Synthesis and insecticidal activity of N-(5-phenylpyrazin-2-yl)-benzamide derivatives: Elucidation of mode of action on chitin biosynthesis through symptomology and genetic studies.

Among the six-membered heterocycles, the pyrazine ring is poorly explored in crop protection and does not feature in any product listed in the current IRAC MoA classification. In an effort to identify new leads for internal research, we synthesized a series of N-(5-phenylpyrazin-2-yl)-benzamide derivatives and evaluated them for their insecticidal activity. N-(5-phenylpyrazin-2-yl)-benzamide derivatives 3 were prepared using an automated two-step synthesis protocol. These compounds were tested for their initial biological activity against a wide range of sucking and chewing insect pests and found to be active against lepidopterans only. More detailed experiments, including symptomology studies on the diamondback moth, Plutella xylostella (L.) and the Egyptian cotton leafworm, Spodoptera littoralis (Boisduval) showed that analog 3q causes severe abnormalities in the lepidopteran cuticle leading to larval mortality. Compound 3q shows strong potency against both P. xylostella and S. littoralis, whereas analog 3i shows better potency against S. littoralis causing also impaired cuticular structure and death of the larvae. Additionally, P. xylostella genetic studies showed that compound 3q resistance is linked to Chitin Synthase 1. Our studies show that N-(5-phenylpyrazin-2-yl)-benzamide derivatives 3, and in particular analogs 3i and 3q, act as insect growth modulator insecticides. Conformational similarities with lufenuron are discussed.

An Active Member of the EFMC: The Division of Medicinal Chemistry and Chemical Biology of the Swiss Chemical Society.

The Division of Medicinal Chemistry and Chemical Biology (DMCCB) of the Swiss Chemical Society is an active contributor to the dynamics of the Swiss and European scientific communities. Founded in 1987, it pursues its mission to foster relationships among its academic and industrial members, to facilitate exchange by organizing symposia and courses, and to encourage scientific excellence. This article presents the DMCCB and highlights both its offer to the community and its participation in the activities of EFMC, the European Federation for Medicinal chemistry and Chemical biology.

Structural Biology-Guided Design, Synthesis, and Biological Evaluation of Novel Insect Nicotinic Acetylcholine Receptor Orthosteric Modulators.

The development of novel and safe insecticides remains an important need for a growing world population to protect crops and animal and human health. New chemotypes modulating the insect nicotinic acetylcholine receptors have been recently brought to the agricultural market, yet with limited understanding of their molecular interactions at their target receptor. Herein, we disclose the first crystal structures of these insecticides, namely, sulfoxaflor, flupyradifurone, triflumezopyrim, flupyrimin, and the experimental compound, dicloromezotiaz, in a double-mutated acetylcholine-binding protein which mimics the insect-ion-channel orthosteric site. Enabled by these findings, we discovered novel pharmacophores with a related mode of action, and we describe herein their design, synthesis, and biological evaluation.

Catalytic enantiospecific [3+2] annulation of aminocyclopropanes with ketones.

An almost familiar ring: The first enantiospecific [3+2] annulation of donor-acceptor aminocyclopropanes with ketones is reported (see scheme; Phth=phthaloyl). The reaction is catalysed by tin(IV) chloride (5 mol %) at -78 °C and gives aminotetrahydrofurans bearing a quaternary C5 atom in high yield, diastereoselectivity and enantiospecificity (see scheme).

Iron-catalyzed [3 + 2] annulation of aminocyclopropanes with aldehydes: stereoselective synthesis of aminotetrahydrofurans.

The first method for the [3 + 2] annulation of donor-acceptor aminocyclopropanes with aldehydes is reported. The reaction is catalyzed by iron trichloride on alumina in yields up to 99% and with excellent cis selectivities (up to >20:1) and represents a stereoselective and atom economic access to valuable 2-aminotetrahydrofurans, which constitute the core of DNA and RNA.

Formal homo-Nazarov and other cyclization reactions of activated cyclopropanes.

The Nazarov cyclization of divinyl ketones gives access to cyclopentenones. Replacing one of the vinyl groups by a cyclopropane leads to a formal homo-Nazarov process for the synthesis of cyclohexenones. In contrast to the Nazarov reaction, the cyclization of vinyl-cyclopropyl ketones is a stepwise process, often requiring harsh conditions. Herein, we describe two different approaches for further polarization of the three-membered ring of vinyl-cyclopropyl ketones to allow the formal homo-Nazarov reaction under mild catalytic conditions. In the first approach, the introduction of an ester group α to the carbonyl on the cyclopropane gave a more than tenfold increase in reaction rate, allowing us to extend the scope of the reaction to non-electron-rich aryl donor substituents in the ß position to the carbonyl on the cyclopropane. In this case, a proof of principle for asymmetric induction could be achieved using chiral Lewis acid catalysts. In the second approach, heteroatoms, especially nitrogen, were introduced ß to the carbonyl on the cyclopropane. In this case, the reaction was especially successful when the vinyl group was replaced by an indole heterocycle. With a free indole, the formal homo-Nazarov cyclization on the C3 position of indole was observed using a copper catalyst. In contrast, a new cyclization reaction on the N1 position was observed with Brønsted acid catalysts. Both reactions were applied to the synthesis of natural alkaloids. Preliminary investigations on the rationalization of the observed regioselectivity are also reported.

Organocatalytic stereoselective alpha-alkylation of aldehydes with stable carbocations.

The organocatalytic stereoselective alkylation of aldehydes is carried out with the four stable carbocations 1-4 in the presence of a catalytic amount (20 mol%) of MacMillan imidazolidinones 5-6. In all reactions, lutidine was used as a base. The alkylation reactions are investigated at different temperatures with linear and branched aldehydes. In the case of carbocation tropylium fluoroborate, an interesting reversal of alkylation product configuration was observed, which is driven by entropic effects in the reaction. The absolute configuration of the products obtained is determined by chemical correlation and found to be in general agreement with the model proposed by MacMillan to justify the stereoselectivity obtained in the reactions promoted by catalysts of type 5-6.

Catalytic stereoselective benzylic C-H functionalizations by oxidative C-H activation and organocatalysis.

An organocatalytic stereoselective alpha-alkylation reaction of aldehydes based on C-H activation is presented.

Me(2)Zn as a radical source in Reformatsky-type reactions.

Experimental evidence for the generation of radicals by Me(2)Zn used in Reformatsky reactions was unequivocally established with a radical trap.

Organocatalytic asymmetric alkylation of aldehydes by S(N)1-type reaction of alcohols.

Work-alcoholic! The elusive enantioselective catalytic alpha-alkylation of aldehydes, a widely sought transformation, was brought to execution by the use of alcohols capable of forming stabilized carbocations (see scheme, TFA = trifluoroacetic acid).

Me2Zn mediated, tert-butylhydroperoxide promoted, catalytic enantioselective Reformatsky reaction with aldehydes.

A practical and highly enantioselective catalytic Reformatsky reaction with aldehydes using a cheap, commercially available aminoalcohol as ligand is described.

Synthesis of dehydro-beta-amino esters via highly regioselective amination of allylic carbonates.

The allylic amination of acetates and carbonates affords dehydro-beta-aminoesters, which are useful precursors of biologically active compounds. The uncatalyzed reaction proceeds via a S(N)2' mechanism. On the other hand, under palladium-catalyzed conditions, the reaction shows a strong solvent-dependent regiocontrol, affording exclusively one of the two possible regioisomers with complete transfer of chirality from the substrates to the products.

Synthesis and biological evaluation of non-peptide alpha(v)beta(3)/alpha(5)beta(1) integrin dual antagonists containing 5,6-dihydropyridin-2-one scaffolds.

Small constrained non-peptidic molecules consisting of a polyfunctionalized rigid core, carrying appendages corresponding to arginine and aspartic acid side chains, have been recently reported to be promising for drug development. In this work, the 5,6-dihydropyridin-2-one was envisaged as a scaffold to turn into potential integrin ligands, introducing a carboxylic acid and a basic appendage. The synthesis and the antiadhesion activity of a small library of peptidomimetics capable to recognize alpha(v)beta(3) and alpha(5)beta(1) integrins has been herein reported.

Synthesis and biological evaluation of unprecedented classes of spiro-beta-lactams and azido-beta-lactams as acyl-CoA:cholesterol acyltransferase inhibitors.

Unprecedented classes of four- and five-membered hydroxyl-spiro-beta-lactams and hydroxyl-azido-beta-lactams were prepared via regioselective ring opening of hydroxyl-epoxides. The potential of these particular beta-lactams as biologically active compounds has been confirmed by the results obtained in ACAT inhibition assays.

Synthesis and biological evaluation of azido- and aziridino-hydroxyl-beta-lactams through stereo- and regioselective epoxide ring opening.

Two new classes of azido- and aziridino-hydroxyl-beta-lactam containing structures have been prepared by means of a stereo- and regioselective epoxide ring opening. The straightforwardness of the procedure makes this strategy useful for the synthesis of potentially bioactive compounds. Some selected examples showed promising activity in acyl CoA-cholesterol acyltransferase inhibition assays.