Strategies for discovering resistance-breaking, safe and sustainable commercial herbicides with novel modes of action and chemotypes.

Farmers need to manage weeds to grow and harvest crops that are essential to our food and energy supply, and herbicides are the most important tool in the farmers' armory to combat weeds. There is now a crisis in agriculture that has been brought about by herbicides being rendered ineffective by resistant weeds or withdrawn from the market due to safety concerns. Efficacious herbicides with novel modes of action (MoAs) and chemotypes are urgently needed to control resistant weeds and satisfy public and regulators' stringent requirements for safe and sustainable products. This article explores the main strategies being deployed by academic and industrial institutions to discover the next generation of commercial herbicides: phenotypic and in vitro target based approaches. There are early signs that much needed innovation and herbicidal products with novel MoAs are on the horizon from start-ups and established agrochemical companies. © 2021 Society of Chemical Industry. © 2021 Society of Chemical Industry.

Herbicidal aryldiones incorporating a 5-methoxy-[1,2,5]triazepane ring.

Novel 2-aryl-cyclic-1,3-diones containing a 5-methoxy-[1,2,5]triazepane unit were explored towards an effective and wheat safe control of grass weeds. Their preparation builds on the ease of synthetic access to 7-membered heterocyclic [1,2,5]triazepane building blocks. Substitution and pattern hopping in the phenyl moiety revealed structure-activity relationships in good agreement with previously disclosed observations amongst the pinoxaden family of acetyl-CoA carboxylase inhibitors. In light of basic physicochemical, enzyme inhibitory and binding site properties, the N-methoxy functionality effectively acts as a bioisostere of the ether group in the seven-membered hydrazine ring.

Geometry-Retentive C-Alkenylation of Lithiated α-Aminonitriles: Quaternary α-Alkenyl Amino Acids and Hydantoins.

α-Amino nitriles tethered to alkenes through a urea linkage undergo intramolecular C-alkenylation on treatment with base by attack of the lithionitrile derivatives on the N'-alkenyl group. A geometry-retentive alkene shift affords stereospecifically the E or Z isomer of the 5-alkenyl-4-iminohydantoin products from the corresponding starting E- or Z-N'-alkenyl urea, each of which may be formed from the same N-allyl precursor by stereodivergent alkene isomerization. The reaction, formally a nucleophilic substitution at an sp2 carbon atom, allows the direct regioselective incorporation of mono-, di-, tri-, and tetrasubstituted olefins at the α-carbon of amino acid derivatives. The initially formed 5-alkenyl iminohydantoins may be hydrolyzed and oxidatively deprotected to yield hydantoins and unsaturated α-quaternary amino acids.

Stereocontrolled synthesis of the AB rings of samaderine C.

A concise synthesis of the AB rings of samaderine C (12 steps, 8 isolation steps, 7.8% overall yield), a quassinoid with antifeedant and insecticidal activity, is described. The development of the first general approach to the trans-1,2-diol A-ring motif in samaderine C and other quassinoids is a key feature. The trans-1,2-diol is crafted via stereoselective α-hydroxylation (of a silyl enol ether) and reduction, a strategy that has much potential for quassinoid synthesis.

Catalytic asymmetric synthesis of butane diacetal-protected (4S,5S)-dihydroxycyclohexen-1-one and use in natural product synthesis.

Due to the lack of availability of unnatural (+)-quinic acid as a starting material, a 6-step synthesis of butane diacetal-protected (4S,5S)-dihydroxycyclohexen-1-one (formally derived from (+)-quinic acid) has been devised. The key catalytic asymmetric step involves a chiral Co-salen-catalysed epoxide ring-opening reaction. (4S,5S)-Dihydroxycyclohexen-1-one was utilised in the synthesis of two cyclohexenone natural products isolated from the mycelia of Lasiodiplodia theobromae.

Stereocontrolled syntheses of kainoid amino acids from 7-azabicyclo[2.2.1]heptadienes using tandem radical addition-homoallylic radical rearrangement.

[reaction; see text] N-Boc syn-7-(2-hydroxyethyl)-4-(alkyl or aryl)sulfonyl-2-azabicyclo[2.2.1]hept-5-enes serve as precursors in syntheses of the neuroexcitants 3-(carboxymethyl)pyrrolidine-2,4-dicarboxylic acid 43, alpha-kainic acid 12, alpha-isokainic acid 14, and alpha-dihydroallokainic acid 77. The key step in these syntheses is the intermolecular radical addition of 2-iodoethanol to a N-Boc 2-(alkyl or aryl)sulfonyl-7-azabicyclo[2.2.1]heptadiene 7 to induce nitrogen-directed homoallylic radical rearrangement. Oxidative cleavage of the resulting 2-azabicyclo[2.2.1]hept-5-enes provide straightforward access to polysubstituted pyrrolidines and, in particular, an efficient entry to the kainoid amino acids.

Synthesis of alpha-kainic acid from a 7-azabicyclo[2.2.1]heptadiene by tandem radical addition-homoallylic radical rearrangement.

Reductive radical addition of 2-iodoethanol to N-Boc 2-tosyl-7-azabicyclo[2.2.1]heptadiene gives N-Boc syn-7-(2-hydroxyethyl)-4-tosyl-2-azabicyclo[2.2.1]hept-5-ene, which is converted into the neuroexcitants 3-(carboxymethyl)pyrrolidine-2,4-dicarboxylic acid and alpha-kainic acid. [structure: see text]