The novel one step solution phase synthesis of an array of 3-aminoimidazo[1,2-a]pyridines is reported. Reactions were performed in methanol by mixing a α-amino-pyridine, aldehyde and trimethylsilylcyanide (TMSCN) to give the desired product. Mediated by microwave irradiation and catalyzed by scandium triflate, the methodology represents the first one pot preparation of 3-aminoimidazo[1,2-a]pyridines that avoids the use of an isonitrile and subsequent de-protection strategy. The reaction is an example of a formal three-centre-three-component multi-component reaction.
The following report describes novel methodology for the rapid synthesis of unique conformationally constrained norstatine analogs of potential biological relevance. A PADAM (Passerini reaction-Amine Deprotection-Acyl Migration reaction) sequence is followed by a TFA-mediated microwave-assisted cyclization to generate the final benzimidazole isostere of the norstatine scaffold in moderate to good yields. The applicability of this solution phase methodology to the preparation of a small collection of compounds is discussed. © 2012 Elsevier Ltd. All rights reserved.
This report presents a novel three step solution phase protocol to synthesize 3-(tetrazol-5-yl)quinoxalin-2(1H)-ones. The strategy utilizes ethyl glyoxalate and mono-N-Boc-protected-o-phenylenediamine derivatives in the Ugi-Azide multi-component reaction (MCR) to generate a unique 1,5-disubstituted tetrazole. Subsequent acid treatment stimulates a simultaneous Boc deprotection and intramolecular cyclization leading to bis-3,4-dihydroquinoxalinone tetrazoles. Direct oxidation using a stable solid-phase radical catalyst (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) with ceric ammonium nitrate (CAN) in catalytic fashion initiating aerobic oxidation, completes the entire procedure to generate a series of original unique bis-quinoxalinone tetrazoles. The method was also expanded to produce a bis-benzodiazepine tetrazole.
Synthesis of a comformationally restrained bicyclic γ-lactam dipeptide mimetic, involving a diastereoselective bicyclisation reaction is described. © 1993.
A new 4-point pharmacophore method for molecular similarity and diversity that rapidly calculates all potential pharmacophores/pharmacophoric shapes for a molecule or a protein site is described. The method, an extension to the ChemDiverse/Chem-X software (Oxford Molecular, Oxford, England), has also been customized to enable a new internally referenced measure of pharmacophore diversity. The 'privileged' substructure concept for the design of high-affinity ligands is presented, and an example of this new method is described for the design of combinatorial libraries for 7- transmembrane G-protein-coupled receptor targets, where 'privileged' substructures are used as special features to internally reference the pharmacophoric shapes. Up to 7 features and 15 distance ranges are considered, giving up to 350 million potential 4-point 3D pharmacophores/molecule. The resultant pharmacophore 'key' ('fingerprint') serves as a powerful measure for diversity or similarity, calculable for both a ligand and a protein site, and provides a consistent frame of reference for comparing molecules, sets of molecules, and protein sites. Explicit 'on-the- fly' conformational sampling is performed for a molecule to enable the calculation of all geometries accessible for all combinations of four features (i.e., 4-point pharmacophores) at any desired sampling resolution. For a protein site, complementary site points to groups displayed in the site are generated and all combinations of four site points are considered. In this paper we report (i) the details of our customized implementation of the method and its modification to systematically measure 4-point pharmacophores relative to a 'special' substructure of interest present in the molecules under study; (ii) comparisons of 3- and 4-point pharmacophore methods, highlighting the much increased resolution of the 4-point method; (iii) applications of the 4-point potential pharmacophore descriptors as a new measure of molecular similarity and diversity and for the design of focused/biased combinatorial libraries.