Simple plate-based, parallel synthesis of disulfide fragments using the CuAAC click reaction.

Disulfide exchange screening is a site-directed approach to fragment-based lead discovery that requires a bespoke library of disulfide-containing fragments. Previously, we described a simple one-pot, two-step synthesis of disulfide fragments from amine- or acid-bearing starting materials. Here, we describe the synthesis of disulfide fragments that bear a 1,4-substituted-1,2,3-triazole linkage between disulfide and molecular diversity element. This work establishes the compatibility of copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) chemistry with a one-pot, two-step reaction sequence that can be readily parallelized. We performed 96 reactions in a single deep-well microtiter plate, employing 48 alkynes and two different azide linker reagents. From this effort, a total of 81 triazole-containing disulfide fragments were obtained in useful isolated yields. Thus, CuAAC chemistry offers an experimentally convenient method to rapidly prepare disulfide fragments that are structurally distinct from fragments accessed via amide, sulfonamide, or isocyanate chemistries.