Ce mémoire décrit le développement d’une nouvelle méthodologie d’expansion de cycle irréversible à partir de N-alkyl-3,4-déhydroprolinols pour former des N-alkyl tétrahydropyridines 3-substituées en passant par un intermédiaire aziridinium bicyclique. Cette méthode permet l’introduction d’un vaste éventail de substituants à la position 3 et tolère bien la présence de groupements aux positions 2 et 6, donnant accès à des pipéridines mono-, di- ou trisubstituées avec un excellent diastéréocontrôle. De plus, il est démontré que l’information stéréogénique du 3,4-déhydroprolinol de départ est totalement transférée vers le produit tétrahydropyridine. Additionnellement, une méthodologie fut dévelopée pour la préparation des produits de départ 3,4-déhydroprolinols en forme énantiopure, avec ou sans substituants aux positions 2 et 5, avec un très bon stéréocontrôle. Le premier chapitre présente un résumé de la littérature sur le sujet, incluant un bref survol des méthodes existantes pour la synthèse de pipéridines 3-substituées, ainsi qu’une vue d’ensemble de la chimie des aziridiniums. L’hypothèse originale ainsi que le raisonnement pour l’entreprise de ce projet y sont également inclus. Le second chapitre traite de la synthèse des N-alkyl-3,4-déhydroprolinols utilisés comme produits de départ pour l’expansion de cycle vers les tétrahydropyridines 3-substituées, incluant deux routes synthétiques différentes pour leur formation. Le premier chemin synthétique utilise la L-trans-4-hydroxyproline comme produit de départ, tandis que le deuxième est basé sur une modification de la réaction de Petasis-Mannich suivie par une métathèse de fermeture de cycle, facilitant l’accès aux précurseurs pour l’expansion de cycle. Le troisième chapitre présente une preuve de concept de la viabilité du projet ainsi que l’optimisation des conditions réactionnelles pour l’expansion de cycle. De plus, il y est démontré que l’information stéréogénique des produits de départs est transférée vers les produits. iv Au quatrième chapitre, l’étendue des composés pouvant être synthétisés par cette méthodologie est présentée, ainsi qu’une hypothèse mécanistique expliquant les stéréochimies relatives observées. Une synthèse énantiosélective efficace et divergente de tétrahydropyridines 2,3-disubstituées est également documentée, où les deux substituants furent introduits à partir d’un intermédiaire commun en 3 étapes. / This thesis describes the development of a novel methodology of irreversible ring expansion from N-alkyl-3,4-dehydroprolinols to N-alkyl-3-substituted tetrahydropyridines through a bicyclic aziridinium ion intermediate. This method allows a wide variety of substituents at the 3-position, and also permits substitution at the 2- and 6-positions of the tetrahydropyridine giving mono-, di- or tri-substituted piperidines with excellent diasterocontrol. Complete transfer of the stereogenic information of the 3,4- dehydroprolinol to the tetrahydropyridine product is demonstrated. Also, a methodology was developed to prepare the 3,4-dehydroprolinol starting materials in enantiopure form, with the possibility of substitution at the 2- and 5-positions with excellent diasterocontrol. The first chapter presents the literature background, including a brief summary of methodologies for the synthesis of 3-substituted piperidines, and an overview of aziridinium ion chemistry. Also presented is the original hypothesis of the project, and our reasoning for undertaking this project. The second chapter describes the synthesis of N-alkyl-3,4-dehydroprolinols used as precursors for the ring expansion to 3-substituted tetrahydropyridines, including two different synthetic routes. The first route route converts L-trans-4-hydroxyproline to enantioenriched N-benzyl-3,4-dehydroprolinol in 6 steps. The second synthetic route was developed using a variant of the Petasis-Mannich reaction and a ring closing metathesis,making the precursors more readily available and simple to synthesize. The third chapter presents the proof of concept of the viability of the project and optimization studies. Moreover, the transfer of stereogenic information to the resulting product is demonstrated. The fourth chapter demonstrates the broad scope of the ring expansion and mechanistic insight is given based on the relative configuration of the products. An expedient divergent enantioselective synthesis of a 2,3-disubstituted tetrahydropyridine is also shown, with both substituents being chosen from a common intermediate in 3 steps.

This thesis describes the development of new synthetic methodologies for preparation of bioactive interesting compounds, e.g. substituted pyridines, piperidines or piparazines. Thesecompounds are synthesized from commercially available, cheap and easily prepared reagents, videlicet the reaction between Grignard reagents and heterocyclic N-oxides.  The first part of this thesis deals with an improvement for synthesis of dienal-oximes and substituted pyridines. This was accomplished by a rapid addition of Grignard reagents to pyridine N-oxides at rt. yielding a diverse set of substituted dienal-oximes. During these studies, it was observed that the obtained dienal-oxmies are prone to ring-close upon heating. By taking advantage of this, a practical synthesis of substituted pyridines was developed. In the second part, an ortho-metalation of pyridine N-oxides using Grignard reagents is discussed. The method can be used for incorporation of a range of different electrophiles, including aldehydes, ketones and halogens. Furthermore, the importance for incorporation of halogens are exemplified through a Suzuki–Miyaura coupling reaction of 2-iodo pyridine N-oxides and different boronic acids. Later it was discovered that if the reaction temperature is kept below -20 °C, the undesired ringopening can be avoided. Thus, the synthesis of 2,3-dihydropyridine N-oxide, by reacting Grignard reagents with pyridine N-oxides at -40 °C followed by sequential addition of aldehyde or ketone, was accomplished. The reaction provides complete regio- and stereoselectivity yielding trans-2,3-dihydropyridine N-oxides in good yields. These intermediate products could then be used for synthesis of either substituted piperidines, by reduction, or reacted in a Diels–Alder cycloaddtion to give the aza-bicyclo compound. In the last part of this thesis, the discovered reactivity for pyridine N-oxides, is applied on pyrazine N-oxides in effort to synthesize substituted piperazines. These substances are obtained by the reaction of Grignard reagents and pyrazine N-oxides at -78 °C followed by reduction and protection, using a one-pot procedure. The product, a protected piperazine, that easily can be orthogonally deprotected, allowing synthetic modifications at either nitrogens in a fast and step efficient manner. Finally, an enantioselective procedure using a combination of PhMgCl and (-)-sparteine is discussed, giving opportunity for a stereoselective synthesis of substituted piperazines.

Ce mémoire décrit le développement d’une nouvelle méthodologie d’expansion de cycle irréversible à partir de N-alkyl-3,4-déhydroprolinols pour former des N-alkyl tétrahydropyridines 3-substituées en passant par un intermédiaire aziridinium bicyclique. Cette méthode permet l’introduction d’un vaste éventail de substituants à la position 3 et tolère bien la présence de groupements aux positions 2 et 6, donnant accès à des pipéridines mono-, di- ou trisubstituées avec un excellent diastéréocontrôle. De plus, il est démontré que l’information stéréogénique du 3,4-déhydroprolinol de départ est totalement transférée vers le produit tétrahydropyridine. Additionnellement, une méthodologie fut dévelopée pour la préparation des produits de départ 3,4-déhydroprolinols en forme énantiopure, avec ou sans substituants aux positions 2 et 5, avec un très bon stéréocontrôle. Le premier chapitre présente un résumé de la littérature sur le sujet, incluant un bref survol des méthodes existantes pour la synthèse de pipéridines 3-substituées, ainsi qu’une vue d’ensemble de la chimie des aziridiniums. L’hypothèse originale ainsi que le raisonnement pour l’entreprise de ce projet y sont également inclus. Le second chapitre traite de la synthèse des N-alkyl-3,4-déhydroprolinols utilisés comme produits de départ pour l’expansion de cycle vers les tétrahydropyridines 3-substituées, incluant deux routes synthétiques différentes pour leur formation. Le premier chemin synthétique utilise la L-trans-4-hydroxyproline comme produit de départ, tandis que le deuxième est basé sur une modification de la réaction de Petasis-Mannich suivie par une métathèse de fermeture de cycle, facilitant l’accès aux précurseurs pour l’expansion de cycle. Le troisième chapitre présente une preuve de concept de la viabilité du projet ainsi que l’optimisation des conditions réactionnelles pour l’expansion de cycle. De plus, il y est démontré que l’information stéréogénique des produits de départs est transférée vers les produits. iv Au quatrième chapitre, l’étendue des composés pouvant être synthétisés par cette méthodologie est présentée, ainsi qu’une hypothèse mécanistique expliquant les stéréochimies relatives observées. Une synthèse énantiosélective efficace et divergente de tétrahydropyridines 2,3-disubstituées est également documentée, où les deux substituants furent introduits à partir d’un intermédiaire commun en 3 étapes. / This thesis describes the development of a novel methodology of irreversible ring expansion from N-alkyl-3,4-dehydroprolinols to N-alkyl-3-substituted tetrahydropyridines through a bicyclic aziridinium ion intermediate. This method allows a wide variety of substituents at the 3-position, and also permits substitution at the 2- and 6-positions of the tetrahydropyridine giving mono-, di- or tri-substituted piperidines with excellent diasterocontrol. Complete transfer of the stereogenic information of the 3,4- dehydroprolinol to the tetrahydropyridine product is demonstrated. Also, a methodology was developed to prepare the 3,4-dehydroprolinol starting materials in enantiopure form, with the possibility of substitution at the 2- and 5-positions with excellent diasterocontrol. The first chapter presents the literature background, including a brief summary of methodologies for the synthesis of 3-substituted piperidines, and an overview of aziridinium ion chemistry. Also presented is the original hypothesis of the project, and our reasoning for undertaking this project. The second chapter describes the synthesis of N-alkyl-3,4-dehydroprolinols used as precursors for the ring expansion to 3-substituted tetrahydropyridines, including two different synthetic routes. The first route route converts L-trans-4-hydroxyproline to enantioenriched N-benzyl-3,4-dehydroprolinol in 6 steps. The second synthetic route was developed using a variant of the Petasis-Mannich reaction and a ring closing metathesis,making the precursors more readily available and simple to synthesize. The third chapter presents the proof of concept of the viability of the project and optimization studies. Moreover, the transfer of stereogenic information to the resulting product is demonstrated. The fourth chapter demonstrates the broad scope of the ring expansion and mechanistic insight is given based on the relative configuration of the products. An expedient divergent enantioselective synthesis of a 2,3-disubstituted tetrahydropyridine is also shown, with both substituents being chosen from a common intermediate in 3 steps.

Les tétrahydropyranes et les pipéridines sont des motifs que l'on retrouve dans de nombreuses molécules naturelles bioactives. L'intérêt pour ces familles de composés ne cesse de croître. En effet le noyau pipéridine est le troisième motif cyclique le plus retrouvé dans les molécules thérapeutiques après les noyaux phényle et pyridine alors que le tétrahydropyrane prend lui la 6ème place. Il apparaît donc opportun de développer des voies d'accès simples et efficaces afin d'obtenir de façon stéréosélective (diastéréo et/ou énantiosélective) ces motifs structuraux. Les travaux de recherche présentés dans ce manuscrit concernent le développement de deux nouvelles méthodologies de la cyclisation d'aza-Prins. La cyclisation d'aza-Prins permet par la réaction entre une amine homoallylique et un aldéhyde en présence d'un acide (Lewis ou Brønsted) la formation de pipéridine. La première a été développée pour pallier à l'absence dans la littérature de méthodologie applicable à tous types d'amines homoallyliques. Cette nouvelle méthodologie repose sur la promotion de la réaction par un effet synergétique entre un acide de Lewis (TiCl4 1 éq.) et un acide de Brønsted (p-TSA 0.1 éq.). Cette méthodologie a permis l'obtention de pipéridine avec de bons rendements et une excellente diastéréosélectivité a été obtenue selon la nature de l'amine homoallylique utilisé. La deuxième méthodologie qui a été développée permet l'aminolyse de pipéridine-lactone. Ces pipéridine-lactones, obtenues par une réaction d'aza-Prins, sont ainsi aminolysées par un acide aminé en présence d'un promoteur puissant LiNTf2. Ces deux méthodologies combinées nous ont permis d'obtenir divers motifs pipéridines. Un certain nombre de ces pipéridines synthétisées seront testées afin de mettre en évidence une éventuelle activité biologique. / Tetrahydropyrans and piperidines are cyclic motifs found in numerous bioactive natural products. Interest in these families of compounds is continuously growing. Indeed, piperidine is the 3rd most common cyclic motif found in therapeutic molecules after phenyl and pyridine structures, while the tetrahydropyran takes the 6th place. Thus the development of simple and effective methodologies to obtain these structures stereoselectively (diastereo and/or enantioselectively) is of great interest. The research presented in this manuscript concerns the development of two new methodologies for aza-Prins cyclization. These reactions involve condensation of homoallylic amines with aldehydes in the presence of a Lewis or Brønsted acid to give piperidine compounds. The first method was promoted by a synergistic combination of a Lewis acid and a Brønsted acid and employs N-alkyl, N-aryl, and unprotected homoallylamines to efficiently form piperidines with good yields and excellent diastereoselectivity, which was controlled by the nature homoallylamine. The second method allows piperidine-lactone aminolysis in presence of aminoacids with the help of a powerful promoter LiNTf2. These two combined methodologies allowed us to obtain a library of piperidine structures, some of which will be tested in order to assess their possible biological activity.

Thermal reactions and flash photolysis are used to study the olefin bond-migration promoted by tungsten carbonyls. Substitution of piperidine (pip) by 2- allylphenyldiphenylphosphine (adpp) in the cis-(pip)(η^1- adpp)W(CO)-4 complex was investigated, and no olefin bond-migration was observed. This suggests that a vacant coordinated site adjacent to the coordinated olefin is an essential requirement for olefin bond rearrangement. The rates of olefin attack on the photogenerated coordinatively unsaturated species, cis-[(CB)(η^1-ol- P)W(CO)-4] (CB = chlorobenzene, p-ol = Ph-2P(CH-2)-3CH=CH-2; n = 1-4) were measured. Kinetics data obtained both in pure CB and in CB/cyclohexane mixtures support a dissociative mechanism in which the W-CB bond is broken in the transition state. In contrast to results observed in studies of other related systems, no olefin bond-migration is noted. This observation is attributed to P-W coordination at all stages of the reaction, which precludes formation of a reactive intermediate containing a vacant coordination site adjacent to a P-ol bond.

1,2-Diazetidine is a four-membered ring heterocyclic compound which has two adjacent nitrogen atoms. However, the syntheses of C-unsubstituted 1,2-diazetidines are rarely reported in the literature. C-unsubstituted 1,2-diazetidines were synthesized through an operationally simple intermolecular vicinal disubstitution reaction between 1,2-dibromoethane and hydrazine with N-arylsulfonyl as the protecting group. Several different types of C-unsubstituted 1,2-diazetidines derivatives were synthesized with either two of the same or two different N-arylsulfonyl groups. The electronic and steric properties were analyzed using Raman spectroscopy and computational calculations. Then, several synthetic applications were demonstrated with 1,2-ditosyl-1,2-diazetidine (DTD). As a synthetic application, a nucleophilic ring-opening reaction of the diazetidine was identified through various thiol selective cleavage of the N‒N bond, resulting in the stereoselective formation of a new class of N-sulfenylimine. Furthermore, DTD underwent FeBr2-catalyzed retro [2+2] ring-opening and sustained release of formaldimine (FI) in situ in a reaction medium which is the simplest imine used amidomethylative reagent. Therefore, the effective available concentration can be controlled at low levels in the reaction medium. Moreover, the sustained release of FI was able to interrupt the amidomethylative process with α- methylstyrene and FeBr2 as the catalyst and resulted in 4-phenyl-1,2,3,6-tetrahydropyrimidine (PTPH) as a product. The PTPH is a neurotoxic compound used to induce Parkinson’s disease in animal models. In addition, sustained release of FI allowed to switch the selectivity from alkene, imine, and imine arrangement into alkene, imine, and alkene arrangement in [2+2+2] cycloaddition reaction and led to form piperidines as a product which is the most observed heterocycle in marketed drug molecules. Chromane derivatives are observed in pharmaceuticals and natural products. Chirally pure chromane derivatives were synthesized through ruthenium-catalyzed chiral transient directing-mediated enantioselective C–H activation. Interestingly, a phosphate was involved in the deprotonation step, the rate-determining step with a 5.3 KIE value.

Pumiliotoxinas e seus congêneres são compostos isolados da pele de algumas espécies de sapos das famílias Dendrobatidae, Mantellidae, Bufonidae, e Myobatrachidae, apresentando interessantes propriedades farmacológicas. As pumiliotoxinas, embora tóxicas, apresentam consideráveis atividades cardiotônicas, assim, acredita-se que as homopumiliotoxinas, as desmetilpumiliotoxinas e as desidrodesmetilpumiliotoxinas também devam apresentar. Nesse sentido, a síntese destes compostos é de extrema valia para a comunidade científica. As diazocetonas α,β-insaturadas são intermediários promissores para a síntese rápida e eficiente de diversos tipos de esqueletos químicos, entre eles, a construção do esqueleto indolizidínico presentes nas pumiliotoxinas. Cabe ressaltar que para as diazocetonas α,β-insaturadas com geometria Z provenientes de amino aldeídos, elas já apresentam a estereoquímica correta para uma direta ciclização para a construção de esqueletos indolizidínicos. Dessa forma, as etapas chaves do trabalho consistiram na preparação de amino aldeídos N-protegidos, na avaliação da reação de Horner-Wadsworth-Emmons para fornecer as diazocetonas α,β-insaturadas com geometria Z, e na reação de inserção N-H intramolecular para a obtenção do ciclo indolizidínico. Outra parte do trabalho consistiu na síntese de imino açúcares de esqueleto piperidínico com cadeias laterais alifáticas (aplicação na química medicinal) e da (-)-1deoxi-altronojirimicina, utilizando-se a mesma metodologia (uso de diazocetonas α,β-insaturadas com geometria Z). / Pumiliotoxins and their congeners are a class of compounds isolated from the skin of some frogs from the Dendrobatidae, Mantellidae, Bufonidae, e Myobatrachidae families, possessing interesting pharmacological activities (cardiotonic activity in low concentrations). Because of the big number of compounds among these toxins (about 100), synthetic methodologies that provide the preparation of these compounds (as well as analogues) in great amounts and in a fast and efficient way using common intermediates, are very important for application in chemical-biology. The α,β-unsaturated diazoketones are promising intermediates for the rapid and efficient synthesis of a range of chemical skeletons, among them, the construction of indolizidine skeleton that pumiliotoxins present. It is important to note that α,β-unsaturated diazoketones with Z geometry (prepared from amino aldehydes) have already the correct stereochemistry for a direct cyclization to construct indolizidine skeletons. The key steps of the work consisted in the preparation of N-protected amino aldehydes, evaluation of Horner-Wadsworth-Emmons reaction in order to obtain α,β-unsaturated diazoketones with Z geometry, and the intramolecular N-H insertion reaction to provide the indolizidine cycle. Another part of the work consisted in the synthesis of iminosugars with piperidine core and aliphatic side chains (application in medicinal chemistry) and in the synthesis of (-)-1-deoxy-altronojirimycin, applying the same methodology (use of α,β-unsaturated diazoketones with Z geometry).

Pumiliotoxinas e seus congêneres são compostos isolados da pele de algumas espécies de sapos das famílias Dendrobatidae, Mantellidae, Bufonidae, e Myobatrachidae, apresentando interessantes propriedades farmacológicas. As pumiliotoxinas, embora tóxicas, apresentam consideráveis atividades cardiotônicas, assim, acredita-se que as homopumiliotoxinas, as desmetilpumiliotoxinas e as desidrodesmetilpumiliotoxinas também devam apresentar. Nesse sentido, a síntese destes compostos é de extrema valia para a comunidade científica. As diazocetonas α,β-insaturadas são intermediários promissores para a síntese rápida e eficiente de diversos tipos de esqueletos químicos, entre eles, a construção do esqueleto indolizidínico presentes nas pumiliotoxinas. Cabe ressaltar que para as diazocetonas α,β-insaturadas com geometria Z provenientes de amino aldeídos, elas já apresentam a estereoquímica correta para uma direta ciclização para a construção de esqueletos indolizidínicos. Dessa forma, as etapas chaves do trabalho consistiram na preparação de amino aldeídos N-protegidos, na avaliação da reação de Horner-Wadsworth-Emmons para fornecer as diazocetonas α,β-insaturadas com geometria Z, e na reação de inserção N-H intramolecular para a obtenção do ciclo indolizidínico. Outra parte do trabalho consistiu na síntese de imino açúcares de esqueleto piperidínico com cadeias laterais alifáticas (aplicação na química medicinal) e da (-)-1deoxi-altronojirimicina, utilizando-se a mesma metodologia (uso de diazocetonas α,β-insaturadas com geometria Z). / Pumiliotoxins and their congeners are a class of compounds isolated from the skin of some frogs from the Dendrobatidae, Mantellidae, Bufonidae, e Myobatrachidae families, possessing interesting pharmacological activities (cardiotonic activity in low concentrations). Because of the big number of compounds among these toxins (about 100), synthetic methodologies that provide the preparation of these compounds (as well as analogues) in great amounts and in a fast and efficient way using common intermediates, are very important for application in chemical-biology. The α,β-unsaturated diazoketones are promising intermediates for the rapid and efficient synthesis of a range of chemical skeletons, among them, the construction of indolizidine skeleton that pumiliotoxins present. It is important to note that α,β-unsaturated diazoketones with Z geometry (prepared from amino aldehydes) have already the correct stereochemistry for a direct cyclization to construct indolizidine skeletons. The key steps of the work consisted in the preparation of N-protected amino aldehydes, evaluation of Horner-Wadsworth-Emmons reaction in order to obtain α,β-unsaturated diazoketones with Z geometry, and the intramolecular N-H insertion reaction to provide the indolizidine cycle. Another part of the work consisted in the synthesis of iminosugars with piperidine core and aliphatic side chains (application in medicinal chemistry) and in the synthesis of (-)-1-deoxy-altronojirimycin, applying the same methodology (use of α,β-unsaturated diazoketones with Z geometry).

The large pine weevil, Hylobius abietis L., is a major insect pest on conifer seedlings in northern Europe. Due to its feeding newly planted trees get girdled, resulting in high seedling mortality (up to 80%). As a consequence great financial losses to the forest industry occur. Today the seedlings are protected with the pyrethroid insecticide cypermethrin. This insecticide is toxic to aquatic organisms and is, from 2010, prohibited for use in Sweden by the Swedish Chemicals Inspectorate. An alternative to insecticides is to protect the seedlings with antifeedants, compounds that, either through taste or smell or both, deter the weevils from feeding. This thesis describes the search for and the synthesis of such antifeedant compounds. Bark extracts of several woody species, known to be non-palatable to the weevil, were prepared and found to display antifeedant activity against H. abietis. The major chemical constituents of the extracts were tested for antifeedant activity. Antifeedants such as eugenol, 2-phenylethanol and benzylalcohol, but also feeding stimulants such as β-sitosterol and linoleic acid, were identified. An extract of linden bark, Tilia cordata, was shown to contain nonanoic acid, a highly active antifeedant. Other aliphatic carboxylic acids were also found to display high antifeedant activities against the weevil, both in laboratory and in field tests. The enantiomers of dihydropinidine, a piperidine alkaloid present in several conifer species, were prepared by dimethylzinc mediated allylation of 2- methyltetrahydropyridine-N-oxide. When tested in micro feeding assays, no difference in antifeedant activity was found for the enantiomers. In a field test high antifeedant activity, comparable with that of the presently used insecticide cypermethrin, was found for (±)-dihydropindine. Other naturally occurring piperidine alkaloids were synthesised and also found to display high antifeedant activities in laboratory tests. Structure-activity relationships were evaluated for methoxy substituted benzaldehydes, benzoic acids and cinnamic aldehydes, -acids, -esters and -alcohols. While the carboxylic acids were inactive or even feeding stimulants, the aldehydes were the most active antifeedants / QC 20110124

<p>The large pine weevil, Hylobius abietis L., is a major insect pest on conifer seedlings in northern Europe. Due to its feeding newly planted trees get girdled, resulting in high seedling mortality (up to 80%). As a consequence great financial losses to the forest industry occur. Today the seedlings are protected with the pyrethroid insecticide cypermethrin. This insecticide is toxic to aquatic organisms and is, from 2010, prohibited for use in Sweden by the Swedish Chemicals Inspectorate. An alternative to insecticides is to protect the seedlings with antifeedants, compounds that, either through taste or smell or both, deter the weevils from feeding. This thesis describes the search for and the synthesis of such antifeedant compounds.</p><p>Bark extracts of several woody species, known to be non-palatable to the weevil, were prepared and found to display antifeedant activity against H. abietis. The major chemical constituents of the extracts were tested for antifeedant activity. Antifeedants such as eugenol, 2-phenylethanol and benzylalcohol, but also feeding stimulants such as β-sitosterol and linoleic acid, were identified. An extract of linden bark, Tilia cordata, was shown to contain nonanoic acid, a highly active antifeedant. Other aliphatic carboxylic acids were also found to display high antifeedant activities against the weevil, both in laboratory and in field tests.</p><p>The enantiomers of dihydropinidine, a piperidine alkaloid present in several conifer species, were prepared by dimethylzinc mediated allylation of 2- methyltetrahydropyridine-N-oxide. When tested in micro feeding assays, no difference in antifeedant activity was found for the enantiomers. In a field test high antifeedant activity, comparable with that of the presently used insecticide cypermethrin, was found for (±)-dihydropindine. Other naturally occurring piperidine alkaloids were synthesised and also found to display high antifeedant activities in laboratory tests.</p><p>Structure-activity relationships were evaluated for methoxy substituted benzaldehydes, benzoic acids and cinnamic aldehydes, -acids, -esters and -alcohols. While the carboxylic acids were inactive or even feeding stimulants, the aldehydes were the most active antifeedants</p>