Rapid reaction scanning of solid phase chemistry using resins incocorporating analytical constructs (original) (raw)
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Angewandte Chemie, 2000
The development of chemistry directly on solid phase is often hampered by difficulties associated with monitoring the progress of reactions and establishing product purity. One remedial approach has involved introduction of a dual-linker analytical construct comprising a linear sequence of two chemically orthogonal linkers separated by an analytical component. [2, 3] Cleavage at one linker releases only the substrate of interest in a conventional manner, whereas cleavage at the other affords the substrate attached to the analytical unit, which facilitates identification of that product. This principle was further developed in a recently reported construct [3] that was designed to release an analytical fragment composed of an amine group (generated at the point of cleavage), which enhanced detection by electrospray mass spectrometry (MS; a MS sensitizer), and an isotope label which gave rise to a characteristic split-peak pattern in the mass spectrum (a MS splitter).
A Novel Cleavage Technique To Generate Small Molecule Compounds and Libraries via a Two-Resin System
Journal of Organic Chemistry, 1998
Application of organic synthesis to solid supports has led to the successful implementation of combinatorial chemistry in the drug discovery process. This paper describes a novel use of the Hofmann elimination of tetrasubstituted amine salts on solid-phase resin to generate diverse combinatorial libraries of trisubstituted amines. Highly pure compounds were isolated without further purification by the addition of a second resin as the source reagent to promote the required elimination. The use of mixed resin systems to generate compounds is a novel application of beadbased technologies.
Versatile Dde-based primary amine linkers for solid phase synthesis
Tetrahedron Letters, 1998
Linkers based on the Dde primary amine protecting strategy have been developed and their utility demonstrated in the solid phase synthesis of a naturally occurring spider toxin. The linkers are stable to both acid and base conditions and cleaved either with 2% v/v hydrazine hydrate or by transamination with a volatile primary alkylamine in a variety of organic solvents.
A Nonacid Degradable Linker for Solid-Phase Synthesis
Organic Letters, 2007
Commercial grade reagents and solvents were used without further purification. AMresin (aminomethylated polystyrene, 100-200 mesh, f = 1.2 mmol/g) and HOBt were purchased from NovaBiochem. All other reagents used were purchased from Aldrich. Apparatus Reversed-phase analytical HPLC was performed on a Waters Alliance separation module 2695 using a Waters XTerra MS C 18 column (150 x 4.6 mm, 5 µm) and a Waters 996 PDA with a photodiode array detector. UV detection was performed at 210 nm and linear gradients of CH 3 CN (+0.01% HCOOH) into H 2 O (+0.01% HCOOH) were run at a 1.0 mL/min flow rate and in the gradient specified. ES-MS analyses were performed in a PerSeptive Biosystems Voyager DE RP using an ACH matrix, in a Waters alliance 2795 HPLC and in a 2487 UV-Vis detector. Electrospray mass detection was run with MeCN (0.07% HCO 2 H) and H 2 O (0.1% HCO 2 H). HRMS were performed on a Bruker Autoflex high-resolution mass spectrometer by the Unidad de
Photochemical intramolecular amination for the synthesis of heterocycles
Green Chemistry, 2017
All reactions that were carried out under anhydrous conditions were performed under an inert argon or nitrogen atmosphere in glassware that had previously been dried overnight at 120 o C or had been flame dried and cooled under a stream of argon or nitrogen. 1 All chemical products were obtained from Sigma-Aldrich Chemical Company or Alfa Aesar and were reagent quality. The following products were prepared according to their respective literature procedures: Methyl (2Z,4E)-2-azido-5-phenylpenta-2,4-dienoate Technical solvents were obtained from VWR International Co. Anhydrous solvents (CH 2 Cl 2 , Et 2 O, THF, DMF, toluene, and n-hexane) were dried and deoxygenated using a GlassContour system (Irvine, CA). Isolated yields reflect the mass obtained following flash column silica gel chromatography. Organic compounds were purified using the method reported by W. C. Still 2 and using silica gel obtained from Silicycle Chemical division (40-63 nm; 230-240 mesh). Analytical thin-layer chromatography (TLC) was performed on glass-backed silica gel 60 coated with a fluorescence indicator (Silicycle Chemical division, 0.25 mm, F 254 .). Visualization of TLC plate was performed by UV (254 nm), KMnO 4 or p-anisaldehyde stains. All mixed solvent eluents are reported as v/v solutions. Concentration refers to removal of volatiles at low pressure on a rotary evaporator. All reported compounds were homogeneous by thin layer chromatography (TLC) and by 1 H NMR. NMR spectra were taken in deuterated CDCl 3 using Bruker AV-300 and AV-400 instruments unless otherwise noted. Signals due to the solvent served as the internal standard (CHCl 3 : δ 7.27 for 1 H, δ 77.0 for 13 C). The acquisition parameters are shown on all spectra. The 1 H NMR chemical shifts and coupling constants were determined assuming first-order behavior. Multiplicity is indicated by one or more of the following: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad); the list of couplings constants (J) corresponds to the order of the multiplicity assignment. High resolution mass spectroscopy (HRMS) was done by the Centre régional de spectrométrie de masse at the Département de Chimie, Université de Montréal from an Agilent LC-MSD TOF system using ESI mode of ionization unless otherwise noted.
J. Am. Chem. …, 1997
A new methodology for solution-phase chemical library synthesis and purification is described. This approach applies fundamental properties of complementary molecular reactivity and recognition (CMR/R) as the basis for a general purification strategy. Specifically, parallel solution-phase reactions are purified by resins containing molecular recognition or molecular reactivity functionalities complementary to those of solution-phase reactants, reagents, and byproducts. When used in sequential or simultaneous combinations, various CMR/R resins remove excess reactants, reagents, and byproducts from solution-phase reaction products, which are isolated in purified form by filtration. Where reactions involve the need to remove byproducts or reagents that do not inherently contain sequestrable functionality, sequestration can be effected by the design and use of tagged reactants or reagents containing artificially-imparted molecular recognition functionality. An extension of this methodology utilizes CMR/R resins as the "quench phase" instead of a liquid-phase workup commonly used in other library purification strategies. Hence, the essential features of complementary molecular reactivity or molecular recognition required for reaction workup are expressed on resins. The CMR/R library purification strategy is general and highly amenable to automation. Examples are illustrated with amine acylations, the Moffatt oxidation, and the reaction of organometallics with carbonyl compounds.