With the rapid development of combinatorial chemistry using solid phase synthesis, there is a great deal of interest in developing new solid phase linkers, which are stable during the solid phase synthesis process and yet readily cleavable under mild conditions. By taking advantage of a "trimethyl lock"-facilitated lactonization reaction, we have developed a redox-sensitive resin linker for the synthesis of C-terminal-modified peptides. The cleavage only requires mild reducing agents such as sodium hydrosulfite, which is not expected to cause any problem with the commonly seen organic functional groups. Using this new linker, three short peptides were synthesized with high isolated yields (70-90%). Such a linker could potentially be used for the synthesis of modified peptide libraries, which allows for the ready cleavage of the linker under mild conditions.

The interest in developing new linkers for solid-phase peptide and organic synthesis has increased tremendously as a result of the rapid development of combinatorial chemistry. Herein, we report the development of a new redox-sensitive linker for solid-phase peptide synthesis. This linker can be readily cleaved under mild conditions by using two sequential mild reactions, a reduction followed by a base (Bu4N+F-)-catalyzed cyclic ether formation. By using this new linker, two short peptides, a tetrapeptide [Boc-Trp-Ala-Gly-Gly-OH] and a pentapeptide [Boc-Asn-Ala-Ser(OBn)-Gly-Glu(OBn)-OH)], were synthesized. Because the cleavage does not use acidic conditions, this resin linker provides an alternative when acidic conditions are not desirable. Furthermore, the cleavage conditions do not affect most of the side chain protecting group. Therefore, the peptides synthesized can be used for the segment synthesis of larger peptides without the need to reprotect the side chain functional groups.

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