Revisiting synthetic preparation of the quorum sensing substrate S-D-ribosyl-L-homocysteine (SRH)

Cleavage of the thioether bond of S-D-ribosyl-L-homocysteine (SRH) by the enzyme S-ribosylhomocysteinase (LuxS) serves as the final biosynthetic step in the generation of the quorum sensing autoinducer AI-2 by bacteria. Herein, a revised chemical synthesis of SRH is presented at convenient scale and purity for in vitro studies of LuxS. Potassium bis(trimethylsilyl) amide (KHMDS) is identified as a judicious base for the formation of the thioether of the target compound from readily-accessible precursors: a thiol nucleophile derived from L-homocystine and a sulfonate-activated D-ribosyl electrophile. The exclusive use of acid-labile protecting groups allows for facile deprotection to the final product, producing the TFA salt of SRH in five synthetic steps and 26% overall yield. The chemically-synthesized material is isolated at high purity and demonstrated to serve as the LuxS substrate by an in vitro assay. (C) 2014 Elsevier Ltd. All rights reserved.