Characterization of Soluble Polymer Supported Organic Molecules by Mass Spectrometry

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JJ5.2.1

Characterization of Soluble Polymer Supported Organic Molecules by Mass Spectrometry C. Enjalbal, F. Lamaty, P. Ribière, S. Varray, E. Suberchicot, N. Yadav-Bhatnagar,± J. Martinez, J-L. Aubagnac UMR 5810, Laboratoire des Aminoacides Peptides et Protéines, Universités Montpellier 1 et 2, Place E. Bataillon, 34095 Montpellier Cedex 5 ± Aventis Pharma, 102 route de Noisy, 93325 Romainville Cedex, France

ABSTRACT Syntheses carried out on soluble polymers, such as polyethylene glycol (PEG), benefit the advantages of both solution-phase and solid-phase syntheses. The choice of the reaction solvent governs the polymer solubility. Synthetic steps are conducted under homogeneous conditions whereas purifications are performed by filtration after polymer precipitation. This alternative strategy, known as liquid-phase chemistry, has been investigated to prepare combinatorial libraries. The fact that soluble polymer supported molecules are directly amenable to standard spectroscopic methods, including NMR (1H, 13C) and ESI or MALDI mass spectrometry (ElectroSpray and Matrix Assisted Laser Desorption Ionization) allows to perform to in situ reaction monitoring without the need to release the compound from the polymeric support. We report a general methodology to characterize step by step soluble polymer supported organic molecules by MALDI and ESI mass spectrometry. High throughput analyses were targeted to fullfil combinatorial chemistry requirements. Data acquisition and interpretation were automated through the design of specific experimental protocols and a data managment software. MALDI mass spectrometry was appropriate to analyze pure supported molecules whereas ESI mass spectrometry coupled to liquid chromatography was required to unravel PEG mixtures.

INTRODUCTION The concept of a soluble polymer supported synthesis1-3 has been introduced to alleviate the difficulties encountered in solid-phase chemistry. First, performing reactions on organic molecules anchored onto insoluble polymeric supports could present some difficulties since reaction conditions established in solution may not be valid and thus necessitate time-consuming optimization. On the contrary, organic syntheses in solution are generally easily translated on a soluble polymer supported substrate since reactions are conducted in homogeneous media. Second, solid-phase synthesis carried out on insoluble polymeric support relies on the “Cleave and Analyze” strategy to characterize the growing compounds. Using liquid-phase chemistry, reaction monitoring is performed without releasing the synthesized compound from the support by simply dissolving the derivatized polymer in the appropriate analytical solvent. In combinatorial chemistry using PEG as soluble support,4 complete automation of the three successive steps, synthesis, analytical control, and biological test, is thus accessible providing on-line high throughput processes.

JJ5.2.2

Among all reported polymers, bifunctional PEG 3400 possessing an average molecular weight centered around 3400 mas

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