Monitoring in Combinatorial Chemistry
Guest Editors: J-L. Aubagnac/C. Enjalbal
Quality Assessment of Combinatorial Pooled Libraries
Using Mass Spectrometry
Pp.317-332
P.-H. Lambert, S. Bertin, J.-L. Fauchère
and J.-P. Volland
High
Resolution Magic Angle Spinning NMR in Combinatorial Chemistry. Pp.333-351
G. Lippens, R. Warrass, J.-M. Wieruszeski,
P. Rousselot-Pailley and G. Chessari
Qualitative
and Quantitative Analyses of Resin-Bound Organic Compounds Pp.353-362
Mark Irving, Jason Cournoyer, Rongshi Li,
Chris Santos and Bing Yan
Mass
Spectrometry and Combinatorial Chemistry New Approaches for Direct
Support-Bound Compound Identification Pp.363-373
C. Enjalbal, D. Maux, J. Martinez, R.
Combarieu and J-L. Aubagnac
[Back to top]Quality Assessment of Combinatorial Pooled Libraries Using
Mass Spectrometry
Parallel synthesis techniques aim to prepare collections of single compounds, which, once tested, can easily be identified by their sole location in the synthesic array. On the other hand, true combinatorial chemistry produces libraries of compounds as mixtures of variable size, which require a deconvolution procedure for identification of the active hits or leads. In the latter case, analytical methods are crucial for the success of the strategy and mass spectrometry plays a major role. If the goal is to identify all the library components, including expected products as well as by-products, various mass spectrometric techniques may be necessary. Library components can be separated according to their mass by increasing mass resolution or by their elution time by coupling liquid chromatography and mass spectrometry. The efficiency of such separation techniques is discussed as a function of the size and the degeneracy of the library. Library members possess common structural features, which impart similar fragmentation patterns after ionization in the gas phase. This feature can be exploited by tandem mass spectrometry to specifically detect subfamilies of products. Examples of precursor ion scans, product ion scans and constant neutral loss scans will be shown that facilitate partial characterization of libraries. To solve the difficult problem of the quantitative analysis of libraries, i.e., to evaluate their equimolarity, the use of an evaporative light scattering detector (ELSD) or a chemiluminescent nitrogen detector (CLND) is suggested as more appropriate.
[Back to top] High Resolution Magic Angle Spinning NMR
in Combinatorial Chemistry
Solid
phase organic chemistry coupled with combinatorial methods promises to increase
dramatically the diversity and number of small molecules available for medical
and biological applications. However, optimizing the reaction conditions can be
a time consuming step, especially since analytical tools to monitor reaction
progress and detect impurities for solid phase chemistry are less developed than
for solution chemistry. The use of high-resolution magic angle spinning (HRMAS)
NMR is described here as such an analytical tool. Whereas initial applications
of molecular identification using deuterated organic solvents to swell the
resins presented a significant gain in time over the cleave-and-analysis
methods, the introduction of a differential diffusion filter has made immediate
recording of spectra possible without any sample treatment. The applications of
HRMAS NMR to different solid supports that are used in combinatorial chemistry
will be described in terms of rapidity, robustness and sensitivity.
[Back to top] Qualitative
and Quantitative Analyses of Resin-Bound Organic Compounds
Methods
for qualitative and quantitative analyses of resin-bound organic compounds are
essential tools for chemistry development in solid-phase combinatorial and
parallel syntheses. Here we discuss the use of gel-phase 19F NMR,
the fluoride ion-selective electrode method, and spectrophotometry for
monitoring solid-phase reactions. Our results indicate that the application of
these diverse methods for analyzing the outcome of solid-phase combinatorial
synthesis is sensitive and conclusive.
.
[Back to top] Mass
Spectrometry and Combinatorial Chemistry New Approaches for Direct
Support-Bound Compound Identification
Mass
spectrometry is a powerful analytical tool allowing rapid and sensitive
structural elucidation of a wide range of molecules issued from solution-,
solid- and liquid-phase syntheses. Therefore, mass spectrometry has become the
most widely used tool to probe combinatorial libraries. A significant portion
of the reported combinatorial data is being produced using solid phase organic
synthesis. In contrast to indirect strategies where the tethered structures
were released from the support into solution to undergo standard mass
spectrometric analyses, static - secondary ion mass spectrometry (S-SIMS) has
enabled the identification of support-bound molecules without any chemical
treatment of the resin bead. Such non-destructive characterization was applied
at the bead level and facilitated the step-by-step monitoring of solid-phase
peptide syntheses. Side-reactions were also detected. The relevance of S-SIMS
in the rehearsal phase of combinatorial chemistry is demonstrated by comparison
with infrared and nuclear magnetic resonance (NMR) spectroscopies, the two
other techniques investigated in that field. An alternative to solid-phase
synthesis consists of assembling molecules on a soluble polymer. This
methodology is termed liquid-phase synthesis. Compound characterization is
facilitated since the derivatized support is soluble in spectroscopic solvents
used in NMR or in electrospray ionization mass spectrometry. The advantages and
drawbacks of this approach will be discussed in terms of the direct monitoring
of supported reactions during chemistry optimization and rehearsal library
validation