On the stability of S‐(alkylsulfanyl) cysteine derivatives during solid‐phase synthesis

Abstract N‐Acetyl‐S‐(alkylsulfanyl)cysteine benzyl esters were synthesized as models for N‐acylated S‐(alkylsulfanyl)cysteine residues linked via an ester bond to a solid phase. The S‐protections involved were: the ethylsulfanyl, the well‐established tert‐butylsulfanyl and the newly developed tritylsulfanyl group. We investigated the chemical behaviour of the disulfides in reagents commonly applied in solid‐phase peptide synthesis using the Fmoc strategy (Fmoc SPPS). It was found that the tritylsulfanyl group as a thiol protection is comparable with the tert‐butylsulfanyl group in these respects. It is stable in trifluoroacetic acid and is rapidly reduced by thiols and phosphines. For all three cysteine esters rapid racemization was observed in piperidine (25%) in DMF, the amides being chirally stable. The demonstrated chiral instability of cysteine esters has consequences for the solid‐phase synthesis of peptides using the Fmoc protocol.