The Front Cover shows shows the influence of reaction solvent on the reaction of purin-2-yl Grignards with carbonyl compounds. In the ether (THF), the reaction gives 8-carbinol products due to a rapid isomerisation to the purin-8-yl, whereas performing the reaction in dichloromethane stops the isomerisation and yields 2-carbinols in good yields. In contrast to aldehydes, reactions with ketones require prior complexation with LaCl3.2LiCl before addition to the Grignard reagent. More information can be found in the Full Paper by M. R. Gordon, S. Gazzola et al.

The generation of positionally stable purin-2- and 6-yl magnesium halides is complicated by the often very rapid isomerization to give the 8-yl Grignards. By conducting the reaction in dichloromethane (DCM), we demonstrated that the anion isomerization can be stopped and these stable purin-2- and 6-yl Grignards react directly with a broad scope of aldehydes in good yields. Furthermore, purine functionalization with ketones has been achieved for the first time in the presence of LaCl3 center dot 2LiCl. Density functional theory calculations offer a possible explanation of the special role played by solvent in this chemistry and show that in DCM the C-Mg bond has a less polar character, whereas in THF it is predominantly ionic and much more basic in nature.

Mode of action studies showed that 5-methyl-N,N-bis[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-amine (4), a representative from a new class of herbicidal tris-pyridyl amines, is an inhibitor of cellulose biosynthesis (CB). The compound undergoes an oxidative photocyclization, when exposed to UV-B light (300-340 nm) in the presence of oxygen, to give a new class of herbicidal pyrrolodipyridines. These compounds are potent inhibitors of the herbicide target enzyme phytoene desaturase and no longer inhibit CB.

Inhibitors of the enzyme adenosine monophosphate deaminase (AMPD) show interesting levels of herbicidal activity. An enzyme mechanism-based approach has been used to design new inhibitors of AMPD starting from nebularine (6) and resulting in the synthesis of 2-deoxy isonebularine (16). This compound is a potent inhibitor of the related enzyme adenosine deaminase (ADA; IC50 16 nM), binding over 5000 times more strongly than nebularine. It is proposed that the herbicidal activity of compound 16 is due to 5́-phosphorylation in planta to give an inhibitor of AMPD. Subsequently, an enzyme structure-based approach was used to design new non-ribosyl AMPD inhibitors. The initial lead structure was discovered by in silico screening of a virtual library against plant AMPD. In a second step, binding to AMPD was further optimised via more detailed molecular modeling leading to 2-(benzyloxy)-5-(imidazo[2,1-f][1,2,4]triazin-7-yl)benzoic acid (36) (IC50 300 nM). This compound does not inhibit ADA and shows excellent selectivity for plant over human AMPD.

Treatment of a solution of a 9-alkyl- or 9-aryl-2-iodopurine in dichloromethane with an ethereal solution of ethylmagnesium bromide at –5 °C generates the corresponding purin-2-ylmagnesium bromide, which reacts with aldehydes to give the corresponding 2-(hydroxyalkyl)purines in yields of 53–84%. The purin-2-yl Grignard reagents show good functional-group tolerance to ester and nitro groups, and the method permits the synthesis of the previously unknown 6-unsubstituted 2-magnesiopurines for the first time. Performing the same procedure in THF as solvent resulted either in extensive decomposition or rapid isomerization to give purin-8-ylmagnesium halides.

Resistance to 157 different herbicides and 88% of known sites of action has been observed, with many weeds resistant to two or more modes. Coupled with tighter environmental regulation, this demonstrates the need to identify new modes of action and novel herbicides. The plant sphingolipid biosynthetic enzyme, inositol phosphorylceramide synthase (IPCS), has been identified as a novel, putative herbicide target. The non-mammalian nature of this enzyme offers the potential of discovering plant specific inhibitory compounds with minimal impact on animals and humans, perhaps leading to the development of new non-toxic herbicides. The best characterised and most highly expressed isoform of the enzyme in the model-dicot Arabidopsis, At IPCS2, was formatted into a yeast-based assay which was then utilized to screen a proprietary library of over 11,000 compounds provided by Bayer AG. Hits from this screen were validated in a secondary in vitro enzyme assay. These studies led to the identification of a potent inhibitor that showed selectivity for At IPCS2 over the yeast orthologue, and activity against Arabidopsis seedlings. This work highlighted the use of a yeast-based screening assay to discover herbicidal compounds and the status of the plant IPCS as a novel herbicidal target.

Treatment of a dichloromethane solution of 9-benzyl or 9-phenyl 6-iodopurine with ethereal ethylmagnesium bromide at ambient temperature gives the corresponding purin-6-yl magnesium halides. Addition of an aldehyde followed by heating at 100 degrees C in a microwave reactor yielded the corresponding carbinols in 52-81% yield. (C) 2018 Elsevier Ltd. All rights reserved.

Trifluoromethyl vinyl sulfide, a potential building block for pharmaceutically and agrochemically relevant products, is prepared and used for the first time in high-pressure-mediated 1,3-dipolar cycloaddition reactions with nitrones to synthesize (trifluoromethyl)sulfanyl isoxazolidines.

A cyanoborohydride-promoted radical cyclization methodology has been developed to access α-chlorolactams in a simple and efficient way using NaBH3 CN and trichloroacetamides easily available from allylic and homoallylic secondary amines. This methodology allowed the synthesis of a library of α-chlorolactams (mono- and bicyclic), which were tested for herbicidal activity, trans-3-chloro-4-methyl-1-(3-trifluoromethyl)phenyl-2-pyrrolidinone being the most active.

Treatment of a solution of 9-benzyl or 9-phenyl 6-iodopurine in dichloromethane with an ethereal solution of ethylmagnesium bromide at ambient temperature generates the corresponding purin-6-yl magnesium halides which react with aldehydes to give carbinols in 55–80% yield. Performing the same procedure with THF as solvent gave carbinols in much lower yields (≤15%).

Modern agricultural practices are facing a major challenge to their sustainability due to the worldwide spread of herbicide resistant weeds. To combat this problem, it is important that existing herbicides are preserved and that new herbicidal solutions are developed. Herbicide-safener combinations, as exemplified by the HPPD inhibitor pyrasulfotole, which is sold as a mixture with the safener mefenpyr-diethyl for broadleaf weed control in cereals, offer a new way to manage resistance issues. The safener ensures good crop selectivity, which had previously been problematic with this mode of action (MoA) and had prevented the use of HPPD chemistry in cereals. This represents the first new MoA introduced into cereal cultivation for over 20 years and provides cereal farmers with a valuable tool for the management of resistant weed populations. The usage has been extended to enable the control of herbicide resistant Amaranths in grain sorghum.

Securing food security for 9 billion people in 2050, addressing the realities of climate change and reduced resources such as land and water are the “Grand Challenges” facing feeding the world today1. Over the past fifty years, very significant advances have been made in improving agricultural productivity; however, resistance issues are currently threatening some of these hard won gains. Successfully combating resistance will be an essential component of securing food security and protecting the food we have from pests such as insects, nematodes, fungi and weeds. If ignored, pest resistance will significantly reduce worldwide agricultural production at a time when crop yields have to increase in order to feed everyone healthily and equitably. This special edition of the Journal of Chemical Biology highlights the role chemical biology plays in addressing the challenges associated with combating chemical resistance in agriculture. The articles are from a symposium entitled “Biological and Chemical Approaches Towards Combating Resistance in Agriculture” which was sponsored by the Biological and Medicinal Chemistry Sector and Chemical Biology Interface Division of the Royal Society of Chemistry, in partnership with the AGRI-net, Bayer CropScience, Syngenta and the Biochemical Society. The symposium was held at Imperial College, London on the 26th of September 2013. Unusually, it brought together expert scientists from all three of the most important resistance areas, namely fungal, insect, and plant (weed) resistance. The special edition features six papers from authors who participated in the London symposium. The articles exemplify the diversity of science needed to combat resistance, ranging from modelling and prediction (van Westen), metabolism (Parker et al.) and biochemistry (Hahn) to molecular characterisation of complex receptors (Crossthwaite et al.) and how herbicide resistance parallels can be drawn between insecticide and fungicide resistance mechanisms (Strek). Chemical Biology is developing rapidly as a scientific discipline in agricultural research; it relies on the integration of a wide range of scientific disciplines and has been greatly facilitated by the creation of a BBSRC-funded network in agricultural chemical biology, the AGRI-Net, who co-hosted the symposium. It also relies on the availability of chemical and biological tools to generate and test hypotheses. The article by Torsten Meiners on EU-OPENSCREEN illustrates an exciting opportunity for researchers to access chemical and screening tools across the European Union. This enables the creation of a chemical biology infrastructure facilitating research in plant biology, ecology, marine, and microbial biology. Gerard van Weken from EMBL writes about another tool needed to realise the potential of chemical biology in agriculture: molecular modelling. He discusses proteochemometric modelling (PCM) as an aid in the quantification and prediction of resistance, comparing the opportunity to the successful application of PCM in medicinal chemistry. Along with a toolkit, we also need knowledge of the molecular mechanisms of resistance. Andrew Crossthwaite and his colleagues from Syngenta illustrate the challenges associated with combatting Neonicotinoid resistance where we do not have a key piece of knowledge; how the target protein, the multi-meric nicotinic acetylcholine receptor, nAChR, assembles in vivo. To date, no one has successfully expressed a multi-meric insect nAChR in a heterologous cell system. Despite this, we know a lot about both metabolic and target-site resistance to Neonicotinoids. The paper discusses both mechanisms and focuses on the complexity of the system and the implications for chemical design. Harry Strek from Bayer CropScience also discussed the mechanisms of resistance but this time focusing on herbicides and how other disciplines have influenced herbicide resistance research. Weed resistance is such a big issue that some farmers in the USA have gone back to mechanical weeding, despite the negative implications in terms of cost and soil erosion which this entails. This paper raises the spectre that herbicide resistance threatens modern agriculture and could be as problematic as late potato blight and the spread of Colorado potato beetle in the past. Without modern herbicides, crop yields will not be sufficient to address the challenges we face in feeding a growing population. The final two papers in this special edition focus on fungicide resistance. In the past, infection by fungal pathogens has caused major crop failures resulting in widespread famine. These pathogens are still present in our fields but are held in check by the application of fungicides. Matthias Hahn discusses the rising threat of fungicide resistance using Botrytis as a case study, which illustrates the diversity of metabolic mechanisms underpinning resistance. During the symposium, Steve Kelly focused on the resistance mechanisms of the azole fungicides that act on the P450 enzyme CYP51. This important mode-of-resistance work is detailed in the paper by Parker et al. The symposium was unique in bringing together over 70 delegates from both industry and academia to focus on the issues associated with agrochemical resistance, and the role chemical biology can play in finding solutions. This special edition of the Journal is intended to stimulate informed scientific debate by highlighting the challenges we face in combatting resistance and its impact upon the grand challenge of feeding an increasing world population.

Combinatorial and parallel chemistry concepts and techniques have a large impact upon the way in which the search for new biologically active lead structures is conducted in modern laboratories. Typically, a library of compounds, synthesized using these techniques, is screened against a biological target to identify small molecule hits which inhibit the target. These are then further elaborated to optimize biological potency and generate lead structures. The way in which the compound library is designed or selected is a key criterion for determining the eventual success of such a research process. Although most libraries will give biological hits, not all small molecule hit structures are suitable for further optimization into leads. The chapter discusses the important concepts, including bioavailability, chemical space, and privileged structures, which are important in successful library design. Modern fragment-, ligand-, and structure-based design approaches are compared and the differences and synergies, strengths and weaknesses are analyzed. Throughout the chapter the most important concepts and methodologies are illustrated using examples taken from the recent literature.

Aspercyclide A (1) is a biaryl ether containing 11-membered macrocyclic natural product antagonist of the human IgE-FcεRI protein-protein interaction (PPI); a key interaction in the signal transduction pathway for allergic disorders such as asthma. Herein we report a novel approach to the synthesis of the C19 methyl ether of aspercyclide A, employing a Pd(0)-catalysed, fluorous-tagged alkenylgermane/arylbromide macrocyclisation (germyl-Stille reaction) as the key step, and evaluation of both enantiomers of this compound via ELISA following optical resolution by CSP-HPLC. A crystal structure for germyl hydride 27 is also reported.

The solid-phase synthesis of 3-aryl-7-amino imidazotriazines 5 via palladium-­catalyzed direct arylation was achieved. Thus, 7-amino imidazotriazines 4 were prepared by reductive amination of resin support 1 with alkyl amines followed by coupling with 3. The arylation of triazines 4 with aryl bromides in the presence of Pd(OAc)2, Ph3P, and AcOK in DMA afforded the resin-supported 3-aryl-7-amino imidazotriazines which were subject to the resin cleavage to give 5 in 16-91% overall yield (20 examples).

ADVERTISEMENT RETURN TO ISSUEPREVReportNEXTSynthesis of a Solid-Phase Amino Imidazotriazine Library via Palladium Catalyzed Direct ArylationSimon Maechling*, James Good, and Stephen D. Lindell*View Author Information Bayer CropScience GmbH, Werk Höchst, G836, D-65926, Frankfurt am Main, Germany* To whom correspondence should be addressed. E-mail: [email protected] (S.M.) or [email protected] (S.D.L.).Cite this: J. Comb. Chem. 2010, 12, 6, 818–821Publication Date (Web):September 29, 2010Publication History Received5 August 2010Published online29 September 2010Published inissue 8 November 2010https://doi.org/10.1021/cc1001617Copyright © 2010 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views623Altmetric-Citations9LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (297 KB) Supporting Info (2)»Supporting Information Supporting Information SUBJECTS:Aromatic compounds,Chemical reactions,Organic polymers,Organic reactions,Solid phase synthesis Get e-Alerts

The total syntheses of (+/-)-aspercyclide A (1) and its C19 methyl ether (15a) featuring Heck-Mizoroki macrocyclisation to form the 11-membered (E)-styrenyl biaryl ether lactone core are described.