Scalable total synthesis and comprehensive structure–activity relationship studies of the phytotoxin coronatine

Abstract

Natural phytotoxins are valuable starting points for agrochemical design. Acting as a jasmonate agonist, coronatine represents an attractive herbicidal lead with novel mode of action, and has been an important synthetic target for agrochemical development. However, both restricted access to quantities of coronatine and a lack of a suitably scalable and flexible synthetic approach to its constituent natural product components, coronafacic and coronamic acids, has frustrated development of this target. Here, we report gram-scale production of coronafacic acid that allows a comprehensive structure–activity relationship study of this target. Biological assessment of a >120 member library combined with computational studies have revealed the key determinants of potency, rationalising hypotheses held for decades, and allowing future rational design of new herbicidal leads based on this template.

Jasmonates: News on Occurrence, Biosynthesis, Metabolism and Action of an Ancient Group of Signaling Compounds

“…Obviously, in bacteria, coronatine has been evolved next to JA in a type of co-evolution to achieve higher activity [ 127 ]. Based on the diverse action of the bacterial-derived coronatine in plant growth and development, studies on structure-activity relationship resulted in the fact that coronatine has been regarded as an attractive herbicidal lead compound [ 128 ]. It is, however, difficult to imagine a specific herbicidal action of coronatine regarding the numerous processes affected by jasmonates.…”

Recent Advances in Plant Chemical Biology of Jasmonates

“…COR is widely used in JA bioscience instead of JA because of the chemical stability of bioactive (7R, 3R)-form, and its most important contribution so far has been the development of the coi1-1 mutant, which incorporates a mutation in gene encoding the COI1 protein (a component of COI1-JAZ coreceptor) and is insensitive to COR [23]. Today, COR is considered as a structural and functional mimic of JA-Ile, and has been accessible in multigram quantities and good optical purity since the landmark work of Watson's and Ueda's groups [24][25][26].…”

A scalable synthesis of (+)‐coronafacic acid

“…Under the cryogenic conditions, this reaction predominantly affords the anti‐ product . In contrast, the syn isomer is predominantly obtained at room temperature . Therefore, we planned to carry out the reaction at room temperature to obtain the desired syn isomer.…”

“…10 In contrast, the syn isomer is predominantly obtained at room temperature. 7,11 Therefore, we planned to carry out the reaction at room temperature to obtain the desired syn isomer. However, the preparation of boron enolate at −78 C followed by the addition of 8 having allowed the enolate solution to warm to room temperature did not improve the reproducibility (entry 2).…”

“…Past syntheses of 1 have been accomplished on a small scale by synthesizing 3 and condensing it with 4 (which can be easily prepared at scale), 6 but no published route to 3 is of any practical use, 6 being unable to supply sufficient optically pure 3 for subsequent experimentation. Recently, however, Watson reported a synthesis of (±)-3 in only 10 steps and 10% overall yield on a scale of 2.7 g. 7 However, there were some drawbacks with this method: the boron aldol step was low-yielding and capricious, and no procedure to obtain optically pure 3 from the racemic product of the reaction was disclosed. In this study, we improved the Watson method, perfected a method for the resolution of the racemic product, and finally obtained scalable quantities of optically pure (+)-3 in 15% overall yield.…”