Thesis advisor: Amir H. Hoveyda / We have devised a broadly applicable catalytic cross-metathesis method for stereoretentive synthesis of Z- and E-trisubstituted α,β-unsaturated esters. Several new Mo-bisaryloxide complexes were prepared, and they showed superior efficiency in synthesizing the Z-trisubstituted enoates (vs. corresponding mono-aryloxide pyrrolide complexes). Synthetic utility of the method was demonstrated through several concise syntheses of bioactive triterpenoids and value-added derivatives of prenyl-containing compounds such as citronellal, citronellol, and geraniol, all of which are isolated from essential oils. This transformation offers a valuable alternative to carbonyl olefination approaches such as Wittig and Horner-Wadsworth-Emmons reactions. / Thesis (MS) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Chemical modification of naturally occurring cellulose into ester and ether derivatives has been of growing interest due to inexhaustible cellulose resources, and to excellent properties and extremely broad applications of these derivatives. However, traditional esterification and etherification involve relatively harsh conditions (strongly acidic or strongly alkaline), greatly limiting the content and range of functional groups that may be installed onto the cellulose backbone. Amorphous solid dispersion (ASD) is an effective method to promote oral delivery of poorly-soluble drugs by dispersing crystalline drugs in a polymer matrix, creating drug supersaturation upon release. Cellulose 𝜔-carboxyesters have been proven to be effective ASD matrices for many different drugs; however, synthesis of such polymers involves protecting-deprotecting chemistry and one synthetic route only leads to one structure. Developing a new generation of cellulosic polymers for oral drug delivery such as ASD matrices requires new synthetic techniques and powerful tools. Olefin cross-metathesis (CM) is a mild, efficient and modular chemistry with extensive applications in organic, polymer, and polysaccharide chemistry. Successful CM can be achieved by appending olefin “handles” from cellulose esters and reacting with electron-deficient olefins like acrylic acid. Cellulose ethers have much better hydrolytic stability compared to esters and are also commercially very important. The overarching theme of this dissertation is to investigate modification of cellulose ether derivatives, and to design and synthesize effective ASD polymers by olefin CM. We first validated the strategy of performing CM by appending metathesis “handles” through etherification and then subjected these terminal olefins to various partners (acrylic acid and different acrylates). After demonstration of the concept, we applied different starting materials (e.g. ethyl cellulose, methyl cellulose, microcrystalline cellulose, and hydroxypropyl cellulose) with distinctive hydrophobicity/hydrophilicity balance. Furthermore, α,β-unsaturated CM products tended to undergo radical crosslinking through abstraction of 𝛾-protons and recombination of polymer radicals. In order to resolve this issue, we first applied post-CM hydrogenation and then explored a thiol-Michael addition to the α,β-unsaturation, which also incorporates an extra functional group through the thioether. We have successfully prepared a collection of cellulose 𝜔-carboxyether derivatives through the above-mentioned method and preliminary drug induction experiments also revealed that these derivatives hold high promise for ASD application. We also explored the possibility of conducting CM in a reverse order: i.e. appending electron-deficient acrylate groups to the polymer, then subjecting it to electron-rich small molecule terminal olefins. The failure of this metathesis approach was speculated to be due mainly to low acrylate reactivity on an already crowded polymer backbone and the high reactivity of rapidly diffusing, small molecule terminal olefins. Last but not least, we further utilized olefin CM to conjugate bile salt derivatives (e.g. lithocholic acid and deoxycholic acid) to a cellulose backbone by converting bile salts into acrylate substrates. Successful CM of bile salt acrylates to cellulose olefin “handles” further demonstrated the great versatility, excellent tolerance, and very broad applicability of this strategy. Overall, we have founded the strategy for performing successful olefin CM in many cellulose ether derivatives with acrylic acid and a variety of different acrylates. Post-CM hydrogenation efficiently removes the α,β-unsaturation and provides stable and effective cellulose 𝜔-carboxyether derivatives for ASD application. Tandem CM/thiol-Michael addition not only eliminates the crosslinking tendency but also enables an even broader library of polymer structures and architectures for structure-property investigations. We anticipate these methods can be readily adapted by polysaccharide chemists and applied with numerous complex structures, which would greatly broaden the range of cellulose and other polysaccharide derivatives for applications including ASDs, P-glycoprotein inhibition, antimicrobial, coating, and other biomedical applications. / Ph. D. / When it comes to drug administration, oral delivery is often preferred over other methods like intravenous injection since it is cheap, convenient, painless and easily conducted without requiring professional training or clinical environment. However, one of the most common issues for oral drugs to be absorbed by human body is that a large portion of drugs do not dissolve in water. An effective method to conquer this problem is to blend a properly designed polymer with the poorly dissolving drug, making the drug dissolve in water more effectively and thus be able to enter the bloodstream. Such polymers have to be safe, stable, non-toxic, and biodegradable. Cellulose is one of the most abundant polysaccharides on earth and it has inexhaustible source from wood, cotton and many other plants. Natural cellulose is a linear polymer and is highly crystalline and therefore does not tend to dissolve in water or any other simple organic solvents. Chemical modifications of cellulose to make derivatives (e.g. cellulose esters and ethers) will disrupt the crystallinity and make it more soluble and processible for many applications including coating, packaging, food and pharmaceuticals. The Edgar and Taylor groups have demonstrated that some cellulose derivatives with specific properties are very good polymer matrices to facilitate the delivery of poorly soluble drugs. These cellulose-based polymers can stabilize the active drugs, protect drug from the acidic stomach and make them more soluble in the digestive tract so they can be absorbed by human body. However, previous synthetic methods to prepare such cellulose derivatives are very timeand effort- consuming. Meanwhile, one polymer is usually not suitable for every drug since each drug will have different issues, for example different water solubility and/or stability in acidic stomach. Therefore, design and preparation of new polymers with enhanced performance is extremely desirable, which highly depends on development of new chemistry. This dissertation focuses on investigating novel chemistry to modify cellulose ethers and creating a broad range of polymer candidates for oral drug delivery. Unlike traditional methods, the new method is very mild and efficient with short reaction time, neutral pH, complete conversion and almost quantitative yield. It also allows incorporation with all kinds of functional groups to afford a variety of polymer structures. As a result, this method has enabled a library of polymers with diverse structures for drug delivery application and for structure-property relationship evaluations, which will further provide valuable information for designing nextgeneration polymers with optimized performance. The cellulose derivatives prepared in this way are also very promising for coating, food additive, and other biomedical applications.

In this study, we were particularly interested in looking at the possibility that cross metathesis of olefins in melt phase could be used to produce polydimethylsiloxane (PDMS) modified polypropylene (PP). The intention of this project was also to study and quantify relationships among the main experimental factors in the reaction: temperature, catalyst concentration and molar ratio of PP to PDMS, through a 2-level factorial statistical design. In order to examine if PP-PDMS copolymers were synthesized in the melt phase, measurement of the chemical, physical and viscoelastic properties of the synthesized copolymers was necessary. Techniques including proton (¹H)-nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), rheometry and scanning electron microscopy (SEM), were all used to characterize the synthesized copolymers. ¹H NMR measurements confirmed the presence of PDMS in the copolymers. They also provided a quantitative measurement of PP to PDMS molar ratio in copolymers by determining the integration of PP PDMS repeating unit signals in NMR spectra. Compared to virgin PP, a lower melting enthalpy of the PP phase in the copolymer was observed from DSC results. This implied that the PDMS component influenced the thermal behavior of the PP crystalline phase in the copolymers. Moreover, TGA measurements indicated that a higher thermal stability was obtained for PP-PDMS copolymers than that for virgin PP wax and this was expected since PDMS is known for its excellent stability at high temperature. Rheological analysis showed that the presence of PDMS in the copolymers gave lower complex viscosities and loss moduli, but higher storage moduli than those for virgin PP. Furthermore, the morphology of copolymers was examined by SEM and elemental analysis at the surface using an energy dispersive X-ray (EDX) analyzer on the SEM. It was found that micrographs of copolymers showed round domains on the surface, which were not observed in virgin PP wax and those round segments were confirmed to contain silicon. Torque values used in a batch mixer for polymerizations and the remaining weight % of copolymers at 350°C were used to conduct statistical analysis, through which models used to describe the relationships between experimental factors and these physical responses were determined.

In this study, we were particularly interested in looking at the possibility that cross metathesis of olefins in melt phase could be used to produce polydimethylsiloxane (PDMS) modified polypropylene (PP). The intention of this project was also to study and quantify relationships among the main experimental factors in the reaction: temperature, catalyst concentration and molar ratio of PP to PDMS, through a 2-level factorial statistical design. In order to examine if PP-PDMS copolymers were synthesized in the melt phase, measurement of the chemical, physical and viscoelastic properties of the synthesized copolymers was necessary. Techniques including proton (¹H)-nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), rheometry and scanning electron microscopy (SEM), were all used to characterize the synthesized copolymers. ¹H NMR measurements confirmed the presence of PDMS in the copolymers. They also provided a quantitative measurement of PP to PDMS molar ratio in copolymers by determining the integration of PP PDMS repeating unit signals in NMR spectra. Compared to virgin PP, a lower melting enthalpy of the PP phase in the copolymer was observed from DSC results. This implied that the PDMS component influenced the thermal behavior of the PP crystalline phase in the copolymers. Moreover, TGA measurements indicated that a higher thermal stability was obtained for PP-PDMS copolymers than that for virgin PP wax and this was expected since PDMS is known for its excellent stability at high temperature. Rheological analysis showed that the presence of PDMS in the copolymers gave lower complex viscosities and loss moduli, but higher storage moduli than those for virgin PP. Furthermore, the morphology of copolymers was examined by SEM and elemental analysis at the surface using an energy dispersive X-ray (EDX) analyzer on the SEM. It was found that micrographs of copolymers showed round domains on the surface, which were not observed in virgin PP wax and those round segments were confirmed to contain silicon. Torque values used in a batch mixer for polymerizations and the remaining weight % of copolymers at 350°C were used to conduct statistical analysis, through which models used to describe the relationships between experimental factors and these physical responses were determined.

Le myricanol est un [7,0]-métacyclophane naturel qui appartient à la famille des diarylheptanoïdes cycliques et qui possède des propriétés structurales et biologiques intéressantes (activité anti-Alzheimer ou anticancéreuse). L’objectif de ce travail de thèse est la préparation ambitieuse en voie racémique puis atropostéréosélective du myricanol, rendue délicate de part la tension de cycle existante. Pour se faire, deux nouvelles approches rétrosynthétiques ont été considérées. Une première route racémique a été envisagée et a permis de préparer le macrocycle par le biais d’une réaction de métathèse croisée suivie d’une réaction de Suzuki-Miyaura domino intramoléculaire avec un rendement de 2.55% en 11 étapes. Une autre voie racémique a également été explorée où la préparation du noyau biarylique du myricanol a été envisagé par une réaction de couplage intermoléculaire métallo-catalysée suivie d’une réaction de métathèse cyclisante. Des intermédiaires avancés ont également été préparés. / The myricanol, a natural [7.0]-meta-cyclophane which belongs to the family of strained and cyclic diarylheptanoids, possess an interesting structure and attractive biologically activities (anti Alzheimer and anti cancer properties). Actually only two synthesis of racemic (+/-)-myricanol have been reported in the literature. The goal of this research was to prepare this strained cyclophane in a racemic and then in an atropostereoselective route taking into account the challenging ring closure. Thus a linear diarylheptanoid was prepared using an efficient cross-metathesis reaction followed by an intramolecular Suzuki-Miyaura domino reaction giving rise to the desired cyclophane with 2.55% overall yield in 11 steps. On the other side, the biaryl core of myricanol was envisaged by an intermolecular metallo-catalysed coupling reaction between already highly functionalized fragments, followed by a ring closure metathesis. Two advanced intermediates were already attempted.

Le fluor a gagné un intérêt croissant dans de nombreux domaines de la chimie organique. De nombreuses méthodes de fluoration ont vu le jour afin de répondre à une demande croissante en molécules fluorées les plus diverses. Cependant certains synthons restent difficiles à obtenir par des moyens efficaces. Une réaction de fluoration électrophile d’allylsilanes a été développé afin d’accéder à des motifs α-fluroénamides hautement fonctionnalisés. Ces α-fluroénamides peuvent être de types variés : benzylamines, anilines, ou alkyles… Un accent particulier a été mis sur des dérivés d’acides aminés pouvant ainsi servir de peptido-mimétiques. Dans un souci d’accéder à une plus grande variété moléculaire, la réactivité de ces motifs fluorés allyliques vis-à-vis des réactions de métathèses croisées, très peu étudiée, a été investiguée. La faisabilité de ces deux méthodologies a été démontrée par la synthèse d’une molécule cible originale. Le fluor, principalement utilisé pour ses propriétés physico-chimiques et pharmacocinétiques a ici pu être exploité pour sa réactivité. Une réaction d’amination catalytiques sur les dérivés α-fluroénamides fonctionnalisés a été développée, permettant l’incorporation de nucléophiles aminés variés. Cette réaction permet de produire des motifs γ-aminomides-α,β-insaturés, mis à profit dans la synthèse d’alcaloïdes bicycliques. / Fluor has gained popularity in various fields of organic chemistry. Numerous fluorination reactions have been developed to answer increasing demand in diverse Fluor-containing molecules. Nevertheless, the syntheses of some structures are still unanswered. In this work, the electrophilic fluorination of allylsilanes has been developed allowing access to highly functionalised fluoroenamides. Said α-fluroenamides can be of various types such as benzylamines, anilines or alkyls. Focus has been brought on amino acids derivatives which could be used as peptidomimetics. Reactivity of those allylic fluorides towards cross-metathesis reactions has been investigated which has been very rarely reported yet. Validation of those two methodologies has been made in a form of the synthesis of a novel active molecule. Fluorine has been mainly used for the properties it brings in molecules it is incorporated in. In this case, fluorine has been exploited for its reactivity. A catalytic amination reaction has been developed on functionalised α-fluroénamides giving access to α,β-insatured-γ-aminomides.

In this thesis a methodology to synthesize anti-β-hydroxy-α-amino esters possessing olefins has been investigated. The developed procedures originate from two already established procedures in which α-amido-β-keto esters, which do not contain olefins, has been stereoselectively reduced to the corresponding anti-β-hydroxy-α-amino alcohols via asymmetric transfer hydrogenation coupled with dynamic kinetic resolution. Both established methods, one solvent free and one emulsion procedure, have been investigated on the expanded substrate scoop. Four different α-amido-β-keto ester containing olefins were tested and it was found that the ketones were reduced to desired anti-β-hydroxy-α-amino esters in both procedures, but also side products were formed where the olefins were reduced. The ratio of the different products was dependent on the structure of the starting α-amido-β-keto ester, ligand used on the catalyst and reaction conditions such as number of equivalents of base and reaction temperature. The diastereoselectivity for the desired products was in favor of the anti stereoisomer, however, the dr was worse than in the established procedures. The usefulness of this methodology was then demonstrated by a formal total synthesis of Sphingosine.

La réaction de métathèse a connu un essor considérable au cours de ces dernières années et le prix Nobel décerné aux chimistes Yves Chauvin, Robert H. Grubbs et Richard R.Schrock est venu récompenser ce travail. Cette réaction a été impliquée pour la synthèse de molécules naturelles d’origine marine. Les thiocyanatines A et B isolées en 2001 ont été ainsi préparées en utilisant la réaction de métathèse croisée. Il s’agit du premier exemple de métathèse en présence de groupements thiocyanates. De plus, ces deux synthèses utilisent la technologie micro-ondes. Le largazole, isolé en 2008, est une cible synthétique très important du fait de son activité anticancéreuse. Ce manuscrit retrace la synthèse d’une partie de cette molécule mais également une étude méthodologique pour la formation de motifs thiazoles par micro-ondes. Enfin, la rugulactone, isolée en 2009, a été préparée selon une stratégie tandem de métathèse cyclisante / métathèse croisée et cette dernière a été appliquée à la synthèse d’analogues. / The metathesis realized an important development during the last few years and the Nobelprize given to the chemists Yves Chauvin, Robert H. Grubbs et Richard R. Schrock came toreward this work. This reaction has been involved for the synthesis of natural molecules of marine origin. Thiocyanatines A and B, isolated in 2001, have been so prepared by using the reaction of cross metathesis. This is the first example of metathesis with the presence ofthiocyanates groups. Moreover, these two syntheses are using the microwave technology. Largazole, isolated in 2008, is a very important synthetic target because of its anticancerous activity. This manuscript is explaining the synthesis of one part of this molecule but it also provides a methodological study for the formation of thiazoles motives by microwave. Then,Rugulactone, isolated in 2009, has been prepared with a tandem strategy of ring clossing metathesis / cross metathesis and this one has been applied to the synthetis of analogues.

This thesis is divided into four separate parts with amino alcohols as the common feature. The first part of the thesis describes the development of an efficient three-component approach to the synthesis of α-hydroxy-β-amino esters. Utilizing a highly diastereoselective Rh(II)-catalyzed 1,3-dipolar cycloaddition of carbonyl ylides to various aldimines, syn-α-hydroxy-β-amino esters are formed in high yields and excellent diastereoselectivities. An asymmetric version was also developed by employing chiral α-methylbenzyl imines as dipolarophiles yielding enantiomerically pure syn-α-hydroxy-β-amino esters. This methodology was also applied on a short asymmetric synthesis of the paclitaxel side-chain as well as in an asymmetric synthetic approach towards the proteasome inhibitor omuralide. Furthermore, the use of chiral Rh(II) carboxylates furnishes the syn-α-hydroxy-β-amino esters in moderate enantioselectivity (er up to 82:18), which indicates that the reaction proceeds via a metal-associated carbonyl ylide. The second part describes the development of a 1,3-dipolar cycloaddition reaction of azomethine ylides to aldehydes for the synthesis of α-amino-β-hydroxy esters. Different methods for the generation of the ylides, including Vedejs’ oxazole methology and an Ag(I)/phosphine-catalyzed approach have been evaluated. The best results were obtained with the Ag(I)/phosphine approach, which yielded the desired α-amino-β-hydroxy ester in 68% yield and 3.4:1 syn:anti-selectivity. The last two parts deals with the total synthesis of the amino alcohol-containing natural products D-erythro-sphingosine and (−)-stemoamide. The key transformation in the sphingosine synthesis is a cross-metathesis reaction for the assembly of the polar head group and the aliphatic chain. In the stemoamide synthesis, the key feature is an iodoboration/Negishi/RCM-sequence for the construction of the β,γ-unsaturated azepine core of stemoamide followed by a stereoselective bromolactonization/1,4-reduction strategy for the installation of the requisite C8-C9 trans-stereochemistry. / QC 20100820

<p>This thesis is divided into three separate parts with amino alcohols as the common feature. The first part describes the development of a novel three-component approach to the synthesis of α-hydroxy-β-amino esters. Utilizing a highly diastereoselective Rh(II)-catalyzed 1,3-dipolar cycloaddition of carbonyl ylides to various aldimines, syn-α-hydroxy-β-amino esters formed in high yields and excellent diastereoselectivities. This methodology was also applied in a short enantioselective synthesis of the C-13 side-chain of Taxol.</p><p>The second part of the thesis describes a total synthesis of D-erythro- Sphingosine based on a cross-metathesis approach to assemble the polar head group and the aliphatic chain.</p><p>The last part deals with the application of amino alcohols as scaffolds in a diversity-oriented protocol for the development of libraries of small polycyclic molecules. The design of the libraries is based on the iterative use of two powerful ring-forming reactions; a ring-closing metathesis and an intramolecular Diels-Alder reaction, to simultaneously introduce structural complexity and diversity.</p>