Solid-phase synthesis chemistry assessment

The optimized reaction conditions to make the same library in solution or on SP differ significantly in most examples because of the influence exerted by the heterogeneous support (see Chapter 1), which may lead to different purities and yields of the final compounds. When the chemistry assessment, either in solution or on solid phase, does not give satisfactory results after having exploited all the reasonable experimental conditions, the other phase should at least be considered before abandoning the library synthesis. 

Classical peptide chemists were steeped in the tradition of organic chemistry in which intermediates are carefully analyzed and purified to homogeneity. Since the assembly of a desired peptide by solid-phase peptide synthesis occurs without purification of intermediates it is likely that truncated peptides and other impurities accumulate on the resin these are difficult to separate from the desired product. Prior to the 1970s, thin layer chromatography, paper chromatography, paper electrophoresis, and microchemical analysis were used to assess peptide homogeneity. None of these were sufficiently sensitive to distinguish the impurities that were expected from the solid-phase approach. 

In July 1963, an article by R. B. Merrifield entitled Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide appeared in The Journal of the American Chemical Society It is very difficult today to try to assess the enormous impact on the further development of chemistry and biology of this pioneering article, as well as related work from the same laboratory that soon started appearing regularly. To some extent the Nobel Prize awarded to Merrifield in 1984 was the first acknowledgement of this impact. The seminal 1963 Merrifield paper has been cited more than 4000 times in the scientific literature (Figure 1). 

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