The synthesis of natural products has always been, and still is, of great interest for various reasons. Firstly, the molecular diversity of natural products pushes organic chemists to develop and apply new strategies and methods in organic synthesis. Secondly, the practice of natural product synthesis remains one of the best way to confirm the structure of a natural product. Meanwhile, it also provides a way for examining the true robustness of novel synthetic methods, which has to be highly selective and efficient to be applied in total synthesis. Thirdly, developing a total synthesis of a natural product, which is in most cases isolated with low yields and after intensive purifications, will in general allow to produce sufficient quantities for the study of its biological properties. Finally, chemists also have the opportunity to synthesize a series of analogs of a natural product by slight modifications of the synthetic route, these analogues enabling the study of structure/activity relationships and potentially possessing better pharmacological and physicochemical properties compared to the original natural product. In that context, this thesis work has focused on the total synthesis of two natural macrocyclic alkaloids by using copper catalysis in the key steps. In the case of synthesis of (-)-melanthioidine, a member of the dimeric macrocyclic diaryl ether tetrahydroisoquinoline alkaloid, copper catalysis was utilized in the key cyclodimerization step to form a diaryl ether bond bridged 20-membered ring constituted by two phenethyltetrahydroisoquinoline subunites. In this synthesis the configuration of the phenethyltetrahydroisoquinoline was controlled by a Bischler-Napieralski cyclization / Noyori asymmetric hydrogenation sequence starting from the corresponding amide, which could be readily prepared by a multi-step sequence from commercially available compounds. With the success we met in the synthesis of (-)-melanthioidine, we next turned our attention to the synthesis of paliurine F, which is a member of cyclopeptide alkaloids. In this synthesis, the copper-mediated cross coupling was implemented to install not only C(sp2)-O bond but also more challengingly to form C(sp2)-N bond to construct the 13-member ring of paliurine F in the regio-, chemo- and diastereo-selective manner, which eventually enabled us to develop a highly convergent approach to paliurine F.Finally, we also put our effort to the development of an efficient copper-mediated domino double Ullmann coupling-double Claisen rearrangement process starting from readily availble ene-diols and vinyl iodides. In this synthesis, the double Ullmann coupling product in situ underwent a single Claisen rearrangement followed by a microwave-assisted Claisen rearrangement to provide a highly functionalized 1,6-dicarbonyl compounds. In addition, our process was also shown to be successful for the functionalization of glycals. In conclusion, our work further highlight the efficiency of copper-mediated transformation in the synthesis of natural products and provide new strategies for the formation of symmetrial or, even more interestingly, non-symmetrical macrocyclic molecules. Moreover, combining copper-mediated reactions with pericyclic process such as Claisen rearrangement was also shown to be an efficient way for the development of novel synthetic methods. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

The aim of this project was to develop a cascade approach towards perhydropyrrolo-[1,2-a]-quinolines and to apply this to the asymmetric synthesis of the gephyrotoxin alkoids. Chapters Two and Three outline the development of a synthetic route towards a range of cascade precursors, whilst Chapter Four outlines investigations into the enamine-Michael cascade. Central to understanding the cascade process was the discovery that the major product of the enamine-Michael cascade was the unusual tricyclic hydroquinium salt. This can subsequently be engaged in a diastereoselective inter- or intramolecular reduction to afford either a trans-perhydro-[1,2-a]-quinoline or a tetracyclic aminal in high overall yield depending on the C1 oxygen substituent.

Thesis advisor: James P. Morken / This dissertation describes the first enantioselective 1,2-diboration of cis-substituted 1,3-dienes. In the presence of a platinum catalyst and TADDOL-derived phosphonite ligands, both 4,4-disubstituted and mono-cis-substituted 1,3-dienes undergo regioselective 1,2-diboration to afford the corresponding 1,2-diols upon oxidation in up to 98:2 er and high yield. By achieving enantioselective 1,2-diboration of 1,3-dienes, a new synthetic route to α-chiral (Z)-allylboronate reagents has been developed. In the presence of an aldehyde, these allyl bis(boronate) esters undergo highly diastereoselective allylboration reaction to afford enantioenriched 1,5-homoallylic alcohols bearing all-carbon quaternary centers or syn-propionate motifs. In the presence of 1,4-dicarbonyl compounds, the (Z)-allylboronates undergo a double allylation reaction to afford cyclohexanols with four contiguous stereocenters in good yield and moderate to excellent diastereoselectivity. The tandem diboration/double allylation has been applied to the total synthesis of pumilaside B aglyon, and the partial synthesis 1β-hydroxy arbusculin A and bromophycolide F. / Thesis (PhD) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: T. Ross Kelly / Total Synthesis is a field of Organic Chemistry that focuses on the construction of various compounds. These compunds can be known, such is the case in the synthesis of natural products like Lactonamycin, or they can be creations of the imagination, like the Molecular Motor. In both cases, this particular concentration of science involves a keen use of intellect as well as a substantial amount of creativity. / Thesis (BS) — Boston College, 2003. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Chemistry. / Discipline: College Honors Program.

Thesis advisor: Amir H. Hoveyda / Chapter 1. Ligand-Controlled Site-Selective NHC–Cu-Catalyzed Protoboration of Monosubstituted Allenes. Site-selective proto–boryl additions to monosubstituted allenes promoted by NHC–Cu complexes are disclosed. Synthetically useful 1,1-disubstituted and Z-trisubstituted alkenylboron compounds are afforded in high efficiency (71%–92% yield) and site selectivity (88% to >98%) through proper choice of NHC ligands. Mechanistic study with the assistance of DFT calculations indicates that protonation of 2-boron-substituted allylcopper complex occurs through six-membered cyclic transition state. The utility of this protocol is demonstrated through application to fragment synthesis of an antibiotic macrolide natural product elansolid A. Chapter 2. Cu-Catalyzed Chemoselective Copper–Boron Additions to Monosubstituted Allenes Followed by Allyl Additions to Carbonyl Compounds. The first examples of catalytic generation of 2-boron-substituted allylcopper species and their in situ use for C–C bond formation are described. The reactions are performed in the presence of bisphosphine– or NHC–Cu complexes at 22 oC. High-value alcohol-containing alkenylboron compounds are provided in high efficiency (68–92% yield after oxidation) and stereoselectivity (88:12 to >98:2 dr). The reactions proceed with exclusive γ-addition mode through a cyclic six-membered transition state. Enantioselectivity can be achieved with chiral bisphosphine ligands in up to 97:3 enantiomeric ratio. Chapter 3. Chemo-, Site- and Enantioselective Copper–Boron Additions to 1,3-Enynes Followed by Site- and Diastereoselective Additions of the Resulting Allenylcopper Complexes to Aldehydes. Catalytic enantioselective multicomponent reactions involving 1,3-enynes, aldehydes and B2(pin)2 are described. The resulting products contain a primary C–B(pin) bond, as well as alkyne- and hydroxyl-substituted tertiary stereogenic centers. A critical feature is high enantioselectivity of the initial Cu–B addition to an alkyne-substituted terminal alkene. The key mechanistic issues are investigated by DFT calculations. Reactions are promoted in the presence of the Cu complex of an enantiomerically pure C1-symmetric bisphosphine and are complete in 8 h at ambient temperature. Products are generated in 66–94% yield (after oxidation or catalytic cross-coupling), 90:10 to >98:2 diastereomeric ratio, and 85:15–99:1 enantiomeric ratio. Aryl-, heteroaryl-, alkenyl-, and alkyl-substituted aldehydes and enynes are suitable substrates. Utility is demonstrated through catalytic alkylation and arylation of the organoboron compounds as well as applications to synthesis of fragments of tylonolide and mycinolide IV. Chapter 4. Multifunctional Alkenylboron Compounds through Single-Catalyst-Controlled Multicomponent Reactions and Their Applications in Scalable Natural Product Synthesis. A facile multicomponent catalytic process that begins with a chemo-, site- and diastereoselective copper–boron addition to a monosubstituted allene followed by addition of the resulting boron-substituted organocopper intermediate to an allylic phosphate, generating products that contain a stereogenic center, a monosubstituted alkene and an easily functionalizable Z-trisubstituted alkenylboron group in up to 89% yield with >98% branch selectivity and stereoselectivity and an enantiomeric ratio greater than 99:1. The copper-based catalyst is derived from a robust heterocyclic salt that can be prepared in multigram quantities from inexpensive starting materials and without costly column chromatography purification. The utility of the method is demonstrated through enantioselective synthesis of gram quantities of two natural products, rottnestol and herboxidiene/GEX1A. Chapter 5. Cu-Catalyzed Enantioselective Allyl and Propargyl 1,6-Conjugate Additions through 3,3’-Reductive Elimination. Catalytic enantioselective 1,6-conjugate additions of allyl-type nucleophiles promoted by NHC–Cu complexes are reported. Propargyl and 2-boron allyl 1,6-conjugate products are formed in high efficiency, diastereo- and enantioselectivity. The unique mechanistic feature is that the transformations proceed through Cu-catalyzed 3,3’-reductive elimination, that is unprecedented for copper catalysis. Further mechanistic study and application to complex molecule synthesis will be conducted. / Thesis (PhD) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Salvinorin A [(2S,4aR,6aR,7R,9S,10aS,10bR)-9-(acetyloxy)-2-(3-furanyl)-dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naptho[2,1-c]pyran-7-carboxylic acid methyl ester] is a trans-neoclerodane diterpene from the leaves of the hallucinogenic Mexican sage Salvia divinorum and has been identified as the principal psychoactive component in this plant of traditional spiritual importance. Salvinorin A is the most potent naturally occurring hallucinogen found so far and is reported to act selectively as a ƒÛ-opioid receptor agonist. Synthetic modification of the natural product has contributed to a number of proposed pharmacophores to identify the key structural features necessary for biological activity and a direct strategy for the asymmetric synthesis of the natural product is desirable since it allows access to a more diverse range of analogues. An ambitious retrosynthetic study of salvinorin A indicated the C(3)-heterosubstituted furan as an appropriate starting material for a Diels-Alder approach towards the ketone ring of the natural product. An expedient and high yielding methodology for the preparation of 3-furylamines is described, allowing the flexible introduction of alkyl substituents in the C(5) position. Optically pure ephedrine isomers have been explored as chiral amine auxiliaries and have been successfully attached as 3-furylamine substituents using the general methodology described. The 3-furylamines are electron rich dienes that are highly reactive towards Diels-Alder cycloaddition reactions with methyl acrylate. Diastereoisomers of the 7-oxanorbornane species methyl 1-methyl-5-oxo-7-oxa-bicyclo[2.2.1]heptane-2-carboxylate were prepared as new compounds from the hydrolysis of Diels-Alder cycloadducts and are functionalised bicyclic intermediates to access the ketone of the natural product. Diels-Alder reactions between the non-racemic (2S)-ephedrine-derived furans and methyl acrylate gave spiro-oxazolidine adducts that underwent hydrolysis to give the desired ketone. X-ray crystallography data for the derivatised cycloadduct established diastereoselectivity in favor of the (1S,4S)-enantiomer, as desired for the asymmetric natural product synthesis. A procedure for the ether cleavage of methyl 1-methyl-5-oxo-7-oxa-bicyclo[2.2.1]heptane-2-carboxylate was required to access the convergent precursor methyl 5-acetoxy-2-methyl-4-oxocyclohex-2-enecarboxylate. Successful C-O cleavage was achieved using Lewis-acid catalysis with BBr3 followed by mixing with the hindered base 2,4,6-collidine to yield methyl 5-hydroxy-2-methyl-4-oxocyclohex-2-enecarboxylate albeit only at high dilution. Acetylation proceeded in excellent yield in the same reaction vessel to give methyl 1-methyl-5-oxo-7-oxa-bicyclo[2.2.1]heptane-2-carboxylate in excellent yield. The devised synthetic pathway is shown to successfully construct the ketone ring of salvinorin A and stereoselectivity for the (1S,4S)-enantiomer can be achieved using the ephedrine derived furans as desired for the asymmetric natural product synthesis. The ƒÔ-lactone ring 6-(furan-3-yl)-5,6-dihydro-4-methyl-3-vinylpyran-2-one was derived from rudimentary precursors as a convergent reagent to introduce the lactone ring of salvinorin A. A short synthesis for the racemic compound is described starting from the aldol reaction between 3-furaldehyde and acetone to give the 3-furfurol, 4-(furan-3-yl)-4-hydroxybutan-2-one in quantitative yield. The 3-furfurol was reacted to form the ƒÑ-bromovinyl ester, 1-(furan-3-yl)-3-oxobutyl 2-bromobut-3-enoate using a deconjugation/esterification protocol with 2-bromobut-3-enoyl chloride. Intramolecular ring closure to the ƒÔ-lactone was achieved using a Reformatsky reaction and dehydration under acidic conditions yielded the racemic convergent precursor 6-(furan-3-yl)-5,6-dihydro-4-methyl-3-vinylpyran-2-one in high yield. A possible strategy for joining the ketone and lactone fragments for the total synthesis of salvinorin A is proposed.

The field of metal-catalyzed C–H bond functionalizations is an incredibly vibrant and spans beyond the formations of biaryl motifs. The introduction chapter will cover the mechanistic aspects of the C–H bond functionalization with metal-carboxylate complexes. The mechanistic facets of this reaction will be the main conducting line between the different sections and chapters of the first part of this thesis. In the second chapter, will be described additives that can readily promoted C–H bond arylation of poorly reactive substrates. More specifically, we will revisit the intramolecular direct arylation reaction we will demonstrate the effect of pivalic acid as a co-catalyst by developing milder reaction conditions. In the third chapter we be described experimental and computational studies which suggested that the a single pathway might be involved in the palladium-catalyzed C–H bond functionalization of a wide range of (hetero)arene. Following this we will describe a general set of conditions for the direct arylation of wide range of heteroarenes. Also, we will present two different strategies to selectively and predictably arylate substrates containing multiple functionalizable C–H bonds. In the fourth chapter will be presented our efforts toward the development of new C–H bond functionalization methods in which we could apply our knowledge on the C–H bond cleavage and apply it to the formation of new scaffolds. The development of two new palladium-catalyzed methods were also described. In the fifth chapter, our effort toward the development of ligands to specifically promoted C–H bond cleavage will be presented. In the sixth chapter will be presented the latest results on the study of the mechanism of the C–H bond cleavage combining experimental and computational studies. In part B of this thesis will be presented our strategy toward the total synthesis of ginkgolide C that included two gold(I)-catalyzed reactions as key steps in the preparation of the spiro[4.4]nonane core of this natural product. The first studies on the feasibility of the key steps of the synthesis will be described.

The field of metal-catalyzed C–H bond functionalizations is an incredibly vibrant and spans beyond the formations of biaryl motifs. The introduction chapter will cover the mechanistic aspects of the C–H bond functionalization with metal-carboxylate complexes. The mechanistic facets of this reaction will be the main conducting line between the different sections and chapters of the first part of this thesis. In the second chapter, will be described additives that can readily promoted C–H bond arylation of poorly reactive substrates. More specifically, we will revisit the intramolecular direct arylation reaction we will demonstrate the effect of pivalic acid as a co-catalyst by developing milder reaction conditions. In the third chapter we be described experimental and computational studies which suggested that the a single pathway might be involved in the palladium-catalyzed C–H bond functionalization of a wide range of (hetero)arene. Following this we will describe a general set of conditions for the direct arylation of wide range of heteroarenes. Also, we will present two different strategies to selectively and predictably arylate substrates containing multiple functionalizable C–H bonds. In the fourth chapter will be presented our efforts toward the development of new C–H bond functionalization methods in which we could apply our knowledge on the C–H bond cleavage and apply it to the formation of new scaffolds. The development of two new palladium-catalyzed methods were also described. In the fifth chapter, our effort toward the development of ligands to specifically promoted C–H bond cleavage will be presented. In the sixth chapter will be presented the latest results on the study of the mechanism of the C–H bond cleavage combining experimental and computational studies. In part B of this thesis will be presented our strategy toward the total synthesis of ginkgolide C that included two gold(I)-catalyzed reactions as key steps in the preparation of the spiro[4.4]nonane core of this natural product. The first studies on the feasibility of the key steps of the synthesis will be described.

Ansamycin natural products have historically been a rich source of new drugs for the treatment of bacterial infections and cancer. The C17-benzene ansamycins in particular have shown excellent preclinical results as potential anti-fungal and anti-cancer medicines. However, their thorough clinical evaluation has been hampered by the absence of a concise synthetic strategy. In order to address this issue, recently developed hydrogenative carbon-carbon bond forming methods were applied toward a short total synthesis of C17-benzene ansamycins. This class of natural products provides a challenging testing ground for these methods while facilitating the further development of compounds which may be used as treatments for life threatening diseases. In the first synthetic approach to the C17-benzene ansamycins key bond formations include direct iridium catalyzed carbonyl crotylation from the alcohol oxidation level followed by chelation-controlled dienylation to form the stereotriad, which is attached to the arene via Suzuki cross-coupling. The diene-containing carboxylic acid is prepared using rhodium catalyzed acetylene-aldehyde reductive C-C coupling mediated by gaseous hydrogen. Finally, ring-closing metathesis delivers the cytotrienin core. The second approach toward triene-containing C17-benzene ansamycins resulted in the syntheses of trienomycins A and F, which were prepared in 16 steps (longest linear sequence) and 28 total steps. The C11-C13 stereotriad was generated via enantioselective ruthenium-catalyzed alcohol CH syn crotylation followed by chelation-controlled carbonyl dienylation. Finally, diene-diene ring closing metathesis to form the macrocycle. The present approach is 14 steps shorter (LLS) than the prior syntheses of trienomycins A and F, and eight steps shorter than any prior synthesis of a triene-containing C17-benzene ansamycin. / text

This thesis describes synthetic studies directed towards the total synthesis of the natural products TEO3.1, hamigerone and embellistatin. Chapter One provides an overview, which details the role of antifungal natural products in the pharmaceutical and agrochemical industries, and describes the association between total synthesis and natural products. Three structurally related natural products TEO3.1, hamigerone and embellistatin are introduced as synthetic targets and a strategy for their synthesis is proposed involving an intramolecular Diels-Alder (IMDA) reaction, followed by addition-elimination chemistry. Investigations into the application of the IMDA reaction to the synthesis of the bicyclic core are described in Chapter Two. A Julia olefination reaction was used to install the diene moiety and allowed for the successful synthesis of a model triene precursor. The IMDA cyclisation of the triene was shown to proceed with high endo-selectivity. However, efforts to generate the diene-containing bicyclic core failed and, as a result, this approach to the natural products was abandoned. Chapter Three introduces the diene-regenerative Diels-Alder reaction as an alternative strategy for the direct installation of the diene moiety. The preparation of a model system is described, which established methodology for the efficient preparation of the pyrone-containing Diels-Alder substrate. Cyclisation of this material via a [4 + 2] cycloaddition reaction, followed by extrusion of carbon dioxide, proved a viable method for generating the desired cyclohexadiene system. In Chapter Four, the previously established methodology is applied to the synthesis of the fully functionalised bicyclic core of TEO3.1, hamigerone and embellistatin. The preparation of the racemic Diels-Alder substrate and its successful cyclisation to the bicyclic core is described. An investigation into the preparation of chiral material is also discussed, as well as the description of a model study for the installation of the various side-chains of the natural products. The chapter concludes with a brief discussion of the future studies required to complete the total synthesis of the TEO3.1, hamigerone and embellistatin.