ABSTRACT
[reaction: see text] A new strategy for the synthesis and purification of synthetic intermediates is described using anthracene-tagged ester substrates in conjunction with an N-benzylmaleimide resin. Anthracene chemical tags permit use of standard solution-phase reaction conditions and reaction-monitoring techniques.
Subject(s)
Anthracenes/chemistry , Anthracenes/chemical synthesis , Esters/chemical synthesis , Esters/chemistry , Indicators and Reagents , Kinetics , Maleimides , Models, Molecular , Molecular Conformation , Molecular Structure , Resins, Plant , Structure-Activity RelationshipABSTRACT
A parallel solution-phase library synthesis of functionalized diaminobenzamides is described. The four-step library synthesis is accomplished using polymer-assisted solution-phase (PASP) synthesis techniques. This high-yielding, multi-step sequence utilizes sequestering resins for the removal of reactants, reactant by-products, and employs a resin capture/release strategy as a key library synthesis step. Step one of the sequence relies on the displacement of an activated fluoro-group from the aromatic ring of 1a, b with a variety of primary amines to introduce the first diversity position. Step two is hydrolysis of the benzoate ester to a benzoic acid which is subsequently captured on a polyamine resin, washed, and released to give 4a, b in pure form. Step three utilizes PASP resins to mediate the amide coupling of a benzoic acid with a variety of primary amines to give the aminonitrobenzamides 5a, b and introduces the second diversity position. Step four is the parallel reduction of the aminonitrobenzamides 5a, b to the functionalized diaminobenzamides 6a, b. This library synthesis proceeds with high overall purities which average 80 % over the 4-step sequence.
Subject(s)
Benzamides/chemical synthesis , Combinatorial Chemistry Techniques/methods , Amines/chemical synthesis , Chromatography, High Pressure Liquid , Mass Spectrometry , Molecular Structure , Polymers/chemistryABSTRACT
A parallel solution-phase library synthesis of alpha-ketoamides is described. The two-step library synthesis is accomplished using polymer-assisted solution-phase (PASP) synthesis techniques. This high-yielding, multi-step sequence utilizes sequestering resins for the removal of reactants, reactant by-products, and tagged reagents. The first step of the library synthesis utilizes PASP resins to mediate the amide coupling of an alpha-hydroxy acid with an amine. The second step uses PASP resins for the periodinane oxidation of the alpha-hydroxy acid to an alpha-ketoamide leaving highly pure products after simple filtration and evaporation.
Subject(s)
Amides/chemical synthesis , Databases as Topic , Amides/chemistry , Ketones/chemical synthesis , Models, Molecular , Molecular Conformation , Polymers , SolutionsABSTRACT
During the past few years, polymer-assisted solution-phase synthesis has become a prevalent method for the parallel synthesis of chemical libraries. This methodology allows for intermediate and final product purification by various resin-based sequestration techniques, which allow for the removal of excess reactants, by-products or side products from solution-phase reactions. The methodology has continued to expand, providing the practitioner with a broad range of ingenious purification methods, allowing single-step transformations as well as multistep syntheses to be performed in solution. The polymer-assisted solution-phase technology is currently being utilized for both the synthesis of lead generation and lead optimization libraries in the pharmaceutical arena and has also expanded into other disciplines.
Subject(s)
Chemistry, Organic/methods , Organic Chemicals/isolation & purification , Organic Chemicals/chemistry , Polymers , SolutionsABSTRACT
A general method for high-throughput product purification of Mitsunobu reactions is described. Tagged phosphine and azodicarboxylate reagents are used to synthesize individual library members in solution-phase. Workup and purification are easily accomplished by post-reaction sequestration of the tagged reagents and reagent byproducts by a complementary functionalized ion exchange resin. The reagents are utilized in a 3 step library synthesis.
Subject(s)
Chemistry, Organic/methods , Databases as Topic , Dicarboxylic Acids/chemistry , Drug Design , Phosphines , Indicators and Reagents , Ion Exchange Resins , Solutions , Structure-Activity RelationshipABSTRACT
A polymer-bound calcium sulfonate resin is prepared and used to sequester tetrabutylammonium fluoride. The simultaneous use of the calcium sulfonate resin with a sulfonic acid resin is used for the quenching and purification of desilylating reactions involving tetrabutylammonium fluoride as the reagent. Employment of this resin workup technique eliminates the need for a liquid-phase extractive protocol allowing the procedure to be easily automated.
Subject(s)
Chemistry, Organic/methods , Quaternary Ammonium Compounds , Resins, Synthetic , Silanes , Automation , Detergents , Fluorides , Indicators and Reagents , Kinetics , Molecular Conformation , Molecular Structure , Structure-Activity RelationshipABSTRACT
A combinatorial library containing mixtures of amides and esters was prepared through solid-phase chemistry. The advantages of using solid-phase chemistry over solution-phase chemistry to prepare this library are discussed. The library was screened through a high-throughput whole organism herbicidal assay upon which a mixture containing amides was found to have herbicidal activity. Deconvolution of the mixture provided N-(3-benzoylphenyl)-3-(1,1-dimethylethyl)-1-methyl)-1 H-pyrazole-5-carboxamide as a herbicidal lead with broadleaf and narrowleaf pre-emergence herbicidal activity as low as 100 g/ha on some weed species. This study represents the first report of an agrochemical discovered using a combinatorial approach.
