Development of a Synthetic Process for Cyphenovaline: A Potent, Selective Abscisic Acid Receptor Agonist

Abstract Abscisic acid is one of the six major naturally occurring phytohormones and has substantial potential for agricultural applications. However, its practical use in agriculture remains highly limited in both scale and scope because of the challenges associated with its synthesis and its intrinsic structural instability. Consequently, the development of abscisic acid analogs with improved properties has become an important and active area of research. Cyphenovaline, a selective abscisic acid receptor agonist developed by our group, exhibits strong antidrought activity and inhibits seed germination, among other desirable functions. Nevertheless, an industrial-scale manufacturing process for this compound has not yet been established. Here, we report a more economical and efficient four-step synthetic route than the original process. The route comprises glyoxylic acid-mediated electrophilic dibromination, deaminative cyanation, EDCI-mediated amide bond formation followed by methyl ester saponification, and a final Suzuki coupling to install the dicyclopropyl group, affording cyphenovaline. The reaction conditions for each step were systematically screened and optimized. In addition, a scale-up experiment conducted on the 100 g scale demonstrated the feasibility of the process, confirming its suitability for industrial production.