Side reaction during the deprotection of (S‐acetamidomethyl)cysteine in a peptide with a high serine and threonine content

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Abstract
The acetamidomethyl (Acm) group is a widely used protecting group for the thiol of cysteine during the SPPS process. We prepared the amino terminal loop of the snake α‐neurotoxin, [Cys3, Cys23, Ser17(1–24) amide, from the linear peptide [Cys(Acm)3,23,Ser17](1–24) amide obtained by SPPS. Three different methods of deprotection of Cys(Acm) and disulfide bond formation were used: iodine, thallium(III) trifluoroacetate and mercuric acetate/potassium ferricyanide. The iodine method failed to yield the expected peptide, and gave instead the mono‐iodinated tyrosine analog. The disulfide cyclized peptide obtained by thallium(III) or Hg(II) procedures displayed a MW value observed by mass spectrometry that was higher than the calculated value. The difference (MWobs ‐ MWcalc) corresponded to a multiple of the Acm moiety, which is shifted intra‐and/or intermoleculary. Furthermore, we observed, in addition to the Acm shift in the disulfide cyclized decapeptide with a high Ser and Thr content (model peptide II), the dimerization phenomenon in the Tl(TFA)3 process. Therefore we conclude that a side reaction, a S–O(Ser,Thr) Acm shift, occured during the Cys(Acm) deprotection. This shift was supported by the demonstration of Ser(O‐Acm) formation in the reaction of Boc‐(L)‐Cys(Acm) with Tl(TFA)3 in the presence of an equimolar amount of (L)Ser. We report here the efficiency of a trivalent alcohol, glycerol, as scavenger in the both Tl(TFA)3 and mercuric/ferricyanide methods, in an attempt to circumvent this side‐reaction during the disulfide bond formation step starting from a bis‐Cys(Acm) peptide with a high Ser and Thr content, such as the N‐terminal loop of neurotoxin, model peptide II or a similar peptide.

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