The oral microbiome represents an extremely diverse environment that harbors many species of bacteria; over 700 different species have been identified overall. These organisms may be either commensal or pathogenic, and reside in multi-species communities of bacterial biofilms. As such, these bacteria may be 100-1000 times less susceptible to antibiotic treatment than their planktonic counterparts. One pathogenic organism that exists as a biofilm in the oral cavity is Streptococcus mutans, the main etiologic agent contributing to dental caries. Recently, the myxobacterial natural product carolacton was isolated and shown to be lethal to S. mutans cells in a biofilm at low (10 nM) concentration. As part of an endeavor to take inspiration from natural products to develop new therapeutics to combat biofilms, our group became interested in carolacton. This dissertation describes research conducted into the synthesis and biological evaluation of carolacton. Total synthesis enabled the biological evaluation of carolacton as well as several analogs. A novel compound was identified that was shown to elicit a phenotypic response from S. mutans that was different from that elicited by carolacton. In an effort to uncover novel simplified carolacton derivatives that maintain bioactivity and/or act via a different mechanism, we have exploited the power of diverted total synthesis in order to obtain a 1st-generation library of carolacton analogs. By leveraging a common intermediate that we were then able to diversify, we have obtained a library of simplified aryl analogs. Preliminary testing of these analogs has revealed a compound that inhibits growth and formation of S. mutans biofilms. This research has enabled us to obtain compounds that will serve to guide future drug discovery efforts, as well as act as tool compounds to help identify novel drug targets in S. mutans biofilms. / Chemistry

Le sujet principal de cette thèse est l'approche synthétique d'une macrolactone naturelle : la wortmannilactone C. Comme la wortmannilactone C possède deux motifs triéniques conjugués, nous nous sommes particulièrement intéressés à la préparation de ces motifs et une méthode a été mise au point pour former des triénols conjugués à l'aide d'un couplage de type Heck entre des iodures diéniques conjugués et des alcools allyliques non protégés. Cette méthode s'est révélée être régiosélective, chimiosélective et compatible avec une large variété d'alcools allyliques. Les conditions de couplage que nous avons mises au point pour former le motif triénol se sont révélées inefficaces pour coupler les fragments complexes devant permettre d'accéder à la wortmannilactone C. De nombreuses autres conditions de couplage ont alors été testées et parmi celles-ci des conditions de type Liebeskind ont permis d'assembler les fragments en formant le triénol conjugué désiré. Cependant la macrolactone obtenue s'est révélée être un diastéréoisomère de la wortmannilactone C, qui a été synthétisé en 23 étapes en considérant la séquence linéaire la plus longue. / The principal subject of this thesis is the synthetic approach to a natural macrolactone: wortmannilactone C. As wortmannilactone C possesses two conjugated trienic moieties, we were particularly interested in the preparation of these moieties and a method was developed to obtain conjugated trienols from conjugated iododienes and allylic alcohols under Heck-type coupling conditions. This method proved to be regioselective, stereoselective and compatible with a large variety of allylic alcohols. The coupling conditions that were developed for the formation of the trienol moiety, revealed to be ineffective to couple the complex fragments to access wortmannilactone C. Numerous other coupling conditions were tested and among them the Liebeskind conditions allowed the coupling of the fragments to access the desired conjugated trienol. However, the obtained macrolactone revealed to be a diastereomer of wortmannilactone C which was synthetized in 23 steps for the longest linear sequence.

No description available.

Le développement de méthodes efficaces de dédoublement cinétique d'amines représente, encore aujourd'hui, un défi en chimie organique. C'est dans ce contexte que nous avons montré que le (1S,2S)-N-acetyl-1,2-bis-trifluoromethanesulfonamidocyclohexane pouvait être utilisé comme réactif d'acylation hautement efficace pour le dédoublement cinétique d'amines propargyliques. En effet, ce réactif est capable de fournir les acétamides correspondants avec des ees pouvant atteindre jusqu'à 96% (τc = 50%)) lorsqu'un sel tel que l'AliquatTM 336 est utilisé alors qu'une inversion de la sélectivité est observée en absence de sel. Nous avons aussi été capable de réaliser le dédoublement cinétique d'amines allyliques (ees jusqu'à 88%, τc = 45%) en utilisant le même donneur d'acyle mais cette fois combiné à un sel d'ammonium supporté recyclable. Enfin, nous avons obtenu des résultats encourageant en développant une méthode catalytique impliquant une espèce chirale et un donneur d'acyle achiral. Une approche synthétique du lyngbouilloside a aussi été étudiée. De précédents travaux au sein de notre groupe ont montré qu'une erreur avait été commise lors de la détermination structurale du produit naturel suggérant une possible inversion du centre stéréogène en C11 qui ne serait donc pas de configuration (R) mais (S). C'est en tenant compte de cette hypothèse que nous avons développer une stratégie de synthèse convergente permettant d'accéder au lyngbouilloside avec le centre en C11 inversé avec l'idée de confirmer notre hypothèse et de réviser la structure initialement décrite. En résumé, la synthèse de l'aglycone du lyngbouilloside a été réalisée en 19 étapes et avec 2% de rendement global. / The development of a general and effective non-enzymatic acylative process for the kinetic resolution (KR) of amines remains, still today, a challenging field of research. In the course of this study, we were able to establish that (1S,2S)-N-acetyl-1,2-bis-trifluoromethanesulfonamidocyclohexane could be used as a highly selective acetylating agent for the kinetic resolution of primary propargylamines affording the corresponding acetamide with ees up to 96% (τc = 50%) when using an ammonium salt such as AliquatTM 336. Interestingly, a reversal of selectivity was observed in the absence of salt. We were also able to promote the kinetic resolution of primary allylamines with unprecedented levels of selectivity (ees up to 88%, τc = 45%) using a fully recyclable solid-supported ammonium salt instead of AliquatTM 336. In addition, we managed to obtain promising results in the development of a catalytic version using an achiral acyl donor in conjunction with a chiral catalyst. A synthetic approach of lyngbouilloside was also studied. Preliminary results in our group showed that the structure of the natural product may had been originally misassigned and suggested a stereochemical reassignment at C11. We managed to synthesize lyngbouilloside aglycone with the reversed stereogenic center at C11 in 19 steps and 2% overall yield.

The thesis describes the synthesis and application of various alkynones derived from the bis-Weinreb amide of tartaric acid in the total synthesis of macrolactone natural products. The thesis is divided into three sections. First section of the thesis describes the optimization and generalization of the procedure for the addition of alkynyl Grignard / lithium reagents to the bis-Weinreb amide derived from tartaric acid to yield the mono alkynyl ketones was developed. Application of the formed γ-oxo amides was demonstrated in the synthesis of polyols with varied substitutions particularly the synthesis of 1,2,4-triols was accomplished using Ley’s dithianylation as the key step. Scheme 1: Synthesis of polyols from the bis-weinreb amide of tartaric acid. Application of the strategy to the total synthesis of decanolactone natural products achaetolide and (Z)-isomer of (6S,7R,9R)-6,7-dihydroxy-9-propylnon-4-eno-9-lactone was featured. Section B of the thesis deals with the enantiospecific total synthesis of 14-membered macrolactone Sch 725674. Key reactions in the synthesis include the synthesis of the 1,2,4-triol unit from tartaric acid, olefin cross metathesis and ring closing metathesis. Scheme 4: Enantiospecific total synthesis of Sch 725674. Section C of the thesis describes the enantiospecific synthesis of the C9-C22 fragment of the 28-membered polyene polyol macrolide pentamycin. Although isolated in 1958, total synthesis of this antifungal compound was not reported. In application of the methodology developed, the alkynone prepared from the bis-Weinreb amide was elaborated to the required fragment.

This thesis is an investigation of the natural products deriving from marine algae and cyanobacteria and has resulted in the discovery of eleven new secondary metabolites. The structure elucidations of these new molecules were performed using a variety of spectroscopic techniques. Four new macrolides were isolated and characterized from the Madagascar marine cyanobacterium Geitlerinema sp. These ankaraholides are structurally similar to the potently cytotoxic swinholides and were found to have cytotoxicities ranging from 178 nM to 354 nM against human lung cancer (NCI-H460) and mouse neuro-2a cell lines. Since swinholide-type compounds were previously localized to the heterotrophic bacteria of sponges, these findings raise intriguing questions about their true metabolic source. Geitlerinema sp. was found to be particularly rich in chemistry, and also produced the new linear lipopeptide mitsoamide with unusual structural features including an aminal moiety, a homolysine residue and a polyketide unit (3,7- dimethoxy-5-methyl- nonanedioic acid) (DMNA). A collection of the red marine alga Portieria hornemannii from the south of Madagascar (Tolagniaro, Fort Dauphin), led to the isolation of the previously reported halogenated monoterpene, halomon, and the discovery of three new related metabolites. These molecules were found to inhibit DNA methyltransferase 1 (DNMT-1). As a result of efforts to identify bioactive agents from the marine cyanobacterium Lyngbya majuscula, tanikolide dimer, a novel SIRT2 inhibitor (IC50 = 176 nM), and tanikolide seco-acid were isolated. The depside molecular structure of tanikolide dimer, which is likely a meso compound, was established by NMR, MS and chiral HPLC analyses. The structure of tanikolide dimer raises a number of intriguing configurational and biosynthetic questions for further study. The bioassay guided fractionation of a collection of the brown marine alga Dictyota sp. from Netherland Antilles Playa Fort, led to the identification of a novel HDAC inhibitor with a dolastane carbon skeleton. The novel molecule was also found to possess antimalarial activity. Other known HDAC inhibitors with interesting antimalarial activity have been reported previously, and based on this efficacy against malaria, HDAC appears to be a viable target for the development of antiparasitic agents. / Graduation date: 2006