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212 SOLID-PHASE ORGANIC SYNTHESIS ON RADIATION-GRAFTED POLYMER SURFACES
Figure 6.3. Back (left to right): P-series SynPhase crown; l-series SynPhase crown. Front (left to right): polypropylene stem with transponder encapsulated (TranStem); transponder; ╬-series crown attached to TranStem.
to place a given crown (and stem) into a particular reaction flask. The reading step is repeated for each crown and the reaction carried out. When the reaction is complete, all the crowns can be combined for the washing step to reduce handling time. The sort-reaction-combine-wash-resort cycle (Figure 6.4) is repeated for each reaction step in the combinatorial synthesis, except when all crowns are to be treated with the same reagent. Steps that involve treating all crowns with the same reagent can be carried out in a single large flask. TranSort tracks the reaction history of each crown and at the completion of the synthesis may be used to place the crowns in a predefined pattern in the 96-well format for cleavage, hence greatly simplifying the final cleavage step. The program also provides an output file defining the reaction history (i.e., the predicted product) for each position in the 96-well plates, which can be imported into a variety of chemical structure compatible data-handling programs. Furthermore, the program has the capability to interface with other commonly used chemical library software. The synthesis tagging method has also been fully auto-
6.4. TAGGING METHODS FOR IDENTIFYING INDIVIDUAL CROWNS 213
w %** %**
REACTION STEP 2
Figure 6.4. The sort-reaction-combine-wash-resort cycle for library synthesis using radiofrequency tagging of individual SynPhase crowns.
214 SOLID-PHASE ORGANIC SYNTHESIS ON RADIATION-GRAFTED POLYMER SURFACES
mated and is currently being used for the production of libraries of thousands of compounds.32
6.5. FUTURE DEVELOPMENTS
SynPhase crowns have been used routinely in our laboratory for the synthesis of small-molecule libraries for the last six years and for peptide and peptide mimetic synthesis since the late 1980s. This has been possible due to improvements in the graft polymers and an expansion of the range of linker systems available on crowns. The method has recently been extended to allow for the synthesis of thousands of compounds using TranStem to tag and TranSort to track syntheses. Both crowns and their applications are being constantly assessed and improved. The compound loading on crowns has been significantly increased and the void volume decreased, thus allowing more final product while using less solvent and reagents. New base polymers are being developed to allow high-temperature stability, permitting the use of reaction temperatures in excess of 200░C. The TranSort program is being upgraded to provide greater synthetic flexibility. The most exciting advances, however, have been in automation. An automated version of the TranSort system is already in existence and in regular use to prepare libraries of thousands of compounds. This robotic system is being continuously refined. All of these improvements indicate that SynPhase crowns will continue to be a useful tool to the combinatorial chemist both in the development of novel chemistries and linkers and in the synthesis of multi-milligram quantities of tens to thousands of individual compounds on solid support.
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4. James, I. W. A Compendium of Solid-Phase Chemistry Publications, in Annual Reports in Combinatorial Chemistry and Molecular Diversity, Vol. 1, Moos, W. H., Pavia, M. R., Ellington, A. D., Kay, ┬. K., Eds.; ESCOM: Leiden, The Netherlands, 1997, p. 326.
5. Tregear, G. W. Graft Copolymers as Insoluble Supports in Peptide Synthesis, in Chemistry and Biology of Peptides, Proceedings of the 3rd American Peptide Symposium, Meienhofer, J., Ed.; Ann Arbor Science: Ann Arbor, MI, 1972, p. 175.
6. Berg, R. H.; Almdal, K.; Pedersen, W. B.; Holm, A.; Tam, J. P; Merrifield, R. B. Long-Chain Polystyrene-Grafted Polyethylene Film Matrix: A New Support for Solid-Phase Peptide Synthesis, J. Am. Chem. Soc. 1989, 111, 8024.
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