Among nature's creation, terpenoids are more versatile and exciting natural products. In a remarkable display of synthetic ingenuity and creativity, nature has endowed terpenes, more so sesquiterpenes, with a bewildering array of carbocyclic frameworks with unusual assemblage of rings and functionality. This phenomenal structural diversity of this class of natural products makes them ideal targets for developing and testing new synthetic strategies for efficient articulation of carbocyclic frameworks. The present thesis entitled "Synthesis of sesquiterpenes containing two vicinal quaternary carbon atoms" describes the synthesis of a number of herbertane sesquiterpenoids, antimicrobial sesquiterpenes enokipodins A and Bf and spirocyclic sesquiterpenes acorone and isoacorones based on ring-closing metathesis reaction. In the thesis, the compounds are sequentially numbered (bold), and references are marked sequentially as superscript and listed at the end of thesis. All the figures included in-the thesis were obtained by DIRECT XEROX OF THE ORIGINAL NMR SPECTRA, and in some of them uninformative areas have been cut to save the space. The herbertane sesquiterpenes are relatively a new class of aromatic sesquiterpenes, containing sterically crowded l-aryl-l,2,2-trimethylcyclopentane carbon framework incorporating two vicinal quaternary carbon atoms on a cyclopentane ring. The sterically crowded molecular framework coupled with the novel biological properties associated with the phenolic herbertanes made the herbertenoids challenging synthetic targets. In the present investigations, to begin with, a formal total synthesis of (±)-herbertenediol and (±)~ mastigophorenes A-D was developed starting from vanillin, based on a combination of Wacker oxidation and intramolecular aldol reactions. A general ring-closing metathesis (RCM) based methodology was developed for a-cuparenone and the herbertane sesquiterpenes herbertene, a-herbertenol, f)~herbertenol and herbertenediol starting from the appropriately substituted acetophenones. The acetophenones on Horner-Wadsworth-Emmons reaction followed by regioselective reduction generated 5-arylbut-2-enols, which on Claisen rearrangement furnished 3~aryl-3-methylpent-4-enals. Grignard reaction with vinylmagnesium bromide followed by RCM reaction and oxidation transformed 3-aryl-3-methylpent~4-enals into 4~aryl-4-methylcylopentenones, which were further transformed into 3-aryl-2,2,3-trimethylcyclopentanones, thus, completing the formal synthesis of the sesquiterpenes (±)-a-cuparenone, (±)-herbertene, (±)-a-herbertenol, (±)-pherbertenol and (±)'herbertenediol. In continuation of the synthesis of herbertane sesquiterpenes, a Claisen rearrangement and RCM reaction based strategy was developed for the synthesis of (±)~lt14-herbertenediol and (±)-71-epi-herbertenolide, and marine sesquiterpenes {£)-tochuinyl acetate and (±)-dihydrotochuinyl acetate. Ortho ester Claisen rearrangement of 3-arylbut-2~ enols generated 3-aryl~3-methylpent-4-enoates, which on allylation and RCM reactions generated 2~methyl-2-arylcyclopent-3-encarboxylates. Stereoselective alkylation followed by functional group manipulations transformed 2-methyl'2-arylcyclopent'3-encarboxylates into the marine sesquiterpenes (±)-tochuinyl acetate and (±)-dihydrotochuinyl acetate, (±)-ll-epiherbertenolide and (±)~l,,14-herbertenediol. Total synthesis of (±)-lt13-herbertenediol has been accomplished employing an RCM reaction as the key step. The requisite starting material 2-methoxy-5-methylphenyl acetate was obtained from p-cresol. Two sequential allylation reactions followed by RCM reaction transformed 2-methoxy-5-methylphenyl acetate into 1 -arylcyclopent-3-en-l-carboxylate. Allylic oxidation and alkylation followed by functional group manipulation transformed I-arylcyclopent-3-en-l-carboxylate into (±)-U3-herbertenediol. For the enantiospecific synthesis of (+)-a-herbertenol, an aromatic Claisen rearrangement based strategy was developed starting from the readily available monoterpene (R)-limonene. To begin with, limonene was converted into 5-isopropenyl-2-methylcyclopent-l-enemethanol which on Mitsunobu reaction with p-cresol followed by Claisen rearrangement of the resultant aryl ether generated a mixture of3-isopropenyl-3a,7,8b-trimethyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofurans. Degradation of the isopropenyl group and cleavage of the central ether ring transformed the major cyclopentabenzofuran into 3-aryl-2,3-dimethylcyclopentanone, which was further elaborated into (+)-a-herbertenol. The general RCM reaction methodology developed for the herbertenoids has been further extended to the first total synthesis of the antimicrobial sesquiterpenes (±)~ enokipodins A andB, and a formal total syntheses of (±)-cuparene-l,4-diol, (±)-cuparene-lt4-quinone and (±)~HM-1 methyl ether star*w« from 2,5~dimethoxy~4-methylacetophenone. It has been further extended to the formal synthesis of spirocydic sesquiterpenes (±)-acorone and (±)-isoacorones starting from cyclohexane-1,4-dione.

beta-Turns in many biologically active peptides are important secondary structural elements which are critical for their biological activities. Hence, it is not surprising that beta-turn based pharmacophore design including beta-turn mimetics has become a central topic in medicinal chemistry in addition to alpha-helix or helical peptides. One of the advantages of such beta-turn mimetics is that they can better control torsion angles of the backbone of peptides and to some degree dihedral angles chi (X). These beta-turn mimicking scaffolds are designed to have a higher avidity for the acceptor by overcoming what otherwise is the inherent entropic cost paid for beta-turn formation upon binding to the acceptor. Among different synthetic strategies to bicyclic structures as beta-turn mimetics, consecutive formation of bicyclic structures using tandem acid-catalyzed N-acyliminium ion cyclization is attractive since this methodology was well established in the synthesis of natural product alkaloids. 1,3,6,8-Substituted tetrahydro-2H-pyrazino[1,2-a]pyrimidine-4,7-diones were designed and synthesized as internal beta-turn mimetics through an acid-catalyzed tandem acyliminium ion cyclization. Its development and synthesis are decribed in Chapter 2 to Chapter 4. Its application toward the development and synthesis of a small molecule ligand for melanocortin receptors is described in Chapter 5. In addition, the development of peptidomimetics for opioid receptors is explained in Chapter 6. On the other hand, a dicarba analogue having opioid receptor agonist, and dicarba analogues for MCRs were synthesized through solid phase synthesis including a ring closing metathesis reaction using Grubbs' catalyst (I) in Chapter 8.

Thesis (Ph, D.)--Miami University, Dept. of Chemistry and Biochemistry, 2008. / Title from second page of PDF document. Includes bibliographical references (p. 77-83).

Taxol™, isolated from the bark of Taxus brevifolia in the late 1960s, and the semisynthetic analog Taxotere™ have proven clinical importance for the treatment of ovarian and breast cancer. Taxol™ exerts its biological effect by binding to polymerized tubulin and stabilizing the resulting microtubules. Studies aimed at understanding the biologically active conformation of taxol and its binding environment on β-tubulin are described. This knowledge is important because it could lead to the design of structurally less complicated drugs with better efficacy and better bioavailability. Moreover, the information can be extended to other natural products that possess microtubule-stabilizing properties similar to Taxol™. In this work, the synthesis of a triply labeled taxol analog is described as well as REDOR studies of this compound complexed to tubulin are in progress. Macrocyclic analogs of taxol have been prepared and their biological activities were evaluated. Chemical modeling of these analogs and their activities agrees with the hypothesis that Taxol™ adopts T-shaped conformation. Difficulties were encountered with the key ring-closing metathesis strategy, suggesting that a more flexible and efficient macrocyclization method will be needed to synthesize additional macrocyclic analogs. / Ph. D.

No description available.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Thesis advisor: Amir H. Hoveyda / Abstract Chapter 1: Development of Efficient and Kinetically E-Selective Cross-Metathesis to Generate Alkenyl Halides We have devised a broadly applicable strategy to achieve kinetically E-selective cross-metathesis to generate a valuable set of E-alkenyl chlorides and fluorides in high efficiency. The synthetic utility was demonstrated through several concise syntheses of E-alkenyl chloride and fluoride precursors to biologically active molecules. The design principles delineated in this study are expected to initiate a wider range of efficient and kinetically controlled E-selective olefin metathesis processes where there is a diminished preference for the E isomer such as macrocyclic ring-closing metathesis. Chapter 2: Development of Efficient and Kinetically E-Selective Macrocyclic Ring-Closing Metathesis We devised a strategy to achieve high E selectivity in ring-closing metathesis to afford E-macrocyclic alkenes of various ring sizes regardless of the associated thermodynamic preferences. The key findings revealed that E-alkenylB(pin), widely recognized for its broad use in catalytic cross-coupling chemistry, possesses the appropriate steric and electronic attributes to serve as a suitable cross-partner in ring-closing metathesis with Mo alkylidenes. Synthetic utility was demonstrated through ring-closing metathesis at a late stage of a multi-step route. The investigation described herein offers a practical solution to a compelling problem in olefin metathesis, further elevating the utility of this widely used transformation. Chapter 3: Stereoselective Synthesis of E- and Z-Trisubstituted Alkenes by Combining Stereoretentive Catalytic Cross-Metathesis and Catalytic Cross-Coupling We introduced a general solution to a longstanding and compelling problem in olefin metathesis: a broadly applicable strategy for the reliable and efficient synthesis of acyclic E- and Z-trisubstituted alkenyl halides. Complications resulted from the formation of an unstable methylidene species or less reactive disubstituted alkylidene complexes can be addressed by utilizing a stereo-defined E- or Z-trisubstituted alkene and a 1,2-disubstituted olefin as substrates. By merging two central catalytic transformations in organic synthesis, cross-coupling and CM, various E- or Z-trisubstituted alkenyl chloride and bromides were readily accessed by the same catalytic system without the need for directing groups. The synthetic utility of the present protocol was demonstrated through several concise and efficient synthesis of biologically active natural products/synthetic precursors. Notably, the E- or Z-trisubstituted alkenyl halides prepared by CM may be readily converted to other trisubstituted olefins with complete retention of stereochemical purity by means of a second cross-coupling reaction. Based on the new findings, we revisited previously unaddressed problems and establish that readily available isoprenoid alkenes can serve as a suitable surrogate for unhindered terminal alkenes in CM. Chapter 4: In situ Protection/Deprotection for Catalytic Olefin Metathesis in the Presence of Polar Protic Functional Groups We demonstrated that protic groups such as alcohols and carboxylic acids that are problematic with high-oxidation-state alkylidenes could be effectively masked in situ prior to CM reactions by an appropriate borane reagent. The commercial sample of alkenes that are usually contaminated with protic impurities could be ‘purified’ in situ by a sub-stoichiometric amount of pinacolborane. Deprotection of the in situ boron-based protecting group proceeded under mild conditions and could be performed in the same vessel. The one-pot protection/cross-metathesis/deprotection of alcohol and carboxylic acid-containing alkenes described herein is likely to have an impact on the diversity of organic molecules that can be prepared in a laboratory setting. / Thesis (PhD) — Boston College, 2018. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Cette thèse s'inscrit dans le cadre du programme PentoRaf, dans la thématique « Transformation par voie chimique d'agromolécules en produits bioactifs ». Le travail de ce projet porte sur la synthèse de nouveaux azépanes tétrahydroxylés comportant un bras anomérique fonctionnel et sur l'évaluation des propriétés inhibitrices sur des glycosidases. La séquence réactionnelle a la particularité de valoriser les co produits issus du son et de la paille de blé.Dans une première partie, l'accès à un synthon polyfonctionnel, développé à partir des travaux précédents, a été réalisé avec des groupements protecteurs pivaloylés et méthoxyméthylés sur les hydroxyles communs aux sucres de départ (D-xylose et L-arabinose).La deuxième partie de ce travail consiste d'abord à introduire les différents groupements électroattracteurs : CO2Et, CN, PO(OEt)2, (CO2Et)PO(OEt)2 via une réaction de Wittig-Horner-Emmons. Les problèmes rencontrés lors de l'addition de l'allylamine ont clôturé les travaux sur la préparation d'azépanes avec un substituant phosphonate. Seuls les azépanes insaturés, comportant les fonctions : ester et nitrile, sont isolés.Une stratégie visant à obtenir les différentes distributions des hydroxyles (cis et trans) sur l'insaturation des azépanes obtenus est établie, dans une troisième partie, sur les composés fonctionnalisés avec un ester. Une réaction de déprotection finale donne ainsi accès à une famille de diastéréoisomères d'azépanes comportant un bras anomérique avec une fonction acide carboxylique, dont un composé a montré une activité biologique intéressante. Cette stratégie a été reproduite sur les azépanes comportant un nitrile jusqu'aux tétrahydroxyazépanes cis protégés. / This thesis is part of the PentoRaf program, in the theme “Chemical Transformation of agromolecules into bioactive products”. The aim of this project is the synthesis of new tetrahydroxylated azepanes containing a functional anomeric arm and the evaluation of their inhibitive properties on glycosidases. The reactive sequence advantageously values the co-products obtained from wheat bran and wheat straw.In the first part, the access to a polyfunctional synthon, developed from previous research, is carried out by protecting the common hydroxyl groups of the starting sugars (D-xylose and L-arabinose) with pivaloyl and methoxymethyl groups.The second part of this work is to introduce the various electroattracting groups: CO2Et, CN, PO(OEt)2, (CO2Et)PO(OEt)2 via a Wittig-Horner-Emmons reaction. The problems encountered during the addition of the allylamine ended our approach to prepare azepanes with a phosphonate substituent. Only the unsaturated azepanes containing ester and nitrile functions are isolated.A strategy is developed in the third part in order to achieve a specific distribution (cis and trans) of the hydroxyl groups on the unsaturation of the resulting azepanes by functionalizing these compounds with an ester. A final deprotection reaction leads to a family of azepane diastereoisomers containing an anomeric arm with a carboxylic acid function, among which one compound showed an interesting biological activity. This strategy was applied to azepanes containing a nitrile and lead to cis-protected tetrahydroxyazepanes.

In this thesis, carbohydrate mimicry is investigated through the syntheses of carbohydrate analogues and evaluation of their inhibitory effects on carbohydrate-processing enzymes. Galactofuranosides are interesting structures because they are common motifs in pathogenic microorganisms but not found in mammals. M.tuberculosis, responsible for the disease tuberculosis, has a cell wall containing a repeating unit of alternating (1→5)- and (1→6)-linked β-D-galactofuranosyl residues. Synthetic inhibitors of the enzymes involved in the biosynthesis of the cell wall could find great therapeutic use. The first part of this thesis describes the first synthesis of the hydrolytically stable carbasugar analogue of galactofuranose, 4a-carba-β-D-Galf, and the synthetic work of synthesising β-linked pseudodisaccharides containing carba-Galf, which were tested for glycosyltransferease inhibitory activity. The pseudodisaccharide carba-Galf-(β1→5)-carba-Galf was found to be a moderate inhibitor of the glycosyltransferase GlfT2 of M.tuberculosis. The thesis also describes how a general method towards biologically relevant α-linked carba-Galf ethers was developed. The final part of this thesis is focussed on the formation of nitrogen-linked monosaccharides without the participation of the anomeric centre. Such a mode of coupling is called tail-to-tail neodisaccharide formation. The couplings of carbohydrate derivatives via the Mitsunobu reaction are successfully reported herein. The method describes the key introduction of an allylic alcohol in the electrophile and the subsequent functionalisation of the alkene to obtain the neodisaccharide. Two synthesised neodisaccharides presented in this thesis have been sent to be tested for glycosidase inhibitory activity. / At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript. Paper 5: Manuscript. Paper 6: Manuscript.

Les macrocycles ont longtemps attiré l'attention des chimistes. Malgré cet intérêt, peu de méthodes générales et efficaces pour la construction de macrocycles ont été développés. Récemment, notre groupe a développé un programme de recherche visant à développer de nouvelles voies vers la synthèse de paracyclophanes et ce mémoire présente l pluspart des efforts les plus récents dans ce domaine. Traditionnellement, la synthèse de paracyclophanes rigides est facilitée par l'installation d'un groupe fonctionnel capable de contrôler la structure de la molécule en solution (ex un élément de contrôle de conformation (ECC)). Cependant, cette approche utilisant des auxiliaires exige que le ECC soit facilement installé avant macrocyclisation et facilement enlevé après la cyclisation. Le présent mémoire décrit une méthode alternative pour guider la macrocyclisations difficile à travers l'utilisation d'additifs comme ECC. Les additifs sont des hétérocycles aromatiques N-alkylé qui sont bon marché, faciles à préparer et peuvent être facilement ajoutés à un mélange de réaction et enlevés suite à la macrocyclisation par simple précipitation et de filtration. En outre, les ECCs sont recyclables. L'utilisation du nouveau ECC est démontré dans la synthèse des para-et métacyclophanes en utilisant soit la métathèse de fermeture de cycle (RCM) ou couplage de Glaser-Hay. / Macrocycles have long attracted the attention of chemists. Despite that interest, few general and efficient methods for the construction of macrocycles have been developed. Recently our group has developed a research program aimed at developing novel routes towards the synthesis of paracyclophanes and the present thesis details the most recent efforts in this area. Traditionally, the synthesis of rigid paracyclophanes is aided by the installation of functional groups capable of controlling the solution state structure of the molecules (ie. a conformational control element (CCE)). However, this auxiliary-like approach requires that the CCE be readily installed prior to macrocyclization and easily removed following the cyclization. In the present thesis describes an alternative method to guiding difficult macrocyclizations through the use of additives as CCEs is described. The additives are N-alkylated aromatic heterocycles that are cheap, easily prepared and can be easily added to a reaction mixture and removed following the macrocyclization through simple precipitation and filtration. In addition, the CCEs are recyclable. The use of the new CCEs is demonstrated in the synthesis of para- and metacyclophanes using either ring closing metathesis (RCM) or Glaser-Hay couplings.