Abstract Amide groups are pervasive across the chemical space continuum, where their structural and pharmacological importance, juxtaposed with the hydrolytic vulnerabilities, continues to fuel bioisostere development. Alkenyl fluorides have a venerable history as effective mimics (ΨCF=CH) owing to the planarity of the motif and intrinsic polarity of the C(sp2)−F bond. However, emulating the s‐cis to the s‐trans isomerisation of a peptide bond with fluoro‐alkene surrogates remains challenging, and current synthetic solutions only enable access to a single configuration. Through the design of an ambiphilic linchpin based on a fluorinated β‐borylacrylate, it has been possible to leverage energy transfer catalysis to affect this unprecedented isomerisation process: this provides geometrically‐programmable building blocks that can be functionalised at either terminus. Irradiation at λmax=402 nm with inexpensive thioxanthone as a photocatalyst enables rapid, effective isomerisation of tri‐ and tetra‐substituted species (up to E/Z 98 : 2 in 1 h), providing a stereodivergent platform for small molecule amide and polyene isostere discovery. Application of the methodology in target synthesis and initial laser spectroscopic studies are disclosed together with crystallographic analyses of representative products.
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