Scaffold Hopping in Agrochemical Research: Discovery of Insecticidal 4-Pyridyl Isobenzofurans.

The insecticidal activity of pyridine compounds substituted at the 4-position with lipophilic groups has been reported in recent agrochemical patent applications. Encouraged by these reports, 4-pyridyl dihydroisobenzofuran(one)s were designed to test scaffold-hopping hypotheses with the goal of discovering new insecticidally active areas of chemistry. A series of 4-pyridyl dihydroisobenzofuran(one)s were synthesized, and their activity against key sap-feeding insect pests (silverleaf whitefly, Bemisia tabaci; green peach aphid, Myzus persicae) was assessed. Many of these compounds showed strong activity (comparable to commercial standards) against B. tabaci and were also active against M. persicae, although activity on this pest was somewhat weaker. Investigative biology studies indicated that these compounds were active on early life stages of B. tabaci but lacked significant activity on adults.

Discovery of novel insecticidal 3-aminopyridyl ureas.

BACKGROUND: Commercial compound databases represent rich sources of potential starting points for pharmaceutical and agrochemical product development. Routine insecticidal screening of compounds ordered from these sources led to the identification of a 3-aminopyridyl urea with activity against Myzus persicae (Sulzer) (green peach aphid). Based on this activity and its structural novelty, further exploration of the chemical space around this hit was initiated. RESULTS: A series of ureas based on the structure of the initial hit were synthesized and screened for insecticidal activity. A broad range of tail groups derived from cyclic secondary amines were explored, and many of these compounds were found to be insecticidally active. However, only compounds featuring a 3-aminopyridine or 4-aminopyridazine head group exhibited significant insecticidal potency. Although activity against M. persicae was consistently observed, these ureas were largely inactive against another key sap-feeding insect pest, Bemisia tabaci (Glennadius) (sweetpotato whitefly). CONCLUSIONS: Follow-up of an insecticide hit identified from commercial compound acquisition led to the discovery of a novel class of ureas with activity against M. persicae. Despite considerable effort to identify related compounds with additional insecticidal spectrum, however, activity on other important pests remains limited. © 2019 Society of Chemical Industry.

Physicochemical property guidelines for modern agrochemicals.

The relentless need for the discovery and development of new agrochemicals continues as a result of driving forces such as loss of existing products through the development of resistance, the necessity for products with more favorable environmental and toxicological profiles, shifting pest spectra, and the changing agricultural needs and practices of the farming community. These new challenges underscore the demand for novel, high-quality starting points to accelerate the discovery of new agrochemicals that address market challenges. This article discusses the efforts to identify the optimum ranges of physicochemical properties of agrochemicals through analysis of modern commercial products. Specifically, we reviewed literature studies examining physicochemical property effects and analyzed the properties typical of successful fungicides, herbicides, and insecticides (chewing and sap-feeding pests). From the analysis, a new set of physicochemical property guidelines for each discipline, as well as building block class, are proposed. These new guidelines should significantly aid in the discovery of next-generation agrochemicals. © 2018 Society of Chemical Industry.

Insecticidal activity of novel thioureas and isothioureas.

BACKGROUND: We hypothesized that the exploration of chemical space around compounds with reported insecticidal activity could be a viable strategy for discovering novel, insecticidally active areas of chemistry. RESULTS: A series of thioureas and isothioureas were prepared as part of a scaffold-hopping effort around known insecticidal compounds. Many of these compounds showed excellent activity against key sap-feeding insect pests in insecticidal bioassays. While analogs bearing monocyclic thiophene head groups showed activity against Myzus persicae (green peach aphid), analogs with diarylethane head groups were active against both M. persicae and Bemisia tabaci (sweetpotato whitefly). Despite compelling activity in these laboratory tests, these compounds showed diminished activity when applied to host plants via tracksprayer. CONCLUSIONS: The initial hypothesis that structural modification of molecules reported to have insecticidal activity would yield novel compounds that also exhibit insecticidal activity was validated. Despite excellent activity in laboratory bioassays, these new compounds failed to show compelling activity in more demanding tracksprayer tests. © 2016 Society of Chemical Industry.

Synthesis of the A-B subunit of angelmicin B.

[reaction: see text] An efficient synthesis of the tricyclic A-B subunit 2 of angelmicin B is described. A formal three-component coupling of aldehydes 4 and 6 with gamma-silylallylborane 7 was employed to assemble the tetrahydrofuranyl core of 2, a strategy highlighted by the stereoselective [3 + 2] annulation of allylsilanes 5a/5b with aldehyde 4. The efficiency of the [3 + 2] annulation was greatly improved by using the allylic benzhydryldimethylsilane 5b compared to the allylic phenyldimethylsilane 5a.

Halichondrin B: synthesis of the C1-C22 subunit.

[Reaction: see text]. Two efficient routes to the C1-C22 subunit of halichondrin B are described. The cage ketal 7, which contains 11 asymmetric centers embedded within the ABCDEF-ring framework, was assembled from (+)-conduritol E (27) in 18 steps and 4% overall yield. In a separate route, 7 was also synthesized in 18 steps and 2% overall yield from a derivative of alpha-d-glucoheptonic acid gamma-lactone (62). While the former route installs the fully elaborated C-ring endowed with the correct C12 stereochemistry early in the synthesis, the latter features a late-stage introduction of the C12 stereocenter during the ultimate one-pot Michael addition/ketalization cascade to form the CDE-ring system of the cage. The importance of the C12 stereocenter to the crucial ketalization event is discussed through comparison of these two strategies.

Efficient protiodesilylation of unactivated C(sp3)-SiMe2Ph bonds using tetrabutylammonium fluoride.

[reaction: see text] The protiodesilylation of unactivated C(sp3)-SiMe2Ph bonds proceeds efficiently by treatment with tetrabutylammonium fluoride in wet DMF or THF via isolable dimethylsilanol intermediates.

A comparison of the ring conformational properties of two derivatives prepared from the same diene diacetate precursor.

Results of single-crystal X-ray experiments performed for the title compounds, (1S,2R,3S,4R,5R)-4-benzyloxy-2-[1-(benzyloxy)allyl]-5-hydroxymethyl-2,3,4,5-tetrahydrofuran-3-ol, C(22)H(26)O(5), (I), and (3R,5S,6S,7S,8S)-3,6-bis(benzyloxy)-5-iodomethyl-2,3,4,5-tetrahydrofuro[3,2-b]furan-2-one, C(21)H(21)IO(5), (II), demonstrate that the tetrahydrofuran ring that is common to both structures adopts a different conformation in each molecule. Structural analyses of (I) and (II), which were prepared from the same precursor, indicate that their different conformations are caused by hydrogen-bonding interactions in the case of (I) and the presence of a fused bicyclic ring system in the case of (II). Density functional theory calculations on simplified analogs of (I) and (II) are also presented.

Halichondrin B: synthesis of a C1-C14 model via desymmetrization of (+)-conduritol E.

[reaction: see text] A model C1-C14 segment (1) of halichondrin B was synthesized from (+)-conduritol E (7) in 18 steps and 2.9% overall yield. Key features of the synthesis include the novel ozonolytic desymmetrization of C(2)-symmetric diol 6, the early-stage construction of the C-ring which accompanies installation of the crucial C12 stereocenter, and the use of an enol ether C14-ketone surrogate as a precursor to the CDE-"caged" ketal.