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.

Fig. 1

Structure, current SAR and route design plan for (+)-7-iso-JA-L-Ile (JA-Ile) and coronatine (1). a Structural similarities between the natural bioactive ligand JA-Ile and 1 are highlighted. Coronatine can be considered as comprising of two component parts; the bicyclic core, coronafacic acid 2, amino acid moiety, and coronamic acid 3. b, c A summary of the known SAR at the outset of this work. d Retrosynthesis and route design plan for SAR interrogation

Fig. 2

Gram-scale synthesis of (±)-CFA. Five step synthesis of aldehyde 7, followed by syn-selective room temperature aldol addition with ester 8. Aldol addition product 9 undergoes dehydration and IMDA cyclization of the resultant triene at elevated temperature. DHP: dihydropyran, DMSO: dimethyl sulfoxide, PPTS: pyridinium p-toluenesulfonate, DIPEA: N,N-diisopropylethylamine, DIC: N,N’-diisopropylcarbodiimide, PTSA: p-toluenesulfonic acid, PDC: pyridinium dichromate

Fig. 3

Representative examples of COR analogue synthesis. a HATU coupling of (±)-2 and amino acid methyl esters, which were then hydrolysed to afford the free-acids. HATU, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate. b Alternative core coupling to (±)-CMA and L-Ile. c CFA core oxime and core analogues

Fig. 4

Computational modelling. a COR (1) in the protein binding site (COI1) and main interactions. b Docked structures showing the interactions with 1 and 16. Steric clashes are identified by dashed lines. c Common toxicophore model