Imaging polymer supported organic molecules by mass spectrometry Application in combinatorial chemistry
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Imaging polymer supported organic molecules by mass spectrometry Application in combinatorial chemistry C. Enjalbal, D. Maux, R. Combarieu,± J. Martinez and J-L. Aubagnac UMR 5810, Laboratoire des Aminoacides Peptides et Protéines, Universités Montpellier 1 et 2, Place E. Bataillon, 34095 Montpellier Cedex 5 ± UMR 7635, CEMEF, Ecole des Mines de Paris, 06904 Sophia Antipolis, France
ABSTRACT In combinatorial chemistry, most libraries are prepared according to solid-phase synthesis strategies using resins or pins. Although synthesis and purification steps are facilitated, reaction monitoring presents difficulties. Since the polymeric support is not soluble, an analytical method able to cope with a solid sample is thus required to perform direct identification of the anchored molecules without any chemical treatment. Static-Secondary Ion Mass Spectrometry (S-SIMS) was investigated in that purpose. Positive and negative ion mass spectra were acquired to identify single beads whereas mixtures (Mix and Split libraries or pooled beads issued from different batches) were profiled through imaging experiments.
INTRODUCTION Organic syntheses are often carried out on insoluble polymeric supports (resins, pins) especially when automated high throughput preparations are required in combinatorial chemistry.1 The most common supports used in solid-phase syntheses are polystyrene resins.2 Polystyrene cross-linked with 1% of divinylbenzene produces resin beads. One gram of resin contains approximately one million beads. Plastic pins constitute an alternative to resins.3,4 A pin can be described as a polymer-grafted polypropylene shape (crown or lantern as shown in Scheme 1) that can be mounted on an inert polypropylene stem (the assembled unit constitutes the pin). Regarding resins or pins, the polymer is functionalized by a linker to introduce a functional group acting as an anchoring site upon which synthesis is performed (Scheme 2). The average loading capacities of resins and pins are in the range of 1 mmol/g and 10 µmol/g, respectively. Reactions are driven to completion by using excess reagents and purifications are simply achieved by support filtration.
Scheme 1: Part of the pin (lanterns on the left and crowns on the right) upon which synthesis is performed
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linker linker
linker linker
FG
Molecule Molecule
Synthetic steps
FG = Functional group
Cleavage from the polymeric support linker linker
+
Molecule Molecule
Scheme 2: General strategy of solid-phase synthesis Solid-phase syntheses of biomolecules such as peptides and oligonucleotides are wellestablished strategies. On the contrary, organic syntheses that are developed in solution are generally less easily translated on an insoluble polymeric support and may require chemistry optimization. In that case, direct supported step by step molecule characterization is the method of choice. Mass spectrometry was chosen due to its sensitivity, specificity, speed and analyses automation as required in combinatorial synthetic processes.5 Among all io
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