Fmoc Chemistry
The most widely used chemical strategy for solid-phase peptide synthesis, using fluorenylmethyloxycarbonyl (Fmoc) as a temporary protecting group for amino groups. Fmoc is removed under mild basic conditions, making it compatible with a wide range of amino acid side chain protections and modifications.
Technical Context
Fmoc (9-fluorenylmethyloxycarbonyl) SPPS displaced the older Boc (tert-butyloxycarbonyl) strategy because: Fmoc removal uses mild base (piperidine/DMF) rather than strong acid (TFA for Boc), enabling orthogonal protection strategies; Fmoc cleavage can be monitored by UV absorbance (dibenzofulvene has strong UV absorption at 301nm, allowing real-time coupling efficiency monitoring); and acid-labile side chain protections are stable during Fmoc removal. Standard Fmoc amino acid side chain protections: Trt (trityl) for Cys, His, Asn, Gln; tBu (tert-butyl) for Ser, Thr, Tyr, Asp, Glu; Boc for Lys, Trp; Pbf for Arg. All side chain protections are removed simultaneously during TFA cleavage from resin. Difficult sequences (aggregation-prone regions, repeated amino acids) may require: pseudoproline dipeptide insertions, backbone protecting groups (Dmb, Hmb), or microwave-assisted synthesis to improve coupling efficiency.