Regiospecific synthesis of 3,5-bis(bromomethyl)benzoic acid, a cysteine crosslinking agent

Article abstract of DOI:10.1016/S0040-4020(01)81898-6

Bridging two molecules of an organic thiol with the 3,5-dimethylenebenzoic acid (Dmb) group produces a rigid five-carbon Dmb crosslink that is stable to disulfide reducing agents. Radical bromination of 3,5-dimethylbenzoic acid or its succinimido ester gave four α-brominated products. So NMR-pure 3,5-bis(bromomethyl)benzoic acid (Br₂Dmb) was regiospecifically synthesized in 38% overall yield by a four-step route from 1,3,5-benzenetricarboxylic acid. S-Alkylation of cysteine methyl ester, a model thiol, with Br₂Dmb provided the 2:1 adduct (Cys-OCH₃)₂Dmb in 79% yield. Subsequent N-protection with di(tert-butyl) dicarbonate gave (Boc-Cys-OCH₃)₂Dmb in 60% overall yield from cysteine methyl ester. This protected diamino acid is suitable for assembly of two Dmb-crosslinked peptide chains.