Preprint Communication Version 1 Preserved in Portico This version is not peer-reviewed

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

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Version 1 : Received: 5 May 2023 / Approved: 9 May 2023 / Online: 9 May 2023 (14:32:34 CEST)

A peer-reviewed article of this Preprint also exists.

Derra, S.; Schlotte, L.; Hahn, F. Suzuki–Miyaura Reaction in the Presence of N-Acetylcysteamine Thioesters Enables Rapid Synthesis of Biomimetic Polyketide Thioester Surrogates for Biosynthetic Studies. Chemistry 2023, 5, 1407-1418. Derra, S.; Schlotte, L.; Hahn, F. Suzuki–Miyaura Reaction in the Presence of N-Acetylcysteamine Thioesters Enables Rapid Synthesis of Biomimetic Polyketide Thioester Surrogates for Biosynthetic Studies. Chemistry 2023, 5, 1407-1418.

Abstract

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. This is especially detrimental to transition metal-catalyzed 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, particularly oxygen heterocycle-forming cyclase domains. The method is based on a one-pot sequence of hy-droboration and Suzuki-Miyaura reaction. Optimization of the reaction conditions made it possi-ble to suppress potential side reactions and to introduce the highly functionalized SNAC meth-acrylate unit in high yield. The versatility of the sequence was demonstrated on a dienal precur-sor, which was subjected to Brown crotylation followed by the hydroboration-Suzuki-Miyaura reaction sequence and deprotection, finally giving a complex polyketide SNAC thioester. Back-bone extension by six carbons and a terminal SNAC enethioate was achieved, introducing an E-configured double bond and two adjacent stereocenters in a highly selective manner. The pre-sented method allows for the synthesis of the target motif in significantly fewer steps and with higher overall yield than previously described approaches, while maintaining higher flexibility and control over the stereogenic elements. It is also the first reported example of a transition met-al-catalyzed cross-coupling reaction in the presence of an SNAC thioester.

Keywords

Suzuki-Miyaura reaction; biomimetic thioesters; polyketide synthases; enzymes; cyclases

Subject

Chemistry and Materials Science, Organic Chemistry

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