Work

A Streamlined Synthesis of Adenosine Vinylsulfonamide Probes for Aminoacyl‐AMP Mimicry in NRPS

Year: 2026

Type: article

Abstract: Adenosine vinylsulfonamide (AVS) probes provide a powerful means of stabilizing the thioesterification state in nonribosomal peptide synthetases (NRPSs) by mimicking aminoacyl‐AMP intermediates. Existing synthetic strategies have enabled broad application of this probe class, yet they often rely on strongly basic conditions for constructing the key CC bond from α‐amino aldehydes, substrates that are inherently prone to epimerization. These features limit practical access to AVS derivatives from nonproteinogenic amino acids, many of which are central to NRPS‐mediated natural product biosynthesis. To address these constraints, we developed a concise three‐step route beginning from N ‐Boc amino alcohols that proceeds under operationally simple and stereochemically controlled conditions. A preassembled adenosine phosphinyl sulfonamide serves as an effective coupling partner in a Ba(OH) 2 ‐mediated Horner reaction performed near 0°C, enabling highly diastereoselective AVS formation with minimal epimerization under mild, open‐air conditions. The method tolerates diverse amino acid‐derived substrates, including electron‐rich L‐Tyr derivatives relevant to tetrahydroisoquinoline alkaloid biosynthesis. Functional evaluation by LC–MS/MS confirmed covalent capture of the NRPS SfmC by an L‐Tyr‐derived probe, demonstrating that AVS constructs prepared by this route retain full biochemical competence. This streamlined synthesis enhances reliable access to stereochemically well‐defined AVS probes and supports structural and mechanistic studies across diverse NRPS systems.

Source: ChemBioChem

DOI: 10.1002/cbic.70275