PEGylation of Thiol Groups

Vinyl sulfone 37 reacts selectively with -SH group of cysteine in slightly basic conditions in Michael-type addition reaction to afford stable thioether linkages (Equation 3.15). It has been indicated that lysine conjugation also occurs at more basic pH (pH 9.3) when large excesses of 36 are used. 

A simple one-step click method for the preparation of vinyl sulfone 36, among other hydroxyl-terminated polymers, has been published. In this method, bis-vinyl sulfone is employed, which upon reaction with mPEG-alkoxide gives 36 in a single step and with high yield [175]. 

The synthesis of mPEG reagent 37 has been published in the patent literature as depicted in Equation 3.18. Tosylation of mPEG under standard conditions, followed by nucleophilic displacement reaction with aqueous ammonia solution gives mPEG-amine 42. Acylation 

Although other methodologies for synthesis of 37 have been published, it has been indicated that these methods afford xmdesirable high amounts of byproducts [177-179]. 

More recently it has been claimed that mPEG-amine 42 can react with N-methoxycarbonylmaleimide in aqueous basic solution, rendering the required mPEG maleimide 37 in a single step [180]. 

---