Merrifield SPPS uses the tert-butoxycarbonyl (BOC) group to protect the a-amino group (Scheme B.25.1). After coupling to the N-terminus of the growing peptide chain the BOC groups are removed with trifluoroacetic acid (TFA). Before a subsequent coupling reaction the resulting trifluoroacetates are neutralized with diisopropylethylamine (DIPEA) in CH2Cl2. To protect the side-chains of trifunctional a-amino acids, a range of benzyl-based protective groups has been developed; these are cleaved, with the linker, by action of HF. Although the Merrifield method has proven very efficient, the use of highly toxic HF and the need for Teflon-lined equipment has prevented many from applying the technique.

An alternative method, which uses the base-labile 9-fluorenylmethoxy-carbonyl (Fmoc) group to protect the a-amino group in combination with

(i) Piperidine/DMF

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