affinity for rat brain opiate receptors in the [3H]naloxone competition assay than natural [Leu5]-enkephalin. Like [Leu5]-enkephalin and Na-acetyl-[Leu5]-enkephalin, the N-terminal tripeptide fragment, H Tyr-Gly-Gly OH, had no melanotropic activity in the Rana pipiens frog skin assay. A convenient, direct synthesis of methyl t-butoxycarbonyl-L-o-carboranylalaninate from methyl t-butoxycarbonyl-L-propargylglycinate is described, and the 13C-NMR, spectra of L-O-carboranylalanine recorded. The procedure was extended to the preparation of BOC Car-Leu OMe from BOC Pra-Leu OMe. A number of new propargylglycine derivatives are reported.
- Fauchere,Leukart,Eberle,Schwyzer
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p. 1385 - 1395
(2007/10/06)
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