Suzuki-Miyaura Reaction in the Presence of N-Acetylcysteamine Thioesters Enables Rapid Synthesis of Biomimetic Polyketide Thioester Surrogates for Biosynthetic Studies

Biomimetic N-acetylcysteamine thioesters are essential for the study of polyketide synthases, non-ribosomal peptide synthetases and fatty acid synthases. The chemistry for their preparation is, however, limited by their specific functionalization and their susceptibility to undesired side reactions. Here we report a method for the rapid preparation of N-acetylcysteamine (SNAC) 7-hydroxy-2-enethioates, which are suitable for the study of various enzymatic domains of megasynthase enzymes. The method is based on a one-pot sequence of hydroboration and the Suzuki-Miyaura reaction. The optimization of the reaction conditions made it possible to suppress potential side reactions and to introduce the highly functionalized SNAC methacrylate unit in a high yield. The versatility of the sequence was demonstrated by the synthesis of the complex polyketide-SNAC thioesters 12 and 33. Brown crotylation followed by the hydroboration to Suzuki-Miyaura reaction sequence enabled the introduction of the target motif in significantly fewer steps and with a higher overall yield and stereoselectivity than previously described approaches. This is the first report of a transition-metal-catalyzed cross-coupling reaction in the presence of an SNAC thioester.