The new age of insecticide discovery-the crop protection industry and the impact of natural products.

Improvements in food production and disease vector control, to feed and protect an expanding global population, require new options and approaches for insect control. A changing and an increasingly stringent regulatory landscape, shifts in pest spectrum due to changes in agronomic practices, and insect resistance to existing insecticides, all contribute to the challenges of, and need for, developing new insect control agents. The nature of insecticides emanating from discovery R&D-based companies in the European Union, Japan, and the United States have evolved from a concentration on a few classes of insecticides and modes of action (MoA), to a far more diversified collection of insecticidal molecules that embody many new, or under-utilized MoAs. Since 1990 there has arguably been a new age of insecticide discovery, with more new classes of insecticides introduced, with greater economic impact, than the prior 50 years combined. Although there has been an on-going evolution and consolidation in the size and shape of the crop protection industry, for the past two decades the output of new insecticides has remained relatively constant. The diversity of approaches employed in the insecticide discovery process (competitor inspired, bioactive hypothesis and natural products) has contributed to the discovery of these new classes of insecticides. Insecticide discovery is today a global enterprise, that armed with new tools and capabilities, will continue to build and provide the future insect control products to meet global grower and consumer demands.

Studies toward understanding the SAR around the sulfoximine moiety of the sap-feeding insecticide sulfoxaflor.

BACKGROUND: The discovery of sulfoxaflor (Isoclast™ active) stemmed from a novel scaffold-based approach toward identifying bioactive molecules. It exhibits broad-spectrum control of many sap-feeding insect pests, including aphids, whiteflies, hoppers and Lygus. Systematic modifications of the substituents flanking each side of the sulfoximine moiety were carried out to determine whether these changes would improve potency. RESULTS: Structure-activity relationship (SAR) studies showed that, with respect to the methylene linker, both mono- and disubstitution with alkyl groups of varying sizes as well as cyclic analogs exhibited excellent control of cotton aphids. However, against green peach aphids a decrease in activity was observed with substituents larger than ethyl as well as larger cycloalkyl groups. At the terminal tail there appeared to be a narrow steric tolerance as well, with linear groups or small rings more active against green peach aphids than bulkier groups. CONCLUSION: A novel series of compounds exploring the substituents flanking the sulfoximine moiety of sulfoxaflor were prepared and tested for bioactivity against cotton aphids and green peach aphids. SAR studies indicated that a decrease in green peach aphid potency was observed at the methylene linker as well as at the terminal tail with bulkier substituents. A quantitative structure-activity relationship analysis of the compounds revealed significant correlation of activity with two molecular descriptors, vol (volume of a molecule) and GCUT_SMR_3 (molar refractivity). This predictive model helps to explain the observed activity with the various substituents. © 2016 Society of Chemical Industry.

SAR studies directed toward the pyridine moiety of the sap-feeding insecticide sulfoxaflor (Isoclast™ active).

Sap-feeding insect pests constitute a major insect pest complex that includes a range of aphids, whiteflies, planthoppers and other insect species. Sulfoxaflor (Isoclast™ active), a new sulfoximine class insecticide, targets sap-feeding insect pests including those resistant to many other classes of insecticides. A structure activity relationship (SAR) investigation of the sulfoximine insecticides revealed the importance of a 3-pyridyl ring and a methyl substituent on the methylene bridge linking the pyridine and the sulfoximine moiety to achieving strong Myzus persicae activity. A more in depth QSAR investigation of pyridine ring substituents revealed a strong correlation with the calculated logoctanol/water partition coefficient (SlogP). Model development resulted in a highly predictive model for a set of 18 sulfoximines including sulfoxaflor. The model is consistent with and helps explain the highly optimized pyridine substitution pattern for sulfoxaflor.

Adaptation of a small-molecule hydrogen-bond donor catalyst to an enantioselective hetero-Diels-Alder reaction hypothesized for brevianamide biosynthesis.

Chiral diamine-derived hydrogen-bond donors were evaluated for their ability to effect stereocontrol in an intramolecular hetero-Diels-Alder (HDA) reaction hypothesized in the biosynthesis of brevianamides A and B. Collectively, these results provide proof of principle that small-molecule hydrogen-bond catalysis, if even based on a hypothetical biosynthesis construct, holds significant potential within enantioselective natural product synthesis.

Expanding the structure-activity relationship of sulfoxaflor: the synthesis and biological activity of N-heterocyclic sulfoximines.

BACKGROUND: Sulfoxaflor, a new insect control agent developed by Dow AgroSciences, exhibits broad-spectrum control of many sap-feeding insect pests, including aphids, whiteflies, leafhoppers, planthoppers and lygus bugs. During the development of sulfoxaflor, structure-activity relationship (SAR) exploration of the sulfoximine functional group revealed that the nature of the sulfoximine nitrogen substituent significantly affects insecticidal acitivity. As part of the investigation to probe the various electronic, steric and lipophilic parameters at this position, a series of N-heterocyclic sulfoximines were synthesized and tested for bioactivity against green peach aphid. RESULTS: Using a variety of chemistries, the nitrile substituent was replaced with different substituted five- and six-membered heterocycles. The compounds in the series were then tested for insecticidal acitivty against green peach aphid in foliar spray assays. In spite of the larger steric demand of these substituents, the resulting N-heterocyclic sulfoximine analogs displayed good levels of efficacy. In particular, the N-thiazolyl sulfoximines exhibited the greatest activity, with LC50 values as low as 1 ppm. CONCLUSIONS: The novel series of N-heterocyclic sulfoximines helped to advance the current knowledge of the sulfoxaflor SAR, and demonstrated that the structural requirement for the sulfoximine nitrogen position was not limited to small, electron-deficient moeities, but rather was tolerant of larger functionality.

Discovery and characterization of sulfoxaflor, a novel insecticide targeting sap-feeding pests.

The discovery of sulfoxaflor [N-[methyloxido[1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]-λ(4)-sulfanylidene] cyanamide] resulted from an investigation of the sulfoximine functional group as a novel bioactive scaffold for insecticidal activity and a subsequent extensive structure-activity relationship study. Sulfoxaflor, the first product from this new class (the sulfoximines) of insect control agents, exhibits broad-spectrum efficacy against many sap-feeding insect pests, including aphids, whiteflies, hoppers, and Lygus, with levels of activity that are comparable to those of other classes of insecticides targeting sap-feeding insects, including the neonicotinoids. However, no cross-resistance has been observed between sulfoxaflor and neonicotinoids such as imidacloprid, apparently the result of differences in susceptibility to oxidative metabolism. Available data are consistent with sulfoxaflor acting via the insect nicotinic receptor in a complex manner. These observations reflect the unique structure of the sulfoximines compared with neonicotinoids.

Chiral proton catalysis: a catalytic enantioselective direct aza-Henry reaction.

Despite Nature's longstanding ability to use a proton, the most prevalent Lewis acid, to both activate and orient a substrate during an enantioselective reaction, this work represents the first example of this phenomenon outside of a protein. A chiral, nonracemic BisAMidine (BAM) ligand was designed, synthesized, and complexed to the proton of a Brønsted acid. The resulting coordination compound catalyzed the production of enantioenriched product from the combination of a Schiff base and nitroalkane (the aza-Henry reaction). This particular reaction is also considered a model for many analogous carbon-carbon bond-forming reactions catalyzed by enzymes (e.g., the Mannich reaction). This discovery suggests the use of ionic hydrogen bonds in asymmetric catalysis may not only be more general than previously thought, but also a viable "green" approach to single-enantiomer organic compounds.

Free radical-mediated vinyl amination: access to N,N-dialkyl enamines and their beta-stannyl and beta-thio derivatives.

[reaction: see text] The first examples of free radical-mediated vinyl amination are described by nonconventional vinyl radical addition to azomethine nitrogen. This new vinyl amination protocol is mild and provides convenient synthetic access to nonstabilized N,N-dialkyl enamines and tandem bond-forming processes.