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

Abstract

The alkylation of cysteine residue by different classes of carbonium ions, derived from the cleavage of side chain protective groups in anhydrous HF, was investigated. It was found that side chain protection as beta-2,4-dimethylpent-3-yl ester (Dmp) or 2,4-dimethylpent-3-yloxycarbonyl (Doc) groups resulted in more than seven-fold lower level of alkylated byproducts. This makes Dmp and Doc protection of amino acid side chain during solid phase synthesis particularly valuable in the synthesis of peptides containing cysteine residues or other functional groups prone to alkylation by carbonium ions.

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“…A study has also been reported on the unwanted alkylation of cysteine residues by side-chain PG-derived cations during HF deprotection following SPPS using Boc chemistry. 73 It was found that side-chain protection as b-2,4-dimethylpent-3-yl (Dmp) esters (e.g. of aspartic acid) and as 2,4-dimethylpent-3-yloxycarbonyl (Doc) carbamates (e.g.…”

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“…The use of a 1-isopropyl-2-methylpropyl group for the protection of the side chain carboxylic acid function of Asp and a 1-isopropyl-2-methylpropoxycarbonyl group for the protection of the phenolic hydroxy function of Tyr markedly suppress this side reaction. 181 Bulky heptafluorotrityl-and phenylfluorenyl groups have been developed for the side chain protection of glutamic acid. 182 These esters exhibit increased stability compared to trityl esters, but they can still be removed under mild conditions, with 1% TFA and morpholine, respectively.…”