Total synthesis of herbicidin C and aureonuclemycin: impasses and new avenues.

The undecose nucleoside antibiotics herbicidin C and aureonuclemycin are biologically highly active and represent challenging targets for total synthesis. Herein, the gradual evolution of our synthetic strategy toward these natural products is described in detail. The initial route encompasses metalate addition chemistry but suffers from poor stereochemical control. In contrast, the ultimately successful strategy benefits from a variety of reagent-controlled stereoselective transformations, including a surprisingly facile and highly diastereoselective N-glycosylation process. The presented work also describes new building blocks that might find further application in carbohydrate chemistry.

A Study in Scaffold Hopping: Discovery and Optimization of Thiazolopyridines as Potent Herbicides That Inhibit Acyl-ACP Thioesterase.

In the search for new chemical entities that can control resistant weeds by addressing novel modes of action (MoAs), we were interested in further exploring a compound class that contained a 1,8-naphthyridine core. By leveraging scaffold hopping methodologies, we were able to discover the new thiazolopyridine compound class that act as potent herbicidal molecules. Further biochemical investigations allowed us to identify that the thiazolopyridines inhibit acyl-acyl carrier protein (ACP) thioesterase (FAT), with this being further confirmed via an X-ray cocrystal structure. Greenhouse trials revealed that the thiazolopyridines display excellent control of grass weed species in pre-emergence application coupled with dose response windows that enable partial selectivity in certain crops.

Stereoselective total syntheses of herbicidin†C and aureonuclemycin through late-stage glycosylation.

Better late than never! Two herbicidins, members of an important family of nucleoside antibiotics, have been synthesized for the first time. The route integrates a stereoselective C-glycosylation with several reagent-controlled stereoselective transformations and a surprisingly facile and highly diastereoselective late-stage N-glycosylation.

The design, synthesis and screening of a muscarinic acetylcholine receptor targeted compound library.

Potent new agonists of the insect muscarinic acetylcholine receptor (mAChR) have been discovered by synthesizing and screening a library of 225 oxime ether amines. Library evaluation was facilitated by the development of a high throughput test enabling the rapid determination of muscarinic agonist activity. The most interesting compounds were the thiadiazole 17 and the isoxazole 24 which were potent muscarinic agonists (EC50 13 and 21 nM, respectively) and showed lead levels of insecticidal activity.

RCM-mediated synthesis of trifluoromethyl-containing nitrogen heterocycles.

A ring-closing metathesis mediated pathway to trifluoromethyl-containing piperidines is detailed. This involves the development of a synthetic route to a new (trifluoromethyl)allylating reagent via a Diels-Alder/retro-Diels-Alder strategy, its application in the synthesis of a series of trifluormethyl-substituted diolefin precursors for ring-closing metathesis, and eventually the successful cyclization of these precursor molecules into the corresponding functionalized piperidines.