Front Cover: Analogues of Abscisic Acid – Insights into their Activity in Vitro and in Vivo (Eur. J. Org. Chem. 12/2018)

Abstract

The Front Cover shows common iterative steps of modern agrochemical research in the foreground with ears of wheat plants close to being harvested in the background. Inspired by nature, that is, by plant hormone abscisic acid (ABA), novel lead structures targeting drought stress in crops such as wheat or canola have been identified. In vivo SAR studies based on greenhouse trials and chemical optimization were supported by systems biology, in vitro analyses, and X‐ray crystallography. It could thus be explored how modification of the key structural features of ABA influences receptor affinity and in vivo efficacy. As a result, cyano‐cyclopropyl groups proved to be suitable replacements for the cyclohexanone headgroup motif. More information can be found in the full papers by J. Frackenpohl, E. Grill et al. (https://doi.org/10.1002/ejoc.201701687 and https://doi.org/10.1002/ejoc.201701769)

Potent Analogues of Abscisic Acid – Identifying Cyano‐Cyclopropyl Moieties as Promising Replacements for the Cyclohexenone Headgroup

“…( Z )‐Vinyl iodides 15c – 15g were prepared starting from substituted alkynes in two steps via carboxylation and subsequent hydroiodination . In our hands, this methodology proved to be clearly superior towards related approaches using hydrozirconation and a Negishi‐type cross‐coupling to establish the ( E , Z )‐diene side chain . As a result, ABA‐analogues 16c – 16g could be prepared in 5 linear steps with overall yields in the range of 30–50 % (Scheme ).…”

“…Based on our experiences from total synthesis studies in the field of ABA we decided to apply our versatile approach using a Stille coupling as the key step to prepare cyano‐cyclopropyl analogues of ABA . LDA‐mediated coupling of cyclopropyl nitrile with a pivaloyl‐based Weinreb amide, followed by direct alkynylation afforded crystalline alkynol 13a in good yield (Scheme ).…”

“…Coupling of ( E )‐stannane 14a with a suitable freshly prepared vinyl iodide 15c – 15g via an optimized Stille‐coupling protocol using Pd(MeCN) 2 Cl 2 and CuI in N , N ‐DMF at slightly elevated temperatures (40–50 °C) afforded desired cyano‐cyclopropyl analogues of ABA 16c – 16g . ( Z )‐Vinyl iodides 15c – 15g were prepared starting from substituted alkynes in two steps via carboxylation and subsequent hydroiodination .…”

“…With this robust synthetic approach in hand we could prepare a broad range of compounds with modified head groups (Scheme ; entries 2–27, Table ). The i Pr group (R 1 ) could thus be replaced by a wide variety of alkyl, cycloalkyl and aryl substituents, such as cyclopropyl, cyclopentyl, tert ‐butyl, adamantyl, phenyl or tolyl, emphasizing the versatility of our synthetic approach ( 16m , 16u , 16z , Scheme , Table , Table ) …”

“…Substituted aryl sulfonamides, e.g. pyrabactin 8a , closely related pyrimidine 8b , as well as thiazoles and pyrazoles 9a – b , have shown promising initial receptor affinity and beneficial effects within in vivo tests (Figure ). More recently, tetrahydroquinolinyl sulfonamides have shown improved in vitro activity .…”