- Enantioselective Synthesis of Quaternary Δ4- and Δ5-Dehydroprolines Based on a Two-Step Formal [3+2] Cycloaddition of α-Aryl and α-Alkyl Isocyano(thio)acetates with Vinyl Ketones
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A divergent synthesis of optically active quaternary Δ4- and Δ5-dehydro prolines is developed based on the first catalytic enantioselective conjugate addition of α-substituted isocyano(thio)acetates to vinyl ketones that is general for both α-aryl and α-alkyl isocyano(thio)acetates. The new tetrasubstituted C?N stereocenter is formed without the need of any metal salt due to a bifunctional tertiary amine/squaramide catalyst, featuring a bulky polyaryl sidearm and an unusually short squaramide diamide H???H interatomic distance in the solid state.
- Odriozola, Amaiur,Oiarbide, Mikel,Palomo, Claudio
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supporting information
p. 12758 - 12762
(2017/09/25)
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- Formyloxyacetoxyphenylmethane as an N-Formylating Reagent for Amines, Amino Acids, and Peptides
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Formyloxyacetoxyphenylmethane is a stable, water-tolerant, N-formylating reagent for primary and secondary amines that can be used under solvent-free conditions at room temperature to prepare a range of N-formamides, N-formylanilines, N-formyl-α-amino acids, N-formylpeptides, and an isocyanide.
- Chapman, Robert S. L.,Lawrence, Ruth,Williams, Jonathan M. J.,Bull, Steven D.
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supporting information
p. 4908 - 4911
(2017/09/23)
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- Mild and convenient N-formylation protocol in water-containing solvents
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We have realized that N-formylations of free amines of some drug leads can improve PK/PD property of parent molecules without decreasing their biological activities. In order to selectively formylate primary amines of polyfunctional molecules, we have sought a mild and convenient formylation reaction. In our screening of N-formylation of an α-amino acid, l-phenylalanine, none of formylation conditions reported to date yielded the desired HCO-l-Phe-OH with satisfactory yield. N-formylations of amino acids with HCO2H require a water-containing media and suppress polymerization reactions due to the competitive reactions among carboxylic acids. We found that N-formylations of α-amino acids could be achieved with a water-soluble peptide coupling additive, an Oxyma derivative, (2,2-dimethyl-1,3-dioxolan-4-yl)methyl-2-cyano-2- (hydroxyimino)acetate (2), EDCI, and NaHCO3 in water or a mixture of water and DMF system, yielding N-formylated α-amino acids with excellent yields. Moreover, these conditions could selectively formylate primary amines over secondary amines at a controlled temperature. A usefulness of these conditions was demonstrated by selective formylation of daptomycin antibiotic which contains three different amino groups.
- Aleiwi, Bilal A.,Mitachi, Katsuhiko,Kurosu, Michio
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p. 2077 - 2081
(2013/05/08)
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- Activity-based proteome profiling of potential cellular targets of orlistat - An FDA-approved drug with anti-tumor activities
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Orlistat, or tetrahydrolipstatin (THL), is an FDA-approved antiobesity drug with potential antitumor activities. Cellular off-targets and potential side effects of Orlistat in cancer therapies, however, have not been extensively explored thus far. In this study, we report the total of synthesis of THL-like protein-reactive probes, in which extremely conservative modifications (i.e., an alkyne handle) were introduced in the parental THL structure to maintain the native biological properties of Orlistat, while providing the necessary functionality for target identification via the bio-orthogonal click chemistry. With these natural productlike, cell-permeable probes, we were able to demonstrate, for the first time, this chemical proteomic approach is suitable for the identification of previously unknown cellular targets of Orlistat. In addition to the expected fatty acid synthase (FAS), we identified a total of eight new targets, some of which were further validated by experiments including Western blotting, recombinant protein expression, and site-directed mutagenesis. Our findings have important implications in the consideration of Orlistat as a potential anticancer drug at its early stages of development for cancer therapy. Our strategy should be broadly useful for off-target identification against quite a number of existing drugs and/or candidates, which are also covalent modifiers of their biological targets.
- Yang, Peng-Yu,Liu, Kai,Ngai, Mun Hong,Lear, Martin J.,Wenk, Markus R.,Yao, Shao Q.
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supporting information; experimental part
p. 656 - 666
(2010/03/25)
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- Synthesis of chiral pentacyclo-undecane ligands and their use in the enantioselective alkylation of benzaldehyde with diethylzinc
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The synthesis of a new class chiral cage annulated bidentate ligands is reported. The ability of the chiral amino alcohols to catalyse the enantioselective addition of diethyl zinc to benzaldehyde was investigated. The cage annulated amino alcohols have C1 symmetry and showed poor to good enantioselectivity with high chemical yields. The system could be utilised as a versatile probe into the reaction mechanism. The synthesis of a new class of chiral pentacycloundecane cage annulated bidentate ligands is reported. This class of ligands can be used in many reactions that are catalysed by amino alcohol ligands. The ability of the chiral ligands to asymmetrically catalyse the reaction between diethylzinc and benzaldehyde was investigated. The cage annulated bidentate ligands have C1 symmetry and showed poor to good enantioselectivity with high yields compared to previous systems reported using other amino alcohol ligands. An important conclusion from the results is that both ligands should be involved in the mechanism as the bidentate ligands gives much improved enantioselectivity when compared with a single chiral source molecule. This system could be utilised as a versatile probe for examining the reaction mechanism.
- Boyle, Grant A.,Govender, Thavendran,Kruger, Hendrik G.,Maguire, Glenn E.M.
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p. 2661 - 2666
(2007/10/03)
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- Short synthesis of protease inhibitors via modified Passerini condensation of N-Boc-α-aminoaldehydes
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Extension of the previously reported modification of Passerini multicomponent reaction (involving condensation with N-Boc-α-aminoaldehydes followed by a deprotection-transacylation step) to α-aminoacid derived carboxylic or isocyanide components, allowed the highly convergent and short synthesis of complex peptidomimetic structures, including known potent inhibitors of serine proteases.
- Banfi, Luca,Guanti, Giuseppe,Riva, Renata,Basso, Andrea,Calcagno, Emiliano
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p. 4067 - 4069
(2007/10/03)
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- Process for producing N-formylleucine of high purity
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A process for producing N-formylleucine includes reacting leucine with formamide, precipitating the N-formylleucine, once the reaction is complete, at a temperature of approximately 0° to 40° C., by mixing the reaction medium with water and an acid, so that the final pH of the mixture is approximately 2 to 3, wherein the amount of water used in between approximately 1.5 and 5 parts per part by weight of starting formamide.
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- STUDY OF THE STRUCTURE OF FREE RADICALS IN IRRADIATED MONOCRYSTALS OF N-FORMYL-L-LEUCINE AT ROOM TEMPERATURE
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A study was carried out on the structure of the radical formed upon γ-radiolysis of monocrystals of N-formyl-L-leucine by ESR spectroscopy and quantum chemical calculations.The calculated ESR parameters for the radical conformations, corresponding to an e
- Almanov, G. A.,Bogdanchikov, G. A.,Usov, O. M.
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p. 912 - 916
(2007/10/02)
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