The spinosyns, spinosad, spinetoram, and synthetic spinosyn mimics - discovery, exploration, and evolution of a natural product chemistry and the impact of computational tools.

Natural products (NPs) have long been a source of insecticidal crop protection products. Like many macrolide NPs, the spinosyns originated from a soil inhibiting microorganism (Saccharopolyspora spinosa). More than 20 years after initial registration, the spinosyns remain a unique class of NP-based insect control products that presently encompass two insecticidal active ingredients, spinosad, a naturally occurring mixture of spinosyns, and spinetoram, a semi-synthetic spinosyn product. The exploration and exploitation of the spinosyns has, unusually, been tied to an array of computational tools including artificial intelligence (AI)-based quantitative structure activity relationship (QSAR) and most recently computer-aided modeling and design (CAMD). The AI-based QSAR directly lead to the discovery of spinetoram, while the CAMD studies have recently resulted in the discovery and building of a series of synthetic spinosyn mimics. The most recent of these synthetic spinosyn mimics show promise as insecticides targeting lepidopteran insect pests as demonstrated by field studies wherein the efficacy has been shown to be comparable to spinosad and spinetoram. These and a range of other aspects related to the exploration of the spinosyns over the past 30 years are reviewed herein. © 2020 Society of Chemical Industry.

Pro-insecticidal approach towards increasing in planta activity.

BACKGROUND: The adrenergic mode of action was investigated for the development of potential new insecticides. Clonidine-related analogs were tested against Myzus persicae (Sulzer) and Bemisia tabaci (Gennadius). Clonidine analogs lack translation owing to a possible vacuole-trapping mechanism. Physical property modulation via a prodrug approach was attempted to overcome this mechanism. RESULTS: Clonidine showed insecticidal activity against M. persicae and B. tabaci. A prodrug of a known open-chain analog of clonidine was developed. While the prodrug had decreased pKa and increased lipophilicity and displayed good activity against M. persicae B. tabaci, the activity did not translate to cotton. Metabolic studies showed that the prodrug was quickly metabolized to the parent compound, and was further metabolized to a known vacuole-trapped oxazoline analog. CONCLUSIONS: Adrenergic active compounds, such as clonidine analogs, show potential as insecticides; however, a designed prodrug approach did not overcome the lack of translation in this case. Studies confirmed that the synthesized prodrug analog metabolized in planta to the proposed vacuole-trapped compound. One possible explanation for the failure of this approach is that the rate of metabolism and vacuole trapping is faster than translaminar flow, and therefore the released pesticide is not biologically available to the target organism. © 2016 Society of Chemical Industry.

Synthesis of Novel Fluoropicolinate Herbicides by Cascade Cyclization of Fluoroalkyl Alkynylimines.

The cascade cyclization of fluoroalkyl alkynylimines with primary amines has been modified to allow the synthesis of 4-amino-5-fluoropicolinates. Use of N-trityl and acetal protecting groups in the cyclization precursor led to 5-fluoropyridines that were easily deprotected to picolinaldehyde derivatives for further elaboration to structures of interest as potential herbicides. This method provided access to picolinic acids with alkyl or aryl substituents at the 6-position that were previously inaccessible via cross-coupling chemistry.

Asymmetric tandem Wittig rearrangement/Mannich reactions.

The choice is yours: a highly stereoselective synthesis of α-alkyl-α-hydroxy-ß-amino esters is accomplished through a tandem Wittig-rearrangement/Mannich reaction sequence. Transformations of N-benzyl or N-Boc imines proceed with high selectivity for formation of syn-amino alcohol derivatives, whereas N-Boc-2-(phenylsulfonyl)amines generate anti-amino alcohol products. Auxiliary cleavage (transesterification or reduction) yields enantiomerically enriched products with up to 96 % ee.

Asymmetric tandem wittig rearrangement/Aldol reactions.

A new method for the asymmetric synthesis of alpha-alkyl-alpha,beta-dihydroxy esters that involves tandem Wittig rearrangement/aldol reactions of O-benzyl- or O-allylglycolate esters derived from 2-phenylcyclohexanol is described. This sequence constructs two C-C bonds and two stereocenters, one of which is quaternary, to afford syn diol products with excellent stereocontrol. Cleavage of the chiral auxiliary affords enantiomerically enriched products with up to 95% ee. The application of this method to the preparation of a key intermediate in the synthesis of the antifungal agent alternaric acid is also described.

Influence of hydroxylamine conformation on stereocontrol in Pd-catalyzed isoxazolidine-forming reactions.

Palladium-catalyzed carboamination reactions between N-Boc-O-(but-3-enyl)hydroxylamine derivatives and aryl or alkenyl bromides afford cis-3,5- and trans-4,5-disubstituted isoxazolidines in good yield with up to >20:1 dr. The diastereoselectivity observed in the formation of cis-3,5-disubstituted isoxazolidines is superior to selectivities typically obtained in other transformations, such as 1,3-dipolar cycloaddition reactions, that provide these products. In addition, the stereocontrol in the C-N bond-forming Pd-catalyzed carboamination reactions of N-Boc-O-(but-3-enyl)hydroxylamines is significantly higher than that of related C-O bond-forming carboetherification reactions of N-benzyl-N-(but-3-enyl)hydroxylamine derivatives. This is likely due to a stereoelectronic preference for cyclization via transition states in which the Boc group is placed in a perpendicular orientation relative to the plane of the developing ring, which derives from the conformational equilibria of substituted hydroxylamines.

Stereoselective synthesis of cis- or trans-3,5-disubstituted pyrazolidines via Pd-catalyzed carboamination reactions: use of allylic strain to control product stereochemistry through N-substituent manipulation.

The stereoselective synthesis of either trans- or cis-3,5-disubstituted pyrazolidines is accomplished via Pd-catalyzed carboamination reactions of unsaturated hydrazine derivatives. The products are obtained in good yield with up to >20:1 diastereoselectivity. Stereocontrol is achieved by modulating the degree of allylic strain in the transition state for syn-aminopalladation through a simple modification of the substrate N(2)-substituent. The pyrazolidine products can be further transformed to 3,5-disubstituted pyrazolines via deprotection/oxidation, or to substituted 1,3-diamines via N-N bond cleavage.