Transition metal-catalyzed olefin hydroacylation represents an atom-economical approach for the synthesis of valuable ketone products. To date, the intermolecular variant of this reaction suffers from several drawbacks, which include limited substrate scope, poor reactivity and/or regioselectivity for non-activated, non-chelating alkene substrates, and competitive reductive decarbonylation pathways that lead to catalyst decomposition. Herein, we report the linear-selective intermolecular hydroacylation of a wide range of electronically diverse olefins with salicylaldehydes employing catalyst loadings as low as 2 mol%. A unique reactivity profile is observed for the chiral C2-symmetric phosphoramidite ligand employed in our catalyst system, and thus, we outline progress made towards the synthesis of new phosphoramidite ligands. We have applied our methodology in the total synthesis of nine octaketide natural products belonging to the dothiorelone, cytosporone, and phomopsin families. Due to recent reports demonstrating the anticancer activity of cytosporone B (Csn-B), we will also discuss progress towards the synthesis of Csn-B analogues.

Gold was considered for a long time to be an inert metal and was only in 1986 that the first homogeneous gold-catalyzed transformation was reported. In our laboratory, we isolated a surprisingly stable vinyl complex that resulted from an unexpected 1,2-silyl migration while working on a gold(I)-catalyzed reaction for the synthesis of polyprenylated polycyclic acylphloroglucinols (PPAPs). We herein report the isolation of a variety of organogold species where we could control the silyl migration based on the nature of the silyl group installed on the terminal alkyne. Silyl groups bearing an aromatic ring inhibited the silyl migration while the aliphatic silyl group afforded the 1,2-silyl migrated adduct. After mechanistic investigation of this intriguing migration, we believe that this process goes through a relatively rare gold vinylidene intermediate. More than 15 organogold complexes were isolated in good yield and characterized by x-ray crystallography. Investigation of their reactivity led to the formation of C(sp3)-C(sp2) bonds using electrophilic reagents without the use of Pd-based catalysts. We have also developed a new gold(I)-catalyzed dehydro Diels-Alder reaction using a simple monocyclic silyl enol ether. This methodology proceeds effectively with a wide scope by the use of [JackiephosAu(NCMe)]SbF6 in toluene. This methodology was then applied to the synthesis of magellanine, an architecturally complexed angular natural product isolated in 1976 from the club moss Lycopodium Magellanicum. The key step precursor was rapidly constructed via a Mitsunobu/Diels-Alder reaction that generated the requisite carboxaldehyde. The dehydro Diels-Alder reaction afforded the molecular skeleton of magellanine diastereoselectively in 91% yield. The synthesis was successfully accomplished in 11 steps demonstrating the ability of the gold(I) salt to rapidly construct complex molecules. Since the discovery of salvinorin A, a lot of efforts were exerted in order to optimize the biological activity for treatment of central nervous system disorders. Development of a new synthetic routes to salvinorins are essential to afford novel functionalized analogues. The decalin framework of salvinorin A was assembled with a Diels-Alder reaction with Et2AlCl followed by a gold(I)-catalyzed 6-endo-dig carbocyclization with [JohnphosAu(NCMe)]SbF6. Further functionalization afforded an elaborated intermediate which possesses the correct stereochemistry of the natural product. Following these promising results, efforts are currently in progress for the completion of the total synthesis.

First isolated from the myxobacterium Sorangium cellulosm So Ce12 in 1994, the chivosazoles have been reported to possess antiproliferative activity against human cancer cell lines, as well as antifungal activity. This thesis focuses on studies towards the total synthesis of chivosazole F. Some developments towards the total synthesis of chivosazole A are also discussed. Chapter 1 discusses the isolation, characterisation and biological activity of the chivosazoles, as well as the first total synthesis of chivosazole F reported by the Kalesse group and the previous work towards synthesising chivosazole F in our group. Chapter 2 describes the synthesis of the three key fragments A, B and C, their coupling reactions and subsequent modifications for assembling the backbone of chivosazole F. Paterson boron aldol methodology and Evans-Tishchenko reduction were utilised to construct the 1,4-syn and 1,3-anti stereochemical relationships within both fragment A and fragment B. Di-tert-butyl silyl group was used for the efficient and precise protection of the terminal diol of B. The key stereochemistry of fragment C was defined with a vinylogous Mukaiyama aldol reaction. Site-selective Stille cross-coupling reactions of the three fragments, via a one-pot process, rapidly installed the requisite stereodefined polyene motifs within chivosazole F. Optimised Still-Gennari-type HWE olefination conditions were applied to install the (2Z,4E)-dienoate in D. MnO2-mediated double oxidation of D turned the terminal alcohol into an aldehyde and the oxazoline into an oxazole, followed by a Stork-Zhao olefination transforming the aldehyde to a Z-vinyl iodide for a macro-Stille coupling reaction, which achieved the ring closure to afford macrocycle E. Chapter 3 discusses the developments towards the synthesis of the southern fragment F of chivosazole A. Sugar I was prepared first and conditions were screened for the glycosylation of H and I to afford G. Chapter 4 outlines the achievements of this research and points out some future issues that need to be tackled.

New Carbanion Rearrangement of Sulfur Compounds and Its Application Abstract This thesis reports the investigation of an unusual reversal in the metalation selectivity of alkyl aryl sulfones and sulfoxides and its application. Such compounds undergo initial directed ortho-metalation at −78 řC despite having an acidic α-hydrogen atom and the resulting aryllithiums rearrange subsequently completely to the initially expected α-sulfonyllithiums on warming. The scope and the limitations for this process were identified. Both carbanion types of sulfones were applied in reactions with various electrophiles. α-Lithiated sulfones generated upon the transmetalation process were used in Julia olefinations. A mechanistic study of the course of the transmetalation reaction is presented. The kinetics of the transmetalation were determined. Investigations concerning the concentration dependence, proton transfer equilibria between the different ortho-sulfonyllithium intermediates and crossover experiments provided the evidence that a concerted intermolecular pathway prevails. On this basis a new integrated synthetic approach to naturally occurring iridoids was developed. It is based on a tandem alkoxycarbonylation/oxidative radical cyclization of the olefins synthesized by the Julia reaction after the investigated...

(+)-Neopeltolide is a highly potent marine polyketide natural product with activity against multiple cancer cell lines in vitro. The nanomolar range of antifungal and anticancer cytotoxicity in this tetrahydropyran (THP)-containing polyketide, combined with its limited natural supply, has led to several syntheses. In this study, the feasibility of an oxa-Michael conjugate addition route to cis-2,6-THP rings is examined through the efforts toward a total synthesis of the macrocyclic core of (+)-neopeltolide using a highly convergent route. This study is based on the successful preliminary results with a simple 14-member ring model system and the synthesis of the key aldehyde intermediate shown below. The highlighted transformation of this synthesis will be a transannular oxa-conjugate addition to generate the cis-2,6-tetrahydropyran ring system. This route also highlights a highly convergent Wittig coupling to generate the full carbon framework of (+)-neopeltolide. One of the key goals of this project is to compare this synthesis with a chemo-enzymatic total synthesis that relies on chemistry catalyzed by polyketide synthase enzymes in the late stage of the synthesis.

This thesis describes tin and non-tin mediated approaches towards the total synthesis of chaetochalasin A 1 through an intramolecular domino Diels-Alder approach, and subsequent synthesis of the Diels-Alder analogues exo NH 13E-272, endo NH 13E-273, exo NH 13Z-287 and endo NH 13Z-288 through an intramolecular Diels-Alder approach.The initial tin mediated route involved the initial formation of alcohol 119, which exhibited a 2,4-syn methyl arrangement, put in place through the use of two chiral auxiliary mediated asymmetric alkylations. Subsequent functionalisation of alcohol 119 led to aldehyde 215, which incorporated a vinyl stannane functional group. The α,β-unsaturated aldehyde 215 was then reacted with β,γ-BT-sulphone 120 under trans selective Julia conditions to give predominantly the (1E,7E,9E,11E) isomer of vinyl stannane 117. However, subsequent Stille reactions to form the Z,E diene functional group, between vinyl stannane 117 and vinyl iodide 118 resulted in a product that exhibited extreme isomerisation of the triene functional group.A subsequent non-tin mediated route involved the synthesis of aldehyde 229 from alcohol 119, which then underwent a trans selective Julia olefination with BT-sulphone 120 to give predominantly the (2E,8E,10E,12E) isomer of ester 228. Ester 228 was then converted into aldehyde 227, which then underwent a Z-selective olefination to put in place the 2Z,4E diene of methyl ester 226. Further functionalisation of methyl ester 226 using past methodology within the Thomas group led to pyrrolinone 110. Subsequent small scale attempts to convert pyrrolinone 110 into chaetochalasin A 1 through a domino Diels-Alder reaction proved ineffective.Formation of the exo NH 13E-272, endo NH 13E-273, exo NH 13Z-287 and endo NH 13Z-288 Diels-Alder analogues involved the initial conversion of alcohol 119 into aldehyde 275, followed by trans selective Julia olefination with BT-sulphone 120 to give predominantly the (4E,10E,12E,14E) isomer of ester 274. Further functionalisation of ester 274 using past methodology within the Thomas group, led to pyrrolinone 243, which then underwent an intramolecular Diels-Alder reaction to give the 13E : 13Z isomers in a 1 : 1 ratio, with each isomer exhibiting an exo : endo geometry in a 5 : 4 ratio.

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

Glucan phosphate is a water‐soluble, yeast‐derived, (1 → 3)‐β‐D‐glucopyranose polymer that has been demonstrated to be a potent immune stimulant. Glucan phosphate administration is associated with stimulation of immunity and a concomitant increase in resistance to a variety of experimentally induced disease states. Preclinical safety evaluation indicates that glucan phosphate does not induce mortality or significant toxicity over a wide dose range. Phase I clinical data indicate that glucan phosphate will ameliorate immunosuppression, stimulate immunity, decrease susceptibility to infection and alter ultimate outcome in trauma patients following laparotomy or thoracotomy. This work reviews the development, characterization, preclinal and clinical evaluation of glucan phosphate.

Natural products are an important resource for cancer therapy, with highly potent and diverse anticancer activities. Natural product biosynthesis is well comprehended, however the evolutionary principles governing the alteration of enzymatic assembly lines to yield molecules with activity toward distinct various cellular targets are not understood. This gap in knowledge hinders efforts to synthetically combinatorialize assembly lines to yield “unnatural” natural products with important or hybrid activity toward up-regulated targets in cancer. Furthermore, natural products did not evolve in the context of mammalian systems and would benefit from a delivery mechanism to cancerous cells to improve their ability to generate successful clinical outcomes. Consequently, natural products were linked to antibodies targeted to cell surface proteins up-regulated on cancer cells, generating antibody-drug conjugates (ADC). The conjugation methodology is problematic by yielding ADCs with varying numbers of drugs loaded per antibody. This lack of batch-to-batch standardization limits our ability to completely evaluate the safety profiles and efficacy of ADCs and determine proper dosages for patients. In this research, light was shed on biosynthetic evolutionary changes through the study of the antimycin-type family of depsipeptides, specifically demonstrating that modular insertions or deletions lead to natural product structural diversification. Additionally, a novel biosynthetic enzymatic method was established to site-selectively conjugate natural products to antibodies in order to facilitate the development of more sophisticated cancer therapies. / Thesis / Master of Science (MSc)

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