Reaction Monitoring and Optimization

Flow injection mass spectrometry analysis (FIA-MS) has been used extensively in reaction monitoring and optimization due to its simplicity and easy of use. Detection of enantiomers in stereospecific reactions has been reported. Reetz et al. [23] prepared isotopically labeled pseudoenantiomers and pseu-doprochiral compounds that behave chemically as a racemate or as a meso compound. Kinetic resolution of a racemate gives two products with different molecular weights, which enables the ratio to be determined with mass spectrometry. The authors used FIA-MS with a microplate autosampler to allow analysis of up to 1000 reactions/day. Guo et al. [24] reported an alternative mass-tagging approach to the measurement of enantiomeric excess by FIA-MS. In their method, an equimolar mixture of pseudoenantiomeric mass-tagged pairs of reagents was prepared that differ in a substituent remote to the chiral center. Szewczyk et al. developed a quantitative method to monitor the progress of the tagging experiment and to optimize the reaction by conversion of the product ketones into ESI-active derivatives [25]. The method was used to monitor three experiments involving 33 different substrates with more than 170 determinations of yield. McKeown et al. incorporated mass spectrometry-sensitive linkers into the synthesis of combinatorial libraries [26]. Upon photochemical cleavage after synthesis, these linkers can be monitored by high throughput FIA-MS to provide information about the yield of the synthesis and the photocleavage processes. A similar strategy that incorporates analytical constructs into the library synthesis for analysis and quality control was used by Lorthioir et al. [27]. These researchers selected an analytical fragment that is highly sensitive in ESI-MS for this purpose. The usefulness of the method was demonstrated by assessment of synthesis of library compounds that are otherwise not detected in ESI-MS analysis due to low sensitivity. Congreve and Jamieson have recently reviewed strategies with high throughput analytical techniques for reaction optimization [28].

In library synthesis that involves a solid-state polymer-bead support, matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and secondary ion mass spectrometry (SIMS) have been used to monitor products of reaction either through direct analysis of bead-bound compounds or in situ analysis of the compounds after cleavage. These approaches have been reviewed extensively in the literature [5-20]. A recent development in the use of MALDI-TOF and SIMS in reaction monitoring and optimization was reported by Enjalbal et al. [29]

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