Synthesis and SAR of 2,3‐Dihydro‐1‐benzofuran‐4‐carboxylates: Potent Salicylic Acid‐Based Lead Structures against Plant Stress

Abstract

New 2,3‐dihydro‐1‐benzofuran‐4‐carboxylic acid derivatives have been identified as potent lead structures against drought and cold stress in crops starting from the synthetic exploration of stabilized analogs of the natural product lunularic acid. An optimized Lewis‐acid mediated cyclization gave a short and efficient access to the envisaged 2,3‐dihydro‐1‐benzofuran‐4‐carboxylates. Enantioselective approaches were investigated to assess the potential impact of the chiral center on in vivo activity. Whilst 2,3‐dihydro‐1‐benzofuran‐4‐carboxamides and 2,3‐dihydro‐1‐benzofuran‐4‐carboxylates carrying phenyl substituents with electron‐withdrawing groups exhibited only low to moderate in vivo activity, the corresponding 2,3‐dihydro‐1‐benzofuran‐4‐carboxylates carrying optimized electron‐donating substituents in the phenyl moiety revealed strong in vivo activity, both against drought stress in several broad‐acre crops, as well as against cold stress in corn. Remarkably, several 2,3‐dihydro‐1‐benzofuran‐4‐carboxylates showed stronger efficacy than the internal standards used in our in vivo SAR study.

Inspired by Nature: Isostere Concepts in Plant Hormone Chemistry

“…With emphasis on preserving the beneficial physicochemical properties of a salicylate moiety the carbon C2-bridge of lunularic acid 130 can be included in a 5-membered dihydrofuryl ring preserving the salicylate as is shown in structure 130 (Figure ). Remarkably, 130 and closely related analogues revealed strong in vivo activity, both against drought stress in several broad-acre crops, as well as against cold stress in corn …”

“…113 Remarkably, 130 and closely related analogues revealed strong in vivo activity, both against drought stress in several broad-acre crops, as well as against cold stress in corn. 114…”

La(OTf)3-Catalyzed [3+2] Cycloaddition Reactions for the Synthesis of Benzo[d]oxazoles/Benzofurans

“…Tu et al developed a Cu/SPDO-catalyzed [3+2] cycloaddition to construct 2-aryl-2,3-dihydrobenzofuran scaffolds by quinone esters and styrenes . Recently, Feackenpohl et al reported the lewis acid-catalyzed [3+2] cycloaddition of quinones with phenyl acetylenes to synthesize 2,3-dihydro-1-benzo-furan-4-carboxylates . Unfortunately, there is no report about the [3+2] cyclization of quinones with cyanide compounds to form the benzo­[ d ]­oxazoles.…”

Oxidative Coupling of Hydroquinone Derivatives with Olefins to Dihydrobenzofurans

“…2,3-Dihydrobenzofurans (DHBs) are important skeletons for bioactive compounds and natural products, and various synthetic approaches have been developed. [1][2][3][4] Among them, benzoquinones (BQs) have been widely utilized as substrates in [3 + 2] cycloaddition with olefins (e.g., styrenes, [5][6][7][8] enol ethers, [9][10][11] allyl silane 12) ) to afford versatile DHBs (Chart 1A). BQs are prepared by the oxidation of hydroquinones (HQs), which can be easily modified by Friedel-Crafts type reactions to the corresponding C2-functionalized hydroquinone (such as compounds bearing an electron-withdrawing group (EWG) at the C2 position, 1, Chart 1C).…”