Laura Quaranta

New ventures in the chemistry of avermectins.

An overview is given on recent work towards new avermectin derivatives of extremely high insecticidal and acaricidal activity. These compounds were prepared from commercially available abamectin (avermectin B1) 1. For the synthesis, many novel entries have been opened up, making use of modern synthetic methods and applying them, for the first time, to the chemistry of avermectins. Several types of avermectin derivatives can be regarded as key innovations in the field. These are, in particular, 4-deoxy-4-(S)-amino avermectins 3, 4-O-alkoxyalkyl avermectin monosaccharides 5, 4-deoxy-4-C-substituted 4-amino avermectins 6 and 2-substituted avermectins 7. 4-Deoxy-4-(S)-amino avermectins 3 were obtained by the consecutive application of the Staudinger and Aza-Wittig reaction. 4-O-Alkoxyalkyl avermectin monosaccharides 5 were prepared by alkoxyalkylation of 5-O-protected avermectin monosaccharide. For the synthesis of 4-deoxy-4-C-substituted 4-amino avermectins 6, several methods were used to construct the fully substituted 4-carbon centre, such as a modified Strecker synthesis, the addition of organometallics to a 4-sulfinimine and a modified Ugi approach. In order to prepare 2-substituted avermectins 7, 5-O-protected avermectin monosaccharide was coupled with carbohydrate building blocks. An alternative synthesis involved the hitherto unknown enol ether chemistry of 4-oxo-avermectin and the conjugate addition of a cuprate to an avermectin 2,3-en-4-one. In addition, a number of other highly potent derivatives were synthesised. Examples are 4-O-amino avermectins 8, as well as products arising from intramolecular rhodium catalysed amidations and carbene insertions. A radical cyclisation led to an intriguing rearrangement of the avermectin skeleton. Many of the new avermectins surpassed the activity of abamectin 1 against insects and mites.

A chemical potentiator of copper-accumulation used to investigate the iron-regulons of Saccharomyces cerevisiae

The extreme resistance of Saccharomyces cerevisiae to copper is overcome by 2‐(6‐benzyl‐2‐pyridyl)quinazoline (BPQ), providing a chemical‐biology tool which has been exploited in two lines of discovery. First, BPQ is shown to form a red (BPQ)2Cu(I) complex and promote Ctr1‐independent copper‐accumulation in whole cells and in mitochondria isolated from treated cells. Multiple phenotypes, including loss of aconitase activity, are consistent with copper‐BPQ mediated damage to mitochondrial iron–sulphur clusters. Thus, a biochemical basis of copper‐toxicity in S. cerevisiae is analogous to other organisms. Second, iron regulons controlled by Aft1/2, Cth2 and Yap5 that respond to mitochondrial iron–sulphur cluster status are modulated by copper‐BPQ causing iron hyper‐accumulation via upregulated iron‐import. Comparison of copper‐BPQ treated, untreated and copper‐only treated wild‐type and fra2Δ by RNA‐seq has uncovered a new candidate Aft1 target‐gene (LSO1) and paralogous non‐target (LSO2), plus nine putative Cth2 target‐transcripts. Two lines of evidence confirm that Fra2 dominates basal repression of the Aft1/2 regulons in iron‐replete cultures. Fra2‐independent control of these regulons is also observed but CTH2 itself appears to be atypically Fra2‐dependent. However, control of Cth2‐target transcripts which is independent of CTH2 transcript abundance or of Fra2, is also quantified. Use of copper‐BPQ supports a substantial contribution of metabolite repression to iron‐regulation.

Synthesis and fungicidal activity of quinolin-6-yloxyacetamides, a novel class of tubulin polymerization inhibitors

A novel class of experimental fungicides has been discovered, which consists of special quinolin-6-yloxyacetamides. They are highly active against important phytopathogens, such as Phytophthora infestans (potato and tomato late blight), Mycosphaerella graminicola (wheat leaf blotch) and Uncinula necator (grape powdery mildew). Their fungicidal activity is due to their ability to inhibit fungal tubulin polymerization, leading to microtubule destabilization. An efficient synthesis route has been worked out, which allows the diverse substitution of four identified key positions across the molecular scaffold.

Synthesis and anti-oomycete activity of novel quinazolin- and benzothiazol-6-yloxyacetamides: Potent aza-analogs and five-ring analogs of quinoline fungicides

Novel quinazolin- and benzothiazol-6-yloxyacetamides show excellent in vivo activity against the three economically most important Oomycete pathogens Phytophthora infestans, Plasmopara viticola and Pythium ultimum. They are polar analogs of known quinolin-6-yloxyacetamides, which are not active against the soil-borne damping-off disease caused by Pythium ultimum. The Bogert quinazoline synthesis, an almost forgotten heterocyclization technique, proved to be highly useful for the concise construction of required quinazolin-6-ol building blocks.

The Significance of Organosulfur Compounds in Crop Protection: Current Examples from Fungicide Research

GRAPHICAL ABSTRACT Abstract Approximately 30% of todays agrochemicals contain at least one sulfur atom. This review article highlights the most important reasons for the fundamental role of sulfur functions in crop protection, such as the occurrence of sulfur in agrochemical pharmacophores, the application of sulfur-containing natural products as lead compounds, the role of sulfur in procidal action, fine-tuning of physico-chemical properties and patent breaking as well as the advantage of sulfur-containing heterocycles compared to their nonsulfur ring isosteres. Case studies from three different mode of action classes give proof, how state-of-the-art organosulfur chemistry enables the synthesis and influences the structure-activity relationships of fungicidally active compounds in the classes of Succinate dehydrogenase inhibitors, tubulin polymerization inhibitors and Cellulose synthase inhibitors.