Dissertations / Theses on the topic 'Polypropionates'

La réaction d'aldolisation est une des méthodes les plus importantes et plus utilisées pour former des liaisons C-C. La réaction tandem d'isomérisation-aldolisation catalytique d'alcools allyliques permet d'effectuer cette réaction avec de nombreux avantages synthétiques et nous avons préparé par ce moyen des beta-hydroxyacylsilanes à partir d'alpha-hydroxyallylsilanes. Tout d'abord, nous avons cherché à mettre au point une version catalytique asymétrique de cette réaction tandem et nous avons aussi synthétisé des beta-hydroxyacylsilanes par aldolisation directe. Ensuite, nous avons utilisé des alpha-hydroxyallylsilanes pour préparer des aldolsalpha-silylés au moyen de réactions d'époxydation. Dans une troisième partie, nous avons synthétisé des aldols à partir de beta-hydroxyacylsilanes protégés de manière simple et efficace, ce qui nous a permis d'effectuer des réactions d'aldolisation itératives. Nous avons illustré le potentiel de cette méthode par la synthèse d'un fragment de (±)-pironetine. Enfin, nous avons synthétisé, à partir des mêmes beta-hydroxyacylsilanes protégés, des éthers d'énol silylés qui ont été ensuite utilisés avec succès comme substrats pour des réactions de Mukaiyama
The aldol reactions is one of the most important and commonly used methods to form C-C bonds. The catalytic tandem isomerization-aldol reaction of allylic alcohols allows to perform this reaction with many synthetic advantages. Thus, we have prepared by this method beta-hydroxyacylsilanes from alpha-hydroxyallylsilanes. First, we have attempted to develop a catalytic asymmetric version of this reaction, and also to synthesize beta-hydroxyacylsilanes by direct aldol reaction. Then, we used alpha-hydroxyallylsilanes to prepare alpha-silyl aldols trough epoxidation reactions. Next, we synthesized aldols from protected beta-hydroxyacylsilanes in a simple and efficient fashion which allowed us to perform iterative aldol reactions. We have illustrated the potential of this method by the synthesis of a fragment of (±)-pironetine. Finally, we have synthesized, from the same protected beta-hydroxyacylsilanes, silyl enol ethers that next have been used successfully as substrates for Mukaiyama aldol reactions

Polypropionate marine natural products have emerged as a class of compounds that display a high degree of structural diversity. Specifically, metabolites such as that reported as tridachiahydropyrone (7), isolated from sacoglossan molluscs, display novel ring systems. The introductory chapter gives some background on tridachione marine natural products and outlines the isolation of metabolites from several species of sacoglossan mollusc. Chapter One also gives examples of the utility of the tandem conjugate addition-Dieckmann condensation approach being applied to the synthesis of these compounds. Chapter Two describes the development of the tandem conjugate addition-Dieckmann condensation and subsequent trans methylation approach to cyclohexenone rings. The synthetic strategy utilised chiral, functionalised cyclohexenone rings as synthons in the formation of bicyclic ring systems, so development of the carbocyclic ring formation was of vital importance to the overall strategy. Examples are given which confirm the viability of the proposed synthetic route to cyclohexenones such as 91, 92 and 104 from the reaction of [alpha,beta]-unsaturated carbonyl compounds 39 and 59 with dialkyl and dialkenyl Gilman cuprates. Chapter Three describes the incorporation of chiral cyclohexenone 117 into the bicyclic framework of model compound 105, analogous to the marine natural product reported as tridachiahydropyrone (7). The chapter explores the use of cyclohexenone precursor 43 that contained the total carbon framework of the bicyclic core of the desired pyrone. Once again, a tandem conjugate addition-cyclisation reaction was employed using a dialkyl Gilman cuprate, followed by trans methylation to give the requisite cyclohexenone synthon 117. A novel Eaton’s reagent-promoted intramolecular cyclisation of acid 122 to pyrone 123 was then effected. Subsequent O-methylation afforded [alpha]-methoxy-[beta]-methyl-[gamma]-pyrone 105 as a single enantiomer, which had the identical core structure to the natural product. The structure, including relative stereochemistry of 105, was confirmed by single crystal X-ray analysis. Chapter Four builds on the previous two chapters and describes the conjugate addition-cyclisation with a higher order Gilman cuprate derived from vinyl bromide 44, which would deliver the vinyl side-chain required for the synthesis of reported natural product 7. The same acyclic precursor 43 as used in Chapter Three was cyclised and methylated to yield yet another cyclohexenone synthon 41. A single crystal X-ray analysis of related alcohol 162 confirmed the relative stereochemistry and structure. Another novel P2O5-mediated intramolecular cyclisation was achieved to give pyrone 168 and O-methylation provided a compound with the reported structure of natural product 7 as a single enantiomer. The structure of synthetic 7 was established unequivocally through extensive NMR studies. Comparisons of spectral data confirmed that natural tridachiahydropyrone was not the same as synthetic compound 7, so revision of the assigned natural product structure is warranted. Several other analogues were also synthesised using this methodology, highlighting the versatility of the method under development.

Ce manuscrit présente le développement d'une méthode de synthèse de motifs polypropionates et son application à la synthèse totale de deux molécules naturelles cytotoxiques : le Dolabélide A et le (+)-Discodermolide. Cette méthode, par analogie avec les voies de biosynthèse des polypropionates, permet la synthèse séquentielle et itérative de ces motifs par l'association de trois réactions : l'hydrogénation asymétrique de béta-cétoesters et de béta-hydroxycétones catalysée par des complexes chiraux du ruthénium, la méthylation diastéréosélective de Fráter-Seebach et la condensation de Claisen. Pour le Dolabélide A, deux fragments avancés ont été préparés, et 7 des 11 centres stéréogènes ont été installés par hydrogénation asymétrique avec des sélectivités supérieures à 95 %. Pour le (+)-Discodermolide, trois fragments intermédiaires ont été élaborés et 10 centres stéréogènes mis en place dont 7 par hydrogénation asymétrique ou méthylation diastéréosélective, ici encore avec des sélectivités supérieures à 95 %.

Synthèse biomimétique de motifs polypropionates par hydrogénation asymétrique à l’aide de complexes chiraux du ruthénium. Application aux synthèses du Dolabélide A et du (+) Discodermolide Ce manuscrit présente le développement d’une méthode de synthèse de motifs polypropionates et son application à la synthèse totale de deux molécules naturelles cytotoxiques : le Dolabélide A et le (+)-Discodermolide. Cette méthode, par analogie avec les voies de biosynthèse des polypropionates, permet la synthèse séquentielle et itérative de ces motifs par l’association de trois réactions : l’hydrogénation asymétrique de béta-cétoesters et de béta-hydroxycétones catalysée par des complexes chiraux du ruthénium, la méthylation diastéréosélective de Fráter-Seebach et la condensation de Claisen. Pour le Dolabélide A, deux fragments avancés ont été préparés, et sept des onze centres stéréogènes ont été installés par hydrogénation asymétrique avec des sélectivités supérieures à 95 %. Pour le (+)-Discodermolide, trois fragments intermédiaires ont été élaborés et dix centres stéréogènes mis en place dont sept par hydrogénation asymétrique ou méthylation diastéréosélective, ici encore avec des sélectivités supérieures à 95 %.

L'océan est un vaste réservoir de molécules potentiellement anticancéreuses. Ce manuscrit présente l'approche synthétique de deux molécules naturelles cytotoxiques : le (+)-discodermolide et le dolabélide A. Les motifs polypropionates de ces molécules ont été construits par l'association de trois réactions : la condensation de Claisen pour introduire le motif β-cétoester, l'hydrogénation asymétrique du β-cétoester catalysée par des complexes chiraux de ruthénium puis la méthylation diastéréosélective du β-hydroxyester. Pour le (+)-discodermolide, trois fragments avancés ont été élaborés et 12 des 13 centres stéréogènes mis en place, dont 8 par hydrogénation asymétrique ou méthylation diastéréosélective avec d'excellentes stéréosélectivités. Pour le dolabélide A, deux fragments avancés ont été préparés, et 7 des 8 groupements hydroxyles ont été installés par hydrogénation asymétrique avec des stéréosélectivités supérieures à 95 %.

Since the middle of the 20th century, significant interest has evolved from the scientific community towards the polypropionate family of marine natural products. A number of these compounds have been shown to possess significant biological activity, and this property, as well as their structural complexity, has driven numerous efforts towards their synthesis. The first chapter provides an introduction into the world of polypropionates, with a discussion on synthetic studies into a number of members of the tridachiapyrone family. Fundamental synthetic concepts utilised in this thesis towards the preparation of polyketides are also described, with a focus on their application towards the synthesis of 9,10-deoxytridachione, anti tridachiahydropyrone and syn tridachiahydropyrone. Chapter 2 describes the work undertaken towards the total synthesis of 9,10-deoxytridachione. The novel tandem conjugate addition-Dieckmann condensation of complex enones developed previously in the Perkins group was used to generate anti methylated cyclohexenones as key synthetic intermediates. The conversion of the cyclohexenones into the corresponding cyclohexadienes via allylic alcohols was attempted, utilising a Grignard-mediated reaction to achieve the selective 1,2-reduction. Studies into the Grignard-mediated reduction were also undertaken on seven additional cyclohexenones, in order to investigate the utility and scope of the reaction. The extension of the methodology previously developed for the synthesis of cyclohexenones is the subject of Chapter 3. This section describes investigations into the synthesis of stereochemically-diverse cyclohexenones from complex enones. The conjugate addition-Dieckmann condensation strategy was extended successfully towards the synthesis of a syn methylated cyclohexenone, which allowed the synthesis of the proposed true structure of tridachiahydropyrone to be pursued. The methodology developed in Chapter 3 was utilised in Chapter 4 to synthesise a model system of syn tridachiahydropyrone. A comparative analysis of the NMR data of the syn model, an anti model and anti tridachiahydropyrone with the natural product indicated that the true structure of tridachiahydropyrone may indeed have syn stereochemistry. The synthesis of syn tridachiahydropyrone was attempted, and to this end a suitable cyclohexanone was successfully synthesised. However, the subsequent methylation-elimination cascade failed to furnish the desired syn methylated cyclohexenone, producing only an anti methylated cyclohexanone. The stereochemistry of the methylation was deduced using high and low variable temperature NMR coupled with selective irradiation NOESY.

This thesis presents research into the development of sustainable methodology for the synthesis of amides, esters and polypropionate fragments. As well as a literature review of efficient natural product synthesis. Acylals are a known class of reagent that have been utilized within literature for a wide range of synthetic methodologies. Herein we present acylals as new highly active reagents for the N-/O-acylation of amines and alcohol nucleophiles for the synthesis of a range of formamides, acetamides, formate esters and acetate esters. It has been demonstrated that a range of acyl groups can be transferred including short and long chain alkyls, acryloyl, benzoyl, phenyl acetyl and biologically important trifluoroacetyl group, thus enabling the synthesis of a range of benzylamides and esters. These acylation reagents have also been shown to demonstrate inherent N-/O- selectivity towards the amine and alcohol groups of serine methyl ester. The scope and limitations of these reagents of the use of acylals has been investigated through the N-formylation of a range of unprotected amino acids, and for the synthesis of the biologically important tripeptide f-MLP. As well as the acylation/formylation of the ω-amino residue of a lysine residue within a decapeptide. Finally, it has also been demonstrated that a simple switch in pH from basic to acidic conditions for diols can change from O-acylation to acetal formation. The synthesis of enantiomerically enriched dihydropyrans from the heteo-Diels-Alder reaction of 1-alkoxy dienes and ethyl glyoxalate has been presented. A series of stereoselective derivatisation reactions were developed including, hydroboration, hydrogenation, epoxidation, dihydroxylation and epimerization which procced with stereoselectivity to afford a range of complex enantiomerically enriched polypropionate based building blocks, which are ideally suited for the synthesis of polyketide natural products through a “plug and play” approach. Chemistry has also been presented which makes use of the orthogonally addressable synthetic handles of the pyran building blocks. Utilization of either the masked aldehyde character or the ester functionality present allows for further elaboration of the pyran building blocks by selectively introducing new functionality.

Durant ma thèse, je me suis intéressée à la synthèse du myxovirescine A2, possédant des propriétés antibiotiques, et du (–)-doliculide, possédant des propriétés antitumorales. Le myxovirescine A2 est un macrocycle naturel à 28 chaînons produit par la bactérie Myxococcus. La synthèse des quatres fragments permettant d’accéder à ce composé a pu être réalisée en contrôlant de tous les centres stéréogènes présents dans ces fragments. . La synthèse du: fragment (C19–C28) a pu être réalisée en utilisant comme réaction clef une réaction d’alkylation de Myers suivie d’une réaction de Julia et d’une réduction, fragment (C15–C18) a été effectuée par alkylation de type Evans de l’oxazolidinone , fragment (C2–C3) a été synthétisé par nitrosation de la L-norvaline, fragment (C5–C14) a été envisagé par réarrangement énantiosélectif d’aminoalcool. Pour relier les fragments C15–C18 et C19–C28 du myxovirescine A2, une réaction de métathèse croisée a été réalisée. D’autre part, je me suis également intéressée à la synthèse formelle du fragment C1–C9 du (–)-doliculide, un dipeptide cyclique présent chez le lièvre de mer la Dolabella auricularia. Contrairement aux synthèses linéaires précédentes publiées dans la littérature, nous avons envisagé une voie convergente en réalisant aldolisation stéréosélective entre l’éthylcétone C1–C6 et l’aldéhyde C7–C9. L’aldéhyde C7–C9 a été obtenu grâce à l’utilisation d’une allylboration de type Roush. Une réaction d’alkylation Myers a permis de synthétiser l’éthylcétone et de contrôler les centres en C2 et C4. Si la condensation aldolique entre les fragment C1-C6 et C7-C9 a bien eut lieu, des problèmes de désoxygénation ont été rencontrés

In recent decades the emergence of marine polypropionate natural products as compounds of diverse structural complexity and intriguing biological activity has influenced the advancement of asymmetric synthesis and predicated detailed studies of marine ecology. The introductory chapter of this thesis explores the nature of marine natural products, including their structure, biological activity and biosynthesis. Additionally, a brief review of the aldol reaction is presented. This well established biomimetic chemical transformation underpins polyketide synthesis and was utilised extensively in the research contributing to this dissertation. Chapter Two describes the first asymmetric total synthesis of the two marine polypropionates isolated from specimens of Siphonaria australis by Hochlowski et al. in 1984. Spectroscopic analysis revealed hemiacetal 22 and ester 23 to be identical to the secondary metabolites extracted from the marine pulmonate. The synthetic approach to hemiacetal 22 utilised lactate derived ketone (S)-67 to control the configuration of the C7 and C8 stereocentres and involved the discovery of a mild protocol for the synthesis of trimethylsilyl enol ether 109, which was employed for a Mukaiyama aldol homologation reaction. Additionally, ester 23 was synthesised from hemiacetal 22 via a retro-Claisen fragmentation. The retro-Claisen approach utilised in the synthesis of ester 23 was extended in Chapter Three to serve as the pivotal transformation in an attempted total synthesis of the unusual marine polypropionate dolabriferol (30). The strategy toward dolabriferol (30) involved an iterative homologation of chiral ketone (S)-67 to install all but one of the requisite stereocentres in the natural product. Chemoselective deprotection of acyclic precursor 160 gave the elaborate 2,4,6-trioxaadamantane 167, whose participation as a protecting group mimic lead to the formation of ester 169 after reaction of the polycycle 167 with base. The synthesis of ester 169, which represents a direct precursor to dolabriferol (30), was achieved in 16 steps with an overall yield of 24%. Unfortunately, a robust protecting group on ester 169 prohibited a synthesis of dolabriferol (30), but intriguingly in one deprotection of ester 169 with aqueous hydrofluoric acid, spiroacetal 172 was isolated. Chapter Four describes the first total synthesis of cytotoxic marine polypropionate auripyrone A (78) and establishes the absolute configuration of this important natural product as that depicted for compound 78. The requisite C8-C12 stereopentad of auripyrone A (78) was formulated from Evans� dipropionate equivalent 53 in a double stereodifferentiating aldol reaction, followed by syn-reduction to give diol 206. Differentiation of the secondary alcohols in compound 206 was achieved by migration of the PMB protecting group and protection at C11 with the requisite acyloxy group of auripyrone A (78). Differential protection was critical to achieving selective spiroacetalisation to afford the unique spiroacetal dihydropyrone core of the natural product. The utility of LiHMDS for highly selective double stereodifferentiating aldol homologations of sensitive fragments is also discussed. This mild aldol protocol was pivotal to forming the carbogenic skeleton of auripyrone A, in particular, elaborate adduct 278.

Le portentol est un polypropionate qui possède une structure spirocyclique très originale. Cette molécule, dont il n'existe encore aucune synthèse totale, a été isolée du lichen Rocella portentosa à la fin des années 1960. Dans le but d'accéder au squelette du portentol, nous avons développé une méthodologie visant à synthétiser des spirotétrahydropyranes fonctionnalisés via une cyclisation de Prins. Au cours de ce travail, un phénomène de dédoublement cinétique dynamique a aussi été mis en évidence. La stachybotrine C, isolée à partir de la bactérie Stachybotrys parvispora, possède des propriétés neurotrophiques et neuroprotectrices très intéressantes. Deux voies de synthèse ont été envisagées pour préparer ce produit naturel. La première voie repose sur une réaction d'hydroarylation d'un éther propargylique catalysée à l'or, suivie d'une oxydation régiosélective du chromène résultant. La seconde voie fait intervenir une étape clé d'époxydation/cyclisation d'un alkénylphénol obtenu suite à un réarrangement de Claisen. Ces travaux nous ont permis d'accomplir la synthèse totale de la stachybotrine C, de réviser sa structure et de déterminer sa configuration absolue
Portentol is a polypropionate with an unusual spirocylic structure. This natural product, which has never been synthesized, has been isolated from the lichen Rocella portentosa. To access the spiranic moiety of the portentol, we have developed a methodology to synthesize spirotetrahydropyranes through a Prins cyclization. Through the study of the scope of this reaction, an usual dynamic kinetic resolution has been highlighted. Stachybotrin C, isolated from the bacteria Stachybotrys parvispora, exhibits interesting neuritogenic and neuroprotective properties. To prepare this natural product, two synthetic routes have been investigated. The first one is based on a gold-catalyzed hydroarylation of a propargyllic ether followed by a regioselective oxidation of the resulting chromene. The second pathway involves as a key step an epoxydation/cyclisation of a phenol prepared via a Claisen rearrangment. We accomplished the synthesis of stachybotrin C, revised its structure and established its absolute configuration

Leiodolide A is a unique natural product isolated from Pacific marine sponges which has provided an interesting target for total synthesis due to its complex structure and undefined stereochemistry. Although synthetic work towards the synthesis of sister compound leiodolide B has been published, the total synthesis of leiodolide A is yet to be achieved but remains an important target due to high potency against leukaemia, non-small lung and ovarian cancers. The convergent strategy towards the synthesis of leiodolide A involved the synthesis of three subunits; a synthetic route to the C21-C25 vinyl stannane is described, and efforts towards the synthesis of the bidirectional C11-C20 subunit are detailed. Asymmetric vinylogous aldol methodology was developed for the installation of the 1,2-syn propionate motif found in the C1-C10 subunit and in other polypropionate natural products, and was shown to be applicable to a range of substrates in moderate diastereoselectivity and excellent enantioselectivity.

Cet ouvrage traite principalement de la synthèse de motifs polypropionates de type stéréopentade ainsi qu’une application à la synthèse d’une molécule naturelle possèdant des propriétés biologiques. La stratégie envisagée pour l’élaboration de ces motifs récurrents dans plusieurs structures d’origine naturelle fait appel à la chimie des radicaux. Cette thèse se divise en différents chapitres dans lesquels la versatilité de la méthodologie développée sera démontrée. En premier lieu, il sera question de présenter l’importance de la synthèse de motifs polypropionates. Le domaine couvert par la chimie de ces molécules complexes hautement fonctionnalisées a contribué énormément à l’avancement de nos connaissances en synthèse organique, particulièrement dans le contexte des réactions impliquant des molécules acyliques. Une brève description des méthodes connues est présentée afin de saisir l’étendue des défis restants pour construire efficacement tous les isomères possibles des polypropionates de type stéréopentade. La stratégie proposée est basée sur une approche contrôlée entièrement par le substrat. Ce contrôle s’appuie sur le choix judicieux de l’acide de Lewis activant les deux réactions impliquées, soit la réaction de Mukaiyama et le transfert d’hydrogène. La seconde section de cette thèse concerne principalement le développement d’une réaction de Mukaiyama impliquant un éther d’énol silylé portant un lien pouvant être homolytiquement brisé dans la réaction suivante et un aldéhyde de type propionate. Le contrôle de l’aldolisation provient de la nature de l’acide de Lewis. Une espèce monodentate (BF3·OEt2) génère une relation 3,4-syn selon le modèle dit Felkin-Anh tandis que les acides de Lewis bidentates mènent à la relation 3,4-anti via un état de transition définit comme Cram-chélate. Une optimisation des conditions réactionnelles en variant l’acidité et la stoechiométrie de l’acide de Lewis de titane a permis de construire diastéréosélectivement le produit de Mukaiyama ayant une relation 3,4-anti. En outre, la nature des complexes impliqués dans ces réactions a été élucidée par des études RMN 13C à basse température. Une fois les précurseurs radicalaires synthétisés, notre méthodologie de réduction par transfert d’hydrogène contrôlée également par les acides de Lewis s’avère très efficace. Les acides de Lewis dérivés d’aluminium mènent sélectivement à la relation 2,3-syn selon un contrôle endocyclique tandis que les acides de Lewis de bore permettent la création des relations 2,3-anti en se basant sur une stabilisation par les divers facteurs de contrôle de molécules acycliques. Cette stratégie novatrice nous a ainsi permis de construire efficacement les 16 diastéréoisomères possibles. Le chapitre suivant concerne l’application de cette méthodologie à la synthèse de l’hémisphère ouest de la salinomycine et de la narasine. Plusieurs défis synthétiques ont été relevés à cette occasion par la présence de nombreux centres stéréogènes contigus. Nous avons réalisé que la relation stéréochimique 2,3-anti de la salinomycine n’est pas accessible sélectivement par la chimie des radicaux via l’effet exocyclique. Des études ont été entreprises afin de comprendre cette perte de sélectivité. Les conclusions suggèrent que les substituants sur le cycle imposent un biais conformationnel conduisant à des faibles sélectivités. Une alternative utilisant un réactif de crotylsilane chiral a été développée pour arriver à la molécule cible. Cette situation est différente dans le cas de la narasine où la présence du méthyle sur le carbone en position β du radical bloque efficacement l’approche d’une des faces d’attaque par l’hydrure. Des sélectivités impressionnantes nous ont permis de construire le fragment C1-C9 de la narasine de manière expéditive et efficace. Finalement, l’élongation sélective utilisant à nouveau la séquence d’aldolisation de Mukaiyama/réduction radicalaire suivie d’un couplage de type aldol stéréosélectif conduit au fragment C1-C17 de la narasine (hémisphère ouest)en 19 étapes avec un rendement global de l’ordre de 7 %. En dernier lieu, nous nous sommes penchés sur la réactivité des α-bromo-β- alkoxycétones lors de transfert d’hydrogène. Nous avons découvert que la chimie de ces derniers pourrait s’avérer utile dans le contexte de la synthèse de motifs complexes polypropionates. La présence d’un centre stéréogène de l’autre coté de la cétone semble avoir un impact sur la sélectivité.
This thesis focuses on a new methodology for the synthesis of polypropionate stereopentads with an application to the synthesis of a natural molecule that possess interesting biological properties. The key steps of our strategy to elaborate those motifs will use radical chemistry previously developped in our group. First, the importance of synthesizing polypropionate motifs is presented. In recent years, polypropionate systems have stimulated extensive interest due to their association with a broad spectrum of biologically active targets with proven or potential use in medicine, including those with antibiotic and anticancer properties. Many of the approaches reported used chiral reagents and took advantage of double asymmetric induction. Not surprisingly, mismatched scenarios were at times noticed and yet, no single strategy has been reported leading directly to all 16 stereopentad diastereoisomers. Thus, the rapid and facile assembly of the polypropionate framework would be very beneficial and is still an active area of research. The second section of this work describes our contribution to this area with the development of a fully substrate-controlled sequence of Mukaiyama aldol reaction followed by a hydrogen transfer reaction on aldehydes having the stereotriad array. The aldol reaction can be performed under Felkin-Anh or Cram-chelate pathway to give either the 3,4-syn or 3,4-anti relationship, respectively. This reaction was optimized using different Lewis acids to give excellent yield and diastereoselectivity. We found that an excess of TiCl3(OiPr) in our Mukaiyama reactions increased the chelating ability of the Lewis acid, thus leading to improved diastereoselectivity. Low temperature 13C NMR was performed to obtain more information on the complexes present in solution. Once the radical precursors were obtained, the hydrogen transfer step was performed. Aluminum-containing Lewis acids led to the exclusive formation of the 2,3- syn isomer under the endocyclic effect while controlling factors described for acyclic molecules were sufficient enough to give the 2,3-anti as a sole diastereoisomer, such as cases in which a boron-containing Lewis acid was added prior to the tin hydride. One limitation was observed with this scenario and resolved using the exocyclic effect to access all 16 polypropionate stereopentad motifs. To further demonstrate the synthethic potential of our methodology, we engaged on the synthesis of the western hemisphere of both salinomycin and narasin. The synthetic challenges related with these molecules are numerous due to the large number of adjacent stereogenic centers. We realized that the 2,3-anti stereochemical relation of salinomycin was not selectively accessible via radical chemistry under the exocyclic effect. Different substrates were tested to understand this limitation and we concluded that the substituents on the ring impose a conformationnal bias unfavorable to good selectivty. Still, we found an alternative employing a chiral crotylsilane to access this 2,3-anti relationship α to the six-membered ring. This situation is different in the case of narasin where the β-methyl substituent blocks efficiently the hydride attack from the upper face. Impressive selectivities were observed and the synthesis of the C1-C9 fragment of narasin was accomplished in an expeditive manner. Finally, the elongation using a second sequence of stereoselective Mukaiyama aldol reaction/radical reduction followed by an aldol coupling led to the construction of the western hemisphere of narasin in 19 synthethic steps with an overall yield of 7 %. Finally, we decided to focus our attention to the chemistry of α-bromo-β- alkoxyketones in hydrogen transfer reactions. We found that their ability to give selective transformations could be beneficial in the context of synthesizing complex polypropionate motifs. The presence of a stereogenic center on the other side of the ketone seemed to have a great impact on the selectivity.

The construction of polypropionate stereotriads in the synthesis of many non-aromatic polyketide natural products has typically been achieved through the "Roche ester" approach. This process starts with one of the stereocenters purchased as the Roche ester, followed by multiple redox and protecting group manipulations and only one carbon-carbon bond-forming aldol or crotylation reaction to attain the other two stereocenters of the stereotriad. Motivated by a desire for a more direct and rapid synthesis of these stereotriad constructs, we have built upon previous group methodology to develop a new approach utilizing a three step sequence of alkyne silylformylation-crotylation-Tamao oxidation. This strategy was first utilized in the synthesis of the C1-C9 fragment of the epothilones, and then this route applied to the synthesis of a C6 methyl-modified analog of epothilone B. We have also pursued the synthesis of versatile polypropionate building blocks as a way of generalizing our new approach.

In the Ward Group, stereoselective aldol reactions of thiopyran derived templates play an important role in polypropionate natural product syntheses. Central to this approach is the diastereo- and enantioselective synthesis of all possible aldol adducts 3 arising from tetrahydro-4H-thiopyran-4-one (1) and 1,4-dioxa-8-thiaspiro[4.5] decane-6- carboxaldehyde (2). There are four possible diastereomers of 3 indicated by the relative configurations at positions 3 and 1’ (syn or anti) and positions 1’ and 6’ (syn or anti). Up to date, the asymmetric aldol reaction of 1 with 2 catalyzed by L-proline or its tetrazole analogue 12 provides efficient access to 3,1’-anti-1’,6’-syn-3 (3-AS) without need for chromatography (>40 g scale; 75% yield, >98% ee) and 3,1’-syn-1’,6’-syn-3(3-SS) (via isomerization of 3-AS; >75% yield, 2 cycles); however, the preparation of enantiopure 3,1’-anti-1’,6’-anti-3 (3-AA) and 3,1’-anti-1’,6’-syn-3 (3-SA) still requires the use of enantiopure aldehyde 2 in a diastereoselective synthesis. Without a simple and scalable route, access to enantioenriched iterative aldol adducts and polypropionate natural products that are based on 3-AA and 3-SA skeletons are hindered. It was observed that conducting the asymmetric aldol synthesis of 3-AS on large scale gave enantioenriched 3-AA as a very minor product. This observation triggered the hypothesis of using L-proline to resolve racemic 3-AA via a retro-aldol reaction.In this thesis, the development, optimization, and application of an unprecedented L-proline catalyzed enantioselective retro-aldol reaction is described. Interesting mechanistic insights were uncovered. An unexpected isomerization process between 3-AA and 3-SA occurs in parallel with the retro-aldol process. The method was demonstrated to be a robust, flexible, and readily scalable process to access highly enantioenriched 3-AA (ee > 95%) and 3-SA (ee > 95%). To the best of our knowledge, this reaction represents the only reported enantioselective retro-aldol reaction catalyzed by L-proline.

Muamvatin (30) is a polypropionate natural product isolated from Siphonaria normalis by Ireland et al. in 1986. Muamvatin (30) is made from eight propionate units and contains an extraordinary trioxaadamantane ring system. This ring system exists in only one other naturally occurring polypropionate known as caloundrin B. Regarding the rare muamvatin trioxaadamantane ring system, it was hypothesized this ring system may not be formed via an enzymatic process and the actual natural product could be the linear precursor ent-71 which cyclizes to muamvatin (30) during isolation. The first total synthesis of muamvatin (30) by Paterson et al. confirmed its absolute and relative configuration, but the ambiguity regarding the origin of the trioxaadamantane ring system in this molecule remains unresolved. This work describes two approaches to make the linear precursor ent-71 from triol ketone 153. The carbon skeleton of muamvatin was synthesized through two iterative diastereoselective aldol reactions. In the first approach, “the thiopyran route”, the diene moiety of aldehyde 73 required protection to avoid reduction during desulfurization. Although use of the tircarbonyliron complex was successful, the trihydroxy ketone revealed upon desulfurization was unstable and spontaneously cyclized to bicyclic acetal 156. Molecular mechanics revealed that the relative configurations embedded in C3, C7, and C8 dramatically effected the stability of the corresponding bicyclic acetal. With that lesson learned, the fully assembled linear precursor 197 was made in our second approach “the acyclic route”. The oxidation state of the backbone oxygens were manipulated via an unusual chemoselective double Swern oxidation. Finally, revealing the sensitive 5-hydroxy-3,7,9-trione functionality formed the precursor 202. Efficient cyclization of precursor 202 and removal of the protecting group at C11-OH produced the desired natural product 30. The cyclization conditions tested on the linear precursor 202, suggested that although the cyclization to the trioxaadamantane is strongly favored thermodynamically, the process is very slow and unlikely to occur during the isolation process. Thus, formation of the trioxaadamantane ring system could be an enzyme-mediated process as was concluded for caloundrin B.

Under the conditions of transfer hydrogenation utilizing chromatographically purified ortho-cyclometallated iridium C,O-benzoate precatalysts, enantioselective carbonyl crotylation and methallylation can be performed in the absence of stoichiometric metallic reagents and stoichiometric chiral modifiers. In the case of carbonyl crotylation, use of a preformed precatalyst rather than an in situ generated catalyst results in lower reaction temperatures, providing generally higher diastereoselectivity and yields. By utilizing a more reactive leaving group in chloride over acetate on our methallyl donor, the inherently shorter lifetime of the olefin π-complex is compensated for, giving our group’s first report of reactivity utilizing 1,1-disubstituted allyl donors.
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