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Basic Concepts of using Solid Phase Synthesis to Build Small Organic Molecules using 2-Chlorotrityl Chloride Resin

Blake Bonkowski, Jason Wieczorek, Mimansa Patel, Chelsea Craig, Alison Gravelin and Tracey Boncher

Solid Phase Synthesis (SPS) is a chemical strategy that was developed and refined by Bruce Merrifield in the early 1960s and later led to a Nobel Prize in 1984. This discovery paved the way for chemists to be able to construct proteins with high yields, less timeconsuming purification and much faster synthetic routes. The strategy utilizes an insoluble solid polystyrene cross-linked support resin, 2-chlorotrityl-chloride (2-CCR), to form an ester linkage with an acid so proteins or small molecules can be built from the N terminal one amino acid at a time. This same chemistry can be employed to construct peptidomimetics and small non-peptide molecules. This chemistry is especially useful for building molecules that require temporary protection of a carboxylic acid during the synthetic route. This article will provide the basic concepts and considerations when practicing SPS for small non-peptide molecule construction. Significant considerations in employing this chemistry include: resin selection, swelling of resin, coupling agents, solvents, mechanism, loading of resin, nucleophilic substitution, and cleavage from resin support, amine protecting groups, general reaction techniques as well as purification of final product.