1. Practical preparation and deblocking conditions for N-alpha-(2-(p-biphenylyl)-2-propyloxycarbonyl)-amino acid (N-a-Bpoc-Xxx-OH) derivatives
D S Kemp, N Fotouhi, J G Boyd, R I Carey, C Ashton, J Hoare Int J Pept Protein Res. 1988 Apr;31(4):359-72. doi: 10.1111/j.1399-3011.1988.tb00045.x.
Reproducible preparations are given for salts of the following L-amino acid derivatives: Bpoc-Ala-OH, Bpoc-Arg(Mtr)-OH, Bpoc-Asn-OH, Bpoc-Asp(OtBu)-OH, Bpoc-Cys(Acm)-OH, Bpoc-Cys(S-tBu)-OH, Bpoc-Gln-OH, Bpoc-Glu(OtBu)-OH, Bpoc-Gly-OH, Bpoc-Ile-OH, Bpoc-Leu-OH, N-alpha-Bpoc-Lys(epsilon-Boc)-OH, Bpoc-Met-OH, Bpoc-Phe-OH, Bpoc-Pro-OH, Bpoc-Ser(OtBu)-OH, Bpoc-Thr(OtBu)-OH, Bpoc-Tyr-OH, Bpoc-Val-OH. A study of the deblocking of N-alpha-Bpoc peptides in dichloromethane containing 0.5% trifluoroacetic acid revealed that a rapid equilbrium is established between the first-formed monomeric alkene 2-p-biphenylylpropene and the hindered dimer 2,4-bis(p-biphenylyl)-4-methyl-1-pentene. Thioethers were found to be inefficient carbocation scavengers for the deblocking reaction. The most efficient scavengers were found to be thiophenol and benzyl mercaptan, and the following approximate reactivity order was established: benzyl mercaptan approximately thiophenol greater than indole much greater than 1,3-dimethoxybenzene approximately resorcinol greater than 1,3,5-trimethoxybenzene approximately dimethyl sulfide approximately thioanisole.
2. N alpha-trifluoroacetylation of N-terminal hydroxyamino acids: a new side reaction in peptide synthesis
G Hübener, W Göhring, H J Musiol, L Moroder Pept Res. 1992 Sep-Oct;5(5):287-92.
In the synthesis of the double-chain bis-cystinyl hinge fragment 225-232/225'-232' of the human IgG1, which contains two N-terminal threonine residues, the final acidolytic deprotection step, with 99% aqueous trifluoroacetic acid, was accompanied by formation of remarkable amounts of an unknown side product. This has been identified as the N alpha-mono-trifluoroacetylated product; however, even bis-trifluoroacetylation was found to occur by prolonged exposure of the parallel dimer to the reaction medium. Similarly, the model compounds H-Thr(tBu)-Phe-OH, [Boc-Thr(tBu)-Cys-OH]2 and Boc-Thr(tBu)-Cys(StBu)-Ala-OH were acylated by treatment with trifluoroacetic acid at rates that suggest a rather pronounced sequence dependency. Since, on the other hand, the model compound [Boc-Ala-Cys-OH]2 was not trifluoroacetylated at all under identical conditions, the reaction has to proceed prevalently via intermediate formation of the trifluoroacetyl ester of N-terminal hydroxyamino acids, followed by O-->N shift according to the hydroxyoxazolidine mechanism. The experimental data indicate also that under favored conditions aminolysis of the trifluoroacetyl ester via an inter- or intramolecular pathway may contribute to the overall reaction rate.
