- Silver-Catalyzed Acyl Nitrene Transfer Reactions Involving Dioxazolones: Direct Assembly of N-Acylureas
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Dioxazolones and isocyanides are useful synthetic building blocks, and have attracted significant attention from researchers. However, the silver-catalyzed nitrene transfer reaction of dioxazolones has not been investigated to date. Herein, a silver-catalyzed acyl nitrene transfer reaction involving dioxazolones, isocyanides, and water was realized in the presence of Ag2O to afford a series of N-acylureas in moderate to good yields.
- Yang, Zheng-Lin,Xu, Xin-Liang,Chen, Xue-Rong,Mao, Zhi-Feng,Zhou, Yi-Feng
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supporting information
p. 648 - 652
(2020/12/21)
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- Rapid Discovery of Aspartyl Protease Inhibitors Using an Anchoring Approach
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Pharmacophore searches that include anchors, fragments contributing above average to receptor binding, combined with one-step syntheses are a powerful approach for the fast discovery of novel bioactive molecules. Here, we are presenting a pipeline for the rapid and efficient discovery of aspartyl protease inhibitors. First, we hypothesized that hydrazine could be a multi-valent warhead to interact with the active site Asp carboxylic acids. We incorporated the hydrazine anchor in a multicomponent reaction and created a large virtual library of hydrazine derivatives synthetically accessible in one-step. Next, we performed anchor-based pharmacophore screening of the libraries and resynthesized top-ranked compounds. The inhibitory potency of the molecules was finally assessed by an enzyme activity assay and the binding mode confirmed by several soaked crystal structures supporting the validity of the hypothesis and approach. The herein reported pipeline of tools will be of general value for the rapid generation of receptor binders beyond Asp proteases.
- ünver, M. Yagiz,Camacho, Carlos Jamie,D?mling, Alexander,Haupenthal, J?rg,Heine, Andreas,Hirsch, Anna K. H.,Jumde, Varsha R.,Klebe, Gerhard,Konstantinidou, Markella,Magari, Francesca,Sutanto, Fandi
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supporting information
(2020/04/10)
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- Optimized synthesis process of anticancer drug dacarbazine
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The invention provides an optimized synthesis process of an anticancer drug dacarbazine. The optimized synthesis process of the anticancer drug dacarbazine comprises the following steps: synthesis ofglycine methyl ester, synthesis of N-formylglycine methyl ester, synthesis of alpha-methyl isocyanoacetate, synthesis of alpha-isocyanoacetamide, synthesis of 5-amino-4-imidazolecarboxamide and synthesis of dacarbazine. Synthesis of the glycine methyl ester comprises the following steps: weighing 7.5 g of glycine and adding the glycine into a 500 mL round-bottom flask, taking 200 mL of redistilledmethanol as a solvent and cooling with stirring in an ice bath for 15 min; weighing 22 mL of thionyl chloride by a syringe and slowly dropwise adding the thionyl chloride into the reaction flask to react overnight at room temperature; and removing excess thionyl chloride and methanol by rotary evaporation at the room temperature, dissolving the residues by using as little hot methanol as possible, quickly adding a large amount of cold diethyl ether, and cooling in the reaction bottle in an ice bath. By improving the synthesis process of the anticancer drug dacarbazine, the optimized synthesisprocess of the anticancer drug dacarbazine has the advantages of reasonable synthesis circuit, cheap raw materials, mild reaction conditions and high total yield, thereby effectively solving the problems and defects in the prior art.
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Paragraph 0026; 0027
(2019/10/17)
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- Multicomponent Ugi Reaction of Indole- N-carboxylic Acids: Expeditious Access to Indole Carboxamide Amino Amides
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A novel multicomponent Ugi-type reaction for the synthesis of indole carboxamide amino amides from aldehydes, amines, isocyanides, and indole-N-carboxylic acids, which were simply prepared from indoles and CO2, is described. This method provides an expeditious and practical access to indole tethered peptide units, along with the achievement of remarkable structural diversity and brevity. Gram-scale reaction was conducted to demonstrate the scalability, and the products could be transformed to new indole derivatives.
- Zeng, Linwei,Sajiki, Hironao,Cui, Sunliang
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supporting information
p. 5269 - 5272
(2019/07/03)
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- 4,5-Disubstituted N-Methylimidazoles as Versatile Building Blocks for Defined Side-Chain Introduction
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Fungerin is a 1,4,5-trisubstituted imidazole natural product characterised by a broad spectrum of antifungal activities. We planned to develop flexible strategies to access to such compounds. Imidazoles bearing suitable anchor groups at C-4 and C-5 allow the introduction of various substituted side-chains, generating libraries of fungerin derivatives for biological tests. Starting from commercially available reactants, two N-methyl 4,5-substituted imidazole core units were synthesised. Derivatives of type 1 contained two orthogonally protected C-1 anchors. Selective side-chain introduction was achieved through a sequence of Grignard coupling at C-5 to replace a tosylate and a Horner olefination through an aldehyde attached to C-4. Two target fungerin derivatives were synthesised. Since the organometallic substitution of the C-5-CH2-positioned leaving group proved to suffer from limitations concerning potential competing side-reactions, a type 2 imidazole core was built up. These structures had a halogen centre at C-4 and a hydroxyethyl anchor at C-5. Now, selective side-chain introduction allowed us to use Julia olefination to form the allyl side-chain at C-5 and Heck reactions to introduce the C-4 acryl substituents. Eight derivatives, including fungerin, were synthesised by this latter strategy, without producing any regioisomers. The second approach had the advantage that various side-chains could be coupled at C-4 and C-5 in two final steps. Thus, this strategy represents a versatile way to build up libraries of fungerin derivatives for biological testing.
- Przybyla, Daniel,Nubbemeyer, Udo
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supporting information
p. 695 - 703
(2017/02/05)
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- Formamide Synthesis through Borinic Acid Catalysed Transamidation under Mild Conditions
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A highly efficient and mild transamidation of amides with amines co-catalysed by borinic acid and acetic acid has been reported. A wide range of functionalised formamides was synthesized in excellent yields, including important chiral α-amino acid derivatives, with minor racemisation being observed. Experiments suggested that the reaction rely on a cooperative catalysis involving an enhanced boron-derived Lewis acidity rather than an improved Br?nsted acidity of acetic acid. Amide bonds are reputedly difficult to activate due to their high resonance stabilization. An unusual mild activation of dimethylformamide and formamide by borinic acid 1 (see scheme), illustrated by a general formylation of a wide range of amines, including chiral α-amino esters, has been reported.
- Mohy El Dine, Tharwat,Evans, David,Rouden, Jacques,Blanchet, Jér?me
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supporting information
p. 5894 - 5898
(2016/04/26)
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- Isocyanides as influenza A virus subtype H5N1 wild-type M2 channel inhibitors
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Basic bulky amines such as amantadine are well-characterized M2 channel blockers, useful for treating influenza. Herein we report our surprising findings that charge-neutral, bulky isocyanides exhibit activities similar to - or even higher than - that of amantadine. We also demonstrate that these isocyanides have potent growth inhibitory activity against the H5N1 virus. The -NH2 to -N≡C group replacement within current anti-influenza drugs was found to give compounds with high activities at low-micromolar concentrations. For example, a tenfold improvement in potency was observed for 1-isocyanoadamantane (27), with an EC50 value of 0.487 μm against amantadine-sensitive H5N1 virus as determined by both MTT and plaque-reduction assays, without showing cytotoxicity. Furthermore, the isocyanide analogues synthesized in this study did not inhibit the V27A or S31N mutant M2 ion channels, according to electrophysiology experiments, and did not exhibit activity against amantadine-resistant virus strains. Charge-neutral bulky isocyanides were found to exhibit antiviral activities similar to - or even higher than - that of amantadine. Moreover, we demonstrated that these isocyanides have potent growth inhibitory activity against the wild-type H5N1 virus. The NH2 to N≡C group replacement within current anti-influenza drugs was found to result in compounds with low-micromolar activities.
- Wu, Shuwen,Huang, Jing,Gazzarrini, Sabrina,He, Si,Chen, Lihua,Li, Jun,Xing, Li,Li, Chufang,Chen, Ling,Neochoritis, Constantinos G.,Liao, George P.,Zhou, Haibing,D?mling, Alexander,Moroni, Anna,Wang, Wei
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p. 1837 - 1845
(2015/11/10)
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- Transamidation of carboxamides catalyzed by Fe(III) and water
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The highly efficient transamidation of several primary, secondary, and tertiary amides with aliphatic and aromatic amines (primary and secondary) is described. The reaction is performed in the presence of a 5 mol % concentration of different hydrated salts of Fe(III), and the results show that the presence of water is crucial. The methodology was also applied to urea and phthalimide to demonstrate its versatility and wide substrate scope. An example of its use is an intramolecular application in the synthesis of 2,3-dihydro-5H-benzo[b]-1,4- thiazepin-4-one, which is the bicyclic core of diltiazem and structurally related drugs (Budriesi, R.; Cosimelli, B.; Ioan, P.; Carosati, E.; Ugenti, M. P.; Spisani, R. Curr. Med. Chem. 2007, 14, 279-287). A plausible mechanism that explains the role of water is proposed on the basis of experimental observations and previous mechanistic suggestions for transamidation reactions catalyzed by transition metals such as copper and aluminum. This methodology represents a significant improvement over other existing methods; it can be performed in air and with wet or technical grade solvents.
- Becerra-Figueroa, Liliana,Ojeda-Porras, Andrea,Gamba-Sánchez, Diego
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p. 4544 - 4552
(2014/06/09)
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- Efficient synthesis of conformationally constrained, amino- triazoloazepinone-containing di- and tripeptides via a one-pot Ugi-Huisgen tandem reaction
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Herein we describe a catalyst-free procedure employing an Ugi-4CR between a β-azido-α-amino acid, propargylamine, an isocyanide and an aldehyde, followed by a thermal azide-alkyne Huisgen cycloaddition to generate a 16-member library of amino-triazoloazepinone-bearing di- and tripeptides with up to four points of diversification and high atom economy. This journal is the Partner Organisations 2014.
- Barlow,Jida,Tourwe,Ballet
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p. 6986 - 6989
(2014/10/15)
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- Enantioselective Rh-catalyzed hydrogenation of N-formyl dehydroamino esters with monodentate phosphoramidite ligands
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Enantioselectivities up to >99% ee were achieved in the rhodium-catalyzed asymmetric hydrogenation of N-formyl dehydroamino esters using monodentate phosphoramidites as chiral ligands. The substrates were synthesized by condensation of methyl isocyanoacetate with a range of aldehydes and with cyclohexanone. A highly convenient multigram scale one step synthesis of methyl 2-(formamido)acrylate was developed. This compound was used in the synthesis of methyl 2-(formamido)cinnamate via a solvent free Heck reaction. Moreover, full conversion and >99% ee were obtained in 1 h in the hydrogenation of methyl 2-(formamido)acrylate with 0.2 mol% catalyst and 2 bar hydrogen pressure. The versatility of the formyl protection was established by its removal under mild conditions.
- Panella, Lavinia,Aleixandre, Alicia Marco,Kruidhof, Gerlof J.,Robertus, Jort,Feringa, Ben L.,De Vries, Johannes G.,Minnaard, Adriaan J.
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p. 2026 - 2036
(2007/10/03)
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- Solution and solid phase combinatorial synthesis of peptidomimetic library containing diversified α-methylated amino acids
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A combinatorial peptidomimetic library containing diversified α- methylated amino acids was generated by the Ugi four component condensation (4cc) reaction from acids, amines, isocyanides and ketones in both solution and solid phase synthesis procedures. This one-pot methodology overall gave fair to good yields, which compare well with multi-step syntheses.
- Kim, Sang Woong,Shin, You Seung,Ro, Seonggu
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p. 1665 - 1668
(2007/10/03)
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- THE TRANSFORMYLATION REACTION - TRANSFER OF AN N-FORMYL RESIDUE IN AMINO ACID AND PEPTIDE DERIVATIVES TO NUCLEOPHILIC GROUPS - AS A SIDE REACTION OF PEPTIDE SYNTHESIS
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In the course of a study of the enzymatic synthesis of peptides from N-formylamino acids, the transfer of a formyl group to nucleophilic acceptors present in the aqueous-organic reaction medium - amino acid esters, peptides, and aromatic amines - has been detected, and this to the greater degree the higher the nucleophilicity of the acceptor.The transfer of a formyl group from a number of formylamino acids and formylpeptides to phenylalanine methyl ester has been studied.A fall in the yield of the transformylation reaction on passing from formyl derivatives with a free carboxy group to formyl peptides or esterified formylamino acids has been found.No transfer of an acetyl group was observed under these conditions.On the use of formyl derivatives in peptide synthesis the possibility of the occurrence of the transformylation reaction and the resulting appearance of by-products must be taken into account.Key words: peptide; enzymatic synthesis; transformylation.
- Kotlova, E. K.,Levin, E. D.,Yusupova, M. P.,Rozynov, B. V.,Stepanov, V. M.
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p. 678 - 686
(2007/10/02)
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- Method for preparation of N-phosphonomethylglycine
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A method for the production of N-phosphonomethylglycine is disclosed which comprises the steps of: (a) reacting formaldehyde with formamide at a pH of 9-10 to form N-(hydroxymethyl)formamide, (b) reacting N-(hydroxymethylformamide with triethylphosphite to form diethyl, N-(formyl)aminomethylphosphonate, (c) reacting diethyl, N-(formyl)aminomethylphosphonate with methylchloroacetate to form N-(diethylphosphonomethyl), N-(formyl)glycinemethyl ester, and (d) reacting N-(diethylphosphonomethyl), N-(formyl)glycinemethyl ester with hydrochloric acid to form N-phosphonomethylglycine.
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