The 2,4-dimethylpent-3-yloxycarbonyl (Doc) group as a new, nucleophile-resistant protecting group for tyrosine in solid phase peptide synthesis

Amino Acid-Protecting Groups

“…434,435 It cannot be used in the Fmoc/ t Bu strategy because being a carbonate it is very sensitive to bases and nucleophiles. 438 -3-Pentyl (Pen). 439 It is a relatively new protecting group, stable to 50% TFA, bases and catalytic hydrogenation and readily removed with HF.…”

Study of the alkylation propensity of cations generated by acidolytic cleavage of protecting groups in Boc chemistry

“…The sequence Mnp‐Lys(Alloc)‐[Tyr(R ′′ )‐Cys(MeBzl)‐Asp(OR)‐Pro] 3 ‐Lys(Alloc)‐NH 2 , where R = cHx or Dmp and R ′′ = 2‐BrZ or Doc, was synthesized in an analogous way to that described above. Boc‐Tyr(2‐BrZ)OH and Boc‐Lys(Alloc)OH were purchased from Propeptide, Boc‐Tyr(Doc)‐OH was synthesized as described earlier (7) and (4‐methoxy‐3‐nitro‐phenyl)‐acetic acid was prepared by nitration of 4‐methoxy‐acetic acid.…”

“…This type of protection has been introduced for aspartic acid (2–4), histidine (5), tryptophan (6) and tyrosine (7). We have shown that these protective groups suppress common side reactions such as aspartimide formation (2–4) and premature cleavage by nucleophiles (5–7). Furthermore, in the case of tryptophan and histidine, these new protective groups can be cleaved in HF without any separate deprotection, as in the case of formyl‐tryptophan and Dnp‐histidine.…”

Protecting groups

“…Unden and co-workers reported that the 2,4-dimethylpentan- 3-yloxycarbonyl (Doc) group can be used for protecting the hydroxy group of tyrosine. 6 The protection is achieved in the reaction of tyrosine derivative 14 with 2,4-dimethylpentan-3-yl chloroformate and ethyldiisopropylamine (Scheme 5). The Doc group is 1000-fold more stable towards nucleophilic piperidine than the commonly used 2-bromobenzyloxycarbonyl (2-BrCbz) group and it is completely cleaved by hydrogen fluoride.…”