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Novel disulfide reducing agent

Novel disulfide reducing agent
07 December 2019 - Orgo

Mthembu et al. report on a new reducing agent for disulfides (DOI). A range of such agents widely used in biochemistry are 2-mercaptoethanol, dithiothreitol (DTT) and TCEP and serve deprotection purpose and can cleave spacers. They all tend to suffer from poor reducing power, low reactivity, limited pH range, limited solubility range and notably bad smell. The South-African / Spanish collective have designed a new agent aimed at removing some of those disadvantages. They did so building on another reducing agent, 2-(dibenzylamino)butane-1,4-dithiol (DABDT) introduced in 2012 by An American group (Lukesh et al. DOI) as an alternative for DTT. DTT works by thiol-disulfide exchange with formation of an internal disulfide. The compound is basic and will therefore only work in acidic environments. In DTBA two hydroxyl groups are replaced by a single amino group making it less basic.
In the new work the molecule was modified to introduce solubility in organic solvents by adding two benzyl groups to the amine moiety. Starting from aspartic acid, a reaction with benzyl chloride formed a new compound with four benzyl groups added. The ester groups were then cleaved with lithium aluminium hydride to the corresponding diol. Converting the alcohol groups to a thiol proved difficult as the reagent of first choice Lawesson's reagent did not work. The alternative sequence that did work was conversion to the di-thioester and sodium borohydride reduction. Lithium aluminum hydride is a stronger reducing agent but was found to oxidize DABDT. DABDT is soluble in solvents such as DMF and dichloromethane but reaction still requires a base such as N,N-siisopropylethylamine. A test reaction was the deprotection of the cysteine terminal of a solid Ac-Cys-(SDMP)-Gly-Phe-Leu-Rink amide resin in DMF / water with DIEA.