Improvements in the efficacy and spectrum of the spinosyns, novel fermentation derived insecticide, has long been a goal within Dow AgroSciences. As large and complex fermentation products identifying specific modifications to the spinosyns likely to result in improved activity was a difficult process, since most modifications decreased the activity. A variety of approaches were investigated to identify new synthetic directions for the spinosyn chemistry including several explorations of the quantitative structure activity relationships (QSAR) of spinosyns, which initially were unsuccessful. However, application of artificial neural networks (ANN) to the spinosyn QSAR problem identified new directions for improved activity in the chemistry, which subsequent synthesis and testing confirmed. The ANN-based analogs coupled with other information on substitution effects resulting from spinosyn structure activity relationships lead to the discovery of spinetoram (XDE-175). Launched in late 2007, spinetoram provides both improved efficacy and an expanded spectrum while maintaining the exceptional environmental and toxicological profile already established for the spinosyn chemistry.

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The reaction of allyl chloride (7), at -40 °C to -20 °C, with in situ generated phenylsulfenyl chloride (6) affords exclusively the anti-Markovnikov product 1,3-dichloro-2-(phenylthio)propane (8) in 85-90% yield. Oxidation of 8 with 1 equiv of MCPBA to sulfoxide 9 followed by DBU-catalyzed dehydrochlorination yields 3-chloro-2-(phenylsulfinyl)-l-propene (Id) (70%). Treatment of 8 with 2 equiv of MCPBA yields sulfone 10 which is similarly dehydrochlorinated to 3-chloro-2-(phenylsulfonyl)-l-propene (le) (81%). The reaction of pyrrolidine enamines of cyclic ketones with Id and 1.1 equiv of triethylamine in Me2SO at 95-100 °C affords moderate yields of bicyclic keto thioenol ethers, formed via an , '-annelation-Pummérer reaction sequence, together with noncyclized, 2-(phenylsulfinyl)allylated ketone. Similar reactions with le provide good yields of bicyclic keto sulfones as approximate 1:1 mixtures of endo and exo isomers, which may be equilibrated to mixtures containing predominantly the exo compounds by treatment with methanolic sodium methoxide.

An asymmetric enantioselective aryl transfer reaction was developed to give access to the diarylmethanol 7 and ultimately acetate 2 which is useful for the preparation of mGlu2 receptor potentiators (Scheme 3). The aryl transfer chemistry involved the preparation of a proposed arylalkylzinc species 14 from boroxine 16 and diethylzinc (DEZ), and reacting this mixture with aldehyde 5 in the presence of chiral ligand 15. During the course of optimizing the preparations of proposed intermediate 14 and diarylmethanol 7, an understanding of optimal stoichiometry and reaction times was gained through empirical observation, the use of solution IR, and analyzing off-gases via real time gas analysis/mass spectroscopy. The preparation of diarylmethanol 7 and subsequent conversion into acetate 2 required carefully selected workups, selective extractions, and azeotropic distillations to generate a series of stock solutions to accommodate oil intermediates that finally gave acetate 2 as a crystalline solid with >99% ee.